PMID- 26095931 TI - The Disconnect Between Novel Oral Anticoagulant Eligibility and Provincial Drug Coverage: An Albertan Anticoagulation Clinic Audit. AB - Canadian practice guidelines for nonvalvular atrial fibrillation (NVAF) recommend that most patients receive a novel oral anticoagulant (NOAC) in preference to warfarin to prevent stroke, but not all patients have insurance that covers NOACs. The gap between optimal therapy and drug coverage is unknown. We retrospectively assessed eligibility for NOACs in patients with NVAF at our single-centre anticoagulation clinic and ascertained whether provincial drug coverage would be in place. Most patients (89%-95%) were eligible, but only 39% 41% qualified for drug coverage. Our findings suggest most Albertans with NVAF might not have drug coverage for optimal medical therapy for stroke prevention. PMID- 26095932 TI - Pharmacologic Options for the Management of Systolic Heart Failure: Examining Underlying Mechanisms. AB - The optimal management of systolic heart failure includes combination therapy to influence myocardial remodelling favourably by affecting neurohormonal activation and underlying maladaptive pathophysiological pathways. These medications include modulators of the renin-angiotensin-aldosterone system (eg, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists) and beta-adrenergic receptor blockers. In addition, an agent with a distinct and complementary mechanism of bradycardic action, the selective pacemaker-current (If) inhibitor ivabradine, provides further reduction of heart rate. Also, a new drug that incorporates neprilysin inhibition combined with angiotensin receptor blockade shows incremental effectiveness. The primary goal of this review is to provide a mechanistic explanation of the complementary role of therapeutic interventions in modulating pathways leading to progressive systolic heart failure. A secondary goal is to summarize the key findings of the pivotal clinical trials that have demonstrated the efficacy of these agents in this population. PMID- 26095930 TI - CD47 deficiency ameliorates autoimmune nephritis in Fas(lpr) mice by suppressing IgG autoantibody production. AB - CD47, a self-recognition marker, plays an important role in both innate and adaptive immune responses. To explore the potential role of CD47 in activation of autoreactive T and B cells and the production of autoantibodies in autoimmune disease, especially systemic lupus erythematosus (SLE), we have generated CD47 knockout Fas(lpr) (CD47(-/-) -Fas(lpr) ) mice and examined histopathological changes in the kidneys, cumulative survival rates, proteinuria, extent of splenomegaly and autoantibodies, serum chemistry and immunological parameters. In comparison with Fas(lpr) mice, CD47(-/-) -Fas(lpr) mice exhibit a prolonged lifespan and delayed autoimmune nephritis, including glomerular cell proliferation, basement membrane thickening, acute tubular atrophy and vacuolization. CD47(-/-) -Fas(lpr) mice have lower levels of proteinuria, associated with reduced deposition of complement C3 and C1q, and IgG but not IgM in the glomeruli, compared to age-matched Fas(lpr) mice. Serum levels of antinuclear antibodies and anti-double-stranded DNA antibodies are significantly lower in CD47(-/-) -Fas(lpr) than in Fas(lpr) mice. CD47(-/-) -Fas(lpr) mice also display less pronounced splenomegaly than Fas(lpr) mice. The mechanistic studies further suggest that CD47 deficiency impairs the antigenic challenge-induced production of IgG but not IgM, and that this effect is associated with reduction of T follicular cells and impairment of germinal centre development in lymphoid tissues. In conclusion, our results demonstrate that CD47 deficiency ameliorates lupus nephritis in Fas(lpr) mice via suppression of IgG autoantibody production. PMID- 26095933 TI - Risk and Causes of Death in Patients After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. AB - BACKGROUND: Because the final myocardial scar might be theoretically associated with an increased risk of sudden cardiac death, the long-term clinical course of patients who undergo alcohol septal ablation (ASA) is still a matter of debate. In this retrospective multicentre study, we report outcomes after ASA, including survival, analysis of causes of deaths, and association between time and cause of death. METHODS: We enrolled 366 consecutive patients (58 +/- 12 years, 54% women) who were treated using ASA and followed-up for 5.1 +/- 4.5 years. RESULTS: The in hospital and 30-day mortality were 0.5% and 0.8%, respectively; the ASA-related morbidity was < 20%. Overall, 52 patients died during 1867 patient-years, which means the all-cause mortality rate was 2.8% per year. The mortality rates of sudden death and sudden death with an appropriate implantable cardioverter defibrillator (ICD) discharge were 0.4% and 1% per year, respectively. Patients with sudden death or appropriate ICD discharge experienced these mortality events at younger age than patients who died of other hypertrophic obstructive cardiomyopathy-related causes (60.8 years [range, 52-71.5 years] vs 72.4 years [range, 64.2-75.2 years]; P = 0.048). A total of 292 patients (80%) had an outflow gradient <= 30 mm Hg, and 327 patients (89%) were in New York Heart Association class <= II at the last clinical check-up. CONCLUSIONS: ASA had low procedure-related mortality, with subsequent 1% occurrence of sudden mortality events per year and 2.8% mortality rate per year in the long-term follow-up. Patients with sudden death or ICD discharge experienced the mortality events approximately 1 decade earlier than patients who died from other causes not related to hypertrophic cardiomyopathy. PMID- 26095934 TI - Estimating the Risk of Cardiac Mortality After Exposure to Conducted Energy Weapons. AB - BACKGROUND: Conducted energy weapons (CEWs), commonly known as Tasers, are a reputed nonlethal law enforcement weapon. Nevertheless high profile cases have suggested a causal association with cardiac death but the magnitude of any putative risk is unclear. METHODS: An electronic systematic review of all real world, cohort studies of consecutive CEW cases was performed. "Pessimistic" and "optimistic" previous beliefs about CEW mortality were derived from an unbounded internet search, including case series but excluding the previously identified cohort publications. A Bayesian analysis updated these previous beliefs with the published objective cohort data. RESULTS: Pessimistic and optimist previous beliefs with modes of 1/700 and 1/7000, respectively, and upper limits (< 2.5% probability) of 1/100 and 1/1000, respectively, were constructed. Three cohort studies formed the objective data source and their combined mortality was 1 in 2728 cases or 3.67/10,000 (95% confidence interval, 1/107,751 - 1/490). The maximum a posteriori estimated risks of CEW mortality for the pessimistic and optimistic prior distributions were 5.3 and 2.2 deaths per 10,000 exposures, respectively. The upper limits (< 1% probability of occurrence) of the posterior distribution were 1 death per 408 and 982 CEW exposures for the pessimistic and optimistic previous beliefs, respectively. CONCLUSIONS: Limited available evidence can be used to construct approximate boundaries for CEW mortality risk and suggests that the population risk of CEW mortality is likely small but not negligible. More high quality data are required to refine these estimates and extreme caution must be exercised before applying these population risks to individual cases. PMID- 26095935 TI - Emergency Transcatheter Aortic Valve Implantation for Acute and Early Failure of Sutureless Perceval Aortic Valve. AB - We report the case of a 78-year-old woman admitted for cardiogenic shock related to acute and early failure (severe aortic regurgitation) of a Perceval sutureless aortic bioprosthesis (Sorin Group, Saluggia, Italy). Clinical stability was achieved using rescue transfemoral transcatheter aortic valve-in-valve implantation with an Edwards SAPIEN 3 prosthesis (Edwards Lifesciences, Irvine, CA). To our knowledge, we report herein the first case of successful valve-in valve implantation using a SAPIEN 3 transcatheter heart valve in a sutureless bioprosthetic aortic valve with acute and early deterioration. PMID- 26095936 TI - Left Atrial Compression After Laparoscopic Gastric Banding. PMID- 26095937 TI - Percutaneous Revascularization in a Patient With a "Double Heart". PMID- 26095938 TI - Biodegradable Stent Platforms: Are We Heading in the Right Direction? PMID- 26095939 TI - Coronary Microembolization Induces Cardiomyocyte Apoptosis Through the LOX-1 Dependent Endoplasmic Reticulum Stress Pathway Involving JNK/P38 MAPK. AB - BACKGROUND: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein associated with apoptosis. Endoplasmic reticulum (ER) stress induced apoptosis has been determined in several cardiovascular diseases. Mitogen activated protein kinase (MAPK) signalling is involved in apoptosis. The aim of this study was to investigate whether LOX-1, ER stress, and MAPKs play a role in cardiomyocyte apoptosis after coronary microembolization (CME) and the exact mechanisms involved. METHODS: Thirty swine were randomized into the following groups (n = 5 per group): sham, CME, CME + LOX-1 small-interfering RNA (siRNA), CME + control siRNA, CME + JNK inhibitor, and CME + p38 inhibitor. The CME model was established by injecting microspheres into the left anterior descending (LAD) artery, whereas swine in the sham group received normal saline instead. Twelve hours after the sham operation or CME, cardiac function, serum c-troponin I level, microinfarcts, and apoptotic index were determined. Relative expression levels of LOX-1, ER stress markers (glucose-regulated protein 78 [GRP 78], C/EBP homologous protein [CHOP], and cleaved caspase-12), cleaved caspase-3, c-Jun NH2 terminal protein kinases (JNK), p38, and extracellular signal-related protein kinases (ERK1/2) were measured. RESULTS: CME induced cardiac dysfunction, microinfarction, increased serum c-troponin I levels, and cardiomyocyte apoptosis. Additionally, the expression of LOX-1, ER stress markers, and cleaved caspase-3, and the phosphorylation of JNK, p38, and ERK1/2 were all enhanced. LOX 1 siRNA inhibited these effects except the phosphorylation of ERK1/2. Pretreatment with a JNK inhibitor or a p38 inhibitor attenuated the expression of ER stress markers and apoptosis. CONCLUSIONS: Our results indicated that CME induced cardiomyocyte apoptosis through the LOX-1-dependent ER stress pathway, in which the phosphorylation of JNK and p38 were involved. This might provide a new approach for the prevention and treatment of CME. PMID- 26095940 TI - Monodisperse AgSbS2 nanocrystals: size-control strategy, large-scale synthesis, and photoelectrochemistry. AB - We report an efficient approach to the synthesis of AgSbS2 nanocrystals (NCs) by colloidal chemistry. The size of the AgSbS2 NCs can be tuned from 5.3 to 58.3 nm with narrow size distributions by selection of appropriate precursors and fine control of the experimental conditions. Over 15 g of high-quality AgSbS2 NCs can be obtained from one single reaction, indicative of the up-scalability of the present synthesis. The resulting NCs display strong absorptions in the visible-to NIR range and exceptional air stability. The photoelectrochemical measurements indicate that, although the pristine AgSbS2 NC electrodes generate a cathodic photocurrent with a relatively small photocurrent density and poor stability, both of them can be significantly improved subject to CdS surface modification, showing promise in solar energy conversion applications. PMID- 26095941 TI - Breathable and Stretchable Temperature Sensors Inspired by Skin. AB - Flexible electronics attached to skin for healthcare, such as epidermal electronics, has to struggle with biocompatibility and adapt to specified environment of skin with respect to breath and perspiration. Here, we report a strategy for biocompatible flexible temperature sensors, inspired by skin, possessing the excellent permeability of air and high quality of water-proof by using semipermeable film with porous structures as substrate. We attach such temperature sensors to underarm and forearm to measure the axillary temperature and body surface temperature respectively. The volunteer wears such sensors for 24 hours with two times of shower and the in vitro test shows no sign of maceration or stimulation to the skin. Especially, precise temperature changes on skin surface caused by flowing air and water dropping are also measured to validate the accuracy and dynamical response. The results show that the biocompatible temperature sensor is soft and breathable on the human skin and has the excellent accuracy compared to mercury thermometer. This demonstrates the possibility and feasibility of fully using the sensors in long term body temperature sensing for medical use as well as sensing function of artificial skin for robots or prosthesis. PMID- 26095942 TI - Observation of isotropic-isotropic demixing in colloidal platelet-sphere mixtures. AB - Mixtures of colloids with different sizes and shapes are ubiquitous in nature and industry. The possible existence of isotropic-isotropic (I1-I2) demixing of platelets and spheres remains an open question. Here we present direct experimental evidence of I1-I2 demixing using platelets with a very small thickness-to-diameter ratio mixed with silica spheres at the size ratio q = R(sphere)/R(disk) = 0.0901 +/- 0.0004. The platelets cause the isotropic-to nematic phase transition at a very low volume fraction because of their highly anisometric shape. The presence of silica spheres in the suspension accelerates the phase transition and packs the nematic phase more densely via depletion interaction. Increasing the sphere volume fraction to 0.0014, a tri-phase region emerges. This direct observation of I1-I2 demixing seems to validate the free volume scaled particle theory and indicates the need for refinement of the fundamental measure density functional theory. PMID- 26095943 TI - The value of oropharyngoesophageal scintigraphy in the management of aspiration into the tracheobronchial tree in neurological patients. AB - AIM: Dysphagia and bolus aspiration are two of the most frequent and invalidating symptoms of various neurological diseases. Swallowing disorders often lead to tracheobronchial aspiration with consequent pneumonia episodes. Aspiration pneumonia per se constitutes the most frequent cause of death in these patients, with mortality rate ranging from 20% to 62%. Oropharyngoesophageal scintigraphy (OPES) permits functional quantitative assessment of the different stages of swallowing, together with the detection and quantitative measurement of bolus aspiration. In this work, we analyzed the role of OPES in patients with different neurological conditions to evaluate swallowing and to detect and quantify bolus aspiration. MATERIAL AND METHODS: We enrolled 43 neurological patients (25 women and 18 men, mean age 67.3+/-12.4 yr) complaining of dysphagia with suspected inhalation. All patients underwent OPES with (99m)Tc-nanocolloid using a liquid bolus first, followed by a semi-solid bolus. We evaluated the following parameters: Oral, Pharyngeal and Esophageal Transit Time, Oro-Pharyngeal Retention Index, Esophageal Emptying Rate, and Aspiration Rate (% AR). RESULTS: OPES detected some airway aspiration in 26/43 patients. 19 patients had tracheal aspiration (with a mean 18.1% AR) and the remaining 7 patients had bilateral broncho-pulmonary aspiration (mean 44.9% AR). CONCLUSIONS: OPES is a feasible, repeatable and noninvasive method that allows quantitative assessment of bolus aspiration into the tracheobronchial tract, thus representing a useful and accurate tool to guide the most appropriate treatment and to monitor response to therapy in neurological patients with dysphagia. PMID- 26095944 TI - Importance of End-Diastolic Rather than End-Systolic Right Atrial Size in Chronic Pulmonary Hypertension. AB - BACKGROUND: Right atrial (RA) enlargement has been associated with worse clinical outcomes in chronic pulmonary hypertension (cPH) patients. Even though current guidelines only recommend measurement of RA dimensions at the end of ventricular systole in these patients, there is paucity of information regarding the potential utility of RA dimensions obtained at the end of ventricular diastole. METHODS: In this retrospective study, standard echocardiographic data were collected from 80 studies. The population studied was divided into Group I that consisted of 35 patients (52 +/- 10 years) without PH while Group II included 45 patients (56 +/- 14 years; P = 0.2) with cPH. RA measurements were obtained not only at the end of ventricular systole, but also at the end of ventricular diastole to determine which RA measurement was more indicative of abnormal right ventricular afterload. RESULTS: Even though all RA measurements were abnormal, RA area (>8.4 cm(2) ) measured at the end of ventricular diastole was the most useful RA variable to identify cPH patients with elevated pulmonary pressures (P < 0.0001) and with an abnormal pulmonary vascular resistance (P = 0.001). CONCLUSIONS: Based on these results, it appears that isolated RA measurements made at the end of ventricular systole are insufficient to fully explain the hemodynamic load of cPH. Additional studies are now required to determine whether sequential monitoring of the composite change in RA dimensions that occur throughout the cardiac cycle over time correlates better with response to vasodilator therapy and overall clinical outcomes. PMID- 26095945 TI - High-resolution mass spectrometry for thymosins detection and characterization. AB - OBJECTIVES: The aim of this study was to characterize beta and alpha thymosins and their proteoforms in various tissues and bodily fluids by mass spectrometry and to look at their association with a wide variety of pathologies. METHODS: A top-down proteomic platform based on high-performance liquid chromatography (HPLC) coupled to high-resolution LTQ-Orbitrap mass spectrometry (MS) was applied to the characterization of naturally occurring peptides. RESULTS: In addition to thymosin beta4 (Tbeta4) and beta10 (Tbeta10), several post-translational modifications of both these peptides were identified not only in bodily fluids but also in normal and pathological tissues of different origins. The analysis of tissue specimens allowed the characterization of different C-terminal truncated forms of Tbeta4 and Tbeta10 together with other proteolytic fragments. The sulfoxide derivative of both Tbeta4 and Tbeta10 and the acetylated derivatives at lysine residues of Tbeta4 were also characterized. Different proteoforms of prothymosin alpha, parathymosin alpha, thymosin alpha1 and thymosin alpha11 together with diverse proteolytic fragments were identified too. CONCLUSION: The clinical and prognostic significance and the origin of these proteoforms have to be deeply investigated. PMID- 26095946 TI - High-level production of Arthrobacter aurescens CYC705 nitrilase in Escherichia coli for biosynthesis of iminodiacetic acid. AB - Nitrilase from Arthrobacter aurescens CYC705 can hydrolyze the iminodiacetonitrile to iminodiacetic acid (IDA) efficiently, and its high-level production in Escherichia coli has not been established. In the present work, the production of this nitrilase expressed in E. coli BL21(DE3) with a recombinant plasmid pET28a-cyc705 was optimized. Various culture conditions and process parameters including medium components and concentrations, inducer types and concentrations, inducing temperature and time were systematically examined in a shake flask. After optimization, the OD600 , nitrilase activity, and productivity were obviously improved and achieved to 40.91 +/- 1.341, 98.12 +/- 1.248 U/mL, and 2,230 +/- 28.36 U L(-1) H(-1) , respectively, about 2.1-, 30-, and 33-fold increases as compared with those in the primary medium. Furthermore, four different fermentation strategies were adopted to scale up cultivation of the recombinant E. coli BL21(DE3)/pET28a-cyc705 in a 3.7-L fermenter. Substituting the peanut powder with fish peptone and accompanying with 1.0% glycerol feeding could significantly reduce the bubble production and shorten the fermentation time, which resulted in a nitrilase productivity of 4,653 +/- 38.16 U L(-1) H(-1) that was about two times higher than that in a shake flask. The high-level production of A. aurescens CYC705 nitrilase established in this study will meet the need of industrial biosynthesis of IDA. PMID- 26095947 TI - Cytosolic Ca2+ buffering determines the intra-SR Ca2+ concentration at which cardiac Ca2+ sparks terminate. AB - Single ryanodine receptor (RyR) Ca(2+) flux amplitude (i(Ca-RyR)) decreases as intra-sarcoplasmic reticulum (SR) Ca(2+) levels fall during a cardiac Ca(2+) spark. Since i(Ca-RyR) drives the inter-RyR Ca(2+)-induced Ca(2+) release (CICR) that underlies the spark, decreasing i(Ca-RyR) may contribute to spark termination because RyRs that spontaneously close may stay closed. To test this possibility, we simultaneously measured local cytosolic and intra-SR ([Ca(2+)]cyto and [Ca(2+)]SR) during Ca(2+) sparks in permeabilized rabbit ventricular myocytes. Local cytosolic or intra-SR Ca(2+) dynamics were manipulated using Ca(2+) buffers. Buffer manipulations applied in cells had no effect on individual RyR channels reconstituted in planar lipid bilayers. Presence of a fast cytosolic Ca(2+) buffer (BAPTA) significantly suppressed Ca(2+) spark activity and sparks terminated earlier at a higher than usual [Ca(2+)]SR level (~80% vs. ~62%). When cytosolic Ca(2+) buffer power was reduced (i.e. cytosolic EGTA level decreased), sparks terminated later and at a lower than usual [Ca(2+)]SR level (~45% vs. ~62%). When intra-SR Ca(2+) buffer power was increased, sparks also terminated later and at a lower than usual [Ca(2+)]SR (~48% vs. ~62%). These results suggest that cytosolic local control of inter-RyR CICR by i(Ca-RyR) plays a substantial role during the spark termination process. Thus, alterations in local cytosolic Ca(2+) handling dynamics in the dyadic cleft (Ca(2+) buffering, extrusion, etc.) likely influence Ca(2+) spark termination. PMID- 26095948 TI - Effects of rotigotine transdermal patch in patients with Parkinson's disease presenting with non-motor symptoms - results of a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND AND PURPOSE: Non-motor symptoms (NMS) of Parkinson's disease (PD) have a major impact on health-related quality of life. This is the first randomized controlled trial to use the NMS Scale (NMSS) as a primary outcome to assess treatment effects on NMS in PD. METHODS: In this double-blind trial (NCT01300819), patients with PD and a total NMSS score >=40 were randomized (2:1) to rotigotine or placebo, titrated over 1-7 weeks to optimal dose (<=8 mg/24 h for patients not receiving levodopa, <=16 mg/24 h for patients receiving levodopa), maintained for 12 weeks. The primary outcome was change in NMSS total score from baseline to end of maintenance. Secondary outcomes were the nine NMSS domains, Unified Parkinson's Disease Rating Scale (UPDRS) III (motor) and the 39 item Parkinson's Disease Questionnaire (PDQ-39). RESULTS: In total, 283/349 (81.1%) randomized patients completed the trial; 211 rotigotine and 122 placebo were included in the full analysis set. The NMSS total score decreased by 23 (rotigotine) and 19 (placebo) points; the treatment difference was not statistically significant (-3.58; 95% confidence interval -8.43, 1.26; P = 0.147). Numerically greater than placebo improvements were detected in the 'mood/apathy' and 'miscellaneous' NMSS domains (P < 0.05). Treatment differences in UPDRS III (-2.60; -4.27, -0.92; P = 0.002) and PDQ-39 (-2.79; -5.21, -0.37; P = 0.024) favoured rotigotine. Adverse events reported more frequently with rotigotine were nausea, application site reactions, somnolence and headache. CONCLUSIONS: Rotigotine improvement in the multi-domain NMSS total score was not superior to placebo. A different sensitivity of individual NMSS domains to dopaminergic therapy and a large placebo effect may have contributed to these findings. PMID- 26095950 TI - About people, pig movements and pork 'tapeworms'. PMID- 26095949 TI - Application of small RNA technology for improved control of parasitic helminths. AB - Over the last decade microRNAs (miRNAs) and small interfering RNAs (siRNAs) have emerged as important regulators of post-transcriptional gene expression. miRNAs are short, non-coding RNAs that regulate a variety of processes including cancer, organ development and immune function. This class of small RNAs bind with partial complementarity to their target mRNA sequences, most often in the 3'UTR, to negatively regulate gene expression. In parasitic helminths, miRNAs are being increasingly studied for their potential roles in development and host-parasite interactions. The availability of genome data, combined with small RNA sequencing, has paved the way to profile miRNAs expressed at particular developmental stages for many parasitic helminths. While some miRNAs are conserved across species, others appear to be unique to specific parasites, suggesting important roles in adaptation and survival in the host environment. Some miRNAs are released from parasites, in exosomes or in protein complexes, and the potential effects of these on host immune function are being increasingly studied. In addition, release of miRNAs from schistosome and filarial parasites into host plasma can be exploited for the development of specific and sensitive diagnostic biomarkers of infection. Interfering with miRNA function, as well as silencing key components of the pathways they regulate, will progress our understanding of parasite development and provide a novel approach to therapeutic control. RNA interference (RNAi) by siRNAs has proven to be inconsistent in parasitic nematodes. However, the recent successes reported for schistosome and liver fluke RNAi, encourage further efforts to enhance delivery of RNA and improve in vitro culture systems and assays to monitor phenotypic effects in nematodes. These improvements are important for the establishment of reliable functional genomic platforms for novel drug and vaccine development. In this review we focus on the important roles of miRNAs and siRNAs in post transcriptional gene regulation in veterinary parasitic helminths and the potential value of these in parasite diagnosis and control. PMID- 26095951 TI - Setting the proportion of CD4+ and CD8+ T-cells co-cultured with canine macrophages infected with Leishmania chagasi. AB - New methods for evaluating the canine immune system are necessary, not only to monitor immunological disorders, but also to provide insights for vaccine evaluations and therapeutic interventions, reducing the costs of assays using dog models, and provide a more rational way for analyzing the canine immune response. The present study intended to establish an in vitro toll to assess the parasitological/immunological status of dogs, applicable in pre-clinical trials of vaccinology, prognosis follow-up and therapeutics analysis of canine visceral leishmaniasis. We have evaluated the performance of co-culture systems of canine Leishmania chagasi-infected macrophages with different cell ratios of total lymphocytes or purified CD4(+) and CD8(+) T-cells. Peripheral blood mononuclear cells from uninfected dogs were used for the system set up. Employing the co culture systems of L. chagasi-infected macrophages and purified CD4(+) or CD8(+) T-cell subsets we observed a microenvironment compatible with the expected status of the analyzed dogs. In this context, it was clearly demonstrated that, at this selected T-cell:target ratio, the adaptive immune response of uninfected dogs, composed by L. chagasi-unprimed T-cells was not able to perform the in vitro killing of L. chagasi-infected macrophages. Our data demonstrated that the co culture system with T-cells from uninfected dogs at 1:5 and 1:2 ratio did not control the infection, yielding to patent in vitro parasitism (>= 80%), low NO production (<= 5 MUM) and IL-10 modulated (IFN-gamma/IL-10 <= 2) immunological profile in vitro. CD4(+) or CD8(+) T-cells at 1:5 or 1:2 ratio to L. chagasi infected macrophages seems to be ideal for in vitro assays. This co-culture system may have great potential as a canine immunological analysis method, as well as in vaccine evaluations, prognosis follow-up and therapeutic interventions. PMID- 26095952 TI - Serum antibody responses in pigs trickle-infected with Ascaris and Trichuris: Heritabilities and associations with parasitological findings. AB - A humoral immune response following helminth infection in pigs is well documented. However, it has been difficult to confirm the existence of antibody mediated resistance against the large roundworm, Ascaris suum, and whipworm, Trichuris suis, in experimental settings by correlating worm burdens or egg excretion with specific antibody levels. We set out to investigate the association between worm load and T. suis and A. suum specific serum antibody levels (IgG1, IgG2 and IgA) against excretory-secretory products of adults and third stage larvae, respectively, measured at 0, 7 and 14 weeks p.i. in a trickle infected F1-resource-population of crossbred pigs (n=195). Furthermore, we wanted to determine the heritability of these antibody isotypes during the course of infection. Most pigs remained infected with A. suum throughout the experiment while they expelled T. suis between 7 and 14 weeks post infection (p.i.). Parasite specific IgG1 and IgA were significantly (P<0.001) elevated after 7 and 14 weeks of infection, whereas parasite specific IgG2 levels only changed slightly at 14 weeks p.i.. However, the observed association between specific antibody isotype levels and faecal egg counts and macroscopic worm load was weak. The relative heritabilities of the different parasite specific isotypes were assessed and resulted in significant heritability estimates for parasite specific IgG1 and IgA. The highest heritabilities were found for A. suum specific IgG1 (h(2)=0.41 and 0.46 at 7 and 14 weeks p.i., respectively). Thus, the present study demonstrates that host genetic factors influence the IgG1 and IgA antibody isotype responses specific to two of the most common gastrointestinal nematodes of swine whereas specific antibody levels were poorly associated with egg excretion and the presence of macroscopic worms. PMID- 26095953 TI - Persistency and flexibility of complex brain networks underlie dual-task interference. AB - Previous studies on multitasking suggest that performance decline during concurrent task processing arises from interfering brain modules. Here, we used graph-theoretical network analysis to define functional brain modules and relate the modular organization of complex brain networks to behavioral dual-task costs. Based on resting-state and task fMRI we explored two organizational aspects potentially associated with behavioral interference when human subjects performed a visuospatial and speech task simultaneously: the topological overlap between persistent single-task modules, and the flexibility of single-task modules in adaptation to the dual-task condition. Participants showed a significant decline in visuospatial accuracy in the dual-task compared with single visuospatial task. Global analysis of topological similarity between modules revealed that the overlap between single-task modules significantly correlated with the decline in visuospatial accuracy. Subjects with larger overlap between single-task modules showed higher behavioral interference. Furthermore, lower flexible reconfiguration of single-task modules in adaptation to the dual-task condition significantly correlated with larger decline in visuospatial accuracy. Subjects with lower modular flexibility showed higher behavioral interference. At the regional level, higher overlap between single-task modules and less modular flexibility in the somatomotor cortex positively correlated with the decline in visuospatial accuracy. Additionally, higher modular flexibility in cingulate and frontal control areas and lower flexibility in right-lateralized nodes comprising the middle occipital and superior temporal gyri supported dual-tasking. Our results suggest that persistency and flexibility of brain modules are important determinants of dual-task costs. We conclude that efficient dual-tasking benefits from a specific balance between flexibility and rigidity of functional brain modules. PMID- 26095954 TI - Administration of DNA Encoding the Interleukin-27 Gene Augments Antitumour Responses through Non-adaptive Immunity. AB - DNA-mediated immunization of a tumour antigen is a possible immunotherapy for cancer, and interleukin (IL)-27 has diverse functions in adaptive immunity. In this study, we examined whether IL-27 DNA administration enhanced antitumour effects in mice vaccinated with DNA encoding a putative tumour antigen, beta galactosidase (beta-gal). An intramuscular injection of cardiotoxin before DNA administration facilitated the exogenous gene expression. In mice received beta gal and IL-27 DNA, growth of beta-gal-positive P815 tumours was retarded and survival of the mice was prolonged. Development of beta-gal-positive Colon 26 tumours was suppressed by vaccination of beta-gal DNA and further inhibited by additional IL-27 DNA administration or IL-12 family cytokines. Nevertheless, a population of beta-gal-specific CD8(+) T cells did not increase, and production of anti-beta-gal antibody was not enhanced by IL-27 DNA administration. Spleen cells from mice bearing IL-27-expressing Colon 26 tumours showed greater YAC-1 targeted cytotoxicity although CD3(-)/DX5(+) natural killer (NK) cell numbers remained unchanged. Recombinant IL-27 enhanced YAC-1-targeted cytotoxicity of IL 2-primed splenic NK cells and augmented a phosphorylation of signal transducer and activator of transcription 3 and an expression of perforin. These data collectively indicate that IL-27 DNA administration activates NK cells and augments vaccination effects of DNA encoding a tumour antigen through non adaptive immune responses. PMID- 26095956 TI - Water-Promoted Generation of a Diazairida Homobarrelene by C-C Coupling Between an Iridacyclic Alkylidene and Acetonitrile. AB - The stable cationic iridacyclopentenylidene [Tp(Me2)Ir(=CHC(Me)=C(Me)CH2(NCMe)]PF6 (A; Tp(Me2)=hydrotris(3,5 dimethylpyrazolyl)borate) has been obtained by alpha-hydride abstraction from the iridacyclopent-2-ene [Tp(Me2)Ir(CH2C(Me)=C(Me)CH2)(NCMe)]. Complex A exhibits Bronsted-Lowry acidity at the Ir-CH2 and proximal (relative to Ir-CH2 ) methyl sites. The coordination of an extra molecule of acetonitrile to the iridium center initiates the reversible isomerization of the chelating carbon chain of A to the monodentate butadienyl ligand of complex [Tp(Me2)Ir(CH=C(Me)C(Me)=CH2)(NCMe)2]PF6, which is capable to engage in a water promoted C-C coupling with the MeCN co-ligands. The product is an aesthetically appealing bicyclic structure that resembles the hydrocarbon barrelene. PMID- 26095957 TI - Complement C5a-C5aR interaction enhances MAPK signaling pathway activities to mediate renal injury in trichloroethylene sensitized BALB/c mice. AB - We have previously shown complement activation as a possible mechanism for trichloroethylene (TCE) sensitization, leading to multi-organ damage including the kidneys. In particular, excessive deposition of C5 and C5b-9-the membrane attack complex, which can generate significant tissue damage, was observed in the kidney tissue after TCE sensitization. The present study tested the hypothesis that anaphylatoxin C5a binding to its receptor C5aR mediates renal injury in TCE sensitized BALB/c mice. BALB/c mice were sensitized through skin challenge with TCE, with or without pretreatment by the C5aR antagonist W54011. Kidney histopathology and the renal functional test were performed to assess renal injury, and immunohistochemistry and fluorescent labeling were carried out to assess C5a and C5aR expressions. TCE sensitization up-regulated C5a and C5aR expressions in kidney tissue, generated inflammatory infiltration, renal tubule damage, glomerular hypercellularity and impaired renal function. Antagonist pretreatment blocked C5a binding to C5aR and attenuated TCE-induced tissue damage and renal dysfunction. TCE sensitization also caused the deposition of major pro inflammatory cytokines IL-2, TNF-alpha and IFN-gamma in the kidney tissue (P < 0.05); this was accompanied by increased expression of P-p38, P-ERK and P-JNK proteins (P < 0.05). Pretreatment with the C5aR antagonist attenuated the increase of expression of P-p38, P-ERK and P-JNK proteins (P < 0.05) and also consistently reduced the TCE sensitization-induced increase of IL-2, TNF-alpha and IFN-gamma (P < 0.05). These data identify C5a binding to C5aR, MAP kinase activation, and inflammatory cytokine release as a novel mechanism for complement mediated renal injury by sensitization with TCE or other environmental chemicals. PMID- 26095959 TI - Characteristics of visiting nurse agencies with high home death rates: A prefecture-wide study in Japan. AB - AIM: The purpose of the present study was to identify characteristics of visiting nurse agencies (VNA) in Japan with high home death rates by a prefecture-wide survey. METHODS: A cross-sectional study of visiting nurse agencies (n = 101) in Ibaraki Prefecture, Japan, was completed. Data included the basic characteristics of each VNA, the type of services provided, level of coordination with other service providers, total number of VNA patients who died per year and place of death and contractual relationship with home-care supporting clinics providing end-of-life care services in the home 24 h a day. The VNA characteristics were analyzed by logistic regression, using the home death rate per VNA as a dependent variable. RESULTS: A total 69 agencies, excluding those that did not report number of deaths (n = 14) and those without deaths during the year (n = 6), were analyzed. The median home death rate of the 69 VNA was 29.8%. The results of logistic regression analysis showed that higher home death rate was significantly associated with lack of attachment to a hospital, existence of a contractual relationship with home-care supporting clinics and existence of an interactive information exchange through telephone/face-to-face communication with attending physicians. CONCLUSIONS: In order to increase the home death rate of people using VNA, policymakers must consider establishing home-based service systems within the community that can provide home end-of-life care services 24 h a day, and support the interactive exchange of information between the visiting nurse and the attending physician. PMID- 26095958 TI - Phylogeny and biogeography of the American live oaks (Quercus subsection Virentes): a genomic and population genetics approach. AB - The nature and timing of evolution of niche differentiation among closely related species remains an important question in ecology and evolution. The American live oak clade, Virentes, which spans the unglaciated temperate and tropical regions of North America and Mesoamerica, provides an instructive system in which to examine speciation and niche evolution. We generated a fossil-calibrated phylogeny of Virentes using RADseq data to estimate divergence times and used nuclear microsatellites, chloroplast sequences and an intron region of nitrate reductase (NIA-i3) to examine genetic diversity within species, rates of gene flow among species and ancestral population size of disjunct sister species. Transitions in functional and morphological traits associated with ecological and climatic niche axes were examined across the phylogeny. We found the Virentes to be monophyletic with three subclades, including a southwest clade, a southeastern US clade and a Central American/Cuban clade. Despite high leaf morphological variation within species and transpecific chloroplast haplotypes, RADseq and nuclear SSR data showed genetic coherence of species. We estimated a crown date for Virentes of 11 Ma and implicated the formation of the Sea of Cortes in a speciation event ~5 Ma. Tree height at maturity, associated with fire tolerance, differs among the sympatric species, while freezing tolerance appears to have diverged repeatedly across the tropical-temperate divide. Sympatric species thus show evidence of ecological niche differentiation but share climatic niches, while allopatric and parapatric species conserve ecological niches, but diverge in climatic niches. The mode of speciation and/or degree of co-occurrence may thus influence which niche axis plants diverge along. PMID- 26095960 TI - Evaluation of the antiemetic efficacy of maropitant in dogs medicated with morphine and acepromazine. AB - OBJECTIVE: To evaluate whether maropitant (1 mg kg(-1)) injected subcutaneously (SC), administered simultaneously or 30 minutes prior to intramuscular (IM) administration of morphine (0.5 mg kg(-1)) and acepromazine (0.05 mg kg(-1)), reduces the incidence of salivation, retching and emesis in dogs. STUDY DESIGN: Randomized, controlled, prospective clinical trial. ANIMALS: Sixty dogs scheduled for an ovariohysterectomy as part of a population control program. METHODS: Dogs were randomly allocated to be administered maropitant (1 mg kg(-1)) SC simultaneously (group M0) or 30 minutes prior to (group M30) administration of morphine (0.5 mg kg(-1)) and acepromazine (0.05 mg kg(-1)) IM. A control group was administered normal saline (C) at T-30 and T0. Dogs were observed for 30 minutes after morphine-acepromazine administration. The occurrence of vomiting, retching and salivation were recorded, as well as the time to first emesis and the number of emetic events per dog. RESULTS: The occurrence of salivation was not different between the groups. Retching and vomiting occurred significantly less frequently in M30 than in the other two groups (p < 0.02). The number of emetic events was also significantly less for M30 than for the other two groups (p = 0.01). When emesis occurred, the time to the first emetic event was similar among the groups. CONCLUSIONS AND CLINICAL RELEVANCE: Maropitant (1 mg kg(-1)) SC reduced the frequency of morphine-induced emesis by as much as 70% when administered 30 minutes in advance. Simultaneous administration of maropitant and morphine-acepromazine produced no measurable effect on the frequency of retching or vomiting. PMID- 26095961 TI - In-field Volatile Analysis Employing a Hand-held Portable GC-MS: Emission Profiles Differentiate Damaged and Undamaged Yellow Starthistle Flower Heads. AB - INTRODUCTION: Understanding the complex chemical signalling of plants and insects is an important component of chemical ecology. Accordingly, the collection and analysis of chemical cues from plants in their natural environment is integral to elucidation of plant-insect communications. Remote plant locations and the need for a large number of replicates make in situ headspace analyses a daunting logistical challenge. A hand-held, portable GC-MS system was used to discriminate between damaged and undamaged Centaurea solstitialis (yellow starthistle) flower heads in both a potted-plant and natural setting. OBJECTIVE: To determine if a portable GC-MS system was capable of distinguishing between undamaged and mechanically damaged plant treatments, and plant environments. METHODOLOGY: A portable GC-MS utilising needle trap adsorbent technology was used to collect and analyse in situ headspace volatiles of varying yellow starthistle treatments. Principal component analysis (PCA) was used to distinguish treatments and identify biomarker volatiles. Analysis of variance (ANOVA) was used to determine differences between treatment volatile amounts. RESULTS: The portable GC-MS system detected 31 volatiles from the four treatments. Each GC-MS run was completed in less than 3 min. PCA showed four distinct clusters representing the four treatments - damaged and undamaged potted plant, and damaged and undamaged natural plant. Damage-specific volatiles were identified. CONCLUSION: The portable GC-MS system distinguished the treatments based on their detected volatile profiles. Additional statistical analysis identified five possible biomarker volatiles for the treatments, among them cyclosativene and copaene, which indicated damaged flower heads. PMID- 26095962 TI - Introduction: Beyond Illustrations. PMID- 26095963 TI - The Illustrious Anatomist: Authorship, Patronage, and Illustrative Style in Anatomy Folios, 1700-1840. AB - A number of anatomists working in the period 1700-1840 used expensive illustrated books to depict their greatest scientific work, establish priority of discovery for posterity, and enlist patrons. These anatomists drew on the grand traditions of anatomical illustration and asserted their right to a place within that history. But with artists mediating the expression of anatomists' vision, it was important that an anatomist assert his control over the illustrations commemorating his expertise. Anatomists used stylistic signatures to signal that a work was their own. Very different styles of illustration in the works of different anatomists, therefore, were made easily recognizable, and sometimes a single artist adopted notably different styles for different anatomists who employed him. Style became a marker of authorship, identifiable with the anatomist, even when he employed an artist to do the drawing and engraving, and it was also an important method of appealing to patrons. PMID- 26095964 TI - The Rise of Pathological Illustrations: Baillie, Bleuland, and Their Collections. AB - This essay examines the illustrated pathological works by Matthew Baillie (London, 1799-1803) and Jan Bleuland (Utrecht, 1826-28). Both works relied on extensive collections of specimens preserved in London and Utrecht, respectively. The essay discusses changing notions of disease, the erosion of the boundaries between surgeons and physicians, the role and significance of pathological collections, and the relations between preserved specimens and their representations. PMID- 26095965 TI - Two Australian Fetuses: Frederic Wood Jones and the Work of an Anatomical Specimen. AB - A close analysis of two fetal specimens is used to explore of role of material specimens in anatomical practice of the late nineteenth and early twentieth centuries, the significance of Indigenous bodies in that era's quest for an understanding of human difference, and the postcolonial legacies of the global project of creating collections of human specimens. PMID- 26095967 TI - Debating Diseases in Nineteenth-Century Colombia: Causes, Interests, and the Pasteurian Therapeutics. AB - This article explores the medical conceptualization of the causes of diseases in nineteenth-century Colombia. It traces the history of some of the pathologies that were of major concern among nineteenth-century doctors: periodic fevers (yellow fever and malaria), continuous fevers (typhoid fever), and leprosy (Greek elephantiasis). By comparing the transforming conceptualizations of these diseases, this article shows that their changing pattern, the idea of climatic determinism of diseases (neo-Hippocratism and medical geography), the weak standing of the medical community in Colombian society, as well as Pasteurian germ practices were all crucial in the uneven and varied reshaping of their understanding. PMID- 26095966 TI - Women Doctors and Lady Nurses: Class, Education, and the Professional Victorian Woman. AB - The lives of the first women doctors in Britain have been well studied by historians, as have the many debates about the right of women to train and practice as doctors. Yet the relationship between these women and their most obvious comparators and competitors-the newly professionalized hospital nurses has not been explored. This article makes use of a wide range of sources to explore the ways in which the first lady doctors created "clear water" between themselves and the nurses with whom they worked and trained. In doing so, it reveals an identity that may seem at odds with some of the cliches of Victorian femininity, namely that of the intelligent and ambitious lady doctor. PMID- 26095969 TI - What's in a Game?: A Survey of Digital Game Opportunities for Medical Historians. PMID- 26095972 TI - Patient non-attendance: utilising clinical time. AB - BACKGROUND: In undergraduate dental or medical programmes clinical time with exposure to patients is limited. A priority for all those involved in the delivery of a clinical programme is to ensure that this time is used effectively and to maximum potential. Patient non-attendance is a reality, and developing organised activities to provide alternative learning opportunities is important. METHODS: We have developed a range of close-contact teaching and learning activities (CCTLs) for dental students to productively use patient non-attendance time. CCTLs are short, skills-based tasks that are directly observed and have structured assessment criteria. Used formatively, they are performed in the clinical environment utilising the materials, equipment and clinical staff usually available during the clinical session. FINDINGS: The CCTLs have proved particularly useful for early-stage clinical students, by developing understanding and skills, reinforcing protocols and promoting the role of the wider dental team in teaching. Students have welcomed these activities and engagement has been high. In addition to improving skills, they have proved helpful in familiarising students with direct observation, and have inspired peer collaboration and feedback. DISCUSSION: The CCTLs have promoted opportunities for students to receive direct feedback, which may be difficult to deliver if a patient were present. Empowering students to lead on their own learning requirements also promotes the ethos of lifelong learning that will be fundamental to future professional development. Investment of resources to develop these activities has proved worthwhile, as we have found that CCTLs can complement and maximise the potential of clinical attachments. Patient non attendance is a reality, and developing organised activities to provide alternative learning opportunities is important. PMID- 26095973 TI - Performance of the SA-VA Difference to Differentiate Atrioventricular Nodal Reentrant Tachycardia from Orthodromic Reentrant Tachycardia in a Large Cohort of Consecutive Patients. AB - BACKGROUND: The stimulus-atrial (SA) interval minus ventriculoatrial (VA) interval (SA-VA) difference represents a simple diagnostic maneuver to distinguish between atrioventricular nodal reentrant tachycardia (AVNRT) and orthodromic reentrant tachycardia (ORT) during electrophysiology study. However, its usefulness has largely been studied in selected patient subgroups. The purpose of this study was to evaluate the performance of the SA-VA difference against commonly used diagnostic maneuvers in a large cohort of consecutive patients. METHODS: Consecutive patients with inducible supraventricular tachycardia and successful entrainment through pacing trains from right ventricular apex during an electrophysiological study were included. Atrial tachycardias were excluded. The following intervals were calculated for each patient: SA-VA difference, His potential, and atrial electrogram during entrainment minus His potential and atrial electrogram during tachycardia, and the corrected return cycle. RESULTS: A total of 456 patients fulfilled the inclusion criteria, of which electrophysiological study revealed 265 typical AVNRT, 38 atypical AVNRT, and 54 and 108 ORT through a septal and free-wall accessory pathway, respectively. An SA-VA difference >99 ms identified AVNRT in all patients with sensitivity, specificity, and positive and negative predictive values of 97.7%, 96.9%, 98.3%, and 95.7%, respectively. CONCLUSIONS: This study confirms the high ability to distinguish AVNRT from ORT using the SA-VA difference, not only in selected patient subgroups, but as whole when a cut-off of >99 ms is used. PMID- 26095974 TI - Graphene quantum dot-doped polyaniline nanofiber as high performance supercapacitor electrode materials. AB - Graphene quantum dot-doped polyaniline composites have been prepared by the chemical oxidation of aniline. Synthesized novel fibrous composites show an excellent specific capacitance value of ~1044 F g(-1) at a current density of 1 A g(-1) as well as moderate cyclic stability with a retention of life time of 80.1% after 3000 cycles. PMID- 26095975 TI - The human clinical phenotypes of altered CHRNA7 copy number. AB - Copy number variants (CNVs) have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability (ID). Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR). Several of these CNVs have been overrepresented in individuals with neuropsychiatric disorders; yet variable expressivity and incomplete penetrance are commonly seen. Dosage sensitivity of the CHRNA7 gene, which encodes for the alpha7 nicotinic acetylcholine receptor in the human brain, has been proposed to have a major contribution to the observed cognitive and behavioral phenotypes, as it represents the smallest region of overlap to all the 15q13.3 deletions and duplications. Individuals with zero to four copies of CHRNA7 have been reported in the literature, and represent a range of clinical severity, with deletions causing generally more severe and more highly penetrant phenotypes. Potential mechanisms to account for the variable expressivity within each group of 15q13.3 CNVs will be discussed. PMID- 26095976 TI - Enhanced BDNF signalling following chronic hypoxia potentiates catecholamine release from cultured rat adrenal chromaffin cells. AB - KEY POINTS: We investigated the role of the neurotrophin BDNF signalling via the TrkB receptor in rat adrenomedullary chromaffin cells (AMCs) exposed to normoxia (Nox; 21% O2) and chronic hypoxia (CHox; 2% O2) in vitro for ~ 48 h. TrkB receptor expression was upregulated in primary AMCs and in immortalized chromaffin (MAH) cells exposed to CHox; this effect was absent in MAH cells deficient in the transcription factor, hypoxia inducible factor (HIF)-2alpha. Relative to normoxic controls, activation of the TrkB receptor in chronically hypoxic AMCs led to a marked increase in membrane excitability, intracellular [Ca(2+)], and catecholamine secretion. The BDNF-induced rise of intracellular [Ca(2+)] in CHox cells was sensitive to the selective T-type Ca(2+) channel blocker TTA-P2 and tetrodotoxin (TTX), suggesting key roles of low threshold T type Ca(2+) and voltage-gated Na(+) channels in the signalling pathway. Environmental stressors, including chronic hypoxia, enhance the ability of adrenomedullary chromaffin cells (AMCs) to secrete catecholamines; however, the underlying molecular mechanisms remain unclear. Here, we investigated the role of brain-derived neurotrophic factor (BDNF) signalling in rat AMCs exposed to chronic hypoxia. In rat adrenal glands, BDNF and its tropomyosin-related kinase B (TrkB) receptor are highly expressed in the cortex and medulla, respectively. Exposure of AMCs to chronic hypoxia (2% O2; 48 h) in vitro caused a significant increase to TrkB mRNA expression. A similar increase was observed in an immortalized chromaffin cell line (MAH cells); however, it was absent in MAH cells deficient in the transcription factor HIF-2alpha. A specific TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), stimulated quantal catecholamine secretion from chronically hypoxic (CHox; 2% O2) AMCs to a greater extent than normoxic (Nox; 21% O2) controls. Activation of TrkB by BDNF or 7,8-DHF increased intracellular Ca(2+) ([Ca(2+)]i), an effect that was significantly larger in CHox cells. The 7,8-DHF-induced [Ca(2+)]i rise was sensitive to the tyrosine kinase inhibitor K252a and nickel (2 mm), but not the Ca(2+) store-depleting agent cyclopiazonic acid. Blockade of T-type calcium channels with TTA-P2 (1 MUm) or voltage-gated Na(+) channels with TTX inhibited BDNF-induced [Ca(2+)]i increases. BDNF also induced a dose-dependent enhancement of action potential firing in CHox cells. These data demonstrate that during chronic hypoxia, enhancement of BDNF-TrkB signalling increases voltage-dependent Ca(2+) influx and catecholamine secretion in chromaffin cells, and that T-type Ca(2+) channels play a key role in the signalling pathway. PMID- 26095978 TI - Ultrastructural and Phylogenetic Description of Kudoa orbicularis n. sp. (Myxosporea: Multivalvulida): A Parasite Infecting the Muscle of the Fish Chaetobranchopsis orbicularis (Teleostei: Cichlidae) in the Amazon Region. AB - A new myxosporean species is described from the muscle of the Amazonian freshwater fish Chaetobranchopsis orbicularis (Teleostei, Cichlidae), with basis on morphometric, ultrastructural and molecular data. Numerous myxospores were observed within pseudocysts located on the hosts' dorsal and ventral muscles, near the neural spines and neural canal (spinal cord). Mature myxospores quadrangular with rounded ends in apical view, measuring 4.3 (3.6-5.0) MUm in length and 5.1 (4.2-5.8) MUm in width. The myxospores wall is formed by four symmetric valves. Within, four pyriform polar capsules, 2.1 (1.7-2.6) MUm long and 1.3 (0.9-1.7) MUm wide, located two by two in opposite sides of the myxospores longitudinal axis, each containing a polar filament forming 2-3 coils. Molecular analysis of the SSU rRNA gene by maximum likelihood, neighbor-joining and maximum parsimony confirms the parasite as a new member of the genus Kudoa, herein named Kudoa orbicularis n. sp., the second species of its genus reported from the South American freshwater fauna, and the fourth species worldwide known to occur in the freshwater environment. Furthermore, its sequence of the SSU rRNA gene constitutes the first entry of a freshwater Kudoa species in GenBank. PMID- 26095977 TI - Neuroimaging of the dopamine/reward system in adolescent drug use. AB - Adolescence is characterized by heightened risk-taking, including substance misuse. These behavioral patterns are influenced by ontogenic changes in neurotransmitter systems, particularly the dopamine system, which is fundamentally involved in the neural coding of reward and motivated approach behavior. During adolescence, this system evidences a peak in activity. At the same time, the dopamine (DA) system is neuroplastically altered by substance abuse, impacting subsequent function. Here, we describe properties of the dopamine system that change with typical adolescent development and that are altered with substance abuse. Much of this work has been gleaned from animal models due to limitations in measuring dopamine in pediatric samples. Structural and functional neuroimaging techniques have been used to examine structures that are heavily DA-innervated; they measure morphological and functional changes with age and with drug exposure. Presenting marijuana abuse as an exemplar, we consider recent findings that support an adolescent peak in DA-driven reward seeking behavior and related deviations in motivational systems that are associated with marijuana abuse/dependence. Clinicians are advised that (1) chronic adolescent marijuana use may lead to deficiencies in incentive motivation, (2) that this state is due to marijuana's interactions with the developing DA system, and (3) that treatment strategies should be directed to remediating resultant deficiencies in goal-directed activity. PMID- 26095979 TI - A potential mechanism by which torque output is preserved in cerebral palsy during fatiguing contractions of the knee extensors. AB - INTRODUCTION: The purpose of this study was to compare agonist and antagonist electromyography (EMG) during an isokinetic fatigue protocol in subjects with cerebral palsy (CP) and typical development (TD). METHODS: Nine individuals with CP and 11 with TD completed 50 repetitions of maximum concentric knee extensions (KE) and flexions (KF) at 60 degrees /second. RESULTS: Rate of decline in peak torque for KE was significantly less in CP compared with TD. Rate of decline in agonist EMG was not significantly different between groups, but the rate of decline in antagonist EMG was significantly greater in CP. There were no differences between groups for KF. CONCLUSIONS: Declining agonist EMG occurred in parallel with declining antagonist hamstring activity in CP, decreasing the relative opposing force and resulting in a lesser decline in net torque. This finding illustrates a potential mechanism by which net torque is preserved in those with CP who are inherently weaker. PMID- 26095980 TI - Resting heart rate variability is associated with inhibition of conditioned fear. AB - Startle blink as well as skin conductance responses (SCR) are widely used indices of learning processes associated with fear conditioning and extinction. During safety learning, the amygdala is under top-down inhibitory control by the prefrontal cortex (PFC). The capacity of the PFC to exert inhibitory control over subcortical brain structures may be indexed by resting state vagally mediated heart rate variability (HRV). The present study investigated the association of resting HRV with startle blink and SCR during conditioned fear inhibition and extinction. Participants first learned to discriminate a threat cue (A) signaling an aversive unconditioned stimulus from a safety signal (B), which were each presented together with a third stimulus X (AX+/BX-). Then, both the threat and safety signal were presented together (AB) to test whether the presence of the learned safety signal inhibits the fear response to the danger signal. Finally, AX was presented without reinforcement (AX-) to investigate fear extinction. Higher HRV was associated with pronounced fear inhibition and fear extinction. Resting HRV levels were associated with fear extinction as indexed by startle blink potentiation but not SCR, which presumably reflect more cognitive aspects of learning. Resting HRV may reflect the capacity of the prefrontal cortex to inhibit subcortical fear responses in the presence of safety or when former threat cues are presented in the absence of threat. PMID- 26095981 TI - Probabilistic Model for Untargeted Peak Detection in LC-MS Using Bayesian Statistics. AB - We introduce a novel Bayesian probabilistic peak detection algorithm for liquid chromatography-mass spectroscopy (LC-MS). The final probabilistic result allows the user to make a final decision about which points in a chromatogram are affected by a chromatographic peak and which ones are only affected by noise. The use of probabilities contrasts with the traditional method in which a binary answer is given, relying on a threshold. By contrast, with the Bayesian peak detection presented here, the values of probability can be further propagated into other preprocessing steps, which will increase (or decrease) the importance of chromatographic regions into the final results. The present work is based on the use of the statistical overlap theory of component overlap from Davis and Giddings (Davis, J. M.; Giddings, J. Anal. Chem. 1983, 55, 418-424) as prior probability in the Bayesian formulation. The algorithm was tested on LC-MS Orbitrap data and was able to successfully distinguish chemical noise from actual peaks without any data preprocessing. PMID- 26095983 TI - LCA of management strategies for RDF incineration and gasification bottom ash based on experimental leaching data. AB - The main characteristics and environmental properties of the bottom ash (BA) generated from thermal treatment of waste may vary significantly depending on the type of waste and thermal technology employed. Thus, to ensure that the strategies selected for the management of these residues do not cause adverse environmental impacts, the specific properties of BA, in particular its leaching behavior, should be taken into account. This study focuses on the evaluation of potential environmental impacts associated with two different management options for BA from thermal treatment of Refuse Derived Fuel (RDF): landfilling and recycling as a filler for road sub bases. Two types of thermal treatment were considered: incineration and gasification. Potential environmental impacts were evaluated by life-cycle assessment (LCA) using the EASETECH model. Both non toxicity related impact categories (i.e. global warming and mineral abiotic resource depletion) and toxic impact categories (i.e. human toxicity and ecotoxicity) were assessed. The system boundaries included BA transport from the incineration/gasification plants to the landfills and road construction sites, leaching of potentially toxic metals from the BA, the avoided extraction, crushing, transport and leaching of virgin raw materials for the road scenarios, and material and energy consumption for the construction of the landfills. To provide a quantitative assessment of the leaching properties of the two types of BA, experimental leaching data were used to estimate the potential release from each of the two types of residues. Specific attention was placed on the sensitivity of leaching properties and the determination of emissions by leaching, including: leaching data selection, material properties and assumptions related to emission modeling. The LCA results showed that for both types of BA, landfilling was associated with the highest environmental impacts in the non toxicity related categories. For the toxicity related categories, the two types of residues behaved differently. For incineration BA the contribution of metal leaching to the total impacts had a dominant role, with the highest environmental loads resulting for the road scenario. For the gasification BA, the opposite result was obtained, due to the lower release of contaminants observed for this material compared to incineration BA. Based on the results of this study, it may be concluded that, depending on the type of BA considered, its leaching behavior may significantly affect the results of a LCA regarding its management strategies. PMID- 26095982 TI - Accounting for observed small angle X-ray scattering profile in the protein protein docking server ClusPro. AB - The protein-protein docking server ClusPro is used by thousands of laboratories, and models built by the server have been reported in over 300 publications. Although the structures generated by the docking include near-native ones for many proteins, selecting the best model is difficult due to the uncertainty in scoring. Small angle X-ray scattering (SAXS) is an experimental technique for obtaining low resolution structural information in solution. While not sufficient on its own to uniquely predict complex structures, accounting for SAXS data improves the ranking of models and facilitates the identification of the most accurate structure. Although SAXS profiles are currently available only for a small number of complexes, due to its simplicity the method is becoming increasingly popular. Since combining docking with SAXS experiments will provide a viable strategy for fairly high-throughput determination of protein complex structures, the option of using SAXS restraints is added to the ClusPro server. (c) 2015 Wiley Periodicals, Inc. PMID- 26095984 TI - Monotone spline-based least squares estimation for panel count data with informative observation times. AB - This article discusses the statistical analysis of panel count data when the underlying recurrent event process and observation process may be correlated. For the recurrent event process, we propose a new class of semiparametric mean models that allows for the interaction between the observation history and covariates. For inference on the model parameters, a monotone spline-based least squares estimation approach is developed, and the resulting estimators are consistent and asymptotically normal. In particular, our new approach does not rely on the model specification of the observation process. The proposed inference procedure performs well through simulation studies, and it is illustrated by the analysis of bladder tumor data. PMID- 26095985 TI - Human health risk assessment of pesticide residues in snappers (Lutjanus) fish from the Navachiste Lagoon complex, Mexico. AB - Organochlorine pesticides (OCPs) residues were determined in fillets of Lutjanus colorado, L. argentiventris, and L. novemfasciatus. Fillet samples were collected bimonthly from February 2012 to February 2013. OCPs average concentrations do not differ significantly according to size, weight, or season, nor do they relate with the physico-chemical parameters of the sea water. The highest concentration and most frequently encountered OCPs were endosulfan sulfate, delta-HCH, and heptachlor epoxide, which indicates their use in the recent past and confirms their persistence. Average concentrations of ?HCHs, ?chlordane, and ?heptachlor in samples were above cancer MRLs according to data from monthly consumed portions. HCHs and heptachlor are listed in Appendix III of the Rotterdam Convention of chemicals placed on a prior informed consent procedure for import and export purposes; they are considered illegal in Mexico. The OCPs concentrations above cancer MRLs in Lutjanus spp. turn its frequent consumption into a human health risk. PMID- 26095986 TI - Validation of algal viability treated with total residual oxidant and organic matter by flow cytometry. AB - Algal cell growth after starch and oxidant treatments in seawater species (Isochrysis galbana and Phaeodactylum tricornutum) and freshwater species (Selenastrum capricornutum and Scenedesmus obliquus) were evaluated by flow cytometry with fluorescein diacetate (FDA) staining to determine algal viability. Growth of algal cell was found to be significantly different among groups treated with NaOCl, starch and/or sodium thiosulfate, which are active substance (Total Residual Oxidant; TRO as Cl2), organic compound to meet efficacy testing standard and neutralizer of TRO by Ballast Water Management Convention of International Maritime Organization, respectively. The viability of algal cell treated with TRO in starch-add culture of 5days after treatment and neutralization was decreased significantly. ATP contents of the treated algal cells corresponded to the FL1 fluorescent signal of flow cytometry with FDA staining. I. galbana was the most sensitive to TRO-neutralized cultures during viability analysis. PMID- 26095987 TI - Radiocesium monitoring in Indonesian waters of the Indian Ocean after the Fukushima nuclear accident. AB - As data on anthropogenic radionuclide concentrations (i.e., (134)Cs and (137)Cs) in Indonesian marine environments including the Indian Ocean are scarce, offshore monitoring has been performed in the West Sumatra and South Java Seas. The activity concentration of (137)Cs ranges from below minimum detectable activity (MDA) to 0.13Bqm(-3) in the surface seawater of the South Java Sea and from lower than MDA to 0.28Bqm(-3) in the surface seawater of the West Sumatra Sea. The concentrations of (137)Cs in the surface seawater of the West Sumatra and South Java Seas are lower than the estimation of (137)Cs concentration in the subsurface waters owing to the input of the North Pacific Ocean via the Indonesian Throughflow (ITF). The concentrations of (134)Cs in the sampling locations were lower than MDA. These results have indicated that these Indonesian marine waters have not yet been influenced by the Fukushima radioactive release. PMID- 26095988 TI - Impact of seaweed beachings on dynamics of delta(15)N isotopic signatures in marine macroalgae. AB - A fine-scale survey of delta(15)N, delta(13)C, tissue-N in seaweeds was conducted using samples from 17 sampling points at two sites (Grandcamp-Maisy (GM), Courseulles/Mer (COU)) along the French coast of the English Channel in 2012 and 2013. Partial triadic analysis was performed on the parameter data sets and revealed the functioning of three areas: one estuary (EstA) and two rocky areas (GM(*), COU(*)). In contrast to oceanic and anthropogenic reference points similar temporal dynamics characterized delta(15)N signatures and N contents at GM(*) and COU(*). Nutrient dynamics were similar: the N-concentrations in seawater originated from the River Seine and local coastal rivers while P concentrations mainly from these local rivers. delta(15)N at GM(*) were linked to turbidity suggesting inputs of autochthonous organic matter from large-scale summer seaweed beachings made up of a mixture of Rhodophyta, Phaeophyta and Chlorophyta species. This study highlights the coupling between seaweed beachings and nitrogen sources of intertidal macroalgae. PMID- 26095989 TI - Trends in celiac disease research. AB - BACKGROUND: To improve diagnosis and treatment of celiac disease (CD), research efforts are being made in many different areas. However, the focus, trend, and direction of such efforts require clarity, so that future efforts and directions can be appropriately planned. METHOD: In this study, MEDLINE was used to search for trends in CD research. The keyword 'celiac disease' and its variants were searched in tandem with keywords commonly associated with CD. This search was done for each year from 1960 to 2013. Year of first instance of the associated keyword, linear regression coefficient, and trend in terms of the slope of the regression line were tabulated. For perspective, the same keywords were searched in tandem with 'inflammatory bowel disease' (IBD). RESULTS: CD appeared in the medical literature prior to 1960, and IBD first appeared in 1964. However, IBD overtook CD in terms of the number of research papers published per year, beginning in 1988. Keywords with strong positive trends (r(2)>0.7) in association with CD were: 'diagnosis', 'gluten', 'serology', 'autoimmune', 'treatment', 'gluten-free diet', 'endoscopy', 'villous atrophy', 'wasting', 'inflammation', and 'microbiome'. The keyword 'malabsorption' had the sole strong negative trend in association with CD. Keywords with strong positive trends (r(2)>0.7) in association with IBD also had strong positive association with CD: 'autoimmune', 'treatment, 'inflammation', and 'microbiome'. CONCLUSIONS: The MEDLINE search approach is helpful to show first instance, association, and trend of keywords that are affiliated with CD in published biomedical research, and to compare CD research trends with those of other diseases. PMID- 26095990 TI - Enzyme- and transporter-mediated beverage-drug interactions: An update on fruit juices and green tea. AB - Beverage-drug interactions have remained an active area of research and have been the subject of extensive investigations in the past 2 decades. The known mechanisms of clinically relevant beverage-drug interactions include modulation of the activity of cytochrome P450 (CYP) 3A and organic anion-transporting polypeptide (OATP). For CYP3A-mediated beverage-drug interaction, the in vivo CYP3A inhibitory effect is limited to grapefruit juice (GFJ), which increases the bioavailability of several orally administered drugs that undergo extensive first pass metabolism via enteric CYP3A. In contrast, clinically significant OATP mediated beverage-drug interactions have been observed with not only GFJ but also orange juice, apple juice, and, most recently, green tea. Fruit juices and green tea are all a mixture of a large number of constituents. The investigation of specific constituent(s) responsible for the enzyme and/or transporter inhibition remains an active area of research, and many new findings have been obtained on this subject in the past several years. This review highlights the multiple mechanisms through which beverages can alter drug disposition and provides an update on the new findings of beverage-drug interactions, with a focus on fruit juices and green tea. PMID- 26095993 TI - Reactions with a Metalloid Tin Cluster {Sn10[Si(SiMe3)3]4}(2-): Ligand Elimination versus Coordination Chemistry. PMID- 26095991 TI - Transition from Initial Hypoactivity to Hyperactivity in Cortical Layer V Pyramidal Neurons after Traumatic Brain Injury In Vivo. AB - Traumatic brain injury (TBI) often results in structural damage and a loss of neurons that is commonly accompanied by early changes in neuronal electrical activity. Loss of neuronal activity has been hypothesized to contribute to post traumatic epileptogenesis through the regulation of homeostatic plasticity. The existence of activity loss in cortical neurons after TBI and its subsequent transition into hyperactivity over time is not well characterized, however, particularly in models of TBI in vivo. In the current study, changes in neuronal activity in the primary motor cortex after moderate controlled cortical impact (CCI) in mice were studied using a single-unit recording technique in vivo. Recordings were made at different time points after CCI from cortical layer V pyramidal neurons that were within 1-2 mm from the anterior edge of the injured foci. Within 1-4 h after CCI, the frequency of spontaneous single-unit activity depressed significantly, with the mean firing frequency decreasing from 2.59 +/- 0.18 Hz in the sham group to 1.05 +/- 0.20 Hz of the injured group. The firing frequencies recovered to the normal level at 1 day and 7 days post-CCI, but became significantly higher at 3 days and 14 days post-CCI. The results suggest that TBI caused initial loss of activity in neurons of the perilesional cortical region, which was followed by compensatory recovery and enhancement of activity. These time-dependent changes in neuronal activity may contribute to the development of hyperexcitability through homeostatic activity regulation. PMID- 26095997 TI - Clinical implications of mucinous components correlated with microsatellite instability in patients with colorectal cancer. AB - AIM: Colorectal cancer (CRC) with microsatellite instability (MSI) is characterized by frequent poor differentiation or mucinous histology. The purpose of this study was to evaluate the association of MSI with clinicopathological features and the oncological outcome in patients with a mucinous component. METHOD: CRC tissue samples were analysed for histology and MSI. Patients were grouped according to the mucinous content of the tumour, as follows: > 50%, mucinous adenocarcinoma (MA); <= 50%, adenocarcinoma with mucinous component (AMC); none, nonmucinous adenocarcinoma (NMA). Clinicopathological parameters and survival were compared between patient groups. RESULTS: Of 2025 patients, 84 (4%) had MA and 124 (6%) had AMC. In addition, 202 (10%) had MSI. Patients with MA and AMC tended to have a younger age of onset, right-colon predilection, large-sized tumour and high frequency of MSI compared with those with NMA (P < 0.001). MA and AMC patients with MSI showed a trend towards right-colon predilection and infrequent lymph-node metastasis compared with those with microsatellite stability (MSS; P = 0.005-0.03). There were no survival differences between the three groups, but patients with MSI-MA demonstrated lower 4-year recurrence and better overall survival rates than those with MSS-MA (P = 0.018 and P = 0.046, respectively). CONCLUSION: Clinicopathological features of AMC and MA were similar and closely associated with MSI status. Although the prognoses of AMC and MA were no different from that of NMA, survival of patients with an MSI-MA tumour was significantly better than for those with MSS-MA tumours. PMID- 26095998 TI - Epigenetic control of juvenile-to-adult phase transition by the Arabidopsis SAGA like complex. AB - During growth and development, plants undergo a series of phase transitions from the juvenile-to-adult vegetative phase to the reproductive phase. In Arabidopsis, vegetative phase transitions and flowering are regulated by SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) factors. SPL mRNAs are post-transcriptionally regulated by miR156 in an age-dependent manner; however, the role of other mechanisms in this process is not known. In this study, we demonstrate that the HAG1/GCN5- and PRZ1/ADA2b-containing SAGA-like histone acetyltransferase (HAT) complex directly controls the transcription of SPLs and determines the time for juvenile-to-adult phase transition. Thus, epigenetic control by the SAGA-like HAT complex determines the transcriptional output of SPLs, which might be a prerequisite for the subsequent post-transcriptional regulation by miR156. Importantly, this epigenetic control mechanism is also crucial for miR156 independent induction of SPLs and acceleration of phase transition by light and photoperiod or during post-embryonic growth. PMID- 26095999 TI - A surgical technique using the ovarian vein in non-human primate models of potential living-donor surgery of uterus transplantation. AB - AIM: Living donor surgery in organ transplantation should be performed in a minimally invasive manner under conditions that are as safe as possible. The objective of this study is to examine whether the procedure for using the ovarian vein makes donor surgery less invasive in a cynomolgus monkey model of potential living-donor surgery of uterus transplantation. MATERIAL AND METHODS: Twenty-two female cynomolgus monkeys aged 6-9 years and with body weights of 3.55 +/- 1.28 kg were used in the study. Vessels and tissues surrounding the uterus were dissected while preserving the uterine artery/vein. The deep uterine vein was used as a venous pedicle in four monkeys (Group 1), and the ovarian vein was used instead of the deep uterine vein in 18 monkeys (Group 2). With the uterine artery/vein and deep uterine vein (Group 1) or ovarian vein (Group 2) connected to the uterus, the vaginal canal was cut. The vessels were then clamped to produce a donor surgery model. Surgical time, intraoperative organ and vascular injury were examined in each animal. RESULTS: The average surgical time from laparotomy to clamping of vessels was 230 +/- 112 min in all 22 cynomolgus monkeys, and significantly longer in Group 1 (n = 4) than in Group 2 (n = 18) (393 +/- 71 vs. 194 +/- 84 min, p < 0.05). Surgical time in Group 2 showed a tendency to decrease in animals treated later in the study, with a significantly longer time in the first 10 monkeys compared with the last 8 (253 +/- 65 vs. 120 +/- 26 min, p < 0.05). All monkeys had no complications, including no injuries to other organs and no unanticipated vascular injury. CONCLUSION: The procedure using the ovarian vein was less invasive than that using the deep uterine vein in mimicking living-donor surgery in a cynomolgus monkey model of uterus transplantation. PMID- 26096000 TI - Evolution and maintenance of haploid-diploid life cycles in natural populations: The case of the marine brown alga Ectocarpus. AB - The evolutionary stability of haploid-diploid life cycles is still controversial. Mathematical models indicate that niche differences between ploidy phases may be a necessary condition for the evolution and maintenance of these life cycles. Nevertheless, experimental support for this prediction remains elusive. In the present work, we explored this hypothesis in natural populations of the brown alga Ectocarpus. Consistent with the life cycle described in culture, Ectocarpus crouaniorum in NW France and E. siliculosus in SW Italy exhibited an alternation between haploid gametophytes and diploid sporophytes. Our field data invalidated, however, the long-standing view of an isomorphic alternation of generations. Gametophytes and sporophytes displayed marked differences in size and, conforming to theoretical predictions, occupied different spatiotemporal niches. Gametophytes were found almost exclusively on the alga Scytosiphon lomentaria during spring whereas sporophytes were present year-round on abiotic substrata. Paradoxically, E. siliculosus in NW France exhibited similar habitat usage despite the absence of alternation of ploidy phases. Diploid sporophytes grew both epilithically and epiphytically, and this mainly asexual population gained the same ecological advantage postulated for haploid-diploid populations. Consequently, an ecological interpretation of the niche differences between haploid and diploid individuals does not seem to satisfactorily explain the evolution of the Ectocarpus life cycle. PMID- 26096001 TI - Glanzmann thrombasthenia in Pakistan: molecular analysis and identification of novel mutations. AB - Glanzmann thrombasthenia (GT) is an inherited genetic disorder affecting platelets, which is characterized by spontaneous mucocutaneous bleeding and abnormally prolonged bleeding in response to injury or trauma. The underlying defect is failure of platelet aggregation due to qualitative and/or quantitative deficiency of platelet integrin alphaIIbbeta3 resulting from molecular genetic defects in either ITGA2B or ITGB3. Here, we examine a Pakistani cohort of 15 patients with clinical symptoms of GT who underwent laboratory and molecular genetic analysis. In patients with a broad range of disease severity and age of presentation, we identified pathogenic mutations in ITGA2B in 11 patients from 8 different families, including 2 novel homozygous mutations and 1 novel heterozygous mutation. Mutations in ITGB3 were identified in 4 patients from 3 families, two of which were novel homozygous truncating mutations. A molecular genetic diagnosis was established in 11 families with GT, including 5 novel mutations extending the spectrum of mutations in this disease within a region of the world where little is known about the incidence of GT. Mutational analysis is a key component of a complete diagnosis of GT and allows appropriate management and screening of other family members to be performed. PMID- 26096002 TI - Transcriptome-Wide Identification of miRNA Targets under Nitrogen Deficiency in Populus tomentosa Using Degradome Sequencing. AB - miRNAs are endogenous non-coding small RNAs with important regulatory roles in stress responses. Nitrogen (N) is an indispensable macronutrient required for plant growth and development. Previous studies have identified a variety of known and novel miRNAs responsive to low N stress in plants, including Populus. However, miRNAs involved in the cleavage of target genes and the corresponding regulatory networks in response to N stress in Populus remain largely unknown. Consequently, degradome sequencing was employed for global detection and validation of N-responsive miRNAs and their targets. A total of 60 unique miRNAs (39 conserved, 13 non-conserved, and eight novel) were experimentally identified to target 64 mRNA transcripts and 21 precursors. Among them, we further verified the cleavage of 11 N-responsive miRNAs identified previously and provided empirical evidence for the cleavage mode of these miRNAs on their target mRNAs. Furthermore, five miRNA stars (miRNA*s) were shown to have cleavage function. The specificity and diversity of cleavage sites on the targets and miRNA precursors in P. tomentosa were further detected. Identification and annotation of miRNA mediated cleavage of target genes in Populus can increase our understanding of miRNA-mediated molecular mechanisms of woody plants adapted to low N environments. PMID- 26096003 TI - Transcriptional Profiling Reveals Differential Gene Expression of Amur Ide (Leuciscus waleckii) during Spawning Migration. AB - Amur ide (Leuciscus waleckii), an important aquaculture species, inhabits neutral freshwater but can tolerate high salinity or alkalinity. As an extreme example, the population in Dali Nor lake inhabits alkalized soda water permanently, and migrates from alkaline water to neutral freshwater to spawn. In this study, we performed comparative transcriptome profiling study on the livers of Amur ide to interrogate the expression differences between the population that permanently inhabit freshwater in Ganggeng Nor lake (FW) and the spawning population that recently migrated from alkaline water into freshwater (SM). A total of 637,234,880 reads were generated, resulting in 53,440 assembled contigs that were used as reference sequences. Comparisons of these transcriptome files revealed 444 unigenes with significant differential expression (p-value <= 0.01, fold change >= 2), including 246 genes that were up-regulated in SM and 198 genes that were up-regulated in FW. The gene ontology (GO) enrichment analysis and KEGG pathway analysis indicated that the mTOR signaling pathway, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, and oxidative phosphorylation were highly likely to affect physiological changes during spawning migration. Overall, this study demonstrates that transcriptome changes played a role in Amur ide spawning migration. These results provide a foundation for further analyses on the physiological and molecular mechanisms underlying Amur ide spawning migration. PMID- 26096004 TI - Adsorption of Silver Nanoparticles onto Different Surface Structures of Chitin/Chitosan and Correlations with Antimicrobial Activities. AB - Size-controlled spherical silver nanoparticles (Ag NPs) can be simply prepared by autoclaving mixtures of glass powder containing silver with glucose. Moreover, chitins with varying degrees of deacetylation (DDAc < 30%) and chitosan powders and sheets (DDAc > 75%) with varying surface structure properties have been evaluated as Ag NP carriers. Chitin/chitosan-Ag NP composites in powder or sheet form were prepared by mixing Ag NP suspensions with each of the chitin/chitosan based material at pH 7.3, leading to homogenous dispersion and stable adsorption of Ag NPs onto chitin carriers with nanoscale fiber-like surface structures, and chitosan carriers with nanoscale porous surface structures. Although these chitins exhibited mild antiviral, bactericidal, and antifungal activities, chitin powders with flat/smooth film-like surface structures had limited antimicrobial activities and Ag NP adsorption. The antimicrobial activities of chitin/chitosan Ag NP composites increased with increasing amounts of adsorbed Ag NPs, suggesting that the surface structures of chitin/chitosan carriers strongly influence adsorption of Ag NPs and antimicrobial activities. These observations indicate that chitin/chitosan-Ag NPs with nanoscale surface structures have potential as antimicrobial biomaterials and anti-infectious wound dressings. PMID- 26096005 TI - Leaf Age-Dependent Photoprotective and Antioxidative Response Mechanisms to Paraquat-Induced Oxidative Stress in Arabidopsis thaliana. AB - Exposure of Arabidopsis thaliana young and mature leaves to the herbicide paraquat (Pq) resulted in a localized increase of hydrogen peroxide (H2O2) in the leaf veins and the neighboring mesophyll cells, but this increase was not similar in the two leaf types. Increased H2O2 production was concomitant with closed reaction centers (qP). Thirty min after Pq exposure despite the induction of the photoprotective mechanism of non-photochemical quenching (NPQ) in mature leaves, H2O2 production was lower in young leaves mainly due to the higher increase activity of ascorbate peroxidase (APX). Later, 60 min after Pq exposure, the total antioxidant capacity of young leaves was not sufficient to scavenge the excess reactive oxygen species (ROS) that were formed, and thus, a higher H2O2 accumulation in young leaves occurred. The energy allocation of absorbed light in photosystem II (PSII) suggests the existence of a differential photoprotective regulatory mechanism in the two leaf types to the time-course Pq exposure accompanied by differential antioxidant protection mechanisms. It is concluded that tolerance to Pq-induced oxidative stress is related to the redox state of quinone A (QA). PMID- 26096006 TI - A Comparative Proteomic Analysis of the Buds and the Young Expanding Leaves of the Tea Plant (Camellia sinensis L.). AB - Tea (Camellia sinensis L.) is a perennial woody plant that is widely cultivated to produce a popular non-alcoholic beverage; this beverage has received much attention due to its pleasant flavor and bioactive ingredients, particularly several important secondary metabolites. Due to the significant changes in the metabolite contents of the buds and the young expanding leaves of tea plants, high-performance liquid chromatography (HPLC) analysis and isobaric tags for relative and absolute quantitation (iTRAQ) analysis were performed. A total of 233 differentially expressed proteins were identified. Among these, 116 proteins were up-regulated and 117 proteins were down-regulated in the young expanding leaves compared with the buds. A large array of diverse functions was revealed, including roles in energy and carbohydrate metabolism, secondary metabolite metabolism, nucleic acid and protein metabolism, and photosynthesis- and defense related processes. These results suggest that polyphenol biosynthesis- and photosynthesis-related proteins regulate the secondary metabolite content of tea plants. The energy and antioxidant metabolism-related proteins may promote tea leaf development. However, reverse transcription quantitative real-time PCR (RT qPCR) showed that the protein expression levels were not well correlated with the gene expression levels. These findings improve our understanding of the molecular mechanism of the changes in the metabolite content of the buds and the young expanding leaves of tea plants. PMID- 26096007 TI - Fungal Community Successions in Rhizosphere Sediment of Seagrasses Enhalus acoroides under PAHs Stress. AB - Seagrass meadows represent one of the highest productive marine ecosystems and are of great ecological and economic values. Recently, they have been confronted with worldwide decline. Fungi play important roles in sustaining the ecosystem health as degraders of polycyclic aromatic hydrocarbons (PAHs), but fewer studies have been conducted in seagrass ecosystems. Hence, we investigated the dynamic variations of the fungal community succession under PAH stress in rhizosphere sediment of seagrasses Enhalus acoroides in this study. Polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE), quantitative PCR (qPCR) and a clone library have been employed to analyze the fungal community's shifts. Sequencing results of DGGE and the clone library showed that the predominant species belong to phyla Ascomycota and Basidiomycota. The abundance of three groups decreased sharply over the incubation period, whereas they demonstrated different fungal diversity patterns. Both the exposure time and the PAH concentrations affected the microbial diversity as assessed by PCR-DGGE analysis. Redundancy analysis (RDA) indicated that significant factors driving community shifts were ammonium and pH (p < 0.05). Significant amounts of the variations (31.1%) were explained by pH and ammonium, illustrating that those two parameters were the most likely ones to influence or be influenced by the fungal communities' changes. Investigation results also indicated that fungal communities in seagrass meadow were very sensitive to PAH-induced stress and may be used as potential indicators for the PAH contamination. PMID- 26096009 TI - Targeted sequencing of cancer-associated genes in hepatocellular carcinoma using next generation sequencing. AB - Liver cancer is one of the most common causes of cancer-associated mortality. Hepatocellular carcinoma (HCC) is the major histological subtype among types of primary liver cancer. China is an area of high incidence of HCC, and >50% of the cases of HCC worldwide are in China. At present, the mechanism underlying the development of HCC remains to be fully elucidated, and previous studies have predominantly focused on HCC in southern and eastern China, with molecular data of the HCC cases in Western China remains limited. In the present study, a panel of 372 cancer-associated genes were screened using a next generation sequencing platform, which included a total of 12 cases from western China. The results confirmed mutations in previously identified HCC drivers, including p53 and Kras. Additionally, mutations in several cancer genes, which had not been previously associated with HCC, were identified, including RUNX1 and JAK3. The present study provided a mutation spectrum of HCC tissue in cases from western China, assisting in the investigation of the mechanism of liver carcinogenesis. PMID- 26096010 TI - New South Wales Agency for Clinical Innovation--Pain Management Network website: a useful resource for patients and clinicians. PMID- 26096011 TI - The Four Square Step Test. PMID- 26096008 TI - Is Correction of Iron Deficiency a New Addition to the Treatment of the Heart Failure? AB - Anemia is present in about 40% of heart failure (HF) patients. Iron deficiency (ID) is present in about 60% of the patients with anemia (about 24% of all HF patients) and in about 40% of patients without anemia (about 24% of all HF patients). Thus ID is present in about half the patients with HF. The ID in HF is associated with reduced iron stores in the bone marrow and the heart. ID is an independent risk factor for severity and worsening of the HF. Correction of ID with intravenous (IV) iron usually corrects both the anemia and the ID. Currently used IV iron preparations are very safe and effective in treating the ID in HF whereas little information is available on the effectiveness of oral iron. In HF IV iron correction of ID is associated with improvement in functional status, exercise capacity, quality of life and, in some studies, improvement in rate of hospitalization for HF, cardiac structure and function, and renal function. Large long-term adequately-controlled intervention studies are needed to clarify the effect of IV iron in HF. Several heart associations suggest that ID should be routinely sought for in all HF patients and corrected if present. In this paper we present our approach to diagnosis and treatment of iron deficiency in heart failure. PMID- 26096012 TI - Intention-to-treat analysis. PMID- 26096013 TI - Non-invasive ventilation used as an adjunct to airway clearance treatments improves lung function during an acute exacerbation of cystic fibrosis: a randomised trial. AB - QUESTION: During an acute exacerbation of cystic fibrosis, is non-invasive ventilation beneficial as an adjunct to the airway clearance regimen? DESIGN: Randomised controlled trial with concealed allocation and intention-to-treat analysis. PARTICIPANTS: Forty adults with moderate to severe cystic fibrosis lung disease and who were admitted to hospital for an acute exacerbation. INTERVENTION: Comprehensive inpatient care (control group) compared to the same care with the addition of non-invasive ventilation during airway clearance treatments from Day 2 of admission until discharge (experimental group). OUTCOME MEASURES: Lung function and subjective symptom severity were measured daily. Fatigue was measured at admission and discharge on the Schwartz Fatigue Scale from 7 (no fatigue) to 63 (worst fatigue) points. Quality of life and exercise capacity were also measured at admission and discharge. Length of admission and time to next hospital admission were recorded. RESULTS: Analysed as the primary outcome, the experimental group had a greater rate of improvement in forced expiratory volume in 1 second (FEV1) than the control group, but this was not statistically significant (MD 0.13% predicted per day, 95% CI -0.03 to 0.28). However, the experimental group had a significantly higher FEV1 at discharge than the control group (MD 4.2% predicted, 95% CI 0.1 to 8.3). The experimental group reported significantly lower levels of fatigue on the Schwartz fatigue scale at discharge than the control group (MD 6 points, 95% CI 1 to 11). There was no significant difference between the experimental and control groups in subjective symptom severity, quality of life, exercise capacity, length of hospital admission or time to next hospital admission. CONCLUSION: Among people hospitalised for an acute exacerbation of cystic fibrosis, the use of non invasive ventilation as an adjunct to the airway clearance regimen significantly improves FEV1 and fatigue. TRIAL REGISTRATION: ANZCTR 12605000437662. PMID- 26096014 TI - Dipeptide-Derived Multifunctional Quaternary Phosphonium Salt Catalyzed Asymmetric Cyclizations via a Tandem Michael Addition/SN 2 Sequence. AB - A novel family of dipeptide-based multifunctional quaternary phosphonium salts has been developed as chiral phase-transfer catalysts, which feature ready accessibility and structure modularity, allowing easy fine-tunings of activity. They demonstrated high efficiency in catalyzing the tandem asymmetric Michael addition/intramolecular SN 2 reaction between 6 or 7-substituted conjugate enones and malonates, providing synthetically important five or six-membered carbocycles and heterocycles in good yields and with good to excellent enantioselectivities. PMID- 26096015 TI - Cholesterol-induced astrocyte activation is associated with increased amyloid precursor protein expression and processing. AB - Cholesterol is essential for maintaining lipid raft integrity and has been regarded as a crucial regulatory factor for amyloidogenesis in Alzheimer's disease (AD). The vast majority of studies on amyloid precursor protein (APP) metabolism and amyloid beta-protein (Abeta) production have focused on neurons. The role of astrocytes remains largely unexplored, despite the presence of activated astrocytes in the brains of most patients with AD and in transgenic models of the disease. The role of cholesterol in Abeta production has been thoroughly studied in neurons and attributed to the participation of lipid rafts in APP metabolism. Thus, in this study, we analyzed the effect of cholesterol loading in astrocytes and analyzed the expression and processing of APP. We found that cholesterol exposure induced astrocyte activation, increased APP content, and enhanced the interaction of APP with BACE-1. These effects were associated with an enrichment of ganglioside GM1-cholesterol patches in the astrocyte membrane and with increased ROS production. GLIA 2015;63:2010-2022. PMID- 26096016 TI - Adherence to the lymphadenectomy recommendations of the 2009 clinical guidelines in the 2010 National Prostate Cancer Registry. AB - OBJECTIVE: To assess the adherence to the recommendations of the 2009 clinical guidelines in the implementation of lymphadenectomy during radical prostatectomy and analysis of the variables that influence this decision in the 2010 National Prostate Cancer Registry. MATERIAL AND METHOD: Analysis of 1,272 patients who underwent prostatectomy in 25 national hospitals. Patient classification according to the pathological node-positive (pN+) risk criteria included in the clinical guidelines of the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN). Calculation of the raw agreement and index of agreement kappa. Logistic regression to assess the predictors in the decision to perform lymphadenectomy. RESULTS: Lymphadenectomy was performed on 225 (17.7%) patients, with a variability among centers of 0-62.2% (p<.001). There was lymphocytic invasion (pN+) in 17 (7.5%) patients. The raw agreement with the EAU 09 clinical guidelines was .672 (.48-.96 in the various centers), and the kappa index was .289. The raw agreement with the NCCN-09 clinical guidelines was.814 (.51-1 in the various centers), and the kappa index was .228. In the multivariate analysis, the independent predictors for performing lymphadenectomy were the Gleason score, the clinical stage, the prostate-specific antigen, the hospital center and the surgical approach route to prostatectomy (all P<.001). CONCLUSIONS: In our study, adherence to the recommendations of the clinical guidelines on the implementation of lymphadenectomy was moderate. When deciding on lymphadenectomy, the determinants (in addition to the classic clinical variables) were the approach route and the hospital where the prostatectomy was performed. PMID- 26096017 TI - Priming the immune system of Penaeid shrimp by bacterial HSP70 (DnaK). AB - This study was conducted to test the effect of DnaK on priming immune responses in Penaeid shrimp. Juvenile-specific pathogen-free (SPF) P. vannamei shrimp were injected with 0.05 MUg recombinant DnaK. One hour post-DnaK priming, a non-lethal dose of Vibrio campbellii (10(5) CFU shrimp(-1)) was injected. Other treatments include only DnaK or V. campbellii injection or control with blank inocula. The haemolymph of three shrimp from each treatment was collected at 1.5, 6, 9 and 12 h post-DnaK priming (hpp). It was verified that injection with DnaK and V. campbellii challenge affected the transcription of 3 immune genes, transglutaminase-1 (TGase-1), prophenoloxidase-2 (proPO-2) and endogenous HSP70 (lvHSP70). In P. monodon, shrimp were first injected with DnaK at a dose of 10 MUg shrimp(-1) and one hour later with 10(6) CFU of V. harveyi (BB120) shrimp( 1). Shrimp injected with DnaK showed a significant increase in proPO expression compared to the control (P < 0.05). Yet a double injection (DnaK and Vibrio) seemed to cause an antagonistic response at the level of expression, which was not equalled at the level of PO activity. Those results suggest that DnaK is able to modulate immune responses in P. vannamei and P. monodon. PMID- 26096018 TI - Substrate channeling between the human dihydrofolate reductase and thymidylate synthase. AB - In vivo, as an advanced catalytic strategy, transient non-covalently bound multi enzyme complexes can be formed to facilitate the relay of substrates, i. e. substrate channeling, between sequential enzymatic reactions and to enhance the throughput of multi-step enzymatic pathways. The human thymidylate synthase and dihydrofolate reductase catalyze two consecutive reactions in the folate metabolism pathway, and experiments have shown that they are very likely to bind in the same multi-enzyme complex in vivo. While reports on the protozoa thymidylate synthase-dihydrofolate reductase bifunctional enzyme give substantial evidences of substrate channeling along a surface "electrostatic highway," attention has not been paid to whether the human thymidylate synthase and dihydrofolate reductase, if they are in contact with each other in the multi enzyme complex, are capable of substrate channeling employing surface electrostatics. This work utilizes protein-protein docking, electrostatics calculations, and Brownian dynamics to explore the existence and mechanism of the substrate channeling between the human thymidylate synthase and dihydrofolate reductase. The results show that the bound human thymidylate synthase and dihydrofolate reductase are capable of substrate channeling and the formation of the surface "electrostatic highway." The substrate channeling efficiency between the two can be reasonably high and comparable to that of the protozoa. PMID- 26096021 TI - Enjoyment of high-intensity interval training in an overweight/obese cohort: a short report. AB - Exercise enjoyment has been shown to be important for adherence. Minimal data exist on enjoyment of intense exercise, especially in clinical populations. The purpose of this study was to evaluate enjoyment levels of overweight and obese subjects undergoing 3 weeks of high-intensity interval training. Forty-two generally healthy overweight and obese men and women (body mass index = 30.8 +/- 4.8 kg * m-2 ) volunteered for this study. Exercise enjoyment was quantified using the Exercise Enjoyment Scale before and after each of nine total interval training sessions, over a three-week period. Heart rate and ratings of perceived exertion (RPE) were measured at the end of each interval and training session. There were no significant differences in enjoyment between training groups (P > 0.05). Exercise enjoyment improved significantly over the three-week training phase (P < 0.05). Enjoyment levels were relatively high to begin training: mean +/- SD: 4.2 +/- 1.0 out of a 7 point scale. Heart rate and RPE were significantly reduced (P < 0.05) from pre- (day 1) to post-training (day 9). High-intensity interval training may be an enjoyable form of exercise for overweight and obese men and women. Enjoyment levels may continue to increase following initial introduction to this type of training. Due to the small time demand and high enjoyment, interval training may be an effective exercise approach in a sedentary population. PMID- 26096019 TI - Ovarian cancer treatment: The end of empiricism? AB - The diagnosis, investigation, and management of ovarian cancer are in a state of flux-balancing ever rapid advances in our understanding of its biology with 3 decades of clinical trials. Clinical trials that started with empirically driven selections have evolved in an evidence-informed manner to gradually improve outcome. Has this improved understanding of the biology and associated calls to action led to appropriate changes in therapy? In this review, the authors discuss incorporating emerging data on biology, combinations, dose, and scheduling of new and existing agents with patient preferences in the management of women with ovarian cancer. PMID- 26096022 TI - ER stress-induced autophagy in melanoma. AB - The activation of RAF-MEK-extracellular signal-regulated kinase (ERK) mitogen activated protein kinase cascade by v-raf murine sarcoma viral oncogene homolog B1 (BRAF)(V600E) mutation is a key alteration in melanoma. Although BRAF inhibitor (BRAFi) has achieved remarkable clinical success, the positive response to BRAFi is not sustainable, and the initial clinical benefit is eventually barred by the development of resistance to BRAFi. There is growing evidence to suggest that endoplasmic reticulum (ER) stress-induced autophagy could be a potential pro-survival mechanism that contributes to genesis of melanoma and to the resistance to BRAFi. ER stress-induced autophagy is an evolutionarily conserved membrane process. By degrading and recycling proteins and organelles via the formation of autophagous vesicles and their fusion with lysosomes, the autophagy plays a key role in homeostasis as well as pathological processes. In this review, we examine the autophagy phenomenon in melanocytic nevus, primary and metastatic melanoma, and its significance in BRAFi-resistant melanoma. PMID- 26096023 TI - Anisotropic relaxation of a CuO/TiO2 surface under an electric field and its impact on visible light absorption: ab initio calculations. AB - Ab initio calculations on the anisotropic relaxation of a CuO/TiO2 surface under electric fields and the visible light absorption of these relaxed surfaces are reported. We compare the relaxation of the CuO/TiO2 surface under the electric fields in the direction of [001] or [010]. Fewer Cu-O bonds with highly coordinated Cu-ions are found in the CuO/TiO2 relaxed surface under the electric field in the [010] direction. The Cu-O bonds in the interface of the CuO/TiO2 surface led to an improved visible light absorption in the polarization direction of [001]. The CuO/TiO2 relaxed surface under the electric field in the [010] direction exhibits a more effective absorption of visible light. However, the electric field in the [001] direction induces more relaxation on the CuO/TiO2 surface, breaking the Cu-O bonds. This leads to the partial reduction of CuO to Cu2O on the CuO/TiO2 relaxed surface under the electric field in the [001] direction and inefficient absorption of visible light is observed for this surface. PMID- 26096024 TI - Numb Protects Human Renal Tubular Epithelial Cells From Bovine Serum Albumin Induced Apoptosis Through Antagonizing CHOP/PERK Pathway. AB - In recent studies, we found that Numb is involved in oxidative stress-induced apoptosis of renal proximal tubular cells; however, its function on ER stress induced apoptosis in proteinuric kidney disease remains unknown. The objective of the present study is to explore the role of Numb in urinary albumin-induced apoptosis of human renal tubular epithelial cells (HKCs). In this study, we demonstrate that incubation of HKCs with bovine serum albumin (BSA) resulted in caspase three-dependent cell death. Numb expression was down-regulated by BSA in a time- and dose-dependent manner. Knockdown of Numb by siRNA sensitized HKCs to BSA-induced apoptosis, whereas overexpression of Numb protected HKCs from BSA induced apoptosis. Moreover, BSA activated CHOP/PERK signaling pathway in a time- and dose-dependent manner as indicated by increased expression of CHOP, PERK, and P-PERK. Furthermore, knockdown of CHOP or PERK significantly attenuated the promoting effect of Numb on BSA-induced apoptosis, while overexpression of CHOP impaired the protective effect of Numb on BSA-induced apoptosis. Taken together, our findings demonstrate that Numb plays a protective role on BSA-induced apoptosis through inhibiting CHOP/PERK signaling pathway in human renal tubular epithelial cells. Therefore, the results from this study provides evidence that Numb is a new target of ER-associated apoptotic signaling networks and Numb may serve as a promising therapeutic target for proteinuric diseases. PMID- 26096025 TI - Meet our new editor. PMID- 26096026 TI - Traceability of human sperm samples by direct tagging with polysilicon microbarcodes. AB - The increasing number of patients undergoing assisted reproductive technology (ART) treatments and of cycles performed in fertility centres has led to some traceability errors. Although the incidence of mismatching errors is extremely low, any error is unacceptable, therefore different strategies have been developed to further minimize these errors, such as manual double-witnessing or electronic witnessing systems. More recently, our group developed a direct tagging method consisting of attaching microbarcodes directly to the zona pellucida of human oocytes/embryos. Here, this method is taken a step further by using these microbarcodes to tag human semen samples, demonstrating that the barcodes are not toxic and do not interfere in the selection of motile spermatozoa nor in the cryopreservation of the sperm samples. In addition, when this tagging system was applied to an animal model (rabbit), pregnancy rate and kitten viability were not affected. PMID- 26096027 TI - Patients' views on the embryo storage time limits. AB - The establishment of the length of embryo storage has been based on socio political criteria. There are different regulations, guidelines and health care policies worldwide. This mixed-methods study aimed to assess the opinion of patients about the embryo storage time limit, and the perception of the criteria underlying the establishment of the storage period offered to them. Between August 2011 and December 2012, 534 IVF patients from Portugal participated in a quantitative questionnaire and 34 couples were interviewed. Overall, 38% of participants preferred the duration of 4-5 years, 38% extended it beyond 5 years and 23% indicated 3 years. Having experienced at least one previous cycle was directly associated with agreeing with a duration of storage longer than 5 years, for both women and men. Having children was inversely associated with longer duration of storage, among women. One-third of the 34 interviewed couples stated that their knowledge concerning embryo storage was insufficient. Nevertheless, all the interviewees reported at least one possible reason for the legal establishment of the storage period offered to them, highlighting financial costs and decreased embryo quality. There are misconceptions and gaps in awareness of cryopreservation, which may shape patients' opinions. Accurate information regarding policy on storage of embryos is needed. PMID- 26096028 TI - Deliveries from trophectoderm biopsied, fresh and vitrified blastocysts derived from polar body biopsied, vitrified oocytes. AB - This longitudinal study reports preliminary findings of six patients who underwent first polar body biopsy followed by oocyte vitrification. All oocytes were warmed, inseminated by intracytoplasmic sperm injection and cultured to blastocyst. All suitable blastocysts underwent trophectoderm biopsy for aneuploidy screening, and supernumerary blastocysts were vitrified. Euploid blastocysts were transferred either fresh or in a subsequent programmed cycle. Of the 91 metaphase II oocytes, 30 had euploid first polar bodies. Development to blastocyst was more likely in oocytes with a euploid first polar body (66.7% versus 24.6%; P < 0.001). Nineteen euploid blastocysts were produced: 10 from oocytes with a euploid first polar body and nine from oocytes with an aneuploid first polar body. Five out of six patients (83%) had a live birth or ongoing pregnancy at the time of analysis. Eleven euploid blastocysts have been transferred and seven implanted (64%). Although the chromosomal status of the first polar body was poorly predictive of embryonic ploidy, an association was found between chromosomal status of the first polar body and development to blastocyst. Further study is required to characterize these relationships, but proof of concept is provided that twice biopsied, twice cryopreserved oocytes and embryos can lead to viable pregnancies. PMID- 26096029 TI - Is it justified to transfer two embryos in oocyte donation? A pilot randomized clinical trial. AB - Multiple pregnancies involve high obstetric and perinatal risks. The aim of this study is to evaluate, in a pilot randomized control study, if the cumulative pregnancy and live birth rates of elective single embryo transfer (eSET) are comparable to the ones obtained with elective double embryo transfer (eDET). A total of 65 patients with at least two good quality embryos was randomized, 34 (52.3%) assigned to the eSET group and 31 (47.7%) to the eDET group. The cumulative pregnancy rates (eSET: 73.5% and eDET: 77.4%. RR: 0.95 95% CI: 0.72 1.25) and live birth rates (eSET: 58.8% and eDET: 61.3%. RR: 0.96 95% CI: 0.64 1.42) were similar in the two groups. The twin pregnancy rate in the fresh transfers of eDET group was 47.7% and 0% in the eSET group. The medical team decided to interrupt the study for reasons related to risks associated with elevated twin pregnancy rate, leaving low numbers of patients within the study as a result. When considering cumulative success rates, eSET and eDET are similar in terms of efficacy. However, eDET involves an increased and unacceptable twin pregnancy rate. The only prevention strategy is single embryo transfer. PMID- 26096030 TI - Response: IVF and intrauterine insemination cannot be compared. PMID- 26096032 TI - Letter: IVF and intrauterine insemination cannot be compared. PMID- 26096031 TI - FISH and array CGH characterization of de novo derivative Y chromosome (Yq duplication and partial Yp deletion) in an azoospermic male. AB - This study presents a 28-year-old infertile male who was referred to the cytogenetic laboratory for chromosomal analysis after 4 years of regular unprotected intercourse in whom non-obstructive azoospermia was revealed. Standard cytogenetic G-banding was performed on metaphase spreads and a de-novo karyotype 46,X,der(Y)(q11.22;p11.3) was identified. This analysis was followed by flourescence in-situ hybridization(FISH) and array comparative genomic hybridization (aCGH). Finally, the patient's karyotype was identified as 46,X,der(Y)(qter->q11.221::p11.31->qter).ish der(Y) (qter+,pter ,SHOX+,SRY+,Ycen+,DYZ3+;DYZ1+,qter+).arrYq11.221q12(14,448,863-59,288,511) x2, Yp11.32p11.31(104,062-266,388) x0. It is proposed that de-novo derivative monocentric Y chromosome with duplicated region Y qter->q11.221::p11.31->qter with partial deletion of Yp PAR1 region most probably can perturb the conjugation of sex chromosomes during first meiotic division of spermatogenic arrested differentiation (development). PMID- 26096033 TI - Should sperm DNA fragmentation testing be included in the male infertility work up? AB - A response to the editorial 'Are we ready to incorporate sperm DNA fragmentation testing into our male infertility work-up? A plea for more robust studies' by Erma Drobnis and Martin Johnson. PMID- 26096034 TI - Association of skewed X chromosome inactivation and idiopathic recurrent spontaneous abortion: a systematic review and meta-analysis. AB - Evidence of an association between skewed X chromosome inactivation (SXCI) and idiopathic recurrent spontaneous abortion (RSA) is conflicting. No consensus has been reached on the degree of SXCI and the number of pregnancy losses in patients who have experienced RSA. In this systematic review and meta-analysis, different degrees of skewing and definitions of RSA are used to establish an association between SXCI and idiopathic RSA. Twelve studies comprising 1594 women who had experienced RSA and 1924 controls were included. No significant association was found between SXCI and RSA when 80 or 90% was used as cut-off value of skewing; more stringent 95% or greater SXCI was significantly higher in women who had experienced RSA than in controls (odds ratio [OR] = 4.27, 95% confidence interval [CI] 1.46 to 12.46). A significantly higher incidence of SXCI when defined as greater than 90% (or >=90%) was found in women who had experienced RSA with three or more pregnancy losses (OR = 2.31, 95% CI 1.41, 3.78); significance diminished when RSA was defined as two or more losses. Extreme skewing of SXCI is associated with idiopathic RSA with three or more losses. More studies are needed to validate the potential genetic mechanism. PMID- 26096035 TI - Wilfordonols A-D: four new norsesquiterpenes from the leaves of Tripterygium wilfordii. AB - Four new norsesquiterpenes wilfordonols A-D (1-4), along with three known compounds, sarmentol B (5), boscialin (6), and (+)-loliolide (7), were isolated from the leaves of Tripterygium wilfordii Hook.f.. The structures of the new compounds were elucidated on the basis of their spectroscopic analysis, and the absolute configuration of the compounds was confirmed by CD and modified Mosher's method. At a concentration of 10 MUM, compounds 4, 6, and 7 inhibited signal transducer and activator of transcription 1 translocation by 34.27 +/- 1.02%, 48.93 +/- 1.76%, and 70.31 +/- 2.20%, respectively. PMID- 26096036 TI - Thresholds and accuracy in screening tools for early detection of psychopathology. AB - BACKGROUND: The accuracy of any screening instrument designed to detect psychopathology among children is ideally assessed through rigorous comparison to 'gold standard' tests and interviews. Such comparisons typically yield estimates of what we refer to as 'standard indices of diagnostic accuracy', including sensitivity, specificity, positive predictive value (PPV), and negative predictive value. However, whereas these statistics were originally designed to detect binary signals (e.g., diagnosis present or absent), screening questionnaires commonly used in psychology, psychiatry, and pediatrics typically result in ordinal scores. Thus, a threshold or 'cut score' must be applied to these ordinal scores before accuracy can be evaluated using such standard indices. To better understand the tradeoffs inherent in choosing a particular threshold, we discuss the concept of 'threshold probability'. In contrast to PPV, which reflects the probability that a child whose score falls at or above the screening threshold has the condition of interest, threshold probability refers specifically to the likelihood that a child whose score is equal to a particular screening threshold has the condition of interest. METHOD: The diagnostic accuracy and threshold probability of two well-validated behavioral assessment instruments, the Child Behavior Checklist Total Problem Scale and the Strengths and Difficulties Questionnaire total scale were examined in relation to a structured psychiatric interview in three de-identified datasets. RESULTS: Although both screening measures were effective in identifying groups of children at elevated risk for psychopathology in all samples (odds ratios ranged from 5.2 to 9.7), children who scored at or near the clinical thresholds that optimized sensitivity and specificity were unlikely to meet criteria for psychopathology on gold standard interviews. CONCLUSIONS: Our results are consistent with the view that screening instruments should be interpreted probabilistically, with attention to where along the continuum of positive scores an individual falls. PMID- 26096037 TI - Nicotine delivery and pharmacologic response from Verve, an oral nicotine delivery product. AB - Verve, an oral nicotine delivery product (ONDP), was introduced by Nu Mark (Altria Client Group, Richmond VA) for smokers to use in places where smoking is prohibited. This study assessed the effect of this ONDP on plasma nicotine levels, heart rate, product satisfaction, and ability to suppress smoking urge and cigarette cravings. Thirteen daily cigarette smokers [8 men and 5 women; average age 33.4years] attended two laboratory sessions, one occurred after overnight tobacco abstinence. Plasma samples were collected before and after ONDP use and measured for nicotine. In non-abstinent smokers, mean plasma nicotine levels increased from 18.3 to 21.0ng/mL. In abstinent smokers, average nicotine levels increased from 3.1 to 4.5ng/mL. After overnight tobacco abstinence, ONDP use significantly (p<0.01) increased heart rate from 69beats per minute (bpm) to 75bpm; while urge to smoke decreased significantly (p<0.01) from a score of 8.6 to 4.9. Participants indicated moderate product satisfaction that was not changed by tobacco abstinence. Analysis of unused ONDP revealed total nicotine levels of 1.68+/-0.09mg/disc. Spent ONDP discs were also analyzed to determine % nicotine liberated during chewing; results were 80% in the non-abstinent and 82% in the abstinent conditions (ns). Our study results indicate that ONDP use can increase plasma nicotine levels and heart rate and reduce cigarette cravings in abstinent smokers. PMID- 26096038 TI - Epigenetic modulation of Wnt signaling contributes to neuropathic pain in rats. AB - Previous studies have demonstrated that the Wnt/beta-catenin signaling pathway is critical to the induction and maintenance of chronic neuropathic pain caused by peripheral inflammation and nerve damage. Emerging evidence from recent studies suggests that epigenetic mechanisms may also be critical to the pathogenesis of chronic pain. The present study aimed to elucidate the epigenetic mechanisms underlying altered Wnt signaling and their involvement in CCI-induced neuropathic pain in rat sciatic nerves. The results of the present study demonstrated a significant increase in the expression levels of Wnt3a in the dorsal horn of the rats with CCI. In addition, a significant increase in histone H3 acetylation, and a significant decrease in cytosine methylation in the promoter region of Wnt3a was observed in the dorsal horn of the rats with CCI. Intrathecal application of XAV939, which acts as an inhibitor of Wnt signaling, significantly decreased the expression levels of active beta-catenin, and attenuated the rat behavioral responses to thermal and mechanical pain stimuli. These results suggest that the epigenetic upregulation of Wnt3a in the dorsal horn contributes to the maintenance of pain-induced behavior in rats with CCI. PMID- 26096039 TI - Dynamical behavior of Borospherene: A Nanobubble. AB - The global minimum structure of borospherene (B40) is a cage, comprising two hexagonal and four heptagonal rings. Born-Oppenheimer Molecular Dynamics simulations show that continuous conversions in between six and seven membered rings take place. The activation energy barrier for such a transformation is found to be 14.3 kcal . mol(-1). The completely delocalized sigma- and pi frameworks, as well as the conservation of the bonding pattern during rearrangement, facilitate the dynamical behavior of B40. B40 is predicted to act as a support-free spherical two-dimensional liquid at moderate temperature. In other words, B40 could be called as a nanobubble. PMID- 26096040 TI - Hypoxia worsens the impact of intracellular triglyceride accumulation promoted by electronegative low-density lipoprotein in cardiomyocytes by impairing perilipin 5 upregulation. AB - Plasma lipoproteins are a source of lipids for the heart, and the proportion of electronegative low density lipoprotein [LDL(-)] is elevated in cardiometabolic diseases. Perilipin 5 (Plin5) is a crucial protein for lipid droplet management in the heart. Our aim was to assess the effect of LDL(-) on intracellular lipid content and Plin5 levels in cardiomyocytes and to determine whether these effects were influenced by hypoxia. HL-1 cardiomyocytes were exposed to native LDL [LDL(+)], LDL(-), and LDL(+) enriched in non-esterified fatty acids (NEFA) by phospholipase A2 (PLA2)-mediated lipolysis [PLA2-LDL(+)] or by NEFA loading [NEFA LDL(+)] under normoxia or hypoxia. LDL(-), PLA2-LDL(+) and NEFA-LDL(+) raised the intracellular NEFA and triglyceride (TG) content of normoxic cardiomyocytes. Plin5 was moderately upregulated by LDL(+) but more highly upregulated by LDL(-), PLA2-LDL(+) and NEFA-LDL(+) in normoxic cardiomyocytes. Hypoxia enhanced the effect of LDL(-), PLA2-LDL(+) and NEFA-LDL(+) on intracellular TG and NEFA concentrations but, in contrast, counteracted the upregulatory effect of these LDLs on Plin5. Fluorescence microscopy experiments showed that hypoxic cardiomyocytes exposed to LDL(-), PLA2-LDL(+) and NEFA-LDL(+) have an increased production of reactive oxygen species (ROS). By treating hypoxic cardiomyocytes with WY-14643 (PPARalpha agonist), Plin5 remained high. In this situation, LDL(-) failed to enhance intracellular NEFA concentration and ROS production. In conclusion, these results show that Plin5 deficiency in hypoxic cardiomyocytes exposed to LDL(-) dramatically increases the levels of unpacked NEFA and ROS. PMID- 26096042 TI - Erratum to: Basal cell cystadenoma of the lacrimal gland: diagnostic pitfalls of a basaloid pattern in lacrimal tumours. PMID- 26096041 TI - Long-term control of diabetes in immunosuppressed nonhuman primates (NHP) by the transplantation of adult porcine islets. AB - Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig-to-nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen-free (DPF) miniature pigs and infused intraportally into streptozotocin induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti-thymocyte globulin (ATG) induction and maintenance with anti-CD154 monoclonal antibody and low-dose sirolimus. Ex vivo expanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90-110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow-up period showed excellent glucose disposal capacity and porcine C-peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy. PMID- 26096043 TI - The impact of septoplasty on health-related quality of life in paediatric patients. AB - OBJECTIVES: To assess the impact that septoplasty had on health-related quality of life (HRQoL) in paediatric patients and to determine whether there were patient characteristics that predicted better outcomes. DESIGN: Retrospective cohort study. SETTING: Academic paediatric otolaryngology practice. PARTICIPANTS: All paediatric patients who underwent septoplasty during the study period. MAIN OUTCOME MEASURES: The current HRQoL was assessed using the Paediatric Quality of Life Inventory (PedsQL). The Glasgow Children's Benefit Inventory (GCBI) was used to evaluate the perceived change in HRQoL following septoplasty. RESULTS: A total of 29 patients (16 boys, mean age 13 years) and their caregivers responded (response rate of 72.5%). There was a statistically significant improvement in HRQoL following septoplasty, as demonstrated by the positive mean GCBI subscores and the total GCBI score (35.1, sd = 28.4). The total mean PedsQL score for child self-report was 95.2 (sd = 6.9) and for parent-proxy report was 91.8 (sd = 8.6), which indicated good current HRQoL. The enhancement in HRQoL post-septoplasty was moderately correlated with self-reported degree of nasal obstruction pre septoplasty (r = 0.621 for total GCBI). Also, there were differences in GCBI scores between the groups of children who wanted to have the surgery versus those who did not want to have the surgery. CONCLUSIONS: There was a significant positive change in HRQoL following paediatric septoplasty in our study population. Children who reported more severe nasal obstruction and those who wanted to have the surgery were more likely to experience enhancement of HRQoL following their surgery. PMID- 26096044 TI - Beta-globin gene evolution in the ruminants: evidence for an ancient origin of sheep haplotype B. AB - Domestic sheep (Ovis aries) can be divided into two groups with significantly different responses to hypoxic environments, determined by two allelic beta globin haplotypes. Haplotype A is very similar to the goat beta-globin locus, whereas haplotype B has a deletion spanning four globin genes, including beta-C globin, which encodes a globin with high oxygen affinity. We surveyed the beta globin locus using resequencing data from 70 domestic sheep from 42 worldwide breeds and three Ovis canadensis and two Ovis dalli individuals. Haplotype B has an allele frequency of 71.4% in O. aries and was homozygous (BB) in all five wild sheep. This shared ancestry indicates haplotype B is at least 2-3 million years old. Approximately 40 kb of the sequence flanking the ~37-kb haplotype B deletion had unexpectedly low identity between haplotypes A and B. Phylogenetic analysis showed that the divergent region of sheep haplotype B is remarkably distinct from the beta-globin loci in goat and cattle but still groups with the Ruminantia. We hypothesize that this divergent ~40-kb region in haplotype B may be from an unknown ancestral ruminant and was maintained in the lineage to O. aries, but not other Bovidae, evolving independently of haplotype A. Alternatively, the ~40-kb sequence in haplotype B was more recently acquired by an ancestor of sheep from an unknown non-Bovidae ruminant, replacing part of haplotype A. Haplotype B has a lower nucleotide diversity than does haplotype A, suggesting a recent bottleneck, whereas the higher frequency of haplotype B suggests a subsequent spread through the global population of O. aries. PMID- 26096045 TI - With Great Brain Hub Connectivity Comes Great Vulnerability. PMID- 26096046 TI - Compound MQA, a Caffeoylquinic Acid Derivative, Protects Against NMDA-Induced Neurotoxicity and Potential Mechanisms In Vitro. AB - AIMS: Compound MQA (1,5-O-dicaffeoyl-3-O-[4-malic acid methyl ester]-quinic acid) is a natural derivative of caffeoylquinic acid isolated from Arctium lappa L. roots. However, we know little about the effects of MQA on the central nervous system. This study aims to investigate the neuroprotective effects and underlying mechanisms of MQA against the neurotoxicity of N-methyl-d-aspartate (NMDA). METHODS AND RESULTS: Pretreatment with MQA attenuated the loss of cell viability after SH-SY5Y cells treated with 1 mM NMDA for 30 min by MTT assay. Hoechst 33342 and Annexin V-PI double staining showed that MQA inhibited NMDA-induced apoptosis. In addition to preventing Ca(2+) influx, the potential mechanisms are associated with increases in the Bcl-2/Bax ratio, attenuation of cytochrome c release, caspase-3, caspase-9 activities, and expressions. Also, MQA inhibited NMDA-induced phosphorylation of ERK1/2, p38, and JNK1/2. Furthermore, deactivation of CREB, AKT, and GSK-3beta, upregulation of GluN2B-containing NMDA receptors (NMDARs), and downregulation of GluN2A-containing NMDARs were significantly reversed by MQA treatment. Computational docking simulation indicates that MQA possesses a well affinity for NMDARs. CONCLUSION: The protective effects of MQA against NMDA-induced cell injury may be mediated by blocking NMDARs. The potential mechanisms are related with mitochondrial apoptosis, ERK-CREB, AKT/GSK-3beta, p38, and JNK1/2 pathway. PMID- 26096047 TI - Modulation of mTOR Activity by MU-Opioid Receptor is Dependent upon the Association of Receptor and FK506-Binding Protein 12. AB - AIMS: Mechanistic/mammalian target of rapamycin (mTOR) activation by MU-opioid receptor (OPRM1) participates in antinociceptive tolerance, hyperalgesia, and physical dependence. Our previous study also showed that mTOR activation by OPRM1 could attenuate beta amyloid oligomers-induced neurotoxicity. OPRM1 is demonstrated to interact with FK506-binding protein 12 (FKBP12). It is our great interest to investigate whether OPRM1-mediated mTOR signaling is related to receptor-FKBP12 association. METHODS: The activities of mTOR and its downstream effector p70 S6K were measured by immunoblotting their phosphorylation status. The interaction of receptor with mTOR was detected by co-immunoprecipitation and immunofluorescence. RESULTS: OPRM1 activation by morphine-induced time-dependent mTOR activation. PI3K-specific inhibitor LY294002 only blocked the late phase of mTOR activation. However, morphine-induced mTOR activation was totally blocked at all time points in cells expressing FKBP12 association-deficient mutant receptor. FKBP12 knockdown also blocked morphine-induced mTOR activation. Further analysis demonstrated that morphine treatment enhanced the association of receptor with phosphorylated mTOR, whereas decreased association was observed after FKBP12 knockdown, mTOR inhibition or in cells expressing FKBP12 association-deficient mutant. CONCLUSIONS: OPRM1-FKBP12 association played a key role in OPRM1-mediated mTOR activation, which could underlie the mechanisms of multiple physiological and pathological processes. Thus, our findings provide new avenue to modulating these processes. PMID- 26096048 TI - Mobile Stroke: An Experience of Intravenous Thrombolysis Guided by Teleconsultation Based on Google Glass. PMID- 26096049 TI - Lymphomatoid Granulomatosis with Central Nervous System Involvement Successfully Treated with Cyclophosphamide, High-dose Cytarabine, Dexamethasone, Etoposide, and Rituximab (CHASER therapy) Followed by Brain Irradiation: A Case Study. PMID- 26096051 TI - Spatial variability of helminth parasites and evidence for stock discrimination in the round sardinella, Sardinella aurita (Valenciennes, 1847), off the coast of Tunisia. AB - Three digeneans - Parahemiurus merus (Linton, 1910), Aphanurus stossichii (Monticelli, 1891) and Lecithochirium sp. - and one tetraphyllidean cestode larva were used as biological tags to discriminate the stock of Sardinella aurita (Valenciennes, 1847). In total, 579 fish were examined in five zones off the Tunisian coast, including Bizerte and Kelibia in the north, Mahdia in the east, Gabes and Zarzis in the south. Discriminant analyses used for the separation of S. aurita allowed for the identification of two discrete stocks. Sardinella aurita from Bizerte, Kelibia and Zarzis clumped together as a single stock. Parahemiurus merus and A. stossichii were the most important species in determining the location of sampled fish from these regions. Specimens from Mahdia and Gabes were grouped as one stock characterized by the presence of Lecithochirium sp. and larvae of the Tetraphyllidea. These results were corroborated by comparing the parameters of prevalence and mean abundance of parasites among zones. The separation of S. aurita between localities after pooling specimens from Bizerte, Kelibia and Zarzis and separately pooling those from Mahdia and Gabes also allowed the identification of two discrete stocks, one in offshore waters from Bizerte, Kelibia and Zarzis characterized by the digeneans P. merus and A. stossichii and one in inshore waters from Mahdia and Gabes characterized by Lechithochirium sp. and tetraphyllidean larvae. PMID- 26096050 TI - Adolescent-onset GABAA alpha1 silencing regulates reward-related decision making. AB - The GABAA receptor mediates fast, inhibitory signaling, and cortical expression of the alpha1 subunit increases during postnatal development. Certain pathological stimuli such as stressors or prenatal cocaine exposure can interfere with this process, but causal relationships between GABAA alpha1 deficiency and complex behavioral outcomes remain unconfirmed. We chronically reduced GABAA alpha1 expression selectively in the medial prefrontal cortex (prelimbic subregion) of mice using viral-mediated gene silencing of Gabra1. Adolescent onset Gabra1 knockdown delayed the acquisition of a cocaine-reinforced instrumental response but spared cocaine seeking in extinction and in a cue induced reinstatement procedure. To determine whether response acquisition deficits could be associated with impairments in action-outcome associative learning and memory, we next assessed behavioral sensitivity to instrumental contingency degradation. In this case, the predictive relationship between familiar actions and their outcomes is violated. Adolescent-onset knockdown, although not adult-onset knockdown, delayed the expression of goal-directed response strategies in this task, resulting instead in inflexible habit-like modes of response. Thus, the maturation of medial prefrontal cortex GABAA alpha1 systems during adolescence appears necessary for goal-directed reward-related decision making in adulthood. These findings are discussed in the light of evidence that prolonged Gabra1 deficiency may impair synaptic plasticity. PMID- 26096052 TI - Survival and patient satisfaction of short implants during the first 2 years of function: a retrospective cohort study with 694 implants in 416 patients. AB - OBJECTIVES: The present study aimed to evaluate the influence of implant length on implant survival and patient satisfaction during the first 24 months in function. MATERIAL AND METHODS: A retrospective cohort of 312 "short" Straumann((r)) SLActive((r)) implants (length <= 8 mm) in 224 patients, which were inserted between 2008 and 2010 in private practice, were evaluated. The mean observation period was 26.7 +/- 9.7 months. Three hundred and eighty-two Straumann SLActive((r)) implants in 192 patients with a length >= 12 mm served as control group. The mean observation period in the control group was 28.3 +/- 10.1 months. Implant survival rate, crown-to-implant ratio, resonance frequency analysis, and patient satisfaction were evaluated. RESULTS: Implant survival rate was 99% in the test vs. 98.7% in the control group. The crown-to-implant ratio was significantly higher in the control group (P < 0.0001). Resonance frequency analysis showed slightly higher values for the short implants. There was a tendency to higher satisfaction (Oral Health Impact Profile [OHIP]) in the test group without statistical significant differences but a high overall satisfaction in both groups. CONCLUSION: Within the limits of the present investigation, implant length had no significant influence on implant survival during the first 24 months of function of the specific implant system with hydrophilic surface (SLActive((r)) ). Further follow-up studies are required to evaluate long-term results of the reduced implant length. PMID- 26096053 TI - Coaches' implicit associations between size and giftedness: implications for the relative age effect. AB - The relative age effect (RAE) is a well-established phenomenon in education and sports. Coaches have been assumed to be important social agents of RAE via biased selection decisions in favour of children with maturation advantages. In the present research, we used the Implicit Association Test to investigate automatic associations between body size and a player's domain-specific giftedness amongst youth baseball (N = 18) and youth soccer coaches (N = 34). We found medium to strong automatic associations between body size and player giftedness (baseball: MD = 0.62; soccer: MD = 0.51). Specifically, taller players were associated with positive performance-related attributes, whereas smaller players were associated with negative attributes. The results are in line with theories of grounded cognition by showing that the abstract concept of "sport giftedness" is partly grounded in the perception of physical height amongst youth sports coaches. We argue that this grounded cognition has the potential to influence coaches' selection decisions and in turn account for RAE as coaches are biased towards physically more matured players, even when no apparent performance advantage is evident. PMID- 26096054 TI - Cutaneous epithelioid malignant peripheral nerve sheath tumour: a clinicopathological analysis of 11 cases. AB - AIMS: Epithelioid malignant peripheral nerve sheath tumour (E-MPNST) is a distinctive variant of malignant peripheral nerve sheath tumour characterized by the predominance of epithelioid cells, diffuse S100 positivity and infrequent association with neurofibromatosis type 1. The aim of this study was to further delineate clinicopathological features of cutaneous E-MPNST, correlate them with disease outcome and discuss differential diagnosis. METHODS AND RESULTS: We analysed 11 cutaneous E-MPNSTs (six males, five females, median age 49 years, median size 1.6 cm). Tumours showed a predilection for lower extremities (45%) and trunk (45%), followed by upper extremity (9%). Follow-up was available for nine of 11 patients (range 24-100 months, median 52 months). Four patients had an uneventful clinical course (44%), two developed local recurrence(s) (22%) and three died due to disseminated disease (33%). No histological parameters were found to predict local recurrence(s), development of distant metastases or disease outcome, including size, percentage of epithelioid component, number of mitoses per 10 high-power fields, degree of nuclear atypia or site of occurrence (dermis, dermis/subcutis, subcutis) (P > 0.05). Immunohistochemically, all tumours were diffusely S100-positive, with a subset displaying loss of integrase interactor 1 (INI1) expression (50%). CONCLUSIONS: Cutaneous E-MPNST has the potential to pursue an aggressive clinical course, associated with wide dissemination and unfavourable disease outcome. PMID- 26096055 TI - Total Synthesis and Structural Revision of Antibiotic CJ-16,264. AB - The total synthesis and structural revision of antibiotic CJ-16,264 is described. Starting with citronellal, the quest for the target molecule featured a novel bis transannular Diels-Alder reaction that casted stereoselectively the decalin system and included the synthesis of six isomers before demystification of its true structure. PMID- 26096056 TI - History of the Tinnitus Research Consortium. AB - This article describes the creation and accomplishments of the Tinnitus Research Consortium (TRC), founded and supported through philanthropy and intended to enrich the field of tinnitus research. Bringing together a group of distinguished auditory researchers, most of whom were not involved in tinnitus research, over the fifteen years of its life it developed novel research approaches and recruited a number of new investigators into the field. The purpose of this special issue is to highlight some of the significant accomplishments of the investigators supported by the TRC. This article is part of a Special Issue entitled "Tinnitus". PMID- 26096058 TI - Maturation and Dysgenesis of the Human Olfactory Bulb. AB - The olfactory bulb with its unique architecture was studied for neuronal maturation in human fetuses. Neuroblasts stream into the olfactory bulb from the rostral telencephalon and secondarily migrate radially. The transitory olfactory ventricular recess regresses postnatally. Olfactory is the only sensory system without thalamic projections but incorporates intrinsic thalamic equivalents. The bulb is a repository of progenitor cells. Maturation of the bulb and tract was studied in 18 normal human fetuses of 16-41 weeks gestation; mid-gestational twins with hydrocephalus; 7 arrhinencephaly/holoprosencephaly; 2 olfactory dysgeneses. Multiple immunoreactivities were performed. Synaptophysin around mitral neurons, in a few synaptic glomeruli and concentric lamination of the outer granular layer, was seen at 16 weeks. Outer granular neurons exhibited NeuN at 16 weeks, only 2/3 were reactive at term. Concentric alternating sheets of granular neurons and their dendrodendritic synapses are seen during maturation. Calretinin reactivity is seen in neurons and neurites, primary olfactory nerve axons, periglomerular cells and neuroepithelial cells surrounding the ventricular recess; reactivity occurs later in synaptic glomeruli than with synaptophysin; not all glomeruli are strongly reactive even at term. Nestin- and vimentin reactive bipolar progenitor cells were demonstrated at all ages and extend into the olfactory tract. Myelin is demonstrated by Luxol fast blue (LFB) only postnatally. In hydrocephalus, the olfactory recess is dilated. Mitral cell dispersion, disrupted glomeruli, heterotopia and maturational delay are seen in some dysgeneses. Malformations exhibit unique findings. Fusion of hypoplastic bulbs can occur. Abnormal architecture is seen in hemimegalencephaly. More documentation of olfactory dysgenesis is needed in other major brain malformations. PMID- 26096057 TI - Peptidyl-prolyl isomerization targets rice Aux/IAAs for proteasomal degradation during auxin signalling. AB - In plants, auxin signalling is initiated by the auxin-promoted interaction between the auxin receptor TIR1, an E3 ubiquitin ligase, and the Aux/IAA transcriptional repressors, which are subsequently degraded by the proteasome. Gain-of-function mutations in the highly conserved domain II of Aux/IAAs abolish the TIR1-Aux/IAA interaction and thus cause an auxin-resistant phenotype. Here we show that peptidyl-prolyl isomerization of rice OsIAA11 catalysed by LATERAL ROOTLESS2 (LRT2), a cyclophilin-type peptidyl-prolyl cis/trans isomerase, directly regulates the stability of OsIAA11. NMR spectroscopy reveals that LRT2 efficiently catalyses the cis/trans isomerization of OsIAA11. The lrt2 mutation reduces OsTIR1-OsIAA11 interaction and consequently causes the accumulation of a higher level of OsIAA11 protein. Moreover, knockdown of the OsIAA11 expression partially rescues the lrt2 mutant phenotype in lateral root development. Together, these results illustrate cyclophilin-catalysed peptidyl-prolyl isomerization promotes Aux/IAA degradation, as a mechanism regulating auxin signalling. PMID- 26096059 TI - Sydenham's chorea: beyond involuntary movements. PMID- 26096060 TI - Treatment of pediatric lymphoma in Japan: Current status and plans for the future. AB - Results of pediatric lymphoma treatment have improved markedly over the past 30 years. In Hodgkin's lymphoma, the 5 year event-free survival (EFS) was 81.5% in a retrospective study. In the ALB-NHL03 study, the 5 year EFS according to clinical stage in patients with lymphoblastic T-cell lymphoma (T-LBL) was 70.6% for stage III and 88.9% for stage IV. In mature B-cell lymphoma, the B-NHL03 study indicated that the 4 year EFS according to treatment group was 94% for group 1, 98% for group 2, 84% for group 3, and 78% for group 4. Moreover, the 2 year EFS rate was 81% in Japanese advanced stage patients based on the international ALCL99 study. Thus, EFS >80% was achieved in any subtype of pediatric lymphoma. With regard to refractory or recurrent lymphoma, however, treatment methods for improvement of the survival rate in these patients still need to be developed. Also the difference between child, and adolescent and young adult patients still needs to be clarified, and treatment protocols developed. Although lymphoma treatment does not greatly change according to country, it does differ between other countries and Japan for some subtypes of lymphoma. In particular, the results of treatment of stage III T-LBL in Japan are worse than those in the USA and Europe. The priority in future studies will be to collect data on these differences, and the reasons for these differences. PMID- 26096061 TI - A nationwide assessment of outcomes after bile duct reconstruction. AB - BACKGROUND: Bile duct reconstruction (BDR) is used to manage benign and malignant neoplasms, congenital anomalies, bile duct injuries and other non-malignant diseases. BDR outcomes overall, by year, and by indication were compared. METHODS: Retrospective analysis of Nationwide Inpatient Sample discharges (2004 2011) including ICD-9 codes for BDR. All statistical testing was performed using survey weighting. Univariate analysis of admission characteristics by chi square testing. Multivariate modelling for inpatient complications and inpatient death by logistic regression. RESULTS: Identified 67 160 weighted patient admissions: 2.5% congenital anomaly, 37.4% malignant neoplasm, 2.3% benign neoplasm, 9.9% biliary injury, 47.9% other non-malignant disease. Most BDRs were performed in teaching hospitals (69.6%) but only 25% at centres with a BDR volume more than 35/year. 32.3% involved >= 1 complication, and 84.7% were discharges home. There was a 4.2% inpatient death rate. The complication rate increased but the inpatient death rate decreased over time. The rates of acute renal failure increased. Significant multivariate predictors of inpatient death include indication of biliary injury or malignancy, and predictors of any complication include public insurance and non-elective admission. CONCLUSION: This is the first national description of BDRs using a large database. In this diverse sampling, both procedure indication and patient characteristics influence morbidity and mortality. PMID- 26096062 TI - The Radiative Lifetime in Near-IR-Luminescent Ytterbium Cryptates: The Key to Extremely High Quantum Yields. AB - A powerful strategy for the improvement of near-IR lanthanoid luminescence has been successfully employed for the first time, which involves the rational and deliberate shortening of the radiative luminescence lifetimes tau(rad) in molecular ytterbium complexes. In this context, the bidentate chelating unit 2,2' bipyridine-N,N'-dioxide has been identified as being responsible for decreasing tau(rad) substantially in macrobicyclic Yb cryptates. This strategy, when combined with conventional approaches, yields unprecedented absolute near-IR quantum yields of up to 12%. This extraordinary efficiency represents the highest value measured for any molecular lanthanoid near-IR emitter. The proof-of-concept for the implementation of the new strategy opens up entirely new prospects for the field of lanthanoid luminescence. PMID- 26096063 TI - A preliminary study on the use and effect of hand antiseptics in veterinary practice. AB - OBJECTIVES: To assess use and effect of hand antiseptics in veterinary clinical practice. MATERIALS AND METHODS: Veterinary practice nurses were questioned concerning their use of hand antiseptics, in particular waterless hand rubs. Subsequent clinical trials assessed the effect of single applications of alcohol based and quaternary ammonium compound-based hand rubs at reducing bacterial counts on the hands of theatre nurses in a neutering clinic. RESULTS: The majority of responding practices used waterless hand rubs (alcohol-based, 67.5% and quaternary ammonium compound-based, 9.5%) as their primary hand hygiene agent and believed them to be effective. 23% of practices favoured an antiseptic hand wash. In clinical trials, alcohol-based rubs were potentially more effective at reducing bacterial counts than quaternary ammonium compound-based rubs especially in the period immediately after application. However, over 3 hours there was no significant change between these and a control group. There were more adverse skin effects in the group using alcohol-based than in the quaternary ammonium compound-based and control groups. The bacterial counts after application were unaffected by variables such as the number of animals contacted. CLINICAL SIGNIFICANCE: The studies provide useful baseline data for evaluation of efficacy of more frequent applications of the most common antiseptic hand rubs used in veterinary practice. PMID- 26096064 TI - Screen time is independently associated with health-related quality of life in overweight and obese adolescents. AB - AIM: Excessive screen time and diminished health-related quality of life (HRQoL) are greater problems for obese than nonobese adolescents, but no research has examined the relationship between these two variables. This study examined the association between screen time and HRQoL in overweight and obese adolescents. METHODS: A sample of 358 overweight and obese adolescents aged 14-18 years were assessed at baseline between 2005 and 2010 as part of the Canadian Healthy Eating, Aerobic and Resistance Training in Youth (HEARTY) trial. We used the Pediatric Quality of Life (PEDS-QL) and other self-report measures to assess HRQoL and screen time, defined as how long the 261 females and 97 males spent viewing TV, using the computer and playing video games. RESULTS: After adjusting for socio-demographic variables, adiposity, physical activity and diet, screen time duration was associated with reduced overall HRQoL (adjusted r = -0.16, beta = -0.16, p = 0.009) and psychosocial HRQoL (adjusted r = -0.16, beta = -0.18, p = 0.004), but not physical HRQoL. No differences were found between males and females. CONCLUSION: Screen time was associated with reduced overall and psychosocial HRQoL in overweight and obese adolescents. Future research should determine whether reducing screen time improves overall and psychosocial HRQoL in obese adolescents. PMID- 26096065 TI - Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia. AB - Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-kappaB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-kappaB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)alpha, as zVAD.fmk, necrostatin-1 or TNFalpha-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups. PMID- 26096066 TI - Retinoic acid-inducible gene 1 and sensing of hepatitis B virus revisited. PMID- 26096067 TI - King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation. AB - Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean +/- SD], 64.38 +/- 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 +/- 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 +/- 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD. PMID- 26096068 TI - Activation of the FGFR1 signalling pathway by the Epstein-Barr virus-encoded LMP1 promotes aerobic glycolysis and transformation of human nasopharyngeal epithelial cells. AB - Non-keratinizing nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1) is believed to play an important role in NPC pathogenesis by virtue of its ability to activate multiple cell signalling pathways which collectively promote cell proliferation, transformation, angiogenesis, and invasiveness, as well as modulation of energy metabolism. In this study, we report that LMP1 increases cellular uptake of glucose and glutamine, enhances LDHA activity and lactate production, but reduces pyruvate kinase activity and pyruvate concentrations. LMP1 also increases the phosphorylation of PKM2, LDHA, and FGFR1, as well as the expression of PDHK1, FGFR1, c-Myc, and HIF-1alpha, regardless of oxygen availability. Collectively, these findings suggest that LMP1 promotes aerobic glycolysis. With respect to FGFR1 signalling, LMP1 not only increases FGFR1 expression, but also up-regulates FGF2, leading to constitutive activation of the FGFR1 signalling pathway. Furthermore, two inhibitors of FGFR1 (PD161570 and SU5402) attenuate LMP1-mediated aerobic glycolysis, cellular transformation (proliferation and anchorage-independent growth), cell migration, and invasion in nasopharyngeal epithelial cells, identifying FGFR1 signalling as a key pathway in LMP1-mediated growth transformation. Immunohistochemical staining revealed that high levels of phosphorylated FGFR1 are common in primary NPC specimens and that this correlated with the expression of LMP1. In addition, FGFR1 inhibitors suppress cell proliferation and anchorage-independent growth of NPC cells. Our current findings demonstrate that LMP1-mediated FGFR1 activation contributes to aerobic glycolysis and transformation of epithelial cells, thereby implicating FGF2/FGFR1 signalling activation in the EBV-driven pathogenesis of NPC. PMID- 26096070 TI - Does Insert Type Affect Clinical and Functional Outcome in Total Knee Arthroplasty? A Randomised Controlled Clinical Trial With 5-Year Follow-Up. AB - New insert types have been developed to improve clinical and functional outcome in mobile bearing (MB-TKA) and fixed bearing total knee arthroplasty (FB-TKA). A prospective single blinded randomised controlled clinical trial was performed to evaluate 2 types of MB-TKA inserts and 2 types of FB-TKA inserts of the Genesis II prosthesis (Smith & Nephew) in 146 patients with 5-years follow-up. A significant difference (P=.042) between the MB-TKA inserts was found in KSS function scores, but clinical significance is expected to be limited. Goniometry, temporal gait parameters and QoL were similar in all groups. Survival was significantly better (P=.047) for FB-TKA. The comparable outcome and higher revision rate in MB-TKA indicate that FB-TKA may be preferential for the Genesis II implant system. PMID- 26096071 TI - Comparison of Patient Function during the First Six Weeks after Direct Anterior or Posterior Total Hip Arthroplasty (THA): A Randomized Study. AB - The purpose of this single-surgeon randomized study was to determine if functional recovery during the early postoperative period differs between the direct anterior (DAA) and posterior approaches (PA). An a priori power analysis indicated that 26 patients per group were needed, and 6-week follow-up data were available for 51 THAs to date. Hospitals stays were significantly shorter for the DAA group (1.4 vs. 2.0 days, P=0.01), and the change in Pain Scores was significantly greater for the DAA group (P=0.04). The DAA group also discontinued use of an assistive ambulatory device at an earlier time (33.0 vs. 43.1 days, P=0.03). Despite these differences, no other subjective or objective functional measures differed between the 2 groups at the 6-week follow-up. PMID- 26096072 TI - Single-Stage Hip and Knee Exchange for Periprosthetic Joint Infection. AB - Periprosthetic joint infections following hip and knee arthroplasty are challenging complications for Orthopaedic surgeons to manage. The single-stage exchange procedure is becoming increasingly popular with promising results. At our Institute we have demonstrated favourable or similar outcomes compared to the 'gold-standard' two-stage exchange, and other published single-stage results. The aim of this study is to describe the patient selection criteria and perioperative steps in a single-stage exchange for hip and knee arthroplasty undertaken at our Institute. The outlined protocol can be performed using standard debridement, attention to detail and well-recognised reconstructive techniques. PMID- 26096073 TI - Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer. AB - Recent studies have demonstrated that long non-coding RNAs (lncRNAs) are regarded as useful tools for cancer detection, particularly for the early stage; however, little is known about their diagnostic impact on gastric cancer (GC). We hypothesized that GC-related lncRNAs might release into the circulation during tumor initiation and could be utilized to detect and monitor GC. 8 lncRNAs which previously found to be differently expressed in GC were selected as candidate targets for subsequent circulating lncRNA assay. After validating in 20 pairs of tissues and plasma in training set, H19 was selected for further analysis in another 70 patients and 70 controls. Plasma level of H19 was significantly higher in GC patients compared with normal controls (p < 0.0001). By receiver operating characteristic curve (ROC) analysis, the area under the ROC curve (AUC) was 0.838; p < 0.001; sensitivity, 82.9%; specificity, 72.9%). Furthermore, H19 expression enabled the differentiation of early stage GC from controls with AUC of 0.877; sensitivity, 85.5%; specificity, 80.1%. Besides, plasma levels of H19 were significantly lower in postoperative samples than preoperative samples (p = 0.001). In conclusion, plasma H19 could serve as a potential biomarker for diagnosis of GC, in particular for early tumor screening. PMID- 26096074 TI - Bioorthogonal Labeling, Bioimaging, and Photocytotoxicity Studies of Phosphorescent Ruthenium(II) Polypyridine Dibenzocyclooctyne Complexes. AB - The synthesis, characterization, photophysics, lipophilicity, and cellular properties of new phosphorescent ruthenium(II) polypyridine complexes functionalized with a dibenzocyclooctyne (DIBO) or amine moiety [Ru(N^N)2 (L)](PF6 )2 are reported (L=4-(13-N-(3,4:7,8-dibenzocyclooctyne-5-oxycarbonyl) amino-4,7,10-trioxa-tridecanyl-aminocarbonyl-oxy-methyl)-4'-methyl-2,2' bipyridine bpy-DIBO, N^N=2,2'-bipyridine bpy (1 a), 1,10-phenanthroline phen (2 a); L=4-(13-amino-4,7,10-trioxa-tridecanylaminocarbonyl-oxy-methyl)-4'-methyl 2,2'-bipyridine bpy-NH2 , N^N=bpy (1 b), phen (2 b)). The strain-promoted alkyne azide cycloaddition (SPAAC) reaction of the DIBO complexes 1 a and 2 a with benzyl azide were studied. Also, the DIBO complexes 1 a and 2 a can selectively label N-azidoglycans located on the surface of CHO-K1 and A549 cells that were pretreated with 1,3,4,6-tetra-O-acetyl-N-azidoacetyl-D-mannosamine (Ac4 ManNAz). Additionally, the intracellular trafficking and localization of these biomolecules were monitored using laser-scanning confocal microscopy. Interestingly, the biolabeling and cellular uptake efficiency of the DIBO complexes 1 a and 2 a were cell-line dependent, as revealed by flow cytometry and ICP-MS. Furthermore, the complexes showed good biocompatibility toward the Ac4 ManNAz-pretreated cells in the dark, but exhibited photoinduced cytotoxicity due to the generation of singlet oxygen. PMID- 26096075 TI - Polyelectrolyte brushes in external fields: molecular dynamics simulations and mean-field theory. AB - A mean-field model is developed to predict the layer-thickness of sparse and salt free polyelectrolyte brushes, exposed to an external electric field, which attracts the polyelectrolytes to the substrate. In molecular dynamics simulations, it is shown that a fraction of polymers collapses entirely to screen the charge of the substrate. The remaining brushes are then treated as field-free brushes at reduced grafting density. The mean-field model may thus be applied to field-free brushes, both in their osmotic and their weak charge regimes. It yields simple, closed equations for the brush height and for the partition of counterions in- and outside the brushes, and accurately reproduces simulation data of the collapse of the brushes during the crossover between both charge regimes. PMID- 26096076 TI - Right Ventricular Structure and Function in Idiopathic Pulmonary Fibrosis with or without Pulmonary Hypertension. AB - AIMS: To elucidate right ventricular (RV) function in patients with idiopathic pulmonary fibrosis (IPF) with and without pulmonary hypertension (PH) and its relation to other features of the disease. METHODS AND RESULTS: Clinical evaluation, standard Doppler echo, Doppler myocardial imaging (DMI), and 2D strain echocardiography (STE) of RV septal and lateral walls were performed in 52 IPF patients (66.5 +/- 8.5 years; 27 males) and in 45 age- and sex-comparable controls using a commercial US system (MyLab Alpha, Esaote). Pulmonary artery mean pressure (mPAP) was estimated by standard echo Doppler. RV global longitudinal strain (RV GLS) was calculated by averaging RV local strains. The IPF patients were divided into 2 groups by noninvasive assessment of PH: no PH (mPAP<25 mmHg; 36 pts) and PH (mPAP >=25 mmHg; 16 pts). Left ventricular diameters and ejection fraction were comparable between controls and IPF, while GLS was impaired in IPF (P < 0.01). RV end-diastolic diameters, wall thickness andmPAP were increased in IPF patients with PH. In addition, pulsed DMI detected in PH IPF impaired myocardial RV early diastolic (Em) peak velocity. Also peak systolic RV strain was reduced in basal and middle RV lateral free walls in IPF, as well as RV GLS (P < 0.0001). The impairment in RV wall strain was more evident when comparing controls with the no PH group than comparing the no PH group with the PH group. By multivariate analysis, independent association of RV strain with both six-minute walking test distance (P < 0.001), mPAP (P < 0.0001), as well as with forced vital capacity (FVC) % (P < 0.005) in IPF patients were observed. CONCLUSIONS: Impaired RV diastolic and systolic myocardial function were present even in IPF patients without PH, which indicates an early impact on RV function and structure in patients with IPF. PMID- 26096077 TI - The role of thymosin-beta4 in kidney disease. AB - Therapies that modulate inflammation and fibrosis have the potential to reduce the morbidity and mortality associated with chronic kidney disease (CKD). A promising avenue may be manipulating thymosin-beta4, a naturally occurring peptide, which is the major G-actin sequestering protein in mammalian cells and a regulator of inflammation and fibrosis. Thymosin-beta4 is already being tested in clinical trials for heart disease and wound healing. This editorial outlines the evidence that thymosin-beta4 may also have therapeutic benefit in CKD. PMID- 26096079 TI - Gaining momentum: New options and opportunities for the treatment of advanced melanoma. AB - Before 2011, patients with advanced or metastatic melanoma had a particularly poor long-term prognosis. Since traditional treatments failed to confer a survival benefit, patients were preferentially entered into clinical trials of investigational agents. A greater understanding of the epidemiology and biology of disease has underpinned the development of newer therapies, including six agents that have been approved in the EU, US and/or Japan: a cytotoxic T lymphocyte antigen-4 inhibitor (ipilimumab), two programmed cell death-1 receptor inhibitors (nivolumab and pembrolizumab), two BRAF inhibitors (vemurafenib and dabrafenib) and a MEK inhibitor (trametinib). The availability of these treatments has greatly improved the outlook for patients with advanced melanoma; however, a major consideration for physicians is now to determine how best to integrate these agents into clinical practice. Therapeutic decisions are complicated by the need to consider patient and disease characteristics, and individual treatment goals, alongside the different efficacy and safety profiles of agents with varying mechanisms of action. Long-term survival, an outcome largely out of reach with traditional systemic therapies, is now a realistic goal, creating the additional need to re-establish how clinical benefit is evaluated. In this review we summarise the current treatment landscape in advanced melanoma and discuss the promise of agents still in development. We also speculate on the future of melanoma treatment and discuss how combination and sequencing approaches may be used to optimise patient care in the future. PMID- 26096078 TI - Pregnancy as a window to future health: Excessive gestational weight gain and obesity. AB - Metabolic and behavioral changes that occur during pregnancy have well-known effects on maternal and fetal health during the immediate pregnancy and now are thought to be a catalyst for future health throughout later life. Recommendations for appropriate gestational weight gain (GWG) and lifestyle modifications during pregnancy have changed throughout history as more is known about this crucial time. Herein we discuss the current GWG recommendations and the impact of pregnancy and excess GWG gain on the current and future health of women and children including risk of obesity, gestational diabetes, type 2 diabetes, cardiovascular disease, and metabolic syndrome. PMID- 26096081 TI - Right ventricular reconstruction after resection of cardiac fibroma. AB - Cardiac fibromas are rare neoplasms of myocardial fibroblasts. We present a case of a right ventricular fibroma and review the surgical management of these neoplasms. PMID- 26096080 TI - Wavelet-based regularity analysis reveals recurrent spatiotemporal behavior in resting-state fMRI. AB - One of the major findings from multimodal neuroimaging studies in the past decade is that the human brain is anatomically and functionally organized into large scale networks. In resting state fMRI (rs-fMRI), spatial patterns emerge when temporal correlations between various brain regions are tallied, evidencing networks of ongoing intercortical cooperation. However, the dynamic structure governing the brain's spontaneous activity is far less understood due to the short and noisy nature of the rs-fMRI signal. Here, we develop a wavelet-based regularity analysis based on noise estimation capabilities of the wavelet transform to measure recurrent temporal pattern stability within the rs-fMRI signal across multiple temporal scales. The method consists of performing a stationary wavelet transform to preserve signal structure, followed by construction of "lagged" subsequences to adjust for correlated features, and finally the calculation of sample entropy across wavelet scales based on an "objective" estimate of noise level at each scale. We found that the brain's default mode network (DMN) areas manifest a higher level of irregularity in rs fMRI time series than rest of the brain. In 25 aged subjects with mild cognitive impairment and 25 matched healthy controls, wavelet-based regularity analysis showed improved sensitivity in detecting changes in the regularity of rs-fMRI signals between the two groups within the DMN and executive control networks, compared with standard multiscale entropy analysis. Wavelet-based regularity analysis based on noise estimation capabilities of the wavelet transform is a promising technique to characterize the dynamic structure of rs-fMRI as well as other biological signals. PMID- 26096082 TI - Structural Elucidation of the Bispecificity of A Domains as a Basis for Activating Non-natural Amino Acids. AB - Many biologically active peptide secondary metabolites of bacteria are produced by modular enzyme complexes, the non-ribosomal peptide synthetases. Substrate selection occurs through an adenylation (A) domain, which activates the cognate amino acid with high fidelity. The recently discovered A domain of an Anabaenopeptin synthetase from Planktothrix agardhii (ApnA A1) is capable of activating two chemically distinct amino acids (Arg and Tyr). Crystal structures of the A domain reveal how both substrates fit into to binding pocket of the enzyme. Analysis of the binding pocket led to the identification of three residues that are critical for substrate recognition. Systematic mutagenesis of these residues created A domains that were monospecific, or changed the substrate specificity to tryptophan. The non-natural amino acid 4-azidophenylalanine is also efficiently activated by a mutant A domain, thus enabling the production of diversified non-ribosomal peptides for bioorthogonal labeling. PMID- 26096083 TI - Mouse genetic models for temporomandibular joint development and disorders. AB - The temporomandibular joint (TMJ) is a synovial joint essential for hinge and sliding movements of the mammalian jaw. Temporomandibular joint disorders (TMD) are dysregulations of the muscles or the TMJ in structure, function, and physiology, and result in pain, limited mandibular mobility, and TMJ noise and clicking. Although approximately 40-70% adults in the USA have at least one sign of TMD, the etiology of TMD remains largely unknown. Here, we highlight recent advances in our understanding of TMD in mouse models. PMID- 26096084 TI - Pedigree-based analysis of derivation of genome segments of an elite rice reveals key regions during its breeding. AB - Analyses of genome variations with high-throughput assays have improved our understanding of genetic basis of crop domestication and identified the selected genome regions, but little is known about that of modern breeding, which has limited the usefulness of massive elite cultivars in further breeding. Here we deploy pedigree-based analysis of an elite rice, Huanghuazhan, to exploit key genome regions during its breeding. The cultivars in the pedigree were resequenced with 7.6* depth on average, and 2.1 million high-quality single nucleotide polymorphisms (SNPs) were obtained. Tracing the derivation of genome blocks with pedigree and information on SNPs revealed the chromosomal recombination during breeding, which showed that 26.22% of Huanghuazhan genome are strictly conserved key regions. These major effect regions were further supported by a QTL mapping of 260 recombinant inbred lines derived from the cross of Huanghuazhan and a very dissimilar cultivar, Shuanggui 36, and by the genome profile of eight cultivars and 36 elite lines derived from Huanghuazhan. Hitting these regions with the cloned genes revealed they include numbers of key genes, which were then applied to demonstrate how Huanghuazhan were bred after 30 years of effort and to dissect the deficiency of artificial selection. We concluded the regions are helpful to the further breeding based on this pedigree and performing breeding by design. Our study provides genetic dissection of modern rice breeding and sheds new light on how to perform genomewide breeding by design. PMID- 26096085 TI - Advances in real-time phase-contrast flow MRI using asymmetric radial gradient echoes. AB - PURPOSE: To provide multidimensional velocity compensation for real-time phase contrast flow MRI. METHODS: The proposed method introduces asymmetric gradient echoes for highly undersampled radial FLASH MRI with phase-sensitive image reconstruction by regularized nonlinear inversion (NLINV). Using an adapted gradient delay correction the resulting image quality was analyzed by simulations and experimentally validated at 3 Tesla. For real-time flow MRI the reduced gradient-echo timing allowed for the incorporation of velocity-compensating waveforms for all imaging gradients at even shorter repetition times. RESULTS: The results reveal a usable degree of 20% asymmetry. Real-time flow MRI with full velocity compensation eliminated signal void in a flow phantom, confirmed flow parameters in healthy subjects and demonstrated signal recovery and phase conservation in a patient with aortic valve insufficiency and stenosis. Exemplary protocols at 1.4-1.5 mm resolution and 6 mm slice thickness achieved total acquisition times of 33.3-35.7 ms for two images (7 spokes each) with and without flow-encoding gradient. CONCLUSION: Asymmetric gradient echoes were successfully implemented for highly undersampled radial trajectories. The resulting temporal gain offers full velocity compensation for real-time phase-contrast flow MRI which minimizes false-positive contributions from complex flow and further enhances the temporal resolution compared with acquisitions with symmetric echoes. PMID- 26096086 TI - The toxic effects of Bisphenol A on the mouse spermatocyte GC-2 cell line: the role of the Ca2+-calmodulin-Ca2+/calmodulin-dependent protein kinase II axis. AB - Bisphenol A (BPA), an endocrine-disrupting chemical (EDC), is known to induce male reproductive toxicity in rodents. However, its toxic effects on the germ cells are still poorly understood. It has been proposed that Ca(2+) homeostasis and Ca(2+) sensors, including calmodulin (CaM) and calmodulin-dependent protein kinase II (CaMKII), play critical roles in spermatogenesis. Therefore, in the present study, we aimed to investigate whether a perturbation in Ca(2+)-CaM CaMKII signaling was involved in the BPA-induced injury to mouse spermatocyte GC 2spd (ts) (GC-2) cells. Our results showed that BPA (range from 0.2 to 20 MUM) induced obvious GC-2 cell injury, including decreased cell viability, the release of mitochondrial cytochrome c and the activation of caspase-3. However, these processes could be partially abrogated by pretreatment with a Ca(2+) chelator (BAPTA/AM), a CaM antagonist (W7) or a CaMKII inhibitor (KN93). These results, taken together, indicate that BPA exposure contributes to male germ cell injury, which may be partially mediated through a perturbation in Ca(2+)/CaM/CaMKII signaling and the mitochondrial apoptotic process. PMID- 26096087 TI - How to investigate rheumatological diseases? PMID- 26096088 TI - How to investigate multisystem disease. AB - The investigation of the patient with possible systemic autoimmune rheumatic disease is potentially one of the most challenging areas of rheumatology as the differential diagnosis is potentially very broad. The investigative approach should not only be directed at confirming the diagnosis of an autoimmune rheumatic disease but also at excluding as best as possible the major alternative diagnoses of malignancy and infection. A systematic approach should yield a positive diagnosis in the majority of cases based on excluding infection by appropriate cultures and serology, malignancy using imaging including 18 fluorodeoxyglucose positron emission tomography/computerized tomography (FDG PET/CT). The most important part of the assessment is the history, in particular covering systems that may not previously been assessed such as ears, nose, throat or eyes. The clue to the diagnosis of an autoimmune rheumatic disease often lies in detecting the multisystem nature of the condition and the cumulative effects of multiorgan involvement. Investigation may therefore need to cover different systems. Although stratified approaches have been described, they have not been subjected to a detailed investigation as to their effectiveness. PMID- 26096089 TI - How to investigate new-onset polyarthritis. AB - Polyarthritis comprises a large number of conditions ranging from rheumatoid arthritis (RA) to metabolic conditions such as ochronosis. Differential diagnosis begins with delineation of inflammatory from non-inflammatory disorders using laboratory markers of inflammation. The latter are good but they can be misleading. Laboratory tests help in the diagnosis of rheumatic diseases as well as their prognostication. The choice of serological tests should be based on clinical differential diagnosis and not 'arthritis panels'. The point of time when the test is performed in the clinical course of disease can have an important influence on the result obtained. Anti-citrullinated protein antibody (ACPA), rheumatoid factor, human leucocyte antigen (HLA) B27 and imaging are routinely employed for the early diagnosis of RA and spondyloarthritis (SpA). Despite advances in musculoskeletal imaging modalities such as ultrasonography (USG) with power Doppler, conventional as well as extremity magnetic resonance imaging (MRI) and dual-energy computed tomography (DECT), their exact place in clinical rheumatology remains to be defined. Synovial fluid examination has only a limited role in the investigations of new-onset polyarthritis. PMID- 26096090 TI - How to investigate: Chronic pain. AB - Chronic pain is defined as an unpleasant sensory and emotional experience persisting longer than the normal process of healing, usually longer than 3 months. About a fifth of the world's population is believed to suffer from chronic pain. In Europe, chronic pain accounts for nearly 500 m lost working days, and it costs the European economy >?34 billion (L28 billion) every year. Establishing a reliable diagnosis is the primary challenge in evaluating a patient with chronic pain. Common diagnoses not to miss include seronegative spondyloarthritides, endocrine abnormalities including severe vitamin D deficiency and polymyalgia rheumatica. Once important or treatable diagnoses have been ruled out, the history can be used as a tool to establish a therapeutic plan for shared decision-making using the biopsychosocial model. Onward referral to pain clinics can be helpful for more involved patient management, but often good outcomes are achieved with the support of primary care. PMID- 26096091 TI - Assessment of spinal pain. AB - Spinal pain or back pain is a very common symptom that can have many reasons. The most studied location is low back pain, and it is considered to be nonspecific in the majority of cases. Only a small proportion of patients have axial inflammation as the major cause of their back complaints with chronic inflammatory back pain (IBP) as the most prominent clinical feature of spondyloarthritis (SpA). The recognition of IBP and patients with axial spondyloarthritis (axSpA) is challenging in primary care, and it is important to further facilitate the early diagnosis of SpA. Proposals for improving the referral of patients with a possible diagnosis of axSpA include clinical parameters, human leukocyte antigen (HLA) B27, and imaging parameters. Imaging is crucial for the visualization, objective validation, and understanding of back pain. Numerous diseases such as degenerative disk disease, degenerative changes in the intervertebral (facet) joints and the associated ligaments, spinal instability, herniation of the intervertebral disk, and spinal stenosis have to be differentiated in interpreting imaging of the spine. The sacroiliac joints and the spine are of major importance for the diagnosis and classification of axSpA. Conventional radiographs and magnetic resonance imaging (MRI) are the most important imaging technologies for visualization of structural changes such as syndesmophytes and axial inflammation such as sacroiliitis and spondylitis. The pathogenesis of axSpA is largely genetically determined. HLA B27 has the strongest contribution to the total genetic burden, but other major contributors such as endoplasmic reticulum aminopeptidase (ERAP)-1 and interleukin (IL)-23R have also been identified. PMID- 26096092 TI - The child with joint pain in primary care. AB - Joint pains are a common reason for children to present to primary care. The differential diagnosis is large including some diseases that do not primarily affect the musculoskeletal system. Although the cause for many patients will be benign and self-resolving, in rare cases the diagnosis is associated with long term morbidity and mortality if not detected early and appropriately treated. These include primary and secondary malignancies, septic arthritis, osteomyelitis, inflammatory arthritis, slipped upper femoral epiphysis (SUFE) and non-accidental injury. We highlight the importance of a thorough history and directed yet comprehensive examination. A diagnostic algorithm is provided to direct primary care physicians' clinical assessment and investigation with the evidence base where available. In many cases, tests are not required, but if there is suspicion of malignancy, infection or inflammatory conditions, laboratory tests including full blood count, blood film, erythrocyte sedimentation rate, C-reactive protein and lactate dehydrogenase help to support or exclude the diagnosis. Autoimmune tests, such as antinuclear antibodies and rheumatoid factor, have no diagnostic role in juvenile idiopathic arthritis; therefore, we advise against any form of 'rheumatological/autoimmune disease screen' in primary care. Imaging does have a place in the diagnosis of joint pains in children, with plain radiographs being most appropriate for suspected fractures and SUFE, whilst ultrasound is better for the detection of inflammatory or infective effusions. The appropriate referral of children to paediatric rheumatologists, oncologists, orthopaedic surgeons and the emergency department are discussed. PMID- 26096093 TI - Role of autoantibody testing. AB - Autoantibodies are the serological hallmark of autoimmune disease. Though their pathogenic role is debatable, they play an important role in the management of a patient with rheumatic disease. However, due to their presence in the general population as well as in multiple autoimmune diseases, the presence of an autoantibody alone does not make a diagnosis; the result has to be interpreted along with clinical findings. Similarly, the absence of autoantibody does not exclude a disease. The common autoantibodies used in clinical practice include rheumatoid factor, anti-CCP antibodies, antinuclear antibodies (ANAs), anti neutrophil cytoplasmic antibodies (ANCA) and anti-phospholipid antibodies. Once an autoantibody to a broad antigen is detected in a patient, sub-specificity analysis can improve the utility of the antibody. Autoantibodies are detected in the serum using different assays and results of which can vary; thus, it is important for a clinician to know the method used, its sensitivity and specificity to help in the proper interpretation of the laboratory results. This review will address these issues. PMID- 26096095 TI - Infections and arthritis. AB - Bacteria, viruses, fungi, and parasites can all cause arthritis of either acute or chronic nature, which can be divided into infective/septic, reactive, or inflammatory. Considerable advances have occurred in diagnostic techniques in the recent decades resulting in better treatment outcomes in patients with infective arthritis. Detection of emerging arthritogenic viruses has changed the epidemiology of infection-related arthritis. The role of viruses in the pathogenesis of chronic inflammatory arthritides such as rheumatoid arthritis is increasingly being recognized. We discuss the various causative agents of infective arthritis and emphasize on the approach to each type of arthritis, highlighting the diagnostic tests, along with their statistical accuracy. Various investigations including newer methods such as nucleic acid amplification using polymerase chain reaction are discussed along with the pitfalls in interpreting the tests. PMID- 26096094 TI - The use and abuse of diagnostic/classification criteria. AB - In rheumatic diseases, classification criteria have been developed to identify well-defined homogenous cohorts for clinical research. Although they are commonly used in clinical practice, their use may not be appropriate for routine diagnostic clinical care. Classification criteria are being revised with improved methodology and further understanding of disease pathophysiology, but they still may not encompass all unique clinical situations to be applied for diagnosis of heterogenous, rare, evolving rheumatic diseases. Diagnostic criteria development is challenging primarily due to difficulty for universal application given significant differences in the prevalence of rheumatic diseases based on geographical area and clinic settings. Despite these shortcomings, the clinician can still use classification criteria for understanding the disease as well as a guide for diagnosis with a few caveats. We present the limits of current classification criteria, their use and abuse in clinical practice, and how they should be used with caution when applied in clinics. PMID- 26096096 TI - Cost-effective use of investigations in developing countries. AB - In recent years, the cost of health care around the world has risen at a rate that is deemed unsustainable. It has been estimated that 20% of this could be saved by rationalising laboratory investigations and reducing inappropriate requisitioning of the investigations. There are several reasons for the excessive, redundant, inappropriate or unnecessary investigations and procedures, which in some instances are unethical practices. The impact in financial terms is more in developing countries such as India with <5% of the population having medical insurance and hardly any other third-party payer system. The 'Choosing Wisely' campaign of the American Board of Internal Medicine, Canadian Rheumatology Association's Choosing Wisely Committee and the 'Society for Less Investigative Medicine' (SLIM) initiative of the doctors of All-India Institute of Medical Sciences (AIIMS), New Delhi, all have provided recommendations to reduce unnecessary investigations, and these are among some of the efforts to reduce the cost of investigations without compromising the quality of care. PMID- 26096097 TI - Travel- and immigration-related problems in rheumatology. AB - Health problems are self-reported by up to 64% of travellers to the developing world. Traditionally, rheumatic symptoms are accorded little significance, but many travellers do return home with musculoskeletal complaints. The assessment of these patients is often hindered by the Western clinician's lack of familiarity with the types of infections that the patient may have encountered while travelling. Standard serological tests for autoimmune diseases can be unreliable in the setting of concomitant tropical infection, and these infections themselves can have musculoskeletal manifestations. Even in the absence of tropical infection, laboratory investigation of musculoskeletal symptoms in individuals of different ethnicities is challenging due to genetic and physiological variation. This review focusses on addressing the impact global migration has had on rheumatological clinical practice. PMID- 26096098 TI - Development of a Rapid Immunochromatographic Strip Test for the Detection of Mulberroside A. AB - INTRODUCTION: Mulberroside A (MuA) is the major active anti-tyrosinase compound in the root bark extract of Morus alba L. (Moraceae). Typically, MuA is widely employed as an active ingredient in whitening cosmetics. A rapid and simple assay system utilizing a small quantity of test sample is essential for the detection of MuA in large number of samples. An immunoassay using highly specific MuA polyclonal antibodies may be useful for the determination of small quantities of MuA in test samples. OBJECTIVE: To establish a rapid qualitative MuA test, an immunochromatographic strip test was developed using anti-MuA polyclonal antibodies (anti-MuA PAb). METHODOLOGY: The qualitative assay was based on a competitive immunoassay where the detection reagent consisted of anti-MuA PAb colored with colloidal gold particles. The capture reagent was a MuA-ovalbumin (MuA-OVA) conjugate immobilized on the test strip membrane. RESULTS: A sample containing MuA and the detection reagent were incubated together with immobilized capture reagent on a nitrocellulose membrane. When MuA was present, it competed with the immobilized conjugates on the strip membrane to bind a limited amount of colored antibodies; thus, a positive sample showed no color on the capture spot zone. The detection limit for the strip test was 2 ug/mL. The developed immunochromatographic strip test was utilized to determine MuA in plants, medical preparations and cosmetic samples. CONCLUSION: This immunochromatographic strip test is advantageous as a rapid, simple and sensitive screening method for the detection of MuA in plant extracts, cosmetic samples and pharmaceutical products. PMID- 26096099 TI - Colonization from divergent ancestors: glaciation signatures on contemporary patterns of genomic variation in Collared Pikas (Ochotona collaris). AB - Identifying the genetic structure of a species and the factors that drive it is an important first step in modern population management, in part because populations evolving from separate ancestral sources may possess potentially different characteristics. This is especially true for climate-sensitive species such as pikas, where the delimitation of distinct genetic units and the characterization of population responses to contemporary and historical environmental pressures are of particular interest. We combined a restriction site-associated DNA sequencing (RADSeq) data set containing 4156 single nucleotide polymorphisms with ecological niche models (ENMs) of present and past habitat suitability to characterize population composition and evaluate the effects of historical range shifts, contemporary climates and landscape factors on gene flow in Collared Pikas, which are found in Alaska and adjacent regions of northwestern Canada and are the lesser-studied of North America's two pika species. The results suggest that contemporary environmental factors contribute little to current population connectivity. Instead, genetic diversity is strongly shaped by the presence of three ancestral lineages isolated during the Pleistocene (~148 and 52 kya). Based on ENMs and genetic data, populations originating from a northern refugium experienced longer-term stability, whereas both southern lineages underwent population expansion - contradicting the southern stability and northern expansion patterns seen in many other taxa. Current populations are comparable with respect to generally low diversity within populations and little-to-no recent admixture. The predominance of divergent histories structuring populations implies that if we are to understand and manage pika populations, we must specifically assess and accurately account for the forces underlying genetic similarity. PMID- 26096100 TI - Forward together (Excelsior!). PMID- 26096101 TI - Scientific misconducts: Debunking myths. PMID- 26096102 TI - Dosimetry in dentistry. AB - AIM: The purpose of this paper was to review various dosimeters used in dentistry and the cumulative results of various studies done with various dosimeters. MATERIALS AND METHODS: Several relevant PubMed indexed articles from 1999 to 2013 were electronically searched by typing "dosimeters", "dosimeters in dentistry", "properties of dosimeters", "thermoluminescent and optically stimulated dosimeters", "recent advancements in dosimetry in dentistry." The searches were limited to articles in English to prepare a concise review on dental dosimetry. Titles and abstracts were screened, and articles that fulfilled the criteria of use of dosimeters in dental applications were selected for a full-text reading. Article was divided into four groups: (1) Biological effects of radiation, (2) properties of dosimeters, (3) types of dosimeters and (4) results of various studies using different dosimeters. CONCLUSION: The present review on dosimetry based on various studies done with dosimeters revealed that, with the advent of radiographic technique the effective dose delivered is low. Therefore, selection of radiological technique plays an important role in dental dose delivery. PMID- 26096103 TI - Use of minimally invasive gingival biopsies in the study of inflammatory mediators expression and their correlation with gingival fluid in patients with chronic periodontitis. AB - BACKGROUND: There are no studies comparing the gingival crevicular fluid (GCF) cytokines expression with its corresponding values from the same tissue's sites. Such comparison might be of great value since most of the cytokine function is related to cell and/or tissue receptors. AIMS: Our aim was to use minimally invasive biopsies to evaluate the expression of interferon-gamma, interleukin 1 (IL-1) beta, IL-6, IL-17A, IL-17F, and their correlation with the expression in gingival fluid in patients with chronic periodontitis. MATERIALS AND METHODS: The collection of gingival fluid comprised 22 samples from 11 patients (mean age 46.73 +/- 10.16 standard deviation years) with chronic periodontitis. The collection of biopsies comprised 22 samples from the same patients. Gingival fluid and biopsy were taken from the same site in one shallow and one deep site per patient. Gingival fluid samples were collected with periopaper(r) and analyzed using Luminex(r). Biopsies were taken with a 2 mm diameter punch and analyzed for the same mediators using immunohistochemistry. RESULTS: The gingival fluid showed higher amounts for IL-1-beta in deep sites. Immunohistochemical markers were observed in the analyzed cells groups, both in deep and shallow sites, without significant differences between them. In the comparative analysis between immunohistochemical markers and GCF, IL-1-beta showed high concordance in shallow and deep sites. CONCLUSIONS: The use of a standardized punch of 2 mm diameter for periodontal tissue biopsies seems to be suitable for immunohistochemistry analysis and showed that the GCF may not express all the markers in the same proportion at the corresponding tissue. PMID- 26096104 TI - Microshear bonding effectiveness of different dentin regions. AB - AIM: The aim of this in vitro study was to evaluate the influence of dentin surfaces with different tubule orientation on bond strength of a multimode adhesive system. MATERIALS AND METHODS: Twenty human molars were selected and prepared in different ways in order to produce different dentin regions. The teeth were randomized (n = 5) according to the application modes of a multimode adhesive system (etch-and-rinse and self-etching) and to the dentin region (occlusal and proximal - 1.5 mm depth from dentinoenamel junction). Cylindrical restorations were performed on dentin with a starch tube. The samples remained immersed in distilled water for 24 h and the microshear bond strength (MUSBS) test was performed. The MUSBS values were expressed in MPa and analyzed with ANOVA and Tukey's test (P < 0.05). RESULTS: There was no significant difference in the bond strength values between the application modes of the adhesive system (P = 0.19); however, the dentin regions (P < 0.05) significantly affected the MUSBS. The proximal dentin presented higher bond strength values than occlusal dentin. CONCLUSION: The dentin surfaces with different tubule orientation influenced the bonding effectiveness of the adhesive system tested. PMID- 26096105 TI - An in vivo study to correlate the relationship of the extraoral and intraoral anatomical landmarks with the occlusal plane in dentulous subjects. AB - BACKGROUND: The occlusal plane position is considered to be the primary link between esthetic and function. AIM: To evaluate the relationship between extraoral and intraoral soft tissue landmarks with the occlusal plane in dentulous subjects on both sides and to check for any variations. STUDY AND DESIGN: An in vivo study and 100 subjects with all healthy permanent teeth in normal arch and alignment were selected from Modern Dental College and Research Centre, Indore. MATERIALS AND METHODS: Three custom made instruments (occlusal plane analyzer, buccinator groove relator, and level analyzer) were indigenously designed to check parallelism of the interpupillary line, ala-tragus line, buccinator groove with the occlusal plane. Relation of retromolar pad with the occlusal plane was checked with the metallic scale. STATISTICAL ANALYSIS: Chi square test. RESULTS: In 20.0% subjects, the occlusal plane was parallel to the interpupillary line. The posterior reference point for ala-tragus line was middle point on right side in 56% and left side in 58% subjects. Intraorally, right side 59% and left side 62% subjects had the occlusal plane at the same level as that of buccinator groove. Right side 48% and left side 45% subjects showed occlusal plane at the middle one-third of retromolar pad. CONCLUSION: The occlusal plane is not generally parallel to interpupillary line. The occlusal plane is parallel to the ala-tragus line with middle point of tragus as posterior reference point on right and left sides. Both sides, the buccinator groove and the middle one third retromolar pad are coinciding with occlusal plane level. PMID- 26096106 TI - Dimensional change in soft tissues with complete dental prosthesis and its effect on airway space and natural head position. AB - BACKGROUND: Insertion of the intraoral prosthesis causes deflection of the tongue, soft palate affecting the patency of the airway. AIMS: To evaluate the cephalometric soft tissue variation in tongue, soft palate, and its effect on posterior airway space in edentulous patients with the insertion of the denture. SETTINGS AND DESIGN: Randomized controlled trial. MATERIALS AND METHODS: Complete denture (CD) prosthesis was fabricated for first time denture wearers comprising 22 males and 18 females within the age range of 50-65 years. Lateral skull radiographs were taken for each of the subjects in their resting position without CDs (T0), with CDs (T1) at least 1-week postinsertion and after 6 months of usage (T2), respectively. The reference points, lines, and angles on the cephalometric films were used to evaluate the position or inclination of the head, variations in tongue position and length, the changes in the anteroposterior dimension of the soft palate, and posterior airway space variations. Intra-investigator error variance was not found to be statistically significant (P < 0.05). STATISTICAL ANALYSIS USED: Using Statistical Package for the Social Sciences (SPSS) v16.0 the significant difference in the paired samples (without CD and with CD) was found using the paired t-test. The probability value P = 0.05 is considered as a significant level. RESULTS: On comparison of T1 and T0, the heads were more extended with the downward position of the tongue with an increase in its length and the posterior airway space was decreased in T1. Significant differences in values were not observed between T1 and T2. CONCLUSIONS: With CDs, the change in airway space was related to alteration in soft palate and tongue dimension. There were no changes in dimension at 6 months follow-up. PMID- 26096107 TI - Does the bracket composition material influence initial biofilm formation? AB - CONTEXT: Orthodontic treatment has been reported to contribute to the development and accumulation of dental biofilm, which is commonly found on bracket and adjacent surfaces. AIMS: The aim of this work is to test the hypothesis if there are differences in dental biofilm formation on the surface of orthodontic brackets according to the type of composition material. SUBJECTS AND METHODS: Three bracket types (metallic, composite, and ceramic) had been evaluated. Subjects wore acrylic palatal orthodontic appliances, containing 6 brackets each, for two 3-day cycles. On the end of first cycle, the amount of dental biofilm formed on the samples was extracted using 1.0-M NaOH and analyzed by spectrophotometry for quantification. An additional cycle was carried out to verify the dental biofilm formation using scanning electronic microscope analysis. STATISTICAL ANALYSIS USED: Three-way ANOVA was used to analyze the difference among the materials (metallic, ceramic and composite) concerning the dental biofilm absorbance spectrum. Multiple comparisons were made using the Tukey's test (alpha =0.05). RESULTS: Composite brackets showed greater values concerning biofilm formation, when compared with the metallic and ceramic ones, both of which presented similar scores. The hypothesis is accepted. There are differences on the biofilm formation according to the type of material. CONCLUSIONS: The in situ model tested was found to be effective in evaluating the accumulation and development of biofilm on orthodontic brackets. In the quantitative analysis, composite brackets showed greater biofilm adhesion values while metallic and ceramic presented similar biofilm absorbance spectrum. PMID- 26096108 TI - Estimation of N-terminal telopeptides of type I collagen in periodontal health, disease and after nonsurgical periodontal therapy in gingival crevicular fluid: A clinico-biochemical study. AB - AIM: This study explored gingival crevicular fluid (GCF) N-terminal telopeptides of type I collagen (NTx) levels in periodontal health, disease and after nonsurgical periodontal therapy along with its association with the clinical parameters. MATERIALS AND METHODS: Study comprised of three groups of 10 subjects each: Healthy (Group I), gingivitis (Group II), and periodontitis (Group III), while Group III patients after scaling and root planning (SRP) constituted Group IV. Gingival index (GI), probing pocket depth (PPD), clinical attachment loss (CAL), and radiological parameters were recorded. GCF samples were analyzed by competitive-enzyme-linked immunosorbent assay. RESULTS: Samples in Group III and Group IV tested positive for NTx whereas in Group I and Group II, NTx was not detected. Mean NTx levels were higher in Group III (6.79 +/- 0.94 nanomole bone collagen equivalents per liter [nm BCE/L]) compared to Group IV (5.73 +/- 0.95 nm BCE/L) which was statistically significant. Positive correlation was seen between the clinical parameters and the NTx levels in Group III and IV. CONCLUSION: As NTx is specific bone turnover marker, it is detected only in periodontitis Group and the values decline after SRP. Failure to detect NTx in Group I and II, relates to the minimum or no resorption at the sample sites. PMID- 26096109 TI - Evaluation of effect of topical ozone therapy on salivary Candidal carriage in oral candidiasis. AB - BACKGROUND AND AIM: Ozone is highly valued for various therapeutic applications such as antimicrobial, antihypoxic, analgesic, and immunostimulating for more than a century in the medical profession. Ozone therapy is now gaining a strong foothold in dentistry. Ozone has bactericidal, fungicidal, and virucidal properties. Oral candidiasis is one of the most common opportunistic fungal infections of the oral cavity. Hence, a study was conducted to evaluate and compare the ability of ozonated water and topical clotrimazole in reducing the Candidal species colony-forming unit (CFU) count in oral candidiasis. MATERIALS AND METHODS: The study included 40 candidiasis patients of either sex aged between 18 and 60 years attending the Department of Oral Medicine and Radiology. The patients were randomly assigned to either topical ozone therapy or topical clotrimazole groups. Salivary Candidal CFU counts were assessed during and after the treatments. RESULTS AND CONCLUSION: There was gradual but significant reduction in Candidal CFU count in both groups. At the end of the treatment, Candidal CFU count reduction in ozone group (60.5% reduction) was more than the clotrimazole group (32.3% reduction). 14 patients (70%) with candidiasis in ozone group were reduced to 6 (30%) whereas only 8 patients (40%) out of 13 (65%) in clotrimazole group, although intergroup comparison was not statistically significant. Ozone therapy was much more effective in reducing the patients with candidiasis to a state of carriers. These findings suggest that ozonated water might be useful to treat oral candidiasis. PMID- 26096110 TI - Effect of denture cleansers on color stability and surface roughness of denture base acrylic resin. AB - BACKGROUND: Color stability of acrylic resin is one of the most important feature for denture wearers. Many patients use detergent solutions to remove denture stains. The purpose of this study was to evaluate color stability and surface roughness of two common acrylic resins in different detergent and tea solutions. MATERIALS AND METHODS: 112 acrylic resin blocks of Meliodent and Acropars (each 56 blocks) were divided into seven groups of different treatment: 1% sodium hypochlorite for 10 min a day for 1 month (H10m), 1% sodium hypochlorite for 8 hours a day for 1 week (H&h), Correga tabs solution for 8 hours a day for 1 month (C&H), tea bag for 2 hours a day for 1 month (T2 h), tea bag for 2 hours a day then 10 min in 1% sodium hypochlorite for 1 month (T-H), tea bag for 2 hours then 8 hours in the Correga tab solution a day for 1 month (T-C), and finally distilled water for 1 month as a control group (con). After specimen's treatment, color (CIE Lab) and surface roughness (Ra, um) of samples were measured. The results were analyzed by analysis of variance (ANOVA), followed by Tukey's HSD and Dunnett T3. RESULTS: Group T2h exhibited a significant (P<;0.05) color change and control specimens exhibited the lowest color change. Sodium hypochlorite caused a significant (P<0.05) color change in the Acropars group in comparison with the Meliodent group. In the Correga tab solution the difference was not significant (P=0.155). There was a significant (P<0.05) color change in the T-H treatment. The Acropars and Meliodent acrylic resin did not a show significant difference in surface roughness after different treatments. CONCLUSION: Sodium hypochlorite 1% for 10 minutes a day in a month is the recommended hygiene protocol. The color stability of acryl is brand-type dependent but surface roughness is not. PMID- 26096111 TI - Effect of protective coating on marginal integrity of nanohybrid composite during bleaching with carbamide peroxide: A microleakage study. AB - AIM: The aim of the study was to evaluate the microleakage on the marginal integrity of nanohybrid composite during bleaching with carbamide peroxide after applying a protective coating of G-Coat plus (GC, Japan). MATERIALS AND METHODS: Class V cavities were prepared and restored with nanohybrid composite restoration in 60 freshly extracted noncarious premolars extracted for orthodontic reasons. Then they were divided into 3 groups. Group 1 - bleaching with carbamide peroxide without G coat plus (n = 20), Group 2 - bleaching with carbamide peroxide with G Coat plus (n = 20), Group 3 - without bleaching procedure (n = 20) (control group). In Group 2, G coat plus was applied over the restorative surface and margins. Then all teeth in Groups 1 and 2 were taken and mounted in dental stone. Bleaching trays were custom fabricated over the cast with the help of a heated vacuum-forming machine. 10% carbamide peroxide (opalescence PF) was applied over the tooth, and the bleaching process was done for about 2 weeks. Then all samples underwent thermocycling and were then immersed in the 2% methylene blue solution for 24 h and observed under a stereomicroscope to evaluate the amount of dye penetration. Data were compared using Kruskal-Wallis test and Mann-Whitney test using SPSS Inc.; Chicago, IL, USA, Version 17.0. RESULTS: Mann-Whitney test shows that the difference in microleakage between Group 1-Group 2 and Group 2-Group 3 is statistically significant (P < 0.05). CONCLUSION: Significant reduction in microleakage was seen in Group 2 when compared to other groups. PMID- 26096112 TI - Comparative evaluation of shear bond strength of nano-hydroxyapatite incorporated glass ionomer cement and conventional glass ionomer cement on dense synthetic hydroxyapatite disk: An in vitro study. AB - AIM: The aim was to evaluate and compare the shear bond strength of nano hydroxyapatite (Nano-HAp) incorporated and conventional glass ionomer cement (GIC). MATERIALS AND METHODS: Nano-HAp GIC was prepared by replacing 8 wt% of GIC powder with nano-HAp powder. Twenty-six HAp disks were used as substrate for bonding and divided into two equal groups. Before bonding the HAp disk was prepared by silicon carbide (no. 2500) followed by 10% polyacrylic acid conditioning. The standardized samples were prepared using split teflon mold on customized bonding jig so as to adhere testing materials to pretreated HAp disk. These samples were stored in distilled water for 24 h at 37 degrees C before bond strength testing. RESULTS: The descriptive statistical analysis and independent samples t-test were used. The nano-HAp incorporated and conventional GIC had the mean shear bond strength of 3.28 +/- 0.89 MPa and 5.25 +/- 0.88 MPa, respectively. Nano-HAp incorporated GIC had lower shear bond strength with very high level of significance (P < 0.001). The nano-HAp incorporated GIC showed mainly mixed type of failure whereas conventional GIC showed mainly a cohesive failure. CONCLUSION: The lower shear bond strength of nano-HAp incorporate GIC revealed that the addition of nano-HAp interfered with the bonding ability of GIC to the substrate interface, but the mixed type of failure in nano-HAp incorporated GIC suggests that it increases the strength of the matrix. However, the role of nano-size particles on the micro-size particles of GIC for the bonding mechanism and the ratio and proportions of nano-HAp to the GIC needs further elucidation. PMID- 26096113 TI - Comparative evaluation of two different remineralizing agents on the microhardness of bleached enamel surface: Results of an in vitro study. AB - CONTEXT: Various agents are studied for their remineralization potential. AIM: To evaluate the effect of GC Tooth Mousse and Toothmin Tooth Cream on microhardness of bleached enamel. SETTINGS AND DESIGN: In vitro- study. METHODS AND MATERIAL: Twenty freshly extracted anterior teeth were cut sagittally and impregnated in cold cure acrylic resin. Specimens were kept in artificial saliva to prevent from dehydration. After measuring baseline hardness, teeth were randomly divided into two groups. Everbrite In - Office Tooth whitening kit (Dentamerica) was used to demineralize the teeth following which hardness was measured again. Teeth in group one (n=10) and group two (n=10) were treated with GC tooth mousse (Recaldent) and Toothmin tooth cream (Abbott Healthcare Pvt.Ltd) daily for seven days and microhardness of enamel surface was measured. STATISTICAL ANALYSIS USED: Mean, SD, and percentage change in the microhardness were calculated. Student's paired t-test was used to evaluate the signifi cance of change from initial, after bleaching for 5 min and after 1-week remineralization Unpaired't' test was used to compare difference between groups. RESULTS: Microhardness significantly decreased in both groups after bleaching (% change group one: 3.24% group two: 3.26% in group; P<0.01 in both groups). Both products significantly increased mineralization after seven days of treatment (P<0.01). Remineralization was numerically better in Toothmin group (Abbott Healthcare Pvt.Ltd ) compared to GC Mousse(Recaldent) (% change 3.27% vs 6.34%). However, difference was not significant (P >0.05). CONCLUSION: Both GC Tooth Mousse (Recaldent) and Toothmin Tooth cream (Abbott Healthcare Pvt.Ltd) increase the microhardness of bleached enamel. Toothmin tooth cream is a better agent for increasing microhardness, although difference is not significant. PMID- 26096114 TI - "Comparative evaluation of surface modified elastomeric ligatures for microbial colonization": An in vivo study. AB - INTRODUCTION: Elastomeric ligatures are observed to reduce chair side time; however, they are also seen to have greater bacterial adhesion. Polymeric coating utilizing the Metafasix Technology and the OrthoShield Technology have been introduced in the Super SlickTM** and Safe-T-TiesTM** by TP Orthodontics, Ortho Organizers, respectively, to reduce bacterial adhesion. While each of the elastomers has been individually evaluated, no study compares the two elastomers manufactured by differing technologies together; hence the need for this study was felt. This in vivo study compared the Super Slick and Safe-T-Ties with their unmodified counterparts for bacterial adhesion. MATERIALS AND METHODS: Thirty patients undergoing orthodontic treatment, between 12 and 25 years age group were selected and the modified, and the unmodified elastomers were randomly placed quadrant wise, on all the premolar brackets. After a period of 4 weeks, the elastomeric rings were removed and transported for culture on Mitis-Salivarius, Rogosa SL agar for Streptococcus mutans and Lactobacilli, respectively. The colonies were digitally counted (HiMedia) after 48 h of incubation at 37 degrees C. RESULTS: There was a significant difference in the S. mutans and Lactobacilli counts in both surface modified and unmodified elastomeric modules (P < 0.01). Unmodified elastomeric modules Mini StixTM**, Hand-EE-LastsTM** was associated with higher mean values of colony-forming units/millimeter than the surface modified Super SlickTM** and Safe-T-TiesTM** ligatures. When compared pair-wise, the surface modified elastomers showed less bacterial accumulations than the unmodified counterparts for both S. mutans and Lactobacillus, and the differences were statistically significant. CONCLUSION: Technological modifications of the elastomers using the Metafasix or OrthoShield Technology, is a definite improvement over the regular elastomers with regard to adhesion of S. mutans and Lactobacilli. PMID- 26096115 TI - Evaluation of soft tissue marginal stability achieved after excision with a conventional technique in comparison with laser excision: A pilot study. AB - BACKGROUND: Soft tissue excision around natural teeth is carried out to increase the clinical crown lengths, expose the caries apical to the gingival margins and to correct irregular and un-esthetic soft-tissue contours. AIMS: The study was carried out with an aim to evaluate the stability of the soft tissue margins after excision either with a laser or scalpel. MATERIALS AND METHODS: A total of 20 patients indicated for soft tissue excision for correcting soft tissue discrepancies were selected. The patients with thick gingival biotype were included in the study. They were grouped randomly into excision by laser or scalpel methods. The change in the soft tissue positions from the time of excision to 1-month follow-up were evaluated immediate postoperatively, after 2 weeks and after 1-month postrestoration. RESULTS: The soft tissues remained stable in the laser group at 1-month follow-up, in contrast to the scalpel group and were found to be statistically significant, (Student's t-test) (P < 0.05). CONCLUSION: The soft tissue margins are more stable and stay at the point they were excised with lasers when compared with scalpel. PMID- 26096116 TI - Prevalence of eight putative periodontal pathogens in atherosclerotic plaque of coronary artery disease patients and comparing them with noncardiac subjects: A case-control study. AB - BACKGROUND: The study was aimed to assess the prevalence of periodontal pathogens namely Tannerella forsythia (T.f), Campylobacter rectus (C.r), Eikenella corrodens (E.c), Porphyromonas gingivalis (P.g), Treponema denticola (T.d), Prevotella nigrescens (P.n) ,Aggregatibacter actinomycetemcomitans (A.a), P.g (fi mA gene) and Prevotella intermedia (P.i), in the subgingival and the atheromatous plaque of patients with coronary artery disease (CAD), and comparing them with the noncardiac subjects thereby indicating the role of periodontal pathogenic bacteria in the progression of atherosclerosis in south Indian population. MATERIALS AND METHODS: 51 cardiac and non cardiac subjects within the age group of 40-80 years,who met the eligibility criteria, were selected and categorized as the experimental and control group respectively. Total number of teeth was recorded, and oral hygiene was evaluated using Plaque Index and Oral Hygiene Index (OHI). Periodontal pocket depth and clinical attachment level were also assessed as a part of periodontal examination. Subgingival plaque samples were collected with the help of with Gracey's curette in both the groups. In experimental group, biopsy was obtained from the atherosclerotic plaque during Coronary artery bypass grafting CABG procedure. Both, subgingival and the coronary atherosclerotic plaque samples were subjected to polymerase chain reaction (PCR) analysis for identification of the periodontal bacteria. STATISTICAL ANALYSIS: Mean, standard deviation and test of significance of quantitative variables such as periodontal parameters were compared between experimental group and control group. Kappa measures of agreement was done to analyze the relationship between the presence/absence of microorganisms in the subgingival and atherosclerotic plaque samples in the experimental group. RESULTS: The mean Plaque Index, Gingival Index, Russel's Periodontal Index, OHI, clinical attachment level, Pocket Depth Index was statistically significant in both the groups. Association of T.f, E.c, C.r, P.g, P.g (fi mA), T.d, P.i, P.n was significantly associated. A.a was absent in the control group, whereas only one patient in the experimental group was positive for the bacteria. Kappa analysis showed the significant association of periodontal bacteria T.f, C.r, P.g, P.g (fi mA), P.i and P.n in subgingival plaque and atherosclerotic plaque of the same patients of the experimental group. CONCLUSION: It is concluded that CAD subjects had higher prevalence of periodontal pathogens in subgingival biofilms as compared to the non cardiac subjects. Further, the number of bacteria was significantly associated between the subgingival and atherosclerotic plaques of the cardiac patients in south Indian population. PMID- 26096117 TI - Prevalence of habits and oral mucosal lesions in Jaipur, Rajasthan. AB - INTRODUCTION: Dental health and oral health are used almost synonymously when stating the goals of oral health; such statements are only valid for dental health. This may lead to severe underestimation of the need of total oral health care. When planning measures of oral health care, the lack of data may lead to a risk of overlooking diseases of the soft tissue in, and adjacent to, the oral cavity. Prevalence data of oral mucosal lesions are available from many countries, but the information is usually restricted to very few lesions in each survey. MATERIALS AND METHODS: The present study is an attempt to assess and compare the various deleterious habits and its associated oral mucosal lesions among patients visiting outpatient department of Jaipur Dental College, Jaipur, Rajasthan. RESULTS: It was found that the prevalence of habits was 51.4% including both the sexes and prevalence of oral mucosal lesions were 9.9%. DISCUSSION: The prevalence of habits and oral mucosal lesions is very high as compared with other studies. The habit of smoking was higher in males as compared to females. PMID- 26096118 TI - Effect of highly active antiretroviral therapy use on oral manifestations in pediatric patients infected with HIV. AB - AIMS: The aim was to assess the prevalence of oral lesions in HIV-infected children undergoing highly active anti-retroviral therapy (HAART), and the association between the duration of HAART usage and oral lesions. SUBJECTS AND METHODS: Totally, 111 medical and dental records of HIV-infected children, aged from 2 to 16 years old were reviewed for medical data, presence of oral lesions, and caries prevalence. According to the type of medication, the children were grouped as follows: 51 were under HAART (G1), 46 were using anti-retroviral medication (G2), and 14 were using no medication (G3). RESULTS: The majority of the HIV children had AIDS (65.8%), of which 86.3% were in G1, 63% in G2, and 0% in G3. The mean length of therapy was 34.4 months, with no difference between groups (Kruskal-Wallis; P = 0.917). The prevalence of the oral lesions was 23.4%, namely, G1 was 27.5%, G2 was 21.7%, and G3 was 14.3% (P > 0.05). Gingivitis was the most common oral manifestation (15.3%) seen in the three groups, followed by gingival linear erythema and pseudomembranous candidiasis in G1 and G2. The mean values regarding deft and DMFT indexes were, respectively, 3.2 and 1.9 (G1), 2.8 and 1.6 (G2), and 3.8 and 3.0 (G3). For the patients without AIDS (n = 38), oral manifestations were seen in 29.4% of G2 compared to G1, with 0% (Chi-square; P > 0.05). In terms of therapy duration, 47.65% of the patients who had been under HAART for 18 months or less had oral manifestations, compared to 13.3% of those who had been treated for a longer time (Chi-square; P = 0.007). CONCLUSIONS: Although the prevalence of oral lesions was similar between the groups, it was less in patients without AIDS and those under HAART. The duration of HAART usage had a significant influence on the prevalence of these lesions. PMID- 26096119 TI - Dental implants for severely atrophied jaws due to ectodermal dysplasia. AB - The aim was to present the successful esthetical and functional rehabilitation of partial anodontia in a case of severe ectodermal dysplasia with complete atrophy of the jaws. A 17-year-old male with Class III malocclusion with partial anodontia sought dental implant treatment. His expectation was that of Class I occlusion. The challenge in the case was to match the expectation, reality, and the clinical possibilities. Ridge augmentation was performed with a combination of rib graft and recombinant human bone morphogenetic protein-2. Simultaneously, 6 implants (Nobel BiocareTM - Tapered Groovy) were placed in maxillary arch and 10 in the mandible. Simultaneous placement ensured faster and better osseointegration though a mild compromise of the primary stability was observed initially. After adequate healing, Customized Zirconia ProceraTM system was used to build the framework. Zirconia crown was cemented to the framework. Radiological and clinical evidence of osseointegration was observed in all 16 dental implants. Successful conversion of Class III to Class I occlusion was achieved with the combination of preprosthetic alveolar ridge augmentation, ProceraTM Implant Bridge system. Abnormal angulations and or placement of dental implants would result in failure of the implant. Hence conversion of Class III to Class I occlusion needs complete and complex treatment planning so that the entire masticatory apparatus is sufficiently remodeled. Planning should consider the resultant vectors that would otherwise result in failure of framework or compromise the secondary stability of the dental implant during function. A successful case of rehabilitation of complex partial anodontia is presented. PMID- 26096120 TI - Non-syndromic bilateral condylar aplasia: A rare case. AB - The temporomandibular joint is one of the most complex joints of the human body. It consists of the mandibular condyle, glenoid fossa and the articular eminence of the temporal bone. Aplasia of the condyle is usually seen as part of a syndrome otherwise it is rare. We report a case of bilateral condylar aplasia in a 20-year-old male not associated with any syndrome. The patient reported to the department with a chief complaint of the underdeveloped lower jaw. Clinical examination, conventional radiographs, and 3D computer tomography images revealed a complete absence of condyle on the right and left sides. PMID- 26096121 TI - Dental complications of herpes zoster: Two case reports and review of literature. AB - Herpes zoster (HZ) (shingles) results due to reactivation of varicella-zoster virus. Unusual dental complications like osteonecrosis, exfoliation of teeth, periodontitis, and calcified and devitalized pulps, periapical lesions, and resorption of roots as well as developmental anomalies such as irregular short roots and missing teeth may arise secondary to involvement of 2nd or 3rd division of trigeminal nerve by HZ. Such cases pose both a diagnostic as well as a therapeutic challenge. We report two such rare dental complications of HZ spontaneous tooth exfoliation and osteonecrosis of the maxilla in a 70-year-old female patient; and multiple periapical pathoses affecting right half of the mandibular teeth in a 45-year-old female patient. Both the patients did not have any associated systemic illness. The aim of this paper was to compare the present cases with all the 46 cases of osteonecrosis and 6 cases of multiple periapical pathoses secondary to trigeminal zoster reported in literature till date The article also throws light that the occurrence of such dental complications of HZ is not entirely dependent on the immune status of the host. PMID- 26096122 TI - A simple ear splint for microtia patients. AB - Microtia is a congenital anomaly of the ear can occur as an isolated birth defect or as part of a spectrum of anomalies or as a syndrome. Microtia is often associated with impaired hearing and or total loss of hearing. Such patients typically require treatment for surgical ear reconstruction and for hearing impairment. Maintenance of ear projection and post auricular sulcus in staged ear reconstruction in microtia is a trying problem. So also is the maintenance of the patency of the external auditory meatus following recanalization and meatoplasty.This case report describes a simple effective way of fabrication of ear splint prosthesis. PMID- 26096123 TI - Aesthetic and Functional Outcomes of Neovaginoplasty Using Penile Skin in Male-to Female Transsexuals. AB - INTRODUCTION: In the treatment of transgender women, the surgical construction of a neo-vagina, or vaginoplasty, is the final stage in the transition to the desired gender. Surgeons aim to create a neovagina that is in function and appearance as close to a biological vagina as possible. However, to date, it is insufficiently clear whether transgender women are satisfied with the functional and cosmetic outcomes of vaginoplasty. AIMS: Our aim was to assess if penile skin inversion neovaginoplasty performed in transgender women meet the objectives strived for, by determining functional and aesthetic outcomes, as well as the physical and sexual well-being and satisfaction. METHODS: We performed a retrospective survey study on 49 transgender women who underwent vaginoplasty using the penile skin inversion technique. Participants were asked to fill out the Female Sexual Function Index (FSFI), a combination of the Amsterdam Hyperactive Pelvic Floor Scale--Women (AHPFS-W) and the Female Genital Self Imaging Scale, and a short questionnaire for self-evaluation of vaginoplasty. Photographs of the genitalia were taken for objective assessment by an independent panel. MAIN OUTCOME MEASURES: Primary outcomes were the functional and aesthetic evaluation as perceived by the trangender women themselves. Secondary outcomes were the aesthetic evaluation of the vaginoplasty by an independent panel. RESULTS: Functionality and appearance were both given an average score of 8 out of 10. Despite this high score, 56% is sexually dysfunctional according to the FSFI, mainly because of not being sexually active, or due to problems with lubrication and discomfort. In 75%, the result met the expectation and 70% thinks their genital is feminine enough. CONCLUSION: This study demonstrates that, despite relatively low FSFI scores, this group of transgender women is very satisfied with both the functional and aesthetic results of neovaginoplasty using penile skin inversion. PMID- 26096124 TI - Antimicrobial peptide shows enhanced activity and reduced toxicity upon grafting to chitosan polymers. AB - Here we report that grafting of a short antimicrobial peptide, anoplin, to chitosan polymers is a strategy for abolishing the hemolytic propensity, and at the same time increasing the activity of the parent peptide. Anoplin-chitosan conjugates were synthesized by CuAAC reaction of multiple peptides through 2 azidoacetyl groups on chitosan. PMID- 26096125 TI - Three-Dimensional Cardiac Mapping Characterizes Ventricular Contractile Patterns during Cardiac Resynchronization Therapy Implant: A Feasibility Study. AB - BACKGROUND: Electroanatomic mapping systems track the position of electrodes in the heart. We assessed the feasibility of characterizing left ventricular (LV) performance during cardiac resynchronization therapy (CRT) implant utilizing an electroanatomic mapping system to track the motion of CRT lead electrodes, thus deriving ventricular contractility surrogates. METHODS: During CRT implant, atrial, right ventricular (RV), and LV leads were connected to the EnSite NavXTM mapping system (St. Jude Medical Inc., St. Paul, MN, USA). The relative displacement of electrodes was averaged over 10 cardiac cycles during RV, LV, and biventricular (BiV) pacing in DOO mode. Three contractility surrogates indicative of ventricular performance were extracted from the RV-LV distance waveform: systolic slope (SS), time to peak systolic contraction (TPSC), and fractional shortening (FS). RESULTS: In the 20 patients included, there were detectable differences in each of the three contractility surrogates responding to the different pacing configurations. Median SS varied 42%, median TPSC varied 35%, and median FS varied 19% across RV, LV, and BiV pacing interventions. The RV-LV distance waveform showed subtle sensitivity to varying pacing timing cycles when measured in a subset of patients. For all pacing configurations, RV-LV distance waveforms were stable during 2-minute recordings. CONCLUSIONS: Tracking the motion of CRT pacing electrodes with a mapping system to derive contractility surrogates during implant is feasible. PMID- 26096126 TI - A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats. AB - Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. Here, we tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R following intracisternal (i.c.) WIN55,212-2 (15MUg/rat) in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response because (i) selective blockade of central CB1R (AM251, 30MUg/rat; i.c.) abrogated WIN55,212-2-evoked increases in RVLM orexin-A level, (ii) the selective OX1R antagonist SB-408124 (10nmol/rat; i.c.) attenuated orexin-A (3nmol/rat; i.c.) or WIN55,212-2 (15MUg/rat; i.c.)-evoked pressor response while selective CB1R blockade (AM251) had no effect on orexin-A (3nmol/rat; i.c.)-evoked pressor response, (iii) direct CB1R activation in the RVLM (WIN55,212-2; 0.1MUg/rat) increased RVLM orexin-A and BP. Finally, SB-408124 attenuated WIN55,212-2-evoked increases in RVLM nNOS and ERK1/2 phosphorylation and BP. Our findings suggest that orexin-A/OX1R dependent activation of the RVLM nNOS/ERK1/2 cascade is essential neurochemical mechanism for the central CB1R-mediated pressor response in conscious rats. PMID- 26096128 TI - Anxiety Assessment: Psychometric Properties of the Spanish Version of the Burns Anxiety Inventory. AB - The main purpose of this study was to analyze the psychometric properties of the Spanish version of the Burns Anxiety Inventory (Burns-A: Burns, 1993). The sample consisted of 417 participants, 387 (29.71% male) healthy participants (control group: M = 35.5 years; SD = 8.40) and 30 (36.66% female) patients (clinical group: M = 35.8 years; SD = 12.94). The internal consistency evaluated through Cronbach' Alpha was 0.95 for the Total Score in both subsamples. The test-retest reliability (two weeks) for Total Score was 0.86 (F = 13.2, p <= .001) for the non-clinical subsample, and 0.95 (F = 36.5, p <= .001) for the clinical subsample. Confirmatory factor analyses supported the initial three-factor model. However, modifications to the initial three-factor model improved the goodness-of fit indices. Results showed statistically significant differences in the mean scores of the Burns-A between the clinical and control groups. This study supports the Spanish version of the Burns-A as a brief and useful tool for the screening of anxiety symptoms in adult populations. Future studies should investigate measurement invariance across cultures. PMID- 26096127 TI - Two key temporally distinguishable molecular and cellular components of white adipose tissue browning during cold acclimation. AB - KEY POINTS: White to brown adipose tissue conversion and thermogenesis can be ignited by different conditions or agents and its sustainability over the long term is still unclear. Browning of rat retroperitoneal white adipose tissue (rpWAT) during cold acclimation involves two temporally apparent components: (1) a predominant non-selective browning of most adipocytes and an initial sharp but transient induction of uncoupling protein 1, peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha, PPARgamma and PPARalpha expression, and (2) the subsistence of relatively few thermogenically competent adipocytes after 45 days of cold acclimation. The different behaviours of two rpWAT beige/brown adipocyte subsets control temporal aspects of the browning process, and thus regulation of both components may influence body weight and the potential successfulness of anti-obesity therapies. ABSTRACT: Conversion of white into brown adipose tissue may have important implications in obesity resistance and treatment. Several browning agents or conditions ignite thermogenesis in white adipose tissue (WAT). To reveal the capacity of WAT to function in a brownish/burning mode over the long term, we investigated the progression of the rat retroperitoneal WAT (rpWAT) browning during 45 days of cold acclimation. During the early stages of cold acclimation, the majority of rpWAT adipocytes underwent multilocularization and thermogenic-profile induction, as demonstrated by the presence of a multitude of uncoupling protein 1 (UCP1)-immunopositive paucilocular adipocytes containing peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha (PGC-1alpha) and PR domain-containing 16 (PRDM16) in their nuclei. After 45 days, all adipocytes remained PRDM16 immunopositive, but only a few multilocular adipocytes rich in mitochondria remained UCP1/PGC-1alpha immunopositive. Molecular evidence showed that thermogenic recruitment of rpWAT occurred following cold exposure, but returned to starting levels after cold acclimation. Compared with controls (22 +/- 1 degrees C), levels of UCP1 mRNA increased in parallel with PPARgamma (PPARalpha from days 1 to 7 and PGC-1alpha on day 1). Transcriptional recruitment of rpWAT was followed by an increase in UCP1 protein content (from days 1 to 21). Results clearly showed that most of the adipocytes within rpWAT underwent transient brown-fat-like thermogenic recruitment upon stimulation, but only a minority of cells retained a brown adipose tissue-like phenotype after the attainment of cold acclimation. Therefore, browning of WAT is dependent on both maintaining the thermogenic response and retaining enough brown-like thermogenically competent adipocytes in the long-term. Both aspects of browning could be important for long-term energy homeostasis and body-weight regulation. PMID- 26096129 TI - Reply: To PMID 25787697. PMID- 26096130 TI - A systematic review of the mismatch negativity as an index for auditory sensory memory: From basic research to clinical and developmental perspectives. AB - Auditory sensory memory is an important ability for successful language acquisition and processing. The mismatch negativity (MMN) in response to auditory stimuli has been proposed as an objective tool to measure the existence of auditory sensory memory traces. By increasing interstimulus intervals, attenuation of MMN peak amplitude and increased MMN peak latency have been suggested to reflect duration and decay of sensory memory traces. The aim of the present study is to conduct a systematic review of studies investigating sensory memory duration with MMN. Searches of electronic databases yielded 743 articles. Of these, 37 studies met final eligibility criteria. Results point to maturational changes in the time span of auditory sensory memory from birth on with a peak in young adulthood, as well as to a decrease of sensory memory duration in healthy aging. Furthermore, this review suggests that sensory memory decline is related to diverse neurological, psychiatric, and pediatric diseases, including Alzheimer's disease, alcohol abuse, schizophrenia, and language disorders. This review underlines that the MMN provides a unique window to the cognitive processes of auditory sensory memory. However, further studies combining electrophysiological and behavioral data, and further studies in clinical populations are needed, also on individual levels, to validate the MMN as a clinical tool for the assessment of sensory memory duration. PMID- 26096131 TI - Maximum A Posteriori Bayesian Estimation of Chromatographic Parameters by Limited Number of Experiments. AB - The aim of this work was to develop a nonlinear mixed-effect chromatographic model able to describe the retention times of weak acids and bases in all possible combinations of organic modifier content and mobile-phase pH. Further, we aimed to identify the influence of basic covariates, like lipophilicity (log P), dissociation constant (pK(a)), and polar surface area (PSA), on the intercompound variability of chromatographic parameters. Lastly, we aimed to propose the optimal limited experimental design to the estimation process of parameters through a maximum a posteriori (MAP) Bayesian method to facilitate the method development process. The data set comprised retention times for two series of organic modifier content collected at different pH for a large series of acids and bases. The obtained typical parameters and their distribution were subsequently used as priors to improve the estimation process from reduced design with a variable number of preliminary experiments. The MAP Bayesian estimator was validated using two external-validation data sets. The common literature model was used to relate analyte retention time with mobile-phase pH and organic modifier content. A set of QSRR-based covariate relationships was established. It turned out that four preliminary experiments and prior information that includes analyte pK(a), log P, acid/base type, and PSA are sufficient to accurately predict analyte retention in virtually all combined changes of pH and organic modifier content. The MAP Bayesian estimator of all important chromatographic parameters controlling retention in pH/organic modifier gradient was developed. It can be used to improve parameter estimation using limited experimental design. PMID- 26096132 TI - Heats of formation of platonic hydrocarbon cages by means of high-level thermochemical procedures. AB - Hydrocarbon cages are key reference materials for the validation and parameterization of computationally cost-effective procedures such as density functional theory (DFT), semiempirical molecular orbital theory, and molecular mechanics. We obtain accurate total atomization energies (TAEs) and heats of formation (Deltaf H degrees 298) for platonic and prismatic hydrocarbon cages by means of the Wn-F12 explicitly correlated thermochemical protocols. We consider the following kinetically stable (CH)n polycyclic hydrocarbon cages: (i) platonic hydrocarbons (tetrahedrane, cubane, and dodecahedrane), (ii) prismatic hydrocarbons (triprismane, cubane, and pentaprismane), and (iii) one truncated tetrahedrane (octahedrane). Our best theoretical heat of formation for cubane (144.8 kcal mol(-1)) suggests that the experimental value adopted by the NIST thermochemical database (142.7 +/- 1.2 kcal mol(-1)) should be revised upwards by ~2 kcal mol(-1). Our best heat of formation for dodecahedrane (20.2 kcal mol(-1)) suggests that the semiexperimental value (22.4 +/- 1 kcal mol(-1)) should be revised downward by ~2 kcal mol(-1). We use our benchmark Wn-F12 TAEs to evaluate the performance of a variety of computationally less demanding composite thermochemical procedures. These include the Gaussian-n (Gn) and the complete basis set (CBS) methods. The CBS-QB3 and CBS-APNO procedures show relatively poor performance with root-mean-squared deviations (RMSDs) of 4.2 and 2.5 kcal mol( 1), respectively. The best performers of the Gn procedures are G4 and G3(MP2)B3 (RMSD = 0.5 and 0.6 kcal mol(-1), respectively), while the worst performers are G3 and G4(MP2)-6X (RMSD = 2.1 and 2.9 kcal mol(-1), respectively). Isodesmic and even homodesmotic reactions involving these species are surprisingly challenging targets for DFT computations. PMID- 26096133 TI - Editorial overview: Systems biology: Advances diseases understanding and metabolic engineering. PMID- 26096134 TI - Agglomerative joint clustering of metabolic data with spike at zero: A Bayesian perspective. AB - In many biological applications, for example high-dimensional metabolic data, the measurements consist of several continuous measurements of subjects or tissues over multiple attributes or metabolites. Measurement values are put in a matrix with subjects in rows and attributes in columns. The analysis of such data requires grouping subjects and attributes to provide a primitive guide toward data modeling. A common approach is to group subjects and attributes separately, and construct a two-dimensional dendrogram tree, once on rows and then on columns. This simple approach provides a grouping visualization through two separate trees, which is difficult to interpret jointly. When a joint grouping of rows and columns is of interest, it is more natural to partition the data matrix directly. Our suggestion is to build a dendrogram on the matrix directly, thus generalizing the two-dimensional dendrogram tree to a three-dimensional forest. The contribution of this research to the statistical analysis of metabolic data is threefold. First, a novel spike-and-slab model in various hierarchies is proposed to identify discriminant rows and columns. Second, an agglomerative approach is suggested to organize joint clusters. Third, a new visualization tool is invented to demonstrate the collection of joint clusters. The new method is motivated over gas chromatography mass spectrometry (GCMS) metabolic data, but can be applied to other continuous measurements with spike at zero property. PMID- 26096135 TI - Voice Rehabilitation After Transoral Laser Microsurgery of the Larynx. AB - Voice rehabilitation after transoral laser microsurgery to the larynx is challenging. We wait at least 6 months before surgical intervention. Only a few patients after total or extended cordectomy requested voice restoration. Subjective perception of voice using the Voice Handicap Index in medialization thyroplasty was significantly better. Medialization thyroplasty with elevation of the fibrous tissue from the inner surface of the thyroid cartilage is critical in achieving success. We preferred the Montgomery Thyroplasty Implant System. Transoral larynx anterior commissure stent placement after laser-assisted sectioning of anterior synechiae with application of mitomycin C is an effective procedure for anterior synechiae. PMID- 26096136 TI - Evaluation of the Dysphonic Patient (in: Function Preservation in Laryngeal Cancer). AB - The evaluation of the dysphonic patient begins with a complete understanding of the laryngeal anatomy and physiology of voice production. A thorough history must be taken regarding the dysphonia qualities, alarming symptoms, and confounding factors. The complete head and neck examination culminates in a detailed visualization of the vocal folds using image-capturing laryngoscopy as well as stroboscopy or high-speed digital imaging to fully evaluate the viscoelastic properties of the vocal fold cover-body structure and function. Finally, the evaluation leads to the biopsy of any concerning lesions either under magnification in the operating room or topical anesthesia in the office. PMID- 26096137 TI - Voice Outcomes of Transoral Laser Microsurgery of the Larynx. AB - Transoral laser microsurgery (TLM) is the mainstay in the treatment of early (TisT1T2) glottic cancer. Current knowledge concerning voice quality and voice related quality of life in patients treated using TLM is based on small cohort studies using various instruments to evaluate these functional results. The bulk of the literature indicates that subjective and objective measurements of voice quality can return to normal or almost normal values after TLM, generally after 6 to 12 months and particularly after cordectomy types I, II, and III. PMID- 26096138 TI - Role of Advanced Laryngeal Imaging in Glottic Cancer: Early Detection and Evaluation of Glottic Neoplasms. AB - Laryngeal cancer accounts for approximately 2.4% of new malignancies worldwide each year. Early identification of laryngeal neoplasms results in improved prognosis and functional outcomes. Imaging plays an integral role in the diagnosis, staging, and long-term follow-up of laryngeal cancer. This article highlights advanced laryngeal imaging techniques and their application to early glottic neoplasms. PMID- 26096139 TI - Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer. AB - Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ~5- and ~10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng . h/mL vs 421 [67] ng . h/mL, respectively). In mCRPC patients, abiraterone AUC was ~2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng . h/mL and 1264 [65] vs 1185 [90] ng . h/mL, respectively). Adverse events (all grade <= 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety. PMID- 26096140 TI - A Longitudinal Assessment of Structural and Chemical Alterations in Mixed Martial Arts Fighters. AB - Growing evidence suggests that temporally proximal acute concussions and repetitive subconcussive head injuries may lead to long-term neurological deficits. However, the underlying mechanisms of injury and their relative time scales are not well documented in human injury models. The current study therefore investigated whether biomarkers of brain chemistry (magnetic resonance [MR] spectroscopy: N-acetylaspartate [NAA], combined glutamate and glutamine [Glx], total creatine [Cre], choline compounds [Cho], and myo-inositol [mI]) and structure (cortical thickness, white matter [WM]/subcortical volume) differed between mixed martial artists (MMA; n = 13) and matched healthy controls (HC) without a history of contact sport participation (HC; n = 14). A subset of participants (MMA = 9; HC = 10) returned for follow-up visits, with MMA (n = 3) with clinician-documented acute concussions also scanned serially. As expected, MMA self-reported a higher incidence of previous concussions and significantly more cognitive symptoms during prior concussion recovery. Fighters also exhibited reduced memory and processing speed relative to controls on neuropsychological testing coupled with cortical thinning in the left posterior cingulate gyrus and right occipital cortex at baseline assessment. Over a 1-year follow-up period, MMA experienced a significant decrease in both WM volume and NAA concentration, as well as relative thinning in the left middle and superior frontal gyri. These longitudinal changes did not correlate with self-reported metrics of injury (i.e., fight diary). In contrast, HC did not exhibit significant longitudinal changes over a 4-month follow-up period (p > 0.05). Collectively, current results provide preliminary evidence of progressive changes in brain chemistry and structure over a relatively short time period in individuals with high exposure to repetitive head hits. These findings require replication in independent samples. PMID- 26096141 TI - An alternative approach to PEPPSI catalysts: from palladium isonitriles to highly active unsymmetrically substituted PEPPSI catalysts. AB - A series of new pyridine-enhanced precatalyst preparation, stabilization, and initiation (PEPPSI)-type complexes bearing different types of carbene ligands was prepared by the modular and convergent template synthesis strategy. Nitrogen acyclic carbenes, saturated and unsaturated five-membered NHC, saturated six membered NHCs, and five-membered N-heterocyclic oxo-carbene (NHOC) ligands on palladium were prepared this way. These new organometallic compounds then were tested in Suzuki and Negishi cross-coupling reactions by using substrates with one or two substituents in ortho-position of the new C?C bond being formed. Both aryl chlorides and bromides were tested as coupling partners. In some cases, the new ligands gave results similar to Organ's successful IPr-based and IPent-based PEPPSI derivatives, with aryl bromides 0.05 mol % catalyst load still gave satisfactory results, with aryl chlorides 0.5 mol % were needed. PMID- 26096142 TI - Hand-sewn coloanal anastomosis for low rectal cancer: technique and long-term outcome. AB - AIM: This study compared the operative outcome and long-term survival of three types of hand-sewn coloanal anastomosis (CAA) for low rectal cancer. METHOD: Patients presenting with low rectal cancer at a single centre between 2006 and 2014 were classified into three types of hand-sewn CAA: type 1 (supra-anal tumours undergoing transabdominal division of the rectum with transanal mucosectomy); type 2 (juxta-anal tumours, undergoing partial intersphincteric resection); and type 3 (intra-anal tumours, undergoing near-total intersphincteric resection with transanal mesorectal excision). RESULTS: Seventy one patients with low rectal cancer underwent CAA: 17 type 1; 39 type 2; and 15 type 3. The median age of patients was 61.6 years, with a male/female ratio of 2:1. Neoadjuvant therapy was given to 56 (79%) patients. R0 resection was achieved in 69 (97.2%) patients. Adverse events occurred in 25 (35.2%) of the 71 patients with a higher complication rate in type 1 vs type 2 vs type 3 (47.1% vs 38.5% vs 13.3%, respectively; P = 0.035). Anastomotic separation was identified in six (8.5%) patients and pelvic haematoma/seroma in five (7%); two (8.3%) female patients developed a recto-vaginal fistula. Ten (14.1%) patients were indefinitely diverted, with a trend towards higher long-term anastomotic failure in type 1 vs type 2 vs type 3 (17.6% vs 15.5% vs 6.7%). The type of anastomosis did not influence the overall or disease-free survival. CONCLUSION: CAA is a safe technique in which anorectal continuity can be preserved either as a primary restorative option in elective cases of low rectal cancer or as a salvage procedure following a failed stapled anastomosis with a less successful outcome in the latter. CAA has acceptable morbidity with good long-term survival in carefully selected patients. PMID- 26096143 TI - Arabidopsis ACT11 modifies actin turnover to promote pollen germination and maintain the normal rate of tube growth. AB - Actin is an ancient conserved protein that is encoded by multiple isovariants in multicellular organisms. There are eight functional actin genes in the Arabidopsis genome, and the precise function and mechanism of action of each isovariant remain poorly understood. Here, we report the characterization of ACT11, a reproductive actin isovariant. Our studies reveal that loss of function of ACT11 causes a delay in pollen germination, but enhances pollen tube growth. Cytological analysis revealed that the amount of filamentous actin decreased, and the rate of actin turnover increased in act11 pollen. Convergence of actin filaments upon the germination aperture was impaired in act11 pollen, consistent with the observed delay of germination. Reduction of actin dynamics with jasplakinolide suppressed the germination and tube growth phenotypes in act11 pollen, suggesting that the underlying mechanisms involve an increase in actin dynamics. Thus, we demonstrate that ACT11 is required to maintain the rate of actin turnover in order to promote pollen germination and maintain the normal rate of pollen tube growth. PMID- 26096144 TI - Confirming, Validating, and Norming the Factor Structure of Systemic Therapy Inventory of Change Initial and Intersession. AB - Progress or feedback research tracks and feeds back client progress data throughout the course of psychotherapy. In the effort to empirically ground psychotherapeutic practice, feedback research is both a complement and alternative to empirically supported manualized treatments. Evidence suggests that tracking and feeding back progress data with individual or nonsystemic feedback systems improves outcomes in individual and couple therapy. The research reported in this article pertains to the STIC((r)) (Systemic Therapy Inventory of Change)-the first client-report feedback system designed to empirically assess and track change within client systems from multisystemic and multidimensional perspectives in individual, couple, and family therapy. Clients complete the STIC Initial before the first session and the shorter STIC Intersession before every subsequent session. This study tested and its results supported the hypothesized factor structure of the six scales that comprise both STIC forms in a clinical outpatient sample and in a normal, random representative sample of the U.S. POPULATION: This study also tested the STIC's concurrent validity and found that its 6 scales and 40 of its 41 subscales differentiated the clinical and normal samples. Lastly, the study derived clinical cut-offs for each scale and subscale to determine whether and how much a client's score falls in the normal or clinical range. Beyond supporting the factorial and concurrent validity of both STIC forms, this research supported the reliabilities of the six scales (Omegahierarchical ) as well as the reliabilities of most subscales (alpha and rate-rerate). This article delineates clinical implications and directions for future research. PMID- 26096145 TI - Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. AB - The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a recently identified hereditary cancer syndrome. Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies. The molecular functions of the gene as well as the clinical phenotype of the syndrome are still being clarified. We sought to conduct a comprehensive review of published research into BAP1-TPDS to more thoroughly delineate the clinical implications of germline BAP1 mutations. We also report two additional families with germline BAP1 mutations. Current evidence demonstrates that germline BAP1 mutations predispose families to uveal melanoma, renal cell carcinoma, malignant mesothelioma, cutaneous melanoma, and possibly to a range of other cancers as well. Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations as compared to non-predisposed patients with equivalent cancers. Although further research is necessary, this information can aid in the management, diagnosis, and therapy of these patients and their families, and highlights the importance of genetic counseling. PMID- 26096146 TI - Human Keratoconus Cell Contractility is Mediated by Transforming Growth Factor Beta Isoforms. AB - Keratoconus (KC) is a progressive disease linked to defects in the structural components of the corneal stroma. The extracellular matrix (ECM) is secreted and assembled by corneal keratocytes and regulated by transforming growth factor-beta (TGF-beta). We have previously identified alterations in the TGF-beta pathway in human keratoconus cells (HKCs) compared to normal corneal fibroblasts (HCFs). In our current study, we seeded HKCs and HCFs in 3D-collagen gels to identify variations in contractility, and expression of matrix metalloproteases (MMPs) by HKCs in response the TGF-beta isoforms. HKCs showed delayed contractility with decreased Collagen I:Collagen V ratios. TGF-beta1 significantly increased ECM contraction, Collagen I, and Collagen V expression by HKCs. We also found that HKCs have significantly decreased Collagen I:Collagen III ratios suggesting a potential link to altered collagen isoform expression in KC. Our findings show that HKCs have significant variations in collagen secretion in a 3D collagen gel and have delayed contraction of the matrix compared to HCFs. For the first time, we utilize a collagen gel model to characterize the contractility and MMP expression by HKCs that may contribute to the pathobiology of KC. PMID- 26096147 TI - Controlled Delivery of Human Cells by Temperature Responsive Microcapsules. AB - Cell therapy is one of the most promising areas within regenerative medicine. However, its full potential is limited by the rapid loss of introduced therapeutic cells before their full effects can be exploited, due in part to anoikis, and in part to the adverse environments often found within the pathologic tissues that the cells have been grafted into. Encapsulation of individual cells has been proposed as a means of increasing cell viability. In this study, we developed a facile, high throughput method for creating temperature responsive microcapsules comprising agarose, gelatin and fibrinogen for delivery and subsequent controlled release of cells. We verified the hypothesis that composite capsules combining agarose and gelatin, which possess different phase transition temperatures from solid to liquid, facilitated the destabilization of the capsules for cell release. Cell encapsulation and controlled release was demonstrated using human fibroblasts as model cells, as well as a therapeutically relevant cell line-human umbilical vein endothelial cells (HUVECs). While such temperature responsive cell microcapsules promise effective, controlled release of potential therapeutic cells at physiological temperatures, further work will be needed to augment the composition of the microcapsules and optimize the numbers of cells per capsule prior to clinical evaluation. PMID- 26096150 TI - Metal-Organic Frameworks (MOFs) as Multivalent Materials: Size Control and Surface Functionalization by Monovalent Capping Ligands. AB - Control over particle size and composition are pivotal to tune the properties of metal organic frameworks (MOFs), for example, for biomedical applications. Particle-size control and functionalization of MIL-88A were achieved by using stoichiometric replacement of a small fraction of the divalent fumarate by monovalent capping ligands. A fluorine-capping ligand was used to quantify the surface coverage of capping ligand at the surface of MIL-88A. Size control at the nanoscale was achieved by using a monovalent carboxylic acid-functionalized poly(ethylene glycol) (PEG-COOH) ligand at different concentrations. Finally, a biotin-carboxylic acid capping ligand was used to functionalize MIL-88A to bind fluorescently labeled streptavidin as an example towards bioapplications. PMID- 26096149 TI - Reducing progression of experimental lupus nephritis via inhibition of the B7/CD28 signaling pathway. AB - The aim of the present study was to evaluate the effects of the B7/cluster of differentiation (CD)28 signaling pathway on experimental lupus nephritis and examine the molecular mechanism involved by inhibiting the B7/CD28 signaling pathway. A lupus nephritis model in C57BL/6 J mice was induced via intraperitoneal injection of pristane. A recombinant B7-1 short hairpin RNA (shRNA) lentivirus vector was constructed by synthesis and splicing. A neutralizing mouse anti-human B7-1 antibody termed 4E5 was also prepared. The mouse model of lupus nephritis was treated with B7-1 shRNA and 4E5 via injection through the tail vein. The silencing effects of B7-1 shRNA lentiviral infection on target molecules were evaluated using immunofluorescence and flow cytometry. The levels of protein in the urine were detected using Albustix test paper each month over 10 months. The concentration of interleukin (IL)-4 and interferon gamma in the serum was determined using an ELISA. The immune complex (IC) deposits in the kidney were analyzed using direct immunofluorescence. The results demonstrated that the C57BL/6 J mouse lupus nephritis model was successfully constructed with immune cells activated in the spleen of the mice, increases in the concentration of anti-nuclear antibody (ANA) and anti-double stranded DNA antibodies as well as positive IC formation. Following B7-1 shRNA lentivirus or 4E5 treatment, CD11b+B7-1+, CD11c+B7-1+ and CD21+B7-1+ cells in the spleen of the mice were significantly reduced. The concentration of ANA and IL-4 in the serum was also decreased. The concentration of urine protein was reduced and it was at its lowest level in the 4E5 early intervention group. It was also revealed that the immunofluorescence intensity of the IC deposits was weak in the 4E5 early intervention group. In conclusion, inhibiting the B7-1/CD28 signaling pathway is able to alleviate experimental lupus nephritis and provides an experimental basis for the therapeutic use of blocking the B7-1/CD28 signaling pathway in human lupus nephritis and other autoimmune disorders. PMID- 26096148 TI - Cell Surface and Membrane Engineering: Emerging Technologies and Applications. AB - Membranes constitute the interface between the basic unit of life-a single cell and the outside environment and thus in many ways comprise the ultimate "functional biomaterial". To perform the many and often conflicting functions required in this role, for example to partition intracellular contents from the outside environment while maintaining rapid intake of nutrients and efflux of waste products, biological membranes have evolved tremendous complexity and versatility. This article describes how membranes, mainly in the context of living cells, are increasingly being manipulated for practical purposes with drug discovery, biofuels, and biosensors providing specific, illustrative examples. Attention is also given to biology-inspired, but completely synthetic, membrane based technologies that are being enabled by emerging methods such as bio-3D printers. The diverse set of applications covered in this article are intended to illustrate how these versatile technologies-as they rapidly mature-hold tremendous promise to benefit human health in numerous ways ranging from the development of new medicines to sensitive and cost-effective environmental monitoring for pathogens and pollutants to replacing hydrocarbon-based fossil fuels. PMID- 26096151 TI - Generation of iPSC line HEL47.2 from healthy human adult fibroblasts. AB - Human iPSC line HEL47.2 was generated from healthy 83-year old male dermal fibroblasts using non-integrative reprogramming method. Reprogramming factors Oct3/4, Sox2, Klf4, and cMyc were delivered using Sendai viruses. PMID- 26096152 TI - Combined negative effect of donor age and time in culture on the reprogramming efficiency into induced pluripotent stem cells. AB - Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSC) by the forced expression of the transcription factors OCT4, SOX2, KLF4 and c-MYC. Pluripotent reprogramming appears as a slow and inefficient process because of genetic and epigenetic barriers of somatic cells. In this report, we have extended previous observations concerning donor age and passage number of human fibroblasts as critical determinants of the efficiency of iPSC induction. Human fibroblasts from 11 different donors of variable age were reprogrammed by ectopic expression of reprogramming factors. Although all fibroblasts gave rise to iPSC colonies, the reprogramming efficiency correlated negatively and declined rapidly with increasing donor age. In addition, the late passage fibroblasts gave less reprogrammed colonies than the early passage cell counterparts, a finding associated with the cellular senescence-induced upregulation of p21. Knockdown of p21 restored iPSC generation even in long-term passaged fibroblasts of an old donor, highlighting the central role of the p53/p21 pathway in cellular senescence induced by both donor age and culture time. PMID- 26096153 TI - [Pain and fear in the ICU]. AB - Pain and fear are still the most common memories that refer patients after ICU admission. Recently an important politician named the UCI as the branch of the hell. It is necessary to carry out profound changes in terms of direct relationships with patients and their relatives, as well as changes in environmental design and work and visit organization, to banish the vision that our society about the UCI. In a step which advocates for early mobilization of critical patients is necessary to improve analgesia and sedation strategies. The ICU is the best place for administering and monitoring analgesic drugs. The correct analgesia should not be a pending matter of the intensivist but a mandatory course. PMID- 26096155 TI - Prenatal exposure to inflammatory conditions increases Cx43 and Panx1 unopposed channel opening and activation of astrocytes in the offspring effect on neuronal survival. AB - Several epidemiological studies indicate that children born from mothers exposed to infections during gestation, have an increased risk to develop neurological disorders, including schizophrenia, autism and cerebral palsy. Given that it is unknown if astrocytes and their crosstalk with neurons participate in the above mentioned brain pathologies, the aim of this work was to address if astroglial paracrine signaling mediated by Cx43 and Panx1 unopposed channels could be affected in the offspring of LPS-exposed dams during pregnancy. Ethidium uptake experiments showed that prenatal LPS-exposure increases the activity of astroglial Cx43 and Panx1 unopposed channels in the offspring. Induction of unopposed channel opening by prenatal LPS exposure depended on intracellular Ca2+ levels, cytokine production and activation of p38 MAP kinase/iNOS pathway. Biochemical assays and Fura-2AM/DAF-FM time-lapse fluorescence images revealed that astrocytes from the offspring of LPS-exposed dams displayed increased spontaneous Ca2+ dynamics and NO production, whereas iNOS levels and release of IL-1beta/TNF-alpha were also increased. Interestingly, we found that prenatal LPS exposure enhanced the release of ATP through astroglial Cx43 and Panx1 unopposed channels in the offspring, resulting in an increased neuronal death mediated by the activation of neuronal P2X7 receptors and Panx1 channels. Altogether, this evidence suggests that astroglial Cx43 and Panx1 unopposed channel opening induced by prenatal LPS exposure depended on the inflammatory activation profile and the activation pattern of astrocytes. The understanding of the mechanism underlying astrocyte-neuron crosstalk could contribute to the development of new strategies to ameliorate the brain abnormalities induced in the offspring by prenatal inflammation. GLIA 2015;63:2058-2072. PMID- 26096156 TI - Estimating Time Since Death from Postmortem Human Gut Microbial Communities. AB - Postmortem succession of human-associated microbial communities ("human microbiome") has been suggested as a possible method for estimating postmortem interval (PMI) for forensic analyses. Here we evaluate human gut bacterial populations to determine quantifiable, time-dependent changes postmortem. Gut microflora were repeatedly sampled from the proximal large intestine of 12 deceased human individuals as they decayed under environmental conditions. Three intestinal bacterial genera were quantified by quantitative PCR (qPCR) using group-specific primers targeting 16S rRNA genes. Bacteroides and Lactobacillus relative abundances declined exponentially with increasing PMI at rates of Nt=0.977e(-0.0144t) (r2=0.537, p<0.001) and Nt=0.019e(-0.0087t) (r2=0.396, p<0.001), respectively, where Nt is relative abundance at time (t) in cumulative degree hours. Bifidobacterium relative abundances did not change significantly: Nt=0.003e(-0.002t) (r2=0.033, p=0.284). Therefore, Bacteroides and Lactobacillus abundances could be used as quantitative indicators of PMI. PMID- 26096157 TI - Loaded treadmill walking and cycle ergometry to assess work capacity: a retrospective comparison in 424 firefighters. AB - The fitness of firefighters is regularly evaluated using exercise tests. We aimed to compare, with respect to age and body composition, two test modalities for the assessment work capacity. A total of 424 Swedish firefighters with cycle ergometer (CE) and treadmill (TM) tests available from Jan 2004 to Dec 2010 were included. We compared results from CE (6 min at 200 W, 250 W or incremental ramp exercise) with TM (6 min at 8 degrees inclination, 4.5 km h-1 or faster, wearing 24-kg protective equipment). Oxygen requirements were estimated by prediction equations. It was more common to pass the TM test and fail the supposedly equivalent CE test (20%), than vice versa (0.5%), P<0.001. Low age and tall stature were significant predictors of passing both CE and TM tests (P<0.05), while low body mass predicted accomplishment of TM test only (P = 0.006). Firefighters who passed the TM but failed the supposedly equivalent CE test within 12 months had significantly lower body mass, lower BMI, lower BSA and shorter stature than did those who passed both tests. Calculated oxygen uptake was higher in TM tests compared with corresponding CE tests (P<0.001). Body constitution affected approval differently depending on the test modality. A higher approval rate in TM testing suggests lower cardiorespiratory requirements compared with CE testing, even though estimated oxygen uptake was higher during TM testing. The relevance of our findings in relation to the occupational demands needs reconsidering. PMID- 26096158 TI - Realizing chemical codoping in TiO2. AB - We demonstrate experimentally a chemical codoping approach that would simultaneously narrow the band gap and control the band edge positions of TiO2 semiconductors. It is shown that a sequential doping scheme with nitrogen (N) leading the way, followed by phosphorus (P), is crucial for the incorporation of both N and P into the anion sites. Various characterization techniques confirm the formation of the N-P bonds, and as a consequence of chemical codoping, the band gap of TiO2 is reduced from 3.2 eV to 1.8 eV. The realization of chemical codoping could be an important step forward in improving the general performance of electronic and optoelectronic materials and devices. PMID- 26096159 TI - Insights into the virulence-related genes of Edwardsiella tarda isolated from turbot in Europe: genetic homogeneity and evidence for vibrioferrin production. AB - Edwardsiella tarda has long been known as a pathogen that causes severe economic losses in aquaculture industry. Insights gained on E. tarda pathogenesis may prove useful in the development of new methods for the treatment of infections as well as preventive measures against future outbreaks. In this report, we have established the correlation between the presence of virulence genes, related with three aspects typically involved in bacterial pathogenesis (chondroitinase activity, quorum sensing and siderophore-mediated ferric uptake systems), in the genome of E. tarda strains isolated from turbot in Europe and their phenotypic traits. A total of 8 genes were tested by PCR for their presence in 73 E. tarda isolates. High homogeneity was observed in the presence/absence pattern of all the strains. Positive results in the amplification of virulence-related genes were correlated with the detection of chondroitinase activity in agar plates, in vivo AHL production during fish infection and determination of type of siderophore produced by E. tarda. To the best of our knowledge, this is the first study carried out with European strains on potential virulence factors. Furthermore, we demonstrated for the first time that E. tarda produces the siderophore vibrioferrin. PMID- 26096160 TI - Suppressive role of neddylation in dendritic cells during Mycobacterium tuberculosis infection. AB - Multiple strategies evolved by Mycobacterium tuberculosis (M. tb) have contributed to its successful prevalence. We previously identified specific genes in the cysteine protease and calcium-calmodulin pathways that regulated immune responses from dendritic cells (DCs). In this study we have characterized the role of neddylation in regulating various defense responses from DCs during mycobacterial infection. Neddylation is a process that is similar to ubiquitination. It however has its own enzyme machinery. It is coupled to ubiquitination and is important for maintaining cellular homeostasis. Here we show that stimulation of DCs with M. tb antigens Rv2463 and Rv3416 as well as infection with live M. tb modulates the expression levels of key proteins in the neddylation pathway. Further, stimulation with the two antigens promoted the association of NEDD8 with its target Cullin-1. The modulation in the expression levels of NEDD8 and SENtrin specific Protein 8 (SENP8) by the two antigens was in a calcium, MAPK and TLR dependent mechanism. Further, knockdown of specific genes of neddylation promoted the generation of oxidative burst, promoted phagolysosome fusion in mycobacteria infected DCs and induced higher expression of autophagy and apoptosis associated proteins in DCs. These results point toward a unique strategy employed by mycobacteria and its antigens towards immune suppression via modulating neddylation in DCs. PMID- 26096161 TI - Characteristics of primary splenic diffuse large B-cell lymphoma and role of splenectomy in improving survival. AB - BACKGROUND: Primary splenic diffuse large B-cell lymphoma (PS-DLBCL), an uncommon type of non-Hodgkin lymphoma, has been investigated only in small patient series before the rituximab era. The therapeutic role of splenectomy in addition to immunochemotherapy is unknown. METHODS: The databases of 7 medical centers in Israel were searched for patients diagnosed with PS-DLBCL in 1982-2013, and clinical, treatment, and outcome data were collected for 87 patients. The mean patient age was 59.6 years; 57.5% were male. RESULTS: Patients presented with abdominal pain (81%), B symptoms (59%), splenomegaly (84%), splenic masses (97%), and high lactate dehydrogenase (LDH) levels (84%); 61% had stage I or II disease. The diagnosis was made with core-needle biopsy in 46 patients and with diagnostic splenectomy in 39 patients. Eighty patients (92%) were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone; 68 (78%) received rituximab. A complete response was achieved in 67 patients (77%), and a partial response was achieved in 8 (9%). At 5 years, the overall survival (OS) rate was 77%, and the progression-free survival (PFS) rate was 67%. When patients were stratified by splenectomy at diagnosis, the OS rates were 91% for splenectomized patients and 68% for nonsplenectomized patients (P = .08), and the PFS rates were 85% and 55%, respectively (P = .02). The respective values for the subgroup with early-stage disease were 96% and 63% for OS (P = .009) and 90% and 51% for PFS (P = .01). In a multivariate analysis, a low Eastern Cooperative Oncology Group performance status and splenectomy independently predicted better PFS (P < .03). CONCLUSIONS: Patients with PS-DLBCL usually present with abdominal pain, high LDH levels, and a splenic mass. This study shows for the first time that splenectomy at diagnosis improves survival, specifically in patients with early-stage disease. PMID- 26096162 TI - Electronic assessment of peri-implant mucosal esthetics around three implant abutment configurations: a randomized clinical trial. AB - OBJECTIVES: To objectively assess the influence that three different implant abutment interface designs had on peri-implant mucosal esthetics at 1 year post implant placement via the pink esthetic score (PES). Additionally, to demonstrate the novel employment of a tablet-based digital imaging format to reliably assess and score clinical images as part of a multicenter clinical trial according to PES criteria. MATERIALS AND METHODS: Adult subjects (n = 141) with healed tooth bound edentulous sites in the anterior maxilla as well as first premolar region were randomized to receive one of three different implant-abutment interface designs (conical interface = CI; flat-to-flat interface = FI; or platform switch interface = PS). Immediate provisionalization was performed with prefabricated titanium abutments, with definitive custom CAD/CAM zirconia abutments and all ceramic cement-based crowns being delivered 12-week post-implant placement. Bilateral (anterior sites) or unilateral (premolar sites) digital clinical photographs were made at 1, 3, 6, and 12 months post-implant placement. Five calibrated faculty evaluators of different clinical backgrounds scored images during a 4-week timeframe on a standardized, tablet-based, digital imaging format. RESULTS: Six hundred and forty-nine clinical photographs were evaluated resulting in a total of 3245 sum PES values and 22,715 individual PES values. Faculty evaluator intra- and inter-rater reliability was found to be "strong" (ICC = 0.84) and "substantial" (ICC = 0.64), respectively, demonstrating repeatability of both the PES, evaluator calibration, and standardization of tablet-based scoring. All implant-abutment interface groups demonstrated significant improvements in mean sum PESs up to 1 year, with the largest improvement between restoration delivery and 6 months. No significant differences were found between groups in mean sum PESs both for individual study visits as well as for changes between study visits. CONCLUSIONS: No significant differences in mean sum PESs were found between subjects randomized to three different implant-abutment interfaces. However, significant differences were found as a function of time for all three groups, with the largest improvement in mean sum PESs occurring between definitive abutment and restoration delivery and 6 months. Use of electronic, tablet-based digital imaging scoring formats represents a novel and repeatable methodology for scoring PES images in large, multicenter clinical trials. PMID- 26096163 TI - Signaling pathway factors expression in renal tissue of apoE-knockout mice. AB - Apolipoprotein E (apoE) is regarded as one of the major plasma lipoproteins, and it plays an important role in the transport and metabolism of lipids. apoE can be found in multiple tissues, such as liver, kidney, jejunum, urinary bladder, ileum, colon, brain, adrenal glands, lung, ovary, spleen, pancreas, and testis, etc. As a secreted protein, it plays an important role in the systemic lipoprotein metabolism and vascular wall homeostasis and in the pathogenesis of renal diseases. apoE-knockout (apoE(-/-)) mice is a classic model of atherosclerosis and renal diseases. However, no review summed up the signaling pathway factors expression in renal tissue of apoE-knockout mice. The literatures were searched extensively and this review was performed to review the signaling pathway factors expression in renal tissue of apoE-knockout mice. PMID- 26096164 TI - The mechanism of protriptyline-induced Ca2+ movement and non-Ca2+-triggered cell death in PC3 human prostate cancer cells. AB - Protriptyline, a tricyclic anti-depressant, is used primarily to treat the combination of symptoms of anxiety and depression. However, the effect of protriptyline on prostate caner is unknown. This study examined whether the anti depressant protriptyline altered Ca(2+) movement and cell viability in PC3 human prostate cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)](i). Protriptyline evoked [Ca(2+)](i) rises concentration dependently. The response was reduced by removing extracellular Ca(2+). Protriptyline-evoked Ca(2+) entry was inhibited by store-operated channel inhibitors (nifedipine, econazole and SKF96365), protein kinase C activator (phorbol 12-myristate 13 acetate, PMA) and protein kinase C inhibitor (GF109203X). Treatment with the endoplasmic reticulum Ca(2+) pump inhibitor 2,5 di-tert-butylhydr-oquinone (BHQ) in Ca(2+)-free medium inhibited 60% of protriptyline-evoked [Ca(2+)](i) rises. Conversely, treatment with protriptyline abolished BHQ-evoked [Ca(2+)](i) rises. Inhibition of phospholipase C with U73122 suppressed 50% of protriptyline-evoked [Ca(2+)](i) rises. At concentrations of 50 70 uM, protriptyline decreased cell viability in a concentration-dependent manner; which were not reversed by chelating cytosolic Ca(2+) with 1,2-bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Collectively, in PC3 cells, protriptyline evoked [Ca(2+)](i) rises by inducing phospholipase C-associated Ca(2+) release from the endoplasmic reticulum and other stores, and Ca(2+) influx via protein kinase C-sensitive store-operated Ca(2+) channels. Protriptyline caused cell death that was independent of [Ca(2+)](i) rises. PMID- 26096165 TI - Comparative transcriptional and translational analysis of heme oxygenase expression in response to sulfur mustard. AB - Sulfur mustard (SM) is a potent alkylating agent which reacts with nucleophilic groups on DNA, RNA and proteins. It is capable of inducing cellular toxicity and oxidative stress via production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The accumulation of high amounts of the reactive species causes harmful effects such as DNA damage, lipid peroxidation, protein oxidation, inflammation and apoptosis. Although SM (also known as mustard gas) and its derivatives are rapidly removed from the body, long-term damages are much more serious than the short-term effects and may be correlated with the subsequent changes occurred on the genome. In order to defend against oxidative properties of this toxic molecule, cells trigger several anti-oxidant pathways through up regulating the corresponding genes. Enzymes like heme oxygenase-1, superoxide dismutase and glutathione-S-transferase are the examples of such genes. These enzymes produce anti-oxidant substances that are able to scavenge the reactive species, alleviate their noxious effects and protect the cells. Following SM gas exposure, gene transcription (mRNA levels) of these enzymes are ramped up to help detoxify the cells. Yet, some studies have reported that the up-regulated transcription does not necessarily translate into higher protein expression levels. The exact reason why this phenomenon happens is not clear. Creation of mutations in the genome sequence may lead to protein structure changes. Phosphorylation or other post-translational alterations of proteins upon SM exposure are also considered as possible causes. In addition, alterations in some microRNAs responsible for regulating post-translation events may inhibit the expression of the anti-oxidant proteins in the poisoned cells at translational level. PMID- 26096166 TI - Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. AB - The generic mitogen-activated protein kinases (MAPK) signaling pathway is shared by four distinct cascades, including the extracellular signal-related kinases (ERK1/2), Jun amino-terminal kinases (JNK1/2/3), p38-MAPK and ERK5. Mitogen activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathway is reported to be associated with the cell proliferation, differentiation, migration, senescence and apoptosis. The literatures were searched extensively and this review was performed to review the role of MAPK/ERK signaling pathway in cell proliferation, differentiation, migration, senescence and apoptosis. PMID- 26096167 TI - Potential signal pathway between all-trans retinoic acid and LMX1B in hypoxia induced renal tubular epithelial cell injury. AB - All-trans retinoic acid (ATRA), an active metabolite of vitamin A, exerts various effects on physiological processes such as cell growth, differentiation, apoptosis and inflammation. LMX1B, a developmental LIM-homeodomain transcription factor, is widely expressed in vertebrate embryos, and it takes part in the development of diverse structures such as limbs, kidneys, eyes, brains, etc. Renal tubular epithelial cell culture was performed, and mRNA and protein expression of some factors were detected. We recently demonstrated that ATRA up regulated the LMX1B, and down-regulated the transforming growth factor-beta1, collagen IV and fibronectin in a hypoxia/reoxygenation (H-R) injury system in renal tubular epithelial cells (RTEC). In conclusion, ATRA acts as a positive regulator of LMX1B in H-R RTEC. PMID- 26096168 TI - Mild alcohol intake exacerbates metabolic syndrome in rodents: a putative role of GSK-3beta. AB - Metabolic syndrome is characterized with abdominal obesity, insulin resistance, dyslipidemia and hepatic dysfunction. Glycogen synthase kinase-3beta (GSK-3beta) expression has been observed in adipose tissues in obese and diabetic humans, and in rodents. The aim of study was to investigate role of GSK-3beta in modulation of metabolic alterations in alcoholic fed rats. Male Wistar albino rats (180-220 g) were used. High fat diet (HFD) for 8 weeks and alcohol (2%) from third to eighth week were given. Lithium chloride (LiCl), a GSK-3beta inhibitor (60 mg/kg) was used orally from third to eighth week. HFD treatment caused significant (p < 0.05) increase in the percentage of body weight gain, BMI, Lee index, different fat pads, liver weights, serum glucose, leptin, triglyceride, LDL, VLDL, cholesterol, alanine transaminase, aspartate transaminase, tissue thio-barbituric acid reactive substances, nitrate/nitrite and significant decrease in food intake (g), serum HDL and tissue GSH in HFD control rats, as compared to normal control (NC). Administration of alcohol (2%) ad libitum potentiated the effect of normal and HFD, respectively, in NC and HFD control rats, respectively. Administration of LiCl produced significant amelioration in biochemical and pathological changes caused in the form of metabolic syndrome in HFD alone and HFD and alcohol-treated rats. The histological observations also showed similar findings in liver tissue. It may be concluded that inactivation of GSK-3beta consequently leads to increased leptin and insulin sensitivity as evidenced by the reversal of alterations caused due to metabolic syndrome in rodents fed with HFD and mild alcohol. PMID- 26096169 TI - Mapping inhibitor response to the in-frame deletions, insertions and duplications of epidermal growth factor receptor (EGFR) in non-small cell lung cancer. AB - Human epidermal growth factor receptor (EGFR) has become a well-established target for the treatment of non-small cell lung cancer (NSCLC). However, a large number of in-frame deletion, insertion and duplication mutations in the EGFR tyrosine kinase (TK) domain have been observed to alter drug response to such a kinase target. Thus, a systematic investigation of the intermolecular interactions between the clinical small-molecule agents and various EGFR in-frame mutants would help to establish a complete picture of drug response to kinase mutations in lung cancer, and to design new EGFR inhibitors with high potency and selectivity to target drug-resistant mutants. Here, we describe a combined pipeline to explore the drug response of five representative EGFR inhibitors, including three FDA-approved agents (gefitinib, erlotinib and lapatinib) and two compounds under clinical development (AEE788 and TAK-285) to a number of clinically relevant EGFR in-frame mutations, aiming at a comprehensive understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity to EGFR in-frame mutations. It was found that the insertion and duplication mutations in exon 20 can generally cause drug resistance to EGFR due to the reduced size of kinase's active pocket, while deletion mutations in exon 19 associate closely with increased inhibitor sensitivity to EGFR by establishing additional non-bonded interactions across complex interface, including hydrogen bonds, cation-pi interactions and hydrophobic contacts. PMID- 26096170 TI - Expression of Duffy antigen receptor for chemokines (DARC) is down-regulated in colorectal cancer. AB - Duffy antigen receptor for chemokines (DARC) is a silent chemokine receptor which selectively binds angiogenic chemokines without inducing conventional signaling responses. DARC has been reported to inhibit the development of multiple cancers through clearance of angiogenic chemokines. However, its role in colorectal cancer (CRC) remains unclear. We investigated the expression of DARC in CRC and explored correlation of DARC expression with clinical pathological features and microvessel density (MVD). The protein expression levels of DARC were detected by immunohistochemistry in 90 CRC and 64 paired unaffected tissues. The mRNA levels of DARC were detected by quantitative real-time PCR in 15 CRC and paired unaffected tissues. MVD in CRC was also assessed by immunohistochemistry of CD34. We found that the mRNA and protein expression levels of DARC were significantly lower in CRC than in the unaffected tissues (p < 0.05). The DARC protein expression levels were positively correlated with DARC mRNA expression levels in both CRC (p < 0.001) and unaffected tissues (p < 0.001). We also found that DARC expression was significantly correlated with tumor differentiation (p < 0.001), lymph node metastasis (p < 0.01) and TNM stage (p < 0.05). Moreover, we observed a strong negative relationship between DARC expression and MVD in CRC (p < 0.001). We showed that DARC expression is down-regulated in CRC and associated with clinical pathological features and MVD of CRC. DARC might be involved in tumorigenesis, progression, angiogenesis, and metastasis of CRC. PMID- 26096171 TI - Buckling-induced retraction of spherical shells: A study on the shape of aperture. AB - Buckling of soft matter is ubiquitous in nature and has attracted increasing interest recently. This paper studies the retractile behaviors of a spherical shell perforated by sophisticated apertures, attributed to the buckling-induced large deformation. The buckling patterns observed in experiments were reproduced in computational modeling by imposing velocity-controlled loads and eigenmode affine geometric imperfection. It was found that the buckling behaviors were topologically sensitive with respect to the shape of dimple (aperture). The shell with rounded-square apertures had the maximal volume retraction ratio as well as the lowest energy consumption. An effective experimental procedure was established and the simulation results were validated in this study. PMID- 26096172 TI - The retrotrapezoid nucleus stimulates breathing by releasing glutamate in adult conscious mice. AB - The retrotrapezoid nucleus (RTN) is a bilateral cluster of neurons located at the ventral surface of the brainstem below the facial nucleus. The RTN is activated by hypercapnia and stabilises arterial Pco2 by adjusting lung ventilation in a feedback manner. RTN neurons contain vesicular glutamate transporter-2 (Vglut2) transcripts (Slc17a6), and their synaptic boutons are Vglut2-immunoreactive. Here, we used optogenetics to test whether the RTN increases ventilation in conscious adult mice by releasing glutamate. Neurons located below the facial motor nucleus were transduced unilaterally to express channelrhodopsin-2 (ChR2) enhanced yellow fluorescent protein, with lentiviral vectors that employ the Phox2b-activated artificial promoter PRSx8. The targeted population consisted of two types of Phox2b-expressing neuron: non-catecholaminergic neurons (putative RTN chemoreceptors) and catecholaminergic (C1) neurons. Opto-activation of a mix of ChR2-expressing RTN and C1 neurons produced a powerful stimulus frequency dependent (5-15 Hz) stimulation of breathing in control conscious mice. Respiratory stimulation was comparable in mice in which dopamine-beta-hydroxylase (DbetaH)-positive neurons no longer expressed Vglut2 (DbetaH(C) (re/0);;Vglut2(fl/fl)). In a third group of mice, i.e. DbetaH(+/+);;Vglut2(fl/fl) mice, we injected a mixture of PRSx8-Cre lentiviral vector and Cre-dependent ChR2 adeno-associated virus 2 unilaterally into the RTN; this procedure deleted Vglut2 from ChR2-expressing neurons regardless of whether or not they were catecholaminergic. The ventilatory response elicited by photostimulation of ChR2 positive neurons was almost completely absent in these mice. Resting ventilatory parameters were identical in the three groups of mice, and their brains contained similar numbers of ChR2-positive catecholaminergic and non-catecholaminergic neurons. From these results, we conclude that RTN neurons increase breathing in conscious adult mice by releasing glutamate. PMID- 26096174 TI - Bone mineral density measurements in otosclerosis using dual-energy X-ray absorptiometry. AB - OBJECTIVES: This study aims to evaluate patients with otosclerosis with respect to bone mineral density (BMD) at different regions of interest (ROI), using dual energy X-ray absorptiometry (DXA). DESIGN: Cross-sectional controlled study. SETTING: Tertiary referral hospital. PARTICIPANTS: The patients with a definite diagnosis of otosclerosis confirmed intra-operatively were defined as the study group (n = 30). The control group consisted of volunteer, healthy subjects with normal hearing (n = 43). MAIN OUTCOME MEASURES: Following an audiometric evaluation, a venous blood sample was obtained and a single BMD measurement using DXA was applied to each participant. RESULTS: The mean BMD, T and Z scores were higher in the otosclerosis group than in the control group in all the regions considered, but not significantly; only the L2-L3 lateral BMD and its T and Z scores were significant (P = 0.036, P = 0.029 and P = 0.036, respectively). CONCLUSION: This study shows that the BMD does not decrease in the presence of otosclerosis despite its genetic and metabolic relevance with osteoporosis. Concerning the L2-L3 lateral BMD measurements, the BMD increased in otosclerosis. PMID- 26096175 TI - PRDM1, a Tumor-Suppressor Gene, is Induced by Genkwadaphnin in Human Colon Cancer SW620 Cells. AB - Genkwadaphnin (GD-1) is isolated from the flower buds of Daphne genkwa Siebold et Zuccarini (Thymelaeaceae), and it has been used as a traditional Korean and Chinese medicine. In this study, the authors observe that GD-1 inhibits the growth of the colon cancer cell line, SW620, through the up-regulation of p21 expression in a PRDM1-dependent manner. After treatment with GD-1, the transcriptional repressor PRDM1 is prominently induced in SW620 cells. Furthermore, GD-1 induce the phosphorylation of PKD1 and MEK and subsequently provide PRDM1 enhancement, resulting in the suppression of c-Myc expression and the up-regulation of p21. PKD1 knockdown using siRNA abrogates PRDM1 expression by GD-1 and subsequently disrupts the regulation of c-Myc and p21 expression. Treating SW620 cells with GD-1 inhibits cell-cycle progression and is characterized by the down-regulation of c-Myc followed by the up-regulation of p21 expression. The up-regulation of p21 by GD-1 induces the growth arrest of the SW620 colon cancer cell line. Based on these data, the authors propose that GD-1 has tumor-suppressor activity that may contribute to the anti-tumor effects of PRDM1 in colon cancer. PMID- 26096176 TI - Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction via tight junction regulation in a rabbit model of atherosclerosis. AB - Vascular endothelial dysfunction (VED) is an important factor in the initiation and development of atherosclerosis (AS). Previous studies have demonstrated that endothelial permeability is increased in diet-induced AS. However, the precise underlying mechanisms remain poorly understood. The present study aimed to analyze whether the myosin light chain kinase (MLCK) inhibitor ML7 is able to improve VED and AS by regulating the expression of the tight junction (TJ) proteins zona occludens (ZO)-1 and occludin via mechanisms involving MLCK and MLC phosphorylation in high-fat diet-fed rabbits. New Zealand white rabbits were randomly divided into three groups: Control group, AS group and ML7 group. The rabbits were fed a standard diet (control group), a high-fat diet (AS group) or a high-fat diet supplemented with 1 mg/kg/day ML7 (ML7 group). After 12 weeks, endothelium-dependent relaxation and endothelium-independent relaxation were measured using high-frequency ultrasound. Administration of a high-fat diet significantly increased the levels of serum lipids and inflammatory markers in the rabbits in the AS group, as compared with those in the rabbits in the control group. Furthermore, a high-fat diet contributed to the formation of a typical atherosclerotic plaque, as well as an increase in endothelial permeability and VED. These symptoms of AS were significantly improved following treatment with ML7, as demonstrated in the ML7 group. Hematoxylin & eosin and immunohistochemical staining indicated that ML7 was able to decrease the expression of MLCK and MLC phosphorylation in the arterial wall of rabbits fed a high-fat diet. A similar change was observed for the TJ proteins ZO-1 and occludin. In addition, western blot analysis demonstrated that ML7 increased the expression levels of occludin in the precipitate, but reduced its expression in the supernatant of lysed aortas. These results indicated that occludin, which is a dynamic protein at the TJ, is associated with remodeling from cell membrane to cytoplasm. The present study was the first, to the best of our knowledge, to indicate that ML7 may ameliorate VED and AS by regulating the TJ proteins ZO-1 and occludin via mechanisms involving MLCK and MLC phosphorylation. PMID- 26096177 TI - In vitro activity of essential oils of free and nanostructured Melaleuca alternifolia and of terpinen-4-ol on eggs and larvae of Haemonchus contortus. AB - Haemonchus contortus is one of the major gastrointestinal nematodes responsible for significant economic and production losses of sheep. Diseases caused by this species lack effective anthelmintic products, and the search for new compounds to replace synthetic anthelmintics has been extensive. The present investigation assesses the in vitro activity of the essential oil of melaleuca (Melaleuca alternifolia), both free (TTO) and nanostructured (nanoTTO), and terpinen-4-ol (terp-4-ol) on eggs and larvae of H. contortus. Tests of egg hatching (EHT) and inhibition of larval migration (LMIT) were used to assess the in vitro efficacy of TTO, nanoTTO and terp-4-ol. Using EHT, at a concentration of 3.5 mg/ml, 100% inhibition occurred using TTO and terp-4-ol, with LC50 values of 0.43 and 0.63 mg/ml, and LC90 values of 1.75 mg/ml and 3.12 mg/ml, respectively. NanoTTO had lower activity, with 82.6% inhibition at the same concentration. Using LMIT, TTO and nanoTTO had a similar activity with 88.0% and 84.8% inhibition, respectively, at a concentration of 56 mg/ml. Terp-4-ol had a greater effect on larvae, with 85.7% inhibition at a concentration of 56 mg/ml and 82.4% at 3.5 mg/ml, demonstrating high activity at the lowest concentration tested. Therefore, the results indicate that all substances tested showed ovicidal and larvicidal activity against H. contortus. TTO, terp-4-ol and, mainly, nanoTTO may be targeted in in vivo studies, besides being a promising line of research into the control and treatment of veterinary important helminths. PMID- 26096178 TI - Influence of diffusion on the kinetics of multisite phosphorylation. AB - When an enzyme modifies multiple sites on a substrate, the influence of the relative diffusive motion of the reactants cannot be described by simply altering the rate constants in the rate equations of chemical kinetics. We have recently shown that, even as a first approximation, new transitions between the appropriate species must also be introduced. The physical reason for this is that a kinase, after phosphorylating one site, can rebind and modify another site instead of diffusing away. The corresponding new rate constants depend on the capture or rebinding probabilities that an enzyme-substrate pair, which is formed after dissociation from one site, reacts at the other site rather than diffusing apart. Here we generalize our previous work to describe both random and sequential phosphorylation by considering inequivalent modification sites. In addition, anisotropic reactive sites (instead of uniformly reactive spheres) are explicitly treated by using localized sink and source terms in the reaction diffusion equations for the enzyme-substrate pair distribution function. Finally, we show that our results can be rederived using a phenomenological approach based on introducing transient encounter complexes into the standard kinetic scheme and then eliminating them using the steady-state approximation. PMID- 26096179 TI - Four new alkylamides from the roots of Zanthoxylum nitidum. AB - Phytochemical investigation on the roots of Zanthoxylum nitidum led to the isolation of four new unsaturated alkylamides, zanthoxylumamides A-D. Their structures were established via the detailed spectroscopic analyses. PMID- 26096180 TI - Mutation Analysis of COQ2 in Chinese Patients with Cerebellar Subtype of Multiple System Atrophy. AB - AIMS: Recently, mutations in COQ2 encoding para-hydroxybenzoate-polyprenyl transferase have been identified to increase the risk of multiple system atrophy (MSA) in multiplex families and sporadic cases. The prevalence of COQ2 mutations was showed to be higher in cerebellar subtype (MSA-C) than parkinsonism subtype (MSA-P). The aim of this study was to investigate the association between COQ2 mutations and MSA-C in Chinese patients. METHODS: A Chinese cohort of 116 patients with MSA-C and 192 healthy control individuals were recruited. Sanger sequencing of COQ2 was performed in all these subjects. RESULTS: Two missense mutations (p.L402F and p.R173H) and one synonymous mutation (p.A32A) were detected in 3 patients, respectively. They were not found in the 192 controls as well as the 1000 Genomes Database. The p.L402F and p.A32A were novel. CONCLUSION: Our results indicated that COQ2 tended to play a population-specific and subtype depended role in conferring susceptibility to MSA. PMID- 26096181 TI - Organ Procurement Organization Liver Acquisition Costs Could More Than Double With Proposed Redistricts. PMID- 26096182 TI - Surveillance colonoscopy for colitis-associated dysplasia and cancer in ulcerative colitis patients. AB - Long-standing ulcerative colitis patients are known to be at high risk for the development of colorectal cancer. Therefore, surveillance colonoscopy has been recommended for these patients. Because colitis-associated colorectal cancer may be difficult to identify even by colonoscopy, a random biopsy method has been recommended. However, the procedure of carrying out a random biopsy is tedious and its effectiveness has also not yet been demonstrated. Instead, targeted biopsy with chromoendoscopy has gained popularity in European and Asian countries. Chromoendoscopy is generally considered to be an effective tool for ulcerative colitis surveillance and is recommended in the guidelines of the British Society of Gastroenterology and the European Crohn's and Colitis Organisation. Although image-enhanced endoscopy, such as narrow-band imaging and autofluorescence imaging, has been investigated as a potential ulcerative colitis surveillance tool, it is not routinely applied for ulcerative colitis surveillance in its present form. The appropriate intervals of surveillance colonoscopy have yet to be determined. Although the Japanese and American guidelines recommend annual or biannual colonoscopy, the British Society of Gastroenterology and the European Crohn's and Colitis Organisation stratified their guidelines according to the risks of colorectal cancer. A randomized controlled trial comparing random and targeted biopsy methods has been conducted in Japan and although the final analysis is still ongoing, the results of this study should address this issue. In the present review, we focus on the current detection methods and characterization of dysplasia/cancer and discuss the appropriate intervals of colonoscopy according to the stratified risks. PMID- 26096183 TI - Pleomorphic adenoma-like tumour of the breast. AB - AIMS: Pleomorphic adenoma (PA) of the breast is a rare tumour seen usually in postmenopausal women. Although PA of the salivary glands (SG) is recognized to be a benign tumour, the nature and biology of similar tumours seen in the breast remains to be defined. The aim of this study was to describe PA of the breast that was reported on core biopsy as an invasive matrix-producing metaplastic breast carcinoma (MBC). METHODS AND RESULTS: A core biopsy from a clinically malignant retroareolar mass showed mildly atypical polygonal cells with surrounding myxoid stroma. Immunohistochemistry showed expression of basal and luminal cytokeratins, but oestrogen receptor, human epidermal growth factor receptor 2 (HER2) and myoepithelial markers were negative. The excision specimen showed similar features, but in addition the stroma showed cartilage and bone. Also it was clear that the lesion was circumscribed and merged with a sclerosed papillary lesion consistent with what has been described as mammary PA. CONCLUSION: This lesion shows an overlap of morphology and immunophenotype with SG-PA and with MBC. The majority of mammary PAs have a benign behaviour, but local recurrence and development of carcinoma occur. We propose a new terminology of pleomorphic adenoma-like tumour of the breast to reflect the uncertain nature of these tumours and help guide management decisions. PMID- 26096184 TI - Targeting the podocyte to treat glomerular kidney disease. AB - The majority of chronic kidney disease (CKD) cases have their origin in the glomerulus, the microvascular unit of the nephron that serves as a filter tasked with forming primary urine. This selective filtration process is determined to a large extent by the functional capacity of the podocyte, a highly differentiated cell type that enwraps the outer aspect of the glomerular capillary wall. In this short review, we describe the biology of the podocyte, its central role in the etiology of various glomerulopathies and highlight current and future opportunities to exploit the unique properties of this cell type for developing kidney-specific therapeutics. PMID- 26096186 TI - Effects of atomoxetine on heart rhythm in children and adolescents. AB - BACKGROUND: The aim of this study was to examine the effects of atomoxetine on heart rhythm using 12-lead electrocardiography (ECG) and 24 h Holter monitoring. METHODS: Children and adolescents who were diagnosed with attention deficit hyperactivity disorder according to DSM-IV-TR were referred to a pediatric cardiology clinic for cardiologic examination before and after 4 or 5 weeks of atomoxetine treatment. Cardiac examination, complete blood count, biochemistry, thyroid function tests, 12-lead ECG and 24 h Holter monitoring were performed routinely in all patients. Each subject underwent 24 h Holter ECG monitoring before atomoxetine was started and after 4 or 5 weeks of effective dose atomoxetine treatment. RESULTS: Forty-one patients were included in this prospective study. No statistically significant change was found in QT, QTc or QT interval dispersion or blood pressure before and after 4 or 5 weeks of atomoxetine treatment. There was a statistically significant increase in heart rate (both during the day and at night) and QRS duration, and a statistically significant decrease in P wave dispersion. Three patients had rhythm disturbances. All of these three patients were asymptomatic and none of these arrhythmias reached clinical significance. CONCLUSION: Atomoxetine did not cause significant changes in ECG or Holter variables. In two patients, who had undiagnosed subclinical extrasystoles, extra beats were increased after 4th week of treatment, but still remained clinically insignificant. Before and after atomoxetine treatment, listening to the heart sounds for a longer time, may help clinicians to notice an extra beat. If an extra beat is identified then 24 Holter monitoring is recommended. PMID- 26096185 TI - Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of "de novo" SCN1A Mutations in Children with Dravet Syndrome. AB - The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered "de novo" by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low-level mosaicism in parents of families with seemingly "de novo" mutations will allow for better informed genetic counseling. PMID- 26096187 TI - Headache and Nausea after Treatment with High-Dose Subcutaneous versus Intravenous Immunoglobulin. AB - Treatment with intravenous immunoglobulin (IVIG) leads to transient side effects such as headache and nausea during and after the infusion. We hypothesized that subcutaneous administration of smaller doses of immunoglobulin (SCIG) given more frequently leads to less severe headache and nausea and could be an alternative in patients experiencing side effects. Fifty-nine patients diagnosed with neurological disorders (chronic inflammatory demyelinating polyneuropathy (CIDP), multi-focal motor neuropathy (MMN) or post-polio syndrome) were treated with IVIG, and 27 CIDP or MMN patients with SCIG. For two consecutive weeks daily, registration of the severity of headache and nausea was registered on a visual analogue scale (VAS) from 0 to 100 mm. In the SCIG group, headache reached a peak value of 1 (0-13) mm at day 6 versus 11 (0-96) mm in the IVIG group at day 4 (p < 0.0001). For nausea, the SCIG group had a stable value of 0 (0-21) mm at all days, whereas a peak value of 3 (0-90) mm was reached at day 4 in the IVIG group (p < 0.0001). SCIG leads to less severe headache and nausea than IVIG without fluctuations of side effects in relation to the injections. PMID- 26096188 TI - Immuno-stimulatory activity of a polysaccharide-enriched fraction of Sutherlandia frutescens occurs by the toll-like receptor-4 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sutherlandia frutescens (L.) R. Br. is an indigenous plant of southern Africa that has been traditionally used for various cancers, infections, and inflammatory conditions. AIM OF THE STUDY: Our aim was to investigate the potential immuno-stimulatory activity of a polysaccharide enriched fraction (SFPS) from a decoction of S. frutescens. MATERIALS AND METHODS: RAW 264.7 cells (a murine macrophage cell line) were used to determine the activities of SFPS on macrophage function. The production of reactive oxygen species (ROS), nitric oxide (NO), and inflammatory cytokines were evaluated in the cells treated with or without SFPS. CLI-095, a toll-like receptor (TLR) 4 specific inhibitor, was used to identify whether or not SFPS exerts its effects through TLR4. An antagonist of endotoxin, polymyxin B, was used to evaluate whether endotoxin present in SFPS contributed to its immune-stimulatory activity. RESULTS: SFPS exhibited potent immune-stimulatory activity by macrophages. The production of ROS, NO, and tumor necrosis factor (TNF-alpha) were increased upon exposure to SFPS in a dose-dependent manner. All of these activities were completely blocked by co-treatment with CLI-095, but only partially diminished by polymyxin B. CONCLUSION: We demonstrate for the first time potent immune stimulatory activity in a decoction prepared from S. frutescens. We believe that this immune stimulatory activity is due, in part, to the action of polysaccharides present in the decoction that acts by way of TLR4 receptors and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathway. These findings provide a plausible mechanism through which we can understand some of the medicinal properties of S. frutescens. PMID- 26096189 TI - Sunburn, sun exposure, and sun sensitivity in the Study of Nevi in Children. AB - PURPOSE: To examine the joint effect of sun exposure and sunburn on nevus counts (on the natural logarithm scale; log nevi) and the role of sun sensitivity. METHODS: We describe an analysis of cross-sectional data from 443 children enrolled in the prospective Study of Nevi in Children. To evaluate the joint effect, we partitioned the sum of squares because of interaction between sunburn and sun exposure into orthogonal components representing (1) monotonic increase in log nevi with increasing sun exposure (rate of increase of log nevi depends on sunburn), and (2) nonmonotonic pattern. RESULTS: In unadjusted analyses, there was a marginally significant monotonic pattern of interaction (P = .08). In adjusted analyses, sun exposure was associated with higher log nevi among those without sunburn (P < .001), but not among those with sunburn (P = .14). Sunburn was independently associated with log nevi (P = .02), even though sun sensitivity explained 29% (95% confidence interval: 2%-56%, P = .04) of its effect. Children with high sun sensitivity and sunburn had more nevi, regardless of sun exposure. CONCLUSIONS: A program of increasing sun protection in early childhood as a strategy for reducing nevi, when applied to the general population, may not equally benefit everyone. PMID- 26096190 TI - [Economic environment and blood transfusion]. AB - The increasing pressure on healthcare resources affects blood donation and transfusion. We attempted a survey of the efficiency of different strategies, actual or proposed to improve the management of blood products. We found an important disconnect between the cost effectiveness ratio of strategies and their uptake by policy makers. In other words, the least efficient strategies are those which increase transfusion safety by increasing the number of biological markers and are those preferred by health authorities in developed countries. Other more efficient strategies are more slowly implemented and included a systematic use of transfusion guidelines, reducing blood losses or increasing pre operative blood levels in elective surgeries. PMID- 26096191 TI - Relationship between wild greylag and European domestic geese based on mitochondrial DNA. AB - The origins of the European domestic goose are uncertain. The available information comes from archaeological findings and historical literature, but genetic evidence has hitherto been scarce. The domestic goose in Europe is derived from the greylag goose (Anser anser), but it is not known where the initial domestication took place and which of the two subspecies of greylag goose was ancestral. We aimed to determine the amount and geographical distribution of genetic diversity in modern populations of greylag geese as well as in different breeds of the domestic goose to make inferences about goose domestication. We studied DNA sequence variation in the mitochondrial control region of greylag geese from multiple populations across Europe and western Asia as well as specimens of domestic geese representing 18 modern breeds and individuals not belonging to any recognised breed. Our results show notable differences in genetic diversity between different greylag goose populations and the presence of six mitochondrial haplogroups which show a degree of geographical partitioning. The genetic diversity of the domestic goose is low, with 84% of sampled individuals having one of two major closely related haplotypes, suggesting that modern European domestic geese may derive from a narrow genetic base. The site of domestication remains unresolved, but domestic geese in Turkey were unusually diverse, indicating the importance of further sampling in the vicinity of the eastern Mediterranean and the Near East. There appears to be past or ongoing hybridisation between greylags and domestic geese in particular areas, consistent with field observations. PMID- 26096192 TI - Longitudinal associations with changes in outdoor recreation area use for physical activity during a community-based intervention. AB - Outdoor recreation areas (ORA) are important resources for physical activity (PA) and health promotion. While past research has identified correlates of ORA use, few studies have examined predictors of longitudinal changes in park- and trail based PA in community settings. Using data from a 6-month community-based walking intervention study, we examined cross-sectional and longitudinal predictors of PA in ORAs. Data were collected from baseline and 6-month assessments from participants (n=295) in a group walking intervention in South Carolina; participants enrolled from January 2012-May 2013. A decomposition scheme was used to examine the cross-sectional and longitudinal predictors of average group ORA use for PA, including social support, self-efficacy for PA, perceptions of neighborhood environment, and accelerometer-based PA, adjusting for gender. On average, participants were 49.4+13.3years old, 66.1% were Black, and the majority were women. There was a mean increase in group ORA use of 2.1+0.4days/month from baseline to 6months. Cross-sectionally, higher levels of the percentage of time in MVPA, self-efficacy, and social support were associated with greater group average ORA use. Longitudinally, increased social support from friends and rating of lighter motorized traffic were associated with increased group ORA use. Additionally, longitudinal increases in percentage of MVPA and more favorable rating of the neighborhood as a place to walk were both associated with decreased group ORA use. Better understanding how social and physical environmental characteristics impact ORA use for PA can lead to more effective intervention strategies and warrants greater attention in future research and public health promotion efforts. PMID- 26096193 TI - Motor difficulties and mental health in children who are deaf. PMID- 26096194 TI - Linking Executive Function and Peer Problems from Early Childhood Through Middle Adolescence. AB - Peer interactions and executive function play central roles in the development of healthy children, as peer problems have been indicative of lower cognitive competencies such as self-regulatory behavior and poor executive function has been indicative of problem behaviors and social dysfunction. However, few studies have focused on the relation between peer interactions and executive function and the underlying mechanisms that may create this link. Using a national sample (n = 1164, 48.6% female) from the Study of Early Child Care and Youth Development (SECCYD), we analyzed executive function and peer problems (including victimization and rejection) across three waves within each domain (executive function or peer problems), beginning in early childhood and ending in middle adolescence. Executive function was measured as a multi-method, multi-informant composite including reports from parents on the Children's Behavior Questionnaire and Child Behavior Checklist and child's performance on behavioral tasks including the Continuous Performance Task, Woodcock-Johnson, Tower of Hanoi, Operation Span Task, Stroop, and Tower of London. Peer problems were measured as a multi-informant composite including self, teacher, and afterschool caregiver reports on multiple peer-relationship scales. Using a cross-lagged design, our Structural Equation Modeling findings suggested that experiencing peer problems contributed to lower executive function later in childhood and better executive function reduced the likelihood of experiencing peer problems later in childhood and middle adolescence, although these relations weakened as a child moves into adolescence. The results highlight that peer relationships are involved in the development of strengths and deficits in executive function and vice versa. PMID- 26096195 TI - Video-assisted hepatic abscess debridement. AB - BACKGROUND: Pyogenic liver abscesses are currently treated by either percutaneous computer tomography (CT)-guided drainage or by laparoscopic and a conventional liver resection when conservative treatment fails but may be associated with substantial morbidity and mortality. METHODS: A minimally invasive technique involving debridement of right liver abscesses was employed using a minimally invasive video-assisted hepatic abscess debridement (VAHD) after unsuccessful percutaneous CT-guided drainage. Clinical data, complication rates and outcomes of patients were recorded retrospectively. RESULTS: Between 2011 and 2014, VAHD was performed on 10 patients at two centres with no observed recurrence of a liver abscess. The median age of the patients was 57 years (range 42-78) with a median pre-operative size of a liver abscess of 78 mm (range 40-115). The median operation time was 47 min (range 23-75), and the median postoperative hospital stay was 9 days (range 7-69). One patient developed a subcutaneous abscess that required further surgery. No patient died, and there were no major complications related to the VAHD. CONCLUSIONS: Video-assisted hepatic abscess debridement is a feasible technique that shows promising results for the treatment of a recurrent right liver abscess. PMID- 26096196 TI - Different proteomic strategies to identify genuine Small Ubiquitin-like MOdifier targets and their modification sites in Trypanosoma brucei procyclic forms. AB - SUMOylation is an important post-translational modification conserved in eukaryotic organisms. In Trypanosoma brucei, SUMO (Small Ubiquitin-like MOdifier) is essential in procyclic and bloodstream forms. Furthermore, SUMO has been linked to the antigenic variation process, as a highly SUMOylated focus was recently identified within chromatin-associated proteins of the active variant surface glycoprotein expression site. We aimed to establish a reliable strategy to identify SUMO conjugates in T. brucei. We expressed various tagged variants of SUMO from the endogenous locus. His-HA-TbSUMO was useful to validate the tag functionality but SUMO conjugates were not enriched enough over contaminants after affinity purification. A Lys-deficient SUMO version, created to reduce contaminants by Lys-C digestion, was able to overcome this issue but did not allow mapping many SUMOylation sites. This cell line was in turn useful to demonstrate that polySUMO chains are not essential for parasite viability. Finally, a His-HA-TbSUMO(T106K) version allowed the purification of SUMO conjugates and, after digestion with Lys-C, the enrichment for diGly-Lys peptides using specific antibodies. This site-specific proteomic strategy led us to identify 45 SUMOylated proteins and 53 acceptor sites unambiguously. SUMOylated proteins belong mainly to nuclear processes, such as DNA replication and repair, transcription, rRNA biogenesis and chromatin remodelling, among others. PMID- 26096197 TI - A pH-Responsive MRI Agent that Can Be Activated Beyond the Tissue Magnetization Transfer Window. AB - A terbium-based complex that displays a water exchange CEST resonance well outside the normal magnetization transfer (MT) frequency range of tissues provides a direct readout of pH values by MRI. Deprotonation of the phenolic proton in this complex results in a frequency shift of 56 ppm in a bound water molecule exchange peak between pH 5 and 8. This allows direct imaging of pH without prior knowledge of the agent concentration and with essentially no interference from the tissue MT signal. PMID- 26096198 TI - Mental health problems are rising more in Swedish adolescents than in other Nordic countries and the Netherlands. AB - Mental health problems increased in adolescents and young adults in Europe between 1950 and 1990, and the cause is largely unknown. Denmark, Finland, the Netherlands, Norway and Sweden form a relatively homogenous group of countries with favourable conditions for children. Our review examined the time trends for mental health problems in these countries between 1990 and 2010. CONCLUSION: In general, there were only small changes in mental health problems in the countries studied. However, we did note a marked rising trend in mental health problems among adolescents in Sweden, which also has more issues with school achievement and unemployment rates. PMID- 26096199 TI - Evolutionary plant radiations: where, when, why and how? PMID- 26096200 TI - Measuring the tempo of plant death and birth. PMID- 26096201 TI - Back to the past: a new take on the timing of flowering plant diversification. PMID- 26096202 TI - High-performance flexible perovskite solar cells exploiting Zn2SnO4 prepared in solution below 100 degrees C. AB - Fabricating inorganic-organic hybrid perovskite solar cells (PSCs) on plastic substrates broadens their scope for implementation in real systems by imparting portability, conformability and allowing high-throughput production, which is necessary for lowering costs. Here we report a new route to prepare highly dispersed Zn2SnO4 (ZSO) nanoparticles at low-temperature (<100 degrees C) for the development of high-performance flexible PSCs. The introduction of the ZSO film significantly improves transmittance of flexible polyethylene naphthalate/indium-doped tin oxide (PEN/ITO)-coated substrate from ~75 to ~90% over the entire range of wavelengths. The best performing flexible PSC, based on the ZSO and CH3NH3PbI3 layer, exhibits steady-state power conversion efficiency (PCE) of 14.85% under AM 1.5G 100 mW.cm(-2) illumination. This renders ZSO a promising candidate as electron-conducting electrode for the highly efficient flexible PSC applications. PMID- 26096204 TI - June 2015 at a glance. PMID- 26096203 TI - Human papillomavirus prevalence and type-distribution in cervical glandular neoplasias: Results from a European multinational epidemiological study. AB - Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type distribution by country. Age at diagnosis differed by ADC subtype, with usual type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV. PMID- 26096205 TI - BNP in heart failure: even leucocytes cannot escape its influence. PMID- 26096206 TI - The Pilot European Survey of Atrial Fibrillation: how to look at heart failure through a keyhole. PMID- 26096207 TI - The prognostic value of arterial blood gas analysis in high-risk acute heart failure patients: an analysis of the Korean Heart Failure (KorHF) registry. AB - AIMS: In acute heart failure (AHF) patients, pulmonary oedema and low tissue perfusion may lead to changes in the acid-base balance, which may be associated with worse outcomes. METHODS AND RESULTS: In this prospective nationwide cohort study from 24 academic hospitals, arterial blood gas (ABG) was measured in 1982 AHF patients at hospital admission. Acidosis was defined as pH <7.36, and alkalosis as pH >7.44. Mortality was stratified according to ABG results. Overall, 19% had acidosis, 37% had normal pH, and 44% had alkalosis. The most common type of acidosis was the mixed type (42%) followed by metabolic acidosis (40%), and the most common type of alkalosis was respiratory alkalosis (58%). At 12 months' follow-up 304 patients (15%) died. Patients with acidosis had higher mortality (acidosis 19.5%, neutral pH 13.7%, alkalosis 14.9%; P = 0.007). In the Cox proportional-hazards regression model, acidosis was a significant predictor of mortality (hazard ratio 1.93; 95% confidence intervals 1.27-2.93) along with N terminal pro-brain type natriuretic peptide (NT-proBNP), among others. In contrast, alkalosis was not associated with increased mortality. pH had an incremental prognostic value over NT-proBNP (net reclassification improvement 30%; P < 0.001), and ABG analysis identified extra patients at increased risk for mortality among patients with an NT-proBNP level less than the median (12-month mortality 17.5% vs. 9.9%; P = 0.009). CONCLUSION: In high-risk AHF patients, the most common acid-base imbalance is respiratory alkalosis. Acidosis is observed in every fifth patient and is a significant predictor of mortality. pH provides an additional prognostic value and may be used to optimize risk stratification in high-risk AHF patients. PMID- 26096208 TI - Corrigendum. PMID- 26096209 TI - Specific hepatic delivery of procollagen alpha1(I) small interfering RNA in lipid like nanoparticles resolves liver fibrosis. AB - Fibrosis accompanies the wound-healing response to chronic liver injury and is characterized by excessive hepatic collagen accumulation dominated by collagen type I. Fibrosis often progresses to cirrhosis. Here we present in vivo evidence of an up to 90% suppression of procollagen alpha1(I) expression, a reduction of septa formation, and a 40%-60% decrease of collagen deposition in mice with progressive and advanced liver fibrosis that received cationic lipid nanoparticles loaded with small interfering RNA to the procollagen alpha1(I) gene. After intravenous injection, up to 90% of lipid nanoparticles loaded with small interfering RNA to the procollagen alpha1(I) gene were retained in the liver of fibrotic mice and accumulated in nonparenchymal more than parenchymal cells for prolonged periods, significantly ameliorating progression and accelerating regression of fibrosis. CONCLUSION: Our lipid nanoparticles loaded with small interfering RNA to the procollagen alpha1(I) gene specifically reduce total hepatic collagen content without detectable side effects, potentially qualifying as a therapy for fibrotic liver diseases. PMID- 26096210 TI - Proposing a Parkinson's disease-specific tremor scale from the MDS-UPDRS. AB - BACKGROUND: This article proposes an International Parkinson and Movement Disorder Society (MDS)-UPDRS tremor-based scale and describes its measurement properties, with a view to developing an improved scale for assessing tremor in Parkinson's disease (PD). METHODS: This was a cross-sectional, multicenter study of 435 PD patients. Rasch analysis was performed on the 11 MDS-UPDRS tremor items. Construct validity, precision, and test-retest reliability were also analyzed. RESULTS: After some modifications, which included removal of an item owing to redundancy, the obtained MDS-UPDRS tremor scale showed moderate reliability, unidimensionality, absence of differential item functioning, satisfactory convergent validity with medication, and better precision than the raw sum score. However, the scale displayed a floor effect and a need for more items measuring lower levels of tremor. CONCLUSIONS: The MDS-UPDRS tremor scale provides linear scores that can be used to assess tremor in PD in a valid, reliable way. The scale might benefit from modifications and studies that analyze its responsiveness. PMID- 26096211 TI - The clonal relationships between pre-cancer and cancer revealed by ultra-deep sequencing. AB - The study of the relationships between pre-cancer and cancer and identification of early driver mutations is becoming increasingly important as the value of molecular markers of early disease and personalised drug targets is recognized, especially now the extent of clonal heterogeneity in fully invasive disease is being realized. It has been assumed that pre-cancerous lesions exhibit a fairly passive progression to invasive disease; the degree to which they, too, are heterogeneous is unknown. We performed ultra-deep sequencing of thousands of selected mutations, together with copy number analysis, from multiple, matched pre-invasive lesions, primary tumours and metastases from five patients with oral cancer, some with multiple primary tumours presenting either synchronously or metachronously, totalling 75 samples. This allowed the clonal relationships between the samples to be observed for each patient. We expose for the first time the unexpected variety and complexity of the relationships between this group of oral dysplasias and their associated carcinomas and, ultimately, the diversity of processes by which tumours are initiated, spread and metastasize. Instead of a series of genomic precursors of their adjacent invasive disease, we have shown dysplasia to be a distinct dynamic entity, refuting the belief that pre-cancer and invasive tumours with a close spatial relationship always have linearly related genomes. We show that oral pre-cancer exhibits considerable subclonal heterogeneity in its own right, that mutational changes in pre-cancer do not predict the onset of invasion, and that the genomic pathway to invasion is neither unified nor predictable. Sequence data from this study have been deposited in the European Nucleotide Archive, Accession No. PRJEB6588. PMID- 26096212 TI - Reply to letter on "Improving rehabilitation following critical illness through outpatient physiotherapy classes and essential amino acid supplement: A randomised, controlled trial". PMID- 26096213 TI - Pharmacokinetics/pharmacodynamics of micafungin in a surgical critically ill patient during extracorporeal carbon dioxide removal and continuous renal replacement therapy. PMID- 26096214 TI - Synthesis of chiral polymorph A-enriched zeolite Beta with an extremely concentrated fluoride route. AB - Chiral zeolitic materials with intrinsically chiral frameworks are highly desired because they can combine both shape selectivity and enantioselectivity. In the field of zeolite, the synthesis of chiral polymorph A of zeolite Beta or chiral polymorph A-enriched zeolite Beta is one of the biggest challenges. We demonstrate here a generalized extremely concentrated fluoride route for the synthesis of chiral polymorph A-enriched zeolite Beta in the presence of five achiral organic structure-directing agents. The polymorph A-enriched Ti-Beta shows a higher enantioselectivity for the asymmetric epoxidation of alkenes than the normal Ti-Beta. PMID- 26096215 TI - A Nitro-Functionalized Metal-Organic Framework as a Reaction-Based Fluorescence Turn-On Probe for Rapid and Selective H2 S Detection. AB - The toxic gas H2 S has recently emerged as one of the important signaling molecules in biological systems. Thus understanding the production, distribution, and mode of action of H2 S in biological system is important, but the fleeting and reactive nature of H2 S makes it a daunting task. Herein we report a biocompatible, nitro-functionalized metal-organic framework as reaction-based fluorescence turn-on probe for fast and selective H2 S detection. The selective turn-on performance of MOF remains unaffected even in presence of competing biomolecules. PMID- 26096216 TI - Self-assembling amphiphilic poly(propargyl methacrylate) grafted DNA copolymers into multi-strand helices. AB - DNA was covalently grafted onto poly(propargyl methacrylate) (PPMA) via "click" chemistry to synthesize the amphiphilic polymer brush. The PPMA-g-DNA brush could assemble into a primary structure of a nanofiber, which can be compactly spun into a multiple-strand helix in micron-length. The brush could also self-assemble with DNA labelled gold nanoparticles. PMID- 26096217 TI - Association of Right Atrial Mechanics with Hemodynamics and Physical Capacity in Patients with Idiopathic Pulmonary Arterial Hypertension: Insight from a Single Center Cohort in Northern Sweden. AB - AIMS: Role of right atrial mechanics has not been studied in idiopathic pulmonary arterial hypertension (IPAH). We sought to investigate the correlation between the right sided, particularly right atrial mechanics, hemodynamic parameters, and functional capacity prior to initiation of treatment. METHODS AND RESULTS: Twenty five subjects (63 +/- 17 years, 13 males) with newly diagnosed IPAH by right heart catheterization (RHC) underwent speckle tracking echocardiography (STE) of the right ventricle (RV) and right atrium (RA). All the patients had a six-minute walk test (6MWD) performed, functional class (WHO-FC) assessed, and plasma NT proBNP estimated. STE strain imaging of RA and RV was performed offline. STE of the RA myocardium yielded characteristic strain (S%) and strain rate (SR) curves with clear delineation of its reservoir (RA-RS%), conduit (RA-SR E), and booster pump functions (RA-SR A). In IPAH, RHC-obtained pulmonary vascular resistance (PVR) and pulmonary artery systolic pressure (PASP), respectively, were 7.3 +/- 5.6 Wood units and 66 +/- 24 mmHg. RA-RS% was associated negatively with PVR (r = -0.46; P < 0.05) and positively with stroke volume and cardiac output (all P < 0.05). Both right atrial pressure (RAP) obtained by RHC as well as RA-SR E had significant association with WHO-FC (Multiple R = 0.7; P = 0. 01 and 0.007, respectively). RA strain rate during systole and RAP had significant association with 6MWD (Multiple R = 0.7; P = 0.01 and 0.006, respectively). CONCLUSION: Right atrium mechanics not only correlate well with RHC-obtained hemodynamics, but also correlate with functional capacity in treatment-naive IPAH. PMID- 26096218 TI - Identification of PDGF-BB binding to thymosin beta4 by chemical cross-linking. AB - INTRODUCTION: The purpose of our work was to identify unknown interaction partners of thymosin beta4 (Tbeta4). It was suggested that Tbeta4 could be an antifibrotic drug for treatment of liver fibrogenesis, because Tbeta4 prevents the platelet-derived growth factor-BB (PDGF-BB)-induced activation of hepatic stellate cells (HSCs). Very little information is available how Tbeta4 counteracts the PDGF-BB-induced activation of HSCs. We propose the hypothesis that Tbeta4 could bind directly to PDGF-BB and thereby reduce the concentration of free PDGF-BB available for binding to the PDGF-beta receptor. METHODS: To prove our suggestion of a direct interaction between Tbeta4 and PDGF-BB, we carried out chemical as well as photochemical cross-linking experiments between the two pure proteins in vitro. RESULTS: We identified an interaction between Tbeta4 and PDGF-BB by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) cross linking as well as through biotin label transfer using a bifunctional photoactivatable derivative of Tbeta4. In an in vitro system, PDGF-BB was identified as the first extracellular partner interacting with Tbeta4. This interaction could influence PDGF-BB binding to its receptor and abolish PDGF-BB related effects. CONCLUSION: Direct interaction of Tbeta4 with extracellular factors should be considered as a potential mechanism to explain the pleiotropic effects of beta-thymosins. PMID- 26096219 TI - Editorial. PMID- 26096220 TI - Multiple Displaced Metacarpal Fractures. PMID- 26096221 TI - Dupuytren Contracture Recurrence Following Treatment With Collagenase Clostridium histolyticum (CORDLESS [Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study]): 5-Year Data. AB - PURPOSE: Collagenase Option for Reduction of Dupuytren Long-Term Evaluation of Safety Study was a 5-year noninterventional follow-up study to determine long term efficacy and safety of collagenase clostridium histolyticum (CCH) treatment for Dupuytren contracture. METHODS: Patients from previous CCH clinical studies were eligible. Enrolled patients were evaluated annually for contracture and safety at 2, 3, 4, and 5 years after their first injection (0.58 mg) of CCH. In successfully treated joints (<= 5 degrees contracture following CCH treatment), recurrence was defined as 20 degrees or greater worsening (relative to day 30 after the last injection) with a palpable cord or any medical/surgical intervention to correct new/worsening contracture. A post hoc analysis was also conducted using a less stringent threshold (>= 30 degrees worsening) for comparison with criteria historically used to assess surgical treatment. RESULTS: Of 950 eligible patients, 644 enrolled (1,081 treated joints). At year 5, 47% (291 of 623) of successfully treated joints had recurrence (>= 20 degrees worsening)-39% (178 of 451) of metacarpophalangeal and 66% (113 of 172) of proximal interphalangeal joints. At year 5, 32% (198 of 623) of successfully treated joints had 30 degrees or greater worsening (metacarpophalangeal 26% [119 of 451] and proximal interphalangeal 46% [79 of 172] joints). Of 105 secondary interventions performed in the successfully treated joints, 47% (49 of 105) received fasciectomy, 30% (32 of 105) received additional CCH, and 23% (24 of 105) received other interventions. One mild adverse event was attributed to CCH treatment (skin atrophy [decreased ring finger circumference from thinning of Dupuytren tissue]). Antibodies to clostridial type I and/or II collagenase were found in 93% of patients, but over the 5 years of follow-up, this did not correspond to any reported clinical adverse events. CONCLUSIONS: Five years after successful CCH treatment, the overall recurrence rate of 47% was comparable with published recurrence rates after surgical treatments, with one reported long-term treatment-related adverse event. Collagenase clostridium histolyticum injection proved to be an effective and safe treatment for Dupuytren contracture. For those receiving treatment during follow-up, both CCH and fasciectomy were elected options. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 26096222 TI - A global assessment of the social and conservation outcomes of protected areas. AB - Protected areas (PAs) are a key strategy for protecting biological resources, but they vary considerably in their effectiveness and are frequently reported as having negative impacts on local people. This has contributed to a divisive and unresolved debate concerning the compatibility of environmental and socioeconomic development goals. Elucidating the relationship between positive and negative social impacts and conservation outcomes of PAs is key for the development of more effective and socially just conservation. We conducted a global meta analysis on 165 PAs using data from 171 published studies. We assessed how PAs affect the well-being of local people, the factors associated with these impacts, and crucially the relationship between PAs' conservation and socioeconomic outcomes. Protected areas associated with positive socioeconomic outcomes were more likely to report positive conservation outcomes. Positive conservation and socioeconomic outcomes were more likely to occur when PAs adopted comanagement regimes, empowered local people, reduced economic inequalities, and maintained cultural and livelihood benefits. Whereas the strictest regimes of PA management attempted to exclude anthropogenic influences to achieve biological conservation objectives, PAs that explicitly integrated local people as stakeholders tended to be more effective at achieving joint biological conservation and socioeconomic development outcomes. Strict protection may be needed in some circumstances, yet our results demonstrate that conservation and development objectives can be synergistic and highlight management strategies that increase the probability of maximizing both conservation performance and development outcomes of PAs. PMID- 26096223 TI - Measuring embeddedness: Hierarchical scale-dependent information exchange efficiency of the human brain connectome. AB - This article presents a novel approach for understanding information exchange efficiency and its decay across hierarchies of modularity, from local to global, of the structural human brain connectome. Magnetic resonance imaging techniques have allowed us to study the human brain connectivity as a graph, which can then be analyzed using a graph-theoretical approach. Collectively termed brain connectomics, these sophisticated mathematical techniques have revealed that the brain connectome, like many networks, is highly modular and brain regions can thus be organized into communities or modules. Here, using tractography-informed structural connectomes from 46 normal healthy human subjects, we constructed the hierarchical modularity of the structural connectome using bifurcating dendrograms. Moving from fine to coarse (i.e., local to global) up the connectome's hierarchy, we computed the rate of decay of a new metric that hierarchically preferentially weighs the information exchange between two nodes in the same module. By computing "embeddedness"-the ratio between nodal efficiency and this decay rate, one could thus probe the relative scale-invariant information exchange efficiency of the human brain. Results suggest that regions that exhibit high embeddedness are those that comprise the limbic system, the default mode network, and the subcortical nuclei. This supports the presence of near-decomposability overall yet relative embeddedness in select areas of the brain. The areas we identified as highly embedded are varied in function but are arguably linked in the evolutionary role they play in memory, emotion and behavior. PMID- 26096224 TI - Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model. AB - OBJECTIVE: Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjogren's syndrome and type 1 diabetes. METHODS: The alpha-7 nicotinic acetylcholine receptor (alpha7nAChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. alpha7nAChR expression, focus scores, and salivary flow were evaluated in salivary glands (SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. RESULTS: alpha7nAChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. CONCLUSION: Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes. PMID- 26096225 TI - Copper-Catalyzed Regioselective Hydroalkylation of 1,3-Dienes with Alkyl Fluorides and Grignard Reagents. AB - Copper complexes generated in situ from CuCl2, alkyl Grignard reagents, and 1,3 dienes play important roles as catalytic active species for the 1,2 hydroalkylation of 1,3-dienes by alkyl fluorides through C-F bond cleavage. The alkyl group is introduced to an internal carbon atom of the 1,3-diene regioselectively, thus giving rise to the branched terminal alkene product. PMID- 26096226 TI - Jasmonate in plant defence: sentinel or double agent? AB - Plants and their biotic enemies, such as microbial pathogens and herbivorous insects, are engaged in a desperate battle which would determine their survival death fate. Plants have evolved efficient and sophisticated systems to defend against such attackers. In recent years, significant progress has been made towards a comprehensive understanding of inducible defence system mediated by jasmonate (JA), a vital plant hormone essential for plant defence responses and developmental processes. This review presents an overview of JA action in plant defences and discusses how microbial pathogens evade plant defence system through hijacking the JA pathway. PMID- 26096227 TI - Quantification of aortic stiffness using magnetic resonance elastography: Measurement reproducibility, pulse wave velocity comparison, changes over cardiac cycle, and relationship with age. AB - PURPOSE: To assess MR elastography (MRE)-derived aortic shear stiffness (MUMRE ) measurements for: 1) reproducibility, 2) comparison to pulse wave velocity, 3) changes over the cardiac cycle, and 4) relationship with age. METHODS: Cardiac gated aortic MRE was performed on 20 healthy volunteers (aged 20-73 years). For assessing reproducibility of stiffness measurements, scans were repeated per volunteer. MRE wave images were analyzed to obtain stiffness of the abdominal aorta across the cardiac cycle, and comparisons were made with subject age. RESULTS: Analysis of concordance correlation coefficient between scans 1 and 2 showed that rc = 0.86 (95% confidence interval, 0.77, 0.94) with P < 0.0001. Significantly higher MUMRE was observed for all volunteers during end-systole when compared to end-diastole (P < 0.0001). MUMRE increased with age; end systolic stiffness demonstrated a relatively stronger correlation with age (r = 0.62, P = 0.003) when compared to end-diastolic stiffness (r = 0.51, P = 0.023); and the slopes of end-systole and end-diastole were found to be significantly different (P = 0.011). [Formula: see text] at end-systole and end-diastole correlated linearly with pulse wave velocity, with an r = 0.54 (P = 0.013) and r = 0.58 (P = 0.008), respectively. CONCLUSION: The results of this study indicate that MRE-derived aortic shear stiffness measurements are robust (reproducible and comparable to similar techniques). Mean MUMRE was higher during end-systole when compared to end-diastole. MUMRE was found to increase with age and showed a stronger correlation with end-systolic stiffness than with end-diastolic stiffness. PMID- 26096228 TI - Circulating miR-145 is associated with plasma high-sensitivity C-reactive protein in acute ischemic stroke patients. AB - Stroke is a major cerebrovascular disease threatening human health and life with high morbidity, disability and mortality. We aimed to find effective biomarkers for the early diagnosis on stroke. Nine previously reported stroke-associated miRNAs (miR-21, miR-23a, miR-29b, miR-124, miR-145, miR-210, miR-221, miR-223 and miR-483-5p) were measured by quantitative real time-PCR, and plasma high sensitivity C-reactive protein (hs-CRP) and serum interleukin 6 (IL-6), the pro inflammation markers in brain injury, were examined by enzyme-linked immunosorbent assay in 146 acute ischemic stroke patients and 96 healthy blood donors. We found that serum miR-145 was significantly increased within 24 h after stroke onset and serum miR-23a and miR-221 were decreased in patients. Moreover, serum miR-145 was strong positively correlated with plasma hs-CRP and moderate positively correlated with serum IL-6. Meanwhile, serum miR-23a and miR-221 were moderate negatively correlated with plasma hs-CRP but not serum IL-6. Importantly, the combination of hs-CRP and serum miR-145 gained a better sensitivity/spectivity for prediction of acute ischemia stroke (area under receiver operating characteristic curve from 0.794 to 0.896). Conclusively, our preliminary findings indicate that serum miR-145 upregulated in acute ischemic stroke might be a new biomarker for acute ischemia stroke evaluation. PMID- 26096229 TI - Palaeo-islands as refugia and sources of genetic diversity within volcanic archipelagos: the case of the widespread endemic Canarina canariensis (Campanulaceae). AB - Geographical isolation by oceanic barriers and climatic stability has been postulated as some of the main factors driving diversification within volcanic archipelagos. However, few studies have focused on the effect that catastrophic volcanic events have had on patterns of within-island differentiation in geological time. This study employed data from the chloroplast (cpDNA haplotypes) and the nuclear (AFLPs) genomes to examine the patterns of genetic variation in Canarina canariensis, an iconic plant species associated with the endemic laurel forest of the Canary Islands. We found a strong geographical population structure, with a first divergence around 0.8 Ma that has Tenerife as its central axis and divides Canarian populations into eastern and western clades. Genetic diversity was greatest in the geologically stable 'palaeo-islands' of Anaga, Teno and Roque del Conde; these areas were also inferred as the ancestral location of migrant alleles towards other disturbed areas within Tenerife or the nearby islands using a Bayesian approach to phylogeographical clustering. Oceanic barriers, in contrast, appear to have played a lesser role in structuring genetic variation, with intra-island levels of genetic diversity larger than those between-islands. We argue that volcanic eruptions and landslides after the merging of the palaeo-islands 3.5 Ma played key roles in generating genetic boundaries within Tenerife, with the palaeo-islands acting as refugia against extinction, and as cradles and sources of genetic diversity to other areas within the archipelago. PMID- 26096230 TI - Outcome of Vaginoplasty in Male-to-Female Transgenders: A Systematic Review of Surgical Techniques. PMID- 26096231 TI - Low temperature oxidative desulfurization with hierarchically mesoporous titaniumsilicate Ti-SBA-2 single crystals. AB - Hierarchically porous Ti-SBA-2 with high framework Ti content (up to 5 wt%) was firstly synthesized by employing organic mesomorphous complexes of a cationic surfactant (CTAB) and an anionic polyelectrolyte (PAA) as templates. The material exhibited excellent performance in oxidative desulfurization of diesel fuel at low temperature (40 degrees C or 25 degrees C) due to the unique hierarchically porous structure and high framework Ti content. PMID- 26096232 TI - The association between endometriosis and survival outcomes of ovarian cancer: Evidence-based on a meta-analysis. AB - BACKGROUND: Although it is generally recognized that endometriosis was significantly associated with higher risk of ovarian cancer, the association between endometriosis and the cancer survival outcomes is still not clear. This meta-analysis aims to pool previous studies and to make an update estimate. METHODS: Relevant studies were searched among PubMed, Medline and Embase. Hazard ratio (HR) and the corresponding 95% confidence intervals (CI) of progression free survival (PFS) and overall survival (OS) were pooled with generic inverse variance method. The proportion of the low stage and grade tumors (stage: Stage I and II among total; grade: Grade I among total) in endometriosis-associated ovarian cancer (EAOC) group and in non-EAOC group were assessed with odd ratio and the corresponding 95% CI. RESULTS: Endometriosis-associated ovarian cancer were significantly associated with higher rate of OS in crude analysis (HR: 0.74, 95% CI: 0.63-0.87, P = 0.0003). However, in most of the studies included, the OS benefit was not significant under multivariable survival analysis. EAOC patients generally had early-stage, low histological grade tumors and younger age compared with non-EAOC patients. No difference was observed in PFS between the two groups. CONCLUSION: The OS benefits associated with endometriosis might be closely related to higher prevalence of patients diagnosed at early-stage and greater chance of receiving optimal cytoreductive surgery or chemotherapy. Endometriosis should not be viewed as an independent prognostic factor of ovarian cancer. PMID- 26096233 TI - Blood pressure values in healthy term newborns at a tertiary health facility in Enugu, Nigeria. AB - BACKGROUND: Blood pressure (BP) is a reflection of hemodynamic variables. It is an important vital sign and indicator of clinical stability. Accurate measurement of this physiological signal is essential for the optimal management of the ill infant. An increase in the awareness of hypertension among neonates has resulted to increased ability to diagnose neonates with the disease. OBJECTIVES: This study aimed to determine BP values in apparently healthy term newborns in the first 48 h of life and evaluate the factors affecting BP at birth. METHODS: Three hundred and ten healthy appropriate for gestational age term newborns were consecutively recruited. BP measurements were determined using the oscillometric technique with the neonate supine after an appropriate size cuff was applied on the right arm. The monitor (Dinamap 8100) is switched on while the cuff inflation and deflation is automatically done by the instrument with subsequent display of the BP values on the screen. BP measurements were taken at age 0-24 h and 25-48 h. Their weight was measured with infant's weighing scale, and data analyzed with SPSS version 15. RESULTS: The mean systolic BP (SBP), diastolic and mean arterial BP at 0-24 h were 63.3 +/- 5.5 mmHg, 36.8 +/- 5.3 mmHg and 46.4 +/- 5.2 mmHg respectively. There was a positive correlation between birth weight and SBP at birth. No significant correlation was found between BP and gender, mode of delivery or maternal age. CONCLUSION: This study provides current normative BP values that can be used in neonatal Intensive Care Unit. PMID- 26096234 TI - Biomechanical comparison of osteosynthesis with poly-L-lactic acid and titanium screw in intracapsular condylar fracture fixation: An experimental study. AB - BACKGROUND AND AIMS: The aim of this study was to compare the biomechanical stability of poly-L-lactic acid and titanium screws in the fixation of intracapsular condylar fractures, in 10 polyurethane hemimandibles. MATERIALS AND METHODS: Artificial intracapsular fractures were created with a steel disk and electronic micromotor. The first group was fixed with 15 mm long self-tapping 2.0 mm system titanium screws and the second group was fixed with 15 mm long 2.4 mm bioresorbable screws. Linear loads of 25, 50, 75, 100 N was applied in anteroposterior direction to the hemimandibles and the data were transmitted directly from the load cell to a computer that shows emergent results of material characteristics under same forces as a graphic containing force and displacement. RESULTS: The results show that there were no significant differences between the two methods, with 25 N of loading. (P > 0,05) The difference became significant with a higher value of loading. CONCLUSION: The results suggest that treatment with a single resorbable screw is not functionally stable as a single titanium screw. PMID- 26096235 TI - A study of Staphylococcus aureusnasal carriage, antibacterial resistance and virulence factor encoding genes in a tertiary care hospital, Kayseri, Turkey. AB - AIM: This study was to determine the virulence encoding genes, and the antibiotic resistance patterns of the Staphylococcus aureus isolates, which were isolated from the nasal samples of chest clinic patients. MATERIALS AND METHODS: The nasal samples of the in-patients (431) and out-patients (1857) in Kayseri Training and Research Hospital's Chest Clinic, Kayseri, Turkey, were cultured on CHROMagar (Biolife, Italiana) S. aureus, and subcultured on sheep blood agar for the isolation of S. aureus. Disc diffusion method was used for antimicrobial susceptibility testing. The occurrence of the staphylococcal virulence encoding genes (enterotoksins [sea, seb, sec, see, seg, seh, sei, sej], fibronectin binding proteins A, B [fnbA, fnbB], toxic shock syndrome toxin-1 [tst]) were detected by polymerase chain reaction. RESULTS: Forty-five of the 55 (81.8%) S. aureus isolates from inpatients, and 319 (90.6%) isolates from tested 352 out patient's isolates were suspected to all the antibiotics tested. methicillin resistant S. aureus (MRSA) was detected in 1.2% of S. aureus isolates. Rifampin, trimethoprim-sulfamethoxazole, clindamycin, erythromycin, gentamicin resistance rates were 1.2%, 1.7%, 2.0%, 8.8%, and 1.2%, respectively. The isolates were susceptible to teicoplanin and vancomycin. The genes most frequently found were tst (92.7%), seg (85.8%), sea (83.6%), fnbA (70.9%). There was no statistical significance detected between MRSA and mecA-negative S. aureus isolates in encoding genes distribution (P > 0.05). CONCLUSION: Our results show that virulence factor encoding genes were prevalent in patients with S. aureus carriage, whereas antibiotic resistance was low. These virulence determinants may increase the risk for subsequent invasive infections in carriers. PMID- 26096236 TI - Evaluation of the permeability of five desensitizing agents using computerized fluid filtration. AB - OBJECTIVE: The aim of this study was to evaluate the permeability of five desensitizing agents using computerized fluid filtration (CFF) test method. MATERIALS AND METHODS: Sixty dentin discs of 500 +/- 200-mm-thick were prepared from middle dentin of bovine incisors without exposed the pulp and then randomly divided into five groups (n = 12). The permeability of the discs was measured using the CFF test method before and after application of the following desensitizers: Admira Protect (Voco, Cuxhaven, Germany), Seal and Protect (Dentsply, Konstanz, Germany), Sensi Kill (DFL, Brazil), Systemp Desensitizer (Ivoclar Vivadent, Liechtenstein), BisBlock (Bisco, USA). Fluid movement measurements were made at 2-min intervals for 8 min, and a mean of the values obtained was calculated for each specimen. The results were analyzed using Kruskal-Wallis test and Wilcoxon signed ranks tests with a significance threshold of P < 0.05. RESULTS: There were no significant differences in permeability among desensitizing agents (P > 0.05); however dentin permeability was reduced in all groups (P < 0.05). CONCLUSION: The in vitro fluid conductance of dentin discs were reduced by treating with these five desensitizing agents. PMID- 26096237 TI - Effects of low-level laser therapy on osteoblastic bone formation and relapse in an experimental rapid maxillary expansion model. AB - AIMS AND OBJECTIVES: The aim of this study was to investigate the effects of low level laser therapy (LLLT) on osteoblastic bone formation and relapse during expansion of rat palatal sutures. MATERIALS AND METHODS: Thirty-two Wistar rats were randomly allocated into two groups of 16 rats each. In the first group, LLLT was applied 4 days after expansion commenced. Seven days after expansion, retainers were applied for 10 days. The second group was similarly treated, with the exception of laser therapy. All rats were sacrificed on day 7 (n = 1) (the end of the expansion period; laser group (LG) 1 [LLLT 1] and control group (CG) 1 [control 1]) and day 17 (n = 8) (the end of the retention period; LG 2 [LLLT 2] and CG 2 [control 2]) for histological assessment. RESULTS: The LLLT 1 group had significantly higher numbers of osteoclasts than did the control 1 group (P = 0.036). No significant between-group difference in osteoblast cell or capillary numbers was evident when day 7 and 17 data were compared. CONCLUSION: Histologically, LLLT stimulated bone formation, as revealed by analysis after the retention period. LLLT during expansion may accelerate bone healing. PMID- 26096238 TI - Is there a relationship between Parkinson's disease and Chlamydia pneumoniae? AB - OBJECTIVES: The aim was to investigate a possible relationship between Chlamydia pneumoniae and Parkinson's disease (PD). STUDY DESIGN: Serum samples obtained from a cohort of 51 patients with PD and from 37 age- and sex-matched controls were assessed for the presence of antibodies. The control group was selected from healthy people. In both groups, 5 mL of blood was taken and after centrifugation frozen at -80 degrees C. Presence and concentration for C. pneumoniae IgM and IgG were determined by the enzyme linked immunosorbent assay (ELISA) and immunofluorescence (IFA), using C. pneumoniae IgG and IgM kit (Euroimmun, Germany). RESULTS: Chlamydia pneumoniae IgG was positive in 50 (98%) patients in ELISA study. C. pneumoniae IgG was positive in 34 (92%) control subjects in ELISA study. C. pneumoniae IgG positivity in patients was slightly higher, but the difference did not reach statistical significance (P = 0.17). No statistically significant difference was found between the patient and the control groups in IFA study (P >= 0.5). C. pneumoniae IgM results (both ELISA and IFA study) was negative in the both PD group and control group. PMID- 26096239 TI - Validity of the Demirjian method for dental age estimation for Southern Turkish children. AB - OBJECTIVE: The aim of this study was to evaluate the applicability of the Demirjian method for southern Turkish population. MATERIALS AND METHODS: Panoramic radiographs of 535 patients (276 females, 259 males aged from 10 to 18 years) selected retrospectively. Dental age was calculated using the Demirjian's method. Chronologic age was calculated by subtracting the date of the birth from the date of the panoramic radiograph after having converted both to a decimal age. The chronologic and dental ages were compared using the paired t-test. RESULTS: The mean difference between the chronologic and dental ages ranged from 0.02 to 0.79 years in females. These differences in females between the chronologic and dental ages were statistically significant in total (P < 0.050) and in G1 (10-10.90 years) (P < 0.010) and G2 (11-11.90 years) (P < 0.001). The mean difference between the chronologic and dental ages ranged from 0.04 to 0.85 years in males. These differences in males between the chronologic age and dental age were statistically significant in total (P < 0.010) and in G4 (13-13.90 years) G5 (14-14.90 years) G6 (15-15.90 years) groups (P < 0.050). CONCLUSIONS: It is appropriate to use the Demirjian method in southern Turkish children; however, a revision is needed in some age groups. PMID- 26096240 TI - The seroprevalence of brucellosis among undiagnosed family members of brucellosis positive patients. AB - AIM: This study investigated the seroprevalence, complications and risk factors of Brucella infection in rural areas of Sivas, Turkey. MATERIALS AND METHODS: The study was conducted in three hyperendemic counties for brucellosis known as Gurun, Altinyayla and Kangal in Sivas between April and October in 2011. A total of 1,430 subjects were consulted. RESULTS: Of the 1,430 subjects, 217 (15.2%) with clinical findings compatible with brucellosis were examined by taking blood samples to study both standard tube agglutination test (STAT) and enzyme-linked immunosorbent assay (ELISA) (Genzyme Virotech GmbH, Romicronsselsheim, Germany). The seroprevalance of Brucella was found to be 8.0%. Brucella seropositivity was detected in 114 (52.5%) of the 217 subjects with STAT. There was no significant difference between female and male subjects with regard to Brucella seropositivity (P = 0.214). The seropositivity of subject 16-65 age group was significantly higher than those of subjects in <16 and >65 age groups (P = 0.001). In Brucella ELISA test results, 123 (56.7%) subjects had positive IgG antibodies and 96 (44.2%) IgM antibodies. Skeletal complications were the most frequent; joint, muscle, and waist pain were found in 87.1%, 79.7%, and 74.6% of subjects respectively. Most subjects (90.8%) gave a history of frequent consumption of fresh cheese directly from the cattle they own and contact with animals (77.8%) for risk factors of brucellosis. CONCLUSION: Brucella seropositivity is high in Gurun, Altinyayla and Kangal counties and primary care physicians should keep in mind the clinical and laboratory findings of brucellosis especially in family members of brucellosis patients. PMID- 26096241 TI - Lipoatrophy among patients on antiretroviral therapy in Lagos, Nigeria: Prevalence, pattern and association with cardiovascular risk factors. AB - CONTEXT: Antiretroviral therapy (ART) is linked with morphologic abnormalities such as lipoatrophy (LA), which may accompany metabolic alterations (dysglycemias, dyslipidemia and insulin resistance) that increase cardiovascular disease risk. LA and its association with metabolic alterations have been infrequently studied amongst Nigerians on ART. AIMS: To determine the prevalence, pattern and association of LA with metabolic abnormalities and hypertension among patients on ART attending an ambulatory human immunodeficiency virus clinic in Lagos, Nigeria. SUBJECTS AND METHODS: A cross-sectional study was carried out among patients on ART using a structured interviewer administered questionnaire. Data obtained included patients and physician's assessment of body fat changes, drug history, blood pressure, body composition assessment using bioelectrical impedance analysis and biochemical evaluation (glucose, lipids). LA was defined clinically. Data were analyzed using IBM SPSS statistical software version 21. RESULTS: A total of 48 (33.1%) of the 145 patients had LA. The face was the most frequently affected body region. Patients with LA with lower body circumferences, skin-fold thickness and body fat (P < 0.05). The frequencies of lipid abnormalities were: Reduced high density lipoprotein-cholesterol (47.1%), elevated total cholesterol (35.6%), reduced low density lipoprotein-cholesterol (19.2%), elevated triglycerides (14.4%). Fasting plasma glucose (FPG)>=6.1 mmol/l and hypertension were present among 9.6% and 40.7% respectively. LA was not significantly associated with the presence of glucose intolerance, dyslipidemia or hypertension (P > 0.05). CONCLUSIONS: Lipoatrophy, though commonly encountered in patients on ART in Nigeria was not associated with the presence of dyslipidemia, abnormal FPG or hypertension. Regular monitoring by the physician and increased patients awareness are necessary to reduce its prevalence and impact. PMID- 26096242 TI - Important clinical and laboratory correlates of glomerular filtration rate in sickle cell anemia. AB - BACKGROUND: Renal impairment is routinely assessed using the estimated glomerular filtration rate (eGFR) and it may be helpful to obtain certain clinical or laboratory markers, which show relationship with glomerular filtration rate (GFR) in sickle cell disease (SCD). AIM: To assess the relationship between important clinical and laboratory parameters in SCD, and the eGFR. PATIENTS AND METHODS: Steady state clinical and laboratory data were obtained from 228 homozygous SCD patients seen over a 7-year period. The GFR was estimated using (isotope dilution mass spectrometry) traceable modification of diet in renal disease (MDRD) and Cockroft-Gault methods. The correlation coefficient and independent t-test were done to assess the level of significance between the eGFR_MDRD and the known indicators of disease severity. RESULTS: The serum alkaline phosphatase (ALP) and serum direct bilirubin levels both showed significant inverse relationship with eGFR_MDRD P = 0.012 and P = 0.24, respectively. The patients' age, Hb, leukocyte count, platelet count, serum direct bilirubin and aspartate transaminase did not show a significant correlation. The eGFR_MDRD was more discriminatory revealing that 20.3% of the patients had suboptimal GFR. Proteinuria in steady state was observed in 20.3% of the patients. CONCLUSION: High serum direct bilirubin and ALP are associated with a deteriorating eGFR_MDRD. Other clinical and laboratory indicators of disease severity in SCD do not show the relationship with the GFR. MDRD_GFR estimation seemed to be a more appropriate method of estimating GFR in SCD. PMID- 26096243 TI - Correlation of astrocyte elevated gene-1, basic-fibroblast growth factor, beta catenin, Ki-67, tumor necrosis factor-alfa with prognostic parameters in ductal carcinomas and ductal intraepithelial neoplasms. AB - BACKGROUND: Breast cancer is the second most frequent cancer in the world. Although it is widely accepted that the etiology of breast cancer includes both genetic and environmental factors, the molecular mechanism of its development and progression remains poorly understood, and thus far, no specific signature of breast cancer gene expression has been reported to allow for patient-tailored therapy strategies. Hence, it is of great clinical value to further understand the molecular mechanisms underlying the progression of breast cancer and to identify effective early markers for the diagnosis and prognosis of the disease as well as novel therapeutic targets. MATERIALS AND METHODS: This study was conducted on a total of 90 paraffin-embedded breast tumor samples. Immunohistochemical stains for astrocyte elevated gene-1 (AEG-1), basic fibroblast growth factor (b-FGF), beta-catenin, Ki-67, tumor necrosis factor alpha (TNF-alpha) were performed on tissue microarray using standard procedures. Each patient age, grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) status, size, lymphovascular invasion, metastasis of lymph node (LNM), nipple and ductal hyperplasia areas were assessed. RESULTS: We observed significant relationship between the age and LNM or FGF (P = 0.018, 0.035, respectively). The relationship between histological and nuclear grade, LNM, ER, PR, HER-2 and prognostic parameters was evaluated in cases of ductal carcinomas (DC). There was a significant positive correlation between TNF-alpha, size, LNM (P <= 0.0001, 0.002, 0.005). We found that significant relationship between AEG-1 and TNF-alpha. There was a significant positive correlation between FGF and Ki-67 and negative correlation AEG-1. Although, FGF, TNF-alpha, AEG-1 staining in DC were observed higher than ductal intraepithelial neoplasms, this observation could not statistically (P >= 0.05). CONCLUSIONS: The present work aims to investigate the relationship between the expression of AEG-1, b-FGF, beta-catenin, Ki-67, TNF-alpha other prognostic parameters in DC and ductal intraepithelial neoplasm. We found a relationship between these factors. PMID- 26096244 TI - A retrospective review of intensive care management of organophosphate insecticide poisoning: Single center experience. AB - BACKGROUND: Organophosphate (OP) compounds are used as insecticides. Given the widespread availability and use of these chemicals, OP poisoning is quite common following either accidental or intentional exposures. Immediate intensive care management can save lives in these patients. We aimed to investigate intensive care management provided to OP poisoning patients in a tertiary care hospital in Turkey. SUBJECTS AND METHODS: This was a retrospective chart review of 62 patients, admitted to the Intensive Care Unit (ICU) with OP poisoning between 2000 and 2012. RESULTS: Of the 62 patients studied, 40 (65%) were male, 45 (73%) were suicide attempts, 59 (95%) ingested the OP compounds, and three patients (5%) (two patients with suicide and 1 with accidental exposure) died in the ICU. There were statistically significant differences between survivors and nonsurvivors for Glasgow Coma Scale (GCS) on admission (P = 0.034), Acute Physiology and Chronic Health Evaluation II (APACHE II) score (P = 0.003), Sequential Organ Failure Assessment (SOFA) score (P = 0.024), time to initiation of treatment (P = 0.034) and serum lactate dehydrogenase (LDH) levels (P = 0.007). CONCLUSIONS: Organophosphate poisoning is a life-threatening condition that requires immediate diagnosis and management. GCS, APACHE II score, SOFA score, and time to admission to the emergency department and LDH levels can provide prognostic information and predict outcomes. PMID- 26096245 TI - Effectiveness of trained community volunteers in improving knowledge and management of childhood malaria in a rural area of Rivers State, Nigeria. AB - INTRODUCTION: Malaria accounts for 70% of illnesses and 30% of deaths among children under 5 years in Nigeria. This study was aimed at determining the effectiveness of trained community volunteers in delivering multiple anti-malaria interventions to achieve rapid reduction in morbidity and mortality among under 5 children. MATERIALS AND METHODS: A quasi-experimental study was carried out in two rural communities in Rivers State, Nigeria among 368 mothers/caregivers. A set of 184 of the mothers/caregivers (experimental group) were trained on malaria and provided with bed nets and drugs (artemisinin-lumefantrine) to treat children under 5 years who developed fever during the period of the experiment. Another set of 184 mothers/caregivers (controls) did not receive similar training and drugs. Both groups were compared at baseline and after 6 months of the experiment on their knowledge of malaria prevention and treatment. Level of significance was set at P = 0.05. RESULTS: In the experimental group: Adequate knowledge about malaria increased from 115 (62.5%) to 175 (95.1%) (P < 0.0001), early commencement of treatment of fever increased from 68 (37.0%) to 131 (75.7%) (P < 0.0001), and children cured of malaria increased from 87 (47.3%) to 146 (84.4%) (P < 0.0001). Insecticide-treated bed nets use also increased from 86 (46.7%) to 161 (87.5%) (P < 0.0001). There were no significant changes in the control group. CONCLUSIONS: The study demonstrated the inherent potentials in using community based volunteers in malaria prevention and control for those in rural areas with poor health service delivery. We advocate its adaptation for far-reaching reduction in childhood morbidity and mortality and rapid attainment of millennium development goals 4. PMID- 26096246 TI - The clinical usefulness of initial serum procalcitonin as an aggravation predictor in a hepatobiliary tract infection at emergency department. AB - BACKGROUND AND OBJECTIVES: The ability to predict future clinical deterioration early in patients who present to an emergency care center with a hepatobiliary tract infection is difficult. We studied the clinical usefulness of the initial serum levels of procalcitonin in a hepatobiliary tract infection as an indicator for predicting aggravation in the early stages. METHODS: Of the patients who presented with the clinical symptoms of a hepatobiliary tract infection, 99 were diagnosed with a hepatobiliary tract infection by imaging studies and subsequently enrolled in the study. Laboratory tests were obtained in the early stage of disease after presentation to an emergency care center. We assessed and compared the serum levels of many early inflammatory markers (white blood cell [WBC] counts, C-reactive protein and procalcitonin) between patients whose symptoms were initially stable upon arrival to an emergency care center but then deteriorated to, those whose symptoms remained consistently stable. Thus, we examined if the above serum markers are useful in predicting the possibility of future symptom aggravation. RESULTS: Of a total of 99 patients, 27 were assigned to the symptom aggravation group. The serum levels of WBC counts and C-reactive protein in the aggravation group were elevated. However, the median value (interquartile range) of procalcitonin was relatively increased at 2.28 (0.41 7.84 ng/ml), demonstrating a significant difference. CONCLUSIONS: In conclusion, initial serum levels of procalcitonin might be used as an indicator for aggravation in patients with hepatobiliary tract infection at the emergency department, even though there is hemodynamic stability. PMID- 26096247 TI - Concerns about the knowledge and attitude of multidrug-resistant tuberculosis among health care workers and patients in Delta State, Nigeria. AB - BACKGROUND: Inadequate knowledge and wrong perception of multidrug-resistant tuberculosis (MDR-TB) by Health Care Workers (HCWs) and patients are detrimental to tuberculosis control programs. OBJECTIVE: The aim was to assess the knowledge and attitudes of HCWs and TB patients about MDR-TB in Delta State, Nigeria. MATERIALS AND METHODS: A cross-sectional study was carried out among HCWs and TB patients in Delta State, Nigeria. Data were collected using a structured interviewer-administered questionnaire and analyzed using IBM SPSS Statistics version 20. RESULTS: Ninety-six HCWs and 114 TB patients were studied. The HCWs (mean age 43.0 +/- 10.1 years) were older than the patients (mean age 41.7 +/- 16.9 years). A higher proportion (54.2%) of HCWs had tertiary education, but only 15% of the patients had above secondary education. Eight (8.3%) HCWs and majority (60.5%) of the patients had no knowledge about of MDR-TB. Only 18.4% of patients compared to 61.5% of HCWs had good knowledge of MDR-TB. Both groups demonstrated a positive attitude toward MDR-TB. CONCLUSION: The knowledge of MDR-TB was poor among the TB patients studied as well as among HCWs with low educational status. MDR-TB training program for both HCWs and patients need to be re-structured to allow for greater gain in MDR-TB knowledge among both groups, which in turn may help improve compliance and treatment outcomes among patients. PMID- 26096248 TI - Bad-breath: Perceptions and misconceptions of Nigerian adults. AB - OBJECTIVE: To provide baseline data about bad-breath perception and misconceptions among Nigerian adults. METHODS: Multi-center cross-sectional study of individuals aged 18-64 years using examiner-administered questionnaires. Age comparisons were based on the model of emerging adults versus full adults. Data were recoded for statistical analyses and univariate and secondary log-linear statistics applied. RESULTS: Participants had lopsided perceptions about bad breath. While 730 (90.8%) identified the dentist as the expert on halitosis and 719 (89.4%) knew that bad-breath is not contagious, only 4.4% and 2.5% associated bad-breath with tooth decay and gum disease respectively. There were no significant sex differences but the older adults showed better knowledge in a few instances. Most respondents (747, 92.9%) would tell a spouse about their bad breath and 683 (85%) would tell a friend. CONCLUSIONS: Participants had lop-sided knowledge and perceptions about bad-breath. Most Nigerian adults are their "brothers' keepers" who would tell a spouse or friend about their halitosis so they could seek treatment. PMID- 26096249 TI - Temperature increases on the external root surface during endodontic treatment using single file systems. AB - AIMS: The aim of this study is to evaluate increases in temperature on the external root surface during endodontic treatment with different rotary systems. MATERIALS AND METHODS: Fifty human mandibular incisors with a single root canal were selected. All root canals were instrumented using a size 20 Hedstrom file, and the canals were irrigated with 5% sodium hypochlorite solution. The samples were randomly divided into the following three groups of 15 teeth: Group 1: The OneShape Endodontic File no.: 25; Group 2: The Reciproc Endodontic File no.: 25; Group 3: The WaveOne Endodontic File no.: 25. During the preparation, the temperature changes were measured in the middle third of the roots using a noncontact infrared thermometer. The temperature data were transferred from the thermometer to the computer and were observed graphically. Statistical analysis was performed using the Kruskal-Wallis analysis of variance at a significance level of 0.05. RESULTS: The increases in temperature caused by the OneShape file system were lower than those of the other files (P < 0.05). The WaveOne file showed the highest temperature increases. However, there were no significant differences between the Reciproc and WaveOne files. CONCLUSIONS: The single file rotary systems used in this study may be recommended for clinical use. PMID- 26096250 TI - Epilepsy in primary intracranial tumors in a neurosurgical hospital in Enugu, South-East Nigeria. AB - BACKGROUND: Seizures may be manifestation of intracranial tumor (IT) and demand thorough neurological evaluation. This paper examines epidemiology, lesion characteristics and outcome of seizures associated with primary IT. METHODS: Retrospective analysis of medical records, computed tomography and magnetic resonance imaging of patients diagnosed with IT who presented with seizure from 2003 to 2013 at Memfys Hospital for Neurosurgery Enugu. Postoperative seizure outcome was based on Engel classification and correlated with tumor histology, patient age, anatomical location, time of presentation and extent of tumor resection. Data were analyzed using descriptive and inferential statistics. RESULTS: Sixty-two patients (34.6%) presenting with seizures were analyzed. Peak age at presentation was in 6 th decade. Age of seizure onset had bimodal peak at 4 th and 6 th decades. Apart from IT located in posterior fossa with mortality of 62.5%, postoperative mortality did not depend on anatomical location of tumor. Postoperative seizure outcome and mortality depend on tumor histology (P = 0.025) and preoperative seizure duration (P = 0.036). Seizure duration shorter than 1 month had poor postoperative seizure outcome and high mortality. Although more patients with meningioma experienced seizures compared to glioma (P = 0.025), there was no difference in proportion of patients with meningioma and glioma who presented with seizure (P = 1.00). Extent of resection predicts postoperative seizure outcome based on meningioma sub-group analysis. Overall, 59.7% of patients had good postoperative seizure outcome, 21.0% had poor outcome and 19.3% died. CONCLUSION: Seizures of short duration, IT located in posterior fossa and gliomas are associated with poor postoperative seizure outcome and high patient mortality. Tumor histology does not seem to affect seizure predisposition. Most seizures associated with IT occur in fifth and sixth decades of life and affect frontal lobe most often. PMID- 26096251 TI - A case report on a nasolabial cyst presenting with a nasolacrimal sac cyst. AB - Nasolabial cysts are rare, nonodontogenic soft tissue developmental cysts that occur in the maxillary lip and nasal alar regions. Patients with this type of cyst generally presents with an asymptomatic soft swelling that may obliterate the nasolabial fold, elevate the nasal ala or the floor of the nose and fill the labial vestibule intraorally. The exact origin of nasolabial cysts is uncertain. The seed theory suggests that these cysts develop from a misplaced epithelium of the nasolacrimal duct because of their similar location and histologic appearance. This report aimed to present a case of nasolabial cyst presenting with a nasolacrimal sac cyst. PMID- 26096252 TI - The triad of Iron deficiency anemia, hepatosplenomegaly and growth retardation with normal serum zinc levels in a 14-year-old boy. AB - A triad of iron deficiency anemia, hepatosplenomegaly and growth retardation occurring in tandem with zinc deficiency has been reported in the past as components of either Prasad's syndrome or hypopituitarism. There are no documented cases of such triad occurring in the presence of normal serum zinc levels. We report a case of a 14-year-old boy who presented with iron deficiency anemia, hepatosplenomegaly, geophagia and growth retardation with pubertal delay. Investigations ruled out hypopituitarism and coeliac disease. The patient improved dramatically and attained puberty within 15 months of intense nutritional intervention. In conclusion, iron deficiency anemia occurring in the triad without zinc deficiency as seen in this case report has not been reported before; this calls for more research to be able to explain the findings. PMID- 26096253 TI - A thyrotropin-secreting macroadenoma with positive growth hormone and prolactin immunostaining: A case report and literature review. AB - Thyrotropin (thyroid stimulating hormone [TSH]) secreting pituitary adenomas (TSHoma) are rare adenomas presenting with hyperthyroidism due to impaired negative feedback of thyroid hormone on the pituitary and inappropriate TSH secretion. This article presents a case of TSH-secreting macroadenoma without any clinical hyperthyroidism symptoms accompanying immunoreaction with growth hormone (GH) and prolactin. A 36-year-old female patient was admitted with complaints of irregular menses and blurred vision. On physical exam, she had bitemporal hemianopsia defect. Magnetic resonance imaging (MRI) evaluation showed suprasellar macroadenoma measuring 33 mm * 26 mm * 28 mm was detected on pituitary MRI. She had no hyperthyroidism symptoms clinically. Although free T4 and free T3 levels were elevated, TSH level was inappropriately within the upper limit of normal. Response to T3 suppression and thyrotropin releasing hormone stimulation test was inadequate. Other pituitary hormones were normal. Transsphenoidal adenomectomy was performed due to parasellar compression findings. Immunohistochemically widespread reaction was observed with TSH, GH and prolactin in the adenoma. The patient underwent a second surgical procedure 2 months later due to macroscopic residual tumor, bitemporal hemianopsia and a suprasellar homogenous uptake with regular borders on indium-111 octreotide scintigraphy. After second surgery; due to ongoing symptoms and residual tumor, she was managed with octreotide and cabergoline treatment. On her follow-up with medical treatment, TSH and free T4 values were within normal limits. Although silent TSHomas are rare, they may arise with compression symptoms as in our case. The differential diagnosis of secondary hyperthyroidism should include TSHomas and thyroid hormone receptor resistance syndrome. PMID- 26096254 TI - Bronchial carcinoid tumors: A rare malignant tumor. AB - Bronchial carcinoid tumors (BCTs) are an uncommon group of lung tumors. They commonly affect the young adults and the middle aged, the same age group affected by other more common chronic lung conditions such as pulmonary tuberculosis. Diagnosis is commonly missed or delayed due to a low index of suspicion. Surgery is the mainstay of treatment with an excellent outcome. There are many reports of this rare group of tumors in the Western and Asian regions. The only report around our sub-region is a post mortem report of an atypical variant. We wish to report a case of the typical variant and increase our index of suspicion. A 25 year-old male presented with a 4 years history of cough and haemoptysis. He was repeatedly treated for bronchial asthma and pulmonary tuberculosis with no improvement of symptoms. Chest X-ray and chest computed tomography scan revealed a left upper lobe tumor. Histology reported a typical variant of BCT which was confirmed by immunohistochemistry. He had a left upper lobectomy and has done excellently well thereafter. A high index of suspicion is needed to reduce the risk of missing or delaying the diagnosis. PMID- 26096255 TI - Pulmonary Vein Isolation Using the First-Generation Cryoballoon Technique in Chinese Patients. AB - BACKGROUND: Cryoballoon ablation is an alternative for the treatment of atrial fibrillation (AF). We assess the relationship among pulmonary vein (PV) electrophysiology, balloon temperature, and persistent PV isolation (PVI), and report procedural properties, safety, and efficacy of this technique in a Chinese center for the first time. METHODS: A total of 70 patients with paroxysmal (n = 57) and persistent (n = 13) AF were consecutively enrolled. PVI was performed with cryoballoon catheter. Real-time recording of dissociation of PV potentials was attempted using a circumferential mapping catheter. RESULTS: Successful PVI was achieved in 274 of 282 (97.2%) PVs. Procedural duration was 115.2 +/- 24.8 minutes and fluoroscopy time was 29.6 +/- 8.9 minutes. Real-time PV potential recording was achieved in 232 (84.3%) PVs. Regarding time to isolation, a cut-off value of less than 60 seconds was predictive of persistent PVI with a sensitivity of 0.76 and specificity of 0.82 (area under curve = 0.835; P < 0.0001). The nadir balloon temperature was significantly lower in PVs without early reconduction ( 46.3 +/- 0.5 degrees C vs -40.2 +/- 1.3 degrees C, P < 0.0001). However, there was an insignificant trend that the balloon temperature at isolation was higher in PVs without reconduction (-33.9 +/- 0.7 degrees C vs -36.4 +/- 2.0 degrees C, P = 0.14). The overall complication rate was 5.7%. After a median follow-up of 6.5 (range 3.2-14.9) months, 76% of patients were free of AF recurrence with a blanking period of 3 months. CONCLUSIONS: Real-time PV potentials can be recorded in most PVs. The time to isolation is predictive of the persistency of PVI. The nadir balloon temperature, not the balloon temperature at isolation, is significantly lower in PVs without reconduction. PMID- 26096256 TI - Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia? AB - BACKGROUND: A biomarker of hypoxic exposure would be useful in clinical diagnosis and prognosis. Acute hypoxia stimulates large increases in serum erythropoietin (EPO), and EPO induces formation of characteristic enlarged red blood cells (RBCs). The presence of large RBCs perturbs red cell distribution width (RDW). METHODS: Using a >2M patient medical claims database, the human pathome was scanned for diseases where RDW rose 0-50days following a new diagnosis. The course of RDW after selected diagnoses was visualized by registering RDW measurements by diagnosis date. RESULTS: Acute hemorrhage, which provokes EPO driven erythropoiesis, is followed by increases in RDW but not mean cell volume (MCV). Similar RDW increases follow many acute diseases with risk of hypoxia, including heart failure, pneumonia, atelectasis, pulmonary embolism, pneumothorax, and sepsis. Elevations reach maximum within 1month after onset and subside to pre-disease levels about 6months later. Unlike the case with iron deficiency anemia (IDA), RDW elevations after hypoxia-associated diseases are unaccompanied by discernible change in average RBC size. CONCLUSIONS: As predicted by a model risk pathway linking hypoxia to formation of enlarged RBCs via EPO, acute hypoxemia-related disease episodes induce change in RBC size distribution. Further study is needed to explore whether a more sensitive and specific signal can be extracted from the fine structure of the RBC size distribution routinely measured in automated hemocytometers. PMID- 26096257 TI - Quantitative assessment of human serum transferrin receptor in breast cancer patients pre- and post-chemotherapy using peptide immunoaffinity enrichment coupled with targeted proteomics. AB - BACKGROUND: sTfR, a soluble form of transferrin receptor in serum, has been suggested as an indicator of bone marrow failure in breast cancer patients receiving chemotherapy. However, intensive chemotherapy could also cause a reduction of sTfR to a level below the LOQ of most assays. METHODS: An advanced liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics assay coupled with peptide immunoaffinity enrichment (SISCAPA) was developed and validated for monitoring sTfR. RESULTS: Tryptic peptide 681VEYHFLSPYVSPK693 was selected as a surrogate analyte for quantification. High abundant proteins were first removed from serum, followed by SISCAPA that was effective in surrogate peptide enrichment and sensitivity enhancement. The resulting LOQ can achieve 100ng/ml (~10-fold increase). Then, sTfR levels in breast cancer patients pre- and post-chemotherapy, and healthy volunteers were accurately quantified as 1.77+/-0.53MUg/ml, 0.98+/-0.26MUg/ml and 1.66+/ 0.50MUg/ml, respectively, using a standard addition method. While there was no evidence for a difference between patients and healthy volunteers, differential levels of sTfR pre- and post-chemotherapy were obtained. Comparison between SISCAPA-targeted proteomics and ELISA indicated that the former approach provided a lower value of sTfR. CONCLUSIONS: SISCAPA-targeted proteomics may allow the quantification of low-abundant proteins in a more accurate manner. PMID- 26096259 TI - Assessing Mindfulness on a Sample of Catalan-Speaking Spanish Adolescents: Validation of the Catalan Version of the Child and Adolescent Mindfulness Measure. AB - BACKGROUND: Interest in mindfulness has increased over the last decade, resulting in several mindfulness-based interventions being developed and their efficacy empirically demonstrated. The practice of mindfulness has been associated with low levels of anxiety or depression and improved quality of life or personal well being. The aim of this study is to translate the Child and Adolescent Mindfulness Measure (CAMM) and adapt it to Catalan so as to analyze its internal consistency and construct and convergent validity. METHOD: The CAMM was administered to a sample of secondary school students ranging in age from 11 to 16 years old. RESULTS: The Catalan version of the CAMM shows a good fit with the unidimensional model and internal consistency similar to the original version (alpha = .80). Furthermore, CAMM scores correlated positively with subjective well-being, temperamental dimensions of effortful control and self-esteem. CONCLUSIONS: The Catalan Version of CAMM is a valid and reliable measure of mindfulness skills. PMID- 26096258 TI - Synergistic role of ADP and Ca(2+) in diastolic myocardial stiffness. AB - Diastolic dysfunction in heart failure patients is evident from stiffening of the passive properties of the ventricular wall. Increased actomyosin interactions may significantly limit diastolic capacity, however, direct evidence is absent. From experiments at the cellular and whole organ level, in humans and rats, we show that actomyosin-related force development contributes significantly to high diastolic stiffness in environments where high ADP and increased diastolic [Ca(2+) ] are present, such as the failing myocardium. Our basal study provides a mechanical mechanism which may partly underlie diastolic dysfunction. Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca(2+) ] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca(2+) handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca(2+) ] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca(2+) in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca(2+) both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37 degrees C in the presence of pathological levels of ADP and diastolic [Ca(2+) ] revealed a 76 +/- 1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re lengthening associated with diastolic Ca(2+) overload. In isolated Langendorff perfused rat hearts, CK inhibition increased ventricular stiffness only in the presence of diastolic [Ca(2+) ]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross bridges, even at low Ca(2+) , and thereby increase myocardial stiffness. PMID- 26096260 TI - Stimulated jitter in infant botulism. PMID- 26096261 TI - Type 1 narcolepsy: a CD8(+) T cell-mediated disease? AB - Type 1 narcolepsy is a sleep disorder characterized by excessive daytime sleepiness with unintentional sleep attacks and cataplexy. The disorder is caused by a loss of hypocretinergic neurons in the brain. The specific loss of these neurons in narcolepsy is thought to result from an autoimmune attack, and this is supported by evidence of both environmental and genetic factors pointing toward an involvement of the immune system. However, definitive proof of an autoimmune etiology is still missing. Several different immune-mediated disorders targeting neurons are known, and many of these are believed to be caused by autoreactive CD8(+) T cells. In this paper, we review the current knowledge on CD8(+) T cell mediated neuronal damage on the basis of our understanding of other autoimmune disorders and experimental studies. We identify major histocompatibility complex class I presentation of autoantigens on neurons as a possible mechanism in the development of the disease, and propose T cell-mediated pathogenesis, with cytotoxic CD8(+) T cells targeting the hypocretinergic neurons, as a central element. PMID- 26096262 TI - Predicting the Genetic Stability of Engineered DNA Sequences with the EFM Calculator. AB - Unwanted evolution can rapidly degrade the performance of genetically engineered circuits and metabolic pathways installed in living organisms. We created the Evolutionary Failure Mode (EFM) Calculator to computationally detect common sources of genetic instability in an input DNA sequence. It predicts two types of mutational hotspots: deletions mediated by homologous recombination and indels caused by replication slippage on simple sequence repeats. We tested the performance of our algorithm on genetic circuits that were previously redesigned for greater evolutionary reliability and analyzed the stability of sequences in the iGEM Registry of Standard Biological Parts. More than half of the parts in the Registry are predicted to experience >100-fold elevated mutation rates due to the inclusion of unstable sequence configurations. We anticipate that the EFM Calculator will be a useful negative design tool for avoiding volatile DNA encodings, thereby increasing the evolutionary lifetimes of synthetic biology devices. PMID- 26096264 TI - Airway management with McGrath Series 5 video laryngoscope in a woman with Klippel-Feil syndrome requiring urgent caesarean section. PMID- 26096263 TI - Accelerated molecular dynamics simulations of protein folding. AB - Folding of four fast-folding proteins, including chignolin, Trp-cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred-of-microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2-2.1 A of the native NMR or X-ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second-order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein-folding studies. PMID- 26096266 TI - Bioethics and the capacity to consent - A pragmatic approach. PMID- 26096268 TI - A Delphi study among internal medicine clinicians to determine which therapeutic information is essential to record in a medical record. AB - Several studies have demonstrated that using a template for recording general and diagnostic information in the medical record (MR) improves the completeness of MR documentation, communication between doctors, and performance of doctors. However, little is known about how therapeutic information should be structured in the MR. The aim of this study was to investigate which specific therapeutic information registrars and consultants in internal medicine consider essential to record in the MR. Therefore, we carried out a 2-round Internet Delphi study. Fifty-nine items were assessed on a 5-point scale; an item was considered important if >= 80% of the respondents awarded it a score of 4 or 5. In total, 26 registrars and 30 consultants in internal medicine completed both rounds of the study. Overall, they considered it essential to include information about 11 items in the MR. Subgroup analyses revealed that the registrars considered 8 additional items essential, whereas the consultants considered 1 additional item essential to record. Study findings can be used as a starting point to develop a structured section of the MR for therapeutic information for both paper and electronic MRs. This section should contain at least 11 items considered essential by registrars and clinical consultants in internal medicine. PMID- 26096269 TI - Impact of the United Kingdom national bowel cancer awareness campaigns 2012 on colorectal cancer services and patient survival. AB - AIM: The UK national bowel cancer awareness campaigns in 2012 were intended to improve survival of patients with colorectal cancer (CRC) by raising public awareness and prompting symptomatic individuals to seek medical attention early. The aim of the present study was to compare the number of CRCs diagnosed, tumour stage at diagnosis, survival and number of investigations performed during the campaigns compared with a similar time period in 2011. METHOD: A retrospective study was carried out of 1439 consecutive referrals through the 2-week wait pathway (2WW) to our colorectal unit during the February and September 2012 campaigns. Patient demographics, number of referrals, investigations performed and newly diagnosed cases of CRC with their respective staging were determined and compared with a group in 2011. Two-year survival was evaluated by Kaplan Meier statistics. RESULTS: Referrals through the 2WW increased by 55-60% and endoscopic and the number of radiological investigations performed increased by over 70% during the awareness campaigns. Although new diagnoses of CRC nearly doubled, the increase in the patients referred meant the diagnostic yield remained low at 6%. The bowel cancer awareness campaigns did not alter the tumour stage at presentation, as over 50% of patients were diagnosed with Stage 3 and 4 CRC and there was no significant difference in 2-year survival. CONCLUSION: The UK bowel cancer awareness campaigns appear to have improved public awareness of CRC and encouraged symptomatic individuals to seek urgent medical attention. The increase in 2WW referrals has not translated into better survival for symptomatic patients, partly due to the proportion presenting with advanced disease. PMID- 26096267 TI - Septohippocampal Neuromodulation Improves Cognition after Traumatic Brain Injury. AB - Traumatic brain injury (TBI) often results in persistent attention and memory deficits that are associated with hippocampal dysfunction. Although deep brain stimulation (DBS) is used to treat neurological disorders related to motor dysfunction, the effectiveness of stimulation to treat cognition remains largely unknown. In this study, adult male Harlan Sprague-Dawley rats underwent a lateral fluid percussion or sham injury followed by implantation of bipolar electrodes in the medial septal nucleus (MSN) and ipsilateral hippocampus. In the first week after injury, there was a significant decrease in hippocampal theta oscillations that correlated with decreased object exploration and impaired performance in the Barnes maze spatial learning task. Continuous 7.7 Hz theta stimulation of the medial septum significantly increased hippocampal theta oscillations, restored normal object exploration, and improved spatial learning in injured animals. There were no benefits with 100 Hz gamma stimulation, and stimulation of sham animals at either frequency did not enhance performance. We conclude, therefore, that there was a theta frequency-specific benefit of DBS that restored cognitive function in brain-injured rats. These data suggest that septal theta stimulation may be an effective and novel neuromodulatory therapy for treatment of persistent cognitive deficits following TBI. PMID- 26096270 TI - Energy Transfer in a Hybrid Ir(III) Carbene-Pt(II) Acetylide Assembly for Efficient Hydrogen Production. AB - A new heterometallic supramolecular complex, consisting of an iridium carbene based unit appended to a platinum terpyridine acetylide unit, representing a new Ir(III) -Pt(II) structural motif, was designed and developed to act as an active species for photocatalytic hydrogen production. The results also suggested that a light-harvesting process is essential to realize the solar-to-fuel conversion in an artificial system as illustrated in the natural photosynthetic system. PMID- 26096272 TI - Hydraulic Tomography: Continuity and Discontinuity of High-K and Low-K Zones. AB - Hydraulic tomography is an emerging field and modeling method that provides a continuous hydraulic conductivity (K) distribution for an investigated region. Characterization approaches that rely on interpolation between one-dimensional (1D) profiles have limited ability to accurately identify high-K channels, juxtapositions of lenses with high K contrast, and breaches in layers or channels between such profiles. However, locating these features is especially important for groundwater flow and transport modeling, and for design and operation of in situ remediation in complex hydrogeologic environments. We use transient hydraulic tomography to estimate 3D K in a volume of 15-m diameter by 20-m saturated thickness in a highly heterogeneous unconfined alluvial (clay to sand and-gravel) aquifer with a K range of approximately seven orders of magnitude at an active industrial site in Assemini, Sardinia, Italy. A modified Levenberg Marquardt algorithm was used for geostatistical inversion to deal with the nonlinear nature of the highly heterogeneous system. The imaging results are validated with pumping tests not used in the tomographic inversion. These tests were conducted from three of five clusters of continuous multichannel tubing (CMTs) installed for observation in the tomographic testing. Locations of high-K continuity and discontinuity, juxtaposition of very high-K and very low-K lenses, and low-K "plugs" are evident in regions of the investigated volume where they likely would not have been identified with interpolation from 1D profiles at the positions of the pumping well and five CMT clusters. Quality assessment methods identified a suspect high-K feature between the tested volume and a lateral boundary of the model. PMID- 26096271 TI - Guard cell photosynthesis is critical for stomatal turgor production, yet does not directly mediate CO2 - and ABA-induced stomatal closing. AB - Stomata mediate gas exchange between the inter-cellular spaces of leaves and the atmosphere. CO2 levels in leaves (Ci) are determined by respiration, photosynthesis, stomatal conductance and atmospheric [CO2 ]. [CO2 ] in leaves mediates stomatal movements. The role of guard cell photosynthesis in stomatal conductance responses is a matter of debate, and genetic approaches are needed. We have generated transgenic Arabidopsis plants that are chlorophyll-deficient in guard cells only, expressing a constitutively active chlorophyllase in a guard cell specific enhancer trap line. Our data show that more than 90% of guard cells were chlorophyll-deficient. Interestingly, approximately 45% of stomata had an unusual, previously not-described, morphology of thin-shaped chlorophyll-less stomata. Nevertheless, stomatal size, stomatal index, plant morphology, and whole leaf photosynthetic parameters (PSII, qP, qN, FV '/FM' ) were comparable with wild-type plants. Time-resolved intact leaf gas-exchange analyses showed a reduction in stomatal conductance and CO2 -assimilation rates of the transgenic plants. Normalization of CO2 responses showed that stomata of transgenic plants respond to [CO2 ] shifts. Detailed stomatal aperture measurements of normal kidney-shaped stomata, which lack chlorophyll, showed stomatal closing responses to [CO2 ] elevation and abscisic acid (ABA), while thin-shaped stomata were continuously closed. Our present findings show that stomatal movement responses to [CO2 ] and ABA are functional in guard cells that lack chlorophyll. These data suggest that guard cell CO2 and ABA signal transduction are not directly modulated by guard cell photosynthesis/electron transport. Moreover, the finding that chlorophyll-less stomata cause a 'deflated' thin-shaped phenotype, suggests that photosynthesis in guard cells is critical for energization and guard cell turgor production. PMID- 26096273 TI - Comparison of psychotic bipolar disorder, schizoaffective disorder, and schizophrenia: an international, multisite study. AB - OBJECTIVE: Nosological distinctions among schizoaffective disorder (SA), bipolar I disorder with psychotic features (BDp), and schizophrenia (SZ) remain unresolved. METHOD: We compared 2269 subjects with psychotic features in DSM-IV TR diagnoses (1435 BDp, 463 SZ, 371 SA) from 8 collaborating international sites, by 12 sociodemographic and clinical measures, all between diagnostic pairs. RESULTS: In bivariate comparisons, SA was consistently intermediate between BDp and SZ for 11/12 features (except onset stressors), and SZ vs. BDp differed in all 12 factors. SA differed from both BDp and SZ in 9/12 factors: SA and BDp were similar in education and suicidal ideation or acts; SA and SZ were similar in education, onset stressors, and substance abuse. Meta-analytic comparisons of diagnostic pairs for 10 categorical factors indicated similar differences of SA from both SZ and BDp. Multivariate modeling indicated significantly independent differences between BDp and SZ (8 factors), SA vs. SZ (5), and BDp vs. SA (3). Measurement variance was similar for all diagnoses. CONCLUSION: SA was consistently intermediate between BDp and SZ. The three diagnostic groups ranked: BDp > SA > SZ related to lesser morbidity or disability. The findings are not consistent with a dyadic Kraepelinian categorization, although the considerable overlap among the three DSM-IV diagnostic groups indicates uncertain boundaries if they represent distinct disorders. PMID- 26096274 TI - Characterization of Shrimp Oil from Pandalus borealis by High Performance Liquid Chromatography and High Resolution Mass Spectrometry. AB - Northern shrimp (Pandalus borealis) oil, which is rich in omega-3 fatty acids, was recovered from the cooking water of shrimp processing facilities. The oil contains significant amounts of omega-3 fatty acids in triglyceride form, along with substantial long-chain monounsaturated fatty acids (MUFAs). It also features natural isomeric forms of astaxanthin, a nutritional carotenoid, which gives the oil a brilliant red color. As part of our efforts in developing value added products from waste streams of the seafood processing industry, we present in this paper a comprehensive characterization of the triacylglycerols (TAGs) and astaxanthin esters that predominate in the shrimp oil by using HPLC-HRMS and MS/MS, as well as 13C-NMR. This approach, in combination with FAME analysis, offers direct characterization of fatty acid molecules in their intact forms, including the distribution of regioisomers in TAGs. The information is important for the standardization and quality control, as well as for differentiation of composition features of shrimp oil, which could be sold as an ingredient in health supplements and functional foods. PMID- 26096275 TI - Ecklonia cava Polyphenol Has a Protective Effect against Ethanol-Induced Liver Injury in a Cyclic AMP-Dependent Manner. AB - Previously, we showed that Ecklonia cava polyphenol (ECP) treatment suppressed ethanol-induced increases in hepatocyte death by scavenging intracellular reactive oxygen species (ROS) and maintaining intracellular glutathione levels. Here, we examined the effects of ECP on the activities of alcohol-metabolizing enzymes and their regulating mechanisms in ethanol-treated hepatocytes. Isolated hepatocytes were incubated with or without 100 mM ethanol. ECP was dissolved in dimethylsulfoxide. ECP was added to cultured cells that had been incubated with or without ethanol. The cells were incubated for 0-24 h. In cultured hepatocytes, the ECP treatment with ethanol inhibited cytochrome P450 2E1 (CYP2E1) expression and activity, which is related to the production of ROS when large quantities of ethanol are oxidized. On the other hand, ECP treatment with ethanol increased the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. These changes in activities of CYP2E1 and ADH were suppressed by treatment with H89, an inhibitor of protein kinase A. ECP treatment with ethanol enhanced cyclic AMP concentrations compared with those of control cells. ECP may be a candidate for preventing ethanol-induced liver injury via regulating alcohol metabolic enzymes in a cyclic AMP-dependent manner. PMID- 26096276 TI - Structural Characterization of New Peptide Variants Produced by Cyanobacteria from the Brazilian Atlantic Coastal Forest Using Liquid Chromatography Coupled to Quadrupole Time-of-Flight Tandem Mass Spectrometry. AB - Cyanobacteria from underexplored and extreme habitats are attracting increasing attention in the search for new bioactive substances. However, cyanobacterial communities from tropical and subtropical regions are still largely unknown, especially with respect to metabolite production. Among the structurally diverse secondary metabolites produced by these organisms, peptides are by far the most frequently described structures. In this work, liquid chromatography/electrospray ionization coupled to high resolution quadrupole time-of-flight tandem mass spectrometry with positive ion detection was applied to study the peptide profile of a group of cyanobacteria isolated from the Southeastern Brazilian coastal forest. A total of 38 peptides belonging to three different families (anabaenopeptins, aeruginosins, and cyanopeptolins) were detected in the extracts. Of the 38 peptides, 37 were detected here for the first time. New structural features were proposed based on mass accuracy data and isotopic patterns derived from full scan and MS/MS spectra. Interestingly, of the 40 surveyed strains only nine were confirmed to be peptide producers; all of these strains belonged to the order Nostocales (three Nostoc sp., two Desmonostoc sp. and four Brasilonema sp.). PMID- 26096277 TI - Persistent Contamination of Octopuses and Mussels with Lipophilic Shellfish Toxins during Spring Dinophysis Blooms in a Subtropical Estuary. AB - This study investigates the occurrence of diarrhetic shellfish toxins (DSTs) and their producing phytoplankton species in southern Brazil, as well as the potential for toxin accumulation in co-occurring mussels (Perna perna) and octopuses (Octopus vulgaris). During the spring in 2012 and 2013, cells of Dinophysis acuminata complex were always present, sometimes at relatively high abundances (max. 1143 cells L-1), likely the main source of okadaic acid (OA) in the plankton (max. 34 ng L-1). Dinophysis caudata occurred at lower cell densities in 2013 when the lipophilic toxins pectenotoxin-2 (PTX-2) and PTX-2 seco acid were detected in plankton and mussel samples. Here, we report for the first time the accumulation of DSTs in octopuses, probably linked to the consumption of contaminated bivalves. Perna perna mussels were consistently contaminated with different DSTs (max. 42 ug kg-1), and all octopuses analyzed (n = 5) accumulated OA in different organs/tissues: digestive glands (DGs) > arms > gills > kidneys > stomach + intestine. Additionally, similar concentrations of 7 O-palmytoyl OA and 7-O-palmytoly dinophysistoxin-1 (DTX-1) were frequently detected in the hepatopancreas of P. perna and DGs of O. vulgaris. Therefore, octopuses can be considered a potential vector of DSTs to both humans and top predators such as marine mammals. PMID- 26096278 TI - A Turkish translation of the Nordic Occupational Skin Questionnaire (NOSQ 2002/LONG) adapted for young workers in high-risk jobs. AB - BACKGROUND: Occupational skin diseases (OSDs) represent 10-40% of all occupational diseases in many industrialized countries. Young workers are frequently exposed to toxic substances and chemicals in the workplace. The occupational conditions of young workers can impose a high level of risk for the occurrence of OSDs. The Nordic Occupational Skin Questionnaire (NOSQ-2002) was developed in English as a new, comprehensive, standardized tool with which to screen for OSDs. OBJECTIVES: The purpose of this study was to translate the NOSQ 2002 into Turkish and to culturally adapt the long version of the instrument for use with young workers in jobs with high risk for the occurrence of OSDs. METHODS: Forward and back translations were carried out. Problematic items were modified until the Turkish-language version achieved a satisfactory consensus with the original version of the NOSQ-2002. The final Turkish version was tested in 40 randomly selected young workers with and without OSDs who were studying in the fields of hairdressing, jewelry making, and car mechanics at vocational training schools run by the National Education Ministry. RESULTS: When the original questionnaire had been translated into the target language, a first consensus version was evaluated by an expert panel. The expert panel determined that 36 questions (63.2%) in the Turkish version required some level of modification in order to facilitate clear understanding. Cognitive interviews were then performed. After some modification, the final Turkish version was established and tested among young workers. CONCLUSIONS: The new Turkish version of the NOSQ is a comprehensible, reliable, and useful tool that can be applied to young workers in specific occupations. PMID- 26096279 TI - Animal models to assess the therapeutic efficacy of human serum and serum converted platelet lysates for dry eye syndrome: Seeing is believing. AB - There is much interest in the clinical use of serum-converted human blood or platelet concentrates in regenerative medicine, most specifically for wound healing and tissue repair of soft and hard tissues. The scientific rationale supporting the clinical efficacy of these preparations is based on the expectation that their physiological mixture of natural growth factors can orchestrate cell expansion and differentiation in vivo. However, a lack of standardization and regulatory oversight of these blood materials maintain a perception of uncertainty in the scientific and medical community on the value of these preparations for some clinical indications. More studies are needed to understand the mechanism of action underlying their expected efficacy and standardize their use, and benefit from their biological versatility. One application of serum is as eye drop for treating dry eye syndrome (DES), a multifactorial disease of the ocular surface, which has a prevalence of 15% of more in the population. DES can lead to chronic inflammation of the ocular surface, surface impairment in the cornea and conjunctiva, and, in patients with Sjogren syndrome, result in a disruption of the ocular surface epithelium. Objective experimental assessment of safety and efficacy of serum eye drops can help establish scientific rationale in optimal product composition and use. This can be achieved, first, through cell cultures with relevant cell models, before considering, then, animal studies using DES animal models. Several models have been evaluated and are reported in this concise review. The model we have developed encompasses the use of rabbits, where their eyes are treated with 0.1% benzalkonium chloride (BAC), a common preservative in ophthalmic agents, 3 times daily for 4 weeks. This relatively mild treatment results in moderate DES pathology, with a stable shortage of tear secretion throughout a 7-week study period, which we found suitable for assessing efficacy of serum eye drops. PMID- 26096280 TI - Role of bone morphogenetic protein-2 in osteogenic differentiation of mesenchymal stem cells. AB - Bone mesenchymal stem cells (BMSCs) have been an area of interest in biomedical research and tissue engineering due to their diverse differentiation abilities. In osteogenesis, bone morphogenetic proteins (BMPs), particularly BMP-2, are important. However, the effect of BMP-2 on the osteogenetic capacity of BMSCs remains to be fully elucidated. In the present study, primary rat BMSCs were infected with a recombinant lentivirus carrying the BMP-2 gene (Lenti-BMP-2), and the effects of BMP-2 on the activity of alkaline phosphatase (ALP) on days 3, 7, 14 and 21, and on mineralization on day 21 were evaluated. In addition, the adhesive ability of BMP-2-overexpressed BMSCs was detected using an adhesion assay. Following forced expression of BMP-2 in the BMSCs, the levels of osteogenic genes, including osteopontin (OPN), osteocalcin (OC) and collagen type I (Col-I), were detected and the nuclear accumulation of Runt-related transcription factor (Runx)-2 and phosphorylated small mothers against decapentaplegic (p-Smad) 1/5/8 was also evaluated. The results demonstrated that the rat BMSCs had been isolated, cultured and passaged from Sprague-Dawley rat bone marrow successfully, and the third-generation BMSCs were identified using flow cytometry with CD29 staining. The osteogenetic phenotype of the BMSCs, expressing ALP and osteocalcin, was significantly induced by BMP-2, and the proliferation of the BMSCs was enhanced by BMP-2. Furthermore, the adhesive potential of the BMP-2-overexpressed BMSCs was increased, the expression levels of OPN, OCN and Col-Ie osteogenetic factors were upregulated and the nuclear accumulation of Runx-2 and p-Smads1/5/8 were increased significantly. These data suggested that BMP-2 may facilitate the osteogenetic differentiation of rat BMSCs and provide a favorable cell resource for tissue engineering. PMID- 26096282 TI - "I believe that training in careful dissections is still the best discipline". PMID- 26096281 TI - Tuning the Redox Properties of a Nonheme Iron(III)-Peroxo Complex Binding Redox Inactive Zinc Ions by Water Molecules. AB - Redox-inactive metal ions play important roles in tuning chemical properties of metal-oxygen intermediates. Herein we report the effect of water molecules on the redox properties of a nonheme iron(III)-peroxo complex binding redox-inactive metal ions. The coordination of two water molecules to a Zn(2+) ion in (TMC)Fe(III) -(O2 )-Zn(CF3 SO3 )2 (1-Zn(2+) ) decreases the Lewis acidity of the Zn(2+) ion, resulting in the decrease of the one-electron oxidation and reduction potentials of 1-Zn(2+) . This further changes the reactivities of 1-Zn(2+) in oxidation and reduction reactions; no reaction occurred upon addition of an oxidant (e.g., cerium(IV) ammonium nitrate (CAN)) to 1-Zn(2+) , whereas 1-Zn(2+) coordinating two water molecules, (TMC)Fe(III) -(O2 )-Zn(CF3 SO3 )2 -(OH2 )2 [1 Zn(2+) -(OH2 )2 ], releases the O2 unit in the oxidation reaction. In the reduction reactions, 1-Zn(2+) was converted to its corresponding iron(IV)-oxo species upon addition of a reductant (e.g., a ferrocene derivative), whereas such a reaction occurred at a much slower rate in the case of 1-Zn(2+) -(OH2 )2 . The present results provide the first biomimetic example showing that water molecules at the active sites of metalloenzymes may participate in tuning the redox properties of metal-oxygen intermediates. PMID- 26096283 TI - "Aberrant branch of the superior laryngeal artery passing through the thyroid foramen" by Liu, J.-L., Liang, C.-Y., Xiang, T., Wang, F., Wang, L.-H., Liu, S. X. and Yang, H.-J. PMID- 26096286 TI - Right and left heart dysfunction predict mortality in pulmonary hypertension. AB - In pulmonary hypertension (PH), the right heart dysfunction is a strong predictor of adverse clinical outcome, while the role of the left heart is not fully determined. The aim of this study was to identify predictors of mortality in precapillary PH including measures of both right and left heart function. We studied 34 patients (mean age 64 +/- 13, range 31-82 years, 24 females) with precapillary PH, all of whom underwent detailed Doppler echocardiographic examination of the right and left heart function using conventional and speckle tracking echocardiography. Patients were followed up for up to 8 years (mean 4.2 +/- 1.9 years). At follow-up, 16 patients survived. Left ventricular (LV) filling time (P = 0.007), pulmonary artery acceleration time (P = 0.009), right atrial pressure (RAP) (P<0.001) and tricuspid regurgitation (TR) severity (P = 0.007) were worse in the deceased group. RV global longitudinal strain (GLS) (P = 0.001), RAP (P<=0.001), LV filling time (P<0.001) and TR severity (P<0.001) were the most accurate predictors, having the largest AUC (>0.65) and carried the highest risk for mortality (P<0.001 for all). The strongest predictors of mortality in precapillary PH indirectly reflect both left and right heart dysfunction including atrial structure and function disturbances. While an interaction pattern is observed, it needs to be confirmed in a larger cohort. PMID- 26096287 TI - [Peristomal pyoderma gangrenosum after rectal adenocarcinoma in the context of colonic and complex perianal Crohn's disease]. PMID- 26096288 TI - [Temporomandibular joint dislocation after endoscopy: A rare complication]. PMID- 26096289 TI - [Pseudoaneurysm of the superior mesenteric artery after pancreatoduodenectomy]. PMID- 26096290 TI - [Complete remission of Crohn's disease after high-dose alpha-interferon treatment for malignant melanoma]. PMID- 26096291 TI - Emission spectroscopy of a ruthenium(ii) polypyridyl complex adsorbed on calcium niobate lamellar solids and nanosheets. AB - Ru(ii) tris-diimine complexes are known to exhibit emission at around 630 nm as a result of (1)MLCT photoexcitation. The emission is quenched in the presence of a suitable semiconductor solid due to electron injection from the excited state of a Ru(ii) complex to the conduction band of the adjacent semiconductor. Here we investigated emission quenching behaviour of Ru(II){(4,4'-(CH3)2-bpy)2(4,4' (CH2PO3H2)2-bpy)} (bpy = 2,2'-bipryridine) adsorbed on HCa2Nb3O10 solids having an ordered lamellar structure or a disordered nanostructure. Even though electron injection from the excited state of the Ru complex to the conduction band of nanostructured HCa2Nb3O10 is thermodynamically less favorable than that of layered HCa2Nb3O10, faster electron injection was observed using nanostructured HCa2Nb3O10. Experimental results highlighted that electron injection from the excited Ru complex takes place not only in the conduction band of HCa2Nb3O10 but also mid-gap states whose density is strongly dependent on both the morphological feature and the preparation method of HCa2Nb3O10. PMID- 26096292 TI - Genetic variants of Kudoa septempunctata (Myxozoa: Multivalvulida), a flounder parasite causing foodborne disease. AB - Foodborne disease outbreaks caused by raw olive flounders (Paralichthys olivaceus) parasitized with Kudoa septempunctata have been reported in Japan. Origins of olive flounders consumed in Japan vary, being either domestic or imported, and aquaculture-raised or natural. Although it is unknown whether different sources are associated with different outcomes, it is desirable to identify whether this is the case by determining whether unique K. septempunctata strains occur and if so, whether some are associated with foodborne illness. We here developed an intraspecific genotyping method, using the sequence variation of mitochondrial genes. We collected olive flounder samples from foodborne disease outbreaks, domestic fish farms or quarantine offices and investigated whether K. septempunctata genotype is associated with pathogenicity or geographic origin. The 104 samples were classified into three genotypes, ST1, ST2 and ST3. Frequency of symptomatic cases differed by genotypes, but the association was not statistically significant. Whereas K. septempunctata detected from aquaculture raised and natural fish from Japan were either ST1 or ST2, those from fish inspected at quarantine from Korea to Japan were ST3. Our method can be applied to phylogeographic analysis of K. septempunctata and contribute to containing the foodborne disease. The genotype database is hosted in the PubMLST website (http://pubmlst.org/kseptempunctata/). PMID- 26096293 TI - Pseudomonas aeruginosa quorum-sensing signaling molecule N-3-oxododecanoyl homoserine lactone induces matrix metalloproteinase 9 expression via the AP1 pathway in rat fibroblasts. AB - Quorum sensing is a cell-to-cell communication mechanism, which is responsible for regulating a number of bacterial virulence factors and biofilm maturation and therefore plays an important role for establishing wound infection. Quorum sensing signals may induce inflammation and predispose wounds to infection by Pseudomonas aeruginosa; however, the interaction has not been well investigated. We examined the effects of the P. aeruginosa las quorum-sensing signal, N-3-oxo dodecanoyl homoserine lactone (3OC12-HSL), on matrix metalloproteinase (MMP) 9 expression in Rat-1 fibroblasts. 3OC12-HSL upregulated the expression of the MMP9 gene bearing an activator protein-1 (AP-1) binding site in the promoter region. We further investigated the mechanism underlying this effect. c-Fos gene expression increased rapidly after exposure to 3OC12-HSL, and nuclear translocation of c-Fos protein was observed; both effects were reduced by pretreatment with an AP-1 inhibitor. These results suggest that 3OC12-HSL can alter MMP9 gene expression in fibroblasts via the AP-1 signaling pathway. PMID- 26096294 TI - Polyphenol administration impairs T-cell proliferation by imprinting a distinct dendritic cell maturational profile. AB - Currently little is known as to how nutritionally derived compounds may affect dendritic cell (DC) maturation and potentially prevent inappropriate inflammatory responses that are characteristic of chronic inflammatory syndromes. Previous observations have demonstrated that two polyphenols quercetin and piperine delivered through reconstituted oil bodies (ROBs-QP) can influence DC maturation in response to LPS leading to a modulated inflammatory response. In the present study, we examined the molecular effects of ROBs-QP exposure on DC differentiation in mice and identified a unique molecular signature in response to LPS administration that potentially modulates DC maturation and activity in inflammatory conditions. Following LPS administration, ROBs-QP-exposed DCs expressed an altered molecular profile as compared with control DCs, including cytokine and chemokine production, chemokine receptor repertoire, and antigen presentation ability. In vivo ROBs-QP administration suppresses antigen-specific T-cell division in the draining lymph nodes resulting from a reduced ability to create stable immunological synapse. Our data demonstrate that polyphenols exposure can drive DCs toward a new anti-inflammatory molecular profile capable of dampening the inflammatory response, highlighting their potential as complementary nutritional approaches in the treatment of chronic inflammatory syndromes. PMID- 26096295 TI - 10-year prospective cohort follow-up of immediately restored XiVE implants. AB - OBJECTIVE: The aim of this prospective cohort study was to assess the ten-year performance of the condensing thread, self-tapping apex and internal hexagonal connection XiVE implant supporting partial fixed prostheses placed with an immediate restoration approach. MATERIAL AND METHODS: All patients received a fixed two- to four-unit partial provisional restoration supported by immediately loaded implants. The final gold alloy/ceramic restorations were cemented approximately 28 weeks after implant insertion. Marginal bone level, pocket probing depth and percentage of bleeding on probing, biological or technical complications and any other adverse events were measured annually up to ten years after surgery. The overall success and survival rates at implant level were evaluated following the International Congress of Oral Implantologists (ICOI) Pisa Consensus Conference criteria. Implant placement in post-extractive or healed sites, smoking and a history of periodontal treatment were evaluated to assess whether they had an influence on bone resorption or on implant survival. RESULTS: Of 114 patients, for a total of 284 implants, fulfilled all the inclusion criteria and were enrolled in the study. 78 (27.5%) implants placed in 30 (26.3%) patients were lost to follow-up. Eight of 284 (2.8%) implants failed in 8 of 114 (7.0%) patients: one (12.5% of losses) due to failure to achieve osseointegration and seven (87.5% of losses) due to peri-implantitis. No cluster implant failures were assessed. The failure of the implant caused the failure of the prosthesis due to the strategic position of the implant in four patients. At the final ten-year follow-up, 121 (61.4%) implants exhibited a "full success" status with an optimal health condition, 21 (10.9%) implants scored a "satisfactory survival" condition, while 49 (25.49%) of the implants were classified as "compromised survival" status (Misch et al. 2008). Smoking was found to be statistically associated with "implant failure" (P = 0.010), while no association was found for patients treated for periodontal disease (P = 0.679) and post-extractive surgical sites (P = 0.664). Statistically significant more marginal bone loss was found in patients treated for periodontal disease (P < 0.0001). An increased bone loss was also observed in smokers, but the difference with the non-smokers was not statistically significant (P = 0.06). CONCLUSIONS: The XiVE implants can be successfully used to support immediate prosthesis. Patients with a history of periodontitis show increased bone loss and risk to develop peri-implant disease. Smoking seems to jeopardize the long-term implant survival. PMID- 26096296 TI - Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer: Phase 3 randomized trial. AB - BACKGROUND: In this prospective study, progression-free survival (PFS) and the safety profiles of docetaxel/capecitabine (TX) and vinorelbine/capecitabine (NX) followed by capecitabine maintenance therapy were compared in patients with metastatic breast cancer. METHODS: Patients with advanced metastatic breast cancer were randomly assigned to a TX group (n = 104) and an NX group (n = 102), both of which included capecitabine maintenance medication. The primary endpoint was progression-free survival (PFS). RESULTS: The trial met its primary endpoint and was closed to accrual subsequent to interim analysis. Forty-eight patients in the TX group (46.2%) and 42 patients in the NX group (41.2%) received maintenance medication. The median PFS (8.4 vs 7.1 months; P = .0026; 95% confidence interval, 1.18-2.3; hazard ratio, 1.65), the response duration (7.8 vs 6.6 months; P = .0451), and the median overall survival (OS) (35.3 vs 19.8 months; P = .1349; 95% confidence interval, 0.88-2.47; hazard ratio, 1.48) in the TX group appeared to be longer compared with those in the NX group, although the difference did reach not statistical significance. Patients aged >=40 years who were postmenopausal and presented with visceral metastases were more likely to benefit from the TX regimen in terms of PFS and OS, whereas positive hormone receptor and human epidermal growth factor receptor 2 status or a history of taxane treatments did not affect differences in PFS and OS between the TX and NX groups. Hand-foot syndrome occurred more frequently in the TX group than in the NX group (47% vs 16.7%; P < .0001), but the frequencies of other minor adverse effects were similar in both groups. CONCLUSIONS: A TX regimen for advanced breast cancer followed by capecitabine maintenance medication led to longer PFS and response duration than an NX regimen, even for patients who had previously received taxane in (neo)adjuvant settings. Cancer 2015. (c) 2015 American Cancer Society. Cancer 2015;121:3435-43. (c) 2015 American Cancer Society. PMID- 26096297 TI - The Amur tiger in Northeast Asia: Conservation and ecology of an endangered subspecies. PMID- 26096298 TI - First-principles study on the structural and electronic properties of metallic HfH2 under pressure. AB - The crystal structures and properties of hafnium hydride under pressure are explored using the first-principles calculations based on density function theory. The material undergoes pressure-induced structural phase transition I4/mmm -> Cmma -> P21/m at 180 and 250 GPa, respectively, and all of these structures are metallic. The superconducting critical temperature Tc values of I4/mmm, Cmma, and P21/m are 47-193 mK, 5.99-8.16 K and 10.62-12.8 K at 1 atm, 180 and 260 GPa, respectively. Furthermore, the bonding nature of HfH2 is investigated with the help of the electron localization function, the difference charge density and Bader charge analyses, which show that HfH2 is classified as a ionic crystal with the charges transferring from Hf atom to H. PMID- 26096299 TI - Regulation of Adipose Tissue Stem Cells Angiogenic Potential by Tumor Necrosis Factor-Alpha. AB - Tissue regeneration requires coordinated "teamwork" of growth factors, proteases, progenitor and immune cells producing inflammatory cytokines. Mesenchymal stem cells (MSC) might play a pivotal role by substituting cells or by secretion of growth factors or cytokines, and attraction of progenitor and inflammatory cells, which participate in initial stages of tissue repair. Due to obvious impact of inflammation on regeneration it seems promising to explore whether inflammatory factors could influence proangiogenic abilities of MSC. In this study we investigated effects of TNF-alpha on activity of adipose-derived stem cells (ADSC). We found that treatment with TNF-alpha enhances ADSC proliferation, F actin microfilament assembly, increases cell motility and migration through extracellular matrix. Exposure of ADSC to TNF-alpha led to increased mRNA expression of proangiogenic factors (FGF-2, VEGF, IL-8, and MCP-1), inflammatory cytokines (IL-1beta, IL-6), proteases (MMPs, uPA) and adhesion molecule ICAM-1. At the protein level, VEGF, IL-8, MCP-1, and ICAM-1 production was also up regulated. Pre-incubation of ADSC with TNF-alpha-enhanced adhesion of monocytes to ADSC but suppressed adherence of ADSC to endothelial cells (HUVEC). Stimulation with TNF-alpha triggers ROS generation and activates a number of key intracellular signaling mediators known to positively regulate angiogenesis (Akt, small GTPase Rac1, ERK1/2, and p38 MAP-kinases). Pre-treatment with TNF-alpha enhanced ADSC ability to promote growth of microvessels in a fibrin gel assay and accelerate blood flow recovery, which was accompanied by increased arteriole density and reduction of necrosis in mouse hind limb ischemia model. These findings indicate that TNF-alpha plays a role in activation of ADSC angiogenic and regenerative potential. PMID- 26096301 TI - The D+R Balance application: a novel method of assessing postural sway. AB - BACKGROUND: Postural sway can be assessed clinically using the Romberg test, or quantified using dynamic posturography. We assessed the potential use of a novel iPhone application as a method of quantifying sway. METHODS: Fifty healthy volunteers performed the Romberg and tandem Romberg tests on a hard floor and on foam in soundproofed and normal clinic rooms. Postural sway was recorded using the D+R Balance application and data were compared using paired t-tests. RESULTS: Significantly more postural sway was noted in participants when standing with their eyes closed and feet in the 'tandem' position vs feet together; standing with their eyes closed on foam vs on the floor; and standing with their eyes closed on foam with feet in the tandem position vs on the floor with feet together. CONCLUSION: This feasibility study suggests that the iPhone D+R Balance application deserves further investigation as a means of assessing postural sway and may provide an alternative to current dynamic posturography systems. PMID- 26096300 TI - Marriage outcome and relationship with urban versus rural context for individuals with psychosis in a population-based study in China. AB - PURPOSE: While social integration among individuals with psychosis differs by social context, this has rarely been investigated across urban vs. rural settings. For individuals with psychosis, marriage may be a key component of social integration. This study aims to compare marriage outcomes for individuals with psychosis in urban vs. rural settings in China, where marriage has been almost universal among individuals without psychosis. METHODS: In a large community-based study in four provinces representing 12% of China's population, we identified 393 individuals with psychosis (112 never treated). We used adjusted Poisson regression models to compare marriage status for those living in urban (n = 96) vs. rural (n = 297) contexts. RESULTS: While urban and rural residents had similar impairments due to symptoms, urban female residents were 2.72 times more likely to be unmarried than their rural counterparts (95% CI 1.19 6.22, p < 0.0176). Stratified analyses indicated that this marital disadvantage occurred primarily among urban females with an earlier age of onset. No differences were found among males. CONCLUSIONS: Our findings indicate that urban contexts impeded opportunities for marriage for female individuals with psychosis. These data suggest that urban women with earlier age of onset have difficulty in marrying which may be related to economic expectations of women in urban areas. Research examining contextual mechanisms that affect marriage may further understanding of social integration in China and other contexts. PMID- 26096302 TI - Evaluating the Thickness of Multivalent Glycopolymer Brushes for Lectin Binding. AB - Electrochemical impedance spectroscopy (EIS) is applied for investigating binding of lectins to multivalent glycopolymer brushes grafted from interdigital gold microelectrodes. By variation of the measuring frequency, EIS allows simultaneous analysis of binding at different subnanometer distances from the sensor surfaces. In this way, the binding dynamics along the brushes are quantified, giving an idea about the motion of the lectin through the brush layer. Two different brush lengths are investigated, revealing distinct dynamics of lectin binding due to changing topology of the brushes. Moreover, very low K D values in the nanomolar range are obtained. This unique platform may be used as sophisticated biosensor for detailed investigation of high-affinity protein binding to poly-mer layers. PMID- 26096303 TI - Pericoterpenoid A, a new bioactive cadinane-type sesquiterpene from Periconia sp. AB - Pericoterpenoid A (1), a new cadinane-type sesquiterpene, was isolated from an endolichenic fungal strain Periconia sp. (No. 19-4-2-1). Its structure was characterized by analyzing the spectroscopic data (IR, MS, 1D- and 2D-NMR). The antimicrobial activity against Escherichia coli, Staphylococcus aureus, Aspergillus niger, and Candida albicans was evaluated. Pericoterpenoid A showed moderate antimicrobial activity against A. niger and weak activity against C. albicans. This is the first report of the presence of cadinane-type sesquiterpene in Periconia sp. PMID- 26096304 TI - The Pro-inflammatory Cytokine Interleukin-1beta is a Key Regulatory Factor for the Postictal Suppression in Mice. AB - AIMS: The postictal suppression (PS) is a common and important period following an epileptic seizure but has not been well studied. This study was designed to determine whether interleukin-1beta (IL-1beta) is involved in the PS. METHODS: The effects of IL-1beta on the PS were tested in three independent seizure models induced by hippocampal kindling, maximal electroshock seizure (MES), and 4 aminopyridine, respectively. RESULTS: IL-1R1 knockout or IL-1RA enhanced the seizure refractory phenomenon without influencing the baseline seizure threshold in intermittent MES model. IL-1beta attenuated the seizure refractory phenomenon without affecting the severity of the preceding seizures in hippocampal kindling model, while IL-1RA enhanced it. Besides, IL-1beta reduced the postictal EEG suppression period, while IL-1RA prolonged it. And IL-1beta showed no further effect on the postictal EEG suppression and seizure refractory phenomenon in IL 1R1 knockout mice. In addition, 30 min after intrahippocampal injection of 4 aminopyridine, IL-1beta increased the incidence of SE, while IL-1RA prolonged the intervals between recurrent seizures. CONCLUSIONS: This study provides the first direct evidence that IL-1beta is key regulatory factor for the PS, and its receptor IL-1R1 may be a potential target for adjuvant treatment of postictal problems. PMID- 26096305 TI - Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. AB - Understanding rates and determinants of clinical pathologic progression for recipients with de novo donor-specific antibody (dnDSA), especially subclinical dnDSA, may identify surrogate endpoints and inform clinical trial design. A consecutive cohort of 508 renal transplant recipients (n = 64 with dnDSA) was studied. Recipients (n = 388) without dnDSA or dysfunction had an eGFR decline of -0.65 mL/min/1.73 m(2) /year. In recipients with dnDSA, the rate eGFR decline was significantly increased prior to dnDSA onset (-2.89 vs. -0.65 mL/min/1.73 m(2) /year, p < 0.0001) and accelerated post-dnDSA (-3.63 vs. -2.89 mL/min/1.73 m(2) /year, p < 0.0001), suggesting that dnDSA is both a marker and contributor to ongoing alloimmunity. Time to 50% post-dnDSA graft loss was longer in recipients with subclinical versus a clinical dnDSA phenotype (8.3 vs. 3.3 years, p < 0.0001). Analysis of 1091 allograft biopsies found that dnDSA and time independently predicted chronic glomerulopathy (cg), but not interstitial fibrosis and tubular atrophy (IFTA). Early T cell-mediated rejection, nonadherence, and time were multivariate predictors of IFTA. Independent risk factors for post-dnDSA graft survival available prior to, or at the time of, dnDSA detection were delayed graft function, nonadherence, dnDSA mean fluorescence intensity sum score, tubulitis, and cg. Ultimately, dnDSA is part of a continuum of mixed alloimmune-mediated injury, which requires solutions targeting T and B cells. PMID- 26096306 TI - EZH2 expression in gliomas: Correlation with CDKN2A gene deletion/ p16 loss and MIB-1 proliferation index. AB - Enhancer of zeste homolog 2 (EZH2) mediated down-regulation of CDKN2A/p16 has been observed in cell lines as well as in a few carcinomas. However, there is no study correlating EZH2 expression with CDKN2A/p16 status in gliomas. Hence, the present study was conducted to evaluate EZH2 expression in astrocytic and oligodendroglial tumors and correlate with CDKN2A/p16 status as well as MIB-1 labeling index (LI). Gliomas of all grades (n = 118) were studied using immunohistochemistry to assess EZH2, p16 and MIB-1 LI and fluorescence in situ hybrization to evaluate CDKN2A gene status. EZH2 expression and CDKN2A homozygous deletion (HD) were both significantly more frequent in high-grade gliomas (HGG). Further, strong EZH2 expression (LI >= 25%) was significantly more common in HGGs without CDKN2A HD (48.7%; 19/39) as compared to cases with deletion (15.8%; 3/19). Loss of p16 expression was noted in 100% and 51.3% of CDKN2A deleted and non-deleted tumors, respectively. Notably, 80% (16/20) of the CDKN2A non-deleted HGGs with p16 loss had strong EZH2 expression, in contrast to only 15.8% (3/19) in the deleted group. Loss of p16 expression significantly correlated with MIB-1 LI, irrespective of EZH2 status. Thus, this study shows that EZH2 expression correlates with tumor grade in both astrocytic and oligodendroglial tumors and hence can be used as a diagnostic marker to differentiate between low and HGGs. Further, this is the first report demonstrating an inverse correlation of strong EZH2 expression with CDKN2A HD in HGGs. Loss of p16 protein expression is mostly attributable to CDKN2A HD and correlates significantly with MIB-1 LI. Notably, our study for the first time suggests a possible epigenetic mechanism of p16 loss in CDKN2A non-deleted HGGs mediated by strong EZH2 expression. A hypothetical model for control of proliferative activity in low versus HGGs is therefore proposed. PMID- 26096307 TI - Retraction: 'Osteoporosis prevention education programme for women' by Chan, M. F. and Ko, C.Y. PMID- 26096308 TI - Erratum to "Chan M.F. & Arthur D.G. (2009) Nurses' attitudes towards perinatal bereavement care. Journal of Advanced Nursing 65, 2532-2541.". PMID- 26096310 TI - Chemoprophylactic and therapeutic efficacy of thymol in murine cystic echinococcosis. AB - Cystic echinococcosis is a zoonotic disease caused by the larval stage of the cestode Echinococcus granulosus. The drugs commonly used against cystic echinococcosis are benzimidazoles. Unfortunately, 20%-40% of cases do not respond favorably to such chemotherapy. Consequently, the search of new therapeutic alternatives such as the use of traditional medicinal plants has been increased. The aim of the current experimental work was to investigate the chemoprophylactic and clinical efficacy of thymol on mice infected with E. granulosus metacestodes. Thymol (40 mg/kg) was administered under two different therapeutic schemes: dosing every 24h over 20 days and treatment every 12h for 10 days. Thymol demonstrated efficacy against experimental murine cystic echinococcosis. The chemoprophylactic and therapeutic effects of thymol were comparable to that of albendazole. Due to the lack of toxicity observed in mice at the tested doses; we consider that thymol is a potential alternative to be applied for the treatment of human hydatid disease. PMID- 26096311 TI - A complex of species related to Paradiscogaster glebulae (Digenea: Faustulidae) in chaetodontid fishes (Teleostei: Perciformes) of the Great Barrier Reef. AB - A total of 1523 individuals of 34 species of chaetodontids from the Great Barrier Reef were examined for faustulid trematodes. Specimens resembling Paradiscogaster glebulae Bray, Cribb & Barker, 1994 were found in nine chaetodontid species at three localities. These specimens are shown, on the basis of combined morphological and molecular analyses, to comprise a complex of morphologically similar and partly cryptic species. The complex may comprise as many as six distinct species of which three are resolved here. The true P. glebulae is identified in Chaetodon ornatissimus Cuvier, 1831, Chaetodon aureofasciatus Macleay, 1878, Chaetodon plebeius Cuvier, 1831, Chaetodon rainfordi McCulloch, 1923 and Chaetodon speculum Cuvier, 1831. Two new species are described, Paradiscogaster munozae n. sp. from Heniochus varius (Cuvier, 1829), Heniochus chrysostomus Cuvier, 1831 and Chaetodon citrinellus Cuvier, 1831 and Paradiscogaster melendezi n. sp. from Chaetodon kleinii Bloch, 1790. In terms of morphology the three species differ most clearly in the development of the appendages on the ventral sucker. The three species differ at 3-6consistent bp of ITS2 rDNA. The host-specificity of the three species differs strikingly. P. melendezi n. sp. infects just one fish species, P. glebulae infects species of only one clade of Chaetodon, and P. munozae n. sp. infects quite unrelated species. The basis of this unusual pattern of host-specificity requires further exploration. Two of the species recognised here, P. glebulae and P. munozae n. sp., showed apparent intra-individual variation in the ITS2 rDNA sequences as demonstrated by clear, replicated double peaks in the electropherograms. PMID- 26096312 TI - Role of thrombophilia factors in acute systemic-pulmonary shunt obstruction. AB - BACKGROUND: Systemic-pulmonary shunts are widely used in initial palliation in cyanotic congenital heart disease. The incidence and the relationship between acute shunt obstruction and thrombophilia are not precisely defined. The aim of this study was to determine the frequency of shunt obstruction in the early postoperative period, and to define the frequency and presence of thrombophilia factors in patients treated for acute shunt thrombosis. METHODS: Between October 2010 and October 2012, 77 patients who had systemic-pulmonary shunt operation were included in this prospective study. Patients who developed shunt obstruction were examined in terms of inherited and acquired thrombophilia factors. RESULTS: Median patient age was 61 days and median weight was 4.3 kg. Thirty-three patients were neonates. Diameter of the Gore-Tex grafts used for the shunt ranged from 3 mm to 5 mm. Acute shunt occlusion rate was 10% (8/77), and all of these occurred in the first 24 h. Thrombophilia was found in three of eight patients who underwent intervention (surgical and/or transcatheter) due to shunt thrombosis (presence of anti-phospholipid antibodies, n = 1; protein C deficiency, n = 1; and factor V Leiden mutation, n = 1) and only one patient died. CONCLUSIONS: Acute shunt obstruction developed in 10% of patients who underwent systemic-pulmonary shunt, and emergency surgery or transcatheter intervention can be life saving in this context. Acute shunt obstruction can occur due to mechanical and hemodynamic problems, but clinicians should also consider and evaluate thrombophilia factors. PMID- 26096314 TI - Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication--A Systematic Review with Meta-Analyses of Randomised Trials. AB - Flumazenil is used for the reversal of benzodiazepine overdose. Serious adverse events (SAEs) including seizures and cardiac arrhythmias have been reported in patients treated with flumazenil, and the clinical advantage of flumazenil treatment has been questioned. The objective was to assess the risk of (S)AEs associated with the use of flumazenil in patients with impaired consciousness due to known or suspected benzodiazepine overdose. Studies included in the meta analyses were identified by literature search in Medline, Cochrane Library and Embase using combinations of the words flumazenil, benzodiazepines, anti-anxiety agents, poisoning, toxicity and overdose. Randomised clinical trials (RCTs) in verified or suspected benzodiazepine overdose patients comparing treatment with flumazenil versus placebo were included. Pre-defined outcome measures were AEs, SAEs and mortality. Thirteen trials with a total of 994 randomised (990 evaluable) patients were included. AEs were significantly more common in the flumazenil group (138/498) compared with the placebo group (47/492) (risk ratio: 2.85; 95% confidence interval: 2.11-3.84; p < 0.00001). SAEs were also significantly more common in the flumazenil group compared with the placebo group (12/498 versus 2/492; risk ratio: 3.81; 95% CI: 1.28-11.39; p = 0.02). The most common AEs in the flumazenil group were agitation and gastrointestinal symptoms, whereas the most common SAEs were supraventricular arrhythmia and convulsions. No patients died during the blinded phase of the RCTs. The use of flumazenil in a population admitted at the emergency department with known or suspected benzodiazepine intoxication is associated with a significantly increased risk of (S)AEs compared with placebo. Flumazenil should not be used routinely, and the harms and benefits should be considered carefully in every patient. PMID- 26096313 TI - KIAA0586 is Mutated in Joubert Syndrome. AB - Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum. PMID- 26096315 TI - Oculomotor tasks affect differently postural control in healthy children. AB - Eye movements affect postural stability in children. The present study focuses on the effect of different types of eye movements on postural stability in healthy children. Both eye movements and postural stability have been recorded in 51 healthy children from 6.3 to 15.5 years old. Eye movements were recorded binocularly with a video oculography (MobilEBT((r))), and postural stability was measured while child was standing on a force platform (TechnoConcept((r))). Children performed three oculomotor tasks: saccades, pursuits and reading a text silently. We measured the number of saccades made in the three oculomotor tasks, the number of words read, and the surface area, the length and mean velocity of the center of pressure (CoP). According to previous studies, postural control improves with age until 10-12 years. Saccades toward a target as well as during a reading task reduce significantly the CoP displacement and its velocity, while during pursuit eye movements all children increase postural parameters (i.e., the surface area, the length and mean velocity of the CoP). These results suggest the presence of an interaction between the oculomotor control and the postural system. Visual attention to perform saccades (to stationary targets or to words) influences postural stability more than the frequency of saccade triggering does. PMID- 26096316 TI - Use of Stroke-Related Income Supplements and Predictors of Use in a Working-Aged Finnish Ischemic Stroke Cohort. AB - BACKGROUND: Compared with the direct costs, the indirect costs of stroke may be larger contributors to the socioeconomic burden of stroke, and the need to better understand the indirect costs of stroke is well established. We investigated the indirect costs of stroke according to a novel outcome, the use of stroke-related income supplements, in a Finnish cohort of working-aged patients. METHODS: Consecutive patients (n = 230) who experienced a first-ever ischemic stroke were recruited. Demographic, clinical, and cognitive function data (which were measured using clinical neuropsychological assessments) were collected at baseline and at 6-month and 2-year follow-ups. Data on the use of income supplements within the first 3 years of the stroke were retrieved from national insurance registry files and used to construct survival models. RESULTS: Stroke patients used a mean of 11 months of stroke-related income supplements; this use was associated with atrial fibrillation, cognitive impairment, prestroke income supplement use, higher National Institutes of Health Stroke Scale scores, lower Barthel Index scores, and increased lesion sizes. In multivariate survival models, atrial fibrillation and cognitive impairment were the factors most strongly associated with the use of stroke-related income supplements. CONCLUSIONS: Using stroke-related income supplement data to quantify poststroke productivity losses allowed a working-aged cohort to be investigated without inclusion restrictions based on occupational status or other factors; the use of these data as an outcome emphasized the well-known detrimental effects of atrial fibrillation and cognitive impairment on stroke outcome. The results support stroke-related income supplement use as a complementary outcome for understanding stroke-related productivity losses. PMID- 26096317 TI - The Circle of Willis and White Matter Lesions in Patients with Carotid Atherosclerosis. AB - BACKGROUND: The correlation between cerebral atherosclerosis and white matter lesions (WMLs) in the elderly was controversial in the published articles, where the stenosis was often evaluated by ultrasonography, computed tomography angiography, or magnetic resonance angiography and collaterals were seldom considered. We hypothesized that collaterals influence WMLs. Our study was to explore the relationship between the circle of Willis and WMLs in a retrospective, hospital-based cohort of patients with carotid atherosclerosis. METHODS: Two hundred eighty-six patients with carotid atherosclerosis were enrolled from the Nanjing Stroke Registry. They underwent magnetic resonance imaging evaluating WMLs and digital subtraction angiography evaluating both carotid atherosclerosis and collateral capacity of the circle of Willis. We tested the association between severe carotid atherosclerosis, the circle of Willis, and WMLs by logistic regression analysis. RESULTS: Severity of carotid atherosclerosis was not significantly associated with either periventricular or deep WMLs (P = .656 and .566, respectively). Number of carotid arteries with severe stenosis was not associated with the severity of either periventricular or deep WMLs (P = .721 and .263, respectively). Patency of the communicating arteries (CoA) was not associated with periventricular or deep WMLs (P = .561 and .703, respectively). Advanced age and hypertension were associated with periventricular WMLs (P = .001 and .008, respectively). Advanced age, hypertension, and prior stroke were associated with deep WMLs (P = .049, .048, and .001, respectively). CONCLUSIONS: The circle of Willis and severe carotid atherosclerosis may not be related to WMLs. Further larger studies are warranted to confirm or refute our findings. PMID- 26096318 TI - Task-Based Mirror Therapy Augmenting Motor Recovery in Poststroke Hemiparesis: A Randomized Controlled Trial. AB - BACKGROUND: To establish the effect of the task-based mirror therapy (TBMT) on the upper limb recovery in stroke. METHODS: A pilot, randomized, controlled, assessor-blinded trial was conducted in a rehabilitation institute. A convenience sample of 33 poststroke (mean duration, 12.5 months) hemiparetic subjects was randomized into 2 groups (experimental, 17; control, 16). The subjects were allocated to receive either TBMT or standard motor rehabilitation-40 sessions (5/week) for a period of 8 weeks. The TBMT group received movements using various goal-directed tasks and a mirror box. The movements were performed by the less affected side superimposed on the affected side. The main outcome measures were Brunnstrom recovery stage (BRS) and Fugl-Meyer assessment (FMA)-FMA of upper extremity (FMA-UE), including upper arm (FMA-UA) and wrist-hand (FMA-WH). RESULTS: The TBMT group exhibited highly significant improvement on mean scores of FMA-WH (P < .001) and FMA-UE (P < .001) at postassessment in comparison to the control group. Furthermore, there was a 12% increase in the number of subjects at BRS stage 5 (out of synergy movement) in the experimental group as compared to a 0% rise at the same stage in the control group. CONCLUSIONS: This pilot trial confirmed the role of TBMT in improving the wrist-hand motor recovery in poststroke hemiparesis. MT using tasks may be used as an adjunct in stroke rehabilitation. PMID- 26096319 TI - Blood sweat and tears - tackling the stigma of stigmata. PMID- 26096320 TI - Faecal microbiota transplantation plus selected use of vancomycin for severe complicated Clostridium difficile infection: description of a protocol with high success rate. AB - BACKGROUND: Severe and severe/complicated Clostridium difficile infection (CDI) can result in ICU admission, sepsis, toxic megacolon and death. In this setting, colectomy is the standard of care but it is associated with a 50% mortality. AIM: To evaluate safety and efficacy of a sequential faecal microbiota transplantation (FMT) and antibiotic protocol in severe and severe/complicated CDI patients who are at high risk for colectomy. METHODS: All patients with severe and severe/complicated CDI refractory to oral vancomycin +/- rectal vancomycin and intravenous metronidazole therapy were offered FMT. Treatment consisted of sequential FMTs via colonoscopy with the need for repeat FMT and continued vancomycin guided by clinical response and pseudomembranes at colonoscopy. RESULTS: A total of 29 patients underwent FMT between July 2013 and August 2014. The overall treatment response of endoscopic sequential FMT was 93% (27/29), with 100% (10/10) for severe CDI and 89% (17/19) for severe/complicated CDI. A single FMT was performed in 62%, two FMTs were performed in 31% and three FMTs in 7% of patients. The use of non-CDI antibiotics predicted repeat FMT (odds ratio = 17.5). The 30-day all-cause mortality after FMT was 7%, and the cumulative 3 month survival was 76%. Of the two patients who died within 30 days, one underwent colectomy and succumbed to sepsis; the other died from septic shock related to CDI. CONCLUSION: The success of a treatment protocol for severe and severe/complicated involving faecal microbiota transplantation and continued vancomycin in selected patients was high, and it warrants further evaluation. PMID- 26096321 TI - Alzheimer's disease research in the context of the national plan to address Alzheimer's disease. AB - In 2012, the first National Plan to Address Alzheimer's Disease in the United States (U.S.) was released, a component of the National Alzheimer's Project Act legislation. Since that time, there have been incremental increases in U.S. federal funding for Alzheimer's disease and related dementia research, particularly in the areas of biomarker discovery, genetic link and related biological underpinnings, and prevention studies for Alzheimer's. A central theme in each of these areas has been the emphasis of cross-sector collaboration and private-public partnerships between government, non-profit organizations and for profit organizations. This paper will highlight multiple private-public partnerships supporting the advancement of Alzheimer's research in the context of the National Plan to Address Alzheimer's. PMID- 26096322 TI - Diabetes and obesity not associated with 6-month remission rates for primary care patients with depression. AB - BACKGROUND: Complex interrelationships appear to exist among depression, diabetes, and obesity, and it has been proposed that both diabetes and obesity have an association with depression. OBJECTIVE: The purpose of our study was to explore the effect of obesity and diabetes on response to the treatment of depression. Our hypothesis was that obesity and the diagnosis of diabetes in primary care patients with depression would have no effects on depression remission rates 6 months after diagnosis. METHODS: A retrospective chart review analysis of 1894 adult (age >=18y) primary care patients diagnosed with major depressive disorder or dysthymia and a Patient Health Questionnaire-9 score >=10 from January 1, 2008, through September 30, 2012. Multiple logistic regression modeling retaining all independent variables was performed for the outcome of remission (Patient Health Questionnaire-9 < 5) 6 months after diagnosis. RESULTS: The presence of obesity (odds ratio = 0.937, 95% CI: 0.770-1.140, p = 0.514) or the diagnosis of diabetes (odds ratio = 0.740, 95% CI: 0.535-1.022, p = 0.068) did not affect the likelihood of remission, while controlling for the other independent variables. CONCLUSIONS: In primary care patients treated for depression, the presence of diabetes or obesity at the time of diagnosis of depression does not appear to significantly affect remission of depressive symptoms 6 months after diagnosis. PMID- 26096324 TI - Predicting extremely preterm children's school performance by transient abnormal neurology? PMID- 26096323 TI - Facial transplantation in a blind patient: psychologic, marital, and family outcomes at 15 months follow-up. AB - BACKGROUND: Quality of life has frequently been reported to improve after vascularized composite allotransplantation of the face. However, psychosocial functioning of the partner or of particular patient groups such as blind patients are until now less well investigated. OBJECTIVE: The aim of this study is to investigate psychologic, marital, and family functioning of a blind 54-year-old patient, Mr. A, and his partner after facial transplantation. METHODS: Depressive and anxiety symptoms, hopelessness, personality, coping, resilience, illness cognitions, marital support, dyadic adjustment, family functioning, and quality of life of Mr. A and his partner were assessed before and after facial transplantation and at 15 months follow-up. Reliable change index (RCI) was further calculated to evaluate the magnitude of change. RESULTS: Most psychologic, marital, and family scores of both Mr. A and his partner were within a normative and healthy range before and after transplant and at 15 months follow up. Resilience (RCI: 3.6), affective responsiveness (RCI: -3.6), and disease benefits (RCI: 2.6) of Mr. A further improved at 15 months follow-up whereas the physical quality of life (RCI: -14.8) strongly decreased. Only marital support (RCI: -2.1) and depth (RCI: -2.0) of the partner decreased at 15 months. CONCLUSIONS: The results of this study point to positive psychosocial outcomes in a blind patient after facial transplantation. Further, they may underscore the importance of good psychosocial functioning before transplantation of both partners and of their involvement in psychologic and psychiatric treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 26096325 TI - Use of a titanium alloy (Chest Way) in the surgical stabilization of flail chest. AB - To avoid the complications of internal pneumatic stabilization for flail chest, we performed stabilization of the chest wall with a metal bar using the Nuss procedure. Here, we used a highly elastic lightweight biocompatible titanium alloy Chest Way (Solve Corporation, Kanagawa, Japan), enabling magnetic resonance imaging. The patient was a 37-year-old man who sustained injuries in a car crash. Gradually increasing subcutaneous emphysema was present. Bilateral pleural drainage and tracheal intubation were conducted on the scene, and a peripheral venous line was established. The patient was then transferred to our hospital by helicopter. A titanium alloy Chest Way was inserted to manage his flail chest accompanied by multiple rib fractures on the left side. Two days later, artificial respiration was no longer required. PMID- 26096326 TI - Distribution of core hospitals for patients with fulminant hepatitis and late onset hepatic failure in Japan. PMID- 26096327 TI - African swine fever virus assembles a single membrane derived from rupture of the endoplasmic reticulum. AB - Collective evidence argues that two members of the nucleocytoplasmic large DNA viruses (NCLDVs) acquire their membrane from open membrane intermediates, postulated to be derived from membrane rupture. We now study membrane acquisition of the NCLDV African swine fever virus. By electron tomography (ET), the virion assembles a single bilayer, derived from open membrane precursors that collect as ribbons in the cytoplasm. Biochemically, lumenal endoplasmic reticulum (ER) proteins are released into the cytosol, arguing that the open intermediates are ruptured ER membranes. ET shows that viral capsid assembles on the convex side of the open viral membrane to shape it into an icosahedron. The viral capsid is composed of tiny spikes with a diameter of ~5 nm, connected to the membrane by a 6 nm wide structure displaying thin striations, as observed by several complementary electron microscopy imaging methods. Immature particles display an opening that closes after uptake of the viral genome and core proteins, followed by the formation of the mature virion. Together with our previous data, this study shows a common principle of NCLDVs to build a single internal envelope from open membrane intermediates. Our data now provide biochemical evidence that these open intermediates result from rupture of a cellular membrane, the ER. PMID- 26096328 TI - The Rapid Exfoliation and Subsequent Restacking of Layered Titanates Driven by an Acid-Base Reaction. AB - Two-dimensional (2D) (hydro)oxide materials, that is, nanosheets, enable the preparation of advanced 2D materials and devices. The general synthesis route of nanosheets involves exfoliating layered metal (hydro)oxide crystals. This exfoliation process is considered to be time-consuming, hindering their industrial-scale production. Based on in situ exfoliation studies on the protonated layered titanate H(1.07)Ti(1.73)O4?H2O (HTO), it is now shown that ion intercalation-assisted exfoliation driven by chemical reaction provides a viable and fast route to isolated nanosheets. Contrary to the general expectation, data indicate that direct exfoliation of HTO occurs within seconds after mixing of the reactants, instead of proceeding via a swollen state as previously thought. These findings reveal that ion intercalation-assisted exfoliation driven by chemical reaction is a promising exfoliation route for large-scale synthesis. PMID- 26096329 TI - An interdisciplinary specialist team leads to improved diagnostics and treatment for paediatric patients with vascular anomalies. AB - AIM: Patients with vascular anomalies are often misdiagnosed, leading to delayed or improper treatment. The aim of this study was to evaluate the impact of an interdisciplinary team on the diagnosis and treatment of paediatric patients with vascular anomalies. METHODS: We reviewed the paediatric patients evaluated by our interdisciplinary team between 2002 and 2012, analysing the referral diagnosis, final diagnosis, patient age, sex, clinical history, laboratory tests, imaging studies and treatments. RESULTS: Of the 480 patients who were evaluated, 435 (90.6%) had a vascular anomaly: 30.7% of all patients had a tumour and 55.2% had a malformation. Haemangiomas comprised 93.2% of all tumours, while malformations included capillary (9.8%), lymphatic (30.1%), venous (36.8%), arteriovenous (3.8%) and combined slow-flow (7.9%) malformations. Tumours were initially diagnosed correctly in 89.2% of the patients, but only 38.0% of the malformations were diagnosed correctly. Improper treatment was given to 1.4%, due to incorrect diagnoses. CONCLUSION: This study showed that haemangiomas were likely to be diagnosed correctly, but other tumours and vascular malformations were likely to be misdiagnosed. Misdiagnosis seldom led to improper treatment, but probably led to delayed treatment in many cases. The interdisciplinary approach led to improved diagnostics and treatment. PMID- 26096330 TI - Adapting through glacial cycles: insights from a long-lived tree (Taxus baccata). AB - Despite the large body of research devoted to understanding the role of Quaternary glacial cycles in the genetic divergence of European trees, the differential contribution of geographic isolation and/or environmental adaptation in creating population genetic divergence remains unexplored. In this study, we used a long-lived tree (Taxus baccata) as a model species to investigate the impact of Quaternary climatic changes on genetic diversity via neutral (isolation by-distance) and selective (isolation-by-adaptation) processes. We applied approximate Bayesian computation to genetic data to infer its demographic history, and combined this information with past and present climatic data to assess the role of environment and geography in the observed patterns of genetic structure. We found evidence that yew colonized Europe from the East, and that European samples diverged into two groups (Western, Eastern) at the beginning of the Quaternary glaciations, c. 2.2 Myr before present. Apart from the expected effects of geographical isolation during glacials, we discovered a significant role of environmental adaptation during interglacials at the origin of genetic divergence between both groups. This process may be common in other organisms, providing new research lines to explore the effect of Quaternary climatic factors on present-day patterns of genetic diversity. PMID- 26096331 TI - A two-dimensional spin liquid in quantum kagome ice. AB - Actively sought since the turn of the century, two-dimensional quantum spin liquids (QSLs) are exotic phases of matter where magnetic moments remain disordered even at zero temperature. Despite ongoing searches, QSLs remain elusive, due to a lack of concrete knowledge of the microscopic mechanisms that inhibit magnetic order in materials. Here we study a model for a broad class of frustrated magnetic rare-earth pyrochlore materials called quantum spin ices. When subject to an external magnetic field along the [111] crystallographic direction, the resulting interactions contain a mix of geometric frustration and quantum fluctuations in decoupled two-dimensional kagome planes. Using quantum Monte Carlo simulations, we identify a set of interactions sufficient to promote a groundstate with no magnetic long-range order, and a gap to excitations, consistent with a Z2 spin liquid phase. This suggests an experimental procedure to search for two-dimensional QSLs within a class of pyrochlore quantum spin ice materials. PMID- 26096332 TI - Multicenter experience using simeprevir and sofosbuvir with or without ribavirin to treat hepatitis C genotype 1 in patients with cirrhosis. AB - Interferon (IFN)-free regimens are needed to treat hepatitis C virus (HCV) infection. Combined simeprevir (SMV) and sofosbuvir (SOF) with or without ribavirin (RBV) results in high sustained virological response (SVR) rates along with minimal adverse events (AEs) in patients with hepatitis C genotype 1 (HCV GT1). The aim of this study was to report on the virological response, safety, and tolerability of SOF and SMV with or without RBV in compensated and decompensated patients with cirrhosis with HCV GT1 infection. Patients treated with standardized clinical protocol utilizing SMV+SOF with or without RBV at three transplant centers were retrospectively reviewed. A total of 119 patients (61% male, 87% white, 69% subtype 1a, 30% Child-Pugh-Turcott [CPT]-B liver cirrhosis [LC], and 82% were treatment experienced) received treatment and were followed for a median of 38 weeks (range, 12-58). Sustained virological response (SVR) at week 12 (SVR12) was achieved in 78% (92 of 118) of patients (95% confidence interval: 69-85). Lower pretreatment Model for End Stage Liver Disease (MELD) score was a predictor of SVR12 (P = 0.018). Baseline viral load, previous treatment status, RBV use, or GT1 subtype did not impact SVR 12. The majority of patients with SVR12 showed stability or improvement in MELD score. Treatment was very well tolerated with mild degrees of AEs. CONCLUSIONS: The regimen of SMV+SOF with or without RBV for 12 weeks was very well tolerated and resulted in high SVR12 rates (78%) in HCV GT1 patients with LC. SVR12 was inversely related to pretreatment MELD. SVR12 had favorable short-term impact on MELD score. Long-term impact on disease stability is yet to be determined. Longer treatment duration or the use of different regimen may still be needed in this population. PMID- 26096336 TI - Xingwei Li. PMID- 26096334 TI - Corrigendum: Visible-Light-Mediated 1,2-Acyl Migration: The Reaction of Secondary Enamino Ketones with Singlet Oxygen. PMID- 26096339 TI - Educational attainment and motor burden in Parkinson's disease. AB - OBJECTIVE: Greater educational attainment is a protective factor for neurodegenerative dementias. If education earlier in life leads to greater cerebral reserve, it may play a similar protective role in Parkinson's disease (PD). METHODS: We conducted a cross-sectional clinical imaging study of 142 subjects with PD. All subjects underwent [(11)C]dihydrotetrabenazine PET to confirm nigrostriatal dopaminergic denervation and brain MRI to estimate adjusted cortical gray matter volume (GMV). RESULTS: After adjusting for possible confounders, including cognitive and dopaminergic covariates, as well as nonspecific neurodegeneration covariates (age, disease duration, and total adjusted cortical GMV), lower years of education remained a significant predictor of higher total MDS-UPDRS motor score (t = -3.28; P = 0.001). Education level associated inversely with white matter (WM) hyperintensities in a post-hoc analysis (n = 83). CONCLUSIONS: Higher educational attainment is associated with lower severity of motor impairment in PD. This association may reflect an extranigral protective effect upon WM integrity. PMID- 26096340 TI - Tumour necrosis factor superfamily member 15 (Tnfsf15) facilitates lymphangiogenesis via up-regulation of Vegfr3 gene expression in lymphatic endothelial cells. AB - Lymphangiogenesis is essential in embryonic development but is rare in adults. It occurs, however, in many disease conditions including cancers. Vascular endothelial growth factor-C/D (VEGF-C/D) and VEGF receptor-3 (Vegfr3) play a critical role in the regulation of lymphangiogenesis. We investigated how the VEGF-C/Vegfr3 signalling system is regulated by tumour necrosis factor superfamily member 15 (Tnfsf15), an endothelium-derived cytokine. We report here that Tnfsf15, which is known to induce apoptosis in vascular endothelial cells, can promote lymphatic endothelial cell (LEC) growth and migration, stimulate lymphangiogenesis, and facilitate lymphatic circulation. Treatment of mouse LECs with Tnfsf15 results in up-regulation of Vegfr3 expression; this can be inhibited by gene silencing of death domain-containing receptor-3 (DR3; Tnfrsf25), a cell surface receptor for Tnfsf15, with siRNA, or by blocking Tnfsf15-DR3 interaction with a Tnfsf15 neutralizing antibody, 4-3H. Additionally, Tnfsf15/DR3 signalling pathways in LECs include activation of NF-kappaB. Tnfsf15-overexpressing transgenic mice exhibit a marked enhancement of lymph drainage; this is confirmed by treatment of wild-type mice with intraperitoneal injection of recombinant Tnfsf15. Moreover, systemic treatment of pregnant Tnfsf15 transgenic mice with 4 3H leads to inhibition of embryonic lymphangiogenesis. Our data indicate that Tnfsf15, a cytokine produced largely by endothelial cells, facilitates lymphangiogenesis by up-regulating Vegfr3 gene expression in LECs, contributing to the maintenance of the homeostasis of the circulatory system. This finding also suggests that Tnfsf15 may be of potential value as a therapeutic tool for the treatment of lymphoedema. PMID- 26096341 TI - Association between interleukin-18 gene polymorphism and Helicobacter pylori infection in the Korean population. AB - Interleukin-18 (IL-18) is a pleiotropic, pro-inflammatory cytokine that is capable of promoting the Th1 response. A predominant Th1 response induces chronic and persistent inflammatory changes in the gastric mucosa in response to Helicobacter pylori (H. pylori) infection. The aim of this study was to investigate the potential association between IL-18 gene polymorphisms and susceptibility to H. pylori infection in the Korean population. A total of 678 subjects who underwent a routine health check-up were enrolled. The IL-18 gene polymorphisms at positions -656, -607, -137, +113, and +127 were genotyped. H. pylori positivity was demonstrated in 456 subjects (67.3%). The allele frequencies of IL-18 gene polymorphisms at position -137 (rs187238) were different based on the status of H. pylori infection (G vs. C, adjusted OR 0.64 CI: 0.47-0.87, P = 0.005). The results indicate that the genetic variants in the IL-18 gene may be associated with susceptibility to H. pylori infection in the Korean population, suggesting that IL-18 plays a role in the pathogenesis of H. pylori-associated diseases. However, this finding requires further replication and validation. PMID- 26096342 TI - A Tetraferrocenyl-Resorcinarene Cavitand as a Redox-Switchable Host of Ammonium Salts. AB - Tetraannulation of a resorcinarene-octaamino cavitand with ferrocenecarboxaldehyde allows the preparation of a tetrabenzimidazole resorcinarene cavitand with four ferrocenyl moieties directly linked to the C2 atom of the imidazole units. Oxidation of the four ferrocenyl moieties produces important structural modifications of the molecule, as indicated by DFT calculations performed for the neutral and tetraoxidized forms of the cavitand. By means of (1) H NMR spectroscopic analysis, the encapsulating properties of the new tetraferrocenyl-resorcinarene cavitand toward a series of ammonium salts were evaluated, and a clear cutoff point in binding affinity with respect to size was observed. Cyclic voltammetric studies allowed us to estimate the relative association constants for the neutral and oxidized forms of the cavitand, thus indicating that the guest was bound to the neutral (reduced) state of the cavitand and was released from the oxidized form. These redox-addressable conformational and binding properties of the resorcinarene-tetraferrocenyl cavitand constitute all the necessary features of a redox-switchable molecular gripper. By means of mass-spectrometric analysis, we could unambiguously confirm the molar stoichiometry of the host-guest complex (1:1) and assess the strong guest encapsulation, as indicated by triggering the covalent coupling between host and guest in the gas phase. PMID- 26096343 TI - Molecular characterization and expression analysis of mouse epidermal growth factor-like domain 8. AB - Epidermal growth factor (EGF)-like (EGFL) domain, a common structural module in numerous secreted or transmembrane proteins, is generally involved in protein protein interactions. To date, several EGFL proteins have been identified and characterized, but little is known about EGFL domain 8 (EGFL8). The present study reported the molecular characterization and expression analysis of EGFL8 in mice. Mouse EGFL8 amplified using a reverse transcription-polymerase chain reaction approach was sequenced and characterized. Mouse EGFL8 encodes a protein of 293 amino acids with two EGFL domains, an Emilin-like domain and a Ca(2+)-binding EGFL domain, which has a molecular mass of 32 kDa. The coding sequence has a high degree of amino acid sequence identity across species, and the EGFL domain has been highly conserved in various species during evolutionary radiation. A phylogenetic tree calculated using the neighbor-joining method revealed that EGFL8 and EGFL7 are more closely associated with each other than either is to EGFL3, and they cluster with EGFL6. It was found that mouse EGFL8 protein was highly expressed in diverse mouse tissue types, including the thymus, lymph nodes, testis, ovaries, epididymis, ductus deferens, ileum, colon, stomach, esophagus, lung, uterus, urinary bladder, skin, spleen, adrenal glands and penis. These results are of great use in understanding the biological roles of mouse EGFL8 for further study. PMID- 26096344 TI - Should the Celiac Artery Be Used as an Anatomical Marker for the Descending Thoracic Aorta During Transesophageal Echocardiography? AB - BACKGROUND: Transesophageal echocardiography (TEE) is a pivotal tool for diagnosis of aortic diseases. However, there are no suitable anatomical markers to describe location of disease in the descending thoracic aorta. In the past, we have used distance from the dental incisors to report location of disease, but this has no anatomical relevance. Our recent data comparing TEE and computed tomography (CT) have shown that the celiac artery is an accurate anatomical marker where disease is described as distance relative to the celiac artery. This study was designed to determine whether utilization of the celiac artery as an anatomical marker with TEE is practically feasible. METHODS: A clinical trial was performed at the University of Illinois at Chicago and the Jesse Brown VA Medical Center. A total of 160 patients referred for TEE were consecutively enrolled over a period of 18 months. RESULTS: The celiac artery was visualized in 97% of the patients. CONCLUSIONS: The celiac artery is a reliable anatomical marker with TEE and should be routinely used to locate disease in the descending thoracic aorta. PMID- 26096345 TI - Historical review on thymosin alpha1 in oncology: preclinical and clinical experiences. AB - INTRODUCTION: Thymosin alpha1 (Talpha1) is a naturally occurring polypeptide that regulates immune cell development and function, and is also capable of interacting with multiple target cells with relevant biological effects. The rationale of Talpha1 use in cancer treatment stems from the consideration that tumor progression is favored by a failure of the immune response and in turn induces immune suppression. This paper will review the historical background of Talpha1 use in oncology, aiming to highlight the importance of Talpha1 as an immunotherapeutic tool to be used in combination with chemotherapy, a concept that is not yet fully established in clinic. AREAS COVERED: The efficacy and safety of combining Talpha1 with chemotherapy and cytokines were first evaluated in murine tumor models, providing essential information about effects, mechanisms of action, doses and treatment protocols. The therapeutic potential of the chemo immunotherapy protocol on metastatic melanoma and lung cancer has been confirmed in controlled clinical trials. Critical for the efficacy of the chemo immunotherapy protocol is the dual action of Talpha1 on immune effector and tumor cells. EXPERT OPINION: On the basis of the preclinical and clinical results available, the use of the chemo-immunotherapy protocol, in which the role of Talpha1 is central, is strongly recommended. PMID- 26096346 TI - Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration: Data from an Observational Study. AB - PURPOSE: To analyze the long-term outcomes of eyes with neovascular age-related macular degeneration (AMD) starting treatment with vascular endothelial growth factor (VEGF) inhibitors at least 5 years earlier. DESIGN: Database observational study. PARTICIPANTS: Treatment-naive eyes with neovascular AMD tracked by the Fight Retinal Blindness outcome registry that received at least 1 anti-VEGF injection. METHODS: Locally weighted scatterplot smoothing curves were used to display visual acuity (VA) results. MAIN OUTCOME MEASURES: Change in mean VA and number of injections and visits from baseline up to 7 years after initiating treatment. RESULTS: The mean follow-up time of all 1212 identified eyes was 53.5 months, and 549 (45%) continued attending after 60 months. Mean VA improved from 55.1 to 61.4 letters after 6 months and remained above the mean presenting VA for approximately 6 years. After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA >=70 (20/40) letters, and 18% had VA <=35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years. Geographic atrophy affecting the fovea was thought to be the cause of a >=10-letter loss after 6.5 years in 37% of a subset of such eyes that were retrospectively analyzed. A median of 6 injections and 9 visits were recorded over the first 12 months, and then 5 treatments and 7 to 9 visits per annum thereafter through 7 years. Treatment was discontinued for 663 eyes (53%) within the first 5 years. Despite initial gains in vision, the mean VA of these eyes had deteriorated to baseline or worse around the time treatment was discontinued. The rate of serious adverse events was low. CONCLUSIONS: Good long term outcomes of VEGF inhibition for neovascular AMD were found in this study. These results may be better than other reports because more injections were given to our patients, possibly associated with a greater incentive for the physician to treat. Further studies to determine how to maximize the proportion of eyes that retain the initial VA gains of anti-VEGF are warranted. PMID- 26096347 TI - Depression and prospection. AB - OBJECTIVES: Prospection, the mental representation of possible futures, is usually adaptive. When it goes awry, however, it disrupts emotion and motivation. A negative view of the future is typically seen as one symptom of depression, but we suggest that such negative prospection is the core causal element of depression. Here, we describe the empirical evidence supporting this framework, and we explore the implications for clinical interventions. METHODS: We integrate several literatures: Using the database PsycInfo, we retrieved empirical studies with the keywords prospection, prediction, expectation, pessimism, mental simulation, future-thinking, future-directed thinking, foresight, and/or mental time travel, in conjunction with depression, depressed, or depressive. RESULTS: Three kinds of faulty prospection, taken together, could drive depression: Poor generation of possible futures, poor evaluation of possible futures, and negative beliefs about the future. Depressed mood and poor functioning, in turn, may maintain faulty prospection and feed a vicious cycle. Future-oriented treatment strategies drawn from cognitive-behavioural therapy help to fix poor prospection, and they deserve to be developed further. CONCLUSIONS: Prospection-based techniques may lead to transdiagnostic treatment strategies for depression and other disorders. PMID- 26096348 TI - [Forceps delivery: Professionals' knowledge of forceps application in the area of Lyon]. AB - OBJECTIVES: The aim of this study is to describe knowledge on forceps delivery in the area of Lyon. MATERIAL AND METHODS: It is a multicentric observational study carried between January 1, 2013 and June 9, 2013. A questionnaire was sent to obstetricians and residents of the area of Lyon. It related prerequisites for operative vaginal delivery, the method used to apply forceps, practices and preferences of operators. RESULTS: Seventy-five responses were obtained (47 obstetricians, 28 residents). About prerequisites: 6.4% of the obstetricians and 14.3% of the residents never do urinary catheterization. Instrumental delivery is never performed when the fetal head is not engaged. Mid-pelvic operative vaginal delivery is performed by 51.1% of obstetricians. Trans-abdominal ultrasound assessment is conducted in cases of clinical doubts about the fetal head position. For occipital anterior and left anterior positions, the left blade is first applied. A flexion of the fetal head is applied for anterior positions but not in posterior positions. Most of operators do not perform instrumental rotation. Vacuum extractor is the privileged instrument for obstetricians and forceps is often used in second line. CONCLUSION: This study shows that most of the recommendations for forceps delivery are followed. In front of the lake of statistical power of this study, it might be interesting to improve a largest study with a comparison between obstetricians and residents' practices. PMID- 26096349 TI - [Interest of complex tasks on laparoscopic virtual reality simulator]. AB - OBJECTIVES: The purpose of this study was to assess the contribution of complex tasks on virtual reality simulator (VRS) for novice surgeons in laparoscopy learning. MATERIALS AND METHODS: Fifty-five medical students were prospectively randomized in two groups (A: basic skills, n=28 and B: basic and complex skills, n=27) and then trained during two sessions on VRS. Evaluations took place before and after each training. These evaluations consisted of the achievement of an intracorporeal suture, recorded on video, with the left then with the right hand. Two independent experts evaluated those gestures blindly. RESULTS: A significant progression in terms of times and technical scores was observed in both groups between the first and the last evaluations (P between 0.001 and 0.04). Students in group B improved slower and longer than those in group A. However, left and right hands results confused did not highlight significant differences between the two groups. At the third session, the first hand to train is significantly faster in group B than in group A (P=0.04). CONCLUSION: This study found only a late and minimal impact of complex skills to reduce the execution time of intracorporeal suture. It also showed an slower and longer overall progression for those who use them compared to subjects using basic skills only. PMID- 26096350 TI - [Case report: Vasa previa diagnosis and management. How to prevent Benckiser's hemorrhage?]. AB - Benckiser's haemorrhage is a serious obstetrical complication, following a vasa previa rupture. Incidence of vasa previa is estimated between 1/1150 and 1/5000 pregnancies. This case report illustrates the consequences of a suspected vasa previa rupture. There is no French recommendation of how to treat vasa previa. Different methods of prevention are described and examined thanks to a literature review. PMID- 26096351 TI - [Tubo-ovarian abscesses treatment: Faisability and results of trans-vaginal ultrasound-guided aspiration]. AB - OBJECTIVE: Two years after the French guidelines, the objective was to assess the feasibility and efficiency of ultrasound-guided trans-vaginal drainage of tubo ovarian abscesses (TOA) and to study the responsible germs. MATERIAL AND METHODS: All the patients with a larger abscess than 20mm were included prospectively from May 2011 to July 2014 in the university hospital of Lille. RESULTS: Sixty-nine drainages were performed among 50 patients. Success rate was 94%. No complication occurred. One germ was found in 55% of patients, the TOA was polymicrobian in 20% of cases. CONCLUSION: Ultrasound-guided trans-vaginal drainage of TOA is safe and effective with more than 90% of success rate. PMID- 26096352 TI - [Detailed in utero ultrasound description of 34 cases of congenital cytomegalovirus infection]. AB - OBJECTIVES: To describe precisely prenatal ultrasound features in congenital cytomegalovirus (CMV) infection. MATERIAL AND METHODS: We retrospectively evaluated the ultrasound descriptions of cases of congenital CMV infection between 2004 and 2013. RESULTS: In 74 congenital CMV infections, related ultrasound abnormalities were reported in 34 cases (45.9%). Abnormalities reported were either cerebral (11 cases), either extracerebral (6 cases), or associated (17 cases). A total of 22/34 cases presented extracerebral features of 11 different sorts of abnormalities, mainly intra-uterine growth retardation (11 cases) and hyperechogenic bowel (10 cases) and 26/34 cases presented cerebral features of 14 different sorts, mainly brain calcifications (12 cases) and occipital horn cavity (12 cases). MRI was performed in 25 cases and have found additional abnormalities in 8 cases. These abnormalities are not specific to CMV infection. However, a frequent finding attracted our attention: the anechogenic cavity located on the extremity of the occipital horn. CONCLUSION: A potentially specific sign, inexistent in other fetal pathologies, is an anechogenic cavity located on the extremity of the occipital and/or temporal horn, a germinal region which contains numerous proliferating and differentiating germinal cells. A better understanding of these signs could increase the sensitivity of ultrasound, and clarify the pathophysiology of congenital CMV infection. PMID- 26096353 TI - [Evaluation of the CNGOF foetal heart rate classification]. AB - INTRODUCTION: The 2007 CNGOF guidelines for good practice on "Methods of foetal surveillance during labour" proposed a consensual definition of intra-partum foetal heart rate (FHR) patterns. In order to facilitate its application, Carbon et al. published in 2013 a simplified table of the classification with 5 types of tracing. OBJECTIVES: To evaluate the diagnosis value of this FHR classification to determine the risk of foetal acidosis. METHODS: Retrospective single-centre study including 252 single pregnancies beyond 34 weeks of gestation with a record of at least 60minutes before delivery. The primary endpoint was a pH at birth < 7.20. RESULTS: When pH was < 7.20, type 3 tracing was significantly more frequent during the first stage of labour while types 4 and 5 were more frequently found during active second stage. A pH<7.20 was significantly associated with more instrumental extractions, emergency caesarean section, Apgar score < 7 and neonatal respiratory distress. The areas under the curve were 0.63 for the analysis during the first stage of labour, 0.69 for second stage, and 0.68 when the two stages were combined. CONCLUSION: Our study found that the CNGOF classification improved the FHR interpretation but its diagnosis value to predict acidosis remained limited. PMID- 26096354 TI - [Absent or hypoplastic thymus: A marker for 22q11.2 microdeletion syndrome in case of polyhydramnios]. AB - OBJECTIVES: In prenatal diagnosis of 22q11.2 microdeletion syndrome, without cardiac malformation or multiple associated congenital anomalies, we study the presence of polyhydramnios and its association with thymic dysgenesis. MATERIALS AND METHODS: This was a multicenter retrospective observational study. It was performed in two multidisciplinary centers for prenatal diagnosis in the south of France between January 1, 2010 and June 30, 2013. Inclusion criteria were prenatal diagnosis of 22q11.2 deletion syndrome. We excluded from the study any fetus with cardiac malformation or multiple associated congenital anomalies. RESULTS: During the inclusion period, eleven antenatal diagnoses of 22q11.2 microdeletion syndrome have been made. Six cases were excluded: 5 fetuses with cardiac malformation and one with multiple associated congenital anomalies. Therefore, five cases of isolated polyhydramnios were included. All 5 fetuses had a thymic dysgenesis: 3 had a thymic agenesis and 1 thymic hypoplasia diagnosed by sonography and 1 had a thymic agenesis diagnosed by retrospective reading of fetal MRI. CONCLUSION: When faced with a polyhydramnios, the presence of a thymic dysgenesis should be search for by ultrasound screening and would alert to the possibility of a 22q11.2 microdeletion syndrome. The confirmation of this is diagnosis by amniocentesis would enable improved antenatal support for parents and would enable early implementation of the multidisciplinary neonatal care that is required to avoid serious complications of this syndrome. PMID- 26096355 TI - Acquisition of morphine conditioned place preference increases the dendritic complexity of nucleus accumbens core neurons. AB - Contexts associated with opioid reward trigger craving and relapse in opioid addiction. Effects of reward-context associative learning on nucleus accumbens (NAc) dendritic morphology were studied using morphine conditioned place preference (CPP). Morphine-conditioned mice received saline and morphine 10 mg/kg subcutaneous (s.c.) on alternate days. Saline-conditioned mice received saline s.c. each day. Morphine-conditioned and saline-conditioned groups received injections immediately before each of eight daily conditioning sessions. Morphine homecage controls had no CPP training, but received saline and morphine in the homecage concomitantly with the morphine-conditioned group. Morphine conditioning produced greater place preference than saline conditioning. Mice were sacrificed 1 day after CPP expression. Dendritic changes were studied using Golgi-Cox staining and digital tracing of NAc core and shell neurons. In the NAc core, morphine homecage administration increased spine density, while morphine conditioning increased dendritic complexity, as defined by increased dendritic count, length and intersections. Place preference positively correlated with dendritic length and intersections in the NAc core. The core may mediate reward consolidation and determine how context-related signals from the shell lead to motor behavior. The combination of drug and conditioning in the morphine conditioned group produced unique morphological effects different from the effects of drug or conditioning procedures by themselves. An additional study found no differences in neuron morphology between saline-conditioned mice, trained as described earlier, and mice that were not conditioned, but received saline in the homecage. The unique effect of morphine reward learning on NAc core dendrites reflects a brain substrate that could be targeted for therapeutic intervention in addiction. PMID- 26096356 TI - Reduced cerebellar gray matter is a neural signature of physical frailty. AB - Physical frailty has been recognized as a clinical syndrome resulting from declines in various physiological systems; however, the role of the central nervous system in the pathophysiology of frailty remains unclear. The I-Lan Longitudinal Aging Study randomly sampled community-dwelling people aged 50 or older for a brain magnetic resonance imaging study. All participants were assessed for frailty status (robust, prefrail, and frail) based on the presence of five frailty components: slow walking speed, muscle weakness, low physical activity, exhaustion and weight loss (Fried criteria). Gray matter volume (GMV) changes associated with frailty status and individual frailty components were examined. Overall, 456 participants (64.0 +/- 8.5 years, 47.6% women) were included in this study. The prefrail (n = 178, 39.0%) and frail (n = 19, 4.2%) subjects were grouped for analysis. The prefrail-frail group showed reduced GMV, compared to the robust group (n = 259, 56.8%), in the cerebellum, hippocampi, middle frontal gyri, and several other cerebral regions (corrected P < 0.05). Each frailty component was associated with GMV changes in functionally related brain areas. Hierarchical cluster analysis categorized these components into three subsets. Motor-related components, including weakness, low activity, and slowness, comprised one subset with a common cerebellar involvement. Exhaustion and weight loss were the other two subsets without cerebellar changes. To conclude, physical frailty is associated with a decreased reserve in specific brain regions, especially cerebellum. Further longitudinal studies are needed to explore if the cerebellum- and noncerebellum-based frailty components reflect a distinctive future risk for developing frailty. PMID- 26096358 TI - Quantifying the squeezing or stretching of fisheries as they adapt to displacement by marine reserves. AB - The designation of no-take marine reserves involves social and economic concerns due to the resulting displacement of fishing effort, when fishing rights are removed from those who traditionally fished within an area. Displacement can influence the functioning of the fishery and success of the reserve, yet levels of displacement are seldom quantified after reserve implementation and very rarely before that. We devised a simple analytical framework based on set theory to facilitate reserve placement. Implementation of the framework requires maps of fishing grounds, fishing effort, or catch per unit effort for at least 2 years. The framework quantifies the level of conflict that a reserve designation might cause in the fishing sector due to displacement and the opportunities to offset the conflict through fisher spatial mobility (i.e., ability of fishers to fish elsewhere). We also considered how the outputs of the framework can be used to identify targeted management interventions for each fishery. We applied the method in Honduras, where the largest marine protected area in Central America is being placed, for which spatial data on fishing effort were available for 6 fisheries over 3 years. The proposed closure had a greater negative impact on the shrimp and lobster scuba fisheries, which concentrated respectively 28% and 18% of their effort inside the reserve. These fisheries could not accommodate the displacement within existing fishing grounds. Both would be forced to stretch into new fishing grounds, which are available but are of unknown quality. These stakeholders will likely require compensation to offset costly exploratory fishing or to travel to fishing grounds farther away from port. PMID- 26096357 TI - Interspecies gene transfer provides soybean resistance to a fungal pathogen. AB - Fungal pathogens pose a major challenge to global crop production. Crop varieties that resist disease present the best defence and offer an alternative to chemical fungicides. Exploiting durable nonhost resistance (NHR) for crop protection often requires identification and transfer of NHR-linked genes to the target crop. Here, we identify genes associated with NHR of Arabidopsis thaliana to Phakopsora pachyrhizi, the causative agent of the devastating fungal disease called Asian soybean rust. We transfer selected Arabidopsis NHR-linked genes to the soybean host and discover enhanced resistance to rust disease in some transgenic soybean lines in the greenhouse. Interspecies NHR gene transfer thus presents a promising strategy for genetically engineered control of crop diseases. PMID- 26096359 TI - Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine-2,3-dioxygenase (IDO) as Potential Target for Anticancer Activity. AB - Natural quinones, often linked with cellular oxidation processes, exhibit pronounced biological activity. In particular, the structurally unique isothiazolonaphthoquinone aulosirazole, isolated from blue-green alga, possesses selective antitumor cytotoxicity, although its mechanism of action is unknown. The first synthesis of aulosirazole uses a route centered upon a late-stage regioselective Diels-Alder reaction. The structurally related natural product pronqodine A, an inhibitor of prostaglandin release, and analogues thereof, were also prepared for comparison. Biological evaluation of the compounds identified one potential target as the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO). The isothiazoloquinones are also efficient substrates for the human quinone reductase NQO1, and undergo intracellular NQO1-dependent redox cycling resulting in the generation of reactive oxygen species, and at lower doses have the potential to alter the ratio of intracellular oxidized to reduced pyridine nucleotides. PMID- 26096360 TI - Work-related factors associated with occupational exposure to static magnetic stray fields from MRI scanners. AB - PURPOSE: This study aims to identify work-related and personal factors associated with workers' exposure to static magnetic fields (SMF) and motion-induced time varying magnetic fields (TVMF) from MRI scanners. METHODS: Measurements of personal exposure to SMF and TVMF were performed among MRI staff during 439 work shifts at 14 different workplaces using portable magnetic field dosimeters. These data were coupled with contextual workplace and worker information. After data cleanup, 324 remaining observations were used to develop linear mixed effects models for various measures of peak and time-weighted average (TWA) exposure. RESULTS: Exposure levels near whole-body closed-bore scanners increased by 30% to 76% for each additional tesla of scanner strength, depending on exposure metric. Small-bore animal scanners, on the other hand, showed a reversed association with scanner strength. Measures of peak and TWA exposure were differently associated with specific tasks and scan procedures. In addition, body height of the worker was negatively associated with measured exposure levels. CONCLUSION: The study revealed workplace characteristics, scan activities, and personal characteristics associated with SMF and TVMF exposure levels of MRI staff and was able to quantify the unique contribution of each of these factors while adjusting for the presence of others. PMID- 26096361 TI - Extramedullary Hematopoiesis in a Pyogenic Granuloma. PMID- 26096363 TI - Hsa-miR-132 inhibits proliferation of hepatic carcinoma cells by targeting YAP. AB - MicroRNAs and Yes-associated protein (YAP) play an important role in the occurrence and development of hepatic carcinomas. However, the interaction between microRNAs and YAP was seldom elucidated. In this study, we showed that miR-132 could target YAP gene by using dual-luciferase reporter system. Further quantitative polymerase chain reaction analysis and western blotting showed that miR-132 could significantly reduce the expression of YAP at mRNA and protein levels. Results of annexin V-fluorescein isothiocyanate, 5-ethynyl-2' deoxyuridine staining and transwell assays showed that miR-132 significantly promoted the cell apoptosis and effectively inhibited the proliferation and invasion of hepatoma cells. These results indicated that miR-132 could inhibit the growth of hepatoma cells by targeting YAP gene and reducing its expression level. Taken together, results from this study would help us to understand the mechanisms for occurrence and development of hepatic carcinoma and provide new targets for diagnosis and treatment of liver cancer. PMID- 26096364 TI - Evolution of egg coats: linking molecular biology and ecology. AB - One central goal of evolutionary biology is to explain how biological diversity emerges and is maintained in nature. Given the complexity of the phenotype and the multifaceted nature of inheritance, modern evolutionary ecological studies rely heavily on the use of molecular tools. Here, we show how molecular tools help to gain insight into the role of egg coats (i.e. the extracellular structures surrounding eggs and embryos) in evolutionary diversification. Egg coats are maternally derived structures that have many biological functions from mediating fertilization to protecting the embryo from environmental hazards. They show great molecular, structural and functional diversity across species, but intraspecific variability and the role of ecology in egg coat evolution have largely been overlooked. Given that much of the variation that influences egg coat function is ultimately determined by their molecular phenotype, cutting-edge molecular tools (e.g. proteomics, glycomics and transcriptomics), combined with functional assays, are needed for rigorous inferences on their evolutionary ecology. Here, we identify key research areas and highlight emerging molecular techniques that can increase our understanding of the role of egg coats in the evolution of biological diversity, from adaptation to speciation. PMID- 26096365 TI - Trends in the Utilization of Penile Prostheses in the Treatment of Erectile Dysfunction in the United States. AB - BACKGROUND: The utilization of penile prosthesis (PP) insertion in the general population for medically refractory erectile dysfunction (ED) has not been well characterized. This study assessed the national temporal trends in the surgical management of ED utilizing PP. MATERIALS AND METHODS: An analysis of the 5% Medicare Public Use Files from 2001 to 2010 was performed to assess the use of PP. Regression analysis was performed to identify factors associated with PP placement, type of PP utilized, and factors associated with revisions. RESULTS: A total of 1,763,260 men were diagnosed with ED, 3% (53,180) of whom underwent PP insertion. The utilization of PP for ED decreased from 4.6% in 2002 to 2.3% in 2010 (P < 0.01). This temporal decline in utilization was significant across all demographic factors including age, ethnicity, and geographic location. Men aged 65-74, from the U.S. South and West, and those with Charlson comorbidity scores >1 were more likely to have a PP inserted for ED (P < 0.01). African American men were more likely to have a semirigid PP placed compared with a multicomponent inflatable PP, and were more likely to undergo a revision or removal of the PP compared with Caucasian men (P < 0.01). CONCLUSIONS: The surgical management of ED with PP changed significantly between 2001 and 2010. The overall utilization of PP decreased, but its use in patients with significant medical comorbidities increased. Age >65, ethnicity, and geography influenced the likelihood of PP placement, prosthesis type, as well as the likelihood of prosthesis removal or revision. PMID- 26096366 TI - Amphiphilic sugar poly(orthoesters) as pH-responsive nanoscopic assemblies for acidity-enhanced drug delivery and cell killing. AB - A sugar poly(orthoester)-based drug delivery system was constructed to achieve acidity-enhanced drug delivery and cell killing. PMID- 26096367 TI - Early life exposure to chronic intermittent hypoxia causes upper airway dilator muscle weakness, which persists into young adulthood. AB - NEW FINDINGS: What is the central question of this study? Chronic intermittent hypoxia (CIH) is a dominant feature of respiratory control disorders, which are common. We sought to examine the effects of exposure to CIH during neonatal development on respiratory muscle form and function in male and female rats. What is the main finding and its importance? Exposure to CIH during neonatal development caused sternohyoid muscle weakness in both sexes; an effect that persisted into young adult life upon return to normoxia. Upper airway dilator muscle dysfunction in vivo could predispose to airway collapse, leading to impaired respiratory homeostasis. Chronic intermittent hypoxia (CIH) is a feature of sleep-disordered breathing, which is very common. Exposure to CIH is associated with aberrant plasticity in the respiratory control system including the final effector organs, the striated muscles of breathing. We reasoned that developmental age and sex are key factors determining the functional response of respiratory muscle to CIH. We tested the hypothesis that exposure to CIH causes persistent impairment of sternohyoid muscle function due to oxidative stress and that males are more susceptible to CIH-induced muscle impairment than females. Wistar rat litters (with respective dams) were exposed to intermittent hypoxia for 12 cycles per hour, 8 h per day for 3 weeks from the first day of life [postnatal day (P) 0]. Sham experiments were run in parallel. Half of each litter was studied on P22; the other half was returned to normoxia and studied on P42. Functional properties of the sternohyoid muscle were determined ex vivo. Exposure to CIH significantly decreased sternohyoid muscle force in both sexes; an effect that persisted into young adult life. Chronic intermittent hypoxia had no effect on sternohyoid muscle endurance. Chronic intermittent hypoxia did not affect sternohyoid myosin fibre type, succinate dehydrogenase or glycerol-3-phosphate dehydrogenase activities, or protein free thiol and carbonyl content. Muscles exposed to CIH had smaller cross-sectional areas, consistent with the observation of muscle weakness. In human infants with disordered breathing, CIH-induced upper airway dilator muscle weakness could increase the propensity for airway narrowing or collapse, which could serve to perpetuate impaired respiratory homeostasis. PMID- 26096368 TI - Adversity and Adjustment in Children in Institutions, Family Foster Care, and Adoption. AB - This study's objective was to identify the adversity profiles of children in different childcare placements, and to analyze their relationship with subsequent psychological adjustment. We studied a group of 230 children 4 to 10 years old indifferent childcare placements (international adoption, institutional care, non kin foster care, and kinship care), as well as a control group. Information was collected from parent or caregiver interviews and the Strengths and Difficulties Questionnaire (SDQ). The results showed that children in the child welfare system had experienced significant adversity before their current placement, especially among institutional care cases and international adoptees. Meanwhile, children in kinship care had experienced less adversity (p .50 to d > .80). After a period of time in their respective placements, children's psychological adjustment was generally positive, but children living in institutional care exhibited the most problems and difficulties, followed by non-kin foster care cases (p .50 to d > .80). Finally, we found that children's early adversity levels (p < .05; r = .16), age of current placement (p < .01; r = .23), and duration of current placement (p < .05: r = -.19) were all tied to current psychological adjustment. PMID- 26096369 TI - Mifepristone by prescription: a dream in the United States but reality in Australia. AB - The requirement that mifepristone be dispensed only by physicians in offices, clinics or hospitals - and not by prescription in pharmacies - has likely limited uptake by providers in the United States. However, in several other countries, provision by prescription in pharmacies is allowed, including in Australia. Mifepristone was first registered in Australia in 2012, and in 2015, a composite package including 200 mg mifepristone and four tablets of misoprostol 200 mcg was registered. Both were approved as Schedule 4 medications, which require prescribing by a physician and may be dispensed at pharmacies. As part of the registration for both products, a risk management plan was instituted that has several components. First, physicians must be certified to prescribe mifepristone. General practitioners wishing to become certified must complete online training that includes prescribing requirements and managing the medical abortion process; obstetrician-gynecologists are exempt from the online learning module. Pharmacists must also be certified in order to dispense the medication, although this does not require additional training. When a pharmacist receives a prescription for mifepristone, she or he must confirm through a secure website that the prescriber is certified. In every region of the country, there are more certified prescribers and dispensers of mifepristone than the number of facilities providing abortion care. The experience in Australia demonstrates the feasibility of mifepristone by prescription and should be a model for expanding access to early medical abortion in the United States. PMID- 26096371 TI - Measurement of DNA Polymerase Incorporation Kinetics of Dye-Labeled Nucleotides Using Total Internal Reflection Fluorescence Microscopy. AB - We report a method for the rapid and automated measurements of the incorporation kinetics of fluorescent dye-labeled nucleotides by DNA polymerases without using stopped-flow and quench-flow methods. Total internal reflection fluorescence microscopy is used to monitor the incorporation of fluorescently labeled nucleotides by DNA polymerase into surface-bound primed DNA templates, and a microfluidic system is used to perform the reactions. We successfully demonstrated the method using Bst DNA polymerase and a set of coumarin-labeled nucleotides. Our method allows the rapid acquisition of polymerase kinetics for implementing and improving DNA sequencing technologies that rely on labeled nucleotides and DNA polymerases. PMID- 26096372 TI - QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1). AB - CYP19A1 aromatase is a member of the Cytochrome P450 family of hemeproteins, and is the enzyme responsible for the final step of the androgens conversion into the corresponding estrogens, via a three-step oxidative process. For this reason, the inhibition of this enzyme plays an important role in the treatment of hormone dependent breast cancer. The first catalytic subcycle, corresponding to the hydroxilation of androstenedione, has been proposed to occur through a first hydrogen abstraction and a subsequent oxygen rebound step. In present work, we have studied the mechanism of the first catalytic subcycle by means of hybrid quantum mechanics/molecular mechanics methods. The inclusion of the protein flexibility has been achieved by means of Free Energy Perturbation techniques, giving rise to a free energy of activation for the hydrogen abstraction step of 13.5 kcal/mol. The subsequent oxygen rebound step, characterized by a small free energy barrier (1.5 kcal/mol), leads to the hydroxylated products through a highly exergonic reaction. In addition, an analysis of the primary deuterium kinetic isotopic effects, calculated for the hydrogen abstraction step, reveals values (~10) overpassing the semiclassical limit for the C?H, indicating the presence of a substantial tunnel effect. Finally, a decomposition analysis of the interaction energy for the substrate and cofactor in the active site is also discussed. According to our results, the role of the enzymatic environment consists of a transition state stabilization by means of dispersive and polarization effects. PMID- 26096370 TI - Neuromyelitis optica and the evolving spectrum of autoimmune aquaporin-4 channelopathies: a decade later. AB - The discovery of AQP4-IgG (a pathogenic antibody that targets the astrocytic water channel aquaporin-4), as the first sensitive and specific biomarker for any inflammatory central nervous system demyelinating disease (IDD), has shifted emphasis from the oligodendrocyte and myelin to the astrocyte as a central immunopathogenic player. Neuromyelitis optica (NMO) spectrum disorders (SDs) represent an evolving spectrum of IDDs extending beyond the optic nerves and spinal cord to include the brain (especially in children) and, rarely, muscle. NMOSD typical brain lesions are located in areas that highly express the target antigen, AQP4, including the circumventricular organs (accounting for intractable nausea and vomiting) and the diencephalon (accounting for sleep disorders, endocrinopathies, and syndrome of inappropriate antidiuresis). Magnetic resonance imaging brain abnormalities fulfill Barkoff criteria for multiple sclerosis in up to 10% of patients. As the spectrum broadens, the importance of highly specific assays that detect pathogenic AQP4-IgG targeting extracellular epitopes of AQP4 cannot be overemphasized. The rapid evolution of our understanding of the immunobiology of AQP4 autoimmunity necessitates continuing revision of NMOSD diagnostic criteria. Here, we describe scientific advances that have occurred since the discovery of NMO-IgG in 2004 and review novel targeted immunotherapies. We also suggest that NMOSDs should now be considered under the umbrella term autoimmune aquaporin-4 channelopathy. PMID- 26096373 TI - High co-expression of Sp1 and HER-2 is correlated with poor prognosis of gastric cancer patients. AB - The aim of this study was to investigate co-expression of HER-2 and Sp1 in gastric cancer (GC) so as to determine whether these two proteins may be correlated with poor prognosis of GC patients. We examined the HER-2 overexpression and amplification and expression levels of Sp1 in 227 GC patients using immune-histochemical staining and fluorescence in situ hybridization. Data on clinicopathological features and relevant prognostic factors in these patients were analyzed. Of the 227 gastric cancer samples, 11.89% were positive for HER-2 overexpression/amplification under the new scoring system, and the frequency of negative, weak positive and strong positive expression of Sp1 was 14.98%, 48.01% and 37.0% respectively. No statistically positive correlation was observed between the expression levels of HER-2 and Sp1 in GC tissues. HER-2 overexpression was closely correlated to the Lauren type, degree of differentiation, tumor size and lymph node metastasis, and Sp1 as well (P < 0.05). Overexpression of HER-2 and Sp1 predicted poor survival in univariate analysis as well as in a Cox proportional hazards model. PMID- 26096374 TI - Minimally invasive esophagectomy: Lateral decubitus vs. prone positioning; systematic review and pooled analysis. AB - The uptake of minimally invasive esophagectomy (MIE) has increased vastly over the last decade, with proven short-term benefits over an open approach. The aim of this pooled analysis was to compare clinical outcomes of Minimally Invasive Esophagectomy (MIE) performed in the prone and lateral decubitus positions. A systematic literature search (2000-2015) was undertaken for publications that compared patients who underwent MIE in the lateral decubitus (LD) or prone (PR) positions. Weighted mean difference (WMD) was calculated for the effect size of LD positioning on continuous variables and Pooled odds ratios (POR) for discrete variables. Ten relevant publications comprising 723 patients who underwent minimally invasive esophagectomy were included; 387 in the LD group and 336 in the PR group. There was no significant difference between the groups in terms of in-hospital mortality, total morbidity, anastomotic leak, chylothorax, laryngeal nerve palsy, average operative time, and length hospital stay. LD MIE was associated with a non-significant increase in pulmonary complications (POR = 1.65; 95% C.I. 0.93 to 2.92; P = 0.09), and significant increases in estimated blood loss (WMD = 36.03; 95% 14.37 to 57.69; P = 0.001) and a reduced average mediastinal lymph node harvest (WMD = -2.17; 95% C.I. -3.82 to -0.52; P = 0.01) when compared to prone MIE. Pooled analysis suggests that prone MIE is superior to lateral decubitus MIE with reduced pulmonary complications, estimated blood loss and increased mediastinal lymph node harvest. Further studies are needed to explain performance-shaping factors and their influence on oncological clearance and short-term outcomes. PMID- 26096375 TI - Neprilysin gene transfer: A promising therapeutic approach for Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of amyloid-beta (Abeta) in the neuropil and around blood vessels, and formation of neurofibrillary tangles. Abeta accumulation is considered the major pathological change in AD progression. In recent years, several therapeutic strategies for treating AD have focused on reducing the Abeta burden in the brain. Among these approaches, the expression of Abeta-degrading enzymes in the brain has been effective but, so far, impractical for treating patients. Neprilysin (NEP), the most prominent of the Abeta-degrading enzymes in vivo, has been successfully delivered intracranially by viral vectors and is a promising therapeutic approach for reducing Abeta accumulation and treating AD. However, some challenges are associated with the use of viral and nonviral vectors, including secondary toxicity, activation of the immune response, and low efficiency. Therefore, safe and efficient NEP delivery systems that could avoid the viral problems with minor injury and high transfection efficiency are required to deliver AD medical applications. This Mini-Review summarizes NEP gene transfer technologies that use viral and nonviral vectors and discusses the rationale and benefits of these delivery systems for AD treatment trials, providing a reference for basic and clinical studies on AD. PMID- 26096376 TI - Dabigatran: Experience in standard clinical practice. AB - INTRODUCTION AND OBJECTIVES: Dabigatran is an anticoagulant drug and a direct thrombin inhibitor and has been approved for the prevention of ischaemic stroke secondary to nonvalvularauricular auricular fibrillation. The aim of this study was to determine the efficacy of dabigatran in clinical practice for preventing cerebral ischaemic events associated with nonvalvularauricular auricular fibrillation, as well as its tolerance and safety profile. MATERIAL AND METHODS: A descriptive and retrospective study was conducted, which included all patients who started anticoagulant treatment with dabigatran between November 2011 and September 2012. Follow-up was performed from the start of treatment until June 2013. The incidence of ischaemic events of cerebral, cardiac and peripheral origin was recorded, as was the onset of adverse effects and haemorrhagic complications, whose location and severity were determined. RESULTS: We analysed 316 patients, with a mean age of 76.46+/-8.37 years, of whom 53.5% were men. Two patients (0.55/100 patient-years) presented ischaemic stroke (including one amaurosis fugax). Eight (2.18/100 patient-years) patients had an adverse ischaemic event, whose origin was cardiac in 5 (1.36/100 patient-years) cases and peripheral in 3 (0.81/100 patient-years). Forty (10.91/100 patient-years) patients had a haemorrhagic complication: 32 minor (8.73/100 patient-years) and 8 major (2.18/100 patient-years) haemorrhages. CONCLUSIONS: Dabigatran is effective in standard clinical practice in preventing stroke and has a safety profile similar to that reported in the clinical trials. PMID- 26096377 TI - Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. AB - Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a > 90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve > 90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a > 90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of <= 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs. PMID- 26096378 TI - A Modular Approach To Study Protein Adsorption on Surface Modified Hydroxyapatite. AB - Biocompatible inorganic nano- and microcarriers can be suitable candidates for protein delivery. This study demonstrates facile methods of functionalization by using nanoscale linker molecules to change the protein adsorption capacity of hydroxyapatite (HA) powder. The adsorption capacity of bovine serum albumin as a model protein has been studied with respect to the surface modifications. The selected linker molecules (lysine, arginine, and phosphoserine) can influence the adsorption capacity by changing the electrostatic nature of the HA surface. Qualitative and quantitative analyses of linker-molecule interactions with the HA surface have been performed by using NMR spectroscopy, zeta-potential measurements, X-ray photoelectron spectroscopy, and thermogravimetric analyses. Additionally, correlations to theoretical isotherm models have been calculated with respect to Langmuir and Freundlich isotherms. Lysine and arginine increased the protein adsorption, whereas phosphoserine reduced the protein adsorption. The results show that the adsorption capacity can be controlled with different functionalization, depending on the protein-carrier selections under consideration. The scientific knowledge acquired from this study can be applied in various biotechnological applications that involve biomolecule-inorganic material interfaces. PMID- 26096379 TI - Nanocarriers for treatment of ocular neovascularization in the back of the eye: new vehicles for ophthalmic drug delivery. AB - Pathologic neovascularization of the retina is a major cause of substantial and irreversible loss of vision. Drugs are difficult to deliver to the lesions in the back of the eye and this is a major obstacle for the therapeutics. Current pharmacological approach involves an intravitreal injection of anti-VEGF agents to prevent aberrant growth of blood vessels, but it has limitations including therapeutic efficacy and side-effects associated with systemic exposure and invasive surgery. Nanotechnology provides novel opportunities to overcome the limitations of conventional delivery system to reach the back of the eye through fabrication of nanostructures capable of encapsulating and delivering small molecules. This review article introduces various forms of nanocarrier that can be adopted by ocular drug delivery systems to improve current therapy. The application of nanotechnology in medicine brings new hope for ocular drug delivery in the back of the eye to manage the major causes of blindness associated with ocular neovascularization. PMID- 26096380 TI - Pocket technique or pocket technique combined with modified orbital rim anchorage for the replacement of a prolapsed gland of the third eyelid in dogs: 353 dogs. AB - The aim of this retrospective study was to evaluate the results obtained in 353 dogs (420 eyes) using two different surgical techniques for correction of a prolapsed gland of the third eyelid: the Morgan's pocket technique and a technique combining Morgan's approach with a slightly modified periosteal anchoring technique of Stanley and Kaswan. The pocket technique was used in 234 eyes and the combined technique in 186 eyes. Successful repositioning was obtained in 95% of all cases, with recurrence occurring in 5%. The recurrence rate in large breed dogs such as the English Bulldog and Boxer was lower with the combined technique than with the pocket technique. PMID- 26096381 TI - Dynamics of protein and polar lipid recruitment during lipid droplet assembly in Chlamydomonas reinhardtii. AB - In plants, neutral lipids are frequently synthesized and stored in seed tissues, where the assembly of lipid droplets (LDs) coincides with the accumulation of triacylglycerols (TAGs). In addition, photosynthetic, vegetative cells can form cytosolic LDs and much less information is known about the makeup and biogenesis of these LDs. Here we focus on Chlamydomonas reinhardtii as a reference model for LDs in a photosynthetic cell, because in this unicellular green alga LD dynamics can be readily manipulated by nitrogen availability. Nitrogen deprivation leads to cellular quiescence during which cell divisions cease and TAGs accumulate. The major lipid droplet protein (MLDP) forms a proteinaceous coat surrounding mature LDs. Reducing the amount of MLDP affects LD size and number, TAG breakdown and timely progression out of cellular quiescence following nitrogen resupply. Depending on nitrogen availability, MLDP recruits different proteins to LDs, tubulins in particular. Conversely, depolymerization of microtubules drastically alters the association of MLDP with LDs. LDs also contain select chloroplast envelope membrane proteins hinting at an origin of LDs, at least in part, from chloroplast membranes. Moreover, LD surface lipids are rich in de novo synthesized fatty acids, and are mainly composed of galactolipids which are typical components of chloroplast membranes. The composition of the LD membrane is altered in the absence of MLDP. Collectively, our results suggest a mechanism for LD formation in C. reinhardtii involving chloroplast envelope membranes by which specific proteins are recruited to LDs and a specialized polar lipid monolayer surrounding the LD is formed. PMID- 26096382 TI - Temporal Hyporheic Zone Response to Water Table Fluctuations. AB - Expansion and contraction of the hyporheic zone due to temporal hydrologic changes between stream and riparian aquifer influence the biogeochemical cycling capacity of streams. Theoretical studies have quantified the control of groundwater discharge on the depth of the hyporheic zone; however, observations of temporal groundwater controls are limited. In this study, we develop the concept of groundwater-dominated differential hyporheic zone expansion to explain the temporal control of groundwater discharge on the hyporheic zone in a third order stream reach flowing through glacially derived terrain typical of the Great Lakes region. We define groundwater-dominated differential expansion of the hyporheic zone as: differing rates and magnitudes of hyporheic zone expansion in response to seasonal vs. storm-related water table fluctuation. Specific conductance and vertical hydraulic gradient measurements were used to map changes in the hyporheic zone during seasonal water table decline and storm events. Planar and riffle beds were monitored in order to distinguish the cause of increasing hyporheic zone depth. Planar bed seasonal expansion of the hyporheic zone was of a greater magnitude and longer in duration (weeks to months) than storm event expansion (hours to days). In contrast, the hyporheic zone beneath the riffle bed exhibited minimal expansion in response to seasonal groundwater decline compared to storm related expansion. Results indicated that fluctuation in the riparian water table controlled seasonal expansion of the hyporheic zone along the planar bed. This groundwater induced hyporheic zone expansion could increase the potential for biogeochemical cycling and natural attenuation. PMID- 26096384 TI - Trends in Tuberculosis Cases Among Nursing Home Residents, California, 2000 to 2009. AB - OBJECTIVES: To examine trends in tuberculosis (TB) incidence and to compare demographic and clinical characteristics of nursing home (NH) residents and community-dwelling older adults. DESIGN: Prospective TB surveillance. SETTING: TB cases reported in California from 2000 to 2009. PARTICIPANTS: TB patients aged 65 and older. MEASUREMENTS: Trends in TB incidence per 100,000 population were assessed using Poisson regression. Demographic and clinical characteristics were compared using the chi-square or Wilcoxon rank-sum test. Among NH residents, risk factors for death during TB treatment were identified using logistic regression. RESULTS: From 2000 to 2009, TB incidence rates decreased significantly, from 15.9/100,000 to 8.4/100,000 (-44%, 95% confidence interval (CI) = -66% to -7%) for NH residents and from 21.2/100,000 to 15.0/100,000 (-27%, 95% CI = -29% to 24%) for community-dwelling older adults. Overall, 211 TB cases among NH residents and 6,518 cases among community-dwelling older adults were reported. NH residents were more likely than community-dwelling older adults to be older (median age 81 vs 75, P < .001), have a negative acid-fast bacilli sputum smear and positive culture (37% vs 28%, P < .001), and die while undergoing TB treatment (44% vs 14%, P < .001), and were less likely to have a positive tuberculin skin test (TST) (28% vs 44%, P < .001) and have TB care provided by a health department (20% vs 59%, P < .001). In multivariable analysis, NH residents who had a positive TST were less likely to die while undergoing TB treatment (odds ratio = 0.39, 95% CI = 0.16-0.96). CONCLUSION: TB incidence rates were lower, and reductions in incidence were greater among NH residents; community dwelling older adults had higher TB rates and smaller reductions in incidence. Interventions that promote timely detection and treatment of TB infection and disease may be needed to reduce morbidity and mortality among NH residents. PMID- 26096383 TI - Relationship Between Type 2 Diabetes Mellitus and Cognitive Change in a Multiethnic Elderly Cohort. AB - OBJECTIVES: To examine the association between diabetes mellitus and cognitive functioning at baseline and cognitive change over time in a large, ethnically diverse sample of older adults. DESIGN: Prospective cohort study. SETTING: Washington Heights-Inwood Columbia Aging Project, a community-based, prospective study of risk factors for dementia in northern Manhattan, New York City. PARTICIPANTS: Hispanic, non-Hispanic black, and non-Hispanic white men and women aged 65 and older without dementia at baseline (N = 1,493). MEASUREMENTS: Participants underwent baseline and follow-up cognitive and health assessments approximately every 18 months. Generalized estimating equations were used to examine the longitudinal association between diabetes mellitus and cognition. RESULTS: Diabetes mellitus was associated with poorer baseline cognitive performance in memory, language, processing speed and executive functioning, and visuospatial abilities. After adjusting for age, education, sex, race and ethnicity, and apolipoprotein-epsilon4, participants with diabetes mellitus performed significantly worse at baseline than those without in language and visuospatial abilities. There were no differences between those with and without diabetes mellitus in terms of rate of cognitive change over a mean follow-up time of 6 years. CONCLUSION: The rate of cognitive change in elderly persons with and without diabetes mellitus is similar, although cognitive performance is poorer in persons with diabetes mellitus. These findings suggest that cognitive changes may occur early during the diabetes mellitus process and highlight the need for studies to follow participants beginning at least in midlife, before the typical later-life onset of dementia. PMID- 26096385 TI - Longitudinal Analysis of Physical Performance, Functional Status, Physical Activity, and Mood in Relation to Executive Function in Older Adults Who Fall. AB - OBJECTIVES: To examine whether good executive function (EF; the cognitive processes important for goal-oriented and controlled behavior) at baseline and maintenance of EF over time predict maintenance of physical performance, functional status, physical activity, and mood over a 1-year period, and conversely, to examine whether baseline functioning in these noncognitive domains predicts maintenance of EF over the same period of time. DESIGN: 12-month prospective cohort study. SETTING: Vancouver Falls Prevention Clinic. PARTICIPANTS: Community-dwelling older adults (N = 199; mean age 81.6 +/- 6.5; 63% female) referred to the clinic after a fall. MEASURMENTS: At each time point, structural equation modeling created a latent EF variable from performance on five EF tasks. Physical performance (physiological falls risk and gait speed), instrumental activities of daily living (IADLs), physical activity, and depressive symptoms were also assessed at each time point. RESULTS: Higher baseline EF predicted decreases in depressive symptoms (P = .005) and maintenance of IADLs (P = .006) from baseline to follow-up. Improvements in EF correlated with increases in gait speed (P = .005) and physical activity (P = .03) and with the maintenance of IADLs (P = .002) over follow-up. All effects were independent of demographic characteristics and global cognitive function. Baseline performance in the noncognitive domains did not predict changes in EF. CONCLUSION: In older fallers, EF is a marker of resiliency in several noncognitive domains and should therefore be assessed. Furthermore, interventions to improve EF should be tested in older fallers with EF deficits. PMID- 26096386 TI - Frailty Before Critical Illness and Mortality for Elderly Medicare Beneficiaries. AB - OBJECTIVES: To estimate the effect of pre-intensive care unit (ICU) health categories on mortality during and after critical illness, focusing specifically on the effect of pre-ICU frailty on short- and long-term mortality. DESIGN: Retrospective cohort study. SETTING: Medicare claims data from 2004 to 2008. PARTICIPANTS: A nationally representative sample of elderly Medicare beneficiaries admitted to an ICU in 2005. MEASUREMENTS: Participants were classified into four pre-ICU health categories (robust, cancer, chronic organ failure, frailty) using claims data from the year before admission, allowing for assignment to multiple categories. The association between pre-ICU health category and hospital and 3-year mortality was assessed using multivariable logistic regression and Cox proportional hazards models. RESULTS: Of 47,427 elderly individuals in the ICU, 18.8% were robust, 28.6% had cancer, 68.1% had chronic organ failure, and 34.0% were frail; 41.3% qualified for multiple categories. Overall hospital mortality was 12.6%, with the lowest mortality for robust participants (9.7%). Participants with pre-ICU frailty had higher hospital mortality than those with the same pre-ICU health categories without frailty. (Adjusted odds ratios ranged from 1.27 (95% confidence interval (CI) 1.10-1.47) to 1.52 (95% CI = 1.35-1.63).) Robust hospital survivors had the lowest 3-year mortality (24.6%). Pre-ICU frailty conferred higher 3-year mortality than pre-ICU categories without frailty. (Adjusted hazard ratios ranged from 1.54 (95% CI = 1.45-1.64) to 1.84 (95% CI = 1.70-1.99).) CONCLUSION: Critically ill elderly adults can be categorized according to pre-ICU health categories. These categories, particularly pre-ICU frailty, may be important for understanding risk of death during and after critical illness. PMID- 26096387 TI - Decline in Fast Gait Speed as a Predictor of Disability in Older Adults. AB - OBJECTIVES: To determine whether fast gait speed at study baseline and change in gait speed had independent associations with disability onset. DESIGN: Cohort study with 11-year follow-up (1999-2010). SETTING: Three-City Study center, Dijon, France. PARTICIPANTS: Community-dwelling individuals aged 65 to 85 (N = 3,814, 61% female). MEASUREMENTS: Fast gait speed (over 6 m) was assessed up to five times and disability (mobility (Rosow-Breslau scale), instrumental activities of daily living (IADLs; Lawton-Brody scale), basic activities of daily living (ADLs; Katz scale)) six times. A hierarchical disability indicator was constructed; participants were considered disabled if they reported difficulties with mobility and IADLs or with mobility, IADLs, and ADLs. The association between baseline fast gait speed and its slope of change and disability incidence was examined using joint models for longitudinal and time-to-event data. RESULTS: Over follow-up, 628 participants (68% women) developed disability. Mean fast gait speed at baseline was 1.54 m/s, and annual decline was 0.017 m/s. The hazard ratio of disability per standard deviation (SD) (-0.22 m/s) slower baseline fast gait speed was 1.77 (95% confidence interval (CI) = 1.60-1.94) and for one-SD ( 0.013 m/s) faster annual decline was 1.38 (95% CI = 1.10-1.73) when both parameters were included in a sex- and age-adjusted model. All associations remained statistically significant in multivariable models, except for slope of change when chronic conditions were added to the model; of chronic conditions, dyspnea was the main contributor. CONCLUSION: Accelerated decline in fast gait speed was associated with disability independent of baseline fast gait speed. These results confirm the importance of measuring gait speed repeatedly in elderly adults to identify those at higher risk of disability and the need to identify determinants of decline, because they are likely to be targets for prevention and treatment to reduce disability risk. PMID- 26096389 TI - Hospice Care in Assisted Living Facilities Versus at Home: Results of a Multisite Cohort Study. AB - OBJECTIVES: To compare residents of assisted living facilities receiving hospice with people receiving hospice care at home. DESIGN: Electronic health record based retrospective cohort study. SETTING: Nonprofit hospices in the Coalition of Hospices Organized to Investigate Comparative Effectiveness network. PARTICIPANTS: Individuals admitted to hospice between January 1, 2008, and May 15, 2012 (N = 85,581; 7,451 (8.7%) assisted living facility, 78,130 (91.3%) home). MEASUREMENTS: Hospice length of stay, use of opioids for pain, and site of death. RESULTS: The assisted living population was more likely than the home hospice population to have a diagnosis of dementia (23.5% vs 4.7%; odds ratio (OR) = 13.3, 95% confidence interval (CI) = 12.3-14.4; P < .001) and enroll in hospice closer to death (median length of stay 24 vs 29 days). Assisted living residents were less likely to receive opioids for pain (18.1% vs 39.7%; OR = 0.33, 95% CI = 0.29-0.39, P < .001) and less likely to die in an inpatient hospice unit (9.3% vs 16.1%; OR = 0.53, 95% CI = 0.49-0.58, P < .001) or a hospital (1.3% vs 7.6%; OR = 0.16, 95% CI = 0.13-0.19, P < .001). CONCLUSION: Three are several differences between residents of assisted living receiving hospice care and individuals living at home receiving hospice care. A better understanding of these differences could allow hospices to develop guidelines for better coordination of end-of-life care for the assisted living population. PMID- 26096390 TI - Self-Reported Hearing Status Is Associated with Lower Limb Physical Performance, Perceived Mobility, and Activities of Daily Living in Older Community-Dwelling Men and Women. AB - OBJECTIVES: To explore the associations between self-reported hearing problems and physical performance and self-reported difficulties in mobility and activities of daily living (ADLs) in community-dwelling older adults. DESIGN: Cross-sectional cohort study. SETTING: Community. PARTICIPANTS: Men and women aged 75 to 90 (N = 848). MEASUREMENTS: Structured face-to-face interviews to assess perceived hearing problems in the presence of noise, mobility difficulties (moving indoors, stair-climbing, 0.5-km walk, 2-km walk), and difficulties in ADLs and instrumental ADLs. The Short Physical Performance Battery (SPPB) was administered. Age; years of education; cognitive functioning; and self-reported cardiac, circulatory, and locomotor diseases were used as covariates. RESULTS: Persons who reported major hearing problems had a lower SPPB total score than those who reported good hearing (mean 9.8 vs 10.9, P = .009), indicating poorer performance, and more difficulties in ADLs (mean 1.8 vs 1.4, P = .002) and IADLs (mean 4.6 vs 3.4, P = .002), after controlling for covariates. They were also more likely to have more difficulty in stair-climbing (odds ratio (OR) = 2.8, P < .001) and walking 2 km (OR = 2.1, P = .003) and tended to have more difficulty in walking 0.5 km (OR = 1.7, P = .05) but not moving indoors (P = .18). Persons who reported only some hearing problems did not differ from those who reported good hearing in any of the variables studied. CONCLUSION: Perceived major hearing problems in older adults may contribute to poorer lower limb performance and difficulties in mobility and ADLs. Longitudinal studies are needed to determine whether poor hearing is a risk factor for decline in physical performance. PMID- 26096388 TI - Association Between Hearing Impairment and Risk of Hospitalization in Older Adults. AB - OBJECTIVES: To determine the association between hearing impairment (HI) and risk and duration of hospitalization in community-dwelling older adults in the United States. DESIGN: Prospective observational study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Well-functioning community-dwelling white and black Medicare beneficiaries aged 70 to 79 at study enrollment in 1997-98 were followed for a median of 12 years. MEASUREMENTS: Incidence, annual rate, and duration of hospitalization were the primary outcomes. Hearing was defined as the pure-tone average (PTA) of hearing thresholds in decibels re: hearing level (dB HL) at octave frequencies from 0.5 to 4.0 kHz. Mild HI was defined as a PTA from 25 to 40 dB HL, and moderate or greater HI was defined as a PTA greater than 40 dB HL. RESULTS: Of the 2,148 participants included in the analysis, 1,801 (83.5%) experienced one or more hospitalizations, with 7,007 adjudicated hospitalization events occurring during the study period. Eight hundred eighty-two (41.1%) participants had normal hearing, 818 (38.1%) had mild HI, and 448 (20.9%) had moderate or greater HI. After adjusting for demographic characteristics and cardiovascular comorbidities, persons with mild HI experienced a 16% (hazard ratio (HR) = 1.16, 95% confidence interval (CI) = 1.04-1.29) greater risk of incident hospitalization and a 17% (incidence rate ratio (IRR) = 1.17, 95% CI = 1.04-1.32) greater annual rate of hospitalization, and those with moderate or greater HI experienced a 21% (HR = 1.21, 95% CI = 1.06-1.38) greater risk of incident hospitalization and a 19% (IRR = 1.19, 95% CI = 1.04-1.38) greater annual rate of hospitalization than persons with normal hearing. There was no significant association between HI and mean duration of hospitalization. CONCLUSION: Hearing-impaired older adults experience a greater incidence and annual rate of hospitalization than those with normal hearing. Investigating whether rehabilitative therapies could affect the risk of hospitalization in older adults requires further study. PMID- 26096391 TI - Assessing Upper Extremity Motion: An Innovative Method to Identify Frailty. AB - OBJECTIVES: To objectively identify frailty using wireless sensors and an innovative upper extremity motion assessment routine that does not rely on gait. DESIGN: Validation study. SETTING: Southwestern tertiary academic medical center, Tucson, Arizona. PARTICIPANTS: Convenience subsample of the Arizona Frailty Cohort, a community-dwelling older adults (>=65; n = 117; 50 nonfrail, 51 prefrail, 16 frail). MEASUREMENTS: Wireless sensors were attached to the upper arm and forearm with bands, and subjects performed repetitive elbow flexion for 20 seconds on each side. Information was extracted on objective slowness, weakness, exhaustion, and flexibility measures, and associations between parameters and Fried frailty categories were determined. RESULTS: Speed of elbow flexion (slowness) was 29% less in prefrail and 59% less in frail than in nonfrail controls (P < .001), power of movement (weakness) was 61% less in prefrail and 89% less frail (P < .001), and speed variation (exhaustion) was 35% more in prefrail and 272% more in frail (P < .001). Using elbow flexion parameters in regression models, sensitivity and specificity of 100% were achieved in predicting frailty and sensitivity of 87% and specificity of 95% in predicting prefrailty compared to Fried frailty category. CONCLUSION: The suggested innovative upper extremity frailty assessment method integrates low cost sensors, and the physical assessment is easily performed in less than 1 minute. The uniqueness of the proposed technology is its applicability in older nonambulatory individuals, such as those in emergency settings. Further improvement is warrant to make it suitable for routine clinical applications. PMID- 26096392 TI - Assessing Older Adults' Masticatory Efficiency. AB - OBJECTIVES: To determine internal consistency and criterion validity of a questionnaire assessing perception of masticatory efficiency in community dwelling older adults. DESIGN: Secondary cross-sectional analysis of baseline data from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). SETTING: NuAge is a 5-year (2003-08) observational study of 1,793 men and women aged 67 to 84 in good general health at recruitment. PARTICIPANTS: A sample of 1,789 was used to determine internal consistency of the questionnaire. A subsample (n = 94) of the cohort who underwent a clinical test directly measuring masticatory efficiency was used to determine criterion validity of the questionnaire. MEASUREMENTS: The questionnaire was a subset of the Oral Health Impact Profile containing 7 Likert-scale questions (score 0-28 points). Masticatory efficiency was assessed using a validated clinical test measuring ability to chew a raw carrot (Swallowing Threshold Test Index, score 0-100%). For perceived and measured data, a higher score indicated better masticatory efficiency. RESULTS: Internal consistency of the questionnaire was deemed good (Cronbach alpha = 0.803). Mean scores were generally high (men, 25.3, 95% confidence interval (CI) = 24.7-25.9; women, 24.3, 95% CI = 23.7-25.0), indicating good perceived masticatory efficiency for men and women. Mean performance test scores were low (men, 60.8%, 95% CI = 57.3-64.2; women, 61.2%, 95% CI = 57.7-64.7). No significant relationship between perceived and measured masticatory efficiency was observed (Pearson correlation coefficient = -0.14, P = .22). CONCLUSION: Despite good internal consistency of the questionnaire and the recognized validity of the test, people's perception of their masticatory efficiency does not reflect objective efficiency as measured using a clinical test. PMID- 26096393 TI - Risk of Injury in Older Adults Using Gastrointestinal Antispasmodic and Anticholinergic Medications. AB - OBJECTIVES: To determine the risk of injury associated with gastrointestinal (GI) antispasmodic and anticholinergic use in elderly adults. DESIGN: Retrospective case-control study. SETTING: Integrated healthcare system. PARTICIPANTS: Healthcare system members aged 65 and older (N = 260,010; 54,152 cases, 205,858 controls). MEASUREMENTS: Cases were identified as individuals with an injury resulting in a hospitalization, emergency department, or urgent care visit (index date) from January 2009 through December 2010. Cases and controls were matched in a 1:4 ratio based on age and sex. GI antispasmodic and anticholinergic current and past exposure for cases and controls was evaluated. Individuals were classified as current users if the days' supply of the GI prescription overlapped the index date and past users if the days' supply ended more than 60 days before the index date. Duration of use for current users was analyzed for short- and long-term use. Conditional logistic regression produced adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Of the total population, 1,068 (0.4%) had current exposure to a GI antispasmodic or anticholinergic (302 (0.6%) cases, 766 (0.4%) controls). Current users had a small but significantly greater risk of injury than nonusers (OR = 1.16, 95% CI = 1.01-1.34, P = .03). Past use was not significantly different from no use. Short-term users had a significantly greater risk of injury (OR = 1.31, 95% CI = 1.01-1.70, P = .04) than nonusers. Long-term use was associated with greater risk, but the difference was not statistically significant. CONCLUSION: Older adults using GI antispasmodic and anticholinergic drugs have greater risk of injury. These findings support recommendations to limit the prescribing of GI antispasmodics and anticholinergics in elderly adults. PMID- 26096394 TI - The Aging Brain Care Medical Home: Preliminary Data. AB - The Aging Brain Care (ABC) Medical Home aims to improve the care, health outcomes, and medical costs of Medicare beneficiaries with dementia or depression across central Indiana. This population health management program, funded by the Centers for Medicare and Medicaid Services Innovation Center, expanded an existing collaborative dementia and depression care program to serve 1,650 older adults in a local safety-net hospital system. During the first year, 20 full-time clinical staff were hired, trained, and deployed to deliver a collaborative care intervention. In the first 18 months, an average of 13 visits was provided per person. Thirty percent of the sample had a diagnosis of dementia, and 77% had a diagnosis of depression. Sixty-six percent of participants with high depression scores (Patient Health Questionnaire-9 score >=14) had at least a 50% reduction in their depressive symptoms. Fifty-one percent of caregivers of individuals with dementia had at least a 50% reduction in caregiver stress symptoms (measured by the Healthy Aging Brain Care Monitor-Caregiver Version). After 18 months, the ABC Medical Home has demonstrated progress toward improving the health of older adults with dementia and depression. Scalable and practical models like this show initial promise for answering the challenges posed by the nation's rapidly aging population. PMID- 26096395 TI - Elder Abuse: Systematic Review and Implications for Practice. AB - This article is based on the lecture for the 2014 American Geriatrics Society Outstanding Scientific Achievement for Clinical Investigation Award. Elder abuse is a global public health and human rights problem. Evidence suggests that elder abuse is prevalent, predictable, costly, and sometimes fatal. This review will highlight the global epidemiology of elder abuse in terms of its prevalence, risk factors, and consequences in community populations. The global literature in PubMed, MEDLINE, PsycINFO, BIOSIS, Science Direct, and Cochrane Central was searched. Search terms included elder abuse, elder mistreatment, elder maltreatment, prevalence, incidence, risk factors, protective factors, outcomes, and consequences. Studies that existed only as abstracts, case series, or case reports or recruited individuals younger than 60; qualitative studies; and non English publications were excluded. Tables and figures were created to highlight the findings: the most-detailed analyses to date of the prevalence of elder abuse according to continent, risk and protective factors, graphic presentation of odds ratios and confidence intervals for major risk factors, consequences, and practical suggestions for health professionals in addressing elder abuse. Elder abuse is common in community-dwelling older adults, especially minority older adults. This review identifies important knowledge gaps, such as a lack of consistency in definitions of elder abuse; insufficient research with regard to screening; and etiological, intervention, and prevention research. Concerted efforts from researchers, community organizations, healthcare and legal professionals, social service providers, and policy-makers should be promoted to address the global problem of elder abuse. PMID- 26096396 TI - Aging in Orange. PMID- 26096397 TI - At the Intersection of Alzheimer's and Blessing. PMID- 26096398 TI - Remembering My Yiayia's Swing. PMID- 26096399 TI - Generativity for the Cognitively Frail. PMID- 26096400 TI - Vitamin D Deficiency and Incident Onset of Orthostatic Hypotension in Older Adults: Preliminary Results from the 'MERE' Study. PMID- 26096401 TI - Exercise Training Improves Plasma Lipid and Inflammatory Profiles and Increases Cholesterol Transfer to High-Density Lipoprotein in Elderly Women. PMID- 26096402 TI - Depression and Memory Loss in African Americans with Diabetic Retinopathy. PMID- 26096403 TI - Adults Aged 65 and Older Use Potentially Distracting Electronic Devices While Driving. PMID- 26096404 TI - Associations Between Medication Use and Mental Health in Older Women: A Cross Sectional Analysis of 5,502 Women Aged 76 to 81. PMID- 26096405 TI - Dementia Diagnosis and Influenza Vaccination in French Nursing Home Residents. PMID- 26096406 TI - Outcomes of Cognitive Fluctuations in Dementia Patients. PMID- 26096407 TI - Cognitive Impairment and Slow Gait Speed in Elderly Outpatients with Arterial Hypertension: The Effect of Blood Pressure Values. PMID- 26096408 TI - Active and Passive Methods of Detecting Parkinson's Disease. PMID- 26096409 TI - Does the Prescription of Anxiolytic and Hypnotic Drugs Increase Mortality in Older Adults? PMID- 26096410 TI - Increasing Home Healthcare Referrals upon Discharge from U.S. Hospitals: 2001 2012. PMID- 26096411 TI - Medication Management Skills in Older Skilled Nursing Facility Residents Transitioning Home. PMID- 26096412 TI - Probable Creutzfeldt-Jakob Disease Mimicking a Perioperative Stroke in an Elderly Adult. PMID- 26096413 TI - A Rare Cause of Cauda Equina Syndrome by Infiltration: Case of a Sacral Chordoma. PMID- 26096414 TI - Solitary Rectal Ulcer Syndrome in an Elderly Adult. PMID- 26096415 TI - Astaxanthin Improves Nonalcoholic Fatty Liver Disease in Werner Syndrome with Diabetes Mellitus. PMID- 26096416 TI - Reversible Methotrexate-Induced Dementia: A Case Report. PMID- 26096417 TI - Pseudotumor After Metal-on-Metal Hip Arthroplasty. PMID- 26096418 TI - Idiopathic Presentation of Remitting Seronegative Symmetrical Synovitis with Pitting Edema in an Older Man. PMID- 26096419 TI - Abdominal "Heaviness". PMID- 26096420 TI - Absence of Pleocytosis in Cerebrospinal Fluid does not Exclude Herpes Simplex Virus Encephalitis in Elderly Adults. PMID- 26096421 TI - Associations Between Inflammation and Cognitive Function in African Americans and European Americans. PMID- 26096422 TI - Response to Mehmet I. Naharci. PMID- 26096423 TI - Response to Kara and Colleagues. PMID- 26096424 TI - Only Frailty? What About Other Factors Affecting Cognition? PMID- 26096425 TI - Response to Dr. Alain Braillon. PMID- 26096426 TI - Forest Plots and Prediction of Postoperative Delirium: Missing the Forest for the Trees? PMID- 26096427 TI - Geriatrics and Gerontology: Neglected Areas of Research in Most Developing Countries. PMID- 26096428 TI - Beyond Prediction of Stroke Risk in Nonvalvular Atrial Fibrillation. PMID- 26096429 TI - Erratum. PMID- 26096431 TI - Topical Anti-inflammatory Activity of New Hybrid Molecules of Terpenes and Synthetic Drugs. AB - The aim of the study was to assess changes in the activity of anti-inflammatory terpenes from Chilean medicinal plants after the formation of derivatives incorporating synthetic anti-inflammatory agents. Ten new hybrid molecules were synthesized combining terpenes (ferruginol (1), imbricatolic acid (2) and oleanolic acid (3)) with ibuprofen (4) or naproxen (5). The topical anti inflammatory activity of the compounds was assessed in mice by the arachidonic acid (AA) and 12-O-tetradecanoyl phorbol 13-acetate (TPA) induced ear edema assays. Basal cytotoxicity was determined towards human lung fibroblasts, gastric epithelial cells and hepatocytes. At 1.4 umol/mouse, a strong anti-inflammatory effect in the TPA assay was observed for oleanoyl ibuprofenate 12 (79.9%) and oleanoyl ibuprofenate methyl ester 15 (80.0%). In the AA assay, the best activity was observed for 12 at 3.2 umol/mouse, with 56.8% reduction of inflammation, in the same range as nimesulide (48.9%). All the terpenyl-synthetic anti inflammatory hybrids showed better effects in the TPA assay, with best activity for 6, 12 and 15. The cytotoxicity of the compounds 8 and 10 with a free COOH, was higher than that of 2. The derivatives from 3 were less toxic than the triterpene. Several of the new compounds presented better anti-inflammatory effect and lower cytotoxicity than the parent terpenes. PMID- 26096432 TI - Understanding the Mechanism of Action of Triazine-Phosphonate Derivatives as Flame Retardants for Cotton Fabric. AB - Countless hours of research and studies on triazine, phosphonate, and their combination have provided insightful information into their flame retardant properties on polymeric systems. However, a limited number of studies shed light on the mechanism of flame retardancy of their combination on cotton fabrics. The purpose of this research is to gain an understanding of the thermal degradation process of two triazine-phosphonate derivatives on cotton fabric. The investigation included the preparation of diethyl 4,6-dichloro-1,3,5-triazin-2 ylphosphonate (TPN1) and dimethyl (4,6-dichloro-1,3,5-triazin-2-yloxy) methyl phosphonate (TPN3), their application on fabric materials, and the studies of their thermal degradation mechanism. The studies examined chemical components in both solid and gas phases by using attenuated total reflection infrared (ATR-IR) spectroscopy, thermogravimetric analysis coupled with Fourier transform infrared (TGA-FTIR) spectroscopy, and 31P solid state nuclear magnetic resonance (31P solid state NMR), in addition to the computational studies of bond dissociation energy (BDE). Despite a few differences in their decomposition, TPN1 and TPN3 produce one common major product that is believed to help reduce the flammability of the fabric. PMID- 26096433 TI - Phytochemical Profiling and Evaluation of Pharmacological Activities of Hypericum scabrum L. AB - Phytochemical investigations of ethyl acetate-soluble part of the aerial part of Hypericum scabrum L. delivered eight pure phenolic compounds 1-8. The pure compounds were identified through physico-chemical, NMR (1D, 2D) and mass spectrometric studies as: 3-8''-bisapigenin (1), quercetin (2), quercetin-3-O alpha-l-arabinofuranoside (3), quercetin-3-O-alpha-l-rhamnoside (4), quercetin-3 O-beta-d-glucopyranoside (5), quercetin-3-O-beta-d-galactopyranoside (6), (-) epicatechin (7), (+)-catechin (8). Total polyphenolic compounds and total flavonoids contents were determined in the extract as 0.107 mg?mg-1 and 0.023 mg?mg-1 of the dried extract, respectively. Antioxidant activity using DPPH free radical scavenging assay delivered very strong activity for compounds 2 and 5, 6 and crude extract 10. Protein tyrosine phosphatase 1B (PTP-1B) inhibition experiment of isolated compounds and crude extracts resulted in significant inhibition activity for samples 2, 7a, 8a, 11 and 12 with IC50 values ranging from 1.57 to 2.91 uM. Antimicrobial activity of the pure compounds and extracts produced average results against Staphylococcus aureus, Escherichia coli and Candida albicans strains. From our literature survey, it appears that all pure compounds except 2 were isolated and reported for the first time in H. scabrum. PMID- 26096434 TI - Selected Compounds Structurally Related to Acyclic Sesquiterpenoids and Their Antibacterial and Cytotoxic Activity. AB - By implementing a common and industrially used method, 30 compounds which are structurally related to geranyl acetone, nerolidol, farnesal, farnesol and farnesyl acetate were obtained. Their antimicrobial activity against Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii bacteria was investigated. Pharmacophore models were proposed based on the obtained results and 3D QSAR modelling. Cytotoxic effects against mainly human immortalised and normal cell lines of different origin (malignant melanoma MeWo, colorectal adenocarcinoma HT29, promyelocytic leukemia HL60, gingival fibroblasts HFIG, skin keratinocytes HaCaT and rat small intestine epithelium IEC6) were examined. The odour descriptions of newly synthesised compounds are given. PMID- 26096435 TI - New observations of intraoperative dermoscopic features of the nail matrix and bed in longitudinal melanonychia. AB - BACKGROUND: In recent years, the following four patterns have been defined in intraoperative dermoscopy of the nail matrix and bed in longitudinal melanonychia (LM): (i) a regular gray pattern; (ii) a regular brown pattern; (iii) a regular brown pattern with globules or blotches; and (iv) an irregular pattern. Histopathological findings in these patterns are, respectively: (i) melanocyte activation; (ii) mostly melanocytic hyperplasia (melanocytic activation and melanoma can also be seen); (iii) only melanocytic nevi; and (iv) only melanoma. OBJECTIVE: This study was conducted to compare these patterns with intraoperative dermoscopic findings in another series of five patients with LM. METHODS: Nail plate dermoscopy, intraoperative nail matrix and bed dermoscopy, and histopathological examinations in five patients with LM were retrospectively reviewed. RESULTS: Intraoperative dermoscopy of the nail bed and matrix in patients in whom nail plate dermoscopy demonstrated regular brown lines showed a regular brown pattern with globules in two cases, only globules in one case, and a regular gray pattern in one case. An irregular pattern with globules and blotches was observed in one patient who exhibited irregular brown lines in nail plate dermoscopy. Histopathological examinations showed only hypermelanosis in one case with a regular gray pattern, hypermelanosis and melanophages in cases with a regular brown pattern with globules, blue nevus in one case with an irregular brown pattern with globules and blotches, and only melanophages in one case with globules only. CONCLUSIONS: Histopathological findings that differ from the patterns previously reported were found. An irregular pattern may also be seen in benign melanocytic nevi such as subungual blue nevus. A globular pattern may be defined as a new pattern corresponding to melanophages only. Additional dermoscopic and histopathological images should be shared to facilitate the development of further understanding and the standardization of the intraoperative dermoscopy of LM. PMID- 26096436 TI - Posterior urethral valves: Metabolic consequences in a cohort of patients. AB - BACKGROUND: Despite the improvements in diagnosis and management of posterior urethral valves (PUVs), about one third of patients develop chronic kidney disease (CKD). Children with PUVs might have abnormal calcium, phosphorus, vitamin D and parathyroid hormone levels, which could affect their bone growth and overall health. OBJECTIVE: The aim was to determine the relationship between kidney function, vitamin D deficiency and secondary hyperparathyroidism in children with PUVs. PATIENTS AND METHODS: Sixty-four children with PUVs were followed for a period of 3.64 +/- 2.50 years after their initial presentation and management. Their laboratory parameters were compared with 20 age-, gender- and race-matched children in a control group, including: serum calcium, phosphorus, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D levels, and kidney function. RESULTS: Children with PUVs had significantly lower estimated kidney function (P = 0.006) and vitamin D levels (P < 0.001) and higher iPTH levels (P = 0.042). There were no significant between-group differences in serum calcium, phosphorus, alkaline phosphatase, sodium, potassium, and bicarbonate levels. There was a strong correlation between the degree of vitamin D deficiency and hyperparathyroidism and the degree of kidney dysfunction (r = 0.52 and -0.52, respectively) in the PUV group. On a multivariate analysis, the kidney dysfunction was the only independent predictor of vitamin D deficiency (rho = 0.271, P < 0.001), while kidney dysfunction, serum calcium and alkaline phosphatase were independent predictors for hyperparathyroidism (rho = 0.925, P<0.001, rho = 0.933, P<0.001 and rho = 0.913, P < 0.001, respectively). DISCUSSION: The prevalence of CKD in children with PUVs ranges from 30 to 60%. Patients with CKD are more likely to have vitamin D deficiency and display more prominent hyperparathyroidism. Compared with a control group with normal kidney function, the present cohort had lower 25-hydroxyvitamin D and higher iPTH serum levels. Abnormal kidney function was a major predictor for both serum levels. In this cohort, there were no significant differences in serum calcium and phosphorus between children with PUVs and the control group, and also between those with and without CKD. On the contrary, vitamin D level decreased early in the disease and progressively declined thereafter, while iPTH was the opposite. These findings were comparable to previous studies. This study had some limitations because it was a single center cross-sectional non-randomized study. However, the findings in this study can be extrapolated to children with PUVs and CKD from other origins because the unit is considered as a referral center in the Middle East region. CONCLUSION: Abnormal kidney function, vitamin D deficiency, and secondary hyperparathyroidism are prevalent in children with PUVs. Kidney function is the main determinant of vitamin D and parathyroid hormone levels. Efforts should be directed toward managing CKD, and controlling vitamin D deficiency and hyperparathyroidism in children after ablation of PUV. PMID- 26096437 TI - Urinary NGAL, KIM-1 and L-FABP concentrations in antenatal hydronephrosis. AB - INTRODUCTION: The clinical tests currently in use for obstructive nephropathy (such as renal ultrasonography, differential radionuclide renal scans and urinary creatinine concentration data) are not efficient predictors of the subsequent clinical course. Novel and simple biomarkers are required which, if proven, could be clinically beneficial in determining if a patient is eligible for surgery or reno-protective therapy. More recently, the interest of clinicians has focused on the potential of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary kidney injury molecule-1 (uKIM-1) and urinary liver-type fatty acid binding proteins (uL-FABP) as biomarkers for renal function in children with hydronephrosis (HN). OBJECTIVE: The purpose of this study was to investigate possible clinical applications of uNGAL, uKIM-1 and uL-FABP as beneficial non invasive biomarkers to determine whether or not surgical intervention is required in children with HN. STUDY DESIGN: Renal ultrasonography and radionuclide renal scans were used as diagnostic tools to detect HN. Patients were divided into two groups based on the antero-posterior diameter of their renal pelvis and the presence of dysfunction. Group 1 included 26 children with severe HN (with dysfunction), and group 2 consisted of 36 children with mild HN (without dysfunction). Urine samples were collected from 62 children with HN and 20 healthy children. RESULTS: Hydronephrosis was more common in males than in females, with a male to female ratio of 9:1 in the study sample. The incidence of left kidney involvement (32 patients) was slightly higher than right kidney involvement (28 patients). Compared with controls and group 2, the ratio of uNGAL to creatinine was significantly higher in group 1 (p < 0.05). The biomarker uNGAL/Cr exhibited fairly good diagnostic accuracy, with an area under the curve of 0.68 [95% confidence interval 0.6-0.7] and an optimal cut-off value of 0.16 ng/mg Cr (sensitivity 58%, specificity 75%) (p < 0.05). There was a positive correlation between the uNGAL/Cr ratio and the uKIM-1/Cr ratio (r = 0.582, p < 0.05) and uL-FABP/Cr ratio (r = 0675, p < 0.05) in group 1. DISCUSSION: The results clearly demonstrated that children with hydronephrosis and dysfunction had significantly increased uNGAL, and uNGAL/Cr concentrations. However, uKIM-1, uKIM-1/Cr, uL-FABP and uL-FABP/Cr concentrations were not significantly different when compared with controls. These results support the use of uNGAL concentrations as an early marker for renal dysfunction in HN. CONCLUSIONS: The study clearly demonstrated that pediatric patients with hydronephrosis and dysfunction had significantly higher uNGAL to creatinine concentrations as compared with controls. PMID- 26096438 TI - Investigation of the effect of dorsal penile block to penile tissue. AB - BACKGROUND: Dorsal penile block (DPB) is a frequently used technique for regional anesthesia, but the effect of DPB on penile tissue has not been reported so far. OBJECTIVE: An experimental study was conducted to evaluate the acute effects of DPB on penile tissue. METHODS: Eighteen male rats were included and randomly assigned to three groups. No intervention was made in the control group (CG, n = 6). In the sham group (SG, n = 6) 1 ml normal saline, and in DPB group (PBG, n = 6) 1 ml of 0.25% bupivacaine without adrenaline (0.5 mg/kg), was infused with a 30 mm, 23 gauge needle. DPB was performed by inserting the needle in the midline when pulling down the penis and directing the needle to the 11 and 1 o'clock positions. Another puncture was done at the midline on the ventral side and the remaining drug was infused slowly. The penile tissues were harvested for biochemical (malonyldialdehyde: MDA; nitric oxide: NO; superoxide dismutase: SOD) and histopathological examination. Histopathological assessments were made of inflammation, edema and fibrosis; epithelial degradation in the urethra; vascular obliteration in periurethral tissue; and the peripheral nerve cells. RESULTS: Concentrations of NO and SOD were significantly decreased in the PBG compared with the CG and SG (p < 0.05). The concentration of MDA was significantly increased in the PBG compared with the CG and SG (p < 0.05) (Table). Histopathological examination revealed no significant difference between groups regarding edema, inflammation, or fibrosis (p > 0.05). In hematoxylin and eosin stain samples, vascular structures of the corpus cavernosa were slightly decreased in number in the SG and PBG compared with the CG, but that difference was not statistically significant (p > 0.05). The S-100 staining was significantly higher in the PBG and SG compared with the CG (p < 0.05), and significantly higher in the SG compared with the PBG (p < 0.05). DISCUSSION: DPB causes alteration in oxidative stress markers because of an unknown effect. Although the results revealed increased inflammatory reaction in penile tissue after DPB, they are not enough to suggest not using bupivacaine for DPB in clinical practice. CONCLUSION: Although DPB does not cause any major histopathological alteration, it results in an increase in inflammatory response in the penile tissue in the short term. PMID- 26096439 TI - Training potential in minimally invasive surgery in a tertiary care, paediatric urology centre. AB - BACKGROUND: Minimally invasive surgery (MIS) is being utilized more frequently as a surgical technique in general surgery and in paediatric urology. It is associated with a steep learning curve. Currently, the centre does not offer a MIS training programme. It is hypothesized that the number of MIS procedures performed in the low-volume specialty of paediatric urology will offer insufficient training potential for surgeons. OBJECTIVE: To assess the MIS training potential of a highly specialized, tertiary care, paediatric urology training centre that has been accredited by the Joint Committee of Paediatric Urology (JCPU). STUDY DESIGN: The clinical activity of the department was retrospectively reviewed by extracting the annual number of admissions, outpatient consultations and operative procedures. The operations were divided into open procedures and MIS. Major ablative procedures (nephrectomy) and reconstructive procedures (pyeloplasty) were analysed with reference to the patients' ages. The centre policy is not to perform major MIS in children who are under 2 years old or who weigh less than 12 kg. RESULTS: Every year, this institution provides approximately 4300 out-patient consultations, 600 admissions, and 1300 procedures under general anaesthesia for children with urological problems. In 2012, 35 patients underwent major intricate MIS: 16 pyeloplasties, eight nephrectomies and 11 operations for incontinence (seven Burch, and four bladder neck procedures). In children >=2 years of age, 16/21 of the pyeloplasties and 8/12 of the nephrectomies were performed laparoscopically. The remaining MIS procedures included 25 orchidopexies and one intravesical ureteral reimplantation. DISCUSSION: There is no consensus on how to assess laparoscopic training. It would be valuable to reach a consensus on a standardized laparoscopic training programme in paediatric urology. Often training potential is based on operation numbers only. In paediatric urology no minimum requirement has been specified. The number of procedures quoted for proficiency in MIS remains controversial. The MIS numbers for this centre correspond to, or exceed, numbers mentioned in other literature. To provide high quality MIS training, exposure to laparoscopic procedures should be expanded. This may be achieved by centralizing patients into a common centre, collaborating with other specialities, modular training and training outside the operating theatre. CONCLUSION: Even in a high-volume, paediatric urology educational centre, the number of major MIS procedures performed remains relatively low, leading to limited training potential. PMID- 26096440 TI - HER 2/neu protein expression in gastric cancer is associated with poor survival. PMID- 26096441 TI - New Activities for Isolated Compounds from Convolvulus austro-aegyptiacus as Anti ulcerogenic, Anti-Helicobacter pylori and Their Mimic Synthesis Using Bio-guided Fractionation. AB - Bio-guided fractionation of the total alcoholic extract of Convolvulus austro aegyptiacus was screened for its anti-ulcerogenic activity, using an absolute ethanol-induced ulcer model at 500 and 1000 mg/kg doses. Two compounds were isolated from the butanol extract of C. austro-aegyptiacus and identified by 1 H and 13 C nuclear magnetic resonance as scopoletin and scopolin. The isolated compounds (50 mg/kg) showed a remarkable anti-ulcerogenic activity because they exhibited control-ulcer protection by 16.7% and 90.8%, respectively. The acute toxicity study showed that the extract is highly safe; the median lethal dose (LD50) was more than 4000 mg/kg. Moreover, the obtained results were confirmed by the sub-chronic toxicity because the rats that have been administered 1000 mg/kg of the extract for 15 consecutive days showed no alteration in the liver and kidney functions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096442 TI - The 'four-hour target' and the impact on Australian metropolitan acute surgical services. AB - BACKGROUND: The National Emergency Access Targets (NEAT), introduced in 2012, guides the clearance of emergency department (ED) presentations within 4 h of initial presentation. We aim to assess the impact of NEAT on acute surgical services at a large metropolitan centre. METHODS: A retrospective cohort study was performed and data were collected from electronic patient management systems. The control group was represented by ED presentations between June and September 2011, 1 year prior to the introduction of NEAT. The two study groups consisted of ED presentations between June and September 2012 and 2013 respectively. Outcome measures included time to appendicectomy and cholecystectomy, inpatient length of stay (IPLOS) (for operative and non-operative cases), out-of-hours operating and hospital mortality rates. RESULTS: In total, 2619 inpatient episodes were included, with a trend showing increasing admissions throughout the study periods (P < 0.001). Time to surgical review and ED length of stay decreased significantly (P < 0.001). Time from emergency presentation to emergency appendicectomy and cholecystectomy remained unchanged and procedures performed out-of-hours increased significantly from 20.9% to 42.9% (P < 0.001). Median IPLOS for operative and non-operative patients was reduced during the study from 2.05 to 1.84 days (P < 0.001). Inter-unit transfers within 48 h of presentation increased significantly from 5.3% to 14.7% (P < 0.001). CONCLUSIONS: The early results following the implementation of NEAT have been correlated with increased efficiency in ED clearance and increased burden on surgical operative and inpatient outcomes. While improvements in IPLOS were observed, they must be considered in the context of increased lower-acuity admissions and out-of-hours operating. PMID- 26096443 TI - Evaluation of clinically relevant landmarks of the marginal mandibular branch of the facial nerve: A three-dimensional study with application to avoiding facial nerve palsy. AB - Injury to the marginal mandibular branch of the facial nerve (MMN) during surgery often results in poor functional and cosmetic outcomes. A line two finger breadths or 2 cm inferior to the border of the mandible is commonly used in planning neck incisions to avoid injury to the MMN. The purpose was to compare the two finger breadth/2 cm landmarks in predicting MMN course, and their accuracy/reliability. Thirty-one cadaveric specimens were scanned to obtain 3D surface topography (FARO(r) scanner). Four independent raters pinned the inferior border of the mandible and a two finger breadth line and 2cm line below. The location of each pin was digitized (MicroscribeTM). A preauricular flap was raised, and MMN branches were digitized and modelled (Geomagic(r)/Maya(r)) enabling quantification of the accuracy of these landmarks. The location of the two-finger breadth line was variable, spanning 25-51 mm below the inferior border of the mandible (ICC = 0.10). The most inferior MMN branch did not pass below the two-finger breadth line in any specimen, but a narrow clearance zone (<=5 mm) was found in two. In contrast, in 7/31 specimens, the most inferior MMN branch coursed below the 2 cm line and would be at risk of injury. It was concluded that an incision two finger breadths below the inferior border of the mandible could provide safer access than the 2 cm line. After an incision has been placed using the two finger-breadth landmark, caution must be exercised during dissection as branches of the MMN may lie only a few millimeters superior to the incision. PMID- 26096445 TI - [Perceptions of patients and health professionals about the quality of diabetes care in Spain: Results of the study Diabetes Attitudes, Wishes and Needs 2]. PMID- 26096446 TI - Detection of Bonamia exitiosa in the European flat oyster Ostrea edulis in southern Portugal. PMID- 26096447 TI - A bilayer composite composed of TiO2-incorporated electrospun chitosan membrane and human extracellular matrix sheet as a wound dressing. AB - We designed bilayer composites composed of an upper layer of titanium dioxide (TiO2)-incorporated chitosan membrane and a sub-layer of human adipose-derived extracellular matrix (ECM) sheet as a wound dressing for full-thickness wound healing. The dense and fibrous top layer, which aims to protect the wound from bacterial infection, was prepared by electrospinning of chitosan solution followed by immersion in TiO2 solution. The sponge-like sub-layer, which aims to promote new tissue regeneration, was prepared with acellular ECM derived from human adipose tissue. Using a modified drop plate method, there was a 33.9 and 69.6% reduction in viable Escherichia coli and Staphylococcus aureus on the bilayer composite, respectively. In an in vivo experiment using rats, the bilayer composites exhibited good biocompatibility and provided proper physicochemical and compositional cues at the wound site. Changes in wound size and histological examination of full-thickness wounds showed that the bilayer composites induced faster regeneration of granulation tissue and epidermis with less scar formation, than control wounds. Overall results suggest that the TiO2-incorporated chitosan/ECM bilayer composite can be a suitable candidate as a wound dressing, with an excellent inhibition of bacterial penetration and wound healing acceleration effects. PMID- 26096448 TI - The effect of the size and shape on the bond number of quantum dots and its relationship with thermodynamic properties. AB - Through introducing the size (Nt) and the shape factor (lambda), the size- and shape-dependent bond number Ba of quantum dots, respectively, with icosahedral, truc-decohedral, cuboctahedral, octahedral, decohedral and tetrahedral structures is established in this work. It is found that Nt and lambda have reverse contribution to Ba, that is, Ba increases with increase in Nt, while it decreases with increase in lambda. As the basic parameter, the size- and shape-dependent Ba function is extended to predict the cohesive energy Ec(Nt) of quantum dots. Similar to Ba, Ec(Nt) shows strong dependence on both the size and shape. Larger Nt leads to higher Ec(Nt), whereas larger lambda results in a smaller Ec(Nt) value. There is a sequence: Ec(IH) > Ec(CO) > Ec(truc-DH) > Ec(OT) > Ec(DH) > Ec(TH) if Nt is certain, which is similar to Ba since Ba(IH) > Ba(CO) > Ba(truc DH) > Ba(OT) > Ba(DH) > Ba(TH) is tested in the whole size range. To some extent, this is due to lambda(IH) = lambda(truc-DH) < lambda(CO) < lambda(OT) < lambda(DH) < lambda(TH), however, Ba(IH) > Ba(truc-DH) despite lambda(IH) = lambda(truc-DH). In addition, lambda is no longer constant and increases with increase in Nt when the shape is given. The fact that whatever the shape is, Ba or Ec(Nt) increases upon increasing Nt, meaning that the shape is a secondary factor if compared with the size. The validity of the size- and shape-related model for the Ec(Nt) function is also confirmed by the simulation results of the size- and shape-dependent thermodynamic stability of Au, Ag, Cu, Ca, Sr, and Si quantum dots with different atomic structures. PMID- 26096449 TI - c-IAP ubiquitin protein ligase activity is required for 4-1BB signaling and CD8(+) memory T-cell survival. AB - Cellular inhibitor of apoptosis proteins (c-IAP) 1 and 2 are widely expressed ubiquitin protein ligases that regulate a variety of cellular functions, including the sensitivity of T cells to costimulation. 4-1BB is a TNF receptor family member that signals via a complex that includes TRAF family members and the c-IAPs to upregulate NF-kappaB and ERK, and has been implicated in memory T cell survival. Here, we show that effector and memory T cells from mice expressing a dominant negative E3-inactive c-IAP2 (c-IAP2(H570A)) have impaired signaling downstream of 4-1BB. When infected with lymphocytic choriomeningitis virus, unlike mice in which c-IAPs were acutely downregulated by c-IAP antagonists, the primary response of c-IAP2(H570A) mice was normal. However, the number of antigen-specific CD8(+) but not CD4(+) T cells declined more rapidly and to a greater extent in c-IAP2(H570A) mice than in WT controls. Studies with T cell adoptive transfer demonstrated that the enhanced decay of memory cells was T cell intrinsic. Thus, c-IAP E3 activity is required for 4-1BB coreceptor signaling and maintenance of CD8(+) T-cell memory. PMID- 26096450 TI - Radiographic evaluation of conical tapered platform-switched implants in the posterior mandible: 1-year results of a two-center prospective study. AB - OBJECTIVE: Long-term success of dental implants depends on healthy peri-implant soft tissues and adequate bone levels. This prospective study aims to assess bone level changes around implants with internal conical connection and platform switching abutments in the posterior mandible. MATERIAL AND METHODS: Adult patients missing at least two teeth in the posterior mandible and with a natural tooth mesial to the implant site received two or three adjacent internal conical connection implants. After a minimum transmucosal healing period of 8 weeks, single crown restorations were cemented over platform-switching abutments. Changes in marginal bone levels were measured in standardized periapical radiographs from surgery and loading (baseline) to 12 months post-loading. RESULTS: Twenty-four patients received 52 implants. Bone remodeling took place between surgery and loading (-0.53 +/- 0.40 mm). From loading to 12 months, there was a mean bone gain of 0.12 +/- 0.42 mm which occurred mainly in the first 6 months after prosthesis delivery (0.11 +/- 0.36 mm) and stabilized afterward. A total of 71.7% of all implants presented bone preservation or gain. No implant was lost at 1 year and the success rate was 100%. Patient inquiry revealed high satisfaction. CONCLUSION: Internal conical connection implants with platform switching abutments presented high success rate and enhancement or preservation of marginal bone levels after 1 year of loading. PMID- 26096451 TI - Stimulus-selective induction of the orphan nuclear receptor NGFIB underlies different influences of angiotensin II and potassium on the human adrenal gland zona glomerulosa-specific 3beta-HSD isoform gene expression in adrenocortical H295R cells. AB - In the adrenal, the type I 3beta-hydroxysteroid dehydrogenase (HSD3B1) is expressed exclusively in the zona glomerulosa (ZG), where aldosterone is produced. Angiotensin II (AngII) and potassium (K(+)) are the major physiological regulators of aldosterone synthesis. However, their respective roles in regulation of aldosterone synthesis are not fully defined, particularly in terms of transcriptional regulation of steroidogenic enzyme genes. We previously showed that AngII can stimulate expression of HSD3B1. But, K(+) responsiveness of this gene has remained unexplored. Here, we report that K(+) stimulation lacks the ability to induce HSD3B1 expression in human adrenocortical H295R cells. Both AngII and K(+) were able to enhance transcription of the aldosterone synthase gene (CYP11B2). Promoter analysis revealed that although both AngII and K(+) activate transcription from the Ca(2+)/cAMP-responsive element (CRE) located in the CYP11B2 promoter, the orphan nuclear receptor NGFIB-responsive element (NBRE) located in the HSD3B1 promoter fails to respond to K(+), being only able to enhance transcription after AngII treatment. We found that induction of de novo protein synthesis of NGFIB occurs only after AngII treatment. This sharply contrasts with the phosphorylation that occurs in response to both AngII and K(+) on the CREB/ATF family transcription factor ATF2. Chromatin immunoprecipitation assay confirmed that the NGFIB protein occupies the HSD3B1 promoter only after AngII, while ATF2 binds to the CYP11B2 promoter in response to both AngII and K(+). These data provide evidence that downstream signals from AngII and K(+) can be uncoupled in the regulation of HSD3B1 in the human adrenocortical H295R cells. PMID- 26096452 TI - Overexpression of insulin receptor partially improves obese and diabetic phenotypes in db/db mice. AB - Type 2 diabetes mellitus (T2DM) is one of the major health concern among the world. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues, and improving insulin sensitivity by insulin sensitizers. However, increasing the amount of insulin receptor in insulin-target tissues has not been explored. In order to test the efficacy of insulin receptor overexpression for improving glucose control, we established a transgenic mouse line expressing human insulin receptor (INSR). We analyzed, growth, energy balance, and glucose control of INSR overexpressing db/db mice (INSR; db/db), which we produced by mating INSR transgenic mice with db/db mice, a genetic model of obesity due to insufficient leptin signaling. Compared to db/db mice, INSR; db/db mice were rescued from hyperphagia and obesity, leading to improved blood glucose levels. Unexpectedly, however, INSR; db/db mice presented with stunted growth, accompanied by decreased plasma levels of free IGF1 and IGFBP-3, indicating the down-regulation of GH/IGF1 axis. These phenotypes were observed in INSR; db/db mice but not in INSR littermates. Meanwhile, bone defects observed in db/db male mice were not rescued. Moreover, improved blood glucose was not accompanied by improved insulin sensitivity. Therefore, overexpression of insulin receptor improves obese and diabetic phenotypes in db/db mice, with consequences on growth. PMID- 26096453 TI - Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions (exon20ins) represent approximately 10% of EGFR-mutant lung adenocarcinomas, and are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Clinical outcomes in comparison with patients with sensitizing EGFR mutations are not well established. METHODS: Patients with stage IV lung adenocarcinomas with EGFR exon20ins were identified through routine molecular testing. Clinicopathologic data were collected. Overall survival (OS) was measured from the diagnosis of stage IV disease, and in patients treated with EGFR TKIs, the time to progression (TTP) on erlotinib was measured. RESULTS: One thousand eight hundred and eighty-two patients with stage IV lung adenocarcinomas were identified: 46 patients had EGFR exon20ins (2%), and 258 patients had an EGFR exon 19 deletion (exon19del)/L858R point mutation (14%). Among 11 patients with lung adenocarcinomas with EGFR exon20ins who received erlotinib, 3 patients (27%) had a partial response (FQEA, 1; ASV, 1; and unknown variant, 1). TTP for patients with EGFR exon20ins and patients with EGFR exon19del/L858R on erlotinib were 3 and 12 months, respectively (P < .01). Responses to chemotherapy were similar for patients with lung adenocarcinomas with EGFR exon20ins and patients with lung adenocarcinomas with EGFR exon19del/L858R. Median OS from the diagnosis of stage IV disease for patients with EGFR exon20ins and patients with EGFR exon19del/L858R was 26 months (95% confidence interval, 19 months-not reached n = 46) and 31 months (95% confidence interval, 28-33 months; n = 258), respectively (P = .53). CONCLUSIONS: The majority of patients with advanced lung adenocarcinomas harboring EGFR exon20ins do not respond to EGFR TKI therapy. Standard chemotherapy should be used as first-line therapy. These patients have an OS similar to that of patients with sensitizing EGFR mutations. Individuals with certain variants such as FQEA and ASV may respond to erlotinib. PMID- 26096454 TI - Radiofrequency Ablation with an Enhanced-Irrigation Flexible-Tip Catheter versus a Standard-Irrigation Rigid-Tip Catheter. AB - BACKGROUND: The flexible-tip irrigated ablation catheter Cool FlexTM (St. Jude Medical, St. Paul, MN, USA) was introduced to enhance cooling of the catheter tissue interface and to conform to endocardial surface with better contact. Little is known about the performance of such catheter design compared to the widely used rigid-tip catheters. METHODS: In a thigh muscle preparation, ablation using the flexible-tip and rigid-tip catheters was performed in seven pigs across a range of ablation settings and catheter orientation. Postprocedure, the thigh muscle was stained with 2,3,5-triphenyltetrazolium-chloride injected into the femoral artery. The muscle was excised, fixed with formalin, and examined grossly. RESULTS: A total of 196 lesions (95 flexible tip, 101 rigid tip) were evaluated. The flexible-tip catheter was associated with enhanced cooling of catheter-tissue interface (31.1 +/- 3.3 degrees C vs 36.3 +/- 3.7 degrees C, P = 0.0001) in both perpendicular and nonperpendicular catheter orientations. This allowed more energy delivery (37.3 +/- 8.9 W vs 33.7 +/- 8.1 W, P = 0.004) to targeted tissue and resulted in larger lesions (median 194.7 [interquartile range: 113.1-333.8] mm(3) vs 170.9 [88.7-261.6] mm(3) , P = 0.03) than the rigid tip catheter with larger maximum diameter (11.1 +/- 2.6 mm vs 10.3 +/- 2.1 mm, P = 0.03) and larger diameter at tissue surface (10.3 +/- 2.4 mm vs 9.6 +/- 1.7 mm, P = 0.01). Catheter orientation during ablation affected the efficiency of rigid tip but not the flexible-tip catheter. The use of the flexible-tip catheter was associated with significantly less char formation on tissue (none vs 5.1% with rigid tip, P = 0.009). CONCLUSION: The Cool FlexTM catheter performed better than a rigid-tip catheter with enhanced cooling, larger ablation lesions, and no charring of targeted tissue. PMID- 26096455 TI - Investigation of Structural Determinants for the Substrate Specificity in the Zinc-Dependent Alcohol Dehydrogenase CPCR2 from Candida parapsilosis. AB - Zinc-dependent alcohol dehydrogenases (ADHs) are a class of enzymes applied in different biocatalytic processes ranging from lab to industrial scale. However, one drawback is the limited substrate range, necessitating a whole array of different ADHs for the relevant substrate classes. In this study, we investigated structural determinants of the substrate spectrum in the zinc-dependent ADH carbonyl reductase 2 from Candida parapsilosis (CPCR2), combining methods of mutational analysis with in silico substrate docking. Assigned active site residues were genetically randomized, and the resulting mutant libraries were screened with a selection of challenging carbonyl substrates. Three variants (C57A, W116K, and L119M) with improved activities toward different substrates were detected at neighboring positions in the active site. Thus, all possible combinations of the mutations were generated and characterized for their substrate specificity, yielding several improved variants. The most interesting were a C57A variant, with a 27-fold increase in specific activity for 4' acetamidoacetophenone, and the double mutant CPCR2 B16-(C57A, L119M), with a 45 fold improvement in the kcat ?KM (-1) value. The obtained variants were further investigated by in silico docking experiments. The results indicate that the mentioned residues are structural determinants of the substrate specificity of CPCR2, being major players in the definition of the active site. Comparison of these results with closely related enzymes suggests that these might even be transferred to other ADHs. PMID- 26096456 TI - Neuroendocrine factors regulate retinoic acid receptors in normal and hypoplastic lung development. AB - KEY POINTS: Retinoic acid (RA) and ghrelin levels are altered in human hypoplastic lungs when compared to healthy lungs. Although considerable data have been obtained about RA, ghrelin and bombesin in the congenital diaphragmatic hernia (CDH) rat model, neuroendocrine factors have never been associated with the RA signalling pathway in this animal model. In this study, the interaction between neuroendocrine factors and RA was explored in the CDH rat model. The authors found that normal fetal lung explants treated with RA, bombesin and ghrelin showed an increase in lung growth. Hypoplastic lungs presented higher expression levels of the RA receptors alpha and gamma. Moreover bombesin and ghrelin supplementation, in vitro, to normal lungs increased RA receptor alpha/gamma expression whereas administration of bombesin and ghrelin antagonists to normal and hypoplastic lungs decreased it. These data reveal for the first time that there is a link between neuroendocrine factors and RA, and that neuroendocrine factors sensitise the lung to the RA action through RA receptor modulation. ABSTRACT: Congenital diaphragmatic hernia (CDH) is characterised by a spectrum of lung hypoplasia and consequent pulmonary hypertension, leading to high morbidity and mortality rates. Moreover, CDH has been associated with an increase in the levels of pulmonary neuroendocrine factors, such as bombesin and ghrelin, and a decrease in the action of retinoic acid (RA). The present study aimed to elucidate the interaction between neuroendocrine factors and RA. In vitro analyses were performed on Sprague-Dawley rat embryos. Normal lung explants were treated with bombesin, ghrelin, a bombesin antagonist, a ghrelin antagonist, dimethylsulfoxide (DMSO), RA dissolved in DMSO, bombesin plus RA and ghrelin plus RA. Hypoplastic lung explants (nitrofen model) were cultured with bombesin, ghrelin, bombesin antagonist or ghrelin antagonist. The lung explants were analysed morphometrically, and retinoic acid receptor (RAR) alpha, beta and gamma expression levels were assessed via Western blotting. Immunohistochemistry analysis of RAR was performed in normal and hypoplastic lungs 17.5 days post conception (dpc). Compared with the controls, hypoplastic lungs exhibited significantly higher RARalpha/gamma expression levels. Furthermore considering hypoplastic lungs, bombesin and ghrelin antagonists decreased RARalpha/gamma expression. Normal lung explants (13.5 dpc) treated with RA, bombesin plus RA, ghrelin plus RA, bombesin or ghrelin exhibited increased lung growth. Moreover, bombesin and ghrelin increased RARalpha/gamma expression levels, whereas the bombesin and ghrelin antagonists decreased RARalpha/gamma expression. This study demonstrates for the first time that neuroendocrine factors function as lung growth regulators, sensitising the lung to the action of RA through up-regulation of RARalpha and RARgamma. PMID- 26096457 TI - Near-infrared spectroscopy for intracoronary detection of lipid-rich plaques to understand atherosclerotic plaque biology in man and guide clinical therapy. AB - Ischaemic heart disease is the leading cause of death worldwide. The common denominator for plaques causing acute coronary syndrome (ACS) is lipid accumulation, either as a lipid core or lipid pools. An intracoronary imaging device to detect lipid-rich plaques (LRPs) could therefore identify most of the plaques causing ACS and sudden death. Near-infrared spectroscopy combined with intravascular ultrasound (NIRS-IVUS) is a promising new intracoronary imaging method that is able to specifically quantify lipid accumulation measured as the lipid core burden index (LCBI). NIRS-IVUS is highly specific for the identification of ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) culprit plaques usually in the form of a circular LRP. NIRS-IVUS may assist in defining the aetiology of coronary events. The effect of cholesterol-lowering therapy on the lipid core can be measured in coronary plaques in patients, and NIRS-IVUS may be a useful tool for drug development in phase II studies as a surrogate end-point for future ACS. Plaques with a high LCBI have an increased risk of peri-procedural events. NIRS-IVUS can help to define the diameter and length of stents to avoid procedure-related complications. Increased coronary LCBI predicts a higher risk of future cardiovascular events. Lipid core detection using NIRS may help to identify vulnerable plaques to treat them before they cause ACS or sudden death. PMID- 26096458 TI - Amur tiger conservation education program: A pilot study on program effectiveness. AB - Anthropogenic impacts are the primary threats to Amur tigers (Panthera tigris altaica) and their habitat. Villagers living in proximity to tigers tend to view them negatively and, often, as a source of revenue on black markets. We aim to reduce human-tiger conflict by working with young students of Ternei County in the heart of tiger habitat in Primorskii Krai (Province). To inform and influence Ternei County's future decision-makers, we developed "Safe Conduct", a year-long education program held in 6 villages, culminating in a multi-school conference. We tested the efficacy of Safe Conduct as a potential model for tiger conservation educational programs. We measured levels of student knowledge about tiger ecology, their attitude towards tigers, and their willingness to engage in tiger conservation activites prior to, immediately after and 6 months following the completion of our program. Results supported the fundamental premise of Safe Conduct that knowledge and attitude towards tigers are correlated. Knowledge of tiger ecology and attitude towards tigers increased by the project's completion; both remained high after 6 months. However, commitment to participation in conservation efforts rose temporarily post-program and then dropped. Results varied by village. We recommend that the reasons for the high performance measures of students in 2 villages be investigated, and that lessons learned be applied to villages that underperformed. Safe Conduct represents a potential model for environmental education programs in Ternei County and elsewhere to educate future generations, to eventually develop a strong commitment to Amur tiger conservation at the community level. PMID- 26096459 TI - Accumulation of nanoparticles in "jellyfish" mucus: a bio-inspired route to decontamination of nano-waste. AB - The economic and societal impacts of nano-materials are enormous. However, releasing such materials in the environment could be detrimental to human health and the ecological biosphere. Here we demonstrate that gold and quantum dots nanoparticles bio-accumulate into mucus materials coming from natural species such as jellyfish. One strategy that emerges from this finding would be to take advantage of these trapping properties to remove nanoparticles from contaminated water. PMID- 26096460 TI - TRPV5/V6 Channels Mediate Ca(2+) Influx in Jurkat T Cells Under the Control of Extracellular pH. AB - Regulation of cytoplasmic free calcium concentration [Ca(2+)]i is a key factor for the maintenance of cellular homeostasis in different cell types, including lymphocytes. During T lymphocyte activation as well as production of cytokines, sustained Ca(2+) influx is essential, however, it remains unclear how this influx is regulated. Previously, we reported the expression and functional activity of calcium channels TRPV5 and TRPV6 (transient receptor potential vanilloid type 5 and 6) in human leukemia Jurkat T cells. In this study, using single channel recordings, we found that activity of calcium channels TRPV5/V6 in Jurkat T cells is subject to strong control of external stimuli such as a low- or high-pH stressor. We showed that extracellular acidic pH reduces the activity of TRPV5/V6 channels, whereas alkaline pH increases the activity of TRPV5/V6 channels in Jurkat T cells. Using calcium imaging, we found that Ca(2+) influx in Jurkat T cells displayed sensitivity to extracellular pH, similar to that shown for the calcium channels TRPV5/V6. Double immunostaining of Jurkat T cells revealed that TRPV5 and TRPV6 channels colocalize with clathrin and the early endocytosis marker, EEA1. Moreover, we demonstrated that a specific inhibitor of clathrin dependent endocytosis, dynasore, blocked TRPV5/V6 activity, and Ca(2+) influx into Jurkat T cells. Overall, our findings indicate that strong environmental cues may affect the intracellular calcium level in Jurkat T cells by influencing the traffic of TRPV5/V6 channels in lymphocytes. PMID- 26096462 TI - Polypeptide-b-Poly(Phenyl Isocyanide) Hybrid Rod-Rod Copolymers: One-Pot Synthesis, Self-Assembly, and Cell Imaging. AB - Hybrid rod-rod diblock copolymers, poly(gamma-benzyl L-glutamate)-poly(4-cyano benzoic acid 2-isopropyl-5-methyl-cyclohexyl ester) (PBLG-PPI), with determined chirality are facilely synthesized through sequential copolymerization of gamma benzyl-L-glutamate N-carboxyanhydride (BLG-NCA) and phenyl isocyanide monomers bearing chiral menthyl pendants using a Ni(cod)(bpy) complex as the catalyst in one-pot. Circular dichroism and absorption spectra reveal that each block of the block copolymers possesses a stable helical conformation with controlled helicity in solution due to the induction of chiral pendants. The two diastereomeric polymers self-assemble into helical nanofibrils with opposite handedness due to the different chiral induction of the L- and D-menthyl pendants, confirmed by transmission electron microscopy (TEM). Deprotection of the benzyl groups of the PBLG segment affords biocompatible amphiphilic diblock copolymers, poly(L glutamic acid)-poly(4-cyano-benzoic acid 2-isopropyl-5-methyl-cyclohexyl ester) (PLGA-PPI), that can self-assemble into well-defined micelles by cosolvent induced aggregation. Very interestingly, a chiral rhodamine chromophores RhB(D) can be selectively encapsulated into the chiral polymeric micelles, which is efficiently internalized into living cells when directly monitored with a confocal microscope. This contribution will be useful for developing novel rod rod biocompatible hybrid block copolymers with a controlled helicity, and may also provide unique chiral materials for potential bio-medical applications. PMID- 26096461 TI - Longitudinal changes of dopamine transporters in heroin users during abstinence. AB - RATIONALE: Chronic exposure to heroin results in decreased dopamine transporter levels. Jitai tablets, a traditional Chinese medicine, have been effective at increasing striatal dopamine transporter availability after 6 months of treatment. However, it remains unknown how long the heroin-induced impairment persists and whether dopamine transporter can be normalized following long-term abstinence or treatment. OBJECTIVES: This study was to evaluate the time course of dopamine transporter changes in heroin users undergoing long-term abstinence and treatment with Jitai tablets for 1 year. METHODS: Single-photon emission computed tomography using [(99m)Tc]TRODAT-1 was performed on 64 heroin users and 20 healthy subjects to assess striatal dopamine transporter availability at baseline, 3, 6, and 12 months. Heroin users were randomly assigned to treatment with either placebo or Jitai tablets. Depression and anxiety scores were measured before each imaging session. RESULTS: Compared with healthy controls, significant reduction in dopamine transporter availability was found in heroin users at baseline in both the right (by ~ 31.6%) and left striatum (by ~ 33.2%). At 6 months, dopamine transporter availability was significantly higher in Jitai tablet-treated group than placebo group in the bilateral striatum (p < 0.01). At 12 months, dopamine transporter levels in both groups were upregulated substantially from baseline but still not recovered to normal levels in the left striatum (p < 0.05). Depression and anxiety scores significantly decreased at 3, 6, and 12 months (p < 0.05). CONCLUSIONS: Our results confirmed that heroin abuse induces pronounced, long-term reduction in dopamine transporter. Treatment with Jitai tablets appears to stimulate recovery. PMID- 26096463 TI - Maternal depressive symptoms during pregnancy, placental expression of genes regulating glucocorticoid and serotonin function and infant regulatory behaviors. AB - BACKGROUND: Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors. METHOD: Bi-weekly self ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 +/- 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother rated at 15.6 +/- 4.2 days. RESULTS: Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05). CONCLUSIONS: Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors. PMID- 26096464 TI - Early endoscopic treatment of blunt traumatic pancreatic injury. AB - Blunt pancreatic trauma is a rare and challenging situation. In many cases, there are other associated injuries that mandate urgent operative treatment. Morbidity and mortality rates are high and complications after acute pancreatic resections are common. The diagnosis of pancreatic injuries can be difficult and often requires multimodal approach including Computed Tomography scans, Magnetic resonance imaging and Endoscopic retrograde cholangiopancreaticography (ERCP). The objective of this paper is to review the application of endoprothesis in the settings of pancreatic injury. A review of the English literature available was conducted and the experience of our centre described. While the classical recommended treatment of Grade III pancreatic injury (transection of the gland and the pancreatic duct in the body/tail) is surgical resection this approach carries high morbidity. ERCP was first reported as a diagnostic tool in the settings of pancreatic injury but has in recent years been used increasingly as a treatment option with promising results. This article reviews the literature on ERCP as treatment option for pancreatic injury and adds further to the limited number of cases reported that have been treated early after the trauma. PMID- 26096466 TI - Response to Kalbfleish and Schaubel: "A Perspective on the Scientific Registry of Transplant Recipients Migration to Bayesian Methods". PMID- 26096465 TI - Lovastatin Differentially Affects Neuronal Cholesterol and Amyloid-beta Production in vivo and in vitro. AB - BACKGROUND AND AIMS: Epidemiological and experimental studies indicate that high cholesterol may increase susceptibility to age-associated neurodegenerative disorders, such as Alzheimer's disease (AD). Thus, it has been suggested that statins, which are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), may be a useful therapeutic tool to diminish the risk of AD. However, several studies that analyzed the therapeutic benefits of statins have yielded conflicting results. Herein, we investigated the role of lovastatin on neuronal cholesterol homeostasis and its effects on amyloid beta protein production in vivo and in vitro. METHODS AND RESULTS: Lovastatin effects were analyzed in vitro using differentiated human neuroblastoma cells and in vivo in a lovastatin-fed rat model. We demonstrated that lovastatin can differentially affect the expression of APP and Abeta production in vivo and in vitro. Lovastatin-induced HMGCR inhibition was detrimental to neuronal survival in vitro via a mechanism unrelated to the reduction of cholesterol. We found that in vivo, dietary cholesterol was associated with increased Abeta production in the cerebral cortex, and lovastatin was not able to reduce cholesterol levels. However, lovastatin induced a remarkable increase in the mature form of the sterol regulatory element-binding protein-2 (SREBP-2) as well as its target gene HMGCR, in both neuronal cells and in the brain. CONCLUSIONS: Lovastatin modifies the mevalonate pathway without affecting cholesterol levels in vivo and is able to reduce Abeta levels only in vitro. PMID- 26096467 TI - An autopsy case of familial amyotrophic lateral sclerosis with a TARDBP Q343R mutation. AB - We describe a Japanese autopsy case of familial amyotrophic lateral sclerosis (FALS) with a TARDBP Q343R mutation. This male patient developed dysarthria at the age of 52 years, and bulbar symptoms progressed, with weakness and atrophy in the extremities. His mental status was normal, but he became bedridden, received artificial respiratory support at 54 years of age, and gradually acquired a locked-in state and died at 58 years of age. Microscopically, marked diffuse myelin pallor was observed in the anterolateral columns of the spinal cord. The remaining anterior horn cells contained Bunina bodies and phosphorylation dependent transactivation response DNA-binding protein of 43 kDa (pTDP-43) positive neuronal cytoplasmic inclusions (NCIs). Glial cytoplasmic inclusions (GCIs) were also observed. The number of ubiquitin- and p62-positive inclusions was markedly lower than that of pTDP-43-positive inclusions. NCIs and many fine dot-like pTDP-43-positive granules in the neuropil were mainly seen in the temporal and motor cortices, and striatum. NCIs were rare in hippocampal granular cells. Immunoblotting of samples from the cerebral cortex using an anti-pTDP-43 antibody was slightly different from previous TDP-43 pathological subtypes. PMID- 26096468 TI - Factors that Influence Chaplains' Suicide Intervention Behavior in the Army. AB - We surveyed 868 Army chaplains and 410 chaplain assistants (CAs) about their role in identifying, caring for, and referring soldiers at risk of suicide to behavioral health care. We applied structural equation modeling to identify how behaviors and attitudes related to intervention behavior. In both samples, reluctance and stigma were related to intervention behaviors; efficacy was correlated with intervention behaviors only among chaplains. Training was associated with increased efficacy and lower levels of stigma among chaplains. Improved training may be warranted, but research needs to identify why chaplains and CAs are reluctant to refer soldiers in distress to behavioral health care. PMID- 26096469 TI - Resolution of superimposed pre-eclampsia, and improvement in umbilical artery flow in a surviving twin after intrauterine demise of its co-twin. AB - Pre-eclampsia has a progressive clinical course, and is only cured by delivery of the placenta. We report a 30-year-old G1P0 with dichorionic twins, discordant growth and chronic hypertension who developed superimposed pre-eclampsia in her 21st week of gestation. After intrauterine demise of the severely growth restricted twin, the superimposed pre-eclampsia resolved. The surviving twin initially had absent end diastolic flow, which resolved after the demise. A healthy 1935-g neonate with Apgar 9/9 was delivered at 34 weeks. Antenatal resolution of pre-eclampsia is extremely rare and resolution of superimposed pre eclampsia has not, to our knowledge, been reported. PMID- 26096470 TI - Factors associated with long-term patient-reported outcomes after three-column osteotomies. AB - BACKGROUND CONTEXT: Studies have demonstrated sustained improvements in patient reported outcomes (PROs) after three-column osteotomies (three-COs), but no study has evaluated what factors impact long-term outcomes. PURPOSE: The aim was to investigate factors associated with PROs in patients who underwent three-CO at minimum 5 years postoperatively. STUDY DESIGN/SAMPLE: This was a retrospective review of prospective database. PATIENT SAMPLE: All patients who had a three-CO at a single institution and completed clinical evaluations after at least 5 years postoperative were included. OUTCOME MEASURES: Oswestry Disability Index (ODI), Scoliosis Research Society (SRS) scores, and radiographic parameters were assessed at baseline and a minimum 5 years postoperatively. METHODS: Analysis of 120 patients who underwent three-CO (96-pedicle subtraction osteotomy/24 vertebral column resection) was performed. The mean age was 48 years (range 8 79), and clinical follow-up was 7 years (range 5-14). Separate multivariable linear regression analyses were performed to determine factors associated with ODI, SRS average, and SRS satisfaction while controlling for time since surgery and baseline outcome scores. RESULTS: Average PROs were significantly improved from baseline at a minimum 5-year follow-up (ODI: 48-28, p<.01; SRS: 2.8-3.5, p<.01). The average SRS satisfaction score was 4.0. Average sagittal alignment (C7 plumb) improved 74 mm, with 81% of patients' alignment less than 95 mm. Major surgical complications occurred in 32 patients (27%) with major reoperations in 30 patients (25%). Multivariable regression analysis found that prior surgery and major reoperations were risk factors for worse ODI scores. A diagnosis of adult idiopathic scoliosis and final sagittal alignment less than 95 mm were associated with improved SRS scores. Improvement in major coronal Cobb and final pelvic tilt less than 30 degrees were associated with increased SRS satisfaction. CONCLUSIONS: With a minimum 5-year follow-up, PROs in patients undergoing three CO were associated with improvements in radiographic alignment but negatively affected by prior surgery and complications necessitating revision surgery. PMID- 26096471 TI - A rare cause of chronic neck pain: accessory cervical spinous process. PMID- 26096472 TI - Creating a sustainable model of spine care in underserved communities: the World Spine Care (WSC) charity. PMID- 26096473 TI - Intradural extramedullary spinal hydatid cyst causing bone destruction. PMID- 26096475 TI - Sudden paraplegia because of dumbbell-shaped metastatic neuroendocrine tumor (carcinoid tumor). PMID- 26096474 TI - Randomized clinical trial assessing whether additional massage treatments for chronic neck pain improve 12- and 26-week outcomes. AB - BACKGROUND CONTEXT: This is the first study to systematically evaluate the value of a longer treatment period for massage. We provide a framework of how to conceptualize an optimal dose in this challenging setting of nonpharmacologic treatments. PURPOSE: The aim was to determine the optimal dose of massage for neck pain. STUDY DESIGN/SETTING: Two-phase randomized trial for persons with chronic nonspecific neck pain. Primary randomization to one of five groups receiving 4 weeks of massage (30 minutes 2x/or 3x/wk or 60 minutes 1x, 2x, or 3x/wk). Booster randomization of participants to receive an additional six massages, 60 minutes 1x/wk, or no additional massage. PATIENT SAMPLE: A total of 179 participants from Group Health and the general population of Seattle, WA, USA recruited between June 2010 and August 2011 were included. OUTCOME MEASURES: Primary outcomes self-reported neck-related dysfunction (Neck Disability Index) and pain (0-10 scale) were assessed at baseline, 12, and 26 weeks. Clinically meaningful improvement was defined as greater than or equal to 5-point decrease in dysfunction and greater than or equal to 30% decrease in pain from baseline. METHODS: Clinically meaningful improvement for each primary outcome with both follow-up times was analyzed using adjusted modified Poisson generalized estimating equations (GEEs). Secondary analyses for the continuous outcomes used linear GEEs. RESULTS: There were no observed differences by primary treatment group at 12 or 26 weeks. Those receiving booster dose had improvements in both dysfunction and pain at 12 weeks (dysfunction: relative risk [RR]=1.56 [1.08 2.25], p=.018; pain: RR=1.25 [0.98-1.61], p=.077), but those were nonsignificant at 26 weeks (dysfunction: RR=1.22 [0.85-1.74]; pain: RR=1.09 [0.82-1.43]). Subgroup analysis by primary and booster treatments found the booster dose only effective among those initially randomized to one of the 60-minute massage groups. CONCLUSIONS: "Booster" doses for those initially receiving 60 minutes of massage should be incorporated into future trials of massage for chronic neck pain. PMID- 26096476 TI - Posterior epidural lumbar disc fragment mimicking epidural mass. PMID- 26096477 TI - Kinematic relationship between missed ligamentum flavum bulge and degenerative factors in the cervical spine. AB - BACKGROUND CONTEXT: Bulging of ligamentum flavum can happen with the aging process and can lead to compression of the spinal cord and nerves. However, the distribution and the risk factors associated with a missed ligamentum flavum bulge (LFB) are unknown. PURPOSE: The aim was to evaluate the distribution and risk factors associated with missed LFB in the cervical spine. STUDY DESIGN: This was a retrospective analysis of kinematic magnetic resonance images (kMRI). PATIENT SAMPLE: Patients diagnosed with symptomatic neck pain or radiculopathy between March 2011 and October 2012 were included. OUTCOME MEASURES: The outcome measures were missed LFB and degenerative factors. METHODS: A total of 200 patients (1,000 cervical segments) underwent upright kMRI in neutral, flexion, and extension postures. The LFB, sagittal cervical angles, disc herniation, disc degeneration, disc height, angular motion, translational motion, age, and gender were recorded. After excluding segments with LFB in neutral and flexion position, Pearson and Spearman correlation coefficients were used to evaluate the relation between the risk factors and missed LFB in the extension position. RESULTS: The average depth of LFB was 0.24+/-0.71 mm at C2-C3, 1.02+/-1.42 mm at C3-C4, 1.65+/ 1.48 mm at C4-C5, 2.13+/-1.37 mm at C5-C6, and 1.05+/-1.54 mm at C6-C7. The distribution of LFB was the most frequent at C5-C6 level (76.58%) followed by C4 C5 (63.06%). Disc herniation, disc degeneration, angular variation, and translational motion were significantly correlated with missed LFB at C4-C5 andC5 C6. Disc degeneration was the only factor significantly correlated with missed LFB at all cervical segments. CONCLUSIONS: Occurrence and depth of missed LFB was the highest at C4-C5 and C5-C6 compared with other cervical levels. Disc degeneration, disc herniation, angular variation, and translational motion could play a role in the development of LFB at C4-C5 andC5-C6. PMID- 26096478 TI - A rare case of noncontiguous multiple spinal Langerhans cell histiocytosis involving atlantoaxial instability. PMID- 26096479 TI - Unusual presentation of an adult filum terminale teratoma associated with diplomyelia. PMID- 26096480 TI - Cervical involvement in Morquio syndrome. PMID- 26096481 TI - Ponticulus posticus. PMID- 26096482 TI - An unusual site of lung adenocarcinoma metastasis: cauda equina. PMID- 26096483 TI - Immature ganglioneuroma of the thoracic spine with lipomatous component: a rare cause of scoliosis. PMID- 26096485 TI - Benign osteoblastoma of cervical spine. PMID- 26096484 TI - Can patient characteristics predict benefit from epidural corticosteroid injections for lumbar spinal stenosis symptoms? AB - BACKGROUND CONTEXT: Epidural corticosteroid injections are commonly used to treat back and leg pain associated with lumbar spinal stenosis. However, little is known about which patient characteristics may predict favorable responses. PURPOSE: The aim was to identify patient characteristics associated with benefits from epidural injections of corticosteroid with lidocaine versus epidural injections of lidocaine only for lumbar spinal stenosis symptoms. STUDY DESIGN/SETTING: This was a secondary analysis of Lumbar Epidural steroid injections for Spinal Stenosis randomized controlled trial data from 16 US clinical sites. PATIENT SAMPLE: Patients aged older than or equal to 50 years with moderate-to-severe leg pain and lumbar central spinal stenosis randomized to epidural injections of corticosteroids with lidocaine (n=200) or lidocaine only (n=200) were included. OUTCOME MEASURES: Primary outcomes were the Roland-Morris Disability Questionnaire (RMDQ) and 0 to 10 leg pain intensity ratings. Secondary outcomes included the Brief Pain Inventory Interference Scale and the Swiss Spinal Stenosis Questionnaire. METHODS: At baseline, clinicians rated severity of patient spinal stenosis, and patients completed predictor and outcome measures. Patients completed outcome measures again 3 and 6 (primary end point) weeks after randomization/initial injection. Analysis of covariance was used with treatment by covariate interactions to identify baseline predictors of greater benefit from corticosteroid+lidocaine versus lidocaine alone. We also identified nonspecific (independent of treatment) predictors of outcomes. RESULTS: Among 21 candidate predictors and six outcomes, only one baseline variable predicted greater benefit from corticosteroid+lidocaine versus lidocaine only at 3 or 6 weeks. Compared with patients who rated their health-related quality of life as high on the EQ-5D Index, patients who rated it as poor had greater improvement with corticosteroid than with lidocaine only in leg pain at 6 (but not 3) weeks (interaction coefficient=2.94; 95% confidence interval [CI]=0.11-5.76; p=.04) and in RMDQ disability scores at 3 (but not 6) weeks (interaction coefficient=4.77, 95% CI= 0.04 to 9.59; p = .05). Several baseline patient characteristics predicted outcomes regardless of treatment assignment. CONCLUSIONS: Among 21 baseline patient characteristics examined, none, including clinician-rated spinal stenosis severity, were consistent predictors of benefit from epidural injections of lidocaine+corticosteroid versus lidocaine only. PMID- 26096486 TI - An unusual cause of chronic abdominal pain in a child: thoracic spinal dermoid cyst. PMID- 26096487 TI - Spontaneous cervicothoracic epidural hematoma. PMID- 26096488 TI - A rare cause of chronic backache: paraspinal hydatid cyst with neural foraminal extension. PMID- 26096489 TI - Kummel disease and successful percutaneous vertebroplasty treatment. PMID- 26096490 TI - Disagreement between parents on assessment of child temperament traits. AB - BACKGROUND: Accuracy of temperament assessment is a prerequisite in research studies. To identify the extent to which parental assessment of child temperament is biased by their personal attributes, we proposed a new structural equation model, in which biases of parental attributes in their assessment of child temperament can be separated from the true (i.e. non-biased) associations between the two. METHODS: We examined 234 father-mother pairs using questionnaires including Emotionality, Activity, Sociability, and Impulsivity; Social Desirability Scale; Hospital Anxiety and Depression Scale; Temperament and Character Inventory; and State-Trait Anger Expression Inventory. RESULTS: Paternal Depression and Persistence, maternal Trait Anger, and parental Novelty Seeking showed significant bias in assessment of Emotionality. Maternal Self transcendence showed significant bias in assessment of child Impulsivity. CONCLUSION: Researchers should be cautious about biases in parental assessment of children's Emotionality and Impulsivity, but other temperament traits may be free from such biases. PMID- 26096491 TI - The morphology of the pineal gland of the yellow-toothed cavy (Galea Spixii Wagler, 1831) and red-rumped agouti (Dasyprocta leporina linnaeus, 1758). AB - The pineal gland is an endocrine gland found in all mammals. This article describes the morphology of this important gland in two species of Caviideae, namely the yellow-toothed cavy and the red-rumped agouti. Ten adult animals of the two species used in current analysis were retrieved from the Center for the Multiplication of Wild Animals (CEMAS/UFERSA) and euthanized. The glands were removed and photographed in situ and ex situ. They were fixed in a paraformaldehyde solution 4% or glutaraldehyde 2.5% solution and submitted to routine histological techniques respectively for light and scanning electron microscopy. Macroscopically, the pineal gland with its elongated structure may be found between the cerebral hemispheres facing the rostral colliculi. Microscopically, pinealocytes and some glia cells were predominant. Contrastingly, to the cavy's pineal gland, a capsule covered the organ in the agouti, with the emission of incomplete septa to the interior, which divided it into two lobules. Light and scanning electron microscopes failed to show calcareous concretions in the pineal gland. Based on the topography of the cavy's and agouti's pineal gland, it may be classified as supra-callosum and ABC type. PMID- 26096492 TI - Ketamine. PMID- 26096493 TI - Retention challenge facing Australia's rural community mental health services: Service managers' perspectives. AB - OBJECTIVE: This paper aims to contribute to the development of a more sustainable Australian rural community mental health workforce by comparing the findings from a literature search investigating impacting factors on retention with the experiences of community mental health service managers running services in rural Australia. DESIGN: Semi-structured interviews. SETTING: Public health sector, rural New South Wales. PARTICIPANTS: Five community mental health managers, running services in rural Australia. MAIN OUTCOME MEASURES: Interviews were undertaken as a pilot for a broader qualitative study investigating factors influencing the decision to stay or leave among community mental health professionals working in rural positions. The purpose of undertaking this pilot study was to test for validity and relevance of the retention phenomena and help inform the research design for the main study. RESULTS: Three key retention focussed themes were identified: (i) Staffing is a persistent challenge; (ii) Small remote towns pose the biggest challenge; and (iii) The decision to stay or leave is complex and multifactorial. CONCLUSIONS: The findings of this pilot study support previous research and contribute to the understanding of influences on retention among health professionals working in rural community mental health services. Importantly, those who have worked for several years in rural positions hold important information through which to explore factors that impact retention in rural and remote regions. PMID- 26096494 TI - Characterization of Campylobacter jejuni DNA gyrase as the target of quinolones. AB - Quinolones have long been used as the first-line treatment for Campylobacter infections. However, an increased resistance to quinolones has raised public health concerns. The development of new quinolone-based antibiotics with high activity is critical for effective, as DNA gyrase, the target of quinolones, is an essential enzyme for bacterial growth in several mechanisms. The evaluation of antibiotic activity against Campylobacter jejuni largely relies on drug susceptibility tests, which require at least 2 days to produce results. Thus, an in vitro method for studying the activity of quinolones against the C. jejuni DNA gyrase is preferred. To identify potent quinolones, we investigated the interaction of C. jejuni DNA gyrase with a number of quinolones using recombinant subunits. The combination of purified subunits exhibited DNA supercoiling activity in an ATP dependent manner. Drug concentrations that inhibit DNA supercoiling by 50% (IC50s) of 10 different quinolones were estimated to range from 0.4 (sitafloxacin) to >100 MUg/mL (nalidixic acid). Sitafloxacin showed the highest inhibitory activity, and the analysis of the quinolone structure-activity relationship demonstrated that a fluorine atom at R-6 might play the important role in the inhibitory activity against C. jejuni gyrase. Measured quinolone IC50s correlated well with minimum inhibitory concentrations (R = 0.9943). These suggest that the in vitro supercoiling inhibition assay on purified recombinant C. jejuni DNA gyrase is a useful and predictive technique to monitor the antibacterial potency of quinolones. And furthermore, these data suggested that sitafloxacin might be a good candidate for clinical trials on campylobacteriosis. PMID- 26096495 TI - In vitro neuraminidase inhibitory activity of four neuraminidase inhibitors against clinical isolates of the influenza virus circulating in the Japanese 2013 2014 season. AB - To assess the extent of viral resistance, we measured the 50% inhibitory concentration (IC50) of neuraminidase inhibitors (NAIs) for the influenza virus isolates in the 2013-2014 influenza season and compared the results to those of the 2010-2011 to 2012-2013 influenza seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype of influenza was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 327 influenza viruses were isolated: 172 influenza A(H1N1)pdm09 (52.6%), 49 A(H3N2) (15.0%), and 106 B (32.4%). Numbers of Victoria and Yamagata lineage isolates were 36 and 70, respectively. Two A(H1N1)pdm09 isolates showed a high IC50 for oseltamivir (130 and 150 nM) exceeding by 100 times the geometric mean of the IC50 of oseltamivir for A(H1N1)pdm09 isolates (0.76 nM). No isolate showed a very high IC50 for A(H3N2) or B. The IC50 of the NAIs except for oseltamivir for A(H1N1) pdm09 were significantly higher than those of the 2010-2011 season (P < 0.05). The IC50 of all four NAIs for A(H3N2) were significantly lower than those of the 2012-2013 season (P < 0.001). The IC50 of the NAIs for B except for oseltamivir were significantly lower than those of the 2012-2013 season (P < 0.001). Although there are some isolates that show highly reduced sensitivity to oseltamivir among A(H1N1)pdm09 isolates, the currently epidemic influenza A(H1N1)pdm09, A(H3N2) and B viruses are susceptible to all four NAIs with no trend toward decreased sensitivity. PMID- 26096496 TI - Environmental exposure to manganese in air: Associations with cognitive functions. AB - Manganese (Mn), an essential element, can be neurotoxic in high doses. This cross sectional study explored the cognitive function of adults residing in two towns (Marietta and East Liverpool, Ohio, USA) identified as having high levels of environmental airborne Mn from industrial sources. Air-Mn site surface emissions method modeling for total suspended particulate (TSP) ranged from 0.03 to 1.61 MUg/m(3) in Marietta and 0.01-6.32 MUg/m(3) in East Liverpool. A comprehensive screening test battery of cognitive function, including the domains of abstract thinking, attention/concentration, executive function and memory was administered. The mean age of the participants was 56 years (+/-10.8 years). Participants were mostly female (59.1) and primarily white (94.6%). Significant relationships (p<0.05) were found between Mn exposure and performance on working and visuospatial memory (e.g., Rey-O Immediate beta=-0.19, Rey-O Delayed beta= 0.16) and verbal skills (e.g., Similarities beta=-0.19). Using extensive cognitive testing and computer modeling of 10-plus years of measured air monitoring data, this study suggests that long-term environmental exposure to high levels of air-Mn, the exposure metric of this paper, may result in mild deficits of cognitive function in adult populations. PMID- 26096497 TI - Short-term use of glucocorticoids and risk of peptic ulcer bleeding: a nationwide population-based case-crossover study. AB - BACKGROUND: Controversy exists regarding glucocorticoids therapy and the risk of peptic ulcer bleeding (PUB). AIM: The present study was undertaken to determine whether short-term use of glucocorticoids is associated with the occurrence of peptic ulcer bleeding. METHODS: The records of adult patients hospitalised for newly diagnosed peptic ulcer bleeding from 2000 to 2012 were retrieved from the Taiwan National Health Insurance Research Database, a nationwide population-based registry system. The association between systemic glucocorticoids usage and peptic ulcer bleeding was determined with a conditional logistic regression model comparing cases and controls during time windows of 7, 14 and 28 days using a case-crossover design. RESULTS: Of the 8894 enrolled patients, the adjusted self matched odds ratios for peptic ulcer bleeding after exposure to the glucocorticoids were 1.37 (95% CI: 1.12-1.68, P = 0.003) for the 7-day window, 1.66 (95% CI: 1.38-2.00, P < 0.001) for the 14-day window and 1.84 (95% CI: 1.57 2.16, P < 0.001) for the 28-day window. Moderate to high, but not low dose glucocorticoids (methylprednisolone <4 mg/day or its equivalence) were associated with an increased risk of peptic ulcer bleeding. Concomitant use of a nonselective nonsteroidal anti-inflammatory drug (NSAID) or aspirin further elevated the risk. However, it does not eliminate the effect of underlying diseases flare-up that may have placed the patients at risk for peptic ulcer bleeding in this kind of study design. CONCLUSIONS: Short-term (7-28 days) exposure to glucocorticoids is significantly associated with peptic ulcer bleeding; this risk seems dose-dependent and is higher when nonselective NSAIDs or aspirin are used concurrently. PMID- 26096498 TI - Overexpression of MdSOS2L1, a CIPK protein kinase, increases the antioxidant metabolites to enhance salt tolerance in apple and tomato. AB - Soil salinity hinders the growth of most higher plants and becomes a gradually increasing threat to the agricultural production of such crops as the woody plant apple. In this study, a calcineurin B-like protein (CBL)-interacting protein kinase, MdCIPK24-LIKE1 (named as MdSOS2L1), was identified. Quantitative real time polymerase chain reaction (qRT-PCR) assay revealed that the expression of MdSOS2L1 was upregulated by CaCl2 . Yeast two-hybrid (Y2H) assay and transiently transgenic analysis demonstrated that the MdSOS2L1 protein kinase physically interacted with MdCBL1, MdCBL4 and MdCBL10 proteins to increase salt tolerance in apple. Furthermore, iTRAQ proteome combined with liquid chromatography-tandem mass spectrometry (LC/MS) analysis found that several proteins, which are involved in reactive oxygen species (ROS) scavenging, procyanidin biosynthesis and malate metabolism, were induced in MdSOS2L1-overexpressing apple plants. Subsequent studies have shown that MdSOS2L1 increased antioxidant metabolites such as procyanidin and malate to improve salt tolerance in apple and tomato. In summary, our studies provide a mechanism in which SOS2L1 enhances the salt stress tolerance in apple and tomato. PMID- 26096499 TI - Purification of His-Tagged Proteins. AB - Ni-NTA affinity purification of His-tagged proteins is a bind-wash-elute procedure that can be performed under native or denaturing conditions. Here, protocols for purification of His-tagged proteins under native, as well as under denaturing conditions, are given. The choice whether to purify the target protein under native or denaturing conditions depends on protein location and solubility, the accessibility of the His tag, and the desired downstream application. His tagged proteins can be purified by a single-step affinity chromatography, namely immobilized metal ion affinity chromatography (IMAC), which is commercially available in different kinds of formats, Ni-NTA matrices being the most widely used. The provided protocols describe protein purification in the batch binding mode and apply gravity-assisted flow in disposable columns; this procedure is simple to conduct and extremely robust. IMAC purification can equally be performed in prepacked columns using FPLC or other liquid chromatography instrumentation, or using magnetic bead-based methods (Block et al., 2009). PMID- 26096501 TI - Immunoaffinity Purification of Proteins. AB - This protocol entails a single-step, high-affinity purification of proteins using an immobilized antibody column. PMID- 26096500 TI - Affinity Purification of a Recombinant Protein Expressed as a Fusion with the Maltose-Binding Protein (MBP) Tag. AB - Expression of fusion proteins such as MBP fusions can be used as a way to improve the solubility of the expressed protein in E. coli (Fox and Waugh, 2003; Nallamsetty et al., 2005; Nallamsetty and Waugh, 2006) and as a way to introduce an affinity purification tag. The protocol that follows was designed by the authors as a first step in the purification of a recombinant protein fused with MBP, using fast protein liquid chromatography (FPLC). Cells should have been thawed, resuspended in binding buffer, and lysed by sonication or microfluidization before mixing with the amylose resin or loading on the column. Slight modifications to this protocol may be made to accommodate both the protein of interest and the availability of equipment. PMID- 26096502 TI - Affinity Purification of Protein Complexes Using TAP Tags. AB - This protocol is used for the isolation and analysis of protein complexes using the tandem affinity purification (TAP) tag system. The protocol describes the purification of a protein fused to a TAP tag comprised of two protein A domains and the calmodulin binding peptide separated by a TEV cleavage site. This is a powerful technique for rapid purification of protein complexes and the analysis of their stoichiometric composition, posttranslational modifications, structure, and functional activities. PMID- 26096503 TI - Strep-Tagged Protein Purification. AB - The Strep-tag system can be used to purify recombinant proteins from any expression system. Here, protocols for lysis and affinity purification of Strep tagged proteins from E. coli, baculovirus-infected insect cells, and transfected mammalian cells are given. Depending on the amount of Strep-tagged protein in the lysate, a protocol for batch binding and subsequent washing and eluting by gravity flow can be used. Agarose-based matrices with the coupled Strep-Tactin ligand are the resins of choice, with a binding capacity of up to 9 mg ml(-1). For purification of lower amounts of Strep-tagged proteins, the use of Strep Tactin magnetic beads is suitable. In addition, Strep-tagged protein purification can also be automated using prepacked columns for FPLC or other liquid-handling chromatography instrumentation, but automated purification is not discussed in this protocol. The protocols described here can be regarded as an update of the Strep-Tag Protein Handbook (Qiagen, 2009). PMID- 26096504 TI - Proteolytic Affinity Tag Cleavage. AB - Here, we present protocols describing the use of the dipeptidyl-aminopeptidase-1 (DPP1, DAPase) exoprotease-based TAGZyme system and the endoprotease, Factor Xa. Both enable the recovery of proteins free of any amino acids encoded by the vector and/or protease recognition site. They also provide the possibility of removing the proteases from the preparation of the target protein by a simple subtractive chromatography step. TAGZyme enzymes contain an uncleavable His tag for removal by Immobilized Metal Ion Affinity Chromatography (IMAC). Factor Xa can be removed using Xa Removal Resin. PMID- 26096506 TI - Protein Affinity Purification using Intein/Chitin Binding Protein Tags. AB - Isolation of highly purified recombinant protein is essential for a wide range of biochemical and biophysical assays. Affinity purification in which a tag is fused to the desired protein and then specifically bound to an affinity column is a widely used method for obtaining protein of high purity. Many of these methods have the drawbacks of either leaving the recombinant tag attached to the protein or requiring the addition of a protease which then must be removed by further chromatographic steps. The fusion of a self-cleaving intein sequence followed by a chitin-binding domain (CBD) allows for one-step chromatographic purification of an untagged protein through the thiol-catalyzed cleavage of the intein sequence from the desired protein. The affinity purification is highly specific and can yield pure protein without any undesired N- or C-terminal extensions. This protocol is based on the IMPACTTM-System (intein mediated purification with an affinity chitin-binding tag) marketed by New England Biolabs. PMID- 26096505 TI - Affinity Pull-Down of Proteins Using Anti-FLAG M2 Agarose Beads. AB - FLAG is an affinity tag widely used for rapid and highly specific one-step protein purification. Native elution of protein from anti-FLAG antibody resins allows the identification of protein and nucleic acid binding partners and functional analysis using biochemical activity assays. PMID- 26096507 TI - Purification of GST-Tagged Proteins. AB - This protocol describes the purification of recombinant proteins fused to glutathione S-transferase (GST, GST-tagged proteins) by Glutathione Affinity purification. The GST tag frequently increases the solubility of the fused protein of interest and thus enables its purification and subsequent functional characterization. The GST-tagged protein specifically binds to glutathione immobilized to a matrix (e.g., agarose) and can be easily separated from a cell lysate by a bind-wash-elute procedure. GST-tagged proteins are often used to study protein-protein interactions, again making use of glutathione affinity in a procedure called a GST pull-down assay. The protocol is designed to process 200 ml of E. coli culture expressing intermediate to high amounts of a GST-tagged protein (~25 mg l(-1)). Depending on the expression rate or the available culture volume, the scale can be increased or decreased linearly. The protocol can also be used to purify GST-tagged proteins from other expression systems, such as insect or mammalian cells. Tips are provided to aid in modifying certain steps if proteins shall be recovered from alternative expression systems. PMID- 26096508 TI - Preface. Laboratory Methods in Enzymology: Protein Part D. PMID- 26096509 TI - Valproic acid hypersensitivity and desensitization. AB - Rash, a hypersensitivity reaction, is a common cause of withdrawal from an effective antiepileptic drug (AED) in patients with epilepsy. We present a case of successful desensitization to valproic acid in a 12-year-old male with childhood absence epilepsy and a hypersensitivity reaction, whose epilepsy did not respond to other AEDs. Desensitization is a practical therapeutic solution for patients who develop a non-life-threatening hypersensitivity reaction to an AED for which there may be no substitute. PMID- 26096510 TI - Does Stroke Imaging Provide Insights into the Neural Basis of Cognition? AB - Since the advent of in vivo imaging, first with CT, and then MRI, structural neuroimaging in patients has been widely used as a tool to explore the neural correlates of a wide variety of cognitive functions. Findings from studies using this methodology have formed a core component of current accounts of cognition, but there are a number of problematic issues related to inferring cognitive functions from structural imaging data in stroke and more generally, lesion-based neuropsychology as a whole. This review addresses these concerns in the context of spatial neglect, a common disorder most frequently encountered following right hemisphere stroke. Recent literature, including attempts to address some of these questions, is discussed. Novel approaches and findings from related fields that may help to put stroke-based lesion mapping studies into perspective are reviewed, allowing critical but constructive evaluation of previous work in the field. PMID- 26096511 TI - The Inflammatory Form of Cerebral Amyloid Angiopathy or "Cerebral Amyloid Angiopathy-Related Inflammation" (CAARI). AB - Cerebral amyloid angiopathy-related inflammation (CAARI) is a recently recognized syndrome of reversible encephalopathy seen in a subset of patients with cerebral amyloid angiopathy (CAA). CAA is a disorder of the elderly in which amyloid peptides are deposited in the walls of cerebral arteries, leading to microhemorrhages, macrohemorrhages, and eventually dementia. In a few cases, the amyloid deposition is accompanied by inflammation or edema. The clinical syndrome of CAARI is distinguished by subacute neurobehavioral symptoms, headaches, seizures, and stroke-like signs, contrasting the acute intracranial hemorrhage typically seen in CAA. Magnetic resonance imaging findings may be symmetric or asymmetric and involve patchy or confluent T2 hyperintense lesions in the cortex and subcortical white matter. Recent diagnostic criteria have been proposed which help distinguish CAARI from alternative diagnoses. Improvement has been reported in most cases with immunosuppression, although a few cases have had recurrent symptoms. Here, we review the clinical and radiologic features of CAARI and compare these with CAA. PMID- 26096512 TI - Erratum to: New Genes for Focal Epilepsies with Speech and Language Disorders. PMID- 26096513 TI - Substrate recognition by the zinc metalloprotease effector NleC from enteropathogenic Escherichia coli. AB - Upon infection of epithelial cells, enteropathogenic Escherichia coli suppresses host cell inflammatory signalling in a type III secretion system (T3SS) dependent manner. Two key T3SS effector proteins involved in this response are NleE and NleC. NleC is a zinc metalloprotease effector that degrades the p65 subunit of NF kappaB. Although the site of p65 cleavage by NleC is now well described, other areas of interaction have not been precisely defined. Here we constructed overlapping truncations of p65 to identify regions required for NleC cleavage. We determined that NleC cleaved both p65 and p50 within the Rel homology domain (RHD) and that two motifs, E22IIE25 and P177VLS180 , within the RHD of p65 were important for recognition and binding by NleC. Alanine substitution of one or both of these motifs protected p65 from binding and degradation by NleC. The E22IIE25 and P177VLS180 motifs were located within the structurally distinct N terminal subdomain of the RHD involved in DNA binding by p65 on adjacent, parallel strands. Although these motifs have not been recognized previously, both were needed for the correct localization and function of p65. In summary, this work has identified two regions of p65 within the RHD needed for binding and cleavage by NleC and provides further insight into the molecular basis of substrate recognition by a T3SS effector. PMID- 26096514 TI - Telaprevir versus simeprevir for the treatment of recurrent hepatitis C after living donor liver transplantation. AB - AIM: Our aim was to evaluate the clinical outcomes of telaprevir (TVR)- or simeprevir (SMV)-based triple therapy for recurrent hepatitis C after living donor liver transplantation. METHODS: Twenty-six patients received antiviral therapy, consisting of either TVR (n = 12) or SMV (n = 14) in combination with pegylated interferon and ribavirin, plus cyclosporin. RESULTS: More patients had a dose reduction of the direct-acting agent (36.3% vs 0.0%, P = 0.02) or required blood transfusion for anemia (58.3% vs 7.1%, P < 0.01) in the TVR group. The cyclosporin trough/dose ratio increased significantly from week 0 to week 4 in the TVR group (1.6 +/- 0.4 to 5.1 +/- 2.0, P < 0.01), but not in the SMV group (1.2 +/- 0.3 to 1.3 +/- 0.2, P = 0.68). The 24-week cumulative viral clearance rate was 91.7% and 85.7% in the TVR and in SMV groups, respectively. The early viral response and sustained viral response rates were 91.7% and 83.3%, respectively, in the TVR group, compared with 85.7% and 64.3%, respectively, in the SMV group. Interferon-mediated graft dysfunction occurred in four and five patients in the TVR and SMV groups, respectively; two patients were treated by oral steroids, five by steroid pulse and two by thymoglobulin, resulting in viral breakthrough in one case. CONCLUSION: SMV-based triple therapy was associated with fewer adverse events and drug interactions with cyclosporin, and possibly less antiviral properties to TVR. Interferon-mediated graft dysfunction is a significant clinical problem that warrants particular caution following living donor liver transplantation. PMID- 26096515 TI - Acetone-Linked Peptides: A Convergent Approach for Peptide Macrocyclization and Labeling. AB - Macrocyclization is a broadly applied approach for overcoming the intrinsically disordered nature of linear peptides. Herein, it is shown that dichloroacetone (DCA) enhances helical secondary structures when introduced between peptide nucleophiles, such as thiols, to yield an acetone-linked bridge (ACE). Aside from stabilizing helical structures, the ketone moiety embedded in the linker can be modified with diverse molecular tags by oxime ligation. Insights into the structure of the tether were obtained through co-crystallization of a constrained S-peptide in complex with RNAse S. The scope of the acetone-linked peptides was further explored through the generation of N-terminus to side chain macrocycles and a new approach for generating fused macrocycles (bicycles). Together, these studies suggest that acetone linking is generally applicable to peptide macrocycles with a specific utility in the synthesis of stabilized helices that incorporate functional tags. PMID- 26096516 TI - Robust electron pairing in the integer quantum hall effect regime. AB - Electron pairing is a rare phenomenon appearing only in a few unique physical systems; for example, superconductors and Kondo-correlated quantum dots. Here, we report on an unexpected electron pairing in the integer quantum Hall effect regime. The pairing takes place within an interfering edge channel in an electronic Fabry-Perot interferometer at a wide range of bulk filling factors, between 2 and 5. We report on three main observations: high-visibility Aharonov Bohm conductance oscillations with magnetic flux periodicity equal to half the magnetic flux quantum; an interfering quasiparticle charge equal to twice the elementary electron charge as revealed by quantum shot noise measurements, and full dephasing of the pairs' interference by induced dephasing of the adjacent inner edge channel-a manifestation of inter-channel entanglement. Although this pairing phenomenon clearly results from inter-channel interaction, the exact mechanism that leads to electron-electron attraction within a single edge channel is not clear. We believe that substantial efforts are needed in order to clarify these intriguing and unexpected findings. PMID- 26096517 TI - Rhodium-Catalyzed ortho-Selective C-F Bond Borylation of Polyfluoroarenes with Bpin-Bpin. AB - An ortho-selective C-F bond borylation between N-heterocycle-substituted polyfluoroarenes and Bpin-Bpin with simple and commercially available [Rh(cod)2 ]BF4 as a catalyst is now reported. The reaction proceeds under mild reaction conditions with high efficiency and broad substrate scope, even toward monofluoroarene, thus providing a facile access to a wide range of borylated fluoroarenes that are useful for photoelectronic materials. Preliminary mechanistic studies reveal that a Rh(III/V) catalytic cycle via a key intermediate rhodium(III) hydride complex [(H)Rh(III) Ln (Bpin)] may be involved in the reaction. PMID- 26096518 TI - Rapid and sensitive analysis of polymorphisms from breastmilk shows that ibuprofen is safe during certain stages of breastfeeding. PMID- 26096519 TI - Effect of cataract surgery on cognition, mood, and visual hallucinations in older adults. AB - PURPOSE: To assess the impact of cataract surgery on cognition, mood, and visual hallucinations in a cohort of patients aged 75 years and older. SETTING: Secondary care ophthalmology unit in Northeast England. DESIGN: Prospective observational cohort study. METHODS: Participants aged 75 years or older with bilateral cataract and scheduled for cataract surgery were recruited consecutively. Participants were assessed preoperatively and followed for 1 year postoperatively. Cognition was assessed using the revised Addenbrooke's Cognitive Examination (ACE-R), mood was measured with the 15-item Geriatric Depression Scale, visual hallucinations were elicited using the North East Visual Hallucinations Inventory, and visual acuity was assessed using a logMAR chart. RESULTS: One hundred twelve participants were recruited at baseline; 91 (81%) completed 1 year of follow-up. Significant improvements in ACE-R scores were seen between baseline and 1 year postoperatively (95% confidence interval for improvement, 0.5-2.8; P = .005). Improved cognition did not correlate with improved visual acuity (r = -0.13, P = .22). No significant changes in mood were seen during the course of the study (P = .314, repeated-measures 1-way analysis of variance). Complete resolution of complex visual hallucinations occurred in 2 patients after surgery. CONCLUSIONS: Small improvements in cognition and reports of resolved complex visual hallucinations indicate that the benefits of cataract surgery might extend beyond visual improvement. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26096520 TI - Refractive outcomes of Descemet membrane endothelial keratoplasty triple procedures (combined with cataract surgery). AB - PURPOSE: To describe the refractive outcomes of triple Descemet membrane endothelial keratoplasty (DMEK). DESIGN: Retrospective case series. METHODS: The study included patients with Fuchs endothelial dystrophy and cataract without coincident pathology. RESULTS: Outcomes of 108 sequential triple DMEK procedures were evaluated. With a mean follow-up of 11.9 months, the median corrected distance visual acuity (CDVA) was 20/20 (range 20/15 to 20/40) and the median uncorrected distance visual acuity in eyes with a distance target (n = 84) was 20/40 (range 20/20 to 20/200). Forty-five percent of patients gained 3 or more lines of CDVA. The median refractive error was +0.43 diopter (D) (interquartile range, -0.34 to +1.17 D). Aspheric intraocular lenses (IOLs) (n = 91) did not significantly change refractive astigmatism (mean: preoperative +0.926 D +/- 0.144 [SD]; postoperative +0.945 +/- 0.129 D) (P = .83), while toric IOLs (n = 9) did (mean: preoperative +2.47 +/- 0.36 D; postoperative +0.94 +/- 0.90 D) (P = .0015). The anterior curvature measured by Scheimpflug imaging (Pentacam) did not significantly change (mean -0.06 +/- 0.47) (P = .41); however, keratometry by partial coherence interferometry (IOLMaster) did (mean -0.6 +/- 0.9 D) (P < .0001). CONCLUSIONS: Triple DMEK safely achieved excellent CDVA. Selection of the optimum IOL power is complicated by several factors. Because Fuchs dystrophy induces changes predominately in the central cornea, measurements averaging curvature over a larger area might underreport significant refractive deviations. In the absence of an algorithm to more precisely individualize IOL calculations, a refractive target of -0.75 to -1.00 D will help reduce the proportion of eyes left hyperopic. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26096521 TI - Influence of light filters in intraocular lenses on color perception and contrast acuity. AB - PURPOSE: To compare contrast acuity at different illumination levels, color vision, and the subjective visual impression in patients after bilateral cataract surgery with mixed implantation of a yellow-tinted intraocular lens (IOL) and an orange-tinted IOL. SETTING: Department of Ophthalmology, Hietzing Hospital, Vienna, Austria. DESIGN: Prospective case series. METHODS: Consecutive patients with age-related cataract had standardized small-incision cataract surgery with IOL implantation in the capsular bag. Patients were randomly assigned to receive a yellow Polylens Y30 in 1 eye and an Orange Series model PC 440Y in the contralateral eye. The main outcome measures were contrast acuity, color vision, and subjective visual impression. Contrast acuity was measured at illumination levels of 5.0 lux and 0.5 lux and contrast levels of 50.0%, 25.0%, and 12.5%. Color vision was assessed using the Heidelberg-multicolor anomaloscope, and the subjective visual impression was evaluated using a questionnaire. RESULTS: This study included 64 eyes of 32 patients. The intraindividual comparison showed no significant difference in contrast sensitivity at different contrast and illumination levels or in color vision. On questioning, 3 patients reported a difference in subjective color perception between the 2 IOL types. CONCLUSION: There were no differences in contrast sensitivity or color vision between yellow tinted IOLs and orange-tinted IOLs. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26096522 TI - Managing residual refractive error after cataract surgery. AB - We present a review of keratorefractive and intraocular approaches to managing residual astigmatic and spherical refractive error after cataract surgery, including laser in situ keratomileusis (LASIK), photorefractive keratectomy (PRK), arcuate keratotomy, intraocular lens (IOL) exchange, piggyback IOLs, and light-adjustable IOLs. Currently available literature suggests that laser vision correction, whether LASIK or PRK, yields more effective and predictable outcomes than intraocular surgery. Piggyback IOLs with a rounded-edge profile implanted in the sulcus may be superior to IOL exchange, but both options present potential risks that likely outweigh the refractive benefits except in cases with large residual spherical errors. The light-adjustable IOL may provide an ideal treatment to pseudophakic ametropia by obviating the need for secondary invasive procedures after cataract surgery, but it is not widely available nor has it been sufficiently studied. PMID- 26096523 TI - Incidence of corneal infections after laser in situ keratomileusis and surface ablation when moxifloxacin and tobramycin are used as postoperative treatment. AB - PURPOSE: To assess the incidence, culture results, and visual outcomes of infectious keratitis after laser in situ keratomileusis (LASIK) and surface ablation when topical moxifloxacin was added to postoperative prophylaxis with tobramycin. SETTING: Clinica Baviera, Instituto Oftalmologico Europeo, Bilbao, Spain. DESIGN: Retrospective case series review. METHODS: The medical records of 55 255 patients (108 014 eyes) who had LASIK and surface ablation were reviewed to identify cases of infectious keratitis. The incidence, risk factors, clinical course, days to diagnosis, treatment, and final visual outcomes were recorded. These data were compared with previously published data of 221 437 eyes that received postoperative tobramycin alone. RESULTS: Post-LASIK infectious keratitis was diagnosed in 10 eyes (9 patients) and post-surface ablation infectious keratitis in 11 eyes (10 patients). The onset of infection was early in 40.00% of cases after LASIK and in 36.36% after surface ablation. Cultures were positive in 2 cases after surface ablation. Immediate flap lifting and irrigation with antibiotics were performed in all eyes after LASIK. The final corrected distance visual acuity was 20/20 or better in 7 cases after LASIK (70.00%) and 7 cases after surface ablation (63.64%) and 20/40 or better in all cases after LASIK or surface ablation. CONCLUSIONS: The incidence of infectious keratitis decreased from 0.025% to 0.011% (P < .001) per procedure after LASIK and from 0.200% to 0.066% (P < .001) after surface ablation. Infectious keratitis was less frequent after LASIK than after surface ablation. The frequency of infection, mainly early onset infection, was lower when the postoperative treatment was tobramycin and moxifloxacin rather than tobramycin alone. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26096524 TI - Re: Letter to the editor regarding microelectrode recordings and deep brain stimulation surgery--Reasoned discussion? PMID- 26096525 TI - Crosstalk between nitric oxide and glutathione is required for NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1)-dependent defense signaling in Arabidopsis thaliana. AB - Nitric oxide (NO) is a ubiquitous signaling molecule involved in a wide range of physiological and pathophysiological processes in animals and plants. Although its significant influence on plant immunity is well known, information about the exact regulatory mechanisms and signaling pathways involved in the defense response to pathogens is still limited. We used genetic, biochemical, pharmacological approaches in combination with infection experiments to investigate the NO-triggered salicylic acid (SA)-dependent defense response in Arabidopsis thaliana. The NO donor S-nitrosoglutathione (GSNO) promoted the nuclear accumulation of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1) protein accompanied by an elevated SA concentration and the activation of pathogenesis-related (PR) genes, leading to induced resistance of A. thaliana against Pseudomonas infection. Moreover, NO induced a rapid change in the glutathione status, resulting in increased concentrations of glutathione, which is required for SA accumulation and activation of the NPR1-dependent defense response. Our data imply crosstalk between NO and glutathione, which is integral to the NPR1-dependent defense signaling pathway, and further demonstrate that glutathione is not only an important cellular redox buffer but also a signaling molecule in the plant defense response. PMID- 26096526 TI - Visible-Light-Driven Intermolecular [2+2] Cycloadditions between Coumarin-3 Carboxylates and Acrylamide Analogs. AB - This paper reports a room temperature visible-light-driven protocol for the intermolecular [2+2] cycloadditions between coumarin-3-carboxylates and acrylamides analogs by an energy-transfer process. Using an iridium complex FIrPic as a photosensitizer and a 3 W blue LED as a light source, an array of cyclobutabenzocypyranones were prepared in moderate to excellent yields. PMID- 26096527 TI - The functional-cognitive framework as a tool for accelerating progress in cognitive neuroscience: On the benefits of bridging rather than reducing levels of analyses. AB - The subject matter of neuroscience research is complex, and synthesising the wealth of data from this research to better understand mental processes is challenging. A useful strategy, therefore, may be to distinguish explicitly between the causal effects of the environment on behaviour (i.e. functional analyses) and the mental processes that mediate these effects (i.e. cognitive analyses). In this article, we describe how the functional-cognitive (F-C) framework can accelerate cognitive neuroscience and also advance a functional treatment of brain activity. We first highlight that cognitive neuroscience can particularly benefit from the F-C approach by providing an alternative to the problematic practice of reducing cognitive constructs to behavioural and/or neural proxies. Next, we outline how functional (behaviour-environment) relations can serve as a bridge between cognitive and neural processes by restoring mental constructs to their original role as heuristic tools. Finally, we give some examples of how both cognitive neuroscience and traditional functional approaches can mutually benefit from the F-C framework. PMID- 26096528 TI - Apolipoprotein E and protection against hepatitis E viral infection in American non-Hispanic blacks. AB - Hepatitis E viral (HEV) infection imposes a heavy health burden worldwide and is common in the United States. Previous investigations of risks addressed environmental and host behavioral/lifestyle factors, but host genetic factors have not been examined. We assessed strength of associations between antibody to HEV (anti-HEV) immunoglobulin G seropositivity indicating past or recent HEV infection and human genetic variants among three major racial/ethnic populations in the United States, involving 2434 non-Hispanic whites, 1919 non-Hispanic blacks, and 1919 Mexican Americans from the Third National Health and Nutrition Examination Survey, 1991-1994. We studied 497 single-nucleotide polymorphisms across 190 genes (particularly those associated with lipid metabolism). The genomic control method was used to adjust for potential population stratification. Non-Hispanic blacks had the lowest seroprevalence of anti-HEV immunoglobulin G (15.3%, 95% confidence interval [CI] 12.3%-19.0%) compared with non-Hispanic whites (22.3%, 95% CI 19.1%-25.7%) and Mexican Americans (21.8%, 95% CI 19.0%-25.3%; P<0.01). Non-Hispanic blacks were the only population that showed association between anti-HEV seropositivity and functional epsilon3 and epsilon4 alleles of the apolipoprotein E (APOE) gene, encoding the apolipoprotein E protein that mediates lipoprotein metabolism. Seropositivity was significantly lower in participants carrying APOE epsilon4 (odds ratio=0.5, 95% CI 0.4-0.7; P=0.00004) and epsilon3 (odds ratio=0.6, 95% CI 0.4-0.8; P=0.001) compared to those carrying APOE epsilon2. No significant associations were observed between other single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic blacks or between any single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic whites or Mexican Americans. CONCLUSION: Both APOE epsilon3 and epsilon4 are significantly associated with protection against HEV infection in non-Hispanic blacks; additional studies are needed to understand the basis of protection so that preventive services can be targeted to at-risk persons. PMID- 26096529 TI - Detection of highly conductive surface electron states in topological crystalline insulators Pb(1-x)SnxSe using laser terahertz radiation. AB - We suggest a method for detection of highly conductive surface electron states including topological ones. The method is based on measurements of the photoelectromagnetic effect using terahertz laser pulses. In contrast to conventional transport measurements, the method is not sensitive to the bulk conductivity. The method is demonstrated on an example of topological crystalline insulators Pb(1-x)SnxSe. It is shown that highly conductive surface electron states are present in Pb(1-x)SnxSe both in the inverse and direct electron energy spectrum. PMID- 26096530 TI - Chemoprotective effects of a recombinant protein from Pyropia yezoensis and synthetic peptide against acetaminophen-induced Chang liver cell death. AB - In the present study, the chemoprotective effects of recombinant Pyropia yezoensis (P. yezoensis) protein 1 (PYP1) were examined in acetaminophen (APAP) treated Chang liver cells. The analysis of P. yezoensis revealed the presence of both mature and immature variants of PYP1. PYP1s, designated as PYP1 (15 kDa), PYP1-AC (12 kDa) and PYP1-B (5 kDa), were successfully expressed in Escherichia coli, and their chemoprotective effects were then examined. In addition, a peptide of 11 residues (ALEGGKSSGGG), which is a common sequence at the N terminus all of the PYP1s, was synthesized and examined. The effects of treatment with PYP1s and the synthetic peptide (SP) on cell proliferation were determined by MTS assay. Our results clearly demonstrated that treatment with all the PYP1s and SP significantly promoted the proliferation of Chang liver cells, protecting them against APAP. Thus, we concluded that recombinant PYP1s exert protective effects against injury to Chang liver cells. PMID- 26096532 TI - Correlation between Pulmonary Artery Pressure Measured by Echocardiography and Right Heart Catheterization in Patients with Rheumatic Mitral Valve Stenosis (A Prospective Study). AB - INTRODUCTION: Right heart catheterization (RHC) remains the gold standard for hemodynamic assessment of the right heart and pulmonary artery. However, this is an invasive tool, and noninvasive alternatives such as transthoracic echocardiography (TTE) are preferable. Nonetheless, the correlation between measurements by TTE and RHC are debated. In this study, we prospectively examined the correlation between systolic and mean pulmonary artery pressures (sPAP and mPAP) measured by RHC and TTE in patients with hemodynamically significant rheumatic mitral stenosis (MS). MATERIAL AND METHODS: Three hundred patients with hemodynamically significant MS undergoing TTE who were scheduled to undergo RHC within 24 hours were analyzed. PAP measurements were taken for all patients by RHC (sPAP(RHC), mPAP(RHC)). Maximum velocity of tricuspid regurgitation (TR) jet obtained by continuous-wave Doppler with adding right atrial (RA) pressure was used for measuring sPAP by TTE (sPAP(TRVmax)). Mean PAP was measured using either pulmonary artery acceleration time (mPAP(PAAT)) method or by adding RA pressure to velocity-time integral of TR jet (mPAP(TRVTI)). RESULTS: A good correlation between sPAP(RHC) and sPAP(TRVmax) (r = 0.89, P < 0.001), between mPAP(RHC) and mPAP(PAAT) (r = 0.9, P < 0.001), and between mPAP(RHC) and mPAP(TRVTI) (r = 0.92, P < 0.001) was found. Sensitivity and specificity of sPAP(TRV) max in detecting pulmonary hypertension (PH) were 92.8% and 86.6% and of mPAP(PAAT) were 94.1% and 73.3%, respectively. CONCLUSION: The noninvasive assessment of sPAP and mPAP by TTE correlates well with invasive measurements and has an acceptable specificity and sensitivity in detecting PH in patients with hemodynamically significant MS. PMID- 26096533 TI - Seven basic dimensions of personality pathology and their clinical consequences: Are all personalities equally harmful? AB - OBJECTIVES: Dimensional pathology models are increasingly being accepted for the assessment of disordered personalities, but their ability to predict negative outcomes is yet to be studied. We examine the relative clinical impact of seven basic dimensions of personality pathology through their associations with a wide range of clinical outcomes. METHODS: A sample of 960 outpatients was assessed through a 7-factor model integrating the Cloninger, the Livesley, and the DSM taxonomies. Thirty-six indicators of clinical outcome covering three areas - dissatisfaction, functional difficulties, and clinical severity - were also assessed. The unique contribution of each personality dimension to clinical outcome was estimated through multiple regressions. RESULTS: Overall, personality dimensions explained 17.6% of the variance of clinical outcome, but varied substantially in terms of their unique contributions. Negative Emotionality had the greatest impact in all areas, contributing 43.9% of the explained variance. The remaining dimensions led to idiosyncratic patterns of clinical outcomes but had a comparatively minor clinical impact. A certain effect was also found for combinations of dimensions such as Negative Emotionality * Impulsive Sensation Seeking, but most interactions were clinically irrelevant. CONCLUSIONS: Our findings suggest that the most relevant dimensions of personality pathology are associated with very different clinical consequences and levels of harmfulness. PRACTITIONER POINTS: The relative clinical impact of seven basic dimensions of personality pathology is examined. Negative Emotionality (Neuroticism) is 6-14 times as harmful as other pathological dimensions. The remaining dimensions and their interactions have very specific and comparatively minor clinical consequences. LIMITATIONS: We examine only a handful of clinical outcomes. Our results may not be generalizable to other clinical or life outcomes. Our variables are self-reported and hence susceptible to bias. Our design does not allow us to establish causal relationships between personality and clinical outcomes. PMID- 26096534 TI - "Hepatitis C treatment turned me around:" Psychological and behavioral transformation related to hepatitis C treatment. AB - BACKGROUND: Hepatitis C (HCV) is a significant public health problem that primarily affects current and former substance users. However, individuals with a history of substance use are less likely to have access to or engage in HCV care. Psychological and behavioral barriers prevent many HCV-infected individuals from initiating or engaging in HCV treatment. This study aimed to investigate the psychological and behavioral experiences of current and former substance users receiving HCV treatment within a combined methadone and primary care clinic in the United States. METHODS: We conducted 31 semi-structured qualitative interviews with opioid-dependent adults enrolled in an integrated HCV treatment program within a methadone maintenance clinic in the Bronx, NY. We used thematic analysis, informed by grounded theory, and inquired about perceptions of HCV before and after initiating HCV treatment, reasons for initiating HCV treatment, and the decision to participate in individual versus group HCV treatment. RESULTS: Participants described psychological and behavioral transformation over the course of HCV treatment. These included reductions in internalized stigma and shame related to HCV and addiction, increases in HCV disclosure and self-care, reductions in substance use, and new desire to help others who are living with HCV. CONCLUSIONS: Integrating HCV treatment with methadone maintenance has the potential to create psychological and behavioral transformations among substance using adults, including reductions in HCV- and addiction-related shame and improvements in overall self-care. PMID- 26096535 TI - Drug use patterns predict risk of non-fatal overdose among street-involved youth in a Canadian setting. AB - BACKGROUND: Non-fatal drug overdose is a major cause of morbidity among people who use drugs, although few studies have examined this risk among street-involved youth. We sought to determine the risk factors associated with non-fatal overdose among Canadian street-involved youth who reported illicit drug use. METHODS: Using data from a prospective cohort of street-involved youth in Vancouver, Canada, we identified youth without a history of overdose and employed Cox regression analyses to determine factors associated with time to non-fatal overdose between September 2005 and May 2012. RESULTS: Among 615 participants, 98 (15.9%) reported a non-fatal overdose event during follow-up, resulting in an incidence density of 7.67 cases per 100 person-years. In multivariate Cox regression analyses, binge drug use (adjusted hazard ratio [AHR]=1.85; 95% confidence interval [CI]=1.20-2.84), non-injection crystal methamphetamine use (AHR=1.70; 95% CI=1.12-2.58), non-injection prescription opiate use (AHR=2.56; 95% CI=1.36-4.82), injection prescription opiate use (AHR=2.49; 95% CI=1.40-4.45) and injection heroin use (AHR=1.85; 95% CI=1.14-3.00) were positively associated with time to non-fatal overdose. Social, behavioural and demographic factors were not significantly associated with time to non-fatal overdose event. CONCLUSIONS: Rates of non-fatal overdose were high among street-involved youth. Drug use patterns, in particular prescription opiate use, were associated with overdose. These findings underscore the importance of addiction treatment and prevention efforts aimed at reducing the risk of overdose among youth. PMID- 26096536 TI - Genetic overlap between alcohol use disorder and bulimic behaviors in European American and African American women. AB - BACKGROUND: Despite substantial evidence that alcohol use disorder (AUD) and bulimic behaviors (i.e., binge eating and compensatory behaviors) co-occur, insufficient information exists regarding a possible shared etiology. Moreover, although numerous twin studies of European ancestry individuals have reported moderate heritability estimates for AUD and bulimic behaviors, with little evidence for shared environmental factors, research on genetic and environmental risk in African American (AA) individuals is lacking. METHODS: We investigated specific and overlapping genetic and environmental influences on AUD and bulimic behaviors in 3232 European American (EA; 55.38% monozygotic) and 549 AA (42.81% monozygotic) young adult female twins from the Missouri Adolescent Female Twin Study (age range=18-29 years). A structured clinical interview assessed lifetime DSM-5 AUD (minus craving) and bulimic behaviors. Biometrical twin modeling was conducted to generate age-adjusted estimates of genetic and environmental influences on AUD, bulimic behaviors, and their comorbidity. RESULTS: Estimates of genetic and environmental contributions on AUD and bulimic behaviors could be equated across EA and AA women. Additive genetic effects accounted for 59% (95% CI: 50%, 66%) and 43% (33%, 52%) of the variance in AUD and bulimic behaviors, respectively, with the remainder due to non-shared environmental effects. Shared genetic factors (rg=.33 (.18, .49)) were solely responsible for the correlation between phenotypes; the non-shared environmental correlation was not significant (re=.10 (-.05, .25)). CONCLUSIONS: Findings indicate similar magnitudes of genetic and environmental effects on AUD and bulimic behaviors for EA and AA women and implicate common genetic mechanisms underlying liability to these problem behaviors. PMID- 26096537 TI - Health insurance coverage and healthcare utilization among infants of mothers in the national methadone maintenance treatment program in Taiwan. AB - BACKGROUND: Children of heroin-using women have a higher risk of unfavorable health and developmental outcomes. Although methadone maintenance treatment (MMT) has been widely used to treat heroin-using pregnant women, potential effects on accessibility and utilization of healthcare service for their offspring are less explored. METHODS: We used four national registry and health insurance datasets in Taiwan from 2004 to 2009 to form a population-based matched retrospective cohort study. A total of 1056 neonates born to women in the MMT program (857 born before mother's enrollment in the MMT program [BM], 199 born after mother's enrollment in the MMT program [AM]) was established; 10547 matched non-drug [ND] exposed neonates were identified for comparison. Outcome variables included offspring's health insurance coverage and utilization of preventive, outpatient, and emergency room cares in the first year after birth. RESULTS: Infants born to mothers on MMT were more likely to have no or incomplete insurance coverage (BM: adjusted odds ratio [aOR]=1.29, 95% CI: 1.10-1.53; AM: aOR=1.56, 95% CI: 1.14 2.13) as compared with the socioeconomic status-matched ND group. The BM infants appeared to have fewer preventive care visits (adjusted relative risk [aRR]=0.85, 95% CI: 0.80-0.90), whereas the AM infants utilized outpatient and emergency room services more frequently (outpatient: aRR=1.11, 95% CI: 1.01-1.23; emergency: aRR=1.46, 95% CI: 1.11-1.90). CONCLUSIONS: Addiction treatment and harm reduction programs for women of childbearing ages should be delivered in the coordinated framework that ensures comprehensiveness and continuity in healthcare and social services. PMID- 26096538 TI - Thiophene, Selenophene, and Tellurophene-based Three-Dimensional Organic Frameworks. AB - 3D frameworks are important because of their potential to combine the advantageous properties of porous materials with those associated with polymers. A series of novel 3D aromatic frameworks are presented that incorporate the heterocycles thiophene, selenophene, and tellurophene. The specific surface area and pore width of frameworks depends on the element that is used to build the framework. Optoelectronic properties are element-dependent, with heavy atoms red shifting the optical properties and decreasing the energy gap of the solid. The metalloid nature of tellurophene allows the properties of this material to be tuned based on its oxidation state, even as an insoluble solid. The incorporation of the optoelectronic active thiophene, selenophene, and tellurophene units and the effect that they have on properties was studied. A supercapcitor device was fabricated using these frameworks, showing that these 3D frameworks are promising for optoelectronic uses. PMID- 26096539 TI - Interleukin-1 as a pharmacological target in acute brain injury. AB - NEW FINDINGS: What is the topic of this review? This review discusses the latest findings on the contribution of inflammation to brain injury, how inflammation is a therapeutic target, and details of recent and forthcoming clinical studies. What advances does it highlight? Here we highlight recent advances on the role and regulation of inflammasomes, and the latest clinical progress in targeting inflammation. Acute brain injury is one of the leading causes of mortality and disability worldwide. Despite this, treatments for acute brain injuries are limited, and there remains a massive unmet clinical need. Inflammation has emerged as a major contributor to non-communicable diseases, and there is now substantial and growing evidence that inflammation, driven by the cytokine interleukin-1 (IL-1), worsens acute brain injury. Interleukin-1 is regulated by large, multimolecular complexes called inflammasomes. Here, we discuss the latest research on the regulation of inflammasomes and IL-1 in the brain, preclinical efforts to establish the IL-1 system as a therapeutic target, and the promise of recent and future clinical studies on blocking the action of IL-1 for the treatment of brain injury. PMID- 26096540 TI - Breastfeeding practices and policies in WHO European Region Member States. AB - OBJECTIVE: To provide an update on current practices and policy development status concerning breastfeeding in the WHO European Region. DESIGN: National surveys and studies conducted by national health institutions were prioritized. Sub-national data were included where no national data or studies existed. Information on national breastfeeding policies was collected mainly from the WHO Seventh Meeting of Baby-Friendly Hospital Initiative Coordinators and European Union projects. Owing to the different data sources and methods, any comparisons between countries must be made with caution. SETTING: WHO European Member States. RESULTS: Data from fifty-three WHO European Member States were investigated; however, a large proportion had not reported any data. Rates of early initiation of breastfeeding, exclusive breastfeeding and continued breastfeeding to 1 year all varied considerably within the WHO European Region. Exclusive breastfeeding rates declined considerably after 4 months, and were low in infants under 6 months and at 6 months of age. The majority of the countries with existing data reported having a national infant and young child feeding policy and the establishment of a national committee on breastfeeding or infant and young child feeding. The majority of the countries with existing data reported having baby friendly hospitals, although the proportion of baby-friendly hospitals to the total number of national hospitals with maternity units was low in most countries. CONCLUSIONS: Breastfeeding practices within the WHO European Region, especially exclusive breastfeeding rates, are far from complying with the WHO recommendations. There are marked differences between countries in breastfeeding practices, infant and young child feeding policy adoption and proportion of baby friendly hospitals. PMID- 26096541 TI - Disrupted brain network topology in pediatric posttraumatic stress disorder: A resting-state fMRI study. AB - Children exposed to natural disasters are vulnerable to the development of posttraumatic stress disorder (PTSD). Recent studies of other neuropsychiatric disorders have used graph-based theoretical analysis to investigate the topological properties of the functional brain connectome. However, little is known about this connectome in pediatric PTSD. Twenty-eight pediatric PTSD patients and 26 trauma-exposed non-PTSD patients were recruited from 4,200 screened subjects after the 2008 Sichuan earthquake to undergo a resting-state functional magnetic resonance imaging scan. Functional connectivity between 90 brain regions from the automated anatomical labeling atlas was established using partial correlation coefficients, and the whole-brain functional connectome was constructed by applying a threshold to the resultant 90 * 90 partial correlation matrix. Graph theory analysis was then used to examine the group-specific topological properties of the two functional connectomes. Both the PTSD and non PTSD control groups exhibited "small-world" brain network topology. However, the functional connectome of the PTSD group showed a significant increase in the clustering coefficient and a normalized characteristic path length and local efficiency, suggesting a shift toward regular networks. Furthermore, the PTSD connectomes showed both enhanced nodal centralities, mainly in the default mode- and salience-related regions, and reduced nodal centralities, mainly in the central-executive network regions. The clustering coefficient and nodal efficiency of the left superior frontal gyrus were positively correlated with the Clinician-Administered PTSD Scale. These disrupted topological properties of the functional connectome help to clarify the pathogenesis of pediatric PTSD and could be potential biomarkers of brain abnormalities. PMID- 26096542 TI - Array-based detection of persistent organic pollutants via cyclodextrin promoted energy transfer. AB - We report herein the selective array-based detection of 30 persistent organic pollutants via cyclodextrin-promoted energy transfer. The use of three fluorophores enabled the development of an array that classified 30 analytes with 100% accuracy and identified unknown analytes with 96% accuracy, as well as identifying 92% of analytes in urine. PMID- 26096543 TI - Analysis of CCR5 and SDF-1 genetic variants and HIV infection in Indian population. AB - HIV-1 infection and progression exhibits interindividual variation. The polymorphism in the chemokine receptors CCR5 and CXCR4, the principal coreceptors for HIV-1 and their ligands like SDF-1 have a profound effect in altering the HIV 1 disease progression rate. A single nucleotide polymorphism designated SDF1 3'UTR-801G-A has been associated with resistance to HIV-1 infection or delayed progression to AIDS. In this study, the SDF1-3'A polymorphism, CCR5?32 polymorphism and CCR5 promoter polymorphism at positions 58934 G/T, 59029 G/A, 59353 T/C, 59356 C/T, 59402 A/G and 59653 C/T were analysed in Indian population. The polymorphisms in HIV-1 patients and healthy individuals were evaluated by conventional PCR, RFLP-PCR and direct sequencing techniques. The CCR5?32 mutant allele was found to be almost absent in Indian population. The analysis of the CCR5-59356C/T polymorphism revealed a trend towards an association of the C allele with an increased risk of HIV-1 infection. The frequency of allele CCR5 59356C was higher in HIV-1 patients (100%) as compared to healthy control subjects (89%, P = 0.003). The correlation of SDF1-3'A and CCR5 promoter CCR5 58934G/T, CCR5-59029G/A, CCR5-59353T/C, CCR5-59402 A/G and CCR5-59653C/T polymorphisms and protection to HIV-1 infection and progression to AIDS was found to be nonsignificant. Nine haplotypes with more than 1% frequency were detected but were not significant in their protective role against HIV. Comparative analysis with global populations showed a noteworthy difference in CCR5 and SDF-1 polymorphisms' frequency distribution, indicating the ethnic variability of Indians. Although susceptibility to infections cannot be completely dependent on one or few genetic variants, it is important to remember that SDF-1 and CCR5 variants have been correlated globally with HIV-1 infection and disease progression. In the light of that, higher frequency of SDF-1 variants in the Indian population is noteworthy. PMID- 26096544 TI - Breaking DNA in plants: how I almost missed my personal breakthrough. PMID- 26096545 TI - Confined polyelectrolytes: The complexity of a simple system. AB - The interaction between polyelectrolytes and counterions in confined situations and the mutual relationship between chain conformation and ion condensation is an important issue in several areas. In the biological field, it assumes particular relevance in the understanding of the packaging of nucleic acids, which is crucial in the design of gene delivery systems. In this work, a simple coarse grained model is used to assess the cooperativity between conformational change and ion condensation in spherically confined backbones, with capsides permeable to the counterions. It is seen that the variation on the degree of condensation depends on counterion valence. For monovalent counterions, the degree of condensation passes through a minimum before increasing as the confining space diminishes. In contrast, for trivalent ions, the overall tendency is to decrease the degree of condensation as the confinement space also decreases. Most of the particles reside close to the spherical wall, even for systems in which the density is higher closer to the cavity center. This effect is more pronounced, when monovalent counterions are present. Additionally, there are clear variations in the charge along the concentric layers that cannot be totally ascribed to polyelectrolyte behavior, as shown by decoupling the chain into monomers. If both chain and counterions are confined, the formation of a counterion rich region immediately before the wall is observed. Spool and doughnut-like structures are formed for stiff chains, within a nontrivial evolution with increasing confinement. PMID- 26096546 TI - Real-time functional magnetic resonance imaging neurofeedback can reduce striatal cue-reactivity to alcohol stimuli. AB - It has been shown that in alcoholic patients, alcohol-related cues produce increased activation of reward-related brain regions like the ventral striatum (VS), which has been proposed as neurobiological basis of craving. Modulating this activation might be a promising option in the treatment of alcohol addiction. One approach might be real-time functional magnetic resonance imaging neurofeedback (rtfMRI NF). This study was set up to implement and evaluate a rtfMRI approach in a group of non-addicted heavy social drinkers. Thirty-eight heavy drinking students were assigned to a real feedback group (rFB, n = 13), a yoke feedback group (yFB, n = 13) and a passive control group (noFB, n = 12). After conducting a reward task as functional localizer to identify ventral striatal regions, the participants viewed alcohol cues during three NF training blocks in a 3 T MRI scanner. The rFB group received feedback from their own and the yFB from another participants' VS. The noFB group received no feedback. The rFB and the yFB groups were instructed to downregulate the displayed activation. Activation of the VS and prefrontal control regions was compared between the groups. We found significant downregulation of striatal regions specifically in the rFB group. While the rFB and the yFB groups showed significant activation of prefrontal regions during feedback, this activation was only correlated to the reduction of striatal activation in the rFB group. We conclude that rtfMRI NF is a suitable method to reduce striatal activation to alcohol cues. It might be a promising supplement to the treatment of alcoholic patients. PMID- 26096547 TI - Thymosin beta4 significantly reduces the signs of dryness in a murine controlled adverse environment model of experimental dry eye. AB - OBJECTIVE: Dry eye syndrome is a common condition that affects up to 20% of the population aged 45 and older. There are no successful treatments to date. The goal of this research was to determine the efficacy of various doses and the optimal frequency of thymosin beta4 (Tbeta4) treatment in a murine severe dry eye model. RESEARCH DESIGN AND METHODS: The study was performed using a controlled adverse environment chamber (CAE) in combination with scopolamine to induce moderate to severe dry eye in mice. The study included five mice per group and tested six different doses of Tbeta4 twice per day for 12 days. Tbeta4 at 0.1% was also administered 2 - 4 times per day for 12 days. Healing was measured by fluorescein staining. MAIN OUTCOME MEASURES: Tbeta4 significantly reduced the signs of dry eye relative to controls. The treatment effect was more pronounced than the positive controls, doxycycline and Restasis (cyclosporine 0.05%). Active doses of 0.1 and 0.5% were determined, and it was found that the frequency of dosing at 2 times per day was the most effective for healing. CONCLUSIONS: Tbeta4 has the potential to be an important new effective therapeutic for dry eye. PMID- 26096548 TI - Flavonoid profiles of immature and mature fruit tissues of Citrus grandis Osbeck (Dangyuja) and overall contribution to the antioxidant effect. PMID- 26096551 TI - 57(th) Annual Scientifi c Meeting of the American Headache Society. PMID- 26096550 TI - Diagnostic SNPs reveal widespread introgressive hybridization between introduced bighead and silver carp in the Mississippi River Basin. AB - Hybridization among conspecifics in native and introduced habitats has important implications for biological invasions in new ecosystems. Bighead (Hypophthalmichthys nobilis) and silver carp (H. molitrix) are genetically isolated and occur in sympatry within their native range. Following their introduction to North America, however, introgressant hybrids have been reported throughout their expanded range within the Mississippi River Basin (MRB). The extent of introgression, both spatially and generationally, is largely unknown. Therefore, we examined mixed-species populations from across the MRB to characterize the extent of interspecific gene flow. We assayed 2798 individuals from nine locations with a suite of species-diagnostic SNPs (57 nuclear and one mitochondrial). Forty-four per cent (n = 1244) of individuals displayed hybrid genotypes. Moreover, the composition of hybrid genotypes varied among locations and represented complex hybrid swarms with multiple generations of gene flow. Introgressive hybrids were identified from all locations, were bidirectional and followed a bimodal distribution consisting primarily of parental or parental-like genotypes and phenotypes. All described hybrid categories were present among individuals from 1999 to 2008, with parents and later-generation backcrosses representing the largest proportion of individuals among years. Our mitochondrial SNP (COII), tested on a subset of 730 individuals, revealed a silver carp maternal bias in 13 of 21 (62%) F1 hybrids, in all silver carp backcrosses, and maintained throughout many of the bighead carp backcrosses. The application of this suite of diagnostic markers and the spatial coverage permits a deeper examination of the complexity in hybrid swarms between two invasive, introduced species. PMID- 26096553 TI - Layered evolution in the immune system: a view from history. AB - Although much had still to be learned, evidence indicating that B-1a lymphocytes very likely belonged to a distinct lineage was largely in place by the time of the first large B-1a conference in 1991. The widely respected group of immunologists attending that meeting (including Tasuko Honjo and Klaus Rajewsky) developed and ultimately published the B-1a notation still in use today. Here, I briefly review some of the early B-1a findings that underlie current studies. I close with a brief summary of recent studies, mainly from my laboratory, showing that the hematopoietic stem cell (HSC) we all know and love as the origin of the cells that populate the adult lymphoid and myeloid system today is nonetheless not the origin of the B-1a lymphocytes with which most of us work today. PMID- 26096552 TI - Time-Dependent Influence of Cell Membrane Permeability on MR Diffusion Measurements. AB - PURPOSE: To investigate the influence of cell membrane permeability on diffusion measurements over a broad range of diffusion times. METHODS: Human myelogenous leukemia K562 cells were cultured and treated with saponin to selectively alter cell membrane permeability, resulting in a broad physiologically relevant range of 0.011-0.044 MUm/ms. Apparent diffusion coefficient (ADC) values were acquired with the effective diffusion time (Deltaeff ) ranging from 0.42 to 3000 ms. Cosine-modulated oscillating gradient spin echo (OGSE) measurements were performed to achieve short Deltaeff from 0.42 to 5 ms, while stimulated echo acquisitions were used to achieve long Deltaeff from 11 to 2999 ms. Computer simulations were also performed to support the experimental results. RESULTS: Both computer simulations and experiments in vitro showed that the influence of membrane permeability on diffusion MR measurements is highly dependent on the choice of diffusion time, and it is negligible only when the diffusion time is at least one order of magnitude smaller than the intracellular exchange lifetime. CONCLUSION: The influence of cell membrane permeability on the measured ADCs is negligible in OGSE measurements at moderately high frequencies. By contrast, cell membrane permeability has a significant influence on ADC and quantitative diffusion measurements at low frequencies such as those sampled using conventional pulsed gradient methods. PMID- 26096554 TI - Design and methods of the national Vietnam veterans longitudinal study. AB - The National Vietnam Veterans Longitudinal Study (NVVLS) is the second assessment of a representative cohort of US veterans who served during the Vietnam War era, either in Vietnam or elsewhere. The cohort was initially surveyed in the National Vietnam Veterans Readjustment Study (NVVRS) from 1984 to 1988 to assess the prevalence, incidence, and effects of post-traumatic stress disorder (PTSD) and other post-war problems. The NVVLS sought to re-interview the cohort to assess the long-term course of PTSD. NVVLS data collection began July 3, 2012 and ended May 17, 2013, comprising three components: a mailed health questionnaire, a telephone health survey interview, and, for a probability sample of theater Veterans, a clinical diagnostic telephone interview administered by licensed psychologists. Excluding decedents, 78.8% completed the questionnaire and/or telephone survey, and 55.0% of selected living veterans participated in the clinical interview. This report provides a description of the NVVLS design and methods. Together, the NVVRS and NVVLS constitute a nationally representative longitudinal study of Vietnam veterans, and extend the NVVRS as a critical resource for scientific and policy analyses for Vietnam veterans, with policy relevance for Iraq and Afghanistan veterans. PMID- 26096555 TI - Involvement of glucocorticoid in induction of lingual T1R3 in rodents. AB - We previously reported that in rats, chronic exposure to stress inhibits the induction of the common receptor (T1R3) for sweet and umami tastes. Here, we investigated whether endogenous glucocorticoids (GCs) might be responsible for this inhibition. In addition, we used mouse taste-bud cells (TB cells) expressing T1R3 to examine the effect of exogenous GC on T1R3 induction. Both adrenal glands were removed from rats [adrenalectomized (ADX) rats] and T1R3 mRNA expression in fungiform papillae was examined by real-time RT-PCR. T1R3 mRNA expression was significantly reduced in the ADX rats (versus sham-ADX rats). The reduced mRNA expression was restored to the level seen in the sham-ADX rats by administration of dexamethasone (DEX) at the smallest dose tested (0.1ng/kg, i.p.). However, with larger doses of DEX (10 and 1000ng/kg, i.p.) there was no such restoration (i.e., the expression level did not differ from that seen in ADX rats). Expression of the mRNA for the GC receptor-alpha was detected in mouse TB cells by RT-PCR. Significantly reduced T1R3 mRNA expression, as measured by real-time RT-PCR, was observed in TB cells at 24h after application of DEX (0.1, 1.0, or 10MUM). These results suggest that in rodents: (a) a low concentration of endogenous GC is necessary and sufficient for induction of T1R3 expression, and that higher concentrations may actually inhibit such induction, and (b) this inhibitory effect may be due, at least in part, to a direct action of GC on taste cells. PMID- 26096556 TI - Drug induced hypertension--An unappreciated cause of secondary hypertension. AB - Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. PMID- 26096557 TI - Obstructive sleep apnea syndrome, continuous positive airway pressure and treatment of hypertension. AB - Obstructive sleep apnea (OSA), present in ~15% of the general population, increases the risks of stroke, heart failure, and premature death. Importantly, individuals with cardiovascular disease have a higher prevalence yet they often have few symptoms to alert clinicians to its presence. OSA with an apnea-hypopnea index (AHI) >=15 events/hour is present in >=30% of patients with primary hypertension and in up to 80% of those with drug resistant hypertension, suggesting that the neural, hormonal, inflammatory and vascular cascades triggered by OSA may elevate blood pressure chronically. The purpose of this review is to summarize: (1) the epidemiology of OSA and its relation to cardiovascular risk; (2) potential mechanisms by which OSA could promote conditions known to increase the risk of hypertension or contribute to its development and progression; (3) evidence for and against a pro-hypertensive effect of OSA; and, (4) the impact of treatment with continuous positive airway pressure (CPAP) on blood pressure and blood pressure-related morbidities. The prevailing view that the effect of treatment on blood pressure is modest arises from the inability of most contemporary technology to measure accurately the true impact of CPAP on OSA-entrained surges in nocturnal blood pressure. Moreover the exclusive focus on blood pressure, as if this is the principal determinant of cardiovascular event rates in this population, is naive. The capacity to reduce cardiovascular risk by treating OSA with CPAP likely transcends a simple blood pressure effect; formal testing of this hypothesis will require adequately powered randomized clinical trials. PMID- 26096558 TI - About the gut microbiome as a pharmacological target in atherosclerosis. AB - The contribution of intestinal bacterial strains (gut microbiota) in the development of cardiometabolic disease is increasingly recognized as potential diagnostic and pharmacological target. Changes in the intestinal bacterial composition and subsequent altered diversity has been associated with presence of chronic low-grade inflammation of mesenteric visceral adipose tissue, a known feature of malign obesity which can eventually lead to insulin resistance and type 2 diabetes mellitus. However, causality still needs to be proven. In this regard, both fecal transplantation studies as well as multiethnic prospective cohorts can help to identify the causally involved driving intestinal bacterial strains in human cardiometabolism. Ultimately, it is expected that novel diagnostic markers as well as therapeutics (pharmabiotics and vaccine strategies) can be developed. PMID- 26096559 TI - Two Reaction Mechanisms via Iminium Ion Intermediates: The Different Reactivities of Diphenylprolinol Silyl Ether and Trifluoromethyl-Substituted Diarylprolinol Silyl Ether. AB - The reactions of alpha,beta-unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michael-type reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers, which are widely used proline-type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl-substituted catalyst is more reactive in a type B reaction. The iminium ion from an alpha,beta-unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael-type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl-substituted diarylprolinol silyl ether catalyst is preferred for type B reactions. PMID- 26096560 TI - Patient demographics and cardiovascular risk factors differentially influence geometric remodeling of the aorta compared with the peripheral arteries. AB - BACKGROUND: Detailed knowledge of the dimensions and shape of the main arteries of the body and how they change with age and disease is important for understanding arterial pathophysiology and improving minimally invasive devices to treat arterial diseases. Our goal was to describe and compare geometric remodeling of the aorta and peripheral arteries in the context of patient demographics and cardiovascular risk factors. METHODS: Three-dimensional reconstructions of computed tomography angiography scans were performed in 122 subjects 5-93 years of age (mean 47 +/- 24 years, 64 M/58 F). Best-fit arterial diameters, lengths, and tortuosity for the principle named arteries in the chest, abdomen, pelvis, and upper thigh were measured, and multiple linear regression analysis was performed to examine how these morphologic parameters associate with patient demographics and risk factors. RESULTS: Large elastic arteries increased their diameter, length, and tortuosity with age, whereas muscular arteries primarily became more tortuous. Demographics and risk factors explained >70% of the variation in diameters of the abdominal aorta, paravisceral aorta, and the aortic arch; and >75% of variation in tortuosity from the profunda femoris to the brachiocephalic artery. Male sex, larger body mass index, and hypertension contributed to larger diameters, whereas the presence of diabetes was associated with somewhat-straighter arteries. Overall, the effects of cardiovascular risk factors on geometric remodeling were small compared with those of demographics. CONCLUSION: The geometry of the vascular tree is greatly affected by aging, demographics, and some risk factors. Elastic and muscular arteries remodel differently, possibly as the result of differences in their microstructure. PMID- 26096561 TI - Sentinel lymph node biopsy is prognostic but not therapeutic for thick melanoma. AB - BACKGROUND: Sentinel lymph node biopsy (SNB) as a staging and therapeutic procedure in melanomas 1-4 mm in thickness has been investigated extensively, however, the clinical value of SNB in thick melanomas is poorly understood. METHODS: Patients undergoing operation for clinically node-negative melanoma >4 mm in depth between 2003 and 2010 were identified in the Surveillance Epidemiology and End Results registry. Two groups were constructed: one with a wide excision with SNB and the other with wide excision alone. RESULTS: A total of 4,571 patients with clinically node-negative, thick melanoma were identified. The median age was 71 years, 96.9% were white, and 64.3% were male. SNB was performed in 2,746 (60.1%) and was positive in 32.2%. Univariate analysis demonstrated SNB was associated with younger age (64 vs 75 years; P < .001) and extremity primaries (P < .0001). On logistic regression, advanced age (P < .001), female sex (P = .009), and location in the head and neck region (P < .001) were associated with observation. On log-rank analysis, improved 5-year disease specific survival (DSS) was associated with SNB (65 vs 62%; P = .008), location in the extremity versus head and neck or trunk (67 vs 61.5 and 60.3%; P = .004), female sex (69 vs 61%; P < .001), and no ulceration (74 vs 54%; P < .001). On Cox regression analysis, advanced age (P < .001), male sex (P = .01), trunk location (P = .0001), and ulceration (P < .001) continued to be associated with DSS. SNB was not associated with survival (P = .20). SNB status was a robust predictor of survival; a negative SNB had a 5-year DSS of 75.3 versus 44.1% (P < .0001), with a positive node. CONCLUSION: For patients with clinically node-negative, thick melanoma, SNB is a staging but not therapeutic procedure. PMID- 26096562 TI - Successful implantation of an engineered tubular neuromuscular tissue composed of human cells and chitosan scaffold. AB - BACKGROUND: There is an urgent need for gut lengthening secondary to massive resections of the gastrointestinal tract. In this study, we propose to evaluate the remodeling, vascularization, and functionality of a chitosan-based, tubular neuromuscular tissue on subcutaneous implantation in the back of athymic rats. METHODS: Aligned innervated smooth muscle sheets were bioengineered with the use of human smooth muscle and neural progenitor cells. The innervated sheets were wrapped around tubular chitosan scaffolds. The engineered tubular neuromuscular tissue was implanted subcutaneously in the back of athymic rats. The implant was harvested after 14 days and assessed for morphology, vascularization, and functionality. RESULTS: Gross examination of the implants showed healthy color with no signs of inflammation. The implanted tissue became vascularized as demonstrated by gross and histologic analysis. Chitosan supported the luminal patency of the tissue. The innervated muscle remodeled around the tubular chitosan scaffold. Smooth muscle maintained its circumferential alignment and contractile phenotype. The functionality of the implant was characterized further by the use of real-time force generation. A cholinergic response was demonstrated by robust contraction in response to acetylcholine. Vasoactive intestinal peptide , and electrical field stimulation-caused relaxation. In the presence of neurotoxin tetrodotoxin, the magnitude of acetylcholine-induced contraction and vasoactive intestinal peptide-induced relaxation was attenuated whereas electrical field stimulation-induced relaxation was completely abolished, indicating neuronal contribution to the response. CONCLUSION: Our results indicated the successful subcutaneous implantation of engineered tubular neuromuscular tissues. The tissues became vascularized and maintained their myogenic and neurogenic phenotype and function, which provides potential therapeutic prospects for providing implantable replacement GI segments for treating GI motility disorders. PMID- 26096563 TI - Assessment of postdischarge complications after bariatric surgery: A National Surgical Quality Improvement Program analysis. AB - BACKGROUND: Little is reported about postdischarge complications after bariatric surgery. We sought to identify the rates of postdischarge complications, associated risk factors, and their influence on early hospital readmission. METHODS: Using the database of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) (2005-2013), we identified patients >=18 years of age who underwent a bariatric operation with a primary diagnosis of morbid/severe obesity and a body mass index >=35. The incidence of postdischarge complication was the primary outcome, and hospital readmission was the secondary outcome. The association between postdischarge complications and various patient factors was explored by the use of multivariable logistic regression. RESULTS: A total of 113,898 patients were identified with an overall postdischarge complication rate of 3.2% within 30 days of operation. The rates decreased from 2005 to 2006 (4.6%) to 2013 (3.0%) (P < .001). On average, postdischarge complications occurred 10 days postoperatively, with wound infection (49.4%), reoperation (30.7%), urinary tract infection (16.9%), shock/sepsis (12.4%), and organ space surgical-site infection (11.0%) being the most common. Patients undergoing open gastric bypass had the greatest postdischarge complication rate of 8.5%. Of those patients experiencing postdischarge complications, 51.6% were readmitted. The overall readmission rate was 4.9%. The factors associated most strongly with increased odds of postdischarge complications were body mass index >= 50, use of steroids, procedure type, predischarge complication, prolonged duration of stay, and prolonged operative time. CONCLUSION: Postdischarge complications after bariatric surgery represent a substantial source of patient morbidity and hospital readmissions. The majority of postdischarge complications are infection-related, including surgical-site infections and catheter-associated urinary tract infections. Adopting and implementing standardized pre- and postoperative strategies to decrease perioperative infection may help to decrease the rate of postdischarge complications and associated readmissions and enhance overall quality of care. PMID- 26096564 TI - Organ quality metrics are a poor predictor of costs and resource utilization in deceased donor kidney transplantation. AB - BACKGROUND: The desire to provide cost-effective care has lead to an investigation of the costs of therapy for end-stage renal disease. Organ quality metrics are one way to attempt to stratify kidney transplants, although the ability of these metrics to predict costs and resource use is undetermined. METHODS: The Scientific Registry of Transplant Recipients database was linked to the University HealthSystem Consortium Database to identify adult deceased donor kidney transplant recipients from 2009 to 2012. Patients were divided into cohorts by kidney criteria (standard vs expanded) or kidney donor profile index (KDPI) score (<85 vs 85+). Length of stay, 30-day readmission, discharge disposition, and delayed graft function were used as indicators of resource use. Cost was defined as reimbursement based on Medicare cost/charge ratios and included the costs of readmission when applicable. RESULTS: More than 19,500 patients populated the final dataset. Lower-quality kidneys (expanded criteria donor or KDPI 85+) were more likely to be transplanted in older (both P < .001) and diabetic recipients (both P < .001). After multivariable analysis controlling for recipient characteristics, we found that expanded criteria donor transplants were not associated with increased costs compared with standard criteria donor transplants (risk ratio [RR] 0.97, 95% confidence interval [CI] 0.93-1.00, P = .07). KDPI 85+ was associated with slightly lower costs than KDPI <85 transplants (RR 0.95, 95% CI 0.91-0.99, P = .02). When KDPI was considered as a continuous variable, the association was maintained (RR 0.9993, 95% CI 0.999-0.9998, P = .01). CONCLUSION: Organ quality metrics are less influential predictors of short term costs than recipient factors. Future studies should focus on recipient characteristics as a way to discern high versus low cost transplantation procedures. PMID- 26096565 TI - Cancer nanomedicine: addressing the dark side of the enhanced permeability and retention effect. PMID- 26096566 TI - Special Issue: Flavins and Flavoproteins: Introduction. PMID- 26096567 TI - Oncolytic Adenovirus Coated with Multidegradable Bioreducible Core-Cross-Linked Polyethylenimine for Cancer Gene Therapy. AB - Recently, adenovirus (Ad) has been utilized as a viral vector for efficient gene delivery. However, substantial immunogenicity and toxicity have obstructed oncolytic Ad's transition into clinical studies. The goal of this study is to generate an adenoviral vector complexed with multidegradable bioreducible core cross-linked polyethylenimine (rPEI) polymer that has low immunogenicity and toxicity while having higher transduction efficacy and stability. We have synthesized different molecular weight rPEIs and complexed with Ad at varying molar ratios to optimize delivery of the Ad/polymer complex. The size and surface charge of Ad/rPEIs were characterized. Of note, Ad/rPEIs showed significantly enhanced transduction efficiency compared to either naked Ad or Ad/25 kDa PEI in both coxsackievirus and adenovirus receptor (CAR) positive and negative cancer cells. The cellular uptake result demonstrated that the relatively small size of Ad/16 kDa rPEIs (below 200 nm) was more critical to the complex's internalization than its surface charge. Cancer cell killing effect and viral production were significantly increased when oncolytic Ad (RdB/shMet, or oAd) was complexed with 16 kDa rPEI in comparison to naked oAd-, oAd/25 kDa PEI-, or oAd/32 kDa rPEI treated cells. This increased anticancer cytotoxicity was more readily apparent in CAR-negative MCF7 cells, implying that it can be used to treat a broad range of cancer cells. Furthermore, A549 and HT1080 cancer cells treated with oAd/16 kDa rPEI had significantly decreased Met and VEGF expression compared to either naked oAd or oAd/25 kDa PEI. Overall, these results demonstrate that shMet expressing oncolytic Ad complexed with multidegradable bioreducible core-cross linked PEI could be used as efficient and safe cancer gene therapy. PMID- 26096568 TI - Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases. AB - PURPOSE: Assessment of ocular involvement in transthyretin-related familial amyloidosis with polyneuropathy (FAP) in a large cohort of Portuguese patients. METHODS: We reviewed the medical records of 513 Portuguese FAP mutation carriers, at the Ophthalmology Service, Centro Hospitalar do Porto, between 1 January 2008 and 31 January 2013. Abnormal conjunctiva vessels (ACV), Schirmer test, tear break-up time (TBUT), amyloid deposition on the iris (DAI), scalloped iris, amyloid deposition on the anterior capsule of the lens (DAL), vitreous amyloidosis, retinal amyloid angiopathy and glaucoma were evaluated and registered. RESULTS: Of the 513 carriers, 477 (93%) had clinical systemic disease with a median duration of 9.3 (5.1-13.7) years and 247 were men. Of these, 343 (72%) had been liver transplanted, on median of 6.6 (3.3-10.8) years before inclusion in this study. No ocular abnormalities were identified in the asymptomatic carriers (7%). The abnormalities observed with decreasing frequency were abnormal TBUT (379 patients, 79.5%, 751 eyes), abnormal Schirmer test (320 patients, 67%, 635 eyes), DAI (183 patients, 38.4%, 350 eyes), DAL (157 patients, 32.9%, 308 eyes), scalloped iris (133 patients, 27.9%, 238 eyes), glaucoma (97 patients, 20%, 165 eyes), vitreous amyloidosis (83 patients, 17.4%, 139 eyes), ACV (68 patients, 14%, 136 eyes) and amyloidotic retinal angiopathy (21 patients, 4%, 32 eyes). Patients with abnormal Schirmer test (p < 0.001), scalloped iris (p = 0.006) and vitreous amyloidosis (p = 0.007) were significantly older than the others. According to their age of onset of systemic disease, the patients have been split into early-onset (<40 years old), intermediate-onset (40-50 years old), late onset (>50 years old) and asymptomatic carriers. We observed a statistically significant difference in the prevalence of ACV (p = 0.045) and of an abnormal Schirmer test (p = 0.004) between groups. Transplanted patients have a significantly higher prevalence of DAI (p = 0.001), DAL (p = 0.009) and vitreous amyloidosis (p = 0.025) than non-transplanted patients. Of the 165 eyes with glaucoma, 92.1% had scalloped iris (p < 0.001) and of 32 eyes with retinal amyloidotic angiopathy, 68.8% had vitreous amyloidosis (p < 0.001). All prevalences increased with time of disease. The earliest ocular manifestations were abnormal Schirmer test and abnormal TBUT (12% and 17% at 5 years of clinical disease) and the least prevalent was retinal amyloid angiopathy (8% at 15 years of clinical disease). CONCLUSION: Ocular disorders in FAP patients are common, and their prevalence increases with disease duration. Prevalence is influenced by several factors, such as the age at onset of FAP and liver transplantation. PMID- 26096569 TI - DQ2, DQ7 and DQ8 Distribution and Clinical Manifestations in Celiac Cases and Their First-Degree Relatives. AB - HLA-linked genes are relevant to celiac disease (CD); the potential genetic differences present worldwide are not fully understood. Previous results suggest that the distribution of HLA-DQ2/DQ7/DQ8 in Chile may differ from that in Europe and North America. In celiac patients and their first-degree relatives (FDRS), we assessed their clinical, serological and histological characteristics, determined HLA-DQ2, HLA-DQ7 and HLA-DQ8 alleles and genotypes, and evaluated the relations between them. A total of 222 individuals were assessed (56 cases, 166 FDRs). 16.9% of FDRs were tTG positive; 53.6% of them showed overweight/obesity and 3% undernourishment; they spontaneously declared being asymptomatic, but detailed questioning revealed that 60.7% experienced symptoms, which had not been investigated. DQ2 was present in 53.9% and 43.9.0% of cases and FDRs (p < 0.05). The most frequent genotype distribution was DQ2/DQ7 (fr 0.392 (cases) and 0.248 (FDRs), respectively, p < 0.02). The next most common genotypes were HLA-DQ2/DQ8 (fr 0.236 in FDRs and 0.176 in cases, p < 0.05). 3.92% cases were not HLA-DQ2/DQ8 carriers. Among tTG positive FDRs, 57.4%, 22.3% and 20.2% carried DQ2, DQ7 and DQ8, respectively. In cases, 72.7% of the biopsies classified Marsh >= 3 carried at least one DQ2; 91.7% of DQ2/DQ2 and 88.3% of DQ2/DQ7 were Marsh >= 3. Thus, DQ2 frequency is lower than reported; the higher frequency found for DQ8 and DQ7 concur with recent publications from Argentine and Brazil. These results suggest that although CD may manifest clinically in ways similar to those described in other populations, some genetic peculiarities in this region deserve further study. PMID- 26096570 TI - Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts' Criteria. AB - Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts' recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally. PMID- 26096571 TI - Linear mixed-effects model of QTc prolongation for olmesartan medoxomil. PMID- 26096572 TI - Temporal kinetics of macrophage polarization in the injured rat spinal cord. AB - Local activated macrophages derived from infiltrating monocytes play an important role in the damage and repair process of spinal cord injury (SCI). The present study investigates the dynamic change of classically activated proinflammatory (M1) and alternatively activated anti-inflammatory (M2) cells in a rat model with contusive SCI by flow cytometry (FCM) and immunohistochemistry. The macrophage subsets were immunophenotyped by using antibodies against cluster of differentiation (CD)-68, C-C chemokine receptor type 7 (CCR7), CD163, and arginase 1 (Arg1). The CD68(+) CD163(-) and CD68(+) CCR7(+) cells were determined to be M1 subsets, whereas the CD68(+) CD163(+) and CD68(+) Arg1(+) cell subpopulations represented M2 cells. The subsets of macrophages in the injured spinal cord at 1, 3, 5, 7, 14, and 28 days postinjury (dpi) were examined. In the sham-opened spinal cord, few M1 or M2 cells were found. After SCI, the phenotypes of both M1 and M2 cells were rapidly induced. However, M1 cells were detected and maintained at a high level for up to 28 dpi (the longest time evaluated in this study). In contrast, M2 cells were transiently detected at high levels before 7 dpi and returned to preinjury levels at 14 dpi. These results indicate that M1 cell response is rapidly induced and sustained, whereas M2 induction is transient after SCI in rat. Increasing the fraction of M2 cells and prolonging their residence time in the injured local microenvironment is a promising strategy for the repair of SCI. PMID- 26096573 TI - Establishment and Evaluation of the Novel Tetramethylammonium-L-Hydroxyproline Chiral Ionic Liquid Synergistic System Based on Clindamycin Phosphate for Enantioseparation by Capillary Electrophoresis. AB - Much attention has been paid to chiral ionic liquids (ILs) in analytical chemistry, especially its application in capillary electrophoresis (CE) enantioseparation. However, the investigation of chiral ionic liquids synergistic systems based on antibiotic chiral selectors has been reported in only one article. In this work, a novel chiral ionic liquid, tetramethylammonium-L hydroxyproline (TMA-L-Hyp), was applied for the first time in CE chiral separation to evaluate its potential synergistic effect with clindamycin phosphate (CP) as the chiral selector. As observed, significantly improved separation was obtained in this TMA-L-Hyp/CP synergistic system compared to TMA-L Hyp or a CP single system. Several primary factors that might influence the separation were investigated, including CP concentration, TMA-L-Hyp concentration, buffer pH, types and concentrations of organic modifier, applied voltage, and capillary temperature. The best results were obtained with a 40 mM borax buffer (pH 7.6) containing 30 mM TMA-L-Hyp, 80 mM CP, and 20% (v/v) methanol, while the applied voltage and temperature were set at 20 kV and 20 degrees C, respectively. PMID- 26096574 TI - Oviposition by Spodoptera exigua on Nicotiana attenuata primes induced plant defence against larval herbivory. AB - Plants exhibit multifarious defence traits against herbivory that are constitutively expressed or induced upon attack. Insect egg deposition often precedes impending larval attack, and several plants can increase their resistance against larvae after experiencing the oviposition by an herbivore. The nature of such oviposition-mediated resistance remains unknown, and here we aim to determine plant traits that explain it. We test whether oviposition on a host plant can induce plant defence responses or enhance (prime) the induction of defence traits in response to larval herbivory. We exposed Nicotiana attenuata plants to oviposition by moths of a generalist herbivore, Spodoptera exigua. Its larvae suffered higher mortality, retarded development and inflicted less feeding damage on oviposition-experienced than on oviposition-unexperienced plants. While oviposition alone did not induce any of the examined defence traits, oviposited plants exhibited a stronger inducibility of known defence traits, i.e. caffeoylputrescine (CP) and trypsin protease inhibitors (TPIs). We found no effects of oviposition on phytohormone levels, but on the feeding-inducible accumulation of the transcription factor NaMyb8 that is governing biosynthesis of phenylpropanoid-polyamine conjugates, including CP. Comparison of larval performance on wild-type plants, CP-deficient plants (silenced NaMyb8 gene), and TPI-deficient plants (silenced NaPI gene) revealed that priming of plant resistance to larvae by prior oviposition required NaMyb8-mediated defence traits. Our results show that plants can use insect egg deposition as a warning signal to prime their feeding-induced defence. PMID- 26096575 TI - [Vaccines against varicella-zoster virus (VZV)]. AB - In Western countries, two attenuated varicella vaccines derived from the OKA strain are licensed: Varilrix(r) GlaxoSmithKline (OKA/RIT strain) and Varivax(r) Merck Sharp and Dohme (OKA/Merck strain). Currently, in Spain, varicella vaccination is only included in the Ministry of Health, Social Services and Equality official vaccination calendar for administration in adolescents who have not had the disease. Given the good results obtained in Navarra and Madrid with universal administration of the vaccine in children, it would be desirable to include the vaccine in the routine immunization schedule, with the administration of two doses at 15-18 months of age in the future. The protective efficacy of the attenuated herpes zoster vaccine was evaluated in the Shingles Prevention Study, which showed that in the short term (0-4 years) the vaccine reduced the incidence of herpes zoster by 53%, post-herpetic neuralgia by 66%, and the disease burden in immunocompetent persons aged >=60 years by 61%. Another study demonstrated protective efficacy in persons aged 50-59 years. Over time, the protective efficacy decreases, but remains at acceptable levels, especially for post herpetic neuralgia and the disease burden. Recently, the results of a controlled clinical trial (phase III) conducted in 18 countries to assess the protective efficacy of the inactivated subunit vaccine (glycoprotein E) adjuvanted with the adjuvant AS01B were published. The study inferred that the vaccine significantly reduced the incidence of herpes zoster in the short term (3.2 years) in people aged >=50 years. Vaccine protection did not decrease with age at vaccination, ranging between 96.8% and 97.9% in all age groups. PMID- 26096577 TI - Equol, a Metabolite of Daidzein, Is More Efficient than Daidzein for Bone Formation in Growing Female Rats. AB - Few studies have examined the effects of isoflavones and particularly equol, a metabolite of the isoflavone daidzein, on bone formation during the growth period in animals. The present study investigated the effects of orally administered daidzein or equol on bone formation and bone mineral density in growing female rats. Female Sprague-Dawley rats, aged 3 weeks, were divided into four groups (n = 8 per group) as follows: rats were orally administered a corn oil, 8 mg/day of daidzein, 4 mg/day of equol or 8 mg/day of equol in corn oil for 4 weeks. Daidzein and equol increased the bone mineral density of growing female rats by stimulating bone formation without exhibiting a substantial effect on the weight of their reproductive organs. Bone growth caused by increased bone mineralizing surface and bone formation rate in rats administered with equol was approximately twice that of rats administered with daidzein. These results suggest that equol might be more efficient than daidzein for bone formation in growing female rats. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096576 TI - Luteolin exerts an anticancer effect on NCI-H460 human non-small cell lung cancer cells through the induction of Sirt1-mediated apoptosis. AB - Luteolin is a falconoid compound, which exhibits anticancer properties, however, its contribution to Sirt1-mediated apoptosis in human non-small cell lung cancer remains to be elucidated. The present study confirmed that the anticancer effect of luteolin on NCI-H460 cells was through Sirt1-mediated apoptosis. The NCI-H460 cells were treated with different concentrations of luteolin, and a 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphnyl-2H-tetrazolium bromide assay, cell cycle analysis and annexin-V/fluorescein isothiocyanate and propidium double staining were performed to assess the apoptotic effect of luteolin. Wound healing and Transwell assays were performed to confirm the inhibition of NCI-H460 cell migration. The protein levels of Sirt1 were knocked down in the NCI-H460 cells using a lentivirus to further investigate the role of this protein, and the expression levels of the apoptotic associated proteins, Bad, Bcl-2, Bax, caspase 3 and Sirt1, were measured using western blotting. The results of the present study demonstrated that luteolin exerted an anticancer effect against NCI-H460 cells through Sirt1-mediated apoptosis and the inhibition of cell migration. PMID- 26096578 TI - Frequency of body dysmorphic disorder among patients with complaints of hair loss. AB - BACKGROUND: Body dysmorphic disorder (BDD) is a psychiatric condition in which a disabling preoccupation with a non-existent or slight defect in appearance is the main symptom. Hair concerns are frequent in patients with BDD. OBJECTIVES: The purpose of this study was to determine the prevalence of BDD among patients with complaints of hair loss. METHODS: A validated BDD questionnaire (BDDQ) was administered to 150 patients with complaints of hair loss and 150 control subjects who were selected from among general dermatology (GD) patients. Standard statistical tests were performed (descriptive analysis, chi-squared tests, non parametric tests). Differences that achieved a P-value of <0.05 were considered statistically significant. RESULTS: Among patients with complaints of hair loss, 42 of 142 subjects retained in the study (29.6%; 31 females and 11 males) were diagnosed with BDD. Furthermore, 25.6% of female patients and 52.4% of male patients were diagnosed with BDD (P = 0.013). Hair concerns were more common in males than in females (P < 0.05). In the GD group, four control subjects (2.7%, all female) were diagnosed with BDD; all of their concerns focused on the body and acne. CONCLUSIONS: The incidence of BDD is about 10 times higher in patients with complaints of hair loss than it is in GD patients and is higher in males. Awareness of the condition and the referral of selected patients to mental health professionals is crucial. PMID- 26096579 TI - Neutral red-mediated microbial electrosynthesis by Escherichia coli, Klebsiella pneumoniae, and Zymomonas mobilis. AB - The aim of this work was to compare the effects of electrosynthesis on different bacterial species. The effects of neutral red-mediated electrosynthesis on the metabolite profiles of three microorganisms: Escherichia coli, Klebsiella pneumoniae, and Zymomonas mobilis, were measured and compared and contrasted. A statistically comprehensive analysis of neutral red-mediated electrosynthesis is presented using the analysis of end-product profiles, current delivered, and changes in cellular protein expression. K. pneumoniae displayed the most dramatic response to electrosynthesis of the three bacteria, producing 93% more ethanol and 76% more lactate vs. control fermentation with no neutral red and no electron delivery. Z. mobilis showed no response to electrosynthesis except elevated acetate titers. Stoichiometric comparison showed that NAD(+) reduction by neutral red could not account for changes in metabolites during electrosynthesis. Neutral red-mediated electrosynthesis was shown to have multifarious effects on the three species. PMID- 26096580 TI - A 90-liter stackable baffled microbial fuel cell for brewery wastewater treatment based on energy self-sufficient mode. AB - A 90-liter stackable pilot microbial fuel cell was designed and proved to be capable for brewery wastewater treatment and simultaneous electricity harvested. The system was stacked by 5 easily-stackable modules, and operated in an energy self-sufficient manner for more than 6 months. Tests were conducted under two different influent strengths (diluted wastewater, stage 1; raw wastewater, stage 2). The COD, SS removal efficiencies were 84.7% and 81.7% at stage 1, 87.6% and 86.3% at stage 2. The system produced enough energy (0.056 kWh/m(3) at stage 1, 0.097 kWh/m(3) at stage 2) to power the pumping system (0.027 kWh/m(3) at both stages), net electrical energy of 0.021 kWh/m(3) and 0.034 kWh/m(3) were harvested. These results show that this pilot-scale system could be used to effectively treat real wastewater with zero energy input. PMID- 26096581 TI - Adaptive introgression as a resource for management and genetic conservation in a changing climate. AB - Current rates of climate change require organisms to respond through migration, phenotypic plasticity, or genetic changes via adaptation. We focused on questions regarding species' and populations' ability to respond to climate change through adaptation. Specifically, the role adaptive introgression, movement of genetic material from the genome of 1 species into the genome of another through repeated interbreeding, may play in increasing species' ability to respond to a changing climate. Such interspecific gene flow may mediate extinction risk or consequences of limited adaptive potential that result from standing genetic variation and mutation alone, enabling a quicker demographic recovery in response to changing environments. Despite the near dismissal of the potential benefits of hybridization by conservation practitioners, we examined a number of case studies across different taxa that suggest gene flow between sympatric or parapatric sister species or within species that exhibit strong ecotypic differentiation may represent an underutilized management option to conserve evolutionary potential in a changing environment. This will be particularly true where advanced generation hybrids exhibit adaptive traits outside the parental phenotypic range, a phenomenon known as transgressive segregation. The ideas presented in this essay are meant to provoke discussion regarding how we maintain evolutionary potential, the conservation value of natural hybrid zones, and consideration of their important role in adaptation to climate. PMID- 26096582 TI - Effects on Symptoms of Agitation and Depression in Persons With Dementia Participating in Robot-Assisted Activity: A Cluster-Randomized Controlled Trial. AB - OBJECTIVES: To examine effects on symptoms of agitation and depression in nursing home residents with moderate to severe dementia participating in a robot-assisted group activity with the robot seal Paro. DESIGN: A cluster-randomized controlled trial. Ten nursing home units were randomized to either robot-assisted intervention or a control group with treatment as usual during 3 intervention periods from 2013 to 2014. SETTING: Ten adapted units in nursing homes in 3 counties in eastern Norway. PARTICIPANTS: Sixty residents (67% women, age range 62-95 years) in adapted nursing home units with a dementia diagnosis or cognitive impairment (Mini-Mental State Examination score lower than 25/30). INTERVENTION: Group sessions with Paro took place in a separate room at nursing homes for 30 minutes twice a week over the course of 12 weeks. Local nurses were trained to conduct the intervention. MEASUREMENTS: Participants were scored on baseline measures (T0) assessing cognitive status, regular medication, agitation (BARS), and depression (CSDD). The data collection was repeated at end of intervention (T1) and at follow-up (3 months after end of intervention) (T2). Mixed models were used to test treatment and time effects. RESULTS: Statistically significant differences in changes were found on agitation and depression between groups from T0 to T2. Although the symptoms of the intervention group declined, the control group's symptoms developed in the opposite direction. Agitation showed an effect estimate of -5.51, CI 0.06-10.97, P = .048, and depression -3.88, CI 0.43-7.33, P = .028. There were no significant differences in changes on either agitation or depression between groups from T0 to T1. CONCLUSION: This study found a long-term effect on depression and agitation by using Paro in activity groups for elderly with dementia in nursing homes. Paro might be a suitable nonpharmacological treatment for neuropsychiatric symptoms and should be considered as a useful tool in clinical practice. PMID- 26096583 TI - Isolated case of mucosal histoid Hansen's disease of the nasal cavity in a post global elimination era. AB - Histoid Hansen's disease is a rare form of multibacillary leprosy with distinct clinical and histopathological features. This type of leprosy is a variant of lepromatous leprosy with a very high bacterial reserve. Of alarming concern is the discovery of an isolated mucosal histoid leprotic lesion inside the nasal cavity of a patient in the post-global leprosy elimination era. Our case had no history of leprosy or exposure to dapsone/multidrug therapy but had a heavy bacillary index. We are reporting this case to highlight the rarity of mucosal lesions due to histoid leprosy and involvement of the nasal cavity, as well as to create awareness and avoid misdiagnosis. This will help facilitate prompt treatment to minimize the complications and deformities of the patient and prevent its spread throughout the community. PMID- 26096585 TI - New type of excitatory pulse coupling of chemical oscillators via inhibitor. AB - We introduce a new type of pulse coupling between chemical oscillators. A constant inflow of inhibitor in one reactor is interrupted shortly after a time delay after a sharp spike of activity in the other reactor. We proved experimentally and theoretically that this reversed inhibitory coupling is analogous to excitatory coupling. We did this by analyzing phase response curves, dependences of different synchronous regimes of the 1 : 1 resonance on time delay, and other resonances of two coupled chemical oscillators. Dynamical rhythms of two Belousov-Zhabotinsky oscillators coupled via "negative" inhibitory pulses were investigated. PMID- 26096584 TI - Pseudotumor associated with cemented bipolar hemiarthroplasty: an unusual presentation as a granulomatous thigh mass. AB - Although polyethylene wear-induced osteolysis is a common complication of hip arthroplasty, extensile osteolysis developing into a large granulomatous thigh mass at a site distant from the joint is rare. We report a case of a thigh pseudotumor 25 years after cemented bipolar hemiarthroplasty, in which x-rays revealed a radiolucent line around the stem at the proximal site only, not at the diaphysis of the femur. We initially suspected a real tumor because it had a unique appearance, as if the mass resorbed the posterior cortex of the femur, and it was located at a site distant from the proximal osteolytic lesions. We clearly showed the existence of a connection between the thigh mass and the joint space by performing intra-articular injection of contrast medium with continuous pressure. It seemed that polyethylene wear particles were transported distally along the stem-cement interface by fluid pressure, and an osteolytic reaction against polyethylene wear particles had occurred at the posterior middle third of the stem where the cement mantle was nonuniform and polyethylene particles first came into contact with the bone. Our findings suggest that nonuniform cemented prosthesis with osteolysis, even if it is low grade in a limited area, carries the risk of extensile osteolysis with asymptomatic development of an extra articular granulomatous mass. PMID- 26096586 TI - Is Self-Reported Sleep Duration Associated with Osteoporosis? Data from a 4-Year Aggregated Analysis from the National Health and Nutrition Examination Survey. AB - OBJECTIVES: To examine the association between self-reported sleep duration and osteoporosis in a national sample of the U.S. elderly population. DESIGN: Population-based cross-sectional study. SETTING: Four-year National Health and Nutrition Examination Survey data from two survey cycles between 2005-06 and 2007 08. PARTICIPANTS: Men and women aged 50 and older with data in the surveys and medical examination data files (N = 5,288). MEASUREMENTS: Osteoporosis diagnosis was based on bone mineral density measurement and self-report. Sleep duration was ascertained from the sleep survey. Simple and multiple logistic regression models were used to evaluate the association between these two factors. RESULTS: Shorter sleep duration (<6 hours) was found to be significantly associated with osteoporosis after adjusting for potential covariates (odds ratio (OR) = 1.59, 95% confidence interval (CI) = 1.07-2.37). After stratifying according to age group, this association remained significant (OR = 1.80, 95% CI = 1.20-2.68) only in the older age group (>65). CONCLUSION: These results underscore the possible linkage between sleep and osteoporosis and the need for additional research on this topic. PMID- 26096588 TI - Sudden acquired retinal degeneration syndrome (SARDS) - a review and proposed strategies toward a better understanding of pathogenesis, early diagnosis, and therapy. AB - Sudden acquired retinal degeneration syndrome (SARDS) is one of the leading causes of currently incurable canine vision loss diagnosed by veterinary ophthalmologists. The disease is characterized by acute onset of blindness due to loss of photoreceptor function, extinguished electroretinogram with an initially normal appearing ocular fundus, and mydriatic pupils which are slowly responsive to bright white light, unresponsive to red, but responsive to blue light stimulation. In addition to blindness, the majority of affected dogs also show systemic abnormalities suggestive of hyperadrenocorticism, such as polyphagia with resulting obesity, polyuria, polydipsia, and a subclinical hepatopathy. The pathogenesis of SARDS is unknown, but neuroendocrine and autoimmune mechanisms have been suggested. Therapies that target these disease pathways have been proposed to reverse or prevent further vision loss in SARDS-affected dogs, but these treatments are controversial. In November 2014, the American College of Veterinary Ophthalmologists' Vision for Animals Foundation organized and funded a Think Tank to review the current knowledge and recently proposed ideas about disease mechanisms and treatment of SARDS. These panel discussions resulted in recommendations for future research strategies toward a better understanding of pathogenesis, early diagnosis, and potential therapy for this condition. PMID- 26096589 TI - Identifying ecological corridors for Amur tigers (Panthera tigris altaica) and Amur leopards (Panthera pardus orientalis). AB - The rapid explosion of human populations and the associated development of human dominated landscapes have drastically reduced and fragmented habitat for tigers (Panthera tigris) and leopards (Panthera pardus) across Asia, resulting in multiple small populations. However, Amur tiger (Panthera tigris altaica) habitat in Russia has remained largely interconnected, except for a break between tigers in southwest Primorye and the southern Sikhote-Alin Mountains. This habitat patch in southwest Primorye also retains the last population of Amur leopards (Panthera pardus orientalis). Genetic differentiation of tigers in southwest Primorye and the Sikhote-Alin Mountains along with survey data suggest that habitat fragmentation is limiting movement of tigers and leopards across the Razdolnaya River basin. We looked at historical and recent survey data on tigers and leopards and mapped existing cover types to examine land-use patterns of both large felids and humans in the development strip along the Razdolnaya River. We then used least-cost distance analyses to identify the most effective potential corridor to retain connectivity for large felids between Land of the Leopard National Park and Ussuriskii Zapovednik (Reserve). We identified a single potential corridor that still exists with a total distance of 62.5 km from Land of the Leopard National Park to Ussuriskii Zapovednik, mostly (93%) through forested habitat. We recommend formal recognition of a Razdolnaya ecological corridor and provide specific recommendations for each of 3 proposed management sections. PMID- 26096587 TI - Transcriptional programs regulated by both LEAFY and APETALA1 at the time of flower formation. AB - Two key regulators of the switch to flower formation and of flower patterning in Arabidopsis are the plant-specific helix-turn-helix transcription factor LEAFY (LFY) and the MADS box transcription factor APETALA1 (AP1). The interactions between these two transcriptional regulators are complex. AP1 is both a direct target of LFY and can act in parallel with LFY. Available genetic and molecular evidence suggests that LFY and AP1 together orchestrate the switch to flower formation and early events during flower morphogenesis by altering transcriptional programs. However, very little is known about target genes regulated by both transcription factors. Here, we performed a meta-analysis of public datasets to identify genes that are likely to be regulated by both LFY and AP1. Our analyses uncovered known and novel direct LFY and AP1 targets with a role in the control of onset of flower formation. It also identified additional families of proteins and regulatory pathways that may be under transcriptional control by both transcription factors. In particular, several of these genes are linked to response to hormones, to transport and to development. Finally, we show that the gibberellin catabolism enzyme ELA1, which was recently shown to be important for the timing of the switch to flower formation, is positively feedback-regulated by AP1. Our study contributes to the elucidation of the regulatory network that leads to formation of a vital plant organ system, the flower. PMID- 26096591 TI - QRS Duration Changes in Patients with Single Ventricle Physiology: Birth to 10 Years. AB - BACKGROUND: QRS prolongation may be a predictor of mortality in certain forms of congenital heart disease. Minimal data exist describing changes in QRS duration in patients with single ventricles (SVs). The goal was to describe changes in QRS duration in patients with SV and to determine if differences existed between single right ventricle (sRV) versus single left ventricle (sLV) patients. METHODS: Chart review was performed on patients with SV physiology. Patients were divided into sRV and sLV groups. QRS durations were measured monthly for the first 6 months, at 1 year, and then yearly until 10 years. t-tests were used for analysis. RESULTS: One hundred sixty patients were evaluated (95 sRV, 65 sLV). The greatest change in QRS duration for the entire cohort occurred in the first 6 months of life versus 6 months to 10 years of age (1.81 ms/month vs 0.20 ms/month). sRV QRS durations were significantly longer than sLV QRS durations at 1 year (78.9 +/- 12.6 ms vs 73.2 +/- 11.9 ms), 2 year (81.7 +/- 14.7 ms vs 73.4 +/- 12.5 ms), 4 year (84.2 +/- 12.1 ms vs 77.9 +/- 16.4 ms), 6 year (90.8 +/- 12.7 ms vs 83.4 +/- 13.4 ms), 7 year (90.8 +/- 16.5 ms vs 81.2 +/- 16.6 ms), and 8 year (96.7 +/- 13.6 ms vs 84.8 +/- 13.9 ms) time points. CONCLUSION: The greatest change in QRS duration in SV patients occurred in the first 6 months of life when these patients' ventricles were volume loaded. Differences in QRS duration between sRV and sLV patients occurred early in life. Further studies are needed to determine if minimizing volume load early in life decreases the rate of change in QRS duration. PMID- 26096590 TI - Recurrent Kawasaki disease: USA and Japan. AB - BACKGROUND: Descriptive epidemiologic studies of recurrent and non-recurrent Kawasaki disease (KD) may identify other potentially important differences between these illnesses. METHODS: Data from the USA and Japan, the Centers for Disease Control and Prevention (CDC) national KD surveillance(1984-2008) and the 17th Japanese nationwide survey (2001-2002), respectively, were analyzed to examine recurrent KD patients <18 years of age meeting the CDC KD case or atypical KD case definition. These patients were compared with non-recurrent KD patients. RESULTS: Of the 5557 US KD patients <18 years of age during 1984-2008, 97 (1.7%) were identified as having had recurrent KD. Among the US Asian/Pacific Islander KD patients, 3.5% had recurrent KD, which was similar to the percentage identified among KD patients (3.5%) in the Japanese survey. Compared with non recurrent KD patients, KD patients [with recurrent KD] were more likely to be older, fulfill the atypical KD case definition, and have coronary artery abnormalities (CAA) despite i.v. immunoglobulin (IVIG) treatment. CONCLUSIONS: Differences in the age, race, and frequency of CAA exist between recurrent and non-recurrent KD patients. The increased association of CAA with recurrent KD suggests that more aggressive treatment strategies in conjunction with IVIG may be indicated for the second episode of KD. PMID- 26096592 TI - Computational modeling of shear forces and experimental validation of endothelial cell responses in an orbital well shaker system. AB - Vascular endothelial cells are continuously exposed to hemodynamic shear stress. Intensity and type of shear stress are highly relevant to vascular physiology and pathology. Here, we modeled shear stress distribution in a tissue culture well (R = 17.5 mm, fill volume 2 ml) under orbital translation using computational fluid dynamics with the finite element method. Free surface distribution, wall shear stress, inclination angle, drag force, and oscillatory index on the bottom surface were modeled. Obtained results predict nonuniform shear stress distribution during cycle, with higher oscillatory shear index, higher drag force values, higher circular component, and larger inclination angle of the shear stress at the periphery of the well compared with the center of the well. The oscillatory index, inclination angle, and drag force are new quantitative parameters modeled in this system, which provide a better understanding of the hydrodynamic conditions experienced and reflect the pulsatile character of blood flow in vivo. Validation experiments revealed that endothelial cells at the well periphery aligned under flow and increased Kruppel-like Factor 4 (KLF-4), cyclooxygenase-2 (COX-2) expression and endothelial nitric oxide synthase (eNOS) phosphorylation. In contrast, endothelial cells at the center of the well did not show clear directional alignment, did not induce the expression of KLF-4 and COX 2 nor increased eNOS phosphorylation. In conclusion, this improved computational modeling predicts that the orbital shaker model generates different hydrodynamic conditions at the periphery versus the center of the well eliciting divergent endothelial cell responses. The possibility of generating different hydrodynamic conditions in the same well makes this model highly attractive to study responses of distinct regions of the same endothelial monolayer to different types of shear stresses thereby better reflecting in vivo conditions. PMID- 26096593 TI - A Perspective on the Scientific Registry of Transplant Recipients' Migration to Bayesian Methods. PMID- 26096594 TI - The "Mechanostat Theory" of Frost and the OPG/RANKL/RANK System. AB - Frost's great interest to elucidate the principles of action underlying skeletal deformities, during, and after growth, urged him to undertake an extensive study of the mammalian skeleton. He suggested that survival of the skeleton (but also of other tissues, such as fibrous tissue, hyaline cartilage, fibrocartilage, cementum, or dentin) requires the functional coordination of modeling and remodeling. Modeling adapts bone to overloads, by enhancing additions of new bone and by changing bone architecture, and remodeling adapts bone to underloads by removing bone next to marrow and conserving normally used bone. There exists a mechanism that monitors bone metabolism (longitudinal growth, bone modeling, and remodeling activities) in relation to mechanical usage, the "mechanostat." Recent literature has presented new information regarding the physiological procedure of osteoclast and osteoblast activation. It has been understood that the OPG/RANKL/RANK proteinic system regulates bone metabolism by exerting biological effects on osteoblasts or osteoclasts. The same proteinic network, also regulates alveolar remodeling during tooth movement, as well as physiological root resorption and root resorption during orthodontic tooth movement. The aim of the present review is the presentation and evaluation of recent information in the field of osteoclast and osteoblast biology, as regards to the "mechanostat theory" of Frost. An attempt will be made to elucidate, whether recent data can support this remarkable theory and reveal the biological mechanisms behind it. PMID- 26096595 TI - FACTORS ASSOCIATED WITH INDISCRIMINATE FRIENDLINESS IN HIGH-RISK CHILDREN. AB - Indiscriminate friendliness (IF) refers to a lack of reticence with strangers and is well-documented in neglected children. This risky behavior is distinct from attachment insecurity, and persists when parenting/caregiving improves. A previous review has suggested that caregiving quality is not associated with IF. This review aimed to explore factors associated with IF and whether quality of caregiving is important. Ten articles were reviewed using the S.H. Downs and N. Black (1998) Checklist for randomized and nonrandomized studies. Overall quality was high. Results showed that IF is present in fostered populations and postinstitutionalized children. Attachment security was not associated with IF. Length of time in institution and inhibitory control were associated with IF. Inhibitory control moderated the association between IF and number of caregivers. Genetic factors predispose children to IF and may impact on persistence. Quality of caregiving was associated with IF. Emotional availability (i.e., the degree to which carer and child are able to respond to each other's emotional signals) predicted IF. Limitations across studies included heterogeneity in IF measurement and unreliable measures of preadoptive care. Parenting may be a useful target for intervention. Future research should focus on developing a standardized measure of IF as well as evaluating a parental intervention. PMID- 26096596 TI - Pituitary specific retinoid-X receptor ligand interactions with thyroid hormone receptor signaling revealed by high throughput reporter and endogenous gene responses. AB - Disruption of thyroid hormone (TH) signaling can compromise vital processes both during development and in the adult. We previously reported on high-throughput screening experiments for man-made TH disruptors using a stably integrated line of rat pituitary cells, GH3.TRE-Luc, in which a thyroid hormone receptor (TR) response element drives luciferase (Luc) expression. In these experiments, several retinoid/rexinoid compounds activated the reporter. Here we show that all trans and 13-cis retinoic acid appear to function through the heterodimer partners of TRs, retinoid-X receptors (RXRs), as RXR antagonists abrogated retinoid-induced activation. The retinoids also induced known endogenous TR target genes, showing good correlation with Luc activity. Synthetic RXR-specific agonists significantly activated all tested TR target genes, but interestingly, retinoid/rexinoid activation was more consistent between genes than the extent of T3-induced activation. In contrast, the retinoids neither activated the Luc reporter construct in transient transfection assays in the human hepatocarcinoma cell line HuH7, nor two of the same T3-induced genes examined in pituitary cells. These data demonstrate the suitability and sensitivity of GH3.TRE-Luc cells for screening chemical compound libraries for TH disruption and suggest that the extent of disruption can vary on a cell type and gene-specific bases, including an underappreciated contribution by RXRs. PMID- 26096597 TI - Resistance to the atypical retinoid ST1926 in SK-N-AS cells selected the subline rAS-ST with enhanced sensitivity to ATRA mediated by not conventional mechanisms: DNA damage, G2 accumulation and late telomerase inhibition. AB - BACKGROUND AND PURPOSE: 13-cis-Retinoic acid represents a well-established clinical strategy for the management of minimal residual disease of high risk neuroblastoma (NB) patients. However, the clinical efficacy on the overall survival of these patients remains limited, addressing the issue of better understanding the molecular mechanisms and intracellular pathways mediating Retinoic Acid (RA) clinical effects. EXPERIMENTAL APPROACH: This work investigates the mechanism underlying the sensitivity/resistance to RA in NB by taking advantage of the paired SK-N-AS/rAS-ST cells showing different responsivity to ATRA. The subline rAS-ST was selected by inducing resistance to the novel retinoid ST1926 in the NB SK-N-AS cell line. KEY RESULTS: Resistance to ST1926 was neither dependent on cellular uptake nor on multi-drug resistance phenotype. Rather, both delayed/lower DNA damage and apoptosis appeared involved in reduced sensitivity of rAS-ST cells to ST1926. This subline showed enhanced responsivity to ATRA compared to the wt counterpart, that was associated with enhanced RARalpha/beta expression, DNA damage, G2 accumulation, PI3K/AKT pathway inhibition, cellular differentiation and delayed telomerase inhibition, without involvement of either p27/p53 or caspase-mediated apoptosis. CONCLUSIONS AND IMPLICATIONS: The present data add important information to the understanding of RA sensitivity in NB, providing further insights towards a more efficacious clinical use of this drug. PMID- 26096598 TI - Evaluation of an air-liquid interface cell culture model for studies on the inflammatory and cytotoxic responses to tobacco smoke aerosols. AB - In vitro toxicological studies for tobacco product assessment have traditionally been undertaken using the particulate phase of tobacco smoke. However, this does not truly reflect exposure conditions that occur in smokers. Thus in vitro cell culture systems are required in which cells are exposed to tobacco whole smoke (WS) at the air-liquid interface (ALI). In this study bronchial epithelial cells were cultured on semi-permeable membranes, transitioned to the ALI and the robustness and sensitivity of the cells to tobacco WS and vapour phase (VP) assessed. Although no effect of air exposure was observed on cell viability, IL-6 and IL-8 release was increased. Exposure to WS resulted in a significant dose dependent decrease in cell viability and a significant non-dose dependent increase in inflammatory mediator secretion. The VP was found to contribute approximately 90% of the total cytotoxicity derived from WS. The cell culture system was also able to differentiate between two smoking regimens and was sensitive to passage number with increased inflammatory mediator secretion and lower cell viability observed in cell cultures of low passage number following WS exposure. This simple cell culture system may facilitate studies on the toxicological impact of future tobacco products and nicotine delivery devices. PMID- 26096599 TI - Homing in on consciousness in the nervous system: An action-based synthesis. AB - What is the primary function of consciousness in the nervous system? The answer to this question remains enigmatic, not so much because of a lack of relevant data, but because of the lack of a conceptual framework with which to interpret the data. To this end, we have developed Passive Frame Theory, an internally coherent framework that, from an action-based perspective, synthesizes empirically supported hypotheses from diverse fields of investigation. The theory proposes that the primary function of consciousness is well-circumscribed, serving the somatic nervous system. For this system, consciousness serves as a frame that constrains and directs skeletal muscle output, thereby yielding adaptive behavior. The mechanism by which consciousness achieves this is more counterintuitive, passive, and "low level" than the kinds of functions that theorists have previously attributed to consciousness. Passive frame theory begins to illuminate (a) what consciousness contributes to nervous function, (b) how consciousness achieves this function, and (c) the neuroanatomical substrates of conscious processes. Our untraditional, action-based perspective focuses on olfaction instead of on vision and is descriptive (describing the products of nature as they evolved to be) rather than normative (construing processes in terms of how they should function). Passive frame theory begins to isolate the neuroanatomical, cognitive-mechanistic, and representational (e.g., conscious contents) processes associated with consciousness. PMID- 26096601 TI - Insights into endosomal maturation of human holo-transferrin in the enteric parasite Entamoeba histolytica: essential roles of Rab7A and Rab5 in biogenesis of giant early endocytic vacuoles. AB - The pathogenic amoeba Entamoeba histolytica is one of the causative agents of health hazards in tropical countries. It causes amoebic dysentery, colitis and liver abscesses in human. Iron is one of the essential nutritional resources for survival and chronic infection caused by the amoeba. The parasite has developed multiple ways to import, sequester and utilize iron from various iron-binding proteins from its host. In spite of its central role in pathogenesis, the mechanism of iron uptake by the parasite is largely unknown. Here, we carried out a systematic study to understand the role of some of the amoebic homologues of mammalian endocytic Rab GTPases (Rab5 and Rab21, Rab7A and Rab7B) in intracellular transport of human holo-transferrin by the parasite. Flow cytometry and quantitative microscopic image analysis revealed that Rab5 and Rab7A are required for the biogenesis of amoebic giant endocytic vacuoles (GEVs) and regulate the early phase of intracellular trafficking of transferrin. Rab7B is involved in the late phase, leading to the degradation of transferrin in the amoebic lysosome-like compartments. Using time-lapse fluorescence imaging in fixed trophozoites, we determined the kinetics of the vesicular transport of transferrin through Rab5-, Rab7A- and Rab7B-positive compartments. The involvement of Rab7A in the early phase of endocytosis by the parasite marks a significant divergence from its host in terms of spatiotemporal regulation by the Rab GTPases. PMID- 26096602 TI - Radiofrequency ablation in high-risk stage I non-small cell lung cancer. PMID- 26096600 TI - The Swedish CArdioPulmonary BioImage Study: objectives and design. AB - Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started. PMID- 26096603 TI - Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophy. AB - Nuclear receptor subfamily 4, group A, member 3 (NR4A3), also known as neuron derived orphan receptor-1, is a nuclear receptor which plays key roles in cell cycle, neuronal differentiation, apoptosis and metabolism. These processes may be involved in the pathogenesis of certain neurodegenerative diseases. Previous studies have shown that there are high levels of NR4A3 mRNA in the CNS. Moreover, NR4A2, a transcription factor with homology to NR4A3, has been reported to contribute to the pathogenesis of Parkinson's disease. However, it is uncertain whether NR4A3 is also involved in diseases such as dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative disorders such as tauopathies, TDP-43 proteinopathies and polyglutamine diseases. In the present study we used immunohistochemistry to examine the brain and spinal cord from patients with various neurodegenerative diseases and normal control subjects using two polyclonal anti-NR4A3 antibodies. In controls, the cytoplasm of neurons and glial cells was faintly immunostained with anti-NR4A3 antibodies. In tissues from patients with neurodegenerative diseases, immunoreactivity for NR4A3 was observed in cortical and brainstem-type Lewy bodies in Parkinson's disease and in dementia with Lewy bodies, as well as in neuronal and glial cytoplasmic inclusions in multiple system atrophy. A double-labeled immunofluorescence study showed co-localization of NR4A3 and phosphorylated alpha-synuclein in these inclusions. Neuronal and glial inclusions in other neurodegenerative disorders were NR4A3 negative. These findings suggest that accumulation of NR4A3 is specific to alpha-synucleinopathy. PMID- 26096604 TI - ERbeta localization influenced outcomes of EGFR-TKI treatment in NSCLC patients with EGFR mutations. AB - Effects of estrogen receptorbeta (ERbeta) localization on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) are unknown. First, we analyzed the relationship between ERbeta localization determined by immunohistochemistry and EGFR-TKI outcomes in 184 patients with advanced NSCLC and found that ERbeta expression localized in the cytoplasm and/or nucleus. The frequency of cytoplasmic ERbeta (c-ERbeta) and nuclear ERbeta (n-ERbeta) co-expression was 12% (22/184). C-ERbeta and n-ERbeta co-expression was correlated with poor median progression-free survival compared to patients without co-expression. In subsequent in vitro experiments, PC9 cells transfected with ERbeta isoform1 (ERbeta1, strong expression of both c-ERbeta and n-ERbeta) were more resistant to gefitinib than PC9 cells transfected with ERbeta isoform2 or 5 (ERbeta2 or ERbeta5, strong expression of ERbeta in cytoplasm but not nucleus). Resistance was identified due to interactions between ERbeta1 and other isoforms, and mediated by activation of non-genomic pathways. Moreover, gefitinib resistance was reversed by a combination treatment with gefitinib and fulvestrant, both in cell lines and in one NSCLC patient. These results suggested that c-ERbeta and n-ERbeta co-expression was a potential molecular indicator of EGFR-TKI resistance, which might be overcome by combining EGFR-TKI and ER antagonist. PMID- 26096605 TI - Unfavorable Outcome of Thrombolysis in Chinese Patients with Cardioembolic Stroke: a Prospective Cohort Study. AB - BACKGROUND: Thrombolysis with alteplase is an effective and safe treatment for acute ischemic stroke (AIS). It is controversial whether the outcome of thrombolysis in cardioembolic stroke is different from that of other stroke subtypes. This study compares the outcomes at 3 months postthrombolysis in Chinese patients with AIS secondary to cardioembolism (CE) to the outcomes of those with large-artery atherosclerosis (LAA). METHODS: Using the Thrombolysis Implementation and Monitoring of Acute Ischemic Stroke in China (TIMS-China) cohort, we prospectively followed 827 patients treated within 4.5 h of onset symptoms with alteplase as an intravenous thrombolytic agent. CE and LAA were defined according to TOAST criteria. We compared symptomatic intracerebral hemorrhage (SICH), mortality, and functional outcome at 3 months using multivariables logistic regression analysis. RESULTS: In this cohort, 221 (19.6%) had CE and 606 (53.7%) had LAA. Approximately 2/3 of patients with CE had atrial fibrillation. Symptoms at onset were more severe in patients with CE than in those with LAA (NIHSS, 15.0 vs. 11.0; P < 0.0001); increased rate of SICH (5.9% vs. 0.8%; P < 0.0001); higher mortality (18.6% vs. 10.3%; P = 0.0015); and reduced functional independence (43.6% vs. 55.9%; P = 0.0018) at 3-month follow up. After adjustment for baseline variables, the clinical outcome of patients with CE was worse than that of patients with LAA (OR, 0.62; 95% CI, 0.39 to 0.97, P = 0.0378). CONCLUSIONS: Patients with cardioembolic stroke had more SICH after thrombolysis, and worse clinical outcome at 3-month follow-up compared with those with LAA. This emphasizes the importance of preventing cardioembolism. PMID- 26096606 TI - No association between CYP17 -34T/C polymorphism and insulin resistance in Thai polycystic ovary syndrome. AB - AIM: To investigate the association of CYP 17 -34T/C polymorphism with insulin resistance (IR) in Thai polycystic ovary syndrome (PCOS). METHODS: A cross sectional study was performed on 210 Thai women diagnosed with PCOS. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze CYP17 polymorphism at -34T/C. Student's t-test was used to compare the mean of normally distributed variables between A1/A1 and A2/X. Chi-squared or Fisher's exact tests and OR were used to analyze the association at P < 0.05. RESULTS: Out of 210 cases, PCR-RFLP was successful in 199. Mean patient age was 24.4 +/- 4.7 years, with body mass index 25.2 +/- 6.3 kg/m(2) . There were 65 and 134 women in the A1/A1 genotype group and A2/X genotype group, respectively. The A2/X genotype group was statistically significantly younger and had a strong trend toward overweight/obesity compared with the A1/A1 genotype group. The prevalence of IR according to different methods varied from 15.4% to 70.8% and was not different between the two groups. On subgroup analysis, in the overweight/obese PCOS group, the A2/X genotype was not associated with any indices of IR. CONCLUSION: No significant association between CYP17-34T/C polymorphism and IR was found in Thai PCOS women, although the A2/X genotype group was statistically significantly younger than the A1/A1 genotype group. PMID- 26096607 TI - Telomere Dysfunction and Cell Senescence in Chronic Lung Diseases: Therapeutic Potential. AB - Cellular senescence--defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes--might play a causal role in various lung diseases, including chronic obstructive pulmonary disease (COPD), which is predicted to become the third leading cause of death worldwide by 2020. COPD is characterized by slowly progressive airflow obstruction and emphysema due to destruction of the lung parenchyma and is often complicated by pulmonary hypertension (PH). No curative treatment is available. Senescent cells, which accumulate with age, are increased in lungs from patients with COPD and express a robust senescence-associated secretory phenotype (SASP), which is proinflammatory. The aim of this review is to show how senescent cells can drive the lung alterations seen in COPD, which mechanisms may be involved, and whether therapeutic interventions may slow or delay the in vitro cell-senescence process and in vivo lung alterations. PMID- 26096608 TI - How much ablation to eliminate atrial fibrillation: Is less more, or is more more? PMID- 26096609 TI - SCD-HeFT: Use of R-R interval statistics for long-term risk stratification for arrhythmic sudden cardiac death. AB - BACKGROUND: In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), a significant fraction of the patients with congestive heart failure ultimately did not die suddenly of arrhythmic causes. Patients with CHF will benefit from better tools to identify if implantable cardioverter-defibrillator (ICD) therapy is needed. OBJECTIVES: We aimed to identify predictor variables from baseline SCD HeFT patients' R-R intervals that correlate to arrhythmic sudden cardiac death (SCD) and mortality and to design an ICD therapy screening test. METHODS: Ten predictor variables were extracted from prerandomization Holter data from 475 patients enrolled in the ICD arm of the SCD-HeFT by using novel and traditional heart rate variability methods. All variables were correlated to SCD using the Mann-Whitney-Wilcoxon test and receiver operating characteristic analysis. ICD therapy screening tests were designed by minimizing the cost of false classifications. Survival analysis, including log-rank test and Cox models, was also performed. RESULTS: A short-term fractal exponent, alpha1, and a long-term fractal exponent, alpha2, from detrended fluctuation analysis, the ratio of low- to high-frequency power, the number of premature ventricular contractions per hour, and the heart rate turbulence slope are all statistically significant for predicting the occurrences of SCD (P < .001) and survival (log-rank, P < .01). The most powerful multivariate predictor tool using the Cox proportional hazards regression model was alpha2 with a hazard ratio of 0.0465 (95% confidence interval 0.00528-0.409; P < .01). CONCLUSION: Predictor variables extracted from R-R intervals correlate to the occurrences of SCD and distinguish survival functions among patients with ICDs in SCD-HeFT. We believe that SCD prediction models should incorporate Holter-based R-R interval analysis to refine ICD patient selection, especially to exclude patients who are unlikely to benefit from ICD therapy. PMID- 26096610 TI - Temporal trends and sex differences in pulmonary vein isolation for patients with atrial fibrillation. AB - BACKGROUND: Indications for pulmonary vein isolation for the treatment of atrial fibrillation (AF) have expanded over the years. OBJECTIVE: We aimed to describe trends in demographic and clinical characteristics of patients undergoing ablation, with a particular focus on sex differences. METHODS: Patients who underwent first AF ablation between 2003 and 2012 were identified within an AF cohort by using Quebec administrative databases. Descriptive statistics and multivariable analysis were used to examine sex differences and temporal trends in demographic and clinical characteristics, as well as independent predictors of the ablation procedure. RESULTS: A total of 2438 of 173,689 patients in the AF cohort underwent AF ablation. In the span of 10 years, the rate of AF ablation increased from 8.5 to 57.2 per million persons-an almost 7-fold increase. Patients undergoing ablation were younger than patients in the general AF cohort (57.4 +/- 12.2 years vs 75.3 +/- 12.0 years) and had fewer baseline comorbidities (56.7% vs 88.4%). Representing 42.9% of the general AF cohort, the annual proportion of women in the AF ablation cohort has not surpassed 30%, and men had a higher likelihood of undergoing ablation than did women (odds ratio 1.54; 95% confidence interval 1.40-1.69). Over the decade of observation, there were slight increases in patient age, comorbidities, and CHADS2 score, some of which reached clinical significance for men and/or women. CONCLUSION: The uptake of AF ablation over 10 years has expanded, with an increasingly greater number of older patients and with increased presence of comorbidities; however, there has been no increase in the relatively low proportion of women undergoing AF ablation. PMID- 26096611 TI - Outcome in young patients with isolated complete atrioventricular block and permanent pacemaker treatment: A nationwide study of 127 patients. AB - BACKGROUND: Subgroups of pacemaker (PM)-treated children with isolated complete atrioventricular block are at risk of developing left ventricular (LV) dysfunction. OBJECTIVES: We aimed to compare the long-term outcome in anti-SSA Ro/SSB-La antibody-exposed (AB+) and unexposed (AB-) patients and identify preimplantation variables associated with poor outcome. METHODS: In total, 127 PM treated patients aged 0-17 years with isolated complete atrioventricular block were studied retrospectively. RESULTS: Sixty-three patients were diagnosed prenatally, of whom 92% were AB+. Before PM treatment, fractional shortening (FS) z-score was significantly lower in AB+ patients than in AB- patients (-0.14 +/- 3.6 vs 2.03 +/- 2.3). Before PM implantation, there were sex differences (male/female) in median time from diagnosis to PM implantation (0.2 years vs 1.0 years), median neonatal heart rate (50 beats/min vs 60 beats/min), left ventricular end-diastolic dimension (LVEDD) z-score (2.68 +/- 1.41 vs 1.74 +/- 1.40), and FS (-0.19 +/- 3.38 vs 1.42 +/- 2.98). The median age at PM implantation was 3.2 years, and median follow-up was 8.7 years. At follow-up, LVEDD and FS did not differ significantly between AB+ and AB- patients, but LVEDD was higher in patients diagnosed before 1 month of age. Nine patients (8%) developed LV dysfunction, and 4 died. LV dysfunction was associated with diagnosis before 1 month of age and abnormal LV function before PM implantation. CONCLUSION: LV dysfunction at follow-up was seen only in cases diagnosed before 1 month, with abnormal echocardiography before PM implantation. Boys had a more compromised cardiac status and were paced at an earlier age than girls. Fetal AB exposure and male sex were related to abnormal LV function before PM therapy, but not at follow-up. PMID- 26096613 TI - Remote-Controllable Explosive Polymer Multilayer Tubes for Rapid Cancer Cell Killing. AB - Gold nanoshell-functionalized polymer multilayer tubes can be used as potent therapeutic agents for remote killing of cancer cells in a controlled manner due to the emerging pressure wave and tube fragments piercing the cell wall. The explosion is based on rapid evaporation of water inside the tubes caused by photothermal effects. The mechanism of explosion is presented in theory and experiment. The explosion of the tubes depends on the absorption coefficient and size of the gold nanoshells in the tubes, whereby the placement of the gold particles inside or outside of the tubes has no obvious effect on the explosive properties. PMID- 26096612 TI - Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling. AB - Functional expression of voltage-gated Na(+) channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes. PMID- 26096615 TI - Fluorescent Pyrene-Based Bis-azole Compounds: Synthesis and Photophysical Analysis. AB - A rational synthetic procedure for the preparation of a series of pyrene-based neutral and dicationic bis-azole compounds is reported. The method allows the tailored design of pyrene-based azoles with different substituents at the nitrogen atoms of the heterocycles, for which the relative conformation of the resulting bis-azoles can be easily controlled. The bis-azoliums were used for the preparation of the related diplatinum complexes by reaction with [{Pt(ppy)(MU Cl)2 }2 ] (ppy=2-phenylpyridinate). The X-ray molecular structure of one of the resulting compounds, a diplatinum(II) bis(N-heterocyclic carbene) complex, is described. Studies on the photophysical properties of all new species are described. The emission of the bis-azole-based compounds seems to be independent of their substitution patterns, which basically indicates that physical properties such as solubility, melting point, and viscosity can be fine-tuned while maintaining the luminescence properties. Finally, the energies associated with the HOMO and LUMO levels suggest that this family provides versatility to match the energy levels of a wide range of host materials, which is important for the preparation of organic light-emitting devices. PMID- 26096616 TI - Potential mechanism underlying the PNPLA3(I) (148) (M) -Hepatic steatosis connection. PMID- 26096614 TI - ClC-1 mutations in myotonia congenita patients: insights into molecular gating mechanisms and genotype-phenotype correlation. AB - KEY POINTS: Loss-of-function mutations of the skeletal muscle ClC-1 channel cause myotonia congenita with variable phenotypes. Using patch clamp we show that F484L, located in the conducting pore, probably induces mild dominant myotonia by right-shifting the slow gating of ClC-1 channel, without exerting a dominant negative effect on the wild-type (WT) subunit. Molecular dynamics simulations suggest that F484L affects the slow gate by increasing the frequency and the stability of H-bond formation between E232 in helix F and Y578 in helix R. Three other myotonic ClC-1 mutations are shown to produce distinct effects on channel function: L198P shifts the slow gate to positive potentials, V640G reduces channel activity, while L628P displays a WT-like behaviour (electrophysiology data only). Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function. ABSTRACT: Myotonia congenita is an inherited disease caused by loss-of-function mutations of the skeletal muscle ClC 1 chloride channel, characterized by impaired muscle relaxation after contraction and stiffness. In the present study, we provided an in-depth characterization of F484L, a mutation previously identified in dominant myotonia, in order to define the genotype-phenotype correlation, and to elucidate the contribution of this pore residue to the mechanisms of ClC-1 gating. Patch-clamp recordings showed that F484L reduced chloride currents at every tested potential and dramatically right-shifted the voltage dependence of slow gating, thus contributing to the mild clinical phenotype of affected heterozygote carriers. Unlike dominant mutations located at the dimer interface, no dominant-negative effect was observed when F484L mutant subunits were co-expressed with wild type. Molecular dynamics simulations further revealed that F484L affected the slow gate by increasing the frequency and stability of the H-bond formation between the pore residue E232 and the R helix residue Y578. In addition, using patch-clamp electrophysiology, we characterized three other myotonic ClC-1 mutations. We proved that the dominant L198P mutation in the channel pore also right-shifted the voltage dependence of slow gating, recapitulating mild myotonia. The recessive V640G mutant drastically reduced channel function, which probably accounts for myotonia. In contrast, the recessive L628P mutant produced currents very similar to wild type, suggesting that the occurrence of the compound truncating mutation (Q812X) or other muscle-specific mechanisms accounted for the severe symptoms observed in this family. Our results provide novel insight into the molecular mechanisms underlying normal and altered ClC-1 function. PMID- 26096617 TI - In Memoriam: Bengt Arthur Hagberg, MD, PhD August 9, 1923-April 12, 2015. PMID- 26096618 TI - Difficulty of Early Diagnosis and Requirement of Long-Term Follow-Up in Benign Infantile Seizures. AB - PURPOSE: We investigated whether benign infantile seizures can be diagnosed in the acute phase. METHODS: We retrospectively analyzed the medical records of 44 patients initially diagnosed with acute phase benign infantile seizures. All patients were followed for more than 12 months, and we reviewed patients' psychomotor development and presence or absence of seizure recurrence at the last visit. Patients were divided into the following three groups according to the final diagnosis: benign infantile seizures, benign infantile seizures associated with mild gastroenteritis, and non-benign infantile seizures. We defined benign infantile seizures associated with mild gastroenteritis and benign infantile seizures as those associated with normal psychomotor development and no seizure recurrence 3 months after onset of the first seizure, whereas non-benign infantile seizures were associated with delayed psychomotor development and/or seizure recurrence after 3 months of onset of the first seizure. We analyzed the clinical features in the acute phase and compared them between the groups. RESULTS: The median age of seizure onset was 7.6 months. A final diagnosis of benign infantile seizures associated with mild gastroenteritis was made in three patients. In the remaining 41 patients, the final diagnosis was benign infantile seizures in 30 (73.2%) and non-benign infantile seizures in 11 (26.8%). In the non-benign infantile seizure group, intellectual disability was diagnosed in eight patients and seizure recurrence in six. There were no significant differences in clinical features between the groups in the acute phase, such as seizure type or seizure duration. CONCLUSION: About 30% of patients initially diagnosed as having benign infantile seizures did not experience a benign clinical course. Our findings suggest that clinical features in the acute phase are not helpful for predicting benign outcomes in benign infantile seizures and that only long-term follow-up can discriminate benign infantile seizures from non benign infantile seizures. PMID- 26096619 TI - Maternal Iron Deficiency Anemia as a Risk Factor for the Development of Retinopathy of Prematurity. AB - BACKGROUND: Retinopathy of prematurity is a proliferative vascular disease affecting premature newborns and occurs during vessel development and maturation. The aim of this study was to evaluate the maternal iron deficiency anemia as possible risk factors associated with the development of retinopathy of prematurity among premature or very low birth weight infants. METHODS: In this study, mothers of 254 infants with retinopathy of prematurity were analyzed retrospectively, and their laboratory results of medical records during pregnancy were reviewed for possible iron deficiency anemia. RESULTS: In a cohort of 254 mothers of premature infants with retinopathy of prematurity, 187 (73.6%) had iron deficiency, while the remaining 67 (26.4%) mothers had no deficiency. Babies born to mothers with iron deficiency anemia with markedly decreased hemoglobin, hematocrit, mean corpuscular volume, serum iron, and ferritin levels were more likely to develop retinopathy of prematurity. CONCLUSIONS: Our results are the first to suggest that maternal iron deficiency is a risk factor for the development of retinopathy of prematurity. Our data suggest that maternal iron supplementation therapy during pregnancy might lower the risk of retinopathy of prematurity. PMID- 26096620 TI - Association of UBP1 to ribonucleoprotein complexes is regulated by interaction with the trypanosome ortholog of the human multifunctional P32 protein. AB - Regulation of gene expression in trypanosomatid parasitic protozoa is mainly achieved posttranscriptionally. RNA-binding proteins (RBPs) associate to 3' untranslated regions in mRNAs through dedicated domains such as the RNA recognition motif (RRM). Trypanosoma cruzi UBP1 (TcUBP1) is an RRM-type RBP involved in stabilization/degradation of mRNAs. TcUBP1 uses its RRM to associate with cytoplasmic mRNA and to mRNA granules under starvation stress. Here, we show that under starvation stress, TcUBP1 is tightly associated with condensed cytoplasmic mRNA granules. Conversely, under high nutrient/low density-growing conditions, TcUBP1 ribonucleoprotein (RNP) complexes are lax and permeable to mRNA degradation and disassembly. After dissociating from mRNA, TcUBP1 can be phosphorylated only in unstressed parasites. We have identified TcP22, the ortholog of mammalian P32/C1QBP, as an interactor of TcUBP1 RRM. Overexpression of TcP22 decreased the number of TcUBP1 granules in starved parasites in vivo. Endogenous TcUBP1 RNP complexes could be dissociated in vitro by addition of recombinant TcP22, a condition stimulating TcUBP1 phosphorylation. Biochemical and in silico analysis revealed that TcP22 interacts with the RNA-binding surface of TcUBP1 RRM. We propose a model for the decondensation of TcUBP1 RNP complexes in T. cruzi through direct interaction with TcP22 and phosphorylation. PMID- 26096621 TI - An interactive activation and competition model of person knowledge, suggested by proactive interference by traits spontaneously inferred from behaviours. AB - People unconsciously and unintentionally make inferences about others' personality traits based on their behaviours. In this study, a classic memory phenomenon--proactive interference (PI)--is for the first time used to detect spontaneous trait inferences. PI should occur when lists of behaviour descriptions, all implying the same trait, are to be remembered. Switching to a new trait should produce 'release' from proactive interference (or RPI). Results from two experiments supported these predictions. PI and RPI effects are consistent with an interactive activation and competition model of person perception (e.g., McNeill & Burton, 2002, J. Exp. Psychol., 55A, 1141), which predicts categorical organization of social behaviours based on personality traits. Advantages of this model are discussed. PMID- 26096622 TI - Controlling dispersion forces between small particles with artificially created random light fields. AB - Appropriate combinations of laser beams can be used to trap and manipulate small particles with optical tweezers as well as to induce significant optical binding forces between particles. These interaction forces are usually strongly anisotropic depending on the interference landscape of the external fields. This is in contrast with the familiar isotropic, translationally invariant, van der Waals and, in general, Casimir-Lifshitz interactions between neutral bodies arising from random electromagnetic waves generated by equilibrium quantum and thermal fluctuations. Here we show, both theoretically and experimentally, that dispersion forces between small colloidal particles can also be induced and controlled using artificially created fluctuating light fields. Using optical tweezers as a gauge, we present experimental evidence for the predicted isotropic attractive interactions between dielectric microspheres induced by laser generated, random light fields. These light-induced interactions open a path towards the control of translationally invariant interactions with tuneable strength and range in colloidal systems. PMID- 26096623 TI - Reversal of a Single Base-Pair Step Controls Guanine Photo-Oxidation by an Intercalating Ruthenium(II) Dipyridophenazine Complex. AB - Small changes in DNA sequence can often have major biological effects. Here the rates and yields of guanine photo-oxidation by Lambda-[Ru(TAP)2(dppz)](2+) have been compared in 5'-{CCGGATCCGG}2 and 5'-{CCGGTACCGG}2 using pico/nanosecond transient visible and time-resolved IR (TRIR) spectroscopy. The inefficiency of electron transfer in the TA sequence is consistent with the 5'-TA-3' versus 5'-AT 3' binding preference predicted by X-ray crystallography. The TRIR spectra also reveal the differences in binding sites in the two oligonucleotides. PMID- 26096624 TI - Assessment of Cardiac Function by Echocardiography. AB - OPINION STATEMENT: Accurate assessment of cardiac function by transthoracic echocardiography (TTE) plays an essential role in clinical cardiology. While left ventricular ejection fraction (LVEF) assessment has traditionally been the most commonly used objective echocardiographic marker, many other echocardiographic parameters exist that permit an enhanced understanding of cardiac function. These range from 2-dimensional (2D) and 3-dimensional (3D) morphologic parameters to functional parameters such as wall strain and myocardial performance index. In this review, we survey a variety of TTE-based techniques that are utilized in practice to assess the systolic cardiac function of both the left and right ventricles. PMID- 26096625 TI - A Closer Examination of Sexual Trauma During Deployment: Not all Sexual Traumas are Associated with Suicidal Ideation. AB - Military personnel can be exposed to a wide range of sexual trauma while deployed, including sexual harassment and sexual assault. We examined whether different types of sexual trauma during deployment associated with recent suicidal ideation among previously deployed OEF/OIF/OND veterans admitted to trauma-focused treatment (n = 199). More severe forms of sexual trauma (e.g., sexual assault) were significantly and positively associated with suicidal ideation. In contrast, sexual trauma involving verbal remarks (e.g., sexual harassment) was not associated with suicidal ideation. Our findings suggest that sexual harassment and sexual assault during deployment may be differentially associated with suicidal ideation. PMID- 26096626 TI - Borrelia burgdorferi sensu lato and co-infections with Anaplasma phagocytophilum and Rickettsia spp. in Ixodes ricinus in Hamburg, Germany. AB - To obtain initial data on Borrelia burgdorferi sensu lato (Spirochaetales: Spirochaetaceae) in Ixodes ricinus (Ixodida: Ixodidae) ticks in Hamburg, Germany, 1400 questing ticks were collected by flagging at 10 different public recreation areas in 2011 and analysed using probe-based quantitative real-time polymerase chain reaction. The overall rate of infection with B. burgdorferi s.l. was 34.1%; 30.0% of adults were infected (36.7% of females and 26.0% of males), as were 34.5% of nymphs. Significant differences in tick infection rates were observed between the spring and summer/autumn months, as well as among sampling locations. Borrelia genospecies identification by reverse line blotting was successful in 43.6% of positive tick samples. The most frequent genospecies was Borrelia garinii/Borrelia bavariensis, followed by Borrelia afzelii, Borrelia valaisiana, B. burgdorferi sensu stricto, Borrelia spielmanii, Borrelia bissettii and Borrelia lusitaniae. Based on previously published data, co-infection of Borrelia and Rickettsiales spp. was determined in 25.8% of ticks. Overall, 22.9% of ticks were co-infected with Rickettsia spp. (Rickettsiales: Rickettsiaceae), 1.7% with Anaplasma phagocytophilum (Rickettsiales: Anaplasmataceae), and 1.2% with both pathogens. Study results show a high prevalence of Borrelia-positive ticks in recreation areas in the northern German city of Hamburg and the potential health risk to humans in these areas should not be underestimated. PMID- 26096627 TI - Ending sexual HIV transmission: lessons learned from perinatal HIV. PMID- 26096628 TI - The effect of time step, thermostat, and strain rate on ReaxFF simulations of mechanical failure in diamond, graphene, and carbon nanotube. AB - As the sophistication of reactive force fields for molecular modeling continues to increase, their use and applicability has also expanded, sometimes beyond the scope of their original development. Reax Force Field (ReaxFF), for example, was originally developed to model chemical reactions, but is a promising candidate for modeling fracture because of its ability to treat covalent bond cleavage. Performing reliable simulations of a complex process like fracture, however, requires an understanding of the effects that various modeling parameters have on the behavior of the system. This work assesses the effects of time step size, thermostat algorithm and coupling coefficient, and strain rate on the fracture behavior of three carbon-based materials: graphene, diamond, and a carbon nanotube. It is determined that the simulated stress-strain behavior is relatively independent of the thermostat algorithm, so long as coupling coefficients are kept above a certain threshold. Likewise, the stress-strain response of the materials was also independent of the strain rate, if it is kept below a maximum strain rate. Finally, the mechanical properties of the materials predicted by the Chenoweth C/H/O parameterization for ReaxFF are compared with literature values. Some deficiencies in the Chenoweth C/H/O parameterization for predicting mechanical properties of carbon materials are observed. PMID- 26096629 TI - Dyslipidaemia in overweight children and adolescents is associated with an increased risk of kidney stones. AB - AIM: There is conflicting evidence about the role of obesity in paediatric nephrolithiasis. This Polish study explored the influence of nutritional status and lipid disturbances on urinary lithogenic factors and the risk of kidney stone formation in children and adolescents from three to 18 years of age. METHODS: We carried out serum lipid profile evaluations and 24-h urine chemistry analyses on 493 overweight/obese paediatric participants (mean age 13 years) without nephrolithiasis and 492 healthy normal weight sex and age-matched controls. RESULTS: A third (33%) of the study group had blood lipid disturbances, with more acidic urine, lower urinary citrate excretion and a higher fraction of ionised calcium and higher Bonn Risk Index than the controls. The participants' body mass index standard deviation score (BMI Z-score) was positively correlated with urinary oxalate and uric acid and negatively correlated with citrate excretion. Total cholesterol, low-density lipoprotein cholesterol and triglycerides correlated negatively with citraturia, while high-density lipoprotein cholesterol correlated positively. CONCLUSION: The main factor that predisposed overweight and obese children to kidney stones was hypocitraturia. Urinary citrate excretion was related to both BMI Z-scores and all lipid fraction abnormalities. However, hypercholesterolaemia and particularly low-density lipoprotein hypercholesterolaemia seemed to play a major role. PMID- 26096630 TI - Student perceptions of a spiral curriculum. AB - AIM: The aim of this study was evaluation of constructive alignment of student perceptions to a spiral curriculum, as a pre-requisite to successful learning. METHOD: A survey was undertaken to evaluate student thoughts and experiences of a spiral curriculum, by participation in an anonymous voluntary questionnaire. Students were asked to rate their thoughts on their understanding, perceived benefit of and confusion with their spiral curriculum at the current time and retrospectively during previous years, and to answer free-text questions on the impact, effects on learning and future suggestions for their spiral curriculum. RESULTS: Sixty (86%) students completed the questionnaire. Understanding the spiral curriculum worked enhanced with time, with the benefit of the spiral curriculum being felt more conclusively in the latter years, and the majority of students not being confused by the spiral curriculum. Those students who were most confused by the spiral curriculum were the ones who were least likely to appreciate its benefits. The opportunity for consolidation of previously visited knowledge was a perceived predominant advantage, with re-visitation of topics helping to deepen understanding and learning. Clarity on the depth of knowledge at each stage prevents information overload. A spiral curriculum must spiral and not be a repetition of previously delivered topics. CONCLUSIONS: This study provided insights into students' perceptions of an integrated spiral curriculum, and whilst predominantly positive, there are challenges to enhance the student experience. The spiral curriculum provides an opportunity to revisit and consolidate learning to the apparent benefit of the student. PMID- 26096631 TI - Genetic interactions between diverged alleles of Early heading date 1 (Ehd1) and Heading date 3a (Hd3a)/ RICE FLOWERING LOCUS T1 (RFT1) control differential heading and contribute to regional adaptation in rice (Oryza sativa). AB - Initiation of flowering, also called heading, in rice (Oryza sativa) is determined by the florigens encoded by Heading date 3a (Hd3a) and RICE FLOWERING LOCUS T1 (RFT1). Early heading date 1 (Ehd1) regulates Hd3a and RFT1. However, different rice varieties have diverged alleles of Ehd1 and Hd3a/RFT1 and their genetic interactions remain largely unclear. Here we generated three segregating populations for different combinations of diverged Ehd1 and Hd3a/RFT1 alleles, and analyzed their genetic interactions between these alleles. We demonstrated that, in an ehd1 mutant background, Hd3a was silenced, but RFT1 was expressed (although at lower levels than in plants with a functional Ehd1) under short-day (SD) and long-day (LD) conditions. We identified a nonfunctional RFT1 allele (rft1); the lines carrying homozygous ehd1 and Hd3a/rft1 failed to induce the floral transition under SD and LD conditions. Like Hd3a, RFT1 also interacted with 14-3-3 proteins, the florigen receptors, but a nonfunctional RFT1 with a crucial E105K mutation failed to interact with 14-3-3 proteins. Furthermore, analyses of sequence variation and geographic distribution suggested that functional RFT1 alleles were selected during rice adaptation to high-latitude regions. Our results demonstrate the important roles of RFT1 in rice flowering and regional adaptation. PMID- 26096632 TI - Olfactory Dysfunction Evaluation Is Not Affected by Comorbid Depression in Parkinson's Disease. AB - BACKGROUND: Olfactory function assessment is an important screening tool for Parkinson's disease (PD) diagnosis. It is debated whether olfaction is affected by comorbid depression. We assessed the relationship between depression and olfaction in PD and determined whether depression may limit the usefulness of olfactory testing for PD diagnosis. METHODS: Olfaction was evaluated using the Sniffin' Sticks test and the Hyposmia Rating Scale in four groups of subjects: PD patients without depression (n = 30); PD patients with major depression (PDD; n = 30); major depressive disorder (MDD) patients (n = 29); and healthy controls (HCs; n = 30). RESULTS: No differences were found between PD and PDD patients for total Sniffin' Sticks test, threshold, discrimination or identification scores, or in Hyposmia Rating Scale, although both groups differed from HCs and MDD patients (P < 0.05), which, in turn, showed similar olfactory scores. CONCLUSIONS: Lack of differences in olfactory impairment between PD and PDD suggest that depression may not contribute to olfactory dysfunction in PD. PMID- 26096633 TI - Treatment of liver alveococcosis with high-intensity focused ultrasound. AB - This study evaluates the feasibility of using high intensity focused ultrasound (HIFU) for the treatment of liver alveococcosis. HIFU ablation was carried out in 36 patients with alveococcosis of the liver. The median age of patients was 39.24+/-12, 93 years (range: 20-66 years). The efficiency of treatment was monitored in real time with morphological evaluation, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and with morphological cytological and electron microscopy studies. HIFU ablation has shown effectiveness in destroying the protoscolexes, laminar and cell elements of the cuticular and germinal membrane of the alveococcosis larvocyst, causing the death of the cells of initial metamorphosis of alveococcosis, which is responsible for the dissemination of the parasite in the liver. Therefore HIFU-therapy is a promising and effective treatment for liver alveococcosis. PMID- 26096634 TI - Transient Apical Thickening Following Apical Ballooning Syndrome: A Case Series. AB - The authors describe transient apical thickening mimicking apical hypertrophic cardiomyopathy following apical ballooning syndrome. These findings are observed on multimodality cardiac imaging and appear to constitute a novel entity. Possible pathophysiologic mechanisms are explored. PMID- 26096635 TI - Visible-Light-Activated Molecular Switches. AB - The ability to influence key properties of molecular systems by using light holds much promise for the fields of materials science and life sciences. The cornerstone of such systems is molecules that are able to reversibly photoisomerize between two states, commonly referred to as photoswitches. One serious restriction to the development of functional photodynamic systems is the necessity to trigger switching in at least one direction by UV light, which is often damaging and penetrates only partially through most media. This review provides a summary of the different conceptual strategies for addressing molecular switches in the visible and near-infrared regions of the optical spectrum. Such visible-light-activated molecular switches tremendously extend the scope of photoswitchable systems for future applications and technologies. PMID- 26096636 TI - Quantifying Dry Milling in Pharmaceutical Processing: A Review on Experimental and Modeling Approaches. AB - Particle size reduction by mechanical means is an important unit operation in the pharmaceutical industry, used to improve flow, solubility, and in amorphization of drugs. It is usually achieved by the fracturing of particles under the action of applied energy. Despite being pervasive in the pharmaceutical field, it is one of the least understood processes owing to the complexity of material and process variables involved during milling. To comprehend the process, efforts should be focused on techniques that measure the particle size as well as the control the process. With the ongoing initiative of US FDA to encourage design in quality, the review is focused on some process analytical tools to characterize particle size distribution as well as process modeling tools to simulate particle size reduction. Additionally, an overview of some fundamental aspects related to milling is provided. To this end, the review is limited, mainly concentrating on some of experimental and modeling approaches used to quantify and understand the physics behind the process of dry milling. PMID- 26096637 TI - Perampanel efficacy and safety by gender: Subanalysis of phase III randomized clinical studies in subjects with partial seizures. AB - The antiepileptic drug (AED) perampanel is approved in >=40 countries as adjunctive therapy for drug-resistant partial seizures in patients with epilepsy. This post hoc analysis of pooled data from three phase III, double-blind, randomized studies of perampanel examines between-gender differences in perampanel efficacy and safety. Of the 1,478 subjects in the pooled analysis (719 male, 759 female), 1,109 were included in the pharmacokinetic/pharmacodynamic analysis. Perampanel oral clearance was 17% lower in female than in male patients not receiving enzyme-inducing AEDs. Pooled efficacy analysis revealed that seizure frequency was reduced with perampanel treatment regardless of gender; a greater numerical reduction in seizure frequency and increased responder rates occurred in female participants at perampanel doses of 4, 8, and 12 mg. Tolerability was similar between groups, although common adverse events such as dizziness and headache occurred more frequently in female subjects. Modest elevations in perampanel exposure in female patients may result in meaningful between-gender differences in efficacy and safety; therefore, dosing should be individualized and clinical response monitored. PMID- 26096638 TI - Chondrogenic differentiation of human umbilical cord blood-derived mesenchymal stem cells in vitro. AB - Different therapeutic techniques have been developed for regeneration of articular cartilage injuries, but none has provided an optimal solution to their treatment. Human umbilical cord blood-mesenchymal Stem Cells (HUCB-MSCs) have been considered as promising alternative cell source for cartilage repair. OBJECTIVES: Examining the success rate of MSCs isolation from HUCB as well as chondrogenic differentiation potential of HUCB-MSCs in vitro. MATERIALS AND METHODS: 32 UCB samples were collected, in addition to 5 bone marrow (BM) and 5 peripheral blood (PB) samples, taken as reference controls. Samples were used for mononuclear cells isolation from which MSCs were expanded under complete aseptic conditions, were verified morphologically and through the presence of CD44 and CD105, and absence of CD34. RESULTS: Success rate of UCB-MSCs isolation was (25%), a rate that was lower than those of PB (40%) and BM (80%). Accordingly, certain input parameters have been recommended for successful MSCs isolation from UCB. On selecting samples in which recommended parameters were fulfilled, success rate was increased to 72%. This was together with providing optimal experiment conditions; mainly type of expansion medium, success rate reached 80%. Then, successfully expanded MSCs were subjected to chondrogenic differentiation by culturing in pelleted micromass system in presence of transforming growth factor beta-1 and chondrogenic medium devoid of fetal bovine serum to evaluate their ability to undergo chondrogenesis. Differentiation was verified microscopically using special stains, and proved by reverse transcriptase-polymerase chain reaction for expression of aggrecan and collagen II genes. In conclusion, in vitro differentiation into chondrocytes is possible from HUCB-MSCs. PMID- 26096640 TI - Integrating a Photocatalyst into a Hybrid Lithium-Sulfur Battery for Direct Storage of Solar Energy. AB - Direct capture and storage of abundant but intermittent solar energy in electrical energy-storage devices such as rechargeable lithium batteries is of great importance, and could provide a promising solution to the challenges of energy shortage and environment pollution. Here we report a new prototype of a solar-driven chargeable lithium-sulfur (Li-S) battery, in which the capture and storage of solar energy was realized by oxidizing S(2-) ions to polysulfide ions in aqueous solution with a Pt-modified CdS photocatalyst. The battery can deliver a specific capacity of 792 mAh g(-1) during 2 h photocharging process with a discharge potential of around 2.53 V versus Li(+)/Li. A specific capacity of 199 mAh g(-1), reaching the level of conventional lithium-ion batteries, can be achieved within 10 min photocharging. Moreover, the charging process of the battery can proceed under natural sunlight irradiation. PMID- 26096639 TI - Brain tissue compartment density estimated using diffusion-weighted MRI yields tissue parameters consistent with histology. AB - We examined whether quantitative density measures of cerebral tissue consistent with histology can be obtained from diffusion magnetic resonance imaging (MRI). By incorporating prior knowledge of myelin and cell membrane densities, absolute tissue density values were estimated from relative intracellular and intraneurite density values obtained from diffusion MRI. The NODDI (neurite orientation distribution and density imaging) technique, which can be applied clinically, was used. Myelin density estimates were compared with the results of electron and light microscopy in ex vivo mouse brain and with published density estimates in a healthy human brain. In ex vivo mouse brain, estimated myelin densities in different subregions of the mouse corpus callosum were almost identical to values obtained from electron microscopy (diffusion MRI: 42 +/- 6%, 36 +/- 4%, and 43 +/ 5%; electron microscopy: 41 +/- 10%, 36 +/- 8%, and 44 +/- 12% in genu, body and splenium, respectively). In the human brain, good agreement was observed between estimated fiber density measurements and previously reported values based on electron microscopy. Estimated density values were unaffected by crossing fibers. PMID- 26096641 TI - Tissue and sex specificities in Ca2+ handling by isolated mitochondria in conditions avoiding the permeability transition. AB - NEW FINDINGS: What is the central question of this study? The assessment of Ca(2+) handling by isolated mitochondria can be biased by dysfunctions secondary to Ca(2+) -induced mitochondrial permeability transition (MPT). As a result of this uncertainty and the differing experimental conditions between studies, the tissue and sex diversities in mitochondrial Ca(2+) transport are still unsettled questions. What is the main finding and its importance? If MPT is not prevented during Ca(2+) transport assays, some measured variables are biased. Accounting for the implied importance of preventing MPT, we observed substantial tissue specificities in the mitochondrial Ca(2+) handling, particularly in the Ca(2+) efflux pathways. The characteristics of mitochondria, including their Ca(2+) transport functions, may exhibit tissue specificity and sexual dimorphism. Given that measurements of Ca(2+) handling by isolated mitochondria may be biased by dysfunction secondary to Ca(2+) -induced mitochondrial permeability transition (MPT) pore opening, this study evaluated the extent to which MPT inhibition by ciclosporin affected the measurement of Ca(2+) transport in isolated rat liver mitochondria. The results indicate that the steady-state levels of external Ca(2+) and the rates of mitochondrial Ca(2+) efflux through the selective pathways can be overestimated by up to fourfold if MPT pore opening is not prevented. We analysed Ca(2+) transport in isolated mitochondria from the liver, skeletal muscle, heart and brain of male and female rats in incubation conditions containing MPT inhibitors, NAD-linked substrates and relevant levels of free Ca(2+), Mg(2+) and Na(+). The Ca(2+) influx rates were similar among the samples, except that the liver mitochondria displayed values fourfold higher. In contrast, the Ca(2+) efflux rates exhibited more tissue diversity, especially in the presence of Na(+). Interestingly, the Na(+)-independent Ca(2+) efflux was highest in the heart mitochondria (~ 4 nmol mg(-1) min(-1)), thus challenging the view that cardiac mitochondrial Ca(2+) efflux relies almost exclusively on a Na(+) dependent pathway. Sex specificity was observed in only two kinetic indexes of heart mitochondrial Ca(2+) homeostasis and in the ADP-stimulated respiration of liver mitochondria (~ 20% higher in females). The present study shows the methodological importance of preventing MPT when measuring the properties and the physiological variability of the Ca(2+) handling by isolated mitochondria. PMID- 26096642 TI - ZmABA2, an interacting protein of ZmMPK5, is involved in abscisic acid biosynthesis and functions. AB - In maize (Zea mays), the mitogen-activated protein kinase ZmMPK5 has been shown to be involved in abscisic acid (ABA)-induced antioxidant defence and to enhance the tolerance of plants to drought, salt stress and oxidative stress. However, the underlying molecular mechanisms are poorly understood. Here, using ZmMPK5 as bait in yeast two-hybrid screening, a protein interacting with ZmMPK5 named ZmABA2, which belongs to a member of the short-chain dehydrogenase/reductase family, was identified. Pull-down assay and bimolecular fluorescence complementation analysis and co-immunoprecipitation test confirmed that ZmMPK5 interacts with ZmABA2 in vitro and in vivo. Phosphorylation of Ser173 in ZmABA2 by ZmMPK5 was shown to increase the activity of ZmABA2 and the protein stability. Various abiotic stimuli induced the expression of ZmABA2 in leaves of maize plants. Pharmacological, biochemical and molecular biology and genetic analyses showed that both ZmMPK5 and ZmABA2 coordinately regulate the content of ABA. Overexpression of ZmABA2 in tobacco plants was found to elevate the content of ABA, regulate seed germination and root growth under drought and salt stress and enhance the tolerance of tobacco plants to drought and salt stress. These results suggest that ZmABA2 is a direct target of ZmMPK5 and is involved in ABA biosynthesis and functions. PMID- 26096643 TI - Classroom-based interdependent group contingencies increase children's physical activity. AB - This study investigated the effects of 2 interdependent group contingencies (individual vs. cumulative classroom goal setting) on the number of pedometer recorded steps taken per day. Thirty third-grade students in 2 classrooms participated. An ABACX design was conducted in which the X phase referred to a replication of the most successful phase (i.e., B or C). Results indicated that individual goal setting, rather than cumulative classroom goal setting, was more effective in increasing the number of steps taken per day on average. Results suggest that individual feedback may be an important factor in attaining desired results. PMID- 26096645 TI - Combined chemotherapy and photodynamic therapy using a nanohybrid based on layered double hydroxides to conquer cisplatin resistance. AB - A nanohybrid is assembled by ratiometrically co-loading Pt(IV) prodrugs and photosensitizers into layered double hydroxide nanoparticles. The nanohybrid shows synergistic cell-killing effects and is significantly active against the proliferation of cisplatin-resistant human cancer cells with nanomolar IC50 values. Profound mechanistic investigations confirm its action mode of combined chemo- and photodynamic therapy. PMID- 26096646 TI - Acetaminophen induces JNK/p38 signaling and activates the caspase-9-3-dependent cell death pathway in human mesenchymal stem cells. AB - Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. Generally, the therapeutic dose of APAP is clinically safe, however, high doses of APAP can cause acute liver and kidney injury. Therefore, the majority of previous studies have focussed on elucidating the mechanisms of APAP-induced hepatotoxicity and nephrotoxicity, in addition to examining ways to treat these conditions in clinical cases. However, few studies have reported APAP-induced intoxication in human stem cells. Stem cells are important in cell proliferation, differentiation and repair during human development, particularly during fetal and child development. At present, whether APAP causes cytotoxic effects in human stem cells remains to be elucidated, therefore, the present study aimed to investigate the cellular effects of APAP treatment in human stem cells. The results of the present study revealed that high-dose APAP induced more marked cytotoxic effects in human mesenchymal stem cells (hMSCs) than in renal tubular cells. In addition, increased levels of hydrogen peroxide (H2O2), phosphorylation of c-Jun N-terminal kinase and p38, and activation of caspase-9/-3 cascade were observed in the APAP treated hMSCs. By contrast, antioxidants, including vitamin C reduced APAP induced augmentations in H2O2 levels, but did not inhibit the APAP-induced cytotoxic effects in the hMSCs. These results suggested that high doses of APAP may cause serious damage towards hMSCs. PMID- 26096648 TI - Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor. AB - Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency, which represents a heterogeneous group of hypogammaglobulinemias of largely unknown molecular defects. The hallmark of the disease is the elevated susceptibility to recurrent infections of respiratory and gastrointestinal tract, mainly due to encapsulated bacteria while a significant proportion of patients with CVID develop autoimmune and lymphoproliferative complications. The primary cause of CVID is still not known. However, a number of distinct genetic defects including in inducible co-stimulator (ICOS), B-cell activating factor receptor (BAFFR) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been identified in a minority of patients with CVID. Mutations in tumour necrosis factor receptor superfamily (TNFRSF) member, TACI, are more frequently found to be associated to the disease in about 10% of patients with CVID, but may require additional immunologic defects for complete expression of the phenotype, as unaffected heterozygotes have also been described. Clinically, patients with TACI mutations could present with the complete spectrum of complications seen in CVID. Recent animal studies have provided substantial information on TACI signalling, yet it still offers an outstanding opportunity for further exploration of the aetiology, as a large part of it remains poorly understood. In this review, we aim at giving an insight into the genetics underlying the CVID and particularly at outlining the role of TACI and its relative contribution to the development of CVID-like phenotypes in human. PMID- 26096647 TI - The paraventricular nucleus of the thalamus is differentially recruited by stimuli conditioned to the availability of cocaine versus palatable food. AB - The paraventricular nucleus of the thalamus (PVT) is not traditionally considered part of the brain addiction neurocircuitry but has received growing attention with regard to a role in the modulation of drug-seeking behavior. This study sought to establish the pattern of neural activation induced by a response reinstating discriminative stimulus (SD ) conditioned to either cocaine (COC) or a conventional reinforcer using a palatable food substance, sweetened condensed milk (SCM). Male Wistar rats were trained to associate one SD (S+ ; COC or SCM availability) and a distinctly different SD (S- ; non-reward; i.e. the availability of saline or the absence of SCM). Following extinction of COC- and SCM-reinforced responding, rats were presented with the respective S+ or S- alone and tested for the reinstatement of reward seeking. The COC S+ and SCM S+ elicited identical reinstatement, whereas the non-reward S- was behaviorally ineffective. PVT sections were obtained following completion of the reinstatement tests and labeled for Fos. The number of Fos+ neurons was compared among rats that were presented with the COC S+ , SCM S+ or S- . Rats that were presented with the COC S+ exhibited a significant increase in Fos expression compared with rats that were presented with the S- . Moreover, Fos expression was significantly correlated with the number of reinstatement responses that were induced by the COC S+ . In contrast, the SCM S+ and S- produced identical increases in Fos expression, without behaviorally relevant correlations. The findings implicate the PVT as an important site that is selectively recruited during COC-seeking behavior. PMID- 26096649 TI - Assessing Community Quality of Health Care. AB - OBJECTIVE: To determine the agreement of measures of care in different settings hospitals, nursing homes (NHs), and home health agencies (HHAs)-and identify communities with high-quality care in all settings. DATA SOURCES/STUDY SETTING: Publicly available quality measures for hospitals, NHs, and HHAs, linked to hospital service areas (HSAs). STUDY DESIGN: We constructed composite quality measures for hospitals, HHAs, and nursing homes. We used these measures to identify HSAs with exceptionally high- or low-quality of care across all settings, or only high hospital quality, and compared these with respect to sociodemographic and health system factors. PRINCIPAL FINDINGS: We identified three dimensions of hospital quality, four HHA dimensions, and two NH dimensions; these were poorly correlated across the three care settings. HSAs that ranked high on all dimensions had more general practitioners per capita, and fewer specialists per capita, than HSAs that ranked highly on only the hospital measures. CONCLUSION: Higher quality hospital, HHA, and NH care are not correlated at the regional level; regions where all dimensions of care are high differ systematically from regions which score well on only hospital measures and from those which score well on none. PMID- 26096650 TI - Dual effect of Thymosin alpha 1 on human monocyte-derived dendritic cell in vitro stimulated with viral and bacterial toll-like receptor agonists. AB - OBJECTIVES: Thymosin alpha 1 (Talpha1) recently gained interest as immune adjuvant for vaccines because of its ability to modulate the T-cell/dendritic cell (DC) axis and to improve antibody production. The objective of this study was to determine whether Talpha1 would address in vitro the response of human primary monocyte-derived DC, crucial regulators of vaccine-induced immunity, upon exposure to different toll-like receptor (TLR) agonists or infection with viruses or bacteria. METHODS: DC maturation and production of pro-inflammatory cytokines were analyzed. RESULTS: Our data revealed a dual effect of Talpha1 on DC biology upon viral or bacterial stimulation. Interestingly, Talpha1 enhanced human leukocyte antigen (HLA)-I and II surface expression and secretion of IL-6, TNF alpha and IL-8 when DCs were treated with viral TLR3 and TLR7/8 agonists. Similarly, in pandemic H1N1 influenza A-infected DCs, Talpha1 raised the expression of maturation markers and type I and III Interferon (IFN). In contrast, following bacterial TLR2 and 4 stimulation, as well as upon Bacillus Calmette-Guerin infection, the presence of Talpha1 in DC cultures drastically lowered the analyzed cellular parameters. CONCLUSION: The knowledge that Talpha1 pleiotropic effect might ameliorate anti-viral immune responses and, at the same time, dampen inflammation caused by bacterial infections could lay the groundwork for a more appropriate therapeutic application of this molecule. PMID- 26096651 TI - The southwestern Carpathians as an ancient centre of diversity of freshwater gammarid amphipods: insights from the Gammarus fossarum species complex. AB - Gammarus fossarum is a diverse species complex of epigean freshwater amphipods throughout Europe. Due to their poor dispersal capabilities and ubiquity, these crustaceans may serve as a model for investigating the influence of historical factors on the contemporary distribution and diversity patterns of freshwater macrozoobenthos. Here, we investigate the fine-scale phylogeographic structure of this complex across its range in the southwestern Carpathian Mountains, which comprises two areas that are geographically isolated from its main European distribution area as well as from each other. Given the Tertiary age of many freshwater Gammarus species, we hypothesize that the southwestern Carpathian populations reflect a relict distribution pattern. We used two mitochondrial and three nuclear markers from 32 localities to reconstruct phylogenetic relationships and estimate the timings of divergence among southwestern Carpathian and non-Carpathian lineages. Cryptic diversity was evaluated from mitochondrial markers by employing phylogenetic and distance-based methods. We distinguished at least 16 cryptic microendemic taxa, some of them coexisting, distributed in the southwestern Carpathians in a mosaic-like pattern. These lineages form a monophyletic group together with several lineages from southeastern Europe. Estimated divergence times indicate a Middle Miocene origin of this clade, with many deep splits dating back to more than 10 Ma. This time frame corresponds with a period of intense geological subsidence in the region that gave birth to the Pannonian Basin. We conclude that subsidence could have been an important driver of diversification in freshwater Gammarus and that the southwestern Carpathians represent an ancient centre of diversity for these crustaceans. PMID- 26096652 TI - Food insecurity and intimate partner violence against women: results from the California Women's Health Survey. AB - OBJECTIVE: To investigate the association between food insecurity and intimate partner violence in a population-based sample of heterosexual women. DESIGN: Logistic regression was used to evaluate the association between three levels of food insecurity and intimate partner violence. SETTING: Data from 6 years of the California Women's Health Survey. SUBJECTS: Randomly selected women (n 16 562) aged 18 years and older from the State of California, USA. RESULTS: We found: (i) that African-American women had a higher prevalence of food insecurity and were more likely to report severe intimate partner violence; (ii) a strong positive association between food insecurity and intimate partner violence; (iii) evidence of effect modification of the association between food insecurity and intimate partner violence by marital status; and (iv) higher odds of intimate partner violence among those reporting more severe food insecurity. CONCLUSIONS: Food insecurity is an important risk indicator for intimate partner violence among women. Understanding the factors that put women, especially minority women, at greatest risk facilitates intervention development. PMID- 26096653 TI - Multiple microneedling sessions for minimally invasive facial rejuvenation: an objective assessment. AB - BACKGROUND: Microneedling or percutaneous collagen induction is a new modality used for skin rejuvenation, tightening, and scar remodeling. It offers a simple and effective treatment for photoaged skin with minimal disruption of the epidermis, thus limiting adverse effects and minimizing downtime. OBJECTIVES: To evaluate the efficacy, coupled with quantitative assessment, of the histological changes in response to multiple sessions of skin microneedling in the treatment of aging skin. PATIENTS AND METHODS: Ten patients with Fitzpatrick skin type III and IV and Glogau class II to III wrinkles were subjected to six skin microneedling sessions at 2-week intervals. Standard photographs and skin biopsy specimens were obtained at baseline and at one and three months after the start of treatment. Histometry for epidermal thickness and quantitative evaluation of collagen types I, III, and VII, newly synthesized collagen, total elastin, and tropoelastin were performed for all skin biopsies. RESULTS: Skin microneedling produced noticeable clinical improvement of photoaged skin, with corresponding histological enhancement. Compared to the baseline, collagen types I, III, and VII, as well as newly synthesized collagen, together with tropoelastin showed a statistically significant increase (P < 0.05) in response to treatment, while the mean level of total elastin was significantly decreased (P < 0.05) after treatment. CONCLUSIONS: Skin microneedling is a promising minimally invasive treatment option with the advantage of increased collagen production. However, multiple sessions are usually needed to maintain the improvement achieved. PMID- 26096654 TI - Tryptophan Breakdown in Patients with HCV Infection is Influenced by IL28B Polymorphism. AB - Until recently, the standard treatment of chronic hepatitis C virus (HCV) infection was a combination therapy with PEG-IFN-alpha plus ribavirin. Previous studies have proven that several markers predict the outcome of such therapy, e.g., pretreatment plasma levels of interferon inducible protein IP-10, HCV RNA and IL28B-related single nucleotide polymorphisms (SNP). Altered activity of tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been also shown in patients suffering from HCV infection. In this study, we investigated whether IL28B SNP in patients infected with HCV is related to the tryptophan breakdown rate. Before therapy, serum tryptophan and kynurenine concentrations were determined in 25 patients with established HCV infection and the kynurenine to tryptophan ratio (KYN/TRP) was calculated as an estimate of the tryptophan breakdown rate. In parallel, neopterin and nitrite concentrations were determined. A significant difference of serum KYN/TRP existed between the three IL28B polymorphism groups: C/C genotype had the highest and T/T genotype had the lowest KYN/TRP (p < 0.05). Likewise, C/C genotype was associated with higher KYN/TRP than non-C/C genotype (p = 0.01). There was a smaller difference between the three groups regarding the absolute kynurenine concentrations, the C/C genotype being associated with higher kynurenine concentrations. None of the other comparisons revealed any statistical significance. In conclusion, patients with C/C genotype presented with the highest tryptophan breakdown rate already before antiretroviral therapy with IFN-alpha/ribavirin. The differences in tryptophan metabolism might relate to HCV clearance and also to side effects of IFN-alpha therapy. PMID- 26096655 TI - Effects of a Formula Containing Two Types of Prebiotics, Bifidogenic Growth Stimulator and Galacto-oligosaccharide, and Fermented Milk Products on Intestinal Microbiota and Antibody Response to Influenza Vaccine in Elderly Patients: A Randomized Controlled Trial. AB - We investigated the effect of a formula containing two different prebiotics (bifidogenic growth stimulator and galacto-oligosaccharide) and fermented milk products on intestinal microbiota and antibody responses to an influenza vaccine in enterally fed elderly in-patients. Patients were administered either formula containing prebiotics and fermented milk products (group F: n = 12, 79.9 +/- 9.5 years old) or standard formula (group C: n = 12, 80.7 +/- 10.1 years old) via percutaneous endoscopic gastrostomy during a 14-week intervention period. Subjects were immunized with an influenza vaccine (A/H1N1, A/H3N2, and B) at week 4 of the intervention. Blood biochemical indices, intestinal bacteria populations and antibody titers were analyzed. Bifidobacterium counts increased significantly in group F compared with group C. The enhanced antibody titers against A/H1N1 were maintained in group F for a longer period compared with group C. The titers against A/H3N2 were unchanged between both groups, and those against B were significantly lower in group F than in group C, although few subjects had seroprotective titers against A/H3N2 and B. These results suggest that administration of the formula containing prebiotics and fermented milk products may maintain antibody titers for longer periods through the improvement of intestinal microbiota. PMID- 26096656 TI - Oligomeric assembly is required for chaperone activity of the filamentous gamma prefoldin. AB - Prefoldins (PFDs) are molecular chaperones with a distinctive jellyfish-shape that have a general role in de novo protein folding in Archaea and in the biogenesis of cytoskeleton proteins in eukaryotes. In general, PFDs are hetero hexameric protein assemblies consisting of two alpha and four beta subunits. However, a PFD variant called gamma-prefoldin (gammaPFD), isolated from the hyperthermophilic archaeon Methanocaldococcus jannaschii, exhibits a unique filamentous structure that is composed of hundreds of monomeric subunits. In this study, we investigated the relationship between the morphology of the gammaPFD filament and its ability to prevent protein aggregation. A chaperone assay demonstrated that gammaPFD must be in a filamentous assembly for functional activity and the distal regions of the coiled-coils are required for binding of non-native proteins. Molecular dynamic simulations were used to model the interactions between in silico thermally denatured protein substrates and the coiled-coils of a gammaPFD filament. During molecular dynamic simulations at 300 and 353 K, each coiled-coil was highly flexible, enabling it to widen the central cavity of the filament to potentially capture various non-native proteins. Docking molecular dynamic simulations of gammaPFD filaments with unfolded citrate synthase or insulin showed a size-dependence between the substrate and the number of interacting coiled-coils. To confirm this observation, we generated filaments containing specific numbers of subunits, and showed that between six and eight gammaPFD subunits are required for chaperone activity to prevent citrate synthase from thermal aggregation. These results provide insights into structure-function relationships of oligomeric chaperones and illuminate the potential role of gammaPFD in its native environment. PMID- 26096657 TI - Surface-Functionalized Nanoparticles by Olefin Metathesis: A Chemoselective Approach for In Vivo Characterization of Atherosclerosis Plaque. AB - The use of click chemistry reactions for the functionalization of nanoparticles is particularly useful to modify the surface in a well-defined manner and to enhance the targeting properties, thus facilitating clinical translation. Here it is demonstrated that olefin metathesis can be used for the chemoselective functionalization of iron oxide nanoparticles with three different examples. This approach enables, in one step, the synthesis and functionalization of different water-stable magnetite-based particles from oleic acid-coated counterparts. The surface of the nanoparticles was completely characterized showing how the metathesis approach introduces a large number of hydrophilic molecules on their coating layer. As an example of the possible applications of these new nanocomposites, a focus was taken on atherosclerosis plaques. It is also demonstrated how the in vitro properties of one of the probes, particularly its Ca(2+) -binding properties, mediate their final in vivo use; that is, the selective accumulation in atherosclerotic plaques. This opens promising new applications to detect possible microcalcifications associated with plaque vulnerability. The accumulation of the new imaging tracers is demonstrated by in vivo magnetic resonance imaging of carotids and aorta in the ApoE(-/-) mouse model and the results were confirmed by histology. PMID- 26096658 TI - Transforming growth factor-beta1 promotes the migration and invasion of sphere forming stem-like cell subpopulations in esophageal cancer. AB - Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-beta1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-beta1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells. PMID- 26096659 TI - Effects of helium on inflammatory and oxidative stress-induced endothelial cell damage. AB - Helium induces preconditioning in human endothelium protecting against postischemic endothelial dysfunction. Circulating endothelial microparticles are markers of endothelial dysfunction derived in response to injury. Another noble gas, xenon, protected human umbilical vein endothelial cells (HUVEC) against inflammatory stress in vitro. We hypothesised that helium protects the endothelium in vitro against inflammatory and oxidative stress. HUVEC were isolated from fresh umbilical cords and grown upon confluence. Cells were subjected to starving medium for 12h before the experiment and treated for either 3 * 5 min or 1 * 30 min with helium (5% CO2, 25% O2, 70% He) or control gas (5% CO2, 25% O2, 70% N2) in a specialised gas chamber. Subsequently, cells were stimulated with TNF-alpha (40 ng/ml for 24h or 10 ng/ml for 2h) or H2O2 (500 MUM for 2h) or left untreated. Adhesion molecule expression was analysed using real time quantitative polymerase chain reaction. Caspase-3 expression and viability of the cells was measured by flowcytometry. Microparticles were investigated by nanoparticle tracking analysis. Helium had no effect on adhesion molecule expression after TNF-alpha stimulation but in combination with oxidative stress decreased cell viability (68.9 +/- 1.3% and 58 +/- 1.9%) compared to control. Helium further increased TNF-alpha induced release of caspase-3 containing particles compared to TNF-alpha alone (6.4 * 10(6) +/- 1.1 * 10(6) and 2.9 * 10(6) +/- 0.7 * 10(6), respectively). Prolonged exposure of helium increased microparticle formation (2.4 * 10(9) +/- 0.5 * 10(9)) compared to control (1.7 * 10(9) +/- 0.2 * 10(9)). Summarized, helium increases inflammatory and oxidative stress-induced endothelial damage and is thus not biologically inert. A possible noxious effects on the cellular level causing alterations in microparticle formation both in number and content should be acknowledged. PMID- 26096660 TI - Insomnia symptoms, behavioral/emotional problems, and suicidality among adolescents of insomniac and non-insomniac parents. AB - The aim of this study was to examine insomnia symptoms, behavioral problems, and suicidality among adolescents of insomniac parents (IP) and non-insomniac parents (NIP). A family survey of sleep and health was conducted among 1090 adolescents and their parents in Jinan, China. Adolescents completed a sleep and health questionnaire to report their sleep and mental health problems. Parents reported their insomnia symptoms and history of mental disorders. Insomnia, behavioral problems, and suicidal behavior were compared between IP adolescents and NIP adolescents. IP adolescents were more likely than NIP adolescents to report insomnia symptoms, use of sleep medication, suicidal ideation, suicide plan, and suicide attempt. IP adolescents scored significantly higher than NIP adolescents on withdrawn and externalizing behavioral problems. After adjustment for demographics and behavioral problems, parental insomnia remained to be significantly associated with adolescent suicidal ideation and suicide plan. Our findings support the need for early screening and formal assessment of sleep and mental health in adolescents of insomniac parents. PMID- 26096661 TI - Measurement equivalence of the Toronto Structured Interview for Alexithymia across language, gender, and clinical status. AB - The Toronto Structured Interview for Alexithymia (TSIA) has been translated into Dutch, German, and Italian and validated in clinical and nonclinical populations. In order to make valid comparisons across different population groups, it is important to establish measurement equivalence across variables such as language, gender, and clinical status. Our objective in this study was to establish measurement equivalence in relation to language (English, Dutch, German, and Italian), gender, and clinical status (non-clinical, psychiatric, and medical) using differential item functioning (DIF). The sample was composed of 842 adults representing the four language groups, all of whom had undergone the TSIA assessment as part of several earlier studies. Ordinal Logistic Regression was employed to explore DIF of the TSIA items. Although several items were found to exhibit DIF for language, gender, or clinical status, all of these effects were within an acceptable range. These findings provide support for the measurement equivalence of the TSIA, and allow researchers to reliably compare results from studies using the TSIA across the four language groups, gender, and clinical status. PMID- 26096662 TI - Childhood trauma associates with clinical features of schizophrenia in a sample of Chinese inpatients. AB - This study examined the association between childhood trauma and clinical features, comorbid anxiety and post-traumatic stress disorder (PTSD) symptoms, and suicidal and aggressive behaviors in Chinese patients with schizophrenia. The Childhood Trauma Questionnaire - Short Form (CTQ-SF), the Impact of Events Scale Revised (IES-R), and the State-Trait Anxiety Inventory (STAI) were administered to 182 Chinese inpatients with schizophrenia. The relationship between the severity and the number of traumic experiences and clinical features were analyzed. Physical neglect (PN) in childhood was reported in 71.7% of this sample, followed by emotional neglect (EN, 58.6%), sexual abuse (SA, 39.9%), emotional abuse (EA, 31.7%) and physical abuse (PA, 22.2%). Significant negative correlations existed between age of onset and the EA scores. Significant positive correlations were found between the subscores of IES-R, STAI and CTQ-SF. Patients with history of suicidal or aggressive behaviors had significantly higher trauma scores than patients without such behaviors. Exposure to childhood trauma is associated with early age of onset, more PTSD and anxiety symptoms, and history of suicidal and aggressive behaviors. A dose-effect may exist between severity, number of trauma experiences, and clinical features. PMID- 26096663 TI - Red blood cell replacement, or nanobiotherapeutics with enhanced red blood cell functions? AB - Why is this important? Under normal circumstances, donor blood is the best replacement for blood. However, there are exceptions: During natural epidemics (e.g., HIV, Ebola, etc.) or man-made epidemics (terrorism, war, etc.), there is a risk of donor blood being contaminated, and donors being disqualified because they have contracted disease. Unlike red blood cells (RBCs), blood substitutes can be sterilized to remove infective agents. Heart attack and stroke are usually caused by obstruction of arterial blood vessels. Unlike RBCs, which are particulate, blood substitutes are in the form of a solution that can perfuse through obstructed vessels with greater ease to reach the heart and brain, as has been demonstrated in animal studies. Severe blood loss from injuries sustained during accidents, disasters, or war may require urgent blood transfusion that cannot wait for transportation to the hospital for blood group testing. Unlike RBCs, blood substitutes do not have specific blood groups, and can be administered on the spot. RBCs have to be stored under refrigeration for up to 42 days, and are thus difficult to transport and store in times of disaster and at the battlefront. Blood substitutes can be stored at room temperature for more than 1 year, compared to the RBC shelf life of 1 day, at room temperature. In cases of very severe hemorrhagic shock, there is usually a safety window of 60 min for blood replacement, beyond which there could be problems related to irreversible shock. Animal studies show that a particular type of blood substitute, with enhanced RBC enzymes, may be able to prolong the duration of the safety window. PMID- 26096664 TI - Quetiapine induced restless legs syndrome: A series of four cases. PMID- 26096666 TI - PSF mapping-based correction of eddy-current-induced distortions in diffusion weighted echo-planar imaging. AB - PURPOSE: To accurately correct diffusion-encoding direction-dependent eddy current-induced geometric distortions in diffusion-weighted echo-planar imaging (DW-EPI) and to minimize the calibration time at 7 Tesla (T). METHODS: A point spread function (PSF) mapping based eddy-current calibration method is newly presented to determine eddy-current-induced geometric distortions even including nonlinear eddy-current effects within the readout acquisition window. To evaluate the temporal stability of eddy-current maps, calibration was performed four times within 3 months. Furthermore, spatial variations of measured eddy-current maps versus their linear superposition were investigated to enable correction in DW EPIs with arbitrary diffusion directions without direct calibration. For comparison, an image-based eddy-current correction method was additionally applied. Finally, this method was combined with a PSF-based susceptibility induced distortion correction approach proposed previously to correct both susceptibility and eddy-current-induced distortions in DW-EPIs. RESULTS: Very fast eddy-current calibration in a three-dimensional volume is possible with the proposed method. The measured eddy-current maps are very stable over time and very similar maps can be obtained by linear superposition of principal-axes eddy current maps. High resolution in vivo brain results demonstrate that the proposed method allows more efficient eddy-current correction than the image-based method. CONCLUSION: The combination of both PSF-based approaches allows distortion-free images, which permit reliable analysis in diffusion tensor imaging applications at 7T. PMID- 26096665 TI - Neuropsychiatric symptoms as early manifestations of emergent dementia: Provisional diagnostic criteria for mild behavioral impairment. AB - Neuropsychiatric symptoms (NPS) are common in dementia and in predementia syndromes such as mild cognitive impairment (MCI). NPS in MCI confer a greater risk for conversion to dementia in comparison to MCI patients without NPS. NPS in older adults with normal cognition also confers a greater risk of cognitive decline in comparison to older adults without NPS. Mild behavioral impairment (MBI) has been proposed as a diagnostic construct aimed to identify patients with an increased risk of developing dementia, but who may or may not have cognitive symptoms. We propose criteria that include MCI in the MBI framework, in contrast to prior definitions of MBI. Although MBI and MCI can co-occur, we suggest that they are different and that both portend a higher risk of dementia. These MBI criteria extend the previous literature in this area and will serve as a template for validation of the MBI construct from epidemiologic, neurobiological, treatment, and prevention perspectives. PMID- 26096668 TI - Utility of biomarkers to predict bacterial meningitis in elderly patients. PMID- 26096667 TI - Alendronate, a double-edged sword acting in the mevalonate pathway. AB - Aminobisphosphonate aledronate is a compound commonly used clinically for the treatment of osteoporosis and other bone diseases, as a result of it preventing bone resorption. However, in previous years it has also been used to obtain cellular and animal models of a rare genetic disorder termed Mevalonate Kinase Deficiency (MKD). MKD is caused by mutations affecting the mevalonate kinase enzyme, in the cholesterol pathway and alendronate can be used to biochemically mimic the genetic defect as it inhibits farnesyl pyrophosphate synthase in the same pathway. Despite evidence in favor of the inhibition exerted on the mevalonate pathway, there is at least one clinical case of MKD in which alendronate improved not only skeletal and bone fractures, as expected, but also MKD clinical features. Based on this finding, the present study assessed the anti inflammatory properties of this aminobisphosphonate in vitro. No anti inflammatory effects of alendronate were observed in the in vitro experiments. Since MKD lacks specific treatments, these results may assist scientists and physicians in making the decision as to the most suitable choice of therapeutic compounds for this neglected disease. PMID- 26096670 TI - Neuropsychiatric manifestations of Graves' disease in paediatric patients. PMID- 26096669 TI - [Clinical and psychopathological factors associated with impulse control disorders in Parkinson's disease]. AB - INTRODUCTION: Impulse control disorders (ICD) constitute a complication that may arise during the course of Parkinson's disease (PD). Several factors have been linked to the development of these disorders, and their associated severe functional impairment requires specific and multidisciplinary management. The objective of this study was to evaluate the frequency of ICDs and the clinical and psychopathological factors associated with the appearance of these disorders. METHODS: Cross-sectional, descriptive, and analytical study of a sample of 115 PD patients evaluated to determine the presence of an ICD. Clinical scales were administered to assess disease severity, personality traits, and presence of psychiatric symptoms at the time of evaluation. RESULTS: Of the 115 patients with PD, 27 (23.48%) displayed some form of ICD; hypersexuality, exhibited by 14 (12.2%), and binge eating, present in 12 (10.1%), were the most common types. Clinical factors associated with ICD were treatment with dopamine agonists (OR: 13.39), earlier age at disease onset (OR: 0.92), and higher score on the UPDRS-I subscale; psychopathological factors with a significant association were trait anxiety (OR: 1.05) and impulsivity (OR: 1.13). CONCLUSIONS: ICDs are frequent in PD, and treatment with dopamine agonists is the most important risk factor for these disorders. High impulsivity and anxiety levels at time of evaluation, and younger age at disease onset, were also linked to increased risk. However, presence of these personality traits prior to evaluation did not increase risk of ICD. PMID- 26096671 TI - Nanoparticles derived from plant proteins for controlled release and targeted delivery of therapeutics. PMID- 26096673 TI - Detection of Human alpha-L-Fucosidases by a Quinone Methide-Generating Probe: Enhanced Activities in Response to Helicobacter pylori Infection. AB - alpha-L-Fucosidase activity is associated with several diseases. To study the enzymatic activity change under pathological conditions, we developed a quinone methide-generating activity-based probe useful for examining the presence, activity, and localization of human alpha-L-fucosidase in vivo in the context of Helicobacter pylori infection. In particular, an increase in intracellular fucosidase (Fuca1) activity was found in gastric epithelial cells upon bacterial infection. We further studied the effect of several bacterial stimulants on this enhanced Fuca1 activity and identified lipopolysaccharides to be a major contributing factor. PMID- 26096674 TI - Effects of ignoring clustered data structure in confirmatory factor analysis of ordered polytomous items: a simulation study based on PANSS. AB - Statistical theory indicates that hierarchical clustering by interviewers or raters needs to be considered to avoid incorrect inferences when performing any analyses including regression, factor analysis (FA) or item response theory (IRT) modelling of binary or ordinal data. We use simulated Positive and Negative Syndrome Scale (PANSS) data to show the consequences (in terms of bias, variance and mean square error) of using an analysis ignoring clustering on confirmatory factor analysis (CFA) estimates. Our investigation includes the performance of different estimators, such as maximum likelihood, weighted least squares and Markov Chain Monte Carlo (MCMC). Our simulation results suggest that ignoring clustering may lead to serious bias of the estimated factor loadings, item thresholds, and corresponding standard errors in CFAs for ordinal item response data typical of that commonly encountered in psychiatric research. In addition, fit indices tend to show a poor fit for the hypothesized structural model. MCMC estimation may be more robust against clustering than maximum likelihood and weighted least squares approaches but further investigation of these issues is warranted in future simulation studies of other datasets. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096675 TI - Neuroendocrine mechanisms underlying behavioral stability: implications for the evolutionary origin of personality. AB - Personality traits are behaviors that show limited flexibility over time and across contexts, and thus understanding their origin requires an understanding of what limits behavioral flexibility. Here, I suggest that insight into the evolutionary origin of personality traits requires determining the relative importance of selection and constraint in producing limits to behavioral flexibility. Natural selection as the primary cause of limits to behavioral flexibility assumes that the default state of behavior is one of high flexibility and predicts that personality variation arises through evolution of buffering mechanisms to stabilize behavioral expression, whereas the constraint hypothesis assumes that the default state is one of limited flexibility and predicts that the neuroendocrine components that underlie personality variation are those most constrained in flexibility. Using recent work on the neurobiology of sensitive periods and maternal programming of offspring behavior, I show that some of the most stable aspects of the neuroendocrine system are structural components and maternally induced epigenetic effects. Evidence of numerous constraints to changes in structural features of the neuroendocrine system and far fewer constraints to flexibility of epigenetic systems suggests that structural constraints play a primary role in the origin of behavioral stability and that epigenetic programming may be more important in generating adaptive variation among individuals. PMID- 26096676 TI - The role of miR156/SPLs modules in Arabidopsis lateral root development. AB - miR156 is an evolutionarily highly conserved miRNA in plants that defines an age dependent flowering pathway. The investigations thus far have largely, if not exclusively, confined to plant aerial organs. Root branching architecture is a major determinant of water and nutrients uptake for plants. We show here that MIR156 genes are differentially expressed in specific cells/tissues of lateral roots. Plants overexpressing miR156 produce more lateral roots whereas reducing miR156 levels leads to fewer lateral roots. We demonstrate that at least one representative from the three groups of miR156 targets SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes: SPL3, SPL9 and SPL10 are involved in the repression of lateral root growth, with SPL10 playing a dominant role. In addition, both MIR156 and SPLs are responsive to auxin signaling suggesting that miR156/SPL modules might be involved in the proper timing of the lateral root developmental progression. Collectively, these results unravel a role for miR156/SPLs modules in lateral root development in Arabidopsis. PMID- 26096677 TI - An oxidative coupling product of luteolin with cysteine ester and its enhanced inhibitory activity for xanthine oxidase. AB - Oxidative coupling reactions of several flavonoids with a cysteine ester (a radicalic and nucleophilic biochemical) were carried out and the abilities of the coupling products against xanthine oxidase (XO) were screened. One of the products, derived from luteolin, showed a notable inhibitory effect. A potent XO inhibitory compound was isolated from the complex mixture of the product of the coupling of luteolin and cysteine ethyl ester, and its structure was determined by NMR and MS analysis. The compound has a unique 1,4-thiazine ring unit on the luteolin B-ring and is inhibited XO 4.5 times more strongly than it did luteolin. PMID- 26096678 TI - Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands. AB - We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2-P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2-P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV 1 protease was determined at 1.11A resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site. PMID- 26096679 TI - Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40). AB - A screening hit that showed a weak (EC50 = 18 MUM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4 oxadiazoles with significantly improved potency (best EC50 = 0.058 MUM). The lead compounds in each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds reported are significant new starting points for further preclinical development of future diabetic agents with a mechanism of action for which a first-in-class agent is yet to be approved. PMID- 26096680 TI - Exploration on natural product anibamine side chain modification toward development of novel CCR5 antagonists and potential anti-prostate cancer agents. AB - Prostate cancer is one of the leading causes of death among males in the world. Prostate cancer cells have been shown to express upregulated chemokine receptor CCR5, a G protein-coupled receptor (GPCR) that relates to the inflammation process. Anibamine, a natural product containing a pyridine ring and two aliphatic side chains, was shown to carry a binding affinity of 1 MUM at CCR5 as an antagonist with potential anti-cancer activity. However, it is not drug-like according to the Lipinski's rule of five mainly due to its two long aliphatic side chains. In our effort to improve its drug-like property, a series of anibamine derivatives were designed and synthesized by placement of aromatic side chains through an amide linkage to the pyridine ring. The newly synthesized compounds were tested for their CCR5 affinity and antagonism, and potential anti proliferation activity against prostate cancer cell lines. Basal cytotoxicity was finally studied for compounds showing potent anti-proliferation activity. It was found that compounds with hydrophobic substitutions on the aromatic systems seemed to carry more promising CCR5 binding and prostate cancer cell proliferation inhibition activities. PMID- 26096681 TI - Potential therapeutic agents for circulatory diseases from Bauhinia glauca Benth.subsp. pernervosa. (Da Ye Guan Men). AB - Because of platelets as critical factor in the formation of pathogenic thrombi, anti-platelet activities have been selected as therapeutic target for various circulatory diseases. In order to find potential therapeutic agents, bioassay directed separation of Bauhinia glauca Benth.subsp. pernervosa. (called Da Ye Guan Men as a traditional Chinese medicine) was performed to get 29 main components (compounds 1-29) from the bioactive part of this herbal. It was the first time to focus on the composition with anti-platelet aggregation activities for this traditional Chinese medicine. The constituents, characterized from the effective extract, were established on the basis of extensive spectral data analysis. Then their anti-platelet aggregation effects were evaluated systematically. On the basis of the chemical profile and biological assay, it was suggested that the flavonoid composition (5 and 18) should be responsible for the anti-platelet aggregation of the herbal because of their significant activities. The primary structure and activity relationship was also discussed briefly. PMID- 26096682 TI - Effects of enzastaurin and its metabolites on the QT interval in cancer patients. AB - Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72 21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P < .05). PMID- 26096683 TI - Mortality of Amur tigers: The more things change, the more they stay the same. AB - Poaching as well as loss of habitat and prey are identified as causes of tiger population declines. Although some studies have examined habitat requirements and prey availability, few studies have quantified cause-specific mortality of tigers. We used cumulative incidence functions (CIFs) to quantify cause-specific mortality rates of tigers, expanding and refining earlier studies to assess the potential impact of a newly emerging disease. To quantify changes in tiger mortality over time, we re-examined data first collected by Goodrich et al. (; study period 1: 1992-2004) as well as new telemetry data collected since January 2005 (study period 2: 2005-2012) using a total of 57 tigers (27 males and 30 females) monitored for an average of 747 days (range 26-4718 days). Across the entire study period (1992 to 2012) we found an estimated average annual survival rate of 0.75 for all tigers combined. Poaching was the primary cause of mortality during both study periods, followed by suspected poaching, distemper and natural/unknown causes. Since 2005, poaching mortality has remained relatively constant and, if combined with suspected poaching, may account for a loss of 17 19% of the population each year. Canine distemper virus (CDV) may be an additive form of mortality to the population, currently accounting for an additional 5%. Despite this relatively new source of mortality, poaching remains the main threat to Amur tiger survival and, therefore, population growth. PMID- 26096684 TI - Lymph nodes behind the axillary neurovascular bundle: case report and cadaveric study of frequency and distribution. AB - Axillary clearance was undertaken in a 58-year-old male with massive lymph node enlargement caused by melanoma from an unknown primary site. We discovered a group of metastatic lymph nodes behind the axillary neurovascular bundle. This group of nodes (retro-axillary lymph nodes) could represent an extension of the subscapular group, or the seventh group of axillary lymphoid nodes. They were successfully removed using an ad hoc surgical technique, and the subsequent findings are presented herein. To check the frequency of these lymph nodes in this area, we conducted a study on 15 cadavers (30 armpits). The technique of cadaveric sampling is described. Retro-axillary tissue was histologically processed to determine the number of lymph nodes present. It was found that lymph nodes were present in the defined area in 18 of the 30 (60 %) armpits explored. We recommend assessment of the retro-axillary space during surgery entailing massive axillary lymph node involvement. PMID- 26096685 TI - Structure and functions of the placenta in common minke (Balaenoptera acutorostrata), Bryde's (B. brydei) and sei (B. borealis) whales. AB - The structure and functions of placentas were examined in 3 species of rorqual whales, common minke (Balaenoptera acutorostrata), Bryde's (B. brydei) and sei (B. borealis) whales, with the aim of confirming the structural characteristics of the chorion, including the presence of the areolar part, and clarifying steroidogenic activities and fetomaternal interactions in the placentas of these whales. Placentas were collected from the second phase of the Japanese Whale Research Program under Special Permit in the North Pacific (JARPN II). Histological and ultrastructural examinations revealed that these whale placentas were epitheliochorial placentas with the interdigitation of chorionic villi lined by monolayer uninucleate cells (trophoblast cells) and endometrial crypts as well as folded placentation by fold-like chorionic villi. Moreover, well-developed pouch-like areolae were observed in the placentas, and active absorption was suggested in the chorionic epithelial cells of the areolar part (areolar trophoblast cells). Berlin blue staining showed the presence of ferric ions (Fe(3+)) in the uterine glandular epithelial cells and within the stroma of chorionic villi in the areolar part. An immunohistochemical examination revealed tartrate-resistant acid phosphatase (TRAP; known as uteroferrin in uteri) in the cytoplasm of glandular cells and areolar trophoblast cells. This result suggested that, in cetaceans, uteroferrin is used to supply iron to the fetus. Furthermore, immunoreactivity for P450scc and P450arom was detected in trophoblast cells, but not in areolar trophoblast cells, suggesting that trophoblast cells synthesize estrogen in whale placentas. Therefore, we herein immunohistochemically revealed the localization of aromatase and uteroferrin in cetacean placentas during pregnancy for the first time. PMID- 26096686 TI - Altered protein expression pattern in skin fibroblasts from parkin-mutant early onset Parkinson's disease patients. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder caused primarily by selective degeneration of the dopaminergic neurons in substantia nigra. In this work the proteomes extracted from primary fibroblasts of two unrelated, hereditary cases of PD patients, with different parkin mutations, were compared with the proteomes extracted from commercial adult normal human dermal fibroblasts (NHDF) and primary fibroblasts from the healthy mother of one of the two patients. The results show that the fibroblasts from the two different cases of parkin-mutant patients display analogous alterations in the expression level of proteins involved in different cellular functions, like cytoskeleton structure-dynamics, calcium homeostasis, oxidative stress response, protein and RNA processing. PMID- 26096687 TI - Risks and Benefits of Bisphosphonate Therapies. AB - Bisphosphonates are the mainstay of osteoporosis treatment but also play a fundamental role in treating other bone diseases such as Osteogenesis Imperfecta, Pagets' disease, and in the prevention of adverse skeletal effects in certain cancers such as prostate cancer or multiple myeloma. In the last decades, the refinement of bisphosphonates and an increase in the number of new bisphosphonates commercialized has altered the clinical management of these diseases. Despite differences between randomized controlled trials and observational studies, overall all bisphosphonates licensed have proven to reduce the risk of fracture through the inhibition of bone resorption. Other beneficial effects include pain reduction in bone metastasis and potentially a decrease in mortality. However, the chronic nature of most of these disorders implies long term treatments, which can be associated with long-term adverse effects. Some of the adverse effects identified include an increased risk of atypical femur fractures, osteonecrosis of the jaw, gastrointestinal side effects, or atrial fibrillation. The harm/benefit thinking and the constant update regarding these medications are vital in the day-to-day decision-making in clinical practices. The aims of this review are to compile the basic characteristics of these drugs and outline the most important benefits and side effects and provide a clinical context as well as a research agenda to fill the gaps in our knowledge. PMID- 26096689 TI - RNA degradosomes in bacteria and chloroplasts: classification, distribution and evolution of RNase E homologs. AB - Ribonuclease E (RNase E) of Escherichia coli, which is the founding member of a widespread family of proteins in bacteria and chloroplasts, is a fascinating enzyme that still has not revealed all its secrets. RNase E is an essential single-strand specific endoribonuclease that is involved in the processing and degradation of nearly every transcript in E. coli. A striking enzymatic property is a preference for substrates with a 5' monophosphate end although recent work explains how RNase E can overcome the protection afforded by the 5' triphosphate end of a primary transcript. Other features of E. coli RNase E include its interaction with enzymes involved in RNA degradation to form the multienzyme RNA degradosome and its localization to the inner cytoplasmic membrane. The N terminal catalytic core of the RNase E protomer associates to form a tetrameric holoenzyme. Each RNase E protomer has a large C-terminal intrinsically disordered (ID) noncatalytic region that contains sites for interactions with protein components of the RNA degradosome as well as RNA and phospholipid bilayers. In this review, RNase E homologs have been classified into five types based on their primary structure. A recent analysis has shown that type I RNase E in the gamma proteobacteria forms an orthologous group of proteins that has been inherited vertically. The RNase E catalytic core and a large ID noncatalytic region containing an RNA binding motif and a membrane targeting sequence are universally conserved features of these orthologs. Although the ID noncatalytic region has low composition and sequence complexity, it is possible to map microdomains, which are short linear motifs that are sites of interaction with protein and other ligands. Throughout bacteria, the composition of the multienzyme RNA degradosome varies with species, but interactions with exoribonucleases (PNPase, RNase R), glycolytic enzymes (enolase, aconitase) and RNA helicases (DEAD-box proteins, Rho) are common. Plasticity in RNA degradosome composition is due to rapid evolution of RNase E microdomains. Characterization of the RNase E-PNPase interaction in alpha-proteobacteria, gamma-proteobacteria and cyanobacteria suggests that it arose independently several times during evolution, thus conferring an advantage in control and coordination of RNA processing and degradation. PMID- 26096688 TI - Experiences of homophobia among gay and bisexual men: results from a cross sectional study in seven countries. AB - Experiences of homophobic discrimination are associated with an increased prevalence of psychological disorders and increased odds of reporting suicidal ideation among gay and bisexual men. We examine two domains of homophobia- external homophobic discrimination and internalised homophobia--and their associations with sexual orientation, demographic characteristics, relationships and social support among a sample of gay and bisexual men from seven countries. Sexually active gay and bisexual men aged over 18 and residing in Australia, Brazil, Canada, South Africa, Thailand, the UK and the USA were recruited through banner advertisements on Facebook. Two outcomes were examined: reporting experiences of homophobic discrimination and reporting feelings of internalised homophobia. No covariates were consistently significantly associated with experiencing external homophobic discrimination across countries. Across all countries, bisexually identifying respondents reported significantly greater feelings of internalised homophobia. Respondents in Brazil and the UK reporting a main partner, and respondents in Australia, Brazil, Canada, South Africa, Thailand and the USA reporting a larger gay/bisexual social network, reported significantly fewer feelings of internalised homophobia. Results suggest an ameliorative effect of social networks on experiencing homophobia. Additional research should focus on the mechanisms through which social networks reduce feelings of internalised homophobia. PMID- 26096690 TI - Head Transplantation in Mouse Model. AB - AIMS: The mouse model of allo-head and body reconstruction (AHBR) has recently been established to further the clinical development of this strategy for patients who are suffering from mortal bodily trauma or disease, yet whose mind remains healthy. Animal model studies are indispensable for developing such novel surgical practices. The goal of this work was to establish head transplant mouse model, then the next step through the feasible biological model to investigate immune rejection and brain function in next step, thereby promoting the goal of translation of AHBR to the clinic in the future. METHODS AND RESULTS: Our approach involves retaining adequate blood perfusion in the transplanted head throughout the surgical procedure by establishing donor-to-recipient cross circulation by cannulating and anastomosing the carotid artery on one side of the body and the jugular vein on the other side. Neurological function was preserved by this strategy as indicated by electroencephalogram and intact cranial nerve reflexes. CONCLUSIONS: The results of this study support the feasibility of this method for avoiding brain ischemia during transplantation, thereby allowing for the possibility of long-term studies of head transplantation. PMID- 26096692 TI - THE PRENATAL PARENTAL REFLECTIVE FUNCTIONING QUESTIONNAIRE: EXPLORING FACTOR STRUCTURE AND CONSTRUCT VALIDITY OF A NEW MEASURE IN THE FINN BRAIN BIRTH COHORT PILOT STUDY. AB - Parental reflective functioning (PRF) is the capacity to focus on experience and feelings in oneself and in the child. Individual differences in PRF reportedly affect child attachment and socioemotional development. In this study, we report work on developing a questionnaire to assess PRF during pregnancy (Prenatal Parental Reflective Functioning Questionnaire; P-PRFQ). The factor structure of the 33-item version of the P-PRFQ was explored using pilot study data from the Finn Brain Birth Cohort Study (n = 124 mothers, n = 82 fathers). Construct validity was assessed against the Pregnancy Interview (PI; A. Slade, L. Grunebaum, L. Huganir, & M. Reeves, 1987, 2002, 2011) in a subsample of 29 mothers from the same pilot sample. Exploratory and confirmatory factor analysis resulted in a 14-item P-PRFQ, with three factors which seem to capture relevant aspects of prenatal parental mentalization-F1: "Opacity of mental states," F2: "Reflecting on the fetus-child," and F3: "The dynamic nature of the mental states." Functioning of the factor structure was further tested in the large cohort with 600 mothers and 600 fathers. Correlations with the PI result were high, both regarding total and factor scores of the P-PRFQ. Cost-effective tools to assess key areas of early parenting are needed for both research and clinical purposes. The 14-item P-PRFQ seems to be an applicable and promising new tool for assessing very early parental mentalizing capacity. PMID- 26096693 TI - Retrospective evaluation of corneal reconstruction using ACell Vet(TM) alone in dogs and cats: 82 cases. AB - OBJECTIVES: To retrospectively evaluate the complications, graft clarity, and outcomes associated with the use of commercially available porcine urinary bladder submucosa (ACell Vet(TM) ) alone for corneal reconstruction in dogs and cats. PROCEDURES: Dogs or cats receiving an ACell Vet(TM) graft for corneal reconstruction due to severe ulcerative keratitis or after a keratectomy to remove a corneal sequestrum were included. All received a single layer of ACell Vet(TM) , bandage contact lens, and temporary tarsorrhaphy. Bandage contact lens and temporary tarsorrhaphy were removed after graft vascularization or epithelialization. Topical steroids, cyclosporine, tacrolimus were started after epithelialization. Based on their last examination, outcomes were categorized into five groups based on the presence of corneal vessels, appearance of the scar, and the ability to visualize the posterior and/or the anterior segment through the grafted area. RESULTS: There were 82 eyes included in the study, with 68 eyes with sufficient follow-up time for final assessment. Scarring was minimal in 47 eyes, moderate but not enough to obscure visualization of the posterior segment in 12, and severe in nine. There were five eyes that developed phthisis bulbi, glaucoma or were enucleated and nine that were lost to follow up. Graft dehiscence occurred in 19 eyes. Twelve healed without additional surgical intervention while three required a second graft, two became phthisical, and two were enucleated. CONCLUSIONS AND CLINICAL RELEVANCE: Corneal reconstruction with ACell Vet(TM) alone is a viable alternative and results in minimal scarring and complications in cats. In dogs, scarring is more pronounced than in cats and graft dehiscence rate is higher compared to conventional techniques. PMID- 26096691 TI - COMT polymorphism modulates the resting-state EEG alpha oscillatory response to acute nicotine in male non-smokers. AB - Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists, and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting-state electroencephalographic (EEG) oscillations. In a sample of 62 healthy non-smoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo-controlled design was shown to affect alpha oscillatory activity, increasing power of upper alpha oscillations in frontocentral regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak alpha frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower alpha frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain alpha oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT. PMID- 26096694 TI - Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. AB - BACKGROUND: This study evaluated the 2-year overall survival rate, adverse event rate, local control rate, and impact on pulmonary function tests for medically inoperable patients with stage IA non-small cell lung cancer (NSCLC) undergoing computed tomography (CT)-guided radiofrequency ablation (RFA) in a prospective, multicenter trial. METHODS: Fifty-four patients (25 men and 29 women) with a median age of 76 years (range, 60-89 years) were enrolled from 16 US centers; 51 patients were eligible for evaluation (they had biopsy-proven stage IA NSCLC and were deemed medically inoperable by a board-certified thoracic surgeon). Pulmonary function tests were performed within the 60 days before RFA and 3 and 24 months after RFA. Adverse events were recorded and categorized. Patients were followed with CT and fludeoxyglucose positron emission tomography. Local control rate and recurrence patterns were analyzed. RESULTS: The overall survival rate was 86.3% at 1 year and 69.8% at 2 years. The local tumor recurrence-free rate was 68.9% at 1 year and 59.8% at 2 years and was worse for tumors > 2 cm. In the 19 patients with local recurrence, 11 were re-treated with RFA, 9 underwent radiation, and 3 underwent chemotherapy. There were 21 grade 3 adverse events, 2 grade 4 adverse events, and 1 grade 5 adverse event in 12 patients within the first 90 days after RFA. None of the grade 4 or 5 adverse events were attributable to RFA. There was no significant change in the forced expiratory volume in the first second of expiration or the diffusing capacity of lung for carbon monoxide after RFA. A tumor size less than 2.0 cm and a performance status of 0 or 1 were associated with statistically significant improved survival of 83% and 78%, respectively, at 2 years. CONCLUSIONS: RFA is a single, minimally invasive procedure that is well tolerated in medically inoperable patients, does not adversely affect pulmonary function tests, and provides a 2-year overall survival rate that is comparable to the rate reported after stereotactic body radiotherapy in similar patients. PMID- 26096695 TI - Functional traits, convergent evolution, and periodic tables of niches. AB - Ecology is often said to lack general theories sufficiently predictive for applications. Here, we examine the concept of a periodic table of niches and feasibility of niche classification schemes from functional trait and performance data. Niche differences and their influence on ecological patterns and processes could be revealed effectively by first performing data reduction/ordination analyses separately on matrices of trait and performance data compiled according to logical associations with five basic niche 'dimensions', or aspects: habitat, life history, trophic, defence and metabolic. Resultant patterns then are integrated to produce interpretable niche gradients, ordinations and classifications. Degree of scheme periodicity would depend on degrees of niche conservatism and convergence causing species clustering across multiple niche dimensions. We analysed a sample data set containing trait and performance data to contrast two approaches for producing niche schemes: species ordination within niche gradient space, and niche categorisation according to trait-value thresholds. Creation of niche schemes useful for advancing ecological knowledge and its applications will depend on research that produces functional trait and performance datasets directly related to niche dimensions along with criteria for data standardisation and quality. As larger databases are compiled, opportunities will emerge to explore new methods for data reduction, ordination and classification. PMID- 26096696 TI - SOX4 is overexpressed in diffusely infiltrating astrocytoma and confers poor prognosis. AB - The SOX4 (sex-determining region Y-related high-mobility-group box transcription factor 4) gene plays critical roles in embryonic development and cell-fate determination. Recently, SOX4 overexpression has been found in various tumors. However, its expression status and prognostic significance in astrocytoma remain unknown. In this study, SOX4 expression in diffusely infiltrating astrocytoma (WHO grades II-IV) tissues (in comparison with pilocytic astrocytomas) was examined by immunohistochemistry, and its relevance with prognosis was analyzed. Our data showed that SOX4 was over-expressed in diffusely infiltrating astrocytomas and its expression was positively correlated with astrocytoma grade (WHO grades II-IV). Significantly, Kaplan-Meier analysis revealed that SOX4 nuclear overexpression (SOX4-N) was associated with poorer progression-free survival (PFS) and disease-specific survival (DSS) in diffusely infiltrating astrocytoma patients (P < 0.05). Cox regression analysis further showed that nuclear SOX4-N was a significant independent negative prognostic factor for these patients. PMID- 26096697 TI - The Danish urban-rural gradient of allergic sensitization and disease in adults. AB - BACKGROUND: The reported prevalence of allergic sensitization among children is lower in rural areas than in urban areas of the world. The aim was to investigate the urban-rural differences of allergic sensitization to inhalant allergens in adults depending on childhood exposure living in an industrialized country as Denmark. METHODS: A total of 1236 male participants of 30-40 years of age recruited from two epidemiological studies were divided into four groups with regard to place of upbringing; city, town, rural area and farm. Allergic sensitization was assessed by skin prick tests (SPTs) to 10 inhalant allergens and measurements of serum specific IgE (sIgE) to four inhalant allergens (grass, birch, cat and house dust mite). RESULTS: The prevalence of allergic sensitization to inhalant allergens decreased with decreasing degree of urbanized childhood. The risk of being sensitized to one or more allergens also decreased with decreasing degree of urbanized upbringing measured by sIgE to 4 common allergens as odds ratio with 95% confidence intervals with city as reference; town 0.60 (0.39-0.92), rural area 0.34 (0.22-0.52) and farm 0.31 (0.21-0.46). Furthermore, it was measured by SPT to 10 common allergens; town 0.52 (0.33 0.84), rural area 0.34 (0.21-0.53) and farm 0.29 (0.19-0.45). This urban-rural association was also seen for the risk of sensitization to specific allergens, rhinitis and allergic asthma. CONCLUSION: This is the first study to show an urban-rural gradient of overall allergic sensitization and specific allergen sensitization in adults depending on their childhood exposure. In this highly homogenous western population, exposure to a less urbanized childhood was associated with lower risk of allergic sensitization and disease as an adult. PMID- 26096698 TI - Electronic structures of anatase (TiO2)1-x(TaON)x solid solutions: a first principles study. AB - Sensitizing wide band gap photo-functional materials under visible-light irradiation is an important task for efficient solar energy conversion. Although nitrogen doping into anatase TiO2 has been extensively studied for this purpose, it is hard to increase the nitrogen content in anatase TiO2 because of the aliovalent nitrogen substituted for oxygen, leading to the formation of secondary phases or defects that hamper the migration of photoexcited charge carriers. In this paper, electronic structures of (TiO2)1-x(TaON)x (0 <= x <= 1) solid solutions, in which the stoichiometry is satisfied with the co-substitution of Ti for Ta along with O for N, are investigated within the anatase crystal structure using first-principles calculations. Our computational results show that the solid solutions have substantially narrower band gaps than TiO2, without introducing any localized energy states in the forbidden gap. In addition, in comparison with the pristine TiO2, the solid solution has a direct band gap when the content of TaON exceeds 0.25, which is advantageous to light absorption. The valence band maximum (VBM) of the solid solutions, which is mainly composed of N 2p states hybridized with O 2p, Ti 3d or Ta 5d orbitals, is higher in energy than that of pristine anatase TiO2 consisting of non-bonding O 2p states. On the other hand, incorporating TaON into TiO2 causes the formation of d-d bonding states through pi interactions and substantially lowers the conduction band minimum (CBM) because of the shortened distance between some metal atoms. As a result, the anatase (TiO2)1-x(TaON)x is expected to become a promising visible-light absorber. In addition, some atomic configurations are found to possess exceptionally narrow band gaps. PMID- 26096699 TI - Differences in Health at Age 100 According to Sex: Population-Based Cohort Study of Centenarians Using Electronic Health Records. AB - OBJECTIVES: To use primary care electronic health records (EHRs) to evaluate the health of men and women at age 100. DESIGN: Population-based cohort study. SETTING: Primary care database in the United Kingdom, 1990-2013. PARTICIPANTS: Individuals reaching the age of 100 between 1990 and 2013 (N = 11,084, n = 8,982 women, n = 2,102 men). MEASUREMENTS: Main categories of morbidity and an index of multiple morbidities, geriatric syndromes and an index of multiple impairments, cardiovascular risk factors. RESULTS: The number of new female centenarians per year increased from 16 per 100,000 in 1990-94 to 25 per 100,000 in 2010-13 (P < .001) and of male centenarians from four per 100,000 to six per 100,000 (P = .06). The most prevalent morbidities at the age of 100 were musculoskeletal diseases, disorders of the senses, and digestive diseases. Women had greater multiple morbidity than men (odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.42-1.89, P < .001). Geriatric syndromes, including falls, fractures, hearing and vision impairment, and dementia, were frequent; 30% of women and 49% of men had no recorded geriatric syndromes. Women had greater likelihood of having multiple geriatric syndromes (OR = 2.14, 95% CI = 1.90-2.41, P < .001). CONCLUSION: Fewer men than women reach the age of 100, but male centenarians have lower morbidity and fewer geriatric syndromes than women. Research using EHRs offers opportunities to understand the epidemiology of aging and improve care of the oldest old. PMID- 26096700 TI - 5,7-Dihydroxy-6-Methoxy-Flavonoids Eliminate HIV-1 D3-transfected Cytoprotective Macrophages by Inhibiting the PI3K/Akt Signaling Pathway. AB - Flavonoids, well-documented secondary metabolites in many vegetables and plants, exhibit antiinflammatory, anti-oxidant, anti-microbial, and anticancer activities. However, their cytotoxic effects against human immunodeficiency virus type 1 (HIV-1)-infected cytoprotective macrophages have not been studied. In the present study, we investigated their effects and their molecular mechanisms. Treatment with flavonoids in the presence of lipopolysaccharide (LPS)/cycloheximide (CHX) potently eliminated HIV-1 Tat-transduced cytoprotective human microglial CHME5 cells; the 5,7-dihydroxy-6-methoxy-flavonoids oroxylin A and tectorigenin, at a concentration of 10 MUM, most potently eliminated the cytoprotective phenotype. These flavonoids eliminated Tat-transduced CHME5 cells, D3-transfected CHME5 cells, and HIV-1 D3-infected human primary macrophages, in a dose-dependent manner. Furthermore, oroxylin A and tectorigenin potently inhibited LPS/CHX-induced phosphorylation of phosphoinositide 3-kinase (PI3K), pyruvate dehydrogenase lipoamide kinase isozyme 1, Akt, and glycogen synthase kinase-3beta in the Tat-transduced cells, D3-transfected CHME5 cells, and D3 infected human primary macrophages. Based on these findings, 5,7-dihydroxy-6 methoxy-flavonoids may eliminate HIV-1 infected cytoprotective macrophages by inhibiting the PI3K/Akt signaling pathway and deliver anti-HIV-1 effects in vivo by shortening the lifespan of infected macrophages. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096701 TI - CONSUMER PREFERENCES FOR SCANNING MODALITY TO DIAGNOSE FOCAL LIVER LESIONS. AB - OBJECTIVES: Differences in the process of using liver imaging technologies might be important to patients. This study aimed to investigate preferences for scanning modalities used in diagnosing focal liver lesions. METHODS: A discrete choice experiment was administered to 504 adults aged 25 >=years. Respondents made repeated choices between two hypothetical scans, described according to waiting time for scan and results, procedure type, the chance of minor side effects, and whether further scanning procedures were likely to be required. Choice data were analyzed using mixed-logit models with respondent characteristics used to explain preference heterogeneity. RESULTS: Respondents preferred shorter waiting times, the procedure to be undertaken with a handheld scanner on a couch instead of within a body scanner, no side-effects, and no follow-up scans (p<=.01). The average respondent was willing to wait an additional 2 weeks for the scan if it resulted in avoiding side-effects, 1.5 weeks to avoid further procedures or to be told the results immediately, and 1 week to have the scan performed on a couch with a handheld scanner. However, substantial heterogeneity was observed in the strength of preference for desirable imaging characteristics. CONCLUSIONS: An average individual belonging to a general population sub-group most likely to require imaging to characterize focal liver lesions in the United Kingdom would prefer contrast-enhanced ultrasound over magnetic resonance imaging or computed tomography. Insights into the patient perspective around differential characteristics of imaging modalities have the potential to be used to guide recommendations around the use of these technologie PMID- 26096702 TI - Circulating tumor cells are associated with poor overall survival in patients with cholangiocarcinoma. AB - Circulating tumor cells (CTCs) in blood are associated with poor survival of patients with breast, prostate, or colon cancer. We hypothesized that CTCs are associated with poor survival of patients with cholangiocarcinoma (CCA). Eighty eight patients with CCA were prospectively enrolled at Mayo Clinic Rochester between June 2010 and September 2014. The CellSearch system by Veridex was used for detection of CTCs in peripheral blood. Associations between CTC, patient and tumor characteristics, and survival were examined using the Cox's proportional hazards model. Fifteen patients (17%) were positive for CTC >=2 and 8 patients (9%) for CTC >=5. CTCs were associated with tumor extent. CTC >=2 (hazard ratio [HR]: 2.5; 95% confidence interval [CI]: 1.1-5.4; P = 0.02) and CTC >=5 (HR, 4.1; 95% CI: 1.4-10.8; P = 0.01) were both independent predictors of survival. In subgroup analyses, CTC >=2 (HR, 8.2; 95% CI: 1.8-57.5; P < 0.01) and CTC >=5 (HR, 7.7; 95% CI: 1.4-42.9; P = 0.02) were both associated with shorter survival among patients with metastasis. There was a trend toward association of CTC >=5 with shorter survival in patients with nonmetastatic CCA (HR, 4.3; 95% CI: 1.0-13.8; P = 0.06). CTC >=2 (HR, 10.5; 95% CI: 2.2-40.1; P < 0.01) and CTC >=5 (HR, 10.2; 95% CI: 1.5-42.3; P = 0.02) were both associated with shorter survival among patients with perihilar/distal CCA. CTC >=5 was associated with shorter survival of patients with intrahepatic CCA (HR, 4.2; 95% CI: 1.1-14.1; P = 0.04). CONCLUSION: CTCs were associated with more-aggressive tumor characteristics and independently associated with survival in patients with CCA. Assessment of CTCs may be useful for identifying CCA patients at risk of early mortality. PMID- 26096703 TI - QT dynamics evaluated on fully automated QT measurement in children. AB - BACKGROUND: The association between QT interval and heart rate (HR), QT dynamics, has been reported to vary greatly between individuals. We investigated QT dynamics using fully automated QT interval measurement with a commercially available multifunctional electrocardiogram (ECG) recorder. METHODS: The study group included 17 otherwise healthy subjects (mean age, 12.7 years; 11 girls, 6 boys), who were undergoing exercise test for arrhythmia evaluation. The subjects had single premature ventricular contraction. RESULTS: Mean corrected QT interval (Fridericia) at rest was 412 +/- 19 ms (male, 408 +/- 20 ms; female, 414 +/- 19 ms), manually measured with a digitizer, using the tangent method. We assessed QT interval/HR slope during the whole exercise test, the exercise phase, and the recovery from exercise phase; the slopes were calculated offline after excluding wide QRS complex and were -1.15 +/- 0.26 (r(2) = 0.65), -1.18 +/- 0.30 (r(2) = 0.62), and -1.11 +/- 0.25 (r(2) = 0.70), respectively. Estimated QT interval at HR 60 beats/min (QT60) was calculated using the regression line formula and was 383 +/- 24 ms, 387 +/- 28 ms, and 375 +/- 21 ms, respectively. QT60 of the total exercise test correlated with the corrected QT interval at rest (P = 0.04, r(2) = 0.25). CONCLUSIONS: Assessment of QT dynamics is feasible on fully automated QT interval measurement with this ECG recorder. Further studies are required in larger populations to confirm the accuracy and precision of QT measurement and QT dynamics using this new multifunctional ECG. PMID- 26096704 TI - CLE peptide signaling in plants - the power of moving around. AB - The CLAVATA3 (CLV3)/EMBRYO SURROUNDING REGION (ESR)-RELATED (CLE) gene family encodes small secreted peptide ligands in plants. These peptides function non cell autonomously through interactions with plasma membrane-associated LEUCINE RICH REPEAT RECEPTOR-LIKE KINASEs (LRR-RLKs). These interactions are critical for cell-to-cell communications and control a variety of developmental and physiological processes in plants, such as regulation of stem cell proliferation and differentiation in the meristems, embryo and endosperm development, vascular development and autoregulation of nodulation. Here, we review the current knowledge in the field of CLE polypeptide signaling. PMID- 26096705 TI - Sulforaphane Ameliorates 3-Nitropropionic Acid-Induced Striatal Toxicity by Activating the Keap1-Nrf2-ARE Pathway and Inhibiting the MAPKs and NF-kappaB Pathways. AB - The potential neuroprotective value of sulforaphane (SFN) in Huntington's disease (HD) has not been established yet. We investigated whether SFN prevents and improves the neurological impairment and striatal cell death in a 3 nitropropionic acid (3-NP)-induced mouse model of HD. SFN (2.5 and 5.0 mg/kg/day, i.p.) was given daily 30 min before 3-NP treatment (pretreatment) and from onset/progression/peak points of the neurological scores. Pretreatment with SFN (5.0 mg/kg/day) produced the best neuroprotective effect with respect to the neurological scores and lethality among other conditions. The protective effects due to pretreatment with SFN were associated with the following: suppression of the formation of a lesion area, neuronal death, succinate dehydrogenase activity, apoptosis, microglial activation, and mRNA or protein expression of inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NP treatment. Also, pretreatment with SFN activated the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and inhibited the mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) pathways in the striatum after 3-NP treatment. As expected, the pretreatment with activators (dimethyl fumarate and antioxidant response element inducer-3) of the Keap1-Nrf2-ARE pathway decreased the neurological impairment and lethality after 3-NP treatment. Our findings suggest that SFN may effectively attenuate 3-NP-induced striatal toxicity by activating the Keap1-Nrf2-ARE pathway and inhibiting the MAPKs and NF kappaB pathways and that SFN has a wide therapeutic time-window for HD-like symptoms. PMID- 26096706 TI - Depletion of B cell CLL/Lymphoma 11B Gene Expression Represses Glioma Cell Growth. AB - B cell CLL/lymphoma 11B (Bcl11b), a C2H2 zinc finger transcription factor, not only serves as a critical regulator in development but also plays the controversial role in T cell acute lymphoblastic leukemia (T-ALL). We previously found that the enriched expression of Bcl11b was detected in high tumorigenic C6 glioma cells. However, the role of Bcl11b in glioma malignancy and its mechanisms remains to be uncovered. In this study, using the lentivirus-mediated knockdown (KD) approach, we found that Bcl11b KD in tumorigenic C6 cells reduced the cell proliferation, colony formation, and migratory ability. The results were further verified using two human malignant glioma cell lines, U87 and U251 cells. A cyclin-dependent kinase inhibitor p21, a known Bcl11b target, was significantly upregulated in tumorigenic C6, U87, and U251 cells after Bcl11b KD. Cellular senescence was observed by examination of the beta-galactosidase activity in U87 and U251 cells with Bcl11b KD. Reduced expression of stemness gene Sox-2 and its downstream effector Bmi-1 was also observed in U87 and U251 cells with Bcl11b KD. These results suggest that the ablation of Bcl11b gene expression induced glioma cell senescence. Propidium iodide (PI) staining combined with flow cytometry analysis also showed that Bcl11b KD led to the cell cycle arrest of U87 and U251 cells at the G0/G1 or at the S phase, indicating that Bcl11b is required for glioma cell cycle progression. Together, this is the first study to show that the inhibition of Bcl11b suppresses glioma cell growth by regulating the expression of the cell cycle regulator p21 and stemness-associated genes (Sox-2/Bmi-1). PMID- 26096707 TI - Integrative miRNA and Gene Expression Profiling Analysis of Human Quiescent Hepatic Stellate Cells. AB - Unveiling the regulatory pathways maintaining hepatic stellate cells (HSC) in a quiescent (q) phenotype is essential to develop new therapeutic strategies to treat fibrogenic diseases. To uncover the miRNA-mRNA regulatory interactions in qHSCs, HSCs were FACS-sorted from healthy livers and activated HSCs (aHSCs) were generated in vitro. MiRNA Taqman array analysis showed HSCs expressed a low number of miRNAs (n = 259), from which 47 were down-regulated and 212 up regulated upon activation. Computational integration of miRNA and gene expression profiles revealed that 66% of qHSC-associated miRNAs correlated with more than 6 altered target mRNAs (17,28 +/- 10,7 targets/miRNA) whereas aHSC-associated miRNAs had an average of 1,49 targeted genes. Interestingly, interaction networks generated by miRNA-targeted genes in qHSCs were associated with key HSC activation processes. Next, selected miRNAs were validated in healthy and cirrhotic human livers and miR-192 was chosen for functional analysis. Down regulation of miR-192 in HSCs was found to be an early event during fibrosis progression in mouse models of liver injury. Moreover, mimic assays for miR-192 in HSCs revealed its role in HSC activation, proliferation and migration. Together, these results uncover the importance of miRNAs in the maintenance of the qHSC phenotype and form the basis for understanding the regulatory networks in HSCs. PMID- 26096708 TI - Open vs robotic radical gastrectomy for locally advanced gastric cancer. AB - BACKGROUND: This study aims to evaluate the immediate outcomes of robotic and open gastrectomy for patients with locally advanced gastric adenocarcinomas. METHODS: A retrospective analysis was performed on patients undergoing curative intent gastrectomies between 2004 and 2013 in our department. Operative and postoperative outcomes as well as long-term survival data were analysed. RESULTS: Two groups of patients were analysed: the robotic group (n = 18) and the open surgery group (n = 29). Operating time in the robotic group (320.833 +/- 85.186 min) was significantly longer (p = 0.0004) as compared with the open group (243.366 +/- 57.973 min). The number of retrieved lymph nodes was not statistically different between the two groups (p = 0.108) and neither was the rate of postoperative complications (p = 0.294). CONCLUSIONS: Robotic gastrectomy is a safe procedure, with satisfactory short- and long-term outcomes in locally advanced gastric cancer. Studies on a larger number of patients are necessary in order to confirm whether an immediate benefit in survival exists due to robotic surgery. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096710 TI - Identification of Two Novel beta-Thalassemia Mutations (HBB: c.335-346del and HBB: c.108 C > G) in Han Chinese. AB - beta-Thalassemia (beta-thal) is an inherited blood disorder characterized by reduced or absent synthesis of the beta chains of hemoglobin (Hb). Although a number of causative mutations have been reported, here we report two novel mutations detected in Chinese patients. Red blood cell (RBC) indices were indicative of beta-thal, but no mutations were detected by routine methods. Sequencing of the beta-globin gene uncovered one mutant with a 12 bp deletion (TCTGTGTGCTGG) from codon 111 to codon 115 (HBB: c.335-346del12bp) in exon 3. The other was found to be a nonsense mutation at codon 35 (HBB: c.108 C > G). The identification of these novel mutations will facilitate future diagnoses of beta thal caused by either of these mutations and will also be useful for genetic counseling and prenatal diagnosis. PMID- 26096709 TI - A novel method for determining human ex vivo submaximal skeletal muscle mitochondrial function. AB - The present study utilized a novel method aiming to investigate mitochondrial function in human skeletal muscle at submaximal levels and at a predefined membrane potential. The effect of age and training status was investigated using a cross-sectional design. Ageing was found to be related to decreased leak regardless of training status. Increased training status was associated with increased mitochondrial hydrogen peroxide emission. Despite numerous studies, there is no consensus about whether mitochondrial function is altered with increased age. The novelty of the present study is the determination of mitochondrial function at submaximal activity rates, which is more physiologically relevant than the ex vivo functionality protocols used previously. Muscle biopsies were taken from 64 old or young male subjects (aged 60-70 or 20-30 years). Aged subjects were recruited as trained or untrained. Muscle biopsies were used for the isolation of mitochondria and subsequent measurements of DNA repair, anti-oxidant capacity and mitochondrial protein levels (complexes I-V). Mitochondrial function was determined by simultaneous measurement of oxygen consumption, membrane potential and hydrogen peroxide emission using pyruvate + malate (PM) or succinate + rotenone (SR) as substrates. Proton leak was lower in aged subjects when determined at the same membrane potential and was unaffected by training status. State 3 respiration was lower in aged untrained subjects. This effect, however, was alleviated in aged trained subjects. H2 O2 emission with PM was higher in aged subjects, and was exacerbated by training, although it was not changed when using SR. However, with a higher manganese superoxide dismuthase content, the trained aged subjects may actually have lower or similar mitochondrial superoxide emission compared to the untrained subjects. We conclude that ageing and the physical activity level in aged subjects are both related to changes in the intrinsic functionality of the mitochondrion in skeletal muscle. Both of these changes could be important factors in determining the metabolic health of the aged skeletal muscle cell. PMID- 26096711 TI - Rational Design of Biobetters with Enhanced Stability. AB - Biotherapeutics are the fastest growing class of pharmaceutical with a rapidly evolving market facing the rise of biosimilar and biobetter products. In contrast to a biosimilar, which is derived from the same gene sequence as the innovator product, a biobetter has enhanced properties, such as enhanced efficacy or reduced immunogenicity. Little work has been carried out so far to increase the intrinsic stability of biotherapeutics via sequence changes, even though, aggregation, the primary degradation pathway of proteins, leads to issues ranging from manufacturing failure to immunological response and to loss of therapeutic activity. Using our spatial aggregation propensity tool as a first step to a rational design approach to identify aggregation-prone regions, biobetters of rituximab have been produced with enhanced stability by introducing site-specific mutations. Significant stabilization against aggregation was achieved for rituximab with no decrease in its binding affinity to the antigen. PMID- 26096713 TI - Hysteroscopic treatment of Robert's uterus with laparoscopy. AB - Herein is described the case of a 26-year-old woman whose Robert's uterus was treated with hysteroscopy and who then successfully became pregnant and gave birth. The uterus anomaly was diagnosed on combined hysteroscopy and ultrasonography, which showed an asymmetric septate uterus with one blind cavity, causing menstrual retention. The surgery was uncomplicated, with satisfactory results. The patient underwent successful cesarean section delivery of a baby boy weighing 3250 g on 24 March 2014. PMID- 26096712 TI - Circulating interleukin-6 and cancer: A meta-analysis using Mendelian randomization. AB - Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the 174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = -4.23 pg/mL; P < 0.001) and -174C allele (WMD = -3.43 pg/mL; P < 0.001) had circulating IL-6 reduced significantly compared with the non-carriers. In further Mendelian randomization analysis, a reduction of 1 pg/mL in circulating IL-6 was significantly associated with an 12% reduced risk of liver cancer. Long-term genetically-reduced circulating IL-6 might be causally associated with a lower risk of liver cancer. PMID- 26096715 TI - Spatial radial maze procedures and setups to dissociate local and distal relational spatial frameworks in humans. AB - BACKGROUND: Radial maze tasks have been used to assess optimal foraging and spatial abilities in rodents. The spatial performance was based on a capacity to rely on a configuration of local and distant cues. We adapted maze procedures assessing the relative weight of local cues and distant landmarks for arm choice in humans. NEW METHOD: The procedure allowed testing memory of places in four experimental setups: a fingertip texture-groove maze, a tactile screen maze, a virtual radial maze and a walking size maze. During training, the four reinforced positions remained fixed relative to local and distal cues. During subsequent conflict trials, these frameworks were made conflictive in the prediction of reward locations. RESULTS: Three experiments showed that the relative weight of local and distal relational cues is affected by different factors such as cues' nature, visual access to the environment, real vs. virtual environment, and gender. A fourth experiment illustrated how a walking maze can be used with people suffering intellectual disability. COMPARISON WITH EXISTING METHODS: In our procedure, long-term (reference) and short-term (working) memory can be assessed. It is the first radial task adapted to human that enables dissociating local and distal cues, to provides an indication as to their relative salience. Our mazes are moveable and easily used in limited spaces. Tasks are performed with realistic and spontaneous though controlled exploratory movements. CONCLUSION: Our tasks enabled highlighting the use of different strategies. In a clinical perspective, considering the use of compensatory strategies should orient towards adapted behavioural rehabilitation. PMID- 26096716 TI - Host-parasite interactions: an intimate epigenetic relationship. AB - The epigenetics of host-pathogen interactions is emerging as an interesting angle from which to study how parasites have evolved sophisticated strategies to manipulate host gene transcription and protein expression. In this review, we discuss the application of an operational framework to investigate the host cell signalling pathways that are induced by intracellular parasites and the epigenomic consequences in the host nucleus. To illustrate this conceptual approach, we have focused on examples from two eukaryotic intracellular parasites of the apicomplexa phylum: Theileria and Toxoplasma. We review recent findings on intracellular parasitism strategies for hijacking host nuclear functions and discuss how we might think of the parasite and its proteome as an intracellular epigenator. PMID- 26096714 TI - Research aimed at improving both mood and weight (RAINBOW) in primary care: A type 1 hybrid design randomized controlled trial. AB - Effective interventions targeting comorbid obesity and depression are critical given the increasing prevalence and worsened outcomes for patients with both conditions. RAINBOW is a type 1 hybrid design randomized controlled trial. The objective is to evaluate the clinical and cost effectiveness and implementation potential of an integrated, technology-enhanced, collaborative care model for treating comorbid obesity and depression in primary care. Obese and depressed adults (n = 404) will be randomized to usual care enhanced with the provision of a pedometer and information about the health system's services for mood or weight management (control) or with the Integrated Coaching for Better Mood and Weight (I-CARE) program (intervention). The 12-month I-CARE program synergistically integrates two proven behavioral interventions: problem-solving therapy with as needed intensification of pharmacotherapy for depression (PEARLS) and standardized behavioral treatment for obesity (Group Lifestyle Balance(TM)). It utilizes traditional (e.g., office visits and phone consults) and emerging care delivery modalities (e.g., patient web portal and mobile applications). Follow-up assessments will occur at 6, 12, 18, and 24 months. We hypothesize that compared with controls, I-CARE participants will have greater improvements in weight and depression severity measured by the 20-item Depression Symptom Checklist at 12 months, which will be sustained at 24 months. We will also assess I-CARE's cost effectiveness and use mixed methods to examine its potential for reach, adoption, implementation, and maintenance. This study offers the potential to change how obese and depressed adults are treated-through a new model of accessible and integrative lifestyle medicine and mental health expertise-in primary care. PMID- 26096717 TI - Screening of Congenital Heart Diseases by Three-Dimensional Ultrasound Using Spatiotemporal Image Correlation: Influence of Professional Experience. AB - OBJECTIVE: To evaluate the feasibility of the use of spatiotemporal image correlation (STIC) as a screening program for congenital heart disease and the influence of professional experience in those examinations. METHODS: This prospective cross-sectional study included 64 pregnant women at gestational age between 20 and 34 weeks, and 12 physician participants who were divided into two groups: group 1-"STIC specialist"; and group 2-"STIC nonspecialist." Volumes were analyzed to obtain the five axial views for optimal fetal heart screening: abdominal situs, four-chamber view (4CV), outflow tract views (OTV), and three vessels and trachea view (3VT). The chi-square test (chi(2) ) was used to compare the group's results and kappa coefficient to evaluate inter- and intra-observer reproducibility. RESULTS: Spatiotemporal image correlation volume acquisition was successful in 97.3% of cases in which it was attempted (group 1: 100%; group 2:95%). A total of 197 STIC volumes were used in this study. In 71%, it was possible to demonstrate 4CV and OTV (group 1:88.9%; group 2:58.6%). 4CV, OTV, and 3VT were visualized in 55.3% of the volume dataset (group 1:74.1% and group 2:42.2%). In 49% of volumes, all five views for optimal fetal heart screening were seen (group 1:67%; group 2: 36%). A good inter-observer agreement was found in all cardiac views and a good intra-observer agreement in most of views except in OTV. CONCLUSION: We believe that STIC can be used as a tool to improve the cardiac screening examination of the fetus. Professional experience was the most important influence in the image quality of the STIC volume. PMID- 26096718 TI - Nickel-Catalyzed Chemo-, Regio- and Diastereoselective Bond Formation through Proximal C-C Cleavage of Benzocyclobutenones. AB - The first catalytic intermolecular proximal C1-C2 cleavage of benzocyclobutenones (BCB) without prior carbonyl activation or employing noble metals has been developed. This protocol operates at room temperature and is characterized by an exquisite chemo-, regio- and diastereoselectivity profile, constituting a unique platform for preparing an array of elusive carbocyclic skeletons. PMID- 26096719 TI - Sperm DNA-mediated reduction of nonspecific fluorescence during cellular imaging with quantum dots. AB - Salmon sperm DNA was used as a blocking agent to reduce background fluorescence signals from gelatin-coated cell culture dishes. PMID- 26096721 TI - The stability of water- and fat-soluble vitamin in dentifrices according to pH level and storage type. AB - The purpose of this study is to evaluate the vitamin stabilities in dentifrices by analyzing various vitamins according to the level and storage temperature. The stabilities of water- and fat-soluble vitamins were investigated in buffer solution at different pH values (4, 7, 8, 10 and 11) for 14 days and in dentifrices at different pH (7 and 10) for 5 months at two temperature conditions (room and refrigeration temperature) by analyzing the remaining amounts using HPLC methods. In the buffer solution, the stability of vitamins B1 , B6 and C was increased as the pH values increased. Vitamins E and K showed poor stability at pH 4, and vitamin B3 showed poor stability at pH 11. In dentifrices, the storage temperature highly influenced vitamin stability, especially vitamins C and E, but the stabilities of vitamins B1 and C according to pH values did not correspond to the buffer solution tests. Vitamin B group was relatively stable in dentifrices, but vitamin C completely disappeared after 5 months. Vitamin K showed the least initial preservation rates. Vitamins were not detected in commercial dentifrices for adults and detected amounts were less than the advertised contents in dentifrices for children. PMID- 26096720 TI - Grape skin extract-derived polyphenols modify programming-induced renal endowment in prenatal protein-restricted male mouse offspring. AB - PURPOSE: Protein-restricted diet during pregnancy is related to oxidative stress and, as a consequence, damage to nephrogenesis. We investigated the effects of vinifera grape skin extract (ACH09)-derived polyphenols on preserving renal morphology of maternal protein-restricted 1-day-old offspring. METHODS: Female C57/Bl-6 mice were fed two different isocaloric diets: control diet (19.3 % protein) and low-protein diet (6 % protein) with access to water or to the extract dissolved in drinking water (19.3 % protein plus ACH09 200 mg kg(-1) day( 1) and 6 % protein plus ACH09 200 mg kg(-1) day(-1)) throughout gestation. Renal morphology-glomerular number N[glom]; renal maturity-vascular glomeruli and avascular glomeruli ratio (v-N[glom]/a-N[glom]); medullar and cortical volumes, as well as mean glomerular volume, were analyzed in male offspring. Hepatic superoxide dismutase and catalase (CAT) activities were evaluated, and renal lipid peroxidation levels were measured. RESULTS: Maternal protein restriction affected birth weight and naso-anal length in low-protein offspring compared to control and ACH09 restored both parameters. Protein restriction increased lipid peroxidation in kidney and liver and reduced CAT activity in low-protein group compared to control. Supplementation with ACH09 reduced the kidney oxidative damage and restored the antioxidant activity of CAT. ACH09 prevented glomerular loss and renal immaturity in the offspring. CONCLUSION: The treatment of low protein-fed dams during pregnancy with ACH09 provides protection from early-life deleterious renal morphological changes. The protective effect of ACH09 may involve antioxidant action and vasodilator effect of the extract. PMID- 26096722 TI - Comparison of management and outcomes of ED patients with acute decompensated heart failure between the Canadian and United States' settings. AB - Introduction The objective of this study was to compare the emergency department (ED) management and rate of admission of acute decompensated heart failure (ADHF) between two hospitals in Canada and the United States and to compare the outcomes of these patients. METHODS: This was a health records review of adults presenting with ADHF to two EDs in Canada and the United States between January 1 and April 30, 2010. Outcome measures were admission to the hospital, myocardial infarction (MI), and death or relapse rates to the ED. Data were analysed using descriptive, univariate and multivariate analyses. RESULTS: In total, 394 cases were reviewed and 73 were excluded. Comparing 156 Canadian to 165 U.S. patients, respectively, mean age was 76.0 and 75.8 years; male sex was 54.5% and 52.1%. Canadian and U.S. ED treatments were noninvasive ventilation 7.7% v. 12.8% (p=0.13); IV diuretics 77.6% v. 36.0% (p<0.001); IV nitrates 4.5% v. 6.7% (p=0.39). There were significant differences in rate of admission (50.6% v. 95.2%, p<0.001) and length of stay in ED (6.7 v. 3.0 hours, p<0.001). Proportion of Canadian and U.S. patients who died within 30 days of the ED visit was 5.1% v. 9.7% (p=0.12); relapsed to the ED within 30 days was 20.8% v. 17.5% (p=0.5); and had MI within 30 days was 2.0% v. 1.9% (p=1.0). CONCLUSIONS: The U.S. and Canadian centres saw ADHF patients with similar characteristics. Although the U.S. site had almost double the admission rate, the outcomes were similar between the sites, which question the necessity of routine admission for patients with ADHF. PMID- 26096723 TI - Inappropriate prescribing of intravenous fluid in adult inpatients-a literature review of current practice and research. AB - WHAT IS KNOWN AND OBJECTIVE: It is known that mismanagement of intravenous (IV) fluid therapy may cause serious complications. The 2013 NICE guideline on intravenous fluid therapy in hospitalized adults also emphasizes the importance of appropriate prescribing of IV fluid. So far, no systematic review of the incidence and types of inappropriate prescribing of IV fluid has been conducted. Therefore, this study was undertaken to review the research literature on inappropriate prescribing of IV fluid in adult patients and develop corresponding strategies for improving practice. METHODS: A comprehensive literature search was performed. Critical appraisals were conducted on the articles drawn from the search, and an analysis was performed on the results. RESULTS AND DISCUSSION: Incorrect volumes and types of IV fluids prescribed, classified as misprescribing, was the most common type of inappropriate prescribing. Commonly, patients on IV fluid therapy were prescribed a greater volume of fluid and amount of sodium in excess of normal requirements. Doctors did not always check the body weight, serum electrolyte level and serum creatinine before prescribing IV fluid for patients. The other common type of inappropriate prescribing was incomplete/incorrect prescription writing. These common inappropriate prescribing of IV fluid could be caused by insufficient knowledge and training of the prescribers. In addition, the ignorance of the importance of IV fluid prescribing also contributed to this behaviour. WHAT IS NEW AND CONCLUSION: There is an urgent need to make doctors aware of these problems and enhance appropriate training on IV fluid prescribing, especially on the appropriate volume and amount of electrolytes. Pharmacists could exert a role in reviewing the fluid prescription chart for improving clinical practice. PMID- 26096724 TI - Saturn Systems. AB - Several ring systems (Saturn systems) have been studied using DFT methods that include dispersion effects. Comparison with X-ray structures are made with three systems, and the agreement is quite good. Binding enthalpies and binding free energies in dichloromethane and toluene have been computed. The effect of an encapsulated lithium cation is accessed by comparing C60 @(C6 H4 )10 and [Li@C60 @(C6 H4 )10 ](+). The [Li@C60 ](+) cation is a much better acceptor than C60 which leads to greater donor-acceptor interactions and larger charge transfer from the ring to [Li@C60 ](+). PMID- 26096725 TI - Accelerating the dual elimination of mother-to-child transmission of syphilis and HIV: Why now? PMID- 26096726 TI - Advances in the basic and clinical applications of thymosin beta4. AB - INTRODUCTION: Thymosin beta4 (Tbeta4), a multifunctional peptide, has been used successfully in several clinical trials involving tissue repair and regeneration. The review will first update the current information on the common underlying cellular cascades and pathways that are basic to Tbeta4's regenerative activity and second, on the current and potential uses of this protein in the clinic. AREAS COVERED: Significant advances in our understanding of the actions of Tbeta4 have occurred in directing stem cell maturation and in regeneration and repair of injuries. Many of its activities directly affect the repair cascade following injury. Using PubMed, we summarize the discovery and isolation of Tbeta4 as well as the studies on tissue repair, which have provided the scientific foundation for ongoing and projected trials in the treatment of eye injuries, dermal wounds, repair of the heart following myocardial infarction and healing of the brain following stroke, trauma or neurological diseases. EXPERT OPINION: Based on its multifunctional activities during tissue regeneration in various animal studies, Tbeta4 has the potential for new clinical applications such kidney and liver disease, as well as repair of spinal cord, bone and ligament damage. In addition, it may be useful in the treatment of a wide range of other applications, including the consequences of aging and viral infections. PMID- 26096727 TI - Formation of Discrete Ladders and a Macroporous Xerogel Film by the Zipperlike Dimerization of Meso-Meso-Linked Zinc(II) Porphyrin Arrays with Di(pyrid-3 yl)acetylene. AB - Metal porphyrins assemble to form a supramolecular architecture with a characteristic structure and characteristic properties and functions upon complexation with appropriate ligands. However, there are few applications of these assembly processes to the construction of polymeric porphyrin arrays with useful functionalities. In this study, we found that meso-meso-linked Zn(II) porphyrin arrays underwent zipperlike dimerization upon complexation with di(pyrid-3-yl)acetylene (DPA) in chloroform to form discrete double-stranded porphyrin ladders. Similarly, the assembly of poly(zinc(II) porphyrinylene) with DPA gave a thermoresponsive gel, whose three-dimensional network structure was so strong that a macroporous xerogel film was obtained. PMID- 26096728 TI - White matter abnormalities differentiate severe from benign temporal lobe epilepsy. AB - OBJECTIVE: Temporal and extratemporal white matter abnormalities have been identified frequently in patients with refractory mesial temporal lobe epilepsy (rMTLE). However, the identification of potential water diffusion abnormalities in patients with drug-responsive, benign MTLE (bMTLE) is still missing. The aim of this study was to identify markers of refractoriness in MTLE. METHODS: The study group included 48 patients with bMTLE (mean age 42.8 + 13.5 years), 38 with rMTLE (mean age 41.7 + 14.1 years) and 54 healthy volunteers. Diffusion tensor imaging (DTI) was performed to measure mean diffusivity (MD) and fractional anisotropy (FA) in a regions-of-interest analysis comprising hippocampi and temporal lobe gray and white matter regions. The presence of hippocampal sclerosis (Hs) was assessed using automated magnetic resonance imaging (MRI) evaluation. For statistics we used chi-square test; two-tailed, two-sample t test; and stratified linear regression. RESULTS: The significant demographic differences between the two patient groups were sex (p = 0.003), duration of epilepsy (p = 0.003) and complex febrile convulsions (p = 0.0001). In rMTLE, temporal white matter MD was higher and FA lower, as compared to bMTLE. The analysis of diagnostic accuracy (area under the receiver operator characteristic [ROC] curve [AUC]) showed that FA had an AUC for discriminating patients affected from those unaffected by refractory MTLE of 74.0% (p < 0.001), a value that was higher than that of temporal MD (64.0%), hippocampus volume (65.0%), and Hs (66.0%). SIGNIFICANCE: We performed DTI measurements in MTLE and found a significant reduction of FA along the white matter of the temporal lobes in rMTLE, suggesting it as a valuable measure of refractoriness in MTLE. PMID- 26096729 TI - Towards an unbiased view of science. PMID- 26096730 TI - Effects of lunar phase on sleep in men and women in Surrey. AB - Recently, evidence has emerged that the phases of the moon may modulate subjective sleep quality and polysomnographically assessed sleep structure in humans. We aimed to explore further the putative effects of circa-lunar periodicity (~29.5 days) on subjective and objective parameters of human sleep in a retrospective analysis. The baseline sleep recordings of 205 (91 males and 114 females; mean age = 47.47 years, standard deviation =19.01; range: 20-84 years) healthy and carefully screened participants who participated in two clinical trials in the Surrey Clinical Research Centre were included in the analyses. Sleep was recorded in windowless sleep laboratories. For each study night, we calculated the distance, in days, to the date of the closest full moon phase and based on this distance, classified sleep records in three lunar classes. Univariate analysis of variance with factors lunar class, age and sex was applied to each of 21 sleep parameters. No significant main effect for the factor lunar class was observed for any of the objective sleep parameters and subjective sleep quality but some significant interactions were observed. The interaction between lunar class and sex was significant for total sleep time, Stage 4 sleep and rapid eye movement (REM) sleep. Separate analyses for men and women indicated that in women total sleep time, Stage 4 sleep and REM sleep were reduced when sleep occurred close to full moon, whereas in men REM duration increased around full moon. These data provide limited evidence for an effect of lunar phase on human sleep. PMID- 26096731 TI - Stereodivergent Intramolecular C(sp(3))-H Functionalization of Azavinyl Carbenes: Synthesis of Saturated Heterocycles and Fused N-Heterotricycles. AB - A general approach for the formation of five-membered saturated heterocycles by intramolecular C(sp(3))-H functionalization is reported. Using N sulfonyltriazoles as Rh(II) azavinyl carbene equivalents, a wide variety of stereodefined cis-2,3-disubstituted tetrahydrofurans were obtained with good to excellent diastereoselectivity from readily available acyclic precursors. The reaction is shown to be amenable to gram scale, and judicious choice of reaction conditions allowed for stereodivergence, providing selective access to the trans diastereomer in good yield. The resulting products were shown to be valuable intermediates for the direct preparation of fused N-heterotricycles in one step by intramolecular C-H amination or Pictet-Spengler cyclization. PMID- 26096732 TI - A competition mechanism for a homeotic neuron identity transformation in C. elegans. AB - Neuron identity transformations occur upon removal of specific regulatory factors in many different cellular contexts, thereby revealing the fundamental principle of alternative cell identity choices made during nervous system development. One common molecular interpretation of such homeotic cell identity transformations is that a regulatory factor has a dual function in activating genes defining one cellular identity and repressing genes that define an alternative identity. We provide evidence for an alternative, competition-based mechanism. We show that the MEC-3 LIM homeodomain protein can outcompete the execution of a neuropeptidergic differentiation program by direct interaction with the UNC 86/Brn3 POU homeodomain protein. MEC-3 thereby prevents UNC-86 from collaborating with the Zn finger transcription factor PAG-3/Gfi to induce peptidergic neuron identity and directs UNC-86 to induce an alternative differentiation program toward a glutamatergic neuronal identity. Homeotic control of neuronal identity programs has implications for the evolution of neuronal cell types. PMID- 26096733 TI - Cross-Scale Integrin Regulation Organizes ECM and Tissue Topology. AB - The diverse morphologies of animal tissues are underlain by different configurations of adherent cells and extracellular matrix (ECM). Here, we elucidate a cross-scale mechanism for tissue assembly and ECM remodeling involving Cadherin 2, the ECM protein Fibronectin, and its receptor Integrin alpha5. Fluorescence cross-correlation spectroscopy within the zebrafish paraxial mesoderm mesenchyme reveals a physical association between Integrin alpha5 on adjacent cell membranes. This Integrin-Integrin complex correlates with conformationally inactive Integrin. Cadherin 2 stabilizes both the Integrin association and inactive Integrin conformation. Thus, Integrin repression within the adherent mesenchymal interior of the tissue biases Fibronectin fibrillogenesis to the tissue surface lacking cell-cell adhesions. Along nascent somite boundaries, Cadherin 2 levels decrease, becoming anti-correlated with levels of Integrin alpha5. Simultaneously, Integrin alpha5 clusters and adopts the active conformation and then commences ECM assembly. This cross-scale regulation of Integrin activation organizes a stereotypic pattern of ECM necessary for vertebrate body elongation and segmentation. PMID- 26096735 TI - Taranis Protects Regenerating Tissue from Fate Changes Induced by the Wound Response in Drosophila. AB - Regenerating tissue must replace lost structures with cells of the proper identity and function. How regenerating tissue establishes or maintains correct cell fates during regrowth is an open question. We have identified a gene, taranis, that is essential for maintaining proper cell fate in damaged and regenerating Drosophila wing imaginal discs but that is dispensable for these fates in normal wing development. In regenerating tissue with reduced levels of Taranis, expression of the posterior selector gene engrailed is silenced through an autoregulatory silencing mechanism that requires the PRC1 component polyhomeotic, resulting in a transformation of posterior tissue into anterior tissue late in regeneration. An essential component of the wound response, JNK signaling, induces this misregulation of engrailed expression. Taranis can suppress these JNK-induced cell fate changes without interfering with JNK signaling activity. Thus, taranis protects regenerating tissue from deleterious side effects of wound healing and regeneration. PMID- 26096736 TI - Abstracts from the 25th Congress of the International Association of Paediatric Dentistry, 1-4 July 2015, Glasgow, UK. PMID- 26096734 TI - POS-1 Promotes Endo-mesoderm Development by Inhibiting the Cytoplasmic Polyadenylation of neg-1 mRNA. AB - The regulation of mRNA translation is of fundamental importance in biological mechanisms ranging from embryonic axis specification to the formation of long term memory. POS-1 is one of several CCCH zinc-finger RNA-binding proteins that regulate cell fate specification during C. elegans embryogenesis. Paradoxically, pos-1 mutants exhibit striking defects in endo-mesoderm development but have wild type distributions of SKN-1, a key determinant of endo-mesoderm fates. RNAi screens for pos-1 suppressors identified genes encoding the cytoplasmic poly(A) polymerase homolog GLD-2, the Bicaudal-C homolog GLD-3, and the protein NEG-1. We show that NEG-1 localizes in anterior nuclei, where it negatively regulates endo mesoderm fates. In posterior cells, POS-1 binds the neg-1 3' UTR to oppose GLD-2 and GLD-3 activities that promote NEG-1 expression and cytoplasmic lengthening of the neg-1 mRNA poly(A) tail. Our findings uncover an intricate series of post transcriptional regulatory interactions that, together, achieve precise spatial expression of endo-mesoderm fates in C. elegans embryos. PMID- 26096738 TI - Characterization of Diblock Copolymer Order-Order Transitions in Semidilute Aqueous Solution Using Fluorescence Correlation Spectroscopy. AB - The temperature and pH-dependent diffusion of poly(glycerol monomethacrylate) block-poly(2-hydroxypropyl methacrylate) nanoparticles prepared via polymerization-induced self-assembly in water is characterized using fluorescence correlation spectroscopy (FCS). Lowering the solution temperature or raising the solution pH induces a worm-to-sphere transition and hence an increase in diffusion coefficient by a factor of between four and eight. FCS enables morphological transitions to be monitored at relatively high copolymer concentrations (10% w/w) compared to those required for dynamic light scattering (0.1% w/w). This is important because such transitions are reversible at the former concentration, whereas they are irreversible at the latter. Furthermore, the FCS data suggest that the thermal transition takes place over a very narrow temperature range (less than 2 degrees C). These results demonstrate the application of FCS to characterize order-order transitions, as opposed to order disorder transitions. PMID- 26096737 TI - Impaired planning in Parkinson's disease is reflected by reduced brain activation and connectivity. AB - OBJECTIVE: Parkinson's disease (PD) often entails impairments of executive functions, such as planning. Although widely held that these impairments arise from dopaminergic denervation of the striatum, not all executive functions are affected early on, and the underlying neural dynamics are not fully understood. In a combined longitudinal and cross-sectional study, we investigated how planning deficits progress over time in the early stages of PD compared to matched healthy controls. We used functional magnetic resonance imaging (fMRI) to identify accompanying neural dynamics. METHODS: Seventeen PD patients and 20 healthy controls performed a parametric Tower of London task at two time points separated by ~3 years (baseline and follow-up). We assessed task performance longitudinally in both groups; at follow-up, a subset of participants (14 patients, 19 controls) performed a parallel version of the task during fMRI. We performed meta-analyses to localize regions-of-interest (ROIs), that is, the bilateral dorsolateral prefrontal cortex (DLPFC), inferior parietal cortex, and caudate nucleus, and performed group-by-task analyses and within-group regression analyses of planning-related neural activation. We studied task-related functional connectivity of seeds in the DLPFC and caudate nucleus. RESULTS: PD patients, compared with controls, showed impaired task performance at both time points, while both groups showed similar performance reductions from baseline to follow-up. Compared to controls, patients showed lower planning-related brain activation together with decreased functional connectivity. CONCLUSION: These findings support the notion that planning is affected early in the PD disease course, and that this impairment in planning is accompanied by decreases in both task-related brain activity and connectivity. PMID- 26096739 TI - Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability. AB - Loss of function of mismatch repair (MMR) genes, mainly MLH1 and MSH2, manifests as high levels of microsatellite instability (MSI) that occurs in >90% of carcinomas in patients with Lynch syndrome (LS). The MSI-high status has also been described in sporadic colorectal cancer (CRC) associated with BRAF gene mutation (V600E); this mutation was not present in LS-associated cancers. The present study performed MSI analysis on 39 CRC patients selected according to Bethesda guidelines, and BRAF V600E genotyping was performed in 26 cases classified as MSI-high or MSI-low (15 MSI-H and 11 MSI-L). These 26 patients were then screened for MLH1 and MSH2 germ-line mutations. Germ-line mutations in these genes were detected in 11/15 patients with MSI-H tumors (73%) and in 1/11 patients with MSI-L tumors (9%). Overall, 11 germ-line mutations in 12/26 analyzed patients (46%) in these genes were identified. Two of these mutations are novel genetic MLH1 variants not previously described in the literature, c.438A>G and c.1844T>C. A combination of computational approaches, co-segregation analysis and RNA assay suggested that these novel mutations, silent and missense, respectively, were probably pathogenic. The findings of the present study further emphasized the requirement for genetic testing in patients with a risk for hereditary CRC and has broadened the spectrum of known mutations of the MLH1 gene. PMID- 26096740 TI - Foreword. PMID- 26096741 TI - Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry. AB - Study of the natural history of Gaucher disease has revealed marked phenotypic variation. Correlations to genotypes could provide insight into individual susceptibility to varying disease severity, which may impact whole-life medical care, reproductive decisions, and therapeutic choices for affected families. Importantly, pre-symptomatic or prospective interventions or the use of therapies with significant risk require accurate risk-benefit analyses based on the prognosis for individual patients. The body of international data held within the International Collaborative Gaucher Group (ICGG) Gaucher Registry provides an unprecedented opportunity to characterize the phenotypes of Gaucher disease types 1 and 3 and to appreciate demographic and ethnic factors that may influence phenotypes. The diversity of GBA gene mutations from patients with Gaucher disease represented in the ICGG Gaucher Registry database and in the literature provides the basis for initial genotype/phenotype correlations, the outcomes of which are summarized here. PMID- 26096742 TI - Long-term treatment outcomes in Gaucher disease. AB - Following the treatment of the first Gaucher disease patient with enzyme replacement therapy (ERT), it was clear that ERT had the potential to be transformative with dramatic improvements in systemic manifestations of the disease within 2 years. Following over 20 years existence of the International Collaborative Gaucher Group Gaucher Registry and evidence from ~6000 patients, the long-term effects of therapy have been documented. It has been shown that ERT can result in improvements in all clinical and laboratory parameters of nonneuronopathic disease. However, different aspects of the disease, such as hematologic parameters, organ volumes and bone disease do not necessarily respond to therapy at the same rate or to the same extent, and this has had major implications for disease monitoring and for the establishment of therapeutic goals for ERT. Response may be affected by factors such as the timing of therapy initiation, the presence of irreversible complications such as osteonecrosis, and by enzyme dose. It is also apparent that ERT has no impact on neurological aspects of disease and highlights the need for additional or alternative treatment strategies able to meet the needs of patients with neuronopathic disease. PMID- 26096743 TI - The history and accomplishments of the ICGG Gaucher registry. PMID- 26096744 TI - Gaucher disease and comorbidities: B-cell malignancy and parkinsonism. AB - Data emerging from the International Collaborative Gaucher Group (ICGG) Gaucher Registry together with other contemporary clinical surveys have revealed a close association between Gaucher disease and non-Hodgkin's B-cell lymphoma and myeloma and Gaucher disease and Parkinson's disease. Several possible explanations for increased B-cell proliferation and neoplasia in Gaucher disease have been proposed, including the possible influence of sphingosine (derived from the extra lysosomal metabolism of glucosylceramide), gene modifiers, splenectomy and immune system deregulation induced by cytokines, chemokines, and hydrolases released from Gaucher cells. Parkinson's disease is frequently seen in the otherwise healthy relatives of Gaucher disease patients leading to the finding that GBA mutations represent a genetic risk factor for Parkinson's disease. The mechanism of the association between GBA mutations and Parkinson's disease has yet to be elucidated but the pathogenesis appears distinct from that of Gaucher disease. Several pathogenic pathways have been proposed including lysosomal and/or mitochondrial dysfunction. The effect of Gaucher disease specific therapies on the incidence of cancer or Parkinson's disease are not clear and will likely be evaluated in future ICGG Gaucher Registry studies. PMID- 26096745 TI - Afterword. PMID- 26096746 TI - Understanding the natural history of Gaucher disease. AB - Gaucher disease is a rare and extraordinarily heterogeneous inborn error of metabolism that exhibits diverse manifestations, a broad range of age of onset of symptoms, and a wide clinical spectrum of disease severity, from lethal disease during infancy to first age of onset of symptoms in octogenarians. Before the advent of the International Collaborative Gaucher Group (ICGG) Gaucher Registry, the understanding of the natural history and phenotypic range of Gaucher disease was based on isolated case reports and small case series. Limited data hindered understanding of the full spectrum of the disease leading to some early misconceptions about Gaucher disease, notably, that nonneuronopathic (type 1) disease was a disease of adults only. The global scope of the ICGG Gaucher Registry, with its vast body of longitudinal data, has enabled a real appreciation of both the phenotypic spectrum of Gaucher disease and its natural history. This body of evidence represents the foundation for accurate assessment of the response to specific therapies for Gaucher disease and to the development of standard-of-care to monitor disease activity. Here, we outline the key developments in delineating the natural history of this highly complex disease and role of the ICGG Gaucher Registry in this effort. PMID- 26096747 TI - Catch-up growth in infants with laryngomalacia after supraglottoplasty. AB - IMPORTANCE: Laryngomalacia, the most common congenital anomaly of the infant airway, can lead to poor feeding and failure to thrive. The decision to perform the standard surgical treatment, supraglottoplasty, is often based upon a sustained period of poor weight gain or weight loss. OBJECTIVE: To characterize patterns of growth in infants with laryngomalacia, preceding and following supraglottoplasty. DESIGN: Retrospective chart review. Bioinformatics techniques were used to procure data from a clinical data warehouse based on the HL7 Reference Information Model consisting of all infants who underwent supraglottoplasty from June 1, 2005 to October 31, 2013. Height and weight measurements were obtained from 76 operated patients allowing for characterization of growth changes from the time of surgery to an average of 9 months following surgery. Logistic regression analysis was performed to examine the following variables for correlations with changes in weight, height and body mass index percentiles: patient age at surgery, preoperative weight, gender, and ethnic background. SETTING: Academic pediatric tertiary medical center. PARTICIPANTS: Patients under 2 years of age at the time of surgery, who underwent supraglottoplasty for laryngomalacia, with height and weight measurements recorded within 3 months preceding surgery and greater than 3 months following surgery. INTERVENTION: Supraglottoplasty. MAIN OUTCOMES AND MEASURES: Change in weight, height and body mass index (BMI) percentile from pre-op to post-op. RESULTS: BMI increased from a mean of 15.4 to 18.0 and BMI percentile from a mean of 34 to 51 from pre-op to post-op. The largest BMI percentile increases were observed in infants that were 3 months or younger at the time of surgery, as well as in those under 12 months of age, who were in the lowest BMI quintile. CONCLUSIONS AND RELEVANCE: Infants who underwent supraglottoplasty tended to be small in weight and stature, and gained weight after surgery. Most of the weight gain occurred within 6 months of surgery. The largest increases in BMI percentile were observed in infants who were younger and smaller at the time of surgery while the infants older than 18 months had no significant gain. PMID- 26096748 TI - European Code against Cancer 4th Edition: Ultraviolet radiation and cancer. AB - Ultraviolet radiation (UVR) is part of the electromagnetic spectrum emitted naturally from the sun or from artificial sources such as tanning devices. Acute skin reactions induced by UVR exposure are erythema (skin reddening), or sunburn, and the acquisition of a suntan triggered by UVR-induced DNA damage. UVR exposure is the main cause of skin cancer, including cutaneous malignant melanoma, basal cell carcinoma, and squamous-cell carcinoma. Skin cancer is the most common cancer in fair-skinned populations, and its incidence has increased steeply over recent decades. According to estimates for 2012, about 100,000 new cases of cutaneous melanoma and about 22,000 deaths from it occurred in Europe. The main mechanisms by which UVR causes cancer are well understood. Exposure during childhood appears to be particularly harmful. Exposure to UVR is a risk factor modifiable by individuals' behaviour. Excessive exposure from natural sources can be avoided by seeking shade when the sun is strongest, by wearing appropriate clothing, and by appropriately applying sunscreens if direct sunlight is unavoidable. Exposure from artificial sources can be completely avoided by not using sunbeds. Beneficial effects of sun or UVR exposure, such as for vitamin D production, can be fully achieved while still avoiding too much sun exposure and the use of sunbeds. Taking all the scientific evidence together, the recommendation of the 4th edition of the European Code Against Cancer for ultraviolet radiation is: "Avoid too much sun, especially for children. Use sun protection. Do not use sunbeds." PMID- 26096749 TI - Long-term outcomes for primary glomerulonephritis: New Zealand Glomerulonephritis Study. AB - AIMS: Due to the paucity of studies focusing on primary glomerulonephritis, the second commonest cause of end-stage-kidney-disease in most of the developed world, we sought to review outcomes of these renal pathologies. METHODS: We reviewed renal outcomes and mortality for primary glomerulonephritis patients enrolled in the New Zealand Glomerulonephritis Study between 1972 and 1983. RESULTS: There were 765 patients with median follow-up of 30 years (range 0.1-42 years). They were predominantly New Zealand European, male and hypertensive. Poor renal outcomes and increased mortality were associated with hypertension, heavy proteinuria, impaired renal function and older age at diagnosis. Ethnicity was not significantly associated with progression to end-stage-kidney-disease although NZ Maori patients were at significantly increased risk of death. Patients with rapidly progressive glomerulonephritis had the highest risk of reaching end-stage-kidney-disease while the cumulative incidence of end-stage kidney-disease was 20% and 30% for those with immunoglobulin-A nephropathy and membranous nephropathy respectively. Mortality risk was high for patients with rapidly progressive glomerulonephritis and anti-glomerular basement membrane disease. The era of diagnosis did not have much effect on outcomes except for patients with focal segmental glomerulosclerosis or immunoglobulin A nephropathy but this could be type II error. CONCLUSION: We report one of the longest follow up studies on biopsy-proven glomerulonephritides. Age, hypertension, and severity of chronic kidney disease at diagnosis were strong predictors of the development of end-stage-kidney-disease and death. The specific renal pathology had a profound impact upon prognosis and therefore should continue to drive efforts to find targeted therapeutic options for these glomerulonephritides. PMID- 26096750 TI - Regulation Policy for Cell and Tissue Therapies in Australia. AB - In Australia, therapeutic goods are regulated by the Australian Government through the Therapeutic Goods Administration. In recent times, there have been significant changes to legislative instruments to accommodate the emergence of biotherapies, and a new regulatory framework was implemented in 2013. Therapeutic goods are regulated as medicines, devices, or biologics. With some exemptions and exceptions, human cellular and tissue products are regulated as biologics. The new regulation has taken a risk-based approach, with the level of regulation reflecting the perceived risk of the product, and products are classified from class 1 (low risk) to class 4 (highest risk). Other than for class 1 products, manufacturers must demonstrate conformance with the Australian Code of Good Manufacturing Practice and compliance with relevant Therapeutic Goods Orders and Standards through the submission of dossiers. The higher the classification of product, the more rigorous the dossier requirements. Listing of products on the Australian Therapeutic Goods Register is required for all products with some exceptions. The new regulatory framework provides greater clarity for manufacturers and strives to harmonize with international standards. PMID- 26096751 TI - Transferrin-bearing dendrimers for cancer therapy: an update. PMID- 26096752 TI - Molecular detection of novel Anaplasmataceae closely related to Anaplasma platys and Ehrlichia canis in the dromedary camel (Camelus dromedarius). AB - Serological surveys have confirmed Anaplasma marginale and Anaplasma phagocytophilum infections in dromedary camels, but molecular surveys and genetic characterisation of camel-associated Anaplasma species are lacking. In this study, we detected tick-borne Anaplasmataceae in 30 of 100 (30%) healthy dromedary camels screened using a combined 16S rRNA-groEL PCR-sequencing approach. Nucleotide sequencing confirmed Anaplasmataceae genome presence in 28 of the 33 16S rRNA PCR-positive samples, with two additional positive samples, for which 16S rRNA sequence data were ambiguous, being identified by groEL gene characterisation. Phylogenetic analyses of a 1289 nt segment of the 16S rRNA gene confirmed the presence of a unique Ehrlichia lineage and a discrete Anaplasma lineage, comprising three variants, occurring at an overall prevalence of 4% and 26%, respectively. Genetic characterisation of an aligned 559 nt groEL gene region revealed the camel-associated Anaplasma and Ehrlichia lineages to be novel and most closely related to Anaplasma platys and Ehrlichia canis. Based on the confirmed monophyly, minimum pairwise genetic distances between each novel lineage and its closest sister taxon, and the inability to isolate the bacteria, we propose that Candidatus status be assigned to each. This first genetic characterisation of Anaplasmataceae from naturally infected, asymptomatic dromedary camels in Saudi Arabia confirms the presence of two novel lineages that are phylogenetically linked to two pathogenic canid species of increasing zoonotic concern. PMID- 26096753 TI - Serum zinc concentration in cystic fibrosis patients with CFTR I1234V mutation associated with pancreatic sufficiency. AB - OBJECTIVE: To determine serum zinc (Zn) level among cystic fibrosis (CF) patients with homozygous CFTR I1234V mutation associated with pancreatic sufficiency (PS). METHODS: A cross-sectional study was conducted including both pediatric and adult CF patients. Data on age, weight, height, body mass index (BMI), BMI Z-score, FEV1, and chronic Pseudomonas aeruginosa infection were collected. Serum Zn, albumin, and total proteins were measured and analyzed. RESULTS: Forty-five CF patients with homozygous CFTR I1234V mutation belonging to a large Arab kindred tribe and eight CF patients with other mutations associated with pancreatic insufficiency (PI). Patient's age ranged from 2 to 49 years with a mean age of 15.1 +/- 9.1 years and mean plasma Zn of 0.78 +/- 0.15 mcg/mL. Seven (13.2%) patients with CFTR I1234V and PS had low Zn levels (<0.6 mcg/mL). Mean age among Zn deficient group was significantly older. The mean FEV1 in the deficient group was found to be insignificant low. Persistent P. aeruginosa colonization was more prevalent in Zn deficient group. BMI Z-scosre of CF patients were positively correlated with Zn levels. Forty-five healthy subjects belonging to the same Arab tribe were selected in order to assess their Zn levels and their mean plasma Zn of 0.84 +/- 0.11 mcg/mL (range 0.65-1.1 mcg/mL) with mean age 20.4 +/- 10.1 years (range 6-40 years). CONCLUSION: These findings suggest that Zn deficiency can occur in CF patients with PS. The association of Zn levels and the frequency of P. aeruginosa isolated in CF patients need further investigation. PMID- 26096754 TI - Removing silicone artifacts in diffusion-weighted breast MRI by means of shift resolved spatiotemporally encoding. AB - PURPOSE: Evaluate the usefulness of diffusion-weighted spatiotemporally encoded (SPEN) methods to obtain apparent diffusion coefficient (ADC) maps of fibroglandular human breast tissue, in the presence of silicone implants. METHODS: Seven healthy volunteers with breast augmentation were scanned at 3 Tesla (T) using customized SPEN sequences yielding separate silicone and water (1) H images in one scan, together with their corresponding diffusion-weightings. RESULTS: SPEN's ability to deliver multiple spectrally resolved images in a single scan, coupled to the method's substantial robustness to magnetic field heterogeneities, served to acquire ADC maps that could be freed from contributions that did not belong to fibroglandular tissue. CONCLUSION: SPEN based sequences incorporating spectral discrimination and diffusion-weighting enable the acquisition of reliable ADC maps despite the presence of dominant signals from silicone implants, thereby opening new screening possibilities for the identification of malignancies in breast augmented patients. PMID- 26096755 TI - DNA-Encoded Tuning of Geometric and Plasmonic Properties of Nanoparticles Growing from Gold Nanorod Seeds. AB - Systematically controlling the morphology of nanoparticles, especially those growing from gold nanorod (AuNR) seeds, are underexplored; however, the AuNR and its related morphologies have shown promises in many applications. Herein we report the use of programmable DNA sequences to control AuNR overgrowth, resulting in gold nanoparticles varying from nanodumbbell to nanooctahedron, as well as shapes in between, with high yield and reproducibility. Kinetic studies revealed two representative pathways for the shape control evolving into distinct nanostructures. Furthermore, the geometric and plasmonic properties of the gold nanoparticles could be precisely controlled by adjusting the base compositions of DNA sequences or by introducing phosphorothioate modifications in the DNA. As a result, the surface plasmon resonance (SPR) peaks of the nanoparticles can be fine-tuned in a wide range, from visible to second near-infrared (NIR-II) region beyond 1000 nm. PMID- 26096756 TI - [Agranulocytosis related to fluindione: A case report]. AB - INTRODUCTION: While in most countries warfarin is the preferred anti-vitamin K, fluindione, a molecule with a prolonged half-life remains largely prescribed in France. Some of its side effects, including immuno-allergic complications, remain poorly understood. CASE REPORT: A 77-year-old woman presented with a febrile severe neutropenia of immunoallergic mechanism with a favourable outcome associated with fluindione, introduced 25 days earlier for the treatment of atrial fibrillation. CONCLUSION: This rare side effect is a reminder of the importance of biological monitoring in the first weeks following the introduction of fluindione and key diagnostic elements and therapeutic aspects of iatrogenic agranulocytosis. PMID- 26096757 TI - The Utilities of Chemical Reactions and Molecular Tools for O-GlcNAc Proteomic Studies. AB - The post-translational modification of nuclear and cytoplasmic proteins with O linked beta-N-acetylglucosamine (O-GlcNAc) is involved in a wide variety of cellular processes and is associated with the pathological progression of chronic diseases. Considering its emerging biological significance, systematic identification, site mapping, and quantification of O-GlcNAc proteins are essential and have led to the development of several approaches for O-GlcNAc protein profiling. This minireview mainly focuses on the various useful chemical reactions and molecular tools with detailed reaction mechanisms widely adopted for O-GlcNAc protein/peptide enrichment and its quantification for comprehensive O-GlcNAc protein profiling. PMID- 26096758 TI - Colonisation rate and adaptive foraging control the emergence of trophic cascades. AB - Ecological communities are assembled and sustained by colonisation. At the same time, predators make foraging decisions based on the local availabilities of potential resources, which reflects colonisation. We combined field and laboratory experiments with mathematical models to demonstrate that a feedback between these two processes determines emergent patterns in community structure. Namely, our results show that prey colonisation rate determines the strength of trophic cascades - a feature of virtually all ecosystems - by prompting behavioural shifts in adaptively foraging omnivorous fish predators. Communities experiencing higher colonisation rates were characterised by higher invertebrate prey and lower producer biomasses. Consequently, fish functioned as predators when colonisation rate was high, but as herbivores when colonisation rate was low. Human land use is changing habitat connectivity worldwide. A deeper quantitative understanding of how spatial processes modify individual behaviour, and how this scales to the community level, will be required to predict ecosystem responses to these changes. PMID- 26096759 TI - Long-term outcomes of a primary complete endoscopic resection strategy for short segment Barrett's esophagus with high-grade dysplasia and/or early esophageal adenocarcinoma. AB - BACKGROUND AND AIMS: Complete endoscopic resection (CER) of Barrett's esophagus (BE) with high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EEA) is a comprehensive and precise staging tool and may produce a sustained treatment response, preventing metachronous disease. There are limited data on long-term clinical outcomes and the sustainability of dysplasia eradication after CER. We aimed to describe long-term outcomes of a primary CER strategy of BE with HGD/EEA. METHODS: Patients with biopsy-proven HGD and EEA in short-segment BE (<= 3 cm in circumferential length and <= 5 cm in maximal length) underwent staged CER by multiband mucosectomy or the cap method. The primary endpoint was remission of HGD or EEA (complete resection of HGD/EEA), dysplasia (complete resection of any dysplasia), and complete resection of intestinal metaplasia. RESULTS: Of 153 patients (126 HGD, 27 EEA; 83.7% male, median age of 66 years) considered suitable for CER, 138 met all inclusion criteria. CER was technically successful in all patients and was established after a median of 2 sessions. Covert synchronous EEA was found in 1 patient. At a mean follow-up of 40.7 months by intention-to-treat analysis, complete remission of HGD/EEA, dysplasia, and intestinal metaplasia was achieved in 98.5%, 89.1%, and 71.0%, respectively. In 47.1% of patients, CER changed the histological grade compared with pretreatment biopsies (28.1% downstaged and 19.0% upstaged). Esophageal dilation was performed in 36.8% in a mean of 2.5 sessions. At the end of follow-up, 96.4% of patients had no or minimal dysphagia and 90.6% of patients found CER an acceptable treatment. CONCLUSIONS: On long-term follow-up, a primary CER strategy was a highly effective, safe, and durable treatment for HGD and EEA. Despite the need for post-CER dilation in one-third of patients, the majority found it an acceptable treatment on long-term follow-up. PMID- 26096760 TI - Iatrogenic Baclofen Neurotoxicity in ESRD: Recognition and Management. AB - Baclofen is an oral derivative of gamma-aminobutyric acid (GABA) used to treat muscular spasticity from disorders of the central nervous system. However, it is also being used for a variety of other conditions such as musculoskeletal pain, myoclonus, and alcohol withdrawal. The elimination of baclofen is heavily dependent on intact renal function, and the contraindication for use in patients with insufficient renal function is not well recognized by healthcare providers. Here, the authors report a series of mild to severe cases of baclofen intoxication in patients with end-stage renal disease. In all cases, baclofen was initiated by either inpatient or outpatient healthcare providers and the patients generally presented with altered mentation, somnolence, and/or respiratory depression. All patients were treated with aggressive hemodialysis and made a full recovery. This paper will briefly review the literature regarding baclofen intoxication, safety of baclofen use in renal disease, and efficacy of extracorporeal therapy in the treatment of baclofen intoxication. PMID- 26096761 TI - Decision to adopt medical technology under the National Health Insurance System in Taiwan: case study of new molecular targeted drugs among non-small cell lung cancer patients. AB - RATIONALE, AIMS AND OBJECTIVES: Molecular targeted drugs (MTD), gefitinib and erlotinib, have been proven to provide clinical benefits to advanced stage non small cell lung cancer (NSCLC) patients. Therefore, access to such medical innovations in time is critical for patients with the right indications. The aim of this study was to explore determinants of the adoption of MTD among NSCLC patients under Taiwan's National Health Insurance (NHI) system. METHODS: Using Taiwan's Longitudinal Health Insurance Database and Cancer Registry database as the data source, we identified 1555 newly diagnosed NSCLC patients who started their cancer treatment between 2004 and 2009. Patients were categorized into 'non MTD' and 'MTD' groups based on the cancer treatment they received. Hierarchical logistic regression was used to explore potential determinants associated with the adoption of MTD by adjusting for patient-, disease-, doctor-, hospital-level characteristics and changes of reimbursement schemes. RESULTS: During the study period, 562 (36%) NSCLC patients were classified as the 'MTD group and 993 (64%) patients were the 'non-MTD' group. Hierarchical logistic regression model showed that the elderly were less likely to receive MTD (OR = 0.41; 95% CI: 0.28-0.60). In contrast, patients whose cancer type was adenocarcinoma (OR = 2.99; 95% CI: 2.09-4.26) were more likely to receive MTD. Those who went to private hospitals (OR = 1.75; 95% CI: 1.01-3.03) and hospitals with higher economic scale (OR = 3.00; 95% CI: 1.72-5.25) were more likely to receive MTD as well. CONCLUSIONS: Our findings suggest that both patient- and hospital-level characteristics significantly affected the adoption of MTD among NSCLC patients. PMID- 26096762 TI - Improved growth velocity of a patient with Noonan-like syndrome with loose anagen hair (NS/LAH) without growth hormone deficiency by low-dose growth hormone therapy. AB - Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is caused by a heterozygous c.4A>G mutation in SHOC2. Most cases exhibit both growth hormone deficiency (GHD) and growth hormone insensitivity (GHI) and thus require a high dose of growth hormone (GH) therapy (e.g., 35-40 ug/kg/day). We report on a genetically diagnosed NS/LAH patient manifesting severe short stature (-3.85 SDs) with low serum level of IGF1, 30 ng/ml. The peak levels of GH stimulation tests were within the normal range, and GHI was not observed in the IGF1 generation test. However, with low-dose GH therapy (25 ug/kg/day) for two years, IGF1 level and height were remarkably improved (IGF1: 117 ng/ml, height SDs: -2.20 SDs). Further, catch-up of motor development and improvement of the proportion of extending limbs to trunk were observed (the Developmental Quotient score increased from 68 to 98 points, and the relative sitting height ratio decreased from 0.62 to 0.57). Our results suggest that endocrinological causes for short stature are variable in NS/LAH and that GH therapy should be considered as a possible treatment for delayed development in NS/LAH. PMID- 26096763 TI - The orexinergic system in rainbow trout Oncorhynchus mykiss and its regulation by dietary lipids. AB - In this study, we report the distribution of orexin A (OXA), orexin B (OXB), and orexin receptor (OX2R) immunoreactive (ir) cells in the hypothalamus and gastrointestinal tract of Oncorhynchus mykiss fed diets with different dietary fatty acid compositions. Trout were fed five iso-energetic experimental diets containing fish oil, or one of four different vegetable oils (olive, sunflower, linseed, and palm oils) as the added dietary lipid source for 12 weeks. OXA, OXB, and OX2R immunoreactive neurons and nervous fibers were identified in the lateral and ventro-medial hypothalamus. OXA, OXB, and OX2R ir cells were found in the mucosa and glands of the stomach and in the mucosa of both the pyloric cecae and intestine. OX2R ir cells were localized in the mucosa layer of both the pyloric cecae and intestine. These immunohistochemical (IHC) results were confirmed via Western blotting. Antibodies against preproorexin (PPO) crossreacted with a band of ~16 kDa in the hypothalamus, stomach, pyloric cecae, and intestine. Antibodies against OX2R crossreacted with a band of ~38 kDa in the hypothalamus, pyloric cecae, and intestine. The presence and distribution of OXA, OXB, and OX2R ir cells in the hypothalamus and gastrointestinal tract did not appear to be affected by dietary oils. The presence of orexin system immunoreactive cells in the stomach, pyloric cecae, and intestine of rainbow trout, but not in the enteric nervous system, could suggest a possible role of these peptides as signaling of gastric emptying or endocrine modulation, implying a main local action played by orexins. PMID- 26096764 TI - Is the Reg3alpha (HIP/PAP) Protein Really an Obesogenic Factor? PMID- 26096765 TI - Exploration of efficacy and bleeding with combined phosphoinositide 3-kinase beta inhibition and aspirin in man. AB - BACKGROUND: Based on animal and human data, phosphoinositide 3-kinase (PI3K)beta is a promising antithrombotic target. However, the relation between efficacy and bleeding when combined with current antiplatelet therapies is unclear. OBJECTIVE: To strengthen the PI3Kbeta target validation using the short-acting inhibitor AZD6482 alone and in different combinations with P2Y12 and cyclooxygenase (COX)-1 inhibition in vitro (human platelets), in vivo (dog), and in healthy subjects. METHODS AND RESULTS: Evaluation of complete target inhibition of PI3Kbeta (by AZD6482), P2Y12 (by ticagrelor), and COX-1 (by aspirin) alone and in the different combinations vs. concentration responses for a panel of platelet agonists in vitro (adenosine diphosphate, collagen, thrombin receptor activating peptide) indicates that the rank order of antiplatelet efficacy is P2Y12 > PI3Kbeta > COX-1 as monotherapy and P2Y12 plus PI3Kbeta > P2Y12 plus COX-1 > PI3Kbeta plus COX-1 as dual therapy, with little additional effect with triple therapy. Use of a conscious dog model to assess ex vivo antiplatelet effect in parallel with bleeding time prolongation (standard incision in the ear) confirms the wide separation of efficacy vs. bleeding for PI3Kbeta inhibition and that this separation is reduced when combined with aspirin and more reduced when combined with clopidogrel. In healthy subjects, AZD6482, in combination with aspirin, shows a potential for greater antiplatelet potency but less bleeding potential compared with clopidogrel plus aspirin. CONCLUSIONS: PI3Kbeta inhibition, in comparison with P2Y12 and COX-1, delivers medium antiplatelet effect but with minimal bleeding. PI3Kbeta inhibition, in combination with aspirin, in healthy subjects, provides a potential for greater overall antiplatelet effect compared with clopidogrel plus aspirin, but with significantly less bleeding potential. PMID- 26096766 TI - NF-kappaB signaling in B-1 cell development. AB - NF-kappaB transcription factors play essential roles in hematopoiesis. In this review, we summarize the requirements of different components of the NF-kappaB pathway for B-1 cell development and maintenance. The B-1 cell developmental steps are also reviewed, with particular emphasis on stages where NF-kappaB signaling may be critical. PMID- 26096767 TI - Effects of advanced paternal age on trajectories of social behavior in offspring. AB - Our study is the first investigation of the effects of advanced paternal age (APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age-related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring. PMID- 26096768 TI - Heat shock decreases the embryonic quality of frozen-thawed bovine blastocysts produced in vitro. AB - In this study, the effect of heat shock on frozen-thawed blastocysts was evaluated using in vitro-produced (IVP) bovine embryos. In experiment 1, the effects of 6 h of heat shock at 41.0 C on fresh blastocysts were evaluated. HSPA1A expression as a reflection of stress was increased by heat shock (P < 0.05), but the expressions of the quality markers IFNT and POU5F1 were not affected. In experiment 2, frozen-thawed blastocysts were incubated at 38.5 C for 6 h (cryo-con) or exposed to heat shock at 41.0 C for 6 h (cryo-HS). Then, blastocysts were cultured at 38.5 C until 48 h after thawing (both conditions). Cryo-HS blastocysts exhibited a decreased recovery rate: HSPA1A expression was dramatically increased compared with that in fresh or cryo-con blastocysts at 6 h, and IFNT expression was decreased compared with that in cryo-con blastocysts at 6 h (both P < 0.05). Cryo-con blastocysts at 6 h also exhibited higher HSPA1A expression than fresh blastocysts (P < 0.05). At 48 h after thawing, the number of hatched blastocysts and blastocyst diameter were lower in cryo-HS blastocysts (P < 0.05). Cryo-con blastocysts showed lower POU5F1 levels at 48 h than fresh, cryo-con or cryo-HS blastocysts at 6 h (P < 0.05), but their POU5F1 levels were not different from those of cryo-HS blastocysts at 48 h. These results indicated that application of heat shock to frozen-thawed blastocysts was highly damaging. The increase in damage by the interaction of freezing-thawing and heat shock might be one reason for the low conception rate in frozen-thawed embryo transfer in summer. PMID- 26096770 TI - Structural Features and Asymmetric Environment of i-Pr-SPRIX Ligand. AB - Novel chiral diisopropyl spiro bis(isoxazoline) ligands, anti-i-Pr-SPRIX and syn i-Pr-SPRIX, were designed and synthesized. Their catalytic utility, X-ray crystallographic analyses, and complexation studies demonstrated the structural features of tetraisopropyl spiro bis(isoxazoline) ligand, i-Pr-SPRIX, which is a prominent ligand in various enantioselective Pd catalytic processes: All i-Pr groups work in collaboration to create an effective asymmetric environment. PMID- 26096769 TI - Eudaimonic well-being and tumor norepinephrine in patients with epithelial ovarian cancer. AB - BACKGROUND: The impact of psychological well-being on the physiologic processes involved in cancer progression remains unclear. Prior research has implicated adrenergic signaling in tumor growth and metastasis. Given that adrenergic signaling is influenced by both positive and negative factors, the authors examined how 2 different aspects of well-being (eudaimonic and positive affect) and psychological distress were associated with tumor norepinephrine (NE) in patients with ovarian cancer. METHODS: A total of 365 women with suspected ovarian cancer completed psychosocial assessments before surgery and clinical information was obtained from medical records. Study inclusion was confirmed after histological diagnosis. Tumor NE was measured in frozen tissue samples using high-performance liquid chromatography with electrochemical detection. Confirmatory factor analysis was used to model eudaimonic well-being, positive affect, and psychological distress, and structural equation modeling was used to examine associations between these factors and tumor NE. RESULTS: Eudaimonic well being, positive affect, and psychological distress, modeled as distinct but correlated constructs, best fit the data (ie, compared with unitary or 2-factor models) (root mean square error of approximation, 0.048; comparative fit index, 0.982; and standardized root-mean-squared residual, 0.035). Structural equation modeling analysis that included physical well-being, stage of disease, histology, psychological treatment history, beta-blocker use, and caffeine use as covariates was found to have good model fit (root mean square error of approximation, 0.052; comparative fit index, 0.955; and standardized root-mean-squared residual, 0.036) and demonstrated that eudaimonic well-being was related to lower tumor NE (beta = -.24 [P = .045]). In contrast, no effects were found for positive affect or psychological distress. CONCLUSIONS: Eudaimonic well-being was found to be associated with lower tumor NE, independent of positive affect and psychological distress. Because adrenergic signaling is implicated in tumor progression, increasing eudaimonic well-being may improve both psychological and physiologic resilience in patients with ovarian cancer. PMID- 26096771 TI - Prognostic model for patients receiving arterial-embolization for hepatocellular carcinoma: issues to consider. PMID- 26096772 TI - Adolescents who were born extremely preterm demonstrate modest decreases in exercise capacity. AB - AIM: We aimed to investigate exercise capacity in adolescents who were born extremely preterm and to study changes through puberty and associations with neonatal data, exercise habits and lung function. METHODS: This Norwegian population-based controlled cohort study focused on all infants (n = 35) born at a gestational age of <= 28 weeks or with a birthweight of <= 1000 grams in 1991 1992, together with matched term-born controls. Participants underwent spirometry and a maximal cardiopulmonary treadmill exercise test at 10 and 18 years. RESULTS: At 18 years of age, mean (95% confidence interval) peak oxygen consumption (peak VO2 ) was 42.3 (39.2-45.4) vs 45.3 (41.3-49.3) mL/kg/min in the preterm- and term-born groups, while the completed treadmill distance was 915 (837-992) vs 1017 (912-1122) metres. Peak VO2 was unrelated to neonatal factors and current lung function. Changes between 10 and 18 were similar in the two groups, and positive associations between exercise habits and peak VO2 developed during the period. CONCLUSION: Exercise capacity was modestly reduced in adolescents born extremely preterm, but the values were considered normal in most participants. Changes during puberty were similar to those observed for term controls, and the findings suggest similar trainability. PMID- 26096773 TI - Influence of in ovo mercury exposure, lake acidity, and other factors on common loon egg and chick quality in Wisconsin. AB - A field study was conducted in Wisconsin (USA) to characterize in ovo mercury (Hg) exposure in common loons (Gavia immer). Total Hg mass fractions ranged from 0.17 ug/g to 1.23 ug/g wet weight in eggs collected from nests on lakes representing a wide range of pH (5.0-8.1) and were modeled as a function of maternal loon Hg exposure and egg laying order. Blood total Hg mass fractions in a sample of loon chicks ranged from 0.84 ug/g to 3.86 ug/g wet weight at hatch. Factors other than mercury exposure that may have persistent consequences on development of chicks from eggs collected on low-pH lakes (i.e., egg selenium, calcium, and fatty acid mass fractions) do not seem to be contributing to reported differences in loon chick quality as a function of lake pH. However, it was observed that adult male loons holding territories on neutral-pH lakes were larger on average than those occupying territories on low-pH lakes. Differences in adult body size of common loons holding territories on neutral-versus low-pH lakes may have genetic implications for differences in lake-source-related quality (i.e., size) in chicks. The tendency for high in ovo Hg exposure and smaller adult male size to co-occur in low-pH lakes complicates the interpretation of the relative contributions of each to resulting chick quality. PMID- 26096774 TI - Detection of a mammalian-like astrovirus in bird, European roller (Coracias garrulus). AB - Astroviruses are small, non-enveloped viruses with positive sense, single stranded RNA genomes. The family Astroviridae contains two genera, Mamastrovirus and Avastrovirus, which - based upon our current knowledge - infect mammals and birds, respectively. However, recent seroprevalence study indicated that people with contact to turkeys can develop serological responses to the turkey astrovirus and minks might have been infected with the avastrovirus. These data suggest that the "host species/astrovirus genus" association should be permeable; however, mamastrovirus infection has not been reported from avian species, yet. In this study, a novel astrovirus was identified by viral metagenomics and RT-PCR methods in 2 (11%) out of 19 faecal samples collected from a wild, carnivorous bird species, European rollers (Coracias garrulus) from two breeding territories in Hungary. The complete genome sequence of astrovirus Er/SZAL6/HUN/2011 (KP663426) was 7025 nt-long and had some unique genomic features including an unusually long spacer between the subgenomic RNA promoter and the ORF2 initiation codon. Using the BLASTp Er/SZAL6/HUN/2011 had the highest aa identities 35%, 61% and 34% to MAstV 32 (JF713710, host: porcine), to MAstV 23 (JF729316, host: rabbit) and to unclassified porcine astrovirus (JX684071) in ORF1a, ORF1b and ORF2, respectively. The same proteins of Er/SZAL6/HUN/2011 had 25%, 66% and 33% aa identities to the corresponding proteins of murine astrovirus (JX544743) as the closest strain. The sequence- and phylogenetic analysis indicated that Er/SZAL6/HUN/2011 represents the first member of a novel mamastrovirus species. Data suggest that both mammals and birds could have been exposed to mamastroviruses and avastroviruses providing opportunities for cross-species infection and viral adaptation with cross-class astroviruses especially in carnivorous animals. Further investigation is needed to determine the origin, natural host species spectrum, distribution and spread of Er/SZAL6/HUN/2011 among vertebrates. PMID- 26096775 TI - Comparative analysis of Mycobacterium tuberculosis Beijing strains isolated in three remote areas of Japan. AB - A quantitative and qualitative comparison was carried out of Mycobacterium tuberculosis Beijing strains isolated in three remote areas of Japan. A total of 452 strains from Chiba Prefecture, 75 from Yamagata Prefecture, and 315 from Kobe City were analyzed for 24 loci by variable number of tandem repeats typing (24(Beijing)-VNTR). All strains were classified in six Beijing subgroups (B(SUB)), B1 to B5 and T, based on a minimum spanning tree reconstructed using data of a standard set of 15 VNTR loci. No significant difference was found in the distribution of strains in the B(SUB) in the three areas, with one exception due to a B5 outbreak in Yamagata, indicating no significant quantitative difference in the B(SUB) in the three areas (P<0.01, Chi-square test). In addition, when strains in each B(SUB) isolated in the three areas were mixed and standardized index of association (I(A)(s)) and variance (Phi(PT)) values were calculated, no significant qualitative difference in the B(SUB) in the three areas was found. These results suggested that the B(SUB) diverged prior to the introduction of M. tuberculosis Beijing strains into Japan. Differences in the distribution of strains in each B(SUB) between Japan and continental Asian countries suggested there had been genetic drift in the continental Asian countries in which B4 had been dominant. PMID- 26096776 TI - Heterozygous beta-thalassemia with complete absence of hemoglobin A2 in a Chinese adult. PMID- 26096777 TI - Do tutorials on application method enhance adapalene-benzoyl peroxide combination gel tolerability in the treatment of acne? AB - Fixed-dose combination adapalene 0.1% and benzoyl peroxide 2.5% gel (A-BPO) has rarely been studied for Asian acne patients, while they have complained of local irritations more often when applying individual components. In this study, we compared A-BPO gel with benzoyl peroxide (BPO) in terms of efficacy and tolerability in Korean patients first, and assessed the clinical benefit of a dermatological tutorial on application technique in reducing irritations for A BPO. This study was conducted as a single-blind controlled split-face trial for a 12-week period. Each half facial side of 85 patients was randomly assigned to either A-BPO or BPO. Success rate, lesion counts and safety profiles were evaluated (analysis I). During initial assignment, all patients were further randomized to either dermatological tutorial (DT) or non-tutorial (NT) subgroups depending on the presence of dermatologists' tutorials for application methods to their A-BPO sides. Clinical data of the A-BPO side was compared between two subgroups (analysis II). As a result, A-BPO gel outperformed BPO, demonstrating better efficacy in success rates and lesion counts as early as 1 week. However, A BPO proved significantly less tolerable compared with both BPO and previous A-BPO data from Caucasians. Bioengineering measurements further confirmed clinical data (analysis I). The DT subgroup achieved much better tolerability with comparable therapeutic efficacies compared with the NT subgroup (analysis II). In conclusion, A-BPO demonstrated higher efficacies in acne compared with BPO in Korean patients, while skin irritation levels were notable concurrently. Dermatologists' education for application methods would significantly decrease these side-effects, maintaining superior efficacy levels. PMID- 26096778 TI - Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring. AB - Fetal exposure to H2 blockers (H2 Bs) or proton pump inhibitors (PPIs) has been reported to be associated with asthma in children. We evaluated the risk of asthma in offspring following prenatal H2 Bs. We enrolled 91 428 children and their mothers who resided in southern Israel during 1998-2011. The computerized medications database was linked with records from the district hospital. Of the eligible children, 11 227 developed asthma, and overall 5.5% had been exposed to H2 Bs or PPIs prenatally. The risk of developing asthma was slightly higher in the group exposed to H2 Bs or PPIs (RR, 1.09; P = .023). At greater risk were children whose mothers purchased these medications more than 3 times (RR, 1.22; P = .038) or exposed to >20 defined daily doses or prenatally exposed to lansoprazole. The statistical association was significant and depended on magnitude of exposure and specific medication, but the absolute risk was low. The association between maternal consumption of H2 Bs or PPIs and asthma and childhood remained statistically significant 2 years after delivery, raising the possibility of confounding by the indication phenomenon. In view of the findings, a causal relationship could not be ascertained, and an unidentified etiological factor could be operative. PMID- 26096779 TI - The Casuarina NIN gene is transcriptionally activated throughout Frankia root infection as well as in response to bacterial diffusible signals. AB - Root nodule symbioses (RNS) allow plants to acquire atmospheric nitrogen by establishing an intimate relationship with either rhizobia, the symbionts of legumes or Frankia in the case of actinorhizal plants. In legumes, NIN (Nodule INception) genes encode key transcription factors involved in nodulation. Here we report the characterization of CgNIN, a NIN gene from the actinorhizal tree Casuarina glauca using both phylogenetic analysis and transgenic plants expressing either ProCgNIN::reporter gene fusions or CgNIN RNAi constructs. We have found that CgNIN belongs to the same phylogenetic group as other symbiotic NIN genes and CgNIN is able to complement a legume nin mutant for the early steps of nodule development. CgNIN expression is correlated with infection by Frankia, including preinfection stages in developing root hairs, and is induced by culture supernatants. Knockdown mutants were impaired for nodulation and early root hair deformation responses were severely affected. However, no mycorrhizal phenotype was observed and no induction of CgNIN expression was detected in mycorrhizas. Our results indicate that elements specifically required for nodulation include NIN and possibly related gene networks derived from the nitrate signalling pathways. PMID- 26096780 TI - An autopsy case of neuronal intermediate filament inclusion disease with regard to immunophenotypic and topographical analysis of the neuronal inclusions. AB - We report an autopsy case of neuronal intermediate filament inclusion disease (NIFID), in which pyramidal motor dysfunction preceded cognitive disturbance for 3 years from the onset. A 41-year-old Japanese man presented progressive spastic tetraparesis followed by cognitive impairment. His neurological symptoms gradually deteriorated and he died of pneumonia 16 years from the onset. His brain showed severe generalized atrophy with enlargement of ventricles. The microscopic examination revealed severe neuronal loss with gliosis and sponginess predominantly in the fronto-temporal cortices, caudate and putamen. Many hyaline conglomerate inclusions (HC) without immunoreactivity for 'fused in sarcoma' protein (FUS) and some granular and small round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were observed in the remaining neurons. Some neurons with HC had small basophilic inclusions which showed positive FUS ir, attached to HC in the cytoplasm. Otherwise, FUS-ir large compact inclusions (so-called Pick-like) were also observed but were scarce. In the cerebral cortex and the neostriatum, frequency of the inclusions was well correlated with neuronal loss. In the brainstem, neuronal loss was mild and FUS-ir inclusions dominated. In the subthalamic nucleus and red nucleus, there was no HC but there were many FUS-ir inclusions without neuronal loss. The above findings suggest that cytoplasmic mislocalization and aggregation of FUS appear at the early stage of the disease, and the FUS aggregate process may not be a direct precedent structure of HC. PMID- 26096781 TI - Functional characterization of Val60, a key residue involved in the membrane oligomerization of fragaceatoxin C, an actinoporin from Actinia fragacea. AB - Actinoporins are pore-forming toxins produced by different sea anemones that self assemble within the membranes of their target cells and compromise their function as a permeability barrier. The recently published three-dimensional structures of two oligomeric complexes formed by fragaceatoxin C point to Val60 as a key residue involved in the oligomerization of the functional pore. To gain insight into the mechanism of toxin oligomerization, different point mutations have been introduced at this position. Functional characterization of the muteins suggests that Val60 represents a hot-spot where the introduction of mutations hinders protein assembly and reduces the overall affinity for membranes. PMID- 26096782 TI - ZNF10 inhibits HIV-1 LTR activity through interaction with NF-kappaB and Sp1 binding motifs. AB - Kruppel-associated box-containing zinc finger (KRAB-ZNF) genes constitute the single largest gene family of transcriptional repressors in the genomes of higher organisms. In this study, we isolated 52 cDNA clones of KRAB-ZFPs from U1 cell lines and screened them to identify which were capable of regulating HIV-1 gene expression. We identified 5 KRAB-ZFPs that suppressed ?50% of HIV-1 LTR. Of the 5 identified KRAB-ZFPs, the expression of ZNF10 significantly enhanced the transcriptional repression activity of the LTR compared with other ZNFs. In addition, the depletion of endogenous ZNF10 led to the activation of HIV-1 LTR. The repressor activity of ZNF10 was required for TRIM28, SETDB1 and HP1-gamma binding. These results indicate that ZNF10 could be involved in a potent intrinsic antiretroviral defense. PMID- 26096783 TI - Tumour-suppressive microRNA-29s directly regulate LOXL2 expression and inhibit cancer cell migration and invasion in renal cell carcinoma. AB - Here, we found that members of the microRNA-29 family (miR-29a/b/c; "miR-29s") were significantly reduced in clear cell renal cell carcinoma (ccRCC) tissues, suggesting that they functioned as tumour suppressors. Restoration of all mature members of the miR-29 family inhibited cancer cell proliferation, migration and invasion. LOXL2 was a direct target gene of miR-29s, as shown by genome-wide gene expression analysis and luciferase reporter assay. Overexpressed LOXL2 was confirmed in ccRCC clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in ccRCC cell lines. Our data demonstrated that the miR-29s-LOXL2 axis contributed to cancer cell migration and invasion in ccRCC. PMID- 26096784 TI - LINC'ing form and function at the nuclear envelope. AB - The nuclear envelope is an amazing piece of engineering. On one hand it is built like a mediaeval fortress with filament systems reinforcing its membrane walls and its double membrane structure forming a lumen like a castle moat. On the other hand its structure can adapt while maintaining its integrity like a reed bending in a river. Like a fortress it has guarded drawbridges in the nuclear pore complexes, but also has other mechanical means of communication. All this is enabled largely because of the LINC complex, a multi-protein structure that connects the intermediate filament nucleoskeleton across the lumen of the double membrane nuclear envelope to multiple cytoplasmic filament systems that themselves could act simultaneously both like mediaeval buttresses and like lines on a suspension bridge. Although many details of the greater LINC structure remain to be discerned, a number of recent findings are giving clues as to how its structural organization can yield such striking dynamic yet stable properties. Combining double- and triple-helical coiled-coils, intrinsic disorder and order, tissue-specific components, and intermediate filaments enables these unique properties. PMID- 26096786 TI - Diversity of COP9 signalosome structures and functional consequences. AB - The COP9 signalosome (CSN) is a regulator of the ubiquitin (Ub) proteasome system (UPS). It interacts with hundreds of cullin-RING ubiquitin E3 ligases (CRLs) and regulates their activity by removing the Ub-like protein Nedd8 from cullins. In mammalian cells 7 different cullins exist which form CRLs with adaptor proteins and with a large number of substrate recognition subunits such as F-box and BTB proteins. This large variety of CRL-complexes is deneddylated by the CSN. The capacity of the CSN to interact with numerous types of CRL complexes can be explained by its structural diversity, which allows different CSN variants to interact with different binding partners and substrates and enables different subunit expression profiles. Diversity of CSN complexes presumably occurs by: (1) flexibility of CSN holo complex structure; (2) formation of CSN mini complexes and free CSN subunits and (3) generation of CSN variants via integration of CSN subunit isoforms. In this review we will discuss the structural diversity of the CSN complex and possible functional consequences. PMID- 26096787 TI - Regulation of DNA phosphorothioate modifications by the transcriptional regulator DptB in Salmonella. AB - DNA phosphorothioate (PT) modifications, with one non-bridging phosphate oxygen replaced with sulfur, are widely but sporadically distributed in prokaryotic genomes. Short consensus sequences surround the modified linkage in each strain, although each site is only partially modified. The mechanism that maintains this low-frequency modification status is still unknown. In Salmonella enterica serovar Cerro 87, PT modification is mediated by a four-gene cluster called dptBCDE. Here, we found that deletion of dptB led to a significant increase in intracellular PT modification level. In this deletion, transcription of downstream genes was elevated during rapid cell growth. Restoration of dptB on a plasmid restored wild-type levels of expression of downstream genes and PT modification. In vitro, DptB directly protected two separate sequences within the dpt promoter region from DNase I cleavage. Each protected sequence contained a direct repeat (DR). Mutagenesis assays of the DRs demonstrated that each DR was essential for DptB binding. The observation of two shifted species by gel-shift analysis suggests dimer conformation of DptB protein. These DRs are conserved among the promoter regions of dptB homologs, suggesting that this regulatory mechanism is widespread. These findings demonstrate that PT modification is regulated at least in part at the transcriptional level. PMID- 26096788 TI - Quantitative muscle MRI: A powerful surrogate outcome measure in Duchenne muscular dystrophy. AB - In muscular dystrophies quantitative muscle MRI (qMRI) detects disease progression more sensitively than clinical scores. This prospective one year observational study compared qMRI with clinical scores in Duchenne muscular dystrophy (DMD) to investigate if qMRI can serve as a surrogate outcome measure in clinical trials. In 20 DMD patients the motor function measure (MFM) total and subscores (D1-D3) were done for physical examination, and the fat fraction (MFF) of thigh muscle qMRI was obtained using the two-point Dixon method. Effect sizes (ES) were calculated for all measures. Sample size estimation (SS) was done modelling assumed treatment effects. Ambulant patients <7 years at inclusion improved in the MFM total and D1 score (ES 1.1 and 1.0). Ambulant patients >7 years (highest ES in the MFM D1 subscore (1.2)), and non-ambulant patients (highest ES in the total MFM score (0.7)) worsened. In comparison the ES of QMRI was much larger, e.g. SS estimations for qMRI data were up to 17 fold smaller compared to the MFM total score and up to 7 fold to the D1 subscore, respectively. QMRI shows pathophysiological changes in DMD and might serve as a surrogate outcome measure in clinical trials. PMID- 26096789 TI - Eighteen cases of wheat allergy and wheat-dependent exercise-induced urticaria/anaphylaxis sensitized by hydrolyzed wheat protein in soap. AB - BACKGROUND: Glupearl 19S, an acid-hydrolyzed wheat protein (HWP), is used widely in Japan as a moisturizing ingredient in facial soaps. Since 2010, there has been an increasing number of reports of contact urticaria and wheat allergy resulting from the use of products containing this substance. CASE REPORTS: Sixty-one patients who had used HWP-containing facial soap visited our hospital. Thirty five of these experienced urticaria or anaphylaxis after consuming wheat containing food. RESULTS: Eighteen of the 35 patients tested positive to 0.01% Glupearl 19S solution. Wheat-specific IgE and serum gluten-specific IgE were higher in the patients with HWP allergy than in non-HWP allergy patients. Among the patients who tested positive to Glupearl 19S on the skin prick test, nine experienced HWP-wheat-dependent exercise-induced anaphylaxis, and four experienced food-dependent anaphylaxis. Moreover, four of these patients not only experienced food-dependent anaphylaxis but also a worsening of the symptoms during exercise. DISCUSSION: The clinical symptomology was so variable that the patients were classified into six groups. We found that patients with HWP allergy tended to manifest symptoms of both HWP-wheat-dependent exercise-induced anaphylaxis and contact urticaria. The etiology of hydrolyzed wheat protein allergy is unknown. Patients with a history of these symptoms need to be informed about the risk of consuming wheat-containing foods and the importance of excluding such items from their diet. PMID- 26096785 TI - Chromosome domain architecture and dynamic organization of the fission yeast genome. AB - Advanced techniques including the chromosome conformation capture (3C) methodology and its derivatives are complementing microscopy approaches to study genome organization, and are revealing new details of three-dimensional (3D) genome architecture at increasing resolution. The fission yeast Schizosaccharomyces pombe (S. pombe) comprises a small genome featuring organizational elements of more complex eukaryotic systems, including conserved heterochromatin assembly machinery. Here we review key insights into genome organization revealed in this model system through a variety of techniques. We discuss the predominant role of Rabl-like configuration for interphase chromosome organization and the dynamic changes that occur during mitosis and meiosis. High resolution Hi-C studies have also revealed the presence of locally crumpled chromatin regions called "globules" along chromosome arms, and implicated a critical role for pericentromeric heterochromatin in imposing fundamental constraints on the genome to maintain chromosome territoriality and stability. These findings have shed new light on the connections between genome organization and function. It is likely that insights gained from the S. pombe system will also broadly apply to higher eukaryotes. PMID- 26096790 TI - Health-related quality of life and sleep among Chinese children after living donor liver transplantation. AB - LDLT is a well-established treatment for most terminal liver diseases in children. Survival rates have improved, yet few studies have considered HRQoL or sleep problems in LDLT recipients. In this cross-sectional study, we enrolled 51 children who had undergone LDLT in Renji Hospital. PedsQL(TM) 4.0 Generic Core Scales, PedsQL(TM) 3.0 Transplant Module, and Pediatric Sleep Questionnaire were used to assess outcomes. Of all participants, 11.8% (6/51) reported low total HRQoL scores. Participants' scores on most HRQoL subscales were comparable to the scores of healthy children. However, compared with solid organ transplant recipients, LDLT recipients scored significantly lower in About My Medicines II (t = 3.092, p = 0.002) and Worry (t = 2.760, p = 0.006). Sleep problems (41.2%) were common among participants. Hierarchical regression analyses showed that SRBD accounted for significant variance in HRQoL on total generic HRQoL (R(2) = 0.446, p < 0.001), psychosocial health (R(2) = 0.372, p = 0.001), physical health (R(2) = 0.345, p = 0.003), total transplant-specific HRQoL (R(2) = 0.514, p < 0.001), About My Medicines I (R(2) = 0.365, p = 0.013), My Transplant and Others (R(2) = 0.334, p = 0.005), Pain and Hurt (R(2) = 0.544, p < 0.001), Worry (R(2) = 0.401, p = 0.001), Treatment Anxiety (R(2) = 0.526, p < 0.001), How I Look (R(2) = 0.221, p = 0.040), and Communication (R(2) = 0.343, p = 0.012). In conclusion, sleep problems are non-negligible in children after LDLT and predicted significant variance on HRQoL. PMID- 26096791 TI - A Personal History of Quadruplex-Small Molecule Targeting. AB - The story behind some of the early studies in the laboratory of Stephen Neidle on quadruplex-binding small molecules and the structural studies on quadruplexes and their complexes is presented and discussed in the context of his earlier work on drug-DNA interactions. More recent studies and future directions in the rational design of small molecules targeting telomeric and gene promoter quadruplexes are also described. PMID- 26096792 TI - Nitrogen-doped carbon nanotubes via a facile two-step approach as an efficient catalyst for the direct dehydrogenation of ethylbenzene. AB - A novel and efficient nitrogen-doped carbon nanotube (A-M-CNT) catalyst has been prepared by a facile two-step method, including prior air activation and subsequent pyrolysis of the carbon nanotubes with melamine. The as-synthesized A M-CNT affords superior catalytic activity to the nitrogen-doped CNT without air activation (M-CNT) and pristine CNT, ascribed to its unique microstructure and surface chemical properties. PMID- 26096793 TI - Autofluorescence of eccrine sweat glands. AB - BACKGROUND/PURPOSE: The monitoring of autofluorescence in skin tissue samples can have diagnostic and therapy significance. In this study, we are the first to describe autofluorescence of eccrine sweat glands, which is important and helpful for the diagnosis and therapy of diseases that involve the eccrine sweat glands. METHODS: Eccrine sweat gland autofluorescence in haematoxylin-eosin (HE) stained skin tissue sections was observed under a fluorescence microscope, which was compared to the immunofluorescence of keratin 19 and 15 in the skin tissue sections. The single eccrine sweat glands from five volunteers including three males and two females were isolated and also observed under a fluorescence microscope. The autofluorescence intensity of the single eccrine sweat gland was measured using a laser confocal scanning microscope system. RESULTS: Eccrine sweat gland autofluorescence in HE stained skin tissue sections appears green under GFP fliter system (470/40 nm) and red under N2.1 fliter system (515-560 nm). Furthermore, the single eccrine sweat gland showed various autofluorescence colours, including green under wide blue and red under wide green. The autofluorescence intensity of the single eccrine sweat gland was measured. The spectrum excited at 488 nm exhibited two peaks located at approximately 530 nm (11.54 +/- 4.66) and 590 nm (10.38 +/- 4.33). The results suggest flavin and lipopigment as the endogenous fluorophores. CONCLUSION: The autofluorescence of the HE stained eccrine sweat gland sections is simple and helpful for easily determining the structure of eccrine sweat glands. The autofluorescence of the single eccrine sweat gland may be due to the existence of flavin and lipopigment. PMID- 26096794 TI - Prevalence of cross-reactive carbohydrate determinants in UK bakers. PMID- 26096796 TI - Electroencephalographic lateralization, clinical correlates and pharmacological response in untreated Parkinson's disease. AB - BACKGROUND: In Parkinson's disease (PD), different topographically defined cortical-subcortical oscillatory networks have been implicated in motor program dysfunction. Few studies have focused on clinical correlates of cortical activity asymmetry using quantitative electroencephalography. METHODS: We retrospectively selected N = 34 L-dopa naive PD subjects who had undergone standardized electroencephalography. We selected N = 18 subjects group-matched by age, sex and hand dominance with normal electroencephalography and no parkinsonism and/or cognitive decline as controls. A Welch's periodogram was applied to electroencephalographic signal epochs recorded from homologous pairs of electrodes over each hemisphere. An index of lateralization was then obtained as the absolute value of the electroencephalographic asymmetry index, computed by subtracting left from right-sided log power spectral density for each homologous site and frequency band. A standardized L-dopa acute challenge test was performed on all PD subjects to compute short-duration response magnitude. RESULTS: In mid/lateral frontal regions higher index of lateralization for the beta band (p = 0.015) and lower index of lateralization for the theta band (p = 0.036) were found in PD subjects as compared to controls. Both parameters correlated with Hoehn-Yahr staging (beta: r = 0.428, p = 0.012; theta: r = -0.464, p = 0.006). In occipital region lower index of lateralization for the alpha band was found in PD correlating with L-dopa short-duration response magnitude (r = 0.456; p = 0.007). CONCLUSIONS: Lateralization of frontal cortex beta electroencephalographic activity is associated with clinical disability. Occipital cortex alpha activity may relate to L-dopa responsiveness in untreated PD subjects. PMID- 26096797 TI - Thalamic deep brain stimulation for orthostatic tremor: Clinical and neurophysiological correlates. PMID- 26096798 TI - Suicidal behaviors are very rare in antiparkinsonian drug trials. PMID- 26096799 TI - Comparison of the Effects of Epicardial and Endocardial Cardiac Resynchronization Therapy on Transmural Dispersion of Repolarization. AB - BACKGROUND: Despite significant improvements in cardiac output and functional capacity with cardiac resynchronization therapy (CRT), incidence of sudden cardiac death still remains high. Reversal of physiological myocardial activation sequence during epicardial pacing increases the transmural dispersion of repolarization (TDR). The aim of this study was to compare the effects of endocardial and epicardial biventricular pacing on repolarization parameters in the same patient group. METHODS: Seven patients who had transseptal endocardial left ventricle (LV) lead placement, in whom epicardial CRT had failed due to coronary sinus (CS) lead dislodgement after successful implantation, were admitted to the study. LV endocardial leads were implanted through the interatrial septum in a lateral position. Electrocardiograms (ECGs) were scanned before and after successful epicardial and endocardial biventricular pacing and analyzed using digital calipers. ECG markers of TDR (TpTe and TpTe/QT ratio) were measured and compared. RESULTS: Baseline QRS durations (161.7 +/- 15.9 ms vs 162.2 +/- 17.8 ms, P = 0.95), TpTe values (107.1 +/- 20.5 ms vs 108.5 +/- 17.6 ms, P = 0.89), and TpTe/QT ratios (0.24 +/- 0.05 vs 0.24 +/- 0.03, P = 0.88) were similar before epicardial and endocardial CRT. QRS interval reduction was similar (-28.3 +/- 11.6 ms vs -29.1 +/- 11.4 ms, P = 0.89) in both groups. Compared to transseptal endocardial CRT, epicardial CRT was associated with a significant increase in TpTe (17.1 +/- 19.5 ms vs -12.6 +/- 18.9 ms, P = 0.01) and TpTe/QT ratio (0.03 +/- 0.04 vs -0.02 +/- 0.03, P = 0.04). CONCLUSION: Transseptal LV endocardial pacing is associated with significant reduction in TDR characteristics compared to epicardial pacing in CRT. Further studies are warranted to determine whether these effects may contribute to reduction of arrhythmias in patients with CRT. PMID- 26096795 TI - Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases. AB - Intracellular localization has been reported for over three-quarters of receptor tyrosine kinase (RTK) families in response to environmental stimuli. Internalized RTK may bind to non-canonical substrates and affect various cellular processes. Many of the intracellular RTKs exist as fragmented forms that are generated by gamma-secretase cleavage of the full-length receptor, shedding, alternative splicing, or alternative translation initiation. Soluble RTK fragments are stabilized and intracellularly transported into subcellular compartments, such as the nucleus, by binding to chaperone or transcription factors, while membrane bound RTKs (full-length or truncated) are transported from the plasma membrane to the ER through the well-established Rab- or clathrin adaptor protein-coated vesicle retrograde trafficking pathways. Subsequent nuclear transport of membrane bound RTK may occur via two pathways, INFS or INTERNET, with the former characterized by release of receptors from the ER into the cytosol and the latter characterized by release of membrane-bound receptor from the ER into the nucleoplasm through the inner nuclear membrane. Although most non-canonical intracellular RTK signaling is related to transcriptional regulation, there may be other functions that have yet to be discovered. In this review, we summarize the proteolytic processing, intracellular trafficking and nuclear functions of RTKs, and discuss how they promote cancer progression, and their clinical implications. PMID- 26096801 TI - Cardiopulmonary Exercise Testing in Heart Failure. AB - A growing body of literature has underscored the value of ventilatory gas exchange techniques during exercise testing (commonly termed cardiopulmonary exercise testing, or CPX) and their applications in the management of patients with heart failure (HF). The added precision provided by this technology is useful in terms of understanding the physiology and mechanisms underlying exercise intolerance in HF, quantifying the response to therapy, evaluating disability, making activity recommendations, and quantifying the response to exercise training. Importantly, a wealth of data has been published in recent years on the prognostic utility of CPX in patients with HF. These studies have highlighted the concept that indices of ventilatory inefficiency, such as the VE/VCO2 slope and oscillatory breathing, are particularly powerful in stratifying risk in HF. This article provides an overview of the clinical utility of CPX in patients with HF, including the applications of ventilatory inefficiency during exercise, the role of the pulmonary system in HF, respiratory muscle performance (RMP), and the application of CPX as part of a comprehensive clinical and exercise test evaluation. PMID- 26096802 TI - Gene expression profiling analysis of osteosarcoma cell lines. AB - Osteosarcoma (OS) is the most common type of primary bone malignancy and has a poor prognosis. To investigate the mechanisms of osteosarcoma, the present analyzed the GSE28424 microarray. GSE28424 was downloaded from the Gene Expression Omnibus, and included a collective of 19 OS cell lines and four normal bone cell lines, which were used as controls. Subsequently, the differentially expressed genes (DEGs) were screened using the Limma package in Bioconductor. Gene Ontology (GO) and pathway enrichment analysis of the DEGs was performed using the Database for Annotation, Visualization and Integrated Discovery, interactions between the proteins encoded by the DEGs were identified using STRING, and the protein-protein interaction (PPI) network was visualized using Cytoscape. In addition, modular analysis of the PPI network was performed using the Clique Percolation Method (CPM) in CFinder. A total of 1,170 DEGs were screened, including 530 upreguated and 640 downregulated genes. The enriched functions included organelle fission, immune response and response to wounding. In addition, RPL8 was observed to be involved with the ribosomal pathway in module A of the PPI network of the DEGs. PLCG1, SYK and PLCG2 were also involved in the B-cell receptor signaling pathway in module B and the Fc-epsilon RI signaling pathway in module C. In addition, AURKA (degree=39), MAD2L1 (degree=38), CDCA8 (degree=38), BUB1 (degree=37) and MELK (degree=37) exhibited higher degrees of connectivity in module F. The results of the present study suggested that the RPL8, PLCG1, PLCG2, SYK, MAD2L1, AURKA, CDCA8, BUB1 and MELK genes may be involved in OS. PMID- 26096804 TI - Blood Glucose-lowering Effect of T. procumbens L.: A Pilot Clinical Study in Individuals with Type 2 Diabetes. AB - Traditional knowledge, in vitro studies, and studies using animal models suggest that Tridax procumbens L. exhibits blood glucose-lowering properties and antiinflammatory effects. In this study, we evaluated the blood glucose-lowering effect of T. procumbens supplementation in individuals with type 2 diabetes. An extract (asava) of T. procumbens L. was prepared following Ayurveda guidelines. Chemical and microbial analyses indicated presence of phenolics, flavonoids, and carotenoids, and absence of microbial contamination, aflatoxins, heavy metals, and pesticide residues. A chemical fingerprint of T. procumbens L. asava, developed using Ultra high pressure liquid chromatography/electron spray ionization-mass spectrometry (UPLC/ESI-MS) in negative mode, suggest the presence of several compounds including polyphenols. T. procumbens asava demonstrated strong total antioxidant capacity, Fe3+ reducing potential, Fe2+ chelation, H2 O2 scavenging activity, and inhibition of lipid peroxidation. We recruited 20 type 2 diabetic individuals from Kolhapur, India. Participants received 15 mL of T. procumbens asava, twice daily, for 4 weeks, while continuing their prescribed antidiabetic medications. Fasting blood glucose decreased by 11% in men (p < 0.01) and 20% in women (p < 0.05), and post-prandial blood glucose concentrations were lowered by 26% in men (p < 0.001) and 29% in women (p < 0.001) following 4 weeks of asava supplementation. No adverse events or side effects were reported. This is the first clinical study demonstrating a significant blood glucose lowering effect of T. procumbens asava in type 2 diabetes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096803 TI - Physical Activity and Change in Long Distance Corridor Walk Performance in the Health, Aging, and Body Composition Study. AB - OBJECTIVES: To examine the prospective relationship between self-reported physical activity and aerobic fitness in the Health, Aging, and Body Composition Study (Health ABC) using the Long Distance Corridor Walk (LDCW). DESIGN: Cohort study with 7 years of follow-up. SETTING: Two U.S. clinical sites. PARTICIPANTS: Community-dwelling older adults enrolled in Health ABC (N = 3,075, aged 70-79, 52% female, 42% black) with no self-reported difficulty walking one-quarter of a mile or climbing 10 steps. MEASUREMENTS: Participants were classified based on a physical activity questionnaire as being inactive (<=1,000 kcal/wk exercise activity, <=2,719 kcal/wk total physical activity), lifestyle active (<=1,000 kcal/wk exercise activity, >2,719 kcal/wk total physical activity), or exercisers (>=1,000 kcal/wk exercise activity). The LDCW, an endurance walking test (400 m), was administered at Years 1 (baseline), 2, 4, 6, and 8 to assess aerobic fitness. RESULTS: At baseline, LDCW completion times (adjusted for age and sex) were 351.8 seconds (95% confidence interval (CI) = 346.9-356.8 seconds) for the inactive group, 335.9 seconds (95% CI = 332.7-339.1 seconds) for the lifestyle active group, and 307.7 seconds (95% CI = 303.2-312.3 seconds) for the exerciser group (P < .001). From baseline to Year 8, the inactive group slowed 36.1 seconds (95% CI = 28.4-43.8 seconds), the lifestyle active group slowed 38.1 seconds (95% CI = 33.6-42.4 seconds), and the exerciser group slowed 40.8 seconds (95% CI = 35.2 46.5 seconds), and did not differ significantly between groups. In linear mixed effects models, the rate of change in LDCW time did not differ between the groups, although exercisers consistently had the fastest completion times (P < .001 for all pairwise comparisons). CONCLUSION: Decline in LDCW time occurred regardless of baseline activity, although exercisers maintained higher aerobic fitness, which may delay reaching a critically low threshold of aerobic fitness at which independence is impaired. PMID- 26096805 TI - Multidisciplinary rehabilitation in Parkinson's disease: A milestone with future challenges. PMID- 26096806 TI - Vitamin D is Not a Protective Factor in ALS. AB - AIMS: Vitamin D deficiency has been associated with poorer prognosis in ALS. Better understanding of the role of vitamin D in ALS is needed to determine whether trials of systematic supplementation are justified. Our aim was to report vitamin D levels during the course of ALS and to evaluate its relationship with clinical parameters at diagnosis and with disease progression. METHODS: We prospectively collected vitamin D serum concentrations from 125 consecutive ALS patients. Cox proportional hazard models analyzed the relationship between vitamin D concentrations, clinical parameters, and survival. RESULTS: The mean vitamin D concentration was below our laboratory's lower limit of normal (P < 0.0001) and did not change during the course of the disease. The concentrations were higher in patients with bulbar onset (P = 0.003) and were negatively associated with body mass index (BMI) (P = 0.0095). Models with ALSFRS-R (ALS Functional Rating Scale-Revised) and BMI as a covariates showed that vitamin D concentrations predicted worse prognosis. CONCLUSION: The distribution of vitamin D concentrations in our cohort was consistent with previous reports. Surprisingly, we noted a negative effect of higher vitamin D levels on prognosis in ALS. More detailed research is warranted to determine whether manipulation of vitamin D could be beneficial to patients. PMID- 26096807 TI - The DACH/EYA/SIX gene network and its role in tumor initiation and progression. AB - The functional abnormality of developmental genes is a common phenomenon in cancer initiation and progression. The retinal determination gene network (RDGN) is a key signal in Drosophila eye specification, and this conservative pathway is also required for the development of multiple organs in mammalian species. Recent studies demonstrated that aberrant expressions of RDGN components in vertebrates, mainly Dach, Six, and Eya, represent a novel tumor signal. RDGN regulates proliferation, apoptosis, tumor growth and metastasis through interactions with multiple signaling pathways in a co-ordinated fashion; Dach acts as a tumor suppressor, whereas Six and Eya function as oncogenes. Clinical analyses demonstrated that the expression levels of RDGN correlate with tumor stage, metastasis and survival, suggesting that combinational detection of this pathway might be used as a promising biomarker for the stratification of therapy and for the prediction of the prognosis of cancer patients. PMID- 26096808 TI - Tenofovir for Hepatitis Delta. PMID- 26096809 TI - Baby sign but not spontaneous gesture predicts later vocabulary in children with Down Syndrome. AB - Early spontaneous gesture, specifically deictic gesture, predicts subsequent vocabulary development in typically developing (TD) children. Here, we ask whether deictic gesture plays a similar role in predicting later vocabulary size in children with Down Syndrome (DS), who have been shown to have difficulties in speech production, but strengths in spontaneous gesture and baby sign use. We compared the gestures and baby signs produced by twenty-three children with DS (Mage = 2;6) and twenty-three TD children (Mage = 1;6), in relation to their expressive spoken vocabulary size one year later. Children with DS showed significant deficits in gesture production, particularly for deictic gestures, but strengths in baby sign production, compared to their typically developing peers. More importantly, it was the baby signs produced by children with DS, but not deictic gestures, that predicted their spoken vocabulary size one year later. Our results further highlight the important role baby signs can play in language development in children with developmental disorders. PMID- 26096811 TI - Synthesis of Periphery-Decorated and Core-Initiated Borane Polyanionic Macromolecules. AB - A new class of globular polybranched macromolecules that contain multiple anionic metallacarborane clusters at the o-carborane periphery is reported. The water soluble high boron rich containing molecules could be of interest for boron neutron capture therapy (BNCT) as well as for drug delivery. The reinforced electrostatic noncovalent interactions between anionic polyethylene glycol cobaltabisdicarbollide (PEG-COSAN) branches and the ammonium cation have been shown using ESI-MS. PMID- 26096810 TI - A maize ADP-ribosylation factor ZmArf2 increases organ and seed size by promoting cell expansion in Arabidopsis. AB - ADP-ribosylation factors (ARFs) are small GTP-binding proteins that regulate a wide variety of cell functions. Previously, we isolated a new ARF, ZmArf2, from maize (Zea mays). Sequence and expression characteristics indicated that ZmArf2 might play a critical role in the early stages of endosperm development. In this study, we investigated ZmArf2 function by analysis of its GTP-binding activity and subcellular localization. We also over-expressed ZmArf2 in Arabidopsis and measured organ and cell size and counted cell numbers. The expression levels of five organ size-associated genes were also determined in 35S::ZmArf2 transgenic and wild-type plants. Results showed that the recombinant ZmArf2 protein purified from Escherichia coli exhibited GTP-binding activity. Subcellular localization revealed that ZmArf2 was localized in the cytoplasm and plasma membrane. ZmArf2 over-expression in Arabidopsis showed that 35S::ZmArf2 transgenic plants were taller and had larger leaves and seeds compared to wild-type plants, which resulted from cell expansions, not an increase in cell numbers. In addition, three cell expansion-related genes, AtEXP3, AtEXP5 and AtEXP10, were upregulated in 35S::ZmArf2 transgenic lines, while the expression levels of AtGIF1 and AtGRF5, were unchanged. Collectively, our studies suggest that ZmArf2 has an active GTP-binding function, and plays a crucial role in growth and development in Arabidopsis through cell expansion mediated by cell expansion genes. PMID- 26096812 TI - Serum bacterial DNA detection in patients with cholangitis after Kasai procedure. AB - BACKGROUND: The aim of this study was to investigate the detectability of bacterial DNA (bactDNA) and associated clinical factors in patients with cholangitis after the Kasai procedure through the identification of bactDNA in blood. METHODS: A cross-sectional study of 110 patients who had undergone the Kasai procedure was carried out. A total of 77 patients had cholangitis and 33 did not. Blood samples were obtained on admission or on follow up at the outpatient visit. bactDNA was analyzed using a polymerase chain reaction-based method, DNA nucleotide sequencing, for identification of bacterial species. RESULTS: Rate of bactDNA positivity was higher using the 16SrDNA method than the culture method (58.4% vs 14.3%, P < 0.0001), and more patients with cholangitis were positive for bactDNA compared with the patients without cholangitis (58.4% vs 39.4%, P = 0.095). Bacteria identified on blood 16SrDNA primarily consisted of opportunistic pathogens derived from the gut, including Escherichia coli, Klebsiella pneumoniae, Shigella fexneri, and Enterobacteriaceae bacterium. Treatment with probiotics or antibiotics showed a trend toward reduced prevalence of bactDNA. Pediatric end-stage liver disease score, procalcitonin, C-reactive protein, and heart rate were all significantly associated with the presence of bactDNA. CONCLUSION: bactDNA is frequently detected in patients with cholangitis after the Kasai procedure compared with those without cholangitis (and controls), and the bacteria are similar to those in the gut, suggesting that it is useful as an early diagnostic tool for cholangitis and other infections (registration number in Chinese Clinical Trial Registry ChiCTR-ECC-13003759). PMID- 26096813 TI - Safety, feasibility and learning curve of robotic single-site surgery in gynecology. AB - BACKGROUND: Robotic single-site (RSS) surgery has emerged as a novel minimally invasive approach in gynecology. METHODS: Retrospective cohort study of consecutive RSS gynecologic procedures undertaken between October 2013 and March 2014. RESULTS: The 25 RSS completed cases consisted of 11 adnexal and 14 hysterectomy cases of which three included pelvic lymphadenectomies. Mean age, body mass index and estimated blood loss were 51 years, 25 kg/m(2) , 30 mL in the adnexal group, respectively, and 58 years, 27 kg/m(2) , 96 mL in the hysterectomy group, respectively. Mean console time was 20 and 45 min and mean total operative time was 56 and 93 min in adnexal and hysterectomy cases, respectively. The CUSUM method identified two learning phases with significant reduction in console time after the 7th adnexal case and the 5th hysterectomy. CONCLUSION: When performed by advanced minimally invasive surgeons and in appropriately selected patients, RSS surgery is feasible and safe. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096815 TI - Causes of death in patients with childhood-onset type 1 diabetes receiving dialysis in Japan: Diabetes Epidemiology Research International (DERI) Mortality Study. AB - AIMS: To investigate the causes of death and how they changed over time in patients with childhood-onset type 1 diabetes who were receiving dialysis. METHODS: Of the 1384 patients who were diagnosed with type 1 diabetes at<18 years of age between 1965 and 1979, 113 who were subsequently confirmed as having received dialysis and having died as of January 1, 2008 were found eligible for the study. The cause of death trends were expressed according to the duration of dialysis. RESULTS: The leading causes of death were end-stage renal disease (ESRD) (36.3%), cardiovascular disease (CVD) (31.9%), and infections (20.3%). Among CVD, cerebral hemorrhage was the most frequent (38.9%) and showed a significant trend for an increase in the duration of dialysis (P=0.01, the Cochran-Armitage trend test). The mortality from ESRD concentrated within 5 years of dialysis and that from CVD increased after 10 years of dialysis, while the mortality from infections peaked during 5 to 10 years from initiation of dialysis. CONCLUSIONS: The leading causes of death in dialysis patients with type 1 diabetes were ESRD, CVD, and infections. As the duration of dialysis increased, however, CVD contributed more to mortality. Special attention should be paid to CVD, particularly cerebral hemorrhage, to improve the long-term prognosis of patients. PMID- 26096816 TI - Surface chemistry but not aspect ratio mediates the biological toxicity of gold nanorods in vitro and in vivo. AB - Gold nanorods are a promising nanoscale material in clinical diagnosis and treatment. The physicochemical properties of GNRs, including size, shape and surface features, are crucial factors affecting their cytotoxicity. In this study, we investigated the effects of different aspect ratios and surface modifications on the cytotoxicity and cellular uptake of GNRs in cultured cells and in mice. The results indicated that the surface chemistry but not the aspect ratio of GNRs mediates their biological toxicity. CTAB-GNRs with various aspect ratios had similar abilities to induce cell apoptosis and autophagy by damaging mitochondria and activating intracellular reactive oxygen species (ROS). However, GNRs coated with CTAB/PSS, CTAB/PAH, CTAB/PSS/PAH or CTAB/PAH/PSS displayed low toxicity and did not induce cell death. CTAB/PAH-coated GNRs caused minimally abnormal cell morphology compared with CTAB/PSS and CTAB/PSS/PAH coated GNRs. Moreover, the intravenous injection of CTAB/PAH GNRs enabled the GNRs to reach tumor tissues through blood circulation in animals and remained stable, with a longer half-life compared to the other GNRs. Therefore, our results demonstrated that further coating can prevent cytotoxicity and cell death upon CTAB-coated GNR administration, similar to changing the GNR aspect ratio and CTAB/PAH coated GNRs show superior biological properties with better biocompatibility and minimal cytotoxicity. PMID- 26096817 TI - Validation of a criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation. AB - The aim of this study was to validate a criteria-specific long-term survival prediction model (MHCAT) in a large cohort of hepatocellular carcinoma (HCC) patients after liver transplantation (LT) in China. Independent risk factors in MHCAT were retrospectively analysed for HCC patients recorded in the China Liver Transplant Registry. Survival predictions for each patient were calculated using MHCAT scores and the Metroticket formula separately, and the prediction efficacy of MHCAT and Metroticket was compared using the area under ROC curve (c statistic). A total of 1371 LTs for HCC were analysed in the study, with a median follow-up of 22.2 months (IQR 6.1-72.4 months). The proportions meeting the Milan, UCSF, Fudan and Hangzhou criteria were 34.4%, 39.7%, 44.2% and 51.9%, respectively. The c-statistics for MHCAT predictions of 3- and 5-year survival rates of HCC recipients were 0.712-0.727 and 0.726-0.741, respectively. Among these patients, 1298 LTs for HCC were ultimately selected for the comparison analysis for prediction efficacy. The c-statistic of MHCAT for predictions of 3 year survival with reference to the Milan, UCSF and Fudan criteria was significantly increased compared with that for Metroticket (p < 0.05). In conclusion, MHCAT can effectively predict long-term survival for HCC recipients after LT. PMID- 26096818 TI - Skeletal muscle mitochondrial H2 O2 emission increases with immobilization and decreases after aerobic training in young and older men. AB - Currently, it is not known whether impaired mitochondrial function contributes to human ageing or whether potential impairments in mitochondrial function with age are secondary to physical inactivity. The present study investigated mitochondrial respiratory function and reactive oxygen species emission at a predefined membrane potential in young and older men subjected to 2 weeks of one leg immobilization followed by 6 weeks of aerobic cycle training. Immobilization increased reactive oxygen species emission and decreased ATP generating respiration. Subsequent aerobic training reversed these effects. By contrast, age had no effect on the measured variables. The results of the present study support the notion that increased mitochondrial reactive oxygen species production mediates the detrimental effects seen after physical inactivity and that ageing per se does not cause mitochondrial dysfunction. Mitochondrial dysfunction, defined as increased oxidative stress and lower capacity for energy production, may be seen with ageing and may cause frailty, or it could be that it is secondary to physical inactivity. We studied the effect of 2 weeks of one-leg immobilization followed by 6 weeks of supervised cycle training on mitochondrial function in 17 young (mean +/- SEM: 23 +/- 1 years) and 15 older (68 +/- 1 years) healthy men. Submaximal H2 O2 emission and respiration were measured simultaneously at a predefined membrane potential in isolated mitochondria from skeletal muscle using two protocols: pyruvate + malate (PM) and succinate + rotenone (SR). This allowed measurement of leak and ATP generating respiration from which the coupling efficiency can be calculated. The protein content of the anti-oxidants manganese superoxide dismuthase (MnSOD), CuZn superoxide dismuthase, catalase and gluthathione peroxidase 1 was measured by western blotting. Immobilization decreased ATP generating respiration using PM and increased H2 O2 emission using both PM and SR similarly in young and older men. Both were restored to baseline after the training period. Furthermore, MnSOD and catalase content increased with endurance training. The young men had a higher leak respiration at inclusion using PM and a higher membrane potential in State 3 using both substrate combinations. Collectively, the findings of the present study support the notion that increased mitochondrial reactive oxygen species mediates the detrimental effects seen after physical inactivity. Age, on the other hand, was not associated with impairments in anti-oxidant protein levels, mitochondrial respiration or H2 O2 emission using either protocol. PMID- 26096819 TI - Management of secondary infertility following cesarean section: Report from the Subcommittee of the Reproductive Endocrinology Committee of the Japan Society of Obstetrics and Gynecology. AB - AIM: The aim of this study was to examine the current status and management of secondary infertility following cesarean section in Japan. MATERIAL AND METHODS: A two-step questionnaire survey was performed in 1092 facilities, including teaching hospitals and artificial reproductive technology clinics, registered with the Japan Society of Obstetrics and Gynecology. In our questionnaires, we obtained data about symptoms, clinical findings, diagnostic methods, and pregnancy outcomes. Treatments were sorted into three groups, namely typical infertility treatment (group A), conservative treatment (group B), and operative treatment (group C). RESULTS: Of the 1092 facilities, 616 (56%) sent back reply forms to the first questionnaire; 56 (32%) of 176 facilities answered the second questionnaire, and 189 cases were able to be analyzed after completion of the two questionnaires. The commonest symptom was abnormal uterine bleeding during the follicular phase (91 cases; 48% of the 189 eligible cases), and the commonest clinical finding was fluid pooling in the area of cesarean scar dehiscence during the ovulatory phase (142 cases; 75%). The most commonly used diagnostic method was transvaginal ultrasound (153 cases, 81%). The pregnancy rate was 33% in group A, 50% in group B, and 60% in group C. In patients with abnormal uterine bleeding, painful symptoms and fluid pooling at the cesarean scar dehiscence, the pregnancy rate was significantly higher in group C (64%) than in group A (16%; P = 0.0063). CONCLUSIONS: We recommend operative treatment for secondary infertility following cesarean section with painful symptoms and fluid pooling at the site of cesarean scar dehiscence. PMID- 26096820 TI - Trypanosoma cruzi extracellular amastigotes trigger the protein kinase D1 cortactin-actin pathway during cell invasion. AB - Trypanosoma cruzi extracellular amastigotes (EAs) display unique mechanisms for cell invasion that are highly dependent on host actin filaments. Protein kinase D1 (PKD1) phosphorylates and modulates the activity of cortactin, a key regulator of actin dynamics. We evaluated the role of host cortactin and PKD1 in actin filament dynamics during HeLa cell invasion by EAs. Host cortactin, PKD1 and actin are recruited by EAs based on experiments in fixed and live cells by time lapse confocal microscopy. EAs trigger PKD1 and extracellular signal-regulated kinase 1/2 activation, but not Src family kinases, and selectively phosphorylate cortactin. Heat-killed EAs and non-infective epimastigotes both triggered distinct host responses and did not recruit the molecules studied herein. EA invasion was influenced by depletion or overexpression of host cortactin and PKD1, respectively, suggesting the involvement of both proteins in this event. Collectively, these results show new host cell mechanisms subverted during EA internalization into non-phagocytic cells. PMID- 26096821 TI - Phosphorylated alpha-enolase induces autoantibodies in HLA-DR8 pancreatic cancer patients and triggers HLA-DR8 restricted T-cell activation. AB - Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-induced death in the Western World. In PDAC patients, alpha-enolase (ENOA), a glycolytic enzyme that also acts as plasminogen receptor, is up-regulated and elicits the production of autoantibodies. Our previous studies revealed that most PDAC patients specifically produce antibodies to Serine(419)phosphorylated ENOA (Ser(419)P-ENOA) isoforms (ENOA1,2), and that this humoral response correlates with a better clinical outcome. Since autoantibody production can be influenced by HLA polymorphisms, and the ENOA sequence presents multiple peptides predicted to preferentially bind HLA-DR molecules, including the peptide containing Ser(419), we hypothesized that the presence of autoantibodies against ENOA1,2 is associated with specific HLA-DRB1 alleles. Here, we demonstrate that the HLA DRB1*08 allele is significantly more frequent in PDAC patients with autoantibodies to ENOA1,2 (ENOA1,2(+), 8%) compared to healthy controls (3%, p=0.0112). We observed that a Ser(419)P-ENOA peptide, bioinformatically predicted to bind with high affinity to the HLA-DR8 allele coded by HLA-DRB1*08:01 or *08:04 alleles, was able to activate specific CD4(+) T cell clones derived from a HLA-DRB1*08:01. Thus complexes of the Ser(419)P-ENOA peptide with the HLA that trigger T-cell signaling might be relevant for induction of anti-tumor immune response. PMID- 26096823 TI - Three-Dimensional Transesophageal Echocardiography in the Anatomical Assessment of Isolated Parachute Mitral Valve in an Adult Patient. AB - Parachute mitral valve (PMV) is a rare congenital anomaly of the mitral valve apparatus usually evidenced in infants and young children. Adult presentation is extremely rare and is generally mild in terms of mitral stenosis. A 73-year-old woman was admitted to the emergency department due to progressive dyspnea, with NYHA functional class IV symptoms on presentation. The echocardiographic examination identified a PMV with moderate mitral stenosis and a secondary smaller subvalvular mitral orifice. The report shows the usefulness of three dimensional transesophageal echocardiography in the detection and quantification of this rare anomaly. PMID- 26096824 TI - Metal-Free Dehydrogenative Diels-Alder Reactions of 2-Methyl-3-Alkylindoles with Dienophiles: Rapid Access to Tetrahydrocarbazoles, Carbazoles, and Heteroacenes. AB - An unprecedented strategy for in situ generation of indole-based ortho quinodimethanes (oQDMs) from 2-methyl-3-alkylmethylindoles by either a metal-free DDQ- or BQ-mediated dehydrogenative process was developed. These oQDMs were trapped by electron-deficient dienophiles to provide a facile approach to synthetically valuable tetrahydrocarbazoles, carbazoles, and hetereoacenes. The salient features of this transformation include direct C(sp(3))-H bond functionalizations, readily available starting materials, metal-free conditions, high efficiency, operational simplicity, and ease of scale-up. PMID- 26096825 TI - Revealing highly unbalanced energy barriers in the extension and contraction of the muscle-like motion of a [c2]daisy chain. AB - Nanoscale muscle-like materials have aroused great interest as they may provide controllable mechanical operations by artificial actuations. Molecular designs to achieve the desired motion at the macroscopic scale in experiments require atomic level understanding. By systematic quantum chemical and molecular dynamics calculations we reveal that the length change is not only due to the linear telescoping from the dibenzo[24]crown-8 recognition at two docking stations but also the folding/unfolding of two bulky stoppers. The extension and contraction processes of a [c2]daisy chain under acidic vs. basic conditions are exothermic but need to cross very different energy barriers, being at least double the height under acidic compared to basic conditions, hindering balanced cyclic motions at moderate excitation. Our result suggests that to realize the desired muscle-like motion one should adopt sufficiently high external excitation, using for example reasonably high temperature and further optimizing the solution used. PMID- 26096826 TI - Size does matter-a closer look on Anguillicola morphology. AB - The present study deals with morphological differences between two closely related parasitic nematode species (Anguillicola crassus Kuwahara et al., 1974 and Anguillicola novaezelandiae Moravec & Taraschewski, 1988) in two different experimentally infected eel species (Anguilla anguilla Linnaeus, 1758 and Anguilla japonica Temminck & Schlegel, 1847). Furthermore, it considers the question whether size differences between those two species are ontogenetically determined or host species-dependent. In order to analyse these questions, experimental infections with the four possible host-parasite systems have been performed, followed by precise morphometric measurements related to body size and head structures of all resulting nematodes 120 days post infection. Body size measurements (length and width) of A. crassus generally exceeded those of A. novaezelandiae, while both Anguillicola species turned out to be smaller in Japanese eels than in European eels. Comparative measurements of neck width, maximum oesophagus width, and posterior head end width were found to be highly significant with regard to the different host-parasite systems. Shape and width of neck have been identified as reliable discriminating factors for species distinction. Generally, the relation of anterior head end width and neck width proved to be distinctly species-specific and can thus serve as a decisive and easily measureable distinguishing feature. PMID- 26096827 TI - Activity of synthetic chalcones in hamsters experimentally infected with Leishmania (Viannia) braziliensis. AB - The purpose of this study is to evaluate the toxicity of synthetic chalcones 1 and 2 in uninfected hamsters and anti-Leishmania activity of synthetic chalcones 1 and 2 in hamsters infected with Leishmania (Viannia) braziliensis. For the toxicity test, uninfected animals were treated with chalcones 1 and 2, and clinical and biochemical parameters and histological aspects of the liver and kidneys were assessed. Chalcones 1 and 2 were then intraperitoneally or topically administered (10 mg/kg body weight) three times per week in animals infected with promastigotes of L. (V.) braziliensis. We monitored the thickness of the infected footpads, determined parasitic load, performed histological analysis, and detected apoptosis in situ. The results were analyzed using Student's t test and Mann-Whitney test at a significance level of 5%. Neither of the chalcones showed toxicity. Chalcone 2 administered intraperitoneally significantly reduced the thickness of the infected footpad compared with the beginning of treatment. The parasite load of the lymph node and spleen was reduced in the groups treated with chalcones 1 (topical) and 2 (intraperitoneal). Chalcone 2 (topical) reduced parasite burden only in the lymph node. The histological analysis revealed reconstitution of the tissue and reductions of inflammation and apoptosis in the infected footpad in these groups. The synthetic chalcones 1 (topical) and 2 (intraperitoneal and topical) at a dose of 10 mg/kg showed anti-Leishmania activity in vivo, no renal or hepatic toxicity, and a reduction of apoptosis of the cells in the lesions. These chalcones may have substantial potential for the treatment of cutaneous leishmaniasis. PMID- 26096828 TI - Reflecting on 'An economic model of social capital and health'. PMID- 26096829 TI - Femoral Strength Changes Faster With Age Than BMD in Both Women and Men: A Biomechanical Study. AB - Although a large number of studies have addressed the age-related changes in bone mineral density (BMD), there is a paucity of data for the assessment of femoral strength loss with age in both genders. We determined the variation of strength with age in femurs of women and men by mechanical tests on a cohort of 100 cadaveric femurs. In addition, the age-related neck BMD loss in our cadaveric cohort was found to be similar with BMD loss of four published population-based studies. Given the strong correlation found in our cadaveric study between BMD and femoral strength, we also estimated the femoral strength of the four populations based on their reported neck BMDs. Our study showed that men's femurs in our cadaveric cohort were stronger than women's femurs by about 800 N at the same BMD level, and by 1750 N at the same age. The strength differences were not explained satisfactorily by the size difference between men's and women's bones. Similar to the findings of clinical studies, the BMD values of men at all ages were larger than that of women. The age-related loss rates in BMD and strength were not statistically different between the two genders of our cadaveric cohort. After normalization, strength decreased more than 40% faster than BMD. On average, men reached a certain BMD value about 16 years later than women, and for strength about 23 years later, which may explain the higher rate of hip fracture in postmenopausal women. In patient population cohorts men reached a similar BMD value about 16 to 25 years later than women, whereas for estimated strength, sometimes more than 40 years later. PMID- 26096830 TI - Risk Analysis. From the Editors. PMID- 26096831 TI - Applying Risk Analysis to Two Divisive Topics: Hydraulic Fracking and Marijuana Use. PMID- 26096822 TI - Challenges and future perspectives of T cell immunotherapy in cancer. AB - Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signalling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer. PMID- 26096832 TI - Paradoxical adipose hyperplasia secondary to cryolipolysis: An underreported entity? AB - BACKGROUND AND OBJECTIVE: Cryolipolysis is a non-invasive, safe, and effective treatment for localized fat reduction. Paradoxical adipose hyperplasia (PAH) is a rare adverse effect in which patients develop painless, firm, and well-demarcated tissue masses in the treatment areas approximately 3-6 months following cryolipolysis. The incidence of PAH has been estimated at 0.0051% or 1 in 20,000 treated patients. We report two cases of PAH seen in our practice, which may suggest the incidence is greater than previously reported. STUDY DESIGN/PATIENTS AND METHODS: A 44-year-old man underwent cryolipolysis for unwanted fat in the pectoral region. At 4 month follow-up, the patient had well-demarcated tissue growth in the treatment areas. He elected to undergo additional cryolipolysis treatment to the areas. Two months later, he was found to have further tissue growth in the treatment areas. The patient then underwent corrective treatment with liposuction. A 52-year-old man underwent cryolipolysis for unwanted lower abdominal fat. At one year follow-up, he had a well-demarcated, subcutaneous mass on the lower abdomen corresponding to the treatment site. The patient elected to undergo corrective treatment with liposuction. Adipose tissue samples from the treated and non-treated areas, for control, were collected, processed, and stained to evaluate cellularity and tissue structure. RESULTS: In our practice, the incidence of PAH is 0.47% or 2 in 422 cryolipolysis treatments. This is 100 times greater than the device manufacturer's reported incidence. Histopathologic examination of the subcutaneous tissue mass showed an increased number of adipocytes, fibrosis, and scar tissue in the treated areas when compared to controls. No lipoblasts, a marker of malignant neoplastic proliferation, were identified on the histopathologic examination of the affected tissues. CONCLUSION: The incidence of PAH is likely underreported. Further investigation is necessary to elucidate its mechanism of action. By understanding the pathogenesis, this rare adverse effect may be avoided, or even utilized as a therapeutic alternative for the treatment of congenital or acquired lipodystrophy. PMID- 26096833 TI - The paradox of obesity cardiomyopathy and the potential for weight loss as a therapy. AB - Obesity is an independent risk factor for developing heart failure and the combination of the two disease states will prove to be a significant health burden over the coming years. Obesity is likely to contribute to the development of heart failure through a variety of mechanisms, including structural and functional changes, lipotoxicity and steatosis and altered substrate selection. However, once heart failure has developed, it seems that obesity confers a beneficial influence on prognosis in what has been termed the 'obesity paradox'. This may be a statistical phenomenon, but it should be considered that there is truly a protective state in the physiology of obesity. There is little evidence regarding the impact of weight loss in obese heart failure and whether or not this is beneficial. There have been small studies regarding the cardiovascular effects of both dietary weight loss and bariatric surgery, but few in heart failure. This is an important and increasingly relevant clinical question which must be addressed. PMID- 26096834 TI - Transitions Within the JPHC Editorial Advisory Board. PMID- 26096835 TI - Parental Vaccine Hesitancy: Clinical Implications for Pediatric Providers. AB - Despite being recognized as one of the greatest public health achievements, vaccines are increasingly under scrutiny for a multitude of reasons. "Parental vaccine hesitancy," an emerging term in today's literature, encompasses a wide range of concerns regarding vaccines and is believed to be responsible for decreasing coverage of many childhood vaccines. The threat to herd immunity posed by poor vaccine uptake increases the risk for resurgence of vaccine-preventable diseases. Pediatric primary health care providers have an obligation to respond to the increasing prevalence of vaccine hesitancy by providing education related to vaccines to ensure the safety and health of the population. The purpose of this article is to examine the most common concerns surrounding vaccine hesitancy and outline strategies for pediatric providers to address concerns with parents in the clinical setting. PMID- 26096836 TI - Development of a novel AIDS vaccine: the HIV-1 transactivator of transcription protein vaccine. AB - INTRODUCTION: Classical approaches aimed at targeting the HIV-1 envelope as well as other structural viral proteins have largely failed. The HIV-1 transactivator of transcription (Tat) is a key HIV virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. Notably, anti-Tat Abs are uncommon in natural infection and, when present, correlate with the asymptomatic state and lead to lower or no disease progression. Hence, targeting Tat represents a pathogenesis-driven intervention. AREAS COVERED: Here, we review the rationale and the translational development of a therapeutic vaccine targeting the Tat protein. Preclinical and Phase I studies, Phase II trials with Tat in anti-Tat Ab-negative, virologically suppressed highly active antiretroviral therapy-treated subjects in Italy and South Africa were conducted. The results indicate that Tat-induced immune responses are necessary to restore immune homeostasis, to block the replenishment and to reduce the size of the viral reservoir. Additionally, they may help in establishing key parameters for highly active antiretroviral therapy intensification and a functional cure. EXPERT OPINION: We propose the therapeutic setting as the most feasible to speed up the testing and comparison of preventative vaccine candidates, as the distinction lies in the use of the vaccine in uninfected versus infected subjects and not in the vaccine formulation. PMID- 26096837 TI - X-linked focal epilepsy with reflex bathing seizures: Characterization of a distinct epileptic syndrome. AB - OBJECTIVE: We recently reported a Q555X mutation of synapsin 1 (SYN1) on chromosome Xp11-q21 in a family segregating partial epilepsy and autistic spectrum disorder. Herein, we provide a detailed description of the epileptic syndrome in the original family. METHODS: A total of 34 members from a large French-Canadian family were evaluated. Family members with seizures or epilepsy underwent (when possible) clinical, neuropsychological, electrophysiologic, and neuroimaging assessments. RESULTS: Epilepsy was diagnosed in 10 family members (4 deceased, 6 living). In addition to occasional spontaneous complex partial seizures, seven family members clearly had reflex seizures triggered by bathing or showering. Hippocampal atrophy was found in two of five epileptic family members family members who underwent magnetic resonance (MR) imaging. Video electroencephalography (EEG) recordings of three triggered seizures in two affected members showed rhythmic theta activity over temporal head regions. Ictal single-photon emission computed tomography (SPECT) showed temporoinsular perfusion changes. Detailed neuropsychological assessments revealed that SYN1 Q555X male mutation carriers showed specific language impairment and mild autistic spectrum disorder. Female carriers also exhibited reading impairments and febrile seizures but no chronic epilepsy. SIGNIFICANCE: Available evidence suggests that impaired SYN1 function is associated with hyperexcitability of the temporoinsular network and disturbance of high mental functions such as language and social interaction. The presence of reflex bathing seizures, a most peculiar clinical feature, could be helpful in identifying other patients with this syndrome. PMID- 26096839 TI - Napping in older people 'at risk' of dementia: relationships with depression, cognition, medical burden and sleep quality. AB - Sleep disturbance is prevalent in older adults, particularly so in those at a greater risk of dementia. However, so far the clinical, medical and neuropsychological correlates of daytime sleep have not been examined. The aims of this study were to investigate the characteristics and effects of napping using actigraphy in older people, particularly in those 'at risk' of dementia. The study used actigraphy and sleep diaries to measure napping habits in 133 older adults 'at risk' of dementia (mean age = 65.5 years, SD = 8.4 years), who also underwent comprehensive medical, psychiatric and neuropsychological assessment. When defined by actigraphy, napping was present in 83.5% (111/133) of participants; however, duration and timing varied significantly among subjects. Nappers had significantly greater medical burden and body mass index, and higher rates of mild cognitive impairment. Longer and more frequent naps were associated with poorer cognitive functioning, as well as higher levels of depressive symptoms, while the timing of naps was associated with poorer nocturnal sleep quality (i.e. sleep latency and wake after sleep onset). This study highlights that in older adults 'at risk' of dementia, napping is associated with underlying neurobiological changes such as depression and cognition. Napping characteristics should be more routinely monitored in older individuals to elucidate their relationship with psychological and cognitive outcomes. PMID- 26096840 TI - Identification of tert-Butyl Cations in Zeolite H-ZSM-5: Evidence from NMR Spectroscopy and DFT Calculations. AB - Experimental evidence for the presence of tert-butyl cations, which are important intermediates in acid-catalyzed heterogeneous reactions, on solid acids has still not been provided to date. By combining density functional theory (DFT) calculations with (1)H/(13)C magic-angle-spinning NMR spectroscopy, the tert butyl cation was successfully identified on zeolite H-ZSM-5 upon conversion of isobutene by capturing this intermediate with ammonia. PMID- 26096841 TI - The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts. AB - Recent studies have demonstrated that 7,8-dihydroxyflavone (7,8-DHF), a newly identified tyrosine kinase receptor B agonist, is a potent antioxidant agent. The present study was designed to confirm the cytoprotective effects of 7,8-DHF against oxidative stress-induced cellular damage and to further elucidate the underlying mechanisms in C2C12 myoblasts. We found that 7,8-DHF attenuated hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against intracellular reactive oxygen species (ROS) that were induced by H2O2. We also observed that 7,8-DHF significantly attenuated H2O2-induced comet tail formation, and decreased the phosphorylation levels of the histone, H2AX, as well as the number of Annexin V-positive cells, suggesting that 7,8-DHF prevents H2O2-induced DNA damage and cell apoptosis. Furthermore, 7,8-DHF increased the levels of heme oxygenase-1 (HO-1), which is a potent antioxidant enzyme associated with the induction and phosphorylation of nuclear factor-erythroid 2 related factor 2 (Nrf2), as well as the translocation of Nrf2 from the cytosol to the nucleus. However, the protective effects of 7,8-DHF against H2O2 -induced ROS generation and growth inhibition were significantly diminished by zinc protoporphyrin IX, an HO-1 competitive inhibitor. Moreover, the potential of 7,8 DHF to mediate HO-1 induction and protect the cells against H2O2 -mediated growth inhibition was abrogated by transient transfection with Nrf2-specific small interfering RNA (siRNA). In addition, 7,8-DHF induced the activation of Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K), and also that of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), while specific inhibitors of PI3K and ERK, but not a p38 MAPK inhibitor, abolished the 7,8-DHF induced HO-1 upregulation and Nrf2 induction and phosphorylation. Collectively, these results demonstrate that 7,8-DHF augments the cellular antioxidant defense capacity through activation of the Nrf2/HO-1 pathway, which also involves the activation of the PI3K/Akt and ERK pathways, thereby protecting C2C12 myoblasts from H2O2-induced oxidative cytotoxicity. PMID- 26096842 TI - Galectin signature of the choriocarcinoma JAr cells: Galectin-1 as a modulator of invasiveness in vitro. AB - Our previous findings showed that galectin-1 (LGALS1) plays an important role in the in vitro invasion of normal human trophoblast cells. In the present study, choriocarcinoma JAr cells were found to express LGALS1, -2, -3, -8, -10, and -13 mRNA and at least LGALS1, -3, and -8 protein, as determined by reverse transcriptase PCR and Western blot, respectively. The galectin mRNA signature of JAr cells thus differed from that of normal first-trimester extravillous trophoblasts. A Matrigel migration assay was also used to investigate and confirm the relevance and effect of LGALS1 on the invasive potential of JAr cells, as observed in other trophoblast models. This modulation in behavior was achieved by specific lectin-glycan binding. PMID- 26096838 TI - Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis. AB - The anterior bed nucleus of the stria terminalis (BNST) has been recognized as a critical structure in regulating trait anxiety, contextual fear memory, and appetitive behavior, and is known to be sensitive to stress manipulations. As one of the most complex structures in the central nervous system, the intrinsic circuitry of the BNST is largely unknown; however, recent technological developments have allowed researchers to begin to untangle the internal connections of the nucleus. This research has revealed the possibility of two opposing circuits, one anxiolytic and one anxiogenic, within the BNST, the relative strength of which determines the behavioral outcome. The balance of these pathways is critical in maintaining a normal physiological and behavioral state; however, stress and drugs of abuse can differentially affect the opposing circuitry within the nucleus to shift the balance to a pathological state. In this review, we will examine how stress interacts with the neuromodulators, corticotropin-releasing factor, norepinephrine, dopamine, and serotonin to affect the circuitry of the BNST as well as how synaptic plasticity in the BNST is modulated by stress, resulting in long-lasting changes in the circuit and behavioral state. PMID- 26096843 TI - Anti-proliferative effects of gamma-tocotrienol are associated with suppression of c-Myc expression in mammary tumour cells. AB - OBJECTIVES: Aberrant c-Myc activity plays a central role in cancer transformation. gamma-tocotrienol is a member of the vitamin E family that displays potent anti-cancer activity. Here, studies were conducted to determine the role of c-Myc in mediating anti-proliferative effects of gamma-tocotrienol in mammary cancer cells. MATERIALS AND METHODS: Treatment effects on mouse +SA and human MCF-7 mammary cancer cell proliferation were determined by MTT assay and Ki 67 staining. Protein expression was determined by western blot analysis. Immunofluorescence staining and qRT-PCR were used to characterize cellular c-Myc and MYC levels respectively. RESULTS: Anti-proliferative effects of gamma tocotrienol were associated with reduction in total c-Myc and phosphorylated-c Myc-serine 62, and increase in phosphorylated-c-Myc-threonine 58 levels. gamma tocotrienol also reduced PI3K/Akt/mTOR and Ras/MEK/Erk mitogenic signalling, cyclin D1 and cyclin-dependent kinase 4 levels, and increased p27 levels. However, gamma-tocotrienol had no effect on MYC mRNA levels. gamma-tocotrienol also increased levels of FBW7 (E3 ligase that initiates ubiquitination of c-Myc), but had no effect on serine/threonine phosphatase PP2A or isomerase Pin 1 levels. Combined treatment with GSK3alpha/beta inhibitor LiCl or proteasome inhibitor MG132 blocked gamma-tocotrienol-induced reductions in c-Myc. CONCLUSIONS: These findings indicate that anti-proliferative effects of gamma-tocotrienol are associated with reduction in c-Myc that results from increase in GSK-3alpha/beta dependent ubiquitination and degradation, rather than from reduction in c-Myc synthesis in +SA and MCF-7 mammary cancer cells. PMID- 26096846 TI - Smoking as an independent risk factor for macrocytosis in middle-aged adults: a population-based observational study. PMID- 26096847 TI - Evaluation of delivered dose for a clinical daily adaptive plan selection strategy for bladder cancer radiotherapy. AB - PURPOSE: To account for variable bladder size during bladder cancer radiotherapy, a daily plan selection strategy was implemented. The aim of this study was to calculate the actually delivered dose using an adaptive strategy, compared to a non-adaptive approach. MATERIAL AND METHODS: Ten patients were treated to the bladder and lymph nodes with an adaptive full bladder strategy. Interpolated delineations of bladder and tumor on a full and empty bladder CT scan resulted in five PTVs for which VMAT plans were created. Daily cone beam CT (CBCT) scans were used for plan selection. Bowel, rectum and target volumes were delineated on these CBCTs, and delivered dose for these was calculated using both the adaptive plan, and a non-adaptive plan. RESULTS: Target coverage for lymph nodes improved using an adaptive strategy. The full bladder strategy spared the healthy part of the bladder from a high dose. Average bowel cavity V30Gy and V40Gy significantly reduced with 60 and 69ml, respectively (p<0.01). Other parameters for bowel and rectum remained unchanged. CONCLUSIONS: Daily plan selection compared to a non adaptive strategy yielded similar bladder coverage and improved coverage for lymph nodes, with a significant reduction in bowel cavity V30Gy and V40Gy only, while other sparing was limited. PMID- 26096844 TI - Effect of in-painting on cortical thickness measurements in multiple sclerosis: A large cohort study. AB - A comprehensive analysis of the effect of lesion in-painting on the estimation of cortical thickness using magnetic resonance imaging was performed on a large cohort of 918 relapsing-remitting multiple sclerosis patients who participated in a phase III multicenter clinical trial. An automatic lesion in-painting algorithm was developed and implemented. Cortical thickness was measured using the FreeSurfer pipeline with and without in-painting. The effect of in-painting was evaluated using FreeSurfer's paired analysis pipeline. Multivariate regression analysis was also performed with field strength and lesion load as additional factors. Overall, the estimated cortical thickness was different with in-painting than without. The effect of in-painting was observed to be region dependent, more significant in the left hemisphere compared to the right, was more prominent at 1.5 T relative to 3 T, and was greater at higher lesion volumes. Our results show that even for data acquired at 1.5 T in patients with high lesion load, the mean cortical thickness difference with and without in-painting is ~2%. Based on these results, it appears that in-painting has only a small effect on the estimated regional and global cortical thickness. Hum Brain Mapp 36:3749-3760, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26096845 TI - Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules. AB - Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response. PMID- 26096848 TI - The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFalpha mediated in head and neck squamous cell carcinoma. AB - BACKGROUND AND PURPOSE: Second mitochondria-derived activator of caspase (SMAC) mimetics are a new class of targeted drugs that specifically induce apoptotic cancer cell death and block pro-survival signaling by antagonizing selected members of the inhibitor of apoptosis protein (IAP) family. MATERIAL AND METHODS: The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 in vitro and in vivo. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-alpha) signaling were examined. RESULTS: In vitro, Debio 1143 displayed anti-proliferative activity and enhanced intrinsic radiation sensitivity in 5/6 head and neck squamous cell carcinoma (HNSCC) cell lines in a synergistic manner. In vivo, Debio 1143 dose-dependently radio-sensitized FaDu and SQ20B xenografts, resulting in complete tumor regression in 8/10 FaDu xenografted mice at the high dose level. At the molecular level, Debio 1143 combined with radiotherapy (RT) induced enhancement of caspase-3 activity, increase in Annexin V-positive cells and karyopyknosis, and increase in TNF-alpha mRNA levels. Finally, in a neutralization experiment using a TNF-alpha-blocking antibody and a caspase inhibitor, it was shown that the radiosensitizing effect of Debio 1143 is mediated by caspases and TNF-alpha. CONCLUSIONS: These results demonstrate that the novel SMAC-mimetic Debio 1143 is a radiosensitizing agent that is worthy of further investigation in clinical trials in combination with radiotherapy. PMID- 26096849 TI - Anatomical landmarks accurately determine interfractional lymph node shifts during radiotherapy of lung cancer patients. AB - BACKGROUND AND PURPOSE: Low contrast in the cone-beam computed tomography (CBCT) scans hampers fast online evaluation of interfractional changes in the lymph node position on a daily basis. In this study we have investigated whether high contrast anatomical landmarks in the vicinity of the nodes may be used as surrogates for the lymph node positions. MATERIALS AND METHODS: Forty lung cancer patients were treated with an online CBCT-based setup strategy involving soft tissue match on the primary tumor. One hundred and sixteen lymph nodes were delineated separately on the planning-CT scans and categorized according to the lymph node stations. Five anatomical landmarks were selected as surrogate structures and assigned to the individual nodes. In addition, the carina was delineated. Registrations between the planning-CT and the daily CBCTs were performed retrospectively and positional deviations between the nodes and the surrogate structures or the carina were registered. RESULTS: The mean displacement between lymph nodes and surrogate structures was 1.6mm with systematic/random errors of 0.7/0.7mm, significantly smaller than the mean displacement between nodes and the carina. CONCLUSIONS: The position of the lymph nodes can be evaluated using selected anatomical landmarks on a daily basis using CBCT. PMID- 26096850 TI - EGFR and beta1-integrin targeting differentially affect colorectal carcinoma cell radiosensitivity and invasion. AB - BACKGROUND AND PURPOSE: Simultaneous targeting of beta1 integrin receptor and epidermal growth factor receptor (EGFR) showed higher level of radiosensitization in head and neck cancers than monotherapies. As EGFR inhibition is similarly performed in colorectal cancer (CRC), we investigated the radiosensitizing and anti-invasive potential of beta1-integrin/EGFR inhibition in CRC cell lines grown in more physiological three-dimensional (3D) matrix-based cell cultures. MATERIALS AND METHODS: DLD-1 and HT-29 cells were used for 3D-colony formation, invasion and proliferation assays and Western blotting. beta1 integrin, focal adhesion kinase and EGFR were inhibited by AIIB2, TAE226 and Cetuximab, respectively. KRAS and BRAF knockdown were accomplished using small-interfering RNA technology. Single doses of X-rays ranged from 2Gy to 6Gy and 5-fluorouracil (5-FU) concentration was 10MUM. RESULTS: Neither beta1-integrin/EGFR inhibition nor KRAS or BRAF depletion nor 5-FU significantly modified CRC cell radiosensitivity. Cetuximab, AIIB2 and Cetuximab/AIIB2 differentially modulated MAPK, JNK and AKT phosphorylation. AIIB2 and TAE226 significantly decreased cell invasion. CONCLUSIONS: Our data show inefficiency of Cetuximab and AIIB2 on top of radiochemotherapy. The functions of KRAS and BRAF in therapy resistance remain unanswered and warrant further preclinical molecular-driven investigations. One promising approach might be beta1 integrin targeting for reducing metastatic CRC cell spread. PMID- 26096851 TI - Transmembrane proteins--Mining the cattle tick transcriptome. AB - Managing the spread and load of pathogen-transmitting ticks is an important task worldwide. The cattle tick, Rhipicephalus microplus, not only impacts the economy through losses in dairy and meat production, but also raises concerns for human health in regards to the potential of certain transmitted pathogens becoming zoonotic. However, novel strategies to control R. microplus are hindered by lack of understanding tick biology and the discovery of suitable vaccine or acaricide targets. The importance of transmembrane proteins as vaccine targets are well known, as is the case in tick vaccines with Bm86 as antigen. In this study, we describe the localization and functional annotation of 878 putative transmembrane proteins. Thirty proteins could be confirmed in the R. microplus gut using LC MS/MS analysis and their roles in tick biology are discussed. To the best of our knowledge, 19 targets have not been reported before in any proteomics study in various tick species and the possibility of using the identified proteins as targets for tick control are discussed. Although tissue expression of identified putative proteins through expansive proteomics is necessary, this study demonstrates the possibility of using bioinformatics for the identification of targets for further evaluation in tick control strategies. PMID- 26096852 TI - Molecular-genetic and ultrastructural characteristics of 'Candidatus Ehrlichia khabarensis', a new member of the Ehrlichia genus. AB - Recently, a new Ehrlichia genetic variant, Ehrlichia sp. Khabarovsk, was identified in tissue samples of small mammals captured in the Russian Far East. To further characterize Ehrlichia sp. Khabarovsk, tissue homogenate from a naturally infected gray red-backed vole (Myodes rufocanus) was passaged three times in newborn laboratory mice. Using nested PCR Ehrlichia sp. Khabarovsk DNA was detected in tissue samples from infected mice at 1-4 weeks post inoculation. Electron microscopic examination revealed morulae containing gram-negative bacterial cells in monocytes of mouse spleen and liver. The size and ultrastructure of these cells corresponded to those described previously and allowed us to identify the bacteria as Ehrlichia sp. The comparison of ehrlichial 16S rRNA, groEL and gltA genes and putative GroEL and GltA amino acid sequences has demonstrated that Ehrlichia sp. Khabarovsk, like Ehrlichia ruminantium, is more distant from all other Ehrlichia species than these species are between themselves. Phylogenetic analysis has shown that Ehrlichia sp. Khabarovsk belongs to the clade formed by Ehrlichia spp. but clusters separately from other Ehrlichia species and genetic variants. These data indicate that Ehrlichia sp. Khabarovsk can be considered as a new candidate species. We propose to designate it as 'Candidatus Ehrlichia khabarensis' according to the territory where this species was found. PMID- 26096853 TI - Detection and identification of Rickettsia species in Ixodes tick populations from Estonia. AB - A total of 1640 ticks collected in different geographical parts of Estonia were screened for the presence of Rickettsia species DNA by real-time PCR. DNA of Rickettsia was detected in 83 out of 1640 questing ticks with an overall prevalence of 5.1%. The majority of the ticks infected by rickettsiae were Ixodes ricinus (74 of 83), while 9 of the 83 positive ticks were Ixodes persulcatus. For rickettsial species identification, a part of the citrate synthase gltA gene was sequenced. The majority of the positive samples were identified as Rickettsia helvetica (81 out of 83) and two of the samples were identified as Rickettsia monacensis and Candidatus R. tarasevichiae, respectively. Genetic characterization based on the partial gltA gene showed that the Estonian sequences within the R. helvetica, R. monacensis and Candidatus R. tarasevichiae species demonstrated 100% similarity with sequences deposited in GenBank, originating from Rickettsia species distributed over large territories from Europe to Asia. PMID- 26096854 TI - Aetiology and clinical characteristics of patients with bronchiectasis in a Chinese Han population: A prospective study. AB - BACKGROUND AND OBJECTIVE: Bronchiectasis is a chronic respiratory disease with diverse causes that may differ in clinical features and thus treatment options. However, few large-scale studies on the aetiology of bronchiectasis are currently available. This study aims to determine aetiology and clinical features of bronchiectasis in a Chinese Han population. METHODS: This prospective study enrolled adult patients diagnosed with bronchiectasis as confirmed by high resolution computed tomography at five general hospitals in Shandong from January 2010 to August 2014. Causes of bronchiectasis were sought by analysis of clinical history and auxiliary examinations (including serum immunoglobulin determination, saccharin test, Aspergillus skin prick test, autoantibody detection and electronic bronchoscopy). RESULTS: A total of 476 adult patients with bronchiectasis were included, and all patients were of Chinese Han ethnicity. Idiopathic (66.0%) was the most common cause, followed by post-tuberculosis (16.0%). Other uncommon causes included post-infective (3.8%), immunodeficiency (3.8%), allergic bronchopulmonary aspergillosis (4.0%), rheumatic diseases (4.4%) and primary ciliary dyskinesia (0.9%). Patients with post-tuberculosis bronchiectasis had a higher frequency of upper lobe involvement (P < 0.05). Cylindrical bronchiectasis was the most common type of all causes, with varicose bronchiectasis occurring more frequently in post-tuberculosis bronchiectasis and allergic bronchopulmonary aspergillosis (P < 0.05). However, patients with different causes did not differ in lung function and sputum isolation rate of Pseudomonas aeruginosa (P > 0.05). CONCLUSIONS: In a Chinese Han population in Shandong, idiopathic bronchiectasis is the most common form of bronchiectasis followed by post-tuberculosis bronchiectasis. Patients with different causes differ in distribution and pattern of bronchiectasis on computed tomography. PMID- 26096855 TI - Regulation of Cell- and Tissue-Based Therapeutic Products in Singapore. AB - The regulatory environment for cell- and tissue-based therapeutic (CTT) products is rapidly evolving and drug regulatory agencies are working toward establishing a risk-based system in their regulatory approach. In Singapore, CTT products such as cell therapy products, stem cell products, and tissue-engineered products in regenerative medicine are regulated as medicinal products. CTT products are defined as articles containing or consisting of autologous or allogeneic human or xenogeneic cells or tissues that are used for or administered to, or intended to be used for or administered to human beings for the diagnosis, treatment, or prevention of human diseases or conditions. Currently, we have applied a risk based tiered approach whereby high-risk CTT products (substantially manipulated products, products intended for nonhomologous use or combined/used in conjunction with a drug, biologic, or device) are regulated under the Medicines Act. A new standalone regulation for CTT products is being proposed under the Health Products Act where we propose to regulate the entire spectrum (high and low risk) of CTT products. PMID- 26096856 TI - One-Pot Synthesis of Allylic Sulfones, Ketosulfones, and Triflyl Allylic Alcohols from Domino Reactions of Allylic Alcohols with Sulfinic Acid under Metal-Free Conditions. AB - A metal-free tandem procedure by using a sulfonylation reaction of aryl allylic alcohols followed by an iodobenzenediacetate (PIDA)-promoted oxidative functionalization has been established. Allylic sulfones, gamma-ketosulfones, and triflyl allylic alcohols have been constructed in a single operation. The methodology incorporates the sulfonyl (both aryl and triflyl) functionality with a simple work-up procedure. PMID- 26096857 TI - Effect of oestradiol benzoate on oestrus intensity and pregnancy rate in CIDR treated anoestrus nulliparous and multiparous buffalo. AB - The objective of the present study was to examine if administration of oestradiol benzoate (OEB) after removal of control internal drug releasing device (CIDR) could enhance oestrous intensity and pregnancy rate in anovular nulliparous and multiparous Nili-Ravi buffalo. For this, a total of 298 nulliparous (n=91) and multiparous (n=207) buffaloes received a CIDR on Day 0, and were administered PGF2alpha on Day 6 followed by removal of CIDR on Day 7. At Day 8, OEB was administered in approximately half of nulliparous (n=45/91) and multiparous (n=100/207) buffalo. All animals were fixed time inseminated 48 and 60h after CIDR removal, respectively. The results showed that administration of OEB but not the parity, improved oestrous intensity (3.15+/-0.05 vs 2.99+/-0.05; P=0.0026) compared to those not received OEB, respectively. However, OEB did not affect (46.2 vs 44.1; P=0.8) pregnancy per AI (P/AI). In addition, P/AI was greater (50.7 vs 39.6; P=0.036) in multiparous compared to nulliparous buffalo, respectively. The oestrous intensity (P=0.025) and response to OEB (P=0.0002) was greater in buffalo having a greater body condition (>3.0). Though, non significant, timing of ovulation was more synchronous (62.9+/-1.8 vs 72.4+/-3.6h; P>0.05) and ovulation rate was greater (91% vs 64%; P>0.05) in buffalo after OEB administration. It is concluded that administration of OEB in conjunction with the CIDR improves oestrous intensity without affecting P/AI in nulliparous and multiparous anovular buffalo. PMID- 26096858 TI - Alterations of the neutrophil-lymphocyte ratio during the period of stable and acute exacerbation of chronic obstructive pulmonary disease patients. AB - OBJECTIVES: We aimed to investigate the importance of neutrophil-lymphocyte ratio (NLR) in patients with chronic obstructive pulmonary disease (COPD) for identifying the severity of inflammation and recognition of acute exacerbation. METHODS: We retrospectively enrolled 100 patients with a diagnosis of COPD exacerbation who were admitted to our clinic. Complete blood count (CBC), measurement of C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined within 2 h of hospital admission. Three months after an acute exacerbation, these measurements were obtained from the same patients during the stable period of COPD. The control group included 80 healthy subjects. NLR was calculated from CBC. RESULTS: NLR and other inflammatory markers, such as WBC, CRP and ESR were found to be significantly elevated in exacerbated COPD compared to stable COPD and control participants. There was a significant correlation of NLR with CRP (r = 0.415, P < 0.001), WBC (r = 0.304, P = 0.002) and ESR (r = 0.275, P = 0.035). For an NLR cutoff of 3.29, sensitivity for detecting exacerbation of COPD was 80.8% and specificity was 77.7% (AUC 0.894, P = 0.001). Some patients presenting with acute exacerbation of COPD and CRP, WBC or ESR levels lower than the optimal cut-off value had high NLR values. CONCLUSIONS: Elevated NLR can be used as a marker similar to CRP, WBC and ESR, in the determination of increased inflammation in acutely exacerbated COPD. NLR could be beneficial for the early detection of potential acute exacerbations in patients with COPD who have normal levels of traditional markers. PMID- 26096859 TI - MRI methods for the evaluation of high intensity focused ultrasound tumor treatment: Current status and future needs. AB - Thermal ablation with high intensity focused ultrasound (HIFU) is an emerging noninvasive technique for the treatment of solid tumors. HIFU treatment of malignant tumors requires accurate treatment planning, monitoring and evaluation, which can be facilitated by performing the procedure in an MR-guided HIFU system. The MR-based evaluation of HIFU treatment is most often restricted to contrast enhanced T1 -weighted imaging, while it has been shown that the non-perfused volume may not reflect the extent of nonviable tumor tissue after HIFU treatment. There are multiple studies in which more advanced MRI methods were assessed for their suitability for the evaluation of HIFU treatment. While several of these methods seem promising regarding their sensitivity to HIFU-induced tissue changes, there is still ample room for improvement of MRI protocols for HIFU treatment evaluation. In this review article, we describe the major acute and delayed effects of HIFU treatment. For each effect, the MRI methods that have been-or could be-used to detect the associated tissue changes are described. In addition, the potential value of multiparametric MRI for the evaluation of HIFU treatment is discussed. The review ends with a discussion on future directions for the MRI-based evaluation of HIFU treatment. PMID- 26096860 TI - Redox-Controlled Exchange Bias in a Supramolecular Chain of Fe4 Single-Molecule Magnets. AB - Tetrairon(III) single-molecule magnets [Fe4(pPy)2(dpm)6] (1) (H3pPy=2 (hydroxymethyl)-2-(pyridin-4-yl)propane-1,3-diol, Hdpm=dipivaloylmethane) have been deliberately organized into supramolecular chains by reaction with Ru(II)Ru(II) or Ru(II)Ru(III) paddlewheel complexes. The products [Fe4(pPy)2(dpm)6][Ru2(OAc)4](BF4)x with x=0 (2 a) or x=1 (2 b) differ in the electron count on the paramagnetic diruthenium bridges and display hysteresis loops of substantially different shape. Owing to their large easy-plane anisotropy, the s=1 diruthenium(II,II) units in 2 a act as effective s(eff)=0 spins and lead to negligible intrachain communication. By contrast, the mixed valent bridges (s=3/2, s(eff)=1/2) in 2 b introduce a significant exchange bias, with concomitant enhancement of the remnant magnetization. Our results suggest the possibility to use electron transfer to tune intermolecular communication in redox-responsive arrays of SMMs. PMID- 26096861 TI - Magnesium, zinc, and chromium levels in children, adolescents, and young adults with type 1 diabetes. AB - BACKGROUND & AIMS: Several trace elements are involved in insulin signal transduction and glucose metabolism. Our aim for this present study was to determine the levels of three important elements-magnesium, chromium, and zinc-as well as one oxidative stress marker-malondialdehyde (MDA)-in young type 1 diabetic patients at different periods of their growth, and to realize the relationships between trace elements, oxidative stress, and growth stages. METHODS: A total of 88 patients with type 1 diabetes mellitus in different growth stages and 76 gender- and age-matched healthy subjects were included in this study. The levels of MDA were measured through HPLC using a C-18 column. Zinc, magnesium, and chromium concentrations in serum were assessed using atomic absorption spectrophotometry. RESULTS: We found higher levels of blood malondialdehyde (MDA; p < 0.001), significantly lower levels of magnesium (p < 0.001), and no differences in zinc and chromium levels (p = 0.153 and 0.515, respectively) in younger type 1 diabetic subjects relative to those of control subjects. Only 3.4% (3/88) of younger diabetic subjects exhibited hypomagnesemia; similar results were obtained when comparing different subgroups: children, adolescents, and adults. We also observed no differences in the levels of the three elements between the genders and among the growth stages (p > 0.05) of the diabetic subjects. There were no correlations between the three trace elements and HbA1C, diabetes duration, and insulin dose/BMI (all p > 0.05), but there was a significant difference between zinc levels and insulin dose/BMI (p = 0.043) in the diabetic patients. CONCLUSIONS: We found elevated blood MDA, decreased magnesium, and no changes in zinc and chromium levels in younger type 1 diabetic subjects relative to those of control subjects. Only 3.4% of younger diabetic subjects exhibited hypomagnesemia. Whether magnesium supplementation is suitable for improving insulin sensitivity and decreasing oxidative stress and inflammation will require confirmation through additional studies. PMID- 26096862 TI - Reply, Letter to Editor - Combined intervention of protein supplementation and resistance training in medical patients. PMID- 26096864 TI - Down Syndrome with Patent Ductus Venosus and Hepato-Biliary-Pancreatic Abnormalities. AB - The association between Down syndrome and congenital portosystemic shunts, most commonly caused by patent ductus venosus, remains relatively unknown. The authors present a girl with Down syndrome with patent ductus venosus, pancreaticobiliary maljunction and paucity of interlobular bile ducts, presenting with neonatal cholestasis and transient abnormal myeloproliferative disorder. To the best of authors' knowledge, no report of the concurrent presence of the above in Down syndrome has been published. PMID- 26096863 TI - Land use intensification alters ecosystem multifunctionality via loss of biodiversity and changes to functional composition. AB - Global change, especially land-use intensification, affects human well-being by impacting the delivery of multiple ecosystem services (multifunctionality). However, whether biodiversity loss is a major component of global change effects on multifunctionality in real-world ecosystems, as in experimental ones, remains unclear. Therefore, we assessed biodiversity, functional composition and 14 ecosystem services on 150 agricultural grasslands differing in land-use intensity. We also introduce five multifunctionality measures in which ecosystem services were weighted according to realistic land-use objectives. We found that indirect land-use effects, i.e. those mediated by biodiversity loss and by changes to functional composition, were as strong as direct effects on average. Their strength varied with land-use objectives and regional context. Biodiversity loss explained indirect effects in a region of intermediate productivity and was most damaging when land-use objectives favoured supporting and cultural services. In contrast, functional composition shifts, towards fast-growing plant species, strongly increased provisioning services in more inherently unproductive grasslands. PMID- 26096865 TI - Rare Lung Diseases: Congenital Malformations. AB - Increasingly, congenital thoracic malformations (CTMs) are diagnosed on antenatal ultrasound, but we lack the evidence to suggest rational management, not least because descriptive terms are used inconsistently. This review describes a simplified clinical classification of CTMs, and contrasts it with pathological descriptions. The age related presentations of CTM are described, together with the differential diagnoses of cystic masses presenting both antenatally and postnatally. Antenatally diagnosed CTMs rarely require intervention before birth; and urgent treatment is only required postnatally if the baby is symptomatic and does not respond to medical management. The asymptomatic baby with an antenatal diagnosis of a CTM presents a management conundrum. Definitive imaging is with high-resolution computed tomography (HRCT), but the optimal timing of imaging is unclear. Whether surgery should be offered to asymptomatic infants is also unclear; in the medium term, 5 % of asymptomatic babies will require surgery for complications of the disease. The most vexed question is malignant change; the risk in the medium term is probably less than 5 %, but we have no way of delineating a high-risk group. Indeed, malignancy has been described even after complete resection of a CTM. The author's personal management is to advocate surgery in the second year of life for all except for the most trivial CTMs, but many would differ and advocate conservative management. More data are needed if we are to rationalise our approach to these infants. PMID- 26096866 TI - Bone and Joint Infections in Children: Acute Hematogenous Osteomyelitis. AB - Acute hematogenous osteomyelitis (AHO) is one of the commonest bone infection in childhood. Staphylococcus aureus is the commonest organism causing AHO. With use of advanced diagnostic methods, fastidious Kingella kingae is increasingly becoming an important organism in etiology of osteoarticular infections in children under the age of 3 y. The diagnosis of AHO is primarily clinical. The main clinical symptom and sign in AHO is pain and tenderness over the affected bone especially in the metaphyseal region. However, in a neonate the clinical presentation may be subtle and misleading. Laboratory and radiological investigations supplement the clinical findings. The acute phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are frequently elevated. Ultrasonography and MRI are key imaging modalities for early detection of AHO. Determination of infecting organism in AHO is the key to the correct antibiotic choice, treatment duration and overall management and therefore, organism isolation using blood cultures and site aspiration should be attempted. Several effective antibiotics regimes are available for managing AHO in children. The choice of antibiotic and its duration and mode of delivery requires individualization depending upon severity of infection, causative organism, regional sensitivity patterns, time elapsed between onset of symptoms and child's presentation and the clinical and laboratory response to the treatment. If pus has been evidenced in the soft tissues or bone region, surgical decompression of abscess is mandatory. PMID- 26096868 TI - Retinopathy of Prematurity (ROP) and its Associated Pain. PMID- 26096867 TI - Urine Neutrophil Gelatinase Associated Lipocalin to Creatinine Ratio: A Novel Index for Steroid Response in Idiopathic Nephrotic Syndrome. AB - OBJECTIVE: To find the value of urine neutrophil gelatinase associated lipocalin (NGAL) in differentiating steroid response in children with idiopathic nephrotic syndrome (INS). METHODS: A total of 52 children with INS (n = 27, steroid resistant; n = 25, steroid responsive) aged 1-16 y, along with 18 healthy control children were enrolled in this study. Urine NGAL as well as urine protein, and serum creatinine were analyzed during active phase of INS. RESULTS: Serum creatinine (P 0.032), and urine NGAL/Cr (P 0.001) were significantly higher in steroid resistant than steroid sensitive patients. The optimal cutoff value for urine NGAL/Cr with the highest sensitivity and specificity was 0.46 ng/mg and cut off value of 0.01 and 1.15 ng/mg had maximum sensitivity and specificity, respectively. CONCLUSIONS: Urine NGAL/Cr could be considered as a marker of steroid resistance in children with idiopathic nephrotic syndrome. PMID- 26096869 TI - Chemometric Model Development and Comparison of Raman and (13)C Solid-State Nuclear Magnetic Resonance-Chemometric Methods for Quantification of Crystalline/Amorphous Warfarin Sodium Fraction in the Formulations. AB - Warfarin sodium (WS) exists in multiple solid-state forms. The solid-state forms differ in physicochemical properties, and crystalline changes in the drug formulation may influence on the drug product quality and/or clinical performance. It is, therefore, critically important to have a good and reliable analytical method to monitor and quantitate this transformation during stability studies. The aim of the present research was to investigate Raman spectroscopy and solid-state nuclear magnetic resonance ((13)C ssNMR) methods in conjunction with chemometry to quantitate the amorphous and crystalline WS fractions in the drug products. Compositionally identical formulations of amorphous and crystalline WS were prepared, and mixed in various proportions to make 0%-100% amorphous/crystalline sample matrices. Raman and (13)C ssNMR spectra were collected and subjected to partial-least-squares and principle component regressions after mathematical treatment of the data. The model performance parameters such as root-mean-square error of prediction, standard error of prediction, and bias were low for Raman models in comparison to (13)C ssNMR models. Models predicted values of the independent sample matrices match closely with the actual values at high level of crystalline WS. Thus, the developed methods provide means to control and quantitate the WS forms fraction in the drug product. PMID- 26096870 TI - Spontaneously hypertensive rats have more orexin neurons in the hypothalamus and enhanced orexinergic input and orexin 2 receptor-associated nitric oxide signalling in the rostral ventrolateral medulla. AB - NEW FINDINGS: What is the central question of this study? Our previous study demonstrates that elevated orexin 2 receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs), and a lower OX2R protein level was detected in their RVLM. The present study aims to explore the mechanisms underlying elevated orexinergic activity in the RVLM of SHRs, compared with their normotensive counterparts, Wistar-Kyoto rats. What is the main finding and its importance? Increased orexinergic input into the RVLM and enhanced OX2R responsiveness in the RVLM, which was mainly mediated by augmented OX2R-neuronal nitric oxide synthase signalling, may underlie the elevated OX2R activity within the RVLM of SHRs. Our previous study showed that elevated orexin 2 receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs). Herein, we investigated the mechanism(s) underlying the elevated OX2R activity. The following results were found. (i) More hypothalamic orexin A-immunoreactive (OXA-IR) cells existed in SHRs than in Wistar-Kyoto (WKY) rats at either 4 (2217 +/- 43 versus 1809 +/- 69) or 16 weeks of age (1829 +/- 59 versus 1230 +/- 84). The number of OXA-IR cells that project to the RVLM was higher in 16-week-old SHRs than in WKY rats (91 +/- 11 versus 52 +/- 11). (ii) Higher numbers of OXA-IR and RVLM-projecting OXA-IR cells were found in the dorsomedial and perifornical hypothalamus of 16-week-old SHRs. (iii) Spontaneously hypertensive rats had higher levels of orexin A and B in the hypothalamus and higher levels of orexin A in the RVLM than did WKY rats. (iv) Unilateral intra-RVLM application of OX2R agonist, orexin A or [Ala(11), d Leu(15)]-orexin B (50 pmol) induced a larger pressor response in SHRs than in WKY rats. (v) Intra-RVLM pretreatment with a neuronal nitric oxide synthase (NOS) inhibitor, 7-nitro-indazole (2.5 pmol), or a soluble guanylate cyclase inhibitor, methylene blue (250 pmol), reduced the intra-RVLM [Ala(11), d-Leu(15) ]-orexin B induced pressor response in both WKY rats and SHRs. In contrast, an inducible NOS inhibitor, aminoguanidine (100 pmol), was ineffective. (vi) Neuronal NOS was co expressed with OX2R in RVLM neurons. In conclusion, increased orexinergic input and enhanced OX2R-neuronal NOS signalling may underlie elevated OX2R activity in the RVLM and contribute to the pathophysiology of hypertension in SHRs. PMID- 26096871 TI - "Out of Sight, Out of Mind": The Failed Renal Allograft as a Cause of ESA Resistance. AB - Approximately 10% of patients treated with erythropoiesis-stimulating agents (ESAs) for the anemia of chronic kidney disease are unresponsive or relatively resistant to therapy. The etiology of this is usually linked to iron deficiency or an independent underlying illness. We describe a hemodialysis patient with a failed renal transplant 1.5 years earlier, who developed progressive erythropoietin resistance and anemia without an apparent cause. He simultaneously developed nonspecific malaise and fatigue. By exclusion, the only possible cause of these signs and symptoms was inflammation from acute and chronic rejection in the retained failed renal allograft. Following pulse steroids and transplant nephrectomy, the patient's symptoms resolved and both his hemoglobin improved and his erythropoietin requirements decreased significantly. The patient never required a blood transfusion and was successfully relisted for a deceased donor renal transplant. Hence, inflammation from a retained transplant allograft may be an under-recognized cause of erythropoietin resistance in dialysis patients. Although transplant nephrectomy remains a controversial practice due to concerns of alloantibody production, it may be considered in patients with failed renal allografts and anemia refractory to treatment with ESAs. PMID- 26096872 TI - Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome in a boy with Loeys-Dietz syndrome. AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder, caused by heterozygous mutations in TGFBR1 or TGFBR2 and characterized by vascular complications (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations. We here report the first patient with LDS presenting with reversible cerebral vasoconstriction syndrome (RCVS), a clinico-radiological condition characterized by recurrent thunderclap headaches, with or without neurological symptoms, and reversible vasoconstriction of cerebral arteries. The patient was a 9-year-old boy with a heterozygous TGFBR2 mutation, manifesting camptodactyly, talipes equinovarus, and lamboid craniosynostosis. He complained of severe recurrent headaches 2 months after total aortic replacement for aortic root dilatation and a massive Stanford type B aortic dissection. A thoracic CT scan revealed a left subclavian artery dissection. Brain MRI and MRA detected bilateral internal carotid artery constriction along with a cortical subarachnoid hemorrhage without intracranial aneurysms. Subsequently, he developed visual disturbance and a generalized seizure associated with multiple legions of cortical and subcortical increased signals including the left posterior lobe, consistent with posterior reversible encephalopathy syndrome (PRES), a condition characterized by headaches, visual disorders, seizures, altered mentation, consciousness disturbances, focal neurological signs, and vasogenic edema predominantly in the white matter of the posterior lobe. Vasoconstriction of the internal carotid artery was undetectable 2 months later, and he was diagnosed as having RCVS. Endothelial dysfunction, associated with impaired TGF-beta signaling, might have been attributable to the development of RCVS and PRES. PMID- 26096873 TI - Combining fluorescence and bioluminescence microscopy. AB - Bioluminescence microscopy has revealed that gene expression in individual cells can respond differently to the same stimulus. To understand this phenomenon, it is important to sequentially observe the series of events from cellular signal transduction to gene expression regulated by specific transcription factors derived from signaling cascades in individual cells. However, these processes have been separately analyzed with fluorescence and bioluminescence microscopy. Furthermore, in culture medium, the background fluorescence of luciferin-a substrate of luciferase in promoter assays of gene expression in cultured cells confounds the simultaneous observation of fluorescence and bioluminescence. Therefore, we optimized conditions for optical filter sets based on spectral properties and the luciferin concentration based on cell permeability for fluorescence observation combined with bioluminescence microscopy. An excitation and emission filter set (492-506 nm and 524-578 nm) was suitable for green fluorescent protein and yellow fluorescent protein imaging of cells, and >100 MUM luciferin was acceptable in culture medium based on kinetic constants and the estimated intracellular concentration. Using these parameters, we present an example of sequential fluorescence and bioluminescence microscopic observation of signal transduction (translocation of protein kinase C alpha from the cytoplasm to the plasma membrane) coupled with activation of gene expression by nuclear factor of kappa light polypeptide B in individual cells and show that the gene expression response is not completely concordant with upstream signaling following stimulation with phorbol-12-myristate-13-acetate. Our technique is a powerful imaging tool for analysis of heterogeneous gene expression together with upstream signaling in live single cells. PMID- 26096874 TI - Adaptation and innovation: a grounded theory study of procedural variation in the academic surgical workplace. AB - RATIONALE, AIMS AND OBJECTIVES: Surgical research struggles to describe the relationship between procedural variations in daily practice and traditional conceptualizations of evidence. The problem has resisted simple solutions, in part, because we lack a solid understanding of how surgeons conceptualize and interact around variation, adaptation, innovation, and evidence in daily practice. This grounded theory study aims to describe the social processes that influence how procedural variation is conceptualized in the surgical workplace. METHOD: Using the constructivist grounded theory methodology, semi-structured interviews with surgeons (n = 19) from four North American academic centres were collected and analysed. Purposive sampling targeted surgeons with experiential knowledge of the role of variations in the workplace. Theoretical sampling was conducted until a theoretical framework representing key processes was conceptually saturated. RESULTS: Surgical procedural variation was influenced by three key processes. Seeking improvement was shaped by having unsolved procedural problems, adapting in the moment, and pursuing personal opportunities. Orienting self and others to variations consisted of sharing stories of variations with others, taking stock of how a variation promoted personal interests, and placing trust in peers. Acting under cultural and material conditions was characterized by being wary, positioning personal image, showing the logic of a variation, and making use of academic resources to do so. Our findings include social processes that influence how adaptations are incubated in surgical practice and mature into innovations. CONCLUSIONS: This study offers a language for conceptualizing the sociocultural influences on procedural variations in surgery. Interventions to change how surgeons interact with variations on a day-to-day basis should consider these social processes in their design. PMID- 26096875 TI - Mussel-Inspired Modification of Nanofibers for REST siRNA Delivery: Understanding the Effects of Gene-Silencing and Substrate Topography on Human Mesenchymal Stem Cell Neuronal Commitment. AB - In this study, we promote neuronal differentiation of human mesenchymal stem cells (MSCs) through scaffold-mediated sustained release of siRNA targeting RE-1 silencing transcription factor (REST). Poly (epsilon-caprolactone) nanofibers were surface modified with mussel inspired DOPA-melanin (DM) coating for adsorption of REST siRNA. DM modification increased siRNA-loading efficiency and reduced the initial burst release. Fiber alignment and DM modification enhanced REST knockdown efficiencies. Under non-specific differentiation condition, REST silencing and fiber topography enhanced MSC neuronal markers expressions and reduced glial cell commitment. Such scaffolds may find useful applications in enhancing MSCs neuronal differentiation under non-specific conditions such as an in vivo environment. PMID- 26096877 TI - Development and validation of TLC-densitometric method for simultaneous determination of two binary antihypertensive mixtures containing felodipine in fixed dose combinations. AB - A new densitometric thin-layer chromatographic method has been developed for simultaneous determination of two binary mixtures containing felodipine in combination with either metoprolol (mixture I) or ramipril (mixture II). The two mixtures were quantitatively separated on 60 F254 silica gel plates using toluene ethyl acetate-methanol-ammonia as mobile phase with UV detection at 233 and 229 nm for mixtures I and II, respectively. The studied drugs were satisfactorily resolved with retention factor (Rf ) values of 0.34 +/- 0.03 and 0.65 +/- 0.03 for metoprolol and felodipine, respectively, in mixture I and 0.35 +/- 0.03 and 0.74 +/- 0.03 for ramipril and felodipine, respectively, in mixture II. Linearity ranges were 2000-7000 and 200-700 ng/band for metoprolol and felodipine, respectively, in mixture I and 1500-4000 ng/band for both ramipril and felodipine in mixture II. Correlation coefficient (r) values were 0.9968 for both metoprolol and felodipine in mixture I and 0.9993 for ramipril and 0.9989 for felodipine in mixture II. The method has been validated according to International Conference on Harmonization guidelines and has been successfully applied for determination of the studied drugs in their dosage forms without interference from commonly encountered excipients. PMID- 26096876 TI - Tamoxifen Inhibits TGF-beta-Mediated Activation of Myofibroblasts by Blocking Non Smad Signaling Through ERK1/2. AB - Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine which stimulates the differentiation of fibroblasts into myofibroblasts. Myofibroblasts are critical for normal wound healing, but also accumulate pathologically in a number of chronic inflammatory conditions where they are key contributors to aberrant tissue remodeling and fibrosis, and in cancer stroma. In the current study, we identified a role for tamoxifen as a potent inhibitor of the TGF-beta mediated activation of primary human skin and breast fibroblasts. Our data indicate that tamoxifen does not interfere with canonical Smad signaling downstream of TGF-beta but rather blocks non-Smad signaling through ERK1/2 MAP kinase and the AP-1 transcription factor FRA2. We further demonstrate by siRNA mediated knockdown that FRA2 is critical for the induced expression of myogenic proteins in response to TGF-beta. Functionally, TGF-beta-stimulated fibroblast mediated contraction of collagen gels was impaired in the presence of tamoxifen. Altogether, these data demonstrate that tamoxifen prevents myofibroblast differentiation and, therefore, may provide therapeutic benefits to patients suffering from chronic inflammatory conditions or cancer. PMID- 26096878 TI - Replication study implicates COMT val158met polymorphism as a modulator of probabilistic reward learning. AB - Previous studies suggest that a single nucleotide polymorphism in the catechol-O methyltransferase (COMT) gene (val158met) may modulate reward-guided decision making in healthy individuals. The polymorphism affects dopamine catabolism and thus modulates prefrontal dopamine levels, which may lead to variation in individual responses to risk and reward. We previously showed, using tasks that index reward responsiveness (measured by responses bias towards reinforced stimuli) and risk taking (measured by the Balloon Analogue Risk Task), that COMT met homozygotes had increased reward responsiveness and, thus, an increased propensity to seek reward. In this study, we sought to replicate these effects in a larger, independent cohort of Caucasian UK university students and staff with similar demographic characteristics (n = 101; 54 females, mean age: 22.2 years). Similarly to our previous study, we observed a significant trial * COMT genotype interaction (P = 0.047; eta(2) = 0.052), which was driven by a significant effect of COMT on the incremental acquisition of response bias [response bias at block 3 - block 1 (met/met > val/val: P = 0.028) and block 3 - block 2 (met/met > val/val: P = 0.007)], suggesting that COMT met homozygotes demonstrated higher levels of reward responsiveness by the end of the task. However, we failed to see main effects of COMT genotype on overall response bias or risk-seeking behaviour. These results provide additional evidence that prefrontal dopaminergic variation may have a role in reward responsiveness, but not risk-seeking behaviour. Our findings may have implications for neuropsychiatric disorders characterized by clinical deficits in reward processing such as anhedonia. PMID- 26096879 TI - Recent Advances in Stereoselective Drug Targeting. AB - Reviewed here are some recent examples of medically important protein targets for which stereoselective drugs have been identified. These include heat shock protein 90 (Hsp90) inhibitors as anticancer agents; transient receptor potential vanilloid type 1 antagonists as new analgesics; stereospecific inhibition of human mutT homolog MTH1 for cancer treatment; the stereoselective binding of R- and S-propranolol by the alpha1-acid glycoprotein transporter; metallohelical complexes that are nonpeptide alpha-helical mimetics that enantioselectively target Abeta amyloid for the treatment of Alzheimer's disease; metallohelical assemblies with promising antimicrobial activity that enantioselectively target DNA of resistant bacteria; nonpeptide alpha-helical metallohelices that target the DNA of cisplatin-resistant cancer cells; diastereomeric selectivity of phenanthriplatin-guanine adducts; and phenazine biosynthetic enzyme active sites that can host both enantiomers of a racemic ligand simultaneously. PMID- 26096880 TI - [Society of the Members, by the Members, for the Members]. PMID- 26096881 TI - Thromboelastometric evaluation of hemostasis in dogs infected with Leishmania infantum. AB - OBJECTIVE: Evaluation of hemostasis using thromboelastometry in dogs with leishmaniasis before and after treatment. DESIGN: Longitudinal observational study. SETTING: University veterinary teaching hospital. ANIMALS: Eighty-four adult, client-owned dogs. MEASUREMENTS AND MAIN RESULTS: Whole blood samples for the coagulation profile were collected from symptomatic dogs with leishmaniasis (group S), asymptomatic dogs with leishmaniasis after treatment (group T), and a control group of healthy dogs (group H). Hemostasis was evaluated by means of standard coagulation profile (prothrombin time, activated partial thromboplastin time, and fibrinogen) and by thromboelastometry (ROTEM). Prothrombin time and activated partial thromboplastin time were within the upper reference range in all 3 groups. Comparison of the ROTEM variables between the 3 groups showed statistically significant differences between group S versus groups T and H, but remaining within the reference ranges. Statistically significant differences in hematocrit and fibrinogen concentrations were noted between groups (group S vs. H: hematocrit P = 0.001, fibrinogen P = 0.002; Group S vs. T: hematocrit P = 0.001, fibrinogen P = 0.001). These variations have interfered with some parameters of the ROTEM profile. CONCLUSIONS: This study showed normal standard coagulation profiles in all 3 groups evaluated. The ROTEM results did not fall outside of the maximum values of the reference ranges. PMID- 26096882 TI - Detection and quantification of pipe damage from change in time of flight and phase. AB - The use of ultrasonic guided waves for damage detection in pipes is continuously increasing. Generally longitudinal (axial symmetric) modes are excited and detected by PZT (Lead Zirconate Titanate) transducers in transmission mode for this purpose. In most studies the change in the received signal strength with the extent of damage has been investigated while in this study the change in the phase and the time-of-flight (TOF) of the propagating wave modes with the damage size is investigated. The cross-correlation technique is used to record the small changes in the TOF as the damage size varies in steel pipes. Dispersion curves are calculated to carefully identify the propagating wave modes. Differential TOF is recorded and compared for different propagating wave modes. Feature extraction techniques are used for extracting phase and time-frequency information. The main advantage of this approach is that unlike the recorded signal strength the TOF and the phase are not affected by the bonding condition between the transducer and the pipe. Therefore, if the pipe is not damaged but the transducer-pipe bonding is deteriorated then although the received signal strength is altered the TOF and phase remain same avoiding the false positive alarms of damage. PMID- 26096883 TI - Strain estimation by a Fourier Series-based extrema tracking algorithm for elastography. AB - In this paper, a new strain estimator using extrema tracking based on Fourier Series expansion (ETBFS) is proposed for ultrasonic elastography. In this method, the extremum is determined by solving an equation constructed by obtaining the first order derivative of the Fourier Series expansion and setting it to zero. Unlike other tracking algorithms, the ETBFS method can locate the extrema of radio frequency (RF) signals exactly between two adjacent sampling points and achieve a sub-sample accuracy without additional explicit interpolation. The correspondence between the located extrema in the pre- and post-compressed RF signal segments are constructed with a fine matching technique, with which the displacements and strains are estimated. Experimental results on a finite-element modeling (FEM) simulation phantom show that the new proposed method can provide a more accurate displacement estimation than the standard cross-correlation (CC) based method and the scale-invariant keypoints tracking (SIKT) algorithm. Moreover, performance analysis in terms of elastographic signal-to-noise ratio (SNRe), elastographic contrast-to-noise ratio (CNRe) and the real-versus estimated strain error (RESE) also indicate that the dynamic range of the strain filter and its sensitivity can be improved with this new method. PMID- 26096884 TI - Inadequate vitamin D levels are associated with culture positive sepsis and poor outcomes in paediatric intensive care. AB - AIM: This study aimed to assess vitamin D status, and its determinants, in paediatric patients with suspected sepsis who were admitted to a paediatric intensive care unit (PICU). We also investigated the association between vitamin D status and clinical outcomes. METHODS: Serum 25-hydroxy vitamin D (25OHD) and clinical determinants were prospectively assessed in children with suspected sepsis (<12 years old) admitted to the PICU. The relationship between 25OHD and clinical outcomes was evaluated. Vitamin D status was also assessed in control children of a similar age. RESULTS: We enrolled 120 children with suspected sepsis admitted to the PICU and 30 paediatric controls. 25OHD was <50 nmol/L in 59% of the children admitted to the PICU and 25OHD was lower than in the controls (47 +/- 29 vs 66 +/- 26 nmol/L, p < 0.001). After adjusting for potential confounders, 25OHD was strongly associated with culture positive sepsis (p < 0.001), the paediatric index of mortality (p = 0.026) and the duration of mechanical ventilation (p = 0.008). There was a negative correlation between 25OHD and C-reactive protein (CRP): each 0.1% decrease in 25OHD increased CRP (p = 0.04). CONCLUSION: Children admitted to the PICU with suspected sepsis had lower 25OHD than controls and inadequate 25OHD status was associated with confirmed sepsis and poor outcomes. PMID- 26096885 TI - Bioaccumulation, subcellular distribution, and acute effects of chromium in Japanese medaka (Oryzias latipes). AB - Chromium (Cr) is an essential element but is toxic to aquatic organisms at elevated concentrations. In the present study, adult Japanese medaka (Oryzias latipes) were exposed to a sublethal hexavalent chromium (Cr(VI)) concentration via dissolved and dietary exposures for 6 d. Various measurements of Cr were made: bioaccumulation in different tissues, subcellular distribution in the liver, effects on antioxidants and acetylcholinesterase (AChE), and Cr-induced lipid peroxidation. The results showed that bioaccumulation increased dramatically in all tested tissues from dissolved exposure but only significantly in the intestine from dietary treatment, implying that dissolved exposure may be predominant for Cr accumulation in medaka. Subcellular distribution revealed that Cr accumulated in the liver was mainly (46%) associated with the heat-stable protein fraction. Among the antioxidants examined, catalase (CAT) responded to dissolved Cr exposure in most tissues whereas superoxide dismutase (SOD) was less responsive. Malondialdehyde concentrations were significantly elevated in most tissues examined in the dissolved Cr-exposed fish, but were only elevated in the liver and intestine in the dietary Cr-exposed fish. The AChE activity in the brain was stimulated by 49% in the dissolved Cr-exposed fish. Reductions in condition factor and gonadosomatic index were also observed. These data help in an understanding of Cr tissue distribution and the acute effects of Cr in Japanese medaka. PMID- 26096886 TI - Fumaric acid esters prevent the NLRP3 inflammasome-mediated and ATP-triggered pyroptosis of differentiated THP-1 cells. AB - Fumaric acid esters (FAEs) exert therapeutic effects in patients with psoriasis and multiple sclerosis, however their mode of action remains elusive. Pyroptosis is a caspase-1-dependent pro-inflammatory form of programmed cell death, mediated by the activation of inflammasomes. To understand the pharmacological basis of the therapeutic effects of FAEs, the anti-pyroptotic activity of dimethyl fumarate (DMF) and its hydrolysis metabolite monomethyl fumarate (MMF) was studied in a model of NLRP3 inflammasome-mediated pyroptosis of human macrophages. Phorbol myristate acetate-differentiated THP-1 cells were exposed to lipopolysaccharide (5 MUg/ml; 4h), then pulsed with ATP (5mM; 1h). MMF, DMF, or parthenolide (positive control) were added 1h before the ATP pulse. The pyroptotic cell death was evaluated by morphological examination and quantified by measuring the lactate dehydrogenase leakage. The ATP-triggered death of THP-1 cells (60.4 +/- 4.0%) was significantly (P<0.01) prevented by DMF, in a time- and concentration-dependent manner (pIC50 and maximal effect were 6.6 and 67.6 +/- 1.2%, respectively). MMF was less efficacious than DMF. These effects were accompanied by a decreased intracellular activation of caspase-1 and interleukin 1beta release from ATP-treated cells, thus suggesting that FAEs antagonise the effects of ATP by preventing the activation of the pyroptotic molecular cascade leading to cell death. These results indicate that FAEs are endowed with anti pyroptotic activity, which may contribute to their therapeutic effects. PMID- 26096888 TI - Accelerated nail elongation speed in psoriasis patients during treatment. PMID- 26096887 TI - Mechanisms of human lymphotoxin beta receptor activation on upregulation of CCL5/RANTES production. AB - Human lymphotoxin-beta receptor (LTbetaR), a member of the tumor necrosis factor receptor superfamily, plays an essential role in secondary lymphoid organ development, host defense, chemokine secretion, and apoptosis. In our study, LTbetaR activations by different stimulations were all found to induce RANTES secretion. Overexpression of LTbetaR or stimulation LTbetaR by ligands or agonistic antibody in human lung epithelial cells induced RANTES secretion However, the regulatory mechanism and the signaling cascade have not been fully elucidated. Therefore, the aim of this study was to elucidate the mechanism underlying LTbetaR-mediated RANTES production. Our study indicated that activation of JNK and ERK was important for the regulation of RANTES secretion. In addition, dominant negative mutants of ASK1, TAK1, and MEKK1 inhibited LTbetaR induced RANTES expression. The dominant negative mutants of TRAF2, 3, and 5 also inhibited LTbetaR-mediated RANTES secretion. Chromatin immunoprecipitation analysis showed that LTbetaR activation induced the binding of c-Jun and NF kappaB to the RANTES promoter. The results of this study show that LTbetaR activates ASK1, TAK1, and MEKK1 cascades via TRAF2, 3, and 5, resulting in the activation of JNK and ERK, which promotes the binding of c-Jun and NF-kappaB to the RANTES promoter, thereby increasing RANTES expression and secretion. PMID- 26096889 TI - Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects. AB - In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP 08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product. PMID- 26096890 TI - Chloride-inducible transient apoplastic alkalinizations induce stomata closure by controlling abscisic acid distribution between leaf apoplast and guard cells in salt-stressed Vicia faba. AB - Chloride stress causes the leaf apoplast transiently to alkalize, an event that is presumed to contribute to the ability of plants to adapt to saline conditions. However, the initiation of coordinated processes downstream of the alkalinization is unknown. We hypothesize that chloride-inducible pH dynamics are a key chemical feature modulating the compartmental distribution of abscisic acid (ABA) and, as a consequence, affecting stomata aperture. Apoplastic pH and stomata aperture dynamics in intact Vicia faba leaves were monitored by microscopy-based ratio imaging and porometric measurements of stomatal conductance. ABA concentrations in leaf apoplast and guard cells were compared with pH dynamics by gas chromatography-mass-spectrometry (GC-MS) and liquid-chromatography-tandem-mass spectrometry (LC-MS/MS). Results demonstrate that, upon chloride addition to roots, an alkalizing factor that initiates the pH dynamic propagates from root to leaf in a way similar to xylem-distributed water. In leaves, it induces a systemic transient apoplastic alkalinization that causes apoplastic ABA concentration to increase, followed by an elevation of endogenous guard cell ABA. We conclude that the transient alkalinization, which is a remote effect of chloride stress, modulates the compartmental distribution of ABA between the leaf apoplast and the guard cells and, in this way, is instrumental in inducing stomata closure during the beginning of salinity. PMID- 26096891 TI - Current approaches to enhance glutamate transporter function and expression. AB - L-glutamate is the predominant excitatory neurotransmitter in the CNS and has a central role in a variety of brain functions. The termination of glutamate neurotransmission by excitatory amino acid transporters (EAATs) is essential to maintain glutamate concentration low in extracellular space and avoid excitotoxicity. EAAT2/GLT-1, being the most abundant subtype of glutamate transporter in the CNS, plays a key role in regulation of glutamate transmission. Dysfunction of EAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, amyotrophic lateral sclerosis, Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression of EAAT2/GLT-1 could serve as a potential therapy for these conditions. Translational activators of EAAT2/GLT-1, such as ceftriaxone and LDN/OSU-0212320, have been described to have significant protective effects in animal models of amyotrophic lateral sclerosis and epilepsy. In addition, pharmacological activators of the activity of EAAT2/GLT-1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators. This review describes the current status of the search for EAAT2/GLT-1 activators and addresses challenges and limitations that this approach might encounter. Termination of glutamate neurotransmission by glutamate transporter EAAT2 is essential to maintain homeostasis in the brain and to avoid excitotoxicity. Dysfunction of EAAT2 has been correlated with various neurological pathologies. Therefore, activators of the function or enhancers of the expression of EAAT2 (green arrows) could serve as a potential therapy for these conditions. This review describes the current status of the search for EAAT2 activators and addresses challenges and limitations of this approach. PMID- 26096892 TI - We know less than we should about methods of meta-analysis. PMID- 26096893 TI - Amine-Catalyzed Highly Regioselective and Stereoselective C(sp(2) )-C(sp(2) ) Cross-Coupling of Naphthols with trans-alpha,beta-Unsaturated Aldehydes. AB - A metal-free C(sp(2) )-C(sp(2) ) cross-coupling approach to highly congested (E) alpha-naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4-bromination of 1 naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4-bromo-1-naphthols with the alpha-C(sp(2) ) of enals through a Michael type Friedel-Crafts alkylation-dearomatization followed by a cyclopropanation ring-opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp(2) )-C(sp(2) ) bond from readily available unfunctionalized naphthols and enals catalyzed by non-metal, readily available cyclic secondary amines under mild reaction conditions. PMID- 26096895 TI - Atherogenic index of plasma in non-obese women with androgenetic alopecia. AB - BACKGROUND: Androgenetic alopecia (AGA) is characterized by the local and gradual transformation of terminal scalp hair into vellus hair, which has a shorter and thinner shaft. Several studies have analyzed the relationship between AGA and cardiovascular disease in males, and few were conducted in females. The current study aimed to investigate lipid profile and atherogenic index of plasma in non obese females with AGA. METHODS: Forty non-obese females with early-onset AGA were selected with 40 age- and gender-matched healthy subjects as a control group. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured, and the atherogenic index of plasma was calculated for all cases and control subjects. RESULTS: Mean values of total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P = 0.03), and triglycerides (P = 0.001) were significantly higher in cases than controls. Mean value of high-density lipoprotein cholesterol was significantly lower in cases than controls (P = 0.008). The atherogenic index of plasma was significantly higher in cases than controls (P < 0.001). CONCLUSION: Current findings support the relationship between early-onset AGA and unfavorable lipid profile and cardiovascular risk in affected females. Assessment and follow-up of these cases will allow early intervention to avoid cardiovascular complications. PMID- 26096894 TI - Neurological complications of breast cancer: A prospective cohort study. AB - OBJECTIVES: Neurological complications secondary to breast cancer treatment may be an important contributor to these patients morbidity. We aimed to quantify the incidence of neurological complications of breast cancer treatment during the first year after diagnosis. MATERIALS AND METHODS: We performed a prospective cohort study with 506 patients recruited at the Portuguese Institute of Oncology of Porto, among those newly diagnosed. Participants underwent a neurological examination before treatment, after surgery, after chemotherapy (whenever applicable) and at one year after enrollment. The Montreal Cognitive Assessment was used to assess cognitive function, at baseline and at one year. We computed one-year cumulative incidence estimates and the corresponding 95% confidence intervals (95%CI) for each of the neurological complications. RESULTS: Just over half of women had breast cancer stage 0 or I. A total of 6.9% were submitted to neoadjuvant chemotherapy but most of them completed adjuvant treatment - endocrine therapy, radiotherapy or chemotherapy (83.9%, 73.0% and 52.5%, respectively). The cumulative incidence of at least one oncological-related neurological complication during the first year after diagnosis was 48.4% (95%CI: 44.1-52.8); the most frequent were neuropathic pain (30.8%, 95%CI: 27.0-35.0), chemotherapy-induced peripheral neuropathy (16.8%, 95%CI: 13.8-20.3), phantom breast pain/syndrome (16.6%, 95%CI: 13.6-20.1) and cognitive decline (8.1%, 95%CI: 5.8-11.1). CONCLUSIONS: Neurological complications were a frequent side effect of breast cancer management in the first year after diagnosis, especially neuropathic pain and chemotherapy-induced peripheral neuropathy. Accurate diagnosis and treatment of these complications are important to minimize the burden associated with breast cancer treatment in breast cancer survivors. PMID- 26096896 TI - Assessing the treatment effect in a randomized controlled trial with extensive non-adherence: the EVOLVE trial. PMID- 26096897 TI - High-throughput approach for the identification of anilinium-based ionic liquids that are suitable for electropolymerisation. AB - We report the synthesis of new protic ionic liquids (PILs) based on aniline derivatives and the use of high-throughput (HT) techniques to screen possible candidates. In this work, a simple HT method was applied to rapidly screen different aniline derivatives against different acids in order to identify possible combinations that produce PILs. This was followed by repeating the HT process with a Chemspeed robotic synthesis platform for more accurate results. One of the successful combinations were then chosen to be synthesised on a larger scale for further analysis. The new PILs are of interest to the fields of ionic liquids, energy storage and especially, conducting polymers as they serve as solvents, electrolytes and monomers at the same time for possible electropolymerisation (i.e. a self-contained polymer precursor). PMID- 26096898 TI - Materials used to simulate physical properties of human skin. AB - BACKGROUND: For many applications in research, material development and testing, physical skin models are preferable to the use of human skin, because more reliable and reproducible results can be obtained. PURPOSE: This article gives an overview of materials applied to model physical properties of human skin to encourage multidisciplinary approaches for more realistic testing and improved understanding of skin-material interactions. METHODS: The literature databases Web of Science, PubMed and Google Scholar were searched using the terms 'skin model', 'skin phantom', 'skin equivalent', 'synthetic skin', 'skin substitute', 'artificial skin', 'skin replica', and 'skin model substrate.' Articles addressing material developments or measurements that include the replication of skin properties or behaviour were analysed. RESULTS: It was found that the most common materials used to simulate skin are liquid suspensions, gelatinous substances, elastomers, epoxy resins, metals and textiles. Nano- and micro fillers can be incorporated in the skin models to tune their physical properties. CONCLUSION: While numerous physical skin models have been reported, most developments are research field-specific and based on trial-and-error methods. As the complexity of advanced measurement techniques increases, new interdisciplinary approaches are needed in future to achieve refined models which realistically simulate multiple properties of human skin. PMID- 26096899 TI - Mucocutaneous lupus erythematosus in dogs (21 cases). AB - BACKGROUND: The diagnosis of dogs with chronic juxtamucosal erosive lesions and histopathology typical of cutaneous lupus erythematosus (CLE) is unclear. HYPOTHESIS/OBJECTIVES: We report herein 21 dogs with mucocutaneous erosive lesions and lupus-specific histopathology that we propose to be affected with mucocutaneous lupus erythematosus (MCLE), another variant of chronic CLE. METHODS: Inclusion criteria were the presence of the following: (i) a >2 month history of chronic or recurrent skin lesions; (ii) erosions or ulcers predominating at mucosae or mucocutaneous junctions; (iii) microscopic lesions of CLE (i.e. a lymphocyte-rich interface dermatitis with basal keratinocyte damage); and (iv) a lack of complete remission following antimicrobials. Clinical questionnaires and skin biopsies were reviewed. Direct immunofluorescence and antinuclear antibody serology were performed whenever possible. RESULTS: More than half of the 21 dogs were German shepherds or their crosses. The disease affected mostly dogs in their mid-adulthood and there was an over-representation of females. Erosions and ulcers predominated at genital/perigenital and anal/perianal areas, with a lower frequency of involvement of periocular, perioral and perinasal regions. In these dogs, there were no clinical signs suggestive of an associated systemic lupus erythematosus. Microscopic lesions were specific for CLE, but they were patchy and often infected with bacteria. The most common immunological finding was focal IgG deposition at the basement membrane zone. Lesions responded to varying interventions, but oral glucocorticoids led to a shorter time to complete remission. Relapses were common upon treatment tapering. CONCLUSIONS AND CLINICAL IMPORTANCE: These observations support MCLE being another variant of canine CLE. PMID- 26096900 TI - The crystal structure of Helicobacter pylori HP1029 highlights the functional diversity of the sialic acid-related DUF386 family. AB - The proteins of the YhcH/YjgK/YiaL (DUF386) family have been implicated in the bacterial metabolism of host-derived sialic acids and biofilm formation, although their precise biochemical function remains enigmatic. We present here the crystal structure of protein HP1029 from Helicobacter pylori. The protein is a homodimer, in which each monomer comprises a molecular core formed by 12 antiparallel beta strands arranged in two beta-sheets flanked by helices. The sandwich formed by the sheets assumes the shape of a funnel opened at one end, with a zinc ion present at the bottom of the funnel. The crystal structure unequivocally shows that HP1029 belongs to the DUF386 family. Although no bioinformatics evidence has been found for sialic acid catabolism in H. pylori, the genomic context of HP1029 in Helicobacter and related organisms suggests a possible role in the metabolism of bacterial surface saccharides, such as pseudaminic acid and its derivatives. PMID- 26096901 TI - The stiff shoulder; A case study. AB - Clinicians working in outpatient departments and advanced practitioner clinics frequently encounter patients presenting with multidirectional stiffness of the glenohumeral joint. This case report describes the assessment and treatment of a patient presenting with glenohumeral joint stiffness and describes the possible differential diagnoses. The evidence base used to inform the decision-making process is presented and the use of radiology that helped to ultimately establish the diagnosis is discussed. The clinical reasoning process of applying knowledge and experience to identify patient problems and to make appropriate decisions that result in positive patient outcomes is discussed. The case report highlights the importance of early diagnosis. PMID- 26096902 TI - The Effect of Right Ventricular Apical and Nonapical Pacing on the Short- and Long-Term Changes in Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized-Controlled Trials. AB - BACKGROUND: The right ventricular apex (RVA) is the traditional lead site for chronic pacing but in some patients may cause impaired left ventricular (LV) systolic function over time. Comparisons with right ventricular nonapical (RVNA) pacing sites have generated inconsistent results and recent meta-analyses have demonstrated unclear benefit due to heterogeneity across studies. METHODS AND RESULTS: A systematic search for randomized controlled trials that compared LV ejection fraction (LVEF) outcomes between RVNA and RVA pacing was performed up to October 2014. Twenty-four studies (n = 1,628 patients) met the inclusion criteria. To avoid between study heterogeneity two homogenous groups were created; group 1 where studies reported a difference (in favor of RVNA pacing) and group 2 where studies reported no difference between pacing sites. For group 1, weighted mean difference between RVNA and RVA pacing in terms of LVEF at follow-up was 5.40% (95% confidence interval [CI]: 3.94-6.87), related in part to group one's RVA arm demonstrating a significant reduction (mean loss -3.31%; 95% CI: -6.19 to -0.43) in LVEF between study baseline and end of follow-up. Neither of these finding were seen in group 2. Weighted regression modeling demonstrated that inclusion of poor baseline LVEF (<40%) in combination with greater than 12 months follow-up was three times more common in group 1 compared to group 2 (weighted relative risk 2.82; 95% CI: 1.03-7.72; P = 0.043). CONCLUSIONS: In patients requiring chronic right ventricular pacing where there is inclusion of impaired baseline LVEF (<40%), RVA pacing is associated with deterioration in LV function relative to RVNA pacing. PMID- 26096903 TI - Overexpression of Indian hedgehog partially rescues short stature homeobox 2 overexpression-associated congenital dysplasia of the temporomandibular joint in mice. AB - The role of short stature homeobox 2 (shox2) in the development and homeostasis of the temporomandibular joint (TMJ) has been well documented. Shox2 is known to be expressed in the progenitor cells and perichondrium of the developing condyle. A previous study by our group reported that overexpression of shox2 leads to congenital dysplasia of the TMJ via downregulation of the Indian hedgehog (Ihh) signaling pathway, which is essential for embryonic disc primordium formation and mandibular condylar growth. To determine whether overexpression of Ihh may rescue the overexpression of shox2 leading to congenital dysplasia of the TMJ, a mouse model in which Ihh and shox2 were overexpressed (Wnt1-Cre; pMes-stop shox2; pMes stop Ihh mice) was utilized to assess the consequences of this overexpression on TMJ development during post-natal life. The results showed that the developmental process and expression levels of runt-related transcription factor 2 and sex determining region Y-box 9 in the TMJ of the Wnt1-Cre; pMes-stop shox2; pMes-stop Ihh mice were similar to those in wild-type mice. Overexpression of Ihh rescued shox2 overexpression-associated reduction of extracellular matrix components. However, overexpression of Ihh did not inhibit the shox2 overexpression associated increase of matrix metalloproteinases (MMPs) MMP9, MMP13 and apoptosis in the TMJ. These combinatory cellular and molecular defects appeared to account for the observed congenital dysplasia of TMJ, suggesting that overexpression of Ihh partially rescued shox2 overexpression-associated congenital dysplasia of the TMJ in mice. PMID- 26096904 TI - Prevalence of Deafness-Associated Connexin-26 (GJB2) and Connexin-30 (GJB6) Pathogenic Alleles in a Large Patient Cohort from Eastern Sicily. AB - Mutations in the gene encoding the gap junction protein connexin 26 (GJB2) and connexin 30 (GJB6) have been shown to be a major contributor to prelingual, sensorineural, nonsyndromic deafness. The aim of this study was to characterize and establish the prevalence of GJB2 and GJB6 gene alterations in 196 patients affected by sensorineural, nonsyndromic hearing loss, from Eastern Sicily. We performed sequence analysis of GJB2 and identified sequence variants in 68 out of 196 patients (34.7%); (28 homozygous for c.35delG, 22 compound heterozygous and 11 with only one variant allele). We found 12 different allelic variants, the most prevalent being c.35delG, which was found on 89 chromosomes (65.5%), followed by other alleles with different frequencies (p.E47X, c.-23+1G>A, p.L90P, p.R184W, p.M34T, c.167delT, p.R127H, p.M163V, p.V153I, p.W24X, and p.T8M). Importantly, for the first time we present the frequency and spectrum of GJB2 mutations in NSHL patients from Eastern Sicily. No alterations were found in the GJB6 gene, confirming that alterations in this gene are uncommon in our geographic area. Note that 65.3% and 23.5% of our patients, respectively were found to be negative or carriers by GJB2 molecular screening. This emphasizes the need to broaden the genetic analysis to other genes involved in hearing loss. PMID- 26096905 TI - Salicin from Willow Bark can Modulate Neurite Outgrowth in Human Neuroblastoma SH SY5Y Cells. AB - Salicin from willow bark has been used throughout centuries in China and Europe for the treatment of pain, headache, and inflammatory conditions. Recently, it could be demonstrated that salicin binds and activates the bitter taste receptor TAS2R16. Studies on rodent tissues showed the general expression of bitter taste receptors (TAS2Rs) in rodent brain. Here, we demonstrate the expression of hTAS2R16 in human neuronal tissues and the neuroblastoma cell line SH-SY5Y. The functionality was analyzed in the neuroblastoma cell line SH-SY5Y after stimulation with salicin, a known TAS2R16 agonist. In this setting salicin induced in SH-SY5Y cells phosphorylation of ERK and CREB, the key transcription factor of neuronal differentiation. PD98059, an inhibitor of the ERK pathway, as well as probenecid, a TAS2R16 antagonist, inhibited receptor phosphorylation as well as neurite outgrowth. These data show that salicin might modulate neurite outgrowth by bitter taste receptor activation. PMID- 26096906 TI - No evidence for substrate accumulation in Parkinson brains with GBA mutations. AB - BACKGROUND: To establish whether Parkinson's disease (PD) brains previously described to have decreased glucocerebrosidase activity exhibit accumulation of the lysosomal enzyme's substrate, glucosylceramide, or other changes in lipid composition. METHODS: Lipidomic analyses and cholesterol measurements were performed on the putamen (n = 5-7) and cerebellum (n = 7-14) of controls, Parkinson's disease brains with heterozygote GBA1 mutations (PD+GBA), or sporadic PD. RESULTS: Total glucosylceramide levels were unchanged in both PD+GBA and sporadic PD brains when compared with controls. No changes in glucosylsphingosine (deacetylated glucosylceramide), sphingomyelin, gangliosides (GM2, GM3), or total cholesterol were observed in either putamen or cerebellum. CONCLUSIONS: This study did not demonstrate glucocerebrosidase substrate accumulation in PD brains with heterozygote GBA1 mutations in areas of the brain with low alpha-synuclein pathology. PMID- 26096908 TI - Hepatitis C virus addiction to liver miR-122 takes its Toll on the host. PMID- 26096907 TI - Role of B cell receptor signaling in IL-10 production by normal and malignant B-1 cells. AB - B-1 cells are considered innate immune cells, which produce the majority of natural antibodies. B-1 cell responses to B cell receptor (BCR) and Toll-like receptor ligation are tightly regulated owing to the cross-reactivity to self antigens. CD5 has been shown to play a major role in downregulation of BCR responses in B-1 cells. Here, we provide evidence for another mechanism by which BCR response is regulated in B-1 cells. B-1 cells, as well as their malignant counterpart, B cell chronic lymphocytic leukemia (B-CLL) cells, produce interleukin-10 (IL-10) constitutively. IL-10 secretion by normal B-1 cells downregulates their proliferation responses to BCR ligation. However, we found that CLL cells appear to be unique in not responding to IL-10-mediated feedback suppressive effects in comparison to normal B-1 cells. In addition, we describe a novel role of the BCR signaling pathway in constitutive IL-10 secretion by normal and malignant B-1 cells. We found that inhibition of Src family kinases, spleen tyrosine kinase, Syk, or Bruton's tyrosine kinase reduces constitutive IL-10 production by both normal and malignant B-1 cells. PMID- 26096909 TI - Dimensionality of stress experiences: Factorial structure of the Perceived Stress Questionnaire (PSQ) in a population-based Swedish sample. AB - We investigated the factorial structure of the Perceived Stress Questionnaire (PSQ-recent; Levenstein, Prantera, Varvo et al., 1993) in a large (N = 1516; 35 95 years) population-based Swedish sample (Nilsson, Adolfsson, Backman et al., 2004; Nilsson, Backman, Erngrund et al., 1997). Exploratory principal components analysis (PCA) was conducted on a first, randomly drawn subsample (n = 506). Next, the model based on the PCA was tested in a second sample (n = 505). Finally, a third sample (n = 505) was used to cross-validate the model. Five components were extracted in the PCA (eigenvalue > 1) and labeled "Demands," "Worries/Tension," "Lack of joy," "Conflict," and "Fatigue," respectively. Twenty one out of the 30 original PSQ items were retained in a confirmatory factor analysis (CFA) model that included the five (first-order) factors and, additionally, a general (second-order) stress factor, not considered in prior models. The model showed reasonable goodness of fit [chi(2)(184) = 511.2, p < 0.001; CFI = 0.904; RMSEA = 0.059; and SRMR = 0.063]. Multigroup confirmatory factor analyses supported the validity of the established model. The results are discussed in relation to prior investigations of the factorial structure of the PSQ. PMID- 26096911 TI - Conformational Plasticity in Glycomimetics: Fluorocarbamethyl-L-idopyranosides Mimic the Intrinsic Dynamic Behaviour of Natural Idose Rings. AB - Sugar function, structure and dynamics are intricately correlated. Ring flexibility is intrinsically related to biological activity; actually plasticity in L-iduronic rings modulates their interactions with biological receptors. However, the access to the experimental values of the energy barriers and free energy difference for conformer interconversion in water solution has been elusive. Here, a new generation of fluorine-containing glycomimetics is presented. We have applied a combination of organic synthesis, NMR spectroscopy and computational methods to investigate the conformational behaviour of idose- and glucose-like rings. We have used low-temperature NMR spectroscopic experiments to slow down the conformational exchange of the idose-like rings. Under these conditions, the exchange rate becomes slow in the (19) F NMR spectroscopic chemical shift timescale and allows shedding light on the thermodynamic and kinetic features of the equilibrium. Despite the minimal structural differences between these compounds, a remarkable difference in their dynamic behaviour indeed occurs. The importance of introducing fluorine atoms in these sugars mimics is also highlighted. Only the use of (19) F NMR spectroscopic experiments has permitted the unveiling of key features of the conformational equilibrium that would have otherwise remained unobserved. PMID- 26096910 TI - Long-term and perioperative outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma with propensity score matching: a multi institutional Japanese study. AB - BACKGROUND: The aim of this study was to compare the long-term outcomes and perioperative outcomes of laparoscopic liver resection (LLR) with those of open liver resection (OLR) for hepatocellular carcinoma (HCC) between well-matched patient groups. METHODS: Hepatocellular carcinoma patients underwent primary liver resection between 2000 and 2010, were collected from 31 participating institutions in Japan and were divided into LLR (n = 436) and OLR (n = 2969) groups. A one-to-one propensity case-matched analysis was used with covariates of baseline characteristics, including tumor characteristics and surgical procedures of hepatic resections. Long-term and short-term outcomes were compared between the matched two groups. RESULTS: The two groups were well balanced by propensity score matching and 387 patients were matched. There were no significant differences in overall survival and disease-free survival between LLR and OLR. The median blood loss (158 g vs. 400 g, P < 0.001) was significantly less with LLR, and the median postoperative hospital stay (13 days vs. 16 days, P < 0.001) was significantly shorter for LLR. Complication rate (6.7% vs. 13.0%, P = 0.003) was significantly less in LLR. CONCLUSION: Compared with OLR, LLR in selected patients with HCC showed similar long-term outcomes, associated with less blood loss, shorter hospital stay, and fewer postoperative complications. PMID- 26096912 TI - Application of a laser-guided docking system in robot-assisted urologic surgery. AB - BACKGROUND: This work explores the clinical significance of a laser-guided docking system for robot-assisted urologic surgery. MATERIALS AND METHODS: Between July 2013 and June 2014, 40 patients underwent robot-assisted laparoscopic prostatectomy (RALP), and 32 patients underwent robot-assisted laparoscopic partial nephrectomy (RAPN) performed by a single surgeon. In the RALP and RAPN groups, the robot was docked in the traditional way in 20 and 16 cases, respectively. A laser guiding system was used in the other cases. The docking time and the time required to adjust the angles were recorded. RESULT: The docking time was significantly shorter for the laser-guided process performed by inexperienced nurses. The time required to adjust the angles was also lower. There were no significant differences between the processes performed by experienced nurses. CONCLUSION: A laser-guided docking system may simplify and standardize the docking process and shorten the learning curve. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26096913 TI - Edge co-occurrences can account for rapid categorization of natural versus animal images. AB - Making a judgment about the semantic category of a visual scene, such as whether it contains an animal, is typically assumed to involve high-level associative brain areas. Previous explanations require progressively analyzing the scene hierarchically at increasing levels of abstraction, from edge extraction to mid level object recognition and then object categorization. Here we show that the statistics of edge co-occurrences alone are sufficient to perform a rough yet robust (translation, scale, and rotation invariant) scene categorization. We first extracted the edges from images using a scale-space analysis coupled with a sparse coding algorithm. We then computed the "association field" for different categories (natural, man-made, or containing an animal) by computing the statistics of edge co-occurrences. These differed strongly, with animal images having more curved configurations. We show that this geometry alone is sufficient for categorization, and that the pattern of errors made by humans is consistent with this procedure. Because these statistics could be measured as early as the primary visual cortex, the results challenge widely held assumptions about the flow of computations in the visual system. The results also suggest new algorithms for image classification and signal processing that exploit correlations between low-level structure and the underlying semantic category. PMID- 26096915 TI - Rapid and sensitive detection of Dasheen mosaic virus infecting elephant foot yam by reverse transcription loop mediated isothermal amplification of coat protein gene. AB - Dasheen mosaic virus (DsMV), the pathogen causing mosaic disease of elephant foot yam (Amorphophallus paeoniifoilius) is disseminated mainly through vegetative propagation of the tubers. For the rapid and sensitive detection of the virus, a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay based on the coat protein gene has been developed. A final concentration of 5.4 mM magnesium sulphate and 0.7 M betaine in the reaction mixture was found to be optimum for getting characteristic ladder like bands of the amplified product after gel electrophoresis. The reaction was set at 65 degrees C for 50 min followed by reaction termination at 86 degrees C for 5 min in a water bath. The sensitivity of the assay was found to be 100 times higher than that of RT-PCR. The virus was indexed successfully from tubers of elephant foot yam. In tube detection of the DsMV was carried out using fluorescence detection reagents. The assay was validated with field samples from various regions of Kerala state, India. PMID- 26096914 TI - Cortical actin regulation modulates vascular contractility and compliance in veins. AB - Most cardiovascular research focuses on arterial mechanisms of disease, largely ignoring venous mechanisms. Here we examine ex vivo venous stiffness, spanning tissue to molecular levels, using biomechanics and magnetic microneedle technology, and show for the first time that venous stiffness is regulated by a molecular actin switch within the vascular smooth muscle cell in the wall of the vein. This switch connects the contractile apparatus within the cell to adhesion structures and facilitates stiffening of the vessel wall, regulating blood flow return to the heart. These studies also demonstrate that passive stiffness, the component of total stiffness not attributable to vascular smooth muscle activation, is severalfold lower in venous tissue than in arterial tissue. We show here that the activity of the smooth muscle cells plays a dominant role in determining total venous stiffness and regulating venous return. The literature on arterial mechanics is extensive, but far less is known about mechanisms controlling mechanical properties of veins. We use here a multi-scale approach to identify subcellular sources of venous stiffness. Portal vein tissue displays a severalfold decrease in passive stiffness compared to aortic tissues. The alpha adrenergic agonist phenylephrine (PE) increased tissue stress and stiffness, both attenuated by cytochalasin D (CytoD) and PP2, inhibitors of actin polymerization and Src activity, respectively. We quantify, for the first time, cortical cellular stiffness in freshly isolated contractile vascular smooth muscle cells using magnetic microneedle technology. Cortical stiffness is significantly increased by PE and CytoD inhibits this increase but, surprisingly, PP2 does not. No detectable change in focal adhesion size, measured by immunofluorescence of FAK and zyxin, accompanies the PE-induced changes in cortical stiffness. Probing with phospho-specific antibodies confirmed activation of FAK/Src and ERK pathways and caldesmon phosphorylation. Thus, venous tissue stiffness is regulated both at the level of the smooth muscle cell cortex, via cortical actin polymerization, and by downstream smooth muscle effectors of Src/ERK signalling pathways. These findings identify novel potential molecular targets for the modulation of venous capacitance and venous return in health and disease. PMID- 26096916 TI - The Dermatophagoides farinae group 22 allergen: cloning and expression in Escherichia coli. AB - BACKGROUND: Dermatophagoides farinae (Hughes) (Acari: Pyroglyphidae) and other domestic mites produce allergens that affect people worldwide. Here, the complementary DNA (cDNA) coding for group 22 allergen of D. farinae (Der f 22) from China was cloned, sequenced, and expressed successfully. METHODS: The cDNA encoding Der f 22 was synthesized by reverse transcription polymerase chain reaction (RT-PCR), then ligated to the pCold-TF for expression in Escherichia coli BL21 cells. The purified recombinant fusion protein was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western-blotting, and tandem matrix-assisted laser desorption ionization time-of-flight (MALDI TOF/TOF). RESULTS: The full-length cDNA comprised 468 nucleotides and was 99.57% (466/468) identical with the reference sequence (GenBank: DQ643992). After the plasmid pCold-TF-Der f 22 was transformed into E. coli BL21 and expressed with the induction of IPTG, SDS-PAGE showed a specific band for the recombinant fusion protein. The recombinant fusion protein, which was purified by chromatography, bound with a His-tagged antibody by Western blotting. MALDI-TOF/TOF mass spectrometry revealed that the structure of the recombinant protein was identical to the predicted Der f 22 structure. The hydrophilic protein contains a signal peptide of 20 amino acids, and the mature Der f 22 consists of 135 amino acid residues with a molecular weight of 14.7 kDa and theoretical isoelectric points (pI) of 6.38. Its secondary structure comprises an alpha helix (38.5%), beta sheet (45.9%), random coils (11.85%), and beta-turns (11.1%). CONCLUSION: This work represents the first reported full-length sequence and successful cloning of Der f 22 from D. farinae in China; bioinformatics analysis can be used to further study the allergenicity and clinical utility of the recombinant Der f 22. PMID- 26096917 TI - The thermal unfolding of the ribosome-inactivating protein saporin-S6 characterized by infrared spectroscopy. AB - Saporin-S6 is a plant toxin belonging to the type 1 ribosome-inactivating protein (RIP) family. Since it was extracted and isolated from Saponaria officinalis for the first time almost thirty years ago, the protein has been widely studied mainly for its potential applications in anti-tumour and anti-viral infection therapy. Like other RIPs, saporin-S6 is particularly effective in the form of immunotoxin conjugated with monoclonal antibodies and its chemico-physical characteristics made the protein a perfect candidate for the synthesis, development and use of saporin-S6-based chimeric toxins. The high stability of the protein against different denaturing agents has been broadly demonstrated, however, its complete thermal unfolding characterization has not already been performed. In this work we analyse in detail structure, thermostability and unfolding features by means of infrared spectroscopy coupled with two-dimensional correlation spectroscopy. Our data showed that saporin-S6 in solution at neutral pH exhibits a secondary structure analogue to that of the crystal and confirmed its good stability at moderately high temperatures, with a temperature of melting of 58 degrees C. Our results also demonstrated that the thermal unfolding process is non-cooperative and occurs in two steps, and revealed the sequence of the events that take place during the denaturation, showing a higher stability of the N-terminal domain of the protein. PMID- 26096918 TI - Type 1 diabetes and risk of fracture: meta-analysis and review of the literature. AB - AIMS: To conduct a systematic review and meta-analysis of observational studies in order to assess the association between Type 1 diabetes and fractures. BACKGROUND: The risk of fracture in men and women with Type 1 diabetes has not been studied in a large prospective well designed cohort. METHODS: Data were selected from Medline and Embase and abstracts from annual scientific meetings of various diabetes and bone and mineral societies. Published studies that reported the fracture risk in people with Type 1 diabetes in comparison with people without diabetes between 1990 and July 2014 and abstracts from various annual meeting (2005 onwards) were included in the present meta-analysis. Data were extracted from the text of included publications or from abstracts of conferences. RESULTS: The 14 studies that met the inclusion criteria reported 2066 fracture events among 27 300 people with Type 1 diabetes (7.6%) and 136 579 fracture events among 4 364 125 people without diabetes (3.1%). The pooled relative risk of any fracture in people with Type 1 diabetes was 3.16 (95% CI 1.51-6.63; P = 0.002). Women and men with Type 1 diabetes had a four and two times higher risk of any fractures, respectively, compared with people without diabetes. The pooled relative risks of hip fractures and spinal fractures were 3.78 (95% CI 2.05-6.98; P < 0.001) and 2.88 (95% CI 1.71-4.82; P < 0.001), respectively, among people with Type 1 diabetes. CONCLUSIONS: Our meta-analysis suggests that both men and women with Type 1 diabetes might have an increased risk of any fractures. A large prospective epidemiological study is needed to confirm our findings. PMID- 26096919 TI - Formation of the Delta(18,19) Double Bond and Bis(spiroacetal) in Salinomycin Is Atypically Catalyzed by SlnM, a Methyltransferase-like Enzyme. AB - Salinomycin is a widely used polyether coccidiostat and was recently found to have antitumor activities. However, the mechanism of its biosynthesis remained largely speculative until now. Reported herein is the identification of an unprecedented function of SlnM, homologous to O-methyltransferases, by correlating its activity with the formation of the Delta(18,19) double bond and bis(spiroacetal). Detailed in vivo and in vitro investigations revealed that SlnM, using positively charged S-adenosylmethionine (SAM) or sinefungin as the cofactor, catalyzed the spirocyclization-coupled dehydration of C19 in a highly atypical fashion to yield salinomycin. PMID- 26096920 TI - Recurrent breast carcinoma presenting as postmenopausal vaginal bleeding: A case report. AB - *We discuss the recurrence of breast carcinoma presenting as postmenopausal vaginal bleeding in a patient on Tamoxifen therapy.*Case report illustrates widespread genital tract manifestation of recurrent disease at time of presentation and rapid disease progression.*Discusses the importance of maintaining broad differential in diagnosis of postmenopausal vaginal bleeding. PMID- 26096921 TI - Intense NIR emissions at 0.8 MUm, 1.47 MUm, and 1.53 MUm from colloidal LiYbF4:Ln(3+) (Ln = Tm(3+) and Er(3+)) nanocrystals. AB - We report on the synthesis of diamond shaped Ln(3+)-doped LiYbF4 (Ln = Tm and Er) nanocrystals with flat edges via the thermal decomposition method. Strong near infrared emissions at 0.8 MUm, 1.47 MUm and 1.53 MUm are observed from colloidal dispersions of Tm(3+)-doped and Er(3+)-doped LiYbF4 nanocrystals, respectively, under 0.98 MUm diode laser excitation. The NIR emission intensities for Tm(3+) doped and Er(3+)-doped LiYbF4 nanocrystals are comparable with those of the sodium counterpart NaYbF4, suggesting that LiYbF4 is also an excellent host matrix for lanthanide ions to obtain strong NIR emissions in colloidal solutions of LiYbF4 (Tm(3+) or Er(3+)) nanocrystals. PMID- 26096922 TI - Comparison of Care Provided in Practices With Nurse Practitioners and Physician Assistants Versus Subspecialist Physicians Only: A Cohort Study of Rheumatoid Arthritis. AB - OBJECTIVE: The Affordable Care Act proposes wider use of nurse practitioners (NPs) and physician assistants (PAs), but little is known about outcomes of care provided by them in medical specialties. We compared the outcomes of care for patients with rheumatoid arthritis (RA) seen in practices with NPs or PAs and rheumatologists versus practices with rheumatologists only. METHODS: We enrolled 7 rheumatology practices in the US (4 with NPs or PAs and 3 without). RA disease activity (categorized as in remission, low, moderate, or high, using standardized measures) was abstracted from medical records from the most recent 2 years. We performed a repeated-measures analysis using generalized linear regression to compare disease activity for visits to practices with NPs or PAs versus rheumatologist-only practices, adjusting for disease duration, serologic status, RA treatments, and disease activity measures. RESULTS: Records from 301 patients, representing 1,982 visits, were reviewed. The patients' mean age was 61 years and 77% were female. In the primary adjusted analysis, patients seen in practices with NPs or PAs were less likely to have higher disease activity (odds ratio 0.32, 95% confidence interval 0.17-0.60; P = 0.004) than those seen in rheumatologist-only practices. However, there were no differences in the change in disease activity. CONCLUSION: Patients seen in practices with NPs or PAs had lower RA disease activity over 2 years compared to those seen in rheumatologist only practices; no differences were observed in the change in disease activity between visits either within or between the different types of provider practice. PMID- 26096923 TI - Multifocal noninfectious osteitis as a presentation of pediatric granulomatosis with polyangiitis (Wegener's). PMID- 26096924 TI - Bone Geometry, Volumetric Density, Microarchitecture, and Estimated Bone Strength Assessed by HR-pQCT in Adult Patients With Type 1 Diabetes Mellitus. AB - The primary goal of this cross-sectional in vivo study was to assess peripheral bone microarchitecture, bone strength, and bone remodeling in adult type 1 diabetes (T1D) patients with and without diabetic microvascular disease (MVD+ and MVD-, respectively) and to compare them with age-, gender-, and height-matched healthy control subjects (CoMVD+ and CoMVD-, respectively). The secondary goal was to assess differences in MVD- and MVD+ patients. Fifty-five patients with T1DM (MVD+ group: n = 29) were recruited from the Funen Diabetes Database. Dual energy X-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT) of the ultradistal radius and tibia, and biochemical markers of bone turnover were performed in all participants. There were no significant differences in HR-pQCT parameters between MVD- and CoMVD- subjects. In contrast, MVD+ patients had larger total and trabecular bone areas (p = 0.04 and p = 0.02, respectively), lower total, trabecular, and cortical volumetric bone mineral density (vBMD) (p < 0.01, p < 0.04, and p < 0.02, respectively), and thinner cortex (p = 0.03) at the radius, and lower total and trabecular vBMD (p = 0.01 and p = 0.02, respectively) at the tibia in comparison to CoMVD+. MVD+ patients also exhibited lower total and trabecular vBMD (radius p = 0.01, tibia p < 0.01), trabecular thickness (radius p = 0.01), estimated bone strength, and greater trabecular separation (radius p = 0.01, tibia p < 0.01) and network inhomogeneity (radius p = 0.01, tibia p < 0.01) in comparison to MVD- patients. These differences remained significant after adjustment for age, body mass index, gender, disease duration, and glycemic control (average glycated hemoglobin over the previous 3 years). Although biochemical markers of bone turnover were significantly lower in MVD+ and MVD- groups in comparison to controls, they were similar between the MVD+ and MVD- groups. The results of our study suggest that the presence of MVD was associated with deficits in cortical and trabecular bone vBMD and microarchitecture that could partly explain the excess skeletal fragility observed in these patients. PMID- 26096926 TI - Erythematous Abdominal Papule. PMID- 26096925 TI - Exposure to Mixtures of Metals and Neurodevelopmental Outcomes: A Multidisciplinary Review Using an Adverse Outcome Pathway Framework. AB - Current risk assessment guidance calls for an individual chemical-by-chemical approach that fails to capture potential interactive effects of exposure to environmental mixtures and genetic variability. We conducted a review of the literature on relationships between prenatal and early life exposure to mixtures of lead (Pb), arsenic (As), cadmium (Cd), and manganese (Mn) with neurodevelopmental outcomes. We then used an adverse outcome pathway (AOP) framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD). Toxicological evidence suggests a greater than additive effect of combined exposures to As-Pb-Cd and to Mn with any other metal, and several epidemiologic studies also suggest synergistic effects from binary combinations of Pb-As, Pb-Cd, and Pb-Mn. The exposure levels reported in these epidemiologic studies largely fall at the high-end (e.g., 95th percentile) of biomonitoring data from the National Health and Nutrition Examination Survey (NHANES), suggesting a small but significant potential for high-end exposures. This review integrates multiple data sources using an AOP framework and provides an initial application of the OECD guidance in the context of potential neurodevelopmental toxicity of several metals, recognizing the evolving nature of regulatory interpretation and acceptance. PMID- 26096928 TI - A central role of TRAX in the ATM-mediated DNA repair. AB - DNA repair is critical for the maintenance of genome stability. Upon genotoxic stress, dysregulated DNA repair may induce apoptosis. Translin-associated factor X (TRAX), which was initially identified as a binding partner of Translin, has been implicated in genome stability. However, the exact role of TRAX in DNA repair remains largely unknown. Here, we showed that TRAX participates in the ATM/H2AX-mediated DNA repair machinery by interacting with ATM and stabilizing the MRN complex at double-strand breaks. The exogenous expression of wild-type (WT) TRAX, but not a TRAX variant lacking the nuclear localization signal (NLS), rescued the vulnerability of TRAX-null mouse embryo fibroblasts (MEFs). This finding confirms the importance of the nuclear localization of TRAX in the repair of DNA damage. Compared with WT MEFs, TRAX-null MEFs exhibited impaired DNA repair (for example, reduced phosphorylation of ATM and H2AX) after treatment with ultra violet-C or gamma-ray irradiation and a higher incidence of p53 mediated apoptosis. Our findings demonstrate that TRAX is required for MRN complex-ATM-H2AX signaling, which optimizes DNA repair by interacting with the activated ATM and protects cells from genotoxic stress-induced apoptosis. PMID- 26096929 TI - Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress. AB - In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer. PMID- 26096930 TI - Resistance to HSP90 inhibition involving loss of MCL1 addiction. AB - Inhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality. PMID- 26096932 TI - Integrin alpha1beta1 expression is controlled by c-MYC in colorectal cancer cells. AB - The alpha1beta1 collagen receptor is only present in a few epithelial cell types. In the intestine, it is specifically expressed in proliferating crypt cells. This integrin has been reported to be involved in various cancers where it mediates the downstream activation of the Ras/ERK proliferative pathway. We have recently shown that integrin alpha1beta1 is present in two-thirds of colon adenocarcinomas, but the mechanism by which ITGA1 expression is regulated is not known. DNA methylation, involved in ITGA1 repression during megakaryocyte differentiation, is not the mechanism of ITGA1 regulation in colorectal cancer cells. Our in silico analysis of the ITGA1 promoter revealed two response elements for MYC, an oncogenic factor known to regulate cancer cell proliferation, invasion and migration. In situ, the expressions of both MYC and ITGA1 are localized in the lower crypt of the normal colon and correlate in 72% of the 65 analyzed colorectal cancers. MYC pharmacological inhibition or downregulation of expression with short hairpin RNA in HT29, T84 and SW480 cells resulted in reduced ITGA1 expression at both the transcript and protein levels. Chromatin immunoprecipitation assays revealed that MYC was bound to the chromatin region of the ITGA1 proximal promoter, whereas MYC overexpression enhanced ITGA1 promoter activity that was reduced with MAD co-transfection or by the disruption of the response elements. We concluded that MYC is a key regulating factor for the control of ITGA1 expression. PMID- 26096931 TI - A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development. AB - Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects-latency and tumor load-were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice. PMID- 26096933 TI - Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents. AB - Many human malignancies lack de novo biosynthesis of arginine (Arg) as the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate-early event of Arg-auxotrophic response involves reactive oxygen species-mediated secretion of Gas6, which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression, which provides a feedback mechanism to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 provides a feedback mechanism to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response, consisting of Axl, c-Myc and ASS1, which regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg-deprivation strategies. PMID- 26096935 TI - DeltaNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer. AB - During physiological aerobic metabolism, the epidermis undergoes significant oxidative stress as a result of the production of reactive oxygen species (ROS). To maintain a balanced oxidative state, cells have developed protective antioxidant systems, and preliminary studies suggest that the transcriptional factor p63 is involved in cellular oxidative defence. Supporting this hypothesis, the DeltaNp63alpha isoform of p63 is expressed at high levels in the proliferative basal layer of the epidermis. Here we identify the CYGB gene as a novel transcriptional target of DeltaNp63 that is involved in maintaining epidermal oxidative defence. The CYGB gene encodes cytoglobin, a member of the globin protein family, which facilitates the diffusion of oxygen through tissues and acts as a scavenger for nitric oxide or other ROS. By performing promoter activity assays and chromatin immunoprecipitation, reverse transcriptase quantitative PCR and western blotting analyses, we confirm the direct regulation of CYGB by DeltaNp63alpha. We also demonstrate that CYGB has a protective role in proliferating keratinocytes grown under normal conditions, as well as in cells treated with exogenous hydrogen peroxide. These results indicate that DeltaNp63, through its target CYGB has an important role in the cellular antioxidant system and protects keratinocytes from oxidative stress-induced apoptosis. The DeltaNp63 CYGB axis is also present in lung and breast cancer cell lines, indicating that CYGB-mediated ROS-scavenging activity may also have a role in epithelial tumours. In human lung cancer data sets, the p63-CYGB interaction significantly predicts reduction of patient survival. PMID- 26096934 TI - Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism. AB - Therapy resistance remains a major problem in estrogen receptor-alpha (ERalpha) positive breast cancer. A subgroup of ERalpha-positive breast cancer is characterized by mosaic presence of a minor population of ERalpha-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ERalpha and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ERalpha-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ERalpha+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ERalpha-positive breast cancers. PMID- 26096936 TI - Hyperactivated FRS2alpha-mediated signaling in prostate cancer cells promotes tumor angiogenesis and predicts poor clinical outcome of patients. AB - Metastasis of tumors requires angiogenesis, which is comprised of multiple biological processes that are regulated by angiogenic factors. The fibroblast growth factor (FGF) is a potent angiogenic factor and aberrant FGF signaling is a common property of tumors. Yet, how the aberration in cancer cells contributes to angiogenesis in the tumor is not well understood. Most studies of its angiogenic signaling mechanisms have been in endothelial cells. FGF receptor substrate 2alpha (FRS2alpha) is an FGF receptor-associated protein required for activation of downstream signaling molecules that include those in the mitogen-activated protein and AKT kinase pathways. Herein, we demonstrated that overactivation and hyperactivity of FRS2alpha, as well as overexpression of cJUN and HIF1alpha, were positively correlated with vessel density and progression of human prostate cancer (PCa) toward malignancy. We also demonstrate that FGF upregulated the production of vascular endothelial growth factor A mainly by increasing expression of cJUN and HIF1alpha. This then promoted recruitment of endothelial cells and vessel formation for the tumor. Tumor angiogenesis in mouse PCa tissues was compromised by tissue-specific ablation of Frs2alpha in prostate epithelial cells. Depletion of Frs2alpha expression in human PCa cells and in a preclinical xenograft model, MDA PCa 118b, also significantly suppressed tumor angiogenesis accompanied with decreased tumor growth in the bone. The results underscore the angiogenic role of FRS2alpha-mediated signaling in tumor epithelial cells in angiogenesis. They provide a rationale for treating PCa with inhibitors of FGF signaling. They also demonstrate the potential of overexpressed FRS2alpha as a biomarker for PCa diagnosis, prognosis and response to therapies. PMID- 26096937 TI - Comprehensive translational control of tyrosine kinase expression by upstream open reading frames. AB - Post-transcriptional control has emerged as a major regulatory event in gene expression and often occurs at the level of translation initiation. Although overexpression or constitutive activation of tyrosine kinases (TKs) through gene amplification, translocation or mutation are well-characterized oncogenic events, current knowledge about translational mechanisms of TK activation is scarce. Here, we report the presence of translational cis-regulatory upstream open reading frames (uORFs) in the majority of transcript leader sequences of human TK mRNAs. Genetic ablation of uORF initiation codons in TK transcripts resulted in enhanced translation of the associated downstream main protein-coding sequences (CDSs) in all cases studied. Similarly, experimental removal of uORF start codons in additional non-TK proto-oncogenes, and naturally occurring loss-of-uORF alleles of the c-met proto-oncogene (MET) and the kinase insert domain receptor (KDR), was associated with increased CDS translation. Based on genome-wide sequence analyses we identified polymorphisms in 15.9% of all human genes affecting uORF initiation codons, associated Kozak consensus sequences or uORF related termination codons. Together, these data suggest a comprehensive role of uORF-mediated translational control and delineate how aberrant induction of proto oncogenes through loss-of-function mutations at uORF initiation codons may be involved in the etiology of cancer. We provide a detailed map of uORFs across the human genome to stimulate future research on the pathogenic role of uORFs. PMID- 26096938 TI - Translational regulation of inhibin betaA by TGFbeta via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells. AB - The epithelial-to-mesenchymal transition (EMT) is a cellular process that functions during embryonic development and tissue regeneration, thought to be aberrantly activated in epithelial-derived cancer and has an important role in the process of metastasis. The transforming growth factor (TGF)-beta signaling pathway is a key inducer of EMT and we have elucidated a posttranscriptional mechanism by which TGFbeta modulates expression of select transcripts via the RNA binding protein hnRNP E1 during EMT. One such transcript inhibin betaA is a member of the TGFbeta superfamily. Here, we show by polysome profiling that inhibin betaA is translationally regulated by TGFbeta via hnRNP E1. TGFbeta treatment or knockdown of hnRNP E1 relieves silencing of the inhibin betaA transcript, resulting in increased protein expression and secreted levels of the inhibin betaA homodimer, activin A. Our data indicate that the translational upregulation of inhibin betaA enhances the migration and invasion of cells that have undergone an EMT and promotes cancer progression in vivo. PMID- 26096939 TI - Minimal nocturnal oxygen saturation predicts future subclinical carotid atherosclerosis: the Wisconsin sleep cohort. AB - Previous data on the associations between nocturnal oxygen saturation parameters and carotid atherosclerosis are conflicting. We examined the prospective associations of nocturnal oxygen saturation (SaO2 ) and cardiovascular disease (CVD) risk factors with carotid intima-media thickness (IMT) and plaques. We used data on 689 Wisconsin sleep cohort participants who had baseline overnight polysomnography followed by carotid ultrasonography a mean (SD) of 7.8 (2.5) years later. Far wall common carotid IMT was measured using B-mode ultrasound. Bilateral common, bifurcation and internal carotid artery segments were evaluated for plaque score. Participants (8) were aged 56 years (55% male); 32% had hypertension and mean body mass index (BMI) was 31 (7) kg m(2). Mean and minimum nocturnal SaO2 were 95% (2) and 86% (7), respectively. Mean percentage sleep time with SaO2 < 90% was 2% (8). Both mean (odds ratio [OR]: 0.60 lower plaque count per 5% higher mean SaO2, 95% confidence interval [CI]: 0.38-0.96, P = 0.033) and minimum SaO2 (OR: 0.88 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.80-0.97, P = 0.013) predicted carotid plaque score after adjusting for age, sex and BMI. Minimum SaO2 predicted future plaque score after adding adjustment for traditional CVD risk factors (OR: 0.90 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.81-0.99, P = 0.038). Mean SaO2 was not associated with carotid IMT after CVD risk factor adjustment. We conclude that minimum nocturnal SaO2 is an independent predictor of future carotid plaque burden. Other nocturnal SaO2 parameters are not associated with future carotid IMT or plaques after adjusting for traditional CVD risk factors. PMID- 26096940 TI - Meiotic wave adds extra asymmetry to the development of female chicken gonads. AB - Development of female gonads in the chicken is asymmetric. This asymmetry affects gene expression, morphology, and germ cell development; consequently only the left ovary develops into a functional organ, whereas the right ovary remains vestigial. In males, on the other hand, both gonads develop into functional testes. Here, we revisited the development of asymmetric traits in female (and male) chicken gonads between Hamburger Hamilton stage 16 (HH16) and hatching. At HH16, primordial germ cells migrated preferentially to the left gonad, accumulating in the left coelomic hinge between the gut mesentery and developing gonad in both males and females. Using the meiotic markers SYCP3 and phosphorylated H2AFX, we identified a previously undescribed, pronounced asymmetryc meiotic progression in the germ cells located in the central, lateral, and extreme cortical regions of the left female gonad from HH38 until hatching. Moreover, we observed that--in contrast to the current view--medullary germ cells are not apoptotic, but remain arrested in pre-leptotene until hatching. In addition to the systematic analysis of the asymmetric distribution of germ cells in female chicken gonads, we propose an updated model suggesting that the localization of germ cells--in the left or right gonad; in the cortex or medulla of the left gonad; and in the central part or the extremities of the left cortex- has direct consequences for their development and participation in adult reproduction. PMID- 26096941 TI - Acid-Triggered Degradable Reagents for Differentiation of Adaptive and Innate Immune Responses to Leishmania-Associated Sugars. AB - Lipopolysaccharides (LPS) of Leishmania spp are known to alter innate immune responses. However, the ability of these sugars to specifically alter adaptive T cell responses is unclear. To study cap sugar-T-cell interactions, pathogen mimics (namely glycodendrimer-coated latex beads with acid-labile linkers) were synthesized. Upon lysosomal acidification, linker breakdown releases glycodendrimers for possible loading on antigen presenting molecules to induce T cell growth. T-cell proliferation was indeed higher after macrophage exposure to mannobioside or -trioside-containing glycodendrimers than to non-functionalized beads. Yet, blocking phagolysosomal acidification only reduced T-cell proliferation with macrophages exposed to beads with an acid-labile-linker and not to covalently-linked beads. These sugar-modified reagents show that oligosaccharides alone can drive T-cell proliferation by acidification-requiring presentation, most significantly in NKT receptor (CD160)-restricted T cells. PMID- 26096942 TI - Growth inhibition of luteolin on HepG2 cells is induced via p53 and Fas/Fas ligand besides the TGF-beta pathway. AB - Flavonoids, a class of natural polyphenolic compounds, inhibit cell cycle progression and induce apoptosis. This study was performed to investigate the antiproliferative effect of luteolin, the flavonoid isolated from Ixeris sonchifolia Hance, and to elucidate the detailed apoptotic mechanism in HCC cells. According to the result of MTT assay luteolin possessed antiproliferative effect, and HepG2 cells were the most sensitive to luteolin. Propidium iodide staining, fluorescence activated cell sorting analysis, western blot analysis and RT-PCR were applied to compare the difference of apoptotic event between the two HCC cell lines, with wild-type p53 (HepG2) or not (Hep3B) based on time and concentration. The treatment of luteolin upregulated the expression levels of transforming growth factor beta1 (TGF-beta1), p21WAF1/CIP1, p27KIP1, Smad4, and Fas in HCC cells. Thus, the expression of p21WAF1/CIP1 was controlled by another factor, such as TGF-beta1 in addition to p53, and notably the key factor might be p21WAF1/CIP1 in the remarkable switch to G1 cell cycle arrest in HepG2 cells rather than p27KIP1. Luteolin induced apoptotic cell death in Hep3B cells while caused G1 arrest in HepG2 cells. Taken together, we conclude that luteolin induces apoptosis from G1 arrest via three signaling pathways of TGF-beta1, p53, and Fas/Fas-ligand in HCC cells. PMID- 26096943 TI - Altered amygdalar resting-state connectivity in depression is explained by both genes and environment. AB - Recent findings indicate that alterations of the amygdalar resting-state fMRI connectivity play an important role in the etiology of depression. While both depression and resting-state brain activity are shaped by genes and environment, the relative contribution of genetic and environmental factors mediating the relationship between amygdalar resting-state connectivity and depression remain largely unexplored. Likewise, novel neuroimaging research indicates that different mathematical representations of resting-state fMRI activity patterns are able to embed distinct information relevant to brain health and disease. The present study analyzed the influence of genes and environment on amygdalar resting-state fMRI connectivity, in relation to depression risk. High-resolution resting-state fMRI scans were analyzed to estimate functional connectivity patterns in a sample of 48 twins (24 monozygotic pairs) informative for depressive psychopathology (6 concordant, 8 discordant and 10 healthy control pairs). A graph-theoretical framework was employed to construct brain networks using two methods: (i) the conventional approach of filtered BOLD fMRI time series and (ii) analytic components of this fMRI activity. Results using both methods indicate that depression risk is increased by environmental factors altering amygdalar connectivity. When analyzing the analytic components of the BOLD fMRI time-series, genetic factors altering the amygdala neural activity at rest show an important contribution to depression risk. Overall, these findings show that both genes and environment modify different patterns the amygdala resting-state connectivity to increase depression risk. The genetic relationship between amygdalar connectivity and depression may be better elicited by examining analytic components of the brain resting-state BOLD fMRI signals. PMID- 26096944 TI - Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011. AB - The World Health Organization classification of non-Hodgkin lymphoma (NHL) was introduced in 2001. However, its incorporation into clinical practice is not well described. We studied the distribution of NHL subtypes in adults diagnosed from 1998 to 2011, evaluated time trends, geo-demographic correlates, and changes in 5 year overall survival (OS). We obtained data prospectively collected by the National Cancer Data Base, which covers 70% of US cancer cases. There were 596,476 patients diagnosed with NHL. The major subtypes were diffuse large B-cell (32.5%), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 18.6%), follicular (17.1%), marginal zone (8.3%), mantle cell (4.1%), peripheral T-cell not-otherwise-specified (1.7%), Burkitt (1.6%), hairy cell (1.1%), lymphoplasmacytic (1.1%), and NHL not-otherwise-specified (10.8%). Over the study period, the proportion of NHL not-otherwise-specified declined by half, while marginal zone lymphoma doubled. The distribution of major and rare NHL subtypes varied according to demographics but less so geographically or by type of treatment facility. We noted several novel findings among Hispanics (lower proportion of CLL/SLL, but higher Burkitt lymphoma and nasal NK/T-cell lymphoma), Asians (higher enteropathy-associated T-cell and angioimmunoblastic T-cell lymphomas), Blacks (higher hepatosplenic T-cell lymphoma), and Native Americans (similar proportions of CLL/SLL and nasal NK/T-cell lymphoma as Asians). With the exception of peripheral T-cell not-otherwise-specified and hairy cell leukemia, 5 year OS has improved for all the major NHL subtypes. PMID- 26096945 TI - Experimental and theoretical dosimetry of the RIC-100 phosphorus-32 brachytherapy source for implant geometries encountered in the intraoperative setting. AB - PURPOSE: Experimental and theoretical dosimetry of the RIC-100 phosphorus-32 brachytherapy source is presented for implant geometries that may occur in an intraoperative setting during treatment of localized spinal tumors with temporary superficial radiation. Dose variation, due to source shape and size, is evaluated, and nonideal implant conditions are simulated. METHODS AND MATERIALS: Calibration, depth dose, and dose profiles were evaluated for several implant geometries and source sizes. Experimental measurements were performed using EBT3 gafchromic film. Theoretical calculations were performed using dose point kernel (DPK) formalism, which simulates isotropic, monoenergetic point sources distributed uniformly throughout the source and emitting electrons radially outward. RESULTS: Calibration and depth dose for RIC-100 are independent of source size for diameters >1 cm. Sources should be ordered with physical dimensions ~0.2 cm larger than the target size, in all dimensions, to deliver >90% prescription dose to target edges. Relative dose profile shape is approximately constant as a function of target depth. Air gaps between the source and target cause narrower dose profile widths and shallower depth dose in the therapeutic range. DPK for RIC-100 agrees with published P-32 kernels, and DPK calculations agree with measurement (within 5%) for many depths and geometries. CONCLUSIONS: Intraoperative placement and measurement dosimetry of RIC-100 require careful setup due to steep dose gradients. Physical source dimensions should be chosen carefully based on treatment site dimensions, and air gaps between source and target should be minimized, to prevent underdosing the target in the lateral extent. Radiological scaling should be used to calculate expected dose when nonwater materials are used in experimental measurements, such as calibration or depth dose. PMID- 26096946 TI - Pyrrolo-dC Metal-Mediated Base Pairs in the Reverse Watson-Crick Double Helix: Enhanced Stability of Parallel DNA and Impact of 6-Pyridinyl Residues on Fluorescence and Silver-Ion Binding. AB - Reverse Watson-Crick DNA with parallel-strand orientation (ps DNA) has been constructed. Pyrrolo-dC (PyrdC) nucleosides with phenyl and pyridinyl residues linked to the 6 position of the pyrrolo[2,3-d]pyrimidine base have been incorporated in 12- and 25-mer oligonucleotide duplexes and utilized as silver ion binding sites. Thermal-stability studies on the parallel DNA strands demonstrated extremely strong silver-ion binding and strongly enhanced duplex stability. Stoichiometric UV and fluorescence titration experiments verified that a single (2py) PyrdC-(2py) PyrdC pair captures two silver ions in ps DNA. A structure for the PyrdC silver-ion base pair that aligns 7-deazapurine bases head to-tail instead of head-to-head, as suggested for canonical DNA, is proposed. The silver DNA double helix represents the first example of a ps DNA structure built up of bidentate and tridentate reverse Watson-Crick base pairs stabilized by a dinuclear silver-mediated PyrdC pair. PMID- 26096947 TI - Predicting long-term temperature increase for time-dependent SAR levels with a single short-term temperature response. AB - PURPOSE: Present a novel method for rapid prediction of temperature in vivo for a series of pulse sequences with differing levels and distributions of specific energy absorption rate (SAR). THEORY AND METHODS: After the temperature response to a brief period of heating is characterized, a rapid estimate of temperature during a series of periods at different heating levels is made using a linear heat equation and impulse-response (IR) concepts. Here the initial characterization and long-term prediction for a complete spine exam are made with the Pennes' bioheat equation where, at first, core body temperature is allowed to increase and local perfusion is not. Then corrections through time allowing variation in local perfusion are introduced. RESULTS: The fast IR-based method predicted maximum temperature increase within 1% of that with a full finite difference simulation, but required less than 3.5% of the computation time. Even higher accelerations are possible depending on the time step size chosen, with loss in temporal resolution. Correction for temperature-dependent perfusion requires negligible additional time and can be adjusted to be more or less conservative than the corresponding finite difference simulation. CONCLUSION: With appropriate methods, it is possible to rapidly predict temperature increase throughout the body for actual MR examinations. PMID- 26096949 TI - Phenotypic plasticity and divergence in gene expression. AB - The extent to which phenotypic plasticity, or the ability of a single genotype to produce different phenotypes in different environments, impedes or promotes genetic divergence has been a matter of debate within evolutionary biology for many decades (see, for example, Ghalambor et al. ; Pfennig et al. ). Similarly, the role of evolution in shaping phenotypic plasticity remains poorly understood (Pigliucci ). In this issue of Molecular Ecology, Dayan et al. () provide empirical data relevant to these questions by assessing the extent of plasticity and divergence in the expression levels of 2272 genes in muscle tissue from killifish (genus Fundulus) exposed to different temperatures. F. heteroclitus (Fig. A) and F. grandis are minnows that inhabit estuarine marshes (Fig. B) along the coasts of the Atlantic Ocean and Gulf of Mexico in North America. These habitats undergo large variations in temperature both daily and seasonally, and these fish are known to demonstrate substantial phenotypic plasticity in response to temperature change (e.g. Fangue et al. ). Furthermore, the range of F. heteroclitus spans a large latitudinal gradient of temperatures, such that northern populations experience temperatures that are on average ~10 degrees C colder than do southern populations (Schulte ). By comparing gene expression patterns between populations of these fish from different thermal habitats held in the laboratory at three different temperatures, Dayan et al. () address two important questions regarding the interacting effects of plasticity and evolution: (i) How does phenotypic plasticity affect adaptive divergence? and (ii) How does adaptive divergence affect plasticity? PMID- 26096948 TI - Recombinant Expression and Phenotypic Screening of a Bioactive Cyclotide Against alpha-Synuclein-Induced Cytotoxicity in Baker's Yeast. AB - We report for the first time the recombinant expression of fully folded bioactive cyclotides inside live yeast cells by using intracellular protein trans-splicing in combination with a highly efficient split-intein. This approach was successfully used to produce the naturally occurring cyclotide MCoTI-I and the engineered bioactive cyclotide MCoCP4. Cyclotide MCoCP4 was shown to reduce the toxicity of human alpha-synuclein in live yeast cells. Cyclotide MCoCP4 was selected by phenotypic screening from cells transformed with a mixture of plasmids encoding MCoCP4 and inactive cyclotide MCoTI-I in a ratio of 1:5*10(4). This demonstrates the potential for using yeast to perform phenotypic screening of genetically encoded cyclotide-based libraries in eukaryotic cells. PMID- 26096952 TI - Thermodynamic Solubility Profile of Carbamazepine-Cinnamic Acid Cocrystal at Different pH. AB - Pharmaceutical cocrystal formation is a direct way to dramatically influence physicochemical properties of drug substances, especially their solubility and dissolution rate. Because of their instability in the solution, thermodynamic solubility of cocrystals could not be determined in the common way like other compounds; therefore, the thermodynamic solubility is calculated through concentration of their components in the eutectic point. The objective of this study is to investigate the effect of an ionizable coformer in cocrystal with a nonionizable drug at different pH. Carbamazepine (CBZ), a nonionizable drug with cinnamic acid (CIN), which is an acidic coformer, was selected to prepare CBZ-CIN cocrystal and its thermodynamic solubility was studied in pH range 2-7. Instead of HPLC that is a costly and time-consuming method, a chemometric-based approach, net analyte signal standard addition method, was selected for simultaneous determination of CBZ and CIN in solution. The result showed that, as pH increases, CIN ionization leads to change in CBZ-CIN cocrystal solubility and stability in solution. In addition, the results of this study indicated that there is no significant difference between intrinsic solubility of CBZ and cocrystal despite the higher ideal solubility of cocrystal. This verifies that ideal solubility is not good parameter to predict cocrystal solubility. PMID- 26096951 TI - Prosthetic joint infections in the elderly. AB - INTRODUCTION: Recent age-projection showed that the number of elderly is expected to rise significantly over the next decades worldwide. Accordingly, the prevalence of chronic and degenerative diseases will increase, among them osteoarthritis, resulting in more and older patients undergoing total joint arthroplasty and thereby also being at risk for associated complications. Among those, prosthetic joint infections are feared as threatening complication with a mortality approaching 8 % and causing long-term antibiotic therapy, immobilization and often account for operative revision. MATERIALS AND METHODS: This review summarizes epidemiological, microbiological, and therapeutic aspects of prosthetic joint infection in the elderly population. CONCLUSION: Considering the increase in the number of PJIs in the forthcoming years in most countries, a common action to reduce the associated morbidity and mortality is strongly encouraged in Europe. PMID- 26096953 TI - Fluid restriction during exercise in the heat reduces tolerance to progressive central hypovolaemia. AB - NEW FINDINGS: What is the central question of this study? Interactions between dehydration, as occurs during exercise in the heat without fluid replacement, and hyperthermia on the ability to tolerate central hypovolaemia are unknown. What is the main finding and its importance? We show that inadequate fluid intake during exercise in the heat can impair tolerance to central hypovolaemia even when it elicits only mild dehydration. These findings suggest that hydration during physical work in the heat has important military and occupational relevance for protection against the adverse effects of a subsequent haemorrhagic injury. This study tested the hypothesis that dehydration induced via exercise in the heat impairs tolerance to central hypovolaemia. Eleven male subjects (32 +/- 7 years old, 81.5 +/- 11.1 kg) walked (O2 uptake 1.7 +/- 0.4 l min(-1) ) in a 40 degrees C, 30% relative humidity environment on three occasions, as follows: (i) subjects walked for 90 min, drinking water to offset sweat loss (Hydrated, n = 11); (ii) water intake was restricted, and exercise was terminated when intestinal temperature increased to the same level as in the Hydrated trial (Isothermic Dehydrated, n = 11); and (iii) water intake was restricted, and exercise duration was 90 min (Time Match Dehydrated, n = 9). For each trial, tolerance to central hypovolaemia was determined following exercise via progressive lower body negative pressure and quantified as time to presyncope. Increases in intestinal temperature prior to lower body negative pressure were not different (P = 0.91) between Hydrated (1.1 +/- 0.4 degrees C) and Isothermic Dehydrated trials (1.1 +/ 0.4 degrees C), but both were lower than in the Time Match Dehydrated trial (1.7 +/- 0.5 degrees C, P < 0.01). Prior to lower body negative pressure, body weight was unchanged in the Hydrated trial (-0.1 +/- 0.2%), but was reduced in Isothermic Dehydrated (-0.9 +/- 0.4%) and further so in Time Match Dehydrated trial (-1.9 +/- 0.6%, all P < 0.01). Time to presyncope was greater in Hydrated (14.7 +/- 3.2 min) compared with Isothermic Dehydrated (11.9 +/- 3.3 min, P < 0.01) and Time Match Dehydrated trials (10.2 +/- 1.6 min, P = 0.03), which were not different (P = 0.19). These data indicate that inadequate fluid intake during exercise in the heat reduces tolerance to central hypovolaemia independent of increases in body temperature. PMID- 26096954 TI - Multi-objective LQR with optimum weight selection to design FOPID controllers for delayed fractional order processes. AB - An optimal trade-off design for fractional order (FO)-PID controller is proposed with a Linear Quadratic Regulator (LQR) based technique using two conflicting time domain objectives. A class of delayed FO systems with single non-integer order element, exhibiting both sluggish and oscillatory open loop responses, have been controlled here. The FO time delay processes are handled within a multi objective optimization (MOO) formalism of LQR based FOPID design. A comparison is made between two contemporary approaches of stabilizing time-delay systems withinLQR. The MOO control design methodology yields the Pareto optimal trade-off solutions between the tracking performance and total variation (TV) of the control signal. Tuning rules are formed for the optimal LQR-FOPID controller parameters, using median of the non-dominated Pareto solutions to handle delayed FO processes. PMID- 26096955 TI - Guaranteed cost control of mobile sensor networks with Markov switching topologies. AB - This paper investigates the consensus seeking problem of mobile sensor networks (MSNs) with random switching topologies. The network communication topologies are composed of a set of directed graphs (or digraph) with a spanning tree. The switching of topologies is governed by a Markov chain. The consensus seeking problem is addressed by introducing a global topology-aware linear quadratic (LQ) cost as the performance measure. By state transformation, the consensus problem is transformed to the stabilization of a Markovian jump system with guaranteed cost. A sufficient condition for global mean-square consensus is derived in the context of stochastic stability analysis of Markovian jump systems. A computational algorithm is given to synchronously calculate both the sub-optimal consensus controller gains and the sub-minimum upper bound of the cost. The effectiveness of the proposed design method is illustrated by three numerical examples. PMID- 26096956 TI - Stability of uncertain impulsive complex-variable chaotic systems with time varying delays. AB - In this paper, the robust exponential stabilization of uncertain impulsive complex-variable chaotic delayed systems is considered with parameters perturbation and delayed impulses. It is assumed that the considered complex variable chaotic systems have bounded parametric uncertainties together with the state variables on the impulses related to the time-varying delays. Based on the theories of adaptive control and impulsive control, some less conservative and easily verified stability criteria are established for a class of complex variable chaotic delayed systems with delayed impulses. Some numerical simulations are given to validate the effectiveness of the proposed criteria of impulsive stabilization for uncertain complex-variable chaotic delayed systems. PMID- 26096957 TI - Robust stability criterion for fractional-order systems with interval uncertain coefficients and a time-delay. AB - This study investigates the robust stability of fractional-order systems with interval coefficients and a time-delay. By the Minkowski Sum, the vertices of value set with respect to the characteristic function of the investigated fractional-order system are offered, avoiding the calculations of the redundant vertices. Meanwhile, a function depending on the obtained vertices is defined to represent the position relationship between the origin and the value set. Based on the zero exclusion principle, we propose sufficient and necessary conditions to determine the robust stability of fractional-order systems with interval uncertain coefficients and a time-delay. Finally, illustrative examples are offered to verify the effectiveness of the proposed robust stability criterion. PMID- 26096958 TI - Maternal and fetal capillary malformation-arteriovenous malformation (CM-AVM) due to a novel RASA1 mutation presenting with prenatal non-immune hydrops fetalis. AB - RASA1 mutations have been shown to cause capillary malformation-arteriovenous malformation (CM-AVM). We describe a patient with CM-AVM and a fetus who presented with non-immune hydrops fetalis during the pregnancy. Sequencing revealed a novel RASA1 mutation in the RASGAP domain that results in a loss of function of p120-RasGap. This report expands our current genetic and clinical understanding of CM-AVM in pregnancy. PMID- 26096959 TI - pH-Responsive H-Type PMAA2 -b-HTPBN-b-PMAA2 Four-Arm Star Block Copolymer Micelles for PTX Drug Release. AB - pH-Responsive H-type poly(methylacrylic acid-block-four hydroxyl terminated poly(butadiene-acrylobitrile)-block-poly(methylacrylic acid (PMAA2 -b-HTPBN-b PMAA2 ) block copolymers were synthesized via atom transfer radical polymerization and the follow-up hydrolysis, and characterized by (1) H NMR, FT IR and SEC. The block copolymers could self-assemble into nanoscale spherical core-shell micelle aggregates in aqueous solution, and the physicochemical properties depended on the system composition and pH media, with pH phase transition at 5.7-6.1. The copolymer micelle aggregates exhibited pH-triggered drug release and cytotoxicity, and could potentially be used as drug targeting release carriers. PMID- 26096960 TI - Optimization of Picrosirius red staining protocol to determine collagen fiber orientations in vaginal and uterine cervical tissues by Mueller polarized microscopy. AB - Polarized microscopy provides unique information on anisotropic samples. In its most complete implementation, namely Mueller microscopy, this technique is well suited for the visualization of fibrillar proteins orientations, with collagen in the first place. However, the intrinsic optical anisotropy of unstained tissues has to be enhanced by Picrosirius Red (PR) staining to enable Mueller measurements. In this work, we compared the orientation mapping provided by Mueller and second harmonic generation (SHG) microscopies on PR stained samples of vaginal and uterine cervix tissues. SHG is a multiphoton technique that is highly specific to fibrillar collagen, and was taken as the "gold standard" for its visualization. We showed that Mueller microscopy can be safely used to determine collagen orientation in PR stained cervical tissue. In contrast, in vaginal samples, Mueller microscopy revealed orientations not only of collagen but also of other anisotropic structures. Thus PR is not fully specific to collagen, which necessitates comparison to SHG microscopy in every type of tissue. In addition to this study of PR specificity, we determined the optimal values of the staining parameters. We found that staining times of 5 min, and sample thicknesses of 5 um were sufficient in cervical and vaginal tissues. PMID- 26096961 TI - Simultaneous quantification of atenolol and chlorthalidone in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry. AB - A simple, sensitive and reproducible ultra-performance liquid chromatography tandem mass spectrometry method has been developed for the simultaneous determination of atenolol, a beta-adrenergic receptor-blocker and chlorthalidone, a monosulfonamyl diuretic in human plasma, using atenolol-d7 and chlorthalidone d4 as the internal standards (ISs). Following solid-phase extraction on Phenomenex Strata-X cartridges using 100 MUL human plasma sample, the analytes and ISs were separated on an Acquity UPLC BEH C18 (50 mm * 2.1 mm, 1.7 um) column using a mobile phase consisting of 0.1% formic acid-acetonitrile (25:75, v/v). A tandem mass spectrometer equipped with electrospray ionization was used as a detector in the positive ionization mode for both analytes. The linear concentration range was established as 0.50-500 ng/mL for atenolol and 0.25-150 ng/mL for chlorthalidone. Extraction recoveries were within 95-103% and ion suppression/enhancement, expressed as IS-normalized matrix factors, ranged from 0.95 to 1.06 for both the analytes. Intra-batch and inter-batch precision (CV) and accuracy values were 2.37-5.91 and 96.1-103.2%, respectively. Stability of analytes in plasma was evaluated under different conditions, such as bench-top, freeze-thaw, dry and wet extract and long-term. The developed method was superior to the existing methods for the simultaneous determination of atenolol and chlorthalidone in human plasma with respect to the sensitivity, chromatographic analysis time and plasma volume for processing. Further, it was successfully applied to support a bioequivalence study of 50 mg atenolol + 12.5 mg chlorthalidone in 28 healthy Indian subjects. PMID- 26096962 TI - G-CSF contributes at the healing of tunica media of arteriotomy-injured rat carotids by promoting differentiation of vascular smooth muscle cells. AB - Restenosis is a complex pathophysiological disease whose causative mechanisms are not fully understood. Previous studies allowed us to demonstrate the efficacy of bone marrow mesenchymal stromal cells (MSCs) transplantation in limiting the pathophysiological remodeling in a model of arteriotomy-induced (re) stenosis. In the current research we studied the effectiveness of G-CSF treatment on male rate rats that were subjected carotid arteriotomy in order to evaluate a potentially effective non-invasive strategy that recapitulates the MSC-mediated recovery of injured vessels. WKY male rats were subjected carotid arteriotomy and given a nine day treatment (3 days pre- to 6 days post-arteriotomy) with G-CSF or saline. Carotids were harvested 7 and 30 days following arteriotomy (early- and late phase, respectively). Although morphometrical analysis did not reveal differences in lumen narrowing between G-CSF- and PBS-carotids 30 days following arteriotomy, we detected a noticeable conservative effect of G-CSF treatment on vascular wall morphology. Histological and molecular analysis revealed an increase in cellularity within the tunica media with a concomitant increase of the VSMCs differentiation markers both at early- and late-phases of (re) stenotic response in G-CSF-treated carotids (Sm22-alpha, Myocd, and Smtn). These findings were accompanied by the downregulation of oxidative stress-related genes in G-CSF injured rats. The effect exerted by G-CSF in our model of arteriotomy-induced (re) stenosis seemed support the recovery of the architecture of the tunica media of injured vessels by: (i) inducing VSMCs differentiation; and (ii) limiting the oxidative-stress response induced by arteriotomy. PMID- 26096963 TI - Glycosaminoglycan and DNA Binding Induced Intra- and Intermolecular Exciton Coupling of the bis-4-Aminoquinoline Surfen. AB - Despite the diverse biological activities of the glycosaminoglycan (GAG) antagonist surfen, the molecular details of its interaction with biomacromolecules remain poorly understood. Therefore, heparin and DNA binding properties of surfen were studied by circular dichroism (CD) and UV absorption spectroscopy methods. High-affinity (Ka ~ 10(7) M(-1)) association of surfen to the chiral heparin chain gives rise to a characteristic biphasic CD pattern due to the conformational twist of the aminoquinoline moieties around the central urea bridge. At higher drug loading, intermolecular stacking of surfen molecules alters the induced CD profile and also provokes strong UV hypochromism. In contrast to the right-handed heparin template, binding of surfen to the left helicity chondroitin sulfate chains produces inverted CD pattern. Large UV hypochromism as well as polyphasic induced ellipticity bands indicate that surfen intercalates between the base pairs of calf-thymus DNA. Extensive CD spectroscopic changes observed at higher drug binding ratios refer to cooperative binding interactions between the intercalated drug molecules. The inherent conformational flexibility of surfen demonstrated here for the first time is important in its binding to distinct macromolecular targets and should be considered for rational drug design of novel GAG antagonists. PMID- 26096964 TI - Epidemiology and genetic characterization of BVDV, BHV-1, BHV-4, BHV-5 and Brucella spp. infections in cattle in Turkey. AB - The aim of the study was to determine the epidemiological data of bovine viral diarrhea virus (BVDV), bovine herpesvirus-1 (BHV-1), bovine herpesvirus-4 (BHV 4), bovine herpesvirus-5 (BHV-5) and Brucella-associated cattle that were previously reported to have abortion and infertility problems in Ankara, Corum, Kirikkale and Yozgat provinces, Turkey. Whole blood and sera samples were obtained from 656 cattle, and antibodies against Brucella spp. were detected in 45 (6.86%) and 41 (6.25%) animals by Rose Bengal plate and serum tube agglutination tests, respectively. The seropositivity rates against BVDV, BHV-1 and BHV-4 were 70.89%, 41.3% and 28.78%, respectively. RT-PCR and PCR were performed to detect RNA and DNA viruses in blood samples, respectively. The BVDV 5'-untranslated region and BHV-1 gB gene detected in this study were phylogenetically analyzed. The BVDV strains analyzed in this study were closely related to those previously reported from Turkey. The nucleotide sequence from the BHV-1 strain detected in this study is the first nucleotide sequence of BHV-1 circulating in this area of Turkey deposited in the GenBank. The presence of Brucella spp. and prevalence of BHV-1, BHV-4 and BVDV in cattle should be further investigated throughout these regions. PMID- 26096965 TI - Immunohistochemical analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity on the developmental dentate gyrus and hippocampal fimbria in fetal mice. AB - Dioxins are widespread persistent environmental contaminants with adverse impacts on humans and experimental animals. Behavioral and cognitive functions are impaired by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. TCDD exerts its toxicity via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. The hippocampus, which plays important roles in episodic memory and spatial function, is considered vulnerable to TCDD-induced neurotoxicity, because it contains the AhR. We herein investigated the effects of TCDD toxicity on hippocampal development in embryonic mice. TCDD was administered to dams at 8.5 days postcoitum with a single dose of 20, 200, 2,000 and 5,000 ng/kg body weight (groups T20, T200, T2000 and T5000, respectively), and the brains were dissected from their pups at embryonic day 18.5. Immunohistochemical analysis demonstrated that the Glial Fibrillary Acidic Protein (GFAP) immunoreactivities in the dentate gyrus (DG) were reduced in the T5000 group. Granular GFAP immunoreactivity was observed in the hippocampal fimbria, and the number of immunoreactive fimbria was significantly decreased in the T5000 group. The number of Proliferating Cell Nuclear Antigen (PCNA)-positive cells was decreased in all TCDD-exposed groups and significantly reduced in the T20, T200 and T5000 groups. Together, these results demonstrate that maternal TCDD exposure has adverse impacts on neural stem cells (NSCs), neural precursor cells (NPCs) and granular cells in the DG and disrupts the NSC maintenance and timing of differentiation in the hippocampal fimbria, which in turn interrupt neuronal development in future generations of mice. PMID- 26096967 TI - Perception of photoperiod in individual buds of mature trees regulates leaf-out. AB - Experimental data on the perception of day length and temperature in dormant temperate zone trees are surprisingly scarce. In order to investigate when and where these environmental signals are perceived, we carried out bagging experiments in which buds on branches of Fagus sylvatica, Aesculus hippocastanum and Picea abies trees were exposed to natural light increase or kept at constant 8-h days from December until June. Parallel experiments used twigs cut from the same trees, harvesting treated and control twigs seven times and then exposing them to 8- or 16-h days in a glasshouse. Under 8-h days, budburst in Fagus outdoors was delayed by 41 d and in Aesculus by 4 d; in Picea, day length had no effect. Buds on nearby branches reacted autonomously, and leaf primordia only reacted to light cues in late dormancy after accumulating warm days. Experiments applying different wavelength spectra and high-resolution spectrometry to buds indicate a phytochrome-mediated photoperiod control. By demonstrating local photoperiodic control of buds, revealing the time when these signals are perceived, and showing the interplay between photoperiod and chilling, this study contributes to improved modelling of the impact of climate warming on photosensitive species. PMID- 26096969 TI - Innovation and cross-fertilization in systematic reviews and meta-analysis: The influence of women investigators. PMID- 26096968 TI - The production of KIR-Fc fusion proteins and their use in a multiplex HLA class I binding assay. AB - Soluble recombinant proteins that comprise the extracellular part of a surface expressed receptor attached to the Fc region of an IgG antibody have facilitated the determination of ligand specificity for an array of immune system receptors. Among such receptors is the family of killer cell immunoglobulin-like receptors (KIR) that recognize HLA class I ligands. These receptors, expressed on natural killer (NK) cells and T cells, play important roles in both immune defense and placental development in early pregnancy. Here we describe a method for the production of two domain KIR-Fc fusion proteins using baculovirus infected insect cells. This method is more scalable than traditional mammalian cell expression systems and produces efficiently folded proteins that carry posttranslational modifications found in native KIR. We also describe a multiplex binding assay using the Luminex platform that determines the avidity and specificity of two domain KIR-Fc for a panel of microbeads, each coated with one of 97 HLA class I allotypes. This assay is simple to perform, and represents a major improvement over the assays used previously, which were limited in the number of KIR and HLA class I combinations that could be assayed at any one time. The results obtained from this assay can be used to predict the response of NK cell and T cells when their KIR recognize HLA class I. PMID- 26096970 TI - Dynamics of Inductive ERK Signaling in the Drosophila Embryo. AB - Transient activation of the highly conserved extracellular-signal-regulated kinase (ERK) establishes precise patterns of cell fates in developing tissues. Quantitative parameters of these transients are essentially unknown, but a growing number of studies suggest that changes in these parameters can lead to a broad spectrum of developmental abnormalities. We provide a detailed quantitative picture of an ERK-dependent inductive signaling event in the early Drosophila embryo, an experimental system that offers unique opportunities for high throughput studies of developmental signaling. Our analysis reveals a spatiotemporal pulse of ERK activation that is consistent with a model in which transient production of a short-ranged ligand feeds into a simple signal interpretation system. The pulse of ERK signaling acts as a switch in controlling the expression of the ERK target gene. The quantitative approach that led to this model, based on the integration of data from fixed embryos and live imaging, can be extended to other developmental systems patterned by transient inductive signals. PMID- 26096971 TI - Effects of Anxiety on Spontaneous Ritualized Behavior. AB - Environmental uncertainty and uncontrollability cause psycho-physiological distress to organisms, often impeding normal functioning. A common response involves ritualization, that is, the limitation of behavioral expressions to predictable stereotypic and repetitive motor patterns. In humans, such behaviors are also symptomatic of psychopathologies like obsessive-compulsive disorder (OCD) and autism spectrum disorders (ASDs). Although these reactions might be mediated by different neural pathways, they serve to regain a sense of control over an uncertain situation by engaging in behavioral patterns characterized by redundancy (superfluous actions that exceed the functional requirements of a goal), repetitiveness (recurrent behaviors or utterances), and rigidity (emphasis on fidelity and invariance). We examined whether ritualized behavior will manifest spontaneously as a dominant behavioral strategy in anxiogenic situations. Manipulating anxiety, we used motion-capture technology to quantify various characteristics of hand movements. We found that induced anxiety led to an increase in repetitiveness and rigidity, but not redundancy. However, examination of both psychological and physiological pathways revealed that repetitiveness and rigidity were predicted by an increase in heart rate, while self-perceived anxiety was a marginally significant predictor of redundancy. We suggest that these findings are in accordance with an entropy model of uncertainty, in which anxiety motivates organisms to return to familiar low entropy states in order to regain a sense of control. Our results might inform a better understanding of ritual behavior and psychiatric disorders whose symptoms include over-ritualization. PMID- 26096972 TI - Parallel Emergence of True Handedness in the Evolution of Marsupials and Placentals. AB - Recent studies have demonstrated a close resemblance between some handedness patterns in great apes and humans. Despite this, comparative systematic investigations of manual lateralization in non-primate mammals are very limited. Among mammals, robust population-level handedness is still considered to be a distinctive human trait. Nevertheless, the comprehensive understanding of handedness evolution in mammals cannot be achieved without considering the other large mammalian lineage, marsupials. This study was designed to investigate manual lateralization in non-primate mammals using the methodological approach applied in primate studies. Here we show that bipedal macropod marsupials display left-forelimb preference at the population level in a variety of behaviors in the wild. In eastern gray and red kangaroos, we found consistent manual lateralization across multiple behaviors. This result challenges the notion that in mammals the emergence of strong "true" handedness is a unique feature of primate evolution. The robust lateralization in bipedal marsupials stands in contrast to the relatively weak forelimb preferences in marsupial quadrupeds, emphasizing the role of postural characteristics in the evolution of manual lateralization as previously suggested for primates. Comparison of forelimb preferences in seven marsupial species leads to the conclusion that the interspecies differences in manual lateralization cannot be explained by phylogenetic relations, but rather are shaped by ecological adaptations. Species' postural characteristics, especially bipedality, are argued to be instrumental in the origin of handedness in mammals. PMID- 26096973 TI - Misato Controls Mitotic Microtubule Generation by Stabilizing the TCP-1 Tubulin Chaperone Complex [corrected]. AB - Mitotic spindles are primarily composed of microtubules (MTs), generated by polymerization of alpha- and beta-Tubulin hetero-dimers. Tubulins undergo a series of protein folding and post-translational modifications in order to fulfill their functions. Defects in Tubulin polymerization dramatically affect spindle formation and disrupt chromosome segregation. We recently described a role for the product of the conserved misato (mst) gene in regulating mitotic MT generation in flies, but the molecular function of Mst remains unknown. Here, we use affinity purification mass spectrometry (AP-MS) to identify interacting partners of Mst in the Drosophila embryo. We demonstrate that Mst associates stoichiometrically with the hetero-octameric Tubulin Chaperone Protein-1 (TCP-1) complex, with the hetero-hexameric Tubulin Prefoldin complex, and with proteins having conserved roles in generating MT-competent Tubulin. We show that RNAi mediated in vivo depletion of any TCP-1 subunit phenocopies the effects of mutations in mst or the Prefoldin-encoding gene merry-go-round (mgr), leading to monopolar and disorganized mitotic spindles containing few MTs. Crucially, we demonstrate that Mst, but not Mgr, is required for TCP-1 complex stability and that both the efficiency of Tubulin polymerization and Tubulin stability are drastically compromised in mst mutants. Moreover, our structural bioinformatic analyses indicate that Mst resembles the three-dimensional structure of Tubulin monomers and might therefore occupy the TCP-1 complex central cavity. Collectively, our results suggest that Mst acts as a co-factor of the TCP-1 complex, playing an essential role in the Tubulin-folding processes required for proper assembly of spindle MTs. PMID- 26096974 TI - WHAMM Directs the Arp2/3 Complex to the ER for Autophagosome Biogenesis through an Actin Comet Tail Mechanism. AB - Nucleation-promoting factors (NPFs) control the spatio-temporal activity of Arp2/3 complex in cells]. Thus, WASP and the WAVE complex direct the formation of branched actin networks at the leading edge during cell motility and endo/exocytosis, whereas the WASH complex is involved in endosomal transport. Less understood are WHAMM and JMY, two NPFs with similar domain architecture. JMY is found in the nucleus and the cytosol and is involved in transcriptional regulation, cell motility, and trans-Golgi transport. WHAMM was reported to bind microtubules and to be involved in ER to cis-Golgi transport. Here, we show that WHAMM directs the activity of Arp2/3 complex for autophagosome biogenesis through an actin-comet tail motility mechanism. Macroautophagy--the process by which cytosolic material is engulfed into autophagosomes for degradation and/or recycling--was recently shown to involve actin, but the mechanism is unknown. We found that WHAMM forms puncta that colocalize and comigrate with the autophagy markers LC3, DFCP1, and p62 through a WHAMM-dependent actin-comet tail mechanism. Under starvation, WHAMM and actin are observed at the interface between neighboring autophagosomes, whose number and size increase with WHAMM expression. Interfering with actin polymerization, inhibiting Arp2/3 complex, knocking down WHAMM, or blocking its interaction with Arp2/3 complex through mutagenesis all inhibit comet tail formation and reduce the size and number of autophagosomes. Finally, JMY shows similar localization to WHAMM and could be involved in similar processes. These results reveal a link between Arp2/3-complex-dependent actin assembly and autophagy. PMID- 26096975 TI - Reward Pays the Cost of Noise Reduction in Motor and Cognitive Control. AB - Speed-accuracy trade-off is an intensively studied law governing almost all behavioral tasks across species. Here we show that motivation by reward breaks this law, by simultaneously invigorating movement and improving response precision. We devised a model to explain this paradoxical effect of reward by considering a new factor: the cost of control. Exerting control to improve response precision might itself come at a cost--a cost to attenuate a proportion of intrinsic neural noise. Applying a noise-reduction cost to optimal motor control predicted that reward can increase both velocity and accuracy. Similarly, application to decision-making predicted that reward reduces reaction times and errors in cognitive control. We used a novel saccadic distraction task to quantify the speed and accuracy of both movements and decisions under varying reward. Both faster speeds and smaller errors were observed with higher incentives, with the results best fitted by a model including a precision cost. Recent theories consider dopamine to be a key neuromodulator in mediating motivational effects of reward. We therefore examined how Parkinson's disease (PD), a condition associated with dopamine depletion, alters the effects of reward. Individuals with PD showed reduced reward sensitivity in their speed and accuracy, consistent in our model with higher noise-control costs. Including a cost of control over noise explains how reward may allow apparent performance limits to be surpassed. On this view, the pattern of reduced reward sensitivity in PD patients can specifically be accounted for by a higher cost for controlling noise. PMID- 26096976 TI - Restorative Justice in Children. AB - An important, and perhaps uniquely human, mechanism for maintaining cooperation against free riders is third-party punishment. Our closest living relatives, chimpanzees, will not punish third parties even though they will do so when personally affected. Until recently, little attention has been paid to how punishment and a sense of justice develop in children. Children respond to norm violations. They are more likely to share with a puppet that helped another individual as opposed to one who behaved harmfully, and they show a preference for seeing a harmful doll rather than a victim punished. By 6 years of age, children will pay a cost to punish fictional and real peers, and the threat of punishment will lead preschoolers to behave more generously. However, little is known about what motivates a sense of justice in children. We gave 3- and 5-year old children--the youngest ages yet tested--the opportunity to remove items and prevent a puppet from gaining a reward for second- and third-party violations (experiment 1), and we gave 3-year-olds the opportunity to restore items (experiment 2). Children were as likely to engage in third-party interventions as they were when personally affected, yet they did not discriminate among the different sources of harm for the victim. When given a range of options, 3-year olds chose restoration over removal. It appears that a sense of justice centered on harm caused to victims emerges early in childhood and highlights the value of third-party interventions for human cooperation. PMID- 26096978 TI - Selective Growth and Structural Analysis of Regular MnO Nanooctapods Bearing Multiple High-Index Surface Facets. AB - Although numerous morphologies of MnO nanostructures have been reported, an exact structural analysis and mechanistic study has been lacking. In the present study, the formation of regular MnO octapods was demonstrated in a simple procedure, comprising the thermal decomposition of manganese oleate. Because of their structural uniformity, an ideal three-dimensional model was successfully constructed. The eight arms protruded from the cubic center with tip angles of 38 degrees and surface facets of {311} and {533} with rounded edges. The concentrations of oleate and chloride ions were the determining factors for the octapod formation. Selective coordination of the oleate ions to the {100} faces led to edge growth along the <111> direction, which was then limited by the chloride ions bound to the high-index surface facets. These structural and mechanistic analyses should be helpful for understanding the complex nanostructures and for tuning their structure-related properties. PMID- 26096977 TI - TARANIS Functions with Cyclin A and Cdk1 in a Novel Arousal Center to Control Sleep in Drosophila. AB - Sleep is an essential and conserved behavior whose regulation at the molecular and anatomical level remains to be elucidated. Here, we identify TARANIS (TARA), a Drosophila homolog of the Trip-Br (SERTAD) family of transcriptional coregulators, as a molecule that is required for normal sleep patterns. Through a forward-genetic screen, we isolated tara as a novel sleep gene associated with a marked reduction in sleep amount. Targeted knockdown of tara suggests that it functions in cholinergic neurons to promote sleep. tara encodes a conserved cell cycle protein that contains a Cyclin A (CycA)-binding homology domain. TARA regulates CycA protein levels and genetically and physically interacts with CycA to promote sleep. Furthermore, decreased levels of Cyclin-dependent kinase 1 (Cdk1), a kinase partner of CycA, rescue the short-sleeping phenotype of tara and CycA mutants, while increased Cdk1 activity mimics the tara and CycA phenotypes, suggesting that Cdk1 mediates the role of TARA and CycA in sleep regulation. Finally, we describe a novel wake-promoting role for a cluster of ~14 CycA expressing neurons in the pars lateralis (PL), previously proposed to be analogous to the mammalian hypothalamus. We propose that TARANIS controls sleep amount by regulating CycA protein levels and inhibiting Cdk1 activity in a novel arousal center. PMID- 26096979 TI - Attitudes toward Catheter Ablation for Atrial Fibrillation: A Nationwide Survey among Danish Cardiologists. AB - BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an important but expensive procedure that is the subject of some debate. Physicians' attitudes toward catheter ablation may influence promotion and patient acceptance. This is the first study to examine the attitudes of Danish cardiologists toward catheter ablation for AF, using a nationwide survey. METHODS AND RESULTS: We developed a purpose-designed questionnaire to evaluate attitudes toward catheter ablation for AF that was sent to all Danish cardiologists (n = 401; response n = 272 (67.8%)). There was no association between attitudes toward ablation and the experience or age of the cardiologist with respect to patients with recurrent AF episodes with a duration of <48 hours or >7 days and/or need for cardioversion. The majority (69%) expected a recurrence of AF after catheter ablation in more than 30% of the cases. For patients with persistent longstanding AF with a duration of >1 year, the attitude toward ablation for longstanding AF was more likely to be positive with increasing age (P < 0.01) and years of experience of the cardiologist (P = 0.002). CONCLUSIONS: Danish cardiologists generally have a positive attitude toward catheter ablation for AF, maintain up-to-date knowledge of the procedure, and are aware what information on ablation treatment should be given to patients with AF. The cardiologists had a positive attitude toward ablation for AF in patients with AF episodes <48 hours and patients with episodes >7 days, or those who needed medical/electrical conversion, but a more negative attitude toward treating longstanding AF patients. PMID- 26096980 TI - Effect of the chloride ion as a hole scavenger on the photocatalytic conversion of CO2 in an aqueous solution over Ni-Al layered double hydroxides. AB - The photocatalytic conversion of CO2 into useful chemical compounds in water without using organic sacrificial reagents is a promising method to overcome environmental and energy problems. Various synthesized layered double hydroxides (LDHs) are capable of reducing CO2 to CO in an aqueous solution under UV light irradiation. However, it is difficult to oxidize H2O to O2 in a photocatalytic system using LDHs as photocatalysts. In this study, we investigated the photocatalytic conversion of CO2 using a Ni-Al LDH in an aqueous solution of NaCl. Hypochlorous acid (HClO) was produced as an oxidation product of Cl(-) with the formation of reduction products such as CO and H2 under photoirradiation. We propose the inclusion of Cl(-) in the reaction solution to be one of the most promising ways for obtaining a hole scavenger, an approach that would enable the construction of an artificial photosynthesis system for the conversion of CO2. PMID- 26096982 TI - Image reconstruction of compressed sensing MRI using graph-based redundant wavelet transform. AB - Compressed sensing magnetic resonance imaging has shown great capacity for accelerating magnetic resonance imaging if an image can be sparsely represented. How the image is sparsified seriously affects its reconstruction quality. In the present study, a graph-based redundant wavelet transform is introduced to sparsely represent magnetic resonance images in iterative image reconstructions. With this transform, image patches is viewed as vertices and their differences as edges, and the shortest path on the graph minimizes the total difference of all image patches. Using the l1 norm regularized formulation of the problem solved by an alternating-direction minimization with continuation algorithm, the experimental results demonstrate that the proposed method outperforms several state-of-the-art reconstruction methods in removing artifacts and achieves fewer reconstruction errors on the tested datasets. PMID- 26096984 TI - Editorial statement on negative findings. PMID- 26096983 TI - The relationship of the local food environment with obesity: A systematic review of methods, study quality, and results. AB - OBJECTIVE: To examine the relationship between local food environments and obesity and assess the quality of studies reviewed. METHODS: Systematic keyword searches identified studies from US and Canada that assessed the relationship of obesity to local food environments. We applied a quality metric based on design, exposure and outcome measurement, and analysis. RESULTS: We identified 71 studies representing 65 cohorts. Overall, study quality was low; 60 studies were cross sectional. Associations between food outlet availability and obesity were predominantly null. Among non-null associations, we saw a trend toward inverse associations between supermarket availability and obesity (22 negative, 4 positive, 67 null) and direct associations between fast food and obesity (29 positive, 6 negative, 71 null) in adults. We saw direct associations between fast food availability and obesity in lower income children (12 positive, 7 null). Indices including multiple food outlets were most consistently associated with obesity in adults (18 expected, 1 not expected, 17 null). Limiting to higher quality studies did not affect results. CONCLUSIONS: Despite the large number of studies, we found limited evidence for associations between local food environments and obesity. The predominantly null associations should be interpreted cautiously due to the low quality of available studies. PMID- 26096985 TI - GDNF gene is associated with tourette syndrome in a family study. AB - BACKGROUND: Tourette syndrome is a disorder characterized by persistent motor and vocal tics, and frequently accompanied by the comorbidities attention deficit hyperactivity disorder and obsessive-compulsive disorder. Impaired synaptic neurotransmission has been implicated in its pathogenesis. Our aim was to investigate the association of 28 candidate genes, including genes related to synaptic neurotransmission and neurotrophic factors, with Tourette syndrome. METHODS: We genotyped 506 polymorphisms in a discovery cohort from the United States composed of 112 families and 47 unrelated singletons with Tourette syndrome (201 cases and 253 controls). Genes containing significant polymorphisms were imputed to fine-map the signal(s) to potential causal variants. Allelic analyses in Tourette syndrome cases were performed to check the role in attention deficit hyperactivity disorder and obsessive-compulsive disorder comorbidities. Target polymorphisms were further studied in a replication cohort from southern Spain composed of 37 families and three unrelated singletons (44 cases and 73 controls). RESULTS: The polymorphism rs3096140 in glial cell line-derived neurotrophic factor gene (GDNF) was significant in the discovery cohort after correction (P = 1.5 * 10(-4) ). No linkage disequilibrium was found between rs3096140 and other functional variants in the gene. We selected rs3096140 as target polymorphism, and the association was confirmed in the replication cohort (P = 0.01). No association with any comorbidity was found. CONCLUSIONS: As a conclusion, a common genetic variant in GDNF is associated with Tourette syndrome. A defect in the production of GDNF could compromise the survival of parvalbumin interneurons, thus altering the excitatory/inhibitory balance in the corticostriatal circuitry. Validation of this variant in other family cohorts is necessary. PMID- 26096986 TI - Correlation Between Acoustic Measurements and Self-Reported Voice Disorders Among Female Teachers. AB - OBJECTIVE: Many studies focused on teachers' voice problems and most of them were conducted using questionnaires, whereas little research has investigated the relationship between self-reported voice disorders and objective quantification of voice. This study intends to explore the relationship of acoustic measurements according to self-reported symptoms and its predictive value of future dysphonia. STUDY DESIGN: This is a case-control study. METHODS: Voice samples of 80 female teachers were analyzed, including 40 self-reported voice disorders (VD) and 40 self-reported normal voice (NVD) subjects. The acoustic measurements included jitter, shimmer, and noise-to-harmonics ratio (NHR). Levene's t test and logistic regression were used to analyze the differences between VD and NVD and the relationship between self-reported voice conditions and the acoustic measurements. To examine whether acoustic measurements can be used to predict further voice disorders, we applied a receiver operating characteristic (ROC) curve to determine the cutoff values and the associated sensitivity and specificity. RESULTS: The results showed that jitter, shimmer, and the NHR of VD were significantly higher than those of NVD. Among the parameters, the NHR and shimmer demonstrated the highest correlation with self-reported voice disorders. By using the NHR >=0.138 and shimmer >=0.470 dB as the cutoff values, the ROC curve displayed 72.5% of sensitivity and 75% of specificity, and the overall positive predictive value for subsequent dysphonia achieved 60%. CONCLUSIONS: This study demonstrated a significant correlation between acoustic measurements and self-reported dysphonic symptoms. NHR and ShdB are two acoustic parameters that are more able to reflect vocal abnormalities and, probably, to predict subsequent subjective voice disorder. Future research recruiting more subjects in other occupations and genders shall validate the preliminary results revealed in this study. PMID- 26096987 TI - Unstructural biology of the Dengue virus proteins. AB - In this study, we used a wide spectrum of bioinformatics techniques to evaluate the extent of intrinsic disorder in the complete proteomes of genotypes of four human dengue virus (DENV), to analyze the peculiarities of disorder distribution within individual DENV proteins, and to establish potential roles for the structural disorder with respect to their functions. We show that several proteins (ER, E, 1, 2A and 4A) are predicted to be mostly ordered, whereas four proteins (C, 2k, NS3 and NS5) are expected to have high disorder levels. The profiles of disorder propensities are similar across the four genotypes, except for the NS5 protein. Cleavage sites are depleted in polymorphic sites, and have a high propensity for disorder, especially relative to neighboring residues. Disordered regions are highly polymorphic in type 1 DENV but have a relatively low number of polymorphic sites in the type 4 virus. There is a high density of polymorphisms in proteins 2A and 4A, which are depleted in disorder. Thus, a high density of polymorphism is not unique to disordered regions. Analysis of disorder/function association showed that the predominant function of the disordered regions in the DENV proteins is protein-protein interaction and binding of nucleic acids, metals and other small molecules. These regions are also associated with phosphorylation, which may regulate their function. PMID- 26096988 TI - The devil's triangle of steatosis, obesity, and liver stiffness. PMID- 26096989 TI - Generation of Molecular Complexity from Cyclooctatetraene: Preparation of Aminobicyclo[5.1.0]octitols. AB - A series of eight stereoisomeric N-(tetrahydroxy bicyclo-[5.1.0]oct-2S* yl)phthalimides were prepared in one to four steps from N-(bicyclo[5.1.0]octa-3,5 dien-2-yl)phthalimide (+/-)-7, which is readily available from cyclooctatetraene (62 % yield). The structural assignments of the stereoisomers were established by (1) H NMR spectral data as well as X-ray crystal structures for certain members. The outcomes of several epoxydiol hydrolyses, particularly ring contraction and enlargement, are of note. The isomeric phthalimides as well as the free amines did not exhibit beta-glucosidase inhibitory activity at a concentration of less than 100 MUM. PMID- 26096990 TI - Spatial Expression of Otolith Matrix Protein-1 and Otolin-1 in Normally and Kinetotically Swimming Fish. AB - Kinetosis (motion sickness) has been repeatedly shown to affect some fish of a given clutch following the transition from 1g to microgravity or from hypergravity to 1g. This susceptibility to kinetosis may be correlated with irregular inner ear otolith growth. Otoliths are mainly composed of calcium carbonate and matrix proteins, which play an important role in the process of otolith mineralization. Here, we examine the morphology of otoliths and the expression pattern of the major otolith proteins OMP-1 and otolin-1 in a series of hypergravity experiments. In the utricle, OMP-1 is present in centripetal (medial) and centrifugal (lateral) regions of the meshwork area. In the saccule, OMP-1 was expressed within a dorsal and a ventral narrow band of the meshwork area opposite to the periphery of the sulcus acusticus. In normal animals, the spatial expression pattern of OMP-1 reaches more posteriorly in the centrifugal aspect and is considerably broader in the centripetal portion of the utricle compared to kinetotic animals. However, otolin-1 was not expressed in the utricule. In the saccule, no differences were observed for either gene when comparing normal and kinetotically behaving fish. The difference in the utricular OMP-1 expression pattern between normally and kinetotically swimming fish indicates a different otolith morphology and thus a different geometry of the otoliths resting on the corresponding sensory maculae. As the utricle is the endorgan responsible for sensing gravity, the aberrant morphology of the utricular otoliths, based on OMP-1 expression, likely leads to the observed kinetotic behavior. PMID- 26096991 TI - GONAD: Genome-editing via Oviductal Nucleic Acids Delivery system: a novel microinjection independent genome engineering method in mice. AB - Microinjection is considered the gold standard technique for delivery of nucleic acids (NAs; transgenes or genome editing tools such as CRISPR/Cas9 systems) into embryos, for creating genetically modified organisms. It requires sophisticated equipment as well as well-trained and highly skilled personnel to perform the micro-injection technique. Here, we describe a novel and simple microinjection independent technique, called Genome-editing via Oviductal Nucleic Acids Delivery (GONAD). Using GONAD, we show that NAs (e.g., eGFP mRNA or Cas9 mRNA/sgRNAs) can be effectively delivered to pre-implantation embryos within the intact mouse oviduct by a simple electroporation method, and result in the desired genetic modification in the embryos. Thus GONAD can bypass many complex steps in transgenic technology such as isolation of zygotes, microinjection of NAs into them, and their subsequent transfer to pseudo-pregnant animals. Furthermore, this method can potentially be used for genome editing in species other than mice. PMID- 26096992 TI - Germline mutations and genotype-phenotype associations in head and neck paraganglioma patients with negative family history in China. AB - The aim of this study was to assess the frequency of germline mutations and to explore genotype-phenotype associations in Chinese head and neck paraganglioma (HNPGL) patients without family history. Twenty-six Chinese patients with a diagnosis of HNPGL(14 male and 12 female, respectively)were recruited, who were followed up from 2000 to 2012. Genomic DNA was obtained from resected tumor tissues and peripheral blood samples. Seven genes, Succinate dehydrogenase complex A,B,C,D (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), TMEM127 (transmembrane protein 127) and VHL (Von Hippel-Lindau), were screened by direct sequencing and multiplex ligation dependent probe amplification (MLPA) was performed to search for potential large deletions or duplications of SDHB, SDHC, SDHD, SDHAF1 and SDHAF2. The total frequency of germline mutations was 30.8% (8/26), including 5 cases with missense mutation p.Met1Ile in SDHD, 1 case with missense mutation p.Tyr216Cys in SDHB, and 1 case with a novel truncation mutation p.Gln44Ter in SDHAF2. MLPA showed one patient with malignant HNPGL had heterozygous deletions of exon1, 2, 3, 7 and 8 in SDHB. Mutations in SDHD were the leading cause of HNPGL in this study. Mutation carriers were younger than non-mutation carriers (p < 0.01) and more likely to suffer from multiple tumors (p = 0.048), especially with mutations in SDHD. The presence of mutation was associated with the development of larger tumors (p = 0.021). This study confirmed that the missense mutation p.Met1Ile at the start codon in SDHD was a hotspot in chinese patients with HNPGLs. We recommend genetic analysis in patients below 45 years, especially SDHD gene. PMID- 26096993 TI - Progressive brain atrophy in Schinzel-Giedion syndrome with a SETBP1 mutation. AB - Schinzel-Giedion syndrome is a rare congenital malformation syndrome. Recently, SETBP1 was identified as the causative gene. Herein, we present a Japanese boy with Schinzel-Giedion syndrome resulting from a novel mutation in SETBP1 in order to establish the clinical features and serial MRI findings associated with the syndrome. On the third day of life, the boy was referred to our hospital because of facial abnormalities and feeding difficulty. Midfacial retraction, frontal bossing, deep groove under the eyes, upturned nose, low-set ears, bilateral cryptorchidism, and generalized hypertrichosis were identified on admission. At the age of 7 months, epileptic spasms in series occurred. Based on characteristic facial and skeletal abnormalities and severe developmental delay, we clinically diagnosed him with Schinzel-Giedion syndrome. Direct sequencing of the SETBP1 gene revealed a heterozygous mutation (p.Ile871Ser) in exon 4. Although neither cardiac defect nor choanal stenosis were present in our case, the phenotype of our case was nearly identical to those of previously reported cases confirmed by genetic analysis. Serial MRI from the age of 1 month-3 years revealed progressive brain atrophy, especially in the white matter and basal ganglia. However, myelination was age-appropriate and no obvious abnormal signals in the white matter were seen. Diffusion weighted imaging revealed no abnormal findings. Accumulation of MRI data including diffusion weighted imaging from Schinzel Giedion syndrome cases is needed to understand the mechanism underlying progressive brain atrophy in this syndrome. PMID- 26096994 TI - FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies. AB - Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism. No clinical diagnosis could be established based on the clinical findings and testing of several genes associated with brachydactyly and symphalangism failed to identify mutations. Via next generation sequencing (NGS) panel approach we then identified a novel de novo missense FGFR2 mutation affecting an amino acid reported to be mutated in Pfeiffer syndrome. Since our patient shows typical radiological findings of Pfeiffer syndrome in hands and feet but at the same time lacks several characteristic features such as clinical signs of craniosynostosis and prominent eyes we suggest introducing the term "FGFR2 associated phenotypes" for similar cases. Our results highlight the emerging role of combined NGS and phenotype based bioinformatics strategies to establish clinical diagnoses. PMID- 26096995 TI - Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings. AB - WDR45 and POLR3A are newly recognized genes; each is associated with a distinct neurodegenerative disease. WDR45 is an X-linked gene associated with a dominant form of Neurodegeneration with Brain Iron Accumulation (NBIA), manifested by progressive disabilities, dystonia, cognitive decline, spastic paraplegia, neuropsychiatric abnormalities and iron deposition in the basal ganglia on brain imaging. POLR3A, on the other hand, is an autosomal gene, and its mutations cause a recessive form of a hypomyelination with leukodystrophy disease, also known as 4H syndrome, characterized by congenital Hypomyelination with thinning of the corpus callosum, Hypodontia and Hypogonadotropic Hypogonadism. We report on a female child with severe intellectual disability, aphasia, short stature, ataxia, failure to thrive and structural brain abnormalities. Brain MRI obtained in late infancy showed hypomyelination involving the central periventricular white matter and thinning of the corpus callosum with no evidence of iron accumulation. Brain MRI obtained in childhood showed stable hypomyelination, with progressive iron accumulation in the basal ganglia, in particular in the globus pallidus and substantia nigra. Whole Exome Sequencing (WES) identified a novel WDR45 frameshift deleterious mutation in Exon 9 (c.587-588del) and also revealed three POLR3A missense heterozygous variants. The first is a maternally inherited novel missense variant in exon 4 (c.346A > G). Exon 13 carried two heterozygous missense variants, a maternally inherited variant (c.1724A > T) and a paternally inherited variant (1745G > A). These variants are considered likely damaging. The patient's complex clinical phenotype and mixed brain MRI findings might be attributed to the confounding effects of the expression of these two mutant genes. PMID- 26096996 TI - Novel fluorescence resonance energy transfer-based reporter reveals differential calcineurin activation in neonatal and adult cardiomyocytes. AB - Novel fluorescence resonance energy transfer-based genetically encoded reporters of calcineurin are constructed by fusing the two subunits of calcineurin with P2A based linkers retaining the expected native conformation of calcineurin. Calcineurin reporters display robust responses to calcium transients in HEK293 cells. The sensor responses are correlated with NFATc1 translocation dynamics in HEK293 cells. The sensors are uniformly distributed in neonatal myocytes and respond efficiently to single electrically evoked calcium transients and show cumulative activation at frequencies of 0.5 and 1 Hz. In adult myocytes, the calcineurin sensors appear to be localized to the cardiac z-lines, and respond to cumulative calcium transients at frequencies of 0.5 and 1 Hz. The phosphatase calcineurin is a central component of many calcium signalling pathways, relaying calcium signals from the plasma membrane to the nucleus. It has critical functions in a multitude of systems, including immune, cardiac and neuronal. Given the widespread importance of calcineurin in both normal and pathological conditions, new tools that elucidate the spatiotemporal dynamics of calcineurin activity would be invaluable. Here we develop two separate genetically encoded fluorescence resonance energy transfer (FRET)-based sensors of calcineurin activation, DuoCaN and UniCaN. Both sensors showcase a large dynamic range and rapid response kinetics, differing primarily in the linker structure between the FRET pairs. Both sensors were calibrated in HEK293 cells and their responses correlated well with NFAT translocation to the nucleus, validating the biological relevance of the sensor readout. The sensors were subsequently expressed in neonatal rat ventricular myocytes and acutely isolated adult guinea pig ventricular myocytes. Both sensors demonstrated robust responses in myocytes and revealed kinetic differences in calcineurin activation during changes in pacing rate for neonatal versus adult myocytes. Finally, mathematical modelling combined with quantitative FRET measurements provided novel insights into the kinetics and integration of calcineurin activation in response to myocyte Ca transients. In all, DuoCaN and UniCaN stand as valuable new tools for understanding the role of calcineurin in normal and pathological signalling. PMID- 26096997 TI - Increased expression of NAPDH oxidase 4 in systemic sclerosis dermal fibroblasts: regulation by transforming growth factor beta. AB - OBJECTIVE: Systemic sclerosis (SSc) is characterized by severe and often progressive fibrosis of the skin and multiple internal organs. The mechanisms responsible for these alterations remain obscure, although excessive reactive oxygen species (ROS)-mediated oxidative stress has been implicated. NOX-4 is 1 of 7 isoforms of NADPH oxidase responsible for the generation of ROS. The purpose of this study was to examine NOX-4 expression in skin and cultured dermal fibroblasts from SSc patients and to examine its regulation by transforming growth factor beta1 (TGFbeta1). METHODS: NOX-4 was assessed in normal and SSc skin by immunohistologic analysis and in normal and SSc cultured dermal fibroblasts by quantitative polymerase chain reaction analysis, fluorescence microscopy, and Western blotting. ROS levels were assessed by fluorescence measurement of H2 O2 production. Specific kinase inhibitors were used to study the TGFbeta1 signaling involved in NOX-4 stimulation. NOX-4 inhibition/down regulation was induced with a selective NOX-4 small-molecule inhibitor and NOX-4 small interfering RNA (siRNA). RESULTS: In contrast with normal skin fibroblasts, those from SSc skin showed intense NOX-4 staining. Cultured SSc fibroblasts displayed increased NOX-4 expression. TGFbeta1 caused potent NOX-4 protein and messenger RNA stimulation in normal and SSc fibroblasts, which was mediated by the protein kinase Cdelta (PKCdelta) and Smad2/3 pathways. NOX-4 knockdown in SSc fibroblasts reduced the production of ROS and lowered the expression of type I collagen. CONCLUSION: NOX-4 expression and production were found to be constitutively elevated in SSc skin and cultured SSc dermal fibroblasts. TGFbeta1 stimulated NOX-4 expression in normal and SSc fibroblasts through PKCdelta and Smad2/3 signaling pathways. A small-molecule NOX-4 inhibitor decreased collagen and fibronectin production by normal and SSc fibroblasts, and NOX-4 siRNA knockdown reduced ROS and collagen production by SSc fibroblasts. These results demonstrate the involvement of NOX-4 in SSc-associated fibrosis and indicate NOX 4 inhibitors as novel therapeutic approaches for SSc. PMID- 26096998 TI - Frequency of Intracranial Aneurysms Determined by Magnetic Resonance Angiography in Children (Mean Age 16) Having Operative or Endovascular Treatment of Coarctation of the Aorta (Mean Age 3). AB - Coarctation of the aorta (CofA) has been associated with an increased risk of intracranial aneurysm (IA). This magnetic resonance angiography (MRA) study investigates the prevalence of IAs in 80 children treated in early life for CofA. MRA was performed at mean age of 15.7 +/- 7.1 years, and surgical or endovascular treatment for CofA occurred at a mean age of 2.6 +/- 4.4 years. No IA was found. In contrast with earlier findings in adult patients with late treatment for CofA, this first systematic study of very early treated patients for CofA failed to confirm the association between CofA and IAs. Our results call the abnormal developmental relation between CofA and IAs into question and suggest that modifiable risk factors like hypertension may be responsible for IA development in patients with CofA with adult diagnosis and treatment. In conclusion, our data suggest that early treatment of CofA can reduce the formation of IAs in children so as to make MRA screening less valuable in this young population. PMID- 26097000 TI - Selective Monoarylation of Primary Amines Using the Pd-PEPPSI-IPent(Cl) Precatalyst. AB - A single set of reaction conditions for the palladium-catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI IPent(Cl) catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6-di-tert-butyl-hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination. PMID- 26096999 TI - Comparison of Inhospital Outcomes and Hospitalization Costs of Peripheral Angioplasty and Endovascular Stenting. AB - The comparative data for angioplasty and stenting for treatment of peripheral arterial disease are largely limited to technical factors such as patency rates with sparse data on clinical outcomes like mortality, postprocedural complications, and amputation. The study cohort was derived from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample database from 2006 to 2011. Peripheral endovascular interventions were identified using appropriate International Classification of Diseases, Ninth Revision (ICD-9) Diagnostic and procedural codes. Two-level hierarchical multivariate mixed models were created. The primary outcome includes inhospital mortality, and secondary outcome was a composite of inhospital mortality and postprocedural complications. Amputation was a separate outcome. Hospitalization costs were also assessed. Endovascular stenting (odds ratio, 95% confidence interval, p value) was independently predictive of lower composite end point of inhospital mortality and postprocedural complications compared with angioplasty alone (0.96, 0.91 to 0.99, 0.025) and lower amputation rates (0.56, 0.53 to 0.60, <0.001) with no significant difference in terms of inhospital mortality alone. Multivariate analysis also revealed stenting to be predictive of higher hospitalization costs ($1,516, 95% confidence interval 1,082 to 1,950, p <0.001) compared with angioplasty. In conclusion, endovascular stenting is associated with a lower rate of postprocedural complications, lower amputation rates, and only minimal increase in hospitalization costs compared with angioplasty alone. PMID- 26097001 TI - Mini-Residency in Musculoskeletal Care: An Interprofessional, Mixed-Methods Educational Initiative for Primary Care Providers. AB - OBJECTIVE: A structured educational effort to train primary care providers (PCPs) to perform joint injections has been projected to be cost effective. The US Department of Veterans Affairs (VA) is developing a national continuing professional development program to train PCPs in the evaluation and management of patients with common musculoskeletal conditions. The objective of this pilot project was to confirm initial projections of cost effectiveness and to inform further efforts to develop this program on a national scale. METHODS: The Salt Lake City VA served as the national hub for this pilot project. The initial phase included 19 providers, who participated in a weeklong mixed-methods course. Evaluation was conducted by the VA Employee Education System. Assessments included anonymous surveys, structured telephone interviews, and a review of de identified procedure codes. RESULTS: The survey response rate was 100%, with uniformly positive results. All participants recommended the expansion of this program. The mean number of joint injections performed each month increased from 0.3 (precourse) to 3.5 (postcourse), congruent with prior analyses projecting program cost effectiveness. CONCLUSION: The musculoskeletal mini-residency is a well-received program, with early evidence of cost effectiveness and impact aligned with course objectives. This pilot program is a foundation for efforts in the national dissemination of this initiative. PMID- 26097002 TI - Asiaticoside attenuates diabetes-induced cognition deficits by regulating PI3K/Akt/NF-kappaB pathway. AB - Diabetes-associated cognitive dysfunction, referred as "diabetic encephalopathy", has been confirmed in a great deal of literature. Current evidence support that oxidative stress, inflammation, energy metabolism imbalance, and aberrant insulin signaling are associated with cognition deficits induced by diabetes. The present study explore the effect of asiaticoside on the cognition behaviors, synapses, and oxidative stress in diabetic rats. Asiaticoside could markedly ameliorate the performance in the Morris Water Maze (decreased latency time and path length, and increased time spent in the target quadrant), which was correlated with its capabilities of suppressing oxidative stress, restoring Na(+)-K(+)-ATPase activity and protecting hippocampal synapses. In vitro, asiaticoside could up regulate synaptic proteins expression via modulating Phosphoinositide 3-kinase (PI3K)/Protein Kinase B(AKT)/Nuclear Factor -kappa B (NF-kappaB)-mediated inflammatory pathway in SH-SY5Y cells incubated with high glucose chronically. In conclusion, asiaticoside had beneficial effects on the prevention and treatment of diabetes-associated cognitive deficits, which was involved in oxidative stress, PI3K/Akt/NF-kappaB pathway and synaptic function in the development of cognitive decline induced by diabetes. PMID- 26097003 TI - Intermittent-access binge consumption of sweet high-fat liquid does not require opioid or dopamine receptors in the nucleus accumbens. AB - Binge eating disorders are characterized by episodes of intense consumption of high-calorie food. In recently developed animal models of binge eating, rats given intermittent access to such food escalate their consumption over time. Consumption of calorie-dense food is associated with neurochemical changes in the nucleus accumbens, including dopamine release and alterations in dopamine and opioid receptor expression. Therefore, we hypothesized that binge-like consumption on intermittent access schedules is dependent on opioid and/or dopamine neurotransmission in the accumbens. To test this hypothesis, we asked whether injection of dopamine and opioid receptor antagonists into the core and shell of the accumbens reduced consumption of a sweet high-fat liquid in rats with and without a history of intermittent binge access to the liquid. Although injection of a MU opioid agonist increased consumption, none of the antagonists (including MU opioid, delta opioid, kappa opioid, D1 dopamine and D2 dopamine receptor antagonists, as well as the broad-spectrum opioid receptor antagonist naltrexone) reduced consumption, and this was the case whether or not the animals had a prior history of intermittent access. These results suggest that consumption of sweet, fatty food does not require opioid or dopamine receptor activation in the accumbens even under intermittent access conditions that resemble human binge episodes. PMID- 26097004 TI - The effect of observers on behavior and the brain during aggressive encounters. AB - What effect does an audience have on an animal's behavior and where is this influence registered in the brain? To answer these questions, we analyzed male cichlid fish fighting in the presence of audiences of various compositions and measured expression of immediate early genes in the brain as a proxy for neural activity. We hypothesized their behavior would change depending on who was watching them. We measured behavioral responses from both the "watchers" and the "watched" during aggressive encounters and found that males fighting in the presence of an audience were more aggressive than males fighting without an audience. Depending on the nature of the audience, immediate early gene expression in key brain nuclei was differentially influenced. Both when an audience of larger males watched fighting males, and when they were watching larger males fighting, nuclei in the brain considered homologous with mammalian nuclei known to be associated with anxiety showed increased activity. When males were in the presence of any audience or when males saw any other males fighting, nuclei in the brain known to be involved in reproduction and aggression were differentially activated relative to control animals. In all cases, there was a close relationship between patterns of brain gene expression between fighters and observers. This suggests that the network of brain regions known as the social behavior network, common across vertebrates, are activated not only in association with the expression of social behavior but also by the reception of social information. PMID- 26097005 TI - Impairment of social behaviour persists two years after embryonic alcohol exposure in zebrafish: A model of fetal alcohol spectrum disorders. AB - Zebrafish naturally form social groups called shoals. Previously, we have shown that submerging zebrafish eggs into low concentrations of alcohol (0.00, 0.25, 0.50, 0.75 and 1.00 vol/vol% external bath concentration) during development (24h post-fertilization) for two hours resulted in impaired shoaling response in seven month old young adult zebrafish. Here we investigate whether this embryonic alcohol exposure induced behavioural deficit persists to older age. Zebrafish embryos were exposed either to fresh system water (control) or to 1% alcohol for two hours, 24h after fertilization, and were raised in a high-density tank system. Social behaviour was tested by presenting the experimental fish with a computer animated group of zebrafish images, while automated tracking software measured their behaviour. Control fish were found to respond strongly to animated conspecific images by reducing their distanceand remaining close to the images during image presentation, embryonic alcohol treated fish did not. Our results suggest that the impaired shoaling response of the alcohol exposed fish was not due to altered motor function or visual perception, but likely to a central nervous system alteration affecting social behaviour itself. We found the effects of embryonic alcohol exposure on social behaviour not to diminish with age, a result that demonstrates the deleterious and potentially life-long consequences of exposure to even small amount of alcohol during embryonic development in vertebrates. PMID- 26097007 TI - Bis[(dialkylamino)cyclopropenimine]-Stabilized P(III) - and P(V) -Centered Dications. AB - The treatment of bis[(dialkylamino)cyclopropenimines] with dihalophosphines in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) to form diimine stabilized P(III) -centered dications is reported. The structures of the new compounds were determined by using X-ray diffraction analysis and their donor abilities as ligands evaluated through electrochemical methods. Despite the two positive charges that they bear, these compounds depict intermediate behavior between that of phosphines and phosphites. The coordination of the [L2 PR](2+) moiety to Au(I) and Ag(I) is also reported. Even more surprisingly, these phosphorus centers can be oxidized to the corresponding P(V) dications in the presence of strong oxidants such as peroxides or XeF2 . PMID- 26097006 TI - A Light-Controlled TLR4 Agonist and Selectable Activation of Cell Subpopulations. AB - The spatial and temporal aspects of immune cell signaling are key parameters in defining the magnitude of an immune response. Toll-like receptors (TLRs) on innate immune cells are important in the early detection of pathogens and initiation of an immune response. Controlling the spatial and temporal signaling of TLRs would enable further study of immune synergies and assist in the development of new vaccines. Here, we show a light-based method for the spatial control of TLR4 signaling. A TLR4 agonist, pyrimido[5,4-b]indole, was protected with a cage at a position critical for receptor binding. This afforded a photocontrollable agonist that was inactive while caged, yet effected NF-kappaB activity in cells following UV photocontrolled deprotection. We demonstrated spatial control of NF-kappaB activation within a population of cells by treating all cells with the caged TLR4 agonist and constraining light exposure and consequent activation to a region of interest. PMID- 26097008 TI - A feature based comparison of pen and swipe based signature characteristics. AB - Dynamic Signature Verification (DSV) is a biometric modality that identifies anatomical and behavioral characteristics when an individual signs their name. Conventionally signature data has been captured using pen/tablet apparatus. However, the use of other devices such as the touch-screen tablets has expanded in recent years affording the possibility of assessing biometric interaction on this new technology. To explore the potential of employing DSV techniques when a user signs or swipes with their finger, we report a study to correlate pen and finger generated features. Investigating the stability and correlation between a set of characteristic features recorded in participant's signatures and touch based swipe gestures, a statistical analysis was conducted to assess consistency between capture scenarios. The results indicate that there is a range of static and dynamic features such as the rate of jerk, size, duration and the distance the pen traveled that can lead to interoperability between these two systems for input methods for use within a potential biometric context. It can be concluded that this data indicates that a general principle is that the same underlying constructional mechanisms are evident. PMID- 26097009 TI - Sub-Picosecond Singlet Exciton Fission in Cyano-Substituted Diaryltetracenes. AB - Thin films of 5,11-dicyano-6,12-diphenyltetracene (TcCN) have been studied for their ability to undergo singlet exciton fission (SF). Functionalization of tetracene with cyano substituents yields a more stable chromophore with favorable energetics for exoergic SF (2E(T1)-E(S1)=-0.17 eV), where S1 and T1 are singlet and triplet excitons, respectively. As a result of tuning the triplet-state energy, SF is faster in TcCN relative to the corresponding endoergic process in tetracene. SF proceeds with two time constants in the film samples (tau=0.8+/-0.2 ps and tau=23+/-3 ps), which is attributed to structural disorder within the film giving rise to one population with a favorable interchromophore geometry, which undergoes rapid SF, and a second population in which the initially formed singlet exciton must diffuse to a site at which this favorable geometry exists. A triplet yield analysis using transient absorption spectra indicates the formation of 1.6+/-0.3 triplets per initial excited state. PMID- 26097010 TI - Validity of a New Patient Engagement Measure: The Altarum Consumer Engagement (ACE) Measure. AB - OBJECTIVE: The objective of this study was to report on the validation of new scales [called the Altarum Consumer Engagement (ACE) Measure] that are indicative of an individual's engagement in health and healthcare decisions. The instrument was created to broaden the scope of how engagement is measured and understood, and to update the concept of engagement to include modern information sources, such as online health resources and ratings of providers and patient health. METHODS: Data were collected through an online survey with a US population of 2079 participants. A combination of Principal Component Analysis (PCA) and detailed Rasch analyses were conducted to identify specific subscales of engagement. Results were compared to another commonly used survey instrument, and outcomes were compared for construct validity. RESULTS: The PCA identified a four factor structure composed of 21 items. The factors were named Commitment, Informed Choice, Navigation, and Ownership. Rasch analyses confirmed scale stability. Relevant outcomes were correlated in the expected direction, such as health status, lifestyle behaviors, medication adherence, and observed expected group differences. CONCLUSIONS: This study confirmed the validity of the new ACE Measure and its utility in screening for and finding group differences in activities related to patient engagement and health consumerism, such as using provider comparison tools and asking about medical costs. PMID- 26097011 TI - Quantitative Structure-Activity Relationship Analysis of the Effect of Metoclopramide and Related Compounds on the Surface Ionization of Fumed Silica. AB - Potentiometric titration curves were generated for fumed silica with various concentrations of dissolved metoclopramide. The effects of various benzamide analogs of metoclopramide, which are positively charged in the titration medium and differ solely by their aromatic substituents, as well as lidocaine, which is also structurally analogous but is mainly in the unionized form, were also studied. At sufficiently high pH, pH 7.0 and above, the silica surface charge was independent of the metoclopramide concentration. A reasonable linear relationship with a positive slope was found between the logarithmic octanol-water partition coefficient (log P) values of the compounds and the negative surface charge determined at pH 7.0 and 7.2. These results can be attributed to specific adsorbate-surface interactions rather than concentration effects. The carbonyl oxygens of the benzamide structures most likely form hydrogen bonds with the neutral silanols. The use of positively charged triethylamine and ephedrine resulted in surface charge values that were the least negative in the aforementioned quantitative structure-activity relationship analyses. These results are consistent with ionic interactions between the positively charged aliphatic amine groups and the negatively charged surface silanols occurring simultaneously with the nonionic interactions. PMID- 26097012 TI - Total body irradiation in a patient with fragile X syndrome for acute lymphoblastic leukemia in preparation for stem cell transplantation: A case report and literature review. AB - Fragile X syndrome (FXS) is a congenital disorder caused by expansion of CGG trinucleotide repeat at the 5' end of the fragile X mental retardation gene 1 (FMR1) on the X chromosome that leads to chromosomal instability and diminished serum levels of fragile X mental retardation protein (FMRP). Afflicted individuals often have elongated features, marfanoid habitus, macroorchidism and intellectual impairment. Evolving literature suggests the condition may actually protect from malignancy while chromosomal instability would presumably elevate the risk. Increased sensitivity to ionizing radiation should also be predicted by unstable sites within the DNA. Interestingly, in this report, we detail a patient with FXS diagnosed with acute lymphoblastic leukemia treated with induction followed by subsequent cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with a complete response who then was recommended to undergo peripheral stem cell transplantation. The patient underwent total body irradiation (TBI) as a component of his conditioning regimen and despite the concern of his clinicians, developed minimal acute toxicity and successful engraftment. The pertinent literature regarding irradiation of patients with FXS is also reviewed. PMID- 26097013 TI - Soft PEG-Hydrogels with Independently Tunable Stiffness and RGDS-Content for Cell Adhesion Studies. AB - Poly(ethylene)glycol (PEG)-based hydrogels are often used as matrix material for cell culturing. An efficient method to prepare soft PEG gels is by cross-linking via copper-free strain-promoted azide-alkyne cycloaddition (SPAAC). Here, the effect of polymer density and RGDS-content on hydrogel formation and cell adhesion was studied, by varying the total polymer content (10, 20 and 30 mg . mL(-1) ) and the amount of RGDS moieties (0-100%) independently of each other. Rheology studies confirmed the soft nature of the hydrogels (G' = 25-2 298 Pa). HOS cells are able to adhere well to all RGDS-containing gels. Interestingly, both HeLa cells and NIH 3T3 fibroblasts showed substantial adherence to 10 and 20 mg . mL(-1) gels, but with increased hydrogel stiffness (30 mg . mL(-1) ), their cellular adhesion decreased significantly. PMID- 26097014 TI - Silk fibroin for vascular regeneration. AB - Cardiovascular disease is the primary cause of morbidity and mortality in today's world. Due to the lack of healthy autologous vessels, more tissue-engineered blood vessels are needed to repair or replace the damaged arteries. Biomaterials play an indispensable role in creating a living neovessel with biological responses. Silk fibroin produced by silkworms possesses good cytocompatibility, tailorable biodegradability, suitable mechanical properties, and minimal inflammatory reactions. In addition, regenerated silk fibroin solutions can be processed into various forms of scaffolds such as films, fibers, tubes, and porous sponges. These features make silk fibroin a promising biomaterial for small-diameter vascular grafts. The present article focuses on the applications of silk fibroin for vascular regeneration. A brief overview of the properties of silk fibroin is provided, following which the current research status and future directions of the main types of silk fibroin scaffolds for vascular regeneration are reviewed and discussed. Microsc. Res. Tech. 80:280-290, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26097015 TI - Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy. AB - Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1alpha; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk. PMID- 26097016 TI - Efficacy of caudal epidural injection of lidocaine, xylazine and xylazine plus hyaluronidase in reducing discomfort produced by electroejaculation in bulls. AB - To test the hypothesis that epidural administration of lidocaine, xylazine or xylazine plus hyaluronidase provides reduced pain and stress during electroejaculation in bulls, eight 30-month-old Nellore bulls received saline solution (control), 2% lidocaine, 2% xylazine or 2% xylazine plus hyaluronidase injected into the first intercoccygeal (Co1-Co2) epidural space in randomized order. Heart rate, respiratory rate, mean arterial pressure, analgesia, animal behavior and motor blockade were evaluated before treatment and at predetermined intervals during and after treatment. Pain and stress were scored subjectively, and semen quality was evaluated. The onset of anesthetic action was significantly faster with lidocaine (3.0 +/- 1.2 min) than with xylazine or xylazine plus hyaluronidase (8.9 +/- 1.5 and 5.5 +/- 2.6 min, P=0.021 and P=0.012, respectively), and the onset of anesthesia with xylazine plus hyaluronidase was significantly faster than that with xylazine alone (P=0.032). Treatment with xylazine or xylazine plus hyaluronidase resulted in less discomfort than treatment with lidocaine, as indicated by animal behavior. Changes in heart rate, respiratory rate and arterial pressure were within acceptable limits. Penile protrusion and semen emission occurred in all animals during all four treatments. Our results suggest that xylazine plus hyaluronidase reduced discomfort during electroejaculation more effectively than xylazine or lidocaine alone. Further experiments are necessary to determine whether electroejaculation with xylazine plus hyaluronidase is feasible for obtaining semen from Nellore bulls unaccustomed to being handled or restrained. PMID- 26097017 TI - Downregulation of the expression of inhibin alpha subunit and betaglycan in porcine cystic follicles. AB - Inhibins, as members of the transforming growth factor beta (TGF-beta) superfamily, downregulate the synthesis and secretion of follicle-stimulating hormone (FSH) in an endocrine manner. The role of inhibin/betaglycan in the ovary regulation recently gained attention. To date, no data exist on the function of inhibin alpha subunit and betaglycan in cystic follicles. In this study, the expressions of inhibin alpha subunit and betaglycan in cystic follicles were investigated using immunohistochemistry, real-time PCR and Western blot analysis. Both inhibin alpha subunit and betaglycan immunoreactivities were mainly localized in the granulosa cells of follicles. Expression of inhibin alpha subunit and betaglycan was inferior in cystic follicles compared with that in normal large follicles. However, the result of enzyme-linked immunosorbent assay showed no significant difference in the decreasing in concentration of inhibin alpha subunit in cystic follicular fluid compared with the control (P>0.05). In this study, we explored the effects of FSH on betaglycan expression in granulosa cells in vitro. As expected, a significant increase in the expressions of betaglycan mRNA and protein in granulosa cells was observed in response to exogenous FSH (30 ng/ml) (P<0.05) compared with the control. Consequently, this study provides evidence that the expressions of inhibin alpha subunit and betaglycan are inferior in cystic follicles, and this may be caused by the decrease in FSH in the presence of a cystic follicle. PMID- 26097018 TI - Introduction to the special issue on the origins of modern meta-analysis. AB - This issue of Research Synthesis Methods is devoted to discussion of the origins of modern meta-analysis. Three articles by pioneers in development meta-analysis are by Gene Glass, Frank Schmidt, and Robert Rosenthal, respectively. They reflect on their own experiences about how they made these developments. The fourth article is by William Shadish, and seeks to analyze the impact of meta analysis and the reasons why meta-analysis developed at the time it did, and by the people who did so. The articles are followed by commentaries by Douglas Altman, Iain Chalmers, Harris Cooper, Kay Dickersin, Larry Hedges, David Hoaglin, and Hannah Rothstein, who each comment on both the four target articles and on their own perspectives about how and why meta-analysis developed when and how it did. PMID- 26097019 TI - A Solution-Processable Molecule using Thieno[3,2-b]thiophene as Building Block for Efficient Organic Solar Cells. AB - A solution-processed acceptor-pi-donor-pi-acceptor (A-pi-D-pi-A) type small molecule, namely DCATT, has been designed and synthesized for the application as donor material in organic solar cells. The fused aromatic unit thieno[3,2 b]thiophene (TT) flanked with thiophene is applied as pi bridge, while 4,8 bisthienyl substituted benzodithiophene (BDT) and 2-ethylhexyl cyanoacetate are chosen as the central building block and end group, respectively. Introduction of fused ring to the small molecule enhances the conjugation length of the main chain, and gives a strong tendency to form pi-pi stacking with a large overlapping area which favors to high charge carrier transport. Small-molecule organic solar cells based on blends of DCATT and fullerene acceptor exhibit power conversion efficiencies as high as 5.20 % under the illumination of AM 1.5G, 100 mW cm(-2) . PMID- 26097020 TI - Unusual trend in the prevalence of trisomy 13 in mothers aged 35 and older: A population based study of national congenital anomaly data. AB - BACKGROUND: Trisomy 13 is one of the three autosomal trisomies compatible with viability. It is associated with structural anomalies, learning disability and poor survival. Advanced maternal age is the most frequently suggested risk factor. This is a population based register study to investigate the temporal trends of trisomy 13. METHODS: Chromosomal trisomies were reviewed by the Welsh Congenital Anomaly Register using data from 1998-2012. All pregnancy outcomes were included. Prevalence rates and trends for all cases and for cases with mothers aged below 35 years and those aged 35 years and older were plotted for trisomy 13, 18 and 21. Possible risk factors contributing to the trend in older mothers were compared in the early and late period of the study. RESULTS: There were 124 cases of trisomy 13 over the 15 year period with 55 mothers aged 35 years and older. Overall prevalence was 2.5 per 10,000 total births. A significant declining trend in the prevalence of trisomy 13 in mothers aged 35 and older (chi(2) trend = 4.98, p=0.026) was noted. Rates for younger mothers were lower and remained stable. Prevalence of trisomy 18 and 21 in older mothers remained stable. CONCLUSION: The unexpected declining trend in trisomy 13 in older mothers could not be explained by the risk factors examined in this study. There have been no other reports of trends in the prevalence of trisomy 13 in older mothers in recent years. There is further need for surveillance of trends in future and in other populations. PMID- 26097022 TI - Fifteen year natural history of lower eyelid syringocystadenoma papilliferum in a young girl. PMID- 26097021 TI - Protection from diet-induced obesity and insulin resistance in mice lacking CCL19 CCR7 signaling. AB - OBJECTIVE: Several chemokines play important roles in recruiting the monocyte/macrophage lineage into adipose tissues. We previously found CCL19 was highly expressed in adipocytes cocultured with macrophages stimulated by endotoxin. This study aimed to evaluate the role of CCL19-CCR7 axis on obesity and insulin resistance. METHODS: Serum CCL19 concentration was examined in obese model mice challenged by endotoxin. CCL19 receptor-null, Ccr7(-/-), mice and wild type mice fed a high-fat diet or normal diet were used to investigate the role of CCL19 signals on obesity-associated inflammation. RESULTS: CCL19 protein was elevated in the sera of obese model mice challenged by endotoxin. Ccr7(-/-) mice were protected from diet-induced obesity and insulin resistance. The adipose tissue and liver expression of inflammatory genes of Ccr7(-/-) mice was much lower than in diet-induced obese mice. Ccr7(-/-) mice were protected from fatty liver and dyslipidemia and exhibited increased thermogenesis on high-fat feeding. CCL19 attracts activated dendritic cells (DC). The expression of the DC markers, CD11b and 11c, was not observed in the adipose tissues of Ccr7(-/-) mice fed a high-fat diet, which might be closely associated with the protection of these mice from obesity. CONCLUSIONS: The CCL19-CCR7 pathway associates with the development of high-fat-induced obesity and insulin resistance. PMID- 26097023 TI - Images in Emergency Medicine. Woman With Syncope. Twiddler's Syndrome. PMID- 26097024 TI - Twiddle Me This! A Look at Twiddler's Syndrome. PMID- 26097025 TI - Commentary. PMID- 26097026 TI - Change of shift. Mourning Theresa. PMID- 26097027 TI - Annals of Emergency Medicine Journal Club. "Am I Having a Heart Attack, Doc?" Patient-Physician Communication for Possible Acute Coronary Syndromes. PMID- 26097028 TI - Images in Emergency Medicine. Elderly Female With Abdominal Pain. Palpebral Emphysema From Endoscopic Retrograde Cholangiopancreatography-Related Retroperitoneal Perforation. PMID- 26097029 TI - EM:RAP Commentaries in the Annals of Emergency Medicine: Peer Review and Financial Disclosure Needed. PMID- 26097030 TI - In reply. PMID- 26097031 TI - The Negative Predictive Value of the Head Impulse Test, Nystagmus, and Test of Skew Deviation Bedside Oculomotor Examination in Acute Vestibular Syndrome. PMID- 26097032 TI - In reply. PMID- 26097033 TI - Rings May Be Removed With a Tie From a Surgical Mask. PMID- 26097034 TI - The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes. AB - Enzymes capable of inactivating tetracycline are paradoxically rare compared with enzymes that inactivate other natural-product antibiotics. We describe a family of flavoenzymes, previously unrecognizable as resistance genes, which are capable of degrading tetracycline antibiotics. From soil functional metagenomic selections, we discovered nine genes that confer high-level tetracycline resistance by enzymatic inactivation. We also demonstrate that a tenth enzyme, an uncharacterized homolog in the human pathogen Legionella longbeachae, similarly inactivates tetracycline. These enzymes catalyze the oxidation of tetracyclines in vitro both by known mechanisms and via previously undescribed activity. Tetracycline-inactivation genes were identified in diverse soil types, encompass substantial sequence diversity, and are adjacent to genes implicated in horizontal gene transfer. Because tetracycline inactivation is scarcely observed in hospitals, these enzymes may fill an empty niche in pathogenic organisms, and should therefore be monitored for their dissemination potential into the clinic. PMID- 26097036 TI - Determination of Secondary Follicle Characteristics, Density, Activity, and Hoxc13 Expression Pattern of Hexi Cashmere Goats Breed. AB - This experiment was conducted to identify some aspects of secondary follicle (SF) characteristics of Hexi cashmere goats at five different growing stages in one year in order and discover the expression pattern of Hoxc13 in a SF cycling to provide morphological basis for studying the growth of cashmere. Ten cashmere goats of one-year old (5 males, 5 females) were included in this study. The density and activity of SF were observed and measured by making paraffin sections, the ultra-structural features of SF were studied under transmission electron microscopy (TEM) by making ultra-thin sections, and the expression of Hoxc13 was investigated through the immunohistochemistry method. The average diameter of SF had the smallest value in the anagen stage, and significant difference (P < 0.05) was found between the anagen stage and other stages. The density of SF increased gradually through the different growing stages, and significant difference was found between the anagen and procatagen stages (P < 0.05). With an increase in time (months), the percentage of SF activity increased, and significant difference in the percentage of SF activity was found between the telogen and anagen stages (P < 0.05). At the telogen stage, the layers of connective tissue sheath (CTS) of SF were unclear, hemidesmosomes between the outer root sheath (ORS) and basement membrane disappeared, and dead cells were found at the top of the SF. The rudiments of new SF were found in the proanagen stage, CTS was thickened, and the cells of ORS were stretched out like fingers. At the anagen stage, the structure of SF was integral, and the inner root sheath (IRS) consisted of three concentric layers (Helen, Huxley, and Cuticle layers). The cells of Huxley's layer degenerated gradually, and pseudopodia were formed on the cells of ORS in the procatagen stage. At the catagen stage, the ORS was separated from the IRS, and IRS disappeared. Huxley's layer was absent in the inactive SF while, the ORS was present in the active SF. Hoxc 13 was expressed in the epidermis and sebaceous gland o, ORS, IRS, hair shaft of SF in the skin. Hoxc13 was expressed weakly during procatagen, catagen, and telogen stage, while with an increase in proanagen and anagen stage, significant difference was found between them. These findings demonstrated the ultra-structural features of SF could provide the useful activity criteria, and Hoxc13 associated with the SF activity. PMID- 26097035 TI - Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG. AB - To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target. PMID- 26097037 TI - Chronic exposure to manganese sulfate leads to adverse dose-dependent effects on the neurobehavioral ability of rats. AB - Manganese sulfate is the main combustion product of methylcyclopentadienyl manganese tricarbonyl (MMT). Currently, little is known about the neurobehavioral consequences of chronic manganese sulfate exposure. In this study, rats were treated with 0, 5.0, 10.0, and 20.0 mg/kg MnSO4 .H2 O for 24 consecutive weeks via intraperitoneal injection. During the treatment period, spatial learning memory ability was measured using the Morris water maze (MWM). At the end of the exposure period, spontaneous motor behavior and emotional status, hippocampal histologic changes, and Hsp70 mRNA levels were measured using the open-field test (OFT), hematoxylin-eosin staining and real-time quantitative PCR (RT-PCR), respectively. A dose-dependent decrease was noted in the spatial learning-memory ability and the spontaneous activities of rats (P < 0.05), and negative emotions differed significantly between the exposed groups and the control group (P < 0.05). Moreover, overt morphological changes in the hippocampuses of the exposed rats were detected. Cellular degeneration and death were also found. The Hsp70 mRNA levels of the hippocampal areas in the 20.0 mg/kg group (1.567 +/- 0.236) were significantly increased compared with the control group (P < 0.05). These results suggest that chronic exposure to manganese sulfate can have adverse dose dependent effects on rats' neurobehavioral ability, and the mechanism of abnormal hippocampal Hsp70 expression needs to be further explored. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1571-1579, 2016. PMID- 26097038 TI - Articular cartilage endurance and resistance to osteoarthritic changes require transcription factor Erg. AB - OBJECTIVE: To determine whether and how the transcription factor Erg participates in the genesis, establishment, and maintenance of articular cartilage. METHODS: Floxed Erg mice were mated with Gdf5-Cre mice to generate conditional mutants lacking Erg in their joints. Joints of mutant and control mice were subjected to morphologic and molecular characterization and also to experimental surgically induced osteoarthritis (OA). Gene expression, promoter reporter assays, and gain- and loss-of-function in vitro tests were used to characterize molecular mechanisms of Erg action. RESULTS: Conditional Erg ablation did not elicit obvious changes in limb joint development and overall phenotype in juvenile mice. However, as mice aged, joints of mutant mice degenerated spontaneously and exhibited clear OA-like phenotypic defects. Joints in juvenile mutant mice were more sensitive to surgically induced OA and became defective sooner than operated joints in control mice. Global gene expression data and other studies identified parathyroid hormone-related protein (PTHrP) and lubricin as possible downstream effectors and mediators of Erg action in articular chondrocytes. Reporter assays using control and mutated promoter-enhancer constructs indicated that Erg acted on Ets DNA binding sites to stimulate PTHrP expression. Erg was up-regulated in severely affected areas in human OA articular cartilage but remained barely appreciable in areas of less affected cartilage. CONCLUSION: The study shows for the first time that Erg is a critical molecular regulator of the endurance of articular cartilage during postnatal life and that Erg can mitigate spontaneous and experimental OA. Erg appears to do this through regulating expression of PTHrP and lubricin, factors known for their protective roles in joints. PMID- 26097039 TI - Maintenance of Clinical Efficacy and Radiographic Benefit Through Two Years of Ustekinumab Therapy in Patients With Active Psoriatic Arthritis: Results From a Randomized, Placebo-Controlled Phase III Trial. AB - OBJECTIVE: To evaluate the efficacy and safety of ustekinumab through 2 years in adult patients with active psoriatic arthritis (PsA). METHODS: A total of 615 adult patients with active PsA were randomized to placebo, ustekinumab 45 mg, or ustekinumab 90 mg, at weeks 0, 4, and every 12 weeks through week 88 (last dose). At week 16, patients with <5% improvement in both tender and swollen joint counts entered blinded early escape (placebo to 45 mg, 45 mg to 90 mg, and 90 mg to 90 mg). All remaining placebo patients crossed over to ustekinumab 45 mg at week 24. Clinical efficacy measures included American College of Rheumatology criteria for 20% improvement (ACR20), Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and >=75% improvement in the Psoriasis Area and Severity Index (PASI75). Radiographic progression was evaluated using the modified Sharp/van der Heijde score (SHS). RESULTS: At week 100, ACR20, DAS28-CRP moderate/good response, and PASI75 rates ranged from 56.7-63.6%, 71.9-76.7%, and 63.9-72.5%, respectively, across the 3 treatment groups. In both ustekinumab groups, the median percent improvement in dactylitis and enthesitis was 100% at week 100. The mean changes in SHS score from week 52 to week 100 were similar to those observed from week 0 to week 52 in the ustekinumab groups. Through week 108, 70.7% and 9.7% of patients had an adverse event (AE) or serious AE, respectively. The rates and type of AEs were similar between the dose groups. CONCLUSION: Clinical and radiographic benefits from ustekinumab treatment were maintained through week 100 in the PSUMMIT 1 study. No unexpected safety events were observed; the safety profile of ustekinumab in this population was similar to that previously observed in psoriasis patients treated with ustekinumab. PMID- 26097040 TI - Posttranslational modification of a vanadium nitrogenase. AB - In microbes that fix nitrogen, nitrogenase catalyzes the conversion of N2 to ammonia in an ATP-demanding reaction. To help conserve energy some bacteria inhibit nitrogenase activity upon exposure to ammonium. The purple nonsulfur phototrophic bacterium Rhodopseudomonas palustris strain CGA009 can synthesize three functional nitrogenase isoenzymes: a molybdenum nitrogenase, a vanadium nitrogenase, and an iron nitrogenase. Previous studies showed that in some alphaproteobacteria, including R. palustris, molybdenum nitrogenase activity is inhibited by ADP-ribosylation when cells are exposed to ammonium. Some iron nitrogenases are also posttranslationally modified. However, the posttranslational modification of vanadium nitrogenase has not been reported. Here, we investigated the regulation of the alternative nitrogenases of R. palustris and determined that both its vanadium nitrogenase and its iron nitrogenase activities were inhibited and posttranslationally modified when cells are exposed to ammonium. Vanadium nitrogenase is not found in all strains of R. palustris, suggesting that it may have been acquired by horizontal gene transfer. Also, phylogenetic analyses of the three nitrogenases suggest that VnfH, the target of ADP-ribosylation, may be the product of a gene duplication of nifH, the molybdenum nitrogenase homolog. PMID- 26097041 TI - Preparation, Characterization, and Oxygenase Activity of a Photocatalytic Artificial Enzyme. AB - A bicyclo[6,1,0]nonyne-substituted 9-mesityl-10-methyl-acridinium cofactor was prepared and covalently linked to a prolyl oligopeptidase scaffold containing a genetically encoded 4-azido-L-phenylalanine residue in its active site. The resulting artificial enzyme catalyzed sulfoxidation when irradiated with visible light in the presence of air. This reaction proceeds by initial electron abstraction from the sulfide within the enzyme active site, and the protein scaffold extended the fluorescence lifetime of the acridium cofactor. The mode of sulfide activation and placement of the acridinium cofactor (5) in POP-ZA4 -5 make this artificial enzyme a promising platform for developing selective photocatalytic transformations. PMID- 26097042 TI - Study on clarithromycin lactobionate based dual selector systems for the enantioseparation of basic drugs in capillary electrophoresis. AB - In this paper, the use of clarithromycin lactobionate, a kind of antibiotic chiral selector, in combination with four neutral cyclodextrin derivatives (glucose-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta cyclodextrin and hydroxypropyl-beta-cyclodextrin) was reported for the first time. As a result, these dual systems gave much better resolution of nefopam (the Rs increased to 3.58, 2.72, 1.49 and 1.42, respectively) compared to the single systems. The effects of buffer pH and selector concentration on the separation of nefopam were also investigated. Additionally, some other basic drugs including metoprolol, atenolol, propranolol, bisoprolol, esmolol and ritodrine were tested for the investigation and evaluation of the enantiorecognition capability of the four dual systems. As expected, the synergistic effect was observed in four systems. Different results of these dual systems were also summarized. PMID- 26097044 TI - Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1 c.772G>A; R258G): A report of two patients. AB - Severe variants of fibrodysplasia ossificans progressiva (FOP) affect <2% of all FOP patients worldwide, but provide an unprecedented opportunity to probe the phenotype-genotype relationships that propel the pathology of this disabling disease. We evaluated two unrelated children who had severe reduction deficits of the hands and feet with absence of nails, progressive heterotopic ossification, hypoplasia of the brain stem, motor and cognitive developmental delays, facial dysmorphology, small malformed teeth, and abnormal hair development. One child had sensorineural hearing loss, microcytic anemia, and a tethered spinal cord and the other had a patent ductus arteriosus and gonadal dysgenesis with sex reversal (karyotype 46, XY female). Both children had an identical mutation in ACVR1 c.772A>G; p.Arg258Gly (R258G), not previously described in FOP. Although many, if not most, FOP mutations directly perturb the structure of the GS regulatory subdomain and presumably the adjacent alphaC helix, substitution with glycine at R258 may directly alter the position of the helix in the kinase domain, eliminating a key aspect of the autoinhibitory mechanism intrinsic to the wild type ACVR1 kinase. The high fidelity phenotype-genotype relationship in these unrelated children with the most severe FOP phenotype reported to date suggests that the shared features are due to the dysregulated activity of the mutant kinase during development and postnatally, and provides vital insight into the structural biology and function of ACVR1 as well as the design of small molecule inhibitors. PMID- 26097045 TI - Promoting Cell Survival and Proliferation in Degradable Poly(vinyl alcohol) Tyramine Hydrogels. AB - A photopolymerizable-tyraminated poly(vinyl alcohol) (PVA-Tyr) system that has the ability to covalently bind proteins in their native state was evaluated as a platform for cell encapsulation. However, a key hurdle to this system is the radicals generated during the cross-linking that can cause oxidative stress to the cells. This research hypothesized that incorporation of anti-oxidative proteins (sericin and gelatin) into PVA-Tyr gels would mitigate any toxicity caused by the radicals. The results showed that although incorporation of 1 wt% sericin promoted survival of the fibroblasts, both sericin and gelatin acted synergistically to facilitate long-term 3D cell function. The encapsulated cells formed clusters with deposition of laminin and collagen, as well as remaining metabolically active after 21 d. PMID- 26097046 TI - The early history of meta-analysis. PMID- 26097047 TI - Aggregation of Beta-Amyloid Peptides Proximal to Zwitterionic Lipid Bilayers. AB - One of the hallmarks of Alzheimers disease is the deposition of amyloid plaques, which consist of beta-amyloid (Abeta) peptides in fibrillar states. Nonfibrillar Abeta aggregates have been considered as an important intermediate in the pathway of fibrillization, but little is known about the formation mechanism. The on pathway beta-sheet intermediates of Abeta40 peptides can be trapped by incubating the peptides in liposomes formed by zwitterionic lipids. The aggregates of Abeta40 peptides have been prepared at a peptide concentration of less than 10 MUm. Solid-state NMR spectroscopy data show that the backbone conformation of the aggregates is almost identical to that of the fibrils formed in free solution. In contrast to anionic lipids, zwitterionic lipids, which are typical of neuronal soma, did not induce any significant conformational difference in Abeta40 fibrils. This liposome-Abeta system may serve as a useful model to study the fibril formation mechanism. PMID- 26097048 TI - Reflections on the etiology of structural birth defects: Established teratogens and risk factors. AB - BACKGROUND: Various experts in clinical teratology have proposed what they consider to be well-established teratogens. With the recent growth in the number of resources and investigations, there has been a notable proliferation of proposed risk factors as potential causes of human congenital structural defects. The purpose of this Commentary is to provide a concise summary of the current state of knowledge regarding known causes and environmental risk factors of structural defects. METHODS: We performed a comprehensive search of PubMed for papers in English and in humans only, 2010 to 2014, that included birth defects, risk factors, and teratogens as key terms. RESULTS: Our search led to over 9000 papers dealing with these categories. From this, we were able to construct a timetable documenting the recognition of human teratogens and list several proposed environmental risk factors. Three relevant current trends were noticed: An increase of prescription and nonprescription medication use by women during pregnancy; the rise in obesity and its association with structural defects; and a growing body of work regarding outcomes associated with assisted reproductive technology. CONCLUSION: There are numerous risk factors, some modifiable, that have been proposed in recent years. These factors (associations) are only at the preliminary level in the causal chain and require replication. There is a need for more work on protective factors. The phenotypic characterization of cases with congenital defects has improved remarkably in recent years. However, there remains considerable concern with the precise characterization of exposures and the documentation of timing during embryologic development. PMID- 26097049 TI - The effect of metformin on cancer-specific survival outcomes in diabetic patients undergoing radical cystectomy for urothelial carcinoma of the bladder. AB - PURPOSE: Metformin, a first-line oral therapy for diabetes, has anticancer properties. Our objective was to evaluate the association between metformin use and oncologic outcomes in diabetic patients undergoing radical cystectomy (RC) for bladder cancer (BC). METHODS: A single-institution retrospective cohort (January 1997-June 2013) of diabetic patients undergoing RC was assembled. Medication use was assessed at time of surgery. Outcome measures were recurrence free survival (RFS), BC-specific survival (BCSS), and overall survival (OS). Multivariable Cox proportional hazards models were used. To create parsimonious models, the change of estimate approach (10% threshold) was used as a variable selection strategy for final model inclusion separately for each outcome measure. RESULTS: Of 421 patients, 85 (20%) had diabetes. There were 39 (46%) patients on metformin therapy. Among diabetic patients, there were 21 patients with BC recurrence, 16 who died of BC, and 30 who died overall. In univariate analyses, metformin use among diabetic patients was associated with improved RFS (hazard ratio = 0.54, 95% CI: 0.33-0.88, P = 0.013) and trended toward improved BCSS (hazard ratio = 0.65, 95% CI: 0.40-1.07, P = 0.087), but not with OS (P = 0.87). In multivariable models, metformin use among diabetic patients was associated with significantly improved RFS (adjusted hazard ratio = 0.38, 95% CI: 0.20-0.72, P = 0.003) and BCSS (adjusted hazard ratio = 0.57, 95% CI: 0.35-0.91, P = 0.019), but not with OS (P = 0.89). Use of other oral hypoglycemic agents or insulin was not associated with oncologic outcomes. CONCLUSIONS: Our study is among the first to report an association between metformin use and improved RFS and BCSS in diabetic patients undergoing RC. Given its low cost and demonstrated safety among nondiabetic patients, further studies are warranted to evaluate potential therapeutic and preventive roles of metformin in BC. PMID- 26097050 TI - Margin details matter: The prognostic significance of pseudocapsule invasion at the site of involved margin in prostatectomy specimens. AB - BACKGROUND: An involved surgical margin at prostatectomy has long been associated with elevated risk of prostate cancer recurrence; however, not all patients with an involved margin will relapse, and thus details of the involved margin may provide an opportunity for risk subset stratification. The present investigation seeks to determine whether a difference exists in recurrence rates when the margin involvement is at a site of prostate pseudocapsule invasion vs. within the prostate parenchyma proper. METHODS: Patients were retrospectively identified for inclusion by clinically localized disease and prostate-specific antigen (PSA) level of< 30 ng/ml at diagnosis, managed with prostatectomy alone and identified to have involvement of surgical margin(s). Exclusion criteria were: pT3b or pN1 disease, immediate/nonsalvage postoperative radiation or hormone therapy, or insufficient follow-up (<12 mo). Pathology slides were reviewed by a pathologist blinded to outcome, for determination of pseudocapsule invasion at a site of margin involvement. Disease recurrence was defined as PSA level of >= 0.2 ng/ml and rising, per contemporary guidelines. Kaplan-Meier method was used for construction of disease control estimate confidence intervals; Cox Proportional Hazards Model was used to compare disease control across groups. RESULTS: Between 2003 and 2010, 155 patients were identified for inclusion in the present study. The median age was 61 years, and all had clinical stage T1 and T2 disease (75% T1c). At diagnosis, the Gleason score was 6, 7, and 8-9 for 103 (66%), 42 (27%), and 10 (6%) patients, respectively, with median PSA level of 5.6 ng/ml (85%<= 10). For 149 patients with reviewable margin site data, 51 (34%) demonstrated involvement within or beyond the pseudocapsule. At a median follow-up of 68 months (range: 13-137), 62 patients had experienced PSA relapse. The estimated 5 year PSA relapse rates for patients with an involved margin at the site of pseudocapsule invasion vs. prostate parenchyma were 49% vs. 34%, respectively (P = 0.017; hazard ratio = 1.853). CONCLUSIONS: Early PSA relapse rates are high for patients with involved surgical margin(s) without seminal vesicle or node involvement at prostatectomy; however, for patients who are followed without immediate adjuvant therapy, presence of tumor cells at the margin in a site of pseudocapsule invasion or penetration confers a higher risk of recurrence. PMID- 26097051 TI - Heritability of the Human Craniofacial Complex. AB - Quantifying normal variation and the genetic underpinnings of anatomical structures is one of the main goals of modern morphological studies. However, the extent of genetic contributions to normal variation in craniofacial morphology in humans is still unclear. The current study addresses this gap by investigating the genetic underpinnings of normal craniofacial morphology. The sample under investigation consists of 75 linear and angular measurements spanning the entire craniofacial complex, recorded from lateral cephalographs of 1,379 participants in the Fels Longitudinal Study. Heritabilities for each trait were estimated using SOLAR, a maximum-likelihood variance components approach utilizing all pedigree information for parameter estimation. Trait means and mean effects of the covariates age, sex, age(2) , sex * age, and sex * age(2) were simultaneously estimated in the analytic models. All traits of the craniofacial complex were significantly heritable. Heritability estimates ranged from 0.10 to 0.60, with the majority being moderate. It is important to note that we found similar ranges of heritability occurring across the different functional/developmental components of the craniofacial complex, the splanchnocranium, the basicranium, and the neurocranium. This suggests that traits from different regions of the craniofacial complex are of comparable utility for the purposes of population history and phylogeny reconstruction. At the same time, this genetic influence on craniofacial morphology signals a caution to researchers of nongenetic studies to consider the implications of this finding when selecting samples for study given their project design and goals. PMID- 26097052 TI - SCAI: Enhancing patient care through quality. PMID- 26097053 TI - Is the left main just another artery to FFR? AB - This meta-analysis includes all prospective FFR studies of the left main artery with outcomes. Patients who had deferral of revascularization in FFR-negative stenoses had no difference in cardiovascular events compared with patients who underwent revascularization. FFR-guided revascularization of left main stenosis is safe and effective. PMID- 26097054 TI - Intraprocedural thrombotic events: What's the real cost? AB - Intraprocedural thrombotic events (IPTE) during PCI occur in 4% of patients with NSTEACS and 12% of STEACS. IPTE increases hospital cost by $3,592. With an incidence of 4%, additional therapy to completely prevent IPTE in 100 patients would need to cost $144 to make it cost neutral. Further studies are necessary to determine cost-benefit of therapies to prevent IPTE such as cangrelor or newer P2Y12 inhibitors with more rapid onset. PMID- 26097055 TI - Transulnar angiography and intervention: The next frontier in vascular access? AB - This study demonstrates that in a single center, single operator experience, ulnar artery catheterization is feasible, though even compared to radial access, a significant learning curve remains. Although ulnar access is a reasonable alternative approach to catheterization, the true benefits of ulnar access, compared to radial are unclear. Further large randomized multicenter, multi operator trials are needed to assess the true feasibility and benefit of ulnar artery catheterization. PMID- 26097056 TI - Predicting paravalvular leak after balloon-expandable TAVR. AB - Objective measurement of a Valve Calcification Index (calcium volume/BSA) may predict PVL after TAVR using a cutoff value > 418 mm(3) /mm(2) Oversizing the balloon-expandable SAPIEN valve with a goal ratio of valve diameter: average annulus diameter > 1.055 may reduce PVL after TAVR Single parameters are unlikely to provide adequate sensitivity to reduce PVL; a thorough analysis of root sizing, calcification, and morphology is important to balloon-expandable TAVR safety and efficacy. PMID- 26097057 TI - A call for long-term data in clinical studies of infrainguinal peripheral arterial revascularization: The DURABILITY II Study delivers. AB - The DURABILITY II study provides outcomes in 220 patients treated with nitinol self-expanding stent placement for femoro-popliteal disease out to three years. In this core lab adjudicated study, the EverFlexTM (Covidien, Plymouth, MN) self expanding stents had a low stent fracture rate (0.9%). The study demonstrated a freedom from clinically driven target lesion revascularization (TLR) of nearly 70% at 3 years. Based on this study, primary angioplasty and stenting of these lesions is a reasonable strategy though results are better with lesions less than 8 cm compared to those greater than 8 cm. Further research is need comparing this strategy to use of drug-coated stents and that of atherectomy with drug eluting balloons and with longer term follow-up. PMID- 26097058 TI - Dysregulated osteoclastogenesis is related to natural killer T cell dysfunction in rheumatoid arthritis. AB - OBJECTIVE: To investigate the role played by natural killer T (NKT) cells in osteoclastogenesis and their effects on inflammatory bone destruction. METHODS: Patients with rheumatoid arthritis (RA) (n = 25) and healthy controls (n = 12) were enrolled in this study. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells (PBMCs) in the presence of macrophage colony-stimulating factor and RANKL. PBMCs were cultured in vitro with alpha-galactosylceramide (alphaGalCer), and proliferation indices of NKT cells were estimated by flow cytometry. In vivo effects of alphaGalCer-stimulated NKT cells on inflammation and bone destruction were determined in mice with collagen induced arthritis. RESULTS: In vitro osteoclastogenesis was found to be significantly inhibited by alphaGalCer in healthy controls but not in RA patients. Proliferative responses of NKT cells and STAT-1 phosphorylation in monocytes in response to alphaGalCer were impaired in RA patients. Notably, alphaGalCer-stimulated NKT cells inhibited osteoclastogenesis mainly via interferon-gamma production in a cytokine-dependent manner (not by cell-cell contact) and down-regulated osteoclast-associated genes. Mice treated with alphaGalCer showed less severe arthritis and reduced bone destruction. Moreover, proinflammatory cytokine expression in arthritic joints was found to be reduced by alphaGalCer treatment. CONCLUSION: This study primarily demonstrates that alphaGalCer-stimulated NKT cells have a regulatory effect on osteoclastogenesis and a protective effect against inflammatory bone destruction. However, it also shows that these effects of alphaGalCer are diminished in RA patients and that this is related to NKT cell dysfunction. These findings provide important information for those searching for novel therapeutic strategies to prevent bone destruction in RA. PMID- 26097059 TI - Epidemiology and Treatment of New-Onset and Established Rheumatoid Arthritis in an Insured US Population. AB - OBJECTIVE: To investigate the epidemiology and treatment of rheumatoid arthritis (RA) in a population broadly representative of employed adults in the US, using a retrospective cohort design. METHODS: Incident and prevalent RA cohorts were defined from a sample of 4.66 million adults with complete followup data from the period of January 2005 through September 2008 in the Pharmetrics medical claims database. Demographics, comorbidity, and medical therapies were summarized using descriptive statistics. RESULTS: Median duration in the database was 5.7 years. Age- and sex-adjusted incidence in 2006 was 0.71 per 1,000 persons at risk (n = 3,992) and prevalence in 2005 was 0.63% (n = 30,530). Within 12 months after diagnosis, 65%, 64%, and 20% of the incident cohort had been prescribed corticosteroids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and tumor necrosis factor (TNF) inhibitors, respectively. Median time to first anti TNF prescription was 6 months; 31% switched to a second drug and 15% to a third. An aggressive subcohort (11% of incident patients) received more DMARDs (83%) and TNF inhibitors (43%), and was more likely to switch. Twenty-eight percent of incident patients received only symptomatic therapy over a minimum of 1.75 years of followup; these patients were older with more comorbidities and contraindications to methotrexate. CONCLUSION: In this insured population-based cohort, only two-thirds of newly diagnosed RA patients were prescribed a DMARD in year 1 and 28% received no antirheumatic therapy. Although limited by lack of clinical information and by left-censoring, administrative databases capture clinical practice and suggest that gaps exist in treatment options available to a significant number of patients. PMID- 26097061 TI - Foldamers as Anticancer Therapeutics: Targeting Protein-Protein Interactions and the Cell Membrane. AB - Targeting important protein-protein interactions involved in carcinogenesis or targeting the cell membrane of a cancer cell directly are just two of the ways in which foldamers (oligomeric molecules that fold into distinct shapes in solution) hold considerable potential in the treatment of cancer. From mimicking the local topography of the helical compound of interest by using covalently constrained foldamers to mimicking the topography of the natural helix such that the positions of key functional motifs are in an identical spatial orientation to match those presented by the original alpha-helix, synthetic foldamers have been used to mimic the natural foldamers that interact with proteins or the cell membrane. These targeted approaches have become established over a timeframe of more than a decade, and they continue to be included in the assortment of cancer targets being studied and the arsenal of chemotherapy compounds in development. These approaches are reviewed herein. PMID- 26097060 TI - Male soy food intake was not associated with in vitro fertilization outcomes among couples attending a fertility center. AB - Male factor etiology may be a contributing factor in up to 60% of infertility cases. Dietary intake of phytoestrogens has been related to abnormal semen quality and hormone levels. However, its effect on couple fecundity is still unclear. Intake of soy products was assessed in 184 men from couples undergoing infertility treatment with in vitro fertilization. Couples were recruited between February 2007 and May 2014 and prospectively followed to document treatment outcomes including fertilization, implantation, clinical pregnancy and live birth. Multivariate generalized linear mixed models with random intercepts, binomial distribution and logit link function were used to examine this relation while accounting for repeated treatment cycles and adjusting for potential confounders. Male partner's intake of soy foods and soy isoflavones was unrelated to fertilization rates, the proportions of poor quality embryos, accelerated or slow embryo cleavage rate, and implantation, clinical pregnancy and live birth. The adjusted live birth rates per initiated cycle (95% CI) for partners of men in increasing categories of soy food intake were 0.36 (0.28-0.45), 0.42 (0.29-0.56), 0.36 (0.24-0.51), and 0.37 (0.24-0.52), respectively. Soy food intake in men was not related to clinical outcomes among couples presenting at an infertility clinic. Data on the relation between phytoestrogens and male reproductive potential remain scarce and additional research is required to clarify its role in human reproduction. PMID- 26097062 TI - High-performance liquid chromatography separation of unsaturated organic compounds by a monolithic silica column embedded with silver nanoparticles. AB - The optimization of a porous structure to ensure good separation performances is always a significant issue in high-performance liquid chromatography column design. Recently we reported the homogeneous embedment of Ag nanoparticles in periodic mesoporous silica monolith and the application of such Ag nanoparticles embedded silica monolith for the high-performance liquid chromatography separation of polyaromatic hydrocarbons. However, the separation performance remains to be improved and the retention mechanism as compared with the Ag ion high-performance liquid chromatography technique still needs to be clarified. In this research, Ag nanoparticles were introduced into a macro/mesoporous silica monolith with optimized pore parameters for high-performance liquid chromatography separations. Baseline separation of benzene, naphthalene, anthracene, and pyrene was achieved with the theoretical plate number for analyte naphthalene as 36,000 m(-1). Its separation function was further extended to cis/trans isomers of aromatic compounds where cis/trans stilbenes were chosen as a benchmark. Good separation of cis/trans-stilbene with separation factor as 7 and theoretical plate number as 76,000 m(-1) for cis-stilbene was obtained. The trans isomer, however, is retained more strongly, which contradicts the long- established retention rule of Ag ion chromatography. Such behavior of Ag nanoparticles embedded in a silica column can be attributed to the differences in the molecular geometric configuration of cis/trans stilbenes. PMID- 26097063 TI - Heterozygous mutations in ERF cause syndromic craniosynostosis with multiple suture involvement. AB - Craniosynostosis is a clinically and genetically heterogeneous condition. Knowledge of the specific genetic diagnosis in patients presenting with this condition is important for surgical and medical management. The most common single gene causes of syndromic craniosynostosis are mutations in FGFR1, FGFR2, FGFR3, TWIST1, and EFNB1. Recently, a new single gene cause of craniosynostosis was published, together with phenotype data that highlight the clinical importance of making this specific molecular diagnosis. Phenotypic features of "ERF-related craniosynostosis" include sagittal or multiple-suture synostosis, Chiari malformation, and language delay. In order to determine the contribution of ERF mutations to genetically undiagnosed patients with craniosynostosis, we sequenced the coding regions of ERF in 40 patients with multi-suture or sagittal suture synostosis. We identified heterozygous ERF mutations in two individuals (5%). One mutation positive individual had pansynostosis, while the second had bilateral coronal and metopic synostosis. Both presented in infancy or childhood (age 3 months, and 6 years 9 months, respectively). One had CNS abnormalities including Chiari I malformation. Dysmorphic features included hypertelorism, proptosis, depressed nasal bridge, and retrognathia, in keeping with previously reported cases. The individuals did not require repeated cranial surgeries. ERF related craniosynostosis should be suspected in patients presenting with multiple suture or sagittal synostosis. PMID- 26097064 TI - PEGylation to Improve Protein Stability During Melt Processing. AB - Biopharmaceuticals are some of the most effective drugs on the market, however, delivery remains a challenge. Melt processing is a viable protein encapsulation method because it is solvent free, is high throughput, and yields very high encapsulation efficiencies. Problematically, proteins can lose activity during melt processing due to high heat and shear forces. Covalent attachment of poly(ethylene glycol), or PEGylation, has been widely used to increase thermal stability and prevent aggregation in solution. This study explored the effect of PEGylation on protein stability during melt processing using lysozyme and PLGA. The results indicate that PEGylation increases the retained activity of lysozyme, increases dispersion in the melt, and reduces the biphasic release profile in melt processed systems. PMID- 26097065 TI - Transformations of Ferric Chloride-Generated Stilbene Cation Radicals. The Effect of Aromatic Substitution and a Comparison with Anodic Oxidation. AB - A systematic study on the FeCl3-induced oxidation of 1,2-diarylalkenes was carried out with the focus on the variation of product type as a function of aromatic substitution, as well as to compare the reactivity of stilbene cation radicals generated via Fe(III) oxidation with those generated by anodic oxidation. The aromatic substituents were found to fall into three main categories, namely those that give rise to tetralins and/or dehydrotetralins, those that give products possessing pallidol and ampelopsin F-type carbon skeletons, and last, those that give rise to trimeric products, indanes, and dehydrotetralins/tetralins. The latter are those stilbenes with a para-methoxy substituent in one ring and a para- or meta-EWG (CF3, NO2, Cl, F) in the other, and represent the most prominent departure when compared with the behavior of the same stilbenes under the conditions of anodic oxidation. Reaction pathways to rationalize the formation of the different products are presented. PMID- 26097066 TI - Article Alerts: items from 2011, Part II. AB - This sixth 'Article Alerts' installment's print component includes 100 methodological articles about research synthesis published in 2011. Since the preceding installment, more than 2100 items have been added to the archive component, mostly from 2010 to 2011, and identifying codes have been added to more than 2400 previous archive items. The associated online library, available for free via CiteULike, now contains 2000 items from this feature. PMID- 26097067 TI - Obituary. Edward W. Carney, 1959-2015. PMID- 26097068 TI - Flawed Analysis? A Response to Myhrvold. PMID- 26097069 TI - Renal denervation for the treatment of hypertension: Making a new start, getting it right. AB - The renal nerves contribute to hypertension through effects in the kidney that enhance sodium retention and renin secretion, and by effects in the central nervous system that increase systemic sympathetic activity. Therefore, targeting the renal nerves provides a logical basis for treating hypertension. Several trials of renal denervation--achieved by applying radiofrequency energy through catheters placed in the renal arteries--have been completed. Clinical results have been inconsistent, however, partly because of factors related to the ablation technique and partly because these studies have been performed in patients with the inadequately defined clinical condition of "treatment-resistant hypertension." This statement now explains our conclusion that future studies of renal denervation should be guided by the established randomized, controlled clinical trial designs used for studying antihypertensive drugs and other treatments for hypertension. PMID- 26097070 TI - Effect of thermal processing on mealworm allergenicity. AB - SCOPE: The growing world population requires the exploration of new sustainable protein sources to ensure food security. Insects such as mealworm are promising candidates. For safety reasons, a risk assessment, including allergy risks, is needed. Since allergenicity can be influenced by thermal processing, it is highly important to take this into account. METHODS AND RESULTS: Fresh mealworm was heat processed and extracted by a sequential extraction method using in succession Tris, urea, and a combined SDS/DTT buffer. Extracts were tested using immunoblot, basophil activation test and skin prick test in 15 shrimp allergic patients, previously indicated as population at risk for mealworm allergy. Immunoblots showed a difference in IgE binding between processed and unprocessed mealworm extracts. However, this was due to change in solubility. Some allergens were soluble in urea buffer, but became more soluble in Tris buffer and vice versa. IgE binding was seen for all extracts in blot and basophil activation test. The results from 13 skin prick tests showed a skin reaction similar between processed and unprocessed mealworm. CONCLUSION: Thermal processing did not lower allergenicity but clearly changed solubility of mealworm allergens. A sequential extraction method allowed for assessment of a broader protein panel. PMID- 26097071 TI - Organic monolith frits encased in polyether ether ketone tubing with improved durability for liquid chromatography. AB - This study introduces a preparation method for polymer-encased monolith frits with improved durability for liquid chromatography columns. The inner surface of the polyether ether ketone tubing is pretreated with sulfuric acid in the presence of catalysts (vanadium oxide and sodium sulfate). The tubing was rinsed with water and acetone, flushed with nitrogen, and treated with glycidyl methacrylate. After washing, the monolith reaction mixture composed of lauryl methacrylate, ethylene glycol dimethacrylate, initiator, and porogenic solvent was filled in the tubing and subjected to in situ polymerization. The tubing was cut into thin slices and used as frits for microcolumns. To check their durability, the frit slices were placed in a vial and a heavy impact was applied on the vial by a vortex mixer for various periods. The frits made in the presence of catalysts were found to be more durable than those made without catalysts. Furthermore, when the monolith-incorporated tubing was used as a chromatography column, the column prepared in the presence of catalysts resulted in a better separation efficiency. The separation performance of the columns installed with the polyether ether ketone encased monolith frits was comparable to that of the columns installed with the commercial stainless-steel screen frits. PMID- 26097073 TI - Association between etiologic factors in infertile couples and fertilization failure in conventional in vitro fertilization cycles. AB - The aim of this study was to investigate the relationship between the etiology of the couples and risk of fertilization failure (FF) in conventional in vitro fertilization (IVF) cycles and the effect of rescue intracytoplasmic sperm injection (ICSI) technique to offspring. A total of 2542 IVF cycles were divided into four groups according to infertile etiology: Group A - primary infertility with normal semen parameters; Group B - secondary infertility with oligoasthenozoospermia; Group C - primary infertility with oligoasthenozoospermia; and Group D - secondary infertility with normal semen parameters. The results showed that there were significant differences in incidence of FF among Group A (16.8%), Group B (20.9%), Group C (48.7%), and Group D (0.9%) (p < 0.001). Logistic regression models demonstrated that primary infertility (OR: 10.898, 95% CI: 4.651-25.583, p < 0.001) and oligoasthenozoospermia (OR: 12.215, 95% CI: 5.903-25.276, p < 0.001) were independent risk factors for FF. There were no significant differences in main outcomes between conventional ICSI and rescue ICSI. In conclusion, the patients with primary infertility and oligoasthenozoospermia might be at higher risk of FF. The rescue ICSI technique is safe and helpful for IVF cycles of FF. PMID- 26097072 TI - Super-Resolution Imaging and Quantitative Analysis of Membrane Protein/Lipid Raft Clustering Mediated by Cell-Surface Self-Assembly of Hybrid Nanoconjugates. AB - Super-resolution imaging was used to quantify organizational changes in the plasma membrane after treatment with hybrid nanoconjugates. The nanoconjugates crosslinked CD20 on the surface of malignant B cells, thereby inducing apoptosis. Super-resolution images were analyzed by using pair-correlation analysis to determine cluster size and to count the average number of molecules in the clusters. The role of lipid rafts was investigated by pre-treating cells with a cholesterol chelator and actin destabilizer to prevent lipid raft formation. Lipid raft cluster size correlated with apoptosis induction after treatment with the nanoconjugates. Lipid raft clusters had radii of ~ 200 nm in cells treated with the hybrid nanoconjugates. Super-resolution images provided precise molecule location coordinates that could be used to determine density of bound conjugates, cluster size, and number of molecules per cluster. PMID- 26097074 TI - The role of candidate-gene CNTNAP2 in childhood apraxia of speech and specific language impairment. AB - Childhood apraxia of speech (CAS) is a debilitating pediatric speech disorder characterized by varying symptom profiles, comorbid deficits, and limited response to intervention. Specific Language Impairment (SLI) is an inherited pediatric language disorder characterized by delayed and/or disordered oral language skills including impaired semantics, syntax, and discourse. To date, the genes associated with CAS and SLI are not fully characterized. In the current study, we evaluated behavioral and genetic profiles of seven children with CAS and eight children with SLI, while ensuring all children were free of comorbid impairments. Deletions within CNTNAP2 were found in two children with CAS but not in any of the children with SLI. These children exhibited average to high performance on language and word reading assessments in spite of poor articulation scores. These findings suggest that genetic variation within CNTNAP2 may be related to speech production deficits. PMID- 26097075 TI - Cellular Uptake Behavior of Doxorubicin-Conjugated Nanodiamond Clusters for Efficient Cancer Therapy. AB - This paper describes the design and fabrication of doxorubicin (Dox)-conjugated nanodiamond (ND) clusters with controlled sizes and cellular uptake behaviors of free Dox and Dox-conjugated ND clusters. The ND clusters with an average size of 45.84 nm exhibited a higher amount of cellular uptake as compared to the ND clusters with larger sizes. The amount of Dox taken up as free Dox increased initially and then decreased over time. In contrast, the amount of Dox taken up as Dox-ND clusters continuously increased and reached a plateau, resulting in high ablation efficiency. At the same Dox concentration, the cell viabilities after treatment with free Dox and Dox-ND clusters were 26.38 and 5.31%, respectively. The Dox-ND clusters potentially could be employed as efficient drug carriers for efficient cancer therapy. PMID- 26097076 TI - Visible-Light Photoredox Catalysis: Direct Synthesis of Sulfonated Oxindoles from N-Arylacrylamides and Arylsulfinic Acids by Means of a Cascade C-S/C-C Formation Process. AB - A novel photocatalytic synthesis of sulfonated oxindoles from N-arylacrylamides and arylsulfinic acids was developed by means of a cascade C-S/C-C bond-formation process. This method provides mild, efficient, and atom-economical access to various sulfonated oxindoles in water. PMID- 26097077 TI - Comments on the recently published "Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma". PMID- 26097078 TI - Sol-gel synthesis and luminescent properties of red-emitting Y(P,V)O4:Eu(3+) phosphors. AB - Eu(3+)-activated Y(P,V)O4 phosphors were prepared by the EDTA sol-gel method, and the corresponding morphologies and luminescent properties were investigated. The sample particles were relatively spheroid with size of 2-3 um and had a smooth surface. The excitation spectra for Y(P,V)O4:Eu(3+) consisted of three strong excitation bands in the 200-350 nm range, which were attributed to a Eu(3+)- O(2 ) charge-transfer band and (1)A1-(1) T1/(1) T2 transitions in VO4(3-). The as synthesized phosphors exhibited a highly efficient red luminescence at 613 nm due to the Eu(3+5) D0-(7) F2 electric dipole transition. With the increase in the V(5+)/P(5+) ratio, the luminescence intensity of the red phosphor under UV excitation was greatly improved due to enhanced VO4(3-) -> Eu(3+) energy transfer. PMID- 26097079 TI - Handicap-Recover Evolution Leads to a Chemically Versatile, Nucleophile Permissive Protease. AB - Mutation of the tobacco etch virus (TEV) protease nucleophile from cysteine to serine causes an approximately ~104 -fold loss in activity. Ten rounds of directed evolution of the mutant, TEVSer , overcame the detrimental effects of nucleophile exchange to recover near-wild-type activity in the mutant TEVSer X. Rather than respecialising TEV to the new nucleophile, all the enzymes along the evolutionary trajectory also retained the ability to use the original cysteine nucleophile. Therefore the adaptive evolution of TEVSer is paralleled by a neutral trajectory for TEVCys , in which mutations that increase serine nucleophile reactivity hardly affect the reactivity of cysteine. This apparent nucleophile permissiveness explains how nucleophile switches can occur in the phylogeny of the chymotrypsin-like protease PA superfamily. Despite the changed key component of their chemical mechanisms, the evolved variants TEVSer X and TEVCys X have similar activities; this could potentially facilitate escape from adaptive conflict to enable active-site evolution. PMID- 26097085 TI - Separation of salvianic acid A from the fermentation broth of engineered Escherichia coli using macroporous resins. AB - Salvianic acid A (also known as danshensu) is a plant-derived polyphenolic acid, and has a variety of physiological and pharmacological activities. Our laboratory previously constructed an unprecedented artificial biosynthetic pathway in Escherichia coli and established the fermentation process to produce salvianic acid A. Here, we developed an efficient method for separating salvianic acid A from the fermentation broth of engineered Escherichia coli by macroporous resins. Among ten tested macroporous resins, the static and dynamic adsorption/desorption experiments demonstrated that X5 resin was the best to separate salvianic acid A from fermentation broth. Other parameters during static and dynamic procedures were also investigated. Under the optimum separation conditions, the average adsorption capacity of SAA were 10.66+/-0.54 mg/g dry resin and the desorption ratio was 85.6+/-4.1%. The purity and recovery yield of salvianic acid A in the final dry product were 90.2+/-1.5 and 81.5+/-2.3%, respectively. The results show that adsorption separation with macroporous resin X5 was an efficient method to prepare salvianic acid A from fermentation broth. This work will benefit the development and application of plant-derived salvianic acid A and its derivatives. PMID- 26097086 TI - Effect of ribonucleic acid (RNA) isolation methods on putative reference genes messenger RNA abundance in human spermatozoa. AB - Although the male gamete participates in a significant proportion of infertility cases, there are currently no proven molecular markers of sperm quality. The search for significant gene expression markers is partially hindered by the lack of a recognized set of reference genes (RGs) to normalize reverse transcription quantitative PCR (RT-qPCR) data across studies. The aim of this study is to define a set of RGs in assisted reproduction patients undergoing different sample collection and RNA isolation methods. Twenty-two normozoospermic men were included in the study. From each man, semen was either cryopreserved by slow freezing or analyzed fresh, and, for each, RNA was extracted with either phenol free or phenol-based methods. In two cases, both methods were used to isolate RNA. Twenty putative RGs were analyzed and their mRNA abundance across samples was estimated by RT-qPCR. To determine the genes whose steady-state mRNA abundance remains unchanged, three different algorithms (geNorm, BestKeeper and NormFinder) were applied to the qPCR data. We found that RGs such as GAPDH or ACTB, useful in other biological contexts, cannot be used as reference for human spermatozoa. It is possible to compare gene expression from fresh and cryopreserved sperm samples using the same isolation method, while the mRNA abundance of expressed genes becomes different depending on the RNA isolation technique employed. In our conditions, the most appropriate RGs for RT-qPCR analysis were RPLP1, RPL13A, and RPLP2. Published discrepancies in gene expression studies in human spermatozoa may be due in part to inappropriate RGs selection, suggesting a possible different interpretation of PCR data in several reports, which were normalized using unstable RGs. PMID- 26097087 TI - Distinguishing 2N gamete nuclei from doublets in pollen using flow cytometry and pulse analysis. AB - The value of flow cytometry for quantifying unreduced (2N) pollen production in plants is well recognized; however, the approach has been limited by technical obstacles to obtaining high quality nuclei fluorescence histograms and the difficulty in distinguishing 2N nuclei from 1N doublets. Here, we use mathematical arguments and observations of fluorescence properties of angiosperm pollen nuclei to generate guidelines for applying pulse analysis to correct for doublets in pollen nuclei data. We show that the theoretical requirements for applying pulse analysis for doublet correction are met when nucleus fluorescence height and/or width measures in the unreduced gamete (2C DNA content) region exhibit bimodality (reflecting singlets and doublets) in combination with unimodal distributions of the same parameters in the reduced gamete (1C) region. These conditions are regularly met in the family Brassicaceae but not in the Asteraceae and Poaceae. We further show that when these requirements are met, pulse analysis estimates of doublet proportions are well correlated with estimates obtained with microscopy. We propose guidelines for doublet correction when estimating frequencies of unreduced male gametes. PMID- 26097088 TI - A Mechanochromic Luminescent Dye Exhibiting On/Off Switching by Crystalline Amorphous Transitions. AB - A mechanochromic luminescent dye based on a simple aminomaleimide skeleton was readily synthesized in a one-pot process. It exhibited an on/off mechanochromic luminescent switching property dependent on external stimuli, unlike a traditional mechanochromic color change. The green emission was turned on by grinding in a mortar and turned off by heating or treatment with dichloromethane. In the crystalline state, two molecules were stacked by cofacial pi-pi interactions, which caused concentration self-quenching. The crystalline-to amorphous transition induced by grinding removed cofacial pi-pi stacking, which led to intensive emission. Crystallizing processes recovered the cofacial pi-pi stacking, resulting in elimination of the emission. Theoretical calculations and X-ray diffraction analyses revealed that the dye molecule was distorted in the crystalline state; thus even a mechanical stimulus caused the crystalline-to amorphous transition. PMID- 26097089 TI - Effects of generalist herbivory on resistance and resource allocation by the invasive plant, Phytolacca americana. AB - Successful invasions by exotic plants are often attributed to a loss of co evolved specialists and a re-allocation of resources from defense to growth and reproduction. However, invasive plants are rarely completely released from insect herbivory because they are frequently attacked by generalists in their introduced ranges. The novel generalist community may also affect the invasive plant's defensive strategies and resource allocation. Here, we tested this hypothesis using American pokeweed (Phytolacca americana L.), a species that has become invasive in China, which is native to North America. We examined resistance, tolerance, growth and reproduction of plant populations from both China and the USA when plants were exposed to natural generalist herbivores in China. We found that leaf damage was greater for invasive populations than for native populations, indicating that plants from invasive ranges had lower resistance to herbivory than those from native ranges. A regression of the percentage of leaf damage against mass showed that there was no significant difference in tolerance between invasive and native populations, even though the shoot, root, fruit and total mass were larger for invasive populations than for native populations. These results suggest that generalist herbivores are important drivers mediating the defensive strategies and resource allocation of the invasive American pokeweed. PMID- 26097090 TI - Interprofessional anatomy education in the United Kingdom and Ireland: Perspectives from students and teachers. AB - There is increasing recognition of multiprofessional learning in anatomy and its role in medical and healthcare professions. This study utilized two components to investigate anatomy interprofessional education (AIPE) in the United Kingdom and Ireland. First, a survey involving qualitative and quantitative components asked Heads of Anatomy to report on their institutions' uptake of AIPE. Second, a series of case studies explored the experiences of students by using evaluation forms and an in-depth analysis of thematic concepts to understand the learners' perspectives on designing and delivering AIPE. Out of the 13 institutions that took part in the survey, eight did not offer an AIPE program. Between the remaining five institutions that deliver AIPE programs, 10 different modules are offered with the majority involving healthcare professions. The AIPE component is rated highly by students. The themes from the case studies highlight how valuable AIPE is from the student perspective both in terms of engaging them in anatomy as well as in the broader skills of teamwork and communication. The case studies also revealed how AIPE can be engaging for groups of students who might not have previously had access to cadaveric anatomy, for example, engineers and archeologists. The results of this study have implications for curriculum design in medicine and healthcare but also for further engagement of professional groups from non-healthcare backgrounds. PMID- 26097091 TI - Determination of diflubenzuron and chlorbenzuron in fruits by combining acetonitrile-based extraction with dispersive liquid-liquid microextraction followed by high-performance liquid chromatography. AB - In this study, a simple and low-organic-solvent-consuming method combining an acetonitrile-partitioning extraction procedure followed by "quick, easy, cheap, effective, rugged and safe" cleanup with ionic-liquid-based dispersive liquid liquid microextraction and high-performance liquid chromatography with diode array detection was developed for the determination of diflubenzuron and chlorbenzuron in grapes and pears. Ionic-liquid-based dispersive liquid-liquid microextraction was performed using the ionic liquid 1-hexyl-3-methylimidazolium hexafluorophosphate as the extractive solvent and acetonitrile extract as the dispersive solvent. The main factors influencing the efficiency of the dispersive liquid-liquid microextraction were evaluated, including the extractive solvent type and volume and the dispersive solvent volume. The validation parameters indicated the suitability of the method for routine analyses of benzoylurea insecticides in a large number of samples. The relative recoveries at three spiked levels ranged between 98.6 and 109.3% with relative standard deviations of less than 5.2%. The limit of detection was 0.005 mg/kg for the two insecticides. The proposed method was successfully used for the rapid determination of diflubenzuron and chlorbenzuron residues in real fruit samples. PMID- 26097092 TI - Silica Nanopills for Targeted Anticancer Drug Delivery. AB - Multifunctional SiO2 microtubes for targeted drug delivery are produced with precise control over shape and size by combining lithography and electrochemical etching. The hollow core is loaded with a lipophilic anticancer drug generating nanopills and an antibody is conjugated to the external surface for cancer cell targeting. Results demonstrate selective killing of neuroblastoma cells that express the cognate receptor. PMID- 26097094 TI - A Domino Oxidation/Arylation/Protodecarboxylation Reaction of Salicylaldehydes: Expanded Access to meta-Arylphenols. AB - A method that allows salicylaldehydes to be efficiently transformed into meta arylated phenol derivatives through a cascade oxidation/arylation/protodecarboxylation sequence is presented. We demonstrate that the aldehyde functional group can be used as a convenient removable directing group to control site selectivity in C-H activation. Aldehydes are easily introduced into the starting materials and the group is readily cleaved after the C-H functionalization event. PMID- 26097096 TI - The rising world of flow cytometric analysis of pollen grains. PMID- 26097095 TI - Fusion peptide P15-CSP shows antibiofilm activity and pro-osteogenic activity when deposited as a coating on hydrophilic but not hydrophobic surfaces. AB - In the context of porous bone void filler for oral bone reconstruction, peptides that suppress microbial growth and promote osteoblast function could be used to enhance the performance of a porous bone void filler. We tested the hypothesis that P15-CSP, a novel fusion peptide containing collagen-mimetic osteogenic peptide P15, and competence-stimulating peptide (CSP), a cationic antimicrobial peptide, has emerging properties not shared by P15 or CSP alone. Peptide-coated surfaces were tested for antimicrobial activity toward Streptoccocus mutans, and their ability to promote human mesenchymal stem cell (MSC) attachment, spreading, metabolism, and osteogenesis. In the osteogenesis assay, peptides were coated on tissue culture plastic and on thin films generated by plasma-enhanced chemical vapor deposition to have hydrophilic or hydrophobic character (water contact angles 63 degrees , 42 degrees , and 92 degrees , respectively). S. mutans planktonic growth was specifically inhibited by CSP, whereas biofilm formation was inhibited by P15-CSP. MSC adhesion and actin stress fiber formation was strongly enhanced by CSP, P15-CSP, and fibronectin coatings and modestly enhanced by P15 versus uncoated surfaces. Metabolic assays revealed that CSP was slightly cytotoxic to MSCs. MSCs developed alkaline phosphatase activity on all surfaces, with or without peptide coatings, and consistently deposited the most biomineralized matrix on hydrophilic surfaces coated with P15-CSP. Hydrophobic thin films completely suppressed MSC biomineralization, consistent with previous findings of suppressed osteogenesis on hydrophobic bioplastics. Collective data in this study provide new evidence that P15-CSP has unique dual capacity to suppress biofilm formation, and to enhance osteogenic activity as a coating on hydrophilic surfaces. PMID- 26097098 TI - Enhancing the stability and ecological safety of mass-reared transgenic strains for field release by redundant conditional lethality systems. AB - The genetic manipulation of agriculturally important insects now allows the development of genetic sexing and male sterility systems for more highly efficient biologically-based population control programs, most notably the Sterile Insect Technique (SIT), for both plant and animal insect pests. Tetracycline-suppressible (Tet-off) conditional lethal systems may function together so that transgenic strains will be viable and fertile on a tetracycline containing diet, but female-lethal and male sterile in tetracycline-free conditions. This would allow their most efficacious use in a unified system for sterile male-only production for SIT. A critical consideration for the field release of such transgenic insect strains, however, is a determination of the frequency and genetic basis of lethality revertant survival. This will provide knowledge essential to evaluating the genetic stability of the lethality system, its environmental safety, and provide the basis for modifications ensuring optimal efficacy. For Tet-off lethal survival determinations, development of large-scale screening protocols should also allow the testing of these modifications, and test the ability of other conditional lethal systems to fully suppress propagation of rare Tet-off survivors. If a dominant temperature sensitive (DTS) pupal lethality system proves efficient for secondary lethality in Drosophila, it may provide the safeguard needed to support the release of sexing/sterility strains, and potentially, the release of unisex lethality strains as a form of genetic male sterility. Should the DTS Prosbeta2(1) mutation prove effective for redundant lethality, its high level of structural and functional conservation should allow host-specific cognates to be created for a wide range of insect species. PMID- 26097097 TI - Intracellular calcium movements of boar spermatozoa during 'in vitro' capacitation and subsequent acrosome exocytosis follow a multiple-storage place, extracellular calcium-dependent model. AB - This work analysed intracellular calcium stores of boar spermatozoa subjected to 'in vitro' capacitation (IVC) and subsequent progesterone-induced acrosome exocytosis (IVAE). Intracellular calcium was analysed through two calcium markers with different physico-chemical properties, Fluo-3 and Rhod-5N. Indicative parameters of IVC and IVAE were also evaluated. Fluo-3 was located at both the midpiece and the whole head. Rhod-5N was present at the sperm head. This distribution did not change in any of the assayed conditions. Induction of IVC was concomitant with an increase in both head and midpiece Ca(2+) signals. Additionally, while IVC induction was concurrent with a significant (p < 0.05) increase in sperm membrane permeability, no significant changes were observed in O2 consumption and ATP levels. Incubation of boar spermatozoa in the absence of calcium showed a loss of both Ca(2+) labellings concomitantly with the sperm's inability to achieve IVC. The absence of extracellular calcium also induced a severe decrease in the percentage of spermatozoa exhibiting high mitochondrial membrane potential (hMMP). The IVAE was accompanied by a fast increase in both Ca(2+) signalling in control spermatozoa. These peaks were either not detected or much lessened in the absence of calcium. Remarkably, Fluo-3 marking at the midpiece increased after progesterone addition to sperm cells incubated in a medium without Ca(2+) . The simultaneous addition of progesterone with the calcium chelant EGTA inhibited IVAE, and this was accompanied by a significant (p < 0.05) decrease in the intensity of progesterone Ca(2+) -induced peak, O2 consumption and ATP levels. Our results suggest that boar spermatozoa present different calcium deposits with a dynamic equilibrium among them and with the extracellular environment. Additionally, the modulation role of the intracellular calcium in spermatozoa function seems to rely on its precise localization in boar spermatozoa. PMID- 26097099 TI - Interprofessional education: The magical mystery tour now less of a mystery. AB - Interprofessional education (IPE) is on today's agenda in medical education as a response to advances in medicine, the changes that have taken place in healthcare delivery, and pressures from the public and the profession. Although attention has focused on IPE in the later stages of the education program, there are benefits to be gained from the introduction of IPE in the early years. Curriculum developments supporting this include the adoption of outcome-based education and vertical integration. There is also a recognition that students' attitudes and biases are formed early in their education and the appropriate learning environment in the early years is important. Interprofessional education in the early years can also be seen as a part of a more general trend to greater collaboration in the delivery of an education program in the healthcare professions. Anatomy by incorporating IPE can help shape the future of medical education as well as being shaped by it. The possibility of success or failure with IPE can be captured with the equation IPE = (V * I)/N, where V = the IPE vision, I = the implementation strategy and N = negative perceptions of the approach. Success is more likely where there is a well thought out and shared vision for what is to be achieved, an appropriate implementation strategy and a plan to counteract a negative mind-set. PMID- 26097100 TI - Multiresidue analysis of 36 pesticides in soil using a modified quick, easy, cheap, effective, rugged, and safe method by liquid chromatography with tandem quadruple linear ion trap mass spectrometry. AB - A new method for simultaneous determination of 36 pesticides, including 15 organophosphorus, six carbamate, and some other pesticides in soil was developed by liquid chromatography with tandem quadruple linear ion trap mass spectrometry. The extraction and clean-up steps were optimized based on the quick, easy, cheap, effective, rugged, and safe method. The data were acquired in multiple reaction monitoring mode combined with enhanced product ion to increase confidence of the analytical results. Validation experiments were performed in soil samples. The average recoveries of pesticides at four spiking levels (1, 5, 50, and 100 MUg/kg) ranged from 63 to 126% with relative standard deviation below 20%. The limits of detection of pesticides were 0.04-0.8 MUg/kg, and the limits of quantification were 0.1-2.6 MUg/kg. The correlation coefficients (r(2) ) were higher than 0.990 in the linearity range of 0.5-200 MUg/L for most of the pesticides. The method allowed for the analysis of the target pesticides in the lower MUg/kg concentration range. The optimized method was then applied to the test of real soil samples obtained from several areas in China, confirming the feasibility of the method. PMID- 26097101 TI - Coupling Solar Energy into Reactions: Materials Design for Surface Plasmon Mediated Catalysis. AB - Enabled by surface plasmons, noble metal nanostructures can interact with and harvest incident light. As such, they may serve as unique media to generate heat, supply energetic electrons, and provide strong local electromagnetic fields for chemical reactions through different mechanisms. This solar-to-chemical pathway provides a new approach to solar energy utilization, alternative to conventional semiconductor-based photocatalysis. To provide readers with a clear picture of this newly recognized process, this review presents coupling solar energy into chemical reactions through plasmonic nanostructures. It starts with a brief introduction of surface plasmons in metallic nanostructures, followed by a demonstration of tuning plasmonic features by tailoring their physical parameters. Owing to their tunable plasmonic properties, metallic materials offer a platform to trigger and drive chemical reactions at the nanoscale, as systematically overviewed in this article. The design rules for plasmonic materials for catalytic applications are further outlined based on existing examples. At the end of this article, the challenges and opportunities for further development of plasmonic-mediated catalysis toward energy and environmental applications are discussed. PMID- 26097102 TI - Palladium-Catalyzed One-Pot Carbonylative Sonogashira Reaction Employing Formic acid as the CO Source. AB - A convenient palladium-catalyzed carbonylative coupling of aryl iodides and terminal alkynes with formic acid as the CO precursor has been developed. A variety of alkynones were obtained in good yields in a one-pot manner for the first time. PMID- 26097104 TI - Computationally efficient multidimensional analysis of complex flow cytometry data using second order polynomial histograms. AB - Many methods have been described for automated clustering analysis of complex flow cytometry data, but so far the goal to efficiently estimate multivariate densities and their modes for a moderate number of dimensions and potentially millions of data points has not been attained. We have devised a novel approach to describing modes using second order polynomial histogram estimators (SOPHE). The method divides the data into multivariate bins and determines the shape of the data in each bin based on second order polynomials, which is an efficient computation. These calculations yield local maxima and allow joining of adjacent bins to identify clusters. The use of second order polynomials also optimally uses wide bins, such that in most cases each parameter (dimension) need only be divided into 4-8 bins, again reducing computational load. We have validated this method using defined mixtures of up to 17 fluorescent beads in 16 dimensions, correctly identifying all populations in data files of 100,000 beads in <10 s, on a standard laptop. The method also correctly clustered granulocytes, lymphocytes, including standard T, B, and NK cell subsets, and monocytes in 9-color stained peripheral blood, within seconds. SOPHE successfully clustered up to 36 subsets of memory CD4 T cells using differentiation and trafficking markers, in 14-color flow analysis, and up to 65 subpopulations of PBMC in 33-dimensional CyTOF data, showing its usefulness in discovery research. SOPHE has the potential to greatly increase efficiency of analysing complex mixtures of cells in higher dimensions. PMID- 26097105 TI - A20-Binding Inhibitor of NF-kappaB Activation 1 is a Physiologic Inhibitor of NF kappaB: A Molecular Switch for Inflammation and Autoimmunity. PMID- 26097107 TI - Foraging in Semantic Fields: How We Search Through Memory. AB - When searching for concepts in memory--as in the verbal fluency task of naming all the animals one can think of--people appear to explore internal mental representations in much the same way that animals forage in physical space: searching locally within patches of information before transitioning globally between patches. However, the definition of the patches being searched in mental space is not well specified. Do we search by activating explicit predefined categories (e.g., pets) and recall items from within that category (categorical search), or do we activate and recall a connected sequence of individual items without using categorical information, with each item recalled leading to the retrieval of an associated item in a stream (associative search), or both? Using semantic representations in a search of associative memory framework and data from the animal fluency task, we tested competing hypotheses based on associative and categorical search models. Associative, but not categorical, patch transitions took longer to make than position-matched productions, suggesting that categorical transitions were not true transitions. There was also clear evidence of associative search even within categorical patch boundaries. Furthermore, most individuals' behavior was best explained by an associative search model without the addition of categorical information. Thus, our results support a search process that does not use categorical information, but for which patch boundaries shift with each recall and local search is well described by a random walk in semantic space, with switches to new regions of the semantic space when the current region is depleted. PMID- 26097106 TI - Hematopoietic androgen receptor deficiency promotes visceral fat deposition in male mice without impairing glucose homeostasis. AB - Androgen deficiency in men increases body fat, but the mechanisms by which testosterone suppresses fat deposition have not been elucidated fully. Adipose tissue macrophages express the androgen receptor (AR) and regulate adipose tissue remodeling. Thus, testosterone signaling in macrophages could alter the paracrine function of these cells and thereby contribute to the metabolic effects of androgens in men. A metabolic phenotyping study was performed to determine whether the loss of AR signaling in hematopoietic cells results in greater fat accumulation in male mice. C57BL/6J male mice (ages 12-14 weeks) underwent bone marrow transplant from either wild-type (WT) or AR knockout (ARKO) donors (n = 11 13 per group). Mice were fed a high-fat diet (60% fat) for 16 weeks. At baseline, 8 and 16 weeks, glucose and insulin tolerance tests were performed, and body composition was analyzed with fat-water imaging by MRI. No differences in body weight were observed between mice transplanted with WT bone marrow [WT(WTbm)] or ARKO bone marrow [WT(ARKObm)] prior to initiation of the high-fat diet. After 8 weeks of high-fat feeding, WT(ARKObm) mice exhibited significantly more visceral and total fat mass than WT(WTbm) animals. Despite this, no differences between groups were observed in glucose tolerance, insulin sensitivity, or plasma concentrations of insulin, glucose, leptin, or cholesterol, although WT(ARKObm) mice had higher plasma levels of adiponectin. Resultant data indicate that AR signaling in hematopoietic cells influences body fat distribution in male mice, and the absence of hematopoietic AR plays a permissive role in visceral fat accumulation. These findings demonstrate a metabolic role for AR signaling in marrow-derived cells and suggest a novel mechanism by which androgen deficiency in men might promote increased adiposity. The relative contributions of AR signaling in macrophages and other marrow-derived cells require further investigation. PMID- 26097109 TI - Flexible integration of visual cues in adolescents with autism spectrum disorder. AB - Although children with autism spectrum disorder (ASD) show atypical sensory processing, evidence for impaired integration of multisensory information has been mixed. In this study, we took a Bayesian model-based approach to assess within-modality integration of congruent and incongruent texture and disparity cues to judge slant in typical and autistic adolescents. Human adults optimally combine multiple sources of sensory information to reduce perceptual variance but in typical development this ability to integrate cues does not develop until late childhood. While adults cannot help but integrate cues, even when they are incongruent, young children's ability to keep cues separate gives them an advantage in discriminating incongruent stimuli. Given that mature cue integration emerges in later childhood, we hypothesized that typical adolescents would show adult-like integration, combining both congruent and incongruent cues. For the ASD group there were three possible predictions (1) "no fusion": no integration of congruent or incongruent cues, like 6-year-old typical children; (2) "mandatory fusion": integration of congruent and incongruent cues, like typical adults; (3) "selective fusion": cues are combined when congruent but not incongruent, consistent with predictions of Enhanced Perceptual Functioning (EPF) theory. As hypothesized, typical adolescents showed significant integration of both congruent and incongruent cues. The ASD group showed results consistent with "selective fusion," integrating congruent but not incongruent cues. This allowed adolescents with ASD to make perceptual judgments which typical adolescents could not. In line with EPF, results suggest that perception in ASD may be more flexible and less governed by mandatory top-down feedback. PMID- 26097110 TI - The next generation of insecticides: dsRNA is stable as a foliar-applied insecticide. AB - BACKGROUND: RNAi is a powerful tool used to study gene function. It also has been hypothesized to be a promising new method for control of insect pests on crops, although the perceived instability of dsRNA in the environment has constrained thinking about the options for this new type of pest control. RESULTS: We confirmed that foliar application of Colorado potato beetle dsRNA actin is highly effective for control, demonstrated that treatment with actin-dsRNA protects potato plants for at least 28 days under greenhouse conditions and found that the dsRNA is not readily removed by water once dried on the leaves. CONCLUSION: These new results suggest that foliar application of dsRNA could be a valuable control strategy for some pests. Technological aspects of spraying dsRNA that need to be considered in the future are discussed. PMID- 26097108 TI - 3D Printing of Scaffolds for Tissue Regeneration Applications. AB - The current need for organ and tissue replacement, repair, and regeneration for patients is continually growing such that supply is not meeting demand primarily due to a paucity of donors as well as biocompatibility issues leading to immune rejection of the transplant. In order to overcome these drawbacks, scientists have investigated the use of scaffolds as an alternative to transplantation. These scaffolds are designed to mimic the extracellular matrix (ECM) by providing structural support as well as promoting attachment, proliferation, and differentiation with the ultimate goal of yielding functional tissues or organs. Initial attempts at developing scaffolds were problematic and subsequently inspired an interest in 3D printing as a mode for generating scaffolds. Utilizing three-dimensional printing (3DP) technologies, ECM-like scaffolds can be produced with a high degree of complexity, where fine details can be included at a micrometer level. In this Review, the criteria for printing viable and functional scaffolds, scaffolding materials, and 3DP technologies used to print scaffolds for tissue engineering are discussed. Creating biofunctional scaffolds could potentially help to meet the demand by patients for tissues and organs without having to wait or rely on donors for transplantation. PMID- 26097112 TI - Finely Resolved Threshold for the Sharp M12L24/M24L48 Structural Switch in Multi Component M(n)L(2n) Polyhedral Assemblies: X-ray, MS, NMR, and Ultracentrifugation Analyses. AB - In the self-assembly of M(n)L(2n) polyhedra, the bend angle (theta) of the divalent ligand components determines the final structure. The threshold for the sharp structural switch between M12L24 and M24L48 was finely resolved to within just 4 degrees by demonstrating the exclusive formation of M12L24 cuboctahedra or M24L48 rhombicuboctahedra from two similar ligands with theta values of 130 degrees and 134 degrees . This sharp structural switch was fully confirmed by X ray crystallography, mass spectrometry, NMR spectroscopy, and ultracentrifugation analyses. PMID- 26097111 TI - The Sequence-Specific Cellular Uptake of Spherical Nucleic Acid Nanoparticle Conjugates. AB - The sequence-dependent cellular uptake of spherical nucleic acid nanoparticle conjugates (SNAs) is investigated. This process occurs by interaction with class A scavenger receptors (SR-A) and caveolae-mediated endocytosis. It is known that linear poly(guanine) (poly G) is a natural ligand for SR-A, and it has been proposed that interaction of poly G with SR-A is dependent on the formation of G quadruplexes. Since G-rich oligonucleotides are known to interact strongly with SR-A, it is hypothesized that SNAs with higher G contents would be able to enter cells in larger amounts than SNAs composed of other nucleotides, and as such, cellular internalization of SNAs is measured as a function of constituent oligonucleotide sequence. Indeed, SNAs with enriched G content show the highest cellular uptake. Using this hypothesis, a small molecule (camptothecin) is chemically conjugated with SNAs to create drug-SNA conjugates and it is observed that poly G SNAs deliver the most camptothecin to cells and have the highest cytotoxicity in cancer cells. Our data elucidate important design considerations for enhancing the intracellular delivery of spherical nucleic acids. PMID- 26097113 TI - Fermentation broth components influence droplet coalescence and hinder advanced biofuel recovery during fermentation. AB - Developments in synthetic biology enabled the microbial production of long chain hydrocarbons, which can be used as advanced biofuels in aviation or transportation. Currently, these fuels are not economically competitive due to their production costs. The current process offers room for improvement: by utilizing lignocellulosic feedstock, increasing microbial yields, and using cheaper process technology. Gravity separation is an example of the latter, for which droplet growth by coalescence is crucial. The aim of this study was to study the effect of fermentation broth components on droplet coalescence. Droplet coalescence was measured using two setups: a microfluidic chip and regular laboratory scale stirred vessel (2 L). Some fermentation broth components had a large impact on droplet coalescence. Especially components present in hydrolysed cellulosic biomass and mannoproteins from the yeast cell wall retard coalescence. To achieve a technically feasible gravity separation that can be integrated with the fermentation, the negative effects of these components on coalescence should be minimized. This could be achieved by redesign of the fermentation medium or adjusting the fermentation conditions, aiming to minimize the release of surface active components by the microorganisms. This way, another step can be made towards economically feasible advanced biofuel production. PMID- 26097115 TI - Corrigendum: Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for Ultraviolet-A-Induced Photouncaging. PMID- 26097118 TI - Light-Driven Reversible Alignment Switching of Liquid Crystals Enabled by Azo Thiol Grafted Gold Nanoparticles. AB - Stimuli-directed alignment control of liquid crystals (LCs) with desired molecular orientation is currently in the limelight for the development of smart functional materials and devices. Here, photoresponsive azo thiol (AzoSH) was grafted onto gold nanoparticles (GNPs). The resulting hybrid GNPs were able to homogeneously mix with a commercially available nematic LC host, as evidenced by Cryo-TEM. Interestingly, the LC nanocomposites were found to undergo reversible alignment transition upon light irradiation as a consequence of the trans-cis photoisomerization of the azo groups on the GNP surface. LC molecules in either planar or bare glass cells were able to change their alignment to vertical upon UV irradiation, while the vertically aligned LC molecules returned to the planar or random orientation under visible irradiation. Neither the azo thiol molecules nor the unfunctionalized GNPs alone promoted the alignment of the LC molecules in the system upon light irradiation. The photoinduced vertical alignment without applied electric or magnetic field was very stable over time and with respect to temperature. Furthermore, an optically switchable device based on the photostimulated reversible alignment control of LCs was demonstrated. PMID- 26097120 TI - Therapeutic advances in the treatment of Peyronie's disease. AB - Peyronie's disease (PD) is an under-diagnosed condition with prevalence in the male population as high as 9%. It is a localized connective tissue disorder of the penis characterized by scarring of the tunica albuginea. Its pathophysiology, however, remains incompletely elucidated. For the management of the acute phase of PD, there are currently numerous available oral drugs, but the scientific evidence for their use is weak. In terms of intralesional injections, collagenase clostridium histolyticum is currently the only Food and Drug Administration approved drug for the management of patients with PD and a palpable plaque with dorsal or dorsolateral curvature >30 degrees . Other available intralesional injectable drugs include verapamil and interferon-alpha-2B, however, their use is considered off-label. Iontophoresis, shockwave therapy, and radiation therapy have also been described with unconvincing results, and as such, their use is currently not recommended. Traction therapy, as part of a multimodal approach, is an underused additional tool for the prevention of PD-associated loss of penile length, but its efficacy is dependent on patient compliance. Surgical therapy remains the gold standard for patients in the chronic phase of the disease. In patients with adequate erectile function, tunical plication and/or incision/partial excision and grafting can be offered, depending on degree of curvature and/or presence of destabilizing deformity. In patients with erectile dysfunction non-responsive to oral therapy, insertion of an inflatable penile prosthesis with or without straightening procedures should be offered. PMID- 26097119 TI - Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. AB - OBJECTIVE: Antiphospholipid antibodies (aPL), especially those targeting beta2 glycoprotein I (beta2 GPI), are well known to activate endothelial cells, monocytes, and platelets, with prothrombotic implications. In contrast, the interaction of aPL with neutrophils has not been extensively studied. Neutrophil extracellular traps (NETs) have recently been recognized as an important activator of the coagulation cascade, as well as an integral component of arterial and venous thrombi. This study was undertaken to determine whether aPL activate neutrophils to release NETs, thereby predisposing to the arterial and venous thrombosis inherent in the antiphospholipid syndrome (APS). METHODS: Neutrophils, sera, and plasma were prepared from patients with primary APS (n = 52) or from healthy volunteers and characterized. No patient had concomitant systemic lupus erythematosus. RESULTS: Sera and plasma from patients with primary APS had elevated levels of both cell-free DNA and NETs, as compared to healthy volunteers. Freshly isolated neutrophils from patients with APS were predisposed to high levels of spontaneous NET release. Further, APS patient sera, as well as IgG purified from APS patients, stimulated NET release from control neutrophils. Human aPL monoclonal antibodies, especially those targeting beta2 GPI, also enhanced NET release. The induction of APS NETs was abrogated with inhibitors of reactive oxygen species formation and Toll-like receptor 4 signaling. Highlighting the potential clinical relevance of these findings, APS NETs promoted thrombin generation. CONCLUSION: Our findings indicate that NET release warrants further investigation as a novel therapeutic target in APS. PMID- 26097121 TI - The Role of Sequential Dependence in Creative Semantic Search. PMID- 26097122 TI - Targeted Therapy for Breast Cancer Stem Cells by Liposomal Delivery of siRNA against Fibronectin EDB. AB - Targeted therapy for breast cancer stem cell (BCSC): A novel liposomal system (APTEDB -LS-siRNA(EDB) ) that enables simultaneous targeting and knockdown of extra domain B of fibronectin (EDB-FN) shows potent therapeutic efficacy in the BCSC-derived tumors in vivo. PMID- 26097123 TI - Genetic basis of Spodoptera frugiperda (Lepidoptera: Noctuidae) resistance to the chitin synthesis inhibitor lufenuron. AB - BACKGROUND: An understanding of the genetic basis of insect resistance to insecticides is important for the establishment of insect resistance management (IRM) strategies. In this study we evaluated the inheritance pattern of resistance to the chitin synthesis inhibitor lufenuron in Spodoptera frugiperda. RESULTS: The LC50 values (95% CI) were 0.23 ug lufenuron mL(-1) water (ppm) (0.18 0.28) for the susceptible strain (SUS) and 210.6 ug mL(-1) (175.90-258.10) for the lufenuron-resistant strain (LUF-R), based on diet-overlay bioassay. The resistance ratio was ~ 915-fold. The LC50 values for reciprocal crosses were 4.89 ug mL(-1) (3.79-5.97) for female LUF-R and male SUS and 5.74 ug mL(-1) (4.70 6.91) for female SUS and male LUF-R, indicating that the inheritance of S. frugiperda resistance to lufenuron is an autosomal, incompletely recessive trait. Backcrosses of the progeny of reciprocal crosses with the parental LUF-R showed a polygenic effect. The estimated minimum number of independent segregations was in the 11.02 range, indicating that resistance to lufenuron is associated with multiple genes in S. frugiperda. CONCLUSIONS: Based on genetic crosses, the inheritance pattern of lufenuron resistance in S. frugiperda was autosomal, incompletely recessive and polygenic. Implications of this finding to IRM are discussed in this paper. PMID- 26097124 TI - Capturing C90 Isomers as CF3 Derivatives: C90 (30)(CF3)14, C90 (35)(CF3)16/18 , and C90 (45)(CF3)16/18. AB - High-temperature trifluoromethylation of a C90 isomeric mixture with CF3 I followed by HPLC separation of C90 (CF3)n isomers resulted in the isolation of several individual C90 (CF3)14-18 compounds. Single crystal X-ray diffraction with the use of synchrotron radiation resulted in the structure determination of C90 (30)(CF3)14 , C90 (35)(CF3)16/18 , and C90 (45)(CF3)16/18 . Their addition patterns are discussed and compared with the known isomers C90 (30)(CF3)18 and C90 (35)(CF3)14 , respectively. The presence of the most stable C90 isomer, C90 (45), in the fullerene soot has been confirmed for the first time. PMID- 26097125 TI - Coculture with Low-Dose SWCNT Attenuates Bacterial Invasion and Inflammation in Human Enterocyte-like Caco-2 Cells. AB - Single walled carbon nanotubes (SWCNTs) have been shown to be highly effective against a wide range of bacteria. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) infection is a well-known mediator to prolong hospitalization and initiate chronic inflammation, yet the biological effects of SWCNTs on the pathogen-infected enterocytes remain unclear. Herein, it is shown that the low dose SWCNT treatment attenuates the human enterocyte-like Caco-2 cells from the damage of E. coli and S. aureus infection by suppressing NLRP3 inflammasome activation. The relatively low-dose (1 and 10 MUg mL(-1) ) SWCNT treatments reduce the adhesion and invasion of E. coli and S. aureus to Caco-2 cells, increase the cell viability and proliferation, reduce the tight junction permeability, and restitute the integrity of cell surface microvilli structure, meanwhile has low cytotoxicity to the host cells. The low-dose SWCNT treatment further reduces the NLRP3-mediated IL-1beta secretion in the infected cells. The results identify that a low-dose SWCNT treatment serves a protective function for the E. coli- and S. aureus-infected Caco-2 cells by negatively regulating mitochondrial reactive oxygen species-mediated NLRP3 inflammasome activation. PMID- 26097126 TI - High-content imaging with micropatterned multiwell plates reveals influence of cell geometry and cytoskeleton on chromatin dynamics. AB - Understanding the mechanisms underpinning cellular responses to microenvironmental cues requires tight control not only of the complex milieu of soluble signaling factors, extracellular matrix (ECM) connections and cell-cell contacts within cell culture, but also of the biophysics of human cells. Advances in biomaterial fabrication technologies have recently facilitated detailed examination of cellular biophysics and revealed that constraints on cell geometry arising from the cellular microenvironment influence a wide variety of human cell behaviors. Here, we create an in vitro platform capable of precise and independent control of biochemical and biophysical microenvironmental cues by adapting microcontact printing technology into the format of standard six- to 96 well plates to create MicroContact Printed Well Plates (MUCP Well Plates). Automated high-content imaging of human cells seeded on MUCP Well Plates revealed tight, highly consistent control of single-cell geometry, cytoskeletal organization, and nuclear elongation. Detailed subcellular imaging of the actin cytoskeleton and chromatin within live human fibroblasts on MUCP Well Plates was then used to describe a new relationship between cellular geometry and chromatin dynamics. In summary, the MUCP Well Plate platform is an enabling high-content screening technology for human cell biology and cellular engineering efforts that seek to identify key biochemical and biophysical cues in the cellular microenvironment. PMID- 26097127 TI - Long-term in vitro hydrolytic stability of thermoplastic polyurethanes. AB - Long-term in vitro stability of thermoplastic polyurethanes (TPUs) was studied for up to 52 weeks in phosphate buffer solution at 37, 55, and 80 degrees C. Water uptake, molecular weights, and tensile properties were measured at regular intervals of 4, 8, 16, 32, and 52 weeks. The rate of molecular weight reduction increased with increasing temperature, and after 52 weeks at 80 degrees C, all commercial polycarbonate (Bionate-55D, Quadrathane-80A, and Chronoflex-80A), poly(dimethylsiloxane) (ElastEon-2A) and polyether (Elasthane-55D) TPUs showed significant (43-51%) molecular weight (Mn ) reduction. The polyisobutylene (PIB) based TPU exhibited a significantly lower decrease in Mn (26%) after 52 weeks at 80 degrees C. For Bionate-55D and ElastEon-2A, at 80 degrees C in dry nitrogen atmosphere substantial thermal degradation was observed, while for the other TPUs the effect of thermal degradation is small. The temperature dependent reduction of molecular weight was interpreted by simple second order kinetics. From the approximately linear Arrhenius plots the activation energies were calculated, which were highest for PIB-PU-020 and lowest for ElastEon-2A. For Elasthane-55D the in vitro molecular weight reduction was compared with that of explanted leads. The molecular weight reduction in vivo was much smaller than that predicted from in vitro data, which may suggest that the in vitro model does not adequately describe the hydrolysis in vivo. In the absence of validation for the other TPUs that in vitro methods closely reproduce in vivo degradation, it is unknown how these results correlate with in vivo performance. PMID- 26097128 TI - Aqueous Bronsted-Lowry Chemistry of Ionic Liquid Ions. AB - Ionic liquids have become commonplace materials found in research laboratories the world over, and are increasingly utilised in studies featuring water as co solvent. It is reported herein that proton activities, aH (+) , originating from auto-protolysis of H2O molecules, are significantly altered in mixtures with common ionic liquids comprised of Cl(-), [HSO4 ](-), [CH3SO4 ](-), [CH3COO](-), [BF4](-), relative to pure water. paH (+) values, recorded in partially aqueous media as -log(aH (+)), are observed over a wide range (~0-13) as a result of hydrolysis (or acid dissociation) of liquid salt ions to their associated parent molecules (or conjugate bases). Bronsted-Lowry acid-base character of ionic liquid ions observed is rooted in equilibria known to govern the highly developed aqueous chemistry of classical organic and inorganic salts, as their well-known aqueous pKs dictate. Classical salt behaviour observed for both protic and aprotic ions in the presence of water suggests appropriate attention need be given to relevant chemical systems in order to exploit, or avoid, the nature of the medium formed. PMID- 26097129 TI - Is anogenital distance associated with semen quality in male partners of subfertile couples? AB - Experimental studies have shown that anogenital distance (AGD) at birth reflects androgen concentrations during prenatal development and predicts adult AGD. In male rodents, shortened AGD is associated with compromised reproductive function. The aim of this study was to examine associations between AGD measures and semen quality in male partners of subfertile couples. All men were attending an infertility service and provided a semen sample and completed epidemiological questionnaires on lifestyle and general health. Two variants of AGD [from the anus to the posterior base of the scrotum (AGDAS) and to the cephalad insertion of the penis (AGDAP)] were assessed in 91 men. Semen parameters (semen volume, sperm concentration, total sperm counts, motility, and morphology) were determined following WHO guidelines. Associations between AGD measures and semen quality were tested using multiple regression analyses controlling for appropriate covariates. Significant positive associations between AGDAS measures and sperm concentration, total sperm count, and total sperm motile count were detected (p-values < 0.05). This study represents the first analysis of AGD in potential infertile European men showing an association between perineal length and semen parameters. However, it is still uncertain the utility to clinical practice, therefore further studies are warranted to confirm and extent these findings. PMID- 26097130 TI - Interfacing Mind and Environment: The Central Role of Search in Cognition. AB - Search can be found in almost every cognitive activity, ranging across vision, memory retrieval, problem solving, decision making, foraging, and social interaction. Because of its ubiquity, research on search has a tendency to fragment into multiple areas of cognitive science. The proposed topic aims at providing integrative discussion of the central role of search from multiple perspectives. We focus on controlled search processes, which require (a) a goal, (b) uncertainty about the nature, location, or acquisition method of the objects to be searched for, and (c) a method for sampling through the search environment. While this definition of search is general and applicable to different domains, the specific mechanisms in the search process will likely differ. The goal of this issue is to compare and contrast how these search processes are similar and differ in different cognitive activities, with the goal of understanding the general nature of search in terms of the three characteristics stated above. We expect that given its cross-domain nature, the topic on search will be of broad interest to cognitive scientists, including psychologists, behavioral ecologists, computer scientists, neuroscientists, linguists, and sociologists. PMID- 26097131 TI - Inhibition of Cancer Cell Migration by Multiwalled Carbon Nanotubes. AB - Inhibiting cancer cell migration and infiltration to other tissues makes the difference between life and death. Multiwalled carbon nanotubes (MWCNTs) display intrinsic biomimetic properties with microtubules, severely interfering with the function of these protein filaments during cell proliferation, triggering cell death. Here it is shown MWCNTs disrupt the centrosomal microtubule cytoskeletal organization triggering potent antimigratory effects in different cancer cells. PMID- 26097132 TI - Genetic basis, evolutionary origin and spread of resistance to herbicides inhibiting acetolactate synthase in common groundsel (Senecio vulgaris). AB - BACKGROUND: Following control failure by herbicides inhibiting acetolactate synthase (ALS) in French wheat fields and vineyards, we aimed to confirm resistance evolution and investigate the evolutionary origin and spread of resistance in the tetraploid species Senecio vulgaris (common groundsel), a widespread, highly mobile weed. RESULTS: Sequencing of two ALS homeologues in S. vulgaris enabled the first identification and characterisation of ALS-based resistance in this species. Cross-resistance patterns associated with Leu-197 and Ser-197 ALS1 were established using eight herbicides. Sequencing and genotyping showed that ALS-based resistance evolved by multiple, independent appearances of mutant ALS1 and ALS2 alleles followed by spread. Spread of a mutant ALS1 allele issued from one particular appearance event was observed over 60 km. Independent resistance appearance events and easy seed dispersion are the most likely reasons for populations of S. vulgaris containing different mutant ALS alleles. Accumulation of different alleles probably due to sexual reproduction was observed in the same plant. CONCLUSION: Mutant ALS alleles and possibly other mechanisms cause resistance to ALS inhibitors in S. vulgaris. Management strategies should aim at limiting S. vulgaris establishment and seed set. Considering the mobility of this species, control coordination at a regional level is clearly necessary if resistance spread is to be contained. PMID- 26097133 TI - Nano PdAu Bimetallic Alloy as an Effective Catalyst for the Buchwald-Hartwig Reaction. AB - It is highly challenging but desirable to develop efficient heterogeneous catalysts for C-Cl bond activation in coupling reactions. Here, we succeeded in synthesizing bimetallic Pd-Au nanoparticles through a convenient one-pot wet chemical route. The composition and alloyed structure of the as-prepared nanoparticles were fully characterized. We have evaluated the catalytic activity of these Pd-Au alloy catalysts in Buchwald-Hartwig reactions of aryl chlorides. The excellent catalytic activity of the as-obtained Pd-Au nanoparticles indicates that exploiting the catalytic power of nano-alloy catalysts could enable effective C-Cl bond activation suitable for cross-coupling reactions. PMID- 26097134 TI - Bioinspired, Ultrastrong, Highly Biocompatible, and Bioactive Natural Polymer/Graphene Oxide Nanocomposite Films. AB - Tough and biocompatible nanocomposite films: A new type of bioinspired ultrastrong, highly biocompatible, and bioactive konjac glucomannan (KGM)/graphene oxide (GO) nanocomposite film is fabricated on a large scale by a simple solution-casting method. Such KGM-GO composite films exhibit much enhanced mechanical properties under the strong hydrogen-bonding interactions, showing great potential in the fields of tissue engineering and food package. PMID- 26097135 TI - Engineering surface hydrophobicity improves activity of Bacillus thermocatenulatus lipase 2 enzyme. AB - Bacillus thermocatenulatus lipase 2 (BTL2) is a promising industrial enzyme used in biodiesel production. Although BTL2 has high thermostability and good resistance to organic solvents, the activity of BTL2 is suboptimal for industrial processes. To improve BTL2 activity, we engineered BTL2 lipase by modulating hydrophobicity of its lid domain. Through site-directed mutagenesis, we constructed three mutants, namely Y225F+S232A, S232A+T236V and Q185L, to cover all uncharged hydrophilic amino acids within the lid domain. Activities of these mutants were characterized. Our findings suggest that one mutant (Y225F+S232A) showed ~35% activity increase in catalyzing heterogeneous hydrolytic reactions relevant for industrial applications. A mathematical framework was established to account for different molecular events that contribute to the observed apparent catalytic activities. Increases in hydrophobicity of lid domains were associated with increased interfacial adsorption of lipases and lower molecular enzymatic activities. The measured apparent activities of lipases include contributions from both events. Lid hydrophobicity can thus result in different changes in lipase activities depending on the mutation site. Our work demonstrates the feasibility of increasing BTL2 activity by modulating the hydrophobicity of lid domains and provides some guidelines for further improving BTL2 activity. PMID- 26097136 TI - Rapid fabrication system for three-dimensional tissues using cell sheet engineering and centrifugation. AB - Three-dimensional (3D) tissues can be reconstructed by cell sheet technology, and various clinical researches using these constructed tissues have already been initiated to regenerate damaged tissues. While 3D tissues can be easily fabricated by layering cell sheets, the attachment period for cell adhesion between a cell sheet and a culture dish, or double-layered cell sheets normally takes 20-30 min. This study proposed a more rapid fabrication system for bioengineered tissue using cell sheet technology and centrifugation. A C2C12 mouse myoblast sheet harvested from a temperature-responsive culture dish will attach tightly to a culture dish or another cell sheet at 37 degrees C after a 20 min-incubation. However, the same cell sheet centrifuged (12-34 * g) for 3 min also attached tightly to a dish or another cell sheet at 37 degrees C after only a 3 min-incubation. The manipulation time was reduced by approximately two-thirds by centrifugation. The rapid attachments were also cross-sectionally confirmed by optical coherence tomography. These rapidly constructed cell sheet-tissues using centrifugation showed active cell metabolism, cell viability, and very high production of vascular endothelial growth factor, like those prepared by the conventional method; indicating complete cell sheet-attachment without any cell damage. This new system will be a powerful tool in the fields of cell sheet-based tissue engineering and regenerative medicine, and accelerate the use of cell sheets in clinical applications. PMID- 26097137 TI - Modeling the HCOOH/CO2 Electrocatalytic Reaction: When Details Are Key. AB - Our first principles simulations of the electrooxidation of formic acid over nickel identify the reorientation of the formate intermediate and the desorption of CO2 as the rate-limiting steps. Although they are not associated with an electron transfer, these barriers are strongly modified when the electrochemical potential is explicitly accounted for and when modeling the influence of the solvent. Hence, such a level of modeling is key to understand the kinetic limitations that penalize the reaction. PMID- 26097138 TI - Strongyloides stercoralis hyperinfection causing eosinophilic ascites. AB - Strongyloidiasis is associated with Strongyloides stercoralis, an intestinal nematode with greater prevalence in tropical and subtropical regions. Hyperinfection syndrome with dissemination may occur in immunosuppressed individuals. However, invasion of peritoneal cavity with peritoneal effusion is rarely reported in the literature. We report a case of S. stercoralis hyperinfection in a young alcoholic patient with Diabetes mellitus, liver disease and ascites. Diagnostic paracentesis showed numerous filariform larvae of S. stercoralis against a background of eosinophils. PMID- 26097139 TI - Associations of sedentary time patterns and TV viewing time with inflammatory and endothelial function biomarkers in children. AB - OBJECTIVE: Investigate associations of TV viewing time and accelerometry-derived sedentary time with inflammatory and endothelial function biomarkers in children. METHODS: Cross-sectional analysis of 164 7-10-year-old children. TV viewing time was assessed by parental proxy report and total and patterns of sedentary time accumulation (e.g. prolonged bouts) were assessed by accelerometry. C-reactive protein (CRP), homeostasis model assessment of insulin resistance, interleukin-2, -6, -8, -10, tumour necrosis factor alpha, adiponectin, resistin, brain-derived neurotrophic factor, soluble intercellular and vascular adhesion molecule 1, plasminogen activator inhibitor 1 and soluble E-selectin were assessed. Generalised linear models assessed the associations of TV viewing and sedentary time with biomarkers, adjusting for sex, waist circumference, moderate- to vigorous-intensity physical activity and diet density. RESULTS: Each additional h week(-1) of TV viewing was associated with 4.4% (95% CI: 2.1, 6.7) greater CRP and 0.6% (0.2, 1.0) greater sVCAM-1 in the fully adjusted model. The association between frequency and duration of 5-10 min bouts of sedentary time and CRP was positive after adjustment for sex and waist circumference but attenuated after adjustment for diet density. CONCLUSIONS: This study suggests that TV viewing was unfavourably associated with several markers of inflammation and endothelial dysfunction. The detrimental association between 5 and 10 min bouts of sedentary time and CRP approached significance, suggesting that further research with a stronger study design (longitudinal and/or experimental) is needed to better understand how the accumulation of sedentary time early in life may influence short and longer term health. PMID- 26097140 TI - Schwann Cell Contact Guidance versus Boundary -Interaction in Functional Wound Healing along Nano and Microstructured Membranes. AB - Peripheral nerve transection is often encountered after trauma and can lead to long-term/permanent loss of sensor/motor functionality. Here, the effect of pure contact interaction of nano/microgrooved substrates on Schwann cells (SCs) is studied in view of their possible use for nerve-repair applications. Elastomeric gratings (GRs; i.e., alternating lines of ridges and grooves) are developed with different lateral periods (1-20 MUm) and depths (0.3-2.5 MUm), leading to two distinct cell-material interaction regimes: contact guidance (grating period < cell body diameter) and boundary guidance (grating period >= cell body diameter). Here, it is shown that boundary guidance leads to the best single-cell polarization, actin organization, and single-cell directional migration. Remarkably, contact guidance is instead more effective in driving collective SC migration and improves functional wound healing. It is also demonstrated that this behavior is linked to the properties of the SC monolayers on different GRs. SCs on large-period GRs are characterized by N-Cadherin downregulation and enhanced single-cell scattering into the wound with respect to SCs on small period GRs, indicating a less compact monolayer characterized by looser cell-cell junctions in the boundary guidance regime. The present results provide information on the impact of specific sub-micrometer topographical elements on SC functional response, which can be exploited for nerve-regeneration applications. PMID- 26097141 TI - Plasmon-Assisted Production of Reactive Oxygen Species by Single Gold Nanorods. PMID- 26097142 TI - Novel Highly Energetic Pyrazoles: N-Trinitromethyl-Substituted Nitropyrazoles. AB - A new family of energetic compounds, nitropyrazoles bearing a trinitromethyl moiety at the nitrogen atom of the heterocycle, was designed. The desirable high energy dense oxidizers 3,4-dinitro- and 3,5-dinitro-1-(trinitromethyl)pyrazoles were synthesized in good yields by destructive nitration of the corresponding 1 acetonylpyrazoles. All of the prepared compounds were fully characterized by multinuclear NMR and IR spectroscopy, as well as by elemental analysis. Single crystal X-ray diffraction studies show remarkably high density. Impact sensitivity tests and thermal stability measurements were also performed. All of the pyrazoles possess positive calculated heats of formation and exhibit promising energetic performance that is the range of 1,3,5-trinitroperhydro-1,3,5 triazine and pentaerythritol tetranitrate. The new pyrazoles exhibit positive oxygen balance and are promising candidates for new environmentally benign energetic materials. PMID- 26097143 TI - Sublethal doses of fipronil intensify synapsin immunostaining in Atta sexdens rubropilosa (Hymenoptera: Formicidae) brains. AB - BACKGROUND: Although ants are common insects in agricultural ecosystems, few studies have considered how xenobiotics might induce physiological and morphological alterations in these insects. This study aimed to verify the neurotoxic action of sublethal doses of fipronil on the mushroom bodies of brains from the leaf-cutting ant Atta sexdens rubropilosa through immunocytochemistry analysis for the protein synapsin. RESULTS: The LD50 value was established as 1.42 ng ant(-1), and the sublethal doses used were LD50/10 and LD50/100. Synapsin labelling was more evident in the brains extracted from ants exposed to the insecticide, specifically in the regions of glia in the mushroom bodies, compared with the control group. It was possible to measure the intensity of emitted fluorescence in the areas of the mushroom bodies, and a statistical test showed differences between the control group and the treatment group. CONCLUSION: Thus, it is concluded that sublethal doses of the insecticide fipronil intensified synapsin immunostaining, suggesting an increased release of neurotransmitters, which may be linked to neurotoxicity and overexcitation. These sublethal doses may have two different effects: compromising the operation and maintenance of the colony and leading to the establishment of resistance in insects. PMID- 26097144 TI - Polycan suppresses osteoclast differentiation and titanium particle-induced osteolysis in mice. AB - Particle-induced osteolysis is a major issue, and it is most likely the result of enhanced osteoclast activation in the pathogenesis of various skeletal diseases. This study investigated whether the inhibitory effect that Polycan has on osteoclast differentiation can be used to treat osteolysis induced by titanium (Ti) particles. To this end, the effects of Polycan were examined in terms of the cytotoxicity, osteoclast differentiation, cytokine expression, and Ti-induced calvarial osteolysis. Polycan had no significant cytotoxic effects on bone marrow macrophages (BMMs) but instead increased BMM proliferation. High levels of interleukin (IL)-6, IL-12, and macrophage colony-stimulating factor (M-CSF) were expressed in BMM cells in the presence of Polycan, suggesting that Polycan drives the differentiation of BMMs into M1 macrophages. Polycan significantly inhibited osteoclast differentiation induced by M-CSF and the receptor activator of nuclear factor kappa-B ligand (RANKL). The expression levels of the osteoclast marker genes significantly decreased, and Polycan induced and maintained the expression of IL-12, which suppressed osteoclast differentiation. In contrast, the RANKL signaling pathway was not inhibited by Polycan. An in vivo calvarial osteolysis model revealed that Polycan significantly decreased the osteoclast numbers and suppressed osteolysis. Our results suggest that the natural compound Polycan is a good candidate for therapeutic intervention against enhanced osteoclast differentiation and Ti particle-induced osteolysis. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1170-1175, 2016. PMID- 26097145 TI - Why Is the Spontaneous Deprotonation of [Cu(uracil)2](2+) Complexes Accompanied by Enolization of the System? AB - The reaction-force formalism is applied to carry out a detailed analysis of the mechanisms behind the enolization processes undergone by the complexes formed on interaction of uracil dimers with Cu(2+) ions after spontaneous deprotonation of the resulting complexes. These enolization processes apparently involve a single proton transfer (PT) from an NH group to a carbonyl group of the same uracil moiety, which should involve a rather high activation barrier that prevents the process occurring. However, the reaction-force, chemical-potential, and electronic-flux profiles unambiguously indicate that the actual mechanism involves three low-barrier elementary steps, and this explains why enolization of the [Cu(uracil-H)(uracil)](+) complexes is a highly facile, assisted PT process. All of the observed PT processes show a typical profile for both the chemical potential and the electronic flux associated with the bond-breaking and the bond formation processes. PMID- 26097146 TI - Calcium phosphate nanoparticles carrying BMP-7 plasmid DNA induce an osteogenic response in MC3T3-E1 pre-osteoblasts. AB - Functionalized calcium phosphate nanoparticles with osteogenic activity were prepared. Polyethyleneimine-stabilized calcium phosphate nanoparticles were coated with a shell of silica and covalently functionalized by silanization with thiol groups. Between the calcium phosphate surface and the outer silica shell, plasmid DNA which encoded either for bone morphogenetic protein 7 (BMP-7) or for enhanced green fluorescent protein was incorporated as cargo. The plasmid DNA loaded calcium phosphate nanoparticles were used for the transfection of the pre osteoblastic MC3T3-E1 cells. The cationic nanoparticles showed high transfection efficiency together with a low cytotoxicity. Their potential to induce an osteogenic response by transfection was demonstrated by measuring the alkaline phosphatase (ALP) activity and calcium deposition with alizarin red staining. The expression of the osteogenic markers Alp, Runx2, ColIa1 and Bsp was investigated by means of real-time quantitative polymerase chain reaction. It was shown that phBMP-7-loaded nanoparticles can provide a means of transient transfection and localized production of BMP-7 in MC3T3-E1 cells, with a subsequent increase of two osteogenic markers, specifically ALP activity and calcium accumulation in the extracellular matrix. Future strategies to stimulate bone regeneration focus into enhancing transfection efficiency and achieving higher levels of BMP-7 produced by the transfected cells. PMID- 26097147 TI - Re-programming CHO cell metabolism using miR-23 tips the balance towards a highly productive phenotype. AB - microRNA engineering of CHO cells has already proved successful in enhancing various industrially relevant phenotypes and producing various recombinant products. A single miRNA's ability to interact with multiple mRNA targets allows their regulatory capacity to extend to processes such as cellular metabolism. Various metabolic states have previously been associated with particular CHO cell phenotypes such as glycolytic or oxidative metabolism accommodating growth and productivity, respectively. miR-23 has previously been demonstrated to play a role in glutamate metabolism resulting in enhanced oxidative phosphorylation through the TCA cycle. Re-programming cellular bioenergetics through miR-23 could tip the balance, forcing mammalian production cells to be more productive by favoring metabolic channelling into oxidative metabolism. CHO clones depleted of miR-23 using a miR-sponge decoy demonstrated an average ~three-fold enhanced specific productivity with no impact on cell growth. Using a cell respirometer, mitochondrial activity was found to be enhanced by ~30% at Complex I and II of the electron transport system. Additionally, label-free proteomic analysis uncovered various potential novel targets of miR-23 including LE1 and IDH1, both implicated in oxidative metabolism and mitochondrial activity. These results demonstrate miRNA-based engineering as a route to re-programming cellular metabolism resulting in increased productivity, without affecting growth. PMID- 26097148 TI - Low grandparental social support combined with low parental socioeconomic status is closely associated with obesity in preschool-aged children: a pilot study. AB - While the influence of parental socioeconomic status (SES) on children's weight status is well known, the impact of other family-related aspects such as parental and grandparental social support is less understood. This study investigates the importance of parents' SES and social support (functional and structural) for weight status in a clinical sample of preschoolers 4-6 years old with obesity (n = 39, 56% girls; 73% of parents were overweight/obese, 50% were of non-Swedish origin). Linear regression analyses, simple and multiple, were performed on SES and social support with child BMI SDS (body mass index standard deviation score) as the dependent variable. The results show that parents' income and low emotional support from paternal grandparents were significantly associated with more severe obesity. The association between parental income and the child's BMI SDS was stronger among parents who had low emotional support from their own parents. In conclusion, grandparental social support may be protective against childhood obesity. PMID- 26097149 TI - Cardiac phenotype determines survival in Duchenne muscular dystrophy. AB - OBJECTIVE: To identify determinants of survival by comparing cardiopulmonary function in two patient groups: prolonged survivors of Duchenne muscular dystrophy (DMD) versus DMD patients who experienced early death (ED). METHODS: Retrospective chart review of our DMD patients from 1999 to 2013. Prolonged Survival (PS) was defined as alive and >=30 years old. Early death (ED) was defined as death at < 30 years old. EXCLUSION CRITERIA: steroid therapy. RESULTS: Eleven patients met criteria for PS and 14 patients for ED (mean age +/- SD: 34.3 +/- 4.3 years vs. 21.7 +/- 3.8 years, respectively; P < 0.001). Pulmonary function was better in the ED patients: all PS patients had a vital capacity of 0 ml (n = 11) versus 23% (3/13) of the ED patients (P < 0.001). Thirteen of 14 ED patients and all PS patients received assisted ventilation. Heart function was worse in the ED patients: ejection fraction (EF) was 42.2 +/- 14.2% in the PS patients (n = 11) versus 29.2 +/- 14.1% in the ED patients (n = 13; P = 0.035). Dilated cardiomyopathy was present in 36% (4/11) of PS patients versus 78% (11/14) of ED patients (P =0.048). Among ED patients, 57% (8/14) died from progressive cardiomyopathy. CONCLUSION: In our study group, good heart function was a pre-condition for PS and poor heart function was the primary cause of early death. Our results suggest that, when DMD patients are treated with assisted ventilation, heart function is the main determinant of their survival. PMID- 26097151 TI - Selective Nanotrench Filling by One-Pot Electroclick Self-Constructed Nanoparticle Films. AB - Integration of nanoparticles (NPs) into nanodevices is a challenge for enhanced sensor development. Using NPs as building blocks, a bottom-up approach based on one-pot morphogen-driven electroclick chemistry is reported to self-construct dense and robust conductive Fe3O4 NP films. Deposited covalent NP assemblies establish an electrical connection between two gold electrodes separated by a 100 nm-wide nanotrench. PMID- 26097150 TI - Surface Tension Triggered Wetting and Point of Care Sensor Design. AB - Rapid, simple, and inexpensive point-of-care (POC) medical tests are of significant need around the world. The transition between nonwetting and wetted states is used to create instrument-free surface tension sensors for POC diagnosis, using a layered electrospun mesh with incorporated dye to change color upon wetting. PMID- 26097152 TI - Probing the Primary Photochemical Processes of Octahedral Iron(V) Formation with Femtosecond Mid-infrared Spectroscopy. AB - Species containing iron at an oxidation state higher than +III are often termed "high-valent iron" and are considered to be key catalytic intermediates in biochemistry. Here, we report the direct time-domain probing of the photochemical formation of an octahedral nitrido iron(V) complex through dinitrogen cleavage from an diazido iron(III) precursor by using femtosecond mid-infrared (MIR) spectroscopy. From the time-resolved vibrational spectra, a mechanism is suggested for the photooxidation of the metal within 10 ps. This mechanism involves an initial ultrafast non-adiabatic transition, followed by a quasithermal N-N bond rupture on the ground-state surface. PMID- 26097153 TI - The influence of mesh topology in the abdominal wall repair process. AB - The tissue integration and the formation of adhesions in the repair of abdominal wall defects are principally led to the topology and the mechanical properties of implanted prosthesis. In this study we analyzed the influence of the topology of the meshes for abdominal wall repair, made of polypropylene (PP), evaluating its ability to prevent and to minimize the formation of adhesions, and to promote tissue ingrowth. Two series of in vivo studies were performed. In the first, two types of PP meshes, a lightweight macroporous mesh (LWM) and a heavyweight microporous mesh (HWM) were compared with determine the optimal porosity for tissue integration. In the second, a composite mesh, Clear Mesh Composite (CMC), made of a LWM sewn on a PP planar smooth film, was compared with a PP planar film, to demonstrate how two different topologies of same material are able to induce different tissue integration with the abdominal wall and different adhesion with internal organs. In both studies, the prostheses were implanted in Wistar rats and histological analysis and mechanical characterization of tissue coupled with the implants were performed. LWM showed better host tissue ingrowth in comparison to HWM. CMC prosthesis showed no adhesions to the viscera and no strong foreign body reaction, moreover its elasticity and anisotropy index were more similar to that of natural tissue. These results demonstrated that the surface morphology of PP surgical meshes allowed to modulate their repair ability. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1220-1228, 2016. PMID- 26097154 TI - Extended plasma cannabinoid excretion in chronic frequent cannabis smokers during sustained abstinence and correlation with psychomotor performance. AB - Cannabis smoking increases motor vehicle accident risk. Empirically defined cannabinoid detection windows are important to drugged driving legislation. Our aims were to establish plasma cannabinoid detection windows in frequent cannabis smokers and to determine if residual cannabinoid concentrations were correlated with psychomotor performance. Twenty-eight male chronic frequent cannabis smokers resided on a secure research unit for up to 33 days with daily blood collection. Plasma specimens were analyzed for Delta(9) -tetrahydrocannabinol (THC), 11 hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH) by gas chromatography mass spectrometry. Critical tracking and divided attention tasks were administered at baseline (after overnight stay to ensure lack of acute intoxication) and after 1, 2, and 3 weeks of cannabis abstinence. Twenty-seven of the twenty-eight participants were THC-positive at admission (median 4.2 ug/L). THC concentrations significantly decreased 24 h after admission, but were still >=2 ug/L in 16 of the 28 participants 48 h after admission. THC was detected in 3 of 5 specimens on day 30. The last positive 11-OH-THC specimen was 15 days after admission. THCCOOH was measureable in 4 of 5 participants after 30 days of abstinence. Years of prior cannabis use significantly correlated with THC concentrations on admission, and days 7 and 14. Tracking error, evaluated by the Divided Attention Task, was the only evaluated psychomotor assessment significantly correlated with cannabinoid concentrations at baseline and day 8 (11-OH-THC only). Median THC was 0.3 ug/L in 5 chronic frequent cannabis smokers' plasma samples after 30 days of sustained abstinence. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26097155 TI - Leisure Time Activities and Mental Health in Informal Dementia Caregivers. AB - OBJECTIVES: Dementia prevalence and the demand for dementia care are increasing. Informal caregiving accounts for a large proportion of dementia care, but can come at high cost for caregivers. Informal dementia caregivers are at higher risk for mental health problems than the general population. This study examines whether perceived change in leisure activities is one working mechanism linking stress and burden experience in dementia caregiving to lower mental health (depressive symptoms, anxiety symptoms, and reduced satisfaction with life), and whether there are group-based leisure activities that can buffer this detrimental effect. METHODS: A total of 346 informal Australian dementia caregivers (88.15% female, age 18-82 years) participated in an online study. RESULTS: Mediation and moderation analyses using multiple regression demonstrated that perceived changes in leisure activities linked caregiving stress and burden to lower mental health, and that membership in groups engaging in affiliation or social activities attenuates negative effects of caregiving. CONCLUSION: Informal dementia caregivers benefit from satisfying leisure activities. In particular, engaging in social activities and self-help groups buffered the negative impact of caregiving. PMID- 26097156 TI - Reply: To PMID 25417958. PMID- 26097157 TI - Reply: To PMID 25545240. PMID- 26097158 TI - Influence of respiratory physiotherapy on gastro-oesophageal reflux in infants: A systematic review. AB - PURPOSE: To provide a survey on the literature concerning the influence of respiratory physiotherapy on gastro-oesophageal reflux (GOR) in infants and young children. METHODS: Electronic databases (Pubmed, Web of Science, PEDro) and reference lists of articles and narrative reviews were searched. Articles were included when infants and small children underwent oesophageal pH monitoring or pH-multichannel intraluminal impedance monitoring while respiratory physiotherapy was administered. Descriptive analysis was performed and two researchers scored the methodological quality of these studies. RESULTS: Out of 985 articles, seven (six English, one French) have been included, In total 277 patients were involved, 71 with cystic fibrosis. Depending on the technique used, four studies showed GOR to be aggravated during therapy, three studies reported no effect. CONCLUSION: The evidence is not conclusive on whether respiratory physiotherapy induces or aggravates GOR in infants and small children. Age, disease, and treatment options play an important role. More specific research, also focussing on the influence of respiratory physiotherapy on non-acid reflux and the impact of recently developed airway clearance techniques (ACT's) on GOR is necessary. PMID- 26097159 TI - Ultra-small Palladium Nanoparticle Decorated Carbon Nanotubes: Conductivity and Reactivity. AB - Carbon nanotubes decorated with ultra-small metal nanoparticles are of great value in catalysis. We report that individual multiwalled carbon nanotubes decorated with ultra-small palladium nanoparticles can be detected by using the nano-impacts method. The high conductivity and reactivity of each decorated carbon nanotube is directly evidenced; this is achieved through studying the proton-reduction reaction for the underpotential deposition of hydrogen onto the nanoparticles decorated on the carbon nanotube walls. The reductive spikes from current amplification are analyzed to estimate the approximate length of the decorated carbon nanotubes, revealing that the decorated carbon nanotubes are electroactive along its entire length of several micrometers. PMID- 26097160 TI - Developmental nicotine exposure enhances inhibitory synaptic transmission in motor neurons and interneurons critical for normal breathing. AB - Nicotine exposure in utero negatively affects neuronal growth, differentiation, and synaptogenesis. We used rhythmic brainstems slices and immunohistochemistry to determine how developmental nicotine exposure (DNE) alters inhibitory neurotransmission in two regions essential to normal breathing, the hypoglossal motor nucleus (XIIn), and preBotzinger complex (preBotC). We microinjected glycine or muscimol (GABAA agonist) into the XIIn or preBotC of rhythmic brainstem slices from neonatal rats while recording from XII nerve roots to obtain XII motoneuron population activity. Injection of glycine or muscimol into the XIIn reduced XII nerve burst amplitude, while injection into the preBotC altered nerve burst frequency. These responses were exaggerated in preparations from DNE animals. Quantitative immunohistochemistry revealed a significantly higher GABAA receptor density on XII motoneurons from DNE pups. There were no differences in GABAA receptor density in the preBotC, and there were no differences in glycine receptor expression in either region. Nicotine, in the absence of other chemicals in tobacco smoke, alters normal development of brainstem circuits that are critical for normal breathing. PMID- 26097161 TI - Titanium and hydroxyapatite coating of polyetheretherketone and carbon fiber reinforced polyetheretherketone: A pilot study in sheep. AB - PURPOSE: The purpose of this study was to evaluate the bone formation capability of polyetheretherketone (PEEK) and carbon fiber-reinforced PEEK (CFR-PEEK) implants coated with different titanium and hydroxyapatite plasma-sprayed layers after 2 and 12 weeks. METHODS: In six sheep 108 implants were placed in the pelvis. Altogether six different surface modifications were tested. After 2 and 12 weeks, n = 3 implants per group were examined histologically and n = 6 implants per group were tested by a pull-out test. RESULTS: Biomechanically (p = 0.001) as well as histologically (p > 0.05) surface coating of PEEK/CFR-PEEK led to an increase of osseointegration from 2 to 12 weeks. After 12 weeks, coated implants demonstrated significant (p < 0.001) higher pull-out values in comparison to uncoated implants. Overall, the double coating (titanium bond layer and hydroxyapatite top layer) showed the most favorable results after 2 and 12 weeks. CONCLUSIONS: Plasma-sprayed titanium and hydroxyapatite coatings on PEEK or CFR-PEEK demonstrated a significant improvement of osseointegration. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1182 1191, 2016. PMID- 26097162 TI - Identification of six cell surface proteins for specific liver targeting. AB - PURPOSE: Cell surface proteins are the primary means for a cell to sense and interact with its environment and their dysregulation has been linked to numerous diseases. In particular, the identification of proteins specific to a single tissue type or to a given disease phenotype may enable the characterization of novel therapeutic targets. We tested here the feasibility of a cell surface proteomics approach to identify pertinent markers directly in a clinically relevant tissue. EXPERIMENTAL DESIGN: We analyzed the cell surface proteome of freshly isolated primary heptatocytes using a glycocapture-specific approach combined with a robust bioinformatics filtering. RESULTS: Using primary lung epithelial cell cultures as negative controls, we identified 32 hepatocyte specific cell surface proteins candidates. We used mRNA expression to select six markers that may provide adequate specificity for targeting therapeutics to the liver. CONCLUSIONS AND CLINICAL RELEVANCE: We demonstrate the feasibility and the importance of conducting such studies directly in a clinically relevant tissue. In particular, the cell surface proteome of freshly isolated hepatocytes differed substantially from cultured cell lines. PMID- 26097163 TI - Losing sight of science in the regulatory push to ban microbeads from consumer products and industrial use. PMID- 26097164 TI - Hair analysis for Delta(9) -tetrahydrocannabinolic acid A (THCA-A) and Delta(9) tetrahydrocannabinol (THC) after handling cannabis plant material. AB - A previous study has shown that Delta(9) -tetrahydrocannabinolic acid A (THCA-A), the non-psychoactive precursor of Delta(9) -tetrahydrocannabinol (THC) in the cannabis plant does not get incorporated in relevant amounts into the hair through the bloodstream after repeated oral intake. However, THCA-A can be measured in forensic hair samples in concentrations often exceeding the detected THC concentrations. To investigate whether the handling of cannabis plant material prior to consumption is a contributing factor for THC-positive hair results and also the source for THCA-A findings in hair, a study comprising ten participants was conducted. In this study, the participants rolled a marijuana joint on five consecutive days and hair samples of each participant were obtained. Urine samples were taken to exclude cannabis consumption prior to and during the study. THCA-A and THC could be detected in the hair samples from all participants taken at the end of the exposure period (concentration range: 15 1800 pg/mg for THCA-A and < 10-93 pg/mg for THC). Four weeks after the first exposure, THCA-A could still be detected in the hair samples of nine participants (concentration range: 4-57 pg/mg). Furthermore, THC could be detected in the hair samples of five participants (concentration range: < 10-17 pg/mg). Based on these results, it can be concluded that at least parts of the THC as well as the major part of THCA-A found in routine hair analysis derives from external contamination caused by direct transfer through contaminated fingers. This finding is of particular interest in interpreting THC-positive hair results of children or partners of cannabis users, where such a transfer can occur due to close body contact. Analytical findings may be wrongly interpreted as a proof of consumption or at least passive exposure to cannabis smoke. Such misinterpretation could lead to severe consequences for the people concerned. PMID- 26097165 TI - A Rationally Designed Thymidine-Based Self-Assembled Monolayer on a Gold Electrode for Electroanalytical Applications. AB - A self-assembled monolayer (SAM) of 1-(3,5-epidithio-2,3,5-trideoxy-beta-D-threo pentofuranosyl)thymine (EFT) on a gold electrode was prepared and characterized by Raman spectral and electrochemical measurements. Voltammetric and electrochemical impedance measurements show that the SAM of EFT on a Au electrode impedes the electron-transfer reaction. The SAM of EFT was successfully used for the voltammetric sensing of urate in neutral solution. The coexisting ascorbate anion does not interfere and therefore the EFT-based electrode was able to quantify urate at the micromolar level in the presence of a large excess amount of ascorbate. To demonstrate the practical applications, the amount of urate in two different human serum samples was quantified by using the EFT-based electrode; the results are in good agreement with those determined by the clinical method. DFT calculations show that both ascorbate and urate have noncovalent interactions including hydrogen-bonding interactions with EFT. PMID- 26097167 TI - Has the possible inclusion of nonradiographic axial spondyloarthritis been factored into the ABILITY-2 study? Comment on the article by Mease et al. PMID- 26097166 TI - Medication Nonadherence Is Associated With Increased Subsequent Acute Care Utilization Among Medicaid Beneficiaries With Systemic Lupus Erythematosus. AB - OBJECTIVE: We examined whether nonadherence to hydroxychloroquine (HCQ) or immunosuppressive medications (ISMs) was associated with higher subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus (SLE). METHODS: We utilized US Medicaid data from 2000-2006 to identify adults ages 18-64 years with SLE who were new users of HCQ or ISMs. We defined the index date as receipt of HCQ or ISMs without use in the prior 6 months. We measured adherence using the medication possession ratio (MPR), the proportion of days covered by total days' supply dispensed, for the 1-year post-index date. Our outcomes were all-cause and SLE-related emergency department (ED) visits and hospitalizations in the subsequent year. We used multivariable Poisson regression models to examine the association between nonadherence (MPR <80%) and acute care utilization, adjusting for sociodemographics and comorbidities. RESULTS: We identified 9,600 HCQ new users and 3,829 ISM new users with SLE. The mean +/- SD MPR for HCQ was 47.8% +/- 30.3% and for ISMs was 42.7% +/- 30.7%. Seventy-nine percent of HCQ users and 83% of ISM users were nonadherent (MPR <80%). In multivariable models, among HCQ users, the incidence rate ratio (IRR) of ED visits was 1.55 (95% confidence interval [95% CI] 1.43-1.69) and the IRR of hospitalizations was 1.37 (95% CI 1.25-1.50), comparing nonadherers to adherers. For ISM users, the IRR of ED visits was 1.64 (95% CI 1.42-1.89) and of hospitalizations was 1.67 (95% CI 1.41-1.96) for nonadherers versus adherers. CONCLUSION: In this cohort, nonadherence to HCQ and ISMs was common and was associated with significantly higher subsequent acute care utilization. PMID- 26097168 TI - Breakthrough therapies: Cystic fibrosis (CF) potentiators and correctors. AB - Cystic Fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene resulting in abnormal protein function. Recent advances of targeted molecular therapies and high throughput screening have resulted in multiple drug therapies that target many important mutations in the CFTR protein. In this review, we provide the latest results and current progress of CFTR modulators for the treatment of cystic fibrosis, focusing on potentiators of CFTR channel gating and Phe508del processing correctors for the Phe508del CFTR mutation. Special emphasis is placed on the molecular basis underlying these new therapies and emerging results from the latest clinical trials. The future directions for augmenting the rescue of Phe508del with CFTR modulators are also emphasized. PMID- 26097169 TI - Detection of silent cells, synchronization and modulatory activity in developing cellular networks. AB - Developing networks in the immature nervous system and in cellular cultures are characterized by waves of synchronous activity in restricted clusters of cells. Synchronized activity in immature networks is proposed to regulate many different developmental processes, from neuron growth and cell migration, to the refinement of synapses, topographic maps, and the mature composition of ion channels. These emergent activity patterns are not present in all cells simultaneously within the network and more immature "silent" cells, potentially correlated with the presence of silent synapses, are prominent in different networks during early developmental periods. Many current network analyses for detection of synchronous cellular activity utilize activity-based pixel correlations to identify cellular based regions of interest (ROIs) and coincident cell activity. However, using activity-based correlations, these methods first underestimate or ignore the inactive silent cells within the developing network and second, are difficult to apply within cell-dense regions commonly found in developing brain networks. In addition, previous methods may ignore ROIs within a network that shows transient activity patterns comprising both inactive and active periods. We developed analysis software to semi-automatically detect cells within developing neuronal networks that were imaged using calcium-sensitive reporter dyes. Using an iterative threshold, modulation of activity was tracked within individual cells across the network. The distribution pattern of both inactive and active, including synchronous cells, could be determined based on distance measures to neighboring cells and according to different anatomical layers. PMID- 26097170 TI - Risk factors contributing to postoperative delirium in geriatric patients postorthopedic surgery. AB - INTRODUCTION: Postoperative delirium is a common clinical manifestation in geriatric patients, resulting in prolonged hospitalization and increased economic burden, in addition to higher morbidity and mortality rates. Therefore, identifying non-obvious risk factors that contribute to the development of postoperative delirium in geriatric patients is crucial. METHODS: From January 2011 to June 2013, 200 geriatric patients of over 65 years of age scheduled for orthopedic surgery were randomly selected and statistically analyzed with respect to the effects of the following 12 factors on postoperative delirium: sex, age, anesthesia type, surgical type (i.e. spine, hip replacement, and pelvic or femoral fracture repair), operative duration, intraoperative hypoxia, intraoperative hypercapnia, intraoperative hypotension, intraoperative blood loss, preoperative affective state, postoperative sleep disorders, and underlying disease (i.e. hypertension, coronary heart disease, diabetes, hyperlipidemia, and chronic bronchitis). RESULTS: Seven factors--age, anesthesia type, duration of operation, intraoperative hypercapnia, intraoperative hypotension, preoperative affective state, and postoperative sleep disorders--were found to be significantly differentiated, suggesting that these factors have an impact on the development of postoperative delirium. Sex, surgical type, intraoperative hypoxia, intraoperative blood loss (with 300 ml as a cutoff value), and underlying disease were not directly related to the development of postoperative delirium. DISCUSSION: Advanced age (>70 years), the use of general anesthesia, longer surgical duration (>3 hours), the presence of intraoperative hypercapnia and hypotension, the presence of preoperative affective dysfunction, and the presence of postoperative sleep disorders appear to be associated with the development of postoperative delirium in geriatric patients after orthopedic surgery. PMID- 26097171 TI - Imaging of subchondral bone by optical coherence tomography upon optical clearing of articular cartilage. AB - Optical clearing is an effective method to reduce light scattering of biological tissues that provides significant enhancement of light penetration into the biological tissues making non-invasive diagnosis more feasible. In current report Optical Coherence Tomography (OCT) in conjunction with optical clearing is applied for assessment of deep cartilage layers and cartilage-bone interface. The solution of Iohexol in water has been used as an optical clearing agent. The cartilage-bone boundary becomes visible after 15 min of optical clearing that enabling non-invasive estimation of its roughness: Sa = 10 +/- 1 um. The results show that for 0.9 mm thick cartilage optical clearing is stopped after 50 min with an increase of refractive index from 1.386 +/- 0.008 to 1.510 +/- 0.009. Current approach enables more reliable detection of arthroscopically inaccessible regions, including cartilage-bone boundary and subchondral bone, and potentially improves accuracy of the osteoarthritis diagnosis. PMID- 26097176 TI - Marfan syndrome database information unreliable for diagnoses. PMID- 26097172 TI - Visible light crosslinking of methacrylated hyaluronan hydrogels for injectable tissue repair. AB - Tissue engineering hydrogels are primarily cured in situ using ultraviolet (UV) radiation which limits the use of hydrogels as drug or cell carriers. Visible green light activated crosslinking systems are presented as a safe alternative to UV photocrosslinked hydrogels, without compromising material properties such as viscosity and stiffness. The objective of this study was to fabricate and characterize photocrosslinked hydrogels with well-regulated gelation kinetics and mechanical properties for the repair or replacement of soft tissue. An anhydrous methacrylation of hyaluronan (HA) was performed to control the degree of modification (DOM) of HA, verified by (1) H-NMR spectroscopy. UV-activated crosslinking was compared to visible green light activated crosslinking. While the different photocrosslinking techniques resulted in varied crosslinking times, comparable mechanical properties of UV and green light activated crosslinked hydrogels were achieved using each photocrosslinking method by adjusting time of light exposure. Methacrylated HA (HA-MA) hydrogels of varying molecular weight, DOM, and concentration exhibited compressive moduli ranging from 1 kPa to 116 kPa, for UV crosslinking, and 3 kPa to 146 kPa, for green light crosslinking. HA MA molecular weight and concentration were found to significantly influence moduli values. HA-MA hydrogels did not exhibit any significant cytotoxic effects toward human mesenchymal stem cells. Green light activated crosslinking systems are presented as a viable method to form natural-based hydrogels in situ. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1229 1236, 2016. PMID- 26097173 TI - "CHARGE-like presentation, craniosynostosis and mild Mowat-Wilson Syndrome diagnosed by recognition of the distinctive facial gestalt in a cohort of 28 new cases" American Journal of Medical Genetics Part A. 164:2557-2566, 2014. PMID- 26097177 TI - Respectful communication by geneticists important for parents of children with undiagnosed disorders. PMID- 26097179 TI - Levels of lipocalin-2 in crevicular fluid and tear fluid in chronic periodontitis and obesity subjects. AB - AIM: Lipocalin-2, a 25 kDa secretory glycoprotein, was first found in the neutrophilic granules of humans and in mouse kidney cells. It has been shown to have an important role in inflammation. The aim of this study was to determine the levels of lipocalin-2 in gingival crevicular fluid and tear fluid in patients with obesity and chronic periodontitis. METHODS: A total of 40 subjects in the age group 25-40 years were divided into four groups based on probing depth, gingival index, clinical attachment level, body mass index, and radiographic evidence of bone loss. The groups were: nonobese healthy group; obese healthy group; nonobese chronic periodontitis group; obese chronic periodontitis group Gingival crevicular fluid and tear fluid samples were collected on the subsequent day. RESULTS: There was an increase in lipocalin-2 levels from group 1 to group 4 (with the nonobese healthy group showing the least levels and obese chronic periodontitis group showing the highest levels) in both gingival crevicular fluid and tear fluid. CONCLUSION: Lipocalin-2 may be an important inflammatory marker that may help link obesity and chronic periodontitis. PMID- 26097181 TI - Rheumatology-Specific Electronic Health Record Software: Comment on the Article by Newman et al. PMID- 26097182 TI - Robotic sleeve gastrectomy for morbid obesity: report of a 5 year experience. AB - BACKGROUND: Robotic bariatric procedures are nowadays in the surgeon's arsenal for the treatment of morbid obesity. With proven efficacy and advantages in gastric bypass procedures, we attempted to employ robotics and study the results in the other major bariatric procedure, sleeve gastrectomy. METHODS: We used the da Vinci S(r) system to perform 19 robotic sleeve gastrectomies (RSGs) and reviewed the 5-year results as far as excess body weight loss is concerned, and amelioration of obesity-related comorbidities. RESULTS: Mean percentage of excess body weight loss (%EWL) was 64.4%, 67.1%, 61.7%, 63.1%, 64.8% for the first, second, third, fourth and fifth year, respectively. Neither of our two patients with diabetes mellitus (0%) or hypertension (0%) showed remission, while all six of our patients (100%) showed remission of their sleep apnoea after 5 years. CONCLUSIONS: Robotic sleeve gastrectomy is an effective procedure as far as initial excess weight loss is concerned and this loss is well maintained 5 years post-operatively, a finding similar to relevant data after conventional laparoscopic sleeve gastrectomy. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26097180 TI - ZFIN, The zebrafish model organism database: Updates and new directions. AB - The Zebrafish Model Organism Database (ZFIN; http://zfin.org) is the central resource for genetic and genomic data from zebrafish (Danio rerio) research. ZFIN staff curate detailed information about genes, mutants, genotypes, reporter lines, sequences, constructs, antibodies, knockdown reagents, expression patterns, phenotypes, gene product function, and orthology from publications. Researchers can submit mutant, transgenic, expression, and phenotype data directly to ZFIN and use the ZFIN Community Wiki to share antibody and protocol information. Data can be accessed through topic-specific searches, a new site wide search, and the data-mining resource ZebrafishMine (http://zebrafishmine.org). Data download and web service options are also available. ZFIN collaborates with major bioinformatics organizations to verify and integrate genomic sequence data, provide nomenclature support, establish reciprocal links, and participate in the development of standardized structured vocabularies (ontologies) used for data annotation and searching. ZFIN-curated gene, function, expression, and phenotype data are available for comparative exploration at several multi-species resources. The use of zebrafish as a model for human disease is increasing. ZFIN is supporting this growing area with three major projects: adding easy access to computed orthology data from gene pages, curating details of the gene expression pattern changes in mutant fish, and curating zebrafish models of human diseases. PMID- 26097183 TI - A BAFF receptor His159Tyr mutation in Sjogren's syndrome-related lymphoproliferation. AB - OBJECTIVE: To study the prevalence, clinical associations, and functional implications of the His159Tyr mutation of the BAFF receptor (BAFF-R) in patients with Sjogren's syndrome (SS). METHODS: The BAFF-R His159Tyr mutation was evaluated using polymerase chain reaction (PCR)-based assays in 247 patients with SS (of whom 70 had SS complicated by lymphoma [SS-lymphoma]), 145 with systemic lupus erythematosus (SLE), and 101 with rheumatoid arthritis (RA), as well as 180 healthy controls. Real-time PCR and Western blotting were performed for the quantification of both NF-kappaB1 and NF-kappaB2 messenger RNA (mRNA) transcript and protein levels in isolated B cells from patients with SS-lymphoma carrying the mutation (SS-lymphoma-BAFF-RHis159Tyr -derived B cells) compared to B cells from patients with SS-lymphoma who were not carriers of the mutation and healthy controls. RESULTS: Both the SS-lymphoma and SS-nonlymphoma patient subgroups exhibited significantly higher frequencies of the His159Tyr BAFF-R mutation compared to healthy controls (8.6% of SS-lymphoma patients and 6.2% of SS nonlymphoma patients versus 1.7% of healthy controls; P = 0.02 and P = 0.04, respectively). The corresponding frequencies of the His159Tyr BAFF-R mutation in SLE and RA patients were 3.5% and 3%, respectively. Of interest, 71.4% of the SS patients with mucosa-associated lymphoid tissue (MALT) lymphoma who were between the ages of 31 and 40 years at disease onset were mutation carriers. The generalized odds ratio for the development of SS-related MALT lymphoma in the younger age at onset (age <40 years) group in the presence of the BAFF-R mutation was 6.1 (95% confidence interval 2.0-18.7) (P < 0.01). Expression of NF-kappaB at both the mRNA and protein level was up-regulated in SS-lymphoma-BAFF-RHis159Tyr derived B cells. CONCLUSION: This study identifies an increased prevalence of the BAFF-R His159Tyr mutation in patients with SS, particularly in those with SS complicated by MALT lymphoma whose disease onset occurred at a younger age. BAFF RHis159Tyr -mediated activation of the alternate NF-kappaB pathway might contribute to the pathogenesis of SS-related lymphoproliferative disease. PMID- 26097186 TI - Quantitative proteomics using SILAC: Principles, applications, and developments. AB - SILAC is based on direct addition of selected stable isotope amino acids into the cell culture medium, allowing superior quantitative analysis of the cellular proteome compared to other labeling methods. The great advantages of SILAC lie in its straight-forward implementation, quantitative accuracy, and reproducibility over chemical labeling or label-free quantification strategies, favoring its adoption for proteomic research. SILAC has been widely applied to characterize the proteomic changes between different biological samples, to investigate dynamic changes of protein PTMs, to distinguish specific interacting proteins in interaction proteomic analysis, and to analyze protein turnover in the proteome wide scale. The present review summarizes the principles of SILAC technology, its applications in biological research, and the present state of this technology. PMID- 26097187 TI - History and development of the Schmidt-Hunter meta-analysis methods. AB - In this article, I provide answers to the questions posed by Will Shadish about the history and development of the Schmidt-Hunter methods of meta-analysis. In the 1970s, I headed a research program on personnel selection at the US Office of Personnel Management (OPM). After our research showed that validity studies have low statistical power, OPM felt a need for a better way to demonstrate test validity, especially in light of court cases challenging selection methods. In response, we created our method of meta-analysis (initially called validity generalization). Results showed that most of the variability of validity estimates from study to study was because of sampling error and other research artifacts such as variations in range restriction and measurement error. Corrections for these artifacts in our research and in replications by others showed that the predictive validity of most tests was high and generalizable. This conclusion challenged long-standing beliefs and so provoked resistance, which over time was overcome. The 1982 book that we published extending these methods to research areas beyond personnel selection was positively received and was followed by expanded books in 1990, 2004, and 2014. Today, these methods are being applied in a wide variety of areas. PMID- 26097191 TI - De novo 4q duplication/deletion in a fetus with a congenital heart defect. PMID- 26097188 TI - Extended evolution: A conceptual framework for integrating regulatory networks and niche construction. AB - This paper introduces a conceptual framework for the evolution of complex systems based on the integration of regulatory network and niche construction theories. It is designed to apply equally to cases of biological, social and cultural evolution. Within the conceptual framework we focus especially on the transformation of complex networks through the linked processes of externalization and internalization of causal factors between regulatory networks and their corresponding niches and argue that these are an important part of evolutionary explanations. This conceptual framework extends previous evolutionary models and focuses on several challenges, such as the path-dependent nature of evolutionary change, the dynamics of evolutionary innovation and the expansion of inheritance systems. PMID- 26097193 TI - Assessment of jawbone trabecular bone structure amongst osteoporotic women by cone-beam computed tomography: the OSTEOSYR project. AB - OBJECTIVE: To assess the trabecular bone structure of jawbones and the dens (the odontoid process of the second cervical vertebra) amongst osteoporotic and nonosteoporotic women using cone-beam computed tomography (CBCT). Analysis of the dens trabecular bone structure aimed to test the validity of CBCT in such analysis. METHODS: Thirty-eight women who went under dual-energy X-ray absorptiometry (DXA) examination were scanned by CBCT. Cuboids from different areas of jawbones and the dens were extracted from each scan. Trabecular thickness (Tb.Th), trabecular separation (Tb.S), bone volume fraction (BV/TV), specific bone surface (BS/TV) and connectivity density were calculated. Student's t-test, Pearson correlation, and logistic regression analysis were used to explore differences in these measures between groups. RESULTS: Jawbone-derived measures showed insignificant differences (P > 0.05) between osteoporotic and non osteoporotic groups, and weak correlations with femoral neck and lumbar vertebrae T-scores (r <= 0.4). Dens-derived measures, however, resulted in the opposite (r = 0.34-0.38 [P value = 0.02-0.036] and r = 0.48-0.61 [P value <= 0.003]) and the highest accuracy of osteoporosis prediction: 84.2% and 78.9% respectively. CONCLUSION: Trabecular bone structure of the mandible and maxilla is not affected in osteoporosis as assessed by CBCT. Dens trabecular bone analysis revealed the opposite, so some trabecular bone measures may be assessed by CBCT, which may aid in predicting osteoporosis. PMID- 26097192 TI - Cross-organism analysis using InterMine. AB - InterMine is a data integration warehouse and analysis software system developed for large and complex biological data sets. Designed for integrative analysis, it can be accessed through a user-friendly web interface. For bioinformaticians, extensive web services as well as programming interfaces for most common scripting languages support access to all features. The web interface includes a useful identifier look-up system, and both simple and sophisticated search options. Interactive results tables enable exploration, and data can be filtered, summarized, and browsed. A set of graphical analysis tools provide a rich environment for data exploration including statistical enrichment of sets of genes or other entities. InterMine databases have been developed for the major model organisms, budding yeast, nematode worm, fruit fly, zebrafish, mouse, and rat together with a newly developed human database. Here, we describe how this has facilitated interoperation and development of cross-organism analysis tools and reports. InterMine as a data exploration and analysis tool is also described. All the InterMine-based systems described in this article are resources freely available to the scientific community. PMID- 26097195 TI - Learning a new robotic surgical device: Telelap Alf X in gynaecological surgery. AB - BACKGROUND: To assess the learning curve associated with tele-assisted surgery. METHODS: We performed a training box-based study, describing speed and accuracy in volunteers performing basic and complex laparoscopic tasks, to assess performance and in the skill acquisition of inexperienced users, using the Telelap Alf X system. Ten surgeons in gynaecology who had never received formal instruction on this new surgical device, completed four modules during a consecutive 3 day training programme. RESULTS: All the participants completed the training programme with a good learning curve. CONCLUSIONS: Use of the TELELAP Alf X advanced surgical robotic system is associated with a rapid learning curve among experienced surgeons. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26097194 TI - Etanercept-Methotrexate Combination Therapy Initiators Have Greater Adherence and Persistence Than Triple Therapy Initiators With Rheumatoid Arthritis. AB - OBJECTIVE: To estimate adherence and persistence with etanercept plus methotrexate (ETN-MTX) combination therapy and MTX, hydroxychloroquine, and sulfasalazine triple therapy at 1 year following treatment initiation in adults with rheumatoid arthritis (RA). METHODS: This retrospective analysis used data from the Truven Health MarketScan Commercial and Medicare Supplemental databases from January 2009 to July 2013. Adherence was defined as having percentage of days covered >80% for all drugs within each regimen. Persistence was defined as no treatment gap >45 days for any drug and no addition or switching to other disease-modifying antirheumatic drugs. Multiple logistic regression models were employed in the analyses to control for potential confounders. RESULTS: A total of 3,724 ETN-MTX patients and 818 triple therapy patients were eligible. At 1 year, 27.9% who were taking ETN-MTX and 18.2% using triple therapy were adherent to all agents in their regimen (P < 0.0001), and 29.4% who were taking ETN-MTX and 23.2% using triple therapy were persistent (P < 0.001). After adjusting for confounders, ETN-MTX patients had significantly greater odds of being adherent (odds ratio [OR] 1.79, 95% confidence interval [95% CI] 1.47-2.17) and persistent (OR 1.45, 95% CI 1.20-1.72) compared with patients using triple therapy. CONCLUSION: Patients with RA initiating treatment with ETN-MTX combination therapy demonstrated greater adherence and persistence at 1 year than patients initiating triple therapy. PMID- 26097196 TI - Rational design of antirheumatic prodrugs specific for sites of inflammation. AB - OBJECTIVE: Biologic drugs, such as the anti-tumor necrosis factor (anti-TNF) antibody adalimumab, have represented a breakthrough in the treatment of rheumatoid arthritis. Yet, concerns remain over their lack of efficacy in a sizable proportion of patients and their potential for systemic side effects such as infection. Improved biologic prodrugs specifically targeted to the site of inflammation have the potential to alleviate current concerns surrounding biologic anticytokine therapies. The purpose of this study was to design, construct, and evaluate in vitro and ex vivo the targeting and antiinflammatory capacity of activatable bispecific antibodies. METHODS: Activatable dual variable domain (aDVD) antibodies were designed and constructed to target intercellular adhesion molecule 1 (ICAM-1), which is up-regulated at sites of inflammation, and anti-TNF antibodies (adalimumab and infliximab). These bispecific molecules included an external arm that targets ICAM-1 and an internal arm that comprises the therapeutic domain of an anti-TNF antibody. Both arms were linked to matrix metalloproteinase (MMP)-cleavable linkers. The constructs were tested for their ability to bind and neutralize both in vitro and ex vivo targets. RESULTS: Intact aDVD constructs demonstrated significantly reduced binding and anti-TNF activity in the prodrug formulation as compared to the parent antibodies. Human synovial fluid and physiologic concentrations of MMP enzyme were capable of cleaving the external domain of the antibody, revealing a fully active molecule. Activated antibodies retained the same binding and anti-TNF inhibitory capacities as the parent molecules. CONCLUSION: The design of a biologic prodrug with enhanced specificity for sites of inflammation (synovium) and reduced specificity for off target TNF is described. This construct has the potential to form a platform technology that is capable of enhancing the therapeutic index of drugs for the treatment of RA and other inflammatory diseases. PMID- 26097197 TI - Extraction of natural red colorants from the fermented broth of Penicillium purpurogenum using aqueous two-phase polymer systems. AB - Safety concerns related to the increasing and widespread application of synthetic coloring agents have increased the demand for natural colorants. Fungi have been employed in the production of novel and safer colorants. In order to obtain the colorants from fermented broth, suitable extraction systems must be developed. Aqueous two-phase polymer systems (ATPPS) offer a favorable chemical environment and provide a promising alternative for extracting and solubilizing these molecules. The aim of this study was to investigate the partitioning of red colorants from the fermented broth of Penicillium purpurogenum using an ATPPS composed of poly(ethylene glycol) (PEG) and sodium polyacrylate (NaPA). Red colorants partitioned preferentially to the top (PEG-rich phase). In systems composed of PEG 6,000 g/mol/NaPA 8,000 g/mol, optimum colorant partition coefficient (KC ) was obtained in the presence of NaCl 0.1 M (KC = 10.30) while the PEG 10,000 g/mol/NaPA 8,000 g/mol system in the presence of Na2 SO4 0.5 M showed the highest KC (14.78). For both polymers, the mass balance (%MB) and yield in the PEG phase (%etaTOP ) were close to 100 and 79%, respectively. The protein selectivity in all conditions evaluated ranged from 2.0-3.0, which shows a suitable separation of the red colorants and proteins present in the fermented broth. The results suggest that the partitioning of the red colorants is dependent on both the PEG molecular size and salt type. Furthermore, the results obtained support the potential application of ATPPS as the first step of a purification process to recover colorants from fermented broth of microorganisms. PMID- 26097199 TI - Form meets function: A commentary on meta-analytic history. PMID- 26097200 TI - Low-Temperature Synthesis of Hierarchical Amorphous Basic Nickel Carbonate Particles for Water Oxidation Catalysis. AB - Amorphous nickel carbonate particles are catalysts for the oxygen evolution reaction (OER), which plays a critical role in the electrochemical splitting of water. The amorphous nickel carbonate particles can be prepared at a temperature as low as 60 degrees C by an evaporation-induced precipitation (EIP) method. The products feature hierarchical pore structures. The mass-normalized activity of the catalysts, measured at an overpotential of 0.35 V, was 55.1 A g(-1) , with a Tafel slope of only 60 mV dec(-1) . This catalytic activity is superior to the performance of crystalline NiOx particles and beta-Ni(OH)2 particles, and compares favorably to state-of-the-art RuO2 catalysts. The activity of the amorphous nickel carbonate is remarkably stable during a 10 000 s chronoamperometry test. Further optimization of synthesis parameters reveals that the amorphous structure can be tuned by adjusting the H2 O/Ni ratio in the precursor mixture. These results suggest the potential application of easily prepared hierarchical basic nickel carbonate particles as cheap and robust OER catalysts with high activity. PMID- 26097198 TI - Applications of targeted proteomics in systems biology and translational medicine. AB - Biological systems are composed of numerous components of which proteins are of particularly high functional significance. Network models are useful abstractions for studying these components in context. Network representations display molecules as nodes and their interactions as edges. Because they are difficult to directly measure, functional edges are frequently inferred from suitably structured datasets consisting of the accurate and consistent quantification of network nodes under a multitude of perturbed conditions. For the precise quantification of a finite list of proteins across a wide range of samples, targeted proteomics exemplified by selected/multiple reaction monitoring (SRM, MRM) mass spectrometry has proven useful and has been applied to a variety of questions in systems biology and clinical studies. Here, we survey the literature of studies using SRM-MS in systems biology and clinical proteomics. Systems biology studies frequently examine fundamental questions in network biology, whereas clinical studies frequently focus on biomarker discovery and validation in a variety of diseases including cardiovascular disease and cancer. Targeted proteomics promises to advance our understanding of biological networks and the phenotypic significance of specific network states and to advance biomarkers into clinical use. PMID- 26097201 TI - The Authors Reply: "Changes to inpatient versus outpatient hospitalization: Medicare's 2-midnight rule". PMID- 26097202 TI - Low, rather than high, body mass index confers increased risk for post-liver transplant death and graft loss: Risk modulated by model for end-stage liver disease. AB - With increasing attention being paid to optimizing patient outcomes, it has been proposed that liver transplantation (LT) for individuals with elevated body mass index (BMI) values and high Model for End-Stage Liver Disease (MELD) scores may adversely affect post-LT outcomes. We investigated the impact of BMI on post-LT outcomes in the context of MELD at LT. Using United Network for Organ Sharing data, we identified all adult (>= 18 years) primary LT recipients from March 1, 2002 to September 30, 2011. BMI categories included the following: underweight, normal, overweight, class I obese, class II obese, and class III obese (<18.5; 18.5-24.9; 25-29.9; 30-34.9; 35-39.9; >= 40 kg/m(2), respectively). One-year post LT death and graft loss were modeled using Cox regression, including interactions between BMI and MELD. A total of 45,551 adult recipients were identified: 68% male; median (interquartile range [IQR]) age 55 years (IQR, 49-60 years); MELD, 19 (IQR, 13-26); and donor risk index, 1.39 (IQR, 1.12-1.69). Representations in the BMI categories were underweight (n = 863, 2%), normal (n = 13,262, 29%), overweight (n = 16,329, 36%), class I obese (n = 9639, 21%), class II obese (n = 4062, 9%), and class III obese (n = 1396, 3%). In adjusted analyses, elevated BMI was not associated with increased risk for death or graft loss. Among the underweight, there were significant interactions between BMI and MELD with respect to death (P = 0.02) and graft loss (P = 0.01), with significantly increased risks for death (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.38-2.09; P = 0.006) and graft loss (HR, 1.45; 95% CI, 1.21-1.74; P = 0.02) among those with low MELD (<= 26), compared to normal BMI recipients with low MELD. In conclusion, overweight and obese LT recipients do not have increased risk of death or graft loss regardless of MELD. Underweight patients are at increased risk for poor outcomes post-LT, specifically underweight recipients with low MELD have increased risk for death and graft loss. Mechanisms underlying this phenomenon warrant further investigation. PMID- 26097203 TI - Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance. AB - The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors. PMID- 26097204 TI - Significance of urethral fibrosis evaluated by preoperative magnetic resonance imaging as a predictor of continence status after robot-assisted radical prostatectomy. AB - BACKGROUND: The objective of this study was to assess the impact of urethral fibrosis on the continence status following robot-assisted radical prostatectomy (RARP). METHODS: The findings of fibrosis of the urethral wall and periurethral tissue in 185 patients undergoing RARP were each divided into grade 0 to 3 based on preoperative T2-weighted magnetic resonance imaging. Urethral fibrosis was defined as the sum of both grades, and scores <= 2 and >= 3 were considered as 'no/mild' and 'severe' fibrosis, respectively. RESULTS: The incidences of continence in patients with no/mild fibrosis were significantly higher at 3, 6, and 12 months after RARP than those with severe fibrosis. Furthermore, urethral fibrosis was identified as an independent predictor of the postoperative continence status at 3, 6, and 12 months after RARP. CONCLUSIONS: Assessment of urethral fibrosis could be a significant predictor of recovery of the urinary continence status after RARP. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26097205 TI - Stimulatory effects of histamine on migration of nasal fibroblasts. AB - BACKGROUND: Fibroblast migration is crucial for normal wound repair after sinonasal surgery. Histamine is known to be involved in wound healing by its effects on cell proliferation and migration. This study aimed to determine whether histamine affects the migration of nasal fibroblasts and to investigate the mechanism of action of histamine on nasal fibroblasts. METHODS: Primary cultures of nasal fibroblasts were established from inferior turbinate samples. Fibroblast migration was evaluated with scratch assays. Cells were treated with histamine and/or histamine receptor-selective antagonists. U-73122 and pertussis toxin, which are selective inhibitors of the lower signaling pathway of H1R and H4R, were used to confirm the modulation of nasal fibroblast migration by histamine. Fibroblast cytoskeletal structures were visualized with immunocytochemistry. RESULTS: Histamine significantly stimulated the migration of nasal fibroblasts. Antagonists selective for HR1 and HR4 significantly reduced nasal fibroblast migration. In immunocytochemical staining, histamine treatment increased membrane ruffling and pyrilamine, diphenhydramine, fexofenadine, and JNJ7777120 decreased histamine-induced membrane ruffling. U-73122 and pertussis toxin also decreased histamine-induced migration of fibroblasts. Histamine maintains its stimulatory effects on fibroblast migration in the presence of mitomycin C, which blocks proliferation of cells. CONCLUSION: We showed that histamine stimulates fibroblast migration in nasal fibroblasts. This effect appeared to be mediated by HR1 and HR4. However, because fibroblast migration also can be involved in scaring and fibrosis, more research is necessary to determine the effects of antihistamine on wound healing after sinus surgery. PMID- 26097206 TI - Salmonella typhimurium and Escherichia coli dissimilarity: Closely related bacteria with distinct metabolic profiles. AB - Live attenuated strains of Salmonella typhimurium have been extensively investigated as vaccines for a number of infectious diseases. However, there is still little information available concerning aspects of their metabolism. S. typhimurium and Escherichia coli show a high degree of similarity in terms of their genome contents and metabolic networks. However, this work presents experimental evidence showing that significant differences exist in their abilities to direct carbon fluxes to biomass and energy production. It is important to study the metabolism of Salmonella to elucidate the formation of acetate and other metabolites involved in optimizing the production of biomass, essential for the development of recombinant vaccines. The metabolism of Salmonella under aerobic conditions was assessed using continuous cultures performed at dilution rates ranging from 0.1 to 0.67 h(-1), with glucose as main substrate. Acetate assimilation and glucose metabolism under anaerobic conditions were also investigated using batch cultures. Chemostat cultivations showed deviation of carbon towards acetate formation, starting at dilution rates above 0.1 h(-1). This differed from previous findings for E. coli, where acetate accumulation was only detected at dilution rates exceeding 0.4 h(-1), and was due to the lower rate of acetate assimilation by S. typhimurium under aerobic conditions. Under anaerobic conditions, both microorganisms mainly produced ethanol, acetate, and formate. A genome-scale metabolic model, reconstructed for Salmonella based on an E. coli model, provided a poor description of the mixed fermentation pattern observed during Salmonella cultures, reinforcing the different patterns of carbon utilization exhibited by these closely related bacteria. PMID- 26097207 TI - Interleukin-21 receptor blockade inhibits secondary humoral responses and halts the progression of preestablished disease in the (NZB * NZW)F1 systemic lupus erythematosus model. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin-21 (IL-21) or IL-21 receptor (IL-21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL-21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL-21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB * NZW)F1 (NZB/NZW) mouse model of SLE. METHODS: Humoral and cellular immune responses to immunization with sheep red blood cells (SRBCs) were measured in mice dosed with IL-21R blocking antibodies. Progression of nephritis and markers of immune activation was monitored in NZB/NZW mice following different anti-IL-21R treatment regimens. RESULTS: IL-21R blockade specifically inhibited secondary IgG responses to SRBC immunization. In NZB/NZW mice, IL-21R blockade completely inhibited the onset of nephritis, which was associated with dramatic reductions in splenomegaly and in B cell and T cell activation. When administered to mice with preexisting disease, anti-IL-21R antibody halted the disease progression and mortality and reversed the nephritis in a subset of mice. Furthermore, treatment cessation was not followed by rapid reemergence of disease. CONCLUSION: Our results highlight the importance of IL-21 in promoting humoral recall responses and in sustaining autoimmune inflammation. PMID- 26097209 TI - "Opinions differ significantly": Early experiences with meta-analysis and the people who made it possible. PMID- 26097208 TI - Gene Expression Factor Analysis to Differentiate Pathways Linked to Fibromyalgia, Chronic Fatigue Syndrome, and Depression in a Diverse Patient Sample. AB - OBJECTIVE: To determine if independent candidate genes can be grouped into meaningful biologic factors, and whether these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS), while controlling for comorbid depression, sex, and age. METHODS: We included leukocyte messenger RNA gene expression from a total of 261 individuals, including healthy controls (n = 61), patients with FMS only (n = 15), with CFS only (n = 33), with comorbid CFS and FMS (n = 79), and with medication-resistant (n = 42) or medication-responsive (n = 31) depression. We used exploratory factor analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine whether these factors were associated with specific diagnoses. RESULTS: EFA resulted in 4 independent factors with minimal overlap of genes between factors, explaining 51% of the variance. We labeled these factors by function as 1) purinergic and cellular modulators, 2) neuronal growth and immune function, 3) nociception and stress mediators, and 4) energy and mitochondrial function. Regression analysis predicting these biologic factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (Quick Inventory for Depression Symptomatology score), but not associated with FMS. CONCLUSION: Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters, but in opposite directions, when controlling for comorbid FMS. Given high comorbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression. PMID- 26097210 TI - In reference to "Changes to inpatient versus outpatient hospitalization: Medicare's 2-Midnight rule". PMID- 26097211 TI - The Challenge of Electrochemical Ammonia Synthesis: A New Perspective on the Role of Nitrogen Scaling Relations. AB - The electrochemical production of NH3 under ambient conditions represents an attractive prospect for sustainable agriculture, but electrocatalysts that selectively reduce N2 to NH3 remain elusive. In this work, we present insights from DFT calculations that describe limitations on the low-temperature electrocatalytic production of NH3 from N2 . In particular, we highlight the linear scaling relations of the adsorption energies of intermediates that can be used to model the overpotential requirements in this process. By using a two variable description of the theoretical overpotential, we identify fundamental limitations on N2 reduction analogous to those present in processes such as oxygen evolution. Using these trends, we propose new strategies for catalyst design that may help guide the search for an electrocatalyst that can achieve selective N2 reduction. PMID- 26097212 TI - Needles in the blue sea: sub-species specificity in targeted protein biomarker analyses within the vast oceanic microbial metaproteome. AB - Proteomics has great potential for studies of marine microbial biogeochemistry, yet high microbial diversity in many locales presents us with unique challenges. We addressed this challenge with a targeted metaproteomics workflow for NtcA and P-II, two nitrogen regulatory proteins, and demonstrated its application for cyanobacterial taxa within microbial samples from the Central Pacific Ocean. Using METATRYP, an open-source Python toolkit, we examined the number of shared (redundant) tryptic peptides in representative marine microbes, with the number of tryptic peptides shared between different species typically being 1% or less. The related cyanobacteria Prochlorococcus and Synechococcus shared an average of 4.8 +/- 1.9% of their tryptic peptides, while shared intraspecies peptides were higher, 13 +/- 15% shared peptides between 12 Prochlorococcus genomes. An NtcA peptide was found to target multiple cyanobacteria species, whereas a P-II peptide showed specificity to the high-light Prochlorococcus ecotype. Distributions of NtcA and P-II in the Central Pacific Ocean were similar except at the Equator likely due to differential nitrogen stress responses between Prochlorococcus and Synechococcus. The number of unique tryptic peptides coded for within three combined oceanic microbial metagenomes was estimated to be ~4 * 10(7) , 1000-fold larger than an individual microbial proteome and 27-fold larger than the human proteome, yet still 20 orders of magnitude lower than the peptide diversity possible in all protein space, implying that peptide mapping algorithms should be able to withstand the added level of complexity in metaproteomic samples. PMID- 26097213 TI - End-ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature. AB - A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation. PMID- 26097214 TI - Direct Synthesis of Palladium Catalyst on Supporting WS2 Nanotubes and its Reactivity in Cross-Coupling Reactions. AB - Palladium nanoparticles were deposited on multiwall WS2 nanotubes. The composite nanoparticles were characterized by a variety of techniques. The Pd nanoparticles were deposited uniformly on the surface of WS2 nanotubes. An epitaxial relationship between the (111) plane of Pd and the (013) plane of WS2 was mostly observed. The composite nanoparticles were found to perform efficiently as catalysts for cross-coupling (Heck and Suzuki) reactions. The role of the nanotubes' support in the catalytic process is briefly discussed. PMID- 26097216 TI - Intestinal malrotation in Rubinstein-Taybi syndrome. AB - Rubinstein-Taybi syndrome (RSTS) is a multiple congenital anomaly syndrome which may include malformations of the central nervous system, heart, genitourinary tract, and other organs. However, intestinal malrotation has not been previously known to be associated with RSTS. This report documents six persons with RSTS who also had malrotation of the intestine requiring surgical repair. This suggests a possible increased frequency of malrotation in RSTS. Diagnostic studies for malrotation should be considered if recurrent vomiting, abdominal pain, and other symptoms of possible malrotation are present. PMID- 26097215 TI - Long-term safety, efficacy, and quality of life in patients with juvenile idiopathic arthritis treated with intravenous abatacept for up to seven years. AB - OBJECTIVE: The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease modifying antirheumatic drugs were previously established in a phase III study that included a 4-month open-label lead-in period, a 6-month double-blind withdrawal period, and a long-term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient-reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup. METHODS: Patients enrolled in the phase III trial could enter the open label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double-blind period. RESULTS: One hundred fifty-three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient years) of adverse events decreased during the LTE phase (433.61 events during the short-term phase [combined lead-in and double-blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. CONCLUSION: Long-term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality-of-life benefits in patients with JIA. PMID- 26097217 TI - Improved assembly of bispecific antibodies from knob and hole half-antibodies. AB - A process was developed for large-scale assembly of IgG1 and IgG4 bispecific antibodies from knob and hole half-antibodies. We optimized assembly conditions such as pH, temperature, stabilizers, and reducing agent. We also identified and exploited structural changes unique to knob and hole half-antibodies with the result of improving assembly outcome, specifically storing half-antibodies at higher pH will condition them to assemble more rapidly and produce fewer high molecular-weight species (HMWS). Application of heat to the assemblies resulted in an acceleration of assembly rate, with optimal formation of bispecific achieved at 37 degrees C. IgG4 half-antibodies were unusually sensitive to temperature-dependent formation of HMWS in pre-assembly conditioning as well as during assembly. We selected l-histidine and Polyvinylpyrrolidone (PVP) as stabilizers to prevent HMWS formation in IgG4 , and achieved rapid and high efficiency assemblies. Using optimized assembly conditions, we developed and scaled up a method for assembling bispecific antibody with 90% assembly efficiency over 6 h with minimal impact to product quality, generating a pool with bispecific antibody for downstream processing. PMID- 26097218 TI - Dosing of sublingual immunotherapy for allergic rhinitis: evidence-based review with recommendations. AB - BACKGROUND: Since the mid 1980s, the clinical use of sublingual immunotherapy (SLIT) has dramatically increased. However, 1 of the primary barriers to providing SLIT is lack of a published dosing recommendations. The purpose of this work is to provide a range of effective SLIT dosing based upon a rigorous review of the existing evidence base. An appendix with SLIT dosing recommendations is also included. METHODS: A comprehensive search of the past 25 years of the medical literature using PubMed was performed for specific antigens. Inclusion criteria for articles included: randomized, placebo-controlled studies of SLIT, studies with clinical allergic rhinitis outcomes, and dosing units available to determine the micrograms per month of major allergen administered. The extracted data was used to compile a range of effective SLIT dosing for individual antigens. RESULTS: Seventy-five articles met the inclusion criteria, providing a range of effective dosing for some allergens. There was commonly a wide range in doses for particular antigens between the individual studies. For some antigens, there was significant overlap in dosage amount between studies showing efficacy and lack of efficacy. Clinical trials meeting inclusion criteria are not available for many allergens. CONCLUSION: This study provided a comprehensive review of the published sublingual dosing ranges for specific antigens. The review provided a range of effective sublingual doses for some allergens, whereas for other allergens there was insufficient published data to determine specific doses. Recommendations for SLIT dosing were produced based on the data revealed in the review and expert opinion. PMID- 26097219 TI - Physician Preferences and Variations in Prescription of Biologic Drugs for Rheumatoid Arthritis: A Register-Based Study of 4,010 Patients in Sweden. AB - OBJECTIVE: The prescription of biologic drugs for rheumatoid arthritis (RA) patients has varied considerably across different regions. Previous studies have shown physician preferences to be an important determinant in the decision to select biologic disease-modifying antirheumatic drugs (bDMARDs) rather than nonbiologic, synthetic DMARDs (sDMARDs) alone. The aim of this study was to test the hypothesis that physician preferences are an important determinant for prescribing bDMARDs for RA patients in Sweden. METHODS: Using data from the Swedish Rheumatology Quality Register, we identified 4,010 RA patients who were not prescribed bDMARDs during the period 2008-2012, but who, on at least 1 occasion, had an sDMARD prescription and changed treatment for the first time to either a new sDMARD or a bDMARD. Physician preference for the use of bDMARDs was calculated using data on each physician's prescriptions during the study period. The relationship between prescription of a bDMARD and physician preference, controlling for patient characteristics, disease activity, and the physician's local context was evaluated using multivariate logistic regression. RESULTS: When adjusting for patient characteristics, disease activity, and the physician's local context, physician preference was an important predictor for prescription of bDMARDs. Compared with patients of a physician in the lowest preference tertile, patients of physicians in the highest and middle tertiles had an odds ratio for receiving bDMARDs of 2.8 (95% confidence interval [95% CI] 2.13-3.68) and 1.28 (95% CI 1.05-1.57), respectively. CONCLUSION: Physician preference is an important determinant for prescribing bDMARDs. PMID- 26097220 TI - Commentary for history special issue of Research Synthesis Methods. PMID- 26097221 TI - Catalytic production of branched small alkanes from biohydrocarbons. AB - Squalane, C30 algae-derived branched hydrocarbon, was successfully converted to smaller hydrocarbons without skeletal isomerization and aromatization over ruthenium on ceria (Ru/CeO2 ). The internal CH2 ?CH2 bonds located between branches are preferably dissociated to give branched alkanes with very simple distribution as compared with conventional methods using metal-acid bifunctional catalysts. PMID- 26097222 TI - Hospital medicine in 2015: Remarkable successes and a crucial crossroads. PMID- 26097223 TI - Co-Culture of Human Endothelial Cells and Foreskin Fibroblasts on 3D Silk-Fibrin Scaffolds Supports Vascularization. AB - A successful strategy to enhance the in vivo survival of engineered tissues would be to prevascularize them. In this study, fabricated silk fibroin scaffolds from mulberry and non-mulberry silkworms are investigated and compared for supporting the co-culture of human umbilical vein endothelial cells and human foreskin fibroblasts. Scaffolds are cytocompatible and when combined with fibrin gel support capillary-like structure formation. Density and interconnectivity of the formed structures are found to be better in mulberry scaffolds. ELISA shows that levels of vascular endothelial growth factor (VEGF) released in co-cultures with fibrin gel are significantly higher than in co-cultures without fibrin gel. RT PCR shows an increase in VEGFR2 expression in mulberry scaffolds indicating these scaffolds combined with fibrin provide a suitable microenvironment for the development of capillary-like structures. PMID- 26097224 TI - Photon-Quantitative 6pi-Electrocyclization of a Diarylbenzo[b]thiophene in Polar Medium. AB - The high reactivity of 6pi-electrocyclization in polar solvents has remained one of the important challenges for diarylethenes because of the emergence of a twisted intramolecular charge transfer (TICT) state at the excited state in such polar media, which usually quenches the photocyclization reaction. Herein we report on the preparation and highly efficient photocyclization of 2,3 diarylbenzo[b]thiophenes with nonsymmetric side-aryl units in a polar solvent. While the dithiazolylbenzo[b]thiophene showed a suppressed quantum yield of 6pi electrocyclization of 54 % in methanol, the replacement of a thiazole unit with a thiophene ring led to a photon-quantitative 6pi-cyclization reaction. The nonsymmetrical modification into the side-aryl units was considered to enhance the CH/pi interactions between side-aryl units to support a photoreactive conformation in methanol. The stabilization of the photochromic reactive conformation is expected to suppress the formation of the TICT state at the excited state, leading to highly efficient photoreactivity. PMID- 26097225 TI - Use of ultrasound-guided small joint biopsy to evaluate the histopathologic response to rheumatoid arthritis therapy: recommendations for application to clinical trials. AB - OBJECTIVE: To examine in a cohort of rheumatoid arthritis (RA) patients undergoing serial ultrasound (US)-guided biopsies of small joints in the context of clinical trials whether sufficient synovial tissue could be obtained at both baseline and second biopsy to: 1) accurately evaluate the synovial immune phenotype, 2) permit adequate RNA extraction to determine molecular signatures, and 3) sensitively detect change in the number of synovial sublining macrophages (CD68+) following effective therapy. METHODS: Synovial samples from RA patients undergoing US-guided biopsy of small joints as part of 2 clinical trials (Barts Early Arthritis Cohort [n = 18] and the Clinical and Pathological Response to Certolizumab Pegol (CLIP-Cert) study [n = 17]) were examined, and the quality and quantity of histologic samples and RNA extracted per joint were determined and compared to synovial thickness and power Doppler scores determined by US before biopsy. Modulation of the number of CD68+ sublining macrophages was correlated with clinical response to treatment. RESULTS: Good quality synovial tissue that accurately reflected the synovial immune phenotype of the total joint was obtained in 80% of US-guided procedures when synovial thickness (higher than grade 2) was documented before biopsy. In 100% of the procedures, sufficient RNA was extracted to permit molecular analysis. There was a significant correlation between change in CD68+ sublining macrophage number and clinical response to treatment. CONCLUSION: This study provides minimum standards for sample retrieval for small joint biopsy. Furthermore, our findings confirm the clinical utility of the procedure in the largest reported cohort of US-guided small joint biopsies. The demonstration that small joint synovial tissue can be readily accessed by a technically simple, minimally invasive procedure is likely to facilitate critical advancements in the knowledge of RA pathobiology and personalized health care. PMID- 26097226 TI - Annual Incidence of Knee Symptoms and Four Knee Osteoarthritis Outcomes in the Johnston County Osteoarthritis Project. AB - OBJECTIVE: To estimate annual incidence rates (IRs) of knee symptoms and 4 knee osteoarthritis (OA) outcomes (radiographic, symptomatic, severe radiographic, and severe symptomatic), overall and stratified by sociodemographic characteristics and knee OA risk factors. METHODS: We analyzed baseline (1991-1997) and first followup (1999-2003) data (n = 1,518) from the Johnston County Osteoarthritis Project. Participants were African American and white adults, ages >=45 years, living in Johnston County, North Carolina, US. Knee symptoms were pain, aching, or stiffness on most days in a knee. Radiographic OA was Kellgren/Lawrence grade <=2 (severe radiographic >=3) in at least 1 knee. Symptomatic OA was defined as symptoms in a radiographically affected knee; severe symptomatic OA was defined as severe symptoms and severe radiographic OA. RESULTS: The median followup time was 5.5 years. Average annual IRs were 6% for symptoms, 3% for radiographic OA, 2% for symptomatic OA, 2% for severe radiographic OA, and 0.8% for severe symptomatic OA. Across outcomes, IRs were highest among those with the following baseline characteristics: age >=75 years, obese, a history of knee injury, or an annual household income <=$15,000. CONCLUSION: The annual onset of knee symptoms and 4 OA outcomes in Johnston County was high. This may preview the future of knee OA in the US and underscores the urgency of clinical and public health collaborations that reduce risk factors for, and manage the impact of, these outcomes. Inexpensive, convenient, and proven strategies (e.g., physical activity, self-management education courses) complement clinical care and can reduce pain and improve quality of life for people with arthritis. PMID- 26097227 TI - Management of the orbit during endoscopic sinonasal tumor surgery. AB - BACKGROUND: The primary aims of the study were to report preoperative imaging characteristics and intraoperative management of the orbit during endoscopic resection of benign and malignant sinonasal tumors. METHODS: This study was a case series at an academic tertiary care center. Retrospective chart review and prospective imaging assessment was performed on 159 cases treated between July 2009 and December 2012. RESULTS: A total of 41 patients met predetermined inclusion criteria. Squamous cell carcinoma (17.1%) and inverted papilloma (31.7%) were the most common malignant and benign histology, respectively. Preoperative computed tomography (CT) scanning most commonly demonstrated erosion of the lamina papyracea (80.5%), whereas magnetic resonance imaging (MRI) most commonly illustrated loss of fat plane between tumor and extraocular muscle (53.1%). Endoscopic procedures to address the orbital interface included lamina papyracea resection (85.4%), dacryocystorhinostomy (26.8%), periorbita resection (26.8%), optic nerve decompression (7.3%), and orbital exenteration (2.4%). Oculoplastic surgery involvement was required in 31.7% of cases. Orbital complications included epiphora in 3 (7.3%) and diplopia in 2 (5.1%) patients. Postoperatively, no recurrences were noted in the benign group, whereas 6 (28.6%) recurrences were noted in 21 patients in the malignant group treated with intent to cure. Two patients died of disease due to distant metastases from mucosal melanoma and squamous cell carcinoma. CONCLUSION: This represents the largest series to date on endoscopic management of the orbit in benign and malignant sinonasal tumors. A majority of these cases can be managed by a purely endoscopic approach with low complication and recurrence rates, although a subset still require adjunct open approaches for successful tumor extirpation. PMID- 26097228 TI - Elucidating the role of copper in CHO cell energy metabolism using (13)C metabolic flux analysis. AB - (13)C-metabolic flux analysis was used to understand copper deficiency-related restructuring of energy metabolism, which leads to excessive lactate production in recombinant protein-producing CHO cells. Stationary-phase labeling experiments with U-(13)C glucose were conducted on CHO cells grown under high and limiting copper in 3 L fed-batch bioreactors. The resultant labeling patterns of soluble metabolites were measured by GC-MS and used to estimate metabolic fluxes in the central carbon metabolism pathways using OpenFlux. Fluxes were evaluated 300 times from stoichiometrically feasible random guess values and their confidence intervals calculated by Monte Carlo simulations. Results from metabolic flux analysis exhibited significant carbon redistribution throughout the metabolic network in cells under Cu deficiency. Specifically, glycolytic fluxes increased (25%-79% relative to glucose uptake) whereas fluxes through the TCA and pentose phosphate pathway (PPP) were lower (15%-23% and 74%, respectively) compared with the Cu-containing condition. Furthermore, under Cu deficiency, 33% of the flux entering TCA via the pyruvate node was redirected to lactate and malate production. Based on these results, we hypothesize that Cu deficiency disrupts the electron transport chain causing ATP deficiency, redox imbalance, and oxidative stress, which in turn drive copper-deficient CHO cells to produce energy via aerobic glycolysis, which is associated with excessive lactate production, rather than the more efficient route of oxidative phosphorylation. PMID- 26097229 TI - Possible confounding by axial involvement in the ABILITY-2 study: comment on the article by Mease et al. PMID- 26097230 TI - Evaluation of olfactory function in adults with primary hypothyroidism. AB - BACKGROUND: Sufficient clinical data are not available on the effect of hypothyroidism on olfactory function in adults. In this study, we aimed to evaluate the olfactory function of adult patients diagnosed with primary hypothyroidism. METHODS: Forty-five patients aged between 18 and 60 years who were diagnosed with clinical primary hypothyroidism and 45 healthy controls who had normal thyroid function tests were included in the study. Sniffin' Sticks olfactory test results of the 2 groups were compared. The relationships between thyroid function tests and olfactory parameters were evaluated. RESULTS: Odor threshold, identification, and discrimination scores of the hypothyroid group were significantly lower than those of the control group (p < 0.001). A significant positive correlation was detected between free triiodothyronine (FT3) levels and odor threshold, identification, and discrimination scores (p < 0.001). There was no significant relationship between thyroid-stimulating hormone (TSH) or free thyroxine (FT4) levels and olfactory parameters. CONCLUSION: Our study revealed diminished olfactory function in adults with hypothyroidism. FT3 levels were found to have a more significant relationship with olfactory parameters than TSH or FT4 levels. PMID- 26097231 TI - Cause-Specific Mortality in Male US Veterans With Rheumatoid Arthritis. AB - OBJECTIVE: There has been limited investigation into cause-specific mortality and the associated risk factors in men with rheumatoid arthritis (RA). We investigated all-cause and cause-specific mortality in men with RA, examining determinants of survival. METHODS: Men from a longitudinal RA registry were followed from enrollment until death or through 2013. Vital status and cause of death were determined using the National Death Index. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all-cause, cardiovascular disease (CVD), cancer, and respiratory mortality. Associations with all-cause and cause-specific mortality were examined using multivariable Cox proportional hazards and competing-risks regression. RESULTS: There were 1,652 men with RA and 332 deaths. The leading causes of death were CVD (31.6%; SMR 1.77 [95% confidence interval (95% CI) 1.46-2.14]), cancer (22.9%; SMR 1.50 [95% CI 1.20-1.89]), and respiratory disease (15.1%; SMR 2.90 [95% CI 2.20-3.83]). Factors associated with all-cause mortality included older age, white race, smoking, low body weight, comorbidity, disease activity, and prednisone use. Rheumatoid factor concentration and nodules were associated with CVD mortality. There were no associations of methotrexate or biologic agent use with all-cause or cause-specific mortality. CONCLUSION: Men in this RA cohort experienced increased all-cause and cause-specific mortality, with a 3-fold risk of respiratory-related deaths compared to age-matched men in the general population. Further studies are needed in order to examine whether interventions targeting potentially modifiable correlates of mortality might lead to improved long-term survival in men with RA. PMID- 26097232 TI - Application of multivariate analysis and mass transfer principles for refinement of a 3-L bioreactor scale-down model--when shake flasks mimic 15,000-L bioreactors better. AB - Characterization of manufacturing processes is key to understanding the effects of process parameters on process performance and product quality. These studies are generally conducted using small-scale model systems. Because of the importance of the results derived from these studies, the small-scale model should be predictive of large scale. Typically, small-scale bioreactors, which are considered superior to shake flasks in simulating large-scale bioreactors, are used as the scale-down models for characterizing mammalian cell culture processes. In this article, we describe a case study where a cell culture unit operation in bioreactors using one-sided pH control and their satellites (small scale runs conducted using the same post-inoculation cultures and nutrient feeds) in 3-L bioreactors and shake flasks indicated that shake flasks mimicked the large-scale performance better than 3-L bioreactors. We detail here how multivariate analysis was used to make the pertinent assessment and to generate the hypothesis for refining the existing 3-L scale-down model. Relevant statistical techniques such as principal component analysis, partial least square, orthogonal partial least square, and discriminant analysis were used to identify the outliers and to determine the discriminatory variables responsible for performance differences at different scales. The resulting analysis, in combination with mass transfer principles, led to the hypothesis that observed similarities between 15,000-L and shake flask runs, and differences between 15,000-L and 3-L runs, were due to pCO2 and pH values. This hypothesis was confirmed by changing the aeration strategy at 3-L scale. By reducing the initial sparge rate in 3-L bioreactor, process performance and product quality data moved closer to that of large scale. PMID- 26097233 TI - Skeletal fluorosis--a tricky diagnosis. PMID- 26097234 TI - Identification of Onodi cell and new classification of sphenoid sinus for endoscopic sinus surgery. AB - BACKGROUND: There is no effective classification method for the opening of the sphenoid sinus. The objective of this study was to examine the effectiveness of identification of the Onodi cell and classification of the sphenoid sinus using sagittal computed tomography (CT) for sphenoidotomy. METHODS: CT images of the sinuses of surgical patients (n = 261; 522 sides) were studied. Using sagittal CT, the relationships between the lateral side of the anterior wall of the sphenoid sinus and the optic nerve, and between the middle of the anterior wall of the sphenoid sinus and the skull base or pituitary gland were studied. Images were classified as demonstrating skull base (without the Onodi cell), optic canal, sella, or infra-sella (all with the Onodi cell) type. RESULTS: Two hundred and fifty-eight sides (49.2%) were of the skull-base type, 181 (34.7%) were of the optic-canal type, 58 (11.1%) were of the sella type, and 26 (5.0%) were of the infra-sella type; ie, the Onodi cell was present in 50.8% of sides. The width of the anterior wall of the sphenoid sinus became narrower as it shifted from the skull-base type to the infra-sella type. CONCLUSION: Classification of the anterior wall of the sphenoid sinus based on the Onodi cell allows 3-dimensional assessment of the shape of the sphenoid sinus. We believe that the sphenoid sinus can be opened safely by full preoperative assessment of the anterior wall type, the position of the superior turbinate, and the position of the ostium of the sphenoid sinus. PMID- 26097235 TI - Characterizing the release of bioactive N-glycans from dairy products by a novel endo-beta-N-acetylglucosaminidase. AB - Endo-beta-N-acetylglucosaminidase isolated from B. infantis ATCC 15697 (EndoBI-1) is a novel enzyme that cleaves N-N'-diacetyl chitobiose moieties found in the N glycan core of high mannose, hybrid, and complex N-glycans. These conjugated N glycans are recently shown as a new prebiotic source that stimulates the growth of a key infant gut microbe, Bifidobacterium longum subsp. Infantis. The effects of pH (4.45-8.45), temperature (27.5-77.5 degrees C), reaction time (15-475 min), and enzyme/protein ratio (1:3,000-1:333) were evaluated on the release of N glycans from bovine colostrum whey by EndoBI-1. A central composite design was used, including a two-level factorial design (2(4)) with four center points and eight axial points. In general, low pH values, longer reaction times, higher enzyme/protein ratio, and temperatures around 52 degrees C resulted in the highest yield. The results demonstrated that bovine colostrum whey, considered to be a by/waste product, can be used as a glycan source with a yield of 20 mg N glycan/g total protein under optimal conditions for the ranges investigated. Importantly, these processing conditions are suitable to be incorporated into routine dairy processing activities, opening the door for an entirely new class of products (released bioactive glycans and glycan-free milk). The new enzyme's activity was also compared with a commercially available enzyme, showing that EndoBI-1 is more active on native proteins than PNGase F and can be efficiently used during pasteurization, streamlining its integration into existing processing strategies. PMID- 26097236 TI - Promotion of hypercoagulability in antineutrophil cytoplasmic antibody-associated vasculitis by C5a-induced tissue factor-expressing microparticles and neutrophil extracellular traps. AB - OBJECTIVE: Patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) have a high frequency of venous thromboembolic events and a hypercoagulable state. As C5a-primed neutrophils play an important role in the development of AAV, we investigated whether C5a-induced neutrophil tissue factor (TF)-expressing microparticles (MPs) and neutrophil extracellular traps (NETs) might promote hypercoagulability in AAV. METHODS: TF-expressing MPs were measured by flow cytometry. TF-expressing NETs were assessed by confocal microscopy. Levels of thrombin-antithrombin complexes were determined by enzyme-linked immunosorbent assay. The effect of C5a in sera from AAV patients was evaluated by treating neutrophils with C5a receptor antagonist before incubation with sera from AAV patients with active disease. RESULTS: Treatment of C5a-primed neutrophils with antineutrophil cytoplasmic antibody (ANCA)-positive IgG resulted in the release of TF-bearing MPs and NETs. Neutrophils from healthy donors treated with sera from patients with active AAV released TF-bearing MPs and NETs, which were abolished by treatment with C5a receptor antagonist. Involvement of TF in MP- or NET-dependent thrombin generation was indicated by the findings of antibody neutralization studies. NETs with thrombin-generating capacity were demonstrated by DNase I treatment. CONCLUSION: C5a-primed neutrophils produce TF expressing MPs and NETs after stimulation with ANCAs, indicating a mechanism for hypercoagulability in AAV that was not previously recognized. PMID- 26097237 TI - Staphylococcus aureus triggers nitric oxide production in human upper airway epithelium. AB - BACKGROUND: Nitric oxide (NO) is an important antibacterial defense molecule produced by upper airway (sinonasal) epithelial cells. We previously showed that a bitter taste receptor expressed in airway epithelium detects quorum-sensing molecules secreted by Gram-negative bacteria and subsequently triggers bactericidal NO production. We hypothesized that the upper airway epithelium may also be able to detect the Gram-positive aerobe Staphylococcus aureus and mount an NO response. METHODS: Human sinonasal air-liquid interface (ALI) cultures were treated with methicillin-resistant S. aureus (MRSA)-conditioned medium (CM), and NO production was measured using fluorescence imaging. Inhibitors of bitter taste receptor signaling were used to pharmacologically determine if this pathway was involved in the production of NO. RESULTS: A low-molecular-weight, heat, and protease-stabile product found in MRSA CM induced differential, NO synthase (NOS) mediated NO production. This response varied markedly between individual patients. The MRSA-stimulated NO production was not dependent on 2 important components of bitter taste signaling: phospholipase C isoform beta-2 or the transient receptor potential melastatin isoform 5 (TRPM5) ion channel. CONCLUSION: This study shows that a S. aureus product elicits an NO-mediated innate defense response in human upper airway epithelium. The active bacterial product is likely a small, nonpeptide molecule that triggers a pathway independent of bitter taste receptors. Patient variation in the NO response to MRSA product(s), potentially due to genetic differences, might play a role in pathophysiology of Gram-positive upper respiratory infections and/or pathogenesis of chronic rhinosinusitis. PMID- 26097238 TI - Atom-Economic Synthesis of Fully Substituted 2-Aminopyrroles via Gold-Catalyzed Formal [3+2] Cycloaddition between Ynamides and Isoxazoles. AB - A concise and flexible synthesis of fully substituted 2-aminopyrroles via gold catalyzed formal [3+2] cycloaddition between ynamides and isoxazoles has been developed. Under mild reaction conditions, various 2-aminopyrrole derivatives were obtained in good to excellent yields, thus providing an efficient and atom economic way for the construction of fully substituted 2-aminopyrroles. PMID- 26097239 TI - Brief report: association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 With Behcet's disease in Iranians. AB - OBJECTIVE: To independently replicate the top findings from 4 published genome wide association studies (GWAS) of susceptibility genes in Behcet's disease (BD). METHODS: We tested 14 single-nucleotide polymorphisms (SNPs) in 13 genomic loci (excluding the major histocompatibility complex [MHC], IL10, and IL23R-IL12RB2, which have already been associated with BD in Iranians) for allelic and genotypic associations with BD in 973 patients and 828 controls from Iran and performed meta-analyses of the significantly associated markers. RESULTS: Six SNPs (in decreasing order of significance, rs7616215 located 38 kb downstream of CCR1, rs2617170 [p.Asn104Ser] in KLRC4, rs17810546 in IL12A-AS1, rs7574070 in STAT4, and rs10050860 [p.Asp575Asn] and rs13154629 in ERAP1) were nominally associated with BD in both allelic association tests (5.05 * 10(-9) <= Pallele <= 7.55 * 10( 3) ) and sex-adjusted genotypic association tests (6.01 * 10(-9) <= adjusted P value <= 1.30 * 10(-2) ). For all 6 SNPs tested by meta-analysis (Pmeta ), the association with BD was strengthened, because the direction and magnitude of association were similar across populations (e.g., for rs7574070, odds ratio [OR] for A allele 1.29 [95% confidence interval (95% CI) 1.21-1.37], Pmeta = 2.34 * 10(-16) ; for rs7616215, OR for C allele 0.70 [95% CI 0.65-0.76], Pmeta = 1.54 * 10(-19) ; for rs17810546, OR for A allele 0.60 [95% CI 0.52-0.70], Pmeta = 6.34 * 10(-11) ; for rs2617170, OR for T allele 0.76 [95% CI 0.70-0.81], Pmeta = 2.75 * 10(-14) ; for rs13154629, OR for TT genotype 2.76 [95% CI 2.01-3.80], Pmeta = 3.57 * 10(-10) ). CONCLUSION: This study reinforces the notion that CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 are bona fide susceptibility genes for BD, in addition to the MHC, IL10, and IL23R-IL12RB2 loci. Future genetic and functional studies are now warranted to uncover the roles of these genes in the pathogenesis of BD. PMID- 26097240 TI - Shifts in indigenous culture relate to forest tree diversity: a case study from the Tsimane', Bolivian Amazon. AB - Understanding how indigenous peoples' management practices relate to biological diversity requires addressing contemporary changes in indigenous peoples' way of life. This study explores the association between cultural change among a Bolivian Amazonian indigenous group, the Tsimane', and tree diversity in forests surrounding their villages. We interviewed 86 informants in six villages about their level of attachment to traditional Tsimane' values, our proxy for cultural change. We estimated tree diversity (Fisher's Alpha index) by inventorying trees in 48 0.1-ha plots in old-growth forests distributed in the territory of the same villages. We used multivariate models to assess the relation between cultural change and alpha tree diversity. Cultural change was associated with alpha tree diversity and the relation showed an inverted U-shape, thus suggesting that tree alpha diversity peaked in villages undergoing intermediate cultural change. Although the results do not allow for testing the direction of the relation, we propose that cultural change relates to tree diversity through the changes in practices and behaviors that affect the traditional ecological knowledge of Tsimane' communities; further research is needed to determine the causality. Our results also find support in the intermediate disturbance hypothesis, and suggest that indigenous management can be seen as an intermediate form of anthropogenic disturbance affecting forest communities in a subtle, non-destructive way. PMID- 26097241 TI - Gender, Friendship Networks, and Delinquency: A Dynamic Network Approach. AB - Researchers have examined selection and influence processes in shaping delinquency similarity among friends, but little is known about the role of gender in moderating these relationships. Our objective is to examine differences between adolescent boys and girls regarding delinquency-based selection and influence processes. Using longitudinal network data from adolescents attending two large schools in AddHealth (N = 1,857) and stochastic actor-oriented models, we evaluate whether girls are influenced to a greater degree by friends' violence or delinquency than boys (influence hypothesis) and whether girls are more likely to select friends based on violent or delinquent behavior than boys (selection hypothesis). The results indicate that girls are more likely than boys to be influenced by their friends' involvement in violence. Although a similar pattern emerges for nonviolent delinquency, the gender differences are not significant. Some evidence shows that boys are influenced toward increasing their violence or delinquency when exposed to more delinquent or violent friends but are immune to reducing their violence or delinquency when associating with less violent or delinquent friends. In terms of selection dynamics, although both boys and girls have a tendency to select friends based on friends' behavior, girls have a stronger tendency to do so, suggesting that among girls, friends' involvement in violence or delinquency is an especially decisive factor for determining friendship ties. PMID- 26097242 TI - Sleep, Memory & Brain Rhythms. AB - Sleep occupies roughly one-third of our lives, yet the scientific community is still not entirely clear on its purpose or function. Existing data point most strongly to its role in memory and homeostasis: that sleep helps maintain basic brain functioning via a homeostatic mechanism that loosens connections between overworked synapses, and that sleep helps consolidate and re-form important memories. In this review, we will summarize these theories, but also focus on substantial new information regarding the relation of electrical brain rhythms to sleep. In particular, while REM sleep may contribute to the homeostatic weakening of overactive synapses, a prominent and transient oscillatory rhythm called "sharp-wave ripple" seems to allow for consolidation of behaviorally relevant memories across many structures of the brain. We propose that a theory of sleep involving the division of labor between two states of sleep-REM and non-REM, the latter of which has an abundance of ripple electrical activity-might allow for a fusion of the two main sleep theories. This theory then postulates that sleep performs a combination of consolidation and homeostasis that promotes optimal knowledge retention as well as optimal waking brain function. PMID- 26097243 TI - Are ecologically important tree species the most useful? A case study from indigenous people in the Bolivian Amazon. AB - Researchers have argued that indigenous peoples preferably use the most apparent plant species, particularly for medicinal uses. However, the association between the ecological importance of a species and its usefulness remains unclear. In this paper we quantify such association for six use categories (firewood, construction, materials, food, medicines and other uses). We collected data on the uses of 58 tree species, as reported by 93 informants in 22 villages in the Tsimane' territory (Bolivian Amazon). We calculated the ecological importance of the same species by deriving their importance value index (IVI) in 48 0.1-ha old growth forest plots. Matching both data sets, we found a positive relation between the IVI of a species and its overall use value (UV) as well as with its UV for construction and materials. We found a negative relation between IVI and UV for species that were reportedly used for medicine and food uses, and no clear pattern for the other categories. We hypothesize that species used for construction or crafting purposes because of their physical properties are more easily substitutable than species used for medicinal or edible purposes because of their chemical properties. PMID- 26097244 TI - Effects of a Multitier Support System on Calculation, Word Problem, and Prealgebraic Performance Among At-Risk Learners. AB - The focus of the present study was enhancing word-problem and calculation achievement in ways that support pre-algebraic thinking among 2nd-grade students at risk for mathematics difficulty. Intervention relied on a multi-tier support system (i.e., responsiveness-to-intervention or RTI) in which at-risk students participate in general classroom instruction and receive supplementary small group tutoring. Participants were 265 students in 110 classrooms in 25 schools. Teachers were randomly assigned to 3 conditions: calculation RTI, word-problem RTI, and business-as-usual control. Intervention lasted 17 weeks. Multilevel modeling indicated that calculation RTI improved calculation but not word-problem outcomes; word-problem RTI enhanced proximal word-problem outcomes as well as performance on some calculation outcomes; and word-problem RTI provided a stronger route than calculation RTI to pre-algebraic knowledge. PMID- 26097246 TI - Uterine Artery Embolization (UAE) for Fibroid Treatment - Results of the 5th Radiological Gynecological Expert Meeting. PMID- 26097245 TI - Magnetic Resonance Guided Focused Ultrasound for Fibroid Treatment - Results of the Second Radiological Gynecological Expert Meeting. PMID- 26097247 TI - Radiofrequency Volumetric Thermal Ablation of Fibroids and Laparoscopic Myomectomy: Long-Term Follow-up From a Randomized Trial. AB - Aims: Laparoscopic myomectomy (LM) has been the gold standard treatment for uterine fibroids in women desiring uterine conservation. To evaluate a new fibroid treatment modality - radiofrequency volumetric thermal ablation (RFVTA) - we compare 12-month results in women who had symptomatic uterine fibroids and who were randomized to laparoscopic ultrasound-guided RFVTA or LM. Materials and Methods: Our study is a 1 : 1 parallel, randomized, prospective, single-center, longitudinal, comparative analysis of RFVTA to LM for fibroid treatment in women >= 18 years of age who desired uterine conservation. Fifty women were randomized intraoperatively to RFVTA (n = 25) or to LM (n = 25) after laparoscopic ultrasound mapping of the uterus. Results: Post surgery, ablation and myomectomy subjects took pain medications for 4 days (range: 1-46) and 7 days (range: 1-83 days) respectively (p = 0.60). Ablation and myomectomy subjects missed 10.0 workdays (range: 2-86 days) and 17.0 workdays (range: 7-30 days) (p = 0.28), resumed normal activities in 20.5 days (range: 5-103 days) versus 28.0 days (range: 10-42 days) (p = 0.86) respectively. Mean symptom severity scores decreased (improved) by - 7.8 for the ablation subjects and by - 17.9 for the myomectomy subjects (p = 0.16). Health-related quality of life improved (increased) by 7.5 and 13.1, respectively, for the two groups (p = 0.46). Two myomectomy subjects had pregnancies that ended in a Cesarean delivery and a vaginal delivery of healthy infants. Two pregnancies in the RFVTA group ended in full-term vaginal deliveries of healthy infants. Conclusions: Early postoperative recovery and twelve-month results attest to similar clinical benefits from RFVTA and LM. PMID- 26097248 TI - Duration of Sick Leave, Patient's Postoperative Satisfaction and Impairment of Daily Living after Open Abdominal Myoma Enucleation in Dependence on Myoma Size. AB - Purpose: What is the average duration of sick leave and the postoperative impairment to daily living in dependence on the size of the removed myoma? Does patient satisfaction depend on the size of the removed myoma? Is there a difference in the rate of improvement of symptoms depending on the size of the myoma? Patient Collective: This is a retrospective survey of the data of 377 consecutive female patients treated for symptomatic uterus myomatosus by open abdominal myoma enucleation between 2/2002 and 12/2009; the number of removed myomas, myoma size and localisation, myoma-associated complaints, length of sick leave, postoperative impairments of daily living and scar length were assessed. Results: The response rate amounted to 61 % (230/377 patients). The average sick leave of patients with a myoma diameter >= 10 cm was 1.5 days shorter than that for patients with myomas < 10 cm. Depending on the symptoms between 7 and 75 % of the patients reported an improvement of their complaints. For those patients with myomas > 10 cm the proportion with an improvement in symptoms was smaller than that for the patients with smaller myomas - exception "feeling of pressure in the bladder". Conclusions: Even for relatively large myomas, the quality of life is not impaired more strongly or for longer periods than that after removal of smaller myomas. Activities of daily life are impaired for about 4 weeks. PMID- 26097249 TI - Deciding Factors for the Referral of a Female Patient to a Specific Hospital from the Viewpoint of Practice-Based Specialists. AB - Background: One of the key points of patient care is the cooperation between practice-based specialists and clinical facilities. The present study was undertaken in order to illustrate the deciding factors, from the viewpoint of practice-based specialists, for the referral of a female patient to a specific hospital. Methods: Altogether a total of 322 practice-based specialists from various disciplines were contacted in writing and sent a questionnaire. In this survey the recipients were questioned about the criteria, in order of importance, applied for the referral of a (female) patient to a specific clinical facility. Results: In the foreground for the referral of a patient to a specific hospital are the aspects of medical quality and competence. On a closer look we find the surgical spectrum, especially the availability of endoscopic and special operations as a main factor. Further factors are a low rate of complications and the availability of modern diagnostic methods. Also evaluated as an important aspect was the easy reachability of a competent consultant. Factors of lower relevance for referral behaviour were personal familiarity with the colleagues employed in the hospital, specific further training events and the course of previous cooperation. Conclusions: A modern diagnostic and therapeutic spectrum coupled with an easy reachability of competent contact partners are the main factors for cooperation from the viewpoint of the practice-based specialist. Of lowest relevance, among others, was the aspect of previous cooperation. Thus, it can be seen that by means of changes in cooperation an improvement in patient care can be achieved at any time. PMID- 26097250 TI - Supporting and Inhibiting Factors When Coping with Endometriosis From the Patients' Perspective. AB - Aim: Endometriosis is a chronic gynaecological disorder with manifold symptoms and psychosocial effects on the lives of affected women. The prevalence of endometriosis is estimated to be up to ten percent of women of reproductive age. As a result of its unclear aetiology, only limited treatment options are available. The treatment and care of affected women is therefore a challenge for their doctors. There is a need for healthcare services to provide affected women with support to cope with the disorder better. The aim of the study was to identify supporting and inhibiting factors on disease management to develop new support ideas. Materials and Methods: The results are based on a content analysis evaluation of text responses from 135 women with confirmed endometriosis. Open questions about disease management were posed in a patient questionnaire. A classification system was developed according to Mayrings Qualitative Content Analysis, which allowed the main topics to be identified and summarised qualitatively using a quantitative intermediate step. Results: Social support, treatment, as well as professional and healthcare system performance were found to be particularly supportive by patients. However, when questioned about inhibiting factors, healthcare system professionals and their performance were most commonly criticised. Just over 50 % of women expressed their criticism of doctors. Quality of care and empathy towards the patients were especially criticised. There is also a need for improvement with regard to communication and general support from doctors. The results illustrate the importance of doctors for women affected by endometriosis, but make it clear that there is a great need for improvement with regard to the profession. Conclusion: The results provide the first indication of problem areas in the management of endometriosis from which approaches could be developed to improve care. However, it must be pointed out that the perspective of affected women was solely investigated. For a comprehensive analysis, it would be necessary to include the perspective of care providers and the influence of society as well as the healthcare system. PMID- 26097251 TI - Magnetic Resonance Force Microscopy Detected Long-Lived Spin Magnetization. AB - Magnetic resonance force microscopy (MRFM), which combines magnetic resonance imaging with scanning probe microscopy together, is capable of performing ultra sensitive detection of spin magnetization. In an attempt to observe dynamic nuclear polarization (DNP) in an MRFM experiment, which could possibly further improve its sensitivity towards a single proton spin, a film of perdeuterated polystyrene doped with a nitroxide electron-spin probe was prepared. A high compliance cantilever with a 4 MUm diameter magnetic tip was brought near the film at a temperature of 7.3 K and in a background magnetic field of ~0.6 T. The film was irradiated with 16.7 GHz microwaves while the resulting transient change in cantilever frequency was recorded in real time. In addition to observing the expected prompt change in cantilever frequency due to saturation of the nitroxide's electron-spin magnetization, we observed a persistent cantilever frequency change. Based on its magnitude, lifetime, and field dependence, we tentatively attribute the persistent signal to polarized deuteron magnetization created via transfer of magnetization from electron spins. Further measurements of the persistent signal's dependence on the cantilever amplitude and tip-sample separation are presented and explained by the cross-effect DNP mechanism in high magnetic field gradients. PMID- 26097252 TI - Cryptic extended brood care in the facultatively eusocial sweat bee Megalopta genalis. AB - As a result of different brood cell provisioning strategies, nest-making insects may differ in the extent to which adults regularly provide extended parental care to their brood beyond nest defense. Mass-provisioning species cache the entire food supply needed for larval development prior to the oviposition and typically seal the brood cell. It is usually assumed that there is no regular contact between the adult(s) and brood. Here, we show that the bee, Megalopta genalis, expresses a form of cryptic brood care, which would not be observed during normal development. Following experimental injections of different provisioning materials into brood cells, foundresses reopened manipulated cells and the brood were aborted in some cases, implying that the foundresses assessed conditions within the cells. In aborted cells, foundresses sometimes laid a second egg after first removing dead larvae, previously stored pollen and contaminants. Our results show that hygienic brood care can be cryptic and hence may be more widespread than previously believed, lending support to the hypothesis that extended parental care is a preadaptation toward eusociality. PMID- 26097253 TI - The Relationship Between Multiple Forms of Discrimination, Neighborhood Characteristics, and Depression Among Illicit Drug Users in New York City. AB - It is plausible that features of the social environment combined with experiences of discrimination may help further explain experiences of depression among illicit drug users. We examined the influence of census tract-level characteristics and multiple forms of individual-level discrimination on lifetime depression among illicit drug users in New York City enrolled in the "Social Ties Associated With Risk of Transition" study. Population average models accounted for clustering of individuals within census tracts. Discrimination based on prior incarceration explained Hispanic/White differences in depression and was independently associated with depression after accounting for neighborhood characteristics. Neighborhood poverty was only marginally related to lifetime depression. These data provide evidence supporting the influence of discrimination on depression among drug users. Research is needed to confirm these findings and highlight specific mechanisms through which discrimination and neighborhood socioeconomic status may operate to influence mental health. PMID- 26097254 TI - The Thermal Instability of 2,4 and 2,6-N-Alkylamino Disubstituted and 2-N Alkylamino Substituted Nitrobenzenes in Weakly Alkaline Solution: sec-Amino Effect. AB - We report herein the preparation of two families of secondary amines by the reactions of two equivalents of monoamines with either 2,4 or 2,6 difluoronitrobenzenes in N,N-dimethylacetamide in the presence of anhydrous potassium carbonate, as precursors of biologically important nitric oxide donating N-nitrosamines. In both instances, these compounds could be prepared in quantitative yield when the reaction temperature was held below 130 degrees C. Above this reaction temperature, an unexpected cyclization reaction between the nitro and newly formed adjacent secondary amine group leads to the formation of benzimidazole or quinoxaline rings in low yields. Reasonable reaction mechanisms for the cyclization reaction are proposed. PMID- 26097255 TI - Gender Wage Disparities among the Highly Educated. AB - In the U.S. college-educated women earn approximately 30 percent less than their non-Hispanic white male counterparts. We conduct an empirical examination of this wage disparity for four groups of women-non-Hispanic white, black, Hispanic, and Asian-using the National Survey of College Graduates, a large data set that provides unusually detailed information on higher-level education. Nonparametric matching analysis indicates that among men and women who speak English at home, between 44 and 73 percent of the gender wage gaps are accounted for by such pre market factors as highest degree and major. When we restrict attention further to women who have "high labor force attachment" (i.e., work experience that is similar to male comparables) we account for 54 to 99 percent of gender wage gaps. Our nonparametric approach differs from familiar regression-based decompositions, so for the sake of comparison we conduct parametric analyses as well. Inferences drawn from these latter decompositions can be quite misleading. PMID- 26097256 TI - Experimental and Computational Studies of Sound Transmission in a Branching Airway Network Embedded in a Compliant Viscoelastic Medium. AB - Breath sounds are often used to aid in the diagnosis of pulmonary disease. Mechanical and numerical models could be used to enhance our understanding of relevant sound transmission phenomena. Sound transmission in an airway mimicking phantom was investigated using a mechanical model with a branching airway network embedded in a compliant viscoelastic medium. The Horsfield self-consistent model for the bronchial tree was adopted to topologically couple the individual airway segments into the branching airway network. The acoustics of the bifurcating airway segments were measured by microphones and calculated analytically. Airway phantom surface motion was measured using scanning laser Doppler vibrometry. Finite element simulations of sound transmission in the airway phantom were performed. Good agreement was achieved between experiments and simulations. The validated computational approach can provide insight into sound transmission simulations in real lungs. PMID- 26097258 TI - Accounting for Impact? The Journal Impact Factor and the Making of Biomedical Research in the Netherlands. AB - The range and types of performance metrics has recently proliferated in academic settings, with bibliometric indicators being particularly visible examples. One field that has traditionally been hospitable towards such indicators is biomedicine. Here the relative merits of bibliometrics are widely discussed, with debates often portraying them as heroes or villains. Despite a plethora of controversies, one of the most widely used indicators in this field is said to be the Journal Impact Factor (JIF). In this article we argue that much of the current debates around researchers' uses of the JIF in biomedicine can be classed as 'folk theories': explanatory accounts told among a community that seldom (if ever) get systematically checked. Such accounts rarely disclose how knowledge production itself becomes more-or-less consolidated around the JIF. Using ethnographic materials from different research sites in Dutch University Medical Centers, this article sheds new empirical and theoretical light on how performance metrics variously shape biomedical research on the 'shop floor.' Our detailed analysis underscores a need for further research into the constitutive effects of evaluative metrics. PMID- 26097259 TI - The Academic Manifesto: From an Occupied to a Public University. AB - Universities are occupied by management, a regime obsessed with 'accountability' through measurement, increased competition, efficiency, 'excellence', and misconceived economic salvation. Given the occupation's absurd side-effects, we ask ourselves how management has succeeded in taking over our precious universities. An alternative vision for the academic future consists of a public university, more akin to a socially engaged knowledge commons than to a corporation. We suggest some provocative measures to bring about such a university. However, as management seems impervious to cogent arguments, such changes can only happen if academics take action. Hence, we explore several strategies for a renewed university politics. PMID- 26097260 TI - Studies toward the synthesis of cinachyramine. An efficient route to 1,5 diazabicyclo[4.4.0]dec-5-enes. AB - Hydrogenation (3 atm) of readily available pyrido[1,2-a]pyrimidines 10, 14, and 17 over 5% Rh/Al2O3 forms 1,5-diazabicyclo[4.4.0]dec-5-enes 9, 15, and 18 in > 95% yield, providing a general route to this little-studied class of compounds. All attempts to form the tetrahydro-1,2,4-triazine moiety of cinachyramine (1) by rearrangement of amidinium dimethylhydrazone 8 using the procedures developed by Kamatori to convert hydrazone 3a to tetrahydro-1,2,4-triazine 4a were unsuccessful. PMID- 26097261 TI - Spirastrellolide E: Synthesis of an advanced C(1)-C(24) southern hemisphere. AB - The synthesis of a C(1)-C(24) advanced southern hemisphere fragment towards the total synthesis of spirastrellolide E has been achieved. Highlights of the route include a highly convergent Type I Anion Relay Chemistry (ARC) tactic for fragment assembly, in conjunction with a directed, regioselective gold-catalyzed alkyne functionalization to generate the central unsaturated [6,6]-spiroketal. PMID- 26097262 TI - Computational studies of electronic circular dichroism spectra predict absolute configuration assignments for the guanine oxidation product 5-carboxamido-5 formamido-2-iminohydantoin. AB - Oxidation of the guanine heterocycle by two electrons can yield the chiral product 5-carboxamido-5-formamido-2-iminohydantoin (2Ih). The 2Ih free base enantiomers were synthesized from 2'-deoxyguanosine oxidized with a Cu(II)/H2O2 oxidant system followed by hydrolysis of the N-glycosidic bond. These isomers were each studied by electronic circular dichroism spectroscopy for determination of their absolute configurations. Time-dependent density functional theory calculations of the expected spectra were completed in both the gas phase and with solvent modeling in order to interpret the experimental spectra and provide the absolute configuration assignments. PMID- 26097263 TI - Construction of the 5,6,7-tricyclic skeleton of lancifodilactone F. AB - We report herein the synthesis of a fully functionalized B,C,D-ring system of lancifodilactone F. The key transformations involve an arene-olefin meta photocycloaddition reaction and a palladium-catalyzed oxidative C-C cleavage reaction to establish its B,C-rings. PMID- 26097264 TI - Multigram Synthesis of 1-O-Acetyl-3-O-(4-methoxybenzyl)-4-N-(9 fluorenylmethoxycarbonyl)-4-N-methyl-L-pyrrolosamine. AB - A synthesis of 1-O-acetyl-3-O-(4-methoxybenzyl)-4-N-(9-fluorenylmethoxycarbonyl) 4-N-methyl-L-pyrrolosamine (7), which constitutes a protected form of the N,N dimethyl-L-pyrrolosamine residues found within the antiproliferative bacterial metabolites (-)-lomaiviticins A and B (1 and 2, respectively), is reported. The synthetic route to 7 proceeds in eight steps and 13% overall yield from (E) crotyl alcohol. The protected carbohydrate 7 is envisioned to be a useful derivative for syntheses of 1 and 2. PMID- 26097265 TI - LiOOt-Bu as a terminal oxidant in a titanium alkoxide-mediated [2+2+2] reaction cascade. AB - LiOOt-Bu is an effective oxidant for converting the penultimate organometallic intermediate generated in a titanium alkoxide-mediated [2+2+2] reaction cascade to an allylic alcohol. Oxidation of the presumed allylic titanium species is highly regioselective, providing direct access to substituted hydroindanes containing a primary allylic alcohol. In addition to demonstrating the feasibility of this oxidation process, we document the ability to convert the primary allylic alcohol products to angularly substituted cis-fused hydroindanes. PMID- 26097266 TI - Synthesis of N-substituted aryl amidines by strong base activation of amines. AB - We describe an efficient method for the direct preparation of N-substituted aryl amidines from nitriles and primary amines. The protocol employs activation of amines by a strong base and provides greater access to a pharmaceutically relevant functional group. This synthetic approach tolerates deactivated nitriles, nitriles with competing substitution sites, and aryl amines. PMID- 26097267 TI - Traditional Livelihoods, Conservation and Meadow Ecology in Jiuzhaigou National Park, Sichuan, China. AB - Jiuzhaigou National Park (JNP) is a site of global conservation significance. Conservation policies in JNP include the implementation of two national reforestation programs to increase forest cover and the exclusion of local land use. We use archaeological excavation, ethnographic interviews, remote sensing and vegetation surveys to examine the implications of these policies for non forest, montane meadows. We find that Amdo Tibetan people cultivated the valley for >2,000 years, creating and maintaining meadows through land clearing, burning and grazing. Meadows served as sites for gathering plants and mushrooms and over 40 % of contemporary species are ethnobotanically useful. Remote sensing analyses indicate a substantial (69.6 %) decline in meadow area between 1974 and 2004. Respondents report a loss of their "true history" and connections to the past associated with loss of meadows. Conservation policies intended to preserve biodiversity are unintentionally contributing to the loss of these ecologically and culturally significant meadow habitats. PMID- 26097269 TI - Reactive and proactive aggression and suicide attempts among criminal offenders. AB - Outwardly-directed aggression is associated with suicide attempts, but aggression is a heterogeneous construct. Increased specificity in our understanding of the link between aggression and suicide attempts can be attained by examining subtypes of aggression. We studied the relationships of reactive and proactive aggression to history of a suicide attempt among 96 criminal offenders in a pretrial supervision program. Consistent with prior findings in non-offender samples, reactive aggression was associated with a history of suicide attempt after controlling for gender and depression. Proactive aggression was unrelated to suicide attempts. Results indicate that suicide risk assessments in forensic settings may be informed by the measurement of reactive aggression. PMID- 26097268 TI - Whole Trait Theory. AB - Personality researchers should modify models of traits to include mechanisms of differential reaction to situations. Whole Trait Theory does so via five main points. First, the descriptive side of traits should be conceptualized as density distributions of states. Second, it is important to provide an explanatory account of the Big 5 traits. Third, adding an explanatory account to the Big 5 creates two parts to traits, an explanatory part and a descriptive part, and these two parts should be recognized as separate entities that are joined into whole traits. Fourth, Whole Trait Theory proposes that the explanatory side of traits consists of social-cognitive mechanisms. Fifth, social-cognitive mechanisms that produce Big-5 states should be identified. PMID- 26097270 TI - Sensitivity of Optimal Solutions to Control Problems for Second Order Evolution Subdifferential Inclusions. AB - In this paper the sensitivity of optimal solutions to control problems described by second order evolution subdifferential inclusions under perturbations of state relations and of cost functionals is investigated. First we establish a new existence result for a class of such inclusions. Then, based on the theory of sequential [Formula: see text]-convergence we recall the abstract scheme concerning convergence of minimal values and minimizers. The abstract scheme works provided we can establish two properties: the Kuratowski convergence of solution sets for the state relations and some complementary [Formula: see text] convergence of the cost functionals. Then these two properties are implemented in the considered case. PMID- 26097271 TI - Ionization of covalent immobilized poly(4-vinylphenol) monolayers measured by ellipsometry, QCM and SPR. AB - Covalently immobilized poly(4-vinylphenol) (PVP) monolayer films were fabricated by spin coating PVP on perfluorophenyl azide (PFPA)-functionalized surface followed by UV irradiation. The pH-responsive behavior of these PVP ultrathin films was evaluated by ellipsometry, quartz crystal microbalance (QCM) and surface plasmon resonance (SPR). By monitoring the responses of these films to pH in situ, the ionization constant of the monolayer thin films was obtained. The apparent pKa value of these covalently immobilized PVP monolayers, 13.4 by SPR, was 3 units higher than that of the free polymer in aqueous solution. PMID- 26097273 TI - Hard Times and Heart Break: Linking Economic Hardship and Relationship Distress. AB - We used the Fragile Families and Child Well-Being Study to examine an integrated mediational model linking economic hardship to relationship distress. Depressive symptoms, partner's discord, parenting stress, and coparenting are combined into a joint model linking economic hardship to relationship distress among mothers and fathers in intimate relationships. Although economic hardship is significantly associated with each mediating factor, only discord is associated with both relationship distress and dissolution in the full model. Moreover, comparisons using multigroup structural equation modeling indicate that while economic hardship is associated with higher discord among both mothers and fathers, the influence is substantially larger among fathers. We suggest that the link between hardship and relationship distress is largely contingent on interactional processes (i.e., discord) and how mothers perceive their child's father in the midst of economic hard times. PMID- 26097274 TI - Reading, Mathematics, and Behavioral Difficulties Interrelate: Evidence from a Cross-lagged Panel Design and Population-based Sample. AB - We examined three questions. First, do reading difficulties increase children's risk of behavior difficulties? Second, do behavioral difficulties increase children's risk of reading difficulties? Third, do mathematics difficulties increase children's risk of reading or behavioral difficulties? We investigated these questions using a sample of 9,324 children followed from third to fifth grade as they participated in a nationally representative dataset, conducting multilevel logistic regression modeling and including statistical control for many potential confounds. Results indicated that poor readers in third grade were significantly more likely to display poor task management, poor self-control, poor interpersonal skills, internalizing behavior problems, and externalizing behavior problems in fifth grade (odds ratio [OR] range = 1.30 - 1.57). Statistically controlling for a prior history of reading difficulties, children with poor mathematics skills in third grade were also significantly more likely to display poor task management, poor interpersonal skills, internalizing behavior problems, and reading difficulties in fifth grade (OR range = 1.38 - 5.14). In contrast, only those children exhibiting poor task management, but not other types of problem behaviors, in third grade were more likely to be poor readers in fifth grade (OR = 1.49). PMID- 26097275 TI - The effects of synthesis method on the physical and chemical properties of dextran coated iron oxide nanoparticles. AB - Iron oxide nanoparticles coated with dextran were synthesized via four variations on the co-precipitation method. The methods ranged from in situ formation of the nanoparticles within the dextran solution to the adsorption of dextran to the nanoparticle surface following nucleation and extensive washing. The timing of the addition of dextran into the reaction mixture was found to greatly influence the physical and chemical properties of the magnetic nanoparticles. Batches of dextran coated iron oxide nanoparticles were synthesized by each method in triplicate, and the nanoparticles were further crosslinked with epichlorohydrin. The properties of the nanoparticles such as size, percentage of dextran coating, stability in solution, crystallinity, and magnetic properties were evaluated. The simultaneous semi-two-step method injected the reducing agent and the dextran solution into the reaction vessel at the same time. This method resulted in the greatest batch-to-batch reproducibility of nanoparticle properties and the least variation in nanoparticles synthesized in the same batch. The two-step method resulted in the greatest variation of the characteristics examined between batches. The one-step method was synthesized with both five grams and one gram of dextran to investigate the effects of solution viscosity on the resulting nanoparticle characteristics. The one-step method with five grams of dextran resulted in nanoparticles with significantly smaller crystal sizes (5.4 +/- 1.9 nm) and lower specific adsorption rate (SAR) values (138.4 +/- 13.6 W/g) in an alternating magnetic field (58 kA/m, 292 kHz). However, this method resulted in nanoparticles that were very stable in PBS over 12 hours, which is most likely due to the greater dextran coating (60.0 +/- 2.7 weight percent). For comparison, the simultaneous semi-two-step method generated nanoparticles 179.2 +/- 18.3 nm in diameter (crystal size 12.1 +/- 0.2 nm) containing 18.3 +/- 1.2 weight percent dextran with a SAR value of 321.1 +/- 137.3 W/g. PMID- 26097276 TI - Barremian decapod crustaceans from Serre de Bleyton (Drome, SE France). AB - Based on mostly small-sized isolated cheliped fingers, a new decapod crustacean assemblage is described from the Barremian of Serre de Bleyton (Drome, SE France). The assemblage is composed mostly of representatives of the crab family Dynomenidae. In addition, remains of astacidean lobsters, axiidean shrimps, paguroid hermit crabs and brachyurous crabs of the families Necrocarcinidae and ?Cenomanocarcinidae occur in low numbers. Graptocarcinus moosleitneri (Dynomenidae) and ?Paranecrocarcinus schloegli (Necrocarcinidae) are introduced as new species. They both exhibit presence of multi-setal pores on dactyli that are interpreted as parts of a sieving mechanism used in feeding. The stratigraphic range of Graptocarcinus is extended herein to the Barremian. PMID- 26097272 TI - Encapsulated microbubbles and echogenic liposomes for contrast ultrasound imaging and targeted drug delivery. AB - Micron- to nanometer-sized ultrasound agents, like encapsulated microbubbles and echogenic liposomes, are being developed for diagnostic imaging and ultrasound mediated drug/gene delivery. This review provides an overview of the current state of the art of the mathematical models of the acoustic behavior of ultrasound contrast microbubbles. We also present a review of the in vitro experimental characterization of the acoustic properties of microbubble based contrast agents undertaken in our laboratory. The hierarchical two-pronged approach of modeling contrast agents we developed is demonstrated for a lipid coated (SonazoidTM) and a polymer shelled (poly D-L-lactic acid) contrast microbubbles. The acoustic and drug release properties of the newly developed echogenic liposomes are discussed for their use as simultaneous imaging and drug/gene delivery agents. Although echogenicity is conclusively demonstrated in experiments, its physical mechanisms remain uncertain. Addressing questions raised here will accelerate further development and eventual clinical approval of these novel technologies. PMID- 26097277 TI - The frequency of explosive volcanic eruptions in Southeast Asia. AB - There are ~750 active and potentially active volcanoes in Southeast Asia. Ash from eruptions of volcanic explosivity index 3 (VEI 3) and smaller pose mostly local hazards while eruptions of VEI >= 4 could disrupt trade, travel, and daily life in large parts of the region. We classify Southeast Asian volcanoes into five groups, using their morphology and, where known, their eruptive history and degassing style. Because the eruptive histories of most volcanoes in Southeast Asia are poorly constrained, we assume that volcanoes with similar morphologies have had similar eruption histories. Eruption histories of well-studied examples of each morphologic class serve as proxy histories for understudied volcanoes in the class. From known and proxy eruptive histories, we estimate that decadal probabilities of VEI 4-8 eruptions in Southeast Asia are nearly 1.0, ~0.6, ~0.15, ~0.012, and ~0.001, respectively. PMID- 26097278 TI - Augmentation of spelling therapy with transcranial direct current stimulation in primary progressive aphasia: Preliminary results and challenges. AB - BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative disease that primarily affects language functions and often begins in the fifth or sixth decade of life. The devastating effects on work and family life call for the investigation of treatment alternatives. In this article, we present new data indicating that neuromodulatory treatment, using transcranial direct current stimulation (tDCS) combined with a spelling intervention, shows some promise for maintaining or even improving language, at least temporarily, in PPA. AIMS: The main aim of the present article is to determine whether tDCS plus spelling intervention is more effective than spelling intervention alone in treating written language in PPA. We also asked whether the effects of tDCS are sustained longer than the effects of spelling intervention alone. METHODS & PROCEDURES: We present data from six PPA participants who underwent anodal tDCS or sham plus spelling intervention in a within-subject crossover design. Each stimulation condition lasted 3 weeks or a total of 15 sessions with a 2-month interval in between. Participants were evaluated on treatment tasks as well as on other language and cognitive tasks at 2-week and 2-month follow-up intervals after each stimulation condition. OUTCOMES & RESULTS: All participants showed improvement in spelling (with sham or tDCS). There was no difference in the treated items between the two conditions. There was, however, consistent and significant improvement for untrained items only in the tDCS plus spelling intervention condition. Furthermore, the improvement lasted longer in the tDCS plus spelling intervention condition compared to sham plus spelling intervention condition. CONCLUSIONS: Neuromodulation with tDCS offers promise as a means of augmenting language therapy to improve written language function at least temporarily in PPA. The consistent finding of generalisation of treatment benefits to untreated items and the superior sustainability of treatment effects with tDCS justifies further investigations. However, the small sample size still requires caution in interpretation. Present interventions need to be optimised, and particular challenges, such as ways to account for the variable effect of degeneration in each individual, are discussed. PMID- 26097279 TI - Sensitivity analysis of imaging geometries for prostate diffuse optical tomography. AB - Endoscopic and interstitial diffuse optical tomography have been studied in clinical investigations for imaging prostate tissues, yet, there is no comprehensive comparison of how these two imaging geometries affect the quality of the reconstruction images. In this study, the effect of imaging geometry is investigated by comparing the cross-section of the Jacobian sensitivity matrix and reconstructed images for three-dimensional mathematical phantoms. Next, the effect of source-detector configurations and number of measurements in both geometries is evaluated using singular value analysis. The amount of information contained for each source-detector configuration and different number of measurements are compared. Further, the effect of different measurements strategies for 3D endoscopic and interstitial tomography is examined. The pros and cons of using the in-plane measurements and off-plane measurements are discussed. Results showed that the reconstruction in the interstitial geometry outperforms the endoscopic geometry when deeper anomalies are present. Eight sources 8 detectors and 6 sources 12 detectors are sufficient for 2D reconstruction with endoscopic and interstitial geometry respectively. For a 3D problem, the quantitative accuracy in the interstitial geometry is significantly improved using off-plane measurements but only slightly in the endoscopic geometry. PMID- 26097280 TI - Initial results from a prototype whole-body photon-counting computed tomography system. AB - X-ray computed tomography (CT) with energy-discriminating capabilities presents exciting opportunities for increased dose efficiency and improved material decomposition analyses. However, due to constraints imposed by the inability of photon-counting detectors (PCD) to respond accurately at high photon flux, to date there has been no clinical application of PCD-CT. Recently, our lab installed a research prototype system consisting of two x-ray sources and two corresponding detectors, one using an energy-integrating detector (EID) and the other using a PCD. In this work, we report the first third-party evaluation of this prototype CT system using both phantoms and a cadaver head. The phantom studies demonstrated several promising characteristics of the PCD sub-system, including improved longitudinal spatial resolution and reduced beam hardening artifacts, relative to the EID sub-system. More importantly, we found that the PCD sub-system offers excellent pulse pileup control in cases of x-ray flux up to 550 mA at 140 kV, which corresponds to approximately 2.5*1011 photons per cm2 per second. In an anthropomorphic phantom and a cadaver head, the PCD sub-system provided image quality comparable to the EID sub-system for the same dose level. Our results demonstrate the potential of the prototype system to produce clinically-acceptable images in vivo. PMID- 26097281 TI - Context-dependent evaluation of prospective mates in a fish. AB - Female choice is often assumed to be based on absolute preference, driven by a threshold value of mate attractiveness. However, increasing evidence suggests that females may instead perform a comparative evaluation of prospective mates, possibly incurring in violation of rational decision rules (e.g. independence from irrelevant alternative, IIA). A prototypical case is the 'asymmetrically dominated decoy' effect where the preference for a target option over a competitor is altered by the addition of an irrelevant alternative. Here, we test for this effect in the peacock blenny Salaria pavo. Females, in binary test (i.e. focal option dyad differing in body size and extension of a yellow spot), strongly preferred one of the options. The effect of decoys, asymmetrically dominating the focal options for either yellow spot extension or body size, varied according to the initially preferred trait and the decoy type. Indeed, the addition of a decoy caused a shift in preference only when the decoy exhibited the intermediate expression of the trait less preferred initially. By contrast, females did not modify their preference in the presence of the decoy for their preferred trait. Although females' evaluation was context-dependent, the violation of IIA was clearly observed only with respect to the initially less preferred trait. This does not exclude that females are in any case using comparative decision rules. Indeed, when faced with three alternatives, two of which are proportionally closer to each other than to the third one, they might not be able to discriminate among them, perceiving stimulus absolute magnitude. PMID- 26097282 TI - Differences in exploration behaviour in common ravens and carrion crows during development and across social context. AB - Exploration is particularly important for young animals, as it enables them to learn to exploit their surroundings. It is likely to be affected by species ecology and social context, though there are few comparative, longitudinal studies that control for effects of early experience. Here, we investigated group level exploration behaviour in two closely related and identically reared, generalist corvid species: common ravens (Corvus corax) and carrion crows (C. corone, C. cornix), during development and across social context. Subjects were repeatedly presented with a range of novel items, whilst alone and in a dyad/ subgroup, at the fledging (1-2 months old), juvenile (3-8 months old) and sub adult (14-18 months old) stages. Whilst alone, they were also presented with a novel and familiar person, at the fledging and juvenile stages. We expected developmental differences and a facilitating influence of social context on exploration. Developmental differences were present, with both species interacting most frequently with novel items as juveniles, which may relate to major developmental steps, such as dispersal and a neophobia increase as sub adults. When a conspecific(s) was present, subjects generally interacted more frequently, though took longer to interact, with novel items. Additionally, we found unexpected species differences, with the most striking difference being the crows' significantly lower rate of interaction with the novel person, though not the familiar person; a species difference that was present from fledging. We discuss these findings by relating to potential differences in the two species ecology and behaviour, such as habitat use and caching proficiency. PMID- 26097283 TI - Friendship chemistry: An examination of underlying factors?. AB - Interpersonal chemistry refers to a connection between two individuals that exists upon first meeting. The goal of the current study is to identify beliefs about the underlying components of friendship chemistry. Individuals respond to an online Friendship Chemistry Questionnaire containing items that are derived from interdependence theory and the friendship formation literature. Participants are randomly divided into two subsamples. A principal axis factor analysis with promax rotation is performed on subsample 1 and produces 5 factors: Reciprocal candor, mutual interest, personableness, similarity, and physical attraction. A confirmatory factor analysis is conducted using subsample 2 and provides support for the 5-factor model. Participants with agreeable, open, and conscientious personalities more commonly report experiencing friendship chemistry, as do those who are female, young, and European/white. Responses from participants who have never experienced chemistry are qualitatively analyzed. Limitations and directions for future research are discussed. PMID- 26097284 TI - Perceptual Integration of Visual Evidence of the Airstream from Aspirated Stops. AB - This study investigates whether indirect visual evidence of aspiration can influence speech perception as previously found for tactile information. Participants were shown video of a speaker producing the sequence "pom" and "bomb" in a noisy setting. In some tokens, a candle was visibly perturbed by aspiration. All participants were more likely to correctly identify "pom" and incorrectly identify "bomb" in the presence of visible perturbation, indicating that perceptual integration was taking place. This effect was stronger for participants who reported being consciously aware of the candle as a predictor. This indicates that ambient information can be incorporated in speech perception even when presented via an indirect modality, and that active attention can amplify this effect. PMID- 26097285 TI - Inference for local autocorrelations in locally stationary models. AB - For non-stationary processes, the time-varying correlation structure provides useful insights into the underlying model dynamics. We study estimation and inferences for local autocorrelation process in locally stationary time series. Our constructed simultaneous confidence band can be used to address important hypothesis testing problems, such as whether the local autocorrelation process is indeed time-varying and whether the local autocorrelation is zero. In particular, our result provides an important generalization of the R function acf() to locally stationary Gaussian processes. Simulation studies and two empirical applications are developed. For the global temperature series, we find that the local autocorrelations are time-varying and have a "V" shape during 1910-1960. For the S&P 500 index, we conclude that the returns satisfy the efficient-market hypothesis whereas the magnitudes of returns show significant local autocorrelations. PMID- 26097288 TI - Container-based sanitation: assessing costs and effectiveness of excreta management in Cap Haitien, Haiti. AB - Container-based sanitation (CBS) - in which wastes are captured in sealable containers that are then transported to treatment facilities - is an alternative sanitation option in urban areas where on-site sanitation and sewerage are infeasible. This paper presents the results of a pilot household CBS service in Cap Haitien, Haiti. We quantify the excreta generated weekly in a dense urban slum,(1) the proportion safely removed via container-based public and household toilets, and the costs associated with these systems. The CBS service yielded an approximately 3.5-fold decrease in the unmanaged share of faeces produced, and nearly eliminated the reported use of open defecation and "flying toilets" among service recipients. The costs of this pilot small-scale service were higher than those of large-scale waterborne sewerage, but economies of scale have the potential to reduce CBS costs over time. The paper concludes with a discussion of planning and policy implications of incorporating CBS into the menu of sanitation options for rapidly growing cities. PMID- 26097287 TI - The effect of spontaneous curvature on a two-phase vesicle. AB - Vesicles are membrane-bound structures commonly known for their roles in cellular transport and the shape of a vesicle is determined by its surrounding membrane (lipid bilayer). When the membrane is composed of different lipids, it is natural for the lipids of similar molecular structure to migrate towards one another (via spinodal decomposition), creating a multi-phase vesicle. In this article, we consider a two-phase vesicle model which is driven by nature's propensity to maintain a minimal state of elastic energy. The model assumes a continuum limit, thereby treating the membrane as a closed three-dimensional surface. The main purpose of this study is to reveal the complexity of the Helfrich two-phase vesicle model with non-zero spontaneous curvature and provide further evidence to support the relevance of spontaneous curvature as a modelling parameter. In this paper, we illustrate the complexity of the Helfrich two-phase model by providing multiple examples of undocumented solutions and energy hysteresis. We also investigate the influence of spontaneous curvature on morphological effects and membrane phenomena such as budding and fusion. PMID- 26097286 TI - Feasibility of intensive parent-child interaction therapy (I-PCIT): Results from an open trial. AB - OBJECTIVE: The current pilot study examined the feasibility, acceptability, and initial outcome of an intensive and more condensed version of Parent-Child Interaction Therapy (90 minute sessions for 5 days/week over the course of 2 weeks). METHOD: Using an open trial design, 11 children (M child age = 5.01 years) and their mothers completed a baseline period of 2 weeks, a treatment period of 2 weeks, and a post-treatment evaluation. A follow-up evaluation was also conducted 4 months following treatment completion. Across all assessments, mothers completed measures of child behavior and parenting stress, and observational data was collected during three 5-minute standard situations that vary in the degree of parental control (child-led play, parent-led play, & clean up). RESULTS: All 11 families completed the intervention with extremely high attendance and reported high satisfaction. Results across both mother report and observations showed that: a) externalizing behavior problems were stable during the baseline period; b) treatment was effective in reducing externalizing behavior problems (ds = 1.67-2.50), improving parenting skills (ds = 1.93-6.04), and decreasing parenting stress (d = .91); and c) treatment gains were maintained at follow-up (ds = .53-3.50). CONCLUSIONS: Overall, preliminary data suggest that a brief and intensive format of a parent-training intervention is a feasible and effective treatment for young children with externalizing behavior problems with clinical implications for improving children's behavioral impairment in a very brief period of time. PMID- 26097289 TI - Long-chain omega-3 from low-trophic-level fish provides value to farmed seafood. AB - Low-trophic-level fish are a crucial source of long-chain (LC) omega-3 fatty acids for farmed fish and humans. Many farm-raised fish species have a clear need for these nutrients. Farmed fish deposit the LC omega-3s in their flesh and transfer them up the food chain. However, the content of LC omega-3s in farm raised seafood continues to decline, while the content of shorter-chain plant sourced omega-3s, and pro-inflammtory omega-6s continue to increase. This reduces its nutritional worth. The value of low-trophic-level fish is often viewed merely as its price at the dock. Some reports and metrics steer public attention towards the mass balance between quantities of low-trophic-level fish and farmed seafood. However, the the nutritional value of seafood is more important than its mere quantities. The role of low-trophic-level fish in human nutrition, health, and wellbeing is a fundamental component of its economic value to society. PMID- 26097290 TI - Dietary sources, current intakes, and nutritional role of omega-3 docosapentaenoic acid. AB - Fish oils and long-chain omega-3 fatty acids are well recognized for their critical role in human diets. Docosapentaenoic acid (DPA, 22 : 5n-3) has always been a part of healthy nutrition, since infants obtain almost as much DPA as DHA from human milk. Fish oil supplements and ingredients, oily fish, and grass-fed beef can serve as the primary DPA sources for the general population. Although the DPA levels in fish oils are substantially lower than those of EPA and DHA, concentrated DPA products are now becoming commercially available, and DPA-based drugs are under development. Epidemiological studies show that similar to eicosapentaenoic (EPA, 20 : 5n-3) and docosahexaenoic (DHA, 22 : 6n-3) acids, DPA is linked to various improvements in human health, perhaps owing to its structural similarity to the other two molecules. Studies in mammals, platelets, and cell cultures have demonstrated that DPA reduces platelet aggregation, and improves lipid metabolism, endothelial cell migration, and resolution of chronic inflammation. Further, other in vivo and in vitro studies have shown that DPA can improve neural health. A human supplementation trial with 99.8% pure DPA suggested that it serves as a storage depot for EPA and DHA in the human body. Future randomized controlled human trials with purified DPA will help clarify its effects on human health. They may confirm the available evidence pointing to its nutritional and biological functions, unique or overlapping with those of EPA and DHA. PMID- 26097291 TI - Rapid ecosystem change challenges the adaptive capacity of Local Environmental Knowledge. AB - The use of Local Environmental Knowledge has been considered as an important strategy for adaptive management in the face of Global Environmental Change. However, the unprecedented rates at which global change occurs may pose a challenge to the adaptive capacity of local knowledge systems. In this paper, we use the concept of the shifting baseline syndrome to examine the limits in the adaptive capacity of the local knowledge of an indigenous society facing rapid ecosystem change. We conducted semi-structured interviews regarding perceptions of change in wildlife populations and in intergenerational transmission of knowledge amongst the Tsimane', a group of hunter-gatherers of Bolivian Amazonia (n = 300 adults in 13 villages). We found that the natural baseline against which the Tsimane' measure ecosystem changes might be shifting with every generation as a result of (a) age-related differences in the perception of change and (b) a decrease in the intergenerational sharing of environmental knowledge. Such findings suggest that local knowledge systems might not change at a rate quick enough to adapt to conditions of rapid ecosystem change, hence potentially compromising the adaptive success of the entire social-ecological system. With the current pace of Global Environmental Change, widening the gap between the temporal rates of on-going ecosystem change and the timescale needed for local knowledge systems to adjust to change, efforts to tackle the shifting baseline syndrome are urgent and critical for those who aim to use Local Environmental Knowledge as a tool for adaptive management. PMID- 26097292 TI - Amperometric immunosensor for rapid detection of Mycobacterium tuberculosis. AB - Tuberculosis (TB) has been a major public health problem, which can be better controlled by using accurate and rapid diagnosis in low-resource settings. A simple, portable, and sensitive detection method is required for point-of-care (POC) settings. This paper studies an amperometric biosensor using a microtip immunoassay for a rapid and low cost detection of Mycobacterium Tuberculosis (MTB) in sputum. MTB in sputum is specifically captured on the functionalized microtip surface and detected by electric current. According to the numerical study, the current signal on microtip surface is linearly changed with increasing immersion depth. Using a reference microtip, the immersion depth is compensated for a sensing microtip. On the microtip surface, target bacteria are concentrated and organized by a coffee ring effect, which amplifies the electric current. To enhance the signal-to-noise ratio, both the sample processing- and rinsing steps are presented with use of deionized water as a medium for the amperometric measurement. When applied to cultured MTB cells spiked into human sputum, the detection limit was 100 CFU/mL, comparable to a more labor-intensive fluorescence detection method reported previously. PMID- 26097293 TI - Piecewise Approximate Bayesian Computation: fast inference for discretely observed Markov models using a factorised posterior distribution. AB - Many modern statistical applications involve inference for complicated stochastic models for which the likelihood function is difficult or even impossible to calculate, and hence conventional likelihood-based inferential techniques cannot be used. In such settings, Bayesian inference can be performed using Approximate Bayesian Computation (ABC). However, in spite of many recent developments to ABC methodology, in many applications the computational cost of ABC necessitates the choice of summary statistics and tolerances that can potentially severely bias the estimate of the posterior. We propose a new "piecewise" ABC approach suitable for discretely observed Markov models that involves writing the posterior density of the parameters as a product of factors, each a function of only a subset of the data, and then using ABC within each factor. The approach has the advantage of side-stepping the need to choose a summary statistic and it enables a stringent tolerance to be set, making the posterior "less approximate". We investigate two methods for estimating the posterior density based on ABC samples for each of the factors: the first is to use a Gaussian approximation for each factor, and the second is to use a kernel density estimate. Both methods have their merits. The Gaussian approximation is simple, fast, and probably adequate for many applications. On the other hand, using instead a kernel density estimate has the benefit of consistently estimating the true piecewise ABC posterior as the number of ABC samples tends to infinity. We illustrate the piecewise ABC approach with four examples; in each case, the approach offers fast and accurate inference. PMID- 26097295 TI - Message from IAOMP President. PMID- 26097294 TI - Modeling the Dynamics of the U.S. Healthcare Expenditure Using a Hyperbolastic Function. AB - In this paper, we investigate the dynamics of the U.S. national healthcare expenditures from 1960 to 2011. The data were obtained from the U.S. Department of Health and Human Services, Center for Medicare and Medicaid Services. The analytical method allows extracting the long-run deterministic trend from the cyclical and the random components. The long-run trend is estimated using six classical growth models and three more recent growth curves called Hyperbolastic growth models of types I, II, and III, denoted by H1, H2, and H3, respectively. The statistical results indicate that the H1 model provides the best fit of the data. The study is complemented by a mathematical analysis of the deterministic long-run component of the national healthcare expenditure (NHE) as modeled by H1. This analysis is performed by examining the behavior of the absolute growth rate (pace of increase curve), the relative growth rate, and the acceleration of the U.S. NHE over the 52-year time frame. To the best of our knowledge, this paper provides the first application of Hyperbolastic models to economics data. This study can be used by researchers and policy makers as a descriptive as well as a predictive tool. PMID- 26097296 TI - Message from the IAOMP secretary. PMID- 26097297 TI - From the Editor's desk. PMID- 26097298 TI - CANCER CONUNDRUM. PMID- 26097299 TI - CELLULAR CANNIBALISM. PMID- 26097300 TI - Prevalence of fungal hyphae in potentially malignant lesions and conditions-does its occurrence play a role in epithelial dysplasia? AB - BACKGROUND: Oral cancer is a major public health problem in India. A key factor that has led to lack of improvement in prognosis of oral cancer over the years, is delay in diagnosis and treatment. In many instances, a significant proportion of oral squamous cell carcinomas develop from premalignant lesions and conditions. Identification of such lesions and conditions is very important in order to prevent malignant transformation. The role of fungal infections has been studied and holds promise as an indicator to predict malignant transformation. So we designed a study to analyze the prevalence of fungal hyphae in biopsies of patients with clinically diagnosed cases of premalignant lesions and conditions. AIMS AND OBJECTIVES: To determine and compare the prevalence of fungal hyphae in biopsies of patients with clinically diagnosed cases of potentially malignant lesions and conditions and to assess the possible association between the degree of epithelial dysplasia and presence or absence of fungal hyphae. MATERIALS AND METHODS: Clinically suspected and histopathologically diagnosed 70 cases of potentially malignant lesions and conditions (29 leukoplakia, 16 submucous fibrosis and 25 lichen planus) made up the study group. Three tissue sections (5MUm) of each were stained with hematoxylin and eosin (H and E), periodic acid Schiff's reagent (PAS) and Grocott's methenamine silver (GMS) and evaluated for fungal hyphae. The data collected was statistically analyzed by using Chi-square test and Statistical Package for Social Sciences (SPSS) software. RESULTS: The estimated prevalence of fungal hyphae in cases with or without dysplasia in leukoplakia was 41.4%, lichen planus 36% and submucous fibrosis 25%. There was a significant association between degree of epithelial dysplasia with presence or absence of fungal hyphae in all the study groups. CONCLUSION: Presence of fungal hyphae in potentially malignant lesions and conditions may prove to be a useful indicator in predicting malignant transformation. PMID- 26097302 TI - The master switch: Comparative study of mast cell in oral epithelial dysplasia, oral submucous fibrosis and oral squamous cells carcinoma and their association with inflammation and angiogenesis. AB - BACKGROUND: Dental and medical practitioners encounter wide spectrum of oral lesions in their day-to-day practice. Many of the lesions such as leukoplakia, oral submucous fibrosis (OSF), etc., are associated with tobacco and betel nut chewing. Oral leukoplakia, OSF, oral lichen planus and oral squamous cell carcinoma (OSCC) are the most commonly occurring oral diseases associated with characteristic clinical and histological features and are associated with chronic inflammation at some stage of the disease process. AIMS: To study and compare the number, morphology and topographical distribution of mast cells in oral epithelial dysplasia (OED), OSF and OSCC and to correlate different types of mast cells with the inflammatory infiltrate and vascularity of the lesions. MATERIALS AND METHODS: Total number of subjects was 120 and equally divided into four groups of 30 as controls, OED, OSF and OSCC cases. Two sections of from each tissue embedded in paraffin wax block were made which were stained with hematoxylin and eosin and toluidine blue stain. Mast cells were counted in five different zones. RESULTS: In the present study, increased numbers of mast cells were seen in all lesions. The cases with mild, moderate and severe inflammation showed increased number of typical (TMCs), atypical (AMCs) and granular mast cells (GMCs), respectively. CONCLUSION: The result of the present study concludes that the mast cells play a key role in mediating the cross links between external angiogenic agent and local immunologic factors. PMID- 26097301 TI - Evaluation of histomorphological and immunohistochemical parameters as biomarkers of cervical lymph node metastasis in squamous cell carcinoma of oral cavity: A retrospective study. AB - INTRODUCTION: Oral squamous cell carcinoma (OSCC) is seen worldwide but is more common in India. Lymph node (LN) metastasis has been shown to be the strongest prognostic factor in OSCC. Many histopathological and immunohistochemical markers have been studied to predict the LN metastasis. AIMS: To identify clinicopathological factors and immunohistochemical (IHC) biomarkers which predict cervical metastasis in OSCC patients. STUDY AND DESIGN: A total of 105 cases of OSCC were taken up for our study. Histopathological parameters such as tumor thickness, depth, degree of differentiation, pattern of invasion (POI), lymphovascular and neural invasion were assessed. IHC was done on all cases using antibodies against Ki-67, cyclin D, E-cadherin, p53, CD31 and each antibody was assessed according to the standard protocol. STATISTICAL ANALYSIS: To calculate the relation between clinical, histopathological parameter, IHC marker and the occurrence of LN metastasis, chi-square test was used. Variables were tested using multivariate logistic regression method to assess the predictive significance. RESULTS: Out of 105 cases studied, 29 cases showed LN metastasis. Maximum numbers of cases affected were females with involvement of buccal mucosa. We found significant association of cervical LN metastasis with high grade of differentiation, lack of E-cadherin expression, high Ki-67 and cyclin D1 expression. In our study; tumor depth, thickness, extent of peritumoral lympho plasmacytic infiltration, presence of eosinophils, tumor nest type, p53 and microvessel density (MVD) showed no significant correlation. CONCLUSION: Significant association of cervical LN metastasis with high grade of differentiation, lack of E-cadherin expression, high Ki-67 and cyclin D1 expression was seen. PMID- 26097304 TI - Prevalence of Hepatitis B surface antigen in dental personnel. AB - CONTEXT: Hepatitis B, a viral disease affecting the liver has high morbidity and mortality. Hepatitis B surface antigen (HBsAg) in serum is used to detect presence of active disease and chronic carrier status. The disease is transmitted predominantly through blood and saliva, hence dental professionals are considered a high risk group. AIM: To detect presence of HBsAg in serum of dental professionals. SUBJECTS AND METHODS: The study was conducted in two parts viz., one in the year 1991 on 100 dental professionals in Nagpur using reverse passive hemagglutination and the other in 2012 on 50 dental professionals in Chennai using immunochromatography. RESULTS: Ten percent of dental professionals screened in 1991 and 2% of dental professionals screened in 2012 showed HBsAg positive status and were predominantly periodontists with a history of needle-stick injury. CONCLUSION: This study highlights the importance of Hepatitis B vaccination and periodic evaluation of antibody titer to prevent spread of the disease. PMID- 26097303 TI - Immunohistochemical analysis of CD34 expression in salivary gland tumors. AB - BACKGROUND: Tumor growth depends on angiogenesis which is assessed by measuring the tumor microvessel density (MVD) through CD34 immunostaining. The present study was performed to evaluate the situation of angiogenic activity in salivary gland neoplasms. The possible role of CD34 in progression and invasion of salivary gland tumors is also investigated. MATERIALS AND METHODS: Tissue specimens of 15 pleomorphic adenoma (PA) and 15 malignant salivary gland tumors including mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC) were immunostained for CD34 protein. The most vascularized areas at low power magnification (hotspots) were selected for vessel counting at *400 magnification. Then, the mean number of microvessels in three fields within the tumor mass was calculated. RESULTS: MVD in PA and malignant salivary gland tumors were 10.93 +/- 5.95 and 26.46 +/- 7.32, respectively. Tumor angiogenesis in PA was much lower than other lesions (P < 0.05). No significant difference was observed between malignant tumors (P > 0.05). CONCLUSION: Salivary gland carcinomas demonstrated higher vascular density than benign PA despite of cell types and architecture. The reason for this higher angiogenic activity could be related to metabolic characteristics of malignant cells. PMID- 26097305 TI - Aphthous ulcers, salivary peroxidase and stress: Are they related? AB - BACKGROUND: In today's high strung lifestyle, stress plays a major role on our health. Studies using ultraweak chemiluminescence have been able to demonstrate this effect, of psychological stress on the immune system, using saliva as a psychological stress marker. The impact of psychosocial factors on the oral mucosal lesions of individuals found that stress can contribute to weakened immunity and increased susceptibility to infection. AIM: To study the role of salivary peroxidase (SPOx) in psychologically stressed individuals with and without the presence of aphthous ulcer. MATERIALS AND METHODS: The study involved evaluating subjects for stress, using Perceived Stress Scale. Depending on the stress scores and the presence or absence of oral aphthae, they were assigned into 3 groups of 30 each. After a thorough oral examination, individual samples of saliva was collected and subjected to microprotein estimation using a biochemical analyzer. STATISTICAL ANALYSIS USED: Analysis of variance (ANOVA) and Student's t-test. RESULTS: Decreased levels of peroxidase were found in individuals' with aphthous ulcers, while the same was increased when no lesions were found and also on a lower stress scale. CONCLUSIONS: Our study analysis does show a variation in enzyme levels between the different groups highlighting the influence of stress on the peroxidase levels, which in turn when imbalanced, results in tissue damage, leading to aphthous formation. PMID- 26097306 TI - Evaluation of myofibroblasts in oral squamous cell carcinoma using H1 calponin: An immunohistochemical study. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral mucosa. Stromal myofibroblasts play an important role in tumor invasion and metastasis, due to its ability to modify the extracellular matrix. The purpose of this study was to evaluate and compare the presence of myofibroblasts in normal mucosa, early invasive carcinoma and different grades of OSCC. MATERIALS AND METHODS: The study included the archival tissues of 18 OSCC of well, moderate and poorly differentiated grades, three early invasive carcinomas and five normal mucosa. Myofibroblasts were identified by immunohistochemical detection of h1 calponin. RESULTS: The percentage and intensity of h1 calponin were examined and positive immunostaining was observed in the myofibroblasts of all SCCs and early invasive carcinomas; however, these cells did not stain in the normal epithelium specimens. The presence of myofibroblasts was significantly higher in invasive pattern of OSCCs compared to normal mucosa cases (P < 0.070). A significant difference was not observed between the different grades of OSCC (P <= 0.812). CONCLUSION: These findings show the presence of myofibroblasts in OSCC but not in normal mucosa, suggesting that the genetically altered epithelium (carcinomatous epithelium) may have an inductive effect on the adjacent stroma to produce myofibroblasts. Also transdifferentiation of myofibroblasts is induced somewhere in the invasive stage of SCC irrespective of the epithelial cell differentiation. PMID- 26097307 TI - Primary malignant epithelial salivary gland tumors in an Iranian population: A retrospective study of 81 cases. AB - BACKGROUND: Salivary gland tumors of epithelial origin are rare lesions. Few epidemiologic studies on prevalence of such condition in Iranian population have been published. This study with the aim of determining the relative frequency of epithelial salivary tumors was performed in Yazd city from 2001 to 2012. MATERIALS AND METHODS: Cases diagnosed as primary malignant epithelial salivary gland tumor were collected from the Pathology Department of main hospitals and Health Department of Medical Science Yazd University from 2001-2012. Histopathologic type, tumor location, age, gender and whether patients were native or non-native were analyzed. RESULTS: Eighty-one cases of primary malignant epithelial salivary gland tumors were recorded. Male to female ratio was 1:1.3. The most common malignancy was adenoid cystic carcinoma (35.8%) and the most common effected site was the parotid gland. Mean age for malignancy was 52.57 +/- 18.25 years. CONCLUSION: According to the findings of this study, predilection of adenoid cystic carcinoma was more in non-natives as compared to natives (from Yazd). This could suggest the influence of racial and environmental factors on prevalence of such malignancies. PMID- 26097308 TI - Heat shock protein (HSP70) as a marker of epithelial dysplasia in oral dysplastic lesions: A clinicopathological study. AB - OBJECTIVE: In the present study, expression of heat shock protein (HSP70) was evaluated and compared in oral dysplastic lesions, in particular leukoplakia (study group) and in normal mucosal tissues (control group). Additionally, correlation of HSP70 expression with clinical disease status was investigated. SUBJECTS AND METHODS: A total of 60 fresh tissue specimens were obtained from the oral cavity, consisting of 30 dysplastic cases and 30 normal mucosal tissues. The presence of epithelial dysplasia and its histologic grading was evaluated. Immunohistochemistry was carried out with the monoclonal HSP70 antibodies and expression of cytoplasmic HSP70 within the epithelium was compared between dysplastic and normal mucosal samples using Student's t-test. RESULTS: Expression of HSP70 was detected in 93% of the oral dysplastic tissues and 20% of the normal mucosal tissues. Statistical significant difference in the HSP70 expression was seen between oral dysplastic tissues and normal oral mucosal tissues (P < 0.000). The interexaminer reliability was 93.3%. Statistical significant difference was seen in the HSP70 expression between controls and different grades of dysplasia (mild, moderate and severe). There was no relationship of HSP70 expression with clinical parameters like age, sex, site of the lesion, history of adverse habits and duration of adverse habits. CONCLUSION: In the present study, HSP70 activity was significantly higher in oral dysplastic (leukoplakia) group than in the control group. Further, as the grade of dysplasia increased, the staining intensity and/or distribution increased, indicating that enhanced HSP70 expression occurs during oral carcinogenesis. Hence, it is concluded that increased HSP70 immunoexpression could be an objective marker for the presence of epithelial dysplasia. PMID- 26097309 TI - Relationship of long-term highly active antiretroviral therapy on salivary flow rate and CD4 Count among HIV-infected patients. AB - OBJECTIVES: To determine if long-term highly active antiretroviral therapy (HAART) therapy alters salivary flow rate and also to compare its relation of CD4 count with unstimulated and stimulated whole saliva. MATERIALS AND METHODS: A cross-sectional study was performed on 150 individuals divided into three groups. Group I (50 human immunodeficiency virus (HIV) seropositive patients, but not on HAART therapy), Group II (50 HIV-infected subjects and on HAART for less than 3 years called short-term HAART), Group III (50 HIV-infected subjects and on HAART for more than or equal to 3 years called long-term HAART). Spitting method proposed by Navazesh and Kumar was used for the measurement of unstimulated and stimulated salivary flow rate. Chi-square test and analysis of variance (ANOVA) were used for statistical analysis. RESULTS: The mean CD4 count was 424.78 +/- 187.03, 497.82 +/- 206.11 and 537.6 +/- 264.00 in the respective groups. Majority of the patients in all the groups had a CD4 count between 401 and 600. Both unstimulated and stimulated whole salivary (UWS and SWS) flow rates in Group I was found to be significantly higher than in Group II (P < 0.05). Unstimulated salivary flow rate between Group II and III subjects were also found to be statistically significant (P < 0.05). ANOVA performed between CD4 count and unstimulated and stimulated whole saliva in each group demonstrated a statistically significant relationship in Group II (P < 0.05). There were no significant results found between CD4 count and stimulated whole saliva in each groups. CONCLUSION: The reduction in CD4 cell counts were significantly associated with salivary flow rates of HIV-infected individuals who are on long term HAART. PMID- 26097310 TI - Loricrin - an overview. AB - Loricrin is a terminally differentiating structural protein comprising more than 70% of the cornified envelope. It contributes to the protective barrier function of the stratum corneum. In vivo, loricrin is expressed inall mammalian stratified epithelia with the highest levels of expression in humid tissues such as newborn epidermis, the epithelia of oral and anal mucosa, esophagus, foreskin, vagina and the epidermal parts of sweat ducts. Loricrin is not expressed in non keratinizing epithelia and its expression at these sites actually represents a defensive or protective mechanismof the body. An insight into this protein- "Loricrin" can shed light to its potential as a marker in the early stages of potentially malignant disorders like oral sub mucous fibrosis and leukoplakia. This compilation has been done by taking into account the existing literature, reviews and original studies on loricrin, a major component of the cornifiedcell envelope, its structure and the alterations that result due to its absence or presence of both the epidermis and the oral mucosa. PMID- 26097311 TI - Various terminologies associated with areca nut and tobacco chewing: A review. AB - Globally, arecanut and tobacco are among the most common addictions. Tobacco and arecanut alone or in combination are practiced in different regions in various forms. Subsequently, oral mucosal lesions also show marked variations in their clinical as well as histopathological appearance. However, it has been found that there is no uniformity and awareness while reporting these habits. Various terminologies used by investigators like 'betel chewing','betel quid chewing','betel nut chewing','betel nut habit','tobacco chewing'and 'paan chewing' clearly indicate that there is lack of knowledge and lots of confusion about the exact terminology and content of the habit. If the health promotion initiatives are to be considered, a thorough knowledge of composition and way of practicing the habit is essential. In this article we reviewed composition and various terminologies associated with areca nut and tobacco habits in an effort to clearly delineate various habits. PMID- 26097312 TI - Polymorphous low grade adenocarcinoma. AB - Polymorphous low-grade adenocarcinoma (PLGA), is a rare, salivary gland intraoral tumor with complexities in diagnosis and this review highlights the difficulties. PMID- 26097313 TI - Linear IgA dermatosis adult variant with oral manifestation: A rare case report. AB - Linear immunoglobulin A (IgA) dermatosis (LAD) is a rare autoimmune disorder that presents as a vesiculo-bullous lesion with cutaneous manifestations, but rare oral mucosal involvement. Here we discuss a case of a vesiculobullous lesion with severe oral and ocular mucosal involvement mimicking pemphigoid with histopathological evidence of subepithelial blisters. Direct immunofluorescence (DIF) confirmed the lesion as LAD of adult variant, although with atypical clinical features. PMID- 26097314 TI - Cervical ganglioneuroma in collision with a metastatic undifferentiated carcinoma. AB - Cervical ganglioneuromas are extremely rare with approximately six case reports. The current report highlights a unique collision tumor between a cervical ganglioneuroma and a metastatic undifferentiated carcinoma arising from a primary gingival mass. A 53-year-old male presented with a 2 cm left gingival mass that was excised and treated with systemic chemotherapy. Consequently, 9 months later, he developed a 3.2 cm left submandibular mass followed by recurrence of the left gingival mass. From the clinicopathologic perspective, this had to be separated from the differentials: ganglioneuroblastoma or metastatic involvement of a lymph node from primary gingival undifferentiated carcinoma. PMID- 26097315 TI - Lipomatous hemangiopericytoma in a child: A case report with immunohistochemical evaluation. AB - Lipomatous hemangiopericytomas are rare soft-tissue tumors that show areas of hemangiopericytoma like vascular pattern admixed with lipid containing cells. It is now considered a subtype of solitary fibrous tumor due to histopathological and immunohistochemical similarities. To date, only a few cases have been adequately reported in the medical literature. A case of lipomatous hemangiopericytoma in an 11-year-old female patient is presented and the clinical, histopathological and immunohistochemical features are discussed, along with a literature review. To the best of our knowledge, this is the first known case of a lipomatous hemangiopericytoma in a pediatric patient. Our case report further emphasizes that a number of studies should be evaluated to delineate hemangiopericytomas from solitary fibrous tumors. PMID- 26097316 TI - An uncommon oral infection in a diabetic patient. PMID- 26097317 TI - Age estimation by modified Demirjian's method (2004) and its applicability in Tibetan young adults: A digital panoramic study. AB - CONTEXT: Estimation of the age is a procedure adopted by anthropologists, archeologists and forensic scientists. Different methods have been undertaken. However none of them meet the standards as Demirjian's method since 1973. Various researchers have applied this method, in both original and modified form (Chaillet and Demirjian in 2004) in different ethnic groups and the results obtained were not satisfactory. AIMS: To determine the applicability and accuracy of modified Demirjian's method of dental age estimation (AE) in 8-18 year old Tibetan young adults to evaluate the interrelationship between dental and chronological age and the reliability between intra- and inter observer relationship. SETTINGS AND DESIGN: Clinical setting and computerized design. SUBJECTS AND METHODS: A total of 300 Tibetan young adults with an age range from 8 to 18 years were recruited in the study. Digital panoramic radiographs (DPRs) were evaluated as per the modified Demirjian's method (2004). STATISTICAL ANALYSIS USED: Pearson correlation, paired t-test, linear regression analysis. RESULTS: Inter -and intraobserver reliability revealed a strong agreement. A positive and strong association was found between chronological age and estimated dental age (r = 0.839) with P < 0.01. Modified Demirjian method (2004) overestimated the age by 0.04 years (2.04 months)in Tibetan young adults. CONCLUSIONS: Results suggest that, the modified Demirjian method of AE is not suitable for Tibetan young adults. Further studies: With larger sample size and comparision with different methods of AE in a given population would be an interesting area for future research. PMID- 26097318 TI - Basal cell adenoma of the parotid gland: Cytological diagnosis of an uncommon tumor. AB - Basal cell adenoma (BCA) is a rare benign epithelial tumor of the salivary gland, displaying monomorphic basaloid cells without a myxochondroid component, representing 1-3% of all salivary gland neoplasms seen predominantly in women over 50 years of age. It is uncommon in young adults. Cytodiagnosis of basaloid tumors chiefly basal cell adenoma of the salivary gland, is extremely challenging. The cytological differential diagnoses range from benign to malignant, neoplastic to non- neoplastic lesions. Histopathological examination is a must for definitive diagnosis, as these entities differ in prognosis and therapeutic aspects. We present a 22-years-old male with this uncommon diagnosis with a discussion on the role of cytological diagnosis. Fine needle aspiration cytology is a simple, minimally invasive method for the preoperative diagnosis of various types of neoplastic and non-neoplastic lesions. The knowledge of its pitfalls and limitations contributes to a more effective approach to treatment. PMID- 26097319 TI - Actinomycosis of submandibular gland: An unusual presentation of a rare entity. AB - Actinomycosis is a chronic suppurative infection that can occur in the head and neck region. Though cervico-facial actinomycosis is well described, primary actinomycosis of the salivary gland is rare and can present as any other suppurative infection or can simulate malignancy. We hereby report a case of a young male with primary actinomycosis of submandibular gland, presenting as acute suppurative infection and diagnosed on histopathology. PMID- 26097320 TI - Benign lymphoepithelial cysts of parotid and submandibular glands in a HIV positive patient. AB - Patients with human immunodeficiency virus (HIV) infection have been reported to have parotid swellings of various types such as diffuse infiltrative lymphocytosis syndrome, parotitis, intraparotid lymphadenopathy, benign lymphoepithelial cyst (BLEC), as well as salivary gland neoplasms such as adenoid cystic carcinoma, Kaposi sarcoma and lymphoma. LECs in the parotid gland are uncommon benign entities with increased incidence associated with HIV infection. We are presenting a case of 28-year-old HIV-positive patient with BLECs in the parotid and submandibular glands. PMID- 26097321 TI - Sinonasal hemangiopericytoma: A rare case report with review of literature. AB - Hemangiopericytoma (HPC) is a rare tumor of uncertain malignant potential. Stout and Murray described HPC as "vascular tumor arising from Zimmerman's pericyte" in 1942. The World Health Organization (WHO) reclassified HPC as a fibroblastic/myofibroblastic tumor, after further characterization. HPC is found mostly wherever there is increased vascularity seen. The incidence of the tumor in head and neck area is only 15%, mostly seen in adults. We report here a case of HPC of a 22-year-old female, who presented to our department with a tender swelling in maxillary anterior region and the mass was well-circumscribed, sessile and soft on palpation. The skin over the tumor was intact and normal. The tumor was completely removed with wide surgical resection. The histopathological staining supported the diagnosis of HPC, this was further confirmed by immunohistochemistry (IHC) in which CD99 showed strong positivity. PMID- 26097322 TI - Angiolymphoid hyperplasia with eosinophilia in the angle region of the mandible. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE), also called epithelioid hemangioma, is a rare benign vascular lesion usually affecting the muscular arteries of the head and neck in female patients. Here, we report a 30-year-old male patient who presented with painless swelling in the angle region of the mandible. The diagnosis of the specimen, which was surgically removed under local anesthesia, was made as ALHE. The patient has remained uneventful for 3 years. PMID- 26097323 TI - Giant cell tumor of the mandible. AB - Giant cell tumor (GCT) of bone is a distinctive neoplasm characterized by abundance of multinucleated giant cells scattered throughout the stroma of mononuclear cells. Its importance lies in recognizing and differentiating the characteristic histology, which at times may mimic several other bone tumors and endocrine disorders ranging from locally aggressive giant cell granulomas to hyperparathyroidism to malignant tumors. The jaw bones account for less than 1% of the lesion. Ina literature search, we found only five cases of GCT of jaw bones based on the new criteria. We present a rare case of GCT of the mandible which occurred in a 12-year-old female. PMID- 26097324 TI - Axenfeld-Rieger syndrome associated with severe maxillofacial and skeletal anomalies. AB - This article reports an unusual case of Axenfeld-Rieger Syndrome (ARS) associated with severe maxillofacial and skeletal anomalies. A 55-year-old man with ARS revealed interesting and unexpected radiological findings. Severe maxillofacial and skeletal anomalies, in addition to the well-recognized extraocular findings, that occurs in patients with ARS is reported and our case highlights this possible rare association between ARS and maxillofacial and skeletal anomalies. PMID- 26097325 TI - Bizarre parosteal osteochondromatous proliferation presenting in the nasal dorsum. AB - We present the first bizarre parosteal osteochondromatous proliferation (BPOP) in the nasal dorsum. These lesions have been described since 1983; however, the vast majority of these lesions do not present in the head and neck, although five cases exist in the literature. An understanding of the potential sites for bizarre paraosteal osteochondromatous proliferations will help lead to successful diagnosis and proper treatment. PMID- 26097326 TI - Dentin dysplasia type I - A rare entity. AB - Dentin dysplasia is a rare disturbance of dentin formation characterized by normal enamel but atypical dentin formation with abnormal pupal morphology. The teeth appear clinically normal in morphologic appearance and color. The teeth characteristically exhibit extreme mobility and are commonly exfoliated prematurely. Radiograph shows obliteration of all pulp chambers, short, blunted and malformed or absent roots with periapical radiolucencies involving apparently intact tooth. This case is reported here because of its rarity along with the description of various clinical, radiological and histological features. PMID- 26097327 TI - Osteochondroma at the angle of mandible: A rare case. AB - Osteochondroma (OC) is one of the most common benign tumor of osseous and cartilaginous origin. It usually occurs in the skeletal bones and very rarely in craniofacial region. In the craniofacial region, condyle and coronoid process of the mandible are the most commonly affected areas. The present article reports the extremely rare case of OC arising from the angle of the mandible causing facial asymmetry. PMID- 26097328 TI - Pleomorphic adenoma of the buccal salivary gland. AB - Salivary gland swellings can result from tumors, an inflammatory process or cysts. It can sometimes be difficult to establish; whether pathology arises from the salivary gland itself or adjacent structures. Neoplasms of the salivary glands account for less than 1% of all tumors, 3-5% of all head and neck tumors and benign pleomorphic adenoma (PA) of minor salivary glands arising de novo is very rare. PA is the most common tumor of the salivary gland. While the majority arises from the parotid gland, only a small percentage arises from the buccal minor salivary gland. A case of PA of minor salivary glands in the buccal mucosa in a 70-year-old female is discussed. It includes review of literature, clinical features, histopathology, radiological findings and treatment of the tumor; with emphasis on diagnosis. PMID- 26097329 TI - Voluntary blood donation in India: Achievements, expectations and challenges. PMID- 26097330 TI - Advances in detection of antenatal alloimmunization and its management. PMID- 26097331 TI - Automation in Blood Centre: Its impact on Blood Safety. PMID- 26097332 TI - Anti-tobacco campaign: Together we can.... PMID- 26097333 TI - Microbiologic Evaluation of Matricaria and Chlorhexidine against E. faecalis and C. albicans. AB - OBJECTIVE: To evaluate the antimicrobial activity of different concentrations of Matricaria chamomilla and Chlorhexidine gel against Candida albicans and Enterococcus faecalis. MATERIALS AND METHODS: The agar diffusion test was used to evaluate the antimicrobial activity of 15%, 25% Matricaria chamomilla in aq. base and 2% chlorhexidine gel against C. albicans (ATCC 24433) and E. faecalis (ATCC 24212) strains. Vancomycin was used as the positive control for E. faecalis and fluconazole for C. albicans . The agar plates were incubated at 37 degrees C for 48 h after which the zone of inhibition were measured separately for each material. Data thus obtained were statistically analyzed using the Wilcoxon rank order test. RESULTS: 2% chlorhexidine showed maximum inhibitory zone for C. albicans (33.26 mm) and E. faecalis (24.54 mm). 25% Matricaria showed zones of 24.16 mm and 20.62 mm for C. albicans and E. faecalis, respectively. 15% Matricaria did not show any antimicrobial activity (0 mm). CONCLUSION: The results of the current in vitro study suggest that 25% Matricaria can be used as an antimicrobial agent, but it is less effective than 2% chlorhexidine gluconate gel against C. albicans and E. faecalis. Matricaria at a lesser concentration of 15% aq. base is ineffective against both the microorganisms. PMID- 26097334 TI - Estimation of salivary nitric oxide levels in children with congenital heart diseases. AB - INTRODUCTION: Oral health problems, especially dental caries are known to be common in children with severe heart disease, especially at early ages. The role of nitric oxide (NO) in protection against oral diseases owing to its strong antimicrobial action has been a topic of interest. OBJECTIVE: The current study was carried out to estimate the NO levels in the salivary samples of children diagnosed with congenital heart diseases (CHDs) and to determine whether salivary NO can serve as a potential biomarker for the evaluation of dental caries-risk. METHODOLOGY: This prospective study was performed on 50 children suffering from CHDs who reported to the department of pediatrics and the levels were compared with those of 50 healthy caries-free children. NO levels in the collected salivary levels were determined spectrophotometrically using the Griess reaction method. RESULTS: Subjects between the age group of 6 and 12 years had maximum decayed teeth (20.95%). The mean NO level in children in study group (60.63) was decreased in comparison to the control group (132.40), which was statistically significant (P value of 0.001). The mean age of the subjects in the study group was 7.24 and the salivary NO levels decreased with age, which was statistically significant. CONCLUSION: Children are suffering from medically compromising conditions such as CHDs are at a higher risk for dental caries and decreased salivary NO levels in these patients may prove as a critical indicator of the same. Saliva can be further utilized as an important biomarker for the determination of the relationship between salivary NO levels and development of dental caries. PMID- 26097335 TI - Immunoexpression of vascular endothelial growth factor and Ki-67 in human gingival samples: An observational study. AB - AIM: To evaluate immunohistochemically vascular endothelial growth factor (VEGF) and Ki-67 in human gingival samples and to compare these factors between healthy and diabetic patients. MATERIALS AND METHODS: A total of 50 subjects were included in the study. They were categorized into three groups: Periodontally healthy group, periodontally diseased gingiva without any systemic disease group and periodontally diseased gingiva with controlled type II diabetes mellitus (DM) group. Gingival biopsies were performed and immunohistochemical analysis were done for VEGF and Ki-67 staining in gingival samples. RESULTS: The present study found moderate intensity staining for VEGF in periodontitis group and periodontitis with controlled type II DM group and mild intensity staining for VEGF in periodontally healthy group. With regard to Ki-67, negative staining was observed in periodontally healthy group and mild staining in periodontitis group and periodontitis with controlled type II DM group. CONCLUSION: Further investigation needs to be conducted to identify how VEGF and Ki-67 are involved in the tissue inflammation associated processes and the relationship between VEGF and Ki-67 in progression of periodontitis. PMID- 26097336 TI - The relationship of forensic odontology with various dental specialties in the articles published in the Journal of Forensic odonto-stomatology from 2005 to 2012. AB - BACKGROUND: There is a paucity of information about the relationship of forensic odontology with various dental specialties in the articles published in the Journal of Forensic Odonto-Stomatology. This study aimed to find the relationship of forensic odontology with various dental specialties in the articles published in the Journal of Forensic Odonto-Stomatology from 2005 to 2012 over an 8-year period. METHODS: Bibliometric analysis was performed using web-based search during December 2013. RESULTS: Out of the total 97 published articles, the maximum number of published articles were related to oral medicine and radiology (20) and community dentistry (20), followed by orthodontics (18), prosthodontics (15), and oral pathology and microbiology (8), pedodontics (7), oral and maxillofacial surgery (4) and conservative dentistry and endodontics (3). Among the articles published in Journal of Forensic Odonto-Stomatology, mass disasters (10) and bite mark analysis (10), followed by sexual dimorphism (8) and dental fraud and malpractice (8), followed by craniofacial superimposition (6) and identification (6) form the major attraction of the contributors. CONCLUSION: This paper has tried to evaluate the new working classification proposed for forensic odontology based on its relationship with other dental specialties. PMID- 26097337 TI - Association of lipid profile test values, type-2 diabetes mellitus, and periodontitis. AB - OBJECTIVE: A two-way relationship between diabetes and periodontal disease has been suggested; whereas obesity and impaired lipid profile are risk factors for type-2 diabetes mellitus. This study examined the relationship between lipid profile, oral glucose tolerance test (OGTT) with periodontal health/disease dependent variables in healthy, diabetic and impaired glucose tolerance subjects. MATERIALS AND METHODS: 120 patients were selected for the study and were determined to be periodontally healthy or diseased. All these patients underwent biochemical tests for OGTT and Lipid profile analysis and data was compared using Z-test. RESULTS: The OGTT results deteriorated with deteriorating periodontal condition. A similar correlation was also observed between worsening lipid profile test values, OGTT score, and periodontal condition. CONCLUSION: This study indicates that hyperlipidemia may be one of the factors associated with periodontitis and that periodontitis may itself lead to abnormal serum lipid levels. Therefore, in addition to effects on diabetes, periodontitis may contribute to elevated serum lipid levels and therefore potentially to systemic disease arising from chronic hyperlipidemia. PMID- 26097338 TI - An in-vitro evaluation of the effect of 980 nm diode laser irradiation on intra canal dentin surface and dentinal tubule openings after biomechanical preparation: Scanning electron microscopic study. AB - CONTEXT: Very recently, diode laser has been used for disinfecting the root canals in endodontic treatment and increasing its success rate and longevity utilizing the thermal effect of laser on surrounding tissues. AIMS: The aim of this study is to evaluate the effect of 980 nm laser irradiation on intra-canal dentin surface - scanning electron microscopic (SEM) - in-vitro study. METHODS: A total of 40 single-rooted freshly extracted permanent teeth were collected. Teeth were sectioned at the cemento-enamel junction using diamond disc. Root canals of all samples were prepared using hand ProTaper, which were randomly assigned into two groups (n = 20 each). Group 1: Receiving no treatment after biomechanical preparation; Group 2: 980 nm diode laser-treated root canals. Teeth were prepared for SEM analysis to check the size of intra-canal dentinal tubule openings. STATISTICAL ANALYSIS USED: Data were analyzed using SPSS V.16 software and compared using Levene's and independent t-test. RESULTS: On statistical analysis, width of intracanal dentinal tubule openings in Group 1 (control) was significantly higher than those observed in Group 2 (diode laser-treated) (P < 0.001). CONCLUSION: This study showed that the application of 980 nm diode laser on intra-radicular dentin resulted in ultrastructural alterations resulting in melting of dentin. PMID- 26097339 TI - Role of human papillomavirus in oral squamous cell carcinoma and oral potentially malignant disorders: A review of the literature. AB - Human papillomaviruses (HPVs) are epitheliotropic viruses with an affinity for keratinocytes and are principally found in the anogenital tract, urethra, skin, larynx, tracheobronchial and oral mucosa. On the basis of high, but variable frequency of HPV in oral squamous cell carcinoma (OSCC), malignant potential of HPV infection has been hypothesized but not definitely confirmed. The aim of this review was to highlight the genomic structure and possible mechanism of infection and carcinogenesis by HPV in the oral mucosa and to review the frequency of HPV prevalence in OSCC and oral potentially malignant disorders. A computer database search was performed through the use of PubMed from 1994 to 2014. Search keywords used were: HPV and oral cancer, HPV and oral leukoplakia, HPV and oral lichen planus, HPV and OSCC, HPV and verrucous carcinoma, HPV and proliferative verrucous leukoplakia, HPV and oral papilloma. PMID- 26097340 TI - Enamel hypoplasia and its role in identification of individuals: A review of literature. AB - Identification of individuals is the mainstay of any forensic investigation especially in cases of mass disasters when mutilated remains are brought for examination. Dental examination helps in establishing the identity of an individual and thus, has played a vital role in forensic investigation process since long. In this regard, description on the role of enamel hypoplasia is limited in the literature. The present article reviews the literature on the enamel hypoplasia and discusses its utility in forensic identification. Enamel hypoplasia is a surface defect of the tooth crown caused by disturbance of enamel matrix secretion. Enamel defects can be congenital or acquired. In cases of mass disasters, or when the body is completely charred, putrefied and mutilated beyond recognition, the unique dental features can help in identification of the victims. PMID- 26097341 TI - Fixed drug eruptions with intraoral presentation. AB - Fixed-drug eruption (FDE) is an unusual and rare adverse drug reaction. This type of reaction is actually a delayed type of hypersensitivity reaction that occurs as lesions recurring at the same skin site due to repeated intake of an offending drug. Here is a case report of a 58-year-old male patient who developed intraoral FDEs after ingestion of the first dose of ornidazole. PMID- 26097342 TI - Bilateral mandibular fracture related to osteoradionecrosis. AB - Mandible is the most frequently affected bone during head and neck irradiation. Late changes in the mandible may manifest in the form of reduced bone density, dental caries, loss of spongiosa trabeculations, delayed healing following dental extraction, pathologic fractures, osteoradionecrosis, trismus, growth defects in children or second malignancies. Pathologic fractures of mandibular bone are rare and may be spontaneous or traumatic (following dental extraction). We report the case of a 55-year lady, who had undergone surgery and adjuvant radiotherapy for carcinoma oral tongue T2N0M0 on a cobalt-60 unit and was disease-free. After a follow-up of 8 years post-irradiation, she presented with sudden onset oral pain and inability to open mouth. Pantomogram showed fracture at the junction of body and ramus of the mandible bilaterally. PMID- 26097343 TI - The doppelganger tooth: A diagnostic conundrum! AB - Abnormalities in tooth morphology and number are not uncommon. However, an exact clone of a normal tooth is a recondite clinical finding. Presence of supplementary teeth is mostly noticed in maxillary anterior, molar or premolar region, followed by mandibular premolar region in descending order of its site of occurrence. Supplemental tooth in mandibular anterior has a low prevalence of 0.01%. This paper reports one such rare case of nonsyndromic incisive jumeaux in mandibular anterior region during mixed dentition period. PMID- 26097344 TI - Current views and implications of journal impact factor: A key note. PMID- 26097345 TI - Tobacco (Electronic cigarette): An evil in many faces. PMID- 26097346 TI - High-risk human papilloma virus in archival tissues of oral pathosis and normal oral mucosa. AB - OBJECTIVES: Oral cancer ranks third among all cancers in the Indian population. Human papilloma virus (HPV) plays a significant role in oral carcinogenesis. Population-based subtype variations are present in the HPV prevalence. This study gives an emphasis on the parameters to be considered in formalin fixed paraffin embedded tissues for polymerase chain reaction (PCR)-based research work. MATERIALS AND METHODS: Cross-sectional study on archival paraffin-embedded tissue samples of oral squamous cell carcinoma (OSCC), epithelial dysplasia, and normal oral mucosa surrounding impacted tooth was amplified by PCR for the E6 gene of HPV type 16 and E1 gene of HPV type 18. RESULTS: HPV 18 was positive in three OSCC cases. There was no statistically significant association of the positivity of HPV with the age, gender or habit. The HPV positive patients had a tobacco habit and were of a younger age group. CONCLUSION: The presence of HPV in carcinomatous tissue highlights the possible role of HPV in carcinogenesis and archival paraffin embedded tissue specimen can be used for this analysis. Recent studies on genomic analyses have highlighted that the HPV positive tumors are a separate subgroup based on genomic sequencing. The results of a larger retrospective study will help further in our understanding of the role of HPV in carcinogenesis, this study could form the baseline for such follow-up studies. PMID- 26097347 TI - Clinical evaluation and comparison of the efficacy of coronally advanced flap alone and in combination with platelet rich fibrin membrane in the treatment of Miller Class I and II gingival recessions. AB - BACKGROUND: The aim of this study was to compare the clinical efficacy of coronally advanced flap (CAF) alone and in combination with autologous platelet rich fibrin membrane (PRF) in Miller's class I and II gingival recessions. MATERIALS AND METHOD: Thirty isolated Miller class I or II sites in 26 subjects were randomly divided into test (15 sites- CAF+PRF) and control (15 sites- CAF alone). Parameters probing pocket depth (PPD), Recession depth (RD), Clinical attachment loss (CAL), Keratinised tissue width (KTW) and Gingival tissue thickness (GTH) were evaluated at baseline, 3 months and 6 months postoperatively. Data was subjected to statistical analysis. P< 0.05 was considered statistically significant. RESULTS: Mean percentage root coverage was 91.00+/-19.98% and 86.60+/-23.83% for test and control group respectively. Difference between the groups in all parameters at baseline, 3 months and 6 months was non significant. Complete root coverage was obtained in 12 (80%) and 11 (73.3%) subjects in test and control group respectively. The difference was found to be non-significant. Both groups showed significant differences in all parameters at 3 and 6 months respectively except difference in gingival tissue thickness which was non-significant in control group at 3 months. CONCLUSION: Combination of PRF to CAF procedure did not provide any added advantage in term of recession coverage in Miller class I and II recessions. Long term trials with more sample size are needed to validate these findings. PMID- 26097348 TI - A comparative evaluation of the marginal accuracy of crowns fabricated from four commercially available provisional materials: An in vitro study. AB - PURPOSE: The purpose of this in vitro study was to evaluate and compare the primary marginal accuracy of four commercially available provisional materials (Protemp 4, Luxatemp Star, Visalys Temp and DPI tooth moulding powder and liquid) at 2 time intervals (10 and 30 min). MATERIALS AND METHODS: A customized stainless steel master model containing two interchangeable dies was used for fabrication of provisional crowns. Forty crowns (n = 10) were fabricated, and each crown was evaluated under a stereomicroscope. Vertical marginal discrepancies were noted and compared at 10 min since the start of mixing and then at 30 min. OBSERVATIONS AND RESULTS: Protemp 4 showed the least vertical marginal discrepancy (71.59 MU), followed by Luxatemp Star (91.93 MU) at 10 min. DPI showed a marginal discrepancy of 95.94 MU while Visalys Temp crowns had vertical marginal discrepancy of 106.81 MU. There was a significant difference in the marginal discrepancy values of Protemp 4 and Visalys Temp. At 30 min, there was a significant difference between the marginal discrepancy of Protemp 4 crowns (83.11 MU) and Visalys Temp crowns (128.97 MU) and between Protemp 4 and DPI (118.88 MU). No significant differences were observed between Protemp 4 and Luxatemp Star. CONCLUSION: The vertical marginal discrepancy of temporary crowns fabricated from the four commercially available provisional materials ranged from 71 to 106 MU immediately after fabrication (at 10 min from the start of mix) to 83-128 MU (30 min from the start of mix). The time elapsed after mixing had a significant influence on the marginal accuracy of the crowns. PMID- 26097349 TI - Determination of antibacterial activity of green coffee bean extract on periodontogenic bacteria like Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans: An in vitro study. AB - BACKGROUND: The aim of this study was to evaluate the antibacterial activity of pure green coffee bean extract on periodonto pathogenic bacteria Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Fusobacterium nucleatum (Fn) and Aggregatibacter actinomycetemcomitans (Aa). MATERIALS AND METHODS: Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBC) were used to assess the antibacterial effect of pure green coffee bean extract against periodonto pathogenic bacteria by micro dilution method and culture method, respectively. RESULTS: MIC values of Pg, Pi and Aa were 0.2 MUg/ml whereas Fn showed sensitive at concentration of 3.125 MUg/ml. MBC values mirrors the values same as that of MIC. CONCLUSION: Antimicrobial activity of pure green coffee bean extract against Pg, Pi, Fn and Aa suggests that it could be recommended as an adjunct to mechanical therapy in the management of periodontal disease. PMID- 26097350 TI - Enamel morphology after microabrasion with experimental compounds. AB - BACKGROUND: Enamel microabrasion is an esthetic treatment for removing superficial stains or defects of enamel. AIM: This study evaluated the roughness after enamel microabrasion using experimental microabrasive systems. MATERIALS AND METHODS: One hundred and ten samples (5 * 5 mm) were obtained from bovine incisors and divided into 11 groups (n = 10) in accordance with the treatment: Microabrasion using 6.6% hydrochloric acid (HCl) or 35% phosphoric acid (H3PO4) associated with aluminum oxide (AlO3) or pumice (Pum) with active application (using rubber cup coupled with a micro-motor of low rotation) or passive application (just placing the mixture on the enamel surface); just the use of acids in a passive application (negative control), and a group without treatment (positive control). Roughness analysis was performed before and after treatments. The statistical analysis used analysis of variance (PROC MIXED), Tukey-Kramer and Dunnet tests (P < 0.05). Representative specimens were evaluated using scanning electron microscopy (SEM). RESULTS: There was no significant difference between the acids used (P = 0.0510) and the applications (P = 0.8989). All of the treated groups were statistically different from the positive control. When using passive application, the use of HCl + AlO3 resulted in higher roughness when compared with HCl + Pum. Additionally, this treatment was statistically different from the passive application of H3PO4 (negative control) (P < 0.05). However, SEM analysis showed that the treatment with AlO3 resulted in an enamel surface with a more polished aspect when compared with Pum. CONCLUSION: AlO3 may be a suitable particle for use in microabrasive systems. PMID- 26097351 TI - Study of the association between the interleukin-1 beta c.3954C>T polymorphism and periodontitis in a population sample from Bahia, Brazil. AB - BACKGROUND: Periodontitis is an inflammatory disease characterized by the loss of connective tissue and alveolar bone. Different factors are associated with the onset and prognosis of this disease, both environmental and genetic. The latter particularly relate to molecules secreted as a function of the host immune response, such as pro-inflammatory cytokines. Studies indicate that the polymorphism c. 3954C > T in the interleukin-1 beta encoding gene (IL1B) can be considered as an aggravating factor in the periodontitis condition. AIMS: This study aimed to evaluate whether there is an association between the IL1B c. 3954C > T gene polymorphism and the prevalence of periodontitis in the population from Vitoria da Conquista-Bahia, Brazil. MATERIALS AND METHODS: A total of 347 subjects (134 cases and 213 controls) who provided epithelial tissue of the oral cavity and saliva samples for DNA extraction and quantification of IL1B, respectively, were selected. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism followed by electrophoresis in agarose gel. The evaluation of the cytokine concentration was performed by enzyme linked immunosorbent assay. STATISTICAL ANALYSIS: Statistical calculations involved in this work include Chi-square test, Fisher Exact test, Mann-Whitney and Kruskal-Wallis tests. RESULTS: Our findings revealed that: (i) No statistically significant relationship between periodontitis and the polymorphism studied was observed; (ii) no significant difference between the concentrations of IL1B in saliva between the case and control subjects and between the genotypes of these individuals and the concentrations of this cytokine. CONCLUSIONS: We conclude that, in the sample evaluated, the IL1B c. 3954C > T polymorphism did not present as an etiological factor for periodontitis. PMID- 26097353 TI - Comparative evaluation of the amount of gingival displacement produced by three different gingival retraction systems: An in vivo study. AB - STATEMENT OF PROBLEM: Tetrahydrozoline has been introduced as new gingival retraction agent but its clinical efficacy with widely used conventional retraction agents has not been tested. PURPOSE: The study was designed to clinically evaluate efficacy of newer retraction agent tetrahydrozoline with two widely used retraction systems i.e., Expasyl retraction system and medicated retraction cords on basis of amount of gingival retraction. MATERIALS AND METHODS: 30 subjects were selected according to inclusion and exclusion criteria. Maxillary Impressions were made with irreversible hydrocolloid for all subjects. Tray material was used for making the special tray. Latin Block Design was Used in the Study to avoid tissue fatigue. Retraction was done with aluminium chloride; Tetrahydrozoline and Expasyl according to Latin block design. Impressions were poured with die stone. Casts were retrieved and sections were made with die cutter. 3 mm thin slices were obtained. Each slice was used to measure the amount of retraction under stereomicroscope under 20x and images were transferred to image analyser. RESULTS: The amount of gingival retraction obtained by using aluminium chloride as gingival retraction agent was maximum (148238.33 MUm(2)) compared to tetrahydrozoline (140737.87 MUm(2)) and Expasyl (67784.90 MUm(2)). PMID- 26097352 TI - Cephalometric norms for the upper airway in a healthy North Indian population. AB - OBJECTIVE: The aim was to obtain normative data for cephalometric measurements of the upper airway in the North Indian population. DESIGN: Observational study. SETTING: University department and teaching hospital out-patient clinic. SUBJECTS AND METHODS: A total of 180 healthy patients were included out of which 90 were males (age range, 8-16 years), and 90 were females (age range, 8-16 years), with normal skeletal facial profile, no history of snoring, sleep apnea, upper airway disease, tonsillectomy or adenoidectomy, obesity, or pathology in the pharynx. Twenty cephalometric airway measurements, including size of the tongue, soft palate, nasopharynx, oropharynx, hypopharynx, and relative position of the hyoid bone and valleculae were obtained. Landmarks on cephalometric radiographs were digitized and measurements were made using a specially designed computer program. Error analysis of measurements was performed and comparison of measurements according to sex was made. RESULTS: Significant sex dimorphism was seen for the majority of measurements, with the exception of minimal depth of the airway, oropharyngeal depth of the airway, and the soft palate angle with the hard palate. CONCLUSION: A minimum sagittal dimension of the upper airway was evident despite differences in measurements between sexes. Findings from this study should be a useful reference for the assessment of sleep apnea in the North Indian population. PMID- 26097354 TI - Comparison of shear bond strength of two porcelain repair systems after different surface treatment. AB - INTRODUCTION: Intraoral chair side porcelain repair system is a quick, painless and highly patient acceptable procedure, without removal of restoration or fabrication of new restoration. There are very limited studies conducted to evaluate the shear bond strength of repair systems after different surface treatment. OBJECTIVES OF RESEARCH: The objective of research was to evaluate the shear bond strength of two intraoral porcelain repair systems Clearfil repair system (Kuraray) and Ceramic repair system (Ivoclar) to repair metal-ceramic restoration after three different surface treatment. MATERIALS AND METHODS: Totally, 120 discs of base metal alloy were fabricated. The opaque, dentine and enamel of ceramic were applied to achieve the uniform thickness. Defect was created, and repair was done using two repair systems after different surface treatment. Shear bond strength was measured. RESULTS: Analysis of variance was utilized. Ceramic repair system after 40% phosphoric acid surface treatment showed the highest mean value and Clearfil repair system after surface treatment with 37% phosphoric acid showed the lowest. The statistical difference was found to be significant between the groups. CONCLUSION: The shear bond strength of Ceramic repair system with 40% phosphoric acid etching showed highest shear bond strength as compared to other system and surface treatment used in the study. PMID- 26097355 TI - Decalcifying capability of irrigating solutions on root canal dentin mineral content. AB - BACKGROUND: Chelating agents are believed to aid root canal irrigation and to be able to remove the inorganic smear layer. AIMS: The purpose of the present study was to evaluate and to compare the decalcifying capability of different irrigating solutions (Tubuliclean, Largal Ultra, ethylenediaminetetraacetic acid 17%, Tetraclean, Tetraclean NA). MATERIALS AND METHODS: Sixty maxillary central incisors were used. Root canals were instrumented and irrigated. From each root, four comparable slices of cervical dentin were obtained. At three successive 5 min interval immersion times, the concentration of calcium extracted from root canal dentin was assessed with an inductively coupled plasma-atomic emission spectrometer. STATISTICAL ANALYSIS USED: Data were analyzed by means of Kruskal Wallis and Mann-Whitney tests. Significance was predetermined at P < 0.05. RESULTS AND CONCLUSIONS: For all irrigating solutions, the maximum amount of Ca(2+) extracted from root canal dentin samples was reached after 10 min contact time except for citric acid-based agents (Tetraclean and Tetraclean NA) which induced a higher and still increasing calcium release even after 10 min contact time. In order to obtain an efficient decalcifying action on dentin and to facilitate the biomechanical procedures, citric acid-based irrigants can be applied. PMID- 26097356 TI - Evaluation of glutathione level in gingival crevicular fluid in periodontal health, in chronic periodontitis and after nonsurgical periodontal therapy: A clinicobiochemical study. AB - CONTEXT: Periodontitis is predominantly due to exaggerated host response to pathogenic microorganisms and their products which causes an imbalance between the reactive oxygen species-antioxidant in gingival crevicular fluid (GCF). Glutathione is an important redox regulator in GCF and maintenance of stable reduced glutathione (GSH):oxidized glutathione (GSSG) ratio is essential for periodontal health. AIMS: The present study was undertaken to evaluate and compare the level of glutathione and redox balance (GSH: GSSG ratio) in GCF of chronic periodontitis patients, periodontally healthy controls and also to evaluate the effect of nonsurgical periodontal therapy on the level of glutathione and redox balance during 3 months postoperative visit. STUDY DESIGN: Baseline GCF samples were collected from 20 chronic periodontitis patients and 20 periodontally healthy subjects for GSH and GSSG levels estimation. Periodontitis patients were recalled 3 months postnonsurgical periodontal therapy to re-sample GCF. MATERIALS AND METHODS: GSH and GSSG levels were measured by high-performance liquid chromatography. The values were statistically analyzed by Paired t-test. RESULTS: The mean GSH and GSSG values in GCF were found to be significantly lower in periodontitis patients pre- and 3 months post-nonsurgical periodontal therapy, compared with those in the control group subjects. In addition, the successful nonsurgical therapy even though leading to a significant improvement in the GSH and GSSG levels, does not restore glutathione concentration to the levels seen in healthy subjects. CONCLUSION: Successful nonsurgical periodontal therapy leads to significant improvement in the redox balance (GSH: GSSG ratio) in chronic periodontitis patients. PMID- 26097357 TI - Influence of nail biting and finger sucking habits on the oral carriage of Enterobacteriaceae. AB - BACKGROUND: Oral habits like thumb sucking and nail biting are pernicious habits that act as an adaptive function in obtaining pleasure and subduing anxiety. These habits may also act as carriers of numerous microorganisms into the oral cavity, of which, Enterobacteriaceae members are transient pathogens, which might result in debilitating systemic conditions. AIM: To study the oral carriage of Enterobacteriaceae in children having habit of nail biting and thumb sucking. And to study the association of the organism with the individual's respective plaque indices. SUBJECTS AND METHODS: Totally, 40 chronic nail biters, 40 chronic thumb suckers, and 20 controls (no habit) (8-15 years old) were enrolled in the study. Appropriate history and their plaque indices recorded. Sterile containers were used to collect the salivary samples and later cultured on Agar plates. Biochemical tests categorized the organisms into subspecies. STATISTICAL ANALYSIS USED: ANNOVA, Student's t-test. RESULTS: Presence of a nail biting habit indicated a higher plaque index, which in turn showed a higher carriage of Enterobacteria spps, predominantly Escherichia coli. CONCLUSIONS: Oral surgical intervention in individuals with pernicious oral habits need to be counseled and educated on the possible complications, which might otherwise provide an environment that disseminates these microorganisms resulting in a broad range of local and systemic infections. PMID- 26097358 TI - Evaluation of anxiety, depression and suicidal intent in undergraduate dental students: A cross-sectional study. AB - BACKGROUND: There is an increasing amount of stress in undergraduate dental students leading to anxiety, depression, and suicidal attempts/suicide. AIMS: This study aims to evaluate anxiety, depression and suicidal intent in undergraduate dental students and to find out the various areas of stress. MATERIALS AND METHODS: A cross-sectional study was conducted using a semi structured questionnaire (to assess academic and nonacademic areas of stress) and three scales-Hamilton scale for anxiety (HAM-A); Hamilton depression rating scale (HDRS) and Beck's Suicide Intent Scale (BSI). Descriptive statistics; Pearson's Chi-square test; Multiple ANOVA; Kruskal-Wallis test and Mann-Whitney test were used to analyze the data at the significant level of P <= 0.05. RESULTS: In a total of 258 dental undergraduate students, academic areas of stress that were found to be statistically significant were long teaching hours (P = 0.002); high workload (P <= 0.001); frequency of tests (P <= 0.001) and competition/fear of failure (P = 0.009). Lack of interest in the profession was a statistically significant nonacademic area for stress (P <= 0.001). The students of first and final year reported higher anxiety (HAM-A 13.93 +/- 6.908 and 16.44 +/- 7.637 respectively) and depression (HDRS 14.29 +/- 6.302 and 14.22 +/- 5.422); whereas suicidal intent was reported almost the same throughout the study sample (BSI 5.65 +/- 5.465). CONCLUSION: An increasing level of anxiety, depression and suicidal intent due to various stressors in undergraduate dental students indicate a need to modify current education system and timely help to have psychological healthy dental professionals in future. PMID- 26097359 TI - Hyperactive lesions of gingiva associated with severe alveolar bone loss: A rare finding. AB - Pyogenic granuloma (PG) is an inflammatory reactive hyperplasia of connective tissue. It usually arises in response to various stimuli such as low-grade local irritation, traumatic injury, hormonal factors or certain kinds of drugs. It predominantly occurs in the second decade of life in young females and rarely may cause significantly alveolar bone loss. It managed by conservative surgical excision and removal of causative irritants. This paper presents the case of a PG in a 55-year-old male with severe alveolar bone loss in the affected site, managed by surgical intervention. PMID- 26097360 TI - Distalization of maxillary arch and correction of Class II with mini-implants: A report of two cases. AB - This article reports the successful use of mini-screws in the maxilla to treat two patients of age 21-year and 17-year-old girls. Both the patients had a skeletal Class II malocclusion with protrusive maxillary teeth and angels Class II mal-occlusion. Temporary anchorage devices (TADs) in the posterior dental region between maxillary second premolar and maxillary first molar teeth on both sides were used as anchorage for the retraction and intrusion of her maxillary anterior teeth. Those appliances, combined with a compensatory curved maxillary archwire, eliminated spacing, deep bite, forwardly placed and proclined upper front teeth and the protrusive profile, corrected the molar relationship from Class II to Class I. With no extra TADs in the anterior region for intrusion, the treatment was workable and simple. The patient received a satisfactory occlusion and an attractive smile. This technique requires minimal compliance and is particularly useful for correcting Class II patients with protrusive maxillary front teeth and dental deep bite. PMID- 26097361 TI - Lipoid proteinosis: A review with two case reports. AB - Lipoid proteinosis (LP) is a rare autosomal recessive genodermatoses characterized by deposition of amorphous hyaline material in different parts of the body, especially the skin, mucous membranes of the upper aerodigestive tract, and internal organs. Oral cavity is most extensively affected area by the disease. This paper reports two classic cases of LP with oral manifestations but without a history of consanguinity along with a concise review of the literature on the disease. PMID- 26097362 TI - Regional odontodysplasia: Report of an unusual case involving mandibular arch. AB - Regional odontodysplasia (RO) is a rare developmental anomaly involving both mesodermal and ectodermal components in primary or permanent dentition. It affects the maxilla and the mandible or both; however, maxilla is more commonly involved. This article reports the case of 33-month-old boy who came with the chief complaint of delayed eruption of mandibular teeth. Findings of clinical and radiographic examination were consistent with those of RO. Maxillary dentition was unaffected. Clinical and radiographic features and treatment options are discussed. PMID- 26097363 TI - "Whisking of ugly tissue"... A surgical management of gingival fibromatosis in a 15-year-old girl: A rare case report. AB - Gingival fibromatosis is a condition characterized by a slow, progressive increase in the gingival tissue that develops as either an isolated disorder or as part of the clinical characteristics of diverse syndrome. The present case report describes a rare case of gingival fibromatosis and its management using scalpel in combination with electrosurgery. A 15-year-old girl patient presented with a chief complaint of gingival overgrowth covering all the surfaces upper and lower teeth. The growth was excised with periodontal knife in combination with electrosurgery under local anesthesia. After 1-year of follow-up, healing was uneventful with no recurrence. Combined technique for the removal of gingival overgrowth represents a unique treatment approach where minimal postoperative bleeding and discomfort were observed. PMID- 26097364 TI - Bilateral maxillary sinus floor augmentation with tissue-engineered autologous osteoblasts and demineralized freeze-dried bone. AB - The pneumatization of the maxillary sinus often results in a lack of sufficient alveolar bone for implant placement. In the last decades, maxillary sinus lift has become a very popular procedure with predictable results. Sinus floor augmentation procedures are generally carried out using autologous bone grafts, bone substitutes, or composites of bone and bone substitutes. However, the inherent limitations associated with each of these, have directed the attention of investigators to new technologies like bone tissue engineering. Bone marrow stromal cells have been regarded as multi-potent cells residing in bone marrow. These cells can be harvested from a person, multiplied outside his body using bioengineering principles and technologies and later introduced into a tissue defect. We present a case where tissue-engineered autologous osteoblasts were used along with demineralized freeze-dried bone for sinus floor augmentation. PMID- 26097365 TI - A benign salivary gland tumor of minor salivary gland mimicking an epithelial malignancy. AB - Pleomorphic adenoma (PA) is the most common benign tumor of major or minor salivary glands. Microscopically, PA exhibits a great diversity of morphological aspects. Here, we present an unusual case of PA with extensive squamous metaplasia and keratin-filled cysts in the left retromolar region of a 50-year old edentulous person whose microscopic finding may represent a diagnostic dilemma for pathologists. PMID- 26097366 TI - Amalgamation of allogenic bone graft, platelet-rich fibrin gel, and PRF membrane in auto-transplantation of an impacted central incisor. AB - "Social six" teeth refers to the maxillary incisors and canines that play a vital role in the appearance of an individual and absence of any one of them has a significant psycho-social impact. Hence, early treatment and rehabilitation of the same are extremely important. A multitude of treatment options ranging from orthodontic extrusion, extraction followed by implant placement, fixed partial denture, and auto-transplantation have been advocated. This case report discusses the unique amalgamation of platelet-rich fibrin (PRF), demineralized freeze-dried bone graft with use of PRF membrane during auto-transplantation of an impacted central incisor. The authors have focused on maximum usage of autogenous materials in the most economic and least invasive manner. Furthermore, this amalgamation has been used to provide rehabilitation in the least span of time. PMID- 26097367 TI - Phlebolith in arteriovenous malformation in buccal fat pad masquerading sialolith: A rare case report. AB - Arteriovenous malformations (AVMs) are rare vascular lesion in the buccal fat pad (BFP). One of the important complications associated with these lesions is phlebolith formation within it. To the best of authors' knowledge, there is no medical literature on AVM with phlebolith formation in BFP till date. The present case is a 12-year-old boy who presented with a swelling in the right side of the face, clinically diagnosed to be sialocele with sialolith. Excision of the mass was done, and histopathology revealed AVM with the formation of phlebolith. This rare entity needs to be kept in mind while evaluating a case of calcification in BFP. The first case of AVM with phlebolith formation in BFP is reported here along with brief review of literature. PMID- 26097368 TI - Cone-beam computed tomography: An inevitable investigation in cleidocranial dysplasia. AB - Cleidocranial dysplasia is a heritable skeletal dysplasia and one of the most common features of this syndrome is multiple impacted supernumerary teeth. Cone beam computed tomography, the most recent advancement in maxillofacial imaging, provides the clinician to view the morphology of the skull and the dentition in all three dimensions and help in treatment planning for the patient. PMID- 26097369 TI - Bilateral nephrocalcinosis and amelogenesis imperfecta: A case report. AB - Amelogenesis imperfecta (AI) is a group of hereditary disorders that affect the quality and/or quantity of dental enamel. This paper describes the clinicopathological features of a patient who was born of nonconsanguineous parents and who presented with oral alterations, including yellow and misshapen teeth, intrapulpal calcifications, delayed tooth eruption, and gum enlargement. Scanning electron microscopy of the teeth revealed hypoplastic enamel, and a renal ultrasound detected bilateral nephrocalcinosis, leading to a diagnosis of AI and nephrocalcinosis syndrome. Since nephrocalcinosis is often asymptomatic and can be associated with impaired renal function, dentists who see children with a generalized and thin hypoplastic AI should consider a renal ultrasound scan and referral to a Nephrologist. Children with nephrocalcinosis should also be considered for a dental check. PMID- 26097370 TI - Lipoma or hemangioma: A diagnostic dilemma? AB - Lipomas and hemangiomas are well-known benign lesions of the body. However, their occurrence in the oral cavity is rare. Lipoma accounts for 1-4% of benign neoplasms of mouth affecting predominantly the buccal mucosa, floor of mouth and tongue. Hemangiomas occur mostly on the lips, buccal mucosa, tongue, and palate. Lipomas when superficially placed show yellowish surface discoloration and hemangiomas usually have reddish blue to deep blue color. Here, we report an unusual case of benign tumor occurring in the buccal vestibule. PMID- 26097371 TI - Management of Class II malocclusion with ectopic maxillary canines. AB - Correction of Class II relationship, deep bite and ectopically erupting canines is an orthodontic challenge for the clinician. A 13-year-old male patient presented with Class II malocclusion, ectopically erupting canines, and cross bite with maxillary left lateral incisor. He was treated with a combination of Headgear, ForsusTM fatigue resistant device [FFRD] with fixed mechanotherapy for the management of space deficiency and correction of Class II malocclusions. Headgear was used to distalize upper first molars and also to prevent further downward and forward growth of the maxilla. Then ForsusTM FFRD was used for the advancement of the mandible. The molar and canine relationship were corrected from a Class II to a Class I. The objectives were to establish good occlusion and enable eruption of unerupted canines. All these objectives were achieved and remained stable. PMID- 26097372 TI - Christ Siemens Touraine syndrome: Two case reports and felicitous approaches to prosthetic management. AB - Ectodermal dysplasia is a heterogeneous group of inherited disorders, which exhibit a classic triad of hypohydrosis, hypotrichosis, and hypodontia. Hypohidrotic or anhidrotic ectodermal dysplasia or Christ Siemens Touraine syndrome is the most common condition among ectodermal dysplasia patients. This is a case report on two Christ Siemens Touraine syndrome cases and two different approaches to prosthetic management. PMID- 26097373 TI - A roentgenographic assessment of regenerative efficacy of bioactive Gengigel((r)) in conjunction with amnion membrane in grade II furcation defect. AB - BACKGROUND: Nowadays, techniques are being developed to guide and instruct the specialized cellular components of the periodontium to participate in the regenerative process. This approach of reconstruction makes use of understanding of the development of the periodontium and the cellular processes that are involved. Hyaluronic acid is a naturally occurring non-sulfated high molecular weight glycosaminoglycan that forms a critical component of the extracellular matrix and contributes significantly to tissue hydrodynamics, cell migration, and proliferation. Hence, its administration to periodontal wound sites could achieve comparable beneficial effects in periodontal tissue regeneration. Hence, the purpose of the present case report was to assess roentgenographically, the regenerative capacity of Gengigel((r)) in conjunction with bioactive amnion guided tissue regeneration (GTR) membrane in a patient with Grade II furcation defect. CASE PRESENTATION: A patient complained of bleeding gums from the lower back tooth region, reportedly found Grade II furcation in the lower right mandibular first molar. After Phase, I therapy, Gengigel((r)) along with bioactive amnion membrane was placed in the furcation area during the surgical phase. Roentgenographic assessment was done at 4 months and 6 months postoperatively. It resulted in complete defect-fill and loss of radiolucency at 6 months. CONCLUSION: Surgical placement of Gengigel((r)) along with amnion membrane in the furcation defect can significantly improve the periodontal defect morphology. PMID- 26097374 TI - Autotetraploid plant regeneration by indirect somatic embryogenesis from leaf mesophyll protoplasts of diploid Gentiana decumbens L.f. AB - Somaclonal variation, often manifested as the increased ploidy of plants observed following in vitro culture, can be advantageous in ornamental species or those used for secondary metabolite production. Polyploidy occurs especially when plantlets are produced by protoplast and callus cultures. Plants were regenerated from green leaf mesophyll protoplasts of diploid Gentiana decumbens L.f. through somatic embryogenesis. A yield of more than 9 * 105 protoplasts per gram of fresh weight was achieved by incubating fully expanded young leaves in an enzyme mixture containing 1.0% (w/v) cellulase and 0.5% (w/v) macerozyme. Protoplasts, cultured in agarose beads using a modified Murashige and Skoog medium, divided and formed microcalli, with the highest plating efficiency obtained on medium containing 2.0 mg l-1 1-naphthaleneacetic acid and 0.1 mg l-1 thidiazuron. Callus proliferation was also promoted by including thidiazuron in agar-solidified medium, while somatic embryogenesis was induced from microcalli on medium supplemented with 1.0 mg l-1 kinetin, 0.5 mg l-1 gibberellic acid, and 80 mg l-1 adenine sulfate. Flow cytometric analysis and chromosome counting revealed that all regenerants were tetraploid. PMID- 26097375 TI - Rely to Vogel et al. PMID- 26097376 TI - HIV-Risk Reduction with Juvenile Offenders on Probation. AB - Youth involved in the juvenile justice system are at elevated risk for HIV as a result of high rates of sexual risk taking, substance use, mental health problems and sexually transmitted infections. Yet few HIV prevention programs exist for young offenders. This pilot study examined change in juvenile offenders' sexual activity, drug/alcohol use, HIV testing and counseling, and theoretical mediators of risk taking following participation in PHAT Life, an HIV-prevention program for teens on probation. Participants (N=54) were 13-17 year-old arrested males and females remanded to a detention alternative setting. Youth participated in a uniquely tailored HIV prevention intervention and completed a baseline and 3 month follow up assessment of their HIV and substance use knowledge, attitudes, beliefs, and behaviors. At 3-month follow up, teens reported less alcohol use, more positive attitudes toward peers with HIV, greater ability to resist temptation to use substances, and for males, improved HIV prevention self efficacy and peer norms supporting prevention. Teens were also more likely to seek HIV counseling and males were more likely to get tested for HIV. Effect sizes revealed moderate change in sexual behavior. Findings support PHAT Life as a promising intervention to reduce HIV-risk among youth in juvenile justice. PMID- 26097377 TI - Crossover Effects Among Parental Hostility and Parent-Child Relationships During the Preschool Period. AB - Parental hostility may have widespread effects across members of the family, whereby one parent's hostility might disrupt the other parent's ability to maintain a positive relationship with his or her children. The present study prospectively examined crossover effects of parental hostility on parent-child relationship quality in a sample of 210 families. At child ages 3, 4, and 5, mothers and fathers completed questionnaires assessing feelings of hostility. In addition, mother-child and father-child dyadic relationship quality were coded at each age during naturalistic home observations. Results from structural equation analyses indicated that mother and father hostility were relatively stable over the two year period. Further, results were consistent with notions of fathering vulnerability, such that the father-child relationship might be especially susceptible to parental hostility. Possible compensatory processes, wherein mothers may compensate for father hostility, were also explored. Child and parent gender add further complexity to the results, as the father-son relationship appears most susceptible to crossover effects of parental hostility, whereas the father-daughter relationship might be somewhat protected in the early childhood period. Findings from the current investigation highlight the need for broader perspectives on family functioning, considering influences across family subsystems and the effects of both parent and child gender. PMID- 26097379 TI - The expression of LGR5 in healthy human stem cell niches and its modulation in inflamed conditions. AB - PURPOSE: The aims of this study are to investigate the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) protein in the normal human cornea and limbus and to analyze modifications of this expression under inflammatory conditions. METHODS: The expression of LGR5 was evaluated in seven limbal epithelial crypts (LECs), collected from healthy cadaver donors, and five inflamed LECs obtained from enucleated eyes. Central corneal buttons were used as controls. LGR5 protein distribution was determined by immunohistochemistry staining analysis. RESULTS: The cytoplasmic expression of LGR5 protein was observed in 100% of healthy LECs. Three out of five inflamed tissues analyzed were completely negative, while in the two remaining cases, we observed a moderate positivity in the basal cells of LECs. No relation was found between the expression of LGR5 and the grade of inflammatory cells. CONCLUSIONS: These findings demonstrate the presence of LGR5-positive cells in human LECs and their decrease in inflamed conditions, which suggests a critical role of this protein during inflammation and its possible use as a marker in normal crypts. PMID- 26097378 TI - Phenotypes of trypsin- and collagenase-prepared bovine corneal endothelial cells in the presence of a selective Rho kinase inhibitor, Y-27632. AB - PURPOSE: To optimize isolation of viable bovine corneal endothelial cells (BCECs), we evaluated the effectiveness of various preparation protocols. This entailed comparing the effects of collagenase A and trypsin in the presence and absence of a Rho kinase inhibitor, Y-27632, on proliferation and tight junctional and cytoskeletal integrity during their expansion. METHODS: 5-bromo-2' deoxyuridine (BrdU) incorporation evaluated cell proliferation. Western blot analysis evaluated F-actin, zonule occludin, and ZO-1 associated nucleic acid binding protein (ZONAB) and RhoA expression. Rho A pulldown assay evaluated Rho A activity. RESULTS: In the trypsin (TrypLE)-prepared BCECs, BrdU incorporation decreased whereas nuclear ZONAB expression increased and became stable from day 3 to 7. In contrast, in the collagenase-A-prepared BCECs, we observed preserved ZO 1 integrity, invariant nuclear ZONAB expression, and dense cortical F-actin expression, and BrdU incorporation was invariant from days 1 to 7. Y-27632 did not increase BrdU incorporation and nuclear ZONAB expression in the TrypLE prepared and the collagenase-A-prepared BCECs. Moreover, Y-27632 increased irregular cellular morphology and downregulated the expression of ZO-1 in the collagenase-A-prepared BCECs from days 1 to 7. Y-27632 inhibited RhoA activation irrespective of whether the cells were isolated with trypsin or collagenase A. CONCLUSIONS: It is preferable to isolate BCECs with collagenase A and expand them without Y-27632. With this protocol, proliferative activity and tight junctional and cytoskeletal integrity are better preserved than if trypsin is used in the presence or absence of Y-27632. PMID- 26097380 TI - Novel targeted therapies in chordoma: an update. AB - Chordomas are rare, locally aggressive skull base neoplasms known for local recurrence and not-infrequent treatment failure. Current evidence supports the role of maximal safe surgical resection. In addition to open skull-base approaches, the endoscopic endonasal approach to clival chordomas has been reported with favorable albeit early results. Adjuvant radiation is prescribed following complete resection, alternatively for gross residual disease or at the time of recurrence. The modalities of adjuvant radiation therapy reported vary widely and include proton-beam, carbon-ion, fractionated photon radiotherapy, and photon and gamma-knife radiosurgery. As of now, no direct comparison is available, and high-level evidence demonstrating superiority of one modality over another is lacking. While systemic therapies have yet to form part of any first line therapy for chordomas, a number of targeted agents have been evaluated to date that inhibit specific molecules and their respective pathways known to be implicated in chordomas. These include EGFR (erlotinib, gefitinib, lapatinib), PDGFR (imatinib), mTOR (rapamycin), and VEGF (bevacizumab). This article provides an update of the current multimodality treatment of cranial base chordomas, with an emphasis on how current understanding of molecular pathogenesis provides a framework for the development of novel targeted approaches. PMID- 26097381 TI - Nanotechnology in the Regeneration of Complex Tissues. AB - Modern medicine faces a growing crisis as demand for organ transplantations continues to far outstrip supply. By stimulating the body's own repair mechanisms, regenerative medicine aims to reduce demand for organs, while the closely related field of tissue engineering promises to deliver "off-the-self" organs grown from patients' own stem cells to improve supply. To deliver on these promises, we must have reliable means of generating complex tissues. Thus far, the majority of successful tissue engineering approaches have relied on macroporous scaffolds to provide cells with both mechanical support and differentiative cues. In order to engineer complex tissues, greater attention must be paid to nanoscale cues present in a cell's microenvironment. As the extracellular matrix is capable of driving complexity during development, it must be understood and reproduced in order to recapitulate complexity in engineered tissues. This review will summarize current progress in engineering complex tissue through the integration of nanocomposites and biomimetic scaffolds. PMID- 26097382 TI - Ionizing radiation-induced foci persistence screen to discover enhancers of accelerated senescence. AB - Much like replicative senescence, the irreversible cell-cycle arrest induced by eroded telomeres, accelerated senescence occurs when replicative cells suffer irreparable DNA double-strand breaks (DSBs). Along with apoptosis and necrosis, senescence is a desirable outcome in cancer treatment with ionizing radiation (IR) or chemotherapy. In both normal and cancer cells, DSBs promote the assembly of IR-induced foci (IRIF), domains of modified chromatin that serve a key role in DNA damage signaling. IRIF persistence is a critical determinant of accelerated senescence, making drugs that promote persistent IRIF an attractive strategy to sensitize cancer to genotoxic therapy. As an IRIF reporter, we have expressed an inducible green fluorescent protein (GFP) fusion to the IRIF-binding domain (IBD) of 53BP1 (GFP-IBD) in the breast cancer cell line MCF7. Within minutes of exposure to IR, the GFP-IBD relocalizes to form fluorescent nuclear foci, which disperse within several hours. A pair of high-content screening assays for IRIF formation and persistence were established in multiwell plates based on imaging and quantifying GFP-IBD foci per Hoechst-stained MCF7 nucleus at 2 hours and 24 hours. Using the ataxia telangiectasia-mutated inhibitor CGK733 to block IRIF formation and the topoisomerase II inhibitor etoposide to prevent IRIF resolution, we obtained a Z' >0.8 both for IRIF formation at 2 hours and IRIF persistence at 24 hours. Screening the diverse drugs and natural products in the National Cancer Institute Developmental Therapeutics Program Approved Oncology Drugs Set, the National Institutes of Health Clinical Collection, and the MicroSource Spectrum Collection yielded multiple hits that significantly delayed IRIF resolution. Secondary screening suggested some of these otherwise nontoxic drugs also enhance accelerated senescence, indicating strong potential for their repurposing as radiation sensitizers to improve the efficacy of cancer therapy. PMID- 26097383 TI - New method for identifying abnormal milling states of an otological drill. AB - Surgeons are continuing to strive toward achieving higher quality minimally invasive surgery. With the growth of modern technology, intelligent medical devices are being used to improve the safety of surgery. Milling beyond the bone tissue wall is a common abnormal milling state in ear surgery, as well as entanglement of the drill bit with the cotton swab, which will do harm to the patient's encephalic tissues. Various methods have been investigated by engineers and surgeons in an effort to avoid this type of abnormal milling state during surgery. This paper outlines a new method for identifying these two types of abnormal milling states. Five surgeons were invited to perform experiments on calvarial bones. The average recognition rate for otological drill milling through a bone tissue wall was 93%, with only 2% of normal millings being incorrectly identified as milling faults. The average recognition rate for entanglement of the drill bit with a cotton swab was 92%, with only 2% of normal millings being identified as milling faults. The method presented here can be adapted to the needs of the individual surgeon and reliably identify milling faults. PMID- 26097384 TI - Patchy distributions of myelin and vesicular glutamate transporter 2 align with cytochrome oxidase blobs and interblobs in the superficial layers of the primary visual cortex. AB - Blobs are a modular component of the primary visual cortex (area 17) of all primates, but not of other mammals closely related to primates. They are characterized as an even distribution of patches, puffs, or blobs of dense cytochrome oxidase (CO) expression in layer III of area 17, and are now known to differ from surrounding, nonblob cortex in thalamic, intrinsic, and extrastriate connections. Previous studies have also recognized a blob-like pattern of myelin dense patches in layer III of area 17 of primates, and more recently the vesicular glutamate transporter (VGLUT)-2 isoform of the VGLUT family has been found to selectively distribute to layer III patches in a similar blob-like pattern. Here, we sought to determine if the blob-like patterns all identify the same modular structures in area 17 of primates by staining alternate brain sections cut parallel to the surface of area 17 of a prosimian primate (Otolemur garnettii) for CO, myelin, and VGLUT2. By aligning the sections from the three preparations, we provide clear evidence that the three preparations all identify the same modular blob structures. The results provide a further understanding of the functional nature of the blobs by demonstrating that their higher level of CO activity is related to thalamic inputs from the lateral geniculate nucleus that use VGLUT2 as their main glutamate transporter, and via myelinated axons. PMID- 26097385 TI - Correlation of ultrasound estimated placental volume and umbilical cord blood volume in term pregnancy. AB - OBJECTIVE: To investigate the correlation between ultrasound measured placental volume and collected umbilical cord blood (UCB) volume in term pregnancy. MATERIAL AND METHODS: An observational cross-sectional study of term singleton pregnant women in the labor ward at Maha Chakri Sirindhorn Medical Center was conducted. Placental thickness, height, and width were measured using two dimensional (2D) ultrasound and calculated for placental volume using the volumetric mathematic model. After the delivery of the baby, UCB was collected and measured for its volume immediately. Then, birth weight, placental weight, and the actual placental volume were analyzed. The Pearson's correlation was used to determine the correlation between each two variables. RESULTS: A total of 35 pregnant women were eligible for the study. The mean and standard deviation of estimated placental volume and actual placental volume were 534+/-180 mL and 575+/-118 mL, respectively. The median UCB volume was 140 mL (range 98-220 mL). The UCB volume did not have a statistically significant correlation with the estimated placental volume (correlation coefficient 0.15; p=0.37). However, the UCB volume was significantly correlated with the actual placental volume (correlation coefficient 0.62; p<0.001) and birth weight (correlation coefficient 0.38; p=0.02). CONCLUSION: The estimated placental volume by 2D ultrasound was not significantly correlated with the UCB volume. Further studies to establish the correlation between the UCB volume and the estimated placental volume using other types of placental imaging may be needed. PMID- 26097386 TI - Labial adhesion and bacteriuria. AB - OBJECTIVE: The purpose of this study is to evaluate the clinical presentation, laboratory findings, and response to treatment in girls with labial adhesion younger than 23 months. MATERIAL AND METHODS: A retrospective chart review of all girls younger than 23 months with the diagnosis of labial adhesion was referred to Dr Sheikh children's clinic in Mashhad in northeast Iran between 1998 and 2013. RESULTS: Sixty-three patients were diagnosed with labial adhesion during the review period. Most patients were diagnosed by physicians during the physical examination or during the evaluation for their voiding problems. The most prevalent symptom among patients was dysuria and restlessness while voiding. Twenty-one (33.3%) patients had a history of urinary tract infection. 17 (26.9%) patients had sterile pyuria and 69.8% showed presence of bacteria in their urine samples. CONCLUSION: Physicians may frequently encounter pre-pubertal girls whose urinalysis may show sterile pyuria or presence of bacteria with colony counts <105 in the absence of urinary tract infection symptoms. In these cases, labial adhesion should always be suspected and genital examination should be performed. PMID- 26097387 TI - The Great Recession of 2007 in the United States and the male: female ratio at birth. AB - OBJECTIVE: Male live births slightly exceed female live births by approximately 3%. The ratio of male to total live births is conventionally represented as M/F. Many factors have been shown to affect M/F, mainly privation, toxins, and stress, all of which reduce M/F. Population stress may be engendered by natural phenomena such as earthquakes and man-made events such as short wars, terrorist attacks, and contracting economies. This study was conducted to ascertain whether the onset of the "Great Recession" (2007) was associated with changes in M/F in the United States (US). MATERIAL AND METHODS: Annual monthly live births by gender for January 2006 to December 2008 were obtained from United States Centres for Disease Control and Prevention. RESULTS: In 2007, there were 4316233 live births [M/F: 0.51157; 95% confidence intervals: 0.51110-0.51205). M/F rose between January and June, and then fell sharply between August and December. M/F was statistically significantly lower in the second half of 2007 (p=0.007). The dip in M/F from June to July was also significant (p=0.02). These findings were not replicated in the amalgamated data for 2006 and 2008. CONCLUSION: The United States housing boom of the mid-2000s was fueled by rising house prices and cheap mortgages given to credit-poor buyers. A halt in rising house prices resulted in defaults and foreclosures, triggering the worst financial crisis since the Great Depression. The associated stress appears to have decreased M/F in the US. PMID- 26097388 TI - The impact of intrahepatic cholestasis of pregnancy on fetal cardiac and peripheral circulation. AB - OBJECTIVE: The aim of this study was to evaluate changes in fetal cardiac and peripheral circulation in pregnancies complicated with intrahepatic cholestasis. MATERIAL AND METHODS: The Doppler examination results of 22 pregnant subjects complicated with intrahepatic cholestasis of pregnancy (ICP) and 44 healthy controls were compared. The parameters of fetal cardiac circulation were pulmonary artery and aortic (Ao) peak systolic velocity (PSV), pulmonary vein (Pv), peak velocity index (PVI) and pulsatility index (PI), mitral valve (MV) and tricuspid valve (TV), early diastole (E)- and atrial contraction (A)-wave peak velocity ratio (E/A), and isthmus aortic peak systolic velocity (IAo PSV). The parameters of fetal peripheral circulation were middle cerebral artery (MCA) and umbilical artery (UA) PI, resistance index (RI), systolic/diastolic (S/D) ratio. Fetal obstetric Doppler monitoring was conducted weekly before 36 weeks and biweekly after that, and the results were compared with the normal reference values for gestational age. RESULTS: The Doppler parameters of fetal cardiac and peripheral circulation did not significantly differ between the two groups. S/D ratio readings in the ICP group were significantly above 2 SD before 35 weeks of gestation. Women with ICP had increased risks of preterm delivery, neonatal unit admission, and meconium-stained amniotic fluid compared with those in the controls. CONCLUSION: Fetuses of pregnant women with ICP showed no differences in the evaluation of cardiac and peripheral Doppler measurements compared with fetuses of healthy mothers. The Doppler investigation of the umbilical artery may be useful in monitoring of pregnancies complicated by early onset intrahepatic cholestasis. PMID- 26097389 TI - Comparison of effects of nifedipine and ritodrine on maternal and fetal blood flow patterns in preterm labor. AB - OBJECTIVE: The aim of this study was to investigate and compare the effects of nifedipine and ritodrine treatment on fetomaternal blood flow parameters in women with preterm labor. MATERIAL AND METHODS: Sixty women with gestational age between 24 and 36 weeks admitted to the obstetrics clinic for preterm labor were enrolled in this study. Patients were randomly assigned to receive either nifedipine (n=30) or ritodrine (n=30) treatment. Demographic features, clinic and laboratory parameters, fetal and maternal side effects, and Doppler ultrasound indices of the umbilical artery (UA), uterine arteries (UtA), and middle cerebral artery (MCA) before, 2 hours after, and 48 hours after the initiation of tocolytic treatments were compared between the two groups. RESULTS: In both the groups, early- and late-onset changes in the pulsatility index (PI) and other Doppler indices for UA, UtA, and MCA were similar. In addition, time elapsed till delivery, fetal mortality, and maternal morbidity in both the groups were not statistically significant (p>0.05). However, maternal side effects such as tachycardia was more frequent (p<0.05) in the ritodrine group. Besides, in the ritodrine group, anxiety was only minimally observed. CONCLUSION: Nifedipine and ritodrine used as tocolytic agents did not significantly alter early- and late onset changes in Doppler ultrasonography parameters in fetal and fetomaternal circulation. PMID- 26097390 TI - Hyperprolactinemia has no effect on plasma ghrelin levels in patients with prolactinoma. AB - OBJECTIVE: Accumulating evidence suggests that prolactin is a modulator of body weight and composition and that it regulates some transporters in adipose tissue. It was demonstrated that hyperprolactinemia is associated with weight gain and obesity. Ghrelin is a novel hormone secreted from many organs including the pituitary gland. Ghrelin acts by regulating energy homeostasis and stimulating appetite. The aim of this study is to investigate whether ghrelin has a role in the case of weight gain in patients with prolactinoma. MATERIAL AND METHODS: Forty-four patients with prolactinoma, both newly diagnosed and undergoing cabergoline treatment, were included in this study. Age- and sex-matched healthy subjects were included in the control group. Serum fasting glucose, insulin, lipid profile, and ghrelin levels were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) was also calculated. Body mass index (BMI) and total fat ratio (%) of all the participants were assessed by bioelectrical impedance analysis using TBF-310GSTM (Tanita Corporation, Tokyo, Japan). RESULTS: Patients with prolactinoma demonstrated significantly higher serum levels of fasting insulin, triglyceride, and waist and hip circumference measurement. No significant difference was found between the fasting glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and HOMA-IR levels. BMI was significantly higher in the patients with prolactinoma than that in the control group (p<0.05). Additionally, the total body fat percentage was higher in the patients with prolactinoma than that in the control group; however, the difference was not significant (p>0.05). Furthermore, there was no significant difference in terms of the ghrelin levels between these groups. There was a correlation with serum ghrelin and growth hormone levels (p<0.02, rho=0.489). However, no significant correlation was obtained between serum prolactin or ghrelin levels and body fat percentage. CONCLUSION: According to the results of our study, ghrelin has no effect on weight gain in patients with prolactinoma. Further studies are needed to evaluate whether ghrelin affects the prevalence of obesity in patients with prolactinoma. PMID- 26097391 TI - Mislocated extrauterine intrauterine devices: Diagnosis and surgical management. AB - OBJECTIVE: Presentation of the diagnostic and surgical treatment methods of our extrauterine intrauterine device (IUD) cases. MATERIAL AND METHODS: We retrospectively evaluated the data of 21 extrauterine IUD cases at our clinic between 2008 and 2010. The symptoms, diagnostic methods, and surgical treatments were evaluated. RESULTS: A total of 14 copper and seven levonorgestrel (LNG) IUDs were used. IUD had been inserted during lactation in 71.4% of the patients. The reasons for presentation of patients were unintended pregnancy in 19.05%, pelvic pain in 19.05%, and pelvic pain with vaginal bleeding in 23.8%. IUD in two patients were located the retroperitoneal area. IUD string had not been visible during routine follow-up in 38.1% of the patients. Laparoscopy was performed in 14 patients and laparotomy was performed for dense adhesions in seven patients. CONCLUSION: Extrauterine IUDs can present with various clinical symptoms. Ultrasonography and X-Ray are sufficient for the diagnosis. Surgical removal is needed to prevent possible complications, and the preferred surgical technique in appropriate patients is laparoscopy. PMID- 26097392 TI - Addition of gonadotropin releasing hormone agonist for luteal phase support in in vitro fertilization: an analysis of 2739 cycles. AB - OBJECTIVE: Luteal phase is defective in in vitro fertilization (IVF) cycles, and many regimens were tried for the very best luteal phase support (LPS). Gonadotropin releasing hormone (GnRH) agonist use, which was administered as an adjunct to the luteal phase support in IVF cycles, was suggested to improve pregnancy outcome measures in certain randomized studies. We analyzed the effects of addition of GnRH agonist to standard progesterone luteal support on pregnancy outcome measures, particularly the live birth rates. MATERIAL AND METHODS: This is a retrospective cohort study, including 2739 IVF cycles. Long GnRH agonist and antagonist stimulation IVF cycles with cleavage-stage embryo transfer were included. Cycles were divided into two groups: Group A included cycles with single-dose GnRH agonist plus progesterone LPS and Group B included progesterone only LPS. Live birth rates were the primary outcome measures of the analysis. Miscarriage rates and multiple pregnancy rates were the secondary outcome measures. RESULTS: Live birth rates were not statistically different in GnRH agonist plus progesterone (Group A) and progesterone only (Group B) groups in both the long agonist and antagonist stimulation arms (40.8%/41.2% and 32.8%/34.4%, p<0.05 respectively). Moreover, pregnancy rates, implantation rates, and miscarriage rates were found to be similar between groups. Multiple pregnancy rates in antagonist cycles were significantly higher in Group A than those in Group B (12.0% and 6.9%, respectively). CONCLUSION: A beneficial effect of a single dose of GnRH agonist administration as a luteal phase supporting agent is yet to be determined because of the wide heterogeneity of data present in literature. Well-designed randomized clinical studies are required to clarify any effect of luteal GnRH agonist addition on pregnancy outcome measures with different doses, timing, and administration routes of GnRH agonists. PMID- 26097393 TI - Bilateral sacrospinous fixation without hysterectomy: 18-month follow-up. AB - OBJECTIVE: The aim of this study was to evaluate the results of bilateral sacrospinous fixation (SSF), which was performed with surgical mesh interposition and bilateral vaginal repair. MATERIAL AND METHODS: Twenty-two patients underwent SSF between 2010 and 2012, and the results were evaluated retrospectively. The results at preoperative and postoperative 6(th), 12(th), and 18(th) months of the pelvic organ prolapse quantification system (POP-Q) and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 (PISQ-12) were compared using Friedman and Wilcoxon Signed Ranks tests. Values of p<0.05 and <0.01 were considered statistically significant. RESULTS: According to the POP-Q, significant healing was observed on all vaginal vault points (p=0.001), and no prolapse was observed until the 18-month follow-up stage. There were also prominent patients who felt satisfactory with respect to their sexual life according to PISQ-12 (p=0.001). CONCLUSION: This technique appears to provide an adequate clinical resolution, and it may be the primary surgical option for women with pelvic organ prolapse. PMID- 26097394 TI - PARP inhibitors and more. AB - Polyadenosine diphosphate (ADP) ribose polymerase (PARP) lends a panoramic view to the inner mystery of protection of integrity of deoxyribonucleic acid (DNA) in a cell genome. They are a balancing part of an even more dynamic equilibrium of normalcy against daily assaults. PARP finds its companion candidates in other tumor suppressors, with the most prominent and glaring one being breast cancer (BRCA) 1 and 2. The strength of both is split by PARP inhibitors, inculcating the synthetic lethality of tumor cell, which is now in the market for ovarian cancer treatment. There are many reasons for the resistance of such inhibitors, which are now becoming clinically important. These are seen along with other damage repair approaches. PMID- 26097396 TI - Prenatal diagnosis and management of a fetal neck mass. AB - We report the case of a benign mesenchymal spindle-cell tumor located on fetal neck, diagnosed during prenatal ultrasound and magnetic resonance investigation. A 30-year-old woman (gravida 2, para 1) was referred to our perinatology unit for evaluation of a fetal neck mass that had been identified on ultrasonography at 29 weeks gestation. A right lateral neck mass was observed (size: 42*40 mm) that extended from the preauricular region to right clavicula. Fetal MRI revealed a solid heterogeneous mass arising from the right lateral neck and there was no invasion around tissue and no extension of the mass into the chest. At 37 weeks after birth, we observed that the mass was subcutaneous and there was no invasion to the surrounding tissue. The trachea was not compressed and there was no extension of the mass into the chest. Then, the neck mass was completely resected after birth without any complications. Histopathological examination of tumor was consistent with mesenchymal spindle-cell tumor. Immunohistochemical staining with CD34 and actin was positive; however, caldesmone, epithelial membrane antigen (EMA), and S-100 was negative. Fetal MRI performed during the pregnancy for investigation of fetal neck masses detected on ultrasound gives compatible results observed in the neonate after birth and maintains adequate findings for follow-up and planning of treatment. PMID- 26097395 TI - Impact of obesity on infertility in women. AB - The prevalence of obesity and overweight are increasing and have become an epidemic worldwide. Obesity has detrimental influences on all systems, including reproductive health. The prevalence of obesity in infertile women is high, and it is well known that there is an association between obesity and infertility. The relationship between obesity and reproductive functions is still being explored. Overweight women have a higher incidence of menstrual dysfunction and anovulation. Overweight and obese women are at a high risk for reproductive health. The risk of subfecundity and infertility, conception rates, miscarriage rates, and pregnancy complications are increased in these women. They have poor reproductive outcomes in natural as well as assisted conception. These poor reproductive outcomes include assisted reproduction such as ovulation induction, in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), and ovum donation cycles. Weight loss has beneficial effects on the reproductive outcomes in these patients. PMID- 26097397 TI - What is your diagnosis? PMID- 26097398 TI - Drug use and/or exposure in pregnancy: Presence of risk versus quantity of risk. PMID- 26097399 TI - Prior vaginal delivery is a predictive factor affecting success in trial of labor after cesarean section. PMID- 26097400 TI - A clinician's quick guide of evidence-based approaches: Childhood anxiety disorders. PMID- 26097401 TI - Risky Bodies in the Plasma Bioeconomy: A Feminist Analysis. AB - In 2003 the UK National Blood Service introduced a policy of 'male donor preference' which involved women's plasma being discarded following blood collection. The policy was based on the view that data relating to the incidence of Transfusion-Related Acute Lung Injury (TRALI) was linked to transfusion with women's plasma. While appearing to treat female donors as equal to male donors, exclusion criteria operate after donation at the stage of processing blood, thus perpetuating myths of universality even though only certain 'extractions' from women are retained for use in transfusion. Many women in the UK receive a plasma derived product called Anti-D immunoglobulin which is manufactured from pooled male plasma. This article examines ways in which gender has significance for understanding blood relations, and how the blood economy is gendered. In our study of relations between blood donors and recipients, we explore how gendered bodies are produced through the discursive and material practices within blood services. We examine both how donation policies and the manufacturing and use of blood products produces gendered blood relations. PMID- 26097402 TI - One Bioregion/One Health: An Integrative Narrative for Transboundary Planning along the US-Mexico Border. AB - Global megatrends-including climate change, food and water insecurity, economic crisis, large-scale disasters and widespread increases in preventable diseases are motivating a bioregionalisation of planning in city-regions around the world. Bioregionalisation is an emergent process. It is visible where societies have begun grappling with complex socio-ecological problems by establishing place based (territorial) approaches to securing health and well-being. This article examines a bioregional effort to merge place-based health planning and ecological restoration along the US-Mexico border. The theoretical construct underpinning this effort is called One Bioregion/One Health (OBROH). OBROH frames health as a transborder phenomenon that involves human-animal-environment interactions. The OBROH approach aims to improve transborder knowledge networking, ecosystem resilience, community participation in science-society relations, leadership development and cross-disciplinary training. It is a theoretically informed narrative to guide action. OBROH is part of a paradigm shift evident worldwide; it is redefining human-ecological relationships in the quest for healthy place making. The article concludes on a forward-looking note about the promise of environmental epidemiology, telecoupling, ecological restoration, the engaged university and bioregional justice as concepts pertinent to reinventing place based planning. PMID- 26097403 TI - A thermodynamic study of the cyclodextrin-UC781 inclusion complex using a HPLC method. AB - UC781, a very potent HIV-1 non-nucleoside reverse transcriptase inhibitor with extreme hydrophobicity and poor water solubility, is under development as a topical vaginal microbicide product to prevent HIV transmission. In this study, the thermodynamic behavior of the interaction between UC781 with three cyclodextrins (CDs): beta-cyclodextrin (betaCD), hydroxypropyl-beta-cyclodextrin (HPbetaCD) and methyl-beta-cyclodextrin (MbetaCD), was investigated using a reversed-phase HPLC method. A mobile phase consisting of acetonitrile: H2O (30:70) solution containing various CD concentrations was used. The retention time at different temperatures was determined to evaluate the inclusion process. The influence of betaCDs on the solubility and hydrophobicity of UC781 was characterized by retention time values. The results showed that the inclusion capacity of cyclodextrins follows the order MbetaCD > betaCD > HPbetaCD. An enthalpy-entropy compensation effect was also observed. In addition, the results revealed that the change of DeltaH is greater than that of DeltaS. These results suggested that the complexation of UC781 with betaCDs is an enthalpy driven process. The modification on beta-cyclodextrin will influence the inclusion process. PMID- 26097405 TI - Large-Scale Synthesis of Crystalline 1,2,3,4,6,7-Hexa-O-acetyl-l-glycero-alpha-d manno-heptopyranose. AB - The higher-carbon sugar l-glycero-d-manno-heptose is a major constituent of the inner core region of the lipopolysaccharide (LPS) of many Gram-negative bacteria. All preparative routes used to date require multiple steps, and scalability has been rarely addressed. Here a highly practical synthesis of crystalline 1,2,3,4,6,7-hexa-O-acetyl-l-glycero-alpha-d-manno-heptopyranose by a simple four step sequence starting from l-lyxose is disclosed. Only two recrystallisations are required and the process was demonstrated on a >100 mmol scale, yielding 41 g of the target compound. PMID- 26097404 TI - Toward the correction of effective electrostatic forces in explicit-solvent molecular dynamics simulations: restraints on solvent-generated electrostatic potential and solvent polarization. AB - Despite considerable advances in computing power, atomistic simulations under nonperiodic boundary conditions, with Coulombic electrostatic interactions and in systems large enough to reduce finite-size associated errors in thermodynamic quantities to within the thermal energy, are still not affordable. As a result, periodic boundary conditions, systems of microscopic size and effective electrostatic interaction functions are frequently resorted to. Ensuing artifacts in thermodynamic quantities are nowadays routinely corrected a posteriori, but the underlying configurational sampling still descends from spurious forces. The present study addresses this problem through the introduction of on-the-fly corrections to the physical forces during an atomistic molecular dynamics simulation. Two different approaches are suggested, where the force corrections are derived from special potential energy terms. In the first approach, the solvent-generated electrostatic potential sampled at a given atom site is restrained to a target value involving corrections for electrostatic artifacts. In the second approach, the long-range regime of the solvent polarization around a given atom site is restrained to the Born polarization, i.e., the solvent polarization corresponding to the ideal situation of a macroscopic system under nonperiodic boundary conditions and governed by Coulombic electrostatic interactions. The restraints are applied to the explicit-water simulation of a hydrated sodium ion, and the effect of the restraints on the structural and energetic properties of the solvent is illustrated. Furthermore, by means of the calculation of the charging free energy of a hydrated sodium ion, it is shown how the electrostatic potential restraint translates into the on-the-fly consideration of the corresponding free-energy correction terms. It is discussed how the restraints can be generalized to situations involving several solute particles. Although the present study considers a very simple system only, it is an important step toward the on-the-fly elimination of finite-size and approximate-electrostatic artifacts during atomistic molecular dynamics simulations. PMID- 26097406 TI - Generation and Trapping of Ketenes in Flow. AB - Ketenes were generated by the thermolysis of alkoxyalkynes under flow conditions, and then trapped with amines and alcohols to cleanly give amides and esters. For a 10 min reaction time, temperatures of 180, 160, and 140 degrees C were required for >95 % conversion of EtO, iPrO, and tBuO alkoxyalkynes, respectively. Variation of the temperature and flow rate with inline monitoring of the output by IR spectroscopy allowed the kinetic parameters for the conversion of 1-ethoxy 1-octyne to be easily estimated (Ea = 105.4 kJ/mol). Trapping of the in-situ generated ketenes by alcohols to give esters required the addition of a tertiary amine catalyst to prevent competitive [2+2] addition of the ketene to the alkoxyalkyne precursor. PMID- 26097408 TI - Interference effects in BSM processes with a generalised narrow-width approximation. AB - A generalisation of the narrow-width approximation (NWA) is formulated which allows for a consistent treatment of interference effects between nearly mass degenerate particles in the factorisation of a more complicated process into production and decay parts. It is demonstrated that interference effects of this kind arising in BSM models can be very large, leading to drastic modifications of predictions based on the standard NWA. The application of the generalised NWA is demonstrated both at tree level and at one-loop order for an example process where the neutral Higgs bosons h and H of the MSSM are produced in the decay of a heavy neutralino and subsequently decay into a fermion pair. The generalised NWA, based on on-shell matrix elements or their approximations leading to simple weight factors, is shown to produce UV- and IR-finite results which are numerically close to the result of the full process at tree level and at one-loop order, where an agreement of better than [Formula: see text] is found for the considered process. The most accurate prediction for this process based on the generalised NWA, taking into account also corrections that are formally of higher orders, is briefly discussed. PMID- 26097410 TI - Rare exclusive hadronic W decays in a [Formula: see text] environment. AB - The large cross section for [Formula: see text] production at the large hadron collider (LHC) and at any future hadron collider provides a high-statistics and relatively clean environment for a study of W boson properties: after tagging on a leptonic decay of one of the Ws and the two b jets, an additional W still remains in the event. We study the prospect of making the first exclusive hadronic decay of a fundamental boson of the standard model, using the decay modes [Formula: see text] and [Formula: see text], and other related decays. By using strong isolation criteria, which we impose by searching for jets with a single particle constituent, we show that the three-particle hadronic W decays have potential to be measured at the LHC. The possibility of measuring an involved spectrum of decay products could considerably expand our knowledge of how the W decays, and experimental techniques acquired in making these measurements would be useful for application to future measurements of exclusive hadronic Higgs boson decays. PMID- 26097409 TI - Hadronic Higgs production through NLO [Formula: see text] PS in the SM, the 2HDM and the MSSM. AB - The next-to-leading order (NLO) cross section of the gluon fusion process is matched to parton showers in the MC@NLO approach. We work in the framework of MadGraph5_aMC@NLO and document the inclusion of the full quark-mass dependence in the Standard Model (SM) as well as the state-of-the-art squark and gluino effects within the Minimal Supersymmetric SM embodied in the program SusHi. The combination of the two programs is realized by a script which is publicly available and whose usage is detailed. We discuss the input cards and the relevant parameter switches. One of our focuses is on the shower scale which is specifically important for gluon-induced Higgs production, particularly in models with enhanced Higgs-bottom Yukawa coupling. PMID- 26097412 TI - The residential segregation of detailed Hispanic and Asian groups in the United States: 1980-2010. AB - BACKGROUND: Racial and ethnic diversity continues to grow in communities across the United States, raising questions about the extent to which different ethnic groups will become residentially integrated. OBJECTIVE: While a number of studies have examined the residential patterns of pan-ethnic groups, our goal is to examine the segregation of several Asian and Hispanic ethnic groups - Cubans, Dominicans, Mexicans, Puerto Ricans, Salvadorans, Asian Indians, Chinese, Filipinos, Japanese, Koreans, and Vietnamese. We gauge the segregation of each group from several alternative reference groups using two measures over the 1980 to 2010 period. RESULTS: We find that the dissimilarity of Hispanics and Asians from other groups generally held steady or declined, though, because most Hispanic and Asian groups are growing, interaction with Whites also often declined. Our analyses also indicate that pan-ethnic segregation indexes do not always capture the experience of specific groups. Among Hispanics, Mexicans are typically less residentially segregated (as measured using the dissimilarity index) from Whites, Blacks, Asians, and other Hispanics than are other Hispanic origin groups. Among Asian ethnic groups, Japanese and Filipinos tend to have lower levels of dissimilarity from Whites, Blacks, and Hispanics than other Asian groups. Examining different dimensions of segregation also indicates that dissimilarity scores alone often do not capture to what extent various ethnic groups are actually sharing neighborhoods with each other. Finally, color lines vary across groups in some important ways, even as the dominant trend has been toward reduced racial and ethnic residential segregation over time. CONCLUSIONS: The overarching trend is that ethnic groups are becoming more residentially integrated, suggestive of assimilation, though there is significant variation across ethnic groups. PMID- 26097415 TI - Clinical Trials and Molecular Radiotherapy. PMID- 26097418 TI - Management of Radioactive Spills in Nuclear Medicine; Teaching and Assessing with Objectively Structured Assessment of Technical Skills. AB - Routine work in nuclear medicine requires the careful elution of radioactivity and its subsequent, storage and handling. Though all effort is maintained to prevent any "spill" of this radioactivity, accidents are bound to happen. The response to this spill is a methodically worked out a plan that is written and adopted as a "standard operating procedure." This protocol is taught to all involved in the area of working as a mock drill/apprenticeship model. No formal evaluation of learning is in place except for the mock drills. The objectively structured assessment of technical skills (OSATS) is a variation on the Objective Structured Clinical Examination, which is a form of workplace based assessment. The OSATS is cited in the Accreditation Council of Graduate Medical Education evaluation toolbox on the website as the most desirable evaluation tool for the patient care topics. It is the objective of this paper is to introduce the "OSATS" for teaching, and assessment of the learning, of the protocol for the management of radioactive spill. As a review of the literature on the subject failed to reveal any such teaching protocol/material/document for this important technical skill, we hope that it may act as a landmark for the development of teaching and assessment of other technical skills also. PMID- 26097414 TI - Describing the factors that influence the process of making a shared-agenda in Japanese family physician consultations: a qualitative study. AB - BACKGROUND: Patients cannot always share all necessary relevant information with doctors during medical consultations. Regardless, in order to ensure the best quality consultation and care, it is imperative that a doctor clearly understands each patient's agenda. The purpose of this study was to analyze the process of developing a shared-agenda during family physician consultations in Japan. METHODS: We interviewed 15 first time patients visiting the outpatient clinic of the Department of Family Medicine in the hospital chosen for the investigation, and the 8 family physicians who examined them. In total we observed 16 consultations. We analyzed both patients' and doctors' narratives using a modified grounded theory approach. RESULTS: For patients, we found four main factors that influenced the process of making a shared-agenda: past medical experiences, undisclosed but relevant information, relationship with the family physician, and the patient's own explanatory model. In addition, we found five factors that influenced the shared agenda making process for family physicians: understanding the patient's explanatory model, constructing the patient-doctor relationship, physical examination centered around the patient's explanatory model, discussion-styled explanation, and self-reflection on action. CONCLUSIONS: The findings suggest that patient satisfaction would be increased if family physicians are proactive in considering these factors with respect to both the patient's agenda, and their own. PMID- 26097413 TI - Flexibility is everything: prey capture throughout the seasonal habitat switches in the smooth newt Lissotriton vulgaris. AB - Transitions between aquatic and terrestrial habitats are significant steps in vertebrate evolution. Due to the different biophysical demands on the whole organism in water and air, such transitions require major changes of many physiological functions, including feeding. Accordingly, the capability to modulate the pre-programmed chain of prey-capture movements might be essential to maintain performance in a new environment. Newts are of special interest in this regard as they show a multiphasic lifestyle where adults change seasonally between an aquatic and a terrestrial stage. For instance, the Alpine newt is capable of using tongue prehension to feed on land only when in the terrestrial stage, but still manages to suction feed if immersed whilst in terrestrial stage. During the aquatic stage, terrestrial feeding always involved grasping prey by the jaws. Here, we show that this seasonal shift in feeding behavior is also present in a species with a shorter terrestrial stage, the smooth newt Lissotriton vulgaris. Behavioral variability increases when animals change from aquatic to terrestrial strikes in the aquatic stage, but prey-capture movements seem to be generally well-coordinated across the feeding modes. Only suction feeding in the terrestrial stage was seldom performed and appeared uncoordinated. Our results indicate that newts exhibit a high degree of seasonal flexibility of the prey-capture behavior. The similarity between movement patterns of suction feeding and terrestrial feeding suggests that only relatively subtle neuromotoric adjustments to the ancestral, suction-feeding motor program are required to successfully feed in the new environment. PMID- 26097417 TI - Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra-Articular Administration of (177)Lu-Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience. AB - The aim of this study is to assess the effectiveness of Radiosynovectomy (RSV) using (177)Lu-labeled hydroxyapatite ((177)Lu-HA) in the treatment of painful synovitis and recurrent joint effusion of knee joints in rheumatoid arthritis (RA). Ten patients, diagnosed with RA and suffering from chronic painful resistant synovitis of the knee joints were referred for RSV. The joints were treated with 333 +/- 46 MBq of (177)Lu-HA particles administered intra articularly. Monitoring of activity distribution was performed by static imaging of knee joint and whole-body gamma imaging. The patients were evaluated clinically before RSV and at 6 months after the treatment by considering the pain improvement from baseline values in terms of a 100-point visual analog scale (VAS), the improvement of knee flexibility and the pain remission during the night. RSV response was classified as poor (VAS < 25), fair (VAS >= 25-50), good (VAS >= 50-75) and excellent (VAS >= 75), with excellent and good results considered to be success, while fair and poor as failure and also by range of motion. Three phase bone scan (BS) was repeated after 6 months and changes in the second phase of BS3 were assessed visually, using a four-degree scale and in the third phase, semiquantitatively with J/B ratio to see the response. Biochemical analysis of C-reactive protein (CRP) and fibrinogen was repeated after 48 h, 4 and 24 weeks. In all 10 patients, no leakage of administered activity to nontarget organs was visible in the whole-body scan. Static scans of the joint at 1 month revealed complete retention of (177)Lu-HA in the joints. All patients showed decreased joint swelling and pains, resulting in increased joint motion after 6 months. The percentage of VAS improvement from baseline values was 79.5 +/- 20.0% 6 months after RS and found to be significantly related to patients' age (P = 0.01) and duration of the disease (P = 0.03). Knees with Steinbrocker's Grades 0 and I responded better than those with more advanced changes (Steinbrocker's Grades III and IV) in terms of VAS improvement (75% vs. 45.8%) (P < 0.001). The overall success rate (VAS >= 50) was 80%. Remission of pain during the night was achieved in 100%, and knee flexibility was improved in 80%. The changes in the blood pool phase before RSV were 3.2 +/- 0.7 and after the therapy 1.4 +/- 0.7 (P < 0.001). The J/B ratio was: Before RSV 2.4 +/- 0.3; after treatment 1.0 +/- 0.2 (P < 0.05). CRP concentration 4 and 24 weeks after the therapy was significantly lower than before treatment. The fibrinogen level was not different before and after RSV. RSV side-effects assessed for the whole follow-up period were minor and not significant. RSV with (177)Lu-HA was safe and effective in patients with knee joint chronic painful synovitis of rheumatoid origin. It exhibited significant therapeutic effect after 6 months follow-up period with no significant side-effects. The preliminary investigations reveal that (177)Lu-labeled HA particles hold considerable promise as a cost-effective agent for RSV. More elaborate and controlled clinical trials are necessary to evaluate the therapeutic efficacy and safety of the agent compared with the treatment with other radionuclides and glucocorticosteroids. PMID- 26097416 TI - Advances in SPECT for Optimizing the Liver Tumors Radioembolization Using Yttrium 90 Microspheres. AB - Radioembolization (RE) with Yttrium-90 ((90)Y) microspheres is an effective treatment for unresectable liver tumors. The activity of the microspheres to be administered should be calculated based on the type of microspheres. Technetium 99m macroaggregated albumin ((99m)Tc-MAA) single photon emission computed tomography/computed tomography (SPECT/CT) is a reliable assessment before RE to ensure the safe delivery of microspheres into the target. (90)Y bremsstrahlung SPECT imaging as a posttherapeutic assessment approach enables the reliable determination of absorbed dose, which is indispensable for the verification of treatment efficacy. This article intends to provide a review of the methods of optimizing (90)Y bremsstrahlung SPECT imaging to improve the treatment efficacy of liver tumor RE using (90)Y microspheres. PMID- 26097419 TI - Studies on the Labeling of Ethylenediaminetetramethylene Phosphonic Acid, Methylene Diphosphonate, Sodium Pyrophosphate and Hydroxyapatite with Lutetium 177 for use in Nuclear Medicine. AB - For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various (177)Lu-labeled bone-seeking complexes such as (177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), (177)Lu-methylene diphosphonate (MDP) and (177)Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and (177)Lu Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). (177)Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for (177)Lu-MDP, (177)Lu-EDTMP and (177)Lu-PYP at 3.37 +/- 0.06 cm, 5.53 +/- 0.15 cm and 7.03 +/- 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with (177)Lu in injectable solution form. HA particulates could too be labeled with (177)Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and the later could be applied for the treatment of Rheumatoid arthritis of small joints. The study has also indicated the possibility of developing other numerous radiolanthanide analogs with the potentials of possible use in radiation therapy. PMID- 26097420 TI - Utility of (99m)Tc-Hynic-TOC in 131I Whole-Body Scan Negative Thyroid Cancer Patients with Elevated Serum Thyroglobulin Levels. AB - Several studies have reported on the expression of somatostatin receptors (SSTRs) in patients with differentiated thyroid cancer (DTC). The aim of this study was to evaluate the imaging abilities of a recently developed Technetium-99m labeled somatostatin analog, (99m)Tc-Hynic-TOC, in terms of precise localization of the disease. The study population consisted of 28 patients (16 men, 12 women; age range: 39-72 years) with histologically confirmed DTC, who presented with recurrent or persistent disease as indicated by elevated serum thyroglobulin (Tg) levels after initial treatment (serum Tg > 10 ng/ml off T4 suppression for 4-6 weeks). All patients were negative on the Iodine-131 posttherapy whole-body scans. Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was performed in all patients. SSTR scintigraphy was true positive in 23 cases (82.1%), true negative in two cases (7.1%) and false negative in three cases (10.7%) which resulted in a sensitivity of 88.46%, specificity of 100% and an accuracy of 89.2%. Sensitivity of (99m)Tc-Hynic-TOC scan was higher (93.7%) for patients with advanced stages, that is stages III and IV. (18)F-FDG showed a sensitivity of 93.7%, a specificity of 50% and an accuracy of 89.3%. (18)F-FDG PET was found to be more sensitive, with lower specificity due to false positive results in 2 patients. Analysis on a lesion basis demonstrated substantial agreement between the two imaging techniques with a Cohen's kappa of 0.66. Scintigraphy with (99m)Tc-Hynic-TOC might be a promising tool for treatment planning; it is easy to perform and showed sufficient accuracy for localization diagnostics in thyroid cancer patients with recurrent or metastatic disease. PMID- 26097421 TI - Metastatic Bone Pain Palliation using (177)Lu-Ethylenediaminetetramethylene Phosphonic Acid. AB - (177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using (177)Lu-EDTMP for MBP palliation. (177)Lu EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. (177)Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 +/- 1.78 h lasting for 38.4 +/- 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. (177)Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients with bone metastasis. PMID- 26097422 TI - A Comprehensive Software and Database Management System for Glomerular Filtration Rate Estimation by Radionuclide Plasma Sampling and Serum Creatinine Methods. AB - Glomerular filtration rate (GFR) estimation by plasma sampling method is considered as the gold standard. However, this method is not widely used because the complex technique and cumbersome calculations coupled with the lack of availability of user-friendly software. The routinely used Serum Creatinine method (SrCrM) of GFR estimation also requires the use of online calculators which cannot be used without internet access. We have developed user-friendly software "GFR estimation software" which gives the options to estimate GFR by plasma sampling method as well as SrCrM. We have used Microsoft Windows((r)) as operating system and Visual Basic 6.0 as the front end and Microsoft Access((r)) as database tool to develop this software. We have used Russell's formula for GFR calculation by plasma sampling method. GFR calculations using serum creatinine have been done using MIRD, Cockcroft-Gault method, Schwartz method, and Counahan Barratt methods. The developed software is performing mathematical calculations correctly and is user-friendly. This software also enables storage and easy retrieval of the raw data, patient's information and calculated GFR for further processing and comparison. This is user-friendly software to calculate the GFR by various plasma sampling method and blood parameter. This software is also a good system for storing the raw and processed data for future analysis. PMID- 26097423 TI - Value of Oblique View in Nodular Thyroid Disease; Revisiting Fundamentals. AB - Thyroid scintigraphy plays an important role in the anatomical and functional evaluation of thyroid nodules which carry the risk of malignancy. The presence of multiple nodules carries overall smaller risk of cancer than solitary nodule. Missing nodules, whether solitary or multiple, may mean delaying detection of possible cancer. Therefore, it is important to improve the delectability of thyroid scintigraphy using most optimal imaging techniques. For pinhole thyroid imaging, there is a recent trend to omit oblique projections by some laboratories. The objective of this study was to reevaluate the impact of oblique projections in the detection of thyroid nodules. A total of 92 cases with nodular thyroid disease on routine pinhole thyroid scintigraphy was reviewed retrospectively. Two nuclear medicine physicians recorded the number of nodules based on the anterior view only and another time with adding the oblique views. A total of 192 nodules was detected using the three views. Sixty nodules (31%) were only seen on the oblique views and were missed on the anterior projections. Oblique pinhole projections are mandatory for adequate thyroid scintigraphy since 31% of nodules are missed if only anterior projection was used for interpretation. Following proper techniques will avoid missing of detection of nodule that may harbor cancer. PMID- 26097424 TI - Primary Retroperitoneal Seminoma Staging and Surveillance by Means of Fluoro-2 Deoxyglucose-Positron Emission Tomography/Computed Tomography. AB - Primary retroperitoneal seminoma is a very rare entity. We present a case of 39 year-old male with primary retroperitoneal seminoma with staging and surveillance by means of F-18 fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). The case demonstrates that primary retroperitoneal seminoma can be easy to identify with FDG-PET/CT and potential follow-up on recurrence, or metastatic disease can be performed using this technique. PMID- 26097425 TI - Retroperitoneal Endometriosis: A Possible Cause of False Positive Finding at (18)F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography. AB - Endometriosis is a frequent and clinically relevant problem in young women. Laparoscopy is still the gold standard for the diagnosis of endometriosis, but frequently both morphologic and functional imaging techniques are involved in the diagnostic course before achieving a conclusive diagnosis. We present a case of a patient affected by infiltrating retroperitoneal endometriosis falsely interpreted as a malignant mass by contrast-enhanced magnetic resonance imaging and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 26097426 TI - A Unique Case of Diffuse Metastatic Neuroendocrine Cancer with Subcutaneous Nodules on (18)F-Fluorodeoxyglucose Positron Emission Tomography/Computer Assisted Tomography. AB - Neuroendocrine tumors (NETs) account for 8-10% of cases of carcinomas of unknown primary. Most of these cases are poorly differentiated with metastatic disease at the time of diagnosis. However, cutaneous metastatic presentation is rare. We present an interesting case of a 74-year-old woman presenting with cutaneous metastatic involvement from high grade poorly differentiated NET of unknown origin. She was referred to us with a diagnosis of lymphoma. (18)F fluorodeoxyglucose positron emission tomography/computer assisted tomography imaging at our institution offered a differential diagnosis, including neuroendocrine cancer. Repeat skin lesion biopsy demonstrated "non-Merkel cell" carcinoma, favoring metastatic high-grade neuroendocrine carcinoma. PMID- 26097427 TI - Hybrid Single-Photon Emission Computed Tomography/Computed Tomography Imaging Features of Tumoral Calcinosis in Technetium-99m Methylene Diphosphonate Bone Scintigraphy. AB - Tumoral calcinosis (TC) is an uncommon ectopic calcification syndrome. TC is a benign condition characterized by the presence of large calcific soft tissue deposits occurring predominantly in a periarticular location. It generally occurs as a complication of renal dialysis or trauma, and is rarely seen in familial and sporadic cases. Bone scintigraphy is a sensitive method for diagnosing TC. We report a case of year old female with. She underwent bone scintigraphy to see the sites of involvement, which showed intense foci of tracer activity in soft tissue in bilateral thigh and gluteal region. Hybrid single-photon emission computed tomography/computed tomography of the pelvis and thigh localized tracer uptake to the calcification in the gluteal and thigh region. PMID- 26097429 TI - Increasing Specificity of (99m)Tc-HDP Three-phase bone Scintigraphy and (99m)Tc Besilesomab Scan in Case of Osteomyelitis Complicated with Necrotizing Fasciitis. PMID- 26097428 TI - Giant Schmorl's Node may Cause High Uptake and Mimic a Bone Metastasis on (18)F Choline Positron Emission Tomography/Computed Tomography. AB - Bone metastasis in prostate cancer are detected by choline positron emission tomography/computed tomography (PET/CT) with high sensitivity and specificity. We report the case of a patient with previous prostatectomy for prostate cancer who underwent F-choline PET/CT for a recent increased of prostate-specific antigen value and showed focal vertebral uptake suggestive for skeletal metastasis; magnetic resonance imaging revealed unexpectedly a Schmorl's node (SN). False positives on choline PET-CT caused by SN has not be reported in the literature and the present case highlights that this possibility should be considered in case of choline vertebral increased uptake in the patient with prostate cancer. PMID- 26097430 TI - Profiles of importance, readiness and confidence in quitting tobacco use. AB - OBJECTIVE: This study examined whether rulers of importance, readiness and confidence (IRC) in quitting smoking could be used to identify subgroups of smokers, with the future goal of potentially tailoring interventions to specific readiness profiles. METHODS: Consecutive emergency department patients >=18 years old were considered for enrolment. Participants provided information on their tobacco use and motivation to quit smoking using 10-point IRC rulers. We used latent profile analysis on the IRC rulers to identify subgroups of smokers and examined associations between profile membership and participant's nicotine dependence and demographics. RESULTS: A total of 1549 patients were screened, yielding a sample of 609 tobacco users. According to statistical fit indices, a four-profile solution fits best: 32% displayed maximum importance and readiness with strong confidence, 43% of the sample displayed relatively average levels of all three variables, 17% displayed below average importance with least favourable readiness and confidence and 7% displayed least favourable importance and readiness but relatively high confidence. Profiles were then shown to differ on nicotine dependence and educational level. CONCLUSIONS: Four distinct profiles of IRC responses were observed. Identifying and describing these patterns has the potential to enhance future targeted intervention efforts and has implications for theory development. PMID- 26097431 TI - Optimising web site designs for people with learning disabilities. AB - Much relevant internet-mediated information is inaccessible to people with learning disabilities because of difficulties in navigating the web. This paper reports on the methods undertaken to determine how information can be optimally presented for this cohort. Qualitative work is outlined where attributes relating to site layout affecting usability were elicited. A study comparing web sites of different design layouts exhibiting these attributes is discussed, with the emphasis on methodology. Eight interfaces were compared using various combinations of menu position (vertical or horizontal), text size and the absence or presence of images to determine which attributes of a site have the greatest performance impact. Study participants were also asked for their preferences, via a 'smiley-face' rating scale and simple interviews. 'Acquiescence bias' was minimised by avoiding polar ('yes/no') interrogatives, achieved by asking participants to compare layouts (such as horizontal versus vertical menu), with reasons coaxed from those able to articulate them. Preferred designs were for large text and images. This was the reverse of those facilitating fastest retrieval times, a discrepancy due to preferences being judged on aesthetic considerations. Design recommendations that reconcile preference and performance findings are offered. These include using a horizontal menu, juxtaposing images and text, and reducing text from sentences to phrases, thus facilitating preferred large text without increasing task times. PMID- 26097432 TI - IEEN workshop report: Teaching and learning in interdisciplinary and empirical ethics. AB - Bioethics is an interdisciplinary field that accommodates a broad range of perspectives and disciplines. This inherent diversity sets a number of challenges for both teachers and students of bioethics, notably in respect to the appropriate aims and methods of bioethics education, standards and criteria for evaluating performance and disciplinary identity. The Interdisciplinary and Empirical Ethics Network (IEEN) was established, with funding from the Wellcome Trust, to facilitate critical and constructive discussion about the ongoing development of bioethics as an evolving field of interdisciplinary study. In November 2012 the IEEN organised a workshop at the University of Birmingham to discuss the issues relating to teaching and learning in interdisciplinary and empirical bioethics. This paper reports on that meeting. PMID- 26097433 TI - IEEN workshop report: Professionalism in interdisciplinary and empirical bioethics. AB - The Interdisciplinary and Empirical Ethics Network was established in 2012 with funding from the Wellcome Trust in order to facilitate critical and constructive discussion around the nature of the disciplinary diversity within bioethics and to consider the ongoing development of bioethics as an evolving field of interdisciplinary study. In April 2013, the Interdisciplinary and Empirical Ethics Network organized a workshop at the Centre for Public Policy Research, King's College London, which discussed the nature and possibility of professionalism within interdisciplinary and empirical bioethics. This paper provides a report of that workshop. PMID- 26097434 TI - Economic evaluation of a single-pill triple antihypertensive therapy with valsartan, amlodipine, and hydrochlorothiazide against its dual components. AB - The aim of this study was to compare the cost-utility of the first available single-pill triple combination antihypertensive therapy containing valsartan (V), amlodipine (A) and hydrochlorothiazide (H), with each of the same components dual combinations in patients with moderate to severe hypertension. A Markov model with eight health states was constructed. The short-term effect of antihypertensive treatment on blood pressure was extrapolated through the Hellenic SCORE and Framingham risk equations, estimating the long-term survival and quality-adjusted life-years (QALYs) saved. Costs and outcomes were evaluated over lifetime, divided into annual cycles and discounted at 3.0 % with 2013 as reference year. The analysis was conducted by the Greek third-party-payer perspective. The triple combination treatment cost was estimated at ?16,525 compared to ?15,480 for V/A, ?14,125 for V/H and ?11,690 for A/H. The QALYs saved with the triple combination were 12.76 vs. 12.64, 12.61 and 12.38 for double combinations respectively. The incremental cost-effectiveness ratio of the triple combination versus V/A and A/H was far lower than the Greek GDP per capita (?8,690/QALY and ?12,695/QALY, respectively) and really close for V/H (?16,192/QALY), suggesting V/A/H combination to be cost-effective. Extensive sensitivity analyses confirmed the robustness of the results. The probability that the triple combination is cost effective was more than 90 % at a willingness to-pay threshold of ?18,000/QALY. This is the first study to evaluate the cost utility of a single-pill triple combination. The single-pill V/A/H therapy is a cost-effective antihypertensive choice for the treatment of moderate to severe hypertension, compared to its dual components. PMID- 26097435 TI - Level of agreement between patient-reported EQ-5D responses and EQ-5D responses mapped from the SF-12 in an injury population. AB - BACKGROUND: Comparing health-related quality of life (HRQL) outcomes between studies is difficult due to the wide variety of instruments used. Comparing study outcomes and facilitating pooled data analyses requires valid "crosswalks" between HRQL instruments. Algorithms exist to map 12-item Short Form Health Survey (SF-12) responses to EQ-5D item responses and preference weights, but none have been validated in populations where disability is prevalent, such as injury. METHODS: Data were extracted from the Validating and Improving injury Burden Estimates Study (Injury-VIBES) for 10,166 adult, hospitalized trauma patients, with both the three-level EQ-5D (EQ-5D-3L) and SF-12 data responses at six and 12 months postinjury. Agreement between actual (patient-reported) and estimated (mapped from SF-12) EQ-5D-3L item responses and preference weights was assessed using Kappa, Prevalence-Adjusted Bias-Adjusted Kappa statistics and Bland-Altman plots. RESULTS: Moderate agreement was observed for usual activities, pain/discomfort, and anxiety/depression. Agreement was substantial for mobility and self-care items. The mean differences in preference weights were -0.024 and 0.012 at six and 12 months (p < 0.001), respectively. The Bland-Altman plot limits of agreement were large compared to the range of valid preference weight values (-0.56 to 1.00). Estimated EQ-5D-3L responses under-reported disability for all items except pain/discomfort. CONCLUSIONS: Caution should be taken when using EQ-5D-3L responses mapped from the SF-12 to describe patient outcomes or when undertaking economic evaluation, due to the underestimation of disability associated with mapped values. The findings from this study could be used to adjust expected EQ-5D-3L preference weights when estimated from SF-12 item responses when combining data from studies that use either instrument. PMID- 26097436 TI - Predicting visceral adipose tissue by MRI using DXA and anthropometry in adolescents and young adults. AB - OBJECTIVE: Accumulation of intra-abdominal (visceral) adipose tissue, independent of total adiposity, is associated with development of metabolic abnormalities such as insulin resistance and type-2 diabetes in children and adults. The objective of this study was to develop prediction equations for estimating visceral adiposity (VAT) measured by magnetic resonance imaging (MRI) using anthropometric variables and measures of abdominal fat mass from DXA in adolescents and young adults. METHODS: Cross-sectional data was collected from a multiethnic population of seventy males and females, aged 12-25 years, with BMI ranging from 14.5-38.1 kg/m2. Android (AFM; android region as defined by manufacturers instruction) and lumbar L1-L4 regional fat masses were assessed using DXA (GE Lunar Prodigy; GE Lunar Corp, Madison, WI, USA). Criterion measures of intra-abdominal visceral fat were obtained using single-slice MRI (General Electric Signa Model 5x 1.5T) and VAT area was analyzed at the level OF L4-L5. Image analysis was carried out using ZedView 3.1. RESULTS: DXA measures of AFM (r=0.76) and L1-L4 (r=0.71) were significantly (P<0.0001) correlated with MRI measured VAT. DXA AFM, together with gender and weight, explained 62% of the variance in VAT (SEE=10.06 cm2). DXA L1-L4 fat mass with gender explained 54% of the variance in VAT (SEE=11.08 cm2). Addition of the significant interaction, gender * DXA fat mass, improved prediction of VAT from AFM (Radj2=0.61, SEE=10.10cm2) and L1-L4 (Radj2=0.59, SEE=10.39cm2). CONCLUSION: These results demonstrate that VAT is accurately estimated from regional fat masses measured by DXA in adolescents and young adults. PMID- 26097437 TI - Exploring Intergenerational Discontinuity in Problem Behavior: Bad Parents with Good Children. AB - Using data from the Rochester Youth Development Study, a series of regression models are estimated on offspring problem behavior with a focus on the interaction between parental history of delinquency and the parent-child relationship. Good parenting practices significantly interact with the particular shape of parental propensity of offending over time, functioning as protective factors to protect against problematic behaviors among those who are most at risk. The moderation effects vary slightly by the age of our subjects. Accordingly, it is important to distinguish the effect of not only the level of parental delinquency at one point in time, but also the shape of the delinquency trajectory on outcomes for their children. Good parenting holds the hope of breaking the vicious cycle of intergenerational transmission of delinquency. PMID- 26097438 TI - Co-Immunoprecipitation of Membrane-Bound Receptors. AB - The study of cell-surface receptor dynamics is critical for understanding how cells sense and respond to changing environments. Therefore, elucidating the mechanisms by which signals are perceived and communicated into the cell is necessary to understand immunity, development, and stress. Challenges in testing interactions of membrane-bound proteins include their dynamic nature, their abundance, and the complex dual environment (lipid/soluble) in which they reside. Co-Immunoprecipitation (Co-IP) of tagged membrane proteins is a widely used approach to test protein-protein interaction in vivo. In this protocol we present a method to perform Co-IP using enriched membrane proteins in isolated microsomal fractions. The different variations of this protocol are highlighted, including recommendations and troubleshooting guides in order to optimize its application. This Co-IP protocol has been developed to test the interaction of receptor-like kinases, their interacting partners, and peptide ligands in stable Arabidopsis thaliana lines, but can be modified to test interactions in transiently expressed proteins in tobacco, and potentially in other plant models, or scaled for large scale protein-protein interactions at the membrane. PMID- 26097439 TI - A single word in a population of words. AB - Carey and Bartlett introduced a new method for studying lexical development, one of presenting the child with a word and a single context of use and asking what was learned from that one encounter. They also reported a then new finding: By using what they already knew about previously learned words, young children could narrow the range of possibilities for likely meanings in a single encounter. This papers honors that original contribution and the robust literature and set of phenomena it generated by considering how newly learned categories must fit into a population of already learned categories. This paper presents an overview of Packing Theory, a formal geometrical analysis of how local interactions in a large population of categories create a global structure of feature relevance such that near categories in the population of have similar generalization patterns. The implications of these ideas for learning from a single encounter, their relation to the evidence of artificial word learning studies, and new predictions are discussed. PMID- 26097440 TI - Sodium bicarbonate intake improves high-intensity intermittent exercise performance in trained young men. AB - BACKGROUND: Sodium bicarbonate intake has been shown to improve exercise tolerance, but the effects on high-intensity intermittent exercise are less clear. Thus, the aim of the present study was to determine the effect of sodium bicarbonate intake on Yo-Yo intermittent recovery test level 2 performance in trained young men. METHOD: Thirteen men aged 23 +/- 1 year (height: 180 +/- 2 cm, weight: 78 +/- 3 kg; VO2max: 61.3 +/- 3.3 mlO2 . kg(-1) . min(-1); means +/- SEM) performed the Yo-Yo intermittent recovery test level 2 (Yo-Yo IR2) on two separate occasions in randomized order with (SBC) and without (CON) prior intake of sodium bicarbonate (0.4 g . kg(-1) body weight). Heart rate and rating of perceived exertion (RPE) were measured during the test and venous blood samples were taken frequently. RESULTS: Yo-Yo IR2 performance was 14 % higher (P = 0.04) in SBC than in CON (735 +/- 61 vs 646 +/- 46 m, respectively). Blood pH and bicarbonate were similar between trials at baseline, but higher (P = 0.003) immediately prior to the Yo-Yo IR2 test in SBC than in CON (7.44 +/- 0.01 vs 7.32 +/- 0.01 and 33.7 +/- 3.2 vs 27.3 +/- 0.6 mmol . l(-1), respectively). Blood lactate was 0.9 +/- 0.1 and 0.8 +/- 0.1 mmol . l(-1) at baseline and increased to 11.3 +/- 1.4 and 9.4 +/- 0.8 mmol . l(-1) at exhaustion in SBC and CON, respectively, being higher (P = 0.03) in SBC. Additionally, peak blood lactate was higher (P = 0.02) in SBC than in CON (11.7 +/- 1.2 vs 10.2 +/- 0.7 mmol . l( 1)). Blood glucose, plasma K(+) and Na(+) were not different between trials. Peak heart rate reached at exhaustion was 197 +/- 3 and 195 +/- 3 bpm in SBC and CON, respectively, with no difference between conditions. RPE was 7% lower (P = 0.003) in SBC than in CON after 440 m, but similar at exhaustion (19.3 +/- 0.2 and 19.5 +/- 0.2). CONCLUSION: In conclusion, high-intensity intermittent exercise performance is improved by prior intake of sodium bicarbonate in trained young men, with concomitant elevations in blood alkalosis and peak blood lactate levels, as well as lowered rating of perceived exertion. PMID- 26097442 TI - Approaching Ultimate Intrinsic SNR in a Uniform Spherical Sample with Finite Arrays of Loop Coils. AB - We investigated to what degree and at what rate the ultimate intrinsic (UI) signal-to-noise ratio (SNR) may be approached using finite radiofrequency detector arrays. We used full-wave electromagnetic field simulations based on dyadic Green's functions to compare the SNR of arrays of loops surrounding a uniform sphere with the ultimate intrinsic SNR (UISNR), for increasing numbers of elements over a range of magnetic field strengths, voxel positions, sphere sizes, and acceleration factors. We evaluated the effect of coil conductor losses and the performance of a variety of distinct geometrical arrangements such as "helmet" and "open-pole" configurations in multiple imaging planes. Our results indicate that UISNR at the center is rapidly approached with encircling arrays and performance is substantially lower near the surface, where a quadrature detection configuration tailored to voxel position is optimal. Coil noise is negligible at high field, where sample noise dominates. Central SNR for practical array configurations such as the helmet is similar to that of close-packed arrangements. The observed trends can provide physical insights to improve coil design. PMID- 26097441 TI - Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. AB - BACKGROUND: Nitric oxide (NO) is endogenously synthesized from L-arginine and L citrulline. Due to its effects on nitric oxide synthase (NOS), reduced glutathione (GSH) may protect against the oxidative reduction of NO. The present study determined the effectiveness of L-citrulline and/or GSH on markers indicative of NO synthesis in in vivo conditions with rodents and humans and also in an in vitro condition. METHODS: In phase one, human umbilical vein endothelial cells (HUVECs) were treated with either 0.3 mM L-citrulline, 1 mM GSH (Setria(r)) or a combination of each at 0.3 mM. In phase two, Sprague-Dawley rats (8 weeks old) were randomly assigned to 3 groups and received either purified water, L citrulline (500 mg/kg/day), or a combination of L-citrulline (500 mg/kg/day) and GSH (50 mg/kg/day) by oral gavage for 3 days. Blood samples were collected and plasma NOx (nitrite + nitrate) assessed. In phase three, resistance-trained males were randomly assigned to orally ingest either cellulose placebo (2.52 g/day), L citrulline (2 g/day), GSH (1 g/day), or L-citrulline (2 g/day) + GSH (200 mg/day) for 7 days, and then perform a resistance exercise session involving 3 sets of 10 RM involving the elbow flexors. Venous blood was obtained and used to assess plasma cGMP, nitrite, and NOx. RESULTS: In phase one, nitrite levels in cells treated with L-citrulline and GSH were significantly greater than control (p < 0.05). In phase two, plasma NOx with L-citrulline + GSH was significantly greater than control and L-citrulline (p < 0.05). In phase three, plasma cGMP was increased, but not significantly (p > 0.05). However, nitrite and NOx for L citrulline + GSH were significantly greater at 30 min post-exercise when compared to placebo (p < 0.05). CONCLUSIONS: Combining L-citrulline with GSH augments increases in nitrite and NOx levels during in vitro and in vivo conditions. PMID- 26097443 TI - Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non-high-risk organ-type LCH (LCH-RO (-)); this difference was significant. LCH-RO (-) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (-), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions. METHODS: Plasma sample from 12 patients with LCH-RO (-) (5 MS-LCH and 7 SS-LCH) and 5 non-LCH patients were analyzed by peptidomics. Mass spectrometry (MS) spectra were acquired and peptides exhibiting quantitative differences between MS-LCH and SS-LCH patients were targeted. RESULTS: One new candidate biomarker, m/z 3145 was selected and identified after obtaining a MS/MS fragmentation pattern using liquid chromatography-MS/MS. This peak was identified as a proteolytic fragment derived from inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]). CONCLUSIONS: Peptidomics of LCH have revealed that the level of acute-phase ITIH4 distinguishes MS-LCH-RO (-) from SS-LCH-RO (-). Acute phase proteins serve non-specific, physiological immune functions within the innate immune system. LCH may be a reactive disorder with both underlying neoplastic potential of antigen presenting cells harboring BRAF mutations and hyper-immunity of other inflammatory cells against MCPyV infection. Among LCH-RO (-), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection. PMID- 26097444 TI - Magnetically Decorated Multi-Walled Carbon Nanotubes as Dual MRI and SPECT Contrast Agents. AB - Carbon nanotubes (CNTs) have been proposed as one of the most promising nanomaterials to be used in biomedicine for their applications in drug/gene delivery as well as biomedical imaging. The present study developed radio-labeled iron oxide decorated multi-walled CNTs (MWNT) as dual magnetic resonance (MR) and single photon emission computed tomography (SPECT) imaging agents. Hybrids containing different amounts of iron oxide were synthesized by in situ generation. Physicochemical characterisations revealed the presence of superparamagnetic iron oxide nanoparticles (SPION) granted the magnetic properties of the hybrids. Further comprehensive examinations including high resolution transmission electron microscopy (HRTEM), fast Fourier transform simulations (FFT), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) assured the conformation of prepared SPION as gamma-Fe2O3. High r2 relaxivities were obtained in both phantom and in vivo MRI compared to the clinically approved SPION Endorem(r). The hybrids were successfully radio-labeled with technetium-99m through a functionalized bisphosphonate and enabled SPECT/CT imaging and gamma-scintigraphy to quantitatively analyze the biodistribution in mice. No abnormality was found by histological examination and the presence of SPION and MWNT were identified by Perls stain and Neutral Red stain, respectively. TEM images of liver and spleen tissues showed the co-localization of SPION and MWNT within the same intracellular vesicles, indicating the in vivo stability of the hybrids after intravenous injection. The results demonstrated the capability of the present SPION-MWNT hybrids as dual MRI and SPECT contrast agents for in vivo use. PMID- 26097445 TI - Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted SiRNA Delivery to HER2+ Breast Cancer. AB - In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2-) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation. PMID- 26097446 TI - Role of serotonin in fish reproduction. AB - The neuroendocrine mechanism regulates reproduction through the hypothalamo pituitary-gonadal (HPG) axis which is evolutionarily conserved in vertebrates. The HPG axis is regulated by a variety of internal as well as external factors. Serotonin, a monoamine neurotransmitter, is involved in a wide range of reproductive functions. In mammals, serotonin regulates sexual behaviors, gonadotropin release and gonadotropin-release hormone (GnRH) secretion. However, the serotonin system in teleost may also play unique role in the control of reproduction as the mechanism of reproductive control in teleosts is not always the same as in the mammalian models. In fish, the serotonin system is also regulated by natural environmental factors as well as chemical substances. In particular, selective serotonin reuptake inhibitors (SSRIs) are commonly detected as pharmaceutical contaminants in the natural environment. Those factors may influence fish reproductive functions via the serotonin system. This review summarizes the functional significance of serotonin in the teleosts reproduction. PMID- 26097447 TI - Rapid P300 brain-computer interface communication with a head-mounted display. AB - Visual ERP (P300) based brain-computer interfaces (BCIs) allow for fast and reliable spelling and are intended as a muscle-independent communication channel for people with severe paralysis. However, they require the presentation of visual stimuli in the field of view of the user. A head-mounted display could allow convenient presentation of visual stimuli in situations, where mounting a conventional monitor might be difficult or not feasible (e.g., at a patient's bedside). To explore if similar accuracies can be achieved with a virtual reality (VR) headset compared to a conventional flat screen monitor, we conducted an experiment with 18 healthy participants. We also evaluated it with a person in the locked-in state (LIS) to verify that usage of the headset is possible for a severely paralyzed person. Healthy participants performed online spelling with three different display methods. In one condition a 5 * 5 letter matrix was presented on a conventional 22 inch TFT monitor. Two configurations of the VR headset were tested. In the first (glasses A), the same 5 * 5 matrix filled the field of view of the user. In the second (glasses B), single letters of the matrix filled the field of view of the user. The participant in the LIS tested the VR headset on three different occasions (glasses A condition only). For healthy participants, average online spelling accuracies were 94% (15.5 bits/min) using three flash sequences for spelling with the monitor and glasses A and 96% (16.2 bits/min) with glasses B. In one session, the participant in the LIS reached an online spelling accuracy of 100% (10 bits/min) using the glasses A condition. We also demonstrated that spelling with one flash sequence is possible with the VR headset for healthy users (mean: 32.1 bits/min, maximum reached by one user: 71.89 bits/min at 100% accuracy). We conclude that the VR headset allows for rapid P300 BCI communication in healthy users and may be a suitable display option for severely paralyzed persons. PMID- 26097448 TI - Integration of exteroceptive and interoceptive information within the hippocampus: a computational study. AB - Many episodic memory studies have critically implicated the hippocampus in the rapid binding of sensory information from the perception of the external environment, reported by exteroception. Other structures in the medial temporal lobe, especially the amygdala, have been more specifically linked with emotional dimension of episodic memories, reported by interoception. The hippocampal projection to the amygdala is proposed as a substrate important for the formation of extero-interoceptive associations, allowing adaptive behaviors based on past experiences. Recently growing evidence suggests that hippocampal activity observed in a wide range of behavioral tasks could reflect associations between exteroceptive patterns and their emotional valences. The hippocampal computational models, therefore, need to be updated to elaborate better interpretation of hippocampal-dependent behaviors. In earlier models, interoceptive features, if not neglected, are bound together with other exteroceptive features through autoassociative learning mechanisms. This way of binding integrates both kinds of features at the same level, which is not always suitable for example in the case of pattern completion. Based on the anatomical and functional heterogeneity along the septotemporal and transverse axes of the hippocampus, we suggest instead that distinct hippocampal subregions may be engaged in the representation of these different types of information, each stored apart in autoassociative memories but linked together in a heteroassociative way. The model is developed within the hard constraint of rapid, even single trial, learning of episodic memories. The performance of the model is assessed quantitatively and its resistance to interference is demonstrated through a series of numerical experiments. An experiment of reversal learning in patients with amnesic cognitive impairment is also reproduced. PMID- 26097449 TI - A Time Series Approach to Random Number Generation: Using Recurrence Quantification Analysis to Capture Executive Behavior. AB - The concept of executive functions plays a prominent role in contemporary experimental and clinical studies on cognition. One paradigm used in this framework is the random number generation (RNG) task, the execution of which demands aspects of executive functioning, specifically inhibition and working memory. Data from the RNG task are best seen as a series of successive events. However, traditional RNG measures that are used to quantify executive functioning are mostly summary statistics referring to deviations from mathematical randomness. In the current study, we explore the utility of recurrence quantification analysis (RQA), a non-linear method that keeps the entire sequence intact, as a better way to describe executive functioning compared to traditional measures. To this aim, 242 first- and second-year students completed a non-paced RNG task. Principal component analysis of their data showed that traditional and RQA measures convey more or less the same information. However, RQA measures do so more parsimoniously and have a better interpretation. PMID- 26097450 TI - Electrophysiological correlates associated with contributions of perceptual and conceptual fluency to familiarity. AB - The present research manipulated the fluency of unstudied items using masked repetition priming procedures during an explicit recognition test. Based on fluency-attribution accounts, which posit that familiarity can be driven by multiple forms of fluency, the relationship between masked priming-induced fluency and familiarity was investigated. We classified pictographic characters into High-Meaningfulness (High-M) and Low-Meaningfulness (Low-M) categories on the basis of subjective meaningfulness ratings and identified the distinct electrophysiological correlates of perceptual and conceptual fluency. The two types of fluency differed in associated ERP effects: 150-250 ms effects for perceptual fluency and FN400 effects for conceptual fluency. The ERPs of Low-M MP same (items that were preceded by matching masked items) false alarms were more positive than correct rejections during 150-250 ms, whereas the ERPs of High-M MP same false alarms were more positive than correct rejections during 300-500 ms. The topographic patterns of FN400 effects between High-M MP-same false alarms and Low-M MP-same false alarms were not different from those of High-M hits and Low-M hits. These results indicate that both forms of fluency can contribute to familiarity, and the neural correlates of conceptual fluency are not different from those of conceptual priming induced by prior study-phase exposure. We conclude that multiple neural signals potentially contribute to recognition memory, such as numerous forms of fluency differing in terms of their time courses. PMID- 26097451 TI - Altered sleep composition after traumatic brain injury does not affect declarative sleep-dependent memory consolidation. AB - Individuals with a history of traumatic brain injury (TBI) often report sleep disturbances, which may be caused by changes in sleep architecture or reduced sleep quality (greater time awake after sleep onset, poorer sleep efficiency, and sleep stage proportion alterations). Sleep is beneficial for memory formation, and herein we examine whether altered sleep physiology following TBI has deleterious effects on sleep-dependent declarative memory consolidation. Participants learned a list of word pairs in the morning or evening, and recall was assessed 12-h later, following an interval awake or with overnight sleep. Young adult participants (18-22 years) were assigned to one of four experimental groups: TBI Sleep (n = 14), TBI Wake (n = 12), non-TBI Sleep (n = 15), non-TBI Wake (n = 15). Each TBI participant was >1 year post-injury. Sleep physiology was measured with polysomnography. Memory consolidation was assessed by comparing change in word-pair recall over 12-h intersession intervals. The TBI group spent a significantly greater proportion of the night in SWS than the non-TBI group at the expense of NREM1. The TBI group also had marginally lower EEG delta power during SWS in the central region. Intersession changes in recall were greater for intervals with sleep than without sleep in both groups. However, despite abnormal sleep stage proportions for individuals with a TBI history, there was no difference in the intersession change in recall following sleep for the TBI and non-TBI groups. In both Sleep groups combined, there was a positive correlation between Intersession Change and the proportion of the night in NREM2 + SWS. Overall, sleep composition is altered following TBI but such deficits do not yield insufficiencies in sleep-dependent memory consolidation. PMID- 26097452 TI - Linear summation of outputs in a balanced network model of motor cortex. AB - Given the non-linearities of the neural circuitry's elements, we would expect cortical circuits to respond non-linearly when activated. Surprisingly, when two points in the motor cortex are activated simultaneously, the EMG responses are the linear sum of the responses evoked by each of the points activated separately. Additionally, the corticospinal transfer function is close to linear, implying that the synaptic interactions in motor cortex must be effectively linear. To account for this, here we develop a model of motor cortex composed of multiple interconnected points, each comprised of reciprocally connected excitatory and inhibitory neurons. We show how non-linearities in neuronal transfer functions are eschewed by strong synaptic interactions within each point. Consequently, the simultaneous activation of multiple points results in a linear summation of their respective outputs. We also consider the effects of reduction of inhibition at a cortical point when one or more surrounding points are active. The network response in this condition is linear over an approximately two- to three-fold decrease of inhibitory feedback strength. This result supports the idea that focal disinhibition allows linear coupling of motor cortical points to generate movement related muscle activation patterns; albeit with a limitation on gain control. The model also explains why neural activity does not spread as far out as the axonal connectivity allows, whilst also explaining why distant cortical points can be, nonetheless, functionally coupled by focal disinhibition. Finally, we discuss the advantages that linear interactions at the cortical level afford to motor command synthesis. PMID- 26097453 TI - Corrigendum: Harnessing modern web application technology to create intuitive and efficient data visualization and sharing tools. AB - [This corrects the article on p. 71 in vol. 8, PMID: 25206330.]. PMID- 26097454 TI - Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective. AB - The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val/Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype. In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations. PMID- 26097455 TI - Outcome measures for hand function naturally reveal three latent domains in older adults: strength, coordinated upper extremity function, and sensorimotor processing. AB - Understanding the mapping between individual outcome measures and the latent functional domains of interest is critical to a quantitative evaluation and rehabilitation of hand function. We examined whether and how the associations among six hand-specific outcome measures reveal latent functional domains in elderly individuals. We asked 66 healthy older adult participants (38F, 28M, 66.1 +/- 11.6 years, range: 45-88 years) and 33 older adults (65.8 +/- 9.7 years, 44 81 years, 51 hands) diagnosed with osteoarthritis (OA) of the carpometacarpal (CMC) joint, to complete six functional assessments: hand strength (Grip, Key and Precision Pinch), Box and Block, Nine Hole Pegboard, and Strength-Dexterity tests. The first three principal components suffice to explain 86% of variance among the six outcome measures in healthy older adults, and 84% of variance in older adults with CMC OA. The composition of these dominant associations revealed three distinct latent functional domains: strength, coordinated upper extremity function, and sensorimotor processing. Furthermore, in participants with thumb CMC OA we found a blurring of the associations between the latent functional domains of strength and coordinated upper extremity function. This motivates future work to understand how the physiological effects of thumb CMC OA lead upper extremity coordination to become strongly associated with strength, while dynamic sensorimotor ability remains an independent functional domain. Thus, when assessing the level of hand function in our growing older adult populations, it is particularly important to acknowledge its multidimensional nature-and explicitly consider how each outcome measure maps to these three latent and fundamental domains of function. Moreover, this ability to distinguish among latent functional domains may facilitate the design of treatment modalities to target the rehabilitation of each of them. PMID- 26097456 TI - Inositols affect the mating circadian rhythm of Drosophila melanogaster. AB - Accumulating evidence indicates that the molecular circadian clock underlies the mating behavior of Drosophila melanogaster. However, information about which food components affect circadian mating behavior is scant. The ice plant, Mesembryanthemum crystallinum has recently become a popular functional food. Here, we showed that the close-proximity (CP) rhythm of D. melanogaster courtship behavior was damped under low-nutrient conditions, but significantly enhanced by feeding the flies with powdered ice plant. Among various components of ice plants, we found that myo-inositol increased the amplitude and slightly shortened the period of the CP rhythm. Real-time reporter assays showed that myo-inositol and D-pinitol shortened the period of the circadian reporter gene Per2-luc in NIH 3T3 cells. These data suggest that the ice plant is a useful functional food and that the ability of inositols to shorten rhythms is a general phenomenon in insects as well as mammals. PMID- 26097457 TI - Computational identification of potential multi-drug combinations for reduction of microglial inflammation in Alzheimer disease. AB - Like other neurodegenerative diseases, Alzheimer Disease (AD) has a prominent inflammatory component mediated by brain microglia. Reducing microglial inflammation could potentially halt or at least slow the neurodegenerative process. A major challenge in the development of treatments targeting brain inflammation is the sheer complexity of the molecular mechanisms that determine whether microglia become inflammatory or take on a more neuroprotective phenotype. The process is highly multifactorial, raising the possibility that a multi-target/multi-drug strategy could be more effective than conventional monotherapy. This study takes a computational approach in finding combinations of approved drugs that are potentially more effective than single drugs in reducing microglial inflammation in AD. This novel approach exploits the distinct advantages of two different computer programming languages, one imperative and the other declarative. Existing programs written in both languages implement the same model of microglial behavior, and the input/output relationships of both programs agree with each other and with data on microglia over an extensive test battery. Here the imperative program is used efficiently to screen the model for the most efficacious combinations of 10 drugs, while the declarative program is used to analyze in detail the mechanisms of action of the most efficacious combinations. Of the 1024 possible drug combinations, the simulated screen identifies only 7 that are able to move simulated microglia at least 50% of the way from a neurotoxic to a neuroprotective phenotype. Subsequent analysis shows that of the 7 most efficacious combinations, 2 stand out as superior both in strength and reliability. The model offers many experimentally testable and therapeutically relevant predictions concerning effective drug combinations and their mechanisms of action. PMID- 26097458 TI - Response: Behind the closed doors of mentalizing. A commentary on "Another step closer to measuring the ghosts in the nursery: preliminary validation of the Trauma Reflective Functioning Scale". PMID- 26097459 TI - Happiness and arousal: framing happiness as arousing results in lower happiness ratings for older adults. AB - Older adults have been shown to describe their happiness as lower in arousal when compared to younger adults. In addition, older adults prefer low arousal positive emotions over high arousal positive emotions in their daily lives. We experimentally investigated whether or not changing a few words in the description of happiness could influence a person's rating of their happiness. We randomly assigned 193 participants, aged 22-92 years, to one of three conditions (high arousal, low arousal, or control). In line with previous findings, we found that older participants rated their happiness lower when framed as high in arousal (i.e., ecstatic, to be bursting with positive emotions) and rated their happiness higher when framed as low in arousal (i.e., satisfied, to have a life filled with positive emotions). Younger adults remained uninfluenced by the manipulation. Our study demonstrates that arousal is essential to understanding ratings of happiness, and gives support to the notion that there are age differences in the preference for arousal. PMID- 26097460 TI - Social justice in education: how the function of selection in educational institutions predicts support for (non)egalitarian assessment practices. AB - Educational institutions are considered a keystone for the establishment of a meritocratic society. They supposedly serve two functions: an educational function that promotes learning for all, and a selection function that sorts individuals into different programs, and ultimately social positions, based on individual merit. We study how the function of selection relates to support for assessment practices known to harm vs. benefit lower status students, through the perceived justice principles underlying these practices. We study two assessment practices: normative assessment-focused on ranking and social comparison, known to hinder the success of lower status students-and formative assessment-focused on learning and improvement, known to benefit lower status students. Normative assessment is usually perceived as relying on an equity principle, with rewards being allocated based on merit and should thus appear as positively associated with the function of selection. Formative assessment is usually perceived as relying on corrective justice that aims to ensure equality of outcomes by considering students' needs, which makes it less suitable for the function of selection. A questionnaire measuring these constructs was administered to university students. Results showed that believing that education is intended to select the best students positively predicts support for normative assessment, through increased perception of its reliance on equity, and negatively predicts support for formative assessment, through reduced perception of its ability to establish corrective justice. This study suggests that the belief in the function of selection as inherent to educational institutions can contribute to the reproduction of social inequalities by preventing change from assessment practices known to disadvantage lower-status student, namely normative assessment, to more favorable practices, namely formative assessment, and by promoting matching beliefs in justice principles. PMID- 26097461 TI - The benefit of amplification on auditory working memory function in middle-aged and young-older hearing impaired adults. AB - Untreated hearing loss can interfere with an individual's cognitive abilities and intellectual function. Specifically, hearing loss has been shown to negatively impact working memory function, which is important for speech understanding, especially in difficult or noisy listening conditions. The purpose of the present study was to assess the effect of hearing aid use on auditory working memory function in middle-aged and young-older adults with mild to moderate sensorineural hearing loss. Participants completed two objective measures of auditory working memory in aided and unaided listening conditions. An aged matched control group followed the same experimental protocol except they were not fit with hearing aids. All participants' aided scores on the auditory working memory tests were significantly improved while wearing hearing aids. Thus, hearing aids worn during the early stages of an age-related hearing loss can improve a person's performance on auditory working memory tests. PMID- 26097462 TI - Four converging measures of temporal discounting and their relationships with intelligence, executive functions, thinking dispositions, and behavioral outcomes. AB - Temporal discounting is the tendency to devalue temporally distant rewards. Past studies have examined the k-value, the indifference point, and the area under the curve as dependent measures on this task. The current study included these three measures and a fourth measure, called the interest rate total score, which differentiated good from poor choices. The interest rate total score was based on scoring only those items in which the delayed choice should be preferred given the expected return based on simple interest rates. In addition, associations with several individual difference measures were examined including intelligence, executive functions (inhibition, working memory, and set-shifting), thinking dispositions [Need for Cognition and Consideration of Future Consequences (CFCs)] and engagement in substance use and gambling behavior. A staircase temporal discounting task was examined in a sample of 99 university students. Replicating previous studies, temporal discounting increased with longer delays to reward and decreased with higher reward magnitudes. A hyperbolic function accounted for more variance in temporal discounting than an exponential function. Reaction time at the indifference point was significantly longer than at the other choice points. The four dependent measures of temporal discounting were all significantly correlated and were also significantly associated with our individual difference measures. That is, the tendency to wait for a larger delayed reward on all of the temporal discounting measures was associated with higher intelligence, higher executive functions, and more CFCs. Associations between our measures of temporal discounting and outcomes related to substance use and gambling behavior were modest in our university sample. PMID- 26097463 TI - Gene Expression Associated with Early and Late Chronotypes in Drosophila melanogaster. AB - The circadian clock provides the temporal framework for rhythmic behavioral and metabolic functions. In the modern era of industrialization, work, and social pressures, clock function is jeopardized, and can result in adverse and chronic effects on health. Understanding circadian clock function, particularly individual variation in diurnal phase preference (chronotype), and the molecular mechanisms underlying such chronotypes may lead to interventions that could abrogate clock dysfunction and improve human (and animal) health and welfare. Our preliminary studies suggested that fruit-flies, like humans, can be classified as early rising "larks" or late rising "owls," providing a convenient model system for these types of studies. We have identified strains of flies showing increased preference for morning emergence (Early or E) from the pupal case, or more pronounced preference for evening emergence (Late or L). We have sampled pupae the day before eclosion (fourth day after pupariation) at 4 h intervals in the E and L strains, and examined differences in gene expression by RNA-seq. We have identified differentially expressed transcripts between the E and L strains, which provide candidate genes for subsequent studies of Drosophila chronotypes and their human orthologs. PMID- 26097464 TI - Social and Behavioral Determinants of Perceived Insufficient Sleep. AB - Insufficient sleep is associated with cardiometabolic disease and poor health. However, few studies have assessed its determinants in a nationally representative sample. Data from the 2009 behavioral risk factor surveillance system were used (N = 323,047 adults). Insufficient sleep was assessed as insufficient rest/sleep over 30 days. This was evaluated relative to sociodemographics (age, sex, race/ethnicity, marital status, region), socioeconomics (education, income, employment, insurance), health behaviors (diet, exercise, smoking, alcohol), and health/functioning (emotional support, BMI, mental/physical health). Overall, insufficient sleep was associated with being female, White or Black/African-American, unemployed, without health insurance, and not married; decreased age, income, education, physical activity; worse diet and overall health; and increased household size, alcohol, and smoking. These factors should be considered as risk factors for insufficient sleep. PMID- 26097466 TI - A Pediatric Patient with Refractory Seizures and a Mesial Temporal Lobe Lesion. AB - A 12-year-old adolescent presented with refractory seizures and was found to have a mesial temporal lobe lesion. The patient underwent biopsy and was diagnosed with an arteriovenous malformation. Supratentorial lesions in the pediatric population can have a large variety of underlying etiologies, which can be challenging to differentiate on neuroimaging. In this report, we discuss the key features on MRI of several neoplastic, vascular, and infectious processes that can aide in the diagnosis. PMID- 26097467 TI - Epigenetic Regulation of Non-Lymphoid Cells by Bisphenol A, a Model Endocrine Disrupter: Potential Implications for Immunoregulation. AB - Endocrine disrupting chemicals (EDC) abound in the environment since many compounds are released from chemical, agricultural, pharmaceutical, and consumer product industries. Many of the EDCs such as Bisphenol A (BPA) have estrogenic activity or interfere with endogenous sex hormones. Experimental studies have reported a positive correlation of BPA with reproductive toxicity, altered growth, and immune dysregulation. Although the precise relevance of these studies to the environmental levels is unclear, nevertheless, their potential health implications remain a concern. One possible mechanism by which BPA can alter genes is by regulating epigenetics, including microRNA, alteration of methylation, and histone acetylation. There is now wealth of information on BPA effects on non-lymphoid cells and by comparison, paucity of data on effects of BPA on the immune system. In this mini review, we will highlight the BPA regulation of estrogen receptor-mediated immune cell functions and in different inflammatory conditions. In addition, BPA-mediated epigenetic regulation of non lymphoid cells is emphasized. We recognize that most of these studies are on non lymphoid cells, and given that BPA also affects the immune system, it is plausible that BPA could have similar epigenetic regulation in immune cells. It is hoped that this review will stimulate studies in this area to ascertain whether or not BPA epigenetically regulates the cells of the immune system. PMID- 26097468 TI - A balanced perspective on unbalanced growth and thymineless death. AB - The early history of the esoteric phenomenon of thymineless death (TLD) is recounted, from the pioneering discovery by Seymour Cohen and Hazel Barner, through my graduate studies at Yale and postdoctoral research in Copenhagen. My principal contribution was the discovery that restricted synthesis of protein and RNA permits cultures of Escherichia coli to complete their DNA replication cycles without initiating new ones, and that cells held in this physiological state are immune to the lethality of thymine deprivation; unbalanced growth is not the fundamental cause of TLD. The successful synchronization of the DNA replication cycle contributed to formulation of the replicon concept. Studies at Stanford revealed a specific requirement for transcription and led to the discovery of a TLD-resistant mutant in a new gene, termed recQ, with important homologs in humans and most other organisms. The lessons learned from research on TLD underscore the value of basic research in bacterial systems that can have profound implications for human health. PMID- 26097469 TI - Archaeal viruses at the cell envelope: entry and egress. AB - The cell envelope represents the main line of host defense that viruses encounter on their way from one cell to another. The cytoplasmic membrane in general is a physical barrier that needs to be crossed both upon viral entry and exit. Therefore, viruses from the three domains of life employ a wide range of strategies for perforation of the cell membrane, each adapted to the cell surface environment of their host. Here, we review recent insights on entry and egress mechanisms of viruses infecting archaea. Due to the unique nature of the archaeal cell envelope, these particular viruses exhibit novel and unexpected mechanisms to traverse the cellular membrane. PMID- 26097470 TI - A Replisome's journey through the bacterial chromosome. AB - Genome duplication requires the coordinated activity of a multi-component machine, the replisome. In contrast to the background of metabolic diversity across the bacterial domain, the composition and architecture of the bacterial replisome seem to have suffered few changes during evolution. This immutability underlines the replisome's efficiency in copying the genome. It also highlights the success of various strategies inherent to the replisome for responding to stress and avoiding problems during critical stages of DNA synthesis. Here we summarize current understanding of bacterial replisome architecture and highlight the known variations in different bacterial taxa. We then look at the mechanisms in place to ensure that the bacterial replisome is assembled appropriately on DNA, kept together during elongation, and disassembled upon termination. We put forward the idea that the architecture of the replisome may be more flexible that previously thought and speculate on elements of the replisome that maintain its stability to ensure a safe journey from origin to terminus. PMID- 26097471 TI - Discovery of new protein families and functions: new challenges in functional metagenomics for biotechnologies and microbial ecology. AB - The rapid expansion of new sequencing technologies has enabled large-scale functional exploration of numerous microbial ecosystems, by establishing catalogs of functional genes and by comparing their prevalence in various microbiota. However, sequence similarity does not necessarily reflect functional conservation, since just a few modifications in a gene sequence can have a strong impact on the activity and the specificity of the corresponding enzyme or the recognition for a sensor. Similarly, some microorganisms harbor certain identified functions yet do not have the expected related genes in their genome. Finally, there are simply too many protein families whose function is not yet known, even though they are highly abundant in certain ecosystems. In this context, the discovery of new protein functions, using either sequence-based or activity-based approaches, is of crucial importance for the discovery of new enzymes and for improving the quality of annotation in public databases. This paper lists and explores the latest advances in this field, along with the challenges to be addressed, particularly where microfluidic technologies are concerned. PMID- 26097465 TI - Synchronization of Biological Clock Neurons by Light and Peripheral Feedback Systems Promotes Circadian Rhythms and Health. AB - In mammals, the suprachiasmatic nucleus (SCN) functions as a circadian clock that drives 24-h rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase-synchronization between individual cells have consequences on the amplitude of the SCN's electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise) has a positive effect on amplitude. Given that the amplitude of the SCN's electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-h rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders. PMID- 26097472 TI - The Campylobacter jejuni RacRS two-component system activates the glutamate synthesis by directly upregulating gamma-glutamyltranspeptidase (GGT). AB - The highly conserved enzyme gamma-glutamyltranspeptidase (GGT) plays an important role in metabolism of glutathione and glutamine. Yet, the regulation of ggt transcription in prokaryotes is poorly understood. In the human pathogen Campylobacter jejuni, GGT is important as it contributes to persistent colonization of the gut. Here we show that the GGT activity in C. jejuni is dependent on a functional RacRS (reduced ability to colonize) two-component system. Electrophoretic mobility shift and luciferase reporter assays indicate that the response regulator RacR binds to a promoter region ~80 bp upstream of the ggt transcriptional start site, which contains a recently identified RacR DNA binding consensus sequence. RacR needs to be phosphorylated to activate the transcription of the ggt gene, which is the case under low oxygen conditions in presence of alternative electron acceptors. A functional GGT and RacR are needed to allow C. jejuni to grow optimally on glutamine as sole carbon source under RacR inducing conditions. However, when additional carbon sources are present C. jejuni is capable of utilizing glutamine independently of GGT. RacR is the first prokaryotic transcription factor known to directly up-regulate both the cytoplasmic [glutamine-2-oxoglutarate aminotransferase (GOGAT)] as well as the periplasmic (GGT) production of glutamate. PMID- 26097474 TI - SDF-1/CXCL12: A Chemokine in the Life Cycle of HIV. PMID- 26097475 TI - Maraviroc - A CCR5 Antagonist for the Treatment of HIV-1 Infection. PMID- 26097476 TI - Discovery of IL-8/CXCL8 (The Story from Frederick). PMID- 26097473 TI - From ingestion to colonization: the influence of the host environment on regulation of the LEE encoded type III secretion system in enterohaemorrhagic Escherichia coli. AB - Enterohaemorrhagic Escherichia coli (EHEC) binds to host tissue and intimately attaches to intestinal cells using a dedicated type III secretion system (T3SS). This complex multi-protein organelle is encoded within a large pathogenicity island called the locus of enterocyte effacement (LEE), which is subject to extensive regulatory control. Over the past 15 years we have gained a wealth of knowledge concerning how the LEE is regulated transcriptionally by specific, global and phage encoded regulators. More recently, significant advances have been made in our understanding of how specific signals, including host or microbiota derived metabolic products and various nutrient sources, can affect how the LEE-encoded T3SS is regulated. In this review we discuss regulation of the LEE, focusing on how these physiologically relevant signals are sensed and how they affect the expression of this major virulence factor. The implications for understanding the disease process by specific regulatory mechanisms are also discussed. PMID- 26097477 TI - The Duffy Antigen Receptor for Chemokines DARC/ACKR1. PMID- 26097478 TI - D6/ACKR2. PMID- 26097479 TI - Viral Chemokine Receptors. PMID- 26097480 TI - The Structure of a CXCR4:Chemokine Complex. PMID- 26097481 TI - Generation of Adaptive Immune Responses Following Influenza Virus Challenge is Not Compromised by Pre-Treatment with the TLR-2 Agonist Pam2Cys. AB - Immunostimulatory agents provide a new category of anti-microbial agents that activate the host's innate immune system allowing control of viral and/or bacterial infections. The TLR-2 agonist PEG-Pam2Cys has been shown to mediate potent anti-viral activity against influenza viruses when administered prophylactically (1). Here, we demonstrate that the treatment of mice with PEG Pam2Cys does not compromise their ability to generate adaptive immune responses following subsequent challenge with influenza virus. The antibody induced in mice pre-treated with Pam2Cys possessed hemagglutination-inhibiting activities and the CD8(+) T-cell responses that were elicited provided protection against heterologous viral challenge. In the absence of an effective influenza vaccine, an agent that provides immediate protection against the virus and does not compromise the induction of influenza-specific immunity on exposure to infectious virus provides an opportunity for population immunity to be achieved through natural exposure to virus. PMID- 26097482 TI - Animal Models of Interferon Signature Positive Lupus. AB - Human lupus is strongly associated with a gene expression signature characterized by over-expression of Type I interferon-regulated genes. A strong interferon signature generally is not seen in the standard mouse models of lupus, despite considerable evidence for the involvement of toll-like receptor-driven interferon production. In contrast, pristane-induced lupus exhibits a prominent TLR7 dependent interferon signature. Importantly, genetic disorders with dysregulated interferon production in both human beings and mice cause severe autoinflammatory diseases but not the typical manifestations of lupus, suggesting that interferon over-production is insufficient to cause systemic lupus erythematosus itself. Single-gene models in mice suggest that lupus-like disease may result from abnormalities in B-cell activation and the clearance of dead cells. Pristane may mimic human systemic lupus erythematosus by causing synergistic abnormalities in interferon production along with defective clearance of apoptotic cells and over active B-cell signaling. PMID- 26097485 TI - Quantifying the source-sink balance and carbohydrate content in three tomato cultivars. AB - Supplementary lighting is frequently applied in the winter season for crop production in greenhouses. The effect of supplementary lighting on plant growth depends on the balance between assimilate production in source leaves and the overall capacity of the plants to use assimilates. This study aims at quantifying the source-sink balance and carbohydrate content of three tomato cultivars differing in fruit size, and to investigate to what extent the source/sink ratio correlates with the potential fruit size. Cultivars Komeet (large size), Capricia (medium size), and Sunstream (small size, cherry tomato) were grown from 16 August to 21 November, at similar crop management as in commercial practice. Supplementary lighting (High Pressure Sodium lamps, photosynthetic active radiation at 1 m below lamps was 162 MUmol photons m(-2) s(-1); maximum 10 h per day depending on solar irradiance level) was applied from 19 September onward. Source strength was estimated from total plant growth rate using periodic destructive plant harvests in combination with the crop growth model TOMSIM. Sink strength was estimated from potential fruit growth rate which was determined from non-destructively measuring the fruit growth rate at non-limiting assimilate supply, growing only one fruit on each truss. Carbohydrate content in leaves and stems were periodically determined. During the early growth stage, 'Komeet' and 'Capricia' showed sink limitation and 'Sunstream' was close to sink limitation. During this stage reproductive organs had hardly formed or were still small and natural irradiance was high (early September) compared to winter months. Subsequently, during the fully fruiting stage all three cultivars were strongly source-limited as indicated by the low source/sink ratio (average source/sink ratio from 50 days after planting onward was 0.17, 0.22, and 0.33 for 'Komeet,' 'Capricia,' and 'Sunstream,' respectively). This was further confirmed by the fact that pruning half of the fruits hardly influenced net leaf photosynthesis rates. Carbohydrate content in leaves and stems increased linearly with the source/sink ratio. We conclude that during the early growth stage under high irradiance, tomato plants are sink-limited and that the level of sink limitation differs between cultivars but it is not correlated with their potential fruit size. During the fully fruiting stage tomato plants are source-limited and the extent of source limitation of a cultivar is positively correlated with its potential fruit size. PMID- 26097483 TI - Alternative Antigen Processing for MHC Class I: Multiple Roads Lead to Rome. AB - The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for "T cell epitopes associated with impaired peptide processing." TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer's related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing. PMID- 26097484 TI - Epi-fingerprinting and epi-interventions for improved crop production and food quality. AB - Increasing crop production at a time of rapid climate change represents the greatest challenge facing contemporary agricultural research. Our understanding of the genetic control of yield derives from controlled field experiments designed to minimize environmental variance. In spite of these efforts there is substantial residual variability among plants attributable to Genotype * Environment interactions. Recent advances in the field of epigenetics have revealed a plethora of gene control mechanisms that could account for much of this unassigned variation. These systems act as a regulatory interface between the perception of the environment and associated alterations in gene expression. Direct intervention of epigenetic control systems hold the enticing promise of creating new sources of variability that could enhance crop performance. Equally, understanding the relationship between various epigenetic states and responses of the crop to specific aspects of the growing environment (epigenetic fingerprinting) could allow for a more tailored approach to plant agronomy. In this review, we explore the many ways in which epigenetic interventions and epigenetic fingerprinting can be deployed for the improvement of crop production and quality. PMID- 26097486 TI - Proteomic analysis of crop plants under abiotic stress conditions: where to focus our research? PMID- 26097487 TI - Species specific and environment induced variation of delta(13)C and delta(15)N in alpine plants. AB - Stable carbon and nitrogen isotope signals in plant tissues integrate plant environment interactions over long periods. In this study, we hypothesized that humid alpine life conditions are narrowing the scope for significant deviations from common carbon, water and nitrogen relations as captured by stable isotope signals. We explored the variation in delta(13)C and delta(15)N in 32 plant species from tissue type to ecosystem scale across a suite of locations at c. Two thousand five hundred meter elevation in the Swiss Alps. Foliar delta(13)C and delta(15)N varied among species by about 3-40/00 and 7-80/00 respectively. However, there was no overall difference in means of delta(13)C and delta(15)N for species sampled in different plant communities or when bulk plant dry matter harvests of different plant communities were compared. delta(13)C was found to be highly species specific, so that the ranking among species was mostly maintained across 11 habitats. However, delta(15)N varied significantly from place to place in all species (a range of 2.70/00) except in Fabaceae (Trifolium alpinum) and Juncaceae (Luzula lutea). There was also a substantial variation among individuals of the same species collected next to each other. No difference was found in foliar delta(15)N of non-legumes, which were either collected next to or away from the most common legume, T. alpinum. delta(15)N data place Cyperaceae and Juncaceae, just like Fabaceae, in a low discrimination category, well separated from other families. Soil delta(15)N was higher than in plants and increased with soil depth. The results indicate a high functional diversity in alpine plants that is similar to that reported for low elevation plants. We conclude that the surprisingly high variation in delta(13)C and delta(15)N signals in the studied high elevation plants is largely species specific (genetic) and insensitive to obvious environmental cues. PMID- 26097488 TI - Redrawing the frontiers in the age of post-publication review. AB - Publication forms the core structure supporting the development and transmission of scientific knowledge. For this reason, it is essential that the highest standards of quality control be maintained, in particular to ensure that the information being transmitted allows reproducible replication of the described experiments, and that the interpretation of the results is sound. Quality control has traditionally involved editorial decisions based on anonymous pre-publication peer review. Post-publication review of individual articles took the lesser role since it did not feed directly back to the original literature. Rapid advances in computer and communications technologies over the last thirty years have revolutionized scientific publication, and the role and scope of post-publication review has greatly expanded. This perspective examines the ways in which pre- and post-publication peer review influence the scientific literature, and in particular how they might best be redrawn to deal with the twin problems of scientific non-reproducibility and fraud increasingly encountered at the frontiers of science. PMID- 26097490 TI - Has aging ever been considered healthy? PMID- 26097489 TI - Desmin common mutation is associated with multi-systemic disease manifestations and depletion of mitochondria and mitochondrial DNA. AB - Desmin (DES) is a major muscle scaffolding protein that also functions to anchor mitochondria. Pathogenic DES mutations, however, have not previously been recognized as a cause of multi-systemic mitochondrial disease. Here, we describe a 45-year-old man who presented to The Children's Hospital of Philadelphia Mitochondrial-Genetics Diagnostic Clinic for evaluation of progressive cardiac, neuromuscular, gastrointestinal, and mood disorders. Muscle biopsy at age 45 was remarkable for cytoplasmic bodies, as well as ragged red fibers and SDH positive/COX negative fibers that were suggestive of a mitochondrial myopathy. Muscle also showed significant reductions in mitochondrial content (16% of control mean for citrate synthase activity) and mitochondrial DNA (35% of control mean). His family history was significant for cardiac conduction defects and myopathy in multiple maternal relatives. Multiple single gene and panel-based sequencing studies were unrevealing. Whole exome sequencing identified a known pathogenic p.S13F mutation in DES that had previously been associated with desmin related myopathy. Desmin-related myopathy is an autosomal dominant disorder characterized by right ventricular hypertrophic cardiomyopathy, myopathy, and arrhythmias. However, neuropathy, gastrointestinal dysfunction, and depletion of both mitochondria and mitochondrial DNA have not previously been widely recognized in this disorder. Recognition that mitochondrial dysfunction occurs in desmin-related myopathy clarifies the basis for the multi-systemic manifestations, as are typical of primary mitochondrial disorders. Understanding the mitochondrial pathophysiology of desmin-related myopathy highlights the possibility of new therapies for this otherwise untreatable and often fatal class of disease. We postulate that drug treatments aimed at improving mitochondrial biogenesis or reducing oxidative stress may be effective therapies to ameliorate the effects of desmin-related disease. PMID- 26097491 TI - Stabilization Methods for a Multiagent System with Complex Behaviours. AB - The main focus of the paper is the stability analysis of a class of multiagent systems based on an interaction protocol which can generate different types of overall behaviours, from asymptotically stable to chaotic. We present several interpretations of stability and suggest two methods to assess the stability of the system, based on the internal models of the agents and on the external, observed behaviour. Since it is very difficult to predict a priori whether a system will be stable or unstable, we propose three heuristic methods that can be used to stabilize such a system during its execution, with minimal changes to its state. PMID- 26097492 TI - Traditional Ecological Knowledge and Global Environmental Change: Research findings and policy implications. AB - This paper introduces the special feature of Ecology and Society entitled "Traditional Ecological Knowledge and Global Environmental Change. The special feature addresses two main research themes. The first theme concerns the resilience of Traditional Ecological Knowledge (hereafter TEK) and the conditions that might explain its loss or persistence in the face of global change. The second theme relates to new findings regarding the way in which TEK strengthens community resilience to respond to the multiple stressors of global environmental change. Those themes are analyzed using case studies from Africa, Asia, America and Europe. Theoretical insights and empirical findings from the studies suggest that despite the generalized worldwide trend of TEK erosion, substantial pockets of TEK persist in both developing and developed countries. A common trend on the studies presented here is hybridization, where traditional knowledge, practices, and beliefs are merged with novel forms of knowledge and technologies to create new knowledge systems. The findings also reinforce previous hypotheses pointing at the importance of TEK systems as reservoirs of experiential knowledge that can provide important insights for the design of adaptation and mitigation strategies to cope with global environmental change. Based on the results from papers in this feature, we discuss policy directions that might help to promote maintenance and restoration of living TEK systems as sources of social-ecological resilience. PMID- 26097493 TI - Lipodystrophy among HIV-infected patients: a cross-sectional study on impact on quality of life and mental health disorders. AB - BACKGROUND: Lipodystrophy (LD) is a frequent adverse event of combination antiretroviral therapy (ART) and occurs mainly in patients exposed to first generation antiretroviral drugs. The aim of this study was to explore and measure the interaction between LD, mental health, and quality of life of human immunodeficiency virus (HIV) positive individuals seen in a metabolic clinic. METHODS: We conducted a single-site cross-sectional study including all HIV infected patients attending the LIPO group and metabolism day clinic at the University Hospitals of Geneva, Switzerland between January 31, 2008 and November 28, 2013. Data on LD were prospectively collected using the HIV Outpatient Study (HOPS) score, the Lipodystrophy Case Definition (LDCD), ART regimens, anthropometric measures, imaging, and standardized questionnaires. Quality of life was evaluated using a visual analog scale of 0-100. Depression and anxiety were assessed using the Beck Depression Inventory and the State Trait Anxiety Inventory scales, respectively. RESULTS: One hundred ninety-four patients (54.6% male; 45.4% female; median age, 50 years) on successful ART (median CD4 cell count, 569.0 cells/mm(3); median viral load, 20 copies/mL) were evaluated. Among these, 62.7, 63.5 and 35.5% of patients reported at least one body site affected by fat hypertrophy, atrophy or both, respectively. Using the LDCD score conservative definition, including imaging and biological values, 57.8% were diagnosed with LD. Of these, 39.7% suffered from severe/very severe LD. Depression was reported by 35.6% of individuals; 51.9% had anxiety symptoms and 49.5% reported poor quality of life (defined as being inferior to 50% on a scale from 0 to 100%). LD (odds ratio (OR = 5.22, 95% confidence interval (CI) 1.07 25.37, p-value: 0.040), depression (OR = 4.67, 95% CI 1.08-20.31, p-value 0.040), and anxiety (OR = 7.83, 95% CI 1.91-32.03, p-value 0.004) all affected significantly the quality of life. CONCLUSIONS: LD, depression and anxiety were frequent features among HIV-infected individuals seen in the metabolic clinic and significantly impacted on their quality of life. PMID- 26097494 TI - Bayesian models as a unified approach to estimate relative risk (or prevalence ratio) in binary and polytomous outcomes. AB - BACKGROUND: Disadvantages have already been pointed out on the use of odds ratio (OR) as a measure of association for designs such as cohort and cross sectional studies, for which relative risk (RR) or prevalence ratio (PR) are preferable. The model that directly estimates RR or PR and correctly specifies the distribution of the outcome as binomial is the log-binomial model, however, convergence problems occur very often. Robust Poisson regression also estimates these measures but it can produce probabilities greater than 1. RESULTS: In this paper, the use of Bayesian approach to solve the problem of convergence of the log-binomial model is illustrated. Furthermore, the method is extended to incorporate dependent data, as in cluster clinical trials and studies with multilevel design, and also to analyse polytomous outcomes. Comparisons between methods are made by analysing four data sets. CONCLUSIONS: In all cases analysed, it was observed that Bayesian methods are capable of estimating the measures of interest, always within the correct parametric space of probabilities. PMID- 26097495 TI - Risk factors for seizures and antiepileptic drug-associated adverse effects in high-grade glioma patients: A multicentre, retrospective study in Hong Kong. AB - AIM: The aim of this present study was to determine the frequency, as well as risk factors, for seizures and antiepileptic drug (AED)-associated adverse effects among high-grade glioma (HGG) patients. PATIENTS AND METHODS: A multicentre, retrospective study of adult Chinese Hong Kong patients from three neurosurgical centres diagnosed with supratentorial HGG between 1 January 2001 and 31 December 2010 was performed. RESULTS: A total of 198 patients, with a mean age of 55 years (range: 18-88) and a mean follow up of 15 months, was recruited. Most suffered from glioblastoma multiforme (GBM) (63 per cent) followed by anaplastic astrocytoma (25 per cent). Median overall survival for patients with GBM was 8 months, and 11 months for those with grade III gliomas. Prophylactic AED was prescribed in 165 patients (83 per cent), and 64 per cent of patients were continued until end of life or last follow up. A total of 112 patients (57 per cent) experienced seizures at a mean duration of 8 months postoperatively (range: 1 day-75 months). Independent predictors for seizures were a diagnosis of GBM [adjusted odds ratio (OR): 2.33, 95 per cent confidence interval (CI): 1.21 4.52] and adjuvant radiotherapy (adjusted OR: 2.97, 95 per cent CI: 1.49-6.62). One-fifth of patients (21 per cent) experienced AED adverse effects, with idiosyncratic cutaneous reactions and hepatotoxicity most frequently observed. An independent predictor for adverse effects was exposure to aromatic AED, such as phenytoin, carbamazepine and phenobarbital (adjusted OR: 3.32, 95 per cent CI: 1.32-8.40). CONCLUSIONS: Antiepileptic drug prescription for primary seizure prophylaxis is both pervasive and prolonged for HGG patients. Seizures occur frequently, but most were delayed and none were life threatening. Judicious prescription of AED is required, especially when a significant proportion of patients experience adverse effects. Patients with a diagnosis of GBM and exposure to radiotherapy are at risk. We suggest, contrary to present practice, that primary seizure prophylaxis be given only during the perioperative period and resumed when they occur. We also recommend avoidance of aromatic AED due to their association with idiosyncratic adverse effects. PMID- 26097497 TI - Gaps in Glaucoma care: A systematic review of monoscopic disc photos to screen for glaucoma. PMID- 26097496 TI - Human parvovirus B19: a mechanistic overview of infection and DNA replication. AB - Human parvovirus B19 (B19V) is a human pathogen that belongs to genus Erythroparvovirus of the Parvoviridae family, which is composed of a group of small DNA viruses with a linear single-stranded DNA genome. B19V mainly infects human erythroid progenitor cells and causes mild to severe hematological disorders in patients. However, recent clinical studies indicate that B19V also infects nonerythroid lineage cells, such as myocardial endothelial cells, and may be associated with other disease outcomes. Several cell culture systems, including permissive and semipermissive erythroid lineage cells, nonpermissive human embryonic kidney 293 cells and recently reported myocardial endothelial cells, have been used to study the mechanisms underlying B19V infection and B19V DNA replication. This review aims to summarize recent advances in B19V studies with a focus on the mechanisms of B19V tropism specific to different cell types and the cellular pathways involved in B19V DNA replication including cellular signaling transduction and cell cycle arrest. PMID- 26097498 TI - Conducting Ethical Research with Correctional Populations: Do Researchers and IRB Members Know the Federal Regulations? AB - Conducting or overseeing research in correctional settings requires knowledge of specific federal rules and regulations designed to protect the rights of individuals in incarceration. To investigate the extent to which relevant groups possess this knowledge, using a 10-item questionnaire, we surveyed 885 IRB prisoner representatives, IRB members and chairs with and without experience reviewing HIV/AIDS correctional protocols, and researchers with and without correctional HIV/AIDS research experience. Across all groups, respondents answered 4.5 of the items correctly. Individuals who have overseen or conducted correctional research had the highest scores; however, even these groups responded correctly only to slightly more than half of the items. These findings emphasize the need for ongoing training in federal guidelines governing correctional research, particularly for those individuals who are embarking on this type of research. PMID- 26097499 TI - High-Fat Diet Alters the Orosensory Sensitivity to Fatty Acids in Obesity Resistant but not Obesity-Prone Rats. AB - Gene-environment interactions play a role in the development of obesity but specific effects of diet on the orosensory detection of fatty acids have yet to be clarified. The objective of this study is to characterize the effect of prolonged (5-week) exposure to a high-fat (60%) diet on the behavioral sensitivity to the fatty acid linoleate following a conditioned taste aversion in obesity-prone and obesity-resistant rats. Exposure to the high-fat diet significantly enhanced the sensitivity of obesity-resistant (S5B/Pl) rats to linoleate while producing no effect on the fatty acid sensitivity for obesity prone rats. Specifically, high-fat diet fed S5B/Pl rats showed stronger initial avoidance of linoleate and slower extinction rates than their normal diet cohorts. Our study suggests that prolonged dietary fat consumption may alter the behavioral sensitivity to fatty acids particularly in obesity-resistant animals. PMID- 26097500 TI - Treatment of castration-resistant prostate cancer and bone metastases with radium 223 dichloride. AB - Radium-223 dichloride (Ra-223) is the first alpha-particle emitting radiopharmaceutical to be approved for the treatment of patients with castration resistant prostate cancer and associated bone metastases, and the first bone targeting agent to significantly improve patient overall survival whilst reducing pain and the symptomatic skeletal events (SSEs) associated with bone metastases. Ra-223 exhibits a favourable safety profile, with low myelosuppression rates and fewer adverse events than placebo. Compared with other approved radiopharmaceuticals, the alpha-particle emitting Ra-223 has a high biological efficiency and a short penetration range, potentially sparing bone marrow toxicity and limiting unwanted exposure. Ra-223 has a short half-life and decays to a stable product, reducing the problem of storage and disposal associated with radiopharmaceuticals. Ra-223 offers a new treatment option with great potential in this setting. However, concerns remain amongst patients, their families and health care professionals over the use of radiopharmaceuticals. This article, which draws on the experiences of health care workers during the ALSYMPCA (ALpharadin in SYMtomatic Prostate CAncer) study, reviews the clinical development of Ra-223, highlighting the key issues for the uro-oncology nurse who has a pivotal role within the multi-disciplinary team (MDT) to ensure safe and effective treatment to the patient. The role of the uro-oncology nurse is multifaceted, including patient pre-assessment and post-treatment monitoring and coordination of the MDT. In addition, their role in communicating with and educating those involved with Ra-223 on what to expect from the agent can alleviate fears associated with its use. PMID- 26097501 TI - Modeling the CO2-effects of forest management and wood usage on a regional basis. AB - BACKGROUND: At the 15th Conference of Parties of the UN Framework Convention on Climate Change, Copenhagen, 2009, harvested wood products were identified as an additional carbon pool. This modification eliminates inconsistencies in greenhouse gas reporting by recognizing the role of the forest and timber sector in the global carbon cycle. Any additional CO2-effects related to wood usage are not considered by this modification. This results in a downward bias when the contribution of the forest and timber sector to climate change mitigation is assessed. The following article analyses the overall contribution to climate protection made by the forest management and wood utilization through CO2 emissions reduction using an example from the German state of North Rhine Westphalia. Based on long term study periods (2011 to 2050 and 2100, respectively). Various alternative scenarios for forest management and wood usage are presented. RESULTS: In the mid- to long-term (2050 and 2100, respectively) the net climate protection function of scenarios with varying levels of wood usage is higher than in scenarios without any wood usage. This is not observed for all scenarios on short and mid term evaluations. The advantages of wood usage are evident although the simulations resulted in high values for forest storage in the C pools. Even the carbon sink effect due to temporal accumulation of deadwood during the period from 2011 to 2100 is outbalanced by the potential of wood usage effects. CONCLUSIONS: A full assessment of the CO2-effects of the forest management requires an assessment of the forest supplemented with an assessment of the effects of wood usage. CO2-emission reductions through both fuel and material substitution as well as CO2 sink in wood products need to be considered. An integrated assessment of the climate protection function based on the analysis of the study's scenarios provides decision parameters for a strategic approach to climate protection with regard to forest management and wood use at regional and national levels. The short-term evaluation of subsystems can be misleading, rendering long-term evaluations (until 2100, or even longer) more effective. This is also consistent with the inherently long-term perspective of forest management decisions and measures. PMID- 26097502 TI - Monitoring forest carbon in a Tanzanian woodland using interferometric SAR: a novel methodology for REDD. AB - BACKGROUND: REDD+ implementation requires establishment of a system for measuring, reporting and verification (MRV) of forest carbon changes. A challenge for MRV is the lack of satellite based methods that can track not only deforestation, but also degradation and forest growth, as well as a lack of historical data that can serve as a basis for a reference emission level. Working in a miombo woodland in Tanzania, we here aim at demonstrating a novel 3D satellite approach based on interferometric processing of radar imagery (InSAR). RESULTS: Forest carbon changes are derived from changes in the forest canopy height obtained from InSAR, i.e. decreases represent carbon loss from logging and increases represent carbon sequestration through forest growth. We fitted a model of above-ground biomass (AGB) against InSAR height, and used this to convert height changes to biomass and carbon changes. The relationship between AGB and InSAR height was weak, as the individual plots were widely scattered around the model fit. However, we consider the approach to be unique and feasible for large scale MRV efforts in REDD+ because the low accuracy was attributable partly to small plots and other limitations in the data set, and partly to a random pixel to-pixel variation in trunk forms. Further processing of the InSAR data provides data on the categories of forest change. The combination of InSAR data from the Shuttle RADAR Topography Mission (SRTM) and the TanDEM-X satellite mission provided both historic baseline of change for the period 2000-2011, as well as annual change 2011-2012. CONCLUSIONS: A 3D data set from InSAR is a promising tool for MRV in REDD+. The temporal changes seen by InSAR data corresponded well with, but largely supplemented, the changes derived from Landsat data. PMID- 26097503 TI - Quantitative analysis of an engineered CO2-fixing Escherichia coli reveals great potential of heterotrophic CO2 fixation. AB - BACKGROUND: Production of fuels from the abundant and wasteful CO2 is a promising approach to reduce carbon emission and consumption of fossil fuels. Autotrophic microbes naturally assimilate CO2 using energy from light, hydrogen, and/or sulfur. However, their slow growth rates call for investigation of the possibility of heterotrophic CO2 fixation. Although preliminary research has suggested that CO2 fixation in heterotrophic microbes is feasible after incorporation of a CO2-fixing bypass into the central carbon metabolic pathway, it remains unclear how much and how efficient that CO2 can be fixed by a heterotrophic microbe. RESULTS: A simple metabolic flux index was developed to indicate the relative strength of the CO2-fixation flux. When two sequential enzymes of the cyanobacterial Calvin cycle were incorporated into an E. coli strain, the flux of the CO2-fixing bypass pathway accounts for 13 % of that of the central carbon metabolic pathway. The value was increased to 17 % when the carbonic anhydrase involved in the cyanobacterial carbon concentrating mechanism was introduced, indicating that low intracellular CO2 concentration is one limiting factor for CO2 fixation in E. coli. The engineered CO2-fixing E. coli with carbonic anhydrase was able to fix CO2 at a rate of 19.6 mg CO2 L(-1) h(-1) or the specific rate of 22.5 mg CO2 g DCW(-1) h(-1). This CO2-fixation rate is comparable with the reported rates of 14 autotrophic cyanobacteria and algae (10.5-147.0 mg CO2 L(-1) h(-1) or the specific rates of 3.5-23.7 mg CO2 g DCW(-1) h(-1)). CONCLUSIONS: The ability of CO2 fixation was created and improved in E. coli by incorporating partial cyanobacterial Calvin cycle and carbon concentrating mechanism, respectively. Quantitative analysis revealed that the CO2-fixation rate of this strain is comparable with that of the autotrophic cyanobacteria and algae, demonstrating great potential of heterotrophic CO2 fixation. PMID- 26097504 TI - Eubacteria and archaea communities in seven mesophile anaerobic digester plants in Germany. AB - BACKGROUND: Only a fraction of the microbial species used for anaerobic digestion in biogas production plants are methanogenic archaea. We have analyzed the taxonomic profiles of eubacteria and archaea, a set of chemical key parameters, and biogas production in samples from nine production plants in seven facilities in Thuringia, Germany, including co-digesters, leach-bed, and sewage sludge treatment plants. Reactors were sampled twice, at a 1-week interval, and three biological replicates were taken in each case. RESULTS: A complex taxonomic composition was found for both eubacteria and archaea, both of which strongly correlated with digester type. Plant-degrading Firmicutes as well as Bacteroidetes dominated eubacteria profiles in high biogas-producing co digesters; whereas Bacteroidetes and Spirochaetes were the major phyla in leach bed and sewage sludge digesters. Methanoculleus was the dominant archaea genus in co-digesters, whereas Methanosarcina and Methanosaeta were the most abundant methanogens in leachate from leach-bed and sewage sludge digesters, respectively. CONCLUSIONS: This is one of the most comprehensive characterizations of the microbial communities of biogas-producing facilities. Bacterial profiles exhibited very low variation within replicates, including those of semi-solid samples; and, in general, low variation in time. However, facility type correlated closely with the bacterial profile: each of the three reactor types exhibited a characteristic eubacteria and archaea profile. Digesters operated with solid feedstock, and high biogas production correlated with abundance of plant degraders (Firmicutes) and biofilm-forming methanogens (Methanoculleus spp.). By contrast, low biogas-producing sewage sludge treatment digesters correlated with high titers of volatile fatty acid-adapted Methanosaeta spp. PMID- 26097505 TI - On the relative role of different age groups in influenza epidemics. AB - The identification of key "driver" groups in influenza epidemics is of much interest for the implementation of effective public health response strategies, including vaccination programs. However, the relative importance of different age groups in propagating epidemics is uncertain. During a communicable disease outbreak, some groups may be disproportionately represented during the outbreak's ascent due to increased susceptibility and/or contact rates. Such groups or subpopulations can be identified by considering the proportion of cases within the subpopulation occurring before (Bp) and after the epidemic peak (Ap) to calculate the subpopulation's relative risk, RR=Bp/Ap. We estimated RR for several subpopulations (age groups) using data on laboratory-confirmed US influenza hospitalizations during epidemics between 2009-2014. Additionally, we simulated various influenza outbreaks in an age-stratified population, relating the RR to the impact of vaccination in each subpopulation on the epidemic's initial effective reproductive number R_e(0). We found that children aged 5-17 had the highest estimates of RR during the five largest influenza A outbreaks, though the relative magnitude of RR in this age group compared to other age groups varied, being highest for the 2009 A/H1N1 pandemic. For the 2010-2011 and 2012-2013 influenza B epidemics, adults aged 18-49, and 0-4 year-olds had the highest estimates of RR respectively. For 83% of simulated epidemics, the group with the highest RR was also the group for which initial distribution of a given quantity of vaccine would result in the largest reduction of R_e(0). In the largest 40% of simulated outbreaks, the group with the highest RR and the largest vaccination impact was children 5-17. While the relative importance of different age groups in propagating influenza outbreaks varies, children aged 5-17 play the leading role during the largest influenza A epidemics. Extra vaccination efforts for this group may contribute to reducing the epidemic's impact in the whole community. PMID- 26097506 TI - Testing multiple hypotheses through IMP weighted FDR based on a genetic functional network with application to a new zebrafish transcriptome study. AB - In genome-wide studies, hundreds of thousands of hypothesis tests are performed simultaneously. Bonferroni correction and False Discovery Rate (FDR) can effectively control type I error but often yield a high false negative rate. We aim to develop a more powerful method to detect differentially expressed genes. We present a Weighted False Discovery Rate (WFDR) method that incorporate biological knowledge from genetic networks. We first identify weights using Integrative Multi-species Prediction (IMP) and then apply the weights in WFDR to identify differentially expressed genes through an IMP-WFDR algorithm. We performed a gene expression experiment to identify zebrafish genes that change expression in the presence of arsenic during a systemic Pseudomonas aeruginosa infection. Zebrafish were exposed to arsenic at 10 parts per billion and/or infected with P. aeruginosa. Appropriate controls were included. We then applied IMP-WFDR during the analysis of differentially expressed genes. We compared the mRNA expression for each group and found over 200 differentially expressed genes and several enriched pathways including defense response pathways, arsenic response pathways, and the Notch signaling pathway. PMID- 26097507 TI - Low BMI and low TSH value as risk factors related to lower bone mineral density in postmenospausal women under levothyroxine therapy for differentiated thyroid carcinoma. AB - OBJECTIVE: Treatment of differentiated thyroid carcinoma (DTC) includes suppression of TSH with levothyroxine therapy, which may negatively influence bone mineral density (BMD), but the effects are controversial. We aimed to evaluate the relationship between TSH-suppressive therapy and BMD in postmenopausal women with DTC. METHODOLOGY: Cross-sectional study that assessed BMD by densitometry and risk factors for decreased BMD in 109 postmenopausal women under TSH-suppressive therapy for DTC, compared to an age-matched euthyroid women control group. Conditions that might have affected BMD were exclusion criteria. RESULTS: Patients were 58.4 +/- 8.3 years-old, mean serum TSH was 0.21 +/- 0.28MUIU/ml. In BMD evaluation, T-scores were -1.09 +/- 1.43 SD (lumbar spine) and -0.12 +/- 1.18 SD (total femur). No significant differences were found between lumbar or femoral T-scores of patients and control group. Multivariate logistic regression analysis evidenced that low BMI and low mean TSH levels (assessed in the year of BMD measurement) were factors significantly related to lower lumbar and spinal BMD. CONCLUSION: Although low TSH levels and low BMI were correlated with lower BMD, it was not observed an increased prevalence of osteopenia or osteoporosis in this cohort of post-menopausal women under levothyroxine treatment for DTC, when compared to age-matched control women. Nevertheless, such risk factors should be carefully observed in individual patients at high risk of decrease in BMD. PMID- 26097508 TI - Modelling the conditional regulatory activity of methylated and bivalent promoters. AB - BACKGROUND: Predictive modelling of gene expression is a powerful framework for the in silico exploration of transcriptional regulatory interactions through the integration of high-throughput -omics data. A major limitation of previous approaches is their inability to handle conditional interactions that emerge when genes are subject to different regulatory mechanisms. Although chromatin immunoprecipitation-based histone modification data are often used as proxies for chromatin accessibility, the association between these variables and expression often depends upon the presence of other epigenetic markers (e.g. DNA methylation or histone variants). These conditional interactions are poorly handled by previous predictive models and reduce the reliability of downstream biological inference. RESULTS: We have previously demonstrated that integrating both transcription factor and histone modification data within a single predictive model is rendered ineffective by their statistical redundancy. In this study, we evaluate four proposed methods for quantifying gene-level DNA methylation levels and demonstrate that inclusion of these data in predictive modelling frameworks is also subject to this critical limitation in data integration. Based on the hypothesis that statistical redundancy in epigenetic data is caused by conditional regulatory interactions within a dynamic chromatin context, we construct a new gene expression model which is the first to improve prediction accuracy by unsupervised identification of latent regulatory classes. We show that DNA methylation and H2A.Z histone variant data can be interpreted in this way to identify and explore the signatures of silenced and bivalent promoters, substantially improving genome-wide predictions of mRNA transcript abundance and downstream biological inference across multiple cell lines. CONCLUSIONS: Previous models of gene expression have been applied successfully to several important problems in molecular biology, including the discovery of transcription factor roles, identification of regulatory elements responsible for differential expression patterns and comparative analysis of the transcriptome across distant species. Our analysis supports our hypothesis that statistical redundancy in epigenetic data is partially due to conditional relationships between these regulators and gene expression levels. This analysis provides insight into the heterogeneous roles of H3K4me3 and H3K27me3 in the presence of the H2A.Z histone variant (implicated in cancer progression) and how these signatures change during lineage commitment and carcinogenesis. PMID- 26097509 TI - The correlation between postural control and upper limb position sense in people with chronic ankle instability. AB - BACKGROUND: Chronic ankle instability (CAI) is attributed to functional instability driven by insufficient proprioception. However, it is not clear whether the deficits are related to global impaired performance or to specific decrease in ankle motor-control. The aim of this study was to assess the correlation between lower limb postural control and upper limb position sense among people with CAI, in order to further explore the function of the central neural control in people with CAI. METHODS: Fourteen participants (10 males, 4 females) with self-reported CAI and 14 age- and gender-matched, healthy controls participated in this study. Each participant completed single-limb stance postural control tests and shoulder position sense tests. The Overall Stability Index (OSI) was used as a measure of postural stability. The average of the absolute error score (AES) was calculated as a measure of shoulder position sense. Pearson correlations between the scores of the four body sites -lower limb postural stability (preferred/non-preferred), shoulder (preferred/non-preferred) were determined separately for each group. RESULTS: In the control group, significant correlations were found between the OSI score of the right and left ankles (r = 0.887, p < 0.001), between the AES of the right and left shoulders (r = 0.656, p = 0.011), as well as between the OSI score and the AES of the non preferred side (r = 0.649, p = 0.012). In the CAI group, significant correlation was found only between the OSI score at both ankles (r = 0.6, p = 0.002). CONCLUSIONS: Individuals with CAI demonstrated lower limb postural control and upper limb position sense similar to those shown in healthy controls. However, correlations between the lower and upper limbs were observed only in the healthy controls. Clinicians can use this information and employ activities that focus on coordinating the upper and lower extremities when designing neuromuscular control training programs for people with CAI. PMID- 26097510 TI - SANCDB: a South African natural compound database. AB - BACKGROUND: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa. DESCRIPTION: The current research presents a South African natural compound database, named SANCDB. This is a curated and fully-referenced database containing compound information for 600 natural products extracted directly from journal articles, book chapters and theses. There is a web interface to the database, which is simple and easy to use, while allowing for compounds to be searched by a number of different criteria. Being fully referenced, each compound page contains links to the original referenced work from which the information was obtained. Further, the website provides a submission pipeline, allowing researchers to deposit compounds from their own research into the database. CONCLUSIONS: SANCDB is currently the only web-based NP database in Africa. It aims to provide a useful resource for the in silico screening of South African NPs for drug discovery purposes. The database is supported by a submission pipeline to allow growth by entries from researchers. As such, we currently present SANCDB the starting point of a platform for a community-driven, curated database to further natural products research in South Africa. SANCDB is freely available at https://sancdb.rubi.ru.ac.za/. PMID- 26097511 TI - High-fat diet feeding significantly attenuates anagliptin-induced regeneration of islets of Langerhans in streptozotocin-induced diabetic mice. AB - BACKGROUND: DPP-4 inhibitors reportedly exert effects on both alpha and beta cells, and promote the proliferation and survival of beta cells. We investigated the effects of anagliptin on structurally-impaired islets of Langerhans in streptozotocin (STZ)-treated mice, fed either a normal or a high-fat diet. Pdx-1 expression in the pancreas and serum insulin/glucagon concentrations were also examined. FINDINGS: Anagliptin treatment significantly up-regulated pancreatic Pdx-1 expression, with elevated serum glucagon-like peptide-1 concentrations, regardless of whether the diet was normal or high-fat. However, interestingly, the beta cell regeneration, structural normalization of islets of Langerhans including alpha cell: beta cell area ratios, and serum insulin elevation, all observed with anagliptin administration in the animals fed a normal diet, were markedly suppressed in the high-fat fed group. CONCLUSIONS: High-fat diet feeding clearly weakened the regenerative effects of anagliptin on the islets of Langerhans in STZ-treated mice. Our findings suggest the importance of normalizing lipid metabolism for full manifestation of DPP-4 inhibitor effects on the islets of Langerhans. PMID- 26097513 TI - Dynamic intracellular delivery of antibiotics via pH-responsive polymersomes. AB - Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of copolymers consisting of 2-hdroxyethyl methacrylate (HEMA) and poly(ethylene glycol) methyl ether methacrylate (FWavg ~ 950 Da) (O950) with variable comonomer compositions and molecular weights for use as polymeric scaffolds. Reactivity ratios for the monomer pair were determined to be 1.37 and 0.290 respectively. To these scaffolds trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted using carbodiimide chemistry. The resultant graft chain transfer agents (gCTA) were subsequently employed to polymerize dimethylaminoethyl methacrylate (DMAEMA) and (HPMA) between degrees of polymerization (DP) of 25 and 200. Kinetic analysis for the polymerization of DMAEMA targeting a DP of 100 from a 34 arm graft gCTA show linear Mn conversion and pseudo first order rate plots with narrow molecular weight distributions that move toward lower elution volumes with monomer conversion. D values for these polymerizations remain low at around 1.20 at monomer conversions as high as 70 %. pH-responsive endosomalytic brushes capable of spontaneously self-assembling into polymersomes were synthesized and a combination of dynamic light scattering (DLS), cryoTEM, and red blood cell hemolysis were employed to evaluate the aqueous solution properties of the polymeric brush as a function of pH. Successful encapsulation of ceftazidime and pH-dependent drug release properties were confirmed by HPLC. Intracellular antibiotic activity of the drug-loaded polymersomes was confirmed in a macrophage coculture model of infection with B. thailandensis and RAW 264.7 cells. PMID- 26097514 TI - Well-defined single polymer nanoparticles for the antibody-targeted delivery of chemotherapeutic agents. AB - Aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of linear copolymers of N,N-dimethylacrylamide (DMA) and 2-hydroxyethylacrylamide (HEAm) with narrow D values over a molecular weight range spanning three orders of magnitude (103 to 106 Da). Trithiocarbonate based RAFT chain transfer agents (CTAs) were grafted onto these scaffolds using carbodiimide chemistry catalyzed with DMAP. The resultant graft chain transfer agent (gCTA) was subsequently employed to synthesize polymeric brushes with a number of important vinyl monomer classes including acrylamido, methacrylamido, and methacrylate. Brush polymerization kinetics were evaluated for the aqueous RAFT polymerization of DMA from a 10 arm gCTA. Polymeric brushes containing hydroxyl functionality were further functionalized in order to prepare 2nd generation gCTAs which were subsequently employed to prepare polymers with a brushed-brush architecture with molecular weights in excess of 106 Da. These resultant single particle nanoparticles (SNPs) were employed as drug delivery vehicles for the anthracycline-based drug doxorubicin via copolymerization of DMA with a protected carbazate monomer (bocSMA). Cell-specific targeting functionality was also introduced via copolymerization with a biotin-functional monomer (bioHEMA). Drug release of the hydrazone linked doxorubicin was evaluated as function of pH and serum and chemotherapeutic activity was evaluated in SKOV3 ovarian cancer cells. PMID- 26097512 TI - Human resistin and the RELM of Inflammation in diabesity. AB - The initial discovery of resistin and resistin-like molecules (RELMs) in rodents suggested a role for these adipocytokines in molecular linkage of obesity, Type 2 Diabetes mellitus and metabolic syndrome. Since then, it became apparent that the story of resistin and RELMs was very much of mice and men. The putative role of this adipokine family evolved from that of a conveyor of insulin resistance in rodents to instigator of inflammatory processes in humans. Structural dissimilarity, variance in distribution profiles and a lack of corroborating evidence for functional similarities separate the biological functions of resistin in humans from that of rodents. Although present in gross visceral fat deposits in humans, resistin is a component of inflammation, being released from infiltrating white blood cells of the sub-clinical chronic low grade inflammatory response accompanying obesity, rather than from the adipocyte itself. This led researchers to further explore the functions of the resistin family of proteins in inflammatory-related conditions such as atherosclerosis, as well as in cancers such as endometrial and gastric cancers. Although elevated levels of resistin have been found in these conditions, whether it is causative or as a result of these conditions still remains to be determined. PMID- 26097515 TI - Cortical venous thrombosis presenting with subarachnoid haemorrhage. AB - BACKGROUND: Our study retrospectively reviewed the presentation, neuro radiological findings, and outcomes of eight adult patients presenting at our institution with subarachnoid haemorrhage (SAH), which was subsequently proven to be due to cortical venous thrombosis (CVT). METHODS: We reviewed the case records and neuroimaging findings of eight patients diagnosed with SAH and CVT over a span of two years at our institution, a tertiary care centre in Western India. All details pertaining to their presentation, clinical findings, neuroimaging, management, and outcome following therapy with anticoagulants were collected until patient discharge. RESULTS: There were a total of eight patients, with the average age being 34 years (range 25-42). Only one patient was female. Six patients had a history of recent binge drinking. None of the patients had a past or family history of common risk factors for thrombosis. All patients presented acutely, with headache (n=6) and seizures (n=6) being the most common presenting features, occurring in three-quarters of the patients examined. Non-contrast computed tomography (NCCT) was the initial imaging study for all but one of the patients and showed cortical SAH (cSAH) without basilar haemorrhage. Magnetic resonance imaging/magnetic resonance venography (MRI/MRV) confirmed the underlying CVT. Unfractionated heparin was used in all cases. Seven patients improved and were discharged on oral anticoagulation. The eighth patient died. CONCLUSION: Localised cSAH with sparing of basal cisterns can be a presentation for CVT. In patients with cSAH, MRI/MRV can be useful to make a diagnosis of CVT. Anticoagulation for CVT, even in the presence of SAH was related to seven out of eight patients being discharged. PMID- 26097516 TI - Neck of femur fracture management by general surgeons at a rural hospital. AB - BACKGROUND: Neck of femur (NOF) fractures are the most common injury among elderly patients and a significant burden on our healthcare system. AIMS: This study aimed toevaluate if an Australian rural hospital serviced by general surgeons can meet the established standards of care for the management of NOF fractures by undertaking surgery within 48 hours. METHODS: An audit of patients presenting to an Australian rural hospital with NOF fractures over a seven-year period. Patients were excluded if they were transferred or suffered peri prosthetic or multi-trauma-related fractures. Outcomes included time to surgery, length of stay, and in-hospital mortality, and were compared to three similar Australian studies from hospitals with specialist orthopedic units. Descriptive statistics and meta-analysis were performed. RESULTS: Overall, 182 patients presented with NOF fractures and 114 met our inclusion criteria. Only 12 per cent of patients were transferred. Patients were mostly female (74 per cent) and elderly (mean age 84.0 years). A total of 79 per cent of patients were operated on within48 hours; other studies reported 67-86 per cent. Mean length of stay was 11.9 days (versus 7.7-13.7), and in-hospital mortality was 4 per cent (versus 2-7 per cent). CONCLUSION: This audit suggests that an Australian rural hospital serviced by general surgeons can meet the established standards of care for management of most NOF fractures. Some post-surgery outcomes are similar to those reported by larger centers with specialized orthopedics units. PMID- 26097517 TI - General practice and residential aged care: A qualitative study of barriers to access to care and the role of remuneration. AB - BACKGROUND: More than 169,000 people live in residential aged care facilities (RACFs). As people age they use health services, particularly general practitioner (GP) services, more frequently but many GPs do not attend patients in RACFs. AIMS: To examine GPs' perceptions of barriers to providing care to patients in RACFs. METHODS: This study was conducted in June 2014 in the Bayside Medicare Local (BML) region in Victoria, Australia; all participants were drawn from this region. Two focus groups (FGs) were conducted. One was for GPs (n=5) that have a specific interest in practicing in RACFs, the other with RACF staff (n=8) representing public, private, and not-for-profit aged care providers. Results were presented to the Royal Australian College of General Practitioners (RACGP) National Standing Committee for General Practice Advocacy and Support for feedback and validation of the findings against national perspectives of the effect of remuneration on the provision of GP services in RACFs. RESULTS: Remuneration problems are a barrier to the provision of GP services to patients in RACFs. These problems can be grouped into: direct remuneration, opportunity cost, additional administrative burden, and unremunerated work. GPs' perceptions of the effects of these problems on willingness to practice in RACFs are described. CONCLUSION: Innovative models of remuneration for GPs attending RACFs are needed to ameliorate the problems identified. Such models need to capture and pay for activities that are time consuming but often unremunerated. PMID- 26097518 TI - Unilateral anatomical variation of the ansa cervicalis. AB - The ansa cervicalis is a loop of nerves that is usually formed by the union of ventral rami of spinal nerves C1, C2, and C3. It is located in the carotid triangle of the neck, lying superficial to the carotid sheath. During routine dissection, unilateral variation of the ansa cervicalis was observed. The superior root, arising from hypoglossal nerve, was initially bifurcated and later united to form a single superior root. IN addition, the inferior root consisted of fibres arising from the spinal accessory nerve, C1, C2 and C3 spinal nerves that joined separately. Fibres from the spinal accessory and C1 joined to form a single root. Thus, a 'triple form' of ansa cervicalis was observed. An interconnection was observed between the C2 and C3 fibres. Knowledge of such anatomical variations is important for surgery, clinical intervention or trauma involving the carotid triangle or the structures within or deep to this region. PMID- 26097519 TI - Automation of diagnostics by new disruptive technologies supports local general practice and medical screening in the third world. PMID- 26097520 TI - Talin Dependent Mechanosensitivity of Cell Focal Adhesions. AB - A fundamental question in mechanobiology is how mechanical stimuli are sensed by mechanosensing proteins and converted into signals that direct cells to adapt to the external environment. A key function of cell adhesion to the extracellular matrix (ECM) is to transduce mechanical forces between cells and their extracellular environment. Talin, a cytoplasmic adapter essential for integrin mediated adhesion to the ECM, links the actin cytoskeleton to integrin at the plasma membrane. Here, we review recent progress in the understanding of talin dependent mechanosensing revealed by stretching single talin molecules. Rapid progress in single-molecule force manipulation technologies has made it possible to directly study the impact of mechanical force on talin's conformations and its interactions with other signaling proteins. We also provide our views on how findings from such studies may bring new insights into understanding the principles of mechanobiology on a broader scale, and how such fundamental knowledge may be harnessed for mechanopharmacology. PMID- 26097521 TI - Memory in language-impaired children with and without autism. AB - BACKGROUND: A subgroup of young children with autism spectrum disorders (ASD) have significant language impairments (phonology, grammar, vocabulary), although such impairments are not considered to be core symptoms of and are not unique to ASD. Children with specific language impairment (SLI) display similar impairments in language. Given evidence for phenotypic and possibly etiologic overlap between SLI and ASD, it has been suggested that language-impaired children with ASD (ASD + language impairment, ALI) may be characterized as having both ASD and SLI. However, the extent to which the language phenotypes in SLI and ALI can be viewed as similar or different depends in part upon the age of the individuals studied. The purpose of the current study is to examine differences in memory abilities, specifically those that are key "markers" of heritable SLI, among young school age children with SLI, ALI, and ALN (ASD + language normal). METHODS: In this cross-sectional study, three groups of children between ages 5 and 8 years participated: SLI (n = 18), ALI (n = 22), and ALN (n = 20). A battery of cognitive, language, and ASD assessments was administered as well as a nonword repetition (NWR) test and measures of verbal memory, visual memory, and processing speed. RESULTS: NWR difficulties were more severe in SLI than in ALI, with the largest effect sizes in response to nonwords with the shortest syllable lengths. Among children with ASD, NWR difficulties were not associated with the presence of impairments in multiple ASD domains, as reported previously. Verbal memory difficulties were present in both SLI and ALI groups relative to children with ALN. Performance on measures related to verbal but not visual memory or processing speed were significantly associated with the relative degree of language impairment in children with ASD, supporting the role of verbal memory difficulties in language impairments among early school-age children with ASD. CONCLUSIONS: The primary difference between children with SLI and ALI was in NWR performance, particularly in repeating two- and three-syllable nonwords, suggesting that shared difficulties in early language learning found in previous studies do not necessarily reflect the same underlying mechanisms. PMID- 26097407 TI - Search for a standard model Higgs boson produced in association with a top-quark pair and decaying to bottom quarks using a matrix element method. AB - A search for a standard model Higgs boson produced in association with a top quark pair and decaying to bottom quarks is presented. Events with hadronic jets and one or two oppositely charged leptons are selected from a data sample corresponding to an integrated luminosity of 19.5[Formula: see text] collected by the CMS experiment at the LHC in [Formula: see text] collisions at a centre-of mass energy of 8[Formula: see text]. In order to separate the signal from the larger [Formula: see text] + jets background, this analysis uses a matrix element method that assigns a probability density value to each reconstructed event under signal or background hypotheses. The ratio between the two values is used in a maximum likelihood fit to extract the signal yield. The results are presented in terms of the measured signal strength modifier, [Formula: see text], relative to the standard model prediction for a Higgs boson mass of 125[Formula: see text]. The observed (expected) exclusion limit at a 95 % confidence level is [Formula: see text] (3.3), corresponding to a best fit value [Formula: see text]. PMID- 26097522 TI - Discovery of Allostery in PKA Signaling. AB - cAMP-dependent protein kinase (PKA) was the second protein kinase to be discovered and the PKA catalytic (C) subunit serves as a prototype for the large protein kinase superfamily that contains over 500 gene products. The protein kinases regulate much of biology in eukaryotic cells and they are now also a major therapeutic target. Although PKA was discovered nearly 50 years ago and the subsequent discovery of the regulatory subunits that bind cAMP and release the catalytic activity from the holoenzyme followed quickly. Thus in PKA we see the convergence of two major signaling mechanisms - protein phosphorylation and second messenger signaling through cAMP. Crystallography provides a foundation for understanding function, and the structure of the isolated regulatory (R) and C-subunits have been extremely informative. Yet it is the R2C2 holoenzyme that predominates in cells, and one can only appreciate the allosteric features of PKA signaling by seeing the full length protein. The symmetry and the quaternary constraints that one R:C hetero-dimer exerts on the other in the holoenzyme simply are not present in the isolated subunits or even in the R:C hetero-dimer. PMID- 26097523 TI - Antioxidative effects of cerium dioxide nanoparticles ameliorate age-related male infertility: optimistic results in rats and the review of clinical clues for integrative concept of men health and fertility. AB - BACKGROUND: Male infertility has largely idiopathic, multifactorial origin. Oxidative stress is a major factor that affects spermatogenesis, in particular in aging. Cerium dioxide nanoparticles (CNPs) due to their antioxidative properties are promising to impact on the development of male infertility. The aims of this study were to investigate the effects of CNPs on fertility parameters in 24-month male rats and to overview relevant literature in the field of personalized treatments, predictive diagnosis, and preventive measures for male health and fertility. METHODS: We included 30 24-month-old male rats. After a week of adaptation to the standard diet, the rats were randomly divided into three groups with ten rats in each. Group 1 (controls) received only a standard diet. The rats of group 2 and 3 in adjunct to the standard diet during 10 days received intragastrically 10 % sodium citrate and citrate-coated CNPs in dose 1 mg/kg, respectively. We assessed sex hormones, epididymal sperm parameters and spermatogenesis, ultrasound, and morphological data of rat reproductive organs. RESULTS: After a 10-day administration of CNPs, we revealed significant decrease of lipid peroxidation product levels in serum and increase of catalase and SOD activity, associated with increase of sperm count (p < 0.001) and improvement in quantitative sperm parameters (motility, viability, and percentage of spermatozoa). We found no significant changes between sperm quantitative parameters in citrate-treated rats and controls and observed age-related decrease of activated Leydig cell number and focal atrophy of the seminiferous tubules. In CNP group, we observed regeneration of seminiferous tubules, increase number and activation of Leydig cells, and 2.5-fold significant increase of serum testosterone. Ultrasound data showed the slight increase of linear measurement and volume of rat testes in CNP group. Review highlights the benefits for predictive diagnosis, preventive measures, and personalized approaches to manage male infertility in the general concept of male health also related to aging. CONCLUSION: Citrate-coated 2-5-nm CNPs lead to increase in sex hormones levels, sperm count, and quality, as well as the activation of spermatogenesis in 24 month-old male rats. Nanoceria demonstrated the perspectives to be an effective infertility treatment via reduction of oxidative stress in male reproductive organs, in particular in aging. PMID- 26097525 TI - Reorganization of Language Areas in Patient with a Frontal Lobe Low Grade Glioma fMRI Case Study. AB - BACKGROUND: Functional magnetic resonance (fMRI) studies results in case of an adult patient with low grade glioma (LGG) in dominant hemisphere suggest brain plasticity process with acquisition of language functions by the non-dominant hemisphere speech regions. CASE REPORT: A 36-years old right-handed woman was admitted to the Department of Neurosurgery for surgical treatment of brain tumor. An MRI examination revealed a pathological mass in the left frontal lobe, in close topographical relationship to the Broca's area. A left fronto-parietal craniotomy was performed, with an intraoperative awake language mapping procedure. A total resection of the pathological mass was achieved. The tumor was examined histologically as LGG. In the follow-up MRI exam 32 months after the operation a tumor recurrence was suggested. The fMRI exams performed preoperative and 3, 32 and 41 months after the operation showed changes in language regions activation patterns, with a progressive right-sided activation of Broca's and Wernicke's areas. Pre- and postoperative cognitive evaluation by a neuropsychologist did not detect any language impairment. We present a running process of reorganization of language areas in a patient after brain tumor resection, from strong left-sided to symmetrical lateralization. CONCLUSIONS: 1. FMRI results in comparison with the psychological status of the patient proved contribution of functional reorganization to the preservation of language performance. 2. A slow growing LGG as well as the recurrence of the tumor near the left Broca's area might be the factors leading to reorganization of language related areas by recruiting the right hemisphe. PMID- 26097524 TI - Diffuse Subarachnoid Hemorrhage Secondary to Cerebral Venous Sinus Thrombosis. AB - BACKGROUND: Aneurysmal rupture accounts for the majority of nontraumatic subarachnoid hemorrhage (SAH). Increasingly recognized is the occurrence of nontraumatic convexity SAH unaccounted for by aneurysmal rupture. CASE REPORT: These presentations require consideration of rare but clinically significant sources of SAH. We report a patient presenting with prolonged mild headaches and acute onset of seizure like activity found to have diffuse subarachnoid hemorrhage and extensive dural venous sinus thrombosis involving the superior sagittal sinus and right transverse-sigmoid sinuses. CONCLUSIONS: There are few reported cases of SAH secondary to dural sinus thrombosis; however most of these are convexity hemorrhage. Sinus thrombosis presenting as diffuse SAH is extremely rare, as is showcased in this report. PMID- 26097526 TI - Understanding Air Pollution and Cardiovascular Diseases: Is It Preventable? AB - Fine particulate matter (<2.5 um, PM2.5) air pollution is a leading risk factor for morbidity and mortality worldwide. The largest portion of adverse health effects is from cardiovascular diseases. In North America, PM2.5 concentrations have shown a steady decline over the past several decades; however, the opposite trend has occurred throughout much of the developing world whereby daily concentrations commonly reach extraordinarily high levels. While air quality regulations can reduce air pollution at a societal level, what individuals can do to reduce their personal exposures remains an active field of investigation. Here, we review the emerging evidence that several interventions (e.g., air filters) and/or behavioral changes can lower PM pollution exposure and as such, may be capable of mitigating the ensuing adverse cardiovascular health consequences. Air pollution remains a worldwide epidemic and a multi-tiered prevention strategy is required in order to optimally protect global public health. PMID- 26097528 TI - 3,4-dihydroxyphenylethanol suppresses irradiation-induced pulmonary fibrosis in adult rats. AB - The present study demonstrates the effect of DHPEA on suppression of irradiation induced pulmonary fibrosis. A (60)Co irradiator was used to induce pulmonary fibrosis in a rat model at a dose of 22 Gy. The rats of the treatment and positive control group were intraperitoneally injected DHPEA (10 mg/kg) or dexamethasone (DEX; 5 mg/kg) daily for 30 days. Hydroxyproline assay was used to evaluate the fibrosis of pulmonary and lung tissue sections after irradiation. Hematoxylin and eosin (H&E) and Masson's trichrome stained lung section were used for alveolitis and fibrosis score analyses, respectively. Immunohistochemistry was used for surfactant protein-B (SPB) and alpha-SMA expression analysis. Western blot analysis was employed for analysis of nuclear transcription factor NF-E2-related factor 2 (Nrf-2) and its associated antioxidant enzymes like heme oxygenase-1 (HO-1) and NAD (P) H: quinone oxidoreductase-1 (NQO-1). Results revealed a significant decrease in mortality rates and lung index scores, decreased collagen deposition, reduced MDA content and enhanced superoxide dismutase (SOD) activity in DHPEA treated rats compared to DEX-treated rats. DHPEA treatment also inhibited (myo) fibroblast proliferation, and regulated serum levels of TGF-beta1, IL-6, IL-10, and TNF-alpha. In addition, DHPEA treatment activated Nrf-2 and its downstream antioxidant enzymes HO-1 and NQO-1. Thus DHPEA can be a promising agent for the suppression of irradiation-induced pulmonary fibrosis. PMID- 26097527 TI - Preventing effects of joint contracture by high molecular weight hyaluronan injections in a rat immobilized knee model. AB - PURPOSE: To elucidate preventive effects of high molecular weight hyaluronan (HMWHA) on the joint capsule of immobilized knees in rats. MATERIALS AND METHODS: Unilateral knee joints of rats were immobilized with an internal fixator. Either 50 MUl of HMWHA (Im-HA group) or 50 MUl of saline (control group) was administered intra-articularly once a week after surgery. Sagittal sections were prepared from the medial midcondylar region of the knee joints and assessed by histological, histomorphometric, and immunohistochemical methods. Gene expressions related to inflammation, fibrotic conditions, and hypoxia were evaluated by quantitative reverse transcription polymerase chain reaction (qRT PCR). Tissue elasticity of the capsule from both groups was examined using a scanning acoustic microscope (SAM). RESULTS: CD68 positive cells decreased in adhesion areas of the synovial membrane after 1 week in both groups. The length of the superficial layer in the synovial membrane of the Im-HA group was significantly longer than those in the control group over a period of 4 to 8 weeks with significantly small numbers of CD68 positive cells. The gene expressions of IL-6, IL-1beta, TGF-beta, CTGF, COL1a1, COL3a1, SPARC, and HIF1 alpha were significantly lower in the Im-HA group compared to those in the control group. The sound speed of the anterior and posterior synovial membrane increased significantly (a reduction in elasticity) in the control group compared to those in the Im-HA group during weeks 1 to 4. CONCLUSIONS: This study demonstrated that HMWHA injections suppressed inflammatory, fibrotic, and hypoxic conditions observed in the immobilized joint capsule. PMID- 26097529 TI - Anti-inflammatory and antioxidant effects of curcumin on acute lung injury in a rodent model of intestinal ischemia reperfusion by inhibiting the pathway of NF Kb. AB - OBJECTIVE: To investigate the anti-inflammatory and antioxidant effect of curcumin on lung lesion induced by intestinal ischemia reperfusion injury (IIR). METHODS: Rats were divided into four groups: sham, intestinal IIR (IIR), 1 mg/kg of curcumin treatment group (1 mg/kg), and 5 mg/kg of curcumin treatment group (5 mg/kg). Curcumin was given respectively (1 mg/kg and 5 mg/kg) following the above doses. IIR was produced by 1 h of intestinal ischemia followed by 2 h of reperfusion. Rats were sacrificed at the end of reperfusion and lung tissues were collected for biochemical and histopathological examination in 4 groups. Lung tissues histology and bronchoalveolar lavage fluid (BALF) protein were assayed. Serum IL-6, lung superoxide dismutase (SOD) and myeloperoxidase (MPO) were measured. The expression level of NF-kappaB and ICAM-1 (including immunohistochemical analysis and western blot analysis) were also measured. RESULTS: Lung tissue injury induced by IIR was obviously observed through pathology and BALF protein. MPO activity, IL-6 level and ICAM-1 expression were significantly increased with the elevation of NF-kappaB, simultaneously, SOD activity was decreased. With Treatment of curcumin, pathology and BALF protein of lung tissue were improved clearly. Inflammatory indexes (MPO activity, IL-6 level and ICAM-1) were improved and antioxidant index (SOD activity) was enhanced paralleled with NF-kappaB. CONCLUSION: Using curcumin effectively prevented IIR induced lung injury. Anti-inflammatory and antioxidant effects of curcumin could be observed by inhibiting the pathway of NF-kappaB. PMID- 26097530 TI - An enterovirus 71 strain causes skeletal muscle damage in infected mice. AB - OBJECTIVE: To study the target organs for enterovirus 71 (EV71) in infected suckling mice. METHODS: 5-day-old BALB/c suckling mice were infected with an EV71 strain. Tissues of the infected mice were processed for histopathological examination, including immunohistochemistry, in situ hybridization, ultrastructural observation. RESULTS: Some mice developed limb paralysis, trouble walking and loss of balance. Results of the histopathological study showed that a large amount of EV71 existed in the skeletal muscle tissues, accounting for the damage of the skeletal muscles. CONCLUSION: The EV71 clinical isolate used in this study presented evident myotropism. Skeletal muscles are important target organs for EV71 in the infected suckling mice. To clarify the relationship between EV71 infection and muscle diseases may contribute to a better understanding of the pathogenesis of EV71. PMID- 26097531 TI - Collagenous micronodules in prostate cancer revisited: are they solely associated with Gleason pattern 3 adenocarcinomas? AB - Collagenous micronodules (CMs) are microscopic stromal nodular eosinophilic fibrillar collagen deposition of uncertain histogenesis seen in prostatic adenocarcinoma. Per the 2005 International Society of Urologic Pathology (ISUP) consensus conference, they are categorized as Gleason pattern 3. This study analyzes morphological and clinical features of CMs from a large series of radical prostatectomies. Hematoxylin and eosin stained slides for 129 radical prostatectomies for adenocarcinoma of prostate with CMs and for 93 prostatic adenocarcinoma cases without CMs as comparison were examined out of a total of 667 cases performed from January 2010 to December 2011 at Houston Methodist Hospital. CMs were identified in 19% of all radical prostatectomies (129/667 cases). Almost all tumors with CMs were located in the peripheral zone (98%) as single or multiple foci of prostatic cancer glands. The vast majority of cases (96%) were identified in association with mucinous secretion. A cribriform Gleason pattern 4 was associated in 86 cases (67%). The CMs were associated with glomerulation (42%) and amphophilic luminal secretion (59%). 88 cases (68%) showed tumor foci with Gleason pattern >= 4 in close association with CMs. Multivariate analysis revealed CMs of the prostatic adenocarcinoma are closely related to mucinous secretion, cribriform growth pattern, and Gleason pattern 4. This study suggests that CMs are more frequently associated with Gleason pattern 4 cancer warranting morphologic reappraisal of CMs, rather than the consensus assignment of Gleason pattern 3. PMID- 26097533 TI - CB2R orchestrates fibrogenesis through regulation of inflammatory response during the repair of skeletal muscle contusion. AB - Skeletal muscle injuries repair typically is an overlapping event between inflammation and tissue repair. Our previous study has demonstrated that activation of cannabinoid receptor type 2 (CB2R) by JWH-133 alleviates fibrosis in the repair of rat skeletal muscle contusion. Meanwhile, accumulated data show that CB2R stimulation exerts anti-inflammatory property in sepsis and cystitis. However, the effects of CB2R on inflammatory cytokines in response to the repair of skeletal muscle contusion are still unknown. In this study, we used selective agonist or antagonist of CB2R to observe the role of CB2R on inflammation and fibrogenesis during the repair of contused skeletal muscles in rats. Our results revealed that treatment with Gp1a, a selective CB2R agonist, significantly decreased the infiltration of neutrophils and macrophages, the expression of pro inflammatory cytokines MCP-1, TNF-alpha, IL-1beta and IL-6, the expression of pro fibrotic cytokines IL-4, IL-13, TGF-beta and P-Smad3 while increased anti fibrotic cytokine IL-10 production as compared with Vehicle. The opposite results were observed in the CB2R inhibition group with AM630. Our study demonstrated that CB2R orchestrates fibrogenesis through regulation of inflammatory response during the repair of skeletal muscle contusion. PMID- 26097532 TI - Possible antiosteoporotic mechanism of Cicer arietinum extract in ovariectomized rats. AB - OBJECTIVE: The present study aimed to throw the light on the anti-osteoprotic mechanism of Cicer arietinum extract (CAE) seeds against ovariectomized (OVX) rats. METHODS: Seventy female rats were divided into two groups. The first group (14 rats/group) represented normal rats (Sham operated) while the second group (56 rats/group) underwent bilateral ovariectomy (OVX). After one week of recovery from ovariectomy surgery, the second group was randomly subdivided into 4 subgroups (14 rats/ each subgroup). The rats administered orally; distilled water (vehicle) (1st subgroup), Cicer arietinum extract (CAE) (500 or 1000 mg/kg body weight/day) (2nd and 3rd subgroups), alendronate (6.5 mg/kg mg/kg body weight) as a positive control one time/week (4(rh) subgroup), daily for 10 weeks. RESULTS: The present study demonstrated that ovariectomy caused significant decrease in bone mineral; density (BMD) and content (BMC), Bone-specific alkaline phosphatase (BALP), calcium (Ca), phosphorus (P), parathyroid hormone (PTH) and calcitonin levels. Furthermore, ovariectomy induced significant elevation of tartrate resistant acid phosphatase 5b (TRAP 5b) and receptor activator of nuclear factor (NF-kappa beta) ligand (RANKL) concentration. Conversely, osteoprotegerin (OPG) and OPG/RANKL ratio were decreased following ovariectomy. The present work suggests that CAE has antiosteoporotic action against ovariectomy effects and its activity may results from its phytochemical and/or phytoestrogen contents. CONCLUSION: The ongoing study speculates that the CAE exerts its action through regulation of RANK/RANKL/OPG system. As, CAE not only promotes osteoblast differentiation, but also up-regulates OPG and downregulates RANKL secretion in osteoblasts, subsequently prevents bone loss and osteoporosis. PMID- 26097534 TI - Protective effects of calcitriol on diabetic nephropathy are mediated by down regulation of TGF-beta1 and CIP4 in diabetic nephropathy rat. AB - OBJECTIVE: To explore the protective effects of calcitriol on diabetic nephropathy by modulating the expressions of transforming growth factor-beta 1 (TGF-beta1) and Cdc42 interacting protein-4 (CIP4). METHODS: Streptozotocin induced diabetic nephropathy rats (n=36) were randomly divided into control group (control-H, control-M, control-L) and calcitriol group (calcitriol-H, calcitriol M, calcitriol-L). The expression of TGF-beta1 gradually decreased in control-H, control-M and control-L subgroups by injection of different virus vectors. Peanut oil and calcitriol were given to control and calcitriol group, respectively. The expressions of TGF-beta1 and CIP4 in kidney, the pathology, and the renal function and lipid profiles were compared between control and calcitriol treatment groups. RESULTS: In the control group, the higher level of TGF-beta1 was associated with more severe glomerular pathology (P<0.05). There is a positive correlation between the expression of CIP4 and TGF-beta1. Control-H subgroup had significant more severe kidney disease, higher levels of cholesterol, triglyceride, blood glucose, blood urea nitrogen (BUN) and creatinine (Cr) than control-M and control-L subgroups. After calcitriol treatment, the expression of TGF-beta1 and CIP4 were significantly decreased compared to the corresponding control subgroups (all P<0.05). Renal fibrosis and pathological changes were markedly improved. The levels of cholesterol, triglyceride, blood glucose, BUN and Cr were significantly reduced (P<0.05). CONCLUSION: Calcitriol may protect diabetic nephropathy from fibrosis via inhibition of TGF-beta1 and CIP4. PMID- 26097536 TI - Inhibition of 4-nitroquinoline-1-oxide-induced oral carcinogenesis by dietary calcium. AB - Calcium is a strong inducer of keratinocyte differentiation. We have previously demonstrated that extracellular calcium promotes keratinocyte differentiation via E-cadherin-catenin complex-mediated phospholipase C-gamma1 (PLC-gamma1) activation in the plasma membrane. However, it is unclear whether dietary calcium regulates keratinocyte proliferation, differentiation or carcinogenesis. To address this issue, the rates of oral tumor and levels of proliferation and differentiation in the oral epithelium were assessed in mice on different calcium diets and the carcinogen 4-nitroquinoline-1-oxide. The results showed that mice on the high calcium diet had lower rates of oral tumors, lower levels of proliferation and higher levels of differentiation in the normal oral epithelium than those on the normal calcium diet. Higher levels of E-cadherin, beta-catenin, p120-catenin (p120), epidermal growth factor receptor (EGFR), and calcium and lower levels of PLC-gamma1 were also noted in the normal oral epithelium in mice on high calcium diet than the control mice. In contrast, mice on low calcium diet had opposite effects. However, dietary calcium had no effect on the proliferation, differentiation or the levels of E-cadherin, beta-catenin, p120, PLC-gamma1 and EGFR in oral tumors. These data indicate that dietary calcium increases calcium levels in oral epithelium, suppresses oral carcinogenesis, inhibits proliferation and promotes differentiation of normal oral epithelium. Increased E-cadherin, beta-catenin, p120 and EGFR and decreased PLC-gamma1 may participate in the inhibitory effect of dietary calcium in oral carcinogenesis. PMID- 26097535 TI - Combined cancer testis antigens enhanced prediction accuracy for prognosis of patients with hepatocellular carcinoma. AB - Cancer testis antigens (CTAs) are selectively expressed in malignant cells and can serve as ideal targets for immunotherapy. We investigated the expressions of MAGE-A3, MAGE-A4, MAGE-C2 and NY-ESO-1 to determine if combinatorial expressions of CTAs might be as potential prognostic markers for patients with hepatocellular carcinoma (HCC). In tumor tissues of 142 HCC patients, the mRNA expressions of MAGE-A3, MAGE-A4, MAGE-C2 and NY-ESO-1 were 78.9%, 33.8%, 74.6% and 14.1% respectively. Furthermore, the expressions of MAGE-A3, MAGE-A4 and combination of MAGE-A3, MAGE-A4 and NY-ESO-1 (CTAs-A3/A4/NY) showed positive correlations with serum AFP, tumor stages and Ki-67 (P < 0.05). In addition, mRNA expressions of CTAs were significantly consistent with protein expressions of CTAs by immunohistochemistry (P > 0.05). Receiver operating characteristic curves (ROC) analysis showed that CTAs-A3/A4/NY had larger areas under ROC curve (0.768), specificity (99.1%), Youden's index (44.6), positive predictive value (90.9%) and negative predictive value (89.9%) for predicting HCC recurrence than other CTAs. Moreover, the combinatorial expression of CTAs-A3/A4/NY was significantly associated with HCC recurrence by Kaplan-Meier analysis (HR = 69.36, P < 0.01) and multivariate Cox analysis (RR = 17.11, P < 0.01). The combinatorial expression of CTAs-A3/A4/NY mRNA promotes the predictive accuracy of HCC recurrence and itself may be a potential target for immunotherapy of HCC as well. PMID- 26097537 TI - Anti-neoplastic activities of Sepia officinalis ink and Coelatura aegyptiaca extracts against Ehrlich ascites carcinoma in Swiss albino mice. AB - OBJECTIVES: With the development of sophisticated instruments for the isolation and elucidation of natural products structures from marine and freshwater organisms, major advances have been made in the discovery of aquatic derived therapeutics. Present investigations were carried out to evaluate cuttlefish (Sepia officinalis) ink extract (IE) and freshwater clam (Coelatura aegyptiaca) extract (CE) for their anticancer and antioxidant activities as compared to 5 flurouracil (5-Fu), in Ehrlich ascites carcinoma (EAC). METHODS: Sixty female Swiss albino mice were divided into five groups (n = 12). All groups except group I received EAC cells (5 * 10(6) cells/mouse i.p.) and this was taken as the 0th day. Group I served as saline control (5 ml/kg 0.9% NaCl w/v p.o). Group II served as EAC control. Rats of groups III, IV and V received IE, CE (200 mg/kg body weight i.p.), and reference drug (5-Fu, 20 mg/kg body weight i.p.), respectively. RESULTS: The reduction in tumor volume, packed cell volume, tumor cell counts and increase in median survival time and percentage increase in life span in treated animals were observed. There was a significant increase in RBC count; Hb content in treated animals and reduction in total WBC count. There was a significant decrease in AST, ALT, ALP and liver MDA levels and increase in GSH, SOD and NO levels were observed in all treated animals. CONCLUSION: Both IE and CE were effective in inhibiting the tumor growth in ascitic tumor models. The biochemical, antioxidants and histopathological studies were also supported their antitumor properties. PMID- 26097538 TI - Expression of MMP14 in invasive pituitary adenomas: relationship to invasion and angiogenesis. AB - Pituitary adenomas (PAs) are noncancerous tumors, and about 35% of those reported to be invasive have been classified as "invasive pituitary adenomas (IPAs)". In clinical, operative complications, total resection failures, and high relapse rates result from invasive features during the therapeutic process. Invasive mechanism is a complex process, including metalloproteases, inhibitors and tumor microenvironment factors etc. Thus, studying invasive mechanism of PAs might contribute to understanding its biological behavior. In our research, three type tissue samples of human, pituitaries, PAs, IPAs, their mRNA expression of MMP1, MMP2, MMP9, MMP14 and MMP15 were measured using real-time PCR. MMP2 and MMP14 protein levels also were measured with immunohistochemistry in same samples. We confirmed that elevated matrix metalloproteinase-14 expression correlates with invasive characteristics of IPAs. To investigate molecular mechanism of how MMP14 contributes to invasiveness, an ATT20 cell was used in this study. After transient-transfection of the MMP14-shRNA expression vector into ATT20 cells, we observed that mRNA expression of PTTG, VEGF, and TGFbeta was significantly suppressed in interference groups. Meanwhile, ATT20 cells in high concentration TIMP-1 environment exhibit reduced PTTG, VEGF, and TGFbeta expression accompanied with the down-regulation of MMP14. Thus, we propose that MMP14 plays an important role in tumor invasion and angiogenesis and that a novel regulatory pathway for MMP14 may exist through VEGF and PTTG. In brief, MMP14 may be a target for therapeutic treatment. PMID- 26097539 TI - Enhanced circulating ILC2s accompany by upregulated MDSCs in patients with asthma. AB - Group 2 innate lymphoid cells (ILC2s) are considered to be the most significant mediators during the orchestration of immune responses in asthma. Myeloid-derived suppressor cells (MDSCs) has received a great deal of attention for their immunosuppressive activity, and our early studies indicate that the increased Th2 cytokines are associated with MDSCs. In this study, we sought to determine whether MDSCs are also participation in immune imbalance and its relationship with ILC2s in asthma. The data showed that the circulatory ILC2s or MDSCs and their characteristic cytokines or transcription factors were significantly enhanced in asthmatic patients, as well as in chronic obstructive pulmonary disease (COPD) or respiratory viral infections (RVI). Meanwhile, a Th2-dominated phenotype was found in patients with asthma which closely related to the expression levels of ILC2s and MDSCs associated moleculars. These findings indicated that Th2 polarization was close related to synergistically increased ILC2s and MDSCs, it may allow to further the comprehension of the contribution of these cells to the inflammatory response involved in asthma or other respiratory tract inflammatory diseases, such as COPD and RVI, as well as to develop novel therapeutic strategies. PMID- 26097540 TI - LRIG1 enhances the radiosensitivity of radioresistant human glioblastoma U251 cells via attenuation of the EGFR/Akt signaling pathway. AB - The radiotherapy as a local and regional modality is widely applied in treatment of glioma, but most glioblastomas are commonly resistant to irradiation treatment. It remains challengeable to seek out efficient strategies to conquer the resistance of human glioblastoma cells to radiotherapy. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is a newly discovered tumor suppressor which involved in regulation of chemosensitivity in various human cancer cells. In the present study, we established a radioresistant U251 cell line (U251R) to investigate the role of LRIG1 in regulation of radiosensitivity in human glioblastoma cells. Significantly decreased expression level of LRIG1 and enhanced expression of EGFR and phosphorylated Akt were detected in U251R cells compared with the parental U251 cells. U251R cells exhibited an advantage in colony formation ability, which accompanied by remarkably reduced X-ray induced gamma-H2AX foci formation and cell apoptosis. LRIG1 overexpression significantly inhibited the colony formation ability of U251R cells and obviously enhanced X-ray-inducedgamma-H2AX foci formation and cell apoptosis. In addition, up-regulated expression of LRIG1 suppressed the expression level of EGFR and phosphorylated Akt protein. Our results demonstrated that LRIG1 expression was related to the radiosensitivity of human glioblastoma cells and may play an important role in the regulation of cellular radiosensitivity of human glioblastoma cells through the EGFR/Akt signaling pathway. PMID- 26097541 TI - Elevated DNA polymerase iota (Poli) is involved in the acquisition of aggressive phenotypes of human esophageal squamous cell cancer. AB - DNA polymerase iota (Poliota) can repair several types of DNA damage but has extremely low fidelity. Previous studies have shown an aberrantly elevated Poliota expression in human esophageal squamous cell cancer tissues. However, there were few reports describing the role of Poliota in esophageal cancer progression. Based on Real-time PCR assay, we found Poliota expression was up regulated in esophageal cancer tissues compared to adjacent normal tissues and overexpression of Poliota was correlated to lymph node metastasis. Clonogenic assay and transwell chamber assay showed that overexpression of Poliota had higher clongenic capability and invasive tendency in human esophageal squamous cell cancer cells. Expression of cyclin D1, an important cell cycle regulator, was found to be associated with that of Poliota in tissue samples and cancer cells as analyzed by real-time PCR, immunohistochemistry, Western blotting and immunofluorescence assay. Flow cytometry analysis further showed that cell cycle distribution was altered in Poliota overexpressing cells. These results indicated that expression of Poliota correlates significantly with tumor proliferation and invasion. We conclude that Poliota is involved in the degree of aggressiveness of human esophageal squamous cell cancer. PMID- 26097542 TI - Effects of nicotine on a rat model of early stage osteoarthritis. AB - The objective of the study was to investigate the effects of nicotine on articular cartilage degeneration and inflammation in a rat model of early stage osteoarthritis (OA), using T2 mapping. In this study, a rat model of early stage OA was established by immobilizing the left knee joints of adult male rats for two weeks. Subsequently, rats were fed with nicotine for two and four weeks. Changes in the articular cartilage from the medial femoral condylar region of the knee were evaluated by gross observation and histological grading with the contents of cartilage matrix detected. T2 values of the articular cartilage were estimated through high-field magnetic resonance imaging (MRI) (7.0 T). Levels of serum tumor necrosis factor-alpha (TNF-alpha) were assessed by ELISA. The expression of TNF-alpha and the cholinergic receptor, alpha7nAChR, in the synovial tissue was measured by RT-PCR. Nicotine treatment ameliorated cartilage destruction, promoted matrix production, reduced the serum level of TNF-alpha and the expression of TNF-alpha in the synovial tissue, and increased the expression of alpha7nAChR in the synovial tissue in the rat model of early stage OA. In conclusion, nicotine prevented cartilage damage and had an anti-inflammatory effect in a rat model of early stage OA. Thus nicotine may have potential as a therapeutic strategy for early stage OA. PMID- 26097543 TI - HOXA10 controls proliferation, migration and invasion in oral squamous cell carcinoma. AB - Although HOX genes are best known for acting in the regulation of important events during embryogenesis, including proliferation, differentiation and migration, alterations in their expression patterns have been frequently described in cancers. In previous studies we analyzed the expression profile of the members of the HOX family of homeobox genes in oral samples of normal mucosa and squamous cell carcinoma (OSCC) and identified differently expressed genes such as HOXA10. The present study aimed to validate the increased expression of HOXA10 in OSCCs, and to investigate the effects arising from its knockdown in OSCC cells. The levels of HOXA10 mRNA were determined in human OSCC samples and cell lines by quantitative PCR, and HOXA10-mediated effects on proliferation, apoptosis, adhesion, epithelial-mesenchymal transition (EMT), migration and invasion were studied in HSC-3 tongue carcinoma cells by using retrovirus mediated RNA interference. Higher expression of HOXA10 mRNA was observed in OSCC cell lines and in tumor tissues compared to normal controls. HOXA10 knockdown significantly reduced the proliferation of the tumor cells which was accompanied by increased levels of p21. HOXA10 silencing also significantly induced the expression of EMT markers and enhanced the adhesion, migration and invasion of HSC-3 cells. No effects on cell death were observed after HOXA10 knockdown. The results of the current study confirm the overexpression of HOXA10 in OSCCs, and further demonstrate that its expression is functionally associated with several important biological processes related to oral tumorigenesis, such as proliferation, migration and invasion. PMID- 26097544 TI - Effects of early and late adverse experiences on morpho-quantitative characteristics of Sprague-Dawley rat spleen subjected to stress during adulthood. AB - Morpho-quantitative studies of the spleen indicate that the proportions of the compartments and sub-compartments are stable in normal conditions. However, disorders due to stress can influence the number and function of the immune cells in this organ. The aim of this study was to determine, through the model of altering the early mother-infant bond and altering the late social bond through isolation, the effect on the morpho-quantitative characteristics of the spleen in adult Sprague-Dawley rats subjected to intermittent chronic stress in adulthood. Twenty-five newborn female rats were used, kept under the standardized lactation and feeding conditions. The rats were assigned randomly to 2 control groups (C1 and C2) and 3 experimental groups, exposed to early (E1), late (E2) or early-late (E3) adverse experiences and then subjected to intermittent chronic stress in adulthood (C2, E1, E2 and E3). The spleen of each animal was isolated and its morphometric characteristics were determined: volume density (Vv) of the red pulp, white pulp, marginal zone, splenic lymph nodule, periarterial lymphatic sheath and germinal center; areal number density (Na), surface density (Sv), number density (Nv), diameter (D) and total number of splenic lymph nodules. The mass of each compartment was also determined. A one-way analysis of variance (ANOVA) and Scheffe's post hoc test were used for the statistical analysis. The p values were considered significant when they were less than 0.05 (*) and very significant at less than 0.025 (**). There were significant differences in the Vv of the red pulp, white pulp and their sub-compartments between the control and experimental groups. The white pulp increased significantly (P = 0.000) in E1, E2 and E3 compared to C1 and C2. The average Na and D values of the splenic lymph nodules were also higher in the experimental groups. The ANOVA for the mass of the spleen and the red pulp revealed no differences between the groups. The mass of the white pulp and its subcompartments was greater in the experimental groups. A higher proportion of white pulp in the experimental groups could be associated with an increase in spleen immune activity, with alterations depending on certain cell subsets. The chronic stress produced morpho-quantitative changes in the rat spleen, and these depended on the animal's history of stress, whether it had been previously stressed or not, with further exposure to stress in adulthood. PMID- 26097545 TI - Chromosomal imbalances revealed in primary renal cell carcinomas by comparative genomic hybridization. AB - Renal cell carcinoma (RCC) accounts for approximately 3% of all new cancer cases. Although the classification of RCC is based mainly on histology, this method is not always accurate. We applied comparative genomic hybridization (CGH) to determine genomic alterations in 46 cases of different RCC histological subtypes [10 cases of clear cell RCC (CCRCC), 13 cases of papillary RCC (PRCC), 12 cases of chromophobe RCC (CRCC), 9 cases of Xp11.2 translocation RCC (Xp11.2RCC), 2 cases of undifferentiated RCC (unRCC)], and investigated the relationships between clinical parameters and genomic aberrations. Changes involving one or more regions of the genome were seen in all RCC patients; DNA sequence gains were most frequently (>30%) seen in chromosomes 7q, 16p, and 20q; losses from 1p, 3p, 13q, 14q, and 8p. We conclude CGH is a useful complementary method for differential diagnosis of RCC. Loss of 3p21-25, 15q, and gain of 16p11-13 are relatively particular to CCRCC vs. other types of RCC. Gain of 7p13-22, 8q21-24, and loss of 18q12-ter, 14q13-24, and Xp11-q13/Y are more apparent in PRCC, and gain of 8q21-24 is characteristic of type 2 PRCC vs. type 1 PRCC. Loss of 2q12 32, 10p12-15, and 11p11-15, 13p are characteristic of CRCC, and gain of 3p and loss of 11p11-15 and 13p are significant differentiators between common CRCC and CRCC accompanied by sarcomatous change groups. Gain of Xp11-12 is characteristic of the Xp11.2RCC group. Based on Multivariate Cox regression analysis, aberration in 5 chromosome regions were poor prognostic markers of RCC, and include the gain of chromosome 12p12-ter (P = 0.034, RR = 3.502, 95% CI 1.097-11.182), 12q14-ter (P = 0.002, RR = 5.115, 95% CI 1.847-14.170), 16q21-24 (P = 0.044, RR = 2.629, 95% CI 1.027-6.731), 17p12-ter (P = 0.017, RR = 3.643, 95% CI 1.262-10.512) and the loss of 18q12-23 (P = 0.049, RR = 2.911, 95% CI 1.006-8.425), which may provide clues of new genes involved in RCC tumorigenesis. PMID- 26097546 TI - Intestinal mucosal barrier dysfunction participates in the progress of nonalcoholic fatty liver disease. AB - Intestinal mucosal barrier dysfunction is closely related to liver diseases, which implies impaired gut-liver axis may play a role in the pathogenesis of NAFLD. In our study, rats were divided into three groups: normal chow diet (NCD) group, high-fat diet (HFD) group and TNBS-induced colitis with high-fat diet (C HFD) group. Liver tissues were obtained for histological observation and TNF alpha, IL-6 mRNA determination and blood samples were collected for liver enzymes and LPS analysis. Ultrastructural changes of jejuna epithelium, SIBO and amounts of CD103(+)MHCII(+)DCs and CD4(+)CD25(+)FoxP3(+)T-regs in terms of percentage in mesenteric lymph nodes (MLN) were observed by electron microscope, bacterial cultivation and flow cytometry, respectively. The results demonstrated the pathological characteristics accorded with nonalcoholic simple fatty liver (NAFL) and NASH in HFD group by week 8 and 12, respectively. Besides, the degree of hepatic steatosis and steatohepatitis was more severe in C-HFD group compared with HFD-group at the same time point. NAFLD activity score (NAS), liver enzymes, concentration of LPS and mRNA expressions of TNF-alpha, IL-6 were higher significantly in C-HFD group compared with HFD and NCD group at week 4, 8 and 12, respectively. In HFD group, epithelium microvilli atrophy, disruptive tight junctions and SIBO were present, and these changes were more severe in NASH compared with NAFL. The percentage of CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs decreased significantly in NAFL and NASH compared with NCD group. Our conclusion was that gut-liver axis was impaired in NAFLD, which played crucial role in the pathogenesis of NAFLD. PMID- 26097547 TI - Abnormal immunomodulatory ability on memory T cells in humans with severe aplastic anemia. AB - Severe aplastic anemia (SAA) is a bone marrow failure disease induced by hyperfunctional autoimmunic Th1 lymphocytes. Memory T cells (TM) are a component of the adaptive immune system. They ensure the host of more aggressive and faster immune response to efficiently eliminate the specific antigens after re-exposure and thus play a key role in T-cell functions. In this study we investigate the quantities and functions of memory T cells in SAA patients before and after immunosuppressive therapy (IST) to further clarify the mechanism of SAA apoptosis of bone marrow hematopoietic cells. Results showed that the percentage of CD4+ effector T cells in peripheral blood and bone marrow lymphocytes was decreased in SAA patients. The ratio of CD4+ memory T lymphocytes to CD8+ memory T subsets (CD4+/CD8+TM) in SAA patients was also lower. The percentage of CD8+ effector T cells in peripheral blood and CD8+ central memory T cells in the bone marrow lymphocytes was significantly higher in newly diagnosed patients. Furthermore, the median expressions of perforin and granzyme B on memory T cells were higher in SAA patients compared to those in normal controls. After IST, the quantities and functions of memory T cells return to normal level. Therefore, we concluded that the abnormal immunomodulatory ability on memory T cells may contribute to the imbalance of Th1/Th2 subsets and thus lead to over-function of T lymphocytes and hematopoiesis failure in SAA. PMID- 26097548 TI - Role of cd56 and e-cadherin expression in the differential diagnosis of papillary thyroid carcinoma and suspected follicular-patterned lesions of the thyroid: the prognostic importance of e-cadherin. AB - INTRODUCTION: The pathological diagnosis of papillary thyroid carcinoma (PTC) is generally easy on routine sections stained with hematoxylin and eosin (H&E). However, the differentiation of the follicular variant of PTC (FVPTC) from other suspected follicular-patterned lesions of the thyroid is highly difficult. Among these, the lesions for which FVPTC cannot be excluded are classified as well differentiated tumors of uncertain malignant potential (WDT-UMP). The most common immunohistochemical (IHC) markers used in the differential diagnosis include HBME 1, galectin-3, and CK19. However, none of these markers provide a 100% differential diagnosis. OBJECTIVE: The present study compared the diagnostic value of CD56 and E-cadherin for the differentiation of FVPTC from the other benign follicular-patterned lesions, with HBME-1, galectin-3, and CK19. Using these markers, the controversial cases within the WDT-UMP group were reclassified. Additionally, the relationship between the reductions in E-cadherin expression with poor prognostic factors was investigated. MATERIALS AND METHODS: The IHC expressions of CD56, E-cadherin, HBME-1, galectin-3, and CK19 were evaluated in 181 thyroid lesions, including 101 PTCs (45 classical variant PTCs and 56 FVPTCs), 20 WDT-UMPs, 20 follicular adenomas (FAs), 20 hyperplastic nodules (HN), and 20 hyperplastic foci of lymphocytic thyroiditis. The results were statistically compared via SPSS. RESULTS: The expressions of all of the markers were statistically significantly different in PTC and follicular patterned lesions (P<0.05). It was found that the only marker with both sensitivity and specificity above 90% was CD56 negativity (sensitivity 91.1%, specificity 91.7%). The most sensitive and also the most specific double panel was CD56 negativity and galectin-3 positivity (sensitivity 96%, specificity 85%), and the most sensitive and specific triple panel was CD56 negativity, HBME-1 positivity, and galectin-3 positivity (97% and 70%, respectively). PMID- 26097549 TI - Ursolic acid derivative ameliorates streptozotocin-induced diabestic bone deleterious effects in mice. AB - OBJECTIVE: This study was performed to investigate bone deteriorations of diabetic mice in response to the treatment of ursolic acid derivative (UAD). METHODS: The biomarkers in serum and urine were measured, tibias were taken for the measurement on gene and protein expression and histomorphology analysis, and femurs were taken for the measurement on bone Ca and three-dimensional architecture of trabecular bone. RESULTS: UAD showed a greater increase in bone Ca, BMD and significantly increased FGF-23 and OCN, reduced PTH and CTX in diabetic mice. UAD reversed STZ-induced trabecular deleterious effects and stimulated bone remodeling. The treatment of STZ group with UAD significantly elevated the ratio of OPG/RANKL. Moreover, insulin and IGF-1 showed a negative correlation with both FBG and Hb1Ac in STZ group. We attributed down-regulating the level of Hb1Ac in diabetic mice to that ursolic acid derivative could primely control blood sugar levels. After analyzing of two adipocyte markers, PPARgamma and aP2, increased expression in the tibias of diabetic mice, and UAD could improve STZ-induced adipocyte dysfunction. CONCLUSIONS: These results demonstrated that UAD could ameliorate STZ-induced bone deterioration through improving adipocyte dysfunction and enhancing new bone formation and inhibiting absorptive function of osteoclast in the bone of diabetic mice. PMID- 26097550 TI - Golgi phosphoprotein 3 regulates metastasis of prostate cancer via matrix metalloproteinase 9. AB - Recent studies suggest that Golgi phosphoprotein 3 (GOLPH3) protein is a candidate metastasis gene in human cancer. The goal of this study was to determine the function of GOLPH3 in prostate cancer metastasis and to identify GOLPH3-regulated pathways and genes involved in prostate cancer metastasis. GOLPH3 expression was detected in prostate cancer. To investigate its function, PC-3 cells were stably transfected with shRNA targeting GOLPH3. Cell abilities of invasion and migration were measured in vitro. Downstream regulatory pathways of GOLPH3 were characterized using quantitative RT-PCR and Western blotting analysis. Immunohistochemical studies in prostate cancer specimens revealed a positive correlation of GOLPH3 expression with prostate cancer. GOLPH3 was expressed in prostate cancer cell lines. GOLPH3 repression resulted in the reduction of mRNA level and protein level of MMP9, accompanied with reduced phosphorylation of mTOR, EGFR and Src. Our findings suggest GOLPH3 regulate MMP9 expression which impact cell migration and invasion. This regulation is probably mediated by EGFR and Src signaling pathways. PMID- 26097551 TI - Kruppel-like factors 4 and 5 expression and their involvement in differentiation of oral carcinomas. AB - Proliferation-differentiation balance of epithelial cells is regulated by Kruppel like factors (KLF) 4 and 5, and the unbalanced expression relates to carcinoma progression. However, little is known about the expression and role in oral carcinomas. This study examined expression of KLF4 and KLF 5 in the carcinomas by immunohistochemistry (n = 67) and the involvement in proliferation and differentiation of carcinoma cells. KLF4 was detected in keratinizing carcinoma cells and KLF5 in non-keratinizing cells. KLF4 staining declined in the patient with lymph node metastasis (P < 0.05) and in parallel with the histological dedifferentiation (P = 0.09). Exogenous overexpression of KLF4 arranged cells in a cobble-like structure with desmosomes and KLF5 elongated cells like fibroblasts without desmosomes. KLF4 suppressed fibronectin expression, and KLF5 down regulated and degraded E-cadherin. The proliferation was not affected by KLFs. Thus, down-regulation of KLF4 and up-regulation of KLF5 may stimulate oral carcinoma progression through the dedifferentiation of carcinoma cells. PMID- 26097552 TI - Decreased SATB2 expression is associated with metastasis and poor prognosis in human clear cell renal cell carcinoma. AB - In this study, we investigate the expression and role of special AT-rich sequence binding protein-2 (SATB2) in clear cell renal cell carcinoma (ccRCC) tissue, and to evaluate the clinical and prognostic significance of SATB2 protein in patients with ccRCC. The expression of SATB2 and SATB1 was examined in ccRCC tissue by Western blotting, real-time PCR and immunohistochemical staining. The association between clinicopathological features and SATB2 level was investigated. The correlation of SATB2 expression with overall survival was also analyzed. The expression of SATB2 protein in tumor tissues was much lower than that in paired normal tissues. The overall survival of the patients with high SATB2 expression was significantly higher than that of the low SATB2 expression group. Low or negative SATB2 expression was significantly correlated with AJCC staging and Furman grade in ccRCC. In contrast, the expression of SATB1 was significantly higher in adjacent tumor tissue than that in normal and tumor tissues. This study provides the first evidence of the expression and clinical significance of SATB2 in ccRCC. Our data suggest that SATB2 functions as a tumor suppressor in the development and progression of ccRCC, and is thereby implicated as a valuable prognostic marker for ccRCC patients. PMID- 26097553 TI - HGF/MET signaling promotes glioma growth via up-regulation of Cox-2 expression and PGE2 production. AB - Cyclooxygenase2 (Cox-2) is well known for glioma growth through up-regulation of prostaglandin E2 (PGE2) levels. MET, a hepatocyte growth factor (HGF) receptor, is also frequently high expressed in glioma, which promotes glioma growth and invasion. Here, we demonstrate that HGF/MET signaling can promote PGE2 production in glioma cells via Cox-2 up-regulation. RNA inhibition of MET suggested that MET signaling is essential for Cox-2 up-regulation. Moreover, HGF could enhance Cox-2 expression and PGE2 release. Knockdown of Cox-2 inhibited growth-promoting effects of HGF, suggesting that HGF/MET functioned via Cox-2/PGE2 pathway. Therefore, our work reveals a critical relationship of Cox-2/PGE2 and HGF/MET signaling in promoting glioma cells proliferation. Further, targeting MET and Cox 2 may represent an attractive target therapy for glioma. PMID- 26097554 TI - Spatiotemporal expression of BMP7 in the development of anorectal malformations in fetal rats. AB - The aim of this study was to determine the expression patterns of bone morphogenetic protein 7 (BMP7) during anorectal development in normal rat embryos and in embryos with anorectal malformations (ARM), and to investigate the possible role of BMP7 in the pathogenesis of ARM. ARM was induced by treating rat embryos with ethylenethiourea on the 10th gestational day (GD10). Embryos were harvested by Cesarean delivery and the spatiotemporal expression of BMP7 was evaluated in normal (n=168) and ARM embryos (n=171) from GD13 to GD16 using immunohistochemistry staining and western blot analysis. Immunohistochemical staining in normal embryos revealed that BMP7 was abundantly expressed on the epithelium of the urorectal septum (URS) and the hindgut on GD13, and BMP7 immunopositive cells were extensively detected in the URS, hindgut, and cloacal membrane by GD14. Increased positive tissue staining was noted on the fused tissue of the URS and the thin anal membrane on GD15. In ARM embryos, the epithelium of the cloaca, URS, and anorectum were negatively or only faintly immunostained for BMP7. BMP7 protein expression showed time-dependent changes in the developing hindgut according to western blotting, and reached a peak on GD15 during anus formation. BMP7 expression levels from GD14 to GD15 were significantly lower in the ARM group compared with the normal group (P<0.05). Spatiotemporal expression of BMP7 was disrupted in ARM embryos during anorectal morphogenesis from GD13 to GD16. These results suggest that downregulation of BMP7 at the time of cloacal separation into the primitive rectum and UGS might be related to the development of ARM. PMID- 26097555 TI - Trimetazidine protects against hypoxia-reperfusion-induced cardiomyocyte apoptosis by increasing microRNA-21 expression. AB - Myocardial tissue injury caused by ischemia and hypoxia is a major cause of fatal diseases, including coronary atherosclerosis resulting from myocardial infarction and stroke. Trimetazidine (TMZ), as an anti-ischemic and antioxidant agent, has been demonstrated to preventing ischemia/reperfusion-induced cardiomyocyte apoptosis. However, the anti-apoptosis mechanism of TMZ has not been fully elucidated. The present study demonstrated that miR-21 involved trimetazidine induced anti-apoptosis during H/R injury in H9C2 cell. In this study, TMZ increased miR-21 expression which further upregulated the Akt signaling activity via suppressing the expression of phosphatase and tensin homolog (PTEN) in H/R H9C2 cell. The increased activity of Akt signaling decreased the ratio of Bax/Bcl 2 and the expression of caspase-3 and inhibited H/R induced apoptosis. In conclusion, this study revealed the mechanism that TMZ up-regulated miR-21 expression, then miR-21 targeted PTEN increasing the PI3K pathway and finally the activation of this pathway counteracted the apoptotic effect of hypoxia/reperfusion. PMID- 26097556 TI - Expression of androgen receptor in coronary artery in the cases of sudden coronary death. AB - To study the expression of androgen receptor (AR) in the cases of sudden death caused by coronary heart disease (CHD) and relationship between AR and sudden coronary death (SCD) to explore the mechanism of the development of coronary atherosclerosis and provide references for the prevent and treatment of CHD and medicolegal identification of SCD. 53 cases selected from the autopsied cases in our department from 2011 to 2012 were divided into 3 groups: 18 case of SCD, including 11 males and 7 females, as experimental group, another 18 cases, including 11 males and 7 females, with CHD but died of mechanical injuries and poisoning as control group I, and 17 cases without CHD who also died of mechanical injuries and poisoning including 10 males and 7 females, as control group II. After HE-stained and immunohistochemistry-stained (SP) for the slices, the expression of AR in coronary arteries were observed and the average optical density (AOD) of positive signal in each case were detected by using Image-Pro Plus 6.0 software. We found strongly positive expression of AR in control group II, weakly positive expression in control group I and a little weaker in the experimental group. The expression of AR in coronary artery was reduced in CHD patients, which suggested that androgen may have favorable effects on the cardiovascular system. PMID- 26097557 TI - Predictors for contralateral prophylactic mastectomy in breast cancer patients. AB - BACKGROUND: In recent years, radical breast cancer surgery has been largely replaced by breast conservation treatment, due to early diagnosis and more effective adjuvant treatment. While breast conservation is mostly preferred, the trend of bilateral mastectomy has risen in the United States. The aim of this study is to determine factors influencing patients' choice for having contralateral prophylactic mastectomy (CPM). METHODS: This is a retrospective study of 373 patients diagnosed with primary invasive breast cancer who were treated by bilateral or unilateral mastectomy (BM or UM) at the Revlon/UCLA Breast Center between Jan. 2002 and Dec. 2010. In the BM group, only those with unilateral breast cancer who chose CPM were included in the analysis. RESULTS: When compared with the UM group, the following factors were found to be associated with BM: younger age, pre-menopausal, a family history of breast/ovarian cancer, BRCA mutation, more breast biopsies, history of breast augmentation, having MRI study within 6 months before the surgery, more likely to have reconstruction and sentinel lymph node biopsy (SLNB) and fewer had neoadjuvant/adjuvant chemotherapy/radiation. When patients with bilateral breast cancer were excluded, multivariate logistic regression analysis indicated younger patients with negative nodes, SLNB as the only nodal surgery and positive family history were significant factors predicting CPM and immediate reconstruction using tissue expanders or implants. CONCLUSION: Younger age, lower TN stage, requiring only SLNB and high risk family history predict contralateral prophylactic mastectomy. Tissue expander/implant-based reconstructions were more frequently chosen by patients with BM. PMID- 26097558 TI - Decreased expression of long non-coding RNA NBAT-1 is associated with poor prognosis in patients with clear cell renal cell carcinoma. AB - OBJECTIVE: accumulating evidence suggest that long non-coding RNAs (lncRNAs) may play important roles in human cancers. LncRNA neuroblastoma associated transcript 1 (NBAT-1) was initially identified to be involved in the progression of neuroblastoma. However, there is no report about the role of NBAT-1 in clear cell renal cell carcinoma (ccRCC). The purpose of this study is to investigate the clinical significant of NBAT-1 in ccRCC. METHODS: the expression pattern of NBAT 1 in ccRCC patients and renal cancer cell lines was detected by using quantitative real-time PCR (qRT-PCR), and its correlation with clinicopathologic features and prognosis of patients with ccRCC was assessed by Kaplan-Meier method and Cox proportional hazards model, respectively. Small interfering RNA (siRNA) was transfected into 786-O and ACHN cells to determine the effect of NBAT-1 knockdown on renal cancer cells. RESULT: NBAT-1 expression is significantly decreased in ccRCC tissues and renal cancer cells compared with adjacent normal tissues and normal human proximal tubule epithelial cell line HK-2, and its low level is associated with advanced features and poor prognosis. Also, multivariate analysis identified NBAT-1 expression as an independent prognostic factor for ccRCC. In vitro assays indicated that knockdown of NBAT-1 expression increased renal cancer cell proliferation, migration and invasion. CONCLUSIONS: NBAT-1 is a novel molecular correlated with ccRCC progression; and it may represent a prognostic biomarker and therapeutic target in renal cancer diagnosis and treatment. PMID- 26097559 TI - Targeting eradication of chronic myeloid leukemia using chimeric oncolytic adenovirus to drive IL-24 expression. AB - Chronic myeloid leukemia (CML) is a clonal disorder in which cells of the myeloid lineage undergo massive clonal expansion as well as resistance to conventional chemotherapy. Gene therapy hold a great promise for treatment of malignancies based on the transfer of genetic material to the tissues. In this study, we explore whether chimeric oncolytic adenovirus-mediated transfer of human interleukin-24 (IL-24) gene induce the enhanced antitumor potency. Our results showed that chimeric oncolytic adenovirus carrying hIL-24 (AdCN205-11-IL-24) could produce high levels of hIL-24 in CML cancer cells, as compared with constructed double-regulated oncolytic adenovirus expressing hIL-24 (AdCN205-IL 24). AdCN205-11-IL-24 could specifically induce cytotoxocity to CML cancer cells, but little or no effect on normal cell lines. AdCN205-11-IL-24 exhibited remarkable anti-tumor activities and induce higher antitumor activity to CML cancer cells by inducing apoptosis in vitro. Our study may provides a potent and safe tool for CML gene therapy. PMID- 26097560 TI - beta-arrestin1 over-expression is associated with an unfavorable prognosis in lung adenocarcinomas and correlated with vascular endothelial growth factor. AB - The aim of this study was to examine beta-arrestin1 expression in patients with lung adenocarcinoma (ADC) and explore the relationship of beta-arrestin1 protein with clinicopathologic factors, vascular endothelial growth factor (VEGF) and prognosis. A total of 105 surgically resected lung adenocarcinoma patients were recruited for the study. The expression of beta-arrestin1 and VEGF were determined by immunohistochemistry (IHC). The score measuring the beta-arrestin1 and VEGF were calculated by combining the percentage of positive cells and the intensity of staining. Kaplan-Meier method and multivariable Cox proportional hazards regression analyses were used to examine the relationship between beta arrestin1 and survival. The results demonstrated that a notably higher level of beta-arrestin1 expression was found in lung ADC tissues. We also found that an elevated nuclear Beta-arrestin1 correlates with higher intratumoral VEGF (P = 0.007). beta-arrestin 1 over-expression indicated a poor 5-year overall survival (P = 0.016), and the Cox regression model confirmed that beta-arrestin1 over expression were independent prognostic factor for tumor progression (P = 0.027) and unfavorable overall survival (P = 0.015). We conclude that beta-arrestin1 had a high expression in ADC and beta-arrestin1 may be a promising biomarker to identify individuals with poor prognosis for patients with ADC. PMID- 26097561 TI - PABPC1 exerts carcinogenesis in gastric carcinoma by targeting miR-34c. AB - As one of the common malignant tumors that threaten human health severely, gastric carcinoma is the second highest cause of cancer death and the fourth most common cancer globally. However, the mechanism underlying gastric cancer is still not fully understood. PABPC1 plays an important role in translation, control the rate of mRNA deadenylation and participates in mRNA decay, which is involved in carcinogenesis. Here in present study, we reported that PABPC1 is an oncogenic protein in gastric carcinoma. The results showed that PABPC1 is upregulated in gastric carcinoma tissues, and high PABPC1 expression predicts poor survival. PABPC1 regulates proliferation and transformation of gastric cancer cells in vitro and in vivo. PABPC1 knockdown induces apoptosis by upregulating pro apoptotic proteins and downregulating anti-apoptotic proteins. In addition, miR 34c is a target of PABPC1, and miR-34c is critically essential for the function of PABPC1. In summary, PABPC1 exerts carcinogenesis and promotes growth and survival of gastric cancer cells by regulating miR-34c. PMID- 26097562 TI - Carboplatin-docetaxel-induced activity against ovarian cancer is dependent on up regulated lncRNA PVT1. AB - Ovarian cancer is the fourth most ordinary cause of cancer-related deaths in women. In recent, combination chemotherapy with carboplatin and docetaxel was developed as first-line drug to treat ovarian carcinoma. However, the detailed molecular mechanism, which accounts for the cells to apoptosis induced by administration of carboplatin and docetaxel, was unrecognized. In present study, we provide the mechanistic link between mixture of carboplatin plus docetaxel and its anticancer activity. Primarily, a majority of 30 cancer-related long non coding RNA (lncRNA) showed differential alteration in carboplatin-docetaxel treated 3AO cells. Among six up-regulating lncRNAs, we screened out carboplatin docetaxel-induced lncRNA PVT1 which may be a central downstream target of carboplatin plus docetaxel because expression of PVT1 positively correlates with anticancer action of carboplatin plus docetaxel. Besides, p53 and tissue inhibitor of matrix metalloproteinases-1 (TIMP1) were mediated by lncRNA PVT1, which may explain partially the anticancer activity of lncRNA PVT1. Collectively, we have identified a potential mechanism by which PVT1 regulated by carboplatin plus docetaxel contributes to the carboplatin-docetaxel-induced anticancer action in ovarian cancer. These discoveries also give proof of the potential of PVT1 as significant downstream targets for therapeutic intervention in ovarian cancer. PMID- 26097563 TI - Combinatorial effects of miR-20a and miR-29b on neuronal apoptosis induced by spinal cord injury. AB - Neuronal apoptosis is one of the prominent features involved in spinal cord injury (SCI). MicroRNAs (miRNAs) are small non-coding RNAs that functions in a variety of cellular processes including apoptosis. MiRNAs have been implicated as effectors of SCI. However, role of miRNAs in SCI-associated neuronal apoptosis remains to be investigated. A number of bioinformatics approaches have suggested Mcl-1 and BH3-only family genes as potential downstream targets regulated by miR 20a and miR-29b, respectively. To determine whether miR-20a and miR-29b play a role in neuronal apoptosis of SCI by regulating those genes, we transfected Neuro 2A neuroblastoma cells with mimic and inhibitor for the two miRNAs. The miR-20a mimic decreased Mcl-1 expression and the miR-29b mimic reduced the expression of Bad, Bim, Noxa and Puma. The repressor role of miR-20a and miR-29b is confirmed by the transfection of Neuro-2A cells with their inhibitor. Moreover, miR-20a mimic or miR-29b inhibitor attenuated Neuro-2A cell viability and co-transfection of both further diminished the viability of these cells. The in vitro effects of miR-20a and miR-29b on neuronal apoptosis were corroborated by the in vivo studies. Injection of miR-20a mimic or miR-29b inhibitor into the lesion of the injured spinal cord rescued the neuronal death and co-injection of both completely abolished SCI-induced apoptosis. In conclusion, altered expression of miR-20a and miR-29b may cooperatively contribute to the neuronal cell death of SCI through down-regulating anti-apoptotic myeloid cell leukemia sequence-1 (Mcl 1) and up-regulating pro-apoptotic BH3-only proteins. PMID- 26097564 TI - Upregulated expression of N-methyl-D-aspartate receptor 1 and nitric oxide synthase during form-deprivation myopia in guinea pigs. AB - This study aimed to investigate the expression of N-methyl-D-aspartate receptor 1 (NMDAR1) and neuronal constitutive nitric oxide synthase (ncNOS) during form deprivation myopia (FDM). FDM models were established in guinea pigs with facemasks. NMDAR1 expression in the retina was detected by immunohistochemistry and Western blot analysis. ncNOS mRNA expression was examined by in situ hybridization. cGMP content was measured by radioimmunoassay. In control group, NMDAR1 and ncNOS were expressed in binocular retinas, and there was no significant difference in NMDAR1 and ncNOS expression and cGMP content between the two eyes. However, NMDAR1 and ncNOS expression and cGMP content in the retina of FDM eyes were significantly higher than that of contralateral untreated eyes. Furthermore, ncNOS mRNA level and cGMP content was highly correlated. In conclusion, FDM upregulates the expression of NMDAR1 and ncNOS and increases cGMP content in the retina. NMDAR1/NO-cGMP pathway may contribute to abnormal visual signals during myopic progression. PMID- 26097565 TI - miR-106a promotes growth and metastasis of non-small cell lung cancer by targeting PTEN. AB - MicroRNAs are a class of small non-coding RNAs that play essential roles in cancer development and progression. Recent studies suggested that abnormal expression of miRNAs occurs frequently in non-small cell lung cancer (NSCLC) tissues compared to adjacent normal tissues. In this study, we investigated the expression and the biological roles of miR-106a in non-small cell lung cancer. Our results showed that miR-106a was up-regulated in NSCLC tissues and cell lines. Inhibition of miR-106a in NSCLC cells substantially inhibited cell proliferation, migration, and invasion. Phosphatase and tensin homolog (PTEN) was identified as a direct target of miR-106a, and over-expression of miR-106a suppressed PTEN by direct binding to its 3'-untranslated region (3'-UTR). Furthermore, the presence of miR-106a was inversely correlated with PTEN in NSCLC tissues. Overall, this study suggested that miR-106a inhibited the growth and metastasis of NSCLC cells by decreasing PTEN expression. These data provide novel insights with potential therapeutic applications for the treatment of NSCLC. PMID- 26097566 TI - Endogenous neural stem cells in central canal of adult rats acquired limited ability to differentiate into neurons following mild spinal cord injury. AB - Endogenous neural stem cells in central canal of adult mammalian spinal cord exhibit stem cell properties following injury. In the present study, the endogenous neural stem cells were labeled with Dil to track the differentiation of cells after mild spinal cord injury (SCI). Compared with 1 and 14 days post mild injury, the number of endogenous neural stem cells significantly increased at the injured site of spinal cord on 3 and 7 days post-injury. Dil-labeled betaIII-tublin and GFAP expressing cells could be detected on 7 days post-injury, which indicated that the endogenous neural stem cells in central canal of spinal cord differentiated into different type of neural cells, but there were more differentiated astrocytes than the neurons after injury. Furthermore, after injury the expression of inhibitory Notch1 and Hes1 mRNA began to increase at 6 hours and was evident at 12 and 24 hours, which maintained high levels up to 7 days post-injury. These results indicated that a mild SCI in rat is sufficient to induce endogenous neural stem cells proliferation and differentiation. However, the ability to differentiate into neurons is limited, which may be, at least in part, due to high expression of inhibitory Notch1 and Hes1 genes after injury. PMID- 26097567 TI - Nitric oxide donor, NOC7, reveals dose dependently and cGMP pathway independently biphasic effects on contractile force of isolated rat heart after global ischemia. AB - PURPOSE: Our purpose was to investigate whether the 3-(2-hydroxy-1-methyl-2 nitroso-hydrazino)-N-methyl-1-propanamine (NOC7), an ideal NO donor was dose dependently and cGMP-independent in restored cardiac function after global ischemia in an isolated rat heart model. METHODS: Langendorff preparations of an isolated rat heart model were established. Isolated rat hearts (n = 40) were randomly divided into 5 groups (ischemic control group, NOC7 groups and NOC7+NS2028 groups). All groups were subjected to 35 min global ischemia, followed by 30 min reperfusion with Krebs-Henseleit bicarbonate buffer (KHB), and NOC7, NOC7+NS2028 at 2 and 200 MUM, respectively. Left ventricular developed pressure (LVDP), the maximum and the minimal rate of rise in LVP (+/- dP/dt), and coronary flows were measured continuously. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels were measured in myocardium homogenate, using enzyme immunoassay (EIA). RESULTS: 30 min of global ischemia increased LVDP to 121.9 +/- 11.5% at 35 min of reperfusion of 2 MUM NOC7 group and 2 MUM NOC7 associated with NS2028 group from the ischemic control group (P < 0.05). While in 200 MUM NOC7 group and 200 MUM NOC7 associated with NS2028 group, the LVDP value only slightly reduced, resulting in a value of only 45.3 +/- 10.4% and 35.3 +/- 6.0% of baseline (P > 0.05). CONCLUSION: NOC7 has biphasic effect on isolated rat heart after ischemia and reperfusion myocardial contractility. This biphasic effect shows neither concentration-dependent nor the cGMP-dependent characteristics. PMID- 26097568 TI - Mesothelial/monocytic incidental cardiac excrescences (cardiac MICE) associated with acute aortic dissection: a study of two cases. AB - Acute aortic dissection is a life-threatening condition mainly caused by hypertension, atherosclerotic disease and other degenerative diseases of the connective tissue of the aortic wall. Mesothelial/monocytic incidental cardiac excrescences (cardiac MICE) is a rare benign reactive tumor-like lesion composed of admixture of histiocytes, mesothelial cells, and inflammatory cells set within a fibrinous meshwork without a vascular network or supporting stroma. Cardiac MICE occurring in association with aortic dissection is exceptionally rare (only one such case reported to date). We herein report on the surgical repair of two Stanford type A aortic dissections caused by idiopathic giant cell aortitis in a 66-year-old-woman and by atherosclerotic disease in a 58-year-old-man, respectively. In both cases, the dissections could be visualized via computed tomography. Histopathology showed cardiac incidental MICE within the external aortic wall near the pericardial surface which was confirmed by immunohistochemistry. PMID- 26097569 TI - Increased expression of metastasis-associated in colon cancer-1 in renal cell carcinoma is associated with poor prognosis. AB - Metastasis-associated in colon cancer-1 (MACC1) expression in tumor specimens is an independent prognostic indicator of metastasis, which has recently gained considerable attention in cancer research, due to its overexpression in several types of carcinoma. However, MACC1 expression patterns and its possible role in renal cell carcinoma remain unknown. This study aimed to investigate MACC1 expression in renal cell carcinoma via immunohistochemical analysis and determine the relationship between MACC1 expression and cancer prognosis. Positive MACC1 expression was found to significantly correlate with distant metastasis and TNM stage (P < 0.05). A Kaplan-Meier survival analysis revealed that patients with higher MACC1 expression had a significantly lower disease-free rate (P < 0.05). These results indicate that MACC1 expression is significantly associated with prognosis in patients with renal cell carcinoma. To the best of our knowledge, this is the first study on the significance of MACC1 as a prognostic marker in renal cell carcinoma. MACC1 expression may be a useful target for the development of new therapeutic approaches, including molecular targeted therapeutic agents, for renal cell carcinoma. PMID- 26097570 TI - MicroRNA-139-5p inhibits cell proliferation and invasion by targeting insulin like growth factor 1 receptor in human non-small cell lung cancer. AB - INTRODUCTION: Increasing evidence suggested that microRNAs (miRNAs) play a critical role in tumorigenesis. Decreased expression of miRNA-139-5p has been observed in various types of cancers. However, the biological function of miRNA 139-5p in non-small cell lung cancer (NSCLC) is still largely unknown. METHODS: Quantitative real-time PCR (qRT-PCR) was used to explore the expression level of miRNA-139-5p in NSCLC tissues and cell lines. Then, we investigated the role of miRNA-139-5p to determine its potential roles on lung cancer cell proliferation, migration and invasion in vitro. A luciferase reporter assay was performed to confirm the target gene of miRNA-139-5p and the results were validated in renal cancer cells. RESULTS: miRNA-139-5p was significantly decreased in NSCLC tissues and cell lines. Over-expression of miRNA-139-5p could inhibit lung cancer cell proliferation, migration, and invasion in vitro. Furthermore, we identified insulin-like growth factor 1 receptor (IGF1R) as a target of miR-139-5p and miR 139-5p function as a tumor suppressor via targeting IGF1R in NSCLC. CONCLUSIONS: Our results indicated that miR-139-5p acts as a tumor suppressor in NSCLC partially via down-regulating IGF1R expression. PMID- 26097571 TI - SOX9 was involved in TKIs resistance in renal cell carcinoma via Raf/MEK/ERK signaling pathway. AB - Renal cell carcinoma (RCC) is common genitourinary malignancy in human, 30-40% of patients with RCC would be diagnosed with metastatic RCC (mRCC). Even in the era of targeted therapy, patients with mRCC would inevitably progress due to drug resistance. Herein, exploration of the mechanisms of resistance is noteworthy to study. In the present study, we firstly reported the expression profile of SOX9 in renal carcinoma cells and tissues, and found that its expression was significantly associated with Fuhrman grading. Dual luciferase analysis confirmed that Raf/MEK/ERK pathway could directly be regulated by SOX9, and sequential experiments demonstrated that, renal carcinoma cells could sensitize to Sorafenib/Sunitinib through Raf/MEK/ERK signaling pathway inhibition regulated by SOX9 down-regulation. In a small cases with mRCC treated with Sorafenib/Sunitinib (n=38), comparative analysis showed that patients with SOX9 (-) had much better therapeutic response to TKIs than those with SOX9 (+) (PD: 9.1% vs. 56.2%, P=0.002, DCR: 90.9% vs. 43.8%, P=0.002). Based on these findings, we concluded that, SOX9 was firstly described to be highly expressed in renal cell carcinoma, and its expression was involved in TKIs drug resistance through activation of Raf/MEK/ERK pathway. In vitro, patients with SOX9 (-) was related to better response to TKIs treatment than those with SOX9 (+). SOX9 could be expected to be a promising biomarker predicting TKIs response and even expected to be another novel target in the treatment of mRCC. PMID- 26097411 TI - Search for a new resonance decaying to a W or Z boson and a Higgs boson in the [Formula: see text] final states with the ATLAS detector. AB - A search for a new resonance decaying to a W or Z boson and a Higgs boson in the [Formula: see text] final states is performed using 20.3 fb[Formula: see text] of pp collision data recorded at [Formula: see text] 8 TeV with the ATLAS detector at the Large Hadron Collider. The search is conducted by examining the WH / ZH invariant mass distribution for a localized excess. No significant deviation from the Standard Model background prediction is observed. The results are interpreted in terms of constraints on the Minimal Walking Technicolor model and on a simplified approach based on a phenomenological Lagrangian of Heavy Vector Triplets. PMID- 26097572 TI - Expression and clinical significances of Beclin1, LC3 and mTOR in colorectal cancer. AB - Autophagy is related to cancer and other diseases, and compromised autophagy could promote chromosome instability associated with carcinogenesis and tumor progression. The role of autophagy in the growth and metastasis of colorectal cancer (CRC) remains poorly understood. Beclin1 mediates autophagic initiation, and LC3 is a specific marker for autophagy. Inactivation of mTOR caused by cellular hypoxia or energy deficiency induces autophagic activity. This study aims to examine the expression and clinical significance of these proteins in CRC. Immunohistochemistry results showed that the positive expression rates of Beclin1, LC3, and mTOR in cancer tissues were 90.50%, 87.19%, and 46.28%, respectively, which were higher than those in adjacent tissues (P < 0.05). Differentiation degree and lymph node metastasis were associated with LC3 overexpression (P < 0.05) but not with Beclin1 (P > 0.05). Lymph node metastasis was also related to mTOR. Spearman analysis results showed that LC3 expression was positively correlated with Beclin1 but negatively correlated with mTOR (r = 0.593 and -0.165, respectively; P < 0.01). Beclin1 expression was also not associated with mTOR (P > 0.05). Survival analysis further indicated that LC3, mTOR, and lymph node metastasis were independent prognostic factors in CRC. Real time PCR results and Western blot indicated that Beclin1, LC3, and mTOR expression in CRC was significantly higher than that in adjacent tissues (P < 0.01). The aberrant protein expression may be associated with the development and progression of CRC. The LC3 and mTOR genes must be simultaneously detected to evaluate progression and prognosis of CRC. PMID- 26097574 TI - Epithelioid angiosarcoma: a clinicopathological study of 16 Chinese cases. AB - AIMS: To review retrospectively 16 cases of epithelioid angiosarcomas (EAs) with emphasis on their clinical and pathological characteristics, treatment and possible prognostic factors. METHODS AND RESULTS: All eligible cases were searched and acquired from archives of the pathology departments of two hospitals in Shanghai, The Fifth People's Hospital of Shanghai, Fudan University, and the Shanghai Cancer Center, Fudan University, China. The patients ranged in age from 19 to 77 years, and 5 patients were below 50 years of age. Microscopically, the tumors were mostly composed of large, round or polygonal epithelioid cells that were predominantly arranged in solid sheets or nests. The tumor cells had basophilic or eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. Mitotic figures including abnormal mitoses were frequently encountered. In all 16 cases in our series, immunohistochemical studies showed positivity for CD31, and partial positivity for Fli-1, CD34 and factor VIII-related antigen. Of the 14 patients available for follow-up, 3 patients were alive with disease, 9 patients died as a result of the tumor, 1 died of local hemorrhage, and one died of unknown etiology. The median survival was 17.1 months. CONCLUSIONS: EA is highly aggressive and carries a very poor prognosis. Therefore, the clinical recognition and correct diagnosis of EA are essential. PMID- 26097573 TI - LOXL4 is downregulated in hepatocellular carcinoma with a favorable prognosis. AB - Lysyl oxidase like 4 (LOXL4), a member of the secreted copper-dependent amine oxidases that contribute to the assemble and maintenance of the extracellular matrix (ECM), was found to be up-regulated or down-regulated in different cancer types, suggesting its paradoxical roles in cancer. The specific role of LOXL4 in hepatocellular carcinoma (HCC), however, is still yet to be defined. Twenty-eight pairs of HCC specimens were used for LOXL4 mRNA expression analysis. The mRNA expression in HCC cell lines was examined, and HepG2 was selected for LOXL4 small interfering RNA (siRNA) interference to investigate the biological function of LOXL4, LOXL4 immunohistochemical staining was performed using a tissue microarray containing 298 HCC patients. The prognostic and diagnostic value of LOXL4 was evaluated using Cox regression and Kaplan-Meier analysis. LOXL4 mRNA or protein expression was significantly lower in HCC tissues than peritumoral tissues (LOXL4 mRNA expression, P = 0.018; LOXL4 protein expression, P < 0.001). Low LOXL4 expression was associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that LOXL4 was an independent prognostic indicator for OS and time to recurrence (TTR). Our results revealed that LOXL4 was down-regulated in HCC and correlated with aggressive tumors and a worse clinical outcome. LOXL4 may be a potential biomarker to identify the HCC patients with a higher risk of recurrence. PMID- 26097579 TI - Evaluation of oxidative events and copper accumulation in oral tissues of patients with Wilson's disease: three case report. AB - Wilson's disease (WD), also known as hepatolenticular degeneration, was first described in 1912 by Kinnear Wilson. It is an autosomal recessive disorder caused by mutations in the ATP7B gene, a membrane-bound copper transporting ATPase. The disorder is caused by impairment of the copper transporting ATPase, ATP7B, in the liver, which disturbs copper transport, excretion into the bile, and incorporation into apoceruloplasmin. WD is an inherited copper metabolism disorder with pathological copper accumulation in many tissues, but especially in brain and liver. We conducted this study because copper accumulation in oral tissues in patients with WD have not been studied before. We think that copper accumulation and differences of oxidative events in oral tissues can cause tendency to periodontal diseases. PMID- 26097575 TI - Vascular invasion as an independent predictor of poor prognosis in nonmetastatic gastric cancer after curative resection. AB - The prognostic significance of vascular invasion (VI) in nonmetastatic gastric cancer (GC) remains a matter of controversy. The purpose of this study was to assess the impact of VI on survival in this group of GC patients. We enrolled 361 GC patients without metastasis who underwent curative gastrectomy between 1996 and 2009 in Sun Yat-sen University Cancer Center. A retrospective analysis of the clinicopathological data was performed, focusing on the impact of VI detected by routine H&E staining on disease-free survival (DFS) and cancer-specific survival (CSS). The presence of VI was detected in 13.9% of our cohort. The VI status was significantly correlated with the tumor size, infiltration depth, and TNM stage (P < 0.05). Patients with VI showed significantly lower DFS and CSS compared with patients without VI (P < 0.0001 for both). The subgroup analysis indicated that the presence of VI was a negative predictor of DFS in all TNM stages and a predictor of lower CSS only in stage I (P < 0.05 for all). A multivariate Cox proportional analysis identified VI as an independent predictor of CSS (P = 0.022). The presence of VI is a risk factor for recurrence and an independent predictor of poor survival in nonmetastatic GC after curative resection. The VI status should be considered to stratify with this group of GC patients for adjuvant treatment and more effective follow-up protocol. PMID- 26097576 TI - High expression of Zinc-finger protein X-linked is associated with reduced E cadherin expression and unfavorable prognosis in nasopharyngeal carcinoma. AB - Zinc-finger protein X-linked (ZFX), a novel transcription factor required for self-renewal of embryonic stem cells, has recently been implicated in the initiation and progression of various human malignancies. However, its clinical significance in cancer patients remains largely inconclusive and its role in nasopharyngeal carcinoma (NPC) has never been reported. In this study, quantitative real-time polymerase chain reaction, Western blot and Immunohistochemistry were performed to detect ZFX expression in NPC and normal nasopharyngeal tissues. As a result, we found ZFX expression was significantly elevated in NPC tissues compared with that in normal nasopharyngeal tissues. The statistical analysis based on immunohistochemical staining demonstrated that ZFX expression was significantly correlated with lymph node stage and clinical stage. Furthermore, we found NPC patients with high ZFX expression had lower 5-year overall survival rates, progression-free survival rates, loco-regional relapse free survival rates and distant metastasis-free survival rates than those with low ZFX expression (all P<0.05). The multivariate analysis indicated that ZFX expression was an independent prognostic factor for patients with NPC. More importantly, we also detected E-cadherin expression in NPC tissues and found it was inversely correlated with ZFX expression in NPC tissues, suggesting a potential involvement of ZFX in Epithelial-mesenchymal transition (EMT). Therefore, it is speculated that ZFX may promote NPC progression partly by regulating EMT. In summary, our study not only for the first time identified that ZFX could serve as an effective prognostic biomarker for NPC patients, but also suggested that targeting ZFX might be a novel therapeutic strategy for preventing NPC progression and metastasis. PMID- 26097580 TI - Selection of reference genes for expression analyses in liver of rats with impaired glucose metabolism. AB - Hepatic gene expression studies are vital for identification of molecular factors involved in insulin resistance. However, the need of normalized gene expression data has led to the search of stable genes which are useful as a reference in specific experimental conditions. The aim of this study was to evaluate expression stability of potential reference genes for real-time PCR gene expression studies, in rats with insulin resistance, early programmed in intrauterine environment of maternal insulin resistance and triggered by exposure to a high sucrose and fat diet in adult life. Male rats coming from insulin resistant (F1IR) mothers or normal (F1N) mothers were fed a standard rodent diet from postnatal day 21 to day 56, and then divided in two groups each. One of each subgroups were fed a high sucrose and fat diet (groups F1IR + HSFD and F1N + HSFD respectively), the rest were fed a control diet (groups F1IR + CD and F1N + CD) for 14 days. Glucose metabolism related tests were later performed. After liver extraction, RNA was isolated and gene expression analyzes of seven potential reference genes (Actb, Gapdh, Gusb, Hprt1, Ldha, Rpl13a and Rplp1) were carried out. LinRegPCR software was used to analyze raw data and determinate baseline corrections, threshold lines, efficiency of PCR reactions and corrected Cq values. Evaluations of gene expression stabilities as well as the number of necessary genes for normalization were assessed with geNorm tool. All samples from all groups showed acceptable PCR amplification efficiencies. The most stable genes were Rplp1, Ldha, Hprt1 and Rpl13a and the less stable was Gapdh. For all groups, just 2 to 3 of the most stable genes were necessary for optimal gene expression data normalization in rat liver. Genes encoding ribosomal proteins are the most appropriated for normalization of expression data in the presented animal model. By contrast, Gapdh, one of the most used genes in normalization, is not recommendable due to its high intergroup variation. PMID- 26097577 TI - Associations between the properties of the cartilage matrix and findings from quantitative MRI in human osteoarthritic cartilage of the knee. AB - The aim of this study was to investigate the associations between the properties of the cartilage matrix and the results of T2 mapping and delayed gadolinium enhanced magnetic resonance imaging (dGEMRIC) in human knee osteoarthritic cartilage. Osteochondral samples were harvested from the middle part of the femoral condyle and tibial plateaus of 20 patients with knee osteoarthritis (OA) during total knee arthroplasty. Sagittal T2 mapping, T1pre, and T1Gd were performed using 7.0T magnetic resonance imaging (MRI). Glycosaminoglycan (GAG) distribution was evaluated by OARSI, collagen anisotropy was assessed by polarized light microscopy (PLM), and biochemical analyses measured water, GAG, and collagen content. Associations between properties of the cartilage matrix and T2 and DeltaR1 (1/T1Gd-1/T1pre) values were explored using correlation analysis. T2 and DeltaR1 values were significantly correlated with the degree of cartilage degeneration (OARSI grade; Rho = 0.53 and 0.77). T2 values were significantly correlated with water content (r = 0.69; P < 0.001), GAG content (r = -0.43; P < 0.001), and PLM grade (r = 0.47; P < 0.001), but not with collagen content (r = 0.02; P = 0.110). DeltaR1 values were significantly correlated with GAG content (r = -0.84; P < 0.001) and PLM grade (r = 0.41; P < 0.001). Taken together, T2 mapping and dGEMRIC results were correlated with the properties of the cartilage matrix in human knee osteoarthritic cartilage. Combination T2 mapping and dGEMRIC represents a potential non-invasive monitoring technique to detect the progress of knee OA. PMID- 26097578 TI - Bronchogenic cyst of the conus medullaris with spinal cord tethering: a case report and review of the literature. AB - Bronchogenic cysts (BCs) are congenital malformations that originate from remnants of the primitive foregut. Intraspinal BCs, especially those of the conus medullaris are rare with only one case reported until now. To date, a bronchogenic cyst with spinal cord tethering has not been previously reported. We reviewed the clinical course of a 44-year-old woman, who presented with low back pain and leg weakness as well as sphincter disturbance. Magnetic resonance imaging showed an intradural oval mass located at the conus medullaris. A tethered cord was also observed, as well as a dermal sinus tract. The mass was totally removed after an L3-L4 laminectomy without detethering during operation. Pathologic examination confirmed the diagnosis of bronchogenic cyst. By six months after treatment, the patient had experienced nearly complete recovery. The review of literature indicated that detethering was performed in most reported cases of neurenteric cysts with spinal cord tethering, and one of six patients was diagnosed with a postoperative recurrence. The co-existence of bronchogenic cyst and a tethered spinal cord would imply associated developmental errors in embryogenesis. It is worth noting that whether detethering is necessary after the cyst removal. PMID- 26097582 TI - Large palpable ductal carcinoma in situ is Her-2 positive with high nuclear grade. AB - Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group with variable clinical presentation. The exact molecular mechanism is not known why some ductal carcinomas may reach to such a large size but still remains in situ. Although, molecular classification of DCIS lesions and nuclear grading are important for identification of more aggressive lesions but it is not sufficient. Our aim was to examine the expression pattern of immunohistochemical (IHC) markers of ER, PR, HER-2 in palpable DCIS lesions and compare with clinicopathological findings. Our center is referral hospital from South of Iran. Samples were obtained from fifty four patients with a diagnosis of palpable DCIS. Equivocal (2+) case in HER-2 IHC testing was more characterized by chromogenic in situ hybridization. The positive frequency of HER2, ER, and PR was 92%, 48%, and 37% respectively. Palpable DCIS lesions were significantly more HER-2 positive (92%). The DCIS cases were more likely to be of high nuclear grade (grade III) and Her-2 positive cases were more likely to be of high nuclear grade than intermediate grade. All ER negative tumors had high nuclear grade. The Her-2 positivity is suggested as the most important factor responsible for marked in situ proliferation and production of palpable mass. PMID- 26097581 TI - Prognostic significance of phosphorylated 4E-binding protein 1 in non-small cell lung cancer. AB - Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1) results in release of eIF4E, which sequentially relieves translational repression and enhances oncogenic protein synthesis. We assessed the expression of phosphorylated 4E-BP1 (p-4E-BP1) in non-small cell lung cancer (NSCLC) and its correlation with clinicopathological parameters and patient survival. In addition, we investigated whether phosphorylation site made a difference in outcome. Tissue microarray blocks were generated from 73 NSCLC samples and immunohistochemically stained for p-4E-BP1 Thr37/46 and p-4E-BP1 Thr70. Both p-4E-BP1 Thr37/46 and p-4E-BP1 Thr70 were more highly expressed in squamous cell carcinoma than in adenocarcinoma (P = 0.006 and P = 0.003, respectively). Expression of p-4E-BP1 Thr70 was higher in tumours with a diameter larger than 3 cm (P = 0.024) and nodal metastasis (P = 0.053). High p-4E-BP1 Thr70 expression significantly correlated with worse overall survival (P = 0.001) and was an independent prognostic factor (hazard ratio 2.64, P = 0.004). p-4E-BP1 Thr37/46 had no prognostic significance. Phosphorylation site affected the prognostic significance of p-4E-BP1. p-4E-BP1 Thr70 is a candidate biomarker to predict poor prognosis in patients with NSCLC. PMID- 26097583 TI - Effects of Smad decoy ODN on shear stress-induced atherosclerotic ApoE-/-mouse. AB - Atherosclerosis is a complex disease which involves both genetic and environmental factors in its development and progression. Shear stress is the drag force per unit area acting on the endothelium as a result of blood flow, and it plays a critical role in plaque location and progression. TGF-beta1 is often regarded to have pro-atherosclerotic effect on vascular disease. TGF-beta1 downstream targets Smad, for regulating a set of genes associated with atherosclerosis. Therefore, modulation of TGF-beta1 and Smad expression may be the important targets for the prevention and treatment of shear stress-induced vascular disease. However, the precise mechanism of the anti-atherosclerotic effects of novel therapeutic approach has not been elucidated by using animal models regarding the shear stress-induced vascular disease. Therefore, we designed to test whether Smad decoy ODN would prevent the development of atherosclerosis in the shear stress-induced ApoE-/-mice on a western diet. We examined the effect of cast placement on the development of atherosclerosis, and the carotid artery was harvested at the sacrifice to observe histological changes. Also, we evaluated the impact of Smad decoy ODN in the regulation of genes expression related to atherosclerosis, including TGF-beta1, PAI-1, and alpha-SMA. Our results showed that western diet with cast placement developed atherosclerosis in ApoE-/-mouse. Also, administration of Smad decoy ODN decreases the expression of TGF-beta1, PAI-1, and alpha-SMA. These results demonstrate the potential of Smad decoy ODN to prevent the progression of atherosclerosis in ApoE /-mouse model with western diet and shear stress. PMID- 26097584 TI - Differential expression of FOXA1, DUSP6, and HA117 in colon segments of Hirschsprung's disease. AB - OBJECTIVE: To describe the expression profiles of FOXA1, DUSP6, and HA117 in different portions of the colon of patients diagnosed with Hirschsprung's disease (HSCR). METHODS: Colon specimens were collected from 34 HSCR patients and grouped into 3 segments: proximal anastomosis, dilated segment and stenotic segment. Levels of FOXA1, DUSP6, and HA117 RNA were evaluated by real-time PCR. Levels of FOXA1 and DUSP6 protein were analyzed by immunohistochemistry and Western blotting. RESULTS: The levels of FOXA1 and DUSP6 RNA were significantly lower in the stenotic segment compared to proximal anastomosis (P < 0.05). The level of HA117 RNA was significantly higher in the stenotic segment compared to proximal anastomosis (P < 0.05). In proximal anastomosis, FOXA1 and DUSP6 were both expressed at the protein level in ganglion cells and nerve fibers between the circular and longitudinal muscles. In the stenotic segments, positive staining for FOXA1 and DUSP6 was diminished. The levels of FOXA1 and DUSP6 protein were significantly lower in the stenotic segment compared to proximal anastomosis (P < 0.05). CONCLUSION: Suppression of the FOXA1/DUSP6 signaling pathway may contribute to the development of HSCR. LncRNA HA117 may have an anti differentiation function, and play a pivotal role in the progression of HSCR. PMID- 26097585 TI - A novel method to identify and isolate proliferative inflammatory atrophy (PIA) clusters and to extract high-quality PIA RNA. AB - Epidemiological and histopathological studies have indicated that proliferative inflammatory atrophy (PIA) of the prostate is closely associated with the onset and development of prostate cancer (PCa). However, accurate isolation of PIA still remains a difficult matter, as well as high-quality RNA extraction from isolated PIA. These issues generated a lack of molecular evidence to support the mechanistic explanation proposed for the progression of PIA to PCa. Therefore, the isolation of PIA and the extraction of high-quality RNA from isolated PIA are of great importance to further demonstrate the correlation between PIA and the development of PCa at a molecular level. In this study, clinical samples from radical prostatectomy were stored in liquid nitrogen, PIA was identified by H&E staining of cryosections, PIA clusters were isolated by manual microdissection, total RNA was extracted from the PIA clusters by Trizol, and RNA quality was determined using the Agilent 2100 Bioanalyzer. Our results showed that PIA might be isolated by manual microdissection of cryosections stored in liquid nitrogen from clinical radical prostatectomy and used for extracting high-quality RNA (RIN > 7.5) by Trizol. Therefore, the present study established a valid method to discover molecular evidence in support of the correlation between PIA and the development of PCa. PMID- 26097587 TI - Cullin1 is up-regulated and associated with poor patients' survival in hepatocellular carcinoma. AB - Cullin1 (Cul1) is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex, which ubiquitinates a broad range of proteins involved in cell-cycle progression, signal transduction, and transcription. To investigate the role of Cul1 in the development of hepatocellular carcinoma (HCC), we evaluated the Cul1 expression by immunohistochemistry using a tissue microarray (TMA) containing 90 cases HCC tissues and paired adjacent non-cancerous tissues. We analyzed the correlation between Cul1 expression and clinicopathologic variables and patients survival using two independent HCC cohorts TMA. Our data showed that Cul1 expression was apparently increased in HCC tissues compared with paired adjacent non-tumor tissues. We also demonstrated that Cul1 staining was significantly correlated with tumor size, histology grade and TNM stage. Furthermore, we showed a strong correlation between high Cul1 expression and worse 5-year overall and disease specific survival rates in HCC patients. Finally, univariate and multivariate Cox proportional hazards regression analysis investigated that high Cul1 expression was a strong independent prognostic indicator of HCC. Our data indicated that Cul1 may be an important prognosis marker for human HCC. PMID- 26097586 TI - miR-144 regulates transforming growth factor-beta1 iduced hepatic stellate cell activation in human fibrotic liver. AB - OBJECTIVES: Activation of hepatic stellate cells (HSCs) into collagen producing myofibroblasts is critical for pathogenesis of liver fibrosis. Transforming growth factor-beta1 (TGF-beta1) is one of the main profibrogenic mediators for HSC transdifferentiation. Recent studies have shown effect of microRNAs (miRNAs) on regulating TGF-beta1-induced HSC activation during liver fibrosis. Here, we aimed to explore the roles of miR-144 and miR-200c in human liver fibrosis. METHODS: Expression of TGF-beta1 was detected in 42 fibrotic and 18 normal human liver tissues by quantitative real time polymerase chain reaction (qRT-PCR) and immunohistochemistry, and its correlation with alpha-smooth muscle actin (alpha SMA) was calculated. miR-144 and miR-200c expression level in fibrotic liver tissues were also detected by qRT-PCR. The correlation of TGF-beta1 expression with miR-200c and miR-144 in the fibrotic liver was analyzed. RESULTS: The results showed that TGF-beta1 expression was much higher in fibrotic liver than that in normal liver tissues (P<0.05). TGF-beta1 protein high expressing liver fibrosis showed alpha-SMA positive cells in the liver parenchyma indicating activated HSCs. Expression of TGF-beta1 in fibrotic liver was significantly correlated with alpha-SMA expression (R=0.633, P<0.001). Furthermore, miR-144 was less expressed in liver fibrosis (P<0.05) and was significantly correlated with expression of TGF-beta1 in fibrotic liver tissues (R=-0.442, P<0.01). However, miR-200c did not show significant difference between normal and fibrotic liver (P=0.48) and correlation with TGF-beta1 expression (R=0.106, P=0.51). CONCLUSION: All the results indicate that miR-144 can be a novel regulator of TGF-beta1 induced HSC activation during liver fibrosis. PMID- 26097588 TI - Up-regulation of long non-coding RNA Sox2ot promotes hepatocellular carcinoma cell metastasis and correlates with poor prognosis. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have been shown to have important regulatory roles in cancer biology, and the lncRNA Sox2ot is up-regulated in some tumors. However, the contributions of Sox2ot to hepatocellular carcinoma (HCC) remain largely unknown. METHODS: In the present study, expression of lncRNA Sox2ot was evaluated by quantitative real-time PCR in tumor tissues and adjacent non-tumor tissues in 84 HCC patients. The association of lncRNA Sox2ot expression with clinicopathological features and the prognosis of HCC patients were also analyzed. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. Small interfering RNA assay was used to explore the function of lncRNA Sox2ot on HCC cell migration and invasion. RESULTS: lncRNA Sox2ot expression level was significantly higher in HCC tissues compared with adjacent non-tumor tissues (P<0.05). High expression of lncRNA Sox2ot was associated with histological grade, TNM stage, and vein invasion. The 5-year overall survival of high lncRNA Sox2ot expression group was significantly shorter than that of low lncRNA Sox2ot expression group (P<0.05). The multivariate Cox regression analysis indicated that lncRNA Sox2ot expression was an independent prognostic factor for overall survival. In addition, the metastasis ability of HCC cells was significantly decreased by knocking down lncRNA Sox2ot expression. CONCLUSIONS: The results suggested that lncRNA Sox2ot played crucial roles in promoting HCC cell migration and invasion, and might represent a novel prognostic biomarker for HCC. PMID- 26097589 TI - NKD1 down-regulation is associated with poor prognosis in breast invasive ductal carcinoma. AB - As a negative modulator of the canonical Wnt signaling pathway, Naked1 (NKD1) is widely expressed in many normal tissues. However, the expression and clinicopathological significance of NKD1 in patients with breast cancer is still unclear. The aim of this study was to evaluate NKD1 expression in breast cancer and to investigate the question of whether reduced expression of NKD1 may have any pathological significance in breast cancer development or progression. In this study, we performed western blotting and immunohistochemistry to evaluate the expression of NKD1 and relevance with clinicopathological factors in the breast invasive ductal carcinoma. Reduction of NKD1 was significantly correlated with lymph node metastasis, histological grade and ER expression in breast cancer. Patients with negative NKD1 expression had significantly lower cumulative postoperative 5 year survival rate than those with positive NKD1 expression. This interpretation is in keeping with the results obtained from our in vitro experiments on MDA-MB-231 cells, we demonstrated that upregulation of NKD1 expression by infect with an adenovirus containing a NKD1 vector significantly reduced the migration of breast cancer cells. These data suggest that NKD1 plays an important role in invasion in human breast cancer and it appears to be a potential prognostic marker for patients with breast cancer. PMID- 26097590 TI - Combination of CD4(+)CD25(+)CD127(-) regulatory T cells with MLC-BE and BE-Ab2: an efficient evaluation of the therapy of paternal lymphocyte induced immunization in unexplained recurrent spontaneous abortion patients. AB - The aim of this retrospective study was to compare the immune tolerance status of patients suffered from unexplained spontaneous abortion (URSA) before and after treatment with paternal lymphocyte induced immunization (PLII) four times, and its relationship to the pregnancy outcome. 168 URSA patients were included in the present study. Among 168 couples, 138 couples were conceived again, of whom 86 were successfully pregnant till 20 gestational weeks, 31 cases again failed in the first trimester, 21 cases were still under follow-up, another 30 cases still had not conceived. Both the level of one way mixed lymphocyte culture blocking efficiency (MLC-BE) and anti-idio blocking antibody (BE-Ab2) were markedly elevated in succeeded group after PLII. In contrast, although a significant increase could be observed in the failed group after treatment, the elevation of BE-Ab2 was much lower than that in successful group. PLII therapy significantly up-regulated the percentage of peripheral CD4(+)CD25(+)CD127(-) regulatory T cells (Tregs) in successfully pregnant women; however, there was no significant change of Tregs in pregnancy loss cases although receiving PLII therapy. These results suggested a positive correlation between higher frequency of Tregs and rate of successful pregnancies. The sensitivity and specificity of combination of Tregs with MLC-BE and BE-Ab2 were 81.8% and 81.3%, respectively. Therefore, the percentage of Tregs in peripheral blood may hopefully serve as a potential biomarker for monitoring the efficacy of therapy in URSA patients. Combination of Tregs with MLC-BE and BE-Ab2 may expect to better evaluate the efficacy of PLII in URSA patients. PMID- 26097591 TI - Erythropoietin and erythropoietin receptor in hepatocellular carcinoma: correlation with vasculogenic mimicry and poor prognosis. AB - To evaluate erythropoietin (Epo) and erythropoietin receptor (EpoR) expression, its relationship with vasculogenic mimicry (VM) and its prognostic value in human hepatocellular carcinoma (HCC), we examined Epo/EpoR expression and VM formation using immunohistochemistry and CD31/PAS (periodic acid-Schiff) double staining on 92 HCC specimens. The correlation between Epo/EpoR expression and VM formation was analyzed using two-tailed Chi-square test and Spearman correlation analysis. Survival curves were generated using Kaplan-Meier method. Multivariate analysis was performed using Cox regression model to assess the prognostic values. Results showed positive correlation between Epo/EpoR expression and VM formation (P < 0.05). Patients with Epo or EpoR expression exhibited poorer overall survival (OS) than Epo-negative or EpoR-negative patients (P < 0.05). Epo-positive/VM positive and EpoR-positive/VM-positive patients had the worst OS (P < 0.05). In multivariate survival analysis, age, Epo and EpoR were independent prognostic factors related to OS. These results will provide evidence for further research on HCC microcirculation patterns and also will provide new possible targets for HCC diagnosis and treatment. PMID- 26097592 TI - Relationship between MLH-1, MSH-2, PMS-2,MSH-6 expression and clinicopathological features in colorectal cancer. AB - Colorectal cancers are the third most common in both sexes and they are the second most common cause of cancer-related death. 12-15% of colorectal cancers develop through microsatellite instability (the hereditary mutation in at least one of DNA mismatch repair genes) pathway and they are 2-5% hereditary. In this study, we investigated the correlation between the clinicopathological features themselves and also the correlation between them and the immunohistochemical MLH 1, MSH-2, PMS-2, MSH-6 expressions in a total of 186 resection materials with colorectal adenocarcinoma between 2008 and 2012. All the cases were retrospectively evaluated in terms of age, sex, localization, size, accompanying polyp, multiple tumor, arising from polyp, differentiation, mucinous differentiation, pathological tumor stage, lymphovascular and perineural invasion, lymphocyte amount in the tumor microenvironment, surgical border and lymph node metastasis. We prepared multiple tissue blocks which had 4-millimeter tumor. Immunohistochemically, MLH-1, MSH-2, PMS-2, MSH-6 primary antibodies were studied. Statistically, "Kruskal-Wallis" ve "Pearson's chi-squared" tests were used. We found a positive correlation between loss of MLH-1 and PMS-2 expressions and the right-colon location, poor and mucinous differentiation and dense lymphocytic infiltration. In addition, loss of MSH-2 and MSH-6 expressions was correlated with the right-colon location, poor and mucinous differentiation. We found a meaningful relationship between immunohistochemical markers and clinicopathological features usually observed in tumors with microsatellite instability. This finding may arouse suspicion for MSI. However, the findings in our study must be supported with studies conducted in large series including molecular methods. PMID- 26097594 TI - Differential expression of GSK3beta and pS9GSK3beta in normal human tissues: can pS9GSK3beta be an epithelial marker? AB - Glycogen synthase kinase 3beta (GSK3beta) and phosphorylated GSK3beta at Ser9 (pS9GSK3beta) are crucial in cellular proliferation and metabolism. GSK3beta and pS9GSK3beta are deregulated in many diseases including tumors. Data on altered expression of GSK3beta and pS9GSK3beta are mainly limited to tumor tissues, thus the expression of GSK3beta and pS9GSK3beta in normal human tissue has been largely unknown. Thus, we examined the immunohistochemical localization of GSK3beta and pS9GSK3beta in human fetal and adult tissues, and also compared the expression pattern of GSK3beta and pS9GSK3beta with that of the CK7 and CK20. We found GSK3beta expression in neurons of brain, myenteric plexus in gastrointestinal tract, squamous epithelium of skin, and mammary gland. The expression of pS9GSK3beta was restricted to the epithelial cells of breast and pancreaticobiliary duct, distal nephron of kidney, gastrointestinal tract, fallopian tube, epididymis, secretory cell of prostatic gland, and umbrella cell of urinary tract. The staining pattern of pS9GSK3beta and CK7 was overlapped in most organs except for gastrointestinal tract where CK7 was negative and CK20 was positive. Our results show that the expression of GSK3beta may be associated with differentiation of ectodermal derived tissues and pS9GSK3beta with that of epithelial cells of endodermal derived tissues in human. In addition, the expression of pS9GSK3beta in the selective epithelial cells may indicate its association with secretory or barrier function of specific cells and may serve as another immunohistochemical marker for epithelial cells. PMID- 26097593 TI - HK2 is a radiation resistant and independent negative prognostic factor for patients with locally advanced cervical squamous cell carcinoma. AB - The mechanism by which overexpression of hexokinase 2 (HK2) indicates locally advanced cervical squamous cell carcinoma (LACSCC) with radio-resistance is still unknown despite being an independent biomarker of poor prognosis. Here, we retrospectively analyzed 132 female patients receiving radiotherapy for cervical squamous cell carcinoma including 85 radiation-sensitive cases and 47 radiation resistant cases. The expression of HK2 was examined by immunohistochemistry. The percentage of high HK2 expression in the radiation-resistant group differed from the radiation-sensitive group with statistical significance (P < 0.001) even if divided into three subgroups including a lower 5-year progression free survival group (PFS) for comparison (P < 0.001). The Kaplan Meier curve analysis showed that there were differences between the two groups (P < 0.001). Therefore, this study proves a close relationship between HK2 expression and radio-resistance. Multivariate Cox regression analysis implied that HK2 was an independent prognostic indicator of cervical squamous carcinoma (HR (95% CI), 2.940 (1.609, 1.609); P = 0.002). PMID- 26097595 TI - Significance of serum levels of vitamin D and some related minerals in breast cancer patients. AB - Vitamin D and calcium are involved in a wide range of proliferation, apoptosis and cell signaling activities in the body. Suboptimal concentrations may lead to cancer development. The role of phosphate in cancer metabolism is particularly relevant in breast cancer while, magnesium deficiency favors DNA mutations leading to carcinogenesis. OBJECTIVES: To determine serum levels of vitamin D, calcium, phosphorus, magnesium, and parathormone in female breast cancer patients and to assess their association with some prognostic factors in breast cancer. DESIGN AND METHODS: This study is done on 98 newly diagnosed female breast cancer patients and 49 age matched apparently healthy female volunteers as controls. Serum samples from all patients and controls were subjected to 25-OH Vit D, calcium, phosphorus, magnesium, and parathormone measurements. RESULTS: In the breast cancer group, the median serum levels of 25-OH Vit D were 15 ng/ml, while it was 21 ng/ml in the control group. Levels of 25-OH Vit D and other tested minerals were significantly lower while calcium:magnesium (Ca:Mg) ratio, and calcium:phosphorus (Ca:P) ratio were significantly higher in the breast cancer group. Significant negative correlation was detected between phosphorus and calcium, ionized calcium , calcium magnesium ratio, and calcium phosphorus ratio. CONCLUSION: It is not only the deficient levels of Vit D and other related minerals, but the combination of the abnormal levels of all the studied parameters that might contribute to the development of cancer. Further studies with larger number of patient are needed. PMID- 26097596 TI - FRZB up-regulation is correlated with hepatic metastasis and poor prognosis in colon carcinoma patients with hepatic metastasis. AB - Frizzled-related protein (FRZB) was up-regulated in hepatic metastasis samples compared with primary colon cancer samples in our previous work. However, the clinical relevance of FRZB in colon cancer hepatic metastasis remains uncertain. The aim of this study was to assess the prognostic value of FRZB in patients with colon carcinoma hepatic metastasis after hepatic resection. FRZB expression was evaluated by immunohistochemistry in formalin-fixed paraffin embedded (FFPE) primary colon carcinoma and paired hepatic metastasis tissues from 136 patients with liver metastasis from colon carcinoma that underwent hepatic resection. The relation between FRZB expression and clinicopathologic factors and long-term prognosis in these 136 patients was retrospectively examined. The prognostic significance of negative or positive FRZB expression in colon carcinoma hepatic metastasis was assessed using Kaplan-Meier survival analysis and log-rank tests. Positive expression of FRZB was correlated with liver metastasis of colon cancer. Univariate analysis indicated significantly worse overall survival (OS) for patients with a positive FRZB expression in colon carcinoma hepatic metastasis than for patients with a negative FRZB expression. Multivariate analysis showed positive-FRZB in colon carcinoma hepatic metastasis to be an independent prognostic factor for OS after hepatic resection (P = 0.001). Positive expression of FRZB was statistically significantly associated with poor prognosis of patients with colon carcinoma hepatic metastasis. FRZB could be a novel predictor for poor prognosis of patients with colon carcinoma hepatic metastasis after hepatic resection. PMID- 26097597 TI - Interleukin-10 promotor -592A/C polymorphism is associated with slow coronary flow in Han Chinese. AB - An accumulating body of evidence suggests that slow coronary flow (SCF) phenomenon seems to be an early-form of atherosclerosis and low-grade inflammation plays a major role in the atherosclerotic vascular processes. Interleukin (IL)-10 is a multifunctional cytokine involved in both innate and adaptive immune response. The aim of the present study is to investigate the association of IL-10 gene -592A/C polymorphism with SCF in Han Chinese. 250 patients who underwent coronary angiography and had angiographically normal coronary arteries of varying coronary flow rates without any atherosclerotic lesion were enrolled in this study. Patients who had thrombolysis in myocardial infarction frame counts (TFC) above the normal cutoffs were considered to have SCF and those within normal limits were considered to have normal coronary flow (NCF). The PCR-based restriction fragment length polymorphism (PCR-RFLP) technique was used to assess the genotypes frequencies. The distribution of the IL-10 -592A/C genotypes (AA, AC, and CC) was 46.34%, 41.46%, and 12.20% in the NCF group, and 66.51%, 28.71%, and 4.78% in SCF subjects, respectively (P = 0.0280). The frequency of the A allele in the SCF group was significantly higher than that in the NCF group (80.86% vs. 67.07%, P = 0.0054). Compared with the CC genotype, the AA genotype had increased risk of SCF in both unadjusted and adjusted analyses. In SCF patients, the average serum IL-10 levels in AA genotype were statistically lower than in AC + CC genotype (P = 0.0000). These findings suggest that IL-10 -592A/C polymorphism is associated with SCF and the A allele has increased risk for SCF in Han Chinese. PMID- 26097598 TI - Effects of storage conditions on the stability of serum CD163, NGAL, HMGB1 and MIP2. AB - BACKGROUND: Several cytokines have been involved in the diagnosis and prognosis for the pathogenesis and severity of chronic hepatitis B (CHB) such as cluster of differentiation 163 (CD163), neutrophil gelatinase-associated lipocalin (NGAL), high-mobility group box 1 (HMGB1) and macrophage inflammatory protein-2 (MIP-2). Nevertheless, the stability and reliability of these cytokines can be greatly influenced by handling and storage processes. METHODS: In this study, potential utility of serum samples of a CHB cohort was evaluated to investigate several processes that might impact cytokine profiles such as temperature, storage time and number of freeze-thaw cycles. Blood samples collected from 100 patients with CHB were separated immediately and divided into two groups. In one group, samples (n=50) stored at -80 degrees C were subject to 1-3 freeze-thaw cycles. In the other group, samples (n=50) were stored at 4 degrees C and 25 degrees C for 3 h, 9 h, 24 h, 48 h, 72 h, and 7 d time points, respectively. To assess the influence of different storage conditions on cytokines, the levels of CD163, NGAL, HMGB1 and MIP-2 were measured using enzyme-linked immunosorbent assays (ELISA) kits. RESULTS: No significant differences of these four cytokines after 1 3 repeated freeze-thaw cycles. Significant differences of NAGL levels were seen between 9 h and 7 d (P<0.05), and also in HMGB1 at 25 degrees C, while the other cytokines were relatively stable at the two storage temperatures over the various time points. CONCLUSION: This study indicated that these four cytokines remained stable within three freeze-thaw cycles and 7 d at 4 degrees C. No perceptible effects on CD163 and MIP-2 levels were presented under the storage condition of 7 d at room temperature, whereas the degradation of NGAL and HMGB1 were notable. PMID- 26097599 TI - Genetic variability of DNA repair mechanisms influences chemotherapy outcome of gastric cancer. AB - Genetic variability of DNA repair mechanisms influences chemotherapy treatment outcome of gastric cancer. We conducted a cohort study to investigate the role of ERCC1-ERCC2 gene polymorphisms in the chemotherapy response and clinic outcome of gastric cancer. Between March 2011 and March 2013, 228 gastric patients who were newly diagnosed with histopathology were enrolled in our study. Genotypes of ERCC1 rs11615, rs3212986, rs2298881 and ERCC2 rs3212986 were conducted by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. We found that individuals carrying TT genotype of ERCC1 rs11615 and CC genotype of ERCC1 rs2298881 were associated with better response to chemotherapy and longer survival time of gastric cancer. Moreover, individuals with AA genotype of ERCC2 rs1799793 were correlated with shorter survival of gastric cancer. In conclusion, ERCC1 rs11615, rs2298881 and ERCC2 rs1799793 polymorphism play an important role in the treatment outcome of gastric cancer. PMID- 26097600 TI - Association of GSTP1 and XRCC1 gene polymorphisms with clinical outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy. AB - We investigated the association between the clinical outcome and GSTP1 and XRCC1 gene polymorphisms in advanced NSCLC patients with cisplatin-based chemotherapy. We prospectively recruited 325 NSCLC patients between January 2010 and January 2014. Genotypes of GSTP1 A313G, XRCC1 Arg194Trp, Arg280His and Arg399Gln were conducted using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. AG and GG genotypes of GSTP1 A313G were correlated with a higher CR + PR when compared with AA genotype. Furthermore, GA and AA genotypes of XRCC1 Arg399Gln were associated with more CR + PR when compared with GG genotype. In the Cox proportional hazards model, GG genotype of GSTP1 A313G was significantly correlated with a longer median survival time when compared with AA genotype, and it is associated with a heavy decreased risk of death from NSCLC. Moreover, GA and AA genotypes of XRCC1 Arg399Gln had a significantly longer median survival time, and GA and AA genotypes were significantly associated with a moderate reduced risk of death from NSCLC. GSTP1 A313G and XRCC1 Arg399Gln gene polymorphisms might influence the response to cisplatin based chemotherapy and affect the clinical outcome of advanced NSCLC. PMID- 26097601 TI - Whether Alzheimer's diseases related genes also differently express in the hippocampus of Ts65Dn mice? AB - BACKGROUND: Down syndrome is a condition which extra genetic material causes delays in child development, both mentally and physically. Strengthening the study of the neural defects of DS is of great significance. METHODS: Ts65Dn mice were used in this study. We removed the brain and isolated their hippocampus. We customized 54 genes in one PCR arrays, included some important genes related to Alzheimer's disease. The expression of genes were detected by RT-PCR. RESULTS: PCR arrays contained 54 genes related to Alzheimer's disease. After real-time PCR, three genes (Nae1, APP and Mapt) expressed differently in the hippocampus of Ts65Dn, compared with the normal mice. Nae1 was decreased significantly, while APP and Mapt were increased obviously. The levels of fold-changes of Nae1, APP and Mapt were 86.19, 4.49 and 2.89 respectively. Significantly different levels of expression were found in the Ts65Dn mice compared with the normal control group (P=0.00 for Nae1, P=0.02 for APP, P=0.01 for Mapt respectively). CONCLUSIONS: There are differential expressed genes in the hippocampus of Ts65Dn mice that may be closely related to Alzheimer's disease. PCR array technology was used in the screening and identification of these genes. PMID- 26097602 TI - Prognostic significance of long non-coding RNA PCAT-1 expression in human hepatocellular carcinoma. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) play widespread roles in gene regulation and cellular processes. However, the functional roles of lncRNAs in hepatocellular carcinoma (HCC) are not yet well elucidated. The aim of the present study was to measure the levels of lncRNA PCAT-1 expression in HCC and evaluate its clinical significance in the development and progression of HCC. METHODS: We examined the expression of PCAT-1 in 117 HCC tissues and adjacent non tumor tissues using quantitative real-time-PCR and analyzed its correlation with the clinical parameters. RESULTS: Our data showed that PCAT-1 expression in HCC tissues was significantly increased compared with adjacent non-tumor tissues (P<0.05). Up-regulated expression of PCAT-1 was significantly associated with TNM stage and metastasis (P<0.05), but not other clinical parameters. Moreover, Kaplan-Meier survival analysis showed that a high expression level of PCAT-1 resulted in a significantly poor overall survival of HCC patients. The multivariate Cox regression analysis demonstrated that PCAT-1 expression level was an independent prognostic factor for the overall survival rate of HCC patients. CONCLUSIONS: Our data suggested that the increased expression of PCAT-1 was associated with advanced clinical parameters and poor overall survival of HCC patients, indicating that PCAT-1 up-regulation may serve as a novel biomarker of poor prognosis in HCC patients. PMID- 26097604 TI - Inhibitory effect of 5F on development of lung cancer in A/J mice. AB - The purpose of the study is to investigate the effect of ent-11alpha-hydroxy-15 oxo-kaur-16-en-19-oic-acid (5F) on the model of induced A/J mice lung cancer in A/J mice. The expressions of tumor-related molecules including P65 and Bcl-2 at protein level were examined using the immunohistochemical method (IHC). Side effects of 5F were also monitored. The results indicated that 5F significantly suppressed the development of B[a]P and NNK-induced lung cancer in vivo by facilitating cell apoptosis with minimal side effects. Compared to the expressions of P65 and Bcl-2 in model group, the levels were strongly attenuated both in blank and 5F injection groups. Moreover, P65 and Bcl-2 levels varied among different groups receiving 5F treatment. The expressions of P65 and Bcl-2 were much lower in groups receiving high-concentration 5F treatment than those with low-concentration 5F injection. Findings revealed that 5F inhibited the pathogenesis of lung cancer through accelerating apoptosis in a dose-dependent manner. PMID- 26097603 TI - Increased expression of microRNA-196a predicts poor prognosis in human ovarian carcinoma. AB - OBJECTIVE: Overexpression of MicroRNA-196a (miR-196a) has recently been reported in different types of human cancers. However, the prognostic value of miR-196a in ovarian carcinoma remains unknown. In this study, we investigated the expression of miR-196a in ovarian carcinoma and its relationship with tumor progression and clinical prognosis. METHODS: The expression level of miR-196a was examined by quantitative Real-time PCR (qRT-PCR) in surgically removed ovarian cancer tissues and ovarian cancer cell lines. The correlation between miR-196a expression and clinical features and prognosis were statistically analyzed. RESULTS: The results showed that the miR-196a expression was significantly upregulated in tumor tissues and ovarian cancer cell lines compared with that in normal ovarian surface tissues and normal ovarian epithelial cells. Moreover, miR-196a expression was positively correlated with FIGO stage (P<0.001), tumor size (P=0.020), and lymph nodes metastasis (P=0.019). Kaplan-Meier analysis demonstrated that high levels of miR-196a expression was associated with poorer overall survival (P<0.001) and recurrent-free survival (P=0.003), especially in patients with advanced disease (P=0.002). Multivariate analysis suggested that miR-196a expression was an independent prognostic factor for overall survival of patients with ovarian carcinoma. CONCLUSIONS: In conclusion, miR-196a may play an important role in the progression of ovarian carcinoma, and could be used as an independent prognostic biomarker for patients with ovarian carcinoma. PMID- 26097605 TI - Stereological evaluation of fibronectin in the periurethral region of the transitional zone from normal human prostates compared with benign prostatic hyperplasia. AB - The aim of this study was to assess the volumetric density (Vv) of the fibronectin in the periurethral region of patients with benign prostatic hyperplasia (BPH) and compare with a control group. Prostatic periurethral tissue samples were obtained from ten patients (age range 65 to 79 years, mean 66) with clinical symptoms of bladder outlet obstruction who had undergone open prostatectomy. The control group samples (periurethral tissue samples from the transitional zone) were collected from prostates obtained during autopsy of accidental death adults of less than 25 years. The volumetric density (Vv) of the fibronectin was determined with stereological methods from 25 random fields per sample using the point-count method with an M-42 grid test system. The quantitative data were analyzed using the Kolmogorov-Smirnov and Mann-Whitney U tests. The Vv in the control and BPH groups was 21.9% +/- 1.5% and 29.1% +/- 1.2% in the fibronectin, respectively. BPH tissues presented a significant increase of fibronectin in prostatic periurethral region in the transitional zone that may cause lengthening of the prostatic urethra. PMID- 26097606 TI - Prognostic implications of adhesion molecule expression in colorectal cancer. AB - Research on the expression of adhesion molecules, E-cadherin (ECAD), CD24, CD44 and osteopontin (OPN) in colorectal cancer (CRC) has been limited, even though CRC is one of the leading causes of cancer-related deaths. This study was conducted to evaluate the expression of adhesion molecules in CRC and to determine their relationships with clinicopathologic variables, and the prognostic significance. The expression of ECAD, CD24, CD44 and OPN was examined in 174 stage II and III CRC specimens by immunohistochemistry of TMA. Negative ECAD expression was significantly correlated with advanced nodal stage and poor tumor differentiation. Multivariate analysis showed that both negative expression of ECAD and positive expression of CD24 were independent prognostic factors for disease-free survival (DFS) in CRC patients (P<0.001, relative risk [RR] = 5.596, 95% CI = 2.712-11.549; P = 0.038, RR = 3.768, 95% CI = 1.077-13.185, respectively). However, for overall survival (OS), only ECAD negativity showed statistically significant results in multivariate analysis (P<0.001, RR = 4.819, 95% CI = 2.515-9.234). Positive expression of CD24 was associated with poor OS in univariate analysis but was of no prognostic value in multivariate analysis. In conclusion, our study suggests that among these four adhesion molecules, ECAD and CD24 expression can be considered independent prognostic factors. The role of CD44 and OPN may need further evaluation. PMID- 26097607 TI - Clinical experience of uterine tumors resembling ovarian sex cord tumors: a clinicopathological analysis of 6 cases. AB - OBJECTIVE: To compare the clinicopathological features, diagnosis, treatment, and prognosis of two types of uterine sex cord-like tumors. METHODS: The clinicopathological features of four uterine tumors resembling ovarian sex cord tumors (UTROSCTs) and two endometrial stromal tumors with sex cord-like elements (ESTSCLEs) were analyzed retrospectively. RESULTS: All patients were premenopausal women. The most common clinical presentation was vaginal bleeding (four cases). Total hysterectomy with or without bilateral adnexectomy was the most common treatment pattern (five cases). A patient with UTROSCTs, presenting with recurrence 10 months after transvaginal submucous myomectomy, underwent a total hysterectomy (case 2). All tumors were polypoid or intramural masses, usually located in the uterine fundus or submucosa. The majority of UTROSCTs were positive for cytokeratin (4/4 cases), one was positive for Wilms tumor protein, and of two cases with smooth muscle actin immunoreactivity, two were positive for desmin. UTROSCTs were positive for two or more sex cord markers, whereas sex cord markers were less frequently detected in ESTSCLEs. CD10 was variably positive in two UTROSCT patients and strongly positive in all ESTSCLE patients. Three UTROSCTs and one ESTSCLE were positive for both estrogen and progesterone receptors. All patients with UTROSCTs were alive without evidence of recurrence. One patient with ESTSCLEs underwent postoperative chemotherapy after total vaginal hysterectomy but developed recurrence at the vaginal stump (case 5). The other patient with ESTSCLEs was lost to follow-up. CONCLUSION: These UTROSCTs are polymorphic neoplasms with true sex cord differentiation and uncertain malignant potential, which possess a distinct biology from ESTSCLEs. PMID- 26097608 TI - Interactions of central obesity with rs3918242 on risk of non-alcoholic fat liver disease: a preliminary case-control study. AB - NAFLD is a complex disease characterized by inflammation and insulin resistance which is determined by an interaction of genetics and environmental factors. MMP gene has been implicated in relation to inflammation and insulin resistance. The preliminary case-control study aimed to investigate the association between Matrix metalloproteinase (MMP)-9-1562C/T (rs3918242), MMP-2-1306C/T (rs243865) and risk of NAFLD and to further evaluate the interactions of central obesity with rs3918242 and rs243865. Two variants, rs3918242 and rs243865, were genotyped by polymerase chain reaction -restriction fragment length polymorphism. Gene environment interactions on risk of NAFLD was preliminarily investigated by generalized multifactor dimensionality reduction (GMDR) and further confirmed by unconditional logistic regression methods. After adjusting for covariates, increased risk of NAFLD were observed in subjects carrying TT/CT genotypes in rs3918242 ((Adjust)OR=1.64, 95% CI: 1.24, 2.11, P=0.006). However, decreased risk of non-alcoholic fat liver disease was found when MMP-2 rs243865 (TT/CT) genotype carriers compared with CC carrier ((Adjust)OR=0.65, 95% CI: 0.47, 0.72, P=0.000).Interactions of central obesity with rs3918242 was preliminarily found by GMDR, with a maximum prediction accuracy (67.61%) and a maximum Cross validation Consistency (10/10).The unconditional logistic regression method indicated central obesity-positive subject with genotype TT/CT had 4.54 times risk of NAFLD compared to central obesity-negative subjects with genotype CC (OR(add)(a)=4.54, 95% CI: 2.81, 7.21, P(add)(a)=0.000), which further confirmed the interactions. The results indicate that both rs3918242 and rs243865 is associated with risk of NAFLD. Furthermore, rs3918242 and central obesity have synergistic effects on risk of NAFLD. PMID- 26097609 TI - Assoication of XRCC1 gene polymorphisms with risk of non-small cell lung cancer. AB - DNA repair genes is a key factor for cancer susceptibility, and we conducted a case-control study to investigate the association of XRCC1 codons 194 (Arg to Trp), 280 (Arg to His) and 399 (Arg to Gln) with risk of NSCLC. 210 NSCLC patients and 210 health control subjects were randomly selected from Huaihe Hospital between January 2012 and June 2014. The polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was taken to assess the genotyping of XRCC1 Arg194Trp, Arg280His and Arg399Gln. By multivariate logistic regression analysis, we found individuals carrying with Trp/Trp and Arg/Trp + Trp/Trp genotypes were associated with a significantly increased risk of NSCLC compared with Arg/Arg genotype, and the OR (95% CI) were 3.15 (1.32-8.09) and 1.52 (1.02-2.28), respectively. The potential association of Arg/Trp+ Trp/Trp genotype of XRCC1 Arg194Trp with the risk of NSCLC is more evidence in smokers, and the OR (95% CI) was 1.78 (1.01-3.24). In conclusion, we found that XRCC1 Arg194Trp polymorphism may be associated with NSCLC risk, especially in smokers. PMID- 26097610 TI - Association of -308G/A and -238G/A polymorphisms of TNF-alpha and osteosarcoma risk. AB - OBJECTIVE: As a proinflammatory cytokine, TNF-alpha is associated with increased risk of osteosarcoma (OS). Our study aimed to explore the association of TNF alpha polymorphisms and OS susceptibility in the Han Chinese population. METHODS: 80 OS patients and 99 healthy people, matched on the age and sex, participated in the study. Genotyping was conducted by the method of polymerase chain reaction restricted fragment length polymorphisms (PCR-RFLP). Then logistic regression was used to evaluate the effects of TNF-alpha polymorphisms (-308 G/A and -238 G/A) on the pathology of OS. RESULTS: The frequency of AA genotype in -308 G/A locus in the cases was significantly higher than that of the healthy group (20.0% vs. 6.1%). Patients with OS were more likely to possess AA genotype of -308 G/A locus (OR=4.00, 95% CI=1.41-11.38). For the patients with A allele, the risk for OS increased 0.62 fold (OR=1.62, 95% CI=1.04-2.50). There was no remarkable relationship of -238 G/A polymorphisms and OS susceptibility. In addition, we found that patients with G-A and A-A haplotypes was much higher in the cases than that of control group (68.0% and 25.0%, 53.0% and 38.9%, respectively). A-G haplotype appeared to increase the risk for OS (OR=1.93, 95% CI=1.13-2.94). CONCLUSION: The AA genotype of -308 G/A locus of TNF-alpha gene was a risk factor for OS, however there was no correlation between -238 G/A of TNF-alpha and OS. PMID- 26097611 TI - Association of IL-1alpha rs17561 and IL-1 RN rs315952 polymorphisms with Tourette syndrome: a family-based study. AB - AIM: Immune system dysregulation has been implicated to play a key role in pathogenesis of Tourette syndrome (TS). IL-1alpha and IL-1RN are important inflammatory cytokines that mediate the inflammation. In this study, we investigated the relationship between single-nucleotide polymorphisms (SNPs) of IL-1alpha and IL-1RN and the susceptibility to TS in Chinese Han population. METHODS: A total of 276 children with TS and their parents were recruited in the study. All DNA from our subjects were genotyped for SNPs of IL-1alpha rs17561 and IL-1RN rs315952 using predesigned TaqMan SNP genotyping assay. The genetic contributions of two polymorphisms were evaluated using transmission disequilibrium test (TDT) and haplotype relative risk (HRR) design. In addition, to increase the efficiency of the test, the haplotype-based HRR (HHRR) was performed. RESULTS: No significant differences were observed in allelic and genotypic frequency of rs17561 in IL-1alpha and rs315952 in IL-1RN between the transmitted group and non-transmitted group (for IL-1alpha rs17561: TDT=0.890, df=1, P=0.402; HRR=1.011, X(2)=3.016, P=0.082, 95% CI=0.999-1.024; for IL-1RN rs315952: TDT=0.095, df=1, P=0.805; HRR=0.984, X(2)=0.008, P=0.929, 95% CI=0.695 1.394). Similarly, the analysis of HHRR also did not support a significant association (for IL-1alpha rs17561: HHRR=1.226, X(2)=0.915, P=0.339, 95% CI=0.807 1.863; for IL-1RN rs315952: HHRR=0.963, X(2)=0.094, P=0.759, 95% CI=0.758-1.225). CONCLUSION: Our results suggest that IL-1alpha rs17561 and IL-1RN rs315952 polymorphisms may not be associated with susceptibility to TS in Chinese Han population. However, the results still need to be replicated in a larger sample size and different populations. PMID- 26097612 TI - Peripheral T cell lymphoma, not otherwise specified with myelofibrosis: report of a case with review of the literature. AB - A 68-year-old man presented to us with pancytopenia, erythroderma, and multiple lymphadenopathies. Lymph node biopsy led to the diagnosis of peripheral T-Cell lymphoma-not otherwise specified (PTCL-NOS). Immunostaining of the lymph node biopsy specimens for cytokines revealed that the tumor cells were positive for plated-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNF alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), interleukin-2 (IL-2), and transforming growth factor-beta (TGF-beta). Bone marrow biopsy revealed infiltration by the PTCL-NOS and myelofibrosis (MF). Bone marrow blood was negative for JAK-2V617F. Bone marrow immunostaining for cytokines showed that the tumor cells were positive for PDGF, b-FGF, VEGF, TNF-alpha, IFN-gamma, IL 1beta, IL-2, and TGF-beta. The patient was initiated on treatment, and after the first course of CHOP therapy, the bone marrow infiltration by the PTCL-NOS and MF improved. Repeat immunostaining of bone marrow biopsy specimens for cytokines showed that the tumor cells had become negative for PDGF, VEGF, TNF-alpha and TGF beta. However, after the second course of CHOP therapy, the bone marrow infiltration by the PTCL-NOS and MF worsened. Immunostaining of bone marrow specimens for cytokines again revealed positive staining results of the tumor cells for PDGF, TNF-alpha, and TGF-beta. At the completion of the first course of treatment, the infiltration by the PTCL-NOS improved, but not the pancytopenia. PMID- 26097613 TI - P120 catenin attenuates lipopolysaccharide-induced blood-brain barrier dysfunction and inflammatory responses in human brain microvascular endothelial cells. AB - Increasing evidences suggest that p120 catenin (p120ctn) exerts important functions in the regulation of pro-inflammatory molecules. However, the relationship among p120ctn, inflammatory responses and blood-brain barrier (BBB) dysfunction as they are the initiator of sepsis is not unknown. In this study, we found that p120ctn expression was correlated with an increase in the permeability of BBB and a decrease in the expression of tight-junction proteins in human brain microvascular endothelial cells (HBMECs) after LPS challenge. Transfection with p120ctn small interfering RNA (siRNA) induced disruption of BBB integrity, monocyte migration across BBB and inflammatory responses at basal level and after LPS treatment. Conversely, over-expression of p120ctn with adenovirus significantly ameliorated BBB disruption and inflammatory responses in LPS treated cells. Mechanistically, up-regulation of p120ctn inhibited LPS-induced NF kappaB activation by suppressing IKKbeta and IkappaBalpha phosphorylation, IkappaBalpha degradation. Therefore, we conclude that p120ctn improves the BBB dysfunction and inflammatory responses through the inhibition of NF-kappaB activation, suggesting that forced p120ctn expression may provide a novel therapeutic strategy to attenuate LPS-induced BBB compromise and sepsis. PMID- 26097614 TI - Epithelioid inflammatory myofibroblastic sarcoma in abdominal cavity: a case report and review of literature. AB - In this study, we present a rare and difficult case of epithelioid inflammatory myofibroblastic sarcoma (EIMS) in abdominal cavity. A 47-year-old female presented as left upper abdominal pain for 6 months and abdominal distention for 1 month. CT examination showed a solid mass in the left upper intra-abdomen. Grossly, the tumor was found in the mesenterium of colon with the size of 7.5 * 6.5 * 3.5 cm, and was solid and gray-yellowish in the cut surface. Focal myxomatous appearance was observed. Microscopically, stromal myxoid change together with prominant infiltrated lymphocytes, neutrophils and eosinophils were found in the tumor, and the tumor cells were round, epithelioid with vesicular nuclei, large prominant nucleoli and high mitotic rate. Immunohistochemically, strong diffused positive for vimentin, desmin, ALK (nuclear membrane staining pattern) and AAT, focally positive for CD99 and CD30, were showed, Ki67 index was about 20%; Especially, WT-1 and D240 were focally expressed in this tumor. FISH analysis showed rearrangement of ALK, and reverse-transcription polymerase chain reaction (RT-PCR) analysis was used to detect the fusion location of the RANBP2 and ALK gene. The diagnosis of EMIS was made based on its location, typical morphology, the immunohistochemical features especially the nuclear membranous immunostaining of ALK and rearrangement of RANBP2-ALK. The tumor showed higher aggressive behaviors and a poor prognosis. The differential diagnosis and other treatments of EMIS are also discussed in the present study. This finding may increase the case information of EMIS. PMID- 26097615 TI - Transient elastography-derived liver stiffness measurements were found to be useful for predicting liver infiltration in a case of mature T-cell neoplasm involving liver dysfunction. AB - Transient elastography (TE) is a novel, non-invasive imaging technique for measuring liver stiffness (LS). It is considered to be useful for predicting the severity of fibrosis and the risk of cirrhosis or hepatocellular carcinoma. However, the association between the presence of diffuse regions of increased cell density in the liver and elevated LS values has not been assessed. We experienced a case in which a mature T-cell neoplasm had invaded the liver, but the infiltrating lesion was not detected by contrast-enhanced computed tomography (CT) or fluorodeoxyglucose positron emission tomography/CT scans. Instead, the tumor's presence was indicated by the change in the patient's TE-derived LS values after chemotherapy. At diagnosis liver dysfunction was detected in a biochemical examination, and mean LS value was as high as 25.4 kPa [interquartile range (IQR): 0.3, success rate (SR):100%]. After chemotherapy, the patient's mean LS value fell to 4.3 kPa (IQR: 0.8, SR:100%). A follow-up pathological investigation demonstrated that proliferating abnormal T-cells were no longer present in the patient's liver. This is the first report to describe the use of LS data to support a diagnosis of liver infiltration by tumor cells exhibiting a portal and sinusoidal distribution pattern rather than a focal pattern. Elevated TE-derived LS values should lead to hepatic tumor infiltration being considered during initial examinations or a suspicion of recurrence during follow-up examination of lymphoma patients who achieve complete remission, even when radiological investigations do not detect abnormalities in the liver. PMID- 26097616 TI - Fibrosarcoma arising from gouty tophi: report of a unique case and review of literature. AB - Fibrosarcoma is a malignant mesenchymal tumor. To the author's best knowledge, no previous case of fibrosarcoma arising from gouty tophi has been reported. Here we reported the first case of fibrosarcoma arising from gouty tophi. A case of 58 year-old man was presented with a mass with ulcer and infection in the second joint of left middle finger for 2 months, with long standing gouty tophi. The tumor was biopsied and the biopsy showed complete excision of the tumor. With the pathological and immunohistochemical features considered, the diagnosis of fibrosarcoma associated with gouty tophi was made. The clinical findings, pathological characteristics and treatment were described. PMID- 26097617 TI - A case report of sclerosing thymoma of the anterior mediastinum: an exceedingly rare morphology. AB - The morphology of thymoma is diverse, although 5 basic subtypes are recognized in the World Health Organization classification system. Sclerosing thymoma was first documented in 1994 and to date only 13 cases have been reported. Sclerosis itself is considered to be an ancient change and can occur in various histological subtypes. Herein, we present a case of a 62-year-old woman incidentally found to have an anterior mediastinal mass, 31 * 24 * 17 mm in size, without an associated autoimmune disease such as myasthenia gravis. The mass was finally diagnosed as sclerosing thymoma derived from type A thymoma. Intraoperative pathological examination using a limited amount of sample did not allow a definitive diagnosis of thymoma in this case. When dealing with fibrous lesions observed in limited samples such as biopsy and intraoperative frozen specimens, recognizing sclerosing thymoma is important since there are several disease entities accompanying fibrosis in the anterior mediastinum. PMID- 26097618 TI - Endogenous lipoid pneumonia in a cachectic patient after brain injury. AB - Endogenous lipoid pneumonia (EnLP) is an uncommon non-life-threatening inflammatory lung disease that usually occurs in patients with conditions such as lung cancers, primary sclerosing cholangitis, and undifferentiated connective tissue disease. Here we report a case of EnLP in a paralytic and cachectic patient with bronchopneumonia after brain injury. A 40-year-old man experienced a severe brain injury in an automobile accident. He was treated for 1 month and his status plateaued. However, he became paralyzed and developed cachexia and ultimately died 145 days after the accident. Macroscopically, multifocal yellowish firm nodules were visible on scattered gross lesions throughout the lungs. Histologically, many foam cells had accumulated within the alveoli and alveolar walls accompanied by a surrounding interstitial infiltration of lymphocytes. The findings were in accordance with a diagnosis of EnLP. Bronchopneumonia was also noted. To our knowledge, there have been few reports of EnLP associated with bronchopneumonia and cachexia after brain injury. This uncommon pathogenesis should be well recognized by clinicians and forensic pathologists. The case reported here should prompt medical staff to increase the nutritional status and fight pulmonary infections in patients with brain injury to prevent the development of EnLP. PMID- 26097619 TI - Articular nodular fasciitis of the right shoulder joint: report of an unusual case with focus on immunohistochemical differential diagnosis. AB - The mesenchymal lesion nodular fasciitis (NF) can affect various sites of the body but usually arises in subcutaneous tissue or occasionally skeletal muscle. NF is not commonly known to arise in joints, and articular NF is extremely rare. Herein, we present a case of a 54-year-old woman with articular NF. No sign of recurrence was observed after surgical piecemeal removal with a suspected positive surgical margin. In our case, a differential diagnosis of NF, desmoid type fibromatosis, and low-grade myofibroblastic sarcoma was considered. Stromal hyalinization, a characteristic of articular NF, made the diagnosis somewhat difficult, although typical NF morphology was present. Immunohistochemical analysis of alpha-smooth muscle actin, desmin, beta-catenin, and protein gene product 9.5 expression along with close morphological examination provided a reliable distinction. PMID- 26097620 TI - Porokeratosis with follicular involvement: report of three cases and review of literatures. AB - Porokeratosis is characterized clinically by annular plaques with a distinct peripheral keratotic ridge and histologically by the cornoid lamella. Porokeratosis with follicular involvement is rarely reported. To provide the basis of that follicular porokeratosis is a clinical variant or not. Biopsy was taken from three patients who were diagnosed porokeratosis. Routine stain was made and reviewed the literatures about well-documented cases of porokeratosis with follicular involvement. Porokeratosis with follicular involvement may have some clinical features: asymptomatic, erythematous, brownish or skin-color, less than 1 cm in the areas excluding palm and plantar, which commonly involved on middle-age. But there have still not enough proof as an independent clinical variant. PMID- 26097621 TI - Death by aortoesophageal fistula due to disseminated tuberculosis: a case study. AB - Tuberculosis remains a serious public health problem worldwide, especially in Korea. Although tuberculosis is generally considered a non-fatal chronic disease, deaths have occurred. In this case study, a 68-year-old man was admitted to the hospital with dyspepsia, vomiting, and abdominal pain. Nine hours later, he suffered severe hematemesis and died despite cardiopulmonary resuscitation. A medico-legal autopsy was performed and an external examination revealed no external injuries. However, an internal examination revealed an aortoesophageal fistula and a large amount of blood in the stomach. A histologic examination confirmed tuberculous mediastinitis with disseminated tuberculosis involving multiple organs, including the heart, lungs, liver, kidneys, and spleen. Both an aortoesophageal fistula and sudden death due to tuberculosis infection are rare. This paper reports the case of a fatal aortoesophageal fistula associated with disseminated tuberculosis. PMID- 26097622 TI - Primary adrenal leiomyosarcoma: a case report and review of literature. AB - Primary adrenal leiomyosarcoma (PAL) is an extremely rare mesenchymal tumors and originates from the smooth muscle wall of the central adrenal vein and its branches. Herein we report a case of a 49-year-old female suffering from PAL. Computed tomography revealed a well-circumscribed heterogeneously mass measuring 6 * 5 * 5 cm located in the left suprarenal areal, and a left laparoscopic adrenalectomy was underwent. Microscopic examination showed a hypercellular tumor with intersecting fascicled of spindled cells. Immunohistochemical staining showed that the cells were positive for desmin, smooth muscle actin (SMA), vimentin and negative for CD34, CD117, S100, Bcl-2 and Dog1. No oncological treatment underwent after surgery, and the patient had no recurrence or metastasis at 6 months postoperatively. PMID- 26097623 TI - A rare occurrence of lymphoepithelial cyst in the palatine tonsil: a case report and discussion of the etiopathogenesis. AB - Lymphoepithelial cysts are uncommon benign lesions that present as painless yellowish nodules arising from various sites in the oral cavity and other parts of the body. Their etiopathogenesis is controversial, but most authors have assumed that they develop from obstruction of crypts in oral lymphoid aggregates, thus they are not true cysts but pseudocysts of retention. This paper describes a case of a large lymphoepithelial cyst located in the tonsil of a 21-year-old man complaining of a lump in the throat for four months. The patient underwent excisional biopsy, and the histopathological features showed squamous epithelium surrounded by lymphoid tissue, which were characteristically consistent with a lymphoepithelial cyst. We discuss the etiopathogenesis of these lesions and treatment modalities, which can consist of conservative surgery or only follow-up examination. PMID- 26097624 TI - In vitro studies of phenethyl isothiocyanate against the growth of LN229 human glioma cells. AB - Phenethyl isothiocyanate (PEITC) is one of the best studied members of isothiocyanates (ITC), a variety of edible cruciferous vegetables including broccoli, watercress, and cabbage, and have generated particular interest because of its remarkable chemopreventive activity. Many literature reports proved that phenethyl isothiocyanate exhibited significant anti-cancer chemopreventive effects including lung, glioma and leukemia cancer. In this study, we explored the inhibitory effects as well as mechanisms of PEITC on human glioma LN229 cells. Results demonstrated that PEITC possesses the potential ability to inhibit proliferation, induce apoptosis and arrest cell cycling against LN229 human glioma cells. Moreover, investigated results showed that PEITC inhibited the expression of superoxide dismutase (SOD) and glutathione (GSH), and caused oxidative stress to tumor cells. Collective results suggested us to believe that PEITC can inhibit the growth of LN229 cells and its mechanism can be related to the fact that PEITC can cause oxidative stress to tumor cells. PMID- 26097625 TI - A PROOF OF CONVERGENCE OF THE HORN AND SCHUNCK OPTICAL FLOW ALGORITHM IN ARBITRARY DIMENSION. AB - The Horn and Schunck (HS) method, which amounts to the Jacobi iterative scheme in the interior of the image, was one of the first optical flow algorithms. In this article, we prove the convergence of the HS method, whenever the problem is well posed. Our result is shown in the framework of a generalization of the HS method in dimension n >= 1, with a broad definition of the discrete Laplacian. In this context, the condition for the convergence is that the intensity gradients are not all contained in a same hyperplane. Two other articles ([17] and [13]) claimed to solve this problem in the case n = 2, but it appears that both of these proofs are erroneous. Moreover, we explain why some standard results on the convergence of the Jacobi method do not apply for the HS problem, unless n = 1. It is also shown that the convergence of the HS scheme implies the convergence of the Gauss-Seidel and SOR schemes for the HS problem. PMID- 26097626 TI - Chondrogenic differentiation of stem cells in human umbilical cord stroma with PGA and PLLA scaffolds. AB - The stem cells in the umbilical cord stroma, or Wharton's jelly, are referred to as human umbilical cord mesenchymal stromal cells (hUCMSCs) and have been shown to differentiate along a chondrogenic lineage. The aim of this study was to evaluate the chondrogenic differentiation of hUCMSCs in either polyglycolic acid (PGA) or poly-L-lactic acid (PLLA) non-woven mesh scaffolds for cartilage tissue engineering. PGA is widely known to degrade faster than PLLA, and over longer time scales, and differences may be expected to emerge after extended culture periods. Therefore, the focus of this study was to evaluate differences over a shorter duration. After 21 days of culture in PLLA or PGA scaffolds, hUCMSC constructs were analyzed for biochemical content, histology, and gene expression. Overall, there were only minute differences between the two scaffold groups, with similar gene expression and biosynthesis. The most notable difference was a change in shape from cylindrical to spherical by the PGA, but not PLLA, scaffold group. The overall similar behavior of the groups may suggest that in vivo application of hUCMSC-seeded PLLA or PGA scaffolds, following a 21-day pre culture period, may yield similar constructs at the time of implantation. However, differences may begin to become more apparent with in vivo performance following implantation, or with in vitro performance over longer time periods. PMID- 26097627 TI - Isolated posterior malleolus fracture: a rare injury mechanism. AB - Sprain of the ankle is undoubtedly a common injury during athletic activity, and the sprain can be also associated with fracture of the ankle. Isolated posterior malleolus fracture is a very rare condition, which is usually missed. Here, we are presenting a 37 years old female patient, who suffered injury secondary pressing on brake pedal during collision in a traffic accident. Clinical evaluation is based on Ottawa Ankle Rules and a fracture is diagnosed; patient is started on daily activities at postoperative Week 8. This study aims to emphasize that Ottawa Ankle Rules are usually efficient for evaluating fractures of ankle, but clinicians should always make a detailed physical examination. PMID- 26097628 TI - Vaginal metastasis of pancreatic cancer. AB - Vaginal metastasis from pancreatic cancer is an extreme case and often indicates a poor prognosis. We present a case of pancreatic carcinoma with metastasis to the vagina that was discovered by vaginal bleeding. To our knowledge, this is the third case in the world of a primary pancreatic adenocarcinoma discovered of symptoms from a vaginal metastasis. PMID- 26097630 TI - [Acquired vulvar lymphangioma after treatment of a gynecological cancer]. PMID- 26097629 TI - [Prevalence of hepatitis B in people infected with HIV in Parakou in Benin]. PMID- 26097631 TI - A rare case of urinary tract infection due to Trichosporon asahii in a diabetic patient. AB - Trichosporon asahii is a basidiomycete yeast responsible for white piedra and onychomycosis in the immunocompetent host. In the immunocompromised patients, invasive infections are reported; their diagnosis is difficult and they are associated with high mortality rate. Urinary infection due to Trichosporon Asahi is rare but its incidence increasing. We report the case of a 58 year old diabetic patient. The yeast was isolated from urine samples of three consecutive crops in pure form. The patient improved after antifungal therapy. PMID- 26097632 TI - [Healthcare journey of the elderly in Bobo-Dioulasso, Burkina Faso: a cross sectional survey]. PMID- 26097634 TI - [Non secreting paraganglioma of Zuckerkandl organ]. PMID- 26097633 TI - [Blunt and penetrating trauma the abdomen: retrospective analysis of 175 cases and review of literature]. PMID- 26097635 TI - [Cardiac involvement in Steinert myotonic dystrophy: Moroccan experience, about 18 cases]. PMID- 26097636 TI - [Place of non-operative treatment of abdominal contusions in developing countries]. PMID- 26097637 TI - [Allergic asthma in central Tunisia]. PMID- 26097638 TI - [A hemorrhagic stroke revealing Neisseria meningitidis meningitis]. PMID- 26097639 TI - [A carotidynia revealing Takayasu's arteritis in a man of 54 years]. PMID- 26097640 TI - Early seizures in acute stroke. AB - Early seizures (ES) may complicate the clinical course of patients with acute stroke. The aim of this study was to assess the frequency and the predictive factors for early seizures as well the clinical outcome in patients with first ever stroke. A total of 352 consecutive patients with first-ever stroke, admitted to our department, were included in this retrospective study. Early seizures were defined as seizures occurring within 7 days from acute stroke. Patients with history of epilepsy were excluded. About 47 patients (13%) had early seizure, and 8 had a status epilepticus. We had 28 women and 19 men. The mean age was 71.6 +/- 14.6. They were significantly more common in patients with cortical involvement, severe and large stroke, and in patient with cortical associated hemorrhage. ES were associated with an increase in adverse outcome (mortality and disability). Early seizures occurred in about 13% of patients with acute stroke. In these patients hemorrhagic transformation is a predictive factor for ES. ES seem to be associated with a worse outcome after acute stroke. PMID- 26097641 TI - A cross-population extended haplotype-based homozygosity score test to detect positive selection in genome-wide scans. AB - In this article, we developed a cross-population comparison test statistic to detect chromosome regions in which there is no significant excess homozygosity in one population but homozygosity remains high in the other. We treated an extended stretch of homozygosity as a surrogate indicator of a recent positive selection. Conditioned on existing linkage disequilibrium, we proposed to test the haplotype version of the Hardy-Weinberg equilibrium (HWE). For each population, we assumed that a random sample of unrelated individuals were typed on a large number of single nucleotide polymorphisms (SNPs). A pooled-test statistic was constructed by comparing the measurements of homozygosity of the two samples around a core SNP. In the chromosome regions where HWE is roughly true in one population and HWE is not true in the other, the pooled-test statistic led to significant results to detect the positive selection. We evaluated the performance of the test statistic by type I error comparison and power evaluation. We showed that the proposed test statistic was very conservative and it had good power when the selected allele remains polymorphic. Then, we applied the test to HapMap Phase II data to make a comparison with previous results and to search for new candidate regions. PMID- 26097642 TI - Chronic urticaria merits serum vitamin D evaluation and supplementation; a randomized case control study. AB - BACKGROUND: Several studies suggest that Vitamin D (Vit-D3) supplementation reduces Chronic Urticaria (CU) symptoms. OBJECTIVES: Evaluation of serum 25 hydroxyvitamin-D (25 (OH)2D) level and assessment of therapeutic effect of VitD3in CU patients. METHODS: 192 subjects were stratified according to the baseline 25(OH)2D levels and subsequently randomized into three subgroups to receive Vit-D3 alone (VD) or antihistamine and systemic corticosteroid (H+S) or VitD3 with antihistamine and systemic corticosteroid (VD+H+S) for 6 weeks between July 2012 to Oct 2014. 130 healthy controls (HC) were followed without any intervention. The patients were evaluated for reduction in urticarial symptoms using visual analogue scale (VAS) and 5-D itch score. RESULTS: Low serum levels of 25 (OH)2D was observed in 91% of CU patients and 64% of the healthy controls (P < 0.0001). VAS and 5-D Score in subgroups VD, H + S and VD + H + S decreased significantly from 6 . 7 +/- 0 . 043, 6 . 6 +/- 0 . 42 and 6 . 68 +/- 0 . 40 at baseline to 5 . 2 +/- 0 . 70 (P = 0 . 0088), 3 . 3 +/- 0 . 50 (P < 0 . 0001) and1 . 86 +/- 0 . 39 (P < 0 . 0001) after treatment and from 14 . 5 +/- 0 . 72, 13 . 9 +/- 0 . 77 and 13 . 9 +/- 0 . 221 to 12 . 06 +/- 1 . 10 (P = 0 . 0072), 8 . 1 +/- 1 . 13 (P < 0 . 0001) and 5 . 01 +/- 0 . 94 (P < 0 . 0001) respectively. CONCLUSIONS: CU patients have low serum 25(OH)2D levels and Vit-D3 supplementation in combination with antihistamine and systemic corticosteroid show elevated response in resolving the symptoms of CU. This study also warrants that each subject with CU should be screened for serum 25 (OH)2D levels before starting a treatment. PMID- 26097643 TI - Acne-Related Quality of Life Among Female Adults of Different Races/Ethnicities. AB - BACKGROUND: Acne impairs quality of life, but its effect on different races/ethnicities is unclear. This study evaluated racial/ethnic differences in acne-related quality of life and psychological symptoms among female adults. METHODS: A Web-based survey was conducted with U.S. female adults (25-45 years old) with facial acne (>=25 visible lesions). Outcomes included sociodemographics, clinical characteristics, acne-related quality of life (Acne Specific Quality of Life Questionnaire), psychological symptoms (Patient Health Questionnaire), and work/school productivity. Racial/ethnic differences were evaluated using descriptive statistics and analysis of variance/chi-square analyses. RESULTS: Three-hundred twelve subjects (Black = 30.8%, Hispanic = 17.6%, Asian/other = 17.3%, White = 34.3%) completed the survey (mean age = 35.3 +/- 5.9 years). Acne negatively impacted quality of life for all subjects. Black subjects reported significantly less negative impact on self-perception versus Asian/other (Black = 12.6 +/- 9.9, Asian/other = 8.4 +/- 8.6; p = .05). Social functioning was less negatively impacted in White and Black subjects versus Asian/other (White = 12.7 +/- 7.5, Asian/other = 8.4 +/- 7.8, p < .05; Black = 12.1 +/- 9.2, Asian/other = 8.4 +/- 7.8, p = .06). Over one third (total sample = 40.7%, Black = 31.3%, Hispanic = 36.4%, Asian/other = 50.0%, White = 46.7%) reported moderate/severe anxiety/depression symptoms. Acne also impacted ability to concentrate on work/school. CONCLUSION: Racial/ethnic differences were observed in acne-related quality of life and psychological symptoms in female adults; acne negatively impacted self-perceptions and social/emotional functioning. PMID- 26097644 TI - Detection of plant oil addition to cheese by synchronous fluorescence spectroscopy. AB - The fraudulent addition of plant oils during the manufacturing of hard cheeses is a real issue for the dairy industry. Considering the importance of monitoring adulterations of genuine cheeses, the potential of fluorescence spectroscopy for the detection of cheese adulteration with plant oils was investigated. Synchronous fluorescence spectra were collected within the range of 240 to 700 nm with different wavelength intervals. The lowest detection limits of adulteration, 3.0 and 4.4%, respectively, were observed for the application of wavelength intervals of 60 and 80 nm. Multiple linear regression models were used to calculate the level of adulteration, with the lowest root mean square error of prediction and root mean square error of cross validation equalling 1.5 and 1.8%, respectively, for the measurement acquired at the wavelength interval of 60 nm. Lower classification errors were obtained for the successive projections algorithm-linear discriminant analysis (SPA-LDA) rather than for the principal component analysis (PCA)-LDA method. The lowest classification error rates equalled 3.8% (?lambda = 10 and 30 nm) and 0.0% (?lambda = 60 nm) for the PCA-LDA and SPA-LDA classification methods, respectively. The applied technique is useful for detecting the addition of plant fat to hard cheese. PMID- 26097645 TI - New insights about phenotypic heterogeneity within Propionibacterium freudenreichii argue against its division into subspecies. AB - Propionibacterium freudenreichii is widely used in Swiss-type cheese manufacture, where it contributes to flavour and eye development. It is currently divided into two subspecies, according to the phenotype for lactose fermentation and nitrate reduction (lac+/nit- and lac-/nit+ for P. freudenreichii subsp. shermanii and subsp. freudenreichii, respectively). However, the existence of unclassifiable strains (lac+/nit+ and lac-/nit-) has also been reported. The aim of this study was to revisit the relevance of the subdivision of P. freudenreichii into subspecies, by confirming the existence of unclassifiable strains. Relevant conditions to test the ability of P. freudenreichii for lactose fermentation and nitrate reduction were first determined, by using 10 sequenced strains, in which the presence or absence of the lactose and nitrate genomic islands were known. We also determined whether the subdivision based on lac/nit phenotype was related to other phenotypic properties of interest in cheese manufacture, in this case, the production of aroma compounds, analysed by gas chromatography-mass spectrometry, for a total of 28 strains. The results showed that a too short incubation time can lead to false negative for lactose fermentation and nitrate reduction. They confirmed the existence of four lac/nit phenotypes instead of the two expected, thus leading to 13 unclassifiable strains out of the 28 characterized (7 lac+/nit+ and 6 lac-/nit-). The production of the 15 aroma compounds detected in all cultures varied more within a lac/nit phenotype (up to 20 times) than between them. Taken together, these results demonstrate that the division of P. freudenreichii into two subspecies does not appear to be relevant. PMID- 26097646 TI - Gait Analysis in Cervical Spondylotic Myelopathy. AB - STUDY DESIGN: Gait analysis of patients with cervical spondylotic myelopathy (CSM) by using a sheet-type gait analysis system. PURPOSE: The aim of this study was to compare the gait patterns of patients with CSM, evaluated by the Nurick grades, and to determine the threshold values of gait parameters predicting the occurrence of a fall by using a gait recorder. OVERVIEW OF LITERATURE: Gait disorder due to CSM may progress to severe paraplegia, following even a minor trauma such as a fall. The indications for the surgery of CSM without severe paralysis remain controversial. The quantitative gait analysis and the decision for decompressive surgery in patients with CSM are important in order to prevent severe paraplegia from a fall. METHODS: One hundred thirty-two subjects (normal, 34; CSM, 98) underwent gait analysis by using a sensor sheet. Measurements of gait cycle parameters included the step and stride length, step width, foot angle, swing phase, and stance phase. CSM was assessed by Nurick grade. RESULTS: Although the clinical symptoms were lacking, Nurick grade 1 had significant abnormalities in the parameters of velocity, step length, and step angle (p<0.05). Regarding the Nurick grade and walking phase, the length of the stance phase was increased to more than 70% of the entire walking cycle in Nurick grade 4. CONCLUSIONS: Gait analysis was an objective tool for evaluating the gait stability. Our results suggested that when the percentage of the stance phase in the gait cycle increases to above 70%, the CSM patients have an increased fall risk. PMID- 26097647 TI - Detecting Facet Joint and Lateral Mass Injuries of the Subaxial Cervical Spine in Major Trauma Patients. AB - STUDY DESIGN: Radiologic imaging measurement study. PURPOSE: To assess the accuracy of detecting lateral mass and facet joint injuries of the subaxial cervical spine on plain radiographs using computed tomography (CT) scan images as a reference standard; and the integrity of morphological landmarks of the lateral mass and facet joints of the subaxial cervical spine. OVERVIEW OF LITERATURE: Injuries of lateral mass and facet joints potentially lead to an unstable subaxial cervical spine and concomitant neurological sequelae. However, no study has evaluated the accuracy of detecting specific facet joint injuries. METHODS: Eight spinal surgeons scored four sets of the same, randomly re-ordered, 30 cases with and without facet joint injuries of the subaxial cervical spine. Two surveys included conventional plain radiographs series (test) and another two surveys included CT scan images (reference). Facet joint injury characteristics were assessed for accuracy and reliability. Raw agreement, Fleiss kappa, Cohen's kappa and intraclass correlation coefficient statistics were used for reliability analysis. Majority rules were used for accuracy analysis. RESULTS: Of the 21 facet joint injuries discerned on CT scan images, 10 were detected in both plain radiograph surveys (sensitivity, 0.48; 95% confidence interval [CI], 0.26-0.70). There were no false positive facet joint injuries in either of the first two X ray surveys (specificity, 1.0; 95% CI, 0.63-1.0). Five of the 11 cases with missed injuries had an injury below the lowest visible articulating level on radiographs. CT scan images resulted in superior inter- and intra-rater agreement values for assessing morphologic injury characteristics of facet joint injuries. CONCLUSIONS: Plain radiographs are not accurate, nor reliable for the assessment of facet joint injuries of the subaxial cervical spine. CT scans offer reliable diagnostic information required for the detection and treatment planning of facet joint injuries. PMID- 26097648 TI - The Time Course Changes in Bone Metabolic Markers after Administering the Anti Receptor Activator of Nuclear Factor-Kappa B Ligand Antibody and Drug Compliance among Patients with Osteoporosis. AB - STUDY DESIGN: Retrospective study. PURPOSE: We conducted a study to investigate the time course changes in bone metabolic markers after the administration of the anti-receptor activator of nuclear factor-kappa B ligand (RANKL) antibody and to assess drug compliance among osteoporotic patients. OVERVIEW OF LITERATURE: The anti-RANKL antibody is expected to provide an improvement in those with a bone metabolism disorder. However there are only a few clinical reports available on the effect of treatment. METHODS: We included 40 post-menopausal osteoporotic patients who received the anti-RANKL antibody. To determine the time course changes in the bone metabolic markers, we measured the serum tartrate-resistant acid phosphatase 5b (TRACP 5b; a bone resorption marker) and the serum N-terminal propeptide of type 1 collagen (P1NP; a bone formation marker) levels prior to and 1 month after administrating the anti-RANKL antibody. To evaluable drug compliance, we assessed the dropout rate during treatment and at 6 months after treatment. RESULTS: The average TRACP 5b level significantly decreased from 574.8 mU/dL before treatment to 153.2 mU/dL 1 month after treatment (p<0.05). There was no significant difference in the average P1NP level, which was 56.9 uG/L and 35.1 uG/L before and 1 month after treatment, respectively (p>0.05). As for drug compliance, we did not have any dropouts during the treatment or after 6 months (dropout rate: 0%). CONCLUSIONS: Our study suggests that anti-RANKL antibody treatment suppresses bone resorption and maintains bone formation. PMID- 26097649 TI - Demographics of Thoracolumbar Fracture in Indian Population Presenting to a Tertiary Level Trauma Centre. AB - STUDY DESIGN: Prospective, cross-sectional, observational study. PURPOSE: Spine traumata are devastating injuries, which may result in serious disabilities and dire consequences. The current study involves a detailed analysis and description of patients, who were operated at a tertiary care, urban level 1 Spine Centre in India. OVERVIEW OF LITERATURE: Various studies in literature have discussed the epidemiology and patterns of these injuries in trauma patients. However, literature describing the demographic profile and distribution of these traumata in the Indian population is scarce. METHODS: The current study was conducted as a prospective trial involving patients, who were treated at our Spine Centre in India between July 2009 to December 2012. We studied 92 patients with thoraco lumbar spine fracture, who were operated with short or long segment posterior stabilization. Epidemiological details, pre- and post-hospitalisation care received and other injury pattern factors were studied. RESULTS: Fall from height (46 patients, 50%) was the most common mechanism observed in the patients. Sixty three percent injuries belonged to AO type A fractures, while 16.2% and 19.4% of the patients had suffered from AO types B and C injuries, respectively. CONCLUSIONS: We identified interesting epidemiological data and prevailing inadequacies in Emergency Spine care management in the study patients. These observations could facilitate implementation of the changes required to improve current standards of patient care. PMID- 26097650 TI - Restoration of Lumbar Lordosis in Flat Back Deformity: Optimal Degree of Correction. AB - STUDY DESIGN: A retrospective comparative study. PURPOSE: To provide an ideal correction angle of lumbar lordosis (LL) in degenerative flat back deformity. OVERVIEW OF LITERATURE: The degree of correction in degenerative flat back in relation to pelvic incidence (PI) remains controversial. METHODS: Forty-nine patients with flat back deformity who underwent corrective surgery were enrolled. Posterior-anterior-posterior sequential operation was performed. Mean age and mean follow-up period was 65.6 years and 24.2 months, respectively. We divided the patients into two groups based on immediate postoperative radiographs-optimal correction (OC) group (PI-9 degrees <=LL=55 degrees ). Radiological and clinical results were analyzed. RESULTS: Patients in OC group had significantly less correction loss and maintained normal sagittal alignment (sagittal vertical axis<5 cm), as compared to patients in UC group (p<0.05). LL of low PI group significantly maintained within 9 degrees better than high PI group (p<0.05). Oswestry disability index (ODI) significantly decreased at last follow-up, as compared to preoperative state. However, there was no significant difference in last follow-up ODI between the groups. CONCLUSIONS: In flat back deformity, correction of LL to within 9 degrees of PI will result in better sagittal balance. Thus, we recommend sufficient LL to prevent correction loss, especially in patients with high PI. PMID- 26097651 TI - Three Different Methods in Deformity Correction of Degenerative Flat Back: A Single Surgeon's Experience with 64 Consecutive Cases. AB - STUDY DESIGN: Retrospective study. PURPOSE: To evaluate the radiological and clinical results of three different methods in the deformity correction of a degenerative flat back. OVERVIEW OF LITERATURE: There are no comparative studies about different procedures in the treatment of degenerative flat back. METHODS: Sixty-four patients who consecutively underwent corrective surgery for degenerative flat back were reviewed. The operations were performed by three different methods: posterior-only (group P, n=20), one-stage anterior-posterior (group AP, n=12), and two-stage anterior-posterior with iliac screw fixation (group AP-I, n=32). Medical and surgical complications were examined and radiological and clinical results were compared. RESULTS: The majority of medical and surgical complications were found in group AP (5/12) and group P (7/20). The sagittal vertical axes were within normal range immediately postoperatively in all groups, but only group AP-I showed normal sagittal alignment at the final follow-up. Postoperative lumbar lordosis was also significantly higher in group AP-I than in group P or group AP and the finding did not change through the last follow-up. The Oswestry disability index was significantly lower in groups AP and AP-I than in group P at the final follow-up. Meanwhile, the operating time was the longest in group AP-I, and total amount of blood loss was larger in group AP I and group AP than in group P. CONCLUSIONS: Anterior-posterior correction showed better clinical results than posterior-only correction. Two-staged anterior posterior correction with iliac screw fixation showed better radiological results than posterior-only or one-staged anterior-posterior correction. Two-staged anterior-posterior correction with iliac screw fixation also showed a lower complication rate than one-staged anterior-posterior correction. PMID- 26097652 TI - Epidural Fibrosis after Lumbar Disc Surgery: Prevention and Outcome Evaluation. AB - STUDY DESIGN: This is a prospective, randomized, controlled study designed and conducted over 10 years from 2002 to 2012. PURPOSE: The study aimed to monitor the effect of suction drains (SD) on the incidence of epidural fibrosis (EF) and to test, if the use of SD alone, SD with local steroids application, SD combined with fat grafts and local steroids application, or SD combined with fat grafts and without local steroids application, would improve outcome. OVERVIEW OF LITERATURE: EF contributes to significant unsatisfactory failed-back syndrome. Efforts have been tried to reduce postoperative EF, but none were ideal. METHODS: Between September 2002 and 2012, 290 patients with symptomatic unilateral or bilateral, single-level lumbar disc herniation were included in the study. Two groups were included, with 165 patients in group I (intervention group) and 125 patients in group II (control group). Group I was subdivided into four subgroups: group Ia (SD alone), group Ib (SD+fat graft), group Ic (SD+local steroids), and group Id (SD+fat graft+local steroids). RESULTS: The use of SD alone or combined with only fat grafts, fats grafts and local steroids application, or only local steroids application significantly improved patient outcome and significantly reduced EF as measured by magnetic resonance imaging (MRI). CONCLUSIONS: This study has clearly demonstrated the fact that the use of suction drainage alone or combined with only fat grafts, fats grafts and local steroids application, or only local steroids application significantly improved patient outcome with respect to pain relief and functional outcome and significantly reduced EF as measured by an MRI. A simple grading system of EF on MRI was described. PMID- 26097653 TI - Clinical Findings and Results of Surgical Resection in 19 Cases of Spinal Osteoid Osteoma. AB - STUDY DESIGN: Descriptive cases series. PURPOSE: To evaluate clinical findings and results of conventional surgery in patients with spinal osteoid osteoma (OO). OVERVIEW OF LITERATURE: OO is a rare benign tumor with spinal involvement rate of about 10%-20%. METHODS: This descriptive study was conducted on 19 patients (11 males and 8 females with an average age of 19.8 years) with documented histopathological and imaging findings of OO referred to a university hospital. Neurologic symptoms and pain were scored before and after the open surgical excision. Data were analyzed by SPSS ver. 16 software using chi-square and significance level of 0.05. RESULTS: The most common complaint was back or neck pain (84.2%) and in 68.4% spinal deformity (mostly scoliosis) shown with an average cobb angle of 21 degrees at presentation. The sites of involvement were 35% in the lumbar, 35% in the thoracic, 25% in the cervical, and 5% in the sacrum. Lamina was the most common site (50%) of involvement with predilection for the right side (p=0.001). All patients were treated by conventional surgical excision with a complete recovery of pain and deformity. No recurrence occurred after a mean follow up of 44.5 months, but 4 of 19 cases instrumented because of induced instability. In one case there were two levels of involvement (C7-T1) simultaneously. Interestingly, 10 out of 19 of our cases belonged to a specific race (Bakhtiari). CONCLUSIONS: Surgical intra-lesional curettage is potentially an effective method without any recurrence, which can lead to spontaneous scoliosis recovery and pain relief. Race may be a potential risk factor for spinal (OO). PMID- 26097654 TI - Computed Tomography-Guided Biopsy for Potts Disease: An Institutional Experience from an Endemic Developing Country. AB - STUDY DESIGN: A retrospective chart review. PURPOSE: In endemic resource poor countries like Pakistan, most patients are diagnosed and treated for Potts disease on clinical and radiological grounds without a routine biopsy. The purpose of this study was to evaluate the use and effect of computed tomography (CT)-guided biopsy in the management of Potts disease since the technique is becoming increasingly available. OVERVIEW OF LITERATURE: CT-guided biopsy of spinal lesions is routinely performed. Literature on the utility of the technique in endemic resource poor countries is little. METHODS: This study was conducted at the Neurosurgery section of Aga Khan University Hospital Karachi. All the patients with suspected Potts disease who underwent CT-guided biopsy during the 7 year period from 2007 to 2013 were included in this study. Details of the procedure, histopathology and microbiology were recorded. RESULTS: One hundred and seventy-eight patients were treated for suspected Potts disease during the study period. CT-guided biopsies of the spinal lesions were performed in 91 patients (51.12%). Of the 91 procedures, 22 (24.2%) were inconclusive because of inadequate sample (10), normal tissue (6) or reactive tissue (6). Sixty-nine biopsies were positive (75.8%). Granulomatous inflammation was seen in 58 patients (84.05%), positive acid-fast bacillus (AFB) smear in 4 (5.7%) and positive AFB culture in 12 patients (17.3%). All 91 cases in which CT-guided biopsy was performed responded positively to antituberculosis therapy (ATT). CONCLUSIONS: 75.8% of the specimens yielded positive diagnoses. Granulomatous inflammation on histopathology was the commonest diagnostic feature. In this series, the rates of positive AFB smear and culture were low compared to previous literature. PMID- 26097655 TI - Lumbar Spinal Canal Stenosis Classification Criteria: A New Tool. AB - STUDY DESIGN: Case-control study. PURPOSE: To design a new tool for classifying lumbar spinal canal stenosis (CLSCS). OVERVIEW OF LITERATURE: Grading of patients with lumbar spinal canal stenosis (LSCS) is controversial. METHODS: The Oswestry disability index (ODI) and the neurogenic claudication outcome score (NCOS) were recorded. Four parameters, which indicate the severity of LSCS disease, including Hufschmidt-grade, grading of magnetic resonance imaging, self-paced walking test, and stenosis ratio (SR) were employed. For the SR, quartile analysis was applied for classifying LSCS and the Hufschmidt-grade was modified into a 4-grade score. An initial score was assigned to each metric based on the severity of LSCS. Using the inverse-variance weighting method, the relative weights of these domains and their categories were determined. The score for all of the cases was obtained based on their weight by summing up the points of the four variables. Quartile analysis was used and a CLSCS score was proposed. Finally, intra- and interobserver reliability, and validity were assessed. RESULTS: A total of 357 patients were studied. The final CLSCS score for each case ranged from 4 to 16.5. Based on the quartile analysis, using the new criteria set, the CLSCS score was divided into four categories: CLSCS<7 (grade 0); 7<=CLSCS<10 (grade 1); 10<=CLSCS<13 (grade 2); and 13<=CLSCS<=16.5 (grade 3). The kappa values of for the CLSCS score indicated a perfect agreement. The CLSCS was correlated with the ODI and NCOS. All patients with grade 3 CLSCS were observed in the surgical group. CONCLUSIONS: The CLSCS score can be helpful for classifying LSCS patients and in the decision-making process. PMID- 26097656 TI - Adolescent Scoliosis Screening in Nara City Schools: A 23-Year Retrospective Cross-Sectional Study. AB - STUDY DESIGN: Retrospective cross-sectional study. PURPOSE: To determine the prevalence of idiopathic scoliosis, define the distribution of the curve magnitude, evaluate the accuracy of Moire topography as a screening tool, and investigate the cost-effectiveness of our screening system. OVERVIEW OF LITERATURE: Early detection of idiopathic scoliosis provides the opportunity for conservative treatment before the deformity is noticeable. We believe that scoliosis screening in schools is useful for detection; however, screening programs are controversial owing to over referral of students who do not require further testing or follow-up. In Japan, school scoliosis screening programs are mandated by law with individual policies determined by local educational committees. We selected Moire topography as the scoliosis screening tool for schools in Nara City. METHODS: We selected Moire topography as the scoliosis screening tool for schools in Nara City. We screened boys and girls aged 11-14 years and reviewed the school scoliosis screening results from 1990 to 2012. RESULTS: A total of 195,149 children aged 11-14 years were screened. The prevalence of scoliosis (defined as >=10 degrees curvature) was 0.057%, 0.010%, and 0.059% in fifth, sixth, and seventh grade boys and 0.337%, 0.369%, and 0.727% in fifth, sixth, and seventh grade girls, respectively. The false-positive rate of our Moire topography was 66.7%. The minimum cost incurred for scoliosis detection in one student was 2,000 USD. CONCLUSIONS: The overall prevalence of scoliosis was low in the students of Nara City schools. Over 23 years, the prevalence of scoliosis in girls increased compared to that in the first decade of the study. PMID- 26097657 TI - Evaluating Kyphosis and Lordosis in Students by Using a Flexible Ruler and Their Relationship with Severity and Frequency of Thoracic and Lumbar Pain. AB - STUDY DESIGN: A cross-sectional, descriptive study. PURPOSE: This study aimed to investigate the relationship between kyphosis and lordosis measured by using a flexible ruler and musculoskeletal pain in students of Hamadan University of Medical Sciences. OVERVIEW OF LITERATURE: The spine supports the body during different activities by maintaining appropriate body alignment and posture. Normal alignment of the spine depends on its structural, muscular, bony, and articular performance. METHODS: Two hundred forty-one students participated in this study. A single examiner evaluated the angles of lumbar lordosis and thoracic kyphosis by using a flexible ruler. To determine the severity and frequency of pain in low-back and inter-scapular regions, a tailor-made questionnaire with visual analog scale was used. Finally, using the Kendall correlation coefficient, the data were statistically analyzed. RESULTS: The mean value of lumbar lordosis was 34.46 degrees +/-12.61 degrees in female students and 22.46 degrees +/-9.9 degrees in male students. The mean value of lumbar lordosis significantly differed between female and male students (p<0.001). However, there was no difference in the level of the thoracic curve (p=0.288). Relationship between kyphosis measured by using a flexible ruler and inter scapular pain in male and female students was not significant (p=0.946). However, the relationship between lumbar lordosis and low back pain was statistically significant (p=0.006). Also, no significant relationship was observed between abnormal kyphosis and frequency of inter-scapular pain, and between lumbar lordosis and low back pain. CONCLUSIONS: Lumbar lordosis contributes to low back pain. The causes of musculoskeletal pain could be muscle imbalance and muscle and ligament strain. PMID- 26097658 TI - Optimal Timing of Preoperative Skin Preparation with Povidone-Iodine for Spine Surgery: A Prospective, Randomized Controlled Study. AB - STUDY DESIGN: A prospective, randomized, controlled study. PURPOSE: The objective of this study was to evaluate the effectiveness of two techniques of skin preparation with povidone-iodine. OVERVIEW OF LITERATURE: Preoperative skin preparation is important for preventing surgical site infection by reducing the bacteria in the surgical area. Povidone-iodine is a commonly used agent for preoperative skin preparation, and further decrease in surgical site infections can be expected by understanding how to apply it more effectively. METHODS: Eighty-nine spine surgery patients were randomly allocated to two groups. In group A, povidone-iodine was applied to the surgical site just before starting the operation; in group B, povidone-iodine was applied several minutes prior to starting the operation and was allowed to dry. We collected samples from the wound edge before suturing, and we compared the rates of positive culture between the two groups. RESULTS: The rate of positive culture was 30.2% (13 out of 43 patients) in group A, and 6.5% (3 out of 46 patients) in group B. This indicates that there was a significant difference in postoperative infection rates between group A and group B. CONCLUSIONS: Because bacteria on the skin appeared significantly reduced by allowing povidone-iodine to dry for several minutes prior to surgery, we recommend this approach to reduce the incidence of postoperative infections. PMID- 26097659 TI - Radiological Outcome of Short Segment Posterior Instrumentation and Fusion for Thoracolumbar Burst Fractures. AB - STUDY DESIGN: Retrospective study. PURPOSE: To evaluate the radiological outcome of the surgical treatment of thoracolumbar burst fractures by using short segment posterior instrumentation (SSPI) and fusion. OVERVIEW OF LITERATURE: The optimal surgical treatment of thoracolumbar burst fractures remains a matter of debate. SSPI is one of a number of possible choices, yet some studies have revealed high rates of poor radiological outcome for this SSPI. METHODS: Patients treated using the short segment instrumentation and fusion technique at the Spinal Injuries Center (Iizuka, Fukuoka, Japan) from January 1, 2006 to July 31, 2012 were selected for this study. Radiographic parameters such as local sagittal angle, regional sagittal angle, disc angle, anterior or posterior height of the vertebral body at admission, postoperation and final observation were collected for radiological outcome evaluation. RESULTS: There were 31 patients who met the inclusion criteria with a mean follow-up duration of 22.7 months (range, 12-48 months). The mean age of this group was 47.9 years (range, 15-77 years). The mean local sagittal angles at the time of admission, post-operation and final observation were 13.1 degrees , 7.8 degrees and 14.8 degrees , respectively. There were 71% good cases and 29% poor cases based on our criteria for the radiological outcome evaluation. The correction loss has a strong correlation with the load sharing classification score (Spearman rho=0.64, p<0.001). CONCLUSIONS: The loss of kyphotic correction following the surgical treatment of thoracolumbar burst fracture by short segment instrumentation is common and has a close correlation with the degree of comminution of the vertebral body. Patients with high load sharing scores are more susceptible to correction loss and postoperative kyphotic deformity than those with low scores. PMID- 26097660 TI - Effectiveness of Posterolateral Lumbar Fusion Varies with the Physical Properties of Demineralized Bone Matrix Strip. AB - STUDY DESIGN: A randomized, controlled animal study. PURPOSE: To investigate the effectiveness of fusion and new bone formation induced by demineralized bone matrix (DBM) strips with jelly strengths. OVERVIEW OF LITERATURE: The form of the DBM can make a difference to the outcome. The effect of different jelly strengths on the ability of DBM to form new bone is not known. METHODS: Forty-eight rabbits were randomized into a control group and two experimental groups. In the control group (group 1), 1.4 g of autologous iliac crest bone was placed bilaterally. In the experimental groups, a high jelly strength DBM-hyaluronic acid (HA)-gelatin strip (group 2) and a low jelly strength DBM-HA-gelatin strip (group 3) were used. The fusion was assessed with manual manipulation and radiographs. The volume of the fusion mass was determined from computed tomographic images. RESULTS: The fusion rates as determined by manual palpation were 37.5%, 93.8% and 50.0% in group 1, group 2, and group 3, respectively (p<0.05). By radiography, the fusion rate of High jelly strength DBM strip was statistically significantly greater than that of the other alternatives (p<0.05). The mean bone volume of the fusion mass as determined by computed tomography was 2,142.2+/-318.5 mm(3), 3,132.9+/-632.1 mm(3), and 2,741.5+/-380.4 mm(3) in group 1, group 2, and group 3, respectively (p<0.05). CONCLUSIONS: These results indicate that differences in the structural and mechanical properties of gelatin that are associated with jelly strength influenced cellular responses such as cell viability and bony tissue ingrowth, facilitating greater bone fusion around high jelly strength implants. PMID- 26097662 TI - Migrated Disc at Cervicothoracic Junction Presenting as Acute Paraplegia. AB - Herein, we report on an inferior migration of an intervertebral disc C6-7 to the cervicothoracic junction manifesting as acute paraplegia. The patient showed a remarkable recovery after the surgery. The diagnostic dilemma and management difficulties of such an entity are briefly discussed. PMID- 26097661 TI - Short-Term Results of Transforaminal Lumbar Interbody Fusion Using Pedicle Screw with Cortical Bone Trajectory Compared with Conventional Trajectory. AB - STUDY DESIGN: Case-control study. PURPOSE: To evaluate clinical and radiological results of transforaminal lumbar interbody fusion (TLIF) performed with cortical bone trajectory (CBT) pedicle screw insertion with those of TLIF using 'conventional' or percutaneous pedicle screw insertion. OVERVIEW OF LITERATURE: CBT is a new trajectory for pedicle screw insertion in the lumbar spine; clinical and radiological results of TLIF using pedicle screws inserted with CBT are unclear. METHODS: In total, 26 patients (11 males, 15 females) were enrolled in this retrospective study and divided into three groups: TLIF with pedicle screw insertion by conventional minimally invasive methods via the Wiltse approach (M TLIF, n=10), TLIF with percutaneous pedicle screw insertion (P-TLIF, n=6), and TLIF with pedicle screw insertion with CBT (CBT-TLIF, n=10). Surgical results and preand postoperative radiological findings were evaluated and compared. RESULTS: Intraoperative blood loss was significantly less with CBT-TLIF (p=0.03) than with M-TLIF. Postoperative lordotic angles did not differ significantly among the three groups. Complete fusions were obtained in 10 of 12 levels (83%) with M TLIF, in seven levels (100%) with P-TLIF, and in 10 of 11 levels (91%) with CBT TLIF. On postoperative computed tomography, correct positioning was seen in 84.1% of M-TLIF screws, 88.5% of P-TLIF screws, and 90% of CBT-TLIF screws. CONCLUSIONS: CBT-TLIF resulted in less blood loss and a shorter operative duration than M-TLIF or P-TLIF. Postoperative rates of bone union, maintenance of lordotic angles, and accuracy of pedicle screw positions were similar among the three groups. PMID- 26097663 TI - Hemophilia A in a Senior Patient: A Case Report of Spinal Epidural Hematoma as First Presentation. AB - Hemophilia A is a hereditary coagulation disorder. Most cases are diagnosed at birth or at least during childhood. A spontaneous spinal epidural hematoma was developed in a 74-year-old male patient who hadn't had a family or past medical history of bleeding disorders. On magnetic resonance imaging, epidural hematoma at L1-2 was accompanied by spinal stenosis at L4-5 and spondylolytic spondylolisthesis at L5. Hematoma evacuation and surgery for distal lumbar lesions were performed at once. After transient improvement, complete paraplegia was developed due to redevelopment of large epidural hematomas at L1-2 and L4-S1 which blocked epidural canal completely. Emergency evacuation was performed and we got to know that he had a hemophilia A. Factor VIII was 28% of normal value. Mild type hemophilia A could have not been diagnosed until adulthood. Factor VIII should have been replaced before the surgical decompression. PMID- 26097664 TI - Heterotopic Ossification Causing Radiculopathy after Lumbar Total Disc Arthroplasty. AB - To date, no reports have presented radiculopathy secondary to heterotopic ossification following lumbar total disc arthroplasty. The authors present a previously unpublished complication of lumbar total disk arthroplasty (TDA) secondary to heterotopic ossification (HO) in the spinal canal, and they propose a modification to the McAfee classification of HO. The patient had undergone an L5/S1 lumbar TDA two years prior due to discogenic back pain. His preoperative back pain was significantly relieved, but he developed new, atraumatic onset radiculopathy. Radiographs and a computed tomography myelogram revealed an implant malposition posteriorly with heterotopic bone formation in the canal, causing an impingement of the traversing nerve root. Revision surgery was performed with implant extraction, L5/S1 anterior lumbar interbody fusion, supplemental posterior decompression, and pedicle screw fixation. The patient tolerated the procedure well, with complete resolution of the radicular leg pain. At a two-year follow up, the patient had a solid fusion without subsidence or recurrence of heterotopic bone. This case represents a novel pattern of heterotopic ossification, and it describes a previously unreported cause for implant failure in lumbar disc replacement surgery-reinforcing the importance of proper intraoperative component positioning. We propose a modification to the existing McAfee classification of HO after TDA with the addition of Class V and VI HO. PMID- 26097665 TI - A Retained Epidural Catheter Fragment Treated by Surgery. AB - The breakage of an epidural catheter is an extremely rare complication. We describe a unique case where a retained epidural catheter fragment after epidural anesthesia was treated by surgery. The epidural catheter broke during its removal, requiring surgery to remove the retained catheter. Intraoperatively, the removal of the catheter was attempted by simple traction, but was impossible because of the adhesion. The adhesion of the dura mater surface was carefully exfoliated and the successful removal of the catheter was accomplished. Conventionally, it was said that this follow-up was enough for the retained catheter. However, if a catheter is retained within the spinal canal, surgical removal should thus be considered before the adhesion advances. PMID- 26097666 TI - Pitfalls in the Management of Atlanto-Occipital Dislocation. AB - Atlanto-occipital dislocation (AOD) is rarely seen in clinic because it is characteristically immediately fatal. With recent progress in the pre-hospital care, an increasing number of AOD survivors have been reported. However, because the pathophysiology of AOD is not clearly understood yet, the appropriate strategy for the initial management remains still unclear. We report a case of successful AOD treatment and describe important points in the management of this condition. It is important to note that abducens nerve palsy is a warning sign of AOD and that AOD can result in a life-threatening distortion of the arteries and the brain stem. We recommend the application of a halo vest to protect the patient's neural and vascular competence as the immediate initial step in the treatment of AOD. Horn's grading system is useful in assessing indications for surgery. Finally, when performing posterior fixation, C2 should be included because of the anatomy of the ligamentous architecture. PMID- 26097667 TI - Reoperations Following Cervical Disc Replacement. AB - Cervical disc replacement (CDR) has emerged as an alternative surgical option to cervical arthrodesis. With increasing numbers of patients and longer follow-ups, complications related to the device and/or aging spine are growing, leaving us with a new challenge in the management and surgical revision of CDR. The purpose of this study is to review the current literature regarding reoperations following CDR and to discuss about the approaches and solutions for the current and future potential complications associated with CDR. The published rates of reoperation (mean, 1.0%; range, 0%-3.1%), revision (mean, 0.2%; range, 0%-0.5%), and removal (mean, 1.2%; range, 0%-1.9%) following CDR are low and comparable to the published rates of reoperation (mean, 1.7%; range; 0%-3.4%), revision (mean, 1.5%; range, 0%-4.7%), and removal (mean, 2.0%; range, 0%-3.4%) following cervical arthrodesis. The surgical interventions following CDR range from the repositioning to explantation followed by fusion or the reimplantation to posterior foraminotomy or fusion. Strict patient selection, careful preoperative radiographic review and surgical planning, as well as surgical technique may reduce adverse events and the need for future intervention. Minimal literature and no guidelines exist for the approaches and techniques in revision and for the removal of implants following CDR. Adherence to strict indications and precise surgical technique may reduce the number of reoperations, revisions, and removals following CDR. Long-term follow-up studies are needed, assessing the implant survivorship and its effect on the revision and removal rates. PMID- 26097668 TI - Blood Loss in Surgery for Aggressive Vertebral Haemangioma with and without Embolisation. AB - Despite their benign nature some symptomatic aggressive vertebral haemangiomas (AVH) require surgery to decompress spinal cord and/or stabilise pathological fractures. Preoperative embolisation may reduce the considerable blood loss during surgical decompression. This systematic review investigated whether preoperative embolisation reduced surgical blood loss during treatment of symptomatic AVH. PubMed Medline, Web of Science, and Ovid Medline were searched for case reports and clinical studies on surgical AVH treatment. Included were cases from all publications on surgical treatment of AVH where the amount of surgical blood loss and the use of preoperative embolisation were documented. 51 cases with surgically treated AVH were retrieved from the included studies. Blood loss in the embolised treatment group (980+/-683 mL) was lower than the non embolised control group (1,629+/-946 mL). This systematic review found that embolisation prior to AVH resection reduced surgical blood loss (level of evidence, very low) and can be recommended (strong recommendation). PMID- 26097669 TI - Coccygectomy as a Surgical Option in the Treatment of Chronic Traumatic Coccygodynia. PMID- 26097670 TI - Comments on Brown Tumor of Cervical Spines. PMID- 26097671 TI - Effects of opium consumption on coronary artery disease risk factors and oral health: Results of Kerman Coronary Artery Disease Risk factors Study a population based survey on 5900 subjects aged 15-75 years. AB - BACKGROUND: Opium abuse as a relatively common behavior among Iranian population may have an association with the other coronary artery disease (CAD) risk factors. Here, we reported the prevalence of opium abuse and its co-exposures with oral health and other CAD risk factors. METHODS: We recruited 5900 inhabitant aged 15-75 years using a randomized cluster household survey. All were interviewed for level of physical activity (PA), depression, anxiety and opium use and assessed for hypertension, diabetes, hyperlipidemia, and oral health status. Regarding to opium abuse, participants were grouped into: "Non-," "occasional," and "dependent" users. Using logistic regression model for every CAD risk factor, we assessed whether the co-exposure of opium and CAD risk factor is significant. RESULTS: Overall, 10.6% reported ever opium use including 5.6% dependent and 5% occasional users. The prevalence of opium abuse was increased from 2.1% in 15-25 years to 24.5% in 55-64 years group. Opium abuse, in occasional and dependent forms, was associated with depression (adjusted odds ratio [AOR] 1.81 and 2.49) and low PS (AOR 1.43 and 1.71 respectively). Dependents were less obese than nonusers (P < 0.01). Opium abuse had no significant association with hypertension, diabetes, oral health status and lipid profile. CONCLUSIONS: Opium abuse was associated with depression and low PA. No ameliorative effect was observed on hypertension, diabetes, and plasma lipid profile. Therefore, positive association of opium with depression and LPA and the incorrectness of belief on its ameliorative effect on three other important risk factors of CAD should be clearly highlighted in public health messages to the community. PMID- 26097672 TI - Epidemiology of Sexual Dysfunction in Iran: A Systematic Review and Meta analysis. AB - BACKGROUND: The aim of this study was to determine the cumulative prevalence rate of every sexual dysfunctions (SDs) in Iranian population. METHODS: We searched international database such as: PubMed/Medline, Scopus, PsychNET, and Scholar Google and Iranian database such as Iran Psych, IranDoc, IranMedex, and SID. Search duration was between 1990 and 2013. RESULTS: From 449 articles were retrieved, then 11 articles on male with total sample size of 2142 and 8 articles on female with total sample size of 4391 were selected after critical appraisal. For quality assessment check list to evaluate a prevalence article was contained study population, sampling method, sample size, criteria for SD diagnosis, specific rates, study location, and authors list. In male, erectile dysfunction was 56.1%. In female, pooled estimation prevalence of hypoactive sexual desire disorder in complained group was 65.8% (95% confidence interval [CI]: 51.1-80.6%) compared to general population 35% (95% CI: 17.6-52.1%). Sexual arousal disorder in clinical patient was 59.6% (95% CI: 39-80%) against 33.8% (95% CI: 18.3-49.3%) in general population. Orgasmic disorder in complained was 35.5% (95% CI: 16-55%) and in general population was 35.3% (95% CI: 26.8-43.8%). Sexual pain disorder pooled estimation prevalence were 35.2% (95% CI: 14.5-56%) versus 20.1% (95% CI: 6.4-33.8%) in complained and general population consecutively. CONCLUSIONS: The rate of SD in Iran was approximately the same of worldwide except orgasmic disorder which was two times more than the worldwide average. PMID- 26097673 TI - Effect of Chewing Xylitol Containing and Herbal Chewing Gums on Salivary Mutans Streptococcus Count among School Children. AB - BACKGROUND: The present study aims to assess and compare the reduction in salivary Mutans Streptococci counts after chewing Xylitol, herbal and placebo gums among high school children. METHODS: The study was conducted among 72 school children (12-15 years) from 3 randomly selected schools (blocks). Xylitol, herbal and placebo gums were randomly allocated to 3 blocks. Subjects were instructed to chew one pellet four times a day for 21 days. The mean reduction in salivary Streptococcus mutans count was assessed. RESULTS: The 100% Xylitol sweetened chewing gum "Xylitol"has shown statistically significant reduction in salivary Mutans Streptococci colony forming units at the end of 21 days (P < 0.01). The reduction was not statistically significant in herbal and placebo chewing gum. CONCLUSIONS: Hundred percentage Xylitol sweetened chewing gum was found to be more effective in reducing salivary Mutans Streptococci count when compared to herbal and placebo chewing gums. PMID- 26097674 TI - Measuring the value of social engagement in adults with and without autism. AB - BACKGROUND: Differences in social communication are commonly reported in autism spectrum condition (ASC). A recent theory attributes this to a reduced motivation to engage with others, that is, deficits in social motivation. However, there are currently few simple, direct, behavioural ways to test this claim. This study uses a new behavioural measure of social motivation to test if preferences for direct gaze and face stimuli are linked to autistic traits or an ASC diagnosis. Our novel choose-a-movie (CAM) paradigm measures the effort participants invest to see particular stimuli. This aspect of social motivation is also known as social seeking. METHODS: In experiment 1, 80 typical adults completed the CAM task and a measure of autistic traits. In experiment 2, 30 adults with ASC and 24 age/IQ-matched typical adults completed the CAM paradigm. RESULTS: The results from study one showed that typical adults prefer social stimuli over non-social, but this preference is weaker in those with higher levels of autistic traits. In study two, adults with ASC showed a significant reduction in their preference for direct gaze but little difference in their preference for faces without direct gaze. CONCLUSIONS: These data show that social motivation can be measured in a simple, direct, behavioural paradigm. Furthermore, adults with ASC prefer direct gaze less than typical adults but may not avoid faces without direct gaze. This data advance our understanding of how social motivation may differ between those with and without autism. PMID- 26097675 TI - Erratum to: NTRK2 expression levels are reduced in laser captured pyramidal neurons from the anterior cingulate cortex in males with autism spectrum disorder. AB - [This corrects the article DOI: 10.1186/s13229-015-0023-2.]. PMID- 26097676 TI - Erratum: Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder. AB - [This corrects the article DOI: 10.1186/s13229-015-0005-4.]. PMID- 26097677 TI - Metabolomic profiling of Burkholderia pseudomallei using UHPLC-ESI-Q-TOF-MS reveals specific biomarkers including 4-methyl-5-thiazoleethanol and unique thiamine degradation pathway. AB - BACKGROUND: Burkholderia pseudomallei is an emerging pathogen that causes melioidosis, a serious and potentially fatal disease which requires prolonged antibiotics to prevent relapse. However, diagnosis of melioidosis can be difficult, especially in culture-negative cases. While metabolomics represents an uprising tool for studying infectious diseases, there were no reports on its applications to B. pseudomallei. To search for potential specific biomarkers, we compared the metabolomics profiles of culture supernatants of B. pseudomallei (15 strains), B. thailandensis (3 strains), B. cepacia complex (14 strains), P. aeruginosa (4 strains) and E. coli (3 strains), using ultra-high performance liquid chromatography-electrospray ionization-quadruple time-of-flight mass spectrometry (UHPLC-ESI-Q-TOF-MS). Multi- and univariate analyses were used to identify specific metabolites in B. pseudomallei. RESULTS: Principal component and partial-least squares discrimination analysis readily distinguished the metabolomes between B. pseudomallei and other bacterial species. Using multi variate and univariate analysis, eight metabolites with significantly higher levels in B. pseudomallei were identified. Three of the eight metabolites were identified by MS/MS, while five metabolites were unidentified against database matching, suggesting that they may be potentially novel compounds. One metabolite, m/z 144.048, was identified as 4-methyl-5-thiazoleethanol, a degradation product of thiamine (vitamin B1), with molecular formula C6H9NOS by database searches and confirmed by MS/MS using commercially available authentic chemical standard. Two metabolites, m/z 512.282 and m/z 542.2921, were identified as tetrapeptides, Ile-His-Lys-Asp with molecular formula C22H37N7O7 and Pro-Arg Arg-Asn with molecular formula C21H39N11O6, respectively. To investigate the high levels of 4-methyl-5-thiazoleethanol in B. pseudomallei, we compared the thiamine degradation pathways encoded in genomes of B. pseudomallei and B. thailandensis. While both B. pseudomallei and B. thailandensis possess thiaminase I which catalyzes degradation of thiamine to 4-methyl-5-thiazoleethanol, thiM, which encodes hydroxyethylthiazole kinase responsible for degradation of 4-methyl-5 thiazoleethanol, is present and expressed in B. thailandensis as detected by PCR/RT-PCR, but absent or not expressed in all B. pseudomallei strains. This suggests that the high 4-methyl-5-thiazoleethanol level in B. pseudomallei is likely due to the absence of hydroxyethylthiazole kinase and hence reduced downstream degradation. CONCLUSION: Eight novel biomarkers, including 4-methyl-5 thiazoleethanol and two tetrapeptides, were identified in the culture supernatant of B. pseudomallei. PMID- 26097679 TI - Public attitudes and values in priority setting. AB - There is growing recognition that critical decisions concerning investments in new health care technologies and services should incorporate society's values along with the scientific evidence. From a normative perspective, public engagement can help realize the democratic ideals of legitimacy, transparency, and accountability. On a more pragmatic level, public engagement can help stakeholders understand the degree of popular support for policy options, and may enhance public trust in decision-making processes. To better understand public attitudes and values relating to priority setting in health care, researchers and decision-makers will have to employ a range of quantitative and qualitative approaches, drawing on different disciplines and methodological traditions. PMID- 26097678 TI - Leishmaniases diagnosis: an update on the use of immunological and molecular tools. AB - Leishmaniases are caused by obligate intracellular protozoan parasites of the genus Leishmania. They cause a spectrum of diseases, most notably visceral (VL), cutaneous (CL), and mucosal (ML) leishmaniasis, which affect millions of people around the world, each year. Despite scientific advances, leishmaniases cases are expanding, constituting an important public health problem. Immunological and molecular diagnostic tools have been increasingly applied for the early detection of these parasitic infections, since the existence of limitations in clinical and parasitological examinations may provide false results, thus interfering in epidemiological research and diseases control. Although there is a great diversity of available immunological assays, important common deficiencies persist, which explains the current exploration of the molecular biology in research fields, especially the Polymerase Chain Reaction (PCR) and its variants, such as real-time quantitative PCR. However, in the last years, significant results have also been reached inside of immunological context (especially by Flow Cytometry), for humans and dogs, demonstrated by research works of the New and Old worlds. In spite of their potential to clarify and minimize the present global situation of the diseases, the implementation of molecular or immunological innovative reference assays for VL and CL at health services is still a challenge due to several reasons, including lack of standardization among laboratories and structural concerns. In this article we bring classical and current information about technological advances for the immunological and molecular leishmaniases diagnosis, their features, and applications. PMID- 26097680 TI - Prolonged efficacy of the 300IR 5-grass pollen tablet up to 2 years after treatment cessation, as measured by a recommended daily combined score. AB - BACKGROUND: The 300IR (index of reactivity) 5-grass pollen tablet has favorable short-term and sustained clinical efficacy in patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). Here, we report maintenance of efficacy and safety over 2 years following treatment discontinuation. METHODS: Randomized, double-blind, placebo-controlled, parallel-group, multicenter Phase 3 trial in patients aged 18-50 years with ARC. During study years 1-3, patients received a daily sublingual tablet containing either 300IR 5-grass pollen extract or placebo, according to a discontinuous pre- and coseasonal protocol. Study years 4 and 5 were treatment-free. In response to health authorities' recommendations, the daily combined score (DCS) was assessed in a post-hoc analysis as the efficacy endpoint. Components of the DCS were daily rhinoconjunctivitis total symptom score (DRTSS) and daily rescue medication score (DRMS). RESULTS: 633 patients with ARC were randomized to placebo (n = 219) or 300IR 5-grass pollen tablet, beginning 4 months (4 M, n = 207) or 2 months (2 M, n = 207) prior to the estimated start of the grass pollen season and continuing until season's end. During the first post-treatment year, a statistically significant difference versus placebo in least squares (LS) mean DCS was noted in patients previously receiving active treatment (300IR (2 M) point estimate: -0.16, 95% confidence interval (CI95%): [-0.26, -0.06], p = 0.0019; -31.1%; 300IR (4 M) point estimate: -0.13, CI95%: [-0.23, -0.03], p = 0.0103, -25.3%). During the second post treatment year, patients in the 300IR (4 M) group, but not the 300IR (2 M) group, showed a statistically significant difference in LS mean DCS versus placebo (point estimate: -0.11, CI95%: [-0.21; 0.00], p = 0.0478, -28.1%). This significant efficacy seen during the post-treatment years in patients previously treated with 5-grass pollen tablet compared favorably with that during the 3 prior years of active treatment. A statistically significant difference versus placebo was also noted in secondary efficacy measures in both post-treatment years (except for DRTSS in year 5). In the absence of any active treatment, the safety profile was similar in the active groups versus placebo group during either post-treatment year. CONCLUSIONS: In adults with grass pollen-associated ARC, 5-grass pollen tablet therapy beginning 4 months before the pollen season and continuing to season's end demonstrated efficacy across all variables during active treatment, and this effect was prolonged for up to 2 years post-treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00418379. PMID- 26097681 TI - Foot lesions in lame cows on 10 dairy farms in Ireland. AB - BACKGROUND: Little is known about foot lesions in dairy cattle in Ireland, managed under a pasture based system with housing during the winter and grazing for the rest of the year. Ten Irish dairy herds, with a lameness prevalence ranging from 9 to 17 % were locomotion scored routinely during the 2013 grazing season. Lame cows were foot trimmed and foot lesions recorded. FINDINGS: 11.8 % and 89.6 % of cows had lesions recorded on front and hind feet respectively. No lesions were found in 6.9 % of cows. Sole haemorrhage and white line disease were the most prevalent lesions, and overall 76.8 % of lesions affecting the claw horn were diagnosed on the lateral hind claw. CONCLUSIONS: Treatment success, as measured by improved LS post treatment, was not significantly affected by the LS prior to foot trimming, the presence of lesions or the type of lesion identified. Exposure to both risk factors for lameness at housing and pasture may have resulted in the development of a combination of foot lesions typically associated with zero-grazing or all-year-round grazing management systems. PMID- 26097682 TI - Reliability and reproducibility of spectral and time domain optical coherence tomography images before and after correction for patients with age-related macular degeneration. AB - PURPOSE: To evaluate the reproducibility and reliability of Optical Coherence Tomography scans (OCT) obtained using the Time Domain (TD-OCT) StratusTM OCT, and the Spectral Domain (SD-OCT) SpectralisTM and CirrusTM OCT devices before and after manual correction in eyes with either Neovascular (NV-AMD) or Non Neovascular (NNV-AMD) Age-related Macular Degeneration. METHODS: We conducted a prospective observational study of 36 patients (50 eyes) with NV-AMD or NNV-AMD at a university-based retina practice. OCT scans were taken simultaneously using one TD-OCT and two SD-OCT devices. Macular thickness measurements were assessed before and after correction of the OCT algorithm by constructing Bland-Altman plots for agreement and calculating intraclass correlation coefficients (ICCs) and coefficients of repeatability (COR) to evaluate intraclass repeatability. RESULTS: The Spectralis device had the highest number of images needing manual correction. All machines had high ICCs, with Spectralis having the highest. Bland Altman plots indicated that there was low agreement between both CirrusTM and StratusTM and SpectralisTM and StratusTM, while there was good agreement between the CirrusTM and SpectralisTM devices. The CORs were lowest for SpectralisTM and similar with each other and had higher values for CirrusTM and StratusTM. Agreement, CORs, and ICCs generally improved after manual correction, but only minimally. CONCLUSION: Agreement is low between devices, except between both SD OCT machines. Manual correction tends to improve results. PMID- 25580237 TI - Active learning and decision making: an introduction to the collection. AB - The importance of exploratory behaviors by which agents actively sample information has been long appreciated in a wide range of disciplines ranging from machine and robot learning to neuroscience and psychology. Given the complexity of these behaviors, progress in understanding them will require a confluence of ideas from these multiple fields. This collection of articles in F1000Research aims to provide a home for a broad range of studies addressing this topic, including full length research articles, brief communications, single figure studies, and review/opinion articles, and studies using computational, behavioral or neural approaches. Here, we provide an introduction to the collection which we hope will grow and become a valuable resource for the researchers exploring this topic. PMID- 26097684 TI - Oxygen-binding and sensing proteins. AB - This collection of papers is a snapshot of topics presented at the international conference on Oxygen-Binding and Sensing Proteins (O2BiP) held in Sheffield, UK, on 6 (th)-10 (th) July 2014. The collection will grow over time as new papers relating to O2BiP topics are completed and published. PMID- 26097685 TI - Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity. AB - OBJECTIVE: To review the mechanisms of anti-cancer activity of nelfinavir and other protein inhibitors (PIs) based on evidences reported in the published literature. METHODS: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. CONCLUSIONS: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes. PMID- 26097686 TI - ISCB Ebola Award for Important Future Research on the Computational Biology of Ebola Virus. AB - Speed is of the essence in combating Ebola; thus, computational approaches should form a significant component of Ebola research. As for the development of any modern drug, computational biology is uniquely positioned to contribute through comparative analysis of the genome sequences of Ebola strains as well as 3-D protein modeling. Other computational approaches to Ebola may include large-scale docking studies of Ebola proteins with human proteins and with small-molecule libraries, computational modeling of the spread of the virus, computational mining of the Ebola literature, and creation of a curated Ebola database. Taken together, such computational efforts could significantly accelerate traditional scientific approaches. In recognition of the need for important and immediate solutions from the field of computational biology against Ebola, the International Society for Computational Biology (ISCB) announces a prize for an important computational advance in fighting the Ebola virus. ISCB will confer the ISCB Fight against Ebola Award, along with a prize of US$2,000, at its July 2016 annual meeting (ISCB Intelligent Systems for Molecular Biology (ISMB) 2016, Orlando, Florida). PMID- 26097687 TI - Entering new publication territory in chemoinformatics and chemical information science. AB - The F1000Research publishing platform offers the opportunity to launch themed article collections as a part of its dynamic publication environment. The idea of article collections is further expanded through the generation of publication channels that focus on specific scientific areas or disciplines. This editorial introduces the Chemical Information Science channel of F1000Research designed to collate high-quality publications and foster a culture of open peer review. Articles will be selected by guest editor(s) and a group of experts, the channel Editorial Board, and subjected to open peer review. PMID- 26097688 TI - How do we improve peer review for manuscripts from culturally divergent origins? AB - Objective and informed peer review is critically important to the progress of science. These standards can sometimes be at risk in the evaluation of manuscripts from less culturally familiar places and such evaluations therefore require particular vigilance. Alternative publication strategies may be particularly helpful in these circumstances. PMID- 26097689 TI - A communication hub for a decentralized collaboration on studying real-life cognition. AB - Studying the brain's behavior in situations of real-life complexity is crucial for an understanding of brain function as a whole. However, methodological difficulties and a general lack of public resources are hindering scientific progress in this domain. This channel will serve as a communication hub to collect relevant resources and curate knowledge about working paradigms, available resources, and analysis techniques. PMID- 26097690 TI - Digital collaborative learning: identifying what students value. AB - Digital technologies are changing the learning landscape and connecting classrooms to learning environments beyond the school walls. Online collaborations among students, teachers, and scientists are new opportunities for authentic science experiences. Here we present findings generated on PlantingScience ( www.plantingscience.org), an online community where scientists from more than 14 scientific societies have mentored over 14,000 secondary school students as they design and think through their own team investigations on plant biology. The core intervention is online discourse between student teams and scientist mentors to enhance classroom-based plant investigations. We asked: (1) what attitudes about engaging in authentic science do students reveal, and (2) how do student attitudes relate to design principles of the program? Lexical analysis of open-ended survey questions revealed that students most highly value working with plants and scientists. By examining student responses to this cognitive apprenticeship model, we provide new perspectives on the importance of the personal relationships students form with scientists and plants when working as members of a research community. These perspectives have implications for plant science instruction and e-mentoring programs. PMID- 26097691 TI - Teaching and communicating science in a digital age. AB - We assume that digital literacy and access are common to all who teach and communicate their science and to their audiences. We also assume that our digital communication is effective and that by using digital technologies learning experiences are enhanced. But are these reasonable assumptions to make? This F1000Research channel brings together papers developed from presentations made at Teaching and Communicating Science in a Digital Age, a Society for Experimental Biology symposium involving Higher Education Professionals from across the globe to reflect upon the impact that digital technologies have and will have upon aspects of the communication of science. Here I share some thoughts on the discussion that took place and on the papers collated through this channel. PMID- 26097692 TI - Sports cardiology: lessons from the past and perspectives for the future. AB - The possibility of myocardial damage as a result of endurance sport has been known about since ancient times. According to a leg-end, a soldier named Pheidippides (more likely Philippides) dropped dead after run-ning from war-torn Marathon to Athens with the news of victory. Millennia later, we do not know whether he was a soldier or a courier, or whether he really ran the entire 240 km from Athens to Sparta and then back from Marathon to Athens. What is clear however, is that his death went down in history as the first documented exercise related death and provides a tangible starting-point for the discipline of sport cardiology. Sports cardiology today covers a broad range of areas; from patients with cardiomyopathies, coronary disease and metabolic syndrome through to fitness fans, high-performance athletes and those with physically demanding professions. The following editorial introduces the primary topics for discussion to be included in the F1000Research channel Sports cardiology with the hope that this will evoke open, controversial and broad discourse in the form of reviews and original research papers in this important field. PMID- 26097694 TI - The five deadly sins of science publishing. AB - Science cannot progress without scientists reporting their findings. And yet researchers have given control of this central pillar of the scientific process to science publishers, who are in the business of serving the interests of their journals; these are not always the same as the interests of science. This editorial describes the problems with the process of preparing and publishing research findings, and with judging their veracity and significance, and then explains how we at Faculty of 1000 are starting to tackle the 'deadly sins' of science publishing. PMID- 26097693 TI - Linking patient outcome to high throughput protein expression data identifies novel regulators of colorectal adenocarcinoma aggressiveness. AB - A key question in cancer systems biology is how to use molecular data to predict the biological behavior of tumors from individual patients. While genomics data have been heavily used, protein signaling data are more directly connected to biological phenotype and might predict cancer phenotypes such as invasion, metastasis, and patient survival. In this study, we mined publicly available data for colorectal adenocarcinoma from the Cancer Genome Atlas and identified protein expression and signaling changes that are statistically associated with patient outcome. Our analysis identified a number of known and potentially new regulators of colorectal cancer. High levels of insulin growth factor binding protein 2 (IGFBP2) were associated with both recurrence and death, and this was validated by immunohistochemical staining of a tissue microarray for a secondary patient dataset. Interestingly, GATA binding protein 3 (GATA3) was the protein most frequently associated with death in our analysis, and GATA3 expression was significantly decreased in tumor samples from stage I-II deceased patients. Experimental studies using engineered colon cancer cell lines show that exogenous expression of GATA3 decreases three-dimensional colony growth and invasiveness of colon cancer cells but does not affect two-dimensional proliferation. These findings suggest that protein data are useful for biomarker discovery and identify GATA3 as a regulator of colorectal cancer aggressiveness. PMID- 26097695 TI - It's never too late to publish an abandoned trial. AB - It is estimated that half of all trials have never been published which can lead to patients being denied the most effective treatment and being exposed to unnecessary side effects. Furthermore the trial participants have been misinformed since the trial results have not contributed to the care of future patients. However the non-publication of trials is often not due to a deliberate decision to cover up results. Commonly in academia it is due to more understandable reasons such as researchers having busy clinical posts, moving onto other more demanding projects, changing research areas or starting a family. This is called the "file drawer" problem. The examples in this editorial demonstrate that it is possible to go back, even decades later, and make the results available to inform future evidence based medicine. We call on others to look into their "file drawer" for unpublished trials. PMID- 26097696 TI - Enhancement of performance in porous bead-based microchip sensors: Effects of chip geometry on bio-agent capture. AB - Measuring low concentrations of clinically-important biomarkers using porous bead based lab-on-a-chip (LOC) platforms is critical for the successful implementation of point-of-care (POC) devices. One way to meet this objective is to optimize the geometry of the bead holder, referred to here as a micro-container. In this work, two geometric micro-containers were explored, the inverted pyramid frustum (PF) and the inverted clipped pyramid frustum (CPF). Finite element models of this bead array assay system were developed to optimize the micro-container and bead geometries for increased pressure, to increase analyte capture in porous bead based fluorescence immunoassays. Custom micro-milled micro-container structures containing an inverted CPF geometry resulted in a 28% reduction in flow-through regions from traditional anisotropically-etched pyramidal geometry derived from Si-111 termination layers. This novel "reduced flow-through" design resulted in a 33% increase in analyte penetration into the bead and twofold increase in fluorescence signal intensity as demonstrated with C-Reactive Protein (CRP) antigen, an important biomarker of inflammation. A consequent twofold decrease in the limit of detection (LOD) and the limit of quantification (LOQ) of a proof-of concept assay for the free isoform of Prostate-Specific Antigen (free PSA), an important biomarker for prostate cancer detection, is also presented. Furthermore, a 53% decrease in the bead diameter is shown to result in a 160% increase in pressure and 2.5-fold increase in signal, as estimated by COMSOL models and confirmed experimentally by epi-fluorescence microscopy. Such optimizations of the bead micro-container and bead geometries have the potential to significantly reduce the LODs and reagent costs for spatially programmed bead based assay systems of this type. PMID- 26097698 TI - The effect of glycosaminoglycan content on polyethylenimine-based gene delivery within three-dimensional collagen-GAG scaffolds. AB - The design of biomaterials for increasingly complex tissue engineering applications often requires exogenous presentation of biomolecular signals. Integration of gene delivery vectors with a biomaterial scaffold offers the potential to bypass the use of expensive and relatively inefficient growth factor supplementation strategies to augment cell behavior. However, integration of cationic polymer based gene delivery vectors within three-dimensional biomaterials, particularly matrices which can carry significant surface charge, remains poorly explored. We examined the potential of polyethylenimine (PEI) as a gene delivery vector for three-dimensional collagen-glycosaminoglycan (CG) scaffolds under development for tendon repair. While acetylated versions of PEI have demonstrated improved transfection efficiency in 2D culture assays, we investigated translation of this effect to a 3D biomaterial that contains significant electrostatic charge. A reporter gene was used to examine the impact of polymer modification, polymer:DNA ratio, and the degree of sulfation of the biomaterial microenvironment on gene delivery in vitro. We observed highest transgene expression in acetylated and unmodified PEI at distinct polymer:DNA ratios; notably, the enhancement often seen in two-dimensional culture for acetylated PEI did not fully translate to three-dimensional scaffolds. We also found highly sulfated heparin-based CG scaffolds showed enhanced initial luciferase expression but not prolonged activity. While PEI constructs significantly reduced tenocyte metabolic health during the period of transfection, heparin-based CG scaffolds showed the greatest recovery in tenocyte metabolic health over the full 2 week culture. These results suggest that the electrostatic environment of three-dimensional biomaterials may be an important design criterion for cationic polymer-based gene delivery. PMID- 26097699 TI - Short- and long-term reliability of adult recall of vegetarian dietary patterns in the Adventist Health Study-2 (AHS-2). AB - Past dietary patterns may be more important than recent dietary patterns in the aetiology of chronic diseases because of the long latency in their development. We developed an instrument to recall vegetarian dietary patterns during the lifetime and examined its reliability of recall over 5.3 and 32.6 years on average. The short-term/5-year recall ability study (5-RAS) was done using 24 690 participants from the cohort of the Adventist Health Study-2 (mean age 62.2 years). The long-term/33-year recall ability study (33-RAS) included an overlap population of 1721 individuals who joined the Adventist Health Study-1 and Adventist Health Study-2 (mean age 72.5 years). Spearman correlation coefficients for recall of vegetarian status were 0.78 and 0.72 for the 5-RAS and 33-RAS, respectively, when compared with 'reference' data. For both time periods sensitivity and positive predictive values were highest for the lacto-ovo vegetarian and non-vegetarian patterns (vegans, lacto-ovo-vegetarians, pesco vegetarians, semi-vegetarians and non-vegetarians). In the 5-RAS analyses, male, non-black, younger, and more educated participants, lifetime Adventists, and those with more stability of consumption of animal products generally showed higher recall ability. Somewhat similar tendencies were shown for the 33-RAS analyses. Our findings show that the instrument has higher reliability for recalled lacto-ovo-vegetarian and non-vegetarian than for vegan, semi- and pesco vegetarian dietary patterns in both short- and long-term recalls. This is in part because these last dietary patterns were greatly contaminated by recalls that correctly would have belonged in the adjoining category that consumed more animal products. PMID- 26097700 TI - Evaluation of a nutrient-rich food index score in the Netherlands. AB - Nutrient-rich food (NRF) index scores are dietary quality indices based on nutrient density. We studied the design aspects involved in the development and validation of NRF index scores, using the Dutch consumption data and guidelines as an example. We evaluated fifteen NRF index scores against the Dutch Healthy Diet Index (DHD-index), a measure of adherence to the Dutch dietary guidelines, and against energy density. The study population included 2106 adults from the Dutch National Food Consumption Survey 2007-2010. The index scores were composed of beneficial nutrients (protein, fibre, fatty acids, vitamins, minerals), nutrients to limit (saturated fat, sugar, Na) or a combination. Moreover, the influence of methodological decisions was studied, such as the choice of calculation basis (100 g or 100 kcal (418 kJ)). No large differences existed in the prediction of the DHD-index by the fifteen NRF index scores. The score that best predicted the DHD-index included nine beneficial nutrients and three nutrients to limit on a 100-kcal basis, the NRF9.3 with a model R (2) of 0.34. The scores were quite robust with respect to sex, BMI and differences in calculation methods. The NRF index scores were correlated with energy density, but nutrient density better predicted the DHD-index than energy density. Consumption of vegetables, cereals and cereal products, and dairy products contributed most to the individual NRF9.3 scores. In conclusion, many methodological considerations underlie the development and evaluation of nutrient density models. These decisions may depend upon the purpose of the model, but should always be based upon scientific, objective and transparent criteria. PMID- 26097701 TI - Prevalence of nutritional risk in the non-demented hospitalised elderly: a cross sectional study from Norway using stratified sampling. AB - There is a lack of accurate prevalence data on undernutrition and the risk of undernutrition among the hospitalised elderly in Europe and Norway. We aimed at estimating the prevalence of nutritional risk by using stratified sampling along with adequate power calculations. A cross-sectional study was carried out in the period 2011 to 2013 at a university hospital in Norway. Second-year nursing students in acute care clinical studies in twenty hospital wards screened non demented elderly patients for nutritional risk, by employing the Nutritional Risk Screening 2002 (NRS2002) form. In total, 508 patients (48.8 % women and 51.2 % men) with a mean age of 79.6 (sd 6.4) years were screened by the students. Mean BMI was 24.9 (sd 4.9) kg/m(2), and the patients had been hospitalised for on average 5.3 (sd 6.3) d. WHO's BMI cut-off values identified 6.5 % as underweight, 48.0 % of normal weight and 45.5 % as overweight. Patients nutritionally at risk had been in hospital longer and had lower average weight and BMI compared with those not at risk (all P < 0.001); no differences in mean age or sex were observed. The prevalence of nutritional risk was estimated to be 45.4 (95 % CI 41.7 %, 49.0) %, ranging between 20.0 and 65.0 % on different hospital wards. The present results show that the prevalence of nutritional risk among elderly patients without dementia is high, suggesting that a large proportion of the hospitalised elderly are in need of nutritional treatment. PMID- 26097702 TI - Rapid and selective manipulation of milk fatty acid composition in mice through the maternal diet during lactation. AB - Dietary fatty acid (FA) composition in early postnatal life can modulate growth and development and later metabolic health. Investigating programming effects of early dietary FA manipulations in rodents may be stressful and complicated due to the need of artificial feeding techniques. It is largely unknown to what extent breast milk (BM) FA composition can be directly manipulated by the diet. We exposed dams to different dietary FA compositions from postnatal day (PN) 2 until PN28. Dams with litters were randomly assigned to control (CTRL), high-medium chain FA (MCFA), low-linoleic acid (LowLA), high-n-3 long-chain PUFA (n-3LCP) or high-n-3LCP and MCFA (n-3LCP/MCFA) diets, and diets were continued after weaning until PN28. FA compositions were determined in feeds, milk and in erythrocytes. BM MCFA content was independent from dietary MCFA intake. In contrast, the LowLA diet reduced BM LA content by about 50 % compared with the CTRL diet at PN7. BM of dams fed the n-3LCP or n-3LCP/MCFA diet contained about 6-fold more n-3 LCP than BM of the dams fed the CTRL diet at PN7. These changes in milk FA composition established after 5 d of dietary exposure did not further change over the lactation period. At PN28, the erythrocyte FA composition of the male pups correlated with analysed milk FA profiles. In conclusion, manipulation of the diet of lactating mice can strongly and rapidly affect BM FA composition, in particular of n-6 LA and n-3 LCP. Our present findings will facilitate mechanistic studies on the programming of adult metabolic health by dietary FA in the early postnatal period via direct and selective manipulation of the maternal diet. PMID- 26097703 TI - Plate waste and intake of school lunch based on the new Nordic diet and on packed lunches: a randomised controlled trial in 8- to 11-year-old Danish children. AB - The aim of the present study was to compare total food intake, total and relative edible plate waste and self-reported food likings between school lunch based on the new Nordic diet (NND) and packed lunch from home. In two 3-month periods in a cluster-randomised controlled unblinded cross-over study 3rd- and 4th-grade children (n 187) from two municipal schools received lunch meals based on NND principles and their usual packed lunch (control). Food intake and plate waste (n 1558) were calculated after weighing lunch plates before and after the meal for five consecutive days and self-reported likings (n 905) assessed by a web-based questionnaire. Average food intake was 6 % higher for the NND period compared with the packed lunch period. The quantity of NND intake varied with the menu (P < 0.0001) and was positively associated with self-reported likings. The edible plate waste was 88 (sd 80) g for the NND period and 43 (sd 60) g for the packed lunch period whereas the relative edible plate waste was no different between periods for meals having waste (n 1050). Edible plate waste differed between menus (P < 0.0001), with more waste on soup days (36 %) and vegetarian days (23 %) compared with the packed lunch period. Self-reported likings were negatively associated with percentage plate waste (P < 0.0001). The study suggests that portion sizes need to be considered in new school meal programmes. New strategies with focus on reduction of plate waste, children's likings and nutritious school meals are crucial from both a nutritional, economic and environmental point of view. PMID- 26097697 TI - The ocean sampling day consortium. AB - Ocean Sampling Day was initiated by the EU-funded Micro B3 (Marine Microbial Biodiversity, Bioinformatics, Biotechnology) project to obtain a snapshot of the marine microbial biodiversity and function of the world's oceans. It is a simultaneous global mega-sequencing campaign aiming to generate the largest standardized microbial data set in a single day. This will be achievable only through the coordinated efforts of an Ocean Sampling Day Consortium, supportive partnerships and networks between sites. This commentary outlines the establishment, function and aims of the Consortium and describes our vision for a sustainable study of marine microbial communities and their embedded functional traits. PMID- 26097704 TI - Intestinal B(0)AT1 (SLC6A19) and PEPT1 (SLC15A1) mRNA levels in European sea bass (Dicentrarchus labrax) reared in fresh water and fed fish and plant protein sources. AB - The objective of the present study was to examine the effect of diets with descending fish meal (FM) inclusion levels and the addition of salt to the diet containing the lowest FM level on growth performances, feed conversion ratio, and intestinal solute carrier family 6 member 19 (SLC6A19) and oligopeptide transporter 1 (PEPT1) transcript levels, in freshwater-adapted European sea bass (Dicentrarchus labrax). We first isolated by molecular cloning and sequenced a full-length cDNA representing the neutral amino acid transporter SLC6A19 in sea bass. The cDNA sequence was deposited in GenBank database (accession no. KC812315). The twelve transmembrane domains and the 'de novo' prediction of the three-dimensional structure of SLC6A19 protein (634 amino acids) are presented. We then analysed diet-induced changes in the mRNA copies of SLC6A19 and PEPT1 genes in different portions of sea bass intestine using real-time RT-PCR. Sea bass were fed for 6 weeks on different diets, with ascending levels of fat or descending levels of FM, which was replaced with vegetable meal. The salt enriched diet was prepared by adding 3 % NaCl to the diet containing 10 % FM. SLC6A19 mRNA in the anterior and posterior intestine of sea bass were not modulated by dietary protein sources and salt supplementation. Conversely, including salt in a diet containing a low FM percentage up-regulated the mRNA copies of PEPT1 in the hindgut. Fish growth correlated positively with the content of FM in the diets. Interestingly, the addition of salt to the diet containing 10 % FM improved feed intake, as well as specific growth rate and feed conversion ratio. PMID- 26097705 TI - The effect of long-term feeding of skin barrier-fortified diets on the owner assessed incidence of atopic dermatitis symptoms in Labrador retrievers. AB - We investigated the effect of feeding a skin barrier function-augmenting diet early in dogs' lives on the appearance of clinical signs associated with canine atopic dermatitis. Pregnant bitches (starting 5 weeks after mating) and their subsequent litters (up to 1 year of age) were fed either supplemented or unsupplemented diets. Nutrients supplemented were nicotinamide, pantothenate, histidine, inositol and choline. Circulating IgE levels to dust mute allergens Der f and Der p were measured when the puppies were 6 and 12 months old. Two owner questionnaires were used to assess the occurrence of typical signs associated with atopic dermatitis when dogs were between the ages of 22 and 36, and 34 and 48 months. Using linear mixed models we observed higher levels of circulating anti-Der f (P = 0.021) and -Der p IgE (P = 0.01) during the first year in the dogs fed the unsupplemented than in those fed the supplemented diet. The owner-assessed incidence of atopic dermatitis signs amongst the dogs was significantly greater in the unsupplemented group at the time of the second follow-up questionnaire (10/33 dogs v. 2/24 dogs). These outcomes suggest that a nutritionally derived improvement to barrier function early in life may reduce the frequency of signs associated with atopic dermatitis. The effect is possibly the result of making the epidermis, now thought to be a major route of environmental allergen exposure, more resistant to penetration. PMID- 26097706 TI - Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7-36)) amide in C57BL/6J mice. AB - The widespread prevalence of diabetes, caused by impaired insulin secretion and insulin resistance, is now a worldwide health problem. Glucagon-like peptide 1 (GLP-1) is a major intestinal hormone that stimulates glucose-induced insulin secretion from beta cells. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in animals and human subjects. Therefore, GLP-1 secretagogues are attractive targets for the treatment of diabetes. Recent epidemiological studies have reported that an increase in daily coffee consumption lowers diabetes risk. The present study examined the hypothesis that the reduction in diabetes risk associated with coffee consumption may be mediated by the stimulation of GLP-1 release by coffee polyphenol extract (CPE). GLP-1 secretion by human enteroendocrine NCI-H716 cells was augmented in a dose dependent manner by the addition of CPE, and was compatible with the increase in observed active GLP-1(7-36) amide levels in the portal blood after administration with CPE alone in mice. CPE increased intracellular cyclic AMP (cAMP) levels in a dose-dependent manner, but this was not mediated by G protein-coupled receptor 119 (GPR119). The oral administration of CPE increased diet (starch and glyceryl trioleate)-induced active GLP-1 secretion and decreased glucose-dependent insulinotropic polypeptide release. Although CPE administration did not affect diet-induced insulin secretion, it decreased postprandial hyperglycaemia, which indicates that higher GLP-1 levels after the ingestion of CPE may improve insulin sensitivity. We conclude that dietary coffee polyphenols augment gut-derived active GLP-1 secretion via the cAMP-dependent pathway, which may contribute to the reduced risk of type 2 diabetes associated with daily coffee consumption. PMID- 26097707 TI - Levodropropizine for treating cough in adult and children: a meta-analysis of published studies. AB - BACKGROUND: Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and lung specialists. About 40% of the population at any one time report cough. Cough is associated with significantly impaired health-related quality of life. Levodropropizine is an effective and very well tolerated peripheral antitussive drug. We want to compare it to central cough suppressants efficacy (opioids and non-opioids) that may be associated with side effects limiting their use. METHODS: After a comprehensive literature search, a meta-analysis of 7 clinical studies of levodropropizine vs. control, including a total of 1,178 patients, was performed with the aim to evaluate the overall comparative efficacy of levodropropizine in the pediatric and adult population. Three electronic databases and reference list were used to search for studies that assessed the efficacy of levodropropizine for treating cough in children and adults using as standardized efficacy parameters the cough frequency and severity, and number of night awakenings as outcome parameters. RESULTS: The meta-analysis of all standardized efficacy parameters showed a highly statistically significant difference in the overall antitussive efficacy in favor of levodropropizine vs. control treatments (p = 0.0015). The heterogeneity test for the efficacy outcome was not statistically significant (p = 0.0534). Seven studies met out inclusion criteria. A meta-analysis of the eligible ones showed a statistically significant difference in the overall anti tussive effect of levodropropizine versus control (p = 0.0015). CONCLUSIONS: This analysis indicates that levodropropizine is an effective antitussive drug in children and adults, with statistically significant better overall efficacy outcomes vs. central antitussive drugs (codeine, cloperastine, dextromethorphan) in terms of reducing cough intensity and frequency, and nocturnal awakenings. This result further reinforces the favorable benefit/risk profile of levodropropizine in the management of cough. The efficacy of levodropropizine in the treatment of cough in children and adults is higher than that of the common centrally-acting anti-tussive. PMID- 26097708 TI - Aspects of social support and disclosure in the context of institutional abuse - long-term impact on mental health. AB - BACKGROUND: The psychological sequelae of institutionalized abuse and its long term consequences has not been systematically documented in existing literature in regarding social support once disclosure has been made. Reporting abuse is crucial, in particular for adult victims of childhood IA within the Catholic Church. Nevertheless, there is ongoing controversy about the benefits of disclosure. Our study examines the interaction of disclosure and subsequent social support in relation to mental health. We look into the times of disclosure, the behaviour during the disclosure to a commission as adults, different level of perceived social support, and the effect on mental health. METHODS: The data were collected in a sample of financially compensated adult survivors who experienced institutionalized abuse during their childhood, using instruments to measure perceived social support, reaction to disclosure, PTSD, and further symptoms. RESULTS: High levels of perceived social support after early disclosure result in a higher level of mental health and contribute to less emotionally reactive behaviour during disclosure of past institutionalized abuse. Highly perceived levels of social support seem to play a crucial role in mental health, but this inference may be weakened by a possible interference of a lasting competence in looking for social support versus social influences. CONCLUSION: Future research should thus disentangle perceived social support into the competence of looking for social support versus socially influenced factors to provide more clarity about the positive association of perceived social support and mental health. PMID- 26097709 TI - Botulinum toxin-A for the treatment of overactive bladder: UK contributions. AB - BACKGROUND: Botulinum toxin-A (BoNT/A) is now established second-line management for refractory overactive bladder (OAB) and recognised in many incontinence guidelines and pathways. For those with neurogenic detrusor overactivity secondary to spinal cord injury or multiple sclerosis, the toxin is currently licensed in certain parts of the world, including the UK. It is an effective treatment in those in whom antimuscarinics and conservative measures have failed who have symptoms of OAB and or detrusor overactivity (DO). METHODS: Treatment can be given in an outpatient setting and can be administered under local anaesthesia. Its efficacy lasts for between six and 12 months. RESULTS: It has an acceptable safety profile with the biggest risk being urinary tract infection and difficulty emptying the bladder, necessitating clean intermittent self catheterisation (CISC). Medium-term follow-up suggests repeated injections are also safe and efficacious. CONCLUSIONS: The mechanism of action of the toxin is more complicated than originally thought, and it seems likely that it affects motor and sensory nerves of the bladder. In the last 10 years much of the progress of this treatment from early experimental trials to mainstream clinical use, and a better understanding of how it works in the bladder, are as a result of research conducted in the UK. This review summarises the significant and substantial evidence for BoNT/A to treat refractory OAB from UK centres. PMID- 26097710 TI - Erectile dysfunction - an update of current practice and future strategies. PMID- 26097711 TI - Liver X receptors and cholesterol metabolism: role in ventral midbrain development and neurodegeneration. AB - The development of the ventral midbrain is orchestrated by a number of cell extrinsic and -intrinsic factors that control critical processes, such as the patterning of the neural tube along the main body axis and the specification of diverse neuronal cell types in distinct positions of the neural tube. Subsequently, the regulation of neurogenesis and survival- acquire particular relevance in order to define the final size of diverse neuronal populations. In a series of studies during the last few years, we have identified liver X receptors (LXRs) as critical regulators of ventral midbrain development. Moreover, specific cholesterol derivatives present in the midbrain or in the cerebrospinal fluid were identified as LXR ligands, capable of specifically and selectively regulating neurogenesis and the survival of distinct neuronal populations, including midbrain dopamine neurons. These studies have shown that cholesterol derivatives are an entirely new class of factors capable of regulating both neuronal survival and neurogenesis, thus providing a direct link between cholesterol metabolism and brain development. In addition, LXRs and cholesterol metabolism were found to play a critical role in regulating the balance between neuronal survival and death in diverse midbrain neuronal populations. In this review, we will focus on these two aspects and on the possible role of cholesterol metabolism and LXRs in neurodegeneration. PMID- 26097712 TI - Memory CD8 T cell transcriptional plasticity. AB - Memory CD8 T cells generated after acute viral infections or live vaccines can persist for extended periods, in some instances for life, and play an important role in protective immunity. This long-lived immunity is achieved in part through cytokine-mediated homeostatic proliferation of memory T cells while maintaining the acquired capacity for rapid recall of effector cytokines and cytolytic molecules. The ability of memory CD8 T cells to retain their acquired properties, including their ability to remain poised to recall effector functions, is a truly impressive feat given that these acquired properties can be maintained for decades without exposure to cognate antigen. Here, we discuss general mechanisms for acquisition and maintenance of transcriptional programs in memory CD8 T cells and the potential role of epigenetic programming in maintaining the phenotypic and functional heterogeneity of cellular subsets among the pool of memory cells. PMID- 26097713 TI - Recent advances in the prevention and management of preterm birth. AB - The management of preterm birth has seen major transformations in the last few decades with increasing interest worldwide, due to the impact of preterm birth on neonatal morbidity and mortality. The prevention strategies currently available for asymptomatic women at risk of preterm birth include progesterone, cervical cerclage and cervical pessary. Each approach has varying effects depending on the patient's prior history of preterm birth, cervical length and the presence of multiple gestations. There is a shift in the focus of antenatal treatment, with the use of prenatal magnesium sulphate and corticosteroids, to reduce neonatal intensive care admissions and longer-term disabilities associated with preterm birth, consequently relieving emotional and economical burden. This article provides an update on the recent advances in prevention and management approaches available for women at risk of preterm birth. PMID- 26097714 TI - Chicken or the egg: Warburg effect and mitochondrial dysfunction. AB - Compared with normal cells, cancer cells show alterations in many cellular processes, including energy metabolism. Studies on cancer metabolism started with Otto Warburg's observation at the beginning of the last century. According to Warburg, cancer cells rely on glycolysis more than mitochondrial respiration for energy production. Considering that glycolysis yields much less energy compared with mitochondrial respiration, Warburg hypothesized that mitochondria must be dysfunctional and this is the initiating factor for cancer formation. However, this hypothesis did not convince every scientist in the field. Some believed the opposite: the reduction in mitochondrial activity is a result of increased glycolysis. This discrepancy of opinions is ongoing. In this review, we will discuss the alterations in glycolysis, pyruvate metabolism, and the Krebs cycle in cancer cells and focus on cause and consequence. PMID- 26097715 TI - Mitochondria and apoptosis: emerging concepts. AB - As mitochondria are the powerhouses of the cell, their damage during the cell suicide process of apoptosis is essentially responsible for cellular demise in most cells. A key family of proteins, the B-cell lymphoma-2 (BCL-2) family, determines the integrity of mitochondria in the face of apoptotic insult. A comprehensive understanding of the molecular details of how apoptosis is initiated and how it culminates is essential if apoptosis is to fulfil its undoubted potential as a therapeutic target to treat diseases ranging from cancer to neurodegenerative conditions. Recent advances have provided significant insight into the control of this fundamental process while prompting a re evaluation of what was considered dogma in the field. Emerging evidence also points to a potential overarching control network that governs not only apoptosis but other fundamental mitochondrial processes, including mitochondrial fission/fusion and quality control. PMID- 26097716 TI - The problem of dropout from "gold standard" PTSD therapies. AB - Understanding of posttraumatic stress disorder (PTSD) has increased substantially in the past several decades. There is now more awareness of the many different types of trauma that can lead to PTSD, greater refinement of diagnostic criteria, and the development and testing of various treatments for it. As implementation of PTSD therapies has increased, there is also increased attention to the key issues of retention and dropout. Retention refers to the percentage of patients who stay in a treatment for its intended dose, and dropout is the opposite (the percentage who leave prior to the intended dose); both of which have major implications for treatment outcomes. The two PTSD therapies most studied in relation to retention and dropout are Prolonged Exposure and Cognitive Processing Therapy, which have been the subject of massive, formal, multi-year dissemination roll-outs. Both of these evidence-based treatments are defined as gold-standard therapies for PTSD and showed positive outcomes and reasonable retention of patients in randomized controlled trials (RCTs). But an emerging picture based on real-world practice indicates substantial dropout. Such real-world studies are distinct from RCTs, which have consistently evidenced far lower dropout rates, but under much more restricted conditions (e.g. a more selective range of patients and clinicians). In this paper, the phenomena of retention and dropout are described based on real-world studies of Prolonged Exposure and Cognitive Processing Therapy, including rates, characteristics of patients, clinicians, and programs in relation to retention and dropout, and identification of clinical issues and future research on these topics. It is suggested that the term "gold standard" evidence-based treatments should be reserved for treatments that evidence both positive results in RCTs but also feasibility and strong retention in real-world settings. PMID- 26097718 TI - Cochlear implantation: a biomechanical prosthesis for hearing loss. AB - Cochlear implants are a medical prosthesis used to treat sensorineural deafness, and one of the greatest advances in modern medicine. The following article is an overview of cochlear implant technology. The history of cochlear implantation and the development of modern implant technology will be discussed, as well as current surgical techniques. Research regarding expansion of candidacy, hearing preservation cochlear implantation, and implantation for unilateral deafness are described. Lastly, innovative technology is discussed, including the hybrid cochlear implant and the totally implantable cochlear implant. PMID- 26097719 TI - Recent advances in the entirely subcutaneous ICD System. AB - The entirely subcutaneous implantable cardioverter defibrillator (S-ICD((r))) is emerging as a widely accepted therapeutic alternative to a conventional implantable cardioverter defibrillator (ICD) for prevention of sudden cardiac death. Essentially, the S-ICD((r)) is promising in terms of reduction of electrode-related complications such as lead failure and infections. The conventional transvenous ICD has proven efficacy in various randomized clinical trials. The first results of S-ICD((r)) studies confirm efficacy and safety in primary and secondary prevention as well. Owing to basic differences between S ICD((r)) and transvenous ICD-such as limited programming options and lack of pacing-not all patients are eligible for the S-ICD((r)). Concerns exist regarding inappropriate shocks due to T-wave oversensing, dimensions of the device, and shorter battery longevity. However, the S-ICD((r)) should be considered a useful supplementation of ICD therapy in those patients at risk for sudden cardiac death who are not expected to require pacing due to bradycardia or antitachycardic pacing. PMID- 26097720 TI - Non-native invasive species and novel ecosystems. AB - Invasions by non-native species have caused many extinctions and greatly modified many ecosystems and are among the major anthropogenic global changes transforming the earth. Beginning in the mid-1980s, a dramatic burst of research in invasion biology has revealed a plethora of previously unrecognized impacts and laid bare the scope of the phenomenon. Similarly, research on various methods of managing invasions has expanded enormously, yielding incremental improvements in traditional methods and the advent of several new approaches, including the use of species-specific genetic and pheromonal methods. This research has advanced the field of restoration ecology, of which invasion management is a key component. Amidst this research progress, a group of critics has attempted to cast doubt on the extent of damaging impacts caused by non-native invasive species, the feasibility of counteracting them and restoring ecosystems, and the motives of scientists engaged in such endeavors. The criticisms are misguided but can potentially impede management of this pressing problem. PMID- 26097717 TI - Pathogenesis of Crohn's disease. AB - Significant progress in our understanding of Crohn's disease (CD), an archetypal common, complex disease, has now been achieved. Our ability to interrogate the deep complexities of the biological processes involved in maintaining gut mucosal homeostasis is a major over-riding factor underpinning this rapid progress. Key studies now offer many novel and expansive insights into the interacting roles of genetic susceptibility, immune function, and the gut microbiota in CD. Here, we provide overviews of these recent advances and new mechanistic themes, and address the challenges and prospects for translation from concept to clinic. PMID- 26097721 TI - New insights into nucleolar structure and function. AB - The nucleolus is a non-membrane-bound nuclear organelle found in all eukaryotes. It is the quintessential 'RNA-seeded' nuclear body, forming around specific chromosomal features called nucleolar organizing regions that contain arrays of ribosomal DNA. Assembly is triggered by activation of RNA polymerase I-mediated transcription and regulated in mammalian cells in a cell cycle-dependent manner. Although the nucleolus is best known for its role in coordinating ribosome biogenesis, biochemical and proteomic analyses have revealed a much wider functional complexity than previously appreciated, including roles in cell cycle regulation, DNA damage sensing and repair, pre-mRNA processing, telomere metabolism, processing of non-coding RNAs, and coordination of the cellular response to various stresses. Despite these advances, much remains to be learned about the full range of biological processes that occur within, or involve, this organelle and how its assembly/disassembly and functional reorganization in response to various stimuli are regulated. Here, we review the impact of recent studies that provide major insights into these fundamental questions, and we highlight the therapeutic potential of targeting nucleolar pathways. PMID- 26097722 TI - From Darwin's Origin of Species toward a theory of natural history. AB - Darwin is the father of evolutionary theory because he identified evolutionary patterns and, with Natural Selection, he ascertained the exquisitely ecological ultimate processes that lead to evolution. The proximate processes of evolution he proposed, however, predated the discovery of genetics, the backbone of modern evolutionary theory. The later discovery of the laws of inheritance by Mendel and the rediscovery of Mendel in the early 20th century led to two reforms of Darwinism: Neo-Darwinism and the Modern Synthesis (and subsequent refinements). If Darwin's evolutionary thought required much refinement, his ecological insight is still very modern. In the first edition of The Origin of Species, Darwin did not use either the word "evolution" or the word "ecology". "Ecology" was not coined until after the publication of the Origin. Evolution, for him, was the origin of varieties, then species, which he referred to as well-marked varieties, whereas, instead of using ecology, he used "the economy of nature". The Origin contains a high proportion of currently accepted ecological principles. Darwin labelled himself a naturalist. His discipline (natural history) was a blend of ecology and evolution in which he investigated both the patterns and the processes that determine the organization of life. Reductionist approaches, however, often keep the two disciplines separated from each other, undermining a full understanding of natural phenomena that might be favored by blending ecology and evolution through the development of a modern Theory of Natural History based on Darwin's vision of the study of life. PMID- 26097723 TI - Advances in the prevention of Alzheimer's Disease. AB - Alzheimer's disease (AD), the leading cause of dementia, has reached epidemic proportions, with major social, medical and economical burdens. With no currently available curative treatments, both the World Health Organization and the G8 Dementia Summit recently identified dementia and AD prevention as a major public health priority. Dementia and AD have a wide range of risk factors (genetic, vascular/metabolic and lifestyle-related), which often co-occur and thus interact with each other. Previous intervention efforts aimed at preventing dementia and AD focused on the management of single risk factors, with relatively modest findings. Also, the effect of risk factors depends on age at exposure, indicating that the timing of preventive interventions needs to be carefully considered. In view of the complex multifactorial nature of AD, as well as its long pre-clinical (asymptomatic) phase, interventions simultaneously targeting multiple risk factors and disease mechanisms at an early stage of the disease are most likely to be effective. Three large European multidomain prevention trials have been launched with the goal of preventing cognitive decline, dementia and AD in older adults with different risk profiles. Pharmacological trials are also shifting towards prevention of Alzheimer dementia, by targeting at-risk individuals prior to the onset of cognitive symptoms. The current review will summarize and discuss the evidence on risk and protective factors from observational studies, ongoing lifestyle-related and pharmacological randomized controlled trials (RCTs), as well as future directions for dementia and AD prevention. PMID- 26097724 TI - Recent advances in renal transplantation: antibody-mediated rejection takes center stage. AB - Overlooked for decades, antibodies have taken center stage in renal transplantation and are now widely recognized as the first cause of allograft failure. Diagnosis of antibody-mediated rejection has considerably improved with identification of antibody-mediated lesions in graft biopsies and advances made in the detection of circulating donor-specific antibodies. Unfortunately, this progress has not yet translated into better outcomes for patients. Indeed, in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This review provides an overview of the current knowledge of antibody-mediated rejection and discusses future interesting research directions. PMID- 26097725 TI - Advances in the understanding and management of heart transplantation. AB - Cardiac transplantation represents one of the great triumphs in modern medicine and remains the cornerstone in the treatment of advanced heart failure. In this review, we contextualize pivotal developments in our understanding and management of cardiac transplant immunology, histopathology, rejection surveillance, drug development and surgery. We also discuss current limitations in their application and the impact of the left ventricular assist devices in bridging this gap. PMID- 26097726 TI - Advances in the management of basal cell carcinoma. AB - Basal cell carcinoma (BCC), a malignant neoplasm derived from non-keratinizing cells that originate in the basal layer of the epidermis, is the most common cancer in humans. Several factors such as anatomic location, histologic features, primary or recurrent tumors, and patient characteristics influence the choice of treatment modality for BCC. Mohs micrographic surgery (MMS) facilitates optimal margin control and conservation of normal tissue for the management of BCC; however, other treatment modalities may also be implemented in the correct clinical scenario. Other treatment modalities that will be reviewed include simple excision, electrodesiccation and curettage, cryotherapy, topical immunotherapy and chemotherapy, photodynamic therapy, and radiation therapy. In addition, targeted molecular therapeutic options for the treatment of advanced or metastatic BCC will be discussed in this informal review based on recent literature obtained by using PubMed with relevant search terms. PMID- 26097727 TI - Non-celiac gluten hypersensitivity: What is all the fuss about? AB - Non-celiac gluten sensitivity (NCGS) has been introduced recently as a potentially common disease on the basis of studies of patients with claimed reactivity to gluten but without the characteristics of celiac disease (CD). CD is characterized by antibody reactivity toward the autoantigen transglutaminase 2, characteristic histological abnormalities of the small intestine, and an almost obligatory genetic haplotype (HLA-DQ2 or DQ8). The diagnosis of NCGS is based largely on the clinical suspicion of hyper-reactivity to gluten and the absence of the characteristics of CD. Few published studies have used double blind placebo-controlled food challenges (DBPCFCs) for the diagnosis of NCGS, and none in children. Innate immune reactivity to amylase trypsin inhibitors has been suggested as the pathogenic principle in NCGS, but confirmatory evidence is lacking. Also, further clinical studies including DBPCFCs are needed. PMID- 26097728 TI - Recent advances in understanding and managing leiomyosarcomas. AB - Leiomyosarcomas are malignant mesenchymal tumours that derive from the smooth muscle lineage. They are studied and frequently treated as if they are the same as other soft tissue sarcomas. Recent developments suggest that a different approach may be more appropriate. Their underlying genetic mechanisms remain unclear, and complex. Unbalanced karyotypic defects are the only shared features observed across different leiomyosarcoma subtypes. Unlike other soft tissue sarcomas, leiomyosarcomas are particularly sensitive to the combination of gemcitabine and docetaxel. Furthermore, treatment with trabectedin has shown a good efficacy in leiomyosarcomas, mainly in the form of chronic disease stabilisation. PMID- 26097730 TI - Recent advances in the management of peritoneal dialysis patients. AB - Peritoneal dialysis is a form of kidney dialysis that is used to remove accumulated metabolic waste products and water in patients with end stage kidney disease. Long-term exposure to high concentrations of glucose and its by products, both found in peritoneal dialysis fluid, has been implicated in contributing to peritoneal damage over time, in turn limiting long-term use of the technique. Newer peritoneal dialysis solutions have been developed in the hope of reducing the unfavorable effects of peritoneal dialysis solutions. In vitro and in vivo studies have suggested that newer peritoneal dialysis fluids have salutary effects on the peritoneal membrane. Short-term clinical studies have also found some metabolic benefits of glucose-sparing regimens in chronic peritoneal dialysis. Mixed results have been found in studies examining whether newer peritoneal dialysis fluids reduce peritonitis rates. Long-term studies are needed to investigate whether newer peritoneal dialysis fluids provide better peritoneal dialysis technique and/or patient survival, compared to standard glucose-based peritoneal dialysis fluids. PMID- 26097732 TI - Recent advances in understanding and managing rhabdomyosarcoma. AB - Rhabdomyosarcoma is the most common childhood soft tissue sarcoma and the fourth most common pediatric solid tumor. For most patients, treatment consists of a multimodality approach, including chemotherapy, surgery, and/or radiotherapy. To guide treatment, patients with rhabdomyosarcoma are risk stratified based on a number of factors. These factors include clinical group, which depends largely on the extent of resection and nodal involvement, and stage, which takes into account tumor size, invasion, nodal involvement, and disease site. Histology of the tumor and age at diagnosis are also factored into risk stratification. Recent advances in understanding the biology of the disease have allowed for the further sub-classification of rhabdomyosarcoma. In addition, elucidation of additional clinical features associated with poor prognosis has allowed for better understanding of risk and provides more clarity regarding those patients who require more intensive therapy. Many areas of active investigation are ongoing, including the following: further delineation of the biological underpinnings of the various disease subtypes with the possibility of molecularly targeted therapy; a better understanding of clinical risk factors, including the evaluation and management of potentially involved lymph nodes; determination of the appropriate role of post-treatment imaging and assessment of response to therapy; and incorporation of advanced radiotherapeutic techniques, including conformal intensity-modulated photon and proton therapy. PMID- 26097731 TI - Endogenous opioids: opposing stress with a cost. AB - The stress response is characterized by the coordinated engagement of central and peripheral neural systems in response to life-threatening challenges. It has been conserved through evolution and is essential for survival. However, the frequent or continual elicitation of the stress response by repeated or chronic stress, respectively, results in the dysfunction of stress response circuits, ultimately leading to stress-related pathology. In an effort to best respond to stressors, yet at the same time maintain homeostasis and avoid dysfunction, stress response systems are finely balanced and co-regulated by neuromodulators that exert opposing effects. These opposing systems serve to restrain certain stress response systems and promote recovery. However, the engagement of opposing systems comes with the cost of alternate dysfunctions. This review describes, as an example of this dynamic, how endogenous opioids function to oppose the effects of the major stress neuromediator, corticotropin-releasing hormone, and promote recovery from a stress response and how these actions can both protect and be hazardous to health. PMID- 26097733 TI - Management of tachycardia. AB - Tachycardia, conventionally, but arbitrarily, defined as an atrial and/or ventricular rate of >100 beats per minute, is encountered commonly and can be physiological or pathological in origin. Various adverse consequences from tachycardia have been recognized, and an important one is the association between persistent tachycardia and cardiomyopathy. In this article, we provide an up-to date review on the etiology of tachycardia, management strategies, and the prognosis of patients presenting with tachycardia and cardiomyopathy. PMID- 26097734 TI - Recent treatment advances and novel therapeutic approaches in epilepsy. AB - The purpose of this article is to review recent advances in the treatment of epilepsy. It includes five antiepileptic drugs that have been recently added to the pharmacologic armamentarium and surgical techniques that have been developed in the last few years. Finally, we review ongoing research that may have a potential role in future treatments of epilepsy. PMID- 26097729 TI - The search for novel analgesics: targets and mechanisms. AB - The management of the pain state is of great therapeutic relevance to virtually every medical specialty. Failure to manage its expression has deleterious consequence to the well-being of the organism. An understanding of the complex biology of the mechanisms underlying the processing of nociceptive information provides an important pathway towards development of novel and robust therapeutics. Importantly, preclinical models have been of considerable use in determining the linkage between mechanism and the associated behaviorally defined pain state. This review seeks to provide an overview of current thinking targeting pain biology, the use of preclinical models and the development of novel pain therapeutics. Issues pertinent to the strengths and weaknesses of current development strategies for analgesics are considered. PMID- 26097737 TI - Recent advances in understanding and managing cystic fibrosis transmembrane conductance regulator dysfunction. AB - Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians and has been extensively studied for many decades. The cystic fibrosis transmembrane conductance regulator gene was identified in 1989. It encodes a complex protein which has numerous cellular functions. Our understanding of cystic fibrosis pathophysiology and genetics is constantly expanding and being refined, leading to improved management of the disease and increased life expectancy in affected individuals. PMID- 26097735 TI - Advances in understanding Giardia: determinants and mechanisms of chronic sequelae. AB - Giardia lamblia is a flagellated protozoan that is the most common cause of intestinal parasitic infection in children living in resource-limited settings. The pathogenicity of Giardia has been debated since the parasite was first identified, and clinical outcomes vary across studies. Among recent perplexing findings are diametrically opposed associations between Giardia and acute versus persistent diarrhea and a poorly understood potential for long-term sequelae, including impaired child growth and cognitive development. The mechanisms driving these protean clinical outcomes remain elusive, but recent advances suggest that variability in Giardia strains, host nutritional status, the composition of microbiota, co-infecting enteropathogens, host genetically determined mucosal immune responses, and immune modulation by Giardia are all relevant factors influencing disease manifestations after Giardia infection. PMID- 26097736 TI - Insomnia and sleep apnea in midlife women: prevalence and consequences to health and functioning. AB - Sleep disturbance is common during the menopausal transition, with numerous downstream consequences to health and functioning, including reduced quality of life, impaired mental health, and increased physical health morbidity. Insomnia affects approximately 50% of midlife women and is characterized by nocturnal symptoms of difficulties initiating or maintaining sleep (or both) and daytime symptoms that impair occupational, social, or other components of functioning. In addition, approximately 20% of midlife women develop sleep-disordered breathing during the menopausal transition. This commentary summarizes the prevalence, risk factors, and treatment options for each of these sleep disorders in midlife women, with specific focus on first-line treatments for insomnia (cognitive behavioral therapy for insomnia) and sleep-disordered breathing (continuous positive airway pressure) and unique considerations for treating sleep disorders in midlife women. Future directions are also discussed. PMID- 26097738 TI - Advancing our knowledge of the complexity and management of intimate partner violence and co-occurring mental health and substance abuse problems in women. AB - Globally, intimate partner violence (IPV) is a pervasive and insidious human rights problem with significant adverse physical health outcomes for women. Intimate partner violence has also been closely associated with poor mental health and substance use problems. However, little is known about the relationship among these co-occurring problems and how to best intervene or manage them. Here, we present findings from recent systematic reviews and meta analyses (where available) to highlight developments in understanding and managing the complex co-occurring problems of intimate partner violence and mental health and substance use in women. PMID- 26097739 TI - Hematopoietic transcription factor mutations and inherited platelet dysfunction. AB - The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is increasing evidence that mutations in hematopoietic transcription factors are major players in the pathogenesis of defective megakaryopoiesis and platelet dysfunction in patients with inherited platelet disorders. These hematopoietic transcription factors include RUNX1, FLI1, GATA-1, and GFI1B. Mutations involving these transcription factors affect diverse aspects of platelet production and function at the genetic and molecular levels, culminating in clinical manifestations of thrombocytopenia and platelet dysfunction. This review focuses on these hematopoietic transcription factors in the pathobiology of inherited platelet dysfunction. PMID- 26097740 TI - The Brave New World of Personality Disorder-Trait Specified: Effects of Additional Definitions on Coverage, Prevalence, and Comorbidity. AB - The alternative dimensional model for personality disorder (PD) in DSM-5, Section III (DSM-5-III) includes two main criteria: (A) personality-functioning impairment, and (B) personality-trait pathology; provides specific functioning and-trait criteria for six PD-type diagnoses; and introduces PD-trait specified (PD-TS), which requires meeting the general PD criteria and not meeting criteria for any specific PD type. We termed this Simple PD-TS and developed two additional definitions: Mixed PD-TS, meeting criteria for one or two PD types and having five or more additional pathological traits; and Complex PD-TS, meeting criteria for three or more PD types. In a mixed sample of 165 outpatients and 215 community adults screened to be at high-risk for PD, we investigated the effect of these additional definitions on prevalence, coverage, comorbidity, and within diagnosis heterogeneity, and conclude that eliminating the PD-type diagnoses and thus having PD-TS as the only PD diagnosis would be both more parsimonious and more useful clinically. PMID- 26097741 TI - Effectiveness of lower target temperature therapeutic hypothermia in post-cardiac arrest syndrome patients with a resuscitation interval of <=30 min. AB - BACKGROUND: Therapeutic hypothermia (TH) is a standard strategy to reduce brain damage in post-cardiac arrest syndrome (PCAS) patients. However, it is unknown whether the target temperature should be adjusted for PCAS patients in different states. METHODS: Participants in the J-PULSE-Hypo study database were divided into lower (32.0-33.5 degrees C; Group L) or moderate (34.0-35.0 degrees C; Group M) temperature groups. Primary outcome was a favourable neurological outcome (proportion of patients with a Glasgow-Pittsburgh Cerebral Performance Category [CPC] of 1-2 on day 30). We compared between the two groups and in subgroups of patients divided by age and resuscitation interval (interval from collapse to return of spontaneous circulation) by propensity score (PS) analysis. RESULTS: Overall, 467 participants were analysed. The proportions of patients with favourable neurological outcomes were as follows (Group L vs. Group M) (OR; Odds ratio): all patients, 64 % (n = 42) vs. 55 % ((n = 424) (PS; OR 1.381 (0.596 3.197)), P = 0.452) and resuscitation interval <= 30 min, 88 % (n = 24) vs. 64 % ((n = 281) (PS; OR 7.438 (1.769-31.272)), P = 0.007). CONCLUSIONS: PCAS patients with a resuscitation interval of <30 min may be candidates for TH with a target temperature of <34 degrees C. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000001935; available at: https://upload.umin.ac.jp/cgi-open bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000002348&langu ge=J. PMID- 26097742 TI - Global database of paleocurrent trends through the Phanerozoic and Precambrian. AB - Paleocurrents are sedimentological features contained in all sedimentary deposits, enabling the direction of movement of the sediment and the containing fluid at the time of deposition to be determined. This database contains paleocurrent directions and other relevant associated data from published sources and theses and dissertations for the entire Phanerozoic and Precambrian for all continents. Such information may be of general interest to sedimentologists and will be of specific interest in sedimentary basin analysis, and to petroleum geologists and mineralogists seeking source areas. Paleocurrents may also be useful in plate reconstructions and in testing the timing of global tectonic events. PMID- 26097743 TI - Snapshot Serengeti, high-frequency annotated camera trap images of 40 mammalian species in an African savanna. AB - Camera traps can be used to address large-scale questions in community ecology by providing systematic data on an array of wide-ranging species. We deployed 225 camera traps across 1,125 km(2) in Serengeti National Park, Tanzania, to evaluate spatial and temporal inter-species dynamics. The cameras have operated continuously since 2010 and had accumulated 99,241 camera-trap days and produced 1.2 million sets of pictures by 2013. Members of the general public classified the images via the citizen-science website www.snapshotserengeti.org. Multiple users viewed each image and recorded the species, number of individuals, associated behaviours, and presence of young. Over 28,000 registered users contributed 10.8 million classifications. We applied a simple algorithm to aggregate these individual classifications into a final 'consensus' dataset, yielding a final classification for each image and a measure of agreement among individual answers. The consensus classifications and raw imagery provide an unparalleled opportunity to investigate multi-species dynamics in an intact ecosystem and a valuable resource for machine-learning and computer-vision research. PMID- 26097744 TI - A daily global mesoscale ocean eddy dataset from satellite altimetry. AB - Mesoscale ocean eddies are ubiquitous coherent rotating structures of water with radial scales on the order of 100 kilometers. Eddies play a key role in the transport and mixing of momentum and tracers across the World Ocean. We present a global daily mesoscale ocean eddy dataset that contains ~45 million mesoscale features and 3.3 million eddy trajectories that persist at least two days as identified in the AVISO dataset over a period of 1993-2014. This dataset, along with the open-source eddy identification software, extract eddies with any parameters (minimum size, lifetime, etc.), to study global eddy properties and dynamics, and to empirically estimate the impact eddies have on mass or heat transport. Furthermore, our open-source software may be used to identify mesoscale features in model simulations and compare them to observed features. Finally, this dataset can be used to study the interaction between mesoscale ocean eddies and other components of the Earth System. PMID- 26097745 TI - Dynamic Crystallography Reveals Early Signalling Events in Ultraviolet Photoreceptor UVR8. AB - Arabidopsis thaliana UVR8 (AtUVR8) is a long-sought-after photoreceptor that undergoes dimer dissociation in response to UV-B light. Crystallographic and mutational studies have identified two crucial tryptophan residues for UV-B responses in AtUVR8. However, the mechanism of UV-B perception and structural events leading up to dimer dissociation remain elusive at the molecular level. We applied dynamic crystallography to capture light-induced structural events in photoactive AtUVR8 crystals. Here we report two intermediate structures at 1.67A resolution. At the epicenter of UV-B signaling, concerted motions associated with Trp285/Trp233 lead to ejection of a water molecule, which weakens an intricate network of hydrogen bonds and salt bridges at the dimer interface. Partial opening of the beta-propeller structure due to thermal relaxation of conformational strains originating in the epicenter further disrupts the dimer interface and leads to dimer dissociation. These dynamic crystallographic observations provide structural insights into the photo-perception and signaling mechanism of UVR8. PMID- 26097746 TI - Diagnostic accuracy of three different MRI protocols in patients with inflammatory bowel disease. AB - BACKGROUND: Magnetic resonance imaging (MRI) is used for workup and control of inflammatory bowel disease (IBD); however, disagreement remains as to how the MRI should be performed. PURPOSE: To compare prospectively the diagnostic accuracy of MRI with neither oral nor intravenous contrast medium (plain MRI), magnetic resonance follow-through (MRFT) and MR enteroclysis (MRE) using MRE as the reference standard in patients with inflammatory bowel disease. MATERIAL AND METHODS: Plain MRI and MRE were carried out in addition to MRFT. All patients underwent both plain MR and MRFT on the same day and MRE within seven days. For the evaluation, the bowel was divided into nine segments. One radiologist, blinded to clinical findings, evaluated bowel wall thickness, diffusion weighted imaging (DWI), mural hyperenhancement, and other inflammatory changes in each bowel segment. RESULTS: Twenty patients (6 men, 14 women; median age, 43.5 years; age range, 26-76 years) underwent all three examinations; 10 with Crohn's disease (CD), three with ulcerative colitis (UC), and seven with IBD unclassified (IBD U). Sensitivity, specificity, and accuracy were in the range of 0-75%, 81-96%, and 75-95% for wall thickening, and 0-37%, 59-89%, and 50-86% for DWI in plain MRI, respectively. Sensitivity, specificity, and accuracy were in the range of 0 50%, 96-100%, and 90-100% for wall thickening, 0-50%, 84-97%, and 82-95% for DWI, and 0-71%, 94-100%, and 85-100% for mural hyperenhancement in MRFT, respectively. CONCLUSION: The use of oral and intravenous contrast agent improves detection of bowel lesions resulting in MRFT remaining the superior choice over plain MRI for diagnostic workup in patients with IBD. PMID- 26097747 TI - Structure-Dependent Immune Modulatory Activity of Protegrin-1 Analogs. AB - Protegrins are porcine antimicrobial peptides (AMPs) that belong to the cathelicidin family of host defense peptides. Protegrin-1 (PG-1), the most investigated member of the protegrin family, is an arginine-rich peptide consisting of 18 amino acid residues, its main chain adopting a beta-hairpin structure that is linked by two disulfide bridges. We report on the immune modulatory activity of PG-1 and its analogs in neutralizing bacterial endotoxin and capsular polysaccharides, consequently inhibiting inflammatory mediators' release from macrophages. We demonstrate that the beta-hairpin structure motif stabilized with at least one disulfide bridge is a prerequisite for the immune modulatory activity of this type of AMP. PMID- 26097748 TI - Novel GUCY2D Gene Mutations in Japanese Male Twins with Leber Congenital Amaurosis. AB - Purpose. Leber congenital amaurosis (LCA), a genetically and clinically heterogeneous disease, is the earliest onset retinitis pigmentosa (RP) and is the most severe of hereditary retinal dystrophies. This study was conducted to investigate genetic and clinical features of LCA in a set of Japanese male twins with LCA. Methods. To identify causative mutations, 74 genes known to cause RP or LCA were examined by targeted-next generation sequencing (NGS). Targeted-NGS was performed using a custom designed Agilent HaloPlex target enrichment kit with Illumina Miseq sequencer. Identified potential pathogenic mutations were confirmed using Sanger sequencing. Clinical analyses were based on ophthalmic examination, fundus photography, and electroretinography (ERG). Results. Compound heterozygous GUCY2D mutations of novel splicing mutation c.2113+2_2113+3insT and novel missense mutation p.L905P were detected in both twins. Their father and mother were heterozygous for c.2113+2_2113+3insT and p.L905P, respectively. The twins had phenotypic features similar to those previously reported in patients with GUCY2D mutations. This included early childhood onset of visual loss, nystagmus, unrecordable ERG, photophobia, and hyperopia. Conclusions. To the best of our knowledge, this is the first report of genetic and clinical features of Japanese LCA twins with GUCY2D mutation, which were detected using targeted-NGS. PMID- 26097749 TI - Anterior and Posterior Corneal Astigmatism after Refractive Lenticule Extraction for Myopic Astigmatism. AB - Purpose. To assess the amount and the axis orientation of anterior and posterior corneal astigmatism after refractive lenticule extraction (ReLEx) for myopic astigmatism. Methods. We retrospectively examined 53 eyes of 53 consecutive patients (mean age +/- standard deviation, 33.2 +/- 6.5 years) undergoing ReLEx to correct myopic astigmatism (manifest cylinder = 0.5 diopters (D)). Power vector analysis was performed with anterior and posterior corneal astigmatism measured with a rotating Scheimpflug system (Pentacam HR, Oculus) and refractive astigmatism preoperatively and 3 months postoperatively. Results. Anterior corneal astigmatism was significantly decreased, measuring 1.42 +/- 0.73 diopters (D) preoperatively and 1.11 +/- 0.53 D postoperatively (p < 0.001, Wilcoxon signed-rank test). Posterior corneal astigmatism showed no significant change, falling from 0.44 +/- 0.12 D preoperatively to 0.42 +/- 0.13 D postoperatively (p = 0.18). Refractive astigmatism decreased significantly, from 0.92 +/- 0.51 D preoperatively to 0.27 +/- 0.44 D postoperatively (p < 0.001). The anterior surface showed with-the-rule astigmatism in 51 eyes (96%) preoperatively and 48 eyes (91%) postoperatively. By contrast, the posterior surface showed against-the rule astigmatism in all eyes preoperatively and postoperatively. Conclusions. The surgical effects were largely attributed to the astigmatic correction of the anterior corneal surface. Posterior corneal astigmatism remained unchanged even after ReLEx for myopic astigmatism. PMID- 26097751 TI - Translational Research in Bipolar Disorders. PMID- 26097750 TI - The Use of Cannabis as a Predictor of Early Onset of Bipolar Disorder and Suicide Attempts. AB - Introduction. Bipolar disorder (BD) implies risk of suicide. The age at onset (AAO) of BD carries prognostic significance. Substance abuse may precede the onset of BD and cannabis is the most common illicit drug used. The main goal of this study is to review the association of cannabis use as a risk factor for early onset of BD and for suicide attempts. Materials and Methods. PubMed database was searched for articles using key words "bipolar disorder," "suicide attempts," "cannabis," "marijuana," "early age at onset," and "early onset." Results. The following percentages in bipolar patients were found: suicide attempts 3.6-42%; suicide attempts and substance use 5-60%; suicide attempts and cannabis use 15-42%. An early AAO was associated with cannabis misuse. The mean age of the first manic episode in individuals with and without BD and cannabis use disorder (CUD) was 19.5 and 25.1 years, respectively. The first depressive episode was at 18.5 and 24.4 years, respectively. Individuals misusing cannabis showed increased risk of suicide. Discussion. Cannabis use is associated with increased risk of suicide attempts and with early AAO. However, the effect of cannabis at the AAO and suicide attempts is not clear. PMID- 26097752 TI - Coronal Pulpotomy Technique Analysis as an Alternative to Pulpectomy for Preserving the Tooth Vitality, in the Context of Tissue Regeneration: A Correlated Clinical Study across 4 Adult Permanent Molars. AB - Aim. (1) The aim of the clinical study revolves around the accurate diagnosis, proper case selection, and the management of acute irreversible pulpitis in permanent molars with closed apices using conservative and economical treatment modalities like vital pulpotomies with regenerative approaches over conventional root canal procedures. (2) To evaluate the use of autologous substances such as platelet concentrates and calcium silicate based materials in promoting the healing and regeneration of the inflamed pulp. Summary. Vital pulpotomy was performed on 5 carious involved, permanent molars diagnosed with acute irreversible pulpitis in 17- to 22-year-old patients. Taking into consideration the patient's age and the condition of the underlying pulp tissue, PRF pulpotomy was planned in view of preserving the vitality of the intact radicular pulps. Regenerative procedures with second generation blood matrices were chosen to encourage the recovery of the inflamed pulps. The systematic follow-up examinations performed at 3, 6, 9, 12, 18, 22, and 24 months revealed a successful clinical and radiological outcome. Within the limits of the present clinical study and correlating the success across the treated clinical cases, we safely conclude the potential scope of regenerative pulpotomy approaches in acute irreversible pulpitis in adult permanent teeth. PMID- 26097754 TI - Medical Schools for Profit? PMID- 26097753 TI - Deletion of IFT20 in early stage T lymphocyte differentiation inhibits the development of collagen-induced arthritis. AB - IFT20 is the smallest member of the intraflagellar transport protein (IFT) complex B. It is involved in cilia formation. Studies of IFT20 have been confined to ciliated cells. Recently, IFT20 was found to be also expressed in non-ciliated T cells and have functions in immune synapse formation and signaling in vitro. However, how IFT20 regulates T-cell development and activation in vivo is still unknown. We deleted the IFT20 gene in early and later stages of T-cell development by crossing IFT20(flox/flox) (IFT20(f/f) ) mice with Lck-Cre and CD4 Cre transgenic mice, and investigated the role of IFT20 in T-cell maturation and in the development of T cell-mediated collagen-induced arthritis (CIA). We found that both Lck-Cre/IFT20(f/f) and CD4-Cre/IFT20(f/f) mice were indistinguishable from their wild-type littermates in body size, as well as in the morphology and weight of the spleen and thymus. However, the number of CD4- and CD8-positive cells was significantly lower in thymus and spleen in Lck-Cre/IFT20(f/f) mice. Meanwhile, the incidence and severity of CIA symptoms were significantly decreased, and inflammation in the paw was significantly inhibited in Lck Cre/IFT20(f/f) mice compared to Lck-Cre/IFT20(+/+) littermates. Deletion IFT20 in more mature T cells of CD4-Cre/IFT20(f/f) mice had only mild effects on the development of T cells and CIA. The expression of IL-1beta, IL-6 and TGF-beta1 were significantly downregulated in the paw of Lck-Cre/IFT20(f/f) mice, but just slight decreased in CD4-Cre/IFT20(f/f) mice. These results demonstrate that deletion of IFT20 in the early stage of T-cell development inhibited CIA development through regulating T-cell development and the expression of critical cytokines. PMID- 26097755 TI - Clinical Evaluation of the Efficacy of Arthocare Forte, a Chondro-Protective and Anti-Arthritic Drug in the Management of Bacterial Plaque-Induced Chronic Periodontitis. AB - BACKGROUND: Arthocare forte medication is made up of different constituents and the advantages offered by this disposition have not been explored in the management of chronic periodontitis. AIM: The aim was to assess the clinical response of bacterial plaque-induced generalized chronic periodontitis to arthocare medication, and the relationship of age and gender to the prevalence of chronic periodontal disease. SUBJECTS AND METHODS: This study was done at the Dental Surgery Clinic of the University of Calabar Teaching Hospital, Nigeria. It was a Prospective randomized controlled trial evaluating the effect of arthocare treatment on 81/162 patients with teeth mobility over a period of 5 years. All the patients (162) underwent root planing, and 81/162 (50%) were treated with arthocare for comparative analysis. The variables recorded were patient's age, gender, and degree of tooth mobility, periodontal pocket, and bleeding from the pocket after treatment. Statistical analysis was done using EPI INFO 7. RESULTS: Majority of the patients were between 46 and 75 years in both control (n = 59/81, 72.8%) and experimental groups (n = 52/81, 64.2%). There were 86/162 (53.1%) males and 76/162 (46.9%) females, giving a male-to-female ratio of 1.1:1. Seventy seven patients (95.1%) in the experimental group had total remission in comparison to 32/81 (39.5%) in control group which was statistically significant (P < 0.001). CONCLUSION: The arthocare administered to patients in the experimental group speeds up the regenerative capacity and stability of the periodontium when compared with the control. Multicentre clinical trials are recommended to validate the use of arthocare forte in the treatment of generalized chronic periodontitis. PMID- 26097756 TI - Tsutsugamushi Disease (Scrub Typhus) Meningoencephalitis in North Eastern India: A Prospective Study. AB - BACKGROUND: Scrub typhus is rampant in northern, eastern, and southern India. Central nervous system involvement in the form of meningitis or meningoencephalitis is common in scrub typhus. As specific laboratory methods remain inadequate or inaccessible in developing countries, prompt diagnosis is often difficult. AIM: The aim of this study was to characterize neurological complications in scrub typhus from northeastern region of India. SUBJECTS AND METHODS: We did a prospective study of scrub meningoencephalitis at North Eastern Indira Gandhi Regional Institute of Medical Sciences among patients admitted to hospital between October 2009 and November 2011. The diagnosis was made based on the clinical pictures, presence of an eschar, and a positive Weil-Felix test (WFT) with a titer of >1:160 and if required a positive scrub IgM enzyme-linked immunosorbent assay. Lumbar puncture was performed in patients with headache, nuchal rigidity, altered sensorium or cranial nerve deficits, and magnetic resonance imaging (MRI) brain performed if needed. RESULTS: Twenty-three patients of scrub typhus meningitis that were serologically confirmed were included in the study. There were 13 males and 10 females. Fever >=1 week was the most common manifestation (39.1%). Interestingly, none had an eschar. Median cerebrospinal fluid (CSF) cell count, lymphocyte percentage, CSF protein, CSF glucose/blood glucose, CSF ADA were 17 cells/MUL, 90%, 86 mg/dL, 0.6605 and 3.6 U/mL, respectively. All patients were treated with doxycycline. There was no mortality in our study. CONCLUSIONS: Absence of Eschar does not rule out scrub typhus. Clinical features and CSF findings can mimic tuberculous meningitis so misdiagnosis may lead to unwarranted prolonged empirical antituberculous therapy in cases of lymphocytic meningoencephalitis. Delay in treatment can be potentially fatal. WFT still serves as a useful and affordable diagnostic tool for this disease in resource-poor countries. PMID- 26097757 TI - Clinical and Socio-Demographic Profile of Women with Post-Partum Psychiatric Conditions at a Federal Neuropsychiatric Hospital in Southeast Nigeria between 2009 and 2011. AB - BACKGROUND: Pregnancy and labor in areas with high maternal morbidities as in Nigeria could be sufficiently stressful to precipitate mental disorders in women after delivery, which may be a new or a relapse of previously existing one, or an exacerbation of an attenuated mental illness in the nursing mother. Mental illness in a nursing mother, if not treated may result in impaired mother-infant relationship. AIM: To determine the clinical and socio-demographic characteristics of women diagnosed with postpartum psychiatric conditions in a tertiary mental health facility of a developing country. SUBJECTS AND METHODS: A retrospective case note reviews of 76 women diagnosed with postpartum psychiatric conditions for the first time in the Federal Neuropsychiatric Hospital Enugu between January 2009 and December 2011. RESULTS: The mean age of the women was 27.76 years, with 63% (48/76) of them coming from the rural areas. 93% (71/76) of them had at least a secondary education and 78% (59/76) of the women had a family history of psychiatric disorders. Schizophrenia was commonest, 48.7% (37/76) followed by depression, 22% (17/76) and mania, 15% (11/76). Those presenting with schizophrenia were younger when compared with other diagnostic groups, had a lower level of education and presented earlier for treatment. The husbands were the primary caregivers in 48% of them. CONCLUSION: With 63% (48/76) of them being rural dwellers, policy changes become imperative that would encourage establishment of psychiatric services in rural areas to ensure early detection and prompt treatment of postpartum women with a need for psychiatric services. PMID- 26097758 TI - Antihypertensive Medications Adherence Among Nigerian Hypertensive Subjects in a Specialist Clinic Compared to a General Outpatient Clinic. AB - BACKGROUND: Poor adherence to antihypertensive medications has been linked with increased cardiovascular risk and mortality in many population. Africans have been shown to have a worse prognosis from hypertension, poorer blood pressure control, and increased risk of complications arising from hypertension compared to Caucasians. AIM: The aim was to describe the level of adherence to antihypertensive medications, its determinants and whether any difference exist between those attending specialty clinic or general outpatient department (GOPD) Clinic in a Nigerian University Teaching Hospital. SUBJECTS AND METHODS: An analytical cross-sectional study. The Morisky scale was used to assess for adherence to antihypertensive medications. Clinical and demographic data were taken. Statistical analysis was performed using SPSS 17.0. (Chicago, IL, USA). P < 0.05 was taken as statistically significant. RESULTS: A total of 114 hypertensive subjects were recruited for this study. Seventy-nine were from the cardiology clinic whereas 35 were from the GOPD. They consisted of 60 males (52.6%, 60/114) and 54 females (47.4%, 54/110). The mean age was 63.6 (14.1) years. High adherence, low adherence and medium adherence as defined by Morisky scale was found in 36.8% (42/114), 23.9% (27/114) and 39.5% (45/114), respectively. Adherence level was higher among those attending specialty clinic despite shorter duration of hypertension and use of more medications. More than four-fifth of those attending cardiology clinic had at least medium level of adherence compared to a little bit over half of those attending GOPD clinic. Those with good adherence were likely to be older, had a higher level of education and higher average monthly income than those with poor adherence. CONCLUSION: Poor adherence to medications is very common in the hypertensive Nigerians. Hypertensive subjects attending specialty clinic seems to have a better adherence to antihypertensive medications possibly due to the level of health education and information provided to patients. Effective health education and regular screening for compliance and adherence is a potential way to reduce cardiovascular risk associated with uncontrolled hypertension. PMID- 26097759 TI - An Assessment of Female Prisoners' Perception of the Accessibility of Quality Healthcare: A Survey in the Kumasi Central Prisons, Ghana. AB - BACKGROUND: Accessibility of quality healthcare across the globe has generated a lot of attention among public health practitioners. AIM: This study explored the background characteristics of female prisoners and how it influences their assessment of the quality of accessible healthcare in the Kumasi Female Prison. SUBJECTS AND METHODS: This descriptive cross-sectional survey was conducted at the Female section of the Kumasi Central Prisons from June to December 2011. We used pretested questionnaires to obtain quantitative data from all 39 inmates of the female Prisons. An in-depth interview was used to obtain qualitative data from the prison healthcare giver. Data were analyzed with Epi Info Version 3.5.1, (Centers for Disease Control and Prevention), Excel, and Graph Pad Prism version 5.00 for Windows (Graph Pad software, San Diego California USA, www.graphpad.com). RESULTS: Using a 12-point scale inventory questionnaire, inmates with no formal education gave the highest mean health provision assessment score (6.0) whereas those with tertiary education gave the lowest (4.5). Females serving prison sentences gave the highest mean health assessment score whereas remand prisoners gave the lowest. Single females' mean health assessment score was 5.7 whereas that of married inmates was 4.9. Unemployed inmates scored 5.8, informal 5.4 while civil servants scored 5.0. CONCLUSION: Access to quality healthcare was poor and demographic characteristics, marital status, educational background, and occupation influenced inmates' perceptions of accessibility to quality healthcare. Inmates should be encouraged to be proactive in seeking healthcare irrespective of their background characteristics. PMID- 26097760 TI - Effects of Prestorage Leukoreduction on the Rate of Febrile Nonhemolytic Transfusion Reactions to Red Blood Cells in a Tertiary Care Hospital. AB - BACKGROUND: Febrile nonhemolytic transfusion reactions (FNHTRs) are relatively common complications associated with allogenic transfusion. White blood cells (WBCs or leukocytes) are considered to be an important cause of FNHTRs; the rate of WBC derived pro-inflammatory cytokines increase with storage due to active synthesis of cytokines by these cells. The removal of the WBCs before storage will prevent the accumulation of cytokines during storage that leads to a reduction in the number of FNHTRs. AIM: We have conducted a retrospective analysis comparing the rate of FNHTRs in prestorage leukoreduced (PrSLR) and non leukoreduced RBCs transfusion. SUBJECTS AND METHODS: A retrospective review of all the transfusion reactions (TRs) reported to the department over a period of 2 years from July 2012 to June 2014 was done. Patients were stratified by the date of reaction and by component received and then divided into two groups: (1) Patients who received allogeneic PrSLR RBCs and (2) nonleukoreduced RBCs. For the PrSLR RBC units, leukoreduction was performed by using buffy coat method of component preparation by quadruple bags and integral bags containing Sepacell((r)) Pure RC filters (FenwalTM France). RESULTS: 37,232 RBCs units were transfused and out of which 14149 (38% i.e. is 14149/37232) were prestorage leukoreduced (PrSLR) and 23083 (62%) were non leukoreduced. A total of 142 (0.38%) TRs were reported during that time period, of which 62 (0.17%) were classified as FNHTRs. In the nonleukoreduced group 124 TRs were reported, of which 55 were classified as FNHTRs to RBCs and the overall rate of FNHTR to RBCs was 0.24%. In pre storage leukoreduced group, 18 TRs were reported, of which 7 were classified as FNHTRs to RBCs and the overall rate of FNHTR to RBCs was 0.05% (P <= 0.001). This represents a significant reduction in the rate of FNHTR after institution of prestorage leukoreduction. CONCLUSION: The rate of FNHTRs to allogenic RBC units after the implementation of prestorage leukoreduction has decreased significantly. Cytokines and chemokines accumulating during storage of cellular blood products are responsible for residual FNHTRs. PMID- 26097761 TI - Comparison of the Effects of Zonisamide, Ethosuximide and Pregabalin in the Chronic Constriction Injury Induced Neuropathic Pain in Rats. AB - BACKGROUND: Evidence has been generated that various anticonvulsant agents provide relief of several chronic pain syndromes and therefore as an alternative to opioids, nonsteroidal anti-inflammatory, and tricyclic antidepressant drugs in the treatment of neuropathic pain. The results of these studies thus raise the question of whether all anticonvulsant drugs or particular mechanistic classes may be efficacious in the treatment of neuropathic pain syndromes. AIM: The aim was to compare the clinically used anticonvulsant drugs which are differ in their mechanism of action in a chronic pain model, the chronic constriction injury, in order to determine if all anticonvulsants or only particular mechanistic classes of anticonvulsants are analgesic. MATERIALS AND METHODS: The study included zonisamide, ethosuximide and pregabalin. All compounds were anticonvulsant with diverse mechanism of actions. The peripheral neuropathic pain was induced by chronic constriction injury of the sciatic nerve in male Sprague-Dawley rats. Zonisamide (80 and 40 mg/kg), ethosuximide (300 and 100 mg/kg), pregabalin (50 and 20 mg/kg), and saline was administered intraperitoneally in respective groups in a blinded, randomized manner from postoperative day (POD) 7-13. Paw withdrawal duration to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency to mechanical allodynia and thermal hyperalgesia were tested before drug administration on POD7 and after administration on POD 7, 9, 11 and 13. RESULTS: The present study suggests that these drugs could provide an effective alternative in the treatment of neuropathic pain. However, zonisamide and pregabalin appears to have suitable efficacy to treat a wide spectrum of neuropathic pain condition. CONCLUSION: The present findings suggest that the inhibition of N-type calcium channels or voltage-gated sodium and T-type calcium channels provides better analgesic potential instead of inhibition of T-type calcium channels alone. PMID- 26097762 TI - Psychiatric Morbidity among Subjects with Leprosy and Albinism in South East Nigeria: A Comparative Study. AB - BACKGROUND: Skin, which is the largest organ in the body, carries immense psychological significance. Disfiguring skin disorders may impact negatively on the mental health of individuals. AIM: This study compared the psychiatric morbidity of subjects with leprosy and albinism. SUBJECTS AND METHODS: One hundred subjects with leprosy and 100 with albinism were interviewed. Sociodemographic questionnaire and General Health Questionnaire (GHQ-28) assessed the sociodemographic characteristics and psychiatric morbidity, respectively. GHQ positive cases and 10% of noncases for each group were interviewed with Mini International Neuropsychiatric Inventory for specific ICD-10 diagnoses. RESULTS: Fifty-five percent (55/100) subjects with leprosy were GHQ positive cases while 41% (41/100) with albinism were GHQ positive cases. The risk of developing psychiatric morbidity was significantly higher in subjects with leprosy than in subjects with albinism (OR = 1.76, CI = 1.00 - 3.08, P = 0.04). The prevalence of specific psychiatric disorders among subjects with leprosy were depression 49% (49/100), generalized anxiety disorder (GAD) 18% (18/100), alcohol/drug abuse 16% (16/100), whereas in albinism depression was 51% (51/100), GAD 27% (27/100), and alcohol/drug abuse 7% (7/100). Male, married and uneducated subjects with leprosy had significantly higher psychiatric morbidity than the male, married and uneducated subjects with albinism, respectively. CONCLUSION: Psychiatric morbidity was higher in subjects with leprosy than in subjects with albinism. Male, married and uneducated subjects with leprosy significantly had higher morbidity than male, married and uneducated subjects with albinism respectively. PMID- 26097763 TI - Oxidative Stress -a Phenotypic Hallmark of Fanconi Anemia and Down Syndrome: The Effect of Antioxidants. AB - BACKGROUND: Oxidative stress plays a major role in the pathogenesis of leukemia prone diseases such as Fanconi anemia (FA) and Down syndrome (DS). AIM: To explore the oxidative stress state in children with DS and FA by estimating the levels of antioxidants (e.g., malondialdehyde [MDA], total antioxidant capacity, and superoxide dismutase [SOD] activity) and DNA damage, and to evaluate of the effect of antioxidant treatment on these patients. SUBJECTS AND METHODS: The study included 32 children clinically diagnosed with (15 patients) and FA (17 patients) in addition to 17 controls matched for age and sex. MDA, total antioxidant capacity, SOD activity, and DNA damage were measured. Antioxidants including Vitamin A, E, and C were given to the patients according to the recommended daily allowance for 6 months. Clinical follow-up and re-evaluation were conducted for all patients. Laboratory tests including complete blood count, karyotyping, DNA damage, and oxidative stress were re-evaluated. Statistical analysis was performed using statistical computer program Statistical Package for the Social Sciences version 14.0. RESULTS: Children with FA and DS had elevated levels of oxidative stress and more DNA damage than controls. Oxidative stress parameters and DNA damage improved in FA and DS patients after antioxidant administration. CONCLUSION: Early administration of antioxidants to FA and DS patients is recommended for slowing of the disease course with symptoms amelioration and improvement of general health. PMID- 26097764 TI - Periodontal Condition and Treatment Needs of Some Pregnant Women in Ibadan, Nigeria. AB - BACKGROUND: Periodontal diseases had been reported to be worse in the presence of hormonal imbalance as seen during pregnancy, which if that is the case, should resolve following childbirth when the hormonal level of the women should have reverted to normal. SUBJECTS AND METHODS: Periodontal health of 345 pregnant women was assessed once during pregnancy and at 14(th) week following their childbirth. The clinical variant of community periodontal index of treatment needs probe was used in the assessment. RESULTS: During pregnancy, 167/345 (48.4%) of the women had deep pockets, 178/345 (51.6%) had shallow pockets. After childbirth, 5/345 (1.5%) had healthy periodontium, 25/345 (7.2%) had calculus and 7/345 (2.0%) had deep pockets. All of the respondents required oral hygiene instructions (OHI) and prophylaxis and 167/345 (48.4%) required complex treatment during pregnancy. After childbirth, 340/345 (98.5%) of the women required OHI and prophylaxis. Despite the great need for dental treatment among the respondents, majority never sought any treatment as 308/345 (89.3%) of the respondents had never visited a dentist before the study. CONCLUSION: The fact that the deep pocket reduced drastically following childbirth shows that it was not a true pocket. The high unmet treatment needs among the respondents require a concerted effort from dentists and policy makers in order to enlighten the women, especially those of child bearing age concerning the need for preventive dental visitation. PMID- 26097765 TI - Estimation of Stature from Arm Span in Medical Students of Maharashtra, India. AB - BACKGROUND: Stature can be estimated from body parameters in dead and mutilated bodies using regression equation or multiplication factor. However, regression equations and multiplication factors are specific for the region only and can't be used in all population. AIM: To formulate regression equation and multiplication factor for the estimation of stature from arm span (AS) for a region in Maharashtra, India. SUBJECTS AND METHODS: It was a cross-sectional study, did over a period of 2 years, from October 2011 to September 2013. Four hundred students of three Government medical colleges of Maharashtra, aged 18-24 years were enrolled in the study. Stature and AS were measured and subjected to statistical analysis. Unpaired t-test and simple linear regression were used. RESULTS: Stature and AS of 400 medical students (219 males and 181 females) were measured. Subjects were divided into six groups depending upon age. Simple regression equation and multiplication factor for male and female and for each age group were derived for estimation of stature. We found correlation coefficient (R) of 0.89 in male and 0.90 in female using simple regression, which shows strong correlation between stature and AS. CONCLUSION: Mean stature and AS of male were more than female with statistical significance. Stature can be accurately estimated from AS using simple regression equation or multiplication factor. PMID- 26097766 TI - Giant Mucinous Cystadenoma in Nnewi, Nigeria. AB - Mucinous ovarian tumors are the second commonest type of epithelial ovarian tumors. Most of these tumors are benign. Occasionally, these tumors may reach enormous dimensions without being symptomatic. We reported the occurrence of a huge benign ovarian tumor (mucinous cystadenoma) in Nnewi. The data were collected from history taking, clinical examination, laboratory investigation, ultrasonographic examination, operative findings and histopathological examination of the surgical specimen. The case was reported as a massive ovarian mucinous cystadenoma. This case report emphasizes the importance of a thorough evaluation of women who presented with vague abdominal pain. Although the condition is very rare, it is potentially hazardous if early diagnosis and timely intervention is not instituted. PMID- 26097767 TI - Staphylococcal Blood Stream Infections in Cancer Patients. PMID- 26097768 TI - Predictors of Urinary Tract Infections in Nursing Students in India. PMID- 26097769 TI - Biomarkers and genetics of brain injury risk in diabetic ketoacidosis: A pilot study. AB - Diabetic ketoacidosis (DKA) is the primary cause of death for children with diabetes, especially when complicated by cerebral edema. Central nervous system (CNS) involvement is common, however the mechanism of, and predictors of CNS dysfunction/injury are largely unknown. In this observational pilot study, blood was collected from pediatric DKA patients at three time points (consent, 12 hr and 24 hr after beginning treatment), to test genetic markers, ribonucleic acid expression and plasma biomarkers reflecting inflammation (tumor necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6]) and cerebral dysfunction and/or possible injury (S100beta, glial fibrillary acidic protein [GFAP]). Thirty patients were enrolled in the study. The average age was 11.3 yr, 73% were new onset diabetes and 53% were female. Forty percent exhibited abnormal mentation (Glasgow Coma Scale <15), consistent with CNS dysfunction. IL-6 and TNF-alpha were elevated in plasma, suggesting systemic inflammation. GFAP was measurable in 45% of patients and correlated positively with GCS. Only two patients had detectable levels of S100beta. In conclusion, children with DKA often present with evidence of acute neurologic dysfunction or injury. We have demonstrated the feasibility of exploring genetic and biochemical markers of potential importance in the pathophysiology of CNS dysfunction and/or possible injury in DKA. We have identified IL-6, TNF-alpha and GFAP as potentially important markers for further exploration. A larger, follow-up study will help to better understand the extent and type of CNS injury in DKA as well as the mechanism underlying this dysfunction/injury. PMID- 26097770 TI - Motion Planning under Uncertainty for Medical Needle Steering Using Optimization in Belief Space. AB - We present an optimization-based motion planner for medical steerable needles that explicitly considers motion and sensing uncertainty while guiding the needle to a target in 3D anatomy. Motion planning for needle steering is challenging because the needle is a nonholonomic and underactuated system, the needle's motion may be perturbed during insertion due to unmodeled needle/tissue interactions, and medical sensing modalities such as ultrasound imaging and x-ray projection imaging typically provide only noisy and partial state information. To account for these uncertainties, we introduce a motion planner that computes a trajectory and corresponding linear controller in the belief space - the space of distributions over the state space. We formulate the needle steering motion planning problem as a partially observable Markov decision process (POMDP) that approximates belief states as Gaussians. We then compute a locally optimal trajectory and corresponding controller that minimize in belief space a cost function that considers avoidance of obstacles, penalties for unsafe control inputs, and target acquisition accuracy. We apply the motion planner to simulated scenarios and show that local optimization in belief space enables us to compute higher quality plans compared to planning solely in the needle's state space. PMID- 26097772 TI - Methodological problems with population cancer studies: The forgotten confounding factors. AB - Among clinical physicians it is the population study that is considered to be the "gold standard" of medical evidence concerning acceptable treatments. As new information comes to light concerning the many variables and confounding factors that can affect such studies, many older studies lose much of their original impact. While newer population studies take into consideration a far greater number of confounding factors many are still omitted and a number of these omitted factors can have profound effects on interpretation and validity of the study. In this editorial, I will discuss some of the omitted confounding factors and demonstrate how they can alter the interpretation of these papers and their clinical application. PMID- 26097773 TI - A vertebral extra dural chordoma at C5, possibly deriving from a clival chordoma. AB - BACKGROUND: Clival chordomas are a rare type of cancer with low metastatic potential and primary metastasize to the lung or bones. CASE DESCRIPTION: This case report describes a possible metastatic, paravertebral chordoma at level C4 C5 in a patient with a past medical history of a clival chordoma. CONCLUSION: Chordomas are unpredictable and may metastasise. PMID- 26097771 TI - Cancer microenvironment, inflammation and cancer stem cells: A hypothesis for a paradigm change and new targets in cancer control. AB - Since President Nixon officially declared a war on cancer with the National Cancer Act, billions of dollars have been spent on research in hopes of finding a cure for cancer. Recent reviews have pointed out that over the ensuing 42 years, cancer death rates have barely changed for the major cancers. Recently, several researchers have questioned the prevailing cancer paradigm based on recent discoveries concerning the mechanism of carcinogenesis and the origins of cancer. Over the past decade we have learned a great deal concerning both of these central issues. Cell signaling has taken center stage, particularly as regards the links between chronic inflammation and cancer development. It is now evident that the common factor among a great number of carcinogenic agents is activation of genes controlling inflammation cell-signaling pathways and that these signals control all aspects of the cancer process. Of these pathways, the most important and common to all cancers is the NFkappaB and STAT3 pathways. The second discovery of critical importance is that mutated stem cells appear to be in charge of the cancer process. Most chemotherapy agents and radiotherapy kill daughter cells of the cancer stem cell, many of which are not tumorigenic themselves. Most cancer stem cells are completely resistant to conventional treatments, which explain dormancy and the poor cure rate with metastatic tumors. A growing number of studies are finding that several polyphenol extracts can kill cancer stem cells as well as daughter cells and can enhance the effectiveness and safety of conventional treatments. These new discoveries provide the clinician with a whole new set of targets for cancer control and cure. PMID- 26097775 TI - Scoring the Strengths and Weaknesses of Underage Drinking Laws in the United States. AB - Several studies have examined the impact of a number of minimum legal drinking age 21 (MLDA-21) laws on underage alcohol consumption and alcohol-related crashes in the United States. These studies have contributed to our understanding of how alcohol control laws affect drinking and driving among those who are under age 21. However, much of the extant literature examining underage drinking laws use a "Law/No law" coding which may obscure the variability inherent in each law. Previous literature has demonstrated that inclusion of law strengths may affect outcomes and overall data fit when compared to "Law/No law" coding. In an effort to assess the relative strength of states' underage drinking legislation, a coding system was developed in 2006 and applied to 16 MLDA-21 laws. The current article updates the previous endeavor and outlines a detailed strength coding mechanism for the current 20 MLDA-21 laws. PMID- 26097774 TI - Superficial temporal artery to proximal posterior cerebral artery bypass through the anterior temporal approach. AB - BACKGROUND: The superficial temporal artery (STA) to proximal posterior cerebral artery (PCA) (P2 segment) bypass is one of the most difficult procedures to perform because the proximal PCA is located deep and high within the ambient cistern. STA to proximal PCA bypass is usually performed through a subtemporal approach or posterior transpetrosal approach, and rarely through a transsylvian approach. The aim of this study was to describe the operative technique of STA to proximal PCA bypass through a modified transsylvian approach (anterior temporal approach). METHODS: STA to proximal PCA bypass was performed through an anterior temporal approach in three patients with intracranial aneurysm. We describe the details of the surgical technique. RESULTS: The STA was successfully anastomosed to the proximal PCA in all cases. One patient suffered hemiparesis and aphasia due to infarction in the anterior thalamoperforating artery territory. CONCLUSIONS: STA to proximal PCA bypass can be performed through an anterior temporal approach in selected patients. We recommend that every precaution, including complete hemostasis, placement of cellulose sponges beneath the recipient artery to elevate the site of the anastomosis, and placement of a continuous drainage tube at the bottom of the operative field to avoid blood contamination during the anastomosis, should be taken to shorten the temporary occlusion time. PMID- 26097777 TI - Sharing knowledge on dialysis registries worldwide. PMID- 26097776 TI - Renal Function Recovery and HIV Viral Suppression Following Tenofovir Discontinuation for Renal Impairment. AB - BACKGROUND: Tenofovir associated nephrotoxicity (TDFN) is well recognized. This study describes the trend of renal function recovery and virologic consequences after cessation of tenofovir (TDF) for suspected TDFN. METHODS: This was a retrospective chart review of 241 patients who underwent HLA-B*5701 allele testing between January 2007-December 2010. Demographics and clinical characteristics were compared at baseline, 3, 6, and 12 month between patients that continued and discontinued TDF. Factors associated with renal function recovery were assessed by multivariable logistic regression. RESULTS: Eighty patients were identified with TDFN; 84% male, 74% African American (AA) with a median age of 55 years, and median length of TDF use for 122 weeks. Renal recovery at 12 months differed in those who stopped versus (vs.) continued TDF (83% vs. 57% p=0.03). In a crude analysis, baseline chronic kidney disease was negatively associated with renal recovery (p=0.01). An adjusted analysis showed that those who stopped TDF had 3.76 higher odds of renal recovery compared to those who did not stop TDF (95% CI: 1.26-11.27, p=0.02). There were no significant differences in virologic response after switching TDF to an alternative agent. CONCLUSION: In this mostly AA male population with suspected TDFN, discontinuation of TDF was strongly associated with renal function recovery without affecting viral suppression. PMID- 26097778 TI - United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. AB - The United States Renal Data System (USRDS) began in 1989 through US Congressional authorization under National Institutes of Health competitive contracting. Its history includes five contract periods, two of 5 years, two of 7.5 years, and the fifth, awarded in February 2014, of 5 years. Over these 25 years, USRDS reporting transitioned from basic incidence and prevalence of end stage renal disease (ESRD), modalities, and overall survival, as well as focused special studies on dialysis, in the first two contract periods to a comprehensive assessment of aspects of care that affect morbidity and mortality in the second two periods. Beginning in 1999, the Minneapolis Medical Research Foundation investigative team transformed the USRDS into a total care reporting system including disease severity, hospitalizations, pediatric populations, prescription drug use, and chronic kidney disease and the transition to ESRD. Areas of focus included issues related to death rates in the first 4 months of treatment, sudden cardiac death, ischemic and valvular heart disease, congestive heart failure, atrial fibrillation, and infectious complications (particularly related to dialysis catheters) in hemodialysis and peritoneal dialysis patients; the burden of congestive heart failure and infectious complications in pediatric dialysis and transplant populations; and morbidity and access to care. The team documented a plateau and decline in incidence rates, a 28% decline in death rates since 2001, and changes under the 2011 Prospective Payment System with expanded bundled payments for each dialysis treatment. The team reported on Bayesian methods to calculate mortality ratios, which reduce the challenges of traditional methods, and introduced objectives under the Health People 2010 and 2020 national health care goals for kidney disease. PMID- 26097779 TI - Dialysis registries in the world: Korean Dialysis Registry. AB - The Korean Society of Nephrology (KSN) end-stage renal disease (ESRD) registry was established in 1985 in which all KSN members are participating voluntarily: the 'Insan Prof. Byung-Suk Min Memorial ESRD Patient Registry'. The ESRD registry committee of KSN has collected the data through the internet online program that was opened in 2001 and revised in 2013. The registry internet program has collected data throughout the years, which includes dialysis center information, vascular access, dialysis doses, and laboratory data with dialysis adequacy and rehabilitation status. In Korea, the number of dialysis patients has been rapidly growing (~8-9% per year) in recent years, especially elderly patients. The total number of patients with renal replacement therapy (RRT) was 75,042 at the end of 2013. The prevalence of RRT was 1446.4 patients per million population. The proportion of RRT for hemodialysis (HD) is 69.8%, for peritoneal dialysis (PD) is 10.0%, and for renal transplant is 20.2%. In about half (48%) of new dialysis patients, the underlying disease was diabetic nephropathy in 2013. Mean urea reduction ratio in HD was 68.1% in male patients and 74.2% in female patients. Survey on rehabilitation status of dialysis patients showed that 22% of HD patients have full-time job and 8% have part-time job. About 29% of PD patients have full-time job and 17% have part-time job. PMID- 26097780 TI - Fifty years of ERA-EDTA Registry-a registry in transition. AB - In 1964 the ERA-EDTA Registry was started as one of the first renal registries in the world. This meeting report describes how this European registry has developed over the 50 years of its existence. Where the first report presented patient numbers, nowadays the Registry acts as a platform for collaborative renal research in Europe. In addition, it provides training in epidemiology methods to nephrologists and other renal researchers. PMID- 26097781 TI - Japanese society for dialysis therapy renal data registry-a window through which we can view the details of Japanese dialysis population. AB - The Japanese Society for Dialysis Therapy (JSDT) collects the clinical data from all the facilities to create a nation-wide registry system named JSDT Renal Data Registry (JRDR). This survey was begun in 1966 as a form of facility survey. Patient survey started in 1983. More than 95% of facilities respond to the survey on the basis of voluntary work of facility staffs. Therefore, JRDR has the longest history and the most comprehensive coverage. As for the prevalent patients, 304,856 patients are treated by dialysis therapy in Japan as of the year 2011. The demographics of the Japanese dialysis population have been markedly changing in terms of age, primary diagnoses and dialysis vintage. The mean age of prevalent population reaches 66.55 years at the end of 2011. The increase in the numbers of dialysis population is due to the growth of those older than 65 years old. Patients with the vintage longer than 20 years account for 8% of the entire population. Around 38 thousands patients started their dialysis treatments, whereas 31 thousands deceased. The disease burden of cardiovascular diseases as well as infection is substantial due to the demographic changes. Many evidences have been reported from the data obtained from JRDR to date. These findings covers a wide range of dialysis practice and are utilized for the development of JSDT guidelines. Therefore, JRDR has provided indispensable and fundamental data of Japanese dialysis population. PMID- 26097782 TI - Thresholds of iron markers for iron deficiency erythropoiesis-finding of the Japanese nationwide dialysis registry. AB - Reportedly, serum ferritin levels are much lower in Japanese hemodialysis (HD) patients than their Western counterparts. Therefore, the cutoff values of ferritin and transferrin saturation (TSAT) for iron deficiency might differ from other countries. We conducted a cross-sectional observational study using the Japanese nationwide registry data. We enrolled 142,339 maintenance HD patients and assessed the association between these markers, hemoglobin (Hb), and erythropoiesis-stimulating agent (ESA) resistance index (ERI) utilizing restricted cubic spline analyses. Median ferritin and TSAT levels were 73 (IQR: 31-158) ng/ml and 23.7 (16.8-32.0)%, respectively. These lower ferritin ranges may possibly stem from a lower inflammatory state in Japanese patients, as shown in median CRP of 1.0 mg/l. An adjusted nonlinear association between Hb and TSAT showed that Hb levels drop with the decrease in TSAT below 20%, regardless of serum ferritin levels, suggesting the absolute iron deficiency cutoff as 20% for TSAT. In patients with TSAT >20%, the association between Hb and ferritin levels is nearly flat, whereas in patients with TSAT <20%, ferritin <50 ng/ml was associated with low Hb. In long-acting ESAs-users with TSAT >20%, U-shaped relationship was observed between ERI and ferritin with the bottom of ERI around 100 ng/ml of ferritin, possibly because high ferritin levels reflected an inflamed state leading to hyporesponsiveness to ESA. The patient subgroup with TSAT <20% and ferritin >100 ng/ml had significantly higher ERIs compared with the subgroup with TSAT >20% and ferritin <100 ng/ml, implying that TSAT, rather than ferritin, should be a primary iron marker predicting ESA response. PMID- 26097783 TI - Renal registry in Hong Kong-the first 20 years. AB - Renal Registry was started by the Hospital Authority (HA) in Hong Kong in 1995. It is an online system developed by HA. It collects all patients under care in HA, which is about 90-95 % of all requiring renal replacement therapy (RRT) in Hong Kong. The total number of patients treated increased from 3312 in 1996 to 8510 in 2013. In 2013, there were 3501 renal transplant, 1192 hemodialysis (HD) and 3817 peritoneal dialysis (PD) patients. In 2013, 1147 new patients joined the RRT program, 49.6% of them suffered from diabetic nephropathy. Glomerulonephritis and hypertension are the 2nd and 3rd most common causes of RRT in Hong Kong. The median age was 59.1 years with male to female ratio of 1.54 to 1. Hong Kong practices 'PD first' policy and the majority of the patients are on CAPD treatment. The ratio of PD to HD was 76.2% to 23.8%. Eighty-six percent of all PD patients are on CAPD; the remaining 14% are on automated peritoneal dialysis (APD). Sixty-five percent of all dialysis patients are on erythropoiesis stimulating agent treatment. The Hong Kong Renal Registry with online real-time data input and access can provide timely data and information to facilitate patient care and management and also provides invaluable data to help in development and planning of renal services in Hong Kong. PMID- 26097784 TI - Australia and New Zealand Dialysis and Transplant Registry. AB - The ANZDATA Registry includes all patients treated with renal replacement therapy (RRT) throughout Australia and New Zealand. Funding is predominantly from government sources, together with the non-government organization Kidney Health Australia. Registry operations are overseen by an Executive committee, and a Steering Committee with wide representation. Data is collected from renal units throughout Australia and New Zealand on a regular basis, and forwarded to the Registry. Areas covered include demographic details, primary renal disease, type of renal replacement therapy, process measures, and a variety of outcomes. From this data collection a number of themes of work are produced. These include production of Registry reports with an extensive range of national and regional data, a suite of quality assurance reports, key process indicator (KPI) reports, and data sets for a variety of audit and research purposes. The various types of information from the ANZDATA Registry are used in a wide variety of areas, including health services planning, safety and quality programs, and clinical research projects. PMID- 26097785 TI - Nonstationary Gaussian Process Regression for Evaluating Clinical Laboratory Test Sampling Strategies. AB - Sampling repeated clinical laboratory tests with appropriate timing is challenging because the latent physiologic function being sampled is in general nonstationary. When ordering repeated tests, clinicians adopt various simple strategies that may or may not be well suited to the behavior of the function. Previous research on this topic has been primarily focused on cost-driven assessments of oversampling. But for monitoring physiologic state or for retrospective analysis, undersampling can be much more problematic than oversampling. In this paper we analyze hundreds of observation sequences of four different clinical laboratory tests to provide principled, data-driven estimates of undersampling and oversampling, and to assess whether the sampling adapts to changing volatility of the latent function. To do this, we developed a new method for fitting a Gaussian process to samples of a nonstationary latent function. Our method includes an explicit estimate of the latent function's volatility over time, which is deterministically related to its nonstationarity. We find on average that the degree of undersampling is up to an order of magnitude greater than oversampling, and that only a small minority are sampled with an adaptive strategy. PMID- 26097786 TI - Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls. AB - This study evaluated dolutegravir pharmacokinetics (PK) in subjects with moderate hepatic impairment compared to matched, healthy controls. In this open-label, parallel-group study, eight adult subjects with moderate hepatic impairment (Child-Pugh Score 7-9) and eight healthy subjects matched for gender, age, and body mass index received a single dolutegravir 50-mg dose. Following dosing, 72 hour PK sampling was performed to determine total and unbound dolutegravir concentrations. PK parameters were calculated using non-compartmental analysis. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) in subjects with hepatic impairment versus healthy subjects were generated by analysis of variance. Results showed that PK parameters of total plasma dolutegravir were similar between subject groups. The unbound fraction was higher in subjects with moderate hepatic impairment than in healthy subjects with GMR (90% CI) of 2.20 (1.62, 2.99) for unbound fraction at 3 hours post-dose and 1.76 (1.23, 2.51) for unbound fraction at 24 hours post-dose; this correlated with lower serum albumin concentrations and was not considered clinically significant. Dolutegravir was well tolerated in both groups; all adverse events were reported as minor. Although free fraction was increased, no dose adjustment is required for patients treated with dolutegravir who have mild to moderate hepatic impairment. PMID- 26097787 TI - Pharmacokinetics of Eicosapentaenoic Acid in Plasma and Red Blood Cells After Multiple Oral Dosing With Icosapent Ethyl in Healthy Subjects. AB - OBJECTIVE: Icosapent ethyl (IPE) is a prescription form of eicosapentaenoic acid (EPA) ethyl ester. This randomized, open-label study characterized EPA pharmacokinetics. METHODS: Four healthy subject groups received IPE for 28 days: three received 2 g/day (1 * 1,000 mg BID, 2 * 1,000 mg QD, or 2 * 500 mg BID); one received 4 g/day (2 * 1,000 mg BID) administered with meals. Blood sampling was before the morning dose on days 1, 14, 26, 28, and at specified intervals during an 18-day pharmacokinetic period. EPA was measured in plasma (total and unesterified) and red blood cells (RBCs) by liquid chromatography/tandem mass spectrometry. RESULTS: Mean plasma total EPA increased from 19 ug/mL to a peak (Cmax) of 366 ug/mL at 5 hours postdosing 4 g/day IPE on Day 28. Mean RBC EPA Cmax after 4 g/day was 89 ug/mL (baseline, 12 ug/mL). Mean steady state (SD) for half-life, clearance, and volume of distribution of total EPA were 79 (47) hours, 757 (283) mL/h, and 82 (56) L, respectively. Steady state for total and unesterified plasma EPA was reached by Day 28, whereas RBC levels were still increasing. CONCLUSIONS: EPA pharmacokinetic profile demonstrated a slowly cleared, extensively distributed molecule with dose linearity and comparable exposures with BID and QD regimens. PMID- 26097788 TI - Analgesic and Decongestant Efficacy of the Combination of Aspirin with Pseudoephedrine in Patients With Symptoms of Upper Respiratory Tract Infection. AB - The study investigated the efficacy and safety of a combination therapy of 1,000 mg aspirin (ASA) and 60 mg pseudoephedrine (PSE) on the symptoms of pain (combined score for headache and sore throat) and nasal congestion in 833 patients with acute upper respiratory tract viral infection (URTI), over 4 hours after a single dose in the clinic and over 3 days with multiple doses at home. The study demonstrated that over 4 hours in the clinic the combination ASA plus PSE was superior to PSE or placebo for relief of pain symptoms measured subjectively with pain scores, and was superior to ASA or placebo for relief of nasal congestion as measured objectively with rhinomanometry and subjectively with congestion scores. After 3 days of treatment, ASA plus PSE was superior to PSE but not to placebo or ASA for global pain assessments, and ASA plus PSE was superior to ASA and placebo but not to PSE for congestion assessments. No unexpected adverse events occurred and no serious adverse events were attributed to study medicines. This study demonstrates that a combination therapy of ASA plus PSE provides safe and effective relief of both common cold pain related symptoms and nasal congestion. PMID- 26097789 TI - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting beta-Agonist, in Children Aged 5-11 Years with Persistent Asthma: A Randomized Trial. AB - This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once-daily repeat doses of vilanterol 25 ug in children aged 5-11 years. Twenty-eight children with persistent asthma received a single inhaled dose of vilanterol 25 ug or placebo via the ELLIPTATM dry powder inhaler (DPI) on Day 1, followed 7 days later by once-daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 ug and 6 (23%) with placebo. No serious or drug-related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 ug versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 ug were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericia's correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 ug compared with placebo treatment. Vilanterol was well tolerated and no long-acting beta2-agonist (LABA)-mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 ug suggests exposure is similar regardless of age or gender in a pediatric population aged 5-11 years. PMID- 26097790 TI - The pharmacokinetic effect of coadministration of apremilast and methotrexate in individuals with rheumatoid arthritis and psoriatic arthritis. AB - Apremilast is a novel agent for the treatment of inflammatory based autoimmune disorders. The objective of this study was to assess the pharmacokinetic effects of co administration of apremilast and methotrexate on both agents. This was an open-label, multi-center, 3-treatment period, sequential study conducted in otherwise healthy subjects with psoriatic arthritis or rheumatoid arthritis who were receiving a stable oral dose of methotrexate between 7.5 to 20 mg once weekly. Subjects received their dose of methotrexate on Days 1 and 8 of the study in addition to Apremilast 30 mg oral every 12 hours on Days 3-8. Pharmacokinectic profiles of methotrexate and 7-OH methotrexate were characterized after methotrexate alone (Day 1) and after co-administration of methotrexate and Apremilast (on Day 8). The pharmacokinetic profile of Apremilast was characterized after Apremilast alone (on Day 7) and after co-administration of methotrexate and Apremilast (on Day 8). The 90% confidence interval of the ratio of the geometric means for the Cmax and AUC parameters for methotrexate, 7-OH methotrexate, and Apremilast alone and after co-adminstration are all within the FDA acceptance range for equivalency (80-125%). This study showed that methotrexate and apremilast can be co-administered without any effect on the pharmacokinetic exposure of either agent. PMID- 26097791 TI - Absence of QTc Prolongation with Domperidone: A Randomized, Double-Blind, Placebo and Positive-Controlled Thorough QT/QTc Study in Healthy Volunteers. AB - Domperidone effects on QTc duration were assessed in a single-center, double blind, four-way crossover study of 44 healthy participants randomized to one of four treatment sequences consisting of four treatment periods separated by 4-9 days washout. On Day 1 of each 4-day period, participants began oral domperidone 10 or 20 mg q.i.d., matching placebo q.i.d., or single-dose moxifloxacin 400 mg (positive control)/placebo q.i.d. In each period, triplicate 12-lead electrocardiograms were recorded at baseline (30, 20, and 10 minutes predose), 8 timepoints after dosing on Days 1 and 4, and predose on Day 4. In mixed effects models, the largest difference for domperidone in least squares means for change from baseline QTcP versus placebo was 3.4 milliseconds (20 mg q.i.d., Day 4), 90% CI: 1.0-5.9, and <10 milliseconds at all timepoints for both domperidone dosages. Moxifloxacin response confirmed assay sensitivity. Participants achieved expected domperidone plasma exposures. No significant exposure-response relationship was found for QTc increase per ng/mL domperidone (90% CI of the slope estimate included zero at mean Cmax on Day 1 or Day 4). In summary, domperidone at doses up to 80 mg/day did not cause clinically relevant QTc interval prolongation. PMID- 26097792 TI - The Effect of Food and Formulation on the Pharmacokinetics, Safety, and Tolerability of GSK1322322 in Healthy Volunteers. AB - GSK1322322 is the first in a new class of antibiotics that inhibit peptide deformylase, necessary for bacterial protein maturation. Previously, low absolute bioavailability was observed for the 1500-mg oral tablet formulation, resulting in a less than dose-proportional increase from the 1000-mg dose. Furthermore, high variability of pharmacokinetic (PK) parameters within cohorts was suggested to be associated with differences in body weight. This open-label, randomized, 4 period, crossover, single-dose phase I study in healthy individuals compared the PK, safety, and tolerability of free base oral tablets under fasted or fed conditions with intravenous and oral mesylate salt solution of GSK1322322 under fasted conditions. Absolute bioavailability of GSK1322322 1500-mg free base tablets under fasted conditions, fed conditions, and oral mesylate salt solution was 57%, 77%, and 92%, respectively. Moderate-fat/calorie food intake increased area under the concentration-time curve (AUC0-infinity) by 36%, maintained maximum observed concentration (Cmax), and delayed time to Cmax. It appeared that AUC0-infinity decreased with body weight, whereas clearance increased. GSK1322322 administration resulted in only mild-to-moderate adverse events. These results support future clinical investigations of the free base oral tablet formulation of GSK1322322 1500 mg after intake of a moderate-fat/calorie meal, including further investigation of a potential weight-based dosage change. PMID- 26097793 TI - Intravenous Pharmacokinetics, Local Tolerability, and Hemolysis of an SBE7-beta Cyclodextrin Formulation of the Neurokinin-1 Receptor Antagonist Vestipitant. AB - Vestipitant is a potent and selective neurokinin 1 (NK-1) receptor antagonist that was investigated as a potential treatment for post-operative nausea and vomiting (PONV). A previous mannitol-based formulation of vestipitant was associated with hemolytic activity in preclinical studies. In an effort to reduce the hemolytic potential and develop an IV formulation of vestipitant that could be administered more rapidly, an IV formulation containing sulfobutylether-7-beta cyclodextrin (SBE7-beta-CD, CaptisolTM) was developed and tested in a phase 1 clinical study. This was a randomized, single-blind (subjects and investigator blinded, sponsor-unblinded), placebo controlled, dose escalation study in healthy subjects in which 7 cohorts of 8 subjects per cohort received SBE7-beta-CD -based vestipitant (2 mg/mL) or placebo (saline) in a 3:1 ratio (active:placebo) at different doses and infusion rates. The results demonstrated the ability to infuse up to 48 mg vestipitant in a 2 mg/mL formulation over 30 seconds with no evidence of hemolytic effects. Cohorts of subjects at lower doses and longer infusion duration (>1 minute) reported more AEs related to the infusion site than those at the higher doses and faster infusion rates. PMID- 26097794 TI - Effects of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) on Pharmacokinetic Parameters of Rosiglitazone in Healthy Subjects. AB - BACKGROUND: Icosapent ethyl is a high-purity form of eicosapentaenoic acid ethyl ester approved to reduce triglyceride levels in adults with triglycerides >=500 mg/dL. Candidates for triglyceride-lowering therapy include patients with diabetes mellitus who may be receiving rosiglitazone. We assessed the effects of icosapent ethyl on the pharmacokinetic parameters of rosiglitazone. METHODS: Subjects received a single 8-mg oral dose of rosiglitazone alone and with oral icosapent ethyl 4 g/day in this open-label drug-drug interaction study. Pharmacokinetic end points included area under the concentration versus time curve from time zero to infinity (AUC0-inf) and maximum observed concentration (Cmax) for rosiglitazone with and without icosapent ethyl. RESULTS: Of 30 subjects enrolled, 28 completed the study. Icosapent ethyl 4 g/day at steady state did not significantly change the single-dose AUC0-inf or Cmax of rosiglitazone 8 mg. Least squares geometric mean ratios (90% confidence interval) for AUC0-inf and Cmax of rosiglitazone given with icosapent ethyl versus rosiglitazone alone were 0.90 (87.00-93.40) and 1.01 (92.02-109.9), respectively. No serious adverse events were reported and no subject discontinued due to an adverse event. CONCLUSIONS: At steady-state concentrations, icosapent ethyl did not inhibit the pharmacokinetics of rosiglitazone. Co-administration of icosapent ethyl and rosiglitazone was safe and well tolerated. PMID- 26097795 TI - Effects of Ketoconazole on the Pharmacokinetics of Lenvatinib (E7080) in Healthy Participants. AB - BACKGROUND: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein. METHODS: In this Phase I, single-center, randomized, open label, two-period, crossover study, healthy adults (18-55 years; N = 18) were randomized to one of two sequences (ketoconazole -> placebo or vice versa). Ketoconazole (400 mg) or placebo was administered orally once daily for 18 days; a 5 mg dose of lenvatinib was orally administered on Day 5 of each treatment period. Blood samples were collected over 14 days and lenvatinib plasma concentrations measured by high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Systemic exposure to lenvatinib increased slightly (15 19%) with coadministration of ketoconazole. Although the 90% confidence interval (CI) for area under the plasma concentration-time curve (AUC) was within the prespecified bioequivalence interval of 80-125%, Cmax slightly exceeded the 125% CI bound (134%). No changes in tmax, tlag, or t1/2 were observed. Thirteen subjects (72%) experienced treatment-emergent adverse events (11 mild, 2 moderate), most commonly headache (22%) and diarrhea (17%). CONCLUSIONS: Lenvatinib exposure was slightly increased by ketoconazole; however, the magnitude of the change was relatively small, and likely not clinically meaningful. PMID- 26097797 TI - The prognostic impact of specific CD4 T-cell responses is critically dependent on the target antigen in melanoma. AB - The melanoma-associated antigens Melan-A and NY-ESO-1 stimulate different T-cell responses in late-stage melanoma patients. Either CD4+ or CD8+ T-cell reactivity against NY-ESO-1 was associated with better prognosis, but for Melan-A, only CD8+ but not CD4+ T-cell responses were associated with longer survival. PMID- 26097796 TI - Metformin- A Promising Agent for Chemoprevention in BRCA1 Carriers. PMID- 26097798 TI - Review of Abby Kinchy's "Seeds, science and struggle: the global politics of transgenic crops": Cambridge, MA: MIT Press, 2012. PMID- 26097799 TI - Microlearning mApp raises health competence: hybrid service design. AB - Work place health support interventions can help support our aging work force, with mApps offering cost-effectiveness opportunities. Previous research shows that health support apps should offer users enough newness and relevance each time they are used. Otherwise the 'eHealth law of attrition' applies: 90 % of users are lost prematurely. Our research study builds on this prior research with further investigation on whether a mobile health quiz provides added value for users within a hybrid service mix and whether it promotes long term health? We developed a hybrid health support intervention solution that uses a mix of electronic and physical support services for improving health behaviours, including a mobile micro-learning health quiz. This solution was evaluated in a multiple-case study at three work sites with 86 users. We find that both our mobile health quiz and the overall hybrid solution contributed to improvements in health readiness, -behaviour and -competence. Users indicated that the micro learning health quiz courses provided new and relevant information. Relatively high utilization rates of the health quiz were observed. Participants indicated that health insights were given that directly influenced every day health perceptions, -choices, coping and goal achievement strategies, plus motivation and self-norms. This points to increased user health self-management competence. Moreover, even after 10 months they indicated to still have improved health awareness, -motivation and -behaviours (food, physical activity, mental recuperation). A design analysis was conducted regarding service mix efficacy; the mobile micro-learning health quiz helped fulfil a set of key requirements that exist for designing ICT-enabled lifestyle interventions, largely in the way it was anticipated. PMID- 26097800 TI - Assumption Trade-Offs When Choosing Identification Strategies for Pre-Post Treatment Effect Estimation: An Illustration of a Community-Based Intervention in Madagascar. AB - Failure (or success) in finding a statistically significant effect of a large scale intervention may be due to choices made in the evaluation. To highlight the potential limitations and pitfalls of some common identification strategies used for estimating causal effects of community-level interventions, we apply a roadmap for causal inference to a pre-post evaluation of a national nutrition program in Madagascar. Selection into the program was non-random and strongly associated with the pre-treatment (lagged) outcome. Using structural causal models (SCM), directed acyclic graphs (DAGs) and simulated data, we illustrate that an estimand with the outcome defined as the post-treatment outcome controls for confounding by the lagged outcome but not by possible unmeasured confounders. Two separate differencing estimands (of the pre- and post-treatment outcome) have the potential to adjust for a certain type of unmeasured confounding, but introduce bias if the additional identification assumptions they rely on are not met. In order to illustrate the practical impact of choice between three common identification strategies and their corresponding estimands, we used observational data from the community nutrition program in Madagascar to estimate each of these three estimands. Specifically, we estimated the average treatment effect of the program on the community mean nutritional status of children 5 years and under and found that the estimate based on the post-treatment estimand was about a quarter of the magnitude of either of the differencing estimands (0.066 SD vs. 0.26-0.27 SD increase in mean weight-for-age z-score). Choice of estimand clearly has important implications for the interpretation of the success of the program to improve nutritional status of young children. A careful appraisal of the assumptions underlying the causal model is imperative before committing to a statistical model and progressing to estimation. However, knowledge about the data-generating process must be sufficient in order to choose the identification strategy that gets us closest to the truth. PMID- 26097801 TI - Clinical criteria to screen for inpatient diagnostic errors: a scoping review. AB - Diagnostic errors are common and costly, but difficult to detect. "Trigger" tools have promise to facilitate detection, but have not been applied specifically for inpatient diagnostic error. We performed a scoping review to collate all individual "trigger" criteria that have been developed or validated that may indicate that an inpatient diagnostic error has occurred. We searched three databases and screened 8568 titles and abstracts to ultimately include 33 articles. We also developed a conceptual framework of diagnostic error outcomes using real clinical scenarios, and used it to categorize the extracted criteria. Of the multiple criteria we found related to inpatient diagnostic error and amenable to automated detection, the most common were death, transfer to a higher level of care, arrest or "code", and prolonged length of hospital stay. Several others, such as abrupt stoppage of multiple medications or change in procedure, may also be useful. Validation for general adverse event detection was done in 15 studies, but only one performed validation for diagnostic error specifically. Automated detection was used in only two studies. These criteria may be useful for developing diagnostic error detection tools. PMID- 26097802 TI - Hypothermic Oxygenated Liver Perfusion: Basic Mechanisms and Clinical Application. AB - Dynamic preservation strategies such as hypothermic machine perfusion are increasingly discussed to improve liver graft quality before transplantation. This review summarizes current knowledge of this perfusion technique for liver preservation. We discuss optimization of perfusion conditions and current strategies to assess graft quality during cold perfusion. Next, we provide an overview of possible pathways of protection from ischemia-reperfusion injury. Finally, we report on recent clinical applications of human hypothermic machine liver perfusion. PMID- 26097803 TI - Raxibacumab augments hemodynamic support and improves outcomes during shock with B. anthracis edema toxin alone or together with lethal toxin in canines. AB - BACKGROUND: Lethal and edema toxin contribute to shock and lethality with Bacillus anthracis. We showed previously in a 96-h sedated canine model that raxibacumab, a monoclonal antibody against protective antigen, augmented hemodynamic support (HS) and improved survival with lethal toxin challenge. Here we study raxibacumab further. Using this model, we have now studied raxibacumab with 24 h edema toxin challenges (Study 1), and lethal and edema toxin challenges together (Study 2). METHODS: Using our canine model, we have now studied raxibacumab with 24h edema toxin challenges (Study-1), and lethal and edema toxin challenges together (Study-2). RESULTS: In Study 1, compared to no treatment, HS (titrated fluid and norepinephrine) increased mean arterial blood pressure (MAP, p <= 0.05) but not survival [0 of 10 (0/10) animals survived in each group] or median survival time [43.8 h (range 16.8 to 80.3) vs. 45.2 h (21.0 to 57.1)]. Compared to HS, HS with raxibacumab treatment at or 6 h after the beginning of edema toxin increased MAP and survival rate (6/7 and 7/8, respectively) and time [96.0 h (39.5 to 96.0) and 96.0 h (89.5 to 96.0), respectively]; (p <= 0.05). HS with raxibacumab at 12 h increased MAP (p <= 0.05) but not survival [1/5; 55.3 h (12.6 to 96.0)]. In Study-2, survival rate and time increased with HS and raxibacumab at 0 h (4/4) or 6 h after (3/3) beginning lethal and edema toxin compared to HS [0/5; 71.5 h (65 to 93)] (p = 0.01 averaged over raxibacumab groups). CONCLUSIONS: Raxibacumab augments HS and improves survival during shock with lethal and edema toxin. PMID- 26097804 TI - An Overview of Ultraviolet B Radiation-Induced Skin Cancer Chemoprevention by Silibinin. AB - Skin cancer incidences are rising worldwide, and one of the major causative factors is excessive exposure to solar ultraviolet radiation (UVR). Annually, ~5 million skin cancer patients are treated in United States, mostly with nonmelanoma skin cancer (NMSC), which is also frequent in other Western countries. As sunscreens do not provide adequate protection against deleterious effects of UVR, additional and alternative chemoprevention strategies are urgently needed to reduce skin cancer burden. Over the last couple of decades, extensive research has been conducted to understand the molecular basis of skin carcinogenesis, and to identifying novel agents which could be useful in the chemoprevention of skin cancer. In this regard, several natural non-toxic compounds have shown promising efficacy in preventing skin carcinogenesis at initiation, promotion and progression stages, and are considered important in better management of skin cancer. Consistent with this, we and others have studied and established the notable efficacy of natural flavonolignan silibinin against UVB-induced skin carcinogenesis. Extensive pre-clinical animal and cell culture studies report strong anti-inflammatory, anti-oxidant, DNA damage repair, immune-modulatory and anti-proliferative properties of silibinin. Molecular studies have identified that silibinin targets pleotropic signaling pathways including mitogenic, cell cycle, apoptosis, autophagy, p53, NF-kappaB, etc. Overall, the skin cancer chemopreventive potential of silibinin is well supported by comprehensive mechanistic studies, suggesting its greater use against UV induced cellular damages and photocarcinogenesis. PMID- 26097805 TI - Gender susceptibility to mycobacterial infections in patients with non-CF bronchiectasis. AB - Non-tuberculous mycobacteria (NTM) are environmental microbes that cause a variety of diseases both in immunocompromised and immunocompetent patients. Epidemiologic data indicate that there has been a global rise in the incidence of NTM infections. It has also been noted that NTM infections have a predilection to occur in postmenopausal women. In a recent study, it was demonstrated that in patients with non-CF bronchiectasis the probability of NTM isolation was significantly higher in elderly female patients and in those with a low body mass index. However, the mechanisms of causality of these gender differences and morpho-phenotypes remain enigmatic. The present study reviews the data and plausible mechanisms which might provide clues to this gender susceptibility and morpho-phenotypes of patients with bronchiectasis and NTM. PMID- 26097806 TI - RNA-Seq analysis and whole genome DNA-binding profile of the Vibrio cholerae histone-like nucleoid structuring protein (H-NS). AB - The data described in this article pertain to the genome-wide transcription profiling of a Vibrio cholerae mutant lacking the histone-like nucleoid structuring protein (H-NS) and the mapping of the H-NS chromosome binding sites [1, 2]. H-NS is a nucleoid-associated protein with two interrelated functions: organization of the bacterial nucleoid and transcriptional silencing [3]. Both functions require DNA binding and protein oligomerization [4, 5]. H-NS commonly silences the expression of virulence factors acquired by lateral gene transfer [6]. The highly pleiotropic nature of hns mutants in V. cholerae indicates that H NS impacts a broad range of cellular processes such as virulence, stress response, surface attachment, biofilm development, motility and chemotaxis. We used a V. cholerae strain harboring a deletion of hns and a strain expressing H NS tagged at the C-terminus with the FLAG epitope to generate datasets representing the hns transcriptome and DNA binding profile under laboratory conditions (LB medium, 37 degrees C). The datasets are publicly available at the Gene Expression Omnibus (GEO) repository (http://www.ncbi.nlm.nih.gov/geo/) with accession numbers GSE62785 and GSE64249. PMID- 26097807 TI - A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading. AB - Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm*30.5 cm*40.6 cm30.5 cm*30.5 cm*40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their dosimetry properties, this method may find great utility in the implementation of future ground-based studies that examine the combined spaceflight challenges of reduced loading and radiation while using the HLU rodent model. PMID- 26097809 TI - Maternal - Child Health Needs Assessment in Haiti. AB - Maternal and neonatal mortality in Haiti are among the highest in the world. This study investigated maternal-child health needs in Haiti, using a mixed method approach including qualitative and quantitative data collection. Participants (n=119) comprised of 39 healthcare workers and 80 Haitian women. The focus group centered around three major themes: difficult access to healthcare; health issues affecting mothers-child; and healthcare workers training. The interviews revealed that 60% of the deliveries happened at home, 52.5% of them were assisted by a lay birth attendant, 42% of the women gave their newborn a drink other than breast milk within the first week of birth, 70% of the women had not been, or did not know, if they had been tested for HIV, 92% did not use condoms during sexual encounters, and 47.5% justified violence against themselves from their partner. Considering the dearth of research concerning maternal-child health in Haiti that incorporates the opinions of healthcare workers and Haitian women, identifying their needs is essential to developing programs, such as the following that contribute to improving their health: nurse-midwife programs, training for lay birth attendants, obstetric-pediatric training, breastfeeding training, and programs to prevent intimate partner violence and HIV. PMID- 26097808 TI - Heterochromatin, histone modifications, and nuclear architecture in disease vectors. AB - Interactions between a pathogen and a vector are plastic and dynamic. Such interactions can be more rapidly accommodated by epigenetic changes than by genetic mutations. Gene expression can be affected by the proximity to the heterochromatin, by local histone modifications, and by the three-dimensional position within the nucleus. Recent studies of disease vectors indicate that gene regulation by these factors can be important for susceptibility to pathogens, reproduction, immunity, development, and longevity. Knowledge about heterochromatin, histone modifications, and nuclear architecture will help our understanding of epigenetic mechanisms that control gene function at traits related to vectorial capacity. PMID- 26097810 TI - Aging: Molecular insight. PMID- 26097811 TI - Real world data: Additional source for making clinical decisions. PMID- 26097812 TI - The association between abdominal obesity and serum cholesterol level. AB - BACKGROUND: The main aim of this study is to evaluate the association between serum cholesterol level and abdominal obesity in adult men and women in the north of Iran. MATERIALS AND METHODS: This cross-sectional and analytical study was conducted on the 1956 subjects (990 men and 966 women) between 25 and 65 years old chosen by cluster sampling. Plasma cholesterol was measured in the morning after a 12 h fast and determined by auto-analyzer. Hypercholesterolemia (HC) was defined by a total plasma cholesterol level over 200 mg/dl. Waist circumference >=102 cm and >=88 cm in men and women were defined as abdominal obesity. SPSS 16.0 software was used for statistical analysis and P < 0.05 considered as statistical significance. RESULTS: Averagely, the mean of age was 44.2 years and mean +/- standard deviation of plasma total cholesterol level was 203 +/- 11.3 mg/dl. The HC was seen in 50.8% of subjects with a more common in women than in men. Compared with normal subjects, in abdominal obese people, the odds ratio (OR) of HC was (OR = 4.208 [95% confidence interval [CI]: 1.939-9.130]) and (OR = 3.956 [95% CI: 1.821-8.592]) in men aged 25-35 and 35-45 years, respectively. In women aged 25-35 years, it was (OR = 3.444 [95% CI: 1.959-6.056]) in abdominal obese compared with normal subjects. CONCLUSION: Hypercholesterolemia was revealed as a major health problem among adults, and it was associated with abdominal obesity especially in the early middle-age in the north of Iran. This association was not significant in men and women after the age of 45 and 35, respectively. PMID- 26097813 TI - A prescription event monitoring study on the utility of garenoxacin, a newer fluoroquinolone in India. AB - BACKGROUND: Prescription event monitoring (PEM) study is conducted worldwide. The main objective of such study is to monitor the adverse events when a drug is being prescribed in "real life clinical" settings. PEM studies are being looked upon as an essential observational tool of postmarketing surveillance. Garenoxacin, a newer fluoroquinolone offers an excellent spectrum of antimicrobial coverage, which includes Gram-positive, Gram-negative, anaerobes and atypical microorganism. This broad spectrum of activity is attributed to its unique structure. AIM: The aim was to assess the safety profile of garenoxacin in Indian settings. MATERIALS AND METHODS: A total of 400 doctors across the country participated in the study. Data from 12,498 patients was obtained. Monitoring of each patient was done for any adverse events. RESULTS: As an initial line of therapy garenoxacin was preferred in majority of cases of community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis. Adverse events were reported in 159 patients which included 0.5% cases with nausea/vomiting, 0.1% cases with diarrhea. Central nervous system side-effects like drowsiness or dizziness was reported in 0.02% of the cases. All the adverse events were of mild to moderate severity and did not require hospitalization. CONCLUSION: Garenoxacin a novel desfluoroquinolone appears to be an ideal antimicrobial agent for the treatment of various respiratory tract infections including CAP. With superior safety profile, excellent antimicrobial coverage and a convenient once a day dosing garenoxacin appears to improve the patient compliance. PMID- 26097814 TI - Which score should be used in intubated patients' Glasgow coma scale or full outline of unresponsiveness? AB - BACKGROUND AND AIMS: Today Glasgow coma scale (GCS) is the most well-known and common score for evaluation of the level of consciousness and outcome predict after traumatic brain injuries in the world. Regarding to some advantages of the full outline of unresponsiveness (FOUR) score over GCS in intubated patients, we're going to compare the precision of these two scores in predicting the outcome predict in intubated patients. METHODS: This research was a diagnostic based study, which was conducted prospectively on 80 patients with Traumatic brain injury who were intubated and admitted to Intensive Care Unit (ICU) of Educational Hospitals of Mazandaran University of Medical Science during February 2013 to August 2013. The scores of FOUR and GCS were measured by the researcher in the first 24 h of admission in ICU. The information's recorded in the check list including the mortality rate of early and late inside of the hospital interred to excel. The findings were analyzed using SPSS software, through descriptive statistics and regression logistic. RESULTS: The results showed of 80 patients 21 patients (20%) were female and 59 patients (80%) were male. The age average of the samples was 33.80 +/- 12.60 ranging from 16 to 60 years old. 21 patients (26.2%) died during treatment. Of 21 patients, 15 patients died during first 14 days (18.7%) and 6 patients died after 14 years (7.5%). The area under curve (AUC) of FOUR score in early mortality was 0.90 (C1 = 0.95, 0.88-0.90). The amount AUC for GCS was 0.80 (C1 = 0.95, 0.78-0.84), which in delayed mortality it was ordered as 0.86 (C1 = 0.95, 0.84-0.90) and 0.89 (C1 = 0.95, 0.78-0.88). CONCLUSION: The research results indicated that FOUR score is more exact and more practical in intubated patients regarding lack of verbal response factor in early mortality prediction in GCS. Hence, it is recommended for health professionals to use the FOUR score to predict the early outcome of intubated patients with traumatic brain injuries. PMID- 26097815 TI - Volumetric and cost evaluation study of glaucoma medical therapy. AB - AIM: The aim of the study was to evaluate the difference in mentioned volume and measured volume of the eye drops and to find out the yearly cost of various antiglaucoma drugs. METHODS: It was an experimental and purely laboratory study. Total of 245 bottles of 49 different brands, five of each brand of antiglaucoma drug were analyzed. Number of drops were counted, and volume was measured from each bottle. On the basis of data collected yearly cost of each brand was calculated. RESULTS: Of the 245 bottles, 152 bottles (62.04%) had underfilling. Yearly cost of most of the antiglaucoma drugs lies between Rs. 423.40 and Rs. 6263.40. CONCLUSION: Measured volume and drops are the major determinants of the cost of medical therapy of glaucoma. Most of the bottles showed underfilling and it was the significant finding. Less number of drops and lesser volume increases the cost of treatment indirectly. PMID- 26097816 TI - Growth inhibitory effects of crude pomegranate peel extract on chronic myeloid leukemia, K562 cells. AB - BACKGROUND: Pomegranate (Punica granatum) is currently a member of Lythraceae family which has potentially cytotoxic activities. Numerous studies have been done on cytotoxic components of pomegranate's juices, barks and leaves. The peels, which considered as a waste, contain higher antioxidant components compared with other parts of the plant. AIM: To investigate the potential anti cancer activity of pomegranate peel on growth and cell death mechanisms of chronic myeloid leukemic (CML) cells, K562. MATERIALS AND METHODS: Punica granatum peels extract (PGPE) was extracted by successive ethanol extraction, 80% (v/v), freeze dried, diluted to 20 mg/mL working concentration and was subjected to phytochemical screening. K562 cell was treated with crude PGPE for 72 h. Following IC50 concentration, the apoptosis, cell cycle and protein analysis were evaluated. Cell growth inhibition assay was performed by conventional trypan blue exclusion assay. Apoptosis and cell cycle were analyzed by flow-cytometry using BD apoptosis and cell cycle kits and protein analysis by western blotting. All the results are expressed as mean +/- standard error of mean of three independent experiments. Statistical analysis was performed by nonparametric Mann-Whitney U test. RESULTS: Results demonstrated that PGPE promotes growth inhibition of K562 cells mainly via G2/M phase arrest while still conserving apoptosis induction, but at a lower rate. Apoptosis activities were proposed by the up-regulation of caspases and cytochrome c with an elevated level of p21 and p53. CONCLUSION: PGPE caused an inhibition in cell proliferation of CML cell mainly by cell cycle arrest. PMID- 26097817 TI - A comparative study to evaluate the efficacy and safety of combination topical preparations in acne vulgaris. AB - BACKGROUND: The combinations of topical keratolytics with anti-microbials and topical retinoids with antimicrobials are commonly prescribed in the treatment of acne. AIM: The present study was undertaken with the aim of comparing the efficacy and safety of topical benzoyl peroxide and clindamycin versus topical benzoyl peroxide and nadifloxacin versus topical tretinoin and clindamycin in patients of acne vulgaris. MATERIALS AND METHODS: 100 patients between 15 and 35 years having >=2 and <=30 inflammatory and/or noninflammatory lesions with Investigator's Global Assessment (IGA) score 2/3 were randomly divided into 3 groups. Group A was prescribed benzoyl peroxide 2.5% gel and clindamycin 1% gel, Group B was prescribed benzoyl peroxide 2.5% gel and nadifloxacin 1% cream and Group C was prescribed tretinoin 0.025% and clindamycin 1% gel. Total number of lesions and adverse effects during the treatment were assessed at 0, 4, 8, 12 weeks with IGA score. RESULTS: There was statistically significant reduction in total number of lesions with better improvement in Group A. Adverse drug reactions during the study showed a better safety profile of Group B which is found to be statistically significant also. CONCLUSION: These findings confirm that Group A is more efficacious and Group B is safest among the other two groups. PMID- 26097818 TI - Blood utilization in orthopedic and trauma practice. AB - OBJECTIVES: Very little is known about blood utilization in orthopedic and trauma surgery and there is no definite policy in this regard. Our objective is to perform an audit on our practice of blood utilization in the orthopedic department. METHODS: We have retrospectively analyzed the data of patients who were admitted between January 2011 and December 2012 to the orthopedic male, female and pediatric wards for which blood products were requested. RESULTS: Three hundred and eight patients were admitted for surgery during the study period. The average age was 35.12 +/- 20.4 years and postsurgery they stayed in the hospital for 25.60 +/- 10.5 days. Blood products were requested for 223 trauma surgeries. In elective orthopedic procedures, only 42.78% of the blood requested was utilized while in trauma patients it was 55.25%. CONCLUSIONS: A substantial amount of blood and its product was used in trauma and elective orthopedic surgeries. There was a major discrepancy between the blood requested and utilized and secondly in the majority single unit transfusion was utilized, which is not within the fundamentals of blood transfusion. PMID- 26097819 TI - Comparative efficacy of methylphenidate and atomoxetine in oppositional defiant disorder comorbid with attention deficit hyperactivity disorder. AB - BACKGROUND: Oppositional defiant disorder (ODD) is frequently comorbid with attention deficit hyperactivity disorder (ADHD) and is associated with substantial functional impairments. Methylphenidate and atomoxetine are well established drugs for the management of ADHD. Some studies from Western countries have reported these drugs to be effective in the management of ODD comorbid with ADHD. This study aimed to assess if methylphenidate and atomoxetine are efficacious in treating Indian children with ODD comorbid with ADHD. SUBJECTS AND METHODS: In this prospective, open-label study, 37 patients of age 6-14 years with a diagnosis of ODD comorbid with ADHD randomly received either methylphenidate (dose 0.2-1 mg/kg/day) or atomoxetine (dose 0.5-1.2 mg/kg/day) for 8 weeks. Improvements in ADHD and ODD symptoms were assessed using Vanderbilt ADHD diagnostic parent rating scale (VADPRS). RESULTS: At 8 weeks, there were statistically significant improvements in both ADHD and ODD symptoms in both methylphenidate and atomoxetine groups, as per VADPRS. The improvements produced and tolerability was comparable in the two groups. 80% of the patients from methylphenidate group and 64.3% patients from atomoxetine group ceased to fulfill the criteria for the presence of ODD at 8 weeks. CONCLUSIONS: Methylphenidate and atomoxetine are effective in the treatment of ODD comorbid with ADHD in short duration. PMID- 26097820 TI - Clinical profile of human immunodeficiency virus patients with opportunistic infections: A descriptive case series study. AB - BACKGROUND: Human immunodeficiency virus (HIV) virus, causative agent in acquired immunodeficiency syndrome, is fast becoming a major threat in the Indian subcontinent, with an estimated 3.7 million persons being infected with HIV. HIV infection is complicated by various opportunistic infections (OIs) such as tuberculosis (TB), candidiasis, herpes zoster, Pneumocystis jirvoceii, cytomegalovirus (CMV) etc., This study carried out to know the clinical profile of HIV patients with OIs. METHODS: A case series study was carried out at a tertiary care hospital in Bellary, Karnataka, India. A hospital based case series study was conducted among 164 HIV patients with OIs admitted to various wards as well as attending outpatient department at Vijayanagara Institute of Medical Sciences Hospital, Bellary during Jan 2013 to Nov 2013. Both primary and secondary data was collected to gather information on clinical profile. The statistical tests used were descriptive statistics and independent t test. RESULTS: Among 164 patients, 29.3% were females and 68.3% males. High proportions of patients were observed in 28-37 years of age group and heterosexual route was the most common mode of transmission. TB (50%) is the most frequent OI followed by candidiasis (49%), pneumocystis (16%) and others. The mean CD4 cell count in TB was 237.02/mL and in candidiasis 189.07/mL. Low values were observed in promyelocytic leukemia (18.10/mL), CMV (18.5/mL) and in toxoplasmosis (73.1/mL). CONCLUSIONS: Respiratory system was the most common system involved by OIs and most of patients with OIs had CD4 T cell count below 200/mL, whereas there were no patients in the study with counts above 500/mL. PMID- 26097821 TI - A comparative study of visual and auditory reaction times on the basis of gender and physical activity levels of medical first year students. AB - BACKGROUND: Reaction time (RT) is a measure of the response to a stimulus. RT plays a very important role in our lives as its practical implications may be of great consequences. Factors that can affect the average human RT include age, sex, left or right hand, central versus peripheral vision, practice, fatigue, fasting, breathing cycle, personality types, exercise, and intelligence of the subject. AIM: The aim was to compare visual RTs (VRTs) and auditory RTs (ARTs) on the basis of gender and physical activity levels of medical 1(st) year students. MATERIALS AND METHODS: The present cross-sectional study was conducted on 120 healthy medical students in age group of 18-20 years. RT for target stimulus that is, for the beep tone for measuring ART, and red circle for measuring VRT was determined using Inquisit 4.0 (Computer Software) in the laptop. The task was to press the spacebar as soon as the stimulus is presented. Five readings of each stimulus were taken, and their respective fastest RT's for each stimuli were recorded. Statistical analysis was done. RESULTS: In both the sexes' RT to the auditory stimulus was significantly less (P < 0.001) as compared to the visual stimulus. Significant difference was found between RT of male and female medical students (P < 0.001) as well as between sedentary and regularly exercising healthy medical 1(st) year students. CONCLUSION: The ART is faster than the VRT in medical students. Furthermore, male medical students have faster RTs as compared to female medical students for both auditory as well as visual stimuli. Regularly exercising medical students have faster RTs when compared with medical students with sedentary lifestyles. PMID- 26097823 TI - Prevalence of metabolic syndrome in type 2 diabetes mellitus patients. AB - BACKGROUND: The diabetic condition is influenced by several factors, some of which can accelerate the disease's progression to various complications that aggravate the morbidity. AIMS: This study aimed at determining the prevalence of metabolic syndrome (MetS) and its individual components and the most critical predictive risk factors of MetS in type 2 diabetic patients. MATERIALS AND METHODS: This cross-sectional study involved 150 type 2 diabetes mellitus patients and was conducted at the Diabetes Centre of the Komfo Anokye Teaching Hospital in Kumasi, the Ashanti Region of Ghana, from February, 2013 to April, 2013. The study involved the use of a questionnaire to obtain some information on the diabetics, undertaking anthropometric measurements, as well as collecting blood samples for the measurement of some biochemical parameters; fasting blood glucose and lipid profile. MetS was defined according to the National Cholesterol Education Program/Adult Treatment Panel III criteria. RESULTS: The prevalence of MetS was 58% in the studied Ghanaian population. Hypertension was the commonest risk factor (60%), followed by central obesity (48.67%) and dyslipidemia (37%). Female type 2 diabetics had a higher prevalence of MetS, and carried more components than their male counterparts. Regression analysis showed three factors; femininity, high body mass index and low educational status were the most critical predictive risk factors of MetS, according to this study. CONCLUSION: With hypertension being the commonest component, future cardiovascular disease prevention strategies should focus attention on its management and prevention, through education. PMID- 26097822 TI - Long term outcome analysis of role of radiotherapy in Grade I meningiomas: A single centre experience from North India. AB - BACKGROUND: Intracranial meningiomas are the second most common tumor of the central nervous system. Grade I tumors are the most common variety of meningioma and have a benign course. Surgery is the mainstay of treatment. Radiotherapy (RT) decreases the local recurrence rates and progression in patients with subtotal excision (STE). The authors present our institute's experience in combined modality management of 18 successive patients of Grade I meningioma. MATERIALS AND METHODS: We retrospectively reviewed 18 patients of Grade I meningioma treated in our institute from 2003 to 2011. Clinical characteristics and treatment modality in form of surgery and RT were noted. Statistical analysis was done with regards to recurrence free survival and overall survival using Kaplan Meier survival analysis. RESULTS: The median age of the patients was 52.5 years. Seven patients were males and 11 patients were females. The median duration of symptoms was 8 months. Headache was the most common presenting symptom followed by vomiting, seizures, motor weakness and visual deficits. Five patients underwent complete excision while 13 had STE. 11 patients received early RT while 5 patients received RT at recurrence. Median RT dose delivered was 50 Gy. RT had significant effect on local control especially in subtotal resections, with overall 93.75% local control rates. CONCLUSIONS: Grade I meningiomas represent a benign neoplasm. The mainstay of therapy is gross total resection at the initial surgery. Postoperative adjuvant RT should be offered to patients with subtotal resection. Long-term follow-up is important as local recurrences and progression can develop years after the initial treatment. PMID- 26097824 TI - Papillary cystic variant of acinic cell carcinoma presenting as parotid tail tumor. AB - Acinic cell carcinoma (ACC) is an uncommon low-grade tumor of the salivary glands that constitutes 2.5-4% of parotid gland tumors. Papillary cystic variant (PCV) of ACC is even rarer and can be diagnosed on histopathological examination only. It is important to diagnose this variant as it carries a poor prognosis when compared with other variants of ACC and is known to be universally fatal in 10 years. The present case describes ACC-PCV in a 20-year-old male, which presented as a slow growing parotid tail tumor and was misdiagnosed as a benign lesion both cytologically and radiologically. This case emphasizes the importance of histopathological examination in parotid masses as well as the need to consider malignant lesion in the differential diagnosis of a parotid tail tumor. PMID- 26097825 TI - Angiosarcoma of mandible: An uncommon clinical entity. AB - Angiosarcoma is a malignant neoplasm of endothelial cells of blood vessels, representing 2% of all sarcomas. The occurrence of angiosarcoma in the oral cavity is a rare. In general management includes resection and wide-field postoperative radiation therapy. The risk of local-regional failure and distant relapse is still a cause of worry. Herewith, a case of angiosarcoma of mandible in a female patient is presented, who presented with small, innocent-looking mass, which became a highly destructive malignant tumor within few days. PMID- 26097826 TI - Cytological features of malignant eccrine acrospiroma presenting as a soft tissue mass axilla: A rare sweat gland tumor with histologic correlation. AB - Malignant eccrine acrospiroma is an infrequent, highly malignant primary skin tumor derived from eccrine sweat glands. Though fine-needle aspiration cytology (FNAC) is a well-established diagnostic tool, but if a skin adnexal tumor or primary skin lesion is suspected clinically, the usual approach is biopsy due to easy accessibility. Being itself rare, cytologic features of this lesion is hardly encountered in case reports. As a result, very little is known about the appearance of adnexal tumors like malignant eccrine acrospiroma on fine-needle aspiration samples. A 50-year-old man presented with swelling in the left axilla, clinically suspected to be a soft tissue sarcoma. Fine-needle aspiration was advised, and a cytological diagnosis of malignant eccrine acrospiroma was rendered which was later confirmed on histological examination. Rapid, accurate diagnosis of these tumors is imperative as they have very poor prognosis and an aggressive course with recurrence and/or metastasis. FNAC plays a decisive and easy diagnostic modality in these unusual, rare cases of highly malignant primary skin tumor, and awareness of the lesions is indispensable in their management. PMID- 26097827 TI - Inflammatory myofibroblastic tumor of the urinary bladder: A diagnostic challange and therapeutic dilemma. AB - Inflammatory myofibroblastic tumor (IMT) is a rare, aggressive tumor of indeterminate malignant potential with myofibroblastic differentiation. Though bladder location is very uncommon, it arises from the bladder submucosal stroma as a polypoidal growth and is easily mistaken for a malignant neoplasm- clinically, radiologically and histologically. Essential criteria for the diagnosis of IMT are: spindle myoepithelial cell proliferation and lymphoplasmacytic infiltrate. Here we report the case of a 30 years old man who presented with painless gross haematuria for 2 weeks. The patient underwent open partial cystectomy and the final pathological diagnosis was IMT of bladder. PMID- 26097828 TI - Ruptured ovarian pregnancy in a primigravida. AB - Primary ovarian ectopic pregnancy is a rare entity and is associated with rupture very early in the gestation. We present a case of ovarian pregnancy in a primi gravida, which ruptured relatively late in the first trimester. The patient did not have any predisposing factors for ovarian pregnancy. The case was managed laparoscopically, and the diagnosis was based on surgical and histopathological findings. PMID- 26097829 TI - Intraparotid schwannoma: A rare case report. AB - Pleomorphic adenomas are the most common tumors which present as parotid masses. Shwannoma (peripheral nerve sheath tumor) is a rare entity in this region. Very few schwannomas originate from the facial nerve and in the majority of these cases the tumor involves its intratemporal part. The following case is reported because it presented as an asymptomatic parotid swelling with normal seventh nerve function, which masqueraded as pleomorphic adenoma clinically, radiologically and cytologically. However, it turned out to be peripheral nerve sheath tumor on histopathological examination. PMID- 26097830 TI - Phentermine-topiramate: First combination drug for obesity. AB - Obesity is spreading globally at an alarming speed. The management of obesity is multifaceted and includes lifestyle modifications as the cornerstone. Until only orlistat was approved for long term use in obesity. The US Food and Drug Administration granted approval to a fixed dose mid 2012 combination of phentermine immediate release and topiramate extended release in 2012 for treatment of obese patients or overweight patients with comorbid conditions. The new drug has shown significant weight loss compared with placebo for a period up to 2 years. PMID- 26097832 TI - Why a stem cell diagnosis is quite difficult. PMID- 26097831 TI - Phase I Trial of Carboplatin and Gemcitabine Chemotherapy and Stereotactic Ablative Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer. AB - BACKGROUND: We conducted a phase I trial to determine the safety of systemic chemotherapy prior to abdominopelvic robotic stereotactic ablative radiotherapy (SABR) in women with persistent or recurrent gynecologic cancers. METHODS: Patients were assigned to dose-finding cohorts of day 1 carboplatin (AUC 2 or 4) and gemcitabine (600 or 800 mg/m(2)) followed by day 2 to day 4 Cyberknife SABR (8 Gy * three consecutive daily doses). Toxicities were graded prospectively by common terminology criteria for adverse events, version 4.0. SABR target and best overall treatment responses were recorded according to response evaluation criteria in solid tumors, version 1.1. FINDINGS: The maximum tolerated dose of chemotherapy preceding SABR was carboplatin AUC 4 and gemcitabine 600 mg/m(2). One patient experienced manageable, dose-limiting grade 4 neutropenia, grade 4 hypokalemia, and grade 3 nausea attributed to study treatment. One patient had a late grade 3 rectovaginal fistula 16 months after trial therapy. Among 28 SABR targets, 22 (79%) showed a partial response and 6 (21%) remained stable. INTERPRETATION: Systemic chemotherapy may be given safely prior to abdominopelvic robotic SABR with further investigation warranted. PMID- 26097833 TI - Vancomycin minimum inhibitory concentrations and lethality in Staphylococcus aureus bacteremia. AB - BACKGROUND: After the dissemination of penicillin and oxacillin resistance in Staphylococcus aureus, vancomycin-intermediate and vancomycin resistant isolates have been reported. Even between isolates with minimum inhibitory concentrations (MICs) within the susceptible range, some authors have demonstrated that higher MICs correlate with higher lethality. METHODS: To test this hypothesis in our setting, we compared vancomycin MICs evaluated by two methods and clinical outcomes in hospitalized patients with S. aureus bacteremia. RESULTS: We compared lethality in patients infected with isolates that had MICs under or over 2 mg/L. Among patients infected with isolates that had microdilution MICs <2 mg/L, the lethality was 25%; among patients infected with strains that had microdilution MICs >=2 mg/L, 33% died. Among patients infected with isolates that had Etest MICs <2 mg/L, 23% died; in comparison, patients infected with strains that had Etest MICs >=2 mg/L had a lethality of 44%. CONCLUSION: Our results showed a slight tendency of higher lethality when higher MICs were present. However, this difference did not reach statistical significance, possibly due to the relatively small number of patients included in the study. Future prospective studies are needed to further evaluate this correlation and to help clinicians guide antimicrobial therapy. PMID- 26097834 TI - HLA class II alleles in Romanian patients with chronic hepatitis C. AB - INTRODUCTION: The objective of the study was to determine the association of host human leukocyte antigen (HLA) class II genotype DRB1 alleles with the response to interferon therapy, viral loads and extent of liver fibrosis in a group of Romanian patients diagnosed with chronic hepatitis C, with different clinical outcomes. Class II HLA genes, particularly the HLA-DRB1 and DQB1 genes, have been shown to have an important role in self-limiting or persistent viral infection, in different genetic populations. In chronic hepatitis C both susceptible and protective alleles have been described, influencing the development of autoimmunity and progression to cirrhosis and hepatocellular carcinoma. METHODS: The study included 54 patients diagnosed with chronic hepatitis C, registered and monitored from January 2014 to January 2015 at the Clinical Hospital of Infectious Diseases, Constanta, Romania. The selected patients were positive for anti-HCV antibodies and HCV-RNA, with screening laboratory results indicating HCV genotype 1b. The method used for the assignment of alleles at HLA-DRB1 and DQB1 loci was molecular genotyping, by the sequence specific oligonucleotide (SSO) hybridization method, and when required, by the sequence specific primers method (SSP). The presence of different alleles in patients has been analyzed for statistical significance. RESULTS: The presence of HLA-DRB1*0301 had a high frequency (14.8%) in null-responders (NR) while alleles DRB1*0701 (11.1%), DRB1*11# (22.2%) and DRB1*0101 (16.7%) were prevalent in sustained virologic responders (SVR). No significant correlation was found between the presence of HLA-DRB1* alleles and viral loads or liver fibrosis with p values not statistically significant after the Bonferroni correction. CONCLUSION: The presented data suggest that in this group of Romanian patients, certain HLA alleles influence the therapeutic response in HCV infection and genetic predisposition may play a role in hepatitis C virus infection in those patients. PMID- 26097835 TI - Seroprevalence of rubella virus IgG in pregnant women in Harare, Zimbabwe. PMID- 26097836 TI - The Prevalence of Substance use and Associated Risk Factors Among University Students in the City of Jahrom, Southern Iran. AB - BACKGROUND: Substance use among college students in Iran is a serious problem. Determining the pattern of substance use among University students is an important issue for implementing prevention and treatment programs. OBJECTIVES: The present survey attempts to determine the prevalence of substance usage and associated risk factors among the students of Jahrom University of Medical Sciences and Islamic Azad University of Jahrom, Jahrom, Iran. PATIENTS AND METHODS: This cross-sectional study was carried out from December 2012 to February 2013 and included 1149 randomly selected students of two Jahrom universities. A standard questionnaire was used for data gathering. Data were analyzed using the SPSS version 15 for Windows. T-test and Chi-square T-test and Chi-square and Logestic regression tests were used for data analysis. RESULTS: Tobacco (28.3%), alcohol (13.0%), and cannabis and marijuana (5.2%) were the most common substances used by the students. The prevalence of substance use among the male students was significantly higher (OR: 1.5, 95%CI: 1.42 - 2.68, P < 0.001). The risk of at least single episode of substance usage was higher among the students which were living alone (OR: 3.03, 95%CI: 1.74 - 5.28, P < 0.001) The most important motivators for beginning substance use were curiosity, in 46.4%, and seeking pleasure, in 28.8%. CONCLUSIONS: Substance usage is considered as a risk factor for students' health among University students in Iran. Design of educational courses addressing the detrimental effects and dire consequences of substance usage could help to improve control programs. Universities could improve their drug abuse control programs by focusing on the high risk groups determined by relevant studies. PMID- 26097837 TI - Alcohol Consumption, Depression, Insomnia and Colorectal Cancer Screening: Racial Differences. AB - BACKGROUND: Mortality from colorectal cancer (CRC) can be reduced drastically by early detection and early treatment. However, uptake of CRC screening is relatively low, about 50% for those whom the test is highly recommended. OBJECTIVES: We examined the influence of and racial differences in depression, insomnia, alcohol use, and tobacco use on CRC screening uptake in the US. PATIENTS AND METHODS: Analysis of the 2012 National Health Information Survey data was conducted. Both weighted univariate and multiple logistic regression analyses were performed in SAS to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). A total of 21511 participants were included in the analysis. RESULTS: Prevalence of CRC screening in the participants was 19%. Adjusting for all factors, insomnia (OR = 1.18, 95%CI = 1.06 - 1.32), moderate alcohol drinking (OR = 1.16, 95%CI = 1.01 - 1.30), past smoking (OR = 1.17, 95%CI = 1.04 - 1.32), depression (OR = 1.37, 95%CI = 1.18 - 1.58), African American (AA) race, and cancer history were positively associated with CRC screening. Females and Single were inversely associated with CRC screening prevalence. In stratified analysis by races (White and AA), depression was associated with CRC screening in both races. Marital status, smoking, cancer history and insomnia were associated with CRC screening in Whites only; while alcohol use was associated with CRC screening in AAs only. CONCLUSIONS: We have found significant associations between lifestyle factors (alcohol consumption and smoking) and mental health problems (depression and insomnia) and CRC screening uptake. To improve overall CRC screening uptake in the US, it is important to consider racial differences in predictors and tailor appropriate interventions to each racial/ethnic group. PMID- 26097838 TI - QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment. AB - BACKGROUND: QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance. OBJECTIVES: In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 +/- 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared. PATIENTS AND METHODS: ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records. RESULTS: The mean QTc at baseline (pre-methadone) was 426 +/- 34 msec and after being on methadone for an average of 8.72 +/- 4.50 years was significantly higher at 450 +/- 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of >= 24 msec (88.48 +/- 27.20 mg v.s 68.96 +/- 19.84 mg). None of the veterans experienced cardiac arrhythmias. CONCLUSIONS: The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination. PMID- 26097839 TI - Self-Medication With Analgesics and Helicobacter pylori Infection. PMID- 26097840 TI - The Advantages and Disadvantages of Breakfast Clubs According to Parents, Children, and School Staff in the North East of England, UK. AB - The provision of school breakfast has become increasingly popular in the UK in recent years. However, UK-based studies highlighting the views of parents, children, and school staff on school breakfast clubs are lacking. The current study set out to address this dearth in the literature by investigating the views of these key user and stakeholder groups on breakfast clubs within the North East of England. Fourteen parents, 21 children, and 17 school staff were recruited from four primary schools where breakfast clubs were available on site. Parents and school staff took part in semistructured interviews and children participated in focus groups, through which the advantages and disadvantages of breakfast clubs were discussed. Thematic analysis revealed that breakfast clubs provided children with a settled and enjoyable start to the school day. As well as providing children with a healthy and varied breakfast meal and unique opportunities for social interaction, breakfast clubs were recognized as an integral part of the school system that offered support to parents, particularly those who worked and relied on breakfast clubs as a means of affordable and reliable childcare. The few disadvantages identified related to practical issues such as a lack of adherence to school food standards, breakfast club staff missing class preparation time and concerns that some children were being excluded from participating in breakfast clubs particularly due to costs associated with attendance. The findings are discussed in relation to the School Food Plan, and areas for further investigation are proposed. PMID- 26097841 TI - Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. AB - Members of the HSP70/HSP110 family (HSP70s) form a central hub of the chaperone network controlling all aspects of proteostasis in bacteria and the ATP containing compartments of eukaryotic cells. The heat-inducible form HSP70 (HSPA1A) and its major cognates, cytosolic HSC70 (HSPA8), endoplasmic reticulum BIP (HSPA5), mitochondrial mHSP70 (HSPA9) and related HSP110s (HSPHs), contribute about 3% of the total protein mass of human cells. The HSP70s carry out a plethora of housekeeping cellular functions, such as assisting proper de novo folding, assembly and disassembly of protein complexes, pulling polypeptides out of the ribosome and across membrane pores, activating and inactivating signaling proteins and controlling their degradation. The HSP70s can induce structural changes in alternatively folded protein conformers, such as clathrin cages, hormone receptors and transcription factors, thereby regulating vesicular trafficking, hormone signaling and cell differentiation in development and cancer. To carry so diverse cellular housekeeping and stress-related functions, the HSP70s act as ATP-fuelled unfolding nanomachines capable of switching polypeptides between different folded states. During stress, the HSP70s can bind (hold) and prevent the aggregation of misfolding proteins and thereafter act alone or in collaboration with other unfolding chaperones to solubilize protein aggregates. Here, we discuss the common ATP-dependent mechanisms of holding, unfolding-by-clamping and unfolding-by-entropic pulling, by which the HSP70s can apparently convert various alternatively folded and misfolded polypeptides into differently active conformers. Understanding how HSP70s can prevent the formation of cytotoxic protein aggregates, pull, unfold, and solubilize them into harmless species is central to the design of therapies against protein conformational diseases. PMID- 26097842 TI - Preparation and Characterization of Solid Dispersions of Artemether by Freeze Dried Method. AB - Solid dispersions of artemether and polyethylene glycol 6000 (PEG6000) were prepared in ratio 12 : 88 (group-1). Self-emulsified solid dispersions of artemether were prepared by using polyethylene glycol 6000, Cremophor-A25, olive oil, Transcutol, and hydroxypropyl methylcellulose (HPMC) in ratio 12 : 75 : 5 : 4 : 2 : 2, respectively (group-2). In third group, only Cremophor-A25 was replaced with Poloxamer 188 compared to group-2. The solid dispersions and self emulsified solid dispersions were prepared by physical and freeze dried methods, respectively. All samples were characterized by X-ray diffraction, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimeter, scanning electron microscopy, and solubility, dissolution, and stability studies. X-ray diffraction pattern revealed artemether complete crystalline, whereas physical mixture and freeze-dried mixture of all three groups showed reduced peak intensities. In attenuated total reflectance Fourier transform infrared spectroscopy spectra, C-H stretching vibrations of artemether were masked in all prepared samples, while C-H stretching vibrations were representative of polyethylene glycol 6000, Cremophor-A25, and Poloxamer 188. Differential scanning calorimetry showed decreased melting endotherm and increased enthalpy change (DeltaH) in both physical mixture and freeze-dried mixtures of all groups. Scanning electron microscopy of freeze-dried mixtures of all samples showed glassy appearance, size reduction, and embedment, while their physical mixture showed size reduction and embedment of artemether by excipients. In group-1, solubility was improved up to 15 times, whereas group-2 showed up to 121 times increase but, in group-3, when Poloxamer 188 was used instead of Cremophor-A25, solubility of freeze-dried mixtures was increased up to 135 times. In fasted state simulated gastric fluid at pH 1.6, the dissolution of physical mixture was increased up to 12 times and freeze-dried mixtures up to 15 times. The stability of artemether was substantially enhanced in freeze-dried mixtures by using polyethylene glycol 6000, Cremophor-A25, and Poloxamer 188 of self emulsified solid dispersions of artemether in Hank's balanced salt solution at pH 7.4. PMID- 26097843 TI - A Systematic Analysis of Candidate Genes Associated with Nicotine Addiction. AB - Nicotine, as the major psychoactive component of tobacco, has broad physiological effects within the central nervous system, but our understanding of the molecular mechanism underlying its neuronal effects remains incomplete. In this study, we performed a systematic analysis on a set of nicotine addiction-related genes to explore their characteristics at network levels. We found that NAGenes tended to have a more moderate degree and weaker clustering coefficient and to be less central in the network compared to alcohol addiction-related genes or cancer genes. Further, clustering of these genes resulted in six clusters with themes in synaptic transmission, signal transduction, metabolic process, and apoptosis, which provided an intuitional view on the major molecular functions of the genes. Moreover, functional enrichment analysis revealed that neurodevelopment, neurotransmission activity, and metabolism related biological processes were involved in nicotine addiction. In summary, by analyzing the overall characteristics of the nicotine addiction related genes, this study provided valuable information for understanding the molecular mechanisms underlying nicotine addiction. PMID- 26097844 TI - Improved Monosegment Pedicle Instrumentation for Treatment of Thoracolumbar Incomplete Burst Fractures. AB - AIM: Comparing the clinical results of improved monosegment pedicle instrumentation (iMSPI) and short-segment pedicle instrumentation (SSPI) retrospectively. METHOD: 63 patients with thoracolumbar incomplete burst fracture were managed with iMSPI or SSPI. 30 patients were managed with iMSPI and fusion. 33 patients were managed with SSPI and fusion. Operative time, blood loss, postoperative drainage, and complications were recorded. Percentage of anterior body height compression (ABHC%) and sagittal index (SI) were obtained preoperatively, one week postoperatively, and at the last followup. RESULTS: The blood loss and postoperative drainage were significantly less in the iMSPI group than in SSPI group (P < 0.05). The follow-up duration of the two groups was not significantly different (P > 0.05). At 12 months postoperatively posterolateral fusion was obtained satisfactorily. Neither preoperative ABHC% and SI nor postoperative SI were significantly different (P > 0.05), but there was a significant difference in postoperative ABHC% (P = 0.000). The ABHC% and SI were not significantly different between the two groups at the last followup (P > 0.05). There were no fixation failures or other complications. SUMMARY: IMSPI yielded satisfactory results similar to those of SSPI in patients with type A3.1/3.2 thoracolumbar fractures. IMSPI is recommended for minor trauma, reducing one-segment fusion, and maximization of the remaining motor function. PMID- 26097845 TI - Generation and Characterization of a Transgenic Mouse Carrying a Functional Human beta -Globin Gene with the IVSI-6 Thalassemia Mutation. AB - Mouse models that carry mutations causing thalassemia represent a suitable tool to test in vivo new mutation-specific therapeutic approaches. Transgenic mice carrying the beta-globin IVSI-6 mutation (the most frequent in Middle-Eastern regions and recurrent in Italy and Greece) are, at present, not available. We report the production and characterization of a transgenic mouse line (TG-beta IVSI-6) carrying the IVSI-6 thalassemia point mutation within the human beta globin gene. In the TG-beta-IVSI-6 mouse (a) the transgenic integration region is located in mouse chromosome 7; (b) the expression of the transgene is tissue specific; (c) as expected, normally spliced human beta-globin mRNA is produced, giving rise to beta-globin production and formation of a human-mouse tetrameric chimeric hemoglobin (mu) alpha-globin2/(hu) beta-globin2 and, more importantly, (d) the aberrant beta-globin-IVSI-6 RNAs are present in blood cells. The TG-beta IVSI-6 mouse reproduces the molecular features of IVSI-6 beta-thalassemia and might be used as an in vivo model to characterize the effects of antisense oligodeoxynucleotides targeting the cryptic sites responsible for the generation of aberrantly spliced beta-globin RNA sequences, caused by the IVSI-6 mutation. These experiments are expected to be crucial for the development of a personalized therapy for beta-thalassemia. PMID- 26097846 TI - Ethical considerations in sex selection. AB - Advances in modern medicine are resulted from unrestricted and unlimited research disregarding many essentials of a research including ethical issues. Following ethical issues, many of unwanted pregnancies and abortions can be avoided. Several factors such as medical issues including X linked disease, has encouraged couples to select traditional or modern techniques in selecting the gender of their children. Some of these methods are corrected Swim-up method or washing of spermatozoa, Percoll gradient sperm separation method, grass wool column filter method method, albumin separation method, microsort method using FISH (Fluorescence in situ hybridization), free electrophoresis method, Ph adjustment method, pre implantation genetic diagnosis (PGD)/fluorescence in situ hybridization. This technology is confronted with many ethical issues. Ethical considerations PGD in the SEX SELECTION differ in different religions and their perspectives on this issue. In this this review, electronic databases, books and Internet sites were completely searched and full articles including required keywords and techniques were obtained and reviewed. The rites and religions, were different and had legal perspectives and opinions about PGD. In some non-Islamic countries there are strict rules to control the use of technology. Some of these methods are costly and even risky. They also involve ethical issues such as legitimacy of the conceived fetus; recommending final touches in sex selection is still considered a taboo and a big issue in some cultures or mono-sexual families. Islamic views and beliefs are more flexible and the use of these technologies are allowed to preserve the health and lives permit. Islam strongly favors humanity and supports different issues if they are not in conflict with the primary concept of legitimate reproduction and are beneficial to human beings. PMID- 26097847 TI - "Hepatitis" - Prevention and management in dental practice. AB - Today, viral hepatitis has become a silent epidemic worldwide. It is the major cause of liver cirrhosis and liver carcinoma. In a dental office, infections can be expedited through several routes, including direct or indirect contact with blood, oral fluids, droplet splatter, aerosols, etc. The aim of the present review is to increase the awareness among dental practitioners, so as to reduce the burden of hepatitis in their community. Electronic databases like PubMed, Medline, ProQuest, etc. were searched using the keywords hepatitis, dentist, liver disease, and infection control. Manual search of various journals and books was also carried out. Only highly relevant articles from English literature were considered for the present review. The results revealed that the dentists were among the high-risk groups for hepatitis, and they have little information on the factors associated with adherence to hepatitis B vaccination. A dentist can play a major role in the prevention of hepatitis by considering each and every patient as a potential carrier of hepatitis. Proper infection control, sterilization, and prophylactic vaccination protocols should be followed in order to reduce the risk of hepatitis. PMID- 26097848 TI - Introducing a spiritual care training course and determining its effectiveness on nursing students' self-efficacy in providing spiritual care for the patients. AB - INTRODUCTION: How to train nurses to provide spiritual care, as one of the basic competencies of nursing, based on patient's perception and culture has been considered highly important. Although nurses' training is recommended in this area, few researches have studied the format of such programs. This study is conducted with the aim of introducing the training course of spiritual care and determining its effectiveness on nursing students' self-efficacy in providing spiritual care. MATERIALS AND METHODS: The method of this study was of a pre-post interventional research. Senior students (n = 30) of the Shahrekord University of Medical Sciences, passing the training course in the field, were chosen as the studied sample. Study intervention was the implementation of the designed curriculum based on nursing books, focusing on providing the spiritual care for patients. The dependent variable of the study was the students' self-efficacy feeling in providing spiritual care to the patients. A researcher madequestionnaire, as well as the pre-post interventional tests, was used, then, to assess this variable. By means of Statistical Package for the Social Sciences software, data were analyzed, and the level of significance was considered at P <0.05. FINDINGS: The findings of the study showed that self-efficacy mean score of nursing students in providing spiritual care in the pretest was 13.74, showing the average level of perceived self-efficacy. The students' self-efficacy mean, after participating in the training spiritual care programs, however, changed to 21.1, indicating the increased level of self-efficacy. Results of paired t-test, also, showed that self-efficacy mean score of the study samples has significantly increased in the posttest, compared with the pretest. DISCUSSION AND CONCLUSION: According to these findings, it can be concluded that based on this designated curriculum, students have a chance of getting acquaintance with some concepts as: Spirituality and spiritual care, identifying the spiritual needs of patients, and designing a care plan to meet these requirements. These factors, therefore, have a great impact on students' effectiveness in providing spiritual care for patients. PMID- 26097849 TI - A study conducted on the demographic factors of victims of violence in support and administrative departments of hospital in 2013. AB - BACKGROUND: Violence is now regarded as a serious problem and its complication causes heavy costs on the healthcare systems. The present study aimed to investigate the correlation between some demographic characteristics and confrontation with violence. Since there is no study on the prevalence of violence among the support and administration staff of hospitals in Iran, this study was conducted to investigate violence in these departments. MATERIALS AND METHODS: This descriptive-analytical and correlation survey was carried out by census among the support and administrative staff interacting with patients and their companions in Al-Zahra University Hospital of Isfahan in 2013. Research tool was a researcher-made questionnaire including five domains: Personal information, workplace information, verbal violence, physical violence, and other violent acts. Its validity was evaluated by experts reviewing it and its reliability by test-retest (r =0.9). Finally, data were analyzed using descriptive statistical indicators and statistical tests such as Chi-square for sex, marital status, and work department and Mann-Whitney U test for age, level of education, work experience, and violence types by the statistical software SPSS version 20. RESULTS: According to the results obtained, 81% of subjects had been abused at least once and the most reported violence was related to verbal violence (78.4%). There was significant correlation between sex and violence and men were the main victims of violence, but there was no relation between marital status, age, and violence. Work experience was correlated to physical violence and other violent acts conversely. There was also an inverse correlation between physical violence and education; also, security staff faced more violence than others. CONCLUSION: As high prevalence of violence was found especially among the security staff and personnel with less education and work experience, it is suggested to take actions such as educating about patient accompaniment and visiting condition, holding training workshops on confronting with violence and appropriate communication with patients and families, using experienced and patient staff to interact with clients. PMID- 26097850 TI - Watching television by kids: How much and why? AB - INTRODUCTION: Television (TV) viewing by children may be linked to a range of adverse health and behavioral outcomes. This study was aimed at examining the relationship between socioeconomic factors of families and TV watching behavior among 3-5 years old children in Ardakan, Yazd, Iran. MATERIALS AND METHODS: In the cross-sectional study, mothers of 188 children (93 boys and 95 girls) between 3 and 5 years old completed a researcher-designed questionnaire. Data were analyzed by using SPSS, using bivariate correlations and t-test for independent samples. RESULTS: The mean of TV viewing was 2.68 +/- 1.6 h daily, ranging from 0 to 9 h. There were no statistically significant gender differences on the basis of daily TV watching. There were positive associations between the children's daily TV watching and age as well aschildren's daily TV watching and their mothers' time spent on watching TV. Children who lived in houses with the yard and could use it as a playground watched less TV than did the children who lived in houses without the yard. CONCLUSION: The results suggest that health care professionals should be aware of the association between different socioeconomic status aspects of families, such as the children's and mothers' time spent on watching TV and having a yard in the house in an attempt to develop effective strategies and interventions to prevent excess TV watching. PMID- 26097851 TI - Comparison of anxiety prevalence among based and offshore National Iranian Drilling Company staff's children in Ahvaz, 2013. AB - BACKGROUND: Anxiety is one of the most common psychological issues among all age groups including children. The main role of parents has been known to support their children. Being far away from a source of support has been shown to be a potential trigger for childhood anxiety. Periodical jobs, including offshore work, are among the main reasons for absence of one of the parents. Therefore, this study aims to assess anxiety in children of National Iranian Drilling Company offshore staff. MATERIALS AND METHODS: In this historical cohort study, 160 students including 80 boys and 80 girls were selected through convenient random sampling from the schools of National Iranian Drilling Company. Data were collected using Revised Children's Manifest Anxiety Inventory (by Reynolds and Richmond), consisting 37 items and a demographic questionnaire. The collected data were statistically analyzed by t-test and logistic regression tests through SPSS software. RESULTS: The mean anxiety score was 12.80 among offshore staff's children and 11.67 among the children of the based staff. The ratio of manifest anxiety among the offshore workers' children was significantly more than the based ones'. CONCLUSIONS: Based on the findings, offshore fathers' job affects the anxiety of the children. PMID- 26097852 TI - The study of inpatient medical records on hospital deductions: An interventional study. AB - BACKGROUND: The rate of hospital deductions is a commonly cited concern among teaching hospitals in Iran. The objective of the present study is to access the effect of the quantitative and qualitative analysis of inpatient medical records on deductions and identifying the major resources of deductions. There are currently no published interventional studies that have investigated this issue quantitatively. MATERIALS AND METHODS: In an interventional study, we reviewed all the 192 patient's medical records (PMRs) for any documentation errors, to determine the rate of deductions. We conducted a pilot of 30 cases prior to the actual survey. Nonprobability-based consecutive sampling was used. The main study was conducted in three phases: 1. Primary evaluation; 2. Training, performance of intervention and corrective actions; and 3. Final assessment. Comprehensive assessments of medical records and follow-upof error correction were carried out systematically and according to the pre-set schedule. Pre- and post-intervention assessments were compared in order to evaluate the effect of the intervention. Data were analyzed using the SPSS-20 statistical software. Paired-sample t-test was used to compare changes in deduction scores before and after the intervention. Differences at a P value less than 0.05 were considered statistically significant. RESULTS: In the initial survey of 800 PMRs, nearly one quarter (24%) (Or 192 cases) had at least one type of deduction. The three top types of deductions were Laboratory (47.9%), Medical radiation (45.3%), and Physician visit (35.9%). The results showed a 2.7- to about 36-fold lower rate of hospital deductions (average: 6.4-fold; reduction from21131 to 3285 US dollars). CONCLUSION: All in all, the results of the present study indicated that educational interventions and quantitative and qualitative analysis of inpatient medical records are very beneficial and effective in the reduction of medical record deductions. PMID- 26097853 TI - Investigation of educational intervention based on Theory of Planned Behavior on breakfast consumption among middle school students of Qom City in 2012. AB - BACKGROUND: Eating breakfast is crucial for adolescents to be healthy. It also improves students' capacity of learning and doing school homework. Although healthy habits such as eating breakfast, weight control, and regular sleep increase the lifespan in adults, the effects of healthy habits on school-age children have not been studied much. The present study aimed at investigating the impact of an educational program based on Theory of Planned Behavior (TPB) on eating breakfast among middle school students. MATERIALS AND METHODS: This interventional study was conducted on sixth-grade students in Qom City during the academic year 2012-2013. First, 97 students were randomly assigned to the experimental group and 97 other students were assigned to the control group. Then, a questionnaire was developed on eating breakfast by the researchers according to the TPB. A pilot study was conducted to assess the reliability of the questionnaire. To assess the validity of the questionnaire, advice by a panel of experts was sought. To carry out a pre-test, both groups answered the questions. After analyzing the pre-test results, the required content was developed for the experimental group. Educational methods included delivering speech, discussion groups, pamphlets, and posters. The required educationalcontent was provided for students during five sessions and for parents in one session. To determine the effect of educational intervention, a post-test study was carried out 2 months after the intervention. Collected data were analyzed using independent t-test, chi,([2]) and repeated measures. RESULTS: In the experimental group, 36.7% of students were eating breakfast at least in a day of a week, before educational intervention. After implementation of the educational program, only 32.7% of them were continuing their past habit. There was a significant difference between themean scores of attitudes, perceived behavioral control, intention, and practice of eating breakfast in the experimental and control groups (P < 0.05), while there was no significant difference between the mean scores of subjective norms after implementing the educational program in both groups (P < 0.26). CONCLUSION: Using the TPB improved students' intentions and behavior of eating breakfast. Thus, it seems necessary to consider all effective environmental factors on the subjective norms in the education of healthy eating behaviors or improving breakfast-eating practice among students. PMID- 26097854 TI - Risk factors of low birth weight and effect of them on growth pattern of children up to sixth months of life: A cross-sectional study. AB - INTRODUCTION: Children are more risk-prone group of the population and low birth weight (LBW) is the leadingcause of newborns' mortality and morbidity. LBW is defined as child's birth weight lower than 2500 g. Many maternal and fetal factors are determined as risk factors of LBW. This study tries to detect related factors to LBW and effect of them on children's growth pattern up to sixth month of life in Health centers of Urmia city, Iran. MATERIALS AND METHODS: A cross sectional study was carried out in Urmia city using registered data from mothers' documents. All related data such age and weight of infants, mothers' age, gestational age (GA) at the time of delivery, time gap between two pregnancies, past history of abortion, prenatal care history, systemic and underlying diseases, hemoglobin of mothers during pregnancy, and pattern of infant's growth up to sixth month of age were registered in a questionnaire. All registered data were transferred to SPSS 15 software and analyzed. RESULTS: Mean +/- SD of birth weight was 3071 +/- 625.66 g. There was a significant relationship between birth weight and mother's age (P < 0.001) and weight (P < 0.001). Children of mothers younger than 18 years had much birth weights. There was a significant relationship between birth weight and GA during delivery (P < 0.001). Children of preterm labor had lower birth weights. In twins, LBW was more prevalent (P < 0.001). CONCLUSION: Our results show that LBW is related to multiple causes and that most of them are preventable with educational programs and also strict and regular prenatal care. Decreasing incidence of LBW children can be achieved by cooperation between different parts of health and clinical systems. PMID- 26097855 TI - Standardization of European Medical Risk Related History questionnaire for use with Persian-speaking population. AB - BACKGROUND: Today, the dental practitioners are finding many more medically compromised patients in their practice. AIMS: The aim of this study was standardization of the European Medical Risk Related History (EMRRH) questionnaire for use among Persian population. MATERIALS AND METHODS: The English original version of the EMRRH questionnaire was translated into Persian language by a forward-backward translation method. Then reliability was tested on 50 subjects. Also, the sensitivity, specificity, and validity of the questionnaire were assessed. STATISTICAL ANALYSIS USED: Cohen's kappa, a measure of agreement between observers that includes an adjustment for chance agreement, was likewise calculated. RESULTS: The reliability coefficient (Cronbach's alpha) of the EMRRH was above the recommended 0.7 threshold and considered excellent (alpha 0.87). Specificity of the questions was 94% and of per EMRRH item was 93%. Sensitivity per question was 86.1% and of per EMRRH item was 94%. Cohen's kappa for the questionnaire was 0.89 and for subsequent questions was 0.82. CONCLUSIONS: The EMRRH (Persian version) has been shown to be valid in comparison with the gold standard (a medical history taken by a physician experienced) and this instrument would be an effectual method of history taking for the dentist. PMID- 26097856 TI - Contribution of marital conflict to marital quality in short and long-term marriages: An actor-partner interdependence model. AB - AIMS: In the field of family research, previous studies have made great strides toward understanding the relationship between marital conflict and quality. However, they have only studied couples in short-term marriages. Therefore, much remains to be unraveled with regard to long-term marriages. We aimed investigate the comparative contribution of aspects of marital conflict to marital quality in short-and long-term marriages in Iranian families. MATERIALS AND METHODS: Using random clustered sampling, 400 dyads in intact first marriages were surveyed across eight provinces of Iran. Complete surveys for both husbands and wives were returned for 162 households (couple's response rate: 40.5%). Survey measures included demographics questionnaire, Barati and Sanai's Marital Conflict Questionnaire and Blum and Mehrabian's Comprehensive Marital Satisfaction Scale. Structural equation modeling was used to test the actor-partner interdependence model of marital conflict-marital quality. RESULTS: Generalized additive models were incorporated to define what constitutes short-and long-term marriages. Based on the models regressed, duration <= 10 years was defined as short-term, whereas duration >= 25 years was labeled long-term. In short-term marriages (n = 44), decreased sexual relations, increased daily hassles and sidedness in relations with parents were negatively associated with marital quality in both actor and actor-to-partner paths. In long-term married couples (n = 46), only increased daily hassles (P < 0.001) and disagreement over financial affairs (P = 0.005) contributed to actor paths and only sidedness in relationships with parents showed significant negative association to marital quality in actor-to-partner paths. CONCLUSIONS: Different themes of conflict contribute to the diminished level of marital quality in early and late stages of the marriage. Conflicts over sex, relationship with extended family and daily hassles are emphasized in the early years of marriage, while in later years; dispute over money and daily hassles dominate. PMID- 26097857 TI - Comparative study of the density of L2, L3, and L4 vertebrae in menopausal women aged over 50 years with osteoporosis. AB - BACKGROUND: The Index used for osteoporosis detection was BMD measured in L2, L3, and L4 vertebrae. We compared the density of the vertebrae to select the one with maximum change in the density for decreasing the cost and the time. METHODS AND MATERIALS: Ninety seven osteoporotic post-menopausal women with a mean age of 61.78 +/- 8.48 (50 - 86) years and a mean body mass index (BMI) of 24.75 +/- 2.66 (kg/m(2)) (18 - 30) without any known diseases and on any medication affecting bone mineral density (BMD) were examined at osteoporosis section of a teaching hospital. The vertebral bodies (L2 - L4) of participants were measured by using a dual energy X-ray absorptiometry system (DEXA). To investigate if the BMD measurement of a single vertebra could replace the total L2 - L4 measurement, the mean BMDs and the correlations of the L2 - L4 were compared. RESULTS: Among the 97 studied women, the mean BMI was 24.75 +/- 2.66. The mean BMD of L2, L3, and L4 vertebrae were 0.7199, 0.7258, and 0.7402, respectively. There was no significant difference between the mean BMD of L2 and L3 vertebrae (P > 0.05), suggesting a strong relationship between L2 and L3. The mean BMD in the L4 vertebra was significantly higher than the other two vertebrae (P < 0.05), Statistical analysis showed that the BMD in all three L2, L3, and L4 vertebrae were associated with BMI (r > 0 and P < 0.05), but there was no significant relationship between BMD and age in the three L2, L3, and L4 vertebrae (r ? 0 and P > 0.05). CONCLUSION: Since the mean BMDs of L2 and L3 were not significantly different, and due to a very high correlation between L2 and L3, we recommend the measurement of L2 rather than L2 - L4 in order to save patient scanning time, cost, and the patient X-ray exposure. PMID- 26097858 TI - Predicting the educational performance of Isfahan University students of medical sciences based on their behaviour profile, mental health and demographic characteristic. AB - BACKGROUND: The issue of students' academic failure is one of the most important educational, economic, and social issues. Cognizance of the factors related to academic downfall is so efficient in its prevention and control and leads to protecting governmental assets and labor force. In order to achieve this goal, this study intends to determine the predictive factors of the students' academic performance in Isfahan University of Medical Sciences in terms of their personality profile, mental health, and their demographic characteristics. MATERIALS AND METHODS: This study was a descriptive-correlation study on 771 students who entered Isfahan University of Medical Sciences between 2005 and 2007. The information was gathered through using the students' educational and clinical files (for measuring personality characteristics and mental health) and SAMA Software (To get the mean scores). Minnesota Multiphasic Personality Inventory short form and General Health Questionnaire were used for collecting clinical data. The data were analyzed using SPSS 15 (stepwise regression coefficient, variance analysis, Student's t-test, and Spearman correlation coefficient). RESULT: The results showed that the aforementioned students obtained a normal average for their personality profile and mental health indicators. Of all the reviewed variables, education, age, gender, depression, and hypochondria were the predictive factors of the students' educational performance. CONCLUSION: It could be concluded that some of the personality features, mental health indicators, and personality profile play such a significant role in the students' educational life that the disorder in any of them affects the students' educational performance and academic failure. PMID- 26097859 TI - Comparative investigation of the effectiveness of face-to-face verbal training and educational pamphlets on readiness of patients before undergoing non emergency surgeries. AB - BACKGROUND: The thought of having a surgery can be stressful for everyone. Providing the necessary information to the patient can help both the patient and the treatment team. This study was conducted to compare the effectiveness of face to-face verbal training and educational pamphlets on the readiness of patients for undergoing non-emergency surgeries. MATERIALS AND METHODS: The study was a before-after randomized clinical trial. 90 patients scheduled to undergo non emergency surgery who referred to Shahrekord Ayatollah Kashani Hospital in 2013 were distributed randomly and gradually into two experimental groups (group of face-to-face verbal training and group of educational pamphlet) and one control group. Dependent variable of the study was pre-surgery readiness. Data analysis was carried out by using SPSS statistical software. Statistical analysis were analysis of variance (ANOVA) and correlation test. RESULTS: Results showed that the mean scores of pre-surgery readiness in both interventional groups were significantly higher than that in the control group after the intervention (P < 0.05). However, there was no significant difference between the two experimental groups (P > 0.05). CONCLUSIONS: Each of the methods of face-to-face verbal education and using the pamphlet could be equally effective in improving the readiness of the patients undergoing surgery. Therefore, in environments where the health care providers are facing with the pressure of work and lack of sufficient time for face-to-face verbal training, suitable educational pamphlets can be used to provide the necessary information to patients and prepare them for surgery. PMID- 26097860 TI - Exploring nursing students' experience of peer learning in clinical practice. AB - BACKGROUND: Peer learning is an educational process wherein someone of the same age or level of experience level interacts with other students interested in the same topic. There is limited evidence specifically focusing on the practical use of peer learning in Iran. The aim of this study was to explore nursing students' experiences of peer learning in clinical practice. MATERIALS AND METHODS: A qualitative content analysis was conducted. Focus groups were used to find the students' experiences about peerlearning. Twenty-eight baccalaureate nursing students at Bushehr University of Medical Sciences were selected purposively, and were arranged in four groups of seven students each. The focus group interviews were conducted using a semi-structured interview schedule. All interviews were tape-recorded, transcribed verbatim, and analyzed using conventional content analysis method. RESULTS: The analysis identified four themes: Paradoxical dualism, peer exploitation, first learning efficacy, and socialization practice. Gained advantages and perceived disadvantages created paradoxical dualism, and peer exploitation resulted from peer selection and peer training. CONCLUSION: Nursing students reported general satisfaction concerning peer learning due to much more in-depth learning with little stress than conventional learning methods. Peer learning is a useful method for nursing students for practicing educational leadership and learning the clinical skills before they get a job. PMID- 26097861 TI - The effect of four-phase teaching method on midwifery students' emotional intelligence in managing the childbirth. AB - BACKGROUND: An active teaching method has been used widely in medical education. The aim of this study was to determine the effectiveness of the four-phase teaching method on midwifery students' emotional intelligence (EQ) in managing the childbirth. MATERIALS AND METHODS: This was an experimental study that performed in 2013 in Isfahan University of Medical Sciences. Thirty midwifery students were involved in this study and selected through a random sampling method. The EQ questionnaire (43Q) was completed by both the groups, before and after the education. The collected data were analyzed using SPSS 14, the independent t-test, and the paired t-test. The statistically significant level was considered to be <0.05. RESULTS: The findings of the independent t-test did not show any significant difference between EQ scores of the experimental and the control group before the intervention, whereas a statistically significant difference was observed after the intervention between the scores of two groups (P = 0.009). The paired t-test showed a statistically significant difference in EQ scores in the two groups after the intervention in the four-phase and the control group, respectively, as P = 0.005 and P = 0.018. Furthermore, the rate of self-efficiency has increased in the experimental group and control group as 66% and 13% (P = 0.024), respectively. CONCLUSION: The four-phase teaching method can increase the EQ levels of midwifery students. Therefore, the conduction of this educational model is recommended as an effective learning method. PMID- 26097862 TI - Improving the medical records department processes by lean management. AB - BACKGROUND: Lean management is a process improvement technique to identify waste actions and processes to eliminate them. The benefits of Lean for healthcare organizations are that first, the quality of the outcomes in terms of mistakes and errors improves. The second is that the amount of time taken through the whole process significantly improves. AIMS: The purpose of this paper is to improve the Medical Records Department (MRD) processes at Ayatolah-Kashani Hospital in Isfahan, Iran by utilizing Lean management. MATERIALS AND METHODS: This research was applied and an interventional study. The data have been collected by brainstorming, observation, interview, and workflow review. The study population included MRD staff and other expert staff within the hospital who were stakeholders and users of the MRD. STATISTICAL ANALYSIS USED: The MRD were initially taught the concepts of Lean management and then formed into the MRD Lean team. The team then identified and reviewed the current processes subsequently; they identified wastes and values, and proposed solutions. RESULTS: The findings showed that the MRD units (Archive, Coding, Statistics, and Admission) had 17 current processes, 28 wastes, and 11 values were identified. In addition, they offered 27 comments for eliminating the wastes. CONCLUSION: The MRD is the critical department for the hospital information system and, therefore, the continuous improvement of its services and processes, through scientific methods such as Lean management, are essential. ORIGINALITY/VALUE: The study represents one of the few attempts trying to eliminate wastes in the MRD. PMID- 26097863 TI - The Role of Osteoclasts in Early Dissemination of Prostate Cancer Tumor Cells. AB - Prostate cancer (PCa) is one of the most common neoplasms that metastasize to bone. The aim of this study was to determine if osteoclasts play a role in the seeding of disseminated tumor cells to the bone marrow by mobilizing hematopoietic stem cells (HSCs) out of their marrow niche. Human PC-3Luc cells were introduced into male SCID mice by intracardiac (i.c.) injection after mice were treated with the antiresorptive agent Zoledronic Acid (bisphosphonate (BP)) and/or AMD3100, which mobilizes HSCs out of the marrow. Short term homing of PC-3 was assessed at 24 hours by QPCR for human Alu and luciferase and HSC number was determined by FACS. Mice also received pre and/or post treatments of BP by intraperiteneal (i.p.) injections, in addition to PC-3 luc by intratibial (i.t.) injections. TRAP assays were used to determine the osteoclast (OC) number in both studies. AMD3100 enhanced the release of HSCs from the bone marrow, while BP increased the retention of HSCs. PCa entry into bone was facilitated in AMD3100, BP, and AMD3100+BP treatments. Before PCa injection, the number of TRAP+ OC was increased in mice treated with AMD3100, while treatment with BP resulted in relatively lower TRAP+ OCs. TRAP+ OCs were not detected in the AMD3100 + BP treatment. After PCa injection, however, the number of TRAP+ OCs was dramatically increased, but did not differ significantly amongst the treatment groups. The pre and post BP treatments in the Nude mice decreased the size of PCa lesions in the tibia compared to the control. The results indicate that OC activation is not necessary for PCa metastasis to bone at the earliest stages. These findings are critical in proving that OCs' contribution to metastasis occur during the growth phase of the tumor rather than at the initiation phase. PMID- 26097864 TI - New insights into malignant cell survival mechanisms in medulloblastoma. AB - mRNA translation and protein synthesis is an important determinant for cell metabolism and cell homeostasis. Perturbations in cellular homeostasis often result in activation of negative feedback loops as compensatory mechanisms. Although, these mechanisms are important for mammalian cells to adjust to environmental changes, they also pose a major challenge for targeted cancer therapy as they provide escape mechanisms for cancer cells. The mammalian target of rapamycin (mTOR) is a crucial regulator of mRNA translation, protein synthesis and metabolism and represents an attractive target for anticancer therapy. We have recently reported that selective inhibition of mTORC1 by rapamycin or its analogs in medulloblastoma cells results in phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) on serine-209, an event known to be associated with induction of protein translation and cell transformation. We have also previously established that this event is mediated by mitogen-activated protein (MAP) kinase-interacting kinase 2 (Mnk2) independently of MAPKs, the conventional activators of Mnks. Here we discuss the implications for our current understanding of negative feedback regulation by mTOR and Mnk in cancer. PMID- 26097865 TI - Erratum: Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH based etiopathogenic perspective and therapeutic approach to an old cancer question. AB - [This corrects the article on p. 777 in vol. 1, PMID: 25621294.]. PMID- 26097866 TI - Oncogene-induced NAD(+) depletion in tumorigenesis. PMID- 26097868 TI - MiR-148a, a microRNA upregulated in the WNT subgroup tumors, inhibits invasion and tumorigenic potential of medulloblastoma cells by targeting Neuropilin 1. AB - Medulloblastoma, a common pediatric malignant brain tumor consists of four molecular subgroups viz. WNT, SHH, Group 3 and Group 4. MiR-148a is over expressed in the WNT subgroup tumors, which have the lowest incidence of metastasis and excellent survival among all medulloblastomas. MiR-148a was expressed either in a transient manner using a synthetic mimic or in a stable doxycycline inducible manner using a lentiviral vector in non-WNT medulloblastoma cell lines. Expression of miR-148a to levels comparable to that in the WNT subgroup tumors was found to inhibit proliferation, clonogenic potential, invasion potential and tumorigenicity of medulloblastoma cells. MiR-148a expression in medulloblastoma cells brought about reduction in the expression of NRP1, a novel miR-148a target. Restoration of NRP1 expression in medulloblastoma cells was found to rescue the reduction in the invasion potential and tumorigenicity brought about by miR-148a expression. NRP1 is known to play role in multiple signaling pathways that promote tumor growth, invasion and metastasis. NRP1 expression in medulloblastomas was found to be associated with poor survival, with little or no expression in majority of the WNT tumors. The tumor suppressive effect of miR-148a expression accompanied by the down regulation of NRP1 makes miR-148a an attractive therapeutic agent for the treatment of medulloblastomas. PMID- 26097867 TI - AID/APOBEC deaminases and cancer. AB - Mutations are the basis for evolution and the development of genetic diseases. Especially in cancer, somatic mutations in oncogenes and tumor suppressor genes alongside the occurrence of passenger mutations have been observed by recent deep sequencing approaches. While mutations have long been considered random events induced by DNA-replication errors or by DNA damaging agents, genome sequencing led to the discovery of non-random mutation signatures in many human cancer. Common non-random mutations comprise DNA strand-biased mutation showers and mutations restricted to certain DNA motifs, which recently have become attributed to the activity of the AID/APOBEC family of DNA deaminases. Hence, APOBEC enzymes, which have evolved as key players in natural and adaptive immunity, have been proposed to contribute to cancer development and clonal evolution of cancer by inducing collateral genomic damage due to their DNA deaminating activity. This review focuses on how mutagenic events through AID/APOBEC deaminases may contribute to cancer development. PMID- 26097869 TI - Induction of functional Brm protein from Brm knockout mice. AB - Once the knockout of the Brm gene was found to be nontumorigenic in mice, the study of BRM's involvement in cancer seemed less important compared with that of its homolog, Brg1. This has likely contributed to the disparity that has been observed in the publication ratio between BRG1 and BRM. We show that a previously published Brm knockout mouse is an incomplete knockout whereby a truncated isoform of Brm is detected in normal tissue and in tumors. We show that this truncated Brm isoform has functionality comparable to wild type Brm. By immunohistochemistry (IHC), this truncated Brm is undetectable in normal lung tissue and is minimal to very low in Brmnull tumors. However, it is significant in a subset (~40%) of Brg1/Brm double knockout (DKO) tumors that robustly express this truncated BRM, which in part stems from an increase in Brm mRNA levels. Thus, it is likely that this mutant mouse model does not accurately reflect the role that Brm plays in cancer development. We suggest that the construction of a completely new mouse Brm knockout, where Brm is functionally absent, is needed to determine whether or not Brm is actually tumorigenic and if Brm might be a tumor suppressor. PMID- 26097870 TI - The DAXX co-repressor is directly recruited to active regulatory elements genome wide to regulate autophagy programs in a model of human prostate cancer. AB - While carcinoma of the prostate is the second most common cause of cancer death in the US, current methods and markers used to predict prostate cancer (PCa) outcome are inadequate. This study was aimed at understanding the genome-wide binding and regulatory role of the DAXX transcriptional repressor, recently implicated in PCa. ChIP-Seq analysis of genome-wide distribution of DAXX in PC3 cells revealed over 59,000 DAXX binding sites, found at regulatory enhancers and promoters. ChIP-Seq analysis of DNA methyltransferase 1 (DNMT1), which is a key epigenetic partner for DAXX repression, revealed that DNMT1 binding was restricted to a small number of DAXX sites. DNMT1 and DAXX bound close to transcriptional activator motifs. DNMT1 sites were found to be dependent on DAXX for recruitment by analyzing DNMT1 ChIP-Seq following DAXX knockdown (K/D), corroborating previous findings that DAXX recruits DNMT1 to repress its target genes. Massively parallel RNA sequencing (RNA-Seq) was used to compare the transcriptomes of WT and DAXX K/D PC3 cells. Genes induced by DAXX K/D included those involved in autophagy, and DAXX ChIP-Seq peaks were found close to the transcription start sites (TSS) of autophagy genes, implying they are more likely to be regulated by DAXX. In conclusion, DAXX binds active regulatory elements and co-localizes with DNMT1 in the prostate cancer genome. Given DAXX's putative regulatory role in autophagy, future studies may consider DAXX as a candidate marker and therapeutic target for prostate cancer. PMID- 26097871 TI - Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer. AB - Management of ovarian cancer still requires improvements in therapeutic options. A drug delivery strategy was tested that allows specific targeting of tumor cells in combination with a controlled release of a cytotoxic molecule. To this aim, the efficacy of a loco-regional intraperitoneal treatment with a bioconjugate (ONCOFID-S) derived by chemical linking of SN-38, the active metabolite of irinotecan (CPT-11), to hyaluronan was assessed in a mouse model of ovarian carcinomatosis. In vitro, the bioconjugate selectively interacted with ovarian cancer cells through the CD44 receptor, disclosed a dose-dependent tumor growth inhibition efficacy comparable to that of free SN-38 drug, and inhibited Topoisomerase I function leading to apoptosis by a mechanism involving caspase-3 and -7 activation and PARP cleavage. In vivo, the intraperitoneal administration of ONCOFID-S in tumor-bearing mice did not induce inflammation, and evidenced an improved therapeutic efficacy compared with CPT-11. In conclusion, SN-38 conjugation to hyaluronan significantly improved the profile of in vivo tolerability and widened the field of application of irinotecan. Therefore, this approach can be envisaged as a promising therapeutic strategy for loco-regional treatment of ovarian cancer. PMID- 26097872 TI - mTOR pathway activation in multiple myeloma cell lines and primary tumour cells: pomalidomide enhances cytoplasmic-nuclear shuttling of mTOR protein. AB - mTOR is a protein kinase that plays a central role in regulating critical cellular processes. We evaluated the activation and cellular localization of the mTOR pathway in multiple myeloma (MM) and analyzed the role of pomalidomide in regulating mTOR. By immunohistochemistry cytoplasmic p-mTOR stained positive in 57 out 101 (57.6%) cases with a nuclear p-mTOR localization in 14 out 101 samples (13.8%). In the 70 MM samples analyzed for the entire pathway, p-mTOR expression significantly correlated with p-AKT, p-P70S6K, and p-4E-BP1 suggesting that the AKT/mTOR pathway is activated in a subset of MM patients. Immunofluorescence assays demonstrated that mTOR protein is distributed throughout the cytoplasm and the nucleus at baseline in MM cell lines and in plasma cells of 13 MM patients and that pomalidomide facilitated the shift of the mTOR protein in the nucleus. By western blotting, treatment with pomalidomide increased nuclear mTOR and p mTOR expression levels in the nucleus with a concomitant decrease of the cytoplasmic fractions while does not seem to affect significantly AKT phosphorylation status. In MM cells the anti-myeloma activity of pomalidomide may be mediated by the regulation of the mTOR pathway. PMID- 26097873 TI - Sorafenib induces cathepsin B-mediated apoptosis of bladder cancer cells by regulating the Akt/PTEN pathway. The Akt inhibitor, perifosine, enhances the sorafenib-induced cytotoxicity against bladder cancer cells. AB - Sorafenib, a tyrosine kinase inhibitor, has been demonstrated to exert anti-tumor effects. However, the molecular mechanisms underlying its effects on bladder cancer remain unknown. Here, we evaluated the mechanisms responsible for the sorafenib-induced anti-tumor effects on 5637 and T24 bladder cancer cells. We demonstrated that sorafenib reduces cell viability, stimulates lysosome permeabilization and induces apoptosis of bladder cancer cells. These effects are dependent by the activation of cathepsin B released from lysosomes. The sorafenib increased cathepsin B activity induced the proteolysis of Bid into tBid that stimulates the intrinsic pathway of apoptosis characterized by mitochondrial membrane depolarization, oxygen radical generation and cytochrome c release. Moreover, we found that cathepsin B enzymatic activity, induced by sorafenib, is dependent on its dephosphorylation via PTEN activation and Akt inactivation. Pretreatment with orthovanadate rescued bladder cancer cells from apoptosis. In addition, the Akt inhibitor perifosine increased the sensitivity of bladder cancer cells to sorafenib-induced cytotoxicity. Overall, our results show that apoptotic cell death induced by sorafenib in bladder cancer cells is dependent on cathepsin B activity and involved PTEN and Akt signaling pathways. The Akt inhibitor perifosine increased the cytotoxic effects of sorafenib in bladder cancer cells. PMID- 26097874 TI - Epigenetic silencing of S100A2 in bladder and head and neck cancers. AB - S100A2, a member of the S100 protein family, is known to be downregulated in a number of human cancers, leading to its designation as a potential tumor suppressor gene. Here, we investigated the expression and methylation status of S100A2 in head&neck and bladder cancer. Reduced mRNA and protein expression was observed in 8 head&neck and bladder cancer cell lines. To explore the mechanism responsible for the downregulation of S100A2, we treated six cell lines with 5 aza-2'-deoxycytidine. We found S100A2 is silenced in association with aberrant promoter-region methylation and its expression is restored with 5-aza-2' deoxycytidine treatment. Of 31 primary head&neck cancer cases and 31 bladder cancer cases, promoter methylation was detected in 90% and 80% of cases, respectively. Interestingly, only 1/9 of normal head&neck tissues and 2/6 of normal bladder tissues showed promoter methylation. S100A2 promoter methylation can be detected in urine and is more frequent in bladder cancer patients than in healthy subjects (96% vs 48% respectively). Moreover, increased methylation of S100A2 is linked to the progression of the tumor in bladder cancer (p<0.01). Together, this data shows that methylation-associated inactivation of S100A2 is frequent and may be an important event in the tumorigenesis of head&neck and bladder cancer. PMID- 26097875 TI - FS-93, an Hsp90 inhibitor, induces G2/M arrest and apoptosis via the degradation of client proteins in oncogene addicted and derived resistant cancer cells. AB - Inhibition of heat shock protein 90 (Hsp90) abrogates signaling of multiple aberrantly activated oncogenic proteins simultaneously, particularly mutated or amplified kinases, which provides an attractive approach for cancer treatment. Here, we described that FS-93, a potent Hsp90 inhibitor, impacted the survival of several types of oncogene addicted cancer cells through inducing G2/M arrest and apoptosis. Mechanistically, FS-93 treatment triggered the degradation of key client proteins such as HER2, EML4-ALK and c-Met and thereby abolished their downstream signaling pathways. Importantly, FS-93 alone circumvented MET amplification contributed acquired resistance to EGFR inhibition. Our study implicates that targeting Hsp90 is a promising alternative therapeutic tactic in oncogene addicted and derived resistant cancer cells. PMID- 26097876 TI - Circadian disruption-induced microRNAome deregulation in rat mammary gland tissues. AB - Breast cancer is the most common malignancy affecting women worldwide, and evidence is mounting that circadian-disruption-induced breast cancer is a warranted concern. Although studies on the role of epigenetics have provided valuable insights, and although epigenetics has been increasingly recognized in the etiology of breast cancer, relatively few studies have investigated the epigenetic link between circadian disruption (CD) and breast cancer. Using a proven photoperiod-shifting paradigm, differing degrees of CD, various tissue extraction time points, and Illumina sequencing, we investigated the effect of CD on miRNA expression in the mammary tissues of a rodent model system. To our knowledge, our results are the first to illustrate CD-induced changes in miRNA expressions in mammary tissues. Furthermore, it is likely that these miRNA expression changes exhibit varying time frames of plasticity linked to both the degree of CD and length of reentrainment, and that the expression changes are influenced by the light and dark phases of the 24-hour circadian cycle. Of the differentially expressed miRNAs identified in the present study, all but one have been linked to breast cancer, and many have predicted circadian-relevant targets that play a role in breast cancer development. Based on the analysis of protein levels in the same tissues, we also propose that the initiation and development of CD-induced breast cancer may be linked to an interconnected web of increased NF-kappaB activity and increased levels of Tudor-SN, STAT3, and BCL6, with aberrant CD-induced downregulation of miR-127 and miR-146b potentially contributing to this dynamic. This study provides direct evidence that CD induces changes in miRNA levels in mammary tissues with potentially malignant consequences, thus indicating that the role of miRNAs in CD-induced breast cancer should not be dismissed. PMID- 26097877 TI - Expression of cancer stem cell biomarkers as a tool for a correct therapeutic approach to hepatocellular carcinoma. AB - Liver cancer is the fifth most commonly diagnosed malignancy and the second most frequent cause of cancer death in men worldwide. Amongst liver cancers, hepatocellular carcinoma (HCC) represents the major histological subtype and it is one of the most common malignant human tumors worldwide. Research into the molecular biology of hepatocarcinogenesis has identified several biomarkers, which could provide additional informations in order to better understand the biology of HCC. A large number of biomarkers have been shown to have potential predictive significance and a wide variety of molecular markers have been proven to be excellent diagnostic tools for HCC but it is difficult to characterize HCC with a single biomarker. Thus, signatures of a combination of biomarkers may be more valuable for the diagnosis, staging and prognosis of HCC. Specifically, a correlation of HCC-CSCs phenotype to specific hepatic cancer subtypes and to specific clinical and pathological features has not yet been reported in human liver tumors. In this view we will first discuss the possible sources of liver stem cells and their relation with liver cancer development and we will secondly focus on the prognostic significance of clinical and pathological features of HCC. PMID- 26097878 TI - Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds. AB - Copper and gold complexes have clinical activity in several diseases including cancer. Recently, we have reported that the anti-cancer activity of copper (II) pyrithione CuPT and gold (I) complex auranofin is associated with targeting the 19S proteasome-associated deubiquitinases (DUBs), UCHL5 and USP14. Here we discuss metal DUB inhibitors in treating cancer and other diseases. (from Editor). Several copper and gold complexes have clinical activity in treating some human diseases including cancer. Recently, we have reported that the anti cancer activity of copper (II) pyrithione CuPT and gold (I) complex auranofin is tightly associated with their ability to target and inhibit the 19S proteasome associated deubiquitinases (DUBs), UCHL5 and USP14. In this article we review small molecule inhibitors of DUBs and 19S proteasome-associated DUBs. We then describe and discuss the ubique nature of CuPT and auranofin, which is inhibition of 19S proteasome-associated UCHL5 and USP14. We finally suggest the potential to develop novel, specific metal-based DUB inhibitors for treating cancer and other diseases. PMID- 26097879 TI - The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis. AB - Cancers of unknown primary site are metastatic cancers for which primary tumors are not found after detailed investigations. In many cases, the site of origin is not identified even on postmortem examination. These cancers are the fourth most common cause of cancer death. The biological events involved in the development of this type of cancers remain unknown. This manuscript discusses that, like metastatic cells, stem cells have a natural ability to migrate. A cancer of unknown primary site would form when deregulated, premalignant or cancerous stem cells migrated away from their natural tissue and gave rise to a cancer in a new site before or without generating a tumor in their original tissue. It is important to realize that forming a tumor in a tissue is not a prerequisite for stem cells to migrate away from that tissue. This view is in accordance with recent observations that strongly support the tumorigenesis model in which cancer arises from normal stem cells. Evidence has accumulated that cancer stem cells may play a key role in cancer progression and resistance to therapy. Successful treatment of cancer, including that of unknown primary site, may therefore require the development of therapies against cancer stem cells. PMID- 26097880 TI - Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells. AB - Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) holds great promise for cancer treatment. We recently developed CAR T cells targeting the prototypic cancer stem cell marker AC133 and showed that these CAR T cells killed AC133+ glioblastoma stem cells (GBM-SCs) in vitro and inhibited the growth of brain tumors initiated from GBM-SCs in xenograft mouse models in vivo . Upon coincubation with GBM-SCs, we observed strong upregulation of the T cell aging marker CD57, but other phenotypical or functional changes usually associated with terminal T cell differentiation could not immediately be detected. Here, we provide evidence suggesting that CD57 is rapidly and efficiently transferred from CD57+ GBM-SCs to preactivated T cells and that the transfer is greatly enhanced by specific CAR/ligand interaction. After separation from CD57+ tumor cells, CD57 epitope expression on T cells decreased only slowly over several days. We conclude that CD57 transfer from tumor cells to T cells may occur in patients with CD57+ tumors and that it may have to be considered in the interpretation of phenotyping results for tumor-infiltrating lymphocytes and perhaps also in the characterization of tumor-specific T cells from tumor or lymph node homogenates or peripheral blood mononuclear cells. PMID- 26097881 TI - Another small molecule in the oncometabolite mix: L-2-Hydroxyglutarate in kidney cancer. AB - Alterations in metabolism are now considered a hallmark of cancer. One of the clearest links between metabolism and malignancy are oncometabolites. To date, several putative oncometabolites with transforming properties have been identified in the context of tumors due to both gain and loss of function mutations in genes encoding enzymes of intermediary metabolism. Through an unbiased metabolomics approach, we identified elevations of the metabolite 2 hydroxyglutarate (2-HG) in the most common histology of kidney cancer that is among the most common malignancies in both men and women. Subsequent analyses demonstrate that the predominant enantiomer of 2-HG elevated in renal cancer is the L(S) form. Notably, elevations of L-2HG are due in part to loss of expression of the L-2HG dehydrogenase (L2HGDH) which normally serves as an enzyme of "metabolite repair" to keep levels of this metabolite from accumulating. Lowering L-2HG levels in RCC through re-expression of L2HGDH mitigates tumor phenotypes and reverses epigenetic alterations known to be targeted by oncometabolites. These data add to the growing body of evidence that metabolites, similarly to oncogenes and oncoproteins, can play a role in tumor development and/or progression. As such, they represent a unique opportunity to utilize these findings in the clinic setting. PMID- 26097883 TI - Uncovering potential downstream targets of oncogenic GRPR overexpression in prostate carcinomas harboring ETS rearrangements. AB - Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in several human malignancies, including prostate cancer, and has been implicated in multiple important neoplastic signaling pathways. We recently have shown that GRPR is an ERG and ETV1 target gene in prostate cancer, using a genome-wide scale and exon-level expression microarray platform. Due to its cellular localization, the relevance of its function and the availability of blocking agents, GRPR seems to be a promising candidate as therapeutic target. Our present work shows that effective knockdown of GRPR in LNCaP and VCaP cells attenuates their malignant phenotype by decreasing proliferation, invasion and anchorage-independent growth, while increasing apoptosis. Using an antibody microarray we were able to validate known and identify new targets of GRPR pathway, namely AKT1, PKCepsilon, TYK2 and MST1. Finally, we show that overexpression of these GRPR targets is restricted to prostate carcinomas harboring ERG and/or ETV1 rearrangements, establishing their potential as therapeutic targets for these particular molecular subsets of the disease. PMID- 26097882 TI - A meta-analysis to evaluate the cellular processes regulated by the interactome of endogenous and over-expressed estrogen receptor alpha. AB - The nature of the proteins complexes that regulate ERalpha subcellular localization and activity is still an open question in breast cancer biology. Identification of such complexes will help understand development of endocrine resistance in ER+ breast cancer. Mass spectrometry (MS) has allowed comprehensive analysis of the ERalpha interactome. We have compared six published works analyzing the ERalpha interactome of MCF-7 and HeLa cells in order to identify a shared or different pathway-related fingerprint. Overall, 806 ERalpha interacting proteins were identified. The cellular processes were differentially represented according to the ERalpha purification methodology, indicating that the methodologies used are complementary. While in MCF-7 cells, the interactome of endogenous and over-expressed ERalpha essentially represents the same biological processes and cellular components, the proteins identified were not over-lapping; thus, suggesting that the biological response may differ as the regulatory/participating proteins in these complexes are different. Interestingly, biological processes uniquely associated to ERalpha over-expressed in HeLa cell line included L-serine biosynthetic process, cellular amino acid biosynthetic process and cell redox homeostasis. In summary, all the approaches analyzed in this meta-analysis are valid and complementary; in particular, for those cases where the processes occur at low frequency with normal ERalpha levels, and can be identified when the receptor is over-expressed. However special effort should be put into validating these findings in cells expressing physiological ERalpha levels. PMID- 26097884 TI - Methylation changes in the TFAP2E promoter region are associated with BRAF mutation and poorer overall & disease free survival in colorectal cancer. AB - INTRODUCTION: BRAF mutant colorectal cancer carries a poor prognosis which is thought to be related to poor response to conventional chemotherapy. BRAF mutation is associated with the serrated tumour phenotype. We hypothesised that one of the mechanisms by which BRAF mutant colorectal cancer demonstrate poor outcomes with chemotherapy is abnormal gene methylation. METHODS: The Cancer Genome Atlas (TCGA) methylation data was analysed using a linear regression model with BRAF mutation as an independent variable. Expression datasets were also obtained to correlate functional changes. Top differentially methylated probes were taken forward for validation by methylation pyrosequencing. These probes were analysed on a cohort of patients enriched for BRAF mutations taken from the VICTOR and QUASAR2 studies. RESULTS: In an analysis of 91 tumours (9 BRAF mutant, 82 wild type), the Illumina probe cg11835197 was the probe identified as top differentially methylated (p = 2.56*10-7, Bayes Factor (BF) =6.54). This probe covered a region -413bp from the promoter region of TFAP2E. We found a complex pattern of CpG specific methylation of this region which was associated with both overall (p=0.044) and disease free (p=0.046) survival. DISCUSSION: BRAF mutant tumours may attain part of their chemoresistance from abnormal TFAP2E methylation, which has not previously been described. PMID- 26097885 TI - Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. AB - Oncogenic KRas reprograms pancreatic ductal adenocarcinoma (PDAC) cells to states which are highly resistant to apoptosis. Thus, a major preclinical goal is to identify effective strategies for killing PDAC cells. Artesunate (ART) is an anti malarial that specifically induces programmed cell death in different cancer cell types, in a manner initiated by reactive oxygen species (ROS)-generation. In this study we demonstrate that ART specifically induced ROS- and lysosomal iron dependent cell death in PDAC cell lines. Highest cytotoxicity was obtained in PDAC cell lines with constitutively-active KRas, and ART did not affect non neoplastic human pancreatic ductal epithelial (HPDE) cells. We determined that ART did not induce apoptosis or necroptosis. Instead, ART induced ferroptosis, a recently described mode of ROS- and iron-dependent programmed necrosis which can be activated in Ras-transformed cells. Co-treatment with the ferroptosis inhibitor ferrostatin-1 blocked ART-induced lipid peroxidation and cell death, and increased long-term cell survival and proliferation. Importantly, analysis of PDAC patient mRNA expression indicates a dependency on antioxidant homeostasis and increased sensitivity to free intracellular iron, both of which correlate with Ras-driven sensitivity to ferroptosis. Overall, our findings suggest that ART activation of ferroptosis is an effective, novel pathway for killing PDAC cells. PMID- 26097886 TI - Retrospective Review of MET Gene Mutations. AB - C-MET proto-oncogene is a tyrosine kinase situated on chromosome 7. C-MET and its ligand hepatocyte growth factor/scatter factor (HGF/SF) play a role in proliferation, differentiation and organ development. C-MET genetic aberrations are found associated with driving tumorigenesis. In this retrospective study, we reviewed molecular analysis data gathered from a cancer institute during a two year period (2010-2012). Upon detection of tumors harboring c-MET mutations, we determined the status of the other mutations tested and evaluated c-MET expression by fluorescent in-situ hybridization (FISH). Our search resulted in identification of 134 c-MET mutations, 44% of which had mutations of at least one of the other genes tested. No c-MET expression aberrancy was detected in this subset by FISH. Survival amongst the patients with surgically resected metastatic colorectal cancers (CRC) was slightly better in those with only a c-MET mutation compared to those with no mutation detected, although the difference was not statistically significant. When c-MET inhibition becomes an integrated part of chemotherapy practice, our observed frequency of co-mutations will be an argument for utilizing c-MET targeted treatment in combination with other targeted drugs and therapeutic strategies. Larger studies can aid to further parse out c-MET prognostic and therapeutic significance. PMID- 26097887 TI - A quasi-quantitative dual multiplexed immunoblot method to simultaneously analyze ATM and H2AX Phosphorylation in human peripheral blood mononuclear cells. AB - Pharmacologic inhibition of DNA repair may increase the efficacy of many cytotoxic cancer agents. Inhibitors of DNA repair enzymes including APE1, ATM, ATR, DNA-PK and PARP have been developed and the PARP inhibitor olaparib is the first-in-class approved in Europe and the USA for the treatment of advanced BRCA mutated ovarian cancer. Sensitive pharmacodynamic (PD) biomarkers are needed to further evaluate the efficacy of inhibitors of DNA repair enzymes in clinical trials. ATM is a protein kinase that mediates cell-cycle checkpoint activation and DNA double-strand break repair. ATM kinase activation at DNA double-strand breaks (DSBs) is associated with intermolecular autophosphorylation on serine 1981. Exquisite sensitivity and high stoichiometry as well as facile extraction suggest that ATM serine-1981 phosphorylation may be a highly dynamic PD biomarker for both ATM kinase inhibitors and radiation- and chemotherapy-induced DSBs. Here we report the pre-clinical analytical validation and fit-for-purpose biomarker method validation of a quasi-quantitative dual multiplexed immunoblot method to simultaneously analyze ATM and H2AX phosphorylation in human peripheral blood mononuclear cells (PBMCs). We explore the dynamics of these phosphorylations in PBMCs exposed to chemotherapeutic agents and DNA repair inhibitors in vitro, and show that ATM serine-1981 phosphorylation is increased in PBMCs in sarcoma patients treated with DNA damaging chemotherapy. PMID- 26097888 TI - TALEN-mediated apc mutation in Xenopus tropicalis phenocopies familial adenomatous polyposis. AB - Truncating mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are the initiating step in the vast majority of sporadic colorectal cancers, and they underlie familial adenomatous polyposis (FAP) syndromes. Modeling of APC- driven tumor formation in the mouse has contributed substantially to our mechanistic understanding of the associated disease, but additional models are needed to explore therapeutic opportunities and overcome current limitations of mouse models. We report on a novel and penetrant genetic cancer model in Xenopus tropicalis, an aquatic tetrapod vertebrate with external development, diploid genome and short life cycle. Tadpoles and froglets derived from embryos injected with TAL effector nucleases targeting the apc gene rapidly developed intestinal hyperplasia and other neoplasms observed in FAP patients, including desmoid tumors and medulloblastomas. Bi-allelic apc mutations causing frame shifts were detected in the tumors, which displayed activation of the Wnt/beta-catenin pathway and showed increased cellular proliferation. We further demonstrate that simultaneous double bi-allelic mutation of apc and a non relevant gene is possible in the neoplasias, opening the door for identification and characterization of effector or modifier genes in tumors expressing truncated apc. Our results demonstrate the power of modeling human cancer in Xenopus tropicalis using mosaic TALEN-mediated bi-allelic gene disruption. PMID- 26097889 TI - Targeting Matrix Metalloproteinases in Cancer: Bringing New Life to Old Ideas. AB - Since the identification of matrix metalloproteinases (MMPs), a family of zinc dependent endopeptidases, as being a driving factor for cancer progression and patient prognosis, MMPs have been studied extensively. Although early programs targeting MMPs were largely unsuccessful in clinical trials, they remain a viable and highly desirable therapeutic target based on preclinical studies and their role in disease progression. As information regarding the structure and function of these proteinases is compiled and biotechnology evolves, tools to develop better inhibitors is within our grasp. Improved methods for high throughput screening and in silico drug design programs have identified compounds which are highly potent, have high binding affinities, and exhibit favorable pharmacokinetic profiles. More recently, advances in drug delivery methods or compounds which bind outside the active site have brought new light to the field. In this review, we highlight the role of MMPs in cancer, clinical trials for MMP inhibitors, and novel approaches to targeting MMPs in cancer. PMID- 26097890 TI - The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study. AB - Fibroblast growth factor receptors (FGFRs) are recognized therapeutic targets in cancer. We here describe insights underpinning the impact of mutations on FGFR1 and FGFR3 kinase activity and drug efficacy, using a combination of computational calculations and experimental approaches including cellular studies, X-ray crystallography and biophysical and biochemical measurements. Our findings reveal that some of the tested compounds, in particular TKI258, could provide therapeutic opportunity not only for patients with primary alterations in FGFR but also for acquired resistance due to the gatekeeper mutation. The accuracy of the computational methodologies applied here shows a potential for their wider application in studies of drug binding and in assessments of functional and mechanistic impacts of mutations, thus assisting efforts in precision medicine. PMID- 26097891 TI - Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand * Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-Resistant B-Precursor Acute Lymphoblastic Leukemia in Mice. AB - In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after use of very intensive total body irradiation (TBI)-based conditioning regimens, especially in patients with a high "minimal residual disease" (MRD) burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand * soluble TRAIL ("CD19L-sTRAIL") fusion protein. CD19L-sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. Low dose total body irradiation (TBI) combined with CD19L sTRAIL was highly effective against (1) xenografted CD19+ radiochemotherapy resistant human BPL in NOD/SCID (NS) mice challenged with an otherwise invariably fatal dose of xenograft cells derived from relapsed BPL patients as well as (2) radiation-resistant advanced stage CD19+ murine BPL with lymphomatous features in CD22DeltaE12xBCR-ABL double transgenic mice. We hypothesize that the incorporation of CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk BPL will improve their survival outcome after HSCT. PMID- 26097892 TI - Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression. AB - BACKGROUND: Aspirin intake reduces the risk of colorectal cancer (CRC), but the molecular underpinnings remain elusive. Epidermal growth factor receptor (EGFR), which is overexpressed in about 80% of CRC cases, is implicated in the etiology of CRC. Here, we investigated whether aspirin can prevent CRC by normalizing EGFR expression. METHODS: Immunohistochemistry staining was performed on paraffin embedded tissue sections from normal colon mucosa, adenomatous polyps from FAP patients who were classified as regular aspirin users or nonusers. The interplay between cyclooxygenase-2 (COX-2) and EGFR was studied in primary intestinal epithelial cells isolated from ApcMin mice, immortalized normal human colon epithelial cells (HCEC) as well as murine embryonic fibroblasts (MEFs). RESULTS: Immunohistochemistry staining results established that EGFR overexpression is an early event in colorectal tumorigenesis, which can be greatly attenuated by regular use of aspirin. Importantly, EGFR and COX-2 were co-overexpressed and co localized with each other in FAP patients. Further mechanistic studies revealed that COX-2 overexpression triggers the activation of the c-Jun-dependent transcription factor, activator protein-1 (AP-1), which binds to the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation. CONCLUSION: Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions. PMID- 26097893 TI - Impact of binge alcohol on mortality among people who inject drugs. AB - INTRODUCTION: While the impacts of illicit drug use on mortality have been well described, the impact of poly-substance that includes alcohol has received less attention. We examined the impact of binge alcohol use on mortality among a cohort of people who inject drugs (PWID) in a Canadian setting. METHODS: Using data derived from a prospective cohort study of PWID in Vancouver, Canada recruited between May 1996 and November 2013. We ascertained dates and causes of death through a confidential linkage with the provincial registry and examined the impact of binge alcohol use. The primary outcome of interest was all-cause mortality. We used Cox proportional hazard regression to determine factors associated with mortality, including socio-demographic characteristics, drug use patterns and other risk behaviours. RESULTS: During the study period, 2550 individuals were followed (844 of whom were HIV positive at baseline) for a median of 75.4 months (interquartile range 37.9 113.2). Of these, 795 (31%) participants reported binge alcohol use at some time during the study period. In multivariable analyses, binge alcohol use remained independently associated with all-cause-mortality (adjusted hazard ratio=1.41; 95% confidence interval: 1.06 1.88) after adjustment for other drug use patterns. CONCLUSIONS: Binge alcohol use was associated with time to all-cause mortality among PWID in this setting. Since alcohol use is often overlooked as a risk factor for mortality among this population, these findings highlight the continued need to incorporate addiction treatment and public health interventions and policies that address binge alcohol use to reduce alcohol related-harms. PMID- 26097894 TI - The roles of redox enzymes in Parkinson's disease: Focus on glutaredoxin. AB - Parkinson's disease (PD) results from the loss of dopaminergic neurons in the substantia nigra portion of the midbrain, and represents the second most common neurodegenerative disease in the world. Although the etiology of PD is currently unclear, oxidative stress and redox dysfunction are generally understood to play key roles in PD pathogenesis and progression. Aging and environmental factors predispose cells to adverse effects of redox changes. In addition to these factors, genetic mutations linked to PD have been observed to disrupt the redox balance. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with autosomal dominant PD, and several of these mutations have also been shown to increase the levels of reactive oxygen species in cells. Anti-oxidant proteins are necessary to restore the redox balance and maintain cell viability. Over the past decade studies have started to demonstrate the critical importance for redox proteins mediating neuronal protection in models of PD. This commentary briefly describes some of the factors hypothesized to contribute to PD, specifically regarding the redox changes that occur in PD. Dysregulation of redox proteins in PD is highlighted by some of the work detailing the roles of peroxiredoxin-3 and thioredoxin-1 in models of PD. In an attempt to generate novel therapies for PD, several potent inhibitors of LRRK2 have been developed. The use of these compounds, both as tools to understand the biology of LRRK2 and as potential therapeutic strategies is also discussed. This mini-review then provides a historical prospective on the discovery and characterization of glutaredoxin (Grx1), and briefly describes current understanding of the role of Grx1 in PD. The review concludes by highlighting our recent publication describing the novel role for Grx1 in mediating dopaminergic neuronal protection both in vitro and in vivo. PMID- 26097895 TI - Role of Kruppel-like factor 5 in the maintenance of the stem cell niche in the intestinal crypt. AB - The intestinal epithelium is a tissue that undergoes continuous self-renewal initiated at the bottom of the crypts, which harbor the intestinal stem cell (ISC) pool. The ISC pool is sub-divided into crypt base columnar (CBC) cells at the crypt bottom and label retention cells (LRC) at position +4 from the crypt bottom. CBC cells are marked by Leucine-rich repeat-containing G-protein coupled receptor (Lgr5) while LRC cells are identified by several markers including Bmi1, mTert, Hopx, Lrig1, and Sox9. Kruppel-like factors (KLFs) belong to a family of transcription factors that exert important physiological function in various tissues. In the intestine, KLF4 is predominantly expressed in the terminally differentiated, non-proliferating cells lining the villus. Its deletion in the adult mouse intestine results in perturbed homeostasis. In contrast, KLF5 is expressed in actively proliferating cells of the intestinal crypt, including CBC cells and transit amplifying (TA) cells. We recently investigated the effect of Klf5 deletion specifically from the Lgr5-expressing CBC cells in adult mouse intestine using an inducible Cre recombinase system. Shortly (3-5 days) after Cre induction, proliferation of both CBC and TA cells ceased, which was accompanied by an increase in apoptosis in the crypt. Beginning at two weeks following Cre induction, both Klf5 expression and proliferation re-appeared but without the re emergence of Lgr5-positive CBC cells, which were eventually depleted by four months following induction. These findings indicate that KLF5 plays an important role in regulating proliferation and survival of CBC stem cells in the intestine. PMID- 26097897 TI - REPRODUCING SINGLETONS AND FAKE GEMINATES. AB - Thirty-two native American-English speaking children and adults reliably reproduced a non-contrastive segmental length distinction encoded in a set of monomorphemic nonce words. However, participants were unable to explicitly identify the contrast in a same/different judgment task. The results support the view that grammatically irrelevant, lexically specific temporal patterns can be learned and are represented in the lexicon. PMID- 26097896 TI - Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer's disease (AD). AB - According to the 'amyloid cascade hypothesis of Alzheimer's disease' first proposed about 16 years ago, the accumulation of Abeta peptides in the human central nervous system (CNS) is the primary influence driving Alzheimer's disease (AD) pathogenesis, and Abeta peptide accretion is the result of an imbalance between Abeta peptide production and clearance. In the last 18 months multiple laboratories have reported two particularly important observations: (i) that because the microbes of the human microbiome naturally secrete large amounts of amyloid, lipopolysaccharides (LPS) and other related pro-inflammatory pathogenic signals, these may contribute to both the systemic and CNS amyloid burden in aging humans; and (ii) that the clearance of Abeta peptides appears to be intrinsically impaired by deficits in the microglial plasma-membrane enriched triggering receptor expressed in microglial/myeloid-2 cells (TREM2). This brief general commentary-perspective paper: (i) will highlight some of these very recent findings on microbiome-secreted amyloids and LPS and the potential contribution of these microbial-derived pro-inflammatory and neurotoxic exudates to age-related inflammatory and AD-type neurodegeneration in the host; and (ii) will discuss the contribution of a defective microglial-based TREM2 transmembrane sensor-receptor system to amyloidogenesis in AD that is in contrast to the normal, homeostatic clearance of Abeta peptides from the human CNS. PMID- 26097898 TI - TOWARDS UNDERSTANDING THE PROTRACTED ACQUISITION OF ENGLISH RHYTHM. AB - Several global and specific rhythm metrics and speech rate were used to characterize differences in the rhythms of 5- and 8-year-olds' spoken English. The results were that only speech rate and the rate-normalized Pairwise Variability Index (nPVI) differentiated between 5- and 8-year-olds' speech. A further result was that the variance in nPVI values was better explained by a specific measure devised to capture patterns of supralexical accenting than by the factor of age expressed in months. These results are taken to suggest that the protracted acquisition of English rhythm may be due in part to the slow rate at which children acquire prosodically conditioned vowel reduction. PMID- 26097899 TI - A Low-Cost Smartphone-Based Electrochemical Biosensor for Point-of-Care Diagnostics. AB - This paper describes the development of a smartphone-based electrochemical biosensor module. The module contains a low power potentiostat that interfaces and harvests power from a smartphone through the phone's audio jack. A prototype with two different potentiostat designs was constructed and used to conduct proof of concept cyclic voltammetry experiments with potassium ferro-/ferricyanide (K4[Fe(CN)6] / K3[Fe(CN)6]) in a side-by-side comparison with a laboratory grade instrument. Results show that the module functions within the available power budget and that the recovered voltammogram data matches well with the data from an expensive bench top tool. Excluding the loses from supply rectification and regulation, the module consumes either 5.7 mW or 4.3 mW peak power, depending on which of the two discussed potentiostat designs is used. At single quantity pricing, the hardware for the prototype device costs less than $30. PMID- 26097900 TI - A Question of Scope? Direct Comparison of Clear and In-Focus Speech Productions. AB - Parallels in the production of clear speech and words under prosodic focus suggest that both may be realized in the same way: as hyper-articulated speech. To directly investigate this possibility, school-aged children and college-aged adults produced target words in a default conversational style, a clear speech style, and with prosodic focus. The results were that children and adults both produced target vowels more distinctly and with greater mouth opening in the clear speech and prosodic focus conditions than in the default condition. Whereas the temporal scope of production changes varied as a function of condition in adults' speech, there was no evidence of this in children's speech. PMID- 26097901 TI - Daclatasvir for the treatment of chronic hepatitis C virus infection. AB - Daclatasvir is a nonstructural protein 5A (NS5A) replication complex inhibitor that has shown potent in vitro activity against multiple hepatitis C virus (HCV) genotypes (GT). It is currently in advanced clinical development as a component of combination treatment regimens in a variety of HCV-infected patient populations. In studies conducted thus far, it has been generally well tolerated. It has been approved for the treatment of HCV GTs 1-4 in the European Union. The combination of daclatasvir and asunaprevir (an HCV NS3/4A protease inhibitor) has been approved in Japan for the treatment of patients with GT1 HCV infection. Here we review the available literature on daclatasvir, including its information on its discovery, mechanism of action, pharmacology, preclinical and clinical activity, resistance and safety. PMID- 26097902 TI - Faldaprevir for the treatment of hepatitis C. AB - Enormous progress has been made in the understanding of the hepatitis C virus and the development of novel therapeutic agents since the identification of the virus, from initial interferon monotherapy to PEGylated interferon in combination with ribavirin for 48-72 weeks that used to be the standard of care in hepatitis C virus therapy. However, this combination has limited efficacy and a significant side effect profile including flu-like symptoms, anemia, leukopenia, autoimmune disorders and depression, so it is often poorly tolerated. Recently, direct acting antiviral agents, such as the first-generation NS3/4A protease inhibitors, have been added to this combination, improving the percentage of successful treatments. Faldaprevir is a first-generation, second wave, protease inhibitor that, when combined with PEGylated interferon and ribavirin, has been shown to increase treatment success with shorter treatment duration. Various direct-acting antiviral agent combinations in interferon-free regimens have been effective in over 95% of patients and are now in licensed use. PMID- 26097903 TI - Working together to tackle HCV infection: ombitasvir/paritaprevir/ritonavir and dasabuvir combination. AB - An estimated 184 million people worldwide have hepatitis C virus (HCV) infection. Chronic infection can ultimately result in liver cirrhosis and hepatic failure. Eradication of the virus by antiviral treatment can hinder the development of the aforementioned complications. Historically, the combination therapy of PEGylated interferon/ribavirin was considered the standard-of-care therapy for HCV. Such therapy did not demonstrate satisfactory cure rates and had significant side effects that precluded its widespread use among HCV patients. In view of this situation, scientific advances have led to the development of new interferon-free regimens that are better tolerated, more effective and with shorter duration of therapy. One of the newest members of this family is the all-oral regimen (ombitasvir/paritaprevir/ritonavir co-packaged with dasabuvir) that has recently received FDA approval for the treatment of adult patients with genotype 1 HCV infection, including those with compensated cirrhosis. This new combination was found to be safe and well tolerated with high rates of sustained virologic response of up to 100%. An overview of the current knowledge about this regimen is reviewed herein. PMID- 26097904 TI - Current treatment and future prospects of dopa-induced dyskinesias. AB - Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials. PMID- 26097905 TI - A report from the American Association of Urology Annual Meeting 2015 (May 15-19 New Orleans, Louisiana, USA). AB - Sharing knowledge and setting standards were the main goals of the American Urological Association annual meeting 2015 held in the New Orleans Morial Convention Center. A short walk away from the famous French Quarter, and a walk that a very high number of attendees took daily for the duration of the conference to attend plenary, podium and moderated poster sessions wherein the latest research and advances in urologic medicine were being presented. Many novel scientific issues were discussed, notably in the setting of biomarkers cancer diagnosis, treatment and monitoring, but the conference included a vast array of topics covering all diseases affecting the urinary tract. PMID- 26097906 TI - Covalent nitrophenyl diazonium functionalized silicene for spintronics: a first principles study. AB - We predict some novel electronic and magnetic properties of a functionalized silicene sheet by nitrophenyl diazonium (NPD) using first-principles calculations in the framework of density functional theory with dispersion corrections. Our calculations at the HSE06 level show that for the three coverage ratios of NPD considered in this work (i.e., NPD : Si = 1 : 8, 1 : 18 and 1 : 32), spin polarized electronic structures can be always realized with NPD adsorption although the bandgap decreases upon reducing the NPD coverage ratio. The quasi localized pz electrons of Si are identified to be responsible for the ferrimagnetism in these two-dimensional systems. Remarkably, the system with the NPD : Si = 1 : 8 ratio is predicted to be a bipolar magnetic semiconductor. As such, half-metallicity can be realized by applying a gate voltage with reversible spin polarization, making NPD-1/8 a potential candidate for future spintronic applications. This work offers a new tailor-made functionalization approach to realize magnetic semiconducting silicene. PMID- 26097907 TI - 3D silicon neural probe with integrated optical fibers for optogenetic modulation. AB - Optogenetics is a powerful modality for neural modulation that can be useful for a wide array of biomedical studies. Penetrating microelectrode arrays provide a means of recording neural signals with high spatial resolution. It is highly desirable to integrate optics with neural probes to allow for functional study of neural tissue by optogenetics. In this paper, we report the development of a novel 3D neural probe coupled simply and robustly to optical fibers using a hollow parylene tube structure. The device shanks are hollow tubes with rigid silicon tips, allowing the insertion and encasement of optical fibers within the shanks. The position of the fiber tip can be precisely controlled relative to the electrodes on the shank by inherent design features. Preliminary in vivo rat studies indicate that these devices are capable of optogenetic modulation simultaneously with 3D neural signal recording. PMID- 26097908 TI - Synthesis of concave gold nanocuboids with high-index facets and their enhanced catalytic activity. AB - Novel concave gold nanocuboids bounded by 24 high-index {611} facets are synthesized using the seed-mediated growth method via an overgrowth mechanism. The as-synthesized products demonstrated greatly enhanced catalytic activity for the electro-oxidation of glucose and the reduction of 4-nitrothiophenol (4-NTP) under a laser. PMID- 26097909 TI - Multiple single-crystal-to-single-crystal guest exchange in a dynamic 1D coordination polymer. AB - A novel 1D coordination polymer that dynamically expands or shrinks upon the uptake of vapours of volatile small chlorinated molecules, such as 1,2 dichloroethane (DCE), dichloromethane (DCM) and trichloromethane (TCM), is reported. This system is robust enough to withstand multiple guest exchange via single-crystal-to-single-crystal transformation, as proved by (1)H-NMR and X-ray diffraction. The single crystal of guest-free, host framework, stable at 400 K, can also be obtained. PMID- 26097910 TI - High catalytic activity for water oxidation based on nanostructured nickel phosphide precursors. AB - For the first time, noble-metal-free nickel phosphide (Ni2P) was used as an excellent catalyst precursor for water oxidation catalysis. The lowest onset potential was observed at ~1.54 V (vs. RHE) and a Tafel slope of 60 mV dec(-1) was obtained in alkaline solution (pH = 13.6). PMID- 26097911 TI - Effect of microtubule polymerization on photoinduced hydrogen generation. AB - Herein we report a novel reaction field for photoinduced H2 generation by using microtubules as a medium. By controlling the tubulin/microtubule hierarchical structure, synergistic effects by which the Ru(bpy)3(2+)-conjugated microtubule network causes suppression of energy loss by collision are clarified. PMID- 26097912 TI - Hybridization chain reaction engineered dsDNA for Cu metallization: an enzyme free platform for amplified detection of cancer cells and microRNAs. AB - A novel enzyme-free platform for amplified detection of cancer cells and miRNAs was constructed with high sensitivity by fluorescent Cu metallization on HCR engineered dsDNA templates. PMID- 26097913 TI - Azo-functionalized microporous organic polymers: synthesis and applications in CO2 capture and conversion. AB - Azo-functionalized MOPs (Azo-MOPs) were synthesized via oxidative polymerization of aromatic amines catalyzed by t-BuOCl/NaI (25 degrees C, 1 h, yield: >95%), which displayed an excellent coordinating ability with a Ru complex. The resulting Ru-coordinated Azo-MOPs displayed high CO2 capacity and high performances for catalyzing the methylation of amines with CO2 under low pressure (0.5 MPa). PMID- 26097914 TI - Chemical etching of manganese oxides for electrocatalytic oxygen reduction reaction. AB - Mixed-valent MnO(x) (1 < x < 2) was selectively synthesized by chemically etching MnO and Mn2O3 with ceric ammonium nitrate. The obtained MnO(x) exhibited greatly enhanced electrocatalytic activity toward the oxygen reduction reaction (ORR) as compared to the corresponding pristine oxides. PMID- 26097915 TI - Enhanced stability of Zr-doped Ba(CeTb)O(3-delta)-Ni cermet membrane for hydrogen separation. AB - A mixed protonic and electronic conductor material BaCe(0.85)Tb(0.05)Zr(0.1)O(3 delta) (BCTZ) is prepared and a Ni-BCTZ cermet membrane is synthesized for hydrogen separation. Stable hydrogen permeation fluxes can be obtained for over 100 h through the Ni-BCTZ membrane in both dry and humid conditions, which exhibits an excellent stability compared with Ni-BaCe(0.95)Tb(0.05)O(3-delta) membrane due to the Zr doping. PMID- 26097916 TI - The detection of multiple DNA targets with a single probe using a conformation sensitive acoustic sensor. AB - By using an acoustic wave methodology that allows direct sensing of biomolecular conformations, we achieved the detection of multiple target DNAs using a single probe, exploiting the fact that each bound target results in a hybridized product of a different shape. PMID- 26097917 TI - Construction of the [6-7-5-5] tetracyclic core of all the carbocyclic frameworks of yuzurimine-type alkaloids. AB - Yuzurimine-type alkaloids make up a sub-family of Daphniphyllum alkaloids structurally featuring a [6-7-5-5] tetracarbocyclic core framework. In this manuscript, we describe our construction of the [6-7-5-5] tetracarbocyclic core of yuzurimine-type alkaloids by using a unique in situ intramolecular Wittig reaction and Sm-mediated cyclization as key steps. PMID- 26097918 TI - Metal-free hydrogen evolution with nanoparticles derived from pyrene via two photon ionization induced by laser irradiation. AB - Laser irradiation of a cyclohexane solution containing pyrene resulted in hydrogen evolution as pyrene was converted to a metal-free nanoparticle photocatalyst. When C6H12 was replaced by C6D12, D2 was mainly evolved. This result suggests that the hydrogen source is cyclohexane used as a solvent. Photocatalytic hydrogen evolution was also observed in an aqueous solution by using a water-soluble pyrene derivative. PMID- 26097919 TI - A supramolecular approach for designing emissive solid-state carbazole arrays. AB - Reactions of 5-(9H-carbazol-9-yl)-isophthalate and metal salts provide laminar metal organic frameworks (MOFs) wherein interlayer interactions of the pendant carbazoles engender extended aromatic stacks or non-stacked structures with enhanced solid-state emission. These studies emphasize that MOFs serve as versatile supramolecular platforms to direct the aggregation and electroptical behaviours of organic chromophores. PMID- 26097920 TI - An imine-based approach to prepare amine-functionalized Janus gold nanoparticles. AB - An imine-based approach was developed to prepare Janus gold nanoparticles (Janus AuNPs) having amine functionality on one patch of the surface and a polyethylene glycol unit on the other. This unique technique features covalent bonding as the force to immobilize AuNPs on the template, enabling direct modification of AuNPs in both water and organic solvents. Colloidal clusters were then obtained via electrostatic assembly of these Janus AuNPs with citrate stabilized AuNPs or AgNPs. PMID- 26097921 TI - Iridium-catalyzed regioselective decarboxylative allylation of beta-ketoacids: efficient construction of gamma,delta-unsaturated ketones. AB - A highly regioselective protocol for the direct synthesis of gamma,delta unsaturated ketones from beta-ketoacids and allylic alcohols was proposed and accomplished relying on the combination of [Ir(cod)Cl]2 and 10-camphorsulfonic acid via decarboxylative allylation. PMID- 26097922 TI - Increasing Families' Health Care Access and Choice Through Full Practice Authority. PMID- 26097923 TI - NAPNAP Position Statement on Immunizations. PMID- 26097924 TI - Update on Emerging Infections: News From the Centers for Disease Control and Prevention. Pertussis Epidemic-California, 2014. PMID- 26097925 TI - Treatment solution by Miyahara et al.: Treatment of choice for aortic arch aneurysm in a patient with cold agglutinin disease. PMID- 26097926 TI - A new species of Noblella (Anura: Craugastoridae) from the Amazonian Slopes of the Ecuadorian Andes with Ccomments on Noblella lochites (Lynch). AB - We describe a new species of Noblella from wet, montane forest at the Sardinayacu Lake Complex between 1600-1920 m elevation in Morona Santiago, Ecuador. The new species differs from congeners in having three phalanges in the fourth finger, finely tuberculate skin on the dorsal body, pointed digital tips with marginal grooves on the fingers, a yellow to pale yellow venter, and a reduced facial mask not extending beyond the arm. The new species also lacks the pair of inguinal spots on the dorsal flanks of most congeners. Since its discovery in 1976, N. lochites has remained poorly known. We describe variation, color in life, and basic ecology of N. lochites based on a large series from the Cordillera del Condor. PMID- 26097927 TI - Parapleisticantha Yokoya, 1933, a valid genus of deep-sea inachid spider crab from Japan and the Philippines (Crustacea: Decapoda: Brachyura: Majoidea), with the description of a new species. AB - The inachid spider crab genus, Parapleisticantha Yokoya, 1933 [type species: Parapleisticantha japonica Yokoya, 1933] is removed from the synonymy of Pleistacantha Miers, 1879 [type species: Pleistacantha sanctijohannis Miers, 1879], and recognised as a valid genus. Parapleisticantha differs from Pleistacantha sensu stricto primarily by having a less spiny carapace, stouter and more inflated male chelipeds, and by lacking a slender subdistal process on the male first gonopod. We redescribe Parapleisticantha japonica based on the Japanese type material and describe as new a second species, Parapleisticantha ludivinae n. sp., recently discovered in the Philippines. PMID- 26097928 TI - The genus Adicella McLachlan (Trichoptera, Leptoceridae) in Japan. AB - The Japanese species of the genus Adicella McLachlan (Trichoptera, Leptoceridae) are reviewed and confirmed, including a described species and 3 new species: A. makaria Malicky & Chantaramongkol 2002, originally described from Taiwan, A. trichotoma Ito & Kuhara sp. nov., A. paludicola Ito & Kuhara sp. nov., and A. strigillata Katsuma & Ito sp. nov. For clear comparisons, adults of all species are redescribed or described. PMID- 26097929 TI - Three new species of the genus Nothrholaspis (Acari: Macrochelidae) from the Kelkit Valley, Turkey. AB - Three new species of mites of the genus Nothrholaspis Berlese, 1918 are described from specimens collected in the Kelkit Valley, Turkey--Nothrholaspis turcicus sp. nov., N. anatolicus sp. nov. and N. dogani sp. nov. The genus Nothrholaspis is recorded from Turkey for the first time. An identification key for the new species and a tabular key for the all known species of the genus are included. PMID- 26097930 TI - A new species of masked-owl (Aves: Strigiformes: Tytonidae) from Seram, Indonesia. AB - We describe a new species of masked-owl from the lower montane forest of Seram, one of the largest islands in the Moluccas of eastern Indonesia, for which we propose the name Tyto almae (Seram Masked-Owl), sp. nov. Molecular (mitochondrial cyt-b) differences show that Tyto sororcula of Buru and Tanimbar is closely related to T novaehollandiae of Australia and New Guinea (-1% uncorrected pairwise distance), and that Tyto almae of Seram differs by -3% (uncorrected pairwise distance) from both of them. These differences are further corroborated by morphology and colouration. Although a photograph from Seram published in 1987 had already established the presence of a Tyto owl on the island, ours represents the first specimen of this species. The bird was mist-netted in wet, mossy lower montane forest at an elevation of 1,350 m. No further observations of the owl were made during four weeks of fieldwork in Seram. PMID- 26097931 TI - The identity of the cyprinid fishes Rasbora dusonensis and R. tornieri (Teleostei: Cyprinidae). AB - Rasbora dusonensis, R. tornieri and R. myersi are valid species. Rasbora dusonensis sensu Brittan (1954) is R. tornieri and R. dusonensis sensu Kottelat (1991) is R. myersi. Both R. dusonensis and R. tornieri are members of the R. argyrotaenia group and can be distinguished from congeners in having a broad, dark, sharply-defined midlateral stripe on body extending from opercle to caudal fin base and separated from the dark dorsum by a highly contrasting light longitudinal area; 12-14 predorsal scales; the dorsohypural distance equal to or slightly less than the distance between the dorsal-fin origin and the posterior orbital margin and 14 circumpeduncular scale rows. The two species differ from each other by the color and color pattern on the caudal fin, and caudal peduncle depth. PMID- 26097932 TI - On the crab spider genus Angaeus Thorell, 1881 and its junior synonym Paraborboropactus Tang and Li, 2009 (Araneae: Thomisidae). AB - Morphological comparison of the genera Angaeus Thorell, 1881 and Paraborboropactus Tang and Li, 2009 (Araneae: Thomisidae) shows that the latter should be relegated to a junior synonym of the former. Further, I propose the following new synonyms: Angaeus leucomenus (Thorell, 1895), Stephanopis weyersi Simon, 1899 and Paraborboropactus leguminaceus Tang and Li, 2009 = Angaeus rhombifer Thorell, 1890 syn. nov., Paraborboropactus oblatus Tang and Li, 2010 = Angaeus lenticulosus Simon, 1903 syn. nov. The following species are transferred from Paraborboropactus: Angaeus canalis (Tang & Li, 2010) comb. nov., Angaeus liangweii (Tang & Li, 2010) comb. nov., Angaeus rhombus (Tang & Li, 2009) comb. nov. and Angaeus zhengi (Tang & Li, 2009) comb. nov. The holotype of Angaeus pudicus (type species of the genus) is illustrated, and the male and female of Angaeus rhombifer are redescribed and illustrated based partly on fresh material from Singapore. A new species, Angaeus christae sp. nov. is described based on both sexes, and a syntype of Angaeus comatulus Simon, 1909 is illustrated. PMID- 26097933 TI - Four new records of Conidae (Mollusca: Caenogastropoda) from the Andaman Islands, India. AB - The Andaman and Nicobar archipelago comprises 572 islands spread over an area of 8,249 sq. km. These islands are within the 'Indo-Malayan region' and near the 'faunistic centre' from which other Indo-West Pacific regions recruit their tropical marine fauna (Ekman, 1953). The topographically complex nature of the nearshore environments of these islands creates a plethora of niches that support a rich and diverse molluscan fauna. Many of the Conus species (e.g., C. geographus Linnaeus, 1758; C. miles Linnaeus, 1758; and C. striatus Linnaeus, 1758) that occupy these islands are broadly distributed throughout the Indo-West Pacific. However, a few Indo-West Pacific species (e.g., Conus andamanensis Smith, 1878; and C. araneosus nicobaricus Hwass in Bruguiere, 1792) are restricted to small geographic regions (Rockel et. al. 1995). Early oceanographic expeditions of the Andaman and Nicobar Islands that began in 1788 report only 10 Conus species from these islands (Smith, 1878; Melvill & Sykes, 1898; Preston, 1908). More recently, Subba Rao (1980) of the Zoological Survey of India (ZSI) reports a total of 51 Conus species from this region. In the past two decades, the Conus fauna has not been studied extensively due to lack of focused studies in the Andaman and Nicobar Islands. Several recent surveys conducted by the Andaman and Nicobar Centre for Ocean Science and Technology investigated the intertidal and subtidal macrobenthic fauna of the Andaman Islands. The present study reports four Conus species for the first time from this location. The observations of multiple living specimens of each species confirm this report. Three species (Conus leopardus Roding, 1798, C. litoglyphus Hwass in Bruguiere, 1792 and C. striatellus Link, 1807) are new records from Andaman Islands and one (Conus coffeae Gmelin, 1791) represents a new record for India. One specimen of each species was deposited in the National Zoological Collections, ZSI/ANRC, Port Blair, India. PMID- 26097934 TI - A new miniature species of the milliped genus Cleidogona from Costa Rica (Diplopoda, Chordeumatida, Cleidogonidae), with a review of Central American Cleidogonidae. AB - Cleidogona huebnerae, n. sp., is described from La Gamba Tropical Research Station, Costa Rica. A total of sixteen species in three genera of Cleidogonidae are known from Central America (Guatemala south to Panama), and they are reviewed here. PMID- 26097935 TI - Description of the male of Sebasthetops omaliniformis Jach, 1998--a phylogenetically isolated water beetle from South Africa, with notes on its ecology (Coleoptera, Hydraenidae). AB - Sebasthetops omaliniformis Jach, 1998, is a morphologically aberrant hydraenid, known from two female specimens collected from the Western Cape of South Africa in 1988. Recent fieldwork has resulted in the rediscovery of the species, close to the type locality. The male of S. omaliniformis is described from this material, and the opportunity taken to publish a record of Sebasthetops from the Langeberg, where it was collected in 1979. S. omaliniformis lives in deep water riffles in the upper reaches of mountain streams, and is strongly brachypterous. Like a number of other running-water insects known from the Cape fold mountains the species appears to have a narrow geographical and ecological range, deserving of high conservation status. PMID- 26097936 TI - Three new species in the subfamily Eriopeltinae Sulc from Italy (Hemiptera, Coccoidea, Coccidae) with comments on the genus Lecanopsis. AB - Three new coccid species, namely Hadzibejliaspis ferenci Pellizzari n. sp., Lecanopsis sicula Pellizzari n. sp. and L. salvatorei Pellizzari n. sp. are described and illustrated. Identification keys for the genera in the subfamily Eriopeltinae Sulc and to species in the genera Hadzibejliaspis Koteja and Lecanopsis Targioni Tozzetti are provided. PMID- 26097937 TI - Paleocene origin of the cockroach families Blaberidae and Corydiidae: Evidence from Amur River region of Russia. AB - Morphna paleo sp. n., the earliest winged representative of any living cockroach genus and the earliest representative of the family Blaberidae, is described from the Danian Arkhara-Boguchan coal mine in the Amur River region (Russian Far East). The branched Sc and A suggest Ectobiidae (=Blattellidae) probably is not the ancestral family because Blaberidae were derived directly from the extinct family Mesoblattindae. The associated Danian locality Belaya Gora yielded Ergaula stonebut sp. n., the earliest record of the family Corydiidae. Both species belong to genera codominant in the Messel locality, thus validating their dominance in early Cenozoic assemblages. PMID- 26097938 TI - Brachyrhynchus n. gen. n. sp., a new genus of Polycystididae Graff, 1905 (Rhabdocoela: Kalyptorhynchia), with the description of three new species from the Mediterranean and the Indian Ocean. AB - Three new species of Polycystididae are described: Brachyrhynchus triplostylis n. gen. n. sp., B. acutus n. sp. and B. oosterlyncki n. sp. They are the first species of Polycystididae to be described with a second, single-walled accessory stylet connected to a small glandular vesicle in the male system. The three species can be distinguished from each other by the detailed morphology and the relative lengths of the three stylets in the male system. The relationships of these species with other representatives of Polycystididae are discussed. PMID- 26097939 TI - Benthic amphipods (Amphipoda: Gammaridea and Corophiidea) from the Mexican southeast sector of the Gulf of Mexico: checklist, new records and zoogeographic comments. AB - The southeast region of the Gulf of Mexico is considered to be biologically important, because it is a connection and transition zone between the Caribbean and the Gulf of Mexico, harboring great marine biodiversity. Nevertheless, benthic amphipods have been poorly studied in the Mexican southeast sector of the Gulf of Mexico with few studies listing species. The aim of this study is to provide an update checklist of species for the Mexican southeast sector (based on literature review and records from the present study) as well as a brief zoogeographical analysis for the Gulf of Mexico amphipod fauna, putting them in context with the fauna on the tropical western Atlantic. Fifty-five species were listed for the Mexican southeast sector; 36 of them showed a geographical extension to the Yucatan continental shelf representing 23 new records for the Mexican southeast sector, nine for the southeast region and four for the Gulf of Mexico. Based on the zoogeographical analysis, there is support of the application of Carolinian and Caribbean zoogeographic provinces to amphipods in the Gulf of Mexico. PMID- 26097940 TI - Rediscovery of the troglobious palpigrade Eukoenenia draco (Peyerimhoff 1906) (Palpigradi: Eukoeneniidae), with notes on the adaptations to a cave-dwelling life. AB - Several females, a male, and an immature of the species Eukoenenia draco (Peyerimhoff, 1906) have been captured recently in Majorca, more than a century after its description. The male of this enigmatic species is described for the first time and the female is redescribed, with new data and figures. The level of adaptation of this species to a cave-dwelling life is discussed and compared with those of other troglobitic species of palpigrades. Comparison of E. draco draco with E. draco zariquieyi (Conde, 1951) reveals substantial differences that lead us to consider E. zariquieyi stat. nov. as a full species. PMID- 26097941 TI - New species of Macrophyllodromia (Blattaria, Blattellidae) from Ecuador and a key to males of the genus. AB - Representatives of the cockroach genus Macrophyllodromia are widely distributed in Central and South Americas. The genus involves 10 species, including one new species described here, that are divided into 3 species groups--splendida, amabile and maximiliani. Macrophyllodromia onorei sp. n. is described as the fourth species of this genus from Ecuador. A key is provided for males of all known species of Macrophyllodromia and a species distribution map is presented. PMID- 26097942 TI - Description of Megistoleon thaumatopteryx sp. nov. with notes on the genus Megistoleon Navas (Neuroptera, Myrmeleontidae). AB - A new African species of antlion, Megistoleon thaumatopteryx sp. nov., is described from Mozambique. The poorly known genus Megistoleon Navas, 1931 and the only other species currently attributed to it, M. ritsemae (van der Weele, 1907) are redescribed in order to provide a better comparison with the new taxon. These myrmeleontids are easily distinguishable by means of an exclusive set of characters besides a striking appearance. PMID- 26097943 TI - Fifty Shades of Grey: giving colour to the poorly known Angolan Ashy reed frog (Hyperoliidae: Hyperolius cinereus), with the description of a new species. AB - Phylogenetic reconstruction using the mitochondrial 16S marker shows that geographically separated populations of the poorly known Hyperolius cinereus (Anura: Hyperoliidae) from Angola form two distinct clades. The description of H. cinereus was originally based on only a single preserved adult male. Fresh material of both sexes allowed a detailed redescription of the species, which is restricted mainly to the south-draining Cunene and Cubango river systems. Bioacoustic and morphological characters, in conjunction with colouration differences, allow the description of a cryptic sister species from Lagoa Carumbo in north-eastern Angola, occurring in the Luele and Lovuo river systems of the Congo drainage basin. Tadpoles, for H. cinereus and the new species, are described. PMID- 26097944 TI - Mononchida (Nematoda) from Silent Valley National Park, India. AB - Four known and a new species of nematodes belonging to the Order Mononchida Jairajpuri, 1969 are described and illustrated from Silent Valley National Park, India. Cobbonchus vulvastriatus n. sp. has 0.92-0.11 mm long body; buccal cavity 25-27 x 12-13 MUm, dorsal tooth comparatively large with its apex at 72-81% from base of stoma; subventral teeth slightly smaller with their apices at 40-41% from the base of stoma; female genital system amphidelphic, 1-3 pre-vulval and 2-4 post-vulval cuticular infoldings present; spicules 1.2-1.4 times the cloacal body diameter long; gubernaculum trough-shaped with distal thickening; lateral guiding pieces small; ventromedian supplements six, spaced; tail conoid, curved ventrad with a strong angular bending, slender portion of tail about twice the anterior part; caudal glands well developed, arranged in tandem, spinneret terminal. Clarkus sheri (Mulvey, 1967) Jairajpuri, 1970; Mylonchulus amurus Khan & Jairajpuri, 1979; Mylonchulus mulveyi Jairajpuri, 1970 and Mylonchulus paraindex Ahmad, Baniyamuddin & Jairajpuri, 2005 are recorded for the first time from this park. PMID- 26097945 TI - Three new species of Idiops Perty, 1833 (Araneae: Idiopidae) from India. AB - Three new species of the front-eyed trapdoor genus Idiops, viz., Idiops joida sp. nov. from the Western Ghats of Karnataka, I. mettupalayam sp. nov. from the foothills of the Western Ghats in Tamil Nadu and I. oriya sp. nov. from Odhisa, are described. Natural history information for all these species is provided as is an identification key to Idiops species from South and Southeast Asia. PMID- 26097946 TI - Larvae of Amphipsyche species (Trichoptera: Hydropsychidae) from Thailand. AB - Morphological characters and scanning electron microscope images of the larvae of Amphipsyche meridiana and A. gratiosa are given. Pupal identifications are based on genitalic features in common with described adults, and larvae were associated with the pupae based on residual larval sclerites captured in the pupal case. Herein, the final larval instar is described, diagnosed, and photographed for each species. PMID- 26097947 TI - Three new caddisflies species of the fossil genus Archaeotinodes (Insecta: Trichoptera: Ecnomidae) from the Baltic Amber. AB - Three new caddisflies species of the fossil genus Archaeotinodes: Archaeotinodes petropolitana sp. nov., Archaeotinodes regiomontana sp. nov., and Archaeotinodes rossica sp. nov. from the Baltic amber (Upper Eocene, 40 million years old), are described and illustrated. PMID- 26097948 TI - The bioregionalisation revival. AB - The aim of this paper is to review some of the economic drivers of large scale bioregionalisation, using examples from deep sea hydrothermal vent communities, the Antarctic and sub-Antarctic, and Australia. These economic drivers are mainly recent conservation efforts, while early 20th century bioregionalisation was driven by 19th century taxonomy and exploration to assess available biological resources for economic exploitation. Modern regionalisation, particularly of the Antarctic and deep sea hydrothermal vent communities, are driven by conservation studies to protect areas from economic exploitation, rather than biogeographical questions concerning endemism and natural classification. PMID- 26097949 TI - Cyrtodactylus sanook (Squamata: Gekkonidae), a new cave-dwelling gecko from Chumphon Province, southern Thailand. AB - We describe a new cave-dwelling species, Cyrtodactylus sanook sp. nov., from Tham Sanook, Chumphon Province, southern Thailand, characterized by a maximum SVL of 79.5 mm; 18-20 longitudinal rows of dorsal tubercles at midbody; a continuous series of enlarged femoral and precloacal scales, no femoral pores, three or four precloacal pores in males (no pores in females), no precloacal groove nor depression; 19-20 subdigital lamellae on 4th toe; transversally enlarged subcaudal plates; and 6-7 irregular pale narrow dorsal bands between limb insertions. It seems endemic to this cave and is the 7th Thai Cyrtodactylus species that is known only from a cave environment. PMID- 26097950 TI - Hamodactylus macrophthalmus spec. nov., a new coral-associated pontoniine shrimp (Decapoda, Caridea, Palaemonidae) from Indonesia. AB - A new coral-associated species of the genus Hamodactylus is described from Lembeh Strait, NE Sulawesi, Indonesia. The three other known species in the genus have been recorded in association with octocorals. The single ovigerous female specimen of the new species was collected from a scleractinian host. It can be easily separated from its congeners by the very long eyestalks and the chela of the second pereiopods having blunt tips of the fingers with tufts of long simple setae giving it an atyid-like appearance. PMID- 26097951 TI - Two new remarkable Callimicra Deyrolle, 1864 (Coleoptera: Buprestidae: Agrilinae) from Central America. AB - Collections from Panama and the recent Arthropods of La Selva biodiversity inventory project in Costa Rica yielded specimens of two unusual species of the genus Callimicra Deyrolle, both of which exhibit striking color patterns. A brief review of the history of treatment of the genus is presented and the two new species are described and illustrated: Callimicra timmonsae sp.n. species, and C. prenai sp.n. PMID- 26097952 TI - A taxonomic revision of the Meranoplus F. Smith of Madagascar (Hymenoptera: Formicidae: Myrmicinae) with keys to species and diagnosis of the males. AB - The species-level taxonomy of the ant genus Meranoplus F. Smith from Madagascar is revised. Two new species, M. cryptomys sp. n. and sylvarius sp. n. are described from workers and queens; M. mayri Forel, 1910, and M. radamae Forel, 1891, are redescribed, and queens and males for these two species are described for the first time. The first diagnosis of Meranoplus males for any biogeographic region is provided based on Malagasy species. Illustrated keys to all known Malagasy castes and species are presented. Diagnoses are given for two species groups: the M. mayri group and the M. nanus group. The diagnosis of the M. nanus species group from Bolton (1981) is thereby expanded with six new characters. Two species are known from the M. mayri species group and seven described species are known for the M. nanus species group, including the two new species described herein. The mouthparts, genitalia, and all castes, where known, of Malagasy Meranoplus are illustrated. PMID- 26097953 TI - A comparison of external and internal maxilla and mandible morphology of water bugs (Hemiptera: Heteroptera: Nepomorpha). AB - This paper describes the file of the mandible, the apices of the maxillae, the rupturing device on the maxillae, and the internal structures of the mouthparts in sixty representatives of the nepomorphan families (Heteroptera), using scanning electron microscopy. Eight morphologically distinct types of files are identified on the mandibular tip, as well as six distinct types of the maxillary endings, and three distinct types of rupturing devices of the maxillae. The features of the internal maxillary and mandibular structures share a common connection model, differing only by virtue of specific appendages in different subfamilies. The water bugs morphological ground plan is represented by a mandibular file identically serrated, asymmetrical apices of maxillae (left maxilla tapers with lobe + right maxilla tapers and straight), rupturing device evidently exposed ventrally and inner structures: the maxillae are extended dorso laterally, forming a wide lobe; symmetrical processes connect with the mandibles. The main patterns (belostomatid and nepid) together with two more specialized patterns (gelastocorids, corixids, micronectids, and diaprepocorids) and (ochterid, aphelocheirid, naucorid, notonectid, pleid and helotrephid) are reported. Diversity of the elements (maxillae and mandibles) are analyzed from a phylogenetic signals and nutrition perspective. Finally, further lines of study are suggested for future work on the phylogeny of the group based on the studied characters. PMID- 26097954 TI - Diversity within the Redeye Bass, Micropterus coosae (Perciformes: Centrarchidae) species group, with descriptions of four new species. AB - The Redeye Bass, Micropterus coosae, was described from the Mobile River basin, Chattahoochee, and Savannah rivers in Alabama and Georgia, USA, by Hubbs and Bailey (1940). At that time the authors recognized significant variation in the Black Warrior River population, and noted that with further study this form may be recognized as a separate taxon. An examination of variation in morphology and mitochondrial DNA supported this observation, and highlighted additional species level variation, resulting in descriptions of a total of four new species: Micropterus cahabae, new sp., restricted to the Cahaba River system; Micropterus tallapoosae, new sp., restricted to the Tallapoosa River system; Micropterus warriorensis, new sp., from the Black Warrior River system; and Micropterus chattahoochae, new sp., from the Chattahoochee River system. Micropterus coosae is restricted to the Coosa River system. The new species differ from each other and from M. coosae by a combination of pigmentation and scale count characteristics, development of the tooth patch, and divergence within the ND2 gene. While two of these species are relatively common in upland streams within their ranges, M. warriorensis, M. cahabae and M. chattahoochae are uncommon and may warrant protection. PMID- 26097955 TI - The genus Laccobius in China: new species and new records (Coleoptera: Hydrophilidae). AB - The species of the water scavenger beetle genus Laccobius Erichson, 1837 occuring in China are reviewed. Two new species are described: Laccobius (Glyptolaccobius) qinlingensis sp. nov. (Shaanxi) and L. (Cyclolaccobius) hainanensis sp. nov. (Hainan). Five species are recorded for the first time: Laccobius (Dimorpholaccobius) bipunctatus (Fabricius, 1775), L. (D.) striatulus (Fabricius, 1801) and L. (Compsolaccobius) pallidissimus Reitter, 1899 (all from Xinjiang), L. (Microlaccobius) tonkinensis Gentili, 1979 (Shaanxi), and L. (Compsolaccobius) decorus (Gyllenhal, 1827) (Qinghai). Additional faunistic data from China are provided for the following species: L. (Cyclolaccobius) hingstoni Orchymont. 1926, L. (C.) nitidus Gentili, 1984, L. (C.) politus Gentili, 1979, L. (C.) yunnanensis Gentili, 2003, L. (Dimorpholaccobius) simulans Orchymont, 1923, L. (s.str.) binotatus Orchymont, 1934, L. (s.str.) cinereus Motschulsky, 1860, L. (s.str.) colon (Stephens, 1829), L. (s.str.) inopinus Gentili, 1980, L. (s.str.) minutus (Linnaeus, 1758), L. (s.str.) nobilis Gentili, 1979, L. (Microlaccobius) elegans Gentili, 1979, L. (M.) florens Gentili, 1979, L. (M.) formosus Gentili, 1979, L. (M.) hammondi Gentili, 1984, L. (M.) himalayanus Gentili, 1988, and L. (M.) nepalensis Gentili, 1982. An updated checklist of Laccobius species occurring in China is provided. PMID- 26097956 TI - Revision of the peristediid genus Satyrichthys (Actinopterygii: Teleostei) with the description of a new species, S. milleri sp. nov. AB - The Indo-Pacific peristediid genus Satyrichthys Kaup, 1873 was first diagnosed as having a broad head with mesethmoid, postocular, parietal and preopercular spines. Later, most ichthyologists characterized Satyrichthys by its toothless jaws and strong preopercular spine. Kawai (2008) divided Satyrichthys into two genera, Satyrichthys and Scalicus, on the basis of a phylogenetic hypothesis, and redefined Satyrichthys. Seven species of Satyrichthys are recognized here, including one new species: S. clavilapis, S. laticeps, S. longiceps, S. milleri sp. nov., S. moluccensis, S. rieffeli and S. welchi. The new species is distinguished from its congeners in having equilateral-triangular rostral projections, 4 lip and 4 chin barbels, and no anterior directed spines on the upper lateral row of the caudal peduncle. Satyrichthys laticeps, previously treated as a junior synonym of S. moluccensis, is regarded as a valid species. The following new synonyms are noted: S. adeni, S. halyi and S. magnus are all junior synonyms of S. laticeps; S. isokawae is a junior synonym of S. moluccensis; and S. lingi is a junior synonym of S. welchi. In addition, a neotype is designated for S. moluccensis. PMID- 26097957 TI - New species and records of Euphranta Loew and other Adramini (Diptera: Tephritidae: Trypetinae) from south and southeast Asia. AB - Seven new species of Euphranta Loew are described, viz., Euphranta dysoxyli David, sp. nov., E. hyalipennis David & Freidberg, sp. nov, E. diffusa David, sp. nov., E. haldwanica Hancock & Goodger, sp. nov. and E. thandikudi David, sp. nov. from India; E. neochrysopila David, Freidberg, Hancock & Goodger, sp. nov. from Sri Lanka and E. ridleyi Hancock & Goodger, sp. nov. from Singapore. Notes are provided on the identities of E. corticicola (Hering) and E. klugii (Wiedemann); E. signatifacies Hardy is synonymised with E. klugii; E. dissoluta (Bezzi) and E. burtoni Hardy are synonymised with E. crux (Fabricius) and Dimeringophrys parilis (Hardy) is reinstated as a valid species. Coelotrypes latilimbatus (Enderlein), Dimeringophrys pallidipennis Hardy, D. parilis (Hardy) and Hardyadrama excoecariae Lee are newly recorded from India, E. crux from Sri Lanka and E. klugii from Indonesia. An unnamed species of Coelopacidia Enderlein from India is illustrated. An illustrated key to species of Euphranta Loew from India is also provided. PMID- 26097958 TI - A new species of Leposoma (Squamata: Gymnophthalmidae) with four fingers from the Atlantic Forest central corridor in Bahia, Brazil. AB - Leposoma sinepollex sp. nov., a new species of the scincoides group, is described from a mountain region in the Atlantic Forest central corridor in state of Bahia, Brazil. The new species is characterized by elongate dorsal and lanceolate ventral scales arranged in diagonal rows, a single and smooth frontonasal, five supraoculars, absence of pollex, third toe as long as or longer than fourth, absence of striations in lower part of head, parietals longer than wide and as long as interparietal, 27-29 dorsals, 25-29 scales around body, 17-19 ventrals, 12-14 total pores in the male (absent in females), 9-10 and 9-11 subdigital lamellae respectively under IV Finger and IV Toe, and strong sexual color dichromatism with a black pigmentation in the ventral parts of males, creamy in females. The new species is morphologically similar to Leposoma nanodactylus, sharing with it among other features the synapomorphic division of the first supraocular. Phylogenetic analyses of 981 bp of combined sequences (cyt b+ ND4) recovered also a strongly supported (PP = 1,0; BP = 100) sister relationship between both species. The new species and Leposoma nanodactylus are placed sister to all the other Atlantic Forest species, with L. baturitensis being the first to diverge in this radiation. We discuss the distribution of the Atlantic Forest Leposoma, as well as possible scenarios for the origin of the new species. PMID- 26097960 TI - Description of the male of Architis catuaba Santos & Nogueira, 2008 and new records of Architis capricorna Carico, 1981 (Araneae: Pisauridae). PMID- 26097959 TI - New data on Rhyacophila (Trichoptera: Rhyacophilidae) from West Malaysia and Indonesia (Lombok and Bali) with descriptions of two new species. AB - A new species, Rhyacophila langkawia sp. n., belonging to the R. curvata Group sensu Schmid (1970) is described. The samples provide also material of the previously undescribed species cited by Schmid (1970) as R. schmidi, a nomen nudum; this species is described as R. schmidirossia sp. n., also in the R. curvata Group. Other sampled species were Rhyacophila curvata Morton, recorded for the first time from Negeri Sembilan (West Malaysia) and Lombok (Indonesia); Rhyacophila stheneboia Malicky & Prommi (Pahang and Negeri Sembilan, West Malaysia), and Rhyacophila anakbatukau Malicky, recorded for the first time from Lombok (Indonesia). Updated lists of the Rhyacophila species found in West Malaysia and Indonesia are provided. PMID- 26097961 TI - A review of the genera Acathrito Lyneborg, Phycus Walker and Salentia Costa (Diptera: Therevidae: Phycinae) from Egypt. AB - The Egyptian fauna of the three genera Acathrito Lyneborg, Phycus Walker and Salentia Costa of subfamily Phycinae (Therevidae) is revised. Five species are recognized, three species of Phycus (including Phycus rufofemoratus Krober as a new record) and one species for each of Acathrito and Salentia. A key to Egyptian Phycus species is included. Illustrations, specimens examined and distributions are given for each species. PMID- 26097962 TI - The tadpole of Pleurodema cordobae Valetti, Salas & Martino, 2009 (Anura: Leiuperidae) from Cordoba, Argentina. PMID- 26097963 TI - Description of the newly-hatched juvenile of Aegla paulensis (Decapoda, Anomura, Aeglidae). AB - The postembryonic development of Aegla paulensis is epimorphic (= direct), in which the hatching form is a juvenile that morphologically resembles the adult. Hatching is asynchronous, taking 3-5 days for all juveniles from a single brood to hatch. This paper provides a complete description of the external morphology of the newly-hatched juvenile of A. paulensis as analyzed through light microscopy (LM) and scanning electron microscopy (SEM). One of the striking features ob- served in the newly-hatched juvenile of A. paulensis was the presence of four pairs of rudimentary pleopods, a trait never described before in early juveniles of Aegla. Additional novelties include three unique types of setae and two types of pore sensilla. PMID- 26097964 TI - Macrostylopyga gen. nov., a new genus of cockroaches (Dictyoptera: Blattidae), with descriptions of two new species. AB - The genus Macrostylopyga gen. nov. and two species (M. grandis sp. nov. and M. bidupi sp. nov.) are described. A detailed morphological description with special attention to the male genitalic structures is provided. Some aspects of the evolution of wingless cockroaches are briefly discussed. PMID- 26097965 TI - The millipede order Chordeumatida (Diplopoda) in Kazakhstan, with descriptions of three new species. AB - The order Chordeumatida is represented in Kazakhstan by five species in three genera and three families. All species are recorded in the Altai and Dzhungarskii Alatau Mountains. Three species are described here as new to science: Altajosoma arshaty sp. nov., Altajosoma bukhtarma sp. nov. and Tarbagataya zaisanica sp. nov. The family Diplomaragnidae and the genus Altajosoma Gulicka, 1972 are formally new to the fauna of Kazakhstan. Diagnosis of the genus Tarbagataya has been supplemented. All currently known Chordeumatida from Kazakhstan are keyed, including the new species. The distributions of all Kazakhstan chordeumatidan species are mapped. PMID- 26097966 TI - Two new species of ricinuleids of the genus Pseudocellus (Arachnida: Ricinulei: Ricinoididae) from southern Mexico. AB - Two new species of ricinuleids of the genus Pseudocellus are described from Mexico: Pseudocellus cruzlopezi sp. nov. from Oaxaca, and Pseudocellus monjarazi sp. nov. from Chiapas. Both species are described from adult males and females. The first species is epigean and edaphomorphic, whereas the second is cavernicolous and troglomorphic. The number of known species of the genus Pseudocellus increases to 25, and Mexican species to 16, indicating that Mexico has the highest diversity of ricinuleids in the world. An updated identification key to adult males of the 16 described species found in Mexico and southern USA is provided. PMID- 26097967 TI - A survey of the internal oral morphology in larvae of the genus Hylodes Fitzinger, 1826 (Amphibia, Anura, Hylodidae). AB - From the 24 species allocated in the genus Hylodes, 16 have their tadpoles described, which five have information on the oral anatomy. Herein, the internal oral morphology of the tadpoles of H. dactylocinus, H. heyeri, H. aff. lateristrigatus, H. magalhaesi, H. meridionalis, H. phyllodes, H. sazimai, and H. uai is described, along with comparisons among all species in the genus with previously known oral morphology. PMID- 26097968 TI - Four new species of the genus Lobrathium Mulsant & Rey (Coleoptera: Staphylinidae: Paederinae) from China. AB - Four new species of the genus Lobrathium Mulsant & Rey, 1878 from the mainland China are described: L. quadrum sp. n. from Sichuan, L. rutilum sp. n. from Hubei, L. tortuosum sp. n. from Zhejiang and L. zonalis sp. n. from Sichuan. In addition, the paper reviews the history of the research on the Chinese fauna of the genus. Some important morphological characters are illustrated for the new species. PMID- 26097969 TI - The nymph of Anacroneuria payagua Froehlich (Plecoptera: Perlidae) from Brazil. AB - The unknown nymph of Anacroneuria payagua Froehlich is described based on the association with reared adult females from streams located in Mato Grosso do Sul State, Brazil. Anacroneuria guaikuru Froehlich also occurred in these streams. PMID- 26097970 TI - The release call as a diagnostic character between cryptic related species Odontophrynus cordobae and O. americanus (Anura: Cycloramphidae). PMID- 26097971 TI - Description of two new species of Meharia Chretien, 1915 (Lepidoptera: Cossidae) from East Africa. PMID- 26097972 TI - Hypsilara breweri n.sp. from Venezuela: description of new species with notes on the morphology and phylogenetic relationships of the genus (Coleoptera: Elmidae: Larainae). AB - A new species of the genus Hypsilara Maier & Spangler, 2011, collected in the Eastern Venezuela, is described and illustrated. We provide habitus photographs, detail drawings of both male and female genitalia, and description of some morphological features, which were omitted in the description of the genus. Included are also remarks on the distribution and genetic distance of the Hypsilara species and possible relations to other South American Larainae. PMID- 26097973 TI - Designation of a lectotype for Deuterodon pedri Eigenmann, 1908 (Characiformes: Characidae). PMID- 26097974 TI - Nomenclatural changes in the genus Bambusananus Li & Xing, 2011 (Hemiptera: Cicadellidae: Deltocephalinae: Athysanini). PMID- 26097975 TI - Visible-Light Photoexcited Electron Dynamics of Scandium Endohedral Metallofullerenes: The Cage Symmetry and Substituent Effects. AB - Endohedral metallofullerenes (EMFs) have become an important class of molecular materials for optoelectronic applications. The performance of EMFs is known to be dependent on their symmetries and characters of the substituents, but the underlying electron dynamics remain unclear. Here we report a systematic study on several scandium EMFs and representative derivatives to examine the cage symmetry and substituent effects on their photoexcited electron dynamics using ultrafast transient absorption spectroscopy. Our attention is focused on the visible-light (530 nm as a demonstration) photoexcited electron dynamics, which is of broad interest to visible-light solar energy harvesting but is considered to be quite complicated as the visible-light photons would promote the system to a high-lying energy region where dense manifolds of electronic states locate. Our ultrafast spectroscopy study enables a full mapping of the photoinduced deactivation channels involved and reveals that the long-lived triplet exciton plays a decisive role in controlling the photoexcited electron dynamics under certain conditions. More importantly, it is found that the opening of the triplet channels is highly correlated to the fullerene cage symmetry as well as the electronic character of the substituents. PMID- 26097976 TI - The burden of secrecy? No effect on hill slant estimation and beanbag throwing. AB - Slepian, Masicampo, Toosi, and Ambady (2012, Experiment 1) reported that participants who recalled a big secret estimated a hill as steeper than participants who recalled a small secret. This finding was interpreted as evidence that secrets are experienced as physical burdens. In 2 experiments, we tried to replicate this finding, but, despite larger power, did not find a difference in slant estimates between participants who recalled a big secret and those who recalled a small secret. This finding was further corroborated by a meta-analysis that included 8 published data sets of exact replications, which indicates that thinking of a big secret does not affect hill slant estimation. In a third experiment, we also failed to replicate the effect of recalling a secret on throwing a beanbag at a target (Slepian et al., 2012, Experiment 2). Together, our findings question the robustness of the original empirical findings. PMID- 26097977 TI - The snooze of lose: Rapid reaching reveals that losses are processed more slowly than gains. AB - Decision making revolves around weighing potential gains and losses. Research in economic decision making has emphasized that humans exercise disproportionate caution when making explicit choices involving loss. By comparison, research in perceptual decision making has revealed a processing advantage for targets associated with potential gain, though the effects of loss have been explored less systematically. Here, we use a rapid reaching task to measure the relative sensitivity (Experiment 1) and the time course (Experiments 2 and 3) of rapid actions with regard to the reward valence and probability of targets. We show that targets linked to a high probability of gain influence actions about 100 ms earlier than targets associated with equivalent probability and value of loss. These findings are well accounted for by a model of stimulus response in which reward modulates the late, postpeak phase of the activity. We interpret our results within a neural framework of biased competition that is resolved in spatial maps of behavioral relevance. As implied by our model, all visual stimuli initially receive positive activation. Gain stimuli can build off of this initial activation when selected as a target, whereas loss stimuli have to overcome this initial activation in order to be avoided, accounting for the observed delay between valences. Our results bring clarity to the perceptual effects of losses versus gains and highlight the importance of considering the timeline of different biasing factors that influence decisions. PMID- 26097978 TI - The role of attention in motivated behavior. AB - All too frequently, people fail to take actions that are in their best interest (e.g., not taking necessary medications). Researchers have attempted to explain such behaviors by identifying subtle motivational forces that foster an avoidance of attractive outcomes. However, in many cases, such motivational forces have been difficult to identify. We propose that failures such as these to act in valued ways are in some cases caused by insufficient levels of orienting attention. To test this hypothesis, we first created a laboratory analog of real world failures to act in valued ways, 1 in which participants persisted in viewing lower-valenced images even though they could have, at no cost, viewed a higher-valenced image. When we experimentally increased their orienting attention toward a caption stating they had the option to switch, participants more frequently elected to view the higher valenced image (Studies 1a-c). In real world behavioral contexts, increasing attention, without an apparent change in valuation, also led to increased levels of approach motivation in behavioral contexts involving purchasing apples (Study 2) and electing to take the stairs instead of the escalator (Studies 3a-c). In light of these findings, we consider the role of orienting attention in motivated behavior. PMID- 26097979 TI - The Scientific Basis of Uncertainty Factors Used in Setting Occupational Exposure Limits. AB - The uncertainty factor concept is integrated into health risk assessments for all aspects of public health practice, including by most organizations that derive occupational exposure limits. The use of uncertainty factors is predicated on the assumption that a sufficient reduction in exposure from those at the boundary for the onset of adverse effects will yield a safe exposure level for at least the great majority of the exposed population, including vulnerable subgroups. There are differences in the application of the uncertainty factor approach among groups that conduct occupational assessments; however, there are common areas of uncertainty which are considered by all or nearly all occupational exposure limit setting organizations. Five key uncertainties that are often examined include interspecies variability in response when extrapolating from animal studies to humans, response variability in humans, uncertainty in estimating a no-effect level from a dose where effects were observed, extrapolation from shorter duration studies to a full life-time exposure, and other insufficiencies in the overall health effects database indicating that the most sensitive adverse effect may not have been evaluated. In addition, a modifying factor is used by some organizations to account for other remaining uncertainties-typically related to exposure scenarios or accounting for the interplay among the five areas noted above. Consideration of uncertainties in occupational exposure limit derivation is a systematic process whereby the factors applied are not arbitrary, although they are mathematically imprecise. As the scientific basis for uncertainty factor application has improved, default uncertainty factors are now used only in the absence of chemical-specific data, and the trend is to replace them with chemical specific adjustment factors whenever possible. The increased application of scientific data in the development of uncertainty factors for individual chemicals also has the benefit of increasing the transparency of occupational exposure limit derivation. Improved characterization of the scientific basis for uncertainty factors has led to increasing rigor and transparency in their application as part of the overall occupational exposure limit derivation process. PMID- 26097980 TI - Intensive HIV Partner Notification Is Effective in Identifying New and Previously Diagnosed HIV Infections in Edmonton, Canada. PMID- 26097981 TI - Inter-rater reliability for scoring children's dichotic words test responses. AB - OBJECTIVE: To determine whether rater agreement is randomly distributed or varies importantly with test-taker characteristics, test words, or rater experience with the dichotic words test (DWT). DESIGN: DWT was administered to 34 children in 1st 4th grade and responses scored by two raters. The proportion of rater agreement was calculated for each child and for each word. Correlates of inter-rater agreement were explored. STUDY SAMPLE: Two raters judged 6686 total responses from 34 children. RESULTS: Overall agreement between the two raters was 0.97. Test-taker scores ranged from 35%-91% (mean = 81%). Agreement was associated with score but not with test-taker age or sex. Test words spanned the full range of difficulty (pass proportion 0.06-1.00). Rater agreement was not randomly distributed among the words. Inter-rater agreement for test words ranged from 0.82-1.00 and was associated with pass proportion (Spearman's rho = 0.28; p < 0.0001). However, there were words at all pass proportions with perfect or near perfect agreement. Rater agreement improved from 0.94 on the first day of data collection to 0.98 on the fifth day (p = 0.026). CONCLUSIONS: Inter-rater reliability should be considered along with test item difficulty when developing speech audiometry materials, scoring protocols, and rater training. PMID- 26097982 TI - Influence of noise type on speech reception thresholds across four languages measured with matrix sentence tests. AB - OBJECTIVE: To compare speech reception thresholds (SRTs) in noise using matrix sentence tests in four languages: German, Spanish, Russian, Polish. DESIGN: The four tests were composed of equivalent five-word sentences and were all designed and optimized using the same principles. Six stationary speech-shaped noises and three non-stationary noises were used as maskers. STUDY SAMPLE: Forty native listeners with normal hearing: 10 for each language. RESULTS: SRTs were about 3 dB higher for the German and Spanish tests than for the Russian and Polish tests when stationary noise was used that matched the long-term frequency spectrum of the respective speech test materials. This general SRT difference was also observed for the other stationary noises. The within-test variability across noise conditions differed between languages. About 56% of the observed variance was predicted by the speech intelligibility index. The observed SRT benefit in fluctuating noise was similar for all tests, with a slightly smaller benefit for the Spanish test. CONCLUSIONS: Of the stationary noises employed, noise with the same spectrum as the speech yielded the best masking. SRT differences across languages and noises could be attributed in part to spectral differences. These findings provide the feasibility and limits of comparing audiological results across languages. PMID- 26097983 TI - The Relationship Between Plasma Inflammatory Cytokines and Labor Pain. AB - BACKGROUND: Proinflammatory cytokines are increased in maternal blood at term pregnancy and are associated with cervical ripening and the initiation of labor. We hypothesize that maternal plasma cytokines also affect the sensitivity to labor pain. METHODS: By using a previously validated model describing labor pain, we used a deidentified database derived from healthy nulliparous parturients who delivered singleton pregnancies at term. Numerical rating scores for pain were recorded after the onset of regular contractions using an 11-point scale. Maternal blood was drawn for the measurement of interleukin (IL)-1beta, IL-4, IL 6, IL-8, and IL-10; interferon-gamma; and tumor necrosis factor-alpha on admission or at the onset of painful contractions, whichever occurred later. Individual demographic, physiognomic, and cytokine variables that significantly affected labor pain at P < 0.05 were reported and included stepwise into a multivariable model. RESULTS: One hundred sixty parturients provided 411 numerical analog scores for pain that were evaluated with our model. The relationship between numerical analog scores and cervical dilation was significantly affected by the type of membrane rupture, membrane status, induction, oxytocin administration, maternal race, and plasma IL-1beta concentration as individual variables. Only the association between the highest IL-1beta quartile and slower acceleration of pain during labor remained significant in the multivariate model (P = 0.0003). Women with IL-1beta concentration in the highest quartile arrived at the labor room with a more dilated cervix than those with lower plasma concentrations of IL-1beta (5.1 +/- 3.0 vs 4.1 +/- 2.6 cm; P < 0.02) and had faster labor progress. CONCLUSIONS: Inflammatory cytokines including IL-1beta play a role in cervical ripening. High maternal plasma concentrations of IL-1beta may serve as a marker of advanced cervical ripening and readiness for labor that proceeds with less pain. PMID- 26097984 TI - A Recirculatory Model for Pharmacokinetics and the Effects on Bispectral Index After Intravenous Infusion of the Sedative and Anesthetic AZD3043 in Healthy Volunteers. AB - BACKGROUND: AZD3043 is a positive allosteric modulator of the gamma-aminobutyric acid type A receptor, with sedative and anesthetic properties. We describe a population pharmacokinetic (PK) model of arterial and venous concentrations of AZD3043 and the pharmacodynamic effects on bispectral index (BIS) in healthy volunteers. METHODS: Arterial and venous plasma concentrations of AZD3043 and BIS were measured in 2 clinical studies in 125 healthy volunteers, where AZD3043 was given as a 1-minute bolus (1-6 mg/kg), a 30-minute infusion (1-81 mg/kg/h), or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 (mg/kg bolus + mg/kg/h infusion for 30 minutes). Population PK/pharmacodynamic analysis was performed with NONMEM. RESULTS: A recirculatory model, comprising a series of 5 compartments for the transit of drug between venous and arterial plasma, 2 peripheral distribution compartments, and 1 compartment for the nondistributive transit of drug from arterial to venous plasma, described the PK of AZD3043. Systemic clearance was high (2.2 L/min; 95% confidence interval, 2.12-2.25), and apparent volumes of distribution were low, leading to a short elimination half-life. The apparent volumes of distribution of the arterial and peripheral compartments increased with increasing administered dose, giving a total apparent volume of distribution of 15 L after the lowest dose and 37 L after the greatest dose. A sigmoid maximum effect (Emax) model with an EC50 of 15.6 ug/mL and a gamma of 1.7 described the relationship between AZD3043 effect-site concentrations and BIS. The between subject variability in EC50 was 37%. An effect compartment model, with a half life of the equilibration rate constant ke0 of 1.1 min, described the delay in effect in relation to the arterial plasma concentrations. CONCLUSIONS: AZD3043 had a high clearance and a low apparent volume of distribution, leading to a short half-life. However, the apparent volume of distribution was dose dependent (P < 0.001), leading to an increased half-life with increasing dose. The distribution to the effect site was fast and together with the short plasma half life led to a fast onset and offset of effects. PMID- 26097985 TI - A Prospective Observational Comparison Between Arm and Wrist Blood Pressure During Scheduled Cesarean Delivery. AB - BACKGROUND: Shivering is common during cesarean delivery (CD) under neuraxial anesthesia and may disrupt the measurement of noninvasive blood pressure (BP). BP measured at the wrist may be less affected by shivering. There have been no studies comparing trends in BP measured on the upper arm and wrist. We hypothesized that wrist systolic blood pressure (sBP) would accurately trend with upper arm sBP measurements (agree within a limit of +/-10%) in parturients undergoing elective CD under spinal anesthesia or combined spinal-epidural anesthesia. METHODS: After initiation of spinal anesthesia, BP measurements were obtained simultaneously from the upper arm and wrist on opposite arms. The interval between measurements was 1 to 2 minutes, and data were collected for 20 minutes or until delivery. The primary outcome was agreement in dynamic changes in sBP measurements between the upper arm and the wrist. Bland-Altman plots indicating the levels of agreement between the methods were drawn for baseline measurements, over multiple measurements, and over multiple measurements on percentage change from baseline. RESULTS: Forty-nine patients were recruited and completed the study. The wrist sBP tended to overestimate the upper sBP for both baseline data (sBP bias = 13.4 mm Hg; 95% confidence interval = +10.4 to +16.4 mm Hg) and data obtained over multiple measurements (sBP bias = 12.8 mm Hg; 95% confidence interval = +9.3 to +16.3 mm Hg). For change in sBP from baseline over multiple measurements, the mean difference between the wrist and the arm sBP was 0.2 percentage points (99% limits of agreement -25 to +25 percentage points). CONCLUSIONS: The wrist measurement overestimated the reading relative to the upper arm measurement for multiple measurements over time. However, when the time series for each subject was examined for percentage change from baseline, the 2 methods mirrored each other in most cases. Nevertheless, our hypothesis was rejected as the limits of agreement were higher than +/-10%. This finding suggests that wrist BP may not be an accurate method of detecting hypotension or hypertension during spinal or combined spinal-epidural anesthesia for CD. PMID- 26097986 TI - A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers. AB - BACKGROUND: AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics. METHODS: The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1 minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score. RESULTS: Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone. CONCLUSIONS: AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting. PMID- 26097987 TI - Dexmedetomidine Does Not Affect Evoked Potentials During Spine Surgery. AB - BACKGROUND: The effect of dexmedetomidine on evoked potentials (EPs) has not been elucidated. We aimed to investigate the effect of dexmedetomidine on somatosensory, motor, and visual EPs. METHODS: After IRB approval, 40 adult patients scheduled for elective spine surgery using total IV anesthesia with propofol and remifentanil were randomly assigned to receive either dexmedetomidine (n = 20) or placebo (n = 20) in a double-blind, placebo controlled trial. After obtaining informed consent, positioning, and baseline EPs recording, patients were randomly assigned to either IV dexmedetomidine 0.6 MUg/kg infused over 10 minutes, followed by 0.6 MUg/kg/h, or a corresponding volume of IV normal saline (placebo). EP measures at 60 +/- 30 minutes after initiation of study drug were defined as T1 and at 150 +/- 30 minutes were defined as T2. Changes from baseline to T1 (primary end point) and from baseline to T2 (secondary end point) in EP latencies (milliseconds) and amplitudes (microvolts) were compared between groups. Data presented as mean +/- SD (95% confidence interval). RESULTS: Data from 40 patients (dexmedetomidine: n = 20; age, 54 +/- 3 years; 10 males; placebo: n = 20; age, 52 +/- 2 years; 5 males) were analyzed. There was no difference between dexmedetomidine versus placebo groups in primary end points: change of somatosensory EPs at T1, latency: 0.01 +/ 1.3 (-0.64, 0.65) vs 0.01 +/- 1.3 (-0.64, 0.65), P = 0.43 (-1.24, 0.45); amplitude: 0.03 +/- 0.14 (-0.06, 0.02) vs -0.01 +/- 0.13 (-0.07, 0.05), P = 0.76 (-0.074, 0.1); motor EPs amplitude at T1: 65.1 +/- 194.8 (-35, 165; n = 18) vs 109.2 +/- 241.4 (-24, 243; n = 16), P = 0.57 (-113.5, 241.57); visual EPs at T1 (right eye), amplitude: 2.3 +/- 3.6 (-0.4, 5.1; n = 11) vs 0.3 +/- 6.0 (-3.3, 3.9; n = 16), P = 0.38 (-6.7, 2.6); latency N1: 2.3 +/- 3.6 (-0.4, 5.1) vs 0.3 +/ 6.0 (-3.3, 3.9), P = 0.38 (-6.7, 2.6); latency P1: -1.6 +/- 13.4 (-11.9, 8.7) vs -1.4 +/- 8.1 (-6.3, 3.5), P = 0.97 (-9.3, 9.7) or secondary end points. There were no differences between right and left visual EPs either at T1 or at T2. CONCLUSIONS: In clinically relevant doses, dexmedetomidine as an adjunct to total IV anesthesia does not seem to alter EPs and therefore can be safely used during surgeries requiring monitoring of EPs. PMID- 26097988 TI - Bedside Gastric Ultrasonography in Term Pregnant Women Before Elective Cesarean Delivery: A Prospective Cohort Study. AB - BACKGROUND: Bedside gastric ultrasound can reliably assess gastric contents in the perioperative period. We aimed to describe the qualitative and quantitative ultrasound assessment of the gastric antrum in fasted pregnant women at term. METHODS: Pregnant women were examined after a minimum period of overnight fasting (solid food, 6 hours; clear liquids, 2 hours) before their scheduled cesarean delivery. A standardized ultrasound examination of the gastric antrum was performed. Based on the qualitative assessment in the supine and right lateral decubitus positions, women were classified using a 3-point grading system (grade 0, no fluid; grade 1, fluid seen in right lateral decubitus position only; and grade 2, fluid seen in the both supine and right lateral decubitus positions). A quantitative assessment of the antral cross-sectional area (CSA) was performed using still images in the right lateral decubitus position. RESULTS: One hundred three women were included in the study; 53 of 103 exhibited grade 0 and 49 of 103 exhibited grade 1 antrum. One woman presented a grade 2 antrum (1/103 = 0.97%; 95% confidence interval [CI], 0.05%-6.06%). Overall, 95% of fasting subjects presented with an antral CSA <=9.6 cm (95% CI, 8.6-10.3 cm) in the right lateral decubitus position (median [interquartile range] = 4.5 [3.2] cm), corresponding to an estimated gastric volume of <=117 mL (95% CI, 108-127 mL) or <=1.5 mL/kg (95% CI, 1.3-1.7 mL/kg). CONCLUSIONS: All women but one presented with antral CSA compatible with residual gastric fluid. The qualitative 3-point grading system may be used to assess individual risk of perioperative gastric content aspiration. Our results suggest that an antral CSA of 10.3 cm in the right lateral decubitus position more accurately describes the upper limit of normal findings in the fasted pregnant patient at term. PMID- 26097989 TI - Associations Between Age and Dosing of Volatile Anesthetics in 2 Academic Hospitals. AB - BACKGROUND: The inverse relationship between age and dose requirement for potent volatile anesthetics is well established, but the question of whether anesthetic providers consider this relationship in practice remains unanswered. We sought to determine whether there is an association between patient age and the mean dose of volatile anesthetic delivered during maintenance of anesthesia. METHODS: This was a retrospective cross-sectional study of patients receiving a single potent volatile anesthetic at 2 academic hospitals using data recorded in an anesthesia information management system. Multivariate linear models were constructed at each hospital to examine the relationship between age and mean minimum alveolar concentration (MAC) fraction delivered during the maintenance of anesthesia. RESULTS: A total of 7878 cases at the 2 hospitals were included for analysis. For patients aged <65 years, we observed decreasing doses of volatile anesthetics as age increased. Per decade, mean delivered MAC fraction decreased by an estimated 1.8% (95% confidence interval, 1.5-2.2, P < 0.0001), smaller than the 6.7% decrease suggested by previous studies of human anesthetic requirements. At age >65 years, the magnitude of the inverse association between age and MAC fraction was higher (3.8% decrease per decade; 95% confidence interval, 2.9-4.7). CONCLUSIONS: Increasing age is associated with decreased absolute doses of potent volatile anesthetics, an association that seems to strengthen as patients enter the geriatric age range. The observed decreases in absolute anesthetic dose were less than those predicted by previous research and therefore represent an overall increase in "age-adjusted dose" as patients grow older. PMID- 26097990 TI - Mixed-effects varying-coefficient model with skewed distribution coupled with cause-specific varying-coefficient hazard model with random-effects for longitudinal-competing risks data analysis. AB - It is well known that there is strong relationship between HIV viral load and CD4 cell counts in AIDS studies. However, the relationship between them changes during the course of treatment and may vary among individuals. During treatments, some individuals may experience terminal events such as death. Because the terminal event may be related to the individual's viral load measurements, the terminal mechanism is non-ignorable. Furthermore, there exists competing risks from multiple types of events, such as AIDS-related death and other death. Most joint models for the analysis of longitudinal-survival data developed in literatures have focused on constant coefficients and assume symmetric distribution for the endpoints, which does not meet the needs for investigating the nature of varying relationship between HIV viral load and CD4 cell counts in practice. We develop a mixed-effects varying-coefficient model with skewed distribution coupled with cause-specific varying-coefficient hazard model with random-effects to deal with varying relationship between the two endpoints for longitudinal-competing risks survival data. A fully Bayesian inference procedure is established to estimate parameters in the joint model. The proposed method is applied to a multicenter AIDS cohort study. Various scenarios-based potential models that account for partial data features are compared. Some interesting findings are presented. PMID- 26097991 TI - Lanthanide Coordination Polymers with 4,4'-Azobenzoic Acid: Enhanced Stability and Magnetocaloric Effect by Removing Guest Solvents. AB - Three lanthanide coordination polymers (Ln-CPs) formulated as [Ln(azdc)(HCOO)]n [Ln = Gd(III) (1), Tb(III) (2), Dy(III) (3); H2azdc = 4,4'-azobenzoic acid] have been successfully obtained by the solvothermal reaction of Ln(III) ions with H2azdc ligands in the mixed solvent N,N-dimethylformamide (DMF)/H2O. Compared with our previous work on Ln-CPs with H2azdc ligands, [Gd2(azdc)3(DMA)2]n.2nDMA (1'; DMA = dimethylacetamide), in which the DMA molecules coordinate to Gd(III) ions that are replaced by HCOO(-) groups in 1, resulting in the distinct structures and properties of the final products. Adjacent Ln(III) ions in 1-3 are connected by HCOO(-) groups through bridging and chelating modes to give 2D layers, which are further linked by azdc(2-) ligands to produce 3D frameworks. Magnetic results declare that antiferromagnetic couplings exist in 1, although two different magnetic interactions among adjacent Gd(III) ions derived from antiferromagnetic interactions of the smaller Gd-O-Gd angles (Gd...Gd distances) and weak ferromagnetic interactions of the larger Gd-O-Gd angles (Gd...Gd distances) coexist in 1. Furthermore, the magnetocaloric effect (MCE) value of 1 is 1.5 times as large as that of 1'. More importantly, 1 exhibits excellent stabilities toward air, thermal, solvent, and acid/alkaline conditions. The results manifest that the crystalline structure of 1 can be stable at at least 425 degrees C supported by the in situ variable-temperature powder X-ray diffraction patterns and thermogravimetric analyses, in air for at least 3 months, and in common solvents for more than 1 week, as well as in aqueous solutions ranging from pH = 2 to 12 for more than 1 week. PMID- 26097992 TI - Health professionals' perceptions regarding family witnessed resuscitation in adult critical care settings. AB - AIMS AND OBJECTIVES: To deepen our understanding of the perceptions of health professionals regarding family witnessed resuscitation in Jordanian adult critical care settings. BACKGROUND: The issue of family witnessed resuscitation has developed dramatically in the last three decades. The traditional practice of excluding family members during cardiopulmonary resuscitation had been questioned. Family witnessed resuscitation has been described as good practice by many researchers and health organisations. However, family witnessed resuscitation has been perceived by some practitioners to be unhealthy and harmful to the life-saving process. The literature showed that there are no policies or guidelines to allow or to prevent family witnessed resuscitation in Jordan. DESIGN: An exploratory qualitative design was adopted. METHODS: A purposive sample of 31 health professionals from several disciplines was recruited over a period of six months. Individual semi-structured interviews were used. These interviews were transcribed and analysed using thematic analysis. FINDINGS: It was found that most healthcare professionals were against family witnessed resuscitation. They raised several concerns related to being verbally and physically attacked if they allowed family witnessed resuscitation. Almost all of the respondents expressed their fears of patients' family members' interfering in their work. Most of the participants in this study stated that family witnessed resuscitation is traumatic for family members. This was viewed as a barrier to allowing family witnessed resuscitation in Jordanian critical care settings. CONCLUSION: The study provides a unique understanding of Jordanian health professionals' perceptions regarding family witnessed resuscitation. They raised some views that contest some arguments in the broader literature. Further research with patients, family members, health professionals and policy makers is still required. RELEVANCE TO CLINICAL PRACTICE: This is the first study about family witnessed resuscitation in Jordan. Considering multi-disciplinary healthcare professionals' views would be helpful when starting to implement this practice in Jordanian hospitals. PMID- 26097993 TI - Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations. AB - CONTEXT: Calcium metabolism changes in pregnancy and lactation to meet fetal needs, with increases in 1,25-dihydroxyvitamin D [1,25-(OH)2D] during pregnancy playing an important role. However, these changes rarely cause maternal hypercalcemia. When maternal hypercalcemia occurs, further investigation is essential, and disorders of 1,25-(OH)2D catabolism should be carefully considered in the differential diagnosis. CASE: A patient with a childhood history of recurrent renal stone disease and hypercalciuria presented with recurrent hypercalcemia and elevated 1,25-(OH)2D levels during pregnancy. Laboratory tests in the fourth pregnancy showed suppressed PTH, elevated 1,25-(OH)2D, and high normal 25-hydroxyvitamin D levels, suggesting disordered vitamin D metabolism. Analysis revealed low 24,25-dihydroxyvitamin D3 and high 25-hydroxyvitamin D3 levels, suggesting loss of function of CYP24A1 (25-hydroxyvitamin-D3-24 hydroxylase). Gene sequencing confirmed that she was a compound heterozygote with the E143del and R396W mutations in CYP24A1. CONCLUSIONS: This case broadens presentations of CYP24A1 mutations and hypercalcemia in pregnancy. Furthermore, it illustrates that patients with CYP24A1 mutations can maintain normal calcium levels during the steady state but can develop hypercalcemia when challenged, such as in pregnancy when 1,25-(OH)2D levels are physiologically elevated. PMID- 26097994 TI - Feasibility Investigation of Cellulose Polymers for Mucoadhesive Nasal Drug Delivery Applications. AB - The feasibility of various cellulose polymer derivatives, including methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (sodium-CMC), and cationic-hydroxyethylcellulose (cationic HEC), for use as an excipient to enhance drug delivery in nasal spray formulations was investigated. Three main parameters for evaluating the polymers in nasal drug delivery applications include rheology, ciliary beat frequency (CBF), and permeation across nasal tissue. Reversible thermally induced viscosity enhancement was observed at near nasal physiological temperature when cellulose derivatives were combined with an additional excipient, poly(vinyl caprolactam) poly(vinyl acetate)-poly(ethylene glycol) graft copolymer (PVCL-PVA-PEG). Cationic-HEC was shown to enhance acyclovir permeation across the nasal mucosa. None of the tested cellulosic polymers caused any adverse effects on porcine nasal tissues and cells, as assessed by alterations in CBF. Upon an increase in polymer concentration, a reduction in CBF was observed when ciliated cells were immersed in the polymer solution, and this decrease returned to baseline when the polymer was removed. While each cellulose derivative exhibited unique advantages for nasal drug delivery applications, none stood out on their own to improve more than one of the performance characteristics examined. Hence, these data may be useful for the development of new cellulose derivatives in nasal drug formulations. PMID- 26097995 TI - Novel high-sensitivity troponin assay requires higher cut-off value to separate acute myocardial infarction from non-acute myocardial infarction in a high-risk population. AB - PURPOSE: The novel high-sensitivity troponin T assay (hs-cTnT) has been validated for diagnosing AMI in the emergency room. However its utility in high-risk in patient populations is unknown. METHODS: We retrospectively reviewed admissions to a general cardiology unit that had 2 hs-cTnT measurements in the first 12 h of presentation. We assessed 8 diagnostic algorithms that used hs-cTnT concentration and changes in concentration (including the 99th percentile cut-off of 14 ng/L) for their diagnostic utility in separating AMI patients from cardiac/nonACS and non-cardiac chest-pain patients. UA was excluded. RESULTS: There were 233 patients (mean age 67 years, 153 were males (66%)) admitted over a 2 month period, with AMI diagnosed in 118 of these patients (51%). The recommended 99th percentile cut-off had modest accuracy (65%), good sensitivity (88%), and poor specificity (25%); a higher cut-off of 75 ng/L had a better diagnostic accuracy of 73%, p < 0.05. While some hs-cTnT algorithms were either highly sensitive or specific, none were both. CONCLUSION: In high-risk cardiology in-patients, no hs cTnT concentration cut-off or change more accurately diagnosed and excluded AMI, although higher cut-offs had better diagnostic utility. PMID- 26097996 TI - Effects of polyphenol-rich plant products from grape or hop as feed supplements on iron, zinc and copper status in piglets. AB - Polyphenol-rich plant products as feed supplements have been shown to exert beneficial effects on feed efficiency in piglets. However, tannins as components of polyphenol-rich plant products are able to reduce the absorption of various trace elements. The present study investigated the effect of two polyphenol-rich dietary supplements, grape seed and grape marc meal extract (GME) and spent hops (SH), on iron (Fe), zinc (Zn) and copper (Cu) status in piglets supplied adequately with those trace elements. A trial with three groups of piglets which received a Control diet or the same diet supplemented with either 1% GME or 1% SH over a period of 4 weeks was performed. Concentrations of Fe, Zn and Cu in plasma, total iron binding capacity and saturation of transferrin in plasma did not differ between the three groups. Piglets fed the diet supplemented with SH showed no differences in the concentrations of Fe, Zn and Cu in the liver in comparison to the Control group. Piglets fed the diets supplemented with GME showed slightly lower concentrations of Zn and Cu in the liver than Control piglets (p < 0.05); however, concentrations of both elements remained in the physiological range. Overall, this study shows that the polyphenol-rich plant products GME and SH had marginal effect on the status of Fe, Zn and Cu in piglets. PMID- 26097997 TI - Effects of Gold-Nanoparticle Surface and Vertical Coverage by Conducting Polymer between Indium Tin Oxide and the Hole Transport Layer on Organic Light-Emitting Diodes. AB - The effect of varying degrees of surface and vertical coverage of gold nanoparticles (Au-NPs) by poly(styrenesulfonate)-doped poly(3,4 ethylenedioxythiophene) ( PEDOT: PSS), which was used as a capping layer between indium tin oxide (ITO) and a hole transport layer (HTL) on small-molecule fluorescent organic light-emitting diodes (OLEDs), was systemically investigated. With respect to the Au-NP loading amount and size, the resultant current densities influenced the charge balance and, therefore, the OLED device performance. When the capping layer consisted of ITO/Au-NPs/ PEDOT: PSS+Au-NPs, superior device performance was obtained with 10-nm Au-NPs through increased surface coverage in comparison to other Au-NP PEDOT:PSS coverage conditions. Furthermore, the Au-NP size determined the vertical coverage of the capping layer. The current densities of OLEDs containing small Au-NPs (less than 30 nm, small vertical coverage) covered by PEDOT: PSS decreased because of the suppression of the hole carriers by the Au-NP trapping sites. However, the current densities of the devices with large Au-NPs (over 30 nm, large vertical coverage) increased. The increased electromagnetic fields observed around relatively large Au-NPs under electrical bias were attributed to increased current densities in the OLEDs, as confirmed by the finite-difference time-domain simulation. These results show that the coverage conditions of the Au-NPs by the PEDOT: PSS clearly influenced the OLED current density and efficiency. PMID- 26097998 TI - FBXW7 negatively regulates ENO1 expression and function in colorectal cancer. AB - FBXW7 (F-box and WD40 domain protein 7) is a tumor suppressor frequently inactivated in human cancers. The precise molecular mechanisms by which FBXW7 exerts antitumor activity remain under intensive investigation and are thought to relate in part to FBXW7-mediated destruction of key cancer-relevant proteins. Enolase 1 (ENO1) possesses oncogenic activity and is often overexpressed in various human cancers, besides its critical role in glycolysis. However, the detailed regulatory mechanisms of ENO1 expression remain unclear. Here we show that the elevated expression of ENO1 was identified in FBXW7-depletion HCT116 cells through two-dimensional protein electrophoresis and mass spectrometry assays (2DE-MS). Subsequent western blotting and immunohistochemical assays confirmed that ENO1 expression reversely correlates with FBXW7 expression in several cells and colon cancer tissues. Furthermore, we show that FBXW7 physically binds to ENO1 and targets ENO1 for ubiquitin-mediated degradation. Functionally, we found that FBXW7 suppresses the ENO1-induced gene expression, lactate production, cell proliferation and migration. These findings suggest that ENO1 is a novel substrate of FBXW7, and its activity can be negatively regulated by FBXW7 at the posttranslational level. Our work provides a novel molecular insight into FBXW7-directed tumor suppression through regulation of ENO1. PMID- 26097999 TI - The role of iNOS in cholesterol-induced liver fibrosis. AB - Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1alpha stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis. PMID- 26098001 TI - Increased risk of preterm birth in women with autoimmune hepatitis - a nationwide cohort study. AB - BACKGROUND & AIMS: The aim of our study was to investigate the risks of pregnancy and childbirth complications in women with autoimmune hepatitis compared to the population controls. METHODS: In a nationwide cohort study of all pregnancies between 2006 and 2011 we investigated the risks of adverse pregnancy outcome in 171 births in women with diagnosed autoimmune hepatitis using the data from the Swedish Medical Birth and Patient Registries. Births to women without autoimmune hepatitis served as population controls (n = 576 642). Relative risks (RR) with 95% confidence intervals (CI) were calculated using Poisson regression models adjusting for potential confounders. RESULTS: Women with AIH had an increased risk of gestational diabetes (RR = 4.35, 95% CI 2.21-8.57), of preterm birth (RR = 3.21, 95% CI 1.97-4.92) and of low-birth-weight child (RR = 2.51, 95% CI 1.51 4.19). We found no statistically significant association between autoimmune hepatitis and pre-eclampsia, caesarean section, low 5-min Apgar score, small for gestational age birth, congenital malformation and neonatal mortality. CONCLUSIONS: Autoimmune hepatitis is a risk factor for adverse pregnancy outcomes. High quality prenatal and antenatal care is important for women with autoimmune hepatitis and their infants. PMID- 26098002 TI - Terradynamically streamlined shapes in animals and robots enhance traversability through densely cluttered terrain. AB - Many animals, modern aircraft, and underwater vehicles use fusiform, streamlined body shapes that reduce fluid dynamic drag to achieve fast and effective locomotion in air and water. Similarly, numerous small terrestrial animals move through cluttered terrain where three-dimensional, multi-component obstacles like grass, shrubs, vines, and leaf litter also resist motion, but it is unknown whether their body shape plays a major role in traversal. Few ground vehicles or terrestrial robots have used body shape to more effectively traverse environments such as cluttered terrain. Here, we challenged forest-floor-dwelling discoid cockroaches (Blaberus discoidalis) possessing a thin, rounded body to traverse tall, narrowly spaced, vertical, grass-like compliant beams. Animals displayed high traversal performance (79 +/- 12% probability and 3.4 +/- 0.7 s time). Although we observed diverse obstacle traversal strategies, cockroaches primarily (48 +/- 9% probability) used a novel roll maneuver, a form of natural parkour, allowing them to rapidly traverse obstacle gaps narrower than half their body width (2.0 +/- 0.5 s traversal time). Reduction of body roundness by addition of artificial shells nearly inhibited roll maneuvers and decreased traversal performance. Inspired by this discovery, we added a thin, rounded exoskeletal shell to a legged robot with a nearly cuboidal body, common to many existing terrestrial robots. Without adding sensory feedback or changing the open-loop control, the rounded shell enabled the robot to traverse beam obstacles with gaps narrower than shell width via body roll. Such terradynamically 'streamlined' shapes can reduce terrain resistance and enhance traversability by assisting effective body reorientation via distributed mechanical feedback. Our findings highlight the need to consider body shape to improve robot mobility in real-world terrain often filled with clutter, and to develop better locomotor-ground contact models to understand interaction with 3D, multi-component terrain. PMID- 26098003 TI - [25 years after the fall of the Berlin wall - what differences does child and adolescent psychiatry (still) see?]. PMID- 26098000 TI - MicroRNA-19 triggers epithelial-mesenchymal transition of lung cancer cells accompanied by growth inhibition. AB - The miR-19 family (miR-19a and miR-19b-1) are key oncogenic components of the miR 17-92 cluster. Overexpression of miR-19 is strongly associated with cancer invasion and metastasis, and poor prognosis of cancer patients. However, the underlying mechanisms remain largely unknown. In the present study, we found that enforced expression of miR-19 including miR-19a and miR-19b-1 triggered epithelial-mesenchymal transition (EMT) of lung cancer cells A549 and HCC827 as shown by mesenchymal-like morphological conversion, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1 (zona occludens 1), and alpha-catenin), upregulation of mesenchymal proteins (e.g., vimentin, fibronectin 1, N-cadherin, and snail1), formation of stress fibers, and reduced cell adhesion. In addition, enhanced migration and invasion were observed in the cancer cells A549 and HCC827 undergoing EMT. In contrast, silencing of endogenous miR-19 reversed EMT and reduced the migration and invasion abilities of A549 and HCC827 cells. DNA microarray results revealed significant changes of the expression of genes related to EMT, migration, and metastasis of miR-19-expressing A549 cells. Moreover, siRNA-mediated knockdown of PTEN, a target of miR-19, also resulted in EMT, migration, and invasion of A549 and HCC827 cells, suggesting that PTEN is involved in miR-19-induced EMT, migration and invasion of lung cancer cells. Furthermore, lung cancer cells undergoing EMT induced by miR-19 demonstrated reduced proliferation in vitro and in vivo, and enhanced resistance to apoptosis caused by TNF-alpha. Taken together, these findings suggest that miR-19 triggers EMT, which has an important role in the invasion and migration of lung cancer cells, accompanied by the reduced proliferation of cells. PMID- 26098004 TI - [Home treatment - especially effective among boys with externalizing disorders? Age- and sex-specific effectiveness of home treatment for internalizing and externalizing disorders]. AB - OBJECTIVE: Indications for home treatment for specific diagnoses in child and adolescent psychiatry have not yet been evaluated. METHOD: In a recent intervention study (primary outcome: length of stay), 92 patients aged 5 to 17 years were randomized into an intervention group (early discharge followed by home treatment in combination with inpatient treatment, where needed) and a control group (regular length inpatient treatment). The aim of this explorative analysis was to retrieve additional information on "what works for whom." Outcome parameters were as follows: Children's Global Assessment Scale (CGAS), Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA), Strengths and Difficulties Questionnaire (SDQ) and Columbia Impairment Scale (CIS) at T1 (within 14 days after intake), T2 (end of treatment) and T3 (? 8.4-month follow up). Multiple regression was used to investigate the association between diagnoses, treatment setting, age, sex, and improvement in both groups. RESULTS: In children externalizing disorders were predominant, whereas in adolescents internalizing disorders were prominent. Patients improved equally under both types of treatment. Home treatment, however, was rated by the patients to be significantly more effective in adolescents (SDQ p = .017), boys (CIS p = .009, SDQ p < .001), and with externalizing disorders (SDQ p = .005). CONCLUSIONS: Home treatment may be considered an alternative to inpatient treatment, especially in boys with externalizing disorders. PMID- 26098005 TI - [Food addiction - substance use disorder or behavioral addiction?]. AB - This article looks at food addiction as a subject situated between psychiatry, neurobiology, nutritional science, internal medicine, food industry, and public health. Essentially, the question is whether or not individual nutritional components can induce physical dependence, similar to the well-known effects of drugs such as alcohol and cocaine, or whether food addiction is rather a behavioral addiction. The literature describes many overlaps as well as differences of substance-based and non-substance-based addiction in both clinical and neurobiological terms. Until recently it was argued that food addiction appears only in the realms of obesity and eating disorders (e.g., binge-eating disorder, BED). Some studies, however, described the prevalence of food addiction symptoms and diagnoses independent of overweight or that they were in subjects who do not fulfill the criteria for BED. This article sums up the controversial discussion about the phenomenological and neurobiological classification of food addiction. Implications of food addiction for children and adolescents as well as public-health-related issues are also discussed. PMID- 26098006 TI - [The comorbidity of learning difficulties and ADHD symptoms in primary-school-age children]. AB - Children having difficulties in acquiring early literacy and mathematical skills often show an increased rate of inattention, hyperactivity, and impulsivity. This study provides data on the comorbidity rates of specific learning difficulties and ADHD symptoms. We analyzed the data of 273 children with learning difficulties despite an at least average IQ, 57 children with low IQ, and 270 children without learning difficulties and average IQ (comparison group). We assessed children's IQ and school achievement using standardized achievement tests. ADHD symptoms were assessed via parents' ratings. Our results showed that only 5 % of both the control group and the group with solely mathematical difficulties fulfilled the criteria of an ADHD subtype according to the DSM-IV based on parents' ratings. In contrast, this was the case in even 20 % of the children with difficulties in reading/writing and of those with low IQ. Compared to girls, boys in the control group had a 150% higher risk for matching the criteria of one of the ADHD subtypes in parents' ratings, whereas boys with learning difficulties and those with low IQ had an even 200% to 600% higher risk for it. The relationship between learning difficulties and ADHD symptoms can be found predominantly in the inattentive type. Possible reasons for the results are discussed. PMID- 26098007 TI - [Visual perception abilities in children with reading disabilities]. AB - OBJECTIVE: Visual perceptual abilities are increasingly being neglected in research concerning reading disabilities. This study measures the visual perceptual abilities of children with disabilities in reading. METHOD: The visual perceptual abilities of 35 children with specific reading disorder and 30 controls were compared using the German version of the Developmental Test of Visual Perception - Adolescent and Adult (DTVP-A). RESULTS: 11 % of the children with specific reading disorder show clinically relevant performance on the DTVP A. The perceptual abilities of both groups differ significantly. No significant group differences exist after controlling for general IQ or Perceptional Reasoning Index, but they do remain after controlling for Verbal Comprehension, Working Memory, and Processing Speed Index. CONCLUSIONS: The number of children with reading difficulties suffering from visual perceptual disorders has been underestimated. For this reason, visual perceptual abilities should always be tested when making a reading disorder diagnosis. Profiles of IQ-test results of children suffering from reading and visual perceptual disorders should be interpreted carefully. PMID- 26098008 TI - [Screening interview for early detection of high-functioning autism spectrum disorders]. AB - OBJECTIVE: Various different questionnaires are available for the screening of autism spectrum disorders (ASD). These screening instruments show high sensitivity and are able to identify a large number of individuals with ASD, but they lack the specificity to differentiate individuals with ASD from those children and adolescents with other complex neurobehavioural disorders (such as attention-deficit/hyperactivity disorder, emotional disorders, and others), especially for those without intellectual disabilities. METHOD: The present study evaluates the data of 309 individuals (153 with high-functioning ASD, 156 with other psychiatric disorders, IQ > 70) to find out whether selected items of the ADI-R can be used for an economic and sensitive screening of high-functioning ASD. RESULTS: The results show that 8 items of the ADI-R can be used to discriminate high-functioning ASD and other psychiatric disorders. A cutoff of 5 led to a sensitivity of 0.93 and a cutoff of 6 to a specificity of 0.74. CONCLUSION: The combination of early onset, serious abnormalities in social contact with stereotyped or compulsive-ritualized behaviour or interests can be detected with few interview questions for screening of ASD. Nevertheless, a more detailed and specific assessment in an expert setting should follow the screening process. PMID- 26098012 TI - Incivility is (not) the very essence of love: Passion for work and incivility instigation. AB - This study explored the relationship between obsessive passion for work and incivility instigations, as well as the moderating role of a mastery motivational climate. A longitudinal, 3-wave study was conducted among 1,263 employees from a large Norwegian workers' union across a 10-month time span. The results show that obsessive passion for work relates positively to incivility instigations and that this relationship is stable over time. Building on the person-environment fit perspective, we find that the relationship between obsessive passion for work and incivility instigations is stronger for employees with both high levels of obsessive passion and high perceptions of a mastery climate. Our results underline the importance of considering not only the individual in his or her context but also of considering the match between the individual's values and the contextual values. PMID- 26098013 TI - Cerebral cavernous malformations: natural history and clinical management. AB - Cavernous malformations (CMs) are angiographically-occult clusters of dilated sinusoidal channels that may present clinically with seizures, focal neurological deficits and/or hemorrhage. Across natural history studies, the annual hemorrhage rate ranged from 1.6-3.1% per patient-year, decreasing to 0.08-0.2% per patient year for incidental CMs and to 0.3-0.6% for the collective group of unruptured CMs. Prior hemorrhage is a significant risk factor for subsequent CM hemorrhage. Hemorrhage clustering, particularly within the first 2 years, is an established phenomenon that may confound results of natural history studies evaluating the rate of rehemorrhage. Indeed, rehemorrhage rates for hemorrhagic CMs range from 4.5-22.9% in the literature. Surgical resection is the gold standard treatment for surgically-accessible, symptomatic CMs. Incidental CMs or minimally symptomatic, surgically inaccessible eloquent lesions may be considered for observation. Stereotactic radiosurgery is a controversial treatment approach of consideration only for cases of highly aggressive, surgically inaccessible CMs. PMID- 26098014 TI - Musculoskeletal pain may be associated with imatinib withdrawal syndrome in chronic myeloid leukemia patients. PMID- 26098015 TI - Graphical representation of clinical outcomes for patients with myelodysplastic syndromes. AB - The causes of death in patients with myelodysplastic syndromes (MDS) are diverse: infections, hemorrhage, complications of chronic anemia and repeated blood transfusions, and complications of progression to acute myeloid leukemia. Since most patients with MDS are diagnosed late in life, some individuals with MDS will succumb to an unrelated condition, such as one of the disorders that are common in geriatric populations. Currently, only a small proportion of patients with MDS - less than 5% - undergo allogeneic stem cell transplantation, a procedure that offers the only possibility of cure. This brief review summarizes outcomes for patients diagnosed with MDS using a pictographical format that illustrates both the challenges patients face and the pressing need for development of novel therapies, as well as highlighting the potential for increased use of allogeneic stem cell transplant. This informational graphic may be useful for teaching or in counseling certain patients. PMID- 26098016 TI - Surface-Functionalized Porous Lignin for Fast and Efficient Lead Removal from Aqueous Solution. AB - The development of ecofriendly sorbents for fast and efficient removal of heavy metals from aqueous media still remains a significant challenge. Here, we report that this task can be addressed by creating a porous naturally occurring polymer, as illustrated by functionalizing lignin with large numbers of mesopores and functional groups. We show that surface-functionalized porous lignin (SFPL), obtained by a two-step process, has a large surface area of 22.3 m2/g, 12 times that of lignin, and a high density of dithiocarbamate groups (2.8 mmol/g). SFPL was found to exhibit an excellent adsorption performance toward lead ions dissolved in water. For example, 99% of the lead ions from 50 mL of a solution containing 20 mg/L lead ions was removed in just 30 min by 0.01 g of SFPL. The saturated adsorption capacity of SFPL for lead ions was found to be 188 mg/g, which is 13 times that of the original lignin and 7 times that of activated carbon. The adsorption process is endothermic and involves intraparticle diffusion and chemical adsorption between lead ions and the functional groups of SFPL. The cost effectiveness and environmental friendliness of SFPL make it a promising material for removing lead and other heavy metals from wastewater. PMID- 26098017 TI - A Few Case Studies on the Correlation of Particle Network and Its Stability on the Ionic Conductivity of Solid-Liquid Composite Electrolytes. AB - We discuss here the crucial role of the particle network and its stability on the long-range ion transport in solid-liquid composite electrolytes. The solid-liquid composite electrolytes chosen for the study here comprise nanometer sized silica (SiO2) particles having various surface chemical functionalities dispersed in nonaqueous lithium salt solutions, viz. lithium perchlorate (LiClO4) in two different polyethylene glycol based solvents. These systems constitute representative examples of an independent class of soft matter electrolytes known as "soggy sand" electrolytes, which have tremendous potential in diverse electrochemical devices. The oxide additive acts as a heterogeneous dopant creating free charge carriers and enhancing the local ion transport. For long range transport, however, a stable spanning particle network is needed. Systematic experimental investigations here reveal that the spatial and time dependent characteristics of the particle network in the liquid solution are nontrivial. The network characteristics are predominantly determined by the chemical makeup of the electrolyte components and the chemical interactions between them. It is noteworthy that in this study the steady state macroscopic ionic conductivity and viscosity of the solid-liquid composite electrolyte are observed to be greatly determined by the additive oxide surface chemical functionality, solvent chemical composition, and solvent dielectric constant. PMID- 26098018 TI - Deep burn of hand and forearm treated by abdominal wall flap. A case report. AB - AIM: Post-traumatic hand and forearm defects always represent a challenge for reconstructive surgeons, especially when multiple structures are involved, because of a high rate of amputation. MATERIAL OF STUDY: A 21 years old woman arrived to the E.R. with a complex crush-burn trauma of the upper limb caused by an accident with an industrial ironing machine, resulting in a ulnar bone fracture, ulnar artery laceration and a wide burn of the dorsum of the right forearm. RESULT: We achieved toTAL limb salvage with coverage of the "nobles" structures of the forearm. DISCUSSION AND CONCLUSIONS: Different reconstructive methods have been used over time to treat these defects focusing the attention on both functional and cosmetic aspects. The abdominal pedicle flap was one of the achiest reconstructive methods for hand and forearm defects. In an era in which microsurgery takes the lion's share, some basic procedure may be helpful, especially in certain cases. In this study the authors reported a case of a young woman with a complex trauma of the right arm resulting from an occupational accident. PMID- 26098019 TI - Single-cell magnetic imaging using a quantum diamond microscope. AB - We apply a quantum diamond microscope for detection and imaging of immunomagnetically labeled cells. This instrument uses nitrogen-vacancy (NV) centers in diamond for correlated magnetic and fluorescence imaging. Our device provides single-cell resolution and a field of view (~1 mm(2)) two orders of magnitude larger than that of previous NV imaging technologies, enabling practical applications. To illustrate, we quantified cancer biomarkers expressed by rare tumor cells in a large population of healthy cells. PMID- 26098020 TI - A naturally monomeric infrared fluorescent protein for protein labeling in vivo. AB - Infrared fluorescent proteins (IFPs) provide an additional color to GFP and its homologs in protein labeling. Drawing on structural analysis of the dimer interface, we identified a bacteriophytochrome in the sequence database that is monomeric in truncated form and engineered it into a naturally monomeric IFP (mIFP). We demonstrate that mIFP correctly labels proteins in live cells, Drosophila and zebrafish. It should be useful in molecular, cell and developmental biology. PMID- 26098021 TI - Combining protein and mRNA quantification to decipher transcriptional regulation. AB - We combine immunofluorescence and single-molecule fluorescence in situ hybridization (smFISH), followed by automated image analysis, to quantify the concentration of nuclear transcription factors, number of transcription factors bound, and number of nascent mRNAs synthesized at individual gene loci. A theoretical model is used to decipher how transcription factor binding modulates the stochastic kinetics of mRNA production. We demonstrate this approach by examining the regulation of hunchback in the early Drosophila embryo. PMID- 26098022 TI - Multiyear Measurements of Flame Retardants and Organochlorine Pesticides in Air in Canada's Western Sub-Arctic. AB - Fourteen polybrominated diphenyl ethers (PBDEs), 14 non-BDE flame retardants (FRs), and 25 organochlorine pesticides (OCPs) were analyzed in air samples collected at Little Fox Lake (LFL) in Canada's Yukon Territory from August 2011 to December 2014. LFL is a long-term monitoring station operated under the Northern Contaminants Program (NCP) and one of only a few stations that contribute to the assessment of air pollution levels and pathways to the sub Arctic region. BDE-47 was the most abundant congener among the 14 PBDEs, followed by BDE-99. Non-BDE FRs pentabromotoluene (PBT) and dechlorane plus (DP) were detected in all the samples. Dechlorane 602, 2,3-dibromopropyl-2,4,6 tribromophenyl ether (DPTE), hexabromobenzene (HBB), and 2-ethylhexyl-2,3,4,5 tetrabromobenzoate (EH-TBB) were also detected in >75% of all samples. PBDEs have shown a decreasing tendency as of 2013, which may reflect the phase-out of penta- and octa-BDE mixtures has led to significant decline in the atmosphere. The highest concentrations of OCPs were observed for hexachlorobenzene (HCB), with a median concentration of 61 pg/m(3), followed by alpha-hexachlorocyclohexane (alpha-HCH) and alpha-endosulfan. Potential source contribution function (PSCF) highlights Northern Canada, Pacific, and East Asia as potential sources in warm seasons; whereas in cold seasons, the chemicals mainly came from the Pacific Rim. PMID- 26098023 TI - Response-adaptive randomization for multi-arm clinical trials using the forward looking Gittins index rule. AB - The Gittins index provides a well established, computationally attractive, optimal solution to a class of resource allocation problems known collectively as the multi-arm bandit problem. Its development was originally motivated by the problem of optimal patient allocation in multi-arm clinical trials. However, it has never been used in practice, possibly for the following reasons: (1) it is fully sequential, i.e., the endpoint must be observable soon after treating a patient, reducing the medical settings to which it is applicable; (2) it is completely deterministic and thus removes randomization from the trial, which would naturally protect against various sources of bias. We propose a novel implementation of the Gittins index rule that overcomes these difficulties, trading off a small deviation from optimality for a fully randomized, adaptive group allocation procedure which offers substantial improvements in terms of patient benefit, especially relevant for small populations. We report the operating characteristics of our approach compared to existing methods of adaptive randomization using a recently published trial as motivation. PMID- 26098025 TI - Do Drinking Episodes Contribute to Sexual Aggression Perpetration in College Men? AB - OBJECTIVE: Survey and experimental analog studies suggest that alcohol consumption contributes to perpetration of sexual aggression. However, few studies have considered the temporal association between naturally occurring episodes of drinking and subsequent sexual aggression. This daily report study was designed to examine whether alcohol consumption increases the odds of aggressive sexual activity within the next 4 hours. METHOD: First-year male college students (N = 427) completed daily online reports of drinking and sexual activity for up to 56 days. Multilevel modeling was used to determine whether drinking episodes increased the odds of the following outcomes occurring within 4 hours: (a) aggressive sex with a new partner, (b) non-aggressive sex with a new partner, (c) aggressive sex with a previous partner, and (d) non-aggressive sex with a previous partner. RESULTS: Drinking episodes increased the odds of both aggressive and non-aggressive sex with a new partner. In contrast, drinking episodes did not predict aggression involving previous partners and decreased the odds of non-aggressive sex with a previous partner. Contrary to hypotheses, individual difference variables associated with propensity toward sexual aggression (sexual misperception, antisocial behavior, hostility toward women) did not interact with daily alcohol. CONCLUSIONS: The complex pattern of results is more consistent with situational as opposed to pharmacological effects of alcohol on sexual aggression and suggests that prevention efforts focus on drinking contexts known to facilitate sexual activity. PMID- 26098026 TI - Alcohol-Induced Blackouts and Other Negative Outcomes During the Transition Out of College. AB - OBJECTIVE: There is considerable debate about the prospective association between alcohol-dependence symptoms and alcohol-related blackouts. The goal of this study was to examine the associations among alcohol-dependence symptoms, blackouts, and social and emotional consequences during the transition out of college. METHOD: Participants (N = 829; 66% female) were part of a 6-year longitudinal study designed to explore alcohol use and risky behaviors during and after college. Data for these analyses were from Years 4 and 5 of data collection, which most closely corresponded to the transition out of college. Using cross-lagged models, we tested the prospective associations of alcohol-dependence symptoms, blackout frequency, and social and emotional consequences. RESULTS: Alcohol-dependence symptoms in Year 4 predicted increased frequency of blackouts and social and emotional consequences during the subsequent year. Blackouts during Year 4 also significantly predicted increased alcohol-related social and emotional consequences, but not dependence symptoms, in Year 5. CONCLUSIONS: Although blackouts do not predict the development of alcohol-dependence symptoms, they increase the risk for less severe alcohol-related consequences during the transition out of college. This may result from the cognitive reconciliation of negative behaviors that occur during these episodes of amnesia. PMID- 26098027 TI - A Brief Orientation Week Ecological Momentary Intervention to Reduce University Student Alcohol Consumption. AB - OBJECTIVE: Orientation Week is a series of events at the beginning of the university year that introduces incoming students to university life. It is also the period of the academic year when students consume more alcohol than at any other time. Recently, we demonstrated that alcohol consumption during Orientation Week was related to alcohol consumption during the academic year. The aim of the present study was to determine whether a brief Ecological Momentary Intervention (EMI) implemented during Orientation Week could reduce alcohol consumption during Orientation Week and throughout the academic year. METHOD: Participants were 130 freshman-year university students (72 women, 58 men) randomly assigned to either an Ecological Momentary Assessment (EMA) condition or an EMA-EMI condition. In both conditions, participants reported pre-university, Orientation Week, and academic year weekend alcohol consumption. Those in the EMA-EMI condition also received EMI text messages promoting moderation every night during Orientation Week. RESULTS: Although the EMI did not reduce men's drinking, women in the EMA EMI condition, compared with women in the EMA condition, consumed significantly fewer drinks during Orientation Week, M = 17.1, SD = 13.3, vs. M = 26.4, SD = 22.5, respectively, t(70) = -1.927, p < .05, Cohen's d = 0.473, and reported consuming fewer weekend drinks during the academic semester, M = 5.0, SD = 3.3, vs. M = 7.5, SD = 6.3, respectively, t(70) = -2.263, p < .05, d = 0.451. CONCLUSIONS: This study represents the first important step in reducing drinking among university students by developing and using EMIs during Orientation Week. PMID- 26098029 TI - The Relationship of Alcoholism and Alcohol Consumption to All-Cause Mortality in Forty-One-Year Follow-up of the Swedish REBUS Sample. AB - OBJECTIVE: The purpose of this study was to examine the effects of alcoholism, alcohol consumption amount, and alcohol consumption pattern on mortality in a general population sample. METHOD: This study used a 1970 prospective population sample (double-phase random sample) of 2,300 individuals ages 18-65 years in Stockholm County, which was also linked to mortality registers. A total of 1,895 individuals participated in a semi-structured, baseline psychiatric interview with a psychiatrist and social worker. Alcoholism and other mental disorders were recorded according to the eighth revision of the International Classification of Diseases (ICD-8). Information on the usual amount and frequency of alcohol consumption was collected at the psychiatric interview. Mortality up to year 2011 was assessed with Cox proportional hazard regression models. RESULTS: At baseline, there were 65 men and 21 women diagnosed with alcoholism. During followup, there were 873 deaths in the study population of 1,895. Alcoholism was associated with increased mortality rate. Former drinkers, but not never drinkers, also had increased risk for mortality compared with moderate drinkers. We found no associations between heavy consumption and mortality. Frequent heavy episodic drinking was uncommon but related to mortality before, but not after, adjusting for an alcoholism diagnosis. CONCLUSIONS: Our results demonstrated that alcoholism-but not a reported high consumption of alcohol or frequent heavy episodic drinking-predicted a long-term risk of death. PMID- 26098028 TI - Single-Session Alcohol Interventions for Heavy Drinking College Students: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to conduct a meta-analysis summarizing the effectiveness of brief, single-session interventions to reduce alcohol use among heavy drinking college students. METHOD: A comprehensive literature search identified 73 studies comparing the effects of single-session brief alcohol intervention with treatment-as-usual or no-treatment control conditions on alcohol use among heavy drinking college students. Random-effects meta-analyses with robust variance estimates were used to synthesize 662 effect sizes, estimating the average overall effect of the interventions and the variability in effects across a range of moderators. RESULTS: An overall mean effect size of g = 0.18, 95% CI [0.12, 0.24] indicated that, on average, single-session brief alcohol interventions significantly reduced alcohol use among heavy drinking college students relative to comparison conditions. There was minimal variability in effects associated with study method and quality, general study characteristics, participant demographics, or outcome measure type. However, studies using motivational enhancement therapy/motivational interviewing (MET/MI) modalities reported larger effects than those using psychoeducational therapy (PET) interventions. Further investigation revealed that studies using MET/ MI and feedback-only interventions, but not those using cognitive-behavioral therapy or PET modalities, reported average effect sizes that differed significantly from zero. There was also evidence that long-term effects were weaker than short-term effects. CONCLUSIONS: Single-session brief alcohol interventions show modest effects for reducing alcohol consumption among heavy drinking college students and may be particularly effective when they incorporate MET/MI principles. More research is needed to directly compare intervention modalities, to develop more potent interventions, and to explore the persistence of long-term effects. PMID- 26098030 TI - Drinking Level, Drinking Pattern, and Twenty-Year Total Mortality Among Late-Life Drinkers. AB - OBJECTIVE: Research on moderate drinking has focused on the average level of drinking. Recently, however, investigators have begun to consider the role of the pattern of drinking, particularly heavy episodic drinking, in mortality. The present study examined the combined roles of average drinking level (moderate vs. high) and drinking pattern (regular vs. heavy episodic) in 20-year total mortality among late-life drinkers. METHOD: The sample comprised 1,121 adults ages 55-65 years. Alcohol consumption was assessed at baseline, and total mortality was indexed across 20 years. We used multiple logistic regression analyses controlling for a broad set of sociodemographic, behavioral, and health status covariates. RESULTS: Among individuals whose high level of drinking placed them at risk, a heavy episodic drinking pattern did not increase mortality odds compared with a regular drinking pattern. Conversely, among individuals who engage in a moderate level of drinking, prior findings showed that a heavy episodic drinking pattern did increase mortality risk compared with a regular drinking pattern. Correspondingly, a high compared with a moderate drinking level increased mortality risk among individuals maintaining a regular drinking pattern, but not among individuals engaging in a heavy episodic drinking pattern, whose pattern of consumption had already placed them at risk. CONCLUSIONS: Findings highlight that low-risk drinking requires that older adults drink low to moderate average levels of alcohol and avoid heavy episodic drinking. Heavy episodic drinking is frequent among late-middle-aged and older adults and needs to be addressed along with average consumption in understanding the health risks of late-life drinkers. PMID- 26098031 TI - Predictors of Postpartum Change in Alcohol Use in Norwegian Mothers. AB - OBJECTIVE: This study examined the relationship between marital status, family size, and postpartum alcohol use from birth to 36 months postpartum, based on data from the Norwegian Mother and Child Cohort Study. METHOD: Mothers' self reported alcohol frequency and alcohol units per drinking occasion at 0-3 months, 4-6 months, 18 months, and 36 months postpartum were modeled using linear mixed models for repeated measures. RESULTS: There was a strong main effect of time on alcohol use, with increases in alcohol use from childbirth to 36 months after childbirth. Adjusting for covariates, there were threeway interaction effects for Time * Family Structure * Family Size for alcohol units and alcohol frequency, indicating that a change in alcohol use varied as a function of family structure and family size. Single mothers had a lower increase in frequency of alcohol use but a steeper increase in the number of alcohol units. However, this effect was less pronounced with increasing family size. CONCLUSIONS: The patterns of findings are consistent with a differential opportunity perspective on alcohol use. PMID- 26098033 TI - Drinking to Cope Motivation as a Prospective Predictor of Negative Affect. AB - OBJECTIVE: Consistent with research indicating that drinking to cope (DTC) motivation might exacerbate negative affective states within or immediately proximal to discrete drinking episodes, we examined whether yearly deviations in more global levels of DTC motivation prospectively predicted depressive and anxious affect over several weeks. METHOD: College students (N = 521, 52% women) completed baseline measures of drinking motives, recent depression and anxiety symptoms, recent alcohol use, and alcohol use disorder symptoms on a secure website. Approximately 2 weeks after completing this survey, participants completed the 30-day daily diary portion of the study in which they reported on their current-day affective states. This yearly assessment burst in which participants completed a baseline survey and a daily diary assessment was repeated for 3 additional years. RESULTS: We found that changes in DTC motivation were positively associated with changes in depressive and anxious affect in the subsequent month, after we controlled for changes in concurrent anxiety and depressive symptoms, drinking level, enhancement drinking motivation, and alcohol use disorder symptoms. CONCLUSIONS: Our findings are consistent with the notion that DTC motivation confers a unique vulnerability for emotion dysregulation, and that drinking for such reasons possibly prolongs or exacerbates negative affective states. PMID- 26098032 TI - Differences Between African-American and European-American Women in the Association of Childhood Sexual Abuse With Initiation of Marijuana Use and Progression to Problem Use. AB - OBJECTIVE: Childhood sexual abuse (CSA) is associated with elevated risk of early marijuana use and cannabis use disorder (CUD). Both the prevalence of CSA and the course of marijuana use differ between African Americans and European Americans. The current study aimed to determine whether these differences manifest in racial/ ethnic distinctions in the association of CSA with early and problem use of marijuana. METHOD: Data were derived from female participants in a female twin study and a high-risk family study of substance use (n = 4,193, 21% African American). Cox proportional hazard regression analyses using CSA to predict initiation of marijuana use and progression to CUD symptom(s) were conducted separately by race/ethnicity. Sibling status on the marijuana outcome was used to adjust for familial influences. RESULTS: CSA was associated with both stages of marijuana use in African-American and European-American women. The association was consistent over the risk period (hazard ratio [HR] = 1.57, 95% confidence interval [CI] [1.37, 1.79] for initiation; HR = 1.51, 95% CI [1.21, 1.88] for CUD symptom onset) in European-American women. In African-American women, the HRs for initiation were 2.52 (95% CI [1.52, 4.18]) before age 15, 1.82 (95% CI [1.36, 2.44]) at ages 15-17, and nonsignificant after age 17. In the CUD symptom model, CSA predicted onset only at age 21 and older (HR = 2.17, 95% CI [1.31, 3.59]). CONCLUSIONS: The association of CSA with initiation of marijuana use and progression to problem use is stable over time in European-American women, but in African-American women, it varies by developmental period. Findings suggest the importance of considering race/ethnicity in prevention efforts with this high risk population. PMID- 26098034 TI - Depressive Symptoms Anticipate Changes in the Frequency of Alcohol Intoxication Among Low-Accepted Adolescents. AB - OBJECTIVE: There is strong evidence that depression anticipates later drinking problems among adults. These associations have not been consistently documented during adolescence, perhaps because little attention has been given to individual differences in peer relationships, which are the primary setting for adolescent alcohol consumption. This study investigated associations between depressive affect and alcohol misuse as moderated by peer group acceptance. METHOD: A community sample of 1,048 Swedish youth provided self-reports of depressive symptoms and intoxication frequency at annual intervals across the middle school years (seventh grade: M = 13.21 years old; eighth grade: M = 14.27 years old; ninth grade: M = 15.26 years old). Peer nominations provided a measure of individual acceptance. RESULTS: Growth curve analyses revealed differences in the extent to which initial levels of depressive symptoms predicted the slope of increase in intoxication frequency. Higher levels of depressive symptoms at the outset anticipated sharp increases in intoxication frequency from seventh to ninth grades for low-accepted youth but not for average- or high-accepted youth. CONCLUSIONS: poor peer relations and depressive affect are vulnerabilities that set the stage for escalating adolescent alcohol misuse. Across the middle school years, when most youth have their first experiences with alcohol, peer difficulties exacerbated the tendency of depressed youth to drink to excess. PMID- 26098035 TI - The Chicken or the Egg: Examining Temporal Precedence Among Attitudes, Injunctive Norms, and College Student Drinking. AB - OBJECTIVE: The present study was designed to test for projection, conformity, or reciprocal associations among attitudes, injunctive norms, and drinking. Assuming that these constructs are not independent, we proposed three possible trajectories. A conformity model would suggest that injunctive norms should temporally precede drinking or attitudes. Alternatively, a projection model would suggest that attitudes or alcohol use would precede injunctive norms. Furthermore, by examining the processes over three time points, the current study would also examine whether both conformity and projection processes were at work, indicating reciprocal relationships. METHOD: participants included 249 college students (63.1% female), who participated as a control group in a larger intervention trial. Structural equation modeling was used to examine cross sectional and prospective associations among injunctive norms, attitudes, and drinking across each of the three time points. RESULTS: Findings demonstrated three significant cross-lagged associations. Injunctive norms at Time 1 was significantly associated with drinking at Time 2 (conformity), and both attitudes and drinking at Time 2 were significantly associated with injunctive norms at Time 3 (projection). The pattern of cross-lagged associations suggested one meaningful indirect pathway, from Time 1 injunctive norms to Time 2 drinking to Time 3 injunctive norms (reciprocal association). CONCLUSIONS: The present study suggests that both the conformity and the projection processes seem to be important and evident for college student drinking when considering injunctive norms and drinking over time. Interventions that focus on both conformity and projection may be particularly effective at reducing longer-term alcohol use. PMID- 26098036 TI - Readiness to Change and to Accept Help and Drinking Outcomes in Young Adults of Mexican Origin. AB - OBJECTIVE: The purpose of this study was to assess whether readiness to change drinking (RCD) and readiness to accept help (RAH) improve short- and longer term drinking outcomes. METHOD: Data from a randomized controlled trial of screening and brief intervention (SBI) conducted in a U.S. emergency department at the U.S. Mexico border are reported. A total of 620 at-risk and dependent Mexican-origin drinkers (56% male), ages 18-30, received either an assessment only or intervention (SBI). Drinking outcomes included drinking days per week, average and maximum drinks per drinking day, heavy drinking (5+ drinks) days per week, and negative consequences. Random effects longitudinal models predicted baseline, 3-month, and 12-month drinking outcomes from baseline RCD and RAH. Models tested if (a) outcomes were significantly reduced at follow-ups and (b) differential reduction occurred by RCD, RAH, and post-intervention changes in readiness among those receiving SBI. RESULTS: For both study groups, outcomes improved from baseline to each follow-up across RCD and RAH status. RCD was not associated with differential improvement in outcomes for either group. In the SBI group, those RAH reported larger reductions at 3 months in average and maximum quantity than those not RAH but did not differ from those not RAH at 12-month outcomes. Among the SBI group, changing from not ready to ready (RTC or RAH) post-intervention was not associated with greater reductions in drinking compared with remaining not ready or ready post-intervention. CONCLUSIONS: Baseline RCD is not associated with drinking outcomes. Baseline RAH may facilitate greater reductions in drinking for those receiving SBI and should be further examined as a possible mediator of SBI effects for young adults of Mexican origin. PMID- 26098038 TI - Combined Use of Alcohol and Energy Drinks Increases Participation in High-Risk Drinking and Driving Behaviors Among College Students. AB - OBJECTIVE: A recent study suggested that college students who combined alcohol and energy drinks were more likely than students who consumed only alcohol to drive when their blood alcohol concentration (BAC) was higher than the .08% limit and to choose to drive despite knowing they had too much alcohol to drive safely. This study sought to replicate those findings with a larger sample while also exploring additional variables related to impaired driving. METHOD: College students (N = 549) completed an anonymous online survey to assess differences in drinking and driving-related behaviors between alcohol-only users (n = 281) and combined alcohol-energy drink users (n = 268). RESULTS: Combined users were more likely than alcohol-only users to choose to (a) drive when they perceived they were over the .08% BAC limit (35.0% vs. 18.1%, p < .001), (b) drive despite knowing they had too much alcohol to drive safely (36.3% vs. 17.0%, p < .001), and (c) be a passenger when they knew the driver had too much alcohol to drive safely (44.1% vs. 23.6%, p < .001). Combined users were significantly more likely (p < .001) to report indicators of high-risk alcohol use, such as larger number of drinks consumed, number of days drinking, number of days drunk, number of heavy episodic drinking episodes, greatest number of drinks on one occasion, and average hours of consumption. CONCLUSIONS: Combined use of alcohol and energy drinks may place drinkers at greater risk when compared with those who consume only alcohol. College students in this sample who combined alcohol and energy drinks were more likely to participate in high-risk driving behaviors than those who consumed only alcohol. PMID- 26098037 TI - Physical Pain in Alcohol-Dependent Patients Entering Treatment in Poland Prevalence and Correlates. AB - OBJECTIVE: Chronic pain and problematic alcohol use commonly co-exist, as the use of alcohol is commonly considered a useful pain self-management strategy. The purpose of this study was to characterize pain and pain-related problems in a group of primary alcohol-dependent individuals entering treatment facilities. METHOD: A sample of 366 (73.5% men and 26.5% women) alcohol-dependent (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria) subjects was recruited in alcohol treatment centers in Warsaw, Poland. Information was obtained about demographics, social functioning, sexual and physical abuse during childhood, and severity of alcohol and sleep problems as well as level of impulsivity and general psychopathology. The study group was divided into a "mild or no pain" group and a "moderate or greater pain" group. RESULTS: Among the study group, 34.4% of individuals reported moderate or greater physical pain during the last 4 weeks. The statistical analysis revealed that the experience of physical pain was significantly associated with lower level of education, unemployment, experience of sexual abuse before 18 years of age, and severity of alcohol dependence as well as other potential predictors of relapse (impulsivity, sleep problems, general psychopathology). When entered into logistic regression analysis with other dependent variables, the level of general psychopathology, severity of sleep problems, age, and education were all significantly associated with pain severity. CONCLUSIONS: Physical pain is a prevalent and potentially impairing experience in adults seeking treatment for alcohol dependence. Therapeutic interventions aimed at reducing pain in alcohol dependent individuals should be studied to evaluate their impact on improving overall treatment outcomes. PMID- 26098039 TI - Virtual Reality Therapy for the Treatment of Alcohol Dependence: A Preliminary Investigation With Positron Emission Tomography/Computerized Tomography. AB - OBJECTIVE: Virtual reality therapy (VRT) uses multimodal stimulation that includes visual, auditory, olfactory, and gustatory stimuli. The aim of this study was to assess the effectiveness of VRT in treating subjects with alcohol dependence (AD) by evaluating changes in brain metabolism. METHOD: The VRT protocol consisted of three steps: relaxation, presentation of a high-risk situation, and presentation of an aversive situation. Twelve alcohol-dependent subjects underwent 10 sessions of VRT. The alcohol-dependent subjects were assessed with 18F-fluorodeoxyglucose positron emission tomography images before and after VRT, whereas the control group underwent imaging according to the same protocol only at baseline. RESULTS: Compared with the healthy control group, AD subjects showed higher metabolism in the right lentiform nucleus and right temporal lobe (BA20) at baseline (P(FDR < .05) = .026). In addition, the metabolism in the left anterior cingulate was lower in subjects with AD (P(uncorr) = .001). After VRT, alcohol-dependent subjects showed decreased brain metabolism in the right lentiform nucleus (P(FDR < .05) = .026) and right temporal lobe (BA38, P(FDR < .05) = .032) relative to that at baseline. CONCLUSIONS: Our results suggest a neurobiological imbalance, notably, a high sensitivity to stimuli, in the limbic system in subjects with AD. Furthermore, we determined that metabolism decreased in the basal ganglia after VRT, which may explain the limbic-regulated responses of reward and regulation. Therefore, we tentatively recommend VRT to treat AD through its regulating effect on limbic circuits. PMID- 26098040 TI - Relationships Between Minimum Alcohol Pricing and Crime During the Partial Privatization of a Canadian Government Alcohol Monopoly. AB - OBJECTIVE: The purpose of this study was to estimate the independent effects of increases in minimum alcohol prices and densities of private liquor stores on crime outcomes in British Columbia, Canada, during a partial privatization of off premise liquor sales. METHOD: A time-series cross-sectional panel study was conducted using mixed model regression analysis to explore associations between minimum alcohol prices, densities of liquor outlets, and crime outcomes across 89 local health areas of British Columbia between 2002 and 2010. Archival data on minimum alcohol prices, per capita alcohol outlet densities, and ecological demographic characteristics were related to measures of crimes against persons, alcohol-related traffic violations, and non-alcohol-related traffic violations. Analyses were adjusted for temporal and regional autocorrelation. RESULTS: A 10% increase in provincial minimum alcohol prices was associated with an 18.81% (95% CI: +/-17.99%, p < .05) reduction in alcohol-related traffic violations, a 9.17% (95% CI: +/-5.95%, p < .01) reduction in crimes against persons, and a 9.39% (95% CI: +/-3.80%, p < .001) reduction in total rates of crime outcomes examined. There was no significant association between minimum alcohol prices and non alcohol-related traffic violations (p > .05). Densities of private liquor stores were not significantly associated with alcohol-involved traffic violations or crimes against persons, though they were with non-alcohol-related traffic violations. CONCLUSIONS: Reductions in crime events associated with minimum alcohol-price changes were more substantial and specific to alcohol-related events than the countervailing increases in densities of private liquor stores. The findings lend further support to the application of minimum alcohol prices for public health and safety objectives. PMID- 26098041 TI - "Hey Everyone, I'm Drunk." An Evaluation of Drinking-Related Twitter Chatter. AB - OBJECTIVE: The promotion of drinking behaviors correlates with increased drinking behaviors and intent to drink, especially when peers are the promotion source. Similarly, online displays of peer drinking behaviors have been described as a potential type of peer pressure that might lead to alcohol misuse when the peers to whom individuals feel attached value such behaviors. Social media messages about drinking behaviors on Twitter (a popular social media platform among young people) are common but understudied. In response, and given that drinking alcohol is a widespread activity among young people, we examined Twitter chatter about drinking. METHOD: Tweets containing alcohol- or drinking-related keywords were collected from March 13 to April 11, 2014. We assessed a random sample (n = 5,000) of the most influential Tweets for sentiment, theme, and source. RESULTS: Most alcohol-related Tweets reflected a positive sentiment toward alcohol use, with pro-alcohol Tweets outnumbering anti-alcohol Tweets by a factor of more than 10. The most common themes of pro-drinking Tweets included references to frequent or heavy drinking behaviors and wanting/needing/planning to drink alcohol. The most common sources of pro-alcohol Tweets were organic (i.e., noncommercial). CONCLUSIONS: Our findings highlight the need for online prevention messages about drinking to counter the strong pro-alcohol presence on Twitter. However, to enhance the impact of anti-drinking messages on Twitter, it may be prudent for such Tweets to be sent by individuals who are widely followed on Twitter and during times when heavy drinking is more likely to occur (i.e., weekends, holidays). PMID- 26098043 TI - Effect of drug physico-chemical properties on the efficiency of top-down process and characterization of nanosuspension. AB - INTRODUCTION: The top-down approach is frequently used for drug nanocrystal production. A large number of review papers have referred to the top-down approach in terms of process parameters such as stabilizer selection. However, a very important factor, that is, the influence of drug properties, has been not addressed so far. AREAS COVERED: This review will first discuss different nanocrystal technologies in brief. The focus will be on reviewing the different drug properties such as solid state and particle morphology on the efficiency of particle size reduction during top-down processes. Furthermore, the drug properties in the final nanosuspensions are critical for drug dissolution velocity. Therefore, another focus is the characterization of drugs in obtained nanosuspension. EXPERT OPINION: Drug physical properties play an important role in the production efficiency. The combinative technologies using modified drugs could significantly improve the performances of top-down processes. However, further understanding of the drug millability and homogenization will still be needed. In addition, a carefully established characterization system for nansuspension is essential. PMID- 26098042 TI - The Supply of Physicians Waivered to Prescribe Buprenorphine for Opioid Use Disorders in the United States: A State-Level Analysis. AB - OBJECTIVE: The U.S. Food and Drug Administration's approval of buprenorphine in 2002 expanded options for treating opioid use disorder (OUD). Physicians who intend to treat OUD patients with buprenorphine must seek a waiver to prescribe it, which may contribute to state-by-state variation in the supply of waivered physicians. METHOD: This study integrates data extracted from the U.S. Drug Enforcement Agency's database of waivered physicians with state-level indicators of the macro environment, health-related resources, and treatment demand. RESULTS: In December 2013, the average state had 8.0 waivered physicians per 100,000 residents (SD = 5.2). Large regional differences between states in the Northeast relative to states in the Midwest, South, and West were observed. The percentage of residents covered by Medicaid as well as the population-adjusted availability of opioid treatment programs and substance use disorder treatment facilities were positively associated with buprenorphine physician supply. Buprenorphine physician supply was positively correlated with states' rates of overdose deaths, suggesting that physicians may seek the waiver in response to the magnitude of the opioid problem in their state. CONCLUSIONS: States with greater health-related resources, particularly in terms of the supply of opioid treatment programs and substance use disorder treatment programs, had more waivered physicians in 2013. The finding regarding Medicaid coverage suggests that states implementing Medicaid expansion under health reform may experience additional growth in buprenorphine physician supply. However, large regional disparities in the supply of waivered physicians may impede access to care for many Americans with OUD. PMID- 26098044 TI - Cholesterol Modified Self-Assemblies and Their Application to Nanomedicine. AB - Cholesterol is a ubiquitous molecule in biological systems, and in particular plays various important roles in mammalian cellular processes. The presence of cholesterol is integral to the structure and behavior of biological membranes, and profoundly influences membrane involvement in cellular mechanisms. This review focuses on the incorporation of cholesterol into synthetic nanomaterials and assemblies, focusing on LC phase behavior, morphology/self-organization and hydrophobic interactions, all important factors in the design of nanomedicines. We highlight cholesteryl conjugates, liposomes and polymeric micelles, focusing on self-assembly capabilities, drug encapsulation and intracellular delivery. An area of considerable interest identified in this review is the use of cholesteryl functional vectors to deliver drugs or nucleic acids. Such applications depend on the ability of the nanoparticle carrier to associate with both the cellular and endosomal membrane. PMID- 26098045 TI - Trends in cervical intraepithelial neoplasia Grade 2+ after human papillomavirus vaccination: The devil is in the details. PMID- 26098046 TI - Method matters: Understanding diagnostic reliability in DSM-IV and DSM-5. AB - Diagnostic reliability is essential for the science and practice of psychology, in part because reliability is necessary for validity. Recently, the DSM-5 field trials documented lower diagnostic reliability than past field trials and the general research literature, resulting in substantial criticism of the DSM-5 diagnostic criteria. Rather than indicating specific problems with DSM-5, however, the field trials may have revealed long-standing diagnostic issues that have been hidden due to a reliance on audio/video recordings for estimating reliability. We estimated the reliability of DSM-IV diagnoses using both the standard audio-recording method and the test-retest method used in the DSM-5 field trials, in which different clinicians conduct separate interviews. Psychiatric patients (N = 339) were diagnosed using the SCID-I/P; 218 were diagnosed a second time by an independent interviewer. Diagnostic reliability using the audio-recording method (N = 49) was "good" to "excellent" (M kappa = .80) and comparable to the DSM-IV field trials estimates. Reliability using the test-retest method (N = 218) was "poor" to "fair" (M kappa = .47) and similar to DSM-5 field-trials' estimates. Despite low test-retest diagnostic reliability, self-reported symptoms were highly stable. Moreover, there was no association between change in self-report and change in diagnostic status. These results demonstrate the influence of method on estimates of diagnostic reliability. PMID- 26098048 TI - [Operability assessment - simply reasonable]. PMID- 26098047 TI - Progression in substance use initiation: A multilevel discordant monozygotic twin design. AB - Considerable attention has been paid to the "gateway" pattern of drug use initiation in which individuals progress from tobacco and alcohol use to cannabis and other illicit drugs. The extent to which this sequence reflects a causal impact of licit substance use on illicit substance involvement remains unclear. Clarifying the mechanisms underlying substance use initiation may help inform our understanding of risk for psychopathology, as increasing research is demonstrating associations between initiation patterns and heavier involvement. This study examined patterns of substance use initiation using a discordant twin design. Participants were 3,476 monozygotic twins (37% male) from the Australian Twin Registry who reported on their ages of tobacco, alcohol, and cannabis initiation. Multilevel proportional hazard regression models were used to (a) estimate within-twin-pair and between-twin-pair contributions to associations between the ages of onset of different drugs; and (b) examine whether the magnitude of effects differed as a function of the order of substance use initiation. Finding significant effects within twin pairs would support the hypothesis that the age of initiation of a substance causally influences the age of initiation of a subsequent substance. Finding significant effects between twin pairs would support the operation of familial influences that explain variation in the ages of initiation of multiple drugs. Within-twin-pair effects for typical patterns were modest. When initiation was atypical, however, larger within-twin pair effects were observed and causal influences were more strongly implicated. Results support the utility of examining the timing and ordering of substance use initiation within sophisticated, genetically informative designs. PMID- 26098049 TI - [Plasma cell myeloma: good collaboration of the team helps]. PMID- 26098050 TI - [Help me--I do not tolerate my statin]. AB - Statins represent the most widely prescribed drugs. Accordingly, in daily practice statin-related muscle pain and other myopathic sensations are frequently seen. In this practice review the clinical approach to statin myopathy is discussed. PMID- 26098052 TI - [Cardiovascular assessment and management before non-cardiac surgery]. AB - The preoperative cardiovascular risk management accounts for patient-related risk factors, the circumstances leading to the surgical procedure, and the risk of the operation. While urgent operations should not be delayed for cardiac testing, an elective surgical intervention should be postponed in unstable cardiac conditions. In stable cardiac situations, prophylactic coronary interventions to reduce the risk of perioperative complications are rarely indicated. Therefore, in most cases, the planned operation can be performed without previous cardiac stress testing or coronary angiography. Preoperative imaging stress testing is recommended for patients with poor functional capacities that are at high cardiovascular risk prior to a high-risk operation. According to the literature, preoperative prophylactic administration of betablockers and aspirin is controversial. Preoperative discontinuation of dual anti-platelet therapy within six months following drug-eluting stent implantation is not recommended. PMID- 26098053 TI - [Sitting just hurts!]. AB - We report on the history of a 53-year-old patient who went to his primary care physician due to pain while sitting. Clinical, gastroenterological and urological examination did not lead diagnostic. A radiography of the pelvis revealed a kinky sacrum and the MRT showed a tumor mass of about 9 cm in diameter. A plasmacytoma was histologically diagnosed in the biopsy. PMID- 26098055 TI - [Anorexia nervosa: when is an emergency somatic hospitalization indicated?]. PMID- 26098054 TI - [How is agonizing leg pain associated with an intrauterine device?]. AB - We report on a typical clinical course of pelvic actinomycosis: initial uncharacteristic discomfort develops into a systemic illness associated with a pelvic mass, which progresses so fast that along with the systemic infection further symptoms can be reduced to its growth rate--tiredness, abdominal pain, micturition deficiency, and leg pain. Distinction between malignancy and pelvic actinomycosis could be made only intraoperative. After hysterectomy and with antibiotics the patient recovered quickly. PMID- 26098056 TI - [Comprehensive care for patients older than 70 years with femoral neck fractures improves postoperative mobility]. PMID- 26098057 TI - [Pregnancy after bariatric surgery]. PMID- 26098059 TI - [Persistent Achilles tendon pain]. PMID- 26098061 TI - [Personalities in the history of medicine. Marie Francois Xavier Bichat]. PMID- 26098063 TI - C-Terminal-oriented Immobilization of Enzymes Using Sortase A-mediated Technique. AB - In the present study, sortase A-mediated immobilization of enzymes was used for the preparation of immobilized enzymes. Thermobifida fusca YX beta-glucosidase (BGL) or Streptococcus bovis 148 alpha-amylase (AmyA) were produced with C terminal sortase A recognition sequences. The resulting fusion proteins were successfully immobilized on nanoparticle surfaces using sortase A. Some properties (activity, stability, and reusability) of the immobilized fusion proteins were evaluated. Both immobilized BGL and immobilized AmyA prepared by the sortase A-mediated technique retained their catalytic activity, exhibiting activities 3.0- or 1.5-fold (respectively) of those seen with the same enzymes immobilized by chemical crosslinking. Immobilized enzymes prepared by the sortase A-mediated technique did not undergo dramatic changes in stability compared with the respective free enzymes. Thus, the sortase A-mediated technique provides a promising method for immobilization of active, stable enzymes. PMID- 26098062 TI - Renitrosylation of banked human red blood cells improves deformability and reduces adhesivity. AB - BACKGROUND: Transfusion of red blood cells (RBCs) is a frequent health care practice. However, unfavorable consequences may occur from transfusions of stored RBCs and are associated with RBC changes during storage. Loss of S nitrosohemoglobin (SNO-Hb) and other S-nitrosothiols (SNOs) during storage is implicated as a detriment to transfusion efficacy. It was hypothesized that restoring SNOs within banked RBCs would improve RBC functions relevant to successful transfusion outcomes, namely, increased deformability and decreased adhesivity. STUDY DESIGN AND METHODS: Stored human RBCs were incubated with nitric oxide (NO) donors PROLI/NO and DEA/NO (disodium 1-[2-(carboxylato) pyrrolidin-1-yl]diazen-1-ium-1,2-diolate and diethylammonium (Z)-1-(N,N diethylamino)diazen-1-ium-1,2-diolate) under varying experimental conditions (e.g., aerobic/anaerobic incubation, NO donor to RBC ratio). SNO restoration was evaluated in vitro and in vivo as a means to improve RBC function after storage. RESULTS: Incubation of RBCs with the NO donors resulted in 10-fold greater levels of SNO-Hb versus untreated control or sham RBCs, with significantly higher Hb bound NO yields from an NO dose delivered by DEA/NO. RBC incubation with DEA/NO at a stoichiometry of 1:62.5 NO:Hb significantly increased RBC deformabilty and reduced adhesion to cultured endothelial cells. RBC incubation with DEA/NO also increased S-nitrosylation of RBC cytoskeletal and membrane proteins, including the beta-spectrin chain. Renitrosylation attenuated both RBC sequestration in the lung and the mild blood oxygen saturation impairments seen with banked RBCs in a mouse model of transfusion. CONCLUSIONS: RBC renitrosylation using NO donors has promise for correcting deficient properties (e.g., adhesivity, rigidity, and SNO loss) of banked RBCs and in turn improving transfusion outcomes. PMID- 26098064 TI - A highly sensitive pressure sensor using a double-layered graphene structure for tactile sensing. AB - In this paper, we propose a graphene sensor using two separated single-layered graphenes on a flexible substrate for use as a pressure sensor, such as for soft electronics. The working pressure corresponds to the range in which human perception recognizes surface morphologies. A specific design of the sensor structure drives the piezoresistive character due to the contact resistance between two graphene layers and the electromechanical properties of graphene itself. Accordingly, sensitivity in resistance change is given by two modes for low pressure (-0.24 kPa(-1)) and high pressure (0.039 kPa(-1)) with a crossover pressure (700 Pa). This sensor can detect infinitesimal pressure as low as 0.3 Pa with uniformly applied vertical force. With the attachment of the artificial fingerprint structure (AFPS) on the sensor, the detection ability for both the locally generated shear force and actual human touch confirms recognition of the surface morphology constructed by periodic structures. PMID- 26098065 TI - [Physical inactivity is the new smoking]. PMID- 26098066 TI - [Passing the staff]. PMID- 26098067 TI - [Physical inactivity and chronic diseases]. AB - The genetic program of contemporary human beings is still that of hunters and gatherers of the Stone Age, dedicated to optimal storage of energy for physical activities in hunger periods. Life-style of humans living in western industrial countries however, is often characterized by physical inactivity and overeating. The resulting positive energy balance is associated with fat accumulation (abdomen, liver, skeletal and heart muscle) followed by insulin resistance, glucose intolerance, mitochondrial dysfunction, oxidative stress and reduced production of nitric oxide, endothelial dysfunction and chronic inflammatory processes. All these changes and their interactions are involved in the complex pathomechanisms of many metabolic, cardiovascular and neurodegenerative disorders. PMID- 26098068 TI - [The athletes' ECG and the exercise related sudden cardiac death]. AB - Regular physical activity induces structural, electrical and functional cardiac adaptations. The main challenge for the athletes' physician is to distinguish abnormal structural changes of the heart from training-induced adaptations (so called "athlete's heart"). In athletes with underlying cardiac disease, physical activity may be a trigger, not the cause of exercise-induced tachyarrhythmia's and sudden cardiac death (SCD). To identify athletes with cardiac diseases and increased risk for an SCD, the European society of cardiology (ESC) recommends a pre-participation screening in elite athletes which was adopted by the Swiss society of sports medicine. The screening includes a specific medical history, cardiac auscultation and a resting ECG. Due to the high number of false-positive cases of athletes' ECGs based on traditional criteria, the ESC assessment criteria were adjusted to account for training-related changes of the ECG. The sensitivity and especially the specificity could be improved in the "revised Seattle criteria" in 2014. During the last years main attention has been shifted to the early repolarization pattern: additionally to (endurance-) training there is a clear association with male gender, ethnicity, changes in autonomic nervous system activity and high QRS-voltage criteria PMID- 26098069 TI - [Laboratory analyses in sports medicine]. AB - Laboratory analyses in sports medicine are relevant for three reasons: 1. In actively exercising individuals laboratory analysis are one of the central elements in the diagnosis of diseases and overreaching. 2. Regularly done laboratory analysis in competitive athletes with high load of training and competition may help to detect certain deficiencies early on. 3. Physical activity in general and competitive exercise training specifically do change certain routine laboratory parameters significantly although not reflecting pathological changes. These so-called preanalytic variations should be taken into consideration while interpreting laboratory data in medical emergency and routine diagnostics. This article intends to help the physician to interprete laboratory data of actively exercising sportsmen. PMID- 26098070 TI - [Cardiopulmonary exercise testing (CPET) - indication and clinical impact]. AB - Dyspnoea is a common symptom of exercice intolerance. Tests performed at rest often leave the reason open. Cardiopulmonary exercise testing (CPET) is a tool for the qualitative and quantitative assessment of the cardio-circulatory, pulmonary and metabolic response to exercise. It is the gold-standard in the evaluation of dyspnoea and identifying its etiology (obstructive/restrictive lung disease, heart failure, physical fitness ...). CPET is particularly useful, if previous evaluations including history, physical examination, ECG, pulmonary function testing (PFT), X-ray, blood tests, and blood gases do not lead to a decisive diagnosis. The measurement of peak oxygen consumption, carbon dioxide production, minute ventilation and heart rate provides substantial diagnostic and prognostic information in a wide variety of clinical settings. Interpreting CPET requires pathophysiological knowledge and can sometimes be challenging. An easy to-use algorithm may provide a useful assistance for interpretation the results. In addition to its use as a diagnostic tool, CPET can be used to support sportsmen reaching their training goals and evaluate subject's ability to work. PMID- 26098071 TI - [Exercise guidelines for health-oriented recreational sports]. AB - Physical inactivity is one the biggest Public Health problems of the 21th century. Regular physical activity and sports can contribute to a reduction of overall mortality and morbidity and, thus, can have a considerable health impact for individuals as well as for the society as a whole. The beneficial health effects of exercise are convincingly evaluated yet and there is further evidence that physical activity can result in improvements in specific cardiorespiratory and metabolic diseases similar to pharmacological treatments. It is the aim of this review article to outline evidence-based guidelines for exercise to improve physical fitness and health in primary prevention in healthy adults. Based on the current scientific evidence a dose-response-relationship between physical activity and health markers as well as physical fitness is likely. Health oriented exercise training should allow for an exercise-induced energy expenditure of at least 1000 kcal per week. This should be approached by an appropriate combination of exercises targeting on an improvement in cardiorespiratory and metabolic functioning as well as muscular fitness. It is recommended to supplement such a training regimen by appropriate amounts of functional and flexibility exercises. Usually, sports targeting on these particular fitness areas are recommended, for instance, typical endurance sports like cycling, jogging, (Nordic) walking or swimming for the cardiorespiratory and metabolic domains and strength training for muscular fitness. In recent years, scientific studies have evaluated potentially more attractive sports like football, dancing and Tai Chi and reported promising results. Such sports may contribute to an increased long-term compliance to health-oriented exercise programmes. Although regular physical activity is associated with considerable health benefits, risks and side effects should be taken into account. The most frequent side effects are injuries, and the most severe are fatal cardiac events. Preventive measures should be applied to reduce the risk of these side effects. Health-oriented exercise guidelines should incorporate individual preferences and training responses to support a permanent adaptation towards a sportive life style. PMID- 26098072 TI - [Health-related strength and power training in seniors: Purpose and recommendations]. AB - The proportion of older people in western societies rapidly increases. Aging induced disease conditions accompanied with declines in cardiocirculatory and neuromuscular performance constitute a major individual and economic health burden. Besides decreasing vascular and cardiac function during the process of aging, a loss of skeletal muscle mass, muscle structure and function seem to mainly account for decreasing maximal strength, strength development and strength endurance. These findings adversely interfer with static and dynamic postural control and may lead to an increased risk of falling with impairments of autonomy and quality of life. Traditional strength training recommendations basing on health-related exercise prescriptions for elderly people have been proven to counteract or at least attenuate aging-induced declines of neuromuscular muscular function. Multimodal and combined strength and balance training deliver additional improvements of neuromuscular capacity. Recent evidence additionally underpin the need of trunk muscle training and claimed for regimes considering explosive and high-velocity strength training in seniors. High quality RCTs revealed notable strength training effects on mobility, autonomy, quality of life and the reduction of the risk of falling (up to 50%). Available evidence also indicates that various strength training regimes elicit preventive and therapeutic effects on osteoporosis, diabetes type 2 and other chronic diseases, with effect sizes comparable to medication intake. Thus, health care providers, health insurances, Employers' Liability Insurance Associations and politicians should promote infrastructural developments that enable feasible and cost effective access to health-related fitness centers or other sport facilities (e. g. sport clubs). These environmental requirements should be embedded in multi centric education programs and campaigns that might enable regularly conducted strength and endurance training perceived as beneficial and valuable from an individual health care perspective. PMID- 26098073 TI - [Running and the association with anthropometric and training characteristics]. AB - Running can be performed as a sprint discipline on the track over a few meters up to 10 km to the marathon and ultramarathon running distances over hundreds to thousands of kilometers. Running performance is influenced by a variety of anthropometric and training factors. Morphological features such as skin fold thickness, body fat percentage, circumferences and length of limbs, body weight, body height and body mass index (BMI) seem to have an influence on the running performance. The training volume and running speed during training are also correlated with running performance. When all variables were investigated comparatively, body fat and running speed during training were usually the most important influencing factors. For longer running performances (over 6 hours or 100 km, respectively), the aspects of experience (number of successfully finished races) and personal best times were, however, far more important than training volume or morphological characteristics such as body fat. It was also shown that ultra runners prepare differently (lower running speed and higher running volume) as runners competing over shorter distances such as half-marathon and marathon. PMID- 26098074 TI - A new route for the synthesis of highly substituted 4-aminoquinoline drug like molecules via aza hetero-Diels-Alder reaction. AB - We have demonstrated for the first time the use of 2H-indazole as a diene partner in an aza hetero-Diels-Alder reaction leading to highly substituted 4 aminoquinolines via a heterocylic-heterocylic (H-H) strategy and have further developed a tandem one-pot method starting from 2-azidobenzaldehyde by the formation of 2C-N, 1N-N and 1C-C bonds. The key features of the present protocol are readily available starting materials, mild reaction conditions, being work-up free and having easy purification. This is the first time where the synthesis of 4-aminoquinoline drug like molecules has been achieved starting from simple starting materials in an atom economical manner. PMID- 26098075 TI - Understanding of sub-band gap absorption of femtosecond-laser sulfur hyperdoped silicon using synchrotron-based techniques. AB - The correlation between sub-band gap absorption and the chemical states and electronic and atomic structures of S-hyperdoped Si have been extensively studied, using synchrotron-based x-ray photoelectron spectroscopy (XPS), x-ray absorption near-edge spectroscopy (XANES), extended x-ray absorption fine structure (EXAFS), valence-band photoemission spectroscopy (VB-PES) and first principles calculation. S 2p XPS spectra reveal that the S-hyperdoped Si with the greatest (~87%) sub-band gap absorption contains the highest concentration of S(2 ) (monosulfide) species. Annealing S-hyperdoped Si reduces the sub-band gap absorptance and the concentration of S(2-) species, but significantly increases the concentration of larger S clusters [polysulfides (Sn(2-), n > 2)]. The Si K edge XANES spectra show that S hyperdoping in Si increases (decreased) the occupied (unoccupied) electronic density of states at/above the conduction-band minimum. VB-PES spectra evidently reveal that the S-dopants not only form an impurity band deep within the band gap, giving rise to the sub-band gap absorption, but also cause the insulator-to-metal transition in S-hyperdoped Si samples. Based on the experimental results and the calculations by density functional theory, the chemical state of the S species and the formation of the S dopant states in the band gap of Si are critical in determining the sub-band gap absorptance of hyperdoped Si samples. PMID- 26098076 TI - Effect of Reduction in the Use of Computed Tomography on Clinical Outcomes of Appendicitis. AB - IMPORTANCE: Advanced diagnostic imaging is commonly used in the evaluation of suspected appendicitis in children. Despite its inferior diagnostic performance, ultrasonography (US) is now preferred to computed tomography (CT) owing to concerns about ionizing radiation exposure. With changes in imaging modalities, the influence on outcomes should be assessed. OBJECTIVES: To review trends in the use of US and CT for children with appendicitis and to investigate simultaneous changes in the proportions of negative appendectomy, appendiceal perforation, and emergency department (ED) revisits. DESIGN, SETTING, AND PARTICIPANTS: We reviewed the Pediatric Health Information System administrative database for children who presented to the ED with the diagnosis of appendicitis or who underwent an appendectomy in 35 US pediatric institutions from January 1, 2010, through December 31, 2013. MAIN OUTCOMES AND MEASURES: We studied the use of US and CT for trends and their association with negative appendectomy, appendiceal perforation, and 3-day ED revisits. RESULTS: Our investigation included 52,153 children with appendicitis. Use of US increased 46% (from 24.0% in 2010 to 35.3% in 2013; absolute difference, 11.3%; adjusted test for linear trend, P = .02), whereas use of CT decreased 48% (from 21.4% in 2010 to 11.6% in 2013; absolute difference, -9.8%; adjusted test for linear trend, P < .001). The proportion of negative appendectomy declined during the 4-year study period from 4.7% in 2010 to 3.6% in 2013 (test for linear trend, P = .002), whereas the proportion of perforations (32.3% in 2010 to 31.9% in 2013) and ED revisits (5.6% in 2010 and 2013) did not change (adjusted tests for linear trend, P = .64 and P = .84, respectively). CONCLUSIONS AND RELEVANCE: Among children with suspected appendicitis, the use of US imaging has increased substantially as the use of CT has declined. Despite the increased reliance on the diagnostically inferior US, important condition-specific quality measures, including the frequency of appendiceal perforation and ED revisits, remained stable, and the proportion of negative appendectomy declined slightly. PMID- 26098077 TI - Faster Drug Approvals Are Not Always Better and Can Be Worse. PMID- 26098078 TI - Physical Fitness in Older People with Mild Cognitive Impairment and Dementia. AB - Maintenance of physical activity and good physical fitness is important for functional independence. This study had two aims: examine the physical fitness level in older persons with mild cognitive impairment (MCI) or dementia, and examine the relationship between the components of physical fitness and cognitive domains in this group. The cross-sectional study included community-living older people >= 65 years of age with MCI or dementia. Physical fitness and cognition were assessed using the Senior Fitness Test and five cognitive tests. Most of the participants scored below the criteria for maintaining physical independence in later years. There were significant associations between the components of physical fitness and cognition, except flexibility. Declines in executive function were most related to declines in physical fitness. These factors should receive more attention in people with MCI and dementia because they risk losing independence. PMID- 26098080 TI - [Risk Factors for Depression an Anxiety Disorders and Use of Light Therapy]. PMID- 26098079 TI - The Competitive Influences of Perceptual Load and Working Memory Guidance on Selective Attention. AB - The perceptual load theory in selective attention literature proposes that the interference from task-irrelevant distractor is eliminated when perceptual capacity is fully consumed by task-relevant information. However, the biased competition model suggests that the contents of working memory (WM) can guide attentional selection automatically, even when this guidance is detrimental to visual search. An intriguing but unsolved question is what will happen when selective attention is influenced by both perceptual load and WM guidance. To study this issue, behavioral performances and event-related potentials (ERPs) were recorded when participants were presented with a cue to either identify or hold in memory and had to perform a visual search task subsequently, under conditions of low or high perceptual load. Behavioural data showed that high perceptual load eliminated the attentional capture by WM. The ERP results revealed an obvious WM guidance effect in P1 component with invalid trials eliciting larger P1 than neutral trials, regardless of the level of perceptual load. The interaction between perceptual load and WM guidance was significant for the posterior N1 component. The memory guidance effect on N1 was eliminated by high perceptual load. Standardized Low Resolution Electrical Tomography Analysis (sLORETA) showed that the WM guidance effect and the perceptual load effect on attention can be localized into the occipital area and parietal lobe, respectively. Merely identifying the cue produced no effect on the P1 or N1 component. These results suggest that in selective attention, the information held in WM could capture attention at the early stage of visual processing in the occipital cortex. Interestingly, this initial capture of attention by WM could be modulated by the level of perceptual load and the parietal lobe mediates target selection at the discrimination stage. PMID- 26098081 TI - [Obsessive Compulsive Symptoms in Persons with Intellectual Disabilities]. AB - BACKGROUND: Obsessive-compulsive symptoms are common with a high prevalence of 3.5 % in adults with intellectual disabilities (ID). The present article reviews different aspects (epidemiology, aetiology, clinical features, diagnostic methods and treatment). METHOD: A computerized search of the relevant literature was done using Pubmed and Cochrane databases. RESULTS: Difficulties in diagnosing obsessive-compulsive disorder in adults with ID result from difficulties in differentiating true compulsions from stereotypical and repetitive behaviors as also from the fact that patients with ID have cognitive and language impairments. Genetic diseases are most frequently the cause of congenital intellectual disability but only a few with ID are affected by OCD symptoms. Low-dose serotonergic anti-depressants are used in the treatment of OCD symptoms. However, there are only a few controlled treatment studies of obsessive-compulsive symptoms in people with ID. CONCLUSION: Further research especially regarding treatment of OCD in people with ID is urgently needed. PMID- 26098082 TI - [Common Risk Factors of Depressive and Anxiety Symptomatics in Childhood and Adolescence: A Systematic Review from Transdiagnostic Perspectives]. AB - Common causes of mental disorders are revealed by transdiagnostic perspectives. In this context, based on the study of Epkins and Heckler, the present study investigates common risk factors in depressive and anxiety symptomatics of children and adolescents. In a systematic literature search between 2012 and 2014, 35 studies were identified which demonstrated 44 common risk factors in internalising symptomatics in childhood and adolescence. Female gender, the onset of puberty, compliance with chronic illness, increased stress experience of children and mothers, negative parenting, misuse or rejective experiences in peers are evident factors in the developmental psychopathology of depression and anxiety disorders in childhood or adolescence. These common risk factors suggest a similar treatment of these diseases. PMID- 26098083 TI - [Rehabilitation in Huntington's Disease]. AB - Huntington's disease (HD) is a chronic neurodegenerative disease for which as yet no disease-modifying therapy is available. Even at the early stage of the disease, HD patients suffer from motor and cognitive impairments. They are in need of physical, occupational and speech therapy or (inpatient) multidisciplinary rehabilitation. This paper reviews the available evidence for the usefulness of these therapeutic interventions. Studies using HD animal models have shown that motor training per se or as part of an enriched environment setting may have a positive impact on disease onset and progression. There are four clinical randomized controlled trials (RCT) showing beneficial effects of physical therapy (standardized home-based training program). In particular, inpatient neurological rehabilitation may have positive effects on activities of daily living (ADL) in HD patients. A non-controlled trial on multidisciplinary rehabilitation showed a reduction of oxidative stress and associated neurodegeneration, with another study even demonstrating an increase in the volume of the right caudate and the dorsolateral prefrontal cortex. Among the studies focusing on multidisciplinary rehabilitation, there is only one RCT. Further controlled studies are needed. PMID- 26098084 TI - [Effect of Light Color Temperature on Human Concentration and Creativity]. AB - Light has different biological effects depending on the color temperature and intensity. This may be the reason for its differing effects. We investigated the influence of color temperature (3000 K, 4500 K, 6000 K) under constant high intensity (1000 Lux) on concentration and creativity of 50 students and employees of the Cologne University of Applied Sciences, Campus Gummersbach (age: 30.9 +/- 10.8y.). As test method we used d2-bq-test, creativity test (mean of the number of ideas on 5 themes), word test and logic test. In addition, test subjects were asked to evaluate their impression of light by means of a questionnaire. To exclude the circadian influence and learning effects on the result, we performed tests at the same time of the day using a random order of color temperature. We found that creativity was better under warm light (3000 K) than under colder light (4500 K, 6000 K). Concentration was best under cold light (6000 K). Under the same light intensity conditions, subjects judged blue light (6000 K) to be brighter than red light (3000 K). PMID- 26098085 TI - [Hoarding as a Disorder of the Obsessive-Compulsive Spectrum]. AB - Hoarding often occurs without obsessive-compulsive disorder (OCD), it shows distinguishable neuropsychological and neurobiological correlates and a distinct comorbidity spectrum. Further, it occurs secondarily to other psychiatric and neurobiological disorders. Therefore hoarding disorder has been included as a distinct diagnosis in DSM-5.Neuroimaging studies point to functional and structural abnormalities of networks subserving decision making, attention, action planning and emotional regulation.The cognitive-behavioral model outlines the most important characteristics of pathological hoarding, comprising deficits of information processing, maladaptive beliefs about information processing deficits, maladaptive beliefs about posessions as well as emotional attachment to them accompanied with emotional distress and avoidance.Because of a low willingness for therapy plus a high rate of discontinuation of therapy, a manualized cognitive-behavioral therapy approach for pathological hoarding has been established. It builds on observational learning, cognitive strategies, graduated exposure, response prevention, training/coaching to sort out, and relapse prevention are key components of the treatment. Particularily in case of lacking motivation for any kind of behavioral therapy or other psychological treatments, a pharmacotherapy with SSRIs is recommended. PMID- 26098087 TI - Adrenomedullin Up-regulates the Expression of Vascular Endothelial Growth Factor in Epithelial Ovarian Carcinoma Cells via JNK/AP-1 Pathway. AB - OBJECTIVE: Adrenomedullin (AM), a potent vasodilator peptide, presents in various kinds of tumors and promotes angiogenesis. We have previously reported that AM is expressed in epithelial ovarian carcinoma tissue. Here, we investigated the hypothesis that AM might regulate production of vascular endothelial growth factor (VEGF) in epithelial ovarian carcinoma and further promote angiogenic processes. METHODS: The messenger RNA expression of VEGF in human epithelial ovarian carcinoma cells (HO-8910) was examined by real-time polymerase chain reaction. Transcriptional control was analyzed by transient transfection assay of VEGF promoter-luciferase hybrid genes and chromatin immunoprecipitation assay. Activation of c-Jun N-terminal kinase (JNK) was detected by Western blotting. The formation of capillarylike structures by EA.hy926 cells cocultured with HO-8910 cells on Matrigel was also studied. RESULTS: We found that in HO-8910 cells, AM (10-10 to 10-7 mol/L) enhanced VEGF messenger RNA expression in a time- and concentration-dependent manner, as well as promoter activity. Furthermore, JNK was activated by AM stimulation. The AM-induced increase in VEGF expression was significantly attenuated by SP600125, a specific JNK inhibitor. Chromatin immunoprecipitation assay and promoter activity analysis showed that VEGF expression induced by AM required the activator protein 1 motif on the VEGF promoter. In an in vitro angiogenesis system for endothelial cells (EA.hy926) cocultured with HO-8910 cells, we observed that the addition of AM stimulated endothelial cell tube formation, which could be abolished by VEGF neutralizing antibody. CONCLUSIONS: Our findings suggest that the JNK/Activator protein 1 pathway is involved in AM-induced VEGF expression in HO-8910 cells. PMID- 26098088 TI - Prediction of Optimal Cytoreductive Surgery of Serous Ovarian Cancer With Gene Expression Data. AB - OBJECTIVES: Cytoreductive surgery is the cornerstone of ovarian cancer (OVCA) treatment. Detractors of initial maximal surgical effort argue that aggressive tumor biology will dictate survival, not the surgical effort. We investigated the role of biology in achieving optimal cytoreduction in serous OVCA using microarray gene expression analysis. METHODS: For the initial model, we used a gene expression signature from a microarray expression analysis of 124 women with serous OVCA, defining optimal cytoreduction as removal of all disease greater than 1 cm (with 64 women having optimal and 60 suboptimal cytoreduction). We then applied this model to 2 independent data sets: the Australian Ovarian Cancer Study (AOCS; 190 samples) and The Cancer Genome Atlas (TCGA; 468 samples). We performed a second analysis, defining optimal cytoreduction as removal of all disease to microscopic residual, using data from AOCS to create the gene signature and validating results in TCGA data set. RESULTS: Of the 12,718 genes included in the initial analysis, 58 predicted accuracy of cytoreductive surgery 69% of the time (P = 0.005). The performance of this classifier, measured by the area under the receiver operating characteristic curve, was 73%. When applied to TCGA and AOCS, accuracy was 56% (P = 0.16) and 62% (P = 0.01), respectively, with performance at 57% and 65%, respectively. In the second analysis, 220 genes predicted accuracy of cytoreductive surgery in the AOCS set 74% of the time, with performance of 73%. When these results were validated in TCGA set, accuracy was 57% (P = 0.31) and performance was at 62%. CONCLUSION: Gene expression data, used as a proxy of tumor biology, do not predict accurately nor consistently the ability to perform optimal cytoreductive surgery. Other factors, including surgical effort, may also explain part of the model. Additional studies integrating more biological and clinical data may improve the prediction model. PMID- 26098089 TI - Chemotherapy Response Rates Among Patients With Endometrial Cancer Who Have Elevated Serum Platelets. AB - OBJECTIVE: This retrospective study evaluates the influence of serum platelet count on chemotherapy response rates among women with endometrial cancer. METHODS: From 3 separate cancer centers, a total of 318 patients with endometrial cancer who received postoperative chemotherapy between June 1999 and October 2009 were retrospectively identified. Endometrioid, serous, clear cell, and carcinosarcoma histologies were included. Patients were classified as having an elevated platelet count if their serum platelet count was greater than 400 * 109/L at the time of initial diagnosis. Primary outcome was chemotherapy response, classified as either complete or partial/refractory. Secondary outcomes were disease-free and disease-specific survival. chi2 Test and Student t test were performed as appropriate. Kaplan-Meier curves and Cox proportional hazards models were used to assess serum platelet effect on survival. RESULTS: There were 125 deaths, 76 recurrences, and 48 disease progressions. Of the total group, 53 (16.7%) were categorized as having an elevated platelet count. An elevated platelet count was associated with a lower chemotherapy response rate in univariate analysis (hazard ratio [HR], 2.8; 95% 95% confidence interval [CI], 1.46-5.38; P < 0.01). Multivariate analysis showed elevated platelets to be independently associated with decreased disease-free survival (HR, 2.24; 95% CI, 1.26-3.98; P < 0.01) but not disease-specific survival (HR, 1.03; 95% CI, 0.56 1.88, P = 0.93). CONCLUSIONS: Patients with endometrial cancer who have an elevated serum platelet count greater than 400 * 109/L may have lower chemotherapy response rates and are at increased risk for recurrence when compared with patients with a count within the reference range. PMID- 26098090 TI - The European Network for Gynaecological Oncological Trial Groups Charta for Privileged Partnership. PMID- 26098091 TI - Thrombocytosis is Predictive of Postoperative Pulmonary Embolism in Patients With Gynecologic Cancer. AB - OBJECTIVES: The prompt diagnosis of postoperative pulmonary embolism (PE) in gynecologic oncology patients is imperative, but the clinical presentation is nonspecific in this high-risk group. We sought to determine risk factors and clinical findings that may assist clinicians in diagnosing PE in the inpatient setting. METHODS: Radiology data were queried to identify patients with gynecologic cancer who had a postoperative PE evaluation with computed tomography pulmonary angiography (CT-PA). Patient clinical findings at the time of the PE evaluation were abstracted, and univariate and multivariate regression analyses were performed to identify predictors of PE. RESULTS: For 6 years, there were 2498 major gynecologic oncology surgical procedures performed at our institution. Within 14 days of surgery, 107 CT-PA studies were obtained with a positive study rate of 24.3%. In patients with and without PE, there was no significant difference noted for age, oxygen saturations, body mass index and heart rate. After controlling for stage, history of venous thromboembolism (VTE), heart rate, and oxygen saturation, platelet count (odds ratio, 1.26 per 50 counts increase; 95% confidence interval, 1.07-1.48; P = 0.006) and history of VTE (odds ratio, 17.1; 95% confidence interval, 1.77-Inf, P = 0.014) were identified as independent predictors of PE in the multivariate model. CONCLUSIONS: Although clinicians often use tachycardia and low oxygen saturation as triggers to order PE imaging studies, these signs have a very low specificity. Given the findings of our study, accounting for high platelet count and history of VTE increases the pretest probability of CT-PA study. PMID- 26098092 TI - Cost-Effectiveness of Conventional vs Robotic-Assisted Laparoscopy in Gynecologic Oncologic Indications. AB - OBJECTIVE: Robotic surgical techniques are known to be expensive, but they can decrease the cost of hospitalization and improve patients' outcomes. The aim of this study was to compare the costs and clinical outcomes of conventional laparoscopy vs robotic-assisted laparoscopy in the gynecologic oncologic indications. METHODS: Between 2007 and 2010, 312 patients referred for gynecologic oncologic indications (endometrial and cervical cancer), including 226 who underwent conventional laparoscopy and 80 who underwent robot-assisted laparoscopy, were included in this prospective multicenter study. The direct costs, operating theater costs, and hospital costs were calculated for both surgical strategies using the microcosting method. RESULTS: Based on an average number of 165 surgical cases performed per year with the robot, the total extra cost of using the robot was ?1456 per intervention. The robot-specific costs amounted to ?2213 per intervention, and the cost of the robot-specific surgical supplies was ?957 per intervention. The cost of the surgical supplies specifically required by conventional laparoscopy amounted to ?1432, which is significantly higher than that of the robotic supplies (P < 0.001). Hospital costs were lower in the case of the robotic strategy (?2380 vs ?2841, P < 0.001) because these patients spent less time in intensive care (0.38 vs 0.85 days). Operating theater costs were higher in the case of the robotic strategy (?1490 vs ?1311, P = 0.0004) because the procedure takes longer to perform (4.98 hours vs 4.38 hours). CONCLUSIONS: The main driver of additional costs is the fixed cost of the robot, which is not compensated by the lower hospital room costs. The robot would be more cost-effective if robotic interventions were performed on a larger number of patients per year or if the purchase price of the robot was reduced. A shorter learning curve would also no doubt decrease the operating theater costs, resulting in financial benefits to society. PMID- 26098093 TI - Sexual Activity and Function in Patients With Gynecological Malignancies After Completed Treatment. AB - OBJECTIVE: Sexual activity (SA) and sexual function (SF) after completion of treatment are central for quality of life (QoL) in women affected by gynecological cancer (GC). The aim of this study was to analyze the sexual outcome and overall QoL of women after treatment for primary GC compared with a healthy control group (CG). METHODS: In a multicenter cross-sectional study, 77 women aged 28 to 67 years were surveyed at least 12 months after completion of primary therapy for cervical, endometrial, or vulvar cancer [gynecological cancer group (GCG)]. Data were collected through validated questionnaires (Female Sexual Function Index-d, EORTC Quality of Life Questionnaire-C30, and Sexual Activity Questionnaire) and compared to a control of 60 healthy women (CG). RESULTS: In the GCG, 41.3% were sexually active compared to 78.0% in the CG. Twelve women of the CG and 42 women of the GCG indicated the reasons for their sexual inactivity. The most common reason for sexual inactivity in the GCG was "the-presence-of-a physical-problem" [18/42 (42.9%) vs 2/12 (16.7%) in the CG], whereas in the CG, "because-I-do-not-have-a-partner" was most common [6/12 (50.0%) vs 11/42 (26.2%) in the GCG]. Sexually active patients in the GCG had an SF comparable to the CG. In multivariate analysis of the total cohort (n = 137), relationship status [solid partnership vs living alone; odds ratio (OR), 33.82; 95% confidence interval (CI), 4.83-236.70], smoking (OR, 0.25; 95% CI, 0.06-1.03), and age (OR, 0.87; 95% CI, 0.79-0.94) influenced SA significantly. The probability of SA thereby decreased with increasing age. Quality of life and subjective general health status were not significantly different between the GCG and the CG (EORTC Quality of Life Questionnaire-C30 score 68.25 vs 69.67). CONCLUSIONS: A high number of patients with GC remain sexually inactive after treatment, indicating that women experience persistent functional problems. However, women who regain SA after completed treatment have a good overall SF and vice versa. PMID- 26098094 TI - Retraction. PMID- 26098095 TI - Orchestrated scientific collaboration: critical to the control of MERS-CoV. PMID- 26098096 TI - Virtual High-Throughput Screening To Identify Novel Activin Antagonists. AB - Activin belongs to the TGFbeta superfamily, which is associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways holds promise as a therapeutic approach to these diseases. A small-molecule ligand-binding groove was identified in the interface between the two activin betaA subunits and was used for a virtual high-throughput in silico screening of the ZINC database to identify hits. Thirty-nine compounds without significant toxicity were tested in two well-established activin assays: FSHbeta transcription and HepG2 cell apoptosis. This screening workflow resulted in two lead compounds: NUCC-474 and NUCC-555. These potential activin antagonists were then shown to inhibit activin A-mediated cell proliferation in ex vivo ovary cultures. In vivo testing showed that our most potent compound (NUCC-555) caused a dose-dependent decrease in FSH levels in ovariectomized mice. The Blitz competition binding assay confirmed target binding of NUCC-555 to the activin A:ActRII that disrupts the activin A:ActRII complex's binding with ALK4-ECD-Fc in a dose-dependent manner. The NUCC-555 also specifically binds to activin A compared with other TGFbeta superfamily member myostatin (GDF8). These data demonstrate a new in silico-based strategy for identifying small-molecule activin antagonists. Our approach is the first to identify a first-in-class small molecule antagonist of activin binding to ALK4, which opens a completely new approach to inhibiting the activity of TGFbeta receptor superfamily members. in addition, the lead compound can serve as a starting point for lead optimization toward the goal of a compound that may be effective in activin-mediated diseases. PMID- 26098101 TI - Predicting disability pension - depression as hazard: a 10 year population-based cohort study in Norway. AB - Disability pension (DP) is an escalating challenge to individuals and the welfare state, with mental health problems as imminent hazard. The objective of the present paper was to determine if a diagnosis of depression increased the risk of subsequent DP, and whether the risk differed by gender. A population cohort of 1230 persons were diagnostically interviewed (Composite International Diagnostic Interview, CIDI) in a population study examining mental health, linked to the DP registry and followed for 10 years. The risk for DP following depression was estimated using Cox regression. Life-time depression, as well as current depression, increased the risk of subsequent DP for both genders. The fully adjusted [baseline health, health behavior and socio-economic status (SES)] hazard ratios (HRs) for life-time depressed men and women were 2.9 [95% confidence interval (CI) 1.5-5.8] and 1.6 (95% CI 1.0-2.5) respectively. Men were significantly older at time of DP. There are reasons to believe that depression went under-recognized and under-treated. To augment knowledge in the field, without underestimating depression as risk for DP, a deeper understanding of the nature and effects of other distress is needed. PMID- 26098097 TI - Non Digestible Oligosaccharides Modulate the Gut Microbiota to Control the Development of Leukemia and Associated Cachexia in Mice. AB - We tested the hypothesis that changing the gut microbiota using pectic oligosaccharides (POS) or inulin (INU) differently modulates the progression of leukemia and related metabolic disorders. Mice were transplanted with Bcr-Abl transfected proB lymphocytes mimicking leukemia and received either POS or INU in their diet (5%) for 2 weeks. Combination of pyrosequencing, PCR-DGGE and qPCR analyses of the 16S rRNA gene revealed that POS decreased microbial diversity and richness of caecal microbiota whereas it increased Bifidobacterium spp., Roseburia spp. and Bacteroides spp. (affecting specifically B. dorei) to a higher extent than INU. INU supplementation increased the portal SCFA propionate and butyrate, and decreased cancer cell invasion in the liver. POS treatment did not affect hepatic cancer cell invasion, but was more efficient than INU to decrease the metabolic alterations. Indeed, POS better than INU delayed anorexia linked to cancer progression. In addition, POS treatment increased acetate in the caecal content, changed the fatty acid profile inside adipose tissue and counteracted the induction of markers controlling beta-oxidation, thereby hampering fat mass loss. Non digestible carbohydrates with prebiotic properties may constitute a new nutritional strategy to modulate gut microbiota with positive consequences on cancer progression and associated cachexia. PMID- 26098102 TI - Alleviating Redox Imbalance Enhances 7-Dehydrocholesterol Production in Engineered Saccharomyces cerevisiae. AB - Maintaining redox balance is critical for the production of heterologous secondary metabolites, whereas on various occasions the native cofactor balance does not match the needs in engineered microorganisms. In this study, 7 dehydrocholesterol (7-DHC, a crucial precursor of vitamin D3) biosynthesis pathway was constructed in Saccharomyces cerevisiae BY4742 with endogenous ergosterol synthesis pathway blocked by knocking out the erg5 gene (encoding C-22 desaturase). The deletion of erg5 led to redox imbalance with higher ratio of cytosolic free NADH/NAD+ and more glycerol and ethanol accumulation. To alleviate the redox imbalance, a water-forming NADH oxidase (NOX) and an alternative oxidase (AOX1) were employed in our system based on cofactor regeneration strategy. Consequently, the production of 7-dehydrocholesterol was increased by 74.4% in shake flask culture. In the meanwhile, the ratio of free NADH/NAD+ and the concentration of glycerol and ethanol were reduced by 78.0%, 50.7% and 7.9% respectively. In a 5-L bioreactor, the optimal production of 7-DHC reached 44.49(+/-9.63) mg/L. This study provides a reference to increase the production of some desired compounds that are restricted by redox imbalance. PMID- 26098104 TI - Customized Finite Element Modelling of the Human Cornea. AB - AIM: To construct patient-specific solid models of human cornea from ocular topographer data, to increase the accuracy of the biomechanical and optical estimate of the changes in refractive power and stress caused by photorefractive keratectomy (PRK). METHOD: Corneal elevation maps of five human eyes were taken with a rotating Scheimpflug camera combined with a Placido disk before and after refractive surgery. Patient-specific solid models were created and discretized in finite elements to estimate the corneal strain and stress fields in preoperative and postoperative configurations and derive the refractive parameters of the cornea. RESULTS: Patient-specific geometrical models of the cornea allow for the creation of personalized refractive maps at different levels of IOP. Thinned postoperative corneas show a higher stress gradient across the thickness and higher sensitivity of all geometrical and refractive parameters to the fluctuation of the IOP. CONCLUSION: Patient-specific numerical models of the cornea can provide accurate quantitative information on the refractive properties of the cornea under different levels of IOP and describe the change of the stress state of the cornea due to refractive surgery (PRK). Patient-specific models can be used as indicators of feasibility before performing the surgery. PMID- 26098105 TI - Temporally Unpredictable Sounds Exert a Context-Dependent Influence on Evaluation of Unrelated Images. AB - Temporally unpredictable stimuli influence murine and human behaviour, as previously demonstrated for sequences of simple sounds with regular or irregular onset. It is unknown whether this influence is mediated by an evaluation of the unpredictable sound sequences themselves, or by an interaction with task context. Here, we find that humans evaluate unrelated neutral pictures as more negative when these are presented together with a temporally unpredictable sound sequence, compared to a predictable sequence. The same is observed for evaluation of neutral, angry and fearful face photographs. Control experiments suggest this effect is specific to interspersed presentation of negative and neutral visual stimuli. Unpredictable sounds presented on their own were evaluated as more activating, but not more aversive, and were preferred over predictable sounds. When presented alone, these sound sequences also did not elicit tonic autonomic arousal or negative mood change. We discuss how these findings might account for previous data on the effects of unpredictable sounds, in humans and rodents. PMID- 26098103 TI - Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping. AB - BACKGROUND: The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent. METHODS: We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases. CONCLUSIONS: The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD. PMID- 26098107 TI - Unveiling Undercover Cropland Inside Forests Using Landscape Variables: A Supplement to Remote Sensing Image Classification. AB - The worldwide demand for food has been increasing due to the rapidly growing global population, and agricultural lands have increased in extent to produce more food crops. The pattern of cropland varies among different regions depending on the traditional knowledge of farmers and availability of uncultivated land. Satellite images can be used to map cropland in open areas but have limitations for detecting undergrowth inside forests. Classification results are often biased and need to be supplemented with field observations. Undercover cropland inside forests in the Bale Mountains of Ethiopia was assessed using field observed percentage cover of land use/land cover classes, and topographic and location parameters. The most influential factors were identified using Boosted Regression Trees and used to map undercover cropland area. Elevation, slope, easterly aspect, distance to settlements, and distance to national park were found to be the most influential factors determining undercover cropland area. When there is very high demand for growing food crops, constrained under restricted rights for clearing forest, cultivation could take place within forests as an undercover. Further research on the impact of undercover cropland on ecosystem services and challenges in sustainable management is thus essential. PMID- 26098106 TI - Facilitators and Barriers to Safe Medication Administration to Hospital Inpatients: A Mixed Methods Study of Nurses' Medication Administration Processes and Systems (the MAPS Study). AB - CONTEXT: Research has documented the problem of medication administration errors and their causes. However, little is known about how nurses administer medications safely or how existing systems facilitate or hinder medication administration; this represents a missed opportunity for implementation of practical, effective, and low-cost strategies to increase safety. AIM: To identify system factors that facilitate and/or hinder successful medication administration focused on three inter-related areas: nurse practices and workarounds, workflow, and interruptions and distractions. METHODS: We used a mixed-methods ethnographic approach involving observational fieldwork, field notes, participant narratives, photographs, and spaghetti diagrams to identify system factors that facilitate and/or hinder successful medication administration in three inpatient wards, each from a different English NHS trust. We supplemented this with quantitative data on interruptions and distractions among other established medication safety measures. FINDINGS: Overall, 43 nurses on 56 drug rounds were observed. We identified a median of 5.5 interruptions and 9.6 distractions per hour. We identified three interlinked themes that facilitated successful medication administration in some situations but which also acted as barriers in others: (1) system configurations and features, (2) behaviour types among nurses, and (3) patient interactions. Some system configurations and features acted as a physical constraint for parts of the drug round, however some system effects were partly dependent on nurses' inherent behaviour; we grouped these behaviours into 'task focused', and 'patient-interaction focused'. The former contributed to a more streamlined workflow with fewer interruptions while the latter seemed to empower patients to act as a defence barrier against medication errors by being: (1) an active resource of information, (2) a passive information resource, and/or (3) a 'double-checker'. CONCLUSIONS: We have identified practical examples of system effects on work optimisation and nurse behaviours that potentially increase medication safety, and conceptualized ways in which patient involvement can increase medication safety in hospitals. PMID- 26098108 TI - Prevalence and Correlates of Food Insecurity among Palestinian Refugees in Lebanon: Data from a Household Survey. AB - Lebanon hosts the highest per capita refugee concentration worldwide. The Palestinian presence in Lebanon dates from 1948 and they remain a marginalized population. No information on their food security status has been reported previously. A survey of a representative sample of Palestinian refugee households in Lebanon (n = 2501) was conducted using a stratified two stage cluster sampling approach. We measured food insecurity using a modified USDA household food security module, locally validated. We collected data on household demographic, socioeconomic, health, housing, coping strategies and household intake of food groups and analysed these by food security status. About 41% (CI: 39-43) of households reported being food insecure and 20% (CI: 18-22) severely food insecure. Poor households were more likely to be severely food insecure (OR 1.41 (1.06-1.86)) while higher education of the head of household was significantly associated with protection against severe food insecurity (OR 0.66 (0.52-0.84)). Additionally, higher food expenditure and possession of food-related assets were significantly associated with food security (OR 0.93 (0.89-0.97) and OR 0.74 (0.59-0.92), respectively). After adjusting for confounders, households where at least one member suffered from an acute illness remained significantly more likely to be severely food insecure (OR 1.31(1.02-1.66)), as were households whose proxy respondent reported poor mental health (OR 2.64 (2.07-3.38)) and poor self-reported health (OR 1.62 (1.22-2.13). Severely food insecure households were more likely to eat cheaper foods when compared to non-severely food insecure households (p<0.001) and were more likely to rely on gifts (p<0.001) or welfare (p<0.001). They were also more likely to have exhausted all coping strategies, indicating significantly more frequently that they could not do anything (p = 0.0102). Food insecurity is a significant problem among Palestinian refugees in Lebanon and is likely to be exacerbated at this time when the Syrian crisis amplifies the problem. PMID- 26098109 TI - High Stimulus-Related Information in Barrel Cortex Inhibitory Interneurons. AB - The manner in which populations of inhibitory (INH) and excitatory (EXC) neocortical neurons collectively encode stimulus-related information is a fundamental, yet still unresolved question. Here we address this question by simultaneously recording with large-scale multi-electrode arrays (of up to 128 channels) the activity of cell ensembles (of up to 74 neurons) distributed along all layers of 3-4 neighboring cortical columns in the anesthetized adult rat somatosensory barrel cortex in vivo. Using two different whisker stimulus modalities (location and frequency) we show that individual INH neurons- classified as such according to their distinct extracellular spike waveforms- discriminate better between restricted sets of stimuli (<=6 stimulus classes) than EXC neurons in granular and infra-granular layers. We also demonstrate that ensembles of INH cells jointly provide as much information about such stimuli as comparable ensembles containing the ~20% most informative EXC neurons, however presenting less information redundancy - a result which was consistent when applying both theoretical information measurements and linear discriminant analysis classifiers. These results suggest that a consortium of INH neurons dominates the information conveyed to the neocortical network, thereby efficiently processing incoming sensory activity. This conclusion extends our view on the role of the inhibitory system to orchestrate cortical activity. PMID- 26098110 TI - Imaging of Intracellular and Extracellular ROS Levels in Atherosclerotic Mouse Aortas Ex Vivo: Effects of Lipid Lowering by Diet or Atorvastatin. AB - OBJECTIVE: The first objective was to investigate if intracellular and extracellular levels of reactive oxygen species (ROS) within the mouse aorta increase before or after diet-induced lesion formation. The second objective was to investigate if intracellular and extracellular ROS correlates to cell composition in atherosclerotic lesions. The third objective was to investigate if intracellular and extracellular ROS levels within established atherosclerotic lesions can be reduced by lipid lowering by diet or atorvastatin. APPROACH AND RESULTS: To address our objectives, we established a new imaging technique to visualize and quantify intracellular and extracellular ROS levels within intact mouse aortas ex vivo. Using this technique, we found that intracellular, but not extracellular, ROS levels increased prior to lesion formation in mouse aortas. Both intracellular and extracellular ROS levels were increased in advanced lesions. Intracellular ROS correlated with lesion content of macrophages. Extracellular ROS correlated with lesion content of smooth muscle cells. The high levels of ROS in advanced lesions were reduced by 5 days high dose atorvastatin treatment but not by lipid lowering by diet. Atorvastatin treatment did not affect lesion inflammation (aortic arch mRNA levels of CXCL 1, ICAM-1, MCP-1, TNF alpha, VCAM, IL-6, and IL-1beta) or cellular composition (smooth muscle cell, macrophage, and T-cell content). CONCLUSIONS: Aortic levels of intracellular ROS increase prior to lesion formation and may be important in initiation of atherosclerosis. Our results suggest that within lesions, macrophages produce mainly intracellular ROS whereas smooth muscle cells produce extracellular ROS. Short term atorvastatin treatment, but not lipid lowering by diet, decreases ROS levels within established advanced lesions; this may help explain the lesion stabilizing and anti-inflammatory effects of long term statin treatment. PMID- 26098113 TI - Correction: First Shark from the Late Devonian (Frasnian) Gogo Formation, Western Australia Sheds New Light on the Development of Tessellated Calcified Cartilage. PMID- 26098111 TI - Metabolic Syndrome Is Associated with Increased Oxo-Nitrative Stress and Asthma Like Changes in Lungs. AB - Epidemiological studies have shown an increased obesity-related risk of asthma. In support, obese mice develop airway hyperresponsiveness (AHR). However, it remains unclear whether the increased risk is a consequence of obesity, adipogenic diet, or the metabolic syndrome (MetS). Altered L-arginine and nitric oxide (NO) metabolism is a common feature between asthma and metabolic syndrome that appears independent of body mass. Increased asthma risk resulting from such metabolic changes would have important consequences in global health. Since high sugar diets can induce MetS, without necessarily causing obesity, studies of their effect on arginine/NO metabolism and airway function could clarify this aspect. We investigated whether normal-weight mice with MetS, due to high fructose diet, had dysfunctional arginine/NO metabolism and features of asthma. Mice were fed chow-diet, high-fat-diet, or high-fructose-diet for 18 weeks. Only the high-fat-diet group developed obesity or adiposity. Hyperinsulinemia, hyperglycaemia, and hyperlipidaemia were common to both high-fat-diet and high fructose-diet groups and the high-fructose-diet group additionally developed hypertension. At 18 weeks, airway hyperresponsiveness (AHR) could be seen in obese high-fat-diet mice as well as non-obese high-fructose-diet mice, when compared to standard chow-diet mice. No inflammatory cell infiltrate or goblet cell metaplasia was seen in either high-fat-diet or high-fructose-diet mice. Exhaled NO was reduced in both these groups. This reduction in exhaled NO correlated with reduced arginine bioavailability in lungs. In summary, mice with normal weight but metabolic obesity show reduced arginine bioavailability, reduced NO production, and asthma-like features. Reduced NO related bronchodilation and increased oxo-nitrosative stress may contribute to the pathogenesis. PMID- 26098114 TI - Enhanced Lacto-Tri-Peptide Bio-Availability by Co-Ingestion of Macronutrients. AB - Some food-derived peptides possess bioactive properties, and may affect health positively. For example, the C-terminal lacto-tri-peptides Ile-Pro-Pro (IPP), Leu Pro-Pro (LPP) and Val-Pro-Pro (VPP) (together named here XPP) are described to lower blood pressure. The bioactivity depends on their availability at the site of action. Quantitative trans-organ availability/kinetic measurements will provide more insight in C-terminal tri-peptides behavior in the body. We hypothesize that the composition of the meal will modify their systemic availability. We studied trans-organ XPP fluxes in catheterized pigs (25 kg; n=10) to determine systemic and portal availability, as well as renal and hepatic uptake of a water-based single dose of synthetic XPP and a XPP containing protein matrix (casein hydrolyte, CasH). In a second experiment (n=10), we compared the CasH-containing protein matrix with a CasH-containing meal matrix and the modifying effects of macronutrients in a meal on the availability (high carbohydrates, low quality protein, high fat, and fiber). Portal availability of synthetic XPP was 0.08 +/- 0.01% of intake and increased when a protein matrix was present (respectively 3.1, 1.8 and 83 times for IPP, LPP and VPP). Difference between individual XPP was probably due to release from longer peptides. CasH prolonged portal bioavailability with 18 min (absorption half-life, synthetic XPP: 15 +/- 2 min, CasH: 33 +/- 3 min, p<0.0001) and increased systemic elimination with 20 min (synthetic XPP: 12 +/- 2 min; CasH: 32 +/- 3 min, p<0.0001). Subsequent renal and hepatic uptake is about 75% of the portal release. A meal containing CasH, increased portal 1.8 and systemic bioavailability 1.2 times. Low protein quality and fiber increased XPP systemic bioavailability further (respectively 1.5 and 1.4 times). We conclude that the amount and quality of the protein, and the presence of fiber in a meal, are the main factors that increase the systemic bioavailability of food-derived XPP. PMID- 26098116 TI - Correction: The Effect on Mortality of Fluconazole or Echinocandins Treatment in Candidemia in Internal Medicine Wards. PMID- 26098115 TI - The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression. AB - The phosphatase and actin regulator 1 (PHACTR1) locus is a very commonly identified hit in genome-wide association studies investigating coronary artery disease and myocardial infarction (MI). However, the function of PHACTR1 in the heart is still unknown. We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects. Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day after MI in rats. When the direct myocardial effects of Phactr1 were studied, the skeletal alpha-actin to cardiac alpha-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle. Similarly, the skeletal alpha-actin to cardiac alpha-actin ratio was lower at 2 weeks in infarcted hearts overexpressing Phactr1. In cultured neonatal cardiac myocytes, adenovirus-mediated Phactr1 overexpression for 48 hours markedly increased the skeletal alpha-actin to cardiac alpha-actin ratio, this being associated with an enhanced DNA binding activity of serum response factor. Phactr1 overexpression exerted no major effects on the expression of other cardiac genes or LV structure and function in normal and infarcted hearts during 2 weeks' follow-up period. In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550). Phactr1 seems to regulate the skeletal to cardiac alpha actin isoform ratio. PMID- 26098119 TI - Auditory and motor contributions to the timing of melodies under cognitive load. AB - Current theoretical models and empirical research suggest that sensorimotor control and feedback processes may guide time perception and production. In the current study, we investigated the role of motor control and auditory feedback in an interval-production task performed under heightened cognitive load. We hypothesized that general associative learning mechanisms enable the calibration of time against patterns of dynamic change in motor control processes and auditory feedback information. In Experiment 1, we applied a dual-task interference paradigm consisting of a finger-tapping (continuation) task in combination with a working memory task. Participants (nonmusicians) had to either perform or avoid arm movements between successive key presses (continuous vs. discrete). Auditory feedback from a key press (a piano tone) filled either the complete duration of the target interval or only a small part (long vs. short). Results suggested that both continuous movement control and long piano feedback tones contributed to regular timing production. In Experiment 2, we gradually adjusted the duration of the long auditory feedback tones throughout the duration of a trial. The results showed that a gradual shortening of tones throughout time increased the rate at which participants performed tone onsets. Overall, our findings suggest that the human perceptual-motor system may be important in guiding temporal behavior under cognitive load. PMID- 26098117 TI - Changes in the Acetylome and Succinylome of Bacillus subtilis in Response to Carbon Source. AB - Lysine residues can be post-translationally modified by various acyl modifications in bacteria and eukarya. Here, we showed that two major acyl modifications, acetylation and succinylation, were changed in response to the carbon source in the Gram-positive model bacterium Bacillus subtilis. Acetylation was more common when the cells were grown on glucose, glycerol, or pyruvate, whereas succinylation was upregulated when the cells were grown on citrate, reflecting the metabolic states that preferentially produce acetyl-CoA and succinyl-CoA, respectively. To identify and quantify changes in acetylation and succinylation in response to the carbon source, we performed a stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomic analysis of cells grown on glucose or citrate. We identified 629 acetylated proteins with 1355 unique acetylation sites and 204 succinylated proteins with 327 unique succinylation sites. Acetylation targeted different metabolic pathways under the two growth conditions: branched-chain amino acid biosynthesis and purine metabolism in glucose and the citrate cycle in citrate. Succinylation preferentially targeted the citrate cycle in citrate. Acetylation and succinylation mostly targeted different lysine residues and showed a preference for different residues surrounding the modification sites, suggesting that the two modifications may depend on different factors such as characteristics of acyl group donors, molecular environment of the lysine substrate, and/or the modifying enzymes. Changes in acetylation and succinylation were observed in proteins involved in central carbon metabolism and in components of the transcription and translation machineries, such as RNA polymerase and the ribosome. Mutations that modulate protein acylation affected B. subtilis growth. A mutation in acetate kinase (ackA) increased the global acetylation level, suggesting that acetyl phosphate-dependent acetylation is common in B. subtilis, just as it is in Escherichia coli. Our results suggest that acyl modifications play a role in the physiological adaptations to changes in carbon nutrient availability of B. subtilis. PMID- 26098118 TI - Systematic Review and Meta-Analysis of Human Studies to Support a Quantitative Recommendation for Whole Grain Intake in Relation to Type 2 Diabetes. AB - BACKGROUND: Due to the increasing evidence of their health benefits, whole grains are recommended for consumption worldwide. Such recommendations are, however, rarely quantitative. Our aim was to perform a quantitative evaluation of the relationship between whole grain consumption and the occurrence of type 2 diabetes (T2D) to support a recommendation on the daily consumption of whole grains. METHODS AND FINDINGS: We conducted a systematic review by searching three bibliographic databases. We included human studies addressing the relationship between whole grain consumption and T2D occurrence, and providing quantitative information on daily intake of whole grains. A dose-response meta-regression analysis between whole grain intake and T2D occurrence was performed, using a hierarchical mixed least square linear regression model. Eight observational studies were included (all but one prospective), with a total of 15,573 cases of T2D among 316,051 participants. Quantitative meta-regression demonstrated a significant linear inverse relationship between whole grain intake and T2D occurrence (P<0.0001), with an overall absolute reduction of 0.3% in the T2D rate for each additional 10 g of whole grain ingredient consumed daily. The association persisted when adjusted on sex, age, country, study design, follow up duration, and mode of report of whole grain intakes (as foods or ingredients). CONCLUSIONS: The meta-regression model made it possible to estimate the decrease in T2D risk corresponding to various changes in whole grain intakes, and the results contribute to setting up quantitative recommendations. For instance, consuming three servings of whole grain foods (45 g of whole grain ingredients) daily would induce a 20% relative reduction in the T2D risk as compared to consuming a half serving (7.5 g of whole grain ingredients). These results should be considered for future recommendations, by considering the actual whole grain intake of the concerned populations. The systematic review protocol was published on the PROSPERO register (CRD42013006925). PMID- 26098120 TI - Confirmation bias in visual search. AB - In a series of experiments, we investigated the ubiquity of confirmation bias in cognition by measuring whether visual selection is prioritized for information that would confirm a proposition about a visual display. We show that attention is preferentially deployed to stimuli matching a target template, even when alternate strategies would reduce the number of searches necessary. We argue that this effect is an involuntary consequence of goal-directed processing, and show that it can be reduced when ample time is provided to prepare for search. These results support the notion that capacity-limited cognitive processes contribute to the biased selection of information that characterizes confirmation bias. (PsycINFO Database Record PMID- 26098121 TI - Voluminous oesophageal bronchogenic cyst treated with thoracoscopic approach. AB - AIM: Bronchogenic cysts are congenital lesions deriving from the primitive foregut, and are usually located in close relation to tracheobronchial tree or oesophagus. We report a case of an oesophageal bronchogenic cyst appearing at preoperative examinations as a benign fibromuscular tumour (leiomyoma). CASE REPORT: A 62 years old male patient in good general conditions, was admitted to our Institution because of moderate dysphagia and upper post-prandial abdominal pain. Conventional imaging, endoscopy and echo endoscopy detected a parietal oesophageal wall mass looking like a solid formation, determining extrinsic compression and narrowing of the lumen. RESULTS: The mass has been radically removed with thoracoscopic approach. Postoperative stay was uneventful and the patient was discharged three days after the operation. At histological examination the mass appeared as a cystic formation with fibromuscular wall and ciliated epithelium (so-called disembriogenetic bronchogenic cyst). CONCLUSION: The case we have reported describes a very unusual case of a voluminous symptomatic intramural oesophageal disembriogenetic cyst whose characteristics had not been defined at preoperative examinations. Surgical removal of the mass has been achieved with a minimally invasive approach. PMID- 26098122 TI - An 8-Week Exercise Intervention Based on Zumba Improves Aerobic Fitness and Psychological Well-Being in Healthy Women. AB - BACKGROUND: Although Zumba is practiced by millions of people worldwide, there is a paucity of research about its potential benefits. The objective of this study was to investigate the effects of Zumba on physiological and psychological outcomes in healthy women. METHODS: Cardiovascular fitness, body composition, physical self-perception and psychological well-being were assessed before and immediately after 8 weeks of Zumba performed 3 times weekly (Zumba group, n = 22, age: 26.6 +/- 5.4 years old; height: 165.8 +/- 7.1 cm) or no intervention (control group, n = 22, age: 27.9 +/- 6.0 years old; height: 164.7 +/- 6.2 cm). All variables were analyzed by a 2-way (Group * Time) analysis of variance with repeated measures, and a Bonferroni post hoc test. Pearson correlation coefficient assessed the relationship between changes in anthropometric, physiological and psychological variables. RESULTS: Zumba provided significant positive changes in maximal aerobic fitness (+3.6%), self-perception of physical strength (+16.3%) and muscular development (+18.6%), greater autonomy (+8.0%), and purpose in life (+4.4%). No significant changes were observed in the control group. In addition, some psychological changes were significantly correlated to body fat at baseline, and changes in fitness. CONCLUSIONS: These results highlight that Zumba is beneficial to improve fitness and well-being in healthy women, but does not change body composition. PMID- 26098124 TI - A simple retinal mechanism contributes to perceptual interactions between rod- and cone-mediated responses in primates. AB - Visual perception across a broad range of light levels is shaped by interactions between rod- and cone-mediated signals. Because responses of retinal ganglion cells, the output cells of the retina, depend on signals from both rod and cone photoreceptors, interactions occurring in retinal circuits provide an opportunity to link the mechanistic operation of parallel pathways and perception. Here we show that rod- and cone-mediated responses interact nonlinearly to control the responses of primate retinal ganglion cells; these nonlinear interactions, surprisingly, were asymmetric, with rod responses strongly suppressing subsequent cone responses but not vice-versa. Human psychophysical experiments revealed a similar perceptual asymmetry. Nonlinear interactions in the retinal output cells were well-predicted by linear summation of kinetically-distinct rod- and cone mediated signals followed by a synaptic nonlinearity. These experiments thus reveal how a simple mechanism controlling interactions between parallel pathways shapes circuit output and perception. PMID- 26098123 TI - Promoter nucleosome dynamics regulated by signalling through the CTD code. AB - The phosphorylation of the RNA polymerase II C-terminal domain (CTD) plays a key role in delineating transcribed regions within chromatin by recruiting histone methylases and deacetylases. Using genome-wide nucleosome mapping, we show that CTD S2 phosphorylation controls nucleosome dynamics in the promoter of a subset of 324 genes, including the regulators of cell differentiation ste11 and metabolic adaptation inv1. Mechanistic studies on these genes indicate that during gene activation a local increase of phospho-S2 CTD nearby the promoter impairs the phospho-S5 CTD-dependent recruitment of Set1 and the subsequent recruitment of specific HDACs, which leads to nucleosome depletion and efficient transcription. The early increase of phospho-S2 results from the phosphorylation of the CTD S2 kinase Lsk1 by MAP kinase in response to cellular signalling. The artificial tethering of the Lsk1 kinase at the ste11 promoter is sufficient to activate transcription. Therefore, signalling through the CTD code regulates promoter nucleosomes dynamics. PMID- 26098125 TI - Descriptive norms and expectancies as mediators of a brief motivational intervention for mandated college students receiving stepped care for alcohol use. AB - Stepped care approaches for mandated college students provide individual brief motivational interventions (BMI) only for individuals who do not respond to an initial, low-intensity level of treatment such as Brief Advice (BA). However, how BMIs facilitate change in this higher-risk group of mandated students remains unclear. Perceived descriptive norms and alcohol-related expectancies are the most commonly examined mediators of BMI efficacy but have yet to be examined in the context of stepped care. Participants were mandated college students (N = 598) participating in a stepped care trial in which mandated students first received BA. Those who reported continued risky drinking 6 weeks following a BA session were randomized to either a single-session BMI (N = 163) or an assessment only comparison condition (AO; N = 165). BMI participants reduced alcohol-related problems at the 9 month follow up significantly more than AO participants. Multiple mediation analyses using bootstrapping techniques examined whether perceived descriptive norms and alcohol-related expectancies mediated the observed outcomes. Reductions in perceptions of average student drinking (B = .24; 95% CI [-.61, -.04]) and negative expectancies (B = -.13; 95% CI [-.38, .01]) mediated the BMI effects. Furthermore, perceived average student norms were reduced after the BMI to levels approximating those of students who had exhibited lower risk drinking following the BA session. Findings highlight the utility of addressing perceived norms and expectancies in BMIs, especially for students who have not responded to less intensive prevention efforts. PMID- 26098126 TI - Measurement error and outcome distributions: Methodological issues in regression analyses of behavioral coding data. AB - Behavioral coding is increasingly used for studying mechanisms of change in psychosocial treatments for substance use disorders (SUDs). However, behavioral coding data typically include features that can be problematic in regression analyses, including measurement error in independent variables, non normal distributions of count outcome variables, and conflation of predictor and outcome variables with third variables, such as session length. Methodological research in econometrics has shown that these issues can lead to biased parameter estimates, inaccurate standard errors, and increased Type I and Type II error rates, yet these statistical issues are not widely known within SUD treatment research, or more generally, within psychotherapy coding research. Using minimally technical language intended for a broad audience of SUD treatment researchers, the present paper illustrates the nature in which these data issues are problematic. We draw on real-world data and simulation-based examples to illustrate how these data features can bias estimation of parameters and interpretation of models. A weighted negative binomial regression is introduced as an alternative to ordinary linear regression that appropriately addresses the data characteristics common to SUD treatment behavioral coding data. We conclude by demonstrating how to use and interpret these models with data from a study of motivational interviewing. SPSS and R syntax for weighted negative binomial regression models is included in online supplemental materials. PMID- 26098127 TI - Predictors of patient retention in methadone maintenance treatment. AB - This study sought to determine whether select pretreatment demographic and in treatment clinical variables predict premature treatment discharge at 6 and 12 months among patients receiving methadone maintenance treatment (MMT). Data were abstracted from electronic medical records for 1,644 patients with an average age of 34.7 years (SD = 11.06) admitted to 26 MMT programs located throughout the United States from 2009 to 2011. Patients were studied through retrospective chart review for 12 months or until treatment discharge. Premature discharge at 6 and 12-month intervals were the dependent variables, analyzed in logistic regressions. Clinical predictor variables included average methadone dosage (mg/d) and urinalysis drug screen (UDS) findings for opioids and various nonopioid substances at intake and 6 months. Pretreatment demographic variables included gender, race/ethnicity, employment status, marital status, payment method, and age at admission. UDS findings positive (UDS+) for cocaine at intake and 6 months were found to be independent predictors of premature discharge at 12 months. UDS+ for opioids at 6 months was also an independent predictor of premature discharge at 12 months. Higher average daily methadone dosages were found to predict retention at both 6 and 12 months. Significant demographic predictors of premature discharge at 6 months included Hispanic ethnicity, unemployment, and marital status. At 12 months, male gender, younger age, and self-pay were found to predict premature discharge. Select demographic characteristics may be less important as predictors of outcome after patients have been in treatment beyond a minimum period of time, while others may become more important later on in treatment. PMID- 26098128 TI - Adjuvant Rosa Damascena has a Small Effect on SSRI-induced Sexual Dysfunction in Female Patients Suffering from MDD. AB - BACKGROUND: Treating major depressive disorders (MDD) with selective serotonin reuptake inhibitors (SSRIs) may impact negatively on sexual function. On the other hand, a satisfying sexual life is associated with overall life satisfaction. Therefore, managing this negative side effect of SSRIs may have an important role in the treatment of MDD. In a former study, adjuvant Rosa damascena oil improved sexual dysfunction in male patients suffering from both MDD and SSRI-induced sexual dysfunction (SSRI-I SD). The aim of the present study was to test whether the same pattern of results would be observed among female patients suffering from both SSRI-I SD and MDD. METHOD: In a double-blind, randomized and placebo-controlled clinical trial, a total of 50 female patients (mean age: 34 years) treated with an SSRI and suffering from MDD and SSRI-I SD were randomly assigned either to the verum (Rosa damascena oil) or to the placebo condition. Patients completed self-ratings of depression and sexual function at baseline, 4 weeks later, and at the end of the study 8 weeks after its start. RESULTS: Sexual desire, sexual orgasms, and sexual satisfaction increased over time. Patients in the verum group reported decreased pain. Overall sexual score increased in the verum as compared to the placebo condition. CONCLUSIONS: Whereas in male patients suffering from both MDD and SSRI-I SD adjuvant Rosa damascena oil improved sexual function, data on female patients are less robust and suggest only modest effects on female sexual function. PMID- 26098129 TI - Enforcing Multifunctionality: A Pressure-Induced Spin-Crossover Photomagnet. AB - Photomagnetic compounds are usually achieved by assembling preorganized individual molecules into rationally designed molecular architectures via the bottom-up approach. Here we show that a magnetic response to light can also be enforced in a nonphotomagnetic compound by applying mechanical stress. The nonphotomagnetic cyano-bridged Fe(II)-Nb(IV) coordination polymer {[Fe(II)(pyrazole)4]2[Nb(IV)(CN)8].4H2O}n (FeNb) has been subjected to high pressure structural, magnetic and photomagnetic studies at low temperature, which revealed a wide spectrum of pressure-related functionalities including the light induced magnetization. The multifunctionality of FeNb is compared with a simple structural and magnetic pressure response of its analog {[Mn(II)(pyrazole)4]2[Nb(IV)(CN)8].4H2O}n (MnNb). The FeNb coordination polymer is the first pressure-induced spin-crossover photomagnet. PMID- 26098130 TI - Further Validation of the Female Sexual Function Index: Specificity and Associations With Clinical Interview Data. AB - Female sexual function is a multi-faceted psychophysiological construct. The Female Sexual Function Index (FSFI) is considered a "gold standard" self-report instrument that assesses the various aspects of sexual function. However, researchers have recently proposed potential limitations of the FSFI, highlighting the need for continued validation research. The aims of the current analyses were (a) to assess the correlations between FSFI scores and information regarding specific rates of functional impairment gained via clinical interview; and (b) to assess the specificity of FSFI subscale scores in reflecting corresponding aspects of sexual function (e.g., whether the Sexual Desire subscale reflects sexual desire specifically rather than sexual arousal, orgasm, etc.). The participants were 97 sexually active women who reported impairments in sexual function. Clinical interview data exhibited moderate-to-strong correlations with FSFI scores. Additionally, FSFI subscales generally exhibited adequate specificity in terms of reflecting their corresponding aspects of sexual function more strongly than other aspects. The results generally supported the validity of the FSFI. Implications for the measurement and conceptualization of female sexual function are discussed. PMID- 26098131 TI - Computational Pathology: A Path Ahead. AB - CONTEXT: We define the scope and needs within the new discipline of computational pathology, a discipline critical to the future of both the practice of pathology and, more broadly, medical practice in general. OBJECTIVE: To define the scope and needs of computational pathology. DATA SOURCES: A meeting was convened in Boston, Massachusetts, in July 2014 prior to the annual Association of Pathology Chairs meeting, and it was attended by a variety of pathologists, including individuals highly invested in pathology informatics as well as chairs of pathology departments. CONCLUSIONS: The meeting made recommendations to promote computational pathology, including clearly defining the field and articulating its value propositions; asserting that the value propositions for health care systems must include means to incorporate robust computational approaches to implement data-driven methods that aid in guiding individual and population health care; leveraging computational pathology as a center for data interpretation in modern health care systems; stating that realizing the value proposition will require working with institutional administrations, other departments, and pathology colleagues; declaring that a robust pipeline should be fostered that trains and develops future computational pathologists, for those with both pathology and nonpathology backgrounds; and deciding that computational pathology should serve as a hub for data-related research in health care systems. The dissemination of these recommendations to pathology and bioinformatics departments should help facilitate the development of computational pathology. PMID- 26098132 TI - DNA Yield From Tissue Samples in Surgical Pathology and Minimum Tissue Requirements for Molecular Testing. AB - CONTEXT: Complex molecular assays are increasingly used to direct therapy and provide diagnostic and prognostic information but can require relatively large amounts of DNA. OBJECTIVES: To provide data to pathologists to help them assess tissue adequacy and provide prospective guidance on the amount of tissue that should be procured. DESIGN: We used slide-based measurements to establish a relationship between processed tissue volume and DNA yield by A260 from 366 formalin-fixed, paraffin-embedded tissue samples submitted for the 3 most common molecular assays performed in our laboratory (EGFR, KRAS, and BRAF). We determined the average DNA yield per unit of tissue volume, and we used the distribution of DNA yields to calculate the minimum volume of tissue that should yield sufficient DNA 99% of the time. RESULTS: All samples with a volume greater than 8 mm(3) yielded at least 1 MUg of DNA, and more than 80% of samples producing less than 1 MUg were extracted from less than 4 mm(3) of tissue. Nine square millimeters of tissue should produce more than 1 MUg of DNA 99% of the time. CONCLUSIONS: We conclude that 2 tissue cores, each 1 cm long and obtained with an 18-gauge needle, will almost always provide enough DNA for complex multigene assays, and our methodology may be readily extrapolated to individual institutional practice. PMID- 26098133 TI - A Stable Planar-Chiral N-Heterocyclic Carbene with a 1,1'-Ferrocenediyl Backbone. AB - This paper focuses on the stable, ferrocene-based N-heterocyclic carbene (NHC) rac-[Fe{(eta(5)-t-BuC5H3)NpN}2C:] (A'-Np, Np = neopentyl), which is planar-chiral due to the two tert-butyl substituents in 3,3'-positions. A'-Np was synthesized in nine steps starting from 1,1'-di-tert-butylferrocene (1), the first step being its 3,3'-dilithiation to afford rac-[Fe(eta(5)-t-BuC5H3Li)2] (rac-fc'Li2, 2). The structures of rac-fc'(SiMe3)2 (3), rac-fc'Br2 (4), rac-fc'(N3)2 (5), and the immediate carbene precursor [A'-NpH]BF4 were determined by single-crystal X-ray diffraction (XRD). The chemical properties of A'-Np were found to be very similar to those of its tert-butyl-free congener A-Np, both being ambiphilic NHCs with rather high calculated HOMO energies (ca. -4.0 eV) and low singlet-triplet gaps (ca. 35 kcal/mol). A Tolman electronic parameter value of 2050 cm(-1) was derived from IR data of cis-[RhCl(A'-Np)(CO)2], indicating the high donicity of A'-Np as a ligand. Consistent with its ambiphilic nature, A'-Np was found to react readily with carbon monoxide, affording the betainic enolate (A'-Np)2CO as four stereoisomers, viz. (RpRp-A'-Np)?C(O(-))(RpRp-A'-Np(+)), (SpSp-A'-Np)?C(O( ))(SpSp-A'-Np(+)), (RpRp-A'-Np)?C(O(-))(SpSp-A'-Np(+)), and (SpSp-A'-Np)?C(O( ))(RpRp-A'-Np(+)). The former two isomers were structurally characterized as a racemic compound by single-crystal XRD. A'-Np was found to react swiftly with dichloromethane, affording the addition product A'-NpH-CHCl2 in a reaction that is unprecedented for diaminocarbenes. A-NpH-CHCl2 was obtained analogously. Both compounds were structurally characterized by single-crystal XRD. An electrochemical investigation of A'-Np by cyclic and square wave voltammetry revealed a reversible oxidation of the carbene at a half-wave potential of -0.310 vs ferrocene/ferrocenium (THF/NBu4PF6). The electrochemical data previously published for A-Np were identified to be incorrect, since unnoticed hydrolysis of the NHC had taken place, affording A-Np(H2O). The hydrolysis products of A-Np and A'-Np were found to be reversibly oxidized at half-wave potentials of -0.418 and 0.437 V, respectively. PMID- 26098134 TI - Multilayer Transparent Top Electrode for Solution Processed Perovskite/Cu(In,Ga)(Se,S)2 Four Terminal Tandem Solar Cells. AB - Halide perovskites (PVSK) have attracted much attention in recent years due to their high potential as a next generation solar cell material. To further improve perovskites progress toward a state-of-the-art technology, it is desirable to create a tandem structure in which perovskite may be stacked with a current prevailing solar cell such as silicon (Si) or Cu(In,Ga)(Se,S)2 (CIGS). The transparent top electrode is one of the key components as well as challenges to realize such tandem structure. Herein, we develop a multilayer transparent top electrode for perovskite photovoltaic devices delivering an 11.5% efficiency in top illumination mode. The transparent electrode is based on a dielectric/metal/dielectric structure, featuring an ultrathin gold seeded silver layer. A four terminal tandem solar cell employing solution processed CIGS and perovskite cells is also demonstrated with over 15% efficiency. PMID- 26098135 TI - Mussel-Inspired Artificial Grafts for Functional Ligament Reconstruction. AB - The development of an artificial graft with distinct osteogenetic activity to enhance osseointegration and to induce the formation of biomimetic tissue structure for ligament reconstruction remains a significant challenge. Inspired by mussels, biomimetic calcium phosphate apatite/polydopamine hybridized polyethylene terephthalate (APA/PDA-PET) grafts were successfully prepared. The efficacy and mechanism of APA/PDA-PET grafts to induce osseointegration were systematically investigated. The results from the in vitro study indicated that the prepared APA/PDA-PET grafts support the attachment of bone marrow stromal cells (BMSCs) and stimulate the proliferation and osteogenic/angiogenic differentiation of BMSCs via activation of the PKC/p-ERK1/2 signaling pathway. In vivo, histological and radiological results further demonstrate that the APA/PDA PET grafts significantly improve osseointegration by inducing the formation of new bone tissue and the fibrocartilage transitional zone compared with pure PET grafts. In addition, the pull-out strength of the APA/PDA-PET grafts is significantly higher than that of the pure PET grafts 12 weeks after surgery. These results suggest that this mussel-inspired biomimetic method is an effective strategy for modifying artificial grafts, and the prepared APA/PDA-PET grafts, which possess a beneficial interface, can significantly improve in vivo osseointegration for ligament reconstruction via the synergistic effect of polydopamine and apatite. PMID- 26098136 TI - Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy. [Corrected]. AB - Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 MUm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 MUm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ~180 degrees C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy. PMID- 26098137 TI - Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer. AB - BACKGROUND: In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. MATERIALS & METHODS: We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific (188)Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. RESULTS: The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. CONCLUSION: We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy. PMID- 26098138 TI - Adaptive strategies in designing the simultaneous global drug development program. AB - Many methods have been proposed to account for the potential impact of ethnic/regional factors when extrapolating results from multiregional clinical trials (MRCTs) to targeted ethnic (TE) patients, i.e., "bridging." Most of them either focused on TE patients in the MRCT (i.e., internal bridging) or a separate local clinical trial (LCT) (i.e., external bridging). Huang et al. (2012) integrated both bridging concepts in their method for the Simultaneous Global Drug Development Program (SGDDP) which designs both the MRCT and the LCT prospectively and combines patients in both trials by ethnic origin, i.e., TE vs. non-TE (NTE). The weighted Z test was used to combine information from TE and NTE patients to test with statistical rigor whether a new treatment is effective in the TE population. Practically, the MRCT is often completed before the LCT. Thus to increase the power for the SGDDP and/or obtain more informative data in TE patients, we may use the final results from the MRCT to re-evaluate initial assumptions (e.g., effect sizes, variances, weight), and modify the LCT accordingly. We discuss various adaptive strategies for the LCT such as sample size reassessment, population enrichment, endpoint change, and dose adjustment. As an example, we extend a popular adaptive design method to re-estimate the sample size for the LCT, and illustrate it for a normally distributed endpoint. PMID- 26098139 TI - Discovering What Dimensionality Reduction Really Tells Us About RNA-Seq Data. AB - Biology is being inundated by noisy, high-dimensional data to an extent never before experienced. Dimensionality reduction techniques such as principal component analysis (PCA) are common approaches for dealing with this onslaught. Though these unsupervised techniques can help uncover interesting structure in high-dimensional data they give little insight into the biological and technical considerations that might explain the uncovered structure. Here we introduce a hybrid approach--component selection using mutual information (CSUMI)--that uses a mutual information--based statistic to reinterpret the results of PCA in a biologically meaningful way. We apply CSUMI to RNA-seq data from GTEx. Our hybrid approach enables us to unveil the previously hidden relationship between principal components (PCs) and the underlying biological and technical sources of variation across samples. In particular, we look at how tissue type affects PCs beyond the first two, allowing us to devise a principled way of choosing which PCs to consider when exploring the data. We further apply our method to RNA-seq data taken from the brain and show that some of the most biologically informative PCs are higher-dimensional PCs; for instance, PC 5 can differentiate the basal ganglia from other tissues. We also use CSUMI to explore how technical artifacts affect the global structure of the data, validating previous results and demonstrating how our method can be viewed as a verification framework for detecting undiscovered biases in emerging technologies. Finally we compare CSUMI to two correlation-based approaches, showing ours outperforms both. A python implementation is available online on the CSUMI website. PMID- 26098140 TI - New Method for Super Hydrophobic Treatment of Gas Diffusion Layers for Proton Exchange Membrane Fuel Cells Using Electrochemical Reduction of Diazonium Salts. AB - The purpose of this article is to report a new method for the surface functionalization of commercially available gas diffusion layers (GDLs) by the electrochemical reduction of diazonium salt containing hydrophobic functional groups. The method results in superhydrophobic GDLs, over a large area, without pore blocking. An X-ray photoelectron spectroscopy study based on core level spectra and chemical mapping has demonstrated the successful grafting route, resulting in a homogeneous distribution of the covalently bonded hydrophobic molecules on the surface of the GDL fibers. The result was corroborated by contact angle measurement, showing similar hydrophobicity between the grafted and PTFE-modified GDLs. The electrochemically modified GDLs were tested in proton exchange membrane fuel cells under automotive, wet, and dry conditions and demonstrated improved performance over traditional GDLs. PMID- 26098141 TI - Single-arm Phase II cancer survival trial designs. AB - The current practice for designing single-arm Phase II trials with time-to-event endpoints is limited to using either a maximum likelihood estimate test under the exponential model or a naive approach based on dichotomizing the event time at a landmark time point. A trial designed under the exponential model may not be reliable, and the naive approach is inefficient. The modified one-sample log-rank test statistic proposed in this article fills the void. In general, the proposed test can be used to design single-arm Phase II survival trials under any parametric survival distribution. Simulation results showed that it preserves type I error well and provides adequate power for Phase II cancer trial designs with time-to-event endpoints. PMID- 26098142 TI - Measurement of Gas and Aerosol Phase Absorption Spectra across the Visible and Near-IR Using Supercontinuum Photoacoustic Spectroscopy. AB - We demonstrate a method to measure the absorption spectra of gas and aerosol species across the visible and near-IR (500 to 840 nm) using a photoacoustic (PA) spectrometer and a pulsed supercontinuum laser source. Measurements of gas phase absorption spectra were demonstrated using H2O(g) as a function of relative humidity (RH). The measured absorption intensities and peak shapes were able to be quantified and compared to spectra calculated using the 2012 High Resolution Transmission (HITRAN2012) database. Size and mass selected nigrosin aerosol was used to measure absorption spectra across the visible and near-IR. Spectra were measured as a function of aerosol size/mass and show good agreement to Mie theory calculations. Lastly, we measured the broadband absorption spectrum of flame generated soot aerosol at 5% and 70% RH. For the high RH case, we are able to quantifiably separate the soot and water absorption contributions. For soot, we observe an enhancement in the mass specific absorption cross section ranging from 1.5 at 500 nm (p < 0.01) to 1.2 at 840 nm (p < 0.2) and a concomitant increase in the absorption Angstrom exponent from 1.2 +/- 0.4 (5% RH) to 1.6 +/- 0.3 (70% RH). PMID- 26098143 TI - Adherence to, and effectiveness of, subcutaneous interferon beta-1a administered by RebiSmart(r) in patients with relapsing multiple sclerosis: results of the 1 year, observational SMART study. AB - BACKGROUND: Patients with multiple sclerosis who have poor adherence to treatment have a higher risk of relapse than adherent patients. This study assessed adherence to, and effectiveness and convenience of, treatment with subcutaneous (sc) interferon (IFN) beta-1a (Rebif(r), Merck Serono SA) 44 or 22 MUg three times weekly in patients with relapsing multiple sclerosis (RMS) using the RebiSmart(r) electronic, multidose, autoinjector for 1 year. STUDY DESIGN: European, multicentre, observational study among neurologists: inclusion criteria included RMS, Expanded Disability Status Scale score <= 6, sc IFN beta-1a administered by RebiSmart for <= 6 weeks. The primary endpoint was cumulative adherence recorded by RebiSmart. RESULTS: The safety population included 912 patients, 77.4% (n = 823) of whom completed the Month-12 visit. Mean (+/- standard deviation) cumulative adherence was 97.1 +/- 7.3% (n = 791). The most common reason for missed injection was 'forgot to inject' (37.0%). At Month 12/ED, 79.5% of patients were relapse-free. Of 353 patients who rated the convenience of the device, 68.3% found injecting 'very easy'. No unknown safety issues were detected. CONCLUSIONS: Patients with RMS self-injecting sc IFN beta 1a with RebiSmart had excellent adherence at Month 12/ED, which was associated with good clinical outcomes and no unexpected safety issues. Patients rated RebiSmart as convenient and easy to use. PMID- 26098144 TI - Effect of biofilm on fluorescence measurements derived from fast repetition rate fluorometers. AB - This study evaluates, for the first time, the influence of biofilms on single and double optical window (SOW and DOW, respectively) fast repetition rate fluorometer (FRRF) measurements of microalgal photosystem-II initial fluorescence (F0), maximum fluorescence (Fm), variable fluorescence (Fv = Fm - F0), quantum yield (Fv/Fm) and functional absorption cross section (sigmaPSII)]. Biofilms with chlorophyll > 0.1 MUg cm(-2) and > 0.3 MUgcm(-2) on SOW and DOW, respectively, produced a substantial increase in fluorescence. However, the relative magnitude of biofouling effects depended on sample chlorophyll concentrations, being more critical at concentrations < 1 mg m(-3). In DOW-FRRF, biofilms affected F0 (increased) and Fv/Fm (decreased) but not Fv and sigmaPSII, whereas in SOW-FRRF, biofilms increased fluorescence and showed a variable effect on Fv/Fm and sigmaPSII, because only biofilms on SOW attained actual Fm. As a result, the biofilm effect was substantial on SOW-FRRF measurements. On the other hand, the neutral-density filters (representing non-chlorophyll containing biofilms) with different transmission levels reduced the fluorescence signal. Correction procedures for the above photosystem-II parameters are proposed here. PMID- 26098146 TI - Oral drugs in multiple sclerosis therapy: an overview and a critical appraisal. AB - Multiple sclerosis (MS) is characterized by demyelination and axonal loss that results in progressive disability. Recent advances in understanding the immune pathogenesis of MS resulted in the introduction of numerous effective drugs with diverse mechanisms of actions, routes of administration and benefit-risk profiles. New oral drugs recently approved for MS treatment has led to significant achievements in MS management. The oral route of administration promotes patient satisfaction and increases therapeutic compliance; but their introduction has raised concerns regarding safety and tolerability; and a thorough analysis of the benefit/risk ratio is required. This article reviews the mechanisms of action, safety and efficacy of the licensed and experimental oral drugs in MS. Moreover, we put into perspective the disease, drug and patient related factors that should be taken into account when considering the appropriate oral drug and treatment strategy to the appropriate patient, thus paving the road for personalized medicine in MS. PMID- 26098147 TI - Occurrence and Characterization of Steroid Growth Promoters Associated with Particulate Matter Originating from Beef Cattle Feedyards. AB - Studies of steroid growth promoters from beef cattle feedyards have previously focused on effluent or surface runoff as the primary route of transport from animal feeding operations. There is potential for steroid transport via fugitive airborne particulate matter (PM) from cattle feedyards; therefore, the objective of this study was to characterize the occurrence and concentration of steroid growth promoters in PM from feedyards. Air sampling was conducted at commercial feedyards (n = 5) across the Southern Great Plains from 2010 to 2012. Total suspended particulates (TSP), PM10, and PM2.5 were collected for particle size analysis and steroid growth promoter analysis. Particle size distributions were generated from TSP samples only, while steroid analysis was conducted on extracts of PM samples using liquid chromatography mass spectrometry. Of seven targeted steroids, 17alpha-estradiol and estrone were the most commonly detected, identified in over 94% of samples at median concentrations of 20.6 and 10.8 ng/g, respectively. Melengestrol acetate and 17alpha-trenbolone were detected in 31% and 39% of all PM samples at median concentrations of 1.3 and 1.9 ng/g, respectively. Results demonstrate PM is a viable route of steroid transportation and may be a significant contributor to environmental steroid hormone loading from cattle feedyards. PMID- 26098145 TI - Connecting the speckles: Splicing kinases and their role in tumorigenesis and treatment response. AB - Alternative pre-mRNA splicing in higher eukaryotes enhances transcriptome complexity and proteome diversity. Its regulation is mediated by a complex RNA protein network that is essential for the maintenance of cellular and tissue homeostasis. Disruptions to this regulatory network underlie a host of human diseases and contribute to cancer development and progression. The splicing kinases are an important family of pre-mRNA splicing regulators, , which includes the CDC-like kinases (CLKs), the SRSF protein kinases (SRPKs) and pre-mRNA splicing 4 kinase (PRP4K/PRPF4B). These splicing kinases regulate pre-mRNA splicing via phosphorylation of spliceosomal components and serine-arginine (SR) proteins, affecting both their nuclear localization within nuclear speckle domains as well as their nucleo-cytoplasmic shuttling. Here we summarize the emerging evidence that splicing kinases are dysregulated in cancer and play important roles in both tumorigenesis as well as therapeutic response to radiation and chemotherapy. PMID- 26098149 TI - [Opiates yes, but ....]. PMID- 26098148 TI - Covalent Modification of Synthetic Hydrogels with Bioactive Proteins via Sortase Mediated Ligation. AB - Synthetic extracellular matrices are widely used in regenerative medicine and as tools in building in vitro physiological culture models. Synthetic hydrogels display advantageous physical properties, but are challenging to modify with large peptides or proteins. Here, a facile, mild enzymatic postgrafting approach is presented. Sortase-mediated ligation was used to conjugate human epidermal growth factor fused to a GGG ligation motif (GGG-EGF) to poly(ethylene glycol) (PEG) hydrogels containing the sortase LPRTG substrate. The reversibility of the sortase reaction was then exploited to cleave tethered EGF from the hydrogels for analysis. Analyses of the reaction supernatant and the postligation hydrogels showed that the amount of tethered EGF increases with increasing LPRTG in the hydrogel or GGG-EGF in the supernatant. Sortase-tethered EGF was biologically active, as demonstrated by stimulation of DNA synthesis in primary human hepatocytes and endometrial epithelial cells. The simplicity, specificity, and reversibility of sortase-mediated ligation and cleavage reactions make it an attractive approach for modification of hydrogels. PMID- 26098150 TI - [CME. Idiopathic pulmonary fibrosis (IFP)]. PMID- 26098152 TI - [Relevance and Application of Opioids in the Treatment of Chronic Pain in Switzerland-a National Survey]. AB - METHOD: National survey on treatment with opioids among 1206 Swiss general internists and rheumatologists, using a questionnaire. TYPES OF PAIN: More self declared pain specialists than non-specialists treat neuropathic pain (49,3 vs. 35,8%; p=0,002), whereas other types of pain are similarly often treated by specialists and non-specialists. OPIOID PRESCRIPTION: Pain specialists more often than non-specialists use opioids in visceral (12,8 vs. 5,9%, p=0,004) and postoperative pain (29,3 vs. 20,1%, p=0,013). TUMOR PAIN: Non-specialists rather than specialists prescribe opioids (80,4 vs. 72,8%, p=0,039); younger physicians (<50 years) rather than older ones often prescribe opioids (82,5 vs. 76,9%; p=0,026), and rheumatologists use opioids less often than general internists (43,3 vs. 83,0%, p<0,0001). WHO ANALGESIC LADDER: Specialists more often change directly from level 1 to level 3 analgesics (66,4 vs. 53,8%; p=0,001). PMID- 26098153 TI - [Low Back Pain in Pregnancy: Diagnosis, Treatment Options and Outcomes]. AB - Low back pain in pregnancy is a common occurrence and is mainly caused by hormonal and biomechanical changes. Patients with pregnancy-induced low back pain (PILBP) frequently complain of moderate to severe and disabling pain often restricting their daily activities. In these cases, a "watch and wait" approach cannot be the best solution. On the basis of anamnesis and examination PILBP can be divided into three subgroups: pregnancy-related low back pain (PLBP), pelvic girdle pain (PGP) and the combination of PLBP and PGP. The three entities ask for different diagnostic workups and therapeutic modalities. There are many possible treatments for PLBP, however, only a few are based on sound evidence. Information and advice, exercise and training programs, acupuncture, stabilizing belts and analgesic medication can have a positive impact on pain and disability. PGP und PLBP respond well to chiropractic interventions. PMID- 26098154 TI - [New Aspects and Controversies in the Current European and American Hypertension Guidelines]. AB - At the end of 2013, the long-awaited guidelines of the Eighth Joint National Committee (JNC8) were published. These guidelines developed nine specific recommendations for the management of arterial hypertension. The harmonization of blood pressure treatment thresholds and goals represents a convenient simplification for the practicing physician. However, the recommendations did not come without controversy. Especially the raise of the treatment goal in patients aged 60 years or older was criticized. In this and other aspects, the 2013 guidelines of the European Society of Cardiology and European Society of Hypertension (ESC/ESH 2013) share a different point of view. The article tries to summarize the different viewpoints and to provide an overview over the increasing number of hypertension guidelines. PMID- 26098155 TI - [My Back is Still Hurting!]. AB - We present the case of a 39-year-old man who reported to the primary care physician for low back pain. Pain persisted despite extensive assessment and therapy. During the course, bilateral femoral neck fractures occurred and due to multiple enrichments in scintigraphy chronic multifocal (sterile) osteomyelitis was suspected. In the further follow-up the appropriate diagnosis of osteomalacia was established in bone biopsy and adequate treatment with Vitamin D was initiated. During therapy, the patient was free of pain or discomfort. PMID- 26098156 TI - [What is the value of measles passive vaccination after exposure?]. PMID- 26098157 TI - [Nodes in the thyroid gland: The natural history is better than expected]. PMID- 26098158 TI - [Mindfulness meditation improves sleep quality in the elderly]. PMID- 26098163 TI - Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site. AB - Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and DeltatolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity. PMID- 26098164 TI - The role of proximal social contexts: Assessing stigma-by-association effects on leader appraisals. AB - Prior research suggests that segregation in the U.S. workplace is on the rise (Hellerstein, Neumark, & McInerney, 2008); as such, leaders are more likely to lead groups of followers composed primarily of their own race (Elliot & Smith, 2001; Smith & Elliott, 2002). Drawing from theory on stigma-by-association, the authors posit that such segregated proximal social contexts (i.e., the leader's group of followers) can have detrimental effects on leader appraisals. Specifically, they argue that leaders of mostly Black follower groups experience stigmatization based on race stereotypic beliefs, which affects how they are viewed in the eyes of observers. The results of a large field study show performance evaluations generally tend to be lower when the proportion of Black followers is higher. Moreover, 3 experiments demonstrate that the impact of proximal social contexts extends to other outcomes (i.e., perceptions of market value and competency) but appears limited to those who are less internally and externally motivated to control their prejudice. Taken together, these findings explain how workplace segregation systematically can create a particular disadvantage for Black leaders. PMID- 26098165 TI - Relational energy at work: Implications for job engagement and job performance. AB - Energy is emerging as a topic of importance to organizations, yet we have little understanding of how energy can be useful at an interpersonal level toward achieving workplace goals. We present the results of 4 studies aimed at developing, validating, and testing the relational energy construct. In Study 1, we report qualitative insights from 64 individuals about the experience and functioning of relational energy in the workplace. Study 2 draws from 3 employee samples to conduct exploratory and confirmatory factor analyses on a measure of relational energy, differentiating relational energy from related constructs. To test the predictive validity of the new relational energy scale, Study 3 comprises data from employees rating the level of relational energy they experienced during interactions with their leaders in a health services context. Results showed that relational energy employees experienced with their leaders at Time 1 predicted job engagement at Time 2 (1 month later), while controlling for the competing construct of perceived social support. Study 4 shows further differentiation of relational energy from leader-member exchange (LMX), replicates the positive relationship between relational energy (Time 1) and job engagement (Time 2), and shows that relational energy is positively associated with employee job performance (Time 3) through the mechanism of job engagement. We discuss the theoretical implications of our findings and highlight areas for future research. PMID- 26098166 TI - A review of post-nuclear-catastrophe management. AB - The purpose of this paper is to make radioactive risk more generally understandable. To that end, we compare it to smoking tobacco. Further, we show that the concept of loss of life expectancy permits a quantitative comparison between various aggressions. The demystification of radioactive risk should lead to basic changes in post-catastrophe management, allowing victims to choose whether or not to leave contaminated areas. A less emotional appreciation of radioactive risks should lead to the adaptation of legal practices when dealing with probabilistic situations. PMID- 26098167 TI - Life span decrements in fluid intelligence and processing speed predict mortality risk. AB - We examined life span changes in 5 domains of cognitive performance as predictive of mortality risk. Data came from the Manchester Longitudinal Study of Cognition, a 20-plus-year investigation of 6,203 individuals ages 42-97 years. Cognitive domains were general crystallized intelligence, general fluid intelligence, verbal memory, visuospatial memory, and processing speed. Life span decrements were evident across these domains, controlling for baseline performance at age 70 and adjusting for retest effects. Survival analyses stratified by sex and conducted independently by cognitive domain showed that lower baseline performance levels in all domains-and larger life span decrements in general fluid intelligence and processing speed-were predictive of increased mortality risk for both women and men. Critically, analyses of the combined predictive power of cognitive performance variables showed that baseline levels of processing speed (in women) and general fluid intelligence (in men), and decrements in processing speed (in women and in men) and general fluid intelligence (in women), accounted for most of the explained variation in mortality risk. In light of recent evidence from brain-imaging studies, we speculate that cognitive abilities closely linked to cerebral white matter integrity (such as processing speed and general fluid intelligence) may represent particularly sensitive markers of mortality risk. In addition, we presume that greater complexity in cognition-survival associations observed in women (in analyses incorporating all cognitive predictors) may be a consequence of longer and more variable cognitive declines in women relative to men. PMID- 26098168 TI - Age differences in the effect of framing on risky choice: A meta-analysis. AB - The framing of decision scenarios in terms of potential gains versus losses has been shown to influence choice preferences between sure and risky options. Normative cognitive changes associated with aging have been known to affect decision making, which has led to a number of studies investigating the influence of aging on the effect of framing. Mata, Josef, Samanez-Larkin, and Hertwig (2011) systematically reviewed the available literature using a meta-analytic approach, but did not include tests of homogeneity or subsequent moderator variable analyses. The current review serves to extend the previous analysis to include such tests as well as update the pool of studies available for analysis. Results for both positively and negatively framed conditions were reviewed using 2 meta-analyses encompassing data collected from 3,232 subjects across 18 studies. Deviating from the previous results, the current analysis found a tendency for younger adults to choose the risky option more often than older adults for positively framed items. Moderator variable analyses found this effect likely to be driven by the specific decision scenario, showing a significant effect, with younger adults choosing the risky option more often in small-amount financial and large-amount mortality-based scenarios. For negatively framed items, the current review found no overall age difference in risky decision making, confirming the results from the prior meta-analysis. Moderator variable analyses conducted to address heterogeneity found younger adults to be more likely than older adults to choose the risky option for negatively framed high amount mortality-based decision scenarios. Practical implications for older adults are discussed. PMID- 26098169 TI - Four-year stability, change, and multidirectionality of well-being in very-old age. AB - We examined stability, change, and dedifferentiation of well-being in 124 participants with a baseline age between 87 and 97 years (M = 90.56, SD = 2.92) across 7 measurement occasions over 4 years. Measures of hedonic (life satisfaction, positive affect and negative affect) and eudaimonic well-being (autonomy, purpose in life, self-acceptance, environmental mastery), as well as indicators of mental distress (depressive symptoms, attitudes toward death and dying, disease phobia) were included. Average levels indicated high well-being at all measurement occasions in the majority of indicators analyzed. However, mean numbers of depressive symptoms were close to the cutoff point of clinical depression. Analyses of intra-individual correlations revealed high loadings of depressive symptoms, positive affect, and environmental mastery on a common factor. However, several well-being indicators were not substantially interrelated on the intra-individual level, suggesting their trajectories were rather independent of each other. Acceptance of death and dying was surprisingly high and even increased, whereas mean levels in fear of death were very low and declined over time. Overall, our findings do not suggest late-life dedifferentiation of well-being trajectories in very-old age. Our results rather support the need to consider indicators of hedonic and eudaimonic well-being, as well as mental distress, to understand the multifaceted and multidirectional dynamics of well-being in very-old age. PMID- 26098170 TI - [Imaging of panniculitis-like subcutaneous T-cell lymphoma]. PMID- 26098171 TI - Aerobic Fitness and Context Processing in Preadolescent Children. AB - BACKGROUND: There is a growing trend of inactivity among children, which may not only result in poorer physical health but also poorer cognitive health. The purpose of this study was to investigate the relationship between aerobic fitness and proactive and reactive cognitive control using a continuous performance task (CPT). METHODS: Forty-eight 9- to 10-year-old children (n = 24 higher fit [HF] and n = 24 lower fit [LF]) performed an AX-CPT requiring them to respond to target cue-probe pairs (AX) or nontarget pairs (AY, BX, BY) under 2 different trial duration conditions, which modulated working memory demands. RESULTS: Across trials and conditions, HF children had greater accuracy than LF children. For target trials, the long duration resulted in lower accuracy than the short duration. For nontarget trials, an interaction of duration and trial was observed, indicating that the long duration resulted in decreased BX and BY accuracy relative to the short duration. AY trials had greater accuracy during the long duration compared with the short duration. CONCLUSIONS: These data suggest that fitness may modulate cognitive control strategies during tasks requiring context updating and maintenance, key components of working memory and further support aerobic fitness as a marker of cognitive and brain health in children. PMID- 26098172 TI - Shlnc-EC6 regulates murine erythroid enucleation by Rac1-PIP5K pathway. AB - Long noncoding RNAs (LncRNAs) are longer than 200 nucleotide noncoding RNAs without apparent functional coding capacity that function as regulators of cell growth and development. In recent years, increasing evidence implicates the involvement of LncRNAs in erythropoiesis. shlnc-EC6 is a LncRNA associated with erythroid differentiation but the mechanism remains undefined. In this study, we found that knockdown of shlnc-EC6 in purified mouse fetal liver erythroid progenitor and hematopoietic stem cells (FLEPHSCs) significantly blocked erythroid enucleation. We also showed that Rac1 was negatively regulated by shlnc EC6 at the posttranscriptional level via specific binding to sites within the 3'UTR of Rac1 mRNA. Moreover, we found that knockdown of shlnc-EC6 led to upregulation of Rac1, followed by the activation of the downstream protein PIP5K, and subsequently resulted in the inhibition of enucleation in cultured mouse fetal erythroblasts. Thus, our findings suggest that shlnc-EC6 acts as a novel modulator to regulate mouse erythropoiesis via Rac1/PIP5K signaling pathway. PMID- 26098173 TI - Bis(cyano) Iron(III) Porphyrinates: What Is the Ground State? AB - The synthesis of six new bis(cyano) iron(III) porphyrinate derivatives is reported. The anionic porphyrin complexes utilized tetraphenylporphyrin, tetramesitylporphyrin, and tetratolylporphyrin as the porphyrin ligand. The potassium salts of Kryptofix-222 and 18-C-6 were used as the cations. These complexes have been characterized by X-ray structure analysis, solid-state Mossbauer spectroscopy, and EPR spectroscopy, both in frozen CH2Cl2 solution and in the microcrystalline state. These data show that these anionic complexes can exist in either the (dxz,dyz)(4)(dxy)(1) or the (dxy)(2)(dxz,dyz)(3) electronic configuration and some can clearly readily interconvert. This is a reflection that these two states can be very close in energy. In addition to the effects of varying the porphyrin ligand, subtle effects of the cyanide ligand environment in the solid state and in solution are sufficient to shift the balance between the two electronic states. PMID- 26098174 TI - Design Concepts and Preclinical Results of a Miniaturized HeartWare Platform: The MVAD System. AB - OBJECTIVE: Ventricular assist device (VAD) miniaturization is one design trend that may result in less-invasive implantation techniques and more versatility with patient selection. The MVAD System is a miniature, continuous-flow device implanted in the ventricle. The pump is capable of delivering between 0 and 7 L/min of flow at a mean arterial pressure of 75 mm Hg. The impeller was optimized from its original design to improve hydraulic performance, minimize shear regions, and enhance the impeller's radial stiffness. These studies evaluated the MVAD System with modified impeller in the preclinical setting. METHODS: This modified pump design was tested through chronic studies (n = 6) in a healthy ovine model where 4 animals were implanted for a duration of 30 +/- 5 days and 2 animals were implanted for a duration of 90 +/- 5 days. The pump was placed in the left ventricular apex with the outflow graft anastomosed to the descending aorta. Postoperatively, no anticoagulant or antiplatelet therapies were administered throughout the study duration. RESULTS: All 6 animals reached their elective date of kill, demonstrating no evidence of organ compromise or device related complications. Average pump parameters did not deviate significantly, and average rotational speed, pump flow, and power consumption were 14095 +/- 139 RPM, 4.1 +/- 0.4 L/min, and 4.3 +/- 0.1 W, respectively. Examination of pump components postexplant demonstrated no mechanical wear or thrombus formation. CONCLUSIONS: Hemocompatibility and biocompatibility of the modified MVAD System were demonstrated through pump parameters, blood chemistry panels, and histopathology analysis. PMID- 26098175 TI - Effects of Fabrication on Early Patency and Regeneration of Small Intestinal Submucosa Vascular Grafts. AB - Small intestinal submucosa grafts for vascular regeneration have produced variable patency (0-100%) that has been concurrent with variability in fabrication techniques. We hypothesized that 1) preservation (P) or removal (R) of the stratum compactum layer of the intestine and 2) a dehydrated (D) or hydrated (H) state of the graft, affect early patency and tissue regeneration. We combined both parameters through a 2(2) factorial experimental design into four groups (PD, RD, PH, RH), and compared them in an in vivo early response predictive model (swine, ID 4.5 mm, 7d, n = 4). Patency, thrombogenicity, vascularization, fibroblast infiltration, macrophage polarization profile, endothelialization, and biaxial mechanics were assessed. PD grafts remained patent (4/4) but had scarce vascularization and fibroblast infiltration. RD and RH had extensive vascularization and fibroblast infiltration, however, RD had sustained patency (4/4) and the highest number of regeneration-associated phenotype macrophages (M2), whereas RH had lower patency (3/4) and less M2 macrophages. PH had a modest cellular infiltration, but the lowest patency (2/4) and a dominant adverse macrophage phenotype. Elasticity of R grafts evolved toward that of native carotids (particularly RD), while P grafts kept their initial stiffness. We concluded that fabrication parameters drastically affected early patency and regeneration, with RD providing the best results. PMID- 26098176 TI - First In Vivo Results of a Novel Pediatric Oxygenator with an Integrated Pulsatile Pump. AB - Extracorporeal membrane oxygenation (ECMO) is a pivotal bridge to recovery for cardiopulmonary failure in children. Besides its life-saving quality, it is often associated with severe system-related complications, such as hemolysis, inflammation, and thromboembolism. Novel oxygenator and pump systems may reduce such ECMO-related complications. The ExMeTrA oxygenator is a newly designed pediatric oxygenator with an integrated pulsatile pump minimizing the priming volume and reducing the surface area of blood contact. The aim of our study was to investigate the feasibility and safety of this new ExMeTrA (expansion mediated transport and accumulation) oxygenator in an animal model. During 6 h of extracorporeal circulation (ECC) in pigs, parameters of the hemostatic system including coagulation, platelets and complement activation, and flow rates were investigated. A nonsignificant trend in C3 consumption, thrombin-antithrombin-III (TAT) complex formation and a slight trend in hemolysis were detected. During the ECC, the blood flow was constantly at 500 ml/min using only flexible silicone tubes inside the oxygenator as pulsatile pump. Our data clearly indicate that the hemostatic markers were only slightly influenced by the ExMeTrA oxygenator. Additionally, the oxygenator showed a constant quality of blood flow. Therefore, this novel pediatric oxygenator shows the potential to be used in pediatric and neonatal support with ECMO. PMID- 26098177 TI - Trimetallic PtSnRh Wavy Nanowires as Efficient Nanoelectrocatalysts for Alcohol Electrooxidation. AB - The design and creation of efficient catalysts for alcohol oxidation reaction has attracted great research attention because alcohols are promising fuels for direct fuel cell reactions because of their high energy density, easy storage, and transportation. We herein report an efficient strategy that allows the preparation of ternary PtSnM (M=Co, Ni, and Rh) wavy nanowires (WNWs) with ultrathin diameter of only around 2 nm and tunable compositions in high yield. Detailed catalytic studies show that all the ternary WNWs exhibit high performance for ethanol oxidation reaction (EOR) and methanol oxidation reaction (MOR), and their performance shows interesting composition-dependent electrocatalytic activity with PtSnRh WNWs having the best activity for both EOR and MOR. The PtSnRh WNWs are also more stable than commercial Pt/C catalyst, as revealed by long-time chronoamperometric (CA) measurements. The present work highlights the use of multimetallic WNWs as highly active and durable nanocatalysts in enhancing alcohol electrooxidation, which will open a new way in tuning 1D multimetallic nanostructures for boosting other fuel cell reactions, various heterogeneous reactions, and beyond. PMID- 26098178 TI - Central Adiposity and Cortical Thickness in Midlife. AB - OBJECTIVES: Excessive visceral fat is associated with greater metabolic fluctuation and increased risk for dementia in older adults. The aim of the current study is to directly determine the impact of central adiposity on brain structure at midlife by examining the thickness of the cerebral cortex. METHODS: High-resolution magnetization-prepared rapid acquisition gradient-echo images were obtained from 103 participants aged 40 to 60 years (mean [standard deviation] = 49.63 [6.47] years) on a 3-T Siemens Skyra scanner. Visceral fat was measured using dual-energy x-ray absorptiometry. RESULTS: Individuals with higher visceral fat mass and volume had significantly thicker cortex in the right posterior cingulate gyrus (beta = 0.29 [p = .019] and beta = 0.31 [p = .011], respectively), controlling for age, systolic blood pressure, total cholesterol level, and blood glucose level. CONCLUSIONS: Visceral fat was significantly associated with thicker cortex in the posterior cingulate gyrus. Although future studies are necessary, these results indicate that central adiposity is associated with significant metabolic changes that impinge upon the central nervous system in middle age. PMID- 26098179 TI - Nonlinear Optical Properties of X(C6H5)4 (X = B(-), C, N(+), P(+)): A New Class of Molecules with a Negative Third-Order Polarizability. AB - Organic pi-conjugated materials have been widely used for a variety of nonlinear optical (NLO) applications. Molecules with negative real components Re(gamma) of the third-order polarizability, which leads to nonlinear refraction in macroscopic systems, have important benefits for several NLO applications. However, few organic systems studied to date have negative Re(gamma) in the long wavelength limit, and all inorganic materials show positive nonlinear refraction in this limit. Here, we introduce a new class of molecules of the form X(C6H5)4, where X = B(-), C, N(+), and P(+), that have negative Re(gamma). The molecular mechanism for the NLO properties in these systems is very different from those in typical linear conjugated systems: These systems have a band of excited states involving single-electron excitations within the pi-system, several of which have significant coupling to the ground state. Thus, Re(gamma) cannot be understood in terms of a simplified essential-state model and must be analyzed in the context of the full sum-over-states expression. Although Re(gamma) is significantly smaller than that of other commonly studied NLO chromophores, the introduction of a new molecular architecture offering the potential for a negative Re(gamma) introduces new avenues of molecular design for NLO applications. PMID- 26098180 TI - Correction to Shao et al. (2015). AB - Reports an error in "Selective Inhibition and Naming Performance in Semantic Blocking, Picture-Word Interference, and Color-Word Stroop Tasks" by Zeshu Shao, Ardi Roelofs, Randi C. Martin and Antje S. Meyer (Journal of Experimental Psychology: Learning, Memory, and Cognition, Advanced Online Publication, Jun 1, 2015, np). Antje S. Meyer should not be affiliated with Rice University. All versions of this article have been corrected. (The following abstract of the original article appeared in record 2015-23895-001.) In 2 studies, we examined whether explicit distractors are necessary and sufficient to evoke selective inhibition in 3 naming tasks: the semantic blocking, picture-word interference, and color-word Stroop task. Delta plots were used to quantify the size of the interference effects as a function of reaction time (RT). Selective inhibition was operationalized as the decrease in the size of the interference effect as a function of naming RT. For all naming tasks, mean naming RTs were significantly longer in the interference condition than in the control condition. The slopes of the interference effects for the longest naming RTs correlated with the magnitude of the mean interference effect in both the semantic blocking task and the picture-word interference task, suggesting that selective inhibition was involved to reduce the interference from strong semantic competitors either invoked by a single explicit competitor or strong implicit competitors in picture naming. However, there was no correlation between the slopes and the mean interference effect in the Stroop task, suggesting less importance of selective inhibition in this task despite explicit distractors. Whereas the results of the semantic blocking task suggest that an explicit distractor is not necessary for triggering inhibition, the results of the Stroop task suggest that such a distractor is not sufficient for evoking inhibition either. PMID- 26098181 TI - Reading skill and word skipping: Implications for visual and linguistic accounts of word skipping. AB - We investigated whether high-skill readers skip more words than low-skill readers as a result of parafoveal processing differences based on reading skill. We manipulated foveal load and word length, two variables that strongly influence word skipping, and measured reading skill using the Nelson-Denny Reading Test. We found that reading skill did not influence the probability of skipping five letter words, but low-skill readers were less likely to skip three-letter words when foveal load was high. Thus, reading skill is likely to influence word skipping when the amount of information in the parafovea falls within the word identification span. We interpret the data in the context of visual-based (extended optimal viewing position model) and linguistic based (E-Z Reader model) accounts of word skipping. The models make different predictions about how and why a word and skipped; however, the data indicate that both models should take into account the fact that different factors influence skipping rates for high- and low-skill readers. PMID- 26098182 TI - Language switching-but not foreign language use per se-reduces the framing effect. AB - Recent studies reported reductions of well-established biases in decision making under risk, such as the framing effect, during foreign language (FL) use. These modulations were attributed to the use of FL itself, which putatively entails an increase in emotional distance. A reduced framing effect in this setting, however, might also result from enhanced cognitive control associated with language-switching in mixed-language contexts, an account that has not been tested yet. Here we assess predictions of the 2 accounts in 2 experiments with over 1,500 participants. In Experiment 1, we tested a central prediction of the emotional distance account, namely that the framing effect would be reduced at low, but not high, FL proficiency levels. We found a strong framing effect in the native language, and surprisingly also in the foreign language, independent of proficiency. In Experiment 2, we orthogonally manipulated foreign language use and language switching to concurrently test the validity of both accounts. As in Experiment 1, foreign language use per se had no effect on framing. Crucially, the framing effect was reduced following a language switch, both when switching into the foreign and the native language. Thus, our results suggest that reduced framing effects are not mediated by increased emotional distance in a foreign language, but by transient enhancement of cognitive control, putting the interplay of bilingualism and decision making in a new light. (PsycINFO Database Record PMID- 26098183 TI - Reproductive Justice, Health Disparities And Incarcerated Women in the United States. PMID- 26098184 TI - ["Arterial hypertension again already?"]. PMID- 26098185 TI - [Cardiovascular risk stratification and therapeutic implications in arterial hypertension]. AB - To improve the prevention of cardiovascular complications and events in hypertensive patients, it is of major importance to estimate the patient's individual risk for cardiovascular events. Antihypertensive treatment should not only be based on blood pressure values anymore, but also on the patient's comorbidities and risk profile. Risk stratification takes into account cardiovascular risk factors, diabetes, asymptomatic organ damage and established cardiovascular or renal disease. The most important markers for asymptomatic organ damage which should be searched for are microalbuminuria and LVH. Current guidelines emphasize the importance of the adaption and selection of treatment according to asymptomatic and established organ damage and provide assistance for treatment decisions. They focus also on the different non-pharmacological therapy options and lifestyle modifications. The goal of this article is to summarize the most important innovations and to point out the importance of simple tools for the implementation of cardiovascular risk stratification in hypertensive patients. PMID- 26098186 TI - [Renal hypertension--the role of the kidneys in blood pressure regulation and the kidneys as end organ]. AB - Hypertension affects approximately 25%-30% of the adult population and it is predicted that its prevalence will increase. It is a main risk factor for the development of kidney failure and cardiovascular disease and on the other hand 80 % of patients with chronic kidney disease are hypertensive. The interactions between hypertension and kidney disease are complex and it is important to keep pathophysiology in mind in order to get a better understanding of treating hypertension. Renovascular hypertension or renal hypertension means hypertension in context of renal artery stenosis and kidney disease. Thus, patients with newly diagnosed hypertension should be screened for underlying kidney disease and hypertension should be treated in the sense of optimal "nephroprotective" therapy within the target values (blood pressure<130/80 mmHg and proteinuria<1 g/d). First line antihypertensive drugs for treating patients with kidney disease are ACE-Inhibitors or Angiotensin receptor blockers in combination with diuretics and a low sodium diet. PMID- 26098187 TI - [Arterial hypertension secondary to endocrine disorders]. AB - Endocrine hypertension offers a potentially curative therapy if the underlying cause is identified and treated accordingly. In contrast to the high prevalence of arterial hypertension especially in the elderly, the classical endocrine causes remain a rare entity. Among patients with arterial hypertension the prevalence of Cushing's syndrome or pheochromocytoma is less than 1%. Primary hyperaldosteronism is more frequent with a reported prevalence of up to 9%. In order to avoid unnecessary, costly and potentially harmful evaluations and therapies due to the limited sensitivity and specificity of the critical endocrine tests it is mandatory to limit the exploration for endocrine causes to preselected patients with high pretest probability for an endocrine disorder. Younger age at manifestation of arterial hypertension or drug resistant hypertension together with other clinical signs of an endocrine disorder should raise the suspicion and prompt the appropriate evaluation. PMID- 26098188 TI - [Blood pressure limits--the lower, the better?]. AB - Arterial hypertension is a widespread risk factor for cardiovascular disease. The benefit of a consistent drug therapy is proportionally associated with the degree of blood pressure reduction. By extrapolating the data, the assumption arose "the lower the better" and was widely accepted. However, several studies found an increase in morbidity and mortality with an excessive reduction of blood pressure (J-curve). This seems to affect mainly cardiac risk, and only at lower blood pressures<60 mmHg also the cerebral risk. An important factor here is the diastolic blood pressure. Others found a linear correlation. Overall, a j-shaped connection remains controversial and is not considered equally for all organ systems. At the same time cardiovascular risk seems not to increase with additional reduction in blood pressure of <140 mm Hg to <120 mmHg. This has led to the latest guidelines of all societies recommending higher target values. Reasons for higher targets in drug therapy of arterial hypertension, are increased adverse drug reactions or increased healthcare costs with few additional benefit. The current recommendations of the ESH/ESC, AHA/ACC/ASH and the JNC 8 set a higher target value for some subgroups, but remain inconsistent among themselves. PMID- 26098189 TI - [Therapy-resistant arterial hypertension]. AB - Therapy-resistant hypertension is a frequent finding in clinical practice. It is associated with a significantly increased risk for cardiovascular and renal events. Causes include but are not limited to erroneous blood pressure measurements, compliance issues, blood pressure increasing co-medication, and secondary hypertension. During the last years, several medical and interventional therapeutic approaches have been described and introduced into clinical practice. The goal of this paper is to summarize the clinically relevant diagnostic and therapeutic aspects related to therapy-resistant hypertension and to give an overview on the rational approach to this clinical problem. PMID- 26098190 TI - [Hypertension in the elderly]. AB - Arterial hypertension remains the most important risk factor for cardiovascular and renal diseases. In view of an increasing prevalence with older age and an increasingly aging population, the treatment of elderly patients with arterial hypertension will become increasingly important in daily practice. Arterial hypertension in the elderly differs in many aspects from arterial hypertension in younger patients. For example, isolated systolic hypertension is the predominant form of arterial hypertension in the elderly. In comparison to younger patients, treatment of hypertension in the elderly is less well investigated. However, available data suggest that lowering of blood pressure in the elderly and very elderly reduces the risk of heart failure, stroke, and even mortality. The best evidence for the treatment of hypertension in the elderly exists for diuretics and calcium antagonists. However, the primary choice of antihypertensive therapy should be guided by the presence of existing cardiovascular and/or renal comorbidities. PMID- 26098191 TI - [Hypertensive urgency and emergency]. AB - European and North-American guidelines for the diagnosis and therapy of arterial hypertension refer to hypertensive crisis as an acute and critical increase of blood pressure>180/120 mmHg. Presence of acute hypertensive target organ damage, such as stroke, myocardial infarction or heart failure, in this situation defines a "hypertensive emergency". In these patients, immediate lowering of blood pressure (about 25% within one to two hours) in an intensive care setting is mandatory to prevent further progression of target organ damage. In contrast to hypertensive emergencies, hypertensive urgencies are characterized by an acute and critical increase in blood pressure without signs or symptoms of acute hypertensive target organ damage. In these patients, blood pressure should be lowered within 24 to 48 hours in order to avoid hypertensive target organ damage. In general, hospitalization is not required, and oral antihypertensive therapy usually is sufficient. However, further and continuing outpatient care has to be ensured. PMID- 26098192 TI - Being Sexually Attracted to Minors: Sexual Development, Coping With Forbidden Feelings, and Relieving Sexual Arousal in Self-Identified Pedophiles. AB - This article aims to provide more insight into pedophilic attraction and risk and protective factors for offending in nonclinical pedophiles. Fifteen participants were interviewed about sexuality, coping, and sexual self-regulation. Many participants struggled with acknowledging pedophilic interest in early puberty and experienced psychological difficulties as a result. Furthermore, many committed sex offenses during adolescence when they were still discovering their feelings. Early recognition of risk factors and early start of interventions seem vital in preventing offending. Moreover, results suggest that risk for offending can be diminished by creating more openness about pedophilia and by providing pedophiles with social support and control. PMID- 26098193 TI - Do not forget the joint involvement of sarcoidosis. PMID- 26098194 TI - Sulfamethoxazole-induced thrombocytopenia masquerading as posttransfusion purpura: a case report. AB - BACKGROUND: Drug-induced immune thrombocytopenia (DITP) is a rare clinical disorder characterized by accelerated platelet (PLT) clearance in the presence of drug-dependent antibodies. Distinguishing DITP from other immune-mediated disorders such as posttransfusion purpura (PTP) and autoimmune thrombocytopenia can represent a clinical challenge. CASE REPORT: A 68-year-old male with no prior transfusion history presented to the emergency department (ED) with dyspnea, epistaxis, and severe thrombocytopenia (<10 * 10(9)/L) 12 days after discharge from a hospital admission for a coronary artery bypass graft. Evaluation of the degree of thrombocytopenia and the temporal association between the peri- and postoperative receipt of multiple transfusions and the acute decrease in PLT count indicated PTP as a possible cause of the severe thrombocytopenia. Treatment with 1 g/kg intravenous immunoglobulin (IVIG) was initiated and followed by a rapid 48-hour increase in the PLT count. PLT antibodies lacking serologic specificity were subsequently identified in a sample collected upon presentation. Two weeks later he again presented to the ED with epistaxis and severe thrombocytopenia (<10 * 10(9)/L). Clinical history now revealed that the patient had been treated with trimethoprim-sulfamethoxazole by his primary care physician after his first hospitalization for a "cellulitic-appearing" leg and again before his final presentation for surgical site erythema and edema. IVIG was administered again with a rapid return of PLT count to baseline. Sulfamethoxazole dependent PLT antibodies were subsequently identified in the original patient sample. CONCLUSION: This case report documents a case of IVIG-responsive DITP initially misdiagnosed as PTP, highlighting the clinical overlap of these immunologic-mediated phenomena. PMID- 26098196 TI - Rural nurses: a convenient co-location strategy for the rural mental health care of young people. AB - AIMS AND OBJECTIVES: The aim of this research was to understand new ways that young rural people with mental health problems could be helped at an early point in their mental health decline. BACKGROUND: Rural nurses represent skilled mental health helping capital in their local communities, yet this important mental health helping resource, or helping capital, is both under-recognised and under used in providing early mental health help in rural communities. In recent years international momentum has gathered in support of a paradigm change to reform the delivery of youth mental health services so that they align more closely to the developmental and social needs of young people with mental health problems. DESIGN: A mixed methods case study design was used to explore the early mental health care needs of young rural people. METHODS: A cross-sectional survey was conducted and data were analysed with descriptive techniques. In-depth interviews were conducted and the transcribed data were analysed using thematic techniques. RESULTS: The results of this study demonstrate that in general rural people are willing to seek mental health care, and that rural nurses are well suited to provide initial care to young people. CONCLUSIONS: Non-traditional venues such as community, school and justice settings are ideal places where more convenient first conversations about mental health with young people and their families, and rural nurses should be deployed to these settings. RELEVANCE TO CLINICAL PRACTICE: Rural nurses are able to contribute important initial engagement interventions that enhance the early mental health care for young people when it is needed. PMID- 26098195 TI - CuS Nanodots with Ultrahigh Efficient Renal Clearance for Positron Emission Tomography Imaging and Image-Guided Photothermal Therapy. AB - Translation of nanoparticles (NPs) into clinical practice has been limited by toxic effects induced by nonspecific accumulation of NPs in healthy organs after systemic administration. The ideal NPs should accumulate in the target site, carry out their function, and then ultimately be eliminated from the body. Here, we show a single-compartment, multifunctional ultrasmall copper sulfide nanodot (CuS ND) that is rapidly cleared from the body. These CuS NDs have a hydrodynamic diameter of <6 nm, can efficiently absorb near-infrared light for photothermal ablation therapy, and stably incorporate the copper-64 radioisotope for noninvasive positron emission tomography (PET). Importantly, ~95% of CuS NDs are excreted intact through the renal-urinary system within 24 h with minimal retention in the liver and the spleen. The ultrasmall CuS NDs accumulate in 4T1 tumors in Balb/c mice, as monitored by PET imaging, and mediate tumor ablation when combined with near-infrared light irradiation. As a first example of PET visible, renal-clearable inorganic nanomaterials with peak absorption in the near infrared region, CuS NDs represent a robust platform for cancer imaging and therapy. PMID- 26098197 TI - Co-Eradication of Breast Cancer Cells and Cancer Stem Cells by Cross-Linked Multilamellar Liposomes Enhances Tumor Treatment. AB - The therapeutic limitations of conventional chemotherapeutic drugs have emerged as a challenge for breast cancer therapy; these shortcomings are likely due, at least in part, to the presence of the cancer stem cells (CSCs). Salinomycin, a polyether antibiotic isolated from Streptomyces albus, has been shown to selectively inhibit cancer stem cells; however, its clinical application has been hindered by the drug's hydrophobility, which limits the available administration routes. In this paper, a novel drug delivery system, cross-linked multilamellar liposomal vesicles (cMLVs), was optimized to allow for the codelivery of salinomycin (Sal) and doxorubicin (Dox), targeting both CSCs and breast cancer cells. The results show that the cMLV particles encapsulating different drugs have similar sizes with high encapsulation efficiencies (>80%) for both Dox and Sal. Dox and Sal were released from the particles in a sustained manner, indicating the stability of the cMLVs. Moreover, the inhibition of cMLV(Dox+Sal) against breast cancer cells was stronger than either single-drug treatment. The efficient targeting of cMLV(Dox+Sal) to CSCs was validated through in vitro experiments using breast cancer stem cell markers. In accordance with the in vitro combination treatment, in vivo breast tumor suppression by cMLV(Dox+Sal) was 2-fold more effective than single-drug cMLV treatment or treatment with the combination of cMLV(Dox) and cMLV(Sal). Thus, this study demonstrates that cMLVs represent a novel drug delivery system that can serve as a potential platform for combination therapy, allowing codelivery of an anticancer agent and a CSC inhibitor for the elimination of both breast cancer cells and cancer stem cells. PMID- 26098198 TI - Determining agreement using rater characteristics. AB - When evaluating the usefulness of clinical information for the diagnosis of disease, multiple raters provide a diagnosis for the same set of data. These ratings provide important insights into the performance of the diagnosis, determining the accuracy of each rater's diagnosis compared to the truth standard and the level of agreement among the raters. We demonstrate that the intraclass correlation coefficient (ICC) is dependent on the sensitivities and specificities of the raters involved in the study. Given the sensitivity and specificity of any number of raters, along with the prevalence of disease, the expected ICC can be determined. PMID- 26098199 TI - Combinatorics of RNA Secondary Structures with Base Triples. AB - The structure of RNA has been the subject of intense research over the last decades due to its importance for the correct functioning of RNA molecules in biological processes. Hence, a large number of models for RNA folding and corresponding algorithms for structure prediction have been developed. However, previous models often only consider base pairs, although every base is capable of up to three edge-to-edge interactions with other bases. Recently, Honer zu Siederdissen et al. presented an extended model of RNA secondary structure, including base triples together with a folding algorithm-the first thermodynamics based algorithm that allows the prediction of secondary structures with base triples. In this article, we investigate the search space processed by this new algorithm, that is, the combinatorics of extended RNA secondary structures with base triples. We present generalized definitions for structural motifs like hairpins, stems, bulges, or interior loops occurring in structures with base triples. Furthermore, we prove precise asymptotic results for the number of different structures (size of search space) and expectations for various parameters associated with structural motifs (typical shape of folding). Our analysis shows that the asymptotic number of secondary structures of size n increases exponentially to [Formula: see text] compared to the classic model by Stein and Waterman for which [Formula: see text] structures exist. A comparison with the classic model reveals large deviations in the expected structural appearance, too. The inclusion of base triples constitutes a significant refinement of the combinatorial model of RNA secondary structure, which, by our findings, is quantitatively characterized. Our results are of special theoretical interest, because a closer look at the numbers involved suggests that extended RNA secondary structures constitute a new combinatorial class not bijective with any other combinatorial objects studied so far. PMID- 26098200 TI - Sample size considerations for historical control studies with survival outcomes. AB - Historical control trials (HCTs) are frequently conducted to compare an experimental treatment with a control treatment from a previous study, when they are applicable and favored over a randomized clinical trial (RCT) due to feasibility, ethics and cost concerns. Makuch and Simon developed a sample size formula for historical control (HC) studies with binary outcomes, assuming that the observed response rate in the HC group is the true response rate. This method was extended by Dixon and Simon to specify sample size for HC studies comparing survival outcomes. For HC studies with binary and continuous outcomes, many researchers have shown that the popular Makuch and Simon method does not preserve the nominal power and type I error, and suggested alternative approaches. For HC studies with survival outcomes, we reveal through simulation that the conditional power and type I error over all the random realizations of the HC data have highly skewed distributions. Therefore, the sampling variability of the HC data needs to be appropriately accounted for in determining sample size. A flexible sample size formula that controls arbitrary percentiles, instead of means, of the conditional power and type I error, is derived. Although an explicit sample size formula with survival outcomes is not available, the computation is straightforward. Simulations demonstrate that the proposed method preserves the operational characteristics in a more realistic scenario where the true hazard rate of the HC group is unknown. A real data application of an advanced non-small cell lung cancer (NSCLC) clinical trial is presented to illustrate sample size considerations for HC studies in comparison of survival outcomes. PMID- 26098201 TI - Direct Covalent Biomolecule Immobilization on Plasma-Nanotextured Chemically Stable Substrates. AB - A new method for direct covalent immobilization of protein molecules (including antibodies) on organic polymers with plasma-induced random micronanoscale topography and stable-in-time chemical functionality is presented. This is achieved using a short (1-5 min) plasma etching and simultaneous micronanotexturing process, followed by a fast thermal annealing step, which induces accelerated hydrophobic recovery while preserving important chemical functionality created by the plasma. Surface-bound biomolecules resist harsh washing with sodium dodecyl sulfate and other detergents even at elevated temperatures, losing less than 40% of the biomolecules bound even at the harshest washing conditions. X-ray photoelectron spectroscopy, secondary-ion mass spectrometry, and electron paramagnetic resonance are used to unveil the chemical modification of the plasma-treated and stabilized surfaces. The nanotextured and chemically stabilized surfaces are used as substrates for the development of immunochemical assays for the sensitive detection of C-reactive protein and salmonella lipopolysaccharides through immobilization of the respective analyte specific antibodies onto them. Such substrates are stable for a period of 1 year with ambient storage. PMID- 26098202 TI - Galvanic Cell Type Sensor for Soil Moisture Analysis. AB - Here we report the first potentiometric sensor for soil moisture analysis by bringing in the concept of Galvanic cells wherein the redox energies of Al and conducting polyaniline are exploited to design a battery type sensor. The sensor consists of only simple architectural components, and as such they are inexpensive and lightweight, making it suitable for on-site analysis. The sensing mechanism is proved to be identical to a battery type discharge reaction wherein polyaniline redox energy changes from the conducting to the nonconducting state with a resulting voltage shift in the presence of soil moisture. Unlike the state of the art soil moisture sensors, a signal derived from the proposed moisture sensor is probe size independent, as it is potentiometric in nature and, hence, can be fabricated in any shape or size and can provide a consistent output signal under the strong aberration conditions often encountered in soil moisture analysis. The sensor is regenerable by treating with 1 M HCl and can be used for multiple analysis with little read out hysteresis. Further, a portable sensor is fabricated which can provide warning signals to the end user when the moisture levels in the soil go below critically low levels, thereby functioning as a smart device. As the sensor is inexpensive, portable, and potentiometric, it opens up avenues for developing effective and energy efficient irrigation strategies, understanding the heat and water transfer at the atmosphere-land interface, understanding soil mechanics, forecasting the risk of natural calamities, and so on. PMID- 26098204 TI - Palliative Care Training during Fellowship: A National Survey of U.S. Hematology and Oncology Fellows. AB - BACKGROUND: Despite requirements for palliative care training during fellowship, there is a paucity of recent data regarding the attitudes, knowledge, and skills of hematology/ oncology fellows in palliative care. OBJECTIVE: Our aim was to assess fellows' attitudes toward and quality of training in palliative care during fellowship and perceived preparedness to care for patients at the end of life (EOL). METHODS: In May 2013 a cross-sectional survey of hematology/oncology fellows was conducted. RESULTS: Fellows from 93 of 138 fellowship programs responded (67.4%). Of the 347 fellows e-mailed, 176 participated. Nearly all fellows (99%) indicated that physicians have a responsibility to help patients at EOL. Fellows felt their overall training in fellowship was superior to training in EOL care (4.24+/-0.78 versus 3.53+/-0.99 on a 5-5 scale where 1=poor and 5=excellent, p<0.0001). Fellows who had a rotation in palliative care during fellowship (44.9%) reported better teaching on managing a patient at EOL than those who did not (3.91+/-1.0 versus 3.21+/-0.87, p<0.0001). Fellows reporting better teaching in EOL care felt better prepared to care for patients at EOL (r=0.52, p<0.0001). More than 25% reported not being explicitly taught how to assess prognosis, when to refer a patient to hospice, or how to conduct a family meeting to discuss treatment options. CONCLUSION: Many recent oncology fellows are still inadequately prepared to provide palliative care to their patients. There is significant room for improvement with regards to the quality of palliative care training in U.S. hematology/oncology fellowship programs. PMID- 26098205 TI - The relationship between alloying elements and biologically produced ennoblement in natural waters. AB - A range of stainless steels, nickel-chromium and nickel-chromium-molybdenum alloys were exposed to coastal seawater from Mandapam (Indian Ocean) and freshwater from a perennial pond. Biofilms from both test waters produced an ennoblement of the open circuit potential (OCP) on all alloys as expected, which was slower but substantially larger in freshwater. In both waters an interesting relationship was perceived between the plateau OCP (Emax) and the mass percentage of the major alloying elements. In particular, iron exhibited strong positive correlations with Emax (r(2) >= 0.77; p < 0.0005), while the sum of chromium, nickel and molybdenum presented significant negative correlations (r(2) <= -0.81; p = 0.0002). Consistent with the regression analyses, Euclidean distance clustering yielded patterns where Inconel-600 and the nickel-chromium-molybdenum alloys had the smallest similarities of OCP with other alloys. The results emphatically reinforce a key role for surface passive films in the ennoblement phenomenon in natural waters. PMID- 26098203 TI - Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor. AB - INTRODUCTION: Gastrointestinal stromal tumor (GIST) is the most common nonepithelial malignancy of the GI tract. With the discovery of KIT and later platelet-derived growth factor alpha (PDGFRA) gain-of-function mutations as factors in the pathogenesis of the disease, GIST was the quintessential model for targeted therapy. Despite the successful clinical use of imatinib mesylate, a selective receptor tyrosine kinase (RTK) inhibitor that targets KIT, PDGFRA and BCR-ABL, we still do not have treatment for the long-term control of advanced GIST. AREAS COVERED: This review summarizes the drugs that are under investigation or have been assessed in trials for GIST treatment. The article focuses on their mechanisms of actions, the preclinical evidence of efficacy, and the clinical trials concerning safety and efficacy in humans. EXPERT OPINION: It is known that KIT and PDGFRA mutations in GIST patients influence the response to treatment. This observation should be taken into consideration when investigating new drugs. RECIST was developed to help uniformly report efficacy trials in oncology. Despite the usefulness of this system, many questions are being addressed about its validity in evaluating the true efficacy of drugs knowing that new targeted therapies do not affect the tumor size as much as they halt progression and prolong survival. PMID- 26098206 TI - Epigenetic programming of glucose-regulated insulin release. AB - Pancreatic beta cells support glucose homeostasis with great precision by matching insulin release to the metabolic needs of the moment. Previous gene expression analysis indicates that adult beta cells not only produce cell specific proteins, but also repress a small set of housekeeping genes - such as those encoding lactate dehydrogenase A (LDHA), solute transporter MCT1, and hexokinase 1 (HK1) - that would otherwise interfere with normal beta cell function. In this issue of the JCI, Dhawan et al. elucidate a molecular mechanism involved in beta cell-specific repression of Ldha and Hk1 that is mediated by induction of the de novo DNA methyltransferase DNMT3A during the first weeks after birth. Failure to induce DNMT3A-dependent methylation disrupts normal glucose-induced insulin release in adult life. The results of this study reinforce the idea that the phenotype of adult beta cells has two faces and that failure to achieve selective gene repression undermines beta cell support of normal glucose homeostasis. PMID- 26098207 TI - Fetal-to-maternal signaling to initiate parturition. AB - Multiple processes are capable of activating the onset of parturition; however, the specific contributions of the mother and the fetus to this process are not fully understood. In this issue of the JCI, Gao and colleagues present evidence that steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2) regulate surfactant protein-A (SP-A) and platelet-activating factor (PAF) expression, which increases in the developing fetal lung. WT dams crossed with males deficient for both SRC-1 and SRC-2 had suppressed myometrial inflammation, increased serum progesterone, and delayed parturition, which could be reconciled by injection of either SP-A or PAF into the amnion. Together, the results of this study demonstrate that the fetal lungs produce signals to initiate labor in the mouse. This work underscores the importance of the fetus as a contributor to the onset of murine, and potentially human, parturition. PMID- 26098208 TI - The many faces of type I interferon in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a broad spectrum of clinical presentations involving multiple organ systems. An abnormal response to self-antigens is thought to drive the development of SLE; however, the factors that underlie this dysfunction are not clear. In this issue of the JCI, Li and colleagues present compelling evidence to show that type I interferons (IFNs) produced by plasmacytoid dendritic cells inhibit the clearance of apoptotic cells (ACs) by marginal zone macrophages. Specifically, type I IFNs increase the translocation of marginal zone (MZ) B cells to the follicular region of the spleen, thereby disrupting interactions between these B cells and MZ macrophages (MZMs), which in turn disrupts megakaryoblastic leukemia 1-mediated (MKL1-mediated) mechanosensing and inhibits AC phagocytosis by MZMs. The results of this study provide important insight into factors that inhibit AC clearance and promote the development of SLE. PMID- 26098209 TI - Hypoactivity following perturbed estrogen signaling in the medial amygdala. AB - Activation of estrogen receptor alpha (ERalpha) in the brain prevents obesity as the result of increased energy expenditure and decreased food intake. While ERalpha is present on several neural populations, it is not clear how different regions of the brain mediate the weight-regulating effects of ERalpha activation. In this issue of the JCI, Xu and colleagues provide extensive evidence that ERalpha is abundant on neurons expressing single-minded-1 (SIM1) in the medial amygdala (MeA) and that loss of ERalpha in these cells enhances weight gain in both male and female mice, as the result of reduced physical activity. Moreover, focal deletion of ERalpha from the MeA recapitulated these alterations in energy homeostasis. Conversely, overexpression of ERalpha in the MeA partially prevented mice from diet-induced obesity, while chemogenetic activation of SIM1-expressing neurons in the MeA transiently promoted physical activity. The results of this study provide important insight into the regions of the brain that mediate ERalpha-dependent energy homeostasis. PMID- 26098210 TI - Restoration of synaptic function in sight for degenerative retinal disease. AB - Synaptic disorganization is a prominent feature of many neurological diseases of the CNS, including Parkinson's disease, intellectual development disorders, and autism. Although synaptic plasticity is critical for learning and memory, it is unclear whether this innate property helps restore synaptic function in disease once the primary cause of disease is abrogated. An answer to this question may come from a recent investigation in X-linked retinoschisis, a currently untreatable retinopathy. In this issue of the JCI, Ou, Vijayasarathy, and colleagues showed progressive disorganization of key functional elements of the synapse between photoreceptors and ON-bipolar cells in a retinoschisin-deficient mouse model. Moreover, they demonstrated that adeno-associated virus-mediated (AAV-mediated) delivery of the retinoschisin gene restores structure and function to the photoreceptor to ON-bipolar cell synapse in mouse models, even in adults at advanced stages of the disease. The results of this study hold promise that AAV-based supplemental gene therapy will benefit patients with X-linked retinoschisis in a forthcoming clinical trial. PMID- 26098211 TI - Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus. AB - Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is associated with increased circulating apoptotic cell autoantigens (AC-Ags) as well as increased type I IFN signaling. Here, we describe a pathogenic mechanism in which follicular translocation of marginal zone (MZ) B cells in the spleens of BXD2 lupus mice disrupts marginal zone macrophages (MZMs), which normally clear AC debris and prevent follicular entry of AC-Ags. Phagocytosis of ACs by splenic MZMs required the megakaryoblastic leukemia 1 (MKL1) transcriptional coactivator mediated mechanosensing pathway, which was maintained by MZ B cells through expression of membrane lymphotoxin-alpha1beta2 (mLT). Specifically, type I IFN induced follicular shuttling of mLT-expressing MZ B cells disengaged interactions between these MZ B cells and LTbeta receptor-expressing MZMs, thereby downregulating MKL1 in MZMs. Loss of MKL1 expression in MZMs led to defective F actin polymerization, inability to clear ACs, and, eventually, MZM dissipation. Aggregation of plasmacytoid DCs in the splenic perifollicular region, follicular translocation of MZ B cells, and loss of MKL1 and MZMs were also observed in an additional murine lupus model and in the spleens of patients with SLE. Collectively, the results suggest that lupus might be interrupted by strategies that maintain or enhance mechanosensing signaling in the MZM barrier to prevent follicular entry of AC-Ags. PMID- 26098212 TI - Estrogen receptor-alpha in medial amygdala neurons regulates body weight. AB - Estrogen receptor-alpha (ERalpha) activity in the brain prevents obesity in both males and females. However, the ERalpha-expressing neural populations that regulate body weight remain to be fully elucidated. Here we showed that single minded-1 (SIM1) neurons in the medial amygdala (MeA) express abundant levels of ERalpha. Specific deletion of the gene encoding ERalpha (Esr1) from SIM1 neurons, which are mostly within the MeA, caused hypoactivity and obesity in both male and female mice fed with regular chow, increased susceptibility to diet-induced obesity (DIO) in males but not in females, and blunted the body weight-lowering effects of a glucagon-like peptide-1-estrogen (GLP-1-estrogen) conjugate. Furthermore, selective adeno-associated virus-mediated deletion of Esr1 in the MeA of adult male mice produced a rapid body weight gain that was associated with remarkable reductions in physical activity but did not alter food intake. Conversely, overexpression of ERalpha in the MeA markedly reduced the severity of DIO in male mice. Finally, an ERalpha agonist depolarized MeA SIM1 neurons and increased their firing rate, and designer receptors exclusively activated by designer drug-mediated (DREADD-mediated) activation of these neurons increased physical activity in mice. Collectively, our results support a model where ERalpha signals activate MeA neurons to stimulate physical activity, which in turn prevents body weight gain. PMID- 26098213 TI - DNA methylation directs functional maturation of pancreatic beta cells. AB - Pancreatic beta cells secrete insulin in response to postprandial increases in glucose levels to prevent hyperglycemia and inhibit insulin secretion under fasting conditions to protect against hypoglycemia. beta cells lack this functional capability at birth and acquire glucose-stimulated insulin secretion (GSIS) during neonatal life. Here, we have shown that during postnatal life, the de novo DNA methyltransferase DNMT3A initiates a metabolic program by repressing key genes, thereby enabling the coupling of insulin secretion to glucose levels. In a murine model, beta cell-specific deletion of Dnmt3a prevented the metabolic switch, resulting in loss of GSIS. DNMT3A bound to the promoters of the genes encoding hexokinase 1 (HK1) and lactate dehydrogenase A (LDHA) - both of which regulate the metabolic switch - and knockdown of these two key DNMT3A targets restored the GSIS response in islets from animals with beta cell-specific Dnmt3a deletion. Furthermore, DNA methylation-mediated repression of glucose-secretion decoupling genes to modulate GSIS was conserved in human beta cells. Together, our results reveal a role for DNA methylation to direct the acquisition of pancreatic beta cell function. PMID- 26098214 TI - Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. AB - The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A-deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC 1/-2-deficient embryos. These mothers exhibited decreased myometrial NF-kappaB activation, PGF2alpha, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC 1/-2-deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-kappaB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2 deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2-dependent production of SP-A and PAF is crucial for this process. PMID- 26098215 TI - Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients. AB - BACKGROUND: TGF-beta has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-beta-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-beta may benefit these patients. METHODS: Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high affinity neutralizing antibody that targets all 3 TGF-beta isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-beta regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). RESULTS: In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-beta-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. CONCLUSION: The rapid inhibition of TGF-beta-regulated gene expression in response to fresolimumab strongly implicates TGF-beta in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov NCT01284322. PMID- 26098216 TI - Mature T cell responses are controlled by microRNA-142. AB - T cell proliferation is critical for immune responses; however, the molecular mechanisms that mediate the proliferative response are poorly understood. MicroRNAs (miRs) regulate various molecular processes, including development and function of the immune system. Here, utilizing multiple complementary genetic and molecular approaches, we investigated the contribution of a hematopoietic specific miR, miR-142, in regulating T cell responses. T cell development was not affected in animals with a targeted deletion of Mir142; however, T cell proliferation was markedly reduced following stimulation both in vitro and in multiple murine models of graft-versus-host disease (GVHD). miR-142-deficient T cells demonstrated substantial cell-cycling defects, and microarray and bioinformatics analyses revealed upregulation of genes involved in cell cycling. Moreover, 2 predicted miR-142 target genes, the atypical E2F transcription factors E2f7 and E2f8, were most highly upregulated in miR-142-deficient cells. Clustered regularly interspaced short palindromic repeat interference-mediated (CRISPRi-mediated) silencing of E2F7 and E2F8 in miR-142-deficient T cells ameliorated cell-cycling defects and reduced GVHD, and overexpression of these factors in WT T cells inhibited the proliferative response. Together, these results identify a link between hematopoietic-specific miR-142 and atypical E2F transcription factors in the regulation of mature T cell cycling and suggest that targeting this interaction may be relevant for mitigating GVHD. PMID- 26098217 TI - Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer. AB - Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8 RS1 (AAV8-RS1) vector rescues molecular pathology at the photoreceptor depolarizing bipolar cell (photoreceptor-DBC) synapse and restores function in adult Rs1-KO animals. Initial development of the photoreceptor-DBC synapse was normal in the Rs1-KO retina; however, the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1-signaling (mGluR6/TRPM1-signaling) cascade was not properly maintained. Specifically, the TRPM1 channel and G proteins Galphao, Gbeta5, and RGS11 were progressively lost from postsynaptic DBC dendritic tips, whereas the mGluR6 receptor and RGS7 maintained proper synaptic position. This postsynaptic disruption differed from other murine night-blindness models with an electronegative electroretinogram response, which is also characteristic of murine and human XLRS disease. Upon AAV8-RS1 gene transfer to the retina of adult XLRS mice, TRPM1 and the signaling molecules returned to their proper dendritic tip location, and the DBC resting membrane potential was restored. These findings provide insight into the molecular plasticity of a critical synapse in the visual system and demonstrate potential therapeutic avenues for some diseases involving synaptic pathology. PMID- 26098219 TI - Upcycling of Packing-Peanuts into Carbon Microsheet Anodes for Lithium-Ion Batteries. AB - Porous carbon microsheet anodes with Li-ion storage capacity exceeding the theoretical limit are for the first time derived from waste packing-peanuts. Crystallinity, surface area, and porosity of these 1 MUm thick carbon sheets were tuned by varying the processing temperature. Anodes composed of the carbon sheets outperformed the electrochemical properties of commercial graphitic anode in Li ion batteries. At a current density of 0.1 C, carbon microsheet anodes exhibited a specific capacity of 420 mAh/g, which is slightly higher than the theoretical capacity of graphite (372 mAh/g) in Li-ion half-cell configurations. At a higher rate of 1 C, carbon sheets retained 4-fold higher specific capacity (220 mAh/g) compared to those of commercial graphitic anode. After 100 charge-discharge cycles at current densities of 0.1 and 0.2 C, optimized carbon sheet anodes retained stable specific capacities of 460 and 370 mAh/g, respectively. Spectroscopic and microscopic investigations proved the structural integrity of these high-performance carbon anodes during numerous charge-discharge cycles. Considerably higher electrochemical performance of the porous carbon microsheets are endorsed to their disorderness that facilitate to store more Li-ions than the theoretical limit, and porous 2-D microstructure enabling fast solid-state Li-ion diffusion and superior interfacial kinetics. The work demonstrated here illustrates an inexpensive and environmentally benign method for the upcycling of packaging materials into functional carbon materials for electrochemical energy storage. PMID- 26098218 TI - Engineering the gut microbiota to treat hyperammonemia. AB - Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASF), a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility. PMID- 26098220 TI - Heterogeneous Charge Carrier Dynamics in Organic-Inorganic Hybrid Materials: Nanoscale Lateral and Depth-Dependent Variation of Recombination Rates in Methylammonium Lead Halide Perovskite Thin Films. AB - We reveal substantial luminescence yield heterogeneity among individual subdiffraction grains of high-performing methylammonium lead halide perovskite films by using high-resolution cathodoluminescence microscopy. Using considerably lower accelerating voltages than is conventional in scanning electron microscopy, we image the electron beam-induced luminescence of the films and statistically characterize the depth-dependent role of defects that promote nonradiative recombination losses. The highest variability in the luminescence intensity is observed at the exposed grain surfaces, which we attribute to surface defects. By probing deeper into the film, it appears that bulk defects are more homogeneously distributed. By identifying the origin and variability of a surface-specific loss mechanism that deleteriously impacts device efficiency, we suggest that producing films homogeneously composed of the highest-luminescence grains found in this study could result in a dramatic improvement of overall device efficiency. We also show that although cathodoluminescence microscopy is generally used only to image inorganic materials it can be a powerful tool to investigate radiative and nonradiative charge carrier recombination on the nanoscale in organic-inorganic hybrid materials. PMID- 26098221 TI - From global proteome profiling to single targeted molecules of follicular fluid and oocyte: contribution to embryo development and IVF outcome. AB - The development of in vitro fertilization (IVF) techniques for infertility management has led to the investigation of the proteome of follicular fluid and oocyte. In addition, different markers contributing to oocyte maturation and embryo development potential have been reported in the literature. Different techniques were utilized to analyze whole proteome or single protein markers in follicular fluid and oocytes, particularly in animal models. Data from several studies have generated large amounts of information, however, an ideal profile to predict the best oocytes and embryos suitable for implantation are still to be uncovered. The identification of such profiles and markers from follicular fluid, oocytes and endometrium should help scientists and clinicians develop better strategies to improving clinical outcome of IVF cycles. PMID- 26098222 TI - Conditional knockout of Nlgn2 in the adult medial prefrontal cortex (mPFC) induces delayed loss of inhibitory synapses. PMID- 26098223 TI - Advances in colloidal assembly: the design of structure and hierarchy in two and three dimensions. PMID- 26098224 TI - 3D Coincidence Imaging Disentangles Intense Field Double Detachment of SF6(-). AB - The efficient intense field double detachment of molecular anions observed in SF6(-) is studied by 3D coincidence imaging of the dissociation products. The dissociation anisotropy and kinetic energy release distributions are determined for the energetically lowest double detachment channel by virtue of disentangling the SF5(+) + F fragmentation products. The observed nearly isotropic dissociation with respect to the linear laser polarization and surprisingly high kinetic energy release events suggest that the dissociation occurs on a highly excited state. Rydberg (SF6(+))* states composed of a highly repulsive dication core and a Rydberg electron are proposed to explain the observed kinetic energy release, accounting also for the efficient production of all possible cationic fragments at equivalent laser intensities. PMID- 26098225 TI - Peptide-modified Substrate for Modulating Gland Tissue Growth and Morphology In Vitro. AB - In vitro fabricated biological tissue would be a valuable tool to screen newly synthesized drugs or understand the tissue development process. Several studies have attempted to fabricate biological tissue in vitro. However, controlling the growth and morphology of the fabricated tissue remains a challenge. Therefore, new techniques are required to modulate tissue growth. RGD (arginine-glycine aspartic acid), which is an integrin-binding domain of fibronectin, has been found to enhance cell adhesion and survival; it has been used to modify substrates for in vitro cell culture studies or used as tissue engineering scaffolds. In addition, this study shows novel functions of the RGD peptide, which enhances tissue growth and modulates tissue morphology in vitro. When an isolated submandibular gland (SMG) was cultured on an RGD-modified alginate hydrogel sheet, SMG growth including bud expansion and cleft formation was dramatically enhanced. Furthermore, we prepared small RGD-modified alginate beads and placed them on the growing SMG tissue. These RGD-modified beads successfully induced cleft formation at the bead position, guiding the desired SMG morphology. Thus, this RGD-modified material might be a promising tool to modulate tissue growth and morphology in vitro for biological tissue fabrication. PMID- 26098226 TI - A pH-independent DNA nanodevice for quantifying chloride transport in organelles of living cells. AB - The concentration of chloride ions in the cytoplasm and subcellular organelles of living cells spans a wide range (5-130 mM), and is tightly regulated by intracellular chloride channels or transporters. Chloride-sensitive protein reporters have been used to study the role of these chloride regulators, but they are limited to a small range of chloride concentrations and are pH-sensitive. Here, we show that a DNA nanodevice can precisely measure the activity and location of subcellular chloride channels and transporters in living cells in a pH-independent manner. The DNA nanodevice, called Clensor, is composed of sensing, normalizing and targeting modules, and is designed to localize within organelles along the endolysosomal pathway. It allows fluorescent, ratiometric sensing of chloride ions across the entire physiological regime. We used Clensor to quantitate the resting chloride concentration in the lumen of acidic organelles in Drosophila melanogaster. We showed that lumenal lysosomal chloride, which is implicated in various lysosomal storage diseases, is regulated by the intracellular chloride transporter DmClC-b. PMID- 26098227 TI - Symmetry and scale orient Min protein patterns in shaped bacterial sculptures. AB - The boundary of a cell defines the shape and scale of its subcellular organization. However, the effects of the cell's spatial boundaries as well as the geometry sensing and scale adaptation of intracellular molecular networks remain largely unexplored. Here, we show that living bacterial cells can be 'sculpted' into defined shapes, such as squares and rectangles, which are used to explore the spatial adaptation of Min proteins that oscillate pole-to-pole in rod shaped Escherichia coli to assist cell division. In a wide geometric parameter space, ranging from 2 * 1 * 1 to 11 * 6 * 1 MUm(3), Min proteins exhibit versatile oscillation patterns, sustaining rotational, longitudinal, diagonal, stripe and even transversal modes. These patterns are found to directly capture the symmetry and scale of the cell boundary, and the Min concentration gradients scale with the cell size within a characteristic length range of 3-6 MUm. Numerical simulations reveal that local microscopic Turing kinetics of Min proteins can yield global symmetry selection, gradient scaling and an adaptive range, when and only when facilitated by the three-dimensional confinement of the cell boundary. These findings cannot be explained by previous geometry-sensing models based on the longest distance, membrane area or curvature, and reveal that spatial boundaries can facilitate simple molecular interactions to result in far more versatile functions than previously understood. PMID- 26098228 TI - Graphene on hexagonal boron nitride as a tunable hyperbolic metamaterial. AB - Hexagonal boron nitride (h-BN) is a natural hyperbolic material, in which the dielectric constants are the same in the basal plane (epsilon(t) = epsilon(x) = epsilon(y)) but have opposite signs (epsilon(t)epsilon(z) < 0) in the normal plane (epsilon(z)). Owing to this property, finite-thickness slabs of h-BN act as multimode waveguides for the propagation of hyperbolic phonon polaritons- collective modes that originate from the coupling between photons and electric dipoles in phonons. However, control of these hyperbolic phonon polaritons modes has remained challenging, mostly because their electrodynamic properties are dictated by the crystal lattice of h-BN. Here we show, by direct nano-infrared imaging, that these hyperbolic polaritons can be effectively modulated in a van der Waals heterostructure composed of monolayer graphene on h-BN. Tunability originates from the hybridization of surface plasmon polaritons in graphene with hyperbolic phonon polaritons in h-BN, so that the eigenmodes of the graphene/h-BN heterostructure are hyperbolic plasmon-phonon polaritons. The hyperbolic plasmon phonon polaritons in graphene/h-BN suffer little from ohmic losses, making their propagation length 1.5-2.0 times greater than that of hyperbolic phonon polaritons in h-BN. The hyperbolic plasmon-phonon polaritons possess the combined virtues of surface plasmon polaritons in graphene and hyperbolic phonon polaritons in h-BN. Therefore, graphene/h-BN can be classified as an electromagnetic metamaterial as the resulting properties of these devices are not present in its constituent elements alone. PMID- 26098229 TI - Overcoming recalcitrance - Auxin response factor functions in plant regeneration. AB - De novo meristem formation in tissue culture critically depends on the correct organization of hormonal domains, which is followed by expression shoot meristem pattern genes. The genetic basis of plant regeneration is fragmentary, but mutant studies demonstrate that signaling through MONOPTEROS (MP)/AUXIN RESPONSE FACTOR 5 is necessary for the formation of shoots from Arabidopsis calli. Most strikingly, variants of MP, uncoupling MP activity from negative regulation by Aux/IAA proteins, showed that MP is also sufficient for promoting de novo shoot formation even from normally recalcitrant tissues. In this function MP acts through pathways involving the homeobox transcription factor SHOOT MERISTEMLESS (STM) and AP2 domain transcription factor CYTOKININ RESPONSE FACTOR2 (CRF2). Our findings provide an entry point to better address the molecular genetics underlying divergent regeneration properties and demonstrate the potential of ARF derived constructs as novel genetic tools to develop high frequency regeneration systems in recalcitrant explants and species. PMID- 26098230 TI - A role of nucleus accumbens dopamine receptors in the nucleus accumbens core, but not shell, in fear prediction error. AB - Two experiments used an associative blocking design to study the role of dopamine receptors in the nucleus accumbens shell (AcbSh) and core (AcbC) in fear prediction error. Rats in the experimental groups were trained to a visual fear conditioned stimulus (conditional stimulus [CS]) A in Stage I, whereas rats in the control groups were not. In Stage II, all rats received compound fear conditioning of the visual CSA and an auditory CSB. Rats were later tested for their fear responses to CSB. All rats received microinjections of saline or the D1-D2 receptor antagonist cis-(z)-flupenthixol prior to Stage II. These microinjections targeted either the AcbSh (Experiment 1) or the AcbC (Experiment 2). In each experiment, Stage I fear conditioning of CSA blocked fear learning to CSB. Microinjection of cis-(z)-flupenthixol (10 or 20 MUg) into the AcbSh (Experiment 1) had no effect on fear learning or associative blocking. In contrast, microinjection of cis-(z)-flupenthixol (10 or 20 MUg) into the AcbC (Experiment 2) attenuated blocking and so enabled fear learning to CSB. These results identify the AcbC as the critical locus for dopamine receptor contributions to fear prediction error and the associative blocking of fear learning. PMID- 26098231 TI - A developmental examination of the psychometric properties and predictive utility of a revised psychological self-concept measure for preschool-age children. AB - Accurate assessment of psychological self-concept in early childhood relies on the development of psychometrically sound instruments. From a developmental perspective, the current study revised an existing measure of young children's psychological self-concepts, the Child Self-View Questionnaire (CSVQ; Eder, 1990), and examined its psychometric properties using a sample of preschool-age children assessed at approximately 4 years old with a follow-up at age 5 (N = 111). The item compositions of lower order dimensions were revised, leading to improved internal consistency. Factor analysis revealed 3 latent psychological self-concept factors (i.e., sociability, control, and assurance) from the lower order dimensions. Measurement invariance by gender was supported for sociability and assurance, not for control. Test-retest reliability was supported by stability of the psychological self-concept measurement model during the preschool years, although some evidence of increasing differentiation was obtained. Validity of children's scores on the 3 latent psychological self concept factors was tested by investigating their concurrent associations with teacher-reported behavioral adjustment on the Social Competence and Behavior Evaluation Scale-Short Form (SCBE-SF; LaFreniere & Dumas, 1996). Children who perceived themselves as higher in sociability at 5 years old displayed less internalizing behavior and more social competence; boys who perceived themselves as higher in control at age 4 exhibited lower externalizing behavior; children higher in assurance had greater social competence at age 4, but displayed more externalizing behavior at age 5. Implications relevant to the utility of the revised psychological self-concept measure are discussed. (PsycINFO Database Record PMID- 26098232 TI - Intraoperative nerve monitoring in thyroid surgery. AB - BACKGROUND: Nerve injury is one of the specific complications of thyroid surgery despite many advances in surgical technique. The recurrent laryngeal nerve (RLN) and the external branch of superior laryngeal nerve are the nerves at risk during thyroid surgery (1). Morbidity related to recurrent laryngeal nerve injury varies from changes in voice quality to severe dyspnea requiring tracheal intubation or tracheostomy. To minimize the risk of nerve injury, intraoperative nerve monitoring (IONM) being suggested as a tool for helping visual control for RLN has gained significant interest in recent years (1,2). We aimed to determine the effectiveness of nerve monitoring during thyroid surgery and to provide a clinical experience. MATERIALS AND METHODS: This study was performed from June 2010 to June 2012. We prospectively evaluated 94 patients who had thyroid surgery with or without nerve monitoring. Of those patients 48 were in monitored group (M) and 46 were in unmonitored group (UM). RESULTS: The mean age was 48 (27-76) in M group and 52 (73-17) in UM. There was only one patient had transient hoarseness in M group and also one patient had transient hoarseness in UM group. One each in both groups had persistent hoarseness. No patients experienced airway problem. Operation time was significantly shorter in M group (p<0.001). CONCLUSIONS: Use of a nerve monitoring system does not substitute for careful dissection and visual identification of nerves, but monitoring can assist the surgeon in identifying the RLN anatomic variability and may decrease the operation time during thyroid surgery. PMID- 26098233 TI - Study of the Reactivity of [Hydroxy(tosyloxy)iodo]benzene Toward Enol Esters to Access alpha-Tosyloxy Ketones. AB - The reactivity of enol esters toward [hydroxy(tosyloxy)iodo]benzene (HTIB) was assessed. These substrates were found to be rapidly converted in high yields to their corresponding alpha-tosyloxy ketones. This transformation demonstrates that these substrates can act as ketone surrogates. The scope of the method was investigated and aromatic, aliphatic, and cyclic enol esters were found to be suitable substrates for the reaction. The relative reactivity of a model substrate toward HTIB and m-CPBA was investigated, and it was found that the reaction could be performed under catalytic conditions. PMID- 26098234 TI - [Emergency service - an emergency?]. PMID- 26098235 TI - [CME. Hypertension in pregnancy]. PMID- 26098237 TI - [Abnormal Early Pregnancy: What Matters for Practice]. AB - The first trim ester is referred to as early pregnancy and comprehends the lapse of time between conception and the end of the 12th week of gestation with embryo nic implantation and organogenesis. A pathological early gestation takes place when the embryo does not correctly implant in the cavity of the uterus (extrauterine pregnancy), when th ere is no growth of the embryo (missed abortion) or the embryo is not developing at all (blighted ovum) and sooner or later there is a miscarriage. A special case of missed abortion is the so called vanishing twin, when during a twin gestation, one embryo stops to grow. Rarely gestational trophoblastic disorders as the complete mole (without fetal tissue) or incomplete mole (with fetal tissue) and the invasive mole as villous trophoblastic diseases as well as the non-villous trophoblastic diseases with the extremely rare chorioniccarcinoma are detected. PMID- 26098238 TI - [Medications in Emergency Medicine - an Update]. AB - Every doctor, whether responsible for a hospital or a clinic, should have a solid foundation in the care of the emergent patient. Nearly all specialties require some medications to be administered by in section - a reanimation or an anaphylactic shock must be correctly treated and promptly, before further help arrives. Medications are an essential onerstone in the care of emerge nices. Varying medications are in demand based on specialty, ED structure, and location in which care is provided. This must be synchronised with the eventual likely emergencies, as well as with personal knowledge and experience of the ED staff. PMID- 26098239 TI - [Diabetic Retinopathy and Neuropathy: New in 2015]. AB - In 2014 interesting new results were published in the field of diabetic microangiopathy: (1) In tensive treatment of type 1 diabetes for a mean of 6,5 years confers a lifelong reduction of the risk of diabetic retinopathy; (2) although the rates of diabetes-related complication have declined since 1990, the burden of disease persists because the prevalence of diabetes tripled during the same time; (3) subjects with diabetic neuropathy have structural brain changes, i.e. gray matter loss, findings with possible implications for the prognosis; (4) over 80% of type 2 diabetics who consider their feet to be normal have serious foot pathology. PMID- 26098240 TI - [Jaundice after Herbage Walking Tour of a 44 Year Old Man]. AB - We report about a 44-year old patient with severe acute hepatitis E after herbage walking-to ur. Transmission occurred with ingestion of contaminated herbs. Symptoms were jaundice, dark urine, rheumatic pains and distinctive fatigue. We could document a benign self-limiting course under regular clinical controls. Hepatitis Eisa worldwide common cause for acute hepatitis with jaundice. In Switzerland contamination of this autochthonic infection is aquired by consumption of pork and venison (seroprevalence up to 22%). Infection can be without symptoms but also can result in acute liver failure. Extrahepatic symptoms are not uncommon. PMID- 26098241 TI - ["When to test for and treat H. pylori"]. PMID- 26098242 TI - [Backache in elderly patients - delay imaging?]. PMID- 26098243 TI - [Clindamycin vs. trimethoprim-sulfamethoxazole: equally effective in skin infections]. PMID- 26098245 TI - [CME ultrasound diagnosis. Palpable finding in the thigh]. PMID- 26098247 TI - [Personalities in medical history. Pierre Paul Broca]. PMID- 26098248 TI - Considerations When Disseminating American-Developed, Evidence-Based Health Promotion Programs in China. PMID- 26098250 TI - T1, T2 Mapping and Extracellular Volume Fraction (ECV): Application, Value and Further Perspectives in Myocardial Inflammation and Cardiomyopathies. AB - Cardiac magnetic resonance imaging (CMRI) is a versatile diagnostic tool. One of its main advantages is the possibility of tissue characterization. T1-weighted images for scar and T2-weighted images for edema visualization are key methods for tissue characterization. Otherwise these sequences are strongly limited for the detection of diffuse myocardial pathologies. Recently, rapid technical innovations have generated new techniques. T1, T2 mapping and evaluation of the extracellular volume fraction (ECV) allow quantification of diffuse myocardial pathologies and showed great potential in the visualization of fibrosis, edema, amyloid, iron overload and lipid. In the future these techniques might enable the detection of early cardiac involvement, even act as a prognosticator. Moreover, therapy monitoring and follow-up might be possible due to versatile parameter quantification with these new techniques. KEY POINTS: CMR allows for tissue characterization via T1- and T2-weighted sequences. In cases of diffuse, global myocardial pathologies, correct image interpretation with traditional CMR sequences might be difficult. T1, T2 mapping and ECV can quantify diffuse, global myocardial pathologies. Alterations of myocardial T1 and T2 relaxation times occur in various myocardial diseases (e.g. acute myocarditis). In the future mapping might act as a prognosticator or therapy monitoring tool. PMID- 26098251 TI - [Persistent mesenteric panniculitis after cholecystectomy in chronic cholecystitis]. PMID- 26098252 TI - Comparison of Cine-MRI and Transthoracic Echocardiography for the Assessment of Aortic Root Diameters in Patients with Suspected Marfan Syndrome. AB - PURPOSE: Patients with Marfan syndrome require repeated imaging for monitoring of aortic root aneurysms. Therefore, we evaluated the agreement and reproducibility of cine-MRI and echocardiography measurements of the sinuses of Valsalva in patients with suspected Marfan syndrome. MATERIALS AND METHODS: 51 consecutive patients with suspected Marfan syndrome were prospectively examined using cine MRI and echocardiography. Two readers independently measured aortic root diameters at the level of the sinuses of Valsalva in both cine-MRI and echocardiography. Statistics included intraclass correlation coefficient, Pearson correlation coefficient, Bland-Altman analysis, and two-sided t-test. RESULTS: In 38 of the 51 individuals (74.5 %), the diagnosis of Marfan syndrome was established according to the criteria of the Ghent-2 nosology. Cine-MRI measurements of the sinuses of Valsalva revealed a strong correlation with echocardiography (r = 0.929), but a statistically significant bias of -1.0 mm (p < 0.001). The mean absolute diameter for sinuses of Valsalva obtained by cine-MRI was 32.3 +/- 5.8 mm as compared to 33.4 +/- 5.4 mm obtained by echocardiography. Interobserver agreement of measurements of the sinuses of Valsalva was higher for cine-MRI than for echocardiography (p = 0.029). CONCLUSION: Despite small, but statistically significant differences in terms of agreement and reproducibility, cine-MRI and echocardiographic measurements of aortic root diameters provide comparable results without a significant clinical difference. Therefore both techniques may be used for monitoring of the aortic root in patients with Marfan syndrome. PMID- 26098253 TI - A Conceptual Model of Irritability Following Traumatic Brain Injury: A Qualitative, Participatory Research Study. AB - BACKGROUND: Individuals with a history of traumatic brain injury (TBI) may have chronic problems with irritability, which can negatively affect their lives. OBJECTIVES: (1) To describe the experience (thoughts and feelings) of irritability from the perspectives of multiple people living with or affected by the problem, and (2) to develop a conceptual model of irritability. DESIGN: Qualitative, participatory research. PARTICIPANTS: Forty-four stakeholders (individuals with a history of TBI, family members, community professionals, healthcare providers, and researchers) divided into 5 focus groups. PROCEDURES: Each group met 10 times to discuss the experience of irritability following TBI. Data were coded using grounded theory to develop themes, metacodes, and theories. MEASURES: Not applicable. RESULTS: A conceptual model emerged in which irritability has 5 dimensions: affective (related to moods and feelings); behavioral (especially in areas of self-regulation, impulse control, and time management); cognitive-perceptual (self-talk and ways of seeing the world); relational issues (interpersonal and family dynamics); and environmental (including environmental stimuli, change, disruptions in routine, and cultural expectations). CONCLUSIONS: This multidimensional model provides a framework for assessment, treatment, and future research aimed at better understanding irritability, as well as the development of assessment tools and treatment interventions. PMID- 26098254 TI - Cerebral Blood Flow During Treadmill Exercise Is a Marker of Physiological Postconcussion Syndrome in Female Athletes. AB - OBJECTIVE: Some patients with postconcussion syndrome (PCS) have reduced exercise capacity that may reflect altered central cardiorespiratory control. The purpose of this study was to evaluate control of cerebral blood flow (CBF) during exercise in females with PCS. SETTING: University Concussion Clinic. PARTICIPANTS: Nine female Division 1 collegiate team athletes with PCS (23 +/- 6 years) and a reference group of 13 healthy female recreational aerobic athletes (21 +/- 3 years). DESIGN: A prospective experimental study. All PCS athletes were compared with the reference group at the beginning of the study. Six of the PCS athletes were subsequently measured before and after a subsymptom threshold aerobic exercise treatment program. MAIN MEASURES: Exercise treadmill test during which blood pressure (BP), minute ventilation ((Equation is included in full-text article.)E), end-tidal CO2 (PETCO2), and CBF velocity (CBFV, by transcranial Doppler) were measured. RESULTS: Participants with PCS had significantly lower (Equation is included in full-text article.)E (by 18%) and greater PETCO2 (5%) and CBFV (14%) versus the reference group at similar workloads in association with appearance of symptoms and premature exercise cessation. Subthreshold exercise normalized (Equation is included in full-text article.)E, PETCO2, CBFV and exercise tolerance. Before treatment, PCS had low CO2 sensitivity that blunted their exercise ventilation. CO2 sensitivity and ventilation improved after exercise treatment. CONCLUSION: Some PCS patients have exercise intolerance due to abnormal CBF regulation that may be the result of concussion-induced altered sensitivity to CO2. Return of normal CBF control and exercise tolerance may be physiological markers of recovery from concussion. PMID- 26098255 TI - A Case-control Study Examining the Characteristics of Patients who Fall in an Inpatient Traumatic Brain Injury Rehabilitation Setting. AB - OBJECTIVE: The purpose of the study was to describe the characteristics of patients who fall in the inpatient traumatic brain injury (TBI) rehabilitation setting. SETTING: Specialized inpatient TBI rehabilitation unit. PARTICIPANTS: Fifty-four patients with history of falls and 55 nonequivalent patients without history of falls. DESIGN: Retrospective nonequivalent case-control study. MAIN MEASURES: The Functional Independence Measure, Glasgow Coma Scale, Westmead Post traumatic Amnesia Scale, demographic and functional characteristics, and behavior and medication variables. RESULTS: No significant difference between patients with and without history of falls for age, sex, medication class or total number of medications administered on admission, and median admission Westmead Post traumatic Amnesia Scale score was observed. Patients with history of falls had a significantly longer duration of post-traumatic amnesia, rehabilitation length of stay, and lower mean total admission Functional Independence Measure score and median Glasgow Coma Scale score at the time of injury. Patients with history of falls were more than 10 times more likely than patients without history of falls to require assistance on admission for activities of daily living, transfers, and continence/toileting. Neurobehaviors including noncompliance and anosognosia were significantly associated with patients with history of falls. CONCLUSIONS: A patient in the rehabilitation setting with a more severe TBI characterized by multisystem impairments is at an increased risk of falling, whereas some traditional fall risk factors were not associated with patients who fall. Rehabilitation settings should consider cohort-specific fall risk profiling. The Ontario STRATIFY Falls Risk Screening Tool is perhaps not the best tool to screen for falls in this inpatient population. PMID- 26098256 TI - Use of Visual Cues by Adults With Traumatic Brain Injuries to Interpret Explicit and Inferential Information. AB - OBJECTIVE: Concomitant visual and cognitive impairments following traumatic brain injuries (TBIs) may be problematic when the visual modality serves as a primary source for receiving information. Further difficulties comprehending visual information may occur when interpretation requires processing inferential rather than explicit content. The purpose of this study was to compare the accuracy with which people with and without severe TBI interpreted information in contextually rich drawings. PARTICIPANTS: Fifteen adults with and 15 adults without severe TBI. DESIGN: Repeated-measures between-groups design. MAIN MEASURES: Participants were asked to match images to sentences that either conveyed explicit (ie, main action or background) or inferential (ie, physical or mental inference) information. The researchers compared accuracy between participant groups and among stimulus conditions. RESULTS: Participants with TBI demonstrated significantly poorer accuracy than participants without TBI extracting information from images. In addition, participants with TBI demonstrated significantly higher response accuracy when interpreting explicit rather than inferential information; however, no significant difference emerged between sentences referencing main action versus background information or sentences providing physical versus mental inference information for this participant group. CONCLUSIONS: Difficulties gaining information from visual environmental cues may arise for people with TBI given their difficulties interpreting inferential content presented through the visual modality. PMID- 26098257 TI - Loss to Follow-Up and Social Background in an Inception Cohort of Patients With Severe Traumatic Brain Injury: Results From the PariS-TBI Study. AB - OBJECTIVES: To assess determinants of loss to follow-up (FU) at 2 time points of an inception traumatic brain injury (TBI) cohort. DESIGN AND PARTICIPANTS: The PariS-TBI study consecutively included 504 adults with severe TBI on the accident scene (76% male, mean age 42 years, mean Glasgow Coma Scale 5). No exclusion criteria were used. MAIN MEASURE: Loss to FU at 1 and 4 years was defined among survivors as having no outcome data other than survival status. RESULTS: Among 257 1-year survivors, 118 (47%) were lost to FU at 1 year and 98 (40%) at 4 years. Main reasons for loss to FU were impossibility to achieve contact (109 at 1 year, 52 at 4 years) and refusal to participate (respectively 5 and 24). At 1 year, individuals not working preinjury or with nonaccidental traumas were more often lost to FU in univariate and multivariable analyses. At 4 years, loss to FU was significantly associated with preinjury alcohol abuse and unemployment. Relationship with injury severity was not significant. CONCLUSIONS: Socially disadvantaged persons are underrepresented in TBI outcome research. It could result in overestimation of outcome and biased estimates of sociodemographic characteristics' effects. These persons, particularly unemployed individuals, require special attention in clinical practice. PMID- 26098259 TI - Association of Chronic Pain and Community Integration of Returning Veterans With and Without Traumatic Brain Injury. AB - OBJECTIVE: To evaluate the association between community integration and pain in veterans with and without mild blast-related traumatic brain injury (TBI). DESIGN AND PARTICIPANTS: A cross-sectional study of 198 Operation Enduring Freedom/Operation Iraqi Freedom veterans, 135 with mild TBI and 63 without TBI exposure. MAIN MEASURES: Community Integration Questionnaire (CIQ), Community Reintegration of Injured Service Members Instrument, Brief Pain Inventory. RESULTS: Pain interference was significantly associated with CIQ social integration (P = .037), and pain severity was significantly associated with CIQ home integration (P = .038) and CIQ social integration (P = .044). Pain interference and pain severity had a significant interaction as related to the CIQ total score (P = .046), CIQ job score (P = .034), and CIQ productivity score (P = .034). Pain interference (P = .042) and pain severity (P = .015) were associated with community participation, but not perceived limitations (P > .05) or satisfaction (P > .05) as measures by the Community Reintegration of Injured Service Members Instrument. There was a significant interaction between TBI status and pain severity (P = .021) with community participation. CONCLUSIONS: Chronic pain has a negative association with the community integration of returning veterans. Although TBI status was associated with overall community integration ratings, depression had a stronger association with impairments. These findings suggest, above and beyond the treatment of depression, the importance of effectively managing TBI-related pain to foster improved social functioning and to promote the psychological and social well-being of returning veterans. PMID- 26098258 TI - Association Between Traumatic Brain Injury-Related Brain Lesions and Long-term Caregiver Burden. AB - OBJECTIVE: To investigate the association between traumatic brain injury (TBI) related brain lesions and long-term caregiver burden in relation to dysexecutive syndrome. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: A total of 256 participants: 105 combat veterans with TBI, 23 healthy control combat veterans (HCv), and 128 caregivers. OUTCOME MEASURE: Caregiver burden assessed by the Zarit Burden Interview at 40 years postinjury. DESIGN: Participants with penetrating TBI were compared with HCv on perceived caregiver burden and neuropsychological assessment measures. Data of computed tomographic scans (overlay lesion maps of participants with a penetrating TBI whose caregivers have a significantly high burden) and behavioral statistical analyses were combined to identify brain lesions associated with caregiver burden. RESULTS: Burden was greater in caregivers of veterans with TBI than in caregivers of HCv. Caregivers of participants with lesions affecting cognitive and behavioral indicators of dysexecutive syndrome (ie, left dorsolateral prefrontal cortex and dorsal anterior cingulate cortex) showed greater long-term burden than caregivers of participants with lesions elsewhere in the brain. CONCLUSION AND IMPLICATION: The TBI-related brain lesions have a lasting effect on long-term caregiver burden due to cognitive and behavioral factors associated with dysexecutive syndrome. PMID- 26098260 TI - Comparing Prospectively Recorded Posttraumatic Amnesia Duration With Retrospective Accounts. AB - OBJECTIVE: Limited research has been conducted comparing different methods for determining the duration of posttraumatic amnesia (PTA). This study compared prospectively recorded PTA duration (P-PTA) with retrospective reports of the return of continuous memory (R-PTA). PARTICIPANTS: Fifty-nine individuals admitted to a head injury rehabilitation unit with a traumatic brain injury who had their PTA duration recorded using the Westmead Post-Traumatic Amnesia Scale. Participants were between 6 months and 6 years postinjury at the time of study. MEASURES: P-PTA was determined on the basis of Westmead Post-Traumatic Amnesia Scale responses. R-PTA was ascertained using a semistructured telephone interview. RESULTS: Although the PTA measures were significantly positively correlated (r = 0.76), mean R-PTA was significantly longer than mean P-PTA. In 34 cases (57.6%), R-PTA was longer than P-PTA (13 participants moved to a higher injury severity band), and in 22 cases (37.3%), R-PTA was shorter than P-PTA (8 participants moved to a lower injury severity band). The difference between P-PTA and R-PTA was not significantly associated with age, Glasgow Coma Scale score, overall PTA duration, or the number of days postinjury of the retrospective interview. CONCLUSIONS: Prospective and retrospective estimates of PTA duration were not comparable within the present sample. Further research comparing the two methods is needed. PMID- 26098261 TI - Military Deployment May Increase the Risk for Traumatic Brain Injury Following Deployment. AB - OBJECTIVE: To compare rates of traumatic brain injury (TBI) diagnosis before and after overseas military deployment. DESIGN: We conducted a retrospective examination of a cohort of 119 353 active duty US military service members (Army, Navy, Air Force, and Marines) whose first lifetime overseas deployment began at any time between January 1, 2011, and December 31, 2011, and lasted at least for 30 days. For this cohort, TBI diagnoses were examined during the 76 weeks prior to deployment, during deployment, and 76 weeks following the end of deployment. MAIN MEASURES: 4-week rates of TBI diagnosis. RESULTS: The risk of being diagnosed with TBI within 4 weeks after returning from deployment was 8.4 times higher than the average risk before deployment. The risk gradually decreased thereafter up to 40 weeks postdeployment. However, during the 41 to 76 weeks following deployment, risk stabilized but remained on average 1.7 times higher than before deployment. CONCLUSION: An increased rate of TBI diagnosis following deployment was identified, which may be partly due to delayed diagnosis of TBIs that occurred while service members were deployed. Also, the increased rate may partly be due to riskier behaviors of service members following deployment that results in an increased occurrence of TBIs. PMID- 26098262 TI - The Impact of Traumatic Brain Injury on Self-Identity: A Systematic Review of the Evidence for Self-Concept Changes. AB - OBJECTIVES: This review systematically appraised the evidence for changes to self identity after traumatic brain injury (TBI) in adults and investigated associations between self-concept changes and neurocognitive and psychosocial functioning. METHODS: Systematic searches of 4 databases (PsycINFO, PubMed, CINAHL, and Cochrane Systematic Review Database) were undertaken from January 1983 to July 2014. Empirical studies were included if they used a quantitative measure of pre-/postinjury changes in self-concept after TBI or compared levels of self-concept between TBI and control participants. RESULTS: Fifteen studies met the review criteria and, despite methodological differences, provided mostly evidence of negative changes to self-concept. However, stability in self-concept and positive changes to sense of self were also reported in some studies. Furthermore, levels of self-esteem and personality characteristics did not significantly differ between participants with TBI and orthopedic/trauma controls. Negative self-concept changes were associated with emotional distress in 3 studies. CONCLUSIONS: People with TBI most commonly experience negative changes in self-identity; however, such changes are also reported after other traumatic events or injuries. Greater consistency in measurement of self-identity change and use of longitudinal designs is recommended to improve understanding of factors contributing to self-concept changes after TBI and to guide clinical interventions. PMID- 26098263 TI - Time to Follow Commands and Duration of Posttraumatic Amnesia Predict GOS-E Peds Scores 1 to 2 Years After TBI in Children Requiring Inpatient Rehabilitation. AB - OBJECTIVE: To evaluate the utility of time to follow commands (TFC) in predicting functional outcome after pediatric traumatic brain injury (TBI), as assessed by an outcome measure sensitive to the range of outcomes observed after pediatric TBI, the Glasgow Outcome Scale-Extended, Pediatric Revision (GOS-E Peds). SETTING: Pediatric inpatient rehabilitation hospital and associated multidisciplinary brain injury follow-up clinic. PARTICIPANTS: Sixty-seven children with moderate-to-severe TBI (mean age at injury = 10.9 years; range, 3 18 years). DESIGN: Outcomes were scored retrospectively on the basis of documentation from an outpatient follow-up evaluation 1 to 2 years postinjury (days from injury to follow-up: mean = 518, SD = 137). Correlations between measures of severity and functional outcome were examined. Hierarchical logistic and linear regression analyses were performed to examine predictors of outcome. MAIN MEASURES: Earliest documented Glasgow Coma Scale (GCS), TFC, posttraumatic amnesia (PTA), total duration of impaired consciousness (TFC + PTA), and GOS-E Peds. RESULTS: For the logistic regression, TFC and TFC + PTA were significant predictors of outcome above and beyond GCS. For the linear analysis, PTA was also a significant predictor of functional outcome above and beyond GCS and TFC. The overall models were very comparable, with R values ranging from 0.31 to 0.36 for prediction of GOS-E Peds scores. CONCLUSION: Above and beyond the influence of GCS, TFC, PTA, and TFC + PTA are important predictors of later outcome after TBI. PMID- 26098264 TI - Comparing the Injury Profile, Service Use, Outcomes, and Comorbidities of People With Severe TBI Across Urban, Regional, and Remote Populations in New South Wales: A Multicentre Study. AB - OBJECTIVE: To compare the demographic/injury profile, outcomes, service utilization, and unmet service needs of individuals with severe traumatic brain injury across urban, regional, and remote areas of New South Wales. SETTING: The 11 community-based rehabilitation teams of the New South Wales Brain Injury Rehabilitation Program. PARTICIPANTS: Active clients (N = 503) with severe traumatic brain injury. DESIGN: A prospective cross-sectional multicenter study. MAIN MEASURES: Overt Behaviour Scale, Health of the Nation Outcome Scale-Acquired Brain Injury, Disability Rating Scale, Sydney Psychosocial Reintegration Scale-2, Care and Needs Scale, data protocol on service utilization, and unmet needs. RESULTS: There were no differences in injury severity or functional outcomes across the 3 locations. However, clients in regional and remote areas had significantly higher levels of premorbid and postinjury comorbidities and lower levels of participation in comparison to urban clients. Although accessing the same number of services as their urban counterparts, clients in regional and remote areas had significantly higher levels of unmet needs suggesting problems with under-servicing. CONCLUSIONS: Geographical location had a significant impact on service access and outcomes. PMID- 26098265 TI - Cloth-Based Power Shirt for Wearable Energy Harvesting and Clothes Ornamentation. AB - Harvesting ambient mechanical energy from human body motion has attracted great research interest. In this work, a power shirt based on triboelectrification and the electrostatic induction effect between fluorinated ethylene propylene (FEP) and external objects is demonstrated. This power shirt can effectively convert the ambient mechanical energy into electric power, and the working mechanism is systematically discussed. A maximum short-circuit current density of ~0.37 MUA/cm2 and a maximum peak power density of ~4.65 MUW/cm2 were achieved. Simultaneously, 11 blue LEDs were lit by sliding the sleeve and power shirt, indicating the potential application of the power shirt in clothes ornamentation and risk warning. This study develops an efficient path for harvesting human body energy and promoting the development of wearable electronics and smart garments. PMID- 26098266 TI - Two-dimensional iron-phthalocyanine (Fe-Pc) monolayer as a promising single-atom catalyst for oxygen reduction reaction: a computational study. AB - Searching for low-cost non-Pt catalysts for oxygen reduction reaction (ORR) has been a key scientific issue in the development of fuel cells. In this work, the potential of utilizing the experimentally available two-dimensional (2D) Fe phthalocyanine (Fe-Pc) monolayer with precisely-controlled distribution of Fe atoms as a catalyst of ORR was systematically explored by means of comprehensive density functional theory computations. The computations revealed that O2 molecules can be sufficiently activated on the surface of the Fe-Pc monolayer, and the subsequent ORR steps prefer to proceed on the Fe-Pc monolayer through a more efficient 4e pathway with a considerable limiting potential of 0.68 V. Especially, the Fe-Pc monolayer is more stable than the Fe-Pc molecule in acidic medium, and can present good catalytic performance for ORR on the addition of axial ligands. Therefore, the Fe-Pc monolayer is quite a promising single-atom catalyst with high efficiency for ORR in fuel cells. PMID- 26098267 TI - Structural Design Parameters for Highly Birefringent Coordination Polymers. AB - A series of coordination polymer materials incorporating the highly anisotropic 2 (2-pyridyl)-1,10-phenanthroline (phenpy) building block have been synthesized and structurally characterized. M(phenpy)[Au(CN)2]2 (M = Cd, Mn) are isostructural and form a 1-D chain through bridging [Au(CN)2](-) units and extend into a 2-D sheet through aurophilic interactions. M(phenpy)(H2O)[Au(CN)2]2.2H2O (M = Cd, Mn, and Zn) are also isostructural but differ from the first set via the inclusion of a water molecule into the coordination sphere, resulting in a 1-D topology through aurophilic interactions. In(phenpy)(Cl)2[Au(CN)2].0.5H2O forms a dimer through bridging chlorides and contains a free [Au(CN)2](-) unit. In the plane of the primary crystal growth direction, the birefringence values (Deltan) of 0.37(2) (Cd(phenpy)[Au(CN)2]2), 0.50(3) (In(phenpy)(Cl)2[Au(CN)2].0.5H2O), 0.56(3) and 0.59(6) (M(phenpy)(H2O)[Au(CN)2]2.2H2O M = Cd and Zn, respectively) were determined. beta, a structural parameter defined by phenpy units rotated in the A-C plane relative to the light propagation (C) direction, was found to correlate to Deltan magnitudes. The addition of a carbon-carbon double bond to terpy has increased the molecular polarizability anisotropy of the building block, and all structures have reduced deviation from planarity in comparison to terpy and terpy derivative structures, leading to these higher Deltan values, which are among the highest reported for crystalline solids. PMID- 26098271 TI - Self-Efficacy Manipulation Influences Physical Activity Enjoyment in Chinese Adolescents. AB - PURPOSE: In this study, we examined the effect of the manipulation of exercise self-efficacy on the enjoyment of physical activity in a sample of 44 Chinese adolescents (age = 14.27 +/- .87 y), including 22 boys and 22 girls. METHODS: The participants were randomized into a low-efficacy or high-efficacy condition, and their self-efficacy beliefs for engaging in moderate-intensity physical activity were manipulated by providing false feedback after a submaximal exercise test. The participants' self-efficacy was measured and compared before and after the exercise test and the participants' enjoyment of physical activity was assessed after the exercise test. RESULTS: It was found that exercise self-efficacy was successfully manipulated in the expected direction in both conditions, which significantly influenced the participants' enjoyment of physical activity. After the exercise test, the participants in the low-efficacy condition reported lower enjoyment scores relative to the high-efficacy participants. CONCLUSIONS: These results suggest that self-efficacy may have an important influence on the enjoyment of physical activity among Chinese adolescents. We recommend that physical activity promotion programs should be tailored to enhance adolescents' self-efficacy beliefs and enjoyment of the experience of physical activity. PMID- 26098272 TI - Arch-Taping Techniques for Altering Navicular Height and Plantar Pressures During Activity. AB - CONTEXT: Arch tapings have been used to support the arch by increasing navicular height. Few researchers have studied navicular height and plantar pressures after physical activity. OBJECTIVE: To determine if taping techniques effectively support the arch during exercise. DESIGN: Crossover study. SETTING: Athletic training research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-five individuals (13 men, 12 women; age = 20.0 +/- 1.0 years, height = 172.3 +/- 6.6 cm, mass = 70.1 +/- 10.2 kg) with a navicular drop of more than 8 mm (12.9 +/- 3.3 mm) volunteered. INTERVENTION(S): All individuals participated in 3 days of testing, with 1 day for each tape condition: no tape, low dye, and navicular sling. On each testing day, navicular height and plantar pressures were measured at 5 intervals: baseline; posttape; and after 5, 10, and 15 minutes of running. The order of tape condition was counterbalanced. MAIN OUTCOME MEASURE(S): The dependent variables were navicular height in millimeters and plantar pressures in kilopascals. Plantar pressures were divided into 5 regions: medial forefoot, lateral forefoot, lateral midfoot, lateral rearfoot, and medial rearfoot. Separate repeated-measures analyses of variance were conducted for each dependent variable. RESULTS: Navicular height was higher immediately after application of the navicular-sling condition (P = .004) but was reduced after 5 minutes of treadmill running (P = .12). We observed no differences from baseline to posttape for navicular height for the low-dye (P = .30) and no-tape conditions (P = .25). Both the low-dye and navicular-sling conditions increased plantar pressures in the lateral midfoot region compared with the no-tape condition. The low-dye condition created decreased pressure in the medial and lateral forefoot regions compared with the no-tape condition. All changes were identified immediately after application and were maintained during running. No changes were noted in plantar pressures for the no-tape condition (P > .05). CONCLUSIONS: Both taping techniques effectively changed plantar pressures in the lateral midfoot, and these changes were sustained throughout the 15 minutes of exercise. PMID- 26098274 TI - Reply: To PMID 24978430. PMID- 26098273 TI - Subcutaneous and Intramuscular Hemodynamics and Oxygenation After Cold-Spray Application as Monitored by Near-Infrared Spectroscopy. AB - CONTEXT: Vapocoolant spray, commonly known as cold spray (CS), is a cryotherapy modality used in sports medicine, athletic training, and rehabilitation settings. Proposed physiologic effects of cryotherapy modalities include reductions in tissue blood flow, oxygenation, and cell metabolism in addition to attenuation of pain perception attributed to reduced superficial nerve conduction velocity. OBJECTIVE: To examine the effects of CS on subcutaneous and intramuscular blood flow and oxygenation on the thigh muscle using near-infrared spectroscopy, an optical method to monitor changes in tissue oxygenated (O2Hb), deoxygenated (HHb), and total (tHb) hemoglobin. DESIGN: Cross-sectional study. SETTING: Muscle Biophysics Laboratory. PATIENTS OR OTHER PARTICIPANTS: Participants were 13 healthy adults (8 men, 5 women; age = 37.4 +/- 6 years, body mass index = 27.4 +/ 2.6, adipose tissue thickness = 7.2 +/- 1.8 mm). INTERVENTION(S): Conventional CS was applied to the vastus medialis muscles. MAIN OUTCOME MEASURE(S): Changes in chromophore concentrations of O2Hb, HHb, and tHb at superficial and deep layers were monitored for 5 minutes using a 2-channel near-infrared spectroscopy. RESULTS: Thirty seconds after CS application, we observed a decrease from baseline in O2Hb and tHb only in the superficial layer that was maintained for 3 minutes. CONCLUSIONS: Application of CS induced a transient change in blood flow and oxygenation of the superficial tissues with no change in deeper tissues over the healthy vastus medialis muscle. The limited physiologic effect of CS on the superficial hemodynamics and oxygenation of limb muscles may limit the therapeutic benefit of this cryotherapy modality to a temporary analgesic effect, a hypothesis that warrants a clinical trial on traumatized muscles. PMID- 26098275 TI - Re: Changing Trends in the Management of Diabetic Macular Edema at a Single Institution Over the Past Decade. PMID- 26098276 TI - Reply: To PMID 25590856. PMID- 26098277 TI - Re: Impact of Macula-off Retinal Detachment on Visual Outcome, A Systematic Review and Meta-Analysis of Literature. PMID- 26098279 TI - Nature of the interaction between rare gas atoms and transition metal doped silicon clusters: the role of shielding effects. AB - Mass spectrometry experiments show an exceptionally weak bonding between Si7Mn(+) and rare gas atoms as compared to other exohedrally transition metal (TM) doped silicon clusters and other SinMn(+) (n = 5-10) sizes. The Si7Mn(+) cluster does not form Ar complexes and the observed fraction of Xe complexes is low. The interaction of two cluster series, SinMn(+) (n = 6-10) and Si7TM(+) (TM = Cr, Mn, Cu, and Zn), with Ar and Xe is investigated by density functional theory calculations. The cluster-rare gas binding is for all clusters, except Si7Mn(+) and Si7Zn(+), predominantly driven by short-range interaction between the TM dopant and the rare gas atoms. A high s-character electron density on the metal atoms in Si7Mn(+) and Si7Zn(+) shields the polarization toward the rare gas atoms and thereby hinders formation of short-range complexes. Overall, both Ar and Xe complexes are similar except that the larger polarizability of Xe leads to larger binding energies. PMID- 26098278 TI - Reply: To PMID 25121930. PMID- 26098280 TI - Effects of l-Alanyl-l-Glutamine Ingestion on One-Hour Run Performance. AB - OBJECTIVE: To examine the efficacy of l-alanyl-l-glutamine ingestion with a commercially available sports drink compared to the sports drink only on time to exhaustion and physiological measures during prolonged endurance exercise. METHODS: Twelve endurance-trained men (23.5 +/- 3.7 years; 175.5 +/- 5.4 cm; 70.7 +/- 7.6 kg) performed 4 trials, each consisting of a 1-hour treadmill run at 75% VO2peak followed by a run to exhaustion at 90% VO2peak. One trial consisted of no hydration (NHY), another required ingestion of only a sports drink (ED), and 2 trials required ingestion of a low dose (LD; 300 mg.500 ml(-1)) and high dose (HD) of l-alanyl-l-glutamine (1 g.500 ml(-1)) added to the sports drink. During the fluid ingestion trials, 250 ml was consumed every 15 minutes. Plasma glutamine, glucose, electrolytes, and osmolality were measured prior to the run (PRE) and at 30, 45, and 60 minutes. VO2, respiratory quotient (RQ), and heart rate (HR) were measured every 15 minutes. RESULTS: Time to exhaustion was significantly longer during the LD and HD trials compared to NHY. No differences were noted in time to exhaustion between ED and NHY. Plasma glutamine concentrations were significantly elevated at 45 minutes in LD and HD trials and remained elevated at 60 minutes during HD. Sodium concentrations increased from the beginning of exercise and remained stable for the duration of the 1-hour run. At 60 minutes, plasma sodium was significantly lower in all trials compared to NHY. CONCLUSIONS: Results indicated that ingestion of the alanine-glutamine dipeptide at either the low or high dose significantly improved time to exhaustion during high-intensity exercise compared to a no-hydration trial. PMID- 26098281 TI - L-cysteine functionalized magnetic nanoparticles (LCMNP): a novel magnetically separable organocatalyst for one-pot synthesis of 2-amino-4H-chromene-3 carbonitriles in water. AB - In this study, L-cysteine was chemically grafted to magnetic nanoparticles in order to prepare a reusable magnetic material incorporating an amino acid moiety. For this purpose, silica-coated magnetic nanoparticles (Fe3O4@SiO2) were reacted with trimethoxy(vinyl)silane to produce vinyl-functionalized magnetic nanoparticles (VMNP). Reaction of a VMNP substrate with L-cysteine in the presence of azobisisobutyronitrile (AIBN) resulted in the production of L cysteine-functionalized magnetic nanoparticles (LCMNP). The LCMNP material was characterized using different microscopy and spectroscopy techniques such as FT IR, XRD, TEM, SEM, EDX, VSM, and elemental analysis. Also, LCMNP was analyzed by thermogravimetric analysis (TGA) in order to determine its thermal behavior. The applicability of the LCMNP material was evaluated in a three-component coupling reaction between a nucleophile, salicylaldehyde and malononitrile as the catalyst for one-pot synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives. The catalyst system showed high catalytic activity in this process and target products were obtained in high isolated yields in water as a green solvent. The LCMNP catalyst was reusable in this reaction at least 7 times with no significant decrease in its catalytic activity. PMID- 26098282 TI - Kinetics Tuning of Li-Ion Diffusion in Layered Li(NixMnyCoz)O2. AB - Using ab initio calculations combined with experiments, we clarified how the kinetics of Li-ion diffusion can be tuned in LiNixMnyCozO2 (NMC, x + y + z = 1) materials. It is found that Li-ions tend to choose oxygen dumbbell hopping (ODH) at the early stage of charging (delithiation), and tetrahedral site hopping (TSH) begins to dominate when more than 1/3 Li-ions are extracted. In both ODH and TSH, the Li-ions surrounded by nickel (especially with low valence state) are more likely to diffuse with low activation energy and form an advantageous path. The Li slab space, which also contributes to the effective diffusion barriers, is found to be closely associated with the delithiation process (Ni oxidation) and the contents of Ni, Co, and Mn. PMID- 26098283 TI - A Survey of Teenagers' Attitudes Toward Moving Oral Contraceptives Over the Counter. AB - CONTEXT: Evidence suggests that over-the-counter access to oral contraceptives may help expand use among adult women. Teenagers may particularly benefit from this approach, as they experience disproportionately high rates of unintended pregnancy and face unique challenges accessing contraceptives. However, limited research has explored teenagers' attitudes toward over-the-counter access. METHODS: In 2014, a sample of 348 females aged 14-17, recruited via Facebook advertisements, participated in an online survey assessing teenagers' attitudes toward over-the-counter access and their understanding of how to use oral contraceptives after reading a prototype over-the-counter product label. Differences by participants' characteristics were assessed in bivariate analyses (Pearson chi-square and Fisher's exact tests for categorical measures, and independent t tests and one-way analyses of variance for continuous measures). RESULTS: Seventy-three percent of participants supported over-the-counter access, and 61% reported that they would likely use oral contraceptives available through this approach. Few subgroup differences were found. Notably, sexually experienced participants were significantly more likely than others both to support this approach (85% vs. 63%) and to be interested in obtaining oral contraceptives this way (77% vs. 48%). Participants understood an average of 7.1 of eight key concepts that the prototype product label was intended to convey; no significant differences were found among subgroups. CONCLUSIONS: Over-the-counter access may be a promising approach for providing oral contraceptives to teenagers. Additional research is needed to evaluate whether teenagers can screen themselves for contraindications to oral contraceptive use and correctly use oral contraceptives obtained over the counter. PMID- 26098284 TI - Accurate Characterization of Skeletal Lesions in Tuberous Sclerosis Complex Using 99mTc MDP SPECT/CT. AB - We report a 15-year-old patient with tuberous sclerosis complex or Bourneville's disease with history of generalized tonic-clonic seizure for last 2 years and was currently on antiepileptic medication. He also had a history of left nephrectomy for renal cell carcinoma clear cell type. The patient had multiple adenoma sebaceum over the nasolabial region, ash leaf spots over the lower limbs, a Shagreen patch over the back, and multiple calcified tubers in the subependymal region. He was then referred for the skeletal scintigraphy to look for skeletal lesions, which revealed involvement of bilateral humeri, tibiae, and iliac bones accurately characterized on SPECT/CT. PMID- 26098285 TI - Dual Diagnostic Role of 123I-MIBG Scintigraphy in Inverted-Takotsubo Pattern Cardiomyopathy. AB - We highlight the dual role of I-MIBG scintigraphy in inverted-Takotsubo pattern cardiomyopathy, the diagnosis of which is sometimes challenging: Firstly, I-MIBG scintigraphy can show myocardial sympathetic dysfunction (low I-MIBG uptake) in the hypokinetic basal segments, sparing the left ventricle apex. It is helpful in the imaging diagnosis of inverted-Takotsubo pattern cardiomyopathy and confirms that acute dysfunction of myocardial sympathetic nerve endings occurs with this cardiomyopathy. Secondly, I-MIBG scintigraphy is an accurate imaging examination to detect and localize pheochromocytoma; it can help in the search for an endogenous cause of this adrenergic stress-related cardiomyopathy. PMID- 26098286 TI - FDG PET/CT Findings of the Recurrent Posttransplantation Lymphoproliferative Disorder in a Pediatric Liver Transplant Recipient With Right Leg Pain as the Only Complaint. AB - The most commonly observed symptoms of posttransplantation lymphoproliferative disorder (PTLD) after a liver transplantation were diarrhea and fever. Although PTLD can involve bones, bone pain is a rare manifestation of PTLD, much less to say a sole presentation. We report a case of a pediatric patient with recurrent PTLD after liver transplantation, whose only complaint was right tibial pain. FDG PET/CT revealed not only hypermetabolic activity in the right proximal tibia but also in many other parts of the body. Recurrent PTLD was confirmed after bone biopsy. PMID- 26098287 TI - Prognostic Significance of Intratumoral Metabolic Heterogeneity on 18F-FDG PET/CT in Pathological N0 Non-Small Cell Lung Cancer. AB - PURPOSE: The aim of the study was to evaluate the prognostic significance of intratumoral metabolic heterogeneity on pretreatment F-FDG PET/CT in patients with lung cancer who were pathologically N0 (pN0) after curative surgical resection. METHODS: We examined 119 patients (M/F = 79/40; mean age, 64.6 +/- 9.0 years) who had undergone pretreatment F-FDG PET/CT and were diagnosed as pN0 after curative surgery for adenocarcinoma (ADC; n = 67) or squamous cell carcinoma (SQCC; n = 52). Heterogeneity factor (HF) and other metabolic parameters (SUVmax, metabolic tumor volume [MTV] and total lesion glycolysis [TLG]) for the primary lesions were measured, and the results were analyzed for recurrence. The HF, defined as the derivative of the volume-threshold function from 20% to 80%, was computed for primary lesions. Univariate and multivariate analyses for recurrence were performed using the Kaplan-Meier method and using the Cox proportional hazards model. RESULTS: SUVmax, MTV, TLG, and HF were statistically different between patients with ADC and SQCC. Forty-one (34.5%) of 119 patients experienced recurrence (ADC, 25/67 = 37.3% vs. SQCC, 16/52 = 30.8%). Results of univariate analysis indicate that SUVmax, MTV, TLG, and HF in ADC and TLG and HF in SQCC were predictors for recurrence. After adjusting for sex, age, and histological grade in multivariate analysis, high SUVmax, MTV, TLG, and HF in ADC exhibited an association with increased risk of recurrence. CONCLUSIONS: Metabolic parameters and heterogeneity of primary tumor on pretreatment F-FDG PET/CT can predict recurrence in pN0 NSCLC patients of ADC type who have undergone curative surgery but not in patients of SQCC type. PMID- 26098288 TI - Brain SPECT and MRI Findings in a Uremic Patient With Parkinsonism. AB - Parkinsonism associated with basal ganglia pathology represents a rare complication in uremia patients, characterized by acute hyperkinetic or hypokinetic extrapyramidal movement disorders. We herein present brain SPECT and MR findings of uremic patients with end-stage renal failure exhibiting parkinsonian symptoms. The bilateral basal ganglia exhibited decreased uptake on SPECT, and abnormal signals on MR, suggesting pathology. PMID- 26098289 TI - 18F-FDG PET/CT Findings of Scrub Typhus. AB - Scrub typhus is an acute infectious disease caused by Orienta tsutsugamushi, which is clinically manifested by fever, generalized lymphadenopathy, diffuse myalgia, headache, maculopapular rash, and eschars at the site of chigger feedings. Diagnosis of scrub typhus requires compatible clinical features, history of exposure, and result of selorogic testing. In recent years, F-FDG PET/CT is seen as having increasing potential for use in examination and management of patients with infectious or inflammatory disorders. This is a PET/CT case demonstrating scrub typhus in a patient without evidence of recurrence of thyroid papillary cancer. PMID- 26098290 TI - 18F-FDG PET/CT in Extranodal Burkitt Lymphoma. AB - Burkitt lymphoma (BL) is a poorly differentiated non-Hodgkin B-cell lymphoma, more frequent in children than in adults. The extranodal debut of the disease is rare. We report a 43-year-old male patient with history of dyspnea. Burkitt lymphoma diagnosis was reached after biopsy of a pleural lesion. An initial staging F-FDG-PET/CT revealed large high-uptake lymphatic clusters in mediastinum, lung hilum, and extranodal involvement in pleura, pericardium, periphery of liver and spleen, all the omentum and peritoneum down to the pelvic floor, and bone marrow infiltration. PMID- 26098291 TI - FDG-PET/CT Manifestation of Tumor Seeding Along Percutaneous Biliary Drainage Catheter Tract. AB - A 55-year-old man with liver metastases from colon cancer developed obstructive jaundice secondary to bile duct compression from tumor burden, which required percutaneous biliary drainage until subsequent internal biliary stent could be placed. Follow-up FDG-PET/CT performed 2 months after removal of percutaneous biliary drainage catheter revealed FDG avid metastases along the catheter tract, extending from anterior abdominal wall to the peripheral liver at the insertion site of previous biliary catheter. PMID- 26098292 TI - Is there evidence for anti-TNF drugs in joint involvement in sarcoidosis? PMID- 26098293 TI - Blood donation and blood donor mortality after adjustment for a healthy donor effect. AB - BACKGROUND: Studies have repeatedly demonstrated that blood donors experience lower mortality than the general population. While this may suggest a beneficial effect of blood donation, it may also reflect the selection of healthy persons into the donor population. To overcome this bias, we investigated the relation between blood donation frequency and mortality within a large cohort of blood donors. In addition, our analyses also took into consideration the effects of presumed health differences linked to donation behavior. STUDY DESIGN AND METHODS: Using the Scandinavian Donation and Transfusion database (SCANDAT), we assessed the association between annual number of donations in 5-year windows and donor mortality by means of Poisson regression analysis. The analyses included adjustment for demographic characteristics and for an internal healthy donor effect, estimated among elderly donors exempted from continued donation because of age criteria. RESULTS: Statistical analyses included 1,182,495 donors of whom 15,401 died during 9,526,627 person-years of follow-up. Analyses adjusted only for demographic characteristics showed a 18.6% reduction in mortality per additional annual donation (95% confidence interval [CI], 16.8%-20.4%). After additional adjustment for the internal healthy donor effect, each additional annual donation was associated with a 7.5% decreased mortality risk 7.5% (95% CI, 5.7%-9.4%). CONCLUSION: We observed an inverse relationship between donation frequency and mortality. The magnitude of the association was reduced after adjustment for an estimate of self-selection in the donor population. Our observations indicate that repeated blood donation is not associated with premature death, but cannot be interpreted as conclusive evidence of a beneficial health effect. PMID- 26098294 TI - Bariatric Surgery and Urinary Incontinence. PMID- 26098295 TI - Population-based trends in high-grade cervical lesions in the early human papillomavirus vaccine era in the United States. AB - BACKGROUND: Cervical intraepithelial neoplasia grade 2, 3, and adenocarcinoma in situ (CIN2+) lesions can be monitored as early indicators of human papillomavirus (HPV) vaccine impact. Changes to screening utilization will affect observed reductions in CIN2+ rates and complicate the interpretation of vaccine impact. METHODS: From 2008 to 2012, 9119 cases of CIN2+ among 18- to 39-year-old residents of catchment areas in California, Connecticut, New York, and Oregon were reported to the HPV-IMPACT Project, a sentinel system for monitoring the population impact of HPV vaccine. Age-stratified CIN2+ incidence rates were calculated for each catchment. Annual cervical screening was estimated for California, New York, and Oregon catchments with administrative and survey data. The Cochran-Armitage test was used to examine trends. RESULTS: From 2008 to 2012, the incidence of CIN2+ significantly decreased among 18- to 20-year-olds (California, from 94 to 5 per 100,000 women; Connecticut, from 450 to 57 per 100,000 women; New York, from 299 to 43 per 100,000 women; and Oregon, from 202 to 37 per 100,000 women; Ptrend < .0001) and among 21- to 29-year-olds in Connecticut (from 762 to 589 per 100,000 women) and New York (from 770 to 465 per 100,000 women; Ptrend < .001); rates did not differ among 30- to 39-year-olds. During the same period, screening rates also declined, with the largest decreases among 18- to 20-year-olds (from 67% in Oregon to 88% in California) and with smaller declines among 21- to 29-year-olds (13%-27%) and 30- to 39-year-olds (3% 21%). CONCLUSIONS: The declines in CIN2+ detection in young women were likely due to reduced screening but could also reflect the impact of vaccination. These data illustrate challenges in interpreting CIN2+ ecologic trends in the new era of cervical cancer prevention and emphasize the importance of information such as HPV types detected in lesions to assess the impact of HPV vaccine on cervical precancers. PMID- 26098296 TI - Structure and Redox Properties of 5-Amino-3-nitro-1H-1,2,4-triazole (ANTA) Adsorbed on a Silica Surface: A DFT M05 Computational Study. AB - A cluster approximation was applied at the M05/tzvp level to model an adsorption of 5-amino-3-nitro-1H-1,2,4-triazole (ANTA) on the (001) surface of alpha-quartz. Structures of the obtained ANTA-silica complexes confirm a nearly parallel orientation of the nitro compound toward the surface. The atoms in molecules (AIM) method was applied to analyze binding between ANTA and the silica surface. Attachment or loss of an electron was found to lead to a significant deviation from coplanarity in the complexes and to a strengthening of a hydrogen bonding. Redox properties of the adsorbed ANTA were compared with those of gas-phase and hydrated species by calculation of the ionization potential, electron affinity, oxidation and reduction Gibbs free energies, and oxidation and reduction potentials. It was shown that the adsorbed ANTA has a lower ability to undergo redox transformations as compared to that of the hydrated one. PMID- 26098297 TI - Pediatric post-marketing safety systems in North America: assessment of the current status. AB - PURPOSE: It is critical to have pediatric post-marketing safety systems that contain enough clinical and epidemiological detail to draw regulatory, public health, and clinical conclusions. The pediatric safety surveillance workshop (PSSW), coordinated by the Food and Drug Administration (FDA), identified these pediatric systems as of 2010. This manuscript aims to update the information from the PSSW and look critically at the systems currently in use. METHODS: We reviewed North American pediatric post-marketing safety systems such as databases, networks, and research consortiums found in peer-reviewed journals and other online sources. We detail clinical examples from three systems that FDA used to assess pediatric medical product safety. RESULTS: Of the 59 systems reviewed for pediatric content, only nine were pediatric-focused and met the inclusion criteria. Brief descriptions are provided for these nine. The strengths and weaknesses of three systems (two of the nine pediatric-focused and one including both children and adults) are illustrated with clinical examples. CONCLUSIONS: Systems reviewed in this manuscript have strengths such as clinical detail, a large enough sample size to capture rare adverse events, and/or a patient denominator internal to the database. Few systems include all of these attributes. Pediatric drug safety would be better informed by utilizing multiple systems to take advantage of their individual characteristics. PMID- 26098298 TI - Principal bicorrelation analysis: Unraveling associations between three data sources. AB - In this article, we propose a statistical explorative method for data integration. It is developed in the context of early drug development for which it enables the detection of chemical substructures and the identification of genes that mediate their association with the bioactivity (BA). The core of the method is a sparse singular value decomposition for the identification of the gene set and a permutation-based method for the control of the false discovery rate. The method is illustrated using a real dataset, and its properties are empirically evaluated by means of a simulation study. Quantitative Structure Transcriptional Activity Relationship (QSTAR, www.qstar-consortium.org ) is a new paradigm in early drug development that extends QSAR by not only considering data on the chemical structure of the compounds and on the compound-induced BA, but by simultaneously using transcriptomics data (gene expression). This approach enables, for example, the detection of chemical substructures that are associated with BA, while at the same time a gene set is correlated with both these substructures and the BA. Although causal associations cannot be formally concluded, these associations may suggest that the compounds act on the BA through a particular genomic pathway. PMID- 26098299 TI - Host Subtraction, Filtering and Assembly Validations for Novel Viral Discovery Using Next Generation Sequencing Data. AB - The use of next generation sequencing (NGS) to identify novel viral sequences from eukaryotic tissue samples is challenging. Issues can include the low proportion and copy number of viral reads and the high number of contigs (post assembly), making subsequent viral analysis difficult. Comparison of assembly algorithms with pre-assembly host-mapping subtraction using a short-read mapping tool, a k-mer frequency based filter and a low complexity filter, has been validated for viral discovery with Illumina data derived from naturally infected liver tissue and simulated data. Assembled contig numbers were significantly reduced (up to 99.97%) by the application of these pre-assembly filtering methods. This approach provides a validated method for maximizing viral contig size as well as reducing the total number of assembled contigs that require down stream analysis as putative viral nucleic acids. PMID- 26098300 TI - Improving recombinant protein production in the Chlamydomonas reinhardtii chloroplast using vivid Verde Fluorescent Protein as a reporter. AB - Microalgae have potential as platforms for the synthesis of high-value recombinant proteins due to their many beneficial attributes including ease of cultivation, lack of pathogenic agents, and low-cost downstream processing. However, current recombinant protein levels are low compared to other microbial platforms and stable insertion of transgenes is available in only a few microalgal species. We have explored different strategies aimed at increasing growth rate and recombinant protein production in the Chlamydomonas reinhardtii chloroplast. A novel fluorescent protein (vivid Verde Fluorescent Protein, VFP) was expressed under the control of the native atpA promoter/5'UTR element. VFP levels were detected by western blotting, with increased protein levels observed when co-expressed with a gene encoding the Escherichia coli Spy chaperone. We used these transformant lines to study the effect of temperature, light and media on recombinant protein production and cell growth. VFP levels and fluorescence, assessed by flow cytometry, allowed a determination of improved cultivation conditions as 30 degrees C under mixotrophic mode. These conditions were tested for the accumulation of an antimicrobial endolysin (Cpl-1) of potential commercial interest, observing that the outcome obtained for VFP could not be easily replicated for Cpl-1. This study suggests that recombinant protein expression is product-specific and needs to be optimized individually. PMID- 26098301 TI - Current-Driven Supramolecular Motor with In Situ Surface Chiral Directionality Switching. AB - Surface-supported molecular motors are nanomechanical devices of particular interest in terms of future nanoscale applications. However, the molecular motors realized so far consist of covalently bonded groups that cannot be reconfigured without undergoing a chemical reaction. Here we demonstrate that a platinum porphyrin-based supramolecularly assembled dimer supported on a Au(111) surface can be rotated with high directionality using the tunneling current of a scanning tunneling microscope (STM). Rotational direction of this molecular motor is determined solely by the surface chirality of the dimer, and most importantly, the chirality can be inverted in situ through a process involving an intradimer rearrangement. Our result opens the way for the construction of complex molecular machines on a surface to mimic at a smaller scale versatile biological supramolecular motors. PMID- 26098302 TI - Multi-Stage Tuberculosis Subunit Vaccine Candidate LT69 Provides High Protection against Mycobacterium tuberculosis Infection in Mice. AB - Effective tuberculosis (TB) vaccine should target tubercle bacilli with various metabolic states and confer long-term protective immunity. In this study, we constructed a novel multi-stage TB subunit vaccine based on fusion protein ESAT6 Ag85B-MPT64(190-198)-Mtb8.4-HspX (LT69 for short) which combined early expressed antigens and latency-associated antigen. The fusion protein was mixed with an adjuvant being composed of N, N'-dimethyl-N, N'-dioctadecylammonium bromide (DDA) and polyriboinosinic polyribocytidylic acid (PolyI:C) to construct subunit vaccine, whose immunogenicity and protective ability were evaluated in C57BL/6 mice. The results showed that LT69 had strong immunogenicity and high protective effect against Mycobacterium tuberculosis (M. tuberculosis) H37Rv aerosol challenge. Low-dose (2 MUg) of LT69 generated long-term immune memory responses and provided effective protection, which was even higher than traditional vaccine BCG did at 30 weeks post the last vaccination. In conclusion, multistage subunit vaccine LT69 showed high and long-term protection against M. tuberculosis infection in mice, whose effect could be enhanced by using a relative low dosage of antigen. PMID- 26098303 TI - The combined benefits of motorcycle antilock braking systems (ABS) in preventing crashes and reducing crash severity. AB - OBJECTIVE: Several studies have reported the benefits of motorcycle antilock braking systems (ABS) in reducing injury crashes, due to improved stability and braking performance. Both aspects may prevent crashes but may also reduce the crash severity when a collision occurs. However, it is still unknown to what extent the reductions in injury crashes with ABS may be due to a combination of these mechanisms. METHODS: Swedish hospital and police reports (2003-2012) were used. The risk for permanent medical impairment (RPMI) was calculated, showing the risk of at least 1 or 10% permanent medical impairment. In total, 165 crashes involving ABS-equipped motorcycles were compared with 500 crashes with similar motorcycles without ABS. The analysis was performed in 3 steps. First, the reduction in emergency care visits with ABS was calculated using an induced exposure approach. Secondly, the injury mitigating effects of ABS were investigated. The mean RPMI 1+ and RPMI 10+ were analyzed for different crash types. The distributions of impairing injuries (PMI 1+) and severely impairing injuries (PMI 10+) were also analyzed. In the third step, the total reduction of PMI 1+ and PMI 10+ injured motorcyclists was calculated by combining the reductions found in the previous steps. An additional analysis of combined braking systems (CBS) together with ABS was also performed. RESULTS: The results showed that emergency care visits were reduced by 47% with ABS. In the second step, it was found that the mean RPMI 1+ and RPMI 10+ with ABS were 15 and 37% lower, respectively. Finally, the third step showed that the total reductions in terms of crash avoidance and mitigation of PMI 1+ and PMI 10+ injured motorcyclists with ABS were 67 and 55%, respectively. However, PMI 1+ and PMI 10+ leg injuries were not reduced by ABS to the same extent. Indications were found suggesting that the benefits of ABS together with CBS may be greater than ABS alone. CONCLUSIONS: This article indicated that motorcycle ABS reduced impairing injuries, mostly due to fewer emergency care visits but also due to a reduction in crash severity. This may seem reasonable as the improved stability and braking performance provided by ABS could prevent some crashes but would also decrease crash severity if a collision still occurs. As suggested by previous studies, however, the lower extremities would be more exposed in a crash with ABS. It is recommended that future research should follow up these results with additional data. PMID- 26098304 TI - Improving prediction of secondary structure, local backbone angles, and solvent accessible surface area of proteins by iterative deep learning. AB - Direct prediction of protein structure from sequence is a challenging problem. An effective approach is to break it up into independent sub-problems. These sub problems such as prediction of protein secondary structure can then be solved independently. In a previous study, we found that an iterative use of predicted secondary structure and backbone torsion angles can further improve secondary structure and torsion angle prediction. In this study, we expand the iterative features to include solvent accessible surface area and backbone angles and dihedrals based on Calpha atoms. By using a deep learning neural network in three iterations, we achieved 82% accuracy for secondary structure prediction, 0.76 for the correlation coefficient between predicted and actual solvent accessible surface area, 19 degrees and 30 degrees for mean absolute errors of backbone phi and psi angles, respectively, and 8 degrees and 32 degrees for mean absolute errors of Calpha-based theta and tau angles, respectively, for an independent test dataset of 1199 proteins. The accuracy of the method is slightly lower for 72 CASP 11 targets but much higher than those of model structures from current state-of-the-art techniques. This suggests the potentially beneficial use of these predicted properties for model assessment and ranking. PMID- 26098305 TI - The Association between Provider Practice and Knowledge of ORS and Zinc Supplementation for the Treatment of Childhood Diarrhea in Bihar, Gujarat and Uttar Pradesh, India: A Multi-Site Cross-Sectional Study. AB - INTRODUCTION: Programs aimed at reducing the burden of diarrhea among children under-five in low-resource settings typically allocate resources to training community-level health workers, but studies have suggested that provider knowledge does not necessarily translate into adequate practice. A diarrhea management program implemented in Bihar, Gujarat and Uttar Pradesh, India trained private sector rural medical practitioners (RMPs) and public sector Accredited Social Health Activists (ASHAs) and Anganwadi workers (AWWs) in adequate treatment of childhood diarrhea with oral rehydration salts (ORS) and zinc. We used cross-sectional program evaluation data to determine the association between observed diarrhea treatment practices and reported knowledge of ORS and zinc among each provider cadre. METHODS: We conducted principal components analysis on providers' responses to diarrhea treatment questions in order to generate a novel scale assessing ORS/zinc knowledge. We subsequently regressed a binary indicator of whether ORS/zinc was prescribed during direct observation onto the resulting knowledge scores, controlling for other relevant knowledge predictors. RESULTS: There was a positive association between ORS/zinc knowledge score and prescribing ORS and zinc to young children with diarrhea among private sector RMPs (aOR: 2.32; 95% CI: 1.29-4.17) and public sector ASHAs and AWWs (aOR 2.48; 95% CI: 1.90 3.24). Controlling for knowledge score, receipt of training in the preceding 6 months was a good predictor of adequate prescribing in the public but not the private sector. In the public sector, direct access to ORS and zinc supplies was also highly associated with prescribing. CONCLUSIONS: To enhance the management of childhood diarrhea in India, programmatic activities should center on increasing knowledge of ORS and zinc among public and private sector providers through biannual trainings but should also focus on ensuring sustained access to an adequate supply chain. PMID- 26098306 TI - Lateral Resolution and Image Formation in Scanning Ion Conductance Microscopy. AB - The scanning ion conductance microscope (SICM) is a powerful tool for imaging the topography of soft samples in an aqueous environment. Despite the rising popularity of the SICM, the image formation process and the fundamental limit of the lateral resolution are still a matter of debate. Using microfabricated samples, we investigated the imaging of small cylindrical particles, elongated objects, and topography steps and present the first direct comparison of numerical and experimental data. For the lateral resolution we considered two alternative definitions: the distance at which two small particles can clearly be resolved from each other in an image, and the apparent full width at half-maximum of small particles. For both definitions, we found a lateral resolution of about 3 times the inner opening radius of the pipet. We further validated this resolution limit in measurements on supported lipid bilayers and a polycarbonate sample using pipets with opening radii down to 8 nm. PMID- 26098307 TI - GDM Women's Pre-Pregnancy Overweight/Obesity and Gestational Weight Gain on Offspring Overweight Status. AB - OBJECTIVES: To examine the association of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anthropometry in the offspring of mothers with gestational diabetes mellitus (GDM). METHODS: We performed a retrospective cohort study in 1263 GDM mother-child pairs. General linear models and Logistic regression models were used to assess the single and joint associations of maternal pre-pregnancy BMI (normal weight, overweight, and obesity) and GWG (inadequate, adequate and excessive GWG) with anthropometry and overweight status in the offspring from birth to 1-5 years old. RESULTS: Maternal pre-pregnancy BMI and GWG were positively associated with birth weight for gestational age Z score and birth weight for length for gestational age Z score at birth, and weight for age Z score, length/height for age Z score, and weight for length/height Z score at of 1-5 years old offspring. Maternal pre-pregnancy overweight, obesity, and excessive GWG were associated with increased risks of large for gestational age [ORs 95% CIs = 1.87 (1.37-2.55), 2.98 (1.89-4.69), and 2.93 (2.07-4.13), respectively] and macrosomia [ORs 95% CIs = 2.06 (1.50-2.84), 2.89 (1.78-4.70), and 2.84 (1.98-4.06), respectively] at birth and childhood overweight at 1-5 years old [ORs 95% CIs = 1.26 (0.92-1.73), 1.96 (1.24-3.09), and 1.59 (1.15-2.21), respectively]. CONCLUSIONS: Offspring born to GDM mothers with pre-pregnancy overweight/obesity or excessive GWG were associated with increased risks of large for gestational age and macrosomia at birth, and childhood overweight at 1-5 years old, compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG. PMID- 26098308 TI - Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis. AB - The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage. PMID- 26098309 TI - Regional Variation in Parasite Species Richness and Abundance in the Introduced Range of the Invasive Lionfish, Pterois volitans. AB - Parasites can play an important role in biological invasions. While introduced species often lose parasites from their native range, they can also accumulate novel parasites in their new range. The accumulation of parasites by introduced species likely varies spatially, and more parasites may shift to new hosts where parasite diversity is high. Considering that parasitism and disease are generally more prevalent at lower latitudes, the accumulation of parasites by introduced hosts may be greater in tropical regions. The Indo-Pacific lionfish (Pterois volitans) has become widely distributed across the Western Atlantic. In this study, we compared parasitism across thirteen locations in four regions, spanning seventeen degrees of latitude in the lionfish's introduced range to examine potential spatial variation in parasitism. In addition, as an initial step to explore how indirect effects of parasitism might influence interactions between lionfish and ecologically similar native hosts, we also compared parasitism in lionfish and two co-occurring native fish species, the graysby grouper, Cephalopholis cruentata, and the lizardfish, Synodus intermedius, in the southernmost region, Panama. Our results show that accumulation of native parasites on lionfish varies across broad spatial scales, and that colonization by ectoparasites was highest in Panama, relative to the other study sites. Endoparasite richness and abundance, on the other hand, were highest in Belize where lionfish were infected by twice as many endoparasite species as lionfish in other regions. The prevalence of all but two parasite species infecting lionfish was below 25%, and we did not detect an association between parasite abundance and host condition, suggesting a limited direct effect of parasites on lionfish, even where parasitism was highest. Further, parasite species richness and abundance were significantly higher in both native fishes compared to lionfish, and parasite abundance was negatively associated with the condition index of the native grouper but not that of the lionfish or lizardfish. While two co-occurring native fishes were more heavily parasitized compared to lionfish in Panama any indirect benefits of differential parasitism requires further investigation. Future parasitological surveys of lionfish across the eastern coast of North America and the Lesser Antilles would further resolve geographic patterns of parasitism in invasive lionfish. PMID- 26098310 TI - Polymerase Bypass of N(6)-Deoxyadenosine Adducts Derived from Epoxide Metabolites of 1,3-Butadiene. AB - N(6)-(2-Hydroxy-3-buten-1-yl)-2'-deoxyadenosine (N(6)-HB-dA I) and N(6),N(6)-(2,3 dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (N(6),N(6)-DHB-dA) are exocyclic DNA adducts formed upon alkylation of the N(6) position of adenine in DNA by epoxide metabolites of 1,3-butadiene (BD), a common industrial and environmental chemical classified as a human and animal carcinogen. Since the N(6)-H atom of adenine is required for Watson-Crick hydrogen bonding with thymine, N(6)-alkylation can prevent adenine from normal pairing with thymine, potentially compromising the accuracy of DNA replication. To evaluate the ability of BD-derived N(6) alkyladenine lesions to induce mutations, synthetic oligodeoxynucleotides containing site-specific (S)-N(6)-HB-dA I and (R,R)-N(6),N(6)-DHB-dA adducts were subjected to in vitro translesion synthesis in the presence of human DNA polymerases beta, eta, iota, and kappa. While (S)-N(6)-HB-dA I was readily bypassed by all four enzymes, only polymerases eta and kappa were able to carry out DNA synthesis past (R,R)-N(6),N(6)-DHB-dA. Steady-state kinetic analyses indicated that all four DNA polymerases preferentially incorporated the correct base (T) opposite (S)-N(6)-HB-dA I. In contrast, hPol beta was completely blocked by (R,R)-N(6),N(6)-DHB-dA, while hPol eta and kappa inserted A, G, C, or T opposite the adduct with similar frequency. HPLC-ESI-MS/MS analysis of primer extension products confirmed that while translesion synthesis past (S)-N(6)-HB-dA I was mostly error-free, replication of DNA containing (R,R)-N(6),N(6)-DHB-dA induced significant numbers of A, C, and G insertions and small deletions. These results indicate that singly substituted (S)-N(6)-HB-dA I lesions are not miscoding, but that exocyclic (R,R)-N(6),N(6)-DHB-dA adducts are strongly mispairing, probably due to their inability to form stable Watson-Crick pairs with dT. PMID- 26098311 TI - Performance of HIV Prevention of Mother-To-Child Transmission Programs in Sub Saharan Africa: Longitudinal Assessment of 64 Nevirapine-Based Programs Implemented in 25 Countries, 2000-2011. AB - BACKGROUND: To evaluate the performance and to identify predictive factors of performance in prevention of mother-to-child HIV transmission programs (PMTCT) in sub-Saharan African countries. METHODS: From 2000 to 2011, PMTCT programs included in the Viramune Donation Programme (VDP) were prospectively followed. Each institution included in the VDP provided data on program implementation, type of management institution, number of PMTCT sites, key programs outputs (HIV counseling and testing, NVP regimens received by mothers and newborns). Nevirapine Coverage Ratio (NCR), defined as the number of women who should have received nevirapine (observed HIV prevalence x number of women in antenatal care), was used to measure performance. Included programs were followed every six months through progress reports. RESULTS: A total of 64 programs in 25 sub Saharan African countries were included. The mean program follow-up was 48.0 months (SD = 24.5); 20,084,490 women attended in antenatal clinics were included. The overall mean NCR was 0.52 (SD = 0.25), with an increase from 0.37 to 0.57 between the first and last progress reports (p<.0001); NCR increased by 3.26% per year-program. Between the first and the last report, the number of women counseled and tested increased from 64.3% to 86.0% (p<.0001), the number of women post-counseled from 87.5% to 91.3% (p = 0.08). After mixed linear regression analysis, type of responsible institution, number of women attended in ANC, and program initiation in 2005-2006 were significant predictive factors associated with the NCR. The effect of the time period increased from earlier to later periods. CONCLUSION: A longitudinal assessment of large PMTCT programs shows that scaling-up of programs was increased in sub-Saharan African countries. The PMTCT coverage increased throughout the study period, especially after 2006. Performance may be better for programs with a small or medium number of women attended in ANC. Identification of factors that predict PMTCT program performance may help in the development and expansion of additional large PMTCT services in sub-Saharan Africa. PMID- 26098313 TI - Patent Deployment Strategies and Patent Value in LED Industry. AB - This study applies two variables in the measurement of company patent deployment strategies: patent family depth and earn plan ratio. Patent family depth represents the degree to which certain fields and markets are valued by the patent owner. Earn plan ratio defined as the ratio of the number of patent forward citations to patent family size. Earn plan ratio indicates the degree to which a patent family could be cited by later innovators and competitors. This study applies a logistic regression model in the analysis LED industry data. The results demonstrate that patent value has a positive relationship with the patent family depth, and earn plan ratio. PMID- 26098312 TI - Mest but Not MiR-335 Affects Skeletal Muscle Growth and Regeneration. AB - When skeletal muscle fibers are injured, they regenerate and grow until their sizes are adjusted to surrounding muscle fibers and other relevant organs. In this study, we examined whether Mest, one of paternally expressed imprinted genes that regulates body size during development, and miR-335 located in the second intron of the Mest gene play roles in muscle regeneration. We generated miR-335 deficient mice, and found that miR-335 is a paternally expressed imprinted microRNA. Although both Mest and miR-335 are highly expressed during muscle development and regeneration, only Mest+/- (maternal/paternal) mice show retardation of body growth. In addition to reduced body weight in Mest+/-; DMD null mice, decreased muscle growth was observed in Mest+/- mice during cardiotoxin-induced regeneration, suggesting roles of Mest in muscle regeneration. Moreover, expressions of H19 and Igf2r, maternally expressed imprinted genes were affected in tibialis anterior muscle of Mest+/-; DMD-null mice compared to DMD-null mice. Thus, Mest likely mediates muscle regeneration through regulation of imprinted gene networks in skeletal muscle. PMID- 26098314 TI - Glycoengineered cell models for the characterization of cancer O-glycoproteome: an innovative strategy for biomarker discovery. AB - Glycosylation is one of the most abundant forms of protein posttranslational modification. O-glycosylation is a major type of protein glycosylation, comprising different types and structures expressed in several physiologic and pathologic conditions. The understanding of protein attachment site and glycan structure is of the utmost importance for the clarification of the role glycosylation plays in normal cells and in pathological conditions. Neoplastic transformation frequently shows the expression of immature truncated O-glycans. These aberrantly expressed O-glycans have been shown to induce oncogenic properties and can be detected in premalignant lesions, meaning that they are an important source of biomarkers. This article addresses the recent application of genetically engineered cancer cell models to produce simplified homogenous O glycans allowing the characterization of cancer cells O-glycoproteomes, using advanced mass spectrometry methods and the identification of potential cancer specific O-glycosylation sites. This article will also discuss possible applications of these biomarkers in the cancer field. PMID- 26098316 TI - Small-RNA asymmetry is directly driven by mammalian Argonautes. AB - Asymmetric selection of single-stranded guide RNAs from double-stranded RNA precursors is crucial in RNA silencing-mediated gene regulation. However, the precise mechanisms of small-RNA asymmetry are unclear, especially because asymmetric selection can still occur when the putative asymmetry sensors Drosophila R2D2 and mammalian Dicer are depleted. Here we report a direct contribution of mammalian Argonaute 2 (Ago2) to microRNA (miRNA) asymmetry. Ago2 selects strands with 5'-uridine or 5'-adenosine and thermodynamically unstable 5' ends in parallel through its two sensor regions, which contact the 5' nucleobases and 5'-phosphates of prospective guide strands. Hence, miRNA asymmetry shows superposed patterns reflecting 5'-end nucleotide identity ('digital' pattern) and thermodynamic stability ('analog' pattern). Furthermore, we demonstrate that cancer-associated miRNA variations reprogram asymmetric selection. Finally, our study presents a model of this universal principle, to aid in comprehensive understanding of miRNA function and development of new RNA-silencing therapies in precision medicine. PMID- 26098318 TI - Correction: High Throughput Measurement of gammaH2AX DSB Repair Kinetics in a Healthy Human Population. PMID- 26098317 TI - Crystal structure of human stearoyl-coenzyme A desaturase in complex with substrate. AB - Stearoyl-coenzyme A desaturase-1 (SCD1) has an important role in lipid metabolism, and SCD1 inhibitors are potential therapeutic agents for the treatment of metabolic diseases and cancers. Here we report the 3.25-A crystal structure of human SCD1 in complex with its substrate, stearoyl-coenzyme A, which defines the new SCD1 dimetal catalytic center and reveals the determinants of substrate binding to provide insights into the catalytic mechanism of desaturation of the stearoyl moiety. The structure also provides a mechanism for localization of SCD1 in the endoplasmic reticulum: human SCD1 folds around a tight hydrophobic core formed from four long alpha-helices that presumably function as an anchor spanning the endoplasmic reticulum membrane. Furthermore, our results provide a framework for the rational design of pharmacological inhibitors targeting the SCD1 enzyme. PMID- 26098320 TI - Raynaud?s phenomenon - assessment and differential diagnoses. AB - Raynaud?s phenomenon (RP) is characterised by paroxysmal reversible episodes of vasospasm, usually involving peripheral small vessels of the fingers or toes and resulting in a triple-colour change starting with pallor and followed by cyanosis and erythema. Attacks are typically triggered by cold or emotional stress. The diagnosis of RP can be made on the basis of the patient?s clinical symptoms. Primary RP occurs without underlying disease and is considered a benign condition. A normal erythrocyte sedimentation rate, negative testing for antinuclear antibodies, normal nailfold capillaries and the absence of structural micro- or macrovascular damage and other diseases lead to the diagnosis of primary RP. Digital photoplethysmography and pulse contour analysis can be used as an additional tool to exclude structural macro- or microvascular disease. In contrast, secondary RP is associated with other diseases, mainly connective tissue diseases such as systemic sclerosis. If there is a suspicion of secondary RP, a thorough laboratory and vascular assessment is required to make the diagnosis of underlying disease. Acrocyanosis and erythromelalgia are additional functional vascular disorders that can be easily distinguished when patients are carefully assessed for their history and clinical symptoms. PMID- 26098319 TI - Atherosclerotic plaque neovascularization and inflammation - is there a link? PMID- 26098315 TI - Crystal structure, conformational fixation and entry-related interactions of mature ligand-free HIV-1 Env. AB - As the sole viral antigen on the HIV-1-virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1-Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C 433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like particle and soluble formats providing a new generation of vaccine antigens. PMID- 26098321 TI - Hypothenar hammer syndrome. AB - The diagnosis of hypothenar hammer syndrome (HHS) should be considered in the case of hand ischemia in people who occupationally or recreationally use the hypothenar region literally as a ?hammer?. Routine diagnostics should consist of physical examination including Allen?s test, acral plethysmography and duplex sonography. According to the prevailing opinion angiography remains the "gold standard test" for establishing the diagnosis of HHS. Early diagnosis allows more effective therapeutic strategies and is important to prevent long-term negative medical sequelae. Several basic principles apply to all patients, for example hand protection and smoking cessation. The optimal treatment options, particularly the indication for surgery, remain controversial due to a lack of sound data from case series or prospective randomized trials. PMID- 26098322 TI - Positive correlation between neovascularization degree of carotid atherosclerosis determined by contrast-enhanced ultrasound and level of serum C-reactive protein. AB - BACKGROUND: Neovascularization is one of the most important risk factors for unstable plaque. This study was designed to correlate plaque thickness, artery stenosis and levels of serum C-reactive protein with the degree of intraplaque enhancement determined by contrast-enhanced ultrasound. PATIENTS AND METHODS: Contrast-enhanced ultrasound was performed on 72 carotid atherosclerotic plaques in 48 patients. Contrast enhancement within the plaque was categorized as grade 1, 2 or 3. Maximum plaque thickness was measured in short-axis view. Carotid artery stenosis was categorized as mild, moderate or severe. RESULTS: Plaque contrast enhancement was not associated with the degree of artery stenosis or with plaque thickness. Serum C-reactive protein levels were positively correlated with the number of new vessels in the plaque. C-reactive protein levels increased in the three groups(Grade 1: 3.72+/-1.79mg/L; Grade 2: 7.88+/-4.24 mg/L; Grade 3: 11.02+/-3.52 mg/L), with significant differences among them (F=10.14, P<0.01), and significant differences between each two groups (P<0.05). Spearman?s rank correlation analysis showed that serum C-reactive protein levels were positively correlated with the degree of carotid plaque enhancement (Rs =0.69, P<0.01). CONCLUSIONS: The combination of C-reactive protein levels and intraplaque neovascularization detected by contrast-enhanced ultrasound may allow more accurate evaluation of plaque stability. PMID- 26098323 TI - Catheter-directed thrombolysis plus anticoagulation versus anticoagulation alone in the treatment of proximal deep vein thrombosis - a meta-analysis. AB - BACKGROUND: The aim of this meta-analysis was to compare the clinical outcomes of catheter-directed thrombolysis (CDT) plus anticoagulation with anticoagulation alone in patients with lower-extremity proximal deep vein thrombosis (DVT). PATIENTS AND METHODS: We systematically searched Pubmed, Embase, and the Cochrane Library from inception to October, 2014. All randomized controlled trials (RCTs) and non-randomized studies comparing the clinical outcomes between additional CDT and anticoagulation alone were included. The primary outcomes were postthrombotic syndrome and major bleeding complications. The secondary outcomes included the iliofemoral patency rate, deep venous function, mortality, pulmonary embolism, and recurrent DVT. RESULTS: Three RCTs and 3 non-randomized studies were included. Compared with standard anticoagulation treatment, additional CDT was associated with a significantly higher rate of complete lysis within 30 days (OR = 91; 95 % CI 19.28 to 429.46), a higher rate of 6-month patency (OR = 5.77; 95 % CI 1.99 to 16.73), a lower rate of postthrombotic syndrome (OR = 0.4; 95 % CI 0.19 to 0.96), and a lower rate of venous obstruction (OR = 0.20; 95 % CI 0.09 to 0.44). More major bleeding episodes occurred in the CDT group (Peto OR 2.0; 95 % CI 1.62 to 2.62). CDT was not found to reduce mortality, pulmonary embolism, or recurrent DVT. CONCLUSIONS: Additional CDT therapy appeared to be more effective than standard anticoagulation treatment in improving the venous patency and preventing venous obstruction and postthrombotic syndrome. Caution should be taken when performing CDT given the increased risk of major bleeding. However, no evidence supported benefits of CDT in reducing mortality, recurrent DVT, or pulmonary embolism. PMID- 26098324 TI - Occlusion rate, venous symptoms and patient satisfaction after radiofrequency induced thermotherapy (RFITT(r)): are there differences between the great and the small saphenous veins? AB - BACKGROUND: Previous studies on the therapy of insufficient saphenous veins mainly compare different treatment methods. Only a few investigate differences of a specific treatment option between the great (GSV) and the small saphenous vein (SSV). The aim of this study was to evaluate the efficacy, clinical improvement and patient satisfaction after radiofrequency-induced thermotherapy (RFITT(r)) with regard to the treated vein. PATIENTS AND METHODS: We included 65 patients (40 women, 25 men; mean age 54.75 years) who were treated with RFITT(r) for incompetent saphenous veins (n = 83: 62 GSV, 21 SSV). Occlusion rates were determined by duplex-sonography. Additionally, we performed a prospective analysis of venous symptoms and signs by means of a standardized questionnaire and of patient satisfaction using a semi-quantitative rating (1 = very good, 6 = insufficient). RESULTS: The GSV group showed a significantly greater reduction of venous symptoms in comparison to the SSV group (p = 0.005) despite no significant differences in long term occlusion rates (mean time after operation: 22 months) of 90 % in the GSV group and 81.8 % in the SSV group (p = 0.598). Following the procedure, detailed analysis revealed significantly more swelling (p = 0.022), feeling of heavy legs (p = 0.002) and nightly calf cramps (p = 0.001) in the SSV group. Additionally, RFITT(r) led to a significant improvement in patient satisfaction in the GSV group (from 1.93 at day 1 - 3 to 1.41 after 6 - 12 months, p = 0.009) but not in the SSV group (from 2.29 to 2.07, p = 0.43). CONCLUSIONS: With regard to the improvement of venous symptoms and patient satisfaction, the benefit of RFITT(r) is greater for patients with incompetent GSV compared to those with incompetent SSV. PMID- 26098325 TI - Retrograde thrombendarterectomy vs. ilio-femoral bypass in unilateral iliac TASC C and D lesions. AB - BACKGROUND: To compare short and long term results of retrograde Thrombendarterectomy (rTEA) and ilio-femoral Bypass (IFBP) to treat iliac TASC C and D lesions. PATIENTS AND METHODS: Retrospective analysis of 108 patients treated at a single vascular center by either rTEA (n = 42) or IFBP (n = 66) over a period of 4 years. RESULTS: Both methods did not significantly differ in 30-day (rTEA 0 % vs IFBP 2 %) or long-term mortality (rTEA 24 % vs IFBP 30 % at 4 years) with a median follow-up of 46 months. There were no procedure related deaths. Patency was similar for both groups (rTEA 93 % vs IFBP 98 % at 30 days; rTEA 83 % vs 92 % IFBP at 4 years). We could not find a significant difference in limb salvage rates (rTEA 93 % vs IFBP 100 % at 30 days and at 4 years). The incidence of prolonged lymphorrhea was significantly higher in the IFBP group (rTEA 0 % vs IFBP 21 %). In 4 IFBP patients a prosthetic graft infection occurred. CONCLUSIONS: Regarding short and long term results operative procedures as rTEA and IFBP still represent the gold standard in the treatment of TASC C and D lesions of the external iliac artery especially in patients with additional lesions in the common femoral and profundal femoral artery. Taking into account certain anatomical characteristics (heavily calcified lesions, narrow external iliac arteries or very tortuous iliac segments) and individual local conditions (prior vascular procedures involving the femoral bifurcation) the single incision retrograde approach to the EIA with rTEA may have advantages over IFBP, especially concerning postoperative complications like lymphorrhea and graft infection. PMID- 26098327 TI - Fatal giant cell arteritis of small to medium-sized visceral arteries: atypical manifestation or new entity? PMID- 26098326 TI - Comparison of one-year prognosis of patients classified as chronic critical lower limb ischaemia according to TASC II or European consensus definition in the COPART cohort. AB - BACKGROUND: We compared one-year amputation and survival rates in patients fulfilling 1991 European consensus critical limb ischaemia (CLI) definition to those clas, sified as CLI by TASC II but not European consensus (EC) definition. PATIENTS AND METHODS: Patients were selected from the COPART cohort of hospitalized patients with peripheral occlusive arterial disease suffering from lower extremity rest pain or ulcer and who completed one-year follow-up. Ankle and toe systolic pressures and transcutaneous oxygen pressure were measured. The patients were classified into two groups: those who could benefit from revascularization and those who could not (medical group). Within these groups, patients were separated into those who had CLI according to the European consensus definition (EC + TASC II: group A if revascularization, group C if medical treatment) and those who had no CLI by the European definition but who had CLI according to the TASC II definition (TASC: group B if revascularization and D if medical treatment). RESULTS: 471 patients were included in the study (236 in the surgical group, 235 in the medical group). There was no difference according to the CLI definition for survival or cardiovascular event-free survival. However, major amputations were more frequent in group A than in group B (25 vs 12 %, p = 0.046) and in group C than in group D (38 vs 20 %, p = 0.004). CONCLUSIONS: Major amputation is twice as frequent in patients with CLI according to the historical European consensus definition than in those classified to the TASC II definition but not the EC. Caution is required when comparing results of recent series to historical controls. The TASC II definition of CLI is too wide to compare patients from clinical trials so we suggest separating these patients into two different stages: permanent (TASC II but not EC definition) and critical ischaemia (TASC II and EC definition). PMID- 26098328 TI - Deep vein thrombosis caused by an exostosis in an adolescent patient with peripheral neurofibromatosis type 1. PMID- 26098330 TI - Benefits from invasive treatment in intermittent claudication: It is definitely not IRONIC! PMID- 26098329 TI - Peripheral arterial embolism due to involvement of the aortic arch with hydatid cyst. PMID- 26098331 TI - Expectation Suppression in Early Visual Cortex Depends on Task Set. AB - Stimulus expectation can modulate neural responses in early sensory cortical regions, with expected stimuli often leading to a reduced neural response. However, it is unclear whether this expectation suppression is an automatic phenomenon or is instead dependent on the type of task a subject is engaged in. To investigate this, human subjects were presented with visual grating stimuli in the periphery that were either predictable or non-predictable while they performed three tasks that differently engaged cognitive resources. In two of the tasks, the predictable stimulus was task-irrelevant and spatial attention was engaged at fixation, with a high load on either perceptual or working memory resources. In the third task, the predictable stimulus was task-relevant, and therefore spatially attended. We observed that expectation suppression is dependent on the cognitive resources engaged by a subjects' current task. When the grating was task-irrelevant, expectation suppression for predictable items was visible in retinotopically specific areas of early visual cortex (V1-V3) during the perceptual task, but it was abolished when working memory was loaded. When the grating was task-relevant and spatially attended, there was no significant effect of expectation in early visual cortex. These results suggest that expectation suppression is not an automatic phenomenon, but dependent on attentional state and type of available cognitive resources. PMID- 26098333 TI - Correction: ALIX and ESCRT-III Coordinately Control Cytokinetic Abscission during Germline Stem Cell Division In Vivo. PMID- 26098332 TI - Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory. AB - Presenilin-1 (PS1), the catalytic core of the aspartyl protease gamma-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via beta-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer's disease. PMID- 26098334 TI - Biological fitness and the fundamental theorem of natural selection. AB - Fisher's fundamental theorem of natural selection is proved satisfactorily for the first time, resolving confusions in the literature about the nature of reproductive value and fitness. Reproductive value is defined following Fisher, without reference to genetic variation, and fitness is the proportional rate of increase in an individual's contribution to the demographic population size. The mean value of fitness is the same in each age class, and it also equals the population's Malthusian parameter. The statement and derivation are regarded as settled here, and so the general biological significance of the fundamental theorem can be debated. The main purpose of the theorem is to find a quantitative measure of the effect of natural selection in a Mendelian system, thus founding Darwinism on Mendelism and identifying the design criterion for biological adaptation, embodied in Fisher's ingenious definition of fitness. The relevance of the newly understood theorem to five current research areas is discussed. PMID- 26098335 TI - The phenome-wide distribution of genetic variance. AB - A general observation emerging from estimates of additive genetic variance in sets of functionally or developmentally related traits is that much of the genetic variance is restricted to few trait combinations as a consequence of genetic covariance among traits. While this biased distribution of genetic variance among functionally related traits is now well documented, how it translates to the broader phenome and therefore any trait combination under selection in a given environment is unknown. We show that 8,750 gene expression traits measured in adult male Drosophila serrata exhibit widespread genetic covariance among random sets of five traits, implying that pleiotropy is common. Ultimately, to understand the phenome-wide distribution of genetic variance, very large additive genetic variance-covariance matrices (G) are required to be estimated. We draw upon recent advances in matrix theory for completing high dimensional matrices to estimate the 8,750-trait G and show that large numbers of gene expression traits genetically covary as a consequence of a single genetic factor. Using gene ontology term enrichment analysis, we show that the major axis of genetic variance among expression traits successfully identified genetic covariance among genes involved in multiple modes of transcriptional regulation. Our approach provides a practical empirical framework for the genetic analysis of high-dimensional phenome-wide trait sets and for the investigation of the extent of high-dimensional genetic constraint. PMID- 26098336 TI - No synergy needed: ecological constraints favor the evolution of eusociality. AB - In eusocial species, some individuals sacrifice their own reproduction for the benefit of others. It has been argued that the evolution of sterile helpers in eusocial insects requires synergistic efficiency gains through cooperation that are uncommon in cooperatively breeding vertebrates and that this precludes a universal ecological explanation of social systems with alloparental care. In contrast, using a model that incorporates realistic ecological mechanisms of population regulation, we show here that constraints on independent breeding (through nest-site limitation and dispersal mortality) eliminate any need for synergistic efficiency gains: sterile helpers may evolve even if they are relatively inefficient at rearing siblings, reducing their colony's per-capita productivity. Our approach connects research fields by using hypotheses developed for cooperative breeding to explain the evolution of eusociality. The results suggest that these hypotheses may apply more generally than previously thought. PMID- 26098337 TI - Here's to the losers: evolvable residents accelerate the evolution of high fitness invaders. AB - Recent work has shown that evolvability plays a key role in determining the long term population dynamics of asexual clones. However, simple considerations suggest that the evolvability of a focal lineage of bacteria should also be influenced by the evolvability of its competitors. First, evolvable competitors should accelerate evolution by impeding the fixation of the focal lineage through a clonal interference-like mechanism. Second, evolvable competitors should increase the strength of selection by rapidly degrading the environment, increasing selection for adaptive mutations. Here we tested these ideas by allowing a high-fitness clone of the bacterium Pseudomonas aeruginosa to invade populations of two low-fitness resident clones that differ in their evolvability. Both competition from mutations in the resident lineage and environmental degradation lead to faster adaptation in the invader through fixing single mutations with a greater fitness advantage. The results suggest that competition from mutations in both the successful invader and the unsuccessful resident shapes the adaptive trajectory of the invader through both direct competition and indirect environmental effects. Therefore, to predict evolutionary outcomes, it will be necessary to consider the evolvability of all members of the community and the effects of adaptation on the quality of the environment. This is particularly relevant to mixed microbial communities where lineages differ in their adaptive potential, a common feature of chronic infections. PMID- 26098338 TI - Factors influencing the detectability of early warning signals of population collapse. AB - The recent description of potentially generic early warning signals is a promising development that may help conservationists to anticipate a population's collapse prior to its occurrence. So far, the majority of such warning signals documented have been in highly controlled laboratory systems or in theoretical models. Data from wild populations, however, are typically restricted both temporally and spatially due to limited monitoring resources and intrinsic ecological heterogeneity-limitations that may affect the detectability of generic early warning signals, as they add additional stochasticity to population abundance estimates. Consequently, spatial and temporal subsampling may serve to either muffle or magnify early warning signals. Using a combination of theoretical models and analysis of experimental data, we evaluate the extent to which statistical warning signs are robust to data corruption. PMID- 26098339 TI - Resident-invader phylogenetic relatedness, not resident phylogenetic diversity, controls community invasibility. AB - A central goal of invasion biology is to elucidate mechanisms regulating community invasibility. Darwin's naturalization hypothesis, one of the oldest hypotheses in invasion biology, emphasizes the importance of phylogenetic relatedness (PR) between resident and invader species for predicting invasibility. Alternatively, a recent extension of the diversity-invasibility hypothesis predicts that phylogenetic diversity (PD) of resident communities influences invasibility. Neither of these hypotheses has undergone rigorous experimental testing, and the relative contributions of PR and PD to community invasibility are unknown, in part because their effects tend to be confounded with each other. Here we consider both perspectives together by independently manipulating PR and PD in laboratory bacterial assemblages. We found that, although invader abundance decreased significantly as PR increased, it was unaffected by PD. Likewise, we found that resident-invader functional similarity, not functional diversity of resident communities, was a significant predictor of invader abundance. Nevertheless, invader abundance was better predicted by PR than by functional similarity. These results highlight the importance of considering species evolutionary relationships, especially the PR between resident and invader species, for the prediction, prevention, and management of biological invasions. PMID- 26098340 TI - Competition for light and nutrients in layered communities of aquatic plants. AB - Dominance of free-floating plants poses a threat to biodiversity in many freshwater ecosystems. Here we propose a theoretical framework to understand this dominance, by modeling the competition for light and nutrients in a layered community of floating and submerged plants. The model shows that at high supply of light and nutrients, floating plants always dominate due to their primacy for light, even when submerged plants have lower minimal resource requirements. The model also shows that floating-plant dominance cannot be an alternative stable state in light-limited environments but only in nutrient-limited environments, depending on the plants' resource consumption traits. Compared to unlayered communities, the asymmetry in competition for light-coincident with symmetry in competition for nutrients-leads to fundamentally different results: competition outcomes can no longer be predicted from species traits such as minimal resource requirements ([Formula: see text] rule) and resource consumption. Also, the same two species can, depending on the environment, coexist or be alternative stable states. When applied to two common plant species in temperate regions, both the model and field data suggest that floating-plant dominance is unlikely to be an alternative stable state. PMID- 26098341 TI - Scale-dependent phenological synchrony between songbirds and their caterpillar food source. AB - In seasonal environments, the timing of reproduction has important fitness consequences. Our current understanding of the determinants of reproductive phenology in natural systems is limited because studies often ignore the spatial scale on which animals interact with their environment. When animals use a restricted amount of space and the phenology of resources is spatially variable, selection may favor sensitivity to small-scale environmental variation. Population-level studies of how songbirds track the changing phenology of their food source have been influential in explaining how populations adjust to changing climates but have largely ignored the spatial scale at which phenology varies. We explored whether individual great tits (Parus major) synchronize their breeding with phenological events in their local environment and investigated the spatial scale at which this occurs. We demonstrate marked variation in the timing of food availability, at a spatial scale relevant to individual birds, and that such local variation predicts the breeding phenology of individuals. Using a 45 year data set, we show that measures of vegetation phenology at very local scales are the most important predictors of timing of breeding within years, suggesting that birds can fine-tune their phenology to that of other trophic levels. Knowledge of the determinants of variation in reproductive behavior at different spatial scales is likely to be critical in understanding how selection operates on breeding phenology in natural populations. PMID- 26098342 TI - Evolutionary divergence of adult body size and juvenile growth in sympatric subpopulations of a top predator in aquatic ecosystems. AB - Evolutionary theory predicts that different selective regimes may contribute to divergent evolution of body size and growth rate among populations, but most studies have focused on allopatric populations. Here, we studied five sympatric subpopulations of anadromous northern pike (Esox lucius) in the Baltic Sea subjected to allopatric habitats for a short period of their life cycle due to homing behavior. We report differences in adult body size among subpopulations that were in part due to variation in growth rate. Body size of emigrating juveniles also differed among subpopulations, and differences remained when individuals were reared in a common environment, thus indicating evolutionary divergence among subpopulations. Furthermore, a QST-FST comparison indicated that differences had evolved due to divergent selection rather than genetic drift, possibly in response to differences in selective mortality among spawning habitats during the allopatric life stage. Adult and juvenile size were negatively correlated across subpopulations, and reconstruction of growth trajectories of adult fishes suggested that body size differences developed gradually and became accentuated throughout the first years of life. These results represent rare evidence that sympatric subpopulations can evolve differences in key life-history traits despite being subjected to allopatric habitats during only a very short fraction of their life. PMID- 26098343 TI - Optimal forager against ideal free distributed prey. AB - The introduced dispersal-foraging game is a combination of prey habitat selection between two patch types and optimal-foraging approaches. Prey's patch preference and forager behavior determine the prey's survival rate. The forager's energy gain depends on local prey density in both types of exhaustible patches and on leaving time. We introduce two game-solution concepts. The static solution combines the ideal free distribution of the prey with optimal-foraging theory. The dynamical solution is given by a game dynamics describing the behavioral changes of prey and forager. We show (1) that each stable equilibrium dynamical solution is always a static solution, but not conversely; (2) that at an equilibrium dynamical solution, the forager can stabilize prey mixed patch use strategy in cases where ideal free distribution theory predicts that prey will use only one patch type; and (3) that when the equilibrium dynamical solution is unstable at fixed prey density, stable behavior cycles occur where neither forager nor prey keep a fixed behavior. PMID- 26098344 TI - Rearing-group size determines social competence and brain structure in a cooperatively breeding cichlid. AB - Social animals can greatly benefit from well-developed social skills. Because the frequency and diversity of social interactions often increase with the size of social groups, the benefits of advanced social skills can be expected to increase with group size. Variation in social skills often arises during ontogeny, depending on early social experience. Whether variation of social-group sizes affects development of social skills and related changes in brain structures remains unexplored. We investigated whether, in a cooperatively breeding cichlid, early group size (1) shapes social behavior and social skills and (2) induces lasting plastic changes in gross brain structures and (3) whether the development of social skills is confined to a sensitive ontogenetic period. Rearing-group size and the time juveniles spent in these groups interactively influenced the development of social skills and the relative sizes of four main brain regions. We did not detect a sensitive developmental period for the shaping of social behavior within the 2-month experience phase. Instead, our results suggest continuous plastic behavioral changes over time. We discuss how developmental effects on social behavior and brain architecture may adaptively tune phenotypes to their current or future environments. PMID- 26098345 TI - Frequency-dependent selection on female morphs driven by premating interactions with males. AB - Species showing color polymorphisms-the presence of two or more genetically determined color morphs within a single population-are excellent systems for studying the selective forces driving the maintenance of genetic diversity. Despite a shortage of empirical evidence, it is often suggested that negative frequency-dependent mate preference by males (or diet choice by predators) results in fitness benefits for the rare female morph (or prey type). Moreover, most studies have focused on the male (or predator) behavior in these systems and largely overlooked the importance of female (or prey) resistance behavior. Here, we provide the first explicit test of the role of frequency-dependent and frequency-independent intersexual interactions in female polymorphic damselflies. We identify the stage of the mating sequence when frequency-dependent selection is likely to act by comparing indexes of male mate preference when the female has little (females presented on sticks), moderate (females in cages), and high (females free to fly in the field) ability to avoid male mating attempts. Frequency-dependent male preferences were found only in those experiments where females had little ability to resist male harassment, indicating that premating interactions most likely drive negative frequency-dependent selection in this system. In addition, by separating frequency-dependent male mating preference from the baseline frequency-independent component, we reconcile the seemingly contradictory results of previous studies and highlight the roles of both forms of selection in maintaining the polymorphism at a given equilibrium. We conclude that considering interactions among all players-here, males and females-is crucial to fully understanding the mechanisms underlying the maintenance of genetic polymorphisms in the wild. PMID- 26098346 TI - Trade-offs and coexistence in fluctuating environments: evidence for a key dispersal-fecundity trade-off in five nonpollinating fig wasps. AB - The ecological principle of competitive exclusion states that species competing for identical resources cannot coexist, but this principle is paradoxical because ecologically similar competitors are regularly observed. Coexistence is possible under some conditions if a fluctuating environment changes the competitive dominance of species. This change in competitive dominance implies the existence of trade-offs underlying species' competitive abilities in different environments. Theory shows that fluctuating distance between resource patches can facilitate coexistence in ephemeral patch competitors, given a functional trade off between species dispersal ability and fecundity. We find evidence supporting this trade-off in a guild of five ecologically similar nonpollinating fig wasps and subsequently predict local among-patch species densities. We also introduce a novel colonization index to estimate relative dispersal ability among ephemeral patch competitors. We suggest that a dispersal ability-fecundity trade-off and spatiotemporally fluctuating resource availability commonly co-occur to drive population dynamics and facilitate coexistence in ephemeral patch communities. PMID- 26098347 TI - Correction. PMID- 26098348 TI - Correction. PMID- 26098349 TI - Correction. PMID- 26098350 TI - Correction. PMID- 26098351 TI - Evolution of plant growth and defense in a continental introduction. AB - Substantial research has addressed adaptation of nonnative biota to novel environments, yet surprisingly little work has integrated population genetic structure and the mechanisms underlying phenotypic differentiation in ecologically important traits. We report on studies of the common milkweed Asclepias syriaca, which was introduced from North America to Europe over the past 400 years and which lacks most of its specialized herbivores in the introduced range. Using 10 populations from each continent grown in a common environment, we identified several growth and defense traits that have diverged, despite low neutral genetic differentiation between continents. We next developed a Bayesian modeling approach to account for relationships between molecular and phenotypic differences, confirming that continental trait differentiation was greater than expected from neutral genetic differentiation. We found evidence that growth-related traits adaptively diverged within and between continents. Inducible defenses triggered by monarch butterfly herbivory were substantially reduced in European populations, and this reduction in inducibility was concordant with altered phytohormonal dynamics, reduced plant growth, and a trade off with constitutive investment. Freedom from the community of native and specialized herbivores may have favored constitutive over induced defense. Our replicated analysis of plant growth and defense, including phenotypically plastic traits, suggests adaptive evolution following a continental introduction. PMID- 26098352 TI - The evolution of foraging rate across local and geographic gradients in predation risk and competition. AB - Multiple theories predict the evolution of foraging rates in response to environmental variation in predation risk, intraspecific competition, time constraints, and temperature. We tested six hypotheses for the evolution of foraging rate in 24 spotted salamander (Ambystoma maculatum) populations from three latitudinally divergent sites using structural equation models derived from theory and applied to our system. We raised salamander larvae in a common-garden experiment and then assayed foraging rate under controlled conditions. Gape limited predation risk from marbled salamanders solely explained foraging rate variation among populations at the southern site, which was dominated by this form of selection. However, at the middle and northern sites, populations evolved different foraging rates depending on their unique responses to local intraspecific density. The coupling of gape-limited predation risk from marbled salamanders and high intraspecific density at the middle site jointly contributed to selection for rapid foraging rate. At the northernmost site, intraspecific density alone explained 97% of the interpopulation variation in foraging rate. These results suggest that foraging rate has evolved multiple times in response to varying contributions from predation risk and intraspecific competition. Predation risk often varies along environmental gradients, and, thus, organisms might often shift evolutionary responses from minimizing predation risk to maximizing intraspecific competitive performance. PMID- 26098353 TI - Insight into the Migration Routes of Plutella xylostella in China Using mtCOI and ISSR Markers. AB - The larvae of the diamondback moth, Plutella xylostella, cause major economic losses to cruciferous crops, including cabbage, which is an important vegetable crop in China. In this study, we used the mitochondrial COI gene and 11 ISSR markers to characterize the genetic structure and seasonal migration routes of 23 P. xylostella populations in China. Both the mitochondrial and nuclear markers revealed high haplotype diversity and gene flow among the populations, although some degree of genetic isolation was evident between the populations of Hainan Island and other sampling sites. The dominant haplotypes, LX1 and LX2, differed significantly from all other haplotypes both in terms of the number of individuals with those haplotypes and their distributions. Haplotypes that were shared among populations revealed that P. xylostella migrates from the lower reaches of the Yangtze River to northern China and then to northeastern China. Our results also revealed another potential migration route for P. xylostella, i.e., from southwestern China to both northwestern and southern China. PMID- 26098354 TI - Characterization of ESBL- and AmpC-Producing Enterobacteriaceae from Diseased Companion Animals in Europe. AB - The study aimed to characterize beta-lactam resistance mechanisms of Enterobacteriaceae isolates recovered from diseased dogs and cats between 2008 and 2010 in a European surveillance program (ComPath I) for the antibiotic susceptibility of bacterial pathogens. A total of 608 non-duplicated Enterobacteriaceae isolates were obtained prior antibiotic treatment from diseased dogs (n=464) and cats (n=144). Among the 608 Enterobacteriaceae isolates, 22 presented a minimal inhibitory concentration against cefotaxime above EUCAST breakpoints of susceptibility. All the 22 isolates remained susceptible to carbapenems. Ten isolates were confirmed as extended-spectrum-beta lactamase (ESBL) producers by PCR-sequencing of bla coding genes including 9 blaCTX-M (CTX-M-1, 14, 15, 32,...) and 1 blaTEM-52 and 12 were AmpC-producing isolates (10 plasmidic CMY-2 group and 2 isolates overexpressing their chromosomal AmpC). ESBLs and plasmid-mediated AmpC (pAmpC)-producing isolates were mainly recovered from dogs (n=17) suffering from urinary tract infections (n=13) and originated from eight different countries. ESBL-bearing plasmids were mostly associated with IncFII incompatibility groups while CMY-2 was predominantly associated with plasmid of the IncI1 group. ESBL/pAmpC-producing Escherichia coli belonged to phylogroup A (n=5), B2 (n=4), and D (n=5). Multilocus sequence typing analysis revealed that among three CTX-M-15-producing E. coli, two belong to sequence type (ST) 131 and one to ST405. The presence of CTX-M-15 including on IncFII plasmids in E. coli ST131-B2 has also been described in isolates of human origin. This suggests the possibility of exchanges of these isolates from humans to companion animals or vice-versa. PMID- 26098355 TI - What Determines Habitat Quality for a Declining Woodland Bird in a Fragmented Environment: The Grey-Crowned Babbler Pomatostomus temporalis in South-Eastern Australia? AB - Understanding what constitutes high quality habitat is crucial for the conservation of species, especially those threatened with extinction. Habitat quality frequently is inferred by comparing the attributes of sites where a species is present with those where it is absent. However, species presence may not always indicate high quality habitat. Demographic parameters are likely to provide a more biologically relevant measure of quality, including a species' ability to successfully reproduce. We examined factors believed to influence territory quality for the grey-crowned babbler (Pomatostomus temporalis), a cooperatively breeding woodland bird that has experienced major range contraction and population decline in south-eastern Australia. Across three broad regions, we identified active territories and determined the presence of fledglings and the size of family groups, as surrogates of territory quality. These measures were modelled in relation to habitat attributes within territories, the extent of surrounding wooded vegetation, isolation from neighbouring groups, and the size of the neighbourhood population. Fledgling presence was strongly positively associated with group size, indicating that helpers enhance breeding success. Surprisingly, no other territory or landscape-scale variables predicted territory quality, as inferred from either breeding success or group size. Relationships between group size and environmental variables may be obscured by longer-term dynamics in group size. Variation in biotic interactions, notably competition from the noisy miner (Manorina melanocephala), also may contribute. Conservation actions that enhance the number and size of family groups will contribute towards reversing declines of this species. Despite associated challenges, demographic studies have potential to identify mechanistic processes that underpin population performance; critical knowledge for effective conservation management. PMID- 26098356 TI - High-speed intravascular spectroscopic photoacoustic imaging at 1000 A-lines per second with a 0.9-mm diameter catheter. AB - Intravascular spectroscopic photoacoustic technology can image atherosclerotic plaque composition with high sensitivity and specificity, which is critical for identifying vulnerable plaques. Here, we designed and engineered a catheter of 0.9 mm in diameter for intravascular photoacoustic (IVPA) imaging, smaller than the critical size of 1 mm required for clinical translation. Further, a quasifocusing photoacoustic excitation scheme was developed for the catheter, producing well-detectable IVPA signals from stents and lipids with a laser energy as low as ~30 MUJ/pulse. As a result, this design enabled the use of a low energy, high-repetition rate, ns-pulsed optical parametric oscillator laser for high-speed spectroscopic IVPA imaging at both the 1.2-MUm and 1.7-MUm spectral bands for lipid detection. Specifically, for each wavelength, a 1-kHz IVPA A-line rate was achieved, ~100-fold faster than previously reported IVPA systems offering a similar wavelength tuning range. Using the system, spectroscopic IVPA imaging of peri-adventitial adipose tissue from a porcine aorta segment was demonstrated. The significantly improved imaging speed, together with the reduced catheter size and multiwavelength spectroscopic imaging ability, suggests that the developed high-speed IVPA technology is of great potential to be further translated for in vivo applications. PMID- 26098357 TI - Errata: Simulation study of melanoma detection in human skin tissues by laser generated surface acoustic waves. PMID- 26098358 TI - Change in the Green-Up Dates for Quercus mongolica in Northeast China and Its Climate-Driven Mechanism from 1962 to 2012. AB - The currently available studies on the green-up date were mainly based on ground observations and/or satellite data, and few model simulations integrated with wide coverage satellite data have been reported at large scale over a long time period (i.e., > 30 years). In this study, we combined phenology mechanism model, long-term climate data and synoptic scale remote sensing data to investigate the change in the green-up dates for Quercus mongolica over 33 weather stations in Northeast China and its climate-driven mechanism during 1962-2012. The results indicated that the unified phenology model can be well parameterized with the satellite derived green-up dates. The optimal daily mean temperature for chilling effect was between -27 degrees C and 1 degrees C for Q. mongolica in Northeast China, while the optimal daily mean temperature for forcing effect was above -3 degrees C. The green-up dates for Q. mongolica across Northeast China showed a delayed latitudinal gradient of 2.699 days degree-1, with the earliest date on the Julian day 93 (i.e., 3th April) in the south and the latest date on the Julian day 129 (i.e., 9th May) in the north. The green-up date for Q. mongolica in Northeast China has advanced 6.6 days (1.3 days decade-1) from 1962 to 2012. With the prevailing warming in autumn, winter and spring in Northeast China during the past 51 years, the chilling effect for Q. mongolica has been weakened, while the forcing effect has been enhanced. The advancing trend in the green-up dates for Q. mongolica implied that the enhanced forcing effect to accelerate green-up was stronger than the weakened chilling effect to hold back green-up while the changes of both effects were caused by the warming climate. PMID- 26098359 TI - Ethical Dilemmas in Palliative Care: A Case Study of Fertility Preservation in the Context of Metastatic Cancer. PMID- 26098360 TI - Correction: TreeSeq, a Fast and Intuitive Tool for Analysis of Whole Genome and Metagenomic Sequence Data. PMID- 26098361 TI - Alcohol-Preferring Rats Show Goal Oriented Behaviour to Food Incentives but Are Neither Sign-Trackers Nor Impulsive. AB - Drug addiction is often associated with impulsivity and altered behavioural responses to both primary and conditioned rewards. Here we investigated whether selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats show differential levels of impulsivity and conditioned behavioural responses to food incentives. P and NP rats were assessed for impulsivity in the 5-choice serial reaction time task (5-CSRTT), a widely used translational task in humans and other animals, as well as Pavlovian conditioned approach to measure sign- and goal-tracking behaviour. Drug-naive P and NP rats showed similar levels of impulsivity on the 5-CSRTT, assessed by the number of premature, anticipatory responses, even when the waiting interval to respond was increased. However, unlike NP rats, P rats were faster to enter the food magazine and spent more time in this area. In addition, P rats showed higher levels of goal-tracking responses than NP rats, as measured by the number of magazine nose-pokes during the presentation of a food conditioned stimulus. By contrast, NP showed higher levels of sign-tracking behaviour than P rats. Following a 4-week exposure to intermittent alcohol we confirmed that P rats had a marked preference for, and consumed more alcohol than, NP rats, but were not more impulsive when re-tested in the 5-CSRTT. These findings indicate that high alcohol preferring and drinking P rats are neither intrinsically impulsive nor do they exhibit impulsivity after exposure to alcohol. However, P rats do show increased goal-directed behaviour to food incentives and this may be associated with their strong preference for alcohol. PMID- 26098363 TI - Entinostat (SNDX-275) for the treatment of non-small cell lung cancer. AB - INTRODUCTION: Epigenetic aberrations play an important role in lung carcinogenesis. Chromatin deacetylation is a fundamental mechanism of gene silencing. Histone deacetylase (HDAC) inhibitors are an emerging class of antineoplastic agents that enable the accessibility of DNA to transcription factors, therefore promoting gene expression. Entinostat is a selective HDAC inhibitor that has shown anti-neoplastic activity and tolerability in hematologic and solid tumors, including lung cancer. AREAS COVERED: This article summarizes the pharmacokinetics, pharmacodynamics, mechanisms of action, safety, tolerability, pre-clinical studies and clinical trials of the HDAC inhibitor entinostat, as a novel promissory agent for the treatment of NSCLC. EXPERT OPINION: The field of targeted therapy has increased in lung cancer. However, even now with the current FDA-approved agents, < 15% of patients benefit from these interventions and we are still far from curing lung cancer. New targets are needed. Either in combination with cytotoxic drugs, epigenetic therapy or other molecular targeted drugs, entinostat represents a new potential agent for the treatment of non-small cell carcinomas. However, the preliminary safety and efficacy results from several clinical trials still need to be validated in large Phase III trials. PMID- 26098362 TI - Prevalence and Effect of Cyberbullying on Children and Young People: A Scoping Review of Social Media Studies. AB - IMPORTANCE: Social media has had a profound effect on how children and adolescents interact. While there are many benefits to the use of social media, cyberbullying has emerged as a potential harm, raising questions regarding its influence on mental health. OBJECTIVE: To review existing publications that examine the health-related effects of cyberbullying via social media among children and adolescents. EVIDENCE REVIEW: We searched 11 electronic databases from January 1, 2000, through January 17, 2012 (updated June 24, 2014). Studies were screened by 2 independent reviewers and were included if they reported primary research, described or evaluated the use of a social media tool in the context of cyberbullying, and were conducted with children or adolescents. Data were extracted by 1 reviewer and verified by a second. All studies were assessed by 2 reviewers for methodological quality using the Mixed Methods Appraisal Tool. Results were not pooled owing to heterogeneity in study objectives and outcomes; a narrative analysis is presented. FINDINGS: Thirty-six studies in 34 publications were included. Most were conducted in the United States (21 [58.3%]), sampled middle and high school populations (24 [66.7%]), and included adolescents who were 12 to 18 years of age (35 [97.2%]). The median reported prevalence of cyberbullying was 23.0% (interquartile range, 11.0%-42.6%). Five studies reported inconsistent and/or weak correlations between cyberbullying and anxiety. Ten studies found a statistically significant association between cyberbullying and report of depression. Five studies investigated self-harm or suicidality, with conflicting results. Results indicate that the most common reason for cyberbullying is relationship issues, with girls most often being the recipients. Responses to cyberbullying are most often passive, with a pervasive lack of awareness or confidence that anything can be done. CONCLUSIONS AND RELEVANCE: There is a consistent relationship across studies between cyberbullying and depression among children and adolescents; however, the evidence of the effect of cyberbullying on other mental health conditions is inconsistent. This review provides important information that characterizes cyberbullying within the context of social media, including attributes of the recipients and perpetrators, reasons for and the nature of bullying behaviors, and how recipients react to and manage bullying behaviors. This information is critical to the development of effective prevention and management strategies. PMID- 26098364 TI - Ecological and Landscape Drivers of Neonicotinoid Insecticide Detections and Concentrations in Canada's Prairie Wetlands. AB - Neonicotinoids are commonly used seed treatments on Canada's major prairie crops. Transported via surface and subsurface runoff into wetlands, their ultimate aquatic fate remains largely unknown. Biotic and abiotic wetland characteristics likely affect neonicotinoid presence and environmental persistence, but concentrations vary widely between wetlands that appear ecologically (e.g., plant composition) and physically (e.g., depth) similar for reasons that remain unclear. We conducted intensive surveys of 238 wetlands, and documented 59 wetland (e.g., dominant plant species) and landscape (e.g., surrounding crop) characteristics as part of a novel rapid wetland assessment system. We used boosted regression tree (BRT) analysis to predict both probability of neonicotinoid analytical detection and concentration. BRT models effectively predicted the deviance in neonicotinoid detection (62.4%) and concentration (74.7%) from 21 and 23 variables, respectively. Detection was best explained by shallow marsh plant species identity (34.8%) and surrounding crop (13.9%). Neonicotinoid concentration was best explained by shallow marsh plant species identity (14.9%) and wetland depth (14.2%). Our research revealed that plant composition is a key indicator and/or driver of neonicotinoid presence and concentration in Prairie wetlands. We recommend wetland buffers consisting of diverse native vegetation be retained or restored to minimize neonicotinoid transport and retention in wetlands, thereby limiting their potential effects on wetland-dependent organisms. PMID- 26098365 TI - First Evidence of Rh Nano-Hydride Formation at Low Pressure. AB - Rh-based nanoparticles supported on a porous carbon host were prepared with tunable average sizes ranging from 1.3 to 3.0 nm. Depending on the vacuum or hydrogen environment during thermal treatment, either Rh metal or hydride is formed at nanoscale, respectively. In contrast to bulk Rh that can form a hydride phase under 4 GPa pressure, the metallic Rh nanoparticles (~2.3 nm) absorb hydrogen and form a hydride phase at pressure below 0.1 MPa, as evidenced by the presence of a plateau pressure in the pressure-composition isotherm curves at room temperature. Larger metal nanoparticles (~3.0 nm) form only a solid solution with hydrogen under similar conditions. This suggests a nanoscale effect that drastically changes the Rh-H thermodynamics. The nanosized Rh hydride phase is stable at room temperature and only desorbs hydrogen above 175 degrees C. Within the present hydride particle size range (1.3-2.3 nm), the hydrogen desorption is size-dependent, as proven by different thermal analysis techniques. PMID- 26098366 TI - Redox rhythm reinforces the circadian clock to gate immune response. AB - Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism's metabolic activities. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated. Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis related gene 1) of Arabidopsis is a sensor of the plant's redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism. PMID- 26098367 TI - Rapidly rotating second-generation progenitors for the 'blue hook' stars of omega Centauri. AB - Horizontal branch stars belong to an advanced stage in the evolution of the oldest stellar galactic population, occurring either as field halo stars or grouped in globular clusters. The discovery of multiple populations in clusters that were previously believed to have single populations gave rise to the currently accepted theory that the hottest horizontal branch members (the 'blue hook' stars, which had late helium-core flash ignition, followed by deep mixing) are the progeny of a helium-rich 'second generation' of stars. It is not known why such a supposedly rare event (a late flash followed by mixing) is so common that the blue hook of omega Centauri contains approximately 30 per cent of the horizontal branch stars in the cluster, or why the blue hook luminosity range in this massive cluster cannot be reproduced by models. Here we report that the presence of helium core masses up to about 0.04 solar masses larger than the core mass resulting from evolution is required to solve the luminosity range problem. We model this by taking into account the dispersion in rotation rates achieved by the progenitors, whose pre-main-sequence accretion disk suffered an early disruption in the dense environment of the cluster's central regions, where second-generation stars form. Rotation may also account for frequent late-flash mixing events in massive globular clusters. PMID- 26098368 TI - Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. AB - Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia inducible factor 1 alpha (Hif-1alpha) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen dependent degradation (ODD) domain of Hif-1alpha is fused to the tamoxifen inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific alpha myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals. PMID- 26098369 TI - Engineered CRISPR-Cas9 nucleases with altered PAM specificities. AB - Although CRISPR-Cas9 nucleases are widely used for genome editing, the range of sequences that Cas9 can recognize is constrained by the need for a specific protospacer adjacent motif (PAM). As a result, it can often be difficult to target double-stranded breaks (DSBs) with the precision that is necessary for various genome-editing applications. The ability to engineer Cas9 derivatives with purposefully altered PAM specificities would address this limitation. Here we show that the commonly used Streptococcus pyogenes Cas9 (SpCas9) can be modified to recognize alternative PAM sequences using structural information, bacterial selection-based directed evolution, and combinatorial design. These altered PAM specificity variants enable robust editing of endogenous gene sites in zebrafish and human cells not currently targetable by wild-type SpCas9, and their genome-wide specificities are comparable to wild-type SpCas9 as judged by GUIDE-seq analysis. In addition, we identify and characterize another SpCas9 variant that exhibits improved specificity in human cells, possessing better discrimination against off-target sites with non-canonical NAG and NGA PAMs and/or mismatched spacers. We also find that two smaller-size Cas9 orthologues, Streptococcus thermophilus Cas9 (St1Cas9) and Staphylococcus aureus Cas9 (SaCas9), function efficiently in the bacterial selection systems and in human cells, suggesting that our engineering strategies could be extended to Cas9s from other species. Our findings provide broadly useful SpCas9 variants and, more importantly, establish the feasibility of engineering a wide range of Cas9s with altered and improved PAM specificities. PMID- 26098370 TI - X-ray structure of a mammalian stearoyl-CoA desaturase. AB - Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs. Because the monounsaturated products of SCD are key precursors of membrane phospholipids, cholesterol esters and triglycerides, SCD is pivotal in fatty acid metabolism. Humans have two SCD homologues (SCD1 and SCD5), while mice have four (SCD1-SCD4). SCD1-deficient mice do not become obese or diabetic when fed a high-fat diet because of improved lipid metabolic profiles and insulin sensitivity. Thus, SCD1 is a pharmacological target in the treatment of obesity, diabetes and other metabolic diseases. SCD1 is an integral membrane protein located in the endoplasmic reticulum, and catalyses the formation of a cis-double bond between the ninth and tenth carbons of stearoyl- or palmitoyl-CoA. The reaction requires molecular oxygen, which is activated by a di-iron centre, and cytochrome b5, which regenerates the di-iron centre. To understand better the structural basis of these characteristics of SCD function, here we crystallize and solve the structure of mouse SCD1 bound to stearoyl-CoA at 2.6 A resolution. The structure shows a novel fold comprising four transmembrane helices capped by a cytosolic domain, and a plausible pathway for lateral substrate access and product egress. The acyl chain of the bound stearoyl-CoA is enclosed in a tunnel buried in the cytosolic domain, and the geometry of the tunnel and the conformation of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal centre is coordinated by a unique spacial arrangement of nine conserved histidine residues that implies a potentially novel mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the di-iron centre. PMID- 26098371 TI - Impermanence of dendritic spines in live adult CA1 hippocampus. AB - The mammalian hippocampus is crucial for episodic memory formation and transiently retains information for about 3-4 weeks in adult mice and longer in humans. Although neuroscientists widely believe that neural synapses are elemental sites of information storage, there has been no direct evidence that hippocampal synapses persist for time intervals commensurate with the duration of hippocampal-dependent memory. Here we tested the prediction that the lifetimes of hippocampal synapses match the longevity of hippocampal memory. By using time lapse two-photon microendoscopy in the CA1 hippocampal area of live mice, we monitored the turnover dynamics of the pyramidal neurons' basal dendritic spines, postsynaptic structures whose turnover dynamics are thought to reflect those of excitatory synaptic connections. Strikingly, CA1 spine turnover dynamics differed sharply from those seen previously in the neocortex. Mathematical modelling revealed that the data best matched kinetic models with a single population of spines with a mean lifetime of approximately 1-2 weeks. This implies ~100% turnover in ~2-3 times this interval, a near full erasure of the synaptic connectivity pattern. Although N-methyl-d-aspartate (NMDA) receptor blockade stabilizes spines in the neocortex, in CA1 it transiently increased the rate of spine loss and thus lowered spine density. These results reveal that adult neocortical and hippocampal pyramidal neurons have divergent patterns of spine regulation and quantitatively support the idea that the transience of hippocampal dependent memory directly reflects the turnover dynamics of hippocampal synapses. PMID- 26098372 TI - An early modern human from Romania with a recent Neanderthal ancestor. AB - Neanderthals are thought to have disappeared in Europe approximately 39,000 41,000 years ago but they have contributed 1-3% of the DNA of present-day people in Eurasia. Here we analyse DNA from a 37,000-42,000-year-old modern human from Pestera cu Oase, Romania. Although the specimen contains small amounts of human DNA, we use an enrichment strategy to isolate sites that are informative about its relationship to Neanderthals and present-day humans. We find that on the order of 6-9% of the genome of the Oase individual is derived from Neanderthals, more than any other modern human sequenced to date. Three chromosomal segments of Neanderthal ancestry are over 50 centimorgans in size, indicating that this individual had a Neanderthal ancestor as recently as four to six generations back. However, the Oase individual does not share more alleles with later Europeans than with East Asians, suggesting that the Oase population did not contribute substantially to later humans in Europe. PMID- 26098373 TI - Evidence-based preventive intervention for preadolescent aggressive children: One year outcomes following randomization to group versus individual delivery. AB - OBJECTIVE: Some research suggests that group interventions with antisocial youth may, on occasion, have iatrogenic effects. This is the first study to test the effects of group versus individual delivery of evidence-based intervention for aggressive children. METHOD: Three hundred sixty fourth-grade children were randomly assigned by school to group coping power (GCP) or individual coping power (ICP). Longitudinal assessments of teacher and parent reports of behavior (Behavior Assessment System for Children [BASC]; Peer Affiliation and Social Acceptance [PASA]) were collected from baseline through a 1-year follow-up. RESULTS: Growth curve analyses revealed that children in both conditions reduced teacher- and parent-reported externalizing behavior problems and internalizing behavior problems by the end of the 1-year follow-up. However, the degree of improvement in teacher-reported outcomes was significantly greater for children receiving an individual version of the program. In addition, children's baseline level of inhibitory control moderated intervention effects, showing children with low initial levels of inhibitory control to respond poorly in teacher-rated outcomes to group interventions compared to those delivered individually. CONCLUSIONS: This study suggests overall benefits to children for either group or individual delivery of the Coping Power program under high-fidelity conditions; however, for children with low levels of initial self-regulation, individualized interventions will likely yield the most significant reduction in externalizing behavior in the school setting in preadolescence. PMID- 26098374 TI - Direct-to-consumer marketing of psychological treatments: A randomized controlled trial. AB - OBJECTIVE: Although direct-to-consumer (DTC) marketing of pharmacologic interventions is effective and common, similar approaches have yet to be evaluated in the promotion of psychological treatments (PTs). This is the first randomized controlled trial evaluating the potential of DTC marketing of PTs. METHOD: Participants (N = 344; 75.0% female, mean age = 18.6 years, 48.5% non Hispanic White) were randomly assigned to consume one of four extended commercial campaigns embedded within unrelated programming across 3 weeks. The four campaign conditions were a PT campaign, a PT informing about medication side effects campaign, a medication campaign, and a neutral campaign. Attitudes about and intention to seek psychological treatment were assessed prior to campaign exposure (T1), 1 week following the final week of campaign exposure (T2), and at a 3-month follow-up evaluation (T3). RESULTS: The percentage of participants who newly intended psychological treatment at T2 or T3 differed by condition, with those assigned to the PT campaign slightly more likely to have intended to receive psychological treatment at T2 or T3 than those in other conditions. Baseline reports of emotional symptoms moderated the effect of condition on attitudes toward PT and perceived likelihood of seeking treatment in the future. CONCLUSIONS: Findings support the preliminary utility of DTC marketing of psychological treatments. Increasing consumer knowledge of PTs may be a worthwhile complement to current dissemination and implementation efforts aimed at promoting the uptake of PTs in mental health care. PMID- 26098376 TI - From retrograde signaling to flowering time. AB - Plant's transition from vegetative to reproductive phase is balanced by intricate cascade of genes regulated by both endogenous and environmental inputs. Stress causes suppression of vegetative growth and acceleration of flowering as an emergency response for preservation of the species. Recently, we determined that expression levels of a transcription factor with 2 B-Box motifs, BBX19, is notably reduced in response to accumulation of high levels of Methylerythritol cyclodiphosphate (MEcPP), a plastidial produced isoprenoids intermediate that also functions as a stress-specific retrograde signaling metabolite. We now have identified BBX19 as a repressor of Flower locus T (FT) expression and the corresponding downstream genes, SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), Leafy (LFY) and Fruitful (FUL), through competition with CONSTANS (CO). Collectively our finding identifies BBX19 as a link between the stress-specific retrograde signal MEcPP and regulation of flowering time by depleting the active CO pool required for transcription of FT. PMID- 26098375 TI - Association between physical pain and alcohol treatment outcomes: The mediating role of negative affect. AB - OBJECTIVE: Physical pain and negative affect have been described as risk factors for alcohol use following alcohol treatment. The current study was a secondary analysis of 2 clinical trials for alcohol use disorder (AUD) to examine the associations between pain, negative affect and AUD treatment outcomes. METHOD: Participants included 1,383 individuals from the COMBINE Study (COMBINE Pharmacotherapies and Behavioral Interventions for Alcohol Dependence; COMBINE Study Research Group, 2003; 31% female, 23% ethnic minorities, average age = 44.4 [SD = 10.2]), a multisite combination pharmacotherapy and behavioral intervention study for AUD in the United States, and 742 individuals from the United Kingdom Alcohol Treatment Trial (UKATT Research Team, 2001; 25.9% female, 4.4% ethnic minorities, average age = 41.6 [SD = 10.1]) a multisite behavioral intervention study for AUD in the United Kingdom. The Form-90 was used to collect alcohol use data, the Short Form Health Survey and Quality of Life measures were used to assess pain, and negative affect was assessed using the Brief Symptom Inventory (COMBINE) and the General Health Questionnaire (UKATT). RESULTS: Pain scores were significantly associated with drinking outcomes in both datasets. Greater pain scores were associated with greater negative affect and increases in pain were associated with increases in negative affect. Negative affect significantly mediated the association between pain and drinking outcomes and this effect was moderated by social behavior network therapy (SBNT) in the UKATT study, with SBNT attenuating the association between pain and drinking. CONCLUSION: Findings suggest pain and negative affect are associated among individuals in AUD treatment and that negative affect mediated pain may be a risk factor for alcohol relapse. PMID- 26098377 TI - Emotional switching in borderline personality disorder: A daily life study. AB - Despite large efforts to understand emotional instability in borderline personality disorder (BPD), it is still unclear exactly how this is manifested in the daily lives of people suffering from the disorder. Building on theoretical and clinical observations of BPD, we propose that the emotional instability in BPD particularly consists of the occurrence of strong changes between positive and negative emotional states from 1 moment to the next, labeled emotional switching. We tested this proposal by means of an experience sampling study in which 30 BPD patients and 28 healthy controls reported in their daily lives the level of pleasantness/unpleasantness of their emotional states 10 times a day for 8 consecutive days using handheld palmtops. Results showed that although BPD patients did not differ from healthy controls regarding their overall tendency to switch from a positive to a negative emotional state or vice versa, the size of such changes between positive and negative states was found to be significantly larger in BPD patients. In contrast, the magnitude of emotional changes that remained within the negative emotional range or positive emotional range was not particularly larger for BPD patients compared with healthy participants. These findings imply that the emotional instability in BPD is particularly characterized by larger changes from positive to negative states and vice versa, rather than overall larger changes in intensity, providing insight into possible processes underlying emotion dysfunction in BPD. PMID- 26098378 TI - Narcissism and newlywed marriage: Partner characteristics and marital trajectories. AB - Despite narcissism's relation with interpersonal dysfunction, surprisingly little empirical research has been devoted to understanding narcissism's effect on intimate relationships in general or marital relationships in particular. The current study addressed this gap using longitudinal data from a community sample of 146 newlywed couples assessed 6 times over the first 4 years of marriage. First, we examined partner characteristics associated with higher levels of narcissism to determine the degree to which couples were matched on narcissism and related traits. Second, we examined how narcissism predicted the trajectory of marital quality over time, testing narcissism's association with initial levels of relationship functioning (the intercept) and changes in relationship functioning (the slope). Results indicated a small degree of homophily but otherwise no clear pattern of partner characteristics for individuals higher in narcissism. Hierarchical linear modeling indicated that wives' total narcissism and entitlement/exploitativeness scores predicted the slope of marital quality over time, including steeper declines in marital satisfaction and steeper increases in marital problems. Husbands' narcissism scores generally had few effects on their own marital quality or that of their wives. These findings are notable in indicating that the effects of personality characteristics on marital functioning may take some time to manifest themselves, even if they were present from early in the marriage. Future research into the mediating psychological and interpersonal processes that link wives' narcissism with poorer marital functioning over time would be valuable. PMID- 26098380 TI - [Abstracts SGIM Annual Meeting 2015]. PMID- 26098379 TI - Nonoperative management for major blunt hepatic trauma. A case report. AB - INTRODUCTION: Over the past 20 years the management of blunt liver trauma has evolved from a primary operative approach to a nonoperative one, for both low and high grade injuries, only on the basis of hemodynamic stability. However, in spite of a high success rate of non operative management, it is frequently observed, also in our country, an old fashioned way to approach these patients, based on habit more than observation and evidence based medicine. CASE REPORT: We present a case of successful nonoperative treatment of a grade IV blunt liver trauma (lacero-contusive injury of V, VI and VII segments) in a 34-year-old woman. DISCUSSION: Nowadays more than 85% of liver injuries are managed without operative intervention, irrespective of the injury grade. Success rate of the conservative approach ranges from 82% to 100% and almost all complications (14% in high grade injuries) can be managed with interventional radiology procedures, still avoiding major surgery. CONCLUSION: Today, in the absence of other abdominal injuries requiring surgical exploration, hemodynamic instability from ongoing hemorrhage after primary evaluation and resuscitative treatment, is the only indication to an operative management of traumatic liver injuries. PMID- 26098382 TI - Simple Microfluidic Approach to Fabricate Monodisperse Hollow Microparticles for Multidrug Delivery. AB - Herein, we report the production of monodisperse hollow microparticles from three different polymers, namely, pH-responsive acetylated dextran and hypromellose acetate succinate and biodegradable poly(lactic-co-glycolic acid), at varying polymer concentrations using a poly(dimethylsiloxane)-based microfluidic device. Hollow microparticles formed during solvent diffusion into the continuous phase when the polymer close to the interface solidified, forming the shell. In the inner part of the particle, phase separation induced solvent droplet formation, which dissolved the shell, forming a hole and a hollow-core particle. Computational simulations showed that, despite the presence of convective recirculation around the droplet, the mass-transfer rate of the solvent dissolution from the droplet to the surrounding phase was dominated by diffusion. To illustrate the potential use of hollow microparticles, we simultaneously encapsulated two anticancer drugs and investigated their loading and release profiles. In addition, by utilizing different polymer shells and polymer concentrations, the release profiles of the model drugs could be tailored according to specific demands and applications. The high encapsulation efficiency, controlled drug release, unique hollow microparticle structure, small particle size (<7 MUm), and flexibility of the polymer choice could make these microparticles advanced platforms for pulmonary drug delivery. PMID- 26098381 TI - Targeting hypoxia in inflammatory bowel disease. AB - In this review, I summarize some of the recent insight into pharmacological targeting of hypoxia in disease models. Studies from cultured cell systems, animal models, and translation to human patients have revealed that posttranslational modifications of individual proteins within NF-kappaB and hypoxia-inducible factor pathways serve as ideal targets for analysis in disease models. Studies defining differences and similarities between these responses have taught us a number of important lessons about the complexity of the inflammatory response. A clearer definition of these pathways has provided new insight into disease pathogenesis and, importantly, the potential for new therapeutic targets. PMID- 26098384 TI - Carbon coating stabilized Ti(3+)-doped TiO2 for photocatalytic hydrogen generation under visible light irradiation. AB - Self-doping by Ti(3+) is a useful method to expand the light response of TiO2 into the visible light region. However, to obtain a stable Ti(3+)-doped TiO2 seems to be a challenge due to the easy oxidation of Ti(3+) during the heterogeneous reaction. Here, we propose a simple carbon coating route to stabilize the Ti(3+)-doped TiO2, in which both the Ti(3+) and precursor of the carbon coating layer were in situ formed from the hydrothermal hydrolysis of titanium isopropoxide. The carbon coated Ti(3+)-doped TiO2 exhibited excellent stability for photocatalytic hydrogen production. Based on electron paramagnetic resonance (EPR) analysis, the proposed stabilizing mechanism is that the conductive carbon coating layer as a barrier layer prevents the H2O and O2 from diffusing into the surface of the photocatalyst, which can oxidize the surface O vacancies and Ti(3+) in TiO2. Our findings offer a simple route to prepare a highly stable TiO2-based photocatalyst with visible light response. PMID- 26098383 TI - [Birth in Out-of-Hospital Settings--Differences in Maternal and Neonatal Outcome of Women with their Second Child and a Prior Caesarean Section Compared to First Paras]. AB - BACKGROUND: Vaginal birth after Caesarean (VBAC) in out-of-hospital settings is controversial. With increasing Caesarean rates, more women with a prior Caesarean will decide to give birth in midwife-led birth-centres or at home. Therefore the study explores the question about maternal and neonatal outcomes in German out-of hospital settings. METHOD: A retrospective study of German out-of-hospital data from 2005 to 2011 was undertaken. Included were 66,437 singleton pregnancies in cephalic presentation at term. This study describes the outcome parameters of first paras compared to mothers with their second child who had a prior Caesarean. RESULTS: The VBAC rate was 77.8%, and the first para vaginal birth rate was 89.8% (p<0.001). The intrapartum transfer rate of women with a prior Caesarean section was significantly more than for the first paras (38.2 vs. 27.2%; p<0.001). A prolonged first stage was the most frequently documented indication for intrapartal transfer in both groups. There were no significant differences in rates of maternal postpartum complications, or in postpartum hospital transfer rates. Also, neither neonatal transfer rates nor Apgar scores were statistically different between the groups. DISCUSSION: These results are consistent with other studies which reported that an out-of-hospital setting is an alternative to the clinical setting for women with a prior Caesarean. However, the fact that the intrapartum transfer rate of women with a prior Caesarean was almost 40% should be included in antenatal counselling about the place of labour and birth. PMID- 26098385 TI - CHOROIDAL THICKNESS IN RELATION TO ETHNICITY MEASURED USING ENHANCED DEPTH IMAGING OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To investigate the posterior choroidal thickness in healthy subjects of three different ethnicities. METHODS: In this prospective cross-sectional study, the choroidal thickness of 88 individuals (176 eyes) was measured using enhanced depth imaging-spectral domain optical coherence tomography. Subfoveal choroidal thickness was measured between the retinal pigment epithelium-Bruch membrane complex and chorioscleral interface. Nasal, temporal, superior, and inferior choroidal thicknesses at 0.5, 1.5, and 3.0 mm locations from the fovea were evaluated as well. RESULTS: Males and females were perfectly matched by number in all groups. The mean age of the entire study population was 27.43 +/- 1 years. Mean subfoveal choroidal thicknesses of whites, Africans, Asians, and entire study population were 403.62 +/- 37.4 MUm, 372.47 +/- 31.4 MUm, 383.64 +/- 40 MUm, 386.64 +/- 10.5 MUm, respectively. Mean spherical error of the entire study population was -1.2685 diopter. Whites had the longest eyes on average 24.17 mm > 24.08 mm (Africans) > 23.86 mm (Asians), with the statistical mean of 24.04 mm for the entire study population. Subfoveal choroidal thickness was not significantly correlated with ethnicity in either ethnic group (P > 0.05). Subfoveal choroid thinned by 2.51 MUm per 1 year increase in age (P = 0.282). Subfoveal choroidal thickness and sex were not significantly correlated to (P = 0.402). Subfoveal choroidal thickness was in strong negative correlation only with refractive error (P = 0.01) and axial length (P = 0.008). The intereye difference in subfoveal choroidal thickness was not statistically significant (P = 0.845). CONCLUSION: Enhanced depth imaging-spectral domain optical coherence tomography is a productive imaging method to study the choroidal thickness. Subfoveal choroidal thickness is not significantly correlated with ethnicity. The study reproduced previously found relations between thinner choroids and longer axial lengths, and increasing myopic refraction and showed no significant associations between subfoveal choroidal thickness and age and sex. Either the right or left eye can be used in future studies. PMID- 26098386 TI - IMPACT OF PHYSICIAN COMMUNICATION ON DIABETIC EYE EXAMINATION ADHERENCE: Results From a Retrospective Cohort Analysis. AB - PURPOSE: To evaluate the effect of written communication between an ophthalmologist and a primary care physician (PCP) on patient adherence to diabetic eye examination recommendations. METHODS: In a retrospective cohort study of a multiethnic population at an urban ophthalmology center, records of all patients with diabetes and clinic visits between 2007 and 2010 were reviewed. Data collected included patient demographics, insurance status, hemoglobin A1C, severity of diabetic retinopathy, follow-up examinations, and written communication between a patient's ophthalmologist and PCP. Statistical analyses were performed to examine the relationship between physician communication and adherence to diabetic eye examination based on the American Academy of Ophthalmology-published recommendations. RESULTS: A total of 1,968 people with diabetes were included. Written communication from an ophthalmologist to a PCP was associated with increased adherence to follow-up eye examination recommendations (Odds Ratio: 1.49; 95% Confidence Interval: 1.16-1.92; P = 0.0018). Communication from a PCP to an ophthalmologist was also associated with increased adherence (Odds Ratio: 1.94; 95% Confidence Interval: 1.37-2.77; P = 0.0002). Multivariable analysis controlling for other factors associated with examination adherence confirmed that communication both to and from an ophthalmologist was independently and significantly associated with increased follow-up adherence. CONCLUSION: Patients with communication between ophthalmologists and PCPs are more likely to adhere to diabetic eye examinations. PMID- 26098387 TI - SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY EVIDENCE OF RETINAL NERVE FIBER LAYER AND GANGLION CELL LOSS IN ADULT PATIENTS WITH NEUROFIBROMATOSIS TYPE 1. AB - PURPOSE: To evaluate peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer thickness and analyze their correlations in adult patients with neurofibromatosis Type 1 (NF1) and disease-free controls. METHODS: This cross-sectional study was performed at the Azienda Policlinico Umberto I, University of Rome "La Sapienza." All participants underwent complete ophthalmologic examination. Spectral domain optical coherence tomography was used to evaluate peripapillary retinal nerve fiber layer and obtain retinal segmentation measurements to assess macular retinal nerve fiber layer and ganglion cell layer-inner plexiform layer at 1,000 MUm nasal, temporal, superior, and inferior to the fovea. RESULTS: Thirty-four eyes of 17 patients with NF1 (mean age, 42.2 +/- 14.3 years) and 34 eyes of 17 disease-free control subjects (mean age, 41.4 +/- 12.2 years) were included. All participants had best-corrected visual acuity of 20/20. The mean thickness of peripapillary retinal nerve fiber layer, macular retinal nerve fiber layer, and ganglion cell layer-inner plexiform layer was lower in patients with NF1 with respect to controls (P = 0.003, P = 0.022, P < 0.001, respectively). Regression analysis showed a significant correlation (P < 0.001) between mean ganglion cell layer-inner plexiform layer thickness and mean peripapillary retinal nerve fiber layer thickness in patients with NF1. CONCLUSION: Retinal nerve fiber layer and ganglion cell loss correlate well with each other in adult patients with NF1 in comparison with a healthy control population. PMID- 26098388 TI - A systematic review and meta-analysis of randomized controlled trials of the impact of sleep duration on adiposity and components of energy balance. AB - Recent epidemiological and ecological trends in humans indicate a possible causal relationship between sleep duration and energy balance. We aimed to find experimental evidence that has tested this relationship between sleep duration and measures of body composition, food intake or biomarkers related to food intake. We conducted a systematic literature review using six databases throughout 7 August 2014. We sought reports of randomized controlled trials where sleep duration was manipulated and measured outcomes were body weight or other body composition metrics, food intake, and/or biomarkers related to eating. We found 18 unique studies meeting all criteria: eight studies with an outcome of body weight (4 - increased sleep, 4 - reduced sleep); four studies on food intake; four studies of sleep restriction on total energy expenditure and three of respiratory quotient; and four studies on leptin and/or ghrelin. Few controlled experimental studies have addressed the question of the effect of sleep on body weight/composition and eating. The available experimental literature suggests that sleep restriction increases food intake and total energy expenditure with inconsistent effects on integrated energy balance as operationalized by weight change. Future controlled trials that examine the impact of increased sleep on body weight/energy balance factors are warranted. PMID- 26098392 TI - Correction. PMID- 26098391 TI - Lower Extremity Biomechanics and Self-Reported Foot-Strike Patterns Among Runners in Traditional and Minimalist Shoes. AB - CONTEXT: The injury incidence rate among runners is approximately 50%. Some individuals have advocated using an anterior-foot-strike pattern to reduce ground reaction forces and injury rates that they attribute to a rear-foot-strike pattern. The proportion of minimalist shoe wearers who adopt an anterior-foot strike pattern remains unclear. OBJECTIVE: To evaluate the accuracy of self reported foot-strike patterns, compare negative ankle- and knee-joint angular work among runners using different foot-strike patterns and wearing traditional or minimalist shoes, and describe average vertical-loading rates. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 60 healthy volunteers (37 men, 23 women; age = 34.9 +/- 8.9 years, height = 1.74 +/- 0.08 m, mass = 70.9 +/- 13.4 kg) with more than 6 months of experience wearing traditional or minimalist shoes were instructed to classify their foot-strike patterns. INTERVENTION(S): Participants ran in their preferred shoes on an instrumented treadmill with 3-dimensional motion capture. MAIN OUTCOME MEASURE(S): Self-reported foot-strike patterns were compared with 2 dimensional video assessments. Runners were classified into 3 groups based on video assessment: traditional-shoe rear-foot strikers (TSR; n = 22), minimalist shoe anterior-foot strikers (MSA; n = 21), and minimalist-shoe rear-foot strikers (MSR; n = 17). Ankle and knee negative angular work and average vertical-loading rates during stance phase were compared among groups. RESULTS: Only 41 (68.3%) runners reported foot-strike patterns that agreed with the video assessment (kappa = 0.42, P < .001). The TSR runners demonstrated greater ankle-dorsiflexion and knee-extension negative work than MSA and MSR runners (P < .05). The MSA (P < .001) and MSR (P = .01) runners demonstrated greater ankle plantar-flexion negative work than TSR runners. The MSR runners demonstrated a greater average vertical-loading rate than MSA and TSR runners (P < .001). CONCLUSIONS: Runners often cannot report their foot-strike patterns accurately and may not automatically adopt an anterior-foot-strike pattern after transitioning to minimalist running shoes. PMID- 26098393 TI - At the Mercy of the Gods: Associations Between Weather, Physical Activity, and Sedentary Time in Children. AB - OBJECTIVES: This study investigated associations between weather conditions, physical activity, and sedentary time in primary school-aged children in Australia and Canada. METHODS: Cross-sectional data on 9-11-year-old children from the Australian (n = 491) and Canadian (n = 524) sites of the International Study of Childhood Obesity, Lifestyle and the Environment were used. Minutes of daily moderate-to-vigorous-physical-activity (MVPA) and sedentary time were determined from 7-day, 24-h accelerometry (Actigraph GT3X+ triaxial accelerometer). Day-matched weather data (temperature, rainfall, snowfall, relative humidity, wind speed) were obtained from the closest weather station to participants' schools. Covariates included parental highest education level, day type, sex, and BMI z-scores. Generalized mixed model analyses allowing for clustering of participants within schools were completed. Scatterplots with Loess curves were created for maximum temperature, MVPA, and sedentary time. RESULTS: Daily maximum temperature was significantly associated with MVPA and sedentary time in Australia (MVPA p = .05, sedentary p = .01) and Canada (p < .001, p = .001). Rainfall was negatively associated with MVPA in Australia (p < .001) and positively associated with sedentary time in Canada (p = .02). CONCLUSIONS: MVPA and sedentary time appear to be optimal when the maximum temperature ranges between 20 degrees C and 25 degrees C in both countries. The findings have implications for study design and interpretation for surveillance and intervention studies. PMID- 26098395 TI - Resistance in antimicrobial photodynamic inactivation of bacteria. AB - Antibiotics have increasingly lost their impact to kill bacteria efficiently during the last 10 years. The emergence and dissemination of superbugs with resistance to multiple antibiotic classes have occurred among Gram-positive and Gram-negative strains including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter strains. These six superbugs can "escape" more or less any single kind of antibiotic treatment. That means bacteria are very good at developing resistance against antibiotics in a short time. One new approach is called photodynamic antimicrobial chemotherapy (PACT) which already has demonstrated an efficient antimicrobial efficacy among multi-resistant bacteria. Until now it has been questionable if bacteria can develop resistance against PACT. This perspective summarises the current knowledge about the susceptibility of bacteria towards oxidative stress and sheds some light on possible strategies of the development of photodynamic inactivation of bacteria (PACT)-induced oxidative stress resistance by bacteria. PMID- 26098394 TI - Sunlight and Vitamin D: Necessary for Public Health. PMID- 26098396 TI - A "Caged" Luciferin for Imaging Cell-Cell Contacts. AB - Cell-cell interactions underlie fundamental biological processes but remain difficult to visualize over long times and large distances in tissues and live organisms. Bioluminescence imaging with luciferase-luciferin pairs is sufficiently sensitive to image cells in vivo but lacks the spatial resolution to identify cellular locations and interactions. To repurpose this technology for visualizing cellular networks, we developed a "caged" luciferin that produces light only when cells are in close contact. This molecule comprises a nitroaromatic core that can be selectively reduced ("uncaged") by one cell type, liberating a luciferin that can be selectively consumed by neighboring, luciferase-expressing cells. When the two cell types are in contact, robust light emission is observed. This imaging strategy will enable the noninvasive visualization of cell-cell interactions relevant to organismal biology. PMID- 26098397 TI - Meeting Incarcerated Women's Needs For Pregnancy-Related and Postpartum Services: Challenges and Opportunities. PMID- 26098398 TI - What is the antiallergic potential of DNA vaccination? PMID- 26098400 TI - Quality of Life Among Breast Cancer Survivors 2 Years After Diagnosis: The Relationship With Adverse Childhood Events and Posttraumatic Growth. AB - BACKGROUND: Quality of life (QoL) is an important patient outcome in oncology. Many breast cancer survivors report difficulties with QoL. Adverse childhood events (ACEs) and posttraumatic growth (PTG) may influence QoL in breast cancer survivors after diagnosis. OBJECTIVE: The aim of this study was to determine the association of QoL with ACEs and PTG among breast cancer survivors 2 years after diagnosis. METHODS: This was a cross-sectional study, conducted on 93 Chinese breast cancer survivors diagnosed at least 2 years prior to the study. Measures included a self-reported demographic questionnaire, the Adverse Childhood Experiences questionnaires, the Posttraumatic Growth Inventory, and the Functional Assessment of Cancer Therapy-Breast Cancer QoL questionnaire. RESULTS: Among the 93 participants, more than one-third (34.4%) experienced childhood adversity. We found a negative relationship between ACEs and QoL and a positive relationship between PTG and QoL. CONCLUSIONS: The findings suggest that childhood adversity and PTG are important predictors of QoL among breast cancer survivors at least 2 years after diagnosis. Women who had experienced ACEs had poorer health-related QoL than did those who did not. Individuals who experienced PTG following a cancer diagnosis also reported better QoL than did those who did not. IMPLICATIONS FOR PRACTICE: A better understanding of how ACE and PTG contribute to breast cancer survivors' QoL will help in tailoring and therefore enhancing the efficacy of interventions aimed at improving QoL. PMID- 26098399 TI - Managing One's Symptoms: A Qualitative Study of Low-Income African Americans With Advanced Cancer. AB - BACKGROUND: African Americans endure disproportionately high advanced cancer rates and also are disproportionately represented in the lower socioeconomic strata. These individuals work to manage symptoms in order to function and have a satisfactory quality of life. OBJECTIVE: The purpose of this study was to discover what low-income African American adults with advanced cancer do on a day to-day basis to relieve and manage symptoms. This study viewed the individuals as experts and asked them not what they are told to do, but rather what they actually do. METHODS: A purposive sample of 27 individuals participated in semistructured interviews conducted by 2 research interviewers. This qualitative descriptive approach used content analysis to develop themes to describe symptom self-management. RESULTS: Participants described 2 approaches: making continual adjustments and finding stability through spirituality. In seeking comfort from the distress of their symptoms, they were constantly altering their activities and fine-tuning strategies. They adjusted medical regimens and changed the speed and selection of daily activities, including comfort measures and diet modifications. In contrast, their spirituality was a consistent presence in their lives that provided balance to their unstable symptom experience. CONCLUSIONS: This study illustrates that people with advanced cancer actively engage in multiple complex self-management strategies in response to symptoms. IMPLICATIONS FOR PRACTICE: As providers assess how individuals manage their symptoms, they must find ways to support those efforts. Providers then will recognize the challenges faced by advanced cancer patients in obtaining the best quality of life while managing multiple symptoms, activities, and family responsibilities. PMID- 26098401 TI - Effects of Healing Touch and Relaxation Therapy on Adult Patients Undergoing Hematopoietic Stem Cell Transplant: A Feasibility Pilot Study. AB - BACKGROUND: Stem cell transplant (SCT), considered the current standard of care for adults with advanced cancers, can lead to substantial deconditioning and diminished well-being. Attending to life quality of SCT recipients is now viewed as essential. OBJECTIVE: The objective of this study was to identify the feasibility and preliminary efficacy of healing touch (HT) and relaxation therapy (RT) with patients undergoing SCT. METHODS: A randomized prospective design compared 13 SCT patients who received HT daily while hospitalized to 13 similar SCT patients who received daily RT. The clinical outcomes of the 2 groups were also compared with retrospective clinical data of 20 patients who received SCT during the same year. RESULTS: The mean age of participants was 57 years, with 54% receiving autologous and 46% receiving allogeneic transplants. All patients assigned to the HT group completed the protocol. Only 60% of the relaxation group completed the intervention. Both interventions produced improvement in psychosocial measures and a shorter hospital length of stay (LOS) than the historical group. Differential results for LOS were related to the type of transplant received. The LOS differences were not statistically significant but could be clinically significant. CONCLUSIONS: Healing touch was a better tolerated modality by this population. Future research is needed to validate the LOS advantage of the HT and RT interventions, explore the differences in effect found with different transplant types, and identify patients who can tolerate RT. IMPLICATIONS FOR PRACTICE: The LOS reduction could result in decreased cost. Second, mood and function improvements support quality of life during SCT treatment. PMID- 26098402 TI - Lived Experiences of "Illness Uncertainty" of Iranian Cancer Patients: A Phenomenological Hermeneutic Study. AB - BACKGROUND: For cancer patients, uncertainty is a pervasive experience and a major psychological stressor that affects many aspects of their lives. Uncertainty is a multifaceted concept, and its understanding for patients depends on many factors, including factors associated with various sociocultural contexts. Unfortunately, little is known about the concept of uncertainty in Iranian society and culture. OBJECTIVES: This study aimed to clarify the concept and explain lived experiences of illness uncertainty in Iranian cancer patients. METHODS: In this hermeneutic phenomenological study, 8 cancer patients participated in semistructured in-depth interviews about their experiences of uncertainty in illness. Interviews continued until data saturation was reached. All interviews were recorded, transcribed, analyzed, and interpreted using 6 stages of the van Manen phenomenological approach. RESULTS: Seven main themes emerged from patients' experiences of illness uncertainty of cancer. Four themes contributed to uncertainty including "Complexity of Cancer," "Confusion About Cancer," "Contradictory Information," and "Unknown Future." Two themes facilitated coping with uncertainty including "Seeking Knowledge" and "Need for Spiritual Peace." One theme, "Knowledge Ambivalence," revealed the struggle between wanting to know and not wanting to know, especially if bad news was delivered. CONCLUSION: Uncertainty experience for cancer patients in different societies is largely similar. However, some experiences (eg, ambiguity in access to medical resources) seemed unique to Iranian patients. IMPLICATIONS FOR PRACTICE: This study provided an outlook of cancer patients' experiences of illness uncertainty in Iran. Cancer patients' coping ability to deal with uncertainty can be improved. PMID- 26098403 TI - "From Patient to Survivor": Women's Experience With Breast Cancer After 5 Years. AB - BACKGROUND: Women who have survived breast cancer for 5 years without recurrence are not subject to active follow-up because of limited resources. Their life experiences more than 5 years subsequent to diagnosis and treatment are unknown. OBJECTIVE: The aim of this study was to understand the life experiences and care needs of women who have survived breast cancer for more than 5 years in Taiwan. METHODS: A purposive sampling was used. Women diagnosed with breast cancer more than 5 years previously and without recurrence were recruited in this study. The interviews were conducted in a comfortable and convenient place decided by the participants. The interviews were converted into transcripts and analyzed using content analysis. RESULTS: Thirteen women participated in this study whose ages were between 48 and 72 years. Five main themes were identified: (1) fear of recurrence, with women attempting to use ways to reduce recurrence, including dependence on drugs, desire for information, and promoting health; (2) hoping for alleviation of adverse effects; (3) seeking a body image; (4) expectations for the patient-physician relationship; (5) concerns of a mother; and (6) positive thinking. CONCLUSIONS: Taiwanese women with post 5-year breast cancer survival continue to have physiological and emotional needs. They long for attention and care from their healthcare team. IMPLICATIONS FOR PRACTICE: It is pivotal to formulate a care plan suitable for 5-year-plus survivors of breast cancer and to assist them in gaining an understanding of the latest treatments and self-care information. It is crucial that nurses play a greater role in caring for long term survivors. PMID- 26098404 TI - Implementing evidence-based practices in supported employment on the Gold Coast for people with severe mental illness. AB - AIM: The aim of this project was to evaluate program outcomes following the implementation of an evidence-based approach to supported employment on the Gold Coast, Queensland, Australia. METHOD: A prospective observational design was used to evaluate employment outcomes and fidelity to the evidence-based principles and practices of a specialised form of supported employment. The cohort was defined as all those (n = 114) that entered the program at each of three sites within a 21-month period. Each participant was followed up for a minimum of six months. All three sites implemented the employment program by establishing a partnership between a non-government organisation and the Gold Coast community mental health service. RESULTS: The primary outcome variable was the proportion commencing competitive employment during the follow-up period from among those that commenced receiving assistance (the denominator). This ranged from 12% at Site C to 33.3% at Site A, and 37% at Site B. Fidelity to evidence-based principles was fair at Sites A and C and good at Site B. These results were below expectations based on international-controlled trials. The variation in site effectiveness appeared related to both fidelity to evidence-based principles and to other factors at each site, which could not be clearly identified. CONCLUSIONS: Delivering an effective supported employment program using an inter-agency partnership method is challenging. There are several roles in which occupational therapists can be involved that facilitate improving both the implementation and the effectiveness of supported employment for people with severe mental illness in Australia. PMID- 26098405 TI - Prevalence of Overweight and Obesity in the United States, 2007-2012. PMID- 26098406 TI - Digital Denture Fabrication in Pre- and Postdoctoral Education: A Survey of U.S. Dental Schools. AB - PURPOSE: To survey chairs of prosthodontics or restorative departments and program directors of postdoctoral prosthodontic programs in the United States regarding digital denture fabrication. The key objectives of the survey were to identify the current trends in complete denture fabrication using CAD/CAM technology and to determine how and to what extent this technique is taught and used in U.S. pre- and postdoctoral prosthodontic programs. MATERIALS AND METHODS: An invitation to participate in an online survey was sent to 52 prosthodontics/restorative chairs of U.S. dental schools and to all of the 50 program directors of postdoctoral prosthodontics programs. A version of the survey with the same questions was sent to a national sample of prosthodontics/restorative chairs and program directors of postdoctoral prosthodontics. The 20-item survey took approximately 15 minutes to complete. Dependent samples paired t-test was run on items that were the same in both surveys. RESULTS: The response rate for the survey was 63% for department chairs and 44% for program directors. All respondents with the exception of one department chair were aware of CAD/CAM technology used for denture fabrication. More than half of the program directors (52.4%) compared to 12.1% of chairs have incorporated some aspects of CAD/CAM denture fabrication technology into their curriculum. When asked if the fabrication cost prevented introducing this technology in the predoctoral/postdoctoral curriculum, 52.4% of the department chairs affirmed this response compared to 12.1% of the program directors. There was a significant difference between groups when asked if they had incorporated the CAD/CAM denture fabrication technique into the postgraduate/predoctoral curriculum. Department chairs reported less usage of CAD/CAM technology. Only 12.1% of department chairs reported using some aspects of CAD/CAM technology in the predoctoral curriculum compared to 52.4% in the postdoctoral curriculum (F = 13.528, p <= 0.001). While this technology is used in four predoctoral clinics, none of the chairs reported including CAD/CAM denture fabrication in their preclinical complete denture courses. For the schools using the technology, 33.3% of postdoctoral and 30.3% of predoctoral programs use it to make a denture with a try-in step; however, 19% of the postdoctoral and 18.2% of predoctoral programs process the dentures without a try-in appointment. Slightly less than half (42.9%) of graduate programs are using the technology to make just the denture bases. Only a small proportion (10% or less) of the total number of dentures processed in post- and predoctoral programs are made using CAD/CAM technology. The proportion of postdoctoral programs that process cases using CAD/CAM technology was significantly higher than in predoctoral programs (F = 5.106, p <= 0.028). Many schools indicated that they are in a "trial phase" to evaluate the technique, especially at the predoctoral level. Also, 19% (n = 4) of postdoctoral and 15.2% (n = 5) of predoctoral respondents have created continuing education courses. Of postdoctoral programs, 38.1% (n = 8) plan to introduce this technology at some point in the near future (next 1 to 4 years); 27.3% of predoctoral programs plan to as well. CONCLUSIONS: All program directors and department chairs who participated in the survey are aware of this technology with the exception of one department chair. More than half of the program directors reported that they have incorporated this technology in their curricula compared to only 12% of department chairs. Currently, only 10% or less of complete denture cases are processed using the CAD/CAM technology, at either the post- or predoctoral levels. Both groups reported that the main use of this technology is for the fabrication of denture bases and for processing dentures including the try-in step. The majority of respondents in both groups indicated they plan to add digital denture fabrication into their curricula within the next 1 to 4 years. PMID- 26098407 TI - Emilio Del Giudice, 1940-2014. PMID- 26098408 TI - Testing Models Relating Rejection, Depression, Interpersonal Needs, and Psychache to Suicide Risk in Nonclinical Individuals. AB - OBJECTIVES: Using structural equation modeling, we tested a primary model of suicide risk and 3 competing, alternative models based on 4 psychological variables deemed important in the literature (perception of parental rejection, depression, interpersonal needs comprising perceived burdensomeness and thwarted belongingness, and psychache), in a nonclinical sample of Portuguese adults. METHOD: A convenience sample of 203 adults (100 men, 103 women; aged 18-65 years) participated in this study. RESULTS: Analyses demonstrated that the proposed primary model had the best fit to the observed data. The differences in fit indexes for this model and one of the alternative models, however, were not substantial. CONCLUSION: Perceived parental rejection related directly to suicide risk and indirectly via depression and interpersonal needs. Depression linked indirectly to suicide risk via interpersonal needs and psychache. Interpersonal needs related directly to suicide risk and indirectly via psychache, which related directly to suicide risk. PMID- 26098409 TI - Large Dipolar Spin-Spin Interaction in a Photogenerated U-Shaped Triradical. AB - Transient electron paramagnetic resonance (TREPR) spectroscopy has been used to study the spin-spin interactions in a novel U-shaped electron donor-chromophore acceptor-radical (D-C-A-R(*)) system in which a xanthene bridge holds a tert butylphenyl nitroxide (BPNO(*)) radical in close proximity to a naphthalene 1,8:4,5-bis(dicarboximide) (NDI) acceptor. Photoexcitation of the 4 aminonaphthalene-1,8-dicarboximide (ANI) chromophore results in rapid, two-step electron transfer to generate the triradical (D(+*)-C-A(-*)-R(*)). The large through-bond distance between A(-*) and R(*) makes their spin-spin exchange interaction (2JAR) negligibly small, whereas their short through-space distance results in a strong dipolar interaction (DAR), which is observed as a set of broad lines in the TREPR spectra of D(+*)-C-A(-*)-R(*) in solid toluene solution at 85 K. Transient nutation experiments show that these transitions belong to a species with spin S = 1, whereas experiments on D(+*)-C-A(-*)-R(*) in the oriented nematic liquid crystal 4-cyano-4'-n-pentylbiphenyl at 85 K demonstrate the anisotropy of DAR. PMID- 26098410 TI - Domperidone, cytochrome P450 3A4 isoenzyme inhibitors and ventricular arrhythmia: a nationwide case-crossover study. AB - BACKGROUND: Recent evidence suggested that oral form of domperidone may possess pro-arrhythmic effects and increase the risk of ventricular arrhythmia. The concomitant use of cytochrome P450 (CYP) 3A4 isoenzyme inhibitors may further potentiate this association. Nevertheless, empirical data supporting these associations are very limited. The aim of this study was to investigate the association between oral domperidone, CYP 3A4 inhibitors, and ventricular arrhythmia. METHODS: We identified 25,356 patients who were admitted or were seen in the emergency room for ventricular arrhythmia between 2000 and 2011 from Taiwan's Longitudinal Health Insurance Database. We adopted a case-crossover study design to compare the exposure to oral domperidone for the same patient within a "case period" and within a "control period". RESULTS: Conditional logistic regression models showed that domperidone use was significantly associated with an increased odds of ventricular arrhythmia (aOR 1.56, 95%CI [1.41-1.72]). The association was stronger with a higher daily dose of domperidone (>30 mg, aOR 1.98, 95%CI [1.50-2.63]). Furthermore, the co-exposure of domperidone and CYP 3A4 inhibitors was significantly associated with an increased odds of ventricular arrhythmia, especially considering the lasting effect of CYP 3A4 inhibitors (1 day apart: aOR 1.91, 95%CI [1.33-2.75], 3 days apart: aOR 1.90, 95%CI [1.33-2.71], 7 days apart: aOR 1.80, 95%CI [1.28-2.54]). CONCLUSIONS: Our results suggested that oral domperidone was significantly associated with an increased odds of ventricular arrhythmia and that the association was stronger with exposure to >30 mg of domperidone. In addition, our study reported increased odds of ventricular arrhythmia among those who concomitantly used domperidone and CYP 3A4 inhibitors. PMID- 26098411 TI - Mixed models approaches for joint modeling of different types of responses. AB - In many biomedical studies, one jointly collects longitudinal continuous, binary, and survival outcomes, possibly with some observations missing. Random-effects models, sometimes called shared-parameter models or frailty models, received a lot of attention. In such models, the corresponding variance components can be employed to capture the association between the various sequences. In some cases, random effects are considered common to various sequences, perhaps up to a scaling factor; in others, there are different but correlated random effects. Even though a variety of data types has been considered in the literature, less attention has been devoted to ordinal data. For univariate longitudinal or hierarchical data, the proportional odds mixed model (POMM) is an instance of the generalized linear mixed model (GLMM; Breslow and Clayton, 1993). Ordinal data are conveniently replaced by a parsimonious set of dummies, which in the longitudinal setting leads to a repeated set of dummies. When ordinal longitudinal data are part of a joint model, the complexity increases further. This is the setting considered in this paper. We formulate a random-effects based model that, in addition, allows for overdispersion. Using two case studies, it is shown that the combination of random effects to capture association with further correction for overdispersion can improve the model's fit considerably and that the resulting models allow to answer research questions that could not be addressed otherwise. Parameters can be estimated in a fairly straightforward way, using the SAS procedure NLMIXED. PMID- 26098412 TI - Maximizing the utilization of Laminaria japonica as biomass via improvement of alginate lyase activity in a two-phase fermentation system. AB - Brown seaweed contains up to 67% of carbohydrates by dry weight and presents high potential as a polysaccharide feedstock for biofuel production. To effectively use brown seaweed as a biomass, degradation of alginate is the major challenge due to its complicated structure and low solubility in water. This study focuses on the isolation of alginate degrading bacteria, determining of the optimum fermentation conditions, as well as comparing the conventional single fermentation system with the two-phase fermentation system which is separately using alginate and mannitol extracted from Laminaria japonica. Maximum yield of organic acids production and volatile solids reduction obtained were 0.516 g/g and 79.7%, respectively, using the two-phase fermentation system in which alginate fermentation was carried out at pH 7 and mannitol fermentation at pH 8. The two-phase fermentation system increased the yield of organic acids production by 1.14 times and led to a 1.45-times reduction of VS when compared to the conventional single fermentation system at pH 8. The results show that the two phase fermentation system improved the utilization of alginate by separating alginate from mannitol leading to enhanced alginate lyase activity. PMID- 26098413 TI - A unique in vivo approach for investigating antimicrobial materials utilizing fistulated animals. AB - Unique in vivo tests were conducted through the use of a fistulated ruminant, providing an ideal environment with a diverse and vibrant microbial community. Utilizing such a procedure can be especially invaluable for investigating the performance of antimicrobial materials related to human and animal related infections. In this pilot study, it is shown that the rumen of a fistulated animal provides an excellent live laboratory for assessing the properties of antimicrobial materials. We investigate microbial colonization onto model nanocomposites based on silver (Ag) nanoparticles at different concentrations into polydimethylsiloxane (PDMS). With implantable devices posing a major risk for hospital-acquired infections, the present study provides a viable solution to understand microbial colonization with the potential to reduce the incidence of infection through the introduction of Ag nanoparticles at the optimum concentrations. In vitro measurements were also conducted to show the validity of the approach. An optimal loading of 0.25 wt% Ag is found to show the greatest antimicrobial activity and observed through the in vivo tests to reduce the microbial diversity colonizing the surface. PMID- 26098414 TI - An estimate of the effectiveness of an in-vehicle automatic collision notification system in reducing road crash fatalities in South Australia. AB - OBJECTIVES: The aim of this study was to estimate the potential effectiveness of an in-vehicle automatic collision notification (ACN) system in reducing all road crash fatalities in South Australia (SA). METHODS: For the years 2008 to 2009, traffic accident reporting system (TARS) data, emergency medical services (EMS) road crash dispatch data, and coroner's reports were matched and examined. This was done to initially determine the extent to which there were differences between the reported time of a fatal road crash in the mass crash data and the time EMS were notified and dispatched. In the subset of fatal crashes where there was a delay, injuries detailed by a forensic pathologist in individual coroner's reports were examined to determine the likelihood of survival had there not been a delay in emergency medical assistance. RESULTS: In 25% (N = 53) of fatalities in SA in the period 2008 to 2009, there was a delay in the notification of the crash event, and hence dispatch of EMS, that exceeded 10 min. In the 2-year crash period, 5 people were likely to have survived through more prompt crash notification enabling quicker emergency medical assistance. Additionally, 3 people potentially would have survived if surgical intervention (or emergency medical assistance to sustain life until surgery) occurred more promptly. CONCLUSIONS: The minimum effectiveness rate of an ACN system in SA with full deployment is likely to be in the range of 2.4 to 3.8% of all road crash fatalities involving all vehicle types and all vulnerable road users (pedestrians, cyclists, and motorcyclists) from 2008 to 2009. Considering only passenger vehicle occupants, the benefit is likely to be 2.6 to 4.6%. These fatality reductions could only have been achieved through earlier notification of each crash and their location to enable a quicker medical response. This might be achievable through a fully deployed in-vehicle ACN system. PMID- 26098415 TI - The Leukocyte Immunoglobulin-Like Receptor Family Member LILRB5 Binds to HLA Class I Heavy Chains. AB - OBJECTIVE: The leukocyte immunoglobulin-like receptor (LILR) family includes inhibitory and stimulatory members which bind to classical and non-classical HLA class I. The ligands for many LILR including LILRB5 have not yet been identified. METHODS: We generated C-terminal eGFP and N-terminal FLAG-tagged fusion constructs for monitoring LILR expression. We screened for LILR binding to HLA class I by tetramer staining of 293T cells transfected with LILRA1, A4, A5 A6 and LILRB2 and LILRB5. We also studied HLA class I tetramer binding to LILRB5 on peripheral monocyte cells. LILRB5 binding to HLA-class I heavy chains was confirmed by co-immunoprecipitation. RESULTS: HLA-B27 (B27) free heavy chain (FHC) dimer but not other HLA-class I stained LILRB5-transfected 293T cells. B27 dimer binding to LILRB5 was blocked with the class I heavy chain antibody HC10 and anti-LILRB5 antisera. B27 dimers also bound to LILRB5 on peripheral monocytes. HLA-B7 and B27 heavy chains co-immunoprecipitated with LILRB5 in transduced B and rat basophil RBL cell lines. CONCLUSIONS: Our findings show that class I free heavy chains are ligands for LILRB5. The unique binding specificity of LILRB5 for HLA-class I heavy chains probably results from differences in the D1 and D2 immunoglobulin-like binding domains which are distinct from other LILR which bind to beta2m-associated HLA-class I. PMID- 26098416 TI - Impaired Coronary and Renal Vascular Function in Spontaneously Type 2 Diabetic Leptin-Deficient Mice. AB - BACKGROUND: Type 2 diabetes is associated with macro- and microvascular complications in man. Microvascular dysfunction affects both cardiac and renal function and is now recognized as a main driver of cardiovascular mortality and morbidity. However, progression of microvascular dysfunction in experimental models is often obscured by macrovascular pathology and consequently demanding to study. The obese type 2 diabetic leptin-deficient (ob/ob) mouse lacks macrovascular complications, i.e. occlusive atherosclerotic disease, and may therefore be a potential model for microvascular dysfunction. The present study aimed to test the hypothesis that these mice with an insulin resistant phenotype might display microvascular dysfunction in both coronary and renal vascular beds. METHODS AND RESULTS: In this study we used non-invasive Doppler ultrasound imaging to characterize microvascular dysfunction during the progression of diabetes in ob/ob mice. Impaired coronary flow velocity reserve was observed in the ob/ob mice at 16 and 21 weeks of age compared to lean controls. In addition, renal resistivity index as well as pulsatility index was higher in the ob/ob mice at 21 weeks compared to lean controls. Moreover, plasma L-arginine was lower in ob/ob mice, while asymmetric dimethylarginine was unaltered. Furthermore, a decrease in renal vascular density was observed in the ob/ob mice. CONCLUSION: In parallel to previously described metabolic disturbances, the leptin-deficient ob/ob mice also display cardiac and renal microvascular dysfunction. This model may therefore be suitable for translational, mechanistic and interventional studies to improve the understanding of microvascular complications in type 2 diabetes. PMID- 26098417 TI - Novel Phenanthrene-Degrading Bacteria Identified by DNA-Stable Isotope Probing. AB - Microorganisms responsible for the degradation of phenanthrene in a clean forest soil sample were identified by DNA-based stable isotope probing (SIP). The soil was artificially amended with either 12C- or 13C-labeled phenanthrene, and soil DNA was extracted on days 3, 6 and 9. Terminal restriction fragment length polymorphism (TRFLP) results revealed that the fragments of 219- and 241-bp in HaeIII digests were distributed throughout the gradient profile at three different sampling time points, and both fragments were more dominant in the heavy fractions of the samples exposed to the 13C-labeled contaminant. 16S rRNA sequencing of the 13C-enriched fraction suggested that Acidobacterium spp. within the class Acidobacteria, and Collimonas spp. within the class Betaproteobacteria, were directly involved in the uptake and degradation of phenanthrene at different times. To our knowledge, this is the first report that the genus Collimonas has the ability to degrade PAHs. Two PAH-RHDalpha genes were identified in 13C labeled DNA. However, isolation of pure cultures indicated that strains of Staphylococcus sp. PHE-3, Pseudomonas sp. PHE-1, and Pseudomonas sp. PHE-2 in the soil had high phenanthrene-degrading ability. This emphasizes the role of a culture-independent method in the functional understanding of microbial communities in situ. PMID- 26098418 TI - Multiclass Support Vector Machine-Based Lesion Mapping Predicts Functional Outcome in Ischemic Stroke Patients. AB - PURPOSE: The aim of this study was to investigate if ischemic stroke final infarction volume and location can be used to predict the associated functional outcome using a multi-class support vector machine (SVM). MATERIAL AND METHODS: Sixty-eight follow-up MR FLAIR datasets of ischemic stroke patients with known modified Rankin Scale (mRS) functional outcome after 30 days were used. The infarct regions were segmented and used to calculate the percentage of lesioned voxels in the predefined MNI, Harvard-Oxford cortical and subcortical atlas regions as well as using four problem-specific VOIs, which were identified from the database using voxel-based lesion symptom mapping. An overall of 12 SVM classification models for predicting the corresponding mRS score were generated using the lesion overlap values from the different brain region definitions, stroke laterality information, and the optional parameters infarct volume, admission NIHSS, and patient age. RESULTS: Leave-one-out cross validations revealed that including information about the stroke location in terms of lesion overlap measurements led to improved mRS prediction results compared to classification models not utilizing the stroke location information. Furthermore, integration of the optional features led to improved mRS prediction results in all cases tested. The problem-specific brain regions and additional integration of the optional features led to the best mRS predictions with a precise multi value mRS prediction accuracy of 56%, sliding window multi-value mRS prediction accuracy (mRS+/-1) of 82%, and binary mRS (0-2 vs. 3-5) prediction accuracy of 85%. CONCLUSION: Therefore, a graded SVM-based functional stroke outcome prediction using the problem-specific brain regions for lesion overlap quantification leads to promising results but needs to be further validated using an independent database to rule out a potential methodical bias and overfitting effects. The prediction of the graded mRS functional outcome could be a valuable tool if combined with voxel-wise tissue outcome predictions based on multi parametric datasets acquired at the acute phase. PMID- 26098419 TI - Adjunctive Treatment with Rhodiola Crenulata in Patients with Chronic Obstructive Pulmonary Disease--A Randomized Placebo Controlled Double Blind Clinical Trial. AB - Chronic obstructive pulmonary disease (COPD) is a low grade systemic inflammatory disease characterized by dyspnea and exercise intolerance even under standard therapy. Rhodiola crenulata (RC) has been shown to exert anti-inflammatory effects and to enhance exercise endurance, thereby having the potential to treat COPD. In this 12-week, randomized, double-blind, placebo-controlled clinical trial, 57 patients with stable moderate-to-severe COPD aged 70+/-8.8 years were given RC (250 mg twice/day) (n=38) or a placebo (250 mg twice/day) (n=19) in addition to their standard regimen. There were no significant differences in anthropometrics, quality of life, lung function, six-minute walk and incremental exercise tests between the two groups at enrollment. Over the 12 weeks, RC was well tolerated, significantly reduced triceps skin thickness (Delta=-1 mm, p=.04), change of FEV1 (4.5%, p=.03), and improved workload (Delta=10%, p=.01); although there were no significant differences in these factors between the two groups. However, there were significant between-group differences in tidal volume and ventilation-CO2-output ratio at peak exercise (both p=.05), which were significantly related to peak work rate (both p<.0001). RC tended to protect against acute exacerbation of COPD (p=.1) but not other measurements. RC did not improve the six-minute walk test distance but significantly improved tidal breathing and ventilation efficiency, most likely through improvements in work rate. Further studies with a larger patient population are needed in order to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02242461. PMID- 26098420 TI - 64Cu-ATSM Hypoxia Positron Emission Tomography for Detection of Conduit Ischemia in an Experimental Rat Esophagectomy Model. AB - BACKGROUND: We designed a hypoxia-imaging modality to detect ischemia of the gastric conduit after esophagectomy. MATERIALS AND METHODS: A rat esophagectomy model was created using 12-16-week-old, 300-350 g male Sprague-Dawley rats. In the operation group (n=6), partial gastric devascularization was performed by ligating the left gastric artery and the short gastric arteries and an esophagogastric anastomosis was performed. In the control group (n=6), the esophageal-gastric junction was incised and suturing was performed without gastric devascularization. Positron emission tomography (PET) images were taken using a microPET rodent model scanner, 24 h after the initial operation, after injection of 200 MUCi 64Cu-diacetyl-bis (N4-methylsemicarbazone) (64Cu-ATSM) and pimonidazole 120 mg/kg. After microPET imaging, autoradiography and immunohistochemistry were performed. RESULTS: The PET image revealed 64Cu-ATSM uptake at the fundus in the operation group 3 h after 64Cu-ATSM injection. The maximum percentage of the injected dose per gram of tissue was higher in the operation group (0.047+/-0.015 vs. 0.026+/-0.006, p=0.021). The fundus/liver ratio was also higher in the operation group (0.541+/-0.126 vs. 0.278+/-0.049, p=0.002). Upon autoradiography, 64Cu-ATSM uptake was observed in the fundus in the operation group, and was well-correlated to that observed on the PET image. Upon immunohistochemistry, expression of hypoxia-inducible factor 1a and pimonidazole were significantly increased at the fundus and lesser curvature compared to the greater curvature in the operation group. CONCLUSION: Hypoxia PET imaging with 64Cu-ATSM can detect ischemia in a rat esophagectomy model. Further clinical studies are needed to verify whether hypoxia imaging may be useful in humans. PMID- 26098422 TI - Mortality Dynamics of Spodoptera frugiperda (Lepidoptera: Noctuidae) Immatures in Maize. AB - We characterized the dynamics of mortality factors affecting immature developmental stages of the fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae). Multiple decrement life tables for egg and early larval stages of S. frugiperda in maize (Zea mays L.) fields were developed with and without augmentative releases of Telenomus remus Nixon (Hymenoptera: Platygastridae) from 2009 to 2011. Total egg mortality ranged from 73 to 81% and the greatest egg mortality was due to inviability, dislodgement, and predation. Parasitoids did not cause significant mortality in egg or early larval stages and the releases of T. remus did not increase egg mortality. Greater than 95% of early larvae died from predation, drowning, and dislodgment by rainfall. Total mortality due to these factors was largely irreplaceable. Results indicate that a greater effect in reducing generational survival may be achieved by adding mortality to the early larval stage of S. frugiperda. PMID- 26098421 TI - Oviductal Transcriptome Is Modified after Insemination during Spontaneous Ovulation in the Sow. AB - Gene Expression Microarray technology was used to compare oviduct transcriptome between inseminated and non-inseminated pigs during spontaneous oestrus. We used an in vivo model approaching the study from a physiological point of view in which no hormonal treatment (animals were in natural oestrus) and no artificial sperm selection (selection was performed within the female genital) were imposed. It is therefore emphasised that no surgical introduction of spermatozoa and no insemination at a site other than the physiological one were used. This approach revealed 17 genes that were two-fold or more up-regulated in oviducts exposed to spermatozoa and/or developing embryos and 9 genes that were two-fold or more down regulated. Functional analysis of the genes revealed that the top canonical pathways affected by insemination were related to the inflammatory response and immune system (Network 1) to molecular transport, protein trafficking and developmental disorder (Network 2) and to cell-to-cell signalling and interaction (Network 3). Some of the genes in network 1 had been previously detected in the oviduct of human and animals, where they were over-expressed in the presence of spermatozoa or pre-implantation embryos (C3, IGHG1, ITIH4, TNF and SERPINE1) whereas others were not previously reported (SAA2, ALOX12, CD1D and SPP1). Genes in Network 2 included RAB1B and TOR3A, the latter being described for the first time in the oviduct and clearly expressed in the epithelial cells of the mucosa layer. Network 3 integrated the genes with the highest down-regulation level (CYP51, PTH1R and TMOD3). Data in the present study indicate a change in gene expression during gamete encounter at the site of fertilization after a natural sperm selection within the female genital tract. These changes would indicate a modification of the environment preparing the oviduct for a successful fertilization and for an adequate embryo early development. PMID- 26098423 TI - Age at Mycobacterium bovis BCG Priming Has Limited Impact on Anti-Tuberculosis Immunity Boosted by Respiratory Mucosal AdHu5Ag85A Immunization in a Murine Model. AB - Tuberculosis (TB) remains a global pandemic despite the use of Bacillus Calmette Guerin (BCG) vaccine, partly because BCG fails to effectively control adult pulmonary TB. The introduction of novel boost vaccines such as the human Adenovirus 5-vectored AdHu5Ag85A could improve and prolong the protective immunity of BCG immunization. Age at which BCG immunization is implemented varies greatly worldwide, and research is ongoing to discover the optimal stage during childhood to administer the vaccine, as well as when to boost the immune response with potential novel vaccines. Using a murine model of subcutaneous BCG immunization followed by intranasal AdHu5Ag85A boosting, we investigated the impact of age at BCG immunization on protective efficacy of BCG prime and AdHu5Ag85A boost immunization-mediated protection. Our results showed that age at parenteral BCG priming has limited impact on the efficacy of BCG prime-AdHu5Ag85A respiratory mucosal boost immunization-enhanced protection. However, when BCG immunization was delayed until the maturity of the immune system, longer sustained memory T cells were generated and resulted in enhanced boosting effect on T cells of AdHu5Ag85A respiratory mucosal immunization. Our findings hold implications for the design of new TB immunization protocols for humans. PMID- 26098424 TI - Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate. AB - Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections, yet no vaccines or effective therapeutics are available. ALS-8176 is a first-in-class nucleoside analog prodrug effective in RSV-infected adult volunteers, and currently under evaluation in hospitalized infants. Here, we report the mechanism of inhibition and selectivity of ALS-8176 and its parent ALS 8112. ALS-8176 inhibited RSV replication in non-human primates, while ALS-8112 inhibited all strains of RSV in vitro and was specific for paramyxoviruses and rhabdoviruses. The antiviral effect of ALS-8112 was mediated by the intracellular formation of its 5'-triphosphate metabolite (ALS-8112-TP) inhibiting the viral RNA polymerase. ALS-8112 selected for resistance-associated mutations within the region of the L gene of RSV encoding the RNA polymerase. In biochemical assays, ALS-8112-TP was efficiently recognized by the recombinant RSV polymerase complex, causing chain termination of RNA synthesis. ALS-8112-TP did not inhibit polymerases from host or viruses unrelated to RSV such as hepatitis C virus (HCV), whereas structurally related molecules displayed dual RSV/HCV inhibition. The combination of molecular modeling and enzymatic analysis showed that both the 2'F and the 4'ClCH2 groups contributed to the selectivity of ALS-8112-TP. The lack of antiviral effect of ALS-8112-TP against HCV polymerase was caused by Asn291 that is well-conserved within positive-strand RNA viruses. This represents the first comparative study employing recombinant RSV and HCV polymerases to define the selectivity of clinically relevant nucleotide analogs. Understanding nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules. PMID- 26098425 TI - Expression of OsCAS (Calcium-Sensing Receptor) in an Arabidopsis Mutant Increases Drought Tolerance. AB - The calcium-sensing receptor (CaS), which is localized in the chloroplasts, is a crucial regulator of extracellular calcium-induced stomatal closure in Arabidopsis. It has homologs in Oryza sativa and other plants. These sequences all have a rhodanese-like protein domain, which has been demonstrated to be associated with specific stress conditions. In this study, we cloned the Oryza sativa calcium-sensing receptor gene (OsCAS) and demonstrated that OsCAS could sense an increase of extracellular Ca2+ concentration and mediate an increase in cytosolic Ca2+ concentration. The OsCAS gene was transformed into an Arabidopsis CaS knockout mutant (Salk) and overexpressed in the transgenic plants. OsCAS promoted stomatal closure. We screened homozygous transgenic Arabidopsis plants and determined physiological indices such as the oxidative damage biomarker malondialdehyde (MDA), relative membrane permeability (RMP), proline content, and chlorophyll fluorescence parameters, after 21 days of drought treatment. Our results revealed lower RMP and MDA contents and a higher Proline content in transgenic Arabidopsis plants after drought stress, whereas the opposite was observed in Salk plants. With respect to chlorophyll fluorescence, the electron transport rate and effective PSII quantum yield decreased in all lines under drought stress; however, in the transgenic plants these two parameters changed fewer and were higher than those in wild-type and Salk plants. The quantum yield of regulated energy dissipation and nonregulated energy dissipation in PSII were higher in Salk plants, whereas these values were lower in the transgenic plants than in the wild type under drought stress. The above results suggest that the transgenic plants showed better resistance to drought stress by decreasing damage to the cell membrane, increasing the amount of osmoprotectants, and maintaining a relatively high photosynthetic capacity. In conclusion, OsCAS is an extracellular calcium-sensing receptor that helps to compensate for the absence of CaS in Arabidopsis and increases the drought stress tolerance of transgenic plants. PMID- 26098426 TI - Recombinant Factor VIIa Reduces Bleeding after Blunt Liver Injury in a Pig Model of Dilutional Coagulopathy under Severe Hypothermia. AB - BACKGROUND: Recombinant factor VIIa (rFVIIa) is registered for use in haemophilia with inhibitors and other rare bleeding disorders, but has also been used in various other clinical conditions to terminate life-threatening bleeding. Underlying conditions (e.g. coagulopathy) and dosing may affect treatment efficacy. The objective of the present study was to evaluate the impact of increasing doses of rFVIIa on blood loss and coagulation assays in haemodiluted and hypothermic pigs undergoing blunt liver injury. METHODS: A grade III blunt liver injury was induced in 28 pigs after 70% haemodilution and cooling to 32.6 33.4 degrees C. Ten minutes after trauma, animals randomly received placebo or 90, 180 or 360 MUg/kg rFVIIa. Global coagulation parameters, thromboelastometry (TEM) and plasma thrombin generation (TG) were determined at different time points during the observation period of 120 minutes. RESULTS: Total blood loss was significantly lower following 90 MUg/kg rFVIIa (1206 [1138-1470] mL) relative to placebo (2677 [2337-3068] mL; p<0.05), with no increased effect with higher dose levels of rFVIIa. Following trauma and haemodilution, coagulation was impaired relative to baseline in both TEM and TG analysis. At 60 and 120 minutes after trauma, TEM variables improved in the rFVIIa-treated animals compared with the placebo group. Similarly, rFVIIa improved coagulation kinetics in TG. As was observed with blood loss, no significant effect between different rFVIIa dose levels was found in TEM or TG. Macro- and microscopic post-mortem examination did not reveal any signs of thromboembolic events. CONCLUSION: Early administration of 90 MUg/kg rFVIIa reduced blood loss in pigs undergoing blunt liver injury even after severe haemodilution and hypothermia, with no further effect of higher dose levels. Coagulation assays showed impaired coagulation in coagulopathic animals, with a dose-independent improvement in animals treated with rFVIIa. PMID- 26098427 TI - Vitamin B12 and Folic Acid Improve Gross Motor and Problem-Solving Skills in Young North Indian Children: A Randomized Placebo-Controlled Trial. AB - OBJECTIVES: Deficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children. METHODS: In a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention. RESULTS: Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 MUmol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes. CONCLUSION: Our findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00717730. PMID- 26098429 TI - Modified Early Warning Score Changes Prior to Cardiac Arrest in General Wards. AB - PURPOSE: The frequency, extent, time frame, and implications of changes to the modified early warning score (MEWS) in the 24 hours prior to cardiac arrest are not known. Our aim was to determine the prevalence and trends of the MEWS prior to in-hospital cardiac arrest (IHCA) on a ward, and to evaluate the association between changes in the MEWS and in-hospital mortality. METHODS: A total of 501 consecutive adult IHCA patients who were monitored and resuscitated by a medical emergency team on the ward were enrolled in the study between March 2009 and February 2013. The MEWS was calculated at 24 hours (MEWS24), 16 hours (MEWS16), and 8 hours (MEWS8) prior to cardiac arrest. RESULTS: Out of 380 patients, 268 (70.5%) had a return of spontaneous circulation. The survival rate to hospital discharge was 25.8%. When the MEWS was divided into three risk groups (low: <=2, intermediate: 3-4, high: >=5), the distribution of the low-risk MEWS group decreased at each time point before cardiac arrest. However, even 8 hours prior to cardiac arrest, 45.3% of patients were still in the low MEWS group. The MEWS was associated with in-hospital mortality at each time point. However, increasing MEWS value from MEWS24 to MEWS8 was not associated with in-hospital mortality [OR 1.24 (0.77-1.97), p = 0.38]. CONCLUSIONS: About half of patients were still in low MEWS group 8 hours prior to cardiac arrest and an increasing MEWS only occurred in 46.8% of patients, suggesting that monitoring the MEWS alone is not enough to predict cardiac arrest. PMID- 26098430 TI - Mapping Fishing Effort through AIS Data. AB - Several research initiatives have been undertaken to map fishing effort at high spatial resolution using the Vessel Monitoring System (VMS). An alternative to the VMS is represented by the Automatic Identification System (AIS), which in the EU became compulsory in May 2014 for all fishing vessels of length above 15 meters. The aim of this paper is to assess the uptake of the AIS in the EU fishing fleet and the feasibility of producing a map of fishing effort with high spatial and temporal resolution at European scale. After analysing a large AIS dataset for the period January-August 2014 and covering most of the EU waters, we show that AIS was adopted by around 75% of EU fishing vessels above 15 meters of length. Using the Swedish fleet as a case study, we developed a method to identify fishing activity based on the analysis of individual vessels' speed profiles and produce a high resolution map of fishing effort based on AIS data. The method was validated using detailed logbook data and proved to be sufficiently accurate and computationally efficient to identify fishing grounds and effort in the case of trawlers, which represent the largest portion of the EU fishing fleet above 15 meters of length. Issues still to be addressed before extending the exercise to the entire EU fleet are the assessment of coverage levels of the AIS data for all EU waters and the identification of fishing activity in the case of vessels other than trawlers. PMID- 26098428 TI - Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1alpha Protein and Its Target Genes. AB - This study evaluated HIF-1alpha inhibitors under different hypoxic conditions, physiological hypoxia (5% O2) and severe hypoxia (0.1% O2). We found that chenodeoxy cholic acid (CDCA) reduced the amount of HIF-1alpha protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1alpha protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR), a CDCA receptor and its target gene, Small heterodimer partner (SHP) are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1alpha protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1alpha protein. Furthermore, guggulsterone by itself reduced HIF-1alpha protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1alpha in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1alpha protein. PMID- 26098431 TI - Nickel and iron pincer complexes as catalysts for the reduction of carbonyl compounds. AB - The reductions of aldehydes, ketones, and esters to alcohols are important processes for the synthesis of chemicals that are vital to our daily life, and the reduction of CO2 to methanol is expected to provide key technology for carbon management and energy storage in our future. Catalysts that affect the reduction of carbonyl compounds often contain ruthenium, osmium, or other precious metals. The high and fluctuating price, and the limited availability of these metals, calls for efforts to develop catalysts based on more abundant and less expensive first-row transition metals, such as nickel and iron. The challenge, however, is to identify ligand systems that can increase the thermal stability of the catalysts, enhance their reactivity, and bypass the one-electron pathways that are commonly observed for first-row transition metal complexes. Although many other strategies exist, this Account describes how we have utilized pincer ligands along with other ancillary ligands to accomplish these goals. The bis(phosphinite)-based pincer ligands (also known as POCOP-pincer ligands) create well-defined nickel hydride complexes as efficient catalysts for the hydrosilylation of aldehydes and ketones and the hydroboration of CO2 to methanol derivatives. The hydride ligands in these complexes are substantially nucleophilic, largely due to the enhancement by the strongly trans-influencing aryl groups. Under the same principle, the pincer-ligated nickel cyanomethyl complexes exhibit remarkably high activity (turnover numbers up to 82,000) for catalytically activating acetonitrile and the addition of H-CH2CN across the C?O bonds of aldehydes without requiring a base additive. Cyclometalation of bis(phosphinite)-based pincer ligands with low-valent iron species "Fe(PR3)4" results in diamagnetic Fe(II) hydride complexes, which are active catalysts for the hydrosilylation of aldehydes and ketones. Mechanistic investigation suggests that the hydride ligand is not delivered to the carbonyl substrates but is important to facilitate ligand dissociation prior to substrate activation. In the presence of CO, the amine-bis(phosphine)-based pincer ligands are also able to stabilize low-spin Fe(II) species. Iron dihydride complexes supported by these ligands are bifunctional as both the FeH and NH moieties participate in the reduction of C?O bonds. These iron pincer complexes are among the first iron based catalysts for the hydrogenation of esters, including fatty acid methyl esters, which find broad applications in industry. Our studies demonstrate that pincer ligands are promising candidates for promoting the first-row transition metal-catalyzed reduction of carbonyl compounds with high efficiency. Further efforts in this research area are likely to lead to more efficient and practical catalysts. PMID- 26098433 TI - Correction: Translational Activation of Oskar mRNA: Reevaluation of the Role and Importance of a 5' Regulatory Element. PMID- 26098432 TI - Cardiac Myocyte De Novo DNA Methyltransferases 3a/3b Are Dispensable for Cardiac Function and Remodeling after Chronic Pressure Overload in Mice. AB - BACKGROUND: Recent studies reported altered DNA methylation in failing human hearts. This may suggest a role for de novo DNA methylation in the development of heart failure. Here, we tested whether cardiomyocyte-specific loss of de novo DNA methyltransferases Dnmt3a and Dnmt3b altered cardiac function and remodeling after chronic left ventricular pressure overload. METHODS: Mice with specific ablation of Dnmt3a and Dnmt3b expression in cardiomyocytes were generated by crossing floxed Dnmt3afl and Dnmt3bfl alleles with mice expressing Cre recombinase under control of the atrial myosin light chain gene promoter. The efficacy of combined Dnmt3a/3b ablation (DKO) was characterized on cardiomyocyte specific genomic DNA and mRNA levels. Cardiac phenotyping was carried out without (sham) or with left ventricular pressure overload induced by transverse aortic constriction (TAC). Under similar conditions, cardiac genome-wide transcriptional profiling was performed and DNA methylation levels of promoters of differentially regulated genes were assessed by pyrosequencing. RESULTS: DKO cardiomyocytes showed virtual absence of targeted Dnmt3a and Dnmt3b mRNA transcripts. Cardiac phenotyping revealed no significant differences between DKO and control mice under sham and TAC conditions. Transcriptome analyses identified upregulation of 44 and downregulation of 9 genes in DKO as compared with control sham mice. TAC mice showed similar changes with substantial overlap of regulated genes compared to sham. Promoters of upregulated genes were largely unmethylated in DKO compared to control mice. CONCLUSION: The absence of cardiac pathology in the presence of the predicted molecular phenotype suggests that de novo DNA methylation in cardiomyocytes is dispensable for adaptive mechanisms after chronic cardiac pressure overload. PMID- 26098435 TI - Targeting the VEGF pathway in metastatic bladder cancer. AB - INTRODUCTION: Bladder cancer represents 7% of all new cancers diagnosed in the USA in 2015. Furthermore, the mortality of metastatic bladder cancer has not decreased substantially in the last four decades. Angiogenesis is known to play a major role in the pathogenesis of bladder cancer. AREAS COVERED: The following article provides an overview of the first results of agents targeting the VEGF pathway in the treatment of metastatic bladder cancer. EXPERT OPINION: Despite a few clinical trials providing preliminary encouraging results, the overall outcomes of the first published trials have been rather disappointing. In some instances, especially the case of trials which have investigated the use of new targeted agents as a single agent, no significant improvement in outcomes was seen, or was not sustained. In other cases, such as with combination trials, intolerable adverse effects have compromised the trials, due to overlapping toxicity between the targeted agent and chemotherapeutic agent(s). Further trials are warranted possibly combining different targeted agents or the use of sequential therapy. A better selection of the patient population may also be a key factor to improve patient outcomes, as many predictive factors of response seem to have already been identified. PMID- 26098437 TI - Monosynaptic convergence of somatic and visceral C-fiber afferents on projection and local circuit neurons in lamina I: a substrate for referred pain. AB - Referred pain is a phenomenon of feeling pain at a site other than the site of the painful stimulus origin. It arises from a pathological mixing of nociceptive processing pathways for visceral and somatic inputs. Despite numerous studies based on unit recordings from spinal and supraspinal neurons, the exact mechanism and site of this mixing within the central nervous system are not known. Here, we selectively recorded from lamina I neurons, using a visually guided patch-clamp technique, in thoracic spinal cord preparation with preserved intercostal (somatic) and splanchnic (visceral) nerves. We show that somatic and visceral C fibers converge monosynaptically onto a group of lamina I neurons, which includes both projection and local circuit neurons. Other groups of lamina I neurons received inputs from either somatic or visceral afferents. We have also identified a population of lamina I local circuit neurons showing overall inhibitory responses upon stimulation of both nerves. Thus, the present data allow us to draw two major conclusions. First, lamina I of the spinal cord is the first site in the central nervous system where somatic and visceral pathways directly converge onto individual projection and local circuit neurons. Second, the mechanism of somatovisceral convergence is complex and based on functional integration of monosynaptic and polysynaptic excitatory as well as inhibitory inputs in specific groups of neurons. This complex pattern of convergence provides a substrate for alterations in the balance between visceral and somatic inputs causing referred pain. PMID- 26098438 TI - Dimethylarginine dimethylaminohydrolase 1 is involved in spinal nociceptive plasticity. AB - Activation of neuronal nitric oxide synthase, and consequent production of nitric oxide (NO), contributes to spinal hyperexcitability and enhanced pain sensation. All NOS isoforms are inhibited endogenously by asymmetric dimethylarginine, which itself is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Inhibition of DDAH can indirectly attenuate NO production by elevating asymmetric dimethylarginine concentrations. Here, we show that the DDAH-1 isoform is constitutively active in the nervous system, specifically in the spinal dorsal horn. DDAH-1 was found to be expressed in sensory neurons within both the dorsal root ganglia and spinal dorsal horn; L-291 (NG-[2-Methoxyethyl]-L-arginine methyl ester), a DDAH-1 inhibitor, reduced NO synthesis in cultured dorsal root ganglia neurons. Spinal application of L-291 decreased N-methyl-D-aspartate-dependent postdischarge and windup of dorsal horn sensory neurons--2 measures of spinal hyperexcitability. Finally, spinal application of L-291 reduced both neuronal and behavioral measures of formalin-induced central sensitization. Thus, DDAH-1 may be a potential therapeutic target in neuronal disorders, such as chronic pain, where elevated NO is a contributing factor. PMID- 26098439 TI - Deficits in pain perception in borderline personality disorder: results from the thermal grill illusion. AB - It is well documented that borderline personality disorder (BPD) is characterized by reduced pain sensitivity, which might be related to nonsuicidal self-injury and dissociative experiences in patients with BPD. However, it remains an open question whether this insensitivity relies at least partly on altered sensory integration or on an altered evaluation of pain or a combination of both. In this study, we used the thermal grill illusion (TGI), describing a painful sensation induced by the application of alternating cold and warm nonnoxious stimuli, in patients with either current or remitted BPD as well as matched healthy controls. Two additional conditions, applying warm or cold temperatures only, served as control. We further assessed thermal perception, discrimination, and pain thresholds. We found significantly reduced heat and cold pain thresholds for the current BPD group, as well as reduced cold pain thresholds for the remitted BPD group, as compared with the HC group. Current BPD patients perceived a less intense TGI in terms of induced pain and unpleasantness, while their general ability to perceive this kind of illusion seemed to be unaffected. Thermal grill illusion magnitude was negatively correlated with dissociation and traumatization only in the current BPD patients. These results indicate that higher-order pain perception is altered in current BPD, which seems to normalize after remission. We discuss these findings against the background of neurophysiological evidence for the TGI in general and reduced pain sensitivity in BPD and suggest a relationship to alterations in N-methyl-D-aspartate neurotransmission. PMID- 26098440 TI - Primary preventive effects of a multifaceted workplace intervention on low back pain. PMID- 26098441 TI - Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice. AB - Experiencing early life stress or injury increases a woman's likelihood of developing vulvodynia and concomitant dysregulation of the hypothalamic-pituitary adrenal (HPA) axis. To investigate the outcome of neonatal vaginal irritation (NVI), female mouse pups were administered intravaginal zymosan on postnatal days 8 and 10 and were assessed as adults for vaginal hypersensitivity by measuring the visceromotor response to vaginal balloon distension (VBD). Western blotting and calcium imaging were performed to measure transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) in the vagina and innervating primary sensory neurons. Serum corticosterone (CORT), mast cell degranulation, and corticotropin-releasing factor receptor 1 (CRF1) expression were measured as indicators of peripheral HPA axis activation. Colorectal and hind paw sensitivity were measured to determine cross-sensitization resulting from NVI. Adult NVI mice had significantly larger visceromotor response during VBD than naive mice. TRPA1 protein expression was significantly elevated in the vagina, and calcium transients evoked by mustard oil (TRPA1 ligand) or capsaicin (TRPV1 ligand) were significantly decreased in dorsal root ganglion from NVI mice, despite displaying increased depolarization-evoked calcium transients. Serum CORT, vaginal mast cell degranulation, and CRF1 protein expression were all significantly increased in NVI mice, as were colorectal and hind paw mechanical and thermal sensitivity. Neonatal treatment with a CRF1 antagonist, NBI 35965, immediately before zymosan administration largely attenuated many of the effects of NVI. These results suggest that NVI produces chronic hypersensitivity of the vagina, as well as of adjacent visceral and distant somatic structures, driven in part by increased HPA axis activation. PMID- 26098442 TI - Altered pain modulation in patients with persistent postendodontic pain. AB - Persistent pain may follow nerve injuries associated with invasive therapeutic interventions. About 3% to 7% of the patients remain with chronic pain after endodontic treatment, and these are described as suffering from painful posttraumatic trigeminal neuropathy (PTTN). Unfortunately, we are unable to identify which patients undergoing such procedures are at increased risk of developing PTTN. Recent findings suggest that impaired endogenous analgesia may be associated with the development of postsurgical chronic pain. We hypothesized that patients with PTTN display pronociceptive pain modulation, in line with other chronic pain disorders. Dynamic (conditioned pain modulation, temporal summation) and static (response to mechanical and cold stimulation) psychophysical tests were performed intraorally and in the forearm of 27 patients with PTTN and 27 sex- and age-matched controls. The dynamic sensory testing demonstrated less efficient conditioned pain modulation, suggesting reduced function of the inhibitory endogenous pain-modulatory system, in patients with PTTN, mainly in those suffering from the condition for more than a year. The static sensory testing of patients with PTTN demonstrated forearm hyperalgesia to mechanical stimulation mainly in patients suffering from the condition for less than a year and prolonged painful sensation after intraoral cold stimulus mainly in patients suffering from the condition for more than a year. These findings suggest that PTTN is associated more with the inhibitory rather than the facilitatory arm of pain modulation and that the central nervous system has a role in PTTN pathophysiology, possibly in a time-dependent fashion. PMID- 26098443 TI - Fluarix quadrivalent vaccine for influenza. AB - Influenza A and B infections cause significant morbidity and mortality. Over the past 30 years, two main influenza B strains have been circulating globally. The trivalent influenza vaccine used in the last 25 years contains one B strain, with approximately 31% of B strain disease coverage over the last 10 years. Fluarix quadrivalent vaccine, containing two A and two B strains, combines the components of two existing trivalent vaccines to prevent this mismatch. This review gives an overview of the published data about Fluarix quadrivalent vaccines, showing an immunogenicity and safety profile of the vaccine comparable with the two licensed trivalent vaccines containing the same strains, but with no evidence for efficacy in the literature. Future vaccines aim for a universal influenza vaccine that will give a long-lasting protection against all influenza strains. PMID- 26098444 TI - Retinal arteriolar narrowing is associated with a 4-year risk of incident metabolic syndrome. AB - We aimed to determine whether retinal microvascular changes in vessel calibers at baseline are associated with the future risk of developing the metabolic syndrome over 4 years in an adult cohort of Japanese individuals (n=90) who attended a health-screening program. Retinal vessel caliber was calculated as the central retinal artery equivalent and vein equivalent (CRAE) from non-mydriatic digital fundus images using semiautomated standardized software. There were 18 cases (20%) that developed metabolic syndrome over 4 years. Narrower arteriolar caliber at baseline was associated with an increased risk of incident metabolic syndrome over 4 years after adjusting for potential confounding risk factors including individual cardiovascular risk factors related to the metabolic syndrome (adjusted odds ratio per 1 s.d. change in CRAE: 2.92, 95% confidence interval 1.03, 8.24; P=0.043). Persons with wider venular caliber at baseline were more likely to have incident metabolic syndrome, but this was not statistically significant. Retinal vascular caliber might provide independent and useful information to predict incident metabolic syndrome in a health screening program. PMID- 26098445 TI - Implications of iron deficiency/anemia on the classification of diabetes using HbA1c. AB - BACKGROUND/OBJECTIVES: Nonglycemic factors like iron deficiency (ID) or anemia may interfere with classification of diabetes and prediabetes using hemoglobin A1c (HbA1c). However, few population-based studies of diabetes in areas with endemic ID/anemia have been conducted. We aimed to determine how mutually exclusive categories of ID alone, anemia alone and iron-deficiency anemia (IDA) were each associated with prediabetes and diabetes prevalence using fasting blood glucose (FBG) versus HbA1c in a population-based study of adults with endemic ID/anemia. SUBJECTS/METHODS: We used data from the China Health and Nutrition Survey, a longitudinal, population-based study across 228 communities within nine provinces of China. This analysis included 7308 adults seen in the 2009 survey aged 18-75 years. We used descriptive and covariate-adjusted models to examine relative risk of prediabetes and diabetes using FBG alone, HbA1c alone, HbA1c and FBG, or neither (normoglycemia) by anemia alone, ID alone, IDA or normal iron/hemoglobin. RESULTS: Approximately 65% of individuals with diabetes in our sample were concordantly classified with diabetes using both FBG and HbA1c, while 35% had a discordant diabetes classification: they were classified using either FBG or HbA1c, but not both. Fewer participants with ID alone versus normal iron/hemoglobin were classified with diabetes using HbA1c only. From covariate adjusted, multinomial regression analyses, the adjusted prevalence of prediabetes using HbA1c only was 22% for men with anemia alone, but 13% for men with normal iron/hemoglobin. In contrast, the predicted prevalence of prediabetes using HbA1c only was 8% for women with ID alone, compared with 13% for women with normal iron/hemoglobin. CONCLUSIONS: These findings suggest potential misclassification of diabetes using HbA1c in areas of endemic ID/anemia. Estimating diabetes prevalence using HbA1c may result in under-diagnosis in women with ID and over diagnosis in men with anemia. PMID- 26098446 TI - The endocannabinoid anandamide during lactation increases body fat content and CB1 receptor levels in mice adipose tissue. AB - Type 1 cannabinoid receptors (CB1R) modulate energy balance; thus, their premature activation may result in altered physiology of tissues involved in such a function. Activation of CB1R mainly occurs after binding to the endocannabinoid Anandamide (AEA). The objective of this study was to evaluate the effects of AEA treatment during lactation on epididymal and body fat content, in addition to CB1R protein level at weaning. With this purpose, male mice pups were orally treated with AEA (20 MUg g(-1) body weight) or vehicle during lactation. Mice (21 days old) were killed and epididymal fat was extracted to evaluate its amount, adipocyte size and CB1R protein levels by western blot analysis. Total body fat percentage was also evaluated. Anandamide-treated mice showed an increased body fat content at 21 and 150 days of age. Moreover, epididymal adipose tissue amount, adipocyte size and CB1R protein levels were higher in the AEA-treated group. This in vivo study shows for the first time that a progressive increase in body fat accumulation can be programmed in early stages of life by oral treatment with the endocannabinoid AEA, a fact associated with an increased amount of epididymal fat pads and a higher expression of CB1R in this tissue. PMID- 26098447 TI - Analysis of intronic and exonic reads in RNA-seq data characterizes transcriptional and post-transcriptional regulation. AB - RNA-seq experiments generate reads derived not only from mature RNA transcripts but also from pre-mRNA. Here we present a computational approach called exon intron split analysis (EISA) that measures changes in mature RNA and pre-mRNA reads across different experimental conditions to quantify transcriptional and post-transcriptional regulation of gene expression. We apply EISA to 17 diverse data sets to show that most intronic reads arise from nuclear RNA and changes in intronic read counts accurately predict changes in transcriptional activity. Furthermore, changes in post-transcriptional regulation can be predicted from differences between exonic and intronic changes. EISA reveals both transcriptional and post-transcriptional contributions to expression changes, increasing the amount of information that can be gained from RNA-seq data sets. PMID- 26098448 TI - Transient acquisition of pluripotency during somatic cell transdifferentiation with iPSC reprogramming factors. AB - Somatic cells can be transdifferentiated to other cell types without passing through a pluripotent state by ectopic expression of appropriate transcription factors. Recent reports have proposed an alternative transdifferentiation method in which fibroblasts are directly converted to various mature somatic cell types by brief expression of the induced pluripotent stem cell (iPSC) reprogramming factors Oct4, Sox2, Klf4 and c-Myc (OSKM) followed by cell expansion in media that promote lineage differentiation. Here we test this method using genetic lineage tracing for expression of endogenous Nanog and Oct4 and for X chromosome reactivation, as these events mark acquisition of pluripotency. We show that the vast majority of reprogrammed cardiomyocytes or neural stem cells obtained from mouse fibroblasts by OSKM-induced 'transdifferentiation' pass through a transient pluripotent state, and that their derivation is molecularly coupled to iPSC formation mechanisms. Our findings underscore the importance of defining trajectories during cell reprogramming by various methods. PMID- 26098449 TI - Optogenetics for in vivo cardiac pacing and resynchronization therapies. AB - Abnormalities in the specialized cardiac conduction system may result in slow heart rate or mechanical dyssynchrony. Here we apply optogenetics, widely used to modulate neuronal excitability, for cardiac pacing and resynchronization. We used adeno-associated virus (AAV) 9 to express the Channelrhodopsin-2 (ChR2) transgene at one or more ventricular sites in rats. This allowed optogenetic pacing of the hearts at different beating frequencies with blue-light illumination both in vivo and in isolated perfused hearts. Optical mapping confirmed that the source of the new pacemaker activity was the site of ChR2 transgene delivery. Notably, diffuse illumination of hearts where the ChR2 transgene was delivered to several ventricular sites resulted in electrical synchronization and significant shortening of ventricular activation times. These findings highlight the unique potential of optogenetics for cardiac pacing and resynchronization therapies. PMID- 26098450 TI - Lineage conversion induced by pluripotency factors involves transient passage through an iPSC stage. AB - Brief expression of pluripotency-associated factors such as Oct4, Klf4, Sox2 and c-Myc (OKSM), in combination with differentiation-inducing signals, has been reported to trigger transdifferentiation of fibroblasts into other cell types. Here we show that OKSM expression in mouse fibroblasts gives rise to both induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) under conditions previously shown to induce only iNSCs. Fibroblast-derived iNSC colonies silenced retroviral transgenes and reactivated silenced X chromosomes, both hallmarks of pluripotent stem cells. Moreover, lineage tracing with an Oct4 CreER labeling system demonstrated that virtually all iNSC colonies originated from cells transiently expressing Oct4, whereas ablation of Oct4(+) cells prevented iNSC formation. Lastly, an alternative transdifferentiation cocktail that lacks Oct4 and was reportedly unable to support induced pluripotency yielded iPSCs and iNSCs carrying the Oct4-CreER-derived lineage label. Together, these data suggest that iNSC generation from fibroblasts using OKSM and other pluripotency-related reprogramming factors requires passage through a transient iPSC state. PMID- 26098451 TI - Kinetic fingerprinting to identify and count single nucleic acids. AB - MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers. We introduce a kinetic fingerprinting approach called single-molecule recognition through equilibrium Poisson sampling (SiMREPS) for the amplification-free counting of single unlabeled miRNA molecules, which circumvents thermodynamic limits of specificity and virtually eliminates false positives. We demonstrate high confidence, single-molecule detection of synthetic and endogenous miRNAs in both buffer and minimally treated biofluids, as well as >500-fold discrimination between single nucleotide polymorphisms. PMID- 26098452 TI - Impact of Biofuel Poplar Cultivation on Ground-Level Ozone and Premature Human Mortality Depends on Cultivar Selection and Planting Location. AB - Isoprene and other volatile organic compounds emitted from vegetation play a key role in governing the formation of ground-level ozone. Emission rates of such compounds depend critically on the plant species. The cultivation of biofuel feedstocks will contribute to future land use change, altering the distribution of plant species and hence the magnitude and distribution of emissions. Here we use relationships between biomass yield and isoprene emissions derived from experimental data for 29 commercially available poplar hybrids to assess the impact that the large-scale cultivation of poplar for use as a biofuel feedstock will have on air quality, specifically ground-level ozone concentrations, in Europe. We show that the increases in ground-level ozone across Europe will increase the number of premature deaths attributable to ozone pollution each year by up to 6%. Substantial crop losses (up to ~9 Mt y(-1) of wheat and maize) are also projected. We further demonstrate that these impacts are strongly dependent on the location of the poplar plantations, due to the prevailing meteorology, the population density, and the dominant crop type of the region. Our findings indicate the need for a concerted and centralized decision-making process that considers all aspects of future land use change in Europe, and not just the effect on greenhouse gas emissions. PMID- 26098453 TI - Tandem Alkyne Hydroacylation and Oxo-Michael Addition: Diastereoselective Synthesis of 2,3-Disubstituted Chroman-4-ones and Fluorinated Derivatives. AB - Tandem reactions involving Rh-catalyzed intermolecular hydroacylations of alkynes with salicylaldehydes followed by intramolecular oxo-Michael additions are described for the diastereoselective synthesis of 2,3-disubstituted chroman-4 ones. The tandem hydroacylation/oxo-Michael additions occur to form 2,3 disubstituted chroman-4-ones in high yields from a range of 1,2-disubstituted acetylenes and substituted salicylaldehyes. The resulting 2,3-disubstituted chroman-4-ones are readily fluorinated to form trans-3-fluoro-2,3-disubstituted chroman-4-ones in high yields with excellent diastereoselectivity. PMID- 26098455 TI - Personal discrimination and satisfaction with life: Exploring perceived functional effects of Asian American race/ethnicity as a moderator. AB - OBJECTIVES: This study aims to understand the relations between experiences of racial/ethnic discrimination, perceptions of the harmful or helpful effects of one's Asian American race/ethnicity within educational and occupational contexts (perceived functional effects), and well-being (i.e., satisfaction with life). A primary focus was to evaluate whether the association between racial/ethnic discrimination and satisfaction with life varied based on the degree to which Asian Americans believe that their race or ethnicity is helpful or harmful to educational and occupational functioning. METHOD: This study draws on nationally representative data from ethnically diverse Asian American adults (N = 3,335) and utilizes weighted descriptive, correlational, and logistic regression moderation analyses. RESULTS: Ethnic variations emerged across analyses. Logistic regression analyses revealed a significant moderation effect for Chinese and Filipino Americans. Follow-up analyses revealed a protective effect of perceiving more positive or helpful functional effects in nullifying the link between discrimination and dissatisfaction with life for Chinese Americans. By contrast, viewing more harmful functional effects had a buffering effect for Filipino Americans. CONCLUSIONS: Results have implications for conceptualizing the potential impact of perspectives that imply Asian American advantage or disadvantage. Opportunities to apply and extend these initial findings are discussed. PMID- 26098454 TI - Help-seeking intentions among Asian American and White American students in psychological distress: Application of the health belief model. AB - OBJECTIVE: Underutilization of needed mental health services continues to be the major mental health disparity affecting Asian Americans (Sue, Cheng, Saad, & Chu, 2012). The goal of this study was to apply a social psychological theoretical framework-the health belief model (Rosenstock, 1966)-to understand potential reasons why Asian Americans underutilize mental health services relative to White Americans. METHOD: Using a cross-sectional online questionnaire, this study examined how perceived severity of symptoms, perceived susceptibility to mental health problems, perceived benefits of treatment, and perceived barriers to treatment influenced intentions to seek help among a sample of 395 Asian American and 261 White American students experiencing elevated levels of psychological distress. RESULTS: Analyses using structural equation modeling indicated that Asian Americans in distress had relatively lower intentions to seek help compared with White Americans. Perceived benefits partially accounted for differences in help-seeking intentions. Although Asian Americans perceived greater barriers to help seeking than did White Americans, this did not significantly explain racial/ethnic differences in help-seeking intentions. Perceived severity and barriers were related to help-seeking intentions in both groups. CONCLUSIONS: Outreach efforts that particularly emphasize the benefits of seeking mental health services may be a particularly promising approach to address underutilization. The findings have implications in help-seeking promotion and outreach. (PsycINFO Database Record PMID- 26098456 TI - The privilege and burden of peer review. AB - OBJECTIVES: Peer review is a core value and method of quality control in psychological research, academic psychology, and other disciplines, but little is known about the peer-reviewing behavior of ethnic minority reviewers in particular. The purpose of this study was to examine the self-identified ethnicity of those invited to peer review articles for 76 journals that utilized the American Psychological Association's Journals Back Office (JBO) system from 2003 to 2012. It was hypothesized that a modest increase in the ratio of requests for reviews from self-identified ethnic minority reviewers would be observed over time, that self-identified ethnic minority reviewers would be less likely to refuse a review request than those who do not self-identify as an ethnic minority, and finally that increases in reviewer burden would be evident in significant increases in declines to requests by all reviewers. METHOD: Reviewer requests and responses were examined among the 76 journals that used the JBO system over a 10-year period. RESULTS: Using hierarchical linear models, the percentage of review invitations extended to ethnic minorities was found to significantly increase over time: Initially, an estimated 8.34% of review requests were made to ethnic minority reviewers, and that percentage increased an average of 0.41% per year. CONCLUSIONS: Ethnic minority reviewers were significantly less likely to refuse a review request than ethnic majority reviewers. Results are discussed in terms of perceived pressure to demonstrate scholastic impact and the disproportionate service burden often borne by ethnic minority psychologists. PMID- 26098457 TI - Incidence of Internal Mammary Lymph Nodes with Silicone Breast Implants at MR Imaging after Oncoplastic Surgery. AB - PURPOSE: To assess the incidence of benign and malignant internal mammary lymph nodes (IMLNs) at magnetic resonance (MR) imaging among women with a history of treated breast cancer and silicone implant reconstruction. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant retrospective study and waived informed consent. Women were identified who (a) had breast cancer, (b) underwent silicone implant oncoplastic surgery, and (c) underwent postoperative implant-protocol MR imaging with or without positron emission tomography (PET)/computed tomography (CT) between 2000 and 2013. The largest IMLNs were measured. A benign IMLN was pathologically proven or defined as showing 1 year of imaging stability and/or no clinical evidence of disease. Malignant IMLNs were pathologically proven. Incidence of IMLN and positive predictive value (PPV) were calculated on a per-patient level by using proportions and exact 95% confidence intervals (CIs). The Wilcoxon rank sum test was used to assess the difference in axis size. RESULTS: In total, 923 women with breast cancer and silicone implants were included (median age, 46 years; range, 22-89 years). The median time between reconstructive surgery and first MR imaging examination was 49 months (range, 5 513 months). Of the 923 women, 347 (37.6%) had IMLNs at MR imaging. Median short- and long-axis measurements were 0.40 cm (range, 0.20-1.70 cm) and 0.70 cm (range, 0.30-1.90 cm), respectively. Two hundred seven of 923 patients (22.4%) had adequate follow-up; only one of the 207 IMLNs was malignant, with a PPV of 0.005 (95% CI: 0.000, 0.027). Fifty-eight of 923 patients (6.3%) had undergone PET/CT; of these, 39 (67.2%) had IMLN at MR imaging. Twelve of the 58 patients (20.7%) with adequate follow-up had fluorine 18 fluorodeoxyglucose-avid IMLN, with a median standardized uptake value of 2.30 (range, 1.20-6.10). Only one of the 12 of the fluorodeoxyglucose-avid IMLNs was malignant, with a PPV of 0.083 (95% CI: 0.002, 0.385). CONCLUSION: IMLNs identified at implant-protocol breast MR imaging after oncoplastic surgery for breast cancer are overwhelmingly more likely to be benign than malignant. Imaging follow-up instead of immediate metastatic work-up may be warranted. PMID- 26098458 TI - Prostate Cancer: Interobserver Agreement and Accuracy with the Revised Prostate Imaging Reporting and Data System at Multiparametric MR Imaging. AB - PURPOSE: To evaluate accuracy and interobserver variability with the use of the Prostate Imaging Reporting and Data System (PI-RADS) version 2.0 for detection of prostate cancer at multiparametric magnetic resonance (MR) imaging in a biopsy naive patient population. MATERIALS AND METHODS: This retrospective HIPAA compliant study was approved by the local ethics committee, and written informed consent was obtained from all patients for use of their imaging and histopathologic data in future research studies. In 101 biopsy-naive patients with elevated prostate-specific antigen levels who underwent multiparametric MR imaging of the prostate and subsequent transrectal ultrasonography (US)-MR imaging fusion-guided biopsy, suspicious lesions detected at multiparametric MR imaging were scored by five readers who were blinded to pathologic results by using to the newly revised PI-RADS and the scoring system developed in-house. Interobserver agreement was evaluated by using kappa statistics, and the correlation of pathologic results with each of the two scoring systems was evaluated by using the Kendall tau correlation coefficient. RESULTS: Specimens of 162 lesions in 94 patients were sampled by means of transrectal US-MR imaging fusion biopsy. Results for 87 (54%) lesions were positive for prostate cancer. Kendall tau values with the PI-RADS and the in-house-developed scoring system, respectively, at T2-weighted MR imaging in the peripheral zone were 0.51 and 0.17 and in the transitional zone, 0.45 and -0.11; at diffusion-weighted MR imaging, 0.42 and 0.28; at dynamic contrast material-enhanced MR imaging, 0.23 and 0.24, and overall suspicion scores were 0.42 and 0.49. Median kappa scores among all possible pairs of readers for PI-RADS and the in-house-developed scoring system, respectively, for T2-weighted MR images in the peripheral zone were 0.47 and 0.15; transitional zone, 0.37 and 0.07; diffusion-weighted MR imaging, 0.41 and 0.57; dynamic contrast-enhanced MR imaging, 0.48 and 0.41; and overall suspicion scores, 0.46 and 0.55. CONCLUSION: Use of the revised PI-RADS provides moderately reproducible MR imaging scores for detection of clinically relevant disease. PMID- 26098459 TI - Cost-Effectiveness of Carotid Plaque MR Imaging as a Stroke Risk Stratification Tool in Asymptomatic Carotid Artery Stenosis. AB - PURPOSE: To evaluate the cost-effectiveness of a decision-making rule based on the magnetic resonance (MR) imaging assessment of intraplaque hemorrhage (IPH) in patients with asymptomatic carotid artery stenosis. MATERIALS AND METHODS: Two competing stroke prevention strategies were compared: (a) an intensive medical therapy-based management strategy versus (b) an imaging-based strategy in which the subset of patients with asymptomatic carotid artery stenosis with IPH on MR images would undergo immediate carotid endarterectomy in addition to ongoing intensive medical therapy. Patients in the medical therapy-only group could undergo carotid endarterectomy only with substantial carotid artery stenosis disease progression. Lifetime quality-adjusted life years (QALYs) and costs were modeled for patients with asymptomatic carotid artery stenosis with 70%-89% and 50%-69% carotid artery stenosis at presentation. Risks of stroke and complications from carotid endarterectomy, costs, and quality of life values were estimated from published sources. RESULTS: The medical therapy-based strategy had a lower life expectancy (12.65 years vs 12.95 years), lower lifetime QALYs (9.96 years vs 10.05 years), and lower lifetime costs ($13 699 vs $15 297) when compared with the MR imaging IPH-based strategy. The incremental cost effectiveness ratio (ICER) for the MR imaging IPH strategy compared with the medical therapy-based strategy was $16 000 per QALY by using a base-case 70-year old patient. When using starting patient ages of 60 and 80 years, the ICERs for the MR imaging IPH strategy were $3100 per QALY and $73 000 per QALY, respectively. The ICERs for the MR imaging IPH strategy were slightly higher at all ages for 50%-69% stenosis but remained below a willingness-to-pay threshold of $100 000 per QALY for starting ages of 60 and 70 years. CONCLUSION: MR imaging IPH can be used as a cost-effective tool to identify patients with asymptomatic carotid artery stenosis most likely to benefit from carotid endarterectomy. PMID- 26098460 TI - The Diagnostic Performance of Dynamic Contrast-enhanced MR Imaging for Detection of Small Hepatocellular Carcinoma Measuring Up to 2 cm: A Meta-Analysis. AB - PURPOSE: To determine the performance of dynamic contrast material-enhanced magnetic resonance (MR) imaging in the diagnosis of small (<=2-cm) hepatocellular carcinoma (HCC) and to identify factors that influence this performance. MATERIALS AND METHODS: Medline and Embase databases were searched for studies performed from January 2000 to March 2014 in which the performance of MR imaging was reported for the detection of HCC up to 2 cm on either a lesion- or patient based level, with sufficient data to construct 2 * 2 contingency tables. Diagnostic performance was quantitatively pooled for all studies by using a bivariate random-effects model with exploration involving subgroup analysis, meta regression, and determination of study heterogeneity. RESULTS: Twenty-two studies with 1387 small HCC lesions in 1908 patients met inclusion criteria. Heterogeneity was higher for sensitivity (range, 30%-99%) than specificity (range, 61%-100%). Overall sensitivity was 78% (95% confidence interval [CI]: 68%, 85%; I(2) = 89%), and overall specificity was 92% (95% CI: 88%, 95%; I(2) = 69%). The primary potential source of bias was use of explant as the reference standard in only 13% of studies, although lower sensitivity in such studies was not significant (59% vs 80%, P = .165). Sensitivities were significantly higher for studies that originated from Asia compared with those that originated elsewhere (89% vs 71%, P = .028), those performed with hepatobiliary phase imaging compared with those without (87% vs 65%, respectively; P = .004), and those in which gadoxetate disodium was used versus an extracellular agent (92% vs 67%, P <= .001). Specificity was not significantly different between subgroups (P >= .122). At pairwise meta-regression analysis with either study origin from Asia or performance of hepatobiliary phase imaging, only gadoxetate disodium contrast agent showed significant independent association with higher sensitivity (P = .002-.007). CONCLUSION: Results of this meta-analysis suggest that dynamic contrast-enhanced MR imaging has moderate sensitivity and excellent specificity in the detection of HCC up to 2 cm. Gadoxetate disodium contrast agent showed the strongest association with increased sensitivity. PMID- 26098461 TI - Subcellular Partitioning and Analysis of Gd3+-Loaded Ultrashort Single-Walled Carbon Nanotubes. AB - Magnetic resonance imaging (MRI) is of vast clinical utility, with tens of millions of scans performed annually. Chemical contrast agents (CAs) can greatly enhance the diagnostic potential of MRI, and ~50% of MRI scans use CAs. However, CAs have significant limitations such as low contrast enhancement, lack of specificity, and potential toxicity. Recently developed, Gd3+-loaded ultrashort single-walled carbon nanotubes, also referred to as gadonanotubes or GNTs, exhibit ~40 times the relaxivities of clinical CAs, representing a potential major advance in clinically relevant MRI CA materials. Although initial cytotoxicity and MRI studies have suggested great promise for GNTs, relatively little is known regarding their subcellular interactions, which are crucial for further, safe development of GNTs as CAs. In this work, we administered GNTs to a well-established human cell line (HeLa) and to murine macrophage-like cells (J774A.1). GNTs were not acutely cytotoxic and did not reduce proliferation, except for the highest exposure concentration of 27 MUg/mL for J774A.1 macrophages, yet bulk uptake of GNTs occurred in minutes at picogram quantities, or millions of GNTs per cell. J774A.1 macrophages internalized substantially more GNTs than HeLa cells in a dose-dependent manner, and Raman imaging of the subcellular distribution of GNTs revealed perinuclear localization. Fluorescence intensity and lifetime imaging demonstrated that GNTs did not grossly alter subcellular compartments, including filamentous-actin structures. Together, these results provide subcellular evidence necessary to establish GNTs as a new MRI CA material. PMID- 26098462 TI - Artificial Neural Network Approach for Differentiating Open-Angle Glaucoma From Glaucoma Suspect Without a Visual Field Test. AB - PURPOSE: To increase the effectiveness of treating open-angle glaucoma (OAG), we tried to find a screening method of differentiating OAG from glaucoma suspect (GS) without a visual field (VF) test. METHODS: Data were collected from the Korean National Health and Nutrition Examination Survey (KNHANES) conducted in 2010. Of 8958 participants, 386 suspected OAG subjects underwent a VF test. For the training dataset, five OAG risk prediction models were created using multivariate logistic regression and an artificial neural network (ANN) with various clinical variables. Informative variables were selected by an algorithm of consistency subset evaluation, and cross validation was used to optimize performance. The test dataset was used subsequently to assess OAG-prediction performance using the area under the curve (AUC) of the receiver-operating characteristic. RESULTS: Among five OAG risk prediction models, an ANN model with nine noncategorized factors had the greatest AUC (0.890). It predicted OAG with an accuracy of 84.0%, sensitivity of 78.3%, and specificity of 85.9%. It included four nonophthalmologic factors (sex, age, menopause, and duration of hypertension) and five ophthalmologic factors (IOP, spherical equivalent refractive errors, vertical cup-to-disc ratio, presence of superotemporal retinal nerve fiber layer [RNFL] defect, and presence of inferotemporal RNFL defect). CONCLUSIONS: Though VF tests are considered the most important examination to distinguish OAG from GS, they sometimes are impractical to conduct for small private eye clinics and during large scale medical check-ups. The ANN approach may be a cost-effective screening tool for differentiating OAG patients from GS subjects. PMID- 26098463 TI - Halo and Through-Focus Performance of Four Diffractive Multifocal Intraocular Lenses. AB - PURPOSE: To compare, as a function of pupil size, the through-focus performance and halo features of four diffractive intraocular lenses (IOLs). METHODS: Three diffractive bifocal IOLs (ReSTOR +2.5 D SV25T0, Tecnis +2.75 D ZKB00, and AT LISA +3.75 D 809M) and a diffractive trifocal IOL (AT LISA tri +3.33 D, +1.66 D 839MP) were tested in vitro in a modified International Organization for Standardization eye model. The modulation transfer function (MTF) at the IOLs' foci was obtained with pupils ranging from 2.0 to 5.0 mm. Through-focus MTF curves (at 50 cycles/mm) were compared among all the IOLs. The halo formation and characteristics were obtained from image analysis. RESULTS: The multifocal IOLs studied in this work showed, at their foci, secondary out-of-focus images, which originate halos and whose characteristics depend on the lens design and pupil size. The smallest halo occurred for the distance focus of the SV25T0. The distance and near foci of the SV25T0 yielded, respectively, the best and lowest optical quality among the studied IOLs. The distance focus of the ZKB00, AT LISA, and AT LISA tri were of similar quality, but the near focus of the ZKB00 outperformed the near foci of the rest of the IOLs. The IOLs' optical performance gradually deteriorates as pupil increases. CONCLUSIONS: Differences in the design of the diffractive IOLs translate into differences in optical quality at their foci, through-focus performance, and halo features, which can offer further information to surgeons when selecting which IOL to implant. PMID- 26098464 TI - Quantitative Comparison of Retinal Capillary Images Derived By Speckle Variance Optical Coherence Tomography With Histology. AB - PURPOSE: The purpose of this study was to correlate human retinal capillary network information derived from a prototype speckle variance optical coherence tomography (svOCT) device with histology to determine the utility of this instrument for quantitative angiography. METHODS: A retina location 3 mm superior to the optic disk was imaged with svOCT in 14 healthy human eyes. Qualitative and quantitative features of capillary networks, including capillary diameter and density, were compared with perfusion-labeled histological specimens from the same eccentricity. Twelve human donor eyes with no history of eye disease were used for histological comparisons. RESULTS: svOCT was able to clearly distinguish the morphological features of the nerve fiber layer capillary network, the retinal ganglion cell (RGC) layer capillary network, the capillary network at the border of the inner plexiform layer and superficial boundary of the inner nuclear layer, and the capillary network at the boundary of the deep inner nuclear layer and outer plexiform layer. The morphological features of these networks were highly comparable to those in previous histological studies. There were no statistical differences in mean capillary diameter between svOCT images and histology for all networks other than the RGC capillary network. Capillary density measurements were significantly greater in svOCT images, except in the RGC capillary network. CONCLUSIONS: svOCT has the capacity to provide histology like anatomical information about human retinal capillary networks in vivo. It may have great potential as a research and diagnostic tool in the management of retinal vascular diseases. Further work is required to clarify the cause of some quantitative differences between svOCT and histology. PMID- 26098465 TI - An Assessment of Dynamic Retinal Microvascular Changes in Healthy Subjects. PMID- 26098466 TI - Two Subtypes of Polypoidal Choroidal Vasculopathy: Idiopathic Disease or Age Related Macular Degeneration. PMID- 26098468 TI - Layer-Specific Manganese-Enhanced MRI of the Diabetic Rat Retina in Light and Dark Adaptation at 11.7 Tesla. AB - PURPOSE: To employ high-resolution manganese-enhanced MRI (MEMRI) to study abnormal calcium activity in different cell layers in streptozotocin-induced diabetic rat retinas, and to determine whether MEMRI detects changes at earlier time points than previously reported. METHODS: Sprague-Dawley rats were studied 14 days (n = 8) and 30 days (n = 5) after streptozotocin (STZ) or vehicle (n = 7) injection. Manganese-enhanced MRI at 20 * 20 * 700 MUm, in which contrast is based on manganese as a calcium analogue and an MRI contrast agent, was obtained in light and dark adaptation of the retina in the same animals in which one eye was covered and the fellow eye was not. The MEMRI activity encoding of the light and dark adaptation was achieved in awake conditions and imaged under anesthesia. RESULTS: Manganese-enhanced MRI showed three layers, corresponding to the inner retina, outer retina, and the choroid. In normal animals, the outer retina showed higher MEMRI activity in dark compared to light; the inner retina displayed lower activity in dark compared to light; and the choroid showed no difference in activity. Manganese-enhanced MRI activity changed as early as 14 days after hyperglycemia and decreased with duration of hyperglycemia in the outer retina in dark relative to light adaptation. The choroid also had altered MEMRI activity at 14 days, which returned to normal by 30 days. No differences in MEMRI activity were detected in the inner retina. CONCLUSIONS: Manganese-enhanced MRI detects progressive reduction in calcium activity with duration of hyperglycemia in the outer retina as early as 14 days after hyperglycemia, earlier than any other time point reported in the literature. PMID- 26098467 TI - African Ancestry Analysis and Admixture Genetic Mapping for Proliferative Diabetic Retinopathy in African Americans. AB - PURPOSE: To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D). METHODS: Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software. RESULTS: In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16-1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59-2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1. CONCLUSIONS: In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present. PMID- 26098470 TI - Role of Endothelium in Abnormal Cannabidiol-Induced Vasoactivity in Retinal Arterioles. AB - PURPOSE: Cannabinoids have been reported to mediate changes in vascular resistance through endothelial receptor targets. We examined involvement of the endothelium in cannabinoid-mediated vasoactive responses in resistance arterioles of the retina. METHODS: Vascular responses to both intraluminal (IL) and extraluminal (EL) administration of the atypical cannabinoid, abnormal cannabidiol (abn-CBD), a prototypical agonist at the non-CB1/CB2 endothelial cannabinoid receptor (CBeR), were studied in endothelial intact and endothelial denuded, isolated perfused porcine retinal arterioles with and without endothelin 1 (ET-1) precontraction. The effects of AM251, a CB1 receptor antagonist, and O 1918, an analog of CBD reported to antagonize CBeR, were also studied. RESULTS: Dose-dependent vasocontractile responses were induced by both IL and EL administration of abn-CBD in the absence of precontraction. Significantly greater vasoconstriction was induced by IL administration of abn-CBD than with EL administration. In contrast, only vasodilation to abn-CBD was observed in ET-1 precontracted retinal arterioles. Endothelium removal significantly reduced abn CBD-induced vasoactivity when abn-CBD was used IL but not when applied EL. IL abn CBD-induced vasoactivity was antagonized by O-1918 and AM251. CONCLUSIONS: Cannabinoids show complex vasoactive actions in isolated perfused retinal arterioles. The fact that abn-CBD-mediated vasorelaxation was seen only in precontracted retinal vessels indicates that the abn-CBD-induced vasoactive response is highly dependent on vascular tone. Furthermore, IL and EL administration produced differential responses, and removal of endothelium blunted abn-CBD vasoactivity, highlighting the critical role of endothelium in abn-CBD vasoactivity. AM251 and O-1918 inhibition of abn-CBD-induced vasoactivity suggests the possibility of modulating abn-CBD-induced vasoactivity. PMID- 26098469 TI - A Herpes Simplex Virus Type 1 Human Asymptomatic CD8+ T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a "Humanized" HLA Transgenic Rabbit Model. AB - PURPOSE: A clinical vaccine that protects from ocular herpes simplex virus type 1 (HSV-1) infection and disease still is lacking. In the present study, preclinical vaccine trials of nine asymptomatic (ASYMP) peptides, selected from HSV-1 glycoproteins B (gB), and tegument proteins VP11/12 and VP13/14, were performed in the "humanized" HLA-transgenic rabbit (HLA-Tg rabbit) model of ocular herpes. We recently reported that these peptides are highly recognized by CD8+ T cells from "naturally" protected HSV-1-seropositive healthy ASYMP individuals (who have never had clinical herpes disease). METHODS: Mixtures of three ASYMP CD8+ T-cell peptides derived from either HSV-1 gB, VP11/12, or VP13/14 were delivered subcutaneously to different groups of HLA-Tg rabbits (n = 10) in incomplete Freund's adjuvant, twice at 15-day intervals. The frequency and function of HSV-1 epitope-specific CD8+ T cells induced by these peptides and their protective efficacy, in terms of survival, virus replication in the eye, and ocular herpetic disease were assessed after an ocular challenge with HSV-1 (strain McKrae). RESULTS: All mixtures elicited strong and polyfunctional IFN-gamma- and TNF-alpha producing CD107+CD8+ cytotoxic T cells, associated with a significant reduction in death, ocular herpes infection, and disease (P < 0.015). CONCLUSIONS: The results of this preclinical trial support the screening strategy used to select the HSV-1 ASYMP CD8+ T-cell epitopes, emphasize their valuable immunogenic and protective efficacy against ocular herpes, and provide a prototype vaccine formulation that may be highly efficacious for preventing ocular herpes in humans. PMID- 26098471 TI - The Plane of Vitreoretinal Separation and Results of Vitrectomy Surgery in Patients Given Ocriplasmin for Idiopathic Macular Hole. AB - PURPOSE: We assessed whether ocriplasmin (OCP) given to patients with idiopathic macular hole (IMH) results in an altered plane of vitreoretinal (VR) separation compared to patients without OCP exposure. METHODS: A prospective study was done of 12 patients with IMH and vitreomacular adhesion (VMA) given OCP. Patients in whom the IMH failed to close underwent vitrectomy with peeling of the internal limiting membrane (ILM). The intraoperative staining pattern of the ILM using Brilliant Blue G (BBG) and examination of the excised ILM with transmission electron microscopy (TEM) were compared to results of a matched cohort of 31 patients with IMH who had not received OCP. RESULTS: Among 12 patients treated with OCP, VMA release occurred in 7 (58%) and hole closure was achieved in 3 (25%). Vitrectomy was done on the nine patients without hole closure. In seven of these nine (78%) the ILM had less than 5% of its vitreous surface covered in residual material on TEM, which was significantly less than in the control group (5/31, 16%, P = 0.001). In two OCP patients, large amounts of vitreous side material were present, but the rim of the hole stained evenly with BBG, suggesting that epiretinal material had avulsed with VR separation, a pattern not seen in any of the control patients. All patients had IMH closure after vitrectomy and visual results were not significantly different from the control group. CONCLUSIONS: Ocriplasmin facilitates more complete VR separation in patients undergoing surgery for IMH, although it does not result in more eccentric epiretinal tissue release. PMID- 26098472 TI - Multiscale Investigation of the Depth-Dependent Mechanical Anisotropy of the Human Corneal Stroma. AB - PURPOSE: To investigate the depth-dependent mechanical anisotropy of the human corneal stroma at the tissue (stroma) and molecular (collagen) level by using atomic force microscopy (AFM). METHODS: Eleven human donor corneas were dissected at different stromal depths by using a microkeratome. Mechanical measurements were performed in 15% dextran on the surface of the exposed stroma of each sample by using a custom-built AFM in force spectroscopy mode using both microspherical (38-MUm diameter) and nanoconical (10-nm radius of curvature) indenters at 2 MUm/s and 15-MUm/s indentation rates. Young's modulus was determined by fitting force curve data using the Hertz and Hertz-Sneddon models for a spherical and a conical indenter, respectively. The depth-dependent anisotropy of stromal elasticity was correlated with images of the corneal stroma acquired by two photon microscopy. RESULTS: The force curves were obtained at stromal depths ranging from 59 to 218 MUm. At the tissue level, Young's modulus (ES) showed a steep decrease at approximately 140-MUm stromal depth (from 0.8 MPa to 0.3 MPa; P = 0.03) and then was stable in the posterior stroma. At the molecular level, Young's modulus (EC) was significantly greater than at the tissue level; EC decreased nonlinearly with increasing stromal depth from 3.9 to 2.6 MPa (P = 0.04). The variation of microstructure through the thickness correlated highly with a nonconstant profile of the mechanical properties in the stroma. CONCLUSIONS: The corneal stroma exhibits unique anisotropic elastic behavior at the tissue and molecular levels. This knowledge may benefit modeling of corneal behavior and help in the development of biomimetic materials. PMID- 26098474 TI - Seven Questions for Personalized Medicine. PMID- 26098473 TI - Effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in male rhesus monkeys. AB - One complicating factor in cocaine addiction may be concurrent exposure and potential dependence on nicotine. The aim of the present study was to determine the effects of continuous nicotine treatment and subsequent termination on cocaine versus food choice in rhesus monkeys (Macaca mulatta). For comparison, we also determined effects of the nicotinic receptor antagonist mecamylamine on cocaine versus food choice during continuous saline and nicotine treatment. Rhesus monkeys (N = 3) responded under a concurrent schedule of food pellet (1 g) and intravenous cocaine (0-0.1 mg/kg/injection) availability. Saline and ascending nicotine doses (0.1-1.0 mg/kg/hr, intravenous) were continuously infused for 7-day treatment periods and separated by 24-hr saline treatment periods. Acute effects of mecamylamine (0.32-1.8 mg/kg, intramuscular, 15 min pretreatment) were determined during continuous saline and 0.32-mg/kg/hr nicotine treatments. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice. Nicotine treatment did not alter cocaine versus food choice. In contrast, preference of 0.032 mg/kg/injection cocaine was attenuated 24 hr following termination of 0.32-mg/kg/hr nicotine treatment, despite no somatic abstinence signs being observed. Acute mecamylamine enhanced cocaine choice during saline treatment and mainly suppressed rates of behavior during nicotine treatment. Overall, continuous nicotine exposure, up to 1 mg/kg/hr, does not enhance cocaine choice and does not produce nicotine dependence, as demonstrated by the lack of abstinence signs. PMID- 26098475 TI - Obesity, Metabolic Syndrome, and Dietary Therapeutical Approaches with a Special Focus on Nutraceuticals (Polyphenols): A Mini-Review. AB - More than half of all global deaths in 2010 were related to non-communicable diseases, including obesity, cancers, diabetes, and cardiovascular illnesses. It has been suggested that the alarming increase in the incidence of cardiovascular disease is the epidemiologic result of a nutrition transition characterized by dietary patterns featuring an increase in the intake of total fat, cholesterol, sugars, and other refined carbohydrates, concomitant with low consumption of polyunsaturated fatty acids and fiber. Although traditional dietary approaches have proven successful as part of the treatment for obesity and cardiometabolic derangements within clinical trial scenarios, they lack effectiveness in the long term, mainly due to poor compliance. Research has thus turned its attention to nutraceutics, nutrients that have the ability to modulate physiological and pathophysiological molecular mechanisms, thus resulting in favorable health outcomes. Polyphenols have been considered as among the bioactive molecules as they are thought to yield beneficial effects by exerting antioxidant activity; however, there are other--and even more robust--metabolic pathways through which polyphenols enhance cardiovascular health, such as via promoting vasodilatory, anti-atherogenic, antithrombotic, and anti-inflammatory effects. No standard dose has yet been determined, as the effects greatly vary among polyphenols and food sources; thus, there is an imperative need to generate more evidence in order to support dietary recommendations aimed at the prevention and therapeutics of obesity and its associated cardiometabolic diseases. PMID- 26098476 TI - Effects of Omega-3 Polyunsaturated Fatty Acid Supplementation on Bone Turnover in Older Women. AB - Animal and human studies indicate that omega (n)-3 polyunsaturated fatty acids (PUFA) can influence bone health. We conducted a randomized, double-blind, placebo-controlled trial of the effects of n-3 long chain (LC) PUFA supplementation (N-3 LCPUFA) on red blood cell (RBC) fatty acid levels and bone turnover markers in older postmenopausal women. One hundred and twenty-six postmenopausal women (mean age 75+/-7 years) were treated with n-3 LCPUFA (1.2 g eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA]/day, n=85) or placebo (olive oil, n=41) for 6 months. All women received 315 mg calcium citrate and 1000 IU cholecalciferol. RBC DHA (weight %) increased in the n-3 LCPUFA group, compared to no change in the placebo group (P<0.001). The ratio of DHA+EPA:arachidonic acid (AA) increased by 42 % in the n-3 LCPUFA group and by 5% in the placebo group (P<0.001). Bone-specific alkaline phosphatase and osteocalcin decreased in the n-3 LCPUFA group (P<0.05) with no between-group difference. Short-term n-3 LCPUFA supplementation increased RBC concentrations of DHA and n-3:n-6 ratios. Bone turnover decreased with n-3 LCPUF, but not statistically compared to placebo. The results point to the need for investigations with greater dosages of n-3 LCPUFA for a longer duration to understand the contribution to bone metabolism in postmenopausal women. PMID- 26098477 TI - Successful Management of Type 2 Diabetes with Lifestyle Intervention: A Case Report. AB - BACKGROUND: The prevalence of diabetes is growing worldwide. The primary symptom of diabetes mellitus is elevated blood sugar. This is usually treated with lifestyle intervention and drugs according to an algorithm based on glycated hemoglobin (HbA1c) levels. We present the case of a patient who successfully managed his type 2 diabetes solely through lifestyle modification. CASE REPORT: A 45-year-old businessman with a body mass index of 27 kg/m2 was examined within a secondary prevention program in Austria. His HbA1c was 9.7%-type 2 diabetes mellitus was diagnosed. General recommendations for lifestyle were given and metformin was prescribed. Upon his diagnosis the patient searched for all the information he could get about diabetes and implemented this new knowledge in his everyday life. He had a strong desire to defeat his disease and he wanted to stop using medications. He identified some nutritional ingredients and spices that affected his blood sugar in a positive way. He stopped taking metformin after 4 weeks and handled his diabetes with his personal lifestyle program. Three months after the diagnosis his HbA1c was 6.4%; after 6 months he had an HbA1c of 6.0% without the use of medication. DISCUSSION: Usually, multiple drug therapy is necessary to handle high blood glucose levels. Our business manager ate as much as before his diagnosis but he modified the contents of his diet so that the lifestyle intervention was not hard for him. General recommendations for lifestyle modification usually include: more exercise, reduced sugar and monosaccharides, and less alcohol and nicotine. With the knowledge of the effects of specific dietary ingredients, it might be possible to modify a regular diet in such a way as to benefit people with type 2 diabetes, to substantially improve quality of life. PMID- 26098478 TI - Cytoprotective Effect of Tocotrienol-Rich Fraction and alpha-Tocopherol Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells. AB - Glutamate is the major mediator of excitatory signals in the mammalian central nervous system. Extreme amounts of glutamate in the extracellular spaces can lead to numerous neurodegenerative diseases. We aimed to clarify the potential of the following vitamin E isomers, tocotrienol-rich fraction (TRF) and alpha-tocopherol (alpha-TCP), as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Cells were treated before and after glutamate injury (pre and post-treatment, respectively) with 100-300 ng/ml TRF/alpha-TCP. Exposure to 120 mM glutamate significantly reduced cell viability to 76% and 79% in the pre- and post-treatment studies, respectively; however, pre- and post-treatment with TRF/alpha-TCP attenuated the cytotoxic effect of glutamate. Compared to the positive control (glutamate-injured cells not treated with TRF/alpha-TCP), pre treatment with 100, 200, and 300 ng/ml TRF significantly improved cell viability following glutamate injury to 95.2%, 95.0%, and 95.6%, respectively (p<0.05).The isomers not only conferred neuroprotection by enhancing mitochondrial activity and depleting free radical production, but also increased cell viability and recovery upon glutamate insult. Our results suggest that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Our findings also indicate that both TRF and alpha-TCP could play key roles as anti-apoptotic agents with neuroprotective properties. PMID- 26098479 TI - Vitamin Intake from Food Supplements in a German Cohort - Is there a Risk of Excessive Intake? AB - Food supplements, if not properly used, may lead to potentially harmful nutrient intake. The purpose of this survey was to examine vitamin intake from food supplements. Taking into account the intake from food, as obtained from the National Nutrition Survey, it was determined whether the tolerable upper intake levels (ULs) were exceeded via supplements alone, or in combination with food. Data from 1070 supplement users (18-93 years) was available. The dietary and supplemental vitamin intakes of three groups were analyzed: average intake (50th percentile food+50th percentile supplements), middle-high intake (50th+95th) and high intake (95th+95th). Vitamin C (53%), vitamin E (45%) and B vitamins (37-45%) were consumed most frequently. Few subjects (n=7) reached or exceeded the ULs through supplements alone. The UL for vitamin A and folate was reached by a few men in the middle-high group, and by a few men and women in the high intake group. Otherwise, even in the high intake group, the recommended vitamin D intake of 20 ug/day (in case of insufficient endogenous synthesis) could not be achieved. The use of food supplements was not associated with excessive vitamin intake in this survey, except in a small number of cases. Vitamin A intake above the UL was the result of high dietary intake which also included the intake of beta-carotene, rather than the result of overconsumption of food supplements. Diets mainly included folate from natural sources, which has no associated risk. PMID- 26098480 TI - Curcumin Modulates Muscle Damage but not Oxidative Stress and Antioxidant Defense Following Eccentric Exercise in Rats. AB - AIM: The purpose of this study was to investigate the effects of curcumin on eccentric exercise-induced muscle damage and oxidative stress in rats. METHODS: Thirty male Wistar rats were divided into four groups: Control (C; no curcumin, no exercise; n=6), Curcumin (Cur; n=8), Exercise (E; n=8) and Exercise Plus Curcumin (ECur; n=8). Curcumin was given for 20 days via oral gavage at doses of 200 mg/kg(-1) of body weight per day, dissolved in corn oil. On the 21st day eccentric exercise was provided via a treadmill run and the rats were sacrificed immediately after. RESULTS: Eccentric exercise resulted in significant (p<0.05) increases in all injury markers such as creatine kinase (CK) and myoglobin, but curcumin supplementation tended to decrease CK activity (p>0.05) and significantly decreased myoglobin levels (p<0.05). In blood and muscle samples, malondialdehyde (MDA) levels were not affected by either curcumin or exercise (p>0.05). MDA levels in liver tissue decreased in the ECur group, compared to the control (p<0.05). Superoxide dismutase (SOD) activities and glutathione (GSH) levels were affected by neither curcumin nor exercise (p>0.05), in blood, muscle and liver tissues. CONCLUSION: The results of this study suggest that curcumin has a protective effect on eccentric exercise induced muscle damage, and that this effect might be independent of oxidative stress and antioxidant systems. PMID- 26098481 TI - Vitamin D, Parathormone and Associated Minerals among Students in Zagazig District, Sharkia Governorate, Egypt. AB - AIM: To determine the prevalence of vitamin D deficiency and associated factors among students of age 13-18 years. METHODS: DESIGN: Community-based cross sectional survey. SETTING: Two schools were selected using multistage sampling techniques. SAMPLING: Cluster sampling of all enrolled students (550 students). OUTCOME MEASURES: Serum levels of 25-hydroxyvitamin D (25 OHD), parathyroid hormone and calcium. Data was collected about nutritional intake, physical activity and lifestyle variables that are potential risk factors for hypovitaminosis D. RESULTS: Hypovitaminosis D prevalence was 23.8%, of which 5.3% was deficiency and 18.5% insufficiency. Serum 25 OHD levels inversely correlated with parathyroid hormone levels (r=-0.206, P= 0.00). Low calcium and ionized calcium levels were 40.6% and 45.9%, respectively, and significantly correlated with vitamin D levels. Female students have significantly higher levels of hypovitaminosis D compared to males (29.3% to 15.0%, respectively) and the level of vitamin D significantly improved with increased age. Exposure to sun had a significant effect on vitamin D levels, and physical activity, soft drink consumption and smoking did not. Multinomial regression analysis revealed that age, sun exposure and Ca level were the only significant independent predictors of hypovitaminosis D among the studied group. CONCLUSION: Our findings revealed that hypovitaminosis D is a prevalent health problem in adolescents, especially girls, who were at higher risk, and increased age and sun exposure improved vitamin D status among the studied group. There is therefore a need to consider vitamin D supplementation for school children together with increased awareness through a health education program. PMID- 26098482 TI - The Oral Intake of Organic Germanium, Ge-132, Elevates alpha-Tocopherol Levels in the Plas-ma and Modulates Hepatic Gene Expression Profiles to Promote Immune Activation in Mice. AB - The common water-soluble organic germanium compound poly-trans-[(2-carboxyethyl) germasesquioxane] (Ge-132) exhibits activities related to immune responses and antioxidant induction. In this study, we evaluated the antioxidative effect of dietary Ge-132 in the plasma of mice. Male ICR mice (seven mice per group) received an AIN-76 diet with 0.05% Ge-132; three groups received the Ge-132 containing diet for 0, 1 or 4 days. The plasma alpha-tocopherol (alpha tocopherol) concentration increased from 6.85 to 9.60 MUg/ml after 4 days of Ge 132 intake (p<0.05). We evaluated the changes in hepatic gene expression related to antioxidative activity as well as in the entire expression profile after one day of Ge-132 intake, using DNA microarray technology. We identified 1,220 genes with altered expression levels greater than 1.5-fold (increased or decreased) as a result of Ge-132 intake, and alpha-tocopherol transfer protein (Ttpa) gene expression was increased 1.62-fold. Immune activation was identified as the category with the most changes (containing 60 Gene Ontology (GO) term biological processes (BPs), 41 genes) via functional clustering analysis of altered gene expression. Ge-132 affected genes in clusters related to ATP production (22 GO term BPs, 21 genes), lipid metabolism (4 GO term BPs, 38 genes) and apoptosis (5 GO term BPs). Many GO term BPs containing these categories were significantly affected by the Ge-132 intake. Oral Ge-132 intake may therefore have increased plasma alpha-tocopherol levels by up-regulating alpha-tocopherol transfer protein (Ttpa) gene expression. PMID- 26098483 TI - Effect of Fenugreek Seeds on Serum Metabolic Factors and Adiponectin Levels in Type 2 Diabetic Patients. AB - This triple-blind randomized controlled clinical trial was conducted on 88 type 2 diabetic (T2DM) patients (males and females). Subjects in the fenugreek seed (n=44) and placebo (n=44) groups consumed 10 g/d of powdered whole fenugreek seeds or 5 g/d of wheat starch for 8 weeks. Fasting blood samples, anthropometric measurements and dietary records were collected at the baseline and at the end of the trial. Fenugreek seeds significantly decreased fasting blood glucose (P=0.007) and HbA1c (P=0.0001), serum levels of insulin (P=0.03), homeostatic model assessment for insulin resistance (P=0.004), total cholesterol (P=0.005) and triglycerides (P=0.0001) and increased serum levels of adiponectin (P=0.001) compared with placebo. No significant changes were shown in serum low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in both groups. In conclusion, fenugreek seeds improved glucose metabolism, serum lipid profile and adiponectin levels in studied subjects, and may be useful in the control of diabetes risk factors in TD2M patients. PMID- 26098484 TI - Higher Dietary Acidity is Associated with Lower Bone Mineral Density in Postmenopausal Iranian Women, Independent of Dietary Calcium Intake. AB - Findings of studies on the link between dietary acid-base balance and bone mass are relatively mixed. We examined the association between dietary acid-base balance and bone mineral density (BMD) in a sample of Iranian women, hypothesizing that a higher dietary acidity would be inversely associated with BMD, even when dietary calcium intake is adequate. In this cross-sectional study, lumbar spine and femoral neck BMDs of 151 postmenopausal women aged 50-85 years were measured using dual-energy x-ray absorptiometry. Dietary intakes were assessed using a validated food frequency questionnaire. Renal net acid excretion (RNAE), an estimate of acid-base balance, was then calculated indirectly from the diet using the formulae of Remer (based on dietary intakes of protein, phosphorus, potassium, and magnesium; RNAERemer) and Frassetto (based on dietary intakes of protein and potassium; RNAEFrassetto), and was energy adjusted by the residual method. After adjusting for potential confounders, multivariable adjusted means of the lumbar spine BMD of women in the highest tertiles of RNAERemer and RNAEFrassetto were significantly lower than those in the lowest tertiles (for RNAERemer: mean difference -0.084 g/cm2; P=0.007 and for RNAEFrassetto: mean difference -0.088 g/cm2; P=0.004). Similar results were observed in a subgroup analysis of subjects with dietary calcium intake of >800 mg/day. In conclusion, a higher RNAE (i. e. more dietary acidity), which is associated with greater intake of acid-generating foods and lower intake of alkali-generating foods, may be involved in deteriorating the bone health of postmenopausal Iranian women, even in the context of adequate dietary calcium intake. PMID- 26098485 TI - Regio- and Diastereoselective Synthesis of Highly Substituted, Oxygenated Piperidines from Tetrahydropyridines. AB - Diastereoselective epoxidation and regioselective ring-opening methods were developed for the synthesis of densely substituted, oxygenated piperidines from two classes of tetrahydropyridines with distinct stereochemical displays of functionalities. A new and practical in situ prepared epoxidation reagent was developed for the diastereoselective epoxidation of one class of sterically hindered tetrahydropyridines. The novel bifunctional epoxidation reagent, 2 carboperoxy-3,4,5,6-tetrafluorobenzoic acid, was designed to incorporate highly reactive percarboxy acid and pendant carboxylic acid groups, which through hydrogen bonding to the amino group successfully overrode steric effects and directed epoxidation to occur at the more hindered face of the tetrahydropyridine. Nucleophilic ring-opening of the epoxides with water, alcohols, and HF proceeded with high regioselectivity, affording piperidinol products with adjacent tetrasubstituted carbons. PMID- 26098486 TI - Reduced graphene oxide-coated hydroxyapatite composites stimulate spontaneous osteogenic differentiation of human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) have great potential as cell sources for bone tissue engineering and regeneration, but the control and induction of their specific differentiation into bone cells remain challenging. Graphene-based nanomaterials are considered attractive candidates for biomedical applications such as scaffolds in tissue engineering, substrates for SC differentiation and components of implantable devices, due to their biocompatible and bioactive properties. Despite the potential biomedical applications of graphene and its derivatives, only limited information is available regarding their osteogenic activity. This study concentrates upon the effects of reduced graphene oxide (rGO)-coated hydroxyapatite (HAp) composites on osteogenic differentiation of hMSCs. The average particle sizes of HAp and rGO were 1270 +/- 476 nm and 438 +/- 180 nm, respectively. When coated on HAp particulates, rGO synergistically enhanced spontaneous osteogenic differentiation of hMSCs, without hampering their proliferation. This result was confirmed by determining alkaline phosphatase activity and mineralization of calcium and phosphate as early and late stage markers of osteogenic differentiation. It is suggested that rGO-coated HAp composites can be effectively utilized as dental and orthopedic bone fillers since these graphene-based particulate materials have potent effects on stimulating the spontaneous differentiation of MSCs and show superior bioactivity and osteoinductive potential. PMID- 26098487 TI - [Validity comparison of various biological samples from lower airway and their contribution for the detection of nosocomial pneumonia etiological agents]. AB - BACKGROUND: The aim of the study was to compare the validity of bronchial secretion sampling and bronchoscopy-assisted protected specimen brushing (PSB) in patients with hospital-acquired pneumonia (HAP). MATERIALS AND METHODS: In patients with HAP, bronchial secretion samples (aspiration of lower airway secretions from an orotracheal tube with a suctioning catheter) and PSB (bronchoscopy-assisted sampling from the most affected area of the lung, verified by CT scan) were taken at the same time. Both samples were processed by semiquantitative routine microbiological techniques. Identification of microorganisms was performed by standard microbiological techniques using the MALDI-TOF automated system. For similarity or identity determination of bacterial isolates from bronchial secretion sampling and PSB, pulsed-field gel electrophoresis was used. RESULTS: Thirty patients were enrolled into the study. Thirty pairs of bronchial secretion samples and PSB samples were obtained and processed. The samples were positive in 23 patients (77 %) and 15 patients (50 %), respectively. In 15 cases, the same pathogen was determined in both samples, and in all those cases, the isolates were genetically identical. CONCLUSION: The results of the study show that bronchial secretion samples analysis enabled identification of all pathogens that were identified by PSB. Given the high sensitivity of the bronchial secretion aspiration technique and genetic identity of isolates in both samples, bronchial secretion sampling may be recommended for determining HAP etiological agents as the samples are much easier to obtain from patients. PMID- 26098488 TI - [Bacterial pathogens causing hospital-acquired pneumonia - a multicenter study in the Czech Republic]. AB - INTRODUCTION: The objectives were to assess the prevalence of etiologic agents of hospital-acquired pneumonia (HAP) in patients staying in four big hospitals in the Czech Republic and requiring artificial ventilation. The resistance of the isolated pathogens to antibiotics was determined and initial antibiotic therapy was discussed. METHODS: Included in the study were 155 patients with HAP staying from May 1, 2013 to January 31, 2014 in the Departments of Anesthesiology and Critical Care in the following four centers: Thomayer Hospital Prague, University Hospital Brno, University Hospital Hradec Kralove and University Hospital Olomouc. From these patients, endotracheal secretion samples were processed using standard microbiology methods. In identified bacterial strains, susceptibility to antibiotics was tested with the microdilution method according to the EUCAST recommendations. Production of ESBL and AmpC beta-lactamases was detected by disk diffusion tests specific for the particular enzymes. ESBL- and AmpC-positive isolates were subjected to basic genetic analysis. RESULTS: Over the study period, a total of 266 isolates were obtained from 140 patients, with 15 patients having negative culture result. Late-onset pneumonia was present in 72 %. Gram negative bacteria were most prevalent (81 %), namely Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli. Phenotypic tests for production of broad spectrum beta-lactamases were positive in 37 % of Enterobacteriaceae. Genes for CTX-M, SHV, TEM beta-lactamases or CIT and DHA types of AmpC enzymes were detected. No carbapenemase-producing bacteria, methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci were detected. CONCLUSION: The study showed that HAP in the Czech Republic was mostly of Gram negative etiology. Variable antibiotic susceptibility in the two most frequent etiological agents (Pseudomonas aeruginosa and Klebsiella pneumoniae) resulted in severe therapeutic difficulties. A total of 49 % of patients received inadequate therapy. This fact suggests the impact of antibiotic resistance on intensive care patients' survival or death. Our study confirmed that one in three patients dies because of HAP. PMID- 26098489 TI - [Current view of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections]. AB - The review article interprets recommendations for treating methicillin-resistant Staphylococcus aureus (MRSA) infections with vancomycin. These stem from a 2009 consensus followed by numerous preclinical and clinical studies carried out until now. They are based on defining the predictors of the bactericidal activity of vancomycin that are different from those in beta-lactam and aminoglycoside antibiotics. The predictors are AUC0-24/MIC >400 and Cm?n. Practice requires recommendations on how to achieve maximum effectiveness and safety of vancomycin administered by intermittent vs. continuous infusion by setting target concentrations under dynamically changing conditions. Changes in the kinetics and dynamics of the antibiotic due to pathological covariates (SIRS, sepsis) and treatment should be detected as soon as possible by therapeutic monitoring aimed at individual adjustment of dosage. PMID- 26098490 TI - [When should empirical antibiotic therapy be indicated in acute community-onset diarrhea of suspected bacterial etiology]. AB - BACKGROUND: The aims of this study were to describe the basic parameters of adult patients with acute community-onset salmonellosis or campylobacteriosis responsible for more than 90 % of all cases of community-onset diarrhea in the Czech Republic, and, according to the results of this analysis, to update the diagnostic and therapeutic algorithms. MATERIALS AND METHODS: The data were collected retrospectively between January 1, 2011 and December 31, 2013. Patients with systemic signs of infection having at least 2 signs of systemic inflammatory response syndrome (SIRS) or with elevated serum procalcitonin levels (more than 0.5 ng/ml) were classified as being at risk for the invasive form of the disease. The remaining patients were classified as having the simple intestinal form of the disease. Patients with community-onset post-antibiotic diarrhea were excluded. The data were statistically processed. RESULTS: The following clinical factors were statistically significantly correlated with the high-risk form of the disease: duration of illness of less than 3 days before admission and any of the following (some of them are part of the SIRS classification), even after being adjusted for age: body temperature above 38 degrees C, peripheral blood white cell count (WBC) above 12 * 109/l, neutrophil count above 9 * 109/l and CRP level above 150 mg/l. The risk form of the disease occurred in 60 cases (18.7 %). The mean WBC was 9.4 * 109/l (median, 8.4; range, 1.7-89.0). The WBC within the normal range was seen in 194 cases (60.4 %). The mean CRP level was 92.9 mg/l (median, 77.0; range, 1.0-342.0). An elevated procalcitonin level was seen in 21 patients; the marker was not routinely measured. Positive blood culture results were obtained in 2 persons with salmonellosis; the examination was not routinely performed. There were 34 patients (10.6 %) with documented immune system dysfunction; the risk form of salmonellosis or campylobacteriosis was seen in only 11 of them (3.4 %). A total of 306 patients (95.3 %) were treated with antibiotics; the mean duration of antibiotic therapy was 8.7 days (median, 7; range, 2-31). CONCLUSIONS: Antibiotic treatment in salmonellosis/campylobacteriosis should not be indicated only due to elevated CRP levels but rather after comprehensive evaluation of the duration of symptoms, individual risk factors and dynamic changes in markers of inflammation. Blood culture tests should be carried out more frequently. PMID- 26098492 TI - Faculty Development for Simulation Programs: Five Issues for the Future of Debriefing Training. AB - STATEMENT: Debriefing is widely recognized as a critically important element of simulation-based education. Simulation educators obtain and/or seek debriefing training from various sources, including workshops at conferences, simulation educator courses, formal fellowships in debriefings, or through advanced degrees. Although there are many options available for debriefing training, little is known about how faculty development opportunities should be structured to maintain and enhance the quality of debriefing within simulation programs. In this article, we discuss 5 key issues to help shape the future of debriefing training for simulation educators, specifically the following: (1) Are we teaching the appropriate debriefing methods? (2) Are we using the appropriate methods to teach debriefing skills? (3) How can we best assess debriefing effectiveness? (4) How can peer feedback of debriefing be used to improve debriefing quality within programs? (5) How can we individualize debriefing training opportunities to the learning needs of our educators? PMID- 26098493 TI - A Bone Marrow Aspirate and Trephine Simulator. AB - INTRODUCTION: Bone marrow aspirate and trephine (BMAT) biopsy is a commonly performed procedure in hematology-oncology practice. Although complications are uncommon, they can cause significant morbidity and mortality. Simulation models are an excellent tool to teach novice doctors basic procedural skills before performing the actual procedure on patients to improve patient safety and well being. METHODS: There are no commercial BMAT simulators, and this technical report describes the rationale, technical specifications, and construction of a low-cost, easily constructed, reusable BMAT simulator that reproduced the tactile properties of tissue layers for use as a teaching tool in our resident BMAT simulation course. Preliminary data of learner responses to the simulator were also collected. RESULTS: From April 2013 to November 2013, 32 internal medicine residents underwent the BMAT simulation course. Eighteen (56%) completed the online survey, 11 residents with previous experience doing BMAT and 7 without experience. Despite the difference in operative experience, both experienced and novice residents all agreed or strongly agreed that the model aided their understanding of the BMAT procedure. All agreed or strongly agreed that this enhanced their knowledge of anatomy and 16 residents (89%) agreed or strongly agreed that this model was a realistic simulator. CONCLUSIONS: We present a novel, low-cost, easily constructed, realistic BMAT simulator for training novice doctors to perform BMAT. PMID- 26098494 TI - Interrater Reliability of Standardized Actors Versus Nonactors in a Simulation Based Assessment of Interprofessional Collaboration. AB - INTRODUCTION: There is a need for reliable and practical interprofessional simulations that measure collaborative practice in outpatient/community scenarios where most health care takes place. The authors applied generalizability theory to examine reliability in an ambulatory care scenario using the following 2 trained observer groups: standardized patient (SP, actor) raters and those who received rater training alone (non-SPs). METHODS: Twenty-one graduate health professions students participated as health care providers in an interprofessional care simulation involving an SP, caregiver, and clinicians. Six observers in each group received frame-of-reference training and rated aspects of collaborative care using a behavioral observation checklist. The authors examined sources of measurement variance using generalizability theory and extended this technique to statistically compare the rater types and compute reliability for subsets of raters. RESULTS: Standardized patient ratings were significantly more reliable than non-SPs' despite both groups receiving extensive rater training. A single SP was predicted to generate scores with a reliability of 0.74, whereas a single non-SP rater's scores were predicted at a reliability of 0.40. Removing each rater one by one from the full 6-member SP sample reduced reliability similarly for all raters (reliability, 0.86-0.89). However, removing individual raters from the full 6-member non-SP sample led to more variable reductions in reliability (0.58-0.72). CONCLUSIONS: Ongoing experience rating performance from within a particular simulation-based assessment may be a valuable rater characteristic and more effective than rater training alone. The extensions of reliability estimation introduced here can also be used to support more insightful reliability research and subsequent improvement of rater training and assessment protocols. PMID- 26098495 TI - Cryptococcosis in solid organ transplant recipients. AB - PURPOSE OF REVIEW: Cryptococcosis among solid organ transplant (SOT) recipients is a source of significant morbidity. Its pathogenesis, the etiology of immune reconstitution syndrome, and the optimal therapy in this setting are still not well defined. Herein, we review the epidemiology, the latest findings on pathogenesis, unique clinical manifestations, and the treatment of Cryptococcosis in this specific vulnerable population. RECENT FINDINGS: Cryptococcosis is a common fungal complication among SOT recipients. It follows in frequency only to aspergillosis and candidiasis. Cryptococcal infection carries a high mortality, up to 27% during the first year posttransplantation. Host factors, environmental factors, medications, and the type of transplant all play a role in the clinical presentation and severity of infection. Clinical manifestations can be atypical among SOT recipients, and therefore, clinical suspicion and diagnostic evaluation must consider cryptococcal central nervous system disease. During meningitis treatment, measurement of Flucytosine levels is recommended to increase safety and optimize the therapeutic effect. SUMMARY: Cryptococcosis among SOT recipients is an evolving field. Increased recognition and understanding of the disease pathogenesis, its uncommon clinical manifestations, complications and particular therapeutic strategies are the cornerstone for the optimal outcome of this often fatal condition. PMID- 26098496 TI - Differential diagnosis of diffuse alveolar haemorrhage in immunocompromised patients. AB - PURPOSE OF REVIEW: Diffuse alveolar haemorrhage (DAH) is a life-threatening medical emergency in immunocompromised and immunocompetent patients characterized by haemoptysis, anaemia, acute respiratory failure and diffuse pulmonary infiltrates on radiologic examination. This review describes DAH imaging features, causes and main differential diagnosis. RECENT FINDINGS: In immunosuppressed patients, DAH occurs most frequently in haematologic neoplasms, after haematopoietic stem cell transplantation or solid organ transplantation, secondary to drug reaction or infection, and associated with AIDS. However, differential diagnoses of all of these conditions include several conditions with similar findings. SUMMARY: Imaging patterns of DAH do not differ significantly from those of conditions included in the main differential diagnosis. The differential diagnosis depends on the patient's immunity status. In immunocompromised patients, infection and lung injury of other causes must be considered. PMID- 26098497 TI - Clinical utility of cytomegalovirus viral load in solid organ transplant recipients. AB - PURPOSE OF REVIEW: Quantitative nucleic acid testing (QNAT) to measure viral load has become a mainstay in the management of cytomegalovirus (CMV) infection and disease in solid organ transplant recipients. In this article, we review the clinical applications of CMV QNAT in the management of solid organ transplant recipients. RECENT FINDINGS: Because several platforms were available for CMV QNAT, there was a wide inter-assay variability in the viral load reporting, and this limited the generation of widely applicable viral load thresholds that can be used for various clinical applications. With the recent availability of international standard and certified reference materials, there is now opportunity to standardize viral load reporting, with the goal of deriving viral load thresholds for various clinical applications, such as rapid diagnosis of CMV infection and disease, predicting the risk of disease and assessing the severity of illness, monitoring efficacy of antiviral therapies and assessing the risk of viral relapse and drug resistance. SUMMARY: Recent advances in the field such as CMV QNAT standardization, as discussed in this review, are anticipated to optimize the management of CMV infection and disease in solid organ transplant recipients. PMID- 26098498 TI - Risks to healthcare workers with emerging diseases: lessons from MERS-CoV, Ebola, SARS, and avian flu. AB - PURPOSE OF REVIEW: Several viral diseases have emerged and impacted healthcare systems worldwide. Healthcare personnels (HCPs) are at high risk of acquiring some emerging infections while caring for patients. We provide a review of risk factors, evidence of infection in HCPs, and prevention strategies with Middle East respiratory syndrome coronavirus, Ebola virus disease (Ebola), severe acute respiratory syndrome (SARS), and avian influenza. RECENT FINDINGS: HCP-related infections with Middle East respiratory syndrome coronavirus, Ebola, and SARS have been reported among 1-27%, 2.5-12%, and 11-57% of total cases, respectively. The case fatality rate of Ebola in HCPs has been reported up to 73%. The WHO guidelines for the global surveillance of SARS were developed in 2004 and used as a template for other emerging diseases preparedness. Risks to HCPs with emerging diseases are related to inappropriate and insufficient infection control measures during an initial encounter, at the beginning of outbreak and with an overwhelming number of patient cases. To date, there are no reports of avian influenza transmission to HCPs from affected cases. SUMMARY: Early and rapid detection of suspected infected patients with communicable diseases along with appropriate infection control practice, education, national and global preparedness guidelines would help to prevent disease transmission to HCPs. PMID- 26098499 TI - Approach to drug-resistant cytomegalovirus in transplant recipients. AB - PURPOSE OF REVIEW: The purpose of this study is to provide updated information on diagnosis of cytomegalovirus (CMV) drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds. RECENT FINDINGS: For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug-resistant phenotype and may be genotyping artefacts. Next-generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation. SUMMARY: Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug resistant CMV and their genetic barriers to resistance. PMID- 26098500 TI - Toxoplasma prophylaxis in haematopoietic cell transplant recipients: a review of the literature and recommendations. AB - PURPOSE OF REVIEW: Toxoplasmosis in haematopoietic cell transplant (HCT) recipients is associated with high morbidity and mortality rates. Prophylaxis following HCT is recommended for high-risk pre-HCT toxoplasma-seropositive (pre HCTSP) recipients. However, there is no agreement or consistency among programmes on whether to adopt prophylaxis or not, or if used, on the chosen antitoxoplasma prophylactic regimen. This review discusses the role of prophylaxis, and preemptive treatment, for toxoplasmosis in the setting of HCT. RECENT FINDINGS: Approximately two-thirds of toxoplasmosis cases following HCT are reported in allogeneic pre-HCTSP (allo pre-HCTSP) patients. This finding confirms a major role of reactivation of latent infection in the pathogenesis of toxoplasmosis in this patient population. Toxoplasma disease-related mortality in allo pre-HCTSP patients was reported at 62%, but it can be significantly decreased with early detection and treatment of toxoplasma infection. There are no randomized trials comparing the efficacy of different prophylactic agents to prevent toxoplasmosis after HCT. Several observational studies have demonstrated the efficacy of trimethoprim-sulfamethoxazole (TMP/SMX) in decreasing the incidence of toxoplasmosis following HCT. There is limited information regarding efficacy of other prophylactic agents. Preemptive treatment using routine blood PCR monitoring seems to be beneficial in detecting infection early and preventing disease in several observational studies and has been adopted for allo pre-HCTSP HCT patients when universal prophylaxis is not possible. SUMMARY: Universal prophylaxis with TMP/SMX in allo pre-HCTSP patients should be implemented by all transplant programmes. Preemptive treatment with routine blood PCR monitoring is an option if prophylaxis cannot be used. PMID- 26098501 TI - Operating room myths: what is the evidence for common practices. AB - PURPOSE OF REVIEW: In order to ensure patient safety and prevent surgical site infections (SSIs), operating theaters/rooms have evolved into complex, highly technical environments. Prevention of healthcare-associated infections, and strategies to limit patient harm, have gained momentum over the last decade. This article aims to examine and dispute some commonly held beliefs with specific reference to: laminar airflow, noise and operating theater door openings and how these impact SSI. RECENT FINDINGS: Laminar airflow may not be necessary for prosthetic implant surgery. Some recent data suggest that there may be patient harm. With the development of better surgical techniques and perioperative care, such costly systems may not be needed. Operating rooms with a high number of door openings have also been shown to experience higher SSI rates, as have operating rooms with high noise levels. These may serve as surrogate markers for operating room discipline. Initiatives which target these areas may be worth considering when devising strategies to reduce SSIs. SUMMARY: Improved surveillance systems for SSIs are needed and should include operating theater airflow type. This will allow further analysis of the effect of laminar air flow on SSIs and provide evidence for a decisive recommendation. Cultivating a culture of good operating theater discipline may also reduce SSIs. PMID- 26098503 TI - Cytomegalovirus in immunocompromised children. AB - PURPOSE OF REVIEW: The purpose of this study is to explore the latest developments in the risk factors, prevention and treatment of cytomegalovirus (CMV) infection in immunocompromised children, including those with congenital immunodeficiency or iatrogenic immune suppression related to solid organ transplantation (SOT) or haematopoietic cell transplantation (HCT). RECENT FINDINGS: CMV viral load measurements now have international standards, allowing for more reliable comparison across sites and within individuals. Preemptive and prophylactic therapy with routine CMV monitoring in transplant patients has yielded significant reduction in CMV morbidity and mortality in these patients. The majority of U.S. states have adopted routine newborn screening for severe combined immunodeficiency (SCID). Viral infections, including CMV, are a major obstacle preventing optimal curative transplantation in these patients. Several new antiviral agents are currently being investigated for CMV infection in immunocompromised patients. Knowledge on CMV drug resistance in children is emerging and requires further study. SUMMARY: Conditions that diminish cell mediated immunity impact the development of CMV infection and disease. These conditions include certain congenital immunodeficiencies and SOT and HCT. Infants identified as having SCID should be screened for CMV risk factors. A preemptive or prophylactic strategy should be chosen for CMV management in children who are high risk posttransplantation. In those who develop disease, viral loads should be monitored and resistance testing considered if response is not deemed adequate. Oral valganciclovir is being used as an alternative to ganciclovir in children, although pharmacokinetic data are limited. Other oral antiviral agents under development are promising future options for paediatric CMV therapy. PMID- 26098502 TI - Expanding the statistical toolbox: analytic approaches for cohort studies with healthcare-associated infectious outcomes. AB - PURPOSE OF REVIEW: Healthcare-associated infections (HAIs) are a leading cause of adverse patient outcomes. Further elucidation of the etiology of these infections and the pathogens that cause them has been a primary goal of research in infection control and healthcare epidemiology. Longitudinal studies, in particular, afford a range of statistical methods to better understand the process of pathogen acquisition or HAI development. This review intends to convey the scope of available statistical methodology. RECENT FINDINGS: Despite the range of methods available, logistic regression remains the dominant statistical approach in use. Poisson regression, survival methods, and mechanistic (mathematical) models remain underutilized. Recent studies that use these approaches are looking beyond associations to answer questions about the timing, duration, and mechanism of infectious risk. SUMMARY: Logistic regression remains an important approach to the study of HAIs, but in the context of cohort studies, it is most appropriate for short observation periods, during which mechanism is not of primary interest. Additional statistical methodologies are available to build upon risk factor analysis to better inform the process of risk and infection in the hospital setting. PMID- 26098504 TI - Ebola virus disease: preparedness and infection control lessons learned from two biocontainment units. AB - PURPOSE OF REVIEW: This review details infection control issues encountered in the management of patients with Ebola virus disease (EVD), with emphasis on how these issues were confronted in two biocontainment patient care units in the United States. RECENT FINDINGS: There is a notable paucity of medical literature to guide infection control policies and procedures when caring for patients with EVD. Thus, the experience of the Serious Communicable Diseases Unit at Emory University Hospital and the Nebraska Biocontainment Unit at the University of Nebraska Medical Center serves as the basis for this review. Facility issues, staffing, transportation logistics, and appropriate use of personal protective equipment are detailed. Other topics addressed include the evaluation of patients under investigation and ethical issues concerning the safe utilization of advanced life support. SUMMARY: This review intends to serve as a reference for facilities that are in the process of creating protocols for managing patients with EVD. Given the lack of literature to support many of the recommendations discussed, it is important to utilize the available referenced guidelines, along with the practical experiences of biocontainment units, to optimize the care provided to patients with EVD while strictly adhering to infection control principles. PMID- 26098505 TI - The role of surveillance systems in confronting the global crisis of antibiotic resistant bacteria. AB - PURPOSE OF REVIEW: It is widely accepted that infection control, advanced diagnostics, and novel therapeutics are crucial to mitigate the impact of antibiotic-resistant bacteria. The role of global, national, and regional surveillance systems as part of the response to the challenge posed by antibiotic resistance is not sufficiently highlighted. We provide an overview of contemporary surveillance programs, with emphasis on gram-negative bacteria. RECENT FINDINGS: The WHO and public health agencies in Europe and the United States recently published comprehensive surveillance reports. These highlight the emergence and dissemination of carbapenem-resistant Enterobacteriaceae and other multidrug-resistant gram-negative bacteria. In Israel, public health action to control carbapenem-resistant Enterobacteriaceae, especially Klebsiella pneumoniae carbapenemase producing K. pneumoniae, has advanced together with a better understanding of its epidemiology. Surveillance models adapted to the requirements and capacities of each country are in development. SUMMARY: Robust surveillance systems are essential to combat antibiotic resistance, and need to emphasize a 'one health' approach. Refinements in surveillance will come from advances in bioinformatics and genomics that permit the integration of global and local information about antibiotic consumption in humans and animals, molecular mechanisms of resistance, and bacterial genotyping. PMID- 26098506 TI - Diarrhea in solid organ transplant recipients. AB - PURPOSE OF REVIEW: Diarrhea is a common complaint in the solid organ transplant recipient. Unlike the immune-competent patient, diarrhea in an organ transplant recipient may result in dehydration, increased toxicity of medications, and rejection. There is a wide range of causes for diarrhea in transplant recipients, but the most common causes are Clostridium difficile infection, cytomegalovirus, and norovirus. This review will focus on new epidemiology data as to the cause of diarrhea in the transplant population. RECENT FINDINGS: Recent data have identified C. difficile, cytomegalovirus, and norovirus as important causes of diarrhea in this population, and management should be focused on these causes. Newer diagnostic platforms (such as PCR) are being evaluated, which may help in identification of the cause of diarrhea. SUMMARY: New epidemiologic data and new testing techniques offer an opportunity for research into better testing strategies for transplant patients with diarrhea. These newer testing strategies may offer better insight into the cause of diarrhea and more appropriate treatment for this illness. PMID- 26098507 TI - Acute encephalitis in the immunocompromised individual. AB - PURPOSE OF REVIEW: This article describes recent advances in the diagnosis and management of encephalitis in immunocompromised individuals. RECENT FINDINGS: Herpes simplex virus (HSV) and varicella zoster virus (VZV) are common causes of encephalitis in immunocompromised individuals, although clinical manifestations may be atypical, and thus challenging to recognize. Recently, an increased incidence of HSV and VZV central nervous system infections has been reported in association with novel immunosuppressive and immunomodulatory treatments. The free-living ameba Balamuthia mandrillaris causes granulomatous encephalitis predominantly in immunocompromised individuals and is associated with nearly uniform fatality. In the setting of organ transplantation, the recipient's immunocompromised state along with the potential for donor-transmitted infections can result in a unique epidemiology of encephalitis, including infection by human herpes virus-6 and BK virus. Recent studies utilizing next-generation sequencing techniques have identified several pathogens, including Leptospira santarosai and a neurotropic astrovirus, as causes of encephalitis in immunocompromised individuals. SUMMARY: Diagnosis and management of encephalitis is challenging in immunocompromised individuals, in part because of atypical clinical presentations and the presence of uncommon or novel infectious agents. Unbiased techniques for pathogen discovery are likely to play an increasing role in the diagnosis of central nervous system infections in immunocompromised individuals. PMID- 26098508 TI - The pregnant healthcare worker: fact and fiction. AB - PURPOSE OF REVIEW: A pregnant healthcare worker (HCW) may be at risk of occupational exposure to pathogens associated with increased maternal morbidity and mortality as well as perinatal complications. In this article, we review recent literature on infectious diseases commonly encountered in the healthcare setting and of highest concern for a pregnant HCW, focusing on prevention and management of exposures. RECENT FINDINGS: Pregnancy does not seem to be an independent risk factor for occupationally acquired infectious diseases. Vaccination and standard precautions continue to be the most effective means of preventing transmission to HCWs. Pandemic 2009 influenza A (H1N1) is associated with increased risk of fetal death, highlighting the importance of influenza vaccination. A recent meta-analysis highlights the safety of influenza vaccination during pregnancy. New treatments for hepatitis C have not been studied in pregnancy but pose an important area for research and advancement. Cytomegalovirus immunoglobulin may play a role in postexposure prophylaxis but recent results are inconclusive. SUMMARY: Primary prevention with vaccination and use of appropriate infection control precautions is imperative for prevention of occupationally acquired infectious diseases. Pregnant HCWs with occupational exposure to communicable diseases should be evaluated immediately for appropriate postexposure prophylaxis and followed for development of active infection. PMID- 26098510 TI - Modeling Active Mechanosensing in Cell-Matrix Interactions. AB - Cells actively sense the mechanical properties of the extracellular matrix, such as its rigidity, morphology, and deformation. The cell-matrix interaction influences a range of cellular processes, including cell adhesion, migration, and differentiation, among others. This article aims to review some of the recent progress that has been made in modeling mechanosensing in cell-matrix interactions at different length scales. The issues discussed include specific interactions between proteins, the structure and mechanosensitivity of focal adhesions, the cluster effects of the specific binding, the structure and behavior of stress fibers, cells' sensing of substrate stiffness, and cell reorientation on cyclically stretched substrates. The review concludes by looking toward future opportunities in the field and at the challenges to understanding active cell-matrix interactions. PMID- 26098509 TI - Is the relationship between sedentary behaviour and cardiometabolic health in adolescents independent of dietary intake? A systematic review. AB - Screen time, but not overall sedentary behaviour, is consistently related to cardiometabolic health in adolescents. Because of the associations screen time has with dietary intake, diet may be an important factor in the screen time and health relationship; however, evidence has not previously been synthesized. Thus, the aim of this systematic review was to explore whether the associations between various sedentary behaviours and cardiometabolic risk markers are independent of dietary intake in adolescents. Online databases and personal libraries were searched for peer-reviewed original research articles published in English before March 2014. Included studies assessed associations between sedentary behaviour and cardiometabolic markers in 12- to 18-year-olds and adjusted for dietary intake. Twenty-five studies met the inclusion criteria. From the 21 studies examining sedentary behaviour and adiposity, the majority found significant positive associations between television viewing, screen time and self-reported overall sedentary behaviour with markers of adiposity, independent of dietary intake. No significant associations between screen time with blood pressure and cholesterol were reported. Sedentary behaviour appears to be associated with adiposity in adolescents, irrespective of dietary intake. However, the variability of dietary variables between studies suggests further work is needed to understand the role of dietary intake when examining these associations in youth. PMID- 26098511 TI - Anatomy of Nanoscale Propulsion. AB - Nature supports multifaceted forms of life. Despite the variety and complexity of these forms, motility remains the epicenter of life. The applicable laws of physics change upon going from macroscales to microscales and nanoscales, which are characterized by low Reynolds number (Re). We discuss motion at low Re in natural and synthetic systems, along with various propulsion mechanisms, including electrophoresis, electrolyte diffusiophoresis, and nonelectrolyte diffusiophoresis. We also describe the newly uncovered phenomena of motility in non-ATP-driven self-powered enzymes and the directional movement of these enzymes in response to substrate gradients. These enzymes can also be immobilized to function as fluid pumps in response to the presence of their substrates. Finally, we review emergent collective behavior arising from interacting motile species, and we discuss the possible biomedical applications of the synthetic nanobots and microbots. PMID- 26098512 TI - Biophysics of Channelrhodopsin. AB - Channelrhodopsins (ChRs) are directly light-gated ion channels that function as sensory photoreceptors in flagellated green algae, allowing these algae to identify optimal light conditions for growth. In neuroscience, ChRs constitute the most versatile tools for the light-induced activation of selected cells or cell types with unprecedented precision in time and space. In recent years, many ChR variants have been discovered or engineered, and countless electrical and spectroscopic studies of these ChRs have been carried out, both in host cells and on purified recombinant proteins. With significant support from a high-resolution 3D structure and from molecular dynamics calculations, scientists are now able to develop models that conclusively explain ChR activation and ion conductance on the basis of chromophore isomerization, structural changes, proton transfer reactions, and water rearrangement on timescales ranging from femtoseconds to minutes. PMID- 26098513 TI - Structure and Mechanism of RNA Mimics of Green Fluorescent Protein. AB - RNAs have highly complex and dynamic cellular localization patterns. Technologies for imaging RNA in living cells are important for uncovering their function and regulatory pathways. One approach for imaging RNA involves genetically encoding fluorescent RNAs using RNA mimics of green fluorescent protein (GFP). These mimics are RNA aptamers that bind fluorophores resembling those naturally found in GFP and activate their fluorescence. These RNA-fluorophore complexes, including Spinach, Spinach2, and Broccoli, can be used to tag RNAs and to image their localization in living cells. In this article, we describe the generation and optimization of these aptamers, along with strategies for expanding the spectral properties of their associated RNA-fluorophore complexes. We also discuss the structural basis for the fluorescence and photophysical properties of Spinach, and we describe future prospects for designing enhanced RNA-fluorophore complexes with enhanced photostability and increased sensitivity. PMID- 26098515 TI - Structural Biology of the Major Facilitator Superfamily Transporters. AB - The ancient and ubiquitous major facilitator superfamily (MFS) represents the largest secondary transporter family and plays a crucial role in a multitude of physiological processes. MFS proteins transport a broad spectrum of ions and solutes across membranes via facilitated diffusion, symport, or antiport. In recent years, remarkable advances in understanding the structural biology of the MFS transporters have been made. This article reviews the history, classification, and general features of the MFS proteins; summarizes recent structural progress with a focus on the sugar porter family transporters exemplified by GLUT1; and discusses the molecular mechanisms of substrate binding, alternating access, and cotransport coupling. PMID- 26098516 TI - Specification of Architecture and Function of Actin Structures by Actin Nucleation Factors. AB - The actin cytoskeleton is essential for diverse processes in mammalian cells; these processes range from establishing cell polarity to powering cell migration to driving cytokinesis to positioning intracellular organelles. How these many functions are carried out in a spatiotemporally regulated manner in a single cytoplasm has been the subject of much study in the cytoskeleton field. Recent work has identified a host of actin nucleation factors that can build architecturally diverse actin structures. The biochemical properties of these factors, coupled with their cellular location, likely define the functional properties of actin structures. In this article, we describe how recent advances in cell biology and biochemistry have begun to elucidate the role of individual actin nucleation factors in generating distinct cellular structures. We also consider how the localization and orientation of actin nucleation factors, in addition to their kinetic properties, are critical to their ability to build a functional actin cytoskeleton. PMID- 26098514 TI - Regulation of Rad6/Rad18 Activity During DNA Damage Tolerance. AB - Replicative polymerases (pols) cannot accommodate damaged template bases, and these pols stall when such offenses are encountered during S phase. Rather than repairing the damaged base, replication past it may proceed via one of two DNA damage tolerance (DDT) pathways, allowing replicative DNA synthesis to resume. In translesion DNA synthesis (TLS), a specialized TLS pol is recruited to catalyze stable, yet often erroneous, nucleotide incorporation opposite damaged template bases. In template switching, the newly synthesized sister strand is used as a damage-free template to synthesize past the lesion. In eukaryotes, both pathways are regulated by the conjugation of ubiquitin to the PCNA sliding clamp by distinct E2/E3 pairs. Whereas monoubiquitination by Rad6/Rad18 mediates TLS, extension of this ubiquitin to a polyubiquitin chain by Ubc13-Mms2/Rad5 routes DDT to the template switching pathway. In this review, we focus on the monoubiquitination of PCNA by Rad6/Rad18 and summarize the current knowledge of how this process is regulated. PMID- 26098518 TI - The Synaptic Vesicle Release Machinery. AB - Extensive research has yielded crucial insights into the mechanism of neurotransmitter release, and working models for the functions of key proteins involved in release. The SNAREs Syntaxin-1, Synaptobrevin, and SNAP-25 play a central role in membrane fusion, forming SNARE complexes that bridge the vesicle and plasma membranes and that are disassembled by NSF-SNAPs. Exocytosis likely starts with Syntaxin-1 folded into a self-inhibited closed conformation that binds to Munc18-1. Munc13s open Syntaxin-1, orchestrating SNARE complex assembly in an NSF-SNAP-resistant manner together with Munc18-1. In the resulting primed state, with partially assembled SNARE complexes, fusion is inhibited by Synaptotagmin-1 and Complexins, which also perform active functions in release. Upon influx of Ca(2+), Synaptotagmin-1 activates fast release, likely by relieving the inhibition caused by Complexins and cooperating with the SNAREs in bringing the membranes together. Although alternative models exist and fundamental questions remain unanswered, a definitive description of the basic release mechanism may be available soon. PMID- 26098519 TI - Growth of Thin, Anisotropic, pi-Conjugated Molecular Films by Stepwise "Click" Assembly of Molecular Building Blocks: Characterizing Reaction Yield, Surface Coverage, and Film Thickness versus Addition Step Number. AB - We report the systematic characterization of anisotropic, pi-conjugated oligophenyleneimine (OPI) films synthesized using stepwise imine condensation, or "click" chemistry. Film synthesis began with a self-assembled monolayer (SAM) of 4-formylthiophenol or 4-aminothiophenol on Au, followed by repetitive, alternate addition of terephthalaldehyde (benzene-1,4-dicarbaldehyde) or 1,4-benzenediamine to form pi-conjugated films ranging from 0.6-5.5 nm in thickness. By systematically capping the OPI films with a redox or halogen label, we were able to measure the relative surface coverage after each monomer addition via Rutherford backscattering spectrometry, X-ray photoelectron spectroscopy, spectroscopic ellipsometry, reflection-absorption infrared spectroscopy, and cyclic voltammetry. Nuclear reaction analysis was also employed for the first time on a SAM to calculate the surface coverage of carbon atoms after each stepwise addition. These six different analysis methods indicate that the average extent of reaction is 99% for each addition step. The high yield and molecular surface coverage confirm the efficacy of Schiff base chemistry, at least with the terephthalaldehyde and 1,4-benzenediamine monomers, for preparing high-quality molecular films with pi conjugation normal to the substrate. PMID- 26098517 TI - Structural Symmetry in Membrane Proteins. AB - Symmetry is a common feature among natural systems, including protein structures. A strong propensity toward symmetric architectures has long been recognized for water-soluble proteins, and this propensity has been rationalized from an evolutionary standpoint. Proteins residing in cellular membranes, however, have traditionally been less amenable to structural studies, and thus the prevalence and significance of symmetry in this important class of molecules is not as well understood. In the past two decades, researchers have made great strides in this area, and these advances have provided exciting insights into the range of architectures adopted by membrane proteins. These structural studies have revealed a similarly strong bias toward symmetric arrangements, which were often unexpected and which occurred despite the restrictions imposed by the membrane environment on the possible symmetry groups. Moreover, membrane proteins disproportionately contain internal structural repeats resulting from duplication and fusion of smaller segments. This article discusses the types and origins of symmetry in membrane proteins and the implications of symmetry for protein function. PMID- 26098520 TI - Timely blockade of ICAM-1.LFA-1 interaction prevents disease onset in a mouse model of emphysema. AB - AIM: It is becoming apparent that emphysema is partly driven by self-reactive T cells inducing inflammatory damage. Thus, T cells become targets for therapy similar to other autoimmune diseases. Costimulatory blockade therapy targets disease-specific T cells, rendering them ineffective by blocking a necessary costimulatory event on the T-cell surface. This therapy is tested here in mouse emphysema. MATERIALS & METHODS: Peptides representing contact domains of counter receptors LFA-1 and ICAM-1 were used as blockade therapy in elastase-induced emphysema. RESULTS: When administered during the first week after disease induction, blockade prevented lung destruction, reduced leukocyte infiltration and inhibited the decrease in T-cell CD4:CD8 ratio, also common in human emphysema. CONCLUSION: Costimulatory blockade therapy can affect the progress of emphysema. PMID- 26098521 TI - Transduction of DNA information through water and electromagnetic waves. AB - The experimental conditions by which electromagnetic signals (EMS) of low frequency can be emitted by diluted aqueous solutions of some bacterial and viral DNAs are described. That the recorded EMS and nanostructures induced in water carry the DNA information (sequence) is shown by retrieval of that same DNA by classical PCR amplification using the TAQ polymerase, including both primers and nucleotides. Moreover, such a transduction process has also been observed in living human cells exposed to EMS irradiation. These experiments suggest that coherent long-range molecular interaction must be present in water to observe the above-mentioned features. The quantum field theory analysis of the phenomenon is presented in this article. PMID- 26098522 TI - Illuminating water and life: Emilio Del Giudice. AB - The quantum electrodynamics theory of water put forward by Del Giudice and colleagues provides a useful foundation for a new science of water for life. The interaction of light with liquid water generates quantum coherent domains in which the water molecules oscillate between the ground state and an excited state close to the ionizing potential of water. This produces a plasma of almost free electrons favoring redox reactions, the basis of energy metabolism in living organisms. Coherent domains stabilized by surfaces, such as membranes and macromolecules, provide the excited interfacial water that enables photosynthesis to take place, on which most of life on Earth depends. Excited water is the source of superconducting protons for rapid intercommunication within the body. Coherent domains can also trap electromagnetic frequencies from the environment to orchestrate and activate specific biochemical reactions through resonance, a mechanism for the most precise regulation of gene function. PMID- 26098523 TI - Influence of electromagnetic field on soliton-mediated charge transport in biological systems. AB - It is shown that electromagnetic fields affect dynamics of Davydov's solitons which provide charge transport processes in macromolecules during metabolism of the system. There is a resonant frequency of the field at which it can cause the transition of electrons from bound soliton states into delocalised states. Such decay of solitons reduces the effectiveness of charge transport, and, therefore, inhibits redox processes. Solitons radiate their own electromagnetic field of characteristic frequency determined by their average velocity. This self-radiated field leads to synchronization of soliton dynamics and charge transport processes, and is the source of the coherence in the system. Exposition of the system to the oscillating electromagnetic field of the frequency, which coincides with the eigen-frequency of solitons can enhance eigen-radiation of solitons, and, therefore, will enhance synchronization of charge transpor, stimulate the redox processes and increase coherence in the system. Electromagnetic oscillating field causes also ratchet phenomenon of solitons, i.e., drift of solitons in macromolecules in the presence of unbiased periodic field. Such additional drift enhances the charge transport processes. It is shown that temperature facilitates the ratchet drift. In particular, temperature fluctuations lead to the lowering of the critical value of the intensity and period of the field, above which the drift of solitons takes place. Moreover, there is a stochastic resonance in the soliton dynamics in external electromagnetic fields. This means, that there is some optimal temperature at which the drift of solitons is maximal. PMID- 26098524 TI - Water's quantum structures and life. AB - This article discusses several clues pointing to the spontaneous quantum origin of the recently discovered dissipative structures induced in liquid water by low energy physical perturbations. These structures show an astonishing permanence, so much that large ponderal quantities of supramolecular aggregates of water - at ambient pressure and temperature - subsist even in the solid phase, strongly suggesting the possibility that these structures are the matrix itself of life. PMID- 26098525 TI - The role of coherence in emergent behavior of biological systems. AB - In his research activity, Emilio Del Giudice explored the possibility to move towards a unified view of some long-range dynamics in nature, ranging from quantum field theory in physics up to biology. Such a view is adopted in this contribution by discussing a mathematical model for synchronized electrical behavior of pancreatic beta cells. The stochasticity is a fundamental component of the physiological synchronized behavior of this system. On the contrary, in a pathological type I diabetes scenario, the cells are destroyed by the autoimmune system and their coherent behavior is lost. This phenomenology conceptually links to ideas of coherent dynamics in quantum physics. Possible implications both for physical sciences and for the epistemology of life sciences are outlined. PMID- 26098526 TI - Nanoassociate formation in highly diluted water solutions of potassium phenosan with and without permalloy shielding. AB - Diluted water solutions of anti-oxidant potassium phenosan, kept before explorations in "usual" conditions and in conditions of "permalloy container", i.e. shielding of solution from the influence of external low-frequency electromagnetic and/or geomagnetic fields, were studied. It is shown that in solutions kept in shielded conditions in the area of high dilution with a concentration of solutions lower than "threshold", nanoobjects called "nanoassociates", are not formed, and anomalous physicochemical and biological properties observed in solutions kept in "usual" conditions, are not found. We conclude that anomalous physicochemical and biological properties of highly diluted water solutions of potassium phenosan made under "usual" conditions are determined by "nanoassociates", in which an external low-frequency electromagnetic and/or geomagnetic field is a necessary condition of the formation. PMID- 26098527 TI - The trail from quantum electro dynamics to informative medicine. AB - Several years ago just before Christmas, in a small meeting room at the Institute of Pharmacology at the University of Rome, we had the opportunity to attend a meeting on "The role of QED in medicine" by Emilio Del Giudice and Giuliano Preparata. Before that meeting, we were more oriented towards a mechanistic view of Biochemistry and Medicine, believing that chemical reactions could only take place when a random collision between molecules with a gain in energy takes place. We envisioned water as just a solvent in which was possible to dissolve a solute. After we listened to Giuliano's and Emilio's speech on the "New physics of water", and on "The possible origin of coherence in cell, tissues and the interaction of very weak and low frequency magnetic fields with the ions, systems of the cell", we realized that living organisms are complex electrochemical systems which evolved in a relatively narrow range of well-defined environmental parameters. Environmental natural electro-magnetic fields are an ubiquitous factor in nature. If nature gave certain organisms the ability to receive information about the environment via invisible electromagnetic signals, then there must also the capability to discriminate between significant and meaningless ones. Bearing in mind that electromagnetic fields can be perceived by living organisms by means a resonance effect, we should not be amazed if they can be able to induce different biological effects. The work that we will present in memory of Emilio is based on the hypotheses that an aqueous system a chemical differentiation agent such as retinoic acid (RA) were electronically captured and transferred to the culture medium of Neuroblastoma Cell Line (LAN-5) and the proliferation rate was assessed to assess cell responses to the electromagnetic information transfer through the aqueous system. Like those enfolded in living organisms could play a synergic role in modulating biological functions, generating dissipative structures under appropriate patterns of electromagnetic signals providing basis for storing and retrieving biological activities. An external electro-magnetic stimulus from a source molecule can be stored, translated, and transferred by the aqueous systems to the biological target, selectively driving their endogenous activity and mimicking the effect of a source molecule. PMID- 26098528 TI - Diseases caused by defects of energy level and loss of coherence in living cells. AB - Human and animal diseases are brought about by pathological alterations of production, composition, and conformation of macromolecules and structures in cells. Additional contributing factors include changes in physiological states caused by disturbances of energy supply, energy transduction, energy dissipation in moving or oscillating parts, and parasitic energy consumption. Disturbances of energy states may endanger existence of the system. The cell-mediated immunity (CMI) response of T lymphocytes correlating with their adherence properties was examined using antigen prepared from the serum of inbred laboratory mice strain C3H H(2k) infected with lactate dehydrogenase elevating (LDH) virus. LDH virus is a parasite on the cellular energy system. Significant CMI response was elicited in T lymphocytes prepared from the blood of patients with cancer of different phenotypes, acute myocardial infarctions, schizophrenia, and recurrent spontaneous abortions in early pregnancy from unknown reasons. The CMI response is assumed to monitor transferred information about decreased levels of energy states and decoherence in the cells caused by mitochondrial malfunction, parasitic consumption, production of lactate, and possibly other disturbances. The LDH virus infection or similar pathological processes caused by different agents might be connected with the diseases and monitored by the examined CMI response. A large amount of mitoses with chromosome defects in aborted fetuses suggest increased mutability of genomes caused by defective energy states. PMID- 26098529 TI - Biophysical approach to low back pain: a pilot report. AB - Since biophysical treatment has been reported to be effective in the general management of pain, we decided to assess the specific effect and treatment duration of this therapeutic strategy in low back pain. We were interested in verifying the possibility that a single clinical procedure could reduce pain and improve patients' quality of life within a period of three months. An Electromagnetic Information Transfer Through Aqueous System was employed to record endogenous therapeutic signals from each individual using an electromagnetic recording device (Med Select 729). A highly significant reduction in the Roland Morris low back pain and disability questionnaire score was observed after 3 months following a single biophysical intervention (11.83 +/- 6 at baseline versus 2.3 +/- 3.25 at 3 months, p < 0.0001). This preliminary report provides further evidence of the theoretical implications and clinical applications of Quantum Electro Dynamic concepts in biology and medicine. PMID- 26098530 TI - Stabilizing effects of hydrated fullerenes C60 in a wide range of concentrations on luciferase, alkaline phosphatase, and peroxidase in vitro. AB - Hydrated fullerene (HyFnC60) is a highly hydrophilic supra-molecular complex consisting of unmodified S60 fullerene molecule enclosed into a hydrated shell. It has been shown in numerous experiments that aqueous solutions of HyFnC60 manifest a wide range of biological activities both in vivo and in vitro even at very low concentrations of HyFnC60. We used a spectrophotometric method and a method of biochemoluminescence to demonstrate that HyFnC60 in concentrations below 10(-9) M down to 10(-23) M stabilizes peroxidase, alkaline phosphatase, and bacterial luciferase against inactivation due to long-term incubation of the enzymes at room temperature and also against heat inactivation. In addition, HyFnC60 was able to "revive" heat inactivated enzymes. These effects cannot be explained by the direct action of the fullerene molecules upon the enzymes. We suggest that the effects of HyFnC60 on the enzymes are related to the ability of hydrated fullerene C60 molecules to organize thick aqueous shells around them. One of the specific properties of water phase in these shells is its ability to optimize redox reactions, which can support enzyme stability against factors deteriorating their structure. PMID- 26098531 TI - Copper ion fluxes through the floating water bridge under strong electric potential. AB - We have performed a series of experiments applying high voltage between two electrodes, immersed in two beakers containing bidistilled water in a way similar to experiments conducted by Fuchs and collaborators, which showed that a water bridge can be formed between the two containers. We also observed the formation of water bridge. Moreover, choosing different pairs of electrodes depending on the material they are made up of, we observed that copper ions flow can pass along the bridge if the negative electrode is made up of copper. We show that the direction of the flux not only depends on the applied electrostatic field but on the relative electronegativity of the electrodes too. These results open new perspectives in understanding the properties of water. We suggest a possible explanation of the obtained results. PMID- 26098532 TI - Oral malodour among adolescents and its association with health behaviour and oral health status. AB - OBJECTIVE: To assess oral malodour level and its association with health behaviour, oral health behaviour and oral health status among adolescents. METHOD: A questionnaire survey and clinical examination that included tongue coating and oral malodour status were conducted on 665 senior high school students in Saitama, Japan. Analyses of Pearson chi-square, independent samples t test and logistic regression were conducted using SPSS 19.0 with the significance level set at P < 0.05. RESULTS: There were 173 (26.0%) subjects who had oral malodour and 54.7% of subjects reported they were conscious of their own oral malodour. Logistic regression analysis showed that subjects who skipped breakfast were 1.7 times more likely to have oral malodour than those who had breakfast. Subjects who did not have the habit of cleaning their tongue daily were also 1.7 times more likely to have oral malodour compared to those who had the habit. The odds of having oral malodour increased as the area of tongue coating widened. CONCLUSION: Tongue coating, daily tongue cleaning and breakfast are significant factors for oral malodour among adolescents. Proper tongue coating management together with other healthy lifestyle behaviours, especially having breakfast, should be advocated in adolescents' health education. PMID- 26098533 TI - Structural and functional roles of the N- and C-terminal extended modules in channelrhodopsin-1. AB - Channelrhodopsins have become a focus of interest because of their ability to control neural activity by light, used in a technology called optogenetics. The channelrhodopsin in the eukaryote Chlamydomonas reinhardtii (CrChR-1) is a light gated cation channel responsible for motility changes upon photo-illumination and a member of the membrane-embedded retinal protein family. Recent crystal structure analysis revealed that CrChR-1 has unique extended modules both at its N- and C-termini compared to other microbial retinal proteins. This study reports the first successful expression of a ChR-1 variant in Escherichia coli as a holoprotein: the ChR-1 variant lacking both the N- and C-termini (CrChR-1_82 308). However, compared to ChR-1 having the extended modules (CrChR-1_1-357), truncation of the termini greatly altered the absorption maximum and photochemical properties, including the pKa values of its charged residues around the chromophore, the reaction rates in the photocycle and the photo-induced ion channeling activity. The results of some experiments regarding ion transport activity suggest that CrChR-1_82-308 has a proton channeling activity even in the dark. On the basis of these results, we discuss the structural and functional roles of the N- and C-terminal extended modules in CrChR-1. PMID- 26098534 TI - Are Birth Weight, Early Growth, and Motor Development Determinants of Physical Activity in Children and Youth? A Systematic Review and Meta-Analysis. AB - The purpose of this systematic review was to explore whether birth weight, early growth and motor development act as determinants of physical activity in children and youth. METHODS: We performed a systematic literature search on the possible early life determinants. A meta-analysis was performed on the association between birthweight and objectively measured physical activity. RESULTS: We identified 9 studies examining birth weight, in which none of the studies with objectively measured physical activity observed an association between birth weight and physical activity. The meta-analysis confirmed this result (b=-3.08, 95% CI 10.20, 4.04). The 3 studies examining early growth and physical activity in youth differ in methodology and the results are inconsistent. Two studies suggest an association between earlier motor development and physical activity and sport participation in youth. This was not confirmed in a third study. CONCLUSION: Our meta-analysis suggests that birth weight is not an important determinant of physical activity in youth. Available data does not allow firm conclusions whether early growth and motor development act as determinants of physical activity in youth. PMID- 26098535 TI - Retrieval of Inferior Vena Cava Filters With Prolonged Dwell Time: A Single Center Experience in 648 Retrieval Procedures. PMID- 26098536 TI - Occupational therapists' experiences of career progression following promotion. AB - BACKGROUND/AIM: The recruitment and retention of a skilled occupational therapy workforce is highlighted as a key issue for the profession, and yet there have been relatively few studies into the career progression of occupational therapists. METHODS: A qualitative, naturalistic approach was adopted to answer the research question, using semi-structured interviews to gather data. Eleven purposefully selected participants at an Australian health service were interviewed as part of this study. Categories representing the most common themes and topics supplied by participants within their individual interviews were identified and consolidated by the research team. The trustworthiness of this study was supported by strategies to maximise its credibility, dependability and confirmability. RESULTS: Four main themes were elicited from the data - (i) Readiness for progression, (ii) Tools and processes, (iii) Expectations and (iv) What I wish I had known first. Within these themes, related findings were also identified by both Grade 2 and Grade 3 staff. CONCLUSIONS: This study indicates that the readiness of occupational therapists to climb the career ladder is influenced by the tools and processes they can utilise, and the expectations they have around the realities of their new position. With hindsight, participants highlighted some things they wish they had known at the time of transition, which appeared to have been implicit. SIGNIFICANCE OF STUDY: This study is the first to address the common issues for occupational therapy staff around progression between grade levels. It therefore provides a basis for further research in other practice settings and for the development of supports for therapists climbing the career ladder. PMID- 26098537 TI - Robust variable selection method for nonparametric differential equation models with application to nonlinear dynamic gene regulatory network analysis. AB - The gene regulation network (GRN) evaluates the interactions between genes and look for models to describe the gene expression behavior. These models have many applications; for instance, by characterizing the gene expression mechanisms that cause certain disorders, it would be possible to target those genes to block the progress of the disease. Many biological processes are driven by nonlinear dynamic GRN. In this article, we propose a nonparametric differential equation (ODE) to model the nonlinear dynamic GRN. Specially, we address following questions simultaneously: (i) extract information from noisy time course gene expression data; (ii) model the nonlinear ODE through a nonparametric smoothing function; (iii) identify the important regulatory gene(s) through a group smoothly clipped absolute deviation (SCAD) approach; (iv) test the robustness of the model against possible shortening of experimental duration. We illustrate the usefulness of the model and associated statistical methods through a simulation and a real application examples. PMID- 26098538 TI - What are we treating with opioid and sedative-hypnotic combination therapy? PMID- 26098540 TI - Effects of unregulated anthropogenic activities on mixing ratios of volatile organic air pollutants--A case study. AB - During the months of October to November, many important festivals are celebrated in India. Celebration of these festivals are marked by extensive use of fireworks or pyrotechnics, bonfire, incense burning, open air community cooking, and temporary eateries using crude fuel such as coal, wood, kerosene, cow dung, burning of raw/semiwood, and coconut shells. The present study deals with the influence of these unregulated anthropogenic activities on ambient mixing level of volatile organic compounds (VOCs), especially some carbonyl compounds. The study was undertaken in the metropolitan city of Kolkata, India, with very high population density, which is even higher during festival period. The average total carbonyl level at different sites in Kolkata varied from 134.8 to 516.5 MUg m(-3) in pre-festival season, whereas in post-festival season the same varied from 252.2 to 589.3 MUg m(-3). Formaldehyde to acetaldehyde ratio altered from 0.62 in pre-festival season to 1.78 in post-festival season. Diurnal variation also altered, indicating variation in source composition of carbonyls. The total ozone forming potential calculated for all 14 carbonyls in pre-festival season increased by 35% in post-festival season. The effect of anthropogenic activities typical to the event of Diwali night characterized by intense execution of pyrotechnics resulted in significantly high level of carbonyl VOCs. Principal component analysis study for the event of Diwali shows clear contribution of the event on certain carbonyl VOCs. The results indicate elevated primary emissions of these pollutants and also their effect on formation of secondary pollutants. The study emphasizes the need of generating awareness among the communities in society as well as need for regulations to minimize the emissions and related hazards to the extent possible. IMPLICATIONS: Altered anthropogenic activities typical of festival season including extensive use of pyrotechnics affect ambient level of volatile organic compounds, especially some carbonyls. Such activities have considerable effect on interspecies ratio and diurnal variation. They also affect formation of secondary pollutants such as tropospheric ozone. Principal component analysis (PCA) study shows clear contribution of the pyrotechnics execution on certain carbonyl VOCs. The findings emphasize the need of generating awareness in society and need for regulations to minimize the emissions. PMID- 26098539 TI - Polystyrene-Templated Aerosol Synthesis of MoS2 -Amorphous Carbon Composite with Open Macropores as Battery Electrode. AB - MoS2 -amorphous carbon (MoS2 -AC) composite microspheres with macroporous structure were fabricated by one-pot spray pyrolysis. Single- or few-layered MoS2 were uniformly dispersed and oriented in random directions in the amorphous carbon microsphere with macropores sizes between 50 and 90 nm. The macroporous microspheres having a high contact area with liquid electrolyte exhibited overall superior Li- and Na-ion storage properties compared with those of the dense microspheres. After 250 charge/discharge cycles at a current density of 1.5 A g( 1) , the discharge capacities of the MoS2 -AC microspheres with dense and macroporous structures for Li-ion storage were 694 and 896 mAh g(-1) , respectively. In the case of Na-ion storage, discharge capacities of 336 and 425 mAh g(-1) were achieved for the dense and macroporous microspheres, respectively, after 100 cycles at 0.3 A g(-1) . PMID- 26098541 TI - Accelerated materials design of Na0.5Bi0.5TiO3 oxygen ionic conductors based on first principles calculations. AB - We perform a first principles computational study of designing the Na0.5Bi0.5TiO3 (NBT) perovskite material to increase its oxygen ionic conductivity. In agreement with the previous experiments, our computation results confirm fast oxygen ionic diffusion and good stability of the NBT material. The oxygen diffusion mechanisms in this new material were systematically investigated, and the effects of local atomistic configurations and dopants on oxygen diffusion were revealed. Novel doping strategies focusing on the Na/Bi sublattice were predicted and demonstrated by the first principles calculations. In particular, the K doped NBT compound achieved good phase stability and an order of magnitude increase in oxygen ionic conductivity of up to 0.1 S cm(-1) at 900 K compared to the previous Mg doped compositions. This study demonstrated the advantages of first principles calculations in understanding the fundamental structure-property relationship and in accelerating the materials design of the ionic conductor materials. PMID- 26098542 TI - Conservation of Olfactory Avoidance in Drosophila Species and Identification of Repellents for Drosophila suzukii. AB - Flying insects use olfaction to navigate towards fruits in complex odor environments with remarkable accuracy. Some fruits change odor profiles substantially during ripening and related species can prefer different stages. In Drosophila species attractive odorants have been studied extensively, but little is understood about the role of avoidance pathways. In order to examine the role of the avoidance cue CO2 emitted from fruit on behavior of two species with different ripening stage preferences, we investigated the CO2-detection pathway in Drosophila melanogaster and Drosophila suzukii, a harmful pest of fruits. Avoidance to CO2 is not conserved in D. suzukii suggesting a behavioral adaptation that could facilitate attraction to younger fruit with higher CO2 emission levels. We investigated known innate avoidance pathways from five species at different evolutionary distances: D. melanogaster, D. yakuba, D. suzukii, D. pseudoobscura and D. virilis. Surprisingly, only DEET shows strong repellency across all species, whereas CO2, citronellal and ethyl 3 hydroxybutyrate show only limited conservation. These findings guide us to test recently discovered safe DEET substitutes, and we identify one that protects fruits from D. suzukii thus providing a new behavioral strategy for controlling agricultural pests. PMID- 26098543 TI - Is Inferior Oblique Overaction Associated With Astigmatism? AB - PURPOSE: To study the relationship between inferior oblique muscle overaction and astigmatism, and to explore any change in astigmatism after surgery. METHODS: This was a retrospective chart review of patients undergoing strabismus surgery. Demographic data collected included age, diagnosis, preoperative refraction, presence of inferior oblique overaction, surgery performed, and postoperative refraction. Patients were divided into three groups: those having only horizontal strabismus without inferior oblique overaction (no inferior oblique group) as a control group, those having bilateral inferior oblique overaction (bilateral inferior oblique group), and those having unilateral inferior oblique overaction (unilateral inferior oblique group). Right eyes of the bilateral inferior oblique and no inferior oblique groups were chosen for analysis, whereas the eye with inferior oblique overaction was included in the unilateral cases. Refractions were converted to power vector coordinates for comparison. Statistical analysis was performed to compare the power vectors among groups using the no inferior oblique group as controls and to explore any postoperative change in astigmatism. RESULTS: One hundred eighteen patients undergoing strabismus surgery were included (60 males and 58 females; mean age: 11.31 +/- 10.59 years). Patients were divided into three groups: those having only horizontal strabismus without inferior oblique overaction (no inferior oblique group; 60 patients) as controls, those having bilateral inferior oblique overaction (bilateral inferior oblique group; 41 patients), and those having unilateral inferior oblique overaction (unilateral inferior oblique group; 17 patients). Preoperatively, there were no differences in astigmatism when comparing eyes with and without inferior oblique overaction. Postoperatively, both the no inferior oblique group and the bilateral inferior oblique group equally showed an increase in with-the-rule cylinder power (P = .02 and .01, respectively). CONCLUSIONS: Inferior oblique muscle overaction did not result in an increased prevalence of astigmatism along the axis of the overacting muscle. PMID- 26098544 TI - Three and Four Horizontal Muscle Surgery for Large Angle Exotropia. AB - PURPOSE: Surgery on two horizontal recti typically is most effective for angles less than 40 prism diopters (PD). The authors evaluate their experience operating on three or four rectus muscles for angles exceeding 40 PD. METHODS: Retrospective chart review of 47 patients who underwent a first surgical procedure for a large angle comitant exodeviation. Patients were observed for a minimum of 2 months. Success was defined as deviation +/-10 PD. RESULTS: Median age was 48 years (range: 1 to 79 years). Thirty-four patients underwent three muscle surgery and 13 underwent four muscle surgery. Mean preoperative angles were 55 +/- 9.8 and 72 +/- 8.8 PD, respectively. Following three muscle surgery, rates of success, undercorrection, and overcorrection were 67%, 27%, and 7% at 2 months and 42%, 58%, and 0% at final follow-up (12 +/- 8.7 months), respectively. Rates for four muscle surgery were 44%, 33%, and 22% at 2 months and 50%, 38%, and 13% at final follow-up (11 +/- 12.2 months), respectively. Patients who were successfully aligned at 2 months had a mean preoperative angle of 55 PD, whereas those who were undercorrected had a mean preoperative angle of 67 PD (P = .009). Between 1 week and 2 months, 77% of patients experienced exotropic drift averaging 10 +/- 9.1 PD. By final follow-up, 90% experienced exotropic drift averaging 15 +/- 14.1 PD. Success rates for traditional and adjustable suture surgeries did not differ significantly. CONCLUSIONS: Three and four horizontal muscle surgeries are effective for correcting large angle exotropia. Higher preoperative deviations predisposed to undercorrection. Postoperative exotropic drift should be anticipated. PMID- 26098545 TI - Reduction in Rectus Muscle Recession Depending on the Distance Between Rectus Muscle Suture Placement and Scleral Insertion in Rabbit Eyes. AB - PURPOSE: To quantitatively determine how a large tendon remnant reduces the effect of the rectus muscle recession procedure with respect to the distance between the placement of the muscle suture and the scleral insertion. METHODS: Thirty-six eyes from 18 rabbits were randomly divided into four groups according to the distance between the superior rectus muscle suture placement and the scleral insertion (1, 2, 3, and 4 mm). The superior rectus muscle was sutured at the previously listed distances from the insertion. Each superior rectus muscle was reattached using a scleral pass at a site 4 mm posterior to its original insertion. The amount of recession was measured as the distance between the most anterior aspect of the reattached muscle and the original insertion site. RESULTS: The mean amount of recession was 4.07 +/- 0.25 mm in the 1-mm group and 2.76 +/- 0.55 mm in the 4-mm group at postoperative week 4. There were significant differences in the amount of recession between the four groups. Linear regression analyses revealed a significant relationship between the distance of the muscle suture placement from the scleral insertion and the amount of recession (r(2) = 0.521). The superior rectus muscle was estimated to be reattached 0.437 mm anterior to the desired location for every 1 mm that the muscle suture was placed posterior to the scleral insertion. CONCLUSIONS: The potential error that depends on the distance between the muscle suture placement and the scleral insertion should be considered to reduce undercorrection and ensure a good surgical outcome. PMID- 26098546 TI - Surgical Treatment of V-pattern Exotropia in Crouzon Syndrome. AB - PURPOSE: Strabismus affects as many as 60% to 70% of patients with Crouzon syndrome. V-pattern strabismus is common and is thought to be secondary to severe oblique muscle dysfunction. The complex motility disorders produced by abnormal extraocular muscles in this syndrome can be difficult to manage. Few studies have reported findings regarding the extraocular muscles or how to plan and adapt the required surgery for this condition. METHODS: The surgical management and outcomes of four patients with Crouzon syndrome who had undergone craniofacial reconstruction surgery were retrospectively reviewed. RESULTS: All patients showed significant improvement in the primary eye position, but had residual ocular motility dysfunction postoperatively, especially relating to the up gaze position. During surgery it was noted that the lateral rectus muscle or superior oblique tendons were absent or anomalous in one of the four patients. In two of the patients, there was an absence of both inferior rectus muscles. The extraocular muscles were examined pathologically and revealed evidence of tendon capsule and mild fiber degeneration. CONCLUSIONS: Strabismus in Crouzon syndrome is complex and the absence of certain extraocular muscles is unpredictable. It is not possible to perform strabismus surgery according to a defined surgical plan; one needs to adapt according to the patient's individual anatomy. Also, the strabismus is difficult to completely correct. However, improving ocular motility in the most functional fields of gaze will benefit the quality of life for both children and their families. PMID- 26098547 TI - Revealing Genomic Profile That Underlies Tropism of Myeloma Cells Using Whole Exome Sequencing. AB - Background. Previously we established two cell lines (SNU_MM1393_BM and SNU_MM1393_SC) from different tissues (bone marrow and subcutis) of mice which were injected with single patient's myeloma sample. We tried to define genetic changes specific for each cell line using whole exome sequencing (WES). Materials and Methods. We extracted DNA from SNU_MM1393_BM and SNU_MM1393_SC and performed WES. For single nucleotide variants (SNV) calling, we used Varscan2. Annotation of mutation was performed using ANNOVAR. Results. When calling of somatic mutations was performed, 68 genes were nonsynonymously mutated only in SNU_MM1393_SC, while 136 genes were nonsynonymously mutated only in SNU_MM1393_BM. KIAA1199, FRY, AP3B2, and OPTC were representative genes specifically mutated in SNU_MM1393_SC. When comparison analysis was performed using TCGA data, mutational pattern of SNU_MM1393_SC resembled that of melanoma mostly. Pathway analysis using KEGG database showed that mutated genes specific of SNU_MM1393_BM were related to differentiation, while those of SNU_MM1393_SC were related to tumorigenesis. Conclusion. We found out genetic changes that underlie tropism of myeloma cells using WES. Genetic signature of cutaneous plasmacytoma shares that of melanoma implying common mechanism for skin tropism. KIAA1199, FRY, AP3B2, and OPTC are candidate genes for skin tropism of cancers. PMID- 26098548 TI - Soil Tillage Management Affects Maize Grain Yield by Regulating Spatial Distribution Coordination of Roots, Soil Moisture and Nitrogen Status. AB - The spatial distribution of the root system through the soil profile has an impact on moisture and nutrient uptake by plants, affecting growth and productivity. The spatial distribution of the roots, soil moisture, and fertility are affected by tillage practices. The combination of high soil density and the presence of a soil plow pan typically impede the growth of maize (Zea mays L.).We investigated the spatial distribution coordination of the root system, soil moisture, and N status in response to different soil tillage treatments (NT: no tillage, RT: rotary-tillage, SS: subsoiling) and the subsequent impact on maize yield, and identify yield-increasing mechanisms and optimal soil tillage management practices. Field experiments were conducted on the Huang-Huai-Hai plain in China during 2011 and 2012. The SS and RT treatments significantly reduced soil bulk density in the top 0-20 cm layer of the soil profile, while SS significantly decreased soil bulk density in the 20-30 cm layer. Soil moisture in the 20-50 cm profile layer was significantly higher for the SS treatment compared to the RT and NT treatment. In the 0-20 cm topsoil layer, the NT treatment had higher soil moisture than the SS and RT treatments. Root length density of the SS treatment was significantly greater than density of the RT and NT treatments, as soil depth increased. Soil moisture was reduced in the soil profile where root concentration was high. SS had greater soil moisture depletion and a more concentration root system than RT and NT in deep soil. Our results suggest that the SS treatment improved the spatial distribution of root density, soil moisture and N states, thereby promoting the absorption of soil moisture and reducing N leaching via the root system in the 20-50 cm layer of the profile. Within the context of the SS treatment, a root architecture densely distributed deep into the soil profile, played a pivotal role in plants' ability to access nutrients and water. An optimal combination of deeper deployment of roots and resource (water and N) availability was realized where the soil was prone to leaching. The correlation between the depletion of resources and distribution of patchy roots endorsed the SS tillage practice. It resulted in significantly greater post silking biomass and grain yield compared to the RT and NT treatments, for summer maize on the Huang-Huai-Hai plain. PMID- 26098550 TI - Emergence of complex chemistry on an organic monolayer. AB - In many origin-of-life scenarios, inorganic materials, such as FeS or mineral clays, play an important role owing to their ability to concentrate and select small organic molecules on their surface and facilitate their chemical transformations into new molecules. However, considering that life is made up of organic matter, at a certain stage during the evolution the role of the inorganic material must have been taken over by organic molecules. How this exactly happened is unclear, and, indeed, a big gap separates the rudimentary level of organization involving inorganic materials and the complex organization of cells, which are the building blocks of life. Over the past years, we have extensively studied the interaction of small molecules with monolayer-protected gold nanoparticles (Au NPs) for the purpose of developing innovative sensing and catalytic systems. During the course of these studies, we realized that the functional role of this system is very similar to that typically attributed to inorganic surfaces in the early stages of life, with the important being difference that the functional properties (molecular recognition, catalysis, signaling, adaptation) originate entirely from the organic monolayer rather than the inorganic support. This led us to the proposition that this system may serve as a model that illustrates how the important role of inorganic surfaces in dictating chemical processes in the early stages of life may have been taken over by organic matter. Here, we reframe our previously obtained results in the context of the origin-of-life question. The following functional roles of Au NPs will be discussed: the ability to concentrate small molecules and create different local populations, the ability to catalyze the chemical transformation of bound molecules, and, finally, the ability to install rudimentary signaling pathways and display primitive adaptive behavior. In particular, we will show that many of the functional properties of the system originate from two features: the presence of metal ions that are complexed in the organic monolayer and the multivalent nature of the system. Complexed metal ions play an important role in determining the affinity and selectivity of the interaction with small molecules, but serve also as regulatory elements for determining how many molecules are bound simultaneously. Importantly, neighboring metal ion complexes also create catalytic pockets in which two metal ions cooperatively catalyze the cleavage of an RNA-model compound. The multivalent nature of the system permits multiple noncovalent interactions with small molecules that enhances the affinity, but is also at the basis of simple signal transduction pathways and adaptive behavior. PMID- 26098549 TI - Cardioprotective Signature of Short-Term Caloric Restriction. AB - OBJECTIVE: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR). BACKGROUND: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia. METHODS: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI. RESULTS: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5+/ 2.4% vs. 26.6+/-1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3beta, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1alpha, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function. PMID- 26098552 TI - Prevalence of Low Bone Mass and Osteoporosis in Long-Term Users of the Injectable Contraceptive Depot Medroxyprogesterone Acetate. AB - BACKGROUND: Bone mineral density (BMD) loss among depot medroxyprogesterone acetate (DMPA) users is a controversial issue. Aspects under debate include whether the number of years of use has any effect on continuous BMD loss, whether this loss will stabilise over the years of use or if it will progress to low bone mass, osteoporosis and an increased fracture risk. The aim of this study was to compare the difference in osteoporosis and low bone mass between DMPA and copper intrauterine device (Cu-IUD) users. METHODS: This was a cross-sectional study that evaluated BMD at the lumbar spine and femoral neck in 47 long-term DMPA users and 41 Cu-IUD users as control group. BMD was measured by dual-energy X-ray absorptiometry. The participants were 27 to 57 years of age, had used either DMPA or a Cu-IUD uninterruptedly for at least ten years, had initiated use of the method prior to 40 years of age and had follicle stimulating hormone values <40 mIU/mL. RESULTS: Findings showed that 68.1% and 36.6% of the DMPA and Cu-IUD users, respectively, had low bone mass and 29.8% and 2.4% of DMPA and Cu-IUD users, respectively, had osteoporosis. BMD decreased as the number of years of DMPA use increased. CONCLUSION: Long-term DMPA use was associated with low bone mass and osteoporosis in women who had used the method for 10 years or more. DMPA users with longer time of use showed a greater bone mass loss. PMID- 26098551 TI - Phenotypic Variation Is Almost Entirely Independent of the Host-Pathogen Relationship in Clinical Isolates of S. aureus. AB - BACKGROUND: A key feature of Staphylococcus aureus biology is its ability to switch from an apparently benign colonizer of ~30% of the population to a cutaneous pathogen, to a deadly invasive pathogen. Little is known about the mechanisms driving this transition or the propensity of different S. aureus strains to engender different types of host-pathogen interactions. At the same time, significant weight has been given to the role of specific in vitro phenotypes in S. aureus virulence. Biofilm formation, hemolysis and pigment formation have all been associated with virulence in mice. DESIGN: To determine if there is a correlation between in vitro phenotype and the three types of host pathogen relationships commonly exhibited by S. aureus in the context of its natural human host, we assayed 300 clinical isolates for phenotypes implicated in virulence including hemolysis, sensitivity to autolysis, and biofilm formation. For comparative purposes, we also assayed phenotype in 9 domesticated S. aureus strains routinely used for analysis of virulence determinants in laboratory settings. RESULTS: Strikingly, the clinical strains exhibited significant phenotypic uniformity in each of the assays evaluated in this study. One exception was a small, but significant, correlation between an increased propensity for biofilm formation and isolation from skin and soft tissue infections (SSTIs). In contrast, we observed a high degree of phenotypic variation between common laboratory strains that exhibit virulence in mouse models. These data suggest the existence of significant evolutionary pressure on the S. aureus genome and highlight a role for host factors as a strong determinant of the host-pathogen relationship. In addition, the high degree of variation between laboratory strains emphasizes the need for caution when applying data obtained in one lab strain to the analysis of another. PMID- 26098553 TI - Development of a Multivalent Subunit Vaccine against Tularemia Using Tobacco Mosaic Virus (TMV) Based Delivery System. AB - Francisella tularensis is a facultative intracellular pathogen, and is the causative agent of a fatal human disease known as tularemia. F. tularensis is classified as a Category A Biothreat agent by the CDC based on its use in bioweapon programs by several countries in the past and its potential to be used as an agent of bioterrorism. No licensed vaccine is currently available for prevention of tularemia. In this study, we used a novel approach for development of a multivalent subunit vaccine against tularemia by using an efficient tobacco mosaic virus (TMV) based delivery platform. The multivalent subunit vaccine was formulated to contain a combination of F. tularensis protective antigens: OmpA like protein (OmpA), chaperone protein DnaK and lipoprotein Tul4 from the highly virulent F. tularensis SchuS4 strain. Two different vaccine formulations and immunization schedules were used. The immunized mice were challenged with lethal (10xLD100) doses of F. tularensis LVS on day 28 of the primary immunization and observed daily for morbidity and mortality. Results from this study demonstrate that TMV can be used as a carrier for effective delivery of multiple F. tularensis antigens. TMV-conjugate vaccine formulations are safe and multiple doses can be administered without causing any adverse reactions in immunized mice. Immunization with TMV-conjugated F. tularensis proteins induced a strong humoral immune response and protected mice against respiratory challenges with very high doses of F. tularensis LVS. This study provides a proof-of-concept that TMV can serve as a suitable platform for simultaneous delivery of multiple protective antigens of F. tularensis. Refinement of vaccine formulations coupled with TMV-targeting strategies developed in this study will provide a platform for development of an effective tularemia subunit vaccine as well as a vaccination approach that may broadly be applicable to many other bacterial pathogens. PMID- 26098554 TI - Transporting Cells in Semi-Solid Gel Condition and at Ambient Temperature. AB - Mammalian cells including human cancer cells are usually transported in cryovials on dry ice or in a liquid nitrogen vapor shipping vessel between different places at long distance. The hazardous nature of dry ice and liquid nitrogen, and the associated high shipping cost strongly limit their routine use. In this study, we tested the viability and properties of cells after being preserved or shipped over long distance in Matrigel mixture for different days. Our results showed that cells mixed with Matrigel at suitable ratios maintained excellent viability (>90%) for one week at room temperature and preserved the properties such as morphology, drug sensitivity and metabolism well, which was comparable to cells cryopreserved in liquid nitrogen. We also sent cells in the Matrigel mixture via FedEx service to different places at ambient temperature. Upon arrival, it was found that over 90% of the cells were viable and grew well after replating. These data collectively suggested that our Matrigel-based method was highly convenient for shipping live cells for long distances in semi-solid gel condition and at ambient temperature. PMID- 26098555 TI - Health Facility Graduation from Donor-Supported Intensive Technical Assistance and Associated Factors in Zambia. AB - INTRODUCTION: The FHI360-led Zambia Prevention Care and Treatment partnership II (ZPCT II) with funding from United States Agency for International Development, supports the Zambian Ministry of Health in scaling up HIV/AIDS services. To improve the quality of HIV/AIDS services, ZPCT II provides technical assistance until desired standards are met and districts are weaned-off intensive technical support, a process referred to as district graduation. This study describes the graduation process and determines performance domains associated with district graduation. METHODS: Data were collected from 275 health facilities in 39 districts in 5 provinces of Zambia between 2008 and 2012. Performance in technical capacity, commodity management, data management and human resources domains were assessed in the following services areas: HIV counselling and testing and prevention of mother to child transmission, antiretroviral therapy/clinical care, pharmacy and laboratory. The overall mean percentage score was calculated by obtaining the mean of mean percentage scores for the four domains. Logistic regression models were used to obtain odds ratios (OR) and 95% confidence intervals (CI) for the domain mean percentage scores in graduated versus non-graduated districts; according to rural-urban, and province strata. RESULTS: 24 districts out of 39 graduated from intensive donor supported technical assistance while 15 districts did not graduate. The overall mean percentage score for all four domains was statistically significantly higher in graduated than non-graduated districts (93.2% versus 91.2%, OR = 1.34, 95%CI:1.20 1.49); including rural settings (92.4% versus 89.4%, OR = 1.43,95%CI:1.24-1.65). The mean percentage score in human resource domain was statistically significantly higher in graduated than non-graduated districts (93.6% versus 71.6%, OR = 5.81, 95%CI: 4.29-7.86) and in both rural and urban settings. CONCLUSIONS: QA/QI tools can be used to assess performance at health facilities and determine readiness for district graduation. Human resources management domain was found to be an important factor associated with district graduation. PMID- 26098556 TI - The Application of Auto-Disturbance Rejection Control Optimized by Least Squares Support Vector Machines Method and Time-Frequency Representation in Voltage Source Converter-High Voltage Direct Current System. AB - In order to improve the performance of voltage source converter-high voltage direct current (VSC-HVDC) system, we propose an improved auto-disturbance rejection control (ADRC) method based on least squares support vector machines (LSSVM) in the rectifier side. Firstly, we deduce the high frequency transient mathematical model of VSC-HVDC system. Then we investigate the ADRC and LSSVM principles. We ignore the tracking differentiator in the ADRC controller aiming to improve the system dynamic response speed. On this basis, we derive the mathematical model of ADRC controller optimized by LSSVM for direct current voltage loop. Finally we carry out simulations to verify the feasibility and effectiveness of our proposed control method. In addition, we employ the time frequency representation methods, i.e., Wigner-Ville distribution (WVD) and adaptive optimal kernel (AOK) time-frequency representation, to demonstrate our proposed method performs better than the traditional method from the perspective of energy distribution in time and frequency plane. PMID- 26098558 TI - Cancer Workup after Unprovoked Clot--Less Is More. PMID- 26098557 TI - Targeting Hormone-Related Pathways to Improve Grain Yield in Rice: A Chemical Approach. AB - Sink/source relationships, regulating the mobilization of stored carbohydrates from the vegetative tissues to the grains, are of key importance for grain filling and grain yield. We used different inhibitors of plant hormone action to assess their effects on grain yield and on the expression of hormone-associated genes. Among the tested chemicals, 2-indol-3-yl-4-oxo-4-phenylbutanoic acid (PEO IAA; antagonist of auxin receptor), nordihydroguaiaretic acid (NDGA; abscisic acid (ABA) biosynthesis inhibitor), and 2-aminoisobutyric acid (AIB; ethylene biosynthesis inhibitor) improved grain yield in a concentration dependent manner. These effects were also dependent on the plant developmental stage. NDGA and AIB treatments induced an increase in photosynthesis in flag leaves concomitant to the increments of starch content in flag leaves and grains. NDGA inhibited the expression of ABA-responsive gene, but did not significantly decrease ABA content. Instead, NDGA significantly decreased jasmonic acid and jasmonic acid isoleucine. Our results support the notion that the specific inhibition of jasmonic acid and ethylene biosynthesis resulted in grain yield increase in rice. PMID- 26098559 TI - Factors Associated with Low Levels of HIV Testing among Men Who Have Sex with Men (MSM) in Brazil. AB - The aim of this study was to assess risk factors associated with low levels of HIV testing among MSM recruited through respondent driven sampling (RDS) in Brazil. Of 3,617 participants, 48.4% had never tested previously for HIV. A logistic model indicated that younger age, lower socioeconomic class, education, poor HIV/AIDS knowledge, no history of cruising, and having been tested during the study were characteristics independently associated with low levels of previous HIV testing. The HIV testing rate among MSM in Brazil is still low in spite of the availability of a large number services providing universal and free access to HIV/AIDS diagnosis and treatment. To respond to low utilization, the authors propose a higher priority for testing for key populations such as MSM, expanded education, expanding testing sites and a welcoming and nonjudgmental environment in health services. PMID- 26098560 TI - The MicroRNA-217 Functions as a Potential Tumor Suppressor in Gastric Cancer by Targeting GPC5. AB - Gastric cancer (GC) is one of the most common malignancies worldwide. Emerging evidence has shown that aberrant expression of microRNAs (miRNAs) plays important roles in cancer progression. However, little is known about the potential role of miR-217 in GC. In this study, we investigated the role of miR-217 on GC cell proliferation and invasion. The expression of miR-217 was down-regulated in GC cells and human GC tissues. Enforced expression of miR-217 inhibited GC cells proliferation and invasion. Moreover, Glypican-5 (GPC5), a new ocncogene, was identified as the potential target of miR-217. In addition, overexpression of miR 217 impaired GPC5-induced promotion of proliferation and invasion in GC cells. In conclusion, these findings revealed that miR-217 functioned as a tumor suppressor and inhibited the proliferation and invasion of GC cells by targeting GPC5, which might consequently serve as a therapeutic target for GC patients. PMID- 26098561 TI - Evidence of a Double Burden of Malnutrition in Urban Poor Settings in Nairobi, Kenya. AB - BACKGROUND: Many low- and middle-income countries are undergoing a nutrition transition associated with rapid social and economic transitions. We explore the coexistence of over and under- nutrition at the neighborhood and household level, in an urban poor setting in Nairobi, Kenya. METHODS: Data were collected in 2010 on a cohort of children aged under five years born between 2006 and 2010. Anthropometric measurements of the children and their mothers were taken. Additionally, dietary intake, physical activity, and anthropometric measurements were collected from a stratified random sample of adults aged 18 years and older through a separate cross-sectional study conducted between 2008 and 2009 in the same setting. Proportions of stunting, underweight, wasting and overweight/obesity were dettermined in children, while proportions of underweight and overweight/obesity were determined in adults. RESULTS: Of the 3335 children included in the analyses with a total of 6750 visits, 46% (51% boys, 40% girls) were stunted, 11% (13% boys, 9% girls) were underweight, 2.5% (3% boys, 2% girls) were wasted, while 9% of boys and girls were overweight/obese respectively. Among their mothers, 7.5% were underweight while 32% were overweight/obese. A large proportion (43% and 37%%) of overweight and obese mothers respectively had stunted children. Among the 5190 adults included in the analyses, 9% (6% female, 11% male) were underweight, and 22% (35% female, 13% male) were overweight/obese. CONCLUSION: The findings confirm an existing double burden of malnutrition in this setting, characterized by a high prevalence of undernutrition particularly stunting early in life, with high levels of overweight/obesity in adulthood, particularly among women. In the context of a rapid increase in urban population, particularly in urban poor settings, this calls for urgent action. Multisectoral action may work best given the complex nature of prevailing circumstances in urban poor settings. Further research is needed to understand the pathways to this coexistence, and to test feasibility and effectiveness of context-specific interventions to curb associated health risks. PMID- 26098562 TI - L-Arginine and SDMA Serum Concentrations Are Associated with Subclinical Atherosclerosis in the Study of Health in Pomerania (SHIP). AB - OBJECTIVE: Even though ?-arginine (ARG) derivatives can predict cardiovascular mortality, their role as atherosclerotic biomarkers is unclear. We tested the hypothesis if asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and the sum of both (DMA) are positively, while ARG and ARG/ADMA ratio are inversely associated with carotid intima-media thickness (cIMT) and atherosclerotic plaque in the carotid artery. APPROACH AND RESULTS: Cross sectional data of 1999 subjects (age: 45-81 years; 48.2% ?) from the population based Study of Health in Pomerania (SHIP-0) was used. Analysis of variance and logistic regression models were calculated and all adjusted models were corrected for sex, age, smoking status, waist-to-hip ratio and estimated glomerular filtration rate. Increased cIMT (>75th age-sex specific percentile) was found in 517 subjects (25.7%), while atherosclerotic plaque was detected in 1413 subjects (70.4%). SDMA tertiles were significantly positively associated with larger cIMT among subjects with high SDMA levels [>66th: 0.82 (95%-CI 0.80; 0.85) mm]. High SDMA levels were related to a higher odds ratio (OR) of increased cIMT [OR 1.39 (95%-CI 1.08; 1.79)]. Furthermore, ARG was positively associated with atherosclerotic plaques [OR 1.41 (95%-CI 1.07; 1.85)]. No relation was found for ADMA and atherosclerosis. CONCLUSIONS: In conclusion, the hypothesis of a positive association between SDMA with an increased cIMT was confirmed. Unexpectedly, ARG was positively related to atherosclerotic plaque. In view of these inconsistent findings, the impact of ARG derivatives as atherosclerotic biomarkers deserves further research. PMID- 26098563 TI - Contraceptive use among young women in Estonia: Association with contraceptive services. AB - OBJECTIVES: Our study aimed to explore the association between the use of effective contraceptive methods and access to different contraceptive services, as well as to describe accessibility-related obstacles when using contraceptive services and satisfaction with those services. METHODS: From a population-based cross-sectional study carried out in 2004 (response rate 53.8%), the data of 16- to 24-year-old women requiring contraception (N = 868) were analysed. Factors associated with the use of effective contraceptive methods and, specifically, hormonal methods, were explored using multiple logistic regression analysis. RESULTS: Effective contraception was used by 75.1% of the respondents. The use of effective contraceptive methods was associated with school-based sexuality education (adjusted prevalence odds ratio 2.69; 95% confidence interval 1.32 - 5.50), visiting a youth-friendly clinic (YFC) (1.82; 1.03-3.23) or a private gynaecologist (2.08; 1.11-3.92). The use of hormonal methods was additionally associated with being a native Estonian speaker and visiting a family doctor. More than half of the respondents reported some obstacle in accessing contraceptive services. The highest satisfaction ratings were given to YFCs. CONCLUSIONS: Steps to promote the use of services that are youth-friendly and associated with better uptake of effective contraceptive methods are needed among all 16- to 24-year-old women. PMID- 26098564 TI - Water Stress and Foliar Boron Application Altered Cell Wall Boron and Seed Nutrition in Near-Isogenic Cotton Lines Expressing Fuzzy and Fuzzless Seed Phenotypes. AB - Our previous research, conducted under well-watered conditions without fertilizer application, showed that fuzziness cottonseed trait resulted in cottonseed nutrition differences between fuzzy (F) and fuzzless (N) cottonseed. Under water stress conditions, B mobility is further limited, inhibiting B movement within the plant, affecting seed nutrition (quality). Therefore, we hypothesized that both foliar B and water stress can affect B mobility, altering cottonseed protein, oil, and mineral nutrition. The objective of the current research was to evaluate the effects of the fuzziness seed trait on boron (B) and seed nutrition under water stress and foliar B application using near-isogenic cotton lines (NILs) grown in a repeated greenhouse experiment. Plants were grown under-well watered conditions (The soil water potential was kept between -15 to -20 kPa, considered field capacity) and water stress conditions (soil water potential between -100 and -150 kPa, stressed conditions). Foliar B was applied at a rate of 1.8 kg B ha(-1) as H3BO3. Under well-watered conditions without B the concentrations of seed oil in N lines were higher than in F lines, and seed K and N levels were lower in N lines than in F lines. Concentrations of K, N, and B in leaves were higher in N lines than in F lines, opposing the trend in seeds. Water stress resulted in higher seed protein concentrations, and the contribution of cell wall (structural) B to the total B exceeded 90%, supporting the structural role of B in plants. Foliar B application under well-watered conditions resulted in higher seed protein, oil, C, N, and B in only some lines. This research showed that cottonseed nutrition differences can occur due to seed fuzziness trait, and water stress and foliar B application can alter cottonseed nutrition. PMID- 26098566 TI - Human rotavirus vaccine (Rotarix): focus on effectiveness and impact 6 years after first introduction in Africa. AB - A decade after licensure of the human rotavirus vaccine (HRV), a wealth of evidence supports a reduction of rotavirus (RV) gastroenteritis-associated mortality and hospitalizations following HRV inclusion in national immunization programs. Nevertheless, the majority of real-world data has been generated in high- or middle-income settings. Clinical efficacy trials previously indicated RV vaccine performance may be lower in less-developed countries compared with wealthier counterparts. Using recently published data from Africa, we examine the effectiveness and impact of HRV in resource-deprived areas, exploring whether vaccine performance differs by socioeconomic setting and the potential underlying factors. HRV vaccine effectiveness in early adopting African countries has proven to be similar or even superior to the efficacy results observed in pre-licensure studies. PMID- 26098565 TI - Peripheral Blood Mitochondrial DNA as a Biomarker of Cerebral Mitochondrial Dysfunction following Traumatic Brain Injury in a Porcine Model. AB - BACKGROUND: Traumatic brain injury (TBI) has been shown to activate the peripheral innate immune system and systemic inflammatory response, possibly through the central release of damage associated molecular patterns (DAMPs). Our main purpose was to gain an initial understanding of the peripheral mitochondrial response following TBI, and how this response could be utilized to determine cerebral mitochondrial bioenergetics. We hypothesized that TBI would increase peripheral whole blood relative mtDNA copy number, and that these alterations would be associated with cerebral mitochondrial bioenergetics triggered by TBI. METHODOLOGY: Blood samples were obtained before, 6 h after, and 25 h after focal (controlled cortical impact injury: CCI) and diffuse (rapid non-impact rotational injury: RNR) TBI. PCR primers, unique to mtDNA, were identified by aligning segments of nuclear DNA (nDNA) to mtDNA, normalizing values to nuclear 16S rRNA, for a relative mtDNA copy number. Three unique mtDNA regions were selected, and PCR primers were designed within those regions, limited to 25-30 base pairs to further ensure sequence specificity, and measured utilizing qRT-PCR. RESULTS: Mean relative mtDNA copy numbers increased significantly at 6 and 25 hrs after following both focal and diffuse traumatic brain injury. Specifically, the mean relative mtDNA copy number from three mitochondrial-specific regions pre-injury was 0.84 +/- 0.05. At 6 and 25 h after diffuse non-impact TBI, mean mtDNA copy number was significantly higher: 2.07 +/- 0.19 (P < 0.0001) and 2.37 +/- 0.42 (P < 0.001), respectively. Following focal impact TBI, relative mtDNA copy number was also significantly higher, 1.35 +/- 0.12 (P < 0.0001) at 25 hours. Alterations in mitochondrial respiration in the hippocampus and cortex post-TBI correlated with changes in the relative mtDNA copy number measured in peripheral blood. CONCLUSIONS: Alterations in peripheral blood relative mtDNA copy numbers may be a novel biosignature of cerebral mitochondrial bioenergetics with exciting translational potential for non-invasive diagnostic and interventional studies. PMID- 26098567 TI - Transcriptome Analysis to Identify Cold-Responsive Genes in Amur Carp (Cyprinus carpio haematopterus). AB - The adaptation of fish to low temperatures is the result of long-term evolution. Amur carp (Cyprinus carpio haematopterus) survives low temperatures (0-4 degrees C) for six months per year. Therefore, we chose this fish as a model organism to study the mechanisms of cold-adaptive responses using high-throughput sequencing technology. This system provided an excellent model for exploring the relationship between evolutionary genomic changes and environmental adaptations. The Amur carp transcriptome was sequenced using the Illumina platform and was assembled into 163,121 cDNA contigs, with an average read length of 594 bp and an N50 length of 913 bp. A total of 162,339 coding sequences (CDSs) were identified and of 32,730 unique CDSs were annotated. Gene Ontology (GO), EuKaryotic Orthologous Groups (KOG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to classify all CDSs into different functional categories. A large number of cold-responsive genes were detected in different tissues at different temperatures. A total of 9,427 microsatellites were identified and classified, with 1952 identifying in cold-responsive genes. Based on GO enrichment analysis of the cold-induced genes, "protein localization" and "protein transport" were the most highly represented biological processes. "Circadian rhythm," "protein processing in endoplasmic reticulum," "endocytosis," "insulin signaling pathway," and "lysosome" were the most highly enriched pathways for the genes induced by cold stress. Our data greatly contribute to the common carp (C. carpio) transcriptome resource, and the identification of cold responsive genes in different tissues at different temperatures will aid in deciphering the genetic basis of ecological and environmental adaptations in this species. Based on our results, the Amur carp has evolved special strategies to survive low temperatures, and these strategies include the system-wide or tissue specific induction of gene expression during their six-month overwintering period. PMID- 26098568 TI - Association Between Force-Time Curve Characteristics and Vertical Jump Performance in Trained Athletes. AB - Countermovement jump (CMJ) has been extensively used in training; yet, limited and contradictory kinematic data are available for trained subjects. To our best knowledge, no other studies have evaluated the associations between force-time curve characteristics and CMJ in a large sample of trained athletes using a linear transducer. Thus, the aim of this study was to determine the association between force-time measures and CMJ performance collected with a linear transducer. Thirty-five trained athletes were asked to perform 3 maximal weighted CMJ using a linear transducer attached to a barbell (17 kg). The data indicated that the maximal rate of force development (RFD(max)) was strongly related to CMJ displacement (r = 0.809/0.807, p < 0.001) and also to the percentage of peak force (r = -0.823/-0.809, p < 0.001) at RFD(max). Velocity and displacement at RFD(max) were not correlated to CMJ height. It was therefore concluded that the percentage of PF applied at RFD(max) and RFD(max) were the best predictive variables for CMJ performance in this study. PMID- 26098569 TI - Correction: Self-Organising Maps and Correlation Analysis as a Tool to Explore Patterns in Excitation-Emission Matrix Data Sets and to Discriminate Dissolved Organic Matter Fluorescence Components. PMID- 26098570 TI - Personalized Modeling for Prediction with Decision-Path Models. AB - Deriving predictive models in medicine typically relies on a population approach where a single model is developed from a dataset of individuals. In this paper we describe and evaluate a personalized approach in which we construct a new type of decision tree model called decision-path model that takes advantage of the particular features of a given person of interest. We introduce three personalized methods that derive personalized decision-path models. We compared the performance of these methods to that of Classification And Regression Tree (CART) that is a population decision tree to predict seven different outcomes in five medical datasets. Two of the three personalized methods performed statistically significantly better on area under the ROC curve (AUC) and Brier skill score compared to CART. The personalized approach of learning decision path models is a new approach for predictive modeling that can perform better than a population approach. PMID- 26098571 TI - Magnetic Properties of 3D Heptanuclear Lanthanide Frameworks Supported by Mixed Ligands. AB - Two 3D lanthanide frameworks, [Ln7(DPA)5(NA)3(MU3-OH)8(H2O)3].2.5H2O [H2DPA = diphenic acid; HNA = nicotinic acid; Ln = Gd (1), Dy (2)], were synthesized and structurally characterized. They were rarely seen examples of 3D frameworks constructed from heptanuclear trigonal-antiprismatic lanthanide clusters with mixed H2DPA and HNA ligands. Both 1 and 2 show typical antiferromagnetic interactions. Additionally, complex 1 possesses a large magnetocaloric effect of 34.15 J kg(-1) K(-1). PMID- 26098572 TI - The oncogene c-Jun impedes somatic cell reprogramming. AB - Oncogenic transcription factors are known to mediate the conversion of somatic cells to tumour or induced pluripotent stem cells (iPSCs). Here we report c-Jun as a barrier for iPSC formation. c-Jun is expressed by and required for the proliferation of mouse embryonic fibroblasts (MEFs), but not mouse embryonic stem cells (mESCs). Consistently, c-Jun is induced during mESC differentiation, drives mESCs towards the endoderm lineage and completely blocks the generation of iPSCs from MEFs. Mechanistically, c-Jun activates mesenchymal-related genes, broadly suppresses the pluripotent ones, and derails the obligatory mesenchymal to epithelial transition during reprogramming. Furthermore, inhibition of c-Jun by shRNA, dominant-negative c-Jun or Jdp2 enhances reprogramming and replaces Oct4 among the Yamanaka factors. Finally, Jdp2 anchors 5 non-Yamanaka factors (Id1, Jhdm1b, Lrh1, Sall4 and Glis1) to reprogram MEFs into iPSCs. Our studies reveal c Jun as a guardian of somatic cell fate and its suppression opens the gate to pluripotency. PMID- 26098573 TI - A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy. AB - Autophagy is an essential eukaryotic pathway requiring tight regulation to maintain homeostasis and preclude disease. Using yeast and mammalian cells, we report a conserved mechanism of autophagy regulation by RNA helicase RCK family members in association with the decapping enzyme Dcp2. Under nutrient-replete conditions, Dcp2 undergoes TOR-dependent phosphorylation and associates with RCK members to form a complex with autophagy-related (ATG) mRNA transcripts, leading to decapping, degradation and autophagy suppression. Simultaneous with the induction of ATG mRNA synthesis, starvation reverses the process, facilitating ATG mRNA accumulation and autophagy induction. This conserved post transcriptional mechanism modulates fungal virulence and the mammalian inflammasome, the latter providing mechanistic insight into autoimmunity reported in a patient with a PIK3CD/p110delta gain-of-function mutation. We propose a dynamic model wherein RCK family members, in conjunction with Dcp2, function in controlling ATG mRNA stability to govern autophagy, which in turn modulates vital cellular processes affecting inflammation and microbial pathogenesis. PMID- 26098574 TI - Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival. AB - During metastatic progression, circulating cancer cells become lodged within the microvasculature of end organs, where most die from mechanical deformation. Although this phenomenon was first described over a half-century ago, the mechanisms enabling certain cells to survive this metastasis-suppressive barrier remain unknown. By applying whole-transcriptome RNA-sequencing technology to isogenic cancer cells of differing metastatic capacities, we identified a mutation encoding a truncated form of the pannexin-1 (PANX1) channel, PANX1(1 89), as recurrently enriched in highly metastatic breast cancer cells. PANX1(1 89) functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive PANX1 channels activated by membrane stretch. PANX1-mediated ATP release acts as an autocrine suppressor of deformation-induced apoptosis through P2Y-purinergic receptors. Finally, small-molecule therapeutic inhibition of PANX1 channels is found to reduce the efficiency of breast cancer metastasis. These data suggest a molecular basis for metastatic cell survival on microvasculature-induced biomechanical trauma. PMID- 26098575 TI - Microtubule-associated proteins control the kinetics of microtubule nucleation. AB - Microtubules are born and reborn continuously, even during quiescence. These polymers are nucleated from templates, namely gamma-tubulin ring complexes (gamma TuRCs) and severed microtubule ends. Using single-molecule biophysics, we show that nucleation from gamma-TuRCs, axonemes and seed microtubules requires tubulin concentrations that lie well above the critical concentration. We measured considerable time lags between the arrival of tubulin and the onset of steady state elongation. Microtubule-associated proteins (MAPs) alter these time lags. Catastrophe factors (MCAK and EB1) inhibited nucleation, whereas a polymerase (XMAP215) and an anti-catastrophe factor (TPX2) promoted nucleation. We observed similar phenomena in cells. We conclude that GTP hydrolysis inhibits microtubule nucleation by destabilizing the nascent plus ends required for persistent elongation. Our results explain how MAPs establish the spatial and temporal profile of microtubule nucleation. PMID- 26098577 TI - Dietary calcium and zinc deficiency risks are decreasing but remain prevalent. AB - Globally, more than 800 million people are undernourished while >2 billion people have one or more chronic micronutrient deficiencies (MNDs). More than 6% of global mortality and morbidity burdens are associated with undernourishment and MNDs. Here we show that, in 2011, 3.5 and 1.1 billion people were at risk of calcium (Ca) and zinc (Zn) deficiency respectively due to inadequate dietary supply. The global mean dietary supply of Ca and Zn in 2011 was 684 +/- 211 and 16 +/- 3 mg capita(-1) d(-1) (+/- SD) respectively. Between 1992 and 2011, global risk of deficiency of Ca and Zn decreased from 76 to 51%, and 22 to 16%, respectively. Approximately 90% of those at risk of Ca and Zn deficiency in 2011 were in Africa and Asia. To our knowledge, these are the first global estimates of dietary Ca deficiency risks based on food supply. We conclude that continuing to reduce Ca and Zn deficiency risks through dietary diversification and food and agricultural interventions including fortification, crop breeding and use of micronutrient fertilisers will remain a significant challenge. PMID- 26098576 TI - Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. AB - LC3-associated phagocytosis (LAP) is a process wherein elements of autophagy conjugate LC3 to phagosomal membranes. We characterize the molecular requirements for LAP, and identify Rubicon as being required for LAP but not autophagy. Rubicon is recruited to LAPosomes and is required for the activity of a Class III PI(3)K complex containing UVRAG but lacking ATG14 and Ambra1. This allows for the sustained localization of PtdIns(3)P, which is critical for recruitment of downstream autophagic proteins and stabilization of the NOX2 complex to produce reactive oxygen species. Both PtdIns(3)P and reactive oxygen species are required for conjugation of LC3 to LAPosomes and subsequent association with LAMP1(+) lysosomes. LAP is induced by engulfment of Aspergillus fumigatus, a fungal pathogen that commonly afflicts immunocompromised hosts, and is required for its optimal clearance in vivo. Therefore, we have identified molecules that distinguish LAP from canonical autophagy, thereby elucidating the importance of LAP in response to A. fumigatus infection. PMID- 26098579 TI - Test experience effects in longitudinal comparisons of adult cognitive functioning. AB - It is widely recognized that experience with cognitive tests can influence estimates of cognitive change. Prior research has estimated experience effects at the level of groups by comparing the performance of a group of participants tested for the second time with the performance of a different group of participants at the same age tested for the first time. This twice-minus-once tested method was adapted in the current study to derive estimates of test experience at the level of individual participants. Among the major findings were that experience estimates were smaller at older ages, with measures of vocabulary and speed compared to measures of memory, reasoning, and spatial visualization, and with longer intervals between the first and second occasion. Although relations of overall cognitive ability with test experience effects were weak, there were significant correlations among the experience estimates in different cognitive domains. These results imply that at least in adulthood, simple measures of cognitive change likely underestimate maturational influences on cognitive functioning, and to a greater extent in young adults than in older adults. PMID- 26098578 TI - Patterns of body image concerns and disordered weight- and shape-related behaviors in heterosexual and sexual minority adolescent males. AB - This study investigates body image concerns and disordered weight- and shape related behaviors across adolescence and young adulthood in males and how patterns vary by sexual orientation. Participants were 5,388 males from the U.S. national Growing Up Today Study. In 2001, 2003, and 2005 (spanning ages 15-20 years), participants reported sexual orientation, past-year desire for toned/defined muscles and concerns with weight and shape, and past-year binge eating, restrictive dieting, purging (vomiting or laxative use), and use of products to increase muscularity (e.g., creatine, steroids). Latent class analyses identified 2 patterns at ages 15-16 years and 3 patterns at 17-18 and 19 20 years: healthy (all ages; low body image concerns and weight- and shape related behaviors; 54-74% of observations), muscle-concerned (ages 17-18 and 19 20; relatively high muscularity concern and product use; 18-21% of observations), and lean-concerned (all ages; relatively high weight and shape concern, dieting, and binge eating; 19-28% of observations). Latent transition analyses revealed that sexual minority males (i.e., mostly heterosexual, gay, and bisexual) were more likely than completely heterosexual males to be lean-concerned at ages 17-18 and 19-20 years and to transition to the lean-concerned class from the healthy class. There were no sexual orientation differences in odds of being muscle concerned. Both heterosexual and sexual minority males are at risk for presenting body image concerns and weight- and shape-related behaviors that may have deleterious health consequences. Results suggest the need for screening for concerns and behaviors related to leanness and muscularity in early adolescence among all males, regardless of sexual orientation. PMID- 26098580 TI - Affiliative structures and social competence in Portuguese preschool children. AB - The goal of this study was to determine whether peer social competence (SC), defined as the capacity to use behavioral, cognitive, and emotional resources in the service of achieving personal goals within preschool peer groups, was related to the type of affiliative subgroups to which children belonged. Two hundred forty Portuguese preschool children (152 seen in consecutive years of data collection) from middle-class families participated. Affiliative subgroup type was assessed from observed proximity data. Social competence was assessed using observational and sociometric measures. Children in more cohesive affiliative subgroups had higher levels of SC, whereas ungrouped children had the lowest SC scores. Follow-up analyses indicated that 2 of the measured SC domains (social engagement/motivation, profiles of behavior/personality attributes) were responsible for the overall difference in SC. Further, membership in a more cohesive subgroup in 1 year contributed to increases in scores for 2 of 3 SC domains (i.e., profiles of behavior/personality attributes and peer acceptance) in the following year. Results suggest that affiliative subgroups both reflect and support individual differences in peer SC during early childhood. PMID- 26098581 TI - Does aggregate school-wide achievement mediate fifth grade outcomes for former early childhood education participants? AB - This study used a multilevel mediation model to test the theory that former early childhood education (ECE) attendees' 5th grade achievement is mediated by the aggregate school-wide achievement of their elementary school. Aggregate school wide achievement was defined as the percentage of 5th graders in a school who were at/above academic proficiency in reading or math. Research questions were: (a) Do ECE program participants have better achievement at 5th grade compared with their matched peers who did not participate in an ECE program?; and (b) Is the association between ECE attendance and 5th grade academic performance mediated by school-wide achievement? Results indicated that children who attended prekindergarten (pre-K) and child care outperformed their matched peers who had not attended ECE programs; conversely, those children who did not attend ECE actually outperformed their Head Start counterparts. Mediation analyses indicated that aggregate school-wide achievement at 5th grade partially mediated the association between former ECE attendance and 5th grade performance; however, these mediated effects were small. Overall, the size of the total effects of ECE and the 5th grade academic outcomes were consistent with prior studies. This research confirms the long-term effects of pre-K and child care until 5th grade. PMID- 26098583 TI - Pursuing frequency standards and control: the invention of quartz clock technologies. AB - The quartz clock, the first to replace the pendulum as the time standard and later a ubiquitous and highly influential technology, originated in research on means for determining frequency for the needs of telecommunication and the interests of its users. This article shows that a few groups in the US, Britain, Italy and the Netherlands developed technologies that enabled the construction of the new clock in 1927-28. To coordinate complex and large communication networks, the monopolistic American Telephone and Telegraph Company, and national laboratories needed to determine and maintain a common 'standard' frequency measurement unit. Exploiting novel piezoelectric quartz methods and valve electronics techniques, researchers in these organizations constructed a new crystal-based frequency standard. To ensure its accuracy they compared it to an accepted absolute standard - an astronomical clock, constructing thereby the first quartz clock. Other groups, however, had different, though connected, technological aims, which originated from the diverse interests of the industrial, governmental and academic institutes to which they belonged, and for which they needed to measure, control and manipulate with frequencies of electric oscillations. The present article suggests a comparative examination of the research and development paths of these groups on their incentives, the technological and scientific resources they utilized, and the kind of research carried out in the various institutional settings. PMID- 26098582 TI - Historical improvements in well-being do not hold in late life: Birth- and death year cohorts in the United States and Germany. AB - One key objective of life span research is to examine how individual development is shaped by the historical time people live in. Secular trends favoring later born cohorts on fluid cognitive abilities have been widely documented, but findings are mixed for well-being. It remains an open question whether secular increases in well-being seen in earlier phases of life also manifest in the last years of life. To examine this possibility, we made use of longitudinal data obtained from the mid-1980s until the late 2000s in 2 large national samples in the United States (Health and Retirement Study [HRS]) and Germany (German Socio Economic Panel [SOEP]). We operationally defined historical time from 2 complementary perspectives: birth-year cohorts based on the years in which people were born (earlier: 1930s vs. later: 1940s) and death-year cohorts based on the years in which people died (earlier: 1990s vs. later: 2000s). To control for relevant covariates, we used case-matched groups based on age (at death) and education and covaried for gender, health, and number of observations. Results from both countries revealed that well-being in old age was indeed developing at higher levels among later-born cohorts. However, for later-deceased cohorts, no evidence for secular increases in well-being was found. To the contrary, later dying SOEP participants reported lower levels of well-being at age 75 and 2 years prior to death and experienced steeper late-life declines. Our results suggest that secular increases in well-being observed in old age do not manifest in late life, where "manufactured" survival may be exacerbating age- and mortality related declines. PMID- 26098584 TI - Step-Economical Syntheses of Functional BODIPY-EDOT pi-Conjugated Materials through Direct C-H Arylation. AB - Palladium-catalyzed direct C-H arylations of 4,4-difluoro-4-bora-3a,4a-diaza-s indacene (BODIPY) with 3,4-ethylenedioxythiophene (EDOT) derivatives at relatively low temperature (60 degrees C) provide moderate to good yields (47% 72%) of products having potential applications in fluorescent bioimaging and organic optoelectronics. PMID- 26098585 TI - Paper-Based Device for Rapid Visualization of NADH Based on Dissolution of Gold Nanoparticles. AB - We describe a paper-based device that enables rapid and sensitive room temperature detection of dihydronicotinamide adenine dinucleotide (NADH) via a colorimetric readout and demonstrate its value for monitoring NAD+-driven enzymatic reactions. Our system is based on NADH-mediated inhibition of gold nanoparticle (AuNPs) dissolution in a Au3+-cetyltrimethylammonium bromide (CTAB) solution. We fabricated a device consisting of a mixed cellulose ester paper featuring a wax-encircled, AuNP-coated film atop a cotton absorbent layer sandwiched between two plastic cover layers. In the absence of NADH, the Au3+ CTAB complex dissolves the AuNP layer completely, generating a white color in the test zone. In the presence of NADH, Au3+ is rapidly reduced to Au+, greatly decreasing the dissolution of AuNPs and yielding a red color that becomes stronger at increasing concentrations of NADH. This device exploits capillary force-assisted vertical diffusion, allowing us to apply a 25 MUL sample to a surface-confined test zone to achieve a detection limit of 12.5 MUM NADH. We used the enzyme glucose dehydrogenase as a model to demonstrate that our paper-based device can monitor NAD+-driven biochemical processes with and without selective dehydrogenase inhibitors by naked-eye observation within 4 min at room temperature in a small sample volume. We believe that our paper-based device could offer a valuable and low-cost analytical tool for monitoring NAD+ associated enzymatic reactions and screening for dehydrogenase inhibitors in a variety of testing contexts. PMID- 26098586 TI - Avoidance orientation and the escalation of negative communication in intimate relationships. AB - Avoidance goals heighten the salience of negative social experiences, and in intimate relationships such an orientation may contribute to communication difficulties and the perpetuation of avoidance. We therefore hypothesized that individuals with stronger avoidance goals would be particularly prone to engage in escalating levels of negative communication with their intimate partner, and we tested this prediction by conducting sequential analyses on videotaped observational data (28,470 observations) collected from 365 heterosexual couples engaging in a relationship-related conflict. While less avoidance-oriented spouses showed a decline in their likelihood of negative communication over the course of the 8-min conflict discussion, the likelihood that more avoidance oriented spouses would display negative communication behaviors remained at a high level. The likelihood of negative communication even increased when avoidance-oriented spouses were confronted with negative communication behavior of their partners. The effects of avoidance orientation were independent of relationship satisfaction and neuroticism. These findings demonstrate that avoidance goals underlie individuals' heightened reactivity to the partner's negative behavior, while also clarifying 1 possible reason why some individuals engage in communication behaviors that may prove maladaptive to their relationship. PMID- 26098587 TI - It only takes once: The absent-exempt heuristic and reactions to comparison-based sexual risk information. AB - Three studies (N = 545) investigated the effects of social comparison on the "absent-exempt" (AE) heuristic (feeling exempt from future risk). Study 1 examined how comparison with an infected peer (comparison target) who was similar or nonsimilar in terms of sexual risk (number of partners, lack of condom use), influenced willingness and intentions to engage in sex without a condom, and conditional perceived vulnerability to an STD. Participants generally reported lower willingness and higher conditional vulnerability if they compared with a similar-risk level target. However, high-risk students who compared with a low risk target engaged in what appeared to be AE thinking, reporting the highest willingness and lowest conditional vulnerability. Intentions to have sex without a condom were not influenced. Study 2 included a direct measure of AE thinking and compared the impact of a low-risk comparison target with a Public Service Announcement (PSA) stating that negative outcomes (STDs) can happen even to low risk targets. Among high-risk participants, comparing with the low-risk target increased AE thinking. The effects in Studies 1 and 2 were strongest among participants high in tendencies to socially compare. Study 3 explored whether AE thinking could be decreased by encouraging more reasoned processing. Results indicated that asking participants to think about the illogicality of AE thinking reduces AE endorsement and increases STD testing intentions. Findings suggest that comparison-based information can have a stronger influence on health cognitions than analytic-based information (e.g., most PSAs). Implications for dual-processing models of decision-making and their applicability to health messages are discussed. PMID- 26098588 TI - Building social resilience in soldiers: A double dissociative randomized controlled study. AB - Can social resilience be trained? We report results of a double-dissociative randomized controlled study in which 48 Army platoons were randomly assigned to social resilience training (intervention condition) or cultural awareness training (active control group). The same surveys were administered to all platoons at baseline and after the completion of training to determine the short term training effects, generalization effects beyond training, and possible adverse effects. Multilevel modeling analyses indicated that social resilience, compared with cultural awareness, training produced small but significant improvements in social cognition (e.g., increased empathy, perspective taking, & military hardiness) and decreased loneliness, but no evidence was found for social resilience training to generalize beyond these training foci nor to have adverse effects. Moreover, as predicted, cultural awareness, compared with social resilience, training produced increases in knowledge about and decreases in prejudice toward Afghans. Additional research is warranted to determine the long term durability, safety, and generalizability of social resilience training. PMID- 26098589 TI - Thrombus formation in the left ventricle after large myocardial infarction - assessment with cardiac magnetic resonance imaging. AB - INTRODUCTION: Left ventricular thrombus (LVT) formation may worsen the post infarct outcome as a result of thromboembolic events. It also complicates the use of modern antiplatelet regimens, which are not compatible with long-term oral anticoagulation. The knowledge of the incidence of LVT may therefore be of importance to guide antiplatelet and antithrombotic therapy after acute myocardial infarction (AMI). METHODS: In 177 patients with large, mainly anterior AMI, standard cardiac magnetic resonance imaging (CMR) including cine and late gadolinium enhancement (LGE) imaging was performed shortly after AMI as per protocol. CMR images were analysed at an independent core laboratory blinded to the clinical data. Transthoracic echocardiography (TTE) was not mandatory for the trial, but was performed in 64% of the cases following standard of care. In a logistic model, 3 out of 61 parameters were used in a multivariable model to predict LVT. RESULTS: LVT was detected by use of CMR in 6.2% (95% confidence interval [CI] 3.1%-10.8%). LGE sequences were best to detect LVT, which may be missed in cine sequences. We identified body mass index (odds ratio 1.18; p = 0.01), baseline platelet count (odds ratio 1.01, p = 0.01) and infarct size as assessed by use of CMR (odds ratio 1.03, p = 0.02) as best predictors for LVT. The agreement between TTE and CMR for the detection of LVT is substantial (kappa = 0.70). DISCUSSION: In the current analysis, the incidence of LVT shortly after AMI is relatively low, even in a patient population at high risk. An optimal modality for LVT detection is LGE-CMR but TTE has an acceptable accuracy when LGE CMR is not available. PMID- 26098590 TI - Motor Vehicle Crash Fatalities in States With Primary Versus Secondary Seat Belt Laws: A Time-Series Analysis. AB - BACKGROUND: Motor vehicle crashes (MVCs) remain a leading cause of injury-related deaths in the United States. Primary seat belt laws allow vehicle occupants to be ticketed solely for not wearing seat belts, and secondary laws allow ticketing only for failure to wear seat belts in the setting of other violations. OBJECTIVE: To determine the association between MVC fatality rates and primary versus secondary seat belt laws. DESIGN: Retrospective time-series analysis. SETTING: United States, 2001 to 2010. PARTICIPANTS: MVC fatalities in occupants aged 10 years or older identified in the Fatality Analysis Reporting System. MEASUREMENTS: Population-based rates of fatal crashes. RESULTS: There were 283 183 MVC fatalities in occupants aged 10 years or older from 2001 to 2010 (overall rate, 13.0 per 100 000 persons). In 2001, the mean fatality rate was 14.6 per 100 000 persons, 16 states had primary seat belt laws, and 33 states had secondary laws. In 2010, the mean fatality rate was 9.7 per 100 000 persons, 30 states had primary seat belt laws, and 19 states had secondary laws. In the multivariate regression model, states with primary seat belt laws had lower MVC fatality rates than states with secondary laws (adjusted incidence rate ratio, 0.83 [95% CI, 0.78 to 0.90]). LIMITATION: Only fatalities were analyzed from the database, and the degree of law enforcement could not be ascertained. CONCLUSION: States with primary seat belt laws had lower rates of MVC fatalities than those with secondary laws. Adoption of primary seat belt laws may offer optimal occupant protection. PRIMARY FUNDING SOURCE: None. PMID- 26098592 TI - Ruthenium Catalyzed Stereo/Chemo/Regioselective One-Pot Synthesis of C(2)-C(3) Unsaturated and alpha-D-Mannopyranosyl Sulfones. AB - An efficient and divergent approach to C(2)-C(3) unsaturated glycosyl and alpha-D mannopyranosyl sulfones has been developed via ruthenium-promoted direct glycosylation, oxidation, and dihydroxylation from glycal in one-pot. The presence of stoichiometric amounts of NaIO4 and in situ generation of RuO4 from a RuCl3-NaIO4 reagent system were crucial for chemoselective oxidation of sulfide in the presence of an olefin moiety. The dual-role of ruthenium in sequential glycosylation-oxidation-dihydroxylation is amenable to a wide range of thio acceptors to access alpha-D-mannopyranosyl sulfones in good yields with high regioselectivity. PMID- 26098591 TI - Reversal of the Transcriptome by Prostaglandin E2 during Myofibroblast Dedifferentiation. AB - Myofibroblasts, the major effector cells in pathologic fibrosis, derive from the differentiation of fibroblasts driven by mediators such as transforming growth factor-beta1 (TGF-beta1) and biomechanical signals. Although the myofibroblast has traditionally been considered a terminally differentiated cell, the lipid mediator prostaglandin E2 (PGE2) has been shown to not only prevent but also reverse myofibroblast differentiation, as characterized by the ability of PGE2 to diminish expression of collagen I and alpha-smooth muscle actin in established myofibroblasts. Here, we use microarrays to examine the extent of transcriptomic changes that occur during TGF-beta1-induced differentiation and PGE2-induced dedifferentiation of myofibroblasts. Normal primary human adult lung fibroblasts were cultured for 24 hours with or without TGF-beta1 and treated for 48 hours with PGE2. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. TGF-beta1 up-regulated 588 genes and down-regulated 689 genes compared with control cells. PGE2 reversed the expression of 363 (62%) of the TGF beta1-up-regulated genes and 345 (50%) of the TGF-beta1-down-regulated genes. Genes up-regulated by TGF-beta1 and reversed by PGE2 were enriched in annotations for Cell Adhesion, Contractile Fiber, and Actin Binding, whereas genes down regulated by TGF-beta1 but subsequently reversed by PGE2 were enriched in annotations for Glycoprotein, Polysaccharide Binding, and Regulation of Cell Migration. Surprisingly, the genes whose expression was affected by PGE2 differed between TGF-beta1-induced myofibroblasts and undifferentiated fibroblasts. These data demonstrate the capacity of PGE2 to effect marked global alterations in the transcriptomic program of differentiated myofibroblasts and emphasize the considerable plasticity of these cells. PMID- 26098593 TI - Surface engineering on CeO2 nanorods by chemical redox etching and their enhanced catalytic activity for CO oxidation. AB - Controllable surface properties of nanocerias are desired for various catalytic processes. There is a lack of efficient approaches to adjust the surface properties of ceria to date. Herein, a redox chemical etching method was developed to controllably engineer the surface properties of ceria nanorods. Ascorbic acid and hydrogen peroxide were used to perform the redox chemical etching process, resulting in a rough surface and/or pores on the surface of ceria nanorods. Increasing the etching cycles induced a steady increase of the specific surface area, oxygen vacancies and surface Ce(3+) fractions. As a result, the etched nanorods delivered enhanced catalytic activity for CO oxidation, compared to the non-etched ceria nanorods. Our method provides a novel and facile approach to continuously adjust the surface properties of ceria for practical applications. PMID- 26098594 TI - WITHDRAWN: Antiglucocorticoid treatments for mood disorders. PMID- 26098595 TI - Pneumatic positioning and mesh fixation in laparoscopic ventral/incisional hernia repair. New surgical technique and a new device. AB - AIM: To achieve full-surface contact of a prosthetic mesh with the abdominal wall (avoiding folds and wrinkles) in laparoscopic ventral/ incisional hernia repair (LVHR/ LIHR) and to fix the mesh with glue using a new surgical technique and a new device, developed for this specific procedure. MATERIAL OF STUDY: New surgical technique associated with a new surgical pneumatic device allows perfect positioning and extension of the intraperitoneal mesh and facilitates the glue application and mesh fixation. A polyester composite mesh is used for intraperitoneal placement, cyanoacrylate glue is used for mesh fixation. Pigs cadavers were used to test this new technique and the device*. RESULTS: With the help of a pneumatic device the intraperitoneal mesh can be well positioned and perfectly extended without folds, thus allowing an efficient and strong mesh glue fixation. CONCLUSION: Presented pneumatic positioning device is useful to achieve an ideal alignment of mesh with the abdominal wall and supports the fixation task. The proposed technique enables the glue application safely, by avoiding possible spillage over intestinal loops and offering the necessary time for the distribution of such fast polymerizing glue. This technique could also be applied with other types of glue or self-adhesive mesh. PMID- 26098596 TI - Enhanced photocurrent by the co-sensitization of ZnO with dye and CuInSe nanocrystals. AB - ZnO nanocrystals with a particle size of 20-30 nm have been synthesised for the first time using a template-free method. Chalcopyrite Cu0.28In1.72Se2.72 nanocrystals (5-10 nm) were directly anchored on ZnO nanocrystals by a vacuum one pot-nanocasting process without any long ligands. We further investigated Cu0.28In1.72Se2.72 quantum dots and dye bilayer-sensitized solar cells, which exhibited power conversion efficiency of 57.4% higher than the single-dye sensitized solar cells. PMID- 26098597 TI - Argument for a non-linear relationship between severity of human obesity and dopaminergic tone. AB - Alterations in the dopaminergic system have been implicated in both animal and human obesity. However, to date, a comprehensive model on the nature and functional relevance of this relationship is missing. In particular, human data remain equivocal in that seemingly inconsistent reports exist of positive, negative or even no relationships between dopamine D2/D3 receptor availability in the striatum and measures of obesity. Further, data on receptor availability have been commonly interpreted as reflecting receptor density, despite the possibility of an alternative interpretation, namely alterations in the basal levels of endogenous dopaminergic tone. Here, we provide a unifying framework that is able to explain the seemingly contradictory findings and offer an alternative and novel perspective on existing data. In particular, we suggest (i) a quadratic relationship between alterations in the dopaminergic system and degree of obesity, and (ii) that the observed alterations are driven by shifts in the balance between general dopaminergic tone and phasic dopaminergic signalling. The proposed model consistently integrates human data on molecular and behavioural characteristics of overweight and obesity. Further, the model provides a mechanistic framework accounting not only for the consistent observation of altered (food) reward-responsivity but also for the differences in reinforcement learning, decision-making behaviour and cognitive performance associated with measures of obesity. PMID- 26098598 TI - Observations on home HIV testing. PMID- 26098599 TI - HIV+ patient on suppressive antiretroviral therapy with steroid injection-induced myopathy. PMID- 26098600 TI - Thrombocytopenia and risk of cancer during treated HIV disease. PMID- 26098601 TI - Thrombocytopenia and cancer risk during HIV infection. PMID- 26098602 TI - New study suggests resistance testing may not be best use of resources for HIV treatment programmes in low-income settings. PMID- 26098603 TI - Perioperative quality of life in functionally dependent glioblastoma patients: A prospective study. AB - OBJECTIVE: Functionally dependent patients with glioblastoma have a poor prognosis which may in part be due to a negative treatment selection. Prospective data on patient-reported quality of life (QoL) following surgery, together with an updated survival analysis, are lacking with regard to functionally dependent glioblastoma patients. MATERIALS AND METHODS: Adult patients (>= 18 years) with a histologically confirmed primary glioblastoma with preoperative Karnofsky Performance Status (KPS) <= 60, who were treated between January 1, 2007 and March 30, 2014, were eligible for inclusion. EuroQol 5D (EQ-5D) was scored before surgery and at 4-6 weeks postoperatively. A control group of 20 independent (i.e., KPS >= 70) adult primary glioblastoma patients was constructed. RESULTS: Among the 27 patients included, only 22 patients were willing to participate in QoL research, with complete QoL follow-up data obtained for 16. There were 22 resections and 5 biopsies. In resection cases, the median extent of resection was 93% (IQR 78-99), with gross-total resection achieved in 24%. In the 16 patients with complete QoL data, the EQ-5D index score increased from 0.34 +/- 0.38 preoperatively to 0.45 +/- 0.32 postoperatively (p = 0.30), with 3 patients that deteriorated in QoL following surgery. Median survival was 7.3 months (95%, CI: 4.6-9.9, n = 27), and the perioperative mortality was 7%. Treatment characteristics between dependent and independent patients were similar, as were the unfavorable outcomes defined as QoL reduction, QoL drop-out, and dead before QoL assessment (41% vs. 45%, p = 0.79). However, a difference was seen in 6-month survival (42% vs. 15%, p = 0.05). CONCLUSION: In most functionally dependent patients with glioblastoma, cytoreductive surgery is possible, and improved or unchanged postoperative QoL may be seen in approximately half of the cases. This must be weighed against the risk of complications and the modest effect of cytoreductive surgery. PMID- 26098604 TI - Lipomyelocele with osseous dysraphic hamartoma: A rare case report. AB - Lipomyelocele is the most common occult spinal dysraphism. However, it can rarely be associated with aberrant tissues such as bone--making it one of the rarest of spinal dysraphism type, called as "osseous dysraphic hamartoma." The authors report such a rare case of lipomyelocele with osseous dysraphic hamartoma. CT and MRI play a complimentary role in accurate diagnosis of this rare dysraphism. Detection of aberrant bone helps plan the surgery. PMID- 26098605 TI - Clinical impact of residual lateral spread response after adequate microvascular decompression for hemifacial spasm: A retrospective analysis. AB - OBJECTIVE: Residual lateral spread response (LSR) after seemingly adequate decompression for hemifacial spasms (HFSs) can provide prognostic information about the outcome of microvascular decompression (MVD). In the present study, the main objective was to evaluate the clinical and prognostic impact of residual LSR after adequate MVD for HFS. METHODS: An observational study was conducted in patients who underwent MVD for HFS at the University of Pittsburgh Medical Center between January 2000 and December 2007. Clinical and neurophysiological outcomes after pre- and post-MVD, including spasm relief, amplitude and latency of LSR, and postoperative complications were collected from groups with and without residual LSR after adequate decompression. Data analysis was performed to see the impact of residual LSR on HFS outcomes. RESULTS: There was no significant difference in preoperative clinical characteristics as well as postoperative complications between the two groups. The patient had significantly higher spasm relief in immediate postoperative period (p = 0.01) and at discharge (p = 0.002) when LSR disappeared during the procedure. There is no difference in spasm relief at follow-up period between the two groups (p = 0.69). CONCLUSION: Lateral spread is an invaluable tool in MVD for HFSs. Adequate decompression in patients with residual LSR improved long-term spasm relief. Constant communication between neurophysiologists and the surgeon might be vital to achieve adequate decompression. The amplitude of residual LSR after adequate decompression does not significantly affect the long-term spasm relief. PMID- 26098606 TI - World Health Organization grade III meningiomas. A retrospective study for outcome and prognostic factors assessment. AB - BACKGROUND: Anaplastic meningiomas are uncommon primary intracranial tumours associated with high level of recurrence and low life expectancy. Through three institutions experience, we analysed the clinical characteristics of patients with malignant meningiomas to determine their outcome and identify prognostic factors that may influence recurrence and survival. MATERIAL AND METHODS: A retrospective search identified 62 cases of WHO grade III meningiomas, of whom 9 (14.5%) were not considered in the survival analysis as no follow-up data were available. Thirty patients (48.4%) had a previous history of non-malignant meningioma surgery. The patients underwent a total of 139 surgical resections and 42 courses of radiotherapy of which 27 were given after the WHO grade III meningioma diagnosis. RESULTS: Eighteen patients (29.5%) were re-operated for a relapse of their anaplastic meningioma. Median time between the first and the second surgery was 1.3 years. Median overall survival time was 3.5 years. Overall survival probabilities at 1, 2 and 5 years were 74.6%, 95% confidence interval (CI) [63.8, 87.1], 58.7%, 95% CI [46.4, 74.3] and 37.7%, 95% CI [25, 56.8], respectively. Extent of resection was associated with the survival. DISCUSSION: This retrospective series highlights the poor prognosis associated with the diagnosis of malignant meningioma. Complete or subtotal resection may prolong the patients' survival. We could not confirm the usefulness of postoperative radiotherapy. PMID- 26098607 TI - Recurrence of meralgia paresthetica years after a neurexeresis procedure: A case report. AB - Recurrence of meralgia paresthetica after a pain-free interval following a neurexeresis or neurectomy procedure has not been reported before. We present a case of recurrence 5 years after neurexeresis of the lateral femoral cutaneous nerve. Resection of the proximal stump through a suprainguinal approach in this case again led to complete and long-lasting pain relief. PMID- 26098608 TI - Nonracemic Antifolates Stereoselectively Recruit Alternate Cofactors and Overcome Resistance in S. aureus. AB - While antifolates such as Bactrim (trimethoprim-sulfamethoxazole; TMP-SMX) continue to play an important role in treating community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA), resistance-conferring mutations, specifically F98Y of dihydrofolate reductase (DHFR), have arisen and compromise continued use. In an attempt to extend the lifetime of this important class, we have developed a class of propargyl-linked antifolates (PLAs) that exhibit potent inhibition of the enzyme and bacterial strains. Probing the role of the configuration at the single propargylic stereocenter in these inhibitors required us to develop a new approach to nonracemic 3-aryl-1-butyne building blocks by the pairwise use of asymmetric conjugate addition and aldehyde dehydration protocols. Using this new route, a series of nonracemic PLA inhibitors was prepared and shown to possess potent enzyme inhibition (IC50 values <50 nM), antibacterial effects (several with MIC values <1 MUg/mL) and to form stable ternary complexes with both wild-type and resistant mutants. Unexpectedly, crystal structures of a pair of individual enantiomers in the wild-type DHFR revealed that the single change in configuration of the stereocenter drove the selection of an alternative NADPH cofactor, with the minor alpha-anomer appearing with R-27. Remarkably, this cofactor switching becomes much more prevalent when the F98Y mutation is present. The observation of cofactor site plasticity leads to a postulate for the structural basis of TMP resistance in DHFR and also suggests design strategies that can be used to target these resistant enzymes. PMID- 26098609 TI - Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential. AB - In 2013, cancer immunotherapy was named 'breakthrough of the year' based on the outcome of clinical trials with blocking antibodies to the T-cell co-inhibitory receptors CTLA-4 and PD-1. This success has emphasized that cytotoxic T-cell responses to cancer can occur, but are limited by peripheral tolerance and by immunosuppression in the tumor microenvironment. Targeting of CTLA-4, PD-1 or its ligands partly overcomes these limitations and can now be applied in multiple immunogenic cancer types. Furthermore, an increased success rate is expected from combining CTLA-4 and/or PD-1 blocking with deliberate engagement of T-cell co stimulatory receptors, particularly TNF receptor (R) family members. The TNFR family includes CD27 (Tnfrsf7), for which an agonistic antibody has recently entered clinical trials. In this review, we describe how CD27 co-stimulation impacts the T-cell response, with the purpose to illuminate how CD27 agonism can be exploited in cancer immunotherapy. PMID- 26098610 TI - Effects of thymosin beta4 and its N-terminal fragment Ac-SDKP on TGF-beta-treated human lung fibroblasts and in the mouse model of bleomycin-induced lung fibrosis. AB - Thymosin beta4 (Tbeta4) and its amino-terminal fragment comprising N-acetyl-seryl aspartyl-lysyl-proline (Ac-SDKP) have been reported to act as anti-inflammatory and anti-fibrotic agents in vitro and in vivo. In recent papers, we have shown that Tbeta4 exerts a widely protective role in mice treated with bleomycin, and in particular, we have demonstrated its inhibitory effects on both inflammation and early fibrosis. OBJECTIVES: In this study, the putative anti-proliferative and anti-fibrogenic effects of Tbeta4 and Ac-SDKP were evaluated in vitro. In addition, the effects of Tbeta4 up to 21 days were evaluated in the bleomycin mouse model of lung fibrosis. METHODS: We utilized both control and TGF-beta stimulated primary human lung fibroblasts isolated from both idiopathic pulmonary fibrosis (IPF) and control tissues. The in vivo effects of Tbeta4 were assessed in CD1 mice treated with bleomycin. RESULTS: In the in vitro experiments, we observed significant anti-proliferative effects of Ac-SDKP in IPF fibroblasts. In those cells, Ac-SDKP significantly inhibited TGF-beta-induced alpha-SMA and collagen expression, hallmarks of fibroblast differentiation into myofibroblasts triggered by TGF-beta. In vivo, despite its previously described protective role in mice treated with bleomycin at 7 days, Tbeta4 failed to prevent fibrosis induced by the drug at 14 and 21 days. CONCLUSION: We conclude that, compared to Tbeta4, Ac-SDKP may have greater potential as an anti-fibrotic agent in the lung. Further in vivo experiments are warranted. PMID- 26098611 TI - Generalization of Wertheim's theory for the assembly of various types of rings. AB - We generalize Wertheim's first order perturbation theory to account for the effect in the thermodynamics of the self-assembly of rings characterized by two energy scales. The theory is applied to a lattice model of patchy particles and tested against Monte Carlo simulations on a fcc lattice. These particles have 2 patches of type A and 10 patches of type B, which may form bonds AA or AB that decrease the energy by epsilonAA and by epsilonAB = repsilonAA, respectively. The angle theta between the 2 A-patches on each particle is fixed at 60 degrees , 90 degrees or 120 degrees . For values of r below 1/2 and above a threshold rth(theta) the models exhibit a phase diagram with two critical points. Both theory and simulation predict that rth increases when theta decreases. We show that the mechanism that prevents phase separation for models with decreasing values of theta is related to the formation of loops containing AB bonds. Moreover, we show that by including the free energy of B-rings (loops containing one AB bond), the theory describes the trends observed in the simulation results, but that for the lowest values of theta, the theoretical description deteriorates due to the increasing number of loops containing more than one AB bond. PMID- 26098612 TI - Trismus in patients with head and neck cancer: etiopathogenesis, diagnosis and management. AB - BACKGROUND: Trismus indicates severely restricted mouth opening of any aetiology. A mouth opening of 35 mm or less should be regarded as trismus. Aim of this study was to review the etiopathogenesis, incidence, treatment and prevention of trismus in patients with head and neck cancer. OBJECTIVE OF REVIEW: Trismus is frequently seen in patients suffering from malignant tumours of the head and neck. The reported prevalence of trismus in those patients varies considerably in the literature and ranges from 0 to 100% depending on the tumour site and extension. Trismus may worsen or remain the same over time, or the symptoms may reduce, even in the absence of treatment. When a patient presents with trismus after tumour treatment, it is important to determine whether the trismus is the result of the treatment, or is the first sign of a recurrence. Restricted mouth opening may impede inspection of the oral cavity as needed for dental care, and particularly for oncologic follow-up. CONCLUSIONS: Mouth opening after radiotherapy (RT) decreases on average by approximately 20% compared to mouth opening prior to RT. The prevalence of trismus increases with increasing doses of RT to mastication structures. The use of intensity-modulated RT seems to lower the percentage and severity of RT-induced trismus. Treatment of trismus can be conservative (with either medical or physical therapy) or surgical. Exercise therapy is the mainstay of treatment and exercise should start as soon as possible after treatment. The prevention of trismus, rather than its treatment, is the most important objective. PMID- 26098613 TI - Introduction. PMID- 26098615 TI - Re: "Quantitative analysis of transcranial and intraparenchymal light penetration in human cadaver brain tissue" Lasers in Surgery and Medicine, 2015;47(4):312 322. PMID- 26098616 TI - Effectiveness of a School-Based Fitness Program on Youths' Physical and Psychosocial Health Outcomes. AB - The purpose of this study was to evaluate the impact of an existing physical fitness program (CHAMPIONS) implemented during physical education on health related indices (BMI percentile, waist circumference, cardiorespiratory endurance), self-perceptions, academic performance, and behavioral conduct over a school year. Students in 3 intervention (n = 331) and 3 control (n = 745) middle schools participated in the study that included assessments at pre, mid, and postintervention. Multivariate repeated measures analyses indicated that boys and girls in CHAMPIONS compared favorably (p < .0125) to Controls at postintervention on cardiorespiratory endurance, and boys significantly improved on BMI percentile from pre- to mid- and postintervention (p < .0125). Students in CHAMPIONS maintained healthy BMI percentile and waist circumference values over the year. Findings provide preliminary evidence that CHAMPIONS is effective in improving or maintaining physical health indices among middle school youth. PMID- 26098617 TI - Reducing unnecessary measurements in clinical trials with multiple primary endpoints. AB - Clinical trials often involve two or more primary endpoints. However, observing or measuring high-cost endpoints often reduces the efficiency of the study because of high medical costs, highly invasive measurements, or long-term follow up. Further, the individual powers to demonstrate the overall efficacy of a new intervention for the multiple endpoints often differ under a given sample size. We propose an efficient clinical trial design in which the sample size for each of the endpoints is individually determined, taking into consideration both the cost and the individual power for each endpoint. We compared the efficiency of the proposed design with that of the conventional design using three variables: (1) the number of participants in the study, (2) the total number of measurements for all endpoints, and (3) the cost of enrolling the participants and obtaining the measurements for all endpoints. We extended the proposed design to a group sequential design. Numerical examples show that the proposed design can reduce unnecessary measurements and adjust the individual powers for the endpoints, especially when the individual power for one endpoint is relatively higher than that for other endpoints in a study with multiple co-primary endpoints. PMID- 26098618 TI - Immunocytochemical Localization of Monoamine Oxidase Type B in Rat's Peripheral Nervous System. AB - Immunohistochemistry is used to investigate subcellular localization of monoamine oxidase type B (MAOB) in the axon of the rat's peripheral nervous system. Through light and electron microscopy, the presence of MAOB-immunoreactive structures in the propria lamina of tongue and on the outer membranes of mitochondria in both myelinated and unmyelinated axons can be detected. As a result, MAOB may potentially play a crucial role in the axons of the rat's peripheral nervous system and may be closely associated with both axonal transport and nerve conduction. PMID- 26098619 TI - Generalized allergic contact dermatitis caused by methylisothiazolinone in a spray tan. PMID- 26098620 TI - Urinary Incontinence Before and After Bariatric Surgery. AB - IMPORTANCE: Among women and men with severe obesity, evidence for improvement in urinary incontinence beyond the first year after bariatric surgery-induced weight loss is lacking. OBJECTIVES: To examine change in urinary incontinence before and after bariatric surgery and to identify factors associated with improvement and remission among women and men in the first 3 years after bariatric surgery. DESIGN, SETTING, AND PARTICIPANTS: The Longitudinal Assessment of Bariatric Surgery 2 is an observational cohort study at 10 US hospitals in 6 geographically diverse clinical centers. Participants were recruited between February 21, 2005, and February 17, 2009. Adults undergoing first-time bariatric surgical procedures as part of clinical care by participating surgeons between March 14, 2006, and April 24, 2009, were followed up for 3 years (through October 24, 2012). INTERVENTION: Participants undergoing bariatric surgery completed research assessments before the procedure and annually thereafter. MAIN OUTCOMES AND MEASURES: The frequency and type of urinary incontinence episodes in the past 3 months were assessed using a validated questionnaire. Prevalent urinary incontinence was defined as at least weekly urinary incontinence episodes, and remission was defined as change from prevalent urinary incontinence at baseline to less than weekly urinary incontinence episodes at follow-up. RESULTS: Of 2458 participants, 1987 (80.8%) completed baseline and follow-up assessments. At baseline, the median age was 47 years (age range, 18-78 years), the median body mass index was 46 kg/m2 (range, 34-94 kg/m2), and 1565 of 1987 (78.8%) were women. Urinary incontinence was more prevalent among women (49.3%; 95% CI, 46.9% 51.9%) than men (21.8%; 95% CI, 18.2%-26.1%) (P < .001). After a mean 1-year weight loss of 29.5% (95% CI, 29.0%-30.1%) in women and 27.0% (95% CI, 25.9% 28.6%) in men, year 1 urinary incontinence prevalence was significantly lower among women (18.3%; 95% CI, 16.4%-20.4%) and men (9.8%; 95% CI, 7.2%-13.4%) (P < .001 for all). The 3-year prevalence was higher than the 1-year prevalence for both sexes (24.8%; 95% CI, 21.8%-26.5% among women and 12.2%; 95% CI, 9.0%-16.4% among men) but was substantially lower than baseline (P < .001 for all). Weight loss was independently related to urinary incontinence remission (relative risk, 1.08; 95% CI, 1.06-1.10 in women and 1.07; 95% CI, 1.02-1.13 in men) per 5% weight loss, as were younger age and the absence of a severe walking limitation. CONCLUSIONS AND RELEVANCE: Among women and men with severe obesity, bariatric surgery was associated with substantially reduced urinary incontinence over 3 years. Improvement in urinary incontinence may be an important benefit of bariatric surgery. PMID- 26098621 TI - Association and interaction of PPARalpha, delta, and gamma gene polymorphisms with low-density lipoprotein-cholesterol in a Chinese Han population. AB - AIMS: Elevated low-density lipoprotein-cholesterol (LDL-C) is regarded as one of major risks of cardiovascular diseases and atherosclerotic events. It has been previously reported that peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. In this study, we aimed to investigate the influence of PPARalpha/delta/gamma gene polymorphisms on LDL-C level. Eight hundred twenty unrelated participants were recruited. Ten single nucleotide polymorphisms (SNPs) were genotyped to analyze the gene-gene interactions among these polymorphisms using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS: The results of single-locus analyses indicated that the genotypes with minor allele variants at the rs1800206, rs9794, rs1805192, rs709158, and rs3856806 loci are associated with higher LDL-C levels (p<0.05) after adjusting for covariates. In contrast, individuals that were homozygous for the major allele (CC) of rs10865710 had significantly higher LDL-C than those with either one or more minor type alleles (CG+GG, mean difference: -0.21 mM; 95% confidence interval [CI]: -0.37 to -0.04 mM; p=0.013). Significant gene-gene interactions among PPAR gene polymorphisms on LDL-C were identified by a generalized multifactor dimensionality reduction (GMDR) approach in 2- to 8-locus models (p<0.05). CONCLUSION: Our results provide evidence that multiple PPARalpha/delta/gamma gene polymorphisms are individually associated with increased LDL-C, and that interactions, among these alleles result in additional increased risk suggesting that PPAR genes may contribute substantially to the risk of cardiovascular diseases and atherosclerosis. PMID- 26098623 TI - Assessing multi-variable coupling effects of UV illumination, heat and oxygen on porous ZnO nanocrystalline film through electron concentration and mobility extraction. AB - Porous ZnO nanocrystalline films have been widely used in optoelectronic and gas sensing applications. However, the effect mechanisms of the external fields, such as light, heat and atmosphere, are still controversial. In this work, the multi variable coupling effects of the UV light, heat and oxygen were thoroughly studied by a newly proposed method, the central idea of which was to first isolate each effect of the fields on electron concentration and mobility, and then analyze how the coupling effects were achieved. Our results revealed the important roles of oxygen adsorption-induced interface barriers and photo assisted thermal ionization first proposed here, because of which the positive coupling effect of UV light/heat and oxygen, as well as the negative coupling effect of UV light and heat was observed. Our work provides inspiration for studies on metal oxides from both the whole idea and the detailed argument. PMID- 26098622 TI - Minimally Invasive Monitoring of Chronic Central Venous Catheter Patency in Mice Using Digital Subtraction Angiography (DSA). AB - BACKGROUND: Repetitive administration of medication or contrast agents is frequently performed in mice. The introduction of vascular access mini-ports (VAMP) for mice allows long-term vascular catheterization, hereby eliminating the need for repeated vessel puncture. With catheter occlusion being the most commonly reported complication of chronic jugular vein catheterization, we tested whether digital subtraction angiography (DSA) can be utilized to evaluate VAMP patency in mice. METHODS: Twenty-three mice underwent catheterization of the jugular vein and subcutaneous implantation of a VAMP. The VAMP was flushed every second day with 50 MUL of heparinized saline solution (25 IU/ml). DSA was performed during injection of 100 MUL of an iodine based contrast agent using an industrial X-ray inspection system intraoperatively, as well as 7+/-2 and 14+/-2 days post implantation. RESULTS: DSA allowed localization of catheter tip position, to rule out dislocation, kinking or occlusion of a microcatheter, and to evaluate parent vessel patency. In addition, we observed different ante- and retrograde collateral flow patterns in case of jugular vein occlusion. More exactly, 30% of animals showed parent vessel occlusion after 7+/-2 days in our setting. At this time point, nevertheless, all VAMPs verified intravascular contrast administration. After 14+/-2 days, intravascular contrast injection was verified in 70% of the implanted VAMPs, whereas at this point of time 5 animals had died or were sacrificed and in 2 mice parent vessel occlusion hampered intravascular contrast injection. Notably, no occlusion of the catheter itself was observed. CONCLUSION: From our observations we conclude DSA to be a fast and valuable minimally invasive tool for investigation of catheter and parent vessel patency and for anatomical studies of collateral blood flow in animals as small as mice. PMID- 26098624 TI - Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy. AB - This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype genotype analysis determines that some mutations are well correlated with LMNA related MD. PMID- 26098625 TI - A High Throughput Screening Assay for Anti-Mycobacterial Small Molecules Based on Adenylate Kinase Release as a Reporter of Cell Lysis. AB - Mycobacterium tuberculosis (Mtb) is well-established to be one of the most important bacterial pathogens for which new antimicrobial therapies are needed. Herein, we describe the development of a high throughput screening assay for the identification of molecules that are bactericidal against Mycobacteria. The assay utilizes the release of the intracellular enzyme adenylate kinase into the culture medium as a reporter of mycobacterial cell death. We demonstrate that the assay is selective for mycobactericidal molecules and detects anti-mycobacterial activity at concentrations below the minimum inhibitory concentration of many molecules. Thus, the AK assay is more sensitive than traditional growth assays. We have validated the AK assay in the HTS setting using the Mtb surrogate organism M. smegmatis and libraries of FDA approved drugs as well as a commercially available Diversity set. The screen of the FDA-approved library demonstrated that the AK assay is able to identify the vast majority of drugs with known mycobactericidal activity. Importantly, our screen of the Diversity set revealed that the increased sensitivity of the AK assay increases the ability of M. smegmatis-based screens to detect molecules with relatively poor activity against M. smegmatis but good to excellent activity against Mtb. PMID- 26098626 TI - Modified Leukocyte Filter Removes Tumor Cells from the Salvaged Blood. AB - BACKGROUND: Intraoperative blood salvage, an effective blood conservation strategy, has not been applied in onco-surgery, because of potential malignant cell contamination. In this study we tested effectiveness of a modified leukocyte depletion filter (M-LDF) for removal of tumor cells. MATERIALS AND METHODS: The effects of M-LDF and regular LDF on removal of cells (HepG2 cell line) were compared. The safety of M-LDF was tested with blood (collected and washed during onco-surgery), the salvaged blood mixed with tumor cells from the solid tumor of the same patient, or mixed with HepG2 cells (n=30 in each protocol). Cancer cells were identified by flow cytometry, culture and bioassay with and without filtration. RESULTS: M-LDF removed 5-log of HepG2 and nucleated cells, which was much higher than regular LDF, and cells were destroyed when they passed through M LDF. Cytokeratin-positive cells in all samples were removed by M-LDF. Invasive growth adherent cells were found in most of unfiltered samples and 67% of the inoculated nude mice developed tumors in LDF-treated sample. Neither adherent cells nor nude mice developed tumors were found in M-LDF-treated samples. DISCUSSION AND CONCLUSION: Since M-LDF can effectively remove and destroy cancer cells in the salvaged blood, it has great potential for clinical application. PMID- 26098627 TI - Bio-Inspired Aggregation Control of Carbon Nanotubes for Ultra-Strong Composites. AB - High performance nanocomposites require well dispersion and high alignment of the nanometer-sized components, at a high mass or volume fraction as well. However, the road towards such composite structure is severely hindered due to the easy aggregation of these nanometer-sized components. Here we demonstrate a big step to approach the ideal composite structure for carbon nanotube (CNT) where all the CNTs were highly packed, aligned, and unaggregated, with the impregnated polymers acting as interfacial adhesions and mortars to build up the composite structure. The strategy was based on a bio-inspired aggregation control to limit the CNT aggregation to be sub 20-50 nm, a dimension determined by the CNT growth. After being stretched with full structural relaxation in a multi-step way, the CNT/polymer (bismaleimide) composite yielded super-high tensile strengths up to 6.27-6.94 GPa, more than 100% higher than those of carbon fiber/epoxy composites, and toughnesses up to 117-192 MPa. We anticipate that the present study can be generalized for developing multifunctional and smart nanocomposites where all the surfaces of nanometer-sized components can take part in shear transfer of mechanical, thermal, and electrical signals. PMID- 26098628 TI - An Internet-Based Real-Time Audiovisual Link for Dual MEG Recordings. AB - HYPERSCANNING: Most neuroimaging studies of human social cognition have focused on brain activity of single subjects. More recently, "two-person neuroimaging" has been introduced, with simultaneous recordings of brain signals from two subjects involved in social interaction. These simultaneous "hyperscanning" recordings have already been carried out with a spectrum of neuroimaging modalities, such as functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and functional near-infrared spectroscopy (fNIRS). DUAL MEG SETUP: We have recently developed a setup for simultaneous magnetoencephalographic (MEG) recordings of two subjects that communicate in real time over an audio link between two geographically separated MEG laboratories. Here we present an extended version of the setup, where we have added a video connection and replaced the telephone-landline-based link with an Internet connection. Our setup enabled transmission of video and audio streams between the sites with a one-way communication latency of about 130 ms. Our software that allows reproducing the setup is publicly available. VALIDATION: We demonstrate that the audiovisual Internet-based link can mediate real-time interaction between two subjects who try to mirror each others' hand movements that they can see via the video link. All the nine pairs were able to synchronize their behavior. In addition to the video, we captured the subjects' movements with accelerometers attached to their index fingers; we determined from these signals that the average synchronization accuracy was 215 ms. In one subject pair we demonstrate inter-subject coherence patterns of the MEG signals that peak over the sensorimotor areas contralateral to the hand used in the task. PMID- 26098629 TI - An Exercise-Based Program for Veterans with Substance Use Disorders: Formative Research. AB - Substance use disorders (SUDs) are prevalent among veteran populations. Adjunctive treatments for SUDs are warranted for many reasons, including high relapse rates. Physical exercise has broad health benefits as well as mood enhancing, anxiolytic, and withdrawal-reducing effects, but veterans with SUDs report low rates of regular exercise. Evaluating exercise-based interventions that incorporate evidence-based behavior change strategies tailored to meet the unique needs of veterans with SUDs is warranted. This article describes the formative research conducted to evaluate the following information among veterans receiving treatment for SUDs: (1) interest in an adjunctive exercise program to supplement their current SUD treatment; and (2) exercise program design considerations. A survey and small group interviews were conducted to obtain both quantitative and qualitative data. Results suggested that veterans with SUDs are interested in exercise, and participants provided perceptive suggestions for modifying an existing evidence-based program. These findings will be used to design an exercise-based treatment program tailored specifically for veterans with SUDs. PMID- 26098630 TI - A Novel Protein Interaction between Nucleotide Binding Domain of Hsp70 and p53 Motif. AB - Currently, protein interaction of Homo sapiens nucleotide binding domain (NBD) of heat shock 70 kDa protein (PDB: 1HJO) with p53 motif remains to be elucidated. The NBD-p53 motif complex enhances the p53 stabilization, thereby increasing the tumor suppression activity in cancer treatment. Therefore, we identified the interaction between NBD and p53 using STRING version 9.1 program. Then, we modeled the three-dimensional structure of p53 motif through homology modeling and determined the binding affinity and stability of NBD-p53 motif complex structure via molecular docking and dynamics (MD) simulation. Human DNA binding domain of p53 motif (SCMGGMNR) retrieved from UniProt (UniProtKB: P04637) was docked with the NBD protein, using the Autodock version 4.2 program. The binding energy and intermolecular energy for the NBD-p53 motif complex were -0.44 Kcal/mol and -9.90 Kcal/mol, respectively. Moreover, RMSD, RMSF, hydrogen bonds, salt bridge, and secondary structure analyses revealed that the NBD protein had a strong bond with p53 motif and the protein-ligand complex was stable. Thus, the current data would be highly encouraging for designing Hsp70 structure based drug in cancer therapy. PMID- 26098631 TI - 24-Month-Olds' Selective Learning Is Not an All-or-None Phenomenon. AB - Evidence that children maintain some memories of labels that are unlikely to be shared by the broader linguistic community suggests that children's selective learning is not an all-or-none phenomenon. Across three experiments, we examine the contexts in which 24-month-olds show selective learning and whether they adjust their selective learning if provided with cues of in-context relevance. In each experiment, toddlers were first familiarized with a source who acted on familiar objects in either typical or atypical ways (e.g., used a car to mimic driving or hop like a rabbit) or labeled familiar objects incorrectly (e.g., called a spoon a "brush"). The source then labeled unfamiliar objects using either a novel word (e.g., fep; Experiment 1) or sound (e.g., ring; Experiments 2 and 3). Results indicated that toddlers learnt words from the typical source but not from the atypical or inaccurate source. In contrast, toddlers extended sound labels only when a source who had previously acted atypically provided the sound labels. Thus, toddlers, like preschoolers, avoid forming semantic representations of new object labels that are unlikely to be relevant in the broader community, but will form event-based memories of such labels if they have reason to suspect such labels will have in-context relevance. PMID- 26098632 TI - Serum CD121a (Interleukin 1 Receptor, Type I): A Potential Novel Inflammatory Marker for Coronary Heart Disease. AB - Inflammation is now believed to be responsible for coronary heart disease (CHD). This belief has stimulated the evaluation of various inflammatory markers for predicting CHD. This study was designed to investigate the association between four inflammatory cytokines (CD121a, interleukin [IL]-1beta, IL-8, and IL-11) and CHD. Here, we evaluated 443 patients with CHD and 160 CHD-free controls who underwent coronary angiography. Cytokines were evaluated using flow cytometry, and statistical analyses were performed to investigate the association between cytokine levels and the risk of CHD. Patients with CHD had significantly higher levels of CD121a. The odds ratios for CHD according to increasing CD121a quartiles were 1.00, 1.47 [95% confidence interval (CI): 0.79-2.72], 2.67 (95% CI: 1.47-4.84), and 4.71 (95% CI: 2.65-8.37) in an age- and sex-adjusted model, compared to 1.00, 1.48 (95% CI: 0.70-3.14), 2.25 (95% CI: 1.10-4.62), and 4.39 (95% CI: 2.19-8.79) in a model that was adjusted for multiple covariates. A comparison of the stable angina, unstable angina, and acute myocardial infarction (AMI) subgroups revealed that patients with AMI had the highest CD121a levels, although IL-1beta levels were similar across all groups. IL-8 levels were also increased in AMI patients, and IL-11 levels were higher in CHD patients than in non-CHD patients. Correlation analysis revealed a positive association between CD121a, IL-8, and the Gensini score. Together, the significant increase in CD121a levels among CHD patients suggests that it may be a novel inflammatory marker for predicting CHD. PMID- 26098633 TI - MeCP2 Affects Skeletal Muscle Growth and Morphology through Non Cell-Autonomous Mechanisms. AB - Rett syndrome (RTT) is an autism spectrum disorder mainly caused by mutations in the X-linked MECP2 gene and affecting roughly 1 out of 10.000 born girls. Symptoms range in severity and include stereotypical movement, lack of spoken language, seizures, ataxia and severe intellectual disability. Notably, muscle tone is generally abnormal in RTT girls and women and the Mecp2-null mouse model constitutively reflects this disease feature. We hypothesized that MeCP2 in muscle might physiologically contribute to its development and/or homeostasis, and conversely its defects in RTT might alter the tissue integrity or function. We show here that a disorganized architecture, with hypotrophic fibres and tissue fibrosis, characterizes skeletal muscles retrieved from Mecp2-null mice. Alterations of the IGF-1/Akt/mTOR pathway accompany the muscle phenotype. A conditional mouse model selectively depleted of Mecp2 in skeletal muscles is characterized by healthy muscles that are morphologically and molecularly indistinguishable from those of wild-type mice raising the possibility that hypotonia in RTT is mainly, if not exclusively, mediated by non-cell autonomous effects. Our results suggest that defects in paracrine/endocrine signaling and, in particular, in the GH/IGF axis appear as the major cause of the observed muscular defects. Remarkably, this is the first study describing the selective deletion of Mecp2 outside the brain. Similar future studies will permit to unambiguously define the direct impact of MeCP2 on tissue dysfunctions. PMID- 26098634 TI - Association of Lp-PLA2 Mass and Aysmptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients. AB - BACKGROUND AND PURPOSE: Intracranial arterial stenosis (ICAS) is a common cause of ischemic stroke in Asians, whereas whites tend to have more extracranial lesions. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been associated with ischemic stroke by a large amount of work. However, there are few studies focusing on the relationship of Lp-PLA2 and asymptomatic ICAS or extracranial arterial stenosis (ECAS). Wehereby sought to explore the relationship of Lp-PLA2 and ICAS, ECAS and concurrent stenosis in stroke-free hypertensive patients in Chinese population. METHODS: All the subjects were evaluated for the presence and severity of ICAS and ECAS through computerized tomographic angiography (CTA) covered the whole brain down to the level of aortic arch. Lp-PLA2 mass was measured by enzyme linked immunoassay. The association of Lp-PLA2 and vascular stenosis was analyzed through multivariate logistic regression. RESULTS: Among 414 participants, 163 (39.4%) had no ICAS or ECAS, 63 (15.2%) had ECAS only, 111 (26.8%) had ICAS only and 77 (18.6%) had concurrent extraintracranial stenosis. Lp-PLA2 mass was significantly associated with isolated ICAS (OR: 2.3; 95% CI: 1.14-4.64), and concurrent stenosis (OR: 3.93; 95% CI: 1.62-9.51), but was not related to isolated ECAS (OR: 1.54; 95% CI: 0.68-3.48). Lp-PLA2 mass was also associated with moderate to severe ICAS no matter how was the ECAS. Moreover, patients with higher Lp-PLA2 mass showed more sever ICAS and had more intracranial arterial lesions. CONCLUSION: This study revealed the association of Lp-PLA2 mass with ICAS in stroke-free hypertensive patients in Chinese population. The further long-term cohort study was warranted to elucidate the concrete effect of Lp-PLA2 on the asymptomatic ICAS. PMID- 26098635 TI - Self-Expandable Metal Stents for Persisting Esophageal Variceal Bleeding after Band Ligation or Injection-Therapy: A Retrospective Study. AB - BACKGROUND AND STUDY AIMS: Despite a pronounced reduction of lethality rates due to upper gastrointestinal bleeding, esophageal variceal bleeding remains a challenge for the endoscopist and still accounts for a mortality rate of up to 40% within the first 6 weeks. A relevant proportion of patients with esophageal variceal bleeding remains refractory to standard therapy, thus making a call for additional tools to achieve hemostasis. Self-expandable metal stents (SEMS) incorporate such a tool. METHODS: We evaluated a total number of 582 patients admitted to our endoscopy unit with the diagnosis "gastrointestinal bleeding" according to our documentation software between 2011 and 2014. 82 patients suffered from esophageal variceal bleeding, out of which 11 cases were refractory to standard therapy leading to SEMS application. Patients with esophageal malignancy, fistula, or stricture and a non-esophageal variceal bleeding source were excluded from the analysis. A retrospective analysis reporting a series of clinically relevant parameters in combination with bleeding control rates and adverse events was performed. RESULTS: The initial bleeding control rate after SEMS application was 100%. Despite this success, we observed a 27% mortality rate within the first 42 days. All of these patients died due to non-directly hemorrhage-associated reasons. The majority of patients exhibited an extensive demand of medical care with prolonged hospital stay. Common complications were hepatic decompensation, pulmonary infection and decline of renal function. Interestingly, we found in 7 out of 11 patients (63.6%) stent dislocation at time of control endoscopy 24 h after hemostasis or at time of stent removal. The presence of hiatal hernia did not affect obviously stent dislocation rates. Refractory patients had significantly longer hospitalization times compared to non-refractory patients. CONCLUSIONS: Self-expandable metal stents for esophageal variceal bleeding seem to be safe and efficient after failed standard therapy. Stent migration appeared to be a common incident that did not lead to reactivation of bleeding in any of our patients. SEMS should be considered a reasonable treatment option for refractory esophageal variceal bleeding after treatment failure of ligature and sclerotherapy and non-availability of or contraindication for other measures (e.g. TIPS). PMID- 26098636 TI - High-performance aqueous/organic dye-sensitized solar cells based on sensitizers containing triethylene oxide methyl ether. AB - Metal-free dyes (EO1 to EO4) containing the hydrophilic triethylene oxide methyl ether (TEOME) unit in the spacer have been synthesized and used in dye-sensitized solar cells (DSSCs). Efficient lithium-ion trapping by TEOME results in improved open-circuit voltage (VOC ), leading to excellent conversion efficiency of the cells, ranging from 9.02 to 9.98 % with I(-) /I3 (-) electrolyte in acetonitrile under AM 1.5 illumination. The TEOME unit also enhances the wettability of the dye molecules for application in aqueous-based DSSCs. Aqueous-based DSSCs with a dual TEMPO/iodide electrolyte exhibit high VOC values (0.80-0.88 V) and very promising cell performances of up to 5.97 %. PMID- 26098637 TI - Interference of Overlapping Insect Vibratory Communication Signals: An Eushistus heros Model. AB - Plants limit the range of insect substrate-borne vibratory communication by their architecture and mechanical properties that change transmitted signal time, amplitude and frequency characteristics. Stinkbugs gain higher signal-to-noise ratio and increase communication distance by emitting narrowband low frequency vibratory signals that are tuned with transmission properties of plants. The objective of the present study was to investigate hitherto overlooked consequences of duetting with mutually overlapped narrowband vibratory signals. The overlapped vibrations of the model stinkbug species Eushistus heros, produced naturally or induced artificially on different plants, have been analysed. They represent female and male strategies to preserve information within a complex masked signal. The brown stinkbugs E. heros communicate with species and gender specific vibratory signals that constitute characteristic duets in the calling, courtship and rivalry phases of mating behaviour. The calling female pulse overlaps the male vibratory response when the latency of the latter is shorter than the duration of the female triggering signal or when the male response does not inhibit the following female pulse. Overlapping of signals induces interference that changes their amplitude pattern to a sequence of regularly repeated pulses in which their duration and the difference between frequencies of overlapped vibrations are related inversely. Interference does not occur in overlapped narrow band female calling pulses and broadband male courtship pulse trains. In a duet with overlapped signals females and males change time parameters and increase the frequency difference between signals by changing the frequency level and frequency modulation pattern of their calls. PMID- 26098638 TI - Tennis Play Intensity Distribution and Relation with Aerobic Fitness in Competitive Players. AB - The aims of this study were (i) to describe the relative intensity of simulated tennis play based on the cumulative time spent in three metabolic intensity zones, and (ii) to determine the relationships between this play intensity distribution and the aerobic fitness of a group of competitive players. 20 male players of advanced to elite level (ITN) performed an incremental on-court specific endurance tennis test to exhaustion to determine maximal oxygen uptake (VO2max) and the first and second ventilatory thresholds (VT1, VT2). Ventilatory and gas exchange parameters were monitored using a telemetric portable gas analyser (K4 b2, Cosmed, Rome, Italy). Two weeks later the participants played a simulated tennis set against an opponent of similar level. Intensity zones (1: low, 2: moderate, and 3: high) were delimited by the individual VO2 values corresponding to VT1 and VT2, and expressed as percentage of maximum VO2 and heart rate. When expressed relative to VO2max, percentage of playing time in zone 1 (77 +/- 25%) was significantly higher (p < 0.001) than in zone 2 (20 +/- 21%) and zone 3 (3 +/- 5%). Moderate to high positive correlations were found between VT1, VT2 and VO2max, and the percentage of playing time spent in zone 1 (r = 0.68 0.75), as well as low to high inverse correlations between the metabolic variables and the percentage of time spent in zone 2 and 3 (r = -0.49-0.75). Players with better aerobic fitness play at relatively lower intensities. We conclude that players spent more than 75% of the time in their low-intensity zone, with less than 25% of the time spent at moderate to high intensities. Aerobic fitness appears to determine the metabolic intensity that players can sustain throughout the game. PMID- 26098639 TI - Antioxidant Activity of Caffeic Acid against Iron-Induced Free Radical Generation -A Chemical Approach. AB - Caffeic acid (CA) is a phenolic compound widely found in coffee beans with known beneficial effects in vivo. Many studies showed that CA has anti-inflammatory, anti-mutagenic, antibacterial and anti-carcinogenic properties, which could be linked to its antioxidant activity. Taking in consideration the reported in vitro antioxidant mechanism of other polyphenols, our working hypothesis was that the CA antioxidant activity could be related to its metal-chelating property. With that in mind, we sought to investigate the chemical antioxidant mechanism of CA against in vitro iron-induced oxidative damage under different assay conditions. CA was able to prevent hydroxyl radical formation promoted by the classical Fenton reaction, as determined by 2-deoxyribose (2-DR) oxidative degradation and DMPO hydroxylation. In addition to its ability to prevent hydroxyl radical formation, CA had a great inhibition of membrane lipid peroxidation. In the lipid peroxidation assays CA acted as both metal-chelator and as hydrogen donor, preventing the deleterious action promoted by lipid-derived peroxyl and alkoxyl radicals. Our results indicate that the observed antioxidant effects were mostly due to the formation of iron-CA complexes, which are able to prevent 2-DR oxidation and DMPO hydroxylation. Noteworthy, the formation of iron-CA complexes and prevention of oxidative damage was directly related to the pH of the medium, showing better antioxidant activity at higher pH values. Moreover, in the presence of lipid membranes the antioxidant potency of CA was much higher, indicating its enhanced effectiveness in a hydrophobic environment. Overall, our results show that CA acts as an antioxidant through an iron chelating mechanism, preventing the formation of free hydroxyl radicals and, therefore, inhibiting Fenton-induced oxidative damage. The chemical properties of CA described here--in association with its reported signaling effects--could be an explanation to its beneficial effects observed in vivo. PMID- 26098640 TI - Changing from whole-cell to acellular pertussis vaccines would trade superior tolerability for inferior protection. AB - Notifications of infant deaths, assumed to be related to the introduction of new pentavalent DTwP-Hib-HBV childhood vaccines, caused, during 2008-2010 in few Asian countries, temporary interruptions of the respective vaccination programs. The sudden appearance of fatal cases was due to increased awareness/publicity and improved safety monitoring/reporting in countries with relatively high background infant mortalities. WHO investigations could not establish any causal relationships and vaccinations were again resumed. Recently, questions were raised in one concerned country as to why not to change to less reactogenic acellular pertussis (aP)-containing vaccines that are available in private practice and are generally perceived as 'better'. For resource-poor countries, the financial impacts render such a switch impossible and would also not be supported by external funding. Furthermore, it would be a disservice to the children, as in recent years evidence of inferior long-term efficacy of aP vaccines has accumulated. This report summarizes current knowledge on comparative whole-cell pertussis (wP) and aP vaccine performance, outlines the new July 2014 WHO guidance on the choice of pertussis vaccines and presents recent data on outbreak protection, antibody waning, long-term protection, wP-priming, pathogen adaptation, transmission and herd immunity. PMID- 26098641 TI - Matured Hop Bittering Components Induce Thermogenesis in Brown Adipose Tissue via Sympathetic Nerve Activity. AB - Obesity is the principal symptom of metabolic syndrome, which refers to a group of risk factors that increase the likelihood of atherosclerosis. In recent decades there has been a sharp rise in the incidence of obesity throughout the developed world. Iso-alpha-acids, the bitter compounds derived from hops in beer, have been shown to prevent diet-induced obesity by increasing lipid oxidation in the liver and inhibition of lipid absorption from the intestine. Whereas the sharp bitterness induced by effective dose of iso-alpha-acids precludes their acceptance as a nutrient, matured hop bittering components (MHB) appear to be more agreeable. Therefore, we tested MHB for an effect on ameliorating diet induced body fat accumulation in rodents. MHB ingestion had a beneficial effect but, compared to iso-alpha-acids and despite containing structurally similar compounds, acted via different mechanisms to reduce body fat accumulation. MHB supplementation significantly reduced body weight gain, epididymal white adipose tissue weight, and plasma non-esterified free fatty acid levels in diet-induced obese mice. We also found that uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) was significantly increased in MHB-fed mice at both the mRNA and protein levels. In addition, MHB administration in rats induced the beta adrenergic signaling cascade, which is related to cAMP accumulation in BAT, suggesting that MHB could modulate sympathetic nerve activity innervating BAT (BAT-SNA). Indeed, single oral administration of MHB elevated BAT-SNA in rats, and this elevation was dissipated by subdiaphragmatic vagotomy. Single oral administration of MHB maintained BAT temperature at a significantly higher level than in control rats. Taken together, these findings indicate that MHB ameliorates diet-induced body fat accumulation, at least partly, by enhancing thermogenesis in BAT via BAT-SNA activation. Our data suggests that MHB is a useful tool for developing functional foods or beverages to counteract the accumulation of body fat. PMID- 26098642 TI - The Possible Mechanism of Idiosyncratic Lapatinib-Induced Liver Injury in Patients Carrying Human Leukocyte Antigen-DRB1*07:01. AB - Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the beta chain helix in the HLA-DRB1*07:01 specifically to form a tightly closed binding groove structure and modify a large part of the binding groove. These results indicate that lapatinib affects the ligand binding to HLA-DRB1*07:01 and idiosyncratic lapatinib-induced liver injury might be triggered by this mechanism. This is the first report showing that the clinically available drug can enhance the binding of ligand peptide to HLA class II molecules in vitro and in silico. PMID- 26098643 TI - Correction: Transcriptional Dynamics of Immortalized Human Mesenchymal Stem Cells during Transformation. PMID- 26098644 TI - Higher Serum Angiotensinogen Is an Indicator of IgA Vasculitis with Nephritis Revealed by Comparative Proteomes Analysis. AB - IgA vasculitis (IgAV), previously named as Henoch-Schonlein purpura, is the most common systematic vasculitis with unknown etiology. Lack of appropriate study system and/or animal model limits the understanding of its molecular pathogenesis and hinders the identification of targets for rational therapy, especially for its long-term complication, IgAV nephritis (IgAVN). In this study, we applied comparative analysis of serum proteomes to obtain an insight about disease pathogenesis. This study has utilized high sensitivity nanoscale ultra performance liquid chromatography-mass spectrometry (nanoLC-MS/MS) to investigate the alterations in serum proteomic profiles in patients with IgAV (n=6), IgAVN (n=6) and healthy subjects (n=7). The differentially expressed proteins were subjected to functional pathway analysis by PANTHER and DAVID software. We identified 107 differentially expressed proteins among three different groups, and functional analysis suggested that, in addition to earlier reported pathways, such as acute phase response, immune response, complement and blood coagulation pathways, hemostasis and Wnt signaling pathway were probably involved in pathogenesis of IgAV. A few differentially abundant proteins identified, such as C4a, serum amyloid A, angiotensinogen, and kininogen 1, were further validated by ELISA. More importantly, we found that angiotensinogen concentration is correlated with IgAVN and could be used as a potential marker for the progression of IgAV. This is the first report of analyzing the proteomic alterations in IgAV patients and the differentially proteins identified in this study may enhance understanding of the pathology of IgAV and a few of them may be used to monitor disease progression. PMID- 26098645 TI - Novel Photoresponsive Linear, Graft, and Comb-Like Copolymers with Azobenzene Chromophores in the Main-Chain and/or Side-Chain: Facile One-Pot Synthesis and Photoresponse Properties. AB - Novel photoresponsive linear, graft, and comb-like copolymers with azobenzene chromophores in the main-chain and/or side-chain are prepared via a sequential ring-opening metathesis polymerization (ROMP) and head-to-tail acyclic diene metathesis (ADMET) polymerization in a one-pot procedure using Grubbs ruthenium based catalysts. The diluted solutions of these as-prepared copolymers containing azobenzene chromophores exhibit photochemical trans-cis isomerization under the irradiation of UV light, followed by their cis-trans back-isomerization in visible light. The rates of photoisomerization are found to be slower than those of back-isomerization, and the rate for the comb-like copolymer is found to be from 3 to 7 times slower than that obtained for the linear or graft copolymer. This is ascribed to the differences in structure of the copolymers and the specific location of azobenzene chromophores in the copolymer, which favor a side chain graft structure. PMID- 26098646 TI - Metabolomic analyses reveal that anti-aging metabolites are depleted by palmitate but increased by oleate in vivo. AB - Recently, we reported that saturated and unsaturated fatty acids trigger autophagy through distinct signal transduction pathways. Saturated fatty acids like palmitate (PA) induce autophagic responses that rely on phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3, best known as VPS34) and beclin 1 (BECN1). Conversely, unsaturated fatty acids like oleate (OL) promote non canonical, PIK3C3- and BECN1-independent autophagy. Here, we explored the metabolic effects of autophagy-inducing doses of PA and OL in mice. Mass spectrometry coupled to principal component analysis revealed that PA and OL induce well distinguishable changes in circulating metabolites as well as in the metabolic profile of the liver, heart, and skeletal muscle. Importantly, PA (but not OL) causes the depletion of multiple autophagy-inhibitory amino acids in the liver. Conversely, OL (but not PA) increased the hepatic levels of nicotinamide adenine dinucleotide (NAD), an obligate co-factor for autophagy-stimulatory enzymes of the sirtuin family. Moreover, PA (but not OL) raised the concentrations of acyl-carnitines in the heart, a phenomenon that perhaps is linked to its cardiotoxicity. PA also depleted the liver from spermine and spermidine, 2 polyamines have been ascribed with lifespan-extending activity. The metabolic changes imposed by unsaturated and saturated fatty acids may contribute to their health-promoting and health-deteriorating effects, respectively. PMID- 26098648 TI - [Diagnostic significance of protein NMP22 in bladder cancer]. AB - Bladder cancer is a malignancy that affects mainly the elderly and males. Up to 90% of these cancers originate from urothelial epithelial cells and therefore they are called Transitional (Urothelial) Cell Carcinoma (TCC). Another types are: Squamous Cell Carcionoma (SCC), which involves about 5% of cases and Adenocarcinoma (less than 2%). The factors that may lead to the development of bladder cancer include: genetic disorders, molecular changes, environmental exposures, industrial carcinogens, chemical contaminants and chronic cystitis. This article depicts the current state of diagnostics of bladder cancer, with particular focus on urine-based tests. Although many markers with different structure are under research, only the following have gained FDA approval for bladder cancer screening: BTAstat, BTA TRAK, UroVysion and NMP22 BladderChek. For follow-up NMP22 ELISA and Immunocyt (uCyt+) are approved. This work is mainly focused on mainly on evaluating the diagnostic value of nuclear matrix protein NMP22 for bladder cancer in terms of the outlined researches among people susceptible to environmental toxins. A review of the current literature depicts that no research on correlation between NMP22 and genetic susceptibility has been conducted so far. There is some evidence that NMP22 protein is particularly important in high-risk groups, e.g. among tobacco smokers. The work also describes the methods of detecting NMP22 protein and factors that may influence the results. The review of current literature showed that NMP22 cannot replace invasive cystoscopy neither in screening for bladder cancer nor in follow-up. The NMP22 test could be useful for determining the frequency of cystoscopy and for early detection of high-grade tumors. Research focused on improving the specificity of this marker seems to be crucial, e.g. through the correlation between NMP22 and other parameters (e.g. other laboratory tests), which is confirmed by preliminary data about combining various markers. PMID- 26098647 TI - Broken-Symmetry DFT Computations for the Reaction Pathway of IspH, an Iron-Sulfur Enzyme in Pathogenic Bacteria. AB - The recently discovered methylerythritol phosphate (MEP) pathway provides new targets for the development of antibacterial and antimalarial drugs. In the final step of the MEP pathway, the [4Fe-4S] IspH protein catalyzes the 2e(-)/2H(+) reductive dehydroxylation of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) to afford the isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Recent experiments have attempted to elucidate the IspH catalytic mechanism to drive inhibitor development. Two competing mechanisms have recently emerged, differentiated by their proposed HMBPP binding modes upon 1e(-) reduction of the [4Fe-4S] cluster: (1) a Birch reduction mechanism, in which HMBPP remains bound to the [4Fe-4S] cluster through its terminal C4-OH group (ROH-bound) until the -OH is cleaved as water; and (2) an organometallic mechanism, in which the C4-OH group rotates away from the [4Fe 4S] cluster, allowing the HMBPP olefin group to form a metallacycle complex with the apical iron (eta(2)-bound). We perform broken-symmetry density functional theory computations to assess the energies and reduction potentials associated with the ROH- and eta(2)-bound states implicated by these competing mechanisms. Reduction potentials obtained for ROH-bound states are more negative (-1.4 to 1.0 V) than what is typically expected of [4Fe-4S] ferredoxin proteins. Instead, we find that eta(2)-bound states are lower in energy than ROH-bound states when the [4Fe-4S] cluster is 1e(-) reduced. Furthermore, eta(2)-bound states can already be generated in the oxidized state, yielding reduction potentials of ca. 700 mV when electron addition occurs after rotation of the HMBPP C4-OH group. We demonstrate that such eta(2)-bound states are kinetically accessible both when the IspH [4Fe-4S] cluster is oxidized and 1e(-) reduced. The energetically preferred pathway gives 1e(-) reduction of the cluster after substrate conformational change, generating the 1e(-) reduced intermediate proposed in the organometallic mechanism. PMID- 26098649 TI - [Emotional regulation in aspect of action vs. state orientation, stress and self injurious behavior among people with borderline personality disorder]. AB - In the bordeline personality disorder a large role ascribe to biopsychosocial factors. Studies have shown that more than 70% patients BPD reported experiencing traumatic events in childhood. The findings are confirming that making self harming is a frequent symptom of bordeline disorder and 70-75% patients show at least one act of self-harming. Selfharming can be a reaction to maladaptive emotional regulation. Moreover a lowered tolerance level is characteristic of them to the stress and determined course learning dysfunctional patterns of behavior. AIM: The aim of this study is to determine the level of emotional regulation through the variable action vs state orientation and to investigate their relation to stress, self-harming and suicidal behavior. MATERIALS AND METHODS: In study participated 45 persons with emotionally unstable borderline personality diagnosis. In the group was 33 women and 12 men in age 19-43. A Polish adaptation of standardized questionnaires was used to measure stress and action vs state orientation (SSI-K), self-injurious behavior (SHI) and suicidal tendencies (RFL-I). RESULTS: By patients with borderline personality disorder the level of action control, reasons for living and stress are predictors of selfharming behavior. The mediation analyze showed, that stress and reasons for living are mediators between action vs. state control and the level of self harming behavior. CONCLUSIONS: A high level of stress correlates positively with self-harming and negatively with action control in patients with borderline personality disorder, and a high level of reasons for living correlates positively with action control and negatively with self-harming in people with BPD. PMID- 26098650 TI - [Social awareness related to the rights of the patient and knowledge of the possible actions in case of a breach of those under 30 years old]. AB - Patients' rights are a special case of broadly defined human rights. They specify what patient can expect during treatment process and determine his status in contacts with the healthcare system. AIM: The aim of this study was to investigate the awareness of patients' rights and knowledge of possible proceedings in case of violation of them among people under 30 years of age. MATERIALS AND METHODS: The research was conducted in February and March 2014 on a group of 269 respondents. Research tool was an author-made questionnaire. RESULTS: More than half of respondents (54.6%) had never heard about patients' rights. Among rights, that respondents know the best were: the right to health benefits (58.2%), the right to information (39.3%), the right to consent to health services (33.6%) and the right to the secrecy of information associated with the patient (32%). More than half of respondents declared that they would report a violation of their rights to appropriate institution - 49.2% of respondents indicated the Commissioner for Patients' Rights, 14.8% the National Health Fund, 11.5% Ministry of Health. The study showed also that the main source of acquiring knowledge about patients' rights for the study population is the internet. CONCLUSIONS: Analysis of the results showed that the awareness of the patients' rights and knowledge of possible proceedings for violation of them among the study population is low. PMID- 26098651 TI - [The characteristics of sexual offenders abusing alcohol in view of forensic psychiatric assessments]. AB - The relationship between alcohol consumption and sexual crime appears to be unquestionable. However, the mechanisms that lead to violence and aggression under the influence of alcohol are not entirely understood in this group of offenders. AIM: The aim of this paper was to attempt answering the question: what are the features characterizing sexual offenders declaring alcohol abuse. MATERIALS AND METHODS: The research material consisted of 180 forensic psychiatric- sexology assessments issued by experts from Outpatient Psychiatric Clinic in 10 Military Hospital Clinic in Bydgoszcz between 2004 to 2012. A specially designed questionnaire titled "Charter of Diagnosis of Factors Determining Criminal Sexual Activity" has been used. RESULTS: Relevant statistical dependences were observed. CONCLUSIONS: The obtained results show that, a alcohol abuse has a sexual criminogenic effect especially in the coincidence that there are sustainable personality abnormalities and organic CNS damage. The conducted study prove that the sexual perpetrators who abuse alcohol have a poor level of social functioning and brought up in dysfunction families having alcoholic problems. PMID- 26098652 TI - [The relation of selected psychiatric disorders to occurrence of suicide attempts among teenage psychiatrically hospitalized patients]. AB - Suicide is the third cause of death globally in the age group 10-19. Multiple risk factors (genetic, psychiatric, psychological, familial, social) increased number of suicide attempts. AIM: The aim of this study was to explore whether mental disorders are associated with the number of suicide attempts among psychiatric hospitalized adolescents. MATERIALS AND METHODS: Retrospective, chart based analysis of 119 patients, aged 13-18, treated in 2013-2014 in the Department of Adolescent Psychiatry in Lodz. Inclusion criteria was diagnosis of schizophrenia, schizotypal and delusional disorders, mood disorders, neurotic, stress-related and somatoform disorders, behavioral and emotional disorders according to ICD 10. Exclusion criteria were other psychiatric diagnosis, incomplete information about intention of self-harm behaviors. For statistical analysis used Statistica 9.1. RESULTS: Among psychiatricaly hospitalized patients, 51.2% of people attempted suicide. No relationship was found (p > 0.05) between psychiatric diagnosis and frequency of suicide attempts in adolescents, but the most common suicide attempts related to people with a diagnosis of mood disorders (59.3%) and neurotic disorders (54.6%), and least frequently in patients with a diagnosis of schizophrenia , schizotypal and delusional disorders (40%) and behavioral and emotional disorders (44.4%). CONCLUSIONS: There is no relation between the occurrence of suicide attempts and the type of mental disorders among psychiatrically hospitalized adolescents. PMID- 26098653 TI - [Unusual clinical picture of Meckel's diverticulum intussusception in 19-year-old man - a case report]. AB - Meckel diverticulum is the most common congenital defect of samll intestine. In most cases it remains asymptomatic, however in some patients it may be the cause of many nonspecific signs and symptoms. In this paper we would like to present a case of intestinal obstruction caused by Meckel diverticulum intussusception in the ileum in 19- year-old patient. The patient complaint of dull abdominal pain which have been subsiding for hours and vomiting. Results of laboratory test were within normal limits. Abdomian X-ray suggested mechanic obstruction of small intestine. Patient was qualified for urgent surgery. During the operation intussusception of 10 cm of small intestine was found. The leading point of intussusception was long Meckel diverticulum with single, small connection with omentum. The authors wish to note that in the differential diagnosis of non specific, recurrent pain and mechanical small bowel obstruction, regardless of age, the presence of Meckel diverticulum should always be taken into consideration. PMID- 26098654 TI - [Bilateral external auditory canal cholesteatoma - a case report]. AB - The external auditory canal cholesteatoma is a rare and difficult to diagnose disease. Symptoms are similar to the external ear canal inflammation and can be masked by retained cerumen. In the article we described a case of 22 year old, mentally impairment women with bilateral otorrhea, in the past treated for external ear canal inflammation. The otoscopic examination showed bilateral congenital auditory canal stenosis, with masses obstructing ear canals. Imaging and histopathologic studies revealed bilateral external ear canal cholesteatoma. The patient was qualified for surgery, which, together with a guardian, did not consent. Presented case indicates the necessity for widening the diagnostic of recurrent external ear canal inflammation. PMID- 26098655 TI - [Pituitary apoplexy - not always correctly recognized life-threatening entity]. AB - Pituitary apoplexy is a life-threatening circumstance developing as a result of ischemia or hemorrhage into pre-existing pituitary tumor. Frequency of this condition is hard to be precisely estimated. Clinical course is characteristic and commonly consists of severe headache accompanied by nausea, vomiting, impaired consciousness, visual field impairment as well as eyeballs movement restriction. Symptoms are typically accompanied by secondary adrenal insufficiency. Severe course of pituitary apoplexy requires hospitalization and immediate medical treatment. Corticosteroids are drugs of choice regarding coexisting adrenal insufficiency. In case of a lack of expected both general and neurological improvement during conservative treatment, a surgery might be necessary. Prognosis in case of a proper treatment is good. Every patient after pituitary apople. PMID- 26098656 TI - [Gestational diabetes in the light of current literature]. AB - This paper presents current data on the pathophysiology of gestational diabetes mellitus, classification and new diagnostic methods. Gestational Diabetes Mellitus (GDM) is defined as carbohydrate intolerance first detected during pregnancy. It is the most common metabolic disorder of pregnant women. The frequency of its occurrence depends on inter alia body weight, belonging to a particular ethnic group and diagnostic methods. GDM reveals usually between 24 and 28 weeks of gestation. The development of diabetes in pregnancy poses a threat to both the mother and the fetus. It is associated with an increased incidence of birth defects in newborns, impaired intrauterine fetal growth, higher incidence of premature births and greater percentage of the intrauterine fetus death. Amongst women complicated by gestational diabetes arterial hypertension more often unfolds. In the development of gestational diabetes mellitus important role apart from maternal and fetal hyperinsulinemia play: antagonistic to insulin placental hormones, TNFalpha, placental pro-inflammatory cytokines, resistin, leptin ghrelin. PMID- 26098657 TI - Significance of selenium in thyroid physiology and pathology. AB - Selenium is pivotal element in maintaining homeostasis of human body. It is capable of exerting an influence on immunological responses, cell growth and viral defence. Nevertheless, it is mostly required for the proper thyroid function. There were described 25 selenoproteins, which play various roles in human body. Selenium is an essential particle in the active site of enzymes such as GPXs (glutathione peroxidases), Ds (deiodinases) and TRs (thioredoxin reductases). Owing to this, it has a fundamental importance in the synthesis and function of thyroid hormones, and protects cells against free radicals and oxidative damage. Intake of selenium necessary to maintain suitable selenoenzyme activity ranges from 60 MUg to 75 MUg per day. Selenium deficiency contributes to decreased activity of GPXs, which can lead to oxidative damage, or Ds, which is connected with impaired thyroid activity. Moreover, a low selenium concentration causes autoimmune processes in the thyroid gland, thus selenium deficiency is essential in pathogenesis of autoimmune thyroiditis or Graves' disease. Because of regulation of the cell cycle, a decreased concentration of selenium impacts on the development of thyroid cancer. PMID- 26098658 TI - [Gout - from pathogenesis to treatment - progress in the XXI century]. AB - Gout has recently become the most common arthritis in developed countries. However studies indicate that treatment of gout is still insufficient. New discoveries including the role of inflammasome, inflammatory cytokines ( Il1beta, IL-8,TNF-alpha), but also identification of the URAT -1 transporter or genetic mutation of SLC2A9 has given better understanding of the pathophysiology of gout and enable to use new therapies. New options in treatment significantly reduced the number of patients resistant to existing procedures, and created opportunities for a better individualization of the treatment. In this authors article in a practical way try to summary knowledge about the pathogenesis of the disease and the current guidelines for the diagnosis, the treatment of non pharmacological and pharmacological treatment. PMID- 26098659 TI - [Medical simulation as a professional tool which affect the safety of the patient used in the learning process]. AB - Simulation is the methodology of teaching, learning process using educational equipment from simple simulators, designed to study individual tasks, through advanced mannequins called human patient stimulators faithfully mimic the human and its parameters. The medical simulation's main task is education and improvement patients' safety. Advanced human simulators can realistically cough, vomit with artificial chyme and bleed with artificial blood causing a real stress of medical personnel and the need for immediate action. Medical simulation gives the opportunity to prepare medical personnel to the profession more effectively, in less time than traditional education and also clearly affects the patients' safety. PMID- 26098660 TI - Copper-Catalyzed Synthesis of 2-Arylquinazolinones from 2-Arylindoles with Amines or Ammoniums. AB - A novel copper-catalyzed synthesis of quinazolinones from easily available 2 arylindoles and amines or ammoniums has been developed, which provided various quinazolinones in up to 99% yields for 43 examples. This strategy features tolerance of a wide range of functional groups, easily available starting materials, simple operation, mild reaction conditions, and environmental friendliness. PMID- 26098661 TI - Monitoring the Stability of Perfluorocarbon Nanoemulsions by Cryo-TEM Image Analysis and Dynamic Light Scattering. AB - Perfluorocarbon nanoemulsions (PFC-NE) are disperse systems consisting of nanoscale liquid perfluorocarbon droplets stabilized by an emulsifier, usually phospholipids. Perfluorocarbons are chemically inert and non-toxic substances that are exhaled after in vivo administration. The manufacture of PFC-NE can be done in large scales by means of high pressure homogenization or microfluidization. Originally investigated as oxygen carriers for cases of severe blood loss, their application nowadays is more focused on using them as marker agents in 19F Magnetic Resonance Imaging (19F MRI). 19F is scarce in organisms and thus PFC-NE are a promising tool for highly specific and non-invasive imaging of inflammation via 19F MRI. Neutrophils, monocytes and macrophages phagocytize PFC-NE and subsequently migrate to inflamed tissues. This technique has proven feasibility in numerous disease models in mice, rabbits and mini pigs. The translation to clinical trials in human needs the development of a stable nanoemulsion whose droplet size is well characterized over a long storage time. Usually dynamic light scattering (DLS) is applied as the standard method for determining particle sizes in the nanometer range. Our study uses a second method, analysis of transmission electron microscopy images of cryo-fixed samples (Cryo-TEM), to evaluate stability of PFC-NE in comparison to DLS. Four nanoemulsions of different composition are observed for one year. The results indicate that DLS alone cannot reveal the changes in particle size, but can even mislead to a positive estimation of stability. The combination with Cryo-TEM images gives more insight in the particulate evolution, both techniques supporting one another. The study is one further step in the development of analytical tools for the evaluation of a clinically applicable perfluorooctylbromide nanoemulsion. PMID- 26098662 TI - Role of Subunit Exchange and Electrostatic Interactions on the Chaperone Activity of Mycobacterium leprae HSP18. AB - Mycobacterium leprae HSP18, a major immunodominant antigen of M. leprae pathogen, is a small heat shock protein. Previously, we reported that HSP18 is a molecular chaperone that prevents aggregation of different chemically and thermally stressed client proteins and assists refolding of denatured enzyme at normal temperature. We also demonstrated that it can efficiently prevent the thermal killing of E. coli at higher temperature. However, molecular mechanism behind the chaperone function of HSP18 is still unclear. Therefore, we studied the structure and chaperone function of HSP18 at normal temperature (25 degrees C) as well as at higher temperatures (31-43 degrees C). Our study revealed that the chaperone function of HSP18 is enhanced significantly with increasing temperature. Far- and near-UV CD experiments suggested that its secondary and tertiary structure remain intact in this temperature range (25-43 degrees C). Besides, temperature has no effect on the static oligomeric size of this protein. Subunit exchange study demonstrated that subunits of HSP18 exchange at 25 degrees C with a rate constant of 0.018 min(-1). Both rate of subunit exchange and chaperone activity of HSP18 is found to increase with rise in temperature. However, the surface hydrophobicity of HSP18 decreases markedly upon heating and has no correlation with its chaperone function in this temperature range. Furthermore, we observed that HSP18 exhibits diminished chaperone function in the presence of NaCl at 25 degrees C. At elevated temperatures, weakening of interactions between HSP18 and stressed client proteins in the presence of NaCl results in greater reduction of its chaperone function. The oligomeric size, rate of subunit exchange and structural stability of HSP18 were also found to decrease when electrostatic interactions were weakened. These results clearly indicated that subunit exchange and electrostatic interactions play a major role in the chaperone function of HSP18. PMID- 26098663 TI - Antitumor and Adjuvant Activity of lambda-carrageenan by Stimulating Immune Response in Cancer Immunotherapy. AB - lambda-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of lambda-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of lambda-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4(+)CD8(+) T lymphocytes in spleen. In addition, lambda carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-alpha in tumor, most of which was secreted by infiltrating macrophages. Moreover, lambda-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that lambda-carrageenan was with a good safety profile. Thus, lambda-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy. PMID- 26098664 TI - Getting Everyone to Buckle Up on Every Trip: What More Can Be Done? PMID- 26098666 TI - Correction to: J Neurotrauma 2011;28(3):383-400. PMID- 26098665 TI - Prognostic Value of Circulating Tumor Cells in Ovarian Cancer: A Meta-Analysis. AB - BACKGROUND: The prognostic value of circulating tumor cells (CTCs) in ovarian cancer has been investigated in previous studies, but the results are controversial. Therefore we performed a meta-analysis to systematically review these data and evaluate the value of CTCs in ovarian cancer. MATERIALS AND METHODS: A literary search for relevant studies was performed on Embase, Medline and Web of Science databases. Then pooled hazard ratios (HRs) for survival with 95% confidence intervals (CIs), subgroup analyses, sensitivity analyses, meta regression analyses and publication bias were conducted. RESULTS: This meta analysis is based on 11 publications and comprises a total of 1129 patients. The prognostic value of the CTC status was significant in overall survival (OS) (HR, 1.61;95% CI,1.22-2.13) and progression-free survival (PFS)/disease-free survival (DFS) (HR, 1.44; 95%CI, 1.18-1.75). Furthermore, subgroup analysis revealed that the value of CTC status in OS was significant in "RT-PCR" subgroup (HR, 2.02; 95% CI, 1.34-3.03), whereas it was not significant in "CellSearch" subgroup (HR, 1.15; 95% CI 0.45-2.92) and "other ICC" subgroup (HR, 1.09; 95% CI 0.62-1.90). The presence of CTC was also associated with an increased CA-125 (OR, 4.07; 95%CI, 1.87-8.85). CONCLUSION: Our study demonstrates that CTC status is associated with OS and PFS/DFS in ovarian cancer. PMID- 26098668 TI - Magnetic and dendritic catalysts. AB - The recovery and reuse of catalysts is a major challenge in the development of sustainable chemical processes. Two methods at the frontier between homogeneous and heterogeneous catalysis have recently emerged for addressing this problem: loading the catalyst onto a dendrimer or onto a magnetic nanoparticle. In this Account, we describe representative examples of these two methods, primarily from our research group, and compare them. We then describe new chemistry that combines the benefits of these two methods of catalysis. Classic dendritic catalysis has involved either attaching the catalyst covalently at the branch termini or within the dendrimer core. We have used chelating pyridyltriazole ligands to insolubilize catalysts at the termini of dendrimers, providing an efficient, recyclable heterogeneous catalysts. With the addition of dendritic unimolecular micelles olefin metathesis reactions catalyzed by commercial Grubbs type ruthenium-benzylidene complexes in water required unusually low amounts of catalyst. When such dendritic micelles include intradendritic ligands, both the micellar effect and ligand acceleration promote faster catalysis in water. With these types of catalysts, we could carry out azide alkyne cycloaddition ("click") chemistry with only ppm amounts of CuSO4.5H2O and sodium ascorbate under ambient conditions. Alternatively we can attach catalysts to the surface of superparamagnetic iron oxide nanoparticles (SPIONs), essentially magnetite (Fe3O4) or maghemite (gamma-Fe2O3), offering the opportunity to recover the catalysts using magnets. Taking advantage of the merits of both of these strategies, we and others have developed a new generation of recyclable catalysts: dendritic magnetically recoverable catalysts. In particular, some of our catalysts with a gamma-Fe2O3@SiO2 core and 1,2,3-triazole tethers and loaded with Pd nanoparticles generate strong positive dendritic effects with respect to ligand loading, catalyst loading, catalytic activity and recyclability. In other words, the dendritic catalysts were more efficient and more stable than their nondendritic gamma-Fe2O3@SiO2 analogues. The bulk at the dendritic periphery helps to localize the metal nanoparticles at the SPION core surface, which confers these advantages. We could also use sonification as a remarkably simple and efficient method to impregnate the SPIONs with dendrimer-encapsulated PdNPs. Catalysis within the hydrophobic dendrimer pockets that include ligands leads to rapid turnover with or without a gamma-Fe2O3@SiO2 core. In addition, catalytically active metal nanoparticles are more robust when they are loaded onto the surface of a gamma-Fe2O3@SiO2 dendritic core. Herein, we illustrate this chemistry with examples including olefin metathesis, click chemistry, cross carbon-carbon bond forming reactions, and selective alcohol oxidation. PMID- 26098667 TI - Topical nasal steroids for treating nasal polyposis in people with cystic fibrosis. AB - BACKGROUND: Nasal polyps frequently occur in people with cystic fibrosis. Sinus infections have been shown to be a factor in the development of serious chest complications in these people. Nasal polyps have been linked to a higher risk of lower respiratory tract infections with Pseudomonas aeruginosa . Topical nasal steroids are of proven efficacy for treating nasal polyposis in the non-cystic fibrosis population. There is no clear current evidence for the efficacy of topical steroids for nasal polyps in people with cystic fibrosis. This is an updated version of a previously published review. OBJECTIVES: To assess the effectiveness of topical nasal steroids for treating symptomatic nasal polyps in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Latest search: 10 June 2015. SELECTION CRITERIA: Randomised and quasi-randomised controlled comparing the effects of topical nasal steroids to placebo in people with nasal polyps with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias in the included trial and extracted data. MAIN RESULTS: One single-centred trial (46 participants) was identified comparing a topical steroid (betamethasone) given as nasal drops to placebo. Treatment was given twice daily for six weeks; 22 participants received the active drug.Subjective symptom scores, change in polyp size, and side effects were assessed. There was no difference in nasal symptom scores between the treatment and placebo groups. Betamethasone was effective in reducing the size of polyps, but was associated with increased reports of mild side effects, nasal bleeding and discomfort.Risk of bias was high since over 50% of people enrolled did not complete the study. Follow-up of participants was short (six weeks) also reducing the significance of the results for clinical practice. AUTHORS' CONCLUSIONS: This review suggests topical steroids for nasal polyposis in people with cystic fibrosis have no demonstrable effect on subjective nasal symptom scores. They have some effect in reducing the size of the polyps, but due to the small sample size, poor completion rates and lack of follow-up, the trial is at high risk of bias and evidence for efficacy is limited. Overall there is no clear evidence for using topical steroids in people with cystic fibrosis and nasal polyposis.A well designed randomised controlled trial of adequate power and long-term follow-up is needed. Validated measures of symptoms and physical findings should be performed and quality of life issues addressed. PMID- 26098669 TI - Do You Need to Use a Collar After a 2-level Instrumented ACDF? PMID- 26098670 TI - Acute Spinal Cord Injury. AB - Our understanding of the pathophysiological processes that comprise the early secondary phases of spinal cord injury such as spinal cord ischemia, cellular excitotoxicity, ionic dysregulation, and free-radical mediated peroxidation is far greater now than ever before, thanks to substantial laboratory research efforts. These discoveries are now being translated into the clinical realm and have led to targeted upfront medical management with a focus on tissue oxygenation and perfusion and include avoidance of hypotension, induction of hypertension, early transfer to specialized centers, and close monitoring in a critical care setting. There is also active exploration of neuroprotective and neuroregenerative agents; a number of which are currently in late stage clinical trials including minocycline, riluzole, AC-105, SUN13837, and Cethrin. Furthermore, new data have emerged demonstrating that the timing of spinal cord decompression after injury impacts recovery and that early decompression leads to significant improvements in neurological recovery. With this review we aim to provide a concise, clinically relevant and up-to-date summary of the topic of acute spinal cord injury, highlighting recent advancements and areas where further study is needed. PMID- 26098672 TI - Partial conversion of current collectors into nickel copper oxide electrode materials for high-performance energy storage devices. AB - A novel substrate sacrifice process is proposed and developed for converting part of a current collector into supercapacitor active materials, which provides a new route in achieving high energy density of supercapacitor device. Part of a copper foam current collector is successfully converted into highly porous nickel copper oxide electrode for light- and high-performance supercapacitors. Remarkably, this strategy circumvents the problem associated with poor contact interface between electrode and current collector. Meanwhile, the overall weight of the supercapacitor could be minimized. The charge transfer kinetics is improved while the advantage of the excellent mechanical properties of metal current collector is not traded off. By virtue of this unique current collector self-involved architecture, the material derived from the current collector manifests large areal capacitance of 3.13 F cm(-2) at a current density of 1 A g(-1). The capacitance can retain 2.97 F cm(-2) at a much higher density (4 A g(-1)). Only a small decay of 6.5% appears at 4 A g(-1) after 1600 cycles. The strategy reported here sheds light on new strategies in making additional use of the metal current collector. Furthermore, asymmetric supercapacitor using both solid-state gel electrolyte and liquid counterpart are obtained and analyzed. The liquid asymmetric supercapacitor can deliver a high energy density up to 0.5 mWh cm(-2) (53 Wh kg(-1)) at a power density of 13 mW cm(-2) (1.4 kW kg(-1)). PMID- 26098671 TI - Risk stratification systems for surgically treated localized primary Gastrointestinal Stromal Tumors (GIST). Review of literature and comparison of the three prognostic criteria: MSKCC Nomogramm, NIH-Fletcher and AFIP-Miettinen. AB - PURPOSE: The discovery of Imatinib mesylate (Gleevec(r)) has revolutionized the treatment of GIST, increasing diseasefree survival (DFS) after complete surgical resection of a primary localized GIST and extending overall survival in metastatic disease. The definition of an accurate prognostic system is critical for the therapeutic decision making process. In literature, there are three main prognostic criteria F/NIH consensus, AFIP standards and modified NIH standards. In recent years were added various risk identification methods applying mathematical calculation model, including MSKCC risk nomogram, Rossi nomogram and Joensuu high Hotline Dengjun. Despite all these attempts, it seems that the recurrence risk probability still cannot be predicted accurately. The aim of our study was to assess and compare the real ability of these prognostic instruments in our single-centre clinical experience, and to define if the use of the MSKCC nomogram can bring benefits in the therapeutic decision. METHODS: All data regarding 37 GIST, who underwent surgical resection from 1996 to 2011 in our institution were retrospectively reviewed. We selected only primary GIST without metastatic disease who underwent a radical resection (R0) but no other therapy. The literature data concerning GISTs prognostication criteria were reviewed. All patients were classified according to the three prognostic criteria (NIH, AFIP and Nomogram MSKCC) and the three instruments were compared with the Kaplan-Meier method. Then we compared the three criteria for their c-index value and we assessed the performance of the nomogram with the calibration test. RESULTS: We observed 9 recurrences (24%) with an average time to relapse of 43 months; the median follow-up was 65 months. In the study selected sample occurred 5 relapses. The probability of relapsing after radical surgery was 7.9% (95% CI 0 - 17.3) at 2 years and 13.3% at 5 years (95% CI 0 - 26.4). The C-Index of the three risk assessment tools was 0.93 (95% CI 0.83-1) for the Nomogram at 5 years, 0.86 (95% CI 0.76-0.95) for the NIH risk criteria and 0.88 (95% CI 0.74-1) for the AFIP risk criteria. The calibration analysis of the nomogram showed an overestimating trend both at 2 and 5 years. CONCLUSION: MSKCC nomogram seems to perform better than NIH, NIH modified and AFIP in our sample and can be used in clinical practice to predict the risk of recurrence, being especially helpful for the therapeutic decision making since it is at the same time simple to use and accurate. As showed from calibration, MSKCC doesn't seem to neglect relapses, even though it is not impeccable in predicting the RFS. Among the 2 older criteria AFIP was more precise than NIH, but considering size in not linear way represented a limit in comparison with the MSKCC Nomogram. All the three risk assessement tools criteria con sidered are capable to predict recurrence in high risk GISTs while they performed worse in those with lower risk. MSKCC nomogram main limit remains the not linear consideration of mitotic count. PMID- 26098673 TI - Procurement and Supply Management System for MDR-TB in Nigeria: Are the Early Warning Targets for Drug Stock Outs and Over Stock of Drugs Being Achieved? AB - BACKGROUND: The World Health Organisation (WHO) introduced the twelve early warning indicators for monitoring and evaluating drug Procurement and Supply management (PSM) systems, intended to prevent drug stock-outs and overstocking. Nigeria--one of the high Multi Drug Resistant Tuberculosis (MDR-TB) burden countries, scaled-up treatment in 2012 with the concurrent implementation of a PSM system. METHOD: We evaluated how well this system functioned using the WHO indicators, including all seven MDR-TB treatment centres in the country that were functional throughout 2013. RESULTS: The quantity of MDR-TB drugs ordered for 2013 matched the annual forecast and all central orders placed during the year were delivered in full and on time. Drug consumption was 81%-106% of the quantity allocated for routine consumption. Timely submission of complete inventory reports ranged from 86-100%, late submissions being 5-15 days late. Forty to 71% of treatment centres placed a drug order when stock was below the minimum level of three months. The proportion of drug orders received at the treatment centres in full and on time ranged from 29-80%, late orders being 1-19 days late. CONCLUSION: The PSM was found to be performing well in terms of forecasting and procurement of MDR-TB drugs, but there were shortcomings in drug distribution, reporting at treatment centre level and in drug order placements. Despite these gaps, there were no stock outs. These findings indicate that where it matters most, namely ensuring that no drug stock outs affect patient management, the PSM system is effective. Addressing the observed shortcomings will help to strengthen the existing PSM system in anticipation of a growing MDR-TB case burden in the country. PMID- 26098674 TI - Entrepreneurial Regions: Do Macro-Psychological Cultural Characteristics of Regions Help Solve the "Knowledge Paradox" of Economics? AB - In recent years, modern economies have shifted away from being based on physical capital and towards being based on new knowledge (e.g., new ideas and inventions). Consequently, contemporary economic theorizing and key public policies have been based on the assumption that resources for generating knowledge (e.g., education, diversity of industries) are essential for regional economic vitality. However, policy makers and scholars have discovered that, contrary to expectations, the mere presence of, and investments in, new knowledge does not guarantee a high level of regional economic performance (e.g., high entrepreneurship rates). To date, this "knowledge paradox" has resisted resolution. We take an interdisciplinary perspective to offer a new explanation, hypothesizing that "hidden" regional culture differences serve as a crucial factor that is missing from conventional economic analyses and public policy strategies. Focusing on entrepreneurial activity, we hypothesize that the statistical relation between knowledge resources and entrepreneurial vitality (i.e., high entrepreneurship rates) in a region will depend on "hidden" regional differences in entrepreneurial culture. To capture such "hidden" regional differences, we derive measures of entrepreneurship-prone culture from two large personality datasets from the United States (N = 935,858) and Great Britain (N = 417,217). In both countries, the findings were consistent with the knowledge culture-interaction hypothesis. A series of nine additional robustness checks underscored the robustness of these results. Naturally, these purely correlational findings cannot provide direct evidence for causal processes, but the results nonetheless yield a remarkably consistent and robust picture in the two countries. In doing so, the findings raise the idea of regional culture serving as a new causal candidate, potentially driving the knowledge paradox; such an explanation would be consistent with research on the psychological characteristics of entrepreneurs. PMID- 26098675 TI - Isolation of Vaginal Lactobacilli and Characterization of Anti-Candida Activity. AB - Healthy vaginal microbiota is dominated by Lactobacillus spp., which form a critical line of defence against pathogens, including Candida spp. The present study aims to identify vaginal lactobacilli exerting in vitro activity against Candida spp. and to characterize their antifungal mechanisms of action. Lactobacillus strains were isolated from vaginal swabs of healthy premenopausal women. The isolates were taxonomically identified to species level (L. crispatus B1-BC8, L. gasseri BC9-BC14 and L. vaginalis BC15-BC17) by sequencing the 16S rRNA genes. All strains produced hydrogen peroxide and lactate. Fungistatic and fungicidal activities against C. albicans, C. glabrata, C. krusei, C. tropicalis, C. parapsilosis and C. lusitaniae were evaluated by broth micro-dilution method. The broadest spectrum of activity was observed for L. crispatus BC1, BC4, BC5 and L. vaginalis BC15, demonstrating fungicidal activity against all isolates of C. albicans and C. lusitaniae. Metabolic profiles of lactobacilli supernatants were studied by 1H-NMR analysis. Metabolome was found to be correlated with both taxonomy and activity score. Exclusion, competition and displacement experiments were carried out to investigate the interference exerted by lactobacilli toward the yeast adhesion to HeLa cells. Most Lactobacillus strains significantly reduced C. albicans adhesion through all mechanisms. In particular, L. crispatus BC2, L. gasseri BC10 and L. gasseri BC11 appeared to be the most active strains in reducing pathogen adhesion, as their effects were mediated by both cells and supernatants. Inhibition of histone deacetylases was hypothesised to support the antifungal activity of vaginal lactobacilli. Our results are prerequisites for the development of new therapeutic agents based on probiotics for prophylaxis and adjuvant therapy of Candida infection. PMID- 26098677 TI - Ultralow-power non-volatile memory cells based on P(VDF-TrFE) ferroelectric-gate CMOS silicon nanowire channel field-effect transistors. AB - Nanowire-based ferroelectric-complementary metal-oxide-semiconductor (NW FeCMOS) nonvolatile memory devices were successfully fabricated by utilizing single n- and p-type Si nanowire ferroelectric-gate field effect transistors (NW FeFETs) as individual memory cells. In addition to having the advantages of single channel n and p-type Si NW FeFET memory, Si NW FeCMOS memory devices exhibit a direct readout voltage and ultralow power consumption. The reading state power consumption of this device is less than 0.1 pW, which is more than 10(5) times lower than the ON-state power consumption of single-channel ferroelectric memory. This result implies that Si NW FeCMOS memory devices are well suited for use in non-volatile memory chips in modern portable electronic devices, especially where low power consumption is critical for energy conservation and long-term use. PMID- 26098676 TI - Sudden Death in Patients With Cardiac Implantable Electronic Devices. AB - IMPORTANCE: Interrogations and autopsies of sudden deaths with cardiac implantable electronic devices (CIEDs) are rarely performed. Therefore, causes of sudden deaths with these devices and the incidence of device failure are unknown. OBJECTIVE: To determine causes of death in individuals with CIEDs in a prospective autopsy study of all sudden deaths over 35 months as part of the San Francisco, California, Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD) study. DESIGN, SETTING, AND PARTICIPANTS: Full autopsy, toxicology, histology, and device interrogation were performed on incident sudden cardiac deaths with pacemakers or implantable cardioverter defibrillators (ICDs). The setting was the Office of the Chief Medical Examiner, City and County of San Francisco. Participants included all sudden deaths captured through active surveillance of all deaths reported to the medical examiner and San Francisco residents with an ICD (January 1, 2011, to November 30, 2013). MAIN OUTCOMES AND MEASURES: Identification of a device concern in sudden deaths with CIEDs, including hardware failures, device algorithm issues, device programming issues, and improper device selection. For the ICD population, outcomes were the cumulative incidence of death and sudden cardiac death and the proportion of deaths with an ICD concern. RESULTS: Twenty-two of 517 sudden deaths (4.3%) had CIEDs, and autopsy revealed a noncardiac cause of death in 6. Six of 14 pacemaker sudden deaths and 7 of 8 ICD sudden deaths died of ventricular tachycardia or ventricular fibrillation. Device concerns were identified in half (4 pacemakers and 7 ICDs), including 3 hardware failures contributing directly to death (1 rapid battery depletion with a sudden drop in pacing output and 2 lead fractures), 5 ICDs with ventricular fibrillation undersensing, 1 ICD with ventricular tachycardia missed due to programming, 1 improper device selection, and a pacemaker-dependent patient with pneumonia and concern about lead fracture. Of 712 San Francisco residents with an ICD during the study period, 109 died (15.3% cumulative 35-month incidence of death), and the 7 ICD concerns represent 6.4% of all ICD deaths. CONCLUSIONS AND RELEVANCE: Systematic interrogation and autopsy of sudden deaths in one city identified concerns about CIED function that might otherwise not have been observed. Current passive surveillance efforts may underestimate device malfunction. These methods can provide unbiased data regarding causes of sudden death in individuals with CIEDs and improve surveillance for CIED problems. PMID- 26098678 TI - Synthesis and characterization of manganese triple-decker complexes. AB - The use of the highly sterically demanding Cp(BIG) ligand (Cp(BIG) = C5(4 nBuC6H4)5) and white phosphorus (P4) enables the synthesis of new P-rich derivatives of the rare Pn ligand complexes of manganese. The obtained complexes, [{Cp(BIG)Mn}2(MU,eta(5:5)-P5)] (2) and [{Cp(BIG)Mn}2(MU,eta(2:2)-P2)2] (3), exhibit the highest number of P atoms in this class of manganese compounds identified by X-ray structure analyses. The EPR spectrum of the 29 VE triple decker complex 2 shows one unpaired electron coupling with two 5/2 spin Mn nuclei. PMID- 26098679 TI - Structural analysis of leader peptide binding enables leader-free cyanobactin processing. AB - Regioselective modification of amino acids within the context of a peptide is common to a number of biosynthetic pathways, and many of the resulting products have potential as therapeutics. The ATP-dependent enzyme LynD heterocyclizes multiple cysteine residues to thiazolines within a peptide substrate. The enzyme requires the substrate to have a conserved N-terminal leader for full activity. Catalysis is almost insensitive to immediately flanking residues in the substrate, suggesting that recognition occurs distant from the active site. Nucleotide and peptide substrate co-complex structures of LynD reveal that the substrate leader peptide binds to and extends the beta-sheet of a conserved domain of LynD, whereas catalysis is accomplished in another conserved domain. The spatial segregation of catalysis from recognition combines seemingly contradictory properties of regioselectivity and promiscuity, and it appears to be a conserved strategy in other peptide-modifying enzymes. A variant of LynD that efficiently processes substrates without a leader peptide has been engineered. PMID- 26098680 TI - 5-Formylcytosine can be a stable DNA modification in mammals. AB - 5-Formylcytosine (5fC) is a rare base found in mammalian DNA and thought to be involved in active DNA demethylation. Here, we show that developmental dynamics of 5fC levels in mouse DNA differ from those of 5-hydroxymethylcytosine (5hmC), and using stable isotope labeling in vivo, we show that 5fC can be a stable DNA modification. These results suggest that 5fC has functional roles in DNA that go beyond being a demethylation intermediate. PMID- 26098681 TI - Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir. AB - Several anti-influenza drugs that reduce disease manifestation exist, and although these drugs provide clinical benefits in infected patients, their efficacy is limited by the emergence of drug-resistant influenza viruses. In the current study, we assessed the therapeutic strategy of enhancing the antiviral efficacy of an existing neuraminidase inhibitor, oseltamivir, by coadministering with the leaf extract from Hedera helix L, commonly known as ivy. Ivy extract has anti-inflammatory, antibacterial, antifungal, and antihelminthic properties. In the present study, we investigated its potential antiviral properties against influenza A/PR/8 (PR8) virus in a mouse model with suboptimal oseltamivir that mimics a poor clinical response to antiviral drug treatment. Suboptimal oseltamivir resulted in insufficient protection against PR8 infection. Oral administration of ivy extract with suboptimal oseltamivir increased the antiviral activity of oseltamivir. Ivy extract and its compounds, particularly hedrasaponin F, significantly reduced the cytopathic effect in PR8-infected A549 cells in the presence of oseltamivir. Compared with oseltamivir treatment alone, coadministration of the fraction of ivy extract that contained the highest proportion of hedrasaponin F with oseltamivir decreased pulmonary inflammation in PR8-infected mice. Inflammatory cytokines and chemokines, including tumor necrosis factor-alpha and chemokine (C-C motif) ligand 2, were reduced by treatment with oseltamivir and the fraction of ivy extract. Analysis of inflammatory cell infiltration in the bronchial alveolar of PR8-infected mice revealed that CD11b+Ly6G+ and CD11b+Ly6Cint cells were recruited after virus infection; coadministration of the ivy extract fraction with oseltamivir reduced infiltration of these inflammatory cells. In a model of suboptimal oseltamivir treatment, coadministration of ivy extract fraction that includes hedrasaponin F increased protection against PR8 infection that could be explained by its antiviral and anti-inflammatory activities. PMID- 26098682 TI - Selectivity of pyoverdine recognition by the FpvA receptor of Pseudomonas aeruginosa from molecular dynamics simulations. AB - The Gram-negative bacterium Pseudomonas aeruginosa, a ubiquitous human opportunistic pathogen, has developed resistances to multiple antibiotics. It uses its primary native siderophore, pyoverdine, to scavenge the iron essential to its growth in the outside medium and transport it back into its cytoplasm. The FpvA receptor on the bacterial outer membrane recognizes and internalizes pyoverdine bearing its iron payload, but can also bind pyoverdines from other Pseudomonads or synthetic analogues. Pyoverdine derivatives could therefore be used as vectors to deliver antibiotics into the bacterium. In this study, we use molecular dynamics and free energy calculations to characterize the mechanisms and thermodynamics of the recognition of the native pyoverdines of P. aeruginosa and P. fluorescens by FpvA. Based on these results, we delineate the features that pyoverdines with high affinity for FpvA should possess. In particular, we show that (i) the dynamics and interaction of the unbound pyoverdines with water should be optimized with equal care as the interface contacts in the complex with FpvA; (ii) the C-terminal extremity of the pyoverdine chain, which appears to play no role in the bound complex, is involved in the intermediate stages of recognition; and (iii) the length and cyclicity of the pyoverdine chain can be used to fine-tune the kinetics of the recognition mechanism. PMID- 26098684 TI - Diagnostic efficacy of 3-D hysterosalpingo-contrast sonography in the detection of tubal occlusion: Systematic meta-analysis. AB - AIM: Evaluation of tubal status is critical in the diagnostic work-up of infertile women. The purpose of this study was to explore the diagnostic efficacy of three-dimensional hysterosalpingo-contrast sonography (3-D HyCoSy) for tubal occlusion. METHODS: MedLine, Embase, Cochrane Library, ScienceDirect, CNKI, Chinese VIP Database, Chinese Wanfang Database and Chinese Biomedicine Database were searched for relevant trials published from June 1994 to August 2013. Meta DiSc (version 1.4) was used for the meta-analysis. Diagnostic accuracy was determined by pooled estimates of sensitivity and specificity, as well as area under the curve (AUC) and the pooled diagnostic accuracy (Q*) derived from a summary receiver operating characteristic analysis. The heterogeneity test was done using the Cochran Q statistic and the I(2) statistic. Significant difference was defined as P < 0.10 (Q-statistic) or I(2) > 50% (I(2) -statistic) and a random effect model was used to pool data, otherwise the fixed effects model was used. RESULTS: A total of 11 studies (1037 Fallopian tubes) were included in this meta-analysis. The pooled estimates for diagnostic efficacy of 3-D HyCoSy had a sensitivity of 0.92 (95%CI: 0.89-0.94) and specificity of 0.95 (95%CI: 0.93 0.96). AUC and Q* were 0.976 and 0.929, respectively, but there was significant heterogeneity in sensitivity across the included studies. CONCLUSIONS: 3-D HyCoSy had good diagnostic performance in the detection of tubal occlusion. PMID- 26098683 TI - In vitro Anti-Tumor Effects of Statins on Head and Neck Squamous Cell Carcinoma: A Systematic Review. AB - BACKGROUND: Statins are commonly used against arteriosclerotic disease, but recent retrospective analyses have suggested that statins also prevent cancer. The aim of this systematic review is to verify the vitro anti-tumor effects of statins on head and neck squamous cell carcinoma. METHODS: Studies were gathered by searching Cochrane, MEDLINE, EMBASE, LILACS, and PubMed, up until May 9, 2015, with no time or language restrictions. Only in vitro studies that discuss the effect of statins on head and neck carcinoma were selected. RESULTS: Of 153 identified papers, 14 studies met the inclusion criteria. These studies demonstrated that statins had a significant effect on head and neck squamous cell carcinoma cell lines and influenced cell viability, cell cycle, cell death, and protein expression levels involved in pathways of carcinogenesis, which corroborates with the potential in vitro anti-tumor effects. It provides highlights about the biological mechanisms of statins used alone or associated with traditional therapy for cancer. CONCLUSIONS: Though there are few studies on the topic, currently available evidence suggests that statins shows that preclinical experiments supports the potentiality of statin as an adjuvant agent in chemotherapy and/or radiotherapy approaches routinely used in the management of HNSCC and should undergo further clinical assessment. PMID- 26098685 TI - Childhood hyperactivity/inattention and eating disturbances predict binge eating in adolescence. AB - BACKGROUND: Identifying childhood predictors of binge eating and understanding risk mechanisms could help improve prevention and detection efforts. The aim of this study was to examine whether features of attention-deficit/hyperactivity disorder (ADHD), as well as childhood eating disturbances, predicted binge eating later in adolescence. METHOD: We studied specific risk factors for the development of binge eating during mid-adolescence among 7120 males and females from the Avon Longitudinal Study of Parents and Children (ALSPAC), a cohort study of children in the UK, using data from multiple informants to develop structural equation models. Repeated assessment of eating disturbances during childhood (mid childhood overeating, late-childhood overeating and early-adolescent strong desire for food), as well as teacher- and parent-reported hyperactivity/inattention during mid- and late childhood, were considered as possible predictors of mid-adolescent binge eating. RESULTS: Prevalence of binge eating during mid-adolescence in our sample was 11.6%. The final model of predictors of binge eating during mid-adolescence included direct effects of late childhood overeating [standardized estimate 0.145, 95% confidence interval (CI) 0.038-0.259, p = 0.009] and early-adolescent strong desire for food (standardized estimate 0.088, 95% CI -0.002 to 0.169, p = 0.05). Hyperactivity/inattention during late childhood indirectly predicted binge eating during mid-adolescence (standardized estimate 0.085, 95% CI 0.007-0.128, p = 0.03) via late-childhood overeating and early-adolescent strong desire for food. CONCLUSIONS: Our findings indicate that early ADHD symptoms, in addition to an overeating phenotype, contribute to risk for adolescent binge eating. These findings lend support to the potential role of hyperactivity/inattention in the development of overeating and binge eating. PMID- 26098686 TI - Support for and From Aging Mothers Whose Adult Daughters are Seriously Mentally Ill. AB - This article discusses, from the grandmother's perspective, the ways in which support is exchanged in families coping with serious mental illness. A strengths perspective was utilized to identify ways in which family members help each other. Employing a qualitative approach, this study focuses on interviews obtained from a sample of 22 aging mothers, aged 52-90, who are in contact with their daughters who have a mental illness. Grandmothers provided several kinds of support to their mentally ill adult daughters and to their grandchildren, who also supported the aging mother in numerous ways. As social workers seek to assist individuals with mental illness, it is important to assess the existing strengths of their intergenerational family context. PMID- 26098687 TI - Litter Breakdown and Microbial Succession on Two Submerged Leaf Species in a Small Forested Stream. AB - Microbial succession during leaf breakdown was investigated in a small forested stream in west-central Georgia, USA, using multiple culture-independent techniques. Red maple (Acer rubrum) and water oak (Quercus nigra) leaf litter were incubated in situ for 128 days, and litter breakdown was quantified by ash free dry mass (AFDM) method and microbial assemblage composition using phospholipid fatty acid analysis (PLFA), ribosomal intergenic spacer analysis (RISA), denaturing gradient gel electrophoresis (DGGE), and bar-coded next generation sequencing of 16S rRNA gene amplicons. Leaf breakdown was faster for red maple than water oak. PLFA revealed a significant time effect on microbial lipid profiles for both leaf species. Microbial assemblages on maple contained a higher relative abundance of bacterial lipids than oak, and oak microbial assemblages contained higher relative abundance of fungal lipids than maple. RISA showed that incubation time was more important in structuring bacterial assemblages than leaf physicochemistry. DGGE profiles revealed high variability in bacterial assemblages over time, and sequencing of DGGE-resolved amplicons indicated several taxa present on degrading litter. Next-generation sequencing revealed temporal shifts in dominant taxa within the phylum Proteobacteria, whereas gamma-Proteobacteria dominated pre-immersion and alpha- and beta Proteobacteria dominated after 1 month of instream incubation; the latter groups contain taxa that are predicted to be capable of using organic material to fuel further breakdown. Our results suggest that incubation time is more important than leaf species physicochemistry in influencing leaf litter microbial assemblage composition, and indicate the need for investigation into seasonal and temporal dynamics of leaf litter microbial assemblage succession. PMID- 26098688 TI - Sudden cardiac death in forensic medicine - Swiss recommendations for a multidisciplinary approach. AB - Sudden cardiac death (SCD) is by definition unexpected and cardiac in nature. The investigation is almost invariably performed by a forensic pathologist. Under these circumstances the role of the forensic pathologist is twofold: (1.) to determine rapidly and efficiently the cause and manner of death and (2.) to initiate a multidisciplinary process in order to prevent further deaths in existing family members. If the death is determined to be due to "natural" causes the district attorney in charge often refuses further examinations. However, additional examinations, i.e. extensive histopathological investigations and/or molecular genetic analyses, are necessary in many cases to clarify the cause of death. The Swiss Society of Legal Medicine created a multidisciplinary working group together with clinical and molecular geneticists and cardiologists in the hope of harmonising the approach to investigate SCD. The aim of this paper is to close the gap between the Swiss recommendations for routine forensic post-mortem cardiac examination and clinical recommendations for genetic testing of inherited cardiac diseases; this is in order to optimise the diagnostic procedures and preventive measures for living family members. The key points of the recommendations are (1.) the forensic autopsy procedure for all SCD victims under 40 years of age, (2.) the collection and storage of adequate samples for genetic testing, (3.) communication with the families, and (4.) a multidisciplinary approach including cardiogenetic counselling. PMID- 26098689 TI - Thymosin alpha1 modifies podosome architecture and promptly stimulates the expression of podosomal markers in mature macrophages. AB - BACKGROUND AND AIMS: The immunomodulatory activity of thymosin alpha1 (Talpha1) on innate immunity has been extensively described, but its mechanism of action is not completely understood. We explored the possibility that Talpha1-stimulation could affect the formation of podosomes, the highly dynamic, actin-rich, adhesion structures involved in macrophage adhesion/chemotaxis. METHODS: The following methods were used: optical and scanning electron microscopy for analyzing morphology of human monocyte-derived macrophages (MDMs); time-lapse imaging for visualizing the time-dependent modifications induced at early times by Talpha1 treatment; confocal microscopy and Western blot for analyzing localization and expression of podosome components; and Matrigel Migration Assay and zymography for testing MDM invasive ability and metalloproteinase secretion. RESULTS: We obtained data to support that Talpha1 could affect MDM motility, invasion and chemotaxis by promptly stimulating assembly and disassembly of podosomal structures. At very early times after its addition to cell culture medium and within 1 h of treatment, Talpha1 induces modifications in MDM morphology and in podosomal components that are suggestive of increased podosome turnover. CONCLUSIONS: Since impairment of podosome formation leads to reduced innate immunity and is associated with several immunodeficiency disorders, we confirm the validity of Talpha1 as a potent activator of innate immunity and suggest possible new clinical application of this thymic peptide. PMID- 26098690 TI - Antidrug Antibodies: B Cell Immunity Against Therapy. AB - Chronic inflammatory diseases are now treated with a range of different biopharmaceuticals, often requiring lifelong parenteral administrations. This exposure to drugs is unnatural and can trigger the immune system and result in the formation of antidrug antibodies. Drug-specific antibodies will, if of sufficiently high titre and affinity, block the intended effect of the drug, increase its clearance and make continued treatment worthless. We expect the immune system to react towards therapies against which tolerance has never been established, which is the case for factor VIII treatment in patients with haemophilia A. However, even biopharmaceutical molecules that we should be tolerant against can elicit antidrug antibodies, for instance in treatment of multiple sclerosis patients with recombinant human interferon-beta. Possible immunological mechanisms behind the breaking of tolerance against drugs, the impact this has on continuous treatment success, clinical practice and drug development, will be discussed in this review. PMID- 26098691 TI - Combining alpha-Radioimmunotherapy and Adoptive T Cell Therapy to Potentiate Tumor Destruction. AB - Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. alpha Radioimmunotherapy (alpha-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. alpha-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of alpha-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining alpha-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with alpha-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining alpha-RIT and ACT in the MM model we established. PMID- 26098693 TI - Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and beta2-Adrenergic Receptor Desensitization. AB - Tachyphylaxis of the beta2-adrenergic receptor limits the efficacy of bronchodilatory beta2-agonists in respiratory disease. Cellular studies in airway smooth muscle (ASM) have shown that inflammatory mediators and infectious stimuli reduce beta2-adrenergic responsiveness in a cyclo-oxygenase (COX)-2-mediated, prostaglandin E2 (PGE2)-dependant manner. Herein, we show that sphingosine 1 phosphate (S1P), a bioactive sphingolipid that plays an important role in pathophysiology of asthma, also induces beta2-adrenergic receptor desensitization in bronchial ASM cells and exerts hyporesponsiveness to beta2-agonists. We treated ASM cells with S1P (1 MUM) for up to 24 hours and then examined the temporal kinetics of COX-2 mRNA expression, protein up-regulation, and PGE2 secretion. S1P significantly enhanced COX-2 expression and PGE2 secretion, and this was repressed by the selective COX-2 inhibitor celecoxib, the corticosteroid dexamethasone, or small interfering RNA (siRNA) knockdown of COX-2 expression. In combination with another proinflammatory mediator found elevated in asthmatic airways, the cytokine TNF-alpha, we observed that S1P-induced COX-2 mRNA expression and protein up-regulation and PGE2 secretion from ASM cells were significantly enhanced. Notably, S1P induced heterologous beta2-adrenergic desensitization, as measured by inhibition of cyclic adenosine monophosphate production in response to the short-acting beta2-agonist, salbutamol, and the long-acting beta2-agonist, formoterol. Taken together, these data indicate that S1P represses beta2-adrenergic activity in ASM cells by increasing COX-2-mediated PGE2 production, and suggest that this bioactive sphingolipid found elevated in asthma may contribute to beta2-adrenergic desensitization. PMID- 26098692 TI - Novel Autoantigens Associated with Lupus Nephritis. AB - Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies. PMID- 26098694 TI - Examining the Causes and Consequences of Short-Term Behavioral Change during the Middle Stone Age at Sibudu, South Africa. AB - Sibudu in KwaZulu-Natal (South Africa) with its rich and high-resolution archaeological sequence provides an ideal case study to examine the causes and consequences of short-term variation in the behavior of modern humans during the Middle Stone Age (MSA). We present the results from a technological analysis of 11 stratified lithic assemblages which overlie the Howiesons Poort deposits and all date to ~58 ka. Based on technological and typological attributes, we conducted inter-assemblage comparisons to characterize the nature and tempo of cultural change in successive occupations. This work identified considerable short-term variation with clear temporal trends throughout the sequence, demonstrating that knappers at Sibudu varied their technology over short time spans. The lithic assemblages can be grouped into three cohesive units which differ from each other in the procurement of raw materials, the frequency in the methods of core reduction, the kind of blanks produced, and in the nature of tools the inhabitants of Sibudu made and used. These groups of assemblages represent different strategies of lithic technology, which build upon each other in a gradual, cumulative manner. We also identify a clear pattern of development toward what we have previously defined as the Sibudan cultural taxonomic unit. Contextualizing these results on larger geographical scales shows that the later phase of the MSA during MIS 3 in KwaZulu-Natal and southern Africa is one of dynamic cultural change rather than of stasis or stagnation as has at times been claimed. In combination with environmental, subsistence and contextual information, our high-resolution data on lithic technology suggest that short term behavioral variability at Sibudu can be best explained by changes in technological organization and socio-economic dynamics instead of environmental forcing. PMID- 26098695 TI - Detection of HIV-1 p24 at Attomole Level by Ultrasensitive ELISA with Thio-NAD Cycling. AB - To reduce the window period between HIV-1 infection and the ability to diagnose it, a fourth-generation immunoassay including the detection of HIV-1 p24 antigen has been developed. However, because the commercially available systems for this assay use special, high-cost instruments to measure, for example, chemiluminescence, it is performed only by diagnostics companies and hub hospitals. To overcome this limitation, we applied an ultrasensitive ELISA coupled with a thio-NAD cycling, which is based on a usual enzyme immunoassay without special instruments, to detect HIV-1 p24. The p24 detection limit by our ultrasensitive ELISA was 0.0065 IU/assay (i.e., ca. 10(-18) moles/assay). Because HIV-1 p24 antigen is thought to be present in the virion in much greater numbers than viral RNA copies, the value of 10(-18) moles of the p24/assay corresponds to ca. 10(3) copies of the HIV-1 RNA/assay. That is, our ultrasensitive ELISA is chasing the detection limit (10(2) copies/assay) obtained by PCR-based nucleic acid testing (NAT) with a margin of only one different order. Further, the detection limit by our ultrasensitive ELISA is less than that mandated for a CE marked HIV antigen/antibody assay. An additional recovery test using blood supported the reliability of our ultrasensitive ELISA. PMID- 26098696 TI - Evaluating efficiency and statistical power of self-controlled case series and self-controlled risk interval designs in vaccine safety. AB - The self-controlled case series (SCCS) and self-controlled risk interval (SCRI) designs have recently become widely used in the field of post-licensure vaccine safety monitoring to detect potential elevated risks of adverse events following vaccinations. The SCRI design can be viewed as a subset of the SCCS method in that a reduced comparison time window is used for the analysis. Compared to the SCCS method, the SCRI design has less statistical power due to fewer events occurring in the shorter control interval. In this study, we derived the asymptotic relative efficiency (ARE) between these two methods to quantify this loss in power in the SCRI design. The equation is formulated as [Formula: see text] (a: control window-length ratio between SCRI and SCCS designs; b: ratio of risk window length and control window length in the SCCS design; and [Formula: see text]: relative risk of exposed window to control window). According to this equation, the relative efficiency declines as the ratio of control-period length between SCRI and SCCS methods decreases, or with an increase in the relative risk [Formula: see text]. We provide an example utilizing data from the Vaccine Safety Datalink (VSD) to study the potential elevated risk of febrile seizure following seasonal influenza vaccine in the 2010-2011 season. PMID- 26098697 TI - Ebola virus screening during pregnancy in West Africa: unintended consequences. AB - OBJECTIVE: We hypothesized that predictive value of traditional Ebola virus disease (EVD) screening in West African pregnant women is low because febrile and hemorrhagic complications of pregnancy that can mimic EVD are common. METHODS: Proportions of various categories of pregnancy loss from a hypothetical cohort of West African gravidas were used to construct a Kaplan-Meier curve. The incidence rate of each category was determined by multiplying its proportion by the overall incidence rate, calculated from the inverse of the area under the curve. Incidence rates of Ebola-like illnesses during pregnancy were obtained by multiplying their percentages by the incidence rates of categories of loss with which they coincide. RESULTS: During pregnancy about 1.5% of suspected EVD cases would prove to have EVD. Most of the remaining 98.5% would have hemorrhagic and febrile complications of pregnancy. CONCLUSION: Current guidelines consider obstetrical interventions inappropriate in suspected EVD during pregnancy. However, because the overwhelming majority of cases suspected by screening do not have EVD and might benefit from obstetrical intervention, policy makers must consider whether the small risk to properly protected health care workers from the 1.5% with true EVD justifies withholding potentially life-saving care from the 98.5% who ultimately test negative for EVD. PMID- 26098698 TI - Are there treatments for atypical parkinsonism? An update on actual options. AB - Success in treating patients with atypical parkinsonism remains exceedingly low. It is particularly important for both neurologists and general practicians to have a guideline in the actual possible cure options. This study reviews the limited available literature reporting treatment trials about treatment in parkinsonism. Various therapeutical approaches have been tried with rasagiline, immunoglobulin, autologous mesenchymal stem cells, davunetide, lithium, and tideglusib. Recently, the transdermal rotigotine has been proposed for the treatment of atypical parkinsonism, as well as deep brain stimulation (DBS) of the peduncolopontine nucleus alone or combined with globus pallidus internus stimulation. The outcomes reviewed here highlight the need for the development of randomized, placebo-controlled trials to validate outcomes about rotigotine, DBS, and all other new therapies directed at altering the underlying biological mechanisms involved in the disease process. PMID- 26098699 TI - Anti-hyperlipidemic activity of an extract from roots and rhizomes of Panicum repens L. on high cholesterol diet-induced hyperlipidemia in rats. AB - The hypolipidemic effect of an ethanolic extract from the roots and rhizomes of Panicum repens L. was investigated in rats suffering from high-cholesterol, diet induced hyperlipidemia, and the phytochemicals in the extract were analyzed. The extract was administered p.o. in doses of 250 mg/kg/day together with cholesterol at a dose of 100 mg/kg/day for 7 weeks. The high-cholesterol diet caused a significant increase in total lipids, total cholesterol (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and the atherogenic index, whereas the level of high-density lipoprotein cholesterol (HDL-C) was significantly decreased. Administration of the P. repens extract (p<0.05) significantly reduced the rise of the serum levels of total lipids, TC, TG, and LDL-C, as well as the atherogenic index, whereas it significantly increased (p<0.05) the level of HDL-C. HPLC analysis of the phenolics and flavonoids in the extract revealed the presence of gallic acid, chlorogenic acid, chicoric acid, primulic acid, rutin, apigenin-7-glucoside, and quercetin. In conclusion, the P. repens extract was found to possess hypolipidemic activity in high-fat, diet induced hyperlipidemic rats. PMID- 26098700 TI - Polymorphisms of CYP1A2 and CYP2A6 activity: phenotypes and the effect of age and sex in a Nigerian population. AB - BACKGROUND: CYP1A2 and CYP2A6 are polymorphic enzymes that metabolise several compounds of clinical importance. This study investigated the prevalent phenotypes of these enzymes and the influence of age and sex on enzyme activity in a Nigerian population. METHODS: Caffeine (110 mg) was administered to each of 129 healthy, unrelated subjects (85 males and 44 females) who were non-smokers. Urine voided within 7 h after caffeine administration was collected for a high performance liquid chromatographic assay of caffeine (137X), 1,7-dimethyluric acid (17U) and 1,7-dimethylxanthine (17X). CYP1A2 activity was measured as a ratio of (17U+17X) to 137X, while 17U/17X served as marker for CYP2A6. Transformed data were analysed and the influences of age and sex on activity were also determined. RESULTS: Distribution of CYP1A2 activity in the population was bimodal with a mean+/-SD of 0.82+/-0.41, while that of CYP2A6 was trimodal with a mean+/-SD activity of 0.27+/-0.42 of the log-transformed urinary molar ratio of metabolites. The influences of age and sex on enzyme activity for both CYP1A2 and CYP2A6 were not significant (p>0.05). CONCLUSIONS: The study established the prevalence of polymorphism in phenotypes of CYP1A2 and CYP2A6 activity in the Nigerian population, but no influence of age and sex on enzyme activity was observed in this population. PMID- 26098701 TI - Pathophysiology of hypertension in obese children: a systematic review. AB - Hypertension is increasingly common in overweight and obese children. The mechanisms behind the development of hypertension in obesity are complex, and evidence is limited. In order to effectively treat obese children for hypertension, it is important to have a deeper understanding of the pathophysiology of hypertension in obese children. The present review summarizes the main factors associated with hypertension in obese children and discusses their potential role in its pathophysiology. Systematic searches were conducted in PubMed and EMBASE for articles published up to October 2014. In total, 60 relevant studies were included. The methodological quality of the included studies ranged from weak to strong. Several factors important in the development of hypertension in obese children have been suggested, including endocrine determinants, such as corticosteroids and adipokines, sympathetic nervous system activity, disturbed sodium homeostasis, as well as oxidative stress, inflammation and endothelial dysfunction. Understanding the pathophysiology of hypertension in overweight and obese children is important and could have implications for its screening and treatment. Based on solely cross-sectional observational studies, it is impossible to infer causality. Longitudinal studies of high methodological quality are needed to gain more insight into the complex mechanisms behind the development of hypertension in obese children. PMID- 26098702 TI - Nature of noncovalent carbon-bonding interactions derived from experimental charge-density analysis. AB - In an effort to better understand the nature of noncovalent carbon-bonding interactions, we undertook accurate high-resolution X-ray diffraction analysis of single crystals of 1,1,2,2-tetracyanocyclopropane. We selected this compound to study the fundamental characteristics of carbon-bonding interactions, because it provides accessible sigma holes. The study required extremely accurate experimental diffraction data, because the interaction of interest is weak. The electron-density distribution around the carbon nuclei, as shown by the experimental maps of the electrophilic bowl defined by a (CN)2 C?C(CN)2 unit, was assigned as the origin of the interaction. This fact was also evidenced by plotting the Delta(2) rho(r) distribution. Taken together, the obtained results clearly indicate that noncovalent carbon bonding can be explained as an interaction between confronted oppositely polarized regions. The interaction is, thus electrophilic-nucleophilic (electrostatic) in nature and unambiguously considered as attractive. PMID- 26098703 TI - Human neutralizing antibodies against MERS coronavirus: implications for future immunotherapy. PMID- 26098704 TI - Genotypes of ITS region of rRNA in Microcystis (Cyanobacteria) populations in Erhai Lake (China) and their correlation with eutrophication level. AB - Previous studies on spatiotemporal changes of Microcystis genotypes have shown that the existence and succession of dominant genotypes always occur in eutrophicated freshwater bodies. However, few studies have focused on the correlation between genotype composition and eutrophication level. In the present study, clone libraries of the internal transcribed spacer (ITS) of rrn operon were sequenced from Microcystis populations in Erhai Lake, a subtropical plateau lake in the preliminary eutrophication stage. The genotype composition of the Microcystis populations was highly variable at spatiotemporal scales, and 473 ITS genotypes were identified from the 800 ITS sequences obtained. However, no significantly dominant ITS genotypes existed in the lake. Comparison of Erhai Lake with four major lakes in China, namely, Taihu, Chaohu, Gucheng, and Shijiu Lakes, showed that the Microcystis ITS genotypes and genetic diversity were negatively correlated with eutrophication level. Extensive comparison of the Microcystis ITS genotypes from waters worldwide revealed that 440 ITS genotypes were unique to Erhai Lake, and no obvious phylogenetic correlations can be detected among the dominant genotypes from different water bodies. The high genetic diversity of the Microcystis populations in Erhai Lake may have resulted from the effect of the early stage of eutrophication. PMID- 26098705 TI - Assessment of caecal parameters in layer hens fed on diets containing wheat distillers dried grains with solubles. AB - There is much interest in quantifying the nutritional value of UK wheat distillers dried grains with solubles (W-DDGS) for livestock species. A study was designed to evaluate caecal parameters (pH, short chain fatty acids (SCFAs) and bacterial diversity) in layer hens fed on balanced diets containing graded concentrations of W-DDGS. A total of 32 layer hens (Bovans Brown strain at 27 weeks of age) were randomly allocated to one of 4 dietary treatments containing W DDGS at 0, 60, 120 or 180 g/kg. Each treatment was fed to 8 replicate individually housed layer hens over a 5-d acclimatisation period, followed by a 4 week trial. Individual feed intakes were monitored and all eggs were collected daily for weeks 2, 3 and 4 of the trial, weighed and an assessment of eggshell "dirtiness" made. All hens were culled on d 29 and caecal pH and SCFAs measured. Polymerase chain reaction denaturing gradient gel electrophoresis of the bacterial 16 S rDNA gene was used to assess total bacterial diversity of luminal caecal content from hens fed the 0 and 180 g W-DDGS/kg diets. Unweighted pair group method with arithmetic mean (UPGMA) dendrograms were generated from DGGE banding patterns. Increasing W-DDGS dietary concentrations resulted in a more acidic caecal environment. Caecal SCFAs were unaffected by diet aside from a quadratic effect for molar proportions of isobutyric acid. Diversity profiles of the bacterial 16S rRNA gene from luminal caecal contents were unaffected by W DDGS inclusion. The results of the current study suggest that W-DDGS can be successfully formulated into nutritionally balanced layer diets (supplemented with xylanase and phytase) at up to 180 g/kg with no detrimental effects to the caecal environment. PMID- 26098706 TI - Cost-Effectiveness of Coal Workers' Pneumoconiosis Prevention Based on Its Predicted Incidence within the Datong Coal Mine Group in China. AB - We aimed to estimate the economic losses currently caused by coal workers' pneumoconiosis (CWP) and, on the basis of these measurements, confirm the economic benefit of preventive measures. Our cohort study included 1,847 patients with CWP and 43,742 coal workers without CWP who were registered in the employment records of the Datong Coal Mine Group. We calculated the cumulative incidence rate of pneumoconiosis using the life-table method. We used the dose response relationship between cumulative incidence density and cumulative dust exposure to predict the future trend in the incidence of CWP. We calculate the economic loss caused by CWP and economic effectiveness of CWP prevention by a step-wise model. The cumulative incidence rates of CWP in the tunneling, mining, combining, and helping cohorts were 58.7%, 28.1%, 21.7%, and 4.0%, respectively. The cumulative incidence rates increased gradually with increasing cumulative dust exposure (CDE). We predicted 4,300 new CWP cases, assuming the dust concentrations remained at the levels of 2011. If advanced dustproof equipment was adopted, 537 fewer people would be diagnosed with CWP. In all, losses of 1.207 billion Renminbi (RMB, official currency of China) would be prevented and 4,698.8 healthy life years would be gained. Investments in advanced dustproof equipment would be total 843 million RMB, according to our study; the ratio of investment to restored economic losses was 1:1.43. Controlling workplace dust concentrations is critical to reduce the onset of pneumoconiosis and to achieve economic benefits. PMID- 26098707 TI - Optical regulation of cell chain. AB - Formation of cell chains is a straightforward and efficient method to study the cell interaction. By regulating the contact sequence and interaction distance, the influence of different extracellular cues on the cell interaction can be investigated. However, it faces great challenges in stable retaining and precise regulation of cell chain, especially in cell culture with relatively low cell concentration. Here we demonstrated an optical method to realize the precise regulation of cell chain, including removing or adding a single cell, adjusting interaction distance, and changing cell contact sequence. After injecting a 980 nm wavelength laser beam into a tapered optical fiber probe (FP), a cell chain of Escherichia colis (E. colis) is formed under the optical gradient force. By manipulating another FP close to the cell chain, a targeted E. coli cell can be trapped by the FP and removed from the chain. Further, the targeted cell can be added back to the chain at different positions to change the cell contact sequence. The experiments were interpreted by numerical simulations and the impact of cell sizes and shapes on this method was analyzed. PMID- 26098709 TI - Spindle Cell Atypical Fibroxanthoma: Myofibroblastic Differentiation Represents a Diagnostic Pitfall in This Variant of AFX. AB - Atypical fibroxanthoma (AFX) is a low-grade, dermal, mesenchymal neoplasm, which lacks a specific lineage of differentiation. The classical histologic appearance of AFX is that of a pleomorphic and spindle cell neoplasm with marked nuclear pleomorphism, mitotic figures, and often prominent storiform pattern that superficially resembles a pleomorphic high-grade sarcoma ("malignant fibrous histiocytoma"). Many histologic variants have been described. We have reviewed 15 cases of AFX characterized by a pure spindle cell morphology that could be easily mistaken for other spindle cell dermal neoplasms. All of our cases were stained with CD68, CD163, CD10, S-100p, p63, wide-spectrum keratin, CD31, CD34, smooth muscle actin (SMA), desmin, calponin, and h-caldesmon. All 15 cases showed an immunoprofile consistent with AFX. In 9 cases, SMA was also strongly expressed; this finding, coupled with the malignant spindle cell histomorphology, can lead to an erroneous diagnosis of cutaneous leiomyosarcoma with potential clinical consequences. Awareness of this pattern of immunoreactivity in this unusual variant of AFX is of importance for avoiding diagnostic misinterpretation. This study intends to characterize the nature and frequency of SMA immunoreactivity in AFX and to discuss the potential diagnostic pitfalls of immunohistochemical markers in distinguishing this entity from other malignant spindle cell neoplasms. PMID- 26098708 TI - A Mechanism of Subunit Recruitment in Human Small Heat Shock Protein Oligomers. AB - Small heat shock proteins (sHSPs) make up a class of molecular chaperones broadly observed across organisms. Many sHSPs form large oligomers that undergo dynamic subunit exchange that is thought to play a role in chaperone function. Though remarkably heterogeneous, sHSP oligomers share three types of intermolecular interactions that involve all three defined regions of a sHSP: the N-terminal region (NTR), the conserved alpha-crystallin domain (ACD), and a C-terminal region (CTR). Here we define the structural interactions involved in incorporation of a subunit into a sHSP oligomer. We demonstrate that a minimal ACD dimer of the human sHSP, HSPB5, interacts with an HSPB5 oligomer through two types of interactions: (1) interactions with CTRs in the oligomer and (2) via exchange into and out of the dimer interface composed of two ACDs. Unexpectedly, although dimers are thought to be the fundamental building block for sHSP oligomers, our results clearly indicate that subunit exchange into and out of oligomers occurs via monomers. Using structure-based mutants, we show that incorporation of a subunit into an oligomer is predicated on recruitment of the subunit via its interaction with CTRs on an oligomer. Both the rate and extent of subunit incorporation depend on the accessibility of CTRs within an HSPB5 oligomer. We show that this mechanism also applies to formation of heterooligomeric sHSP species composed of HSPB5 and HSPB6 and is likely general among sHSPs. Finally, our observations highlight the importance of NTRs in the thermodynamic stability of sHSP oligomers. PMID- 26098710 TI - Friction of polymer hydrogels studied by resonance shear measurements. AB - The friction between an elastomer and a hard surface typically has two contributors, i.e., the interfacial and deformation components. The friction of viscoelastic hydrogel materials has been extensively studied between planar gel and planar substrate surfaces from the viewpoint of an interfacial interaction. However, the geometry of the contact in practical applications is much more complex. The contribution of geometric and elastic deformation terms of a gel to friction could not be neglected. In this study, we used resonance shear measurements (RSMs) for characterizing the shear response of a glass sphere on a flat polymer hydrogel, a double network (DN) gel of 2-acrylamide-2 methylpropanesulfonic acid and N,N-dimethylacrylamide. The contact mechanics conformed to the Johnson-Kendall-Roberts theory. The observed resonance curves exhibited rather sharp peaks when the DN gel and the silica sphere were brought into contact, and their intensity and frequency increased with the increase in the normal load. We proposed a simple physical model of the shearing system, and the elastic (k2) and viscous (b2) parameters of the interface between a silica sphere and a flat DN gel were obtained. The friction force from elastic deformation and viscous dissipation terms was then estimated using the obtained parameters. It was revealed that the elastic parameter (k2) increased up to 1780 N m(-1) at a normal load of 524 mN, while the viscous parameter (b2) was zero or quite low (<0.1 N s m(-1)) for a silica sphere (radius of 18.4 mm). Thus, the friction force between a flat DN gel and a silica sphere in air was dominated by the elastic term due to the local deformation by contact with the silica sphere. By adding water, the elastic parameter (k2) remained the same, while the viscous parameter (b2) slightly increased. However, the viscous term fviscous was still much smaller than felastic. To the best of our knowledge, this study was the first quantitative estimation of the contribution of the elastic deformation term to the friction in the case when deformation of non-flat contact regions occurs. The obtained results can be basic knowledge for designing gels for applications such as artificial cartilages and sliding bearings. PMID- 26098712 TI - Efficient Synthesis of Octahydrophenanthrene Derivatives with Mild Cascade Reactions of Isochromenylium Tetrafluoroborates and Bifunctional Styrenes. AB - A highly efficient catalyst-free cascade reaction of air-stable isochromenylium tetrafluoroborates and bifunctional styrenes containing a 1,3-diketone moiety has been developed, affording the corresponding single diastereomeric ocatahydrophenanthrene derivatives (21 examples, up to 86% yield). A cascade process of [4 + 2]-cyclization and subsequent intramolecular nucleophilic addition is proposed to generate the three new C-C bonds diastereoselectively in the reactions. PMID- 26098711 TI - DNA hypomethylation-mediated activation of Cancer/Testis Antigen 45 (CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is a highly lethal malignancy due to a lack of early detection approaches coupled with poor outcomes for patients with clinically advanced disease. Cancer-testis (CT) or cancer-germline genes encode antigens known to generate spontaneous anti-tumor immunity in cancer patients. CT45 genes are a recently discovered 6-member family of X-linked CT genes with oncogenic function. Here, we determined CT45 expression in EOC and fully defined its epigenetic regulation by DNA methylation. CT45 was silent and hypermethylated in normal control tissues, but a large subset of EOC samples showed increased CT45 expression in conjunction with promoter DNA hypomethylation. In contrast, copy number status did not correlate with CT45 expression in the TCGA database for EOC. CT45 promoter methylation inversely correlated with both CT45 mRNA and protein expression, the latter determined using IHC staining of an EOC TMA. CT45 expression was increased and CT45 promoter methylation was decreased in late stage and high-grade EOC, and both measures were associated with poor survival. CT45 hypomethylation was directly associated with LINE-1 hypomethylation, and CT45 was frequently co-expressed with other CT antigen genes in EOC. Decitabine treatment induced CT45 mRNA and protein expression in EOC cells, and promoter transgene analyses indicated that DNA methylation directly represses CT45 promoter activity. These data verify CT45 expression and promoter hypomethylation as possible prognostic biomarkers, and suggest CT45 as an immunological or therapeutic target in EOC. Treatment with decitabine or other epigenetic modulators could provide a means for more effective immunological targeting of CT45. PMID- 26098713 TI - beta-Hydrogen Elimination Mechanism in the Absence of Low-Lying Acceptor Orbitals in EH2(t-C4H9) (E = N-Bi). AB - The beta-hydrogen elimination reactions of group 15 alkyl compounds at the example of EH2(t-C4H9) (element E = N-Bi) were investigated and compared to the group 13 example of GaH2(t-C4H9). With the aid of extensive density functional theory based analysis of atomic and electronic structures at the transition state, we can derive three distinct reaction classes. The gallium compound follows the well-known beta-hydride route with participation of an empty p orbital at the metal in a concerted, synchronous fashion, exhibiting a low barrier. For compounds with group 15 elements, we find highly nonsynchronous reactions with high reaction barriers. In the case of nitrogen, a proton-like H atom is transferred via attack of the nitrogen nonbonding electron pair. For the heavier homologues (P-Bi), E-Calpha bond breaking occurs first and the H atom does not carry charge at the transition state. The reaction barrier in group 15 homologues is thus determined by the E-Calpha bond strength down the group. The results enable a rationale for ligand design for precursors involved in chemical vapor-phase deposition processes because a good ligand needs to stabilize the positive charge at Calpha. PMID- 26098714 TI - Ionizing radiation affects protein composition of exosomes secreted in vitro from head and neck squamous cell carcinoma. AB - Exosomes are membrane vesicles of endocytic origin that participate in inter cellular communication. Environmental and physiological conditions affect composition of secreted exosomes, their abundance and potential influence on recipient cells. Here, we analyzed protein component of exosomes released in vitro from cells exposed to ionizing radiation (2Gy dose) and compared their content with composition of exosomes released from control not irradiated cells. Exosomes secreted from FaDu cells originating from human squamous head and neck cell carcinoma were analyzed using LC-MS/MS approach. We have found that exposure to ionizing radiation resulted in gross changes in exosomal cargo. There were 217 proteins identified in exosomes from control cells and 384 proteins identified in exosomes from irradiated cells, including 148 "common" proteins, 236 proteins detected specifically after irradiation and 69 proteins not detected after irradiation. Among proteins specifically overrepresented in exosomes from irradiated cells were those involved in transcription, translation, protein turnover, cell division and cell signaling. This indicated that exosomal cargo reflected radiation-induced changes in cellular processes like transient suppression of transcription and translation or stress-induced signaling. PMID- 26098715 TI - Mitochondrial DNA variability in Gyimesi Racka and Turcana sheep breeds. AB - The current knowledge and documentation on the origins and relationship between Gyimesi Racka reared in Hungary and the Romanian Turcana is rather controversial. Lack of information and scientific reliable proofs for the divergent theories found in the two countries motivated us to implement a trial using molecular methods to assess the genetic distance and diversity in the two breeds. Hair follicles were collected from Gyimesi Racka (2 phenotypes) and from Turcana (6 ecotypes). The 599 bp segment of the D-loop region of the mitochondrial DNA was sequenced. Altogether, 42 haplotypes were identified, while 23 were found in both populations. Populations were highly diverse according to the haplotype and nucleotide diversity indices. AMOVA analysis showed that most of the variation was observed within populations (98%), indicating a weak genetic structure between the two breeds. Animals were grouped into seven groups based on their phenotype; however genetic distances among them were also low. Tajima's D, Fu's Fs, goodness-of-fit statistics, mismatch distribution and network analysis suggested recent demographic expansion. Current comprehensive mtDNA study indicates that there is very low level of genetic differentiation between the Gyimesi Racka and Turcana populations therefore they are de facto one trans boundary breed. PMID- 26098716 TI - Quantification of 5-methyl-2'-deoxycytidine in the DNA. AB - Methylation at position 5 of cytosine (Cyt) at the CpG sequences leading to formation of 5-methyl-cytosine (m(5)Cyt) is an important element of epigenetic regulation of gene expression. Modification of the normal methylation pattern, unique to each organism, leads to the development of pathological processes and diseases, including cancer. Therefore, quantification of the DNA methylation and analysis of changes in the methylation pattern is very important from a practical point of view and can be used for diagnostic purposes, as well as monitoring of the treatment progress. In this paper we present a new method for quantification of 5-methyl-2'deoxycytidine (m(5)C) in the DNA. The technique is based on conversion of m(5)C into fluorescent 3,N(4)-etheno-5-methyl-2'deoxycytidine (epsilonm(5)C) and its identification by reversed-phase high-performance liquid chromatography (RP-HPLC). The assay was used to evaluate m(5)C concentration in DNA of calf thymus and peripheral blood of cows bred under different conditions. This approach can be applied for measuring of 5-methylcytosine in cellular DNA from different cells and tissues. PMID- 26098717 TI - Association of the DIO2 gene single nucleotide polymorphisms with recurrent depressive disorder. AB - Genetic factors may play a role in the etiology of depressive disorder. The type 2 iodothyronine deiodinase gene (DIO2) encoding the enzyme catalyzing the conversion of T4 to T3 is suggested to play a role in the recurrent depressive disorder (rDD). The current study investigates whether a specific single nucleotide polymorphism (SNP) of the DIO2 gene, Thr92Ala (T/C); rs 225014 or ORFa Gly3Asp (C/T); rs 12885300, correlate with the risk for recurrent depression. Genotypes for these two single nucleotide polymorphisms (SNPs) were determined in 179 patients meeting the ICD-10 criteria for rDD group and in 152 healthy individuals (control group) using a polymerase chain reaction (PCR) based method. The specific variant of the DIO2 gene, namely the CC genotype of the Thr92Ala polymorphism, was more frequently found in healthy subjects than in patients with depression, what suggests that it could potentially serve as a marker of a lower risk for recurrent depressive disorder. The distribution of four haplotypes was also significantly different between the two study groups with the TC (Thr-Gly) haplotype more frequently detected in patients with depression. In conclusion, data generated from this study suggest for the first time that DIO2 gene may play a role in the etiology of the disease, and thus should be further investigated. PMID- 26098719 TI - A novel method of Mycobacterium tuberculosis complex strain differentiation using polymorphic GC-rich gene sequences. AB - Tuberculosis is one of the leading infectious diseases. In this work, a new genotyping method of Mycobacterium tuberculosis (Mtb) complex strain is presented. 27 Mtb genomes were analyzed for the presence of length polymorphism within polymorphic GC-rich gene sequences. Four genes, Rv3345c, Rv3507, Rv0747 and Rv3511, showing variation in length depending on the Mtb strain were selected for designing primer sequences flanking variable regions for the PCR method. Identification of 16 genotypes among 27 analyzed genomes demonstrated usefulness of our genotyping method in differentiation of Mtb genomes based on sequence polymorphism in the four PGRS genes. PMID- 26098718 TI - Quinone- and nitroreductase reactions of Thermotoga maritima thioredoxin reductase. AB - The Thermotoga maritima NADH:thioredoxin reductase (TmTR) contains FAD and a catalytic disulfide in the active center, and uses a relatively poorly studied physiological oxidant Grx-1-type glutaredoxin. In order to further assess the redox properties of TmTR, we used series of quinoidal and nitroaromatic oxidants with a wide range of single-electron reduction potentials (E(1)7, -0.49-0.09 V). We found that TmTR catalyzed the mixed single- and two-electron reduction of quinones and nitroaromatic compounds, which was much faster than the reduction of Grx-1. The reactivity of both groups of oxidants increased with an increase in their E(1)7, thus pointing to the absence of their structural specificity. The maximal rates of quinone reduction in the steady-state reactions were lower than the maximal rates of reduction of FAD by NADH, obtained in presteady-state experiments. The mixed-type reaction inhibition by NAD(+) was consistent with its competition for a NADH binding site in the oxidized enzyme form, and also with the reoxidation of the reduced enzyme form. The inhibition data yielded a value of the standard potential for TmTR of -0.31+/-0.03 V at pH 7.0, which may correspond to the FAD/FADH2 redox couple. Overall, the mechanism of quinone- and nitroreductase reactions of T. maritima TR was similar to the previously described mechanism of Arabidopsis thaliana TR, and points to their prooxidant and possibly cytotoxic role. PMID- 26098720 TI - Diverse expression of N-acetylglucosaminyltransferase V and complex-type beta1,6 branched N-glycans in uveal and cutaneous melanoma cells. AB - Although both uveal (UM) and cutaneous (CM) melanoma cells derive from the transformed melanocytes, their biology varies significantly in several aspects. Malignant transformation is frequently associated with alternations in cell glycosylation, in particular those concerning branched complex-type N-glycans. These changes occur principally in beta1,4-N-acetylglucosaminyltransferase III (GnT-III) that catalyzes the synthesis of glycans with bisected N acetylglucosamine (GlcNAc) and beta1,6-N-acetylglucosaminyltransferase V (GnT-V) that is involved in forming beta1,6-branched antenna in complex-type glycans. We searched for the reasons of a different behavior of CM and UM cells in the expression of GnT-III and GnT-V and their oligosaccharide products. Our study showed that UM cells have more beta1,6-branched glycans than CM cells, what results from a higher expression of MGAT5 gene encoding GnT-V. The higher beta1,6 branching of glycans in UM may contribute to their higher potential to migrate on fibronectin and weaker binding to main extracellular matrix proteins, observed in our previous studies. PMID- 26098721 TI - The avian influenza vaccine Emerflu. Why did it fail? AB - Emerflu is an inactivated, split-virion pandemic preparedness vaccine, containing 30 MUg of hemagglutinin (HA) and 600 MUg of aluminum hydroxide adjuvant. It is administered in two doses, 3 weeks apart. Only moderate immunogenicity was evident from clinical studies with the vaccine in adults, and HA antibody responses were below the criteria established by the EMA and US FDA for licensure. With the exception of Australia, the vaccine remains unlicensed. Further clinical development appears to have been suspended, and newer adjuvants such as MF59 and AS03 have since demonstrated safety and superior immunogenicity with lower HA doses. Emerflu is symbolic of the failure of aluminum salts as an adjuvant for influenza vaccines. Reasons for this failure are unclear, and may reflect problems with the adjuvant-antigen complex or interference in the immune response by heterosubtypic immunity. PMID- 26098722 TI - Anagliptin decreases serum lathosterol level in patients with type 2 diabetes: a pilot study. AB - OBJECTIVE: The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes. METHODS: Thirty patients with type 2 diabetes (20 - 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month. RESULTS: After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed. CONCLUSION: These results of our study show no significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month. Anagliptin therapy decreased the cholesterol synthesis marker lathosterol without changing cholesterol absorption markers. PMID- 26098723 TI - MALDI-TOF-MS Platform for Integrated Proteomic and Peptidomic Profiling of Milk Samples Allows Rapid Detection of Food Adulterations. AB - Adulteration of ovine, caprine, and buffalo milks with more common bovine material occurs for economic reasons and seasonal availability. Frauds are also associated with the use of powdered milk instead of declared, fresh material. In this context, various analytical methods have been adapted to dairy science applications with the aim to evaluate adulteration of milk samples, although time consuming, suitable only for speciation or thermal treatment analysis, or useful for a specific fraud type. An integrated MALDI-TOF-MS platform for the combined peptidomic and proteomic profiling of milk samples is here presented, which allows rapid detection of illegal adulterations due to the addition of either nondeclared bovine material to water buffalo, goat, and ovine milks or of powdered bovine milk to the fresh counterpart. Peptide and protein markers of each animal milk were identified after direct analysis of a large number of diluted skimmed and/or enriched diluted skimmed filtrate samples. In parallel, markers of thermal treatment were characterized in different types of commercial milks. Principal components scores of ad hoc prepared species- or thermal treatment-associated adulterated milk samples were subjected to partial least squares regression, permitting a fast accurate estimate of the fraud extents in test samples at either protein and peptide level. With respect to previous reports on MALDI-TOF-MS protein profiling methodologies for milk speciation, this study extends that approach to the analysis of the thermal treatment and introduces an independent, complementary peptide profiling measurement, which integrates protein data with additional information on peptides, validating final results and ultimately broadening the method applicability. PMID- 26098724 TI - Exploring the Attractiveness of New Psychoactive Substances (NPS) among Experienced Drug Users. AB - A growing number of New Psychoactive Substances (NPS) appear yearly on the European market (81 for the first time in 2013, adding to a total of over 350 NPS). Using semi-structured interviews with 25 Dutch experienced recreational drug users, the role of the Internet and friends in gathering and exchanging information about NPS was elaborated. Furthermore, we investigated how NPS were acquired and which aspects make NPS more or less attractive, including their legal status. It appeared that the Internet was an important source of information about NPS in general. Personal experiences with NPS were preferably shared face-to-face with friends, as for privacy reasons users were cautious to post their experiences on web sites and forums. NPS were usually obtained or bought from friends or-to a lesser extent-purchased via the Internet. The preference for a specific NPS depended on the desired effects (mostly stimulant or psychedelic), price (similar to MDMA or amphetamine), duration of effect (preferably around four hours), and setting (at home, at festivals, or in nightlife). Legal status was not relevant for the decision to use NPS. Most NPS are not superior to the already marketed drugs, and do not displace conventional illicit drugs. PMID- 26098725 TI - Palladium-Catalyzed Carbonylation of (Hetero)Aryl, Alkenyl and Allyl Halides by Means of N-Hydroxysuccinimidyl Formate as CO Surrogate. AB - An efficient Pd-catalyzed carbonylation protocol is described for the coupling of a large panel of aryl, heteroaryl, benzyl, vinyl and allyl halides 2 with the unusual N-hydroxysuccinimidyl (NHS) formate 1 as a CO surrogate to afford the corresponding valuable NHS esters 3. High conversion to the coupling products was achieved with up to 98% yield by means of Pd(OAc)2/Xantphos catalyst system. PMID- 26098726 TI - Vicarious learning of children's social-anxiety-related fear beliefs and emotional Stroop bias. AB - Models of social anxiety suggest that negative social experiences contribute to the development of social anxiety, and this is supported by self-report research. However, there is relatively little experimental evidence for the effects of learning experiences on social cognitions. The current study examined the effect of observing a social performance situation with a negative outcome on children's (8 to 11 years old) fear-related beliefs and cognitive processing. Two groups of children were each shown 1 of 2 animated films of a person trying to score in basketball while being observed by others; in 1 film, the outcome was negative, and in the other, it was neutral. Children's fear-related beliefs about performing in front of others were measured before and after the film and children were asked to complete an emotional Stroop task. Results showed that social fear beliefs increased for children who saw the negative social performance film. In addition, these children showed an emotional Stroop bias for social-anxiety-related words compared to children who saw the neutral film. The findings have implications for our understanding of social anxiety disorder and suggest that vicarious learning experiences in childhood may contribute to the development of social anxiety. PMID- 26098727 TI - Examining factors involved in stress-related working memory impairments: Independent or conditional effects? AB - A large and growing body of research demonstrates the impact of psychological stress on working memory. However, the typical study approach tests the effects of a single biological or psychological factor on changes in working memory. The current study attempted to move beyond the standard single-factor assessment by examining the impact of 2 possible factors in stress-related working memory impairments. To this end, 60 participants completed a working memory task before and after either a psychological stressor writing task or a control writing task and completed measures of both cortisol and mind wandering. We also included a measure of state anxiety to examine the direct and indirect effect on working memory. We found that mind wandering mediated the relationship between state anxiety and working memory at the baseline measurement. This indirect relationship was moderated by cortisol, such that the impact of mind wandering on working memory increased as cortisol levels increased. No overall working memory impairment was observed following the stress manipulation, but increases in state anxiety and mind wandering were observed. State anxiety and mind wandering independently mediated the relationship between change in working memory and threat perception. The indirect paths resulted in opposing effects on working memory. Combined, the findings from this study suggest that cortisol enhances the impact of mind wandering on working memory, that state anxiety may not always result in stress-related working memory impairments, and that high working memory performance can protect against mind wandering. PMID- 26098728 TI - The influence of stimulus sex and emotional expression on the attentional blink. AB - Past studies have demonstrated that angry faces used as the first target (T1) in an attentional blink paradigm interfere with processing of a second, neutral target (T2). However, despite research that suggests that the sex and emotional expression of a face are confounded, no study has investigated whether the sex of a stimulus might interact with emotional expression to influence the attentional blink. In the current study, both the sex and emotional expression of a T1 stimulus were manipulated to assess participants' ability to report the presences of a subsequent neutral target. Although the findings revealed limited evidence to support an interaction between sex and emotion, both the sex and emotional expression of the T1 stimulus were found to independently affect reporting of T2. These findings suggest that both emotional expression and stimulus sex are important in the temporal allocation of attentional resources to faces. PMID- 26098730 TI - Negative emotional stimuli enhance vestibular processing. AB - Recent studies have shown that vestibular stimulation can influence affective processes. In the present study, we examined whether emotional information can also modulate vestibular perception. Participants performed a vestibular discrimination task on a motion platform while viewing emotional pictures. Six different picture categories were taken from the International Affective Picture System: mutilation, threat, snakes, neutral objects, sports, and erotic pictures. Using a Bayesian hierarchical approach, we were able to show that vestibular discrimination improved when participants viewed emotionally negative pictures (mutilation, threat, snake) when compared to neutral/positive objects. We conclude that some of the mechanisms involved in the processing of vestibular information are also sensitive to emotional content. Emotional information signals importance and mobilizes the body for action. In case of danger, a successful motor response requires precise vestibular processing. Therefore, negative emotional information improves processing of vestibular information. PMID- 26098729 TI - Blocking opioids attenuates physical warmth-induced feelings of social connection. AB - "Heartwarming" social experiences, when one feels interpersonally connected to others, have recently been linked with physical warmth. According to one theory (Panksepp, 1998), "social warmth" and physical warmth may be closely linked because both experiences are supported by similar neurobiological mechanisms; however, the neurochemical substrates underlying this overlap have not been explored. Here, an opioid antagonist, naltrexone, was administered in order to examine the role of opioids, previously shown to alter temperature and social bonding behavior, on perceived thermal intensity, general positive affect, and feelings of social connection from physical warmth. Thirty-one participants took both naltrexone and a placebo and completed a temperature manipulation task (held a warm pack, cold pack, and neutral object) while on each drug. Replicating previous research, holding a warm (vs. a cold or neutral) object increased feelings of social connection. Moreover, blocking opioids reduced this effect. Hence, naltrexone specifically reduced feelings of social connection to holding a warm (vs. neutral) object but not to holding a cold (vs. neutral) object. These results lend further support to the theory that social and physical warmth share neurobiological, opioid receptor dependent mechanisms. PMID- 26098731 TI - Control when it counts: Change in executive control under stress predicts depression symptoms. AB - Individual differences in the ability to regulate affect following stressful life events have been associated with an increased risk for experiencing depression symptoms. Research further suggests that emotion regulation may depend on executive control which, in turn, has been shown to decline following stress exposure. Whether individual differences in stress-induced change in executive control predict depression symptoms, however, remains unknown. The current study examined whether trait executive control as well as stress-induced change in executive control predicts depression symptoms during a stressful time of life. The current study recruited 43 individuals during their first year of college. Participants completed an executive control task before and after a laboratory stress induction. Participants reported baseline depression symptoms during the laboratory session and follow-up depression symptoms during the final weeks of the semester. Results demonstrate that stress-induced change in executive control predicted an increase in depression symptoms at the end of the semester. The findings suggest that individual differences in the degree of decline in executive control following stress exposure may be a key factor in explaining why some individuals are vulnerable to depression during a stressful time of life. PMID- 26098732 TI - Emotions facilitate the communication of ambiguous group memberships. AB - It is well known that emotions intersect with obvious social categories (e.g., race), influencing both how targets are categorized and the emotions that are read from their faces. Here, we examined the influence of emotional expression on the perception of less obvious group memberships for which, in the absence of obvious and stable physical markers, emotion may serve as a major avenue for group categorization and identification. Specifically, we examined whether emotions are embedded in the mental representations of sexual orientation and political affiliation, and whether people may use emotional expressions to communicate these group memberships to others. Using reverse correlation methods, we found that mental representations of gay and liberal faces were characterized by more positive facial expressions than mental representations of straight and conservative faces (Study 1). Furthermore, participants were evaluated as expressing more positive emotions when enacting self-defined "gay" and "liberal" versus "straight" and "conservative" facial expressions in the lab (Study 2). In addition, neutral faces morphed with happiness were perceived as more gay than when morphed with anger, and when compared to unmorphed controls (Study 3). Finally, we found that affect facilitated perceptions of sexual orientation and political affiliation in naturalistic settings (Study 4). Together, these studies suggest that emotion is a defining characteristic of person construal that people tend to use both when signaling their group memberships and when receiving those signals to categorize others. PMID- 26098733 TI - Emotion categories and dimensions in the facial communication of affect: An integrated approach. AB - We investigated the role of facial behavior in emotional communication, using both categorical and dimensional approaches. We used a corpus of enacted emotional expressions (GEMEP) in which professional actors are instructed, with the help of scenarios, to communicate a variety of emotional experiences. The results of Study 1 replicated earlier findings showing that only a minority of facial action units are associated with specific emotional categories. Likewise, facial behavior did not show a specific association with particular emotional dimensions. Study 2 showed that facial behavior plays a significant role both in the detection of emotions and in the judgment of their dimensional aspects, such as valence, arousal, dominance, and unpredictability. In addition, a mediation model revealed that the association between facial behavior and recognition of the signaler's emotional intentions is mediated by perceived emotional dimensions. We conclude that, from a production perspective, facial action units convey neither specific emotions nor specific emotional dimensions, but are associated with several emotions and several dimensions. From the perceiver's perspective, facial behavior facilitated both dimensional and categorical judgments, and the former mediated the effect of facial behavior on recognition accuracy. The classification of emotional expressions into discrete categories may, therefore, rely on the perception of more general dimensions such as valence and arousal and, presumably, the underlying appraisals that are inferred from facial movements. PMID- 26098734 TI - Emotional and instrumental support provision interact to predict well-being. AB - Individuals in close relationships help each other in many ways, from listening to each other's problems, to making each other feel understood, to providing practical support. However, it is unclear if these supportive behaviors track each other across days and as stable tendencies in close relationships. Further, although past work suggests that giving support improves providers' well-being, the specific features of support provision that improve providers' psychological lives remain unclear. We addressed these gaps in knowledge through a daily diary study that comprehensively assessed support provision and its effects on well being. We found that providers' emotional support (e.g., empathy) and instrumental support represent distinct dimensions of support provision, replicating prior work. Crucially, emotional support, but not instrumental support, consistently predicted provider well-being. These 2 dimensions also interacted, such that instrumental support enhanced well-being of both providers and recipients, but only when providers were emotionally engaged while providing support. These findings illuminate the nature of support provision and suggest targets for interventions to enhance well-being. PMID- 26098735 TI - When Is Group Membership Zero-Sum? Effects of Ethnicity, Threat, and Social Identity on Dual National Identity. AB - This paper presents an investigation into marginalizing racism, a form of prejudice whereby ingroup members claim that specific individuals belong to their group, but also exclude them by not granting them all of the privileges of a full ingroup member. One manifestation of this is that perceived degree of outgroup membership will covary negatively with degree of ingroup membership. That is, group membership may be treated as a zero-sum quantity (e.g., one cannot be both Australian and Iraqi). Study 1 demonstrated that judges allocate more zero-sum membership assignments and lower combined membership in their country of origin and their adopted country to high-threat migrants than low-threat migrants. Study 2 identified a subtle type of zero-sum reasoning which holds that stronger degree of membership in one's original nationality constrains membership in a new nationality to a greater extent than stronger membership in the new nationality constrains membership in one's original nationality. This pattern is quite general, being replicated in large samples from four nations (USA, UK, India, and China). Taken together, these studies suggest that marginalizing racism is more than a belief that people retain a "stain" from membership in their original group. Marginalizing racism also manifests itself as conditional zero-sum beliefs about multiple group memberships. PMID- 26098736 TI - Prevalence of posttraumatic stress symptoms in United States Air Force intelligence, surveillance, and reconnaissance agency imagery analysts. AB - Imagery analysts are critical to the intelligence capabilities of the United States Air Force (USAF) and are known as the "eyes" of the USAF. The purpose of this study was to assess for posttraumatic disorder (PTSD) symptoms among this cohort. Of the 498 imagery analysts who participated, a total of 4.22% met provisional diagnostic criteria for PTSD as outlined in the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 2000) which was lower than established rates of PTSD (up to 18%) among military personnel returning from deployment. Implications of subclinical PTSD symptoms on occupational functioning and overall diagnostic picture are discussed. PMID- 26098737 TI - Time course of treatment dropout in cognitive-behavioral therapies for posttraumatic stress disorder. AB - A substantial minority of people drop out of cognitive-behavioral therapies (CBTs) for posttraumatic stress disorder (PTSD). There has been considerable research investigating who drops out of PTSD treatment; however, the question of when dropout occurs has received far less attention. The purpose of the current study was to examine when individuals drop out of CBT for PTSD. Women participants (N = 321) were randomized to 1 of several PTSD treatment conditions. The conditions included prolonged exposure (PE), cognitive processing therapy (CPT), CPT-cognitive only (CPT-C), and written accounts (WA). Survival analysis was used to examine temporal pattern of treatment dropout. Thirty-nine percent of participants dropped out of treatment, and those who dropped out tended to do so by midtreatment. Moreover, the pattern of treatment dropout was consistent across CBT conditions. Additional research is needed to examine if treatment dropout patterns are consistent across treatment modalities and settings. PMID- 26098738 TI - The coffee paradox in stroke: Increased consumption linked with fewer strokes. AB - OBJECTIVE: To determine the association in amount of daily coffee consumption with incidence of stroke in a broad cohort, considering other vascular risk factors. METHODS: We utilized the Third National Health and Nutrition Examination Survey (1988-1994; NHANES III) data on participants aged >=17 years old to examine coffee consumption and stroke. Multivariate logistic regression models related the amount of coffee use reported in a food frequency questionnaire with stroke, controlling for other vascular risk factors. RESULTS: Of 33 994 NHANES III subjects, coffee consumption and stroke data in adults >=17 years old were available in 19 994. Daily coffee consumption ranged from 0 to 20 (median 1) cups and 644 (3.2%) participants had a stroke diagnosed by a physician. Coffee intake varied with age, gender, and ethnicity (P < 0.001). Interestingly, heart failure, diabetes, and hypertension were less frequent, and high cholesterol more frequent in those consuming >=3 cups per day (P < 0.001). Smoking was more frequent in all coffee drinkers (P < 0.0001). Multivariate analyses revealed an independent effect of heavier coffee consumption (>=3 cups/day) on reduced stroke (OR 0.44, 95% CI 0.22-0.87, P < 0.02) in healthy subjects that was attenuated by vascular risk factors (OR 0.78, 95% CI 0.58-1.07, P ~ 0.12). CONCLUSION: Heavier daily coffee consumption is associated with decreased stroke prevalence, despite smoking tendency in heavy coffee drinkers. PMID- 26098739 TI - An Improved Instrument Table for Use in Functional Endoscopic Sinus Surgery. AB - BACKGROUND: The clinical motivation for the current study was that various instrument tables are located far away from the patient's head, and the only way for the surgeon to access an instrument is via a scrub nurse. Thus, the idea for this study was the development and evaluation of an improved and conveniently positioned instrument table. MATERIAL AND METHODS: An improved instrument table (IT) was designed, built, and tested. We assessed its use in 150 surgeries from 1 October 2013 to 30 June 2014 (group A), and another 150 surgeries without use of the IT from 1 February 2013 to 31 October 2014 as a control group (group B). RESULTS: With use of the improved IT during functional endoscopic sinus surgery (FESS), preparation-time was extended by 0.1 min and the SLOT-time was reduced by 19.6%. The number of different instruments (35.3%) used was reduced, as well as the number of manual interactions with instruments (7.8%) and the number of manual interactions with the scrub nurse (66.1%). In addition, the ergonomics with use of the IT improved by 40.0%. The only potential disadvantage was a reduction of working space and thereby a constraint of the scope. Compared to the benefits, this problem is minor. CONCLUSIONS: Conclusively, the improved IT is of value for everyday use in surgery and offers a great benefit for FESS, and may be useful in other kinds of surgery (e.g., duraplasty). PMID- 26098740 TI - Summaries for Patients: Motor Vehicle Crash Fatalities and Seat Belt Laws. PMID- 26098741 TI - Steeling Ourselves: Intragroup Communication while Anticipating Intergroup Contact Evokes Defensive Intergroup Perceptions. AB - Two experiments investigated the role of intragroup communication in intergroup conflict (de-)escalation. Experiment 1 examined the effects of intragroup communication (vs. individual thought) and anticipated face-to-face intergroup contact (vs. no anticipated face-to-face intergroup contact). The group discussions of stigmatized group members who anticipated face-to-face intergroup contact revolved more around intergroup hostility. This boosted ingroup identification and increased social creativity but also led to steeling (a hardening of perceived intergroup relations). In Experiment 2, new participants listened to the taped group discussions. The discussions of groups anticipating face-to-face intergroup contact evoked more intergroup anxiety-related discomfort than discussions of groups not anticipating face-to-face intergroup encounters. Together, these results support the idea that steeling is a defensive reaction to prepare for an anxiety-arousing intergroup confrontation. Although steeling is also associated with positive consequences such as increased ingroup solidarity and social creativity, this hardened stance may be an obstacle to conflict de escalation. PMID- 26098743 TI - Correction: Re-Examination of 30-Day Survival and Relapse Rates in Patients with Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome. PMID- 26098742 TI - SNSMIL, a real-time single molecule identification and localization algorithm for super-resolution fluorescence microscopy. AB - Single molecule localization based super-resolution fluorescence microscopy offers significantly higher spatial resolution than predicted by Abbe's resolution limit for far field optical microscopy. Such super-resolution images are reconstructed from wide-field or total internal reflection single molecule fluorescence recordings. Discrimination between emission of single fluorescent molecules and background noise fluctuations remains a great challenge in current data analysis. Here we present a real-time, and robust single molecule identification and localization algorithm, SNSMIL (Shot Noise based Single Molecule Identification and Localization). This algorithm is based on the intrinsic nature of noise, i.e., its Poisson or shot noise characteristics and a new identification criterion, QSNSMIL, is defined. SNSMIL improves the identification accuracy of single fluorescent molecules in experimental or simulated datasets with high and inhomogeneous background. The implementation of SNSMIL relies on a graphics processing unit (GPU), making real-time analysis feasible as shown for real experimental and simulated datasets. PMID- 26098744 TI - Acylation of Antioxidant of Bamboo Leaves with Fatty Acids by Lipase and the Acylated Derivatives' Efficiency in the Inhibition of Acrylamide Formation in Fried Potato Crisps. AB - This study selectively acylated the primary hydroxyl groups on flavonoids in antioxidant of bamboo leaves (AOB) using lauric acid with Candida antarctica lipase B in tert-amyl-alcohol. The separation and isolation of acylated derivatives were performed using silica gel column chromatography with a mixture of dichloromethane/diethyl ether/methanol as eluents. Both thin layer chromatography and high-performance liquid chromatography analyses confirmed the high efficiency of the isolation process with the purified orientin-6"-laurate, isoorientin-6"-laurate, vitexin-6"-laurate, and isovitexin-6"-laurate that were obtained. The addition of AOB and acylated AOB reduced acrylamide formation in fried potato crisps. Results showed that 0.05% AOB and 0.05% and 0.1% acylated AOB groups significantly (p < 0.05) reduced the content of acrylamide in potato crisps by 30.7%, 44.5%, and 46.9%, respectively. PMID- 26098745 TI - Flavonoids in Microheterogeneous Media, Relationship between Their Relative Location and Their Reactivity towards Singlet Oxygen. AB - In this work, the relationship between the molecular structure of three flavonoids (kaempferol, quercetin and morin), their relative location in microheterogeneous media (liposomes and erythrocyte membranes) and their reactivity against singlet oxygen was studied. The changes observed in membrane fluidity induced by the presence of these flavonoids and the influence of their lipophilicity/hydrophilicity on the antioxidant activity in lipid membranes were evaluated by means of fluorescent probes such as Laurdan and diphenylhexatriene (DPH). The small differences observed for the value of generalized polarization of Laurdan (GP) curves in function of the concentration of flavonoids, indicate that these three compounds promote similar alterations in liposomes and erythrocyte membranes. In addition, these compounds do not produce changes in fluorescence anisotropy of DPH, discarding their location in deeper regions of the lipid bilayer. The determined chemical reactivity sequence is similar in all the studied media (kaempferol < quercetin < morin). Morin is approximately 10 times more reactive than quercetin and 20 to 30 times greater than kaempferol, depending on the medium. PMID- 26098746 TI - Exercise rehabilitation following intensive care unit discharge for recovery from critical illness. AB - BACKGROUND: Skeletal muscle wasting and weakness are significant complications of critical illness, associated with degree of illness severity and periods of reduced mobility during mechanical ventilation. They contribute to the profound physical and functional deficits observed in survivors. These impairments may persist for many years following discharge from the intensive care unit (ICU) and can markedly influence health-related quality of life. Rehabilitation is a key strategy in the recovery of patients after critical illness. Exercise-based interventions are aimed at targeting this muscle wasting and weakness. Physical rehabilitation delivered during ICU admission has been systematically evaluated and shown to be beneficial. However, its effectiveness when initiated after ICU discharge has yet to be established. OBJECTIVES: To assess the effectiveness of exercise rehabilitation programmes, initiated after ICU discharge, for functional exercise capacity and health-related quality of life in adult ICU survivors who have been mechanically ventilated longer than 24 hours. SEARCH METHODS: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid SP MEDLINE, Ovid SP EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO host to 15 May 2014. We used a specific search strategy for each database. This included synonyms for ICU and critical illness, exercise training and rehabilitation. We searched the reference lists of included studies and contacted primary authors to obtain further information regarding potentially eligible studies. We also searched major clinical trials registries (Clinical Trials and Current Controlled Trials) and the personal libraries of the review authors. We applied no language or publication restriction. We reran the search in February 2015 and will deal with the three studies of interest when we update the review. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-RCTs and controlled clinical trials (CCTs) that compared an exercise intervention initiated after ICU discharge versus any other intervention or a control or 'usual care' programme in adult (>= 18 years) survivors of critical illness. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by the Cochrane Collaboration. MAIN RESULTS: We included six trials (483 adult ICU participants). Exercise-based interventions were delivered on the ward in two studies; both on the ward and in the community in one study; and in the community in three studies. The duration of the intervention varied according to length of hospital stay following ICU discharge (up to a fixed duration of 12 weeks).Risk of bias was variable for all domains across all trials. High risk of bias was evident in all studies for performance bias, although blinding of participants and personnel in therapeutic rehabilitation trials can be pragmatically challenging. For other domains, at least half of the studies were at low risk of bias. One study was at high risk of selection bias, attrition bias and other sources of bias. Risk of bias was unclear for the remaining studies across domains. We decided not to undertake a meta-analysis because of variation in study design, types of interventions and outcome measurements. We present a narrative description of individual studies for each outcome.All six studies assessed functional exercise capacity, although we noted wide variability in the nature of interventions, outcome measures and associated metrics and data reporting. Overall quality of the evidence was very low. Individually, three studies reported positive results in favour of the intervention. One study found a small short-term benefit in anaerobic threshold (mean difference (MD) 1.8 mL O2/kg/min, 95% confidence interval (CI) 0.4 to 3.2; P value = 0.02). In a second study, both incremental (MD 4.7, 95% CI 1.69 to 7.75 watts; P value = 0.003) and endurance (MD 4.12, 95% CI 0.68 to 7.56 minutes; P value = 0.021) exercise testing results were improved with intervention. Finally self reported physical function increased significantly following use of a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention.Similar variability was evident with regard to findings for the primary outcome of health-related quality of life. Only two studies evaluated this outcome. Individually, neither study reported differences between intervention and control groups for health-related quality of life due to the intervention. Overall quality of the evidence was very low.Four studies reported rates of withdrawal, which ranged from 0% to 26.5% in control groups, and from 8.2% to 27.6% in intervention groups. The quality of evidence for the effect of the intervention on withdrawal was low. Very low quality evidence showed rates of adherence with the intervention. Mortality ranging from 0% to 18.8% was reported by all studies. The quality of evidence for the effect of the intervention on mortality was low. Loss to follow-up, as reported in all studies, ranged from 0% to 14% in control groups, and from 0% to 12.5% in intervention groups, with low quality of evidence. Only one non mortality adverse event was reported across all participants in all studies (a minor musculoskeletal injury), and the quality of the evidence was low. AUTHORS' CONCLUSIONS: At this time, we are unable to determine an overall effect on functional exercise capacity, or on health-related quality of life, of an exercise-based intervention initiated after ICU discharge for survivors of critical illness. Meta-analysis of findings was not appropriate because the number of studies and the quantity of data were insufficient. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others did not. No effect on health-related quality of life was reported. Methodological rigour was lacking across several domains, influencing the quality of the evidence. Wide variability was noted in the characteristics of interventions, outcome measures and associated metrics and data reporting.If further trials are identified, we may be able to determine the effects of exercise-based intervention following ICU discharge on functional exercise capacity and health-related quality of life among survivors of critical illness. PMID- 26098747 TI - Associations between Dietary Antioxidant Intake and Metabolic Syndrome. AB - BACKGROUND: The objective of this study was to evaluate the association between dietary antioxidant intake (carotenoid, vitamin C, E and selenium) intake and metabolic syndrome (MS). METHOD: This cross-sectional study included 2069 subjects undergoing a regular health checkup. Biochemical test results and data on dietary intakes were collected for analysis. Adjustment for energy intake and multi-variable logistic regression were performed to determine adjusted odds ratios (ORs) and corresponding 95% confidence intervals (95%CI) for the relationship between dietary antioxidants intake and MS. The lowest quartile of antioxidant intake was regarded as the reference category. RESULT: Dietary vitamin C intake (P values for trend were 0.02 in energy adjusted analysis and 0.08 in multivariable adjusted analysis) had a negative association with MS, as did selenium intake in the second quartile (energy adjusted OR: 0.60, 95%CI: 0.43 to 0.85; multivariable adjusted OR: 0.60, 95%CI: 0.43 to 0.86). However, there was no significant relationship between dietary carotenoid and vitamin E intake and MS. CONCLUSION: Subjects with low intake of vitamin C might be predisposed to development of MS, while dietary selenium intake had a moderate negative association with MS. Dietary carotenoid and vitamin E intake was not associated with MS. PMID- 26098749 TI - Profiling of Oncogenic Driver Events in Lung Adenocarcinoma Revealed MET Mutation as Independent Prognostic Factor. AB - INTRODUCTION: Oncogenic driver mutations activating receptor tyrosine kinase pathways are promising predictive markers for targeted treatment. We investigated the mutation profile of an updated driver events list on receptor tyrosine kinase/RAS/PI3K axis and the clinicopathologic implications in a cohort of never smoker predominated Chinese lung adenocarcinoma. METHODS: We tested 154 lung adenocarcinomas and adenosquamous carcinomas for EGFR, KRAS, HER2, BRAF, PIK3CA, MET, NRAS, MAP2K1, and RIT1 mutations by polymerase chain reaction-direct sequencing. MET amplification and ALK and ROS1 translocations were assessed by fluorescent in situ hybridizations. MET and thyroid transcription factor-1 protein expressions were investigated by immunohistochemistry. RESULTS: Seventy percent of lung adenocarcinomas carried actionable driver events. Alterations on EGFR (43%), KRAS (11.4%), ALK (6%), and MET (5.4%) were frequently found. ROS1 translocation and mutations involving BRAF, HER2, NRAS, and PIK3CA were also detected. No mutation was observed in RIT1 and MAP2K1. Patients with EGFR mutations had a favorable prognosis, whereas those with MET mutations had poorer overall survival. Multivariate analysis further demonstrated that MET mutation was an independent prognostic factor. Although MET protein expression was detected in 65% of lung adenocarcinoma, only 10% of the MET-immunohistochemistry positive tumors harbor MET DNA alterations that drove protein overexpression. Appropriate predictive biomarker is essential for selecting patients who might benefit from specific targeted therapy. CONCLUSION: Actionable driver events can be detected in two thirds of lung adenocarcinoma. MET DNA alterations define a subset of patients with aggressive diseases that might potentially benefit from anti-MET targeted therapy. High negative predictive values of thyroid transcription factor-1 and MET expression suggest potential roles as surrogate markers for EGFR and/or MET mutations. PMID- 26098751 TI - Single molecule magnet behaviour in a {Dy4P2} octahedron. AB - Two new tetrametallic lanthanide-phosphonate complexes have been structurally and magnetically characterised. The {Dy4} complex is a single molecule magnet. PMID- 26098750 TI - Retrorectal multilocular cyst in a adult female. Case report and review of literature. AB - Tumors occurring in the retrorectal space are heterogeneous and uncommon. Multiple embryologie remnants derived from a variety of tissues are found in this space and this explains the heterogeneous pathology of cysts and tumors that arise in retrorectal space. Presacral cysts are rare in adults. Most of the lesions are benign. The cysts may be unilocular or multilocular. They are often asymptomatic. These tumors pose a diagnostic and therapeutic interest. Presacral epidermoid cysts are classified as a type of developmental cysts. We report the case of a 57-year-old woman who presented with a painless mass posterior of the anus. Imaging studies showed a multilocular cyst (65 * 100 * 60 mm) in the retrorectal space. The patient underwent surgery via a posterior approach. Histological study revealed a epidermoid cyst. A review of literature of this rare tumor is performed. PMID- 26098748 TI - Safety and Efficacy of Buparlisib (BKM120) in Patients with PI3K Pathway Activated Non-Small Cell Lung Cancer: Results from the Phase II BASALT-1 Study. AB - INTRODUCTION: The phosphatidylinositol 3-kinase (PI3K) pathway promotes tumor growth and treatment resistance in non-small cell lung cancer (NSCLC). The aim of the open-label, two-stage, Phase II study BASALT-1 (NCT01820325) was to investigate the pan-PI3K inhibitor buparlisib (BKM120) in patients with PI3K pathway-activated, relapsed NSCLC. METHODS: After prescreening for PI3K pathway activation, patients with PI3K pathway-activated, metastatic, squamous or nonsquamous NSCLC, who had relapsed after prior systemic antineoplastic therapy, were enrolled. In Stage 1, patients received single-agent buparlisib (100 mg/day). A futility analysis was performed independently in each histology group, based on the 12-week progression-free survival rate for the first 30 patients treated in each group being less than 50%. Exploratory biomarker analyses were performed in archival tissue samples and circulating tumor DNA (ctDNA). RESULTS: Of 1242 prescreened patients, 13.5% exhibited PI3K pathway activation. As of June 5, 2014, 63 patients (30 squamous and 33 nonsquamous) were treated in Stage 1. The 12-week progression-free survival rates were 23.3% (95% confidence interval: 9.9-42.3) and 20.0% (95% confidence interval: 7.7-38.6) in the squamous and nonsquamous groups, respectively. Stage 2 was therefore not initiated in either group. PI3K pathway mutations in ctDNA were more concordant with metastatic tissue than with primary biopsies. CONCLUSIONS: Despite preselecting patients for targeted treatment, BASALT-1 did not meet its primary objective during Stage 1. PI3K pathway activation can be detected using ctDNA, but may not be the main oncogenic driver in NSCLC. Combinations of PI3K inhibitors with other agents may demonstrate greater efficacy than monotherapy. PMID- 26098752 TI - Brute-Force Hyperpolarization for NMR and MRI. AB - Hyperpolarization (HP) of nuclear spins is critical for ultrasensitive nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). We demonstrate an approach for >1500-fold enhancement of key small-molecule metabolites: 1-(13)C pyruvic acid, 1-(13)C-sodium lactate, and 1-(13)C-acetic acid. The (13)C solution NMR signal of pyruvic acid was enhanced 1600-fold at B = 1 T and 40 degrees C by pre-polarizing at 14 T and ~2.3 K. This "brute-force" approach uses only field and temperature to generate HP. The noted 1 T observation field is appropriate for benchtop NMR and near the typical 1.5 T of MRI, whereas high-field observation scales enhancement as 1/B. Our brute-force process ejects the frozen, solid sample from the low-T, high-B polarizer, passing it through low field (B < 100 G) to facilitate "thermal mixing". That equilibrates (1)H and (13)C in hundreds of milliseconds, providing (13)C HP from (1)H Boltzmann polarization attained at high B/T. The ejected sample arrives at a room-temperature, permanent magnet array, where rapid dissolution with 40 degrees C water yields HP solute. Transfer to a 1 T NMR system yields (13)C signals with enhancements at 80% of ideal for noted polarizing conditions. High-resolution NMR of the same product at 9.4 T had consistent enhancement plus resolution of (13)C shifts and J-couplings for pyruvic acid and its hydrate. Comparable HP was achieved with frozen aqueous lactate, plus notable enhancement of acetic acid, demonstrating broader applicability for small-molecule NMR and metabolic MRI. Brute-force avoids co solvated free-radicals and microwaves that are essential to competing methods. Here, unadulterated samples obviate concerns about downstream purity and also exhibit slow solid-state spin relaxation, favorable for transporting HP samples. PMID- 26098753 TI - High-Performance Zn-TiC-C Nanocomposite Alloy Anode with Exceptional Cycle Life for Lithium-Ion Batteries. AB - A Zn-based nanocomposite has been prepared through a facile, low-cost high-energy mechanochemical process and employed as an anode material for lithium-ion batteries. Structural characterization reveals that the micrometer-sized Zn-TiC-C nanocomposite is composed of Zn nanocrystals uniformly dispersed in a multifunctional TiC and conductive carbon matrix with a tap density of 1.3 g cm( 3). The Zn-TiC-C nanocomposite exhibits high reversible volumetric capacity (468 mA h cm(-3)), excellent cyclability over 800 cycles (79.2% retention), and good rate performance up to 12.5C (75% of its capacity at 0.25C rate). The enhanced electrochemical performance is mainly due to the presence of the well-mixed TiC+C matrix that plays an important role in providing high conductivity as well as mechanical buffer that mitigates the huge volume expansion and contraction during prolonged cycling. In addition, it prevents the particle growth by uniformly dispersing nanosized Zn within itself during cycling, maintaining high utilization (~100%) and fast reaction kinetics of Zn anode. PMID- 26098754 TI - Influence of carbon dioxide pneumoperitoneum on the growth hormone-insulin-like growth factor I axis in mid- and late-pregnancy rats. AB - AIM: We investigated the influence of carbon dioxide (CO2) pneumoperitoneum on the growth hormone(GH)-insulin-like growth factor I (IGF-I) axis in mid- and late pregnancy Sprague-Dawley rats. METHODS: A total of 48 mid-pregnancy rats were randomly assigned to one of three groups: anesthesia only (control group); 1-h CO2 pneumoperitoneum; or 2-h CO2 pneumoperitoneum. Blood samples were collected immediately after the procedure or in late pregnancy. Maternal concentration of serum GH and IGF-I was measured on enzyme-linked immunosorbent assay and compared between different groups. RESULTS: Under the same CO2 pneumoperitoneum pressure, serum GH and IGF-I concentration in the 2-h pneumoperitoneum group were significantly lower than those of the 1-h pneumoperitoneum group or the control group in both mid- and late pregnancy (P < 0.05), but there was no significant difference between the 1-h pneumoperitoneum group and the control group (P > 0.05). Serum GH and IGF-I concentrations were positively correlated in pregnant rats (R(2) = 0.3434, P < 0.05). CONCLUSIONS: Under the same CO2 pneumoperitoneum pressure, exposure duration was correlated with effect on maternal GH-IGF-I axis in mid- and late-pregnancy rats. Two h of exposure inhibited the GH-IGF-I axis in both mid- and late pregnancy, and therefore may restrict development of the placenta and fetus. PMID- 26098756 TI - A Difference in Fatty Acid Composition of Isocaloric High-Fat Diets Alters Metabolic Flexibility in Male C57BL/6JOlaHsd Mice. AB - Poly-unsaturated fatty acids (PUFAs) are considered to be healthier than saturated fatty acids (SFAs), but others postulate that especially the ratio of omega-6 to omega-3 PUFAs (n6/n3 ratio) determines health. Health can be determined with biomarkers, but functional health status is likely better reflected by challenge tests that assess metabolic flexibility. The aim of this study was to determine the effect of high-fat diets with different fatty acid compositions, but similar n6/n3 ratio, on metabolic flexibility. Therefore, adult male mice received isocaloric high-fat diets with either predominantly PUFAs (HFpu diet) or predominantly SFAs (HFs diet) but similar n6/n3 ratio for six months, during and after which several biomarkers for health were measured. Metabolic flexibility was assessed by the response to an oral glucose tolerance test, a fasting and re-feeding test and an oxygen restriction test (OxR; normobaric hypoxia). The latter two are non-invasive, indirect calorimetry-based tests that measure the adaptive capacity of the body as a whole. We found that the HFs diet, compared to the HFpu diet, increased mean adipocyte size, liver damage, and ectopic lipid storage in liver and muscle; although, we did not find differences in body weight, total adiposity, adipose tissue health, serum adipokines, whole body energy balance, or circadian rhythm between HFs and HFpu mice. HFs mice were, furthermore, less flexible in their response to both fasting re-feeding and OxR, while glucose tolerance was indistinguishable. To conclude, the HFs versus the HFpu diet increased ectopic fat storage, liver damage, and mean adipocyte size and reduced metabolic flexibility in male mice. This study underscores the physiological relevance of indirect calorimetry-based challenge tests. PMID- 26098757 TI - Pathway-specific reorganization of projection neurons in somatosensory cortex during learning. AB - In the mammalian brain, sensory cortices exhibit plasticity during task learning, but how this alters information transferred between connected cortical areas remains unknown. We found that divergent subpopulations of cortico-cortical neurons in mouse whisker primary somatosensory cortex (S1) undergo functional changes reflecting learned behavior. We chronically imaged activity of S1 neurons projecting to secondary somatosensory (S2) or primary motor (M1) cortex in mice learning a texture discrimination task. Mice adopted an active whisking strategy that enhanced texture-related whisker kinematics, correlating with task performance. M1-projecting neurons reliably encoded basic kinematics features, and an additional subset of touch-related neurons was recruited that persisted past training. The number of S2-projecting touch neurons remained constant, but improved their discrimination of trial types through reorganization while developing activity patterns capable of discriminating the animal's decision. We propose that learning-related changes in S1 enhance sensory representations in a pathway-specific manner, providing downstream areas with task-relevant information for behavior. PMID- 26098759 TI - Solvent-like ligand-coated ultrasmall cadmium selenide nanocrystals: strong electronic coupling in a self-organized assembly. AB - Strong inter-nanocrystal electronic coupling is a prerequisite for delocalization of exciton wave functions and high conductivity. We report 170 meV electronic coupling energy of short chain poly(ethylene glycol) thiolate-coated ultrasmall (<2.5 nm in diameter) CdSe semiconductor nanocrystals (SNCs) in solution. Cryo transmission electron microscopy analysis showed the formation of a pearl necklace assembly of nanocrystals in solution with regular inter-nanocrystal spacing. The electronic coupling was studied as a function of CdSe nanocrystal size where the smallest nanocrystals exhibited the largest coupling energy. The electronic coupling in spin-cast thin-film (<200 nm in thickness) of poly(ethylene glycol) thiolate-coated CdSe SNCs was studied as a function of annealing temperature, where an unprecedentedly large, ~400 meV coupling energy was observed for 1.6 nm diameter SNCs, which were coated with a thin layer of poly(ethylene glycol) thiolates. Small-angle X-ray scattering measurements showed that CdSe SNCs maintained an order array inside the films. The strong electronic coupling of SNCs in a self-organized film could facilitate the large-scale production of highly efficient electronic materials for advanced optoelectronic device application. PMID- 26098755 TI - Clinical and Radiologic Disease in Smokers With Normal Spirometry. AB - IMPORTANCE: Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free. OBJECTIVE: To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0. DESIGN, SETTING, AND PARTICIPANTS: Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 >=80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011. MAIN OUTCOMES AND MEASURES: Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life. RESULTS: One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George's Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P < .001) and a lower 6-minute walk distance, and 42.3% (127 of 300) of the GOLD 0 group had CT evidence of emphysema or airway thickening. The FEV1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease. CONCLUSIONS AND RELEVANCE: Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone. PMID- 26098758 TI - Subtype-specific plasticity of inhibitory circuits in motor cortex during motor learning. AB - Motor skill learning induces long-lasting reorganization of dendritic spines, principal sites of excitatory synapses, in the motor cortex. However, mechanisms that regulate these excitatory synaptic changes remain poorly understood. Here, using in vivo two-photon imaging in awake mice, we found that learning-induced spine reorganization of layer (L) 2/3 excitatory neurons occurs in the distal branches of their apical dendrites in L1 but not in the perisomatic dendrites. This compartment-specific spine reorganization coincided with subtype-specific plasticity of local inhibitory circuits. Somatostatin-expressing inhibitory neurons (SOM-INs), which mainly inhibit distal dendrites of excitatory neurons, showed a decrease in axonal boutons immediately after the training began, whereas parvalbumin-expressing inhibitory neurons (PV-INs), which mainly inhibit perisomatic regions of excitatory neurons, exhibited a gradual increase in axonal boutons during training. Optogenetic enhancement and suppression of SOM-IN activity during training destabilized and hyperstabilized spines, respectively, and both manipulations impaired the learning of stereotyped movements. Our results identify SOM inhibition of distal dendrites as a key regulator of learning-related changes in excitatory synapses and the acquisition of motor skills. PMID- 26098760 TI - Evolution of the tRNALeu (UAA) Intron and Congruence of Genetic Markers in Lichen Symbiotic Nostoc. AB - The group I intron interrupting the tRNALeu UAA gene (trnL) is present in most cyanobacterial genomes as well as in the plastids of many eukaryotic algae and all green plants. In lichen symbiotic Nostoc, the P6b stem-loop of trnL intron always involves one of two different repeat motifs, either Class I or Class II, both with unresolved evolutionary histories. Here we attempt to resolve the complex evolution of the two different trnL P6b region types. Our analysis indicates that the Class II repeat motif most likely appeared first and that independent and unidirectional shifts to the Class I motif have since taken place repeatedly. In addition, we compare our results with those obtained with other genetic markers and find strong evidence of recombination in the 16S rRNA gene, a marker widely used in phylogenetic studies on Bacteria. The congruence of the different genetic markers is successfully evaluated with the recently published software Saguaro, which has not previously been utilized in comparable studies. PMID- 26098761 TI - Spatial Change of Cruciate Ligaments in Rat Embryo Knee Joint by Three Dimensional Reconstruction. AB - This study aimed to analyze the spatial developmental changes of rat cruciate ligaments by three-dimensional (3D) reconstruction using episcopic fluorescence image capture (EFIC). Cruciate ligaments of Wister rat embryos between embryonic day (E) 16 and E20 were analyzed. Samples were sectioned and visualized using EFIC. 3D reconstructions were generated using Amira software. The length of the cruciate ligaments, distances between attachment points to femur and tibia, angles of the cruciate ligaments and the cross angle of the cruciate ligaments were measured. The shape of cruciate ligaments was clearly visible at E17. The lengths of the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) increased gradually from E17 to E19 and drastically at E20. Distances between attachment points to the femur and tibia gradually increased. The ACL angle and PCL angle gradually decreased. The cross angle of the cruciate ligaments changed in three planes. The primordium of the 3D structure of rat cruciate ligaments was constructed from the early stage, with the completion of the development of the structures occurring just before birth. PMID- 26098762 TI - AMP-Activated Kinase Regulates Lipid Droplet Localization and Stability of Adipose Triglyceride Lipase in C. elegans Dauer Larvae. AB - Animals have developed diverse mechanisms to adapt to their changing environment. Like many organisms the free-living nematode C. elegans can alternate between a reproductive mode or a diapause-like "dauer" stage during larval development to circumvent harsh environmental conditions. The master metabolic regulator AMP activated protein kinase (AMPK) is critical for survival during the dauer stage, where it phosphorylates adipose triglyceride lipase (ATGL-1) at multiple sites to block lipid hydrolysis and ultimately protect the cellular triglyceride-based energy depot from rapid depletion. However, how the AMPK-mediated phosphorylation affects the function of ATGL-1 has not been characterised at the molecular level. Here we show that AMPK phosphorylation leads to the generation of 14-3-3 binding sites on ATGL-1, which are recognized by the C. elegans 14-3-3 protein orthologue PAR-5. Physical interaction of ATGL-1 with PAR-5 results in sequestration of ATGL 1 away from the lipid droplets and eventual proteasome-mediated degradation. In addition, we also show that the major AMPK phosphorylation site on ATGL-1, Ser 303, is required for both modification of its lipid droplet localization and its degradation. Our data provide mechanistic insight as to how AMPK functions to enhance survival through its ability to protect the accumulated triglyceride deposits from rapid hydrolysis to preserve the energy stores during periods of extended environmental duress. PMID- 26098763 TI - Tumor Necrosis Factor (TNF) -308G>A, Nitric Oxide Synthase 3 (NOS3) +894G>T Polymorphisms and Migraine Risk: A Meta-Analysis. AB - BACKGROUND AND OBJECTIVE: Conflicting data have been reported on the association between tumor necrosis factor (TNF) -308G>A and nitric oxide synthase 3 (NOS3) +894G>T polymorphisms and migraine. We performed a meta-analysis of case-control studies to evaluate whether the TNF -308G>A and NOS3 +894G>T polymorphisms confer genetic susceptibility to migraine. METHOD: We performed an updated meta-analysis for TNF -308G>A and a meta-analysis for NOS3 +894G>T based on studies published up to July 2014. We calculated study specific odds ratios (OR) and 95% confidence intervals (95% CI) assuming allele contrast, dominant model, recessive model, and co-dominant model as pooled effect estimates. RESULTS: Eleven studies in 6682 migraineurs and 22591 controls for TNF -308G>A and six studies in 1055 migraineurs and 877 controls for NOS3 +894G>T were included in the analysis. Neither indicated overall associations between gene polymorphisms and migraine risk. Subgroup analyses suggested that the "A" allele of the TNF -308G>A variant increases the risk of migraine among non-Caucasians (dominant model: pooled OR = 1.82; 95% CI 1.15 - 2.87). The risk of migraine with aura (MA) was increased among both Caucasians and non-Caucasians. Subgroup analyses suggested that the "T" allele of the NOS3 +894G>T variant increases the risk of migraine among non Caucasians (co-dominant model: pooled OR = 2.10; 95% CI 1.14 - 3.88). CONCLUSIONS: Our findings appear to support the hypothesis that the TNF -308G>A polymorphism may act as a genetic susceptibility factor for migraine among non Caucasians and that the NOS3 +894G>T polymorphism may modulate the risk of migraine among non-Caucasians. PMID- 26098764 TI - Bayesian Estimation of the Active Concentration and Affinity Constants Using Surface Plasmon Resonance Technology. AB - Surface plasmon resonance (SPR) has previously been employed to measure the active concentration of analyte in addition to the kinetic rate constants in molecular binding reactions. Those approaches, however, have a few restrictions. In this work, a Bayesian approach is developed to determine both active concentration and affinity constants using SPR technology. With the appropriate prior probabilities on the parameters and a derived likelihood function, a Markov Chain Monte Carlo (MCMC) algorithm is applied to compute the posterior probability densities of both the active concentration and kinetic rate constants based on the collected SPR data. Compared with previous approaches, ours exploits information from the duration of the process in its entirety, including both association and dissociation phases, under partial mass transport conditions; do not depend on calibration data; multiple injections of analyte at varying flow rates are not necessary. Finally the method is validated by analyzing both simulated and experimental datasets. A software package implementing our approach is developed with a user-friendly interface and made freely available. PMID- 26098765 TI - Electronic cigarette: use and perceptions among French military nurses in 2013. AB - AIMS: Paramedical personnel are exposed to tobacco smoking. Electronic cigarettes (e-cigarettes) may be considered as a lower-risk substitute for cigarettes. The aim of the study was to estimate the prevalence of e-cigarette use, the motives for use and the perceptions among French military nurses. METHODS: A cross sectional survey, using self-administered questionnaires, was conducted in 2013 among 300 students and instructors of the French school of military paramedical personnel. Prevalences of e-cigarette use among smokers and nonsmokers were compared using logistic regressions adjusted on age and gender. RESULTS: The prevalence of smoking was 40% among the 200 responders. E-cigarette current use prevalence was 25% (6% daily users), without significant difference according to gender and age. Tobacco smokers reported significantly more e-cigarette current use (51% vs7%). Motives for e-cigarette use reported by smokers were curiosity (48%), intention to reduce tobacco consumption (43%) or to quit smoking (8%). Among users of both tobacco and e-cigarettes, 48% reported a significant decrease in tobacco consumption following e-cigarette initiation (average decrease of 5-10 cigarettes smoked per day; p <0.001). Both tobacco smokers and nonsmokers (88%) estimated that e-cigarette use was potentially harmful for health, but it was perceived as less harmful than tobacco by 46%. CONCLUSIONS: E-cigarette use among military nurses follows the trends observed in the general population in terms of prevalence and motives. E-cigarettes, which are seen as an attractive alternative to cigarettes, may contribute to a reduction in tobacco use among healthcare workers. PMID- 26098766 TI - Conducting Rapid Street Assessment of Drug Users in New York City Using Oral Fluid and Brief Interviews: A Feasibility Study. AB - This study piloted the feasibility of rapidly collecting both self-reports of drug use and saliva specimens for drug toxicology in field settings. The use of oral fluid collection devices to supplement self-reports is unproven in street settings and may pose challenges for field research. Sixty adults who identified as recent illicit drug users were recruited in public settings in New York City and were asked to complete a brief drug screening inventory and provided saliva specimens. Descriptive findings are detailed along with critical best research practices and limitations that provide important directions for researchers looking to employ both toxicology and self-report in rapid field recruitment designs. PMID- 26098767 TI - Parenteral nutrition with fish oil supplements is safe and seems to be effective in severe preterm neonates with respiratory distress syndrome. PMID- 26098768 TI - Historical review of thymosin alpha 1 in infectious diseases. AB - INTRODUCTION: Thymosin alpha 1 (Talpha1) is a peptidic biological response modifier, which plays a significant role in activating and regulating various cells of the immune system. For the above-mentioned activities it is expected to exert a clinical benefit in the treatment of diseases where the immune system is altered. AREAS COVERED: Several clinical trials have been carried out with Talpha1 for treatment or prevention of many different infectious diseases such as hepatitis B and C, sepsis and Aspergillosis in bone marrow-transplanted patients. Data available on the use of Talpha1 in infectious disease as well as a vaccine enhancer will be reviewed to possibly generate new working hypothesis. EXPERT OPINION: Talpha1 has been widely used in thousands of patients. Nevertheless, there are some issues that have not yet been properly addressed (i.e., dose, schedule, combination treatments, end-points to be evaluated in clinical trials). In the most recent clinical trials Talpha1 has been used at higher doses than those commonly used in the past showing a direct proportionality between the dose and the effect. The safety profile of Talpha1 is excellent and it is virtually devoid of toxicity. PMID- 26098769 TI - Correlation between Body Composition and Walking Capacity in Severe Obesity. AB - BACKGROUND: Obesity is associated with mobility reduction due to mechanical factors and excessive body fat. The six-minute walk test (6MWT) has been used to assess functional capacity in severe obesity. OBJECTIVE: To determine the association of BMI, total and segmental body composition with distance walked (6MWD) during the six-minute walk test (6MWT) according to gender and obesity grade. SETTING: University of Sao Paulo Medical School, Brazil; Public Practice. METHODS: Functional capacity was assessed by 6MWD and body composition (%) by bioelectrical impedance analysis in 90 patients. RESULTS: The mean 6MWD was 514.9 +/- 50.3 m for both genders. The male group (M: 545.2 +/- 46.9 m) showed a 6MWD higher (p = 0.002) than the female group (F: 505.6 +/- 47.9 m). The morbid obese group (MO: 524.7 +/- 44.0 m) also showed a 6MWD higher (p = 0.014) than the super obese group (SO: 494.2 +/- 57.0 m). There was a positive relationship between 6MWD and fat free mass (FFM), FFM of upper limps (FFM_UL), trunk (FFM_TR) and lower limbs (FFM_LL). Female group presented a positive relationship between 6MWD and FFM, FFM_UL and FFM_LL and male group presented a positive relationship between 6MWD and FFM_TR. In morbid obese group there was a positive relationship between 6MWD with FFM, FFM_UL, FFM_TR and FFM_LL. The super obese group presented a positive relationship between 6MWD with FFM, FFM_TR and FFM_LL. CONCLUSIONS: Total and segmental FFM is associated with a better walking capacity than BMI. PMID- 26098770 TI - Peroxisome Proliferator-Activated Receptor gamma and microRNA 98 in Hypoxia Induced Endothelin-1 Signaling. AB - Endothelin-1 (ET-1) plays a critical role in endothelial dysfunction and contributes to the pathogenesis of pulmonary hypertension (PH). We hypothesized that peroxisome proliferator-activated receptor gamma (PPARgamma) stimulates microRNAs that inhibit ET-1 and pulmonary artery endothelial cell (PAEC) proliferation. The objective of this study was to clarify molecular mechanisms by which PPARgamma regulates ET-1 expression in vitro and in vivo. In PAECs isolated from patients with pulmonary arterial hypertension, microRNA (miR)-98 expression was reduced, and ET-1 protein levels and proliferation were increased. Similarly, hypoxia reduced miR-98 and increased ET-1 levels and PAEC proliferation in vitro. In vivo, hypoxia reduced miR-98 expression and increased ET-1 and proliferating cell nuclear antigen (PCNA) levels in mouse lung, derangements that were aggravated by treatment with the vascular endothelial growth factor receptor antagonist Sugen5416. Reporter assays confirmed that miR-98 binds directly to the ET-1 3'-untranslated region. Compared with littermate control mice, miR-98 levels were reduced and ET-1 and PCNA expression were increased in lungs from endothelial-targeted PPARgamma knockout mice, whereas miR-98 levels were increased and ET-1 and PCNA expression was reduced in lungs from endothelial targeted PPARgamma-overexpression mice. Gain or loss of PPARgamma function in PAECs in vitro confirmed that alterations in PPARgamma were sufficient to regulate miR-98, ET-1, and PCNA expression. Finally, PPARgamma activation with rosiglitazone regimens that attenuated hypoxia-induced PH in vivo and human PAEC proliferation in vitro restored miR-98 levels. The results of this study show that PPARgamma regulates miR-98 to modulate ET-1 expression and PAEC proliferation. These results further clarify molecular mechanisms by which PPARgamma participates in PH pathogenesis and therapy. PMID- 26098771 TI - The LPA1/ZEB1/miR-21-activation pathway regulates metastasis in basal breast cancer. AB - Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas. PMID- 26098772 TI - Anti-CSF-1 treatment is effective to prevent carcinoma invasion induced by monocyte-derived cells but scarcely by microglia. AB - The mononuclear phagocytic system is categorized in three major groups: monocyte derived cells (MCs), dendritic cells and resident macrophages. During breast cancer progression the colony stimulating factor 1 (CSF-1) can reprogram MCs into tumor-promoting macrophages in the primary tumor. However, the effect of CSF-1 during colonization of the brain parenchyma is largely unknown. Thus, we analyzed the outcome of anti-CSF-1 treatment on the resident macrophage population of the brain, the microglia, in comparison to MCs, alone and in different in vitro co culture models. Our results underline the addiction of MCs to CSF-1 while surprisingly, microglia were not affected. Furthermore, in contrast to the brain, the bone marrow did not express the alternative ligand, IL-34. Yet treatment with IL-34 and co-culture with carcinoma cells partially rescued the anti-CSF-1 effects on MCs. Further, MC-induced invasion was significantly reduced by anti CSF-1 treatment while microglia-induced invasion was reduced to a lower extend. Moreover, analysis of lung and breast cancer brain metastasis revealed significant differences of CSF-1 and CSF-1R expression. Taken together, our findings demonstrate not only differences of anti-CSF-1 treatment on MCs and microglia but also in the CSF-1 receptor and ligand expression in brain and bone marrow as well as in brain metastasis. PMID- 26098773 TI - The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors. AB - The response of BRAF-mutant melanoma patients to BRAF inhibitors is dramatically impaired by secondary resistances and rapid relapse. So far, the molecular mechanisms driving these resistances are not completely understood. Here, we show that, in BRAF-mutant melanoma cells, inhibition of BRAF or its target MEK induces RHOB expression by a mechanism that depends on the transcription factor c-Jun. In those cells, RHOB deficiency causes hypersensitivity to BRAF and MEK inhibitors induced apoptosis. Supporting these results, loss of RHOB expression in metastatic melanoma tissues is associated with an increased progression-free survival of BRAF-mutant patients treated with vemurafenib. Following BRAF inhibition, RHOB activates AKT whose inhibition causes hypersensitivity of BRAF mutant melanoma cells to BRAF inhibitors. In mice, AKT inhibition synergizes with vemurafenib to block tumor growth of BRAF-mutant metastatic melanoma. Our findings reveal that BRAF inhibition activates a c-Jun/RHOB/AKT pathway that promotes tumor cell survival and further support a role of this pathway in the resistance of melanoma to vemurafenib. Our data also highlight the importance of using RHOB tumor levels as a biomarker to predict vemurafenib patient's response and to select those that would benefit of the combination with AKT inhibitors. PMID- 26098774 TI - By recruiting HDAC1, MORC2 suppresses p21 Waf1/Cip1 in gastric cancer. AB - Microrchidia (MORC) family CW-type zinc-finger 2 (MORC2) regulates chromatin remodeling during the DNA-damage response, represses gene transcription, promotes lipogenesis. Here, we found that MORC2 down-regulated p21 by recruiting HDAC1 to the p21 promoter, in a p53-independent manner. MORC2-mediated down-regulation of p21 in turn promoted cell cycle progression in gastric cancer cells. Furthermore, MORC2 expression correlated negatively with p21 expression in gastric tumors in patients. We suggest that MORC2 may be a potential therapeutic target in cancer. PMID- 26098775 TI - Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death. AB - Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing.Our study identify for the first time a fraction of vesicles from lemon juice (Citrus limon L.), obtained as a result of different ultracentrifugation, with density ranging from 1,15 to 1,19 g/ml and specific proteomic profile. By using an in vitro approach, we show that isolated nanovesicles inhibit cancer cell proliferation in different tumor cell lines, by activating a TRAIL-mediated apoptotic cell death. Furthermore, we demonstrate that lemon nanovesicles suppress CML tumor growth in vivo by specifically reaching tumor site and by activating TRAIL-mediated apoptotic cell processes. Overall, this study suggests the possible use of plant-edible nanovesicles as a feasible approach in cancer treatment. PMID- 26098776 TI - Lymphatic dysfunction attenuates tumor immunity through impaired antigen presentation. AB - Tumor growth and metastasis of cancer involve autonomous tumor cell growth and host-tumor interactions. While tumor-specific immunity has been intensively studied in vitro, dynamic roles of lymphatic transport on tumor immunity in vivo have not been fully elucidated. In this study, we examined tumor growth and anti tumor immune responses using kCYC mice, which demonstrate severe lymphatic dysfunction. Primary tumor growth was augmented in kCYC mice (compared to wild type mice) when B16 melanoma or EL-4 lymphoma cells were subcutaneously injected. Expression of inflammatory cytokines such as IFN-gamma, TNF-alpha, and IL-2 as well as IL-10 expression in draining lymph nodes (LNs) was significantly reduced in kCYC mice after tumor inoculation. Moreover, decreased levels of tumor associated antigens were detected in draining LNs in kCYC mice, together with impaired antigen presentation. CD8+ T cells in draining LNs derived from kCYC mice bearing B16 melanoma also showed significantly decreased cytotoxic activity in vitro. Finally, tumor suppression activity of CD8+ T cells derived from kCYC mice bearing B16 melanoma was reduced when adoptively transferred to naive wild type mice. In summary, these findings suggest that lymphatic transport is essential in generating optimal tumor-specific immune responses mediated by CD8+ T cells. PMID- 26098777 TI - Ergosterol purified from medicinal mushroom Amauroderma rude inhibits cancer growth in vitro and in vivo by up-regulating multiple tumor suppressors. AB - We have previously screened thirteen medicinal mushrooms for their potential anti cancer activities in eleven different cell lines and found that the extract of Amauroderma rude exerted the highest capacity in inducing cancer cell death. The current study aimed to purify molecules mediating the anti-cancer cell activity. The extract of Amauroderma rude was subject to fractionation, silica gel chromatography,and HPLC. We purified a compound and identified it as ergosterol by EI-MS and NMR,which was expressed at the highest level in Amauroderma rude compared with other medicinal mushrooms tested. We found that ergosterol induced cancer cell death,which was time and concentration dependent. In the in vivo experiment, normal mice were injected with murine cancer cell line B16 that is very aggressive and caused mouse death severely. We found that treatment with ergosterol prolonged mouse survival. We found that ergosterol-mediated suppression of breast cancer cell viability occurred through apoptosis and that ergosterol up-regulated expression of the tumor suppressor Foxo3. In addition, the Foxo3 down-stream signaling molecules Fas, FasL,BimL, and BimS were up regulated leading to apoptosis in human breast cancer cells MDA-MB-231. Our results suggest that ergosterol is the main anti-cancer ingredient in Amauroderma rude, which activated the apoptotic signal pathway. Ergosterol may serve as a potential lead for cancer therapy. PMID- 26098778 TI - Liposome encapsulated curcumin-difluorinated (CDF) inhibits the growth of cisplatin resistant head and neck cancer stem cells. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer, with 600,000 new cases every year worldwide. Although chemotherapeutics exist, five-year survival is only 50%. New strategies to overcome drug resistance are required to improve HNSCC treatment. Curcumin-difluorinated (CDF), a synthetic analog of curcumin, was packaged in liposomes and used to evaluate growth inhibition of cisplatin resistant HNSCC cell lines CCL-23R and UM-SCC-1R generated from the parental cell lines CCL-23 and UM-SCC-1 respectively. Growth inhibition in vitro and expression levels of the CD44 (cancer stem cell marker), cytokines, and growth factors were investigated after liposomal CDF treatment. The in vivo growth inhibitory effect of liposomal CDF was evaluated in the nude mice xenograft tumor model of UM-SCC-1R and the inhibition of CD44 was measured. Treatment of the resistant cell lines in vitro with liposomal CDF resulted in a statistically significant growth inhibition (p < 0.05). The nude mice xenograft study showed a statistically significant tumor growth inhibition of UM-SCC-1R cells and a reduction in the expression of CD44 (p < 0.05), indicating an inhibitory effect of liposomal CDF on CSCs. Our results demonstrate that delivery of CDF through liposomes may be an effective method for the treatment of cisplatin resistant HNSCC. PMID- 26098780 TI - C-Peptide Is Independently Associated with an Increased Risk of Coronary Artery Disease in T2DM Subjects: A Cross-Sectional Study. AB - OBJECTIVE: C-peptide has been reported to be a marker of subclinical atherosclerosis in type 2 diabetes mellitus (T2DM) patients, whereas its role in coronary artery disease (CAD) has not been clarified, especially in diabetics with differing body mass indices (BMIs). DESIGN AND METHODS: This cross-sectional study included 501 patients with T2DM. First, all subjects were divided into the following two groups: CAD and non-CAD. Then, binary logistic regression was used to determine the risk factors for CAD for all patients. To clarify the role of obesity, we re-divided all subjects into two additional groups (obese and non obese) based on BMI. Finally, binary logistic regression was used to determine the risk factors for CAD for each weight group. RESULTS: The patients with CAD showed a higher BMI and fasting C-peptide level in addition to an increased prevalence of traditional risk factors for CAD, such as hypertension, insulin resistance, higher cholesterol, cysteine-C (Cys-C) and lower estimated glomerular filtration rate (eGFR). Logistic regression analysis showed that fasting C peptide (OR=1.513, p=0.005), insulin treatment (OR=1.832, p=0.027) hypertension (OR=1.987, p=0.016) and hyperlipidemia (OR=4.159, p<0.001) significantly increased the risk of clinical CAD in the T2DM patients independent of age, gender, diabetes duration, smoking and alcohol statuses, fasting insulin and glucose, hypoglycemic episodes, UA and eGFR. Additionally, in both of the obese (OR=1.488, p=0.049) and non-obese (OR=1.686, p=0.037) DM groups, C-peptide was associated with an increased risk of CAD after multiple adjustments. CONCLUSIONS: C-peptide is associated with an increased CAD risk in T2DM patients, no matter whether they are obese or not. PMID- 26098779 TI - Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression. AB - Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy. PMID- 26098782 TI - Adaptive Phase I clinical trial design using Markov models for conditional probability of toxicity. AB - Many Phase I trials in oncology involve multiple-dose administrations on the same patient over multiple cycles, with a typical cycle lasting 3 weeks and having about six cycles per patient with a goal to find the maximum tolerated dose (MTD) and study the dose-toxicity relationship. A patient's dose is unchanged over the cycles and the data are reduced to a binary endpoint and the occurrence of a toxicity and analyzed by considering the toxicity either from the first dose or from any cycle on the study. In this article, an alternative approach allowing an assessment of toxicity from each cycle and dose variations for patient over cycles is presented. A Markov model for the conditional probability of toxicity on any cycle given no toxicity in previous cycles is formulated as a function of the current and previous doses. The extra information from each cycle provides more precise estimation of the dose-toxicity relationship. Simulation results demonstrating gains in using the Markov model as compared to analyses of a single binary outcome are presented. Methods for utilizing the Markov model to conduct a Phase I study, including choices for selecting doses for the next cycle for each patient, are developed and presented via simulation. PMID- 26098781 TI - Impact of Pre-Transplant Anti-T Cell Globulin (ATG) on Immune Recovery after Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation. AB - BACKGROUND: Pre-transplant infusion of rabbit anti-T cell globulin (ATG) is increasingly used as prevention of graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). However, the precise impact of pre-transplant ATG on immune recovery after PBSCT is still poorly documented. METHODS: In the current study, we compared immune recovery after myeloablative PBSCT in 65 patients who either received (n = 37) or did not (n = 28) pre-transplant ATG-Fresenius (ATG-F). Detailed phenotypes of circulating T, B, natural killer (NK) and invariant NKT (iNKT) cells were analyzed by multicolor flow cytometry at serial time-points from day 40 to day 365 after transplantation. Thymic function was also assessed by sjTREC quantification. Serious infectious events were collected up to 2 years post-transplantation. RESULTS: Pre-transplant ATG-F had a prolonged (for at least up to 1-year) and selective negative impact on the T-cell pool, while it did not impair the recovery of B, NK nor iNKT cells. Among T cells, ATG-F selectively compromised the recovery of naive CD4+, central memory CD4+ and naive CD8+ cells, while it spared effector memory T and regulatory T cells. Levels of sjTRECs were similar in both cohorts at 1-year after PBSCT, suggesting that ATG-F unlikely impaired thymopoiesis at long-term after PBSCT. Finally, the incidence and rate of serious infections were similar in both groups, while ATG-F patients had a lower incidence of grade II-IV acute graft-versus-host disease. CONCLUSIONS: Pre transplant ATG-F induces long-lasting modulation of the circulating T-cell pool after myeloablative PBSCT, that may participate in preventing graft-versus-host disease without deeply compromising anti-pathogen defenses. PMID- 26098783 TI - Prevention of Type 1 diabetes through parasite infection. PMID- 26098784 TI - Largely Improving the Robustness and Lifetime of Triboelectric Nanogenerators through Automatic Transition between Contact and Noncontact Working States. AB - Although a triboelectric nanogenerator (TENG) has been developed to be an efficient approach to harvest mechanical energy, its robustness and lifetime are still to be improved through an effective and widely applicable way. Here, we show a rational designing methodology for achieving a significant improvement of the long-term stability of TENGs through automatic transition between contact and noncontact working states. This is realized by structurally creating two opposite forces in the moving part of the TENG, in which the pulling-away force is controlled by external mechanical motions. In this way, TENGs can work in the noncontact state with minimum surface wear and also transit into contact state intermittently to maintain high triboelectric charge density. A wind-driven disk based TENG and a rotary barrel-based TENG that can realize automatic state transition under different wind speeds and rotation speeds, respectively, have been demonstrated as two examples, in which their robustness has been largely improved through this automatic transition. This methodology will further expand the practical application of TENGs for long-time usage and for harvesting mechanical energies with fluctuating intensities. PMID- 26098785 TI - Perfluorooctanoic acid-induced toxicity in primary cultures of chicken embryo cardiomyocytes. AB - Perfluorooctanoic acid (PFOA) is a widespread environmental contaminant that induces developmental cardiotoxicity. It is detectable in late stage chicken embryos and hatchling chickens. To investigate mechanism(s) of cardiotoxicity, primary cultures of cardiomyocytes were prepared from 10-day-old chicken embryos that were (A) pre-exposed to vehicle or 2 mg of PFOA/kg of egg weight in ovo or (B) incubated with PFOA in vitro at concentrations ranging from 0 to 100 ug/mL in medium for 1 or 36 h. When viability was assessed, survival of cardiomyocytes prepared from pre-exposed embryos did not differ from vehicle controls, even under conditions of serum starvation designed to challenge the cells. However, 1 h of exposure to 100 ug/mL of PFOA in vitro and 36 h of exposure to 75 and 100 ug/mL PFOA in vitro decreased viability. When contractility was evaluated, cardiomyocytes cultured from pre-exposed embryos exhibited decreases in time to maximum departure velocity and cell length at peak contraction, whereas cardiomyocytes exposed in vitro exhibited a reduction in the 50% relaxation time at a concentration of 1 ug/mL relative to vehicle controls. Morphological assessment revealed decreased cardiomyocytes axial length following in ovo PFOA exposure and 24 h in vitro PFOA 50 ug/mL exposure. Reactive oxygen species (ROS) generation, which was evaluated only in cardiomyocytes exposed to PFOA in vitro, was significantly elevated following incubation with 50 ug/mL of PFOA for 1 h. These data indicate that while in vitro exposure to relatively high concentrations of PFOA can induce cytotoxicity and ROS, developmental cardiotoxicity observed in ovo is not likely mediated via PFOA-induced overt cytotoxicity, but likely by altering early cardiac morphologic and function processes. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1580-1590, 2016. PMID- 26098786 TI - Correction: Live Birth and Cumulative Live Birth Rates in Expected Poor Ovarian Responders Defined by the Bologna Criteria Following IVF/ICSI Treatment. PMID- 26098787 TI - Do I have enough to write a paper? Where should I start and end? PMID- 26098792 TI - Comparative effects of zinc-nano complexes, zinc-sulphate and zinc-methionine on performance in broiler chickens. AB - Micronutrients, especially zinc, have an important role in normal metabolism and growth of broilers. Using novel technologies helps to synthesise novel zinc complexes to deliver this micronutrient more efficiently. In the present study, the effects of different zinc complexes and nano complexes on broiler performance were compared. Broilers in 6 groups were given basal diet (without zinc) and basal diet supplemented with zinc-sulphate, zinc-methionine, zinc-nano-sulphate, zinc-nano-methionine and zinc-nano-max (that was synthesised based on nanochelating technology) at a concentration of 80 mg/kg of diet. At 1-42 d of age, dietary zinc-nano-sulphate supplementation decreased weight gain and feed intake. However, feed conversion ratio was not influenced by treatments. Carcass yield (%) of birds in the zinc-nano-sulphate and control groups were dramatically reduced at 42 d of age and abdominal fat (%) increased in these groups. Relative to the control group, the antibody titre, spleen and bursa of Fabricius (%) were significantly higher in groups supplemented with zinc. Heterophil (%) was also significantly higher in the zinc-nano-methionine group in blood on d 42 compared to the control, zinc-sulphate and zinc-nano-sulphate. Compared to the controls, the mean malondialdehyde content in thigh tissue was significantly reduced in groups supplemented with zinc at the time 0, 50, 100 and 150 min after oxidation. Tibia zinc concentration in nanoparticle zinc samples was significantly higher relative to the control and zinc-sulphate groups. Taken together, our data indicate that delivery of zinc in the structure of zinc-nano-methionine and zinc nano-max at concentrations of 80 mg/kg of diet improves growth performance. However, dietary zinc-nano-sulphate decreased growth performance in broilers. PMID- 26098791 TI - Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis. AB - OBJECTIVE: To define the interaction between cigarette smoking and HLA polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recently identified amino acid-based HLA model for RA susceptibility. METHODS: We imputed Immunochip data on HLA amino acids and classical alleles from 3 case control studies (the Swedish Epidemiological Investigation of Rheumatoid Arthritis [EIRA] study [1,654 cases and 1,934 controls], the Nurses' Health Study [NHS] [229 cases and 360 controls], and the Korean RA Cohort Study [1,390 cases and 735 controls]). We examined the interaction effects of heavy smoking (>10 pack-years) and the genetic risk score (GRS) of multiple RA-associated amino acid positions (positions 11, 13, 71, and 74 in HLA-DRbeta1, position 9 in HLA-B, and position 9 in HLA-DPbeta1), as well as the interaction effects of heavy smoking and the GRS of HLA-DRbeta1 4-amino acid haplotypes (assessed via attributable proportion due to interaction [AP] using the additive interaction model). RESULTS: Heavy smoking and all investigated HLA amino acid positions and haplotypes were associated with RA susceptibility in the 3 populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA-DRbeta1 4-amino acid haplotype (AP 0.416, 0.467, and 0.796, in the EIRA, NHS, and Korean studies, respectively). We further identified the key interacting variants as being located at HLA-DRbeta1 amino acid positions 11 and 13 but not at any of the other RA risk-associated amino acid positions. For residues in positions 11 and 13, there were similar patterns between RA risk effects and interaction effects. CONCLUSION: Our findings of significant gene-environment interaction effects indicate that a physical interaction between citrullinated autoantigens produced by smoking and HLA-DR molecules is characterized by the HLA-DRbeta1 4-amino acid haplotype, primarily by positions 11 and 13. PMID- 26098794 TI - Assessment of Work-Life Balance of Resident Physicians. PMID- 26098793 TI - Improved cognitive content endures for 2 years among unstable responders to acute phase cognitive therapy for recurrent major depressive disorder. AB - BACKGROUND: The cognitive model of depression suggests that cognitive therapy (CT) improves major depressive disorder (MDD) in part by changing depressive cognitive content (e.g. dysfunctional attitudes, hopelessness). The current analyses clarified: (1) the durability of improvements in cognitive content made by acute-phase CT responders; (2) whether continuation-phase CT (C-CT) or fluoxetine (FLX) further improves cognitive content; and (3) the extent to which cognitive content mediates continuation treatments' effects on depressive symptoms and major depressive relapse/recurrence. METHOD: Out-patients with recurrent MDD who responded to acute-phase CT (n = 241) were randomized to 8 months of C-CT, FLX or pill placebo (PBO) and followed for an 24 additional months. Cognitive content was assessed approximately every 4 months using five standard patient-report measures. RESULTS: Large improvements in cognitive content made during acute-phase CT were maintained for 32 months, with 78-90% of patients scoring in normal ranges, on average. Cognitive content varied little between C-CT, FLX and PBO arms, overall. Small, transient improvements in cognitive content in C-CT or FLX compared with PBO patients did not clearly mediate the treatments' effects on depressive symptoms or on major depressive relapse/recurrence. CONCLUSIONS: Outpatients with recurrent MDD who respond to acute-phase CT show durable improvements in cognitive content. C-CT or FLX may not continue to improve patient-reported cognitive content substantively, and thus may treat recurrent MDD by other paths. PMID- 26098796 TI - The Millennium Development Goals and the social commitment of Nursing research. PMID- 26098797 TI - [Association between the functional capacity of dependent elderly people and the burden of family caregivers]. AB - The aim of this study was to characterize dependent elderly people and their main family caregivers and the association between functional capacity of the elderly and the burden of caregivers. This cross-sectional study was conducted with 112 elderly people and caregivers connected to a primary care service in Porto Alegre, Brazil. The applied instruments related to care and socioeconomic variables were Physical and Instrumental Activities of Daily Living (PADL and IADL) and the Burden Interview. The Spearman correlation coefficient was also used. Average age of the elderly individuals in this study was 81.41 years, while the average score for PADL was 10.36 and 6.25 for IADL. Of the 112 elderly individuals, 71.4% had severe dependence. Among caregivers, 75% were women, 61.6% were the sons or daughters with an average age of 57.98 and an average burden of 29.53, which is equivalent to moderate burden. Results revealed a significant correlation between functional capacity of the elderly and caregiver burden. It was verified that the higher the dependence of elderly people, the greater the burden of caregivers. PMID- 26098795 TI - Huntingtin N-Terminal Monomeric and Multimeric Structures Destabilized by Covalent Modification of Heteroatomic Residues. AB - Early stage oligomer formation of the huntingtin protein may be driven by self association of the 17-residue amphipathic alpha-helix at the protein's N-terminus (Nt17). Oligomeric structures have been implicated in neuronal toxicity and may represent important neurotoxic species in Huntington's disease. Therefore, a residue-specific structural characterization of Nt17 is crucial to understanding and potentially inhibiting oligomer formation. Native electrospray ion mobility spectrometry-mass spectrometry (IMS-MS) techniques and molecular dynamics simulations (MDS) have been applied to study coexisting monomer and multimer conformations of Nt17, independent of the remainder of huntingtin exon 1. MDS suggests gas-phase monomer ion structures comprise a helix-turn-coil configuration and a helix-extended-coil region. Elongated dimer species comprise partially helical monomers arranged in an antiparallel geometry. This stacked helical bundle may represent the earliest stages of Nt17-driven oligomer formation. Nt17 monomers and multimers have been further probed using diethylpyrocarbonate (DEPC). An N-terminal site (N-terminus of Threonine-3) and Lysine-6 are modified at higher DEPC concentrations, which led to the formation of an intermediate monomer structure. These modifications resulted in decreased extended monomer ion conformers, as well as a reduction in multimer formation. From the MDS experiments for the dimer ions, Lys6 residues in both monomer constituents interact with Ser16 and Glu12 residues on adjacent peptides; therefore, the decrease in multimer formation could result from disruption of these or similar interactions. This work provides a structurally selective model from which to study Nt17 self-association and provides critical insight toward Nt17 multimerization and, possibly, the early stages of huntingtin exon 1 aggregation. PMID- 26098798 TI - [Assessment of bariatric surgery results]. AB - The objective was to evaluate the results of bariatric surgery in patients in the late postoperative period using the Bariatric Analysis and Reporting Outcome System (BAROS). This cross-sectional study was conducted from November 2011 to June 2012 at a hospital in the state of Ceara, Brazil. Data were collected from 92 patients using the BAROS protocol, which analyzes weight loss, improved comorbidities, complications, reoperations and Quality of Life (QoL). Data were analysed using the chi-squared test, Fischer's exact test and the Mann-Whitney test. There was a reduction in the Body Mass Index (47.2+/-6.8 kg/m2 in the pre operatory and 31.3+/-5.0 kg/m2 after surgery, p<0.001). The comorbidity with the highest resolution was arterial hypertension (p<0.001), and QV improved in 94.6% of patients. The main complications were hair loss, incisional hernia and cholelithiasis. The surgery provided satisfactory weight loss and improvements in the comorbidities associated to a better QL. Use of the BAROS protocol allows nurses to plan interventions and maintain the good results. PMID- 26098799 TI - [Term base for nursing practices with elderly women with HIV/AIDS]. AB - The aim of this study was to create a term base for nursing practices with elderly women with HIV/AIDS. This documental descriptive research was conducted at the Universidade Federal de Paraiba, from August 2012 to July 2013, based on a list of terms from the Integrated Plan to Combat the Feminization of AIDS and other STDs. These terms were cross-mapped with those of the International Classification for Nursing Practices 2011 (CIPEr 2011) and use of these terms in nursing practices was confirmed with the help of 15 participants. The base comprised 106 constant terms and 69 non-constant terms in the CIPEr 2011. Results revealed the need to reconsider nursing care for elderly women with HIV/AIDS in light of epidemiological changes in relation to aging and feminization of the disease. The term base will support the construction of more appropriate wording for nursing diagnoses, results and interventions for elderly women with HIV/AIDS. PMID- 26098800 TI - [Growth of infants assisted in nursing appointments in childcare]. AB - This study aimed to describe the growth during the introduction of complementary feeding to infants assisted in the nursing appointment in childcare. It is a descriptive, cross-sectional, quantitative study developed through research in 51 medical records of children aged 4-8 months, from September to October 2012 in a university hospital in the city of Recife, PE. Data were analyzed using Epi Info software, version 6.04 and described in simple and relative frequencies. It was found that for 33% of the children. complementary foods were introduced at six months. Of these, 88.2%, 69.2% and 57.1% showed ascending weight-for-age growth curves, and 88.2%, 66.7% and 71.4% ascending length-for-age growth curves at six, seven and eight months respectively. Children with appropriate and timely introduction of complementary feeding showed upward growth curves and adequate nutritional status. PMID- 26098801 TI - [Knowledge of family members on the rights of individuals affected by mental illness]. AB - The objective of this investigation was to understand what family members know about the rights of individuals affected by mental illness. To this end, a qualitative exploratory study was conducted. A semi-structured interview was used for data collection. Eighteen family members were interviewed at a psychosocial care center (CAPS) and a civil society organization (CSO) located in a municipality in the state of Sao Paulo, Brazil, between March and September 2013. Data were analyzed using thematic content analysis and the following categories were constructed: mental health services and the rights of individuals affected by mental illness. We were able to infer that in addition to drug-based therapy, mental health services must provide therapeutic activities. Family members of those affected by mental illness were unaware of the Brazilian Psychiatric Reform Law and mentioned the following rights: welfare benefits, free public transport, basic food basket and medications. PMID- 26098802 TI - [Mothers of children with autistic disorder: perceptions and trajectories]. AB - Childhood autism is characterized by severe and global impairment in several areas of human development and demands extensive care and dependence on the parents. The objective of this study was to understand the perceptions of mothers of children with autism regarding changes suffered by the child and their trajectories in search of an autism diagnosis. This is an exploratory descriptive study with a qualitative approach conducted with ten participant mothers. Data were collected in 2013 by means of semi-structured interviews. Thematic content analysis produced the following categories: perceptions of mothers as to changes in behaviour and/or development of their children; and trajectories of mothers in search of a diagnosis for their children. After the perception of changes in behaviour/development, mothers face an arduous trajectory of healthcare service utilization. PMID- 26098803 TI - [The care for institutionalized elderly perceived by the nursing team]. AB - This article aimed to analyze the perception of the nursing team about the care of institutionalized elderly. It consists of a qualitative and exploratory study developed in the six long-term care nursing homes for elderly in the city of Joao Pessoa/PB, Brazil, from January to June 2013. The sample was comprised 50% of the nurses from all the institutions, totaling 13 participants, whose data were collected through semi-structured questionnaires. Content analysis was used in the study, which enabled the construction of two thematic categories: I) Perceptions of the delivery of care by the nursing staff of the institutions; II) Perceptions of the care activity to be performed by the nursing staff in the institutions. We conclude that the participants are aware of the need for an individualized and systematized care by the nursing staff, aimed to the prevention of diseases, health promotion and active aging. PMID- 26098804 TI - [Perceptions of the family members of children regarding well-child check-ups in the family healthcare strategy]. AB - A qualitative descriptive study aimed at understanding the perceptions of the family members of children regarding well-child check-ups in the context of attention to child healthcare. Data collection was done using semi-structured interviews of 19 families, in the city of Maringa, in the state of Parana, Brazil, from December 2012 to February 2013. The data was analyzed using content analysis, a thematic modality, which resulted in the thematic category "Revealing well-child check-ups from the family's point of view" and two secondary categories. The results showed the interviewees' insipient knowledge of well child check-ups, reflecting the lack of adequate guidance about this type of care. The family members showed a preference for care of children by a pediatrician. Although secondary, the family noted the participation of the nurse in this activity. It is considered extremely important that well-child check-ups are valued by family members in order to promote effective multi-professional participation in this modality of attention. PMID- 26098805 TI - [Profile and motivation for smoking cessation in surgical inpatients]. AB - The aim of this cross-sectional study was to describe the profile of smokers hospitalized for surgery, and investigate their motivation to quit. The sample consisted of 100 patients recruited from a university hospital in southern Brazil. Data were collected between February and May 2013, and analyzed using descriptive statistics. The sample was predominantly male (n=58; 58%) and had a mean age of 54.5+/-13.8 years. Seventy-nine (79%) of the participants were white, 38(38%) were married and 67(67%) had primary education only. Patients started smoking at a mean age of 17+/-6.6 years, smoked approximately 20(10 to 28.7) cigarettes/day and had been smoking for a mean of 37.4+/-14.4 years. Ninety-one (91%) patients wanted to stop smoking, 57(57%) were in the preparation phase, 36(36%) had low nicotine dependence and 35(35%) had been encouraged to quit. We concluded that, although hospitalization is a good moment to address smoking cessation, health care professionals do not enact effective and systematic interventions in this regard. PMID- 26098806 TI - [Sociodemographic and academic profile of nursing students from four Brazilian institutions]. AB - This study aimed to describe the sociodemographic and academic characteristics of nursing students from four Brazilian Educational Institutions. It is a prospective cross-sectional study. The data were collected between April 2011 and March 2012, through a survey form with questions about sociodemographic and academic characteristics of the students. The participants were graduate students enrolled in the nursing course, aged 18 years or older. 705 students participated, and these were mostly women, single, childless, who lived with their families, did not take part in sport activities and performed leisure activities. Also, most students do not participate in research groups, were not granted scholarships, are not employed, are satisfied with the course and do not intend to leave it. This study may become an important tool for the development of strategies that address the needs of students and also improve the quality of the teaching and learning process, reducing dropout rates. PMID- 26098807 TI - [Social representations of adolescents on sexual relations and the use of condoms]. AB - The objective of this investigation was to identify how adolescents structure the social representations of sexual intercourse and use of condoms. Exploratory and descriptive research was conducted with a convenience sample consisting of 234 students of a public secondary school in Fortaleza-CE, Brazil, between July 2009 and April 2010. Data were collected using a questionnaire with variables on socioeconomic status and sexual behaviour, and Free Association test with three terms: 'sex', 'unprotected sex' and 'sex with a condom'. Sexual intercourse was represented by love and affection among the women, while men associated sex to pleasure, desire and attraction toward the female body. The condom was considered important by both groups, but men represented condoms as being something bad that restricts pleasure. Health professionals are granted the opportunity to identify vulnerabilities of this population to DST/HIV/AIDS and work with these vulnerabilities in the most appropriate way. PMID- 26098808 TI - [Mental health care technologies for treating crack users]. AB - The aim of this study was to identify mental health care technologies for treating crack users in a Psychosocial Care Center for Alcohol and other Drugs (CAPsad, as per its acronym in Portuguese). A qualitative, evaluative case study was developed in a CAPSad, using fourth generation evaluation. Data collection occurred from January to March 2013 by means of semi-structured interviews applied to 36 subjects, these being health care professionals, patients, patients' relatives and managers. Data analysis identified the category strategies in mental health work. Results showed that recovery programs should provide spaces for dialogue, aiming to clarify the process of psychiatric internment to the user and family, and involve these in the therapy, implementing educational practices and ongoing consideration of mental health activities. In conclusion, it is important to discuss the technologies used in everyday care services, in light of the complexity of crack use. PMID- 26098809 TI - [Use of narrative as an awareness strategy for a Family-Centered Care model]. AB - The aim of this study was to comprehend the meaning of using illness narratives to raise awareness among nursing students and healthcare professionals toward the family-centred care model. The adopted methodological framework was Qualitative Content Analysis based on the philosophy of Family-Centered Care. Data were collected by means of assessments provided by 29 participants at an event in 2013, in Sao Paulo. The resulting analytical category was "transformed by the family narrative", which consisted of three sub-categories: Favours a better understanding of the family's experience; facilitates learning of family issues; and triggers thought on family-centered care. Results showed that hearing the family narrative on experiences with illness and hospitalization raises awareness among nursing students and healthcare professionals toward the family-centered care model, and facilitates learning of this model of care. PMID- 26098810 TI - [Nursing diagnosis "impaired walking" in elderly patients: integrative literature review]. AB - The impaired walking nursing diagnosis has been included in NANDA International classification taxonomy in 1998, and this review aims to identify the defining characteristics and related factors in elderly patients in recent literature. Integrative literature review based on the following guiding question: Are there more defining characteristics and factors related to the nursing diagnosis impaired walking than those included in NANDA International classification taxonomy in elderly patients? Search conducted in 2007-2013 on international and Portuguese databases. Sample composed of 15 papers. Among the 6 defining characteristics classified at NANDA International, 3 were identified in the search results, but 13 were not included in the classification. Regarding the 14 related factors that are classified, 9 were identified in the sample and 12 were not included in the NANDA International taxonomy. This review allowed the identification of new elements not included in NANDA International Taxonomy and may contribute to the development of taxonomy and nursing knowledge. PMID- 26098811 TI - [Ethical problems experienced by nurses in primary health care: integrative literature review]. AB - The aim of this study is to identify ethical problems experienced by nurses in primary health care and resources for coping based on publications on the subject. An integrative literature review was performed between the months of October and November 2013, using the databases: BDTD, CINAHL, LILACS, MEDLINE, Biblioteca Cochrane, PubMed, RCAAP and SciELO. Articles, dissertations and theses published in Portuguese, English and Spanish were included, totalling 31 studies published from 1992 to 2013. This analysis resulted in four categories: ethical problems in the relationship between team members, ethical problems in the relationship with the user, ethical problems in health services management and resources for coping with ethical problems. Results showed that nurses need to be prepared to face ethical problems, emphasizing the importance of ethics education during the education process before and during professional practice to enhance the development of ethical sensitivity and competence for problem resolution. PMID- 26098812 TI - Men's Intentions to Engage in Behaviors to Protect Against Human Papillomavirus (HPV): Testing the Risk Perception Attitude Framework. AB - Guided by the risk perception attitude framework (RPA), this study examined men's perceptions of risk and efficacy beliefs as predictors of their intentions to engage in self-protective behaviors. The results of multiple regression analyses did not provide support for the RPA prediction that efficacy beliefs moderate the relationship between risk perceptions and self-protective behavior. However, the results provide support for the main effects of risk and efficacy on all four behavioral intentions examined (i.e., Internet information seeking, communication with a health provider, HPV vaccination, and condom use). Risk and efficacy were positively related to (and significant individual predictors of) all four behavioral intentions. Scholarly and practical implications of these findings are discussed. PMID- 26098814 TI - Direct Catalytic Asymmetric Conjugate Addition of Saturated and Unsaturated Thioamides. AB - Direct catalytic asymmetric conjugate addition of thiolactams to alpha,beta unsaturated thioamides was efficiently promoted by a soft Lewis acid/hard Bronsted base cooperative catalyst in a highly stereocontrolled manner. Thioamide functionality was crucial to promote both the efficient enolization of thiolactam pronucleophiles and the subsequent stereoselective conjugate addition to alpha,beta-unsaturated thioamides. Differential manipulation of the two thioamide functionalities of the product highlights the synthetic utility of the present catalytic system. PMID- 26098813 TI - Local chromatin microenvironment determines DNMT activity: from DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase. AB - Insights on active DNA demethylation disproved the original assumption that DNA methylation is a stable epigenetic modification. Interestingly, mammalian DNA methyltransferases 3A and 3B (DNMT-3A and -3B) have also been reported to induce active DNA demethylation, in addition to their well-known function in catalyzing methylation. In situations of extremely low levels of S-adenosyl methionine (SAM), DNMT-3A and -3B might demethylate C-5 methyl cytosine (5mC) via deamination to thymine, which is subsequently replaced by an unmodified cytosine through the base excision repair (BER) pathway. Alternatively, 5mC when converted to 5- hydroxymethylcytosine (5hmC) by TET enzymes, might be further modified to an unmodified cytosine by DNMT-3A and -3B under oxidized redox conditions, although exact pathways are yet to be elucidated. Interestingly, even direct conversion of 5mC to cytosine might be catalyzed by DNMTs. Here, we summarize the evidence on the DNA dehydroxymethylase and demethylase activity of DNMT-3A and 3B. Although physiological relevance needs to be demonstrated, the current indications on the 5mC- and 5hmC-modifying activities of de novo DNA C-5 methyltransferases shed a new light on these enzymes. Despite the extreme circumstances required for such unexpected reactions to occur, we here put forward that the chromatin microenvironment can be locally exposed to extreme conditions, and hypothesize that such waves of extremes allow enzymes to act in differential ways. PMID- 26098815 TI - From Ramachandran Maps to Tertiary Structures of Proteins. AB - Sequence to structure of proteins is an unsolved problem. A possible coarse grained resolution to this entails specification of all the torsional (Phi, Psi) angles along the backbone of the polypeptide chain. The Ramachandran map quite elegantly depicts the allowed conformational (Phi, Psi) space of proteins which is still very large for the purposes of accurate structure generation. We have divided the allowed (Phi, Psi) space in Ramachandran maps into 27 distinct conformations sufficient to regenerate a structure to within 5 A from the native, at least for small proteins, thus reducing the structure prediction problem to a specification of an alphanumeric string, i.e., the amino acid sequence together with one of the 27 conformations preferred by each amino acid residue. This still theoretically results in 27(n) conformations for a protein comprising "n" amino acids. We then investigated the spatial correlations at the two-residue (dipeptide) and three-residue (tripeptide) levels in what may be described as higher order Ramachandran maps, with the premise that the allowed conformational space starts to shrink as we introduce neighborhood effects. We found, for instance, for a tripeptide which potentially can exist in any of the 27(3) "allowed" conformations, three-fourths of these conformations are redundant to the 95% confidence level, suggesting sequence context dependent preferred conformations. We then created a look-up table of preferred conformations at the tripeptide level and correlated them with energetically favorable conformations. We found in particular that Boltzmann probabilities calculated from van der Waals energies for each conformation of tripeptides correlate well with the observed populations in the structural database (the average correlation coefficient is ~0.8). An alpha-numeric string and hence the tertiary structure can be generated for any sequence from the look-up table within minutes on a single processor and to a higher level of accuracy if secondary structure can be specified. We tested the methodology on 100 small proteins, and in 90% of the cases, a structure within 5 A is recovered. We thus believe that the method presented here provides the missing link between Ramachandran maps and tertiary structures of proteins. A Web server to convert a tertiary structure to an alphanumeric string and to predict the tertiary structure from the sequence of a protein using the above methodology is created and made freely accessible at http://www.scfbio iitd.res.in/software/proteomics/rm2ts.jsp. PMID- 26098818 TI - [Postraumatic mental disorders in traders victims of crime]. AB - INTRODUCTION: Crime consequences are not only a security problem; they are also a community health question. Because shop assistants are particularly exposed to crime victimization, they are at risk from suffering posttraumatic stress disorders. OBJECTIVES: To describe posttraumatic symptomatology of crime victimized shop assistants and to explore the relationship between the symptoms and demographic, victim and situational factors. MATERIALS AND METHODS: Self reported information about mental symptomatology was gathered from 126 victimized shop assistants identified during cross-sectional study. Case and control groups were formed to explore association between symptomatology and crime and victim characteristics. RESULTS: The 20.6% of respondents reported information compatible with posttraumatic stress disorder; the 13 %, with moderate/severe depression and the 69.8% with adjustment disorder. The condition of being a case was associated with the violent characteristic of the crime, with the subtraction of goods and the economic value of the goods. PMID- 26098817 TI - Highly Polarizable Triiodide Anions (I3(-)) as Cross-Linkers for Coordination Polymers: Closing the Semiconductive Band Gap. AB - From a hydrothermal reaction using CuI, KI, and 3,3'5,5'-tetramethyl-4,4' bipyrazole (TMBP), the triiodide anion I3(-) has been integrated into the water stable 2D coordination polymer Cu(TMBP)I3 (1). In contrast with other metal triiodide complexes, 1 features remarkably small distortions in the bond distances associated with the I3(-) units (i.e., the Cu-I and I-I bonds), which effectively link up the copper(I) centers into infinite CuI3 chains. The electronic band gaps and electrical conductivity data are also found to be consistent with the I3(-) ion acting as an effective linker across the copper(I) centers. PMID- 26098816 TI - Implantable cardioverter defibrillators in diabetics: efficacy and safety in patients at risk of sudden cardiac death. AB - Diabetes mellitus is a major risk factor for arrhythmogenesis and is associated with a two-fold increase in all-cause mortality and a four-fold increase in cardiovascular mortality including sudden cardiac death when compared with nondiabetics. Implantable cardioverter defibrillators (ICD) have been shown to effectively reduce arrhythmic death and all-cause mortality in patients with severe myocardial dysfunction. With a high competing risk of nonarrhythmic cardiac and noncardiac death, survival benefit of ICD in patients with diabetes mellitus could be reduced, but the subanalysis of diabetic patients in randomized clinical trials provides reassurance regarding a similar beneficial survival effect of ICD and cardiac resynchronization therapy in diabetics, as observed in the overall population with advanced heart disease. In this article, the authors highlight some of the clinical issues related to diabetes, summarize the data on the efficacy of ICD in diabetics when compared with nondiabetics and discuss concerns related to ICD implantation in patients with diabetes. PMID- 26098819 TI - [A new star in the sky of psychiatry: The European College of Neuropsychopharmacology]. AB - A commentary about the activities of the ECNP, whose congresses have become a new destination for many professionals interested in clinic and high level research in psychiatry and brain is made. The author presents the goals of the ECNP, the meeting activities in general, and, in particular, the press conferences that took place during the congresses. The 26th Congress (Barcelona, Spain, October, 2013) and the 27th Congress (Berlin, Germany, October, 2014) are reviewed. The high scientific level of both congresses is highlighted. PMID- 26098821 TI - [Memory is not everything: Behavioral and psychological symptoms of Alzheimer's disease]. PMID- 26098820 TI - [Neurodegenerative disorders]. PMID- 26098822 TI - [Movement from the social cognitive neuroscience: The case of Parkinson's disease]. AB - Parkinson's disease is a multisystemic disorder that affects movement in its different levels of integration from the simplest motor act to the complexity of communication and social inclusion. The study of movement from the social cognitive neuroscience can contribute elements to the development of better rehabilitation treatments for Parkinson's disease patients. As a cognitive and social phenomenon, movement involves perception and action; paradoxical kinesia, as a property of motor system, is shown in this perception-action dialogue. We introduce the internal-external control hypothesis as a possible explanatory model of movement in Parkinson's disease patients. This model can explain the occurrence of paradoxical kinesia and, combined with the mirror neurons theory, accounts for the capability of people with Parkinson's disease to move like healthy controls do when there is a given sensorial space with emotional and ludic languages. Eventually, we highlight the utility of paradoxical kinesia as a rehabilitation tool for movement in people with Parkinson's disease. PMID- 26098823 TI - [Update on the diagnosis and management of vascular cognitive impairment]. AB - INTRODUCTION: The term vascular cognitive impairment refers to a clinical and etiological heterogeneous group of entities that may appear as a result of brain lesions caused by vascular disease. AIM: To update the evidence and recommendations on the diagnosis and management of vascular cognitive impairment. RESULTS: vascular mild cognitive impairment and vascular dementia are entities that capture the entire spectrum of cognitive impairment following stroke or subclinical vascular brain injury. The recent update on the diagnostic criteria of these entities, with the incorporation of biomarkers and genetic tests for concomitant disorders such as Alzheimer's disease, may lead to the development of new epidemiological and therapeutics studies. Different aspects should be considered in the management of these entities: control of vascular risk factors, inclusion in rehabilitation programs, secondary prevention and symptomatic pharmacological therapy. Donepezil can be useful for cognitive enhancement in patients with vascular dementia (Class IIa; Level of Evidence A) and Galantamine can be beneficial for patients with mixed Alzheimer's disease/vascular dementia (Class IIa; Level of Evidence A). CONCLUSIONS: Early detection and accurate diagnosis and management of vascular cognitive impairment can benefit the quality of life of the affected patients. Prevention is still the best medical strategy in cerebrovascular disorders. PMID- 26098824 TI - [Structural neuroimaging in dementia for outpatient clinic visit]. AB - Dementia is a common illness to find in a psychiatric consultation and its incidence is rising as the aged population increases. Traditionally the imagines in dementia were used to rule out etiologies that had pharmacological o surgery treatments. However, in the last years neuroimaging has played a very important role in the field of dementia. Structural imaging (particularly MRI) has become an important tool in the diagnosis of degenerative dementias because of findings that help us to support the diagnosis of different etiologies. Different patterns of atrophy can be identified on visual inspection of MRI in various neurodegenerative conditions. However, it's sometimes difficult to recognize or acknowledge these patterns during a regular outpatient clinic visit. In this review we describe the most important findings in structural neuroimaging in the most common causes of dementia and we analyze the most useful visual scales that can help us in the differential diagnosis of dementia during a regular outpatient clinic visit. PMID- 26098825 TI - [Bioethics and dementia(s)]. AB - Population aging among the world will bring up an exponential increasing of dementia in the next 40 years. This will create more demands in medical care areas. And this will defeated psychiatrists with bioethical issues: capacity to obtain agreement for treatment, participation in research studies, dealing with own economy, institutionalization, and manager of behavioral symptoms. Guidelines delineating probable issues or ethical problems will be defined. The theoretical framework will be defi- ned concerning bioethical issues involved in the different stages of cognitive impairment. PMID- 26098826 TI - [Geriatric vs. non-geriatric psychiatric hospitalization to the psychiatric services of a general hospital in Chile]. AB - INTRODUCTION: It is estimated that Chilean geriatric population (=65 years) will hit 16% in the year 2030. Psychiatric longer stays have been described for those equal 65 years vs. less than 65 years. We aim to describe the characteristics associated with lengths of stay in our psychiatric unit. MATERIAL AND METHODS: Retrospective review of 3112 admissions between July 2001 and June 2010 to the general psychiatric service of the Pontific Catholic University of Chile. RESULTS: 5.1% (n=132) of the sample was geriatric patients. The average length of stay for this group was 12.4 days (p=0.41). Both the geriatric and non-geriatric population presented a high prevalence of affective disorders (63.7% and 55.1%, respectively). In the geriatric group, there was a higher presence of bipolar disorder (27.3 vs. 19.5%; p less than 0.05) and dementia (16.7% vs. 0.5%). In contrast, for = 65 years, there was significantly less prevalence of adaptive and anxiety disorders (3% vs. 13%; p less than 0.01). There was just one case of personality disorder and no cases of eating disorders in the geriatric group. There were no differences in the lengths of stay according to diagnosis. CONCLUSIONS: We did not find longer stay times, in general or associated with specific diagnoses, in geriatric patients versus non-geriatric patients. PMID- 26098827 TI - [From coercion to healing: The moral treatment of Francois Leuret]. PMID- 26098828 TI - Brain Signature Predicts Negative Emotion in Individuals. PMID- 26098829 TI - Association of the COQ2 V393A Variant with Parkinson's Disease: A Case-Control Study and Meta-Analysis. AB - Both Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases of uncertain etiology, but they show similarities in their pathology and clinical course. The fact that the gene encoding alpha synuclein is associated with both diseases also suggests that they share some genetic determinants. Recent studies in Japan associating MSA with a variant in the COQ2 gene led us to question whether variants in the COQ2 gene are associated with PD in Han Chinese in a case-control study. A total of 564 patients with PD were genotyped using the ligase detection rection, together with 484 gender- and age-matched healthy subjects. The M128V and R387X variants of COQ2 were not detected in patients or controls; instead, we detected only the heterozygous V393A variant (CT genotype). The frequency of the CT genotype encoding the V393A mutation was significantly higher in patients PD (4.08%) than in controls (1.86%), corresponding to an odds ratio of 2.24 (95%CI 1.03 to 4.90, p = 0.037). The frequency of the C allele of the V393A variant was significantly higher in patients with PD than in controls (OR 2.22, 95%CI 1.02 to 4.82, p = 0.039), and this was also observed in a meta-analysis of studies from mainland China, Taiwan and Japan. Subgroup analysis of our data showed that the V393A variant was significantly associated with early-onset PD (OR 3.71, 95%CI 1.51 to 9.15, p = 0.002) but not with late-onset disease (OR 1.65, 95%CI 0.69 to 3.95, p = 0.260). Gender was not significantly associated with either genotype or minor allele frequencies. In conclusion, our findings show for the first time that the V393A variant in the COQ2 gene increases risk of PD among the population of east Asia. These results, combined with research on Japanese, lend genetic support to the hypothesis that oxidative stress underlies pathogenesis of both PD and MSA. PMID- 26098830 TI - Invadopodia: a new therapeutic target to block cancer metastasis. AB - Cancer cells become dangerous when they acquire the ability to invade through physical barriers in the body and disseminate to distant sites. Recent evidence has demonstrated that cancer cells utilize specialized structures called invadopodia, unique protrusions that concentrate proteases such as matrix metalloproteinases (MMPs), to escape blood vessels during the process of extravasation. Perhaps most exciting is the fact that inhibition of invadopodia through genetic or pharmacological means reduces the ability of cancer cells to extravasate and effectively blocks metastasis. This opens the door for the development of novel therapies targeting invadopodia and cancer metastasis. PMID- 26098831 TI - ASCONA: Rapid Detection and Alignment of Protein Binding Site Conformations. AB - The usage of conformational ensembles constitutes a widespread technique for the consideration of protein flexibility in computational biology. When experimental structures are applied for this purpose, alignment techniques are usually required in dealing with structural deviations and annotation inconsistencies. Moreover, many application scenarios focus on protein ligand binding sites. Here, we introduce our new alignment algorithm ASCONA that has been specially geared to the problem of aligning multiple conformations of sequentially similar binding sites. Intense efforts have been directed to an accurate detection of highly flexible backbone deviations, multiple binding site matches within a single structure, and a reliable, but at the same time highly efficient, search algorithm. In contrast, most available alignment methods rather target other issues, e.g., the global alignment of distantly related proteins that share structurally conserved regions. For conformational ensembles, this might not only result in an overhead of computation time but could also affect the achieved accuracy, especially for more complicated cases as highly flexible proteins. ASCONA was evaluated on a test set containing 1107 structures of 65 diverse proteins. In all cases, ASCONA was able to correctly align the binding site at an average alignment computation time of 4 ms per target. Furthermore, no false positive matches were observed when searching the same query sites in the structures of other proteins. ASCONA proved to cope with highly deviating backbone structures and to tolerate structural gaps and moderate mutation rates. ASCONA is available free of charge for academic use at http://www.zbh.uni hamburg.de/ascona . PMID- 26098832 TI - Adolescent Sexual Debut and Initiation into New-Type Drug Use among a Sample of Young Adults. AB - We examined the association between adolescent sexual debut and age at new-type drug initiation among a sample of young adult new-type drug users. A total of 276 participants were recruited using respondent-driven sampling (RDS) in Shanghai, China. The analyses were restricted to a total of 201 participants aged between 18 and 30 years. The average age at sexual debut and age at first new-type drug use were 18.8 and 20.9 years, respectively. About 94% of participants reported having sexual experience (n=188); of those, 137 (72.9%) had sexual debut before they first used new-type drugs, while 32 (17.0%) initiated both events at the same age. After adjustment for age, income, education, and sexual orientation, adolescent sexual debut was independently associated with younger age at new-type drug initiation. Adolescent sexual debut is associated with early onset of new type drug use. Our findings underscore the importance of implementing sex education programs for adolescents in schools in China. PMID- 26098833 TI - The Efficacy and Safety of Chinese Herbal Medicine Jinlida as Add-On Medication in Type 2 Diabetes Patients Ineffectively Managed by Metformin Monotherapy: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial. AB - BACKGROUND: Metformin plays an important role in diabetes treatment. Studies have shown that the combined use of oral hypoglycemic medications is more effective than metformin monotherapy. In this double-blind, randomized, placebo-controlled, multicenter trial, we evaluated whether Jinlida, a Chinese herbal medicine, enhances the glycemic control of metformin in type 2 diabetes patients whose HbA1c was ineffectively controlled with metformin alone. METHODS: A total of 186 diabetes patients were enrolled in this double-Blind, randomized, placebo controlled, multicenter trial. Subjects were randomly allocated to receive either Jinlida (9 g) or the placebo TID for 12 consecutive weeks. All subjects in both groups also continuously received their metformin without any dose change. During this 12-week period, the HbA1c, FPG, 2 h PG, body weight, BMI were assessed. HOMA insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta) were also evaluated. RESULTS: At week 12, compared to the HbA1c level from week 0, the level of the Jinlida group was reduced by 0.92 +/- 1.09% and that of the placebo group was reduced by 0.53 +/- 0.94%. The 95% CI was 0.69-1.14 for the Jinlida group vs. 0.34-0.72 for the placebo group. There was a very significant HbA1c reduction between the two groups after 12 weeks (p < 0.01). Both FG and 2 h PG levels of the Jinlida group and placebo group were reduced from week 0. There were a very significant FG and 2 h PG level reductions between the two groups after 12 weeks (both p < 0.01). The Jinlida group also showed improved beta-cell function with a HOMA-beta increase (p < 0.05). No statistical significance was observed in the body weight and BMI changes. No serious adverse events were reported. CONCLUSION: Jinlida significantly enhanced the hypoglycemic action of metformin when the drug was used alone. This Chinese herbal medicine may have a clinical value as an add-on medication to metformin monotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-TRC-13003159. PMID- 26098834 TI - Comparison of two automatic cell-counting solutions for fluorescent microscopic images. AB - Cell counting in microscopic images is one of the fundamental analysis tools in life sciences, but is usually tedious, time consuming and prone to human error. Several programs for automatic cell counting have been developed so far, but most of them demand additional training or data input from the user. Most of them do not allow the users to online monitor the counting results, either. Therefore, we designed two straightforward, simple-to-use cell-counting programs that also allow users to correct the detection results. In this paper, we present the Cellcounter and Learn123 programs for automatic and semiautomatic counting of objects in fluorescent microscopic images (cells or cell nuclei) with a user friendly interface. Although Cellcounter is based on predefined and fine-tuned set of filters optimized on sets of chosen experiments, Learn123 uses an evolutionary algorithm to determine the adapt filter parameters based on a learning set of images. Cellcounter also includes an extension for analysis of overlaying images. The efficiency of both programs was assessed on images of cells stained with different fluorescent dyes by comparing automatically obtained results with results that were manually annotated by an expert. With both programs, the correlation between automatic and manual counting was very high (R(2) < 0.9), although Cellcounter had some difficulties processing images with no cells or weakly stained cells, where sometimes the background noise was recognized as an object of interest. Nevertheless, the differences between manual and automatic counting were small compared to variations between experimental repeats. Both programs significantly reduced the time required to process the acquired images from hours to minutes. The programs enable consistent, robust, fast and accurate detection of fluorescent objects and can therefore be applied to a range of different applications in different fields of life sciences where fluorescent labelling is used for quantification of various phenomena. Moreover, Cellcounter overlay extension also enables fast analysis of related images that would otherwise require image merging for accurate analysis, whereas Learn123's evolutionary algorithm can adapt counting parameters to specific sets of images of different experimental settings. PMID- 26098835 TI - Hydrogen-Bonding Complexes of 5-Azauracil and Uracil Derivatives in Organic Medium. AB - Uracil derivatives form strong complexes with complementary 2,4-diaminotriazine and adenine compounds, whereas derivatives of 5-azauracil (2,4-dioxotriazine) are known to form weak complexes in aqueous medium. However, herein we report that in organic medium (CDCl3), the 5-azauracil moiety forms hydrogen-bond-mediated complexes with complementary 2,4-diaminotriazine and adenine compounds, with strengths comparable to those formed by uracil compounds. Such dichotomous base pairing behavior of the 5-azauracil moiety, in organic versus aqueous media, is found to be consistent with the ionization of the 5-azauracil moiety in aqueous medium leading to competitive interference from water molecules (via solvation), which is absent (lack of such ionization and solvent interference) in organic medium. This discriminating role of solvent (e.g., water) could have been an important factor in the selection of molecules, based on their physicochemical properties, and subsequently in the emergence of potential primordial informational oligomers that would have played a role in the origins of life. PMID- 26098836 TI - Maintained directional navigation across environments in the Morris water task is dependent on vestibular cues. AB - An experiment was designed to test the hypothesis that an internally generated sense of spatial orientation contributes to navigation by rats in the Morris water task and to determine whether this strategy is dependent on vestibular cues. Rats were trained in a standard hidden platform procedure in which they received 8 daily swim trials. In a probe test, rats were carried in an opaque box to a pool located in a novel adjacent environment. During transport, 1 cohort of rats received a disorientation procedure, composed of gentle rotation in the box, while a second cohort served as transport controls. Upon being placed in the pool in the novel room, controls displayed a preference for the pool quadrant predicted by a retained directional response across rooms, whereas disoriented rats failed to display a preference for the same quadrant. Furthermore, control rats swam faster and more directly toward the target quadrant. Together, these findings suggest that rats retain a directional response based on vestibular cues across environments, which can be used to disambiguate geometrically equivalent locations in a novel room and apparatus. (PsycINFO Database Record PMID- 26098837 TI - Analysis of Multiple Brachyspira hyodysenteriae Genomes Confirms That the Species Is Relatively Conserved but Has Potentially Important Strain Variation. AB - The intestinal spirochete Brachyspira hyodysenteriae is an important pathogen in swine, causing mucohemorrhagic colitis in a disease known as swine dysentery. Based on the detection of significant linkage disequilibrium in multilocus sequence data, the species is considered to be clonal. An analysis of the genome sequence of Western Australian B. hyodysenteriae strain WA1 has been published, and in the current study 19 further strains from countries around the world were sequenced with Illumina technology. The genomes were assembled and aligned to over 97.5% of the reference WA1 genome at a percentage sequence identity better than 80%. Strain regions not aligned to the reference ranged between 0.2 and 2.5%. Clustering of the strain genes found on average 2,354 (88%) core genes, 255 (8.6%) ancillary genes and 77 (2.9%) unique genes per strain. Depending on the strain the proportion of genes with 100% sequence identity to WA1 ranged from 85% to 20%. The result is a global comparative genomic analysis of B. hyodysenteriae genomes revealing potential differential phenotypic markers for numerous strains. Despite the differences found, the genomes were less varied than those of the related pathogenic species Brachyspira pilosicoli, and the analysis supports the clonal nature of the species. From this study, a public genome resource has been created that will serve as a repository for further genetic and phenotypic studies of these important porcine bacteria. This is the first intra-species B. hyodysenteriae comparative genomic analysis. PMID- 26098838 TI - Size of Dominant Diatom Species Can Alter Their Evenness. AB - Traditionally, biodiversity has often been estimated on the basis of abundance partly due to the need for complicated measurements of biomass. Here, we conducted robust measurements of the community composition and of the size structure of diatoms in the North Pacific to evaluate the importance of biomass on the biodiversity. We found that the two most useful evenness indices increased in most cases where small species were numerically dominant when calculations were based on biomass compared with those on abundance. Size-abundance spectra of diatoms revealed that numerically dominant small species rarely dominated in terms of biomass. On the other hand, intermediate to large diatom species generally played a dominant role in terms of biomass in diatom community. The results suggest that the size of the dominant species is a crucial factor in determining the role of diatoms in the ecosystem functioning. Because such size variability can also be observed in other organisms, we need to pay attention to the effect of size structures on biodiversity. PMID- 26098839 TI - Effects of Flavonoids from Potamogeton crispus L. on Proliferation, Migration, and Invasion of Human Ovarian Cancer Cells. AB - In order to explore the efficient utilization of plant resources from constructed wetlands, the potential anti-metastatic effects of flavonoids from Potamogeton crispus L. were investigated in human ovarian cancer cells (ES-2). Two major flavonoids, luteolin-3'-O-beta-D-glucopyranoside and flavone-6-C-beta-D glucopyranoside, were isolated from P. crispus and identified. The effects of these flavonoids on cell proliferation, cell morphology, cell cycle, apoptosis, and cell migration and invasion were then investigated. Furthermore, reverse transcriptase polymerase chain reaction assays and western blotting analysis were conducted to examine the expression level of mRNA and protein. Results indicated that Luteolin-3'-O-beta-D-glucopyranoside inhibited ES-2 cell migration and invasion and suppressed the expression of two matrix metalloproteinases (MMPs), MMP-2 and MMP-9, and Flavone-6-C-beta-D-glucopyranoside had no significant inhibitory effects on ES-2 cells. Thus, this study demonstrated the potential anti-metastatic properties of a P. crispus flavonoid, and provided a scientific approach for the screening of promising natural resources from constructed wetlands to identify useful products for use in the pharmaceutical and healthcare industries. PMID- 26098840 TI - Hemispheric dominance underlying the neural substrate for learned vocalizations develops with experience. AB - Many aspects of song learning in songbirds resemble characteristics of speech acquisition in humans. Genetic, anatomical and behavioural parallels have most recently been extended with demonstrated similarities in hemispheric dominance between humans and songbirds: the avian higher order auditory cortex is left lateralized for processing song memories in juvenile zebra finches that already have formed a memory of their fathers' song, just like Wernicke's area in the left hemisphere of the human brain is dominant for speech perception. However, it is unclear if hemispheric specialization is due to pre-existing functional asymmetry or the result of learning itself. Here we show that in juvenile male and female zebra finches that had never heard an adult song before, neuronal activation after initial exposure to a conspecific song is bilateral. Thus, like in humans, hemispheric dominance develops with vocal proficiency. A left lateralized functional system that develops through auditory-vocal learning may be an evolutionary adaptation that could increase the efficiency of transferring information within one hemisphere, benefiting the production and perception of learned communication signals. PMID- 26098841 TI - Herbivory and Stoichiometric Feedbacks to Primary Production. AB - Established theory addresses the idea that herbivory can have positive feedbacks on nutrient flow to plants. Positive feedbacks likely emerge from a greater availability of organic carbon that primes the soil by supporting nutrient turnover through consumer and especially microbially-mediated metabolism in the detrital pool. We developed an entirely novel stoichiometric model that demonstrates the mechanism of a positive feedback. In particular, we show that sloppy or partial feeding by herbivores increases detrital carbon and nitrogen allowing for greater nitrogen mineralization and nutritive feedback to plants. The model consists of differential equations coupling flows among pools of: plants, herbivores, detrital carbon and nitrogen, and inorganic nitrogen. We test the effects of different levels of herbivore grazing completion and of the stoichiometric quality (carbon to nitrogen ratio, C:N) of the host plant. Our model analyses show that partial feeding and plant C:N interact because when herbivores are sloppy and plant biomass is diverted to the detrital pool, more mineral nitrogen is available to plants because of the stoichiometric difference between the organisms in the detrital pool and the herbivore. This model helps to identify how herbivory may feedback positively on primary production, and it mechanistically connects direct and indirect feedbacks from soil to plant production. PMID- 26098842 TI - The cost-effectiveness of UGT1A1 genotyping before colorectal cancer treatment with irinotecan from the perspective of the German statutory health insurance. AB - BACKGROUND: The evidence concerning the cost-effectiveness of UGT1A1*28 genotyping is ambiguous and does not allow drawing valid conclusions for Germany. This study evaluates the cost-effectiveness of UGT1A1 genotyping in patients with metastatic colorectal cancer undergoing irinotecan-based chemotherapy compared to no testing from the perspective of the German statutory health insurance. MATERIAL AND METHODS: A decision-analytic Markov model with a life time horizon was developed. No testing was compared to two genotype-dependent therapy strategies: 1) dose reduction by 25%; and 2) administration of a prophylactic G CSF growth factor analog for homozygous and heterozygous patients. Probability, quality of life and cost parameters used in this study were based on published literature. Deterministic and probabilistic sensitivity analyses were performed to account for parameter uncertainties. RESULTS: Strategy 1 dominated all remaining strategies. Compared to no testing, it resulted in only marginal QALY increases (0.0002) but a cost reduction of ?580 per patient. Strategy 2 resulted in the same health gains but increased costs by ?10 773. In the probabilistic analysis, genotyping and dose reduction was the optimal strategy in approximately 100% of simulations at a threshold of ?50 000 per QALY. Deterministic sensitivity analysis shows that uncertainty for this strategy originated primarily from costs for irinotecan-based chemotherapy, from the prevalence of neutropenia among heterozygous patients, and from whether dose reduction is applied to both homozygotes and heterozygotes or only to the former. CONCLUSION: This model-based synthesis of the most recent evidence suggests that pharmacogenetic UGT1A1 testing prior to irinotecan-based chemotherapy dominates non-personalized colon cancer care in Germany. However, as structural uncertainty remains high, these results require validation in clinical practice, e.g. based on a managed-entry agreement. PMID- 26098845 TI - Gender differences in spatial learning, synaptic activity, and long-term potentiation in the hippocampus in rats: molecular mechanisms. AB - In tests of spatial ability, males outperform females both in rats and in humans. The mechanism underlying this gender differential learning ability and memory in spatial tasks remains unknown. Long-term potentiation (LTP) in the hippocampus is considered the basis for spatial learning and memory. The aims of this work were (a) to assess spatial learning and memory in male and female rats in the radial and Morris mazes; (b) to assess whether basal synaptic activity and LTP in the hippocampus are different in male and female rats; and (c) to identify the molecular mechanisms responsible for the gender differences in LTP. We analyzed in young male and female rats (a) performance in spatial tasks in the radial and Morris water mazes; (b) basal synaptic activity in hippocampal slices; and (c) LTP and some mechanisms modulating its magnitude. The results reported allow us to conclude that female rats show larger AMPA receptor-mediate synaptic responses under basal conditions, likely due to enhanced phosphorylation of GluR2 in Ser880 and increased amounts of GluR2-containing AMPA receptors in postsynaptic densities. In contrast, the magnitude of tetanus-induced LTP was lower in females than in males. This is due to reduced activation of soluble guanylate cyclase and the formation of cGMP, leading to lower activation of cGMP-dependent protein kinase and phosphorylation of GluR1 in Ser845, which results in lower insertion of AMPA receptors in the synaptic membrane and a lower magnitude of LTP. These mechanisms may contribute to the reduced performance of females in the radial and Morris water mazes. PMID- 26098843 TI - Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. AB - BACKGROUND: Because systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern. OBJECTIVE: To identify predictors of adverse pregnancy outcomes (APOs) in patients with inactive or stable active SLE. DESIGN: Prospective cohort. SETTING: Multicenter. PATIENTS: 385 patients (49% non-Hispanic white; 31% with prior nephritis) with SLE in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. Exclusion criteria were urinary protein-creatinine ratio greater than 1000 mg/g, creatinine level greater than 1.2 mg/dL, prednisone use greater than 20 mg/d, and multifetal pregnancy. MEASUREMENTS: APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational age (SGA) neonate (birthweight below the fifth percentile). Disease activity was assessed with the Systemic Lupus Erythematosus Pregnancy Disease Activity Index and the Physician's Global Assessment (PGA). RESULTS: APOs occurred in 19.0% (95% CI, 15.2% to 23.2%) of pregnancies; fetal death occurred in 4%, neonatal death occurred in 1%, preterm delivery occurred in 9%, and SGA neonate occurred in 10%. Severe flares in the second and third trimesters occurred in 2.5% and 3.0%, respectively. Baseline predictors of APOs included presence of lupus anticoagulant (LAC) (odds ratio [OR], 8.32 [CI, 3.59 to 19.26]), antihypertensive use (OR, 7.05 [CI, 3.05 to 16.31]), PGA score greater than 1 (OR, 4.02 [CI, 1.84 to 8.82]), and low platelet count (OR, 1.33 [CI, 1.09 to 1.63] per decrease of 50 * 109 cells/L). Non-Hispanic white race was protective (OR, 0.45 [CI, 0.24 to 0.84]). Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs. Among women without baseline risk factors, the APO rate was 7.8%. For those who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using antihypertensives, the APO rate was 58.0% and fetal or neonatal mortality was 22.0%. LIMITATION: Patients with high disease activity were excluded. CONCLUSION: In pregnant patients with inactive or stable mild/moderate SLE, severe flares are infrequent and, absent specific risk factors, outcomes are favorable. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 26098844 TI - Virulence Structure of Blumeria graminis f. sp. tritici and Its Genetic Diversity by ISSR and SRAP Profiling Analyses. AB - Blumeria graminis f. sp. tritici, which causes wheat powdery mildew, is an obligate biotrophic pathogen that can easily genetically adapt to its host plant. Understanding the virulence structure of and genetic variations in this pathogen is essential for disease control and for breeding resistance to wheat powdery mildew. This study investigated 17 pathogenic populations in Sichuan, China and classified 109 isolates into two distinct groups based on pathogenicity analysis: high virulence (HV, 92 isolates) and low virulence (LV, 17 isolates). Populations from Yibin (Southern region), Xichang (Western region), and Meishan (Middle region) showed lower virulence frequencies than populations from other regions. Many of the previously known resistance genes did not confer resistance in this study. The resistance gene Pm21 displayed an immune response to pathogenic challenge with all populations in Sichuan, and Pm13, Pm5b, Pm2+6, and PmXBD maintained resistance. AMOVA revealed significantly higher levels of variation within populations and lower levels of variation among populations within regions. High levels of gene flow were detected among populations in the four regions. Closely related populations within each region were distinguished by cluster analyses using ISSR and SRAP alleles. Both ISSR and SRAP allele profiling analyses revealed high levels of genetic diversity among pathogenic populations in Sichuan. Although ISSR and SRAP profiling analysis showed similar resolutions, the SRAP alleles appeared to be more informative. We did not detect any significant association between these alleles and the virulence or pathogenicity of the pathogen. Our results suggest that ISSR and SRAP alleles are more efficient for the characterization of small or closely related populations versus distantly related populations. PMID- 26098846 TI - Natural Abundance (17)O DNP Two-Dimensional and Surface-Enhanced NMR Spectroscopy. AB - Due to its extremely low natural abundance and quadrupolar nature, the (17)O nuclide is very rarely used for spectroscopic investigation of solids by NMR without isotope enrichment. Additionally, the applicability of dynamic nuclear polarization (DNP), which leads to sensitivity enhancements of 2 orders of magnitude, to (17)O is wrought with challenges due to the lack of spin diffusion and low polarization transfer efficiency from (1)H. Here, we demonstrate new DNP based measurements that extend (17)O solid-state NMR beyond its current capabilities. The use of the PRESTO technique instead of conventional (1)H-(17)O cross-polarization greatly improves the sensitivity and enables the facile measurement of undistorted line shapes and two-dimensional (1)H-(17)O HETCOR NMR spectra as well as accurate internuclear distance measurements at natural abundance. This was applied for distinguishing hydrogen-bonded and lone (17)O sites on the surface of silica gel; the one-dimensional spectrum of which could not be used to extract such detail. Lastly, this greatly enhanced sensitivity has enabled, for the first time, the detection of surface hydroxyl sites on mesoporous silica at natural abundance, thereby extending the concept of DNP surface-enhanced NMR spectroscopy to the (17)O nuclide. PMID- 26098848 TI - Evaluation of a Brief Personalised Intervention for Alcohol Consumption in College Students. AB - In the current study we investigated the effect of a brief personalised feedback intervention (BPI), compared to an active control intervention, on outcome measures of (i) alcohol consumption (ii) frequency of binge drinking and (iii) readiness to change (RTC). A sample of 103 college students (mean age=23.85) who consumed alcohol regularly provided baseline measures of drinking behaviour and readiness to change before completing an alcohol-related quiz on the UK Department of Health's Change4Life website (active control). The study was a between subjects design and half the participants were randomly allocated to the BPI group (N=52), who received 10 minutes personalised feedback on their drinking in addition to the alcohol-related quiz. At a two-week follow-up, participants (N=103) repeated the questionnaire battery, and attempted to recall the answers to the alcohol quiz. Results indicated that both groups significantly reduced their alcohol consumption and frequency of binge drinking but there were no significant group differences in either of these measures. We conclude that the provision of generalised information can be as efficient as a BPI for the reduction of alcohol consumption in students. PMID- 26098847 TI - The Decrement of Hemoglobin Concentration with Angiotensin II Receptor Blocker Treatment Is Correlated with the Reduction of Albuminuria in Non-Diabetic Hypertensive Patients: Post-Hoc Analysis of ESPECIAL Trial. AB - Blockade of the renin-angiotensin-aldosterone system exhibits a renoprotective effect; however, blockade of this system may also decrease hemoglobin (Hb) and erythropoietin (EPO) levels. We evaluated the correlation between reduced albuminuria and decreased hemoglobin concentrations after treatment with an angiotensin II receptor blocker (ARB). Two hundred forty-five non-diabetic hypertensive participants with established albuminuria and relatively preserved renal function were treated with an ARB (40 mg/day olmesartan) for eight weeks. Subsequent changes in various clinical parameters, including Hb, EPO, and albuminuria, were analyzed following treatment. After the 8-week treatment with an ARB, Hb and EPO levels significantly decreased. Patients with a greater decrease in Hb exhibited a greater reduction in 24-hour urinary albumin excretion compared with patients with less of a decrease or no decrease in Hb, whereas no associations with a decline in renal function and EPO levels were noted. Multivariate logistic regression analysis demonstrated a correlation between the reduction of urine albumin excretion and the decrease in Hb levels (after natural logarithm transformation, adjusted odds ratio 1.76, 95% confidence interval 1.21 2.56, P = 0.003). Linear regression analysis also supported this positive correlation (Pearson correlation analysis; R = 0.24, P < 0.001). Decreased Hb concentrations following ARB treatment were positively correlated with reduced albuminuria in non-diabetic hypertensive patients, regardless of decreased blood pressure and EPO levels or renal function decline. PMID- 26098849 TI - Tumor T1 Relaxation Time for Assessing Response to Bevacizumab Anti-Angiogenic Therapy in a Mouse Ovarian Cancer Model. AB - PURPOSE: To assess whether T1 relaxation time of tumors may be used to assess response to bevacizumab anti-angiogenic therapy. PROCEDURES: 12 female nude mice bearing subcutaneous SKOV3ip1-LC ovarian tumors were administered bevacizumab (6.25ug/g, n=6) or PBS (control, n=6) therapy twice a week for two weeks. T1 maps of tumors were generated before, two days, and 2 weeks after initiating therapy. Tumor weight was assessed by MR and at necropsy. Histology for microvessel density, proliferation, and apoptosis was performed. RESULTS: Bevacizumab treatment resulted in tumor growth inhibition (p<0.04, n=6), confirming therapeutic efficacy. Tumor T1 relaxation times increased in bevacizumab treated mice 2 days and 2 weeks after initiating therapy (p<.05, n=6). Microvessel density decreased 59% and cell proliferation (Ki67+) decreased 50% in the bevacizumab treatment group (p<.001, n=6), but not apoptosis. CONCLUSIONS: Findings suggest that increased tumor T1 relaxation time is associated with response to bevacizumab therapy in ovarian cancer model and might serve as an early indicator of response. PMID- 26098850 TI - N-Linked Glycans Are Assembled on Highly Reduced Dolichol Phosphate Carriers in the Hyperthermophilic Archaea Pyrococcus furiosus. AB - In all three domains of life, N-glycosylation begins with the assembly of glycans on phosphorylated polyisoprenoid carriers. Like eukaryotes, archaea also utilize phosphorylated dolichol for this role, yet whereas the assembled oligosaccharide is transferred to target proteins from dolichol pyrophosphate in eukaryotes, archaeal N-linked glycans characterized to date are derived from a dolichol monophosphate carrier, apart from a single example. In this study, glycan-charged dolichol phosphate from the hyperthermophile Pyrococcus furiosus was identified and structurally characterized. Normal and reverse phase liquid chromatography electrospray ionization mass spectrometry revealed the existence of dolichol phosphate charged with the heptasaccharide recently described in in vitro studies of N-glycosylation on this species. As with other described archaeal dolichol phosphates, the alpha- and omega-terminal isoprene subunits of the P. furiosus lipid are saturated, in contrast to eukaryal phosphodolichols that present only a saturated alpha-position isoprene subunit. Interestingly, an additional 1-4 of the 12-14 isoprene subunits comprising P. furiosus dolichol phosphate are saturated, making this lipid not only the longest archaeal dolichol phosphate described to date but also the most highly saturated. PMID- 26098851 TI - Terminal Restriction Fragment Length Polymorphism Analysis of Soil Bacterial Communities under Different Vegetation Types in Subtropical Area. AB - Soil microbes are active players in energy flow and material exchange of the forest ecosystems, but the research on the relationship between the microbial diversity and the vegetation types is less conducted, especially in the subtropical area of China. In this present study, the rhizosphere soils of evergreen broad-leaf forest (EBF), coniferous forest (CF), subalpine dwarf forest (SDF) and alpine meadow (AM) were chosen as test sites. Terminal-restriction fragment length polymorphisms (T-RFLP) analysis was used to detect the composition and diversity of soil bacterial communities under different vegetation types in the National Natural Reserve of Wuyi Mountains. Our results revealed distinct differences in soil microbial composition under different vegetation types. Total 73 microbes were identified in soil samples of the four vegetation types, and 56, 49, 46 and 36 clones were obtained from the soils of EBF, CF, SDF and AM, respectively, and subsequently sequenced. The Actinobacteria, Fusobacterium, Bacteroidetes and Proteobacteria were the most predominant in all soil samples. The order of Shannon-Wiener index (H) of all soil samples was in the order of EBF>CF>SDF>AM, whereas bacterial species richness as estimated by four restriction enzymes indicated no significant difference. Principal component analysis (PCA) revealed that the soil bacterial communities' structures of EBF, CF, SDF and AM were clearly separated along the first and second principal components, which explained 62.17% and 31.58% of the total variance, respectively. The soil physical-chemical properties such as total organic carbon (TOC), total nitrogen (TN), total phosphorus (TP) and total potassium (TK) were positively correlated with the diversity of bacterial communities. PMID- 26098854 TI - A rare case of Amyand's hernia in a 67-year-old male. A case report and review of the literature. AB - AIM: The aim of the study is to indicate the Amyand's hernia as a possible complication during surgery for hernia repair performed in emergency CASE REPORT: A case Amyand's hernia complicated by the presence of acute gangrenous appendicitis perforated at the base is reported. DISCUSSION: Amyand's hernia is an hernia which is the vermiform appendix inside. This condition may remain asymptomatic and behave like a normal inguinal hernia or can simulate strangulated hernia when the hernia contains inflamed appendix. CONCLUSION: Acute appendicitis in an incarcerated inguinal hernia is a rare event. The preoperative diagnosis is very difficult because it simulates the behavior of a strangulated inguinal hernia. The treatment depends on the severity of appendicitis. The appendicitis status influences the type of surgery and the type of access. PMID- 26098852 TI - The Axolotl Fibula as a Model for the Induction of Regeneration across Large Segment Defects in Long Bones of the Extremities. AB - We tested the ability of the axolotl (Ambystoma mexicanum) fibula to regenerate across segment defects of different size in the absence of intervention or after implant of a unique 8-braid pig small intestine submucosa (SIS) scaffold, with or without incorporated growth factor combinations or tissue protein extract. Fractures and defects of 10% and 20% of the total limb length regenerated well without any intervention, but 40% and 50% defects failed to regenerate after either simple removal of bone or implanting SIS scaffold alone. By contrast, scaffold soaked in the growth factor combination BMP-4/HGF or in protein extract of intact limb tissue promoted partial or extensive induction of cartilage and bone across 50% segment defects in 30%-33% of cases. These results show that BMP 4/HGF and intact tissue protein extract can promote the events required to induce cartilage and bone formation across a segment defect larger than critical size and that the long bones of axolotl limbs are an inexpensive model to screen soluble factors and natural and synthetic scaffolds for their efficacy in stimulating this process. PMID- 26098855 TI - Dimer formation upon deprotonation: synthesis and structure of a m-terphenyl substituted (R,S)-dilithium disiloxanolate disilanol. AB - The synthesis and structural characterization of the first dilithium salt of a tetrahydroxydisiloxane, [DmpSi(OH)OLi]2O (6), is described (Dmp = 2,6 dimesitylphenyl). The solid state structure reveals the presence of a dimeric motif where two disiloxane units are linked by coordinating lithium atoms which differs from those found for the sodium and potassium analogs. The arrangement imposed by the cluster formation leads to diastereomeric silicon atoms exhibiting (R,S) configuration in the solid state. In addition, the intermediates of the reaction, monolithiated and dilithiated silanetriol could be identified by means of high-resolution mass spectrometry and the formation of 6 is discussed. Moreover, the fully protonated tetrahydroxydisiloxane, [DmpSi(OH)2]2O has been obtained as well and its solid state structures with varying hydrogen bond acceptors have been surveyed. PMID- 26098853 TI - The Effects of Game-Based Breathing Exercise on Pulmonary Function in Stroke Patients: A Preliminary Study. AB - BACKGROUND: Reduction of respiratory function along with hemiparesis leads to decreased endurance, dyspnea, and increased sedentary behavior, as well as to an increased risk of stroke. The main purpose of this study was to investigate the preliminary effects of game-based breathing exercise (GBE) on pulmonary function in stroke patients. MATERIAL AND METHODS: Thirty-eight in-patients with stroke (22 men, 16 women) were recruited for the study. Participants were randomly allocated into 2 groups: patients assigned to the GBE group (n=19), and the control group (n=19). The GBE group participated in a GBE program for 25 minutes a day, 3 days a week, during a 5 week period. For the same period, both groups participated in a conventional stroke rehabilitation program. Forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), FEV1/FVC, and maximum voluntary ventilation (MVV) were measured by a spirometer in pre- and post-testing. RESULTS: The GBE group had significantly improved FVC, FEV1, and MVV values compared with the control group (p<0.05), although there was no significant difference in FEV1/FVC value between groups. Significant short-term effects of the GBE program on pulmonary function in stroke patients were recorded in this study. CONCLUSIONS: These findings gave some indications that it may be feasible to include GBE in rehabilitation interventions with this population. PMID- 26098856 TI - Patients with an extraordinarily elevated serum ferritin: think of haemophagocytic lymphohistiocytosis. AB - BACKGROUND: We retrospectively analysed charts of patients with blood ferritin level >5000 ug/l. The aim of the study was to look for the likelihood of haemophagocytic lymphohistiocytosis (HLH) in these patients. METHODS: Forty-two patients demonstrated hyperferritinaemia and could be evaluated. The diagnosis of HLH was based on a recently published HScore and an earlier diagnostic algorithm. RESULTS: According to the algorithm, 20 patients fulfilled the criteria for a diagnosis of HLH. However, patients with Still's disease have macrophage activation and, in this context, a rise in ferritin without having HLH. Fourteen patients with carcinoma, haematological malignancies or infection and hyperferritinaemia remained. Signs and symptoms were: systemic inflammatory response syndrome (SIRS 100%), fever (95%), cytopenia of >=2 lines (70%), immunosuppression (61.5%), splenomegaly (50%), elevated liver enzymes (45%), lymphadenopathy (35%), hepatomegaly (30%). These are nonspecific parameters. Therefore HLH may be overdiagnosed. Using the HScore, only 10 patients had >80% probability of having HLH. Patients demonstrating cytopenia of >=2 cell lines had a >60% mortality rate. Time to death was 13.8 days; death was most often due to multiorgan failure. CONCLUSION: HScore reflects a higher specificity than the algorithm for diagnosing HLH. The discrepancy may indicate the difficulty that a specific marker still is missing. Hyperferritinaemia was strongly associated with HLH in patients with haematological or oncological malignancies. HLH may be underdiagnosed because the majority of these patients suffer from a severe underlying disease, which easily might suggest a flare or infection. In this population, hyperferritinaemia and SIRS should rise suspicion because mortality in HLH is high. PMID- 26098857 TI - Reliability and Validity of the Alberta Context Tool (ACT) with Professional Nurses: Findings from a Multi-Study Analysis. AB - Although organizational context is central to evidence-based practice, underdeveloped measurement hinders its assessment. The Alberta Context Tool, comprised of 59 items that tap 10 modifiable contextual concepts, was developed to address this gap. The purpose of this study to examine the reliability and validity of scores obtained when the Alberta Context Tool is completed by professional nurses across different healthcare settings. Five separate studies (N = 2361 nurses across different care settings) comprised the study sample. Reliability and validity were assessed. Cronbach's alpha exceeded 0.70 for 9/10 Alberta Context Tool concepts. Item-total correlations exceeded acceptable standards for 56/59 items. Confirmatory Factor Analyses coordinated acceptably with the Alberta Context Tool's proposed latent structure. The mean values for each Alberta Context Tool concept increased from low to high levels of research utilization(as hypothesized) further supporting its validity. This study provides robust evidence for reliability and validity of scores obtained with the Alberta Context Tool when administered to professional nurses. PMID- 26098858 TI - Improving the Rank Precision of Population Health Measures for Small Areas with Longitudinal and Joint Outcome Models. AB - OBJECTIVES: The University of Wisconsin Population Health Institute has published the County Health Rankings since 2010. These rankings use population-based data to highlight health outcomes and the multiple determinants of these outcomes and to encourage in-depth health assessment for all United States counties. A significant methodological limitation, however, is the uncertainty of rank estimates, particularly for small counties. To address this challenge, we explore the use of longitudinal and pooled outcome data in hierarchical Bayesian models to generate county ranks with greater precision. METHODS: In our models we used pooled outcome data for three measure groups: (1) Poor physical and poor mental health days; (2) percent of births with low birth weight and fair or poor health prevalence; and (3) age-specific mortality rates for nine age groups. We used the fixed and random effects components of these models to generate posterior samples of rates for each measure. We also used time-series data in longitudinal random effects models for age-specific mortality. Based on the posterior samples from these models, we estimate ranks and rank quartiles for each measure, as well as the probability of a county ranking in its assigned quartile. Rank quartile probabilities for univariate, joint outcome, and/or longitudinal models were compared to assess improvements in rank precision. RESULTS: The joint outcome model for poor physical and poor mental health days resulted in improved rank precision, as did the longitudinal model for age-specific mortality rates. Rank precision for low birth weight births and fair/poor health prevalence based on the univariate and joint outcome models were equivalent. CONCLUSION: Incorporating longitudinal or pooled outcome data may improve rank certainty, depending on characteristics of the measures selected. For measures with different determinants, joint modeling neither improved nor degraded rank precision. This approach suggests a simple way to use existing information to improve the precision of small-area measures of population health. PMID- 26098859 TI - Validation of an IGF-CTP scoring system for assessing hepatic reserve in Egyptian patients with hepatocellular carcinoma. AB - BACKGROUND: The Child-Turcotte-Pugh score (CTP) is the standard tool for hepatic reserve assessment in hepatocellular carcinoma (HCC). Recently, we reported that integrating plasma insulin-like growth factor-1 (IGF-1) level into the CTP score was associated with better patient risk stratification in two U.S. independent cohorts. Our current study aimed to validate the IGF-CTP score in patients who have different demographics and risk factors. PATIENTS AND METHODS: We prospectively recruited 100 Egyptian patients and calculated their IGF-CTP score compared to CTP score. C-index was used to compare the prognostic significance of the two scoring systems. Finally, we compared our results with our U.S. cohorts published data. RESULTS: IGF-CTP score showed significant better patient stratification compared to CTP score in the international validation cohort. Among CTP class A patients, who usually considered for active treatment and clinical trial enrollment, 32.5% were reclassified as IGF-CTP class B with significantly shorter OS than patients reclassified as class A with hazard ratio [HR] = 6.15, 95% confidence interval [CI] = 2.18 -17.37. CONCLUSIONS: IGF-CTP score showed significantly better patient stratification and survival prediction not only in the U.S. population but also in international validation population, who had different demographics and HCC risk factors. PMID- 26098860 TI - Sick Leave within 5 Years of Whiplash Trauma Predicts Recovery: A Prospective Cohort and Register-Based Study. AB - BACKGROUND: 10-22% of individuals sustaining whiplash trauma develop persistent symptoms resulting in reduced working ability and decreased quality of life, but it is poorly understood why some people do not recover. Various collision and post-collision risk factors have been studied, but little is known about pre collision risk factors. In particular, the impact of sickness and socioeconomic factors before the collision on recovery is sparsely explored. The aim of this study was to examine if welfare payments received within five years pre-collision predict neck pain and negative change in provisional situation one year post collision. METHODS AND FINDINGS: 719 individuals with acute whiplash trauma consecutively recruited from emergency departments or primary care after car accidents in Denmark completed questionnaires on socio-demographic and health factors immediately after the collision. After 12 months, a visual analogue scale on neck pain intensity was completed. 3595 matched controls in the general population were sampled, and national public register data on social benefits and any other welfare payments were obtained for participants with acute whiplash trauma and controls from five years pre-collision to 15 months after. Participants with acute whiplash trauma who had received sickness benefit for more than 12 weeks pre-collision had increased odds for negative change in future provisional situation (Odds Ratio (OR) (95% Confidence Interval (CI) = 3.8 (2.1;7.1)) and future neck pain (OR (95%CI) = 3.3 (1.8;6.3)), controlling for other known risk factors. Participants with acute whiplash trauma had weaker attachment to labour market (more weeks of sick leave (chi2(2) = 36.7, p < 0.001) and unemployment (chi2(2) = 12.5, p = 0.002)) pre-collision compared with controls. Experiencing a whiplash trauma raised the odds for future negative change in provisional situation (OR (95%CI) = 3.1 (2.3;4.4)) compared with controls. CONCLUSIONS: Sick leave before the collision strongly predicted prolonged recovery following whiplash trauma. Participants with acute whiplash trauma had weaker attachment to labour market pre-collision compared with the general population. Neck pain at inclusion predicted future neck pain. Acute whiplash trauma may trigger pre-existing vulnerabilities increasing risk of developing whiplash-associated disorders. PMID- 26098861 TI - Formaldehyde migration in aqueous extracts from paper and cardboard food packaging materials in Turkey. AB - Migration of formaldehyde to aqueous extracts from paper and cardboard food packaging materials was determined by an ultraviolet visible-spectrophotometric method at 410 nm. Intraday and interday precision of the method, expressed as coefficient of variation, varied between 1.5 to 4.4% and 7 to 8.8%, respectively. The limit of quantification was 0.28 mg kg(-1) for formaldehyde in aqueous extracts. The recovery of the method was over 90% for two different concentration levels in aqueous extracts. The method was applied to the migration of formaldehyde to aqueous extracts from 31 different paper and cardboard materials collected from the packaging sector, intended for food contact, such as tea filters, hot water filters, paper pouches and folding boxes. The results were between limit of detection 0.23 mg/kg and 40 mg kg(-1) and were evaluated according to the relevant directives. PMID- 26098862 TI - Tubal pregnancy associated with additional conception in a contralateral tube. AB - Pregnancy of unknown location is defined as empty endometrial cavity despite positive pregnancy test, and often develops as overt intrauterine or ectopic pregnancy. The pathophysiology of persistent pregnancy of unknown location, however, which involves continuous low serum human chorionic gonadotropin without any visible implantation site, is unknown. We report a case of left tubal pregnancy associated with additional conception in the contralateral tube. Left tubal pregnancy was suspected in a 40-year-old nulligravid woman after two embryo transfers following in vitro fertilization. Laparoscopic bilateral salpingectomy was performed for bilateral hydrosalpinx. Products from an additional conception were identified in the right tube. Short tandem repeat analysis using genomic DNA from resected specimens indicated two conceptions of different origin. The extra conception identified on microscopy may indicate one pathogenesis of persistent pregnancy of unknown location. Salpingectomy of the contralateral tube with hydrosalpinx is an option to prevent persistent occult pregnancy. PMID- 26098863 TI - Mode-specific study of nanoparticle-mediated optical interactions in an absorber/metal thin film system. AB - We present an experimental and theoretical study of the electromagnetic interaction between a single gold nanoparticle and a thin gold substrate separated by a sub-50 nm-thick optically absorptive polythiophene spacer layer. Single-particle dark-field scattering spectra show distinct resonance features assigned to four different modes: a horizontal image dipole coupling mode, a vertical image dipole coupling mode and horizontal and vertical coupling modes between localized surface plasmon resonances (LSPRs) and surface plasmon polaritons (SPPs). Relatively broadband spectral tuning of the modes can be achieved by modification of the thickness of either the absorptive spacer or the underlying metal film. Dark-field images also reveal the existence of particles for which the signal of the horizontal image dipole coupling mode is suppressed. This is attributed to partial-embedding of gold nanoparticles into the polythiophene spacer and leads to higher scattered light intensities at longer wavelengths. Full-field electromagnetic simulations show good agreement with the experimental results for the various sample conditions. Strong local electric field confinement at longer wavelengths in the polythiophene spacer, due to the vertical image dipole coupling mode and a LSPR-SPP coupling mode, is also observed in simulations and contributes to absorption enhancement in the spacer. Furthermore, we find absorption enhancement in the semiconducting polythiophene spacer increases with decreasing thickness, indicating the increased light trapping ability of the gold nanoparticles for ultra-thin semiconductor layers. The need for ever-thinner semiconductor layers in optoelectronic devices requires effective light trapping at deeply-subwavelength scales. This work demonstrates that light trapping in sub-50 nm-thick semiconductor layers is possible using a "sphere-on-plane" system and offers insight into how coupling modes can be manipulated in this system. PMID- 26098864 TI - Correction: A Novel Approach to Delayed-Start Analyses for Demonstrating Disease Modifying Effects in Alzheimer's Disease. PMID- 26098865 TI - Optimal force magnitude loaded to orthodontic microimplants: A finite element analysis. AB - OBJECTIVE: To find an optimal force that can be loaded onto an orthodontic microimplant to fulfill the biomechanical demands of orthodontic treatment without diminishing the stability of the microimplant. MATERIALS AND METHODS: Using the finite element analysis method, 3-D computer-aided design models of a microimplant and four cylindrical bone pieces (incorporating cortical bone thicknesses of 0.5, 1.2, 2.0, and 3.0 mm) into which the microimplant was inserted were used. Various force magnitudes of 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0 N were then horizontally and separately applied to the microimplant head as inserted into the different bone assemblies. For each bone/force assembly tested, peak stresses developed at areas of intimate contact with the microimplant along the force direction were then calculated using regression analysis and compared with a threshold value at which pathologic bone resorption might develop. RESULTS: The resulting peak stresses showed that bone pieces with thicker cortical bone tolerated higher force magnitudes better than did thinner ones. For cortical bone thicknesses of 0.5, 1.2, 2.0, and 3.0 mm, the maximum force magnitudes that could be applied safely were 3.75, 4.1, 4.3, and 4.45 N, respectively. CONCLUSIONS: For the purpose of diminishing orthodontic microimplant failure, an optimal force that can be safely loaded onto a microimplant should not exceed a value of around 3.75-4.5 N. PMID- 26098866 TI - Loss-of-function variants in ATM confer risk of gastric cancer. AB - Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 * 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1. PMID- 26098867 TI - Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. AB - Clear cell sarcoma of the kidney (CCSK) is one of the major pediatric renal neoplasms, but its associated genetic abnormalities are largely unknown. We identified internal tandem duplications in the BCOR gene (BCL6 corepressor) affecting the C terminus in 100% (20/20) of CCSK tumors but in none (0/193) of the other pediatric renal tumors. CCSK tumors expressed only an aberrant BCOR allele, indicating a close correlation between BCOR aberration and CCSK tumorigenesis. PMID- 26098868 TI - GmHs1-1, encoding a calcineurin-like protein, controls hard-seededness in soybean. AB - Loss of seed-coat impermeability was essential in the domestication of many leguminous crops to promote the production of their highly nutritious seeds. Here we show that seed-coat impermeability in wild soybean is controlled by a single gene, GmHs1-1, which encodes a calcineurin-like metallophosphoesterase transmembrane protein. GmHs1-1 is primarily expressed in the Malpighian layer of the seed coat and is associated with calcium content. The transition from impermeability to permeability in domesticated soybean was caused by artificial selection of a point mutation in GmHs1-1. Interestingly, a number of soybean landraces evaded selection for permeability because of an alternative selection for seed-coat cracking that also enables seed imbibition. Despite the single origin of the mutant allele Gmhs1-1, the distribution pattern of allelic variants in the context of soybean population structure and the detected signature of genomic introgression between wild and cultivated soybeans suggest that Gmhs1-1 may have experienced reselection for seed-coat permeability. PMID- 26098871 TI - The Strength of Association Between Surrogate End Points and Survival in Oncology: A Systematic Review of Trial-Level Meta-analyses. AB - IMPORTANCE: The strength of association between surrogate end points and survival in oncology is important to understand because surrogate end points are frequently used in oncology clinical trials, supporting US Food and Drug Administration approvals and National Comprehensive Cancer Network guideline recommendations. OBJECTIVE: To identify and evaluate trial-level meta-analyses of randomized clinical trials quantifying the association between a surrogate end point and overall survival in medical oncology. Trial-level correlations test whether treatments that improve the surrogate end point also improve the final end point and are widely considered the strongest evidence to validate a surrogate end point. EVIDENCE REVIEW: Our literature search was built on earlier reported data sets and updated with Google Scholar and MEDLINE searches conducted on December 26, 2014. For MEDLINE, search terms included ("regression" or "correlation") and "surrogate" and "end point [or endpoint]" and ("oncology" or "cancer"). For Google scholar, search terms included ("regression" or "correlation") and "surrogate end point [or endpoint]" and "overall survival" and "trial level." A total of 108 abstracts were retrieved, and 62 articles were read in full in addition to articles identified through prior reviews. FINDINGS: We found 36 articles in which 65 specific correlations between a surrogate end point and survival were identified. Surrogate end points were studied in the neoadjuvant, adjuvant, locally advanced, and metastatic settings. The most common sources for trials included in the 36 articles were systematic reviews of the published literature (10 of 36; 28%), and published literature and meeting abstracts (14 of 36; 39%). Four meta-analyses (11%) used a convenience sample, and only 5 studies (14%) attempted to include unpublished trials by surveying clinical trial registries. Among these 5 studies, only 352 of 684 eligible trials (51.1%) were included in the analyses. More than half of reported correlations (34 of 65; 52%) were of low strength (r <= 0.7). Approximately a quarter (16 of 65; 25%) were of medium strength (r > 0.7 to r < 0.85), and 15 of 65 (23%) were highly correlated (r >= 0.85) with survival. CONCLUSIONS AND RELEVANCE: Most trial-level validation studies of surrogate end points in oncology find low correlations with survival. All validation studies use only a subset of available trials. The evidence supporting the use of surrogate end points in oncology is limited. PMID- 26098870 TI - Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity. AB - Hundreds of genes reside in structurally complex, poorly understood regions of the human genome. One such region contains the three amylase genes (AMY2B, AMY2A and AMY1) responsible for digesting starch into sugar. Copy number of AMY1 is reported to be the largest genomic influence on obesity, although genome-wide association studies for obesity have found this locus unremarkable. Using whole genome sequence analysis, droplet digital PCR and genome mapping, we identified eight common structural haplotypes of the amylase locus that suggest its mutational history. We found that the AMY1 copy number in an individual's genome is generally even (rather than odd) and partially correlates with nearby SNPs, which do not associate with body mass index (BMI). We measured amylase gene copy number in 1,000 obese or lean Estonians and in 2 other cohorts totaling ~3,500 individuals. We had 99% power to detect the lower bound of the reported effects on BMI, yet found no association. PMID- 26098869 TI - Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. AB - Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 * 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 * 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 * 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 * 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk. PMID- 26098872 TI - Genetic Interactions between the Members of the SMN-Gemins Complex in Drosophila. AB - The SMN-Gemins complex is composed of Gemins 2-8, Unrip and the survival motor neuron (SMN) protein. Limiting levels of SMN result in the neuromuscular disorder, spinal muscular atrophy (SMA), which is presently untreatable. The most documented function of the SMN-Gemins complex concerns the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). Despite multiple genetic studies, the Gemin proteins have not been identified as prominent modifiers of SMN-associated mutant phenotypes. In the present report, we make use of the Drosophila model organism to investigate whether viability and motor phenotypes associated with a hypomorphic Gemin3 mutant are enhanced by changes in the levels of SMN, Gemin2 and Gemin5 brought about by various genetic manipulations. We show a modifier effect by all three members of the minimalistic fly SMN-Gemins complex within the muscle compartment of the motor unit. Interestingly, muscle-specific overexpression of Gemin2 was by itself sufficient to depress normal motor function and its enhanced upregulation in all tissues leads to a decline in fly viability. The toxicity associated with increased Gemin2 levels is conserved in the yeast S. pombe in which we find that the cytoplasmic retention of Sm proteins, likely reflecting a block in the snRNP assembly pathway, is a contributing factor. We propose that a disruption in the normal stoichiometry of the SMN-Gemins complex depresses its function with consequences that are detrimental to the motor system. PMID- 26098873 TI - A Sensitive and Specific Neural Signature for Picture-Induced Negative Affect. AB - Neuroimaging has identified many correlates of emotion but has not yet yielded brain representations predictive of the intensity of emotional experiences in individuals. We used machine learning to identify a sensitive and specific signature of emotional responses to aversive images. This signature predicted the intensity of negative emotion in individual participants in cross validation (n =121) and test (n = 61) samples (high-low emotion = 93.5% accuracy). It was unresponsive to physical pain (emotion-pain = 92% discriminative accuracy), demonstrating that it is not a representation of generalized arousal or salience. The signature was comprised of mesoscale patterns spanning multiple cortical and subcortical systems, with no single system necessary or sufficient for predicting experience. Furthermore, it was not reducible to activity in traditional "emotion related" regions (e.g., amygdala, insula) or resting-state networks (e.g., "salience," "default mode"). Overall, this work identifies differentiable neural components of negative emotion and pain, providing a basis for new, brain-based taxonomies of affective processes. PMID- 26098875 TI - Enhanced Photocatalytic Performance of the Graphene-V2O5 Nanocomposite in the Degradation of Methylene Blue Dye under Direct Sunlight. AB - A simple and efficient solution mixing method has been developed for the synthesis of the G-V2O5 nanocomposite. By this method, one-dimensional V2O5 rods are decorated onto the two-dimensional graphene sheets. The synthesized nanocomposites are characterized by XRD, SEM with elemental mapping, TEM, FT-IR, Raman, BET, and XPS analyses. The photocatalytic activity of the G-V2O5 nanocomposite studied with methylene blue dye shows strong degradation efficiency with direct sunlight irradiation compared to UV and visible light sources. The mechanism of methylene blue dye degradation by the G-V2O5 nanocomposite has been elucidated through the kinetics of the degradation process by calculating the rate constant and half-life time of the degradation process. PMID- 26098874 TI - Nanomicellar Formulation of Clotrimazole Improves Its Antitumor Action toward Human Breast Cancer Cells. AB - BACKGROUND: Although demonstrated as a selective anticancer drug, the clinical use of clotrimazole (CTZ) is limited due to its low solubility in hydrophilic fluids. Thus, we prepared a water-soluble nanomicellar formulation of CTZ (nCTZ) and tested on the human breast cancer cell line MCF-7 biology. METHODOLOGY/PRINCIPAL FINDINGS: CTZ was nanoencapsulated in tween 80 micelles, which generated nanomicelles of, approximately, 17 nm of diameter. MCF-7 cells were treated with nCTZ and unencapsulated DMSO-solubilized drug (sCTZ) was used for comparison. After treatment, the cells were evaluated in terms of metabolism, proliferation, survival and structure. We found that nCTZ was more efficient than sCTZ at inhibiting glycolytic and other cytosolic and mitochondrial enzymes. Moreover, this increased activity was also observed for lactate production, intracellular ATP content, ROS production and antioxidant potential. As a consequence, nCTZ-treated MCF-7 cells displayed alterations to the plasma membrane, mitochondria and the nucleus. Finally, nCTZ induced both apoptosis and necrosis in MCF-7 cells. CONCLUSIONS/SIGNIFICANCE: MCF-7 cells are more sensible to nCTZ than to sCTZ. This was especially evident on regard to antioxidant potential, which is an important cell defense against drugs that affect cell metabolism. Moreover, this water-soluble formulation of CTZ strengths its potential use as an anticancer medicine. PMID- 26098876 TI - Impact of Antithrombotic Therapy in Atrial Fibrillation on the Presentation of Coronary Artery Disease. AB - BACKGROUND: Little is known about whether atrial fibrillation is a presentation of coronary disease. There is a paucity of knowledge about their causal relationship and also the impact of different antithrombotic strategies on the subsequent presentation of symptomatic coronary disease. METHODS AND RESULTS: We studied 7,526 Chinese patients diagnosed with non-valvular atrial fibrillation and no documented history of coronary artery disease. The primary endpoint was the new occurrence of coronary artery disease--either stable coronary artery disease or acute coronary syndrome. After a mean follow-up of 3.2+/-3.5 years (24,071 patient-years), a primary endpoint occurred in 987 patients (13.1%). The overall annual incidence of coronary artery disease was 4.10%/year. No significant differences in age, sex, and mean CHA2DS2-VASc score were observed between patients with and without the primary endpoint. When stratified according to the antithrombotic strategies applied for stroke prevention, the annual incidence of coronary artery disease was 5.49%/year, 4.45%/year and 2.16%/year respectively in those prescribed no antithrombotic therapy, aspirin, and warfarin. Similar trends were observed in patients with acute coronary syndromes. Diabetes mellitus, smoking history and renal failure requiring dialysis were predictors for primary endpoint in all antithrombotic therapies. CONCLUSION: In patients with non-valvular atrial fibrillation, there is a modest association with coronary artery disease. Patients prescribed warfarin had the lowest risk of new onset coronary artery disease. PMID- 26098877 TI - Weak Evidence of Regeneration Habitat but Strong Evidence of Regeneration Niche for a Leguminous Shrub. AB - The identification of an ecological niche specific to the regeneration phase has mobilised significant attention. However, the importance of the regeneration niche concept remains unclear. Our main objective was to study the existence of such a regeneration niche for a leguminous shrub, Ulex europaeus. This study was carried out in southwest France in the context of water and nutrient stresses (mainly phosphorus limitation) due to the presence of nutrient-poor sandy soils. We analysed the regeneration of the species from the germination of seeds and emergence of new seedlings until the seedlings reached young shrub size. Our design included a P fertilisation treatment. We also investigated microsite characteristics (micro-topography and vegetation development) as they can interact with meteorological conditions and determine water availability for seeds and seedlings. We found that P availability controlled seedling growth and the time necessary to reach young shrub size. Water availability appeared to impact the species germination and seedlings survival. We also found that P and water availability depended on the interactions between microsite characteristics and climatic variations. Finally we found evidence that P and water availability are important ecological factors shaping the regeneration niche of the species, but we found weak evidence that any microsite would be appropriate for the regeneration of the species in the long term. Future studies regarding regeneration niches need to distinguish more clearly the ecological factors important for regeneration (the regeneration niche per se) and the physical world where the seedlings appear and develop (the regeneration habitat). PMID- 26098878 TI - Thymosin alpha1: burying secrets in the thymus. AB - Thymosin alpha1 (Talpha1), an epithelial cell (EC)-derived cytokine, has the strong ability to modulate signals delivered through innate immune receptors on dendritic cells (DCs), thus instructing the initiation of appropriate immune responses to T cells. In its ability to activate indoleamine 2,3-dioxygenase 1 dependent tolerogenic programs in DCs, Talpha1 pivotally contributes to the maintenance of self-tolerance by regulating the function of regulatory T (Treg) cells. How Talpha1 may contribute to the Treg cell ontogeny is not known. The transcriptional regulator autoimmune regulator (AIRE) is known to control central and peripheral tolerance. AIRE is highly expressed in thymic medullary ECs where it controls the ectopic expression of tissue restricted antigens for negative selection. The absence of AIRE-induced tissue-specific antigens in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, AIRE protein has been detected in peripheral lymphoid organs, suggesting that peripheral AIRE may play a complementary role. We have addressed the possible relationship between AIRE and Talpha1 and discovered an intricate crosstalk, whereby AIRE may promote prothymosin cleavage to Talpha1, and Talpha1 in turn transcriptionally regulates AIRE expression. Thus, similar to other members of thymic stromal poietins, Talpha1 expressed within the thymus and peripheral tissues regulates the EC/DC crosstalk required for salutary immune homeostasis. PMID- 26098879 TI - Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet. AB - BACKGROUND: Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD dependent de-acyetylases and is modulated by cellular redox. HYPOTHESIS: We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction. METHODS AND RESULTS: We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARalpha, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARalpha, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP. CONCLUSION: Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression. PMID- 26098880 TI - Phenotypic Characterisation of Shewanella oneidensis MR-1 Exposed to X-Radiation. AB - Biogeochemical processes mediated by Fe(III)-reducing bacteria such as Shewanella oneidensis have the potential to influence the post-closure evolution of a geological disposal facility for radioactive wastes and to affect the solubility of some radionuclides. Furthermore, their potential to reduce both Fe(III) and radionuclides can be harnessed for the bioremediation of radionuclide contaminated land. As some such sites are likely to have significant radiation fluxes, there is a need to characterise the impact of radiation stress on such microorganisms. There have, however, been few global cell analyses on the impact of ionizing radiation on subsurface bacteria, so here we address the metabolic response of S. oneidensis MR-1 to acute doses of X-radiation. UV/Vis spectroscopy and CFU counts showed that although X-radiation decreased initial viability and extended the lag phase of batch cultures, final biomass yields remained unchanged. FT-IR spectroscopy of whole cells indicated an increase in lipid associated vibrations and decreases in vibrations tentatively assigned to nucleic acids, phosphate, saccharides and amines. MALDI-TOF-MS detected an increase in total protein expression in cultures exposed to 12 Gy. At 95 Gy, a decrease in total protein levels was generally observed, although an increase in a putative cold shock protein was observed, which may be related to the radiation stress response of this organism. Multivariate statistical analyses applied to these FT IR and MALDI-TOF-MS spectral data suggested that an irradiated phenotype developed throughout subsequent generations. This study suggests that significant alteration to the metabolism of S. oneidensis MR-1 is incurred as a result of X irradiation and that dose dependent changes to specific biomolecules characterise this response. Irradiated S. oneidensis also displayed enhanced levels of poorly crystalline Fe(III) oxide reduction, though the mechanism underpinning this phenomenon is unclear. PMID- 26098882 TI - Viability of a [2 + 2 + 1] Hetero-Pauson-Khand Cycloaddition Strategy toward Securinega Alkaloids: Synthesis of the BCD-Ring Core of Securinine and Related Alkaloids. AB - Preliminary results related to the development of [2 + 2 + 1]-oxa-hetero-Pauson Khand cycloaddition strategy toward the Securinega alkaloids are reported. The critical tricyclic BCD-ring core was assembled in only nine linear steps from cheap 4-hydroxy-l-proline. The study provides valuable insight into the scope of a rare hetero-Pauson-Khand reaction, a powerful tool for the rapid construction of butenolide-containing natural products. PMID- 26098881 TI - A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer. AB - BACKGROUND: Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC. METHODS AND FINDINGS: We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-beta) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including beta-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC like tumors as compared to unselected CRC cases. CONCLUSIONS: In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-beta/SMAD and Wnt/beta-catenin pathways. This bottleneck-like zone is usually followed by the emergence of invasive tumors with intact PTEN expression but dysregulated TP53 and uniformly high proliferation rates. PMID- 26098883 TI - Caffeine Consumption and Heart Rate and Blood Pressure Response to Regadenoson. AB - BACKGROUND: Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing. METHODS: 332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected. RESULTS: Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change (15.2+/-17.1 vs. 7.2+/-10.2 mmHg, p = 0.001), heart rate change (32.2+/-14 vs. 27.3+/-9.6 bpm, p = 0.038) and maximal predicted heart rate (65.5+/-15.6 vs. 60.7+/-8.6%, p = 0.038) were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12-24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change (13+/-15.8 vs. 7+/-10.2, p = 0.007), and heart rate change (32.1+/-15.3 vs. 27.3+/-9.6, p = 0.017) as compared to those who drank coffee 12 24 hours prior to testing (group 2). CONCLUSIONS: Caffeine exposure 12-24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing. PMID- 26098884 TI - Cardiovascular Risk Factors and Ethnicity Are Independent Factors Associated with Lower Urinary Tract Symptoms. AB - OBJECTIVES: To determine the lower urinary tract symptoms (LUTS) profile and factors affecting its degree of severity including cardiovascular risk profile, age, ethnicity, education level and prostate volume in a multiethnic Asian setting. MATERIALS AND METHODS: We conducted a cross-sectional study of 1021 men aged 40-79 years with no clinical evidence of prostate cancer, prostate surgery or 5alpha-reductase inhibitor treatment of known prostate conditions. The severity of LUTS was assessed using the International Prostate Symptom Score (IPSS). Potential factors associated with LUTS including age, ethnicity, education, history of hypertension, diabetes and hypercholesterolemia, height, weight, and prostate volume were evaluated using univariable and multivariable analyses. RESULTS: There were 506 (50%) men found to have moderate-to-severe LUTS attaining an IPSS above 7. Overall, nocturia (45.5%) was the most frequently reported symptom. Multivariable analysis showed that age, ethnicity, prostate volume and history of hypertension and hypercholesterolemia were independent factors associated with severity of LUTS (p < 0.05). Considering individual lower urinary tract symptoms, we found a strong association of storage symptom with history of hypertension and hypercholesterolemia. Malay men were significantly bothered by post micturition symptom compared to their Chinese and Indian counterparts. Stratified analyses of LUTS demonstrated a mutually exclusive cardiovascular risk factors profile defined by ethnicity. CONCLUSION: Severity of LUTS varies between different ethnicities across all age groups. In addition to age and prostate volume, ethnicity and cardiovascular risk factors including hypertension and hypercholesterolemia may also need to be taken into account in managing men with LUTS. PMID- 26098885 TI - Mutations in the 5' NTR and the Non-Structural Protein 3A of the Coxsackievirus B3 Selectively Attenuate Myocarditogenicity. AB - The 5' non-translated region (NTR) is an important molecular determinant that controls replication and virulence of coxsackievirus B (CVB)3. Previous studies have reported many nucleotide (nt) sequence differences in the Nancy strain of the virus, including changes in the 5' NTR with varying degrees of disease severity. In our studies of CVB3-induced myocarditis, we sought to generate an infectious clone of the virus for routine in vivo experimentation. By determining the viral nt sequence, we identified three new nt substitutions in the clone that differed from the parental virus strain: C97U in the 5' NTR; a silent mutation, A4327G, in non-structural protein 2C; and C5088U (resulting in P1449L amino acid change) in non-structural protein 3A of the virus leading us to evaluate the role of these changes in the virulence properties of the virus. We noted that the disease-inducing ability of the infectious clone-derived virus in three mouse strains was restricted to pancreatitis alone, and the incidence and severity of myocarditis were significantly reduced. We then reversed the mutations by creating three new clones, representing 1) U97C; 2) G4327A and U5088C; and 3) their combination together in the third clone. The viral titers obtained from all the clones were comparable, but the virions derived from the third clone induced myocarditis comparable to that induced by wild type virus; however, the pancreatitis-inducing ability remained unaltered, suggesting that the mutations described above selectively influence myocarditogenicity. Because the accumulation of mutations during passages is a continuous process in RNA viruses, it is possible that CVB3 viruses containing such altered nts may evolve naturally, thus favoring their survival in the environment. PMID- 26098886 TI - Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation. AB - Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on !over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels. PMID- 26098887 TI - Quantitative Measurements in the Human Hippocampus and Related Areas: Correspondence between Ex-Vivo MRI and Histological Preparations. AB - The decrease of volume estimates in different structures of the medial temporal lobe related to memory correlate with the decline of cognitive functions in neurodegenerative diseases. This study presents data on the association between MRI quantitative parameters of medial temporal lobe structures and their quantitative estimate in microscopic examination. Twelve control cases had ex vivo MRI, and thereafter, the temporal lobe of both hemispheres was sectioned from the pole as far as the level of the splenium of the corpus callosum. Nissl stain was used to establish anatomical boundaries between structures in the medial temporal lobe. The study included morphometrical and stereological estimates of the amygdaloid complex, hippocampus, and temporal horn of the lateral ventricle, as well as different regions of grey and white matter in the temporal lobe. Data showed a close association between morphometric MRI images values and those based on the histological determination of boundaries. Only values in perimeter and circularity of the piamater were different. This correspondence is also revealed by the stereological study, although irregular compartments resulted in a lesser agreement. Neither age (< 65 yr and > 65 yr) nor hemisphere had any effect. Our results indicate that ex-vivo MRI is highly associated with quantitative information gathered by histological examination, and these data could be used as structural MRI biomarker in neurodegenerative diseases. PMID- 26098888 TI - Altered Structural and Functional Connectivity in Late Preterm Preadolescence: An Anatomic Seed-Based Study of Resting State Networks Related to the Posteromedial and Lateral Parietal Cortex. AB - OBJECTIVE: Late preterm birth confers increased risk of developmental delay, academic difficulties and social deficits. The late third trimester may represent a critical period of development of neural networks including the default mode network (DMN), which is essential to normal cognition. Our objective is to identify functional and structural connectivity differences in the posteromedial cortex related to late preterm birth. METHODS: Thirty-eight preadolescents (ages 9-13; 19 born in the late preterm period (>=32 weeks gestational age) and 19 at term) without access to advanced neonatal care were recruited from a low socioeconomic status community in Brazil. Participants underwent neurocognitive testing, 3-dimensional T1-weighted imaging, diffusion-weighted imaging and resting state functional MRI (RS-fMRI). Seed-based probabilistic diffusion tractography and RS-fMRI analyses were performed using unilateral seeds within the posterior DMN (posterior cingulate cortex, precuneus) and lateral parietal DMN (superior marginal and angular gyri). RESULTS: Late preterm children demonstrated increased functional connectivity within the posterior default mode networks and increased anti-correlation with the central-executive network when seeded from the posteromedial cortex (PMC). Key differences were demonstrated between PMC components with increased anti-correlation with the salience network seen only with posterior cingulate cortex seeding but not with precuneus seeding. Probabilistic tractography showed increased streamlines within the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus within late preterm children while decreased intrahemispheric streamlines were also observed. No significant differences in neurocognitive testing were demonstrated between groups. CONCLUSION: Late preterm preadolescence is associated with altered functional connectivity from the PMC and lateral parietal cortex to known distributed functional cortical networks despite no significant executive neurocognitive differences. Selective increased structural connectivity was observed in the setting of decreased posterior interhemispheric connections. Future work is needed to determine if these findings represent a compensatory adaptation employing alternate neural circuitry or could reflect subtle pathology resulting in emotional processing deficits not seen with neurocognitive testing. PMID- 26098889 TI - Roux-en-Y Gastric Bypass Surgery Increases Respiratory Quotient and Energy Expenditure during Food Intake. AB - OBJECTIVE: The mechanisms determining long-term weight maintenance after Roux-en Y gastric bypass (RYGB) remain unclear. Cross sectional studies have suggested that enhanced energy expenditure (EE) may play a significant role and the aim of this study was to reveal the impact of RYGB on each major component constituting total EE. DESIGN: Six obese female subjects, without other co-morbidities, were assessed before and at 10 days, 3 and 20 months after RYGB. Indirect calorimetry in a metabolic chamber was used to assess 24 h EE at each study visit. Other measurements included body composition by DEXA, gut hormone profiles and physical activity (PA) using high sensitivity accelerometers. RESULTS: Median Body Mass Index decreased from 41.1 (range 39.1-44.8) at baseline to 28 kg/m2 (range 22.3 30.3) after 20 months (p<0.05). Lean tissue decreased from 55.9 (range 47.5-59.3) to 49.5 (range 41.1-54.9) kg and adipose tissue from 61 (range 56-64.6) to 27 (range 12-34.3) kg (both p<0.05). PA over 24 h did not change after surgery whereas 24 h EE and basal metabolic rate (BMR) decreased. EE after a standard meal increased after surgery when adjusted for total tissue (p<0.05). After an initial drop, RQ (respiratory quotient) had increased at 20 months, both as measured during 24 h and after food intake (p<0.05). CONCLUSION: RYGB surgery up regulates RQ and EE after food intake resulting in an increased contribution to total EE over 24 h when corrected for total tissue. PMID- 26098890 TI - Reduced Incidence of Foot-Related Hospitalisation and Amputation amongst Persons with Diabetes in Queensland, Australia. AB - OBJECTIVE: To determine trends in the incidence of foot-related hospitalisation and amputation amongst persons with diabetes in Queensland (Australia) between 2005 and 2010 that coincided with changes in state-wide ambulatory diabetic foot related complication management. METHODS: All data from cases admitted for the principal reason of diabetes foot-related hospitalisation or amputation in Queensland from 2005-2010 were obtained from the Queensland Hospital Admitted Patient Data Collection dataset. Incidence rates for foot-related hospitalisation (admissions, bed days used) and amputation (total, minor, major) cases amongst persons with diabetes were calculated per 1,000 person-years with diabetes (diabetes population) and per 100,000 person-years (general population). Age-sex standardised incidence and age-sex adjusted Poisson regression models were also calculated for the general population. RESULTS: There were 4,443 amputations, 24,917 hospital admissions and 260,085 bed days used for diabetes foot-related complications in Queensland. Incidence per 1,000 person-years with diabetes decreased from 2005 to 2010: 43.0% for hospital admissions (36.6 to 20.9), 40.1% bed days (391 to 234), 40.0% total amputations (6.47 to 3.88), 45.0% major amputations (2.18 to 1.20), 37.5% minor amputations (4.29 to 2.68) (p < 0.01 respectively). Age-sex standardised incidence per 100,000 person-years in the general population also decreased from 2005 to 2010: 23.3% hospital admissions (105.1 to 80.6), 19.5% bed days (1,122 to 903), 19.3% total amputations (18.57 to 14.99), 26.4% major amputations (6.26 to 4.61), 15.7% minor amputations (12.32 to 10.38) (p < 0.01 respectively). The age-sex adjusted incidence rates per calendar year decreased in the general population (rate ratio (95% CI)); hospital admissions 0.949 (0.942-0.956), bed days 0.964 (0.962-0.966), total amputations 0.962 (0.946-0.979), major amputations 0.945 (0.917-0.974), minor amputations 0.970 (0.950-0.991) (p < 0.05 respectively). CONCLUSIONS: There were significant reductions in the incidence of foot-related hospitalisation and amputation amongst persons with diabetes in the population of Queensland over a recent six year period. PMID- 26098891 TI - Ryanodine Receptor Activation Induces Long-Term Plasticity of Spine Calcium Dynamics. AB - A key feature of signalling in dendritic spines is the synapse-specific transduction of short electrical signals into biochemical responses. Ca2+ is a major upstream effector in this transduction cascade, serving both as a depolarising electrical charge carrier at the membrane and an intracellular second messenger. Upon action potential firing, the majority of spines are subject to global back-propagating action potential (bAP) Ca2+ transients. These transients translate neuronal suprathreshold activation into intracellular biochemical events. Using a combination of electrophysiology, two-photon Ca2+ imaging, and modelling, we demonstrate that bAPs are electrochemically coupled to Ca2+ release from intracellular stores via ryanodine receptors (RyRs). We describe a new function mediated by spine RyRs: the activity-dependent long-term enhancement of the bAP-Ca2+ transient. Spines regulate bAP Ca2+ influx independent of each other, as bAP-Ca2+ transient enhancement is compartmentalized and independent of the dendritic Ca2+ transient. Furthermore, this functional state change depends exclusively on bAPs travelling antidromically into dendrites and spines. Induction, but not expression, of bAP-Ca2+ transient enhancement is a spine-specific function of the RyR. We demonstrate that RyRs can form specific Ca2+ signalling nanodomains within single spines. Functionally, RyR mediated Ca2+ release in these nanodomains induces a new form of Ca2+ transient plasticity that constitutes a spine specific storage mechanism of neuronal suprathreshold activity patterns. PMID- 26098892 TI - A TNM Staging System for Nasal NK/T-Cell Lymphoma. AB - Ann Arbor stage has limited utility in the prognostication and treatment decision making in patients with NK/T-cell lymphoma (NKTCL), as NKTCL is almost exclusively extranodal and the majority is localized at presentation for which radiotherapy is the most important treatment and local invasiveness is the most important prognostic factor. In this study, we attempted to establish a TNM (Tumor-Node-Metastasis) staging system for nasal NKTCL (N-NKTCL). The staging rules of other head and neck cancers were used as reference along with the data of our 271 eligible patients. The primary tumor was classified into T1 to T4, and cervical lymph node metastasis was classified into N0 to N2 according to the extent of involvement. Any lesions outside the head and neck were classified as M1. N-NKTCL thereby was classified into four stages: stage I comprised T1-2N0M0; stage II comprised T1-2N1M0 and T3N0M0; stage III comprised T3N1M0, T1-3N2M0, and T4N0-2M0; and stage IV comprised TanyNanyM1. This staging system showed excellent performance in prognosticating survival. In the current series, the 5-year survival rates of patients with stages I, II, III, and IV N-NKTCL were 92%, 64%, 23%, and 0, respectively. Moreover, the predictive value of several currently used factors was abrogated in the presence of the TNM stage. The TNM staging system is highly effective in stratifying tumor burden and survival risk, which may have significant implications in the treatment decision making for patients with N-NKTCL. PMID- 26098893 TI - A Cysteine Zipper Stabilizes a Pre-Fusion F Glycoprotein Vaccine for Respiratory Syncytial Virus. AB - Recombinant subunit vaccines should contain minimal non-pathogen motifs to reduce potential off-target reactivity. We recently developed a vaccine antigen against respiratory syncytial virus (RSV), which comprised the fusion (F) glycoprotein stabilized in its pre-fusion trimeric conformation by "DS-Cav1" mutations and by an appended C-terminal trimerization motif or "foldon" from T4-bacteriophage fibritin. Here we investigate the creation of a cysteine zipper to allow for the removal of the phage foldon, while maintaining the immunogenicity of the parent DS-Cav1+foldon antigen. Constructs without foldon yielded RSV F monomers, and enzymatic removal of the phage foldon from pre-fusion F trimers resulted in their dissociation into monomers. Because the native C terminus of the pre-fusion RSV F ectodomain encompasses a viral trimeric coiled-coil, we explored whether introduction of cysteine residues capable of forming inter-protomer disulfides might allow for stable trimers. Structural modeling indicated the introduced cysteines to form disulfide "rings", with each ring comprising a different set of inward facing residues of the coiled-coil. Three sets of rings could be placed within the native RSV F coiled-coil, and additional rings could be added by duplicating portions of the coiled-coil. High levels of neutralizing activity in mice, equivalent to that of the parent DS-Cav1+foldon antigen, were elicited by a 4-ring stabilized RSV F trimer with no foldon. Structure-based alteration of a viral coiled-coil to create a cysteine zipper thus allows a phage trimerization motif to be removed from a candidate vaccine antigen. PMID- 26098894 TI - Inhibition of Donor-Reactive CD8+ T Cell Responses by Selective CD28 Blockade Is Independent of Reduced ICOS Expression. AB - Programmed T cell differentiation is critically influenced by the complement of costimulatory and coinhibitory signals transmitted during initial antigen encounter. We previously showed that selective CD28 blockade with novel domain antibodies that leave CTLA-4-mediated coinhibitory signaling intact resulted in more profound attenuation of donor-reactive T cell responses and improved graft survival in a murine transplant model. Selective CD28 blockade was also associated with decreased ICOS expression on donor-reactive CD8+ T cell responses as compared to CTLA-4 Ig, but the functional importance of this reduced ICOS expression was not known. In this study, we created retrogenic donor-reactive CD8+ T cells that overexpress ICOS in order to determine whether reduced ICOS expression mechanistically underlies the increased efficacy of selective CD28 blockade in controlling graft-specific T cell responses as compared to conventional costimulation blockade with CTLA-4 Ig. Results indicated that the ability of selective CD28 blockade to blunt donor-reactive CD8+ T cell expansion following transplantation was independent of its ability to inhibit ICOS expression. Furthermore, we have previously published that 2B4 coinhibitory signals are functionally important for controlling graft-specific CD8+ T cell responses in mice treated with CD28 blockade. Here we used a co-adoptive transfer approach to determine that 2B4 coinhibitory signals on antigen-specific CD8+ T cells function in a cell-intrinsic manner to limit ICOS expression in the setting of selective CD28 blockade. PMID- 26098895 TI - Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway. AB - Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U 87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells. PMID- 26098896 TI - Distribution and Morphology of Calcium-Binding Proteins Immunoreactive Neurons following Chronic Tungsten Multielectrode Implants. AB - The development of therapeutic approaches to improve the life quality of people suffering from different types of body paralysis is a current major medical challenge. Brain-machine interface (BMI) can potentially help reestablishing lost sensory and motor functions, allowing patients to use their own brain activity to restore sensorimotor control of paralyzed body parts. Chronic implants of multielectrodes, employed to record neural activity directly from the brain parenchyma, constitute the fundamental component of a BMI. However, before this technique may be effectively available to human clinical trials, it is essential to characterize its long-term impact on the nervous tissue in animal models. In the present study we evaluated how chronic implanted tungsten microelectrode arrays impact the distribution and morphology of interneurons reactive to calcium binding proteins calbindin (CB), calretinin (CR) and parvalbumin (PV) across the rat's motor cortex. Our results revealed that chronic microelectrode arrays were well tolerated by the nervous tissue, with recordings remaining viable for up to 6 months after implantation. Furthermore, neither the morphology nor the distribution of inhibitory neurons were broadly impacted. Moreover, restricted microglial activation was observed on the implanted sites. On the whole, our results confirm and expand the notion that tungsten multielectrodes can be deemed as a feasible candidate to future human BMI studies. PMID- 26098897 TI - Aboriginal Consumption of Estuarine Food Resources and Potential Implications for Health through Trace Metal Exposure; A Study in Gumbaynggirr Country, Australia. AB - Fishing and resource use continues to be an essential aspect of life for many Aboriginal communities throughout Australia. It is important for dietary sustenance, and also retains deep social, cultural and economic significance, playing a fundamental role in maintaining group cohesion, transferring cultural knowledge and affirming Indigenous identities. We surveyed approximately 20% of the Gumbaynggirr Aboriginal community of Nambucca Heads, New South Wales, Australia. This paper explores Gumbaynggirr Connection to Country and engagement in cultural practice. It quantifies fishing efforts and consumption of seafood within the community. We found 95% of the sample group fish, with the highest rate of fishing being 2-3 times a week (27%). Furthermore, 98% of participants eat seafood weekly or more frequently, up to more than once a day (24%). Survey results revealed that Myxus elongatus (Sand mullet) and naturally recruited Saccostrea glomerata (Sydney rock oysters) continue to be important wild resources to the Gumbaynggirr community. Trace metals were measured in M. elongatus and S. glomerata samples collected by community participants in this study. Maximum levels prescribed in the Australia New Zealand Food Standards Code were not exceeded in the edible tissue for either species, however both species exceeded the generally expected levels for zinc and copper and S. glomerata samples exceeded the generally expected level for selenium. Furthermore the average dietary exposure to trace metals from consuming seafood was calculated for the surveyed population. Trace metal intake was then compared to the provisional tolerable weekly intake prescribed by the Joint Expert Committee on Food Additives. This process revealed that copper and selenium intake were both within the provisional tolerable weekly intake, while there is no guideline for zinc. Furthermore, participants relying heavily on wild resources from the Nambucca River estuary may exceed the provisional tolerable weekly intake for cadmium. This suggests the need for further investigation of this issue to minimize any possible health risk. PMID- 26098898 TI - Next Generation Sequencing and Transcriptome Analysis Predicts Biosynthetic Pathway of Sennosides from Senna (Cassia angustifolia Vahl.), a Non-Model Plant with Potent Laxative Properties. AB - Senna (Cassia angustifolia Vahl.) is a world's natural laxative medicinal plant. Laxative properties are due to sennosides (anthraquinone glycosides) natural products. However, little genetic information is available for this species, especially concerning the biosynthetic pathways of sennosides. We present here the transcriptome sequencing of young and mature leaf tissue of Cassia angustifolia using Illumina MiSeq platform that resulted in a total of 6.34 Gb of raw nucleotide sequence. The sequence assembly resulted in 42230 and 37174 transcripts with an average length of 1119 bp and 1467 bp for young and mature leaf, respectively. The transcripts were annotated using NCBI BLAST with 'green plant database (txid 33090)', Swiss Prot, Kyoto Encylcopedia of Genes & Genomes (KEGG), Cluster of Orthologous Gene (COG) and Gene Ontology (GO). Out of the total transcripts, 40138 (95.0%) and 36349 (97.7%) from young and mature leaf, respectively, were annotated by BLASTX against green plant database of NCBI. We used InterProscan to see protein similarity at domain level, a total of 34031 (young leaf) and 32077 (mature leaf) transcripts were annotated against the Pfam domains. All transcripts from young and mature leaf were assigned to 191 KEGG pathways. There were 166 and 159 CDS, respectively, from young and mature leaf involved in metabolism of terpenoids and polyketides. Many CDS encoding enzymes leading to biosynthesis of sennosides were identified. A total of 10,763 CDS differentially expressing in both young and mature leaf libraries of which 2,343 (21.7%) CDS were up-regulated in young compared to mature leaf. Several differentially expressed genes found functionally associated with sennoside biosynthesis. CDS encoding for many CYPs and TF families were identified having probable roles in metabolism of primary as well as secondary metabolites. We developed SSR markers for molecular breeding of senna. We have identified a set of putative genes involved in various secondary metabolite pathways, especially those related to the synthesis of sennosides which will serve as an important platform for public information about gene expression, genomics, and functional genomics in senna. PMID- 26098899 TI - Sulfate Reducing Bacteria and Mycobacteria Dominate the Biofilm Communities in a Chloraminated Drinking Water Distribution System. AB - The quantity and composition of bacterial biofilms growing on 10 water mains from a full-scale chloraminated water distribution system were analyzed using real time PCR targeting the 16S rRNA gene and next-generation, high-throughput Illumina sequencing. Water mains with corrosion tubercles supported the greatest amount of bacterial biomass (n = 25; geometric mean = 2.5 * 10(7) copies cm(-2)), which was significantly higher (P = 0.04) than cement-lined cast-iron mains (n = 6; geometric mean = 2.0 * 10(6) copies cm(-2)). Despite spatial variation of community composition and bacterial abundance in water main biofilms, the communities on the interior main surfaces were surprisingly similar, containing a core group of operational taxonomic units (OTUs) assigned to only 17 different genera. Bacteria from the genus Mycobacterium dominated all communities at the main wall-bulk water interface (25-78% of the community), regardless of main age, estimated water age, main material, and the presence of corrosion products. Further sequencing of the mycobacterial heat shock protein gene (hsp65) provided species-level taxonomic resolution of mycobacteria. The two dominant Mycobacteria present, M. frederiksbergense (arithmetic mean = 85.7% of hsp65 sequences) and M. aurum (arithmetic mean = 6.5% of hsp65 sequences), are generally considered to be nonpathogenic. Two opportunistic pathogens, however, were detected at low numbers: M. hemophilum (arithmetic mean = 1.5% of hsp65 sequences) and M. abscessus (arithmetic mean = 0.006% of hsp65 sequences). Sulfate-reducing bacteria from the genus Desulfovibrio, which have been implicated in microbially influenced corrosion, dominated all communities located underneath corrosion tubercules (arithmetic mean = 67.5% of the community). This research provides novel insights into the quantity and composition of biofilms in full-scale drinking water distribution systems, which is critical for assessing the risks to public health and to the water supply infrastructure. PMID- 26098900 TI - Effects of Modified Handling on the Physiological Stress of Trawled-and-Discarded Yellowfin Bream (Acanthopagrus australis). AB - Modified handling is often claimed to reduce (sub-)lethal impacts among organisms caught-and-released in fisheries. Improving welfare of discarded fish warrants investigation, when their survival is of both economic and ecological importance. In this study, juvenile yellowfin bream (Acanthopagrus australis) were trawled in an Australian penaeid fishery and then discarded after on-board sorting in either dry or water-filled (modified) trays and with delays in starting sorting of either 2 or 15 mins. Blood plasma cortisol, glucose and potassium were sampled immediately from some yellowfin bream, while others were placed into cages (with controls) and sampled after five days. Irrespective of their on-board handling, all trawled fish incurred a relatively high acute stress response (i.e. an increase in Mean +/- SE cortisol from a baseline of <4 to 122.0 +/- 14.9 ng/mL) that was mostly attributed to the trawling process, and exacerbated by variation in key parameters (low salinity, changes in water temperature and the presence of jellyfish Catostylus mosaicus in catches). When C. mosaicus was present, the potassium concentrations of fish sampled immediately after sorting were significantly elevated, possibly due to nematocyst contact and subsequent inhibition of ion pumps or cytolysis. Stress also increased during handling in response to warmer air temperatures and longer exposure. While most fish had substantially recovered by 120 hours after discarding, deploying selective trawls (to reduce jellyfish) for short periods and then quickly sorting catches in water would benefit discard welfare. PMID- 26098901 TI - Extreme Levels of HbA1c Increase Incident ESRD Risk in Chinese Patients with Type 2 Diabetes: Competing Risk Analysis in National Cohort of Taiwan Diabetes Study. AB - BACKGROUND: Whether HbA1c is a predictor of end-stage renal disease (ESRD) in type 2 diabetes patients remains unclear. This study evaluated relationship between HbA1c and ESRD in Chinese patients with type 2 diabetes. METHODS: Patients aged >= 30 years who were free of ESRD (n = 51 681) were included from National Diabetes Care Management Program from 2002-2003. Extended Cox proportional hazard model with competing risk of death served to evaluate association between HbA1c level and ESRD. RESULTS: A total of 2613 (5.06%) people developed ESRD during a follow-up period of 8.1 years. Overall incidence rate of ESRD was 6.26 per 1000 person-years. Patients with high levels of HbA1c had a high incidence rate of ESRD, from 4.29 for HbA1c of 6.0%-6.9% to 10.33 for HbA1c >= 10.0% per 1000 person-years. Patients with HbA1c < 6.0% particularly had a slightly higher ESRD incidence (4.34 per 1000 person-years) than those with HbA1c of 6.0%-6.9%. A J-shaped relationship between HbA1c level and ESRD risk was observed. After adjustment, patients with HbA1c < 6.0% and >= 10.0% exhibited an increased risk of ESRD (HR: 1.99, 95% CI: 1.62-2.44; HR: 4.42, 95% CI: 3.80-5.14, respectively) compared with those with HbA1c of 6.0%-6.9%. CONCLUSIONS: Diabetes care has focused on preventing hyperglycemia, but not hypoglycemia. Our study revealed that HbA1c level >= 7.0% was linked with increased ESRD risk in type 2 diabetes patients, and that HbA1c < 6.0% also had the potential to increase ESRD risk. Our study provides epidemiological evidence that appropriate glycemic control is essential for diabetes care to meet HbA1c targets and improve outcomes without increasing the risk to this population. Clinicians need to pay attention to HbA1c results on diabetic nephropathy. PMID- 26098902 TI - Mortality in Children with Optic Pathway Glioma Treated with Up-Front BB-SFOP Chemotherapy. AB - BACKGROUND: In terms of overall survival (OS), limited data are available for the very long-term outcomes of children treated for optic pathway glioma (OPG) with up-front chemotherapy. Therefore, we undertook this study with the aim of clarifying long-term OS and causes of death in these patients. METHODS: We initiated and analyzed a historical cohort study of 180 children with OPG treated in France with BB-SFOP chemotherapy between 1990 and 2004. The survival distributions were estimated using Kaplan-Meier method. The effect of potential risk factors on the risk of death was described using Cox regression analysis. RESULTS: The OS was 95% [95% CI: 90.6-97.3] 5 years after diagnosis and significantly decreased over time without ever stabilizing: 91.6% at 10 years [95% CI: 86.5-94.8], 80.7% at 15 years [95% CI: 72.7-86.8] and 75.5% [95% CI: 65.6-83] at 18 years. Tumor progression was the most common cause of death (65%). Age and intracranial hypertension at diagnosis were significantly associated with a worse prognosis. Risk of death was increased by 3.1[95% CI: 1.5-6.2] (p=0.002) for patients less than 1 year old at diagnosis and by 5.2[95% CI: 1.5-17.6] (p=0.007) for patients with initial intracranial hypertension. Boys without diencephalic syndrome had a better prognosis (HR: 0.3 [95% CI: 0.1-0.8], p=0.007). CONCLUSIONS: This study shows that i) in children with OPG, OS is not as favorable as previously described and ii) patients can be classified into 2 groups depending on risk factors (age, intracranial hypertension, sex and diencephalic syndrome) with an OS rate of 50.4% at 18 years [95% CI: 31.4-66.6] in children with the worst prognosis. These findings could justify, depending on the initial risk, a different therapeutic approach to this tumor with more aggressive treatment (especially chemotherapy) in patients with high risk factors. PMID- 26098903 TI - Promoter Hypermethylation Profiling Identifies Subtypes of Head and Neck Cancer with Distinct Viral, Environmental, Genetic and Survival Characteristics. AB - BACKGROUND: Epigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status. METHODOLOGY: The study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR respectively. PRINCIPAL FINDINGS: Unsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31 genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival. CONCLUSIONS: Promoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC. PMID- 26098904 TI - Label-free fluorescence light-up detection of T4 polynucleotide kinase activity using the split-to-intact G-quadruplex strategy by ligation-triggered and toehold mediated strand displacement release. AB - A label-free, fluorescence light-up detection method for T4 polynucleotide kinase activity has been developed using the split-to-intact G-quadruplex strategy. PMID- 26098905 TI - Nitrogen Dioxide Sterilization in Low-Resource Environments: A Feasibility Study. AB - Access to sterilization is a critical need for global healthcare, as it is one of the prerequisites for safe surgical care. Lack of sterilization capability has driven up healthcare infection rates as well as limited access to healthcare, especially in low-resource environments. Sterilization technology has for the most part been static and none of the established sterilization methods has been so far successfully adapted for use in low-resource environments on a large scale. It is evident that healthcare facilities in low-resource settings require reliable, deployable, durable, affordable, easily operable sterilization equipment that can operate independently of scarce resources. Recently commercialized nitrogen dioxide (NO2) sterilization technology was analyzed and adapted into a form factor suitable for use in low-resource environments. Lab testing was conducted in microbiological testing facilities simulating low resource environments and in accordance with the requirements of the international sterilization standard ANSI/AAMI/ISO 14937 to assess effectiveness of the device and process. The feasibility of a portable sterilizer based on nitrogen dioxide has been demonstrated, showing that sterilization of medical instruments can occur in a form factor suitable for use in low-resource environments. If developed and deployed, NO2 sterilization technology will have the twin benefits of reducing healthcare acquired infections and limiting a major constraint for access to surgical care on a global scale. Additional benefits are achieved in reducing costs and biohazard waste generated by current health care initiatives that rely primarily on disposable kits, increasing the effectiveness and outreach of these initiatives. PMID- 26098906 TI - The Role of School Environment in Physical Activity among Brazilian Adolescents. AB - OBJECTIVE: To analyze the association of physical activity facilities and extracurricular sports activities in schools with physical activity among adolescents. METHODOLOGY/PRINCIPAL FINDINGS: We used data collected for the National Survey of School Health in 2012. The national representative sample comprised 109,104 Brazilian students from 2,842 schools. We calculated the prevalence of participation in physical education classes, leisure-time physical activity, and total physical activity level. We also evaluated the following physical activity facilities: sports courts, running/athletics tracks, schoolyard with teacher-directed physical activities, swimming pools, locker rooms; and the offer of extracurricular sports activities. Schools with at least one physical activity facility had increased odds of participation in physical education (OR 1.59; 95% CI 1.20 to 2.10). However, in order to increase leisure-time physical activity (OR1.14; 95% CI 1.03 to 1.26) and total physical activity level (OR 1.15; 95% CI 1.06 to 1.24) at least four and two facilities, respectively, were necessary. Extracurricular sports activities in schools were positively associated with leisure-time physical activity and physical activity level. The number of sports courts and swimming pool in a school were associated with participation in physical education classes. Availability of sports courts, running/athletics tracks, and swimming pool in schools were associated with leisure-time physical activity. Total physical activity was associated with schools with sports courts, schoolyard with teacher-directed physical activities, and swimming pool. CONCLUSIONS: School-level characteristics have important potential to increase the possibility of engagement in physical activity in and out of school, and therefore have a fundamental role in promoting these practices. PMID- 26098907 TI - Reading deficits in very low birthweight children are associated with vocabulary and attention issues at the age of seven. AB - AIM: This Swedish study compared reading skills between seven-year-old children with a very low birthweight (VLBW) and controls with a normal birthweight, exploring associations between reading variables and cognition, parent-rated behaviour, perinatal factors and family factors. METHODS: We studied 51 VLBW children, with no major neurodevelopmental impairments and attending their first year at a regular school, and compared them with the 51 sex- and age-matched controls. The test battery, carried out at 7.8 +/- 0.4 years of age, included reading skills, the Wechsler Intelligence Scale for Children - III and the Child Behaviour Checklist. RESULTS: Very low birthweight children with a mean birthweight of 1105 g (+/- 291 g) and a gestational age of 28.8 (+/- 2.2) weeks scored significantly lower in all reading subtests and cognition and demonstrated more behavioural problems than normal birthweight controls. We also found significant associations between poor vocabulary, combined with attention problems, and phonological awareness, rapid naming and spelling control. Perinatal factors had no association with reading function, and socio-economic factors had very few. CONCLUSION: Very low birthweight children demonstrated deficits in all reading domains and had poorer cognition and more behavioural problems at the age of seven, with reading ability related to vocabulary and attention. PMID- 26098908 TI - Transcriptional responses in male Japanese medaka exposed to antiandrogens and antiandrogen/androgen mixtures. AB - The occurrence of androgenic endocrine disrupting chemicals (EDCs) in water is thought to be linked to deviation from normal male developmental and reproductive functions in exposed aquatic organisms. Because aquatic environments represent a chemically complex medium, the combined effects of androgenic EDCs require urgent attention. In the present study, the effects of two model androgen receptor (AR) antagonists, flutamide (FLU), and vinclozolin (VIN), were first determined individually in male Japanese medaka using the transcriptional response for genes associated with the hypothalamic-pituitary-gonadal axis. The fish were further exposed to binary mixtures of VIN and 17beta-trenbolone (TRE, AR agonist) to confirm the theoretical opposing effects of the AR antagonist and agonist. The results showed that exposure to FLU or VIN alone induced very similar transcriptional responses, demonstrating that gene transcription analysis could be successfully employed in identifying the action of single chemicals. For example, both exposures increased the transcription of cyp17b but decreased that of cyp19b in the gonad, demonstrating the compensatory response for AR blockage. However, in the case of exposure to mixtures, although the joint antagonistic action of TRE and VIN affected the most genes, the transcription profiles after exposure to mixtures were not consistent with expectations based on the results for individual chemicals, such as hepatic vtg, and star or cyp19a in gonads. Therefore, the limitation of gene transcription analyses in exposures to mixtures, as well as the potential for the extrapolation of single chemicals, should be considered in future studies. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1591-1599, 2016. PMID- 26098909 TI - Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep. AB - Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10(-5)) were identified including markers in or near PIK3CB (P = 2.22x10(-6); additive model), KCNB1 (P = 2.93x10(-6); dominance model), ZC3H12C (P = 3.25x10(-6); genotypic model), JPH1 (P = 4.68x20(-6); genotypic model), and MYO3B (P = 5.74x10(-6); recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection. PMID- 26098912 TI - A Calcium-Dependent Mechanism of Neuronal Memory. AB - A neuron's record of its previous activity underlies animal memory. A new study reveals a role for the release of calcium ions from intracellular stores in mediating spatially compartmentalized memory of the activity history of a neuron. PMID- 26098910 TI - The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan. AB - BACKGROUND: Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study. OBJECTIVE: To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study. METHODS: 12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated. RESULTS: The median survival time was 3.39 years (95% confidence interval [CI]: 2.88-3.79) for VaD without medication, 6.62 years (95% CI: 6.24 7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85-3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30-8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73-6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02-9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55-2.83) without medication, 1.46 (95% CI: 1.39-1.54) with nootropics, 1.05 (95% CI: 0.82-1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80-1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15-1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22-2.72). CONCLUSION: Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival. PMID- 26098913 TI - Correction: No Own-Age Advantage in Children's Recognition of Emotion on Prototypical Faces of Different Ages. PMID- 26098911 TI - Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation. AB - Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2alpha1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2alpha1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation. PMID- 26098915 TI - Preferential Accumulation of 14C-N-Glycolylneuraminic Acid over 14C-N Acetylneuraminic Acid in the Rat Brain after Tail Vein Injection. AB - The two main molecular species of sialic acid existing in nature are N acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Neu5Ac is abundant in mammalian brains and plays crucial roles in many neural functions. In contrast, Neu5Gc is present only at a trace level in vertebrate brains. The brain specific suppression of Neu5Gc synthesis, which is a common feature in mammals, suggests that Neu5Gc has toxicity against brain functions. However, in vivo kinetics of Neu5Gc in the whole body, especially in the brain, has not been studied in sufficient detail. To determine the in vivo kinetics of Neu5Gc, 14C Neu5Gc was enzymatically synthesized and injected into rat tail veins. Although most of 14C-Neu5Gc was excreted in urine, a small amount of 14C-Neu5Gc was detected in the brain. Brain autoradiography indicated that 14C-Neu5Gc was accumulated predominantly in the hippocampus. 14C-Neu5Gc transferred into the brain was incorporated into gangliosides including GM1, GD1a, GD1b, GT1b and GQ1b. Reduction of 14C-Neu5Gc after intracerebroventricular infusion was slower than that of 14C-Neu5Ac in the brain and hippocampus. The results suggest that Neu5Gc is transferred from blood into the brain across the blood brain barrier and accumulates in the brain more preferentially than does Neu5Ac. PMID- 26098914 TI - AMP-Activated Protein Kinase Interacts with the Peroxisome Proliferator-Activated Receptor Delta to Induce Genes Affecting Fatty Acid Oxidation in Human Macrophages. AB - AMP-activated protein kinase (AMPK) maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO). The transcription factor peroxisome proliferator-activated receptor delta (PPARdelta) also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARdelta in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKalpha1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARdelta agonist GW501516. Microarray analysis showed that co activation of AMPK and PPARdelta increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKgamma1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARdelta- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL)-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload. PMID- 26098917 TI - Nitrogen Fuelling of the Pelagic Food Web of the Tropical Atlantic. AB - We estimated the relative contribution of atmosphere (ic Nitrogen (N) input (wet and dry deposition and N fixation) to the epipelagic food web by measuring N isotopes of different functional groups of epipelagic zooplankton along 23 degrees W (17 degrees N-4 degrees S) and 18 degrees N (20-24 degrees W) in the Eastern Tropical Atlantic. Results were related to water column observations of nutrient distribution and vertical diffusive flux as well as colony abundance of Trichodesmium obtained with an Underwater Vision Profiler (UVP5). The thickness and depth of the nitracline and phosphocline proved to be significant predictors of zooplankton stable N isotope values. Atmospheric N input was highest (61% of total N) in the strongly stratified and oligotrophic region between 3 and 7 degrees N, which featured very high depth-integrated Trichodesmium abundance (up to 9.4*10(4) colonies m(-2)), strong thermohaline stratification and low zooplankton delta15N (~20/00). Relative atmospheric N input was lowest south of the equatorial upwelling between 3 and 5 degrees S (27%). Values in the Guinea Dome region and north of Cape Verde ranged between 45 and 50%, respectively. The microstructure-derived estimate of the vertical diffusive N flux in the equatorial region was about one order of magnitude higher than in any other area (approximately 8 mmol m(-2) d(1)). At the same time, this region received considerable atmospheric N input (35% of total). In general, zooplankton delta15N and Trichodesmium abundance were closely correlated, indicating that N fixation is the major source of atmospheric N input. Although Trichodesmium is not the only N fixing organism, its abundance can be used with high confidence to estimate the relative atmospheric N input in the tropical Atlantic (r2 = 0.95). Estimates of absolute N fixation rates are two- to tenfold higher than incubation derived rates reported for the same regions. Our approach integrates over large spatial and temporal scales and also quantifies fixed N released as dissolved inorganic and organic N. In a global analysis, it may thus help to close the gap in oceanic N budgets. PMID- 26098916 TI - Phylogenetic Structure of Tree Species across Different Life Stages from Seedlings to Canopy Trees in a Subtropical Evergreen Broad-Leaved Forest. AB - Investigating patterns of phylogenetic structure across different life stages of tree species in forests is crucial to understanding forest community assembly, and investigating forest gap influence on the phylogenetic structure of forest regeneration is necessary for understanding forest community assembly. Here, we examine the phylogenetic structure of tree species across life stages from seedlings to canopy trees, as well as forest gap influence on the phylogenetic structure of forest regeneration in a forest of the subtropical region in China. We investigate changes in phylogenetic relatedness (measured as NRI) of tree species from seedlings, saplings, treelets to canopy trees; we compare the phylogenetic turnover (measured as betaNRI) between canopy trees and seedlings in forest understory with that between canopy trees and seedlings in forest gaps. We found that phylogenetic relatedness generally increases from seedlings through saplings and treelets up to canopy trees, and that phylogenetic relatedness does not differ between seedlings in forest understory and those in forest gaps, but phylogenetic turnover between canopy trees and seedlings in forest understory is lower than that between canopy trees and seedlings in forest gaps. We conclude that tree species tend to be more closely related from seedling to canopy layers, and that forest gaps alter the seedling phylogenetic turnover of the studied forest. It is likely that the increasing trend of phylogenetic clustering as tree stem size increases observed in this subtropical forest is primarily driven by abiotic filtering processes, which select a set of closely related evergreen broad-leaved tree species whose regeneration has adapted to the closed canopy environments of the subtropical forest developed under the regional monsoon climate. PMID- 26098918 TI - De Novo Generated Human Red Blood Cells in Humanized Mice Support Plasmodium falciparum Infection. AB - Immunodeficient mouse-human chimeras provide a powerful approach to study host specific pathogens like Plasmodium (P.) falciparum that causes human malaria. Existing mouse models of P. falciparum infection require repeated injections of human red blood cells (RBCs). In addition, clodronate lipsomes and anti neutrophil antibodies are injected to suppress the clearance of human RBCs by the residual immune system of the immunodeficient mice. Engraftment of NOD-scid Il2rg /- mice with human hematopoietic stem cells leads to reconstitution of human immune cells. Although human B cell reconstitution is robust and T cell reconstitution is reasonable in the recipient mice, human RBC reconstitution is generally poor or undetectable. The poor reconstitution is mainly the result of a deficiency of appropriate human cytokines that are necessary for the development and maintenance of these cell lineages. Delivery of plasmid DNA encoding human erythropoietin and interleukin-3 into humanized mice by hydrodynamic tail-vein injection resulted in significantly enhanced reconstitution of erythrocytes. With this improved humanized mouse, here we show that P. falciparum infects de novo generated human RBCs, develops into schizonts and causes successive reinvasion. We also show that different parasite strains exhibit variation in their ability to infect these humanized mice. Parasites could be detected by nested PCR in the blood samples of humanized mice infected with P. falciparum K1 and HB3 strains for 3 cycles, whereas in other strains such as 3D7, DD2, 7G8, FCR3 and W2mef parasites could only be detected for 1 cycle. In vivo adaptation of K1 strain further improves the infection efficiency and parasites can be detected by microscopy for 3 cycles. The parasitemia ranges between 0.13 and 0.25% at the first cycle of infection, falls between 0.08 and 0.15% at the second cycle, and drops to barely detectable levels at the third cycle of infection. Compared to existing mouse models, our model generates human RBCs de novo and does not require the treatment of mice with immunomodulators. PMID- 26098920 TI - Efficacy of Proprioceptive Exercises in Patients with Subacromial Impingement Syndrome: A Single-Blinded Randomized Controlled Study. AB - OBJECTIVE: The objective of this study was to evaluate the effectiveness of proprioceptive exercises on shoulder proprioception, range of motion, pain, muscle strength, and function in patients with subacromial impingement syndrome. DESIGN: Sixty-one patients with subacromial impingement syndrome participated in this prospective, single-blind randomized controlled trial. All patients were randomly divided into two groups: control group (conventional physiotherapy, n = 30) and intervention group (proprioceptive exercise and conventional physiotherapy, n = 31). The primary outcome measures were sense of kinesthesia and active and passive repositioning for proprioception at 0 degrees and 10 degrees external rotation at 12 wks. The secondary outcome measures were pain at rest, at night, and during activities of daily living with the visual analog scale (0-10 cm), the Western Ontario Rotator Cuff index, the American Shoulder and Elbow Surgeons index, range of motion, and isometric muscle strength at both 6 and 12 wks. RESULTS: After treatment, significant improvement was found in range of motion, pain, isometric muscle strength, kinesthesia at 0 degrees external rotation, and functional tests in both groups. The intervention group showed a significant improvement in kinesthesia at 10 degrees external rotation and active and passive repositioning at 10 degrees external rotation. When groups were compared, there were no statistically significant differences in any of the parameters at 12 wks. CONCLUSIONS: Although proprioceptive exercises may provide better proprioceptive acuity, no additional positive effect on other clinical parameters was observed. PMID- 26098919 TI - Talimogene laherparepvec (T-VEC) for the treatment of advanced melanoma. AB - Melanoma often spreads to cutaneous or subcutaneous sites that are amenable to direct, intralesional injection. As such, developing effective injectable agents has been of considerable interest. Talimogene laherperepvec (T-VEC) is an injectable modified oncolytic herpes virus being developed for the treatment of advanced melanoma. Pre-clinical studies have shown that T-VEC preferentially infects melanoma cells and exerts antitumor activity through directly mediating cell death and by augmenting local and even distant immune responses. T-VEC has now been assessed in Phase II and III clinical trials and has demonstrated a tolerable side-effect profile and promising efficacy, showing an improved durable response rate and a trend toward superior overall survival compared to granulocyte-macrophage colony-stimulating factor. Despite these promising results, responses have been uncommon in patients with visceral metastases. T-VEC is currently being evaluated in combination with other immune therapies (ipilimumab and pembrolizumab) with early signs of activity. In this review, we discuss the preclinical rationale, the clinical experience, and future directions for T-VEC in advanced melanoma. PMID- 26098922 TI - Physiatry Reviews for Evidence in Practice (PREP), Second-Order Peer Reviews of Clinically Relevant Articles for the Physiatrist. AB - The busy clinically active physiatrist who wishes to practice evidence-based medicine has a daunting challenge to keep up to date with the significant amount of new information that is developing and available across the wide spectrum of medical literature. Accordingly, the authors have developed a method to survey the applicable medical literature to identify pertinent and clinically relevant articles. These articles are then critically appraised and presented in a standard format with clinically applicable conclusions. The authors will be presenting these reviews in future issues of the American Journal of Physical Medicine & Rehabilitation. PMID- 26098921 TI - Association of Strength Measurement with Rotator Cuff Tear in Patients with Shoulder Pain: The Rotator Cuff Outcomes Workgroup Study. AB - OBJECTIVE: This study examines the association between strength measurements and supraspinatus tear in patients with shoulder pain. This study characterized determinants of abduction strength among patients with tears. DESIGN: A total of 208 patients with shoulder pain were recruited. Strength was tested using a handheld dynamometer. Supraspinatus tears were diagnosed by combination of clinical assessment and blinded magnetic resonance imaging review. Associations of supraspinatus tear with patient characteristics and strength measurements (abduction, internal rotation and external rotation) were assessed using multivariable logistic regression models. RESULTS: Patients with supraspinatus tear had decreased abduction strength (P = 0.02) and decreased external rotation strength (P < 0.01). When adjusted for age, sex, tear laterality, and body mass index, decreased abduction strength (odds ratio, 1.18/kg; 95% confidence interval, 1.06-1.32) and decreased external rotation strength (odds ratio, 1.29/kg; 95% confidence interval, 1.14-1.48) were associated with supraspinatus tear. In patients with tear, age 60 yrs or older, female sex, and visual analog scale pain score were significantly associated with decreased abduction strength but tear size, fatty infiltration, and atrophy were not. CONCLUSIONS: Decreased abduction and external rotation strength were associated with supraspinatus tear in patients with shoulder pain. In this cohort, the abduction strength of patients with tears was influenced by demographic factors but not tear characteristics. PMID- 26098923 TI - Framework for Assessment of the Usability of Lower-Extremity Robotic Exoskeletal Orthoses. AB - Persons with neurologic conditions such as spinal cord injury, stroke, and multiple sclerosis often lose the ability to stand and walk. Robotic hip-knee ankle-foot exoskeletal orthoses have become commercially available and may allow some of these people to stand and walk again. These devices may also have applications beyond mobility, such as exercise, amelioration of secondary complications related to lack of ambulation, and the promotion of neuroplasticity. The authors present a framework for assessment of the usability of robotic exoskeletal orthoses available now or in the near future. The framework contains six modules: Functional applications, Personal factors, Device factors, External factors, Activities, and Health outcomes. Metrics and measures are suggested for each framework factor. PMID- 26098925 TI - Strengthening Rehabilitation for People with Disabilities: A Human Rights Approach as the Essential Next Step to Accelerating Global Progress. PMID- 26098924 TI - Resident-Perceived Benefit of a Diagnostic and Interventional Musculoskeletal Ultrasound Curriculum: A Multifaceted Approach Using Independent Study, Peer Teaching, and Interdisciplinary Collaboration. AB - Musculoskeletal ultrasound (MSUS) training is now a required component of physiatry residency, but formal curriculum guidelines are not yet required or established. The authors' objective was to assess the educational value of a collaborative residency MSUS training program. The authors designed a structured MSUS training curriculum for residents based on the authors' experience and previous literature. Twenty-five residents participated in this MSUS curriculum designed by faculty and chief residents. Resident volunteers were trained by the faculty as "table trainers" who taught their peers in small groups. Hands-on MSUS training sessions were led by a Physical Medicine and Rehabilitation faculty MSUS expert. A Likert scale-formatted questionnaire assessed resident-perceived value of the curriculum. Response rate was 96% (22 of 23). Self-reported MSUS knowledge comparing precurriculum and postcurriculum implementation resulted in significant improvement (P = 0.001). Peer teaching was highly valued, with 86% of residents rating it "very" or "extremely" beneficial (mean [SD] score, 3.9 [1.1]). Self guided learning, by supplemental scanning and reading, was rated "beneficial" or "very beneficial" by 73% of residents (3.0 [0.7]). The authors' successful pilot program may serve as a teaching model for other residency programs. PMID- 26098926 TI - Atypical Location of Low-Back Pain in a High School Basketball Player. PMID- 26098927 TI - RE: "Review of Secondary Health Conditions in Post-Polio Syndrome" by McNalley TE, Jenson MP, Truitt AR, Schomer KG, Baylor C, Molton IR: Am J Phys Med Rehabil 2015;94: 139-45. PMID- 26098928 TI - Color scaling in sonoelastography. PMID- 26098929 TI - Author reply to "color scaling in sonoelastography". PMID- 26098930 TI - Use of Continuous Femoral and Sciatic Nerve Catheters to Facilitate a Multidisciplinary Inpatient-Based Rehabilitation Plan in a Child with Lower Extremity Type 1 Complex Regional Pain Syndrome. PMID- 26098933 TI - Flow-Driven Rapid Vesicle Fusion via Vortex Trapping. AB - Fusion between suspended lipid vesicles is difficult to achieve without membrane proteins or ions because the vesicles have extremely low equilibrium membrane tension and high poration energy. Nonetheless, vesicle fusion in the absence of mediators can also be achieved by mechanical forcing that is strong enough to induce membrane poration. Here, we employ a strong fluid shear stress to achieve vesicle fusion. By utilizing a unique vortex formation phenomenon in branched channels as a platform for capturing, stressing, and fusing the lipid vesicles, we directly visualize using high-speed imaging the vesicle fusion events, induced solely by shear, on the time scale of submilliseconds. We show that a large vesicle with a size of up to ~10 MUm can be achieved by the fusion of nanoscale vesicles. This technique has the potential to be utilized as a fast and simple way to produce giant unilamellar vesicles and to serve as a platform for visualizing vesicle interactions and fusions in the presence of shear. PMID- 26098932 TI - The Effect of Natural Multidecadal Ocean Temperature Oscillations on Contiguous U.S. Regional Temperatures. AB - Atmospheric temperature time series for the nine climate regions of the contiguous U.S. are accurately reproduced by the superposition of oscillatory modes, representing the Atlantic multidecadal oscillation (AMO) and the Pacific decadal oscillation (PDO), on a monotonic mode representing, at least in part, the effect of radiant forcing due to increasing atmospheric CO2. The relative importance of the different modes varies among the nine climate regions, grouping them into three mega-regions: Southeastern comprising the South, Southeast and Ohio Valley; Central comprising the Southwest, Upper Midwest, and Northeast; and Northwestern comprising the West, Northwest, and Northern Rockies & Plains. The defining characteristics of the mega-regions are: Southeastern--dominated by the AMO, no PDO influence; Central--influenced by the AMO, no PDO influence, Northwestern--influenced by both the AMO and PDO. Temperature vs. time curves calculated by combining the separate monotonic and oscillatory modes agree well with the measured temperature time series, indicating that the 1938-1974 small decrease in contiguous U.S. temperature was caused by the superposition of the downward-trending oscillatory mode on the upward-trending monotonic mode while the 1980-2000 large increase in temperature was caused by the superposition of the upward-trending oscillatory mode on the upward-trending monotonic mode. The oscillatory mode, mostly representing the AMO, was responsible for about 72% of the entire contiguous U.S. temperature increase over that time span with the contribution varying from 86 to 42% for individual climate regions. PMID- 26098931 TI - (17)O relaxation times in the rat brain at 16.4 tesla. AB - PURPOSE: Measurement of the cerebral metabolic rate of oxygen (CMRO2 ) by means of direct imaging of the (17) O signal can be a valuable tool in neuroscientific research. However, knowledge of the longitudinal and transverse relaxation times of different brain tissue types is required, which is difficult to obtain because of the low sensitivity of natural abundance H2 (17) O measurements. METHODS: Using the improved sensitivity at a field strength of 16.4 Tesla, relaxation time measurements in the rat brain were performed in vivo and postmortem with relatively high spatial resolutions, using a chemical shift imaging sequence. RESULTS: In vivo relaxation times of rat brain were found to be T1 = 6.84 +/- 0.67 ms and T2 * = 1.77 +/- 0.04 ms. Postmortem H2 (17) O relaxometry at enriched concentrations after inhalation of (17) O2 showed similar T2 * values for gray matter (1.87 +/- 0.04 ms) and white matter, significantly longer than muscle (1.27 +/- 0.05 ms) and shorter than cerebrospinal fluid (2.30 +/- 0.16 ms). CONCLUSION: Relaxation times of brain H2 (17) O were measured for the first time in vivo in different types of tissues with high spatial resolution. Because the relaxation times of H2 (17) O are expected to be independent of field strength, our results should help in optimizing the acquisition parameters for experiments also at other MRI field strengths. PMID- 26098934 TI - Intelligent Scheduling for Underground Mobile Mining Equipment. AB - Many studies have been carried out and many commercial software applications have been developed to improve the performances of surface mining operations, especially for the loader-trucks cycle of surface mining. However, there have been quite few studies aiming to improve the mining process of underground mines. In underground mines, mobile mining equipment is mostly scheduled instinctively, without theoretical support for these decisions. Furthermore, in case of unexpected events, it is hard for miners to rapidly find solutions to reschedule and to adapt the changes. This investigation first introduces the motivation, the technical background, and then the objective of the study. A decision support instrument (i.e. schedule optimizer for mobile mining equipment) is proposed and described to address this issue. The method and related algorithms which are used in this instrument are presented and discussed. The proposed method was tested by using a real case of Kittila mine located in Finland. The result suggests that the proposed method can considerably improve the working efficiency and reduce the working time of the underground mine. PMID- 26098935 TI - Brief Report: Meta-analysis of Antacid Use and Alzheimer's Disease: Implications for the Aluminum Hypothesis. AB - BACKGROUND: Exposure to aluminum remains a controversial risk factor for Alzheimer's disease. Antacids are aluminum-rich medications that are widely used in substantial amounts, but their association with Alzheimer's disease has not been systematically quantified. METHODS: We conducted electronic searches of PubMed, Embase, and Cochrane Library up to January 2015 for case-control and cohort studies published in any language. Summary risk estimates were derived using random-effects models. RESULTS: Seven case-control studies (n = 5,468; 829 Alzheimer's disease cases) and two cohort studies (n = 842; 110 Alzheimer's disease cases) met the criteria for inclusion. Study quality was limited by imprecise characterization of the timing and duration of antacid use. Regular antacid use was not associated with Alzheimer's disease in either case-control (odds ratio = 1.0; 95% confidence interval = 0.8, 1.2) or cohort studies (relative risk = 0.8; 95% confidence interval = 0.4, 1.8). Sensitivity analysis including studies specifically examining aluminum-containing antacids did not reveal an association. CONCLUSIONS: Although the findings of this meta-analysis do not support an association between aluminum intake and Alzheimer's disease, prospective studies with longer follow-up and more precise characterization of exposure are required to definitively exclude an etiologic role for aluminum. PMID- 26098936 TI - Synthesis of Novel N9-Substituted Purine Derivatives from Polymer Supported alpha Amino Acids. AB - Solid-phase synthesis of purine derivatives bearing an alpha-amino acid motif in position 9 is described herein. Polymer supported amines were acylated with various Fmoc-alpha-amino acids and, after cleavage of the protecting group, arylation with 4,6-dichloro-5-nitropyrimidine or 2,4-dichloro-5-nitropyrimidine was performed. The second chlorine atom was replaced with various amines. Subsequent reduction of the nitro group, followed by reaction with aldehydes, afforded the purine scaffold. After cleavage from the polymer support, the target compounds were obtained in very good crude purity, good overall yields, and excellent enantiomeric purity. The anticancer activity of prepared compounds was tested in vitro against human cancer cell lines MCF7 and K562, and they were found to have mild, but clear dose-dependent effects. PMID- 26098937 TI - Radiosensitization of DNA by Cisplatin Adducts Results from an Increase in the Rate Constant for the Reaction with Hydrated Electrons and Formation of Pt(I). AB - Pulse radiolysis measurements of the decay of hydrated electrons in solutions containing different concentrations of the oligonucleotide GTG with and without a cisplatin adduct show that the presence of a cisplatin moiety accelerates the reaction between hydrated electrons and the oligonucleotide. The rate constant of the reaction is found to be 2.23 * 10(10) mol(-1) L s(-1), which indicates that it is diffusion controlled. In addition, we show for the first time the formation of a Pt(I) intermediate as a result of the reaction of hydrated electrons with GTG-cisplatin. A putative reaction mechanism is proposed, which may form the basis of the radiosensitization of cancer cells in concomitant chemoradiation therapy with cisplatin. PMID- 26098938 TI - Retrovirus-Mediated Expression of E2A-PBX1 Blocks Lymphoid Fate but Permits Retention of Myeloid Potential in Early Hematopoietic Progenitors. AB - The oncogenic transcription factor E2A-PBX1 is expressed consequent to chromosomal translocation 1;19 and is an important oncogenic driver in cases of pre-B-cell acute lymphoblastic leukemia (ALL). Elucidating the mechanism by which E2A-PBX1 induces lymphoid leukemia would be expedited by the availability of a tractable experimental model in which enforced expression of E2A-PBX1 in hematopoietic progenitors induces pre-B-cell ALL. However, hematopoietic reconstitution of irradiated mice with bone marrow infected with E2A-PBX1 expressing retroviruses consistently gives rise to myeloid, not lymphoid, leukemia. Here, we elucidate the hematopoietic consequences of forced E2A-PBX1 expression in primary murine hematopoietic progenitors. We show that introducing E2A-PBX1 into multipotent progenitors permits the retention of myeloid potential but imposes a dense barrier to lymphoid development prior to the common lymphoid progenitor stage, thus helping to explain the eventual development of myeloid, and not lymphoid, leukemia in transplanted mice. Our findings also indicate that E2A-PBX1 enforces the aberrant, persistent expression of some genes that would normally have been down-regulated in the subsequent course of hematopoietic maturation. We show that enforced expression of one such gene, Hoxa9, a proto oncogene associated with myeloid leukemia, partially reproduces the phenotype produced by E2A-PBX1 itself. Existing evidence suggests that the 1;19 translocation event takes place in committed B-lymphoid progenitors. However, we find that retrovirus-enforced expression of E2A-PBX1 in committed pro-B-cells results in cell cycle arrest and apoptosis. Our findings indicate that the neoplastic phenotype induced by E2A-PBX1 is determined by the developmental stage of the cell into which the oncoprotein is introduced. PMID- 26098939 TI - Cardioprotection Resulting from Glucagon-Like Peptide-1 Administration Involves Shifting Metabolic Substrate Utilization to Increase Energy Efficiency in the Rat Heart. AB - Previous studies have shown that glucagon-like peptide-1 (GLP-1) provides cardiovascular benefits independent of its role on peripheral glycemic control. However, the precise mechanism(s) by which GLP-1 treatment renders cardioprotection during myocardial ischemia remain unresolved. Here we examined the role for GLP-1 treatment on glucose and fatty acid metabolism in normal and ischemic rat hearts following a 30 min ischemia and 24 h reperfusion injury, and in isolated cardiomyocytes (CM). Relative carbohydrate and fat oxidation levels were measured in both normal and ischemic hearts using a 1-13C glucose clamp coupled with NMR-based isotopomer analysis, as well as in adult rat CMs by monitoring pH and O2 consumption in the presence of glucose or palmitate. In normal heart, GLP-1 increased glucose uptake (?64%, p<0.05) without affecting glycogen levels. In ischemic hearts, GLP-1 induced metabolic substrate switching by increasing the ratio of carbohydrate versus fat oxidation (?14%, p<0.01) in the LV area not at risk, without affecting cAMP levels. Interestingly, no substrate switching occurred in the LV area at risk, despite an increase in cAMP (?106%, p<0.05) and lactate (?121%, p<0.01) levels. Furthermore, in isolated CMs GLP-1 treatment increased glucose utilization (?14%, p<0.05) and decreased fatty acid oxidation (?15%, p<0.05) consistent with in vivo finding. Our results show that this benefit may derive from distinct and complementary roles of GLP-1 treatment on metabolism in myocardial sub-regions in response to this injury. In particular, a switch to anaerobic glycolysis in the ischemic area provides a compensatory substrate switch to overcome the energetic deficit in this region in the face of reduced tissue oxygenation, whereas a switch to more energetically favorable carbohydrate oxidation in more highly oxygenated remote regions supports maintaining cardiac contractility in a complementary manner. PMID- 26098940 TI - Using Network Methodology to Infer Population Substructure. AB - One of the main caveats of association studies is the possible affection by bias due to population stratification. Existing methods rely on model-based approaches like structure and ADMIXTURE or on principal component analysis like EIGENSTRAT. Here we provide a novel visualization technique and describe the problem of population substructure from a graph-theoretical point of view. We group the sequenced individuals into triads, which depict the relational structure, on the basis of a predefined pairwise similarity measure. We then merge the triads into a network and apply community detection algorithms in order to identify homogeneous subgroups or communities, which can further be incorporated as covariates into logistic regression. We apply our method to populations from different continents in the 1000 Genomes Project and evaluate the type 1 error based on the empirical p-values. The application to 1000 Genomes data suggests that the network approach provides a very fine resolution of the underlying ancestral population structure. Besides we show in simulations, that in the presence of discrete population structures, our developed approach maintains the type 1 error more precisely than existing approaches. PMID- 26098941 TI - Sex-Specific Habitat Utilization and Differential Breeding Investments in Christmas Island Frigatebirds throughout the Breeding Cycle. AB - In seabirds, equal bi-parental care is the rule, as it is considered crucial for raising chicks successfully because seabirds forage in an environment with unpredictable and highly variable food supply. Frigatebirds forage in poor tropical waters, yet males reduce and even stop parental care soon after chick brooding, leaving the female to provision the chick alone for an extended fledging period. Using bird-borne tracking devices, male and female Christmas Island Frigatebirds (Fregata andrewsi) were investigated during the brooding, late chick rearing and post-fledging period to examine whether sexes exhibit foraging strategies that may be linked to differential breeding investments. During brooding, males and females showed similar foraging behaviour under average marine productivity of oceanic waters close to the colony, but males shifted to more distant and more productive habitats when conditions deteriorated to continue with reduced chick provisioning. During the late chick rearing period, females progressively increased their foraging range to the more distant but productive marine areas that only males had visited during brooding. Birds spent the non-breeding period roosting in highly productive waters of the Sunda Shelf. The sex-specific utilisation of three different foraging habitats with different primary productivity (oceanic, coastal, and shelf areas) allowed for temporal and spatial segregation in the exploitation of favourable habitats which seems to enable each sex to optimise its foraging profitability. In addition, post-fledging foraging movements of females suggest a biennial breeding cycle, while limited information on males suggests the possibility of an annual breeding cycle. PMID- 26098942 TI - Health Disparity Still Exists in an Economically Well-Developed Society in Asia. AB - BACKGROUND: The socioeconomic inequalities in child health continue to widen despite improved economy. OBJECTIVE: To investigate the correlation between socio economic factors and health risk behaviors and psychosocial well-being of children in Hong Kong. HYPOTHESIS: The null hypothesis is that for this particular developed region, there exists little or no correlation between social economic factors and health risk behaviors and psychosocial well-being of children. DESIGN: Cross sectional territory wide survey. PARTICIPANTS: Caregivers of 7,000 children in kindergartens in Hong Kong. MEASURING TOOLS: Youth Risk Behavior Surveillance questionnaire, health-related knowledge and hygienic practice questionnaire, and Children Behavior Checklist (CBCL). RESULTS: Children were less likely to have somatic complaints and anxiety/depression as reflected by CBCL scores coming from families of higher income, not being recipients of social assistance, with fathers in employment, and with higher parental education. Children with only mother or father as caretakers had lower odds ratios (ORs) 0.71 (95% CI 0.58-0.89) and 0.53 (95% CI 0.33-0.84) respectively to have the habit of eating breakfast, whilst parental education at post-secondary level and higher family income had higher ORs 1.91 (95% CI 1.31-2.78), and 1.63 (95% CI 1.11-2.39). Fathers unemployed, relatives as main caretakers and living in districts with low median household inome incurred higher ORs, as 1.46 (95% CI 1.10-1.94),1.52 (95% CI 1.27-1.83) and 1.17 (95% CI 1.02-1.34) respectively, of watching television over two hours daily, whilst children with parental education at secondary level or above incurred lower OR 0.33 (95% CI 0.24-0.45). Children with parental education at post-secondary level and higher family income had lower ORs of 0.32 (95% CI 0.48-0.97) and 0.52 (95% CI 0.34-0.79) respectively, with regard to exposing to passive smoking, and reversed for those living in districts with lower median household income, lower family income and recipient of CSSA with ORs 1.24 (95% CI 1.06-1.44) and 1.6 (95% CI 1.09-2.37) respectively. CONCLUSION: Null hypothesis was not supported. A strong gradient was still found to exist among different socio-economic groups for various health-related behaviors in developed society like Hong Kong. PMID- 26098944 TI - Consensual Victim-Perpetrator Intercourse after Nonconsensual Sex: The Impact of Prior Relationship. AB - Some female victims of nonconsensual sex subsequently have consensual sexual intercourse with the perpetrator and are more likely to do so if intercourse occurred during the nonconsensual sex than if it did not. Some evolutionary psychologists have postulated that there is something significant about nonconsensual intercourse that causes women to subsequently have a sexual relationship with the perpetrator (e.g., risk of pregnancy). In this study, we investigated a parsimonious explanation that has previously been overlooked: Intercourse is more likely during nonconsensual sex when the victim and perpetrator have previously had a sexual relationship; thus, subsequent consensual intercourse may simply be a continuation of that prior relationship. A sample of 945 women completed an Internet-based survey, of whom 41% had experienced nonconsensual sex since age 14. As expected, victims who had intercourse with perpetrators prior to the nonconsensual sex event were significantly more likely than other victims to experience nonconsensual intercourse and to engage in subsequent consensual intercourse with the perpetrator. When considering only the small subsample of victims who never had a prior romantic or sexual relationship with the perpetrator, the odds of subsequent consensual intercourse were still significantly greater following nonconsensual sex with intercourse versus without intercourse. PMID- 26098943 TI - Computer-Based Cognitive Programs for Improvement of Memory, Processing Speed and Executive Function during Age-Related Cognitive Decline: A Meta-Analysis. AB - BACKGROUND: Several studies have assessed the effects of computer-based cognitive programs (CCP) in the management of age-related cognitive decline, but the role of CCP remains controversial. Therefore, this systematic review evaluated the evidence on the efficacy of CCP for age-related cognitive decline in healthy older adults. METHODS: Six electronic databases (through October 2014) were searched. The risk of bias was assessed using the Cochrane Collaboration tool. The standardized mean difference (SMD) and 95% confidence intervals (CI) of a random-effects model were calculated. The heterogeneity was assessed using the Cochran Q statistic and quantified with the I2 index. RESULTS: Twelve studies were included in the current review and were considered as moderate to high methodological quality. The aggregated results indicate that CCP improves memory performance (SMD, 0.31; 95% CI 0.16 to 0.45; p < 0.0001) and processing speed (SMD, 0.50; 95% CI 0.14 to 0.87; p = 0.007) but not executive function (SMD, 0.12; 95% CI -0.33 to 0.09; p = 0.27). Furthermore, there were long-term gains in memory performance (SMD, 0.59; 95% CI 0.13 to 1.05; p = 0.01). CONCLUSION: CCP may be a valid complementary and alternative therapy for age-related cognitive decline, especially for memory performance and processing speed. However, more studies with longer follow-ups are warranted to confirm the current findings. PMID- 26098945 TI - Valuable lessons-learned in transcriptomics experimentation. AB - We have collected several valuable lessons that will help improve transcriptomics experimentation. These lessons relate to experiment design, execution, and analysis. The cautions, but also the pointers, may help biologists avoid common pitfalls in transcriptomics experimentation and achieve better results with their transcriptome studies. PMID- 26098946 TI - Investigation of Water Dynamics and the Effect of Evapotranspiration on Grain Yield of Rainfed Wheat and Barley under a Mediterranean Environment: A Modelling Approach. AB - Agro-hydrological models have increasingly become useful and powerful tools in optimizing water and fertilizer application, and in studying the environmental consequences. Accurate prediction of water dynamics in such models is essential for models to produce reasonable results. In this study, detailed simulations were performed for water dynamics of rainfed winter wheat and barley grown under a Mediterranean climate over a 10-year period. The model employed (Yang et al., 2009. J. Hydrol., 370, 177-190) uses easily available agronomic data, and takes into consideration of all key soil and plant processes in controlling water dynamics in the soil-crop system, including the dynamics of root growth. The water requirement for crop growth was calculated according to the FAO56, and the soil hydraulic properties were estimated using peto-transfer functions (PTFs) based on soil physical properties and soil organic matter content. Results show that the simulated values of soil water content at the depths of 15, 45 and 75 cm agreed with the measurements well with the root of the mean squared errors of 0.027 cm(3) cm(-3) and the model agreement index of 0.875. The simulated seasonal evapotranspiration (ET) ranged from 208 to 388 mm, and grain yield was found to correlate with the simulated seasonal ET in a linear manner within the studied ET range. The simulated rates of grain yield increase were 17.3 and 23.7 kg ha(-l) for every mm of water evapotranspired for wheat and barley, respectively. The good agreement of soil water content between measurement and simulation and the simulated relationships between grain yield and seasonal ET supported by the data in the literature indicates that the model performed well in modelling water dynamics for the studied soil-crop system, and therefore has the potential to be applied reliably and widely in precision agriculture. Finally, a two-staged approach using inverse modelling techniques to further improve model performance was discussed. PMID- 26098949 TI - The importance of the tumor microenvironment in the therapeutic management of cancer. AB - Tumor prognosis is generally defined by various tumor parameters. However, it is well known that paracrine, endocrine and cell-cell interactions between the tumor and its microenvironment contribute to its growth. The tumor microenvironment (TME) can also influence disease prognosis and is likely to be considered as an important prognostic factor. In addition, conventional therapies can influence the microenvironment and antitumor immunity. Similarly, the TME will influence the effectiveness of therapy. The purpose of this review is to demonstrate how TME is important in therapeutic management. Key interactions between TME and different cancer therapies as well as their current clinical consequences have been described. More research is needed to establish the important network between tumor cells and their environment to highlight their relationships with conventional therapies and develop global therapeutic strategies. PMID- 26098948 TI - Sequential Cytokine-Induced Killer Cell Immunotherapy Enhances the Efficacy of the Gemcitabine Plus Cisplatin Chemotherapy Regimen for Metastatic Nasopharyngeal Carcinoma. AB - In this study, we investigated the efficacy of sequential cytokine-induced killer cell (CIK) immunotherapy with gemcitabine plus cisplatin (GC) regimen chemotherapy in metastatic nasopharyngeal carcinoma (NPC) patients. Between September 2006 and April 2010, 222 NPC patients with distant metastasis after radiotherapy completion were retrospectively analyzed: 112 patients received 4-6 cycles of GC chemotherapy at 4-week intervals, followed by at least 4 cycles of CIK immunotherapy at 2-week intervals (GC+CIK group); the remaining 110 patients received 4-6 cycles of GC chemotherapy alone (GC group). The evaluation of long term efficacy showed that the progression-free survival (PFS) rate was significantly higher in the GC+CIK group (log-rank test; p = 0.009), as was the overall survival (OS) rate (p = 0.006). In conclusion, sequential CIK treatment may be effective in enhancing the therapeutic efficacy of GC chemotherapy for metastatic NPC patients. This study provides a basis for alternative therapeutic strategies for metastatic NPC. PMID- 26098950 TI - Microwave-Assisted Synthesis of Near-Infrared Fluorescent Indole-Based Squaraines. AB - A microwave-assisted method for the preparation of a wide color range of 2,3,3 trimethylindolenine-based squaraines and their intermediates is described. This practical approach allows the rapid preparation of both symmetrical and nonsymmetrical squaraine dyes, reducing reaction time from days to minutes with more than 2-fold improvement in product yields when compared to conventional methods. PMID- 26098947 TI - Suppression of MAPK Signaling and Reversal of mTOR-Dependent MDR1-Associated Multidrug Resistance by 21alpha-Methylmelianodiol in Lung Cancer Cells. AB - Lung cancer is the leading cause of cancer-related deaths worldwide and remains the most prevalent. Interplay between PI3K/AMPK/AKT and MAPK pathways is a crucial effector in lung cancer growth and progression. These signals transduction protein kinases serve as good therapeutic targets for non-small cell lung cancer (NSCLC) which comprises up to 90% of lung cancers. Here, we described whether 21alpha-Methylmelianodiol (21alpha-MMD), an active triterpenoid derivative of Poncirus trifoliate, can display anticancer properties by regulating these signals and modulate the occurrence of multidrug resistance in NSCLC cells. We found that 21alpha-MMD inhibited the growth and colony formation of lung cancer cells without affecting the normal lung cell phenotype. 21alpha MMD also abrogated the metastatic activity of lung cancer cells through the inhibition of cell migration and invasion, and induced G0/G1 cell cycle arrest with increased intracellular ROS generation and loss of mitochondrial membrane integrity. 21alpha-MMD regulated the expressions of PI3K/AKT/AMPK and MAPK signaling which drove us to further evaluate its activity on multidrug resistance (MDR) in lung cancer cells by specifying on P-glycoprotein (P-gp)/MDR1 association. Employing the established paclitaxel-resistant A549 cells (A549 PacR), we further found that 21alpha-MMD induced a MDR reversal activity through the inhibition of P-gp/MDR1 expressions, function, and transcription with regained paclitaxel sensitivity which might dependently correlate to the regulation of PI3K/mTOR signaling pathway. Taken together, these findings demonstrate, for the first time, the mechanistic evaluation in vitro of 21alpha MMD displaying growth-inhibiting potential with influence on MDR reversal in human lung cancer cells. PMID- 26098951 TI - Preserved in vivo reconstitution ability of PBSCs cryopreserved for a decade at 80 degrees C. AB - PBSC products for auto- and allografting can be cryopreserved in liquid nitrogen with controlled-rate freezing until their use. Alternatively, they can be stored at -80 degrees C in a mechanical chest freezer, but it remains to be clarified whether PBSCs can be stored for the long term. We evaluated viability and functions of PBSCs cryopreserved for more than 10 years with this simplified method. Although recovery rate and viability of CD34(+) cells were significantly decreased, myeloid differentiation potential and in vivo reconstitution and self renewal potential of CD34(+) cells in a xenogeneic engraftment assay were maintained for more than 10 years. These results indicate that PBSCs can be stored at -80 degrees C for years. Although accumulation of clinical engraftment data is required to confirm our results, this simplified cryopreservation will thus meet the increasing worldwide demand for PBSC transplantation in a region with limited resources. PMID- 26098952 TI - High-dose chemotherapy and autologous stem cell transplantation with melphalan, etoposide and carboplatin for high-risk osteosarcoma. PMID- 26098953 TI - Donor choice in haploidentical stem cell transplantation: fetal microchimerism is associated with better outcome in pediatric leukemia patients. PMID- 26098954 TI - Validation of a new integrated prognostic score to predict non-relapse mortality in patients undergoing reduced-intensity conditioning allogeneic hematopoietic cell transplantation. PMID- 26098956 TI - Correction: Reduction of Metal Artifact in Single Photon-Counting Computed Tomography by Spectral-Driven Iterative Reconstruction Technique. PMID- 26098955 TI - X-ray Crystallographic, Multifrequency Electron Paramagnetic Resonance, and Density Functional Theory Characterization of the Ni(P(Cy)2N(tBu)2)2(n+) Hydrogen Oxidation Catalyst in the Ni(I) Oxidation State. AB - The Ni(I) hydrogen oxidation catalyst [Ni(P(Cy)2N(tBu)2)2](+) (1(+); P(Cy)2N(tBu)2 = 1,5-di(tert-butyl)-3,7-dicyclohexyl-1,5-diaza-3,7 diphosphacyclooctane) has been studied using a combination of electron paramagnetic resonance (EPR) techniques (X-, Q-, and D-band, electron-nuclear double resonance, hyperfine sublevel correlation spectroscopy), X-ray crystallography, and density functional theory (DFT) calculations. Crystallographic and DFT studies indicate that the molecular structure of 1(+) is highly symmetrical. EPR spectroscopy has allowed determination of the electronic g tensor and the spin density distribution on the ligands, and revealed that the Ni(I) center does not interact strongly with the potentially coordinating solvents acetonitrile and butyronitrile. The EPR spectra and magnetic parameters of 1(+) are found to be distinctly different from those for the related compound [Ni(P(Ph)2N(Ph)2)2](+) (4(+)). One significant contributor to these differences is that the molecular structure of 4(+) is unsymmetrical, unlike that of 1(+). DFT calculations on derivatives in which the R and R' groups are systematically varied have allowed elucidation of structure/substituent relationships and their corresponding influence on the magnetic resonance parameters. PMID- 26098957 TI - Listen Doctor, the Patient Just Might Be Right. PMID- 26098958 TI - Patterns of Spontaneous Local Network Activity in Developing Cerebral Cortex: Relationship to Adult Cognitive Function. AB - Detecting neurodevelopMUental disorders of cognition at the earliest possible stages could assist in understanding them mechanistically and ultimately in treating them. Finding early physiological predictors that could be visualized with functional neuroimaging would represent an important advance in this regard. We hypothesized that one potential source of physiological predictors is the spontaneous local network activity prominent during specific periods in development. To test this we used calcium imaging in brain slices and analyzed variations in the frequency and intensity of this early activity in one area, the entorhinal cortex (EC), in order to correlate early activity with level of cognitive function later in life. We focused on EC because of its known role in different types of cognitive processes and because it is an area where spontaneous activity is prominent during early postnatal development in rodent models of cortical development. Using rat strains (Long-Evans, Wistar, Sprague Dawley and Brattleboro) known to differ in cognitive performance in adulthood we asked whether neonatal animals exhibit corresponding strain-related differences in EC spontaneous activity. Our results show significant differences in this activity between strains: compared to a high cognitive-performing strain, we consistently found an increase in frequency and decrease in intensity in neonates from three lower performing strains. Activity was most different in one strain considered a model of schizophrenia-like psychopathology. While we cannot necessarily infer a causal relationship between early activity and adult cognition our findings suggest that the pattern of spontaneous activity in development could be an early predictor of a developmental trajectory advancing toward sub-optimal cognitive performance in adulthood. Our results further suggest that the strength of dopaminergic signaling, by setting the balance between excitation and inhibition, is a potential underlying mechanism that could explain the observed differences in early spontaneous activity patterns. PMID- 26098960 TI - Structural Basis for the Brilliant Colors of the Sapphirinid Copepods. AB - Males of sapphirinid copepods use regularly alternating layers of hexagonal shaped guanine crystals and cytoplasm to produce spectacular structural colors. In order to understand the mechanism by which the different colors are produced, we measured the reflectance of live individuals and then characterized the organization of the crystals and the cytoplasm layers in the same individuals using cryo-SEM. On the basis of these measurements, we calculated the expected reflectance spectra and found that they are strikingly similar to the measured ones. We show that variations in the cytoplasm layer thickness are mainly responsible for the different reflected colors and also that the copepod color strongly depends on the angular orientation relative to the incident light, which can account for its appearance and disappearance during spiral swimming in the natural habitat. PMID- 26098959 TI - Electrophysiological Correlates of Subitizing in Healthy Aging. AB - To understand the nature of age-related changes in enumeration abilities we measured two ERP responses -N2pc and CDA, associated respectively to attentive individuation and VWM- and posterior alpha band (8-15 Hz) event-related desynchronization (ERD), traditionally linked to enhanced target processing. Two groups of old and young participants enumerated a variable number (1-6) of targets presented among distractors. Older participants were less accurate in enumerating targets. ERP results in old participants showed a suppression of N2pc amplitudes for all numerosities, and a decrease in CDA only for the largest set (4-6 targets). In contrast with the pattern for young adults, time/frequency results on older adults revealed neither a modulation of alpha oscillations as a function of target numerosity, nor an effect of ERD lateralization. These patterns indicate that both attention and working memory contribute to the age related decline in enumeration, and point to an overall decrease in the activity of the visual areas responsible for the processing of the hemifield where the relevant objects are presented. PMID- 26098962 TI - Association of Paraneoplastic Neurological Disorders With Glutamic Acid Decarboxylase Antibodies. PMID- 26098961 TI - Positive Association of Fibroadenomatoid Change with HER2-Negative Invasive Breast Cancer: A Co-Occurrence Study. AB - BACKGROUND: Risk assessment of a benign breast disease/lesion (BBD) for invasive breast cancer (IBC) is typically done through a longitudinal study. For an infrequently-reported BBD, the shortage of occurrence data alone is a limiting factor to conducting such a study. Here we present an approach based on co occurrence analysis, to help address this issue. We focus on fibroadenomatoid change (FAC), an under-studied BBD, as our preliminary analysis has suggested its previously unknown significant co-occurrence with IBC. METHODS: A cohort of 1667 female patients enrolled in the Clinical Breast Care Project was identified. A single experienced breast pathologist reviewed all pathology slides for each case and recorded all observed lesions, including FAC. Fibroadenoma (FA) was studied for comparison since FAC had been speculated to be an immature FA. FA and Fibrocystic Changes (FCC) were used for method validation since they have been comprehensively studied. Six common IBC and BBD risk/protective factors were also studied. Co-occurrence analyses were performed using logistic regression models. RESULTS: Common risk/protective factors were associated with FA, FCC, and IBC in ways consistent with the literature in general, and they were associated with FAC, FA, and FCC in distinct patterns. Age was associated with FAC in a bell shape curve so that middle-aged women were more likely to have FAC. We report for the first time that FAC is positively associated with IBC with odds ratio (OR) depending on BMI (OR = 6.78, 95%CI = 3.43-13.42 at BMI<25 kg/m2; OR = 2.13, 95%CI = 1.20-3.80 at BMI>25 kg/m2). This association is only significant with HER2 negative IBC subtypes. CONCLUSIONS: We conclude that FAC is a candidate risk factor for HER2-negative IBCs, and it is a distinct disease from FA. Co occurrence analysis can be used for initial assessment of the risk for IBC from a BBD, which is vital to the study of infrequently-reported BBDs. PMID- 26098963 TI - Large vestibular aqueduct syndrome: Impedance changes over time with different cochlear implant electrode arrays. AB - OBJECTIVES: The aim of this study was to assess if large vestibular aqueduct syndrome (LVAS), with the increase in perilymphatic pressure, affects impedance changes over time with different types of Cochlear((r)) implant electrode arrays Contour, Straight, and CI 422. To report speech perception outcomes for these cochlear implant recipients. METHODS: Retrospective case review of impedance levels and categories of auditory performance. Impedance data were collected at switch on, 1 month, 3, 6, 12, and 24 months after cochlear implantation and compared with control (non-LVAS cochlear implant recipient) data for each array type. Forty-seven patients with exclusive LVAS and no other vestibulocochlear abnormalities or other identifiable cause of deafness were eligible for inclusion in the study. RESULTS: In LVAS patients, there was a significant difference in impedance between the three types of device (P < 0.0001). Time since switch on was associated with a decrease in impedance for all three devices (P < 0.0001). The mean impedance reduced between switch on and 1 month and remained relatively constant thereafter. Sound variation with softening of sounds was seen in four CI 422 (Straight Research Array) recipients due to ongoing fluctuations in electrode compliance. DISCUSSION: For all three array types, there was no significant difference in the mean impedance between the LVAS patients and controls over the first 12 months. In keeping with previous studies cochlear implant recipients with LVAS hear very well through the cochlear implant. PMID- 26098964 TI - Summaries for Patients. Pregnancy Outcomes in Patients With Lupus. PMID- 26098966 TI - Donor characteristics and risk of hepatocellular carcinoma recurrence after liver transplantation. AB - BACKGROUND: To date, studies assessing the risk of post-transplant hepatocellular carcinoma (HCC) recurrence have focused on tumour characteristics. This study investigated the impact of donor characteristics and graft quality on post transplant HCC recurrence. METHODS: Using the Scientific Registry of Transplant Recipients patients with HCC who received a liver transplant between 2004 and 2011 were included, and post-transplant HCC recurrence was assessed. A multivariable competing risk regression model was fitted, adjusting for confounders such as recipient sex, age, tumour volume, alpha-fetoprotein, time on the waiting list and transplant centre. RESULTS: A total of 9724 liver transplant recipients were included. Patients receiving a graft procured from a donor older than 60 years (adjusted hazard ratio (HR) 1.38, 95 per cent c.i. 1.10 to 1.73; P = 0.006), a donor with a history of diabetes (adjusted HR 1.43, 1.11 to 1.83; P = 0.006) and a donor with a body mass index of 35 kg/m(2) or more (adjusted HR 1.36, 1.04 to 1.77; P = 0.023) had an increased rate of post-transplant HCC recurrence. In 3007 patients with documented steatosis, severe graft steatosis (more than 60 per cent) was also linked to an increased risk of recurrence (adjusted HR 1.65, 1.03 to 2.64; P = 0.037). Recipients of organs from donation after cardiac death donors with prolonged warm ischaemia had higher recurrence rates (adjusted HR 4.26, 1.20 to 15.1; P = 0.025). CONCLUSION: Donor-related factors such as donor age, body mass index, diabetes and steatosis are associated with an increased rate of HCC recurrence after liver transplantation. PMID- 26098967 TI - A simple Bayesian approach to quantifying confidence level of adverse event incidence proportion in small samples. AB - In both clinical development and post-marketing of a new therapy or a new treatment, incidence of an adverse event (AE) is always a concern. When sample sizes are small, large sample-based inferential approaches on an AE incidence proportion in a certain time period no longer apply. In this brief discussion, we introduce a simple Bayesian framework to quantify, in small sample studies and the rare AE case, (1) the confidence level that the incidence proportion of a particular AE p is over or below a threshold, (2) the lower or upper bounds on p with a certain level of confidence, and (3) the minimum required number of patients with an AE before we can be certain that p surpasses a specific threshold, or the maximum allowable number of patients with an AE after which we can no longer be certain that p is below a certain threshold, given a certain confidence level. The method is easy to understand and implement; the interpretation of the results is intuitive. This article also demonstrates the usefulness of simple Bayesian concepts when it comes to answering practical questions. PMID- 26098965 TI - Immunomodulatory role of vitamin D in the pathogenesis of preeclampsia. AB - Worldwide, preeclampsia is a significant health risk to both pregnant women and their unborn children. Despite scientific advances, the exact pathogenesis of preeclampsia is not yet fully understood. Meanwhile, the incidence of preeclampsia is expected to increase. A series of potential etiologies for preeclampsia has been identified, including endothelial dysfunction, immunological dysregulation and trophoblastic invasion. In this literature review, we have critically reviewed existing literature regarding the research findings that link the role of vitamin D to the pathogenesis and immunoregulation of preeclampsia. The relationship of vitamin D with the suspected etiologies of preeclampsia underscores its clinical potential in the diagnosis and treatment of preeclampsia. PMID- 26098968 TI - Counter-regulating on the Internet: Threat elicits preferential processing of positive information. AB - The Internet is a central source of information. It is increasingly used for information search in self-relevant domains (e.g., health). Self-relevant topics are also associated with specific emotions and motivational states. For example, individuals may fear serious illness and feel threatened. Thus far, the impact of threat has received little attention in Internet-based research. The current studies investigated how threat influences Internet search. Threat is known to elicit the preferential processing of positive information. The self-directed nature of Internet search should particularly provide opportunities for such processing behavior. We predicted that during Internet search, more positive information would be processed (i.e., allocated more attention to) and more positive knowledge would be acquired under threat than in a control condition. Three experiments supported this prediction: Under threat, attention is directed more to positive web pages (Study 1) and positive links (Study 2), and more positive information is acquired (Studies 1 and 3) than in a control condition. Notably, the effect on knowledge acquisition was mediated by the effect on attention allocation during an actual Internet search (Study 1). Thus, Internet search under threat leads to selective processing of positive information and dampens threatened individuals' negative affect. PMID- 26098971 TI - Psychological testing and the German labor market, 1925 to 1965. AB - From the 1920s to the 1950s, the massive German Labor Administration used loosely standardized, pragmatic evaluations of personality to steer young people into appropriate jobs. Starting in the late 1950s, the Administration shifted to American scientific methods of trait and factor psychological testing. Behind this change lay not a change in academic psychology but a power shift in the German labor market. Originally, the Labor Administration had to appeal to employers, for whom pragmatic evaluations of personality seemed most convincing. Thanks to the Economic Miracle in the 1950s, the Administration had to gain the trust of young Germans, their parents, and the public, who, it was hoped, would be won over by science. PMID- 26098970 TI - Translation of the Risk Avoidance Partnership (RAP) for Implementation in Outpatient Drug Treatment Clinics. AB - Scientific literature increasingly calls for studies to translate evidence-based interventions into real-world contexts balancing fidelity to the original design and fit to the new setting. The Risk Avoidance Partnership (RAP) is a health promotion intervention originally designed to train active drug users to become Peer Health Advocates. A theoretically driven approach was used to adapt RAP to fit implementation in outpatient methadone treatment clinics and pilot it with clinic patients. Ethnographic observations and process tracking documented the RAP translation and pilot experience, and clinic and community characteristics relevant to program implementation. Clinic administrators, staff, and patients were interviewed on their values, capacities, interest in RAP, perceived challenges of implementing RAP in drug treatment clinics, and experiences during the pilot. Findings indicated that RAP core components can be met when implemented in these settings and RAP can fit with the goals, interests, and other programs of the clinic. Balancing fidelity and fit requires recognition of the mutual impacts RAP and the clinic have on each other, which generate new interactions among staff and require ongoing specification of RAP to keep abreast of clinic and community changes. Collaboration of multiple stakeholders significantly benefited translation and pilot processes. PMID- 26098969 TI - Overlapping neurobehavioral circuits in ADHD, obesity, and binge eating: evidence from neuroimaging research. AB - Attention-deficit/hyperactivity disorder (ADHD) and conditions involving excessive eating (eg, obesity, binge/loss of control eating) are increasingly prevalent within pediatric populations, and correlational and some longitudinal studies have suggested inter-relationships between these disorders. In addition, a number of common neural correlates are emerging across conditions, eg, functional abnormalities within circuits subserving reward processing and executive functioning. To explore this potential cross-condition overlap in neurobehavioral underpinnings, we selectively review relevant functional neuroimaging literature, specifically focusing on studies probing (i) reward processing, (ii) response inhibition, and (iii) emotional processing and regulation, and we outline 3 specific shared neurobehavioral circuits. Based on our review, we also identify gaps within the literature that would benefit from further research. PMID- 26098972 TI - Estimates of Octanol-Water Partitioning for Thousands of Dissolved Organic Species in Oil Sands Process-Affected Water. AB - In this study, the octanol-water distribution ratios (DOW, that is, apparent KOW at pH 8.4) of 2114 organic species in oil sands process-affected water were estimated by partitioning to polydimethylsiloxane (PDMS) coated stir bars and analysis by ultrahigh resolution orbitrap mass spectrometry in electrospray positive ((+)) and negative ((-)) ionization modes. At equilibrium, the majority of species in OSPW showed negligible partitioning to PDMS (i.e., DOW <1), however estimated DOW's for some species ranged up to 100,000. Most organic acids detected in ESI- had negligible partitioning, although some naphthenic acids (O2( ) species) had estimated DOW ranging up to 100. Polar neutral and basic compounds detected in ESI+ generally partitioned to PDMS to a greater extent than organic acids. Among these species, DOW was greatest among 3 groups: up to 1000 for mono oxygenated species (O(+) species), up to 127,000 for NO(+) species, and up to 203,000 for SO(+) species. A positive relationship was observed between DOW and carbon number, and a negative relationship was observed with the number of double bonds (or rings). The results highlight that nonacidic compounds in OSPW are generally more hydrophobic than naphthenic acids and that some may be highly bioaccumulative and contribute to toxicity. PMID- 26098973 TI - Probing Majorana bound states via counting statistics of a single electron transistor. AB - We propose an approach for probing Majorana bound states (MBSs) in a nanowire via counting statistics of a nearby charge detector in the form of a single-electron transistor (SET). We consider the impacts on the counting statistics by both the local coupling between the detector and an adjacent MBS at one end of a nanowire and the nonlocal coupling to the MBS at the other end. We show that the Fano factor and the skewness of the SET current are minimized for a symmetric SET configuration in the absence of the MBSs or when coupled to a fermionic state. However, the minimum points of operation are shifted appreciably in the presence of the MBSs to asymmetric SET configurations with a higher tunnel rate at the drain than at the source. This feature persists even when varying the nonlocal coupling and the pairing energy between the two MBSs. We expect that these MBS induced shifts can be measured experimentally with available technologies and can serve as important signatures of the MBSs. PMID- 26098975 TI - Recent advances in cyclodextrin delivery techniques. AB - INTRODUCTION: Active pharmaceutical ingredients (APIs) are evolving from low molecular-weight drugs to peptide-, protein-, gene-, oligonucleotide- and cell based drugs. Therefore, advanced pharmaceutical technologies are required to achieve manifestation of the drug efficacy, side effect reduction and the adequate dosage form design. AREAS COVERED: In this review, the authors highlight the recent advances in drug delivery techniques utilizing cyclodextrins (CyDs), and cyclic oligosaccharides consisting of alpha-1,4-linked alpha-D-glucopyranose units, for various drugs described above. Especially, drug delivery system consisting of combination systems of CyDs and functional materials such as dendrimer, liposome and PEG are introduced. Furthermore, the utilities of CyDs as APIs have been also described. EXPERT OPINION: To achieve the controlled release and/or targeting of low-molecular-weight drugs in systemic administration, the construction of novel CyDs and CyD the supramolecular system should be a useful approach because of the stable complexation of drugs with CyDs. In addition, the combination systems of CyDs and various carriers have the potential as advanced drug delivery systems for proteins and nucleic acids. Furthermore, CyDs have great potential as APIs for various diseases with few side effects, although the detailed mechanism, especially cellular uptake of CyDs, should be clarified. PMID- 26098974 TI - DNA methylation mediates the impact of exposure to prenatal maternal stress on BMI and central adiposity in children at age 131/2 years: Project Ice Storm. AB - Prenatal maternal stress (PNMS) in animals and humans predicts obesity and metabolic dysfunction in the offspring. Epigenetic modification of gene function is considered one possible mechanism by which PNMS results in poor outcomes in offspring. Our goal was to determine the role of maternal objective exposure and subjective distress on child BMI and central adiposity at 131/2 years of age, and to test the hypothesis that DNA methylation mediates the effect of PNMS on growth. Mothers were pregnant during the January 1998 Quebec ice storm. We assessed their objective exposure and subjective distress in June 1998. At age 131/2 their children were weighed and measured (n = 66); a subsample provided blood samples for epigenetic studies (n = 31). Objective and subjective PNMS correlated with central adiposity (waist-to-height ratio); only objective PNMS predicted body mass index (BMI). Bootstrapping analyses showed that the methylation level of genes from established Type-1 and -2 diabetes mellitus pathways showed significant mediation of the effect of objective PNMS on both central adiposity and BMI. However, the negative mediating effects indicate that, although greater objective PNMS predicts greater BMI and adiposity, this effect is dampened by the effects of objective PNMS on DNA methylation, suggesting a protective role of the selected genes from Type-1 and -2 diabetes mellitus pathways. We provide data supporting that DNA methylation is a potential mechanism involved in the long-term adaptation and programming of the genome in response to early adverse environmental factors. PMID- 26098976 TI - Nursing execs key to PFCC. PMID- 26098978 TI - A collaborative model for the CNL and CNS. PMID- 26098979 TI - Extending evidence through shared governance. PMID- 26098980 TI - Advanced degrees: Meeting the needs of nurses and patients. PMID- 26098982 TI - How the other half lives. PMID- 26098983 TI - Patient-centered care: Impacting quality with the acuity adaptable model. PMID- 26098984 TI - Regulatory update: CoPs for nursing services. PMID- 26098985 TI - A clinical nurse's perspective on Magnet(r) recognition: Is your staff prepared? PMID- 26098986 TI - More than a cliche: Choosing your battles wisely. PMID- 26098987 TI - Leadership Q&A. Brushing up on patient safety systems. PMID- 26098988 TI - Chiral N,N'-dioxide-FeCl3 complex-catalyzed asymmetric intramolecular Cannizzaro reaction. AB - An environmentally benign catalyst, the N,N'-dioxide-FeCl3 complex, has been developed for the asymmetric intramolecular Cannizzaro reaction. Aryl and alkyl glyoxal monohydrates were applied to obtain alpha-hydroxy acid esters with excellent results. Deuterium-label and control experiments shed light on the reaction mechanism. PMID- 26098989 TI - Humidity Dependence of Tribochemical Wear of Monocrystalline Silicon. AB - The nanowear tests of monocrystalline silicon against a SiO2 microsphere were performed using an atomic force microscope in air as a function of relative humidity (RH=0%-90%) and in liquid water at a contact pressure of about 1.20 GPa. The experimental results indicated that RH played an important role in the nanowear of the Si/SiO2 interface. In dry air, a hillock-like wear scar with a height of ~0.4 nm was formed on the silicon surface. However, with the increase of RH, the wear depth on the silicon surface first increased to a maximum value of ~14 nm at 50% RH and then decreased below the detection limit at RH above 85% or in water. The transmission electron microscopy analysis showed that the serious wear on the silicon surface at low and medium RHs occurred without subsurface damage, indicating that the wear was due to tribochemical reactions between the Si substrate and the SiO2 counter surface, rather than mechanical damages. The RH dependence of the tribochemical wear could be explained with a model involving the formation of "Si-O-Si" chemical bonds (bridges) between two solid surfaces. The suppression of tribochemical wear at high RHs or in liquid water might be attributed to the fact that the thickness of the interfacial water layer is thick enough to prevent the solid surfaces from making chemical bridges. The results may help us understand the nanowear mechanism of silicon that is an important material for dynamic microelectromechanical systems. PMID- 26098990 TI - Bamboo leaf derived ultrafine Si nanoparticles and Si/C nanocomposites for high performance Li-ion battery anodes. AB - Silicon-based nanomaterials are promising anode materials in lithium-ion batteries (LIBs) due to their high theoretical capacity of 4200 mA h g(-1), more than 10 times that of commercial graphite. Si nanoparticles (NPs) with a diameter of or below 10 nm generally exhibit enhanced lithium storage properties due to their small size and large surface area. However, it is challenging to generate such ultrafine Si NPs by a facile and scalable method. This paper reports a scalable method to fabricate ultrafine Si NPs 5-8 nm in size from dead bamboo leaves (BLs) by thermally decomposing the organic matter, followed by magnesiothermic reduction in the presence of NaCl as a heat scavenger. The ultrafine Si NPs show a high capacity of 1800 mA h g(-1) at a 0.2 C (1 C = 4200 mA g(-1)) rate and are thus promising anode materials in lithium-ion batteries. To achieve better rate capability, the BLs-derived ultrafine Si NPs are coated with a thin amorphous carbon layer (Si@C) and then dispersed and embedded in a reduced graphene oxide (RGO) network to produce Si@C/RGO nanocomposites by a layer-by-layer assembly method. The double protection rendered by the carbon shell and RGO network synergistically yield structural stability, high electrical conductivity and a stable solid electrolyte interface during Li insertion/extraction. The Si@C/RGO nanocomposites show excellent battery properties with a high capacity of 1400 mA h g(-1) at a high current density of 2 C and remarkable rate performance with a capacity retention of 60% when the current density is increased 20 times from 0.2 to 4 C. This work provides a simple, low cost, and scalable approach enabling the use of BL waste as a sustainable source for the production of ultrafine Si NPs towards high performance LIBs. PMID- 26098991 TI - Comparative Mutagenesis Studies of Retinal Release in Light-Activated Zebrafish Rhodopsin Using Fluorescence Spectroscopy. AB - Rhodopsin is the visual pigment responsible for initiating scotopic (dim-light) vision in vetebrates. Once activated by light, release of all-trans-retinal from rhodopsin involves hydrolysis of the Schiff base linkage, followed by dissociation of retinal from the protein moiety. This kinetic process has been well studied in model systems such as bovine rhodopsin, but not in rhodopsins from cold-blooded animals, where physiological temperatures can vary considerably. Here, we characterize the rate of retinal release from light activated rhodopsin in an ectotherm, zebrafish (Danio rerio), demonstrating in a fluorescence assay that this process occurs more than twice as fast as bovine rhodopsin at similar temperatures in 0.1% dodecyl maltoside. Using site-directed mutagenesis, we found that differences in retinal release rates can be attributed to a series of variable residues lining the retinal channel in three key structural motifs: an opening in metarhodopsin II between transmembrane helix 5 (TM5) and TM6, in TM3 near E122, and in the "retinal plug" formed by extracellular loop 2 (EL2). The majority of these sites are more proximal to the beta-ionone ring of retinal than the Schiff base, indicating their influence on retinal release is more likely due to steric effects during retinal dissociation, rather than alterations to Schiff base stability. An Arrhenius plot of zebrafish rhodopsin was consistent with this model, inferring that the activation energy for Schiff base hydrolysis is similar to that of bovine rhodopsin. Functional variation at key sites identified in this study is consistent with the idea that retinal release might be an adaptive property of rhodopsin in vertebrates. Our study is one of the few investigating a nonmammalian rhodopsin, which will help establish a better understanding of the molecular mechanisms contributing to vision in cold-blooded vertebrates. PMID- 26098992 TI - Utility of a very high IRT/No mutation referral category in cystic fibrosis newborn screening. AB - Newborn screening for Cystic Fibrosis (CF) began in New York in October, 2002 using immunoreactive trypsinogen (IRT)/DNA methodology. Infants with at least one CFTR mutation or very high IRT and no mutations (VHIRT) are referred for sweat testing. In a preliminary analysis, we noted a very low positive predictive value (PPV) and preponderance of Hispanic infants in the group of infants with CF referred for VHIRT, which led to a decision to revise, but not eliminate, the VHIRT category. Automatic referral for specimens with VHIRT collected on the day of birth was eliminated, and the VHIRT threshold was raised from 0.2% to 0.1%. In this report, we describe outcomes from VHIRT referrals among 2.4 million infants screened between March 2003 and February 2013. Following the algorithm change, referrals decreased by 37.8% overall (annual mean 1,485 vs. 923), and the VHIRT PPV improved (0.6-1.0%). The number of infants diagnosed has remained consistent at 1 in 4,400 births. The proportion of Black/Hispanic/Asian/Other infants with confirmed CF, CFTR-related metabolic syndrome (CRMS), or possible CF/CRMS was 21.3% in infants with 1-2 mutations, but 75.8% in the VHIRT group. In conclusion, although the PPV among VHIRT referrals remains low, had this category never been implemented, 24 infants with confirmed CF, and 9 infants with CRMS or possible CF/CRMS, most of whom were Hispanic, would have been missed over the 10 years. Information from this study may be helpful in assessing the need for the VHIRT category and algorithm changes in other screening programs. PMID- 26098994 TI - In Vitro Determination of Respimat(r) Dose Delivery in Children: An Evaluation Based on Inhalation Flow Profiles and Mouth-Throat Models. AB - BACKGROUND: Aerosol therapy in young children can be difficult. A realistic model based on handling studies and in vitro investigations can complement clinical deposition studies and be used to enable dose-to-the-lung (DTL) predictions. METHODS: Predictions on dose delivery to the lung were based on (1) representative inhalation flow profiles from children enrolled in a Respimat(r) handling study, (2) in vitro measurement of the fine-particle DTL using mouth throat models derived from nuclear magnetic resonance/computed tomography (NMR/CT) scans of children, and (3) a mathematical model to predict the tiotropium DTL. Accuracy of the prediction was confirmed using pharmacokinetic (PK) data from children with cystic fibrosis enrolled in a phase 3 clinical trial of tiotropium Respimat with valved holding chamber (VHC). RESULTS: Representative inhalation flow profiles for each age group were obtained from 56 children who successfully inhaled a volume >0.15 L from the Respimat with VHC. Average dimensions of the mouth-throat region for 38 children aged 1-<2 years, 2-<3 years, 3-<4 years, and 4-<5 years were determined from NMR/CT scans. The DTL from the Respimat plus VHC were determined by in vitro measurement and were 5.1+/ 1.1%, 15.6%+/-1.4%, 17.9%+/-1.5%, and 37.1%+/-1.8% of the delivered dose for child models 0-<2 years, 2-<3 years, 3-<4 years, and 4-<5 years, respectively. This provides a possible explanation for the age dependence of clinical PK data obtained from the phase 3 tiotropium trial. Calculated in vitro DTL per body mass (MUg/kg [+/-SD]) were 0.031+/-0.014, 0.066+/-0.031, 0.058+/-0.024, and 0.059+/ 0.029, respectively, compared to 0.046 in adults. Therefore, efficacy of the treatment was not negatively impacted in spite of the seemingly low percentages of the DTL. CONCLUSIONS: We conclude that the combination of real-life inhalation profiles with respective mouth-throat models and in vitro determination of delivered DTL is a good predictor of the drug delivery to children via the Respimat with VHC. The data provided can be used to support data from appropriate clinical trials. PMID- 26098993 TI - Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort. AB - Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age >=40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making. PMID- 26098995 TI - Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase. AB - The flavivirus methyltransferase (MTase) is an essential enzyme that sequentially methylates the N7 and 2'-O positions of the viral RNA cap, using S-adenosyl-L methionine (SAM) as a methyl donor. We report here that small molecule compounds, which putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function, were identified by using virtual screening. In vitro methylation experiments demonstrated significant MTase inhibition by 13 of these compounds, with the most potent compound displaying sub-micromolar inhibitory activity. The most active compounds showed broad spectrum activity against the MTase proteins of multiple flaviviruses. Two of these compounds also exhibited low cytotoxicity and effectively inhibited viral replication in cell-based assays, providing further structural insight into flavivirus MTase inhibition. PMID- 26098996 TI - Efficient cross-section preparation method for high-resolution imaging of hard polymer composites with a scanning electron microscope. AB - Characterization of distribution and arrangement of filler particles in polymer composites is of primary importance to understand and maximize their mechanical, electrical and thermal properties. An innovative procedure that allows reliable and straightforward preparation of cross-sections of polymer composites with the use of mechanical polishing, ion beam etching and soft gaseous etching is presented in this paper. Because of the inherent difference between the organic amorphous matrix and the inorganic crystalline nature of composite fillers, the removal of matrix layers at the surface of the cross-section at the expense of the inorganic materials allowed characterizing the composite filler particles structure and distribution over the surface. Since beam broadening did not occur before the beam hit the nanoparticles, high-resolution imaging in the scanning electron microscope was possible and true dimensions and orientation of the particles were observed. This provided more flexibility in selecting the primary beam voltage; especially, the use of low beam energy greatly improved the image contrast and reduced charging effects resulting from the primary electron beam bombardment. It was shown that only polymers with a carbonated main chain could be etched selectively by the gaseous etching process. PMID- 26098998 TI - Inhibitory effects of wild bitter melon leaf extract on Propionibacterium acnes induced skin inflammation in mice and cytokine production in vitro. AB - Propionibacterium acnes is a key pathogen involved in acne inflammation. Wild bitter melon (WBM, Momordica charantia L. var. abbreviate Seringe) is consumed as both a vegetable and as folk medicine in Taiwan. We examined the inhibitory activity of the total phenolic extract (TPE) of WBM leaf on P. acnes-induced inflammatory responses in vivo and in vitro. Our data showed that TPE significantly attenuated P. acnes-induced ear swelling in mice along with microabscess. Flow cytometry analysis revealed that TPE treatment significantly decreased the migration of neutrophils and interleukin (IL)-1beta(+) populations in vivo. In P. acnes-stimulated human monocytic THP-1 cells, TPE suppressed the mRNA levels and production of IL-8, IL-1beta, and tumor necrosis factor (TNF) alphain vitro. In addition, TPE suppressed P. acnes-induced matrix metalloproteinase-9 levels. TPE blocked nuclear factor-kappaB (NF-kappaB) activation and inactivated mitogen-activated protein kinases (MAPK); these actions may partially account for its inhibitory effect on cytokine production. The quantitative HPLC analysis revealed gallic, chlorogenic, caffeic, ferulic, and cinnamic acids, myricetin, quercetin, luteolin, apigenin, and thymol in TPE. All these phenolics significantly suppressed P. acnes-induced IL-8 production in vitro. Our results suggest that WBM leaf extract effectively inhibits P. acnes induced inflammatory responses and may be useful to relieve the inflammation of acne. PMID- 26098997 TI - The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. AB - The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1beta (IL-1beta) and IL-18. Whether NLRP3 can shape immunological function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3 deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation. PMID- 26098999 TI - Prepubertal exposure to bisphenol-A induces ERalpha upregulation and hyperplasia in adult gerbil female prostate. AB - Prostate physiology is highly dependent on oestrogenic and androgenic homeostasis. Interferences in this equilibrium, especially in early periods of life, may disrupt the prostate and increase the susceptibility to the development of diseases with ageing. Taking this into account, and considering the increase of environmental chemicals with endocrine-disrupting potential such as bisphenol A (BPA), this study aimed to evaluate the prostates of adult female gerbils exposed to BPA and BPA plus testosterone from pubertal to adult periods. Morphological, stereological and chemical analyses revealed that long-term BPA exposure, even in environmental dosages, increases the proliferative status of the prostate, increases the number of ERalpha-positive stromal cells and elicits the development of prostatic hyperplasia in adult female gerbils. Moreover, we also observed that the association with testosterone did not increase the proliferative status of the gland, which shows that low levels of BPA are enough to cause an oestrogenic disruption of the prostate in young adults. This evidence suggests that this oestrogenic endocrine disruptor may increase the susceptibility to prostatic disorders with ageing. PMID- 26099000 TI - Deep gluteal grounding pad burn after abdominal aortic aneurysm repair. AB - Although skin burns at the site of grounding pad are a known risk of surgery, their exact incidence is unknown. We first report the case of a patient who presented a deep gluteal burn at the site of the grounding pad after an abdominal aortic aneurism repair, the etiology and the challenging treatment required to overcome this complication. PMID- 26099005 TI - Time-trends in assisted and unassisted suicides completed with different methods: Swiss National Cohort. AB - OBJECTIVE: The number of suicides assisted by right-to-die associations has increased in recent years in Switzerland. The aim of our study was to compare time trends in rates of assisted and unassisted suicide from 1991-2008. METHODS: The Swiss National Cohort is a longitudinal study of mortality in the Swiss population; based on linkage of census data with mortality records up to 2008. The Federal Statistical Office coded suspected assisted suicides from 1998 onwards; and from 2003 onwards right-to-die associations reported the suicides they assisted. We used Poisson regression to analyse trends in rates of suicide per 100'000 person-years, by gender and age groups (15-34, 35-64, 65-94 years). RESULTS: A total of 7'940'297 individuals and 24'842 suicides were included. In women, rates changed little in the younger age groups but increased in 65-94-year olds, due to an increase in suicide by poisoning (from 5.1 to 17.2 per 100'000; p <0.001). An increase in suicides by poisoning was also observed in older men (from 8.6 to 18.2; p<0.001). Most suicides by poisoning were assisted. In men, suicide rates declined in all age groups, driven by declines in suicide with firearms. CONCLUSIONS: Research is needed to gain a better understanding of the reasons for the tripling of assisted suicide rates in older women, and the doubling of rates in older men, of attitudes and vulnerabilities of those choosing assisted suicide, and of access to palliative care. Rates of assisted suicide should be monitored; including data on patient characteristics and underlying comorbidities. PMID- 26099006 TI - Correction: Spatiotemporal Patterns and Predictability of Cyberattacks. PMID- 26099007 TI - Efficiency and hospital effectiveness in improving Hospital Consumer Assessment of Healthcare Providers and Systems ratings. AB - BACKGROUND: Efficiency has emerged as a central goal to the operations of health care organizations. There are two competing perspectives on the relationship between efficiency and organizational performance. Some argue that organizational slack is a waste and that efficiency contributes to organizational performance, whereas others maintain that slack acts as a buffer, allowing organizations to adapt to environmental demands and contributing to organizational performance. PURPOSES: As value-based purchasing becomes more prevalent, health care organizations are incented to become more efficient and, at the same time, improve their patients' experiences and outcomes. Unused slack resources might facilitate the timely implementation of these improvements. Building on previous research on organizational slack and inertia, we test whether efficiency and other organizational factors predict organizational effectiveness in improving Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) ratings. METHODOLOGY: We rely on data from the American Hospital Association and HCAHPS. We estimate hospital cost-efficiency by Stochastic Frontier Analysis and use regression analysis to determine whether efficiency, competition, hospital size, and other organizational factors are significant predictors of hospital effectiveness. FINDINGS: Our findings indicate that efficiency and hospital size have a significant negative association with organizational ability to improve HCAHPS ratings. PRACTICE IMPLICATIONS: Although achieving organizational efficiency is necessary for health care organizations, given the changes that are currently occurring in the U.S. health care system, it is important for health care managers to maintain a certain level of slack to respond to environmental demands and have the resources needed to improve their performance. PMID- 26099009 TI - Diagnosis of "Poorly Formed Glands" Gleason Pattern 4 Prostatic Adenocarcinoma on Needle Biopsy: An Interobserver Reproducibility Study Among Urologic Pathologists With Recommendations. AB - Accurate recognition of Gleason pattern (GP) 4 prostate carcinoma (PCa) on needle biopsy is critical for patient management and prognostication. "Poorly formed glands" are the most common GP4 subpattern. We studied the diagnostic reproducibility and the quantitative threshold of grading GP4 "poorly formed glands" and the criteria to distinguish them from tangentially sectioned GP3 glands. Seventeen urologic pathologists were first queried for the definition of "poorly formed glands" using cases representing a spectrum of PCa glandular differentiation. Cancer glands with no or rare lumens, elongated compressed glands, and elongated nests were considered "poorly formed glands" by consensus. Participants then graded a second set of 23 PCa cases that potentially contained "poorly formed glands" with a fair interobserver agreement (kappa = 0.34). The consensus diagnoses, defined as agreement by > 70% participants, were then correlated with the quantitative (<= 5, 6 to 10, >10) and topographic features of poorly formed glands (clustered, immediately adjacent to, and intermixed with other well-formed PCa glands) in each case. Poorly formed glands immediately adjacent to other well-formed glands regardless of their number and small foci of <= 5 poorly formed glands regardless of their location were not graded as GP4. In contrast, large foci of >10 poorly formed glands that were not immediately adjacent to well-formed glands were graded as GP4. Grading "poorly formed glands" is challenging. Some morphologic features are, however, reproducible for and against a GP4 diagnosis. This study represents an important step in standardization of grading of "poorly formed glands" based on quantitative and topographic morphologic features. PMID- 26099008 TI - Morphologic and Molecular Characteristics of Mixed Epithelial Ovarian Cancers. AB - Epithelial ovarian cancer (EOC) consists of 5 major histotypes: high-grade serous carcinoma (HGSC), endometrioid carcinoma (EC), clear cell carcinoma (CCC), mucinous carcinoma (MC), and low-grade serous carcinoma (LGSC). Each can have a broad spectrum of morphologic appearances, and 1 histotype can closely mimic histopathologic features more typical of another. Historically, there has been a relatively high frequency of mixed, defined by 2 or more distinct histotypes present on the basis of routine histopathologic assessment, histotype carcinoma diagnoses (3% to 11%); however, recent immunohistochemical (IHC) studies identifying histotype-specific markers and allowing more refined histotype diagnoses suggest a much lower incidence. We reviewed hematoxylin and eosin stained slides from 871 cases of EOC and found the frequency of mixed carcinomas to be 1.7% when modern diagnostic criteria are applied. Through international collaboration, we established a cohort totaling 22 mixed EOCs, consisting of 9 EC/CCC, 4 EC/LGSC, 3 HGSC/CCC, 2 CCC/MC, and 4 other combinations. We interrogated the molecular differences between the different components of each case using IHC, gene expression, and hotspot sequencing analyses. IHC data alone suggested that 9 of the 22 cases were not mixed tumors, as they presented a uniform immuno-phenotype throughout, and these cases most probably represent morphologic mimicry and variation within tumors of a single histotype. Synthesis of molecular data further reduces the incidence of mixed carcinomas. On the basis of these results, true mixed carcinomas with both morphologic and molecular support for the presence of >1 histotype within a given tumor represent <1% of EOCs. PMID- 26099010 TI - Nuclear Brachyury Expression Is Consistent in Chordoma, Common in Germ Cell Tumors and Small Cell Carcinomas, and Rare in Other Carcinomas and Sarcomas: An Immunohistochemical Study of 5229 Cases. AB - Brachyury is a transcription factor of the T-box family typically expressed in notochord and chordoma. Some studies report brachyury as highly specific for chordoma, whereas others have concluded that brachyury is expressed in many types of common carcinomas by reverse transcription polymerase chain reaction and immunohistochemistry and could be involved in the epithelial-mesenchymal transition and metastatic process. In this study, we immunohistochemically evaluated 5229 different tumors for nuclear brachyury expression using a new rabbit monoclonal antibody and automated immunostaining (Leica Bond Max). Only nuclear labeling was scored, and antibody dilution of 1:2000 was used. In normal tissues, only rare cells in seminiferous tubules were labeled; all other organs were negative. All chordomas (75/76), except a sarcomatous one, were positive, whereas chondrosarcomas were negative. Among epithelial tumors, positivity was often detected in embryonal carcinoma (74%) and seminoma (45%). Pulmonary small cell carcinoma was often positive (41%), whereas pulmonary and pancreatic adenocarcinomas only rarely showed nuclear brachyury positivity (3% to 4%). Common carcinomas such as ductal carcinomas of the breast or adenocarcinomas of the prostate only exceptionally showed nuclear positivity (<1%). No colorectal, hepatocellular, renal cell, squamous cell, thyroid or urothelial carcinoma, or mesothelioma showed nuclear brachyury positivity. Among mesenchymal and neuroectodermal tumors, only isolated cases of melanoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, synovial sarcoma, and follicular lymphoma showed nuclear expression. However, as shown previously with lung carcinoma, experiments with lower antibody dilutions (1:200 to 1:500) showed weak cytoplasmic and nuclear labeling in breast cancers. In addition to chordoma, we show here for the first time that nuclear brachyury expression is prevalent in embryonal carcinoma, seminoma, and small cell carcinoma of the lung but very rare in common carcinomas, sarcomas, and melanoma. With these reservations, we have demonstrated the presence of nuclear brachyury immunoreactivity to be a sensitive and fairly specific marker for chordoma. PMID- 26099011 TI - Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. AB - Mismatch-repair (MMR) immunohistochemistry is used to detect tumor MMR deficiency associated with high-level microsatellite instability (MSI). Rare tumors show heterogenous loss of mutS homolog 6 (MSH6) with immunohistochemistry, defined by areas of retained staining and separate areas of complete loss of staining. To investigate the clinical interpretation of this phenomenon, we identified 22 cases of heterogenous MSH6 loss interpreted at Mayo Clinic from January 2001 through December 2012 and reviewed histologic features, MSH6 and other MMR immunohistochemistry, and accompanying MSI testing results (n=20). Heterogenous MSH6 loss was seen in colorectal carcinoma (n=18), endometrial carcinoma (n=3), and sebaceous neoplasm (n=1). In the 18 colorectal carcinoma cases, it accompanied complete loss of mutL homolog 1 (MLH1) or PMS2, or both. Heterogenous MSH6 loss was characterized by MSI and MSH6 C8 tract instability in treatment naive cases and showed mucinous or signet-ring zones in one quarter of cases. Two cases status post neoadjuvant chemoradiation showed heterogenous MSH6 loss but were microsatellite and C8 tract stable. C8 tracts were unstable in 2 of 4 MSH6 associated Lynch syndrome (LS) tumors, but all 4 showed complete MSH6 loss on immunohistochemistry. Further, 12 such MSH6-associated LS cases showed complete MSH6 loss. In conclusion, heterogenous MSH6 loss is uncommon, usually caused by instability in MSH6 exon 5 polycytosine tract, and not associated with germline MSH6 mutation. Although heterogenous MSH6 loss provides evidence against germline MSH6 mutation, patients whose tumors exhibit this immunolabeling pattern may have LS due to a defect in a different MMR gene. PMID- 26099012 TI - Myocardial Sleeve Tissues in Surgical Lung Specimens. AB - Left atrial myocardial extensions over the pulmonary veins (PVs), known as myocardial sleeves, are present in the physiological anatomy of most individuals. Although this structure has recently received clinical attention as a major origin of paroxysmal atrial fibrillation (AF), it has not been documented in surgical specimens. Here, we examine incidentally identified myocardial sleeve tissue in routinely processed lung resection specimens to determine its incidence and diagnostic implications. Among 694 lung resection specimens with evaluable PV margins, myocardial sleeve tissue was identified in 26 cases (3.7%). The tissue was located within the adventitia of the PVs, mostly in margin preparations, and existed outside the pericardium in the majority of cases. Carcinoma infiltration of the sleeves was evident in 6 cases. No heart injuries were observed, and no tumors invaded the heart. Preoperative electrocardiography showed sinus rhythm in all cases, whereas postoperative monitoring revealed sinus rhythm in all patients except one who showed AF and flutter. Myocardial sleeve tissue is an underrecognized incidental finding in lung resection specimens, and it is not indicative of heart injury. Cancer infiltration into this tissue indicates neither heart invasion nor, by itself, invasion into the pericardium. Although surgical transection of the myocardial sleeve did not evoke immediate arrhythmia in most cases, the overall influence of this procedure on the postsurgical risk of AF remains to be determined in further studies involving extensive rhythm assessment. PMID- 26099013 TI - Beware of R(2): Simple, Unambiguous Assessment of the Prediction Accuracy of QSAR and QSPR Models. AB - The statistical metrics used to characterize the external predictivity of a model, i.e., how well it predicts the properties of an independent test set, have proliferated over the past decade. This paper clarifies some apparent confusion over the use of the coefficient of determination, R(2), as a measure of model fit and predictive power in QSAR and QSPR modeling. R(2) (or r(2)) has been used in various contexts in the literature in conjunction with training and test data for both ordinary linear regression and regression through the origin as well as with linear and nonlinear regression models. We analyze the widely adopted model fit criteria suggested by Golbraikh and Tropsha ( J. Mol. Graphics Modell. 2002 , 20 , 269 - 276 ) in a strict statistical manner. Shortcomings in these criteria are identified, and a clearer and simpler alternative method to characterize model predictivity is provided. The intent is not to repeat the well-documented arguments for model validation using test data but rather to guide the application of R(2) as a model fit statistic. Examples are used to illustrate both correct and incorrect uses of R(2). Reporting the root-mean-square error or equivalent measures of dispersion, which are typically of more practical importance than R(2), is also encouraged, and important challenges in addressing the needs of different categories of users such as computational chemists, experimental scientists, and regulatory decision support specialists are outlined. PMID- 26099014 TI - Aflatoxin B1 and aflatoxins in ground red chilli pepper after drying. AB - In this study, 180 red chilli pepper (RCP) berry samples were obtained from two different croplands of Gaziantep and Kahramanmaras (Turkey) in August, September and October. RCP berry samples were dried under sunlight and grinded. Ground red chilli pepper (GRCP) samples were analysed for aflatoxins (AFs, sum of B1, B2, G1 and G2) and AFB1 contamination. According to the results, in 49 of 180 samples, AFB1 and in 37 samples, AFs were higher than legal limits. The lowest amounts of AFs and AFB1 were obtained in August and the highest amounts in October. chi(2) analysis showed that there were no significant differences (p > 0.05) between cities among 3 months according to number of samples with AFs and AFB1 above legal limits. According to the Duncan multiple-range test, there was no significant difference between all months. Strict measures are necessary to produce high-quality GRCP. RCP berry must be treated to reduce moulds before production of GRCP. PMID- 26099015 TI - Inadequate Diet Is Associated with Acquiring Mycobacterium tuberculosis Infection in an Inuit Community. A Case-Control Study. AB - BACKGROUND: Tuberculosis predominantly affects socioeconomically disadvantaged communities. The extent to which specific dietary and lifestyle factors contribute to tuberculosis susceptibility has not been established. METHODS: A total of 200 residents of a village in Northern Quebec were investigated during a tuberculosis outbreak and identified to have active tuberculosis, latent tuberculosis infection, or neither. Participants completed questionnaires about their intake of food from traditional and commercial sources, and provided blood samples. Adults were asked about recent smoking and drug and alcohol intake. Nutritional adequacy was evaluated with reference to North American standards. Multiple dietary, lifestyle, and housing factors were combined in a logistic regression model evaluating the contributions of each to disease and infection. FINDINGS: After adjusting for potential confounding, new infection was associated with inadequate intake of fruit and vegetables (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.03-4.3), carbohydrates (OR, 4.4; 95% CI, 1.2-16.3), and certain vitamins and minerals. A multivariable model, combining nutrition, housing, and lifestyle factors, found associations between new infection and inadequate fruit and vegetable intake (OR, 2.3; 95% CI, 1.0-5.1), living in the same house as a person with smear-positive tuberculosis (OR, 14.7; 95% CI, 1.6 137.3), and visiting a community gathering house (OR, 3.7; 95% CI, 1.7-8.3). Current smoking was associated with new infection (OR, 9.4; 95% CI, 1.2-72) among adults completing a detailed lifestyle survey. INTERPRETATION: Inadequate nutrition was associated with increased susceptibility to infection, but not active tuberculosis. Interventions addressed at improving nutrition may reduce susceptibility to infection in settings where access to healthy foods is limited. PMID- 26099016 TI - Nanostructural Reorganization Manifests in Sui-Generis Density Trend of Imidazolium Acetate/Water Binary Mixtures. AB - Ionic liquids (ILs) are emerging as a novel class of solvents in chemical and biochemical research. Their range of applications further expands when a small quantity of water is added. Thus, the past decade has seen extensive research on IL/water binary mixtures. While the thermophysical properties of most of these mixtures exhibited the expected trend, few others have shown deviations from the general course. One such example is the increase in density of the 1-alkyl-3 methyl imidazolium acetate ([Rn mim][Ac])-based ILs with the addition of low to moderate concentrations of water. Although such a unique trend was observed for imidazolium cations of different tail lengths and also from independent experiments, the molecular basis of this unique behavior remains unknown. In this study, we examine the nanostructural reordering in [Rn mim][Ac] (n = 2-6) ILs due to added water by means of molecular dynamics simulations, and correlate the observed changes to the sui-generis density trend. Results suggest that the initial rise in density in these ILs mainly pertains to the water-induced increased spatial correlation among the polar components, where high basicity of the acetate anion plays a key role. At moderate water concentration, the density can rise further for ILs with longer cation tails due to hydrophobic clustering. Thus, while [emim][Ac]/water mixtures exhibit the density turnover at Xw = 0.5, [bmim][Ac] and [hmim][Ac] show the turnover at Xw = 0.7. The detailed understanding provided here could help the preparation of optimal IL/water binary mixtures for various biochemical applications. PMID- 26099017 TI - Gender Nonconformity, Homophobic Peer Victimization, and Mental Health: How Same Sex Attraction and Biological Sex Matter. AB - We assessed whether homophobic name-calling accounts for the relationship between gender nonconformity and mental health (social anxiety and psychological distress) in a sample of 1,026 Dutch adolescents (boys: n = 517) ages 11 to 16 (Mage = 13.4). We also explored whether this hypothesized mediation differs by sexual attraction and biological sex. Data were collected by means of paper-and pencil questionnaires at five secondary schools located in urban areas in the Netherlands. Mediation analysis indicated that gender nonconformity was related to both social anxiety and psychological distress partially via homophobic name calling. Moderated mediation analysis further showed that the mediating role of homophobic name-calling varied according to levels of same-sex attraction (SSA) and biological sex. The mediation effects increased in magnitude when levels of SSA increased and were significant only for adolescents with mean and high levels of SSA. The mediation effects were significant for boys and girls in general, although the mediation effects were stronger for boys than for girls. Our findings emphasize the importance of research and school-level interventions to focus on factors that promote acceptance of cross-gender behavior among adolescents. PMID- 26099019 TI - Stabilized Skyrmion Phase Detected in MnSi Nanowires by Dynamic Cantilever Magnetometry. AB - Using dynamic cantilever magnetometry we measure an enhanced skyrmion lattice phase extending from around 29 K down to at least 0.4 K in single MnSi nanowires (NWs). Although recent experiments on two-dimensional thin films show that reduced dimensionality stabilizes the skyrmion phase, our results are surprising given that the NW dimensions are much larger than the skyrmion lattice constant. Furthermore, the stability of the phase depends on the orientation of the NWs with respect to the applied magnetic field, suggesting that an effective magnetic anisotropy, likely due to the large surface-to-volume ratio of these nanostructures, is responsible for the stabilization. The compatibility of our technique with nanometer-scale samples paves the way for future studies on the effect of confinement and surfaces on magnetic skyrmions. PMID- 26099020 TI - P2Et Phosphazene: A Mild, Functional Group Tolerant Base for Soluble, Room Temperature Pd-Catalyzed C-N, C-O, and C-C Cross-Coupling Reactions. AB - The non-nucleophilic organic superbase P2Et phosphazene can enable a broad range of palladium-catalyzed cross-coupling reactions, including C-C, C-N, and C-O couplings of aryl chlorides, bromides, and iodides at room temperature. The mildness and substrate compatibility of this chemistry can deliver immediate synthetic utility for the preparation of complex molecules. PMID- 26099018 TI - The TET2 interactors and their links to hematological malignancies. AB - Ten-eleven translocation (TET) family proteins are dioxygenases that oxidize 5 methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5 carboxylcytosine in DNA, early steps of active DNA demethylation. TET2, the second member of TET protein family, is frequently mutated in patients with hematological malignancies, leading to aberrant DNA methylation profiling and decreased 5hmC levels. Located in the nucleus and acting as a DNA-modifying enzyme, TET2 is thought to exert its function via TET2-containing protein complexes. Identifying the interactome network of TET2 likely holds the key to uncover the mechanisms by which TET2 exerts its function in cells. Here, we review recent literature on TET2 interactors and discuss their possible roles in TET2 loss-mediated dysregulation of hematopoiesis and pathogenesis of hematological malignancies. PMID- 26099021 TI - Response to the letter to the editor. PMID- 26099022 TI - Leukemic Polyradiculopathy Due to Blastic Plasmacytoid Dendritic Cell Neoplasm. PMID- 26099023 TI - Conditional PDK1 Ablation Promotes Epidermal and T-Cell-Mediated Dysfunctions Leading to Inflammatory Skin Disease. AB - Phosphoinositide-dependent kinase-1 (PDK1) is a key signaling molecule downstream of the phosphatidylinositol 3-kinase pathway and is a master regulator of multiple kinases in cells of epithelial and hematopoietic lineages. The physiological role of PDK1 in regulating skin and immune homeostasis is not known. Here we developed a mouse model in which PDK1 is conditionally ablated in activated CD4 T cells, regulatory T cells, and mature keratinocytes through OX40 Cre recombinase expression. The resultant mice (PDK1-CKO) spontaneously developed severe dermatitis, skin fibrosis, and systemic T helper type 2 immunity, succumbing by 11 weeks of age. Through a series of T-cell transfers, bone marrow reconstitutions, and crossing to lymphocyte-deficient backgrounds, we demonstrate that ablation of PDK1 in keratinocytes is the major driver of disease pathogenesis. PDK1-deficient keratinocytes exhibit intrinsic defects in the expression of key structural proteins including cytokeratin-10 and loricrin, resulting in increased keratinocyte turnover, which in turn triggers inflammation, T-cell recruitment, and immune-mediated destruction. Our results reveal PDK1 as a central regulator of keratinocyte homeostasis that prevents skin immune infiltration and inflammation. PMID- 26099024 TI - CCN1, a Pro-Inflammatory Factor, Aggravates Psoriasis Skin Lesions by Promoting Keratinocyte Activation. AB - Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. The pathogenesis of psoriasis is multifactorial and is not fully understood. Here we demonstrate that CCN1 (also called Cyr61, which is short for cysteine-rich 61), an extracellular matrix protein that is also considered a pro-inflammatory factor, is highly expressed in the lesional skin of psoriasis patients, as well as in that of imiquimod (IMQ)- and IL-23-treated psoriasis-like mice. Then we show that blocking CCN1 function in vivo attenuates epidermal hyperplasia and inflammation in psoriasis-like mice. Further, in primary cultured normal human keratinocytes and HaCaT (human keratinocyte cell line) cells, CCN1 promotes keratinocyte activation, including the proliferation and expression of immune-related molecules. Finally, we observe that integrin alpha6beta1 is the receptor of CCN1 in keratinocytes, and CCN1 stimulation activates the downstream phosphoinositide-3 kinase/Akt/NF-kappaB signaling pathway. Taken together, our findings reveal that CCN1 has a critical role in psoriasis pathogenesis. Moreover, as CCN1 is a secreted extracellular matrix (ECM) protein, our study also provides evidence that ECM, which is involved in psoriatic pathogenesis, could be a potent target for psoriasis treatment. PMID- 26099025 TI - Aspartame Attenuates 2, 4-Dinitrofluorobenzene-Induced Atopic Dermatitis-Like Clinical Symptoms in NC/Nga Mice. AB - Atopic dermatitis (AD) is a common multifactorial chronic skin disease that has a multiple and complex pathogenesis. AD is gradually increasing in prevalence globally. In NC/Nga mice, repetitive applications of 2, 4-dinitrofluorobenzene (DNFB) evoke AD-like clinical symptoms similar to human AD. Aspartame (N-L-alpha aspartyl-L-phenylalanine 1-methyl ester) is a methyl ester of a dipeptide, which is used as an artificial non-nutritive sweetener. Aspartame has analgesic and anti-inflammatory functions that are similar to the function of nonsteroidal anti inflammatory drugs such as aspirin. We investigated whether aspartame can relieve AD-like clinical symptoms induced by DNFB treatment in NC/Nga mice. Sucrose did not relieve AD-like symptoms, whereas aspartame at doses of 0.5 MUg kg(-1) and 0.5 mg kg(-1) inhibited ear swelling and relieved AD-like clinical symptoms. Aspartame inhibited infiltration of inflammatory cells including eosinophils, mast cells, and CD4(+) T cells, and suppressed the expression of cytokines including IL-4 and IFN-gamma, and total serum IgE levels. Aspartame may have therapeutic value in the treatment of AD. PMID- 26099026 TI - Dact1 Regulates the Ability of 3T3-J2 Cells to Support Proliferation of Human Epidermal Keratinocytes. PMID- 26099027 TI - IL-10 signaling in dendritic cells attenuates anti-Leishmania major immunity without affecting protective memory responses. PMID- 26099029 TI - Campaigns Against Ionizing Radiation and Changed Practice Patterns for Imaging Use in Pediatric Appendicitis. PMID- 26099030 TI - Effects of long-term chloroquine administration on the natural history of aortic aneurysms in mice. AB - Autophagy regulates cellular homeostasis and integrates the cellular pro-survival machinery. We investigated the role of autophagy in the natural history of murine abdominal aortic aneurysms (AAA). ApoE(-/-) mice were implanted with saline- or angiotensin II (Ang-II)-filled miniosmotic pumps then treated with either the autophagy inhibitor chloroquine (CQ; 50 mg.(kg body mass)(-1).day(-1), by intraperitoneal injection) or saline. Ang-II-elicited aneurysmal expansion of the suprarenal aorta coupled with thrombus formation were apparent 8 weeks later. CQ had no impact on the incidence (50% for Ang-II compared with 46.2% for Ang-II + CQ; P = NS) and categorical distribution of aneurysms. The markedly reduced survival rate observed with Ang-II (57.1% for Ang-II compared with 100% for saline; P < 0.05) was unaffected by CQ (61.5% for Ang-II + CQ; P = NS compared with Ang-II). CQ did not affect the mean maximum suprarenal aortic diameter (1.91 +/- 0.19 mm for Ang-II compared with 1.97 +/- 0.21 mm for Ang-II + CQ; P = NS). Elastin fragmentation, collagen accumulation, and smooth muscle attrition, which were higher in Ang-II-treated mice, were unaffected by CQ treatment. Long-term CQ administration does not affect the natural history and prognosis of experimental AAA, suggesting that global loss of autophagy is unlikely to be a causal factor in the development of aortic aneurysms. Manipulation of autophagy as a mechanism to reduce AAA may need re-evaluation. PMID- 26099028 TI - Transient Alterations of Cutaneous Sensory Nerve Function by Noninvasive Cryolipolysis. AB - Cryolipolysis is a noninvasive, skin cooling treatment for local fat reduction that causes prolonged hypoesthesia over the treated area. We tested the hypothesis that cryolipolysis can attenuate nociception of a range of sensory stimuli, including stimuli that evoke itch. The effects of cryolipolysis on sensory phenomena were evaluated by quantitative sensory testing (QST) in 11 healthy subjects over a period of 56 days. Mechanical and thermal pain thresholds were measured on treated and contralateral untreated (control) flanks. Itch duration was evaluated following histamine iontophoresis. Unmyelinated epidermal nerve fiber and myelinated dermal nerve fiber densities were quantified in skin biopsies from six subjects. Cryolipolysis produced a marked decrease in mechanical and thermal pain sensitivity. Hyposensitivity started between two to seven days after cryolipolysis and persisted for at least thirty-five days post treatment. Skin biopsies revealed that cryolipolysis decreased epidermal nerve fiber density, as well as dermal myelinated nerve fiber density, which persisted throughout the study. In conclusion, cryolipolysis causes significant and prolonged decreases in cutaneous sensitivity. Our data suggest that controlled skin cooling to specifically target cutaneous nerve fibers has the potential to be useful for prolonged relief of cutaneous pain and might have a use as a research tool to isolate and study cutaneous itch-sensing nerves in human skin. PMID- 26099031 TI - Collapse of Particle-Laden Interfaces under Compression: Buckling vs Particle Expulsion. AB - Colloidal particles can bind to fluid interfaces with a capillary energy that is thousands of times the thermal energy. This phenomenon offers an effective route to emulsion and foam stabilization where the stability is influenced by the phase behavior of the particle-laden interface under deformation. Despite the vast interest in particle-laden interfaces, the key factors that determine the collapse of such an interface under compression have remained relatively unexplored. In this study, we illustrate the significance of the particle surface wettability and presence of electrolyte in the subphase on interparticle interactions at the interface and the resulting collapse mode. Various collapse mechanisms including buckling, particle expulsion, and multilayer formation are reported and interpreted in terms of particle-particle and particle-interface interactions. PMID- 26099032 TI - Quantitative Brightness Analysis of Fluorescence Intensity Fluctuations in E. Coli. AB - The brightness measured by fluorescence fluctuation spectroscopy specifies the average stoichiometry of a labeled protein in a sample. Here we extended brightness analysis, which has been mainly applied in eukaryotic cells, to prokaryotic cells with E. coli serving as a model system. The small size of the E. coli cell introduces unique challenges for applying brightness analysis that are addressed in this work. Photobleaching leads to a depletion of fluorophores and a reduction of the brightness of protein complexes. In addition, the E. coli cell and the point spread function of the instrument only partially overlap, which influences intensity fluctuations. To address these challenges we developed MSQ analysis, which is based on the mean Q-value of segmented photon count data, and combined it with the analysis of axial scans through the E. coli cell. The MSQ method recovers brightness, concentration, and diffusion time of soluble proteins in E. coli. We applied MSQ to measure the brightness of EGFP in E. coli and compared it to solution measurements. We further used MSQ analysis to determine the oligomeric state of nuclear transport factor 2 labeled with EGFP expressed in E. coli cells. The results obtained demonstrate the feasibility of quantifying the stoichiometry of proteins by brightness analysis in a prokaryotic cell. PMID- 26099033 TI - K4Fe3F12: An Fe(2+)/Fe(3+) Charge-Ordered, Ferrimagnetic Fluoride with a Cation Deficient, Layered Perovskite Structure. AB - A new mixed-valence iron (Fe(2+)/Fe(3+)) fluoride material with a layered perovskite-related structure has been synthesized and characterized. The material, K4Fe3F12 [K4(Fe(2+))(Fe(3+))2F12], was synthesized using mild hydrothermal conditions. The material exhibits a layered perovskite structure consisting of alternating sheets of apex-linked Fe(2+)F6 and Fe(3+)F6 octahedra; thus, each layer of Fe(2+)F6 centers is sandwiched between two layers of Fe(3+)F6 centers. Magnetization and neutron powder diffraction data show that, upon cooling below 120 K, K4Fe3F12 adopts a magnetically ordered state in which the Fe(3+) and Fe(2+) spins are aligned in an approximately antiparallel manner to each other to yield a pseudoferrimagnetic structure with a net spontaneous moment of 5.41 MUB per formula unit at 10 K. Crystal data: K4Fe3F12, trigonal space group R3m (No. 166), a = b = 5.7649(9) A, c = 28.086(9) A, V = 808.36(3) A(3), Z = 3, T = 296(2) K. PMID- 26099034 TI - Development of a bread delivery vehicle for dietary prebiotics to enhance food functionality targeted at those with metabolic syndrome. AB - Prebiotics are dietary carbohydrates that favourably modulate the gut microbiota. The aims of the present study were to develop a functional prebiotic bread using Bimuno(r), (galactooligosaccharide (B-GOS) mixture), for modulation of the gut microbiota in vitro in individuals at risk of metabolic syndrome. A control bread, (no added prebiotic) and positive control bread (containing equivalent carbohydrate to B-GOS bread) were also developed. A 3-stage continuous in vitro colonic model was used to assess prebiotic functionality of the breads. Bacteria were quantified by fluorescence in situ hybridization and short chain fatty acids by gas chromatography. Ion-exchange chromatography was used to determine GOS concentration after bread production. Following B-GOS bread fermentation numbers of bifidobacteria and lactobacilli were significantly higher compared to controls. There was no significant degradation of B-GOS during bread manufacture, indicating GOS withstood the manufacturing process. Furthermore, based on previous research, increased bifidobacteria and butyrate levels could be of benefit to those with obesity related conditions. Our findings support utilization of prebiotic enriched bread for improving gastrointestinal health. PMID- 26099035 TI - Comparison of asymptotic confidence sets for regression in small samples. AB - In case of small samples, asymptotic confidence sets may be inaccurate, with their actual coverage probability far from a nominal confidence level. In a single framework, we consider four popular asymptotic methods of confidence estimation. These methods are based on model linearization, F-test, likelihood ratio test, and nonparametric bootstrapping procedure. Next, we apply each of these methods to derive three types of confidence sets: confidence intervals, confidence regions, and pointwise confidence bands. Finally, to estimate the actual coverage of these confidence sets, we conduct a simulation study on three regression problems. A linear model and nonlinear Hill and Gompertz models are tested in conditions of different sample size and experimental noise. The simulation study comprises calculation of the actual coverage of confidence sets over pseudo-experimental datasets for each model. For confidence intervals, such metrics as width and simultaneous coverage are also considered. Our comparison shows that the F-test and linearization methods are the most suitable for the construction of confidence intervals, the F-test - for confidence regions and the linearization - for pointwise confidence bands. PMID- 26099036 TI - Genetic drift of human coronavirus OC43 spike gene during adaptive evolution. AB - Coronaviruses (CoVs) continuously threaten human health. However, to date, the evolutionary mechanisms that govern CoV strain persistence in human populations have not been fully understood. In this study, we characterized the evolution of the major antigen-spike (S) gene in the most prevalent human coronavirus (HCoV) OC43 using phylogenetic and phylodynamic analysis. Among the five known HCoV-OC43 genotypes (A to E), higher substitution rates and dN/dS values as well as more positive selection sites were detected in the S gene of genotype D, corresponding to the most dominant HCoV epidemic in recent years. Further analysis showed that the majority of substitutions were located in the S1 subunit. Among them, seven positive selection sites were chronologically traced in the temporal evolution routes of genotype D, and six were located around the critical sugar binding region in the N-terminal domain (NTD) of S protein, an important sugar binding domain of CoV. These findings suggest that the genetic drift of the S gene may play an important role in genotype persistence in human populations, providing insights into the mechanisms of HCoV-OC43 adaptive evolution. PMID- 26099038 TI - Pregnancy in Women With Systemic Lupus Erythematosus: Messages for the Clinician. PMID- 26099037 TI - The Relationship Between Early Maladaptive Schemas, Depression, and Generalized Anxiety among Adults Seeking Residential Treatment for Substance Use Disorders. AB - Previous research has shown that early maladaptive schemas (EMS) play an important role in substance use, depression, and anxiety. However, few studies have examined the role of EMS within the context of all three concurrently. The goal of this study was to determine the role of EMS in predicting symptoms of Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) among adults in residential treatment for substance dependence. We used pre-existing patient records of adults diagnosed with a substance use disorder from a residential substance use treatment facility (N=122). The EMS domains of disconnection and rejection and impaired limits were associated with symptoms of MDD and the domain of impaired autonomy and performance was associated with symptoms of GAD, even after controlling for age, gender, years of education, alcohol use, drug use, and symptoms of MDD (when predicting GAD) and GAD (when predicting MDD). Findings suggest that EMS may play an important role in comorbid mental health problems among men and women in residential substance use treatment. Continued treatment outcome research is needed to examine whether modification of EMS results in improved mental health and substance use outcomes. PMID- 26099039 TI - Left ventricular thrombus formation after acute myocardial infarction: vigilance still required in the modern era. PMID- 26099040 TI - The role of sports and exercise in allergic disease: drawbacks and benefits. AB - Although training and exercise have several benefits, overdoing it might not necessarily be a good thing. For instance, elite athletes have an increased risk for asthma and allergy. Several mechanisms can be implicated for this risk, which include the interplay between environmental training factors and athlete's personal risk factors, such as genetic susceptibility, neurogenic-mediated inflammation, and epithelial sensitivity. However, an overwhelming amount of scientific evidence shows the positive effects of sports as part of a healthy lifestyle. Training reduces breathlessness and asthma symptoms and attenuates Th2 mediated inflammatory responses. Taken together, the benefits far outweigh the potential hazards of training. An easily administered therapeutic healthy lifestyle intervention, which could be used alongside current treatment, must be developed. PMID- 26099041 TI - High surface area and Z' in a thermally stable 8-fold polycatenated hydrogen bonded framework. AB - 1,3,5-Tris(4-carboxyphenyl)benzene assembles into an intricate 8-fold polycatenated assembly of (6,3) hexagonal nets formed through hydrogen bonds and pi-stacking. One polymorph features 56 independent molecules in the asymmetric unit, the largest Z' reported to date. The framework is permanently porous, with a BET surface area of 1095 m(2) g(-1) and readily adsorbs N2, H2 and CO2. PMID- 26099042 TI - A V2O3-ordered mesoporous carbon composite with novel peroxidase-like activity towards the glucose colorimetric assay. AB - It is of great scientific and practical significance to explore inorganic mimetic enzymes to replace natural enzymes due to their instability and high cost. Herein we present an interesting discovery that a V2O3-ordered mesoporous carbon composite (V2O3-OMC) has a novel peroxidase-like activity towards fast redox reaction of typical peroxidase substrates H2O2 and 2,2'-azino-bis(3-ethylbenzo thiazoline-6-sulfonic acid) diammonium salt (ABTS). Due to the small size effect and large surface area of V2O3 nanoparticles supported by OMC, V2O3-OMC exhibited excellent catalytic performance with a k(cat) of 1.28 * 10(4) s(-1), K(M) (ABTS) of 0.067 mM and K(M) (H2O2) of 0.16 mM, and a significantly higher catalytic efficiency (k(cat)/K(M)) towards the oxidation of ABTS in comparison with the natural peroxidases. Furthermore, the Ping-pong BiBi mechanism was proposed to explain the catalytic reaction by V2O3-OMC. Based on this highly active biomimetic peroxidase and the colorimetric detection of H2O2, a facile analytical method was developed to detect glucose by using V2O3-OMC and glucose oxidase, which had a wide linear range (0.01-4 mM glucose), good selectivity and reliability for successful detection of various real samples. Thus, the novel V2O3-OMC peroxidase mimetic holds great promise for broad potential applications. PMID- 26099043 TI - Fenofibrate and diabetic retinopathy. PMID- 26099044 TI - Comment on Larmer et al. "Perceptions of the Living Dead". PMID- 26099045 TI - Subclonal diversification of primary breast cancer revealed by multiregion sequencing. AB - The sequencing of cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer. PMID- 26099046 TI - Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. AB - Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms. Interruption of IL18 action reduces atherosclerosis in mice. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe(-/-) mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe(-/ ) mice or from Apoe(-/-) mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe(-/-) mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis. PMID- 26099047 TI - Inhibition of amyloid-beta plaque formation by alpha-synuclein. AB - Amyloid-beta (Abeta) plaques and alpha-synuclein (alpha-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial alpha-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Abeta plaques. Several studies report binding and coaggregation of Abeta and alpha-syn, yet the precise role of alpha syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of alpha-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, alpha-syn failed to cross-seed Abeta plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 * [A30P]aSYN' double-transgenic mice). This was accompanied by increased Abeta levels in cerebrospinal fluid despite unchanged overall Abeta levels. Notably, the seeding activity of Abeta-containing brain homogenates was considerably reduced by alpha-syn, and Abeta deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Abeta and alpha-syn leads to inhibition of Abeta deposition and to reduced plaque formation. PMID- 26099048 TI - Potential Clinical and Economic Impact of Switching Branded Medications to Generics. AB - Switching branded to generic medications has become a common cost-containment measure. Although this is an important objective for health care systems worldwide, the impact of this practice on patient outcomes needs to be carefully considered. We reviewed the literature summarizing the potential clinical and economic consequences of switching from branded to generic medications on patient outcomes. A literature search of peer-reviewed articles published 2003-2013 using key words of "generic switching" or "substitution" was conducted using PubMed, OvidSP, and ScienceDirect. Of 30 articles identified and reviewed, most were related to the diseases of the central nervous system, especially epilepsy. Based on our review, potential impacts of switching fell into 3 broad categories: patient attitudes and adherence, clinical and safety outcomes, and cost and resource utilization. Although in many cases generics may represent an appropriate alternative to branded products, this may not always be the case. Specifically, several studies suggested that switching may negatively impact medication adherence, whereas other studies found that generic switching was associated with poorer clinical outcomes and more adverse events. In some instances, switching accomplished cost savings but did so at increased total cost of care because of increased physician visits or hospitalizations. Although in many cases generics may represent an appropriate alternative, mandatory generic switching may lead to unintended consequences, especially in certain therapeutic areas. Although further study is warranted, based on our review, it may be medically justifiable for physicians and patients to retain the right to request the branded product in certain cases. PMID- 26099049 TI - British-Pakistani women's perspectives of diabetes self-management: the role of identity. AB - AIMS AND OBJECTIVES: To explore the effects of type 2 diabetes on British Pakistani women's identity and its relationship with self-management. BACKGROUND: Type 2 diabetes is more prevalent and has worse outcomes among some ethnic minority groups. This may be due to poorer self-management and an inadequate match of health services to patient needs. The influence that type 2 diabetes has on British-Pakistani women's identity and subsequent self-management has received limited attention. DESIGN: An explorative qualitative study. METHODS: Face-to face semi-structured English and Urdu language interviews were conducted with a purposively selected heterogeneous sample of 15 British-Pakistani women with type 2 diabetes. Transcripts were analysed thematically. RESULTS: Four themes emerged: Perceived change in self emphasised how British-Pakistani women underwent a conscious adaptation of identity following diagnosis; Familiarity with ill health reflected women's adjustment to their changed identity over time; Diagnosis improves social support enabled women to accept changes within themselves and Supporting family is a barrier to self-management demonstrated how family roles were an aspect of women's identities that was resilient to change. The over arching theme Role re-alignment enables successful self-management encapsulated how self-management was a continuous process where achievements needed to be sustained. Inter-generational differences were also noted: first generation women talked about challenges associated with ageing and co-morbidities; second generation women talked about familial and work roles competing with self management. CONCLUSIONS: The complex nature of British-Pakistani women's self identification requires consideration when planning and delivering healthcare. RELEVANCE TO CLINICAL PRACTICE: Culturally competent practice should recognise how generational status influences self-identity and diabetes self-management in ethnically diverse women. Health professionals should remain mindful of effective self-management occurring alongside, and being influenced by, other aspects of life. PMID- 26099050 TI - Photoinduced Oxidation of Secondary Alcohols Using 4-Benzoylpyridine as an Oxidant. AB - Photoinduced oxidation of secondary alcohols to ketones was achieved by utilizing an equimolar amount of 4-benzoylpyridine as an oxidant. This transformation proceeds at ambient temperature and exhibits high compatibility with polar functionalities including benzoyl, silyl, and methoxymethyl alcohol protecting groups as well as tosyloxy, bromo, sulfonyl, carbamate, ester, and carboxylic acid units. The present oxidation is solely promoted by the action of organic molecules without the aid of metallic reagents. PMID- 26099051 TI - Mild tracheal compression by aberrant innominate artery and chronic dry cough in children. AB - BACKGROUND: In children with aberrant innominate artery (AIA) one of the most prevalent respiratory symptom is dry cough. How frequently this mediastinal vessels anomaly, that can induce tracheal compression (TC) of different degree, may be detected in children with chronic dry cough is not known. METHODS: In a 3 year retrospective study, the occurrence of mediastinal vessels abnormalities and the presence and degree of TC was evaluated in children with recurrent/chronic dry cough. RESULTS: Vascular anomalies were detected in 68 out of the 209 children evaluated. A significant TC was detected in 54 children with AIA, in eight with right aortic arch, in four with double aortic arch but not in two with aberrant right subclavian artery. In AIA patients, TC evaluated on computed tomography scans, was mild in 47, moderate in six and severe in one. During bronchoscopy TC increased in expiration or during cough, but this finding was more pronounced in children with right aortic arch and double aortic arch in which a concomitant tracheomalacia was more evident. Comorbidities were detected in 21 AIA patients, including atopy, reversible bronchial obstruction and gastroesophageal reflux. Aortopexy was performed in eight AIA patients, while the remaining AIA patients were managed medically and showed progressive improvement with time. CONCLUSION: Mild TC induced by AIA can be detected in a sizeable proportion of children with recurrent/chronic dry cough. The identification of this anomaly, that may at least partially explain the origin of their symptom, may avoid further unnecessary diagnostic examinations and ineffective chronic treatments. PMID- 26099052 TI - Febrile reaction associated with the infusion of haploidentical peripheral blood stem cells: incidence, clinical features, and risk factors. AB - BACKGROUND: We reported febrile reaction after the infusion of haploidentical peripheral blood stem cells (PBSCs). The aim of this study was to better characterize this new clinical entity named by infusion-related febrile reaction (IRFR). STUDY DESIGN AND METHODS: A retrospective analysis of 490 patients received allogeneic stem cell transplantation (SCT) between October 2009 and December 2011 at our institution. RESULTS: The distribution of transplant type was 173 patients in HLA-identical siblings, 30 in unrelated, and 287 in haploidentical. IRFR was defined as unexplained fever of more than 38 degrees C within 24 hours after the infusion of allogeneic PBSCs. We did not observe any IRFRs in patients undergoing HLA-identical sibling and unrelated transfusions. After excluding patients with a known source of infection, we classified haploidentical patients into IRFR and non-IRFR groups. Eighty-eight patients (30.7%) of 287 cases after the infusion of haploidentical PBSCs were diagnosed as IRFRs, chills in 3.5% (10/88), diarrhea in 21.6% (19/88), an erythematous skin rash in 0.3% (1/88), hypoxemia in 1.0% (3/88), and no other accompanying symptoms in 62.5% (55/88). Significantly higher elevation of C-reactive protein and complement C3 was seen in the IRFR group compared with the non-IRFR group. Multivariate analysis showed higher CD34+ dose was a significant predictor for IRFR (p = 0.023; hazard ratio = 1.848; 95% confidence interval, 1.087-3.142). CONCLUSION: As a clinical feature belonging to haploidentical SCT, IRFR was associated with the higher numbers of CD34+ from PBSCs. PMID- 26099053 TI - Biphasic decline of beta-cell function with age in euglycemic nonobese diabetic mice parallels diabetes onset. AB - A gradual decline in insulin response is known to precede the onset of type 1 diabetes (T1D). To track age-related changes in the beta-cell function of nonobese diabetic (NOD) mice, the most commonly used animal model for T1D, and to establish differences between those who do and do not become hyperglycemic, we performed a long-term longitudinal oral glucose tolerance test (OGTT) study (10 42 weeks) in combination with immunofluorescence imaging of islet morphology and cell proliferation. We observed a clear biphasic decline in insulin secretion (AUC0-30 min ) even in euglycemic animals. A first phase (10-28 weeks) consisted of a relatively rapid decline and paralleled diabetes development in the same cohort of animals. This was followed by a second phase (29-42 weeks) during which insulin secretion declined much slower while no additional animals became diabetic. Blood glucose profiles showed a corresponding, but less pronounced change: the area under the concentration curve (AUC0-150 min ) increased with age, and fit with a bilinear model indicated a rate-change in the trendline around 28 weeks. In control NOD scids, no such changes were observed. Islet morphology also changed with age as islets become surrounded by mononuclear infiltrates, and, in all mice, islets with immune cell infiltration around them showed increased beta-cell proliferation. In conclusion, insulin secretion declines in a biphasic manner in all NOD mice. This trend, as well as increased beta-cell proliferation, is present even in the NODs that never become diabetic, whereas, it is absent in control NOD scid mice. PMID- 26099054 TI - A Living Systematic Review of Nebulized Hypertonic Saline for Acute Bronchiolitis in Infants. PMID- 26099055 TI - Assessment of Bulbar Redness with a Newly Developed Keratograph. AB - PURPOSE: To determine the validity and reliability of the clinical assessment of bulbar redness (BR) using a newly developed corneal topographer. METHODS: This is a cross-sectional diagnostic evaluation study. The BR scores [Oculus Index (OI)] from 30 eyes of 26 patients with different degrees of conjunctival hyperemia were assessed and scored automatically using a new method: a keratograph equipped with scanning and scoring software. The values obtained via this system were correlated with three image-based comparative subjective scales: the Institute for Eye Research (IER), the Efron, and the Validated Bulbar Redness (VBR) grading scales. The IER and Efron scores were interpolated to 0.1 unit, and the VBR scores were interpolated to 1 unit. We also evaluated the repeatability of each method and the level of agreement between the OI score and the scores achieved using the three other image-based methods. RESULTS: There was a significant correlation between the OI score and the scores obtained with the IER (r = 0.921, p < 0.001), Efron (r = 0.958, p < 0.001), and VBR (r = 0.965, p < 0.001) scales. The intraobserver intraclass correlation coefficients were 0.947, 0.874, 0.810, and 0.920 for the OI, IER, Efron, and VBR, respectively, and the intraobserver coefficients of repeatability were 13.924, 16.111, 17.684, and 16.900, respectively. Furthermore, the interobserver intraclass correlation coefficients were 0.889, 0.880, 0.884, and 0.881 for the OI, IER, Efron, and VBR, respectively, and the interobserver coefficients of repeatability were 15.934, 16.366, 22.059, and 21.373, respectively. CONCLUSIONS: The OI is an objective and reliable method for scoring BR. Its reproducibility was the highest of all the four modalities. The keratograph is recommended, therefore, as a suitable alternative for BR assessment. PMID- 26099056 TI - Efficacy of Blue-Light Cross-linking on Human Scleral Reinforcement. AB - PURPOSE: To evaluate the biomechanical effects of collagen cross-linking by riboflavin/blue light (460 nm) on human sclera. METHODS: Forty-two sclera samples from donated human eyes were treated with riboflavin at 0.5% on the equatorial sclera for 20 minutes and then randomly divided into seven groups and irradiated, respectively, with blue light at different intensities (14.6, 19.5, 22.5, 26, 32.5, and 40.6 mW/cm) for 20 minutes using a light-emitting diode source with an exposure area of 10 mm in diameter. The untreated samples constituted the control group. During irradiation, continuous riboflavin solution infiltration was carried out for 20 minutes. Stress-strain measurements of scleral strips were performed with a biomaterial tester. Stress data and Young modulus values in different groups were compared by one-way analysis of variance. RESULTS: Blue light (460 nm) cross-linking was efficient in stiffening human sclera strips. Interestingly, eyes treated with 22.5 mW/cm exhibited higher Young modulus values (19.12 [+/-4.88] MPa) at 8% strain compared with other groups, representing a 307.68% increase over control eye values (4.69 [+/-1.26] MPa). Stress and Young modulus increased gradually with irradiation intensity from 19.5 to 22.5 mW/cm before decreasing for higher intensities. CONCLUSIONS: The biomechanical strength of human sclera may be enhanced by collagen cross-linking with riboflavin/460 nm blue-light irradiation; the dose of 22.5 mW/cm might be used for blue-light (460 nm) scleral cross-linking to achieve a higher efficacy. PMID- 26099057 TI - Sarcoidosis Presenting with Cicatrizing Conjunctivitis. AB - PURPOSE: To report two patients with sarcoidosis initially presenting with cicatrizing conjunctivitis. CASE REPORTS: Both patients with chronic conjunctivitis were referred for further management. The first patient had conjunctival granulomas, subepithelial fibrosis, and forniceal foreshortening. The second patient had extensive upper and lower conjunctival scarring with forniceal foreshortening and symblepharon formation of both eyes. Conjunctival biopsy specimens revealed noncaseating granulomas. Immunofluorescein studies were negative for immunoreactant deposition in the basement membrane. Because of further diagnostic evaluations, sarcoidosis was determined to be the final cause of the cicatrizing conjunctivitis. CONCLUSIONS: Sarcoidosis should be included in the differential diagnosis of cicatrizing conjunctivitis. Recognition of the characteristic noncaseating granulomas in the conjunctival biopsy and initiation of the appropriate evaluations are essential in establishing the diagnosis and determining the extent of systemic involvement. PMID- 26099058 TI - Repeatability of Associated Phoria Tests. AB - PURPOSE: H.J. Haase developed a set of tests for measuring associated phoria and stereopsis using a variety of different targets for each. This testing method is known as the MKH-Haase method and it is used commonly in Germany. The aim of this study was to investigate the test-retest repeatability of the distance and near associated phoria tests for the MKH-Haase charts and other clinical tests. METHODS: Horizontal and vertical associated phorias were measured at distance and near for 34 symptomatic and 40 asymptomatic participants with different tests. The tests are Cross, Pointer, Double Pointer, and Rectangle tests of MKH-Haase charts at distance and near. The other common tests include the Mallett Test and the American Optical (AO) Slide at distance. At near, there are the Mallett Test, the AO Card, the Saladin Card, the Wesson Card, and the Sheedy Disparometer. RESULTS: The 95% limits of agreement for all of the distance horizontal values for the symptomatic group were within +/-1.25, except for the AO Slide limits, which were larger by 0.43. The limits of agreement for the asymptomatic group were within +/-0.875. At near, the 95% limits of agreement for most of the horizontal associated phoria tests were +/-2.00. The exception was the symptomatic group's Sheedy Disparometer limits, which were -4.25 to 5.75. Except for the Disparometer values for the asymptomatic group, the mean between-session differences were not statistically significant different from zero based on the 95% confidence interval. The asymptomatic group's mean Disparometer value was less eso at the second session. The 95% limits of agreement for all of the vertical values at distance and near for both groups were very narrow (i.e., within +/-0.375). CONCLUSIONS: Most of the tests showed good repeatability for both subject groups at distance and near, except for the Sheedy Disparometer. The reason for the lower repeatability could be the design of the Disparometer. PMID- 26099059 TI - Novel Mutation in BEST1 Associated with Atypical Best Vitelliform Dystrophy. AB - PURPOSE: Best vitelliform macular dystrophy is a hereditary retinal disease characterized by accumulation of lipofuscin in the central macula of both eyes. Lesions typically emerge in the first to second decade and frequently lead to significant visual acuity reduction. The diagnosis is made by the presence of characteristic fundus appearance, identification of a family history, electrooculography abnormalities, and genetic testing for mutations of the BEST1 gene. The following report illustrates a case of an atypical Best vitelliform dystrophy associated with a novel variant in the BEST1 gene. CASE REPORT: A 52 year-old man with a history of Best disease diagnosed at age 16 presented for a routine examination. Retinal examinations and fundus photographs over 13 years demonstrated bilateral paramacular lesions transitioning from vitelliform to atrophic in appearance. Electrooculography testing revealed a reduced Arden ratio of 1.371 OD and 1.291 OS. Optical coherence tomography, fundus autofluorescence, fluorescein angiography, and electroretinography were also performed. Sequence analysis of the BEST1 gene revealed a novel missense mutation. CONCLUSIONS: Genetic sequence analysis of BEST1 is important in the diagnosis of Best vitelliform dystrophy, particularly in unusual cases, and helps to further our knowledge and understanding of this disease. PMID- 26099060 TI - Intrasubject Difference in CCT among POAG versus Normal Individuals. AB - PURPOSE: To evaluate intrasubject asymmetry in central corneal thickness (CCT) among patients with primary open-angle glaucoma (POAG) as compared with that of normal subjects and to determine whether the eye with thinner cornea has more severe glaucomatous visual field damage. METHODS: In this case-control study, CCT of both eyes was measured using an ultrasonic pachymeter (UP-1000; Nidek Technologies, Gamagori, Japan) among POAG patients and normal subjects. The intrasubject difference in CCT was calculated and compared between the study groups; correlations between CCT and intraocular pressure (IOP), vertical cup-to disc ratio (VCDR), and visual field defects were also evaluated. RESULTS: A total of 62 patients with bilateral POAG and 56 normal subjects were included. There was no significant difference between the study groups in terms of age, sex, and ocular parameters except for visual acuity, IOP, and VCDR. The POAG patients demonstrated significantly greater intrasubject asymmetry in CCT (8 +/- 7 MUm vs. 5 +/- 3 MUm; p = 0.041) and a higher prevalence of significant (>10 MUm) intrasubject CCT difference (30.6 vs. 5.4%; p < 0.001) as compared with normal subjects. Although each higher level of glaucomatous damage was associated with 4 MUm thinner CCT, the correlation was not statistically significant (95% confidence interval, -8 to 1 MUm; p = 0.117; GEE analysis). No significant correlation was observed between CCT and IOP or VCDR (p = 0.302 and 0.137, respectively). CONCLUSIONS: Patients with POAG demonstrate a larger amount of intrasubject difference in CCT as compared with normal subjects. PMID- 26099061 TI - Pigmented Lesions of the Retinal Pigment Epithelium. AB - : The primary eye care practitioner assumes an important role in clinical decisions involving the differentiation between malignant and nonmalignant pigmented lesions. A misdiagnosis may have profound consequences on patient management and visual or life prognosis. However, information on these lesions, particularly their appearance using advanced imaging, is fragmented throughout the literature. The purpose of this review is to describe these features in detail, so that the implications of this information on clinical practice are more readily apparent. Clinically relevant descriptions of pigmented lesions of the retinal pigment epithelium using traditional and advanced imaging modalities in the literature were collated and integrated with findings from patients seen at the Centre for Eye Health. The information was then organized and tabulated. Finally, a flow diagram was created to be used as a clinical reference in the differential diagnosis of pigmented lesions of the retinal pigment epithelium. PMID- 26099062 TI - Hemorrhagic Retinopathy after Spondylosis Surgery and Seizure. AB - PURPOSE: To report bilateral hemorrhagic retinopathy in an adult female subject after lumbar spinal surgery and seizure. CASE REPORT: A 38-year-old woman presented with bilateral blurry vision and spots in the visual field. The patient had lumbar spondylosis surgery that was complicated by a dural tear with persistent cerebrospinal fluid leak. Visual symptoms started immediately after witnessed seizure-like activity. At presentation, visual acuity was 20/100 and 20/25 in the right and left eye, respectively. Dilated fundus examination demonstrated bilateral hemorrhagic retinopathy with subhyaloid, intraretinal, and subretinal involvement. At 4-month follow-up, visual acuity improved to 20/60 and 20/20 in the right and left eye, respectively. Dilated fundus examination and fundus photography showed resolution of retinal hemorrhages in both eyes. CONCLUSIONS: The first case of bilateral hemorrhagic retinopathy after lumbar spondylosis surgery and witnessed seizure in an adult was reported. Ophthalmic examination may be warranted after episodes of seizure in adults. PMID- 26099063 TI - Modeling the finger instability in an expanding cell monolayer. AB - Collective motion occurs in many biological processes, such as wound healing, tumor invasion and embryogenesis. Experiments of cell monolayer migration have revealed the spontaneous formation of finger-like instabilities, with leader cells at their tips. We present a particle-based model for collective cell migration, based on several elements that have been found experimentally to influence cellular movement. Inside the bulk we include velocity alignment interactions between neighboring cells. At the border contour of the layer we introduce the following additional forces: surface-elasticity restoring force, curvature-dependent positive feedback, and contractile acto-myosin cables. We find that the curvature-driven instability at the layer edge is necessary and sufficient for the formation of cellular fingers, which are in good agreement with experimental observations. PMID- 26099064 TI - Bilayer Charge Reversal and Modification of Lipid Organization by Dendrimers as Observed by Sum-Frequency Vibrational Spectroscopy. AB - Polyamidoamine (PAMAM) dendrimers are hyperbranched, nanosized polymers with promising biomedical applications as nanocarriers in targeted drug delivery and gene therapy. For the development of safe dendrimer-based biomedical applications it is necessary to gain an understanding of the detailed mechanism of the interactions of both cationic and anionic dendrimers with cell membranes. To characterize dendrimer-membrane interactions we applied solid-supported lipid bilayers as biomembrane models and utilized infrared-visible sum-frequency vibrational spectroscopy to independently probe the interactions of cationic G5 NH2 and anionic G4.5-COONa dendrimers with the two leaflets of the lipid bilayers. Interaction with both dendrimers led to changes in the interfacial water structure and charge density as evidenced by the changes in the OH band intensities in the sum-frequency spectra of the bilayers. Interaction with the G5 NH2 dendrimer also led to a unique inversion of the sign of the OH-stretch amplitudes, in addition to a decrease in their absolute values. We suggest that the positively charged amino groups on the G5-NH2 dendrimer surface bind to the negatively charged bilayer, while uncompensated positive charges not involved in the binding cause a reversal of the electric field and thus an opposite orientation of the interfacial water molecules. More subtle but nonetheless significant changes were seen in the relative magnitudes of the CH amplitudes. The methyl antisymmetric to symmetric stretch amplitude ratios are altered, implying changes in the tilt angles of the phospholipid alkyl chains. The conformational order of the phospholipid alkyl chains of both leaflets is also influenced by the G5-NH2 dendrimer while G4.5-COONa has no effect on the alkyl chain conformation. PMID- 26099065 TI - Coping Strategies and Psychological Outcomes of Patients with Inflammatory Bowel Disease in the First 6 Months After Diagnosis. AB - BACKGROUND: Inflammatory bowel disease (IBD) is associated with reduced physical and mental well-being. The first 6 months after diagnosis is an important time in a patient's life with IBD. On top of the physical symptoms, psychological characteristics, such as coping strategies and personality, may contribute to impaired or improved health-related quality of life (HRQOL), anxiety, and depression. This study aimed to measure the stability of coping strategies and personality over the first 6 months after diagnosis and identify the associations of coping strategies and personality traits with the level of HRQOL and degree of anxiety and depression. This study aimed to measure HRQOL, anxiety, depression, IBD symptoms, coping, and personality at baseline and 6 months. METHODS: Questionnaires about HRQOL, anxiety, depression, IBD symptoms, coping, personality, and demographic information were administered to patients at baseline and 6 months after diagnosis. RESULTS: Personality characteristics were stable over the first 6 months but coping strategies were not. Maladaptive coping strategies were associated with worse outcomes but adaptive coping strategies were not associated with better outcomes. All measures of HRQOL improved. Neuroticism was associated with worse psychological anxiety, depression, and HRQOL outcomes. CONCLUSIONS: This is the first study to psychologically test patients with IBD during the first 6 months after diagnosis. Generally, the HRQOL of patients with IBD improves over this time. Maladaptive coping is associated with worse psychological anxiety, depression, and HRQOL physical outcomes; although until an interventional study is performed, reverse causation cannot be ruled out. PMID- 26099066 TI - Extent of Early Clinical Response to Infliximab Predicts Long-term Treatment Success in Active Ulcerative Colitis. AB - BACKGROUND: The long-term effectiveness of infliximab (IFX) in ulcerative colitis (UC) and predictors of treatment response remain poorly characterized. METHODS: A retrospective cohort study was conducted in 213 consecutive patients with active steroid-refractory or steroid-dependent UC treated with induction and scheduled maintenance IFX at an inflammatory bowel disease referral center. Outcomes included annual steroid-free remission (SFR), IFX failure with discontinuation, colectomy, and serious adverse events. RESULTS: The 1- and 5-year cumulative probabilities for SFR were 39% and 14%, for IFX failure were 31.7% and 55.6%, and for colectomy were 19.2% and 37.4%, respectively. A sensitivity analysis considering the last clinical observation in patients with incomplete follow-up demonstrated a long-term SFR rate of 36%. Among responders to IFX induction therapy, achieving clinical remission before maintenance IFX therapy predicted SFR at 1 year (adjusted odds ratio = 4.50; 95% CI, 1.75-11.53), whereas the need for IFX dose intensification during the first year of therapy predicted a lower odds of SFR at 1 year (adjusted odds ratio = 0.28; 95% CI, 0.11-0.67) and a greater hazard of IFX failure beyond 1 year (adjusted hazard ratio = 2.57; 95% CI, 1.14-5.81). Older age and shorter UC duration at IFX initiation predicted poorer long-term outcomes. CONCLUSIONS: In patients with moderate-to-severe UC treated with scheduled IFX at an inflammatory bowel disease center, close to half of the patients are still on IFX at 5 years, although a smaller proportion of patients achieve long-term SFR. The magnitude and stability of early response to IFX is associated with long-term therapeutic benefit to this agent. PMID- 26099067 TI - Tumor Necrosis Factor-like Cytokine TL1A and Its Receptors DR3 and DcR3: Important New Factors in Mucosal Homeostasis and Inflammation. AB - Tumor necrosis factor (TNF)-like cytokine 1A (TL1A) is a member of the TNF superfamily of proteins (TNFSF15), which signals through association with death domain receptor 3 (DR3). Decoy receptor 3 (DcR3) competes with DR3 for TL1A binding and inhibits functional signaling. These proteins are significantly upregulated in inflamed intestinal tissues, and their pathogenetic importance for inflammatory bowel disease (IBD) is suggested by accumulating evidence. TL1A/DR3 induce costimulatory signals to activated lymphocytes, including the gut-specific populations of CD4+CD161+ and CD4+CCR9+ cells, affecting all major effector pathways and inducing the mucosal upregulation of Th1, Th2, and Th17 factors. They may also participate in mucosal homeostasis and defense against pathogens through their effects on the development and function of the recently described innate lymphoid cells. T-regulatory lymphocytes highly express DR3, and they respond to TL1A stimulation also. Mechanistic studies by transgenic expression of TL1A, deletion of TL1A or DR3, and therapeutic blockade by anti-TL1A antibodies all support the critical involvement of the corresponding pathways in the pathogenesis of chronic mucosal inflammation. Wide genome association studies have identified IBD-specific polymorphisms in TNFSF15 gene, which have functional implications and serve as poor prognostic factors. Recently, TL1A blockade in mice was presented as a unique pharmacological treatment for the reversal of established intestinal fibrosis. Finally, TL1A/DR3 signaling seems to critically participate in extraintestinal inflammatory conditions that are frequently associated with IBD as part of the gut-joint-skin-eye axis. These converging lines of evidence make TL1A/DR3 a suitable model for personalized approaches to IBD therapy. PMID- 26099068 TI - Inference for blocked randomization under a selection bias model. AB - We provide an asymptotic test to analyze randomized clinical trials that may be subject to selection bias. For normally distributed responses, and under permuted block randomization, we derive a likelihood ratio test of the treatment effect under a selection bias model. A likelihood ratio test of the presence of selection bias arises from the same formulation. We prove that the test is asymptotically chi-square on one degree of freedom. These results correlate well with the likelihood ratio test of Ivanova et al. (2005, Statistics in Medicine 24, 1537-1546) for binary responses, for which they established by simulation that the asymptotic distribution is chi-square. Simulations also show that the test is robust to departures from normality and under another randomization procedure. We illustrate the test by reanalyzing a clinical trial on retinal detachment. PMID- 26099069 TI - Therapeutic Potential of 5-HT6 Receptor Agonists. AB - Given its predominant expression in the central nervous system (CNS), 5 hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID- 26099070 TI - Bloodstain Pattern Analysis: implementation of a fluid dynamic model for position determination of victims. AB - Bloodstain Pattern Analysis is a forensic discipline in which, among others, the position of victims can be determined at crime scenes on which blood has been shed. To determine where the blood source was investigators use a straight-line approximation for the trajectory, ignoring effects of gravity and drag and thus overestimating the height of the source. We determined how accurately the location of the origin can be estimated when including gravity and drag into the trajectory reconstruction. We created eight bloodstain patterns at one meter distance from the wall. The origin's location was determined for each pattern with: the straight-line approximation, our method including gravity, and our method including both gravity and drag. The latter two methods require the volume and impact velocity of each bloodstain, which we are able to determine with a 3D scanner and advanced fluid dynamics, respectively. We conclude that by including gravity and drag in the trajectory calculation, the origin's location can be determined roughly four times more accurately than with the straight-line approximation. Our study enables investigators to determine if the victim was sitting or standing, or it might be possible to connect wounds on the body to specific patterns, which is important for crime scene reconstruction. PMID- 26099071 TI - The Global Landscape of Occupational Exposure Limits--Implementation of Harmonization Principles to Guide Limit Selection. AB - Occupational exposure limits (OELs) serve as health-based benchmarks against which measured or estimated workplace exposures can be compared. In the years since the introduction of OELs to public health practice, both developed and developing countries have established processes for deriving, setting, and using OELs to protect workers exposed to hazardous chemicals. These processes vary widely, however, and have thus resulted in a confusing international landscape for identifying and applying such limits in workplaces. The occupational hygienist will encounter significant overlap in coverage among organizations for many chemicals, while other important chemicals have OELs developed by few, if any, organizations. Where multiple organizations have published an OEL, the derived value often varies considerably-reflecting differences in both risk policy and risk assessment methodology as well as access to available pertinent data. This article explores the underlying reasons for variability in OELs, and recommends the harmonization of risk-based methods used by OEL-deriving organizations. A framework is also proposed for the identification and systematic evaluation of OEL resources, which occupational hygienists can use to support risk characterization and risk management decisions in situations where multiple potentially relevant OELs exist. PMID- 26099073 TI - Enhancing cognitive aging: clinical highlights of a report from the Institute of Medicine. PMID- 26099072 TI - Paraneoplastic Neurological Syndromes and Glutamic Acid Decarboxylase Antibodies. AB - IMPORTANCE: Little is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment. OBJECTIVE: To report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study. MAIN OUTCOMES AND MEASURES: Analysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals. RESULTS: Eight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P = .03), more frequently male (60% vs 13%; P < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against gamma-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor. CONCLUSIONS AND RELEVANCE: Patients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell surface antibodies. PMID- 26099074 TI - A Mallory-Weiss tear treated with transarterial embolization complicated by disseminated intravascular coagulation. PMID- 26099075 TI - Adenocarcinoma of a colonic interposition graft for benign esophageal stricture in a young woman. PMID- 26099076 TI - Endoscopic intraluminal cutting technique for indwelling devices using a lithotripter handle and guidewire. PMID- 26099077 TI - Over-the-scope clips for transoral gastric outlet reduction as salvage therapy for weight regain after Roux-en-Y gastric bypass. PMID- 26099078 TI - Proctitis cystica profunda diagnosed by endoscopic submucosal dissection: use of a therapeutic procedure for diagnosis. PMID- 26099079 TI - Porta hepatis schwannoma diagnosed by endoscopic ultrasound-guided fine-needle biopsy. PMID- 26099080 TI - Endoscopic bridge to radiology: a sequential life-saving hemostatic approach. PMID- 26099081 TI - Endoscopic needle knife fistulotomy technique for ileal pouch-to-pouch fistula. PMID- 26099082 TI - Endoscopic ultrasound-guided therapy of a gastrointestinal stromal tumor (GIST). PMID- 26099083 TI - Duodenal ulcer caused by a surgical clip after laparoscopic cholecystectomy. PMID- 26099084 TI - Endoscopic ultrasound-guided pelvic abscess drainage using a dedicated, wide, flared-end, fully covered self-expandable metal stent. PMID- 26099085 TI - Endoscopic submucosal dissection of early duodenal tumor using the Clutch Cutter: a preliminary clinical study. PMID- 26099086 TI - Ectopic varices in a pancreatojejunal anastomosis: a rare cause of hemorrhage. PMID- 26099087 TI - Esophageal involvement by pemphigus vulgaris resulting in dysphagia. PMID- 26099088 TI - External pancreatic fistula treated by endoscopic ultrasound-guided drainage with a novel lumen-apposing metal stent mounted on a cautery-tipped delivery system. PMID- 26099089 TI - Endoscopic ultrasound of pneumatosis cystoides intestinalis. PMID- 26099090 TI - Premature explantation of an EndoBarrier gastrointestinal liner because of sleeve invagination. PMID- 26099091 TI - A rare cause of biliary colic. PMID- 26099092 TI - Use of an over-the-scope clip for endoscopic sealing of anastomotic dehiscence after anterior resection for rectal cancer. PMID- 26099093 TI - Fatal aortic hemorrhage after over-the-scope clipping and subsequent esophageal stenting for sealing of iatrogenic esophageal perforation. PMID- 26099094 TI - Real-time measurement of luminal compliance during transoral incisionless fundoplication. PMID- 26099095 TI - Single-step retrieval of a proximally migrated biliary stent. PMID- 26099096 TI - A new traction method with use of the snare as a "second hand" during endoscopic submucosal dissection. PMID- 26099097 TI - A case of incidental sloughing esophagitis. PMID- 26099098 TI - Inadvertent submucosal esophageal tunnel complicating ERCP. PMID- 26099099 TI - Small-bowel pseudomelanosis. PMID- 26099100 TI - Successful treatment of a proximal esophageal rupture with a luminal sponge. PMID- 26099101 TI - Complete removal of a colonic neoplasm extending into a diverticulum with hybrid endoscopic submucosal dissection-mucosal resection and endoscopic band ligation. PMID- 26099102 TI - A new tissue acquisition technique in pancreatic cystic neoplasm: endoscopic ultrasound-guided through-the-needle forceps biopsy. PMID- 26099103 TI - Endoscopic removal of a migrated and long-indwelling self-expandable metal stent. PMID- 26099104 TI - Over-the-scope-clip two-side closure of a coloduodenal fistula caused by a dislocated prosthesis of the pancreatic duct. PMID- 26099105 TI - Endoscopic ultrasound-guided choledochojejunostomy with a forward-viewing echoendoscope for severe benign bilioenteric stricture in a patient with Child's resection. PMID- 26099106 TI - Safe endoscopic removal of a swallowed partial denture with a grip-seal plastic bag. PMID- 26099107 TI - A combination of the clip-with-line method and the tunnel technique during esophageal endoscopic submucosal dissection: a technical solution? PMID- 26099108 TI - Enhancing Light Emission of ZnO-Nanofilm/Si-Micropillar Heterostructure Arrays by Piezo-Phototronic Effect. AB - n-ZnO nanofilm/p-Si micropillar heterostructure light-emitting diode (LED) arrays for white light emissions are achieved and the light emission intensity of LED array is enhanced by 120% under -0.05% compressive strains. These results indicate a promising approach to fabricate Si-based light-emitting components with high performances enhanced by the piezo-phototronic effect, with potential applications in touchpad technology, personalized signatures, smart skin, and silicon-based photonic integrated circuits. PMID- 26099109 TI - A kirigami approach to engineering elasticity in nanocomposites through patterned defects. AB - Efforts to impart elasticity and multifunctionality in nanocomposites focus mainly on integrating polymeric and nanoscale components. Yet owing to the stochastic emergence and distribution of strain-concentrating defects and to the stiffening of nanoscale components at high strains, such composites often possess unpredictable strain-property relationships. Here, by taking inspiration from kirigami-the Japanese art of paper cutting-we show that a network of notches made in rigid nanocomposite and other composite sheets by top-down patterning techniques prevents unpredictable local failure and increases the ultimate strain of the sheets from 4 to 370%. We also show that the sheets' tensile behaviour can be accurately predicted through finite-element modelling. Moreover, in marked contrast to other stretchable conductors, the electrical conductance of the stretchable kirigami sheets is maintained over the entire strain regime, and we demonstrate their use to tune plasma-discharge phenomena. The unique properties of kirigami nanocomposites as plasma electrodes open up a wide range of novel technological solutions for stretchable electronics and optoelectronic devices, among other application possibilities. PMID- 26099110 TI - In situ NMR and electrochemical quartz crystal microbalance techniques reveal the structure of the electrical double layer in supercapacitors. AB - Supercapacitors store charge through the electrosorption of ions on microporous electrodes. Despite major efforts to understand this phenomenon, a molecular level picture of the electrical double layer in working devices is still lacking as few techniques can selectively observe the ionic species at the electrode/electrolyte interface. Here, we use in situ NMR to directly quantify the populations of anionic and cationic species within a working microporous carbon supercapacitor electrode. Our results show that charge storage mechanisms are different for positively and negatively polarized electrodes for the electrolyte tetraethylphosphonium tetrafluoroborate in acetonitrile; for positive polarization charging proceeds by exchange of the cations for anions, whereas for negative polarization, cation adsorption dominates. In situ electrochemical quartz crystal microbalance measurements support the NMR results and indicate that adsorbed ions are only partially solvated. These results provide new molecular-level insight, with the methodology offering exciting possibilities for the study of pore/ion size, desolvation and other effects on charge storage in supercapacitors. PMID- 26099111 TI - Potential-dependent dynamic fracture of nanoporous gold. AB - When metallic alloys are exposed to a corrosive environment, porous nanoscale morphologies spontaneously form that can adversely affect the mechanical integrity of engineered structures. This form of stress-corrosion cracking is responsible for the well-known 'season cracking' of brass and stainless steel components in nuclear power generating stations. One explanation for this is that a high-speed crack is nucleated within the porous layer, which subsequently injects into non-porous parent-phase material. We study the static and dynamic fracture properties of free-standing monolithic nanoporous gold as a function electrochemical potential using high-speed photography and digital image correlation. The experiments reveal that at electrochemical potentials typical of porosity formation these structures are capable of supporting dislocation mediated plastic fracture at crack velocities of 200 m s(-1). Our results identify the important role of high-speed fracture in stress-corrosion cracking and are directly applicable to the behaviour of monolithic dealloyed materials at present being considered for a variety of applications. PMID- 26099112 TI - Dynamic polymer systems with self-regulated secretion for the control of surface properties and material healing. AB - Approaches for regulated fluid secretion, which typically rely on fluid encapsulation and release from a shelled compartment, do not usually allow a fine continuous modulation of secretion, and can be difficult to adapt for monitoring or function-integration purposes. Here, we report self-regulated, self-reporting secretion systems consisting of liquid-storage compartments in a supramolecular polymer-gel matrix with a thin liquid layer on top, and demonstrate that dynamic liquid exchange between the compartments, matrix and surface layer allows repeated, responsive self-lubrication of the surface and cooperative healing of the matrix. Depletion of the surface liquid or local material damage induces secretion of the stored liquid via a dynamic feedback between polymer crosslinking, droplet shrinkage and liquid transport that can be read out through changes in the system's optical transparency. We foresee diverse applications in fluid delivery, wetting and adhesion control, and material self-repair. PMID- 26099113 TI - PhI(OAc)2-mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-beta-carbolines: synthesis of norharmane, harmane, eudistomin U and eudistomin I. AB - Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation of tetrahydro-beta-carboline acids and dehydrogenation of tetrahydro-beta-carbolines to access the corresponding aromatic beta carbolines. To the best of our knowledge this is the first synthesis of beta carbolines via a one-pot oxidative decarboxylation at ambient temperature. The utility of this protocol has been demonstrated in the synthesis of beta-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12). PMID- 26099114 TI - In-depth comparative proteomic analysis of yeast proteome using iTRAQ and SWATH based MS. AB - Quantitative proteomics using LC-MS has emerged as an essential tool for addressing different biological questions. Various labelling methods have been effectively employed for quantitative proteomics studies. However, these are fraught with several challenges, including reproducibility and the number of samples that can be analysed at a given time. To this end, unlabelled proteomics is a promising field, and the recently developed sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) method aims to address these limitations. In this study, we compared SWATH-MS to isobaric tag for relative and absolute quantitation (iTRAQ), a widely used labelled method for relative quantitation. For this, we used yeast, Saccharomyces cerevisiae, since almost all its proteins are identified. More importantly, the abundance of each protein is well documented. We found that although a similar number of proteins could be quantitated using the two techniques, SWATH had the advantage of quantifying a larger percentage of low abundance proteins (below 60 ppm). Thus, based on our analysis, we believe that these two techniques are complementary and can synergistically improve the number of quantifiable proteins. SWATH's ability to quantify low abundant proteins could be an asset in biomarker discovery studies. PMID- 26099115 TI - Phytotoxicity, Translocation, and Biotransformation of NaYF4 Upconversion Nanoparticles in a Soybean Plant. AB - The increasing uses of rare-earth-doped upconversion nanoparticles (UCNPs) have obviously caused many concerns about their potential toxicology on live organisms. In addition, the UCNPs can be released into the environment, then transported into edible crop plants, and finally entered into food chain. Here, the soybean is chosen as a model plant to study the subchronic phytotoxicity, translocation, and biotransformation of NaYF4 UCNPs. The incubation with UCNPs at a relative low concentration of 10 MUg mL(-1) leads to growth promotion for the roots and stems, while concentration exceeding 50 MUg mL(-1) brings concentration dependent inhibition. Upconversion luminescence imaging and scanning electron microscope characterization show that the UCNPs can be absorbed by roots and parts of the adsorbed UCNPs are then transported through vessels to stems and leaves. The near-edge X-ray absorption fine structure spectra reveal that the adsorbed NaYF4 nanoparticles are relatively stable during a 10 d incubation. Energy-dispersive X-ray spectrum further indicates that a small amount of NaYF4 is dissolved/digested and can transform into Y-phosphate clusters in roots. PMID- 26099116 TI - Ethics in publication. AB - Publication of scientific manuscripts remains our core method of sharing knowledge and advanced scientific inquiry. Pressures to publish for reasons other than pure discovery have the potential to corrupt this process. The core principles of scientific ethics outlined above provide guidance on how to maintain the integrity of our scientific process. We, as journal editors, are committed to the advancement of scientific knowledge and the ethical process of publication. We do the best we can to make sure that the articles we publish fulfill all the criteria of a well-conducted study. PMID- 26099117 TI - Management of dyslipidemia for cardiovascular disease risk reduction: synopsis of the 2014 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline. AB - DESCRIPTION: In December 2014, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline for the management of dyslipidemia for cardiovascular disease risk reduction in adults. This synopsis summarizes the major recommendations. METHODS: On 30 September 2013, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine's tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched and evaluated the literature, developed a simple 1-page algorithm, and rated each of 26 recommendations by using the Grading of Recommendations Assessment, Development, and Evaluation system. RECOMMENDATIONS: This synopsis summarizes key features of the guideline in 5 areas: elimination of treatment targets, additional tests for risk prediction, primary and secondary prevention, and laboratory testing. PMID- 26099118 TI - Strengthening Medical Device Postmarket Safety Surveillance. PMID- 26099121 TI - Hypobaric Decompression Sickness Treatment Model. AB - INTRODUCTION: The Hypobaric Decompression Sickness (DCS) Treatment Model links a decrease in computed bubble volume from increased pressure (DeltaP), increased oxygen (O2) partial pressure, and passage of time during treatment to the probability of symptom resolution [P(SR)]. The decrease in offending volume is realized in two stages: 1) during compression via Boyles law; and 2) during subsequent dissolution of the gas phase via the oxygen window. METHODS: We established an empirical model for the P(SR) while accounting for multiple symptoms within subjects. The data consisted of 154 cases of hypobaric DCS symptoms with ancillary information from tests on 56 men and 18 women. RESULTS: Our best estimated model is P(SR)=1/(1+exp(-(ln(DeltaP)-1.510+0.795*AMB 0.00308*Ts)/0.478)), where DeltaP is pressure difference (psid); AMB=1 if ambulation took place during part of the altitude exposure, otherwise AMB=0; and Ts is the elapsed time in minutes from the start of altitude exposure to recognition of a DCS symptom. DISCUSSION: Values of DeltaP as inputs to the model would be calculated from the Tissue Bubble Dynamics Model based on the effective treatment pressure: DeltaP=P2-P1|=P1*V1/V2-P1, where V1 is the computed volume of a bubble at low pressure P1 and V2 is computed volume after a change to a higher pressure P2. If 100% ground-level oxygen was breathed in place of air, then V2 continues to decrease through time at P2 at a faster rate. PMID- 26099122 TI - Preliminary Results of the LF/HF Ratio as an Indicator for Estimating Difficulty Level of Flight Tasks. AB - INTRODUCTION: The main aim of this study was to differentiate the magnitude of a pilot's heart rate variability (HRV) when performing assisted and unassisted flights, as well as simple and complex flight tasks. METHODS: Cardiac monitoring in flights was carried out using a compact, mobile ECG recorder. A frequency analysis of the heart rate (HR) signal was performed to determine the ratio of low-frequency spectral power (LF) to high-frequency spectral power (HF). RESULTS: The LF/HF ratio observed in the zone (M=1.047, SD=0.059) was significantly different than the LF/HF calculated preflight (M=0.877, SD=0.043) and postflight (M=0.793, SD=0.037). There was no main effect of the flight type (unassisted zone flight vs. zone flight with an instructor) on the LF/HF parameter. However, greater psychophysiological load of a pilot was observed in the training zone flights when compared to simple circle flights (main effect of the flight type). CONCLUSIONS: As the LF/HF ratio turned out to be significantly higher in the zone than pre- and postflight, this parameter can be useful for predicting the risk of excessive stress and arousal of pilots during flights. Based on the LF/HF ratio we can also estimate difficulty level of flight tasks, because our research has shown higher values of this parameter in the training zone flights than in simple circle flights. PMID- 26099123 TI - 5-Day Bed Rest: Portal and Lower Limb Veins With and Without Artificial Gravity Countermeasures. AB - PURPOSE: The objective of the study was to evaluate the effect of short-term, head-down bed rest (HDBR), with and without artificial gravity countermeasures, on splanchnic and lower limb vein properties. METHODS: Data were collected from 12 men before and after 5 d of continuous -6 degrees HDBR without countermeasures (CON) and with two artificial gravity countermeasure protocols: 30-min continuous centrifugation (AG1), and 30-min intermittent centrifugation (AG2). Portal (PV), tibial (TibV), and gastrocnemius (GastV) veins were investigated by echography supine and after 30 min of head-up tilt. RESULTS: After HDBR, there was no change in PV, TibV, or GastV cross-sectional area at rest in any of the three conditions. In response to tilt, GastV and TibV area increased (168+/-141% and 192+/-124%, respectively) with no change in this response post-HDBR in any of the experimental conditions (P>0.05). PV area decreased with tilt (-33+/-13%) and was not different pre- to post-HDBR in the CON or AG1 conditions. However, there was a greater reduction in PV area in the AG2 group post-HDBR (-32+/-10% pre, -49+/-9% post-HDBR, P=0.003). CONCLUSIONS: Calf veins were not significantly affected by 5 d of HDBR and did not appear to be negatively impacted by the artificial gravity countermeasures over this time period. In addition, the intermittent protocol resulted in better splanchnic vasoconstriction in response to head-up tilt, which may have contributed to a better maintenance of orthostatic tolerance post-HDBR. PMID- 26099124 TI - Pulmonary Artery Pressure Response to Simulated Air Travel in a Hypobaric Chamber. AB - BACKGROUND: Hypoxia-induced elevation in pulmonary artery pressure during air travel may contribute to the worldwide burden of in-flight medical emergencies. The pulmonary artery pressure response may be greater in older passengers, who are more likely to require flight diversion due to a medical event. Understanding these effects may ultimately improve the safety of air travel. METHODS: We studied 16 healthy volunteers, consisting of a younger group (aged <25 yr) and an older group (aged >60 yr). Using a hypobaric chamber, subjects undertook a 2-h simulated flight at the maximum cabin pressure altitude for commercial airline flights (8000 ft; 2438 m). Higher and lower altitudes within the aeromedical range were also explored. Systolic pulmonary artery pressure (sPAP) was assessed by Doppler echocardiography. RESULTS: There was a progressive increase in sPAP which appeared to be biphasic, with a small initial increase and a larger subsequent rise. Overall, sPAP increased by 5+/-1 mmHg from baseline to 35+/-1 mmHg at 8000 ft, an increase of 18%. The sPAP response to 8000 ft was greater in the older group than the younger group. CONCLUSIONS: This study confirms that pulmonary artery pressure increases during simulated air travel, and provides preliminary evidence that this response is greater in older people. Advancing age may increase in-flight susceptibility to adverse pulmonary vascular responses in passengers, aircrew, and aeromedical patients. PMID- 26099125 TI - Dose-Effect Relationship Between Mild Levels of Hypergravity and Autonomic Circulatory Regulation. AB - INTRODUCTION: The dose-effect relationships between different levels of hypergravity (>+1.0 Gz) and steady-state hemodynamic parameters have been reported in several studies. However, little has been reported on the dose-effect relationship between hypergravity levels and estimates of autonomic circulatory regulation, such as heart rate variability, arterial pressure variability, and spontaneous cardiac baroreflex sensitivity. We investigated dose-effect relationships between hypergravity levels from +1.0 Gz to +2.0 Gz (Delta0.5 Gz) and autonomic circulatory regulation to test our hypothesis that autonomic circulatory regulation has a linear relationship with hypergravity levels. METHODS: Using a short-arm human centrifuge, 10 healthy seated men were subjected to +1.0 Gz, +1.5 Gz, and +2.0 Gz hypergravity. We evaluated steady-state hemodynamic parameters and autonomic circulatory regulation indices. Heart rate variability, arterial pressure variability, and spontaneous cardiac baroreflex sensitivity between arterial pressure and R-R interval variabilities were assessed by spectral analysis, sequence analysis, and transfer function analysis. RESULTS: Steady-state heart rate, stroke volume, and sequence slope (indicating spontaneous cardiac baroreflex sensitivity in response to rapid changes in arterial pressure) showed linear correlations with increases in gravity (from +1.0 Gz to +2.0 Gz). On the other hand, steady-state cardiac output, steady-state systolic arterial pressure, and low-frequency power of diastolic arterial pressure (indicating peripheral vasomotor sympathetic activity) remained unchanged with gravity increases. CONCLUSION: Contrary to our hypothesis, the present study suggested that autonomic circulatory regulations show complex changes with hypergravity levels. Spontaneous cardiac baroreflex sensitivity reduces in a dose-dependent manner from +1.0 Gz to +2.0 Gz, whereas peripheral vasomotor sympathetic activity seems to be maintained. PMID- 26099126 TI - Low Back Pain in Microgravity and Bed Rest Studies. AB - BACKGROUND: The prevalence of low back pain (LBP) for astronauts in space (68%) is higher than the 1-mo prevalence for the general population on Earth (39%). It is unclear whether differences occur between healthy subjects and astronauts with a history of LBP. Knowledge of this issue is important to assess whether a history of LBP could have an operational impact. METHODS: We evaluated LBP prospectively during short duration spaceflight (15 d; N=20) and compared this with similar data collected during two bed rest studies (N=40). Astronauts completed a questionnaire 5-10 d preflight, during each flight day, and 5-10 d postflight. RESULTS: All astronauts with a history of LBP also developed LBP in flight. These astronauts reported a significantly longer duration of LBP and a different pain location. LBP was most often experienced in the central area of the lower back during spaceflight with an incidence of 70% and a mean pain level of 3 (on a scale of 0-10). Pain resolved within 10 d of flight. No neurological signs were present. The most frequently reported countermeasure was assuming a "knees to chest (fetal tuck) position" combined with stretching. Greater LBP intensity was reported in spaceflight than bed rest with a trend indicating a greater number of days of pain during spaceflight. DISCUSSION: The current study represents a prospective study of LBP in spaceflight. The results indicate that LBP is self-limiting in spaceflight and should not pose an operational risk. Prior LBP on Earth appears to be a risk factor for LBP in spaceflight. PMID- 26099127 TI - Team Composition Issues for Future Space Exploration: A Review and Directions for Future Research. AB - BACKGROUND: Future space exploration, such as a mission to Mars, will require space crews to live and work in extreme environments unlike those of previous space missions. Extreme conditions such as prolonged confinement, isolation, and expected communication time delays will require that crews have a higher level of interpersonal compatibility and be able to work autonomously, adapting to unforeseen challenges in order to ensure mission success. Team composition, or the configuration of member attributes, is an important consideration for maximizing crewmember well-being and team performance. METHODS: We conducted an extensive search to find articles about team composition in long-distance space exploration (LDSE)-analogue environments, including a search of databases, specific relevant journals, and by contacting authors who publish in the area. RESULTS: We review the team composition research conducted in analogue environments in terms of two paths through which team composition is likely to be related to LDSE mission success, namely by 1) affecting social integration, and 2) the team processes and emergent states related to team task completion. DISCUSSION: Suggestions for future research are summarized as: 1) the need to identify ways to foster unit-level social integration within diverse crews; 2) the missed opportunity to use team composition variables as a way to improve team processes, emergent states, and task completion; and 3) the importance of disentangling the effect of specific team composition variables to determine the traits (e.g., personality, values) that are associated with particular risks (e.g., subgrouping) to performance. PMID- 26099128 TI - Spaceflight-Induced Intracranial Hypertension. AB - INTRODUCTION: Although once a widely speculated about and largely theoretical topic, spaceflight-induced intracranial hypertension has gained acceptance as a distinct clinical phenomenon, yet the underlying physiological mechanisms are still poorly understood. In the past, many terms were used to describe the symptoms of malaise, nausea, vomiting, and vertigo, though longer duration spaceflights have increased the prevalence of overlapping symptoms of headache and visual disturbance. Spaceflight-induced visual pathology is thought to be a manifestation of increased intracranial pressure (ICP) because of its similar presentation to cases of known intracranial hypertension on Earth as well as the documentation of increased ICP by lumbar puncture in symptomatic astronauts upon return to gravity. The most likely mechanisms of spaceflight-induced increased ICP include a cephalad shift of body fluids, venous outflow obstruction, blood brain barrier breakdown, and disruption to CSF flow. The relative contribution of increased ICP to the symptoms experienced during spaceflight is currently unknown, though other factors recently posited to contribute include local effects on ocular structures, individual differences in metabolism, and the vasodilator effects of carbon dioxide. This review article attempts to consolidate the literature regarding spaceflight-induced intracranial hypertension and distinguish it from other pathologies with similar symptomatology. It discusses the proposed physiological causes and the pathological manifestations of increased ICP in the spaceflight environment and provides considerations for future long-term space travel. In the future, it will be critical to develop countermeasures so that astronauts can participate at their peak potential and return safely to Earth. PMID- 26099129 TI - Flight Bags as a Cause of Back Injuries Among Commercial Pilots. AB - BACKGROUND: Pilots of fixed wing commercial aircraft face numerous occupational hazards. Low back pain is among the most common and costly workplace injury, though relatively little is known about causes of back injuries among pilots. The awkward lifting and twisting maneuvers in the flight deck to position flight bags has not been described as a cause of occupational back injury among pilots. METHODS: A case series of low back injuries among pilots was identified and described by a retrospective review of charts at an airport-based clinic. Circumstances of occupational back injury, initial direct medical costs, treatment, and work status following evaluation were described. RESULTS: Over a 6 yr period, 37 occupational low back injuries among 35 pilots were evaluated and treated. Of these, 24 (65%) involved flight bags. Only 27% of pilots with flight bag-associated injuries were returned to work after initial evaluation; medications with sedating properties were frequently required for treatment. Injuries due to slips, trips, and falls, typically in jet bridges or associated with hotel shuttles, were common among pilots with back injuries not related to flight bags. CONCLUSIONS: The majority of occupational low back injuries seen among pilots in an airport based clinic were attributable to use of flight bags. Substituting electronic flight bags for traditional flight bags could contribute to back injury prevention among pilots. PMID- 26099130 TI - Fearless Temperament and Overconfidence in an Unsuccessful Special Forces Polar Expedition. AB - BACKGROUND: Assessment of the influence of personality and decision processes on the performance of two-person expedition teams has application for the composition of small teams for planetary exploration and potentially responding to off-nominal situations. CASE REPORT: We studied a two-man Special Forces team with a goal of reaching the North Pole in the shortest amount of time. Both subjects had high scores on measures of leadership/dominance, fearlessness, and achievement, and low scores on harm avoidance (high risk-taking). Differences were noted on scales measuring empathy, agreeableness, extraversion, emotional regulation, and callousness. Individual differences in the primacy of personal values of tradition vs. pleasure-seeking were evident. DISCUSSION: High dominance traits of both team members, incompatibility in other characteristics and values, and minimal pretraining had a significant impact on the decision to abort the trek because of severe frostbite suffered by one subject. Implications for dyads exploring the Mars surface are discussed. PMID- 26099131 TI - AsMA Medical Guidelines for Air Travel: Reported In-Flight Medical Events and Death. AB - INTRODUCTION: Medical Guidelines for Airline Travel provide information that enables healthcare providers to properly advise patients who plan to travel by air. Although there are no publicly available databases providing information on the number of in-flight medical emergencies, the few studies published in the literature indicate that they are uncommon. Minor illnesses such as near fainting, dizziness, and hyperventilation occur more frequently. However, serious illnesses, such as seizures and myocardial infarction, also occur. In-flight deaths are also rare. PMID- 26099132 TI - AsMA Medical Guidelines for Air Travel: In-Flight Medical Care. AB - INTRODUCTION: Medical Guidelines for Airline Travel provide information that enables healthcare providers to properly advise patients who plan to travel by air. All airlines are required to provide first aid training for cabin crew, and the crew are responsible for managing any in-flight medical events. There are also regulatory requirements for the carriage of first aid and medical kits. AsMA has developed recommendations for first aid kits, emergency medical kits, and universal precaution kits. PMID- 26099133 TI - You're the Flight Surgeon. Sore left wrist. PMID- 26099134 TI - You're the Flight Surgeon. Lower chest pain. PMID- 26099135 TI - Hermann von Schrotter (1870-1928): Inventor of the Sealed Cabin. PMID- 26099136 TI - This Month in Aerospace Medicine History. PMID- 26099139 TI - Dual-Energy X-Ray Absorptiometry for Measurement of Phalangeal Bone Mineral Density on a Slot-Scanning Digital Radiography System. AB - OBJECTIVE: In this paper, we assess the feasibility of using two detectors in a slot-scanning digital radiography system to acquire images for measuring bone mineral density (BMD) of the middle phalanx of the middle finger using dual energy X-ray absorptiometry (DXA). METHODS: Simulations were used to evaluate the spectral separation of the low- and high-energy spectra and detective quantum efficiency was used for assessing image quality. Scan parameters were chosen to optimize spectral separation, image quality, and radiation dose. We introduce the measurement of volumetric BMD (vBMD) using basis material decomposition. We assess the accuracy of our methods by comparing measurements taken using bone images against reference data derived from subsequent incineration of the bones. In vivo scans were conducted to evaluate the system precision (repeatability) and agreement with a clinical densitometer. RESULTS: Average errors for bone mineral content (BMC), areal BMD (aBMD), and vBMD were 4.85%, 5.49%, and 12.77%, respectively. Our system had good agreement with a clinical densitometer based on concordance correlation coefficient values of 0.92 and 0.98 for aBMD and BMC, respectively. Precision studies yielded coefficient of variation (CV) values of 1.35% for aBMD, 1.48% for BMC, and 1.80% for vBMD. The CV values of all measurements were within 2%, indicating that the methods have clinically acceptable precision. CONCLUSION: We conclude that our techniques yield bone measurements with high accuracy, clinically acceptable precision, and good agreement with a clinical densitometer. SIGNIFICANCE: We have shown the clinical potential of phalangeal DXA measurements of aBMD and vBMD on a slot-scanning digital radiography system. PMID- 26099138 TI - Prospective multicentre randomised, double-blind, equivalence study comparing clonidine and midazolam as intravenous sedative agents in critically ill children: the SLEEPS (Safety profiLe, Efficacy and Equivalence in Paediatric intensive care Sedation) study. AB - BACKGROUND: Children in paediatric intensive care units (PICUs) require analgesia and sedation but both undersedation and oversedation can be harmful. OBJECTIVE: Evaluation of intravenous (i.v.) clonidine as an alternative to i.v. midazolam. DESIGN: Multicentre, double-blind, randomised equivalence trial. SETTING: Ten UK PICUs. PARTICIPANTS: Children (30 days to 15 years inclusive) weighing <= 50 kg, expected to require ventilation on PICU for > 12 hours. INTERVENTIONS: Clonidine (3 ug/kg loading then 0-3 ug/kg/hour) versus midazolam (200 ug/kg loading then 0 200 ug/kg/hour). Maintenance infusion rates adjusted according to behavioural assessment (COMFORT score). Both groups also received morphine. MAIN OUTCOME MEASURES: Primary end point Adequate sedation defined by COMFORT score of 17-26 for >= 80% of the time with a +/- 0.15 margin of equivalence. Secondary end points Percentage of time spent adequately sedated, increase in sedation/analgesia, recovery after sedation, side effects and safety data. RESULTS: The study planned to recruit 1000 children. In total, 129 children were randomised, of whom 120 (93%) contributed data for the primary outcome. The proportion of children who were adequately sedated for >= 80% of the time was 21 of 61 (34.4%) - clonidine, and 18 of 59 (30.5%) - midazolam. The difference in proportions for clonidine-midazolam was 0.04 [95% confidence interval (CI) -0.13 to 0.21], and, with the 95% CI including values outside the range of equivalence (-0.15 to 0.15), equivalence was not demonstrated; however, the study was underpowered. Non-inferiority of clonidine to midazolam was established, with the only values outside the equivalence range favouring clonidine. Times to reach maximum sedation and analgesia were comparable hazard ratios: 0.99 (95% CI 0.53 to 1.82) and 1.18 (95% CI 0.49 to 2.86), respectively. Percentage time spent adequately sedated was similar [medians clonidine 73.8% vs. midazolam 72.8%: difference in medians 0.66 (95% CI -5.25 to 7.24)]. Treatment failure was 12 of 64 (18.8%) on clonidine and 7 of 61 (11.5%) on midazolam [risk ratio (RR) 1.63, 95% CI 0.69 to 3.88]. Proportions with withdrawal symptoms [28/60 (46.7%) vs. 30/58 (52.6%)] were similar (RR 0.89, 95% CI 0.62 to 1.28), but a greater proportion required clinical intervention in those receiving midazolam [11/60 (18.3%) vs. 16/58 (27.6%) (RR 0.66, 95% CI 0.34 to 1.31)]. Post treatment, one child on clonidine experienced mild rebound hypertension, not requiring intervention. A higher incidence of inotropic support during the first 12 hours was required for those on clonidine [clonidine 5/45 (11.1%) vs. midazolam 3/52 (5.8%)] (RR 1.93 95% CI 0.49 to 7.61). CONCLUSIONS: Clonidine is an alternative to midazolam. Our trial-based economic evaluation suggests that clonidine is likely to be a cost-effective sedative agent in the PICU in comparison with midazolam (probability of cost-effectiveness exceeds 50%). Rebound hypertension did not appear to be a significant problem with clonidine but, owing to its effects on heart rate, specific cardiovascular attention needs to be taken during the loading and early infusion phase. Neither drug in combination with morphine provided ideal sedation, suggesting that in unparalysed patients a third background agent is necessary. The disappointing recruitment rates reflect a reluctance of parents to provide consent when established on a sedation regimen, and reluctance of clinicians to allow sedation to be studied in unstable critically ill children. Future studies will require less exacting protocols allowing enhanced recruitment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02639863. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 71. See the NIHR Journals Library website for further project information. PMID- 26099140 TI - A Multimodal Image Reconstruction Method Using Ultrasonic Waves and Electrical Resistance Tomography. AB - In this paper, a new system that improves the image obtained by an array of ultrasonic sensors using electrical resistance tomography (ERT) is presented. One of its target applications can be in automatic exploration of soft tissues, where different organs and eventual anomalies exhibit simultaneously different electrical conductivities and different acoustic impedances. The exclusive usage of the ERT technique usually leads to some significant uncertainties around the regions' boundaries and usually generates images with relatively low resolutions. The proposed method shows that by properly combining this technique with an ultrasonic-based method, which can provide good localization of some edge points, the accuracy of the shape of individual cells can be improved, if these edge points are used as constraints during the inversion procedure. The performance of the proposed reconstruction method was assessed by conducting extensive tests on some simulated phantoms which mimic soft tissues. The obtained results clearly show the outperformance of this method over single modalities techniques that use either ultrasound or ERT imaging. PMID- 26099141 TI - A Fast Single Image Haze Removal Algorithm Using Color Attenuation Prior. AB - Single image haze removal has been a challenging problem due to its ill-posed nature. In this paper, we propose a simple but powerful color attenuation prior for haze removal from a single input hazy image. By creating a linear model for modeling the scene depth of the hazy image under this novel prior and learning the parameters of the model with a supervised learning method, the depth information can be well recovered. With the depth map of the hazy image, we can easily estimate the transmission and restore the scene radiance via the atmospheric scattering model, and thus effectively remove the haze from a single image. Experimental results show that the proposed approach outperforms state-of the-art haze removal algorithms in terms of both efficiency and the dehazing effect. PMID- 26099142 TI - Non-Rigid Object Contour Tracking via a Novel Supervised Level Set Model. AB - We present a novel approach to non-rigid objects contour tracking in this paper based on a supervised level set model (SLSM). In contrast to most existing trackers that use bounding box to specify the tracked target, the proposed method extracts the accurate contours of the target as tracking output, which achieves better description of the non-rigid objects while reduces background pollution to the target model. Moreover, conventional level set models only emphasize the regional intensity consistency and consider no priors. Differently, the curve evolution of the proposed SLSM is object-oriented and supervised by the specific knowledge of the targets we want to track. Therefore, the SLSM can ensure a more accurate convergence to the exact targets in tracking applications. In particular, we firstly construct the appearance model for the target in an online boosting manner due to its strong discriminative power between the object and the background. Then, the learnt target model is incorporated to model the probabilities of the level set contour by a Bayesian manner, leading the curve converge to the candidate region with maximum likelihood of being the target. Finally, the accurate target region qualifies the samples fed to the boosting procedure as well as the target model prepared for the next time step. We firstly describe the proposed mechanism of two-phase SLSM for single target tracking, then give its generalized multi-phase version for dealing with multi-target tracking cases. Positive decrease rate is used to adjust the learning pace over time, enabling tracking to continue under partial and total occlusion. Experimental results on a number of challenging sequences validate the effectiveness of the proposed method. PMID- 26099143 TI - Detecting Curvilinear Features Using Structure Tensors. AB - Few published articles on curvilinear structures exist compared with works on detecting lines or corners with high accuracy. In medical ultrasound imaging, the structures that need to be detected appear as a collection of microstructures correlated along a path. In this paper, we investigated techniques that extract meaningful low-level information for curvilinear structures, using techniques based on structure tensor. We proposed a novel structure tensor enhancement inspired by bilateral filtering. We compared the proposed approach with five state-of-the-art curvilinear structure detectors. We tested the algorithms against simulated images with known ground truth and real images from three different domains (medical ultrasound, scanning electron microscope, and astronomy). For the real images, we employed experts to delineate the ground truth for each domain. Techniques borrowed from machine learning robustly assessed the performance of the methods (area under curve and cross validation). As a practical application, we used the proposed method to label a set of 5000 ultrasound images. We conclude that the proposed tensor-based approach outperforms the state-of-the-art methods in providing magnitude and orientation information for curvilinear structures. The evaluation methodology ensures that the employed feature-detection method will yield reproducible performance on new, unseen images. We published all the implemented methods as open-source software. PMID- 26099144 TI - Local Sparse Structure Denoising for Low-Light-Level Image. AB - Sparse and redundant representations perform well in image denoising. However, sparsity-based methods fail to denoise low-light-level (LLL) images because of heavy and complex noise. They consider sparsity on image patches independently and tend to lose the texture structures. To suppress noises and maintain textures simultaneously, it is necessary to embed noise invariant features into the sparse decomposition process. We, therefore, used a local structure preserving sparse coding (LSPSc) formulation to explore the local sparse structures (both the sparsity and local structure) in image. It was found that, with the introduction of spatial local structure constraint into the general sparse coding algorithm, LSPSc could improve the robustness of sparse representation for patches in serious noise. We further used a kernel LSPSc (K-LSPSc) formulation, which extends LSPSc into the kernel space to weaken the influence of linear structure constraint in nonlinear data. Based on the robust LSPSc and K-LSPSc algorithms, we constructed a local sparse structure denoising (LSSD) model for LLL images, which was demonstrated to give high performance in the natural LLL images denoising, indicating that both the LSPSc- and K-LSPSc-based LSSD models have the stable property of noise inhibition and texture details preservation. PMID- 26099145 TI - Depth Map Coding Optimization Using Rendered View Distortion for 3D Video Coding. AB - In order to improve 3D video coding efficiency, we propose methods to estimate rendered view distortion in synthesized views as a function of the depth map quantization error. Our approach starts by calculating the geometric error caused by the depth map error based on the camera parameters. Then, we estimate the rendered view distortion based on the local video characteristics. The estimated rendered view distortion is used in the rate-distortion optimized mode selection for depth map coding. A Lagrange multiplier is derived using the proposed distortion metric, which is estimated based on an autoregressive model. Experimental results show the efficiency of the proposed methods, with average savings of 43% in depth map bitrate as compared with encoding the depth maps using the same coding tools but with the rate-distortion optimization based on the conventional distortion metric. PMID- 26099146 TI - Motion Estimation for Dynamic Texture Videos Based on Locally and Globally Varying Models. AB - Motion estimation, i.e., optical flow, of fluid-like and dynamic texture (DT) images/videos is an important challenge, particularly for understanding outdoor scene changes created by objects and/or natural phenomena. Most optical flow models use smoothness-based constraints using terms such as fluidity from the fluid dynamics framework, with constraints typically being incompressibility and low Reynolds numbers (Re ). Such constraints are assumed to impede the clear capture of locally abrupt image intensity and motion changes, i.e., discontinuities and/or high Re over time. This paper exploits novel physics-based optical flow models/constraints for both smooth and discontinuous changes using a wave generation theory that imposes no constraint on Re or compressibility of an image sequence. Iterated two-step optimization between local and global optimization is also used: first, an objective function with varying multiple sine/cosine bases with new local image properties, i.e., orientation and frequency, and with a novel transformed dispersion relationship equation are used. Second, the statistical property of image features is used to globally optimize model parameters. Experiments on synthetic and real DT image sequences with smooth and discontinuous motions demonstrate that the proposed locally and globally varying models outperform the previous optical flow models. PMID- 26099147 TI - Image Restoration Using Gaussian Mixture Models With Spatially Constrained Patch Clustering. AB - In this paper, we address the problem of recovering degraded images using multivariate Gaussian mixture model (GMM) as a prior. The GMM framework in our method for image restoration is based on the assumption that the accumulation of similar patches in a neighborhood are derived from a multivariate Gaussian probability distribution with a specific covariance and mean. Previous methods of image restoration with GMM have not considered spatial (geometric) distance between patches in clustering. Our conducted experiments show that in the case of constraining Gaussian estimates into a finite-sized windows, the patch clusters are more likely to be derived from the estimated multivariate Gaussian distributions, i.e., the proposed statistical patch-based model provides a better goodness-of-fit to statistical properties of natural images. A novel approach for computing aggregation weights for image reconstruction from recovered patches is introduced which is based on similarity degree of each patch to the estimated Gaussian clusters. The results admit that in the case of image denoising, our method is highly comparable with the state-of-the-art methods, and our image interpolation method outperforms previous state-of-the-art methods. PMID- 26099148 TI - Extraction and Classification of Multichannel Electromyographic Activation Trajectories for Hand Movement Recognition. AB - This paper proposes a system for hand movement recognition using multichannel electromyographic (EMG) signals obtained from the forearm surface. This system can be used to control prostheses or to provide inputs for a wide range of human computer interface systems. In this work, the hand movement recognition problem is formulated as a multi-class distance based classification of multi-dimensional sequences. More specifically, the extraction of multi-channel EMG activation trajectories underlying hand movements, and classifying the extracted trajectories using a metric based on multi-dimensional dynamic time warping are investigated. The developed methods are evaluated using the publicly available NINAPro database comprised of 40 different hand movements performed by 40 subjects. The average movement error rate obtained across the 40 subjects is 0.09+/-0.047. The low error rate demonstrates the efficacy of the proposed trajectory extraction method and the discriminability of the utilized distance metric. PMID- 26099149 TI - Comparison Analysis: Granger Causality and New Causality and Their Applications to Motor Imagery. AB - In this paper we first point out a fatal drawback that the widely used Granger causality (GC) needs to estimate the autoregressive model, which is equivalent to taking a series of backward recursive operations which are infeasible in many irreversible chemical reaction models. Thus, new causality (NC) proposed by Hu et al. (2011) is theoretically shown to be more sensitive to reveal true causality than GC. We then apply GC and NC to motor imagery (MI) which is an important mental process in cognitive neuroscience and psychology and has received growing attention for a long time. We study causality flow during MI using scalp electroencephalograms from nine subjects in Brain-computer interface competition IV held in 2008. We are interested in three regions: Cz (central area of the cerebral cortex), C3 (left area of the cerebral cortex), and C4 (right area of the cerebral cortex) which are considered to be optimal locations for recognizing MI states in the literature. Our results show that: 1) there is strong directional connectivity from Cz to C3/C4 during left- and right-hand MIs based on GC and NC; 2) during left-hand MI, there is directional connectivity from C4 to C3 based on GC and NC; 3) during right-hand MI, there is strong directional connectivity from C3 to C4 which is much clearly revealed by NC than by GC, i.e., NC largely improves the classification rate; and 4) NC is demonstrated to be much more sensitive to reveal causal influence between different brain regions than GC. PMID- 26099150 TI - A Global Covariance Descriptor for Nuclear Atypia Scoring in Breast Histopathology Images. AB - Nuclear atypia scoring is a diagnostic measure commonly used to assess tumor grade of various cancers, including breast cancer. It provides a quantitative measure of deviation in visual appearance of cell nuclei from those in normal epithelial cells. In this paper, we present a novel image-level descriptor for nuclear atypia scoring in breast cancer histopathology images. The method is based on the region covariance descriptor that has recently become a popular method in various computer vision applications. The descriptor in its original form is not suitable for classification of histopathology images as cancerous histopathology images tend to possess diversely heterogeneous regions in a single field of view. Our proposed image-level descriptor, which we term as the geodesic mean of region covariance descriptors, possesses all the attractive properties of covariance descriptors lending itself to tractable geodesic-distance-based k nearest neighbor classification using efficient kernels. The experimental results suggest that the proposed image descriptor yields high classification accuracy compared to a variety of widely used image-level descriptors. PMID- 26099151 TI - Adaptive Neural Control of MIMO Nonstrict-Feedback Nonlinear Systems With Time Delay. AB - In this paper, an adaptive neural output-feedback tracking controller is designed for a class of multiple-input and multiple-output nonstrict-feedback nonlinear systems with time delay. The system coefficient and uncertain functions of our considered systems are both unknown. By employing neural networks to approximate the unknown function entries, and constructing a new input-driven filter, a backstepping design method of tracking controller is developed for the systems under consideration. The proposed controller can guarantee that all the signals in the closed-loop systems are ultimately bounded, and the time-varying target signal can be tracked within a small error as well. The main contributions of this paper lie in that the systems under consideration are more general, and an effective design procedure of output-feedback controller is developed for the considered systems, which is more applicable in practice. Simulation results demonstrate the efficiency of the proposed algorithm. PMID- 26099152 TI - Editor's Foreword. PMID- 26099153 TI - Development of a Faith-Based Mental Health Literacy Program to Improve Treatment Engagement Among Caribbean Latinos in the Northeastern United States of America. AB - Depression is one of the leading causes of years lived with disability (YLDs) worldwide. Although depression can be successfully treated, 75% of Americans do not receive care. Treatment rates among Latinos immigrants are significantly lower than non-immigrant Latinos and non-Hispanic Whites. Known factors for mental health-care disparities such as poverty, insurance coverage, language barriers, and access to specialty mental health services in Latino neighborhoods do not fully explain the differences in treatment rates. Significant, but poorly understood factors influencing depression treatment among Latinos in the United States are lack of culturally congruent care, low mental health literacy, and stigma. Even though churches are a major source of health information, social and spiritual support for Latinos, the conceptualization of culturally congruent care rarely addresses religious beliefs. Therefore, one strategy to reduce disparities in depression treatment is to partner with churches to address faith-based stigma. Community-based participatory research is recognized as a methodology particularly well suited for creating successful culturally targeted interventions. The purpose of this article is to describe the process of creating a faith-based mental health literacy intervention in the Caribbean Latino community using the principles of community-based participatory research. PMID- 26099154 TI - The Influence of Cultural Factors on HIV/AIDS Education in Ivorian Schools. AB - This qualitative study focuses on culturally embedded beliefs about the teaching and learning of HIV/AIDS topics in the Ivory Coast. We aim to analyze and describe factors influencing the implementation of the HIV/AIDS curricula in Ivorian sixth-grade classrooms. With continuous spreading of AIDS in the Ivory Coast, education about HIV/AIDS has to increase; therefore, an urgent need to document, evaluate, and disseminate Ivorian perspectives on what is understood as valuable HIV/AIDS knowledge to prioritize such content in the curriculum is needed. Multiple qualitative methods were collected: individual interviews with 39 teachers, 63 sixth-grade students, eight school administrators, 20 community elders as well as field notes, and document analysis. By promoting HIV/AIDS curricula that is responsive to and inclusive of youth cultural beliefs and aligning teaching practice to Ivorian youth cultural interests, there is a chance that HIV/AIDS education could lead to safer sexual behaviors among Ivorian youth. PMID- 26099155 TI - Health Beliefs About Tobacco With Betel Nut Use Among Adults in Yap, Micronesia. AB - Tobacco use is high among Pacific Islanders in general and little tobacco research has been done in Yap, Micronesia. This study aimed to explore perceptions of tobacco use coupled with chewing of betel (areca) nut among adults in Yap using self-administered questionnaires based on the health belief model. A Likert scale (ranging from strongly disagree to strongly agree or very unlikely to very likely) was used to measure susceptibility, severity, benefits, barriers, cues to action, and self-efficacy among individuals aged 18 and older. Older adults felt quitting tobacco or betel nut use would be significantly more difficult because of social reasons and withdrawal problems. Most participants felt susceptible to tobacco-related diseases. These findings possibly indicate a receptive attitude toward any future tobacco use prevention and intervention program. Older Yapese population would need to be especially targeted. Health promotion programs should target smoking behaviors and risk reduction. PMID- 26099156 TI - Influence of Exposure to Sexually Explicit Films on the Sexual Behavior of Secondary School Students in Ibadan, Nigeria. AB - Young people in secondary schools who are prone to engage in risky sexual behaviors spend considerable time watching Television (TV) which often presents sex scenes. The influence of exposure to sex scenes on TV (SSTV) has been little researched in Nigeria. This study was therefore designed to determine the perceived influence of exposure to SSTV on the sexual behavior of secondary school students in Ibadan North Local Government Area. A total of 489 randomly selected students were surveyed. Mean age of respondents was 14.1 +/- 1.9 years and 53.8% were females. About 91% had ever been exposed to sex scenes. The type of TV program from which most respondents reported exposure to sexual scenes was movies (86.9%). Majority reported exposure to all forms of SSTV from secondary storage devices. Students whose TV watching behavior was not monitored had heavier exposures to SSTV compared with those who were. About 56.3% of females and 26.5% of males affirmed that watching SSTV had affected their sexual behavior. Predictor of sex-related activities was exposure to heavy sex scenes. Peer education and school-based programs should include topics to teach young people on how to evaluate presentations of TV programs. PMID- 26099158 TI - Segment Kinematics Differ Between Jump and Drop Landings Regardless of Practice. AB - Joint kinematics differ between jump and drop landings and there is evidence that segment kinematics may also be different. The purpose of this research was to compare lower extremity segment kinematics for jump and drop landings, and to examine if multiple days of practice would influence these kinematics. Men (n = 9) and women (n = 15) performed 4 sessions of jump and drop landings (40 cm and 60 cm) in a motion-capture laboratory. Segment kinematics at initial contact, foot flat, and peak knee flexion were compared between landing types and across visits. At initial contact, foot plantar flexion was greater in jump versus drop landings (P < .05). At initial contact and foot flat, forward leg inclination and pelvis flexion were greater in jump landing (P < .05), while thigh flexion was greater in drop landings (P > .05). The differences in leg and thigh angles at initial contact and foot flat altered lower extremity posture. These results are in contrast to a previous study; this suggests that drop landing can be modified to have the same mechanics as jump landing. As practice did not influence drop landing mechanics (P > .05), specific control strategies and instructions need to be identified. PMID- 26099159 TI - Three-Dimensional Rotations of the Scapula During Arm Abduction: Evaluation of the Acromion Marker Cluster Method in Comparison With a Model-Based Approach Using Biplanar Radiograph Images. AB - Noninvasive methods enabling measurement of shoulder bone positions are paramount in clinical and ergonomics applications. In this study, the acromion marker cluster (AMC) method is assessed in comparison with a model-based approach allowing scapula tracking from low-dose biplanar radiograph images. Six healthy male subjects participated in this study. Data acquisition was performed for 6 arm abduction positions (0 degrees , 45 degrees , 90 degrees , 120 degrees , 150 degrees , 180 degrees ). Scapula rotations were calculated using the coordinate systems and angle sequence was defined by the ISB. The comparison analysis was based on root mean square error (RMSE) calculation and nonparametric statistical tests. RMSE remained under 8 degrees for 0 degrees to 90 degrees arm abduction and under 13.5 degrees for 0 degrees to 180 degrees abduction; no significant differences were found between the 2 methods. Compared with previous works, an improved accuracy of the AMC approach at high arm abduction positions was obtained. This could be explained by the different sources of data used as the "gold standard." PMID- 26099160 TI - The Contribution of Trunk Axial Kinematics to Poststrike Ball Velocity During Maximal Instep Soccer Kicking. AB - To date, biomechanical analyses of soccer kicking have focused predominantly on lower-extremity motions, with little emphasis on the trunk and upper body. The purpose of this study was to evaluate differences in trunk axial kinematics between novice (n = 10) and skilled (n = 10) participants, as well as to establish the relationship of trunk axial motion and sagittal plane thigh rotation to poststrike ball velocity. Three-dimensional body segmental motion data were captured using high-resolution motion analysis (120 Hz) while each participant completed 5 maximal instep soccer-style kicks. The results demonstrate that skilled participants use 53% greater axial trunk range of motion compared with novice participants (P < .01), as well as 62% greater peak trunk rotation velocity (P < .01). The results also show a moderate, positive correlation of peak trunk rotation velocity with poststrike ball velocity (r = .57; P < .01), and peak hip flexion velocity with poststrike ball velocity (r = .63; P < .01). The current study highlights the potential for trunk rotation specific training to improve maximum instep kick velocity in developing soccer athletes. PMID- 26099161 TI - The Effect of Work Boots on Knee Mechanics and the Center of Pressure at the Knee During Static Kneeling. AB - Occupational kneeling is associated with an increased risk for the development of knee osteoarthritis. Previous work studying occupational kneeling has neglected to account for the fact that in many industrial settings, workers are required to wear steel-toe work boots. Thus, the purpose of this study was to evaluate the effect of work boot wear on the center of pressure location of the ground reaction force, knee joint angle, and magnitude of the ground reaction force in a kneeling posture. Fifteen healthy males were fit with 3D motion capture markers and knelt statically over a force plate embedded in the floor. Using the tibial tuberosity as the point of reference, the center of pressure in shod condition was shifted significantly medially (on average 0.009 m [P = .005]) compared with the barefoot condition. The knee was significantly less internally rotated (shod: -12.5 degrees vs. barefoot: -17.4 degrees [P = .009]) and the anterior/posterior shear force was significantly greater in the shod condition (shod: 6.0% body weight vs. barefoot: 1.5% body weight [P = .002]). Therefore, wearing work boots alters the kneeling posture compared with barefoot kneeling, potentially loading different surfaces of the knee, as well as altering knee joint moments. PMID- 26099162 TI - Evaluation of Tai Chi Program Effectiveness for People with Arthritis in the Community: A Randomized Controlled Trial. AB - OBJECTIVE: Evaluate effectiveness of the Arthritis Foundation Tai Chi Program for community participants with arthritis. METHODS: 343 individuals were randomized to either the intervention or wait-list control group. Performance and self reported outcome (SRO) measures were assessed at baseline and eight weeks. At one year, SROs only were assessed. Adjusted means were determined using regression models adjusting for covariates, and effect sizes (ES) were calculated. RESULTS: Average participant age was 66 years, 87% were female, and 87% were Caucasian. Among 284 (83%) participants who returned at eight weeks, balance by reach (ES = 0.30) and helplessness, sleep, and role participation satisfaction (ES = 0.24 0.54) improved significantly; pain, fatigue, and stiffness improvement (ES = 0.15 0.23) approached significance. No change was noted in mobility, lower extremity strength, or single-leg stance balance. At one year, improvements in pain, fatigue, stiffness, helplessness, and role participation satisfaction at eight weeks were maintained; 30% continued tai chi practice. CONCLUSION: Moderate effectiveness of the Arthritis Foundation Tai Chi Program was confirmed. PMID- 26099164 TI - Adverse psychological outcomes following colposcopy and related procedures: a systematic review. AB - BACKGROUND: Although colposcopy is the leading follow-up option for women with abnormal cervical cytology, little is known about its psychological consequences. OBJECTIVES: We performed a systematic review to examine: (1) what, if any, are the adverse psychological outcomes following colposcopy and related procedures; (2) what are the predictors of adverse psychological outcomes post-colposcopy; and (3) what happens to these outcomes over time. SEARCH STRATEGY: Five electronic databases (PubMed, PsychINFO, CINAHL, Web of Science, Scopus) were searched for studies published in English between January 1986 and February 2014. SELECTION CRITERIA: Eligible studies assessed psychological wellbeing at one or more time-points post-colposcopy. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened titles and abstracts. Full texts of potentially eligible papers were reviewed. Data were abstracted from, and a quality appraisal performed of, eligible papers. MAIN RESULTS: Twenty-three papers reporting 16 studies were eligible. Colposcopy and related procedures can lead to adverse psychological outcomes, particularly anxiety. Ten studies investigated predictors of adverse psychological outcomes; management type and treatment had no impact on this. Seven studies investigated temporal trends in psychological outcomes post colposcopy; findings were mixed, especially in relation to anxiety and distress. Studies were methodologically heterogeneous. CONCLUSIONS: Follow-up investigations and procedures for abnormal cervical cytology can cause adverse psychological outcomes among women. However, little is known about the predictors of these outcomes or how long they persist. There is a need for a more standardised approach to the examination of the psychological impact of colposcopy, especially longer-term outcomes. TWEETABLE ABSTRACT: Follow-up investigations for abnormal cervical cytology can cause adverse psychological outcome among women. PMID- 26099165 TI - A computational method for clinically relevant cancer stratification and driver mutation module discovery using personal genomics profiles. AB - BACKGROUND: Personalized genomics instability, e.g., somatic mutations, is believed to contribute to the heterogeneous drug responses in patient cohorts. However, it is difficult to discover personalized driver mutations that are predictive of drug sensitivity owing to diverse and complex mutations of individual patients. To circumvent this problem, a novel computational method is presented to discover potential drug sensitivity relevant cancer subtypes and identify driver mutation modules of individual subtypes by coupling differentially expressed genes (DEGs) based subtyping analysis with the driver mutation network analysis. RESULTS: The proposed method was applied to breast cancer and lung cancer samples available from The Cancer Genome Atlas (TCGA). Cancer subtypes were uncovered with significantly different survival rates, and more interestingly, distinct driver mutation modules were also discovered among different subtypes, indicating the potential mechanism of heterogeneous drug sensitivity. CONCLUSIONS: The research findings can be used to help guide the repurposing of known drugs and their combinations in order to target these dysfunctional modules and their downstream signaling effectively for achieving personalized or precision medicine treatment. PMID- 26099166 TI - Research Review: Use of EEG biomarkers in child psychiatry research - current state and future directions. AB - BACKGROUND: Electroencephalography (EEG) and related measures have a long and productive history in child psychopathology research and are currently experiencing a renaissance in interest, particularly for use as putative biomarkers. METHOD AND SCOPE: First, the recent history leading to the use of EEG measures as endophenotypes and biomarkers for disease and treatment response are reviewed. Two key controversies within the area of noninvasive human electrophysiology research are discussed, and problems that currently either function as barriers or provide gateways to progress. First, the differences between the main types of EEG measurements (event-related potentials, quantitative EEG, and time-frequency measures) and how they can contribute collectively to better understanding of cortical dynamics underlying cognition and behavior are highlighted. Second, we focus on the ongoing shift in analytic focus to specific cortical sources and source networks whose dynamics are relevant to the clinical and experimental focus of the study, and the effective increase in source signal-to-noise ratio (SNR) that may be obtained in the process. CONCLUSIONS: Understanding of these issues informs any discussion of current trends in EEG research. We highlight possible ways to evolve our understanding of brain dynamics beyond the apparent contradictions in understanding and modeling EEG activity highlighted by these controversies. Finally, we summarize some promising future directions of EEG biomarker research in child psychopathology. PMID- 26099167 TI - Inactivation of pathogenic bacteria inoculated onto a BactoTM agar model surface using TiO2-UVC photocatalysis, UVC and chlorine treatments. AB - AIMS: The aim of this study was to study inactivation of different pathogenic bacteria on agar model surface using TiO2-UV photocatalysis (TUVP). METHODS AND RESULTS: A unified food surface model was simulated using Bacto(TM) agar, a routinely used microbial medium. The foodborne pathogenic bacteria Escherichia coli K12 (as a surrogate for E. coli O157:H7), Salmonella Typhimurium, Staphylococcus aureus and Listeria monocytogenes were inoculated onto the agar surface, followed by investigation of TUVP-assisted inactivation and morphological changes in bacterial cells. The TUVP process showed higher bacterial inactivation, particularly for Gram-negative bacteria, than UVC alone and a control (dark reaction). A TUVP treatment of 17.2 mW cm(-2) (30% lower than the UVC light intensity) reduced the microbial load on the agar surface by 4.5 6.0 log CFU cm(-2). UVC treatment of 23.7 mW cm(-2) caused 3.0-5.3 log CFU cm(-2) reduction. CONCLUSIONS: The use of agar model surface is effective for investigation of bacterial disinfection and TUVP is a promising nonthermal technique. SIGNIFICANCE AND IMPACT OF THE STUDY: The results showing effects of photocatalysis and other treatments for inactivation of bacterial pathogens on model surface can be useful for applying such processes for disinfection of fruit, vegetables and other similar surfaces. PMID- 26099168 TI - MicroRNAs as promising novel biomarkers and potential drug targets for inflammatory neurological diseases. PMID- 26099169 TI - CLIPPERS: Long term management? PMID- 26099171 TI - Regulation of BAX/BCL2 gene expression in breast cancer cells by docetaxel-loaded human serum albumin nanoparticles. AB - Today, using nanoparticle-based drug delivery systems has expanded to avoid anticancer side effects. Taxanes are important chemotherapeutic agents in the treatment of metastatic breast cancer. In this study, docetaxel (DTX)-loaded human serum albumin (HSA) nanoparticles (NPs) were prepared and characterized. Drug toxicity of the nanoparticles was measured by MTT assay with different drug concentrations (0.01, 0.1, 0.5, 1 and 5 MUM) at different incubation times (24, 48 and 72 h). Expression of BAX/BCL2 mRNA levels was determined by real-time PCR. The size of NPs prepared and used in our study was about 147 nm with surface charge of -29.6 mV. Results obtained from MTT assay showed that 0.5 MUM of free drug had 50 % toxicity on MCF-7 cells after 48-h incubation. Real-time PCR results showed an increase in expression of BAX and no change for BCL2. In conclusion, a significant overexpression of BAX gene and changes in BAX/BCL2 ratio were observed for DTX-loaded HSA nanoparticles compared with free DTX and may provide a potential therapy to inhibit anticancer drug resistance. PMID- 26099170 TI - GM1 ganglioside in Parkinson's disease: Pilot study of effects on dopamine transporter binding. AB - OBJECTIVE: GM1 ganglioside has been suggested as a treatment for Parkinson's disease (PD), potentially having symptomatic and disease modifying effects. The current pilot imaging study was performed to examine effects of GM1 on dopamine transporter binding, as a surrogate measure of disease progression, studied longitudinally. METHODS: Positron emission tomography (PET) imaging data were obtained from a subset of subjects enrolled in a delayed start clinical trial of GM1 in PD [1]: 15 Early-start (ES) subjects, 14 Delayed-start (DS) subjects, and 11 Comparison (standard-of-care) subjects. Treatment subjects were studied over a 2.5 year period while Comparison subjects were studied over 2 years. Dynamic PET scans were performed over 90 min following injection of [(11)C]methylphenidate. Regional values of binding potential (BPND) were analyzed for several striatal volumes of interest. RESULTS: Clinical results for this subset of subjects were similar to those previously reported for the larger study group. ES subjects showed early symptomatic improvement and slow symptom progression over the study period. DS and Comparison subjects were initially on the same symptom progression trajectory but diverged once DS subjects received GM1 treatment. Imaging results showed significant slowing of BPND loss in several striatal regions in GM1 treated subjects and in some cases, an increased BPND in some striatal regions was detected after GM1 use. INTERPRETATION: Results of this pilot imaging study provide additional data to suggest a potential disease modifying effect of GM1 on PD. These results need to be confirmed in a larger number of subjects. PMID- 26099172 TI - The crucial role of SRPK1 in TGF-beta-induced proliferation and apoptosis in the esophageal squamous cell carcinomas. AB - In recent years, transforming growth factor-beta (TGF-beta) and the serine arginine protein kinase 1 (SRPK1) have been recommended as a key signal mediator that is involved in oncogenesis. However, the mechanisms underlying TGF-beta SRPK1 pathway-mediated proliferation and apoptosis in the esophageal squamous cell carcinomas (ESCC) have not been well featured till now. We used immunohistochemistry, immunoblotting, and RT-PCR to assess the expression of SRPK1 in 120 cases of ESCC samples and cell lines. Subsequently, some in vitro assays were also applied where cells were administrated with TGF-beta. We found that SRPK1 was highly expressed in ESCC tissues and acts as an independent prognostic factor for ESCC patients. In vitro studies indicated that overexpression of wild-type SRPK1 promoted ESCC cell proliferation, while overexpression of the kinase-dead mutant of SRPK1 or RNA interference against SRPK1 suppressed cell growth and enhanced apoptosis. The knockdown of SRPK1 also inhibited subcutaneous xenografts' growth of ESCC cells in nude mice. Furthermore, Western bolt analysis showed SRPK1 can activate Akt phosphorylation and inhibit JNK phosphorylation. In conclusion, SRPK1 mediates TGF-beta-induced proliferation and apoptosis by regulating AKT and JNK in ESCC, which indicates TGF-beta-SRPK1 pathway may be suggested as a useful target to affect the progression of ESCC. PMID- 26099173 TI - Clinical implications of epithelial cell plasticity in cancer progression. AB - In the last few years, the role of epithelial cell plasticity in cancer biology research has gained increasing attention. This concept refers to the ability of the epithelial cells to dynamically switch between different phenotypic cellular states. This programme is particularly relevant during the epithelial-to mesenchymal transition (EMT) in cancer progression. During colonization, epithelial cells first activate the EMT programme to disseminate from a primary tumour to reach a distant tissue site. During this process, cells are transported into the circulation and are able to escape the immune system of the host. Then, a reverse process called mesenchymal-to-epithelial transition (MET) occurs on cells that settle in the distant organs. Although epithelial cell plasticity has an important impact on tumour biology, the clinical relevance of this concept remains to be recapitulated. In this review, we will update the current state of epithelial cell plasticity in cancer progression and its clinical implications for the design of therapeutic strategies, the acquisition of multidrug resistance, and future perspectives for the management of cancer patients. PMID- 26099174 TI - Staged Biventricular Repair-Oriented Strategy in Borderline Biventricular Repair Candidates with Ventricular Septal Defect. AB - Although borderline biventricular repair (BVR) candidates unsuitable for primary BVR are often subjected to single-ventricle repair (SVR), some of them reach BVR by staged strategy. We evaluated our staged BVR-oriented strategy in borderline BVR candidates with ventricular septal defect (VSD) in whom a BVR/SVR decision was deferred beyond the neonatal period. Forty-two patients were treated with the approach between 1991 and 2012. They had been followed toward BVR until it was judged impossible. Outcomes, time course toward definitive repair (DR: BVR, SVR, or 1 + 1/2 ventricle repair), and hemodynamics were reviewed. A total of 57 palliative surgeries were performed before BVR or bidirectional Glenn (BDG), namely procedures to control pulmonary blood flow in 40, to improve mixing in 5, and to promote left ventricle (LV) growth in 5. LV growth was achieved in four patients. There were three cardiac deaths. Except for four awaiting patients, 19 reached BVR (50 %), 11 patients were converted to other than BVR, and 28 patients achieved DR (74 %) at the median age of 30.9 months. Cardiac cath before BVR or BDG performed at the median age of 22.5 months revealed well-preserved pulmonary vasculature with the median pulmonary artery pressure of 14 mmHg, except three patients unsuitable for SVR. In conclusion, our staged BVR-oriented strategy required longer time course and more complex palliative surgeries compared with a simple SVR strategy. Leaving open the possibility of a late crossover to an SVR pathway is mandatory when adopting staged BVR-oriented strategy in these complex patients. PMID- 26099176 TI - Subjective well-being and hookah use among adults in the United States: A nationally-representative sample. AB - BACKGROUND: Using a nationally-representative dataset of adults 18-30 years old in the United States, this study examined the relationship between hookah use and subjective well-being. Levels of sadness, happiness, tiredness, pain, and stress were compared between persons who have used hookah and those who have not. METHODS: Data were merged from the Tobacco Use Supplement of the Current Population Survey, the American Time Use Survey, and the Subjective Well-being Supplement to the American Time Use Survey for the years 2010-2012 for persons 18 30 years old (n=1147). Wald tests were used to compare mean differences in subjective well-being between hookah users and non-users. Lastly, multivariable regression was used to determine whether there were significant differences in subjective well-being between hookah users and non-users, controlling for demographic factors, self-perceived health, and cigarette smoking. RESULTS: The lifetime prevalence rate of hookah use was 5.2% among 18-30 year olds. Hookah users reported higher levels of stress and sadness than non-users. These relationships remained significant after controlling for demographic characteristics, self-perceived health, and cigarette use. The results were robust to the use of different statistical models, different age cut-offs, the inclusion of additional covariates (such as income and population density), and separate analyses by sex. CONCLUSIONS: Hookah use is an emerging public health issue associated with increased levels of stress and sadness. Similar to cigarette use, healthcare providers may consider expanding their screening tests to include hookah use. Public policy geared toward greater prevention and control of hookah use is also recommended. PMID- 26099175 TI - The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron-sulfur proteins. AB - Mitochondria have been derived from alpha-bacterial endosymbionts during the evolution of eukaryotes. Numerous bacterial functions have been maintained inside the organelles including fatty acid degradation, citric acid cycle, oxidative phosphorylation, and the synthesis of heme or lipoic acid cofactors. Additionally, mitochondria have inherited the bacterial iron-sulfur cluster assembly (ISC) machinery. Many of the ISC components are essential for cell viability because they generate a still unknown, sulfur-containing compound for the assembly of cytosolic and nuclear Fe/S proteins that perform important functions in, e.g., protein translation, DNA synthesis and repair, and chromosome segregation. The sulfur-containing compound is exported by the mitochondrial ABC transporter Atm1 (human ABCB7) and utilized by components of the cytosolic iron sulfur protein assembly (CIA) machinery. An appealing minimal model for the striking compartmentation of eukaryotic Fe/S protein biogenesis is provided by organisms that contain mitosomes instead of mitochondria. Mitosomes have been derived from mitochondria by reductive evolution, during which they have lost virtually all classical mitochondrial tasks. Nevertheless, mitosomes harbor all core ISC components which presumably have been maintained for assisting the maturation of cytosolic-nuclear Fe/S proteins. The current review is centered around the Atm1 export process. We present an overview on the mitochondrial requirements for the export reaction, summarize recent insights into the 3D structure and potential mechanism of Atm1, and explain how the CIA machinery uses the mitochondrial export product for the assembly of cytosolic and nuclear Fe/S proteins. PMID- 26099178 TI - [In Process Citation]. PMID- 26099179 TI - [In Process Citation]. PMID- 26099180 TI - [In Process Citation]. PMID- 26099177 TI - Bromodomain inhibitors regulate the C9ORF72 locus in ALS. AB - A hexanucleotide repeat expansion residing within the C9ORF72 gene represents the most common known cause of amyotrophic lateral sclerosis (ALS) and places the disease among a growing family of repeat expansion disorders. The presence of RNA foci, repeat-associated translation products, and sequestration of RNA binding proteins suggests that toxic RNA gain-of-function contributes to pathology while C9ORF72 haploinsufficiency may be an additional pathological factor. One viable therapeutic strategy for treating expansion diseases is the use of small molecule inhibitors of epigenetic modifier proteins to reactivate expanded genetic loci. Indeed, previous studies have established proof of this principle by increasing the drug-induced expression of expanded (and abnormally heterochromatinized) FMR1, FXN and C9ORF72 genes in respective patient cells. While epigenetic modifier proteins are increasingly recognized as druggable targets, there have been few screening strategies to address this avenue of drug discovery in the context of expansion diseases. Here we utilize a semi-high-throughput gene expression based screen to identify siRNAs and small molecule inhibitors of epigenetic modifier proteins that regulate C9ORF72 RNA in patient fibroblasts, lymphocytes and reprogrammed motor neurons. We found that several bromodomain small molecule inhibitors increase the expression of C9ORF72 mRNA and pre-mRNA without affecting repressive epigenetic signatures of expanded C9ORF72 alleles. These data suggest that bromodomain inhibition increases the expression of unexpanded C9ORF72 alleles and may therefore compensate for haploinsufficiency without increasing the production of toxic RNA and protein products, thereby conferring therapeutic value. PMID- 26099181 TI - [Pneumatosis intestinalis]. PMID- 26099182 TI - [Enterolith ileus complicating jejunal diverticulosis]. AB - Jejunal diverticulosis is uncommon and usually asymptomatic. One of the rarest complications is ileus due to migrated enteroliths formed in the diverticula. We present a case of a 95-year-old man admitted with small bowel obstruction. During operation extensive jejunal diverticulosis was found along with intraluminal enteroliths causing obstruction of the ileum. An enterotomy was made and three 3 * 3 * 2 cm enteroliths were removed. The patient was discharged on the sixth post operative day. Less than 50 similar cases have been reported worldwide. PMID- 26099183 TI - [Three-dimensional laparoscopy has the potential to replace two-dimensional laparoscopy in abdominal surgery]. AB - Studies comparing three-dimensional (3D) laparoscopy with 2D laparoscopy have shown shorter operation time, a short learning curve as well as better depth perception. Robotic surgery includes the EndoWrist function in addition to the 3D view; however robotic surgery lacks haptic feedback. No evidence from clinical trials for the potential benefits of robotic surgery exists. Thus, 3D laparoscopy is an eligible alternative to both 2D laparoscopy and robotic surgery. PMID- 26099184 TI - [Sparse evidence for treating whiplash associated disorders]. AB - This article summarises the current evidence for the treatment of whiplash associated disorders. The effect of immobilisation, physiotherapy, information and cognitive behavioural therapy was examined. Immobilisation was associated with a poorer outcome and could not be recommended. Physiotherapy was not more effective than information. Cognitive behavioural therapy seemed effective for the chronic patients. In conclusion, immobilisation cannot be recommended, but physiotherapy seems to be similar in effectiveness to information. PMID- 26099186 TI - [Skin-sparing surgical revision in a woman with necrotizing fasciitis in her face]. AB - Necrotizing fasciitis (NF) is a life-threatening infection which is treated with aggressive debridement, antibiotics, intensive care and hyperbaric oxygen. We present a case where a 66-year-old woman with NF of the face and neck following an eye infection was treated with skin-sparing surgical revision. The affected subcutaneous tissue as well as necrosis around the left eye was removed, but the skin was left untouched. She was reconstructed with a full-skin transplant periorbitally. We suggest using a skin-sparing technique when the skin is unaffected and vital as a means to reduce morbidity. PMID- 26099185 TI - [Field cancerization in the face of a 44-year-old female welder]. AB - Welding generates ultraviolet radiation and has been suggested to cause skin cancer. However, it remains questionable whether welding is in fact causally associated with the development of skin cancer. We report on a 44-year-old female with ten years occupational experience as a welder, who developed multiple squamous cell carcinomas located exclusively on the right side of her face. During welding she had experienced numerous facial burns limited to the right side. This marked anatomical relationship between exposure and illness supports a causal association between welding and skin cancer. PMID- 26099187 TI - [Prolonged disease in a farmer with simultaneous Q fever pneumonia and subacute hypersensitivity pneumonitis]. AB - This case report describes the first incident of a patient with simultaneous occurrence of Q fever pneumonia and subacute hypersensitivity pneumonitis (HP). The 52-year-old patient was from his occupation as a farmer exposed to agents causing both diseases. Except for a weight loss in subacute/chronic incidents of HP the symptoms of Q fever and HP are similar. However, differences in CT findings and histopathology make it possible to differentiate between the two diseases. This report highlights the importance of a thorough occupational history. PMID- 26099188 TI - [Ectopic varices in the terminal ileum causing gastrointestinal bleeding]. AB - Varices of the terminal ileum are not a common complication to portal hypertension but we describe a case where a 60-year-old male patient had massive, recurrent intestinal bleeding due to collateral blood supply from umbilical veins to varicose veins of the terminal ileum. PMID- 26099189 TI - Workshop report: The medaka model for comparative assessment of human disease mechanisms. AB - Results of recent studies showing the utility of medaka as a model of various human disease states were presented at the 7th Aquatic Models of Human Disease Conference (December 13-18, 2014, Austin, TX). This conference brought together many of the most highly regarded national and international scientists that employ the medaka model in their investigations. To take advantage of this opportunity, a cohort of established medaka researchers were asked to stay an extra day and represent the medaka scientific community in a workshop entitled "The Medaka Model for Comparative Assessment of Human Disease Mechanisms." The central purpose of this medaka workshop was to assess current use and project the future resource needs of the American medaka research community. The workshop sought to spur discussions of issues that would promote more informative comparative disease model studies. Finally, workshop attendees met together to propose, discuss, and agree on recommendations regarding the most effective research resources needed to enable US scientists to perform experiments leading to impacting experimental results that directly translate to human disease. Consistent with this central purpose, the workshop was divided into two sessions of invited speakers having expertise and experience in the session topics. The workshop hosted 20 scientific participants (Appendices 1 and 2), and of these, nine scientists presented formal talks. Here, we present a summary report stemming from workshop presentations and subsequent round table discussions and forward recommendations from this group that we believe represent views of the overall medaka research community. PMID- 26099190 TI - Fluoroquinolones in children: update of the literature. AB - The use of fluoroquinolones (FQ), antibiotics, which have excellent pharmacokinetic and pharmacodynamic characteristics and a broad spectrum of action, has increased dramatically in recent years, both in adults and children. Numerous safety and efficacy data are now available on FQ use in children, particularly regarding the treatment of complicated infections of the urinary tract, typhoid fever, pneumonia, acute external otitis, acute media otitis, meningoencephalitis, sepsis in neutropenic children and multidrug-resistant tuberculosis (MDR-TB), though sometimes studies have the limitations that they were conducted in selected populations, such as children with cystic fibrosis. Despite available safety data are encouraging, there is still an open debate on the toxicity of this class of antibiotics on weight-bearing joints in children. Not being able to exclude the possibility that, in rare cases, this event is likely to occur, their use in children should be limited to cases where the cost benefit has been carefully examined, for example, in the case of sepsis or other severe infections from multi-resistant bacteria and not responsive to other classes of drugs. Furthermore, considering the increased use of FQ in children, it is possible that there is an increase in the incidence of infections from resistant germs (such as Escherichia coli, and pneumococci), as occurred in adults. In order to limit the diffusion of resistance, a judicious and appropriate use of this class of drugs is recommended. PMID- 26099191 TI - Giant Left Atrium with Large Thrombus-Comprehensive Evaluation and Management. PMID- 26099193 TI - Association of sedentary behavior with the risk of breast cancer in women: update meta-analysis of observational studies. AB - PURPOSE: Increasing studies focus on the health consequences of sedentary behavior, and whether sedentary behavior is associated with the risk of breast cancer remains uncertain. We applied quantitative techniques to synthesize relevant original observational studies to investigate this issue. METHODS: PubMed and Embase were searched through September 2014 to identify cohort and case-control studies that evaluated the association between sedentary behavior and breast cancer risk in women. Information on the characteristics of the included studies, risk estimates, and control for possible confounding factors, was extracted independently by two authors. A random effects model of meta analysis was used to calculate the pooled risk estimate. RESULTS: Twenty one studies with 34 reports were included in our quantitative analysis. Sedentary behavior was found to slightly increase the risk of breast cancer in women and the pooled odds ratio (OR) and its 95% confidence interval (CI) were 1.08 and 1.04 to 1.13, without substantial heterogeneity (P = .579, I(2) = 0.0%). Subgroup analysis showed that the risks of breast cancer for different domains of sedentary behavior were similar, although only occupational behavior showed statistical significance (OR, 1.10; 95% CI, 1.02-1.18) and the combined ORs of breast cancer are of borderline significance for sedentary behavior of daily life (OR, 1.10; 95% CI, 1.00-1.20) and sedentary behavior of leisure time (OR, 1.08; 95% CI, 0.98-1.19). Exclusion of any single study did not materially alter the combined risk estimate. Visual inspection of funnel plot, Begg's and Egger's tests did not indicate evidence of publication bias. CONCLUSIONS: Integrated evidence from observational studies suggests a statistically significant slightly positive association of sedentary behavior with breast cancer risk. PMID- 26099192 TI - In vitro testing to a panel of potential chemotherapeutics and current concepts of chemotherapy in benign meningiomas. AB - Treatment of benign meningiomas remains a challenge, especially when they involve the skull-base or when surgery and radiation fail. Moreover, a recent in vitro MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) study testing hydroxyurea, temozolomide and other targeting agents failed to identify drugs effective in their treatment; therefore the search for further more effective agents continues. We performed a thorough review of in vitro investigations, animal studies and human clinical trials and endeavoured to integrate our results of MTT assay into current concepts of chemotherapy in benign meningiomas. Our results demonstrated that other chemotherapeutics with various mechanisms of action have the potential to be incorporated into second line therapy. Our study shows for the first time that chemosensitivity/resistance may be associated with histopathological variants of benign meningiomas. PMID- 26099194 TI - Sweet Is the Memory of Past Troubles: NK Cells Remember. AB - Natural killer (NK) cells are important in host defense against tumors and microbial pathogens. Recent studies indicate that NK cells share many features with the adaptive immune system, and like B cells and T cells, NK cells can acquire immunological memory. Here, we review evidence for NK cell memory and the molecules involved in the generation and maintenance of these self-renewing NK cells that provide enhanced protection of the host. PMID- 26099195 TI - The effect of zinc supplementation on pregnancy outcomes: a double-blind, randomised controlled trial, Egypt. AB - The present randomised controlled trial (RCT) was conducted to evaluate the effect of two regimens of Zn supplementation on pregnancy outcomes in Alexandria, Egypt. Healthy pregnant women aged 20-45 years and having low serum Zn level below the estimated median for the gestational age were eligible to participate in the trial. Of 1055 pregnant women assessed for the eligibility of low serum Zn level, 675 were eligible. These women were randomly assigned to one of the three groups: the Zn alone group (n 225) received a daily dose of 30 mg ZnSO4, the combined group (n 227) received 30 mg ZnSO4 plus multivitamins (B1, B6, D3, C and E) and the control group (n 223) received placebo (270 mg lactose). They were followed up from the time of recruitment till 1 week after delivery. Overall, there was no detectable difference in the mean birth weight between the three groups (mean 2929.12 (SD 330.28), 2922.22 (SD 324.05) and 2938.48 (SD 317.39) g for the placebo, Zn and Zn plus multivitamin groups, respectively, P = 0.88). Both the single and the combined Zn supplements were almost equally effective in reducing second- and third-stage complications (relative risk (RR) 0.43, 95% CI 0.31, 0.60 for the Zn group and RR 0.54, 95% CI 0.40, 0.73 for the combined group). Stillbirth and preterm delivery were significantly lower among the two supplemented groups than the placebo group (P = 0.001). Early neonatal morbidity was also significantly lower in the supplemented groups (RR 0.23, 95% CI 0.15, 0.35 for the Zn group and RR 0.25, 95% CI 0.16, 0.37 for the combined group). Collectively, Zn supplementation was effective in reducing pregnancy complications and early neonatal infection among the Zn-deficient women of the present trial. PMID- 26099196 TI - Revealing the planar chemistry of two-dimensional heterostructures at the atomic level. AB - Two-dimensional (2D) atomic crystals and their heterostructures are an intense area of study owing to their unique properties that result from structural planar confinement. Intrinsically, the performance of a planar vertical device is linked to the quality of its 2D components and their interfaces, therefore requiring characterization tools that can reveal both its planar chemistry and morphology. Here, we propose a characterization methodology combining (micro-) Raman spectroscopy, atomic force microscopy and time-of-flight secondary ion mass spectrometry to provide structural information, morphology and planar chemical composition at virtually the atomic level, aimed specifically at studying 2D vertical heterostructures. As an example system, a graphene-on-h-BN heterostructure is analysed to reveal, with an unprecedented level of detail, the subtle chemistry and interactions within its layer structure that can be assigned to specific fabrication steps. Such detailed chemical information is of crucial importance for the complete integration of 2D heterostructures into functional devices. PMID- 26099197 TI - Education, collaboration, and innovation: intelligent biology and medicine in the era of big data. AB - Here we present a summary of the 2014 International Conference on Intelligent Biology and Medicine (ICIBM 2014) and the editorial report of the supplement to BMC Genomics and BMC Systems Biology that includes 20 research articles selected from ICIBM 2014. The conference was held on December 4-6, 2014 at San Antonio, Texas, USA, and included six scientific sessions, four tutorials, four keynote presentations, nine highlight talks, and a poster session that covered cutting edge research in bioinformatics, systems biology, and computational medicine. PMID- 26099198 TI - Reflections on the use of poetry in nurse education: Speaking a credible language of care. AB - Based on the experience of using the poem 'The Nurse's Pockets' by Cortney Davis in reflective practice teaching sessions this paper considers the centrality of language as conveyed in poetry as a way of communicating nursing knowledge and experience. Using this poem facilitated a mutual position between the educator and the students that enhanced the reflective practice environment. An argument for using creative arts based approaches in nurse education is presented as a means of overcoming the threats to the unique nature of nursing knowledge evidenced in healthcare and higher education reform. PMID- 26099200 TI - Mechanical characterization and validation of poly (methyl methacrylate)/multi walled carbon nanotube composite for the polycentric knee joint. AB - Trans femoral amputation is one of the most uncomfortable surgeries in patient's life, where the prosthesis consisting of a socket, knee joint, pylon and foot is used to do the walking activities. The artificial prosthetic knee joint imitates the functions of human knee to achieve the flexion-extension for the above knee amputee. The objective of present work is to develop a light weight composite material for the knee joint to reduce the metabolic cost of an amputee. Hence, an attempt was made to study the mechanical properties of multi walled carbon nanotubes (MWCNT) reinforced Poly (methyl methacrylate) (PMMA) prepared through melt mixing technique and optimize the concentration of reinforcement. The PMMA nanocomposites were prepared by reinforcing 0, 0.1, 0.2, 0.25, 0.3 and 0.4 wt% of MWCNT using injection moulding machine via twin screw extruder. It is observed that the tensile and flexural strength of PMMA, which were studied as per ASTM D638 and D790, respectively, were increased by 32.9% and 26.3% till 0.25 wt% reinforcement of MWCNT. The experimental results of strength and modulus were compared with theoretical prediction, where a good correlation was noted. It is concluded that the mechanical properties of PMMA were found to be increased to maximum at 0.25 wt% reinforcement of MWCNT, where the Pukanszky model and modified Halpin-Tsai model are suggested to predict the strength and modulus, respectively, of the PMMA/MWCNT composite, which can be opted as a suitable materiel for the development of polycentric knee joint. PMID- 26099201 TI - Extracting accurate strain measurements in bone mechanics: A critical review of current methods. AB - Osteoporosis related fractures are a social burden that advocates for more accurate fracture prediction methods. Mechanistic methods, e.g. finite element models, have been proposed as a tool to better predict bone mechanical behaviour and strength. However, there is little consensus about the optimal constitutive law to describe bone as a material. Extracting reliable and relevant strain data from experimental tests is of fundamental importance to better understand bone mechanical properties, and to validate numerical models. Several techniques have been used to measure strain in experimental mechanics, with substantial differences in terms of accuracy, precision, time- and length-scale. Each technique presents upsides and downsides that must be carefully evaluated when designing the experiment. Moreover, additional complexities are often encountered when applying such strain measurement techniques to bone, due to its complex composite structure. This review of literature examined the four most commonly adopted methods for strain measurements (strain gauges, fibre Bragg grating sensors, digital image correlation, and digital volume correlation), with a focus on studies with bone as a substrate material, at the organ and tissue level. For each of them the working principles, a summary of the main applications to bone mechanics at the organ- and tissue-level, and a list of pros and cons are provided. PMID- 26099199 TI - Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice. AB - Itch is relayed to higher centers by projection neurons in the spinal and medullary dorsal horn. We employed a double-label method to map the ascending projections of pruriceptive and nociceptive trigeminal and spinal neurons. The retrograde tracer fluorogold (FG) was stereotaxically injected into the right thalamus or lateral parabrachial area (LPb) in mice. Seven days later, mice received intradermal (id) microinjection of histamine, chloroquine, capsaicin, or vehicle into the left cheek. Histamine, chloroquine, and capsaicin intradermally elicited similar distributions of Fos-positive neurons in the medial aspect of the superficial medullary and spinal dorsal horn from the trigeminal subnucleus caudalis to C2. Among neurons retrogradely labeled from the thalamus, 43%, 8%, and 22% were Fos-positive following id histamine, chloroquine, or capsaicin. Among the Fos-positive neurons following pruritic or capsaicin stimuli, ~1-2% were retrogradely labeled with FG. Trigeminoparabrachial projection neurons exhibited a higher incidence of double labeling in the superficial dorsal horn. Among the neurons retrogradely labeled from LPb, 36%, 29%, and 33% were Fos positive following id injection of histamine, chloroquine, and capsaicin, respectively. Among Fos-positive neurons elicited by id histamine, chloroquine, and capsaicin, respectively, 3.7%, 4.3%, and 4.1% were retrogradely labeled from LPb. The present results indicate that, overall, relatively small subpopulations of pruriceptive and/or nociceptive neurons innervating the cheek project to thalamus or LPb. These results imply that the vast majority of pruritogen- and algogen-responsive spinal neurons are likely to function as interneurons relaying information to projection neurons and/or participating in segmental nocifensive circuits. PMID- 26099202 TI - Integrated analysis of gene expression and DNA methylation changes induced by hepatocyte growth factor in human hepatocytes. AB - Hepatocellular carcinoma (HCC) is the one of most common malignant tumors. The tumor microenvironment has a role in not only supporting growth and survival of tumor cells, but also triggering tumor recurrence and metastasis. Hepatocyte growth factor (HGF), one of the important growth factors in the tumor microenvironment, has an important role in angiogenesis, tumorigenesis and regeneration. However, the exact mechanism by which HGF regulates HCC initiation and development via epigenetic reprogramming has remained elusive. The present study focused on the epigenetic modification and target tumor-suppressive genes of HGF treatment in HCC. Expression profiling and DNA methylation array were performed to investigate the function of HGF and examine global genomic DNA methylation changes, respectively. Integrated analysis of gene expression and DNA methylation revealed potential tumor suppressor genes (TSGs) in HCC. The present study showed the multiple functions of HGF in tumorous and non-tumorous pathways and global genomic DNA methylation changes. HGF treatment upregulated the expression of DNA methyltransferase 1 (DNMT1). Overexpression of DNMT1 in HCC patients correlated with the malignant potential and poor prognosis of HCC. Furthermore, integration analysis of gene expression and DNA methylation changes revealed novel potential tumor suppressor genes TSGs including MYOCD, PANX2 and LHX9. The present study has provided mechanistic insight into epigenetic repression of TSGs through HGF-induced DNA hypermethylation. PMID- 26099204 TI - Correlation of lumbar-hip kinematics between trunk flexion and other functional tasks. AB - OBJECTIVE: The purpose of this study was to explore the relationship between the kinematic profiles of flexion of the upper lumbar and lower lumbar (LL) spine and hip and 3 sagittally dominant functional tasks (lifting, stand-to-sit, and sit-to stand). METHODS: Fifty-three participants were recruited for this study. Four sensors were attached to the skin over the S1, L3, T12, and lateral thigh. Relative angles between adjacent sensors were used to quantify the motion for the hip, LL, and upper lumbar spine. Pearson correlation coefficients were used to explore the relationship between the movements and more functional tasks. One-way analysis of variance was used to determine the significance of differences between the variables. RESULTS: Flexion resulted in a greater or similar range of motion (ROM) to the other tasks investigated for both spinal regions but less ROM for the hip. Strong correlations for ROM are reported between forward flexion tasks and lifting for the LL spine (r = 0.83) and all regions during stand-to-sit and sit-to-stand (r = 0.70-0.73). No tasks were strongly correlated for velocity (r = 0.03-0.55). CONCLUSION: Strong correlations were only evident for the LL spine ROM between lifting and flexion; all other tasks afforded moderate or weak correlations. This study suggests that sagittal tasks use different lumbar-hip kinematics and place different demands on the lumbar spine and hip. PMID- 26099203 TI - Structural basis of the broadly neutralizing anti-interferon-alpha antibody rontalizumab. AB - Interferons-alpha (IFN-alpha) are the expressed gene products comprising thirteen type I interferons with protein pairwise sequence similarities in the 77-96% range. Three other widely expressed human type I interferons, IFN-beta, IFN-kappa and IFN-omega have sequences 29-33%, 29-32% and 56-60% similar to the IFN-alphas, respectively. Type I interferons act on immune cells by producing subtly different immune-modulatory effects upon binding to the extracellular domains of a heterodimeric cell-surface receptor composed of IFNAR1 and IFNAR2, most notably anti-viral effects. IFN-alpha has been used to treat infection by hepatitis-virus type C (HCV) and a correlation between hyperactivity of IFN-alpha-induced signaling and systemic lupus erythematosis (SLE), or lupus, has been noted. Anti IFN-alpha antibodies including rontalizumab have been under clinical study for the treatment of lupus. To better understand the rontalizumab mechanism of action and specificity, we determined the X-ray crystal structure of the Fab fragment of rontalizumab bound to human IFN-alpha2 at 3A resolution and find substantial overlap of the antibody and IFNA2 epitopes on IFN-alpha2. PMID- 26099205 TI - Effect of Connective Tissue Manipulation on Symptoms and Quality of Life in Patients With Chronic Constipation: A Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this study was to examine the effects of connective tissue manipulation (CTM) on the severity of constipation and health-related quality of life in individuals diagnosed with chronic constipation. METHODS: Fifty patients with a diagnosis of chronic constipation according to Rome III criteria were recruited and randomized to an intervention (n = 25) or control group (n = 25). The intervention group received CTM in addition to the lifestyle advice, whereas the control group was given only lifestyle advice for constipation. All assessments were performed at baseline and at the end of 4 weeks. The primary outcome measure was the Constipation Severity Instrument. Secondary outcomes included Patient Assessment of Constipation Quality of Life Questionnaire, Bristol Stool Scale, and 7-day bowel diary. Differences between groups were analyzed with t tests, Mann-Whitney U test and chi(2) test. RESULTS: Compared with the control group, subjects in the intervention group reported significantly greater improvement in total and subscale scores of the Constipation Severity Instrument and Patient Assessment of Constipation Quality of Life Questionnaire (P < .05). Based on the results from bowel diaries, the improvements in the number of bowel movements, duration of defecation, stool consistency, and the feeling of incomplete evacuation in the intervention group were also significantly more than the control group (P < .05). CONCLUSION: This study showed that CTM and lifestyle advice were superior to reducing symptoms of constipation and quality of life compared with lifestyle advice alone for patients with chronic constipation. PMID- 26099206 TI - Efficacy of Hand Behind Back Mobilization With Movement for Acute Shoulder Pain and Movement Impairment: A Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to investigate the effects of hand-behind back (HBB) Mulligan mobilization with movement (MWM) techniques on acute shoulder pain, impairment, and disability. METHODS: This double-blind, randomized, controlled trial recruited 44 patients with acute shoulder pain and movement impairment presenting to an Indian general hospital. Participants were allocated to receive either MWM and exercise/hot pack (n = 22) or exercise/hot pack alone (n = 22). The average duration of symptoms was 4.1 and 4.7 weeks in the exercise and MWM groups, respectively. The primary outcome was HBB range of motion (ROM). Secondary variables were shoulder internal rotation ROM, pain intensity score, and shoulder disability identified by the shoulder pain and disability index. All variables were evaluated by a blinded assessor before and immediately after 9 treatment sessions over 3 weeks. RESULTS: Paired t tests revealed that both groups demonstrated statistically significant improvements (P < .001) with large effect sizes for all variables. However, for all variables, the MWM-with-exercise group showed significantly greater improvements (P < .05) than the exercise group. Hand-behind-back ROM showed a mean difference of 9.31 degrees (95% confidence interval, 7.38-11.27), favoring greater improvement in the MWM-with exercise group. CONCLUSIONS: In this study, the outcomes of patients with acute shoulder pain and disability receiving shoulder HBB MWM with exercise improved greater than those receiving exercise/hot packs alone. PMID- 26099207 TI - Are Parents Getting it Right? A Survey of Parents' Internet Use for Children's Health Care Information. AB - BACKGROUND: The use of the Internet to search for medical and health-related information is increasing and associated with concerns around quality and safety. OBJECTIVE: We investigated the current use and perceptions on reliable websites for children's health information by parents. METHODS: Following institutional ethics approval, we conducted a survey of parents/guardians of children presenting for day surgery. A 20-item survey instrument developed and tested by the investigators was administered. RESULTS: Ninety-eight percent of respondents reported that they used the Internet to search for information about their child's health. Many respondents reported beginning their search at public search engines (80%); less than 20% reported starting their search at university/hospital-based websites. Common conditions such as colds/flu, skin conditions and fever were the most frequently searched, and unique conditions directly affecting the child were second. Despite low usage levels of university/hospital-based websites for health information, the majority of respondents (74%) regarded these as providing safe, accurate, and reliable information. In contrast, only 24% of respondents regarded public search engines as providing safe and reliable information. Fifty percent of respondents reported that they cross-checked information found on the internet with a family physician. CONCLUSIONS: An unprecedented majority of parents and guardians are using the Internet for their child's health information. Of concern is that parents and guardians are currently not using reliable and safe sources of information. Health care providers should begin to focus on improving access to safe, accurate, and reliable information through various modalities including education, designing for multiplatform, and better search engine optimization. PMID- 26099208 TI - Altered baseline brain activity differentiates regional mechanisms subserving biological and psychological alterations in obese men. AB - Obesity as a chronic disease is a major factor for insulin resistance and Type 2 diabetes, which has become a global health problem. In the present study, we used resting state functional MRI to investigate the amplitude of low frequency fluctuations of spontaneous signal during both hunger and satiety states in 20 lean and 20 obese males. We found that, before food intake, obese men had significantly greater baseline activity in the precuneus and lesser activity in dorsal anterior cingulate cortex (dACC) relative to lean subjects. Furthermore, after food intake, obese males had significantly lesser activity in dACC than lean males. We further found a significant positive correlation between precuneus activation and hunger ratings before food intake, while dACC activity was negatively correlated with plasma insulin levels before and after food intake. These results indicated that both precuneus and dACC may play an important role in eating behavior. While precuneus rather seemed to mediate subjective satiety, dACC levels rather reflected indirect measures of glucose utilization. PMID- 26099209 TI - Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part II: Background to a research strategy. AB - STUDY DESIGN: Literature review/semi-structured interviews. OBJECTIVE: To develop a spinal cord injury (SCI) research strategy for Australia and New Zealand. SETTING: Australia. METHODS: The National Trauma Research Institute Forum approach of structured evidence review and stakeholder consultation was employed. This involved gathering from published literature and stakeholder consultation the information necessary to properly consider the challenge, and synthesising this into a briefing document. RESULTS: A research strategy 'roadmap' was developed to define the major steps and key planning questions to consider; next, evidence from published SCI research strategy initiatives was synthesised with information from four one-on-one semi-structured interviews with key SCI research stakeholders to create a research strategy framework, articulating six key themes and associated activities for consideration. These resources, combined with a review of SCI prioritisation literature, were used to generate a list of draft principles for discussion in a structured stakeholder dialogue meeting. CONCLUSION: The research strategy roadmap and framework informed discussion at a structured stakeholder dialogue meeting of 23 participants representing key SCI research constituencies, results of which are published in a companion paper. These resources could also be of value in other research strategy or planning exercises. SPONSORSHIP: This project was funded by the Victorian Transport Accident Commission and the Australian and New Zealand Spinal Cord Injury Network. PMID- 26099210 TI - Incidence of pulmonary embolism after the first 3 months of spinal cord injury. AB - BACKGROUND: Pulmonary embolism (PE) is a significant cause of morbidity and mortality in patients with spinal cord injury (SCI). Prophylactic anticoagulation is associated with a reduction in mortality rates, but there is limited evidence regarding the incidence rate of PE following cessation of anticoagulation after the first 3 months of injury. STUDY DESIGN: Single-centre retrospective study. OBJECTIVE: To estimate the incidence rate of PE after 90 days of SCI. SETTING: The National Spinal Injuries Centre at Stoke Mandeville Hospital, Aylesbury, UK. METHODS: The study includes 640 new-onset SCI patients. All computer tomography pulmonary angiograms (CTPAs) or ventilation-perfusion lung scans between 2008 and 2013 were identified. Medical notes and scans were reviewed and clinical outcomes and radiological findings were recorded. RESULTS: A total of 91 patients with a new-onset SCI had a CTPA or a perfusion lung scan. PE was detected in a total of 8 patients. The incidence of PE was 1.25%; 95% confidence interval (0.39-2.11) over a 6-year period. The duration of injury at the time of PE was 7 months. CONCLUSION: The incidence rate of PE post 3 months of SCI remains significant, though much lower than immediately post injury. PMID- 26099211 TI - Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part III: outcomes. AB - STUDY DESIGN: Focus Group. OBJECTIVES: To develop a unified, regional spinal cord injury (SCI) research strategy for Australia and New Zealand. SETTING: Australia. METHODS: A 1-day structured stakeholder dialogue was convened in 2013 in Melbourne, Australia, by the National Trauma Research Institute in collaboration with the SCI Network of Australia and New Zealand. Twenty-three experts participated, representing local and international research, clinical, consumer, advocacy, government policy and funding perspectives. Preparatory work synthesised evidence and articulated draft principles and options as a starting point for discussion. RESULTS: A regional SCI research strategy was proposed, whose objectives can be summarised under four themes. (1) Collaborative networks and strategic partnerships to increase efficiency, reduce duplication, build capacity and optimise research funding. (2) Research priority setting and coordination to manage competing studies. (3) Mechanisms for greater consumer engagement in research. (4) Resources and infrastructure to further develop SCI data registries, evaluate research translation and assess alignment of research strategy with stakeholder interests. These are consistent with contemporary international SCI research strategy development activities. CONCLUSION: This first step in a regional SCI research strategy has articulated objectives for further development by the wider SCI research community. The initiative has also reinforced the importance of coordinated, collective action in optimising outcomes following SCI. PMID- 26099212 TI - Good validity of the international spinal cord injury quality of life basic data set. AB - STUDY DESIGN: Cross-sectional validation study. OBJECTIVES: To examine the construct and concurrent validity of the International Spinal Cord Injury (SCI) Quality of Life (QoL) Basic Data Set. SETTING: Dutch community. PARTICIPANTS: People 28-65 years of age, who obtained their SCI between 18 and 35 years of age, were at least 10 years post SCI and were wheelchair users in daily life. MEASURE(S): The International SCI QoL Basic Data Set consists of three single items on satisfaction with life as a whole, physical health and psychological health (0=complete dissatisfaction; 10=complete satisfaction). Reference measures were the Mental Health Inventory-5 and three items of the World Health Organization Quality of Life measure. RESULTS: Data of 261 participants were available. Mean time after SCI was 24.1 years (s.d. 9.1); 90.4% had a traumatic SCI, 81.5% a motor complete SCI and 40% had tetraplegia. Mean age was 47.9 years (s.d. 8.8) and 73.2% were male. Mean scores were 6.9 (s.d. 1.9) for general QoL, 5.8 (s.d. 2.2) for physical health and 7.1 (s.d. 1.9) for psychological health. No floor or ceiling effects were found. Strong inter-correlations (0.48-0.71) were found between the items, and Cronbach's alpha of the scale was good (0.81). Correlations with the reference measures showed the strongest correlations between the WHOQOL general satisfaction item and general QoL (0.64), the WHOQOL health and daily activities items and physical health (0.69 and 0.60) and the Mental Health Inventory-5 and psychological health (0.70). CONCLUSIONS: This first validity study of the International SCI QoL Basic Data Set shows that it appears valid for persons with SCI. PMID- 26099213 TI - Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part I: rapid review of SCI prioritisation literature. AB - STUDY DESIGN: This is a rapid evidence review. OBJECTIVES: The objective of this study was to gain an overview of the volume, nature and findings of studies regarding priorities for spinal cord injury (SCI) research. SETTING: A worldwide literature search was conducted. METHODS: Six medical literature databases and Google Scholar were searched for reviews in which the primary aim was to identify SCI research priorities. RESULTS: Two systematic reviews were identified-one of quantitative and one of qualitative studies. The quality of the reviews was variable. Collectively, the reviews identified 31 primary studies; 24 quantitative studies totalling 5262 participants and 7 qualitative studies totalling 120 participants. Despite the difference in research paradigms, there was convergence in review findings in the areas of body impairments and relationships. The vast majority of literature within the reviews focused on the SCI patient perspective. CONCLUSION: The reviews inform specific research topics and highlight other important research considerations, most notably those pertaining to SCI patients' perspectives on quality of life, which may be of use in determining meaningful research outcome measures. The views of other SCI research stakeholders such as researchers, clinicians, policymakers, funders and carers would help shape a bigger picture of SCI research priorities, ultimately optimising research outputs and translation into clinical practice and health policy change. Review findings informed subsequent activities in developing a regional SCI research strategy, as described in two companion papers. SPONSORSHIP: This project was funded by the Victorian Transport Accident Commission and the Australian and New Zealand SCI Network. PMID- 26099214 TI - Staggered multi-site low-frequency electrostimulation effectively induces locomotor patterns in the isolated rat spinal cord. AB - STUDY DESIGN: Experimental animal study. OBJECTIVES: Epidural stimulation has been used to activate locomotor patterns after spinal injury and typically employs synchronous trains of high-frequency stimuli delivered directly to the dorsal cord, thereby recruiting multiple afferent nerve roots. Here we investigate how spinal locomotor networks integrate multi-site afferent input and address whether frequency coding is more important than amplitude to activate locomotor patterns. SETTING: Italy and Belgium. METHODS: To investigate the importance of input intensity and frequency in eliciting locomotor activity, we used isolated neonatal rat spinal cords to record episodes of fictive locomotion (FL) induced by electrical stimulation of single and multiple dorsal roots (DRs), employing different stimulating protocols. RESULTS: FL was efficiently induced through staggered delivery (delays 0.5 to 2 s) of low-frequency pulse trains (0.33 and 0.67 Hz) to three DRs at intensities sufficient to activate ventral root reflexes. Delivery of the same trains to a single DR or synchronously to multiple DRs remained ineffective. Multi-site staggered trains were more efficient than randomized pulse delivery. Weak trains simultaneously delivered to DRs failed to elicit FL. Locomotor rhythm resetting occurred with single pulses applied to various distant DRs. CONCLUSION: Electrical stimulation recruited spinal networks that generate locomotor programs when pulses were delivered to multiple sites at low frequency. This finding might help devising new protocols to optimize the increasingly more common use of epidural implantable arrays to treat spinal dysfunctions. PMID- 26099215 TI - Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. AB - BACKGROUND: Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). OBJECTIVES: The primary objective of the trial is to evaluate the superiority of riluzole, at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury, compared with placebo in improving neurological motor outcomes in patients with C4-C8 level, International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) grade A, B or C acute (within 12 h post injury) SCI. SETTING: Acute trauma centers worldwideMethods:A double-blind, multi-center, placebo-controlled RCT will enroll 351 participants randomized 1:1 to riluzole and placebo. The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score. This study has 90% power to detect a change of nine points in ISNCSCI Motor Score at one-sided alpha=0.025. RESULTS: Currently enrolling in 11 centers. CONCLUSION: This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI. PMID- 26099216 TI - Time-series analysis of the barriers for admission into a spinal rehabilitation unit. AB - STUDY DESIGN: This is a prospective open-cohort case series. OBJECTIVES: The objective of this study was to assess changes over time in the duration of key acute hospital process barriers for patients with spinal cord damage (SCD) from admission until transfer into spinal rehabilitation unit (SRU) or other destinations. SETTING: The study was conducted in Acute hospitals, Victoria, Australia (2006-2013). METHODS: Duration of the following discrete sequential processes was measured: acute hospital admission until referral to SRU, referral until SRU assessment, SRU assessment until ready for SRU transfer and ready for transfer until SRU admission. Time-series analysis was performed using a generalised additive model (GAM). Seasonality of non-traumatic spinal cord dysfunction (SCDys) was examined. RESULTS: GAM analysis shows that the waiting time for admission into SRU was significantly (P<0.001) longer for patients who were female, who had tetraplegia, who were motor complete, had a pelvic pressure ulcer and who were referred from another health network. Age had a non-linear effect on the duration of waiting for transfer from acute hospital to SRU and both the acute hospital and SRU length of stay (LOS). The duration patients spent waiting for SRU admission increased over the study period. There was an increase in the number of referrals over the study period and an increase in the number of patients accepted but not admitted into the SRU. There was no notable seasonal influence on the referral of patients with SCDys. CONCLUSIONS: Time-series analysis provides additional insights into changes in the waiting times for SRU admission and the LOS in hospital for patients with SCD. PMID- 26099217 TI - Hepatolithiasis associated with intrahepatic heterotopic pancreas: a case report and literature review. AB - Intrahepatic heterotopic pancreas is rarely reported in the literature. Here, we report a case of a 39-year-old male with intrahepatic heterotopic pancreas associated with primary cholesterol hepatolithiasis. Computed tomography (CT) scans revealed multiple cholesterol stones in intrahepatic bile ducts of the left lobe concomitant with intrahepatic cholangiectases. These observations were confirmed by magnetic resonance cholangiopaneretography (MRCP). The patient underwent transabdominal left hepatic lobectomy. Postoperative histological examination of the resected specimen showed pancreatic tissues distributed along the wall of the bile duct and composed of acinar cells and duct elements without islets of Langerhans, therefore strongly suggesting that the heterotopic pancreas occurred in response to chronic injury due to the primary cholesterol hepatolithiasis and was derived from the biliary epithelial cells. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1461819267158980 . PMID- 26099218 TI - Dietary Cordyceps militaris protects against Vibrio splendidus infection in sea cucumber Apostichopus japonicus. AB - Vibrio splendidus is the common pathogen that causes infectious diseases widely spread in cultured sea cucumber in China. Therefore, we investigated the ability of Cordyceps militaris to protect against infection caused by V. splendidus. In this study, sea cucumbers were fed with a diet containing 0 (control), 1%, 2% or 3% C. militaris for 28 days, and subsequently challenged with V. splendidus by injection with 1.0 * 10(9) cfu per animal. Parameters of immune response such as phagocytosis (PC), lysozyme (LSZ) activity, superoxide dismutase (SOD) activity, alkaline phosphatase (AKP) activity and acid phosphatase (ACP) activity were determined on days 0, 1, 3, 5 and 7 after injection. The results showed that dietary C. militaris at a dose of 2% or 3% significantly up-regulated (P < 0.05) all the immune parameters on day 0. One day after injection with V. splendidus, all the immune indices except ACP exhibited a tendency to decrease and then increase again, returning to the initial level on days 5 and/or 7 after injection. All the immune parameters of those fed with C. militaris were found significantly higher (P < 0.05) than those of the control group on day 1 after injection. Only LSZ activity of those fed with 1%- or 3%-C. militaris diet on day 5 showed significantly increases (P < 0.05) than the controls. As for ACP activity, the values remained steady with time, but with significant increase (P < 0.05) seen in sea cucumbers fed with 2%-C. militaris diet, and lasted for up to 7 days after V. splendidus injection. The cumulative mortality of sea cucumbers fed with the basal diet followed V. splendidus infection was significantly higher (P < 0.05) than those fed with 2% and 3% C. militaris diet. Under the experimental conditions, dietary C. militaris could enhance the immune responses of Apostichopus japonicus and improve its resistance to infection by V. splendidus. PMID- 26099219 TI - Early protein ORF086 is an effective vaccine candidate for infectious spleen and kidney necrosis virus in mandarin fish Siniperca chuatsi. AB - Infectious spleen and kidney necrosis virus (ISKNV) has caused significant loss in the Mandarin fish (Siniperca chuatsi) aquaculture industry. Vaccination is an important measure to prevent fatal ISKNV infection. In this study, the ORF086 gene encoding an early protein helicase of ISKNV was cloned into the prokaryotic pET32a (+) and eukaryotic pcDNA3.1 (+) expression vectors and designated as pET086 and pcDNA086, respectively. A recombinant 36 kDa protein was detected in Escherichia coli BL21 (harboring pET086) after isopropyl beta-d-1 thiogalactopyranoside (IPTG) induction. Polyclonal antibodies against the purified ORF086 protein were raised in rabbits. The antibody reaction and the pcDNA086 expression in muscle tissues of vaccinated fish were confirmed using Western blot analysis. The protective efficacy of ORF086 was also investigated. The cumulative mortality rates of Mandarin fish were significantly different between immune and control groups (P < 0.05) after ISKNV challenge. The relative percentage survival (RPS) values of the recombinant ORF086 protein emulsified with ISA763A adjuvant and pcDNA086 added with QCDC adjuvant were 73% and 63%, respectively. Transcriptional analysis of non-specific and specific immune related genes revealed that the expression levels of IRF-7, IRAK1, Mx, Viperin, and IgM were strongly up-regulated in the vaccinated groups post-immunization. In particular, the expression levels in the QCDC + pcDNA086 group was higher than those in the control groups (P < 0.05). These results indicated that the early protein ORF086 could be an effective antigen candidate for controlling ISKNV disease in Mandarin fish. PMID- 26099220 TI - Differential innate immune response of European seabass (Dicentrarchus labrax) against Streptococcus iniae. AB - Streptococcus iniae is a Gram-positive bacteria that causes invasive infections with severe septicemia and meningitis, producing high economic losses in marine and continental aquaculture. Head kidney leukocytes of European sea bass (Dicentrarchus labrax) were used to measure the differential innate immune response upon infection with S. iniae. The complete inhibition in the production of intracellular superoxide radicals and total peroxidase content was observed in infected cells. This study also elucidates changes in the relative expression of some immune-related genes. Interleukin 1beta, tumor necrosis factor-alpha and interleukin-6 reached a peak of expression at 4-8 h post-infection, subsequently decreasing significantly up to 48 h post-infection. However, interleukin-10 and Mx protein increased over time, reaching the pick of expression at 48 h post infection, whereas caspase-3 showed down regulation until 48 h post-infection. The in vivo study of immune related genes show the same kinetics of mRNAs expression as in vitro experience. The proinflammatory cytokines mRNA transcription levels peaked at an earlier time in vivo than in vitro system. Our findings indicate that there is a direct relationship between the dissemination of bacteria and the resulting infection-associated inhibition of respiratory burst, apoptosis, and the pro- and anti-inflammatory gene expression profiles. PMID- 26099221 TI - Percutaneous intervention of de novo unprotected left main stenosis in patients with acute coronary syndrome or stable coronary artery disease: in-hospital and long-term results. AB - OBJECTIVES: to assess in-hospital and long-term results of the novo unprotected left main (UPLM) percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) or stable coronary artery disease (CAD), in an unselected population admitted to a single high- volume cathlab without on-site cardiac surgery. METHODS: from 2008 to 2011, among 317 PCI performed in patients with the novo UPLM stenosis, 49 patients presented ST-elevation myocardial infarction (STEMI), 152 non ST-elevation MI/unstable angina (NSTEMI/UA), 116 stable CAD. RESULTS: in-hospital mortality was 20% in STEMI, 5.3% in NSTEMI/UA and 1.7% in stable CAD patients (p<0.001). Two-year total mortality was 24.5%, 25.6% and 6% in the 3 groups, and cardiac death was 20%, 13.8% and 3.4% (p=0.002). Left main target lesion revascularization (TLR) was similar in the 3 groups, as the clinically- driven TLR (10% vs 11% vs 7.7% , p= 0.642), with neither definite nor probable stent thrombosis. Multivariate analysis showed the following independent predictors of 2-year mortality: bare-metal stent use (OR 4.53, p<0.001), Syntax score >32 (OR 3.53, p=0.012), ACS as the indication (OR 3.24, p=0.012), peripheral artery disease (OR 2.20, p=0.042), and age > 75 years (OR 2.09, p=0.05). CONCLUSIONS: our experience showed acceptable results of UPLM PCI in STEMI patients, where short-term prognosis was related to hemodynamic conditions, good results in NSTEMI/UA patients where mortality increased in the follow-up due to comorbidities, and very good results in patients with stable CAD. PMID- 26099222 TI - Role of the old and new echocardiographic technologies in cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an important tool for the treatment of patients with chronic heart failure, as it can correct the heterogeneity of regional left ventricular mechanical contraction, known as dyssynchrony. Although this therapy is strongly indicated in patients with both heart failure with left ventricular systolic dysfunction and wide Q-, R- and S-waves (QRS) on electrocardiogram, about one-third of these patients are non-responders. Since the degree of mechanical dyssynchrony can vary greatly, it is interesting to quantify dyssynchrony by means of imaging methods, such as echocardiography, which might be able to lead to a better selection of CRT candidates. This article will review the role of old and new echocardiographic techniques to predict CRT response. PMID- 26099224 TI - [Structural requirements for the management of patients with highly contagious life-threatening infectious diseases: update 2015]. AB - The care of highly contagious life-threatening infectious diseases (HLID) requires specialized treatment facilities that are capable of strict isolation measures and appropriate medical treatment. The German approach to the management of these diseases, which is maintained by the Permanent Working Group of Medical Competence and Treatment Centers for Highly Contagious and Life-Threatening Diseases (STAKOB) is adjusted in the present publication with regards to recent experiences and upcoming needs. Clear synergies in using infrastructures and bundling of resources have led to similar efforts at the European level. The German concept, therefore, has a pioneering role. This update is intended to improve professional patient care and also minimize the risk of disease spread and transmission. PMID- 26099223 TI - Association of hemoglobin A1c and glycated albumin with carotid atherosclerosis in community-dwelling Japanese subjects: the Hisayama Study. AB - BACKGROUND: It is not clear which glucose measure is more useful in the assessment of atherosclerosis. We investigated the associations of hemoglobin A1c (HbA1c), glycated albumin (GA), 1,5-anhydroglucitol (1,5-AG), fasting plasma glucose (FPG), and 2-hour postload glucose (PG) with carotid intima-media thickness (IMT) in community-dwelling Japanese subjects. METHODS: A total of 2702 subjects aged 40-79 years underwent a 75-g oral glucose tolerance test and measurements of HbA1c, GA, 1,5-AG, and carotid IMT by ultrasonography in 2007 2008. Carotid wall thickening was defined as a maximum IMT of >1.0 mm. The crude and multivariable-adjusted linear and logistic regression models were used to analyze cross-sectional associations between levels of glycemic measures and carotid IMT. RESULTS: The crude average of the maximum IMT increased significantly with rising quartiles of HbA1c, GA, FPG, and 2-hour PG levels in subjects with and without glucose intolerance (GI), while no clear association was observed for 1,5-AG. After adjustment for other confounding factors, positive trends for HbA1c, GA, and FPG (all p for trend < 0.05), but not 2-hour PG (p = 0.07) remained robust in subjects with GI, but no such associations were found in those without GI. When estimating multivariable-adjusted beta values for the associations of 1 SD change in glycemic measures with the maximum IMT in subjects with GI, the magnitude of the influence of HbA1c (beta = 0.021), GA (beta = 0.024), and FPG (beta = 0.024) was larger than that of 2-hour PG (beta = 0.014) and 1,5-AG (beta = 0.003). The multivariable-adjusted odds ratios for the presence of carotid wall thickening increased significantly with elevating HbA1c, GA, and FPG levels only in subjects with GI (all p for trend < 0.001). Among subjects with GI, the area under the receiver operating characteristic curve significantly increased by adding HbA1c (p = 0.04) or GA (p = 0.04), but not 1,5 AG, FPG, or 2-hour PG, to the model including other cardiovascular risk factors. CONCLUSIONS: In community-dwelling Japanese subjects with GI, elevated HbA1c, GA, and FPG levels were significantly associated with increased carotid IMT, and HbA1c and GA provided superior discrimination for carotid wall thickening compared to 1,5-AG, FPG, and 2-hour PG, suggesting that HbA1c and GA are useful for assessing carotid atherosclerosis. PMID- 26099225 TI - [Not Available]. PMID- 26099226 TI - PREventing Delayed Graft Function by Driving Immunosuppressive InduCtion Treatment (PREDICT-DGF): study protocol for a randomized controlled trial. AB - BACKGROUND: In kidney transplantation, the use of Anti-Thymocyte Globulins (ATG) as induction therapy has been described as a possible treatment for reducing the prevalence of Delayed Graft Function (DGF). ATG possesses pharmaceutical proprieties that could help control the lesions caused by ischemia reperfusion injury. However, other studies have questioned this potential protective effect. We hypothesized that the benefits related to ATG for reducing DGF prevalence may be higher and more consistently recognized if only patients with high DGF risk are considered. We recently proposed a scoring system entitled DGFS (Delayed Graft Function Score) for such stratification of kidney transplant recipients according to their risk of DGF. Using the DGFS calculation, we aim to determine whether a short course of ATG can decrease the incidence of DGF in comparison with Basiliximab in kidney transplant recipients with low immunological risk but high DGF risk. METHODS: We conduct a phase IV, open label, randomized, multicentric and prospective study, to compare ATG in parallel with a control group treated by Basiliximab. The 1:1 randomized allocation of patients between groups is stratified on the clinical center, and on the hypothermic machine perfusion device. We aimed to include a total of 384 patients to achieve a statistical power at 0.80. The study was initiated at the Nantes University hospital in July 2014, with data collection continuing until April 2018, and publication of the results proposed for 2019. DISCUSSION: The main expected benefits of this study are i) the reduction of unjustified ATG over-prescriptions associated with serious adverse events, ii) the reduction of chance losses related to ATG under-prescription, iii) the decrease in the incidence of DGF which was described as a risk factor of graft failure and patient death, and iv) the reduction in hospitalization duration and number of post transplantation dialysis sessions, both being associated with reduced medical costs. In conclusion, the current study is innovative by proposing a more efficient and personalized induction therapy. TRIAL REGISTRATION: The study was registered in the Clinical Trials Registry (# NCT02056938, February 5, 2014), and in the European Clinical Trials Database (EudraCT #2014-000332-42, January 30, 2014). PMID- 26099227 TI - Early side effects and first results of radioligand therapy with (177)Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. AB - BACKGROUND: Radioligand therapy (RLT) with (177)Lu-DKFZ-617 PSMA (Lu-PSMA) (prostate-specific membrane antigen) is a novel targeted therapy of metastatic prostate cancer. We analysed retrospectively the early side effects and the response rate in the first patients, who received a therapy with Lu-PSMA in our departments. METHODS: RLT was performed in ten hormone- and/or chemo-refractory patients with distant metastases and progressive disease (mean age 73.5 years). (68)Ga-PSMA HBED-CC PET/CT was performed in all patients prior to RLT. The median PSA level prior to the therapy was 298.5 ng/ml (range 5-853 ng/ml). All patients received CBC, renal and liver function tests the day before and 2 days after application (mean administered activity 5.6 GBq, range 4.1-6.1 GBq), followed by further tests every 2 weeks. All patients were contacted by telephone every week regarding side effects or any positive and negative changes. RESULTS: Eight weeks after the therapy, seven patients (70 %) experienced a PSA decline, of whom six experienced more than 30 % and five more than 50 %. Three patients showed a progressive disease according to the PSA increase. No patient experienced any side effects immediately after injection of Lu-PSMA. Relevant hematotoxicity (grade 3 or 4) occurred 7 weeks after the administration in just one patient. The same patient showed a leucopenia grade 2. Two patients showed a disturbance of only 1 hematologic cell line, whereas one patient showed a reduction of grades 1 and 2 in leucocytes and thrombocytes, respectively. Six patients did not show any hematotoxicity during the 8 weeks after therapy. There was no relevant nephrotoxicity (grade 3 or 4). CONCLUSIONS: Our initial results indicate that RLT with Lu-PSMA is safe and seems to have low early side-effect profile. A relevant PSA decline was detected in 70 % of patients. PMID- 26099228 TI - Relationship of organizational culture, teamwork and job satisfaction in interprofessional teams. AB - BACKGROUND: Team effectiveness is often explained on the basis of input-process output (IPO) models. According to these models a relationship between organizational culture (input = I), interprofessional teamwork (process = P) and job satisfaction (output = O) is postulated. The aim of this study was to examine the relationship between these three aspects using structural analysis. METHODS: A multi-center cross-sectional study with a survey of 272 employees was conducted in fifteen rehabilitation clinics with different indication fields in Germany. Structural equation modeling (SEM) was carried out using AMOS software version 20.0 (maximum-likelihood method). RESULTS: Of 661 questionnaires sent out to members of the health care teams in the medical rehabilitation clinics, 275 were returned (41.6%). Three questionnaires were excluded (missing data greater than 30%), yielding a total of 272 employees that could be analyzed. The confirmatory models were supported by the data. The results showed that 35% of job satisfaction is predicted by a structural equation model that includes both organizational culture and teamwork. The comparison of this predictive IPO model (organizational culture (I), interprofessional teamwork (P), job satisfaction (O)) and the predictive IO model (organizational culture (I), job satisfaction (O)) showed that the effect of organizational culture is completely mediated by interprofessional teamwork. The global fit indices are a little better for the IO model (TLI: .967, CFI: .972, RMSEA .052) than for the IPO model (TLI: .934, CFI: .943, RMSEA: .61), but the prediction of job satisfaction is better in the IPO model (R(2) = 35%) than in the IO model (R(2) = 24%). CONCLUSIONS: Our study results underpin the importance of interprofessional teamwork in health care organizations. To enhance interprofessional teamwork, team interventions can be recommended and should be supported. Further studies investigating the organizational culture and its impact on interprofessional teamwork and team effectiveness in health care are important. PMID- 26099229 TI - The whole spectrum of cystic periventricular leukomalacia of the preterm infant: results from a large consecutive case series. AB - PURPOSE: The purpose of this study is to describe features of cystic periventricular leukomalacia (PVL) in a large consecutive cohort study including long-term neurodevelopmental follow-up. METHODS: We performed a retrospective single-centre cohort study including all preterm infants <=35 weeks of gestational age with PVL diagnosed by ultrasound scans (US) from a tertiary care university hospital between 1988 and 2012. RESULTS: The majority of 160 consecutively diagnosed cases had a gestational age between 28 and 32 weeks (60.6%), and male sex was predominant (60.6%). The most common associated clinical findings included respiratory distress syndrome, preterm premature rupture of the membranes, and chorioamnionitis (57.5, 49.4, and 39.4%, respectively). Infants presented with apnoeas in 66.3 and neonatal seizures in 23.1%. Any kind of respiratory support was present in 75.0%. Associated low-grade intraventricular haemorrhage was evident in 33.1, high-grade haemorrhage in 9.4%. Cysts were located on both hemispheres in 75% and PVL grades 3 and 4 were predominant (75.6%). Neurodevelopmental follow-up of 146 cases at a median age of 72 months revealed normal development in 11.0, mental retardation in 50.0, and cerebral palsy in 83.6%. Visual impairment was diagnosed in 21.9% and hearing impairment in one case. A quarter of cases (27.4%) developed seizure disorders. Outcome data were significantly better in unilateral compared to bilateral PVL. CONCLUSIONS: Long-term neurodevelopmental outcome of bilateral PVL always was adverse and different from unilateral PVL. The latter might be negatively influenced by associated intra- and periventricular haemorrhages. PMID- 26099230 TI - Vertical extraventricular functional hemispherotomy: a new variant for hemispheric disconnection. Technical notes and results in three patients. AB - PURPOSE: Hemispherectomy and disconnective hemispherotomy are the most effective epilepsy surgical procedures for the treatment of epilepsy due to hemispheric pathologies such as Sturge-Weber syndrome, diffuse hemispheric cortical dysplasia, and posttraumatic and postischemic focal lesions. Disconnective hemispherotomy is nowadays preferred to reduce surgical morbidity in term of early and late complications (i.e., cerebral superficial hemosiderosis). Despite the number of existing technical variants conceived to further reduce the amount of brain tissue to be removed, postoperative hydrocephalus still persists and may account for an average incidence of 15-41% according to different series and reviews. A new variant of disconnective vertical hemispherotomy we termed vertical extraventricular parasagittal hemispherotomy is described aiming to further reduce the amount of removed brain tissue and so the risk of postoperative hydrocephalus in favor of a pure hemispheric disconnection. METHODS: Three patients affected by drug-resistant epilepsy due to different hemispheric pathologies (posttraumatic epilepsy, Sturge-Weber syndrome, diffuse hemispheric cortical dysplasia) were considered to be candidates for vertical extraventricular parasagittal hemispherotomy disconnective based on presurgical evaluation protocol. The oldest patient was 15 years old, the two youngest were both 2 years old. RESULTS: None of the patients experienced early and late surgical complications. After a mean follow-up of 36 months (range 12-60 months), two patients were seizure free, one relapsed seizures 18 months later. Postoperative hydrocephalus never occurred. CONCLUSION: Vertical extraventricular parasagittal hemispherotomy may be an efficacious and less invasive technique as it consists in a pure disconnection of the hemisphere with less amount of brain tissue removed and a theoretical reduced risk of postoperative hydrocephalus. PMID- 26099231 TI - The vanishing shunt valve. AB - PURPOSE: Ventriculoperitoneal (VP) shunt is one of the most commonly performed procedures by a neurosurgeon. It is occasionally fraught with the most bizarre complications. Understanding the pathophysiology of these complications can help us make the procedure safe and more effective. METHODS: The authors report a case of 8-year-old boy, previously operated for lumbar myelomeningocele and hydrocephalus with an intra diploic migration of shunt tube and shunt dysfunction, and discuss the pathophysiology, diagnosis, and surgical strategy. RESULTS: After diagnosis of shunt malfunction, shunt revision was done with placement of new system and removal of the old apparatus. Patient had a remarkable recovery after the surgery. CONCLUSION: Intradiploic migration is an extremely rare cause of shunt malfunction and has never been reported in literature before. Possible mechanism is that prolonged pressure on the valve due to recumbent head position in a paraplegic child might have led to new bone formation and subsequent intradiploic migration of the valve. Careful planning the position of shunt valve in relation to head position, especially in children who are recumbent due to paraplegia might avoid this untoward complication. PMID- 26099232 TI - Functional hemispherectomy for catastrophic epilepsy in very young infants: technical considerations and complication avoidance. AB - PURPOSE: We report on our experience in performing peri-insular functional hemispherectomy (PIH) in very young infants with catastrophic epilepsy. METHODS: We retrospectively reviewed the medical charts of all infants with catastrophic epilepsy that underwent PIH under the age of 4 months at our institution. RESULTS: Four infants (three female, one male) were included (median age at time of surgery 2.9 months, range from 2.4 to 4.2 months; median patient's weight at time of surgery 5650 g, range from 4300 to 7500 g). None of the patients experienced hemodynamic instability during surgery. All four patients were given red blood cell replacement (median 435 ml, range from 230 to 800 ml), three of the four patients experienced coagulopathy during surgery and were given platelet cells transfusion in one (50 ml) and fresh frozen plasma in two patients (191 and 320 ml). Two patients experienced severe complications that, however, did not cause a permanent morbidity due to prompt diagnosis and correct management. After a median follow-up time of 4.3 years (range from 1.3 to 7.9 years), three of four patients are completely seizure free. The remaining patient is experiencing brief daily staring episodes. All of them have a hemiparesis but are fully ambulatory and have a useful upper limb function. CONCLUSION: In catastrophic epilepsy, PIH within the first months of life is feasible provided that an experienced multidisciplinary team is involved. Awareness of surgical challenges and potential complications is indispensible when the life-threatening nature of the epilepsy compels neurosurgeons to operate at this very young age. PMID- 26099233 TI - Antibiotics for acute otitis media in children. AB - BACKGROUND: Acute otitis media (AOM) is one of the most common diseases in early infancy and childhood. Antibiotic use for AOM varies from 56% in the Netherlands to 95% in the USA, Canada and Australia. This is an update of a Cochrane review first published in The Cochrane Library in Issue 1, 1997 and previously updated in 1999, 2005, 2009 and 2013. OBJECTIVES: To assess the effects of antibiotics for children with AOM. SEARCH METHODS: We searched CENTRAL (2015, Issue 3), MEDLINE (1966 to April week 3, 2015), OLDMEDLINE (1958 to 1965), EMBASE (January 1990 to April 2015), Current Contents (1966 to April 2015), CINAHL (2008 to April 2015) and LILACS (2008 to April 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing 1) antimicrobial drugs with placebo and 2) immediate antibiotic treatment with expectant observation (including delayed antibiotic prescribing) in children with AOM. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: For the review of antibiotics against placebo, 13 RCTs (3401 children and 3938 AOM episodes) from high-income countries were eligible and had generally low risk of bias. The combined results of the trials revealed that by 24 hours from the start of treatment, 60% of the children had recovered whether or not they had placebo or antibiotics. Pain was not reduced by antibiotics at 24 hours (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.78 to 1.01) but almost a third fewer had residual pain at two to three days (RR 0.70, 95% CI 0.57 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) 20). A quarter fewer had pain at four to seven days (RR 0.76, 95% CI 0.63 to 0.91; NNTB 16) and two-thirds fewer had pain at 10 to 12 days (RR 0.33, 95% CI 0.17 to 0.66; NNTB 7) compared with placebo. Antibiotics did reduce the number of children with abnormal tympanometry findings at two to four weeks (RR 0.82, 95% CI 0.74 to 0.90; NNTB 11), at six to eight weeks (RR 0.88, 95% CI 0.78 to 1.00; NNTB 16) and the number of children with tympanic membrane perforations (RR 0.37, 95% CI 0.18 to 0.76; NNTB 33) and halved contralateral otitis episodes (RR 0.49, 95% CI 0.25 to 0.95; NNTB 11) compared with placebo. However, antibiotics neither reduced the number of children with abnormal tympanometry findings at three months (RR 0.97, 95% CI 0.76 to 1.24) nor the number of children with late AOM recurrences (RR 0.93, 95% CI 0.78 to 1.10) when compared with placebo. Severe complications were rare and did not differ between children treated with antibiotics and those treated with placebo. Adverse events (such as vomiting, diarrhoea or rash) occurred more often in children taking antibiotics (RR 1.38, 95% CI 1.19 to 1.59; number needed to treat for an additional harmful outcome (NNTH) 14). Funnel plots do not suggest publication bias. Individual patient data meta-analysis of a subset of included trials found antibiotics to be most beneficial in children aged less than two years with bilateral AOM, or with both AOM and otorrhoea.For the review of immediate antibiotics against expectant observation, five trials (1149 children) from high-income countries were eligible and had low to moderate risk of bias. Four trials (1007 children) reported outcome data that could be used for this review. From these trials, data from 959 children could be extracted for the meta-analysis of pain at three to seven days. No difference in pain was detectable at three to seven days (RR 0.75, 95% CI 0.50 to 1.12). One trial (247 children) reported data on pain at 11 to 14 days. Immediate antibiotics were not associated with a reduction in the number of children with pain (RR 0.91, 95% CI 0.75 to 1.10) compared with expectant observation. Additionally, no differences in the number of children with abnormal tympanometry findings at four weeks, tympanic membrane perforations and AOM recurrence were observed between groups. No serious complications occurred in either the antibiotic or the expectant observation group. Immediate antibiotics were associated with a substantial increased risk of vomiting, diarrhoea or rash compared with expectant observation (RR 1.71, 95% CI 1.24 to 2.36; NNTH 9).Results from an individual patient data meta-analysis including data from six high-quality trials (1643 children) that were also included as individual trials in our review showed that antibiotics seem to be most beneficial in children younger than two years of age with bilateral AOM (NNTB 4) and in children with both AOM and otorrhoea (NNTB 3). AUTHORS' CONCLUSIONS: This review reveals that antibiotics have no early effect on pain, a slight effect on pain in the days following and only a modest effect on the number of children with tympanic perforations, contralateral otitis episodes and abnormal tympanometry findings at two to four weeks and at six to eight weeks compared with placebo in children with AOM. In high-income countries, most cases of AOM spontaneously remit without complications. The benefits of antibiotics must be weighed against the possible harms: for every 14 children treated with antibiotics one child experienced an adverse event (such as vomiting, diarrhoea or rash) that would not have occurred if antibiotics were withheld. Therefore clinical management should emphasise advice about adequate analgesia and the limited role for antibiotics. Antibiotics are most useful in children under two years of age with bilateral AOM, or with both AOM and otorrhoea. For most other children with mild disease in high-income countries, an expectant observational approach seems justified. PMID- 26099234 TI - Mixed Expectations: Effects of Goal Ambivalence during Pregnancy on Maternal Well Being, Stress, and Coping. AB - BACKGROUND: We hypothesised that experiencing ambivalence toward the childbearing goal would be related to indicators of well-being, stress, and coping among women with planned pregnancies. METHODS: Study 1 (N = 208) tested cross-sectional associations between goal ambivalence and measures of well-being, stress, and coping. It also included a postpartum measurement point (N = 71) to examine prospective effects of goal ambivalence. Study 2 (N = 109) extended the investigation to within-person effects in a three-week daily diary assessment. RESULTS: In Study 1, goal ambivalence in pregnant women was positively associated with depressive symptoms, perceived stress, and pregnancy-specific avoidance oriented coping, and negatively associated with coping self-efficacy. Goal ambivalence also predicted changes in life satisfaction, depressive symptoms, perceived stress, and coping self-efficacy postpartum. Study 2 revealed within person effects of daily fluctuations in goal ambivalence on day-to-day changes in positive emotions, negative activation, and avoidance-oriented coping. CONCLUSIONS: Ambivalence towards the childbearing goal is a source of significant distress to pregnant women with planned pregnancies and its effects seem to extend into the postpartum period. These findings may have important clinical implications for maternal and child well-being. Future studies should examine whether goal ambivalence during pregnancy affects the maternal-child relationship in the long term. PMID- 26099235 TI - Lessons learned about primary weight maintenance and secondary weight maintenance: results from a qualitative study. AB - BACKGROUND: Obesity is now a worldwide problem and Ireland is no exception with approximately two thirds of the adult population now overweight or obese. A recent report has found that 53% of Irish adults aged 50 years and over are classified as centrally obese and at substantially increased risk of metabolic complications. While most studies investigating weight maintenance have been conducted on those who have managed to lose weight and/or achieved weight loss maintenance (secondary weight maintainers), few studies have been undertaken to understand the attitudes, behaviours, motivations and strategies of those who maintain their weight within normal weight ranges over their lifetime, so called primary weight maintainers. This study aims to explore this issue through qualitative exploration of primary weight maintainers in an Irish University. METHODS: Seven focus groups were conducted (including three single interviews) with 17 participants in total across three different groups, 1) primary weight maintainers, 2) secondary weight maintainers, and 3) those unable to sustain or achieve weight loss. The interviews were transcribed and thematic analysis was applied to interpret the findings. RESULTS: After analyzing the participant's interviews, planning and organization or lack of, emerged as themes across the three groups in varying degrees. Strategizing, perseverance and willpower were seen as integral to weight maintenance and weight loss in groups one and two, these were lacking in group three. Prioritizing exercise and perseverance in maintaining a high level of activity was evident in groups one and two and was lacking in group three. Motivational influences were equal across the groups however, group three found it difficult to turn this into action. Group one had behavioural control of calorie intake maintaining a balance between week and weekend eating. Group three found it difficult to control calorie intake and portion size. Self-image differed across the three groups with cognitive dissonance evident amongst those in group three. CONCLUSIONS: This study showed that there are many factors that influence primary weight maintenance. Considering that we live in a society that is predominantly sedentary, predominantly overweight and with poor food choice options facing us every day, fighting our way through to ensure healthy weight maintenance requires active, conscious efforts. The factors identified in this study which are important in healthy weight maintenance are all potentially modifiable with life-coach, nutrition, exercise and cognitive interventions particularly if peer support and a whole family approach are incorporated. PMID- 26099237 TI - Cloning, expression, and partial characterization of FBPA from Schistosoma japonicum, a molecule on that the fluke may develop nutrition competition and immune evasion from human. AB - Carbohydrate metabolism is the most important physiological process for Schistosoma japonicum which resides in host. However, as a key glycolytic enzyme in carbohydrate metabolism, fructose-1,6-bisphosphate aldolase (FBPA), there is no study on its enzymatic kinetics and antigenic peptides. Here, we report the gene cloning, expression, purification, and kinetics of the FBPA from S. japonicum (sjFBPA). After cloning, sjFBPA gene was introduced into pET-28a and transformed BL21, and a soluble His6-sjFBPA was expressed and purified successfully at the expected molecular mass of ~45 kDa. We first reported that the diversities in IGS regions and the features of residues position 346 and 357 362 of sjFBPA may be conferred either through conformational changes influencing easily the active site from a distance and/or causing the C-terminal region to interact directly with the active site, which lead His6-sjFBPA to exhibit a higher specific activity of 197.43 units/mg and degrades FBP with a typical substrate inhibition model and a higher efficiency of k cat = 6261.3/s and K m = 0.061 MUM than human aldolases, which might be the strategy that S. japonicum gaining energy and surviving in its environment with low concentration of carbohydrate, and benefitting to get more metabolic substances for parasites in nutrition competition with their host. sjFBPA exhibits a high similarity of 81.46 % with that of hosts, especially in antigenic peptide regions, and 14 of 15 antigenic peptides of sjFBPA were conserved to those of human aldolase A, B, and/or C with high identity (17, 16, or 16 antigenic peptides, respectively), which may result in a molecular mimicry of FBPA with that of host, and an immune evasion from their hosts. This work would supply an experimental base for using FBPA to prevent the schistosomiasis in the future. PMID- 26099236 TI - Phosphorylation of Pex11p does not regulate peroxisomal fission in the yeast Hansenula polymorpha. AB - Pex11p plays a crucial role in peroxisomal fission. Studies in Saccharomyces cerevisiae and Pichia pastoris indicated that Pex11p is activated by phosphorylation, which results in enhanced peroxisome proliferation. In S. cerevisiae but not in P. pastoris, Pex11p phosphorylation was shown to regulate the protein's trafficking to peroxisomes. However, phosphorylation of PpPex11p was proposed to influence its interaction with Fis1p, another component of the organellar fission machinery. Here, we have examined the role of Pex11p phosphorylation in the yeast Hansenula polymorpha. Employing mass spectrometry, we demonstrate that HpPex11p is also phosphorylated on a Serine residue present at a similar position to that of ScPex11p and PpPex11p. Furthermore, through the use of mutants designed to mimic both phosphorylated and unphosphorylated forms of HpPex11p, we have investigated the role of this post-translational modification. Our data demonstrate that mutations to the phosphorylation site do not disturb the function of Pex11p in peroxisomal fission, nor do they alter the localization of Pex11p. Also, no effect on peroxisome inheritance was observed. Taken together, these data lead us to conclude that peroxisomal fission in H. polymorpha is not modulated by phosphorylation of Pex11p. PMID- 26099238 TI - In vivo evaluation of Phthirus pubis with reflectance confocal microscopy. PMID- 26099239 TI - Juvenile-specific cathepsin proteases in Fasciola spp.: their characteristics and vaccine efficacies. AB - Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is one of the most neglected tropical zoonotic diseases. One sustainable control strategy against these infections is the employment of vaccines that target proteins essential for parasites' invasion and nutrition acquiring processes. Cathepsin proteases are the most abundantly expressed proteins in Fasciola spp. that have been tested successfully as vaccines against fasciolosis in experimental as well as large animals because of their important roles in digestion of nutrients, invasion, and migration. Specifically, juvenile-specific cathepsin proteases are the more effective vaccines because they could block the invasion and migration of juvenile parasites whose immune evasion mechanism has not yet been fully developed. Moreover, because of high sequence similarity and identity of cathepsins from juveniles with those of adults, the vaccines can attack both the juvenile and adult stages. In this article, the characteristics and vaccine potentials of juvenile-specific cathepsins, i.e., cathepsins L and B, of Fasciola spp. were reviewed. PMID- 26099240 TI - Characterization and bioassay for larvicidal activity of Anacardium occidentale (cashew) shell waste fractions against dengue vector Aedes aegypti. AB - Recent studies regarding the harmful effects of synthetic larvicides initiated the need to investigate for unconventional measures that are environmentally safe and target-specific against Aedes aegypti larvae. Thus, the main objectives of the study are to evaluate the larvicidal toxicity of the solvent fractions of Anacardium occidentale shell wastes against the third and fourth instar larvae of A. aegypti and to compare the results with the commercial larvicide product. The shell wastes were extracted with 95% EtOH followed by polarity-based fractionation. The fractions were tested for larvicidal activity according to the World Health Organization bioassay method. These were then characterized by quantitative thin-layer chromatographic (TLC) fingerprinting. The hexane fraction gave the strongest activity among the fractions with an LC50 of 4.01 mg/L and LC90 of 11.29 mg/L highly comparable to the commercial larvicide, which exhibited an LC50 of 1.71 mg/L and LC90 of 8.41 mg/L. The dichloromethane fraction exhibited 9.70 mg/L LC50 and 18.44 mg/L LC90. The remarkable toxicity effects exhibited by these fractions indicate their potential to provide core structures from which sustainable and environmentally safe plant-based larvicidal agents can be synthesized. PMID- 26099241 TI - Exercise capacity impairment in COPD patients with comorbidities. AB - BACKGROUND: Comorbidities are common in COPD and have been associated with reduced health status, increased health care utilization, all-cause hospitalization, and mortality. There is a scarcity of data on the relationship between comorbidities and functional capacity. OBJECTIVE: to evaluate the impact of comorbidities on functional capacity of COPD patients. METHODS: a cross sectional study was conducted at two teaching hospitals in Fortaleza, Brazil. The functional capacity was assessed by spirometry and the 6-min walking test (6MWT). The health status was assessed by the St. George's respiratory questionnaire (SGRQ) and the COPD assessment test (CAT). The sample was stratified as having "none", "one" and "two or three" comorbidities groups. One-way ANOVA was used to compare means of the three groups and a multiple linear regression was run to predict the impact of comorbidities on 6MWT. RESULTS: Comorbidities (hypertension, coronary disease and diabetes) were found in 54% of the studied patients. The mean age of the 79 patients was 67+/-8 years and 55% were male. CAT scores increased from "no comorbidity" (17.9+/-7.7) to "one comorbidity" (22.8+/ 6.8) and "two or three comorbidities" groups (24.2+/-10.2). A post hoc test showed a significant difference in the "no comorbidity" compared to the "two or three comorbidities" groups (p=0.01). The distance walked by the patients decreased from "no comorbidity" (386.1+/-83.2m) to "one comorbidity" (350+/-98m) and "two or three comorbidities" groups (312.6+/-91m). A post hoc test showed significant difference in the "no comorbidity" compared to "two or three comorbidities" groups (p=0.007). Numbers of comorbidities were independently associated with the 6MWT adjusting for age, severity of COPD and CAT scores. CONCLUSION: in the studied sample, the presence of comorbidities contributed to impair exercise capacity in patients with COPD. PMID- 26099242 TI - Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio). AB - Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine. PMID- 26099243 TI - Larva of the greater wax moth, Galleria mellonella, is a suitable alternative host for studying virulence of fish pathogenic Vibrio anguillarum. AB - BACKGROUND: Microbial diseases cause considerable economic losses in aquaculture and new infection control measures often rely on a better understanding of pathogenicity. However, disease studies performed in fish hosts often require specialist infrastructure (e.g., aquaria), adherence to strict legislation and do not permit high-throughput approaches; these reasons justify the development of alternative hosts. This study aimed to validate the use of larvae of the greater wax moth (Galleria mellonella) to investigate virulence of the important fish pathogen, Vibrio anguillarum. RESULTS: Using 11 wild-type isolates of V. anguillarum, these bacteria killed larvae in a dose-dependent manner and replicated inside the haemolymph, but infected larvae were rescued by antibiotic therapy. Crucially, virulence correlated significantly and positively in larva and Atlantic salmon (Salmo salar) infection models. Challenge studies with mutants knocked out for single virulence determinants confirmed conserved roles in larva and fish infections in some cases (pJM1 plasmid, rtxA), but not all (empA, flaA, flaE). CONCLUSIONS: The G. mellonella model is simple, more ethically acceptable than experiments on vertebrates and, crucially, does not necessitate liquid systems, which reduces infrastructure requirements and biohazard risks associated with contaminated water. The G. mellonella model may aid our understanding of microbial pathogens in aquaculture and lead to the timely introduction of new effective remedies for infectious diseases, while adhering to the principles of replacement, reduction and refinement (3Rs) and considerably reducing the number of vertebrates used in such studies. PMID- 26099246 TI - Commentary on "Monosodium glutamate neurotoxicity increases beta amyloid in the rat hippocampus: A potential role for cyclic AMP protein kinase" (Dief et al., 2014). PMID- 26099249 TI - Regio- and Stereoselective Modification of Chiral alpha-Amino Ketones by Pd Catalyzed Allylic Alkylation. AB - Chiral alpha-amino ketones are excellent nucleophiles for stereoselective palladium-catalyzed allylic alkylations. Both chiral as well as achiral allylic substrates can be applied, while the stereochemical outcome of the reaction is controlled by the chiral ketone enolate. The substituted amino ketones formed can be reduced stereoselectively, and up to five consecutive stereogenic centers can be obtained. This approach can be used for the synthesis of highly substituted piperidine derivatives. PMID- 26099244 TI - Reducing HIV Risks in the Places Where People Drink: Prevention Interventions in Alcohol Venues. AB - Apart from individual alcohol drinking behavior, the context or places where people drink play a significant role in HIV transmission risk. In this paper, we review the research that has been conducted on alcohol venues to identify the social and structural factors (e.g., social norms, sexual behavior) that are associated with HIV risk in these places, to review HIV prevention interventions based in alcohol venues, and to discuss appropriate methodologies for alcohol venue research. Alcohol venues are defined here as places that sell or serve alcohol for onsite consumption, including bars, bottle stores, nightclubs, wine shops, and informal shebeens. Despite the many established HIV risk factors at play in alcohol venues, limited prevention strategies have been implemented in such places. A total of 11 HIV prevention interventions or programs were identified. HIV prevention interventions in alcohol venues may be conducted at the individual, social, or structural level. However, multilevel interventions that target more than one level appear to lead to the most sustainable behavior change. Strategies to incorporate alcohol venues in biomedical prevention strategies including antiretroviral therapy for alcohol users are also discussed. PMID- 26099250 TI - Bifunctional non-noble metal oxide nanoparticle electrocatalysts through lithium induced conversion for overall water splitting. AB - Developing earth-abundant, active and stable electrocatalysts which operate in the same electrolyte for water splitting, including oxygen evolution reaction and hydrogen evolution reaction, is important for many renewable energy conversion processes. Here we demonstrate the improvement of catalytic activity when transition metal oxide (iron, cobalt, nickel oxides and their mixed oxides) nanoparticles (~20 nm) are electrochemically transformed into ultra-small diameter (2-5 nm) nanoparticles through lithium-induced conversion reactions. Different from most traditional chemical syntheses, this method maintains excellent electrical interconnection among nanoparticles and results in large surface areas and many catalytically active sites. We demonstrate that lithium induced ultra-small NiFeOx nanoparticles are active bifunctional catalysts exhibiting high activity and stability for overall water splitting in base. We achieve 10 mA cm(-2) water-splitting current at only 1.51 V for over 200 h without degradation in a two-electrode configuration and 1 M KOH, better than the combination of iridium and platinum as benchmark catalysts. PMID- 26099251 TI - Ultrasound signs of pulmonary fibrosis in systemic sclerosis as timely indicators for chest computed tomography. AB - OBJECTIVES: Systemic sclerosis (SSc) patients in the early stages of pulmonary fibrosis (PF) often have few or no symptoms, normal to borderline pulmonary function tests, and negative chest X-ray (CXR); high-resolution computed tomography (HRCT) is the only reliable means of detecting the early signs of PF. However, thoracic ultrasound (TUS) enables detection of pleural thickening, pleural/subpleural nodules, and other subpleural lung abnormalities across 70% of the subpleural surface. We reassessed concordance between TUS abnormalities and HRCT findings in SSc patients, to see whether TUS pleural line thickness (normally <3.0 mm) could be used to earmark those with asymptomatic PF for timely HRCT assessment. METHOD: In total, 175 SSc patients (nine males, 166 females), aged 46.46+/-15.33 years, were given CXR, TUS, HRCT, echocardiography, and pulmonary function tests. RESULTS: In the 26 patients without HRCT signs of PF, pleural line thickness was <=3.0 mm. In diffuse SSc, 97/137 patients showed pleural line thickening (between 3.0 and 5 mm) and subpleural nodules in 32/97; and 35/137 showed major pleural line thickening (>=5.0 mm) with nodules, with good concordance with HRCT patterns indicating lung fibrosis severity. HRCT was normal in 5/137, with pleural line thickness<=3.0 mm. CONCLUSIONS: TUS imaging of pleural/subpleural structures can detect ultrasonographic signs of initial PF prior to the onset of respiratory symptoms and function test abnormalities and, together with current criteria, could thereby enable exclusion of PF in SSc patients. Indicating some patients for selective referral to HRCT can thereby delay unwarranted procedures, provided that pulmonary function and TUS images are stable. PMID- 26099252 TI - Alterations of Bacteroides sp., Neisseria sp., Actinomyces sp., and Streptococcus sp. populations in the oropharyngeal microbiome are associated with liver cirrhosis and pneumonia. AB - BACKGROUND: The microbiomes of humans are associated with liver and lung inflammation. We identified and verified alterations of the oropharyngeal microbiome and assessed their association with cirrhosis and pneumonia. METHODS: Study components were as follows: (1) determination of the temporal stability of the oropharyngeal microbiome; (2) identification of oropharyngeal microbial variation in 90 subjects; (3) quantitative identification of disease-associated bacteria. DNAs enriched in bacterial sequences were produced from low-biomass oropharyngeal swabs using whole genome amplification and were analyzed using denaturing gradient gel electrophoresis analysis. RESULTS: Whole genome amplification combined with denaturing gradient gel electrophoresis analysis monitored successfully oropharyngeal microbial variations and showed that the composition of each subject's oropharyngeal microbiome remained relatively stable during the follow-up. The microbial composition of cirrhotic patients with pneumonia differed from those of others and clustered together in subgroup analysis. Further, species richness and the value of Shannon's diversity and evenness index increased significantly in patients with cirrhosis and pneumonia versus others (p < 0.001, versus healthy controls; p < 0.01, versus cirrhotic patients without pneumonia). Moreover, we identified variants of Bacteroides, Eubacterium, Lachnospiraceae, Neisseria, Actinomyces, and Streptococcus through phylogenetic analysis. Quantitative polymerase chain reaction assays revealed that the populations of Bacteroides, Neisseria, and Actinomycetes increased, while that of Streptococcus decreased in cirrhotic patients with pneumonia versus others (p < 0.001, versus Healthy controls; p < 0.01, versus cirrhotic patients without pneumonia). CONCLUSIONS: Alterations of Bacteroides, Neisseria, Actinomyces, and Streptococcus populations in the oropharyngeal microbiome were associated with liver cirrhosis and pneumonia. PMID- 26099253 TI - Accumulation and toxicity of intravenously-injected functionalized graphene oxide in mice. AB - Graphene and its functionalized derivatives have recently emerged as interesting nanomaterials with promising applications in biomedicine. In this study, the long term in vivo biodistribution of intravenously injected nanographene oxide (NGO) functionalized with poly sodium 4-styrenesulfonate (PSS) was systematically examined and the potential toxicity over 6 months of NGO-PSS nanoparticles was investigated. Our results showed that the nanoparticles mainly accumulate in the lung, liver and spleen, where they persist for at least 6 months. These nanoparticles result in acute liver injury and chronic inflammation of the lung, liver and spleen, as evidenced by blood biochemistry results and histological examinations. PMID- 26099254 TI - Distinguishing between emotional distress and psychiatric disorder in primary care attenders: A cross sectional study of the four-dimensional symptom questionnaire (4DSQ). AB - BACKGROUND: Detection of psychiatric disorder in primary care is a complex issue. Distinctions between 'normal' emotional distress and psychiatric disorder depend on how disorder is conceptualized. Our aim was to explore two different conceptualizations by examining patients' scores on one-dimensional depression measures and scores on the Four Dimensional Symptom Questionnaire (4DSQ), a measure that uniquely has separate dimensions for general distress and depressive disorder. METHODS: This was a cross sectional study of 487 primary care patients attending general clinics in Hampshire, UK. Patients completed the 4DSQ, Patient Health Questionnaire-9 (PHQ-9), General Health Questionnaire-12 (GHQ-12) and the Hospital Anxiety and Depression Scale (HADS) whilst in the waiting room. RESULTS: The 4DSQ classified 26% (126/485) of patients as having heightened distress levels and 8% (38/468) as possible cases of depressive disorder. Casesness was consistently higher across the one-dimensional measures (PHQ-9: 16%, GHQ-12: 28%, HADS-D: 13%). Of those patients deemed possible cases by the PHQ-9 (>= 10), the 4DSQ classified 91% (71/78) as having heightened distress and 44% (32/72) as possible cases of depressive disorder. LIMITATIONS: The sample was predominately older and white, which may limit generalizability of the findings to more diverse patient groups. There are limits to self-report measures in the assessment of complex diagnostic issues. CONCLUSIONS: Inclusion of a distinct general distress dimension alongside a dimension focusing on specific depression symptomatology lowered the number of primary care patients classified as possible cases of disorder. This view of symptoms may have implications for the targeting of existing treatments, and may be useful in guiding the development of novel self management interventions. PMID- 26099255 TI - Transcatheter Structural Heart Interventions for the Treatment of Chronic Heart Failure. PMID- 26099257 TI - Superficial thrombophlebitis (superficial venous thrombosis). PMID- 26099256 TI - Update on strategies limiting iatrogenic hypoglycemia. AB - The prevalence of type 2 diabetes mellitus (T2DM) is increasing all over the world. Targeting good glycemic control is fundamental to avoid the complications of diabetes linked to hyperglycemia. This narrative review is based on material searched for and obtained via PubMed up to April 2015. The search terms we used were: 'hypoglycemia, diabetes, complications' in combination with 'iatrogenic, treatment, symptoms.' Serious complications might occur from an inappropriate treatment of hyperglycemia. The most frequent complication is iatrogenic hypoglycemia that is often associated with autonomic and neuroglycopenic symptoms. Furthermore, hypoglycemia causes acute cardiovascular effects, which may explain some of the typical symptoms: ischemia, QT prolongation, and arrhythmia. With regards to the latter, the night represents a dangerous period because of the major increase in arrhythmias and the prolonged period of hypoglycemia; indeed, sleep has been shown to blunt the sympatho-adrenal response to hypoglycemia. Two main strategies have been implemented to reduce these effects: monitoring blood glucose values and individualized HbA1c goals. Several drugs for the treatment of T2DM are currently available and different combinations have been recommended to achieve individualized glycemic targets, considering age, comorbidities, disease duration, and life expectancy. In conclusion, according to international guidelines, hypoglycemia-avoiding therapy must reach an individualized glycemic goal, which is the lowest HbA1c not causing severe hypoglycemia and preserving awareness of hypoglycemia. PMID- 26099258 TI - Can We Identify Genes with Increased Phylogenetic Reliability? AB - Topological heterogeneity among gene trees is widely observed in phylogenomic analyses and some of this variation is likely caused by systematic error in gene tree estimation. Systematic error can be mitigated by improving models of sequence evolution to account for all evolutionary processes relevant to each gene or identifying those genes whose evolution best conforms to existing models. However, the best method for identifying such genes is not well established. Here, we ask if filtering genes according to their clock-likeness or posterior predictive effect size (PPES, an inference-based measure of model violation) improves phylogenetic reliability and congruence. We compared these approaches to each other, and to the common practice of filtering based on rate of evolution, using two different metrics. First, we compared gene-tree topologies to accepted reference topologies. Second, we examined topological similarity among gene trees in filtered sets. Our results suggest that filtering genes based on clock likeness and PPES can yield a collection of genes with more reliable phylogenetic signal. For the two exemplar data sets we explored, from yeast and amniotes, clock-likeness and PPES outperformed rate-based filtering in both congruence and reliability. PMID- 26099259 TI - Lipophilicity of porphyrins and their retention in IAM, C8-C18 and HILIC chromatographic systems. AB - Porphyrins are a class of photosensitizers used in photodynamic therapy (PDT). Understanding the interaction of porphyrins with membrane cells components is important in order to improve this therapy. Many analytical methods can be used for this aim. High performance liquid chromatography (HPLC) was used for the separation of porphyrins on RP and HILIC stationary phases as well as on a biomimetic membrane IAM phase. Twenty-six tetraphenyl porphyrins (TPP) were successfully separated on an IAM column, a C18 Gravity RP column, a C8 Gravity RP column, a PolarTec RP column and a HILIC column. Stationary phases were chosen as the most appropriate to cover the study of different types of interactions. Elution was performed with a 45 min linear gradient. Obtained gradient retention times were converted to gradient chromatography hydrophobicity index (CHI) and to an apparent retention factor (kapp). The partition coefficients (logP) of the 26 compounds were measured in a 2-octanol/PBS system and estimated in silico. Correlation between kapp values was studied. Moreover, a multivariate analysis was performed to explain columns relationships. Obtained results show that porphyrins are separated mainly according to hydrophobic interactions that are relative to their structure (sugar number and the disposition around the porphyrin macrocycle). PMID- 26099260 TI - High-performance liquid chromatographic separation of paclitaxel intermediate phenylisoserine derivatives on macrocyclic glycopeptide and cyclofructan-based chiral stationary phases. AB - High-performance liquid chromatographic methods were developed for the separation of enantiomers of four unnatural paclitaxel precursor phenylisoserine analogs on chiral stationary phases containing macrocyclic glycopeptides and cyclofructans as chiral selectors. The effects of the mobile phase composition, the nature and concentration of different mobile phase additives (alcohols, amines and acids) in different chromatographic modes, temperature and the structures of the analytes on the separations were investigated. Separations were carried out at constant mobile phase compositions in the temperature range 10-50 degrees C on macrocyclic antibiotic-based and 5-35 degrees C on cyclofructan-based columns and the changes in enthalpy, Delta(DeltaH degrees ), entropy, Delta(DeltaS degrees ), and free energy, Delta(DeltaG degrees ), were calculated. The elution sequence was determined in most cases; no general rule could be observed. PMID- 26099261 TI - Independent comparison study of six different electronic tongues applied for pharmaceutical analysis. AB - Electronic tongue technology based on arrays of cross-sensitive chemical sensors and chemometric data processing has attracted a lot of researchers' attention through the last years. Several so far reported applications dealing with pharmaceutical related tasks employed different e-tongue systems to address different objectives. In this situation, it is hard to judge on the benefits and drawbacks of particular e-tongue implementations for R&D in pharmaceutics. The objective of this study was to compare the performance of six different e-tongues applied to the same set of pharmaceutical samples. For this purpose, two commercially available systems (from Insent and AlphaMOS) and four laboratory prototype systems (two potentiometric systems from Warsaw operating in flow and static modes, one potentiometric system from St. Petersburg, one voltammetric system from Barcelona) were employed. The sample set addressed in the study comprised nine different formulations based on caffeine citrate, lactose monohydrate, maltodextrine, saccharin sodium and citric acid in various combinations. To provide for the fair and unbiased comparison, samples were evaluated under blind conditions and data processing from all the systems was performed in a uniform way. Different mathematical methods were applied to judge on similarity of the e-tongues response from the samples. These were principal component analysis (PCA), RV' matrix correlation coefficients and Tuckers congruency coefficients. PMID- 26099262 TI - Quantitative determination of two polymorphic forms of imatinib mesylate in a drug substance and tablet formulation by X-ray powder diffraction, differential scanning calorimetry and attenuated total reflectance Fourier transform infrared spectroscopy. AB - Imatinib has been identified as a tyrosine kinase inhibitor that selectively inhibits the Abl tyrosine kinases, including Bcr-Abl. The active substance used in drug product is the mesylate salt form of imatinib, a phenylaminopyrimidine derivative and chemically named as N-(3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)-4 methylphenyl)-4-((4-methylpiperazin-1-yl) methyl)-benzamide methanesulfonic acid salt. It exhibits many polymorphic forms and most stable and commercialized polymorphs are known as alpha and beta forms. Molecules in alpha and beta polymorphic forms exhibit significant conformational differences due to their different intra- and intermolecular interactions, which stabilize their molecular conformations and affect their physicochemical properties such as bulk density, melting point, solubility, stability, and processability. The manufacturing process of a drug tablet included granulation, compression, coating, and drying may cause polymorphic conversions. Therefore, polymorphic content of the drug substance should be controlled during quality control and stability testing. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) methods were evaluated for determination of the polymorphic content of the drug substance and drug product; and PXRD was the most accurate technique and selected as preferred method and validated. Prior to development of a quantification method, pure alpha and beta polymorphs were characterized and used throughout the method development and validation studies. Mixtures with different ratios of alpha and beta forms were scanned using X-ray diffractometer with a scan rate of 0.250 degrees /min over an angular range of 19.5-21.0 degrees 2theta and the peak heights for characteristic peak of beta form at 20.5 +/- 0.2 degrees 2theta diffraction angle were used to generate a calibration curve. The detection limit of beta polymorph in alpha form imatinib mesylate tablets was found as 4% and the linear regression analysis data for the calibration plots showed good linear relationship with correlation coefficient of 0.992 with respect to relative peak height in the concentration range of 12-75 wt% beta form containing tablet mixtures. The obtained results at each stage of the validation study proved that the method is specific, repeatable, precise and accurate, and could be used for determination of beta polymorph content in tablets produced by using alpha polymorph of imatinib mesylate. The developed PXRD quantification method was used to monitor the polymorphic purity of alpha form drug substance and corresponding drug products during the quality control analyses and stability studies, and the results indicated that alpha form was stable and not converted to beta form during the manufacturing process and stability period. PMID- 26099263 TI - Forna (force-directed RNA): Simple and effective online RNA secondary structure diagrams. AB - MOTIVATION: The secondary structure of RNA is integral to the variety of functions it carries out in the cell and its depiction allows researchers to develop hypotheses about which nucleotides and base pairs are functionally relevant. Current approaches to visualizing secondary structure provide an adequate platform for the conversion of static text-based representations to 2D images, but are limited in their offer of interactivity as well as their ability to display larger structures, multiple structures and pseudoknotted structures. RESULTS: In this article, we present forna, a web-based tool for displaying RNA secondary structure which allows users to easily convert sequences and secondary structures to clean, concise and customizable visualizations. It supports, among other features, the simultaneous visualization of multiple structures, the display of pseudoknotted structures, the interactive editing of the displayed structures, and the automatic generation of secondary structure diagrams from PDB files. It requires no software installation apart from a modern web browser. AVAILABILITY AND IMPLEMENTATION: The web interface of forna is available at http://rna.tbi.univie.ac.at/forna while the source code is available on github at www.github.com/pkerpedjiev/forna. CONTACT: pkerp@tbi.univie.ac.at SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26099264 TI - Sincell: an R/Bioconductor package for statistical assessment of cell-state hierarchies from single-cell RNA-seq. AB - Cell differentiation processes are achieved through a continuum of hierarchical intermediate cell states that might be captured by single-cell RNA seq. Existing computational approaches for the assessment of cell-state hierarchies from single cell data can be formalized under a general framework composed of (i) a metric to assess cell-to-cell similarities (with or without a dimensionality reduction step) and (ii) a graph-building algorithm (optionally making use of a cell clustering step). The Sincell R package implements a methodological toolbox allowing flexible workflows under such a framework. Furthermore, Sincell contributes new algorithms to provide cell-state hierarchies with statistical support while accounting for stochastic factors in single-cell RNA seq. Graphical representations and functional association tests are provided to interpret hierarchies. The functionalities of Sincell are illustrated in a real case study, which demonstrates its ability to discriminate noisy from stable cell-state hierarchies. AVAILABILITY AND IMPLEMENTATION: Sincell is an open-source R/Bioconductor package available at http://bioconductor.org/packages/sincell. A detailed manual and a vignette are provided with the package. CONTACT: antonio.rausell@isb-sib.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26099265 TI - Bandage: interactive visualization of de novo genome assemblies. AB - Although de novo assembly graphs contain assembled contigs (nodes), the connections between those contigs (edges) are difficult for users to access. Bandage (a Bioinformatics Application for Navigating De novo Assembly Graphs Easily) is a tool for visualizing assembly graphs with connections. Users can zoom in to specific areas of the graph and interact with it by moving nodes, adding labels, changing colors and extracting sequences. BLAST searches can be performed within the Bandage graphical user interface and the hits are displayed as highlights in the graph. By displaying connections between contigs, Bandage presents new possibilities for analyzing de novo assemblies that are not possible through investigation of contigs alone. AVAILABILITY AND IMPLEMENTATION: Source code and binaries are freely available at https://github.com/rrwick/Bandage. Bandage is implemented in C++ and supported on Linux, OS X and Windows. A full feature list and screenshots are available at http://rrwick.github.io/Bandage. CONTACT: rrwick@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26099266 TI - Optimization of a multi-well colorimetric assay to determine haem species in Plasmodium falciparum in the presence of anti-malarials. AB - BACKGROUND: The activity of several well-known anti-malarials, including chloroquine (CQ), is attributed to their ability to inhibit the formation of haemozoin (Hz) in the malaria parasite. The formation of inert Hz, or malaria pigment, from toxic haem acquired from the host red blood cell of the parasite during haemoglobin digestion represents a pathway essential for parasite survival. Inhibition of this critical pathway therefore remains a desirable target for novel anti-malarials. A recent publication described the results of a haem fractionation assay used to directly determine haemoglobin, free haem and Hz in Plasmodium falciparum inoculated with CQ. CQ was shown to cause a dose dependent increase in cellular-free haem that was correlated with decreased parasite survival. The method provided valuable information but was limited due to its low throughput and high demand on parasite starting material. Here, this haem fractionation assay has been successfully adapted to a higher throughput method in 24-well plates, significantly reducing lead times and starting material volumes. METHODS: All major haem species in P. falciparum trophozoites, isolated through a series of cellular fractionation steps were determined spectrophotometrically in aqueous pyridine (5 % v/v, pH 7.5) as a low spin complex with haematin. Cell counts were determined using a haemocytometer and a rapid novel fluorescent flow cytometry method. RESULTS: A higher throughput haem fractionation assay in 24-well plates, containing at most ten million trophozoites was validated against the original published method using CQ and its robustness was confirmed. It provided a minimum six-fold improvement in productivity and 24-fold reduction in starting material volume. The assay was successfully applied to amodiaquine (AQ), which was shown to inhibit Hz formation, while the antifolate pyrimethamine (PYR) and the mitochondrial electron transporter inhibitor atovaquone (Atov) demonstrated no increase in toxic cellular free haem. CONCLUSIONS: This higher throughput cellular haem fractionation assay can easily be applied to novel anti-malarials with a significantly decreased lead time, providing a valuable tool with which to probe the mechanisms of action of both new and established anti-malarials. PMID- 26099267 TI - eHealth, Participatory Medicine, and Ethical Care: A Focus Group Study of Patients' and Health Care Providers' Use of Health-Related Internet Information. AB - BACKGROUND: The rapid explosion in online digital health resources is seen as transformational, accelerating the shift from traditionally passive patients to patients as partners and altering the patient-health care professional (HCP) relationship. Patients with chronic conditions are increasingly engaged, enabled, and empowered to be partners in their care and encouraged to take responsibility for managing their conditions with HCP support. OBJECTIVE: In this paper, we focus on patients' and HCPs' use of health-related Internet information and how it influences the patient-HCP relationship. In particular, we examine the challenges emerging in medical encounters as roles and relationships shift and apply a conceptual framework of relational ethics to examine explicit and nuanced ethical dimensions emerging in patient-HCP interactions as both parties make increased use of health-related Internet information. METHODS: We purposively sampled patients and HCPs in British Columbia, Canada, to participate in focus groups. To be eligible, patients self-reported a diagnosis of arthritis and at least one other chronic health condition; HCPs reported a caseload with >25% of patients with arthritis and multimorbidity. We used a semistructured, but flexible, discussion guide. All discussions were audiotaped and transcribed verbatim. Elements of grounded theory guided our constant comparison thematic analytic approach. Analysis was iterative. A relational ethics conceptual lens was applied to the data. RESULTS: We recruited 32 participants (18 patients, 14 HCPs). They attended seven focus groups: four with patients and three with rehabilitation professionals and physicians. Predominant themes to emerge were how use of health-related Internet information fostered (1) changing roles, (2) patient-HCP partnerships, and (3) tensions and burdens for patients and HCPs. CONCLUSIONS: Relational aspects such as mutual trust, uncertainty, and vulnerability are illuminated in patient-HCP interactions around health-related Internet information and the negotiated space of clinical encounters. New roles and associated responsibilities have key ethical dimensions that make clear the changes are fundamental and important to understand in ethical care. When faced with tensions and burdens around incorporating health-related Internet information as a resource in clinical encounters, participants described a particular ambivalence illustrating the fundamental changes being negotiated by both patients and HCPs. PMID- 26099268 TI - The Methylome of Soybean Roots during the Compatible Interaction with the Soybean Cyst Nematode. AB - The soybean cyst nematode (SCN; Heterodera glycines) induces the formation of a multinucleated feeding site, or syncytium, whose etiology includes massive gene expression changes. Nevertheless, the genetic networks underlying gene expression control in the syncytium are poorly understood. DNA methylation is a critical epigenetic mark that plays a key role in regulating gene expression. To determine the extent to which DNA methylation is altered in soybean (Glycine max) roots during the susceptible interaction with SCN, we generated whole-genome cytosine methylation maps at single-nucleotide resolution. The methylome analysis revealed that SCN induces hypomethylation to a much higher extent than hypermethylation. We identified 2,465 differentially hypermethylated regions and 4,692 hypomethylated regions in the infected roots compared with the noninfected control. In addition, 703 and 1,346 unique genes were identified as overlapping with hyper- or hypomethylated regions, respectively. The differential methylation in genes apparently occurs independently of gene size and GC content but exhibits strong preference for recently duplicated paralogs. Furthermore, a set of 278 genes was identified as specifically syncytium differentially methylated genes. Of these, we found genes associated with epigenetic regulation, phytohormone signaling, cell wall architecture, signal transduction, and ubiquitination. This study provides, to our knowledge, new evidence that differential methylation is part of the regulatory mechanisms controlling gene expression changes in the nematode-induced syncytium. PMID- 26099269 TI - A Potential Role for Mitochondrial Produced Reactive Oxygen Species in Salicylic Acid-Mediated Plant Acquired Thermotolerance. AB - To characterize the function of salicylic acid (SA) in acquired thermotolerance, the effects of heat shock (HS) on wild-type and sid2 (for SA induction deficient 2) was investigated. After HS treatment, the survival ratio of sid2 mutant was lower than that of wild-type. However, pretreatment with hydrogen peroxide (H2O2) rescued the sid2 heat sensitivity. HsfA2 is a key component of acquired thermotolerance in Arabidopsis. The expression of HsfA2 induced by SA was highest among those of heat-inducible Hsfs (HsfA2, HsfA7a, HsfA3, HsfB1, and HsfB2) in response to HS. Furthermore, the application of AsA, an H2O2 scavenger, significantly reduced the expression level of HsfA2 induced by SA. Although SA enhanced the survival of sid2 mutant, no significant effect on the hsfA2 mutant was observed, suggesting that HsfA2 is responsible for SA-induced acquired thermotolerance as a downstream factor. Further, real-time PCR analysis revealed that after HS treatment, SA also up-regulated mRNA transcription of HS protein (Hsp) genes through AtHsfA2. Time course experiments showed an increase in the fluorescence intensity of DCF in the mitochondria occurred earlier than in other regions of the protoplasts in response to SA. The cytochrome reductase activity analysis in isolated mitochondria demonstrated that SA-induced mitochondrial ROS possibly originated from complex III in the respiration chain. Collectively, our data suggest that SA functions and acts upstream of AtHsfA2 in acquired thermotolerance, which requires a pathway with H2O2 production involved and is dependent on increased expression of Hsp genes. PMID- 26099270 TI - Large Cellular Inclusions Accumulate in Arabidopsis Roots Exposed to Low-Sulfur Conditions. AB - Sulfur is vital for primary and secondary metabolism in plant roots. To understand the molecular and morphogenetic changes associated with loss of this key macronutrient, we grew Arabidopsis (Arabidopsis thaliana) seedlings in low sulfur conditions. These conditions induced a cascade of cellular events that converged to produce a profound intracellular phenotype defined by large cytoplasmic inclusions. The inclusions, termed low-sulfur Pox, show cell type- and developmental zone-specific localization. Transcriptome analysis suggested that low sulfur causes dysfunction of the glutathione/ascorbate cycle, which reduces flavonoids. Genetic and biochemical evidence indicated that low-sulfur Pox are the result of peroxidase-catalyzed oxidation of quercetin in roots grown under sulfur-depleted conditions. PMID- 26099271 TI - Comprehensive Tissue-Specific Transcriptome Analysis Reveals Distinct Regulatory Programs during Early Tomato Fruit Development. AB - Fruit formation and early development involve a range of physiological and morphological transformations of the various constituent tissues of the ovary. These developmental changes vary considerably according to tissue type, but molecular analyses at an organ-wide level inevitably obscure many tissue-specific phenomena. We used laser-capture microdissection coupled to high-throughput RNA sequencing to analyze the transcriptome of ovaries and fruit tissues of the wild tomato species Solanum pimpinellifolium. This laser-capture microdissection-high throughput RNA sequencing approach allowed quantitative global profiling of gene expression at previously unobtainable levels of spatial resolution, revealing numerous contrasting transcriptome profiles and uncovering rare and cell type specific transcripts. Coexpressed gene clusters linked specific tissues and stages to major transcriptional changes underlying the ovary-to-fruit transition and provided evidence of regulatory modules related to cell division, photosynthesis, and auxin transport in internal fruit tissues, together with parallel specialization of the pericarp transcriptome in stress responses and secondary metabolism. Analysis of transcription factor expression and regulatory motifs indicated putative gene regulatory modules that may regulate the development of different tissues and hormonal processes. Major alterations in the expression of hormone metabolic and signaling components illustrate the complex hormonal control underpinning fruit formation, with intricate spatiotemporal variations suggesting separate regulatory programs. PMID- 26099273 TI - BMRF-MI: integrative identification of protein interaction network by modeling the gene dependency. AB - BACKGROUND: Identification of protein interaction network is a very important step for understanding the molecular mechanisms in cancer. Several methods have been developed to integrate protein-protein interaction (PPI) data with gene expression data for network identification. However, they often fail to model the dependency between genes in the network, which makes many important genes, especially the upstream genes, unidentified. It is necessary to develop a method to improve the network identification performance by incorporating the dependency between genes. RESULTS: We proposed an approach for identifying protein interaction network by incorporating mutual information (MI) into a Markov random field (MRF) based framework to model the dependency between genes. MI is widely used in information theory to measure the uncertainty between random variables. Different from traditional Pearson correlation test, MI is capable of capturing both linear and non-linear relationship between random variables. Among all the existing MI estimators, we choose to use k-nearest neighbor MI (kNN-MI) estimator which is proved to have minimum bias. The estimated MI is integrated with an MRF framework to model the gene dependency in the context of network. The maximum a posterior (MAP) estimation is applied on the MRF-based model to estimate the network score. In order to reduce the computational complexity of finding the optimal network, a probabilistic searching algorithm is implemented. We further increase the robustness and reproducibility of the results by applying a non parametric bootstrapping method to measure the confidence level of the identified genes. To evaluate the performance of the proposed method, we test the method on simulation data under different conditions. The experimental results show an improved accuracy in terms of subnetwork identification compared to existing methods. Furthermore, we applied our method onto real breast cancer patient data; the identified protein interaction network shows a close association with the recurrence of breast cancer, which is supported by functional annotation. We also show that the identified subnetworks can be used to predict the recurrence status of cancer patients by survival analysis. CONCLUSIONS: We have developed an integrated approach for protein interaction network identification, which combines Markov random field framework and mutual information to model the gene dependency in PPI network. Improvements in subnetwork identification have been demonstrated with simulation datasets compared to existing methods. We then apply our method onto breast cancer patient data to identify recurrence related subnetworks. The experiment results show that the identified genes are enriched in the pathway and functional categories relevant to progression and recurrence of breast cancer. Finally, the survival analysis based on identified subnetworks achieves a good result of classifying the recurrence status of cancer patients. PMID- 26099272 TI - Shell neurons of the master circadian clock coordinate the phase of tissue clocks throughout the brain and body. AB - BACKGROUND: Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. RESULTS: Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50-75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. CONCLUSIONS: Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior. PMID- 26099274 TI - Social Return on Investment (SROI) methodology to account for value for money of public health interventions: a systematic review. AB - BACKGROUND: Increased scarcity of public resources has led to a concomitant drive to account for value-for-money of interventions. Traditionally, cost effectiveness, cost-utility and cost-benefit analyses have been used to assess value-for-money of public health interventions. The social return on investment (SROI) methodology has capacity to measure broader socio-economic outcomes, analysing and computing views of multiple stakeholders in a singular monetary ratio. This review provides an overview of SROI application in public health, explores lessons learnt from previous studies and makes recommendations for future SROI application in public health. METHODS: A systematic review of peer reviewed and grey literature to identify SROI studies published between January 1996 and December 2014 was conducted. All articles describing conduct of public health SROI studies and which reported a SROI ratio were included. An existing 12 point framework was used to assess study quality. Data were extracted using pre developed codes: SROI type, type of commissioning organisation, study country, public health area in which SROI was conducted, stakeholders included in study, discount rate used, SROI ratio obtained, time horizon of analysis and reported lessons learnt. RESULTS: 40 SROI studies, of varying quality, including 33 from high-income countries and 7 from low middle-income countries, met the inclusion criteria. SROI application increased since its first use in 2005 until 2011, declining afterwards. SROI has been applied across different public health areas including health promotion (12 studies), mental health (11), sexual and reproductive health (6), child health (4), nutrition (3), healthcare management (2), health education and environmental health (1 each). Qualitative and quantitative methods have been used to gather information for public health SROI studies. However, there remains a lack of consensus on who to include as beneficiaries, how to account for counterfactual and appropriate study-time horizon. Reported SROI ratios vary widely (1.1:1 to 65:1). CONCLUSIONS: SROI can be applied across healthcare settings. Best practices such as analysis involving only beneficiaries (not all stakeholders), providing justification for discount rates used in models, using purchasing power parity equivalents for monetary valuations and incorporating objective designs such as case-control or before-and after designs for accounting for outcomes will improve robustness of public health SROI studies. PMID- 26099275 TI - Infectious endocarditis caused by Helcococcus kunzii in a vascular patient: a case report and literature review. AB - BACKGROUND: Helcococcus kunzii is a facultative anaerobic bacterium that was first described by Collins et al. in 1993, and was initially considered as a commensal of the human skin, in particular of lower extremities. Human infections caused by H. kunzii remain rare with only a few cases published in the pubmed database. Nevertheless recent reports indicate that this microorganism has to be considered as an opportunistic pathogen that can be involved in severe infections in human. To the best of our knowledge, we describe here the first known case of infectious endocarditis caused by H. kunzii. CASE PRESENTATION: A 79 year-old man reporting severe polyvascular medical history attended the emergency ward for rapid deterioration of his general state of health. After physical examination and paraclinical investigations, the diagnosis of infectious endocarditis on native mitral valve caused by Helcococcus kunzii was established based on Dukes criteria. MALDI-TOF mass spectrometry and 16S rDNA sequencing allowed an accurate identification to the species level of Helcococcus kunzii. The patient was successfully treated by a medico-surgical approach. The treatment consisted in intravenous amoxicillin during four weeks and mitral valve replacement with a bioprosthestic valve. After an in depth review of patient's medical file, the origin of infection remained unknown. However, a cutaneous portal of entry cannot be excluded as the patient and his General Practitioner reported chronic ulcerations of both feet. CONCLUSIONS: We describe here the first case of endocarditis caused by H. kunzii in an elderly patient with polyvascular disease. This report along with previous data found in the literature emphasizes the invasive potential of this bacterial species as an opportunistic pathogen, in particular for patient with polyvascular diseases. MALDI-TOF mass spectrometry and 16S rDNA sequencing are reliable tools for H. kunzii identification. We also sequenced in this work H.kunzii type strain 103932T CIP and deposited in the Genbank under accession number KM403387. We noticed a 14 base difference between our sequence and the original sequence deposited by Collins et al. under Genbank accession number X69837. Hopefully, the spread of next generation sequencing tools would lead to a more accurate classification of clinical strains. PMID- 26099277 TI - Network-based stratification analysis of 13 major cancer types using mutations in panels of cancer genes. AB - BACKGROUND: Cancers are complex diseases with heterogeneous genetic causes and clinical outcomes. It is critical to classify patients into subtypes and associate the subtypes with clinical outcomes for better prognosis and treatment. Large-scale studies have comprehensively identified somatic mutations across multiple tumor types, providing rich datasets for classifying patients based on genomic mutations. One challenge associated with this task is that mutations are rarely shared across patients. Network-based stratification (NBS) approaches have been proposed to overcome this challenge and used to classify tumors based on exome-level mutations. In routine research and clinical applications, however, usually only a small panel of pre-selected genes is screened for mutations. It is unknown whether such small panels are effective in classifying patients into clinically meaningful subtypes. RESULTS: In this study, we applied NBS to 13 major cancer types with exome-level mutation data and compared the classification based on the full exome data with those focusing only on small sets of genes. Specifically, we investigated three panels, FoundationOne (240 genes), PanCan (127 genes) and TruSeq (48 genes). We showed that small panels not only are effective in clustering tumors but also often outperform full exome data for most cancer types. We further associated subtypes with clinical data and identified 5 tumor types (CRC-Colorectal carcinoma, HNSC-Head and neck squamous cell carcinoma, KIRC-Kidney renal clear cell carcinoma, LUAD-Lung adenocarcinoma and UCEC-Uterine corpus endometrial carcinoma) whose subtypes are significantly associated with overall survival, all based on small panels. CONCLUSION: Our analyses indicate that effective patient subtyping can be carried out using mutations detected in smaller gene panels, probably due to the enrichment of clinically important genes in such panels. PMID- 26099276 TI - Effect of full flavor and denicotinized cigarettes exposure on the brain microvascular endothelium: a microarray-based gene expression study using a human immortalized BBB endothelial cell line. AB - BACKGROUND: Tobacco smoke (TS) toxicity to the brain microvasculature is still an understudied area till date. NF-E2 related factor (Nrf2) is a key transcription factor responsible for activating the antioxidant response element (ARE) genes following an oxidative insult. Till date, several studies targeting the blood brain barrier (BBB) have shown some protective role of Nrf2 in ischemia reperfusion (IR) injury, however, its functional role in chronic smokers subjected to a life-long oxidative stress has never been addressed. This is of crucial importance since smokers have a much higher risk for cerebrovascular stroke and tobacco smoke exposure has been clearly shown to enhance BBB damage following an ischemia/reperfusion injury. Thus, the goal of our study was to investigate the defense pathways activated at the BBB endothelial level by TS exposure. Specifically we focused on Nrf2 and nuclear factor kappa-light-chain enhancer of activated B signaling response (NF-kappabeta) as the central protective mechanisms related to oxidative insult. RESULTS: With the exception of Nicotine, both full flavor (3R4F) and decotinized (ULN) cigarettes activated Nrf2 and NFkappabeta pathways in hCMEC/D3 endothelial cells. Several detoxification and anti-oxidant genes including downstream products were also activated including NAD(P)H dehydrogenase quinone 1 (NQO-1), heme oxygenase-1 (HMOX-1), catalytic and modifier subunits of glutamate-cysteine ligase (GCL), solute carrier-SLC7A11). Gene expression levels of cytochrome P450s (CYP2S1 and CYP51A1) and efflux transporters P-glycoprotein (P-gp) and multi-drug resistance protein-4 (MRP4) were also enhanced. Increase of P-gp functional activity and depletion of GSH were also observed. Strikingly, toxicity of denicotinized ("reduced exposure") cigarettes was equivalent to 3R4F (or worse). CONCLUSIONS: This study provides a detailed analysis of Nrf2-related cytoprotective mechanisms activated in response to 3R4F and ULN-derived TS exposure correlating the results with their oxidative and inflammatory potential. Toxicants present in soluble cigarette smoke extracts (CSE) and not nicotine seem to be the primary determinant of vascular toxicity. In this respect our results from this and previous studies suggest that chronic TS exposure can overcome Nrf2 and NFkappaB p65 dependent cytoprotective mechanisms of the brain microvascular endothelium possibly leading to BBB impairment and loss of BBB integrity. PMID- 26099278 TI - Risk of gastrointestinal perforation in cancer patients receiving ramucirumab: a meta-analysis of randomized controlled trials. AB - PURPOSE: Although existing evidence from clinical trials has demonstrated manifestation of gastrointestinal perforation with the use of ramucirumab, overall risks have yet to be reported. Therefore, we performed a meta-analysis of published randomized controlled trials (RCTs) to get a better understanding of the overall incidence and risk of gastrointestinal perforation associated with ramucirumab. METHODS: The PubMed and Web of Science databases as well as abstracts presented at American Society of Clinical Oncology conferences were searched to identify relevant studies published up to 01 May 2015. Eligible studies included randomized trials of ramucirumab either alone or in combination with another agent compared with the control arm without ramucirumab and that reported gastrointestinal perforation event. Overall incidence, relative risk (RR) and 95% confidence intervals (CI) were computed using fixed- or random effects models depending on the heterogeneity of the included studies. RESULTS: A total of 4579 patients with a variety of solid malignancies from six RCTs were included in our meta-analysis. The incidence of gastrointestinal perforation related to ramucirumab was 1.5% (95% CI 1.1-2.1%) with a mortality of 29.8% (95% CI 14.9-50.7%). The RR of gastrointestinal perforation associated with ramucirumab was 2.56 (95% CI 1.29-5.09; P = 0.007). CONCLUSIONS: Treatment with the ramucirumab is associated with a significant increase in risk of gastrointestinal perforation in cancer patients. PMID- 26099280 TI - Giant "turtle-egg tumors": a forgotten complication of quinine injections. PMID- 26099279 TI - Risk of malignancy in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis under immunosuppressive therapy: a single-center experience. AB - Systemic inflammatory rheumatic diseases are associated with an increased risk of malignancy, in particular of lymphoproliferative disorders. Chronic inflammation, due to the disease itself, generates a microenvironment able to promote cancer development, but it is still controversial whether immunosuppressive therapy may contribute to carcinogenesis. The aim of the study was to evaluate the risk of malignancy in 399 patients affected by rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis, all treated with either tumor necrosis factor alpha-inhibitors plus disease-modifying anti-rheumatic drugs (DMARDs) or DMARDs alone. The risk of malignancy in this cohort of patients, observed in the period between 2005 and 2011 at S. Andrea Hospital-Sapienza University of Rome, was compared with that of the general Italian population, matched for age, sex, and area of residence. Fourteen (3.5%) malignancies, five of which were hematologic, have been observed. The overall cancer risk was not significantly increased in comparison to the general population, whereas the risk of hematologic malignancies appeared significantly higher in RA patients (SIR 4.94, 95% CI 1.35-12.64), particularly in female gender (SIR 6.9, 0.95% CI 1.88-17.66). No significant association between therapy and malignancy was demonstrated in RA patients. PMID- 26099282 TI - Osteopontin induces vascular endothelial growth factor expression in articular cartilage through PI3K/AKT and ERK1/2 signaling. AB - The expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) are associated with the severity of cartilage destruction in osteoarthritis. However, the biological connection between OPN and VEGF in osteoarthritis remains to be elucidated. The present study was performed to investigate the effect of OPN on VEGF expression in articular cartilage. Rat articular chondrocytes were isolated and cultured in monolayer conditions, and they were treated with OPN for different time periods (0, 2, 8, 12 or 24 h) and dosages (0, 0.1, 0.25 or 0.5 uM). VEGF expression was assessed by reverse transcription-quantitative polymerase chain reaction and western blotting. The activation of the phosphoinositide 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK)1/2 pathway was analyzed by detecting the expression of pPI3K, pAKT and pERK1/2. To inhibit the PI3K/AKT and ERK1/2 pathway, LY294002 and PD98059 were used, respectively or in combination. It was identified that OPN increased the expression of VEGF in a dose- and time-dependent manner. The PI3K/AKT and ERK1/2 pathways were activated following OPN stimulation and the effect was concomitant with the upregulation of VEGF. Finally, the regulation of VEGF was inhibited by LY294002 and PD98059, and their combination exhibited a synergistic effect. In conclusion, these findings suggest that OPN may directly upregulate VEGF expression through the PI3K/AKT and ERK1/2 pathway. Further studies are required to reveal the mechanism of action of OPN on cartilage angiogenesis and cartilage destruction. PMID- 26099283 TI - Usefulness of intracardiac echocardiography during pulmonary vein isolation with the novel multipolar irrigated ablation catheter (nMARQTM). AB - BACKGROUND: Previous studies reported the usefulness of an irrigated circular radiofrequency ablation catheter (nMARQ(TM), Biosense Webster) for pulmonary vein isolation (PVI). We evaluated the role of intracardiac echocardiography (ICE) to optimize the manipulation of nMARQ(TM) catheter. METHODS: Thirty-seven patients (pts), (mean age 55 +/- 12 years; 28 males) were enrolled to perform PVI. All pts underwent PVI with the nMARQ(TM) catheter. In 20 pts (group 1), we utilized ICE to guide nMARQ(TM) catheter positioning at the PV ostia; in the other 17 pts (group 2), nMARQ(TM) catheter was positioned at the PV ostia guided by fluoroscopy and TissueConnect(TM) technology. RESULTS: Radiofrequency (RF) applications were significantly lower in group 1 compared to group 2 [left PVs: 6 (range 3 to 12) in group 1 and 12 (range 5 to 16) in group 2 (p < 0.001); right PVs: 7 (range 4 to 14) in group 1 and 10 (range 5 to 16) in group 2 (p = 0.04)]; similarly regarding the time of RF delivery [left PVs: 318 +/- 194 s in group 1 vs. 542 +/- 104 s in group 2 (p < 0.001); right PVs: 410 +/- 270 s in group 1 vs. 550 +/- 156 s in group 2 (p = 0.05)]. Fluoroscopy time (23 +/- 9 min vs. 28 +/- 5 min; p = 0.05), procedural time (83 +/- 23 min vs. 160 +/- 42 min; p < 0.001), and radiation dose (109 +/- 20 Gy/cm(2) vs. 127 +/- 29 Gy/cm(2); p = 0.04) were significantly lower in group 1 compared to group 2. CONCLUSION: ICE might be a useful tool to guide nMARQ(TM) catheter position in the left atrium during atrial fibrillation (AF) ablation procedures. PMID- 26099284 TI - Identification and practical management of latex allergy in occupational settings. AB - Allergy to natural rubber latex (NRL) from Hevea brasiliensis is a relevant occupational health hazard. The use of gloves and products manufactured with latex and environmental allergen exposure in the work environment are risks factors for the development of occupational allergy among different job categories. Healthcare workers have been the most commonly affected, but other professions with exposure to latex products such as hairdressers, cleaners, food handlers and those making natural rubber latex (NRL) products are also at risk of developing occupational allergy. Clinical manifestations of IgE-mediated latex allergy can range from troublesome skin disorders to life-threatening systemic reactions. It is very important to identify the occupational allergic diseases in their early stages in order to implement avoidance strategies. For this purpose, the interventions for prevention should emphasize the importance of latex allergy awareness and surveillance among exposed workforces. PMID- 26099285 TI - Principles of Natural Photosynthesis. AB - Nature relies on a unique and intricate biochemical setup to achieve sunlight driven water splitting. Combined experimental and computational efforts have produced significant insights into the structural and functional principles governing the operation of the water-oxidizing enzyme Photosystem II in general, and of the oxygen-evolving manganese-calcium cluster at its active site in particular. Here we review the most important aspects of biological water oxidation, emphasizing current knowledge on the organization of the enzyme, the geometric and electronic structure of the catalyst, and the role of calcium and chloride cofactors. The combination of recent experimental work on the identification of possible substrate sites with computational modeling have considerably limited the possible mechanistic pathways for the critical O-O bond formation step. Taken together, the key features and principles of natural photosynthesis may serve as inspiration for the design, development, and implementation of artificial systems. PMID- 26099286 TI - Sun-screening bioactive compounds mycosporine-like amino acids in naturally occurring cyanobacterial biofilms: role in photoprotection. AB - AIMS: To investigate the occurrence of UV sunscreening biomolecules and their role in photoprotection in cyanobacterial biofilms growing in brightly lit habitats with high UV fluxes. METHODS AND RESULTS: High performance liquid chromatography with photodiode-array and mass spectrometry revealed the presence of mycosporine-like amino acids (MAAs) shinorine (lambda(max) 334 nm, m/z 333), porphyra-334 (lambda(max) 334 nm, m/z 347), mycosporine-glycine (lambda(max) 310 nm, m/z 246) and palythinol (lambda(max) 332 nm, m/z 303). Two unknown MAAs with lambda(max) at 320 (m/z 289) and 329 nm (m/z 318) were also found. Biosynthesis of MAAs was found to increase with increase in exposure time under UV radiation. The MAAs from biofilms showed efficient radical scavenging activity as well as photoprotective potential on the survival of UV-treated Escherichia coli cells. CONCLUSIONS: Biosynthesis of photoprotectants is an important mechanism to prevent photodamage in Cyanobacteria. UV-induction and photoprotective function of MAAs may facilitate them to perform important ecological functions under harsh environmental conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: There are very few reports on qualitative and quantitative characterization of different MAAs in cyanobacterial biofilms. Due to strong UV absorption and photoprotective function, MAAs may be used as an active ingredient in cosmetic and other pharmaceutical industries. PMID- 26099287 TI - Discussion of photoprotection, screening, and risk behaviors with children and grandchildren after melanoma genetic testing. AB - The purpose of the current study was to examine changes in frequency of discussion about melanoma preventive behaviors among adults who received melanoma genetic test reporting and counseling and their children and grandchildren, correspondence of frequency of discussion with intentions, and content of discussions. Participants received CDKN2A/p16 testing and counseling (N = 24, 46 % p16-positive). Discussions about preventive behaviors were assessed before testing and 1 and 6 months post-testing. Intentions to discuss preventive behaviors and perceived preparedness to discuss risk were assessed post-testing. Open-ended questions assessed content of reported discussions. Discussion of preventive behaviors declined following test reporting, with more rapid decline reported by noncarriers. There was a large gap between the percentage of participants who intended to discuss preventive behaviors and who then reported discussions 1 and 6 months after counseling. Participants felt prepared to discuss melanoma risk but also suggested resources to facilitate discussions. Genetic test reporting and counseling alone did not sustain discussions about preventive behaviors for a hereditary cancer with children and grandchildren. The gap between intentions to have discussions and reported discussions has implications for augmentation of counseling to support at-risk families' discussions about preventive behaviors. PMID- 26099288 TI - [Vocal cord paralysis after thyroid surgery : Current medicolegal aspects of intraoperative neuromonitoring]. AB - Intraoperative neuromonitoring (IONM) has been commercially available for approximately 15 years and is highly predictive in thyroid gland surgery concerning either postoperative vocal fold mobility in the case of an intact signal for muscle action electromyogram (EMG, > 99 % right negative) or vocal fold dysfunction in the case of loss of signal (> 70 % right positive). The use of IONM improves the intraoperative identification of recurrent laryngeal nerve function and due to the high predictive value with respect to the expected vocal cord function the result of IONM has to be integrated into the surgical concept of thyroidectomy. Unilateral loss of function of the recurrent laryngeal nerve cannot be completely avoided despite correct application of IONM; however, bilateral vocal fold palsy can be safely avoided when contralateral surgery is cancelled after a loss of signal occurs during resection of the first side in planned bilateral surgery (alternative strategy). Patients have to be informed preoperatively about the limitations of IONM and potential strategy changes during planned bilateral surgery. Surgeons should apply IONM according to the published current recommendations and by selecting a risk-oriented intraoperative strategy in the case of loss of signal from the recurrent laryngeal nerve. PMID- 26099289 TI - [Complications after supra-aortic reconstruction]. AB - BACKGROUND: Surgical interventions on the supra-aortic vessels are common procedures to avoid cerebral ischemia or arm pain during exercise. The safety and efficacy has been confirmed by clinical studies. Complications are rare but have serious consequences. OBJECTIVES: What special indications and recommendations are there for the diagnostics and treatment in the perioperative phase? METHODS: The current article is a literature-based review that considers international studies, guidelines and personal experiences. RESULTS: There is a broad range of complications. A simple systematic physical examination is often sufficient to give indications of the problem. Confirming clinical apparative examinations are mostly intraoperative angiography or sonography, whereas postoperative procedures include color-coded duplex sonography (FKDS) and angiography computed tomography (angio-CT). Important basic principles and aspects of operative procedures are presented. Evidence-based differences between the treatment options with resulting complications are mostly unknown; therefore, clinical management mostly relies on expert recommendations. CONCLUSION: There are several modern treatment options for invasive therapy. Despite a decrease in previous complication rates, typical perioperative complications must be considered. The diagnosis and therapy is carried out according to established strategies. PMID- 26099291 TI - [Complications following vascular surgery interventions: the vascular surgeon must comprehend the spectrum and therapeutic possibilities]. PMID- 26099290 TI - [Bleeding complications in bariatric surgery: Prophylaxis and therapy]. AB - Bariatric surgery is an elective intervention, which is also performed in patients with additional risk factors, e.g. elderly patients over 65 years old, in patients suffering from relevant comorbidities and in patients with a body mass index (BMI) greater than 60 kg/m(2). To reduce the perioperative risks comorbidities require optimal adjustment. Specialized centers have reported complication rates below 1 %. Besides leakage, bleeding is the most common surgical complication in bariatric interventions. Bleeding complications occur in up to 4 % of cases but are much more common in redo surgery. For the management of bleeding, the same general rules apply as those for abdominal surgery and at the end of an operation, all bleeding must be under control. To avoid bleeding, sealing devices are widely used during tissue dissection. Stapler line bleeding is the most common form of intraoperative and postoperative bleeding. Special stapler magazines and stapler line reinforcement materials are available to minimize stapler line bleeding. Such devices result in relevant extra costs; however, they should always be generally available and used in patients with an increased risk of bleeding or an increased intraoperative tendency to bleeding. PMID- 26099292 TI - Retrobulbar blood flow and carotid intima-media thickness alteration may relate to subclinic atherosclerosis in patients with chronic inflammatory diseases. AB - OBJECTIVE: AA amyloidosis occurs in the setting of longstanding inflammation. An increased incidence of coronary artery disease (CAD) was noted in patients with chronic inflammatory disease (CID). Retrobulbar blood flow predicts future macrovascular events including CAD. Increase in carotid artery intima-media thickness is regarded as a marker for early atherosclerosis. The relationship between chronic inflammation and atherosclerosis is well known; however, the connection between amyloidosis-advanced CIDs and retrobulbar microvascular function and carotid intima-media thickness (CIMT) is unidentified. We aimed to investigate whether retrobulbar microcirculation and CIMT were impaired or not in amyloidosis-advanced CID patients compared to normal subjects. METHODS: Fourteen patients with renal AA amyloidosis and a group of healthy volunteers were included in the study. Measurement of CIMT and retrobulbar blood flow velocities was performed with ultrasound scanner and color Doppler ultrasonography. RESULTS: The CIMT of patients with renal amyloidosis was significantly thicker than that of the normal population (p < 0.001). The resistivity index of the ophthalmic artery (OA) of patients with renal amyloidosis was significantly higher than the study group (p < 0.001). CONCLUSION: This study demonstrates that accelerated atherosclerosis which can be shown by increased OA resistivity index and CIMT are found in amyloidal-related CID patients. PMID- 26099293 TI - Comprehensive geriatric assessment: comparison of elderly hemodialysis patients and primary care patients. AB - BACKGROUNDS: The quality of life and survival of elderly depend not only on their age but on many social and health factors. In the present study, comprehensive geriatric assessment (CGA) was made in elderly patients on regular hemodialysis (HD) and those without chronic kidney disease recruited in primary health care in order to compare their sociodemographic characteristics, physical health, functional ability and social support. METHOD: The 106 HD patients and 300 primary care patients aged 70 years and more were studied. Data on sociodemographic characteristics, neurosensory deficits, pain, falls, polypharmacy, basic activities of daily living (ADL) questionnaire, instrumental activities of daily living (IADL) questionnaire were obtained during interview. The Timed Up and Go, Nutritional Health Checklist, Two Question Instrument for depression and Charlson comorbidity index (CCI) were applied. RESULTS: No significant differences were found for age, gender, education level and dwelling between the two groups. A lower percentage of HD patients lived alone when compared with controls. BMI >25 kg/m(2) had 43.4% of HD patients and 49.3% of controls. CCI differed significantly between HD and primary care patients (median: 6 vs. 4) and significantly more HD patients reported depression. No significant difference was found between groups for cognitive dysfunction and ADL, but HD patients had significantly lower IADL scores than controls. The mobility of HD patients was worse; 45.7% of them reported falls in the previous year but only 9.7% from the controls. CONCLUSIONS: CGA revealed that HD patients had significantly higher CCI, worse IADL score, mobility and reported more frequent falls, depression and impaired vision than primary care patients. PMID- 26099294 TI - It is time to review concepts on renal involvement in leprosy: pre- and post treatment evaluation of 189 patients. AB - BACKGROUND: Functional and morphological renal lesions have been widely described in leprosy for decades. Nevertheless few studies have assessed renal function pre and during treatment after the advent of multidrug therapy (MDT). METHODS: This is a prospective study involving 189 consecutive patients, with all forms of leprosy (Ridley-Jopling scale). Laboratory (serum urea and creatinine, estimated GFR, urinalysis, microalbuminuria, urinary RBP) and clinical features of renal disease were evaluated previously and after onset (3 and 8 months later) of MDT. RESULTS: One hundred and eighty-nine patients (M 1.8: F 1; mean age 44 +/- 16 years) were included just after diagnosis of leprosy and before the introduction of MDT. Mean time until manifestation of symptoms and/or signs of leprosy was 29 +/- 56 months (25 days-480 months). Microhematuria and microalbuminuria were detected in 7.5% and 9.6% of the cases, respectively. Elevated serum creatinine was detected in 34% pre-MDT; this was statistically more frequent in males, hypertensive and frequent users of non-steroidal anti-inflammatory drugs (NSAID), as well as in patients with erythema nodosum lepromatosum, 45.5% by the time of diagnosis, 18% after 3 months and 9% after 8 months of MDT (p = 0.039). CONCLUSIONS: Our results suggest that functional renal lesions in leprosy are currently mild and predominantly of glomerular origin, in opposition to the severe involvement described in the past. This improved outcome of renal disease secondary to leprosy is possibly due to the advent of MDT and effective treatment of episodes of reaction, leading to shorter periods of active infectious disease. PMID- 26099295 TI - Admission hypomagnesemia and hypermagnesemia increase the risk of acute kidney injury. AB - BACKGROUND: The association between admission serum magnesium (Mg) levels and risk of in-hospital acute kidney injury (AKI) is limited. The aim of this study was to assess the risk of developing AKI in all hospitalized patients with various admission Mg levels. METHODS: This is a single-center retrospective study conducted at a tertiary referral hospital. All hospitalized adult patients who had admission Mg available from January to December 2013 were analyzed in this study. Admission Mg was categorized based on its distribution into six groups (less than 1.5, 1.5-1.7, 1.7-1.9, 1.9-2.1, 2.1-2.3 and greater than 2.3 mg/dL). The primary outcome was in-hospital AKI occurring after hospital admission. Logistic regression analysis was performed to obtain the odds ratio of AKI of various admission Mg levels using Mg with lowest AKI incidence (1.9-2.1 mg/dL) as the reference group. RESULTS: Of 9241 patients enrolled, AKI occurred in 1124 patients (12.2%). The lowest incidence of AKI was when serum Mg was within 1.7 1.9 and 1.9-2.1 mg/dL. A U-shaped curve emerged demonstrating higher incidences of AKI associated with both hypoMg (<1.7) and hyperMg (>2.1). After adjusting for potential confounders, both hypoMg (<1.5 mg/dL) and hyperMg (>2.3 mg/dL) were associated with an increased risk of developing AKI with odds ratios of 1.70 (95% CI 1.31-2.18) and 1.42 (95% CI 1.11-1.81), respectively. CONCLUSION: Both admission hypoMg and hyperMg were associated with an increased risk for in hospital AKI. PMID- 26099296 TI - Nephrology elective experience during medical residency: a national survey of US nephrology fellowship training program directors. AB - Interest in nephrology careers continues to decline in the United States. The reasons for this declining interest are not fully understood but it is plausible that inadequate exposure to the full spectrum of what a career in nephrology encompasses may be part of the explanation. Inpatient-based nephrology electives have been a common venue for residents to gain exposure to nephrology but little is known regarding the details of such electives and how often they include outpatient experiences. We carried out a national survey of nephrology fellowship training program directors to obtain data on the content of nephrology elective experiences as well as their ideas on how to promote interest in the field. The survey revealed the majority of elective experiences to be either exclusively or heavily inpatient based, with only a small percentage having a substantial outpatient component, particularly in outpatient dialysis or transplantation. Training program directors felt that providing greater outpatient experiences to residents during elective rotations would be an effective means to promote interest in nephrology, along with structured faculty mentoring. Our findings suggest that current approaches to the nephrology elective experience are heavily inpatient-based and might benefit from incorporating much more of the rich spectrum of activities a career in nephrology entails. Hopefully such efforts can create and enhance interest in careers in nephrology and potentially begin a sustained reversal of an unfortunate and serious decline in interest. PMID- 26099297 TI - Clinical study of B-mode ultrasound-guided retroperitoneal and abdominal catheter treatment of severe acute pancreatitis. AB - BACKGROUND: The aim of this study was to investigate the clinical efficacy of B mode ultrasound-guided retroperitoneal and abdominal catheter treatment of severe acute pancreatitis. METHODS: A retrospective analysis was performed, regarding 68 patients diagnosed with severe acute pancreatitis in our hospital from May 2012 to May 2014. Patients were divided into an observation group (N.=38) and a control group (N.=30). Patients in the control group received conventional drug therapy and were given CT-guided catheter or surgical treatment when necessary. The observation group received conventional drug therapy + B-mode ultrasound guided retroperitoneal and abdominal catheter drainage and lavage. The clinical efficacy and complication rate differences of the two groups of patients were compared and analyzed. RESULTS: The total efficacy rates in the observation group were significantly higher than in the control group (P<0.05). The serum calcium levels of the observation group were obviously higher than that of the control group while their CRP levels and APACHE II scores were significantly lower (P<0.05). Complications were significantly lower in the observation group than in the control group (P<0.05). CONCLUSIONS: B-mode ultrasound-guided biopsy for retroperitoneal and abdominal subcutaneous catheter drainage and lavage treatment of severe acute pancreatitis may improve the clinical effect and reduce complications. PMID- 26099298 TI - Grain trapping by filamentous cyanobacterial and algal mats: implications for stromatolite microfabrics through time. AB - Archean and Proterozoic stromatolites are sparry or fine-grained and finely laminated; coarse-grained stromatolites, such as many found in modern marine systems, do not appear until quite late in the fossil record. The cause of this textural change and its relevance to understanding the evolutionary history of stromatolites is unclear. Cyanobacteria are typically considered the dominant stromatolite builders through time, but studies demonstrating the trapping and binding abilities of cyanobacterial mats are limited. With this in mind, we conducted experiments to test the grain trapping and binding capabilities of filamentous cyanobacterial mats and trapping in larger filamentous algal mats in order to better understand grain size trends in stromatolites. Mats were cut into squares, inclined in saltwater tanks at angles from 0 to 75 degrees (approximating the angle of lamina in typical stromatolites), and grains of various sizes (fine sand, coarse sand, and fine pebbles) were delivered to their surface. Trapping of grains by the cyanobacterial mats depended strongly on (i) how far filaments protruded from the sediment surface, (ii) grain size, and (iii) the mat's incline angle. The cyanobacterial mats were much more effective at trapping fine grains beyond the abiotic slide angle than larger grains. In addition, the cyanobacterial mats actively bound grains of all sizes over time. In contrast, the much larger algal mats trapped medium and coarse grains at all angles. Our experiments suggest that (i) the presence of detrital grains beyond the abiotic slide angle can be considered a biosignature in ancient stromatolites where biogenicity is in question, and, (ii) where coarse grains are present within stromatolite laminae at angles beyond the abiotic angle of slide (e.g., most modern marine stromatolites), typical cyanobacterial-type mats are probably not solely responsible for the construction, giving insight into the evolution of stromatolite microfabrics through time. PMID- 26099299 TI - Context Matters for Social-Emotional Learning: Examining Variation in Program Impact by Dimensions of School Climate. AB - This paper examines whether three dimensions of school climate-leadership, accountability, and safety/respect-moderated the impacts of the INSIGHTS program on students' social-emotional, behavioral, and academic outcomes. Twenty-two urban schools and N = 435 low-income racial/ethnic minority students were enrolled in the study and received intervention services across the course of 2 years, in both kindergarten and first grade. Intervention effects on math and reading achievement were larger for students enrolled in schools with lower overall levels of leadership, accountability, and safety/respect at baseline. Program impacts on disruptive behaviors were greater in schools with lower levels of accountability at baseline; impacts on sustained attention were greater in schools with lower levels of safety/respect at baseline. Implications for Social Emotional Learning program implementation, replication, and scale-up are discussed. PMID- 26099301 TI - NMR illuminates the pathways to ALS. AB - A combination of NMR techniques is able to explore the structure of short-lived protein conformations. PMID- 26099300 TI - Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving cytotoxic conformations of Cu, Zn superoxide dismutase (SOD1). A major challenge in understanding ALS disease pathology has been the identification and atomic-level characterization of these conformers. Here, we use a combination of NMR methods to detect four distinct sparsely populated and transiently formed thermally accessible conformers in equilibrium with the native state of immature SOD1 (apoSOD1(2SH)). Structural models of two of these establish that they possess features present in the mature dimeric protein. In contrast, the other two are non-native oligomers in which the native dimer interface and the electrostatic loop mediate the formation of aberrant intermolecular interactions. Our results show that apoSOD1(2SH) has a rugged free energy landscape that codes for distinct kinetic pathways leading to either maturation or non-native association and provide a starting point for a detailed atomic-level understanding of the mechanisms of SOD1 oligomerization. PMID- 26099302 TI - Neural population dynamics in human motor cortex during movements in people with ALS. AB - The prevailing view of motor cortex holds that motor cortical neural activity represents muscle or movement parameters. However, recent studies in non-human primates have shown that neural activity does not simply represent muscle or movement parameters; instead, its temporal structure is well-described by a dynamical system where activity during movement evolves lawfully from an initial pre-movement state. In this study, we analyze neuronal ensemble activity in motor cortex in two clinical trial participants diagnosed with Amyotrophic Lateral Sclerosis (ALS). We find that activity in human motor cortex has similar dynamical structure to that of non-human primates, indicating that human motor cortex contains a similar underlying dynamical system for movement generation. PMID- 26099303 TI - Anti-Mullerian hormone as a diagnostic tool for ovarian remnant syndrome in bitches. AB - Ovariohysterectomy is a surgical procedure performed for sterilization. If part or all of an ovary remains after the surgical procedure, ovarian remnant syndrome (ORS) occurs. After revascularization of the remaining ovarian tissue, the sexual cycle of bitches and queens continues. The aim of this study was to investigate the usefulness of serum anti-Mullerian hormone (AMH) measurement for the diagnosis of ORS in bitches. Forty-six female dogs were divided into four groups: the prepubertal, unspayed, spayed, and ORS groups. The serum AMH, progesterone, and estradiol concentrations of the bitches in all groups were measured by enzyme linked immunosorbent assay. The stage in the sexual cycle of each bitch was determined based on vaginal cytology findings and serum estradiol and progesterone levels. The mean serum AMH concentration of the unspayed bitches (4.26 +/- 0.82 ng/ml) was similar to that of the bitches with ORS (4.40 +/- 1.09 ng/ml). However, the difference between the mean serum AMH level of the bitches with ORS and the spayed bitches (0.28 +/- 0.09 ng/ml) was significant. In conclusion, the present study has demonstrated that the serum AMH level is substantially lower in spayed than in both intact bitches and bitches with ORS. According to this result, measurement of the serum AMH level is a useful tool for diagnosis of ORS in bitches. PMID- 26099304 TI - Iron Oxide Nanoparticles Induce Dopaminergic Damage: In vitro Pathways and In Vivo Imaging Reveals Mechanism of Neuronal Damage. AB - Various iron-oxide nanoparticles have been in use for a long time as therapeutic and imaging agents and for supplemental delivery in cases of iron-deficiency. While all of these products have a specified size range of ~ 40 nm and above, efforts are underway to produce smaller particles, down to ~ 1 nm. Here, we show that after a 24-h exposure of SHSY-5Y human neuroblastoma cells to 10 MUg/ml of 10 and 30 nm ferric oxide nanoparticles (Fe-NPs), cellular dopamine content was depleted by 68 and 52 %, respectively. Increases in activated tyrosine kinase c Abl, a molecular switch induced by oxidative stress, and neuronal alpha-synuclein expression, a protein marker associated with neuronal injury, were also observed (55 and 38 % percent increases, respectively). Inhibition of cell-proliferation, significant reductions in the number of active mitochondria, and a dose-dependent increase in reactive oxygen species (ROS) were observed in neuronal cells. Additionally, using a rat in vitro blood-brain barrier (BBB) model, a dose dependent increase in ROS accompanied by increased fluorescein efflux demonstrated compromised BBB integrity. To assess translational implications, in vivo Fe-NP-induced neurotoxicity was determined using in vivo MRI and post-mortem neurochemical and neuropathological correlates in adult male rats after exposure to 50 mg/kg of 10 nm Fe-NPs. Significant decrease in T 2 values was observed. Dynamic observations suggested transfer and retention of Fe-NPs from brain vasculature into brain ventricles. A significant decrease in striatal dopamine and its metabolites was also observed, and neuropathological correlates provided additional evidence of significant nerve cell body and dopaminergic terminal damage as well as damage to neuronal vasculature after exposure to 10 nm Fe-NPs. These data demonstrate a neurotoxic potential of very small size iron nanoparticles and suggest that use of these ferric oxide nanoparticles may result in neurotoxicity, thereby limiting their clinical application. PMID- 26099305 TI - Dexmedetomidine Dose-Dependently Attenuates Ropivacaine-Induced Seizures and Negative Emotions Via Inhibiting Phosphorylation of Amygdala Extracellular Signal Regulated Kinase in Mice. AB - Ropivacaine (Ropi), one of the newest and safest amino amide local anesthetics, is linked to toxicity, including the potential for seizures, changes in behavior, and even cardiovascular collapse. Dexmedetomidine (Dex), an alpha2-adrenergic receptor agonist, has been widely used in anesthesia and critical care practice. To date, the underlying mechanisms of the effects of Dex premedication on Ropi induced toxicity have not been clearly identified. In the current study, we investigated the effects of increasing doses of Dex premedication on 50% convulsive dose (CD50) of Ropi. With increasing doses of intraperitoneal (i.p.) Dex 10 min prior to each i.p. RopiCD50, the latency and duration of seizure activity were recorded. Open-field (OF) and elevated plus maze (EPM) test were used to measure negative behavioral emotions such as depression and anxiety. Immunohistochemistry and Western blot were utilized to investigate phosphorylation-extracellular regulated protein kinases (p-ERK) expression in the basolateral amygdala (BLA) on 2 h and in the central amygdala (CeA) on 24 h after convulsion in mice. The results of our investigation demonstrated that Dex dose dependently increased RopiCD50, prolonged the latency and shortened the duration of each RopiCD50-induced seizure, improved the negative emotions revealed by both OF and EPM test, and inhibited p-ERK expression in the BLA and the CeA. PMID- 26099306 TI - P2Y6 Receptor-Mediated Microglial Phagocytosis in Radiation-Induced Brain Injury. AB - Microglia are the resident immune cells and the professional phagocytic cells of the CNS, showing a multitude of cellular responses after activation. However, how microglial phagocytosis changes and whether it is involved in radiation-induced brain injury remain unknown. In the current study, we found that microglia were activated and microglial phagocytosis was increased by radiation exposure both in cultured microglia in vitro and in mice in vivo. Radiation increased the protein expression of the purinergic receptor P2Y6 receptor (P2Y6R) located on microglia. The selective P2Y6 receptor antagonist MRS2578 suppressed microglial phagocytosis after radiation exposure. Inhibition of microglial phagocytosis increased inhibitory factor Nogo-A and exacerbated radiation-induced neuronal apoptosis and demyelination. We also found that the levels of protein expression for phosphorylated Ras-related C3 botulinum toxin substrate 1 (Rac1) and myosin light chain kinase (MLCK) were elevated, indicating that radiation exposure activated Rac1 and MLCK. The Rac1 inhibitor NSC23766 suppressed expression of MLCK, indicating that the Rac1-MLCK pathway was involved in microglial phagocytosis. Taken together, these findings suggest that the P2Y6 receptor plays a critical role in mediating microglial phagocytosis in radiation-induced brain injury, which might be a potential strategy for therapeutic intervention to alleviate radiation-induced brain injury. PMID- 26099307 TI - Common Aging Signature in the Peripheral Blood of Vascular Dementia and Alzheimer's Disease. AB - Alzheimer's disease (AD) and vascular dementia (VaD) are the two most dominant forms of dementia in elderly people. Due to the large overlap between AD and VaD in clinical observations, great controversies exist regarding the distinction and connection between these two types of senile dementia. Here for the first time, we resort to the gene expression pattern of the peripheral blood to compare AD and VaD objectively. In our previous work, we have demonstrated that the dysregulation of gene expression in AD is unique among the examined diseases including neurological diseases, cancer, and metabolic diseases. In this study, we found that the dysregulation of gene expression in AD and VaD is quite similar to each other at both functional and gene levels. Interestingly, the dysregulation started at the early stages of the diseases, namely mild cognitive impairment (MCI) and vascular cognitive impairment (VCI). We have also shown that this signature is distinctive from that of peripheral vascular diseases. Comparison with aging studies revealed that the most profound change in AD and VaD, namely ribosome, is consistent with the accelerated aging scenario. This study may have implications to the common mechanism between AD and VaD. PMID- 26099308 TI - Induction of a Proinflammatory Response in Cortical Astrocytes by the Major Metabolites Accumulating in HMG-CoA Lyase Deficiency: the Role of ERK Signaling Pathway in Cytokine Release. AB - 3-Hydroxy-3-methylglutaric aciduria (HMGA) is an inherited metabolic disorder caused by 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. It is biochemically characterized by predominant tissue accumulation and high urinary excretion of 3 hydroxy-3-methylglutarate (HMG) and 3-methylglutarate (MGA). Affected patients commonly present acute symptoms during metabolic decompensation, including vomiting, seizures, and lethargy/coma accompanied by metabolic acidosis and hypoketotic hypoglycemia. Although neurological manifestations are common, the pathogenesis of brain injury in this disease is poorly known. Astrocytes are important for neuronal protection and are susceptible to damage by neurotoxins. In the present study, we investigated the effects of HMG and MGA on important parameters of redox homeostasis and cytokine production in cortical cultured astrocytes. The role of the metabolites on astrocyte mitochondrial function (thiazolyl blue tetrazolium bromide (MTT) reduction) and viability (propidium iodide incorporation) was also studied. Both organic acids decreased astrocytic mitochondrial function and the concentrations of reduced glutathione without altering cell viability. In contrast, they increased reactive species formation (2'-7'-dichlorofluorescein diacetate (DCFHDA) oxidation), as well as IL-1beta, IL 6, and TNF alpha release through the ERK signaling pathway. Taken together, the data indicate that the principal compounds accumulating in HMGA induce a proinflammatory response in cultured astrocytes that may possibly be involved in the neuropathology of this disease. PMID- 26099309 TI - Hypericum perforatum Attenuates Spinal Cord Injury-Induced Oxidative Stress and Apoptosis in the Dorsal Root Ganglion of Rats: Involvement of TRPM2 and TRPV1 Channels. AB - Oxidative stress and cytosolic Ca(2+) overload have important roles on apoptosis in dorsal root ganglion (DRG) neurons after spinal cord injury (SCI). Hypericum perforatum (HP) has an antioxidant property in the DRGs due to its ability to modulate NADPH oxidase and protein kinase C pathways. We aimed to investigate the protective property of HP on oxidative stress, apoptosis, and Ca(2+) entry through transient receptor potential melastatin 2 (TRPM2) and transient receptor potential vanilloid 1 (TRPV1) channels in SCI-induced DRG neurons of rats. Rats were divided into four groups as control, HP, SCI, and SCI + HP. The HP groups received 30 mg/kg HP for three concessive days after SCI induction. The SCI induced TRPM2 and TRPV1 currents and cytosolic free Ca(2+) concentration were reduced by HP. The SCI-induced decrease in glutathione peroxidase and cell viability values were ameliorated by HP treatment, and the SCI-induced increase in apoptosis, caspase 3, caspase 9, cytosolic reactive oxygen species (ROS) production, and mitochondrial membrane depolarization values in DRG of SCI group were overcome by HP treatment. In conclusion, we observed a protective role of HP on SCI-induced oxidative stress, apoptosis, and Ca(2+) entry through TRPM2 and TRPV1 in the DRG neurons. Our findings may be relevant to the etiology and treatment of SCI by HP. Graphical Abstract Possible molecular pathways of involvement of Hypericum perforatum (HP) on apoptosis, oxidative stress, and calcium accumulation through TRPM2 and TRPV1 channels in DRG neurons of SCI induced rats. The TRPM2 channel is activated by ADP-ribose and oxidative stress through activation of ADP-ribose pyrophosphate although it was inhibited by N-(p amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2APB). The TRPV1 channel is activated by oxidative stress and capsaicin and it is blocked by capsazepine. Injury in the DRG can result in augmented ROS release, leading to Ca(2+) uptake through TRPM2 and TRPV1 channels. Mitochondria were reported to accumulate Ca(2+), provided intracellular Ca(2+) rises, thereby leading to depolarization of mitochondrial membranes and release of apoptosis inducing factors such as caspase 3 and caspase 9. HP via regulation of NADPH oxidase and PKC inhibits TRPM2 and TRPV1 channels. The molecular pathway may be a cause of SCI-induced pain and neuronal death, and the subject should be urgently investigated. PMID- 26099310 TI - Anti-amyloid Aggregation Activity of Natural Compounds: Implications for Alzheimer's Drug Discovery. AB - Several plant-derived natural compounds are known to exhibit anti-amyloid aggregation activity which makes them attractive as potential therapies to treat Alzheimer's disease. The mechanisms of their anti-amyloid activity are not well known. In this regard, many natural compounds are known to exhibit direct binding to various amyloid species including oligomers and fibrils, which in turn can lead to conformational change in the beta-sheet assembly to form nontoxic aggregates. This review discusses the mechanism of anti-amyloid activity of 16 natural compounds and gives structural details on their direct binding interactions with amyloid aggregates. Our computational investigations show that the physicochemical properties of natural products do fit Lipinski's criteria and that catechol and catechol-type moieties present in natural compounds act as lysine site-specific inhibitors of amyloid aggregation. Based on these observations, we propose a structural template to design novel small molecules containing site-specific ring scaffolds, planar aromatic and nonaromatic linkers with suitably substituted hydrogen bond acceptors and donors. These studies will have significant implications in the design and development of novel amyloid aggregation inhibitors with superior metabolic stability and blood-brain barrier penetration as potential agents to treat Alzheimer's disease. PMID- 26099311 TI - Effect Comparison of Both Iron Chelators on Outcomes, Iron Deposit, and Iron Transporters After Intracerebral Hemorrhage in Rats. AB - Iron overload plays a key role in brain injury after intracerebral hemorrhage (ICH). We explored the roles of ferric iron chelator-deferiprone (DFP)-and ferrous iron chelator-clioquinol (CQ)-in ICH rats through the outcomes, iron deposits, reactive oxygen species (ROS), brain water content, and related iron transporters. One hundred eight Sprague-Dawley rats received intra-striatal infusions of 0.5 U of type IV collagenase to establish ICH models. The rats were randomly assigned to the sham, vehicle, DFP, and CQ groups. We evaluated the outcomes, iron levels, brain water content, and ROS; meanwhile, immunohistochemistry and real-time quantitative polymerase chain reaction (RT qPCR) were utilized to determine ferritin, transferrin, transferrin receptor, divalent metal transport 1 (DMT1), and ferroportin at 48 and 72 h, 7 and 14 days after surgery. Our results showed ICH induced iron overload, brain edema, ROS formation, and neurological deficits. Both iron chelators decreased iron levels; CQ improved the neurological outcome, attenuated brain edema, and ROS production. DFP reduced iron contents but not brain water content and ROS generation. DFP failed to improve the outcome. ICH initiated endogenous iron chelators and transporters, both exogenous iron chelators enhanced expression of transferrin and transferrin receptor. CQ enhanced expression of ferroportin but not DMT1, while DFP enhanced expression of DMT1 but not ferroportin. Ferrous iron contributed to brain injury, and binding ferrous iron can modestly improve outcome after ICH in rats. The exogenous ferrous iron chelator possibly functioned via endogenous ferrous iron transporters on ICH. Therefore, ferrous iron may be a promising target for ICH in future. PMID- 26099312 TI - The extraction of the new components from electrogastrogram (EGG), using both adaptive filtering and electrocardiographic (ECG) derived respiration signal. AB - Electrogastrographic examination (EGG) is a noninvasive method for an investigation of a stomach slow wave propagation. The typical range of frequency for EGG signal is from 0.015 to 0.15 Hz or (0.015-0.3 Hz) and the signal usually is captured with sampling frequency not exceeding 4 Hz. In this paper a new approach of method for recording the EGG signals with high sampling frequency (200 Hz) is proposed. High sampling frequency allows collection of signal, which includes not only EGG component but also signal from other organs of the digestive system such as the duodenum, colon as well as signal connected with respiratory movements and finally electrocardiographic signal (ECG). The presented method allows improve the quality of analysis of EGG signals by better suppress respiratory disturbance and extract new components from high sampling electrogastrographic signals (HSEGG) obtained from abdomen surface. The source of the required new signal components can be inner organs such as the duodenum and colon. One of the main problems that appear during analysis the EGG signals and extracting signal components from inner organs is how to suppress the respiratory components. In this work an adaptive filtering method that requires a reference signal is proposed. In the present research, the respiratory component is obtained from non standard ECG (NSECG) signal. For purposes of this paper non standard ECG (namely NSECG) is used, because ECG signal was recorded by other than the standard electrodes placement on the surface of the abdomen. The electrocardiographic derived respiration signal (EDR) is extracted using the phenomena of QRS complexes amplitude modulation by respiratory movements. The main idea of extracting the EDR signal from electrocardiographic signal is to obtain the modulating signal. Adaptive filtering is done in the discrete cosine transform domain. Next the resampled HSEGG signal with attenuated respiratory components is low pass filtered and as a result the extended electrogastrographic signals, included EGG signal and components from other inner organs of digestive system is obtained. One of additional features of the proposed method is a possibility to obtain simultaneously recorded signals, such as: non-standard derivation of ECG, heart rate variability signal, respiratory signal, and EGG signal that allow investigating mutual interferences among internal human systems. PMID- 26099313 TI - Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. AB - Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS. PMID- 26099315 TI - Biodegradable Film for the Targeted Delivery of siRNA-Loaded Nanoparticles to Vaginal Immune Cells. AB - The goal of this study was to develop and characterize a novel intravaginal film platform for targeted delivery of small interfering RNA (siRNA)-loaded nanoparticles (NP) to dendritic cells as a potential gene therapy for the prevention of sexually transmitted human immunodeficiency virus (HIV) infection. Poly(ethylene glycol) (PEG)-functionalized poly(D, L-lactic-co-glycolic acid) (PLGA)/polyethylenimine (PEI)/siRNA NP (siRNA-NP) were fabricated using a modified emulsion-solvent evaporation method and characterized for particle size, zeta potential, encapsulation efficiency (EE), and siRNA release. siRNA-NP were decorated with anti-HLA-DR antibody (siRNA-NP-Ab) for targeting delivery to HLA DR+ dendritic cells (DCs) and homogeneously dispersed in a biodegradable film consisting of poly vinyl alcohol (PVA) and lambda-carrageenan. The siRNA-NP-Ab loaded film (siRNA-NP-Ab-film) was transparent, displayed suitable physicomechanical properties, and was noncytotoxic. Targeting activity was evaluated in a mucosal coculture model consisting of a vaginal epithelial monolayer (VK2/E6E7 cells) and differentiated KG-1 cells (HLA-DR+ DCs). siRNA-NP Ab were rapidly released from the film and were able to penetrate the epithelial layer to be taken up by differentiated KG-1 cells. siRNA-NP-Ab demonstrated higher targeting activity and significantly higher knockdown of synaptosome associated 23-kDa protein (SNAP-23) mRNA and protein when compared to siRNA-NP without antibody conjugation. Overall, these data suggest that our novel siRNA-NP Ab-film may be a promising platform for preventing HIV infection within the female genital tract. PMID- 26099314 TI - KIR and HLA under pressure: evidences of coevolution across worldwide populations. AB - KIR (killer cell immunoglobulin-like receptors) and HLA (human leukocyte antigens) are two distinct gene families with remarkable importance for human immune responses. The recognition of HLA molecules by activating and inhibitory KIR promotes a balance of signals that regulates NK cell function and is especially important for the innate defense against pathogens and early placentation. There is no documented gametic association between these two gene families and no evidence of common regulation. However, due to the critical role of KIR recognition for immunity and reproduction, the possibility of KIR-HLA combinations being under selective pressure is not surprising. In this manuscript, we first summarize the HLA-KIR system, the HLA molecules that are the putative ligands for KIR, and then we review the evidences that suggest these two gene families are coevolving as an integrated system. PMID- 26099316 TI - Transversus abdominis plane blockade in laparoscopic colorectal surgery: a double blind randomized clinical trial. AB - INTRODUCTION: Adequate postoperative analgesia is essential for recovery following colorectal surgery. Transversus abdominis plane (TAP) blocks have been found to be beneficial in improving pain following a variety of abdominal operations. The objective of this study was to determine if TAP blocks are useful in improving postoperative recovery following laparoscopic colorectal surgery. MATERIALS AND METHODS: A prospective double-blind randomized clinical trial, involving 226 consecutive patients having laparoscopic colorectal surgery, was performed by a university colorectal surgical department. Patients were randomized to either TAP blockade using ultrasound guidance, or control, with the primary outcome being postoperative pain, as measured by analgesic consumption. Secondary outcomes assessed were pain visual analogue score (VAS), respiratory function, time to return of gut function, length of hospital stay, postoperative complications, and patient satisfaction. RESULTS: A total of 142 patients were followed up to trial completion (74 controls, 68 interventions). Patients were well matched with regard to demographics. No complications occurred as a result of the intervention of TAP blockade. There was no difference between groups with regards to analgesic consumption (161 mEq morphine control vs 175 mEq morphine TAP; p = 0.596). There was no difference between the two groups with regards to the secondary outcomes of daily VAS, respiratory outcome, time to return of gut function, length of hospital stay, postoperative complications, and patient satisfaction. CONCLUSION: We conclude that TAP blockade appears to be a safe intervention but confers no specific advantage following laparoscopic colorectal surgery. PMID- 26099317 TI - A case and review of aseptic liver abscess in Crohn's disease. PMID- 26099318 TI - Does the addition of induction chemotherapy improve outcome in locally advanced rectal carcinoma? PMID- 26099319 TI - Prophylactic stoma mesh did not prevent parastomal hernias. AB - PURPOSE: Parastomal herniation is reported in up to 50 % of patients with a colostomy. A prophylactic stoma mesh has been reported to reduce parastomal hernia rates. The aim of the study was to evaluate the rate of parastomal hernias in a population-based cohort of patients, operated with and without a prophylactic mesh at two different time periods. METHODS: All rectal cancer patients operated with an abdominoperineal excision or Hartmann's procedure between 1996 and 2012 were included. From 2007, a prophylactic stoma mesh was placed in the retro-muscular plane. Patients were followed prospectively with clinical and computed tomography examinations. RESULTS: There were no differences with regard to age, gender, pre-operative albumin levels, ASA score, body mass index (BMI), smoking or type of surgical resection between patients with (n = 71) and without a stoma mesh (n = 135). After a minimum follow-up of 1 year, 187 (91%) of the patients were alive and available for analysis. At clinical and computed tomography examinations, exactly the same parastomal hernia rates were found in the two groups, viz, 25 and 53%, respectively (p = 0.95 and p = 0.18). The hernia sac contained omentum or intestinal loops in 26 (81%) versus 26 (60%) patients with and without a mesh, respectively (p = 0.155). In the multivariate analyses, high BMI was associated with parastomal hernia formation. CONCLUSIONS: A prophylactic stoma mesh did not reduce the rate of clinically or computed tomography-verified parastomal hernias. High BMI was associated with an increased risk of parastomal hernia formation regardless of prophylactic stoma mesh. PMID- 26099320 TI - Perioperative use of tamsulosin significantly decreases rates of urinary retention in men undergoing pelvic surgery. AB - PURPOSE: Urinary retention is a common complication of pelvic surgery, leading to urinary tract infection and prolonged hospital stays. Tamsulosin is an alpha blocker that works by relaxing bladder neck muscles. It is used to treat benign prostatic hypertrophy and retention. We aim to investigate the potential benefits of preemptive tamsulosin use on rates of urinary retention in men undergoing pelvic surgery. METHODS: This is a retrospective review of an institutional colorectal database. All men undergoing pelvic surgery between 2004 and 2013 were included. Patients given 0.4 mg of tamsulosin 3 days prior and after surgery at discretion of surgeon starting in 2007 were compared with patients receiving expectant postoperative management. RESULTS: One hundred eighty-five patients were included in the study (study group: N = 30; control group: N = 155). Study group patients were older (56.8 vs. 50.1 years). Overall urinary retention rate was 22% with significantly lower rates in the study group compared with control (6.7 vs. 25%; p = 0.029). Study group had higher rates of minimally invasive surgery (61 vs. 29.7%); however, this did not impact urinary retention rate (20.6 vs. 22.7% for minimally invasive surgery vs. open surgery; p = 0.85). Independent predictors of urinary retention included lack of preemptive tamsulosin (odds ratio (OR), 7.67; 95% confidence interval (CI), 1.4-41.7) and cancer location in the distal third of the rectum (OR, 18.8; 95% CI, 2.1-172.8). CONCLUSIONS: Preemptive perioperative use of tamsulosin may significantly decrease the incidence of urinary retention in men undergoing pelvic surgery. This may play a role in avoidance of urinary retention, particularly in patients with distal rectal cancer. PMID- 26099321 TI - Visceral fat accumulation affects risk of colonic diverticular hemorrhage. AB - PURPOSES: Factors other than antithrombotic drugs associated with diverticular bleeding remain unknown. Visceral adiposity contributes to atherosclerosis and may affect arteriolar change at the diverticulum. We investigated whether visceral adipose tissue (VAT) measured by computed tomography (CT) is a risk factor for diverticular bleeding. METHODS: A cohort of 283 patients (184 with asymptomatic diverticulosis and 99 with diverticular bleeding) undergoing colonoscopy and CT was analyzed. Associations between body mass index (BMI), VAT, subcutaneous adipose tissue (SAT), and diverticular bleeding were assessed by logistic regression models adjusted for age, gender, alcohol, smoking, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, and antithrombotic drugs (nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, and other antiplatelet drugs). RESULTS: In univariate analysis, hypertension, dyslipidemia, chronic kidney disease, and NSAIDs use, low-dose aspirin, non-aspirin antiplatelets, increasing BMI, and increasing VAT area were associated with diverticular bleeding. In multivariate analysis adjusted for confounding factors, VAT area (p = 0.021), but not BMI (p = 0.551) or SAT area (p = 0.635), was positively associated with diverticular bleeding. When BMI was considered simultaneously, VAT area remained positively associated with diverticular bleeding (p = 0.018). However, none of obesity indices including VAT area were associated with recurrence of diverticular bleeding or prolonged hospitalization. CONCLUSIONS: This study presents new information on risk factors for diverticular bleeding. A large volume of visceral adipose tissue, but not BMI or SAT, appears to entail a risk for diverticular bleeding, after age, gender, metabolic factors, and antithrombotic drugs use adjustments. PMID- 26099323 TI - Effect of Cardiac Resynchronization Therapy on Inflammation in Congestive Heart Failure: A Review. AB - Congestive heart failure is associated with increased levels of several inflammatory mediators, and animal studies have shown that infusion of a number of cytokines can induce heart failure. However, several drugs with proven efficacy in heart failure have failed to affect inflammatory mediators, and anti inflammatory therapy in heart failure patients has thus far been disappointing. Hence, to what extent heart failure is caused by or responsible for the increased inflammatory burden in the patient is still unclear. Over the past couple of decades, resynchronization therapy with a biventricular pacemaker has emerged as an effective treatment in a subset of heart failure patients, reducing both morbidity and mortality. Such treatment has also been shown to affect the inflammation associated with heart failure. In this study, we review recent data on the association between heart failure and inflammation, and in particular how resynchronization therapy can affect the inflammatory process. PMID- 26099322 TI - Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patients with metastatic colorectal cancer. a meta-analysis. AB - BACKGROUND: The clinical benefit of first-line doublet chemotherapy (including oxaliplatin or irinotecan) compared to single-drug therapy (5FU) in elderly patients (>70 or >75 years old) with metastatic colorectal cancer (MCRC) is controversial. Therefore, we undertook a meta-analysis of all published phase III studies. MATERIAL AND METHODS: We performed a PubMed search using keywords metastatic colorectal cancer, phase III studies, oxaliplatin, irinotecan, survival. We also screened Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) proceedings. Few studies have been published corresponding to our inclusion criteria. The efficacy outcomes were overall survival (OS) and progression-free survival (PFS). Toxicity was also examined when available. Hazard ratios (HRs) with their 95 % confidence intervals (CI) were collected from the studies and pooled. By convention, HRs <1 corresponded to a better outcome for doublets. p values <0.05 were considered statistically significant. A fixed-effect model was used. We used Comprehensive Meta-Analysis Software (Biostat, Englewood, NJ, USA). RESULTS: This meta-analysis (MA) included five original studies (Mitry and Venderbosch for CAIRO both assessing irinotecan, De Gramont and Seymour for FOCUS2 and Ducreux assessing oxaliplatin) and an already published MA (Folprecht) of four trials comparing FOLFIRI with 5FU (Saltz, Douillard, Kohne and Seymour). Our MA included 1225 patients (70 % men). For age, we chose a cut-off of 70 years for oxaliplatin and a cut-off of 75 years for irinotecan. The performance status (PS) score was 0-1 in about 90 % of patients except for the studies by Mitry and Seymour FOCUS2 which both included 30 % of PS2 patients. Overall, doublet chemotherapy, compared to 5FU alone, did not improve OS (HR = 1.00; CI: 0.89-1.13) but significantly improved PFS (HR = 0.82; CI: 0.72-0.93). When assessed separately, FOLFIRI and FOLFOX both significantly improved PFS (HR = 0.83; 0.68-1.00 and HR = 0.81; 0.68-0.97, respectively). The main grade 3-4 toxicities for FOLFIRI were diarrhoea, nausea, vomiting and neutropenia, which occurred significantly more often than with 5FU alone. CONCLUSION: Addition of oxaliplatin or irinotecan to 5FU in metastatic CRC significantly improved PFS in elderly patients more than 70 years old but was associated with an increased risk of toxicity as shown for irinotecan. PMID- 26099324 TI - Prediction of promoters and enhancers using multiple DNA methylation-associated features. AB - BACKGROUND: Regulatory regions (e.g. promoters and enhancers) play an essential role in human development and disease. Many computational approaches have been developed to predict the regulatory regions using various genomic features such as sequence motifs and evolutionary conservation. However, these DNA sequence based approaches do not reflect the tissue-specific nature of the regulatory regions. In this work, we propose to predict regulatory regions using multiple features derived from DNA methylation profile. RESULTS: We discovered several interesting features of the methylated CpG (mCpG) sites within regulatory regions. First, a hypomethylation status of CpGs within regulatory regions, compared to the genomic background methylation level, extended out >1000 bp from the center of the regulatory regions, demonstrating a high degree of correlation between the methylation statuses of neighboring mCpG sites. Second, when a regulatory region was inactive, as determined by histone mark differences between cell lines, methylation level of the mCpG site increased from a hypomethylated state to a hypermethylated state, the level of which was even higher than the genomic background. Third, a distinct set of sequence motifs was overrepresented surrounding mCpG sites within regulatory regions. Using 5 types of features derived from DNA methylation profiles, we were able to predict promoters and enhancers using machine-learning approach (support vector machine). The performances for prediction of promoters and enhancers are quite well, showing an area under the ROC curve (AUC) of 0.992 and 0.817, respectively, which is better than that simply based on methylation level, especially for prediction of enhancers. CONCLUSIONS: Our study suggests that DNA methylation features of mCpG sites can be used to predict regulatory regions. PMID- 26099326 TI - A Revision of the Genus Nemobrenthus Sharp (Coleoptera: Brentidae). AB - A systematic revision of the Neotropical genus Nemobrenthus Sharp is carried out on the basis of morphological characters. Prior to this study, the group included eight nominal taxa. Only three species are actually considered valid-Nemobrenthus sublaevis Boheman from Atlantic Brazil, Nemobrenthus helmenreichii Redtenbacher from South-Central Brazil, and Nemobrenthus aeneipennis Sharp from Central America and the northern part of South America-as several new synonymies are proposed: Nemocephalus tonsus Kleine, n. syn. for Brenthus sublaevis Boheman; Nemocephalus gounellei Kleine, n. syn. for B. sublaevis; Brenthus suratus Boheman, n. syn. for B. sublaevis; Nemobrenthus expletus Kleine, n. syn. for Trachelizus helmenreichii Redtenbacher; Nemobrenthus bechynei Soares & Scivittaro, n. syn. for T. helmenreichii; Nemobrenthus pereirai Soares & Scivittaro, n. syn. for T. helmenreichii; Nemobrenthus melzeri Kleine, n. syn. for T. helmenreichii. Lectotypes are designated for B. sublaevis and N. tonsus. A key to the three recognized species of Nemobrenthus is provided. PMID- 26099325 TI - Gender Differences in Searching for Health Information on the Internet and the Virtual Patient-Physician Relationship in Germany: Exploratory Results on How Men and Women Differ and Why. AB - BACKGROUND: Many studies have shown that women use the Internet more often for health-related information searches than men, but we have limited knowledge about the underlying reasons. We also do not know whether and how women and men differ in their current use of the Internet for communicating with their general practitioner (GP) and in their future intention to do so (virtual patient physician relationship). OBJECTIVE: This study investigates (1) gender differences in health-related information search behavior by exploring underlying emotional, motivational, attitudinal as well as cognitive variables, situational involvement, and normative influences, and different personal involvement regarding health-related information searching and (2) gender differences in the virtual patient-physician relationship. METHODS: Gender differences were analyzed based on an empirical online survey of 1006 randomly selected German patients. The sample was drawn from an e-panel maintained by GfK HealthCare. A total of 958 usable questionnaires were analyzed. Principal component analyses were carried out for some variables. Differences between men (517/958) and women (441/958) were analyzed using t tests and Kendall's tau-b tests. The survey instrument was guided by several research questions and was based on existing literature. RESULTS: Women were more engaged in using the Internet for health-related information searching. Gender differences were found for the frequency of usage of various Internet channels for health-related information searches. Women used the Internet for health-related information searches to a higher degree for social motives and enjoyment and they judged the usability of the Internet medium and of the information gained by health information searches higher than men did. Women had a more positive attitude toward Web 2.0 than men did, but perceived themselves as less digitally competent. Women had a higher health and nutrition awareness and a greater reluctance to make use of medical support, as well as a higher personal disposition of being well-informed as a patient. Men may be more open toward the virtual patient-physician relationship. CONCLUSIONS: Women have a stronger social motive for and experience greater enjoyment in health-related information searches, explained by social role interpretations, suggesting these needs should be met when offering health-related information on the Internet. This may be interesting for governmental bodies as well as for the insurance and the pharmaceutical industries. Furthermore, women may be more easily convinced by health awareness campaigns and are, therefore, the primary target group for them. Men are more open to engaging in a virtual relationship with the GP; therefore, they could be the primary target group for additional online services offered by GPs. There were several areas for GPs to reinforce the virtual patient-physician relationship: the fixing of personal appointments, referral to other doctors, writing prescriptions, and discussions of normal test results and doctor's notes/certificates of health. PMID- 26099327 TI - Evaluation of Left Ventricular Volumes and Function by Real Time Three Dimensional Echocardiography in Children with Functional Single Left Ventricle: A Comparison between QLAB and TomTec. AB - BACKGROUND: Real time three-dimensional echocardiography (RT3DE) provides a reliable analysis of left ventricular (LV) volume. Despite a wide spectrum of tracking algorithms presently available, which software is most suitable for evaluating functional single left ventricle (FLSV) is unknown. Herein, we compared two of the most commonly used 3DE algorithms for quantification of LV volumes in the pediatric population with FLSV. METHODS: Thirty-six children with FLSV were prospectively enrolled. The LV volume analysis was performed on QLAB 8.1 (semiautomated border tracking) and TomTec 4D LV 3.0 (manual dominant border tracking) and compared with MRI as the reference standard. RESULTS: 3DE volume quantification was achieved for 32 children with QLAB and 34 children with TomTec. Analysis time was much shorter for QLAB than TomTec (4.8 +/- 1.2 vs. 6.3 +/- 1.8 minutes, P < 0.05). Ejection fraction (EF) by either 3DE modality was significantly lower than the published normal values (P < 0.01 for each). End diastolic volume (EDV), end-systolic volume (ESV), stroke volume, and EF calculated by both 3DE modalities underestimated MRI values. Compared to QLAB, TomTec showed better correlation and smaller intertechnique differences with MRI (the 95% limits of agreement, EDV: -20.84 to 5.18 mL in QLAB, -10.66 to 1.84 mL in TomTec; ESV: -8.94 to 3.07 mL in QLAB, -2.45 to 0.98 mL in TomTec; SV: -13.31 to 3.45 mL in QLAB, -9.34 to 2.0 mL in TomTec; EF: -12.07 to 7.76% in QLAB, -9.64 to 1.52% in TomTec), TomTec was more reproducible with better intraclass correlation coefficients and variation coefficients. CONCLUSIONS: Both 3DE modalities tend to underestimate LV volumes, but the correlation of LV volumes and EF between 3DE and MRI still holds well. Despite a longer operating time, TomTec analysis is more accurate and reproducible. PMID- 26099328 TI - Identification and expression analysis of irak1 gene in common carp Cyprinus carpio L.: indications for a role of antibacterial and antiviral immunity. AB - In this study, the full-length complementary (c)DNA of interleukin-1 receptor associated kinase 1 gene (irak1) was cloned from common carp Cyprinus carpio. The complete open reading frame of irak1 contained 2109 bp encoding a protein of 702 amino acid residues that comprised a death domain, a ProST region, a serine threonine-specific protein kinase catalytic domain and a C-terminal domain. The amino-acid sequence of C. carpio Irak1 protein shared sequence homology with grass carp Ctenopharyngodon idellus (84.5%). The phylogenetic tree of IRAKs separated the polypeptides into four clades, comprising IRAK1s, IRAK2s, IRAK3s and IRAK4s. Cyprinus carpio Irak1 fell into the cluster with previously reported IRAK1s including teleost Irak1s. The irak1 gene was highly expressed in gills, followed by brain, skin, hindgut, buccal epithelium, spleen, foregut, head kidney and liver, and was expressed at lowest levels in gonad and muscle. The irak1 messenger (m)RNA expression was up-regulated in liver, spleen, head kidney, foregut, hindgut, gills and skin after stimulation with Vibrio anguillarum and poly(I:C), and significantly high up-regulated expression was observed in liver and spleen. These results implied that irak1 might participate in antibacterial and antiviral innate immunity. These findings gave the indications that irak1 may participate in antibacterial and antiviral immunity. PMID- 26099329 TI - Erratum to: Baker's Yeast Deficient in Storage Lipid Synthesis Uses cis-Vaccenic Acid to Reduce Unsaturated Fatty Acid Toxicity. PMID- 26099330 TI - Transcriptional remodeling in response to transfer upon carbon-limited or metformin-supplemented media in S. cerevisiae and its effect on chronological life span. AB - One of the factors affecting chronological life span (CLS) in budding yeast is nutrient, especially carbon limitation. Aside from metabolites in the growth medium such as glucose, amino acids, and acetic acid, many pharmaceuticals have also been proven to alter CLS. Besides their impact on life span, these drugs are also prospective chemicals to treat the age-associated diseases, so the identification of their action mechanism and their potential side effects is of crucial importance. In this study, the effects of caloric restriction and metformin, a dietary mimetic pharmaceutical, on yeast CLS are compared. Saccharomyces cerevisiae cells grown in synthetic dextrose complete (SDC) up to mid-exponential phase were either treated with metformin or were subjected to glucose limitation. The impacts of these perturbations were analyzed via transcriptomics, and the common (stimulation of glucose uptake, induction of mitochondrial maintenance, and reduction of protein translation) and divergent (stimulation of aerobic respiration and reprogramming of respiratory electron transport chain (ETC)) cellular responses specific to each treatment were determined. These results revealed that both glucose limitation and metformin treatment stimulate CLS extension and involve the mitochondrial function, probably by creating an efficient mitochondria-to-nucleus signaling of either aerobic respiration or ETC signaling stimulation, respectively. PMID- 26099331 TI - Designing and creating Saccharomyces interspecific hybrids for improved, industry relevant, phenotypes. AB - To remain competitive in increasingly overcrowded markets, yeast strain development programmes are crucial for fermentation-based food and beverage industries. In a winemaking context, there are many yeast phenotypes that stand to be improved. For example, winemakers endeavouring to produce sweet dessert wines wrestle with fermentation challenges particular to fermenting high-sugar juices, which can lead to elevated volatile acidity levels and extended fermentation times. In the current study, we used natural yeast breeding techniques to generate Saccharomyces spp. interspecific hybrids as a non genetically modified (GM) strategy to introduce targeted improvements in important, wine-relevant traits. The hybrids were generated by mating a robust wine strain of Saccharomyces cerevisiae with a wine isolate of Saccharomyces bayanus, a species previously reported to produce wines with low concentrations of acetic acid. Two hybrids generated from the cross showed robust fermentation properties in high-sugar grape juice and produced botrytised Riesling wines with much lower concentrations of acetic acid relative to the industrial wine yeast parent. The hybrids also displayed suitability for icewine production when bench marked against an industry standard icewine yeast, by delivering icewines with lower levels of acetic acid. Additionally, the hybrid yeast produced wines with novel aroma and flavour profiles and established that choice of yeast strain impacts on wine colour. These new hybrid yeasts display the desired targeted fermentation phenotypes from both parents, robust fermentation in high-sugar juice and the production of wines with low volatile acidity, thus establishing their suitability for wine styles that are traditionally troubled by excessive volatile acidity levels. PMID- 26099333 TI - Preconcentration and detection of mercury with bioluminescent bioreporter E. coli ARL1. AB - Cell wall envelopes treated with sodium hydroxide and spray-dried were used as mercury sorbents. The sorbent having sorption capacity 17.7 +/- 0.1 MUmol/g determined was employed for preconcentration of mercury containing 1-10 ng/L. After preconcentration, bioavailable mercury was detected in samples of soil, stream, and tap water via induction of bioluminescence of E. coli ARL1. Iron and manganese at concentrations of tenth microgram per liter interfered bioluminescence detection of mercury. In tap water was detected semiquantitatively 0.127 +/- 0.1 nmol/L by the induction of bioluminescence of E. coli ARL1 in medium with tryptone after preconcentration using a method of standard addition. PMID- 26099332 TI - Pseudomonas putida-a versatile host for the production of natural products. AB - The biosynthesis of natural products by heterologous expression of biosynthetic pathways in amenable production strains enables biotechnological access to a variety of valuable compounds by conversion of renewable resources. Pseudomonas putida has emerged as a microbial laboratory work horse, with elaborated techniques for cultivation and genetic manipulation available. Beyond that, this bacterium offers several particular advantages with regard to natural product biosynthesis, notably a versatile intrinsic metabolism with diverse enzymatic capacities as well as an outstanding tolerance to xenobiotics. Therefore, it has been applied for recombinant biosynthesis of several valuable natural products. This review provides an overview of applications of P. putida as a host organism for the recombinant biosynthesis of such natural products, including rhamnolipids, terpenoids, polyketides and non-ribosomal peptides, and other amino acid-derived compounds. The focus is on de novo natural product synthesis from intrinsic building blocks by means of heterologous gene expression and strain engineering. Finally, the future potential of the bacterium as a chassis organism for synthetic microbiology is pointed out. PMID- 26099334 TI - Ammonia-oxidizing archaea have better adaptability in oxygenated/hypoxic alternant conditions compared to ammonia-oxidizing bacteria. AB - Ammonia oxidation is performed by both ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB). Few studies compared the adaptability of AOA and AOB for oxygenated/hypoxic alternant conditions in water-level-fluctuating zones. Here, using qPCR and 454 high-throughput sequencing of functional amoA genes of AOA and AOB, we examined the changes of abundances, diversities, and community structures of AOA and AOB in periodically flooded soils compared to the non-flooded soils in Three Gorges Reservoir. The increased AOA operational taxonomic unit (OTU) numbers and the higher ratios of abundance (AOA:AOB) in the periodically flooded soils suggested AOA have better adaptability for oxygenated/hypoxic alternant conditions in the water-level-fluctuating zones in the Three Gorges Reservoir and probably responsible for the ammonia oxidation there. Canonical correspondence analysis (CCA) showed that oxidation-reduction potential (ORP) had the most significant effect on the community distribution of AOA (p < 0.01). Pearson analysis also indicated that ORP was the most important factor influencing the abundances and diversities of ammonia-oxidizing microbes. ORP was significantly negatively correlated with AOA OTU numbers (p < 0.05), ratio of OTU numbers (AOA:AOB) (p < 0.01), and ratio of amoA gene abundances (AOA:AOB) (p < 0.05). ORP was also significantly positively correlated with AOB abundance (p < 0.05). PMID- 26099335 TI - Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. AB - BACKGROUND: Defective tumor suppressor genes (TSGs) and hyperactive oncogenes (OCGs) heavily contribute to cell proliferation and apoptosis during cancer development through genetic variations such as somatic mutations and deletions. Moreover, they usually do not perform their cellular functions individually but rather execute jointly. Therefore, a comprehensive comparison of their mutation patterns and network properties may provide a deeper understanding of their roles in the cancer development and provide some clues for identification of novel targets. RESULTS: In this study, we performed a comprehensive survey of TSGs and OCGs from the perspectives of somatic mutations and network properties. For comparative purposes, we choose five gene sets: TSGs, OCGs, cancer drug target genes, essential genes, and other genes. Based on the data from Pan-Cancer project, we found that TSGs had the highest mutation frequency in most tumor types and the OCGs second. The essential genes had the lowest mutation frequency in all tumor types. For the network properties in the human protein-protein interaction (PPI) network, we found that, relative to target proteins, essential proteins, and other proteins, the TSG proteins and OCG proteins both tended to have higher degrees, higher betweenness, lower clustering coefficients, and shorter shortest-path distances. Moreover, the TSG proteins and OCG proteins tended to have direct interactions with cancer drug target proteins. To further explore their relationship, we generated a TSG-OCG network and found that TSGs and OCGs connected strongly with each other. The integration of the mutation frequency with the TSG-OCG network offered a network view of TSGs, OCGs, and their interactions, which may provide new insights into how the TSGs and OCGs jointly contribute to the cancer development. CONCLUSIONS: Our study first discovered that the OCGs and TSGs had different mutation patterns, but had similar and stronger protein-protein characteristics relative to the essential proteins or control proteins in the whole human interactome. We also found that the TSGs and OCGs had the most direct interactions with cancer drug targets. The results will be helpful for cancer drug target identification, and ultimately, understanding the etiology of cancer and treatment at the network level. PMID- 26099336 TI - Association between mild cognitive impairment and dementia and undernutrition among elderly people in Central Africa: some results from the EPIDEMCA (Epidemiology of Dementia in Central Africa) programme. AB - Several studies in Western countries have shown an association between cognitive disorders and low BMI or weight loss in elderly people. However, few data are available in Africa. We analysed the association between cognitive disorders and undernutrition among elderly people in Central Africa. A cross-sectional, multicentre, population-based study using a two-phase design was carried out in subjects aged 65 years and above in the Central African Republic (CAR) and the Republic of Congo (ROC). All subjects were interviewed using the Community Screening Interview for Dementia, and those with low performance were clinically assessed by a neurologist and underwent further psychometrical tests. Diagnostic and Statistical Manual-IV and Petersen's criteria were required for the diagnoses of dementia and mild cognitive impairment (MCI), respectively. Undernutrition was evaluated using mid-upper arm circumference (MUAC) < 24 cm, BMI < 18.5 kg/m(2) and arm muscular circumference (AMC) < 5th percentile. Multivariate binary logistic regression models were used to estimate the associations. In CAR, MCI was associated with MUAC < 24 cm (OR 0.7, 95% CI 0.4, 1.0) and dementia with BMI < 18.5 kg/m(2) (OR 2.3, 95% CI 1.6, 3.1), AMC < 5th percentile (OR 2.3, 95% CI 1.1, 4.6) and MUAC < 24 cm (OR 1.8, 95% CI 1.4, 2.4). In ROC, both MCI and dementia were associated with all markers of undernutrition, but only AMC < 5th percentile was significantly associated with MCI (OR 3.1, 95% CI 1.9, 4.8). In conclusion, cognitive disorders were associated with undernutrition. However, further studies are needed to elucidate the relationship between MCI and undernutrition in CAR. PMID- 26099337 TI - Cognitive impairment in relation to depression, anxiety and virological response in hepatitis C patients in Egypt. AB - OBJECTIVE: Cognitive impairment commonly occurs in hepatitis C virus (HCV) patients. The objective of this study was to estimate the prevalence and sociodemographic and clinical correlates of cognitive impairment in HCV patients before and after 12 weeks of interferon treatment in comparison with a control group. METHODS: Hundred and sixteen consecutive HCV patients were included in the study and divided into treated and untreated groups. All patients were assessed using sociodemographic and clinical questionnaire, Montreal Cognitive Assessment Scale (MOCA) and Hospital Anxiety and Depression Scale (HADS) before and after 12 weeks of treatment or observation. RESULTS: Thirty-eight percent of treated patients showed cognitive impairment at baseline, which increased to 69% after 12 weeks of interferon treatment. This cognitive impairment was reflected in the total MOCA score and in visuo-constructional skills, attention, concentration, working memory, language, and short-term memory, which was not shown by untreated group after 12 weeks of observation. Cognitive impairment was associated with low education, but not with depression, anxiety, or virological response. CONCLUSIONS: Cognitive impairment is common in HCV patients and increases significantly after interferon treatment. It is not related to depression or anxiety in HCV patients. Future research should focus on prevention, treatment and outcome of cognitive impairment in HCV patients, particularly those receiving interferon therapy. PMID- 26099340 TI - Brachyury: A sensitive marker, but not a prognostic factor, for skull base chordomas. AB - Patients with skull base chordomas have a poor prognosis, and the role of the protein expression of brachyury in chordomas remains to be fully elucidated. The present study used immunohistochemistry to analyze 57 cases of skull base chordoma, and analyzed the clinical data of the patients. The results demonstrated that the protein expression of brachyury was negative in 8.8% (5/57) of the cases. The weak/positive, positive and strong/positive rates were 5.3% (3/57), 21.1% (12/57) and 64.9% (37/57), respectively. The association between the expression of brachyury and recurrence was not statistically significant. Kaplan-Meier analysis revealed that the degree of surgery, rather than the expression of brachyury, was associated with tumor recurrence (P=0.001). In conclusion, the results of the present study demonstrated that the expression of Brachyury offers a sensitive marker, but not a risk factor, for skull base chordomas, and radical surgery is recommended. PMID- 26099341 TI - Does parental monitoring moderate the relationship between bullying and adolescent nonsuicidal self-injury and suicidal behavior? A community-based self report study of adolescents in Germany. AB - BACKGROUND: Being a victim of bullying in school is clearly linked to various social, emotional, and behavioral problems including self-harm behavior. However, it is not known whether even occasional victimization has similar negative consequences and whether protective factors such as social support may prevent those harmful developments. The present study therefore focuses on the nonsuicidal self-injury (NSSI) and suicidal behavior (SB) in victims of bullying and the potentially moderating effect of parental monitoring. METHODS: In all, a cross-sectional sample of 647 adolescents (mean age 12.8 years) were surveyed concerning bullying experiences, NSSI and SB, and parental monitoring. RESULTS: A total of 14.4% of respondents reported being a victim of frequent bullying in the past few months (with verbal and social bullying playing the most important role), which increased the risks of both NSSI (OR = 11.75) and SB (OR = 6.08). This relationship could also be shown for occasional victims of bullying (35.6%), although to a lesser extent. Parental monitoring had a significant protective effect on SB in victims of occasional bullying. However, parental monitoring did not show any protective effect in victims of repetitive bullying. CONCLUSIONS: Victims of bullying show a substantial risk for engaging in self-harm behavior. Therefore, the dissemination of anti-bullying programs in schools would probably also prevent such disorders. Parental participation in school-based prevention may increase its effect; this also matches the results of the present study, showing that parental monitoring may be able to buffer the negative effects of bullying victimization, at least to a certain degree. PMID- 26099342 TI - Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function. AB - BACKGROUND: Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described. CASE PRESENTATION: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein. CONCLUSION: We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana. PMID- 26099343 TI - Cytoreductive conditioning for severe combined immunodeficiency--help or hindrance? AB - Use of chemotherapy-based conditioning-facilitated engraftment in patients with severe combined immunodeficiency (SCID) is contentious. In T- and NK lymphocyte negative, B-lymphocyte-positive (T-B+NK+) and T-B-NK+ SCID, the osteo-medullary space is occupied by recipient hematopoietic stem cells and mature B-lymphocytes. The thymic niche is empty in T-B+NK+ SCID but fully occupied by developmentally arrested T-lymphocyte precursors in T-B-NK+ SCID. The outcome of infusion of donor stem cells differs and is dependent on genetic defect and the lymphocyte developmental arrest stage. At best, donor hematopoietic stem cell osteo medullary engraftment induces normal B-lymphocyte function and long-term thymopoiesis; at worst, peripheral expansion of donor T-lymphocytes from the stem cell source results in a restricted T-lymphocyte receptor repertoire with possible B-lymphocyte failure. Conditioning improves immunoreconstitution but causes short- and long-term toxicities, and increased mortality. Newborn screening for SCID will propel the search for safe, effective methods of achieving donor cell engraftment and full immunoreconstitution without toxic sequalae. PMID- 26099344 TI - The immunomodulatory effects of intravenous immunoglobulin therapy in Kawasaki disease. AB - The introduction of intravenous immunoglobulin (IVIG) for modulation of inflammation in acute Kawasaki disease was a great therapeutic triumph. However, three decades later, the mechanisms underlying immune regulation by IVIG are only beginning to be revealed. Stimulation of an immature myeloid population of dendritic cells that secretes IL-10 and the elucidation of Fc-specific natural regulatory T cells provide insights into the mechanisms of IVIG. Other potential mechanisms include provision of agent-specific neutralizing antibody, anti idiotype and anti-cytokine antibodies, blockade of activating Fcgamma receptors and stimulation of the inhibitory FcgammaRIIb receptor. New initiatives must seek to understand the mechanisms of IVIG in order to replace it one day with more affordable and more targeted therapies. PMID- 26099346 TI - The influence of SrO and CaO in silicate and phosphate bioactive glasses on human gingival fibroblasts. AB - In this paper, we investigate the effect of substituting SrO for CaO in silicate and phosphate bioactive glasses on the human gingival fibroblast activity. In both materials the presence of SrO led to the formation of a CaP layer with partial Sr substitution for Ca. The layer at the surface of the silicate glass consisted of HAP whereas at the phosphate glasses it was close to the DCPD composition. In silicate glasses, SrO gave a faster initial dissolution and a thinner reaction layer probably allowing for a continuous ion release into the solution. In phosphate glasses, SrO decreased the dissolution process and gave a more strongly bonded reaction layer. Overall, the SrO-containing silicate glass led to a slight enhancement in the activity of the gingival fibroblasts cells when compared to the SrO-free reference glass, S53P4. The cell activity decreased up to 3 days of culturing for all phosphate glasses containing SrO. Whereas culturing together with the SrO-free phosphate glass led to complete cell death at 7 days. The glasses containing SrO showed rapid cell proliferation and growth between 7 and 14 days, reaching similar activity than glass S53P4. The addition of SrO in both silicate and phosphate glasses was assumed beneficial for proliferation and growth of human gingival fibroblasts due to Sr incorporation in the reaction layer at the glass surface and released in the cell culture medium. PMID- 26099345 TI - Degradation and silicon excretion of the calcium silicate bioactive ceramics during bone regeneration using rabbit femur defect model. AB - The investigation of the bone regeneration ability, degradation and excretion of the grafts is critical for development and application of the newly developed biomaterials. Herein, the in vivo bone-regeneration, biodegradation and silicon (Si) excretion of the new type calcium silicate (CaSiO3, CS) bioactive ceramics were investigated using rabbit femur defect model, and the results were compared with the traditional beta-tricalcium phosphate [beta-Ca3(PO4)2, beta-TCP] bioceramics. After implantation of the scaffolds in rabbit femur defects for 4, 8 and 12 weeks, the bone regenerative capacity and degradation were evaluated by histomorphometric analysis. While urine and some organs such as kidney, liver, lung and spleen were resected for chemical analysis to determine the excretion of the ionic products from CS implants. The histomorphometric analysis showed that the bioresorption rate of CS was similar to that of beta-TCP in femur defect model, while the CS grafts could significantly stimulate bone formation capacity as compared with beta-TCP bioceramics (P < 0.05). The chemical analysis results showed that Si concentration in urinary of the CS group was apparently higher than that in control group of beta-TCP. However, no significant increase of the Si excretion was found in the organs including kidney, which suggests that the resorbed Si element is harmlessly excreted in soluble form via the urine. The present studies show that the CS ceramics can be used as safe, bioactive and biodegradable materials for hard tissue repair and tissue engineering applications. PMID- 26099347 TI - Safety and feasibility of an enhanced recovery pathway after a liver resection: prospective cohort study. AB - BACKGROUND: In contrast to colorectal surgery, enhanced recovery pathways (ERPs) have not yet become standard practice after major upper abdominal surgery. The aim of this study was to assess the feasibility and outcomes after implementation of an ERP after liver a resection. METHODS: Patients who underwent a liver resection in two consecutive 6-month periods before (July-December 2013) and after (January-June 2014) implementation of an ERP were included in a prospective study. Patients who underwent live donation, ALPPS (associating liver partition with portal vein ligation for staged hepatectomy) or concomitant procedures were excluded. Peri-operative outcomes were compared between groups, and multivariate analysis of factors influencing the length of hospital stay (LOS) was performed. RESULTS: Two hundred and eleven patients (93 pre-ERP and 91 post-ERP patients) underwent a liver resection during the study period. There was no significant difference in the median LOS (P = 0.907) and 30-day readmission rates (P = 0.645) between the groups. Severe (Clavien grade III-V) complications were reduced in ERP patients (13.9% versus 4.3%; P = 0.039). On multivariate analysis, an increased age (< 0.001), open resection (< 0.001) and complications (< 0.001) were associated with an increased LOS. CONCLUSION: Enhanced recovery after a liver resection appears to be safe, feasible and may reduce severe complications. However, the LOS was significantly influenced by patient age, open surgery and post-operative complications, but not by an ERP. PMID- 26099348 TI - Orbital lobe resection provides a definite diagnosis of lacrimal gland lesions: a report of three cases. AB - BACKGROUND: Entities of lacrimal gland lesions comprise almost inflammatory and lymphoproliferative processes as well as benign and malignant solid tumors and usually cannot be differentiated by magnetic resonance imaging (MRI) exclusively. Hence, representative tissue samples are needed to arrive at sufficient histopathological diagnosis for further treatment decisions. CASE REPORT: Three women aged between 18 and 67 years were admitted to our center with clinical signs of a space-occupying mass in the lacrimal fossa. MRI revealed a circumscribed lacrimal gland lesion in all three cases. The orbital lobe was resected through a lateral orbitotomy approach for histopathological evaluation. Findings confirmed the diagnoses of pleomorphic adenoma, dacryoadenitis, and low grade B cell non-Hodgkin's lymphoma. Further surgery was not necessary. No recurrence or symptoms of "dry eye" were observed over the course of a 1-year follow-up. CONCLUSION: In cases of non-specific masses in the lacrimal gland on MRI, histopathological diagnoses are vital and can be sufficiently provided by resection of the orbital lobe. Symptoms of dry eye are uncommon, and secondary surgical intervention can be avoided in cases of the presented entities. Further studies with larger patient cohorts are warranted to confirm these findings. PMID- 26099349 TI - Cellular Microparticles in Subarachnoid Hemorrhage. PMID- 26099351 TI - Effect of the mixing ratio during co-treatment of landfill leachate and sewage with a combined stripping and reversed A2/O process. AB - In this study, pilot-scale tests were conducted to evaluate the effect of volumetric mixing ratio of landfill leachate to sewage on the performance of the combined ammonia stripping and reversed anaerobic/anoxic/oxic (A(2)/O) process for co-treatment of landfill leachate and municipal sewage. Stripping, as pre treatment, could significantly remove ammonia nitrogen (NH3-N) and total nitrogen (TN) by 55% and 52%, respectively. Moreover, chemical oxygen demand (COD) was slightly reduced by 6.8%, and little total phosphorus (TP) was removed. The subsequent reversed A(2)/O process appeared to be highly influenced by the volumetric mixing ratio of leachate to sewage. Typically, the effluent COD, NH3 N, TN and TP increased with the increasing ratio from 1:30 to 1:15, namely, the increasing fraction of leachate. Over the all tested mixing ratio range, the effluent COD and NH3-N were satisfied with the primary B standards of Chinese Discharge Standard of Pollutants for municipal waste water treatment plant (GB18918-2002). The standards different from the primary A standards for water reuse are used for discharge into the most surface water bodies in China. However, TN and TP would exceed the primary B standard levels at a mixing ratio of 1:15 or greater. These findings suggest that an appropriate volumetric mixing ratio should be carefully selected to ensure the performance of the reversed A(2)/O process. PMID- 26099352 TI - Actinic keratosis and squamous cell carcinoma: clinical and pathological features. AB - Actinic keratoses (AKs) are the most common keratinocytederived precancerous lesion in humans; they can be observed predominantly in fair-skinned individuals on sun-exposed surfaces. The primary risk factor for AKs is cumulative UV exposure from sunlight and/or tanning salons. AKs may present on a patient as a few detectable lesions. In addition to these, there are subclinical (invisible) AKs that are estimated to occur up to 10 times more often than visible AKs, since unprotected skin receives UV radiation from the sun. Clinical and subclinical AK lesions occurring in photo-damaged skin are called field cancerization. A field of change can be up to 7 cm around the primary lesions, resulting in lesions that are genetically similar. AKs are defined at the histologic level by dysplasia and consist of keratinocytes manifesting atypical nuclei that are enlarged, irregular, and hyperchromatic. The histopathologic changes noted in keratinocytic proliferative lesions involve disturbance of normal surface maturation. The degree and extent of keratinocytic atypia vary in these lesions. The atypical keratinocytes show enlarged nuclei with hyperchromasia, dyskeratosis and mitoses in any layer of the epidermis. In lesions of epidermal dysplasias, surface keratinocytic maturation is present, and a granular cell layer is usually noted. In intraepidermal carcinomas, there is full-thickness involvement of the epidermis by the atypical keratinocytes. While molecular techniques have improved our ability to distinguish squamous cell carcinomas (SCCs) from AKs, they have also reinforced the concept that non-melanoma skin cancers arise through a complex series of aberrations at the molecular level. AKs represent a spectrum along the continuum to invasive cancer. They are the most visible manifestation of field cancerization which creates a population of atypical cells with the potential to progress to invasive malignancy capable of metastasis. As the perilesional epithelium also has abnormalities due to photo exposure, understanding the existence of a "cancerization field" should be explained to the patients, reinforcing the importance of preventive clinical follow-up. The aim of the present review was to emphasize the histopathological aspect of the morphological spectrum in AK, and SCCs, also elucidating the clinicopathology of field canceriziation. PMID- 26099353 TI - Basal cell carcinoma: clinical and pathological features. AB - Basal cell carcinoma (BCC) is a slow-growing, locally invasive malignant epidermal skin neoplasm that represents the most common malignancy in Caucasians. The clinical presentation of BCC can be extremely variable: nodular, ulcerative, superficial, morpheiform, pigmented, and fibroepithelioma of Pinkus are the main clinical variants described. Clinical factors influencing negatively prognosis of BCC are: anatomic location, recurrence and/or persistance at site after treatment, and tumor size. A precise correlations between clinical and histopathological variants is not always possible, especially in biopsy samples. From a histopathological point of view various subtypes has been described: nodular, superficial, infiltrating, morpheiform, micronodular, fibroepithelial BCC and basosquamous carcinoma. A classification system based by growth pattern allows the identification of high-risk subtypes with potential tumor recurrence and aggressive biologic behavior such as infiltrating, morpheiform, micronodular and basosquamous subtypes. Further histopathological aspects determining high risk clinical morbidity are the level of invasion, perineural and lymphovascular invasion, involved surgical margins. The awareness of these clinicopathological features is helpful to better select the appropriate treatment management. PMID- 26099354 TI - Reflectance confocal microscopy for mucosal diseases. AB - Non-invasive, real-time microscopic imaging using in vivo reflectance confocal microscopy (RCM) has been demonstrated to be a useful tool for the evaluation of skin diseases and in particular for skin neoplasms. Recently, the RCM devices dedicated to the skin have also been applied to perform "virtual biopsies" of the oral, genital and ocular mucosa. In fact, mucosa is a sensitive area where non invasive imaging techniques are of high interest in order to spare biopsies and excisions. Mucosa is particularly suitable for RCM because of its thin or absent cornified layer and its thin epithelium that allows a deeper penetration of the laser with the consequent possibility of exploring deeper tissue levels. Besides, being useful for the diagnosis, RCM may be helpful to identify the area to be biopsied in case of large or multifocal lesions and may be regarded as a complementary technique for non invasive assessment of treatment efficacy. The RCM features of healthy mucosa are described and a revision of the literature of the mucosal diseases that can be diagnosed by RCM has been performed. PMID- 26099355 TI - Low glucose-induced ghrelin secretion is mediated by an ATP-sensitive potassium channel. AB - Ghrelin is synthesized in X/A-like cells of the gastric mucosa, which plays an important role in the regulation of energy homeostasis. Although ghrelin secretion is known to be induced by neurotransmitters or hormones or by nutrient sensing in the ghrelin-secreting cells themselves, the mechanism of ghrelin secretion is not clearly understood. In the present study, we found that changing the extracellular glucose concentration from elevated (25 mM) to optimal (10 mM) caused an increase in the intracellular Ca2+ concentration ([Ca2+]i) in ghrelin secreting mouse ghrelinoma 3-1 (MGN3-1) cells (n=32, P<0.01), whereas changing the glucose concentration from elevated to lowered (5 or 1 mM) had little effect on [Ca2+]i increase. Overexpression of a closed form of an ATP-sensitive K+ (KATP) channel mutant suppressed the 10 mM glucose-induced [Ca2+]i increase (n=8, P<0.01) and exocytotic events (n=6, P<0.01). We also found that a low concentration of a KATP channel opener, diazoxide, with 25 mM glucose induced [Ca2+]i increase (n=23, P<0.01) and ghrelin secretion (n>=3, P<0.05). In contrast, the application of a low concentration of a KATP channel blocker, tolbutamide, significantly induced [Ca2+]i increase (n=15, P<0.01) and ghrelin secretion (n>=3, P<0.05) under 5 mM glucose. Furthermore, the application of voltage-dependent Ca2+ channel inhibitors suppressed the 10 mM glucose-induced [Ca2+]i increase (n>=26, P<0.01) and ghrelin secretion (n>=5, P<0.05). These findings suggest that KATP and voltage-dependent Ca2+ channels are involved in glucose-dependent ghrelin secretion in MGN3-1 cells. PMID- 26099350 TI - Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters. AB - Since Otto Warburg reported the 'addiction' of cancer cells to fermentative glycolysis, a metabolic pathway that provides energy and building blocks, thousands of studies have shed new light on the molecular mechanisms contributing to altered cancer metabolism. Hypoxia, through hypoxia-inducible factors (HIFs), in addition to oncogenes activation and loss of tumour suppressors constitute major regulators of not only the "Warburg effect" but also many other metabolic pathways such as glutaminolysis. Enhanced glucose and glutamine catabolism has become a recognised feature of cancer cells, leading to accumulation of metabolites in the tumour microenvironment, which offers growth advantages to tumours. Among these metabolites, lactic acid, besides imposing an acidic stress, is emerging as a key signalling molecule that plays a pivotal role in cancer cell migration, angiogenesis, immune escape and metastasis. Although interest in lactate for cancer development only appeared recently, pharmacological molecules blocking its metabolism are already in phase I/II clinical trials. Here, we review the metabolic pathways generating lactate, and we discuss the rationale for targeting lactic acid transporter complexes for the development of efficient and selective anticancer therapies. PMID- 26099356 TI - Increasing serotonin concentrations alter calcium and energy metabolism in dairy cows. AB - A 4*4 Latin square design in which varied doses (0, 0.5, 1.0, and 1.5 mg/kg) of 5 hydroxy-l-tryptophan (5-HTP, a serotonin precursor) were intravenously infused into late-lactation, non-pregnant Holstein dairy cows was used to determine the effects of serotonin on calcium and energy metabolism. Infusion periods lasted 4 days, with a 5-day washout between periods. Cows were infused at a constant rate for 1 h each day. Blood was collected pre- and 5, 10, 30, 60, 90, and 120 min post-infusion, urine was collected pre- and post-infusion, and milk was collected daily. All of the 5-HTP doses increased systemic serotonin as compared to the 0 mg/kg dose, and the 1.0 and 1.5 mg/kg doses increased circulating glucose and non esterified fatty acids (NEFA) and decreased beta-hydroxybutyrate (betaHBA) concentrations. Treatment of cows with either 1.0 or 1.5 mg/kg 5-HTP doses decreased urine calcium elimination, and the 1.5 mg/kg dose increased milk calcium concentrations. No differences were detected in the heart rates, respiration rates, or body temperatures of the cows; however, manure scores and defecation frequency were affected. Indeed, cows that received 5-HTP defecated more, and the consistency of their manure was softer. Treatment of late-lactation dairy cows with 5-HTP improved energy metabolism, decreased loss of calcium into urine, and increased calcium secretion into milk. Further research should target the effects of increasing serotonin during the transition period to determine any benefits for post-parturient calcium and glucose metabolism. PMID- 26099357 TI - Comparative study on the biodegradability of morpholinium herbicidal ionic liquids. AB - This study focused on evaluating the toxicity as well as primary and ultimate biodegradability of morpholinium herbicidal ionic liquids (HILs), which incorporated MCPA, MCPP, 2,4-D or Dicamba anions. The studied HILs were also subjected to determination of surface active properties in order to assess their influence on toxicity and biodegradability. The study was carried out with microbiota isolated from different environmental niches: sediments from river channel, garden soil, drainage trench collecting agricultural runoff stream, agricultural soil and municipal waste repository. The obtained results revealed that resistance to toxicity and biodegradation efficiency of the microbiota increased in the following order: microbiota from the waste repository > microbiota from agricultural soil ~ microbiota from an agricultural runoff stream > microbiota from garden soil > microbiota from the river sludge. It was observed that the toxicity of HILs increased with the hydrophobicity of the cation, however the influence of the anion was more notable. The highest toxicity was observed when MCPA was used as the anion (EC50 values ranging from 60 to 190 mg L(-1)). The results of ultimate biodegradation tests indicated that only HILs with 2,4-D as the anion were mineralized to some extent, with slightly higher values for HILs with the 4-decyl-4-ethylmorpholinium cation (10-31 %) compared to HILs with the 4,4-didecylmorpholinium cation (9-20 %). Overall, the cations were more susceptible (41-94 %) to primary biodegradation compared to anions (0-61 %). The obtained results suggested that the surface active properties of the studied HILs may influence their toxicity and biodegradability by bacteria in different environmental niches. PMID- 26099358 TI - Challenges in implementation of ISTH diagnostic algorithm for diagnosis and classification of factor XIII deficiency in Iran. PMID- 26099359 TI - P2X7 receptors and Fyn kinase mediate ATP-induced oligodendrocyte progenitor cell migration. AB - Recruitment of oligodendrocyte precursor cells (OPCs) to the lesions is the most important event for remyelination after central nervous system (CNS) injury or in demyelinating diseases. However, the underlying molecular mechanism is not fully understood. In the present study, we found high concentrations of ATP could increase the number of migrating OPCs in vitro, while after pretreatment with oxidized ATP (a P2X7 receptor antagonist), the promotive effect was attenuated. The promotive effect of 2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) (a P2X7 receptor agonist) was more potent than ATP. After incubation with BzATP, the activity of Fyn, one member of the Src family of kinases, was enhanced. Moreover, the interaction between P2X7 and Fyn was identified by co immunoprecipitation. After blocking the activity of Fyn or down-regulating the expression of Fyn, the migration of OPCs induced by BzATP was inhibited. These data indicate that P2X7 receptors/Fyn may mediate ATP-induced OPC migration under pathological conditions. PMID- 26099361 TI - Trade-offs in host choice of an herbivorous insect based on parasitism and larval performance. AB - Herbivore diet breadth is predicted to evolve in response to both bottom-up and top-down selective pressures, including host plant abundance, quality and natural enemy pressure. As the relative importance and strength of interactions change over an herbivore's geographic range, local patterns of host plant use should change in response, altering local diet breadths. Fall webworm (Hyphantria cunea) is a widespread, polyphagous moth species that feeds on hundreds of plant species worldwide. Populations of fall webworm in Colorado remain polyphagous, but their diet breadth is restricted compared to other populations and thus present an ideal opportunity to test the ecological drivers of host use by a polyphagous herbivore. We investigated how host abundance, larval performance, and parasitism affect host use for fall webworm to test how these selective pressures may act individually or in concert, as well as the role of any trade-offs among fitness components, to explain diet breadth and host use. We found that host abundance was a significant predictor of host use, which suggests a selective pressure to reduce search time for oviposition sites by adult females. We also detected an important trade-off between bottom-up and top-down selective pressures: higher quality host plants also had a greater proportion of larval mortality due to parasitism. Local patterns of host plant abundance appear to narrow the set of hosts used by fall webworms in Colorado, while the trade-off between host quality and risk of parasitism helps explain the maintenance of a generalized feeding strategy within this restricted set of hosts. PMID- 26099362 TI - Direct Observation of Two-Step Photon Absorption in an InAs/GaAs Single Quantum Dot for the Operation of Intermediate-Band Solar Cells. AB - We present the first direct observation of two-step photon absorption in an InAs/GaAs single quantum dot (QD) using photocurrent spectroscopy with two lasers. The sharp peaks of the photocurrent are shifted due to the quantum confined Stark effect, indicating that the photocurrent from a single QD is obtained. In addition, the intensity of the peaks depends on the power of the secondary laser. These results reveal the direct demonstration of the two-step photon absorption in a single QD. This is an essential result for both the fundamental operation and the realization of ultrahigh solar-electricity energy conversion in quantum dot intermediate-band solar cells. PMID- 26099360 TI - Post Splenectomy Outcome in beta-Thalassemia. AB - OBJECTIVES: To evaluate changes in annual blood transfusion requirements and complications after splenectomy in patients with beta-thalassemia. METHODS: Forty post-splenectomy beta-thalassemic patients aged 8-33 y, receiving regular blood transfusions and chelation therapy were included and non transfusion dependant patients were excluded from this retrospective cross-sectional study. Details about their surgery, transfusion requirements, and platelet levels were recorded on a standard proforma. All patients underwent a B-mode and color-coded duplex sonography of the hepatoportal system during the study period. RESULTS: The average ferritin level in the year prior to the study was 4432 mcg/L (range 480 12,200 mcg/L). The annual blood transfusion requirement in the first year and 5 y post splenectomy [mean +/- SD (138.41 +/- 90.38 ml/kg/y); (116 +/- 41.44 ml/kg/y)] were significantly different from requirements before splenectomy [(mean +/- SD) 294.85 +/- 226 ml/kg/y; p value <0.001]. There was a significant rise in platelet counts within 24 h post splenectomy with a mean rise of 4,51,000/mm(3) (p value < 0.001). During the follow up period, infections were noted in 50 % of patients, with malaria (18.75 %) being the most common. Doppler study of the portal system in one case showed portal vein thrombosis. CONCLUSIONS: A significant sustained fall in annual blood transfusion requirement and a rise in platelet counts occurred post-splenectomy. Increase in annual blood transfusion requirement should be investigated to find the cause. PMID- 26099363 TI - Exploring associations between multipollutant day types and asthma morbidity: epidemiologic applications of self-organizing map ambient air quality classifications. AB - BACKGROUND: Recent interest in the health effects of air pollution focuses on identifying combinations of multiple pollutants that may be associated with adverse health risks. OBJECTIVE: Present a methodology allowing health investigators to explore associations between categories of ambient air quality days (i.e., multipollutant day types) and adverse health. METHODS: First, we applied a self-organizing map (SOM) to daily air quality data for 10 pollutants collected between January 1999 and December 2008 at a central monitoring location in Atlanta, Georgia to define a collection of multipollutant day types. Next, we conducted an epidemiologic analysis using our categories as a multipollutant metric of ambient air quality and daily counts of emergency department (ED) visits for asthma or wheeze among children aged 5 to 17 as the health endpoint. We estimated rate ratios (RR) for the association of multipollutant day types and pediatric asthma ED visits using a Poisson generalized linear model controlling for long-term, seasonal, and weekday trends and weather. RESULTS: Using a low pollution day type as the reference level, we found significant associations of increased asthma morbidity in three of nine categories suggesting adverse effects when combinations of primary (CO, NO2, NOX, EC, and OC) and/or secondary (O3, NH4, SO4) pollutants exhibited elevated concentrations (typically, occurring on dry days with low wind speed). On days with only NO3 elevated (which tended to be relatively cool) and on days when only SO2 was elevated (which likely reflected plume touchdowns from coal combustion point sources), estimated associations were modestly positive but confidence intervals included the null. CONCLUSIONS: We found that ED visits for pediatric asthma in Atlanta were more strongly associated with certain day types defined by multipollutant characteristics than days with low pollution levels; however, findings did not suggest that any specific combinations were more harmful than others. Relative to other health endpoints, asthma exacerbation may be driven more by total ambient pollutant exposure than by composition. PMID- 26099364 TI - Pleuroparenchymal fibroelastosis: is it also an idiopathic entity? AB - Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that has been recently included in the updated consensus on idiopathic interstitial pneumonias. It shares some clinical features with other chronic interstitial pneumonias (dyspnea, dry cough), and is radiologically characterized by pleural and subpleural parenchymal fibrosis and elastosis, mainly in the upper lobes. The main histological findings include pleural fibrosis and prominent subpleural and parenchymal fibroelastosis. Its characterization is based on the increasing number of cases reported in the literature, so several aspects of the etiology, pathogenesis and natural history are still unknown. Although some cases have been described as idiopathic, PPFE has been reported as a complication after bone marrow transplantation, lung transplantation and chemotherapy, especially with alkylating agents.Spontaneous or iatrogenic pneumothorax is a frequently reported complication of invasive diagnostic tests for identifying PPFE. The disease course is variable, ranging from slow progression to rapid clinical deterioration. No treatment has shown evidence of efficacy, and lung transplantation remains the only option for patients who fulfill the diagnostic criteria for this option. Recognizing and disseminating the specific features of PPFE is essential to raise the level of clinical suspicion for this entity, and to implement appropriate multidisciplinary diagnostic management. PMID- 26099365 TI - Thoracic Surgery Social Media Network: Bringing thoracic surgery scholarship to Twitter. PMID- 26099366 TI - Esophageal adenocarcinoma: Wanted-new models and better targets. PMID- 26099367 TI - Spending 30 minutes to add years to a patient's life: Why is the last step so difficult? PMID- 26099368 TI - Household Transmission of Zoonotic Influenza Viruses in a Cohort of Egyptian Poultry Growers. AB - BACKGROUND: The highly pathogenic avian influenza H5N1 viruses and the low pathogenic H9N2 viruses are enzootic in Egyptian poultry. Several cases of human infection with H5N1 were reported in Egypt. We previously determined that the seroprevalence of H5N1 antibodies in Egyptians exposed to poultry is 2.1% (15/708), suggesting that mild or subclinical infections with this virus occur. We aim to measure the incidence of avian influenza infection in Egyptians exposed to poultry, study risk factors of infection, study the resulting immune response, study household transmission rates, and characterize the viruses causing infections. OBJECTIVE: The objective of the study is to design a 7-year, prospective, household-based cohort investigation to determine incidence and household transmission of avian influenza viruses in humans exposed to poultry. METHODS: At baseline, we will collect sera to measure antibodies against influenza A. Field nurses will visit enrolled subjects at least weekly to check for influenza-like illness symptoms and verify influenza infection by a point of care rapid test. From subjects with influenza infection and their household contacts, we will collect nasal swabs, throat swabs, and nasal washes to characterize the antigenic and genetic makeup of influenza viruses infecting humans. The nurse will also obtain 2x 3-ml blood samples, one for serology, and another for isolating peripheral blood mononuclear cells. RESULTS: Results from this cohort will enhance our understanding of the transmission of avian influenza viruses to humans in a country where such viruses are enzootic. CONCLUSIONS: This may enhance public health efforts aimed at reducing this burden. PMID- 26099370 TI - [In Process Citation]. PMID- 26099372 TI - [In Process Citation]. PMID- 26099373 TI - [In Process Citation]. PMID- 26099369 TI - Effects of low-fat milk consumption at breakfast on satiety and short-term energy intake in 10- to 12-year-old obese boys. AB - PURPOSE: Although controversy exists, some researchers have proposed that dairy products increase the sense of satiety and decrease energy intake; however, data about these effects are lacking in children. Our objective was to assess the effect of low-fat milk compared with iso-volumic and iso-volumic/iso-energetic controls on satiety and energy intake at lunch in obese boys using a randomized three-way crossover controlled clinical trial. METHODS: Thirty-four obese boys aged 10-12 years were randomized to consume a fixed content breakfast with low fat milk (LFM), apple juice (AJ) or water (W) for two consecutive days. Subjective appetite, hunger, fullness, desire to eat and prospective food consumption were measured using a visual analogue scale every 1 h after breakfast followed by an ad libitum buffet lunch at 5 h. RESULTS: All participants completed the study. Energy intake was significantly lower after intake of LFM compared with AJ and W (adjusted mean +/- standard error of energy intake: LFM = 1010 +/- 14 kcal, AJ = 1059 +/- 16 kcal, W = 1236 +/- 20 kcal; P < 0.001). The total appetite score and its components were significantly affected by time for all intervention beverages (P < 0.05). Obese children reported higher satiety score after drinking LFM with breakfast compared with W and AJ (P < 0.05). CONCLUSION: Low-fat milk consumption might have favorable short-term effects on satiety and energy intake in obese boys. Future studies with more participants from both genders and longer follow-up periods are merited. CLINICAL TRIAL REGISTRATION: The study protocol was registered with the Iranian Registry of Clinical Trials (Registration No: IRCT2013022312571N1). PMID- 26099374 TI - [In Process Citation]. PMID- 26099375 TI - [In Process Citation]. PMID- 26099376 TI - [In Process Citation]. PMID- 26099378 TI - [In Process Citation]. PMID- 26099379 TI - [In Process Citation]. PMID- 26099377 TI - [In Process Citation]. PMID- 26099380 TI - [In Process Citation]. PMID- 26099382 TI - [In Process Citation]. PMID- 26099381 TI - [In Process Citation]. PMID- 26099383 TI - [In Process Citation]. PMID- 26099384 TI - [In Process Citation]. PMID- 26099385 TI - [In Process Citation]. PMID- 26099386 TI - [In Process Citation]. PMID- 26099387 TI - [In Process Citation]. PMID- 26099388 TI - [In Process Citation]. PMID- 26099390 TI - [In Process Citation]. PMID- 26099389 TI - [In Process Citation]. PMID- 26099391 TI - [In Process Citation]. PMID- 26099392 TI - [In Process Citation]. PMID- 26099393 TI - [In Process Citation]. PMID- 26099394 TI - [In Process Citation]. PMID- 26099395 TI - [In Process Citation]. PMID- 26099396 TI - [In Process Citation]. PMID- 26099398 TI - [In Process Citation]. PMID- 26099397 TI - [In Process Citation]. PMID- 26099399 TI - [In Process Citation]. PMID- 26099400 TI - [In Process Citation]. PMID- 26099402 TI - [In Process Citation]. PMID- 26099401 TI - [In Process Citation]. PMID- 26099404 TI - [In Process Citation]. PMID- 26099403 TI - [In Process Citation]. PMID- 26099405 TI - [In Process Citation]. PMID- 26099406 TI - [Panfacial aesthetic minimal-invasive approaches]. PMID- 26099407 TI - [Complications associated with aesthetic procedures]. PMID- 26099408 TI - [In Process Citation]. PMID- 26099409 TI - [Subsequent damage following soccer injuries]. PMID- 26099410 TI - [Echinococcosis]. PMID- 26099411 TI - [Endoscopic therapies in inflammatory bowel diseases]. PMID- 26099412 TI - [In Process Citation]. PMID- 26099413 TI - [In Process Citation]. PMID- 26099414 TI - [In Process Citation]. PMID- 26099415 TI - [In Process Citation]. PMID- 26099416 TI - [In Process Citation]. PMID- 26099417 TI - [In Process Citation]. PMID- 26099418 TI - [In Process Citation]. PMID- 26099419 TI - [In Process Citation]. PMID- 26099420 TI - [In Process Citation]. PMID- 26099421 TI - [In Process Citation]. PMID- 26099422 TI - The predictive value of baseline NAA/Cr for treatment response of first-episode schizophrenia: A 1H MRS study. AB - The study focused on the predictive value of baseline metabolite ratios in bilateral hippocampus of first-episode schizophrenia by using proton magnetic resonance spectroscopy ((1)H MRS). (1)H MRS data were acquired from 23 hallucination and 17 non-hallucination first-episode schizophrenia patients compared with 17 healthy participants. Clinical characteristics of patients were rated using the Positive and Negative Syndrome Scale (PANSS) before and after 3 month treatment. The schizophrenia patients showed lower NAA/Cr ratio than healthy participants respectively (p=0.024; p=0.001), and non-hallucination patients had even lower NAA/Cr ratio than hallucination patients (p=0.033). After 3-month treatment, hallucination patients had greater improvement in negative symptoms than non-hallucination patients (p=0.018). The reduction of PANSS total score and negative factor score was positively correlated with the left NAA/Cr in both group patients (p<0.05). Given that the bilateral hippocampal baseline NAA/Cr had predictive value for the whole treatment response, and the left hippocampal NAA/Cr can predict the prognosis of negative symptoms during acute phase medication in first-episode schizophrenia. PMID- 26099423 TI - Interventions for rosacea: abridged updated Cochrane systematic review including GRADE assessments. AB - Rosacea is a common chronic facial dermatosis. This update of our Cochrane review on interventions for rosacea summarizes the evidence, including Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group assessments, of the effects of the currently available treatments. Searches included the following: Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE, EMBASE, LILACS and the Science Citation Index, and ongoing trials registries (July 2014). We included 106 randomized controlled trials (RCTs) with 13 631 participants, a more than 80% increase since the last update in 2011. Pooling of data was feasible for a few outcomes, for topical metronidazole and azelaic acid and both appeared to be more effective than placebo (moderate and high-quality evidence, respectively). Topical ivermectin was more effective than placebo based on two studies (high-quality evidence), and slightly more effective than metronidazole in one study. Brimonidine was more effective than vehicle in reducing erythema in rosacea (high-quality evidence). Ciclosporin ophthalmic emulsion was effective for ocular rosacea (low-quality evidence). For oral treatments there was moderate-quality evidence for the effectiveness of tetracycline based on two old studies, and high-quality evidence for doxycycline 40 mg compared with placebo according to physician assessments. One study at high risk of bias demonstrated equivalent effectiveness for azithromycin and doxycycline 100 mg. Minocycline 45 mg may be effective for papulopustular rosacea (low-quality evidence). Low-dose isotretinoin appeared to be slightly more effective than doxycycline 50-100 mg (high-quality evidence). Laser and light-based therapies for erythema in rosacea were effective (low quality evidence). Further RCTs are required for ocular rosacea. PMID- 26099424 TI - Clinical Role of Human Leukocyte Antigen in Health and Disease. AB - Most of the genes in the major histocompatibility complex (MHC) region express high polymorphism that is fundamental for their function. The most important function of human leukocyte antigen (HLA) molecule is in the induction, regulation of immune responses and the selection of the T cell repertoire. A clinician's attention is normally drawn to a system only when it malfunctions. The HLA system is no exception in this regard, but in contrast to other systems, it also arouses interest when it functions well - too well, in fact. Population studies carried out over the last several decades have identified a long list of human diseases that are significantly more common among individuals that carry particular HLA alleles including inflammatory, autoimmune and malignant disorders. HLA-disease association is the name of this phenomenon, and the mechanism underlying is still a subject of hot debate. Social behaviours are affected by HLA genes and preference for HLA disparate mates may provide 'good genes' for an individual's offspring. Also, certain HLA genes may be associated with shorter life and others with longer lifespan, but the effects depend both on the genetic background and on the environmental conditions. The following is a general overview of the important functional aspects of HLA in health and diseases. PMID- 26099425 TI - Comprehensive genome-wide transcription factor analysis reveals that a combination of high affinity and low affinity DNA binding is needed for human gene regulation. AB - BACKGROUND: High-throughput in vivo protein-DNA interaction experiments are currently widely used in gene regulation studies. Hitherto, comprehensive data analysis remains a challenge and for that reason most computational methods only consider the top few hundred or thousand strongest protein binding sites whereas weak protein binding sites are completely ignored. RESULTS: A new biophysical model of protein-DNA interactions, BayesPI2+, was developed to address the above mentioned challenges. BayesPI2+ can be run in either a serial computation model or a parallel ensemble learning framework. BayesPI2+ allowed us to analyze all binding sites of the transcription factors, including weak binding that cannot be analyzed by other models. It is evaluated in both synthetic and real in vivo protein-DNA binding experiments. Analysing ESR1 and SPIB in breast carcinoma and activated B cell-like diffuse large B-cell lymphoma cell lines, respectively, revealed that the concerted binding to high and low affinity sites correlates best with gene expression. CONCLUSIONS: BayesPI2+ allows us to analyze transcription factor binding on a larger scale than hitherto achieved. By this analysis, we were able to demonstrate that genes are regulated by concerted binding to high and low affinity binding sites. The program and output results are publicly available at: http://folk.uio.no/junbaiw/BayesPI2Plus. PMID- 26099426 TI - [Case report of cholesterolosis bulbi in a Coats disease]. PMID- 26099427 TI - [Ocular hypertension after intravitreal steroid injections: Clinical update as of 2015]. AB - Intravitreal injections are a therapeutic delivery method best suited to the treatment of retinal diseases. Recent years have been marked by the use of anti VEGF agents as well as the arrival of sustained-release corticosteroid implants in France, replacing triamcinolone acetonide. A common complication of IVT steroids is secondary ocular hypertension (OHT) resulting from increased outflow resistance. This article summarizes current understanding. OHT induced by topical steroids has been described for 60 years. Intravitreal use also shows a temporary effect if the exposure is short, dose dependence, and varying incidence depending on the drug used. Sustained release formulations and discontinuing treatment have reduced the risk of induced OHT. Risk factors that induce OHT must be clearly identified prior to an injection. Most cases of OHT can be controlled medically, although differences exist between different drugs. In cases where it cannot be controlled, removal of the implant, selective laser trabeculoplasty, and filtration surgery can be discussed. PMID- 26099428 TI - Approaches to capturing the financial cost of family care-giving within a palliative care context: a systematic review. AB - The economic burden faced by family caregivers of people at the end of life is well recognised. Financial burden has a significant impact on the provision of family care-giving in the community setting, but has seen limited research attention. A systematic review with realist review synthesis and thematic analysis was undertaken to identify literature relating to the financial costs and impact of family care-giving at the end of life. This paper reports findings relating to previously developed approaches which capture the financial costs and implications of caring for family members receiving palliative/end-of-life care. Seven electronic databases were searched from inception to April 2012, for original research studies relating to the financial impact of care-giving at the end of life. Studies were independently screened to identify those which met the study inclusion criteria, and the methodological quality of included studies was appraised using realist review criteria of relevance and rigour. A descriptive thematic approach was used to synthesise data. Twelve articles met the inclusion criteria for the review. Various approaches to capturing data on the financial costs of care-giving at the end of life were noted; however, no single tool was identified with the sole purpose of exploring these costs. The majority of approaches used structured questionnaires and were administered by personal interview, with most studies using longitudinal designs. Calculation of costs was most often based on recall by patients and family caregivers, in some studies combined with objective measures of resource use. While the studies in this review provide useful data on approaches to capturing costs of care-giving, more work is needed to develop methods which accurately and sensitively capture the financial costs of caring at the end of life. Methodological considerations include study design and method of administration, contextual and cultural relevance, and accuracy of cost estimates. PMID- 26099429 TI - Inspiring medical students to love pathology--reply. PMID- 26099430 TI - Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors. AB - Merkel cell polyomavirus is of oncogenic significance in approximately 80% of Merkel cell carcinomas. Morphological subcategories of the tumor differ in regard to viral status, the rare combined type being uniformly virus negative and the predominant pure type being mainly virus positive. Indications that different biological subsets of the tumor exist led us to explore this diversity. In an Eastern Canadian cohort of cases (75 patients; mean age, 76 years [range, 43-91]; male/female ratio, 43:32; 51 [68%] pure and 24 [34%] combined tumors), we semiquantitatively compared the immunohistochemical expression of 3 cellular proteins (p53, Bcl-2, and c-kit) in pure versus combined groups. Viral status was known in a subset of cases. The significant overexpression of p53 in the combined group (mean [SD], 153.8 [117.8] versus 121.6 [77.9]; P = .01) and the increased epidermal expression of this protein (p53 patches) in the same group lend credence to a primary etiologic role for sun damage in these cases. Expression of Bcl-2 and c-kit did not differ significantly between the 2 morphological groups. A relative increase in c-kit expression was significantly associated with a virus negative status (median [interquartile range], 100 [60-115] versus 70 [0-100]; P = .03). Emerging data reveal divergent biological pathways in Merkel cell carcinoma, each with a characteristic immunohistochemical profile. Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression. The potential biological implications of this dichotomy call for consistent stratification of these tumors in future studies. PMID- 26099431 TI - Focus on the legislative approach to short half life radioactive hospital waste releasing. AB - PURPOSE: We propose to summarize the advancements introduced by the new Directive 2013/59/Euratom concerning the concept of clearance, for which the radioactive medical waste represents a typical candidate. We also intend to spotlight disputable points in the regulatory scheme in force in Italy, as well to make a contribution to evaluate whether the practice of patients' urine storing, stated by it, can be regarded to be proper. METHODS: With directing our interest to radionuclides used in Nuclear Medicine, we first present an overview of how the clearance concept, and that of exemption closely related to it, have been developed from the previous Directive 96/29 to the new one; then we describe the implementation of these concepts in the Italian legislation. Subsequently we estimate the exposure due both to keeping the effluent on site and to direct discharging it to the environment. RESULTS: In line with a well established international consensus, the Directive 2013/59 drives simple and harmonized regulation of clearance. On the contrary, some complexity and lack of consistency can be found in the framework of the national legislation affecting the radioactive medical waste handling. In addition the practice of excreta storing is disputed not to be really beneficial. CONCLUSION: The opportunity should be taken to make the whole system of these requirements simpler and more consistent and effective when it is revised to transpose the new Directive. PMID- 26099432 TI - Evaluation of the Distance Between Anterior Commissure of True Vocal Folds and the First Tracheal Ring and Related Laryngeal Indices in 40 Human Cadavers. AB - OBJECTIVE: Distorted anatomy in laryngotracheal pathologies expresses the need to determine a quantitative mean of the distance between the anterior commissure of true vocal folds and the first tracheal ring to better define whether a lesion is in the subglottis or has extended toward the trachea. STUDY DESIGN: This is a descriptive cross-sectional study. METHODS: In 40 cadavers, the larynx was exposed with an apron cut. The laryngofissure cut opened the larynx via the lateral aspect so that the anterior commissure was exposed. A needle was passed through the thyroid cartilage to reach the anterior commissure. The second needle was crossed over the first tracheal ring. The distance between the two needles was measured. RESULTS: The mean distance between the anterior commissure of true vocal folds and the first tracheal ring was 26.82 +/- 4.28 mm (21.3-42.5 mm) in our subjects. This distance was 27.27 +/- 4.45 and 25.05 +/- 3.2 mm, in men and women, respectively. There was no statistically significant correlation between this distance with body mass index (BMI), age, and sex. CONCLUSIONS: The distance between the anterior commissure and the first tracheal ring in patients with laryngotracheal pathologies helps in determining the best therapeutic plan for patients. PMID- 26099433 TI - TDP-35 sequesters TDP-43 into cytoplasmic inclusions through binding with RNA. AB - TDP-43 (TAR DNA binding protein of 43 kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process. PMID- 26099434 TI - Reply: To PMID 24642110. PMID- 26099435 TI - Reply: To PMID 25158922. PMID- 26099436 TI - Reply: To PMID 25083561. PMID- 26099437 TI - Bioelectrochemically-assisted reductive dechlorination of 1,2-dichloroethane by a Dehalococcoides-enriched microbial culture. AB - The aim of this study was to verify the possibility to use a polarized graphite electrode as an electron donor for the reductive dechlorination of 1,2 dichloroethane, an ubiquitous groundwater contaminant. The rate of 1,2-DCA dechlorination almost linearly increased by decreasing the set cathode potential over a broad range of set cathode potentials (i.e., from -300 mV to -900 mV vs. the standard hydrogen electrode). This process was primarily dependent on electrolytic H2 generation. On the other hand, reductive dechlorination proceeded (although quite slowly) with a very high Coulombic efficiency (near 70%) at a set cathode potential of -300 mV, where no H2 production occurred. Under this condition, reductive dechlorination was likely driven by direct electron uptake from the surface of the polarized electrode. Taken as a whole, this study further extends the range of chlorinated contaminants which can be treated with bioelectrochemical systems. PMID- 26099438 TI - Fully reversible current driven by a dual marine photosynthetic microbial community. AB - The electrochemical activity of two seawater microbial consortia were investigated in three-electrode bioelectrochemical cells. Two seawater inocula - from the Sunshine Coast (SC) and Gold Coast (GC) shores of Australia - were enriched at +0.6 V vs. SHE using 12/12 h day/night cycles. After re-inoculation, the SC consortium developed a fully-reversible cathodic/anodic current, with a max. of -62 mA m(-2) during the day and +110 mA m(-2) at night, while the GC exhibited negligible daytime output but +98 mA m(-2) at night. Community analysis revealed that both enrichments were dominated by cyanobacteria, indicating their potential as biocatalysts for indirect light conversion to electricity. Moreover, the presence of gamma-proteobacterium Congregibacter in SC biofilm was likely related to the cathodic reductive current, indicating its effectiveness at catalysing cathodic oxygen reduction at a surprisingly high potential. For the first time a correlation between a dual microbial community and fully reversible current is reported. PMID- 26099439 TI - The question of sperm DNA fragmentation testing in the male infertility work-up: a response to Professor Lewis' commentary. AB - A response to the Commentary 'Should sperm DNA fragmentation testing be included in the male infertility work-up?' by Professor Sheena Lewis. PMID- 26099440 TI - Oocyte cryopreservation for social reasons: demographic profile and disposal intentions of UK users. AB - A small number of studies from the USA and Europe have provided some data on the profile and characteristics of women who have undergone oocyte cryopreservation for what has been termed elective, social or non-medical reasons; however, little is known in a UK context about which women are undergoing oocyte cryopreservation or their reproductive intentions and actions after the procedure. Drawing on data from an exploratory study of 23 UK resident women who had undergone social oocyte cryopreservation, the demographic profile of these women, their reproductive intentions and actions are discussed, as well as their attitudes and intentions towards their cryopreserved oocytes should they never require them in treatment. The study found that, at the time of oocyte cryopreservation, women were on average 36.7 years of age, were university educated, with 65% of the sample holding further postgraduate or professional qualifications. Fifty-seven per cent of the participants were in professional employment. All participants identified as heterosexual and 87% were not in a relationship at the time of cryopreserving their oocytes. Most (88%) participants stated that they would donate unwanted oocytes to research or to other women for use in fertility treatment should they never require them. PMID- 26099441 TI - Forever young? The ethical challenges of using ovarian tissue transplants to treat menopause. AB - Life expectancy statistics predict that in a couple of decades women will enjoy a mean life of 90 years. Assuming a median age for the onset of menopause of 51, women will spend about 40 years in menopause. Harvesting and freezing ovarian cortical tissue at a younger age to permit future transplantation for postponing menopause and its sequelae could become a possible option. However, both medical and ethical issues need to be addressed before this can be offered as a treatment for menopause. PMID- 26099442 TI - Novel use of the ovarian follicular pool to postpone menopause and delay osteoporosis. AB - Life expectancy has increased by more than 30 years during the last century and continues to increase. Many women already live decades in menopause deprived of naturally produced oestradiol and progesterone, leading to an increasing incidence of menopause-related disorders such as osteoporosis, cardiovascular diseases and lack of general well-being. Exogenous oestradiol has traditionally been used to alleviate menopause-related effects. This commentary discusses a radical new method to postpone menopause. Part of the enormous surplus of ovarian follicles can now be cryostored in youth for use after menopause. Excision of ovarian tissue will advance menopause marginally and will not reduce natural fertility. Grafted tissue restores ovarian function with circulating concentrations of sex steroids for years in post-menopausal cancer survivors. Future developments may further utilize the enormous store of ovarian follicles. Currently, the main goal of ovarian cryopreservation is fertility preservation, but grafting of ovarian tissue may also serve endocrine functions as a physiological solution to prevent the massive medical legacy of osteoporosis and menopause-related conditions in the ageing population. This intriguing solution is now technically available; the question is whether this method qualifies for postponing menopause, perhaps initially for those patients who already have cryostored tissue? PMID- 26099443 TI - Early pregnancy care over time: should we promote an early pregnancy assessment unit? AB - In this observational study, the effect of the introduction of the first Early Pregnancy Assessment Unit (EPAU) in a university hospital in The Netherlands in 2008 on early pregnancy care is analysed. Derivatives of quality of care were measured before and after the establishment of the EPAU, with the aim of reducing unnecessary care. Care within three time periods was measured: 2006, 2009 and 2012. In 2006, 14% of women who had experienced a miscarriage were admitted to the hospital, whereas in 2009 and 2012 no women were admitted. The surgical management rate for miscarriage decreased from 79% (2006) to 6% (2009) and 28% (2012). Karyotyping of couples who had experienced recurrent miscarriage decreased from 100% (2006) to 17% (2009) and 33% (2012). The surgical management rate for ectopic pregnancy decreased from 50% (2006) to 25% (2009) and 29% (2012). The mean total cost per woman treated in 2006 was ?1111 (95% CI ?808 to 1426), ?436 (95% CI ?307 to 590) in 2009 and ?633 (95% CI ?586 to 788) in 2012. We can therefore conclude that an EPAU results in higher quality and cost effective care, and has a positive effect on early pregnancy care. PMID- 26099444 TI - Association between p53 Arg72Pro polymorphism and recurrent pregnancy loss: an updated systematic review and meta-analysis. AB - The p53 tumour suppressor gene plays an important role in angiogenesis and apoptosis. The association between Arg72Pro polymorphism and recurrent pregnancy loss (RPL) has been studied but with inconsistent results. A meta-analysis was conducted to examine whether p53 Arg72Pro polymorphism is a risk factor for RPL. Electronic searches of PubMed, Embase and Web of Knowledge were conducted to identify relevant studies. The final meta-analysis included six published articles with 730 RPL cases and 613 controls. The pooled results suggested that the variant genotype was associated with the RPL risk in additive model (Pro versus Arg; odds ratio [OR] = 1.28; 95% confidence interval [CI]: 1.06 to 1.54) and recessive model (Pro/Pro versus Arg/Pro + Arg/Arg; OR = 1.82; 95% CI: 1.21 to 2.73). In the stratified analysis by ethnicity, for white people the results were consistent. The Egger's regression asymmetry test suggested a lack of publication bias. Results of this meta-analysis suggest that p53 codon 72 polymorphism is associated with RPL, especially in white people. Identification of p53 codon 72 mutation would have some implication for primary prevention of RPL and screening of high-risk individuals. Large well-designed studies are needed to fully describe the association between this polymorphism and RPL. PMID- 26099445 TI - Genetic variants associated with female reproductive ageing--potential markers for assessing ovarian function and ovarian stimulation outcome. AB - This study searched for genetic markers of ovarian function, ovarian stimulation and IVF treatment outcome among genetic variants related to female reproductive ageing. It included 471 treatment cycles from 306 women undergoing IVF treatment. Genotypes for 36 single nucleotide polymorphisms (SNPs) were evaluated for their association with early follicular phase parameters together with ovarian stimulation and IVF outcome parameters. Results show that genetic variation related to menopause timing also affects ovarian function, as several selected genetic markers were associated with studied traits. For example, rs2153157 (SYCP2L) was associated with amount of recombinant FSH (rFSH) necessary for obtaining one oocyte (P = 0.049) and the chances of biochemical and clinical pregnancy (P = 0.024 and P = 0.011, respectively), while rs4886238 (TDRD3) showed association with both the number of punctured ovarian follicles and oocytes obtained (P = 0.008 and P = 0.037, respectively). Furthermore, FSHB polymorphisms influence early follicular phase FSH concentrations and IVF treatment outcome, whereas SNPs in FSHR affect early antral follicle count and follicle numbers obtained during ovarian stimulation. This study suggests that genetic markers of female reproductive ageing are potential new biomarker candidates that could be considered in clinical ovarian reserve and function assessment in assisted conception. PMID- 26099446 TI - Recipients' views on payment of sperm donors. AB - The aim of this qualitative study was to explore how recipients viewed payment of sperm donors. The study was conducted in Belgium, where, as in many countries, sperm donors receive recompense for their time and expenses. Face-to-face semi structured interviews were conducted with 34 heterosexual and lesbian couples who, at the time of data collection, had at least one donor-conceived child aged 7-10 years or who were undergoing donor conception treatment. Although participants commonly described the issue of financial compensation as something that did not really concern them, all supported the idea that some level of payment was acceptable or even necessary. The participants also identified several ways in which donor payment offered advantages to their own position as (future) parents. Although the idea is commonly rehearsed that sperm donation is a gift and that monetary transaction for conception is demeaning, the participants of this study did not generally share this view. To them, a small financial return served as a symbolic acknowledgement of the donor's contribution and helped secure the type of relationship they expected from their donor. There was clearly concern, however, over high payments and the risk of attracting the wrong kind of donor. PMID- 26099447 TI - Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement. AB - This study explores the relevance of mid-luteal serum hormonal concentrations in cryopreserved embryo transfer cycles conducted under hormone replacement therapy (HRT) control and which involved single-embryo transfer (SET) of 529 vitrified blastocysts. Widely ranging mid-luteal oestradiol and progesterone concentrations ensued from the unique HRT regimen. Oestradiol had no influence on clinical pregnancy or live birth rates, but an optimal progesterone range between 70 and 99 nmol/l (P < 0.005) was identified in this study. Concentrations of progesterone below 50 nmol/l and above 99 nmol/l were associated with decreased implantation rates. There was no clear interaction between oestradiol and progesterone concentrations but embryo quality grading did show a significant influence on outcomes (P < 0.001 and P = 0.002 for clinical pregnancy and live birth rates, respectively). Multiple comparison analysis showed that the progesterone effect was influential regardless of embryo grading, body mass index or the woman's age, either at vitrification or at cryopreserved embryo transfer. The results support the argument that careful monitoring of serum progesterone concentrations in HRT-cryopreserved embryo transfer is warranted and that further studies should explore pessary adjustments to optimize concentrations for individual women to enhance implantation rates. PMID- 26099448 TI - Prenatal Diagnosis of Fetal Interrupted Aortic Arch Type A by Two-Dimensional Echocardiography and Four-Dimensional Echocardiography with B-Flow Imaging and Spatiotemporal Image Correlation. AB - BACKGROUND: Fetal interrupted aortic arch (IAA) is a rare cardiac anomaly and its prenatal diagnosis is challenging. The purpose of our report is to evaluate the use of two-dimensional echocardiography (2DE) and 4D echocardiography with B-flow imaging and spatiotemporal image correlation (4D BF-STIC) in detecting IAA type A (IAA-A). MATERIALS & METHODS: Twenty-three cases of confirmed IAA-A identified by fetal echocardiography were involved in the study. The fetal echocardiography image data were reviewed to analyze the ratio of right ventricle to left ventricle (RV/LV) diameter, the ratio of main pulmonary artery to ascending aorta (MPA/AAO) diameter, and the correlation of RV/LV diameter ratio and size of ventricular septal defect (VSD). 4D BF-STIC was performed in 21 fetuses using the sagittal view (4D BF-STIC-sagittal) and the four-chamber view (4D BF-STIC-4CV) as initial planes of view. An additional 183 normal fetuses were also included in our study. RV/LV and MPA/AAO ratios were calculated and compared with that of IAA A fetuses. Fetal 2DE, 4D BF-STIC-sagittal, and 4D BF-STIC-4CV were used to visualize the aortic arch and its associated neck vessels. Six subgroups were evaluated according to gestational age. RESULTS: Fetal 2DE, 4D BF-STIC-sagittal, and 4D BF-STIC-4CV made the correct prenatal diagnosis of IAA-A in 19/23 (82.6%), 14/21 (66.7%), and 19/21 (90.5%) of patients, respectively. A significantly enlarged MPA combined with symmetric ventricles was found in the IAA-A fetuses, while the size of the VSD was negatively correlated with RV/LV ratio. 4D BF-STIC sagittal and 4D BF-STIC-4CV were better than traditional 2D ultrasound in detecting the aortic arch and neck vessels between 17 and 28 gestational weeks and 29 to 40 gestational weeks in normal fetuses. CONCLUSION: It is demonstrated that IAA-A could be diagnosed by traditional fetal echocardiography, while 4D technique could better display the anatomic structure and the spatial relationships of the great arteries. Use of volume reconstruction may promote its clinical usage and help prenatal diagnosis. PMID- 26099449 TI - Pharmacokinetics and preliminary safety of high dose linezolid for the treatment of Gram-positive bacterial infections. PMID- 26099450 TI - Negative wound therapy to manage large-for-size liver graft mismatch. AB - Liver volume matching in liver transplantation (LT) is of paramount importance. There is no agreement for its definition, ranging from a graft-to-recipient weight-ratio greater than 4% in paediatric to less than 2.5% in adult LT. Advances have been obtained to avoid small for size grafts, but management of large grafts remains a major challenge in this setting. Consequences include difficult anastomosis, poor vascular alignment, difficult wound closure, graft compression and necrosis. We report on two patients who underwent LT with large grafts and develop major liver graft injury. Technical solutions used in these two cases are presented and discussed. Negative wound therapy allowed a rapid closure of abdominal wall and salvage of the graft. PMID- 26099451 TI - Photocatalytic Properties of Layered Metal Oxides Substituted with Silver by a Molten AgNO3 Treatment. AB - K4Nb6O17 (BG: 3.67 eV) and Na2W4O13 (BG: 3.12 eV) layered oxide photocatalysts with wide band gaps were treated with a molten AgNO3 to substitute K+ and Na+ with Ag+, resulting in red-shifts of absorption edges in diffuse reflectance spectra. A part of Na+ ions in the interlayer of Na2W4O13 was substituted with Ag+ ions by the molten AgNO3 treatment with keeping the layered structure. Both Ag(I)-substituted K4Nb6O17 and Na2W4O13 showed photocatalytic activities for O2 evolution from aqueous solutions containing a sacrificial reagent utilizing the absorption bands newly formed by the Ag(I)-substitution. Notably, the Ag(I) substituted Na2W4O13 produced O2 under visible light irradiation. When ball milled Na2W4O13 was treated with a molten AgNO3, the Ag(I)-substitution rate increased. The Ag(I)-substituted Na2W4O13 with ball-milling showed higher photocatalytic activity for O2 evolution than that without ball-milling. Z schematic water splitting proceeded under visible light irradiation by combining the Ag(I)-substituted Na2W4O13 of an O2-evolving photocatalyst with Ru-loaded SrTiO3 doped with Rh of a H2-evolving photocatalyst. PMID- 26099453 TI - Primary tuberculosis infection in patients treated with tumor necrosis factor alpha antagonists and a negative initial screening. AB - INTRODUCTION: Despite screening for latent tuberculosis (TB), new cases of TB infection are detected in patients treated with anti-TNF-alpha and negative initial screening, some of them after long treatment, which points more to a new infection. OBJECTIVES: To describe the cases that have presumably developed a primary tuberculous infection during treatment with anti-TNF-alpha drugs. METHODS: Retrospective audit (1999-2012). Inclusion criteria were: a) anti-TNF alpha treatment; b) initial latent TB screening negative; c) TB diagnosed during anti-TNF-alpha treatment; d) suspected primary TB infection (diagnosis after at least 12 months on anti-TNF-alpha). Clinical, epidemiological, therapeutic and outcome variables were reviewed. RESULTS: Two cases of primary TB infection were found out of of 771 anti-TNF-alpha treated patients (0.2%). One woman aged 41 suffered TB pneumonia after 35 months of treatment with adalimumab, and a male aged 37 who developed disseminated TB after 107 months of treatment with infliximab. CONCLUSIONS: Although uncommon, during TNF antagonist therapy, TB risk persists despite negative initial screening, so clinicians should be aware of TB during the entire treatment. PMID- 26099452 TI - Network-based survival-associated module biomarker and its crosstalk with cell death genes in ovarian cancer. AB - Ovarian cancer remains a dismal disease with diagnosing in the late, metastatic stages, therefore, there is a growing realization of the critical need to develop effective biomarkers for understanding underlying mechanisms. Although existing evidences demonstrate the important role of the single genetic abnormality in pathogenesis, the perturbations of interactors in the complex network are often ignored. Moreover, ovarian cancer diagnosis and treatment still exist a large gap that need to be bridged. In this work, we adopted a network-based survival associated approach to capture a 12-gene network module based on differential co expression PPI network in the advanced-stage, high-grade ovarian serous cystadenocarcinoma. Then, regulatory genes (protein-coding genes and non-coding genes) direct interacting with the module were found to be significantly overlapped with cell death genes. More importantly, these overlapping genes tightly clustered together pointing to the module, deciphering the crosstalk between network-based survival-associated module and cell death in ovarian cancer. PMID- 26099454 TI - Metallosis as a cause of pain and inflammation in a patient with a knee replacement: A case description. PMID- 26099455 TI - Cyclosporin A-sensitive cytotoxicity of flurbiprofen non-stereoselectively mediated by cytochrome P450 metabolism in three-dimensional cultured rat hepatocytes. AB - OBJECTIVES: 2-Arylpropionic acid (profen) drugs are associated with severe hepatotoxicity; however, risk factors are still poorly understood. Acyl-coenzyme A (acyl-CoA) thioesters of profen drugs play a more important role in the covalent binding to rat hepatocyte proteins than the respective acyl glucuronides. Therefore, we examined whether acyl-glucuronides, acyl-CoA thioesters and oxidative metabolites of profen drugs stereoselectively participated in liver damage. METHODS: Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) leakage from three-dimensional cultured rat hepatocytes. KEY FINDINGS: LDH leakage was not induced by R-2-phenylpropionic acid and R-ibuprofen greatly forming acyl-CoA thioesters. S-Naproxen metabolized mainly by Uridine 5'-diphosphate (UDP)-glucuronosyl-transferase did not enhance LDH leakage. However, flurbiprofen (FLP) induced LDH leakage. A selective cytochrome P450 (CYP) 2C11 inhibitor suppressed 40-50% of the R-FLP and S-FLP induced cytotoxicity. Borneol non-stereoselectively accelerated the FLP-induced cytotoxicity. The R-FLP-induced cytotoxicity decreased intracellular adenosine triphosphate (ATP) levels to 50% of untreated hepatocytes. An inhibitor of mitochondrial permeability transition pore, cyclosporin A (Cys A), rescued ATP levels and LDH leakage back to control levels. CONCLUSION: The reactive acyl-CoA thioesters and acyl-glucuronides were not associated with liver damage, denying one of the leading hypotheses. CYP metabolism of FLP non-stereoselectively participated in Cys A-sensitive cytotoxicity, suggesting mitochondrial injury. PMID- 26099456 TI - The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status. AB - Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0-8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at lower doses whereas wild type cells only at higher doses. Secretion of IL-8 by TP53-/- control cells was many times lower than that by TP53+/+ but increased significantly after irradiation. Transcription of the NFkappaBIA was induced in irradiated TP53+/+ mainly, but in bystanders a higher level was observed in TP53 /- cells, suggesting that TP53 is required for induction of NFkappaB pathway after irradiation but another mechanism of activation must operate in bystander cells. PMID- 26099457 TI - White matter atlas of the human spinal cord with estimation of partial volume effect. AB - Template-based analysis has proven to be an efficient, objective and reproducible way of extracting relevant information from multi-parametric MRI data. Using common atlases, it is possible to quantify MRI metrics within specific regions without the need for manual segmentation. This method is therefore free from user bias and amenable to group studies. While template-based analysis is common procedure for the brain, there is currently no atlas of the white matter (WM) spinal pathways. The goals of this study were: (i) to create an atlas of the white matter tracts compatible with the MNI-Poly-AMU template and (ii) to propose methods to quantify metrics within the atlas that account for partial volume effect. The WM atlas was generated by: (i) digitalizing an existing WM atlas from a well-known source (Gray's Anatomy), (ii) registering this atlas to the MNI-Poly AMU template at the corresponding slice (C4 vertebral level), (iii) propagating the atlas throughout all slices of the template (C1 to T6) using regularized diffeomorphic transformations and (iv) computing partial volume values for each voxel and each tract. Several approaches were implemented and validated to quantify metrics within the atlas, including weighted-average and Gaussian mixture models. Proof-of-concept application was done in five subjects for quantifying magnetization transfer ratio (MTR) in each tract of the atlas. The resulting WM atlas showed consistent topological organization and smooth transitions along the rostro-caudal axis. The median MTR across tracts was 26.2. Significant differences were detected across tracts, vertebral levels and subjects, but not across laterality (right-left). Among the different tested approaches to extract metrics, the maximum a posteriori showed highest performance with respect to noise, inter-tract variability, tract size and partial volume effect. This new WM atlas of the human spinal cord overcomes the biases associated with manual delineation and partial volume effect. Combined with multi-parametric data, the atlas can be applied to study demyelination and degeneration in diseases such as multiple sclerosis and will facilitate the conduction of longitudinal and multi-center studies. PMID- 26099458 TI - Mercury methylation in high and low-sulphate impacted wetland ponds within the prairie pothole region of North America. AB - Using enriched stable (201)Hg injections into intact sediment cores, we provide the first reported Hg methylation potential rate constants (km) in prairie wetland ponds (0.016-0.17 d(-1)). Our km values were similar to other freshwater wetlands and did not differ in ponds categorized with high compared to low surface water concentrations of sulphate. Sites with high sulphate had higher proportions of methylmercury (MeHg) in sediment (2.9 +/- 1.6% vs. 1.0 +/- 0.3%) and higher surface water MeHg concentrations (1.96 +/- 1.90 ng L(-1)vs. 0.56 +/- 0.55 ng L(-1)). Sediment-porewater partitioning coefficients were small, and likely due to high ionic activity. Our work suggests while km measurements are useful for understanding mercury cycling processes, they are less important than surface water MeHg concentrations for assessing MeHg risks to biota. Significant differences in MeHg concentrations between sites with high and low sulphate concentrations may also inform management decisions concerning wetland remediation and creation. PMID- 26099459 TI - Dega osteotomy for the management of developmental dysplasia of the hip in children aged 2-8 years: results of 58 consecutive osteotomies after 13-25 years of follow-up. AB - PURPOSE: Developmental dysplasia of the hip (DDH) is a term used to cover a broad spectrum of anomalies ranging from mild dysplasia to high-riding dislocations. We report the management of DDH in children using the Dega osteotomy and their long term follow-up. METHODS: Fifty-eight hips from 48 children younger than 8 years treated using the Dega osteotomy between January 1988 and October 2000 were included in this multcenter study. Both prospective (41 hips) and retrospective (17 hips) cases were included, and follow-up was for a minimum of 13 years. Radiographs were made preoperatively, immediately postoperatively, after 6 weeks or at removal of the spica cast if any, at 6-month intervals and/or as indicated for 3 years postoperatively and then on annual basis until the last follow-up. A single-cut computed tomographic scan was performed for all prospective patients. Special attention was paid to the predictive measures of hip arthrosis and the survival of the hip after Dega osteotomy. RESULTS: The final clinical outcome was favorable in 44 hips (75.9 %). Eleven hips needed a second surgery (acetabuloplasty and/or arthroplasty) during the follow-up period. CONCLUSIONS: In our pediatric patient population the Dega osteotomy proved to be an adequate measure for the management of this complex condition. The worst complication was avascular necrosis, and all of the affected hips ended with failure (pain, another surgery, or both). PMID- 26099460 TI - Thymoproteasomes produce unique peptide motifs for positive selection of CD8(+) T cells. AB - Positive selection in the thymus provides low-affinity T-cell receptor (TCR) engagement to support the development of potentially useful self-major histocompatibility complex class I (MHC-I)-restricted T cells. Optimal positive selection of CD8(+) T cells requires cortical thymic epithelial cells that express beta5t-containing thymoproteasomes (tCPs). However, how tCPs govern positive selection is unclear. Here we show that the tCPs produce unique cleavage motifs in digested peptides and in MHC-I-associated peptides. Interestingly, MHC I-associated peptides carrying these tCP-dependent motifs are enriched with low affinity TCR ligands that efficiently induce the positive selection of functionally competent CD8(+) T cells in antigen-specific TCR-transgenic models. These results suggest that tCPs contribute to the positive selection of CD8(+) T cells by preferentially producing low-affinity TCR ligand peptides. PMID- 26099461 TI - Citric acid assisted phytoremediation of copper by Brassica napus L. AB - Use of organic acids for promoting heavy metals phytoextraction is gaining worldwide attention. The present study investigated the influence of citric acid (CA) in enhancing copper (Cu) uptake by Brassica napus L. seedlings. 6 Weeks old B. napus seedlings were exposed to different levels of copper (Cu, 0, 50 and 100uM) alone or with CA (2.5mM) in a nutrient medium for 40 days. Exposure to elevated Cu levels (50 and 100uM) significantly reduced the growth, biomass production, chlorophyll content, gas exchange attributes and soluble proteins of B. napus seedlings. In addition, Cu toxicity increased the production of hydrogen peroxide (H2O2), malondialdehyde (MDA) and electrolyte leakage (EL) in leaf and root tissues of B. napus. Activities of antioxidant enzymes such as guaiacol peroxidase (POD), superoxide dismutase (SOD), catalases (CAT), ascorbate peroxidase (APX) in root and shoot tissues of B. napus were increased in response to lower Cu concentration (50uM) but increased under higher Cu concentration (100uM). Addition of CA into nutrient medium significantly alleviated Cu toxicity effects on B. napus seedlings by improving photosynthetic capacity and ultimately plant growth. Increased activities of antioxidant enzymes in CA-treated plants seems to play a role in capturing of stress-induced reactive oxygen species as was evident from lower level of H2O2, MDA and EL in CA-treated plants. Increasing Cu concentration in the nutrient medium significantly increased Cu concentration in in B. napus tissues. Cu uptake was further increased by CA application. These results suggested that CA might be a useful strategy for increasing phytoextraction of Cu from contaminated soils. PMID- 26099462 TI - Effects of exposure to 17-alpha-ethynylestradiol on sperm quality of tench (Tinca tinca). AB - Alterations of sperm quality were studied in tench (Tinca tinca) exposed to sub lethal doses of 17-alpha-ethynylestradiol-EE2-(50, 100 and 500MUg/kg t.w) under semi-static conditions for 30 days. Thus, different biomarkers of sperm quality were assessed: concentration and volume of ejaculate, total number of spermatozoa, percentage of motile spermatozoa, sperm motility and percentage of live and dead spermatozoa. Sperm motility was examined by computer-assisted image analysis and the viability of spermatozoa was assessed through flow cytometry. The most relevant alterations observed were significant reductions in the reproductive parameters such as testicular somatic index, spermatozoa concentration, straight line velocity, curvilinear velocity, average path velocity and wobble in tench exposed to 50MUg/kg t.w of EE2. Our study about the effects of EE2 on the sperm quality in tench provides new evidences which strengthen the fact that this synthetic estrogen is included in the list of non monotonic dose response compounds in animal studies. PMID- 26099463 TI - Soil and plant response to used potassium silicate drilling fluid application. AB - Use of drilling waste generated from the oil and gas industry for land reclamation has potential to be a practical and economical means to improve soil fertility and to decrease landfills. A four month greenhouse experiment with common barley (Hordeum vulgare L.) on three different textured soils was conducted to determine soil and plant response to incorporated or sprayed potassium silicate drilling fluid (PSDF). Two PSDF types (used once, used twice) were applied at six rates (10, 20, 30, 40, 60, 120m(3)ha(-1)) as twelve PSDF amendments plus a control (non PSDF). Effects of PSDF amendment on plant properties were significant, and varied through physiological growth stages. Barley emergence and below ground biomass were greater with used once than used twice PSDF at the same application rate in clay loam soil. Used twice PSDF at highest rates significantly increased barley above ground biomass relative to the control in loam and sand soil. All PSDF treatments significantly increased available potassium relative to the control in all three soils. Soil electrical conductivity and sodium adsorption ratio increased with PSDF addition, but not to levels detrimental to barley. Soil quality rated fair to poor with PSDF amendments in clay loam, and reduced plant performance at the highest rate, suggesting a threshold beyond which conditions are compromised with PSDF utilization. PSDF application method did not significantly affect plant and soil responses. This initial greenhouse research demonstrates that PSDF has potential as a soil amendment for reclamation, with consideration of soil properties and plant species tolerances to determine PSDF types and rates to be used. PMID- 26099464 TI - Effects of chlorpyrifos on the growth and ultrastructure of green algae, Ankistrodesmus gracilis. AB - The effect of the organophosphorus insecticide chlorpyrifos on the growth, biovolume, and ultrastructure of the green microalga Ankistrodesmus gracilis was evaluated. Concentrations of 9.37, 18.75, 37.5, 75 and 150mgL(-1) of chlorpyrifos were assayed along with a control culture. At the end of the bioassay the ultrastructure of algal cells from control culture and from cultures exposed to 37.5 and 150mgL(-1) was observed under transmission (TEM) and scanning electron microscopy (SEM). After 24 and 48h, treatments with 75 and 150mgL(-1) inhibited the growth of A. gracilis; whereas after 72 and 96h, all the treatments except at 9.37mgL(-1) significantly affected the algae growth. The effective concentration 50 (EC50) after 96h was 22.44mgL(-1) of chlorpyrifos. After the exposure to the insecticide, an increase in the biovolume was observed, with a larger increase in cells exposed to 75 and 150mgL(-1). Radical changes were observed in the ultrastructure of cells exposed to chlorpyrifos. The insecticide affected the cell shape and the distribution of the crests in the wall. At 37.5mgL(-1) electodense bodies were observed along with an increase in the size and number of starch granules. At 150mgL(-1) such bodies occupied almost the whole cytoplasm together with lipids and remains of thylakoids. Autospores formation occurred normally at 37.5mgL(-1) while at 150mgL(-1) karyokinesis occurred, but cell separation-phase was inhibited. The present study demonstrates that the exposure of phytoplankton to the insecticide chlorpyrifos leads to effects observed at both cellular and population level. PMID- 26099465 TI - Cytotoxicity, oxidative stress, and apoptosis in HepG2 cells induced by ionic liquid 1-methyl-3-octylimidazolium bromide. AB - The present study aimed to determine the cytotoxicity of 1-methyl-3 octylimidazolium bromide ([C8mim]Br) on the human hepatocellular carcinoma (HepG2) cells in order to elucidate the biochemical and molecular mechanism of [C8mim]Br-cytotoxicity. For this purpose, cell viability, oxidative stress, apoptosis, caspase activity, and apoptosis-related gene expression in HepG2 cells following [C8mim]Br-exposure were evaluated. The results showed that viability of HepG2 cells was decreased by [C8mim]Br-exposure in a concentration-dependent pattern. Moreover, biochemical assays reveal that [C8mim]Br-exposure can induce apoptosis, cause overproduction of reactive oxygen species (ROS), inhibit superoxide dismutase and catalase, reduce glutathione content, and increase the cellular malondialdehyde level of HepG2 cells. The transcriptions of p53 and bax were markedly up-regulated while bcl-2 was significantly down-regulated in HepG2 cells after [C8mim]Br-exposure, suggesting that p53 and bcl-2 family may be involved in the cytotoxicity and apoptosis of HepG2 cells caused by [C8mim]Br. In addition, we also found that caspase-3, caspase-8, and caspase-9 were significantly activated in HepG2 cells following [C8mim]Br-exposure. Our results suggest that ROS may be a key early signal of [C8mim]Br-induced apoptosis and caspases play a key role in the initiation and execution of apoptosis of HepG2 cells. PMID- 26099466 TI - Leaf cDNA-AFLP analysis reveals novel mechanisms for boron-induced alleviation of aluminum-toxicity in Citrus grandis seedlings. AB - Little information is available on the molecular mechanisms of boron (B)-induced alleviation of aluminum (Al)-toxicity. 'Sour pummelo' (Citrus grandis) seedlings were irrigated for 18 weeks with nutrient solution containing different concentrations of B (2.5 or 20MUM H3BO3) and Al (0 or 1.2mM AlCl3.6H2O). B alleviated Al-induced inhibition in plant growth accompanied by lower leaf Al. We used cDNA-AFLP to isolate 127 differentially expressed genes from leaves subjected to B and Al interactions. These genes were related to signal transduction, transport, cell wall modification, carbohydrate and energy metabolism, nucleic acid metabolism, amino acid and protein metabolism, lipid metabolism and stress responses. The ameliorative mechanisms of B on Al-toxicity might be related to: (a) triggering multiple signal transduction pathways; (b) improving the expression levels of genes related to transport; (c) activating genes involved in energy production; and (d) increasing amino acid accumulation and protein degradation. Also, genes involved in nucleic acid metabolism, cell wall modification and stress responses might play a role in B-induced alleviation of Al-toxicity. To conclude, our findings reveal some novel mechanisms on B induced alleviation of Al-toxicity at the transcriptional level in C. grandis leaves. PMID- 26099467 TI - Investigation of Fragment Antibody Stability and Its Release Mechanism from Poly(Lactide-co-Glycolide)-Triacetin Depots for Sustained-Release Applications. AB - Achieving long-term drug release from polymer-based delivery systems continues to be a challenge particularly for the delivery of large hydrophilic molecules such as therapeutic antibodies and proteins. Here, we report on the utility of an in situ-forming and injectable polymer-solvent system for the long-term release of a model antibody fragment (Fab1). The delivery system was prepared by dispersing a spray-dried powder of Fab1 within poly(lactide-co-glycolide) (PLGA)-triacetin solution. The formulation viscosity was within the range 1.0 +/- 0.3 Pa s but it was injectable through a 27G needle. The release profile of Fab1, measured in phosphate-buffered saline (PBS), showed a lag phase followed by sustained-release phase for close to 80 days. Antibody degradation during its residence within the depot was comparable to its degradation upon long-term incubation in PBS. On the basis of temporal changes in surface morphology, stiffness, and depot mass, a mechanism to account for the drug release profile has been proposed. The unprecedented release profile and retention of greater than 80% of antigen binding capacity even after several weeks demonstrates that PLGA-triacetin solution could be a promising system for the long-term delivery of biologics. PMID- 26099470 TI - Twin Polymerization--a New Principle for Hybrid Material Synthesis. AB - Twin polymerization is a novel modular approach for the synthesis of hybrid materials. Using this strategy two distinct polymers of either inorganic or organic nature are produced from a single source monomer in a mechanistically coupled process. Twin polymerization is an elegant way for producing nanostructured organic-inorganic hybrid materials of composition and morphology on demand. The main objective of this Review is the explanation of the principle of various twin polymerization processes and their appropriate terminologies. Different types of twin polymerization are classified with respect to the underlying processes as described in individual examples, demonstrating its potential in material synthesis. Prospects of the synthetic methodology of twin polymerization are demonstrated for different molecular structures of twin monomers and the resulting hybrid materials. A comparison with other scenarios for the synthesis of two different polymers within one procedure is included. PMID- 26099468 TI - dbEMT: an epithelial-mesenchymal transition associated gene resource. AB - As a cellular process that changes epithelial cells to mesenchymal cells, Epithelial-mesenchymal transition (EMT) plays important roles in development and cancer metastasis. Recent studies on cancer metastasis have identified many new susceptibility genes that control this transition. However, there is no comprehensive resource for EMT by integrating various genetic studies and the relationship between EMT and the risk of complex diseases such as cancer are still unclear. To investigate the cellular complexity of EMT, we have constructed dbEMT (http://dbemt.bioinfo-minzhao.org/), the first literature-based gene resource for exploring EMT-related human genes. We manually curated 377 experimentally verified genes from literature. Functional analyses highlighted the prominent role of proteoglycans in tumor metastatic cascades. In addition, the disease enrichment analysis provides a clue for the potential transformation in affected tissues or cells in Alzheimer's disease and Type 2 Diabetes. Moreover, the global mutation pattern of EMT-related genes across multiple cancers may reveal common cancer metastasis mechanisms. Our further reconstruction of the EMT-related protein-protein interaction network uncovered a highly modular structure. These results illustrate the importance of dbEMT to our understanding of cell development and cancer metastasis, and also highlight the utility of dbEMT for elucidating the functions of EMT-related genes. PMID- 26099469 TI - The bacterial tubulin FtsZ requires its intrinsically disordered linker to direct robust cell wall construction. AB - The bacterial GTPase FtsZ forms a cytokinetic ring at midcell, recruits the division machinery and orchestrates membrane and peptidoglycan cell wall invagination. However, the mechanism for FtsZ regulation of peptidoglycan metabolism is unknown. The FtsZ GTPase domain is separated from its membrane anchoring C-terminal conserved (CTC) peptide by a disordered C-terminal linker (CTL). Here we investigate CTL function in Caulobacter crescentus. Strikingly, production of FtsZ lacking the CTL (DeltaCTL) is lethal: cells become filamentous, form envelope bulges and lyse, resembling treatment with beta-lactam antibiotics. This phenotype is produced by FtsZ polymers bearing the CTC and a CTL shorter than 14 residues. Peptidoglycan synthesis still occurs downstream of DeltaCTL; however, cells expressing DeltaCTL exhibit reduced peptidoglycan crosslinking and longer glycan strands than wild type. Importantly, midcell proteins are still recruited to sites of DeltaCTL assembly. We propose that FtsZ regulates peptidoglycan metabolism through a CTL-dependent mechanism that extends beyond simple protein recruitment. PMID- 26099471 TI - Metabolomics reveals impaired maturation of HDL particles in adolescents with hyperinsulinaemic androgen excess. AB - Hyperinsulinaemic androgen excess (HIAE) in prepubertal and pubertal girls usually precedes a broader pathological phenotype in adulthood that is associated with anovulatory infertility, metabolic syndrome and type 2 diabetes. The metabolic derangements that determine these long-term health risks remain to be clarified. Here we use NMR and MS-based metabolomics to show that serum levels of methionine sulfoxide in HIAE girls are an indicator of the degree of oxidation of methionine-148 residue in apolipoprotein-A1. Oxidation of apo-A1 in methionine 148, in turn, leads to an impaired maturation of high-density lipoproteins (HDL) that is reflected in a decline of large HDL particles. Notably, such metabolic alterations occur in the absence of impaired glucose tolerance, hyperglycemia and hypertriglyceridemia, and were partially restored after 18 months of treatment with a low-dose combination of pioglitazone, metformin and flutamide. PMID- 26099472 TI - Hepatic involvement in HELLP syndrome: an update with emphasis on imaging features. AB - HELLP syndrome, which consists of hemolysis, elevated liver enzymes, and low platelet count is an unusual complication of pregnancy that is observed in only 10% to 15% of women with preeclampsia. Hepatic involvement in HELLP syndrome may present with various imaging features depending on the specific condition that includes nonspecific abnormalities such as perihepatic free fluid, hepatic steatosis, liver enlargement, and periportal halo that may precede more severe conditions such as hepatic hematoma and hepatic rupture with hemoperitoneum. Maternal clinical symptoms may be nonspecific and easily mistaken for a variety of other conditions that should be recognized. Because hepatic hematoma occurring in association with preeclampsia and HELLP syndrome is a potentially life threatening complication, prompt depiction is critical and may help reduce morbidity and mortality. This review provides an update on demographics, risk factors, pathophysiology, and clinical features of hepatic complications due to HELLP syndrome along with a special emphasis on the imaging features of these uncommon conditions. PMID- 26099473 TI - Use of vessel patterns on contrast-enhanced ultrasonography using a perflubutane based contrast agent for the differential diagnosis of regenerative nodules from early hepatocellular carcinoma or high-grade dysplastic nodules in patients with chronic liver disease. AB - OBJECTIVE: We evaluated the use of tumor vessel patterns observed during arterial phase contrast-enhanced ultrasonography (US) to differentiate regenerative nodules (RN) from early hepatocellular carcinoma (HCC) or high-grade dysplastic nodules (HGDN) in patients with chronic liver disease. SUBJECTS AND METHODS: Pathologically confirmed lesions (83 early HCC, 6 HGDN, and 13 RN with mean maximal diameters of 15.4, 15.3, and 16.2 mm, respectively) were enrolled in this retrospective study. We performed contrast-enhanced US using a perflubutane-based contrast agent. We then classified the tumor vessels observed during the arterial phase of contrast-enhanced US into two patterns: peripheral vessels (centripetal pattern) and central vessels (centrifugal pattern). RESULTS: Eighty-one (97.6%) of the 83 early HCC exhibited various enhancement patterns (hypovascular, 44.6%; isovascular, 25.3%; and hypervascular, 27.7%) and a peripheral vessel pattern, while the remaining 2 lesions (2.4%) exhibited hypovascular enhancement and a central vessel pattern. All 6 HGDN lesions were hypovascular with a peripheral vessel pattern. Twelve (92.3%) of the 13 RN were hypovascular with a central vessel pattern, and the remaining one (7.7%) was hypervascular with a central vessel pattern. When lesions exhibiting a central vessel pattern during arterial phase contrast-enhanced US were diagnosed as RN, the sensitivity, specificity, and accuracy of these diagnoses were 100%, 97.8%, and 98.0%, respectively. CONCLUSION: The tumor vessel patterns observed during arterial-phase contrast enhanced US may be useful for differentiating RN from early HCC or HGDN in patients with chronic liver disease. PMID- 26099475 TI - Errors in imaging of traumatic injuries. AB - The advent of multi-detector computed tomography (MDCT) has drastically improved the outcomes of patients with multiple traumatic injuries. However, there are still diagnostic challenges to be considered. A missed or the delay of a diagnosis in trauma patients can sometimes be related to perception or other non visual cues, while other errors are due to poor technique or poor image quality. In order to avoid any serious complications, it is important for the practicing radiologist to be cognizant of some of the most common types of errors. The objective of this article is to review the various types of errors in the evaluation of patients with multiple trauma injuries or polytrauma with MDCT. PMID- 26099474 TI - Shortened breath-hold contrast-enhanced MRI of the liver using a new parallel imaging technique, CAIPIRINHA (controlled aliasing in parallel imaging results in higher acceleration): a comparison with conventional GRAPPA technique. AB - PURPOSE: We examined whether the shortened breath-hold 3-dimensional volumetric interpolated breath-hold examination (3D-VIBE) sequence for high acceleration factor (AF) using the controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) could substitute for the conventional sequence using generalized autocalibrating partially parallel acquisition (GRAPPA) in patients undergoing routine gadoxetic acid-enhanced liver MRI. MATERIALS AND METHODS: Thirty patients with clinically suspected focal liver lesions were scanned using 3D-VIBE sequences with GRAPPA with AF = 2 and AF = 4 and CAIPIRINHA with AF = 4 (acquisition times: 21, 14, and 12 s, respectively) during the hepatobiliary phase. Visual evaluations using a 3- or 5-point scale and signal-to-noise ratio (SNR) analysis were performed for the 3 sequences. RESULTS: For CAIPIRINHA with AF = 4, there was significantly less image noise in both visual evaluation and SNR analysis and fewer parallel imaging artifacts than for GRAPPA with AF = 4 (P < 0.0005); it was equal to GRAPPA with AF = 2 and had fewer motion artifacts than GRAPPA with AF = 2 and 4 (P < 0.0012). The liver edge sharpness and hepatic vessel clarity, lesion conspicuity, and overall image quality were rated significantly higher with CAIPIRINHA with AF = 4 than GRAPPA with AF = 2 and AF = 4 (P < 0.009). For GRAPPA with AF = 4, lesion conspicuity and overall image quality were rated significantly lower than for GRAPPA with AF = 2 (P < 0.012). CONCLUSION: The shortened breath-hold 3D-VIBE sequence using the new CAIPIRINHA technique with a high AF of 4 was superior to the conventional GRAPPA sequence. The shortened breath-hold sequence using GRAPPA with a high AF of 4 worsened the image quality and lesion conspicuity. PMID- 26099476 TI - Reduced-port robotic anterior resection for left-sided colon cancer using the Da Vinci single-site((r)) platform. AB - BACKGROUND: Single-Site((r)) port plus one conventional robotic port, a reduced port robotic surgery (RPRS) for left-sided colorectal cancer, can enable lymphovascular dissection using the Endowrist((r)) function; this allows safe rectal transection through an additional port and maintains the cosmetic advantage of single-incision laparoscopic surgery. METHODS: Between August 2014 and December 2014, the study group included 11 patients who underwent a RPRS for left-sided colon cancer. RESULTS: There was one (9.1%) case of descending colon cancer, six (54.5%) cases of sigmoid colon cancer, and four (36.4%) cases of rectosigmoid colon cancer. The mean total operation time and docking time were 289+/-77 and 17+/-7 min. The mean times to soft diet and possible length of stay were 5.6+/-0.8 and 7.4+/-0.7 days. The mean total number of lymph nodes harvested was 18.7+/-7.9. The mean proximal and distal resection margins were 7.8+/-4.7 and 4.7+/-2.4 cm. CONCLUSIONS: Reduced-port robotic surgery for left-sided colon cancer using the Single-Site((r)) system appears to be feasible and safe using the new robotic single-access platform. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26099477 TI - Lessons from meta-analysis in ecology and evolution: the need for trans disciplinary evidence synthesis methodologies. PMID- 26099478 TI - The potential for meta-analysis to support decision analysis in ecology. AB - Meta-analysis and decision analysis are underpinned by well-developed methods that are commonly applied to a variety of problems and disciplines. While these two fields have been closely linked in some disciplines such as medicine, comparatively little attention has been paid to the potential benefits of linking them in ecology, despite reasonable expectations that benefits would be derived from doing so. Meta-analysis combines information from multiple studies to provide more accurate parameter estimates and to reduce the uncertainty surrounding them. Decision analysis involves selecting among alternative choices using statistical information that helps to shed light on the uncertainties involved. By linking meta-analysis to decision analysis, improved decisions can be made, with quantification of the costs and benefits of alternate decisions supported by a greater density of information. Here, we briefly review concepts of both meta-analysis and decision analysis, illustrating the natural linkage between them and the benefits from explicitly linking one to the other. We discuss some examples in which this linkage has been exploited in the medical arena and how improvements in precision and reduction of structural uncertainty inherent in a meta-analysis can provide substantive improvements to decision analysis outcomes by reducing uncertainty in expected loss and maximising information from across studies. We then argue that these significant benefits could be translated to ecology, in particular to the problem of making optimal ecological decisions in the face of uncertainty. PMID- 26099479 TI - The potential for meta-analysis to support decision analysis in ecology. PMID- 26099480 TI - How to critically read ecological meta-analyses. AB - Meta-analysis offers ecologists a powerful tool for knowledge synthesis. Albeit a form of review, it also shares many similarities with primary empirical research. Consequently, critical reading of meta-analyses incorporates criteria from both sets of approaches particularly because ecology is a discipline that embraces heterogeneity and broad methodologies. The most important issues in critically assessing a meta-analysis initially include transparency, replicability, and clear statement of purpose by the authors. Specific to ecology, more so than other disciplines, tests of the same hypothesis are generally conducted at different study sites, have variable ecological contexts (i.e., seasonality), and use very different methods. Clear reporting and careful examination of heterogeneity in ecological meta-analyses is thus crucial. Ecologists often also test similar hypotheses with different species, and in these meta-analyses, the reader should expect exploration of phylogenetic dependencies. Finally, observational studies not only provide the substrate for potential current manipulative experiments in this discipline but also form an important body of literature historically for synthesis. Sensitivity analyses of observational versus manipulative experiments when aggregated in the same ecological meta analysis are also frequent and appropriate. This brief conceptual review is not intended as an instrument to rate meta-analyses for ecologists but does provide the appropriate framing for those purposes and directs the reader to ongoing developments in this direction in other disciplines. PMID- 26099481 TI - How to critically read ecological meta-analyses. PMID- 26099482 TI - Information retrieval for ecological syntheses. AB - Research syntheses are increasingly being conducted within the fields of ecology and environmental management. Information retrieval is crucial in any synthesis in identifying data for inclusion whilst potentially reducing biases in the dataset gathered, yet the nature of ecological information provides several challenges when compared with medicine that should be considered when planning and undertaking searches. We present ten recommendations for anyone considering undertaking information retrieval for ecological research syntheses that highlight the main differences with medicine and, if adopted, may help reduce biases in the dataset retrieved, increase search efficiency and improve reporting standards. They are as follows: (1) plan for information retrieval at an early stage, (2) identify and use sources of help, (3) clearly define the question to be addressed, (4) ensure that provisions for managing, recording and reporting the search are in place, (5) select an appropriate search type, (6) identify sources to be used, (7) identify limitations of the sources, (8) ensure that the search vocabulary is appropriate, (9) identify limits and filters that can help direct the search, and (10) test the strategy to ensure that it is realistic and manageable. These recommendations may be of value for other disciplines where search infrastructures are not yet sufficiently well developed. PMID- 26099483 TI - Quality assessment of qualitative evidence for systematic review and synthesis: Is it meaningful, and if so, how should it be performed? AB - The critical appraisal and quality assessment of primary research are key stages in systematic review and evidence synthesis. These processes are driven by the need to determine how far the primary research evidence, singly and collectively, should inform findings and, potentially, practice recommendations. Quality assessment of primary qualitative research remains a contested area. This article reviews recent developments in the field charting a perceptible shift from whether such quality assessment should be conducted to how it might be performed. It discusses the criteria that are used in the assessment of quality and how the findings of the process are used in synthesis. It argues that recent research indicates that sensitivity analysis offers one potentially useful means for advancing this controversial issue. PMID- 26099485 TI - Reporting and handling missing outcome data in mental health: a systematic review of Cochrane systematic reviews and meta-analyses. AB - OBJECTIVES: The purpose of the study was to provide empirical evidence about the reporting of methodology to address missing outcome data and the acknowledgement of their impact in Cochrane systematic reviews in the mental health field. METHODS: Systematic reviews published in the Cochrane Database of Systematic Reviews after January 1, 2009 by three Cochrane Review Groups relating to mental health were included. RESULTS: One hundred ninety systematic reviews were considered. Missing outcome data were present in at least one included study in 175 systematic reviews. Of these 175 systematic reviews, 147 (84%) accounted for missing outcome data by considering a relevant primary or secondary outcome (e.g., dropout). Missing outcome data implications were reported only in 61 (35%) systematic reviews and primarily in the discussion section by commenting on the amount of the missing outcome data. One hundred forty eligible meta-analyses with missing data were scrutinized. Seventy-nine (56%) of them had studies with total dropout rate between 10 and 30%. One hundred nine (78%) meta-analyses reported to have performed intention-to-treat analysis by including trials with imputed outcome data. Sensitivity analysis for incomplete outcome data was implemented in less than 20% of the meta-analyses. CONCLUSIONS: Reporting of the techniques for handling missing outcome data and their implications in the findings of the systematic reviews are suboptimal. PMID- 26099484 TI - Multivariate meta-analysis using individual participant data. AB - When combining results across related studies, a multivariate meta-analysis allows the joint synthesis of correlated effect estimates from multiple outcomes. Joint synthesis can improve efficiency over separate univariate syntheses, may reduce selective outcome reporting biases, and enables joint inferences across the outcomes. A common issue is that within-study correlations needed to fit the multivariate model are unknown from published reports. However, provision of individual participant data (IPD) allows them to be calculated directly. Here, we illustrate how to use IPD to estimate within-study correlations, using a joint linear regression for multiple continuous outcomes and bootstrapping methods for binary, survival and mixed outcomes. In a meta-analysis of 10 hypertension trials, we then show how these methods enable multivariate meta-analysis to address novel clinical questions about continuous, survival and binary outcomes; treatment-covariate interactions; adjusted risk/prognostic factor effects; longitudinal data; prognostic and multiparameter models; and multiple treatment comparisons. Both frequentist and Bayesian approaches are applied, with example software code provided to derive within-study correlations and to fit the models. PMID- 26099486 TI - Searches for randomized controlled trials of drugs in MEDLINE and EMBASE using only generic drug names compared with searches applied in current practice in systematic reviews. AB - BACKGROUND: It is unclear which terms should be included in bibliographic searches for randomized controlled trials (RCTs) of drugs, and identifying relevant drug terms can be extremely laborious. The aim of our analysis was to determine whether a bibliographic search using only the generic drug name produces sufficient results for the generation of informative systematic reviews (SRs). METHODS: We conducted a retrospective analysis of relevant references included in SRs of drugs. We determined the proportion of references identified by a simplified technique consisting of a systematic search for RCTs in MEDLINE and EMBASE via the search interface Ovid and using only the truncated generic drug name in all search fields. We calculated aggregated sensitivity and also evaluated the unidentified references. RESULTS: Forty-eight SRs contained 873 primary publications, of which we found 829 in MEDLINE and 757 in EMBASE ("gold standard"). The simplified search identified 823 of the 829 MEDLINE references (sensitivity 99.3%) and 754 of the 757 EMBASE references (99.6%). Ultimately, only three references could not be found by additional searches. CONCLUSION: Our findings indicate that when searching for RCTs of drugs in MEDLINE and EMBASE, a search using the truncated generic drug name in all fields produces sufficient results. PMID- 26099488 TI - Understanding sarcopenia as a predictor of response to autologous hematopoietic stem cell transplant. PMID- 26099489 TI - Reply. PMID- 26099487 TI - Broadening public participation in systematic reviews: a case example involving young people in two configurative reviews. AB - BACKGROUND: Arguments supporting the involvement of users in research have even more weight when involving the public in systematic reviews of research. We aimed to explore the potential for public involvement in systematic reviews of observational and qualitative studies. METHODS: Two consultative workshops were carried out with a group of young people (YP) aged 12-17 years to examine two ongoing reviews about obesity: one about children's views and one on the link between obesity and educational attainment. YP were invited to comment on the credibility of themes, to propose elements of interventions, to suggest links between educational attainment and obesity and to comment on their plausibility. RESULTS: Researchers had more confidence in review findings, after checking that themes identified as important by YP were emphasised appropriately. Researchers were able to use factors linking obesity and attainment identified as important by YP to identify limitations in the scope of extant research. CONCLUSION: Consultative workshops helped researchers draw on the perspectives of YP when interpreting and reflecting upon two systematic reviews. Involving users in judging synthesis credibility and identifying concepts was easier than involving them in interpreting findings. Involvement activities for reviews should be designed with review stage, purpose and group in mind. PMID- 26099490 TI - Burden of major diarrheagenic protozoan parasitic co-infection among amoebic dysentery cases from North East India: a case report. AB - Intestinal diarrheagenic polyparasitic infections are among the major public health concerns in developing countries. Here we examined stool specimens by microscopy, DNA dot blot and polymerase chain reaction (PCR) to evaluate the co infection of four principal protozoans among amoebic dysentery cases from Northeast Indian population. The multiplex PCR confirmed Entamoeba histolytica (8.1%), Entamoeba dispar (4.8%) and mixed infection of both the parasites (3.4%) in 68 of 356 stool specimens that were positive in microscopy and/or HMe probe based DNA dot blot screening. The prevailing parasite that co-exists with E. histolytica was Giardia duodenalis (34.1%), followed by Enterocytozoon bieneusi (22.0%), Cryptosporidium parvum (14.6%) and Cyclospora cayetanensis (7.3%, P = 0.017). Symptomatic participants (odds ratio (OR) = 4.07; 95% confidence interval (CI) = 1.06, 15.68; P = 0.041), monsoon season (OR = 7.47; 95% CI = 1.40, 39.84; P = 0.046) and participants with family history of parasitic infection (OR = 4.50; 95% CI = 1.16, 17.51; P = 0.030) have significant association with overall co-infection rate. According to molecular consensus, comprehensive microscopy yielded 3.4% (12/356) false-negative and 7.6% (27/356) false-positive outcome, suggesting an improved broad-spectrum PCR-based diagnostic is required to scale down the poor sensitivity and specificity as well as implementation of integrated control strategy. PMID- 26099492 TI - Oxymatrine suppresses proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating microRNA-29b and downregulating matrix metalloproteinase-2 expression. AB - Oxymatrine, an alkaloid extracted from medicinal plants of the genus Sophora, has a wide range of pharmacological effects. Previous studies have revealed that oxymatrine can inhibit proliferation and metastasis of tumor cells through reducing matrix metalloproteinase-2 (MMP-2) mRNA expression. However, the expression of MMP-2 in ovarian cancer is significantly higher than that in normal ovaries. Furthermore, the expression of microRNA-29b (miR-29b) in ovarian carcinoma is significantly lower than that in normal ovaries. Therefore, MMP-2 and miR-29b are tumor suppressor factors involved in ovarian cancer. To evaluate the anti-cancer effects of oxymatrine the OVCAR-3 ovary cancer cell line was treated with oxymatrine at the concentrations of 0, 0.5, 1 and 2 mg/ml. Assessment of the proliferation and apoptosis of OVCAR-3 cells showed that oxymatrine had an inhibitory effect on ovarian cancer cells. Furthermore, oxymatrine decreased the protein levels of MMP-2 and increased the expression levels of miR-29b in OVCAR-3 cells. Through transfection of miR-29b precursor into OVCAR-3 cells, it was demonstrated that miR-29b regulated MMP-2 expression in OVCAR-3 cells. In addition, anti-miR-29b antibodies were used to verify that the apoptotic effect of oxymatrine was due to upregulating miR-29b and downregulating MMP-2 expression. These results showed that oxymatrine suppresses the proliferation and facilitates apoptosis of human ovarian cancer cells through upregulating miR-29b and downregulating MMP-2 expression. PMID- 26099491 TI - Network-based gene prediction for Plasmodium falciparum malaria towards genetics based drug discovery. AB - BACKGROUND: Malaria is the most deadly parasitic infectious disease. Existing drug treatments have limited efficacy in malaria elimination, and the complex pathogenesis of the disease is not fully understood. Detecting novel malaria associated genes not only contributes in revealing the disease pathogenesis, but also facilitates discovering new targets for anti-malaria drugs. METHODS: In this study, we developed a network-based approach to predict malaria-associated genes. We constructed a cross-species network to integrate human-human, parasite parasite and human-parasite protein interactions. Then we extended the random walk algorithm on this network, and used known malaria genes as the seeds to find novel candidate genes for malaria. RESULTS: We validated our algorithms using 77 known malaria genes: 14 human genes and 63 parasite genes were ranked averagely within top 2% and top 4%, respectively among human and parasite genomes. We also evaluated our method for predicting novel malaria genes using a set of 27 genes with literature supporting evidence. Our approach ranked 12 genes within top 1% and 24 genes within top 5%. In addition, we demonstrated that top-ranked candied genes were enriched for drug targets, and identified commonalities underlying top ranked malaria genes through pathway analysis. In summary, the candidate malaria associated genes predicted by our data-driven approach have the potential to guide genetics-based anti-malaria drug discovery. PMID- 26099493 TI - The nanoscale structure and unoccupied valence electronic states in FeSe1-xTex chalcogenides probed by X-ray absorption measurements. AB - We have studied the nanoscale structure and unoccupied electronic states in FeSe1 xTex by a combined analysis of Se K, Te L1 and Fe K-edges X-ray absorption measurements. Extended X-ray absorption fine structure (EXAFS) results show that iron-chalcogen (Fe-Se and Fe-Te) distances in ternary FeSe1-xTex are similar to those measured for binary FeSe and FeTe. The local Fe-Se/Te distances determined by different absorption edges fit well in the characteristic Z-plot of random alloys, providing unambiguous support to the inhomogeneous nanoscale structure of the ternary FeSe1-xTex system. X-ray absorption near-edge structure (XANES) spectra reveal a gradual evolution of the unoccupied valence electronic states as a function of Te-substitution in FeSe1-xTex. The Fe 3d-Se 4p/Te 5p hybridization is found to decrease with Te-substitution, accompanied by an increase in unoccupied Se 4p states and a decrease in unoccupied Te 5p states. The results are discussed in the frame of local inhomogeneity in the FeSe1-xTex system driven by random alloying of Se/Te atoms. PMID- 26099494 TI - Laser interferometric investigation of solute transport through membrane concentration boundary layer system. AB - We investigate diffusive transport in a membrane system with a horizontally mounted membrane under concentration polarization conditions performed by a laser interferometry method. The data obtained from two different theoretical models are compared to the experimental results of the substance flux. In the first model, the membrane is considered as infinitely thin, while in the second one as a wall of finite thickness. The theoretical calculations show sufficient correspondence with the experimental results. On the basis of interferometric measurements, the relative permeability coefficient (zeta(s)) for the system, consisting of the membrane and concentration boundary layers, was also obtained. This coefficient reflects the concentration polarization of the membrane system. The obtained results indicate that the coefficient zeta(s) of the membrane concentration boundary layer system decreases in time and seems to be independent of the initial concentration of the solute. PMID- 26099495 TI - Doping of inorganic materials in microreactors - preparation of Zn doped Fe3O4 nanoparticles. AB - Microreactor systems are now used more and more for the continuous production of metal nanoparticles and metal oxide nanoparticles owing to the controllability of the particle size, an important property in many applications. Here, for the first time, we used microreactors to prepare metal oxide nanoparticles with controlled and varying metal stoichiometry. We prepared and characterised Zn substituted Fe3O4 nanoparticles with linear increase of Zn content (ZnxFe3-xO4 with 0 <= x <= 0.48), which causes linear increases in properties such as the saturation magnetization, relative to pure Fe3O4. The methodology is simple and low cost and has great potential to be adapted to the targeted doping of a vast array of other inorganic materials, allowing greater control on the chemical stoichiometry for nanoparticles prepared in microreactors. PMID- 26099496 TI - [The situation of emergency psychiatry in Germany]. AB - The impact of psychiatric emergencies for the care of patients in preclinical emergency medicine, in emergency departments and in psychiatric hospitals has been underestimated for a long time. There is still insufficient knowledge and a need for further research. There are, however, sufficient reasons to assume that annually approximately 500,000 patients with a psychiatric emergency receive treatment from a preclinical emergency physician and another 1.5 million in emergency departments in Germany. Further, approximately 500,000 patients are admitted to psychiatric hospitals as an emergency. The most frequent reasons are intoxication, agitation, aggressiveness and suicidal ideation, posing a threat of self-harm to the patient or to other persons and evoking other life-threatening conditions. Emergency psychiatry also plays a role in collective injuries, such as mass disasters, catastrophes and rampage situations. There is some evidence that the number of psychiatric emergencies is increasing. Reasons are, among others, changes in the services provided for inpatient and outpatient treatment, a reduction in stabilizing psychosocial factors and a general increase in the utilization of emergency healthcare services. PMID- 26099497 TI - [Diagnosis and differential diagnostics of acute and emergency psychiatric situations]. AB - Psychiatric emergency situations are common, not only in psychiatric clinics but also in other medical disciplines or the general emergency room. It is crucial for every medical doctor to be able to recognize acute psychiatric symptoms and appreciate them as parts of different medical conditions. This article presents six important acute psychiatric symptoms with reference to the underlying differential diagnosis. PMID- 26099498 TI - [Multiple sclerosis and microbiota. From genome to metagenome?]. AB - The individual risk of contracting multiple sclerosis (MS) is determined by genetic predisposition as well as environmental factors. In monozygotic twins the concordance rate for MS is approximately 30 % indicating that environmental factors are even more important than genetic factors. Observations in a T-cell receptor-transgenic, spontaneous mouse model strongly point to an important contribution of the individual gut microbiome (microbiota). Mice maintained in a germ-free environment are completely protected from experimental autoimmune encephalomyelitis (EAE) in this model, whereas mice that are kept under normal conditions spontaneously develop a relapsing-remitting central nervous system (CNS) disease which is astoundingly similar to human MS. It appears that the autoimmune reaction against CNS tissue is "remotely controlled" by the gut microbiota. This may be explained by the facts that the microbiota influences the gut-associated lymphoid tissue (GALT) and, vice versa, the GALT regulates systemic immunity. The precise role of the microbiota in MS remains to be clarified. New methods of DNA sequencing and bioinformatics allow the analysis of very complex bacterial metagenomes. If individual microbial risk profiles can be identified this would provide completely new perspectives for the prophylaxis and therapy of MS. PMID- 26099500 TI - [Calculating personnel allocation at 100 % implementation of the Psychiatry Personnel Act. Can it be done on the basis of existing routine data?]. AB - From 1 January 2019, after completion of the convergence phase, the Psychiatry Personnel Act (Psych-PV) will no longer be the basis of budget negotiations of psychiatric hospitals and departments with the health insurance funds in Germany. Instead, the new compounding remuneration system for psychiatric and psychosomatic inpatient institutions (PEPP) will provide a new framework. The Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) has been given the task of elaborating a directive on the basis of the expiring Psych-PV in order to redefine standards for personnel allocation within this new framework. This task presupposes the existence of reliable data in the psychiatric hospitals and departments for categorizing patients following the Psych-PV. It presupposes further that these data allow an exact calculation of the personnel to which the clinics are entitled. This article shows that the so-called S-21 dataset from the database of the VIPP project (indicators of patient care in psychiatric and psychosomatic facilities) allows this calculation. The VIPP dataset was used as a basis to calculate the personnel requirements. Exemplary analyses illustrate that the information available regarding the Psych-PV can be transformed in minutes per day, minutes per month and full time positions. Therefore, this information would also be available to the Institute for the Hospital Remuneration System (InEK). PMID- 26099499 TI - [Experiences of stigma and discrimination in patients with first-episode schizophrenia]. AB - BACKGROUND: Patients with mental illnesses, especially with schizophrenia, suffer from stigma and discrimination. In addition, the stigma is a barrier to recognising and treating patients with first-episode psychosis; however, a self rating instrument that assesses the general burden due to stigma experiences is still lacking. MATERIAL AND METHODS: A total of N = 48 patients with first episode schizophrenia who were participants in the multicenter first-episode (long-term) study within the German Research Network on Schizophrenia, completed a newly developed self-rating questionnaire to assess the burden due to stigma experiences (B-STE). The following variables were analyzed as possible correlates: psychopathology (CGI, PANSS, CDSS and HAM-D), global functioning (GAF), social adjustment (SAS), self-esteem (FSKN), as well as quality of life (LQLP), subjective well-being under neuroleptic treatment (SWN) and anticipated stigma (PDDQ). RESULTS: Of the participants 25 % showed an increased burden due to stigma experiences, which correlated with a lower quality of life, lower subjective well-being under neuroleptic treatment, lower self-esteem and higher anticipated stigma. The results indicate that patients rated higher on the CGI scale who are at the same time better socially adjusted (SAS), are more intensely affected by the burden due to stigma experiences. CONCLUSION: The short self rating instrument burden due to stigma experiences (B-STE) can help to identify patients who might benefit from therapeutic or educational interventions to support coping with stigma experiences. PMID- 26099501 TI - Acute kidney injury after open ventral hernia repair: an analysis of the 2005 2012 ACS-NSQIP datasets. AB - PURPOSE: Acute kidney injury (AKI) is a serious postoperative complication, negatively impacting mortality rates, extending length of stay, and raising hospital costs. The purpose of this study was to examine AKI following open ventral hernia repair (OVHR) using a large, heterogeneous database to determine the incidence and identify risk factors for this complication. METHODS: Using the 2005-2012 ACS-NSQIP database, patients undergoing open ventral hernia repair were identified by CPT codes. Patients with acute kidney injury within 30 days of surgery were compared to controls by multivariate logistic regression across preoperative and intraoperative characteristics. RESULTS: Of 48,629 open ventral hernia repair patients identified in the dataset, AKI developed in 1.4% (681 patients). Multivariate logistic regression determined a number of factors associated with AKI. These include WHO Class III obesity (OR = 2.57, p < 0.001), history of cardiovascular disease (OR = 1.81, p < 0.001), diabetes (OR = 1.29, p = 0.028), hypoalbuminemia (OR = 1.42, p = 0.004), and chronic kidney disease (for a baseline GFR of 60-89 mL/min/1.73 m2, OR = 1.62, p = 0.001; for 30-59 mL/min/1.73 m2, OR = 2.25, p < 0.001; for 15-29 mL/min/1.73 m2, OR = 4.96, p < 0.001). Intraoperative factors include prolonged operative time (for >=1 SD above the mean, OR = 1.68, p = 0.002; for >=2SD above the mean, OR = 2.76, p < 0.001) and intraoperative transfusion (OR = 2.44, p < 0.001). CONCLUSIONS: Patients with a history of obesity, chronic kidney disease, cardiovascular history, diabetes, and hypoalbuminemia are at increased risk for AKI when undergoing OVHR. Intraoperative variables such as prolonged operative times and blood transfusions may also suggest increased risk. Preoperative identification of patients with these characteristics and perioperative hemodynamic stabilization are important first steps to minimize this complication. PMID- 26099502 TI - Synthesis, characterization and theoretical calculations of (1,2 diaminocyclohexane)(1,3-diaminopropane)gold(III) chloride complexes: in vitro cytotoxic evaluations against human cancer cell lines. AB - The gold(III) complexes of the type (1,2-diaminocyclohexane)(1,3 diaminopropane)gold(III) chloride, [(DACH)Au(pn)]Cl3, [where DACH = cis-, trans 1,2- and S,S-1,2-diaminocyclohexane and pn = 1,3-diaminopropane] have been synthesized and characterized using various spectroscopic and analytical techniques including elemental analysis, UV-Vis and FTIR spectroscopy; solution as well as solid-state NMR measurements. The solid-state (13)C NMR shows that 1,2 diaminocyclohexane (1,2-DACH) and 1,3-diaminopropane (pn) are strongly bound to the gold(III) center via N donor atoms. The stability of the mixed diamine ligand gold(III) was checked by UV-Vis spectroscopy and NMR measurements. The molecular structure of compound 1 (containing cis-1,2-DACH) was determined by X-ray diffraction analysis. The structure of 1 consists of [(cis-DACH)Au(pn)](3+) complex ion and chloride counter ions. Each gold atom in the complex ion adopts a distorted square-planar geometry. The structural details and relative stabilities of the four possible isomers of the complexes were also estimated at the B3LYP/LANL2DZ level of theoretical calculations. The computational study demonstrates that trans- conformations are slightly more stable than the cis- conformations. The antiproliferative effects and cytotoxic properties of the mixed ligand gold(III) complexes were evaluated in vitro on human gastric SGC7901 and prostate PC3 cancer cells using MTT assay. The antiproliferative study of the gold(III) complexes on PC3 and SGC7901 cells indicate that complex 3 (containing 1S,2S-(+)-1,2-(DACH)) is the most effective antiproliferative agent. The IC50 data reveal that the in vitro cytotoxicity of complex 3 against SGC7901 cancer cells manifested similar and very pronounced cytotoxic effects with respect to cisplatin. Moreover, the electrochemical behavior, and the interaction of complex 3 with two well-known model proteins, namely, hen egg white lysozyme and bovine serum albumin is also reported. PMID- 26099503 TI - Overexpression of protein tyrosine phosphatase 1B impairs glucose-stimulated insulin secretion in INS-1 cells. AB - BACKGROUND: Protein tyrosine phosphatase 1B (PTP1B) has been implicated as a negative regulator of insulin signaling. We reported previously that impaired glucose-stimulated insulin secretion (GSIS) in rats fed high-fat diet was associated with higher PTP1B protein levels in islets. The aim of the present study was to investigate the effect of increasing PTP1B on insulin secretion in beta-cells. METHODS: INS-1 cells were transduced with recombinant adenoviruses containing human PTP1B cDNA (Ad-PTP1B), or no exogenous gene (Ad-ctrl). The expression levels of PTP1B, insulin receptor (IR), insulin receptor substrate 1(IRS-1), glucokinase and glucose transporter-2 were evaluated by Western blot. Then insulin-stimulated IR and IRS tyrosine phosphorylation, and Akt pathway activation were measured. GSIS was also performed to evaluate INS-1 cells function. RESULTS: PTP1B expression level was increased 5.9-fold at 48h post transduction. The overexpression of PTP1B had no effect on proliferation and apoptosis of INS-1 cells. Compared with control cells, INS-1 cells overexpressing PTP1B showed decrease in insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate-1(IRS-1) by 56.4% and 53.1%, respectively. In addition, Akt phosphorylation was reduced 59.6%. Moreover, in Ad PTP1B-transduced cells, 16.7mM glucose caused a 1.6+/-0.2 fold increase (vs. 3.9+/-0.7 fold in nontransduced cells) in insulin secretion relative to secretion at 2.8mM glucose. Further analysis determined that overexpression of PTP1B induced down-regulated expression of glucokinase (42%) and glucose transporter-2 (48%). CONCLUSIONS: Our findings suggested that overexpression of PTP1B can inhibit GSIS in INS-1 cells through negatively regulating insulin signaling. PMID- 26099504 TI - Graphical message transmission using the monotonic vibration function of a smart phone. AB - This study aimed at evaluating four vibrotactile capabilities for perceiving graphical information presented on a smart phone. Thirty-two blindfolded college students participated in four experiments to test their capabilities of two-point discrimination, relative and absolute judgments of line thickness, and recognition of basic shapes. All the information was received through the default vibration function of the phone, sensed by their scanning fingers. The results showed a good two-point discrimination accuracy rate, reaching 98.8% when the distance between two points was set at 3.2 mm; the relative judgment of line thickness reached the level of 78.3% accuracy when the two-line width difference ratio was set at 3%; the absolute judgment reached the level of 78.8% when the participants recognised line thickness from one of two. Overall, especially for the shapes judgment, the information transmitted by the various codes may be quite low. These findings should inspire advanced investigations and provide design guidelines. PRACTITIONER SUMMARY: This study tested four vibrotactile capabilities for perception of graphical information when solely using the monotonic vibration function of a smart phone. The results show low information transmission. These findings encourage advanced investigations of new coding systems so that relevant mobile applications could be developed to help the visually impaired. PMID- 26099505 TI - Redox status of high-mobility group box 1 performs a dual role in angiogenesis of colorectal carcinoma. AB - During inflammation, high-mobility group box 1 in reduced all-thiol form (at HMGB1) takes charge of chemoattractant activity, whereas only disulfide-HMGB1 (ds HMGB1) has cytokine activity. Also as pro-angiogenic inducer, the role of HMGB1 in different redox states has never been defined in tumour angiogenesis. To verify which redox states of HMGB1 induces angiogenesis in colorectal carcinoma. To measure the expression of VEGF-A and angiogenic properties of the endothelial cells (ECs), at-HMGB1 or ds-HMGB1 was added to cell medium, further with their special inhibitors (DPH1.1 mAb and 2G7 mAb) and antibodies of corresponding receptors (RAGE Ab and TLR4 Ab). Also, a co-culture system and conditioned medium from tumour cells were applied to mimic tumour microenvironment. HMGB1 triggered VEGF-A secretion mainly through its disulfide form interacting with TLR4, while co-operation of at-HMGB1 and RAGE mediated migratory capacity of ECs. Functional inhibition of HMGB1 and its receptors abrogated HMGB1-induced angiogenic properties of ECs co-cultured with tumour cells. HMGB1 orchestrates the key events of tumour angiogenesis, migration of ECs and their induction to secrete VEGF-A, by adopting distinct redox states. PMID- 26099506 TI - Quantification of Dynamic [18F]FDG Pet Studies in Acute Lung Injury. AB - PURPOSE: This work aims to investigate lung glucose metabolism using 2-deoxy-2 [(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET) imaging in acute lung injury (ALI) patients. PROCEDURES: Eleven ALI patients and five healthy controls underwent a dynamic [(18)F]FDG PET/X-ray computed tomography (CT) scan. The standardized uptake values (SUV) and three different methods for the quantification of glucose metabolism (i.e., ratio, Patlak, and spectral analysis iterative filter, SAIF) were applied both at the region and the voxel levels. RESULTS: SUV reported a lower correlation than the ratio with the net tracer uptake. Patlak and SAIF analyses did not show any significant spatial or quantitative (R(2) > 0.80) difference. The additional information provided by SAIF showed that in lung inflammation, elevated tracer uptake is coupled with abnormal tracer exchanges within and between lung tissue compartments. CONCLUSIONS: Full kinetic modeling provides a multi-parametric description of glucose metabolism in the lungs. This allows characterizing the spatial distribution of lung inflammation as well as returning the functional state of the tissues. PMID- 26099507 TI - High-resolution brain SPECT imaging by combination of parallel and tilted detector heads. AB - OBJECTIVE: To improve the spatial resolution of brain single-photon emission computed tomography (SPECT), we propose a new brain SPECT system in which the detector heads are tilted towards the rotation axis so that they are closer to the brain. In addition, parallel detector heads are used to obtain the complete projection data set. We evaluated this parallel and tilted detector head system (PT-SPECT) in simulations. METHODS: In the simulation study, the tilt angle of the detector heads relative to the axis was 45 degrees . The distance from the collimator surface of the parallel detector heads to the axis was 130 mm. The distance from the collimator surface of the tilted detector heads to the origin on the axis was 110 mm. A CdTe semiconductor panel with a 1.4 mm detector pitch and a parallel-hole collimator were employed in both types of detector head. A line source phantom, cold-rod brain-shaped phantom, and cerebral blood flow phantom were evaluated. The projection data were generated by forward-projection of the phantom images using physics models, and Poisson noise at clinical levels was applied to the projection data. The ordered-subsets expectation maximization algorithm with physics models was used. We also evaluated conventional SPECT using four parallel detector heads for the sake of comparison. RESULTS: The evaluation of the line source phantom showed that the transaxial FWHM in the central slice for conventional SPECT ranged from 6.1 to 8.5 mm, while that for PT SPECT ranged from 5.3 to 6.9 mm. The cold-rod brain-shaped phantom image showed that conventional SPECT could visualize up to 8-mm-diameter rods. By contrast, PT SPECT could visualize up to 6-mm-diameter rods in upper slices of a cerebrum. The cerebral blood flow phantom image showed that the PT-SPECT system provided higher resolution at the thalamus and caudate nucleus as well as at the longitudinal fissure of the cerebrum compared with conventional SPECT. CONCLUSION: PT-SPECT provides improved image resolution at not only upper but also at central slices of the cerebrum. PMID- 26099508 TI - Dynamic Charge Carrier Trapping in Quantum Dot Field Effect Transistors. AB - Noncrystalline semiconductor materials often exhibit hysteresis in charge transport measurements whose mechanism is largely unknown. Here we study the dynamics of charge injection and transport in PbS quantum dot (QD) monolayers in a field effect transistor (FET). Using Kelvin probe force microscopy, we measured the temporal response of the QDs as the channel material in a FET following step function changes of gate bias. The measurements reveal an exponential decay of mobile carrier density with time constants of 3-5 s for holes and ~10 s for electrons. An Ohmic behavior, with uniform carrier density, was observed along the channel during the injection and transport processes. These slow, uniform carrier trapping processes are reversible, with time constants that depend critically on the gas environment. We propose that the underlying mechanism is some reversible electrochemical process involving dissociation and diffusion of water and/or oxygen related species. These trapping processes are dynamically activated by the injected charges, in contrast with static electronic traps whose presence is independent of the charge state. Understanding and controlling these processes is important for improving the performance of electronic, optoelectronic, and memory devices based on disordered semiconductors. PMID- 26099509 TI - Valorization of cruor slaughterhouse by-product by enzymatic hydrolysis for the production of antibacterial peptides: focus on alpha 1-32 family peptides mechanism and kinetics modeling. AB - Bovine hemoglobin is the major component of the cruor (slaughterhouse by-product) and can be considered as an important source of active peptides that could be obtained by pepsic hydrolysis. The kinetics of appearance and disappearance of several antibacterial peptides from alpha 1-32 family during hydrolysis of synthesized alpha 1-32 peptide, of purified bovine hemoglobin and of cruor was studied, and reaction scheme for the hydrolysis of alpha 1-32 family peptides from these three sources was determined. On this basis, a mathematical model was proposed to predict the concentration of each peptide of interest of this family depending on hydrolysis time, and also on temperature (in the range 15-37 degrees C), pH (in the range 3.5-5.5) and enzyme to substrate ratio (in the range 1/50-1/200 for the synthesized peptide and 1/5-1/20 for purified bovine hemoglobin and cruor). Apparent rate constants of reactions were determined by applying the model on a set of experimental data and it was shown that they depended on the temperature according to Arrhenius's law, that their dependence on the pH was linear, and that enzyme to substrate ratio influence was limited (in the studied range). PMID- 26099510 TI - Accelerated activation of the coagulation pathway during cardiopulmonary bypass in aortic replacement surgery: a prospective observational study. AB - BACKGROUND: Any form of surgery or tissue damage causes release of tissue factor into the circulation. This may lead to the accelerated consumption of coagulation factors, resulting in severe consumptive coagulopathy. In this study, we compared the molecular markers involved in coagulation activation during cardiopulmonary bypass (CPB) between patients who underwent aortic replacement surgery and those who underwent valve surgery. METHODS: This prospective observational study was performed in each 14 patients who underwent aortic replacement surgery or valve surgery. We evaluated the differences in the levels of fibrinogen, activated factor VII (FVIIa), thrombin-antithrombin complex (TAT), and soluble fibrin monomer complex (SFMC) during surgery between these two groups. RESULTS: The change in fibrinogen levels showed no difference between the groups. The magnitude of increase in TAT was much larger in patients who underwent aortic replacement surgery than in those who underwent valve surgery (173.6 vs. 49.4 ng/mL; p = 0.0001). More importantly, the elevation of FVIIa was significantly higher in patients who underwent aortic replacement (28.5 vs. 19.0 mU/mL; p = 0.0122). The magnitude of increase in SFMC was also larger in the aortic replacement surgery. CONCLUSIONS: The activation of coagulation during CPB was dramatically higher in the aortic replacement surgery compared with the valve surgery, probably owing to the activation of the extrinsic coagulation pathway in the former. This could potentially exacerbate consumptive coagulopathy after CPB termination in patients who underwent aortic replacement, possibly resulting in massive hemorrhage due to impaired hemostasis. PMID- 26099511 TI - Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. AB - BACKGROUND: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been intensively studied to lower low-density lipoprotein cholesterol (LDL-C) levels. The purpose of this meta-analysis was to evaluate the safety and efficacy of anti-PCSK9 antibodies in randomized, controlled trials (RCTs). METHODS: PubMed, EMBASE, CENTRAL databases, and recent conferences were searched. Safety outcomes were rates of common adverse events. Efficacy outcomes included percentages of LDL-C lowering and other lipid changes compared with placebo and ezetimibe, respectively. RESULTS: Twenty-five RCTs encompassing 12,200 patients were included. The rates of common adverse events were firstly reported in our study by pooling together all evidence in RCTs, showing largely no significant difference between anti-PCSK9 antibodies and placebo (or ezetimibe), except that alirocumab was associated with reduced rates of death (relative risk (RR): 0.43, 95 % confidence interval (CI): 0.19 to 0.96, P = 0.04) and an increased rate of injection-site reactions (RR: 1.48, 95 % CI: 1.05 to 2.09, P = 0.02); evolocumab reduced the rate of abnormal liver function (RR: 0.43, 95 % CI: 0.20 to 0.93, P = 0.03), both compared with placebo. No significant difference in safety outcomes was detected between monthly 420 mg and biweekly 140 mg evolocumab treatments. Monthly 420 mg evolocumab treatment significantly reduced LDL-C by -54.6 % (95 % CI: -58.7 to -50.5 %) and by absolute -78.9 mg/dl (95 % CI: -88.9 to -68.9 mg/dl) versus placebo, and by -36.3 % (95 % CI: -38.8 to -33.9 %) versus ezetimibe, and increased high-density lipoprotein cholesterol (HDL-C) by 7.6 % (95 % CI: 5.7 to 9.5 %) versus placebo and 6.4 % (95 % CI: 4.3 to 8.4 %) versus ezetimibe. An equal or even greater change was observed following biweekly 140 mg administration. Significant and favorable changes were also detected in other lipids following evolocumab treatment. Biweekly 50 to 150 mg alirocumab lowered LDL-C by -52.6 % (95 % CI: -58.2 to -47.0 %) versus placebo, by -29.9 % (95 % CI: -32.9 to -26.9 %) versus ezetimibe, and increased HDL-C by 8.0 % (95 % CI: 4.2 to 11.7 %) versus placebo. CONCLUSIONS: Evolocumab and alirocumab were safe and well tolerated from our most-powered analyses. Both antibodies substantially reduced the LDL-C level by over 50 %, increased the HDL-C level, and resulted in favorable changes in other lipids. PMID- 26099512 TI - Supervised oral protein supplementation during dialysis in patients with elevated C-reactive protein levels: a two phase, longitudinal, single center, open labeled study. AB - BACKGROUND: Inflammation is considered one of the major causes of protein-energy wasting in maintenance hemodialysis (MHD) patients. It is unclear whether dietary interventions can impact nutritional status and quality of life in MHD patients with elevated C-reactive protein (CRP) levels. Therefore, we examined the hypothesis that supervised intra-dialysis protein supplementation in MHD patients with elevated plasma CRP will improve protein stores and quality of life. METHODS: A 24 week, two phase, longitudinal, single center, open labeled study of 50 MHD patients with plasma CRP > 3 mg/L was conducted. During the 12-week observation phase dietary advice was provided to increase protein intake to 1.2 g/kg/day. In the 12-week treatment phase 45 g of liquid protein supplement was provided at each dialysis treatment. Protein nitrogen appearance (PNA), mid-arm muscle circumference (MAMC), serum albumin, body mass index (BMI) and quality of life (assessed by Short Form-12 questionnaire) were measured at baseline, 12 and 24 weeks. RESULTS: Median plasma CRP at baseline was 16.0 (IQR 7.7 to 25.1) mg/L. The mean MAMC was 26.5 +/- 3.9 cm, BMI 29.2 +/- 6.9 kg/m(2) and plasma albumin 3.8 +/- 0.3 g/dl. During the intervention period, mean PNA increased by 0.13 g/kg/d (p = 0.01) under a mixed effects model. However, there were no clinically or statistically significant effects on MAMC (p = 0.87), plasma albumin (p = 0.70), BMI (p = 0.09), physical (p = 0.32) or mental (p = 0.96) composite scores. CONCLUSIONS: In MHD patients with elevated plasma CRP but otherwise mostly normal nutritional parameters, intra-dialytic oral protein supplement was effective in increasing protein intake but did not provide a detectable impact on nutritional status or quality of life. PMID- 26099513 TI - Study of genetic variability in Vitis vinifera L. germplasm by high-throughput Vitis18kSNP array: the case of Georgian genetic resources. AB - BACKGROUND: Georgia, in the Caucasian region, is considered the first domestication centre of grapevine. This country is characterized by high morphological variability of cultivated (Vitis vinifera L. subsp. sativa (DC.) Hegi) and wild (Vitis vinifera L. subsp. sylvestris (Gmel.) Hegi) compartments. The main objective of this study was to investigate the level of genetic diversity obtained by the novel custom Vitis18kSNP array, in order to analyse 71 grapevine accessions representative of wild and cultivated Georgian germplasms. RESULTS: The number of loci successfully amplified was 15,317 out of 18,775 SNP and 79 % of loci resulted polymorphic. Sixty-eight unique profiles were identified, 42 for the sativa and 26 for the sylvestris compartment. Cluster analysis highlighted two main groups, one for cultivars and another for wild individuals, while a genetic structure according to accession taxonomic status and cultivar geographical origin was revealed by multivariate analysis, differentiating clearly the genotypes into 3 main groups, two groups including cultivars and one for wild individuals, even though a considerable overlapping area was observed. CONCLUSIONS: Pattern of genetic diversity structure presented an additional proof that grapevine domestication events took place in the Caucasian region contributing to the crop evolution. Our results demonstrated a moderate differentiation between sativa and sylvestris compartments, even though a connection between several samples of both subspecies may be assumed for the occurrence of cross hybridization events among native wild populations and the cultivated accessions. Nevertheless, first degree relationships have not been discovered between wild and cultivated individuals. PMID- 26099514 TI - Erratum to: The effect of postoperative wound infections on functional outcome following intra-articular calcaneal fractures. AB - Erratum to: Arch Orthop Trauma Surg DOI 10.1007/s00402-015-2219-5. The original version of this article unfortunately contained a mistake and has been corrected. The fourth author J. Carel Goslings' family name has been published incorrectly. The correct family name should be Goslings. PMID- 26099515 TI - Cost-effectiveness Analysis of Rivaroxaban in the Secondary Prevention of Acute Coronary Syndromes in Sweden. AB - BACKGROUND: Worldwide, coronary heart disease accounts for 7 million deaths each year. In Sweden, acute coronary syndrome (ACS) is a leading cause of hospitalization and is responsible for 1 in 4 deaths. OBJECTIVE: The aim of this analysis was to assess the cost-effectiveness of rivaroxaban 2.5 mg twice daily (BID) in combination with standard antiplatelet therapy (ST-APT) versus ST-APT alone, for the secondary prevention of ACS in adult patients with elevated cardiac biomarkers without a prior history of stroke/transient ischemic attack (TIA), from a Swedish societal perspective, based on clinical data from the global ATLAS ACS 2-TIMI 51 trial, literature-based quality of life data and costs sourced from Swedish national databases. METHODS: A Markov model was developed to capture rates of single and multiple myocardial infarction (MI), ischemic and hemorrhagic stroke, thrombolysis in myocardial infarction (TIMI) major, minor, and "requiring medical attention" bleeds, revascularization events, and associated costs and utilities in patients who were stabilized after an initial ACS event. Efficacy and safety data for the first 2 years came from the ATLAS ACS 2-TIMI 51 trial. Long-term probabilities were extrapolated using safety and effectiveness of acetylsalicylic acid data, which was estimated from published literature, assuming constant rates in time. Future cost and effects were discounted at 3.0%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, the use of rivaroxaban 2.5 mg BID was associated with improvements in survival and quality-adjusted life years (QALYs), yielding an incremental cost per QALY of 71,246 Swedish Krona (SEK) (?8045). The outcomes were robust to changes in inputs. The probabilistic sensitivity analysis demonstrated rivaroxaban 2.5 mg BID to be cost-effective in >99.9% of cases, assuming a willingness-to-pay threshold of SEK 500,000 (?56,458). CONCLUSION: Compared with ST-APT alone, the use of rivaroxaban 2.5 mg BID in combination with ST-APT can be considered a cost-effective treatment option for ACS patients with elevated cardiac biomarkers without a prior history of stroke/TIA in Sweden. FUNDING: Bayer Pharma AG. PMID- 26099516 TI - Consumer Quality Index Chronic Skin Disease (CQI-CSD): a new instrument to measure quality of care from the patient's perspective. AB - BACKGROUND: Assessing quality of care from the patient's perspective is considered to be highly relevant. As a standardized instrument in dermatology was lacking, we developed a patient experience questionnaire regarding chronic skin disease care: the Consumer Quality Index Chronic Skin Disease (CQI-CSD). OBJECTIVES: (i) To evaluate the dimensional structure of the CQI-CSD, (ii) to assess its ability to distinguish between hospitals according to patients' experiences with quality of care, (iii) to explore patients' experiences with dermatological care and priorities for quality improvement according to the patients, and (iv) to optimize the questionnaire based on psychometric results and stakeholders' input. METHODS: In a cross-sectional study 5647 adult patients who received dermatological care in the past 12 months in 20 hospitals were randomly selected and invited to fill out the questionnaire. RESULTS: Overall 1160 of 3989 eligible respondents (29% response rate, 30-87 per hospital) were included for analysis. The CQI-CSD comprised seven scales with high internal consistency (Cronbach's alpha = 0.74-0.92). The instrument's discriminative power was limited. Patients were positive about the care provided by nurses and doctors, but the provision of information by healthcare providers, accessibility of care and patient involvement could be improved. We optimized the CQI-CSD, resulting in a revised questionnaire containing 65 items. CONCLUSIONS: In conclusion, the CQI-CSD is a useful instrument to measure patient experiences with dermatological care. PMID- 26099517 TI - Pachygyria, seizures, hypotonia, and growth retardation in a patient with an atypical 1.33Mb inherited microduplication at 22q11.23. AB - 22q11.2 microduplication syndrome was recently described as a new disorder with variable clinical features that ranged from normal to mental retardation and with congenital defects. According to published reports, majority of patients with 22q11.2 duplications inherit these from unaffected parents rather than by de novo mutations, which is different from most microduplication/microdeletion syndromes. In this study, we report a patient that carried a paternally inherited atypical 1.33Mb duplication at 22q11.23. The proband (or proposita) presented with hypotonia, feeding difficulties, intractable epilepsy, hearing disability, and pachygyria. A pachygyria phenotype had not been previously reported to be associated with a 22q11 microduplication syndrome. Cytogenetic and molecular genetic analyses based on standard G-banding, SNP array, and fluorescence in situ hybridization were performed for the proband and her parents. An atypical 1.33Mb duplication at 22q11.23 was detected in both the proband and her father. Thus, our findings verify the pathogenicity and diverse phenotypes of 22q11.2 microduplication and expand its phenotypic spectrum. PMID- 26099518 TI - MOST+: A de novo motif finding approach combining genomic sequence and heterogeneous genome-wide signatures. AB - BACKGROUND: Motifs are regulatory elements that will activate or inhibit the expression of related genes when proteins (such as transcription factors, TFs) bind to them. Therefore, motif finding is important to understand the mechanisms of gene regulation. De novo discovery of regulatory elements, like transcription factor binding sites (TFBSs), has long been a major challenge to gain insight on mechanisms of gene regulation. Recent advances in experimental profiling of genome-wide signals such as histone modifications and DNase I hypersensitivity sites allow scientists to develop better computational methods to enhance motif discovery. However, existing methods for motif finding suffer from high false positive rates and slow speed, and it's difficult to evaluate the performance of these methods systematically. RESULT: Here we present MOST+, a motif finder integrating genomic sequences and genome-wide signals such as intensity and shape features from histone modification marks and DNase I hypersensitivity sites, to improve the prediction accuracy. MOST+ can detect motifs from a large input sequence of about 100 Mbs within a few minutes. Systematic comparison method has been established and MOST+ has been compared with existing methods. CONCLUSION: MOST+ is a fast and accurate de novo method for motif finding by integrating genomic sequence and experimental signals as clues. PMID- 26099519 TI - Systemic Lupus Erythematosus--A Disease with A Dysregulated Type I Interferon System. AB - Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation and inflammation in multiple organs. The disease is very heterogeneous, and most clinicians consider SLE as a group of diseases with similar features where the pathogenesis is driven by a combination of genetic and environmental factors. One of the most prominent features, shared by the majority of patients with SLE, is a continuous activation of the type I interferon (IFN) system, which manifests as increased serum levels of IFNalpha and/or an increased expression of type I IFN-induced genes, a so-called type I IFN signature. The mechanisms behind this IFN signature have partly been clarified during recent years, although the exact function of the IFN-regulated genes in the disease process is unclear. In this review, we will describe the type I IFN system and its regulation and summarize the numerous findings implicating an important ethiopathogenic role of a dysregulated type I IFN system in SLE. Furthermore, strategies to therapeutically target the type I IFN system that are currently evaluated preclinically and in clinical trials will be mentioned. PMID- 26099520 TI - Safety of daily ethanol locks for urinary catheters in critically ill children: a pilot study. AB - Catheter-associated urinary tract infections represent a significant medical burden in critically ill children. Ethanol locks have been shown to be effective and safe for central line-associated bloodstream infection prevention and we propose utilizing this strategy for urinary catheters. Because this has never been done, we evaluated its safety with a pilot study hypothesizing that ethanol locks in urinary catheters would result in negligible alcohol absorption and negligible irritation of the bladder. PMID- 26099522 TI - [Nursing role in reporting adverse drug reactions]. AB - BACKGROUND: The spontaneous report system, in which suspected adverse drug reaction (ADR) are reported by healthcare workers, is currently one of the primary methods to prevent and discover new and serious ADR to marketed medicinal products. The collaboration of nursing professionals with this task makes it possible to improve patient safety and to reduce ADR costs. Although a total of 781 cases of ADR cases were reported in Navarra in 2011, only 7.33% were reported by nurses. The objectives werw to determine the factors that influence nurses in reporting of ADR, and second, to devise strategies which help to increase reporting. MATERIAL AND METHODS: A bibliographic search for articles that included the words: reacciones adversas medicamentosas (adverse drug reactions), notificacion (reporting) and enfermeria (nursing) was conducted using the PubMed and Cinhal databases. A total of 107 articles were retrieved, of which 27 were selected according to inclusion and exclusion criteria. RESULTS: The conclusion learned by reading and analyzing the selected articles was that the factors that affect the notification depend on the attitude of the notifier, as well as personal and professional factors. The main strategies to encourage notification are education and training, motivation, and the availability of facilitating tools. CONCLUSIONS: The main factors that have an influence on under-notification are the lack of knowledge and motivation among professionals. To solve the problem of under-notification, the main actions and strategies to undertake are education, motivation and persistence. PMID- 26099521 TI - [Perspective of nursing students on the communication and apologies to patients for adverse events: a descriptive study]. AB - OBJECTIVES: To describe the approach to the communication and blame of an adverse by nursing students. METHOD: A descriptive study on disclosure and apologies for adverse events by nursing students in the academic years 2011-12 and 2012-13. The study included group discussion and drafting a written communication to the injured patient about adverse events during hospitalization. An ad hoc checklist was used and an analysis was performed on items related to the disclosure and apologies issues. RESULTS: A total of 126 nursing students were involved, and they created 21 written The facts about adverse events were reported in 81% of written communications, and 47.1% chose an abbreviated disclosure of the facts with no detailed explanation of adverse events. The facts were accurately reproduced in only 9.5% of written communications to the patients. One third (33.3%) apologized for the mistakes, and 47.6% required that the communication was signed by the Management. All (100%) of the nursing students chose not to report the health professionals who had participated during the events. CONCLUSIONS: There is a fear to acknowledge errors within health centers. It is recommended that tools are developed for these future nursing professionals to make an open and honest disclosure of adverse events, as well as the apologies for them. PMID- 26099523 TI - Humeral torsion does not dictate shoulder position, but does influence throwing speed. PMID- 26099524 TI - Pre- and post-training evaluation of dental efficacy and activation measures in carers of adults with disabilities in South Australia - a pilot study. AB - The aim of this pilot study was to train carers to provide oral care for adults with disabilities and to evaluate the training programme. Forty-one carers of 103 care recipients from three disability organisations in South Australia were trained in providing oral care for adults with disabilities (April 2013-April 2014). The training included an oral presentation and practical session by a special needs dentist on completing oral health assessments (OHA), developing oral healthcare plans, providing oral hygiene care and assessing the need for dental referral. Continued support was provided via home visits by dental hygienists for the first 2 months and a dentist visit at 3 months. At 6 months, agreement on OHAs between the dentist and trained carers was assessed. Pre- and post-training questionnaires (at 6 months) collected information on dental behaviours of carers and psychosocial factors: carer activation measure-knowledge (CAM-Knowledge), carer activation measure-skills (CAM-Skills), carer activation measure-confidence (CAM-Confidence) and carer dental efficacy (CDE) items (carer diligence, self-efficacy and priority). Post-training (among 16 retained carers), there were significant increases in the mean scores of CAM-Knowledge and CAM Confidence, but not for CAM-Skills (paired-samples t-tests, alpha = 0.05). Per cent agreement of CDE items varied little between questionnaires. Carer-dentist agreement on OHAs was generally high with kappa values ranging from 0.63 for the assessment of gums to 1.0 for the assessment of tongue, roof of mouth, denture and dental pain. Further, carers were able to assess the need for referral of their care recipients' oral health similar to the dentist. These findings suggest that with combined theoretical and practical training and continued support, non dental professionals like carers can improve their knowledge and confidence in providing oral care for adults with disabilities. However, the findings of this pilot study need to be confirmed by further research in a larger study. PMID- 26099525 TI - Loss of ATOH8 Increases Stem Cell Features of Hepatocellular Carcinoma Cells. AB - BACKGROUND & AIMS: Levels of atonal homolog 8 (ATOH8) are reduced in 48% of hepatitis B virus-associated hepatocellular carcinoma cells (HCCs). ATOH8 downregulation is associated with loss of tumor differentiation, indicating an effect mediated by cancer stem cells. We investigated the effects of loss of ATOH8 in human hepatocellular carcinoma (HCC) cells and cell lines. METHODS: HCC and adjacent nontumor tissues were collected, from 2001 through 2012, from 242 patients undergoing hepatectomy at Sun Yat-Sen University Cancer Center in China; 83% of HCCs were associated with hepatitis B virus (HBV) infection. CD133(+) cells were isolated from tumor tissues by flow cytometry. Experiments were performed in HBV-positive and HBV-negative HCC cell lines, the immortalized liver cell line LO2, and 8 other HCC cell lines. ATOH8 was expressed from lentiviral vectors in PLC8024 and Huh7 cells; levels were knocked down with small interfering RNAs in QSG7701 cells. Cells carrying empty vectors were used as controls. Gene regulation by ATOH8 was assessed in mobility shift and luciferase reporter assays. Cells were analyzed in proliferation, foci formation, and colony formation assays. The tumorigenic and chemo-resistant potential of cells were investigated by assessing growth of xenograft tumors in immunocompromised mice. Metastatic features of cells were assessed in Matrigel invasion assays and wound healing analyses. RESULTS: Levels of ATOH8 mRNA were reduced by more than 4-fold, compared to nontumor tissues, in 118 of 242 HCC samples (48.8%). Patients with tumor reductions in ATOH8 had significantly shorter times of disease-free survival (mean, 41.4 months) than patients with normal tissue levels (mean, 52.6 months). ATOH8 expression was reduced in HepG2, Huh7, PLC8024 and CRL8064 HCC cells, as well as CD133(+) cells isolated from human HCC samples. Transgenic expression of ATOH8 in HCC cell lines significantly reduced proliferation and foci colony formation, as well as their invasive and migratory abilities. Transgenic expression of ATOH8 reduced the ability of HBV-positive PLC8024 cells to form tumors in mice, compared to control cells. Cells with ATOH8 knockdown formed xenograft tumors more rapidly, in more mice, than control cells. ATOH8 repressed transcription of stem-cell associated genes including OCT4, NANOG, and CD133. Knockdown of ATOH8 in CD133-negative QSG7701 cells caused them to express CD133; acquire self-renewal, differentiation, chemo-resistance properties; form more xenograft tumors in mice; and generate induced pluripotent stem cells (based on staining for alkaline phosphatase and their ability to form embryoid bodies and teratomas). Alternatively, expression of ATOH8 in PLC8024 and Huh7 cells significantly reduced the numbers of cells expressing CD133, and increased the chemo-sensitivity of Huh7 cells to 5-fluorouracil (5-FU) and cisplatin, in vitro and in mice. CONCLUSIONS: ATOH8 appears to be a tumor suppressor that induces stem-cell features and chemoresistance in HCC cells. Strategies to restore its levels and activities might be developed to treat patients with liver cancer. PMID- 26099527 TI - Genetic Landscape and Biomarkers of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death. Its mortality has increased in Western populations, with a minority of patients diagnosed at early stages, when curative treatments are feasible. Only the multikinase inhibitor sorafenib is available for the management of advanced cases. During the last 10 years, there has been a clear delineation of the landscape of genetic alterations in HCC, including high-level DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), as well as homozygous deletions in chromosome 9 (CDKN2A). The most frequent mutations affect TERT promoter (60%), associated with an increased telomerase expression. TERT promoter can also be affected by copy number variations and hepatitis B DNA insertions, and it can be found mutated in preneoplastic lesions. TP53 and CTNNB1 are the next most prevalent mutations, affecting 25%-30% of HCC patients, that, in addition to low-frequency mutated genes (eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2), help define some of the core deregulated pathways in HCC. Conceptually, some of these changes behave as prototypic oncogenic addiction loops, being ideal biomarkers for specific therapeutic approaches. Data from genomic profiling enabled a proposal of HCC in 2 major molecular clusters (proliferation and nonproliferation), with differential enrichment in prognostic signatures, pathway activation and tumor phenotype. Translation of these discoveries into specific therapeutic decisions is an unmet medical need in this field. PMID- 26099526 TI - Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans. AB - BACKGROUND & AIMS: Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues to identify molecules associated with ASH progression and focused on the mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets. METHODS: C57BL/6N mice or mice with hepatocyte-specific disruption of Fsp27 (Fsp27(Hep-/-) mice) were fed the Lieber-Decarli ethanol liquid diet (5% ethanol) for 10 days to 12 weeks, followed by 1 or multiple binges of ethanol (5 or 6 g/kg) during the chronic feeding. Some mice were given an inhibitor (GW9662) of peroxisome proliferator-activated receptor gamma (PPARG). Adenoviral vectors were used to express transgenes or small hairpin (sh) RNAs in cultured hepatocytes and in mice. Liver tissue samples were collected from ethanol-fed mice or from 31 patients with alcoholic hepatitis (AH) with biopsy-proved ASH and analyzed histologically and immunohistochemically and by transcriptome, immunoblotting, and real-time PCR analyses. RESULTS: Chronic-plus-binge ethanol feeding of mice, which mimics the drinking pattern of patients with AH, produced severe ASH and mild fibrosis. Microarray analyses revealed similar alterations in expression of many hepatic genes in ethanol-fed mice and humans with ASH, including up regulation of mouse Fsp27 (also called Cidec) and human CIDEC. Fsp27(Hep-/-) mice and mice given injections of adenovirus-Fsp27shRNA had markedly reduced ASH following chronic-plus-binge ethanol feeding. Inhibition of PPARG and cyclic AMP responsive element binding protein H (CREBH) prevented the increases in Fsp27alpha and FSP27beta mRNAs, respectively, and reduced liver injury in this chronic-plus-binge ethanol feeding model. Overexpression of FSP27 and ethanol exposure had synergistic effects in inducing production of mitochondrial reactive oxygen species and damage to hepatocytes in mice. Hepatic CIDEC mRNA expression was increased in patients with AH and correlated with the degree of hepatic steatosis and disease severity including mortality. CONCLUSIONS: In mice, chronic plus-binge ethanol feeding induces ASH that mimics some histological and molecular features observed in patients with AH. Hepatic expression of FSP27/CIDEC is highly up-regulated in mice following chronic-plus-binge ethanol feeding and in patients with AH; this up-regulation contributes to alcohol induced liver damage. PMID- 26099529 TI - Fixed functional appliances show definite skeletal and dental changes in the short term. AB - A meta-analysis of the literature on fixed functional appliances found nine unique data sets (n= 418 patients, mean age = 13.2 years) that fulfilled the criteria. Small but statistically significant changes in SNA, SNB, and ANB occurred, with larger changes in the incisor angulations. The results are compared with a previous meta-analysis on the effects of removable functional appliances by the same team and discussed in regard to their implications for clinical practice. PMID- 26099528 TI - Innovative designs of point-of-care comparative effectiveness trials. AB - One of the provisions of the health care reform legislation in 2010 was for funding pragmatic clinical trials or large observational studies for comparing the effectiveness of different approved medical treatments, involving broadly representative patient populations. After reviewing pragmatic clinical trials and the issues and challenges that have made them just a small fraction of comparative effectiveness research (CER), we focus on a recent development that uses point-of-care (POC) clinical trials to address the issue of "knowledge action gap" in pragmatic CER trials. We give illustrative examples of POC-CER trials and describe a trial that we are currently planning to compare the effectiveness of newly approved oral anticoagulants. We also develop novel stage wise designs of information-rich POC-CER trials under competitive budget constraints, by using recent advances in adaptive designs and other statistical methodologies. PMID- 26099530 TI - Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Delta9-Tetrahydrocannabinol-Mediated Induction of DeltaFosB in the Mouse Forebrain. AB - Delta(9)-Tetrahydrocannabinol (THC), the main psychoactive component of marijuana, produces motor and motivational effects via interactions with the dopaminergic system in the caudate-putamen and nucleus accumbens. However, the molecular events that underlie these interactions after THC treatment are not well understood. Our study shows that pretreatment with dopamine D1 receptor (D1R) antagonists before repeated administration of THC attenuated induction of Delta FBJ murine osteosarcoma viral oncogene homolog B (DeltaFosB) in the nucleus accumbens, caudate-putamen, amygdala, and prefrontal cortex. Anatomical studies showed that repeated THC administration induced DeltaFosB in D1R-containing striatal neurons. Dopamine signaling in the striatum involves phosphorylation specific effects of the dopamine- and cAMP-regulated phosphoprotein Mr 32 kDa (DARPP-32), which regulates protein kinase A signaling. Genetic deletion of DARPP 32 attenuated DeltaFosB expression measured after acute, but not repeated, THC administration in both the caudate-putamen and nucleus accumbens. THC was then acutely or repeatedly administered to wild-type (WT) and DARPP-32 knockout (KO) mice, and in vivo responses were measured. DARPP-32 KO mice exhibited enhanced acute THC-mediated hypolocomotion and developed greater tolerance to this response relative to the WT mice. Agonist-stimulated guanosine 5'-O-(3 [(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding showed that cannabinoid stimulated G-protein activity did not differ between DARPP-32 KO and WT mice treated with vehicle or repeated THC. These results indicate that D1Rs play a major role in THC-mediated DeltaFosB induction in the forebrain, whereas the role of DARPP-32 in THC-mediated DeltaFosB induction and modulation of motor activity appears to be more complex. PMID- 26099531 TI - Antibacterial activity of diketopiperazines isolated from a marine fungus using t butoxycarbonyl group as a simple tool for purification. AB - Nine diketopiperazines were characterized from the culture of marine fungal isolate MR2012 which based on DNA amplification and sequencing of the fungal internal transcribed spacer (ITS) region was identified as Aspergillus fumigatus. The isolated fungal metabolites 4-12 were unambiguously identified as a series of simple and re-arranged diketopiperazines by analysis of spectroscopic data. t Butoxycarbonyl group (BOC) derivatization was used to separate the intractable mixture of 4 and 5. When all compounds were evaluated for antimicrobial activity against gram positive bacteria, the isolated metabolites showed moderate to weak effects, while the semisynthetic derivatives 4a and 5a displayed strong activity comparable to the positive control, tetracycline against gram positive bacteria. PMID- 26099532 TI - Design, synthesis and evaluation of novel anti-HCV molecules that deliver intracellularly three highly potent NS5A inhibitors. AB - The design and synthesis of new non-symmetrical NS5A inhibitors with sulfur containing amino acids is reported along with their ability to block HCV replication in an HCV 1b replicon system. These compounds display EC50 values in the picomolar range with a large therapeutic index (>10(6)). Moreover, cellular pharmacology studies show that our preferred compounds intracellularly deliver three potent NS5A inhibitors. PMID- 26099533 TI - Cytotoxic triterpene saponins from Cercodemas anceps. AB - Seven holostane-type triterpene saponins (1-7), including five new compounds namely cercodemasoides A-E (2-6), were isolated from the sea cucumber Cercodemas anceps. Their structures were elucidated on the basis of spectroscopic evidence including HR ESI MS, ESI MS/MS, 1D and 2D NMR. The cytotoxic effects of isolated compounds were evaluated by SRB method on five human cancer cell lines including Hep-G2 (hepatoma cancer), KB (epidermoid carcinoma), LNCaP (prostate cancer), MCF7 (breast cancer), and SK-Mel2 (melanoma). Compounds 1-7 showed potent cytotoxicity on five tested cancer cell lines with IC50 values ranging from 0.03 +/- 0.01 to 7.36 +/- 0.46 MUM. With respect to the potent cytotoxicity of the isolated saponins, further studies are required to confirm efficacy in vivo and the mechanism of cytotoxic effects. PMID- 26099534 TI - Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H) yl)methanones are P2X7 antagonists. AB - The optimization efforts that led to a novel series of methyl substituted 1-(5,6 dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers. PMID- 26099535 TI - Synthesis of a novel series of fluoroarene derivatives of artemisinin as potent antifungal and anticancer agent. AB - A series of new fluoroarene derivatives of artemisinin were prepared using Suzuki and Sonogashira cross-coupling reactions. An antifungal and antitumor activity was evaluated against opportunistic pathogen Fusarium oxysporum and Hela cancer cell line. All these derivatives have shown moderate to good activity. PMID- 26099537 TI - Identification and purification of target protein using affinity resin bearing a photo-labile linker. AB - This Letter presents an effective method for the identification of target proteins of bioactive compounds such as drugs, natural products, and intrinsic ligands, using an affinity resin. The application of a photo-labile linker to an affinity resin enabled the selective elution of a target protein by irradiation for a short duration at 4 degrees C while leaving a large amount of non-specific binding protein on the resin. We have named this method the 'STEAP' method (selective target elution from affinity resins with photo-labile linker). Only a target protein that can bind the bioactive compound, the so-called 'active' protein, is eluted by the selective cleavage of the linker between the solid matrix and the target compound, and therefore, it is worth considering the potential of this method for the hyper-purification of proteins. PMID- 26099536 TI - Investigation of 7-benzylidenenaltrexone derivatives as a novel structural antitrichomonal lead compound. AB - We evaluated antitrichomonal effects of delta opioid receptor (DOR) agonists and antagonists. Although all the agonists were inactive, the DOR antagonists BNTX (2a) and its derivatives 2b-d showed antitrichomonal activity with MIC of 20-40 MUM. In addition, the development of a more effective synthetic method for the BNTX derivatives was achieved by using the Knoevenagel condensation. PMID- 26099538 TI - Docking of competitive inhibitors to the P2X7 receptor family reveals key differences responsible for changes in response between rat and human. AB - The P2X7 receptor is a calcium permeable cationic channel activated by extracellular ATP, playing a role in chronic pain, osteoporosis and arthritis. A number of potential lead compounds are inactive against the rat isoform, despite good activity against the human homologue, making animal model studies problematic. Here we have produced P2X7 models and docked three structurally distinct inhibitors using in silico approaches and show they have a similar mode of binding in which Phe95 plays a key role by forming pi-stacking interactions. Importantly this residue is replaced by Leu in the rat P2X7 receptor resulting in a significantly reduced binding affinity. This work provides new insights into binding of P2X7 inhibitors and shows the structural difference in human and rat P2X7 receptors which results in a difference in affinity. Such information is useful both for the rational design of inhibitors based on these scaffolds and also the way in which these compounds are tested in animal models. PMID- 26099539 TI - Molecular modeling based approach, synthesis, and cytotoxic activity of novel benzoin derivatives targeting phosphoinostide 3-kinase (PI3Kalpha). AB - The oncogenic potential of phosphatidylinositol 3-kinase (PI3Kalpha) has made it an attractive target for anticancer drug design. In this work, we describe our efforts to optimize the lead PI3Kalpha inhibitor 2-hydroxy-1,2-diphenylethanone (benzoin). A series of 2-oxo-1,2-diphenylethyl benzoate analogs were identified as potential PI3Kalpha inhibitors. Docking studies confirmed that the aromatic interaction is mediating ligand/protein complex formation and identified Lys802 and Val851 as H-bonding key residues. Our biological data in human colon carcinoma HCT116 showed that the structure analogs inhibited cell proliferation and induced apoptosis. PMID- 26099540 TI - Novel dammarane-type triterpenes isolated from hydrolyzate of total Gynostemma pentaphyllum saponins. AB - In this study, five novel triterpenes were isolated from hydrolyzate of total saponins from Gynostemma pentaphyllum and identified as gypensapogenin H (1), gypensapogenin I (2), gypensapogenin L (3), gypensapogenin J (4) and gypensapogenin K (5), three of which (1-3) possess unprecedented ring A. All the isolated compounds were evaluated for cytotoxic activities in five cell lines and all the tested compounds showed significant anti-cancer activities against a series of human cancer cell lines, while having much weaker effect on the growth of normal cell. Among them, compound 1 showed strong inhibition toward MCF-7 human breast cancer cells (IC50 values 6.85 MUM). Further mechanistic study demonstrated that compound 1 significantly induced MCF-7 cell apoptosis. Our results indicated that compound 1 may be a promising lead agent for further study. PMID- 26099541 TI - Novel broad-spectrum inhibitors of bacterial methionine aminopeptidase. AB - With increasing emergence of multi-drug resistant infections, there is a dire need for new classes of compounds that act through unique mechanisms. In this work, we describe the discovery and optimization of a novel series of inhibitors of bacterial methionine aminopeptidase (MAP). Through a high-throughput screening campaign, one azepinone amide hit was found that resembled the native peptide substrate and possessed moderate biochemical potency against three bacterial isozymes. X-ray crystallography was used in combination with substrate-based design to direct the rational optimization of analogs with sub-micromolar potency. The novel compounds presented here represent potent broad-spectrum biochemical inhibitors of bacterial MAP and have the potential to lead to the development of new medicines to combat serious multi-drug resistant infections. PMID- 26099542 TI - Rapid synthesis and antimicrobial activity of novel 4-oxazolidinone heterocycles. AB - The synoxazolidinone family of marine natural products bear an unusual 4 oxazolidinone heterocyclic core and promising antimicrobial activity against several strains of pathogenic bacteria. As part of our research program directed at the synthesis and chemical biology of this family of natural products we have developed a one-step method for the generation of variously substituted 4 oxazolidinone scaffolds from readily available materials. These studies revealed the importance of an electron deficient aromatic ring for antimicrobial activity and serve as the basis for future SAR studies around the 4-oxazolidinone core. PMID- 26099543 TI - BMA annual meeting: Government is run "from cloud 9 rather than number 10," BMA chief says. PMID- 26099544 TI - Efficacy of brief interdisciplinary psychotherapeutic intervention for motor conversion disorder and nonepileptic attacks. AB - OBJECTIVE: The objective was to compare a brief interdisciplinary psychotherapeutic intervention to standard care as treatments for patients recently diagnosed with severe motor conversion disorder or nonepileptic attacks. METHODS: This randomized controlled trial of 23 consecutive patients compared (a) an interdisciplinary psychotherapeutic intervention group receiving four to six sessions by a consultation liaison psychiatrist, the first and last sessions adding a neurological consultation and a joint psychiatric and neurological consultation, and (b) a standard care group. After intervention, patients were assessed at 2, 6 and 12 months with the Somatoform Dissociation Questionnaire (SDQ-20), Clinical Global Impression scale, Rankin scale, use of medical care, global mental health [Montgomery and Asberg Depression Rating Scale, Beck Depression Inventory, mental health component of Short Form (SF)-36] and quality of life (SF-36). We calculated linear mixed models. RESULTS: Our intervention brought a statistically significant improvement of physical symptoms [as measured by the SDQ-20 (P<.02) and the Clinical Global Impression scale (P=.02)] and psychological symptoms [better scores on the mental health component of the SF-36 (P<.05) and on the Beck Depression Inventory (P<.05)] and a reduction in new hospital stays after intervention (P<.05). CONCLUSION: A brief psychotherapeutic intervention taking advantage of a close collaboration with neurology consultants in the setting of consultation liaison psychiatry appears effective. PMID- 26099545 TI - Physicians' attitudes toward integrating consultation-liaison psychiatric services in four major general hospitals in Tehran. AB - OBJECTIVE: Our objective was to validate a scale for the evaluation of attitudes of physicians toward integrating consultation-liaison psychiatric services and then apply it among the nonpsychiatrist attending physicians of four major general hospitals in Tehran. METHOD: The eight-item Doctors' Attitudes toward Collaborative Care for Mental Health (DACC-MH) Scale was translated to Persian and back-translated to English by nonphysician translators and was presented for expert opinion to four psychiatrists for assessment of face validity. The validated questionnaires were presented to nonpsychiatrist attending physicians of four major general university-affiliated hospitals with consultant-liaison psychiatric services in Tehran, and the returned questionnaires were analyzed using the 21st version of SPSS software. The score for each physician was generated by counting positive responses of the eight items questioned. RESULTS: Of the 300 questionnaires presented, 193 (64.3%) were returned. The mean score of the respondents was 6.62 (+/-1.33) for the Farsi version of the DACC-MH which was significantly higher than the assumed mean score of 4, according to the independent-sample t test (P<.001). The mean score of the respondents for the first four items of the DACC-MH was 3.49, which was significantly higher than that of the second four items of the scale which was 3.13 (P<.01) according to the Wilcoxon test. CONCLUSION: The respondents have an above-average positive attitude toward integrating consultation-liaison psychiatric services for the management of psychiatric disorders among inpatients. They had a more positive attitude toward requesting psychiatric consultations than managing the patients' psychiatric disorders themselves. PMID- 26099546 TI - Diet affects the redox system in developing Atlantic cod (Gadus morhua) larvae. AB - The growth and development of marine fish larvae fed copepods is superior to those fed rotifers, but the underlying molecular reasons for this are unclear. In the following study we compared the effects of such diets on redox regulation pathways during development of Atlantic cod (Gadus morhua) larvae. Cod larvae were fed a control diet of copepods or the typical rotifer/Artemia diet commonly used in commercial marine fish hatcheries, from first feeding until after metamorphosis. The oxidised and reduced glutathione levels, the redox potential, and the mRNA expression of 100 genes in redox system pathways were then compared between treatments during larval development. We found that rotifer/Artemia-fed cod larvae had lower levels of oxidised glutathione, a more reduced redox potential, and altered expression of approximately half of the redox system genes when compared to copepod-fed larvae. This rotifer/Artemia diet-induced differential regulation of the redox system was greatest during periods of suboptimal growth. Upregulation of the oxidative stress response transcription factor, nrf2, and NRF2 target genes in rotifer/Artemia fed larvae suggest this diet induced an NRF2-mediated oxidative stress response. Overall, the data demonstrate that nutritional intake plays a role in regulating the redox system in developing fish larvae. This may be a factor in dietary-induced differences observed in larval growth. PMID- 26099547 TI - Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a major health problem requiring an appropriate cell immune response to be controlled. Macrophages play a central role in the response against Mycobacterium tuberculosis (Mtb). Given our prior studies in which adrenal steroids were found to modify the cellular immune responses from TB patients, it was sensible to analyze the immunomodulatory capability of cortisol and DHEA on macrophages infected with Mtb. The human macrophage-like THP-1 cells were infected with the H37Rv strain of Mtb and treated with Cortisol and DHEA at different doses. We monitored phagocytosis, intracellular-bacterial growth, autophagosoma formation, as well as cytokine gene expression and production. Cultures exposed to cortisol showed a decreased production of IL-1beta, TNF alpha, with DHEA being unable to modify the pattern of cytokine production or to reverse the cortisol inhibitory effects. Interestingly the intra-macrophagic bacterial burden was found reduced by DHEA treatment. While this effect was not related to a different cytokine pattern, in terms their production or mRNA expression, DHEA treatment did promote autophagy in Mtb-infected macrophages, irrespective of Cortisol presence. In essence, the better control of Mtb load by DHEA-treated macrophages seems to be dependent on an autophagic mechanism. The present results are relevant for two reasons as autophagy is not only important for clearance of mycobacteria but also for the prevention of tissue damage. PMID- 26099548 TI - Effect of age and gender in the prevalence of excessive daytime sleepiness among a sample of the Saudi population. AB - The aim of this study is to assess whether the effect of gender on the excessive daytime sleepiness (EDS) is influenced by two confounders (age and hours of sleep per night). A cross-sectional study was conducted at King Abdulaziz Medical City Riyadh (KAMC-R). A total of 2095 respondents answered a questionnaire that included questions regarding gender, age, hours of sleep per night, and daytime sleepiness using the Epworth Sleepiness Scale (ESS). The prevalence of EDS was 20.5% (females 22.2%, males 19.5%, p-value=0.136). The EDS did not differ between genders, age groups, or hours of sleep per night (<6 vs. ?6h). However, stratified statistical analysis shows that the prevalence of EDS did differ according to gender (25.3% in females, 19.0% in males, p-value=0.036) in respondents with shorter hours of sleep per night. EDS was strongly related to female gender and young age (ages?29years) in respondents with short hours of sleep. This study reveals that one out of five of the general Saudi population has EDS. The effect of gender on EDS appeared to be influenced by hours of sleep per night. High EDS strongly related to female gender with short hours of sleep. PMID- 26099549 TI - Seizure prediction for therapeutic devices: A review. AB - Research in seizure prediction has come a long way since its debut almost 4 decades ago. Early studies suffered methodological caveats leading to overoptimistic results and lack of statistical significance. The publication of guidelines addressing mainly the question of performance evaluation and statistical validation in seizure prediction helped revising the status of the field. While many studies failed to prove that above chance prediction is possible by applying these guidelines, other studies were successful. Methods based on EEG analysis using linear and nonlinear measures were reportedly successful in detecting preictal changes and using them to predict seizures above chance. In this review, we present a selection of studies in seizure prediction published in the last decade. The studies were selected based on the validity of the methods and the statistical significance of performance results. These results varied between studies and many showed acceptable levels of sensitivity and specificity that could be appealing for therapeutic devices. The relatively large prediction horizon and early preictal changes reported in most studies suggest that seizure prediction may work better in closed loop seizure control devices rather than as seizure advisory devices. The emergence of a large database of annotated long-term EEG recordings should help prospective assessment of prediction methods. Some questions remain to be addressed before large clinical trials involving seizure prediction can be carried out. PMID- 26099550 TI - Nanosheet-assembled ZnFe2O4 hollow microspheres for high-sensitive acetone sensor. AB - Semiconductor oxides with hierarchically hollow architecture can provide significant advantages as sensing materials for gas sensors by facilitating the diffusion of target gases. Herein, we develop a facile template-free solvothermal strategy combined with the subsequent thermal treatment process toward the successful synthesis of novel ZnFe2O4 hollow flower-like microspheres. The images of electron microscopy unambiguously indicated that the ZnFe2O4 nanosheets with thickness of around 20 nm assembled hierarchically to form the unique flower-like architecture. As a proof-of-concept demonstration of the function, the as prepared product was utilized as sensing material for gas sensor. Significantly, in virtue of the porous shell structure, hollow interior, and large surface area, ZnFe2O4 hierarchical microspheres exhibited high response, excellent cyclability, and long-term stability to acetone at the operating temperature of 215 degrees C. PMID- 26099551 TI - In-vivo antioxidant and anti-inflammatory activity of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists in animal model of bronchial asthma. AB - OBJECTIVES: Peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been shown to play an important role in the control of immunological and inflammatory responses. This study aims at investigating the potential role of rosiglitazone, a strong PPAR-gamma agonist in a murine model of bronchial asthma. METHODS: Adult male guinea pigs were administered ovalbumin 100 mg/kg subcutaneous (SC) and 100 mg/kg intraperitoneal (IP). Treatment with rosiglitazone [5 mg/kg/day, per oral (PO)] was assessed for 21 days. On day 21, the animals were challenged with the same dose of ovalbumin. The forced expiratory volume in 1 s (FEV1 ) to forced vital capacity (FVC), FEV1 /FVC, was measured using a spirometer to diagnosis lung obstruction. Serum levels of interleukin-5 (IL-5) and immunoglobulin E (IgE) were assessed. The activity of superoxide dismutase (SOD) and catalase and the level of reduced glutathione (GSH) were determined in lung tissue homogenates. KEY FINDINGS: Our results demonstrated that treatment with rosiglitazone resulted in a statistically significant improvement in lung function and histopathological features. Significant decrease in the serum levels of IL-5 and IgE were observed. The activity of SOD and catalase as well as the GSH level were significantly increased in the lung tissues of treated animals compared with untreated asthmatic animals. Serum IgE concentrations and IL-5 levels were directly correlated to each other and inversely correlated to the SOD, GSH and catalase levels in the all studied guinea pigs. CONCLUSIONS: Our results provide evidence that the PPAR-gamma agonist rosiglitazone may have potential in the development of therapies for bronchial asthma. PMID- 26099552 TI - An integrated approach to reveal miRNAs' impacts on the functional consequence of copy number alterations in cancer. AB - Copy number alteration (CNA) is known to induce gene expression changes mainly through dosage effect, and therefore affect the initiation and progression of tumor. However, tumor samples exhibit heterogeneity in gene dosage sensitivity due to the complicated mechanisms of transcriptional regulation. Currently, no high-throughput method has been available for identifying the regulatory factors affecting the functional consequences of CNA, and determining their effects on cancer. In view of the important regulatory role of miRNA, we investigated the influence of miRNAs on the dosage sensitivities of genes within the CNA regions. By integrating copy number, mRNA expression, miRNA expression profiles of three kinds of cancer, we observed a tendency for high dosage-sensitivity genes to be more targeted by miRNAs in cancer, and identified the miRNAs regulating the dosage sensitivity of amplified/deleted target genes. The results show that miRNAs can modulate oncogenic biological functions by regulating the genes within the CNA regions, and thus play a role as a trigger or balancer in cancer, affecting cancer processes, even survival. This work provided a framework for analyzing the regulation of dosage effect, which will shed a light on understanding the oncogenic and tumor suppressive mechanisms of CNA. Besides, new cancer-related miRNAs were identified. PMID- 26099553 TI - Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine, for patients with osteoarthritis of the knee: a multi-site, randomized, double-blind, placebo controlled phase II clinical trial. AB - OBJECTIVE: To examine the efficacy and safety of Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine (TCM), in patients with knee osteoarthritis (OA). DESIGN: A multi-site, randomized, double-blind, placebo-controlled phase II dose escalation clinical trial was conducted. Eligible patients who fulfilled American College of Rheumatology criteria were randomized to receive either HLXL or placebo. Clinical assessments included measurement of knee pain and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), patient global assessment (PGA), and knee pain scores every 2 weeks. A Data and Safety Monitoring Board (DSMB) was established to review the data for ensuring the quality of the trial. RESULTS: In the first stage, 28 participants were randomized to receive either low-dose HLXL-Dan (2400 mg/day) or placebo for 6 weeks. The results showed no statistical difference between the two groups. The study was then re-designed following the recommendation of DSMB. Ninety-two patients were enrolled in the second stage and were randomized to receive either high-dose HLXL-Dan (4000 mg/day for week 1-2, and 5600 mg/day for week 3-8) or placebo for 8 weeks. All outcome assessments showed significant improvements for both groups after 8 weeks but no significant between-group differences. The change (mean +/- SD) of WOMAC pain and WOMAC function scores of HLXL and placebo group after 8 weeks were -1.2 +/- 1.7 vs -1.4 +/- 1.5, and -1.1 +/- 1.6 vs -1.3 +/- 1.5 respectively. No serious adverse events were reported. CONCLUSION: Although safe to use, an 8-week treatment of HLXL-Dan was not superior to placebo for reduction in pain or functional improvement in patients with knee OA. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT00755326). PMID- 26099554 TI - Chronic Thromboembolic Pulmonary Hypertension: the End Result of Pulmonary Embolism. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when a pulmonary embolism fails to undergo complete thrombolysis leading to vascular occlusion and pulmonary hypertension. Despite the fact that CTEPH is a potential consequence of pulmonary embolism, diagnosis requires a high degree of vigilance as many patients will not have a history of thromboembolic disease. The ventilation perfusion scan is used to evaluate for the possibility of CTEPH although right heart catheterization and pulmonary artery angiogram are needed to confirm the diagnosis. Pulmonary thromboendarterectomy is the first-line treatment for patients who are surgical candidates. Recently, riociguat has been approved for patients with nonsurgical disease or residual pulmonary hypertension despite surgical intervention. This review describes the pathophysiology, risk factors, diagnosis, and management of CTEPH. PMID- 26099555 TI - The contribution of pharmaceutically active compounds from healthcare facilities to a receiving sewage treatment plant in Canada. AB - Concentrations and percent loadings of pharmaceutically active compounds (PhACs) and other emerging contaminants released from healthcare facilities (2 hospitals and a long-term care facility) to a sewage treatment plant (STP) in a large urban sewershed were evaluated. An additional hospital outside the sewershed was also monitored. Fourteen of the 24 steroids/hormones and 88 of the 117 PhACs and emerging contaminants were detected at least once. Commonly used substances, including cotinine, caffeine and its metabolite 1,7-dimethylxanthine, ibuprofen and naproxen (analgesics), venlafaxine (antidepressant), and N,N-diethyl-meta toluamide (insect repellant), were detected in all samples at all sites. Concentrations detected in the large specialty hospital outside the sewershed were similar to those within the sewershed. Cytotoxic drugs (tamoxifen and cyclophosphamide) and x-ray contrast media (iopamidol and diatrizoic acid) were infrequently detected in hospital effluents. Analysis for antibiotics indicated that azithromycin, clarithromycin, ciprofloxacin, erythromycin, ofloxacin, and sulfamethoxazole were consistently detected in hospital wastewaters, as was triclosan (antibacterial agent). Fifteen compounds individually contributed greater than 1% to the total PhAC and emerging contaminant load to the STP from the 2 hospitals in the sewershed, and 9 compounds in the STP effluent exceeded ecotoxicological criteria. The present survey demonstrates that point source discharges from healthcare facilities in this sewershed make a small contribution to the overall PhAC and emerging contaminant loading compared with the total concentrations entering the receiving STP. PMID- 26099556 TI - Maxwell's demon in biochemical signal transduction with feedback loop. AB - Signal transduction in living cells is vital to maintain life itself, where information transfer in noisy environment plays a significant role. In a rather different context, the recent intensive research on 'Maxwell's demon'-a feedback controller that utilizes information of individual molecules-have led to a unified theory of information and thermodynamics. Here we combine these two streams of research, and show that the second law of thermodynamics with information reveals the fundamental limit of the robustness of signal transduction against environmental fluctuations. Especially, we find that the degree of robustness is quantitatively characterized by an informational quantity called transfer entropy. Our information-thermodynamic approach is applicable to biological communication inside cells, in which there is no explicit channel coding in contrast to artificial communication. Our result could open up a novel biophysical approach to understand information processing in living systems on the basis of the fundamental information-thermodynamics link. PMID- 26099557 TI - The Effects of Pretreatment versus De Novo Treatment with Selective Serotonin Reuptake Inhibitors on Short-term Outcome after Acute Ischemic Stroke. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) administered in patients following acute ischemic stroke have shown to improve clinical recovery independently of changes in depression. Animal studies have demonstrated that sustained SSRI treatment is superior to short-term SSRI in evoking neurogenesis but how this benefit translates into humans remains to be answered. We hypothesized that in acute ischemic stroke patients, SSRI treatment started before the event leads to improved short-term outcomes compared to de novo SSRI treatment poststroke. METHODS: We performed an exploratory analysis in consecutive acute ischemic stroke patients and compared patients already receiving fluoxetine, citalopram, or escitalopram with those who started treatment de novo. RESULTS: Of 2653 screened patients, 239 were included (age, 69 +/- 14 years; 42% men, baseline median National Institutes of Health Stroke Scale score, 7 [IQR, 10]). Of these patients, 51 started treatment with SSRI before stroke and 188 were prescribed newly SSRIs during hospitalization. In the adjusted multivariate logistic regression models, SSRI pretreatment was associated with favorable functional outcome at discharge defined as a modified Rankin Scale score of 2 or less (odds ratio [OR], 4.00; 95% confidence interval [CI], 1.68-9.57; P < .005), improved early clinical recovery (OR, 2.35; 95% CI, 1.15-4.81; P = .02), and a trend toward prediction of superior motor recovery (OR, 1.82; 95% CI, .90-3.68; P < .01). CONCLUSIONS: Our data suggest that SSRI pretreatment may improve clinical outcomes in the early stages of acute ischemic stroke supporting the hypothesis that prolonged SSRI treatment started prestroke is superior to poststroke SSRI. PMID- 26099559 TI - Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants. AB - Co-administration of fluvoxamine (FLV) (perpetrator) and ramelteon (victim, high clearance CYP1A2 substrate) reportedly showed a 130-fold increase in the area under blood-ramelteon-levels curve (AUCR), which is unpredictable by any method assuming the traditional well-stirred hepatic extraction (Eh ) model. Thus, in order to predict this drug interaction (DDI), a mathematical method that allows simulation of dynamic changes in blood victim levels in response to metabolic inhibition by a perpetrator, without the use of any specialized tools, was derived using hybridized two-compartment hepatic drug-pool-based tube modeling. Using this method, the ramelteon-victimized DDI could be simulated in comparison with other victim DDIs, assuming a consistent FLV dosing regimen. Despite large differences in AUCRs, CYP1A2 or CYP2C19 substrate-victimized DDIs resulted in equivalent inhibition constants (Ki , around 3 nM) and net enzymatic inhibitory activities calculated by eliminating hepatic availability increases for victims. Thus, the unusually large ramelteon DDI could be attributed to the Eh of ramelteon itself. This DDI risk could also be accurately predicted from Ki s estimated in the other CYP1A2 or CYP2C19-substrate interactions. Meanwhile, dynamic changes in blood perpetrator levels were demonstrated to have a small effect on DDI, thus suggesting the usefulness of a tube-based static method for DDI prediction. PMID- 26099560 TI - Monitoring and evaluating transition and sustainability of donor-funded programs: Reflections on the Avahan experience. AB - PURPOSE: In low and middle-income countries, programs funded and implemented by international donors frequently transition to local funding and management, yet such processes are rarely evaluated. We reflect upon experience evaluating the transition of a large scale HIV/AIDS prevention program in India, known as Avahan, in order to draw lessons about transition evaluation approaches and implementation challenges. RESULTS: In terms of conceptualizing the transition theory, the evaluation team identified tensions between the idea of institutionalizing key features of the Avahan program, and ensuring program flexibility to promote sustainability. The transition was planned in three rounds allowing for adaptations to transition intervention and program design during the transition period. The assessment team found it important to track these changes in order to understand which strategies and contextual features supported transition. A mixed methods evaluation was employed, combining semi-structured surveys of transitioning entities (conducted pre and post transition), with longitudinal case studies. Qualitative data helped explain quantitative findings. Measures of transition readiness appeared robust, but we were uncertain of the robustness of institutionalization measures. Finally, challenges to the implementation of such an evaluation are discussed. CONCLUSIONS: Given the scarceness of transition evaluations, the lessons from this evaluation may have widespread relevance. PMID- 26099561 TI - Development of an educational intervention to promote healthy eating and physical activity in Mexican school-age children. AB - Mexico has the highest and most alarming rates of childhood obesity worldwide. A study conducted in the State of Mexico revealed that one of every three children presents overweight or obesity. The objective of this paper is to provide a step by-step description of the design and implementation of an educational intervention to promote healthy eating and physical activity called "Healthy Recess". The educational intervention was designed using the six stages of the Health Communication Process. This methodological model allowed identifying the needs of school-age children on information and participation in activities. In order to improve the strategy, adjustments were made to the print and audiovisual materials as well as to assessment tools. Typography was modified as well as the color of the images in student's workbook and facilitator's; special effects of the videos were increased; the narration of the radio spots was improved and common words and phrases were included. The Health Communication Process is an effective tool for program planners to design interventions aimed at managing prevalent health problems such as overweight and obesity in school-age children. PMID- 26099562 TI - Analysis of perception of training in graduates of the Faculty of Medicine at Universidad de Castilla-Mancha. AB - INTRODUCTION: Problem-based learning has been a key component of the teaching method employed at the Faculty of Medicine at the University of Castilla La Mancha (UCLM) in Albacete, Spain since its creation. The aim of this study was to evaluate perceptions of training among residents who graduated from the first three years of the UCLM Degree in Medicine. METHODS: Using the Jefferson Medical College postgraduate rating form, residents rated their performance in four areas of clinical competency (medical knowledge, data gathering skills, clinical judgment, and professional attitudes) at the beginning of residency training in comparison with colleagues from other faculties. The construct validity of responses was evaluated using Cronbach's alpha and exploratory factor analysis. RESULTS: Over half the respondents (57.8%) considered that they had received better training than peers from other medical schools, and 98.5% felt that their general performance in the four competencies analyzed was similar or superior to that of their colleagues. Factor analysis revealed two major factors: "the physician as scientist" and "the physician as manager and communicator". CONCLUSIONS: Our study shows that graduates from the UCLM Faculty of Medicine perceive their training, which is largely based on problem-based learning, as satisfactory. PMID- 26099563 TI - Implementation and evaluation of an Exercise is MedicineTM on campus week. AB - Exercise is MedicineTM (EiM) on campus targets physical activity (PA) participation on college campuses. Limited research has addressed how PA initiatives can be operationalized on college campuses. PURPOSE: To describe the implementation of EiM on a large U.S. university campus and present preliminary outcomes on participation and awareness. METHODS: EiM week was implemented on a large university campus. Exercise stations were set-up at campus locations to encourage brief bouts of PA and educate about the benefits of PA. Evaluation included observations of participation, surveys, and intercept surveys to assess awareness and reach. RESULTS: EiM week was implemented during Fall 2013. Exercise stations elicited 1771 exercise bouts from participants. Surveys indicated widespread reach across the university (13 of 17 colleges); most students (50.8%) became aware of the EiM campaign by passing by the exercise stations. Campus intercept surveys 1-week post-event indicated 54% students had heard about EiM, of which 39% had heard/seen the event through messages encouraging exercise. CONCLUSION: The current study was successful in engaging a large, diverse population on a college campus. Lessons learned from the development, implementation, and evaluation of EiM on campus activities provide insight for university campuses looking to target student health and PA participation. PMID- 26099565 TI - Strongly correlated two-dimensional plasma explored from entropy measurements. AB - Charged plasma and Fermi liquid are two distinct states of electronic matter intrinsic to dilute two-dimensional electron systems at elevated and low temperatures, respectively. Probing their thermodynamics represents challenge because of lack of an adequate technique. Here, we report a thermodynamic method to measure the entropy per electron in gated structures. Our technique appears to be three orders of magnitude superior in sensitivity to a.c. calorimetry, allowing entropy measurements with only 10(8) electrons. This enables us to investigate the correlated plasma regime, previously inaccessible experimentally in two-dimensional electron systems in semiconductors. In experiments with clean two-dimensional electron system in silicon-based structures, we traced entropy evolution from the plasma to Fermi liquid regime by varying electron density. We reveal that the correlated plasma regime can be mapped onto the ordinary non degenerate Fermi gas with an interaction-enhanced temperature-dependent effective mass. Our method opens up new horizons in studies of low-dimensional electron systems. PMID- 26099564 TI - Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma. AB - Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington's and Alzheimer's diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC. PMID- 26099566 TI - Characterization of Tribolium castaneum oocyte nuclear structures using microinjection of a fusion nuclear protein mRNA. PMID- 26099567 TI - To be EndMT or not to be, that is the question in pulmonary hypertension. PMID- 26099568 TI - ZnO nanowires array grown on Ga-doped ZnO single crystal for dye-sensitized solar cells. AB - High quality ZnO nanowires arrays were homoepitaxial grown on Ga-doped ZnO single crystal (GZOSC), which have the advantages of high conductivity, high carrier mobility and high thermal stability. When it was employed as a photoanode in the DSSCs, the cell exhibited a 1.44% power-conversion efficiency under the illumination of one sun (AM 1.5G). The performance is superior to our ZnO nanowires/FTO based DSSCs under the same condition. This enhanced performance is mainly attributed to the perfect interface between the ZnO nanowires and the GZOSC substrate that contributes to lower carrier scattering and recombination rates compared with that grown on traditional FTO substrate. PMID- 26099569 TI - Shade Trading: An Emerging Riparian Forest-Based Payment for Ecosystem Services Market in Oregon, USA. AB - This paper describes the regulatory and compliance context for Oregon's emerging ecosystem services (ES) market in riparian shade to meet water quality obligations. In Oregon's market as with many other ES programs, contracts and other regulatory documents not only delimit the obligations and liabilities of different parties, but also constitute a primary mechanism through which ES service delivery is measured. Through a review of compliance criteria I find that under Oregon's shade trades, permittees are held to a number of input-based criteria, which essentially affirm that parties comply with predetermined practices and procedures, and one 'pseudo output based' criterion, in which ES delivery is estimated through a model. The case presented in the paper critically engages with the challenges of measuring ES and in assessing the outcomes of ES projects. It places these challenges as interrelated and proposes that market designers, policymakers, and other stakeholders should consider explicit efficacy, efficiency, and equity targets. PMID- 26099570 TI - Guidelines for Using Movement Science to Inform Biodiversity Policy. AB - Substantial advances have been made in our understanding of the movement of species, including processes such as dispersal and migration. This knowledge has the potential to improve decisions about biodiversity policy and management, but it can be difficult for decision makers to readily access and integrate the growing body of movement science. This is, in part, due to a lack of synthesis of information that is sufficiently contextualized for a policy audience. Here, we identify key species movement concepts, including mechanisms, types, and moderators of movement, and review their relevance to (1) national biodiversity policies and strategies, (2) reserve planning and management, (3) threatened species protection and recovery, (4) impact and risk assessments, and (5) the prioritization of restoration actions. Based on the review, and considering recent developments in movement ecology, we provide a new framework that draws links between aspects of movement knowledge that are likely the most relevant to each biodiversity policy category. Our framework also shows that there is substantial opportunity for collaboration between researchers and government decision makers in the use of movement science to promote positive biodiversity outcomes. PMID- 26099571 TI - Optimizing eukaryotic cell hosts for protein production through systems biotechnology and genome-scale modeling. AB - Eukaryotic cell lines, including Chinese hamster ovary cells, yeast, and insect cells, are invaluable hosts for the production of many recombinant proteins. With the advent of genomic resources, one can now leverage genome-scale computational modeling of cellular pathways to rationally engineer eukaryotic host cells. Genome-scale models of metabolism include all known biochemical reactions occurring in a specific cell. By describing these mathematically and using tools such as flux balance analysis, the models can simulate cell physiology and provide targets for cell engineering that could lead to enhanced cell viability, titer, and productivity. Here we review examples in which metabolic models in eukaryotic cell cultures have been used to rationally select targets for genetic modification, improve cellular metabolic capabilities, design media supplementation, and interpret high-throughput omics data. As more comprehensive models of metabolism and other cellular processes are developed for eukaryotic cell culture, these will enable further exciting developments in cell line engineering, thus accelerating recombinant protein production and biotechnology in the years to come. PMID- 26099572 TI - Biosimilar filgrastim (Zarzio(r)) vs. lenograstim (Myelostim(r)) for peripheral blood stem cell mobilization in adult patients with lymphoma and myeloma: a single center experience. PMID- 26099573 TI - Meta-analysis of time-to-event outcomes from randomized trials using restricted mean survival time: application to individual participant data. AB - Meta-analysis of time-to-event outcomes using the hazard ratio as a treatment effect measure has an underlying assumption that hazards are proportional. The between-arm difference in the restricted mean survival time is a measure that avoids this assumption and allows the treatment effect to vary with time. We describe and evaluate meta-analysis based on the restricted mean survival time for dealing with non-proportional hazards and present a diagnostic method for the overall proportional hazards assumption. The methods are illustrated with the application to two individual participant meta-analyses in cancer. The examples were chosen because they differ in disease severity and the patterns of follow up, in order to understand the potential impacts on the hazards and the overall effect estimates. We further investigate the estimation methods for restricted mean survival time by a simulation study. PMID- 26099574 TI - Phage-fused epitopes from Leishmania infantum used as immunogenic vaccines confer partial protection against Leishmania amazonensis infection. AB - Two mimotopes of Leishmania infantum identified by phage display were evaluated as vaccine candidates in BALB/c mice against Leishmania amazonensis infection. The epitope-based immunogens, namely B10 and C01, presented as phage-fused peptides; were used without association of a Th1 adjuvant, and they were administered isolated or in combination into animals. Both clones showed a specific production of interferon-gamma (IFN-gamma), interleukin-12 (IL-12) and granulocyte/macrophage colony-stimulating factor (GM-CSF) after in vitro spleen cells stimulation, and they were able to induce a partial protection against infection. Significant reductions of parasite load in the infected footpads, liver, spleen, bone marrow and paws' draining lymph nodes were observed in the immunized mice, in comparison with the control groups (saline, saponin, wild-type and non-relevant clones). Protection was associated with an IL-12-dependent production of IFN-gamma, mediated mainly by CD8(+) T cells, against parasite proteins. Protected mice also presented low levels of IL-4 and IL-10, as well as increased levels of parasite-specific IgG2a antibodies. The association of both clones resulted in an improved protection in relation to their individual use. More importantly, the absence of adjuvant did not diminish the cross-protective efficacy against Leishmania spp. infection. This study describes for the first time two epitope-based immunogens selected by phage display technology against L. infantum infected dogs sera, which induced a partial protection in BALB/c mice infected with L. amazonensis. PMID- 26099575 TI - Louhi 2014: Special issue on health text mining and information analysis. PMID- 26099576 TI - Interaction of iron with a wagon wheel-like ultrathin TiOx film grown on Pt(111). AB - The structure and thermal evolution of Fe nanoparticles deposited on a wetting TiOx ultrathin film epitaxially grown on Pt(111) has been characterized by various surface science techniques. Combining the results obtained it is shown that, at room temperature, metallic Fe nucleates randomly and oxidizes at the interface. A thermal treatment causes Fe migration through the TiOx layer, forming a mixed oxide and a new hexagonal ultrathin film phase. Finally, the pristine TiOx phase motif is restored, due to the complete diffusion of Fe into the Pt substrate. PMID- 26099577 TI - Correlation between thyroglobulin gene polymorphisms and autoimmune thyroid disease. AB - The aim of the present study was to detect thyroglobulin (Tg) gene polymorphisms in a Han Chinese population from the Northern regions of Henan province, China, and to study the correlation between Tg gene polymorphisms and autoimmune thyroid disease (AITD). A total of 270 patients with AITD and 135 healthy controls were enrolled. Genomic DNA was extracted and fluorescence polymerase chain reaction analysis was performed; high-resolution melting curve analysis (HRMA) was used to detect single-nucleotide polymorphisms (SNPs) in exons 10, 12 and 33 of the Tg gene. SNPs were then correlated with AITD. Han people from the Northern regions of Henan displayed four Tg exon SNPs: E10SNP24 T/G, E10SNP158 T/C, E12SNP A/G and E33SNP C/T. Several allele and genotype frequencies differed between the AITD group and the healthy control group (Tg E10SNP: Allele T, P<0.01; allele G, P<0.01; and Tg genotype GG, P<0.01; genotype TG, P<0.01. Tg E12SNP: Allele A, P<0.01; allele G, P<0.01; Tg genotype GG, P<0.01; genotype AG, P<0.01). A statistically significant difference in the frequency of selected Tg SNPs haplotypes was also present between AITD patients and healthy controls (P<0.05). There was no significant difference in haplotypes between various types of AITD (hypothyroidism, hyperthyroidism and Hashimoto's disease). The Tg SNP frequency distribution was significantly different between Han populations of the Northern regions of Henan province and the Xi'an regions of Shaanxi province. The results of the present study suggested that specific Tg gene alleles or genotypes were correlated with AITD; specific Tg SNP haplotypes were associated with hypothyroidism, hyperthyroidism and Hashimoto's disease, and the Tg SNP frequency distribution differed depending on the geographical location of the Han Chinese populations. PMID- 26099578 TI - Ni(II)-catalyzed dehydrative alkynylation of unactivated (hetero)aryl C-H bonds using oxygen: a user-friendly approach. AB - Ni(II)-catalyzed dehydrative alkynylation of unactivated C(sp(2))-H bonds with terminal alkynes under atmospheric pressure of oxygen was developped. This reaction features the use of catalytic amounts of nickel as the catalyst and O2 as the sole oxidant, providing a user-friendly approach to the synthesis of aryl alkynes. PMID- 26099579 TI - The Periplasmic Nitrate Reductase NapABC Supports Luminal Growth of Salmonella enterica Serovar Typhimurium during Colitis. AB - The food-borne pathogen Salmonella enterica serovar Typhimurium benefits from acute inflammation in part by using host-derived nitrate to respire anaerobically and compete successfully with the commensal microbes during growth in the intestinal lumen. The S. Typhimurium genome contains three nitrate reductases, encoded by the narGHI, narZYV, and napABC genes. Work on homologous genes present in Escherichia coli suggests that nitrate reductase A, encoded by the narGHI genes, is the main enzyme promoting growth on nitrate as an electron acceptor in anaerobic environments. Using a mouse colitis model, we found, surprisingly, that S. Typhimurium strains with defects in either nitrate reductase A (narG mutant) or the regulator inducing its transcription in the presence of high concentrations of nitrate (narL mutant) exhibited growth comparable to that of wild-type S. Typhimurium. In contrast, a strain lacking a functional periplasmic nitrate reductase (napA mutant) exhibited a marked growth defect in the lumen of the colon. In E. coli, the napABC genes are transcribed maximally under anaerobic growth conditions in the presence of low nitrate concentrations. Inactivation of narP, encoding a response regulator that activates napABC transcription in response to low nitrate concentrations, significantly reduced the growth of S. Typhimurium in the gut lumen. Cecal nitrate measurements suggested that the murine cecum is a nitrate-limited environment. Collectively, our results suggest that S. Typhimurium uses the periplasmic nitrate reductase to support its growth on the low nitrate concentrations encountered in the gut, a strategy that may be shared with other enteric pathogens. PMID- 26099580 TI - Endoplasmic Reticulum Tubule Protein Reticulon 4 Associates with the Legionella pneumophila Vacuole and with Translocated Substrate Ceg9. AB - Intracellular growth of Legionella pneumophila occurs in a replication vacuole constructed by host proteins that regulate vesicular traffic from the host endoplasmic reticulum (ER). This process is promoted by a combination of approximately 300 Icm/Dot translocated substrates (IDTS). One of these proteins, Ceg9, was previously identified in a screen for L. pneumophila IDTS that manipulate secretory traffic when overexpressed in yeast. Using ectopic expression of Ceg9 in mammalian cells, we demonstrate that Ceg9 interacts with isoforms of host reticulon 4 (Rtn4), a protein that regulates ER tubule formation. Binding occurs under conditions that prevent association with other known reticulon binding proteins, arguing that Ceg9 binding is stable. A tripartite complex was demonstrated among Rtn4, Ceg9, and atlastin 1, a previously characterized reticulon interacting partner. The binding of Ceg9 to Rtn4 was not due to bridging by atlastin 1 but resulted from the two interacting partners binding independently to reticulon. When Ceg9 is ectopically expressed in mammalian cells, it shows a localization pattern that is indistinguishable from that of Rtn4, perhaps due to interactions between and similar structural features of the two proteins. Consistent with Rtn4 playing a role in the formation of the Legionella-containing vacuole, it was recruited to almost 50% of the vacuoles within 20 min postinfection. Our studies suggest that L. pneumophila proteins interact with ER tubules at an early stage of replication vacuole formation. PMID- 26099581 TI - Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Staphylococcal Enterotoxin A-Induced Toxic Shock. AB - Adipose tissue-derived stem cells (ASCs), which are mesenchymal stromal cells isolated from adipose tissues, exhibit immunomodulatory effects that are promising for several applications, including the therapeutics of inflammatory diseases. In the present study, the effect of ASCs on bacterial toxin-induced inflammation was investigated. Intraperitoneal administration of ASCs rescued mice from lethal shock induced by staphylococcal enterotoxin A (SEA) potentiated with lipopolysaccharide. In the sera and/or spleens of mice administered ASCs, the production of proinflammatory cytokines, including interferon gamma, tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-2 was reduced. By quantitative real-time PCR, the expression of Foxp3 in the mice administered ASCs was not altered. On the other hand, the expression of IL-12 receptor and STAT4 was decreased with ASC administration. These results imply that the effect of ASCs is not involved in the lineage of regulatory T cells but that these cells may modulate TH1 differentiation. This information provides evidence that ASCs have properties that are effective to attenuate SEA-induced toxic shock and should prompt further exploration on other inflammatory diseases caused by bacterial toxins or bacterial infections. PMID- 26099582 TI - Protection against Shiga-Toxigenic Escherichia coli by Non-Genetically Modified Organism Receptor Mimic Bacterial Ghosts. AB - Shiga-toxigenic Escherichia coli (STEC) causes severe gastrointestinal infections in humans that may lead to life-threatening systemic sequelae, such as the hemolytic uremic syndrome (HUS). Rapid diagnosis of STEC infection early in the course of disease opens a window of opportunity for therapeutic intervention, for example, by administration of agents that neutralize Shiga toxin (Stx) in the gut lumen. We previously developed a recombinant bacterium that expresses a mimic of the Stx receptor globotriaosyl ceramide (Gb3) on its surface through modification of the lipopolysaccharide (A. W. Paton, R. Morona, and J. C. Paton, Nat Med 6:265 270, 2000, http://dx.doi.org/10.1038/73111). This construct was highly efficacious in vivo, protecting mice from otherwise fatal STEC disease, but the fact that it is a genetically modified organism (GMO) has been a barrier to clinical development. In the present study, we have overcome this issue by development of Gb3 receptor mimic bacterial ghosts (BGs) that are not classified as GMOs. Gb3-BGs neutralized Stx1 and Stx2 in vitro with high efficiency, whereas alternative Gb3-expressing non-GMO subbacterial particles (minicells and outer membrane blebs) were ineffective. Gb3-BGs were highly efficacious in a murine model of STEC disease. All mice (10/10) treated with Gb3-BGs survived challenge with a highly virulent O113:H21 STEC strain and showed no pathological signs of renal injury. In contrast, 6/10 mice treated with control BGs succumbed to STEC challenge, and survivors exhibited significant weight loss, neutrophilia, and histopathological evidence of renal damage. Thus, Gb3-BGs offer a non-GMO approach to treatment of STEC infection in humans, particularly in an outbreak setting. PMID- 26099583 TI - Toxicity and SidJ-Mediated Suppression of Toxicity Require Distinct Regions in the SidE Family of Legionella pneumophila Effectors. AB - Intracellular bacteria use a variety of strategies to evade degradation and create a replicative niche. Legionella pneumophila is an intravacuolar pathogen that establishes a replicative niche through the secretion of more than 300 effector proteins. The function of most effectors remains to be determined. Toxicity in yeast has been used to identify functional domains and elucidate the biochemical function of effectors. A library of L. pneumophila effectors was screened using an expression plasmid that produces low levels of each protein. This screen identified the effector SdeA as a protein that confers a strong toxic phenotype that inhibits yeast replication. The toxicity of SdeA was suppressed in cells producing the effector SidJ. The effector SdeA is a member of the SidE family of L. pneumophila effector proteins. All SidE orthologs encoded by the Philadelphia isolate of Legionella pneumophila were toxic to yeast, and SidJ suppressed the toxicity of each. We identified a conserved central region in the SidE proteins that was sufficient to mediate yeast toxicity. Surprisingly, SidJ did not suppress toxicity when this central region was produced in yeast. We determined that the amino-terminal region of SidE was essential for SidJ-mediated suppression of toxicity. Thus, there is a genetic interaction that links the activity of SidJ and the amino-terminal region of SidE, which is required to modulate the toxic activity displayed by the central region of the SidE protein. This suggests a complex mechanism by which the L. pneumophila effector SidJ modulates the function of the SidE proteins after translocation into host cells. PMID- 26099584 TI - ArcA Controls Metabolism, Chemotaxis, and Motility Contributing to the Pathogenicity of Avian Pathogenic Escherichia coli. AB - Avian pathogenic Escherichia coli (APEC) strains cause one of the three most significant infectious diseases in the poultry industry and are also potential food-borne pathogens threating human health. In this study, we showed that ArcA (aerobic respiratory control), a global regulator important for E. coli's adaptation from anaerobic to aerobic conditions and control of that bacterium's enzymatic defenses against reactive oxygen species (ROS), is involved in the virulence of APEC. Deletion of arcA significantly attenuates the virulence of APEC in the duck model. Transcriptome sequencing (RNA-Seq) analyses comparing the APEC wild type and the arcA mutant indicate that ArcA regulates the expression of 129 genes, including genes involved in citrate transport and metabolism, flagellum synthesis, and chemotaxis. Further investigations revealed that citCEFXG contributed to APEC's microaerobic growth at the lag and log phases when cultured in duck serum and that ArcA played a dual role in the control of citrate metabolism and transportation. In addition, deletion of flagellar genes motA and motB and chemotaxis gene cheA significantly attenuated the virulence of APEC, and ArcA was shown to directly regulate the expression of motA, motB, and cheA. The combined results indicate that ArcA controls metabolism, chemotaxis, and motility contributing to the pathogenicity of APEC. PMID- 26099585 TI - Lack of the Transcription Factor Hypoxia-Inducible Factor 1alpha (HIF-1alpha) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas. AB - The establishment of mycobacterial infection is characterized by the formation of granulomas, which are well-organized aggregates of immune cells, namely, infected macrophages. The granuloma's main function is to constrain and prevent dissemination of the mycobacteria while focusing the immune response to a limited area. In some cases these lesions can grow progressively into large granulomas which can undergo central necrosis, thereby leading to their caseation. Macrophages are the most abundant cells present in the granuloma and are known to adapt under hypoxic conditions in order to avoid cell death. Our laboratory has developed a granuloma necrosis model that mimics the human pathology of Mycobacterium tuberculosis, using C57BL/6 mice infected intravenously with a low dose of a highly virulent strain of Mycobacterium avium. In this work, a mouse strain deleted of the hypoxia inducible factor 1alpha (HIF-1alpha) under the Cre lox system regulated by the lysozyme M gene promoter was used to determine the relevance of HIF-1alpha in the caseation of granulomas. The genetic ablation of HIF-1alpha in the myeloid lineage causes the earlier emergence of granuloma necrosis and clearly induces an impairment of the resistance against M. avium infection coincident with the emergence of necrosis. The data provide evidence that granulomas become hypoxic before undergoing necrosis through the analysis of vascularization and quantification of HIF-1alpha in a necrotizing mouse model. Our results show that interfering with macrophage adaptation to hypoxia, such as through HIF-1alpha inactivation, accelerates granuloma necrosis. PMID- 26099586 TI - Manipulation of Autophagy in Phagocytes Facilitates Staphylococcus aureus Bloodstream Infection. AB - The capacity for intracellular survival within phagocytes is likely a critical factor facilitating the dissemination of Staphylococcus aureus in the host. To date, the majority of work on S. aureus-phagocyte interactions has focused on neutrophils and, to a lesser extent, macrophages, yet we understand little about the role played by dendritic cells (DCs) in the direct killing of this bacterium. Using bone marrow-derived DCs (BMDCs), we demonstrate for the first time that DCs can effectively kill S. aureus but that certain strains of S. aureus have the capacity to evade DC (and macrophage) killing by manipulation of autophagic pathways. Strains with high levels of Agr activity were capable of causing autophagosome accumulation, were not killed by BMDCs, and subsequently escaped from the phagocyte, exerting significant cytotoxic effects. Conversely, strains that exhibited low levels of Agr activity failed to accumulate autophagosomes and were killed by BMDCs. Inhibition of the autophagic pathway by treatment with 3 methyladenine restored the bactericidal effects of BMDCs. Using an in vivo model of systemic infection, we demonstrated that the ability of S. aureus strains to evade phagocytic cell killing and to survive temporarily within phagocytes correlated with persistence in the periphery and that this effect is critically Agr dependent. Taken together, our data suggest that strains of S. aureus exhibiting high levels of Agr activity are capable of blocking autophagic flux, leading to the accumulation of autophagosomes. Within these autophagosomes, the bacteria are protected from phagocytic killing, thus providing an intracellular survival niche within professional phagocytes, which ultimately facilitates dissemination. PMID- 26099587 TI - Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability. AB - Moraxella catarrhalis causes otitis media in children and exacerbations of chronic obstructive pulmonary disease in adults. Together, these two conditions contribute to enormous morbidity and mortality worldwide. The oligopeptide permease (opp) ABC transport system is a nutritional virulence factor important for the utilization of peptides. The substrate binding protein OppA, which binds peptides for uptake, is a potential vaccine antigen, but little was known about the regulation of gene expression. The five opp genes oppB, oppC, oppD, oppF, and oppA are in the same open reading frame. Sequence analysis predicted two promoters, one located upstream of oppB and one within the intergenic region between oppF and oppA. We have characterized the gene cluster as an operon with two functional promoters and show that cold shock at 26 degrees C for <= 0.5 h and the presence of a peptide substrate increase gene transcript levels. Additionally, the putative promoter upstream of oppA contributes to the transcription of oppA but is not influenced by the same environmental cues as the promoter upstream of oppB. We conclude that temperature and nutrient availability contribute to the regulation of the Opp system, which is an important nutritional virulence factor in M. catarrhalis. PMID- 26099588 TI - Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM L-Glutamate ABC Transporter in Neisseria meningitidis Internalization into Human Brain Microvascular Endothelial Cells. AB - We previously reported that Neisseria meningitidis internalization into human brain microvasocular endothelial cells (HBMEC) was triggered by the influx of extracellular L-glutamate via the GltT-GltM L-glutamate ABC transporter, but the underlying mechanism remained unclear. We found that the DeltagltT DeltagltM invasion defect in assay medium (AM) was alleviated in AM without 10% fetal bovine serum (FBS) [AM(-S)]. The alleviation disappeared again in AM(-S) supplemented with 500 MUM glutamate. Glutamate uptake by the DeltagltT DeltagltM mutant was less efficient than that by the wild-type strain, but only upon HBMEC infection. We also observed that both GltT-GltM-dependent invasion and accumulation of ezrin, a key membrane-cytoskeleton linker, were more pronounced when N. meningitidis formed larger colonies on HBMEC under physiological glutamate conditions. These results suggested that GltT-GltM-dependent meningococcal internalization into HBMEC might be induced by the reduced environmental glutamate concentration upon infection. Furthermore, we found that the amount of glutathione within the DeltagltT DeltagltM mutant was much lower than that within the wild-type N. meningitidis strain only upon HBMEC infection and was correlated with intracellular survival. Considering that the L-glutamate obtained via GltT-GltM is utilized as a nutrient in host cells, l-glutamate uptake via GltT-GltM plays multiple roles in N. meningitidis internalization into HBMEC. PMID- 26099589 TI - Platelet-Dependent Neutrophil Function Is Dysregulated by M Protein from Streptococcus pyogenes. AB - Platelets are rapidly responsive sentinel cells that patrol the bloodstream and contribute to the host response to infection. Platelets have been reported to form heterotypic aggregates with leukocytes and may modulate their function. Here, we have investigated platelet-neutrophil complex formation and neutrophil function in response to distinct agonists. The endogenous platelet activator thrombin gave rise to platelet-dependent neutrophil activation, resulting in enhanced phagocytosis and bacterial killing. Streptococcus pyogenes is an important causative agent of severe infectious disease, which can manifest as sepsis and septic shock. M1 protein from S. pyogenes also mediated platelet neutrophil complex formation; however, these neutrophils were dysfunctional and exhibited diminished chemotactic ability and bacterial killing. This reveals an important agonist-dependent neutrophil dysfunction during platelet-neutrophil complex formation and highlights the role of platelets during the immune response to streptococcal infection. PMID- 26099590 TI - Moraxella catarrhalis Binds Plasminogen To Evade Host Innate Immunity. AB - Several bacterial species recruit the complement regulators C4b-binding protein, factor H, and vitronectin, resulting in resistance against the bactericidal activity of human serum. It was recently demonstrated that bacteria also bind plasminogen, which is converted to plasmin that degrades C3b and C5. In this study, we found that a series of clinical isolates (n = 58) of the respiratory pathogen Moraxella catarrhalis, which is commonly isolated from preschool children and adults with chronic obstructive pulmonary disease (COPD), significantly binds human plasminogen. Ubiquitous surface protein A2 (UspA2) and hybrid UspA2 (UspA2H) were identified as the plasminogen-binding factors in the outer membrane proteome of Moraxella. Furthermore, expression of a series of truncated recombinant UspA2 and UspA2H proteins followed by a detailed analysis of protein-protein interactions suggested that the N-terminal head domains bound to the kringle domains of plasminogen. The binding affinity constant (KD) values of full-length UspA2(30-539) (amino acids 30 to 539 of UspA2) and full-length UspA2H(50-720) for immobilized plasminogen were 4.8 * 10(-8) M and 3.13 * 10(-8) M, respectively, as measured by biolayer interferometry. Plasminogen bound to intact M. catarrhalis or to recombinant UspA2/UspA2H was readily accessible for a urokinase plasminogen activator that converted the zymogen into active plasmin, as verified by the specific substrate S-2251 and a degradation assay with fibrinogen. Importantly, plasmin bound at the bacterial surface also degraded C3b and C5, which consequently may contribute to reduced bacterial killing. Our findings suggest that binding of plasminogen to M. catarrhalis may lead to increased virulence and, hence, more efficient colonization of the host. PMID- 26099592 TI - More on the danger of inhaling air at reduced fresh gas flows: a self-experiment. PMID- 26099591 TI - In Vivo and Ex Vivo Imaging Reveals a Long-Lasting Chlamydial Infection in the Mouse Gastrointestinal Tract following Genital Tract Inoculation. AB - Intravaginal infection with Chlamydia muridarum in mice can ascend to the upper genital tract, resulting in hydrosalpinx, a pathological hallmark for tubal infertility in women infected with C. trachomatis. Here, we utilized in vivo imaging of C. muridarum infection in mice following an intravaginal inoculation and confirmed the rapid ascent of the chlamydial organisms from the lower to upper genital tracts. Unexpectedly, the C. muridarum-derived signal was still detectable in the abdominal area 100 days after inoculation. Ex vivo imaging of the mouse organs revealed that the long-lasting presence of the chlamydial signal was restricted to the gastrointestinal (GI) tract, which was validated by directly measuring the chlamydial live organisms and genomes in the same organs. The C. muridarum organisms spreading from the genital to the GI tracts were detected in different mouse strains and appeared to be independent of oral or rectal routes. Mice prevented from orally taking up excretions also developed the long-lasting GI tract infection. Inoculation of C. muridarum directly into the upper genital tract, which resulted in a delayed vaginal shedding of live organisms, accelerated the chlamydial spreading to the GI tract. Thus, we have demonstrated that the genital tract chlamydial organisms may use a systemic route to spread to and establish a long-lasting infection in the GI tract. The significance of the chlamydial spreading from the genital to GI tracts is discussed. PMID- 26099593 TI - [Which diagnostics should be used to clarify persistent, newly occurring cardiac complaints in outpatient treatment?]. PMID- 26099594 TI - Role of augmented transferrin during the retraining for undeveloped left ventricle. AB - Transposition of great arteries (TGA) is a common congenital heart disease. Left ventricle (LV) is rapidly regressing and pulmonary artery banding (PAB) is utilized to retrain the undeveloped LV. Hence, it offered a unique human disease model to investigate the process of LV hypertrophy under pressure overload. Eight late referred children with TGA were enrolled. The plasma was collected at the 30 min. before and 48 hrs after PAB, and 25 proteins were identified as having significant change in proteomic analysis. Transferrin (TF) and ceruloplasmin were then confirmed. After 48 hrs incubation with TF, the size of human induced pluripotent stem cell-derived cardiomyocytes increased by two times as large as control. Meanwhile, protein synthesis and the expression of natriuretic peptide precursor A and B were significantly enhanced. TF treatment also activated both extracellular signal-regulated kinase 1/2 and activated protein kinase singling pathways. Our data provided a link to molecular components and pathways that might be involved in LV retraining. TF severed as the carrier to delivery irons, and could directly stimulate cardiomyocytes hypertrophy. TF administration may hold therapeutic potential for the biological LV retraining. PMID- 26099595 TI - Toxicological assessment of hospital wastewater in different treatment processes. AB - This study surveyed the hospital wastewater characters focusing on antibiotic contamination in seven hospitals in Bangkok. It detected 19 antibiotics of which the high-frequent detection were quinolones such as ofloxacin + levofloxacin, norfloxacin, ciprofloxacin including sulfamethoxazole. Norfloxacin and ciprofloxacin appeared the highest concentrations of 12.11 and 9.60 MUg/L, respectively. Most antibiotic concentrations in the wastewaters of the studied hospitals gave a good correlation (r 2 = 0.77-0.99) to the amount of usage. In this study, batch acute toxicity tests were performed to assess the toxicity of hospital wastewater on mixed liquor, freshwater algae (Chlorella vulgaris and Scenedesmus quadricauda), and microcrustacean (Moina macrocopa). The hospital wastewaters could inhibit the mixed liquor growth and gave similar toxic levels among test species: algae and microcrustacean (9.81-13.63 and 2.62-3.09 TU, respectively). The conventional activated sludge (CAS) and rotating biological contactor (RBC) could remove fluoroquinolones and tetracycline via biomass adsorption. After treatment, most of treatment could reduce the toxicity. Nevertheless, the effluent gave slight toxicity on some test species which might be caused from chlorination and a common toxicant (NH3-N). PMID- 26099596 TI - Differential determination of plasticizers and organophosphorus flame retardants in residential indoor air in Japan. AB - A variety of chemicals have been used in a wide range of indoor materials, such as wallpaper and furniture, and some of them are released into the indoor air. The level of consumption as well as the diversity of these chemicals has been increasing. The particle size of the materials in the air is known to affect the depth of human exposure, e.g., particles >10 MUm can only reach the nasal cavity, whereas particles 2.5-10 MUm can reach the respiratory tract and particles <2.5 MUm can reach the bottom of the lungs. However, information on the concentrations and form of these chemicals in indoor air is very limited. In this study, we measured 54 compounds, including plasticizers (phthalates, adipates, and others) and organophosphorus flame retardants, in indoor air samples from the living rooms of 21 dwellings in 11 prefectures across Japan. For sampling, we used a four-stage air sampler (multi-nozzle cascade impactor) equipped with three quartz fiber filters to capture chemical particulates in three size ranges (<2.5, 2.5 10, and >10 MUm) and a C18 solid-phase extraction disk to capture chemicals that exist in a gas phase in indoor air. Each of the chemicals in the three particulate phases and single gas phase was extracted by acetone and measured separately using GC/MS. Of the 54 compounds tested, 37 were detected in the indoor air samples. The highest concentration observed was that of 2-ethyl-1 hexanol (5.1 MUg/m3), which was detected in samples from all 21 houses. The 37 compounds were captured in the four fractions at different rates roughly based on their molecular sizes. Compounds with a smaller molecular size were commonly detected as a gas phase, whereas compounds with a larger molecular size were detected as one or more of the three particulate phases in the indoor air samples. Among the three particulate phases, many of the compounds were detected from the filter capturing the smallest (<2.5 MUm) particles. Therefore, these results suggest that the chemicals measured in this study might penetrate deeply into the lungs as many of them tend to exist as a gas and/or as particles smaller than 2.5 MUm. PMID- 26099597 TI - Integrating ecotoxicity and chemical approaches to compare the effects of ZnO nanoparticles, ZnO bulk, and ZnCl2 on plants and microorganisms in a natural soil. AB - This work compared the toxicity of ZnO nanoparticles (ZnO-NPs), ZnO bulk, and ZnCl2 on microbial activity (C and N transformations and dehydrogenase and phosphatase activities) and their uptake and toxic effects (emergence, root elongation, and shoot growth) on three plant species namely wheat, radish, and vetch in a natural soil at 1000 mg Zn kg(-1). Additionally, plants were also tested at 250 mg Zn kg(-1). The effects of the chemical species on Zn extractability in soil were studied by performing single and sequential extractions. ZnCl2-1000 presented the highest toxicity for both taxonomic groups. For microorganisms, ZnO-NPs demonstrated adverse effects on all measured parameters, except on N transformations. The effects of both ZnO forms were similar. For plants, ZnO-NPs affected the growth of more plant species than ZnO bulk, although the effects were small in all cases. Regarding accumulation, the total Zn amounts were higher in plants exposed to ZnO-NP than those exposed to ZnO bulk, except for vetch shoots. The soil sequential extraction revealed that the Zn concentration in the most labile forms (water soluble (WS) and exchangeable (EX)) was similar in soil treated with ZnO (NP and bulk) and lower than that of ZnCl2-treated soil, indicating the higher availability of the ionic forms. The strong correlations obtained between WS-Zn fraction and the Zn concentrations in the roots, shoots, and the effects on shoot weight show the suitability of this soil extraction method for predicting bioavailable Zn soil for the three plant species when it was added as ZnO-NPs, ZnO bulk, or ZnCl2. In this work, the hazard associated with the ZnO-NPs was similar to ZnO bulk in most cases. PMID- 26099598 TI - A reactive transport model for mercury fate in contaminated soil--sensitivity analysis. AB - We present a sensitivity analysis of a reactive transport model of mercury (Hg) fate in contaminated soil systems. The one-dimensional model, presented in Leterme et al. (2014), couples water flow in variably saturated conditions with Hg physico-chemical reactions. The sensitivity of Hg leaching and volatilisation to parameter uncertainty is examined using the elementary effect method. A test case is built using a hypothetical 1-m depth sandy soil and a 50-year time series of daily precipitation and evapotranspiration. Hg anthropogenic contamination is simulated in the topsoil by separately considering three different sources: cinnabar, non-aqueous phase liquid and aqueous mercuric chloride. The model sensitivity to a set of 13 input parameters is assessed, using three different model outputs (volatilized Hg, leached Hg, Hg still present in the contaminated soil horizon). Results show that dissolved organic matter (DOM) concentration in soil solution and the binding constant to DOM thiol groups are critical parameters, as well as parameters related to Hg sorption to humic and fulvic acids in solid organic matter. Initial Hg concentration is also identified as a sensitive parameter. The sensitivity analysis also brings out non-monotonic model behaviour for certain parameters. PMID- 26099599 TI - Numerical study of a buoyant plume from a multi-flue stack into a variable temperature gradient atmosphere. AB - Air pollution is one of the major global hazards and industries have been one of its major contributors. This paper primarily focuses on analyzing the dispersion characteristics of buoyant plumes of the pollutant released from a multi-flue vertical stack into a variable temperature gradient atmosphere (alpha) in a constant-velocity cross wind using two stack configurations-inline and parallel. The study is conducted for different Froude numbers, Fr = 12.64, 9.55, and 8.27. The atmospheric temperature gradients considered for the study are 0, +1, +1.5, and +2 K/100 m. The numerical study is done using the commercial computational fluid dynamics (CFD) code FLUENT. The effects of stack configuration, alpha, and Fr on the plume characteristics are presented. It is observed that the plume rises higher and disperses over a larger area with the inline configuration due to better mixing and shielding effect. With higher alpha, it is seen that the plume rises initially and then descends due to variation of the buoyant force. The plume rise initially is strongly influenced by the momentum of the jet, and as it moves downstream, it is influenced by the cooling rate of the plume. Furthermore, the plume rises higher and disperses over a larger area with a decrease in Fr. PMID- 26099600 TI - Study of peripheral blood multidrug resistance-associated protein 1 expression of children intractable epilepsy. AB - BACKGROUND: The aim of this study was to analyze multidrug resistance-associated protein 1 (MRP1) expression of peripheral blood of children intractable epilepsy. METHODS: Sixty children with epilepsy admitted to outpatient and inpatient services of Xuzhou Children's Hospital between November 2010 and October 2011 were divided into a refractory epilepsy group and a drug-controlled epilepsy group, with 30 cases each. Thirty healthy children who went to the hospital in the same year for health examination were enrolled as a control group. Reverse transcriptase polymerase chain reaction and Western blot method were used to determine peripheral blood MRP1 level, mRNA, and protein content of the 3 groups. RESULTS: MRP1 expression in the refractory epilepsy group was significantly higher than those of the epilepsy group with good drug control and of the control group. All differences had statistical significance (P<0.05), except for the comparison between the drug-controlled epilepsy group and the control group (P>0.05). CONCLUSIONS: Peripheral blood MRP1 expression in patients with refractory epilepsy increases. PMID- 26099601 TI - Technical considerations and precautions in in situ bronchoalveolar lavage and alveolar infiltrating cells isolation in rats. AB - OBJECTIVE: Bronchoalveolar lavage fluid (BALF) is an important tool in experimental toxicology and pharmacology. A number of researchers have utilized BAL in studies involving rodents. However, the detailed procedure of performing BAL in rodents has rarely been reported. In the present article, in situ BAL in rats has been described with technical points that ensure the quality and validity of BALF samples. MATERIALS AND METHODS: BAL was performed in rats of Wistar strain. Flow cytometry and microscopy were utilized to analyze the BAL cells. RESULTS AND DISCUSSION: The collected volume of BALF was 84.32 +/- 2.7% of instilled volume. Alveolar macrophages were found to be prevalent in normal lungs when analyzed under microscope and by flow cytometry. The main problem that one may face is the accidental contamination of BALF samples with blood of the animal itself. Presence of blood in BALF certainly adds a significant number of cells and other biochemical variables. No blood contamination was detected in BALF. CONCLUSION: Here, a simple procedure for BAL and collection of alveolar cells (macrophages in the present study) is explained with an emphasis on technical steps and precautions, which ensures the quality of the BALF samples. Data exhibit that there is no blood contamination in the BALF and provide evidence that the technical points considered in the procedure here are successful in maintaining the quality and validity of BALF samples. PMID- 26099602 TI - Superantigen staphylococcal enterotoxin C1 mutant can reduce paraquat pulmonary fibrosis. AB - A network of inflammation factors is related to pulmonary fibrosis induced by paraquat (PQ) poisoning. At high doses, the superantigen staphylococcal enterotoxin C1 (SEC1) can induce immunological unresponsiveness and inhibit release of inflammation factors. In this study, site-directed mutagenesis was performed at the H118 and H122 amino acid residues of SEC1 to reduce SEC1 toxicity. The SEC1 mutant showed significantly decreased pyrogenic toxicity, but retained clonal anergy at high dosages in vitro. Pretreatment with the SEC1 mutant prior to PQ poisoning in mice reduced symptom duration and severity, prolonged survival time, and decreased the splenocyte response to ConA induction. The SEC1 mutant also down-regulated several important cytokines related to fibrosis in the plasma after PQ poisoning. SEC1 decreased the expression of genes related to pulmonary fibrosis, including alpha-SMA, COL1a1, COL3 and TGF-beta1, in PQ poisoned mice. Histomorphological observation indicated alleviation of pathological changes in the lungs after SEC1 pretreatment compared to mice in the PQ group. In conclusion, the SEC1 mutant reduced pulmonary interstitial fibrosis induced by PQ poisoning. PMID- 26099603 TI - Efficacy and safety of etoricoxib compared with NSAIDs in acute gout: a systematic review and a meta-analysis. AB - The aim is to study the efficacy and safety of etoricoxib in the treatment of acute gout, as compared with non-steroidal anti-inflammatory drugs (NSAIDs). We conducted a computerized search of electronic databases: PubMed, EMBASE, Web of Science, China Biology Medicine disc, and Cochrane Library. The search terms were as follows: gout arthritis, tophus, etoricoxib, indometacin naproxen, diclofenac, and NSAIDs. Articles were searched from 1983 until August 2014. A manual search of peer-reviewed English documents was performed by cross-checking the bibliographies of selected studies. These trials reported pain relief as the primary outcome. Tenderness, swelling, patients' global assessments of response to treatment, and investigators' global assessments of response to treatment were reported as the secondary outcomes. All adverse events were recorded for safety assessment. Six trials including 851 patients were identified. Both etoricoxib and NSAIDs had an effect on inflammation and analgesia. Compared with indometacin and diclofenac, etoricoxib had a lower incidence of adverse events. Etoricoxib 120 mg administered orally once daily has the same efficacy on acute gout as indometacin and diclofenac. Etoricoxib is tolerated better by patients than NSAIDs such as indometacin and diclofenac. PMID- 26099605 TI - Engineering targeted chromosomal amplifications in human breast epithelial cells. AB - Chromosomal amplifications are among the most common genetic alterations found in human cancers. However, experimental systems to study the processes that lead to specific, recurrent amplification events in human cancers are lacking. Moreover, some common amplifications, such as that at 8p11-12 in breast cancer, harbor multiple driver oncogenes, which are poorly modeled by conventional overexpression approaches. We sought to develop an experimental system to model recurrent chromosomal amplification events in human cell lines. Our strategy is to use homologous-recombination-mediated gene targeting to deliver a dominantly selectable, amplifiable marker to a specified chromosomal location. We used adeno associated virus vectors to target human MCF-7 breast cancer cells at the ZNF703 locus, in the recurrent 8p11-12 amplicon, using the E. coli inosine monophosphate dehydrogenase (IMPDH) enzyme as a marker. We applied selective pressure using IMPDH inhibitors. Surviving clones were found to have increased copy number of ZNF703 (average 2.5-fold increase) by droplet digital PCR and FISH. Genome-wide array comparative genomic hybridization confirmed that amplifications had occurred on the short arm of chromosome 8, without changes on 8q or other chromosomes. Patterns of amplification were variable and similar to those seen in primary human breast cancers, including "sawtooth" patterns, distal copy number loss, and large continuous regions of copy number gain. This system will allow study of the cis- and trans-acting factors that are permissive for chromosomal amplification and provide a model to analyze oncogene cooperativity in amplifications harboring multiple candidate driver genes. PMID- 26099604 TI - Rheumatologic emergencies. AB - Rheumatological conditions can sometimes present as emergencies. These can occur due to the disease process or infection; contrary to what many people think, rheumatologic emergencies like a pain, rheumatic crisis, or attack gout do not compromise the patient's life. This article mentioned only true emergencies: catastrophic antiphospholipid syndrome (cAPS), kidney-lung syndrome, central nervous system (CNS) vasculitis, anti-Ro syndrome (neonatal lupus), and macrophage activation syndrome (MAS). The management of above emergencies includes critical care, immunosuppression when indicated, and use of a diagnostic flowchart as well as fast laboratory profile for making decisions. Anticoagulants have to be used in the management of antiphospholipid syndrome. A good understanding of these conditions is of paramount importance for proper management. PMID- 26099606 TI - Clinical relevance of the deregulated kallikrein-related peptidase 8 mRNA expression in breast cancer: a novel independent indicator of disease-free survival. AB - Examining for new BC biomarkers has proven that kallikrein-related peptidase (KLK) family members represent promising serum and/or tissue molecular tools for early diagnosis, effective prognosis, and treatment monitoring of patients. The aim of this study was to investigate, the previously unexplored, prognostic significance of KLK8 in BC. KLK8 mRNA expression was quantitatively analyzed in 150 cancerous and 100 corresponding normal breast tissue specimens via a SYBR Green-based Real-Time PCR methodology. Expression data and patients' clinicopathological parameters were used for extensive biostatistical analyses, including internal validation. KLK8 mRNA expression was significantly downregulated in the cancerous tissue part relative to the non-cancerous counterpart (P < 0.001), in the majority of the paired breast tissue samples. KLK8 expression was associated with advanced TNM stage (P = 0.019) and positive nodal status involvement (P = 0.044). Triple negative (TNBC) and HER2 overexpressing tumors exhibited higher KLK8 expression levels (P < 0.001), compared to Luminal A and B molecular subtypes. Kaplan-Meier survival curve analysis revealed that BC patients with high KLK8 expression had significantly shorter disease-free survival (DFS) intervals (P < 0.001) compared to those belonging in the KLK8-low expression group. Cox univariate analysis confirmed the association between KLK8 expression, analyzed as a continuous variable, and poor patients' outcome (Hazard ratio [HR] = 3.28, P < 0.001). Most importantly, multivariate analysis showed that KLK8 expression is a strong and independent predictor of adverse DFS in BC ([HR] = 2.74; P = 0.002). Our results show that KLK8 mRNA expression is associated with aggressive tumor characteristics and it can serve as a novel independent biomarker of unfavorable prognosis for BC patients. PMID- 26099607 TI - Effect of the saturation pulse duration on chemical exchange saturation transfer in amide proton transfer MR imaging: a phantom study. AB - Amide proton transfer (APT) contrast imaging is based on the chemical exchange saturation transfer (CEST) of protons between the amide groups and bulk water. Here, we demonstrate the effect of the saturation pulse duration on CEST in APT imaging with use of a clinical MR scanner. Four samples were prepared from chicken egg white diluted with H2O. Experiments were performed on a 3T clinical MR scanner with use of a body coil for two-channel parallel radiofrequency transmission. APT images were acquired at six frequency offsets (+/- 3.0, +/- 3.5, +/- 4.0 ppm) with respect to the water resonance as well as one far off resonant frequency (-160 ppm) for signal normalization. The CEST effect was defined as asymmetry of the magnetization transfer ratio at 3.5 ppm. We measured the CEST effects in the egg white samples with different concentrations at seven saturation pulse durations. The influence of the extension of repetition time (TR) on the CEST effect was also evaluated. The CEST effect was not influenced by the change in TR. The CEST effect was increased significantly with the concentration when the duration was >=1.0 s (P < 0.01). The CEST effect was highly correlated with the concentration at all saturation pulse durations, and its increase ratio was higher at longer saturation pulse durations. In conclusion, a long saturation pulse duration is useful for the sensitive detection of mobile proteins and peptides in APT imaging. PMID- 26099608 TI - [Toxoplasmosis in immunocompromised patients]. AB - In humans, toxoplasmosis mostly occurs as a latent infection, but in immunocompromised individuals, the agent may reactivate and cause severe to life threatening disease. HIV positive individuals and transplant recipients, in particular hematopoietic stem cell transplant and heart transplant recipients, are at highest risk. The disease most often affects the central nervous system but can involve any organ. Because of the alteration of the immune response in these patients, the serodiagnosis is not reliable and direct detection of the causative agent is needed--namely by microscopy and DNA PCR. If inadequately treated or left untreated, toxoplasmosis generally has a fatal prognosis in immunocompromised patients and therefore, the treatment must be started as early and energetically as possible. The gold standard both in the treatment of reactivation and secondary prophylaxis is the pyrimethamine-sulfadiazine combination while co-trimoxazole can be used in the primary prophylaxis for high risk patients. PMID- 26099609 TI - [The possibilities of zoonotic transmission of rotaviruses]. AB - Rotaviruses are significant enteric pathogens of humans and animals. Rotavirus associated mortality is still high in children, especially in developing countries. Rotaviruses also account for important economic losses due to gastrointestinal disease of livestock animals, notably of young cattle and pigs. Increasing numbers of different rotavirus strains stress the necessity of their uniform nomenclature and detailed classification with the use of whole-genome sequencing. Phylogenetic analyses of the rotavirus genome reveal repeated intersections between the evolution of human and animal rotavirus strains which is probably a consequence of multiple events of transmission among various animal species. The interspecies transmission and subsequent gene reassortment are important mechanisms driving the diversity of rotaviruses and enabling the emergence of new pathogenic strains. PMID- 26099610 TI - [Hepatitis E--overview of the latest knowledge]. AB - Hepatitis E (HE) is a ubiquitous infection, occurring both in developing and in developed countries. It is caused by the hepatitis E virus (HEV), a small, non enveloped RNA virus. The reported incidence in the Czech Republic in 2013 was 2 cases per 100,000 inhabitants and the number of HE cases has been growing over the past years. Besides the long known fecal-oral transmission, zoonotic and blood product transmission of HEV has recently been observed in industrialized countries. Most infections are asymptomatic. Symptomatic infection may present as acute hepatitis with nonspecific flu-like symptoms and liver enzymes elevation. In immunocompromised patients, HEV can lead to chronic hepatitis E and can even cause acute liver failure in pregnant women. Several extrahepatic manifestations have also been reported. Antiviral therapy has been successfully used in chronic hepatitis E. The first vaccine available for clinical use is licensed in China so far. PMID- 26099611 TI - [West Nile virus transmission risk in the Czech Republic]. AB - West Nile Virus (WNV) belongs to the family Flaviviridae. It is transmitted to humans by mosquitoes, capable of sucking blood on birds and mammals, most often by mosquitoes of the genus Culex. In humans, the virus was first identified in 1937 in the West Nile region, Uganda, Africa. Later, the virus spread and caused more or less severe epidemics of West Nile fever in North Africa, Europe, Asia, and North and South America. During the last two decades, WNV has been on the rise and is currently ranked as one of the most prevalent arboviruses in the world. In humans, WNV infection mostly occurs as asymptomatic, but may have a more severe or even fatal course in older and weakened patients. Humans may become infected not only by mosquitoes that acquire the virus from infected birds, but also through a blood transfusion, organ transplant, breast milk and transplacental transmission, or contact with infected animals, their blood, and tissues. The first autochthonous human case of West Nile fever in the Czech Republic was reported from South Moravia in 1997. In 2013, another case of West Nile fever emerged in this country, in the Ostrava area. The issue of WNV has recently been studied from many different perspectives, as evidenced by many original and review papers. This article briefly reviews the essential knowledge about this virus and its spread. PMID- 26099612 TI - Prevalence study on carbapenemase-producing Escherichia coli and Klebsiella pneumoniae isolates in Czech hospitals--results from Czech Part of European Survey on Carbapenemase--Producing Enterobacteriaceae (EuSCAPE). AB - OBJECTIVE: One of the most important threats of current medicine is the spread of multiresistant Gram-negative bacteria. We report here data from a six-month prevalence study on carbapenemase-producing K. pneumoniae and E. coli performed in Czech hospitals participating on European Survey on Carbapenemase-Producing Enterobacteriaceae (EuSCAPE). METHODS: Ten hospitals covering all regions of the Czech Republic were selected. During the study period (1st November 2013 to 30th April 2014), first ten carbapenem non-susceptible isolates of K. pneumoniae or E. coli isolated from non-surveillance specimens (i.e., blood, lower respiratory tract secretions, urine, puncture fluids, and wound secretions) of single successive patients were collected. Successive carbapenem-susceptible isolates of the same species were also preserved as controls. Susceptibility to 15 antibiotics was determined using EUCAST recommendations. Carbapenemase activity was detected by MALDI-TOF MS meropenem hydrolysis assay. Positive isolates were subjected for molecular typing (multi-locus sequence typing, identification of carbapenemase gene). RESULTS: During the study period, thirty non-susceptible isolates (K. pneumoniae n=28, E. coli n=2) were identified in 5 hospitals. Only two of them were confirmed to be carbapenemase producers. A NDM-1-producing K. pneumoniae ST11 was recovered from a patient, transferred from Ukraine, being injured during a Maidan revolution. The second isolate, an OXA-48-producing K. pneumoniae, belonging to ST101, was recovered from a patient admitted to a hospital for an ischemic stroke. CONCLUSIONS: This study again confirmed that the Czech Republic still belongs to the countries with low prevalence of carbapenemase-producing Enterobacteriaceae (CPE). Cases of CPE are usually restricted to an import from high-prevalence countries or countries with unknown epidemiological situation. PMID- 26099613 TI - [Diagnosis of infections caused by Clostridium difficile in the Czech Republic: availability, possibilities, and interpretation of laboratory results]. AB - OBJECTIVE: To assess the availability of the laboratory diagnosis of infections caused by C. difficile in the Czech Republic (CR), including the range of tests used, possible combinations, and adequate interpretation of model results. MATERIAL AND METHODS: Data were collected through a web questionnaire survey with the participation of representatives of 61 public and private microbiological laboratories. The questionnaire addressed the use of diagnostic test kits and culture media in the diagnosis of C. difficile infection (CDI). In addition, the respondents were asked to interpret a glutamate dehydrogenase (GDH) positive and, at the same time, toxin A/B negative result, without or with laboratory confirmation if available. RESULTS: In the CR, the most commonly used test in the diagnosis of CDI is the C. DIFF Quik Chek Complete(r) test (Alere) for the detection of GDH and A/B toxins, as reported by 50 (82%) laboratories. Anaerobic culture is performed by 43 (70.5%) laboratories, 21 (48.8%) of which use selective agar (Oxoid). Direct detection of DNA of toxigenic C. difficile is feasible in 17 (27.9%) laboratories, with most of them (15 laboratories) using the closed system Xpert(r) C. difficile (Cepheid). The diagnosis based only on the detection of GDH and A/B toxins is used by 13 (21.3%) laboratories. Two (3.3%) laboratories detect A/B toxins alone and three (4.9%) laboratories carry out the detection of A/B toxins followed by anaerobic culture. A three step scheme: detection of GDH and A/B toxins with subsequent anaerobic culture is used by 26 (42.6%) laboratories. The detection of GDH and A/B toxins along with a PCR assay are provided by three (4.9%) laboratories. A complete diagnostic scheme for CDI (detection of GDH and A/B toxins, direct detection of DNA, and aerobic culture) is feasible in 14 (23%) laboratories. CONCLUSION: This questionnaire survey study identified 24 different testing algorithms to be in use within the study period (April to July 2014) in the CR. Five (8.2%) laboratories have no highly sensitive screening test such as the detection of GDH or nucleic acid amplification test (NAAT) included in their testing algorithm. Thirteen (21.3%) laboratories perform the detection of GDH and A/B toxins but have no confirmation method to be used if only one test turns out positive. In the case of GDH positivity and A/B toxin negativity, the result should be provided with a supplementary comment on further possibilities for the laboratory detection of CDI and the claimed sensitivity of the test used. If no confirmation test is available, the result should be considered as epidemiologically and clinically significant, once other possible causes of diarrhoea are ruled out. PMID- 26099614 TI - [The prevalence of nasal carriage of Staphylococcus aureus aureus and methicillin resistant S. aureus (MRSA) among general medicine students of the Palacky University Olomouc]. AB - INTRODUCTION: Staphylococcus aureus is one of the major agents of both healthcare and community-associated infections. Nasal carriage of S. aureus has been reported in approximately 37% of healthy persons. OBJECTIVES: 1. To investigate the prevalence of nasal carriage of S. aureus and MRSA in healthy persons of the age group 18-26 years (general medicine students of the Palacky University Olomouc). This type of information is not available in the Czech Republic. 2. To find whether the prevalence of nasal carriage strains of S. aureus and MRSA varies over the years of studies. 3. To compare the Year 1 (baseline) and Year 5 (after a long, close contact with the indoor environment of health-care facilities) general medicine students for nasal carriage of S. aureus and MRSA strains. MATERIALS AND METHODS: The prevalence study was conducted for over 12 months in 2012 and 2013. Nasal swabs were taken from the general medicine students participating in the study. Each subject was sampled once. RESULTS: In total, 307 samples were collected: 206 samples from the Year 1 students and 101 from the Year 5 students. Sixty-one (about 32%) Year 1 students and 32 (30%) Year 5 students were positive for S. aureus. Of them, 94 (30.6%) were males and 213 (69.4%) were females. CONCLUSIONS: The observed prevalence of nasal S. aureus carriage is consistent with the literature data. No statistically significant difference in the prevalence of nasal carriage of S. aureus was found between the Year 1 and Year 5 general medicine students. PMID- 26099615 TI - [Enterovirus sequencing as a new approach to the laboratory diagnosis for clinical and epidemiological purposes]. AB - OBJECTIVE: Introducing enterovirus sequencing as an advanced approach to classify the viruses isolated according to the novel nomenclature and to characterize isolates in detail. MATERIAL AND METHODS: Seventy-five specimens collected from 64 patients in two hospitals, Liberec Regional Hospital, and Plzen University Hospital, were analyzed. The study patients' age ranged from four to 54 years, with a median of 15 years in males and 16 years in females. In most patients, the reasons for admission were intense headache, fever, vomiting, tiredness, meningeal symptoms, intestinal symptoms (in two patients), and skin symptoms (in one patient). The specimens collected were rectal and throat swabs, cerebrospinal fluid (CSF) and stool specimens. Molecular detection and typing were performed using the RT-PCR method. A segment of the 5'non-coding RNA was selected for typing. Specimens were amplified using single-step PCR with external primers and with the same primers extended to include M13 sequences (Generi-Biotech). The LASERGENE software (DIASTAR) was used in sequence editing, alignment, and quality check. The sequences obtained were checked against the central GenBank sequence database using the BLAST algorithm. RESULTS: The identification of the study isolates resulted in 61 ECHO viruses 30, three coxsackie viruses B1, one coxsackie virus B3, one coxsackie virus A9, one enterovirus 86, one enterovirus 71, Two ECHO viruses 13/coxsackie virus B5, one ECHO virus 7/30/coxsackie virus B4, one coxsackie virus B4/enterovirus B, one enterovirus 87/ECHO virus 30/enterovirus B, and one ECHO virus 3. All viruses isolated, except enterovirus 71 classified into group A, were of group B. CONCLUSION: The enteroviruses were identified unambigously, although the sequencing only targeted a short, conserved segment that showed considerable variability. The sequencing was an effective alternative to enterovirus identification by the neutralisation test and allowed for detailed characterization of the isolates. The predominance of ECHO 30 as the cause of aseptic meningitis is in accordance with the literature data. PMID- 26099616 TI - Electromagnetic organ tracking allows for real-time compensation of tissue shift in image-guided laparoscopic rectal surgery: results of a phantom study. AB - BACKGROUND: Laparoscopic resection is a minimally invasive treatment option for rectal cancer but requires highly experienced surgeons. Computer-aided technologies could help to improve safety and efficiency by visualizing risk structures during the procedure. The prerequisite for such an image guidance system is reliable intraoperative information on iatrogenic tissue shift. This could be achieved by intraoperative imaging, which is rarely available. Thus, the aim of the present study was to develop and validate a method for real-time deformation compensation using preoperative imaging and intraoperative electromagnetic tracking (EMT) of the rectum. METHODS: Three models were compared and evaluated for the compensation of tissue deformation. For model A, no compensation was performed. Model B moved the corresponding points rigidly to the motion of the EMT sensor. Model C used five nested linear regressions with increasing level of complexity to compute the deformation (C1-C5). For evaluation, 14 targets and an EMT organ sensor were fit into a silicone-molded rectum of the OpenHELP phantom. Following a computed tomography, the image guidance was initiated and the rectum was deformed in the same way as during surgery in a total of 14 experimental runs. The target registration error (TRE) was measured for all targets in different positions of the rectum. RESULTS: The mean TRE without correction (model A) was 32.8 +/- 20.8 mm, with only 19.6% of the measurements below 10 mm (80.4% above 10 mm). With correction, the mean TRE could be reduced using the rigid correction (model B) to 6.8 +/- 4.8 mm with 78.7% of the measurements being <10 mm. Using the most complex linear regression correction (model C5), the error could be reduced to 2.9 +/- 1.4 mm with 99.8% being below 10 mm. CONCLUSION: In laparoscopic rectal surgery, the combination of electromagnetic organ tracking and preoperative imaging is a promising approach to compensating for intraoperative tissue shift in real-time. PMID- 26099617 TI - 10 cm H2O PEEP application in laparoscopic surgery and cerebral oxygenation: a comparative study with INVOS and FORESIGHT. AB - INTRODUCTION: In the present study, changes in hemodynamic parameters and cerebral oxygen saturation (rSO2) associated with 10 cm H2O PEEP application were investigated, which is assumed beneficial for the respiratory functions and oxygenation during laparoscopic cholecystectomy (LC) applied at 30 degrees head up left side position. Data gathered via two devices, namely INVOS and FORESIGHT, were compared. METHODS: After both the ethics committee approval from the hospital and patients' written consents were obtained, patients undergoing elective laparoscopic surgery (only ASA I-II) were randomly divided into two groups (Clinical trials protocol NCT02071550). Sensors of INVOS and FORESIGHT devices were placed on the right side at the forehead region. In total, 11 evaluation periods were formed, namely pre-induction (1st period), post-induction (2nd period), abdominal insufflation outset (3rd period), post-insufflation at 5 min intervals (4th, 5th, 6th, 7th, and 8th period), at the end of insufflation (9th period), at the end of operation (10th period), and at the end of anesthesia (11th period). While one of the groups did not receive PEEP (ZEEP group), the other group received 10 cm H2O along with abdominal insufflation (PEEP group). Demographic data, hemodynamic values, and rSO2 values were recorded for both groups at all 11 periods. RESULTS: A total of 44 patients in two groups, each group containing 22 individuals, were included in the study. Systolic, diastolic, and mean arterial pressures, etCO2 and SO2 values, and demographic data were found to be similar in both groups. Heart rate was observed to be higher in the PEEP group starting with the PEEP administration. INVOS rSO2 values were found similar in both groups. However, FORESIGHT rSO2 values were found to be higher in the PEEP group compared to the ZEEP group. No patient had cerebral desaturation in both groups throughout the study. DISCUSSION: Application of PEEP with 10 cm H2O during abdominal insufflation could increase the rSO2 value and heart rate in patients undergoing laparoscopic cholecystectomy. However, all changes observed were within normal limits. FORESIGHT device yielded more compatible results with hemodynamic data compared to INVOS. PMID- 26099618 TI - Single-incision laparoscopic cholecystectomy with curved versus linear instruments assessed by systematic review and network meta-analysis of randomized trials. AB - BACKGROUND: Single-incision laparoscopic surgery poses significant ergonomic limitations. Curved instruments have been developed in order to address the issue of lack of triangulation. Direct comparison between single-incision laparoscopic surgeries with conventional linear and curved instruments has not been performed to date. METHODS: MEDLINE, CENTRAL and OpenGrey were searched to identify relevant randomized trials. A network meta-analysis was applied to compare operative risks, conversion, duration of surgery and the need for placement of an adjunct trocar in single-incision laparoscopic cholecystectomy with linear and curved instruments. The random-effects model was applied for two sets of comparisons, with conventional laparoscopic cholecystectomy as the reference treatment. Odds ratios, mean differences and 95% confidence intervals were calculated. RESULTS: Twenty-three randomized trials encompassing 1737 patients were included. The use of curved instruments was associated with increased operative time (mean difference 32.53 min, 95% CI 24.23-40.83) and higher odds for the use of an adjunct trocar (odds ratio 22.81, 95% CI 16.69-28.94) compared to the use of linear instruments. Perioperative risks could not be comparatively assessed due to the low number of events. CONCLUSION: Single-incision laparoscopic cholecystectomy with curved instruments may be associated with an increased level of operative difficulty, as reflected by the need for auxiliary measures for exposure and increased operative time as compared to the use of linear instruments. Current instrumentation requires further improvement, tailored to the features of single-incision laparoscopic surgery (CRD42015015721). PMID- 26099619 TI - A pilot functional MRI study in Roux-en-Y gastric bypass patients to study alteration in taste functions after surgery. AB - BACKGROUND: Gastric bypass restricts food intake, with a limited component of malabsorption. Gut and brain hormone changes also facilitate improvements in weight and comorbidities. Patients' perception of taste and smell also change, along with reduced appetite for savory meals. Data on how changes in gastrointestinal physiology affect brain centers of perception and reward are sparse. METHODS: With IRB approval, we recruited 13 patients to undergo pre- and postoperative taste testing and functional MRI (fMRI) in response to sweet and salty solutions. A delivery system to the tongue was used, and patients rated intensity and pleasantness. They then underwent fMRI scanning. Sensory and reward areas of the brain were evaluated for activation. Subjects were then compared to non-obese non-surgical controls with the same taste paradigm and scanning twice, at 1 month apart. RESULTS: All subjects experienced significant weight loss at 1 month and at 1 year after surgery. As expected, after surgery brain activation in the reward center of the brain was significantly decreased in response to sweet solutions, but this effect was also seen in non-surgical controls, making this result inconclusive. In contrast, surgical patients had significantly increased activation in the reward center to salty taste compared both to their preoperative scans and to healthy controls. CONCLUSIONS: After GBS, brain activation in the reward system of obese patients responding to palatable tastes may be significantly changed, and such changes can be detected using fMRI. They do not always correlate with subjective reports of intensity and pleasantness. To verify that such taste-related activation changes are caused specifically by the GBS, taste function of a control group of obese patients should be studied during the same period of time without GBS intervention but with similar weight loss. PMID- 26099620 TI - What errors make a laparoscopic cancer surgery unsafe? An ad hoc analysis of competency assessment in the National Training Programme for laparoscopic colorectal surgery in England. AB - BACKGROUND: The National Training Programme for laparoscopic colorectal surgery in England was implemented to ensure training was supervised, structured, safe and effective. Delegates were required to pass a competency assessment (sign-off) before undertaking independent practice. This study described the types of errors identified and associated these errors with competency to progress to independent laparoscopic colorectal practice. METHODS: All sign-off submissions from the start of the process in January 2008 until July 2013 were included. Content analysis was used to categorise errors. Bayes factor (BF) was used to measure the impact of individual error on assessment outcome. A smaller BF indicates that an error has stronger associations with unsuccessful assessments. Bayesian network was employed to graphically represent the reasoning process whereby the chance of successful assessment diminished with the identification of each error. Quality of the error feedback was measured by the area under the ROC curve which linked the predictions from the Bayesian model to the expert verdict. RESULTS: Among 370 assessments analysed, 240 passed and 130 failed. On average, 2.5 different types of error were identified in each assessment. Cases that were more likely to fail had three or more different types of error (chi(2) = 72, p < 0.0001) and demonstrated poorer technical skills (CAT score <2.7, chi(2) = 164, p < 0.0001). Case complexity or right- versus left-sided resection did not have a significant impact. Errors associated with dissection (BF = 0.18), anastomosis (BF = 0.23) and oncological quality (BF = 0.19) were critical determinants of surgical competence, each reducing the odds of pass by at least fourfold. The area under the ROC curve was 0.84. CONCLUSIONS: Errors associated with dissection, anastomosis and oncological quality were critical determinants of surgical competency. The detailed error analysis reported in this study can guide the design of future surgical education and clinical training programmes. PMID- 26099621 TI - Function of high-resolution manometry in the analysis of peroral endoscopic myotomy for achalasia. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) was introduced as a new effective therapeutic option for esophageal achalasia. METHOD: A total of 112 achalasia patients categorized into three subtypes by HRM who underwent POEM were enrolled in our study. Eckardt score and HRM were performed preoperation, 6 months, and 1 year after POEM to evaluate the effectiveness, safety, and feasibility of POEM and to investigate the treatment response to POEM for the three subtypes of achalasia, classified by high-resolution manometry (HRM). RESULTS: POEM was successfully performed in all patients. Compared with pre-POEM scores, the Eckardt scores were significantly reduced from 7.3 +/- 1.4 to 1.0 +/- 0.8 6 months after POEM and to 1.2 +/- 0.6 1 year after POEM (p < 0.05). The LESP before treatment was 41.8 +/- 15.3 mmHg, compared with a LESP of 18.4 +/- 7.1 mmHg 6 months after POEM and 20.7 +/- 7.5 mmHg 1 year after POEM (p < 0.05). In addition, POEM decreased the 4-s IRP from 33.4 +/- 9.0 to 14.6 +/- 3.8 mmHg 6 months after POEM and to 16.4 +/- 3.9 mmHg 1 year after POEM (p < 0.05). The 4-s IRP was reduced to <15 mmHg in 64 of 112 patients. Type II had the best response to POEM, while type III exhibited the worst response. CONCLUSIONS: POEM appears to be an effective and less invasive treatment for achalasia. HRM can be useful in the classification of achalasia, while these subclassifications help to predict the responsiveness to POEM. PMID- 26099622 TI - Early results of dual approach hernioplasty (DAH): an innovative laparoscopic inguinal hernioplasty technique. AB - BACKGROUND: In this study, the proposed technique is combining the invented method of extraperitoneal dissection utilizing gas insufflation through Veress needle introduced from the groin with the transabdominal approach. Such a combination minimizes operative demands, achieves major goals, and reduce operative time in an attempt to improve laparoscopic hernioplasty techniques. METHODS: The study recruited 211 patients having primary reducible inguinal hernia upon first diagnosis. Abdominal ultrasound examination achieved to exclude any additional pathology and confirming clinical diagnosis. The new technique is applied on all patients without any modification through the whole series. RESULTS: Patients' epidemiology, operative characteristics, and follow-up are all tabulated. Results showed no complications nor conversion to open procedure. CONCLUSIONS: The proposed procedure showed preliminary encouraging results regarding technique, clinical outcome, time-saving, and patients' safety. Combination of extraperitoneal gas-derived dissection, transabdominal field review, and preperitoneal mesh application offers an innovative and promising laparoscopic hernioplasty technique. The study is introducing the technique and as well invites further trials on wider scale to verify the technique. PMID- 26099623 TI - Investigations of the synergistic enhancement of antimicrobial activity in mixtures of magainin 2 and PGLa. AB - Magainins are antimicrobial peptides isolated from the African clawed frog Xenopus laevis. They interact with bacterial membranes where they cause channel formation and membrane disruption. When added as a cocktail magainin 2 and PGLa are considerably more efficient when compared to the corresponding amounts of individual components. In order to investigate this synergistic interaction of PGLa and magainin a number of magainin variants have been prepared and investigated in biological and biophysical assays. In particular we report on the antimicrobial activities and solid-state NMR investigations of magainins that have been extended by a carboxyterminal GGC tripeptide to form covalently linked dimers. Notably, when the formation of the covalent linkage is prevented by exchanging the cystein by serine or alanine no loss in efficiency was observed indicating that the covalent interaction is not necessary for synergistic interaction. In a next step peptides labelled with (15)N and (2)H were reconstituted into oriented membranes and their topology studied by solid-state NMR spectroscopy. The tendency of some of these peptides to adopt membrane spanning alignments does not correlate with their synergistic activities in antimicrobial assays. In contrast, the stable alignment of PGLa parallel to the surface of membranes made of Escherichia coli lipid extracts is strongly suggestive that the peptides develop synergistic activities when in an in-planar configuration. Notably, the phospholipid head groups of these samples show a high degree of disturbance suggesting that the synergistic interactions between the magainin peptides could be mediated through the lipid phase. PMID- 26099624 TI - Management of recurrent or metastatic endometrial cancer in Germany: results of the nationwide AGO pattern of care studies from the years 2013, 2009 and 2006. AB - PURPOSE: The available literature on the treatment options for recurrent or metastatic endometrial cancer (EC) is full of controversies. Therefore, we explore the results of the AGO pattern of care studies from the years 2013, 2009 and 2006. METHODS: A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009, 500 in 2006, respectively). The results of the questionnaires were compared with each other using Fisher's exact test. RESULTS: Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. In 2013 the most preferred endocrine drug was progestin (79.8 %), followed by tamoxifen (42.8 %), aromatase inhibitor (19.8 %), fulvestrant (16.3 %) and a combination (3.9 %) (p < 0.001). 65.3, 59.8, 51.7 and 38.2 % of the participants used platinum, taxane, a combination of cytostatic drugs, anthracycline in metastatic EC, respectively (p = 0.215). 96.2, 92.7, 49.8 and 60.9 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013 because of a local recurrence, respectively (p < 0.001). Compared to 2009 and 2006 these rates remained stable (no p value <0.05). Because of a distant metastasis 50.4, 64.2, 78.5 and 90.8 % of the participants performed an operation, radiotherapy, endocrine therapy and chemotherapy in 2013, respectively (p < 0.001). Compared to 2009 and 2006 more participants performed an operation or radiotherapy and less an endocrine treatment. CONCLUSIONS: Whereas progestin was the favorite drug, the participants of this study did not prefer a specific cytostatic drug for metastatic EC in 2013. This might have reflected the available literature, which did not provide a real standard of care. PMID- 26099625 TI - Could surgeon's expertise resolve the debate about surgery effectiveness in treatment of endometriosis-related infertility? PMID- 26099626 TI - Cost-Effectiveness of Dolutegravir in HIV-1 Treatment-Naive and Treatment Experienced Patients in Canada. AB - INTRODUCTION: The Antiretroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model was adapted to evaluate the cost-effectiveness of dolutegravir (DTG) in Canada in treatment-naive (TN) and treatment-experienced (TE) human immunodeficiency virus (HIV)-1 patients. METHODS: The ARAMIS-DTG model is a microsimulation model with a lifetime analytic time horizon and a monthly cycle length. Markov health states were defined by HIV health state (with or without opportunistic infection). DTG was compared to efavirenz (EFV), raltegravir (RAL), darunavir/ritonavir, rilpivirine (RPV), elvitegravir/cobicistat, atazanavir/ritonavir and lopinavir/ritonavir in TN patients and to RAL in TE patients. The initial cohort, the main efficacy data and safety data were derived from phase III clinical trials. Treatment algorithms were based on expert opinion. Costs normalized to the year 2013 included antiretroviral treatment cost, testing, adverse event, HIV and cardiovascular disease care and were derived from the literature. RESULTS: Dolutegravir was estimated to be the dominant strategy compared with all comparators in both TN and TE patients. Treatment with DTG was associated with additional quality-adjusted life-years that ranged from 0.17 (vs. RAL) to 0.47 (vs. EFV) in TN patients and was 0.60 in TE patients over a lifetime. Cost savings ranged from Can$1393 (vs. RPV) to Can$28,572 (vs. RAL) in TN patients and amounted to Can$3745 in TE patients. Sensitivity analyses demonstrated the robustness of the model. CONCLUSIONS: Dolutegravir is a dominant strategy in the management of TN and TE patients when compared to recommended comparators. This is mainly related to the high efficacy and high barrier to resistance. FUNDING: ViiV Healthcare. PMID- 26099627 TI - Is dementia research ready for big data approaches? AB - The "big data" paradigm has gained a lot of attention recently, in particular in those areas of biomedicine where we face clear unmet medical needs. Coined as a new paradigm for complex problem solving, big data approaches seem to open promising perspectives in particular for a better understanding of complex diseases such as Alzheimer's disease and other dementias. In this commentary, we will provide a brief overview on big data principles and the potential they may bring to dementia research, and - most importantly - we will do a reality check in order to provide an answer to the question of whether dementia research is ready for big data approaches. PMID- 26099629 TI - Lack of myeloid differentiation primary response protein MyD88 L265P mutation in primary cutaneous marginal zone lymphoma. PMID- 26099628 TI - Nigral overexpression of alpha-synuclein in the absence of parkin enhances alpha synuclein phosphorylation but does not modulate dopaminergic neurodegeneration. AB - BACKGROUND: Alpha-synuclein is a key protein in the pathogenesis of Parkinson's disease. Mutations in the parkin gene are the most common cause of early-onset autosomal recessive Parkinson's disease, probably through a loss-of-function mechanism. However, the molecular mechanism by which loss of parkin function leads to the development of the disease and the role of alpha-synuclein in parkin associated Parkinson's disease is still not elucidated. Conflicting results were reported about the effect of the absence of parkin on alpha-synuclein-mediated neurotoxicity using a transgenic approach. In this study, we investigated the effect of loss of parkin on alpha-synuclein neuropathology and toxicity in adult rodent brain using viral vectors. Therefore, we overexpressed human wild type alpha-synuclein in the substantia nigra of parkin knockout and wild type mice using two different doses of recombinant adeno-associated viral vectors. RESULTS: No difference was observed in nigral dopaminergic cell loss between the parkin knockout mice and wild type mice up to 16 weeks after viral vector injection. However, the level of alpha-synuclein phosphorylated at serine residue 129 in the substantia nigra was significantly increased in the parkin knockout mice compared to the wild type mice while the total expression level of alpha-synuclein was similar in both groups. The increased alpha-synuclein phosphorylation was confirmed in a parkin knockdown cell line. CONCLUSIONS: These findings support a functional relationship between parkin and alpha-synuclein phosphorylation in rodent brain. PMID- 26099630 TI - Association between 24-hour blood pressure variability and chronic kidney disease: a cross-sectional analysis of African Americans participating in the Jackson heart study. AB - BACKGROUND: Studies suggest 24-h blood pressure (BP) variability has prognostic value for cardiovascular disease. Several factors associated with high 24-h BP variability are also common among individuals with chronic kidney disease (CKD). We hypothesized 24-h BP variability would be higher for individuals with versus without CKD. METHODS: We analyzed 1,022 Jackson Heart Study participants who underwent ambulatory blood pressure monitoring (ABPM). Twenty-four hour BP variability was defined by two metrics: day-night standard deviation (SDdn) and average real variability (ARV). CKD was defined as ACR >= 30 mg/g or eGFR <60 mL/min/1.73 m(2). RESULTS: The mean SDdn of systolic BP (SBP) was 10.2 +/- 0.2 and 9.1 +/- 0.1 mmHg and the mean ARV of SBP was 9.2 +/- 0.2 and 8.6 +/- 0.1 mmHg for those with and without CKD, respectively (each p <= 0.001). After adjustment for age and sex, SDdn and ARV were 0.98 mmHg (95 % CI 0.59, 1.38) and 0.52 mmHg (95 % CI 0.18, 0.86), respectively, higher among participants with versus without CKD. These differences were not statistically significant after further multivariable adjustment including 24-h mean SBP. Older age, and higher total cholesterol and 24-h mean SBP were associated with higher SDdn and ARV of SBP among participants with CKD. Mean SDdn and ARV of diastolic BP (DBP) were higher for participants with versus without CKD but these associations were not present after multivariable adjustment. CONCLUSION: Data from the current study suggest that CKD is associated with higher 24-h BP variability, but the association is primarily explained by higher mean BP among those with CKD. PMID- 26099631 TI - Differential expression analysis of RNA sequencing data by incorporating non exonic mapped reads. AB - BACKGROUND: RNA sequencing (RNA-seq) is a powerful tool for genome-wide expression profiling of biological samples with the advantage of high-throughput and high resolution. There are many existing algorithms nowadays for quantifying expression levels and detecting differential gene expression, but none of them takes the misaligned reads that are mapped to non-exonic regions into account. We developed a novel algorithm, XBSeq, where a statistical model was established based on the assumption that observed signals are the convolution of true expression signals and sequencing noises. The mapped reads in non-exonic regions are considered as sequencing noises, which follows a Poisson distribution. Given measureable observed and noise signals from RNA-seq data, true expression signals, assuming governed by the negative binomial distribution, can be delineated and thus the accurate detection of differential expressed genes. RESULTS: We implemented our novel XBSeq algorithm and evaluated it by using a set of simulated expression datasets under different conditions, using a combination of negative binomial and Poisson distributions with parameters derived from real RNA-seq data. We compared the performance of our method with other commonly used differential expression analysis algorithms. We also evaluated the changes in true and false positive rates with variations in biological replicates, differential fold changes, and expression levels in non-exonic regions. We also tested the algorithm on a set of real RNA-seq data where the common and different detection results from different algorithms were reported. CONCLUSIONS: In this paper, we proposed a novel XBSeq, a differential expression analysis algorithm for RNA-seq data that takes non-exonic mapped reads into consideration. When background noise is at baseline level, the performance of XBSeq and DESeq are mostly equivalent. However, our method surpasses DESeq and other algorithms with the increase of non-exonic mapped reads. Only in very low read count condition XBSeq had a slightly higher false discovery rate, which may be improved by adjusting the background noise effect in this situation. Taken together, by considering non-exonic mapped reads, XBSeq can provide accurate expression measurement and thus detect differential expressed genes even in noisy conditions. PMID- 26099632 TI - Diffraction evidence for the structure of cellulose microfibrils in bamboo, a model for grass and cereal celluloses. AB - BACKGROUND: Cellulose from grasses and cereals makes up much of the potential raw material for biofuel production. It is not clear if cellulose microfibrils from grasses and cereals differ in structure from those of other plants. The structures of the highly oriented cellulose microfibrils in the cell walls of the internodes of the bamboo Pseudosasa amabilis are reported. Strong orientation facilitated the use of a range of scattering techniques. RESULTS: Small-angle neutron scattering provided evidence of extensive aggregation by hydrogen bonding through the hydrophilic edges of the sheets of chains. The microfibrils had a mean centre-to-centre distance of 3.0 nm in the dry state, expanding on hydration. The expansion on hydration suggests that this distance between centres was through the hydrophilic faces of adjacent microfibrils. However in the other direction, perpendicular to the sheets of chains, the mean, disorder-corrected Scherrer dimension from wide-angle X-ray scattering was 3.8 nm. It is possible that this dimension is increased by twinning (crystallographic coalescence) of thinner microfibrils over part of their length, through the hydrophobic faces. The wide-angle scattering data also showed that the microfibrils had a relatively large intersheet d-spacing and small monoclinic angle, features normally considered characteristic of primary-wall cellulose. CONCLUSIONS: Bamboo microfibrils have features found in both primary-wall and secondary-wall cellulose, but are crystallographically coalescent to a greater extent than is common in celluloses from other plants. The extensive aggregation and local coalescence of the microfibrils are likely to have parallels in other grass and cereal species and to influence the accessibility of cellulose to degradative enzymes during conversion to liquid biofuels. PMID- 26099633 TI - Developing an activity and absorption-based quality control platform for Chinese traditional medicine: Application to Zeng-Sheng-Ping(Antitumor B). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zeng-Sheng-Ping (ZSP), also called antitumor B, is a marketed Chinese traditional medicine used for cancer prevention. AIM OF THE STUDY: Currently, for the quality control of Chinese traditional medicines, marker compounds are not selected based on bioactivities and pharmaceutical behaviors in most of the cases. Therefore, even if the "quality" of the medicine is controlled, the pharmacological effect could still be inconsistent. The aim of this study is to establish an activity and absorption-based platform to select marker compound(s) for the quality control of Chinese traditional medicines. MATERIALS AND METHODS: We used ZSP as a reference Chinese traditional medicine to establish the platform. Activity guided fractionation approach was used to purify the major components from ZSP. NMR and MS spectra were used to elucidate the structure of the isolated compounds. MTT assay against oral carcinoma cell line (SCC2095) was performed to evaluate the activities. UPLC-MS/MS was used to quantify the pure compounds in ZSP and the active fraction. The permeabilities of the identified compounds were evaluated in the Caco-2 cell culture model. The intracellular accumulation of the isolated compounds was evaluated in the SCC2095 cells. RESULTS: The major compounds were identified from ZSP. The contents, anti proliferation activities, permeabilities, and intracellular accumulations of these compounds were also evaluated. The structure of these purified compounds were identified by comparing the NMR and MS data with those of references as rutaevine (1), limonin (2), evodol (3), obacunone (4), fraxinellone (5), dictamnine (6), maackiain (7), trifolirhizin (8), and matrine (9). The IC50 of compounds 5, 6, and 7 against SCC2095 cells were significantly lower than that of ZSP. The uptake permeability of compounds 5, 6, and 7 were 2.58 +/- 0.3 * 10(-5), 4.33 +/- 0.5 * 10(-5), and 4.27 +/- 0.8 * 10(-5) respectively in the Caco-2 cell culture model. The intracellular concentrations of these compounds showed that compounds 5, 6, and 7 were significantly accumulated inside the cells. CONCLUSION: Based on the activity against oral carcinoma cell line as well as the absorption permeability, compound 5, 6, and 7 are selected as quality control markers for ZSP. An activity and absorption-based platform was established and successfully used for the quality control of ZSP. PMID- 26099635 TI - Ethnopharmacological study of plants sold for therapeutic purposes in public markets in Northeast Brazil. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Studies of ethnobiological nature favor the rescue of popular culture, preventing important cultural and biological information from being lost over time. Another interesting point is that it can support bioprospecting studies focusing on the discovery of new drugs. OBJECTIVE OF THE STUDY: Our aim was to conduct a survey of plants sold for therapeutic purposes in public markets in the Crajubar Triangle in Northeast Brazil. MATERIALS AND METHODS: Using a questionnaire, data were collected regarding the part of the plant used, method of preparation, quantity needed, instructions for use and known adverse effects. From the data obtained, we calculated the relative importance of species and informant consensus factor. RESULTS: Vendors indicated 91 useful species from a therapeutic point of view, distributed in 49 plant families. The preparation methods most frequently mentioned by informants were decoction, infusion, sauce with part of the plant in water and lozenge. The informants of this study mentioned bark, leaves, seeds and roots as parts of the plant most sold for therapeutic use. Disorders of the digestive system was the disease/disorder category with the highest consensus among the vendors, and the species Ximenia americana, Lippia gracillis, Stryphnodendron rotundifolium, Anacardium occidentale, Hymenaea courbail, Myracrodruon urundeuva, Amburana cearensis and Himatanthus drasticus were the most versatile among the plants sold in markets. CONCLUSIONS: Vendors indicated 91 species belonging to 49 botanical families and 89 genera. The most frequent forms of preparation were decoction, infusion and sauce made with part of the plant in water. The most common form of administration was oral. Bark and leaves were the plant parts most used. Thirteen species showed great versatility regarding their use. We noted 291 indications for use in 13 disease/disorder categories. PMID- 26099634 TI - Ethnopharmacological reports on anti-Buruli ulcer medicinal plants in three West African countries. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Buruli ulcer (BU) is the third most common mycobacterial infection in the world, after tuberculosis and leprosy and has recently been recognized as an important emerging disease. This disease is common in West Africa where more than 99% of the burden is felt and where most affected people live in remote areas with traditional medicine as primary or only option. Reports indicate that the ethnopharmacological control approach of the disease in such settings has shown promise. However, no or very few compilations of traditional knowledge in using medicinal plants to treat BU have been attempted so far. This review aimed to record medicinal plants used traditionally against BU in three countries in West Africa: Ivory Coast, Ghana and Benin and for which ethnopharmacological knowledge supported by pharmacological investigations has been reported. The information recorded in this review will support further pharmacological research to develop appropriate drugs for a better BU control. MATERIAL AND METHODS: A systematic review of the literature on ethnobotanical use and anti-BU activity of plants reported for BU treatment was performed. The approach consisted to search several resources, including Technical Reports, Books, Theses, Conference proceedings, web-based scientific databases such as publications on PubMed, Science direct, Springer, ACS, Scielo, PROTA, Google and Google scholar reporting ethnobotanical surveys and screening of natural products against Mycobacterium ulcerans. This study was limited to papers and documents published either in English or French reporting ethnopharmacological knowledge in BU treatment or pharmacological potency in vitro. This review covered the available literature up to December 2014. RESULTS: The majority of reports originated from the three most affected West African countries (Cote d'Ivoire, Ghana and Benin). Though, 98 plant species belonging to 48 families have been identified as having anti-BU use, many have received no or little attention. Most of the pharmacological studies were performed only on 54 species. To a lesser extent, ethnopharmacological knowledge was validated in vitro for only 13 species. Of those, seven species including Ricinus comminus, Cyperus cyperoides (cited as Mariscus alternifolius), Nicotiana tabacum, Mangifera indica, Solanum rugosum, Carica papaya, and Moringa oleifera demonstrated efficacy in hospitalised BU patients. Four isolated and characterized compounds were reported to have moderate bioactivity in vitro against M. ulcerans. CONCLUSIONS: This review compiles for the first time ethnopharmacologically useful plants against BU. The phamacological potential of 13 of them has been demonstrated in vitro and support BU evidence-based traditional medicines. In addition, 7 species showed activity in BU patients and have emerged as a promising source of the traditional medicine for treatment of BU. Yet, further safety and efficacy study should be initiated prior any approval as alternative therapy. Overall, a huge gap in knowledge appeared, suggesting further well-planned and detailed investigations of the in vitro, in vivo, and safety properties of the claimed anti-BU plants. Therefore, plants with medicinal potential should be scrutinized for biologically active compounds, using bioassay-guided fractionation approach to provide new insights to find novel therapeutics for BU control. PMID- 26099636 TI - Trichilia catigua ethyl-acetate fraction protects against cognitive impairments and hippocampal cell death induced by bilateral common carotid occlusion in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Trichilia catigua preparations have antinociceptive, antiinflammatory, and neuroprotective activity. Recently, a neuroprotective role for T. catigua was proposed using an in vitro model of ischemia-reperfusion in rat hippocampal slices. The aim of the present study was to evaluate the effects of an ethyl-acetate fraction (EAF) of T. catigua, which has potent antioxidant activity, in mice subjected to an in vivo model of cerebral ischemia. MATERIAL AND METHODS: Male Swiss mice were subject to the bilateral common carotid occlusion (BCCAO) model of cerebral ischemia. The animals were orally administered the T. catigua EAF (200, 400, or 800 mg/kg) 30 min before and once per day for 7 days after BCCAO. Histological and behavioral outcomes were assessed using Nissl staining and the Morris water maze test of cognition, respectively. RESULTS: Mice that were subjected to BCCAO exhibited cognitive impairments in the Morris water maze. The spatial cognitive deficits were counteracted by T. catigua EAF administration (200-800 mg/kg). The T. catigua EAF significantly increased the number of intact-appearing Nissl-stained cells in the hippocampus in BCCAO mice. CONCLUSIONS: These results show that the T. catigua EAF promoted functional recovery, decreased the delayed hippocampal cell loss, and mitigated the ongoing neurodegenerative processes induced by BCCAO in mice. PMID- 26099638 TI - The effectiveness of group reminiscence therapy for loneliness, anxiety and depression in older adults in long-term care: a systematic review. AB - Loneliness, anxiety and depression are common problems for older adults in long term care. Reminiscence therapy is a non-pharmacological intervention that may be of some benefit. In comparison to individual reminiscence therapy, group reminiscence therapy is a preferred option when dealing with the resource constraints of long-term care. The aim of this paper was to systematically review the literature in order to explore the effectiveness of group reminiscence therapy for older adults with loneliness, anxiety and depression in long-term care. Results indicated that group reminiscence therapy is an effective treatment for depression in older adults, however to date, there is limited research support for its effectiveness to treat loneliness and anxiety. Further research and an improvement in methodological quality, such as using qualitative and mixed methods approaches, is recommended to help establish an evidence base and provide better understanding of the effectiveness of group reminiscence therapy. PMID- 26099637 TI - Does the gastroprotective action of a medicinal plant ensure healing effects? An integrative study of the biological effects of Serjania marginata Casar. (Sapindaceae) in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Serjania marginata (Sapindaceae), a medicinal plant commonly found in the Brazilian Cerrado, Paraguay, Bolivia and Argentina, is also known as "cipo-uva" or "cipo-timbo". Ethnopharmacological studies indicate that the leaves from this medicinal plant are used in folk medicine to treat gastric pain. The overall objective of this study was to evaluate the gastroprotective and healing effect of the hydroalcoholic extract obtained from S. marginata (HESM) leaves using rodent experimental models. As part of the integrative study of this medicinal plant, we also evaluated the acute toxicity, antimicrobial, antidiarrheal, (anti)mutagenic, and hemodynamic effects. MATERIAL AND METHODS: We performed a pharmacological study to test the acute toxicity and antimutagenic effect (Ames assay) of the HESM. The HESM was tested against different necrosis-promoting agents and experimental manipulations, such as absolute ethanol, cysteamine, pyloric ligature, and ischemia-reperfusion (I/R) injury. The gastroprotective effect of the HESM was assessed by analyzing the gastric juice (volume, pH, total acidity) and the mucus in the gastric mucosa from rats. We assessed the levels of NO, sulfhydryl compounds, PGE2, vanilloid receptor, glutathione (GSH), and malondialdehyde (MDA), as well as the myeloperoxidase (MPO) activity. The gastric healing effects of the HESM were evaluated during 7 or 14 days of treatment. The intestinal motility, antidiarrheal action, and antibacterial effects (microdilution methods) of the HESM were also evaluated. RESULTS: The phytochemical analysis of the HESM revealed the presence of saponins, flavonoid glycosides, and tannins. The extract exhibited no sign of acute toxicity or mutagenic effect in vitro. In contrast, this extract exhibited a protective effect against the mutagenic action of direct and indirect-acting mutagens. Only the oral administration of HESM (250mg/kg) significantly decreased the severity of gastric damage induced by ethanol (60.13%) and I/R (58.31%). The HESM exerts its gastroprotective effects by decreasing the MPO and MDA activities in the gastric tissue and by increasing the amount of adherent mucus covering the gastric mucosa. In vitro, the extract also displayed evident antimicrobial effects against Helicobacter pylori. However, the preventive effect of the HESM was not accompanied by an ulcer-healing effect. The treatment with HESM (14 days) significantly increased gastric lesions in 99% of the tested animals compared with the control group. This result represents a highly relevant piece of evidence that should resonate as an alert against the chronic use of this medicinal plant as an antiulcer in folk medicine. CONCLUSIONS: Despite the anti-H. pylori and gastroprotective actions of S. marginata in experimental models, the gastric injuries aggravation induced after chronic treatment with the HESM argues against the use of this plant species in folk medicine. PMID- 26099639 TI - CD19-Chimeric Antigen Receptor T Cells for Treatment of Chronic Lymphocytic Leukaemia and Acute Lymphoblastic Leukaemia. AB - Adoptive cell therapy (ACT) for cancer represents a promising new treatment modality. ACT based on the administration of cytotoxic T cells genetically engineered to express a chimeric antigen receptor (CAR) recognizing CD19 expressed by B cell malignancies has been shown to induce complete lasting responses in patients with chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL). So far, eleven clinical trials including 99 CLL and ALL patients treated with CAR T cells targeting CD19 have been published, and the results from these trials are promising with impressive clinical responses in heavily pretreated patients. Thus, CAR T cell therapy has induced complete responses in both CLL and ALL, and surprisingly, current results indicate that patients with ALL are more prone to respond than are CLL patients. Importantly, the majority of CAR cell studies have observed severe therapy-associated toxicities, which needs attention. Herein we review current data and discuss key aspects of this powerful approach to treat and potentially cure B cell malignancies. PMID- 26099640 TI - Skeleton Graph Matching vs. Maximum Weight Cliques aorta registration techniques. AB - Vascular diseases are one of the most challenging health problems in developed countries. Past as well as ongoing research activities often focus on efficient, robust and fast aorta segmentation, and registration techniques. According to this needs our study targets an abdominal aorta registration method. The investigated algorithms make it possible to efficiently segment and register abdominal aorta in pre- and post-operative Computed Tomography (CT) data. In more detail, a registration technique using the Path Similarity Skeleton Graph Matching (PSSGM), as well as Maximum Weight Cliques (MWCs) are employed to realise the matching based on Computed Tomography data. The presented approaches make it possible to match characteristic voxels belonging to the aorta from different Computed Tomography (CT) series. It is particularly useful in the assessment of the abdominal aortic aneurysm treatment by visualising the correspondence between the pre- and post-operative CT data. The registration results have been tested on the database of 18 contrast-enhanced CT series, where the cross-registration analysis has been performed producing 153 matching examples. All the registration results achieved with our system have been verified by an expert. The carried out analysis has highlighted the advantage of the MWCs technique over the PSSGM method. The verification phase proves the efficiency of the MWCs approach and encourages to further develop this methods. PMID- 26099641 TI - Is there a role for Digital X-ray Radiogrammetry as surrogate marker for radiological progression and imaging of structural integrity in rheumatoid arthritis? AB - INTRODUCTION: The established scoring techniques based on radiographs present limitations in the evaluation of structural integrity due to high effectiveness of innovative therapeutic strategies. The aim of this study was to evaluate the periarticular mineralisation as detected by Digital X-ray Radiogrammetry (DXR) as surrogate marker for structural integrity during the course of rheumatoid arthritis (RA). METHODS: 11 centers throughout Germany contributed data of 94 patients with verified RA. The patients were treated with leflunomide or methotrexate during a mean observation period of 22 months. All patients underwent complete computerized calculations of bone mineral density (BMD) and metacarpal index (MCI) by DXR using digitized hand radiographs. The radiological assessment of disease progression was estimated by the Sharp Score. RESULTS: The Sharp Score revealed no significant change during the study period. DXR-BMD revealed minimal decrease of -1.4 % (leflunomide group) versus a higher reduction of -4.3 % (methotrexate group). Regarding DXR-MCI, a reduction of -2.2 % (leflunomide group) and -4.9 % (methotrexate group) was observed. CONCLUSION: Quantitative data of hand bone mass estimated by the presented DXR-technique may be a complementary precise tool in the identification of RA-related radiographic changes and in the assessment of structural integrity. PMID- 26099642 TI - Clinical analysis of preoperative deep vein thrombosis risk factors in patients undergoing total hip arthroplasty. AB - OBJECTIVES: The objective of this retrospective study was to investigate the risk of deep vein thrombosis (DVT) in patients admitted to hospital for total hip arthroplasty (THA). METHODS: From September of 2003 to December of 2010, 505 patients admitted for THA were eligible for the retrospective study. The diagnosis of preoperative DVT, which was based on previous venous thromboembolism (VTE) management studies, was confirmed by Doppler ultrasonography. The prevalence of silent DVT in lower limbs in patients before THA was assessed. And the risk factors for preoperative DVT were investigated the correlation of DVT in the patient's background and medical history. RESULTS: Preoperative DVT was diagnosed in 62 of 505 (12.3%) patients overall. Significantly elevated risks of DVT were found in patients with increased age, a history of major surgery, revision THA, rheumatoid arthritis (RA), and a history of cancer treatment. Multiple linear regression analysis showed that increased age, RA, and history of major surgery were the independent risk factors for preoperative DVT in this study. CONCLUSIONS: A high prevalence (12.3%) of preoperative DVT was found in patients admitted to hospital for THA. Patients with increased age, RA, and a history of major surgery may be at an increased risk of preoperative DVT. The present results suggest that instrumental screening should be encouraged, at least in subgroups at higher risk of preoperative DVT. PMID- 26099643 TI - Procoagulant activity induced by transcatheter closure of atrial septal defects is associated with exposure of phosphatidylserine on microparticles, platelets and red blood cells. AB - The mechanism of hypercoagulable state following transcatheter closure of atrial septal defects (ASDs) remains unclear. We evaluated the exposure of phosphatidylserine (PS) on released microparticles (MPs) and also the cells of their origin from peripheral blood, and the associated increase in procoagulant activity (PCA) following transcatheter ASD closure. We demonstrate that PS(+) MP levels were elevated immediately after device implantation (P <0.002), peaked at 24hour (P <0.002), and persisted at high levels for 1-week post procedure (P <0.002). Flow cytometry analysis indicated that PS(+) MPs were mainly derived from platelets, endothelial cells, and the red blood cells (RBCs). Concomittantly, PS(+) platelet and RBC count also increased after transcatheter closure of ASDs, while PS(+) leukocytes levels remained the same. Compared to the baseline, coagulation time of PS(+) MPs, platelets, and RBCs at 24hours post procedure decreased by about 18.7% (P <0.004), 21.5% (P <0.001), and 26.8% (P <0.001), respectively. Intrinsic factor Xa and prothrombinase were produced abundantly by platelets, RBCs, and MPs leading to materialization of fibrin by 24hours. Additionally, Xase complex formation and thrombin generation was inhibited by about 74% by the addition of lactadherin to the assays. Our results thus demonstrate that PS exposure on MPs, platelets, and RBCs play an important role in hypercoagulability following transcatheter ASD closure. PMID- 26099644 TI - Prognostic significance of arterial and venous thrombosis in resected specimens for non-small cell lung cancer. AB - BACKGROUND: Venous thromboembolism(VTE) is common after pneumonectomy for malignancy and predicts poor survival. Routine screening for VTE with noninvasive tests has low sensitivity and specificity. Biopsy of lung has a place in establishing the nature and severity of the vascular alterations. In this study, we investigated the incidence, clinical and pathological characteristics of thrombosis in excised specimens after pneumonectomy, and its association with survival rate in patients with non-small cell lung cancer (NSCLC). METHODS: The studied population consisted 94 consecutive patients after pneumonectomy for NSCLC in Beijing Chao-Yang Hospital, The excised tissue specimens were stained by haematoxylin & eosin staining (HE) to observe thrombosis events. All the patients were followed up for 2years. The survival data was analyzed by Kaplan-Meier analysis. RESULTS: Overall thrombosis events occurred in 56 (59.6%) of 94 NSCLC cases, pulmonary arterial thrombosis was found in 24 cases, and pulmonary venous thrombosis was found in 32 cases. Furthermore, 30 of 56 cases with thrombosis were accompanied by tumor emboli or tumor vascular infiltrating. Thrombosis risk was associated with cancer grade (P=0.005). Kaplan-Meier analysis showed that patients with thrombosis had lower survival rate than those without thrombosis (P=0.025). CONCLUSIONS: The incidence of thrombosis in excised tissue after pneumonectomy was high in patients with NSCLC, and it may be a marker of poor outcome. PMID- 26099645 TI - [Condensing iliac osteitis as a cause of chronic low back pain]. PMID- 26099646 TI - Distribution of acquired AmpC beta-lactamase genes in Sydney, Australia. AB - Investigation of plasmid-borne AmpC beta-lactamase genes in Escherichia coli and Klebsiella spp. revealed blaCMY-2-like genes predominantly in E. coli and blaDHA genes equally distributed between both species. This distribution remained stable over time, but blaACT/MIR-like genes, initially common in Klebsiella spp., were not identified in more recent isolates. PMID- 26099647 TI - 'Connecting tracks': exploring the roles of an Aboriginal women's cancer support network. AB - Aboriginal Australians are at higher risk of developing certain types of cancer and, once diagnosed, they have poorer outcomes than their non-Aboriginal counterparts. Lower access to cancer screening programmes, deficiencies in treatment and cultural barriers contribute to poor outcomes. Additional logistical factors affecting those living in rural areas compound these barriers. Cancer support groups have positive effects on people affected by cancer; however, there is limited evidence on peer-support programmes for Aboriginal cancer patients in Australia. This paper explores the roles played by an Aboriginal women's cancer support network operating in a regional town in Western Australia. Data were collected through semi-structured interviews with 24 participants including Aboriginal and mainstream healthcare service providers, and network members and clients. Interviews were audiotaped and transcribed verbatim. Transcripts were subjected to inductive thematic analysis. Connecting and linking people and services was perceived as the main role of the network. This role had four distinct domains: (i) facilitating access to cancer services; (ii) fostering social interaction; (iii) providing a culturally safe space; and (iv) building relationships with other agencies. Other network roles included providing emotional and practical support, delivering health education and facilitating engagement in cancer screening initiatives. Despite the network's achievements, unresolved tensions around role definition negatively impacted on the working relationship between the network and mainstream service providers, and posed a threat to the network's sustainability. Different perspectives need to be acknowledged and addressed in order to build strong, effective partnerships between service providers and Aboriginal communities. Valuing and honouring the Aboriginal approaches and expertise, and adopting an intercultural approach are suggested as necessary to the way forward. PMID- 26099648 TI - Neuropelveology: New Groundbreaking Discipline in Medicine. PMID- 26099649 TI - Genetic evidence for the spread of a benzimidazole resistance mutation across southern India from a single origin in the parasitic nematode Haemonchus contortus. AB - It is important to understand how anthelmintic drug resistance mutations arise and spread in order to determine appropriate mitigation strategies. We hypothesised that a molecular genetic study of Haemonchus contortus in southern India, a region where resistance may be less advanced than in western Europe and North America, might provide some important insights into the origin and spread of anthelmintic resistance. The F200Y (TAC) isotype-1 beta-tubulin benzimidazole resistance mutation is common in H. contortus throughout the world and the F167Y (TAC) and E198A (GCA) mutations, although less common, have been reported in a number of different countries. We have investigated the haplotypic diversity and phylogenetic relationship of isotype-1 beta-tubulin benzimidazole resistance alleles for 23 H. contortus populations from small ruminants across southern India. The F200Y (TAC) mutation was most common, being detected in 18/23 populations at frequencies between 9% and 84% and the E198A (GCA) mutation was also detected in 8/23 populations at frequencies between 8% and 18%. The F167Y (TAC) mutation was not detected in any of the 23 populations. Phylogenetic haplotype network analysis suggested that the F200Y (TAC) mutation has arisen multiple independent times in the region with at least three independent origins of resistance alleles across the populations surveyed. In contrast, the E198A (GCA) mutation was present on a single haplotype which, given the high level of haplotypic diversity of the susceptible alleles in the region, suggests this particular mutation has spread from a single origin, likely by anthropogenic animal movement. Population genetic analysis of 12 of the H. contortus populations, using a panel of eight microsatellite markers, revealed extremely low genetic differentiation between populations, consistent with the hypothesis of high gene flow among sites. Additionally, there was no significant genetic differentiation between H. contortus taken from sheep and goats which is consistent with H. contortus populations being freely shared between these two different hosts. Overall, we believe these results provide the first clear genetic evidence for the spread of an anthelmintic resistance mutation to multiple different locations from a single origin. PMID- 26099650 TI - First isolation of a new species of Leishmania responsible for human cutaneous leishmaniasis in Ghana and classification in the Leishmania enriettii complex. AB - An active case detection approach with PCR diagnosis was used in the Ho District of the Volta Region, Ghana that identified individuals with active cutaneous leishmaniasis. Three isolates were successfully cultured and DNA sequences from these were analysed (ribosomal RNA internal transcribed spacer 1; ribosomal protein L23a intergenic spacer; RNA polymerase II large subunit), showing them to be Leishmania, identical to each other but different from all other known Leishmania spp. Phylogenetic analysis showed the parasites to be new members of the Leishmania enriettii complex, which is emerging as a possible new subgenus of Leishmania parasites containing human pathogens. PMID- 26099652 TI - 206th ENMC International Workshop: Care for a novel group of patients - adults with Duchenne muscular dystrophy Naarden, The Netherlands, 23-25 May 2014. PMID- 26099651 TI - Oxidative stability and quality characteristics of whey protein coated rohu (Labeo rohita) fillets. AB - BACKGROUND: Edible coatings have beneficial effect on quality of fish and act as barrier against moisture transfer and uptake of oxygen. Edible coating made up of biodegradable materials is helpful to control the quality deterioration and enhance the shelf life. METHODS: The present study was designed to elucidate the effects of whey based protein using two plasticizers i.e. sorbitol and glycerol on oxidative stability and quality characteristics of Rohu (Labeo rohita). Coating solutions were prepared by incorporating whey (8% protein; w/ w) in distilled water followed addition of sorbitol and glycerol. Dipping method was used to apply coating on fish fillets. The coated fillets were subjected to quality characteristics, pH, color, TBARS, peroxide value, volatile basic nitrogen (TVBN) and sensory evaluation during 40 days of storage. RESULTS: The results showed significant impact on different quality attributes of fish fillets. Highest (TVBN) and TBARS were observed in control samples (T0) (12.60 +/ 0.25, mg/100 g, 0.820 +/- 0.02 mg MDA/kg) while lowest in T3 coated samples (8.81 +/- 0.18 mg/100 g., 0.352 +/- 0.01 mg MDA/kg of meat). Moreover, sensorial findings did not showed adverse effects and T3 coated samples were ranked higher by consumers. CONCLUSION: In conclusion, coating fish with Whey: Glycerol: Sorbitol (1:1:1) in current investigation enhances the storage life and quality of fish fillets. PMID- 26099653 TI - The cauldron of the ethical review process in human participant research. PMID- 26099654 TI - Three year stability of Five-Factor Model personality traits in relation to changes in symptom levels in patients with schizophrenia or related disorders. AB - Five-Factor Model (FFM) personality traits are related to a wide range of clinical outcome in patients with psychotic disorders. However, it is not sufficiently clear whether psychotic illness, particularly fluctuation in negative symptoms and psychotic relapse, affects personality. The current study examined the 3-year temporal stability of FFM traits in 91 patients with non affective psychotic disorders with a maximum duration of illness of 10 years and 32 control subjects without a (family member with) a diagnosis of psychotic illness. In patients, change in negative symptoms predicted changes in Neuroticism and (inversely) in Extraversion and Openness. However, when correcting for depressive symptoms, negative symptoms no longer predicted change in any FFM trait. Clinical characteristics, such as psychotic relapse, were also not found to be related to change in FFM traits. Patients showed a slight increase in Conscientiousness levels, the other FFM traits showed mean-level stability. Rank-order stability of the FFM traits was moderate to strong, although weaker for Neuroticism in patients. Our findings indicate that psychotic symptoms exert limited effect on the stability of FFM traits in patients with psychotic disorders. Consistent with general population findings, one should guard against state-trait confusion between Neuroticism/Extraversion and depression. PMID- 26099655 TI - Trauma and psychosis: The mediating role of self-concept clarity and dissociation. AB - Childhood trauma (CT) and psychosis may be associated. Drawing on the dissociation and social psychological literature, the current study examined the mediating role of structural aspects of self in explaining the relationship between childhood trauma and psychosis. Twenty-nine individuals with psychosis were compared with 31 healthy volunteers regarding childhood trauma, dissociation and self-concept clarity (SCC). High rates of maltreatment were found in the psychosis sample. Additionally, clinical participants reported more dissociation and less self-concept clarity. Mediational analyses were carried out on pooled data from across both clinical and non-clinical samples. These suggested that the influence of physical neglect in increasing the likelihood of experiencing psychosis was explicable through the effects of increased dissociation. Self concept clarity mediated the relationship between psychosis and total childhood trauma, emotional abuse, physical abuse, emotional and physical neglect. Furthermore, dissociation and self-concept clarity were strongly correlated providing evidence that they may form a unitary underlying concept of 'self concept integration'. The study provides further evidence of the link between childhood trauma and psychosis. Self-concept integration may be adversely affected by negative childhood experiences, which increases psychosis risk. Methodological limitations, clinical implications and suggestions for future research are considered. PMID- 26099656 TI - Perceived burdensomeness, thwarted belongingness, and suicide ideation: Re examination of the Interpersonal-Psychological Theory in two samples. AB - The Interpersonal-Psychological Theory of Suicide (IPTS) proposes that suicide ideation is caused by the interaction of perceived burdensomeness and thwarted belongingness, in which each predictor amplifies the harm of the other. Though several studies support this synergy hypothesis, research has not considered potential quadratic effects of perceived burdensomeness and thwarted belongingness, which can distort the sign, size, and significance of interactions, if mistakenly neglected in a model. This investigation examined the synergy hypothesis in samples of university undergraduates and psychiatric inpatients, this time controlling for quadratic effects. Despite adequate power, results showed no interaction between perceived burdensomeness and thwarted belongingness in either sample, regardless of the presence of quadratic effects. Additionally, no quadratic effects were observed. The lower-order, linear perceived burdensomeness term was positively associated with suicide ideation in both samples, but the thwarted belongingness term was not associated with suicide ideation in either sample. The discussion considers implications of current findings for the IPTS, highlighting a need to formally test the impact of sample characteristics on the estimation of theory parameters. Recommendations for systematic evaluation of such sample and theory parameters are offered and their clinical implications are discussed. PMID- 26099657 TI - Impact of childhood adversities on the short-term course of illness in psychotic spectrum disorders. AB - Accumulating evidence indicates an impact of childhood adversities on the severity and course of mental disorders, whereas this impact on psychotic disorders remains to be specified. Effects of childhood adversities on comorbidity, on symptom severity of the Positive and Negative Syndrome Scale and global functioning across four months (upon admission, 1 and 4 months after initial assessment), as well as the course of illness (measured by the remission rate, number of re-hospitalizations and dropout rate) were evaluated in 62 inpatients with psychotic spectrum disorders. Adverse experiences (of at least 1 type) were reported by 73% of patients. Patients with higher overall level of childhood adversities (n=33) exhibited more co-morbid disorders, especially alcohol/substance abuse and dependency, and higher dropout rates than patients with a lower levels of adverse experiences (n=29), together with higher levels of positive symptoms and symptoms of excitement and disorganization. Emotional and physical neglect were particularly related to symptom severity. Results suggest that psychological stress in childhood affects the symptom severity and, additionally, a more unfavorable course of disorder in patients diagnosed with psychoses. This impact calls for its consideration in diagnostic assessment and psychiatric care. PMID- 26099658 TI - Changes in autistic trait indicators in parents and their children with ASD: A preliminary longitudinal study. AB - This study investigated whether the longitudinal changes in symptom severity in children with autism spectrum disorder (ASD) are associated with changes in the parents' autistic traits. The results demonstrated two significant correlations between the changes in children's Social Responsiveness Scale (SRS) scores and the Social Responsiveness Scale (SRS) score changes in either the father or both parents. Autistic symptom mitigation in ASD children was associated with increased empathy levels in their parents. PMID- 26099659 TI - The stability of schizotypy across time and instruments. AB - Little is known about the stability of schizotypy across relatively long time periods and instrumentation. This study assesses the degree of stability between schizotypy and its three factor structure as assessed by the Survey of Attitudes and Experiences (SAE) at age 17, and the Schizotypal Personality Questionnaire (SPQ) at age 23. A sample of 678 at ages 17 and 23 years from a birth cohort in Mauritius were split into two random samples, with initial analyses on the first sample independently replicated on the second sample. Cognitive-perceptual, interpersonal, and disorganized factors at age 17 correlated from 0.28 to 0.32 with their respective factors at age 23. Total scores correlated 0.41 (d=0.90) across this six year time period and increased to 0.58 (d=1.42) after correcting for measurement error. Receiver operating characteristic (ROC) analyses showed an area under the curve value of 0.74, confirmed prediction over time. Findings on predictive validity were closely replicated in the second independent sample. In contrast, social anhedonia at age 17 was unrelated to interpersonal deficits at age 23. Results provide replicable support for the moderate stability of cognitive-perceptual, interpersonal, and disorganized schizotypy across time, instrumentation, and a period of rapid developmental change. PMID- 26099660 TI - Prevalence and predictors of medication non-adherence among Chinese patients with first-episode psychosis. AB - Medication non-adherence is one of the major obstacles to recovery in first episode psychosis (FEP). This study aimed to identify the predictors and rates of medication non-adherence in the first and second year after the start of treatment (baseline) in urban Chinese FEP patients. Relevant information on medication non-adherence and potential baseline predictors, including demographic variables, clinical measures, violence/suicide attempts, stressful life experiences, intervention received, and follow-up attendance, were collected from case records of 1400 FEP patients in Hong Kong. The non-adherence rate was 16.2% in year 1 and 15.4% in year 2. Regression analyses revealed the predictors for non-adherence in year 1 were no hospitalization at baseline, non-schizophrenia diagnosis, and more years of education. Predictors of non-adherence in year 2 included acute/subacute onset and older age of onset. Predictors common in both years were defaulting from psychiatric follow-up during baseline, standard psychiatric care (no early intervention), and lower positive symptoms severity at baseline. In assessing non-adherence risk and for planning phase-specific early interventions for FEP, particularly in a Chinese context, healthcare professionals should consider the common and specific predictors for non adherence identified in the first and second years of treatment and should not overlook patients with less clinically severe symptoms. PMID- 26099661 TI - Relationship between length variations in Ser/Asp-rich repeats in phosphophoryn and in vitro precipitation of calcium phosphate. AB - OBJECTIVE: Phosphophoryn (PP) is generated from the proteolytic cleavage of dentin sialophosphoprotein (DSPP). PP which contains tandem serine/asparatic acid rich repeats (SDrr) is known to enhance dentin mineralization. The nucleotide sequences coding SDrr are identified in the DSPP genes of toothed animals and the length variations of SDrr between intra- and inter-species have been reported. However, it remains unknown about the relationship between the length variations in SDrr and the functions of PP in matrix mineralization. DESIGN: By utilizing a mammalian expression system, we generated several recombinant PP proteins (rPP) containing SDrr of different lengths and analyzed their effects on the precipitation of calcium phosphate with an in vitro gel diffusion system. RESULTS: rPP-Delta37.6 SDrr and rPP-Delta63.5 SDrr, which possessed shortened SDrr that accounted for 62.4 and 36.5% the length of SDrr in full-length rPP (rPP full), respectively, induced the precipitation of calcium phosphate similar to that of rPP-full at the same molar concentration, whereas rPP-DeltaSDrr, in which SDrr were flipped, did not. Furthermore, rPP-Delta63.5 SDrr significantly increased the accumulation of calcium compared with rPP-full at adjusted concentrations so that the same amounts of SDrr were embedded. The results of an ELISA analysis indicated that the amounts of rPP-Delta37.6 SDrr and rPP-Delta63.5 SDrr secreted from transfected cells were 5.2- and 7.1-fold greater than that of rPP-full, respectively. CONCLUSIONS: The generated rPP-Delta63.5 SDrr which can be substituted for rPP-full may be a candidate for a therapeutic molecule to facilitate hard tissue generation such as reparative dentin formation. PMID- 26099662 TI - RANKL pretreatment plays an important role in the differentiation of pit-forming osteoclasts induced by TNF-alpha on murine bone marrow macrophages. AB - BACKGROUND: Osteoclasts differentiated from bone marrow macrophages (BMMs) induced by TNF-alpha alone do not have resorbing activity. When BMMs are stimulated with receptor activator of NF-kappaB ligand (RANKL) before TNF-alpha stimulation, pit-forming osteoclasts are differentiated. However, the details of the effect of RANKL pretreatment on the pit-forming osteoclast differentiation by TNF-alpha have not been established. The aim of this study is to examine the condition of RANKL pretreatment for differentiation of pit-forming osteoclasts induced by TNF-alpha. Murine BMMs were stimulated with various concentrations of RANKL for 24h in the presence of M-CSF, then the medium was changed and TNF-alpha was added. Osteoclasts and pits formation were examined. Osteoprotegerin (OPG), decoy receptor of RANKL, was added to the culture to examine the necessity of co existing RANKL with TNF-alpha on the formation of pit-forming osteoclasts. To investigate the influence of RANKL of sufficient concentration as pretreatment for pit-forming osteoclast formation by TNF-alpha, dose- and time-dependent changes of osteoclast formation were checked. RESULTS: The pit formation by osteoclasts in response to TNF-alpha required 10ng/mL RANKL pretreatment. Stimulation with this concentration of RANKL led to the differentiation of mature osteoclasts in the 72h culture. The pit formation was not inhibited by the OPG. CONCLUSION: These results suggested that the concentration of RANKL pretreatment, which also alone can differentiate BMMs into osteoclasts, may be important in the differentiation of pit-forming osteoclasts by TNF-alpha. In addition, the effects of TNF-alpha after RANKL treatment might be independent of RANKL. PMID- 26099663 TI - The mechanism of acacetin-induced apoptosis on oral squamous cell carcinoma. AB - BACKGROUND: Acacetin (5,7-dihydroxy-40-methoxyflavone), present in safflower seeds, plants, flowers, Cirisium rhinoceros Nakai, has been reported to be able to exert anti-peroxidative, anti-inflammatory, anti-plasmodial, and anti proliferative activities by inducing apoptosis and blocking the progression of cell cycles. OBJECTIVE AND DESIGN: The objective of this study is to investigate the mechanism of acacetin-induced apoptosis of oral squamous cell carcinoma cell line (HSC-3). RESULTS: Acacetin caused 50% growth inhibition (IC50) of HSC-3 cells at 25MUg/mL over 24h in the MTT assay. Apoptosis was characterized by DNA fragmentation and increase of sub-G1 cells and involved activation of caspase-3 and PARP (poly-ADP-ribose polymerase). Maximum caspase-3 activity was observed with 100MUg/mL of acacetin for 24h. Caspase-8 and -9 activation cascades mediated the activation of caspase-3. Acacetin caused reduction of Bcl-2 expression leading to an increase of the Bax:Bcl-2 ratio. It also caused a loss of mitochondrial membrane potential that induced release of cytochrome c into the cytoplasm. Pretreatment with casapse-3 (Z-DEVD-FMK), -8 (Z-IETD-FMK), and 9 inhibitor (z-LEHD-fmk) inhibited the acacetin-induced loss of mitochondrial membrane potential and release of cytochrome c. The mitogen-activated protein kinases (MAPKs) were activated by acacetin. Moreover, pretreating the cells with each of the caspase inhibitor or MAPKs specific inhibitors apparently inhibited acacetin-induced cytotoxicity of HSC-3 cells. CONCLUSION: In conclusion, acacetin induce the apoptosis of oral squamous cell carcinoma cell line, which is closely related to its ability to activate the MAPK-mediated signaling pathways with the subsequent induction of a mitochondria- and caspase-dependent mechanism. These results strongly suggest that acacetin might have cancer inhibition and therapeutic potential. PMID- 26099664 TI - Claims and compensation for complications resulting from blood transfusions in China from 1998 to 2013. AB - The purpose of this study was to find causes, outcomes, and trends in malpractice litigation involving blood transfusions in China. This study examines 108 claims resulting from transfusion-related complications over a period of 15 years. The primary outcomes associated with these claims included transfusion-transmitted infection (98 cases, 90.8%), transfusion reactions (nine cases, 8.3%), and failures to obtain informed consent (one case, 0.9%). The specialty of obstetrics and gynecology was more likely to be accepted in judgment. As the supreme status of law, Blood Donation Law plays an important role in the blood safety, which results in less HCV infection cases occurred after 1998. Though the 2002 and 2010's rules give opposite liability principle, the fault liability and no-fault liability, the statistics shows that rules do not have an effect on different liabilities in judicial practice. The current study concludes that the risk of serious adverse transfusion reactions may be significantly increased by unnecessary transfusions. PMID- 26099665 TI - Stem cell mobilization and collection from patients and healthy donors. PMID- 26099666 TI - Optimizing mobilization strategies in difficult-to-mobilize patients: The role of plerixafor. AB - Peripheral blood stem cell collection is currently the most widely used source for hematopoietic autologous transplantation. Several factors such as advanced age, previous chemotherapy, disease and marrow infiltration at the time of mobilization influence the efficacy of CD34(+) progenitor cell mobilization. Despite the safety and efficiency of the standard mobilization protocols (G-CSF +/- chemotherapy), there is still a significant amount of mobilization failure rate (10-40%), which necessitate novel agents for effective mobilization. Plerixafor, is a novel agent, has been recently approved for mobilization of hematopoietic stem cells (HSCs). The combination of Plerixafor with G-CSF provides the collection of large numbers of stem cells in fewer apheresis sessions and can salvage those who fail with standard mobilization regimens. The development and optimization of practical algorithms for the use Plerixafor is crucial to make hematopoietic stem cell mobilization more efficient in a cost effective way. This review is aimed at summarizing how to identify poor mobilizers, and define rational use of Plerixafor for planning mobilization in hard-to-mobilize patients. PMID- 26099667 TI - A new approach to detection of incomplete antibodies using hydrogel chromatography medium. AB - In assays for incomplete antibody detection, several washing steps are required to remove unbound globulins which may cause false negatives. Here, we present an improved approach employing hydrogel chromatography medium (HCM) in the detection of incomplete antibodies. After a rapid single-step centrifugation, incomplete antibodies, attached to red blood cells (RBCs), were separated from the reaction mixture using HCM and sedimentation. This method obviates the need for multiple centrifugation steps found in conventional Tube-Coombs tests. The HCM-Coombs tests may have a wide range of applications for incomplete antibody detection. PMID- 26099668 TI - Role of 2-Fluoro-2-Deoxyglucose PET/Computed Tomography in Carcinoma of Unknown Primary. AB - FDG-PET/CT is a potentially useful imaging modality in the setting of Carcinoma of Unknown Primary (CUP) from various aspects. The central question is detection of site of primary, where most studies have documented the pooled sensitivity and specificity of FDG PET/CT in the range of 80%-85% and a tumor detection rate (after the failure of conventional imaging procedures) between 30%-37%. The heterogeneity in the (i) population studied and (ii) criteria used for labelling patient as of unknown primary, have been the prime reason for widely varying result amongst various studies. Initiating appropriate treatment strategies owing to simultaneous whole body disease staging can be regarded an added utility PET/CT, even in the case of failure of primary tumor detection. FDG-PET/CT changed the patient management in around 35% of patients (studies reporting heterogeneous results ranging from 18.2% to 60%). The futuristic approach will be to monitor molecular targeted and cystostatic therapies with FDG-PET/CT which obviously has advantages than anatomical imaging alone. PMID- 26099669 TI - PET/Computed Tomography in the Diagnosis and Staging of Gastric Cancers. AB - Although there has been a reduction of the incidence and mortality of gastric cancer, it remains among the commonest causes of cancer-related death. Accurate staging and evaluation of treatment response are vital for management. PET is used to complement anatomic imaging in cancer management. PET/computed tomography (CT) has demonstrated its potential value for preoperative staging, evaluation of response to therapy, and detection of recurrence. Not all types of gastric cancers have a high affinity for fluorodeoxyglucose. PET/CT in the evaluation and staging of gastric cancer is not established, but studies indicate that there may be an evolving role for this imaging modality. PMID- 26099670 TI - FDG PET/CT in Pancreatic and Hepatobiliary Carcinomas: Value to Patient Management and Patient Outcomes. AB - Fludeoxyglucose F 18 ((18)F-FDG) PET/CT has not been shown to offer additional benefit in the initial diagnosis of pancreatic cancer, but studies show benefit of (18)F-FDG PET/CT in initial staging and patient prognosis. There is evidence for (18)F-FDG PET and (18)F-FDG PET/CT in staging and prognosis of cholangiocarcinoma and gallbladder cancer. (18)F-FDG PET/CT has shown promise in staging liver malignancies by detecting extrahepatic metastasis. There is evidence supporting the ability of PET/CT in predicting prognosis in patients with hepatocellular carcinoma. Evidence is evolving for the role of (18)F FDGPET/CT in predicting prognosis and survival in patients with colorectal liver metastasis. PMID- 26099671 TI - Impact of Fluorodeoxyglucose PET/Computed Tomography on the Management of Patients with Colorectal Cancer. AB - Colorectal cancer is one of the most common malignancies in the Western world. Most colorectal cancers show fluorodeoxyglucose (FDG) uptake, although in mucinous adenocarcinoma uptake may be limited. A literature search was conducted regarding the impact of FDG-PET/computed tomography (CT) on management and outcome in patients with colorectal carcinoma. FDG-PET/CT can have a significant clinical impact on patient management in various stages of the disease. In patients with suspected recurrent disease and patients with liver metastases who might be eligible for surgery FDG-PET/CT can have more benefit than conventional imaging. FDG-PET/CT can be a useful modality to monitor treatment response. PMID- 26099673 TI - Value of FDG PET/CT in Patient Management and Outcome of Skeletal and Soft Tissue Sarcomas. AB - Fluorodeoxyglucose (FDG)-PET/computed tomography (CT) has been increasingly used in bone and soft tissue sarcomas and provides advantages in the initial tumor staging, tumor grading, therapy assessment, and recurrence detection. FDG-PET/CT metabolic parameters are reliable predictors of survival in sarcomas and could be implemented in risk stratification models along with other prognostic factors in these patients. PMID- 26099672 TI - PET/Computed Tomography in Renal, Bladder, and Testicular Cancer. AB - Imaging plays an important role in the clinical management of cancer patients. Hybrid imaging with PET/computed tomography (CT) is having a broad impact in oncology, and in recent years PET/CT is beginning to have an impact in urooncology. In both bladder and renal cancers, there is a need to study the efficacy of other tracers than F-18 fluorodeoxyglucose (FDG), particularly tracers with limited renal excretion. Thus, new tracers are being introduced. This review focuses on the clinical role of FDG and other PET agents in renal, bladder, and testicular cancers. PMID- 26099674 TI - Fludeoxyglucose F 18 PET-Computed Tomography: Management Changes Effecting Patient Outcomes in Gynecologic Malignancies. AB - Outcome analysis in oncologic imaging is complex because of the multiple variables that can affect survival, including how early disease is diagnosed, the accuracy of staging at diagnosis, and where and how the patient is treated. Risk for tumor recurrence is estimated based on tumor histologic grade, stage at diagnosis, and other factors, including expressed molecular markers. This article reviews the data supporting the use of F 18 fluorodeoxyglucose PET-computed tomography in endometrial, ovarian, and cervical malignancies, with emphasis on the impact of imaging on treatment stratification and prognosis. PMID- 26099675 TI - PET/Computed Tomography in Neuroendocrine Tumor: Value to Patient Management and Survival Outcomes. AB - PET/computed tomography evaluation of neuroendocrine tumors is gaining prominence with the availability of novel pet radiotracers, such as (18)F-DOPA and gallium 68 somatostatin peptide derivatives. These tumors have unique properties and hence the basis of use of these new radiotracers. Prominent centers worldwide have reported the usefulness of these PET tracers in diagnosis and clinical decision making. Portability of 68Ge/68Ga generators has also helped in more widespread use of these somatostatin peptide derivatives as PET radiotracers. This article reviews established and potential roles of these novel PET radiotracers in diagnosis, management, and prognosis of neuroendocrine tumors. PMID- 26099676 TI - (18)F-Flourodeoxy-Glucose PET/Computed Tomography in Brain Tumors: Value to Patient Management and Survival Outcomes. AB - (18)F-flourodeoxy-glucose (FDG) PET/computed tomography (CT) is most useful in the evaluation of primary central nervous system (CNS) lymphoma, important in diagnosis, pretherapy prognosis, and therapy response evaluation. Utility in working up gliomas is less effective, and FDG PET/CT is most helpful when MR imaging is unclear. FDG avidity correlates with the grade of gliomas. FDG PET/CT can be used to noninvasively identify malignant transformation. Establishing this change in the disease process has significant effects on patient management and survival outcome. PMID- 26099677 TI - 18-Fluoro-deoxyglucose-PET/Computed Tomography in Infection and Aseptic Inflammatory Disorders: Value to Patient Management. AB - This communication is aimed specifically at exploring the possible practical advantages and potentials of 18-fluoro-deoxyglucose (FDG)-PET/ computed tomography (CT) that could translate into routine management of patients with infection and aseptic inflammatory disorders. From viewpoint of patient management, the applications can be classified into two broad categories, based upon primary intent of the investigation: [a] Diagnostic (eg, pyrexia of unknown origin and other localized infectious processes) and [b] Undertaking this as part of objective imaging assessment of early treatment response and thereby tailoring/altering therapy (eg, systemic infectious and non-infectious inflammatory diseases). Over the last decade, this promising FDG-PET/CT application has been debated and there is need to make systematic approach for defining its value to patient management. PMID- 26099678 TI - Cardiac PET/Computed Tomography Applications and Cardiovascular Outcome. AB - Cardiac PET/computed tomography (CT) in conjunction with different blood flow tracers is increasingly applied for the assessment of myocardial perfusion and myocardial flow reserve (MFR) in the detection of coronary artery disease (CAD). The ability of PET/CT to noninvasively determine regional myocardial blood flow at rest and during vasomotor stress allows the calculation of the MFR, which carries important prognostic information in patients with subclinical forms of cardiomyopathy. The measured MFR optimizes the identification and characterization of the extent and severity of CAD burden, and contributes to the flow-limiting effect of single lesions in multivessel CAD. PMID- 26099679 TI - PET/CT: Defining Value to Patients and Health Systems. PMID- 26099680 TI - Host preferences and circadian rhythm of Culicoides (Diptera: Ceratopogonidae), vectors of African horse sickness and bluetongue viruses in Senegal. AB - African horse sickness- and bluetongue virus are orbiviruses transmitted by Culicoides biting midges (Diptera: Ceratopogonidae) to horses and to ruminants, respectively. Since the last epizootic outbreak of African horse sickness in 2007 in Senegal, extensive investigations have been undertaken to improve our knowledge on Culicoides species involved locally in the transmission of the virus. The purpose of this study was to compare and quantify the host preferences of potential vectors of these orbiviruses on horse and sheep and to study their circadian rhythm. We found that Culicoides oxystoma and species of the sub-genus Avaritia (Culicoides imicola, Culicoides bolitinos and Culicoides pseudopallidipennis) had a preference for horse when compared to sheep (the predicted ratio between horse and sheep was 80 for C. oxystoma and 26 for C. imicola), and were mostly crepuscular: C. oxystoma had continuous activity throughout the diel with peaks in numbers collected after sunrise and sunset, while C. imicola was mostly nocturnal with peak after sunset. Unexpectedly, species of the subgenus Lasiohelea was also collected during this study. This diurnal biting species was a nuisance pest for both animal species used as bait. PMID- 26099681 TI - Comparative pathogenicity of Trypanosoma brucei rhodesiense strains in Swiss white mice and Mastomys natalensis rats. AB - We evaluated Mastomys natelensis rat as an animal model for Rhodesian sleeping sickness. Parasitaemia, clinical and pathological characteristics induced by T. b. rhodesiense isolates, KETRI 3439, 3622 and 3637 were compared in Mastomys rats and Swiss white mice. Each isolate was intra-peritonially injected in mice and rat groups (n=12) at 1*10(4) trypanosomes/0.2mL. Pre-patent period (PP) range for KETRI 3439 and KETRI 3622-groups was 3-6 days for mice and 4-5 days for rats while for KETRI 3637-infected mice and rats was 5-9 and 4-12 days, respectively. Pairwise comparison between PP of mice and rats separately infected with either isolate showed no significant difference (p>0.05). The PP's of KETRI 3637 infected mice were significantly (p>0.01) longer than those infected with KETRI 3439 or KETRI 3622, a trend also observed in rats. The second parasitaemic wave was more prominent in mice. Clinical signs included body weakness, dyspnoea, peri orbital oedema and extreme emaciation which were more common in rats. Survival time for KETRI 3439 and 3622-infected groups was significantly (p<0.05) longer in mice than rats but similar in KETRI 3637-infected groups. Inflammatory lesions were more severe in rats than mice. All mice and KETRI 3622-infected rats had splenomegaly, organ congestion with rats additionally showing prominent lymphadenopathy. KETRI 3439-infected rats showed hemorrhagic pneumonia, enteritis with moderate splenomegaly and lymphadenopathy. KETRI 3637-infected rats had the most severe lesions characterized by prominent splenomegaly, lymphadenopathy, hepatomegaly, enlarged adrenal glands, organ congestion, generalized oedemas, gastroenteritis, pneumonia and brain congestion. KETRI 3637-infected Mastomys is a suitable model for studying pathophysiology of HAT. PMID- 26099682 TI - Rotation of the external genitalia in male Phlebotomine sand flies (Diptera, Psychodidae) in laboratory conditions and in captured specimens in Algarve, Portugal. AB - Protozoal parasites are the causative agents of many insect-borne infectious diseases worldwide with impact on human and animal health. Leishmaniasis is caused by Leishmania spp. and transmitted by female Phlebotomine sand flies. In Portugal, two species of Phlebotomus (Larroussius), namely Phlebotomus perniciosus and Phlebotomus ariasi are the proven vectors of Leishmania infantum. Phlebotomine females and males rest and breed in the same sites; and these locations can be predicted according to the male external genitalia maturation. Therefore, this study aimed to determine the timing of complete rotation of the male external genitalia in laboratory conditions and to characterize the external genitalia rotation in field captured males to predict the male and female sand fly breeding and resting sites. This knowledge can be applied in the design and implementation of integrated sand fly control strategies targeting these sites. PMID- 26099683 TI - Modeling hepatitis B virus infection, immunopathology and therapy in mice. AB - Despite the availability of a preventive vaccine, chronic hepatitis B virus (HBV) infection-induced liver diseases continue to be a major global public health problem. HBV naturally infects only humans and chimpanzees. This narrow host range has hindered our ability to study the characteristics of the virus and how it interacts with its host. It is thus important to establish small animal models to study HBV infection, persistence, clearance and the immunopathogenesis of chronic hepatitis B. In this review, we briefly summarize currently available animal models for HBV research, then focus on mouse models, especially the recently developed humanized mice that can support HBV infection and immunopathogenesis in vivo. This article is part of a symposium in Antiviral Research on "From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B: an unfinished story." PMID- 26099685 TI - A missed diagnosis of advanced HIV. AB - HIV is now a manageable chronic condition with a near-normal life expectancy if diagnosed early. Treatment can be a simple 'one tablet, once a day' regimen with minimal side effects or interactions with other medication. Unfortunately, healthcare professionals' perception of risk of HIV infection is often incorrect and patients remain undiagnosed because healthcare professionals assume that their patients are not at risk of HIV. This report demonstrates a case of missed HIV diagnosis in the military primary care setting and its consequences because of incorrect assumption rather than presenting clinical conditions. PMID- 26099684 TI - Type 2 diabetes-related variants influence the risk of developing multiple myeloma: results from the IMMEnSE consortium. AB - Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium. Subjects carrying the KCNQ1rs2237892T allele or the CDKN2A-2Brs2383208G/G, IGF1rs35767T/T and MADDrs7944584T/T genotypes had a significantly increased risk of MM (odds ratio (OR)=1.32-2.13) whereas those carrying the KCNJ11rs5215C, KCNJ11rs5219T and THADArs7578597C alleles or the FTOrs8050136A/A and LTArs1041981C/C genotypes showed a significantly decreased risk of developing the disease (OR=0.76-0.85). Interestingly, a prediction model including those T2D-related variants associated with the risk of MM showed a significantly improved discriminatory ability to predict the disease when compared to a model without genetic information (area under the curve (AUC)=0.645 vs AUC=0.629; P=4.05*10(-) (06)). A gender-stratified analysis also revealed a significant gender effect modification for ADAM30rs2641348 and NOTCH2rs10923931 variants (Pinteraction=0.001 and 0.0004, respectively). Men carrying the ADAM30rs2641348C and NOTCH2rs10923931T alleles had a significantly decreased risk of MM whereas an opposite but not significant effect was observed in women (ORM=0.71 and ORM=0.66 vs ORW=1.22 and ORW=1.15, respectively). These results suggest that TD2-related variants may influence the risk of developing MM and their genotyping might help to improve MM risk prediction models. PMID- 26099686 TI - Early Pregnancy Cravings, Dietary Intake, and Development of Abnormal Glucose Tolerance. AB - BACKGROUND: Little is known about the relationships between pregnancy cravings, maternal diet, and development of abnormal glucose tolerance. OBJECTIVES: We examined relationships of pregnancy cravings with dietary intake and risk of developing isolated hyperglycemia (IH), impaired glucose tolerance (IGT), or gestational diabetes (GDM) later in pregnancy. DESIGN/SETTING: Among 2,022 mothers in Project Viva, a prospective birth cohort recruited from medical practices in eastern Massachusetts between 1999 and 2002, we assessed type of pregnancy craving based on self-report at mean gestation of 10.9 weeks. MAIN OUTCOME MEASURES: The outcomes were cross-sectional dietary intake from a food frequency questionnaire and incident IH, IGT, or GDM determined by glucose tolerance screening at 26 to 28 weeks. STATISTICAL ANALYSES PERFORMED: We used linear regression to analyze the cross-sectional relationships between pregnancy cravings and dietary intake and multinomial logistic regression to analyze the prospective relationships among pregnancy cravings and development of IH, IGT, or GDM. RESULTS: During the first trimester, 443 (22%) women craved sweets, 225 (11%) craved salty foods, 261 (13%) craved savory foods, and 100 (4.9%) craved starchy foods. Sweet cravings were associated with increased intake of sucrose (1.9 g/day; 95% CI 0.1 to 3.7), total fat (1.5 g/day; 95% CI 0.1 to 2.9), and saturated fat (0.8 g/day; 95% CI 0.2 to 1.4); salty cravings were associated with increased fiber (0.7 servings/day; 95% CI -0.1 to 1.6); savory cravings were associated with increased n-3 fatty acids (0.10 g/day; 95% CI 0.02 to 0.17); and starchy cravings were associated with increased carbohydrates (8.0 g/day; 95% CI 0.3 to 15.7) and decreased total fat (-2.6 g/day; 95% CI -5.2 to -0.1). Salty cravings were associated with lower risk of GDM (adjusted odds ratio 0.34, 95% CI 0.12-0.97). CONCLUSIONS: New cravings in the first trimester of pregnancy were associated with dietary intake. Craving salty foods may predict reduced risk of developing GDM, whereas craving sweet food does not appear to alter one's risk. PMID- 26099689 TI - Amorphous Ni-Co Binary Oxide with Hierarchical Porous Structure for Electrochemical Capacitors. AB - A simple and outstanding approach is provided to fabricate amorphous structure Ni Co binary oxide as supercapacitors electrode materials. We can easily obtain porous Ni-Co oxides composite materials via chemical bath deposition and subsequent calcination without any template or complicate operation procedures. The amorphous porous Ni-Co binary oxide exhibits brilliant electrochemical performance: first, the peculiar porous structure can effectively transport electrolytes and shorten the ion diffusion path; second, binary composition and amorphous character introduce more surface defects for redox reactions. It shows a high specific capacitance up to 1607 F g(-1) and can be cycled for 2000 cycles with 91% capacitance retention. In addition, the asymmetric supercapacitor delivers superior energy density of 28 W h kg(-1), and the maximum power density of 3064 W kg(-1) with a high energy density of 10 W h kg(-1). PMID- 26099687 TI - Obesity Risk Knowledge, Weight Misperception, and Diet and Health-Related Attitudes among Women Intending to Become Pregnant. AB - OBJECTIVE: Our aim was to evaluate obesity risk knowledge, weight misperception, and diet and health-related attitudes among women intending to become pregnant compared to those not intending to become pregnant. DESIGN: We conducted a cross sectional survey of health behaviors, including obesity risk knowledge, weight misperception, and diet and health-related attitudes among women (aged 16 to 40 years) attending reproductive health clinics in southeast Texas. Data were collected through self-administered questionnaires and chart review. Multivariable logistic regression analyses were performed to examine the association between pregnancy intention and obesity risk knowledge, weight misperception, and health-related attitudes after adjusting for age, race, income, and gravidity. RESULTS: Overall, 1,726 women completed the survey, of which 1,420 responded to a question on pregnancy intention. Of these, 126 stated they were intending to become pregnant. Obesity risk knowledge (adjusted odds ratio=1.14; 95% confidence interval [CI] 0.74 to 1.77) and weight misperception (adjusted odds ratio=1.17; 95% CI 0.75 to 1.83) did not differ between women intending and not intending to become pregnant. In addition, diet and health related attitudes did not differ between these two groups (P>0.05 for all). Among women intending to become pregnant, 51% had low obesity risk knowledge and 31% misperceived their body weight. Further, 76% of these women felt confused about what constitutes a healthy diet, although 47% believed that their current diet was healthy and saw no reason to change their current eating patterns. While weight misperception did not differ significantly between the two groups, overweight women intending to become pregnant were more likely to misperceive their weight than obese women intending to become pregnant (71% vs 10%; P<0.001). CONCLUSIONS: There is a need for improved preconception counseling, especially for women intending to become pregnant, regarding the risks associated with being overweight or obese, misperception of body weight, and negative diet and health related attitudes. PMID- 26099688 TI - Usefulness of data from magnetic resonance imaging to improve prediction of dementia: population based cohort study. AB - OBJECTIVE: To determine whether the addition of data derived from magnetic resonance imaging (MRI) of the brain to a model incorporating conventional risk variables improves prediction of dementia over 10 years of follow-up. DESIGN: Population based cohort study of individuals aged >= 65. SETTING: The Dijon magnetic resonance imaging study cohort from the Three-City Study, France. PARTICIPANTS: 1721 people without dementia who underwent an MRI scan at baseline and with known dementia status over 10 years' follow-up. MAIN OUTCOME MEASURE: Incident dementia (all cause and Alzheimer's disease). RESULTS: During 10 years of follow-up, there were 119 confirmed cases of dementia, 84 of which were Alzheimer's disease. The conventional risk model incorporated age, sex, education, cognition, physical function, lifestyle (smoking, alcohol use), health (cardiovascular disease, diabetes, systolic blood pressure), and the apolipoprotein genotype (C statistic for discrimination performance was 0.77, 95% confidence interval 0.71 to 0.82). No significant differences were observed in the discrimination performance of the conventional risk model compared with models incorporating data from MRI including white matter lesion volume (C statistic 0.77, 95% confidence interval 0.72 to 0.82; P=0.48 for difference of C statistics), brain volume (0.77, 0.72 to 0.82; P=0.60), hippocampal volume (0.79, 0.74 to 0.84; P=0.07), or all three variables combined (0.79, 0.75 to 0.84; P=0.05). Inclusion of hippocampal volume or all three MRI variables combined in the conventional model did, however, lead to significant improvement in reclassification measured by using the integrated discrimination improvement index (P=0.03 and P=0.04) and showed increased net benefit in decision curve analysis. Similar results were observed when the outcome was restricted to Alzheimer's disease. CONCLUSIONS: Data from MRI do not significantly improve discrimination performance in prediction of all cause dementia beyond a model incorporating demographic, cognitive, health, lifestyle, physical function, and genetic data. There were, however, statistical improvements in reclassification, prognostic separation, and some evidence of clinical utility. PMID- 26099690 TI - Biomarkers for precision medicine in airways disease. AB - Chronic obstructive pulmonary disease (COPD) is a complex clinical entity. In contrast to previously limited diagnostic definitions, it is now apparent that COPD is a clinically and biologically heterogeneous disease process, overlapping with other airways diseases like chronic asthma. As such, symptomatic response to current standard treatment practices is variable. New clinical guidelines have been altered to reflect this, with the inclusion of symptoms and risk factors in diagnostic and management algorithms. However, as our understanding of COPD pathophysiology deepens, many novel physiological, cellular, proteomic, and genetic markers have been identified. Several have been observed to be independently predictive of distinct clinical disease patterns, which at present are not illustrated by conventional measurements of lung impairment. The potential use of these predictive biomarkers to stratify this diverse patient population could transform the care we offer. We should aim for precision medicine to optimize diagnosis and treatment choices and to monitor and improve clinical outcomes in this disease. PMID- 26099691 TI - Preface for companion diagnostics. PMID- 26099692 TI - Effect of gamma irradiation on the wear behaviour of human tooth enamel. AB - Radiotherapy is a frequently used treatment for oral cancer. Extensive research has been conducted to detect the mechanical properties of dental hard tissues after irradiation at the macroscale. However, little is known about the influence of irradiation on the tribological properties of enamel at the micro- or nanoscale. Therefore, this study aimed to investigate the effect of gamma irradiation on the wear behaviour of human tooth enamel in relation to prism orientation. Nanoscratch tests, surface profilometer and scanning electron microscope (SEM) analysis were used to evaluate the friction behaviour of enamel slabs before and after treatment with identical irradiation procedures. X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were performed to analyse the changes in crystallography and chemical composition induced by irradiation. Surface microhardness (SMH) alteration was also evaluated. The results showed that irradiation resulted in different scratch morphologies, friction coefficients and remnant depth and width at different loads. An inferior nanoscratch resistance was observed independent of prism orientation. Moreover, the variation of wear behaviours was closely related to changes in the crystallography, chemical composition and SMH of the enamel. Together, these measures indicated that irradiation had a direct deleterious effect on the wear behaviour of human tooth enamel. PMID- 26099693 TI - Reorganization of the host cell Crk(L)-PI3 kinase signaling complex by the influenza A virus NS1 protein. AB - The non-structural protein-1 (NS1) of influenza A virus binds the p85beta subunit of phosphoinositide 3-kinase (PI3K) to induce PI3K activity in the infected cells. Some virus strains encode NS1 containing a motif that binds tightly to the SH3 domain of the cellular adapter proteins Crk and CrkL to potentiate NS1 induced PI3K activation. Here we show that this potentiation involves reorganization of the natural CrkL-p85beta complex into a novel trimeric complex where NS1 serves as a bridging factor. Of note, NS1 proteins that lack the SH3 binding capacity can also associate with CrkL, but in a less stable trimeric complex mediated by p85beta. The data presented here establish Crk proteins as general host cell cofactors of NS1, and show that the enhanced PI3K activation by SH3 binding-competent NS1 variants is mediated by a more efficient tethering of Crk proteins to the NS1-PI3K complex. PMID- 26099696 TI - Computational fishing of new DNA methyltransferase inhibitors from natural products. AB - DNA methyltransferase inhibitors (DNMTis) have become an alternative for cancer therapies. However, only two DNMTis have been approved as anticancer drugs, although with some restrictions. Natural products (NPs) are a promising source of drugs. In order to find NPs with novel chemotypes as DNMTis, 47 compounds with known activity against these enzymes were used to build a LDA-based QSAR model for active/inactive molecules (93% accuracy) based on molecular descriptors. This classifier was employed to identify potential DNMTis on 800 NPs from NatProd Collection. 447 selected compounds were docked on two human DNA methyltransferase (DNMT) structures (PDB codes: 3SWR and 2QRV) using AutoDock Vina and Surflex Dock, prioritizing according to their score values, contact patterns at 4 A and molecular diversity. Six consensus NPs were identified as virtual hits against DNMTs, including 9,10-dihydro-12-hydroxygambogic, phloridzin, 2',4' dihydroxychalcone 4'-glucoside, daunorubicin, pyrromycin and centaurein. This method is an innovative computational strategy for identifying DNMTis, useful in the identification of potent and selective anticancer drugs. PMID- 26099694 TI - Interaction between unrelated viruses during in vivo co-infection to limit pathology and immunity. AB - Great progress has been made in understanding immunity to viral infection. However, infection can occur in the context of co-infection by unrelated pathogens that modulate immune responses and/or disease. We have studied immunity and disease during co-infection with two unrelated viruses: Ectromelia virus (ECTV) and Lymphocytic Choriomeningitis virus (LCMV). ECTV infection can be a lethal in mice due in part to the blockade of Type I Interferons (IFN-I). We show that ECTV/LCMV co-infection results in decreased ECTV viral load and amelioration of ECTV-induced disease, likely due to IFN-I induction by LCMV, as rescue is not observed in IFN-I receptor deficient mice. However, immune responses to LCMV in ECTV co-infected mice were also lower compared to mice infected with LCMV alone and potentially biased toward effector-memory cell generation. Thus, we provide evidence for bi-directional effects of viral co-infection that modulate disease and immunity. PMID- 26099695 TI - Immunogenicity of Newcastle disease virus vectors expressing Norwalk virus capsid protein in the presence or absence of VP2 protein. AB - Noroviruses are the most common cause of acute gastroenteritis in humans. Development of an effective vaccine is required for reducing their outbreaks. In order to develop a GI norovirus vaccine, Newcastle disease virus vectors, rLaSota and modified rBC, were used to express VP1 protein of Norwalk virus. Co expression of VP1 and VP2 proteins by Newcastle disease virus vectors resulted in enhanced expression of Norwalk virus VP1 protein and self-assembly of VP1 protein into virus-like particles. Furthermore, the Norwalk virus-specific IgG response induced in mice by Newcastle disease virus vectors was similar to that induced by baculovirus-expressed virus-like particles in mice. However, the modified rBC vector in the presence of VP2 protein induced significantly higher levels of cellular and mucosal immune responses than those induced by baculovirus-expressed VLPs. These results indicate that Newcastle disease virus has great potential for developing a live Norwalk virus vaccine by inducing humoral, cellular and mucosal immune responses in humans. PMID- 26099697 TI - Recurrent Ipsilateral Ovarian Torsion: Case Report and Literature Review. AB - BACKGROUND: Recurrent ipsilateral ovarian torsion at pediatric age is a rare event. Different surgical techniques for its prevention are available. We present a case of recurrent ipsilateral ovarian torsion in a prepubertal girl and we reviewed the literature about the management of this condition. CASE: A 6-year old girl presented with right ovarian torsion and underwent a laparoscopic untwisting. Nine months later an ipsilateral recurrence occurred. Laparoscopic untwisting and right-sided oophoropexy with plication to the round ligament was performed. SUMMARY AND CONCLUSION: In addition to our presented case, four cases of recurrent ipsilateral ovarian torsion in pediatric patients were identified in the literature. The few available reports in the pediatric literature show different management techniques. A long-term study is necessary to define the most effective treatment. PMID- 26099698 TI - The Association between Insurance Status and Acceptance of Chlamydia Screening By Teenagers Who Present for Preventive Care Visits. AB - STUDY OBJECTIVE: The purpose of this study was to evaluate whether providers offer chlamydia screening to teenagers and/or whether screening is accepted at different rates depending on insurance type. DESIGN: Retrospective chart review. SETTING: Academic center serving urban and suburban patients between April 2009 and October 2011. PARTICIPANTS: Nine hundred eighty-three health maintenance visits for asymptomatic, insured female adolescents aged 15-19 years. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Dichotomous dependent variables of interest indicated whether chlamydia screening was: (1) offered; and (2) accepted. The key independent variable insurance type was coded as 'public' if Medicaid or Medicaid Managed Care and 'private' if a commercial plan. chi(2) and logistic regression analyses were used to assess the significance of differences in screening rates according to insurance type. RESULTS: Of asymptomatic health maintenance visits 933 (95%) had a documented sexual history and 339 (34%) had a documented history of sexual activity. After excluding those who had a documented chlamydia screen in the 12 months before the visit (n = 79; 23%), 260 visits met eligibility for chlamydia screening. Only 169 (65%) of eligible visits had chlamydia screening offered and there was no difference in offer of screening according to insurance type. Significantly more visits covered by public insurance had chlamydia screening accepted (98%) than those covered by private insurance (82%). Controlling for demographic factors, the odds of accepted chlamydia screening was 8 times higher in visits covered by public insurance than those with private insurance. CONCLUSION: Although publically and privately insured teens were equally likely to be offered chlamydia screening, publically insured teens were significantly more likely to accept screening. Future research should investigate reasons for this difference in screening acceptance. These findings have implications for interventions to improve chlamydia screening because more adolescents are covered by parental insurance under the Affordable Care Act. PMID- 26099699 TI - Sporadic lower motor neuron disease with a snake eyes appearance on the cervical anterior horns by MRI. AB - OBJECTIVE: Lower motor neuron disease (LMND) is the term generally used to describe diseases in which only lower motor neuron signs are detected. A snake eyes appearance on magnetic resonance imaging (MRI) is associated with a wide spectrum of neurological conditions including LMND. The author reports on three unique LMND patients with upper limb muscle weakness and atrophy who show a snake eyes appearance by MRI. PATIENTS AND METHODS: The patients were aged 18, 40 and 52 years, respectively, at the onset of the disease and had a longstanding clinical course (more than 10 years for two patients and 8 years for one patient). They were followed up for more than 6 years. RESULTS: Clinical manifestations were characterized by (1) longstanding slow progression or delayed spontaneous arrest of asymmetric lower motor neuron signs localized exclusively in the upper extremities with unilateral predominance and distal or proximal preponderance; (2) the absence of upper motor neuron signs, bulbar signs, sensory disturbances and respiratory involvement; (3) a snake eyes appearance on the anterior horns of the cervical cord over more than 3 vertebrae by axial T2 weighted MRI and a longitudinal linear-shaped T2-signal hyperintensity by sagittal MRI; (4) neurogenic change with fasciculation and denervation potentials (fibrillation and a positive sharp wave) confined to the affected muscles by needle electromyogram; and (5) normal cerebrospinal fluid and a normal creatine kinase level. These cases did not fall into any existing category of LMND, such as progressive muscular atrophy, flail arm syndrome or Hirayama disease. CONCLUSIONS: These patients should be classified as sporadic LMND with snake eyes on MRI with a relatively benign prognosis. PMID- 26099700 TI - Bacterial brain abscess formation in post-irradiated patients: What is the possible pathogenesis? AB - BACKGROUND: Until recently, post-radiotherapy brain abscess was considered rare, but it has become an increasingly important aetiology. Discussions of the relationship between bacterial brain abscess and radiotherapy (RT) are rare in the literature. Our clinical study was conducted to analyse the role of RT in the pathogenesis of bacterial brain abscess. METHODS: For our retrospective study, 146 patients with bacterial brain abscess were recruited. Ten patients with a history of RT before brain abscess formation were reviewed. RESULTS: Eight of these patients underwent RT treatment for nasopharyngeal carcinoma, one for olfactory neuroblastoma, and another for nasal plasmacytoma. Three showed presence of temporal lobe radiation necrosis neighbouring abscess. Eight patients were shown to have the evidence of tumour invasion. Seven had evidence of nasal infection or otitis media. Statistically significant differences between the RT and non-RT patients were observed for radionecrosis, bone defects between the middle fossa/sphenoid sinus, and the presence of nasal infection/otitis media. The mortality rate was 30%. CONCLUSION: This study shows possible pathogenesis of bacterial brain abscess formation in post-irradiated patients, which is complicated by both radiation effects and tumour effects. Skull base deficits (either from tumour erosion or osteonecrosis) and nasal/ear infection were significantly different in patients who received radiation vs. those who did not. Radiation-related temporal lobe necrosis was also a predisposing factor. Further study based on a proper patient cohort is warranted. PMID- 26099701 TI - Advances in Intra-abdominal Sepsis: What Is New? AB - We have reviewed the literature regarding recent advances in the management of intra-abdominal sepsis, with a focus on antimicrobial agents, duration of therapy, and source control. Several important developments in these areas are discussed in this review. The introduction of a new antimicrobial agent ceftolozane/tazobactam-marks the first novel agent for treating intra-abdominal infections in a number of years, and its indications for use and supporting evidence are reviewed here. In addition, we discuss recent evidence that clarifies the importance of early source control for intra-abdominal infection and new data that suggests that an abbreviated course of antimicrobial therapy for intra-abdominal infection is equally effective as prolonged therapy. PMID- 26099702 TI - Troubles ahead. PMID- 26099708 TI - Heusler alloys: Tuning exchange bias. PMID- 26099709 TI - Dislocation nucleation: Diffusive origins. PMID- 26099710 TI - X-ray microscopy: Beyond ensemble averages. PMID- 26099711 TI - Epidermal electronics: Skin health monitoring. PMID- 26099712 TI - Material witness: The complex costs of faking it. PMID- 26099713 TI - DNA-peptide complexes: Regulation of interferon production. PMID- 26099714 TI - Wound healing: Enzymatically crosslinked scaffolds. PMID- 26099715 TI - Silicon photonics: Large-scale dielectric metasurfaces. PMID- 26099716 TI - Phonon wave interference and thermal bandgap materials. AB - Wave interference modifies phonon velocities and density of states, and in doing so creates forbidden energy bandgaps for thermal phonons. Materials that exhibit wave interference effects allow the flow of thermal energy to be manipulated by controlling the material's thermal conductivity or using heat mirrors to reflect thermal vibrations. The technological potential of these materials, such as enhanced thermoelectric energy conversion and improved thermal insulation, has fuelled the search for highly efficient phonon wave interference and thermal bandgap materials. In this Progress Article, we discuss recent developments in the understanding and manipulation of heat transport. We show that the rational design and fabrication of nanostructures provides unprecedented opportunities for creating wave-like behaviour of heat, leading to a fundamentally new approach for manipulating the transfer of thermal energy. PMID- 26099717 TI - Erratum: Photochemical transformations on plasmonic metal nanoparticles. PMID- 26099718 TI - Nanomaterials and Optical Diagnosis of HIV. AB - The investigators had previously shown that the risk of AIDS/HIV-related illness and transmission reduced (by 96%) with early antiretroviral treatment. Nanomaterials could be applied in early diagnosis of HIV by improving the ability to detect serum biomarkers of the blood-borne infectious diseases, with low sample volume, rapidity, and more sensitivity than currently available FDA approved methods such as ELISA, particle agglutination assay, and Western Blotting assay. We have demonstrated several experimental studies for optical HIV diagnosis based on nanomaterials in three categories (e.g., the fluorescence-, the SPR-, and the SERS- based biosensors), and have explained each assay. PMID- 26099719 TI - Development of Flow Imaging Analysis for Subvisible Particle Characterization in Glatiramer Acetate. AB - Proteins, peptides, colloids, and polymers present a rapidly growing field of pharmaceutical industry. Bringing these products into market, however, is a huge regulatory challenge, especially because many of these therapeutics are intended for parenteral administration. Physicochemical properties of such products--size, shape, surface potential, and extent of particle-particle interaction-have to be well understood and monitored throughout manufacturing, release, and stability testing. First and foremost, size distribution of subvisible particles (SVP) in these products should be reliably measured. We present development of a flow imaging method to assess SVP in the polypeptide injectable therapeutic product glatiramer acetate (Copaxone((r))). Flow imaging comprises optical inspection of a flowing liquid and allows quantitation of particles in the range of 1-500 MUm. The challenges of method development are discussed and the method performance characteristics--accuracy, precision, linearity, and specificity--are demonstrated. PMID- 26099720 TI - Universal elastic-hardening-driven mechanical instability in alpha-quartz and quartz homeotypes under pressure. AB - As a fundamental property of pressure-induced amorphization (PIA) in ice and ice like materials (notably alpha-quartz), the occurrence of mechanical instability can be related to violation of Born criteria for elasticity. The most outstanding elastic feature of alpha-quartz before PIA has been experimentally reported to be the linear softening of shear modulus C44, which was proposed to trigger the transition through Born criteria B3. However, by using density-functional theory, we surprisingly found that both C44 and C66 in alpha-quartz exhibit strong nonlinearity under compression and the Born criteria B3 vanishes dominated by stiffening of C14, instead of by decreasing of C44. Further studies of archetypal quartz homeotypes (GeO2 and AlPO4) repeatedly reproduced the same elastic hardening-driven mechanical instability, suggesting a universal feature of this family of crystals and challenging the long-standing idea that negative pressure derivatives of individual elastic moduli can be interpreted as the precursor effect to an intrinsic structural instability preceding PIA. The implications of this elastic anomaly in relation to the dispersive softening of the lowest acoustic branch and the possible transformation mechanism were also discussed. PMID- 26099721 TI - High-quality sandwiched black phosphorus heterostructure and its quantum oscillations. AB - Two-dimensional materials such as graphene and transition metal dichalcogenides have attracted great attention because of their rich physics and potential applications in next-generation nanoelectronic devices. The family of two dimensional materials was recently joined by atomically thin black phosphorus which possesses high theoretical mobility and tunable bandgap structure. However, degradation of properties under atmospheric conditions and high-density charge traps in black phosphorus have largely limited its actual mobility thus hindering its future applications. Here, we report the fabrication of stable sandwiched heterostructures by encapsulating atomically thin black phosphorus between hexagonal boron nitride layers to realize ultra-clean interfaces that allow a high field-effect mobility of ~1,350 cm(2)V(-1) s(-1) at room temperature and on off ratios exceeding 10(5). At low temperatures, the mobility even reaches ~2,700 cm(2)V(-1) s(-1) and quantum oscillations in black phosphorus two-dimensional hole gas are observed at low magnetic fields. Importantly, the sandwiched heterostructures ensure that the quality of black phosphorus remains high under ambient conditions. PMID- 26099722 TI - 3D Porous Crystalline Polyimide Covalent Organic Frameworks for Drug Delivery. AB - Three-dimensional porous crystalline polyimide covalent organic frameworks (termed PI-COFs) have been synthesized. These PI-COFs feature non- or interpenetrated structures that can be obtained by choosing tetrahedral building units of different sizes. Both PI-COFs show high thermal stability (>450 degrees C) and surface area (up to 2403 m(2) g(-1)). They also show high loading and good release control for drug delivery applications. PMID- 26099723 TI - Effect of hesperidin on mice bearing Ehrlich solid carcinoma maintained on doxorubicin. AB - Doxorubicin (DOX) is widely used in cancer therapy of many carcinomas types. Unfortunately, DOX is not sufficiently effective in many cases, and increasing the dosage of it is limited due to its systemic toxicity. A citrus flavonoid hesperidin (HES) is proved to be potent antioxidant and protective agent against many diseases including cancer. In this context, the objective of this study was to examine effect of HES along with DOX on solid Ehrlich carcinoma (SEC) in mice. Forty male mice were divided into four equal groups (n = 10): control SEC, DOX, HES, and DOX + HES. HES (50 mg/kg body weight orally) was given day after day for 16 days along with DOX (4 mg/kg body weight i.p. injection) for 5 cycles every 4 days in ESC-inoculated mice. After 20 days, tumor volume, tumor weight, survival rate, tumor glutathione, nitric oxide content, and serum glutathione were determined. Tumor tissue was examined for histopathological and immunohistochemical study for p53 and VEGF. Tumor resistance for mdr1a gene was assessed in tumor tissue by RT-PCR. HES induced significant increase in tissue and serum glutathione with significant decrease in tumor volume and tumor weight. A possible role of HES to modulate gene expression of mdr1a in tumor tissue was established. In addition, HES alleviated the histopathological changes with significant decrease in p53 and VEGF expression. The use of HES as adjuvant therapy with DOX would enhance the therapeutic efficacy and alleviate the resistance to DOX in treatment of solid tumors. PMID- 26099725 TI - Retraction Note to: Erucylphosphocholine induces growth inhibition, cell cycle arrest, and apoptosis in human choriocarcinoma cells. PMID- 26099724 TI - The relationship between the expression of VEGF, EGFR, and HER-2 mRNA in esophageal squamous cell carcinoma (ESCC) and clinicopathological features of different ethnic groups in Xinjiang. AB - The purpose of this study was to explore the relationship between the expression of vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER-2), and epidermal growth factor receptor (EGFR) mRNA in esophageal squamous cell carcinoma (ESCC) and the clinicopathological characteristics of the Han, Uyghur, and Kazakh in Xinjiang. Real-time quantitative polymerase chain reaction technology (RT-PCR) was used to detect the expression of VEGF, HER-2, and EGFR mRNA in esophageal squamous cancer tissue of 60 cases and 30 cases of VEGF, HER-2, and EGFR mRNA in esophageal cancer adjacent tissues, and analyze its relationship with clinicopathological features. The results were as follows: (1) There was no statistically significant difference in esophageal tissue VEGF, HER-2, and EGFR mRNA gene expression levels of the Han, Uyghur, and Kazakh patients (P > 0.05). (2) The expression levels of VEGF, HER-2, and EGFR mRNA in ESCC group were higher than those in adjacent esophageal tissue group (P < 0.05). (3) The expression levels of VEGF and HER-2 mRNA in ESCC of the Han patients were higher than those of the Uyghur and Kazakh patients (P < 0.05). (4) The expression levels of VEGF, HER-2, and EGFR mRNA in lymph node metastases were higher than those without lymph node metastasis (P < 0.05). (5) The expression level of HER-2 mRNA was related with the degrees of pathological differentiation, and the higher pathologic degree, the lower expression level in HER-2 mRNA (P < 0.05). Therefore, the following conclusions were drawn: (1) There were ethnic differences in the VEGF and HER-2 gene mRNA expression levels of the Uyghur, Han, and Kazakh patients in Xinjiang. (2) The expressions of VEGF, HER-2, and EGFR mRNA were related to the lymph node metastasis in ESCC and pathologic differentiation degree. PMID- 26099726 TI - Fuzzy clustering demonstrates that codon 72 SNP rs1042522 of TP53 gene associated with HNSCC but not with prognoses. AB - It is estimated that 7.6 million people will die as a consequence of head and neck squamous cell carcinoma (HNSCC). Genetic predisposition has emerged as an important risk factor in the development and prognosis of HNSCC. Considering this, the aim of the current study is to assess whether codon 72 SNP of the TP53 gene (rs1042522) is associated with an increased odds ratio of developing HNSCC or with a worse prognosis in patients with HNSCC. Analysis of the rs1042522 in HNSCC patients and in control individuals. Differences between the case and control groups were determined using chi-squared tests. Multivariate analysis was performed to evaluate the odds ratio of HNSCC. Fussy C Means Clustering was to cluster HNSCC patients for survival analyses. Time of survival was calculated using the Kaplan-Meier estimator and comparing this to the log rank test. Statistical significance was set at p < 0.05. A total of 71.4 % of the Arg/Arg genotype were from HNSCC patients, while only 28.6 % of Arg/Arg genotype were found in the control group. Logistic regression demonstrated that the Arg/Arg genotype, smoking, and alcohol consumption increase the odds ratio of HNSCC. No association between TP53 codon 72 polymorphism and P53 expression. No association between rs1042522 and survival or prognoses was observed. This study identified that individuals carrying the arginine allele at rs1042522 have an increased odds ratio of HNSCC. However, no association between codon 72 SNP of the TP53 gene and HNSCC prognosis or P53 expression was observed. PMID- 26099727 TI - Origin of photovoltaic effect in superconducting YBa2Cu3O6.96 ceramics. AB - We report remarkable photovoltaic effect in YBa2Cu3O6.96 (YBCO) ceramic between 50 and 300 K induced by blue-laser illumination, which is directly related to the superconductivity of YBCO and the YBCO-metallic electrode interface. There is a polarity reversal for the open circuit voltage Voc and short circuit current Isc when YBCO undergoes a transition from superconducting to resistive state. We show that there exists an electrical potential across the superconductor-normal metal interface, which provides the separation force for the photo-induced electron hole pairs. This interface potential directs from YBCO to the metal electrode when YBCO is superconducting and switches to the opposite direction when YBCO becomes nonsuperconducting. The origin of the potential may be readily associated with the proximity effect at metal-superconductor interface when YBCO is superconducting and its value is estimated to be ~10(-8) mV at 50 K with a laser intensity of 502 mW/cm(2). Combination of a p-type material YBCO at normal state with an n-type material Ag-paste forms a quasi-pn junction which is responsible for the photovoltaic behavior of YBCO ceramics at high temperatures. Our findings may pave the way to new applications of photon-electronic devices and shed further light on the proximity effect at the superconductor-metal interface. PMID- 26099728 TI - Risk Factors for Central Compartment Lymph Node Metastasis in Papillary Thyroid Microcarcinoma: A Meta-Analysis. AB - BACKGROUND: The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central lymph node dissection (CLND), remains controversial. This meta-analysis was conducted to investigate the clinicopathologic factors predictive of central compartment lymph node metastasis (CLNM) in patients diagnosed with PTMC. METHODS: PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library were searched from their inception to September 2013. Published studies that explored the association between clinicopathologic factors and CLNM in PTMC patients were included. From the identified studies, we extracted the number of individuals with or without each risk factor to calculate the CLNM-positive proportions and used fixed/random-effects models for the meta analyses of overall relative risk (RR). The pooling analysis on the association between CLNM or the different CLNDs and prognosis was also conducted. RESULTS: A total of 19 eligible studies that included 8345 patients were identified. Three studies did therapeutic CLND, while the other 16 studies performed prophylactic CLND in PTMC patients. Meta-analyses revealed that CLNM was associated with male gender (RR = 1.36; 95 % CI 1.22-1.52, p = 0.001), younger age (<45 years; RR = 1.15; 95 % CI 1.04-1.27, p = 0.006), larger tumor size (>5 mm; RR = 1.51 95 % CI 1.32-1.65, p = 0.001), multifocality (RR = 1.40; 95 % CI 1.27-1.54, p = 0.001), and extrathyroidal extension (RR = 1.81; 95 % CI 1.34-2.43, p = 0.001). Meta regression analysis indicated that a disparity in the proportion of PTMC patients with CLNM in each study was the main factor resulting in heterogeneity among the 19 studies. In addition, the pooling analyses suggested that CLNM did not significantly predict neck recurrences [hazard ratio (HR) = 0.95, 95 % CI 0.67 1.22, p = 0.054], and the prophylactic CLND group did not improve local control significantly compared to the therapeutic group (RR = 0.96, 95 % CI 0.46-2.01, p = 0.544). CONCLUSION: Prophylactic CLND may be performed in PTMC patients with clinically uninvolved central lymph nodes but with high risk factors; multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for central nodes in PTMC. PMID- 26099730 TI - Epigenetic regulatory elements: Recent advances in understanding their mode of action and use for recombinant protein production in mammalian cells. AB - Successful generation of high producing cell lines requires the generation of cell clones expressing the recombinant protein at high levels and the characterization of the clones' ability to maintain stable expression levels. The use of cis-acting epigenetic regulatory elements that improve this otherwise long and uncertain process has revolutionized recombinant protein production. Here we review and discuss new insights into the molecular mode of action of the matrix attachment regions (MARs) and ubiquitously-acting chromatin opening elements (UCOEs), i.e. cis-acting elements, and how these elements are being used to improve recombinant protein production. These elements can help maintain the chromatin environment of the transgene genomic integration locus in a transcriptionally favorable state, which increases the numbers of positive clones and the transgene expression levels. Moreover, the high producing clones tend to be more stable in long-term cultures even in the absence of selection pressure. Therefore, by increasing the probability of isolating a high producing clone, as well as by increasing transcription efficiency and stability, these elements can significantly reduce the time and cost required for producing large quantities of recombinant proteins. PMID- 26099731 TI - A time of change: Dynamics of chromatin and transcriptional regulation during nuclear programming in early Drosophila development. AB - In order for a new organism to form, the genomes of the highly specialized egg and sperm need to be reprogrammed into a totipotent state that is capable of generating all of the cell types that comprise an organism. This reprogramming occurs by erasing chromatin modifications, leaving the cells in a naive state, followed by the induction of specialized programming events. Pioneer factors bind to the genome prior to zygotic genome activation, followed by acetylation of histones and further chromatin specialization by the addition of methylation marks later during differentiation. Genome-wide approaches have provided insight into the genomic and epigenomic regulation of gene expression during development, providing a new perspective on the process of cell specification and differentiation. In this review, we discuss how distal DNA and core promoter elements, RNA polymerase pausing, transcription factors, and co-regulators interact to shape the chromatin landscape and direct tissue-specific expression patterns during embryo development, focusing on the well-characterized Drosophila embryo. PMID- 26099732 TI - Secondary diffuse large B-cell lymphoma of the central nervous system: the need for better predictors. PMID- 26099734 TI - Zeolites for the selective adsorption of sulfur hexafluoride. AB - Molecular simulations have been used to investigate at the molecular level the suitability of zeolites with different topology on the adsorption, diffusion and separation of a nitrogen-sulfur hexafluoride mixture containing the latter at low concentration. This mixture represents the best alternative for the sulfur hexafluoride in industry since it reduces the use of this powerful greenhouse gas. A variety of zeolites are tested with the aim to identify the best structure for the recycling of sulfur hexafluoride in order to avoid its emission to the atmosphere and to overcome the experimental difficulties of its handling. Even though all zeolites show preferential adsorption of sulfur hexafluoride, we identified local structural features that reduce the affinity for sulfur hexafluoride in zeolites such as MOR and EON, providing exclusive adsorption sites for nitrogen. Structures such as ASV and FER were initially considered as good candidates based on their adsorption features. However, they were further discarded based on their diffusion properties. Regarding operation conditions for separation, the range of pressure that spans from 3 * 10(2) to 3 * 10(3) kPa was identified as the optimal to obtain the highest adsorption loading and the largest SF6/N2 selectivity. Based on these findings, zeolites BEC, ITR, IWW, and SFG were selected as the most promising materials for this particular separation. PMID- 26099735 TI - Care episode retrieval: distributional semantic models for information retrieval in the clinical domain. AB - Patients' health related information is stored in electronic health records (EHRs) by health service providers. These records include sequential documentation of care episodes in the form of clinical notes. EHRs are used throughout the health care sector by professionals, administrators and patients, primarily for clinical purposes, but also for secondary purposes such as decision support and research. The vast amounts of information in EHR systems complicate information management and increase the risk of information overload. Therefore, clinicians and researchers need new tools to manage the information stored in the EHRs. A common use case is, given a--possibly unfinished--care episode, to retrieve the most similar care episodes among the records. This paper presents several methods for information retrieval, focusing on care episode retrieval, based on textual similarity, where similarity is measured through domain-specific modelling of the distributional semantics of words. Models include variants of random indexing and the semantic neural network model word2vec. Two novel methods are introduced that utilize the ICD-10 codes attached to care episodes to better induce domain-specificity in the semantic model. We report on experimental evaluation of care episode retrieval that circumvents the lack of human judgements regarding episode relevance. Results suggest that several of the methods proposed outperform a state-of-the art search engine (Lucene) on the retrieval task. PMID- 26099736 TI - The vulnerable aspects of application of "Health Technology Assessment". PMID- 26099737 TI - Activation of the endoplasmic reticulum stress pathway involving CHOP in the lungs of rats with hyperoxia-induced bronchopulmonary dysplasia. AB - The molecular pathomechanisms underlying bronchopulmonary dysplasia (BPD) remain to be fully elucidated, however, lung injury is considered to be a key event. The present study was performed to determine the role of endoplasmic reticulum (ER) stress and investigate the apoptosis of alveolar epithelial cells in a BPD rat model. A total of 48 preterm Sprague-Dawley rats were randomly divided into a control group and a hyperoxia group. The rats in the BPD group were exposed to 85% hyperoxia, while the rats in the control group were exposed to room air. A total of eight rats in each group were sacrificed 7, 14 or 21 days after exposure. The expression levels of 78-kDa glucose-regulated/binding immunoglobulin protein (GRP78) and CCAAT/enhancer binding protein homologous protein (CHOP) in the lung tissues were examined using immunohistochemistry, and the mRNA and protein levels of GRP78 and CHOP were detected using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. In addition, the levels of apoptosis in the lung cells were evaluated suing terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. It was demonstrated that the mRNA and protein levels of GRP78 and CHOP, and the levels of cell apoptosis in the hyperoxia group differed significantly from those in the control group (P<0.05) at different time-points, and increased with extension of the duration of hyperoxic exposure. These data demonstrated that the ER stress pathway, involving CHOP, is activated and is important in the pathogenesis of BPD. PMID- 26099738 TI - Influence of Genotype, Environment, and Gypsy Moth Herbivory on Local and Systemic Chemical Defenses in Trembling Aspen (Populus tremuloides). AB - Numerous studies have explored the impacts of intraspecific genetic variation and environment on the induction of plant chemical defenses by herbivory. Relatively few, however, have considered how those factors affect within-plant distribution of induced defenses. This work examined the impacts of plant genotype and soil nutrients on the local and systemic phytochemical responses of trembling aspen (Populus tremuloides) to defoliation by gypsy moth (Lymantria dispar). We deployed larvae onto foliage on individual tree branches for 15 days and then measured chemistry in leaves from: 1) branches receiving damage, 2) undamaged branches of insect-damaged trees, and 3) branches of undamaged control trees. The relationship between post-herbivory phytochemical variation and insect performance also was examined. Plant genotype, soil nutrients, and damage all influenced phytochemistry, with genotype and soil nutrients being stronger determinants than damage. Generally, insect damage decreased foliar nitrogen, increased levels of salicinoids and condensed tannins, but had little effect on levels of a Kunitz trypsin inhibitor, TI3. The largest damage-mediated tannin increases occurred in leaves on branches receiving damage, whereas the largest salicinoid increases occurred in leaves of adjacent, undamaged branches. Foliar nitrogen and the salicinoid tremulacin had the strongest positive and negative relationships, respectively, with insect growth. Overall, plant genetics and environment concomitantly influenced both local and systemic phytochemical responses to herbivory. These findings suggest that herbivory can contribute to phytochemical heterogeneity in aspen foliage, which may in turn influence future patterns of herbivory and nutrient cycling over larger spatial scales. PMID- 26099739 TI - Pseudo nucleotide composition or PseKNC: an effective formulation for analyzing genomic sequences. AB - With the avalanche of DNA/RNA sequences generated in the post-genomic age, it is urgent to develop automated methods for analyzing the relationship between the sequences and their functions. Towards this goal, a series of sequence-based methods have been proposed and applied to analyze various character-unknown DNA/RNA sequences in order for in-depth understanding their action mechanisms and processes. Compared with the classical sequence-based methods, the pseudo nucleotide composition or PseKNC approach developed very recently has the following advantages: (1) it can convert length-different DNA/RNA sequences into dimension-fixed digital vectors that can be directly handled by all the existing machine-learning algorithms or operation engines; (2) it can contain the desired features and properties according to the selection or definition of users; (3) it can cover considerable sequence pattern information, both local and global. This minireview is focused on the concept of pseudo nucleotide composition, its development and applications. PMID- 26099740 TI - Quantification acuity in spontaneous shoaling decisions of three-spined sticklebacks. AB - The ability to discriminate between different quantities is widespread throughout the animal kingdom, and the underlying mechanisms of quantity discrimination are currently intensely discussed. In contrast, questions elucidating the limits of quantity estimation received rather little attention so far. Here, we examined fine-tuned quantity estimation in the three-spined stickleback (Gasterosteus aculeatus) in a natural context, i.e. during shoaling decisions. Wild-caught focal fish were given the spontaneous choice between two shoals which differed in group size by 1 fish (0 vs. 1, 1 vs. 2, 2 vs. 3, 3 vs. 4, 4 vs. 5, 5 vs. 6 and 6 vs. 7), based on visual assessment. The results show that sticklebacks generally prefer to shoal with the larger group. They discriminated numerical contrasts up to 6 versus 7, equalling a numerical ratio of 0.86. Preference patterns followed Weber's law, i.e. decreased with increasing numerical ratio. This pattern was found across all numerical conditions as well as within the small number range (ranging from 1 vs. 2 to 3 vs. 4). The results suggest that wild-caught three spined sticklebacks are spontaneously able (i.e. without prior learning) to detect subtle differences in shoal sizes. Further, they confirm findings of previous studies highlighting the contribution of the analogue magnitude system to quantity estimation in fishes. PMID- 26099741 TI - Patterns of Care and Clinical Outcomes of First-Line Trastuzumab-Based Therapy in HER2-Positive Metastatic Breast Cancer Patients Relapsing After (Neo)Adjuvant Trastuzumab: An Italian Multicenter Retrospective Cohort Study. AB - BACKGROUND: We evaluated the patterns of care and clinical outcomes of metastatic breast cancer patients treated with first-line trastuzumab-based therapy after previous (neo)adjuvant trastuzumab. MATERIALS AND METHODS: A total of 416 consecutive, HER2-positive metastatic breast cancer patients who had received first-line trastuzumab-based therapy were identified at 14 Italian centers. A total of 113 patients had presented with de novo stage IV disease and were analyzed separately. Dichotomous clinical outcomes were analyzed using logistic regression and time-to-event outcomes using Cox proportional hazards models. RESULTS: In the 202 trastuzumab-naive patients and 101 patients with previous trastuzumab exposure, we observed the following outcomes, respectively: overall response rate, 69.9% versus 61.3% (adjusted odds ratio [OR], 0.62; p = .131), clinical benefit rate, 79.1% versus 72.5% (adjusted OR, 0.73; p = .370), median progression-free survival (PFS), 16.1 months versus 12.0 months (adjusted hazards ratio [HR], 1.33; p = .045), and median overall survival (OS), 52.2 months versus 48.2 months (adjusted HR, 1.18; p = .404). Patients with a trastuzumab-free interval (TFI) <6 months, visceral involvement, and hormone receptor-negative disease showed a worse OS compared with patients with a TFI of >=6 months (29.5 vs. 48.3 months; p = .331), nonvisceral involvement (48.0 vs. 60.3 months; p = .270), and hormone receptor-positive disease (39.8 vs. 58.6 months; p = .003), respectively. CONCLUSION: Despite the inferior median PFS, trastuzumab-based therapy was an effective first-line treatment for patients relapsing after (neo)adjuvant trastuzumab. Previous trastuzumab exposure and the respective TFI, type of first site of disease relapse, and hormone receptor status should be considered in the choice of the best first-line treatment option for HER2 positive metastatic breast cancer patients. PMID- 26099742 TI - Long-Term Follow-Up of Chemotherapy-Induced Ovarian Failure in Young Breast Cancer Patients: The Role of Vascular Toxicity. AB - BACKGROUND: We previously reported that chemotherapy-induced ovarian toxicity may result from acute vascular insult, demonstrated by decreased ovarian blood flow and diminished post-treatment anti-Mullerian hormone (AMH) levels. In the present study, we report the continuous prospective evaluation of ovarian function in that cohort. METHODS: Patients (aged <43 years) with localized breast cancer were evaluated by transvaginal ultrasound prior to initiation of chemotherapy, immediately at treatment completion, and at 6 and 12 months after treatment cessation. Doppler flow velocity indices of the ovarian vasculature (resistance index [RI], pulsatility index [PI]) were visualized. Hormone markers of ovarian reserve were assessed at the same time points. RESULTS: Twenty patients were enrolled in the study. Median age was 34 +/- 5.24 years. Ovarian blood flow was significantly reduced immediately following chemotherapy (both RI and PI; p = .01). These parameters were partially recovered at later points of assessment (6 and 12 months after treatment); patients aged <35 years significantly regained ovarian blood flow compared with patients aged >35 years (p < .05). AMH dropped dramatically in all patients following treatment (p < .001) and recovered in only 10 patients. Hormone markers of ovarian reserve shortly after chemotherapy depicted a postmenopausal profile for most patients, accompanied by related symptoms. Follicle-stimulating hormone (FSH) levels recovered in 14 of 20 patients and significantly returned to the premenopausal range in patients aged <35 years (p = .04); 10 of 20 resumed menses at 12 months. The pattern of vascular impairment was lessened in patients treated with a trastuzumab-based protocol, although results did not reach statistical significance (p = .068). CONCLUSION: Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Age may affect whether patients regain ovarian function, whereas recovery of blood flow and premenopausal FSH levels at later assessment was notable in patients aged <35 years. IMPLICATIONS FOR PRACTICE: This study explored the role of vascular toxicity in mediating ovarian impairment and recovery following chemotherapy. Continuous prospective evaluation of ovarian vasculature and function in a cohort of young patients during and after chemotherapy indicated that ovarian toxicity may derive from acute vascular insult. Future studies are warranted to further characterize patterns of vascular toxicity of various chemotherapies in clinical practice and to assess the role of chemotherapy-induced vascular toxicity for specific end organs such as the ovary with systemic vascular effect. Elucidating the cause of impairment may facilitate development of measures to minimize vascular toxicity and consequences of acute vascular insult. PMID- 26099743 TI - Romidepsin for the Treatment of Peripheral T-Cell Lymphoma. AB - Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis in most subtypes. Diagnosis of this rare disease by expert hematopathologists improves accuracy of subtyping, and referral to academic or specialty centers is recommended. Many patients, however, will receive treatment in the community, and knowledge of approved agents is key to optimizing therapeutic approaches for all patients. There is no current standard of care for patients with PTCL and no approved therapies for first-line treatment. Although many patients initially respond to induction chemotherapy, responses are often brief, and many patients relapse or become treatment refractory. For patients with relapsed or refractory PTCL, achievement of durable responses is challenging, and there are few treatment options. Romidepsin is a histone deacetylase inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with cutaneous T-cell lymphoma who have received one prior systemic therapy or more and patients with PTCL who have received one prior therapy or more. Approval of romidepsin for PTCL was based on a pivotal phase II study of patients with relapsed or refractory PTCL (n = 131) that demonstrated an objective response rate of 25% including 15% with complete response; responses lasted a median of >2 years. Long-term responses to romidepsin were achieved in patients regardless of baseline characteristics, including subtype, heavy pretreatment, response to prior therapy, or advanced disease. Common adverse events included hematologic abnormalities, gastrointestinal or asthenic conditions, and infections; romidepsin was not correlated with clinically meaningful QT prolongation or electrocardiogram abnormalities. IMPLICATIONS FOR PRACTICE: Due to the rarity, severity, and heterogeneous nature of peripheral T-cell lymphoma (PTCL), diagnosis by expert hematopathologists is preferred, and referral to specialty centers is recommended. Many patients, however, will receive treatment in the community, and community oncologists play a key role in the recognition and treatment of PTCL. Knowledge of approved agents is key for optimizing therapeutic approaches. This review provides an overview of PTCL and an in-depth examination of romidepsin, a histone deacetylase inhibitor approved for the treatment of relapsed or refractory PTCL, and highlights difficulties of diagnosis and optimization of treatment modalities for patients with PTCL. PMID- 26099745 TI - Real-Life Use and Effectiveness of Adjuvant Trastuzumab in Early Breast Cancer Patients: A Study of the Southeast Netherlands Breast Cancer Consortium. AB - BACKGROUND: The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed, although it is well recognized that incorrect use may harm patients and may have a significant impact on health care resources. We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials. METHODS: We included all patients with stage I-III invasive breast cancer, irrespective of human epidermal growth factor receptor 2 (HER2) status, diagnosed in five hospitals in the southeast of The Netherlands in 2005-2007. We aimed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice. RESULTS: Of 2,684 patients included, 476 (17.7%) had a HER2-positive tumor. Of these, 251 (52.7%) patients had an indication for trastuzumab treatment of which 196 (78.1%) patients actually received it. Of the 225 patients without an indication, 34 (15.1%) received trastuzumab. Five-year disease-free survival was 80.7% for (n = 230) patients treated with versus 68.2% for (n = 246) patients not treated with trastuzumab (p = .0023), and 5-year overall survival rates were 90.7% and 77.4%, respectively (p = .0002). The hazard ratio for disease recurrence was 0.63 (95% confidence interval, 0.37-1.06) for trastuzumab when adjusting for potential confounders. CONCLUSION: This study shows that in real life, patients treated with trastuzumab in early-stage HER2 positive breast cancer had a 5-year disease-free and overall survival comparable to prior randomized trials. For informative decision making, real-life data are of additional value, providing insight on outcome of patients considered ineligible for treatment. PMID- 26099744 TI - The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer. AB - Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually. While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. IMPLICATIONS FOR PRACTICE: This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease. PMID- 26099746 TI - Metabolic Characteristics of Advanced Biliary Tract Cancer Using 18F Fluorodeoxyglucose Positron Emission Tomography and Their Clinical Implications. AB - BACKGROUND: In advanced biliary tract cancer (BTC), the metabolic landscape has not been evaluated by (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) yet. Furthermore, reports of the clinical implications of these metabolic features are limited. We aimed to evaluate the metabolic features and their clinical relevance in advanced BTC using (18)F-FDG PET. PATIENTS AND METHODS: We consecutively enrolled patients with advanced BTC who underwent (18)F-FDG PET prior to palliative chemotherapy between 2003 and 2013. We evaluated the findings of PET, such as SUV(max), the number of lesions and organs with FDG uptake, pathologic findings, and clinical outcomes. RESULTS: A total of 106 patients were enrolled: (53 intrahepatic cholangiocarcinoma [ICC], 7 extrahepatic BTC, 30 gallbladder cancer [GB Ca], and 16 ampulla of Vater cancer [AoV Ca]). The median SUV(max) differed according to the primary origin (ICC, 9.10; extrahepatic BTC, 5.90; GB Ca, 9.10; and AoV Ca, 6.37; p = .008) and histologic differentiation (well differentiated, 4.95; moderately differentiated, 6.60; poorly differentiated, 14.50; p = .004). Patients in the high metabolic group (SUV(max) of >=7.5) had more poorly differentiated histology and more organs and lesions with FDG uptake than did those in the low metabolic group (SUV(max) of <7.5). The low metabolic group had a significantly longer OS (11.4 vs. 7.4 months, p = .007) and PFS (6.6 vs. 4.3 months, p = .024) than high metabolic group. In multivariate analysis, SUV(max) was a significant prognostic factor for overall survival (OS; p = .047) and progression-free survival (PFS; p = .039). CONCLUSION: Metabolic characteristics of advanced BTC differ according to primary origin and histology. These metabolic features could be prognostic factors for OS and PFS in advanced BTC. PMID- 26099747 TI - Confronting Therapeutic Failure: A Conversation Guide. AB - We reflect on the impact of bad news on both clinician and patient in the setting of cancer treatment failure. We review the classic six-step SPIKES (setting, perception, invitation for information, knowledge, empathy, summarize and strategize) protocol for giving bad news that has been widely adopted since it was first published in this journal in 2005. The goal of such a conversation guide is to describe both the process and the tasks that constitute vital steps for clinicians and to comment on the emotional impact of the conversation on the clinician. Confronting therapeutic failure is the hardest task for oncologists. We offer practical tips derived from a thorough review of the evidence and our clinical experience. PMID- 26099748 TI - One-point carotid wave intensity predicts cardiac mortality in patients with congestive heart failure and reduced ejection fraction. AB - Wave intensity (WI) is a hemodynamic index used to evaluate the interaction between the heart and the arterial system, measured with an echo-Doppler system at the level of the common carotid artery. WI has two peaks: W1 during early systole that represents left ventricular (LV) contractility, and W2 in late systole that is related to the inertia force during isovolumetric relaxation. The aim of this study was to determine whether WI parameters improve the prediction of poor outcome in patients with heart failure and reduced ejection fraction (HFrEF). Sixty-two patients (mean age 69.4 +/- 11.5 years) in NYHA class II-III were followed up for 43.5 months. They underwent routine clinical work-up, transthoracic echocardiography and WI measurement. A stratified survival analysis was conducted using the Kaplan-Meier method. During follow-up, 23 patients died from cardiovascular causes. Survivors and non-survivors were similar in age, blood pressure, heart rate and echocardiographic parameters, except for LV end diastolic volume indexed to body surface area, E/A ratio (higher in non survivors) and deceleration time (lower in non-survivors). W2 (1950 +/- 1006 vs 1117 +/- 708 mmHg m/s(3), p = 0.001) was significantly lower in non-survivors, whereas W1 (6951 +/- 4119 vs 5748 +/- 3891 mmHg m/s(3), p = NS) was similar. At the end of follow-up, cardiovascular mortality was higher in patients with W1 <= 3900 mmHg m/s(3) (p = 0.02) and W2 <= 1000 mmHg m/s(3) (p = 0.0002). Only E/A (cut-off 1.5) was predictive of mortality (p = 0.05). In patients with HFrEF, WI parameters derived from the carotid artery better identified patients with poor prognosis and were significant predictors of cardiovascular mortality. PMID- 26099750 TI - Application of zinc chloride precipitation method for rapid isolation and concentration of infectious Pectobacterium spp. and Dickeya spp. lytic bacteriophages from surface water and plant and soil extracts. AB - This is the first report describing precipitation of bacteriophage particles with zinc chloride as a method of choice to isolate infectious lytic bacteriophages against Pectobacterium spp. and Dickeya spp. from environmental samples. The isolated bacteriophages are ready to use to study various (ecological) aspects of bacteria-bacteriophage interactions. The method comprises the well-known precipitation of phages from aqueous extracts of the test material by addition of ZnCl2, resuscitation of bacteriophage particles in Ringer's buffer to remove the ZnCl2 excess and a soft agar overlay assay with the host bacterium to isolate infectious individual phage plaques. The method requires neither an enrichment step nor other steps (e. g., PEG precipitation, ultrafiltration, or ultracentrifugation) commonly used in other procedures and results in isolation of active viable bacteriophage particles. PMID- 26099749 TI - Sirtuins, aging, and cardiovascular risks. AB - The sirtuins comprise a highly conserved family proteins present in virtually all species from bacteria to mammals. Sirtuins are members of the highly conserved class III histone deacetylases, and seven sirtuin genes (sirtuins 1-7) have been identified and characterized in mammals. Sirtuin activity is linked to metabolic control, apoptosis, cell survival, development, inflammation, and healthy aging. In this review, we summarize and discuss the potential mutual relations between each sirtuin and cardiovascular health and the impact of sirtuins on oxidative stress and so age-related cardiovascular disorders, underlining the possibility that sirtuins will be novel targets to contrast cardiovascular risks induced by aging. PMID- 26099751 TI - Integrative genome-wide analysis reveals HLP1, a novel RNA-binding protein, regulates plant flowering by targeting alternative polyadenylation. AB - Alternative polyadenylation (APA) is a widespread mechanism for gene regulation and has been implicated in flowering, but the molecular basis governing the choice of a specific poly(A) site during the vegetative-to-reproductive growth transition remains unclear. Here we characterize HLP1, an hnRNP A/B protein as a novel regulator for pre-mRNA 3'-end processing in Arabidopsis. Genetic analysis reveals that HLP1 suppresses Flowering Locus C (FLC), a key repressor of flowering in Arabidopsis. Genome-wide mapping of HLP1-RNA interactions indicates that HLP1 binds preferentially to A-rich and U-rich elements around cleavage and polyadenylation sites, implicating its role in 3'-end formation. We show HLP1 is significantly enriched at transcripts involved in RNA metabolism and flowering. Comprehensive profiling of the poly(A) site usage reveals that HLP1 mutations cause thousands of poly(A) site shifts. A distal-to-proximal poly(A) site shift in the flowering regulator FCA, a direct target of HLP1, leads to upregulation of FLC and delayed flowering. Our results elucidate that HLP1 is a novel factor involved in 3'-end processing and controls reproductive timing via targeting APA. PMID- 26099753 TI - Analgesia after major lower limb joint surgery-now a matter of only peripheral interest? PMID- 26099752 TI - [Efficacy of epidural steroid injections for chronic lumbar pain syndromes without neurological deficits. A randomized, double blind study as part of a multimodal treatment concept]. AB - BACKGROUND: Chronic lumbar pain syndromes without neurological deficits are generated by a multitude of causes. Functional, morphological and psychosocial factors are discussed. In many cases a diseased intervertebral disc is found on radiological examination but the clinical relevance of these findings is not clear. For this study it was postulated that a diseased disc results in a local inflammatory reaction therefore causing pain and impairing treatability of patients. An epidural injection of steroids can reduce inflammation and therefore improve treatability and ultimately treatment outcome. METHODS: A double blind randomized prospective trial was carried out. Patients treated in hospital for a chronic lumbar pain syndrome without neurological deficits within a multimodal treatment program were screened for indications for an epidural steroid injection (e.g. diseased lumbar disc and intention to treat). Patients eligible for the study were randomized into two groups. The treatment group received an epidural injection of 80 mg triamcinolone and 8 ml bupivacaine 0.25 %. The control group received only an epidural injection of 8 ml bupivacaine 0.25 %. RESULTS: In both groups pain intensity and treatability showed a statistically significant improvement after the epidural injection. The differences between the control and treatment groups were small and not clinically relevant. A small subgroup might profit from the steroid injection. In addition the treatability was dependent on psychometric values and the long-term outcome from a reduction of muscular skeletal dysfunctions. DISCUSSION: After the epidural injection the decrease in pain and increase in treatability was statistically significant. The mechanism of the improvement is not clear and should be examined further. The epidural injection of a steroid in this subgroup of patients did not lead to a clinical improvement in the outcome. PMID- 26099754 TI - Antibiotic prophylaxis for surgery: time to get our house in order. PMID- 26099755 TI - Spinal anaesthesia with adjunctive intrathecal morphine versus continuous lumbar plexus blockade: a randomised comparison for analgesia after hip replacement. AB - Following elective total hip replacement, both continuous lumbar plexus blockade and spinal anaesthesia (with adjunctive intrathecal morphine) have shown early outcome benefits over opioid analgesia and single-injection nerve block. However, the two techniques have not been compared in a prospective randomised manner. Our study examined 50 patients undergoing elective hip joint replacement who were randomised to receive spinal anaesthesia (with adjunctive intrathecal morphine 0.1 mg) or patient-controlled continuous lumbar plexus blockade. All surgery was conducted under general anaesthesia. Measured outcomes included numerically rated postoperative pain, supplemental opioid consumption and indices of mobilisation together with complications. Results show that block placement time was marginally shorter for the spinal group (5 versus 7 minutes, P=0.01). The primary outcome, worst pain on movement/mobilisation during the first 24 hours, was not statistically significantly different between groups. Patients in the lumbar plexus group were given more intraoperative opioid and rescue morphine in the post-anaesthesia care unit (median = 4 versus 0 mg, P <0.001), with correspondingly higher pain scores (median 5/10 versus 0/10, P <0.001). Pain scores during the subsequent 24 hours were similar between groups, but more patients in the spinal group were given rescue morphine (5 versus 0, P=0.02). Physiotherapy mobilisation indices appeared similar between groups. More spinal group patients reported pruritus (12 versus 5, P=0.01), but antiemetic requirements, episodes of disorientation, arterial oxygen desaturation and falls were all similar between groups. Postoperative symptoms suggestive of neurological irritation or injury did not differ between groups. We found that following elective hip joint replacement, compared to continuous lumbar plexus blockade, spinal anaesthesia incorporating adjunctive intrathecal morphine did not result in a statistically significant difference in worst pain on movement/mobilisation during the first 24 hours, although it was associated with better analgesia in the post-anaesthesia care unit. Subsequently, however, these patients appeared to require more rescue morphine and more of them reported pruritus. PMID- 26099756 TI - A randomised controlled trial comparing three analgesia regimens following total knee joint replacement: continuous femoral nerve block, intrathecal morphine or both. AB - This randomised controlled trial compared three analgesia regimens following primary unilateral total knee joint replacement: continuous femoral nerve block (CFNB), intrathecal morphine (ITM), and both. The primary outcome was pain ratings over the first 24 hours. Secondary outcomes included morphine consumption, nausea, pruritus and sedation ratings, oxygen saturation (SpO2) ratings, and ability to mobilise postoperatively. All patients received a spinal anaesthetic and a postoperative patient-controlled morphine pump. Patients were randomised to receive CFNB, ITM, or both. In patients with no CFNB, the use of ITM was blinded. Eighty-one patients were randomised and there were no withdrawals. At 24 hours, the ITM-only group had higher pain ratings than either of the other groups (P=0.04 versus CFNB, P=0.01 versus combination). In the 18 to 24 hour period, the ITM group used more morphine than either of the other groups. There were no statistically significant differences in pain ratings or morphine consumption at earlier time intervals. The ITM group were less likely to be able to sit out of bed on day one. Patients who received ITM were more likely to have pruritus. There were no statistically significant differences in nausea, SpO2or sedation ratings. This study showed that a CFNB resulted in reduced pain and was also associated with less morphine consumption and improved mobilisation at 24 hours compared to ITM. This study did not show any statistically significant differences between CFNB alone and CFNB+ITM. PMID- 26099757 TI - Surgical site infection-a population-based study in Australian adults measuring the compliance with and correct timing of appropriate antibiotic prophylaxis. AB - Prophylaxis for surgical site infection (SSI) is often at variance with guidelines, despite the prevalence of SSI and its associated cost, morbidity, and mortality. The CareTrack Australia study, undertaken by a number of the authors, demonstrated that appropriate care (in line with evidence- or consensus-based guidelines) was provided at 38% of eligible SSI healthcare encounters. Here, we report the indicator-level CareTrack Australia findings for SSI prophylaxis. Indicators were extracted from Australian and international clinical guidelines and ratified by clinical experts. A sample designed to be representative of the Australian population was recruited (n=1154). Participants' medical records were reviewed and analysed for compliance with the five SSI indicators. The main outcome measure was the percentage of eligible healthcare encounters with documented compliance with indicators for appropriate SSI prophylaxis. Of the 35,145 CareTrack Australia encounters, 702 (2%) were eligible for scoring against the SSI indicators. Where antibiotics were recommended, compliance was 49% for contaminated surgery, 57% for clean-contaminated surgery and 85% for surgery involving a prosthesis: these fell to 8%, 10% and 14%, respectively (an average of 11%), when currently recommended timing of antibiotic administration was included. Where antibiotics were not indicated, 72% of patients still received them. SSI prophylaxis in our sample was poor; over two-thirds of patients were given antibiotics, whether indicated or not, mainly at the wrong time. There is a need for national agreement on clinical standards, indicators and tools to guide, document and monitor SSI prophylaxis, with both local and national measures to increase and monitor their uptake. PMID- 26099758 TI - Comparison of ultrasound-guided supraclavicular, infraclavicular and below-C6 interscalene brachial plexus block for upper limb surgery: a randomised, observer blinded study. AB - This prospective, randomised, observer-blinded study was conducted to compare the ease of performance and surgical effectiveness of interscalene block below the C6 nerve root with supraclavicular and infraclavicular techniques of brachial plexus block for upper arm and forearm surgery. Sixty adult patients of American Society of Anesthesiologists grade 1 to 3, undergoing upper limb surgery, were randomly allocated into three groups. Group SC received supraclavicular blockade, group IC received infraclavicular blockade and Group IS received interscalene blockade. All blocks were guided by ultrasound with nerve stimulator confirmation. The anaesthetic mixture consisted of 0.5 ml/kg of equal volumes of 0.75% ropivacaine and 2% lignocaine-adrenaline. The imaging and block performance time, onset time, success rate, duration of block, and duration of postoperative analgesia were recorded by a blinded observer. The onset time was significantly longer in the interscalene group as compared with supraclavicular and infraclavicular approaches. The imaging time and block performance time were comparable between groups. No significant differences were observed between the three groups in terms of block-related pain scores, success rates, duration of block or of postoperative analgesia. Two patients in the interscalene group developed clinically detectable phrenic nerve palsy. Our findings indicate that, although interscalene block below the C6 nerve root can provide surgical anaesthesia for forearm and hand surgery, it appears to have a longer onset time than supra- and infraclavicular approaches and an unacceptable incidence of phrenic nerve palsy. PMID- 26099759 TI - Applicability of risk scores for postoperative nausea and vomiting in a Taiwanese population undergoing general anaesthesia. AB - Five popular scoring systems for postoperative nausea and vomiting (PONV) were validated and compared with two new predictive models in a Taiwanese population. Nine hundred and ninety-two patients receiving general anaesthesia in a tertiary hospital were investigated in a prospective observational cohort study. Patient demographic data and the incidence of nausea or vomiting in the first 24 hours after surgery were recorded. The overall incidence of PONV was 42%. The area under the curve (AUC) of the five published PONV risk scoring systems was 0.62 to 0.67. Logistic regression analysis in this study cohort showed that female sex and a history of PONV/car sickness were the only statistically significant independent risk factors for PONV (likelihood ratio test P <0.001).The AUCs of our two-predictor and gender-only models were 0.668 and 0.643, respectively (Nagelkerke R2 = 0.122 and 0.109). Goodness-of-fit showed that a two-predictor model predicted outcome that was in agreement with the observed outcome (P=0.973). Both the two-predictor model and the Apfel score had a similar AUC that was significantly different from the AUCs of the other models. The AUC for the gender-only model in our population was similar to that of the simplified Koivuranta and the Palazzo and Evans scores (AUC=0.659 and 0.632; P=0.137 and 0.513 respectively). All AUCs had only moderate discrimination power but our female gender-only model was much simpler. Using female gender as the only predictor of PONV had predictive power with 75% sensitivity and 54% specificity. PMID- 26099760 TI - Randomised controlled trial comparing the Ambu(r) aScopeTM2 with a conventional fibreoptic bronchoscope in orotracheal intubation of anaesthetised adult patients. AB - Fibreoptic intubation remains an essential skill for anaesthetists to master. In addition to the reusable fibrescope, an alternative disposable videoscope is available (aScope(TM)2, Ambu(r), Ballerup, Denmark). A total of 60 anaesthetised adult patients were randomised to either having orotracheal intubation using the aScope 2 or a Karl Storz fibrescope. Intubations were performed by experienced operators who were familiar with both devices. The primary outcome was the Global Rating Scale score. Secondary outcomes included intubation success, number of intubation attempts and intubation time. Other subjective outcomes including practicality, useability and image quality were also recorded. There was no significant difference in the Global Rating Scale score, intubation success orintubation time between the aScope 2 or Karl Storz fibrescope. Global Rating Scale scores were three and two in the aScope 2 and Karl Storz groups respectively (P=0.14). All of the other subjective outcomes were similar between the two groups, except that operators found it easier to use the aScope 2 compared to the fibrescope. There was no significant difference in clinical performance between the aScope 2 and the Karl Storz fibreoptic bronchoscope. The aScope's practicality, disposability and recently improved version (aScope(TM)3) potentially make it an acceptable alternative to the reusable fibrescope. PMID- 26099761 TI - The effect of routine reversal of neuromuscular blockade on adequacy of recurrent laryngeal nerve stimulation during thyroid surgery. AB - Testing of the integrity of the recurrent laryngeal nerve during thyroid surgery has become routine practice for many surgeons to aid dissection and minimise the chance of inadvertent nerve injury. We hypothesised that routine reversal of an intermediate-acting, non-depolarising neuromuscular blocking agent would improve conditions for stimulation of the recurrent laryngeal nerve. We conducted a single-centre, randomised, double-blind placebo-controlled trial of patients undergoing thyroid surgery by the same surgeon. After randomisation, the participants received either neostigmine 2.5 mg with glycopyrrolate 0.4 mg or placebo, at 30 minutes after induction of anaesthesia and administration of 0.4 mg/kg of atracurium. The primary outcome was the subjective assessment by the surgeon as to whether the neuromuscular function was adequate for stimulation of the recurrent laryngeal nerve using a neuromuscular integrity monitor (NIM). Time to NIM stimulation was 44.6 minutes in the placebo group and 41.4 minutes in the intervention group (P=0.268). Of the 21 patients who received the neuromuscular blockade reversal, 20 (95.2%) had adequate surgical conditions for NIM stimulation, compared to 9 out of 18 patients (50%) in the placebo group (P=0.002). Three of the ten patients (30%) with inadequate reversal showed no evidence of residual blockade assessed peripherally. The routine reversal of neuromuscular blockade at 30 minutes post induction appears to result in adequate surgical conditions for safe stimulation of the recurrent laryngeal nerve. Return of neuromuscular function at a peripheral site does not guarantee adequate laryngeal muscle function for use of the NIM. PMID- 26099762 TI - Does adding ICU data to the POSSUM score improve the prediction of outcomes following surgery for upper gastrointestinal malignancies? AB - Surgery for upper gastrointestinal malignancy carries a high postoperative mortality and morbidity risk. The importance of preoperative physiological reserve and intraoperative events in determining clinical outcomes is recognised in the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) score that comprises variables relevant to both phases. Whether adding variables linked to ICU admission characteristics improves the predictive capacity of POSSUM is unclear, especially in an Australian/New Zealand healthcare context. This study aimed to evaluate the predictive capacity of the POSSUM score for 30-day mortality and in-hospital morbidity in 80 patients undergoing resection of oesophageal (28%), gastric (26%) or pancreatic (46%) malignancies and admitted to ICU. The 30-day mortality was 8.8% and 65% of patients developed some postoperative complication. Receiver operating characteristics generated an area under the curve (95% CI) to predict mortality by Portsmouth POSSUM of 0.87 (0.77 to 0.93) and morbidity by POSSUM of 0.67 (0.55 to 0.77). Multiple regression analysis including biochemical variables and vital signs on admission to ICU identified renal function parameters, fluid balance and need for cardiorespiratory support beyond the first postoperative day as independent factors associated with mortality and morbidity (in addition to the POSSUM score) but the inclusion of these variables in a logistic regression model did not significantly improve the predictive capacity for mortality (to area under the curve 0.93 [0.85 to 0.97]) or morbidity (to area under the curve 0.67 [0.55 to 0.78]). In conclusion, the POSSUM score provides clinically useful predictive capacity in patients undergoing surgery for upper gastrointestinal malignancies. The incorporation of ICU admission variables to the pre- and intraoperative POSSUM variables did not significantly enhance the precision. PMID- 26099763 TI - Electromagnetic needle tracking during simulated right internal jugular cannulation. AB - This study used three-dimensional information from Stealth navigation technology during simulated right internal jugular vein cannulation to define the initial needle trajectory taken when using three approaches: landmark (LM), short-axis (SAX) ultrasound and long-axis (LAX) ultrasound. Nineteen volunteers indicated the entry site and needle direction (track) they would use in performing right internal jugular vein cannulation by the three approaches. The likelihood of cannulation success, arterial puncture and needle direction were recorded. Volunteers were asked to assess the suitability of the simulation system for validity and educational benefit. The SAX track crossed the jugular vein more frequently than the LAX and LM tracks (SAX: 94%; LAX: 80%; LM: 47% [SAX versus LM, P <0.01]). The mean indicated needle direction in the coronal plane for LM, SAX and LAX were -4, 13 and 11 degrees, respectively. The track associated with the LAX technique would have entered the carotid artery by 16% of volunteers. At needle depths of over 40 mm, the track crossed the vertebral artery at the following rates (LM: 11%; SAX: 16%; LAX: 16%). The use of Stealth technology to provide three-dimensional feedback of the needle path taken during simulated right internal jugular cannulation was considered realistic (16/19) and of benefit for 18 of 19 (95%) respondents. The SAX track was associated with the highest likelihood of successful jugular cannulation and the lowest cross rate of the carotid artery. The simulation model using Stealth was considered to be valuable and realistic by participants despite some limitations. PMID- 26099764 TI - An audit of the haemodynamic and emergence characteristics of single-shot 'ketofol'. AB - 'ketofol', the single-syringe combination of ketamine and propofol (50 mg of ketamine and 90 mg of propofol in a 10 ml syringe) is becoming increasingly popular for short procedures, progressively replacing the more traditional use of ketamine and diazepam in some settings. This audit examined the haemodynamic, emergence and other characteristics of ketofol administration in 42, otherwise fit, women undergoing bilateral post-partum tubal ligation at Vila Central Hospital in Vanuatu. The combination of ketamine and propofol had no clinically important adverse haemodynamic effects. Wake-up from ketofol was favourable, with low rates of nausea and minimal emergence delirium. However, 43% of patients required airway support. For short procedures such as post-partum tubal ligation in fit patients, ketofol appears to have minimal adverse haemodynamic effects and favourable emergence characteristics. PMID- 26099766 TI - The non-technical skills used by anaesthetic technicians in critical incidents reported to the Australian Incident Monitoring System between 2002 and 2008. AB - The outcome of critical incidents in the operating theatre has been shown to be influenced by the behaviour of anaesthetic technicians (ATs) assisting anaesthetists, but the specific non-technical skills involved have not been described. We performed a review of critical incidents (n=1433) reported to the Australian Incident Monitoring System between 2002 and 2008 to identify which non technical skills were used by ATs. The reports were assessed if they mentioned anaesthetic assistance or had the boxes ticked to identify "inadequate assistance" or "absent supervision or assistance". A total of 90 critical incidents involving ATs were retrieved, 69 of which described their use of non technical skills. In 20 reports, the ATs ameliorated the critical incident, whilst in 46 they exacerbated the critical incident, and three cases had both positive and negative non-technical skills described. Situation awareness was identified in 39 reports, task management in 23, teamwork in 21 and decision making in two, but there were no descriptions of issues related to leadership, stress or fatigue management. Situation awareness, task management and teamwork appear to be important non-technical skills for ATs in the development or management of critical incidents in the operating theatre. This analysis has been used to support the development of a non-technical skills taxonomy for anaesthetic assistants. PMID- 26099765 TI - The changing face of malignant hyperthermia: less fulminant, more insidious.. AB - Modern anaesthetic techniques have resulted in the clinical presentation of malignant hyperthermia to be more often indolent and/or insidious than truly fulminant, as previously known in the anaesthetic community. We present four recently referred cases to illustrate this point: one late-onset case, two patients with slowly progressive hypercapnia as the sole sign and a fourth patient with postoperative myalgias and elevated creatine kinase. We also discuss the reasons for the shift in typical clinical presentation. The more insidious character of malignant hyperthermia is most likely due to the lower triggering potency of modern volatile anaesthetics, the mitigating effects of several intravenous drugs (neuromuscular blocking agents, alpha 2 adrenergic receptor agonists, beta adrenergic blockade) or techniques (neuraxial anaesthesia) and the routine use of end-tidal CO2 monitoring leading to the early withdrawal of triggering drugs. Awareness among anaesthetists of this change in presentation is important since the clinical diagnosis is often more doubtful and, if corroborative evidence is not sought, the diagnosis may be delayed or missed altogether. PMID- 26099767 TI - Sevoflurane for analgesia-testing a modified vaporiser for delivery. AB - The Diamedica Sevoflurane Inhaler (Diamedica UK Ltd, Bratton Fleming, UK) (DSI) is a breathing system which includes a modification of an existing vaporiser (Diamedica Draw-over Vaporiser, Diamedica UK Ltd, Bratton Fleming, UK), to enable the delivery of 0.8% sevoflurane. Previous studies have suggested that self administered sevoflurane at sub-anaesthetic concentration can provide useful pain relief during the first stage of labour and that it may be more effective than Entonox. Further research and potential clinical use have been impeded by the lack of a practical delivery system. In this study, the performance of two versions of the DSI (DSI-1 and DSI-2) was investigated. DSI-1 was tested over a range of minute volumes (1 to 30 l/min) and ambient temperatures (10 degrees C to 40 degrees C). The sevoflurane output increased unacceptably with rising ambient temperature, therefore the design was modified to create the DSI-2. The results from testing this revised version are also described. Mean sevoflurane output from the DSI-2 was found to be within a clinically acceptable range at the minute volumes tested (0.78% to 0.88%) and ambient temperatures tested (0.69% to 0.9%). Based upon these results, the authors propose to undertake further studies of sevoflurane analgesia using the DSI-2. PMID- 26099768 TI - A prospective audit of difficult airway equipment at University of Melbourne affiliated hospitals. PMID- 26099769 TI - Ultrasound-guided lumbar retrolaminar block for acute lumbar trauma. PMID- 26099770 TI - Substance use disorder amongst Australian and New Zealand anaesthetic trainees: an analysis of 30 years of data. PMID- 26099771 TI - Should we really condemn the use of the nasopharyngeal catheter for oxygen therapy? PMID- 26099772 TI - The time has come for a coordinated and centralised approach to substance abuse among anaesthetists. PMID- 26099773 TI - Postoperative care after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy procedures. PMID- 26099774 TI - Inadvertent intra-arterial cannulation due to missed aberrant radial artery anatomy revisited. PMID- 26099775 TI - Failure of intubation with Aintree intubation catheter via Size 3 'Unique' LMA. PMID- 26099776 TI - The evolution of the polyvinyl chloride endotracheal tube. PMID- 26099777 TI - A new approach to avoid unnecessary fluid-fasting in healthy children. PMID- 26099778 TI - The Tunstall manoeuvre for rapid onset spinal anaesthesia for caesarean section lost but not forgotten. PMID- 26099779 TI - Inadvertent carotid artery cannulation. PMID- 26099780 TI - Occupational exposure of anaesthetists to ionising radiation. PMID- 26099781 TI - Airway obstruction due to tumour fragments after pneumonectomy: a critical complication. PMID- 26099782 TI - Efficacy of continuous veno-venous haemofiltration on transpulmonary thermodilution measurements using the EV1000 system. PMID- 26099784 TI - Quantity and Quality of the Lower Extremity Muscles in Women with Knee Osteoarthritis. AB - The objective of the study described here was to compare lower extremity muscle quantity and quality between individuals with and those without knee osteoarthritis (OA). Twenty-one women with knee OA (mild, n = 8; severe, n = 13) and 23 healthy patients participated. Ultrasonography was used to measure muscle thickness (MT) and echo intensity (EI) of the rectus femoris, vastus intermedius, vastus lateralis, vastus medialis, biceps femoris, gluteus maximus, gluteus medius, gastrocnemius, soleus and tibialis anterior. MTs of the vastus medialis and vastus intermedius were smaller, and EIs of the vastus medialis, vastus intermedius, gluteus medius and tibialis anterior were larger, in the severe OA group compared than in the healthy group. Compared with the healthy group, the mild OA group had decreased MT and enhanced EI. Changes in quality and quantity occurring with knee OA progression differed among muscles. In the vastus medialis, change was observed from an earlier stage. PMID- 26099785 TI - Improving problem solving in primary school students: The effect of a training programme focusing on metacognition and working memory. AB - BACKGROUND: Despite doubts voiced on their efficacy, a series of studies has been carried out on the capacity of training programmes to improve academic and reasoning skills by focusing on underlying cognitive abilities and working memory in particular. No systematic efforts have been made, however, to test training programmes that involve both general and specific underlying abilities. If effective, these programmes could help to increase students' motivation and competence. AIMS: This study examined the feasibility of improving problem solving skills in school children by means of a training programme that addresses general and specific abilities involved in problem solving, focusing on metacognition and working memory. PARTICIPANTS: The project involved a sample of 135 primary school children attending eight classes in the third, fourth, and fifth grades (age range 8-10 years). METHOD: The classes were assigned to two groups, one attending the training programme in the first 3 months of the study (Training Group 1) and the other serving as a waiting-list control group (Training Group 2). In the second phase of the study, the role of the two groups was reversed, with Training Group 2 attending the training instead of Training Group 1. RESULTS: The training programme led to improvements in both metacognitive and working memory tasks, with positive-related effects on the ability to solve problems. The gains seen in Training Group 1 were also maintained at the second post-test (after 3 months). CONCLUSIONS: Specific activities focusing on metacognition and working memory may contribute to modifying arithmetical problem-solving performance in primary school children. PMID- 26099786 TI - Diagnosis and treatment of Lemierre syndrome. PMID- 26099787 TI - Effect of Shenfu injection on intestinal mucosal barrier in a rat model of sepsis. AB - PURPOSE: The effects of Shenfu injection on protecting the intestinal mucosal barrier were investigated in rats with sepsis. METHODS: Severe sepsis was established by cecal ligation and puncture (CLP) in 30 healthy Sprague-Dawley rats. Twelve rats that received sham surgery received 10 mL/kg of normal saline. Rats with CLP were randomized to receive 10 mL/kg of normal saline (n = 12) and 5 mL/kg Shenfu (n = 12), and 10 received 10 mL/kg Shenfu injection (n = 12) by tail intravenous injection. Rats were killed after 8 hours. Serum levels of tumor necrosis factor alpha and interleukin-10, and ileal malondialdehyde and superoxide dismutase activity were measured by enzyme-linked immunosorbent assay. Ileum tissue structures and pathological score were observed by microscopy. Ileal mucosal epithelial cell apoptosis index was calculated by TUNEL assay. Ileal proapoptotic protein Bax, antiapoptotic protein Bcl-2, and tight junction transmembrane protein occludin were measured by immunohistochemistry and immunoblot. RESULTS: The level of tumor necrosis factor alpha, the ileal malondialdehyde level, ileum pathological score, apoptosis index of ileal mucosal epithelial cells, and Bax protein level were significantly higher, and serum level of interleukin-10, the ileal superoxide dismutase activity, Bcl-2 protein level, Bcl-2/Bax ratio, and occludin protein level were significantly lower in the CLP group than in the sham group (P < .01 or P < .05). Both low- and high dose Shenfu significantly ameliorated these changes (P < .01 or P < .05), but high-dose injection achieved more significant improvements than did the low-dose injection (P < .01 or P < .05). CONCLUSIONS: Shenfu injection might ameliorate the mucosal barrier function in a model of sepsis in rats in a dose-dependent manner. PMID- 26099789 TI - Is there a possibility of ranking benthic quality assessment indices to select the most responsive to different human pressures? AB - Although a plethora of benthic indices exist, there is no agreement on what index or indices should be used by environmental managers to establish benthic quality. The objective of this investigation was to rank 35 benthic quality assessment indices used in different countries to evaluate the impact produced by 15 different human pressures (including multipressure, aquaculture, sewage discharges, eutrophication, physical alteration, chemical pollution, climate change, etc.). The ranking was determined by taking into account the coverage area of biogeographical provinces, number of citations testing a pressure and number of citations with significant correlation with pressure. We analysed 363 references, of which 169 showed quantitative data. Over a potential total score of 100, the highest values were obtained by the following indices: (i) AZTI's Marine Biotic Index (AMBI), which scored 77, tested by using 14 pressures in 14 provinces from the Arctic to tropical seas; (ii) multivariate AMBI (M-AMBI), which scored 74, tested with 12 pressures in 13 provinces; (iii) Bentix (BENTIX), which scored 68, tested with nine pressures in six provinces; (iv) Benthic Quality Index (BQI), which scored 66, tested with five pressures in seven provinces; and (v) Benthic Opportunistic Polychaetes Amphipods (BOPA) index, which scored 62, tested with eight pressures in six provinces. PMID- 26099788 TI - Plastic in surface waters of the Inside Passage and beaches of the Salish Sea in Washington State. AB - We summarize results of two independent studies on plastic pollution in the marine environment that overlap in time and space. One study evaluated the abundance of anthropogenic debris on 37 sandy beaches bordering the Salish Sea in Washington State while the other characterized plastic debris in surface waters of the Salish Sea and the Inside Passage to Skagway, Alaska. Both studies concluded that foam, primarily expanded polystyrene was the dominant pollutant. Plastic was found in surface waters the full length of the Inside Passage but was concentrated near harbors. At the wrack line, an average square meter of Washington's 1180km of sandy beaches in the Salish Sea had 61 pieces of anthropogenic debris weighing approximately 5g. The total loading for the entire 1m wide band is estimated to be 72,000,000 pieces and 5.8metric tons. Most anthropogenic debris on beaches is generated within the region. PMID- 26099790 TI - Organophosphorus flame retardants (PFRs) and plasticisers in harbour porpoises (Phocoena phocoena) stranded or bycaught in the UK during 2012. AB - A suite of twenty organophosphorus flame retardant compounds have been determined in blubber and liver tissue of twenty harbour porpoises stranded or bycaught in the UK during 2012 in order to establish current levels of contamination. Fourteen of the twenty compounds were below the limits of quantification in all samples. Six could be quantified at maximum concentrations (in blubber) between 6.7 and 246MUgkg(-1) wet weight. These levels do not suggest a high level of concern regarding potential impacts and do not indicate that routine monitoring in UK porpoises is warranted at this time. PMID- 26099791 TI - Effect of Perfusion Fluids on Recovery of Inflammatory Mediators in Microdialysis. AB - Microdialysis is an excellent tool to assess tissue inflammation in patients, but in vitro systems to evaluate recovery of inflammatory mediators have not been standardized. We aimed to develop a reference plasma preparation and evaluate different perfusion fluids with respect to recovery of metabolic and inflammatory markers. The reference preparation was produced by incubation of human blood with lipopolysaccharide and cobra venom factor to generate cytokines and activate complement, respectively. Microdialysis with 100 kDa catheters was performed using different colloid and crystalloid perfusion fluids (hydroxyethyl starch (HES) 130/0.4, HES 200/0.5, hyperosmolar HES 200/0.5, albumin 200 g/l, T1 perfusion fluid and Ringer's acetate) compared to today's recommended dextran 60 solution. Recovery of glucose, glycerol and pyruvate was not significantly different between the perfusion fluids, whereas lactate had lower recovery in HES 200/0.5 and albumin perfusion fluids. Recovery rates for the inflammatory proteins in comparison with the concentration in the reference preparation differed substantially: IL-6 = 9%, IL-1beta = 18%, TNF = 0.3%, MCP-1 = 45%, IL-8 = 48%, MIG = 48%, IP-10 = 25%, C3a = 53% and C5a = 12%. IL-10 was not detectable in microdialysis dialysate. HES 130/0.4 and HES 200/0.5 yielded a recovery not significantly different from dextran 60. Hyperosmolar HES 200/0.5 and albumin showed significantly different pattern of recovery with increased concentration of MIG, IP-10, C3a and C5a and decreased concentration of IL-1beta, TNF, MCP-1 and IL-8 in comparison with dextran 60. In conclusion, microdialysis perfusion fluid dextran 60 can be replaced by the commonly used HES 130/0.4, whereas albumin might be used if specific immunological variables are in focus. The present reference plasma preparation is suitable for in vitro evaluation of microdialysis systems. PMID- 26099792 TI - Challenges for bovine viral diarrhoea virus antibody detection in bulk milk by antibody enzyme-linked immunosorbent assays due to changes in milk production levels. AB - BACKGROUND: Bovine viral diarrhoea (BVD) is considered eradicated from Denmark. Currently, very few (if any) Danish cattle herds could be infected with BVD virus (BVDV). The Danish antibody blocking enzyme-linked immunosorbent assay (ELISA) has been successfully used during the Danish BVD eradication program, initiated in 1994. During the last decade, the cattle herd size has increased while the prevalence of BVDV has decreased. In this study, we investigated how these changes could affect the performance of the Danish blocking ELISA and of the SVANOVIR(r) BVDV-Ab indirect ELISA. The latter has successfully been used to eradicate BVD in Sweden. Data (2003-2010) on changes in median herd size and milk production levels, occurrence of viremic animals and bulk milk surveillance were analysed. Additionally, the Danish blocking ELISA and the SVANOVIR ELISA were compared analyzing milk and serum samples. The prevalence of antibody positive milking cows that could be detected by each test was estimated, by diluting positive individual milk samples and making artificial milk pools. RESULTS: During the study period, the median herd size increased from 74 (2003) to 127 cows (2010), while the prevalence of BVDV infected herds decreased from 0.51 to 0.02 %. The daily milk yield contribution of a single seropositive cow to the entire daily bulk milk was reduced from 1.61 % in 2003 to 0.95 % in 2010 due to the increased herd size. It was observed that antibody levels in bulk milk decreased at national level. Moreover, we found that when testing bulk milk, the SVANOVIR(r) BVDV-Ab can detect a lower prevalence of seropositive lactating cows, compared to the Danish blocking ELISA (0.78 % vs. 50 %). Values in the SVANOVIR(r) BVDV-Ab better relate to low concentrations of antibody positive milk (R(2) = 94-98 %), than values in the blocking ELISA (R(2) = 23-75 %). For sera, the two ELISAs performed equally well. CONCLUSIONS: The SVANOVIR ELISA is recommended for analysis of bulk milk samples in the current Danish situation, since infected dairy herds e.g. due to import of infected cattle can be detected shortly after BVDV introduction, when only few lactating cows have seroconverted. In sera, the two ELISAs can be used interchangeably. PMID- 26099793 TI - Extremity-dedicated low-field MRI shows good diagnostic accuracy and interobserver agreement for the diagnosis of the acutely injured knee. AB - OBJECTIVES: To estimate diagnostic accuracy and interobserver agreement of extremity-dedicated low-field magnetic resonance imaging (lfMRI) for meniscal tears, anterior cruciate ligament (ACL) tears and knee fractures. METHODS: We enrolled 62 patients with acute knee trauma and 19 patients with suspected knee fracture. Arthroscopy/Computed tomography was regarded the gold standard for cruciate ligament and meniscal tears/fractures. RESULTS: Arthroscopy showed 39 meniscal tears. Sensitivity/Specificity of lfMRI was 95.8%/97.4% (reader 1)/100%/100% (reader 2) for medial and 93.3%/100% (reader 1)/93.3%/93.6% (reader 2) for lateral meniscal tears. Sensitivity/Specificity was 100% for ACL tears and fractures. Interobserver agreement was very good. CONCLUSION: lfMRI showed reproducible high sensitivity and specificity for the diagnosis of the acutely injured knee. PMID- 26099794 TI - Prevalence, risk factors and disability associated with fall-related injury in older adults in low- and middle-incomecountries: results from the WHO Study on global AGEing and adult health (SAGE). AB - BACKGROUND: In 2010 falls were responsible for approximately 80 % of disability stemming from unintentional injuries excluding traffic accidents in adults 50 years and over. Falls are becoming a major public health problem in low- and middle-income countries (LMICs) where populations are ageing rapidly. METHODS: Nationally representative standardized data collected from adults aged 50 years and over participating in the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) Wave 1 in China, Ghana, India, Mexico, the Russian Federation and South Africa are analysed. The aims are to identify the prevalence of, and risk factors for, past-year fall-related injury and to assess associations between fall-related injury and disability. Regression methods are used to identify risk factors and association between fall-related injury and disability. Disability was measured using the WHO Disability Assessment Schedule Version 2.0 (WHODAS 2.0). RESULTS: The prevalence of past-year fall-related injuries ranged from 6.6 % in India to 1.0 % in South Africa and was 4.0 % across the pooled countries. The proportion of all past-year injuries that were fall related ranged from 73.3 % in the Russian Federation to 44.4 % in Ghana. Across the six countries this was 65.7 %. In the multivariable logistic regression, the odds of past-year fall-related injury were significantly higher for: women (OR: 1.27; 95 % CI: 0.99,1.62); respondents who lived in rural areas (OR: 1.36; 95 % CI: 1.06,1.75); those with depression (OR: 1.43; 95 % CI: 1.01,2.02); respondents who reported severe or extreme problems sleeping (OR: 1.54; 95 % CI: 1.15,2.08); and those who reported two or more (compared with no) chronic conditions (OR: 2.15; 95 % CI: 1.45,3.19). Poor cognition was also a significant risk factor for fall-related injury. The association between fall-related injury and the WHODAS measure of disability was highly significant (P<0.0001) with some attenuation after adjusting for confounders. Reporting two or more chronic conditions (compared with none) was significantly associated with disability (P<0.0001). CONCLUSIONS: The findings provide a platform for improving understanding of risk factors for falls in older adults in this group of LMICs. Clinicians and public health professionals in these countries must be made aware of the extent of this problem and the need to implement policies to reduce the risk of falls in older adults. PMID- 26099795 TI - An anatomy-based lumped parameter model of cerebrospinal venous circulation: can an extracranial anatomical change impact intracranial hemodynamics? AB - BACKGROUND: The relationship between extracranial venous system abnormalities and central nervous system disorders has been recently theorized. In this paper we delve into this hypothesis by modeling the venous drainage in brain and spinal column areas and simulating the intracranial flow changes due to extracranial morphological stenoses. METHODS: A lumped parameter model of the cerebro-spinal venous drainage was created based on anatomical knowledge and vessels diameters and lengths taken from literature. Each vein was modeled as a hydraulic resistance, calculated through Poiseuille's law. The inputs of the model were arterial flow rates of the intracranial, vertebral and lumbar districts. The effects of the obstruction of the main venous outflows were simulated. A database comprising 112 Multiple Sclerosis patients (Male/Female = 42/70; median age +/- standard deviation = 43.7 +/- 10.5 years) was retrospectively analyzed. RESULTS: The flow rate of the main veins estimated with the model was similar to the measures of 21 healthy controls (Male/Female = 10/11; mean age +/- standard deviation = 31 +/- 11 years), obtained with a 1.5 T Magnetic Resonance scanner. The intracranial reflux topography predicted with the model in cases of internal jugular vein diameter reduction was similar to those observed in the patients with internal jugular vein obstacles. CONCLUSIONS: The proposed model can predict physiological and pathological behaviors with good fidelity. Despite the simplifications introduced in cerebrospinal venous circulation modeling, the key anatomical feature of the lumped parameter model allowed for a detailed analysis of the consequences of extracranial venous impairments on intracranial pressure and hemodynamics. PMID- 26099796 TI - Vulnerability of calbindin, calretinin and parvalbumin in a transgenic/knock-in APPswe/PS1dE9 mouse model of Alzheimer disease together with disruption of hippocampal neurogenesis. AB - The pathogenesis of Alzheimer disease (AD) is characterized by accumulation of beta-amyloid protein in the brain (in both soluble and insoluble forms) and by the presence of intracellular neurofibrillary tangles (NFTs), leading to neurotoxicity. The exact mechanisms whereby Abeta triggers brain alterations are unclear. However, accumulating evidence suggests that a deregulation of Ca(2+) signaling may play a major role in disease progression. Calcium-buffering proteins, including calbindin-D28K (CB), calretinin (CR) and parvalbumin (PV), may offer neuroprotection by maintaining calcium homeostasis. Although marked reductions in these proteins have been observed in the brains of mice and humans with AD, their contribution to AD pathology remains unclear. The aim of the present study was to analyze distribution patterns of CB(+,) CR(+) and PV(+) interneurons in different areas of the hippocampus, a brain region that is severely affected in AD. A transgenic knock-in APPswe/PS1dE9 mouse model of familial AD was used. The data were obtained from the brains of 3- and 12-month old animals. These ages roughly correspond to an early mature adult (prior to clinical manifestations) and a late middle-age (clinical symptoms readily detectable) phase in human AD patients. Immunostaining revealed increases in CB and PV immunoreactivity (IR) in the hippocampus of 3-month-old transgenic mice, compared to wild-type animals. Possibly, these proteins are upregulated in an attempt to control cellular homeostasis and synaptic plasticity. However, the pattern of CB-IR was reversed in 12-month-old animals, potentially indicating a loss of cellular capacity to respond to pathophysiological processes. In addition, at this age, a noticeable increase in PV-IR was observed, suggesting the presence of hippocampal network hyperactivity in older AD-like mice. Our results indicate that CaBP(+) neuronal subpopulations play a role in adult neurogenesis and in AD pathology, particularly at early disease stages, suggesting that these neurons may serve as potential predictors of future AD in non-demented individuals. PMID- 26099798 TI - Ventilation and diaphragm activity during sustained hypoxia in awake canines. AB - In humans, isocapnic hypoxia sustained for 20-30 min elicits a biphasic ventilatory response with an initial increased peak followed by a roll-off to a lesser, intermediate plateau. However, it is uncertain if this hypoxic roll-off is common for all mammals, as canines have been a notable exception. We examined the effect of moderate isocapnic hypoxia (SpO2 80%) sustained for 20 min in 13 adult, awake, intact canines. The ventilatory response to sustained isocapnic hypoxia in these canines was not maintained: after an initial brisk response, ventilation declined significantly to an intermediate plateau. The hypoxic ventilatory decline occurred via a decrease in tidal volume, without change in breathing frequency. Distinct from airflow, costal diaphragm EMG showed a concurrent decline during sustained isocapnic hypoxia. However, the change in ventilation during sustained hypoxia in canines was very different from the response in humans. Although some decline in ventilation during sustained hypoxia may be common to all mammals, there are notable differences among species. PMID- 26099797 TI - Global transcriptome analysis profiles metabolic pathways in traditional herb Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao. AB - BACKGROUND: Astragalus membranaceus Bge. var. mongolicus (Bge.) Hsiao (A. mongolicus, family Leguminosae) is one of the most important traditional Chinese herbs. Among many secondary metabolites it produces, the effective bioactive constituents include isoflavonoids and triterpene saponins. The genomic resources regarding the biosynthesis of these metabolites in A. mongolicus are limited. Although roots are the primary material harvested for medical use, the biosynthesis of the bioactive compounds and its regulation in A. mongolicus are not well understood. Therefore, a global transcriptome analysis on A. mongolicus tissues was performed to identify the genes essential for the metabolism and to profile their expression patterns in greater details. RESULTS: RNA-sequencing was performed for three different A. mongolicus tissues: leaf, stem, and root, using the Illumina Hiseq2000 platform. A total of 159.5 million raw sequence reads were generated, and assembled into 186,324 unigenes with an N50 of 1,524bp. Among them, 129,966 unigenes (~69.7%) were annotated using four public databases (Swiss Prot, TrEMBL, CDD, Pfam), and 90,202, 63,946, and 78,326 unigenes were found to express in leaves, roots, and stems, respectively. A total of 8,025 transcription factors (TFs) were identified, in which the four largest families, bHLH, MYB, C3H, and WRKY, were implicated in regulation of tissue development, metabolisms, stress response, etc. Unigenes associated with secondary metabolism, especially those with isolavonoids and triterpene saponins biosynthesis were characterized and profiled. Most genes involved in the isoflavonoids biosynthesis had the lowest expression in the leaves, and the highest in the stems. For triterpene saponin biosynthesis, we found the genes in MVA and non-MVA pathways were differentially expressed among three examined tissues, indicating the parallel but compartmentally separated biosynthesis pathways of IPP and DMAPP in A. mongolicus. The first committed enzyme in triterpene saponin biosynthesis from A. mongolicus, cycloartenol synthase (AmCAS), which belongs to the oxidosqualene cyclase family, was cloned by us to study the astragalosides biosynthesis. Further co-expression analysis indicated the candidate CYP450s and glycosyltransferases (GTs) in the cascade of triterpene saponins biosynthesis. The presence of the large CYP450 families in A. mongolicus was further compared with those from Medicago truncatula and Arabidopsis thaliana, and the diversity and phylegenetic relationships of the CYP450 families were established. CONCLUSION: A transcriptome study was performed for A. mongolicus tissues to construct and profile their metabolic pathways, especially for the important bioactive molecules. The results revealed a comprehensive profile for metabolic activities among tissues, pointing to the equal importance of leaf, stem, and root in A. mongolicus for the production of bioactive compounds. This work provides valuable resources for bioengineering and in vitro synthesis of the natural compounds for medical research and for potential drug development. PMID- 26099799 TI - Inhaled carbon dioxide causes dose-dependent paradoxical bradypnea in animals anesthetized with pentobarbital, but not with isoflurane or ketamine. AB - INTRODUCTION: In spontaneously breathing mice anesthetized with pentobarbital, we observed unexpected paradoxical bradypnea following 5% inhaled CO2. METHODS: Observational study 7-8 week CB6F1/OlaHsd mice (n = 99), anesthetized with 30 mg/kg intraperitoneal pentobarbital. Interventional study: Adult male Wistar rats (n = 18), anesthetized either with 30 mg/kg intraperitoneal pentobarbital, 100 mg/kg intraperitoneal ketamine or 1.5% isoflurane. Rats had femoral artery cannulas inserted for hemodynamic monitoring and serial arterial blood gas measurements. RESULTS: Observational study: There was a marked reduction in respiratory rate following 4 min of normoxic hypercapnia; average reduction of 9 breaths/min (p < 0.001) (17% reduction from baseline). Interventional study: increasing CO2 caused dose-dependent increase in respiratory rate for ketamine xylazine (p = 0.007) and isoflurane (p = 0.016) but dose-dependent decrease in respiratory rate for pentobarbital (p = 0.046). Increasing inspired CO2 caused dose-dependent acidosis following pentobarbital and isoflurane (p = 0.013 and p = 0.017, respectively); but not following ketamine-xylazine (p = 0.58). CONCLUSIONS: Inhaled CO2 caused paradoxical dose-dependent bradypnea in animals anesthetized with pentobarbital, an observation not hitherto reported as a part of anesthesia-related respiratory depression. PMID- 26099800 TI - Dissociation of skeletal muscle for flow cytometric characterization of immune cells in macaques. AB - The majority of vaccines and several treatments are administered by intramuscular injection. The aim is to engage and activate immune cells, although they are rare in normal skeletal muscle. The phenotype and function of resident as well as infiltrating immune cells in the muscle after injection are largely unknown. While methods for obtaining and characterizing murine muscle cell suspensions have been reported, protocols for nonhuman primates (NHPs) have not been well defined. NHPs comprise important in vivo models for studies of immune cell function due to their high degree of resemblance with humans. In this study, we developed and systematically compared methods to collect vaccine-injected muscle tissue to be processed into single cell suspensions for flow cytometric characterization of immune cells. We found that muscle tissue processed by mechanical disruption alone resulted in significantly lower immune cell yields compared to enzymatic digestion using Liberase. Dendritic cell subsets, monocytes, macrophages, neutrophils, B cells, T cells and NK cells were readily detected in the muscle by the classic human markers. The methods for obtaining skeletal muscle cell suspension established here offer opportunities to increase the understanding of immune responses in the muscle, and provide a basis for defining immediate post-injection vaccine responses in primates. PMID- 26099802 TI - The role of key workers in supporting people with intellectual disability in the self-management of their diabetes: a qualitative New Zealand study. AB - The incidence of diabetes in people with an intellectual disability, although unknown, is indicated to be higher than the general population. Given the challenges individuals with intellectual disability may face, this population is often dependent upon key workers to manage their health and well-being. One aim of a wider study on the self-management of diabetes by people with intellectual disability was to explore how key workers supported their self-management. That aim was the focus of this paper. Between 2009 and 2010, 17 staff from five residential intellectual disability services and two supported independent living services within New Zealand, consented to a semi-structured interview. Transcripts of the interviews were analysed using Thomas' General Inductive Approach. Three overarching themes emerged; having knowledge and understanding, being lifestyle police and ensuring future well-being. While knowledge, skills and perspectives varied, all participants were committed to ensuring that the lifestyle of the person concerned was compatible with the management of their diabetes. A range of perspectives existed between the expectations they had of themselves, colleagues and the individual with diabetes. There was an identified need for initial and ongoing education of permanent and casual staff and the people themselves with diabetes in collaboration with health and disability services to build confidence and promote self-management practices. In so doing, the impacts of this long-term condition may be reduced and the health outcomes improved for people with intellectual disability. PMID- 26099801 TI - Arabidopsis leucine-rich repeat extensin (LRX) proteins modify cell wall composition and influence plant growth. AB - BACKGROUND: Leucine-rich repeat extensins (LRXs) are extracellular proteins consisting of an N-terminal leucine-rich repeat (LRR) domain and a C-terminal extensin domain containing the typical features of this class of structural hydroxyproline-rich glycoproteins (HRGPs). The LRR domain is likely to bind an interaction partner, whereas the extensin domain has an anchoring function to insolubilize the protein in the cell wall. Based on the analysis of the root hair expressed LRX1 and LRX2 of Arabidopsis thaliana, LRX proteins are important for cell wall development. The importance of LRX proteins in non-root hair cells and on the structural changes induced by mutations in LRX genes remains elusive. RESULTS: The LRX gene family of Arabidopsis consists of eleven members, of which LRX3, LRX4, and LRX5 are expressed in aerial organs, such as leaves and stem. The importance of these LRX genes for plant development and particularly cell wall formation was investigated. Synergistic effects of mutations with gradually more severe growth retardation phenotypes in double and triple mutants suggest a similar function of the three genes. Analysis of cell wall composition revealed a number of changes to cell wall polysaccharides in the mutants. CONCLUSIONS: LRX3, LRX4, and LRX5, and most likely LRX proteins in general, are important for cell wall development. Due to the complexity of changes in cell wall structures in the lrx mutants, the exact function of LRX proteins remains to be determined. The increasingly strong growth-defect phenotypes in double and triple mutants suggests that the LRX proteins have similar functions and that they are important for proper plant development. PMID- 26099803 TI - Cecal volvulus caused by endometriosis in a young woman. AB - BACKGROUND: Cecal volvulus is relatively rare. Moreover, to the best of our knowledge, a case of cecal volvulus caused by endometriosis has not yet been reported. CASE PRESENTATION: A 41-year-old woman was admitted to our hospital with a 14-day history of subacute intermittent right lower quadrant abdominal pain. Simple abdominal radiography and abdominal computed tomography findings were suggestive of sigmoid volvulus, and she underwent an emergency colonoscopy. Following colonoscopic reduction, the patient's symptoms resolved quickly, and elective laparoscopic surgery was scheduled 2 weeks after admission. Intraoperative examination revealed a significantly distended cecum and ascending colon, which was twisted around a short rope-like adhesion that connected the cecum and the mesentery of the transverse colon, whereas the sigmoid colon was neither twisted nor extended. We laparoscopically performed an ileocecal resection. The postsurgery histopathological examination revealed the presence of endometrial tissue in the short rope-like adhesion. This finding confirmed that cecal volvulus in this patient was caused by endometriosis. CONCLUSION: Cecal volvulus should be considered in relatively young women who present with atypical right lower abdominal pain. Whenever possible, secondary factors should be evaluated preoperatively, especially in relatively young patients. PMID- 26099804 TI - Survival time according to the year of recurrence and subtype in recurrent breast cancer. AB - BACKGROUND: Survival for patients with recurrent breast cancer has improved over time due to the introduction of modern systemic therapy. The aim of this study was to determine the impact of subtype and the year of recurrence on the survival times of recurrent breast cancer. METHODS: Between 1979 and 2013, 813 patients who underwent initial treatment for primary breast cancer experienced recurrence. They were divided into two groups based on the year of recurrence; before 2000 and after 2001. Survival after recurrence was compared between these groups based on following criteria; subtypes, disease free interval (DFI), and dominant recurrent site. The median follow-up period after recurrence was 4.3 years. RESULTS: Survival improved significantly in the after 2001 group, and a significant improvement in survival was only seen in the HER2-enriched subtype. Multivariate analysis revealed that DFI, ER, HER2 status, dominant recurrent site and the Ki-67 index value were significant prognostic factors. In the HER2 enriched subtype, the year of recurrence, DFI and dominant recurrent site were significant independent factors. In the other subtypes, these factors were not correlated with survival. CONCLUSION: Our study revealed that the survival rate of patients with only the HER2-enriched subtype significantly improved after recurrence. To prolong the survival time after recurrence of both luminal and triple negative subtypes, the development of novel targeting therapies to overcome refractory recurrent breast cancer is extremely important. PMID- 26099805 TI - Is CT cystography an accurate study in the evaluation of spontaneous perforation of augmented bladder in children and adolescents? AB - BACKGROUND: Spontaneous bladder perforation (SBP) is a potentially fatal complication of augmented bladder. Imaging is often used for diagnosis. In this study we present our experience with CT cystography (CTC) in the diagnosis of SBP. OBJECTIVE: To determine CTC accuracy in the evaluation of SBP in children with an augmented bladder. STUDY DESIGN: The institutional review board approved this HIPAA-compliant study; informed consent was waived. All patients under 20 years old, who underwent CTC for SBP evaluation from 2003 to 2013, were identified. Two radiologists independently reviewed CTC studies for contrast extravasation, ascites, and pneumoperitoneum. Ascites was graded: small - confined to the rectovesical pouch (RVP); moderate - beyond the RVP; large - beyond the pelvis. RESULTS: Eighty-nine patients (47 males, age 4.2-19.8 years) had 132 CTCs. SBP was diagnosed in 14% (19/132). Both radiologists found contrast extravasation in 74% (14/19) of patients with SBP; two patients had only pneumoperitoneum, and three had only ascites (large = 2, moderate = 1) (Fig.). SBP was found in 1% of CTCs with no ascites or small ascites (1 of 98 and 92; radiologists 1 and 2, respectively). Findings of extraluminal extravasation, unexplained pneumoperitoneum, or large ascites, yielded a detection rate of 95% for SBP by each radiologist. In eight patients, small bowel obstruction was diagnosed. DISCUSSION: Contrast extravasation was detected in only 74% of patients with SBP. The use of indirect signs of perforation (unexplained pneumoperitoneum and large ascites) in addition to contrast extravasation, increased the detection rate of SBP to 95%. US screening for SBP and selection of patients with moderate or large ascites for CTC, may eliminate the need for most CT scans. In the absence of SBP, other abdominal abnormalities should be evaluated. Bowel obstruction was the most common non-urological emergency detected in this series. The main limitations of the study are: the small number of SBP cases; the diagnosis of SBP not based on surgical findings in three patients; and inability to completely exclude occult SBP in patients not explored surgically. CONCLUSION: Extraluminal contrast was seen on CTC in most cases of SBP, but some patients with sealed bladder perforation had only pneumoperitoneum or moderate/large ascites. Therefore, SBP should be suspected in any patient with moderate/large volumes of pelvic fluid or unexplained pneumoperitoneum, even when there is no evidence of contrast extravasation. Patients with no ascites, or small volumes, are unlikely to have SBP; therefore, US can be used to screen low risk patients. PMID- 26099806 TI - In vivo porcine lipopolysaccharide inflammation models to study immunomodulation of drugs. AB - Lipopolysaccharide (LPS), a structural part of the outer membrane of Gram negative bacteria, is one of the most effective stimulators of the immune system and has been widely applied in pigs as an experimental model for bacterial infection. For this purpose, a variety of Escherichia coli serotypes, LPS doses, routes and duration of administration have been used. LPS administration induces the acute phase response (APR) and is associated with dramatic hemodynamic, clinical and behavioral changes in pigs. Pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 and IL-6 are involved in the induction of the eicosanoid pathway and the hepatic production of acute phase proteins, including C-reactive protein (CRP), haptoglobin (Hp) and pig major acute phase protein (pig-MAP). Prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) play a major role in the development of fever and pulmonary hypertension in LPS-challenged pigs, respectively. The LPS-induced APR can be modulated by drugs. Steroidal and nonsteroidal anti-inflammatory drugs ((N)SAIDs) possess anti inflammatory, antipyretic and analgesic properties through (non)-selective central and peripheral cyclooxygenase (COX) inhibition. Antimicrobial drugs, especially macrolide antibiotics, which are commonly used in veterinary medicine for the treatment of bacterial respiratory diseases, have been recurrently reported to exert clinically important immunomodulatory effects in human and murine research. To investigate the influence of these drugs on the clinical response, production of pro-inflammatory cytokines, acute phase proteins (APP) and the course of the febrile response in pigs, in vivo LPS inflammation models can be applied. Yet, to date, in vivo research on the immunomodulatory properties of antimicrobial drugs in these models in pigs is largely lacking. This review provides acritical overview of the use of in vivo porcine E. coli LPS inflammation models for the study of the APR, as well as the potential immunomodulatory properties of anti-inflammatory and antimicrobial drugs in pigs. PMID- 26099807 TI - Immunomodulatory activity and control of Salmonella Enteritidis colonization in the intestinal tract of chickens by Lactobacillus based probiotic. AB - Lactobacillus-based probiotics (LBP) are used as competitive exclusion to control pathogenic enterobacterial infections and improve the weight gain in broiler chickens. This study assessed the inhibition of Salmonella Enteritidis (SE) infection in one-week-old broiler chicks, using an experimental LBP containing four Lactobacillus strains isolated from chickens (L. acidophilus, L. fermentum, L. reuteri, L. salivarius). The immunomodulatory effects of this treatment were evaluated, through the analysis of cytokines and influx of macrophages, gammadelta, CD4(+) and CD8(+) T cells in the gut. The intestinal colonization by SE was reduced by 1.8 CFU/g (log10) in chicks treated with LBP (p<0.05). The levels of pro-inflammatory cytokines (IL-1beta, LITAF) were significantly reduced in treated chicks (p<0.05), whilst untreated chicks showed elevated inflammatory stimulus and an increased population of CD8(+) T cells in the intestinal mucosa after challenge (p<0.05). Additionally, the LBP stimulated TLR2 expression in caecal tonsils. The adjuvant property of the Lactobacillus cell wall (LCW) was evaluated, demonstrating good capability to stimulate T helper 2 (Th2) cell proliferation. Pretreatment of chicks with LBP decreased the intestinal colonization by SE, minimizing the tissue lesions and inflammation after challenge and showed a potential use as adjuvant with injectable killed vaccines. PMID- 26099808 TI - Effect of dexamethasone on bacteriostatic activity of turkey monocytes and implications for food safety. AB - Stress has been shown to affect the immune system of turkeys making them more susceptible to bacterial infections. Five-week-old male and female turkeys were treated with 3 intra-muscular injections of dexamethasone (Dex) at 0, 0.5 and 2.0mg/kg body weight. Twenty-four hours after the third injection birds were bled and white blood cell (WBC) differentials and bacteriostatic activity of monocytes were measured. Dex at both 0.5 and 2.0mg/kg decreased phagocytic activity in females only. Bacteriostatic activity was decreased at both concentrations of Dex at 8 and 16 h post-infection in both sexes and was lower in males as compared to females. Total WBC counts were increased in females at both concentrations of Dex whereas male total WBC counts were unaffected. Both males and females had an increase in the heterophil to lymphocyte ratio. Within the same study, replicate pens of turkeys were challenged with intra-air sac inoculation of 100 cfu of Escherichia coli. Isolation of E. coli was significantly increased by both Dex and E. coli challenge, but there were no differences between sexes. These results suggest that stress can compromise the bacteriostatic activity of turkey monocytes and increase bacterial colonization of blood and tissues, potentially affecting food safety. PMID- 26099809 TI - Quality control systems in aging. PMID- 26099810 TI - Grading diastolic function by echocardiography: hemodynamic validation of existing guidelines. AB - BACKGROUND: While echocardiographic grading of left ventricular (LV) diastolic dysfunction (DD) is used every day, the relationship between echocardiographic DD grade and hemodynamic abnormalities is uncertain. METHODS: We identified 460 consecutive patients who underwent transthoracic echocardiography within 24 h of elective left heart catheterization and had: normal sinus rhythm, no confounding structural heart disease, no change in medications between catheterization and echo, and complete echocardiographic data. Patients were grouped based on echocardiographic DD grade. Hemodynamic tracings were used to determine time constant of isovolumic pressure decay (Tau), LV end-diastolic pressure (LVEDP) and end-diastolic volume index at a pressure of 20 mmHg (EDVi20). RESULTS: Normal diastolic function was found in 55 (12.0%) patients, while 132 (28.7%) patients had grade 1, 156 (33.9%) grade 2 and 117 (25.4%) grade 3 DD. The median value for Tau was 46.9 ms for the overall population (interquartile range 38.6-58.1 ms), with a prevalence of a prolonged Tau (>48 ms) of 47.5%. While there was an association between DD grade and Tau (p = 0.003), LV dysfunction (ejection fraction <50%) was more strongly associated with increased Tau (p < 0.001) than was DD grade (p = 0.19). There was also an association between DD grade and LVEDP (p < 0.001), with both LV dysfunction (p = 0.029) and DD grade (p < 0.001) independently associated with LVEDP. Calculated EDVi20 was related to DD grade, but this relationship was driven by findings of paradoxically increased compliance in patients with severe DD. CONCLUSIONS: Although echocardiographic grading of DD was related to invasive hemodynamics in this population, the relationship was modest. PMID- 26099811 TI - Additional uses of a vaginal fornices delineator. AB - A vaginal fornices delineator was introduced in the mid-90s by a gynecologic surgeon named Charles Koh as a device that would facilitate total laparoscopic hysterectomy. It is also used in robot-assisted and traditional laparoscopic hysterectomies. The delineator delineates the vaginal fornices and provides improved visualization of vital structures during a hysterectomy. The determination of the anatomic level of the cervix is vital in the identification of the inferior borders of a total hysterectomy and to avoid injury to the ureters and uterine vessels. As such, we describe 3 gynecologic surgeries in which the identification of this level was suboptimal. Our solution was to utilize a vaginal fornices delineator as the cervical "guide" to enhance this visualization and to allow for a complete and safe surgical outcome. The following surgical scenarios and the surgical facilitation provided by the vaginal fornices delineator will be presented: (1) a postpartum cesarean hysterectomy complicated by a large lower uterine fibroid tumor that distorts the cervix, (2) a robotic-assisted placement of an abdominal cerclage in a first trimester pregnancy, (3) abdominal hysterectomy complicated by a necrotizing uterine infection and the associated difficulty in the identification of the cervicouterine junction. PMID- 26099812 TI - Symptom perceptions and help-seeking behaviour prior to lung and colorectal cancer diagnoses: a qualitative study. AB - BACKGROUND: Lung and colorectal cancer are common and have high UK mortality rates. Early diagnosis is important in reducing cancer mortality, but the literature on lung and colorectal cancers suggests many people wait for a considerable time before presenting symptoms. OBJECTIVE: To gain in-depth understanding of patients' interpretations of symptoms of lung and colorectal cancer prior to diagnosis, and to explore processes leading to help-seeking. METHODS: Semi-structured interviews were conducted with patients diagnosed with lung (N=9) or colorectal (N=20) cancer within the previous 12 months. Patients were asked about symptoms experienced in the period preceding diagnosis, their interpretations of symptoms, and decision making for help-seeking. Thematic analysis was conducted and comparisons drawn within and across the patient groups. RESULTS: Patients were proactive and rational in addressing symptoms; many developed alternative, non-cancer explanations based on their knowledge and experience. Discussions with important others frequently provided the impetus to consult, but paradoxically others often initially reinforced alternative explanations. Fear and denial did not emerge as barriers to help-seeking, but help-seeking was triggered when patients' alternative explanations could no longer be maintained, for instance due to persistence or progression of symptoms. CONCLUSION: Patients' reasoning, decision making and interpersonal interactions prior to diagnosis were complex. Prompting patients for additional detail on symptoms within consultations could elicit critical contextual information to aid referral decisions. Findings also have implications for the design of public health campaigns. PMID- 26099813 TI - Chronic heart failure and type 2 diabetes mellitus: The last battle? PMID- 26099814 TI - The voltage-gated sodium channel activator veratrine induces anxiogenic-like behaviors in rats. AB - In this study, we investigated the anxiogenic-like effects of systemically administered veratrine in rat models of anxiety. In the light/dark test, veratrine (0.6 mg/kg, s.c.) significantly and dose-dependently decreased the time rats spent in and the number of entries into a light box 30 min after administration, suggesting that veratrine increases anxiety-like behaviors. These findings were also supported by results from the elevated-plus maze test and the tail-swing behavior test. In addition, veratrine (0.6 mg/kg, s.c.) significantly increased the plasma concentration of corticosterone, an endogenous biomarker for anxiety, compared to vehicle. On the basis of these results, we conclude that veratrine induces anxiogenic-like behaviors in rats. The anxiogenic-like behaviors induced by veratrine (0.6 mg/kg, s.c.) were completely abolished by co treatment with the typical benzodiazepine anxiolytic diazepam (1 mg/kg, s.c.), when assessed in the elevated-plus maze test. Similar results were obtained with co-treatment with riluzole (10 mg/kg, p.o.), which directly affects the glutamatergic system and has recently been suggested to have anxiolytic-like effects. In conclusion, this study provides evidence that systemically administered veratrine induces anxiogenic-like behaviors in rats. We propose the veratrine model as a novel pathological animal model to explore possible candidate drugs for anxiolytics. PMID- 26099815 TI - Effect of transcranial direct current stimulation on semantic discrimination eyeblink conditioning. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a neuromodulation method that has been used to modulate learning. We tested whether anodal tDCS targeted at the left DLPFC could enhance learning in a semantic variant of discrimination eyeblink conditioning, i.e., whether the stimulation would have a specific effect on the discrimination ability, rate of acquisition, amplitude of the conditioned response (CR), or all of these. METHODS: Immediately prior to the eyeblink conditioning, the participants received either active stimulation of 1 mA for 10 min or sham stimulation. The anode was placed over F3 and the cathode over the right supraorbital area. The conditioned stimuli (CSs) were common Finnish male and female names that were presented as text. Male names were reinforced with an unconditioned stimulus. RESULTS: Stimulation had no effect on the learning rate or discrimination ratio, but the stimulated participants showed steeper CR acquisition in the initial phase of the experiment. Nevertheless, the participants in the stimulation group showed greater eyeblink CRs to the non reinforced CS. DISCUSSION: Contrary to our initial hypothesis, the magnitude and rate of CRs to non-reinforced CS was higher in the active stimulation group than in the sham stimulation group, which may suggest deterioration of discrimination and contingency awareness in the used task. Our observations may suggest a lack of effect on the participants' ability to discriminate between two different types of CS. Furthermore, cathodal modulation of the right prefrontal cortex may explain the change in magnitude and rate of CRs to non-reinforced CS. PMID- 26099817 TI - Reply: To PMID 25439369. PMID- 26099816 TI - Doxorubicin and cyclophosphamide induce cognitive dysfunction and activate the ERK and AKT signaling pathways. AB - Chemotherapy is associated with long-term cognitive deficits in breast cancer survivors. Studies suggest that these impairments result in the loss of cognitive reserve and/or induce a premature aging of the brain. This study has been aimed to determine the potential underlying mechanisms that induce cognitive impairments by chemotherapeutic agents commonly used in breast cancer. Intact and ovariectomized (OVX) female rats were treated intravenously with either saline or a combination of cyclophosphamide (40 mg/kg) and doxorubicin (4 mg/kg). All subjects were tested for anxiety, locomotor activity, working, visual and spatial memory consecutively. Although anxiety and visual memory were not affected, chemotherapy significantly decreased locomotor activity and impaired working and spatial memory in female rats, independent of their hormonal status. The cognitive deficits observed are hippocampal dependent. Therefore, as a first step to identity the potential signaling pathways involved in this cognitive dysfunction, the protein levels of extracellular signal-regulated kinase 1/2 (Erk1/2), Akt (neuroprotectant) BDNF and (structural protein) PSD95 in hippocampal lysates were measured. Erk1/2 and Akt pathways are known to modulate synaptic plasticity, neuronal survival, aging and cancer. We found an increased activation of Erk1/2 and Akt as well as an increase in the protein levels of PSD95 in OVX female rodents. However, OVX females had a higher overall BDNF level, independent of chemotherapy. These studies provide additional evidence that commonly used chemotherapeutic agents affect cognitive function and impact synaptic plasticity/aging molecules which may be part of the underlying biology explaining cognitive change and can be potential therapeutic targets. PMID- 26099819 TI - Characterization of ethnicity among children with eosinophilic esophagitis in British Columbia, Canada. PMID- 26099818 TI - IgE Antibody Detection and Component Analysis in Patients with Eosinophilic Esophagitis. AB - BACKGROUND: Although IgE antibodies to cow's milk and wheat are common in patients with eosinophilic esophagitis (EoE), titers are low and responses to diet are not dependent on having IgE antibodies. OBJECTIVE: To better define specific IgE antibody responses to foods, focusing on those foods that appear to play a role in EoE. METHODS: Adult (n = 46) and pediatric (n = 51) patients with EoE were recruited for skin prick testing and serum measurement (whole and diluted) of IgE antibodies specific for aeroallergens, food extracts, and component allergens by ImmunoCAP. Immuno Solid-phase Allergen Chip analysis was also used to measure the specificity of IgE antibodies to 112 allergen molecules. RESULTS: In adults and children, there was a higher prevalence of sensitization to food extracts by ImmunoCAP than by skin prick testing. Using Immuno Solid phase Allergen Chip to assess the specificity of IgE antibodies to 112 allergen molecules, we found that results for food allergens were mostly negative. In contrast, ImmunoCAP assays for specific milk allergens gave positive IgE antibody results in 31 of 34 sera. The correlations between specific IgE antibody to Bos d 4 or Bos d 5 and milk extract were strong (R = 0.89 and 0.76, respectively; P < .001). The evidence that IgE antibodies to foods were directed at minor components of the extracts was further supported by measurements on diluted sera. CONCLUSIONS: The IgE responses in cow's milk-sensitized patients with EoE are frequently to whey proteins Bos d 4 and Bos d 5, minor components of the extract. These IgE assays may be able to identify the proteins that are relevant to EoE even though IgE is not the primary mechanism. PMID- 26099820 TI - Predicting dementia. PMID- 26099821 TI - Dinitrogen binding and cleavage by multinuclear iron complexes. AB - The iron-molybdenum cofactor of nitrogenase has unprecedented coordination chemistry, including a high-spin iron cluster called the iron-molybdenum cofactor (FeMoco). Thus, understanding the mechanism of nitrogenase challenges coordination chemists to understand the fundamental N2 chemistry of high-spin iron sites. This Account summarizes a series of studies in which we have synthesized a number of new compounds with multiple iron atoms, characterized them using crystallography and spectroscopy, and studied their reactions in detail. These studies show that formally iron(I) and iron(0) complexes with three and four-coordinate metal atoms have the ability to weaken and break the triple bond of N2. These reactions occur at or below room temperature, indicating that they are kinetically facile. This in turn implies that iron sites in the FeMoco are chemically reasonable locations for N2 binding and reduction. The careful evaluation of these compounds and their reaction pathways has taught important lessons about what characteristics make iron more effective for N2 activation. Cooperation of two iron atoms can lengthen and weaken the N-N bond, while three working together enables iron atoms to completely cleave the N-N bond to nitrides. Alkali metals (typically introduced into the reaction as part of the reducing agent) are thermodynamically useful because the alkali metal cations stabilize highly reduced complexes, pull electron density into the N2 unit, and make reduced nitride products more stable. Alkali metals can also play a kinetic role, because cation-pi interactions with the supporting ligands can hold iron atoms near enough to one another to facilitate the cooperation of multiple iron atoms. Many of these principles may also be relevant to the iron-catalyzed Haber Bosch process, at which collections of iron atoms (often promoted by the addition of alkali metals) break the N-N bond of N2. The results of these studies teach more general lessons as well. They have demonstrated that N2 can be a redox active ligand, accepting spin and electron density in complexes of N2(2-). They have shown the power of cooperation between multiple transition metals, and also between alkali metals and transition metals. Finally, alkali metal based cation pi interactions have the potential to be broadly useful for bringing metals close together with sufficient flexibility to allow multistep, multielectron reactions. At the same time, the positive charge on the alkali metal cation stabilizes charge buildup in intermediates. PMID- 26099822 TI - Synthesis of calcium oxalate trihydrate: New data by vibrational spectroscopy and synchrotron X-ray diffraction. AB - Calcium oxalate is found in nature in three different crystalline states determined by the number of H2O in the unit formula (whewellite CaC2O4.H2O, COM; weddellite CaC2O4.(2+x)H2O, COD and caoxite CaC2O4.3H2O, COT). The properties of these materials are relevant in the field of biomedicine, cultural heritage and mineralogy. In two previous papers, we have used X-ray diffraction and vibrational spectroscopy (infrared and Raman) to derive information on crystal and molecular structures of COM and COD. In this paper, we complete the synthesis and analysis on the third form, COT, and present a comparative study of the data collected from the three crystalline states. The experiments clearly highlight the role played by the H2O molecules linked within the structure by different kinds of hydrogen bonds. The vibrational assignment of the infrared and Raman bands are critically proposed. The fact relevant for the work in biomedicine, cultural heritage and crystallography is that a simple examination of the spectra allows quickly to determine the chemical nature of the material in an unknown sample even in a minute quantity or in awkward experimental conditions. PMID- 26099823 TI - A dithienosilole-based fluorescent chemosensor for multiple logic operations at the molecular level. AB - A chemosensor consisting of two terpyridines covalently linked to a dithienosilole unit (1) has been synthesized, and its optical and metal sensing properties have been investigated. Due to the metal-organic coordination function, 1 can bind with many transition metal ions and display different fluorescence responses that cause it to function as a "turn-off" fluorescent chemosensor. A significant bathochromic shift in the fluorescence spectra is observed in the presence of Zn(2+). Meanwhile, the emission of 1 is weakened upon exposure to Ag(+) and Fe(2+) and completely quenched by Ni(2+), Co(2+), and Cu(2+). Based on the observed results, several logic gates, such as XNOR, INHIBIT, and IMPLICATION, have been achieved by controlling the chemical inputs. PMID- 26099824 TI - Novel Ge-Ga-Te-CsBr glass system with ultrahigh resolvability of halide. AB - CO2 molecule, one of the main molecules to create new life, should be probed accurately to detect the existence of life in exoplanets. The primary signature of CO2 molecule is approximately 15 MUm, and traditional S- and Se-based glass fibers are unsuitable. Thus, Te-based glass is the only ideal candidate glass for far-infrared detection. In this study, a new kind of Te-based chalcohalide glass system was discovered with relatively stable and large optical band gap. A traditional melt-quenching method was adopted to prepare a series of (Ge15Ga10Te75)100-x (CsBr)x chalcogenide glass samples. Experiment results indicate that the glass-forming ability and thermal properties of glass samples were improved when CsBr was added in the host of Ge-Ga-Te glass. Ge-Ga-Te glass could remarkably dissolve CsBr content as much as 85 at.%, which is the highest halide content in all reports for Te-based chalcohalide glasses. Moreover, DeltaT values of these glass samples were all above 100 degrees C. The glass sample (Ge15Ga10Te75)65 (CsBr)35 with DeltaT of 119 degrees C was the largest, which was 7 degrees C larger than that of Ge15Ga10Te75 host glass. The infrared transmission spectra of these glasses show that the far-infrared cut-off wavelengths of (Ge15Ga10Te75)100-x (CsBr)x chalcogenide glasses were all beyond 25 MUm. In conclusion, (Ge15Ga10Te75)100-x (CsBr)x chalcogenide glasses are potential materials for far-infrared optical application. PMID- 26099825 TI - On a magnetic-luminescent nanocomposite for oxygen sensing application: Construction, characterization and sensing performance. AB - This paper was devoted to the construction of a magnetic-luminescence nanocomposite for oxygen sensing application, where superparamagnetic Fe3O4 and silica molecular sieve MCM-41 were chosen as the inner core and the outer shell, respectively. A Ru(II) complex was grafted into MCM-41 shell through a coupling ligand N1-(5H-cyclopenta[1,2-b:5,4-b']dipyridin-5-ylidene)benzene-1,4-diamine (denoted as Dafo-Ph-NH2). The final composite was analyzed by electron microscope images, XRD, IR spectra, thermogravimetry and N2 adsorption/desorption. Oxygen sensing performance of this composite was evaluated. Sensitivity of 5.8 (the ratio of emission intensity in pure N2 to that in pure O2) and response time of 16s were obtained with good photostability. PMID- 26099826 TI - Applications in environmental bioinorganic: Nutritional and ultrastructural evaluation and calculus of thermodynamic and structural properties of metal oxalate complexes. AB - Lead (Pb) is known by its toxicity both for animals and plants. In order to evaluate its toxicity, plants of Brachiaria brizantha were cultivated on nutritive solution of Hoagland during 90 days and submitted to different concentrations of Pb. The content of macro and micronutrients was evaluated and there was a reduction on root content of Ca, besides the lowest dosages of Pb had induced an increase of N, S, Mn, Cu, Zn and Fe. The cell ultrastructure of leaves and roots were analyzed by transmission electronic microscopy (TEM). Among the main alterations occurred there were invaginations on cell walls, the presence of crystals on the root cells, accumulation of material on the interior of cells and vacuolar compartmentalization. On the leaves the degradation of chloroplasts was observed, as well as the increase of vacuoles. Structures for the formation of oxalate crystals were proposed through molecular modeling and thermodynamic stability. Calculi suggest the formation of highly stable metal-oxalate complexes. PMID- 26099827 TI - Spectroscopic characterisation of the LDH mineral quintinite Mg4Al2(OH)12CO3.3H2O. AB - Raman and infrared spectroscopy coupled with scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX) have been applied to study the natural hydrotalcite quintinite Mg4Al2(OH)12[CO3].3H2O. SEM shows the mineral to be a homogenous phase. Quintinite is composed of Mg and Al as the major elements with minor amounts of Fe. Two Raman bands at 1046 and 1062 cm are assigned to the nu1 symmetric stretching modes of the carbonate anion. Thermal treatment shifts these bands to higher wavenumbers indicating a change in the carbonate bonding. Hydrogen bond distances are calculated using a Libowitzky-type empirical function and varied between 2.61 and 3.00 A. Stronger hydrogen bonds were formed by water units as compared to the hydroxyl units. PMID- 26099828 TI - Synthesis, crystal growth and characterization of an organic material: 2 Aminopyridinium succinate succinic acid single crystal. AB - The 2-aminopyridinium succinate succinic acid (2APS) single crystal was synthesized and grown by slow evaporation method. The crystal structure has been confirmed by powder X-ray diffraction as well as single crystal X-ray diffraction analysis. The crystal perfection has been evaluated by high resolution X-ray diffraction (HRXRD). The grown crystal is transparent in the visible and near infrared region. The optical absorption edge was found to be 348 nm. The fluorescence study was carried out by spectrofluorophotometer. The thermal stability of grown crystal was analyzed by thermal gravimetric and differential thermal gravimetric (TG-DTA) analysis. Vicker's hardness study carried out at room temperature shows increased hardness while increasing the load. Laser damage threshold value was determined by Nd:YAG laser operating at 1064 nm. The grown 2APS crystal was characterized by etching studies using water as etchant. PMID- 26099829 TI - Direct molecular targets of resveratrol: identifying key interactions to unlock complex mechanisms. AB - To truly understand the mechanisms through which resveratrol exerts its biological effects, the key direct interactions between resveratrol and its target biomolecules must be identified. With an increasing number of biochemical tools to measure and quantify direct physical interactions between biomolecules, there have been around 20 proteins identified as having a specific affinity to resveratrol to date. Resveratrol has been described as a promiscuous molecule, and one would expect it to bind with numerous proteins, which would help explain why resveratrol appears to have so many health benefits and has been shown to act upon various different pathways related to a diverse range of conditions. The aim of this review is to present the direct protein targets of resveratrol that are currently known and highlight the consequences of direct binding and the methods used to identify the nature of these interactions. PMID- 26099830 TI - High-Dose Melphalan Plus Thiotepa as Conditioning Regimen before Second Autologous Stem Cell Transplantation for "De Novo" Multiple Myeloma Patients: A Phase II Study. AB - High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m(2)) to high-dose MEL (140 mg/m(2)) before a second ASCT, in a tandem ASCT strategy, in 64 patients with "de novo" MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study. PMID- 26099831 TI - Improved antibacterial activity of nanofiltration polysulfone membranes modified with silver nanoparticles. AB - Polysulfone membranes (PSf) containing silver nanoparticles were prepared by the wet phase-inversion process. Silver nanoparticles (AgNP) were dispersed into the polymer matrix using two different methodologies. In the first one, the AgNP were synthesized and further dispersed into the polymer solution (ex situ process). In the second method, the formation of the AgNP was performed in situ. The AgNP crystalline structure in the PSf membranes was confirmed by X-ray diffraction. Field emission scanning electron microscopy images showed that the addition of AgNP in PSf membranes caused no significant changes to the finger-like morphology. When the ex situ methodology was applied, 45 nm average size AgNP were uniformly distributed in the internal pores of the membranes. However, when the AgNP were formed through the in situ process, the AgNP were uniformly and preferentially distributed on the top and bottom surfaces of the membrane. In the last case, the AgNP showed cubic morphology when present in the bottom and top surfaces, however, when inside the membrane their morphology was spherical. The cubic-like nanoparticles displayed a 38 nm average edge length. The silver ion released from the membrane during water filtration was measured using inductively coupled plasma mass spectrometry, which showed a silver leaching of approximately 2 MUg L(-1). The nanocomposite membranes prepared by the in situ method exhibited a better antibacterial activity, in comparison to those prepared by ex situ, and also a decrease in 90% Escherichia coli adhered cells compared to the pristine PSf membranes. In conclusion, the in situ procedure can be considered a feasible, simple, and reproducible methodology to prepare anti-biofouling polysulfone membranes containing AgNP. PMID- 26099832 TI - Disinfection by-product formation during seawater desalination: A review. AB - Due to increased freshwater demand across the globe, seawater desalination has become the technology of choice in augmenting water supplies in many parts of the world. The use of chemical disinfection is necessary in desalination plants for pre-treatment to control both biofouling as well as the post-disinfection of desalinated water. Although chlorine is the most commonly used disinfectant in desalination plants, its reaction with organic matter produces various disinfection by-products (DBPs) (e.g., trihalomethanes [THMs], haloacetic acids [HAAs], and haloacetonitriles [HANs]), and some DBPs are regulated in many countries due to their potential risks to public health. To reduce the formation of chlorinated DBPs, alternative oxidants (disinfectants) such as chloramines, chlorine dioxide, and ozone can be considered, but they also produce other types of DBPs. In addition, due to high levels of bromide and iodide concentrations in seawater, highly cytotoxic and genotoxic DBP species (i.e., brominated and iodinated DBPs) may form in distribution systems, especially when desalinated water is blended with other source waters having higher levels of organic matter. This article reviews the knowledge accumulated in the last few decades on DBP formation during seawater desalination, and summarizes in detail, the occurrence of DBPs in various thermal and membrane plants involving different desalination processes. The review also identifies the current challenges and future research needs for controlling DBP formation in seawater desalination plants and to reduce the potential toxicity of desalinated water. PMID- 26099833 TI - A worldwide bibliometric analysis of published literature in plastic and reconstructive surgery. AB - BACKGROUND: Bibliometrics is the analysis of the content and citations of journal articles to quantify trends in published data. In this study, we aimed to use bibliometric analysis to identify the contribution of various countries to the plastic surgical literature over a 5-year period. METHODS: In this study, the top 20 countries publishing articles on surgery and 10 plastic surgical journals with the highest impact factors (IFs) were included. The number of scientific articles published in each journal per year (2009-2013) in each country was found using PubMed. As a marker of quality, the mean IF for each country was calculated using the number of articles and journal IF. These data were compared with population, gross domestic product (GDP) and dollars spent on research. RESULTS: A total of 10,051 articles were included. The USA was the largest contributor, with 4008 articles published over 5 years, followed by the UK (1163 articles). The USA's mean IF was 2.084, closely followed by Canada (2.037). The UK had the highest number of publications per million population (PMP; 18.14 publications PMP). When considering the overall research spending per country, Turkey had the most cost effective publication output. The least cost-effective country was South Korea. Sweden, the Netherlands and Canada had the greatest increase in publication quality. CONCLUSIONS: Bibliometric analysis can be used to identify not only major centres of plastic surgical research, such as the USA and UK, but also centres that produce high-quality data, such as Canada, and cost-effective research, such as Turkey. It can also highlight the areas of increasing success in plastic surgical research. PMID- 26099834 TI - Why screening for type 2 diabetes is necessary even in poor resource settings. AB - Screening for type 2 diabetes (T2DM) remains controversial, in spite of the explosive increase in the prevalence of the disorder and the morbidity and mortality associated with its complications. In this review, we attempt to show that T2DM is an ideal candidate disease for screening, and why screening is needed to improve clinical outcomes and prevent complications. We also suggest that screening can be made more cost-effective by adopting a targeted approach and utilizing low-cost tools. We conclude that screening for T2DM is warranted even in resource-constrained settings, and provide examples from rural India showing that such an approach is feasible with meticulous planning and judicious allocation of resources. PMID- 26099835 TI - Colloidal metasurfaces displaying near-ideal and tunable light absorbance in the infrared. AB - Metasurfaces are ultrathin, two-dimensional arrays of subwavelength resonators that have been demonstrated to control the flow of light in ways that are otherwise unattainable with natural materials. These arrays are typically composed of metallic Ag or Au nanostructures shaped like split rings, nanowire pairs or nanorods (commonly referred to as meta-atoms) that are arranged to produce a collective optical response spanning an impressive range of properties, from the perfect absorption of incident light to superresolution imaging. However, metasurfaces pose major challenges in their fabrication over large areas, which can be prohibitively expensive and time consuming using conventional nanolithography techniques. Here we show that differently shaped colloidal nanocrystals can be organized into metasurface architectures using robust, scalable assembly methods. These metasurfaces exhibit extreme in-plane electromagnetic coupling that is strongly dependent on nanocrystal size, shape and spacing. Colloidal metasurfaces that display near-ideal electromagnetic absorbance can be tuned from the visible into the mid-infrared wavelengths. PMID- 26099836 TI - Expression and tissue distribution of hepatocyte growth factor (HGF) and its receptor (c-Met) in alpacas (Vicugna pacos) skins associated with white and brown coat colors. AB - Hepatocyte growth factor (HGF)/c-Met signaling has been considered as a key pathway in both melanocyte development and melanogenesis. To understand better the expression patterns and tissue distribution characterization of HGF and its receptor c-Met in skin of white versus brown alpaca (Vicugna pacos), we detected the tissue distribution of HGF and c-Met using immunohistochemistry and analyzed the expression patterns by using Western blot and quantitative real time PCR (qPCR). Immunohistochemistry analysis demonstrated that HGF staining robustly increased in the dermal papilla and mesenchymal cells of white alpaca skin compared with that of brown. However, c-Met staining showed strongly positive result, particularly inhair matrix and root sheath in brown alpaca skin. Western blot and qPCR results suggested that HGF and c-Met were expressed at significantly high levels in white and brown alpaca skins, respectively, and protein and transcripts possessed the same expression pattern in white and brown alpaca skins. The results suggested that HGF/c-Met signaling functions in alpaca coat color formation offer essential theoretical basis for further exploration of the role of HGF/c-Met signaling in pigment formation. PMID- 26099837 TI - Group velocity mismatch-absent nonlinear frequency conversions for mid-infrared femtosecond pulses generation. AB - A novel group velocity mismatch (GVM) absent scheme for nonlinear optical parametric procedure in mid-infrared was developed with type-I quasi phase matching by use of an off-digital nonlinear optical coefficient d31. This was achieved by matching of the group velocities of the pump and the signal waves, while the phase velocities were quasi phase matched. The system employs MgO-doped periodically poled LiNbO3 as the nonlinear medium. Desired group-velocity dispersion would be obtained via appropriately temperature regulation. To demonstrate its potential applications in ultrafast mid-infrared pulses generation, aiming at a typical mid-infrared wavelength of ~3.2 MUm, design examples of two basic nonlinear frequency conversion procedures are studied for both the narrow-band seeding mid-IR optical parametric amplification (OPA) and the synchronously pumped femtosecond optical parametric oscillation (SPOPO). Compared with the conventional scheme of type-0 QPM, the quantum-efficiency can be more than doubled with nearly unlimited bandwidth. The proposed GVM- absent phase matching design may provide a promising route to efficient and broadband sub-100 fs mid-infrared ultrafast pulses generation without group-velocity walk off. PMID- 26099838 TI - Three-dimensional printing models improve understanding of spinal fracture--A randomized controlled study in China. AB - Three-dimensional printing (3 Dp) is being increasingly used in medical education. Although the use of such lifelike models is beneficial, well-powered, randomized studies supporting this statement are scarce. Two spinal fracture simulation models were generated by 3 Dp. Altogether, 120 medical students (54.2% females) were randomized into three teaching module groups [two-dimensional computed tomography images (CT), 3D, or 3 Dp] and asked to answer 10 key anatomical and 4 evaluative questions. Students in the 3 Dp or 3D group performed significantly better than those in the CT group, although males in the 3D group scored higher than females. Students in the 3 Dp group were the first to answer all questions, and there were no sex-related differences. Pleasure, assistance, effect, and confidence were more predominant in students in the 3 Dp group than in those in the 3D and CT groups. This randomized study revealed that the 3 Dp model markedly improved the identification of complex spinal fracture anatomy by medical students and was equally appreciated and comprehended by both sexes. Therefore, the lifelike fracture model made by 3 Dp technology should be used as a means of premedical education. PMID- 26099839 TI - ACTH administration during formation of preovulatory follicles impairs steroidogenesis and angiogenesis in association with ovulation failure in lactating cows. AB - Ovulation failure, follicular persistence, and formation of follicular cysts are known to impair dairy cow fertility. Although the underlying mechanism is not entirely clear, stress-induced alteration in adrenal hormone secretion can cause these ovarian pathologies. Six synchronized lactating cows were scanned daily by ultrasound, and plasma samples were taken throughout the estrous cycle. Treatment cows (n = 3) were administered with ACTH analog every 12 h from day 15 to day 21 of the cycle to induce formation of follicular cysts. Ovaries were collected at the slaughterhouse on day 23 of the cycle before appearance of follicular pathologies. Control cows (n = 3) were administered placebo, resynchronized, and administered PGF2alpha on day 6 of the new cycle to induce development of a preovulatory follicle. Follicular fluid was aspirated from the preovulatory follicles of each group to determine their steroid milieu. Slices were taken from the follicular wall for total messenger (m) RNA isolation and semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Administration of ACTH increased (P < 0.02) plasma cortisol concentration and reduced (P < 0.01) milk production. Androstenedione and estradiol concentrations in the follicular fluids were lower (P < 0.05) in ACTH-treated follicles than those in controls. The mRNA expression of luteinizing hormone receptor, 3beta-hydroxysteroid dehydrogenase, cytochrome P450 aromatase (P450arom), and cytochrome P450 17alpha-hydroxylase (P450c17) were lower (P < 0.02) in the ACTH-treated vs control cows. On the other hand, the expression of steroidogenic acute regulatory protein and cytochrome P450 side-chain cleavage did not differ between groups. In addition, mRNA expression of vascular endothelial growth factor (VEGF)120 and VEGF164 was higher (P < 0.01) in control than in ACTH-treated follicles, but that for angiopoietin-1 and 2 did not differ between groups. Findings indicated that ACTH administration throughout preovulatory follicle development alters follicular steroidogenesis in association with impaired angiogenesis. Such alterations might explain, in part, the mechanism underlying ovulation failure and the formation of persistent or cystic follicles under stress. PMID- 26099840 TI - Zeno dynamics in quantum open systems. AB - Quantum Zeno effect shows that frequent observations can slow down or even stop the unitary time evolution of an unstable quantum system. This effect can also be regarded as a physical consequence of the statistical indistinguishability of neighboring quantum states. The accessibility of quantum Zeno dynamics under unitary time evolution can be quantitatively estimated by quantum Zeno time in terms of Fisher information. In this work, we investigate the accessibility of quantum Zeno dynamics in quantum open systems by calculating noisy Fisher information when a trace preserving and completely positive map is assumed. We firstly study the consequences of non-Markovian noise on quantum Zeno effect and give the exact forms of the dissipative Fisher information and the quantum Zeno time. Then, for the operator-sum representation, an achievable upper bound of the quantum Zeno time is given with the help of the results in noisy quantum metrology. It is of significance that the noise reducing the accuracy in the entanglement-enhanced parameter estimation can conversely be favorable for the accessibility of quantum Zeno dynamics of entangled states. PMID- 26099841 TI - Analysis of survival by tumor response: have we learnt any better? PMID- 26099842 TI - Dyslipidaemia: No limit to the benefits of LDL-cholesterol lowering. PMID- 26099844 TI - Dyslipidaemia: Promising results for TA-8995 in TULIP. PMID- 26099845 TI - Industrial production of clotting factors: Challenges of expression, and choice of host cells. AB - The development of recombinant forms of blood coagulation factors as safer alternatives to plasma derived factors marked a major advance in the treatment of common coagulation disorders. These are complex proteins, mostly enzymes or co enzymes, involving multiple post-translational modifications, and therefore are difficult to express. This article reviews the nature of the expression challenges for the industrial production of these factors, vis-a-vis the translational and post-translational bottlenecks, as well as the choice of host cell lines for high-fidelity production. For achieving high productivities of vitamin K dependent proteins, which include factors II (prothrombin), VII, IX and X, and protein C, host cell limitation of gamma-glutamyl carboxylation is a major bottleneck. Despite progress in addressing this, involvement of yet unidentified protein(s) impedes a complete cell engineering solution. Human factor VIII expresses at very low levels due to limitations at several steps in the protein secretion pathway. Protein and cell engineering, vector improvement and alternate host cells promise improvement in the productivity. Production of Von Willebrand factor is constrained by its large size, complex structure, and the need for extensive glycosylation and disulfide-bonded oligomerization. All the licensed therapeutic factors are produced in CHO, BHK or HEK293 cells. While HEK293 is a recent adoption, BHK cells appear to be disfavored. PMID- 26099843 TI - Cardiovascular risks and benefits of moderate and heavy alcohol consumption. AB - The heart and vascular system are susceptible to the harmful effects of alcohol. Alcohol is an active toxin that undergoes widespread diffusion throughout the body, causing multiple synchronous and synergistic effects. Alcohol consumption decreases myocardial contractility and induces arrhythmias and dilated cardiomyopathy, resulting in progressive cardiovascular dysfunction and structural damage. Alcohol, whether at binge doses or a high cumulative lifetime consumption-both of which should be discouraged-is clearly deleterious for the cardiovascular system, increasing the incidence of total and cardiovascular mortality, coronary and peripheral artery disease, heart failure, stroke, hypertension, dyslipidaemia, and diabetes mellitus. However, epidemiological, case-control studies and meta-analyses have shown a U-type bimodal relationship so that low-to-moderate alcohol consumption (particularly of wine or beer) is associated with a decrease in cardiovascular events and mortality, compared with abstention. Potential confounding influences-alcohol-dose quantification, tobacco use, diet, exercise, lifestyle, cancer risk, accidents, and dependence-can affect the results of studies of both low-dose and high-dose alcohol consumption. Mendelian methodological approaches have led to doubts regarding the beneficial cardiovascular effects of alcohol, and the overall balance of beneficial and detrimental effects should be considered when making individual and population wide recommendations, as reductions in alcohol consumption should provide overall health benefits. PMID- 26099846 TI - Knowledge and awareness of Canadian Physical Activity and Sedentary Behaviour Guidelines: a synthesis of existing evidence. AB - The aim of this review was to consolidate and synthesize existing evidence regarding current knowledge and awareness of the Canadian Physical Activity (PA) and Sedentary Behaviour (SB) Guidelines. MEDLINE, Embase, and PsycINFO were searched for peer-reviewed publications pertaining to the guidelines. Content experts, key organizations (i.e., ParticipACTION and the Canadian Fitness and Lifestyle Research Institute), journal Web sites, and service organizations (i.e., the Canadian Society for Exercise Physiology (CSEP) and the Public Health Agency of Canada) were consulted for additional evidence. Scientific publications (n = 6) and research from ParticipACTION and the Canadian Fitness and Lifestyle Research Institute reported that awareness of the guidelines is low, especially with respect to the SB guidelines. Less than 10% of survey respondents from the Canadian population were aware of the PA guidelines, and less than 5% were aware of the SB guidelines. Information on the guidelines was available on 51% of public health unit and CSEP partner Web sites. Online metrics (e.g., downloads, site accessions) from CSEP, the Public Health Agency of Canada, and journal Web sites showed that online accession of the guidelines was high (e.g., all "highly accessed" on journal Web sites). This review showed that awareness of the Canadian PA and SB Guidelines is low among the general population but higher among the scientific and stakeholder communities. Governmental, nongovernmental, and stakeholder organizations should collaborate in creating sustained, long term, and well-resourced communication plans to reach the Canadian population to raise awareness of PA and SB guidelines and should implement programs to facilitate their uptake. PMID- 26099847 TI - Maternal nutrition influences angiogenesis in the placenta through peroxisome proliferator activated receptors: A novel hypothesis. AB - Placental angiogenesis is critical to maintain adequate blood flow during gestation, and any alterations in this process can result in an adverse pregnancy. Growing evidence indicates that suboptimal maternal nutrition can alter placental development. Although the underlying mechanisms are not clear, maternal nutrition likely influences the expression of genes involved in placental development through regulation of various transcription factors such as peroxisome proliferator-activated receptors (PPARs), which can be activated by ligands including long-chain polyunsaturated fatty acids. Indeed, several studies demonstrated a role for PPAR in implantation, trophoblast differentiation, and angiogenesis. Alterations in maternal nutrition during pregnancy can affect the expression of PPARs via epigenetic mechanisms or through homocysteine, which is known to compete for PPARs. This review discusses the role of maternal nutrition particularly micronutrients like folate, vitamin B12 , and omega-3 fatty acids-in modulating the activity of PPARs during placentation and angiogenesis, which affects placental and fetal growth. Additional animal and human studies need to be undertaken to elucidate the molecular mechanisms through which maternal nutrition regulates PPARs, specifically to determine whether PPARs affect placental angiogenesis directly through angiogenic factors or indirectly by modulating trophoblast differentiation. PMID- 26099848 TI - Effect of alpha-lipoic acid on boar spermatozoa quality during freezing-thawing. AB - Alpha-lipoic acid (ALA) is known to be a natural antioxidant. The aim of the present study was to evaluate the cryoprotective effect of ALA on the motility of boar spermatozoa and its antioxidant effect on boar spermatozoa during freezing thawing. Different concentrations (2.0, 4.0, 6.0, 8.0 or 10.0 mg/ml) of ALA were added to the extender used to freeze boar semen, and the effects on the quality and endogenous antioxidant enzyme activities of frozen-thawed spermatozoa were assessed. The results indicated that the addition of ALA to the extender resulted in a higher percentage of motile spermatozoa post-thaw (P < 0.05). The activities of superoxide dismutase, lactate dehydrogenase, glutamic-oxaloacetic transaminase and catalase improved after adding ALA to the extender (P < 0.05). Artificial insemination results showed that pregnancy rate and litter size were significantly higher at 6.0 mg/ml in the ALA group than in the control group (P < 0.05). In conclusion, ALA conferred a cryoprotective capacity to the extender used for boar semen during the process of freezing-thawing, and the optimal concentration of ALA for the frozen extender was 6.0 mg/ml. PMID- 26099849 TI - Large-scale preparation of clove essential oil and eugenol-loaded liposomes using a membrane contactor and a pilot plant. AB - Based on our previous study where optimal conditions were defined to encapsulate clove essential oil (CEO) into liposomes at laboratory scale, we scaled-up the preparation of CEO and eugenol (Eug)-loaded liposomes using a membrane contactor (600 mL) and a pilot plant (3 L) based on the principle of ethanol injection method, both equipped with a Shirasu Porous Glass membrane for injection of the organic phase into the aqueous phase. Homogenous, stable, nanometric-sized and multilamellar liposomes with high phospholipid, Eug loading rates and encapsulation efficiency of CEO components were obtained. Saturation of phospholipids and drug concentration in the organic phase may control the liposome stability. Liposomes loaded with other hydrophobic volatile compounds could be prepared at large scale using the ethanol injection method and a membrane for injection. PMID- 26099850 TI - Postmolar gestational trophoblastic neoplasia: beyond the traditional risk factors. AB - OBJECTIVE: To investigate the slope of linear regression of postevacuation serum hCG as an independent risk factor for postmolar gestational trophoblastic neoplasia (GTN). DESIGN: Multicenter retrospective cohort study. SETTING: Academic referral health care centers. PATIENT(S): All subjects with confirmed hydatidiform mole and at least four measurements of beta-hCG titer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Type and magnitude of the relationship between the slope of linear regression of beta-hCG as a new risk factor and GTN using Bayesian logistic regression with penalized log-likelihood estimation. RESULT(S): Among the high-risk and low-risk molar pregnancy cases, 11 (18.6%) and 19 cases (13.3%) had GTN, respectively. No significant relationship was found between the components of a high-risk pregnancy and GTN. The beta-hCG return slope was higher in the spontaneous cure group. However, the initial level of this hormone in the first measurement was higher in the GTN group compared with in the spontaneous recovery group. The average time for diagnosing GTN in the high-risk molar pregnancy group was 2 weeks less than that of the low-risk molar pregnancy group. In addition to slope of linear regression of beta-hCG (odds ratio [OR], 12.74, confidence interval [CI], 5.42-29.2), abortion history (OR, 2.53; 95% CI, 1.27-5.04) and large uterine height for gestational age (OR, 1.26; CI, 1.04-1.54) had the maximum effects on GTN outcome, respectively. CONCLUSION(S): The slope of linear regression of beta-hCG was introduced as an independent risk factor, which could be used for clinical decision making based on records of beta-hCG titer and subsequent prevention program. PMID- 26099851 TI - The R- and S-diastereoisomeric effects on the guanidinohydantoin-induced mutations in DNA. AB - Direct and indirect oxidation of guanine in DNA produces guanidinohydantoin (Gh), which is capable of inhibiting replication and inducing mutations during cellular activities. Although some biochemical studies have proposed that Gh may induce exclusively G to C mutations in DNA, other studies have predicted the occurrence of both G to C and G to T mutations. However, the exact reasons for these mutations and the dubious character of Gh in this context are not yet understood. Further, due to insufficient structural data, the electronic structure of Gh that can participate in the formation of different base pair complexes in DNA is also not known. Here, density functional theory (DFT) is used to find the most stable tautomers of Gh at the base level out of a total 112 possible tautomers and their involvement in mutagenesis is investigated by computing structures, energies and electronic properties of different base pair complexes formed between the syn- and anti-conformations of the most stable tautomer of Gh (aGh) and all the bases of DNA. It is found that aGh can coexist in R- and S-diastereoisomeric configurations. Due to the flexible guanidinium group, it can rotate about the N3 C4 bond in each of the above diastereoisomers to form two different stable conformations (aGh1 and aGh2). It is further shown that among the different base pair complexes involving aGh1, syn-aGh1:G is the most stable. This indicates that G would be easily incorporated against syn-aGh1 giving rise to G to C mutations in DNA. However, in the case of aGh2, G is the preferred base pair partner of syn aGh2 and T is the preferred base pair partner of anti-aGh2. This implies that in addition to G to C mutations, the occurrence of aGh2 in DNA may also induce G to A mutations. Further, due to similarities between base pairing patterns and binding energies of syn-aGh1:A and syn-aGh2:A complexes with those of the T:A complex, DNA polymerases may mistakenly insert A opposite aGh1 or aGh2 by misrecognizing the latter as T. This may ultimately induce G to T mutations in DNA. However, as the constraints imposed by the DNA backbones and stacking interactions were not considered here, the possibilities of aGh2:T and aGh2:A base pairs need to be investigated experimentally. It is further found that the mutagenic character of aGh in the R- and S-diastereoisomeric forms is similar. PMID- 26099852 TI - Investigation of the structure of anti-human seminal plasma protein single-chain antibody and its association with linker peptide length. AB - To enhance the activity of seminoprotein single-chain variable fragment (gamma-Sm ScFv) antibodies, modulation of the length of the linker peptide, which connects the variable region of the heavy chain (VH) and the light chain (VL) of single chain antibodies, was performed in the present study. Homologous modeling of single VH and VL were performed, respectively. Subsequently, modeling of the whole ScFv sequence, which was previously modified with added linkers of different lengths was also performed, and the (Gly4Ser)n peptide chain structure was used as the linker. The similarities between VH and VL prior to and following the addition of the linker were compared by applying the algorithm of protein similarity, based on spherical coordinates layering. In addition, changes in the fore and aft distance, and diffusion radius were calculated using a MATLAB tool, based on which changes in structural stability were analyzed. Finally, the single chain antibody was assessed in a nude mouse model. When n=3 or n=6, the similarity between the original distance and VH and VL were the highest, and the fore and aft distance and diffusion radius were relatively close. In addition, the nude mouse model indicated that, when n=3 or n=6, the inhibitory rate of the single-chain antibody against tumor cells was significantly higher, compared with the other linker peptides of different lengths. The effect of structural changes of the linker peptides in the single-chain antibodies on the whole antibody molecule was examined at different levels using a combination of mathematical modeling, bioinformatics methods and biological experiments. The findings of the present study may provide a foundation for further investigation into the preparation of single-chain antibodies. PMID- 26099853 TI - Using text mining techniques to extract phenotypic information from the PhenoCHF corpus. AB - BACKGROUND: Phenotypic information locked away in unstructured narrative text presents significant barriers to information accessibility, both for clinical practitioners and for computerised applications used for clinical research purposes. Text mining (TM) techniques have previously been applied successfully to extract different types of information from text in the biomedical domain. They have the potential to be extended to allow the extraction of information relating to phenotypes from free text. METHODS: To stimulate the development of TM systems that are able to extract phenotypic information from text, we have created a new corpus (PhenoCHF) that is annotated by domain experts with several types of phenotypic information relating to congestive heart failure. To ensure that systems developed using the corpus are robust to multiple text types, it integrates text from heterogeneous sources, i.e., electronic health records (EHRs) and scientific articles from the literature. We have developed several different phenotype extraction methods to demonstrate the utility of the corpus, and tested these methods on a further corpus, i.e., ShARe/CLEF 2013. RESULTS: Evaluation of our automated methods showed that PhenoCHF can facilitate the training of reliable phenotype extraction systems, which are robust to variations in text type. These results have been reinforced by evaluating our trained systems on the ShARe/CLEF corpus, which contains clinical records of various types. Like other studies within the biomedical domain, we found that solutions based on conditional random fields produced the best results, when coupled with a rich feature set. CONCLUSIONS: PhenoCHF is the first annotated corpus aimed at encoding detailed phenotypic information. The unique heterogeneous composition of the corpus has been shown to be advantageous in the training of systems that can accurately extract phenotypic information from a range of different text types. Although the scope of our annotation is currently limited to a single disease, the promising results achieved can stimulate further work into the extraction of phenotypic information for other diseases. The PhenoCHF annotation guidelines and annotations are publicly available at https://code.google.com/p/phenochf-corpus. PMID- 26099854 TI - FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. AB - AIMS/HYPOTHESIS: Ketogenic diets (KDs) have increasingly gained attention as effective means for weight loss and potential adjunctive treatment of cancer. The metabolic benefits of KDs are regularly ascribed to enhanced hepatic secretion of fibroblast growth factor 21 (FGF21) and its systemic effects on fatty-acid oxidation, energy expenditure (EE) and body weight. Ambiguous data from Fgf21 knockout animal strains and low FGF21 concentrations reported in humans with ketosis have nevertheless cast doubt regarding the endogenous function of FGF21. We here aimed to elucidate the causal role of FGF21 in mediating the therapeutic benefits of KDs on metabolism and cancer. METHODS: We established a dietary model of increased vs decreased FGF21 by feeding C57BL/6J mice with KDs, either depleted of protein or enriched with protein. We furthermore used wild-type and Fgf21-knockout mice that were subjected to the respective diets, and monitored energy and glucose homeostasis as well as tumour growth after transplantation of Lewis lung carcinoma cells. RESULTS: Hepatic and circulating, but not adipose tissue, FGF21 levels were profoundly increased by protein starvation, independent of the state of ketosis. We demonstrate that endogenous FGF21 is not essential for the maintenance of normoglycaemia upon protein and carbohydrate starvation and is therefore not needed for the effects of KDs on EE. Furthermore, the tumour suppressing effects of KDs were independent of FGF21 and, rather, driven by concomitant protein and carbohydrate starvation. CONCLUSIONS/INTERPRETATION: Our data indicate that the multiple systemic effects of KD exposure in mice, previously ascribed to increased FGF21 secretion, are rather a consequence of protein malnutrition. PMID- 26099855 TI - Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. AB - AIMS/HYPOTHESIS: Proinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokine-induced ER stress involves NO production and consequent inhibition of the ER Ca(2+) transporting ATPase sarco/endoplasmic reticulum Ca(2+) pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field. METHODS: Rat and mouse insulin-producing cells, human pancreatic islets and human EndoC-betaH1 cells were exposed to the cytokines IL-1beta, TNF alpha and IFN-gamma, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokine-induced apoptosis of human beta cells. RESULTS: NO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis. CONCLUSIONS/INTERPRETATION: These observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation. PMID- 26099857 TI - Treatment of obesity and pulmonary arterial hypertension with inhibitors of the prostaglandin transporter: evaluation of patent WO2014/204895A1. AB - Prostaglandins display a wide array of pharmacological effects and prostaglandin analogs are already used in the treatment of pulmonary arterial hypertension (PAH). After synthesis and release from cells, prostaglandins undergo reuptake by the prostaglandin transporter (PGT). WO2014/204895 claims the use of a series of trisubstituted triazine derivatives for the treatment of obesity and PAH. Composition of matter of these triazines has been claimed in WO2011/037610 and the compounds are described as potent inhibitors of the PGT. One compound (nr 146) was shown to improve high fat diet-induced glucose tolerance in a mouse model. In addition, this compound has been explored in the rat monocrotaline model of PAH and reduced characteristic features of the pathology. This class of compounds presents a potential new treatment paradigm in the treatment of obesity related disorders and PAH. PMID- 26099856 TI - Prolactin-stimulated survivin induction is required for beta cell mass expansion during pregnancy in mice. AB - AIMS/HYPOTHESIS: Prolactin (PRL)-stimulated beta cell proliferation is critical for maternal pancreatic beta cell mass expansion during pregnancy. However, the molecular effectors of the multiple putative signalling pathways downstream of the PRL receptor (PRL-R) are still elusive. Survivin has been shown to be induced during pregnancy. The aim of the present study was to define the essential role of survivin in gestational beta cell mass expansion. METHODS: Expression of survivin was assessed in mouse islets during pregnancy and in insulinoma cells (INS-1) stimulated with PRL. Pregnant mice with targeted deletion of the survivin gene (also known as Birc5) in beta cells were assessed to determine the essential function of survivin in maternal beta cell mass expansion. INS-1 cells stimulated with PRL were used to explore the role of survivin in signalling pathways downstream of the PRL-R. RESULTS: Survivin was significantly upregulated in maternal islets during pregnancy. With PRL stimulation, induction of survivin expression occurred predominantly in the nucleus and was associated with cell cycle progression to S and G2/M phase. Beta cell-specific survivin-knockout pregnant mice displayed glucose intolerance, attenuated beta cell mass expansion and impaired beta cell proliferation, with significant attenuation in the increased expression of Cdk4/Ccnd1, E2f1, p53 (also known as Trp53) and p21 (also known as Cdkn1a) compared with wild-type controls during pregnancy. Targeted deletion of survivin in INS-1 cells resulted in cell cycle disturbance with an arrest in G1/S phase after PRL stimulation. Inhibitors of Akt, signal transducer and activator of transcription 5 (STAT5), PIM or extracellular signal-regulated kinase (ERK), significantly decreased the expression of survivin in PRL stimulated INS-1 cells. CONCLUSIONS/INTERPRETATION: Survivin directly participates in PRL-mediated beta cell proliferation via Akt, STAT5-PIM and ERK signalling pathways during pregnancy. PMID- 26099858 TI - Nickel-responsive transcriptional regulators. AB - Nickel is an essential micronutrient for a large number of living organisms, but it is also a toxic metal ion when it accumulates beyond the sustainable level as it may result if and when its cellular trafficking is not properly governed. Therefore, the homeostasis and metabolism of nickel is tightly regulated through metal-specific protein networks that respond to the available Ni(II) concentration. These are directed by specific nickel sensors, able to couple Ni(II) binding to a change in their DNA binding affinity and/or specificity, thus translating the cellular level of Ni(II) into a modification of the expression of the proteins devoted to modulating nickel uptake, efflux and cellular utilization. This review describes the Ni(II)-dependent transcriptional regulators discovered so far, focusing on their structural features, metal coordination modes and metal binding thermodynamics. Understanding these properties is essential to comprehend how these sensors correlate nickel availability to metal coordination and functional responses. A broad and comparative study, described here, reveals some general traits that characterize the binding stoichiometry and Ni(II) affinity of these metallo-sensors. PMID- 26099859 TI - Lysosomal Acid Lipase Deficiency (LALD). PMID- 26099860 TI - American Academy of Pediatrics Section on Cardiology Meeting. PMID- 26099861 TI - Quantitative characterization of circadian rhythm of pulmonary function in asthmatic patients treated with inhaled corticosteroids. AB - The aim of this study was to characterize the circadian rhythm observed for forced expiratory volume in 1 s (FEV1) in patients with persistent asthma being treated with inhaled corticosteroids. The database included 3379 FEV1 measurements from 189 patients with mild to moderate asthma. A model using the sum of two Sine functions with periods of 12 and 24 h and a constant component of mean circadian rhythm adequately described the circadian rhythm in FEV1 measurements over time. The model adequateness was evaluated by various approaches including visual predictive check (VPC), prediction-corrected VPC, standardized VPC and normalized prediction distribution error. Covariates tested included age, body weight, height, body mass index, baseline FEV1, and sex. Age and height were found to have significant effects on the mean FEV1 level and no covariate was found to have an effect on the magnitude and timing of circadian rhythm. The model predicted that a minimum FEV1 occurred in the early morning and maximum FEV1 occurred in the early afternoon, with a population mean fluctuation of 170 mL, which is consistent with the finding that asthma symptoms usually exacerbate in the early morning for patients with persistent asthma. This developed model provides the first quantitative approach to describing FEV1 circadian rhythm with ICS background treatment and provided insight in designing future registration trials for asthma drug development. PMID- 26099862 TI - Parkinson's disease and insomnia. AB - There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). The prevalence of symptoms of insomnia and chronic inability to sleep and their association with other sleep disorders were studied. Altogether 1447 randomly selected Parkinson patients, aged 43-89 years, participated in a questionnaire study. A structured questionnaire with 207 items was based on the Basic Nordic Sleep questionnaire. Questions on demographics, PD, REM Sleep Behavior Disorder, and other issues were included. The response rate was 59 % (N = 854), and of these 81 % returned fully answered questionnaire (N = 689). Prevalence of chronic inability to sleep was 36.9 % (95 % CI 33.3-40.5). Difficulty of initiating sleep was 18.0 % (95 % CI 15.1-20.9), disrupted sleep 81.54 % (78.5-84.4), awakenings during night 31.3 % (27.8-34.8), early morning awakenings 40.4 % (36.8-44.1) and non-restorative sleep 38.5 % (34.8-42.1). In the logistic regression models, poor quality of life and restless legs syndrome correlated significantly with chronic insomnia disorder. Disrupted sleep and early morning awakenings were the most common insomnia symptoms. PD patients do not seem to have difficulties in sleep initiation. Insomnia symptoms including disruptive sleep and non-restorative sleep are common in patients with Parkinson's disease. Inability to sleep is more common as comorbidity than a single sleep problem. PMID- 26099863 TI - Digital Identity: Develop One Before You're Given One. PMID- 26099864 TI - Editorial Comment. PMID- 26099865 TI - Reply: To PMID 26099863. PMID- 26099866 TI - Editorial Comment. PMID- 26099867 TI - Reply: To PMID 26099863. PMID- 26099868 TI - Combination of Tramadol and Lidocaine for Pain Control During Transrectal Ultrasound-guided Prostate Biopsy: A Randomized Double-blinded Study. AB - OBJECTIVE: To evaluate the efficacy of tramadol, lidocaine, and a combination of tramadol with lidocaine in pain relief using periprostatic nerve block technique by guidance of transrectal ultrasound (TRUS) before the prostate biopsy (PBx). MATERIALS AND METHODS: For the indication of TRUS-PBx, the patients with a prostate-specific antigen (PSA) level >4.0 ng/mL or abnormal digital examination findings were selected. The patients were randomized through random method. Group 1: patients were administered 5 mL of 2% lidocaine; group 2: patients were administered 5 mL of 25-mg tramadol; and group 3: patients were administered 5 mL of 2% lidocaine + 25-mg tramadol. The procedures were completed in 10 minutes, and a visual pain scale was administered to the patients to question the pain severity. RESULTS: TRUS-guided PBx was performed in 60 patients with an age range of 57-77 years (mean age, 66.2 +/- 7.49 years) and a PSA range of 1-1000 ng/mL. The mean PSA level of the groups was 28.5 (+/-7.5), 16.1 (+/-5.0), and 14.9 (+/ 2.9) ng/mL, respectively. The postprocedural pain scores by visual pain scale were 4.6 +/- 1.2, 5.4 +/- 1.2, and 3.6 +/- 0.9 in lidocaine, tramadol, and lidocaine + tramadol groups, respectively. CONCLUSION: Periprostatic nerve block is the current golden standard method owing to pain management and comfort provided, independent of the patient age and the number of core biopsies. We suggest that tramadol may also be used in this field to achieve better pain management by improving lidocaine's effect or as an alternative to lidocaine. PMID- 26099869 TI - Three-dimensional Technology Facilitates Surgical Performance of Novice Laparoscopy Surgeons: A Quantitative Assessment on a Porcine Kidney Model. AB - OBJECTIVE: To determine whether the use of 3-dimensional (3D) imaging translates into a better surgical performance of naive urologic laparoscopic surgeons during pyeloplasty (PY) and partial nephrectomy (PN) procedures. MATERIALS AND METHODS: Eighteen surgeons without any previous laparoscopic experience were randomly assigned to perform PY and PN in a porcine model using initially 2-dimensional (2D) and 3D laparoscopy. A surgical performance score was rated by an "expert" tutor through a modified 5-item global rating scale contemplating operative field view, bimanual dexterity, efficiency, tissue handling, and autonomy. Overall surgical time, complications, subjective perception of participating surgeons, and inconveniences related to the 3D vision were recorded. RESULTS: No difference in terms if operative time was found between 2D or 3D laparoscopy for both the PY (P = .51) and the PN (P = .28) procedures. A better rate in terms of surgical performance score was noted by the tutors when the study participants were using 3D vs 2D, for both PY (3.6 [0.8] vs 3.0 [0.4]; P = .034) and PN (3.6 [0.51] vs 3.15 [0.63]; P = .001). No complications occurred in any of the procedures. Most (77.2%) of the participating naive laparoscopic surgeons had the perception that 3D laparoscopy was overall easier than 2D. Headache (18.1%), nausea (18.1%), and visual disturbance (18.1%) were the most common issues reported by the surgeons during 3D procedures. CONCLUSION: Despite the absence of translation in a shorter operative time, the use of 3D technology seems to facilitate the surgical performance of naive surgeons during laparoscopic kidney procedures on a porcine model. PMID- 26099870 TI - Individualized Physical 3-dimensional Kidney Tumor Models Constructed From 3 dimensional Printers Result in Improved Trainee Anatomic Understanding. AB - OBJECTIVE: To evaluate the effect of 3-dimensionally (3D) printed physical renal models with enhancing masses on medical trainee characterization, localization, and understanding of renal malignancy. METHODS: Proprietary software was used to import standard computed tomography (CT) cross-sectional imaging into 3D printers to create physical models of renal units with enhancing renal lesions in situ. Six different models were printed from a transparent plastic resin; the normal parenchyma was printed in a clear, translucent plastic, with a red hue delineating the suspicious renal lesion. Medical students, who had completed their first year of training, were given an overview and tasked with completion of RENAL nephrometry scores, separately using CT imaging and 3D models. Trainees were also asked to complete a questionnaire about their experience. Variability between trainees was assessed by intraclass correlation coefficients (ICCs), and kappa statistics were used to compare the trainee to experts. RESULTS: Overall trainee nephrometry score accuracy was significantly improved with the 3D model vs CT scan (P <.01). Furthermore, 3 of the 4 components of the nephrometry score (radius, nearness to collecting system, and location) showed significant improvement (P <.001) using the models. There was also more consistent agreement among trainees when using the 3D models compared with CT scans to assess the nephrometry score (intraclass correlation coefficient, 0.28 for CT scan vs 0.72 for 3D models). Qualitative evaluation with questionnaires filled out by the trainees further confirmed that the 3D models improved their ability to understand and conceptualize the renal mass. CONCLUSION: Physical 3D models using readily available printing techniques improve trainees' understanding and characterization of individual patients' enhancing renal lesions. PMID- 26099871 TI - Editorial Comment. PMID- 26099872 TI - Reply: To PMID 26099870. PMID- 26099873 TI - Repeat Surgery After Ureteroscopic Laser Lithotripsy With Attempted Complete Extraction of Fragments: Long-term Follow-up. AB - OBJECTIVE: To explore repeat surgery as a primary outcome measure in long-term follow-up after ureteroscopic laser lithotripsy (URS) with attempted complete extraction of fragments. METHODS: Retrospective review of the medical records of consecutive patients undergoing URS performed by a single surgeon. Repeat surgery was defined as any return to the operating room for management of stone or complications. For our survival analysis, we used the Kaplan-Meier method. RESULTS: From April 2003 through May 2005 at our institution, URS was performed in 226 renal units in 216 patients. At a median follow-up of 4.1 years, 19 patients required repeat surgery. At 1 year, the cumulative repeat surgery rate (CRR) was 5.8% (95% confidence interval, 3.4%-9.8%), rising to 8.6% (5.6%-13.1%) at 5 years. CRR was strongly related to evidence of residual stone on postoperative computed tomography (P <.001). At 5 years, CRR was 3.5% (1.1% 10.3%) in patients with renal units with no detectable fragments, 8.2% (3.5% 18.6%) with fragments <=4 mm, and 46.2% (24.0%-75.2%) with fragments >4 mm. The Cox proportional hazards ratio was 9.08 (2.11-38.00; P = .003) with fragments that were >2 mm; the ratio was 22.14 (5.15-95.14; P <.001) with fragments >4 mm. CONCLUSION: Repeat surgery after URS is proportional to the size of residual fragments. Repeat surgery is a discrete objective metric that is consistent with, but does not require, rigorous postoperative radiologic assessment. PMID- 26099874 TI - Initial Experience and Comparative Efficacy of the UreTron: A New Intracorporeal Ultrasonic Lithotriptor. AB - OBJECTIVE: To describe the initial clinical experience with the UreTron (Med Sonics, Erie, PA), a new ultrasonic lithotriptor. Historically, ultrasound-only intracorporeal lithotriptors have been considered the gold standard for stone removal during percutaneous nephrolithotomy. Recently, they have lost favor to newer dual and combination devices believed by many to be more efficient. The UreTron features patented technology to precisely control probe vibration and achieve more efficient output potentially improving efficiency of stone clearance. To date, the clinical efficacy of this new device has yet to be tested relative to alternative state-of-the-art lithotriptors. METHODS: Thirty-one patients with renal stones >2 cm undergoing percutaneous nephrolithotomy were studied. All cases were performed by the same surgeon, and data were recorded prospectively using the same protocol established for a separate ongoing comparison study designed to assess performance of 3 separate state-of-the-art lithotriptors (CyberWand, StoneBreaker, and LithoClast Select). Bivariate analysis was performed between the UreTron cohort and the combined cohort of the alternative state-of-the-art lithotriptors (n = 51). RESULTS: The UreTron achieved the highest stone clearance rate (51.9 mm(2)/min) of any device. It also had little decrease in clearance efficiency when used on "hard" stones (48.5 mm(2)/min). The UreTron had a faster clearance rate than the alternative lithotriptor cohort (51.9 vs 36.0 mm(2)/min; P = .02) with no differences in stone-free rate, secondary procedures, clinical complications, or device malfunctions (P >.05). CONCLUSION: The UreTron compares favorably with alternative state-of-the-art intracorporeal lithotriptors with faster stone clearance rates and equivalent clinical outcomes. PMID- 26099875 TI - Autologous Pubovaginal Sling for the Treatment of Concomitant Female Urethral Diverticula and Stress Urinary Incontinence. AB - OBJECTIVE: To describe our experience with concomitant repair of urethral diverticula and stress urinary incontinence (SUI) with autologous pubovaginal sling (PVS). METHODS: A retrospective chart review between January 2006 and 2013 identified 38 women undergoing concomitant diverticulectomy and rectus sheath PVS. Patient demographics, presenting symptoms, prior urethral surgery, concomitant procedures, postoperative outcomes, and complications were evaluated. RESULTS: The mean duration of symptoms was 56.7 months. Eleven patients presented with recurrent diverticula and 5 patients had prior SUI surgery (3 midurethral slings, 1 PVS, and 1 bulking agent). One patient had a prior urethrolysis. All other slings were cut or excised at the time of surgery. All women had demonstrable SUI on cough stress test or urodynamics. The mean follow-up was 12.7 months. All postoperative voiding cystourethrograms were negative for contrast extravasation. One patient required prolonged (>4 weeks) suprapubic tube drainage for urinary retention. Four others required an additional 1 week of suprapubic tube drainage. Eighteen patients (47%) reported mixed urinary symptoms. Of these, 9 had complete resolution, whereas 9 experienced significant improvement. Overall, 97.3% reported resolution of their dysuria, dyspareunia, and pain symptoms and 90% reported complete resolution of their SUI symptoms. There were 2 urethral diverticula recurrences and 2 SUI recurrences. Perioperative complications, including hemorrhage, sling erosion, or urethrovaginal fistulas, were not observed. CONCLUSION: Concomitant PVS placement is a safe and effective treatment option for SUI in patients undergoing urethral diverticulectomy. The risks and benefits should be weighed and management individualized. PMID- 26099877 TI - Editorial Comment. PMID- 26099876 TI - Widespread Psychosocial Difficulties in Men and Women With Urologic Chronic Pelvic Pain Syndromes: Case-control Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network. AB - OBJECTIVE: To determine the extent, severity, and sex differences of psychosocial deficits in men and women with urologic chronic pelvic pain syndromes (UCPPS), which in the past have been considered separate bladder (interstitial cystitis painful bladder syndrome) and prostate (chronic prostatitis-chronic pelvic pain syndrome) disorders. Evaluations of men and women separately suggest UCPPS is associated with increased anxiety and depression. However, studies directly testing deficits in broader psychosocial domains such as cognitive processes, intimate relationships, and trauma history, or tests of sex differences in the pattern of difficulties associated with UCPPS have not been performed. METHODS: A total of 233 female and 191 male UCPPS patients and 235 female and 182 male healthy controls (HCs) were recruited from 6 academic medical centers in the United States and evaluated with a comprehensive battery of symptom, psychosocial, and illness impact measures. Primary comparisons of interest were between UCPPS patients and HCs and between men and women with UCPPS. RESULTS: In addition to greater negative effect, male and female UCPPS patients show higher levels of current and lifetime stress, poorer illness coping, increased self report of cognitive deficits, and more widespread pain symptoms compared with sex and education-matched HCs. Similar problems were found in male and female UCPPS patients although female UCPPS patients showed increased self-report of childhood adversity and more widespread symptoms of pain and discomfort. CONCLUSION: Given the significance of psychosocial variables in prognosis and treatment of chronic pain conditions, the results add substantially to our understanding of the breath of difficulties associated with UCPPS and point to important areas for clinical assessment. PMID- 26099878 TI - Rhabdomyolysis After Major Urologic Surgery: Epidemiology, Risk Factors, and Outcomes. AB - OBJECTIVE: To study the epidemiology, risk factors, and outcomes of rhabdomyolysis (RM) after major urologic surgery. MATERIALS AND METHODS: The National Inpatient Sample (2003-2011) was used to identify patients who underwent radical prostatectomy, radical or partial nephrectomy, or radical cystectomy. Demographics included age, sex, race, and comorbidities. Factors examined included bleeding, hospital teaching status, minimally invasive technique, and development of RM. Multivariate logistic regression was used to identify independent risk factors of RM. Outcomes of mortality, acute kidney injury (AKI), length of stay, and charges in patients with RM were compared with those of controls. RESULTS: A weighted population of 1,016,074 patients was identified with 870 (0.1%) developing RM, which was significantly more likely for radical or partial nephrectomy and radical cystectomy patients compared with radical prostatectomy patients. On multivariate analysis, independent risk factors for RM included younger age, male sex, diabetes, chronic kidney disease, obesity, and bleeding. Race, minimally invasive technique, and teaching status were not associated with RM when controlling for other factors. Patients with RM experienced increases in mortality, AKI, length of stay, and hospital charges. CONCLUSION: Rhabdomyolysis is a rare complication after urologic surgery. Risk factors include male sex, younger age, diabetes, chronic kidney disease, obesity, and perioperative bleeding. Patients who develop RM have a higher risk of AKI, mortality, prolonged hospital stay, and increased charges. PMID- 26099879 TI - NextGen Home Sperm Banking Kit: Outcomes of Offsite vs Onsite Collection- Preliminary Findings. AB - OBJECTIVE: To compare cryosurvival rates between remote collections with NextGen kit (offsite) and onsite collection of semen samples from infertile men and those with cancer. METHODS: Prefreeze and post-thaw sperm motility, total motile sperm, and percent cryosurvival rates were compared between samples collected from infertile men onsite at the Andrology Center (n = 10) and samples collected from infertile patients at home (offsite; n = 9), which were shipped by NextGen to our laboratory. A second group (n = 17) consisted of 10 semen samples from cancer patients collected onsite, which were compared with 7 semen samples from cancer patients shipped by the NextGen. All semen samples were assessed within 18 hours of collection. RESULTS: In the infertile men, percent cryosurvival rates were similar with NextGen compared with those of onsite collection (53.14 +/- 28.9% vs 61.90 +/- 20.46%; P = .51). Similarly, in the cancer patients, all 4 parameters were comparable between the onsite and NextGen. Cryosurvival rates were also similar between NextGen compared with those of onsite collection (52.71 +/- 20.37% vs 58.90 +/- 22.68%; P = .46). CONCLUSION: Cancer patients can bank sperm as effectively as men banking for infertility reasons using the NextGen kit. PMID- 26099880 TI - Editorial Comment. PMID- 26099881 TI - Reply: To PMID 26099879. PMID- 26099882 TI - Kidney Laterality and the Safety of Hand-assisted Live Donor Nephrectomy: Review of 1000 Consecutive Cases at a Single Center. AB - OBJECTIVE: To determine the feasibility of performing right-sided, hand-assisted, laparoscopic donor nephrectomy (HALDN) and compare with the results of left-sided surgeries in both donors and recipients. METHODS: Between September 2006 and September 2013, 1000 consecutive patients underwent HALDN at our institution. Patient characteristics and the intraoperative or postoperative parameters of the donors and recipients were retrospectively evaluated. Preoperative data, including relative renal function, vascular anatomy, and parenchymal abnormalities, were evaluated to determine the reasons for harvesting the right kidney. Intraoperative and postoperative data, including pneumoperitoneum time, warm ischemia time, complications, chronic kidney disease stage, and graft function, were compared between donors and recipients who underwent right- and left-sided procurement. RESULTS: Mean follow-up period was 21 months in donor and 42 months in recipient. Right-sided HALDN was performed on 421 patients (42.1%). The most common reasons for selecting the right kidney was reduced right kidney function (53.4%) followed by multiple left renal arteries (34.2%). None of 1000 patients required conversion to open surgery or developed major complications. Serum creatinine concentrations and chronic kidney disease stage at the last follow-up examinations were similar in donors. There were no significant differences in graft function and ureter-related complications between right- and left-sided kidneys at the last follow-up examination. CONCLUSION: Right-side HALDN is a safe procedure. The donor side can be freely selected using HALDN to benefit both donors and recipients. PMID- 26099883 TI - Editorial Comment. PMID- 26099884 TI - Reply: To PMID 26099882. PMID- 26099885 TI - Trends in Testicular Cancer Survival: A Large Population-based Analysis. AB - OBJECTIVE: To determine whether discrepancies in testicular cancer outcomes between Caucasians and non-Caucasians are changing over time. Although testicular cancer is more common in Caucasians, studies have shown that other races have worse outcomes. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results registry, we identified 29,803 patients diagnosed with histologically confirmed testicular cancer between 1983 and 2011. Of these, 12,650 patients (42%) had 10-year follow-up data. We stratified the patients by age group, stage, race, and year of diagnosis and assessed 10-year overall and cancer-specific survival in each cohort. Cox proportional hazard models were used to determine the relative contributions of each stratum to cancer-specific survival. RESULTS: Predicted overall 10-year survival of Caucasian patients with testicular cancer increased slightly from 88% to 89% over the period studied, whereas predicted cancer-specific 10-year survival dropped slightly from 94% to 93%. In contrast, non-Caucasian men demonstrated larger changes in 10-year overall (84%-86%) and cancer-specific (88%-91%) survival. On univariate analysis, race was significantly associated with testicular cancer death, with non-Caucasian men being 1.69 times more likely to die of testicular cancer than Caucasians (hazard ratio, 1.33-2.16; 95% confidence interval, <.001). CONCLUSION: Historically, non Caucasian race has been associated with poorer outcomes from testicular cancer. These data show a convergence in cancer-specific survival between racial groups over time, suggesting that diagnostic and treatment discrepancies may be improving for non-Caucasians. PMID- 26099886 TI - Trends of Systemic Therapy Use for Renal Cell Carcinoma in the United States. AB - OBJECTIVE: To assess the utilization of immunotherapy after the advent of tyrosine-kinase inhibitors and mammalian target of rapamycin inhibitors for metastatic renal cell carcinoma (RCC) in the United States, as well as to better understand the variables associated with the implementation of these systemic therapies. METHODS: The National Cancer Data Base Participant User File for Renal Cancer was queried. Patients diagnosed with metastatic RCC were identified. From that group, patients who received either immunotherapy or chemotherapy (single or multiagent), given as a first-course therapy from 1998 to 2011 were selected. Multivariate analysis was used to assess patient, disease, and provider factors associated with immunotherapy or chemotherapy overall usage between 2003 and 2011. RESULTS: A total of 25,186 patients diagnosed with metastatic RCC were identified; 3107 received immunotherapy and 8640 received chemotherapy. The use of immunotherapy decreased from 30.3% in 1998 to 3.8% in 2011. The use of chemotherapy increased from 16.2% in 1998 to 54.0% in 2011. The most dramatic period of change was from 2004 to 2006. Independent negative predictors of receiving immunotherapy included progressive years of diagnosis (P <.0001), increasing age (P <.0001), female gender (P = .001), and African American race (P = .04). CONCLUSION: There has been a significant decrease in the use of immunotherapy for metastatic RCC in the United States since the introduction of targeted chemotherapeutic agents in the past decade. PMID- 26099887 TI - Adjustable Continence Balloons in Men: Adjustments Do Not Translate Into Long term Continence. AB - OBJECTIVE: To evaluate the functional results, morbidity, and quality of life of the adjustable continence balloons ProACT for the treatment of male stress urinary incontinence after prostate surgery considering both short- and long-term results. METHODS: Between 2002 and 2012, twenty-two consecutive male patients were implanted with the ProACT device. Continence was defined by the use of 0 pads daily, and the quality of life was assessed by validated questionnaires. RESULTS: Only 1 patient (4.5%) was immediately continent after ProACT implantation, and the other 21 men (95.5%) needed >=1 balloon refillments postoperatively. The baseline daily pad number decreased from a mean of 5.9 pads (range, 3-12 pads) to a mean of 1.7 pads (range, 0-5 pads) per day after refilling but increased to a mean of 3.9 (range, 0-10) at the last follow-up visit. After balloon adjustments, 4 patients (18%) were continent and 18 patients (82%) showed an improvement with a 95% rate of subjective satisfaction. Revision and explantation rates were 73% and 55%, respectively. At a median follow-up of 57 months, only 1 patient (4.5%) remained dry, and only 10 patients (45%) remained satisfied with the procedure, whereas 12 patients (55%) were unchanged and dissatisfied. CONCLUSION: The ProACT device appears to be safe and efficacious in the short term. The postoperative readjustment allows the achievement of a short-term continence status. However, on the long term, the ProACT does not appear to be an ideal device for durable continence and patients' satisfaction. PMID- 26099888 TI - Editorial Comment. PMID- 26099889 TI - Animal Models of Urologic Chronic Pelvic Pain Syndromes: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network. AB - OBJECTIVE: To describe the approach taken by the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network investigators to advance the utility of urologic chronic pelvic pain syndromes (UCPPS) animal models. METHODS: A multidisciplinary team of investigators representing basic science and clinical expertise defined key phenotypic criteria for rodent models of UCPPS. UCPPS symptoms were prioritized based on their clinical significance. Methods for quantifying animal correlates to patient symptoms were developed. The methods were implemented across proposed rodent models for evaluation and comparison of animals for phenotypic characteristics relevant to human symptomatology. RESULTS: Pelvic pain and urinary frequency were deemed primary features of human UCPPS and were prioritized for assessment in animals. Nociception was quantified using visceromotor response to bladder distention and by applying von Frey filaments to the lower abdomen (referred tactile allodynia). Micturition activity was assessed as free voiding using micturition cages or blotting pad assays and in response to bladder filling by cystometry. Models varied in both depth of characterization and degree of recapitulating pelvic pain and urinary frequency characteristics of UCPPS. CONCLUSION: Rodent models that reflect multiple key characteristics of human UCPPS may be identified and provide enhanced clinical significance to mechanistic studies. We have developed a strategy for evaluating current and future animal models of UCPPS based on human symptomatology. This approach provides a foundation for improved translation between mechanistic studies in animals and clinical research and serves as a validation strategy for assessing validity of models for symptom-driven disorders of unknown etiology. PMID- 26099890 TI - Application of a Laparoscopic, Single-port, Double-needle Technique for Pediatric Hydroceles With Multiple Peritoneal Folds: A Trial From a Single-center 5-Year Experience. AB - OBJECTIVE: To report our 5-year experience with a modified single-port, double needle, minilaparoscopic technique for patent processus vaginalis with multiple peritoneal folds in the hydrocele sac orifice. METHODS: A total of 125 consecutive cases of boys with unilateral pediatric hydrocele underwent minilaparoscopic repair between June 2008 and June 2013. The patients were divided into 2 groups. Group 1 consisted of 65 patients who underwent a 2-port laparoscopic procedure, during which a 3-mm grasping forceps was used to grasp the folds around the internal inguinal ring. Group 2 included 60 patients who received a modified single-port, double-needle, minilaparoscopic surgery. An Endo Close needle was used to spread the peritoneal folds and facilitate circular extraperitoneal suturing in group 2. The principal outcome factors were assessed between the groups. RESULTS: A total of 151 minilaparoscopic procedures were performed in 125 patients (age range, 12-68 months; median, 21.5 months). In total, 26 extra procedures were performed for simultaneous repair of a potential contralateral patent processus vaginalis. No significant difference in operation time was noted between group 1 and group 2 (25.9 +/- 6.4 vs 27.1 +/- 5.5 minutes). The procedures were performed successfully without serious preoperative complications. During a median follow-up period of 18 months (range, 6-36 months), no postoperative hydrocele recurrence was encountered. CONCLUSION: Our limited experience suggests that the modified single-port, double-needle, minilaparoscopic technique could be safe, effective, and more cosmetically appealing for the management of complicated pediatric hydroceles. PMID- 26099891 TI - Renal Abscess Due to Community-acquired Extended-spectrum beta-Lactamase producing Escherichia coli in a 15-Year-old Girl. AB - Infections caused by community-acquired (CA) extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are an increasing public health concern. We report a 15-year-old girl with a history of recurrent urinary tract infections who developed a right renal abscess. Percutaneous abscess drainage and subsequent microbiological culture revealed CA-ESBL Escherichia coli. To our knowledge, this is the first reported pediatric case of CA-ESBL E coli renal abscess complicating urinary tract infection. Establishing a definitive diagnosis of ESBL E coli renal abscess may necessitate obtaining a microbiological culture via surgical specimen, especially in children with apparent risk factors for the selection of ESBL-producing organisms. PMID- 26099892 TI - Visual Internal Urethrotomy With Intralesional Mitomycin C and Short-term Clean Intermittent Catheterization for the Management of Recurrent Urethral Strictures and Bladder Neck Contractures. AB - OBJECTIVE: To evaluate our longitudinal experience using visual internal urethrotomy (VIU) with intralesional mitomycin C (MMC) and short-term clean intermittent catheterization (CIC) for urethral strictures and bladder neck contractures (BNC) after failure of endoscopic management. MATERIALS AND METHODS: This case series involved review of our prospectively developed database of all men who underwent VIU with MMC and CIC in a standardized fashion for urethral stricture or BNC between 2010 and 2013 at our tertiary care medical center. Etiology was identified as radiation-induced stricture (RIS) or non-RIS and analyzed by stricture location. Cold knife incisions were made in a tri or quadrant fashion followed by intralesional injection of MMC and 1 month of once daily CIC. RESULTS: All 37 patients previously underwent at least 1 intervention for urethral stricture or BNC before VIU with MMC and CIC. Mean stricture length was 2.0 cm (range, 1-6 cm; standard deviation, 1.0 cm). Over the median follow-up period of 23 months (range, 12-39 months), 75.7% of patients required no additional surgical intervention (RIS, 54.5%; non-RIS, 84.6%; P = .051). In those that did recur, median time to stricture recurrence was 8 months (range, 2-28 months). One patient with recurrence required urethroplasty. CONCLUSION: VIU with MMC followed by short-term CIC provides a minimally invasive and widely available tool to manage complex recurrent urethral strictures (<3 cm) and BNC without significant morbidity. This approach may be most attractive for patients who are poor candidates for open surgery. PMID- 26099893 TI - Editorial Comment. PMID- 26099894 TI - Reply: To PMID 26099892. PMID- 26099895 TI - Novel Technique Prevents Lymphoceles After Transperitoneal Robotic-assisted Pelvic Lymph Node Dissection: Peritoneal Flap Interposition. AB - INTRODUCTION: To determine the efficacy of our novel technique to prevent lymphocele formation after pelvic lymph node dissection (PLND) after robotic assisted radical prostatectomy (RARP) using the existing peritoneum of the bladder. TECHNICAL CONSIDERATIONS: We evaluated 155 consecutive patients undergoing RARP with PLND over 24 months. Group A included the first 77 patients with PLND using standard technique (no peritoneal flap). Group B included the subsequent 78 patients (1 patient excluded) with PLND and peritoneal interposition flap. The peritoneal interposition flap is created by rotating and advancing the peritoneum around the lateral surface of the ipsilateral bladder to the dependent portion of the pelvis and fixing it to the bladder itself. A cystogram was performed in 91% of the patients 7-14 days after the surgery. Lymphocele formation rates were compared (based on symptoms, cystogram findings, and radiographic confirmation). RESULTS: The 2 groups were statistically equivalent in terms of prostate-specific antigen, age, blood loss, body mass index, Gleason score, prostate size, pathology, or heparin use. Lymphocele formation occurred in 9 of 77 (11.6%) group A patients and in 0 of 77 group B patients (P = .003). Mean time to lymphocele detection in group A was 30.4 days. Mean follow-up in groups A and B were 383.97 and 379 days, respectively (P = .91). CONCLUSION: Strategic rotation and fixation of a peritoneal flap around the lateral aspect of the bladder during transperitoneal RARP with PLND is a novel technique to prevent lymphocele formation. Given the sample size and single institutional study, a prospective, randomized, multi-institutional trial is planned. PMID- 26099896 TI - Calculation of Expected Postoperative Renal Function After Radical Nephrectomy: Comments (Urology 2014;84:1402-1407). PMID- 26099897 TI - Factors Affecting Outcomes of Percutaneous Nephrolithotomy in Horseshoe Kidneys. PMID- 26099898 TI - Reply by the Authors. PMID- 26099899 TI - An Extreme Case of Fordyce Angiokeratoma. AB - Angiokeratomas are benign vascular ectasias that can present with bleeding or cosmetic concerns. We present an extreme case of Fordyce angiokeratoma. Usual treatment modalities, including medical management with analgesics and angiotensin-converting enzyme inhibitors, as well as laser treatments, were not viable options in this unique case. Surgical excision with autografting offered a curative treatment option in this case. PMID- 26099900 TI - Prevalence of hospital malnutrition in cancer patients: a sub-analysis of the PREDyCES(r) study. AB - PURPOSE: In oncology patients, hospital malnutrition is associated with a greater risk of morbidity and mortality. The objective of this study was to determine the prevalence of nutritional risk and the clinical and economic consequences of hospital malnutrition in oncology patients hospitalised in Spanish centres. METHODS: This was an observational, cross-sectional, multicentre study. The prevalence of nutritional risk was determined using the Nutrition Risk Screening((r))-2002 (NRS((r))-2002). RESULTS: Four hundred one oncology patients were included; 33.9% (136/401) were at nutritional risk (NRS((r))-2002 >= 3) at admission and 36.4% (135/371) at discharge. On average, patients at nutritional risk were more elderly and had lower weights, body mass indices and arm and calf circumferences, as well as lower serum albumin levels than patients not at risk. Mean duration of hospitalisation and healthcare costs were greater in patients at nutritional risk at discharge (12.1 days; 95% confidence interval (CI) 10.83 13.39) than in well-nourished patients (8.6 days; 95% CI 7.86-9.40). Only a third of the patients at risk of malnutrition at discharge had received any kind of nutritional support. CONCLUSIONS: This study shows that hospital malnutrition is a prevalent and undertreated condition in oncology patients that is associated with longer hospital stays and increased healthcare costs. PMID- 26099902 TI - A Farewell to a Unique Colleague. PMID- 26099901 TI - Using a personalized measure (Patient Generated Index (PGI)) to identify what matters to people with cancer. AB - PURPOSES: Patient Generated Index (PGI) is designed to both ask and document quality of life (QOL) concerns. Its validity with respect to standard QOL measures has not been fully established for advanced cancer when QOL concerns predominate. The specific objective of this study is to identify, for people with advanced cancer, similarities and differences in ratings of global QOL between personalized and standard measures. METHODS: A total of 192 patients completed five QOL measures at study entry: PGI, generic measures (SF-6D, EQ-5D), and cancer-specific measures of QOL (McGill Quality of Life Questionnaire and Edmonton Symptoms Assessment Scale). Comparisons among total scores were compared using Generalized Estimating Equations (GEE). RESULTS: Patients voiced 114 areas of QOL concerns by the PGI with the top three being fatigue, sleep, and pain (39.2, 22.6, and 21.6%, respectively). PGI total QOL score was 25 to 30 percentage points lower than those documented by the other measures, particularly when QOL was poor. Correlations between PGI and other measures were low. CONCLUSION: PGI allowed patients to express a wide range of QOL concerns, many that were not assessed by other QOL measures. If only one QOL measure is to be included, either in a clinical setting or for research, the PGI would satisfy many of the criteria for "best choice." PGI could be considered a cancer-specific QOL measure. IMPLICATIONS FOR CANCER: This study provides evidence that the PGI would be a good measure for patients and clinicians to use together to identify areas of concern that require attention and monitor changing needs. PMID- 26099904 TI - Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. PMID- 26099903 TI - Traumatic Brain Injury-Induced Neuronal Apoptosis is Reduced Through Modulation of PI3K and Autophagy Pathways in Mouse by FTY720. AB - FTY720 is a synthetic compound produced by modification of metabolite from Isaria sinclairii. It is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues, thereby causing peripheral lymphopenia. Growing evidences have suggested that apoptosis and autophagy were involved in the secondary brain injury after traumatic brain injury (TBI) although FTY720 exerted neuroprotective effects in a variety of neurological diseases except TBI. The present study was aimed to investigate the role of FTY720 in a mouse model of TBI. In experiment 1, ICR mice were divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + FTY720 group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 administration after TBI improved neurobehavioral function, alleviated brain edema, accompanied by modulation of apoptotic indicators such as Bcl-2, Bcl-xL, Bax, and cytochrome c. In experiment 2, ICR mice were also divided into four groups: sham group, TBI + vehicle group, TBI + FTY720 group, and TBI + FTY720 + inhibitors group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 increased the expression of phospho-protein kinase B (AKT) and some autophagy markers such as LC3 and Beclin 1. In addition, the apoptosis inhibition effect of FTY720 was partly abrogated by the phosphatidylinositide 3-kinases (PI3K)/AKT pathway inhibitor LY294002 and autophagy inhibitor 3-methyladenine. Collectively, our data provide the first evidence that FTY720 exerted neuroprotective effects after TBI, at least in part, through the activation of PI3K/AKT pathway and autophagy. PMID- 26099905 TI - [Richard Freiherr v. Krafft-Ebing and Sigmund Freud--discourse on the "normality" and "perversion" of human sexuality at the close of the 19th century and the beginning of the 20th century]. AB - Sexuality has been defined a central feature of personal identity since the epoch of enlightenment and has gradually become a decisive issue also in societal and political terms. A major transfer from religion and religious institutions to medicine and medical experts and later on to neuropsychiatrists has to be underlined in the primary position to assess "normal" and "deviant" manifestations of sexuality. Richard Freiherr von Krafft-Ebing and Sigmund Freund play an eminent role in this "discourse on sexuality" (M. Foucault) during the nineteenth and beginning twentieth century on the way to modern sexology. Within this overarching context Krafft-Ebing's and Freud's theoretical conceptualizations of sexuality and perversion will be sketched and basic clinical and societal implications there out will be discussed. PMID- 26099906 TI - Baseline PSA in a Spanish male population aged 40-49 years anticipates detection of prostate cancer. AB - INTRODUCTION: We researched the usefulness of optimizing prostate cancer (PC) screening in our community using baseline PSA readings in men between 40-49 years of age. MATERIAL AND METHOD: A retrospective study was performed that analyzed baseline PSA in the fifth decade of life and its ability to predict the development of PC in a population of Madrid (Spain). An ROC curve was created and a cutoff was proposed. We compared the evolution of PSA from baseline in patients with consecutive readings using the Friedman test. We established baseline PSA ranges with different risks of developing cancer and assessed the diagnostic utility of the annual PSA velocity (PSAV) in this population. RESULTS: Some 4,304 men aged 40-49 years underwent opportunistic screening over the course of 17 years, with at least one serum PSA reading (6,001 readings) and a mean follow-up of 57.1+/-36.8 months. Of these, 768 underwent biopsy of some organ, and 104 underwent prostate biopsy. Fourteen patients (.33%) were diagnosed with prostate cancer. The median baseline PSA was .74 (.01-58.5) ng/mL for patients without PC and 4.21 (.76-47.4) ng/mL for those with PC. The median time from the reading to diagnosis was 26.8 (1.5-143.8) months. The optimal cutoff for detecting PC was 1.9ng/mL (sensitivity, 92.86%; specificity, 92.54%; PPV, 3.9%; NPV, 99.97%), and the area under the curve was 92.8%. In terms of the repeated reading, the evolution of the PSA showed no statistically significant differences between the patients without cancer (p=.56) and those with cancer (P=.64). However, a PSAV value >.3ng/mL/year revealed high specificity for detecting cancer in this population. CONCLUSIONS: A baseline PSA level >=1.9ng/mL in Spanish men aged 40 49 years predicted the development of PC. This value could therefore be of use for opportunistic screening at an early age. An appropriate follow-up adapted to the risk of this population needs to be defined, but an annual PSAV >=.3ng/mL/year appears of use for reaching an early diagnosis. PMID- 26099907 TI - Cervical Spine Fracture Presenting as an Orthostatic Headache Secondary to Cerebral Spinal Fluid Leak. AB - BACKGROUND: Head injuries are a common chief complaint encountered in the emergency department (ED). A cerebrospinal fluid (CSF) leak resulting from such injuries is uncommon, but has potentially debilitating consequences if undiagnosed. CASE REPORT: A 34-year-old male patient presented to the ED with complaints of an orthostatic headache after a bicycle accident that occurred 5 days prior to presentation. He presented with a nonfocal neurologic examination. Computed tomography (CT) of the head was without significant pathology. CT angiography of the neck, performed due to a concern about traumatic arterial dissection, revealed C7 spinal fractures, but no evidence of dissection or occlusion of the arteries in the neck. Lying flat, he appeared comfortable but became quite symptomatic upon sitting upright or standing. Based on this finding, a CSF leak was suspected and he was admitted for symptom control and more detailed imaging to rule out such a leak. He was found, on magnetic resonance imaging, to have epidural CSF collections consistent with the suspected leak. In addition to immobilization for the cervical spine fracture, he was treated for orthostatic headaches conservatively with good outcomes. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although this syndrome is still considered rare compared to other posttraumatic injuries, there is a growing body of evidence suggesting it may be underdiagnosed. Additionally, the signs and symptoms of this syndrome are nonspecific, with the exclusion of the orthostatic headache, and may be readily attributed to other diagnoses. PMID- 26099908 TI - Vaseline: A New Stone in Hair Glue Removal. PMID- 26099909 TI - Acute Vilazodone Toxicity in a Pediatric Patient. AB - BACKGROUND: Vilazodone is a selective serotonin reuptake inhibitor and 5HT1A agonist recently approved to treat depression in adults. To date, there are minimal data available regarding the expected course and treatment of acute vilazodone ingestions. CASE REPORT: We report a case of a previously healthy 19 month-old girl who presented after an acute ingestion of an estimated 37 mg/kg vilazodone. She was taken to an outside emergency department approximately 1 h after an unwitnessed ingestion. Initially, the patient was noted to have decreased responsiveness, sluggish but reactive pupils, altered mental status, and reported seizure activity. She was given intravenous lorazepam for seizure control, intubated, and transferred to a pediatric tertiary care facility, where she continued to show signs of serotonin toxicity and received treatment with benzodiazepines and cyproheptadine. Despite vilazodone's long half-life and the large amount ingested, the patient was extubated within 10 h of presentation, had returned to baseline mental status by 22 h, and was discharged home approximately 57 h after ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Accidental ingestions are common in the pediatric population. Emergency physicians need to be aware of the signs and symptoms of acute medication toxicities, the expected clinical course, and the necessary supportive measures used to treat these patients. Because vilazodone is a recently approved medication, there is little experience with acute vilazodone ingestions. This report considerably increases the understanding of vilazodone's effects in the setting of an acute ingestion. PMID- 26099910 TI - Peer-assisted Learning in Cardiopulmonary Resuscitation: The Jigsaw Model. AB - BACKGROUND: Training a large cohort of the population could, over time, increase the rate of bystander cardiopulmonary resuscitation (CPR) and survival after out of-hospital cardiac arrest. OBJECTIVES: This study investigates 1) the quality of peer-assisted learning (PAL) by means of the jigsaw method compared to direct teaching by an instructor for learning CPR, and 2) the extent to which acquired skills can be passed on from tutor to tutee without loss of learning. METHODS: One hundred thirty-seven master students were randomized into a jigsaw and a control group. In the jigsaw group, subjects were randomly split into a chest compression group (CC) and a ventilation group (VEN). After each group had learned the respective skill by an expert instructor, all students were randomized into pairs and taught their partner the acquired skill. In the control group, both skills were taught by the expert instructor. CPR assessment was individually conducted 1 week prior to intervention (baseline) and 2 weeks after (post) on a manikin using a PC-Skill Reporting System. RESULTS: At baseline, no significant differences were observed between the three groups. At post, all groups met the European Resuscitation Council (ERC) 2010 guidelines. No significant difference was observed between the jigsaw and control group. One significant difference was found between the VEN and CC group for chest compression depth (p < 0.01). CONCLUSION: This study demonstrated that the jigsaw model is as effective as expert instruction to achieve the ERC 2010 guidelines. Only one difference was found between the tutor and tutee group. PMID- 26099911 TI - Should Family-witnessed Resuscitation Become Our Standard? AB - BACKGROUND: There have been several studies published regarding family-witnessed resuscitation (FWR), but fewer studies regarding its effectiveness. In FWR, family members are invited to be present during resuscitation efforts of a loved one. This practice is recognized and approved by the Emergency Nurses Association. DISCUSSION: FWR is increasingly gaining attention, but is not without controversy. This practice is not widely accepted by hospital staff due to fear of legal claims, prolonging futile resuscitative efforts, and violent or abusive reactions from family members. However, there may be several positive factors in performing FWR, including better mental health outcomes for family members and improved satisfaction of family members. SUMMARY: This article represents my professional opinion on the implication and professional recommendation of instituting FWR as standard of care. Education regarding the positive aspects of FWR is urgently needed to improve staff acceptance and promote policies to incorporate the procedure into practice. PMID- 26099912 TI - Avascular Necrosis of the Hip. PMID- 26099913 TI - [Medication reconciliation: a shared responsibility]. PMID- 26099917 TI - Paracetamol poisoning: beyond the nomogram. AB - Paracetamol poisoning is the commonest overdose seen in the UK. The management of patients with paracetamol poisoning has been little changed for the past 40 years, with a weight related dose of antidote (acetylcysteine) and treatment based on nomograms relating paracetamol concentration to time from ingestion. In 2012 the UK Commission on Human Medicines recommended a revision of the nomogram, following the death of a young woman, lowering the treatment threshold for all patients. As a result many more patients were treated. This has resulted in a large increase in admissions and in the proportion suffering adverse reactions to the antidote acetylcysteine since, interestingly, higher paracetamol concentrations inhibit anaphylactoid reactions to the antidote. New approaches to assessing the toxicity of paracetamol are now emerging using new biomarkers in blood. This article discusses new approaches to risk assessment and treatment for paracetamol overdose based on recent research in this area. PMID- 26099918 TI - Patient discomfort and other side effects after bilateral sagittal split osteotomy or distraction osteogenesis of the mandible: a randomized clinical trial. AB - A randomized clinical trial was conducted to compare bilateral sagittal split osteotomy (BSSO) with distraction osteogenesis (DO) for the advancement of the mandible, with a focus on patient discomfort, postoperative pain, the need for analgesics, and occurrence of infection. All patients were non-syndromal, had a class II hypoplastic mandible, and had not undergone previous mandibular surgery. A total of 66 patients were allocated randomly to the BSSO group (32 patients) or the DO group (34 patients). Sixty-three patients were eligible for evaluation, 29 in the BSSO group and 34 in the DO group. Patients in the DO group experienced more pain after 6 days postoperative, and were administered more analgesics after 5 days postoperative than patients in the BSSO group (P=0.030 and P=0.045, respectively). The operating time was significantly shorter for the BSSO group than for the DO group (78 min vs. 100 min, P=0.024). All postoperative infections (12 in total) emerged in the DO group (P=0.005). All patients in the DO group had a second surgery in day care to remove the distractor, while two patients in the BSSO group needed plate removal. It is concluded that patients experienced more pain after DO, needed more analgesics postoperatively, and had more infections in comparison to the BSSO group. PMID- 26099919 TI - The impact of genetic polymorphisms of drug metabolizing enzymes on the pharmacodynamics of clopidogrel under steady state conditions. AB - Clopidogrel is an antiplatelet drug that requires biotransformation steps to its active metabolite via cytochromes P450 (CYP), particularly CYP2C19 and CYP3A5 as well as paraoxonase-1 (PON1). The impact of CYP3A5 and PON1 genetic polymorphisms on the response of this drug is unclear. This study aimed to elucidate the degree of genetic polymorphisms of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel. Thirty-five healthy subjects were treated with 75 mg/day clopidogrel for 7 days and serial blood samples were collected for measurement of antiplatelet effect using whole blood impedance aggregometry and VerifyNow((r)) P2Y12 methods. The areas under the antiplatelet effect-time curves, maximal and minimal antiplatelet effects of clopidogrel obtained from both methods were significantly different among subjects with different CYP2C19 genotypes. In contrast, these pharmacodymamic parameters measured by both methods of subjects with different PON1 or CYP3A5 genotypes were not significantly different. Among the heterozygous CYP2C19*2 subjects, all pharmacodynamic parameters measured by whole blood impedance aggregometry were significantly different between subjects with different CYP3A5*3 genotypes. Our data suggests that CYP2C19 genetic polymorphism play a major role in the clopidogrel response, however, the impact of CYP3A5 genetic polymorphism, may be pronounced in the subjects who carried the loss-functional allele of CYP2C19. PMID- 26099920 TI - BioTech 2014 and 6th Czech-Swiss Biotechnology Symposium. PMID- 26099916 TI - Role of biomarkers of nephrotoxic acute kidney injury in deliberate poisoning and envenomation in less developed countries. AB - Acute kidney injury (AKI) has diverse causes and is associated with increased mortality and morbidity. In less developed countries (LDC), nephrotoxic AKI (ToxAKI) is common and mainly due to deliberate ingestion of nephrotoxic pesticides, toxic plants or to snake envenomation. ToxAKI shares some pathophysiological pathways with the much more intensively studied ischaemic AKI, but in contrast to ischaemic AKI, most victims are young, previously healthy adults. Diagnosis of AKI is currently based on a rise in serum creatinine. However this may delay diagnosis because of the kinetics of creatinine. Baseline creatinine values are also rarely available in LDC. Novel renal injury biomarkers offer a way forward because they usually increase more rapidly in AKI and are normally regarded as absent or very low in concentration, thereby reducing the need for a baseline estimate. This should increase sensitivity and speed of diagnosis. Specificity should also be increased for urine biomarkers since many originate from the renal tubular epithelium. Earlier diagnosis of ToxAKI should allow earlier initiation of appropriate therapy. However, translation of novel biomarkers of ToxAKI into clinical practice requires better understanding of non renal factors in poisoning that alter biomarkers and the influence of dose of nephrotoxin on biomarker performance. Further issues are establishing LDC population-based normal ranges and assessing sampling and analytical parameters for low resource settings. The potential role of renal biomarkers in exploring ToxAKI aetiologies for chronic kidney disease of unknown origin (CKDu) is a high research priority in LDC. Therefore, developing more sensitive biomarkers for early diagnosis of nephrotoxicity is a critical step to making progress against AKI and CKDu in the developing world. PMID- 26099921 TI - Application of a hierarchical enzyme classification method reveals the role of gut microbiome in human metabolism. AB - BACKGROUND: Enzymes are known as the molecular machines that drive the metabolism of an organism; hence identification of the full enzyme complement of an organism is essential to build the metabolic blueprint of that species as well as to understand the interplay of multiple species in an ecosystem. Experimental characterization of the enzymatic reactions of all enzymes in a genome is a tedious and expensive task. The problem is more pronounced in the metagenomic samples where even the species are not adequately cultured or characterized. Enzymes encoded by the gut microbiota play an essential role in the host metabolism; thus, warranting the need to accurately identify and annotate the full enzyme complements of species in the genomic and metagenomic projects. To fulfill this need, we develop and apply a method called ECemble, an ensemble approach to identify enzymes and enzyme classes and study the human gut metabolic pathways. RESULTS: ECemble method uses an ensemble of machine-learning methods to accurately model and predict enzymes from protein sequences and also identifies the enzyme classes and subclasses at the finest resolution. A tenfold cross validation result shows accuracy between 97 and 99% at different levels in the hierarchy of enzyme classification, which is superior to comparable methods. We applied ECemble to predict the entire complements of enzymes from ten sequenced proteomes including the human proteome. We also applied this method to predict enzymes encoded by the human gut microbiome from gut metagenomic samples, and to study the role played by the microbe-derived enzymes in the human metabolism. After mapping the known and predicted enzymes to canonical human pathways, we identified 48 pathways that have at least one bacteria-encoded enzyme, which demonstrates the complementary role of gut microbiome in human gut metabolism. These pathways are primarily involved in metabolizing dietary nutrients such as carbohydrates, amino acids, lipids, cofactors and vitamins. CONCLUSIONS: The ECemble method is able to hierarchically assign high quality enzyme annotations to genomic and metagenomic data. This study demonstrated the real application of ECemble to understand the indispensable role played by microbe-encoded enzymes in the healthy functioning of human metabolic systems. PMID- 26099923 TI - Abscisic Acid Transport and Homeostasis in the Context of Stomatal Regulation. AB - The discovery of cytosolic ABA receptors is an important breakthrough in stomatal research; signaling via these receptors is involved in determining the basal stomatal conductance and stomatal responsiveness. However, the source of ABA in guard cells is still not fully understood. The level of ABA increases in guard cells by de novo synthesis, recycling from inactive conjugates via beta glucosidases BG1 and BG2 and by import, whereas it decreases by hydroxylation, conjugation, and export. ABA importers include the NRT1/PTR family protein AIT1, ATP-binding cassette protein ABCG40, and possibly ABCG22, whereas the DTX family member DTX50 and ABCG25 function as ABA exporters. Here, we review the proteins involved in ABA transport and homeostasis and their physiological role in stomatal regulation. Recent experiments suggest that functional redundancy probably exists among ABA transporters between vasculature and guard cells and ABA recycling proteins, as stomatal functioning remained intact in abcg22, abcg25, abcg40, ait1, and bg1bg2 mutants. Only the initial response to reduced air humidity was significantly delayed in abcg22. Considering the reports showing autonomous ABA synthesis in guard cells, we discuss that rapid stomatal responses to atmospheric factors might depend primarily on guard cell-synthesized ABA, whereas in the case of long-term soil water deficit, ABA synthesized in the vasculature might have a significant role. PMID- 26099922 TI - Halofuginone inhibits phosphorylation of SMAD-2 reducing angiogenesis and leukemia burden in an acute promyelocytic leukemia mouse model. AB - BACKGROUND: Halofuginone (HF) is a low-molecular-weight alkaloid that has been demonstrated to interfere with Metalloproteinase-2 (MMP-2) and Tumor Growth Factor-beta (TGF-beta) function and, to present antiangiogenic, antiproliferative and proapoptotic properties in several solid tumor models. Based on the fact that high levels of Vascular Endothelial Growth Factor (VEGF) and increased angiogenesis have been described in acute myeloid leukemia and associated with disease progression, we studied the in vivo effects of HF using an Acute Promyelocytic Leukemia (APL) mouse model. METHODS: NOD/SCID mice were transplanted with leukemic cells from hCG-PML/RARA transgenic mice (TM) and treated with HF 150 MUg/kg/day for 21 days. The leukemic infiltration and the percentage of VEGF+ cells were evaluated by morphology and flow cytometry. The effect of HF on the gene expression of several pro- and antiangiogenic factors, phosphorylation of SMAD2 and VEGF secretion was assessed in vitro using NB4 and HUVEC cells. RESULTS: HF treatment resulted in hematological remission with decreased accumulation of immature cell and lower amounts of VEGF in BM of leukemic mice. In vitro, HF modulated gene expression of several pro- and antiangiogenic factors, reduced VEGF secretion and phosphorylation of SMAD2, blocking TGF-beta-signaling. CONCLUSION: Taken together, our results demonstrate that HF inhibits SMAD2 signaling and reduces leukemia growth and angiogenesis. PMID- 26099924 TI - A Versatile Phenotyping System and Analytics Platform Reveals Diverse Temporal Responses to Water Availability in Setaria. AB - Phenotyping has become the rate-limiting step in using large-scale genomic data to understand and improve agricultural crops. Here, the Bellwether Phenotyping Platform for controlled-environment plant growth and automated multimodal phenotyping is described. The system has capacity for 1140 plants, which pass daily through stations to record fluorescence, near-infrared, and visible images. Plant Computer Vision (PlantCV) was developed as open-source, hardware platform independent software for quantitative image analysis. In a 4-week experiment, wild Setaria viridis and domesticated Setaria italica had fundamentally different temporal responses to water availability. While both lines produced similar levels of biomass under limited water conditions, Setaria viridis maintained the same water-use efficiency under water replete conditions, while Setaria italica shifted to less efficient growth. Overall, the Bellwether Phenotyping Platform and PlantCV software detected significant effects of genotype and environment on height, biomass, water-use efficiency, color, plant architecture, and tissue water status traits. All ~ 79,000 images acquired during the course of the experiment are publicly available. PMID- 26099925 TI - Responses of the antennal bimodal hygroreceptor neurons to innocuous and noxious high temperatures in the carabid beetle, Pterostichus oblongopunctatus. AB - Electrophysiological responses of thermo- and hygroreceptor neurons from antennal dome-shaped sensilla of the carabid beetle Pterostichus oblongopunctatus to different levels of steady temperature ranging from 20 to 35 degrees C and rapid step-changes in it were measured and analysed at both constant relative and absolute ambient air humidity conditions. It appeared that both hygroreceptor neurons respond to temperature which means that they are bimodal. For the first time in arthropods, the ability of antennal dry and moist neurons to produce high temperature induced spike bursts is documented. Burstiness of the spike trains is temperature dependent and increases with temperature increase. Threshold temperatures at which the two neurons switch from regular spiking to spike bursting are lower compared to that of the cold neuron, differ and approximately coincide with the upper limit of preferred temperatures of the species. We emphasise that, in contrast to various sensory systems studied, the hygroreceptor neurons of P. oblongopunctatus have stable and continuous burst trains, no temporal information is encoded in the timing of the bursts. We hypothesise that temperature dependent spike bursts produced by the antennal thermo- and hygroreceptor neurons may be responsible for detection of noxious high temperatures important in behavioural thermoregulation of carabid beetles. PMID- 26099926 TI - A cross-sectional study of barriers to physical activity among overweight and obese patients with type 2 diabetes in Iran. AB - The objective of this study was to identify common barriers to physical activity practice among overweight/obese patients with type 2 diabetes in Iran and their associations with physical activity level. In this cross-sectional study, 146 overweight/obese volunteers with type 2 diabetes were recruited from diabetes clinics in Tabriz, Iran, between July 2012 and March 2013. A Persian version of the long-format International Physical Activity Questionnaire was used to assess physical activity level. A 12-item structured questionnaire was designed to assess physical activity barriers. The validity and reliability of the latter scale were assessed by related measures. An exploratory factor analysis with the principal component analysis extraction method and varimax rotation was performed to extract the underlying factors. Multivariate regression analysis was used to assess the relationship between barriers and physical activity level. About 73% of patients had moderate physical activity. Factor analysis yielded four factors as barriers to physical activity including: (i) negative attitude towards physical activity, (ii) discouragement, (iii) physical problems and (iv) cost/environmental factors. These factors explained about 51% of the total variance. There was a negative relationship between the factor 'physical problems' and physical activity level (P = 0.024). Overall, there were some barriers to physical activity. Health counsellors should address these barriers to increase the patients' adherence to physical activity recommendations. Physical conditions of the patients must be taken into account. PMID- 26099927 TI - Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo Successor). AB - BACKGROUND: In light of the increased risk of progressive multifocal encephalopathy (PML) development under long-term treatment with the monoclonal antibody natalizumab which is approved for treatment of active relapsing remitting multiple sclerosis (RRMS), there is a clear need for alternative treatment options with comparable efficacy and reduced PML risk. One such option is fingolimod, a functional sphingosin-1-receptor antagonist that has been approved as first oral drug for treatment of active RRMS. However, the optimal switching design in terms of prevention of disease reoccurrence is still unknown. Moreover, potential additive effects of both drugs on immune functions, especially with regard to migration, have not yet been evaluated. METHODS/DESIGN: This is an exploratory, open-label, monocentric, investigator-initiated clinical trial. Fifteen RRMS patients under stable treatment with natalizumab will receive one last natalizumab infusion followed by a wash-out period of 8 weeks before fingolimod treatment initiation for a period of 24 weeks. Disease activity under natalizumab and during switching will be closely monitored by assessment of relapse rate and disease severity as well as high-frequent high-resolution magnetic resonance imaging including quantitative diffusion tensor imaging. Immunological assays include longitudinal assessment of adhesion molecule expression, functional evaluation of the migratory capacity of immune cells in an in-vitro model of the blood-brain-barrier, and the quality of cellular antiviral immune responses. DISCUSSION: Our trial represents the first detailed and longitudinal functional analysis of key immunological parameters in the process of switching from natalizumab and fingolimod, especially with regard to potential additive effects of both drugs on trafficking and immune surveillance. Moreover, our study will generate valuable information about even subtle disease exacerbations as consequence of natalizumab cessation, which will help to understand whether a switching protocol containing a wash-out period of 8 weeks before fingolimod treatment is appropriate in terms of disease stability. PMID- 26099928 TI - Characterization of the bacterial gut microbiota of piglets suffering from new neonatal porcine diarrhoea. AB - BACKGROUND: In recent years, new neonatal porcine diarrhoea (NNPD) of unknown aetiology has emerged in Denmark. NNPD affects piglets during the first week of life and results in impaired welfare, decreased weight gain, and in the worst case scenario death. Commonly used preventative interventions such as vaccination or treatment with antibiotics, have a limited effect on NNPD. Previous studies have investigated the clinical manifestations, histopathology, and to some extent, microbiological findings; however, these studies were either inconclusive or suggested that Enterococci, possibly in interaction with Escherichia coli, contribute to the aetiology of NNPD. This study examined ileal and colonic luminal contents of 50 control piglets and 52 NNPD piglets by means of the qPCR based Gut Microbiotassay and 16 samples by 454 sequencing to study the composition of the bacterial gut microbiota in relation to NNPD. RESULTS: NNPD was associated with a diminished quantity of bacteria from the phyla Actinobacteria and Firmicutes while genus Enterococcus was more than 24 times more abundant in diarrhoeic piglets. The number of bacteria from the phylum Fusobacteria was also doubled in piglets suffering from diarrhoea. With increasing age, the gut microbiota of NNPD affected piglet and control piglets became more diverse. Independent of diarrhoeic status, piglets from first parity sows (gilts) possessed significantly more bacteria from family Enterobacteriaceae and species E. coli, and fewer bacteria from phylum Firmicutes. Piglets born to gilts had 25 times higher odds of having NNPD compared with piglets born to multiparous sows. Finally, the co-occurrence of genus Enterococcus and species E. coli contributed to the risk of having NNPD. CONCLUSION: The results of this study support previous findings that points towards genus Enterococcus and species E. coli to be involved in the pathogenesis of NNPD. Moreover, the results indicate that NNPD is associated with a disturbed bacterial composition and larger variation between the diarrhoeic piglets. PMID- 26099929 TI - Endoscopic submucosal dissection of duodenal gangliocytic paraganglioma: a rare entity. PMID- 26099930 TI - Formation of large esophageal diverticulum after peroral endoscopic myotomy. PMID- 26099931 TI - Two endoscopic resection methods for the removal of an over-the-scope clip. PMID- 26099932 TI - Pancreatic lipid content is not associated with beta cell dysfunction in youth onset type 2 diabetes. AB - OBJECTIVE: To determine whether pancreatic lipid content is associated with type 2 diabetes and beta cell function in Indigenous and Caucasian adolescents. METHODS: This was a cross-sectional study comparing (1)H-magnetic resonance spectroscopy-derived pancreatic triglyceride content in adolescents 13 to 18 years of age with type 2 diabetes (n=20) and body mass index-matched normoglycemic controls (n=34). Beta cell function was measured by the acute insulin response and disposition index derived from intravenous glucose tolerance tests. RESULTS: Pancreatic lipid content was not significantly different in youth with type 2 diabetes and their normoglycemic body mass index-matched peers (2.41 [95% CI: 0.63, 5.60] vs. 1.22 [0.08, 5.93]; p=0.27). Pancreatic triglyceride levels were not associated with measures of beta cell function in the cohort. In subgroup analyses, pancreatic lipid content was ~4-fold higher in youth with type 2 diabetes who were carriers of the G319S mutation in the HNF-1alpha gene (7.45 [2.85, 26.8] vs. 2.20 [0.350, 3.30] % Fat to Water Ratio F/W; p=0.032). CONCLUSIONS: Pancreatic lipid content is not elevated in Indigenous or Caucasian youth with type 2 diabetes compared to normoglycemic youth, nor is it associated with beta cell function. The presence of the G319S mutation in the HNF-1alpha gene in Indigenous youth with type 2 diabetes is associated with higher pancreatic lipid content. Further research is needed to understand the mechanisms that explain beta cell failure in overweight youth with type 2 diabetes. PMID- 26099933 TI - Maternal ambient air pollution exposure preconception and during early gestation and offspring congenital orofacial defects. AB - BACKGROUND: Maternal air pollution exposure has been related to orofacial clefts but the literature is equivocal. Potential chronic preconception effects have not been studied. OBJECTIVES: Criteria air pollutant exposure during three months preconception and gestational weeks 3-8 was studied in relation to orofacial defects. METHODS: Among 188,102 live births and fetal deaths from the Consortium on Safe Labor (2002-2008), 63 had isolated cleft palate (CP) and 159 had isolated cleft lip with or without cleft palate (CL +/-CP). Exposures were estimated using a modified Community Multiscale Air Quality model. Logistic regression with generalized estimating equations adjusted for site/region and maternal demographic, lifestyle and clinical factors calculated the odds ratio (OR) and 95% CI per interquartile increase in each pollutant. RESULTS: Preconception, carbon monoxide (CO; OR=2.24; CI: 1.21, 4.16) and particulate matter (PM) <=10 um (OR=1.72; CI: 1.12, 2.66) were significantly associated with CP, while sulfur dioxide (SO2) was associated with CL +/-CP (OR=1.93; CI: 1.16, 3.21). During gestational weeks 3-8, CO remained a significant risk for CP (OR=2.74; CI: 1.62, 4.62) and nitrogen oxides (NOx; OR=3.64; CI: 1.73, 7.66) and PM <=2.5 um (PM2.5; OR=1.74; CI: 1.15, 2.64) were also related to the risk. Analyses by individual week revealed that positive associations of NOx and PM2.5 with CP were most prominent from weeks 3-6 and 3-5, respectively. CONCLUSIONS: Exposure to several criteria air pollutants preconception and during early gestation was associated with elevated odds for CP, while CL +/-CP was only associated with preconception SO2 exposure. PMID- 26099934 TI - Considerations on treatment recommendations for rheumatoid arthritis. PMID- 26099935 TI - An anatomical study of lumbar epidural catheterization. AB - BACKGROUND: We herein provide an analysis of lumbar epidural catheterization, which outlines a detailed anatomical description of the epidural anatomy, and may improve the success rate of neuraxial cannulation. METHODS: Lumbar epidural catheters were placed in 50 adult embalmed cadavers. After catheterization, the lumbar dura and connecting structures between the epidural space and the vertebral body were separated. The positional relationship between the catheter and the posterior epidural space were observed and photographed. RESULTS: Amongst the 50 specimens, the epidural catheter curled into a circle in three cases, entered the intervertebral foramen in two cases, and caused epidural venous damage in five cases. CONCLUSIONS: Meningo-vertebral ligaments exist in the posterior epidural space and connect to the venous plexus, which may contribute to epidural catheter failure, uneven distribution of anaesthesia and epidural hemorrhage. Our study provides anaesthesiologists with a better understanding of the anatomy and may mitigate complications of lumbar epidural catheter placement. PMID- 26099936 TI - A method to investigate protein association with intact sealed mycobacterial membrane vesicles. AB - In mycobacteria, probing the association of cytoplasmic proteins with the membrane itself, as well as with integral or peripheral membrane proteins, is limited by the difficulty in extracting intact sealed membrane vesicles due to the complex cell wall structure. Here we tested the association of Mycobacterium tuberculosis SecA1 and SecA2 proteins with intact membrane vesicles by a flotation assay using iodixanol density gradients. These protocols have wide applications for studying the association of other mycobacterial cytoplasmic proteins with the membrane and membrane-associated proteins. PMID- 26099937 TI - An acetyltransferase assay for CREB-binding protein based on reverse phase-ultra fast liquid chromatography of fluorescent histone H3 peptides. AB - CREB-binding protein (CBP) is a lysine acetyltransferase that regulates transcription by acetylating histone and non-histone substrates. Defects in CBP activity are associated with hematologic malignancies, neurodisorders, and congenital malformations. Sensitive and quantitative enzymatic assays are essential to better characterize the pathophysiological features of CBP. We describe a sensitive nonradioactive method to measure purified and immunopurified cellular CBP enzymatic activity through rapid reverse phase-ultra-fast liquid chromatography (RP-UFLC) analysis of fluorescent histone H3 peptide substrates. The applicability and biological relevance of the assay are supported by kinetic, inhibition, and immunoprecipitation studies. More broadly, this approach could be easily adapted to assay other lysine acetyltransferases or methyltransferases. PMID- 26099938 TI - Escherichia coli virulence patterns may help to predict vesicoureteral reflux in paediatric urinary tract infections. AB - AIM: Ultrasound and biological tools are used to predict high-grade vesicoureteral reflux, but other markers are needed to better select patients who need voiding cystography. Our aim was to determine whether studying Escherichia coli virulence factors would help to predict vesicoureteral reflux in patients with their first acute pyelonephritis. METHODS: We included children presenting with E. coli-related acute pyelonephritis or cystitis. Vesicoureteral reflux was assessed by voiding cystography. Virulence factors were identified by multiplex polymerase chain reaction. Statistical analysis was performed using logistic regression and the mean c-statistic test. RESULTS: We included 198 patients: 30 with cystitis and 168 with acute pyelonephritis, including 46 with vesicoureteral reflux. High-grade reflux was associated with acute pyelonephritis caused by the E. coli lacking virulence factors papGII (82% versus 47%, p < 0.001) or papC (85% versus 53%, p < 0.001) or belonging to phylogenetic group A or B1. When we added genetic data (lack of papGII, fyuA and phylogenetic groups) to classical predictors of vesicoureteral reflux (ultrasound examination, gender, age), the ability to predict high-grade reflux increased, with the c-statistic rising from 0.88 to 0.93. CONCLUSION: Bacterial virulence factors and clinical factors helped to predict high-grade reflux and may help to avoid unnecessary voiding cystographies. PMID- 26099939 TI - A delivery system for field application of paratransgenic control. AB - BACKGROUND: As an alternative to chemical pesticides, paratransgenesis relies on transformation of symbiotic bacteria of an arthropod vector to deliver molecules that disrupt pathogen transmission. For over a decade paratransgenesis has remained a laboratory-based endeavor owing to regulatory concerns regarding introduction of transformed microorganisms into the environment. To facilitate field application of paratransgenic strategies, risk mitigation approaches that address environmental contamination and gene spread must be developed. RESULTS: Using biopolymer manipulation, we introduce a novel microencapsulation platform for containment and targeted delivery of engineered bacteria to the gut of a disease-transmitting arthropod. We demonstrate the first proof of principle of targeted delivery of EPA-approved Pantoea agglomerans E325 in a paratransgenic system to control spread of Pierce's Disease by glassy-winged sharpshooters, (Homalodisca vitripennis) under simulated field conditions. Engineered microcapsules may address regulatory concerns regarding containment of recombinant bacteria and environmental spread of foreign genetic material and may represent an important step in translating paratransgenic science beyond the lab and into the field. CONCLUSIONS: We present, for the first time, a microencapsulation strategy to deliver recombinant bacteria to an insect and demonstrate targeted release of bacteria into the physiologically relevant region of the insect gut. This is a first step toward addressing concerns related to field application of recombinant bacteria. Engineered microparticles may decrease environmental contamination, horizontal gene transfer and competition with native species by acting as a barrier between recombinant bacteria and the environment. PMID- 26099940 TI - Mapping of the putative epitope domain of Clonorchis sinensis paramyosin (CsPmy) recognized by CsPmy-specific immunoglobulin G in sera of human clonorchiasis. AB - Paramyosin of Clonorchis sinensis (CsPmy) is a myofibrillar protein localized in subtegumental muscle, tegument, and the muscle layer surrounding the intestine of the parasite. Previously, we have identified that CsPmy reacted with sera of human clonorchiasis and this protein had a potential as a candidate antigen for serodiagnosis of clonorchiasis. However, we also found that CsPmy is able to bind to human immunoglobulin G (IgG) in non-specific manners, which can affect the diagnostic value of the protein. Here, we mapped CsPmy-specific IgG binding site on CsPmy to analyze the putative epitopes recognized by CsPmy-specific IgG in sera of human clonorchiasis. The fragmental expression of CsPmy followed by immunoblot analyses with sera from patients with clonorchiasis and non-specific human IgG revealed that the middle portion of CsPmy (CsPmyC: 301-600 amino acid residues) had epitopes responsible for CsPmy-specific IgG recognition. The precise CsPmy-specific IgG binding site was further narrowed down to a fragment (CsPmyC-2), which harbors 151 amino acid residues (375-525) of CsPmy. Specific antibodies for CsPmyC-2 were produced in rats after two-weeks of post experimental infection. The CsPmyC-2 showed low levels of cross reactivity against the sera from patients with other helminth parasites. Our results suggested that CsPmyC-2 has real epitopes recognized by CsPmy-specific IgG in sera of human clonorchiasis and the fragment can be useful as a reliable serodiagnostic antigen to develop a serodiagnostic method for clonorchiasis. PMID- 26099941 TI - Calcium-dependent membrane association of a flagellar calcium sensor does not require calcium binding. AB - Flagellar calcium-binding protein (FCaBP) is a dually acylated Ca(2+) sensor in the Trypanosoma cruzi flagellar membrane that undergoes a massive conformational change upon Ca(2+) binding. It is similar to neuronal Ca(2+) sensors, like recoverin, which regulate their binding partners through a calcium acyl switch mechanism. FCaBP is washed out of permeabilized cells with buffers containing EDTA, indicating Ca(2+)-dependent flagellar membrane association. We hypothesized that, like recoverin, FCaBP projects its acyl groups in the presence of Ca(2+), permitting flagellar membrane and binding partner association and that it sequesters the acyl groups in low Ca(2+), disassociating from the membrane and releasing its binding partner to perform a presumed enzymatic function. The X-ray crystal structure of FCaBP suggests that the acyl groups are always exposed, so we set out to test our hypothesis directly. We generated T. cruzi transfectants expressing FCaBP or Ca(2+)-binding mutant FCaBP(E151Q/E188Q) and recombinant wildtype and mutant proteins as well. Both FCaBP and FCaBP(E151Q/E188Q) were found to associate with lipid rafts, indicating the Ca(2+)-independence of this association. To our initial surprise, FCaBP(E151Q/E188Q), like wildtype FCaBP, exhibited Ca(2+)-dependent flagellar membrane association, even though this protein does not bind Ca(2+) itself [16]. One possible explanation for this is that FCaBP(E151Q/E188Q), like some other Ca(2+) sensors, may form dimers and that dimerization of FCaBP(E151Q/E188Q) with endogenous wildtype FCaBP might explain its Ca(2+)-dependent localization. Indeed both proteins are able to form dimers in the presence and absence of Ca(2+). These results suggest that FCaBP possesses two distinct Ca(2+)-dependent interactions-one involving a Ca(2+)-induced change in conformation and another perhaps involving binding partner association. PMID- 26099942 TI - Recommendations for the use of PET imaging biomarkers in the diagnosis of neurodegenerative conditions associated with dementia: SEMNIM and SEN consensus. AB - The new diagnostic criteria for Alzheimer's disease (AD) acknowledges the interest given to biomarkers to improve the specificity in subjects with dementia and to facilitate an early diagnosis of the pathophysiological process of AD in the prodromal or pre-dementia stage. The current availability of PET imaging biomarkers of synaptic dysfunction (PET-FDG) and beta amyloid deposition using amyloid-PET provides clinicians with the opportunity to apply the new criteria and improve diagnostic accuracy in their clinical practice. Therefore, it seems essential for the scientific societies involved to use the new clinical diagnostic support tools to establish clear, evidence-based and agreed set of recommendations for their appropriate use. The present work includes a systematic review of the literature on the utility of FDG-PET and amyloid-PET for the diagnosis of AD and related neurodegenerative diseases that occur with dementia. Thus, we propose a series of recommendations agreed on by the Spanish Society of Nuclear Medicine and Spanish Society of Neurology as a consensus statement on the appropriate use of PET imaging biomarkers. PMID- 26099943 TI - Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules. AB - With the increasing concerns about chemical pollution and sustainability of resources, among the significant challenges facing synthetic chemists are the development and application of elegant and efficient methods that enable the concise synthesis of natural products, drugs, and related compounds in a step-, atom- and redox-economic manner. One of the most effective ways to reach this goal is to implement reaction cascades that allow multiple bond-forming events to occur in a single vessel. This Account documents our progress on the rational design and strategic application of asymmetric catalytic cascade reactions in constructing diverse scaffolds and synthesizing complex chiral molecules. Our research is aimed at developing robust cascade reactions for the systematic synthesis of a range of interesting molecules that contain structural motifs prevalent in natural products, pharmaceuticals, and biological probes. The strategies employed to achieve this goal can be classified into three categories: bifunctional base/Bronsted acid catalysis, covalent aminocatalysis/N-heterocyclic carbene catalysis, and asymmetric organocatalytic relay cascades. By the use of rationally designed substrates with properly reactive sites, chiral oxindole, chroman, tetrahydroquinoline, tetrahydrothiophene, and cyclohexane scaffolds were successfully assembled under bifunctional base/Bronsted acid catalysis from simple and readily available substances such as imines and nitroolefins. We found that some of these reactions are highly efficient since catalyst loadings as low as 1 mol % can promote the multistep sequences affording complex architectures with high stereoselectivities and yields. Furthermore, one of the bifunctional base/Bronsted acid-catalyzed cascade reactions for the synthesis of chiral cyclohexanes has been used as a key step in the construction of the tetracyclic core of lycorine-type alkaloids and the formal synthesis of alpha-lycorane. Guided by the principles of covalent aminocatalysis and N-heterocyclic carbene catalysis, we synthesized chiral piperidine, indole, and cyclobutane derivatives. The synthesis of chiral cyclobutanes and pyrroloindolones showed unprecedented reactivity of substrates and catalysts. The development of the strategy of asymmetric organocatalytic relay cascades has provided a useful tool for the controlled synthesis of specific diastereomers in complex molecules. This Account gives a panoramic view and the logic of our research on the design, development, and applications of asymmetric catalytic cascade reactions that will potentially provide useful insights into exploring new reactions. PMID- 26099946 TI - Biotherapies targeting T and B cells: from immune suppression to immune tolerance. AB - The field of immunotherapy has undergone a major rejuvenation with the development of monoclonal antibodies and fusion proteins targeting specialized receptors of T and B lymphocytes or cytokines relevant for the differentiation of these cells. This review will focus on autoimmunity, probably the field that benefited most from these new biological therapies that very significantly impacted the modalities of patient's care. The aim is to present the agents which constitute major disease modifying drugs for the treatment of chronic invalidating autoimmune diseases. In doing so, we shall distinguish between agents that globally depress immune responses and those that may selectively target the harmful autoimmune response over long-term while preserving the capacity of the host to react normally to exogenous antigens, in other words, agents promoting 'operational tolerance'. PMID- 26099944 TI - Improved serological detection of rheumatoid arthritis: a highly antigenic mimotope of carbonic anhydrase III selected in a murine model by phage display. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects around 1% of the human population worldwide. RA diagnosis can be difficult as there is no definitive test for its detection. Therefore, the aim of this study was to identify biomarkers that could be used for RA diagnosis. METHODS: Sera from a collagen-induced arthritis mouse model were used to select potential biomarkers for RA diagnosis by phage display technology. In silico and in vitro analyses were performed to characterize and validate the selected peptides. Samples were classified into three groups: RA; two other immune mediated rheumatic diseases (systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS)); and healthy controls (HC). Enzyme-linked immunosorbent assay (ELISA) was carried out to determine antibody levels, and diagnostic parameters were determined by constructing receiver operating characteristic curves. Mass spectrometry and Western blot were performed to identify the putative autoantigen that was mimicked by a highly reactive mimotope. RESULTS: After three rounds of selection, 14 clones were obtained and tested for immunoreactivity analysis against sera from RA and HC groups. The phage-fused peptide with the highest immunoreactivity (M12) was synthesized, and was able to efficiently discriminate RA patients from SLE, AS and HCs (p < 0.0001) by ELISA. The specificity and sensitivity of anti-M12 antibodies for RA diagnosis were 91 % and 84.3 %, respectively. The M12 peptide was identified as one that mimics a predicted antigenic site of the carbonic anhydrase III (CAIII) protein, a ubiquitous biomarker that has been identified in patients with other diseases. CONCLUSION: M12 is the first peptide associated with the CAIII protein that may be used as an antigen for antibody detection to aid in RA diagnosis with high sensitivity and specificity. PMID- 26099945 TI - Resveratrol, in its natural combination in whole grape, for health promotion and disease management. AB - The grape antioxidant resveratrol has been a topic of intense research for the past three decades. Resveratrol and other grape ingredients, as well as whole grape products, have shown considerable promise in health promotion and disease management. Phytochemically, whole grape represents a natural combination of resveratrol and other phytonutrients, as it contains several catechins, anthocyanins, polyphenols, and flavonols. Thus, whole grape products or specific combinations of grape constituents provide us with the possibility of synergistic interactions leading to improved efficacy. Recent research has suggested that whole-grape products may help in maintaining heart health and protect against aging, aging-associated diseases, neurodegeneration, and some cancers. On the basis of available recent literature, the grape fruit or whole-grape products seem to be safer choices for better health and disease prevention. However, for advanced disease conditions, individual grape ingredients (such as resveratrol) or combinations of multiple ingredients, together with existing therapies, appear to be better approaches. Further clinical studies are needed to understand the benefits of grapes and their products in the prevention and management of specific diseases. PMID- 26099947 TI - The neurotransmitters serotonin and glutamate accelerate the heart rate of the mosquito Anopheles gambiae. AB - Serotonin and glutamate are neurotransmitters that in insects are involved in diverse physiological processes. Both serotonin and glutamate have been shown to modulate the physiology of the dorsal vessel of some insects, yet until the present study, their activity in mosquitoes remained unknown. To test whether serotonin or glutamate regulate dorsal vessel physiology in the African malaria mosquito, Anopheles gambiae, live mosquitoes were restrained, and a video of the contracting heart (the abdominal portion of the dorsal vessel) was acquired. These adult female mosquitoes were then injected with various amounts of serotonin, glutamate, or a control vehicle solution, and additional videos were acquired at 2 and 10 min post-treatment. Comparison of the videos taken before and after treatment revealed that serotonin accelerates the frequency of heart contractions, with the cardioacceleration being significantly more pronounced when the wave-like contractions of cardiac muscle propagate in the anterograde direction (toward the head). Comparison of the videos taken before and after treatment with glutamate revealed that this molecule is also cardioacceleratory. However, unlike serotonin, the activity of glutamate does not depend on whether the contractions propagate in the anterograde or the retrograde (toward the posterior of the abdomen) directions. Serotonin or glutamate induces a minor change or no change in the percentage of contractions and the percentage of the time that the heart contracts in the anterograde or the retrograde directions. In summary, this study shows that the neurotransmitters serotonin and glutamate increase the heart contraction rate of mosquitoes. PMID- 26099948 TI - Localization of steroidogenic enzymes and Foxl2a in the gonads of mature zebrafish (Danio rerio). AB - In zebrafish, the identification of the cells expressing steroidogenic enzymes and their regulators is far from completely fulfilled though it could provide crucial information on the elucidation of the role of these enzymes. The aim of this study was to better characterize the expression pattern of steroidogenic enzymes involved in estrogen and androgen production (Cyp17-I, Cyp11c1, Cyp19a1a and Cyp19a1b) and one of their regulators (Foxl2a) in zebrafish gonads. By using immunohistochemistry, we localized the steroid-producing cells in mature zebrafish gonads and determined different expression patterns between males and females. All these steroidogenic enzymes and Foxl2a were detected both in the testis and ovary. In the testis, they were all localized both in Leydig and germ cells except Cyp19a1b which was only detected in germ cells. In the ovary, Cyp17 I, Cyp19a1a and Foxl2a were immunolocalized in both somatic and germ cells while Cyp19a1b was only detected in germ cells and Cyp11c1 in somatic cells. Moreover, Cyp19a1a and Foxl2a did not display exactly the same patterns of spatial localization but their expressions were correlated suggesting a possible regulation of cyp19a1a gene by Foxl2a in zebrafish. Comparative analysis revealed a dimorphic expression of Cyp11c1, Cyp19a1a, Cyp19a1b and Foxl2a between males and females. Overall, our study provides a detailed description of the expression of proteins involved in the biosynthesis of steroidal hormones at the cellular scale within gonads, which is critical to further elucidating the intimate roles of the enzymes and the use of the zebrafish as a model in the field of endocrinology. PMID- 26099949 TI - Quantitative EEG Neurometric Analysis-Guided Neurofeedback Treatment in Dementia: 20 Cases. How Neurometric Analysis Is Important for the Treatment of Dementia and as a Biomarker? AB - Dementia is a debilitating degenerative disorder where the sufferer's cognitive abilities decline over time, depending on the type of dementia. The more common types of dementia include Alzheimer's disease and vascular or multi-infarct dementia. In this study, 20 subjects with dementia (9 of Alzheimer's type, and 11 with vascular dementia) were treated using qEEG-guided neurofeedback training. The Mini Mental Status Examination (MMSE) was used as the primary outcome measure. The results showed an increase of the MMSE scores for all subjects regardless of dementia type with an average MMSE score increase of 6 points, which was found to be significant. To our knowledge this is the first time the same modality was shown to be beneficial in both dementia groups. PMID- 26099951 TI - Smarter Actuator Design with Complementary and Synergetic Functions. AB - A general synthetic strategy for multifunctional actuators is presented, by confining desired functions in separate domains of interpenetrating polymer network materials. Specifically, complementary ionic actuator and shape-memory functions are demonstrated by simultaneous, orthogonal reaction pathways. Synergistic effects also allow dynamic programming and two-way linear shape memory actuation. PMID- 26099950 TI - Subthalamic nucleus stimulation and spontaneous language production in Parkinson's disease: A double laterality problem. AB - BACKGROUND: Asymmetric degeneration of dopaminergic neurons, are characteristic for Parkinson's disease (PD). Despite the lateralized representation of language, the correlation of asymmetric degeneration of nigrostriatal networks in PD with language performance has scarcely been examined. OBJECTIVE/HYPOTHESIS: The laterality of dopamine depletion influences language deficits in PD and thus modulates the effects of subthalamic nucleus (STN) stimulation on language production. METHODS: The spontaneous language production of patients with predominant dopamine depletion of the left (PD-left) and right (PD-right) hemisphere was compared in four stimulation conditions. RESULTS: PD-right made comparatively more verb inflection errors than PD-left. Bilateral STN stimulation improves spontaneous language production only for PD-left. CONCLUSIONS: The laterality of dopamine depletion influences spontaneous language production and the effect of STN stimulation on linguistic functions. However, it is probably only one of the many variables influencing the effect of STN stimulation on language production. PMID- 26099952 TI - Interlayer orientation-dependent light absorption and emission in monolayer semiconductor stacks. AB - Two-dimensional stacks of dissimilar hexagonal monolayers exhibit unusual electronic, photonic and photovoltaic responses that arise from substantial interlayer excitations. Interband excitation phenomena in individual hexagonal monolayer occur in states at band edges (valleys) in the hexagonal momentum space; therefore, low-energy interlayer excitation in the hexagonal monolayer stacks can be directed by the two-dimensional rotational degree of each monolayer crystal. However, this rotation-dependent excitation is largely unknown, due to lack in control over the relative monolayer rotations, thereby leading to momentum-mismatched interlayer excitations. Here, we report that light absorption and emission in MoS2/WS2 monolayer stacks can be tunable from indirect- to direct gap transitions in both spectral and dynamic characteristics, when the constituent monolayer crystals are coherently stacked without in-plane rotation misfit. Our study suggests that the interlayer rotational attributes determine tunable interlayer excitation as a new set of basis for investigating optical phenomena in a two-dimensional hexagonal monolayer system. PMID- 26099954 TI - Are We Ready for Mass Screening to Detect Atrial Fibrillation? PMID- 26099955 TI - Carotid Artery Revascularization: What's the Best Strategy? PMID- 26099953 TI - In-vivo detection of binary PKA network interactions upon activation of endogenous GPCRs. AB - Membrane receptor-sensed input signals affect and modulate intracellular protein protein interactions (PPIs). Consequent changes occur to the compositions of protein complexes, protein localization and intermolecular binding affinities. Alterations of compartmentalized PPIs emanating from certain deregulated kinases are implicated in the manifestation of diseases such as cancer. Here we describe the application of a genetically encoded Protein-fragment Complementation Assay (PCA) based on the Renilla Luciferase (Rluc) enzyme to compare binary PPIs of the spatially and temporally controlled protein kinase A (PKA) network in diverse eukaryotic model systems. The simplicity and sensitivity of this cell-based reporter allows for real-time recordings of mutually exclusive PPIs of PKA upon activation of selected endogenous G protein-coupled receptors (GPCRs) in cancer cells, xenografts of mice, budding yeast, and zebrafish embryos. This extends the application spectrum of Rluc PCA for the quantification of PPI-based receptor effector relationships in physiological and pathological model systems. PMID- 26099957 TI - Evolution of Electrocardiographic and Structural Features Over 3 Decades in Arrhythmogenic Cardiomyopathy. PMID- 26099958 TI - Remembering Kanu Chatterjee: A Gentle Giant of Cardiology. PMID- 26099959 TI - Saving and Improving Lives in the Information Age: Presidential Address at the American Heart Association 2014 Scientific Sessions. PMID- 26099961 TI - Correction. PMID- 26099960 TI - Late Bacterial Endocarditis and Abscess Formation After Implantation of an Amplatzer Septal Occluder Device. PMID- 26099962 TI - Impact of Menopause on Pharmacokinetics of Rosuvastatin Compared with Premenopausal Women. AB - BACKGROUND AND OBJECTIVE: Rosuvastatin is used to treat dyslipidemia and its use is quite frequent among postmenopausal women. Menopause significantly affects the pharmacokinetics of drugs, and altered drug response and therapeutic efficacy may be anticipated in postmenopausal women compared with premenopausal women. The current study is based on assessment of differences in pharmacokinetics of rosuvastatin between pre- and postmenopausal women of Asian ethnicity. METHODS: Volunteers were administered a single oral dose of rosuvastatin 40 mg in an open label and non-controlled pharmacokinetic study. A reversed-phase HPLC method was applied for quantification of rosuvastatin in plasma samples. Student's t test was used to compare the pharmacokinetic parameters of rosuvastatin between pre- and postmenopausal women at the 95 % confidence interval. RESULTS: The C max (premenopausal = 58.2 +/- 29.1, postmenopausal = 12.2 +/- 3.1 ng/ml), [Formula: see text] (premenopausal = 272.6 +/- 107.3 ng.h/ml, postmenopausal = 58.8 +/- 16.6 ng.h/ml), and [Formula: see text] (premenopausal = 366.1 +/- 169, postmenopausal = 66.4 +/- 12.9 ng.h/ml) of rosuvastatin were significantly higher (p < 0.05) in premenopausal compared with postmenopausal women. The Vd/F of rosuvastatin was significantly higher (p < 0.05) in postmenopausal women compared with women, and CL/F was also significantly (p < 0.05) faster in postmenopausal women when compared at the 95 % confidence interval. CONCLUSION: Rosuvastatin plasma level was significantly higher in premenopausal compared with postmenopausal women, which raises the question whether the latter are getting due therapeutic results, as after the menopause women experience more frequent cardiovascular problems and dyslipidemia. PMID- 26099963 TI - Unsupervised segmentation of low-contrast multichannel images: discrimination of tissue components in microscopic images of unstained specimens. AB - Low-contrast images, such as color microscopic images of unstained histological specimens, are composed of objects with highly correlated spectral profiles. Such images are very hard to segment. Here, we present a method that nonlinearly maps low-contrast color image into an image with an increased number of non-physical channels and a decreased correlation between spectral profiles. The method is a proof-of-concept validated on the unsupervised segmentation of color images of unstained specimens, in which case the tissue components appear colorless when viewed under the light microscope. Specimens of human hepatocellular carcinoma, human liver with metastasis from colon and gastric cancer and mouse fatty liver were used for validation. The average correlation between the spectral profiles of the tissue components was greater than 0.9985, and the worst case correlation was greater than 0.9997. The proposed method can potentially be applied to the segmentation of low-contrast multichannel images with high spatial resolution that arise in other imaging modalities. PMID- 26099964 TI - Microzooplankton community associated with phytoplankton blooms in the naturally iron-fertilized Kerguelen area (Southern Ocean). AB - The spatial and temporal community composition of microzooplankton (dinoflagellates and ciliates) was assessed in the Kerguelen area (Southern Ocean) during the KEOPS2 cruise in early spring (October-November) 2011. This naturally iron-fertilized region was characterized by a complex mesoscale circulation resulting in a patchy distribution of phytoplankton blooms. Collectively, 97 morphospecies of dinoflagellates and ciliates belonging to 41 genera were identified by microscopy, and 202 Alveolata-related OTUs (operational taxonomical units) were retrieved with tag-pyrosequencing. Microscopy and pyrosequencing data were in accordance, in that diatom-consuming dinoflagellates were the most enhanced taxa in the blooms. Dinoflagellates also showed significant positive relationships with phytoplankton pigments, while no major differences were found in the ciliate abundances inside and outside the blooms. Cluster analysis showed clear differences in the phytoplankton and microzooplankton community structures between the iron-fertilized and HNLC (high nutrient low chlorophyll) waters, and between the blooms, concerning their location and the fertilization mechanisms. These results were combined with the rates of primary production and mesozooplankton consumption determined for the study area. The potential role of dinoflagellates and ciliates as phytoplankton consumers and as prey for mesozooplankton was then evaluated. Overall, heterotrophic dinoflagellates were probably the most important group of phytoplankton grazers, and a potential food source for copepods. PMID- 26099965 TI - Hologenome theory supported by cooccurrence networks of species-specific bacterial communities in siphonous algae (Caulerpa). AB - The siphonous algae of the Caulerpa genus harbor internal microbial communities hypothesized to play important roles in development, defense and metabolic activities of the host. Here, we characterize the endophytic bacterial community of four Caulerpa taxa in the Mediterranean Sea, through 16S rRNA amplicon sequencing. Results reveal a striking alpha diversity of the bacterial communities, similar to levels found in sponges and coral holobionts. These comprise (1) a very small core community shared across all hosts (< 1% of the total community), (2) a variable portion (ca. 25%) shared by some Caulerpa taxa but not by all, which might represent environmentally acquired bacteria and (3) a large (>70%) species-specific fraction of the community, forming very specific clusters revealed by modularity in networks of cooccurrence, even in areas where distinct Caulerpa taxa occurred in sympatry. Indirect inferences based on sequence homology suggest that these communities may play an important role in the metabolism of their host, in particular on their ability to grow on anoxic sediment. These findings support the hologenome theory and the need for a holistic framework in ecological and evolutionary studies of these holobionts that frequently become invasive. PMID- 26099966 TI - Drug Therapy for Acute Pancreatitis. AB - OPINION STATEMENT: Acute pancreatitis (AP) remains a disease with significant morbidity and mortality, and the reported incidence is increasing. Despite a significant amount of research over the last few decades with greater understanding of the pathophysiology of AP, there are still no specific drugs available. Therefore, the current treatment is limited to supportive care such as fluid, nutrition, and treatment of complications. In this review, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of AP such as anti-secretory agents, protease inhibitors, probiotics, anti-inflammatory agents, anti-oxidants, and anti-TNF-alpha agents. While many drugs were reported to have efficacy in animal experiments, human studies have been largely disappointing. Better understanding of AP pathophysiology likely will facilitate future therapies in AP. PMID- 26099967 TI - The novel beta2-selective proteasome inhibitor LU-102 decreases phosphorylation of I kappa B and induces highly synergistic cytotoxicity in combination with ibrutinib in multiple myeloma cells. AB - PURPOSE: Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (beta1, beta2, beta5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting beta5 subunit. It is unknown whether beta2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of IkappaB and activation of NF-kappaB in MM cells, while ibrutinib inhibits the IkappaB/NF-kappaB axis, suggesting antagonistic signaling. A beta2-selective proteasome inhibitor may lack such antagonistic signaling effects. METHODS: We recently introduced LU-102, the first beta2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pIkappaB/NF-kappaB signaling and their cytotoxic activity in combination with ibrutinib. RESULTS: LU-102 reduced phosphorylation of IkappaB, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-kappaB activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib. CONCLUSION: Ibrutinib is highly synergistic with beta2-selective proteasome inhibition against MM and MCL in vitro. Novel beta2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies. PMID- 26099968 TI - Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy. AB - PURPOSE: We previously reported that a triplet combination of docetaxel, cisplatin, and S-1 (DCS) is active against metastatic gastric cancer with a very high response rate of 87.1 % in a phase II study. Recently, the efficacy of trastuzumab (T-mab) for the treatment of HER2-positive gastric cancer has been reported. Therefore, we investigated the feasibility and preliminary efficacy of DCS + T-mab (DCS-T) for unresectable HER2-positive metastatic gastric cancer. METHODS: Patients received oral S-1 (40 mg/m(2) b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m(2)), docetaxel (50 mg/m(2)), and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. RESULTS: The study included 16 patients: median age, 60 (34-76) years; males/females, 11:5; intestinal-type/diffuse-type histology, 11:5; and HER2 3+/2+(FISH+), 13:3. The completion rate until the third cycle was 87.5 % (14/16) (95 %CI 71.3-103.7 %). Adverse events of grade 3/4 severity during the first 3 cycles were: leukopenia/neutropenia, 50.0:75.0 %; febrile neutropenia, 12.5 %; diarrhea, 12.5 %; and stomatitis, 12.5 %. All of these side effects were manageable and well controlled. There were no treatment-related deaths. The overall response rate was 93.8 % (15/16), and the response rate in patients with measurable lesions was 100 % (15/15). The median cycle to response was only 1 (1 3 cycles). Non-curative factors disappeared in 56.3 % (9/16) of patients, and conversion surgery (R0 resection) was performed in all these cases. Pathological response rates in primary and metastatic lesions were 88.9 % (8/9) and 100 % (9/9), respectively. The median PFS and OS were not reached during the median follow-up time of 18.3 months ranged from 11.0 to 34.3 months. CONCLUSIONS: DCS-T was feasible in patients with unresectable HER2-positive metastatic gastric cancer. The observed response was very promising and warrants further investigation. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000005603. PMID- 26099969 TI - Phase II study of trastuzumab in combination with S-1 and cisplatin in the first line treatment of human epidermal growth factor receptor HER2-positive advanced gastric cancer. AB - PURPOSE: The use of trastuzumab, a monoclonal antibody targeting the HER2 protein, in combination with 5-fluorouracil/platinum-based chemotherapy improves survival in patients with HER2-positive advanced gastric cancer. In addition, TS one (S-1)/platinum is also used as a standard of care in Asian countries. However, little is known about the combination of S-1/cisplatin chemotherapy and trastuzumab in patients with HER2-positive advanced gastric/gastroesophageal junction (GEJ) cancer. METHODS: We conducted a single-arm, two-stage, open-label, multicenter phase II study. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 mg/kg and 6 mg/kg on day 1 of subsequent cycles. Cisplatin was administered intravenously at 60 mg/m(2) on day 1 of each cycle after trastuzumab. S-1 was administered orally [based on body surface area (BSA)] twice a day for 14 days in a 3-weekly cycle. Patients with BSA of <1.25 received a total of 80 mg of S-1, those with BSA >=1.5 received 120 mg, and the remaining received 100 mg daily in two divided doses. RESULTS: All evaluable patients experienced tumor reduction during the trial. The primary end point (overall survival rate) was 59.3 %, with a clinical benefit rate of 66.7 %. Median progression-free survival was 7.4 months; 62.6 % patients were free from disease progression at 6 months. Median overall survival was 14.6 months, and the median time to treatment failure was 6.0 months. CONCLUSION: The combination of trastuzumab with S-1 and cisplatin demonstrated good activity, was generally well tolerated, and is a feasible treatment option in the first-line treatment of HER2 positive advanced gastric/GEJ cancers. PMID- 26099970 TI - Polyethylenimine coated plasmid DNA-surfactant complexes as potential gene delivery systems. AB - Nanometer scaled particles have been prepared from strong association between plasmid DNA (pcDNA3-FLAG-p53) and oppositely charged surfactants. Although these particles present suitable properties for gene delivery purposes, their cytotoxicity could compromise their use in gene therapy applications. To ensure biocompatibility of this potential gene delivery system, the nanoparticles were coated with polyethylenimine (PEI) with various molar ratios of PEI nitrogen to plasmid DNA phosphate groups. This led to a drastic increase in the cell viability of the particles, and in addition particle characteristics such as size, surface charge and loading efficiency, have also been enhanced as a result of the PEI coating process. The dissolution or swelling/deswelling behaviour displayed by these particulate vehicles could be tailored and monitored in time, to promote the controlled and sustained release of plasmid DNA. Moreover, we show that both the surfactant alkyl chain length and the ratio of nitrogen to phosphate groups are important parameters for controlling the plasmid DNA release. Overall, the developed plasmid DNA carriers have the potential as a new nanoplatform to be further explored for advances in the gene therapy field. PMID- 26099971 TI - The construction of puerarin nanocrystals and its pharmacokinetic and in vivo-in vitro correlation (IVIVC) studies on beagle dog. AB - Puerarin is widely used in clinics in China as a therapeutic agent for cardiovascular diseases by intravenous administration. Adverse drug reactions caused by cosolvents often increase the patients' treatment burden (high drug costs and low compliance). The development of oral formulation is urgently needed and nanocrystal technique has become a preferred way to develop oral dosage form, nowadays. In this study, high pressure homogenization (HPH) was employed to prepare puerarin nanocrystals by employing SDS as the stabilizer, and redispersibility of the nanocrystals powder was also studied. The nanocrystals prepared was characterized using DLS, DSC, XRD and SEM. A preferred in vivo-in vitro correlation was also established in this study. Pharmacokinetic studies on beagle dog showed that comparing to raw puerarin powder, both of the Cmax and AUC of puerarin nanocrystals were enhanced. From the above results, we can conclude that nanocrystal technique is an efficient technology to improve the oral bioavailability of puerarin. PMID- 26099973 TI - The complete mitochondrial genome sequence of Eudocimus ruber (Pelecaniformes:Threskiornithidae). AB - The Eudocimus ruber (Scarlet ibis) belongs to the bird order Pelecaniformes. Here, we sequenced the mitochondrial genome of E. ruber. The complete mitochondrial genome of E. ruber is 16 697 bp in length and contains 22 tRNA genes, 2 rRNA genes, 13 protein-coding genes and a non-coding control region. Consistent with other sequenced birds, most genes are encoded on the heavy strand, except for ND6 and 8 tRNA genes. The overall base composition of the E. ruber is 30.8% A, 30.8% C, 13.8%G and 24.6% T. The molecular-based phylogenetic tree suggested that E. ruber has close affinities with birds from family Threskiornithidae as expected. PMID- 26099974 TI - The mitochondrial genome of Pomacea maculata (Gastropoda: Ampullariidae). AB - The golden apple snail, Pomacea maculata Perry, 1810 (Gastropoda: Ampullariidae) is one of the most serious invasive alien species from the native range of South America. The mitochondrial genome of P. maculata (15 516 bp) consists of 37 genes (13 protein-coding genes, two rRNAs, and 22 tRNAs) and a non-coding region with a 16 bp repeat unit. Most mitochondrial genes of P. maculata are distributed on the H-strand, except eight tRNA genes, which are encoded on the L-strand. A phylogenetic analysis showed that there was a close relationship between P. maculata and another invasive golden apple snail species, Pomacea canaliculata (Lamarck, 1822). PMID- 26099972 TI - Th17 and Th17/Treg ratio at early HIV infection associate with protective HIV specific CD8(+) T-cell responses and disease progression. AB - The aim of this study was to analyze Th17 and Treg subsets and their correlation with anti-HIV T-cell responses and clinical parameters during (acute/early) primary HIV infection (PHI) and up to one year post-infection (p.i). Samples from 14 healthy donors (HDs), 40 PHI patients, 17 Chronics, and 13 Elite controllers (ECs) were studied. The percentages of Th17 and Treg subsets were severely altered in Chronics, whereas all HIV-infected individuals (including ECs) showed Th17/Treg imbalance compared to HDs, in concordance with higher frequencies of activated CD8(+) T-cells (HLA-DR(+)/CD38(+)). Better clinical status (higher CD4 counts, lower viral loads and activation) was associated with higher Th17 and lower Treg levels. We found positive correlations between Th17 at baseline and anti-HIV CD8(+) T-cell functionality: viral inhibitory activity (VIA) and key polyfunctions (IFN-gamma(+)/CD107A/B(+)) at both early and later times p.i, highlighting the prognostic value of Th17 cells to preserve an effective HIV T cell immunity. Th17/Treg ratio and the IL-17 relative mean fluorescence intensity (rMFI of IL-17) were also positively correlated with VIA. Taken together, our results suggested a potential link between Th17 and Th17/Treg ratio with key HIV specific CD8(+) T-cell responses against the infection. PMID- 26099975 TI - Mitochondrial DNAs decreased and correlated with clinical features in HCV patients from Yunnan, China. AB - Hepatitis C was the most popular chronic infectious liver disease worldwide. It was identified that Hepatitis C virus (HCV) infection could lead to mitochondrial dysfunction, though the mechanism was not fully understood. To investigate whether mtDNA copy number could be affected by HCV infection and be associated with clinical features of HCV patients, mtDNA copy numbers were analyzed in 242 patients with HCV infection and 226 matched control samples. The results suggested that mtDNA copy numbers significantly decreased in HCV patients (68.80 +/- 3.33) than in control samples (81.54 +/- 4.50) (p = 0.022). When males/females were separated from total patients to compare mtDNA copy numbers with gender matched controls, mtDNA copy numbers still significantly decreased in male HCV patients (p = 0.002). Further analysis indicated that level of high density lipoprotein cholesterol (HDL-C) was negatively correlated with mtDNA copy numbers in total HCV patients (r = -0.128, p = 0.047), and this correlation was more significant in male HCV patients (r = -0.266, p = 0.030). Intriguingly, aspartate amino-transferase (AST) showed positive correlation with mtDNA copy numbers (r = 0.260, p = 0.034) in male HCV patients. Our results indicated that mtDNA copy numbers depleted and correlated with clinical features in male HCV patients. PMID- 26099976 TI - Characteristic of complete mitochondrial genome and phylogenetic relationship of Garrulax sannio (Passeriformes, Timaliidae). AB - Garrulax sannio (Passeriformes, Timaliidae) was the medium-sized bird, whose plumage color was similar for both sexes. The complete sequence of the mitochondrial DNA genome from G. sannio used the polymerase chain reaction method. The genome (17 840 bp in length) contained 13 protein-coding genes, 2 rRNA (12S and 16S) genes, 22 tRNA genes and 2 control regions (D-loop). The base composition of G. sannio mitogenome A + T percentage was 52.22%. It is slightly higher than G + C 47.78% which was similar with other vertebrates. Through constructed phylogenetic tree, we could identify its taxonomic status. Therefore, mitochondrial genome was a best way to preserve genetic resources of species. PMID- 26099977 TI - Complete mitochondrial genome of the brown alga Sargassum vachellianum (Sargassaceae, Phaeophyceae). AB - Sargassum vachellianum C. Agardh is endemic to China. It inhabits in rocky intertidal zones and plays an important role in maintaining the structure and function of littoral ecosystems. In this study, we present the complete mitochondrial genome of S. vachellianum. The circular S. vachellianum mitogenome is 34,877 bp in size and contains the same set of 65 genes as the reported Sargassum mtDNAs. The overall AT content of the genome is 63.79%, and the inter genic spacers constitute only 4.67%. The genome organization including the gene order, overlapping regions between genes, and the total length of inter-genic spacers is conserved among the known Sargassum mitogenomes. High divergence is in inter-genic spacer regions. Phylogenetic analyses indicated that S. vachellianum combined tightly with Sargassum species with strong support values (NJ/ML, 100%). PMID- 26099978 TI - The complete mitochondrial genome sequence of Eimeria innocua (Eimeriidae, Coccidia, Apicomplexa). AB - The complete mitochondrial genome of Eimeria innocua KR strain (Eimeriidae, Coccidia, Apicomplexa) was sequenced. This coccidium infects turkeys (Meleagris gallopavo), Bobwhite quails (Colinus virginianus), and Grey partridges (Perdix perdix). Genome organization and gene contents were comparable with other Eimeria spp. infecting galliform birds. The circular-mapping mt genome of E. innocua is 6247 bp in length with three protein-coding genes (cox1, cox3, and cytb), 19 gene fragments encoding large subunit (LSU) rRNA and 14 gene fragments encoding small subunit (SSU) rRNA. Like other Apicomplexa, no tRNA was encoded. The mitochondrial genome of E. innocua confirms its close phylogenetic affinities to Eimeria dispersa. PMID- 26099979 TI - The complete mitochondrial DNA genome of Aedes vigilax (Diptera: Culicidae). AB - The complete mitochondrial genomes of two main clades of the medically significant saltmarsh mosquito Aedes vigilax Skuse (Diptera: Culicidae) were obtained using combined Illumina and Sanger sequencing. The two 15,877 bp circular genomes share 99.0% nucleotide identity and encode 37 genes with identical gene arrangement similar to previously published Culicidae species with a non-coding A + T rich region between rns and tRNA-Ile. Protein initiation codon is ATN apart from ND5 (GTG) and COX1 (TCG). Eight protein-coding genes encode full TAA stop codon, while five are completed by mRNA polyadenylation. Typical cloverleaf structures containing DHU and TPsiC stem and loops can be inferred for all 22 tRNAs. PMID- 26099982 TI - Melanoma: CheckMate 067--frontline nivolumab improves PFS alone or in combination with ipilimumab. PMID- 26099984 TI - Advances in targeted therapies for hepatocellular carcinoma in the genomic era. PMID- 26099985 TI - Immunotherapy: Combined immunotherapy--a new standard in metastatic melanoma? PMID- 26099988 TI - Processes forming Gas, Tar, and Coke in Cellulose Gasification from Gas-Phase Reactions of Levoglucosan as Intermediate. AB - The gas-phase pyrolysis of levoglucosan (LG), the major intermediate species during cellulose gasification, was studied experimentally over the temperature range of 400-900 degrees C. Gaseous LG did not produce any dehydration products, which include coke, furans, and aromatic substances, although these are characteristic products of the pyrolysis of molten LG. Alternatively, at >500 degrees C, gaseous LG produced only fragmentation products, such as noncondensable gases and condensable C1 -C3 fragments, as intermediates during noncondensable gas formation. Therefore, it was determined that secondary reactions of gaseous LG can result in the clean (tar- and coke-free) gasification of cellulose. Cooling of the remaining LG in the gas phase caused coke formation by the transition of the LG to the molten state. The molecular mechanisms that govern the gas- and molten-phase reactions of LG are discussed in terms of the acid catalyst effect of intermolecular hydrogen bonding to promote the molten phase dehydration reactions. PMID- 26099990 TI - Molecular orientation of organic thin films on dielectric solid substrates: a phase-sensitive vibrational SFG study. AB - Broadband phase-sensitive vibrational sum frequency generation (SFG) spectroscopy was utilized to study the molecular orientation of molecules adsorbed on dielectric solid substrates. A gold thin film was employed to generate a SFG signal as a local oscillator (LO). To simplify the phase measurement, a self assembled monolayer (SAM) of octadecyltrichlorosilane (OTS) was used as a standard sample for phase correction of the phase-sensitive SFG measurements on the solid/air interface. It was demonstrated that the absolute orientation of molecules in the LB films on a fused quartz surface can be clearly distinguished by phase-sensitive SFG measurement. In addition, the observation on the SAM of d35-OTS reveals that the two C-H stretching modes for alpha-CH2 group are in opposite phase. Furthermore, by using the present phase-sensitive SFG setup, the orientation flipping of water molecules on positively and negatively charged solid/liquid interface can be distinguished. PMID- 26099989 TI - Distinct effects of mycophenolate mofetil and cyclophosphamide on renal fibrosis in NZBWF1/J mice. AB - Progression to chronic renal failure varies between patients with lupus nephritis. We compared the effects of mycophenolate mofetil (MMF) and cyclophosphamide (CTX), on renal histology and cellular pathways of fibrosis in murine lupus nephritis. Female NZBWF1/J mice were randomized to treatment with vehicle, methylprednisolone (MP) alone, MMF + MP or CTX + MP for up to 12 weeks, and the effects on clinical parameters, renal histology, and fibrotic processes were investigated. Treatment with MMF + MP or CTX + MP both improved survival, renal function, and decreased anti-dsDNA antibody level and immune complex deposition in kidneys of mice with active nephritis. Vehicle-treated mice showed progressive increase in mesangial proliferation, inflammatory cell infiltration and renal tubular atrophy, associated with PKC-alpha activation, increased TGF beta1 expression and increased matrix protein deposition. MP treatment alone did not have any significant effect. MMF + MP or CTX + MP treatment for 12 weeks reduced these abnormalities. MMF + MP was more effective than CTX + MP in suppressing fibrotic mediators, histological fibrosis score and expression of TGF beta1, fibronectin and collagen I in the kidney. Results from in vitro experiments on human mesangial cells (HMC) showed that mycophenolic acid (MPA) was more effective than CTX in suppressing PKC-alpha activation and TGF-beta1 secretion induced by human polyclonal anti-dsDNA antibodies. While both MPA and CTX decreased TGF-beta1- and TNF-alpha-induced fibronectin synthesis, only MPA decreased IL-6 induced fibronectin synthesis. MPA and CTX show distinct effects on fibrotic and inflammatory processes in NZBWF1/J murine lupus nephritis, suggesting that MMF + MP may be more effective than CTX + MP in preserving normal renal histology in lupus nephritis. PMID- 26099991 TI - The acceptance of the K-SADS-PL - potential predictors for the overall satisfaction of parents and interviewers. AB - The presented study investigated the interviewee (parents) and interviewer acceptance of the semi-structured diagnostic interview Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children Present Lifetime version (KSADS-PL; German version). Seventeen certified interviewers conducted 231 interviews (interviewers conducted several interviews; interviewees were only questioned once). Interviewees and interviewers anonymously rated their acceptance right after the interview was finished. The nested data structure was analysed regarding an individual interviewer bias and potential predictors of overall satisfaction. Therefore, factors improvable by interviewer training were included, as well as fixed factors which cannot be improved by professional training. The overall satisfaction was evaluated as highly positive with significant higher interviewee and interviewer ratings in the research as compared to the clinical recruitment setting. An individual bias of the interviewer on his or her own acceptance over time, but not on the evaluation of the corresponding interviewee was found. Neither the professional background nor the gender of the interviewer had a significant contribution in predicting these differences. The interviewer model showed no significant change over time and only the interview duration and the interviewee acceptance were significant predictors for interviewer overall satisfaction. Regarding the interviewee model, just the interviewer acceptance was a significant predictor. Copyright Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26099992 TI - Thyroid hormones alter the transcriptome of in vitro-produced bovine blastocysts. AB - Thyroid hormones (THs) have been shown to improve in vitro embryo production in cattle by increasing blastocyst formation rate, and the average cell number of blastocysts and by significantly decreasing apoptosis rate. To better understand those genetic aspects that may underlie enhanced early embryo development in the presence of THs, we characterized the bovine embryonic transcriptome at the blastocyst stage, and examined differential gene expression profiles using a bovine-specific microarray. We found that 1212 genes were differentially expressed in TH-treated embryos when compared with non-treated controls (>1.5 fold at P < 0.05). In addition 23 and eight genes were expressed uniquely in control and treated embryos, respectively. The expression of genes specifically associated with metabolism, mitochondrial function, cell differentiation and development were elevated. However, TH-related genes, including those encoding TH receptors and deiodinases, were not differentially expressed in treated embryos. Furthermore, the over-expression of 52 X-chromosome linked genes in treated embryos suggested a delay or escape from X-inactivation. This study highlights the significant impact of THs on differential gene expression in the early embryo; the identification of TH-responsive genes provides an insight into those regulatory pathways activated during development. PMID- 26099993 TI - 3,5-Diarylpyrazole Derivatives Obtained by Ammonolysis of the Total Flavonoids from Chrysanthemum indicum Extract Show Potential for the Treatment of Alzheimer's Disease. AB - Four new 3,5-diarylpyrazole analogues (1-4) were isolated from an extract of the flowers of Chrysanthemun indicum using a combination of ammonolysis of the total flavonoid extract and an Abeta aggregation inhibitory activity guided purification procedure. All four compounds (1-4) showed moderate to potent activity against Abeta aggregation with EC50 values of 4.3, 15.8, 1.3, and 2.9 MUM, respectively. Moreover, compound 3 showed low cytotoxicity and significant neuroprotective activity against Abeta-induced cytotoxicity in the SH-SY5Y cell line. This report is the first to show that 3,5-diarylpyrazole analogues can inhibit Abeta aggregation and exhibit neuroprotective activity with potential for the treatment of Alzheimer's disease. Taken together, the method presented here offers an alternative approach to yield bioactive compounds. PMID- 26099994 TI - Detection of sentence boundaries and abbreviations in clinical narratives. AB - BACKGROUND: In Western languages the period character is highly ambiguous, due to its double role as sentence delimiter and abbreviation marker. This is particularly relevant in clinical free-texts characterized by numerous anomalies in spelling, punctuation, vocabulary and with a high frequency of short forms. METHODS: The problem is addressed by two binary classifiers for abbreviation and sentence detection. A support vector machine exploiting a linear kernel is trained on different combinations of feature sets for each classification task. Feature relevance ranking is applied to investigate which features are important for the particular task. The methods are applied to German language texts from a medical record system, authored by specialized physicians. RESULTS: Two collections of 3,024 text snippets were annotated regarding the role of period characters for training and testing. Cohen's kappa resulted in 0.98. For abbreviation and sentence boundary detection we can report an unweighted micro averaged F-measure using a 10-fold cross validation of 0.97 for the training set. For test set based evaluation we obtained an unweighted micro-averaged F-measure of 0.95 for abbreviation detection and 0.94 for sentence delineation. Language dependent resources and rules were found to have less impact on abbreviation detection than on sentence delineation. CONCLUSIONS: Sentence detection is an important task, which should be performed at the beginning of a text processing pipeline. For the text genre under scrutiny we showed that support vector machines exploiting a linear kernel produce state of the art results for sentence boundary detection. The results are comparable with other sentence boundary detection methods applied to English clinical texts. We identified abbreviation detection as a supportive task for sentence delineation. PMID- 26099995 TI - Bayesian response adaptive randomization using longitudinal outcomes. AB - The response adaptive randomization (RAR) method is used to increase the number of patients assigned to more efficacious treatment arms in clinical trials. In many trials evaluating longitudinal patient outcomes, RAR methods based only on the final measurement may not benefit significantly from RAR because of its delayed initiation. We propose a Bayesian RAR method to improve RAR performance by accounting for longitudinal patient outcomes (longitudinal RAR). We use a Bayesian linear mixed effects model to analyze longitudinal continuous patient outcomes for calculating a patient allocation probability. In addition, we aim to mitigate the loss of statistical power because of large patient allocation imbalances by embedding adjusters into the patient allocation probability calculation. Using extensive simulation we compared the operating characteristics of our proposed longitudinal RAR method with those of the RAR method based only on the final measurement and with an equal randomization method. Simulation results showed that our proposed longitudinal RAR method assigned more patients to the presumably superior treatment arm compared with the other two methods. In addition, the embedded adjuster effectively worked to prevent extreme patient allocation imbalances. However, our proposed method may not function adequately when the treatment effect difference is moderate or less, and still needs to be modified to deal with unexpectedly large departures from the presumed longitudinal data model. PMID- 26099996 TI - Clinical validity of a DPYD-based pharmacogenetic test to predict severe toxicity to fluoropyrimidines. AB - Pre-therapeutic DPYD pharmacogenetic test to prevent fluoropyrimidines (FL) related toxicities is not yet common practice in medical oncology. We aimed at investigating the clinical validity of DPYD genetic analysis in a large series of oncological patients. Six hundred three cancer patients, treated with FL, have been retrospectively tested for eight DPYD polymorphisms (DPYD-rs3918290, DPYD rs55886062, DPYD-rs67376798, DPYD-rs2297595, DPYD-rs1801160, DPYD-rs1801158, DPYD rs1801159, DPYD-rs17376848) for association with Grade >=3 toxicity, developed within the first three cycles of therapy. DPYD-rs3918290 and DPYD-rs67376798 were associated to Grade >=3 toxicity after bootstrap validation and Bonferroni correction (p = 0.003, p = 0.048). DPYD-rs55886062 was not significant likely due to its low allelic frequency, nonetheless one out of two heterozygous patients (compound heterozygous with DPYD-rs3918290) died from toxicity after one cycle. Test specificity for the analysis of DPYD-rs3918290, DPYD-rs55886062 and DPYD rs67376798 was assessed to 99%. Among the seven patients carrying one variant DPYD-rs3918290, DPYD-rs55886062 or DPYD-rs67376798 allele, not developing Grade >=3 toxicity, 57% needed a FL dose or schedule modification for moderate chronic toxicity. No other DPYD polymorphism was associated with Grade >=3 toxicity. Our data demonstrate the clinical validity and specificity of the DPYD-rs3918290, DPYD-rs55886062, DPYD-rs67376798 genotyping test to prevent FL-related Grade >=3 toxicity and to preserve treatment compliance, and support its introduction in the clinical practice. PMID- 26099997 TI - Effects of salinomycin and CGP37157 on head and neck squamous cell carcinoma cell lines in vitro. AB - Surgery, radiation, chemotherapy or a combinations of these are all accepted modalities for the treatment of head and neck squamous cell carcinoma (HNSCC). Despite this, 40-60% of patients suffering from HNSCC develop loco-regional failure and/or distant metastases. Salinomycin has been demonstrated to be >100 fold more effective than paclitaxel at causing cancer stem cell death, therefore, it may offer an important improvement in cancer therapy. However, the toxicity of salinomycin is of concern. A possible solution may be the administration of additive drugs, which reduce the toxicity. By inhibiting the mitochondrial Na+/Ca2+ exchanger using the benzodiazepine derivate, CGP37157 (CGP), a significant reduction in salinomycin neuronal toxicity has been observed. This raises the question of whether CGP also inhibits the tumor toxicity of salinomycin. In the present study, the FaDu and HLaC79 C1 HNSCC cell lines were treated with salinomycin with or without CGP. Comparative viability assessments were performed using microscopy, a fluorescein diacetate assay, an MTT assay, a clonogenic assay and annexin V-propidium iodide staining. The expression levels of MDR-1 were monitored using reverse transcription-quantitative polymerase chain reaction. Salinomycin alone, and in combination with CGP, achieved a significant attenuation of cell viability and increased apoptosis in a dose-dependent manner. However, the tumor toxicity of salinomycin was not inhibited by CGP. The HLaC79 C1 cells were more sensitive to salinomycin, compared with the FaDu cells, with this sensitivity being due to high expression levels of MDR-1 by the HLaC79 C1 cells. In conclusion, CGP did not counteract the tumor toxicity of salinomycin in vitro and may be a promising drug in future anticancer therapy. The results of the present study encourages further investigation of the toxicological aspects of salinomycin, particularly in human cells and animal models. PMID- 26099998 TI - Psychotic disorder and educational achievement: a family-based analysis. AB - BACKGROUND: Early social and cognitive alterations in psychotic disorder, associated with familial liability and environmental exposures, may contribute to lower than expected educational achievement. The aims of the present study were to investigate (1) how differences in educational level between parents and their children vary across patients, their healthy siblings, and healthy controls (effect familial liability), and across two environmental risk factors for psychotic disorder: childhood trauma and childhood urban exposure (effect environment) and (2) to what degree the association between familial liability and educational differential was moderated by the environmental exposures. METHODS: Patients with a diagnosis of non-affective psychotic disorder (n = 629), 552 non-psychotic siblings and 326 healthy controls from the Netherlands and Belgium were studied. Participants reported their highest level of education and that of their parents. Childhood trauma was assessed with the Dutch version of the Childhood Trauma Questionnaire-Short Form. Urban exposure, expressed as population density, was rated across five levels. RESULTS: Overall, participants had a higher level of education than their parents. This difference was significantly reduced in the patient group, and the healthy siblings displayed intergenerational differences that were in between those of controls and patients. Higher levels of childhood urban exposure were also associated with a smaller intergenerational educational differential. There was no evidence for differential sensitivity to childhood trauma and childhood urbanicity across the three groups. CONCLUSION: Intergenerational difference in educational achievements is decreased in patients with psychotic disorder and to a lesser extent in siblings of patients with psychotic disorder, and across higher levels of childhood urban exposure. More research is required to better understand the dynamics between early social and cognitive alterations in those at risk in relation to progress through the educational system and to understand the interaction between urban environment and educational outcomes. PMID- 26099999 TI - The inhibitory effect of zoledronate on early-stage osteoinduction by recombinant human bone morphogenetic protein 2 in an osteoporosis model. AB - This study evaluated the effect of the combined treatment of intravenous zoledronic acid (ZA, 0.08 mg/kg) and rhBMP-2 (5 ug) on osteogenesis in a calvarial defect model of ovariectomized SD rats. New bone formation was evaluated 4 or 8 weeks after calvarial defect implantation using micro-CT and histology. Micro-CT results revealed that the rhBMP-2 group showed significantly higher calvarial defect coverage ratio compared with the ZA + rhBMP-2 group at 4 weeks. In addition, bone formation indices were significantly lower in ZA + rhBMP 2 group when compared with the rhBMP-2 group after 4 weeks, which indicates a negative effect of ZA on the initial bone formation and the bone quality. At 8 weeks, the negative effect induced by ZA treatment was alleviated as time passed. Histological examination showed similar results to the micro-CT measurements. In conclusion, although ZA treatment lowered the new bone formation induced by rhBMP 2 initially, as time passed, the negative effect was decreased. PMID- 26100000 TI - Chemical signals in terrestrial vertebrates: search for design features. AB - We compiled a data set of the compounds that terrestrial vertebrates (amniotes) use to send chemical signals, and searched for relationships between signal compound properties and signal function. Overall, relationships were scarce and formed only small-scale patterns. Terrestrial vertebrate signalling compounds are invariably components of complex mixtures of compounds with diverse molecular weights and functionalities. Signal compounds with high molecular weights (MWs) and low vapour pressures, or that are bound to carrier proteins, are detected during direct contact with the source of the signal. Stable compounds with aromatic rings in their structures are more common in signals of social dominance, including territoriality. Aldehydes are emitted from the sender's body rather than from scent marks. Lipocalin pheromones and carriers have a limited range of MWs, possibly to reduce the metabolic costs of their biosynthesis. Design constraints that might channel signal chemistry into patterns have been relaxed by amniote behavior and biochemistry. Amniote olfaction has such a high sensitivity, wide range and narrow resolution that signal detection imposes no practical constraints on the structures of signalling molecules. Diverse metabolic pathways in amniotes and their microbial commensals produce a wide variety of compounds as chemical signals and as matrix compounds that free signal components from the constraints of stability, vapor pressure, species-specificity etc. that would otherwise constrain what types of compound operate optimally under different conditions. PMID- 26100001 TI - Insulin. PMID- 26100002 TI - KTP and Er:YAG laser dental bleaching comparison: a spectrophotometric, thermal and morphologic analysis. AB - The aim of this study was to compare the results, in terms of temperature, colour change and morphology, of two different laser wavelengths with two different concentrations of hydrogen peroxide (HP). The lasers used were KTP (potassium titanyl-phosphate) laser (lambda = 532 nm (PD = 1.98 W/cm2)) and Er:YAG laser (lambda = 2940 nm (PD = 2.54 W/cm2)). The bleaching gels used were PolaOffice 35% HP gel and PolaOffice+ 6% HP gel (SDI, Australia). Thirty-six extracted human teeth were selected and divided into two groups. For the 35% HP treatment, 18 teeth were randomly assigned to three subgroups: (1) HP gel without laser irradiation vs. HP gel + KTP laser irradiation; (2) HP gel without laser irradiation vs. HP gel + Er:YAG irradiation; and (3) HP gel + KTP laser irradiation vs. HP gel + Er:YAG irradiation. The same protocol was used for the 6% HP bleaching treatment. The bleaching results were analysed by a spectrophotometer, the thermal elevation by K thermocouples and the enamel surface by a scanning electron microscope (SEM). The Kruskal-Wallis test and the Mann-Whitney test were performed, and the data were analysed using the software StatView and the free Web statistics tool BiostaTGV. The thermal elevation of the Er:YAG groups was higher than KTP, while only the group 35% HP gel vs. 35% HP gel + Er:YAG showed significant colour differences (p < 0.05). SEM photographs showed slight enamel surface morphologic alterations after bleaching treatment. The Er:YAG laser may improve the bleaching results of 35% HP even if it increases the gel temperature, when compared to the KTP laser. PMID- 26100003 TI - Assessing the biochemical changes of tendons of rats in an experimental model of tenotomy under therapeutic ultrasound and LEDs (625 and 945 nm) by near-infrared Raman spectroscopy. AB - Given the complexity of the tendon repair process, where the neoformed scar tissue tends to prevent or hamper the tendon from performing its normal functions, ultrasound (US) and light-emitting diode (LED) devices have been applied to modulate the tendon repair process. This study aimed to compare the anti-inflammatory and healing effects of therapeutic US and LED in an experimental model of tenotomy using histomorphometry and Raman spectroscopy. Forty Wistar rats (235 +/- 8.3 g) were separated into four groups: tenotomy (TC; control), tenotomy associated with ultrasound (US; 1 MHz, 0.5 W/cm(2)), tenotomy associated with LED at 625 nm (LR; 4 J/cm(2)), and tenotomy associated with LED at 945 nm (LIR; 4 J/cm(2)), in two experimental periods of 7 and 14 days. Histomorphometry showed a decrease of inflammatory cells (macrophages and polymorphonuclear leukocytes) for the group treated with US compared to the TC group (ANOVA, p < 0.0001) and the LIR group compared to the TC group (p < 0.05) at the seventh day, indicating an anti-inflammatory effect. In relation to the LR and TC groups, there was no significant difference. Raman spectroscopy revealed that the LR group presented an increased synthesis of collagen I compared to the other treatments and the TC groups on the 14th day (p < 0.01). US therapy showed an adjuvant effect with anti-inflammatory action, and the LED therapy at 625 nm showed an increase in collagen synthesis, contributing to the process of tendon healing. PMID- 26100004 TI - The efficacy of cryolipolysis treatment on arms and inner thighs. AB - Cryolipolysis has emerged as a new non-invasive body contouring method using controlled cooling to selectively destroy fat cells. Previous studies demonstrated the safety and efficacy of cryolipolysis for the reduction of localized subcutaneous fat on abdomen and flanks. Recently, the new flat cup vacuum applicator has been developed to treat localized subcutaneous fat on arms and inner thighs. The objective of this study was to determine the efficacy of non-invasive cryolipolysis for body contouring with a flat cup vacuum applicator on arms and inner thighs. Twenty females with excess localized subcutaneous fat on arms or inner thighs received a single cryolipolysis treatment. Forty treatment areas have been treated including 10 arms and 30 inner thighs. Subjects were evaluated using standardized photographs and measurements of body weight and circumference of arms or inner thighs at baseline, 3-month, and 6-month follow-up visits. Physicians' evaluation and patient's satisfaction of clinical improvement were also measured. Of all 20 subjects, 17 (10 arms and 24 inner thighs) completed the treatment protocol and attended all follow-up visits. Three subjects were withdrawn from the study, 1 subject could not complete the treatment session due to pain and numbness during treatment, 1 subject became pregnant after treatment, and the other subject could not attend all required follow-up visits. There was significant circumference reduction of 0.41 and 0.72 cm at 3-month and 6-month follow-up visits (p = 0.017), respectively. Most of the patients were rated to have 1-25% improvement at 6 months after treatment and were satisfied with the treatment outcome. The new cryolipolysis flat cup vacuum applicator provided beneficial effects for circumferential reduction of arms and inner thighs. PMID- 26100005 TI - Does Cox analysis of a randomized survival study yield a causal treatment effect? AB - Statistical methods for survival analysis play a central role in the assessment of treatment effects in randomized clinical trials in cardiovascular disease, cancer, and many other fields. The most common approach to analysis involves fitting a Cox regression model including a treatment indicator, and basing inference on the large sample properties of the regression coefficient estimator. Despite the fact that treatment assignment is randomized, the hazard ratio is not a quantity which admits a causal interpretation in the case of unmodelled heterogeneity. This problem arises because the risk sets beyond the first event time are comprised of the subset of individuals who have not previously failed. The balance in the distribution of potential confounders between treatment arms is lost by this implicit conditioning, whether or not censoring is present. Thus while the Cox model may be used as a basis for valid tests of the null hypotheses of no treatment effect if robust variance estimates are used, modeling frameworks more compatible with causal reasoning may be preferrable in general for estimation. PMID- 26100006 TI - Preface for the JIB Special Issue for the 12th European Biological Inorganic Chemistry Conference (EuroBIC 12) in Zurich, Switzerland, August 24-28, 2014. PMID- 26100007 TI - Evaluation of Kampo medicine in the clinical practice guideline for irritable bowel syndrome. PMID- 26100008 TI - Knowledge, attitudes, and beliefs of healthcare workers regarding stem cell research. PMID- 26100009 TI - Regulation of heme biosynthesis and transport in metazoa. AB - Heme is an iron-containing tetrapyrrole that plays a critical role in regulating a variety of biological processes including oxygen and electron transport, gas sensing, signal transduction, biological clock, and microRNA processing. Most metazoan cells synthesize heme via a conserved pathway comprised of eight enzyme catalyzed reactions. Heme can also be acquired from food or extracellular environment. Cellular heme homeostasis is maintained through the coordinated regulation of synthesis, transport, and degradation. This review presents the current knowledge of the synthesis and transport of heme in metazoans and highlights recent advances in the regulation of these pathways. PMID- 26100010 TI - Computational analysis of antigenic epitopes of avian influenza A (H7N9) viruses. AB - Influenza virus can rapidly change its antigenicity, via mutation in the hemagglutinin (HA) protein, to evade host immunity. The emergence of the novel human-infecting avian H7N9 virus in China has caused widespread concern. However, evolution of the antigenicity of this virus is not well understood. Here, we inferred the antigenic epitopes of the HA protein from all H7 viruses, based on the five well-characterized HA epitopes of the human H3N2 virus. By comparing the two major H7 phylogenetic lineages, i.e., the Eurasian lineage and the North American lineage, we found that epitopes A and B are more frequently mutated in the Eurasian lineage, while epitopes B and C are more frequently mutated in the North American lineage. Furthermore, we found that the novel H7N9 virus (derived from the Eurasian lineage) isolated in China in the year 2013, contains six frequently mutated sites on epitopes that include site 135, which is located in the receptor binding domain. This indicates that the novel H7N9 virus that infects human may already have been subjected to gradual immune pressure and receptor-binding variation. Our results not only provide insights into the antigenic evolution of the H7 virus but may also help in the selection of suitable vaccine strains. PMID- 26100011 TI - Identification of a novel HIV-1 intra-circulating recombinant form 01_AE in China: a descendant of the previously identified CRF01_AE transmission clusters 1 and 6. PMID- 26100012 TI - Are Physiologically Based Pharmacokinetic Models Reporting the Right C(max)? Central Venous Versus Peripheral Sampling Site. AB - Physiologically based pharmacokinetic (PBPK) models can over-predict maximum plasma concentrations (C(max)) following intravenous administration. A proposed explanation is that invariably PBPK models report the concentration in the central venous compartment, rather than the site where the samples are drawn. The purpose of this study was to identify and validate potential corrective models based on anatomy and physiology governing the blood supply at the site of sampling and incorporate them into a PBPK platform. Four models were developed and scrutinised for their corrective potential. All assumed the peripheral sampling site concentration could be described by contributions from surrounding tissues and utilised tissue-specific concentration-time profiles reported from the full-PBPK model within the Simcyp Simulator. Predicted concentrations for the peripheral site were compared to the observed C(max). The models results were compared to clinical data for 15 studies over seven compounds (alprazolam, imipramine, metoprolol, midazolam, omeprazole, rosiglitazone and theophylline). The final model utilised tissue concentrations from adipose, skin, muscle and a contribution from artery. Predicted C(max) values considering the central venous compartment can over-predict the observed values up to 10-fold whereas the new sampling site predictions were within 2-fold of observed values. The model was particularly relevant for studies where traditional PBPK models over-predict early time point concentrations. A successful corrective model for C(max) prediction has been developed, subject to further validation. These models can be enrolled as built-up modules into PBPK platforms and potentially account for factors that may affect the initial mixing of the blood at the site of sampling. PMID- 26100013 TI - Exploring Psychological Distress in Burundi During and After the Armed Conflict. AB - We assessed symptoms of psychological distress among a population-based sample of 9000-plus adults in Burundi during (1998) and after (2007) armed conflict. After exploratory and confirmatory factor analysis to an 8-item, self-report measure, we identified two domains of psychological distress "Depression/Anxiety" and "Functioning" with good fit to data. The questionnaire was invariant in males and females. Depression and Anxiety symptoms during conflict were more frequently reported than Functioning symptoms; all symptoms were more frequently reported by women. Psychological distress was found in 44 % of individuals during conflict and in 29 % 2 years after the conflict. Results call for further research in Burundi that can inform the development of mental health interventions. PMID- 26100014 TI - Eaf1p Is Required for Recruitment of NuA4 in Targeting TFIID to the Promoters of the Ribosomal Protein Genes for Transcriptional Initiation In Vivo. AB - NuA4 (nucleosome acetyltransferase of H4) promotes transcriptional initiation of TFIID (a complex of TBP and TBP-associated factors [TAFs])-dependent ribosomal protein genes involved in ribosome biogenesis. However, it is not clearly understood how NuA4 regulates the transcription of ribosomal protein genes. Here, we show that NuA4 is recruited to the promoters of ribosomal protein genes, such as RPS5, RPL2B, and RPS11B, for TFIID recruitment to initiate transcription, and the recruitment of NuA4 to these promoters is impaired in the absence of its Eaf1p component. Intriguingly, impaired NuA4 recruitment in a Deltaeaf1 strain depletes recruitment of TFIID (a TAF-dependent form of TBP) but not the TAF independent form of TBP to the promoters of ribosomal protein genes. However, in the absence of NuA4, SAGA (Spt-Ada-Gcn5-acetyltransferase) is involved in targeting the TAF-independent form of TBP to the promoters of ribosomal protein genes for transcriptional initiation. Thus, NuA4 plays an important role in targeting TFIID to the promoters of ribosomal protein genes for transcriptional initiation in vivo. Such a function is mediated via its targeted histone acetyltransferase activity. In the absence of NuA4, ribosomal protein genes lose TFIID dependency and become SAGA dependent for transcriptional initiation. Collectively, these results provide significant insights into the regulation of ribosomal protein gene expression and, hence, ribosome biogenesis and functions. PMID- 26100015 TI - Type 1 Insulin-Like Growth Factor Receptor/Insulin Receptor Substrate 1 Signaling Confers Pathogenic Activity on Breast Tumor Cells Lacking REST. AB - Loss of repressor element 1 silencing transcription factor (REST) occurs in 20% of breast cancers and correlates with a poor patient prognosis. However, the molecular basis for enhanced malignancy in tumors lacking REST (RESTless) is only partially understood. We used multiplatform array data from the Cancer Genome Atlas to identify consistent changes in key signaling pathways. Of the proteins screened in the reverse-phase protein array, we found that insulin receptor substrate 1 (IRS1) is the most highly upregulated protein in RESTless breast tumors. Analysis of breast tumor cell lines showed that REST directly represses IRS1, and cells lacking REST have increased levels of IRS1 mRNA and protein. We find that the upregulation of IRS1 function is both necessary and sufficient for enhanced signaling and growth in breast cancer cells lacking REST. IRS1 overexpression is sufficient to phenocopy the enhanced activation of the signaling hubs AKT and mitogen-activated protein kinase (MAPK) of MCF7 cells lacking REST. Loss of REST renders MCF7 and MDA-MB-231 breast tumor cells dependent on IRS1 activity for colony formation in soft agar. Inhibition of the type 1 insulin-like growth factor receptor (IGF1R) reduces the enhanced signaling, growth, and migration in breast tumor cells that occur upon REST loss. We show that loss of REST induces a pathogenic program that works through the IGF1R/IRS1 pathway. PMID- 26100016 TI - p300 Regulates Liver Functions by Controlling p53 and C/EBP Family Proteins through Multiple Signaling Pathways. AB - The histone acetyltransferase p300 has been implicated in the regulation of liver biology; however, molecular mechanisms of this regulation are not known. In this paper, we examined these mechanisms using transgenic mice expressing a dominant negative p300 molecule (dnp300). While dnp300 mice did not show abnormal growth within 1 year, these mice have many alterations in liver biology and liver functions. We found that the inhibition of p300 leads to the accumulation of heterochromatin foci in the liver of 2-month-old mice. Transcriptome sequencing (RNA-Seq) analysis showed that this inhibition of p300 also causes alterations of gene expression in many signaling pathways, including chromatin remodeling, apoptosis, DNA damage, translation, and activation of the cell cycle. Livers of dnp300 mice have a high rate of proliferation and a much higher rate of proliferation after partial hepatectomy. We found that livers of dnp300 mice are resistant to CCl4-mediated injury and have reduced apoptosis but have increased proliferation after injury. Underlying mechanisms of resistance to liver injury and increased proliferation in dnp300 mice include ubiquitin-proteasome-mediated degradation of C/EBPalpha and translational repression of the p53 protein by the CUGBP1-eukaryotic initiation factor 2 (eIF2) repressor complex. Our data demonstrate that p300 regulates a number of critical signaling pathways that control liver functions. PMID- 26100017 TI - RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma. AB - The conserved RNA-binding protein Musashi1 (MSI1) has emerged as a key oncogenic factor in numerous solid tumors, including glioblastoma. However, its mechanism of action has not yet been established comprehensively. To identify its target genes comprehensively and determine the main routes by which it influences glioblastoma phenotypes, we conducted individual-nucleotide resolution cross linking and immunoprecipitation (iCLIP) experiments. We confirmed that MSI1 has a preference for UAG sequences contained in a particular structural context, especially in 3' untranslated regions. Although numerous binding sites were also identified in intronic sequences, our RNA transcriptome sequencing analysis does not favor the idea that MSI1 is a major regulator of splicing in glioblastoma cells. MSI1 target mRNAs encode proteins that function in multiple pathways of cell proliferation and cell adhesion. Since these associations indicate potentially new roles for MSI1, we investigated its impact on glioblastoma cell adhesion, morphology, migration, and invasion. These processes are known to underpin the spread and relapse of glioblastoma, in contrast to other tumors where metastasis is the main driver of recurrence and progression. PMID- 26100018 TI - XRCC4/XLF Interaction Is Variably Required for DNA Repair and Is Not Required for Ligase IV Stimulation. AB - The classic nonhomologous end-joining (c-NHEJ) pathway is largely responsible for repairing double-strand breaks (DSBs) in mammalian cells. XLF stimulates the XRCC4/DNA ligase IV complex by an unknown mechanism. XLF interacts with XRCC4 to form filaments of alternating XRCC4 and XLF dimers that bridge DNA ends in vitro, providing a mechanism by which XLF might stimulate ligation. Here, we characterize two XLF mutants that do not interact with XRCC4 and cannot form filaments or bridge DNA in vitro. One mutant is fully sufficient in stimulating ligation by XRCC4/Lig4 in vitro; the other is not. This separation-of-function mutant (which must function as an XLF homodimer) fully complements the c-NHEJ deficits of some XLF-deficient cell strains but not others, suggesting a variable requirement for XRCC4/XLF interaction in living cells. To determine whether the lack of XRCC4/XLF interaction (and potential bridging) can be compensated for by other factors, candidate repair factors were disrupted in XLF- or XRCC4-deficient cells. The loss of either ATM or the newly described XRCC4/XLF-like factor, PAXX, accentuates the requirement for XLF. However, in the case of ATM/XLF loss (but not PAXX/XLF loss), this reflects a greater requirement for XRCC4/XLF interaction. PMID- 26100019 TI - The DHX33 RNA Helicase Promotes mRNA Translation Initiation. AB - DEAD/DEAH box RNA helicases play essential roles in numerous RNA metabolic processes, such as mRNA translation, pre-mRNA splicing, ribosome biogenesis, and double-stranded RNA sensing. Herein we show that a recently characterized DEAD/DEAH box RNA helicase, DHX33, promotes mRNA translation initiation. We isolated intact DHX33 protein/RNA complexes in cells and identified several ribosomal proteins, translation factors, and mRNAs. Reduction of DHX33 protein levels markedly reduced polyribosome formation and caused the global inhibition of mRNA translation that was rescued with wild-type DHX33 but not helicase defective DHX33. Moreover, we observed an accumulation of mRNA complexes with the 80S ribosome in the absence of functional DHX33, consistent with a stalling in initiation, and DHX33 more preferentially promoted structured mRNA translation. We conclude that DHX33 functions to promote elongation-competent 80S ribosome assembly at the late stage of mRNA translation initiation. Our results reveal a newly recognized function of DHX33 in mRNA translation initiation, further solidifying its central role in promoting cell growth and proliferation. PMID- 26100020 TI - Salmonella Engages Host MicroRNAs To Modulate SUMOylation: a New Arsenal for Intracellular Survival. AB - Posttranslational modifications (PTMs) can alter many fundamental properties of a protein. One or combinations of them have been known to regulate the dynamics of many cellular pathways and consequently regulate all vital processes. Understandably, pathogens have evolved sophisticated strategies to subvert these mechanisms to achieve instantaneous control over host functions. Here, we present the first report of modulation by intestinal pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) of host SUMOylation, a PTM pathway central to all fundamental cellular processes. Both in cell culture and in a mouse model, we observed that S. Typhimurium infection led to a dynamic SUMO-conjugated proteome alteration. The intracellular survival of S. Typhimurium was dependent on SUMO status as revealed by reduced infection and Salmonella-induced filaments (SIFs) in SUMO-upregulated cells. S. Typhimurium-dependent SUMO modulation was seen as a result of depletion of crucial SUMO pathway enzymes Ubc-9 and PIAS1, at both the protein and the transcript levels. Mechanistically, depletion of Ubc-9 relied on upregulation of small noncoding RNAs miR30c and miR30e during S. Typhimurium infection. This was necessary and sufficient for both down-modulation of Ubc-9 and a successful infection. Thus, we demonstrate a novel strategy of pathogen mediated perturbation of host SUMOylation, an integral mechanism underlying S. Typhimurium infection and intracellular survival. PMID- 26100021 TI - Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/beta-Catenin Pathway. AB - Induction of an antiviral innate immune response relies on pattern recognition receptors, including retinoic acid-inducible gene 1-like receptors (RLR), to detect invading pathogens, resulting in the activation of multiple latent transcription factors, including interferon regulatory factor 3 (IRF3). Upon sensing of viral RNA and DNA, IRF3 is phosphorylated and recruits coactivators to induce type I interferons (IFNs) and selected sets of IRF3-regulated IFN stimulated genes (ISGs) such as those for ISG54 (Ifit2), ISG56 (Ifit1), and viperin (Rsad2). Here, we used wild-type, glycogen synthase kinase 3alpha knockout (GSK-3alpha(-/-)), GSK-3beta(-/-), and GSK-3alpha/beta double-knockout (DKO) embryonic stem (ES) cells, as well as GSK-3beta(-/-) mouse embryonic fibroblast cells in which GSK-3alpha was knocked down to demonstrate that both isoforms of GSK-3, GSK-3alpha and GSK-3beta, are required for this antiviral immune response. Moreover, the use of two selective small-molecule GSK-3 inhibitors (CHIR99021 and BIO-acetoxime) or ES cells reconstituted with the catalytically inactive versions of GSK-3 isoforms showed that GSK-3 activity is required for optimal induction of antiviral innate immunity. Mechanistically, GSK 3 isoform activation following Sendai virus infection results in phosphorylation of beta-catenin at S33/S37/T41, promoting IRF3 DNA binding and activation of IRF3 regulated ISGs. This study identifies the role of a GSK-3/beta-catenin axis in antiviral innate immunity. PMID- 26100022 TI - Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing. AB - Accurate replication of DNA is imperative for the maintenance of genomic integrity. We identified Enhancer of Rudimentary Homolog (ERH) using a whole genome RNA interference (RNAi) screen to discover novel proteins that function in the replication stress response. Here we report that ERH is important for DNA replication and recovery from replication stress. ATR pathway activity is diminished in ERH-deficient cells. The reduction in ATR signaling corresponds to a decrease in the expression of multiple ATR pathway genes, including ATR itself. ERH interacts with multiple RNA processing complexes, including splicing regulators. Furthermore, splicing of ATR transcripts is deficient in ERH-depleted cells. Transcriptome-wide analysis indicates that ERH depletion affects the levels of ~1,500 transcripts, with DNA replication and repair genes being highly enriched among those with reduced expression. Splicing defects were evident in ~750 protein-coding genes, which again were enriched for DNA metabolism genes. Thus, ERH regulation of RNA processing is needed to ensure faithful DNA replication and repair. PMID- 26100023 TI - Leucine-Rich Repeat Kinase 1 Regulates Autophagy through Turning On TBC1D2 Dependent Rab7 Inactivation. AB - Autophagy is a conserved process that enables catabolic and degradative pathways. Rab family proteins, which are active in the GTP-bound form, regulate the transport and fusion of autophagosomes. However, it remains unclear how each cycle of Rab activation and inactivation is precisely regulated. Here, we show that leucine-rich repeat kinase 1 (LRRK1) regulates autophagic flux by controlling Rab7 activity in autolysosome formation. Upon induction of autophagy, LRRK1 was recruited via an association with VAMP7 to the autolysosome, where it activated the Rab7 GTPase-activating protein (GAP) TBC1D2, thereby switching off Rab7 signaling. Consistent with this model, LRRK1 deletion caused mice to be vulnerable to starvation and disrupted autolysosome formation, as evidenced by the accumulation of enlarged autolysosomes with undegraded LC3-II and persistently high levels of Rab7-GTP. This defect in autophagic flux was partially rescued by a mutant form of TBC1D2 with elevated Rab7-GAP activity. Thus, the spatiotemporal regulation of Rab7 activity during tunicamycin-induced autophagy is regulated by LRRK1. PMID- 26100024 TI - Cost-effectiveness of the New Zealand diabetes in pregnancy guideline screening recommendations. AB - OBJECTIVE: To compare the cost-effectiveness of 2 possible screening strategies for gestational diabetes mellitus (GDM) from the perspective of the New Zealand health system, developed as part of a gestational diabetes guideline. DESIGN: A decision analytic model was built comparing 2-step screening (glycated haemoglobin (HbA1c) test at first booking and a 2 h 75 g oral glucose tolerance test (OGTT) as a single test at 24-28 weeks) with 3-step screening (HbA1c test at first booking and a 1 h glucose challenge test (GCT) followed by a 2 h 75 g OGTT when indicated from 24-28 weeks) using a 9-month time horizon. SETTING: A hypothetical cohort of 62,000 pregnant women in New Zealand. METHODS: Probabilities, costs and benefits were derived from the literature, and supplementary data was obtained from National Women's Annual Clinical Reports. Main outcome measures, screening and treatment costs (NZ$2013) and effect on health outcomes (incidence of complications). RESULTS: The total cost for both strategies under baseline assumptions shows that the 2-step screening strategy would cost NZ$1.38 m more than the 3-step screening strategy overall. The additional cost per case detected was NZ$12,460 per case. The model found that the 2-step screening strategy identifies 12 more women with diabetes and 111 more women with GDM when compared against the 3-step screening strategy. We assessed the effect of changing the sensitivity and specificity of the OGTT. The baseline model assumed that the 2 h 75 g OGTT has a sensitivity and specificity of 95%. The 2-step strategy becomes more cost-effective when the diagnostic accuracy measures are improved. CONCLUSIONS: Adopting a 2-step strategy would moderately increase the number of GDM cases detected at the same time as moderately increasing the number of women with false negatives at a significant cost to the health system. Further evidence on the benefits of the 2 different approaches would be welcome. PMID- 26100025 TI - Association between environmental tobacco smoke and depression among Korean women. AB - OBJECTIVE: To evaluate the association between environmental tobacco smoke (ETS) exposure and depression among Korean women. METHODS: Between 2008 and 2011, we examined 731 men and 1249 women (aged 39-85 years) for the Korean Genome and Epidemiology Study (KoGES)-Kangwha. Among 1208 never-smoking women, we excluded two women taking antidepressants and five women who did not complete the Beck Depression Inventory (BDI). Therefore, we performed a cross-sectional analysis on 1201 women. ETS exposure was assessed using a self-reported questionnaire, and was classified into three groups: no exposure, occasional exposure and regular exposure. Depression was assessed using the BDI score, which ranged from 0 to 63, and the presence of depression was defined as a BDI score >= 10. RESULTS: Women exposed to ETS were more likely to have depression than those without ETS exposure (p=0.019). When BDI was analysed as a continuous variable, women exposed to ETS had significantly higher BDI scores after full adjustment (overall exposure: beta=1.36, p=0.013; occasional exposure: beta=1.15, p=0.063; regular exposure: beta=1.90, p=0.039). ETS exposure was significantly associated with depression in a dose-response manner even after adjusting for age, body mass index, menopause, socioeconomic status, lifestyle and prevalent chronic diseases. The adjusted OR for depression (95% CI) was 1.72 (1.25 to 2.37) for overall ETS exposure, 1.56 (1.09 to 2.24) for occasional exposure and 2.19 (1.30 to 3.69) for regular exposure, when compared to no exposure. CONCLUSIONS: Exposure to ETS was associated with depression among middle aged and elderly Korean women. PMID- 26100026 TI - A stepped wedge, cluster controlled trial of an intervention to improve safety and quality on medical wards: the HEADS-UP study protocol. AB - INTRODUCTION: The majority of preventable deaths in healthcare are due to errors on general wards. Staff perceptions of safety correlate with patient survival, but effectively translating ward teams' concerns into tangibly improved care remains problematic. The Hospital Event Analysis Describing Significant Unanticipated Problems (HEADS-UP) trial evaluates a structured, multidisciplinary team briefing, capturing safety threats and adverse events, with rapid feedback to clinicians and service managers. This is the first study to rigorously assess a simpler intervention for general medical units, alongside an implementation model applicable to routine clinical practice. METHODS/ANALYSIS: 7 wards from 2 hospitals will progressively incorporate the intervention into daily practice over 14 months. Wards will adopt HEADS-UP in a pragmatic sequence, guided by local clinical enthusiasm. Initial implementation will be facilitated by a research lead, but rapidly delegated to clinical teams. The primary outcome is excess length of stay (a surplus stay of 24 h or more, compared to peer institutions' Healthcare Resource Groups-predicted length of stay). Secondary outcomes are 30-day readmission or excess length of stay; in-hospital death or death/readmission within 30 days; healthcare-acquired infections; processes of escalation of care; use of traditional incident-reporting systems; and patient safety and teamwork climates. HEADS-UP will be analysed as a stepped wedge cluster controlled trial. With 7840 patients, using best and worst case predictions, the study would achieve between 75% and 100% power to detect a 2-14% absolute risk reduction in excess length of stay (two-sided p<0.05). Regression analysis will use generalised linear mixed models or generalised estimating equations, and a time-to-event regression model. A qualitative analysis will evaluate facilitators and barriers to HEADS-UP implementation and impact. ETHICS AND DISSEMINATION: Participating institutions' Research and Governance departments approved the study. Results will be published in peer-reviewed journals and at conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN34806867. PMID- 26100027 TI - Validity and reliability of chronic tic disorder and obsessive-compulsive disorder diagnoses in the Swedish National Patient Register. AB - OBJECTIVES: The usefulness of cases diagnosed in administrative registers for research purposes is dependent on diagnostic validity. This study aimed to investigate the validity and inter-rater reliability of recorded diagnoses of tic disorders and obsessive-compulsive disorder (OCD) in the Swedish National Patient Register (NPR). DESIGN: Chart review of randomly selected register cases and controls. METHOD: 100 tic disorder cases and 100 OCD cases were randomly selected from the NPR based on codes from the International Classification of Diseases (ICD) 8th, 9th and 10th editions, together with 50 epilepsy and 50 depression control cases. The obtained psychiatric records were blindly assessed by 2 senior psychiatrists according to the criteria of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV TR) and ICD-10. PRIMARY OUTCOME MEASUREMENT: Positive predictive value (PPV; cases diagnosed correctly divided by the sum of true positives and false positives). RESULTS: Between 1969 and 2009, the NPR included 7286 tic disorder and 24,757 OCD cases. The vast majority (91.3% of tic cases and 80.1% of OCD cases) are coded with the most recent ICD version (ICD-10). For tic disorders, the PPV was high across all ICD versions (PPV=89% in ICD-8, 86% in ICD-9 and 97% in ICD-10). For OCD, only ICD-10 codes had high validity (PPV=91-96%). None of the epilepsy or depression control cases were wrongly diagnosed as having tic disorders or OCD, respectively. Inter-rater reliability was outstanding for both tic disorders (kappa=1) and OCD (kappa=0.98). CONCLUSIONS: The validity and reliability of ICD codes for tic disorders and OCD in the Swedish NPR is generally high. We propose simple algorithms to further increase the confidence in the validity of these codes for epidemiological research. PMID- 26100029 TI - Cartilage invasion patterns in laryngeal cancer. AB - The cartilaginous invasion determines the T and is one of the most common sources of mistake in tumor staging. Also it is of great importance when planning any therapeutic alternative. In the latest revision of the TNM classification a clear distinction is made between infiltration of cartilage without going through it, considered a T3 recently and that would be a T4 according to the previous classification, and those going through the cartilage, classified as T4a. While this classification makes the difference in depth of infiltration, it does not emphasize the extent of invasion. This paper provides a detailed description of the laryngeal cartilage tumor infiltration by whole organ serial section in which the invasion is considered both horizontal (transcartilaginous) and vertical (extent of invasion) and establishing patterns of three-dimensional infiltration of the cartilage. This is a cross-sectional study of prevalence. 275 records of patients treated for laryngeal squamous cell carcinoma between 1995 and 2000 were reviewed. The pathological processing of laryngectomy surgical specimens was performed following the method of whole organ serial section described by G. F. Tucker. The following patterns of cartilaginous infiltration were defined: (1) transcartilaginous infiltration; (2a) partial focal infiltration of the cartilage: infiltration not going through the cartilage but occupying one third or less of its extent; (2b) partial extensive infiltration of the cartilage: infiltration occupying two thirds or more of its length and (3) no cartilage infiltration: tumor in contact with the cartilage (paraglottic space) but without affecting it. 161 patients met the inclusion criteria. The most frequent tumor location was supraglottic (58 cases) followed by glottic (47). 109 patients (67.7 %) were treated with total laryngectomy. Partial surgical techniques were performed in the remaining cases. TNM tumor staging was performed according to the results of pathological study (pTNM). 72.06 % (116) were classified as advanced laryngeal tumors (pT3 and pT4). 46 % of patients showed some extent of laryngeal cartilage infiltration (thyroid, cricoid, arytenoids, epiglottis). The cartilage most frequently infiltrated was the thyroid in 48 patients (29.8 %) and when it is affected, in most cases (66.7 %), the infiltration is transcartilaginous. The next most common pattern is partial focal infiltration (27 %). In the cricoid cartilage, the most common pattern of infiltration is focal partial infiltration (52.6 %). Of the 19 cases with infiltration of the cricoid, there are 12 cases with extra laryngeal invasion through a cricothyroid membrane perforation. The study of laryngeal cancer by laryngeal whole serial section has been proved to be very useful in offering a high precision pTNM staging and a detailed description of the infiltration of cartilage. We have seen that when the thyroid cartilage is infiltrated the tumor often passes through the cartilage. However, there are cases where the tumor is extremely aggressive, being very widespread in cartilage thickness without actually crossing it. The isolated infiltration of the cricoid cartilage is exceptional. PMID- 26100030 TI - Intratympanic corticosteroids injections: a systematic review of literature. AB - The objective of the study was to determine the evidence of intratympanic steroids injections (ITSI) for efficacy in the management of the following inner ear diseases: Meniere's disease, tinnitus, noise-induced hearing loss (NIHL) and idiopathic sudden sensorineural hearing loss (ISSNHL). The data sources were literature review from 1946 to December 2014, PubMed and Medline. A systematic review of the existing literature was performed. Databases were searched for all human prospective randomized clinical trials using ITSI in at least one treatment group. The authors identified 29 prospective randomized clinical trials investigating the benefits of an intratympanic delivery of steroids. Six articles on Meniere's disease were identified, of which one favored ITSI over placebo in vertigo control. Of the five randomized clinical trials on tinnitus therapy, one study found better tinnitus control with ITSI. The only available trial on NIHL showed significant hearing recovery with combination therapy (ITSI and oral steroids therapy). Seventeen studies were identified on ISSNHL, of which 10 investigated ITSI as a first-line therapy and 7 as a salvage therapy. Studies analysis found benefits in hearing recovery in both settings. Due to heterogeneity in treatment protocols and follow-up, a meta-analysis was not performed. Given the low adverse effects rates of ITSI therapy and good patient tolerability, local delivery should be considered as an interesting adjunct to the therapy of the ISSNHL and NIHL. Only one article over six where ITSI therapy offers potential benefits to patients with Meniere's disease in the control of tinnitus and vertigo was found. ITSI does not seem to be effective in the treatment of tinnitus. PMID- 26100031 TI - Comparison of microporous polysaccharide hemospheres and Ankaferd Blood Stopper in a rabbit epistaxis model. AB - The aim of this study was to evaluate the histopathological impact, effectiveness, and safety of two hemostatic agents, Ankaferd Blood Stopper (ABS) and microporous polysaccharide hemospheres (MPH), in an experimental rabbit epistaxis model. Rabbits were randomly assigned, using a computerized random number generator, to the following three groups of six animals: group 1 (control, irrigated with saline); group 2 (ABS-treated); and group 3 (MPH-treated). In all groups, a standardized rabbit epistaxis model was used. Hemostasis time and extent of nasal bleeding were measured to compare the hemostatic effect of ABS and MPH among groups. Septums were removed for histopathological analysis, 7 days after the procedure. ABS reduced hemostasis time to 104.2 s and amount of bleeding to 20.5 mg. MPH reduced hemostasis time to 71.7 s and amount of bleeding to 11.5 mg. Mean bleeding time in wounds administered ABS and MPH was significantly shorter compared with wounds administered isotonic saline solution (p = 0.004). ABS and MPH application decreased bleeding significantly compared with the control group (p = 0.004). Bleeding time and amount in the MPH group was significantly reduced compared with the ABS group (p = 0.013 and p = 0.004, respectively). There was no significant difference in the histopathological evaluation results between the ABS, MPH, and control groups. Our data indicate that both ABS and MPH represent safe, effective, and fast-acting hemostatic agents in the management of epistaxis. MPH was more effective than ABS in terms of hemostasis time and amount of bleeding. PMID- 26100032 TI - [Hematopoietic stem cell exhaustion and advanced glycation end-products in the unexplained anemia of the elderly]. AB - INTRODUCTION: More than 10% of the aged 65 years and over in the western world suffers anemia and in one third of them the cause of the anemia remains obscure. The unexplained anemia of the elderly (UAE) is considered an exclusion diagnosis, without the existence of a clear consensus to its clinical or experimental approach. There is an association between aging and anemia in studies performed in animals and in humans. OBJECTIVES: To determine if there is evidence in the literature that supports hematopoietic stem cells (HSC) exhaustion and the advanced glycation end-products (AGE's) as a cause of UAE. METHOD: A total of 32 combined texts (28 for HSC exhaustion and 4 for AGEs) were selected after an intensive review. Conclusions were associated with causes and effects of the HSC exhaustion and circulating AGE's over aging and anemia. RESULTS: Only three works try to establish an association between UAE and HSC exhaustion, two of them disagreed in their conclusions, with the third one differing in the type of study. There is a relationship between anemia and AGEs increase and accumulation. CONCLUSIONS: There is evidence in the literature that links the aging molecular and cellular mechanisms with the HSC exhaustion and the increase of AGE's. Furthermore; there is some evidence that both conditions determine the emergence of anemia associated with age in animals and in humans. There is little evidence in the literature to clarify the relationship between aging and UAE. PMID- 26100033 TI - [Association between carbonyl proteins and tumor necrosis factor alpha with muscle strength in young and older women: exploratory study]. AB - INTRODUCTION: It has recently been proposed that there is a close relationship between oxidative stress and low-grade chronic inflammation. Both processes have been related separately to muscle function in older adults (OA). Nevertheless, it still has not been determined if this relationship is present particularly in OA. The objective of this study was to determine the relationship between the plasma levels of TNF-alpha and carbonyl proteins (CP) and muscle strength in a group of young and older women. METHODS: An exploratory study was conducted on 13 older and 8 young women, in whom the plasma levels of CP and TNF-alpha were measured. Muscle strength was measured by handgrip test, quadriceps voluntary maximal isometric strength, arm curl, and the 30 second sit to stand test. RESULTS: There were no differences in the plasma levels of CP and TNF-alpha between the groups, but there was relationship between the biomarkers only in the OA group. A non linear relationship was observed between CP and quadriceps voluntary maximal isometric strength only in the OA group (R(2)=36.2; P=.038). For TNF-alpha there were no significant association with any of the applied tests. CONCLUSIONS: There is an association between CP and quadriceps voluntary maximal isometric strength only in the OA group, which could indicate a deleterious action of oxidative stress on muscle function, particularly in aging. PMID- 26100034 TI - Effects of exposure to direct-to-consumer television advertising for statin drugs on food and exercise guilt. AB - OBJECTIVE: Pharmaceutical direct-to-consumer advertising (DTCA) is widely prevalent on US television. This study tests the relationship between estimated exposure to DTCA for statin drugs, which often feature mixed messages about the efficacy of diet and exercise in reducing risk of cholesterol and heart disease, and guilty feelings regarding food and exercise. METHODS: A series of repeated cross-sectional surveys of the US population between 2001 and 2007 (N=106,859 adults aged 18 and older) were combined with data on the frequency of DTCA appearances on national, cable, and local television during the same time period. RESULTS: Adjusting for potential confounders with ordinary least squares (OLS) regression, increased potential exposure to statin DTCA was associated with increased food guilt (in a dose-response pattern) and exercise guilt (in a threshold pattern). CONCLUSION: This study provides new evidence that DTCA has potential to influence emotional well-being as well as direct behavioral responses emphasized in previous academic research. PRACTICE IMPLICATIONS: Health practitioners should be prepared to encounter and counsel patients who are prompted by DTCA to feel guilty about their food and exercise behaviors, feelings which may impact the likelihood of adherence to prescribed behavioral modification for weight management. PMID- 26100035 TI - Fractionated radiotherapy and radiosurgery of intracranial meningiomas. AB - This review focuses on the role of radiosurgery and fractionated radiotherapy in the management of intracranial meningiomas, which are the most common benign intracranial tumors. Whenever feasible, surgery remains a cornerstone of treatment in effective health care treatment where modern radiotherapy plays an important role. Irradiation can be proposed as first-line treatment, as adjuvant treatment, or as a second-line treatment after recurrence. Stereotactic radiosurgery consists of delivering, a high-dose of radiation with high precision, to the tumor in a single-fraction with a minimal exposure of surrounding healthy tissue. Stereotactic radiosurgery, especially with the gamma knife technique, has reached a high level of success for the treatment of intracranial meningiomas with excellent local control and low morbidity. However, stereotactic radiosurgery is limited by tumor size,<3-4cm, and location, i.e. reasonable distance from the organs at risk. Fractionated radiation therapy is an interesting alternative (5 to 6weeks treatment time) for large inoperable tumors. The results of fractionated radiation therapy seem encouraging as regards both local control and morbidity although long-term prospective studies are still needed. PMID- 26100036 TI - Cutaneous inflammatory myofibroblastic tumours can be anaplastic lymphoma kinase positive: report of the first four cases. AB - AIMS: Inflammatory myofibroblastic tumours (IMTs) usually have a soft tissue and visceral localization, but have been rarely reported in skin. The aim of this study was to characterize the histological and immunohistochemical features of a series of cutaneous IMTs. METHODS AND RESULTS: We retrieved from our archives over 10 years four cutaneous IMTs; one was diagnosed in a child, and three in young adults. Tumours were centred on the dermis, and also involved the subcutis in two cases. Two of them corresponded to the 'myxoid-vascular' pattern of IMT, whereas the others were characterized by compact fascicles of spindle-shaped cells. They stained positively for smooth muscle actin. All samples stained positively for anaplastic lymphoma kinase (ALK). ALK expression was limited to the cytoplasm of myofibroblasts and, in the three investigated cases, correlated with ALK rearrangement as shown by fluorescence in-situ hybridization analysis. CONCLUSIONS: This is the first report of ALK-positive IMTs with a cutaneous localization. Because of their morphological heterogeneity and low incidence in skin, the diagnosis of cutaneous IMTs is often challenging. A cutaneous spindled cell tumour associated with an inflammatory infiltrate should prompt pathologists to perform ALK staining, which, if positive, might be decisive for diagnosis. PMID- 26100037 TI - Inhibitory effect of 5,6-dihydroergosteol-glucoside on atopic dermatitis-like skin lesions via suppression of NF-kappaB and STAT activation. AB - BACKGROUND: Atopic dermatitis (AD) is a Th2-type disease. Keratinocytes, a major type in the skin, produce Th2 chemokines such as thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22, which play pivotal roles in the development of Th2-dominant inflammatory skin diseases. Recently, it was reported that 5,6-dihydroergosterol-glucoside (DHE-Glc) was synthesized and exhibited strong anti-inflammatory activity. OBJECTIVE: We aimed to investigate the effects of DHE-Glc, a synthetic molecule derived from ergosterol, on AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) in mice and to elucidate the effects of DHE-Glc on TNF-alpha/IFN-gamma-induced production of CCL17 and CCL22 in human keratinocytes (HaCaTs) and DNCB induced skin inflammation mice model. METHOD: Mice were sensitized and challenged on the skin of their backs with DNCB. At 30-60 days after sensitization, mice were treated with cutaneous administration of DHE-Glc by skin smear. HaCaT cells were used to evaluate the effects of DHE-Glc on production of CCL17 and CCL22 and investigate mechanisms of action by RT-PCR, ELISA, Western blot, and reporter assays. RESULT: Topical administration of DHE-Glc attenuated AD-like skin inflammatory symptoms. DHE-Glc decreased infiltration of epidermal eosinophils and mast cells, and reduced levels of IgE, histamine, and mRNA expression and protein levels of CCL17/CCL22 in the plasma of DNCB-treated animals. In addition, DHE-Glc suppressed TNF-alpha/IFN-gamma-induced expression of the Th2 chemokines CCL17 and CCL22 by inhibiting NF-kappaB and STAT activation in TNF-alpha/IFN gamma-induced HaCaT cells. CONCLUSION: DHE-Glc improved AD-like skin inflammatory symptoms on the backs of DNCB-induced mice, partly by suppressing production of Th2 chemokines, CCL17 and CCL22 in inflamed skin. Therefore, DHE-Glc is a potential therapeutic agent for skin inflammatory diseases such as AD. PMID- 26100038 TI - Interactions and Localization of Escherichia coli Error-Prone DNA Polymerase IV after DNA Damage. AB - Escherichia coli's DNA polymerase IV (Pol IV/DinB), a member of the Y family of error-prone polymerases, is induced during the SOS response to DNA damage and is responsible for translesion bypass and adaptive (stress-induced) mutation. In this study, the localization of Pol IV after DNA damage was followed using fluorescent fusions. After exposure of E. coli to DNA-damaging agents, fluorescently tagged Pol IV localized to the nucleoid as foci. Stepwise photobleaching indicated ~60% of the foci consisted of three Pol IV molecules, while ~40% consisted of six Pol IV molecules. Fluorescently tagged Rep, a replication accessory DNA helicase, was recruited to the Pol IV foci after DNA damage, suggesting that the in vitro interaction between Rep and Pol IV reported previously also occurs in vivo. Fluorescently tagged RecA also formed foci after DNA damage, and Pol IV localized to them. To investigate if Pol IV localizes to double-strand breaks (DSBs), an I-SceI endonuclease-mediated DSB was introduced close to a fluorescently labeled LacO array on the chromosome. After DSB induction, Pol IV localized to the DSB site in ~70% of SOS-induced cells. RecA also formed foci at the DSB sites, and Pol IV localized to the RecA foci. These results suggest that Pol IV interacts with RecA in vivo and is recruited to sites of DSBs to aid in the restoration of DNA replication. IMPORTANCE: DNA polymerase IV (Pol IV/DinB) is an error-prone DNA polymerase capable of bypassing DNA lesions and aiding in the restart of stalled replication forks. In this work, we demonstrate in vivo localization of fluorescently tagged Pol IV to the nucleoid after DNA damage and to DNA double-strand breaks. We show colocalization of Pol IV with two proteins: Rep DNA helicase, which participates in replication, and RecA, which catalyzes recombinational repair of stalled replication forks. Time course experiments suggest that Pol IV recruits Rep and that RecA recruits Pol IV. These findings provide in vivo evidence that Pol IV aids in maintaining genomic stability not only by bypassing DNA lesions but also by participating in the restoration of stalled replication forks. PMID- 26100039 TI - Catechol Siderophore Transport by Vibrio cholerae. AB - Siderophores, small iron-binding molecules secreted by many microbial species, capture environmental iron for transport back into the cell. Vibrio cholerae synthesizes and uses the catechol siderophore vibriobactin and also uses siderophores secreted by other species, including enterobactin produced by Escherichia coli. E. coli secretes both canonical cyclic enterobactin and linear enterobactin derivatives likely derived from its cleavage by the enterobactin esterase Fes. We show here that V. cholerae does not use cyclic enterobactin but instead uses its linear derivatives. V. cholerae lacked both a receptor for efficient transport of cyclic enterobactin and enterobactin esterase to promote removal of iron from the ferrisiderophore complex. To further characterize the transport of catechol siderophores, we show that the linear enterobactin derivatives were transported into V. cholerae by either of the catechol siderophore receptors IrgA and VctA, which also transported the synthetic siderophore MECAM [1,3,5-N,N',N"-tris-(2,3-dihydroxybenzoyl) triaminomethylbenzene]. Vibriobactin is transported via the additional catechol siderophore receptor ViuA, while the Vibrio fluvialis siderophore fluvibactin was transported by all three catechol receptors. ViuB, a putative V. cholerae siderophore-interacting protein (SIP), functionally substituted for the E. coli ferric reductase YqjH, which promotes the release of iron from the siderophore in the bacterial cytoplasm. In V. cholerae, ViuB was required for the use of vibriobactin but was not required for the use of MECAM, fluvibactin, ferrichrome, or the linear derivatives of enterobactin. This suggests the presence of another protein in V. cholerae capable of promoting the release of iron from these siderophores. IMPORTANCE: Vibrio cholerae is a major human pathogen and also serves as a model for the Vibrionaceae, which include other serious human and fish pathogens. The ability of these species to persist and acquire essential nutrients, including iron, in the environment is epidemiologically important but not well understood. In this work, we characterize the ability of V. cholerae to acquire iron by using siderophores produced by other organisms. We resolve confusion in the literature regarding its ability to use the Escherichia coli siderophore enterobactin and identify the receptor and TonB system used for the transport of several siderophores. The use of some siderophores did not require the ferric reductase ViuB, suggesting that an uncharacterized ferric reductase is present in V. cholerae. PMID- 26100040 TI - Identification of the Final Two Genes Functioning in Methanofuran Biosynthesis in Methanocaldococcus jannaschii. AB - All methanofuran structural variants contain a basic core structure of 4-[N (gamma-l-glutamyl)-p-(beta-aminoethyl)phenoxymethyl]-(aminomethyl)furan (APMF Glu) but have different side chains depending on the source organism. Recently, we identified four genes (MfnA, MfnB, MfnC, and MfnD) that are responsible for the biosynthesis of the methanofuran precursor gamma-glutamyltyramine and 5 (aminomethyl)-3-furanmethanol-phosphate (F1-P) from tyrosine, glutamate, glyceraldehyde-3-P, and alanine in Methanocaldococcus jannaschii. How gamma glutamyltyramine and F1-P couple together to form the core structure of methanofuran was previously unknown. Here, we report the identification of two enzymes encoded by the genes mj0458 and mj0840 that catalyze the formation of F1 PP from ATP and F1-P and the condensation of F1-PP with gamma-glutamyltyramine, respectively, to form APMF-Glu. We have annotated these enzymes as MfnE and MfnF, respectively, representing the fifth and sixth enzymes in the methanofuran biosynthetic pathway to be identified. Although MfnE was previously reported as an archaeal adenylate kinase, our present results show that MfnE is a promiscuous enzyme and that its possible physiological role is to produce F1-PP. Unlike other enzymes catalyzing coupling reactions involving pyrophosphate as the leaving group, MfnF exhibits a distinctive alpha/beta two-layer sandwich structure. By comparing MfnF with thiamine synthase and dihydropteroate synthase, a substitution nucleophilic unimolecular (SN-1) reaction mechanism is proposed for MfnF. With the identification of MfnE and MfnF, the biosynthetic pathway for the methanofuran core structure APMF-Glu is complete. IMPORTANCE: This work describes the identification of the final two enzymes responsible for catalyzing the biosynthesis of the core structure of methanofuran. The gene products of mj0458 and mj0840 catalyze the formation of F1-PP and the coupling of F1-PP with gamma glutamyltyramine, respectively, to form APMF-Glu. Although the chemistry of such a coupling reaction is widespread in biochemistry, we provide here the first evidence that such a mechanism is used in methanofuran biosynthesis. MfnF belongs to the hydantoinase A family (PF01968) and exhibits a unique alpha/beta two-layer sandwich structure that is different from the enzymes catalyzing similar reactions. Our results show that MfnF catalyzes the formation of an ether bond during methanofuran biosynthesis. Therefore, this work further expands the functionality of this enzyme family. PMID- 26100041 TI - Cyclic Di-GMP-Regulated Periplasmic Proteolysis of a Pseudomonas aeruginosa Type Vb Secretion System Substrate. AB - We previously identified a second-messenger-regulated signaling system in the environmental bacterium Pseudomonas fluorescens which controls biofilm formation in response to levels of environmental inorganic phosphate. This system contains the transmembrane cyclic di-GMP (c-di-GMP) receptor LapD and the periplasmic protease LapG. LapD regulates LapG and controls the ability of this protease to process a large cell surface adhesin protein, LapA. While LapDG orthologs can be identified in diverse bacteria, predictions of LapG substrates are sparse. Notably, the opportunistic pathogen Pseudomonas aeruginosa harbors LapDG orthologs, but neither the substrate of LapG nor any associated secretion machinery has been identified to date. Here, we identified P. aeruginosa CdrA, a protein known to mediate cell-cell aggregation and biofilm maturation, as a substrate of LapG. We also demonstrated LapDG to be a minimal system sufficient to control CdrA localization in response to changes in the intracellular concentration of c-di-GMP. Our work establishes this biofilm signaling node as a regulator of a type Vb secretion system substrate in a clinically important pathogen. IMPORTANCE: Here, the biological relevance of a conserved yet orphan signaling system in the opportunistic pathogen Pseudomonas aeruginosa is revealed. In particular, we identified the adhesin CdrA, the cargo of a two partner secretion system, as a substrate of a periplasmic protease whose activity is controlled by intracellular c-di-GMP levels and a corresponding transmembrane receptor via an inside-out signaling mechanism. The data indicate a posttranslational control mechanism of CdrA via c-di-GMP, in addition to its established transcriptional regulation via the same second messenger. PMID- 26100042 TI - Aminoimidazole Carboxamide Ribotide Exerts Opposing Effects on Thiamine Synthesis in Salmonella enterica. AB - In Salmonella enterica, the thiamine biosynthetic intermediate 5-aminoimidazole ribotide (AIR) can be synthesized de novo independently of the early purine biosynthetic reactions. This secondary route to AIR synthesis is dependent on (i) 5-amino-4-imidazolecarboxamide ribotide (AICAR) accumulation, (ii) a functional phosphoribosylaminoimidazole-succinocarboxamide (SAICAR) synthetase (PurC; EC 6.3.2.6), and (iii) methionine and lysine in the growth medium. Studies presented here show that AICAR is a direct precursor to AIR in vivo. PurC-dependent conversion of AICAR to AIR was recreated in vitro. Physiological studies showed that exogenous nutrients (e.g., methionine and lysine) antagonize the inhibitory effects of AICAR on the ThiC reaction and decreased the cellular thiamine requirement. Finally, genetic results identified multiple loci that impacted the effect of AICAR on thiamine synthesis and implicated cellular aspartate levels in AICAR-dependent AIR synthesis. Together, the data here clarify the mechanism that allows conditional growth of a strain lacking the first five biosynthetic enzymes, and they provide additional insights into the complexity of the metabolic network and its plasticity. IMPORTANCE: In bacteria, the pyrimidine moiety of thiamine is derived from aminoimidazole ribotide (AIR), an intermediate in purine biosynthesis. A previous study described conditions under which AIR synthesis is independent of purine biosynthesis. This work is an extension of that previous study and describes a new synthetic pathway to thiamine that depends on a novel thiamine precursor and a secondary activity of the biosynthetic enzyme PurC. These findings provide mechanistic details of redundancy in the synthesis of a metabolite that is essential for nucleotide and coenzyme biosynthesis. Metabolic modifications that allow the new pathway to function or enhance it are also described. PMID- 26100043 TI - A Mannose Family Phosphotransferase System Permease and Associated Enzymes Are Required for Utilization of Fructoselysine and Glucoselysine in Salmonella enterica Serovar Typhimurium. AB - Salmonella enteric serovar Typhimurium, a major cause of food-borne illness, is capable of using a variety of carbon and nitrogen sources. Fructoselysine and glucoselysine are Maillard reaction products formed by the reaction of glucose or fructose, respectively, with the epsilon-amine group of lysine. We report here that S. Typhimurium utilizes fructoselysine and glucoselysine as carbon and nitrogen sources via a mannose family phosphotransferase (PTS) encoded by gfrABCD (glucoselysine/fructoselysine PTS components EIIA, EIIB, EIIC, and EIID; locus numbers STM14_5449 to STM14_5454 in S. Typhimurium 14028s). Genes coding for two predicted deglycases within the gfr operon, gfrE and gfrF, were required for growth with glucoselysine and fructoselysine, respectively. GfrF demonstrated fructoselysine-6-phosphate deglycase activity in a coupled enzyme assay. The biochemical and genetic analyses were consistent with a pathway in which fructoselysine and glucoselysine are phosphorylated at the C-6 position of the sugar by the GfrABCD PTS as they are transported across the membrane. The resulting fructoselysine-6-phosphate and glucoselysine-6-phosphate subsequently are cleaved by GfrF and GfrE to form lysine and glucose-6-phosphate or fructose-6 phosphate. Interestingly, although S. Typhimurium can use lysine derived from fructoselysine or glucoselysine as a sole nitrogen source, it cannot use exogenous lysine as a nitrogen source to support growth. Expression of gfrABCDEF was dependent on the alternative sigma factor RpoN (sigma(54)) and an RpoN dependent LevR-like activator, which we designated GfrR. IMPORTANCE: Salmonella physiology has been studied intensively, but there is much we do not know regarding the repertoire of nutrients these bacteria are able to use for growth. This study shows that a previously uncharacterized PTS and associated enzymes function together to transport and catabolize fructoselysine and glucoselysine. Knowledge of the range of nutrients that Salmonella utilizes is important, as it could lead to the development of new strategies for reducing the load of Salmonella in food animals, thereby mitigating its entry into the human food supply. PMID- 26100045 TI - Topical L-menthol for Postradiotherapy Neuropathic Pain: A Case Report. PMID- 26100046 TI - Successful Palliation of Octreotide-Resistant Diarrhea Using Glycopyrrolate in a Patient With Medullary Thyroid Cancer: A Case Report. PMID- 26100047 TI - No evidence for improved TORS post-treatment feeding tube dependency rate relative to standard therapy in early stage oropharyngeal cancer. PMID- 26100048 TI - Merkel cell carcinoma - Beast with two Backs. AB - Merkel cell carcinoma of cutaneous and mucosal origin shows many differences like in origin, etiology, anatomical site, prognosis etc. This communication focuses briefly on the differences between mucosal MCC and cutaneous MCC. PMID- 26100049 TI - A translational bioinformatic approach in identifying and validating an interaction between Vitamin A and CYP19A1. AB - INTRODUCTION: One major challenge in personalized medicine research is to identify the environmental factors that can alter drug response, and to investigate their molecular mechanisms. These environmental factors include co medications, food, and nutrition or dietary supplements. The increasing use of dietary supplements and their potential interactions with cytochrome P450 (CYP450) enzymes is a highly significant personalized medicine research domain, because most of the drugs on the market are metabolized through CYP450 enzymes. METHODS: Initial bioinformatics analysis revealed a number of regulators of CYP450 enzymes from a human liver bank gene expression quantitative loci data set. Then, a compound-gene network was constructed from the curated literature data. This network consisted of compounds that interact with either CYPs and/or their regulators that influence either their gene expression or activity. We further evaluated this finding in three different cell lines: JEG3, HeLa, and LNCaP cells. RESULTS: From a total of 868 interactions we were able to identify an interesting interaction between retinoic acid (i.e. Vitamin A) and the aromatase gene (i.e. CYP19A1). Our experimental results showed that retinoic acid at physiological concentration significantly influenced CYP19A1 gene expressions. CONCLUSIONS: These results suggest that the presence of retinoic acid may alter the efficacy of agents used to suppress aromatase expression. PMID- 26100052 TI - Proteomic changes occurring in the malaria mosquitoes Anopheles gambiae and Anopheles stephensi during aging. AB - The age of mosquitoes is a crucial determinant of their ability to transmit pathogens and their resistance to insecticides. We investigated changes to the abundance of proteins found in heads and thoraces of the malaria mosquitoes Anopheles gambiae and Anopheles stephensi as they aged. Protein expression changes were assessed using two-dimensional difference gel electrophoresis and the identity of differentially expressed proteins was determined by using either matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry or capillary high-pressure liquid chromatography coupled with a linear ion-trap (LTQ)-Orbitrap XL hybrid mass spectrometer. Protein biomarkers were validated by semi quantitative Western blot analysis. Nineteen and nine age dependent protein spots were identified for A. stephensi and A. gambiae, respectively. Among the proteins down-regulated with age were homologs of ADF/Cofilin, cytochome c1, heat shock protein-70 and eukaryotic translation initiation factor 5A (eIF5a). Proteins up-regulated with age included probable methylmalonate-semialdehyde dehydrogenase, voltage-dependent anion-selective channel and fructose bisphosphate aldolase. Semi quantitative Western blot analysis confirmed expression patterns observed by 2-D DIGE for eIF5a and ADF/Cofilin. Further work is recommended to determine whether these biomarkers are robust to infection, blood feeding and insecticide resistance. Robust biomarkers could then be incorporated into rapid diagnostic assays for ecological and epidemiological studies. BIOLOGICAL SIGNIFICANCE: In this study, we have identified several proteins with characteristic changes in abundance in both A. gambiae and A. stephensi during their aging process. These changes may highlight underlying mechanisms beneath the relationship between mosquito age and factors affecting Plasmodium transmission and mosquito control. The similarity of changes in protein abundance between these species and the primary dengue vector Aedes aegypti, has revealed conserved patterns of aging-specific protein regulation. PMID- 26100053 TI - Transcatheter Leadless Pacemaker Implantation for Complete Heart Block Following CoreValve Transcatheter Aortic Valve Replacement. PMID- 26100051 TI - Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C. AB - Decreased expression of cardiac myosin binding protein-C (cMyBP-C) in the myocardium is thought to be a contributing factor to hypertrophic cardiomyopathy in humans, and the initial molecular defect is likely abnormal cross-bridge (XB) function which leads to impaired force generation, decreased contractile performance, and hypertrophy in vivo. The myosin activator omecamtiv mecarbil (OM) is a pharmacological drug that specifically targets the myosin XB and recent evidence suggests that OM induces a significant decrease in the in vivo motility velocity and an increase in the XB duty cycle. Thus, the molecular effects of OM maybe beneficial in improving contractile function in skinned myocardium lacking cMyBP-C because absence of cMyBP-C in the sarcomere accelerates XB kinetics and enhances XB turnover rate, which presumably reduces contractile efficiency. Therefore, parameters of XB function were measured in skinned myocardium lacking cMyBP-C prior to and following OM incubation. We measured ktr, the rate of force redevelopment as an index of XB transition from both the weakly- to strongly bound state and from the strongly- to weakly-bound states and performed stretch activation experiments to measure the rates of XB detachment (krel) and XB recruitment (kdf) in detergent-skinned ventricular preparations isolated from hearts of wild-type (WT) and cMyBP-C knockout (KO) mice. Samples from donor human hearts were also used to assess the effects of OM in cardiac muscle expressing a slow beta-myosin heavy chain (beta-MHC). Incubation of skinned myocardium with OM produced large enhancements in steady-state force generation which were most pronounced at low levels of [Ca(2+)] activations, suggesting that OM cooperatively recruits additional XB's into force generating states. Despite a large increase in steady-state force generation following OM incubation, parallel accelerations in XB kinetics as measured by ktr were not observed, and there was a significant OM-induced decrease in krel which was more pronounced in the KO skinned myocardium compared to WT skinned myocardium (58% in WT vs. 76% in KO at pCa 6.1), such that baseline differences in krel between KO and WT skinned myocardium were no longer apparent following OM-incubation. A significant decrease in the kdf was also observed following OM incubation in all groups, which may be related to the increase in the number of cooperatively recruited XB's at low Ca(2+)-activations which slows the overall rate of force generation. Our results indicate that OM may be a useful pharmacological approach to normalize hypercontractile XB kinetics in myocardium with decreased cMyBP-C expression due to its molecular effects on XB behavior. PMID- 26100054 TI - What is different for people with MS who have pressure ulcers: A reflective study of the impact upon people's quality of life? AB - BACKGROUND: Multiple Sclerosis (MS) is a progressive, degenerative disease of the central nervous system. People with advanced disease who have compromised mobility, activity, sensory and/or cognitive abilities are at risk of pressure ulcers. Having a pressure ulcer has a substantial impact on a person's quality of life; a generic pressure ulcer Health Related Quality of Life (HRQL) framework has been used in this study. AIM: To explore the views and opinions of patients with MS who have a pressure ulcer using a thematic framework and compare these to the general pressure ulcer population. METHODS: Data for six MS patients was obtained through secondary analysis of transcripts from semi-structured interviews conducted during two studies which were part of a programme of HRQL Research. FINDINGS: Patients with MS reported that their pressure ulcer affected their lives physically, psychologically and socially. All were confined to bed (as part of their pressure ulcer treatment) and therefore unable to participate in activities. Difficulties with movement and activity were partially attributed to the MS. Patients with MS did not report feeling ill with their pressure ulcer and expressed positive emotions and optimism. Pain or discomfort was a feature of the pressure ulcer for most patients. CONCLUSIONS: Pressure ulcers have a major impact on QOL for all patients. Problems with mobility and activity associated with the pressure ulcer were confounded by the MS. PMID- 26100055 TI - Variability and Signatures of RNase-H Amino Acid Domain and Central Polypurine Tract of HIV-1 B-Subtype from Drug-Naive Individuals. AB - BACKGROUND: The conversion to HIV-1 single-stranded RNA into double-stranded DNA for nuclear integration is an essential viral step in replication: this process is mediated by Reverse-Transcriptase (RT) and by central polypurine tract (cPPT), a domain where the plus-strand synthesis requires viral primers produced by RNase H cleavage. Recent studies highlighted the need of investigating the role of RNase-H in RT nucleoside-inhibitors-resistance, because specific mutation(s) could affect cPPT removal and RNase-H cleavage specificity. Thus, the variability of RNase-H and cPPT were studied. METHODS: HIV-1 subtype-B sequences from 746 drug-naive and 806 antiretroviral-(ARV)-treated patients were used and analysed. RESULTS: In drug-naive patients, among 54 RNase-H variable residues, 25 were mutated in >5% of patients, and 7 of them were highly variable (>25%), whilst in ARV-treated individuals, 53 RNase-H variable residues were observed, which 24 were mutated in >5% of patients and 6 of them were highly variable (>25%). Differently, a high conservation was observed in cPPT-area, with no statistically significant differences observed between the two datasets analysed. Nevertheless, in ARV-treated patients the variability of cPPT nucleotide at position 6 was found three times higher with respect to the drug-naive dataset. The topology of the dendrogram has revealed the existence of a cluster (boostrap=0.98) grouping the A6GcPPT with V531I and S519N RNase-H signatures. CONCLUSION: These signatures observed within cPPT and mostly in RNase-H, warrant advanced structural analysis to delineate their potential roles in the affinity/recognition of RT and the cleavage capacity of RNase-H. Exploring further the implications such changes may have on drug-resistance may be relevant. PMID- 26100056 TI - The efficacy of TachoComb on reducing postoperative complications after tonsillectomy in children. AB - OBJECTIVE: A fibrinogen/thrombin-based collagen fleece (TachoComb) is a powerful topical hemostatic agent that has been widely used in various surgical specialties with a favorable outcome. The purpose of this study was to investigate the effect of TachoComb application on postoperative complications after tonsillectomy. MATERIALS AND METHODS: A total of 1633 children had undergone tonsillectomy with or without adenoidectomy were included in this study. After removal of both tonsils, 1057 patients (64.7%) were treated with TachoComb on the tonsillectomy site and 576 without TachoComb. Post-tonsillectomy pain, hemorrhage rates, re-admission rates, and emergency surgery rates for post tonsillectomy hemorrhage were evaluated between patients who received TachoComb and those who did not. RESULTS: TachoComb treatment significantly reduced post tonsillectomy pain and emergency surgery rates for post-tonsillectomy hemorrhage. However, postoperative hemorrhage rate and re-admission rates for post tonsillectomy hemorrhage were not statistically significant between TachoComb treatment group and control group. No patients had complications or adverse reactions after TachoComb treatment. CONCLUSIONS: The use of TachoComb after tonsillectomy significantly reduces pain and emergency surgery for severe post tonsillectomy hemorrhage without an apparent adverse effect. Therefore, TachoComb may be a useful adjuvant in terms of efficacy and safety after tonsillectomy. PMID- 26100058 TI - Mono-allelic mutations of SLC26A4 is over-presented in deaf patients with non syndromic enlarged vestibular aqueduct. AB - OBJECTIVES: Recessive mutations of SLC26A4 are the major cause of hearing impairment associated with enlarged vestibular aqueduct (EVA). In a significant percentage of non-syndromic EVA patients, however, only mono-allelic mutations of SLC26A4 can be identified. In this study, we aimed to evaluate whether presence of mono-allelic mutations of SLC26A4 in those patients was coincidental or etiologically associated with the disorder. METHODS: The exons and flanking splicing sites of SLC26A4 were sequenced in 150 Chinese Han deaf probands with non-syndromic EVA. c.919-2A >G and p.H723R, two frequent mutations of SLC26A4 in Chinese Hans, were screened by an allele-specific PCR-based array in 3056 ethnically-matched normal hearing controls. The frequency of mono-allelic c.919 2A >G and p.H723R mutations was determined in each group. The statistical significance of the difference was analyzed by Fisher's exact test. RESULTS: Bi allelic, mono-allelic and no mutation of SLC26A4 were detected in 98 (65.3%), 18 (12%) and 34 (22.67%) deaf probands with non-syndromic EVA, respectively. The frequency of mono-allelic c.919-2A >G and p.H723R mutations were significantly higher in the 150 deaf probands with non-syndromic EVA (8.67%) than in the 3056 normal hearing controls (1.4%, P=1.8*10(-6)). CONCLUSION: Presence of mono allelic mutations of SLC26A4 in non-syndromic EVA patients is etiologically associated with this disorder. Additional genetic or environmental causes may be present in those patients and demand further investigation and consideration during the genetic diagnosis and counseling. PMID- 26100057 TI - Rigid or flexible laryngoscope: The preference of children. AB - OBJECTIVE: The aim of this study was to evaluate the effects of flexible and rigid endoscopes using a visual analog scale and reveal which one is better tolerated by children. MATERIAL AND METHODS: The pediatric patients with voice disorders examined between July 2012 and October 2014 were included the study. Patients to whom endoscopic visualization had been applied several times were recalled for information about their preference of scope. No local anesthetics were used before both procedures. Pain sensation, gag reflex or vomiting and dyspnea or breathiness were evaluated and graded using a visual analog scale (VAS). RESULTS: A total of 35 patients (77.1% males, 22.9% females) with a median age of 11.3+/-1.8 years (range, 7-15 years) were analyzed. Group 1 consisted of patients who preferred videolaryngostroboscopy (VLS) and Group 2 consisted of patients who preferred flexible fiberoptic nasopharyngoscopy (FFN). Overall, 28 (80%) of the patients preferred videolaryngostroboscopy (VLS) while 7 (20%) of the patients preferred FFN examination. In these examinations 20 patients (57.1%) felt pain, 17 (48.6%) felt irritation, 5 (14.3%) had gag reflex, and 2 (5.7%) had dyspnea. According to this data, the VLS (VAS) scores regarding gag reflex (p=0.017) and dyspnea domains (p=0.022) of the group who preferred FFL were statistically higher than those of the VLS group. No statistically significant difference was determined between the genders in respect of the VLS and FFL scores in all domains. Pain and irritation were the most prominent findings in patients who were reluctant to be examined by FFL. Irritation was statistically significantly higher in Group 1 (p=0.004). Gag reflex was the most disturbing finding described by patients who were reluctant to be examined by VLS. CONCLUSION: In this study, most of the children (80%) preferred rigid laryngoscopy rather than flexible fiberoptic laryngoscopy. Pain and irritation were the most prominent findings for patients who were reluctant to be examined by FFL. Rigid laryngoscopy can be recommended rather than FFN for evaluation of children with vocal fold pathologies. PMID- 26100059 TI - Infraslow status epilepticus: A new form of subclinical status epilepticus recorded in a child with Sturge-Weber syndrome. AB - BACKGROUND: Analysis of infraslow EEG activity (ISA) has shown potential in the evaluation of patients with epilepsy and in the differentiation between focal and generalized epilepsies. Infraslow EEG activity analysis may also provide insights into the pathophysiology of refractory clinical and subclinical status epilepticus. The purpose of this report is to describe a girl with Sturge-Weber syndrome (SWS) who presented with a 96-h refractory encephalopathy and nonischemic hemiparesis and who was identified to have infraslow status epilepticus (ISSE), which successfully resolved after midazolam administration. METHODS: The continuous EEG recording of a 5-year-old girl with known structural epilepsy due to Sturge-Weber syndrome is presented. The patient presented to the ED with acute confusion, eye deviation, and right hemiparesis similar to two previous admissions. Despite administration of lorazepam, fosphenytoin, phenobarbital, and valproic loads, the patient showed no improvement in the clinical condition after 48 h. The continuous video-EEG monitoring (VEM) showed continuous severe diffuse nonrhythmic asymmetric slowing but no apparent ictal activity on continuous conventional EEG recording settings. As brain CT, CTA, CTV, and complete MRI scans including DWI obtained within 72 h of presentation failed to demonstrate any ischemic changes, analysis of the EEG infraslow (ISA) activity was undertaken using LFF: 0.01 Hz and HFF: of 0.1 Hz, respectively. RESULTS: Continuous subclinical unilateral rhythmic ictal ISA was identified. This was only evident on the left hemisphere which correlated with the structural changes due to SWS. A trial of continuous 120 to 240 MUg/kg/h of IV midazolam resulted in immediate resolution of the contralateral hemiparesis and encephalopathy. CONCLUSION: Continuous prolonged rhythmic ictal infraslow activity (ISA) can cause super-refractory subclinical focal status epilepticus. This has not been previously reported, and we propose that this be called infraslow status epilepticus (ISSE). Infraslow EEG activity analysis should be performed in all patients with unexplained subclinical status epilepticus. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26100060 TI - Pregnancy complications and birth outcomes among women experiencing nausea only or nausea and vomiting during pregnancy in the Norwegian Mother and Child Cohort Study. AB - BACKGROUND: To compare pregnancy complications and birth outcomes for women experiencing nausea and vomiting in pregnancy, or nausea only, with symptom-free women. METHODS: Pregnancies from the Norwegian Mother and Child Cohort Study (n = 51 675), a population-based prospective cohort study, were examined. Data on nausea and/or vomiting during gestation and birth outcomes were collected from three questionnaires answered between gestation weeks 15 and 30, and linked with data from the Medical Birth Registry of Norway. Chi-squared tests, one way analysis of variance, multiple linear and logistic regression analyses were used. RESULTS: Women with nausea and vomiting (NVP) totalled 17 070 (33%), while 20 371 (39%) experienced nausea only (NP), and 14 234 (28%) were symptom-free (SF). When compared to SF women, NVP and NP women had significantly increased odds for pelvic girdle pain (adjusted odds ratio, aOR, 2.26, 95% confidence interval, 95% CI, 2.09-2.43, and aOR 1.90, 95% CI, 1.76-2.05, respectively) and proteinuria (aOR 1.50, 95% CI 1.38-1.63, and 1.20, 95% CI 1.10-1.31, respectively). Women with NVP also had significantly increased odds for high blood pressure (aOR 1.40, 95% CI 1.17-1.67) and preeclampsia (aOR 1.13, 95% CI 1.01-1.27). Conversely, the NVP and NP groups had significantly reduced odds for unfavourable birth outcomes such as low birth weight infants (aOR 0.72, 95% CI 0.60-0.88, and aOR 0.73, 95 % CI 0.60-0.88, respectively) and small for gestational age infants (aOR 0.78, 95% CI 0.73-0.84, and aOR 0.87, 95% CI 0.81-0.93, respectively). CONCLUSIONS: We found that women with NVP and NP are more likely to develop pregnancy complications, yet they display mostly favourable delivery and birth outcomes. PMID- 26100061 TI - Putative regulation mechanism for the MSTN gene by a CpG island generated by the SINE marker Ins227bp. AB - BACKGROUND: A single nucleotide polymorphism (SNP) in the first intron of the myostatin gene (MSTN) is associated with aptness of elite Thoroughbreds to race over sprint, middle or long distances. This intronic marker (g.66493737 T ? C), a short interspersed nuclear element (SINE) of 227 bp (Ins227bp) insertion polymorphism in the MSTN promoter, and the adjacent SNP BIEC2-417495 have not been studied for their association with racing aptness of the average Thoroughbreds raced in countries with lower status of the racing industry. This study investigated these markers regarding their prevalence and association with performance in common race horses. Markers were genotyped by amplification refractory mutation system-quantitative PCR (ARMS-qPCR) or amplicon melting. Furthermore, we asked whether the Ins227bp marker might theoretically regulate the expression of myostatin by generating a novel target for DNA methylation or by changing binding sites for transcription factors. Putative sites for DNA methylation or binding of transcription factors were predicted by MethPrimer and by the softwares JASPAR, MatInspector and UniPROBE, respectively. RESULTS: Pairwise linkage disequilibrium between g.66493737 T ? C and Ins227bp was high (r (2) = 0.93). A lower linkage was determined for g.66493737 T ? C and BIEC2-417495 (r (2) = 0.69) as well as for BIEC2-417495 and Ins227bp (r (2) = 0.76). The estimated frequencies for the presence of Ins227bp (I) indel and the C alleles at g.66493737 T ? C and BIEC2-417495 were 0.46, 0.47 and 0.43, respectively. Heterozygotes represented the most abundant genotype at each locus. The best racing distance (BRD) was significantly different between the homozygotes of each SNP (p = 0.01 to 0.03). C allele homozygotes at BIEC2-417495 or g.66493737 T ? C, as well as Ins227bp homozygotes earned most money on a mean distance ranging from 1211 to 1230 m. Heterozygotes earned most money on races over 1690 to 1709 m. The BRD for the T/T carriers at both SNP loci and for the SINE-free genotype was 1812 to 1854 m. Other performance parameters were not significantly different between the genotypes, except of the relative success score (RSS). The RSS was significantly slightly better on a distance of <= 1300 m for all carriers of the C allele and the Ins227bp compared to homozygous T genotypes and SINE-negative horses (p = 0.037 to 0.046). For distances of more than 1300 m the RSS was not significantly different between genotypes. In silico assessment indicated that the Ins227bp promoter insertion might have generated a CpG island and a few novel putative binding sites for transcription factors. CONCLUSIONS: All three target polymorphisms (Ins227bp, g.66493737 T ? C, BIEC2-417495) are suitable markers to assess the ability of non-elite Thoroughbreds to race at short or longer distances. The CpG island generated by Ins227bp may cause training-induced silencing of MSTN expression. PMID- 26100062 TI - Membrane channels and transporters in cancers. PMID- 26100063 TI - Mathematical Modeling of Acupuncture as Cancer Symptom Therapy: First Steps. PMID- 26100064 TI - Acupuncture Research at Memorial Sloan Kettering Cancer Center. AB - Acupuncture may help treat specific cancer-related symptoms. Here, we summarize our clinical trials that sought to determine acupuncture's role in managing cancer-related symptoms. Trials have been conducted to determine acupuncture's ability to mitigate cancer-related symptoms including dyspnea, fatigue, xerostomia, lymphedema, hot flashes, postoperative ileus, pain and dysfunction after neck dissection, and postthoracotomy pain. Published studies indicate that acupuncture versus placebo acupuncture failed to reduce cancer-related dyspnea. Both true and sham acupuncture alleviated fatigue slightly, but no significant differences between groups emerged. Compared with sham acupuncture, our research showed that acupuncture significantly improved saliva production in patients with xerostomia and significantly reduced lymphedema patients' arm circumference in a pilot study. However, acupuncture failed to significantly reduce hot flashes and was no more successful than sham acupuncture in reducing postoperative ileus. Significant reductions in pain and dysfunction occurred in cancer patients after neck dissection. In a feasibility study, acupuncture was found to be acceptable to lung cancer patients and did not interfere with standard postoperative care. In summary, acupuncture is a potential candidate for the treatment of some important cancer-related symptoms. Large clinical trials and research to investigate mechanistic pathways are warranted. PMID- 26100065 TI - Acupuncture Therapy for the Treatment of Myelosuppression after Chemotherapy: A Literature Review over the Past 10 Years. AB - The aim of this study is to review current studies on the effect of acupuncture therapy on bone marrow suppression after chemotherapy. The authors of the present paper have searched related literature over the past 10 years at home and abroad, analyzing the features and the effects of acupuncture therapy (including acupuncture, moxibustion, point injection, point application, etc.) for treating myelosuppression after tumor chemotherapy. We also discuss the year of publication, document type, acupuncture therapy, acupoint selection, and adverse effects with figures. We analyzed 159 articles related to acupuncture therapy from 2004 to 2013, and the analysis revealed that point injection was the most frequently used therapy for clinical applications, and that Zusanli (ST36) was the most frequently used acupoint. The results showed that some problems regarding the design method, acupoint selection, and acupuncture intervention measure existed in those research studies. We hope to provide readers with an overall and objective understanding of acupuncture and moxibustion therapy for treating myelosuppression after tumor chemotherapy. PMID- 26100066 TI - Patient-reported Outcomes of Acupuncture for Symptom Control in Cancer. AB - Acupuncture is increasingly offered as a treatment option for managing cancer related symptoms. In addition to randomized controlled trials, patient-reported outcomes may be needed to establish treatment effectiveness. This study retrospectively examined the symptoms and the satisfaction ratings of 90 patients receiving acupuncture at an integrative oncology clinic. At least two acupuncture sessions were completed by 72% of the sample. The prevalence rates of fatigue, pain, anxiety, physical distress, emotional distress, and poor quality of life before acupuncture were > 62%. Paired t tests revealed a significant reduction in symptoms from baseline until after the first acupuncture session and after the last session (p < 0.05). Fewer (21%) patients reported nausea, which was significantly reduced after the first session, but not the last session. Reductions represented clinically meaningful differences in 33-41% of patients after the first session and in 41-53% of patients after the last session for all symptoms, except nausea. A small subset of patients (0-8%) reported worsening symptoms after acupuncture. The majority were satisfied with the service. The results of this study suggest that acupuncture may be useful as an adjunct treatment for cancer symptom management. While high-quality trials are still needed to establish the treatment's efficacy, patients may benefit from these primarily safe, low-cost services. PMID- 26100067 TI - Antitumor and Wound Healing Properties of Rubus ellipticus Smith. AB - The present investigation has been undertaken to study the antioxidant, antitumor, and wound healing properties of Rubus ellipticus. The R. ellipticus leaves were extracted using organic solvents in Soxhlet and were subjected to in vitro antioxidant assays. R. ellipticus leaf methanol (RELM) extract, which showed higher in vitro antioxidant activity, was taken for the evaluation of in vivo antioxidant, antitumor, and wound healing properties. Acute oral and dermal toxicity studies showed the safety of RELM up to a dose of 2 g/kg. A significant wound healing property was observed in incision, excision, and Staphylococcus aureus-induced infected wound models in the treatment groups compared to the control group. A complete epithelialization period was noticed during the 13(th) day and the 19(th) day. A 250-mg/kg treatment was found to prolong the life span of mice with Ehrlich ascite carcinoma (EAC; 46.76%) and to reduce the volume of Dalton's lymphoma ascite (DLA) solid tumors (2.56 cm(3)). The present study suggests that R. ellipticus is a valuable natural antioxidant and that it is immensely effective for treating skin diseases, wounds, and tumors. PMID- 26100068 TI - Cancer-related Fatigue in Patients with Advanced Cancer Treated with Autonomic Nerve Pharmacopuncture. AB - The purpose of this study was to observe the effects of autonomic nerve pharmacopuncture (ANP) treatment on cancer-related fatigue (CRF) in patients with advanced cancer. This observational case study was conducted at the East West Cancer Center of Daejeon University's Dunsan Korean Medical Hospital. Two patients were observed. One patient was diagnosed with left thymic cancer metastatic to the left pleura. The other patient had terminal-stage cervical cancer with iliac bone and lumbar 5 metastases. We injected mountain ginseng pharmacopuncture (MGP) into acupoints alongside the spine (Hua-Tuo-Jia-Ji-Xue, EX B2). We examined the patients for CRF using the Korean version of the Revised Piper Fatigue Scale (RPFS-K), which is a self-assessment tool. The scores on the RPFS-K for both patients tended to decrease during the treatment. Laboratory findings, including hematological changes, were also checked. Liver and renal function tests showed that the treatment was safe. Although further large population studies are necessary, this case study suggests that ANP has a favorable effect on CRF in patients with advanced cancer. PMID- 26100069 TI - Recurrent Oligodendroglioma Treated with Acupuncture and Pharmacopuncture. AB - Acupuncture and pharmacopuncture have been shown to be effective in tumor treatment. However, their effectiveness for treating oligodendroglioma has not been reported yet. The purpose of this study was to provide an initial report on the effectiveness of acupuncture and pharmacopuncture for the treatment of an oligodendroglioma by presenting a case that was treated successfully. A 54-year old man, who had experienced intracranial hemorrhage, was diagnosed with recurrent oligodendroglioma. His expected survival period was 3-6 months. The patient received daily acupuncture and weekly pharmacopuncture of mountain ginseng and bee venom. After treatment for 18 months, the tumor size was decreased markedly on brain magnetic resonance imaging, and severe seizures had disappeared. In this case, a combination of acupuncture and pharmacopuncture was shown to be effective for the treatment of recurrent oligodendroglioma. PMID- 26100070 TI - Methods to Standardize a Multicenter Acupuncture Trial Protocol to Reduce Aromatase Inhibitor-related Joint Symptoms in Breast Cancer Patients. AB - Robust methods are needed to efficiently conduct large, multisite, randomized, controlled clinical trials of acupuncture protocols. The Southwest Oncology Group (SWOG) S1200 trial is a randomized, controlled (i.e., sham-controlled and waitlist-controlled) trial of a standardized acupuncture protocol for treating aromatase inhibitor (AI)-associated arthralgias in early-stage breast cancer patients (n = 228). The primary objective of this study was to determine whether true acupuncture administered twice weekly for 6 weeks, as compared to sham acupuncture or a waitlist control, reduced AI-associated joint pain at 6 weeks as assessed by patient reports. The study was conducted at 11 institutions across the United States. The true acupuncture protocol was developed using a consensus based process. The true acupuncture and the sham acupuncture protocols each consisted of 12 sessions administered for 6 weeks, followed by one weekly session for 6 weeks. The true acupuncture protocol used standardized protocol points, and the standardized acupoints were tailored to a patient's joint symptoms. The similarly standardized sham acupuncture protocol utilized superficial needling of nonacupoints. Standardized methods were developed to train and monitor acupuncturists and included online and in-person training, study manuals, monthly phone calls, and remote quality assurance monitoring throughout the study period. The research staff similarly received online and in-person training and monthly phone calls. PMID- 26100071 TI - Extremely preterm infants who are small for gestational age have a high risk of early hypophosphatemia and hypokalemia. AB - AIM: Electrolyte balances have not been sufficiently evaluated in extremely preterm infants after early parenteral nutrition. We investigated the risk of early hypophosphatemia and hypokalemia in extremely preterm infants born small for gestational age (SGA) who received nutrition as currently recommended. METHODS: This prospective, observational cohort study included all consecutive extremely preterm infants born at 24-27 weeks who received high amino acids and lipid perfusion from birth. We evaluated the electrolyte levels of SGA infants and infants born appropriate for gestational age (AGA) during the first five days of life. RESULTS: The 12 SGA infants had lower plasma potassium levels from Day One compared to the 36 AGA infants and were more likely to have hypokalemia (58% vs 17%, p = 0.001) and hypophosphatemia (40% vs 9%, p < 0.01) during the five-day observation period. After adjusting for perinatal factors, SGA remained significantly associated with hypophosphatemia (odds ratio 1.39, confidence intervals 1.07-1.81, p = 0.01). CONCLUSION: Extremely preterm infants born SGA who were managed with currently recommended early parenteral nutrition had a high risk of early hypokalemia and hypophosphatemia. Potassium and phosphorus intakes should be set at sufficient levels from birth onwards, especially in SGA infants. PMID- 26100073 TI - Asymmetrical frontal cortical activity associated with differential risk for mood and anxiety disorder symptoms: An RDoC perspective. AB - The recently launched NIMH Research Domain Criteria (RDoC) initiative aims to examine the relationship between core biobehavioral dimensions and symptom profiles that either cut across traditional disorder categories or that are unique to specific clinical phenomenon. A biobehavioral construct that has received considerable attention and that is directly relevant to the Positive Valence Systems domain of the RDoC initiative is approach motivation. One way approach motivation is frequently operationalized is left versus right frontal electroencephalographic (EEG) activity, with greater relative left frontal EEG activity reflecting increased approach motivation and decreased relative left frontal EEG activity reflecting decreased approach motivation or increased withdrawal tendencies. The objective of the present review paper is to examine the relationship between relative left frontal EEG activity and mood and anxiety related symptoms from an RDoC perspective. We first provide an overview of the approach-withdrawal motivational model of frontal EEG asymmetry. Second, we review evidence that relative left frontal EEG activity is associated with a differential risk for unipolar depression versus bipolar disorder. Third, and in line with the mission statement of the RDoC, we move beyond considering mood and anxiety disorders as unitary constructs or homogenous disorders and instead propose that individual differences in relative left frontal EEG activity may be uniquely associated with specific symptom clusters of depression (i.e., anhedonia), hypomania/mania (i.e., symptoms characterized by excessive approach motivation), and anxiety (i.e., anxious apprehension versus anxious arousal). Identifying the relationship between relative left frontal EEG activity and specific mood and anxiety-related symptom clusters has important implications for clinical science, assessment, and treatment. PMID- 26100072 TI - Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment. AB - BACKGROUND: There are several specific inflammatory and oxidative correlates among patients with hypothyroidism, but most studies are cross-sectional and do not evaluate the change in parameters during the treatment. The aim of this study was to investigate the effect of levothyroxine replacement therapy on biomarkers of oxidative stress (OS) and systemic inflammation in patients with hypothyroidism. METHODS: In this prospective open-label study, 17 patients with recently diagnosed primary hypothyroidism due to Hashimoto's thyroiditis who were not taking levothyroxine were included. The following parameters were measured before and at 6 and 12 months of levothyroxine treatment with an average dose of 1.5 to 1.7 MUg/kg/day: thyroid-stimulating hormone (TSH), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP), interleukin 1 (IL-1), IL-6, IL-10, interferon gamma (INF-gamma), tumor necrosis factor alpha (TNF-alpha), thiobarbituric acid-reactive substances (TBARS), activity of aminolevulinic acid dehydratase (delta-ALA-D), nonprotein and total thiol (NP-SH and T-SH) groups, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Generalized estimating equation (GEE) modeling was used to analyze the effects of LRT (at pre-treatment, 6 months and 12 months) on those variables. The hypothyroidism status (i.e., overt or subclinical hypothyroidism) was included as a confounder in all analyses. An additional GEE post hoc analysis was made to compare time points. RESULTS: There was a significant decrease in TSH over time (P < 0.0001), (initial levels were on average 32.4 MUIU/mL and 10.5 MUIU/mL at 12 months). There was a significant increase in FT4 (P < 0.0001) (initial levels were on average 0,8 ng/dL and 2.7 ng/dL at 12 months). There were significant changes in interleukin levels over time, with a significant increase in IL-10 (P < 0.0001) and significant decreases in IL-1 (P < 0.0001), IL-6 (P < 0.0001), INF-gamma (P < 0.0001) and TNF-alpha (P < 0.0001). No significant difference in hs-CRP over time was observed (P < 0.284). There was a significant reduction in NP-SH (P < 0.0001). CONCLUSIONS: This study observed significant changes in the inflammatory profile in hypothyroid patients under treatment, with reduction of pro inflammatory cytokines and elevation of anti-inflammatory cytokine. In these patients, a decrease in low-grade chronic inflammation may have clinical relevance due to the known connection between chronic inflammation, atherosclerosis and cardiovascular events. PMID- 26100074 TI - An outbreak of an unusual strain of Listeria monocytogenes infection in North East Scotland. AB - Listeria monocytogenes infection is an important cause of illness and hospitalization in vulnerable individuals. In the present study, we describe a community outbreak of Listeria monocytogenes in the North-East region of Scotland, which was epidemiologically, environmentally and microbiologically linked to a local meat product and ready-to-eat product manufacturer. Infected individuals were interviewed, and an environmental investigation was conducted. Clinical and environmental samples were tested by culture, and isolates were typed by fluorescent amplified fragment length polymorphism (fAFLP). Three cases of Listeria monocytogenes were linked geographically, had the same serotype (1/2a) and were indistinguishable by fAFLP type XII.6. The human, food and environmental isolates were of the same serotype and were indistinguishable by molecular typing. This is the first community outbreak of L. monocytogenes reported in Scotland since the current outbreak surveillance was established in 1996. Epidemiological and laboratory evidence indicated poor hand hygiene, unhygienic practices and cross-contamination throughout the manufacturing process of ready-to-eat foods as a possible cause of the outbreak. More stringent control of commercial food establishments that provide ready-to-eat food and the need to advise specifically vulnerable groups, e.g., pregnant women, of the risk of L. monocytogenes in ready-to-eat food is urgently needed. PMID- 26100076 TI - (13)C metabolic flux analysis of the extremely thermophilic, fast growing, xylose utilizing Geobacillus strain LC300. AB - Thermophiles are increasingly used as versatile hosts in the biotechnology industry. One of the key advantages of thermophiles is the potential to achieve high rates of feedstock conversion at elevated temperatures. The recently isolated Geobacillus strain LC300 grows extremely fast on xylose, with a doubling time of less than 30 min. In the accompanying paper, the genome of Geobacillus LC300 was sequenced and annotated. In this work, we have experimentally validated the metabolic network model using parallel (13)C-labeling experiments and applied (13)C-metabolic flux analysis to quantify precise metabolic fluxes. Specifically, the complete set of singly labeled xylose tracers, [1-(13)C], [2-(13)C], [3 (13)C], [4-(13)C], and [5-(13)C]xylose, was used for the first time. Isotopic labeling of biomass amino acids was measured by gas chromatography mass spectrometry (GC-MS). Isotopic labeling of carbon dioxide in the off-gas was also measured by an on-line mass spectrometer. The (13)C-labeling data was then rigorously integrated for flux elucidation using the COMPLETE-MFA approach. The results provided important new insights into the metabolism of Geobacillus LC300, its efficient xylose utilization pathways, and the balance between carbon, redox and energy fluxes. The pentose phosphate pathway, glycolysis and TCA cycle were found to be highly active in Geobacillus LC300. The oxidative pentose phosphate pathway was also active and contributed significantly to NADPH production. No transhydrogenase activity was detected. Results from this work provide a solid foundation for future studies of this strain and its metabolic engineering and biotechnological applications. PMID- 26100077 TI - Metabolic engineering of Corynebacterium glutamicum for the production of itaconate. AB - The capability of Corynebacterium glutamicum for glucose-based synthesis of itaconate was explored, which can serve as building block for production of polymers, chemicals, and fuels. C. glutamicum was highly tolerant to itaconate and did not metabolize it. Expression of the Aspergillus terreus CAD1 gene encoding cis-aconitate decarboxylase (CAD) in strain ATCC13032 led to the production of 1.4mM itaconate in the stationary growth phase. Fusion of CAD with the Escherichia coli maltose-binding protein increased its activity and the itaconate titer more than two-fold. Nitrogen-limited growth conditions boosted CAD activity and itaconate titer about 10-fold to values of 1440 mU mg(-1) and 30 mM. Reduction of isocitrate dehydrogenase activity via exchange of the ATG start codon to GTG or TTG resulted in maximal itaconate titers of 60 mM (7.8 g l(-1)), a molar yield of 0.4 mol mol(-1), and a volumetric productivity of 2.1 mmol l(-1) h(-1). PMID- 26100075 TI - PI3K-C2gamma is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. AB - In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes and whether isoform-selective interplays exist is currently unclear. Here we report that insulin signalling triggers the association of the liver-specific class II PI3K isoform gamma (PI3K-C2gamma) with Rab5-GTP, and its recruitment to Rab5-positive early endosomes. In these vesicles, PI3K-C2gamma produces a phosphatidylinositol-3,4-bisphosphate pool specifically required for delayed and sustained endosomal Akt2 stimulation. Accordingly, loss of PI3K-C2gamma does not affect insulin-dependent Akt1 activation as well as S6K and FoxO1-3 phosphorylation, but selectively reduces Akt2 activation, which specifically inhibits glycogen synthase activity. As a consequence, PI3K-C2gamma-deficient mice display severely reduced liver accumulation of glycogen and develop hyperlipidemia, adiposity as well as insulin resistance with age or after consumption of a high-fat diet. Our data indicate PI3K-C2gamma supports an isoenzyme-specific forking of insulin-mediated signal transduction to an endosomal pool of Akt2, required for glucose homeostasis. PMID- 26100078 TI - Spatial behavior of two coral reef fishes within a Caribbean marine protected area. AB - A better understanding of the key ecological processes of marine organisms is fundamental to improving design and effective implementation of marine protected areas (MPAs) and marine biodiversity. The movement behavior of coral reef fish is a complex mechanism that is highly linked to species life-history traits, predation risk and food resources. We used passive acoustic telemetry to study monthly, daily and hourly movement patterns and space use in two species, Schoolmaster snapper (Lutjanus apodus) and Stoplight parrotfish (Sparisoma viride). We investigated the spatial overlap between the two species and compared intra-specific spatial overlap between day and night. Presence-absence models showed different diel presence and habitat use patterns between the two species. We constructed a spatial network of the movement patterns, which showed that for both species when fish were detected by the array of receivers most movements were made around the coral reef habitat while occasionally moving to silt habitats. Our results show that most individuals made predictable daily crepuscular migrations between different locations and habitat types, although individual behavioral changes were observed for some individuals across time. Our study also highlights the necessity to consider multiple species during MPA implementation and to take into account the specific biological and ecological traits of each species. The low number of fish detected within the receiver array, as well as the intraspecific variability observed in this study, highlight the need to compare results across species and individuals to be used for MPA management. PMID- 26100079 TI - Mechanochemical Synthesis of Free-Standing Platinum Nanosheets and Their Electrocatalytic Properties. AB - Robust, 26 nm thick free-standing platinum nanosheets, an extremely rare morphology for metal nanostructures, are obtained by employing fluid induced shearing force of the order of 1.8 N and differential shear-stress of 0.5 kPa across the diameter of a Te template nanorod undergoing galvanic displacement by Pt4+ . Corrugation leads to their large surface area and much improved electrocatalytic properties when compared with conventional Pt catalysts. PMID- 26100080 TI - Quantification of alpha-amanitin in biological samples by HPLC using simultaneous UV- diode array and electrochemical detection. AB - alpha-Amanitin is a natural bicyclic octapeptide, from the family of amatoxins, present in the deadly mushroom species Amanita phalloides. The toxicological and clinical interests raised by this toxin, require highly sensitive, accurate and reproducible quantification methods for pharmacokinetic studies. In the present work, a high-performance liquid chromatographic (HPLC) method with in-line connected diode-array (DAD) and electrochemical (EC) detection was developed and validated to quantify alpha-amanitin in biological samples (namely liver and kidney). Sample pre-treatment consisted of a simple and unique deproteinization step with 5% perchloric acid followed by centrifugation at 16,000*g, 4 degrees C, for 20min. The high recovery found for alpha-amanitin (>=96.8%) makes this procedure suitable for extracting alpha-amanitin from liver and kidney homogenates. The resulting supernatant was collected and injected into the HPLC. Mobile phase was composed by 20% methanol in 50mM citric acid, and 0.46mM octanessulfonic acid, adjusted to pH 5.5. The chromatographic runs took less than 22min and no significant endogenous interferences were observed at the alpha amanitin retention time. Calibration curves were linear with regression coefficients higher than 0.994. The overall inter- and intra-assay precision did not exceed 15.3%. The present method has low interferences with simple and fast processing steps, being a suitable procedure to support in vivo toxicokinetic studies involving alpha-amanitin. In fact, the validated method was successfully applied to quantify alpha-amanitin in biological samples following intraperitoneal alpha-amanitin administration to rats. Moreover, human plasma was also used as matrix and the purposed method was adequate for detection of alpha amanitin in that matrix. The results clearly indicate that the proposed method is suitable to investigate the pharmacokinetic and tissue distribution of alpha amanitin. Additionally, the method will be very useful in the development of novel and potent antidotes against amatoxins poisoning and to improve the knowledge of alpha-amanitin toxicity. PMID- 26100081 TI - RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. AB - BACKGROUND: Mitochondrial metabolism is known to be important for T-cell activation. However, its involvement in effector T-cell differentiation has just begun to gain attention. Importantly, how metabolic pathways are integrated with T-cell activation and effector cell differentiation and function remains largely unknown. OBJECTIVE: We sought to test our hypothesis that RhoA GTPase orchestrates glycolysis for TH2 cell differentiation and TH2-mediated allergic airway inflammation. METHODS: Conditional RhoA-deficient mice were generated by crossing RhoA(flox/flox) mice with CD2-Cre transgenic mice. Effects of RhoA on TH2 differentiation were evaluated based on in vitro TH2-polarized culture conditions and in vivo in ovalbumin-induced allergic airway inflammation. Cytokine levels were measured by using intracellular staining and ELISA. T-cell metabolism was measured by using the Seahorse XF24 Analyzer and flow cytometry. RESULTS: Disruption of RhoA inhibited T-cell activation and TH2 differentiation in vitro and prevented the development of allergic airway inflammation in vivo, with no effect on TH1 cells. RhoA deficiency in activated T cells led to multiple defects in metabolic pathways, such as glycolysis and oxidative phosphorylation. Importantly, RhoA couples glycolysis to TH2 cell differentiation and allergic airway inflammation through regulating IL-4 receptor mRNA expression and TH2 specific signaling events. Finally, inhibition of Rho-associated protein kinase, an immediate downstream effector of RhoA, blocked TH2 differentiation and allergic airway inflammation. CONCLUSION: RhoA is a key component of the signaling cascades leading to TH2 differentiation and allergic airway inflammation at least in part through control of T-cell metabolism and the Rho associated protein kinase pathway. PMID- 26100083 TI - Optimal asthma diagnosis: A destination or a process? PMID- 26100082 TI - Consensus communication on early peanut introduction and the prevention of peanut allergy in high-risk infants. AB - The purpose of this brief communication is to highlight emerging evidence to existing guidelines regarding potential benefits of supporting early, rather than delayed, peanut introduction during the period of complementary food introduction in infants. This document should be considered as interim guidance based on consensus among the following organizations: American Academy of Allergy, Asthma & Immunology, American Academy of Pediatrics, American College of Allergy, Asthma & Immunology, Australasian Society of Clinical Immunology and Allergy, Canadian Society of Allergy and Clinical Immunology, European Academy of Allergy and Clinical Immunology, Israel Association of Allergy and Clinical Immunology, Japanese Society for Allergology, Society for Pediatric Dermatology, and World Allergy Organization. More formal guidelines regarding early-life, complementary feeding practices and the risk of allergy development will follow in the next year from the National Institute of Allergy and Infectious Diseases-sponsored Working Group and the European Academy of Allergy and Clinical Immunology. PMID- 26100085 TI - CpG-DNA enhances the tight junction integrity of the bronchial epithelial cell barrier. PMID- 26100084 TI - Rhinovirus infection interferes with induction of tolerance to aeroantigens through OX40 ligand, thymic stromal lymphopoietin, and IL-33. AB - BACKGROUND: Rhinovirus infection at an early age has been associated with development of asthma, but how rhinovirus influences the immune response is not clear. OBJECTIVE: Tolerance to inhaled antigen is mediated through induction of regulatory T (Treg) cells, and we examined whether rhinovirus infection of the respiratory tract can block airway tolerance by modulating Treg cells. METHODS: The immune response to intranasal ovalbumin in mice was assessed with concomitant infection with RV1B, and the factors induced in vivo were compared with those made by human lung epithelial cells infected in vitro with RV16. RESULTS: RV1B infection of mice abrogated tolerance induced by inhalation of soluble ovalbumin, suppressing the normal generation of forkhead box protein 3-positive Treg cells while promoting TH2 cells. Furthermore, RV1B infection led to susceptibility to asthmatic lung disease when mice subsequently re-encountered aeroantigen. RV1B promoted early in vivo expression of the TNF family protein OX40 ligand on lung dendritic cells that was dependent on the innate cytokine thymic stromal lymphopoietin (TSLP) and also induced another innate cytokine, IL-33. Inhibiting each of these pathways allowed the natural development of Treg cells while minimizing TH2 differentiation and restored tolerance in the face of RV1B infection. In accordance, RV16 infection of human lung epithelial cells upregulated TSLP and IL-33 expression. CONCLUSIONS: These results suggest that infection of the respiratory epithelium with rhinovirus can antagonize tolerance to inhaled antigen through combined induction of TSLP, IL-33, and OX40 ligand and that this can lead to susceptibility to asthmatic lung inflammation. PMID- 26100086 TI - Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. AB - BACKGROUND: Well-differentiated systemic mastocytosis (WDSM) is a rare variant of systemic mastocytosis (SM) characterized by bone marrow (BM) infiltration by mature-appearing mast cells (MCs) often lacking exon 17 KIT mutations. Because of its rarity, the clinical and biological features of WDSM remain poorly defined. OBJECTIVE: We sought to determine the clinical, biological, and molecular features of a cohort of 33 patients with mastocytosis in the skin in association with BM infiltration by well-differentiated MCs and to establish potential diagnostic criteria for WDSM. METHODS: Thirty-three patients with mastocytosis in the skin plus BM aggregates of round, fully granulated MCs lacking strong CD25 and CD2 expression in association with clonal MC features were studied. RESULTS: Our cohort of patients showed female predominance (female/male ratio, 4:1) and childhood onset of the disease (91%) with frequent familial aggregation (39%). Skin involvement was heterogeneous, including maculopapular (82%), nodular (6%), and diffuse cutaneous (12%) mastocytosis. KIT mutations were detected in only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I817V (n = 1) mutations. BM MCs displayed a unique immunophenotypic pattern consisting of increased light scatter features, overexpression of cytoplasmic carboxypeptidase, and aberrant expression of CD30, together with absent (79%) or low (21%) positivity for CD25, CD2, or both. Despite only 9 (27%) of 33 patients fulfilling the World Health Organization criteria for SM, our findings allowed us to establish the systemic nature of the disease, which fit with the definition of WDSM. CONCLUSIONS: WDSM represents a rare clinically and molecularly heterogeneous variant of SM that requires unique diagnostic criteria to avoid a misdiagnosis of cutaneous mastocytosis per current World Health Organization criteria. PMID- 26100087 TI - New wheat allergens related to baker's asthma. PMID- 26100088 TI - Duration of wheezy episodes in early childhood is independent of the microbial trigger. AB - BACKGROUND: Wheezy episodes in young children are often triggered by viral and bacterial respiratory tract infections, but there is little evidence supporting the hypothesis that symptom duration depends on the specific microbial trigger. OBJECTIVE: We sought to investigate whether the duration of wheezy episodes in young children depends on the microbial trigger. METHODS: Two hundred eighty three children from the Copenhagen Prospective Study on Asthma in Childhood2000 at-risk birth cohort were prospectively examined for common airway pathogenic bacteria and viruses during acute wheezy episodes in the first 3 years of life. Findings were related to symptomatic duration of episodes, as monitored in daily diary cards from birth. RESULTS: Eight hundred thirty-seven samples were investigated for viruses, bacteria, or both. Both viruses and bacteria were identified in 55% of episodes, bacteria were identified exclusively in 31% of episodes, and viruses were identified exclusively in 10% of episodes. The median duration of acute symptoms was 9 days (interquartile range, 5-16 days), and duration was independent of bacterial or viral species. CONCLUSIONS: The duration of wheezy episodes was independent of pathogenic airway bacterial or viral species. This suggests that symptom burden from infections is dependent on other factors, such as environmental exposures or host factors. The common term viral wheeze seems inappropriate in view of the finding of pathogenic bacteria in 86% of wheezy episodes. PMID- 26100090 TI - Early growth patterns are associated with intelligence quotient scores in children born small-for-gestational age. AB - OBJECTIVE: To assess whether patterns of growth trajectory during infancy are associated with intelligence quotient (IQ) scores at 4 years of age in children born small-for-gestational age (SGA). METHODS: Children in the Collaborative Perinatal Project born SGA were eligible for analysis. The primary outcome was the Stanford-Binet IQ score at 4 years of age. Growth patterns were defined based on changes in weight-for-age z-scores from birth to 4 months and 4 to 12 months of age and consisted of steady, early catch-up, late catch-up, constant catch-up, early catch-down, late catch-down, constant catch-down, early catch-up & late catch-down, and early catch-down & late catch-up. Multivariate linear regression was used to assess associations between patterns of growth and IQ. RESULTS: We evaluated patterns of growth and IQ in 5640 children. Compared with children with steady growth, IQ scores were 2.9 [standard deviation (SD)=0.54], 1.5 (SD=0.63), and 2.2 (SD=0.9) higher in children with early catch-up, early catch-up and later catch-down, and constant catch-up growth patterns, respectively, and 4.4 (SD=1.4) and 3.9 (SD=1.5) lower in children with early catch-down & late catch-up, and early catch-down growth patterns, respectively. CONCLUSIONS: Patterns in weight gain before 4 months of age were associated with differences in IQ scores at 4 years of age, with children with early catch-up having slightly higher IQ scores than children with steady growth and children with early catch-down having slightly lower IQ scores. These findings have implications for early infant nutrition in children born SGA. PMID- 26100089 TI - TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development. AB - BACKGROUND: Heterozygous C104R or A181E TNF receptor superfamily member 13b (TNFRSF13B) mutations impair removal of autoreactive B cells, weaken B-cell activation, and convey to patients with common variable immune deficiency (CVID) an increased risk for autoimmunity. How mutant transmembrane activator and CAML interactor (TACI) influences wild-type TACI function is unclear; different models suggest either a dominant negative effect or haploinsufficiency. OBJECTIVE: We investigated potential TACI haploinsufficiency by analyzing patients with antibody-deficient Smith-Magenis syndrome (SMS) who possess only 1 TNFRSF13B allele and antibody-deficient patients carrying one c.204insA TNFRSF13B null mutation. METHODS: We tested the reactivity of antibodies isolated from single B cells from patients with SMS and patients with a c.204insA TNFRSF13B mutation and compared them with counterparts from patients with CVID with heterozygous C104R or A181E TNFRSF13B missense mutations. We also assessed whether loss of a TNFRSF13B allele induced haploinsufficiency in naive and memory B cells and recapitulated abnormal immunologic features typical of patients with CVID with heterozygous TNFRSF13B missense mutations. RESULTS: We found that loss of a TNFRSF13B allele does not affect TACI expression, activation responses, or establishment of central B-cell tolerance in naive B cells. Additionally, patients with SMS and those with a c.204insA TNFRSF13B mutation display normal regulatory T-cell function and peripheral B-cell tolerance. The lack of a TNFRSF13B allele did result in decreased TACI expression on memory B cells, resulting in impaired activation and antibody secretion. CONCLUSION: TNFRSF13B hemizygosity does not recapitulate autoimmune features of CVID-associated C104R and A181E TNFRSF13B mutations, which likely encode dominant negative products, but instead reveals selective TACI haploinsufficiency at later stages of B-cell development. PMID- 26100091 TI - Management of Posterior Malleolar Fractures: A Systematic Review. AB - Posterior malleolar fractures are relatively common and usually result from rotational ankle injuries. Although treatment of associated lateral and medial structures is well established, several controversies exist in the management of posterior malleolus fractures. We performed a systematic review of the current published data with regard to the diagnosis, management, and prognosis of posterior malleolus fractures. A total of 33 studies (8 biomechanical and 25 clinical) with >950 patients were reviewed. The outcome of ankle fractures with posterior malleolar involvement was poor; however, the evidence was not enough to prove that the size of the posterior malleolus affects the outcome. Significant heterogeneity was noted in the cutoff size of the posterior malleolar fragment in determining management. The outcome was related to other factors, such as fracture displacement, congruency of the articular surface, and residual tibiotalar subluxation. Indirect evidence showed that large fracture fragments were associated with fracture dislocations and ankle instability and, thus, might require surgical fixation. We have concluded that the evidence to prove that the size of the posterior malleolar affects the outcome of ankle fractures is not enough, and the decision to treat these fractures should be determined by other factors, as stated previously. PMID- 26100092 TI - A systematic review on comparing 2 common models for management of warfarin therapy; pharmacist-led service versus usual medical care. AB - Despite a growing body of literature supporting the potential benefit of pharmacist-managed warfarin therapy (PMWT), comprehensive reviews regarding this topic are still lacking. A systematic search of literature was done in Pubmed/Medline, Scopus, Google Scholar, and Cochrane Library from database inception to January 2014. Studies comparing PMWT with usual medical care (UMC) regarding the control of anticoagulation, bleeding and thromboembolic events, mortality, hospitalization, emergency department visit, cost, patients' satisfaction, and quality of life were included. Of 758 potential articles identified, 24 studies (4 randomized controlled trials [RCT] and 20 non-RCT studies) with a population of 11,607 were included. Among non-RCT studies, the percentage of time in the therapeutic range (72.1% vs 56.7%; P = .013), major bleeding events (0.6% vs 1.7%, P < .001), thromboembolic events (0.6% vs 2.9%; P < .001), hospitalization (3% vs 10%; P < .001), emergency department visits (7.9% vs 23.9%; P < .0001) significantly favored PMWT. The study supported PMWT regarding cost saving and patient satisfaction. The results showed that the PMWT model is superior to UMC in managing warfarin therapy based on observational studies. As well, it is comparable to UMC based on RCT studies. PMID- 26100093 TI - A biodegradable ocular implant for long-term suppression of intraocular pressure. AB - Timolol maleate (TM) has been used for many years for the reduction of intraocular pressure (IOP) in glaucoma patients. However, the topical mode of administration (eyedrops) is far from optimal because of the issues of low bioavailability, high drug wastage, and lack of patient compliance. Suboptimal control of the IOP leads to disease progression and eventually to blindness. Ideally, TM is delivered to the patient so that its action is both localized and sustained for 3 months or more. In this work, we developed a subconjunctival TM microfilm for sustained, long-term delivery of TM to the eyes, using the biodegradable elastomer poly(lactide-co-caprolactone) (PLC). The copolymer is biocompatible and has flexibility and mechanical characteristics suitable for a patient-acceptable implant. Controlling the release of TM for 3 months is challenging, and this work describes how, by using a combination of multilayering and blending with poly(ethylene glycol) (PEG) copolymers, we were able to develop a TM-incorporated biodegradable film that can deliver TM at a therapeutic dose for 90 days in vitro. The data was further confirmed in a diseased primate model, with sustained IOP-lowering effects for 5 months with a single implant, with acceptable biocompatibility and partial degradation. PMID- 26100094 TI - Large and Tunable Polar-Toroidal Coupling in Ferroelectric Composite Nanowires toward Superior Electromechanical Responses. AB - The collective dipole behaviors in (BaTiO3)m/(SrTiO3)n composite nanowires are investigated based on the first-principles-derived simulations. It demonstrates that such nanowire systems exhibit intriguing dipole orders, due to the combining effect of the anisotropic electrostatic interaction of the nanowire, the SrTiO3 layer-modified electrostatic interaction and the multiphase ground state of BaTiO3 layer. Particularly, a strong polar-toroidal coupling that is tunable by the SrTiO3-layer thickness, temperature, external strains and electric fields is found to exist in the nanowires, with the appearance of fruitful dipole states (including those being purely polar, purely toroidal, both polar and toroidal, or distorted toroidal) and phase boundaries. As a consequence, an efficient cross control of the toroidal (polar) order by static (curled) electric field, and superior piezoelectric and piezotoroidal responses, can be achieved in the nanowires. The result provides new insights into the collective dipole behaviors in nanowire systems. PMID- 26100096 TI - Sympathy and Emotions in Academic Research Society. PMID- 26100095 TI - Divergence of dim-light vision among bats (order: Chiroptera) as estimated by molecular and electrophysiological methods. AB - Dim-light vision is present in all bats, but is divergent among species. Old World fruit bats (Pteropodidae) have fully developed eyes; the eyes of insectivorous bats are generally degraded, and these bats rely on well-developed echolocation. An exception is the Emballonuridae, which are capable of laryngeal echolocation but prefer to use vision for navigation and have normal eyes. In this study, integrated methods, comprising manganese-enhanced magnetic resonance imaging (MEMRI), f-VEP and RNA-seq, were utilized to verify the divergence. The results of MEMRI showed that Pteropodidae bats have a much larger superior colliculus (SC)/ inferior colliculus (IC) volume ratio (3:1) than insectivorous bats (1:7). Furthermore, the absolute visual thresholds (log cd/m(2)*s) of Pteropodidae (-6.30 and -6.37) and Emballonuridae (-3.71) bats were lower than those of other insectivorous bats (-1.90). Finally, genes related to the visual pathway showed signs of positive selection, convergent evolution, upregulation and similar gene expression patterns in Pteropodidae and Emballonuridae bats. Different results imply that Pteropodidae and Emballonuridae bats have more developed vision than the insectivorous bats and suggest that further research on bat behavior is warranted. PMID- 26100097 TI - Tribological performance of Graphene/Carbon nanotube hybrid reinforced Al2O3 composites. AB - Tribological performance of the hot-pressed pure Al2O3 and its composites containing various hybrid contents of graphene nanoplatelets (GNPs) and carbon nanotubes (CNTs) were investigated under different loading conditions using the ball-on-disc method. Benchmarked against the pure Al2O3, the composite reinforced with a 0.5 wt% GNP exhibited a 23% reduction in the friction coefficient along with a promising 70% wear rate reduction, and a hybrid reinforcement consisting of 0.3 wt.% GNPs + 1 wt.% CNTs resulted in even better performance, with a 86% reduction in the wear rate. The extent of damage to the reinforcement phases caused during wear was studied using Raman spectroscopy. The wear mechanisms for the composites were analysed based on the mechanical properties, brittleness index and microstructural characterizations. The excellent coordination between GNPs and CNTs contributed to the excellent wear resistance property in the hybrid GNT-reinforced composites. GNPs played the important role in the formation of a tribofilm on the worn surface by exfoliation; whereas CNTs contributed to the improvement in fracture toughness and prevented the grains from being pulled out during the tribological test. PMID- 26100098 TI - Highlights of topic "Recent advances in hepato-biliary-pancreatic science". PMID- 26100099 TI - ASXL2--director of skeletal and metabolic homeostasis. PMID- 26100100 TI - PPAR agonists in pre-eclampsia and hypertension? PMID- 26100101 TI - Effect of pedometer-based walking on depression, anxiety and insomnia among postmenopausal women. AB - OBJECTIVE: Insomnia, anxiety, and depression are some psychological symptoms associated with menopause. The aim of this study was to evaluate the effect of pedometer-based walking on anxiety, insomnia, and depression among postmenopausal women. METHODS: In this randomized, controlled trial, 106 postmenopausal women were randomly assigned to two groups (n = 53 in each group). Their anxiety, insomnia, and depression levels were assessed using the GHQ-28 and Beck questionnaires in the 4th, 8th, and 12th weeks of intervention. The depression level was assessed in the beginning, and in the 12th week of the trial. The members of the intervention group each received a pedometer and were asked to increase their steps by 500 per week. Data were analyzed using the independent t test, chi(2) and repeated-measures tests. RESULTS: The levels of anxiety and insomnia decreased in the 8th (4.2 +/- 2.1 vs. 5.4 +/- 2.3, p = 0.007) and 12th week (4.3 +/- 2.8 vs. 7.2 +/- 2.6, p < 0.001) in the intervention group, compared with the control group. The depression intensity decreased in the intervention group, compared with the control group, after 12 weeks (13.7 +/- 5 vs. 19.6 +/- 4.79, p < 0.001). The intervention group increased their step count from 76,377 steps per month in the first month, to 106 398 in the 3rd month (p < 0.001). CONCLUSION: This study showed that pedometer-based walking had a positive effect on depression, insomnia and anxiety among postmenopausal women. A walking training program can be considered for postmenopausal women in Iran. PMID- 26100102 TI - Mechanisms of AC losses in magnetic fluids based on substituted manganites. AB - The ability to controllably tune the heating efficiency of magnetic nanoparticles in an AC magnetic field is highly desirable for their application as mediators of magnetic hyperthermia. Traditional approaches to understand and govern the behavior of hyperthermia mediators include a combination of quasistatic and high frequency (~100 kHz) magnetic measurements with subsequent simulation of underlying processes. In this paper, we draw attention to the frequently overlooked fact that for an ensemble of magnetic nanoparticles, there is no straightforward complementarity between the dynamic characteristics obtained under different experimental conditions, as well as between corresponding underlying processes. This paper analyzes mechanisms of AC losses in a fluid based on magnetic nanoparticles, with special emphasis on the domains of their validity, and shows that the mechanisms may become qualitatively different as experimental conditions change from magnetostatic to high-frequency ones. Further, the work highlights new important features which can result from the employment of the refined approaches to interpret experimental results obtained on magnetic fluids based on La1-xSrxMnO3 (x = 0.22) nanoparticles. The gained knowledge provides necessary guidelines for tailoring the properties of magnetic nanoparticles to the needs of self-controlled magnetic hyperthermia. PMID- 26100103 TI - Simultaneous presence of fhs and purT genes is disadvantageous for the fitness of Escherichia coli growth. AB - In bacteria, alternate mechanisms are known to synthesize N(10) formyltetrahydrofolate (N(10)-formyl-THF) and formyl glycinamide ribotide (fGAR), which are important in purine biosynthesis. In one of the mechanisms, a direct transfer of one carbon unit from formate allows Fhs to convert tetrahydrofolate to N(10)-formyl-THF, and PurT to convert glycinamide ribotide (GAR) to fGAR. Our bioinformatics analysis of fhs and purT genes (encoding Fhs and PurT) showed that in a majority of bacteria (~94%), their presence was mutually exclusive. A large number of organisms possessing fhs lacked purT and vice versa. The phenomenon is so penetrating that even within a genus (Bacillus) if a species possessed fhs it lacked purT and vice versa. To investigate physiological importance of this phenomenon, we used Escherichia coli, which naturally lacks fhs (and possesses purT) as model. We generated strains, which possessed fhs and purT genes in singles or together. Deletion of purT from E. coli in the presence or absence of fhs did not confer a detectable growth disadvantage in pure cultures. However, growth competition assays revealed that the strains possessing either of the single genes outcompeted those possessing both the genes suggesting that mutual exclusion of purT and fhs in organisms confers fitness advantage in mixed cultures. PMID- 26100104 TI - Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder in humans characterized by complex behavioral deficits, including intellectual disability, impaired social interactions, and hyperactivity. ASD exhibits a strong genetic component with underlying multigene interactions. Candidate gene studies have shown that the neurobeachin (NBEA) gene is disrupted in human patients with idiopathic autism ( Castermans et al., 2003 ). The NBEA gene spans the common fragile site FRA 13A and encodes a signal scaffold protein ( Savelyeva et al., 2006 ). In mice, NBEA has been shown to be involved in the trafficking and function of a specific subset of synaptic vesicles. ( Medrihan et al., 2009 ; Savelyeva et al., 2006 ). Rugose (rg) is the Drosophila homolog of the mammalian and human NBEA. Our previous genetic and molecular analyses have shown that rg encodes an A kinase anchor protein (DAKAP 550), which interacts with components of the epidermal growth factor receptor or EGFR and Notch-mediated signaling pathways, facilitating cross talk between these and other pathways ( Shamloula et al., 2002 ). We now present functional data from studies on the larval neuromuscular junction that reveal abnormal synaptic architecture and physiology. In addition, adult rg loss-of-function mutants exhibit defective social interactions, impaired habituation, aberrant locomotion, and hyperactivity. These results demonstrate that Drosophila NBEA (rg) mutants exhibit phenotypic characteristics reminiscent of human ASD and thus could serve as a genetic model for studying ASDs. PMID- 26100106 TI - Corosolic acid enhances 5-fluorouracil-induced apoptosis against SNU-620 human gastric carcinoma cells by inhibition of mammalian target of rapamycin. AB - 5-Fluorouracil (5-FU), one of the oldest anticancer therapeutic agents, is increasingly being administered in cancer chemotherapy. In the present study, the anticancer effects of 5-FU combined with corosolic acid (CRA) were determined in SNU-620 human gastric carcinoma cells and the underlying mechanisms were examined. A combination treatment of 5-FU and CRA inhibited the viability of cells additively. Furthermore, apoptotic activity following combination treatment was found to be stronger than that of the single treatments, as observed using an Annexin V/propidium iodide assay. The protein level of Bcl-2 was decreased significantly by the combination treatment, whereas the protein level of Bim was increased. The release of mitochondrial cytochrome c was increased as a result of the combination treatment, however, the combination treatment additively increased caspase-3 and poly-(ADP-ribose) polymerase cleavages. Additionally, the mammalian target of rapamycin (mTOR) signaling pathway, which is highly activated in gastric cancer, was regulated by 5-FU and CRA, and additive mTOR/eukaryotic translation initiation factor 4E-binding protein 1 (4-EBP1) inhibition was observed with the combination treatment. Additional rapamycin treatment along with the combination treatment of 5-FU and CRA showed a more marked inhibition of mTOR/4-EBP1 in the cells, as well as increased apoptosis and antiproliferation. Thus, these data indicate that CRA enhances the anticancer activities of 5-FU via mTOR inhibition in SNU-620 human gastric carcinoma cells. PMID- 26100107 TI - Anxiety rating scales in Parkinson's disease: a critical review updating recent literature. AB - BACKGROUND: Assessing anxiety in Parkinson's disease (PD) has been a recent focus, and a number of studies have extensively investigated the validity of anxiety rating scales in PD. The present review aims to provide an overview of anxiety scales widely used and/or validated in PD, and to highlight recommendations for future research required in this area. METHODS: A literature search was performed using terms such as Parkinson* disease, psychiatric, depress*, anxiety, assessment, scales, and valid* in PsycInfo, PubMed, and Web of Science databases. Validation studies and reviews focussed on assessment of anxiety in PD were included. RESULTS: The literature search identified nine anxiety rating scales. The new Parkinson's Anxiety Scale (PAS) showed good psychometric properties. Having a simple design appropriate for older adults and items focussed on cognitive anxiety, the Geriatric Anxiety Inventory (GAI) also appeared promising for use in PD. The Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale, and Hamilton Anxiety Rating Scale (HAM-A) did not demonstrate satisfactory psychometric characteristics when used in PD, while other scales had limited or no evidence of validity or reliability to infer judgments. CONCLUSIONS: PAS and GAI are can be recommended for use in PD without dementia. Usefulness of these scales to assess anxiety in dementia should be examined in the future. Moreover, the complex symptomatology of anxiety relating to "off" PD medication states were not addressed in these scales. Further research is required to develop an anxiety scale tailored for PD. PMID- 26100105 TI - Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project. AB - BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigacion Farmacoepidemiologica en Atencion Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs. PMID- 26100108 TI - Mechanical Heart Valves in Pregnancy: A Sticky Business. PMID- 26100109 TI - Pregnancy in Women With a Mechanical Heart Valve: Data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC). AB - BACKGROUND: Pregnant women with a mechanical heart valve (MHV) are at a heightened risk of a thrombotic event, and their absolute need for adequate anticoagulation puts them at considerable risk of bleeding and, with some anticoagulants, fetotoxicity. METHODS AND RESULTS: Within the prospective, observational, contemporary, worldwide Registry of Pregnancy and Cardiac disease (ROPAC), we describe the pregnancy outcome of 212 patients with an MHV. We compare them with 134 patients with a tissue heart valve and 2620 other patients without a prosthetic valve. Maternal mortality occurred in 1.4% of the patients with an MHV, in 1.5% of patients with a tissue heart valve (P=1.000), and in 0.2% of patients without a prosthetic valve (P=0.025). Mechanical valve thrombosis complicated pregnancy in 10 patients with an MHV (4.7%). In 5 of these patients, the valve thrombosis occurred in the first trimester, and all 5 patients had been switched to some form of heparin. Hemorrhagic events occurred in 23.1% of patients with an MHV, in 5.1% of patients with a tissue heart valve (P<0.001), and in 4.9% of patients without a prosthetic valve (P<0.001). Only 58% of the patients with an MHV had a pregnancy free of serious adverse events compared with 79% of patients with a tissue heart valve (P<0.001) and 78% of patients without a prosthetic valve (P<0.001). Vitamin K antagonist use in the first trimester compared with heparin was associated with a higher rate of miscarriage (28.6% versus 9.2%; P<0.001) and late fetal death (7.1% versus 0.7%; P=0.016). CONCLUSIONS: Women with an MHV have only a 58% chance of experiencing an uncomplicated pregnancy with a live birth. The markedly increased mortality and morbidity warrant extensive prepregnancy counseling and centralization of care. PMID- 26100110 TI - CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic property. AB - We reported that tumor endothelial cells (TECs) differ from normal endothelial cells (NECs) in many aspects, such as gene expression profiles. Although CXCR7 is reportedly highly expressed in blood vessels of several tumors, its function in TECs is still unknown. To investigate this role, we isolated TECs from mouse tumor A375SM xenografts, and compared them with NECs from normal mouse dermis. After confirming CXCR7 upregulation in TECs, we analyzed its function using CXCR7 siRNA and CXCR7 inhibitor; CCX771. CXCR7 siRNA and CCX771 inhibited migration, tube formation and resistance to serum starvation in TECs but not in NECs. ERK1/2 phosphorylation was inhibited by CXCR7 knockdown in TECs. These results suggest that CXCR7 promotes angiogenesis in TECs via ERK1/2 phosphorylation. Using ELISA, we also detected CXCL12, a ligand of CXCR7, in conditioned medium from TECs, but not from NECs. CXCL12 neutralizing antibody significantly inhibited TEC random motility. VEGF stimulation upregulated CXCR7 expression in NECs, implying that VEGF mediates CXCR7 expression in endothelial cells. A CXCR7 inhibitor, CCX771 also inhibited tumor growth, lung metastasis and tumor angiogenesis in vivo. Taken together, the CXCL12-CXCR7 autocrine loop affects TEC proangiogenic properties, and could be the basis for an antiangiogenic therapy that specifically targets tumor blood vessels rather than normal vessels. PMID- 26100111 TI - Modifying microRNAs--another piece of the melanoma puzzle. PMID- 26100112 TI - SNOMED CT in a language isolate: an algorithm for a semiautomatic translation. AB - BACKGROUND: The Systematized Nomenclature of Medicine--Clinical Terms (SNOMED CT) is officially released in English and Spanish. In the Basque Autonomous Community two languages, Spanish and Basque, are official. The first attempt to semi automatically translate the SNOMED CT terminology content to Basque, a less resourced language is presented in this paper. METHODS: A translation algorithm that has its basis in Natural Language Processing methods has been designed and partially implemented. The algorithm comprises four phases from which the first two have been implemented and quantitatively evaluated. RESULTS: Results are promising as we obtained the equivalents in Basque of 21.41% of the disorder terms of the English SNOMED CT release. As the methods developed are focused on that hierarchy, the results in other hierarchies are lower (12.57% for body structure descriptions, 8.80% for findings and 3% for procedures). CONCLUSIONS: We are in the way to reach two of our objectives when translating SNOMED CT to Basque: to use our language to access rich multilingual resources and to strengthen the use of the Basque language in the biomedical area. PMID- 26100113 TI - Prevalence of Helicobacter pylori in dyspeptic patients at a tertiary hospital in a low resource setting. AB - BACKGROUND: More than half of the world's population is infected with Helicobacter pylori (H. pylori), the primary cause of chronic gastritis. Chronic gastritis is associated with peptic ulcer and in advanced stages with an increased risk of developing gastric adenocarcinoma. In many developing countries access to upper gastrointestinal (UGI) endoscopy services is limited. As a result, many UGI diseases are treated empirically. OBJECTIVE: To determine the prevalence of H. pylori in patients presenting with dyspepsia, and the mean time from onset of symptoms to performing an endoscopy examination. METHODS: A cross sectional descriptive study conducted from 5th January to 30th April 2014. Adult patients with dyspepsia who were referred for UGI endoscopy were recruited consecutively. Questionnaires were used to collect data which were analyzed using STATA software. IRB approval was obtained. RESULTS: In total, 111 participants' data were analyzed. The F:M ratio was 1:1.4, mean age 43 years (SD = 16). The prevalence of H. pylori gastritis was 36%. The minimum time to endoscopy was 3 weeks, maximum 1,248 weeks and the mean time 57 weeks. CONCLUSION: The burden of H. pylori infection in patients with dyspepsia was high. Patients had prior empirical antibiotic therapy. Access to endoscopic services is limited. PMID- 26100114 TI - Core-shell InGaN/GaN nanowire light emitting diodes analyzed by electron beam induced current microscopy and cathodoluminescence mapping. AB - We report on the electron beam induced current (EBIC) microscopy and cathodoluminescence (CL) characterization correlated with compositional analysis of light emitting diodes based on core/shell InGaN/GaN nanowire arrays. The EBIC mapping of cleaved fully operational devices allows to probe the electrical properties of the active region with a nanoscale resolution. In particular, the electrical activity of the p-n junction on the m-planes and on the semi-polar planes of individual nanowires is assessed in top view and cross-sectional geometries. The EBIC maps combined with CL characterization demonstrate the impact of the compositional gradients along the wire axis on the electrical and optical signals: the reduction of the EBIC signal toward the nanowire top is accompanied by an increase of the CL intensity. This effect is interpreted as a consequence of the In and Al gradients in the quantum well and in the electron blocking layer, which influence the carrier extraction efficiency. The interface between the nanowire core and the radially grown layer is shown to produce in some cases a transitory EBIC signal. This observation is explained by the presence of charged traps at this interface, which can be saturated by electron irradiation. PMID- 26100115 TI - Description of Three New alpha Variants and Four New beta Variants: Hb Montluel [alpha110(G17)Ala -> Val; HBA1: c.332C > T], Hb Cap d'Agde [alpha131(H14)Ser -> Cys; HBA2: c.395C > G] and Hb Corsica [alpha100(G7)Leu -> Pro; HBA1: 302T > C]; Hb Nimes [beta104(G6)Arg -> Gly; HBB: c.313A > G], Hb Saint Marcellin [beta112(G14)Cys -> Gly; HBB: c.337T > G], Hb Saint Chamond [beta80(EF4)Asn -> 0; HBB: c.241_243delAAC] and Hb Dompierre [beta29(B11)Gly -> Arg; HBB: c.88G > C]. AB - We present here seven new hemoglobin (Hb) variants identified during routine Hb analysis. All of them are caused by a missense mutation except Hb Saint Chamond, which results from an in-frame deletion of the asparagine residue at beta80. All these variants are clinically silent in the heterozygous state but two of them (Hb Cap d'Agde and Hb Dompierre) may be unstable, whereas Hb Nimes could present a very slightly elevated oxygen affinity. These data are to be confirmed by appropriate biochemical tests. PMID- 26100116 TI - Using Data Independent Acquisition (DIA) to Model High-responding Peptides for Targeted Proteomics Experiments. AB - Targeted mass spectrometry is an essential tool for detecting quantitative changes in low abundant proteins throughout the proteome. Although selected reaction monitoring (SRM) is the preferred method for quantifying peptides in complex samples, the process of designing SRM assays is laborious. Peptides have widely varying signal responses dictated by sequence-specific physiochemical properties; one major challenge is in selecting representative peptides to target as a proxy for protein abundance. Here we present PREGO, a software tool that predicts high-responding peptides for SRM experiments. PREGO predicts peptide responses with an artificial neural network trained using 11 minimally redundant, maximally relevant properties. Crucial to its success, PREGO is trained using fragment ion intensities of equimolar synthetic peptides extracted from data independent acquisition experiments. Because of similarities in instrumentation and the nature of data collection, relative peptide responses from data independent acquisition experiments are a suitable substitute for SRM experiments because they both make quantitative measurements from integrated fragment ion chromatograms. Using an SRM experiment containing 12,973 peptides from 724 synthetic proteins, PREGO exhibits a 40-85% improvement over previously published approaches at selecting high-responding peptides. These results also represent a dramatic improvement over the rules-based peptide selection approaches commonly used in the literature. PMID- 26100117 TI - Functional Analysis of GLRX5 Mutants Reveals Distinct Functionalities of GLRX5 Protein. AB - Glutaredoxin 5 (GLRX5) is a 156 amino acid mitochondrial protein that plays an essential role in mitochondrial iron-sulfur cluster transfer. Mutations in this protein were reported to result in sideroblastic anemia and variant nonketotic hyperglycinemia in human. Recently, we have characterized a Chinese congenital sideroblastic anemia patient who has two compound heterozygous missense mutations (c. 301 A>C and c. 443 T>C) in his GLRX5 gene. Herein, we developed a GLRX5 knockout K562 cell line and studied the biochemical functions of the identified pathogenic mutations and other conserved amino acids with predicted essential functions. We observed that the K101Q mutation (due to c. 301 A>C mutation) may prevent the binding of [Fe-S] to GLRX5 protein, while L148S (due to c. 443 T>C mutation) may interfere with [Fe-S] transfer from GLRX5 to iron regulatory protein 1 (IRP1), mitochondrial aconitase (m-aconitase) and ferrochelatase. We also demonstrated that L148S is functionally complementary to the K51del mutant with respect to Fe/S-ferrochelatase, Fe/S-IRP1, Fe/S-succinate dehydrogenase, and Fe/S-m-aconitase biosynthesis and lipoylation of pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex. Furthermore, we demonstrated that the mutations of highly conserved amino acid residues in GLRX5 protein can have different effects on downstream Fe/S proteins. Collectively, our current work demonstrates that GLRX5 protein is multifunctional in [Fe-S] protein synthesis and maturation and defects of the different amino acids of the protein will lead to distinct effects on downstream Fe/S biosynthesis. PMID- 26100118 TI - A temporal correlation function for the association between patient-reported outcome and clinical endpoints. AB - For clinical trials with multiple endpoints, the primary interest is usually to evaluate the relationship of these endpoints and treatment interventions. Studying the correlation of two clinical trial endpoints can also be of interests. For example, the association between patient-reported outcome and clinically assessed endpoint could answer important research questions and also generate interesting hypothesis for future research. However, it is not straightforward to quantify such association. In this article, we proposed a multiple event approach to profile such association with a temporal correlation function, visualized by a correlation function plot over time with a confidence band. We developed this approach by extending the existing methodology in recurrent event literature. This approach was shown to be generally unbiased and could be a useful tool for data visualization and inference. We demonstrated the use of this method with data from a real clinical trial. Although this approach was developed to evaluate the association between patient-reported outcome and adverse events, it can also be used to evaluate the association of any two endpoints that can be translated to time-to-event endpoints. PMID- 26100120 TI - Influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients. AB - INTRODUCTION: Tight glucose control therapy (TGC) has been implemented to control hyperglycemia in ICU patients. TGC may also influence serum potassium concentrations. We therefore investigated the influence of TGC on both serum glucose and serum potassium concentrations and associated mortality. METHOD: We performed a retrospective analysis including all patients admitted to the ICU of a tertiary hospital for 24 hours or more and with at least three serum glucose and serum potassium concentrations between 1999-2001 (conventional period), 2002 2006 (implementation period) or 2007-2009 (TGC period). Segmented regression analysis was used to estimate changes in outcomes that occurred after the intervention controlling for pre-intervention trends. Means and standard deviations (SDs) of serum glucose and serum potassium concentrations, and rate of severe hypoglycemia (<= 2.2 mmol/L) and hypokalemia (<= 3 mmol/L), were compared between the TGC and conventional period. RESULTS: Although mean serum glucose concentrations dropped 2.1 mmol/L (95% CI =-1.8 to -2.3 mmol/L, p<0.002), mean serum potassium concentrations did not change (absolute increase 0.02 mmol/L; 95% CI = -0.06 to 0.09 mmol/L, p=0.64). The rate of severe hypoglycemia increased with 5.9% (95% CI=-3.0 to -8.9, p<0.002), but the rate of hypokalemia remained equal (absolute reduction 4.8%; 95% CI = -11.1% to 1.5%, p=0.13). The SD of serum glucose concentrations within a patient did not change, while the SD of serum potassium concentrations even decreased 0.04 mmol/L (95% CI = -0.01 to -0.07, p = 0.01). ICU mortality decreased but this decrease was not significant (absolute difference -3.63%; 95% CI = -9.33 to 2.09, p = 0.20). Mean serum glucose concentrations, mean serum potassium concentrations and SDs of both serum glucose and serum potassium concentrations were all independently associated with ICU mortality. Highest mortality rates were seen at both the lowest and highest mean values (U/J-shaped association) and mortality rates increased with increasing variability (SDs) for both serum glucose and serum potassium concentrations. CONCLUSION: Our study shows that a TGC was not associated with an increased risk of serum potassium related events. Low and high mean values and high variability of both serum glucose and serum potassium concentrations are predictors for high ICU mortality. PMID- 26100121 TI - Comparative study on surface reconstruction accuracy of stereo imaging devices for microsurgery. AB - PURPOSE: Processing stereoscopic image data is an emerging field. Especially in microsurgery that requires sub-millimeter accuracy, application of stereo-based methods on endoscopic and microscopic scenarios is of major interest. In this context, direct comparison of stereo-based surface reconstruction applied to several camera settings is presented. METHODS: A method for stereo matching is proposed and validated on in-vitro data. Demonstrating suitability for surgical scenarios, this method is applied to two custom-made stereo cameras, a miniaturized, bendable surgical endoscope and an operating microscope. Reconstruction accuracy is assessed on a custom-made reference sample. Subsequent to its fabrication, a coordinate measuring arm is used to acquire ground truth. Next, the sample is positioned by a robot at varying distances to each camera. Surface estimation is performed, while the specimen is localized based on. markers. Finally, the error between estimated surface and ground truth is computed. RESULTS: Sample measurement with the coordinate measuring arm yields reliable ground truth data with a root-mean-square error of 11.2 MUm. Overall surface reconstruction with analyzed cameras is quantified by a root-mean-square error of less than 0.18 mm. Microscope setting with the highest magnification yields the most accurate measurement, while the maximum deviation does not exceed 0.5 mm. Custom-made stereo cameras perform similar but with outliers of increased magnitude. Miniaturized, bendable surgical endoscope produces the maximum error of approximately 1.2 mm. CONCLUSIONS: Reconstruction results reveal that microscopic imaging outperforms investigated chip-on-the-tip solutions, i.e., at higher magnification. Nonetheless, custom-made cameras are suitable for application in microsurgery. Although reconstruction with the miniaturized endoscope is more inaccurate, it provides a good trade-off between accuracy, outer dimensions and accessibility to hard-to-reach surgical sites. PMID- 26100122 TI - Robust surface tracking combining features, intensity and illumination compensation. AB - PURPOSE: Recovering tissue deformation during robotic-assisted minimally invasive surgery procedures is important for providing intra-operative guidance, enabling in vivo imaging modalities and enhanced robotic control. The tissue motion can also be used to apply motion stabilization and to prescribe dynamic constraints for avoiding critical anatomical structures. METHODS: Image-based methods based independently on salient features or on image intensity have limitations when dealing with homogeneous soft tissues or complex reflectance. In this paper, we use a triangular geometric mesh model in order to combine the advantages of both feature and intensity information and track the tissue surface reliably and robustly. RESULTS: Synthetic and in vivo experiments are performed to provide quantitative analysis of the tracking accuracy of our method, and we also show exemplar results for registering multispectral images where there is only a weak image signal. CONCLUSION: Compared to traditional methods, our hybrid tracking method is more robust and has improved convergence in the presence of larger displacements, tissue dynamics and illumination changes. PMID- 26100123 TI - Glucocorticosteroids for sepsis: systematic review with meta-analysis and trial sequential analysis. AB - INTRODUCTION: Glucocorticosteroids (steroids) are widely used for sepsis patients. However, the potential benefits and harms of both high and low dose steroids remain unclear. A systematic review of randomised clinical trials with meta-analysis and trial sequential analysis (TSA) might shed light on this clinically important question. METHODS: A systematic review was conducted according to a published protocol and The Cochrane Handbook methodology including meta-analyses, TSA of randomised clinical trials, and external validity estimation (GRADE). Randomised clinical trials evaluating steroids were included for sepsis patients (systemic inflammatory response syndrome, sepsis, severe sepsis or septic shock) aged >18 years. Cochrane Central Register of Controlled Trials (CENTRAL), PubMed/Medline, Embase, Web of Science and Cinahl were searched until 18 February 2015. No language restrictions were applied. Primary outcomes were mortality at longest follow-up and serious adverse events. RESULTS: A total of 35 trials randomising 4682 patients were assessed and reviewed in full text. All trials but two had high risk of bias. No statistically significant effect was found for any dose of steroids versus placebo or no intervention on mortality at maximal follow-up [relative risk (RR) 0.89; TSA adjusted confidence interval (CI) 0.74-1.08]. Two trials with low risk of bias also showed no statistically significant difference (random-effects model RR 0.38, 95% CI 0.06-2.42). Similar results were obtained in subgroups of trials stratified according to high (>500 mg) or low (<= 500 mg) dose hydrocortisone (or equivalent) (RR 0.87; TSA-adjusted CI 0.38-1.99; and RR 0.90; TSA-adjusted CI 0.49-1.67, respectively). There were also no statistically significant effects on serious adverse events other than mortality (RR 1.02; TSA-adjusted CI 0.7-1.48). The effects did not vary according to the degree of sepsis. TSA showed that many more randomised patients are needed before definitive conclusions may be drawn. CONCLUSION: Evidence to support or negate the use of steroids in any dose in sepsis patients is lacking. The results of ongoing and future well-designed, large randomised clinical trials are needed. PMID- 26100124 TI - Neuropsychologic outcomes from paediatric cardiac arrest: an important step forward. PMID- 26100125 TI - Do you know how much it costs? PMID- 26100126 TI - Veno-venous extracorporeal CO2 removal improves pulmonary hypertension in acute exacerbation of severe COPD. PMID- 26100127 TI - Plasma suPAR as a prognostic biological marker for ICU mortality in ARDS patients. AB - PURPOSE: We investigated the prognostic value of plasma soluble urokinase plasminogen activator receptor (suPAR) on day 1 in patients with the acute respiratory distress syndrome (ARDS) for intensive care unit (ICU) mortality and compared it with established disease severity scores on day 1. METHODS: suPAR was determined batchwise in plasma obtained within 24 h after admission. RESULTS: 632 ARDS patients were included. Significantly (P = 0.02) higher median levels of suPAR were found with increasing severity of ARDS: 5.9 ng/ml [IQR 3.1-12.8] in mild ARDS (n = 82), 8.4 ng/ml [IQR 4.1-15.0] in moderate ARDS (n = 333), and 9.0 ng/ml [IQR 4.5-16.0] in severe ARDS (n = 217). Non-survivors had higher median levels of suPAR [12.5 ng/ml (IQR 5.1-19.5) vs. 7.4 ng/ml (3.9-13.6), P < 0.001]. The area under the receiver operator characteristic curve (ROC-AUC) for mortality of suPAR (0.62) was lower than the ROC-AUC of the APACHE IV score (0.72, P = 0.007), higher than that of the ARDS definition classification (0.53, P = 0.005), and did not differ from that of the SOFA score (0.68, P = 0.07) and the oxygenation index (OI) (0.58, P = 0.29). Plasma suPAR did not improve the discrimination of the established disease severity scores, but did improve net reclassification of the APACHE score (29%), SOFA score (23%), OI (38%), and Berlin definition classification (39%). CONCLUSION: As a single biological marker, the prognostic value for death of plasma suPAR in ARDS patients is low. Plasma suPAR, however, improves the net reclassification, suggesting a potential role for suPAR in ICU mortality prediction models. PMID- 26100128 TI - Evidence for functional redundancy in arbuscular mycorrhizal fungi and implications for agroecosystem management. AB - Arbuscular mycorrhizal (AM) fungi provide benefits to host plants and show functional diversity, with evidence of functional trait conservation at the family level. Diverse communities of AM fungi ought therefore to provide increased benefits to the host, with implications for the management of sustainable agroecosystems. However, this is often not evident in the literature, with diversity saturation at low species number. Growth and nutrient uptake were measured in onions in the glasshouse on AM-free phosphorus (P)-poor soil, inoculated with between one and seven species of AM fungi in all possible combinations. Inoculation with AM fungi increased shoot dry weight as well as P and copper concentrations in shoots but reduced the concentration of potassium and sulphur. There was little evidence of increased benefit from high AM fungal diversity, and increasing diversity beyond three species did not result in significantly higher shoot weight or P or Cu concentrations. Species of Glomeraceae had the greatest impact on growth and nutrient uptake, while species of Acaulospora and Racocetra did not have a significant impact. Failure to show a benefit from high AM fungal diversity in this and other studies may be the result of experimental conditions, with the benefits of AM fungal diversity only becoming apparent when the host plant is faced with multiple stress factors. Replicating the complex interactions between AM fungi, the host plant and their environment in the laboratory in order to fully understand these interactions is a major challenge to AM research. PMID- 26100129 TI - PCR melting profile as a tool for outbreak studies of Salmonella enterica in chickens. AB - BACKGROUND: Salmonellosis is of great economic concern in all phases of the poultry industry, from production to marketing, leading to severe economic losses. Monitoring the source of the bacterial contamination has fundamental importance in the spreading of salmonellosis. RESULTS: We applied a ligation mediated PCR method, PCR MP (PCR melting profile), to type S. enterica ssp. enterica ser. Enteritidis (56 strains) and 43 control strains classified to other serovars isolated from poultry. We demonstrated the PCR MP potential for salmonellosis spreading monitoring. Our rapid test presents higher discriminatory power (0.939 vs. 0.608) compared to current molecular subtyping tool such as pulsed-field gel electrophoresis (PFGE), which ineffectiveness underlies the high degree of clonality of S. Enteritidis. CONCLUSIONS: PCR MP was found to be a highly discriminating, sensitive and specific method that could be a valuable molecular tool, particularly for analyzing epidemiological links of limited number of S. enterica ser. Enteritidis strains. PMID- 26100130 TI - Lysyl oxidase is associated with the epithelial-mesenchymal transition of gastric cancer cells in hypoxia. AB - PURPOSE: It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelial-mesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia. METHODS: Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of LOX small interfering RNA (siRNA) on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by reverse transcription PCR, Western blot, a wound-healing assay, and an invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically. RESULTS: Hypoxic conditions increased the number of polygonal or spindle-shaped cells resulting from EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. The number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival. CONCLUSION: LOX affects the EMT of gastric cancer cells in hypoxic conditions. LOX expression is a useful prognostic factor for patients with gastric cancer. PMID- 26100132 TI - Three Positive Parenting Practices and Their Correlation with Risk of Childhood Developmental, Social, or Behavioral Delays: An Analysis of the National Survey of Children's Health. AB - OBJECTIVES: (1) Investigate the relationship between three specific positive parenting practices (PPP)-reading to children, engaging in storytelling or singing, and eating meals together as a family-and parent-reported risk of developmental, behavioral, or social delays among children between the ages of 1 5 years in the US. (2) Determine if a combination of these parenting practices has an effect on the outcome. METHODS: Chi square and multiple logistic regression analyses were used to analyze cross-sectional data from the National Survey of Children's Health 2011/2012 in regards to the relationship between each of the three individual PPP as well as a total PPP score and the child's risk of being developmentally, socially, or behaviorally delayed (N = 21,527). Risk of delay was calculated using the Parents' Evaluation of Developmental Status Questionnaire, which is a parental self-report measure that has been correlated with diagnosed child delays. These analyses controlled for poverty and parental education. All analyses were completed using SAS Version 9.3. RESULTS: A strong correlation was found between each of the three PPP as well as the total PPP score and the child's risk of developmental, social, or behavioral delays (p < 0.05 for each test). These associations were found to have a dose-response relationship (p < 0.05 in all but one analysis). CONCLUSIONS: Daily engagement in PPP could possibly reduce children's risk of delay, and specifically engaging in all three PPP may have greater benefit. PMID- 26100131 TI - The Effects of Maternal Mortality on Infant and Child Survival in Rural Tanzania: A Cohort Study. AB - OBJECTIVES: The full impact of a maternal death includes consequences faced by orphaned children. This analysis adds evidence to a literature on the magnitude of the association between a woman's death during or shortly after childbirth, and survival outcomes for her children. METHODS: The Ifakara and Rufiji Health and Demographic Surveillance Sites in rural Tanzania conduct longitudinal, frequent data collection of key demographic events at the household level. Using a subset of the data from these sites (1996-2012), this survival analysis compared outcomes for children who experienced a maternal death (42 and 365 days definitions) during or near birth to those children whose mothers survived. RESULTS: There were 111 maternal deaths (or 229 late maternal deaths) during the study period, and 46.28 % of the index children also subsequently died (40.73 % of children in the late maternal death group) before their tenth birthday-a much higher prevalence of child mortality than in the population of children whose mothers survived (7.88 %, p value <0.001). Children orphaned by early maternal deaths had a 51.54 % chance of surviving to their first birthday, compared to a 94.42 % probability for children of surviving mothers. A significant, but lesser, child survival effect was also found for paternal deaths in this study period. CONCLUSIONS: The death of a mother compromises the survival of index children. Reducing maternal mortality through improved health care-especially provision of high-quality skilled birth attendance, emergency obstetric services and neonatal care-will also help save children's lives. PMID- 26100133 TI - Diet, Pre-pregnancy BMI, and Gestational Weight Gain in Puerto Rican Women. AB - OBJECTIVES: To describe the dietary patterns in pregnant woman and determine the association between diet factors, pre-pregnancy Body Mass Index (BMI) and socio demographic characteristics with gestational weight gain (GWG). METHODS: This is a secondary analysis of a longitudinal cohort study of pregnant women exploring the risk factors for preterm birth, the Puerto Rico Testsite for Exploring Contamination Threats program. Recruitment was conducted during 2011-2014. Data was collected from multiple sources. GWG was calculated using maternal weight recorded in the medical records at the first and last prenatal visits and classified according to the Institute of Medicine guidelines. Sociodemographic characteristics were obtained at baseline using an interviewed-based questionnaire. Participants completed a self-administered food frequency questionnaire at 20-28 weeks to assess dietary patterns. Analysis of associations between variables was conducted using Chi Square tests. RESULTS: A total of 160 women with term pregnancies were included in this analysis. Mean pre-pregnancy BMI was 25.4 +/- 5.48 kg/m(2), with 44.4 % classified as overweight/obese. Excessive GWG was observed in 24.4 % of the participants. Socio-demographic characteristics were not associated with GWG. Being overweight/obese at the start of pregnancy was significantly associated with excessive GWG (p < 0.05). In addition, women consuming one or more fruit drinks per day were more likely to have an excessive GWG while those consuming less than one fruit drink per day were more likely to have an adequate GWG (p < 0.05). CONCLUSIONS FOR PRACTICE: Being obese before pregnancy and frequently consuming fruit drinks were important determinants of excessive GWG in this group. PMID- 26100135 TI - Unconventional screening approaches for antibiotic discovery. AB - The dramatic rise in microbial drug resistance in recent years has led to ongoing searches for novel drugs to add to the armory against infectious disease. Nevertheless, a paucity of new antibacterial drugs in discovery and development pipelines using traditional approaches has prompted a variety of unconventional and disruptive strategies for antibacterial drug discovery. Herein, we review recent nontraditional approaches that have been piloted for early drug discovery efforts. These unique methodologies open new avenues for finding the next generation of antimicrobials. PMID- 26100136 TI - Naringenin enhances NK cell lysis activity by increasing the expression of NKG2D ligands on Burkitt's lymphoma cells. AB - Natural killer (NK) cells are capable of identifying and killing tumor cells as well as virus infected cells without pre-sensitization. NK cells express activating and inhibitory receptors, and can distinguish between normal and tumor cells. The present study was designed to demonstrate the importance of the expression level of NKG2D ligands on the Burkitt's lymphoma cell line, Raji, in enhancing NK cell cytolytic activity. Various flavonoids were used as stimulants to enhance the expression of NKG2D ligands. NK cell lysis activity against Raji was not changed by pre-treatment of Raji with luteolin, kaempferol, taxifolin and hesperetin. However, treatment of Raji with naringenin showed increased sensitivity to NK cell lysis than untreated control cells. The activity of naringenin was due to enhanced NKG2D ligand expression. These results provide evidence that narigenin's antitumor activity may be due to targeting of NKG2D ligand expression and suggests a possible immunotherapeutic role for cancer treatment. PMID- 26100134 TI - The green tea catechin epigallocatechin gallate induces cell cycle arrest and shows potential synergism with cisplatin in biliary tract cancer cells. AB - BACKGROUND: The green tea catechin epigallocatechin gallate (EGCG) was shown to effectively inhibit tumor growth in various types of cancer including biliary tract cancer (BTC). For most BTC patients only palliative therapy is possible, leading to a median survival of about one year. Chemoresistance is a major problem that contributes to the high mortality rates of BTC. The aim of this study was to investigate the cytotoxic effect of EGCG alone or in combination with cisplatin on eight BTC cell lines and to investigate the cellular anti cancer mechanisms of EGCG. METHODS: The effect of EGCG treatment alone or in combination with the standard chemotherapeutic cisplatin on cell viability was analyzed in eight BTC cell lines. Additionally, we analyzed the effects of EGCG on caspase activity, cell cycle distribution and gene expression in the BTC cell line TFK-1. RESULTS: EGCG significantly reduced cell viability in all eight BTC cell lines (p < 0.05 or p < 0.01, respectively, for most cell lines and EGCG concentrations > 5 MUM). Combined EGCG and cisplatin treatment showed a synergistic cytotoxic effect in five cell lines and an antagonistic effect in two cell lines. Furthermore, EGCG reduced the mRNA levels of various cell cycle related genes, while increasing the expression of the cell cycle inhibitor p21 and the apoptosis-related death receptor 5 (p < 0.05). This observation was accompanied by an increase in caspase activity and cells in the sub-G1 phase of the cell cycle, indicating induction of apoptosis. EGCG also induced a down regulation of expression of stem cell-related genes and genes that are associated with an aggressive clinical character of the tumor, such as cd133 and abcg2. CONCLUSIONS: EGCG shows various anti-cancer effects in BTC cell lines and might therefore be a potential anticancer drug for future studies in BTC. Additionally, EGCG displays a synergistic cytotoxic effect with cisplatin in most tested BTC cell lines. Graphical abstract Summary illustration. PMID- 26100137 TI - Association between eating rate and obesity: a systematic review and meta analysis. AB - BACKGROUND: The association between eating rate and obesity has recently been reported. However, the findings remain inconclusive. OBJECTIVES: We undertook a systematic review with a meta-analysis of published epidemiological studies to provide a reliable close estimate of the association between eating rate and obesity. METHODS: A comprehensive search of MEDLINE, EMBASE and CINAHL was conducted to identify studies that reported quantitative estimates for indices of obesity based on the category of eating rate. Interventional studies or studies conducted using children as subjects were excluded. Two independent researchers extracted the data. A summary estimate was calculated using a random-effects model, and subgroup analyses were conducted to identify sources of heterogeneity. RESULTS: Data from 23 published studies were eligible for inclusion. The mean difference in body mass indices (BMIs) between individuals who ate quickly and those who ate slowly was 1.78 kg m(-2) (95% confidence interval (CI), 1.53-2.04 kg m(-2)). The pooled odds ratio of eating quickly on the presence of obesity was 2.15 (95% CI, 1.84-2.51). There was evidence of significant quantitative heterogeneity in the magnitudes of the association across studies (I2=78.4%, P value for heterogeneity <0.001 for BMI, I2=71.9%, P-value for heterogeneity <0.001 for obesity), which may be partially explained by differences in the type of study population (a weaker association was observed for BMI in diabetic patients). CONCLUSIONS: Eating quickly is positively associated with excess body weight. Further studies are warranted to determine whether interventions to slow the speed of eating are effective for weight control. PMID- 26100139 TI - Hearing loss in Waardenburg syndrome: a systematic review. AB - Waardenburg syndrome (WS) is a rare genetic disorder characterized by hearing loss (HL) and pigment disturbances of hair, skin and iris. Classifications exist based on phenotype and genotype. The auditory phenotype is inconsistently reported among the different Waardenburg types and causal genes, urging the need for an up-to-date literature overview on this particular topic. We performed a systematic review in search for articles describing auditory features in WS patients along with the associated genotype. Prevalences of HL were calculated and correlated with the different types and genes of WS. Seventy-three articles were included, describing 417 individual patients. HL was found in 71.0% and was predominantly bilateral and sensorineural. Prevalence of HL among the different clinical types significantly differed (WS1: 52.3%, WS2: 91.6%, WS3: 57.1%, WS4: 83.5%). Mutations in SOX10 (96.5%), MITF (89.6%) and SNAI2 (100%) are more frequently associated with hearing impairment than other mutations. Of interest, the distinct disease-causing genes are able to better predict the auditory phenotype compared with different clinical types of WS. Consequently, it is important to confirm the clinical diagnosis of WS with molecular analysis in order to optimally inform patients about the risk of HL. PMID- 26100138 TI - Independent associations between child and parent perceived neighborhood safety, child screen time, physical activity and BMI: a structural equation modeling approach. AB - OBJECTIVE: The main objective of this study was to investigate whether children's perceptions of neighborhood safety are associated with their weight status and weight-related behaviors, independently of their parents' perceptions. METHODS: Data were from the baseline wave (collected in 2005-2008) of the Quebec Adipose and Lifestyle Investigation in Youth (QUALITY), an ongoing prospective study of 630 children aged 8-10 years (from Quebec, Canada) at risk of obesity. Weight and height were measured, and World Health Organization age- and sex-specific body mass index (BMI) z-scores were computed. Physical activity was measured by accelerometry, and time spent watching television, playing computer and video games during week and weekend days was self-reported. Structural equation modeling was used to simultaneously estimate the associations between parent and child perceived safety, with children's BMI z-score, physical activity and screen time. RESULTS: The results suggest that, when parent perceived safety was at the mean, children who perceived their neighborhood as being safest had nearly an additional 70 daily activity counts per minute (representing an ~10% increase in overall physical activity level) compared with children who perceived it as being least safe. Among children who perceived a mean level of safety, those whose parents perceived their neighborhood as being safest spent approximately an hour less per day in front of screens compared with those whose parents perceived their neighborhood as being least safe. Parent and child perceptions of safety both indirectly contribute to children's weight status by differentially impacting weight-related behaviors. CONCLUSION: Findings indicate that targeting both parent and child perceived neighborhood safety could bolster efforts to promote healthy weight and weight-related behaviors among children. PMID- 26100140 TI - Checks and balances on cholinergic signaling in brain and body function. AB - A century after the discovery of acetylcholine (ACh), we recognize both ACh receptors, transporters, and synthesizing and degrading enzymes and regulators of their expression as contributors to cognition, metabolism, and immunity. Recent discoveries indicate that pre- and post-transcriptional ACh signaling controllers coordinate the identity, functioning, dynamics, and brain-to-body communication of cholinergic cells. Checks and balances including epigenetic mechanisms, alternative splicing, and miRNAs may all expand or limit the diversity of these cholinergic components by consistently performing genome-related surveillance. This regulatory network enables homeostatic maintenance of brain-to-body ACh signaling as well as reactions to nicotine, Alzheimer's disease anticholinesterase therapeutics, and agricultural pesticides. Here I review recent reports on the functional implications of these controllers of cholinergic signaling in and out of the brain. PMID- 26100143 TI - Primary Care Medication Safety Surveillance with Integrated Primary and Secondary Care Electronic Health Records: A Cross-Sectional Study. AB - INTRODUCTION: The extent of preventable medication-related hospital admissions and medication-related issues in primary care is significant enough to justify developing decision support systems for medication safety surveillance. The prerequisite for such systems is defining a relevant set of medication safety related indicators and understanding the influence of both patient and general practice characteristics on medication prescribing and monitoring. OBJECTIVE: The aim of the study was to investigate the feasibility of linked primary and secondary care electronic health record data for surveillance of medication safety, examining not only prescribing but also monitoring, and associations with patient- and general practice-level characteristics. METHODS: A cross-sectional study was conducted using linked records of patients served by one hospital and over 50 general practices in Salford, UK. Statistical analysis consisted of mixed effects logistic models, relating prescribing safety indicators to potential determinants. RESULTS: The overall prevalence (proportion of patients with at least one medication safety hazard) was 5.45 % for prescribing indicators and 7.65 % for monitoring indicators. Older patients and those on multiple medications were at higher risk of prescribing hazards, but at lower risk of missed monitoring. The odds of missed monitoring among all patients were 25 % less for males, 50 % less for patients in practices that provide general practitioner training, and threefold higher in practices serving the most deprived compared with the least deprived areas. Practices with more prescribing hazards did not tend to show more monitoring issues. CONCLUSIONS: Systematic collection, collation, and analysis of linked primary and secondary care records produce plausible and useful information about medication safety for a health system. Medication safety surveillance systems should pay close attention to patient age and polypharmacy with respect to both prescribing and monitoring failures; treat prescribing and monitoring as different statistical processes, rather than a combined measure of prescribing safety; and audit the socio economic equity of missed monitoring. PMID- 26100142 TI - Regulation of dendrite morphogenesis by extrinsic cues. AB - Dendrites play a central role in the integration and flow of information in the nervous system. The morphogenesis and maturation of dendrites is hence an essential step in the establishment of neuronal connectivity. Recent studies have uncovered crucial functions for extrinsic cues in the development of dendrites. We review the contribution of secreted polypeptide growth factors, contact mediated proteins, and neuronal activity in distinct phases of dendrite development. We also highlight how extrinsic cues influence local and global intracellular mechanisms of dendrite morphogenesis. Finally, we discuss how these studies have advanced our understanding of neuronal connectivity and have shed light on the pathogenesis of neurodevelopmental disorders. PMID- 26100144 TI - Changes in Side Effect Risk Communication in Patient Information Leaflets over the Past Decade: Results of a Survey. AB - INTRODUCTION: Patients' perceptions of side effect risks are important influences on their medicine-taking behaviour. A previous survey of Patient Information Leaflets (PILs) showed considerable variation in the terms used to communicate risks. OBJECTIVE: Our objective was to assess the methods used to describe risk of side effects in recent PILs and to compare them with PILs sampled in 2006. METHOD: We sampled PILs for the 50 most frequently dispensed medicines in England and Wales in 2012 and PILs for the 50 most recently licensed medicines. We assessed the use of risk frequency terms or numbers, and the use of the risk format recommended by the European Medicines Agency (EMA). RESULTS: A majority (76 %) of PILs for the most frequently dispensed medicines included a risk frequency descriptor, with 66 % using the recommended format. No difference was seen between PILs for branded and generic medicines. All 50 PILs for the most recently licensed medicines used the EU recommended risk format. PILs from the 2012 sample were much more likely than those from the 2006 sample to include risk descriptors and to use a consistent approach. CONCLUSION: The increased use and consistency of risk descriptors in PILs should benefit patients, particularly those using multiple medicines produced by different market authorisation holders. A need remains for further research evaluating the risk format recommended by the EMA. There is also a need for research evaluating spoken information and other sources of printed risk information about medicines that is available to patients. PMID- 26100141 TI - The ubiquitous nature of multivesicular release. AB - 'Simplicity is prerequisite for reliability' (E.W. Dijkstra [1]) Presynaptic action potentials trigger the fusion of vesicles to release neurotransmitter onto postsynaptic neurons. Each release site was originally thought to liberate at most one vesicle per action potential in a probabilistic fashion, rendering synaptic transmission unreliable. However, the simultaneous release of several vesicles, or multivesicular release (MVR), represents a simple mechanism to overcome the intrinsic unreliability of synaptic transmission. MVR was initially identified at specialized synapses but is now known to be common throughout the brain. MVR determines the temporal and spatial dispersion of transmitter, controls the extent of receptor activation, and contributes to adapting synaptic strength during plasticity and neuromodulation. MVR consequently represents a widespread mechanism that extends the dynamic range of synaptic processing. PMID- 26100145 TI - Chemoprevention of Post-ERCP Pancreatitis with Rectal NSAIDs: Does Poking Both Ends Justify the Means? PMID- 26100146 TI - 3D Hybrid Plasmonic Nanomaterials for Highly Efficient Optical Absorbers and Sensors. AB - 3D hybrid plasmonic nanomaterials are composed of 3D-stacked Ag nanowires and nanoparticles separated by a nanoscale-thick alumina interlayer. The 3D hybrid plasmonic nanostructures exhibit strong plasmonic coupling between the ultrahigh populations of plasmonic nanomaterials, overcoming the physical limitation of inefficient plasmonic coupling of the Ag nanowire stacks. PMID- 26100147 TI - Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin. AB - The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 (-/-)) mice lacking brain serotonin and serotonin transporter (SERT) deficient (SERT(-/-)) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 (-/-) mice, whereas no significant changes were observed in SERT(-/-) mice. Furthermore, BDNF levels were increased in the prefrontal cortex of Tph2 (-/-) but not of SERT(-/-) mice. Our results emphasize the interaction between serotonin signaling and BDNF. Complete lack of brain serotonin induces BDNF expression. PMID- 26100148 TI - Autonomic imbalance during apneic episodes in pediatric obstructive sleep apnea. AB - OBJECTIVES: To investigate the activity of the autonomic nervous system (ANS) during sleep in children with obstructive sleep apnea (OSA), in order to detect a possible cardiac ANS imbalance analyzing heart rate variability (HRV). METHODS: 43 subjects between 4 and 12 years of age (7.26 +/- 2.8 years), undergoing a diagnostic assessment for OSA were evaluated. A time domain index (R-apnea index) was developed to evaluate HRV strictly related to obstructive events during sleep. Poincare plot of RR intervals during the whole night was calculated. RESULTS: R-apnea index was negatively correlated with apnea hypopnea index (AHI) (r=-0.360, p=0.028). AHI and the duration of the disease were the only variables that were significantly correlated with R-apnea index. Three groups were subsequently created according to polysomnographic findings considering AHI. R apnea index resulted significantly lower in patient with severe OSA compared to primary snoring/mild OSA subjects (p<0.05). Looking at Poincare plot, SD1 showed a diminishing trend with severity of OSA, however not reaching statistical significance. CONCLUSIONS: Our findings suggest an autonomic impairment in OSA children evidenced by the altered HRV both in the very short term (R-apnea index) and in short term (SD1). SIGNIFICANCE: R-apnea index is an easy and cheap method to undelay early ANS imbalance. PMID- 26100149 TI - High Frequency Oscillations and spikes: Separating real HFOs from false oscillations. AB - OBJECTIVE: To demonstrate and quantify the occurrence of false High Frequency Oscillations (HFOs) generated by the filtering of sharp events. To distinguish real HFOs from spurious ones using analysis of the raw signal. METHOD: We developed a new method to prevent false HFO detections due to the filtering effect by detecting oscillations in the raw signal at the time of sharp events. We specified temporal features to classify sharp events with and without HFOs using support vector machine in both ripple and fast ripple bands. The traditionally used time-frequency representation served as the gold standard to indicate real and false HFOs. RESULTS: 44% of ripples and 43% of FRs concurring with sharp events were found to be false HFOs. Sharp events with HFOs had significantly more oscillations in the raw signal than sharp events without. They could be distinguished from false HFOs with accuracy of 76.6% in the ripple band and 72.6% in the fast ripple band. CONCLUSION: It may be most appropriate to detect HFOs as oscillations not only on the filtered signal but also on the raw signal. The classical time-frequency display used for identifying HFOs should be used with great care due to the possible masking effect of broadband activities. SIGNIFICANCE: The separation of real HFOs from broadband activities will raise the validity of HFO detection methods and will therefore support future HFO investigations. PMID- 26100150 TI - Anticonvulsant and Neurotoxicity of Some Novel 1-([1,3,4]thiadiazino[6,5- b]indol 3-yl Semicarbazides. AB - In the present study a series of new N(4)-(4-substituted benzylidene)-N(1) ([1,3,4]thiadiazino [6,5-b]indol-3-yl)semicarbazide (1-6), N(4) ([1,3,4]thiadiazino[6,5-b]indol-3-yl)-N(1)-(1-(4-substituted phenyl)ethylidene)semicarbazide (7-10), N(4)-([1,3,4]thiadiazino[6,5-b]indol-3 yl)-N(1)-((4-substituted phenyl)(phenyl)methylene) semicarbazide. (11-14) have been synthesized from isatin and thiosemicarbazide through multiple steps to meet structural necessities for the anticonvulsant activity. All the newly prepared compounds were characterized by spectral techniques like FT-IR, (1)H and (13)C NMR, EI-MS and elemental analysis. All the newly synthesized compounds were investigated for the anticonvulsant activity against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) models and their neurotoxicity were also evaluated by rotarod test. The results obtained showed that 64% of the compounds showed protection in the MES test and 36% of the compounds showed protection in ScPTZ test. Some of the compounds also showed good activity after oral administration. Among the synthesized compounds, compound 14 was shown to be the most active compound showing activity at 100 and 300 mg/kg in MES and ScPTZ test with prolonged duration of action. In the present study, semicarbazones of hydroxy containing carbonyl compounds were depicted to be the potent molecule with low neurotoxicity and prolong duration of action on oral administration. The result of the present study may be used for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity. PMID- 26100151 TI - Characterization of exercise limitations by evaluating individual cardiac output patterns: a prospective cohort study in patients with chronic heart failure. AB - BACKGROUND: Patients with chronic heart failure (CHF) suffer from exercise intolerance due to impaired central hemodynamics and subsequent alterations in peripheral skeletal muscle function and structure. The relative contribution of central versus peripheral factors in the reduced exercise capacity is still subject of debate. The main purpose was to investigate heterogeneity in the nature of exercise intolerance by evaluating individual cardiac output (Q) patterns. The secondary purpose was to evaluate whether patient and disease characteristics were associated with a central hemodynamic exercise limitation. METHODS: Sixty-four stable CHF patients performed a symptom limited incremental exercise test with respiratory gas analysis and simultaneous assessment of Q, using a radial artery pulse contour analysis method. A central hemodynamic exercise limitation was defined as a plateau or decline in Q from 90 to 100 % of exercise duration. RESULTS: Data from 61 patients were analyzed. A central hemodynamic exercise limitation was observed in 21 patients (34 %). In these patients, a higher occurrence of a plateau/decrease in oxygen uptake (VO2) (52 % vs 23 %, p = 0.02), stroke volume (SV) (100 % vs. 75 %, p = 0.01) and chronotropic incompetence (31 % vs. 2.5 %, p = 0.01) was observed, while presence of a left bundle branch block (LBBB) occurred significantly less (19 % vs 48 %, p = 0.03) There was no difference in disease characteristics such as etiology, duration, NYHA class, mitral regurgitation or ischemia. CONCLUSIONS: The study revealed considerable heterogeneity in the nature of exercise limitations between moderately impaired CHF patients. In one third of the study population a plateau or decrease in Q towards peak exercise was demonstrated, which is indicative of a central hemodynamic exercise limitation. A central hemodynamic exercise limitation was associated with an impairment to augment stroke volume and heart rate. PMID- 26100152 TI - Immunotherapy with mutated onchocystatin fails to enhance the efficacy of a sub lethal oxytetracycline regimen against Onchocerca ochengi. AB - Human onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, has been successfully controlled by a single drug, ivermectin, for over 25 years. Ivermectin prevents the disease symptoms of severe itching and visual impairment by killing the microfilarial stage, but does not eliminate the adult parasites, necessitating repeated annual treatments. Mass drug administration with ivermectin does not always break transmission in forest zones and is contraindicated in individuals heavily co-infected with Loa loa, while reports of reduced drug efficacy in Ghana and Cameroon may signal the development of resistance. An alternative treatment for onchocerciasis involves targeting the essential Wolbachia symbiont with tetracycline or its derivatives, which are adulticidal. However, implementation of antibiotic therapy has not occurred on a wide scale due to the prolonged treatment regimen required (several weeks). In the bovine Onchocerca ochengi system, it has been shown previously that prolonged oxytetracycline therapy increases eosinophil counts in intradermal nodules, which kill the adult worms by degranulating on their surface. Here, in an "immunochemotherapeutic" approach, we sought to enhance the efficacy of a short, sub-lethal antibiotic regimen against O. ochengi by prior immunotherapy targeting onchocystatin, an immunomodulatory protein located in the adult female worm cuticle. A key asparagine residue in onchocystatin was mutated to ablate immunomodulatory activity, which has been demonstrated previously to markedly improve the protective efficacy of this vaccine candidate when used as an immunoprophylactic. The immunochemotherapeutic regimen was compared with sub lethal oxytetracycline therapy alone; onchocystatin immunotherapy alone; a gold standard prolonged, intermittent oxytetracycline regimen; and no treatment (negative control) in naturally infected Cameroonian cattle. Readouts were collected over one year and comprised adult worm viability, dermal microfilarial density, anti-onchocystatin IgG in sera, and eosinophil counts in nodules. Only the gold-standard antibiotic regimen achieved significant killing of adult worms, a profound reduction in microfilarial load, and a sustained increase in local tissue eosinophilia. A small but statistically significant elevation in anti onchocystatin IgG was observed for several weeks after immunisation in the immunotherapy-only group, but the antibody response in the immunochemotherapy group was more variable. At 12 weeks post-treatment, only a transient and non significant increase in eosinophil counts was apparent in the immunochemotherapy group. We conclude that the addition of onchocystatin immunotherapy to a sub lethal antibiotic regimen is insufficient to induce adulticidal activity, although with booster immunisations or the targeting of additional filarial immunomodulatory proteins, the efficacy of this strategy could be strengthened. PMID- 26100153 TI - Diagnostic challenges and the unwritten stories of dog and cat parasites. AB - Is it still possible to discover new parasites of dogs and cats? Do we really know enough about them? To what extent do limitations in the diagnosis of dog and cat parasites represent an obstacle for a deeper understanding of their biology? Diagnosis in parasitology has a profound impact on animal health and welfare and, in some cases, public health. Although, over the last few years, advances in the diagnosis of parasitic diseases have largely paralleled knowledge of their biology, gaps in the diagnosis of cat and dog parasites still exist. For instance, difficulties in obtaining samples for research purposes (due to ethical issues or to the invasive nature of the sampling procedures), inappropriate sample storage and poor sensitivity of the commonly used techniques, may represent major obstacles in diagnosing parasitic diseases. Other hurdles are often associated with the biology of parasites (e.g., the intermittent presence in blood of tick-borne pathogens) or, simply, through the fact that some parasites of pets are largely ignored by the scientific community. This article provides key examples of parasites of dogs and cats, which are currently considered of minor importance, also because of the limitations in their diagnosis. Among them, new or, in some cases, previously "misdiagnosed parasites" with overlapping morphological features, biology or ecology, represent a major challenge when trying to correctly diagnose "unknown parasites" (for which only occasional reports are available). Further research is needed in order to provide the scientific community with more reliable, cost-effective diagnostic tools, which ultimately, will assist our understanding of some mis- or less-diagnosed parasitoses. PMID- 26100154 TI - Endovascular flow diversion therapy for an actively hemorrhaging aneurysm after intraoperative rupture. AB - We report a 56-year-old woman who had an unruptured posterior communicating artery aneurysm. Given the size and location of the aneurysm, as well as her history of smoking and age, she received endovascular treatment with the pipeline embolization device (PED; ev3 Endovascular, Plymouth, MN, USA), complicated by intraoperative rupture (IOR). Flow diversion therapy with the PED has become an increasingly popular method of aneurysmal embolization and parent vessel remodeling. While its on-label approval is for large unruptured aneurysms of the internal carotid artery, success in off-label scenarios has been reported, including ruptured aneurysms. IOR complicates endovascular aneurysm treatment and can cause devastating morbidity or mortality, necessitating acute embolization of the hemorrhaging aneurysm. This patient illustrates the feasibility of treating an IOR with a stand-alone flow diversion device by using PED. PMID- 26100155 TI - A novel minimally invasive technique for lumbar decompression, realignment, and navigated interbody fusion. AB - We present a novel, minimally invasive, navigation-guided approach for surgical treatment of degenerative spondylolisthesis (DS) that is a hybrid of the two most common techniques, posterior interbody fusion (PLIF) and transforaminal interbody fusion (TLIF). DS is an acquired condition with intersegmental instability of one or more lumbar motion segments. Seven patients with single level lumbar DS underwent lumbar arthrodesis utilizing the hybrid technique (HLIF) in our center. Using a standard unilateral midline approach a decompression and partial facetectomy on one side was performed, allowing for implantation of a specially designed interbody cage. Pedicle screws were placed using neuronavigation in a vertical vector on the side of the partial facetectomy and dorsolaterally (percutaneous) on the contralateral side. Patient and operative data, numeric rating scale (NRS) pain scores, core outcome measures index (COMI) and Oswestry disability index (ODI) were recorded preoperatively as well as 6 weeks, 3 months, 6 months and 1 year after surgery. All patients completed the 1 year follow-up. There was significant postoperative improvement of NRS, COMI and ODI scores at all postoperative follow-up time points (p<0.05). The radiological assessments of realignment showed a reduction of listhesis from an average of 21.04% (standard deviation [SD] 5.1) preoperatively to 9.14% (SD 4.0) postoperatively (p<0.001). The average blood loss was 492 ml. Post-procedure CT scans demonstrated correct implant placement in all but one patient who required a revision of a single pedicle screw. HLIF allows thorough decompression as well as realignment and interbody fusion for patients with DS and may help reduce tissue trauma in comparison to other minimally invasive lumbar fusion techniques. PMID- 26100156 TI - Central nervous system complications after liver transplantation. AB - We investigated the diversity of central nervous system complications after liver transplantation in terms of clinical manifestations and temporal course. Liver transplantation is a lifesaving option for end stage liver disease patients but post-transplantation neurologic complications can hamper recovery. Between 1 January 2001 and 31 December 2010, patients who had undergone liver transplantation at a single tertiary university hospital were included. We reviewed their medical records and brain imaging data and classified central nervous system complications into four categories including vascular, metabolic, infectious and neoplastic. The onset of central nervous system complications was grouped into five post-transplantation intervals including acute (within 1 month), early subacute (1-3 months), late subacute (3-12 months), chronic (1-3 years), and long-term (after 3 years). During follow-up, 65 of 791 patients (8.2%) experienced central nervous system complications, with 30 occurring within 1 month after transplantation. Vascular etiology was the most common (27 patients; 41.5%), followed by metabolic (23; 35.4%), infectious (nine patients; 13.8%), and neoplastic (six patients). Metabolic encephalopathy with altered consciousness was the most common etiology during the acute period, followed by vascular disorders. An initial focal neurologic deficit was detected in vascular and neoplastic complications, whereas metabolic and infectious etiologies presented with non-focal symptoms. Our study shows that the etiology of central nervous system complications after liver transplantation changes over time, and initial symptoms can help to predict etiology. PMID- 26100158 TI - Sacrum fracture following L5-S1 stand-alone interbody fusion for isthmic spondylolisthesis. AB - We report a 72-year-old man with a rare sacral fracture following stand-alone L5 S1 anterior lumbar interbody fusion for isthmic spondylolisthesis. The man underwent a minimally invasive management strategy using posterior percutaneous pedicle fixation and partial reduction of the deformity. We also discuss the current literature on fusion procedures for isthmic spondylolisthesis. PMID- 26100157 TI - Botulinum toxin injections for the treatment of hemifacial spasm over 16 years. AB - The aim of this study was to investigate the efficacy and side effects of botulinum toxin (BTX) in the treatment of hemifacial spasm (HFS). We also focused on the divergence between different injection techniques and commercial forms. We retrospectively evaluated 470 sessions of BTX injections administered to 68 patients with HFS. The initial time of improvement, duration and degree of improvement, and frequency and duration of adverse effects were analysed. Pretarsal and preseptal injections and Botox (Allergan, Irvine, CA, USA) and Dysport (Ipsen Biopharmaceuticals, Paris, France) brands were compared in terms of efficacy and side effects, accompanied by a review of papers which reported BTX treatment of HFS. An average of 34.5 units was used per patient. The first improvement was felt after 8 days and lasted for 14.8 weeks. Patients experienced a 73.7% improvement. In 79.7% of injections, no adverse effect was reported, in 4.9% erythema, ecchymosis, and swelling in the injection area, in 3.6% facial asymmetry, in 3.4% ptosis, in 3.2% diplopia, and in 2.3% difficulty of eye closure was detected. Patients reported 75% improvement on average after 314 sessions of pretarsal injections and 72.7% improvement after 156 sessions of preseptal injections (p=0.001). The efficacy and side effects of Botox and Dysport were similar. BTX is an effective and safe treatment option for HFS. No difference was determined between Botox and Dysport, and pretarsal injection is better than preseptal injection regarding the reported degree of improvement. PMID- 26100159 TI - A massive pelvic mucocele presenting as a cystic sacral mass. AB - We present a man, with a complex medical and surgical history, who had a large pelvic non-appendiceal cystadenoma, presenting as a cystic sacral mass causing obstructive urinary symptoms and renal failure. Mucocele should be included in the differential diagnosis of patients who present with large sacral masses, and who have a significant history of pelvic and abdominal surgery and inflammatory bowel disease. PMID- 26100160 TI - Serum lactate as a potential biomarker of non-glial brain tumors. AB - We assess whether serum lactate is a potential biomarker for non-glial cell brain tumors. Rapidly growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin and produce lactate even in the presence of oxygen. This phenomenon is called the Warburg effect. We recently showed that serum lactate levels can be used as a potential non-invasive biomarker in glial cell brain tumors, which correlates with both tumor grade and the extent of malignancy. In the present study, we found that patients with metastatic brain tumors had significantly higher baseline serum lactate levels compared to patients with meningioma and pituitary tumors. There was a statistically significant association between metastatic brain tumors and elevated serum lactate. We demonstrate that lactate can be used as a non-invasive biomarker to determine malignancy for brain tumors. Further analyses of larger populations will be needed to establish the value of serum lactate in determining the response to therapy or early recurrence. PMID- 26100161 TI - Neuroprotective effects of N-acetylcysteine amide on experimental focal penetrating brain injury in rats. AB - We examined the effects of N-acetylcysteine amide (NACA) in the secondary inflammatory response following a novel method of focal penetrating traumatic brain injury (TBI) in rats. N-acetylcysteine (NAC) has limited but well documented neuroprotective effects after experimental central nervous system ischemia and TBI, but its bioavailability is very low. We tested NACA, a modified form of NAC with higher membrane and blood-brain barrier permeability. Focal penetrating TBI was produced in male Sprague-Dawley rats randomly selected for NACA treatment (n=5) and no treatment (n=5). In addition, four animals were submitted to sham surgery. After 2 hours or 24 hours the brains were removed, fresh frozen, cut in 14 MUm coronal sections and subjected to immunohistochemistry, immunofluorescence, Fluoro-Jade and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analyses. All treated animals were given 300 mg/kg NACA intraperitoneally (IP) 2 minutes post trauma. The 24 hour survival group was given an additional bolus of 300 mg/kg IP after 4 hours. NACA treatment decreased neuronal degeneration by Fluoro-Jade at 24 hours with a mean change of 35.0% (p<0.05) and decreased TUNEL staining indicative of apoptosis at 2 hours with a mean change of 38.7% (p<0.05). Manganese superoxide dismutase (MnSOD) increased in the NACA treatment group at 24 hours with a mean change of 35.9% (p<0.05). Levels of migrating macrophages and activated microglia (Ox-42/CD11b), nitric oxide-producing inflammatory enzyme iNOS, peroxynitrite marker 3-nitrotyrosine, NFkappaB translocated to the nuclei, cytochrome C and Bcl 2 were not affected. NACA treatment decreased neuronal degeneration and apoptosis and increased levels of antioxidative enzyme MnSOD. The antiapoptotic effect was likely regulated by pathways other than cytochrome C. Therefore, NACA prevents brain tissue damage after focal penetrating TBI, warranting further studies towards a clinical application. PMID- 26100162 TI - A mosquito lipoxin/lipocalin complex mediates innate immune priming in Anopheles gambiae. AB - Exposure of Anopheles gambiae mosquitoes to Plasmodium infection enhances the ability of their immune system to respond to subsequent infections. However, the molecular mechanism that allows the insect innate immune system to 'remember' a previous encounter with a pathogen has not been established. Challenged mosquitoes constitutively release a soluble haemocyte differentiation factor into their haemolymph that, when transferred into Naive mosquitoes, also induces priming. Here we show that this factor consists of a Lipoxin/Lipocalin complex. We demonstrate that innate immune priming in mosquitoes involves a persistent increase in expression of Evokin (a lipid carrier of the lipocalin family), and in their ability to convert arachidonic acid to lipoxins, predominantly Lipoxin A4. Plasmodium ookinete midgut invasion triggers immune priming by inducing the release of a mosquito lipoxin/lipocalin complex. PMID- 26100163 TI - Neuroendoscopy Followed by Radiotherapy in Cystic Craniopharyngiomas--a Long-Term Follow-Up. AB - BACKGROUND: Treatment of cystic craniopharyngiomas is often complicated because of adherence of craniopharyngiomas to adjacent brain structures. A strategy involving neuroendoscopic procedures followed by stereotactic radiotherapy is less invasive, avoiding brain damage. However, long-term follow-up of this strategy has not been investigated in depth. METHODS: Cystic craniopharyngiomas in 9 patients were treated with neuroendoscopic cyst aspiration and fenestration, followed by fractionated stereotactic radiotherapy (FSRT). The neuroendoscopic procedure focused on widening of cyst fenestration and extensive irrigation of the cyst contents. FSRT was performed using 6 fixed beams, an 8-mm margin to cover the gross tumor volume with a 95% isodose line, and a target delivered dose of 50.4 Gy in 28 fractions. RESULTS: The median follow-up period was 72.9 months. Tumor control was achieved in 8 of 9 patients (88.9%). Marked tumor volume reduction was obtained with the neuroendoscopic procedure alone (26.1%) at 6 months (20.4%), 1 year (11.0%), and 2 years (3.1%). One recurrent case showed multilobulated cysts, and a second surgery was required 1 year after the treatment. Clinical symptoms such as headache and visual disruption were rapidly alleviated after the neuroendoscopic procedure. No new visual disturbances, endocrinopathy, or hypothalamic dysfunction was observed during follow up. CONCLUSIONS: Neuroendoscopic cyst aspiration and fenestration followed by FSRT is a less invasive, powerful strategy for treating adult cystic craniopharyngiomas. PMID- 26100164 TI - The Diagnosis and Management of Brain Arteriovenous Malformations in a Single Regional Center. AB - BACKGROUND: Cerebral arteriovenous malformations are vascular abnormalities in which arteriovenous shunting occurs through an abnormal vascular network (nidus) in the parenchyma. These lesions typically present by the third decade of life with cerebral bleeding, seizures, headache, or neurologic deficits; however, they are sometimes found incidentally. METHODS: A retrospective analysis of intracranial AVMs referred to a single regional center, over a 7-year period, was performed to review the clinical presentation, pathologic features and management outcomes from January 2005 to December 2012. RESULTS: We identified 142 patients (56% female, age range 4-69 years). Emergency referrals accounted for 87% of the cohort with the most frequent presentation being headache and/or hemorrhage. More than half (52%) of the cases were observed to have a neurologic deficit on examination. The modal Spetzler-Martin Grade was 3 with 76% of lesions located in areas of eloquent brain and 57% of cases in the dominant hemisphere. Half of the cases had multiple feeder vessels, and 29% were associated with aneurysms. The nidus was obliterated in 91% of cases actively managed. Two thirds of patients were successfully treated with a single modality, the most common being embolization. Only 8% of cases were managed conservatively. Additionally, 93% of aneurysms identified were treated successfully. The complication rate was 7% with 2% of reported infection. CONCLUSIONS: The burden of AVM management is significantly enhanced by the number of emergency referrals. Interestingly, complication rates are higher in the unruptured cohort. Surgical management is the most effective modality, but it carries the highest complication rate. This accompanied by the challenges of AVM anatomy and associated pathology argue for expert service provision in a single center. PMID- 26100165 TI - Spontaneous Intracerebral Hemorrhage. PMID- 26100166 TI - Minimally Invasive Muscle Sparing Posterior-Only Approach for Lumbar Circumferential Decompression and Stabilization to Treat Spine Metastasis- Technical Report. AB - OBJECTIVE: Palliative tumor resection and subsequent stabilization are important for maximizing function and quality of life for patients suffering from spinal metastases. However, traditional operative techniques for spinal metastases with vertebral body destruction involve extensive soft tissue dissection. In the lumbar spine, open 2-staged spine procedures are routinely required with an anterior retroperitoneal approach for corpectomy and cage insertion and posterior decompression and stabilization with pedicle screws and rods. Both stages require extensive soft tissue dissection that results in significant surgical morbidity, long recovery time, and subsequent delay in initiating postoperative chemoradiotherapy, as well as initially hampering patients' overall quality of life. A minimally invasive approach is desirable for achieving spinal stability, pain control, functional recovery, rapid initiation of adjuvant therapies, and overall patient satisfaction, especially in patients whose medical and surgical therapies are aimed at palliation rather than cure. PRESENTATION: A 59-year-old man with renal cell carcinoma and a known L1 vertebral body metastasis presented with severe progressive low back pain and was found to have a pathologic L1 vertebral body fracture with focal kyphosis. INTERVENTION: Here, we describe a minimally invasive muscle-sparing, posterior-only approach for L1 transpedicular hemicorpectomy and expandable cage placement, L1 laminectomy, and T11-L3 posterior instrumented stabilization. The surgical corridor was achieved through the Wiltse muscle plane between the multifidus and longissimus muscles so that minimal muscle detachment was required to achieve transpedicular access to the anterior and middle spinal columns. The L1 nerve root was completely skeletonized to allow adequate lumbar hemicorpectomy, tumor resection, and expandable titanium cage insertion. Lastly, percutaneous pedicle screws and rods were inserted from T11 to L3 for stabilization. RESULT: The patient tolerated the procedure well with no complications and less than 200 mL estimated blood loss. Postoperative computed tomography revealed restoration of intervertebral height and adequate tumor resection with excellent placement of the expandable cage and posterior construct. The patient was discharged on postoperative day 4 and had nearly no back pain 3 weeks after surgery. Adjuvant therapies were started soon after. At the 6-month follow-up, the patient required minimal narcotic pain medication. Computed tomography scan demonstrated stable hardware with no evidence of failure. CONCLUSION: A minimally invasive muscle-sparing, posterior-only approach is a promising surgical strategy for 360-degree decompression and stabilization for the treatment of lumbar spinal metastases with minimized blood loss, muscle detachment and postoperative pain, and fast postoperative recovery and initiation of adjuvant therapy. PMID- 26100167 TI - Ventriculostomy Simulation Using Patient-Specific Ventricular Anatomy, 3D Printing, and Hydrogel Casting. AB - BACKGROUND: Educational simulators provide a means for students and experts to learn and refine surgical skills. Educators can leverage the strengths of medical simulators to effectively teach complex and high-risk surgical procedures, such as placement of an external ventricular drain. OBJECTIVE: Our objective was to develop a cost-effective, patient-derived medical simulacrum for cerebral lateral ventriculostomy. METHODS: A cost-effective, patient-derived medical simulacrum was developed for placement of an external lateral ventriculostomy. Elastomeric and gel casting techniques were used to achieve realistic brain geometry and material properties. 3D printing technology was leveraged to develop accurate cranial properties and dimensions. An economical, gravity-driven pump was developed to provide normal and abnormal ventricular pressures. A small pilot study was performed to gauge simulation efficacy using a technology acceptance model. RESULTS: An accurate geometric representation of the brain was developed with independent lateral cerebral ventricular chambers. A gravity-driven pump pressurized the ventricular cavities to physiologic values. A qualitative study illustrated that the simulation has potential as an educational tool to train medical professionals in the ventriculostomy procedure. CONCLUSION: The ventricular simulacrum can improve learning in a medical education environment. Rapid prototyping and multi-material casting techniques can produce patient derived models for cost-effective and realistic surgical training scenarios. PMID- 26100168 TI - Comparative Effectiveness Analysis of Treatment Options for Single Brain Metastasis. AB - BACKGROUND: Brain metastases (BMs) occur in up to 30% of patients with cancer. Treatments include surgery, whole-brain radiotherapy (WBRT), and stereotactic radiosurgery (SRS), alone or in combination. Although guidelines exist, data to inform individualized approaches to therapy remain sparse. We sought to compare semiquantitatively the effectiveness of various modalities in the treatment of single brain metastasis. METHODS: We performed a comparative effectiveness analysis (CEA) that integrated efficacy, cost, and quality of life (QoL) data for alternate BM treatments. Efficacy data were obtained from a comprehensive review of current literature. Cost estimates were based on publicly available data. QoL data included the Karnofsky Performance Status (KPS) and other questionnaires. Six treatment strategies using combinations of surgery, WBRT, and SRS were compared with decision tree software. RESULTS: The clinical efficacy, cost, and QoL effects of each strategy were scored semiquantitatively. We constructed a model to integrate individual preferences regarding the relative importance of efficacy, QoL, and cost to provide personalized rankings of the effectiveness of each strategy. CONCLUSION: The choice of strategy must be individualized for patients with a single BM. Our CEA and decision model combines empirical data with patient priorities to produce a ranking of alternate management strategies. PMID- 26100169 TI - Does Obesity Affect Outcomes After Decompressive Surgery for Lumbar Spinal Stenosis? A Multicenter, Observational, Registry-Based Study. AB - OBJECTIVE: To evaluate the association between obesity and outcomes 1 year after laminectomy or microdecompression for lumbar spinal stenosis (LSS). METHODS: The primary outcome measure was the Oswestry Disability Index (ODI). Obesity was defined as body mass index (BMI) >= 30. Prospective data were retrieved from the Norwegian Registry for Spine Surgery. RESULTS: For all patients (n = 1473) the mean improvement in ODI at 1 year was 16.7 points (95% CI 15.7-17.7, P < 0.001). The improvement in ODI was 17.5 points in nonobese and 14.3 points in obese patients (P = 0 .007). Obese patients were less likely to achieve a minimal clinically important difference in ODI (defined as >= 8 points improvement) than nonobese patients (62.2 vs. 70.3%, P = 0.013). Obesity was identified as a negative predictor for ODI improvement in a multiple regression analysis (P < 0.001). Nonobese patients experienced more improvement in both back pain (0.7 points, P = 0.002) and leg pain (0.8 points, P = 0.001) measured by numeric rating scales. Duration of surgery was shorter for nonobese patients for both single- (79 vs. 89 minutes, P = 0.001) and 2-level (102 vs. 114 minutes, P = 0.004) surgery. There was no difference in complication rates (10.4% vs. 10.8%, P = 0.84). There was no difference in length of hospital stays for single- (2.7 vs. 3.0 days, P = 0.229) or 2-level (3.5 vs. 3.6 days, P = 0.704) surgery. CONCLUSIONS: Both nonobese and obese patients report considerable clinical improvement 1 year after surgery for LSS, but improvement was less in obese patients. Obese patients were less likely to achieve a minimal clinically important difference. PMID- 26100170 TI - Educational Resources "Over the Head" of Neurosurgical Patients: The Economic Impact of Inadequate Health Literacy. AB - BACKGROUND: Health literacy is the ability with which individuals can obtain, understand, and apply basic health information. Approximately 36% of Americans have basic or below basic health literacy skills. This low health literacy is particularly prevalent in neurosurgery, a growing field of medicine with considerable complexity and a patient population commonly affected with disease related cognitive impairment. Consequences of poor patient understanding range from increased emergency department admissions rates to reduced adherence to preoperative medication instructions. Economic implications include increasing health care expenditures, decreasing access to health care, and decreasing quality of care. Health literacy costs the United States $106-236 billion per year. METHODS: Consequences of inadequate patient understanding vary widely. This article reviews and addresses the economic impact of the failure to address low health literacy in neurosurgery. RESULTS: Various groups have proposed techniques and devised outlines to improve health literacy, such as detailing principles targeting the underlying issues of health care illiteracy. The government, through legislation including the Affordable Care Act and the National Action Plan to Improve Health Literacy, has also shown its desire to remedy the effects of insufficient health literacy. CONCLUSIONS: Despite current efforts, further action is still needed. Health literacy is a key determinant in ensuring longevity and quality of life. PMID- 26100171 TI - "A Lot of Things Passed Me by": Rural Stroke Survivors' and Caregivers' Experience of Receiving Education From Health Care Providers. AB - PURPOSE: The purpose of this study is to examine rural Appalachian Kentucky stroke survivors' and caregivers' experiences of receiving education from health care providers with the long-term goal of optimizing educational interactions and interventions for an underserved population. METHODS: An interprofessional research team, representing nursing, occupational therapy, physical therapy, and speech language pathology, conducted a qualitative descriptive study involving semistructured interviews with 13 stroke survivors and 12 caregivers. Qualitative content analysis included predetermined and emerging coding. This article presents an in-depth analysis of a subset of data from the coding scheme of a larger study that examined the overall experience of stroke for participants. FINDINGS: Findings are presented within a developing model of patient and caregiver education constructs including providers and receivers of education and the content, timing, and delivery of information. CONCLUSIONS: Understanding the experience of receiving education for survivors and caregivers will help practitioners provide the right education, to the right people, at the right time, and in the right way to better support underserved groups. Improving patient and caregiver education is paramount to supporting health behavior change to optimize life poststroke and prevent future strokes. Our results suggest the need for improved access to educational providers, proactive identification of informational needs by providers, greater inclusion of caregivers in education, enhanced communication with information provision, and education from multiple providers using multiple delivery methods at multiple time points. PMID- 26100172 TI - Bronchoscopy techniques in Japan: Transbronchial biopsy of small peripheral pulmonary lesions. PMID- 26100173 TI - Cigarette smoke augments MUC5AC production via the TLR3-EGFR pathway in airway epithelial cells. AB - BACKGROUND: Viral infections are a major cause of chronic obstructive pulmonary disease (COPD) exacerbations. Toll-like receptor 3 (TLR3) reacts with double stranded RNA (dsRNA) and participates in the immune response after viral infection. In the present study, we examined whether cigarette smoke, which is involved in the pathogenesis of COPD, enhances mucin production via the TLR3 epidermal growth factor receptor (EGFR) pathway in airway epithelial cells. METHODS: We studied the effects of cigarette smoke extract (CSE) on signal transduction and the production of mucin 5AC (MUC5AC) in NCI-H292 cells and differentiated primary human bronchial epithelial cells stimulated with a synthetic dsRNA analogue, polyinosinic-polycytidylic acid [poly(I:C)], used as a TLR3 ligand. RESULTS: CSE significantly potentiated the production of MUC5AC in epithelial cells stimulated with poly(I:C). Antibodies to EGFR or EGFR ligands inhibited CSE-augmented MUC5AC release in poly(I:C)-treated cells. Treatment with poly(I:C) or CSE alone increased the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK). However, after poly(I:C) stimulation, CSE did not enhance EGFR phosphorylation, but did augment ERK phosphorylation. EGFR inhibitors and an ERK inhibitor inhibited the augmented release of MUC5AC. In addition, treatment with N-acetylcysteine, an antioxidant, inhibited the CSE augmented phosphorylation of ERK and MUC5AC. CONCLUSIONS: These data show that cigarette smoke increases TLR3-stimulated MUC5AC production in airway epithelial cells, mainly via ERK signaling. The effect might be mediated in part by oxidative stress. Modulation of this pathway might be a therapeutic target for viral-induced mucin overproduction in COPD exacerbation. PMID- 26100174 TI - Pleuroparenchymal fibroelastosis: Distinct pulmonary physiological features in nine patients. AB - BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial pneumonia defined by pleural and subpleural parenchymal fibrosis predominantly in the upper lobes. Although the radiological and pathological characteristics of PPFE have become increasingly recognized, its pulmonary physiological features are not well understood. METHODS: We reviewed nine patients with radiologically and histologically proven PPFE, and evaluated pulmonary physiological data. RESULTS: Of the nine patients, six were male and three were female. The median age at presentation was 61 years. Common symptoms were dyspnea on exertion, weight loss, and nonproductive cough. Recurrent pneumothorax was found in eight patients and pneumonia in four. Median pulmonary function test results were as follows: forced vital capacity, 55.4% predicted; total lung capacity (TLC), 67.1% predicted; residual volume (RV), 102.3% predicted; and RV/TLC, 143.6% predicted. RV/TLC was increased without evidence of small airway disease according to clinico-radiologic-pathologic evaluation. The median partial pressure of oxygen in arterial blood and the alveolar-arterial gradient of oxygen were within normal limits, although there was a slightly elevated partial pressure of carbon dioxide in arterial blood (PaCO2). PPFE progressed in all patients despite treatment with pirfenidone, corticosteroids, and immunosuppressive agents. Seven patients died during the follow-up, five because of hypercapnic respiratory failure. CONCLUSIONS: PPFE is characterized by severe mechanical restriction with high RV/TLC, causing increased PaCO2 and eventual hypercapnic respiratory failure. These physiological findings may be useful as an adjunct in the diagnosis of PPFE. PMID- 26100175 TI - Weekly irinotecan combined with carboplatin for patients with small-cell lung cancer: A phase I study. AB - BACKGROUND: We conducted a phase I dose escalation study to evaluate the feasibility, maximum tolerated dose (MTD), and recommended dose (RD) of weekly irinotecan combined with fixed-dose carboplatin for patients with untreated small cell lung cancer (SCLC). METHODS: Fifteen patients with chemotherapy-naive SCLC less than 75 years old were enrolled from 3 institutions. Patients received irinotecan (50-80mg/m(2) on days 1 and 8) and carboplatin (area under the curve, 5.0 on day 1) every 3 weeks, with 3-6 patients treated at each irinotecan dosage level (levels I-IV). The MTD was defined as the dose at which 33% of patients experienced dose-limiting toxicity. RESULTS: Eleven patients had a performance status of 1, and 7 patients were more than 70 years old. All but 1 patient were diagnosed with extensive disease. In total, 2 of 3 patients enrolled at level IV (80mg/m(2)) experienced grade 3 diarrhea. Therefore, the MTD was defined as the level IV dose, and the RD was defined as the level III dose (70mg/m(2)). Grade 3 or 4 neutropenia was observed in 60% of patients, and febrile neutropenia was observed in 13% of patients. Four patients experienced grade 3 or 4 anemia, and 6 patients experienced grade 3 or 4 thrombocytopenia. The most common non hematological adverse events were nausea/vomiting, diarrhea, hypokalemia, and hyponatremia. CONCLUSIONS: The MTD of weekly irinotecan was 80mg/m(2), resulting in an RD of 70mg/m(2) for phase II trials. PMID- 26100176 TI - Propionibacterium acnes catalase induces increased Th1 immune response in sarcoidosis patients. AB - BACKGROUND: Propionibacterium acnes is one of the most commonly implicated etiologic agents of sarcoidosis. We screened antigenic proteins from this indigenous bacterium that increase Th1 responses in sarcoidosis patients. METHODS: Antigenic bacterial proteins were screened by probing western blots of P. acnes whole cell lysates with blood plasma samples from 52 sarcoidosis patients and 34 healthy volunteers. Soluble protein antigens from the bands most frequently detected on blotting membranes were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS). Recombinant proteins were prepared from DNA sequences of the proteins identified by MALDI-TOF/MS and analyzed by immunologic assays. RESULTS: MALDI-TOF/MS analysis identified propionyl-CoA carboxylase subunit beta, arginine deiminase (ADI), catalase (KAT), and UDP-N-acetylglucosamine pyrophosphorylase (UAP). Successfully prepared recombinant proteins from ADI, KAT, and UAP provoked humoral and cellular immune responses in mice immunized with P. acnes when measured by enzyme-linked immunosorbent assay for serum antibodies and enzyme linked immunospot assay for interferon (IFN)-gamma-secreting cells (ELISPOT IFN gamma assay) with lymph node cells. Plasma IgG and IgA titers to KAT and UAP were significantly higher in sarcoidosis patients than in healthy volunteers. When Th1 immune responses to ADI, KAT, and UAP were measured by ELISPOT IFN-gamma assay with peripheral blood mononuclear cells from 12 sarcoidosis patients, 13 other pneumonitis patients, and 11 healthy volunteers, only the KAT protein provoked a significantly higher response in sarcoidosis patients (p=0.0032). CONCLUSION: These results suggest that P. acnes KAT is an antigen that provokes allergic Th1 immune responses in sarcoidosis patients. PMID- 26100177 TI - Recurrence of a mediastinal liposarcoma 20 years after surgery: A case of carbon ion radiotherapy resulting in fatal tracheoesophageal fistula. PMID- 26100178 TI - Triple therapy vs. dual bronchodilator therapy for chronic obstructive pulmonary disease: Is it worth the cost? PMID- 26100179 TI - An RNA secondary structure prediction method based on minimum and suboptimal free energy structures. AB - The function of an RNA-molecule is mainly determined by its tertiary structures. And its secondary structure is an important determinant of its tertiary structure. The comparative methods usually give better results than the single sequence methods. Based on minimum and suboptimal free energy structures, the paper presents a novel method for predicting conserved secondary structure of a group of related RNAs. In the method, the information from the known RNA structures is used as training data in a SVM (Support Vector Machine) classifier. Our method has been tested on the benchmark dataset given by Puton et al. The results show that the average sensitivity of our method is higher than that of other comparative methods such as CentroidAlifold, MXScrana, RNAalifold, and TurboFold. PMID- 26100180 TI - Local densities connect spatial ecology to game, multilevel selection and inclusive fitness theories of cooperation. AB - Cooperation plays a crucial role in many aspects of biology. We use the spatial ecological metrics of local densities to measure and model cooperative interactions. While local densities can be found as technical details in current theories, we aim to establish them as central to an approach that describes spatial effects in the evolution of cooperation. A resulting local interaction model neatly partitions various spatial and non-spatial selection mechanisms. Furthermore, local densities are shown to be fundamental for important metrics of game theory, multilevel selection theory and inclusive fitness theory. The corresponding metrics include structure coefficients, spatial variance, contextual covariance, relatedness, and inbreeding coefficient or F-statistics. Local densities serve as the basis of an emergent spatial theory that draws from and brings unity to multiple theories of cooperation. PMID- 26100181 TI - Distributed transit compartments for arbitrary lifespan distributions in aging populations. AB - Transit compartment models (TCM) are often used to describe aging populations where every individual has its own lifespan. However, in the TCM approach these lifespans are gamma-distributed which is a serious limitation because often the Weibull or more complex distributions are realistic. Therefore, we extend the TCM concept to approximately describe any lifespan distribution and call this generalized concept distributed transit compartment models (DTCMs). The validity of DTCMs is obtained by convergence investigations. From the mechanistic perspective the transit rates are directly controlled by the lifespan distribution. Further, DTCMs could be used to approximate the convolution of a signal with a probability density function. As example a stimulatory effect of a drug in an aging population with a Weibull-distributed lifespan is presented where distribution and model parameters are estimated based on simulated data. PMID- 26100183 TI - Overdiagnosis and the information problem. AB - There are several factors which increase our propensity to overdiagnose, whereas the root cause of overdiagnosis is imperfect information and the trade-offs as a result of that imperfection. PMID- 26100182 TI - Biodiversity, productivity, and the spatial insurance hypothesis revisited. AB - Accelerating rates of biodiversity loss have led ecologists to explore the effects of species richness on ecosystem functioning and the flow of ecosystem services. One explanation of the relationship between biodiversity and ecosystem functioning lies in the spatial insurance hypothesis, which centers on the idea that productivity and stability increase with biodiversity in a temporally varying, spatially heterogeneous environment. However, there has been little work on the impact of dispersal where environmental risks are more or less spatially correlated, or where dispersal rates are variable. In this paper, we extend the original Loreau model to consider stochastic temporal variation in resource availability, which we refer to as "environmental risk", and heterogeneity in species dispersal rates. We find that asynchronies across communities and species provide community-level stabilizing effects on productivity, despite varying levels of species richness. Although intermediate dispersal rates play a role in mitigating risk, they are less effective in insuring productivity against global (metacommunity-level) than local (individual community-level) risks. These results are particularly interesting given the emergence of global sources of risk such as climate change or the closer integration of world markets. Our results offer deeper insights into the Loreau model and new perspectives on the effectiveness of spatial insurance in the face of environmental risks. PMID- 26100184 TI - An overview of methodologies in detecting overdiagnosis. PMID- 26100185 TI - Can advanced imaging reduce overdiagnosis and overtreatment? PMID- 26100186 TI - Overdiagnosis of thyroid cancer: answers to five key questions. AB - Thyroid cancer fulfills the criteria for overdiagnosis by having a reservoir of indolent cancers and practice patterns leading to the diagnosis of incidental cancers from the reservoir. The occurrence of overdiagnosis is also supported by population-based data showing an alarming rise in thyroid cancer incidence without change in mortality. Because one of the activities leading to overdiagnosis is the workup of incidental thyroid nodules detected on imaging, it is critical that radiologists understand the issue of overdiagnosis and their role in the problem and solution. This article addresses 1) essential thyroid cancer facts, 2) the evidence supporting overdiagnosis, 3) the role of radiology in overdiagnosis, 4) harms of overdiagnosis, and 5) steps radiologists can take to minimize the problem. PMID- 26100187 TI - Will supplemental screening ultrasound increase breast cancer overdiagnosis? AB - Overdiagnosis refers to the detection of cancers that would never come to light in a patient's lifetime and are only identified by means of screening. Exactly how much overdiagnosis currently exists with screening mammography is uncertain. Because we do not know for certain which tumors would ultimately lead to death if left untreated and which would not, we cannot directly measure overdiagnosis and how best to estimate it is a matter of controversy. A conservative estimate of overdiagnosis with mammography would be on the order of 10%, but estimates have ranged as high as 54%. We know from multiple studies that ultrasound (US) screening mostly detects small, invasive, node-negative cancers; and in the ACRIN 6666 study, there was a greater tendency for US-only-detected tumors to be low grade than those detected with mammography. However, the population of patients undergoing screening US can be expected to differ from the average screening mammography population in that they will have higher breast density, they will be younger, and they may also have higher breast cancer risk than the population undergoing screening mammography. These factors may be associated with more aggressive tumors. There is no way to know whether we will be increasing overdiagnosis without performing a large randomized controlled study with very long-term follow-up. Even if some cancers are overdiagnosed with US, there will be a greater proportion of lethal breast cancers that are successfully treated because of screening US. The more important task is to learn how to correctly diagnose and appropriately treat nonlethal cancers. PMID- 26100188 TI - Screening mammography: update and review of publications since our report in the New England Journal of Medicine on the magnitude of the problem in the United States. AB - RATIONALE AND OBJECTIVES: After a half century of clinical trials, expansive observations, vigorous advocacy and debate, screening mammography could not be in a more controversial condition, especially the potential harm of overdiagnosis. Despite a simple rationale (catch the cancer early and either prevent death or at least decrease the amount of therapy needed for cure), the estimates to date of overdiagnosis rates are conflicting and the interpretations complex. MATERIALS AND METHODS: Since the author's 2012 publication in the New England Journal of Medicine (NEJM), the peer-reviewed publications on overdiagnosis caused by screening mammography are reviewed and the NEJM analyses updated with three additional calendar years of results. RESULTS: The recent peer-reviewed medical literature on screening mammography induced overdiagnosis of breast cancer has increased exponentially, nearly 10-fold in 10 years. The average estimate of overdiagnosis is about 30%, but the range extends from 0% to 70+%. An update of the NEJM report estimates that in the US, 78,000 women and 30%-31% of those diagnosed with breast cancer at the age of 40 years or older during 2011 were overdiagnosed. CONCLUSIONS: Until we have better screening procedures that identify who really has cancer and needs to be treated, the risk of overdiagnosis relative to the benefit of screening merits more effective public and professional education. Radiologists, pathologists, and other professionals involved with screening mammography should recognize that the potential harm of overdiagnosis is downplayed or not discussed with the patient and family, despite agreement that the objective is informed choice. PMID- 26100189 TI - Radiologists and overdiagnosis. PMID- 26100190 TI - Analysis of statistical biases in studies used to formulate guidelines: the case of arrhythmogenic right ventricular cardiomyopathy (ARVC) the case of ARVC. AB - RATIONALE AND OBJECTIVES: To analyze the statistical biases in the studies used to derive cardiac magnetic resonance-based major and minor criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). MATERIALS AND METHODS: ARVC is a rare disorder of the heart that can lead to sudden death in young adults. Cardiac magnetic resonance imaging (CMR) plays a role in the diagnosis by contributing to the criteria set by experts. The original criteria emphasized qualitative analysis of CMR. The criteria were modified in 2010 to provide quantitative cutoffs. RESULTS: We apply the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for systematic review of diagnostic accuracy to the studies cited in the guidelines written in 1994 and revised in 2010. We use the signaling questions in QUADAS-2 to identify different types of statistical bias. CONCLUSIONS: The studies have understandable biases that affect the sensitivity and specificity of CMR in the diagnosis of ARVC, as well as the truth of the disease state. There is potential to overdiagnose ARVC particularly in low prevalence populations. PMID- 26100191 TI - Balancing underdiagnosis and overdiagnosis: the case of mild traumatic brain injury. PMID- 26100192 TI - Will PET amyloid imaging lead to overdiagnosis of Alzheimer dementia? AB - Alzheimer disease (AD), a progressive neurodegenerative disease that causes dementia, affects millions of elderly Americans and represents a growing problem with the aging of the population. There has been an increasing effort for improved and earlier diagnosis for AD. Several newly developed radiolabeled compounds targeting beta-amyloid plaques, one of the major pathologic biomarkers of AD, have recently become available for clinical use. These radiopharmaceuticals allow for in vivo noninvasive visualization of abnormal beta amyloid deposits in the brain using positron emission tomography (PET). Amyloid PET imaging has demonstrated high sensitivity for pathologic cerebral amyloid deposition in multiple studies. Principal drawbacks to this new diagnostic test are declining specificity in older age groups and uncertain clinical role given lack of disease-modifying therapy for AD. Although there is strong evidence for the utility of amyloid PET in certain situations, detailed in a set of guidelines for appropriate use from the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging, the question of overdiagnosis, the diagnosis of a disease that would result in neither symptoms nor deaths, using this new medical tool needs to be carefully considered in light of efforts to secure reimbursement for the new technology that is already widely available for use as a clinical tool. PMID- 26100193 TI - The road to overdiagnosis: the case of subsegmental pulmonary embolism. PMID- 26100194 TI - Responding to the challenge of overdiagnosis. PMID- 26100195 TI - Evaluation of the patient with asymptomatic microscopic hematuria. AB - Asymptomatic microscopic hematuria (AMH) is relatively common in clinical practice but the etiology remains unclear in the majority of patients; it is rarely related to genitourinary malignancies. The 2012 guidelines of the American Urological Association recommend an evaluation after a single positive urinalysis with mandatory upper tract evaluation in all patients, preferably with CT urography (CTU). The likelihood of detecting significant upper track abnormalities, particularly malignancies is low with CTU, while incidental extraurinary abnormalities are often found, the majority of which are not clinically significant. The workup for these incidental findings has significant financial and clinical implications. Primary care physicians, who are most apt to encounter patients with AMH, have a low rate of adherence to the AUA guidelines, possibly as a result of the broadening of criteria for AMH evaluation by the AUA, with resultant uncertainty amongst primary care physicians about the appropriate candidates for such evaluation. Selection of subgroups of patients with risk factors for GU malignancies who may benefit from a complete evaluation is essential, as opposed to evaluation of all patients classified as having AMH. PMID- 26100196 TI - Mammogram trials. PMID- 26100197 TI - Utilization and reporting of bone densitometry: what can the musculoskeletal radiologist do to help, rather than to hurt? AB - Osteoporosis is a highly prevalent disease that predisposes patients to fragility fractures. These fractures carry serious risks, including increased mortality and the potential loss of functional independence. Effective treatments for osteoporosis are available, but these should be initiated before a fragility fracture actually occurs; to do so, osteoporosis must be diagnosed while it is still asymptomatic. The gold standard screening test used to detect low bone mass is dual-energy x-ray absorptiometry (DXA). Despite its clinical importance, the DXA report is sometimes neglected by radiologists-as though it were somehow less significant in diagnosis than our other modalities. If musculoskeletal radiologists are to help, rather than to hurt, we must raise the profile of this critical test with evidence-based utilization and coherent reporting: detailed recommendations for doing so are available from professional organizations such as the International Society for Clinical Densitometry and the National Osteoporosis Foundation. This brief survey will seek to remind the radiologist that a good densitometry report requires more than just copying numbers from a scanner. PMID- 26100198 TI - Can precision medicine reduce overdiagnosis? AB - Precision Medicine promises to get the right patient, the right test, the right diagnosis, the right treatment, and in the right amount. Is this hope or hype? PMID- 26100199 TI - Thinking beyond the treatment effect in screening for lung cancer. AB - In the optimism surrounding screening for lung cancer, the downsides of screening should not be ignored. The article examines the dark side of screening, which is not an unmitigated good. PMID- 26100200 TI - Barriers to reducing overdiagnosis. PMID- 26100201 TI - It is overtreatment, not overdiagnosis. PMID- 26100202 TI - The Blackstone Ratio and medicine's "n" problem. PMID- 26100203 TI - Left Atrial Appendage Morphology and Physiology: "The Missing Piece in the Puzzle". PMID- 26100204 TI - Kinetics of the ATP and dATP-mediated formation of a functionally-active RecA ssDNA complex. AB - The kinetics of the ATP and dATP-mediated formation of a functionally-active RecA ssDNA complex were examined by stopped-flow fluorescence spectroscopy, using a modified version of the RecA protein that contains a fluorescent reporter group in the ssDNA binding site. The results indicated that: i) an active RecA-ssDNA complex was formed more rapidly on dT200 than on dT50 when either ATP or dATP was provided as the nucleotide cofactor, and ii) active complex formation occurred more rapidly with dATP than with ATP on either dT50 or dT200. The dependence on both the identity of the nucleotide cofactor and the length of the ssDNA effector indicated that active complex formation occurs by a cooperative mechanism and that dATP is more effective than ATP in mediating the interactions between RecA monomers that drive this process. Interestingly, the time courses of dATP mediated active complex formation were closely similar to those that were obtained with ATPgammaS, an effectively non-hydrolyzable ATP analog that strongly stabilizes the active conformation of the RecA-ssDNA complex. These results provide mechanistic insight into the enhanced ssDNA binding and DNA strand exchange activities that are observed when dATP is provided in place of ATP in RecA biochemical assays. PMID- 26100205 TI - Development and characterization of a hydrogen peroxide-resistant cholangiocyte cell line: A novel model of oxidative stress-related cholangiocarcinoma genesis. AB - Oxidative stress is a cause of inflammation-related diseases, including cancers. Cholangiocarcinoma is a liver cancer with bile duct epithelial cell phenotypes. Our previous studies in animal and human models indicated that oxidative stress is a major cause of cholangiocarcinoma development. Hydrogen peroxide (H2O2) can generate hydroxyl radicals, which damage lipids, proteins, and nucleic acids, leading to cell death. However, some cells can survive by adapting to oxidative stress conditions, and selective clonal expansion of these resistant cells would be involved in oxidative stress-related carcinogenesis. The present study aimed to establish H2O2-resistant cell line from an immortal cholangiocyte cell line (MMNK1) by chronic treatment with low-concentration H2O2 (25 MUM). After 72 days of induction, H2O2-resistant cell lines (ox-MMNK1-L) were obtained. The ox-MMNK1 L cell line showed H2O2-resistant properties, increasing the expression of the anti-oxidant genes catalase (CAT), superoxide dismutase-1 (SOD1), superoxide dismutase-2 (SOD2), and superoxide dismutase-3 (SOD3) and the enzyme activities of CAT and intracellular SODs. Furthermore, the resistant cells showed increased expression levels of an epigenetics-related gene, DNA methyltransferase-1 (DNMT1), when compared to the parental cells. Interestingly, the ox-MMNK1-L cell line had a significantly higher cell proliferation rate than the MMNK1 normal cell line. Moreover, ox-MMNK1-L cells showed pseudopodia formation and the loss of cell-to-cell adhesion (multi-layers) under additional oxidative stress (100 MUM H2O2). These findings suggest that H2O2-resistant cells can be used as a model of oxidative stress-related cholangiocarcinoma genesis through molecular changes such as alteration of gene expression and epigenetic changes. PMID- 26100206 TI - Role of epididymal anti sticking factor in sperm capacitation. AB - Sperm capacitation depends on several features like hormones, ions, intracellular signaling, sperm associated molecules, etc. Anti sticking factor (ASF) is a novel sperm surface associated glycoprotein isolated from epididymal plasma. Function of ASF in vivo has not been revealed yet. The current study is an attempt to highlight the surface localization of ASF and corresponding biochemical changes that occurs in sperm cells during in vitro capacitation. In the presence of 1 nM ASF, percentage of bicarbonate and BSA induced capacitated cells in modified Tyrode medium (7.2) decreased from 72.45% to 16.25% as per Merocyanine 540 (M540)/DAPI stained flowcytometric analysis. Indirect immunocytostaining and western blot analysis shows that the amount of sperm surface bound residual ASF decline during in vitro capacitation. ASF at its effective concentrations notably reduced the bicarbonate and BSA induced cholesterol efflux. These data help in concluding ASF as a majorly responsible molecule that maintains caprine sperm membrane integrity by inhibiting cholesterol efflux. As the capacitation process, progress at in vitro condition, ASF is found to be released from the sperm surface and cell moved from non-capacitated to the capacitated state. PMID- 26100207 TI - Crystal structure of syndesmos and its interaction with Syndecan-4 proteoglycan. AB - Syndesmos, nucleoside diphosphate linked moiety X (nudix)-type motif 16-like 1 (Nudt16l1), is evolutionarily divergent from the Nudt16 family. Syndesmos, which is co-localized with syndecan-4 cytoplasmic domain (Syn4(cyto)) in focal contacts, interacts with various cell adhesion adaptor proteins to control cell signaling. We determined the X-ray crystal structure of syndesmos; it is composed of seven alpha-helices and seven beta-strands. Although syndesmos has a molecular topology similar to that of nudix hydrolase proteins, the structure of the nudix motif differs from that of X29. The dimeric interface of syndesmos is composed of alpha-helix 4, 7 and beta-strand 2, 7, which primarily form hydrophobic interactions. The binding interaction between syndesmos and syn4(cyto) was characterized as a low-affinity interaction (Kd = 62 MUM) by surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR). The NMR resonances of Lys (177, 178, 179), Gly182, and Ser183 in the C1 region and Lys193 and Lys194 in the V region of syndecan-4 are perturbed upon syndesmos binding. Our results provide structural insight into the molecular function of syndesmos in the regulation of cell signaling via binding to syndecan-4. PMID- 26100208 TI - Classification of proximal tibial epiphysis fractures in children: Four clinical cases. PMID- 26100209 TI - Long-term outcomes of individuals injured in motor vehicle crashes: A population based study. AB - BACKGROUND: Despite decline in U.S. traffic fatalities, non-fatal injuries remain a main cause of reduced self-reported health. The authors used a nationally representative survey to examine the long-term (>=1 year) implications of traffic injuries on self-care, depression, mobility, pain and activity domains of a widely used measure assessing Health-Related Quality of Life (HRQOL). METHODS: 30,576 participants from panels (2000-2002) of the Medical Expenditure Panel Survey (MEPS) were followed for about two years. The associations between reporting a traffic injury in the first follow-up year and the five domains of the Euroqol Health index (EQ-5D) were assessed using mixed logistic models with outcome severe/moderate problem in each domain. Models adjustment variables included age, gender, education, income, diabetes, asthma, smoking and insurance status. RESULTS: 590 participants reported traffic injuries. In the first follow up analysis, having an injury was associated with deficits in all domains of the EQ-5D. With the exception of self-care, similar findings were reported in the second follow-up (>=1 year) after injuries with strongest associations between traffic injuries and both mobility and activity (both OR=2.9, P<0.01). CONCLUSIONS: Traffic injuries are significantly associated with long-term reduced HRQOL. Injured individuals may benefit from early intervention programs to prevent the development of secondary complications and reduced HRQOL. PMID- 26100210 TI - Treatment with a neutralising anti-rat interleukin-17 antibody after multiple trauma reduces lung inflammation. AB - BACKGROUND: It has been well recognised that a deficit of numbers and function of CD4(+)CD25(+)Foxp3(+) cells (Treg) is attributed to the development of autoimmune diseases and inflammatory diseases; additionally, IL-17-producing cells (Th17) have a pro-inflammatory role. The balance between Th17 and Treg may be essential for maintaining immune homeostasis and has long been thought as one of the important factors in the development/prevention of autoimmune diseases and inflammatory diseases. In our previous research, we explored that cytokines (IL 17) and the balance of Treg/Th17 had a significant relevance with tissue (lung) inflammation and injury in acute-phase after multiple-trauma. OBJECTIVE: To more verify whether an imbalance of Treg/Th17 is characteristic of rats suffering from multiple trauma. METHODS AND SUBJECTIVE: Using IL-17 monoclonal antibody (IL 17mAb)-treated multiple-trauma rat, we tested the pathogenic role of IL-17 in the development of multiple-trauma. Rat models were treated respectively with IL 17mAb or rat IgG 2A isotype control or phosphate-buffered solution after model was established. Normal rats only received anaesthesia and cannulation were taken as sham. Rats in each group were killed respectively at the end of 1h, 4h, 8h after injection. Collected serum and lung samples for assessment dynamically of MPO, IL-17, IL-6, and TGF-beta-mRNA, and cytokine (IL-17, IL-6, TGF-beta) and lung tissue for pulmonary histological analysis. RESULTS: Neutralisation of IL-17 with anti-IL-17 can decrease serum IL-17 level and the IL-17-mRNA transcript level in lung, and ameliorate tissue inflammatory, defer disease course. CONCLUSION: Our data suggest that IL-17 is crucially involved in the pathogenesis of multiple-trauma in rat, IL-17 inhibition might ameliorate the lung inflammation in acute-phase after multiple-trauma. PMID- 26100211 TI - MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma. AB - AIMS: We aimed to investigate MYC expression and chromosomal aberration in mantle cell lymphoma (MCL), and the clinical significance of these factors. METHODS AND RESULTS: Sixty-five patients with MCL, including 54 classic, nine blastoid and two pleomorphic variants, were enrolled. Expression of MYC, Ki67 and p53 was assessed by immunohistochemistry. MYC amplification or translocation was examined by fluorescence in-situ hybridization. MYC expression was higher in blastoid/pleomorphic MCL variants (mean, 19.0%) than in classic MCL (mean, 1.9%; P < 0.001). Expression of p53 and Ki67 was also significantly higher in these variants. MYC amplification was found in two of 53 cases tested, both of which were blastoid variants with high MYC expression (29.7% and 20.4%). MYC translocation was found in two of 52 cases tested, both of which were pleomorphic variants with remarkably high MYC expression (68.5% and 71.0%). High MYC or p53 expression was significantly associated with shortened overall survival and progression-free survival in univariable and multivariable analyses (all P < 0.05). CONCLUSIONS: MYC overexpression is a negative predictor of MCL patient outcomes. MYC gene amplification or translocation might be related to the pathogenesis of MCL, particularly in blastoid/pleomorphic variants. PMID- 26100212 TI - Assessing phage therapy against Pseudomonas aeruginosa using a Galleria mellonella infection model. AB - The Galleria mellonella infection model was used to assess the in vivo efficacy of phage therapy against laboratory and clinical strains of Pseudomonas aeruginosa. In a first series of experiments, Galleria were infected with the laboratory strain P. aeruginosa PAO1 and were treated with varying multiplicity of infection (MOI) of phages either 2h post-infection (treatment) or 2h pre infection (prevention) via injection into the haemolymph. To address the kinetics of infection, larvae were bled over a period of 24h for quantification of bacteria and phages. Survival rates at 24h when infected with 10 cells/larvae were greater in the prevention versus treatment model (47% vs. 40%, MOI=10; 47% vs. 20%, MOI=1; and 33% vs. 7%, MOI=0.1). This pattern held true when 100 cells/larvae were used (87% vs. 20%, MOI=10; 53% vs. 13%, MOI=1; 67% vs. 7%, MOI=0.1). By 24h post-infection, phages kept bacterial cell numbers in the haemolymph 1000-fold lower than in the non-treated group. In a second series of experiments using clinical strains to further validate the prevention model, phages protected Galleria when infected with both a bacteraemia (0% vs. 85%) and a cystic fibrosis (80% vs. 100%) isolate. Therefore, this study validates the use of G. mellonella as a simple, robust and cost-effective model for initial in vivo examination of P. aeruginosa-targeted phage therapy, which may be applied to other pathogens with similarly low infective doses. PMID- 26100213 TI - Previous failure of interferon-based therapy does not alter the frequency of HCV NS3 protease or NS5B polymerase inhibitor resistance-associated variants: longitudinal analysis in HCV/HIV co-infected patients. AB - Since 2011, treatment of chronic hepatitis C virus (HCV) includes direct-acting antivirals (DAAs) in addition to pegylated interferon-alpha (peg-IFN) and ribavirin (RBV). IFN-based treatment induces strong cytotoxic T-lymphocyte activity directed to the protease- and polymerase-derived epitopes. This enhanced immunological pressure could favour the emergence of viral epitope variants able to evade immune surveillance and, when resistance-associated variants (RAVs) are implicated, could also be co-selected as a hitchhiking effect. This study analysed the dynamics of the frequency of protease and polymerase inhibitor RAVs that could affect future HCV treatment in human immunodeficiency virus (HIV) co infected patients on stable antiretroviral therapy with previous IFN-based treatment failure. HCV genotype 1a RNA was extracted from plasma samples of 18 patients prior to and during (24h and 4, 12, 24 and 48 weeks) therapy with peg IFN+RBV. Next-generation sequencing was performed on HCV-RNA populations using NS3 and NS5B PCR-amplified coding regions. Two measures of genetic diversity were used to compare virus populations: average pairwise nucleotide diversity (pi) and Tajima's D statistic. Several protease and polymerase RAVs were detected in all subjects at very low frequencies (<5%), and in most cases their presence was not constant during follow-up. Only samples from two patients for each region exhibited Q80R/K/L and A421V as highly predominant variants. No significant differences were observed among sampling times for either pi or D values. In conclusion, previous therapy and failure of peg-IFN+RBV were not associated with an increase in DAA-targeting NS3 or NS5B RAVs that naturally exist in HIV co infected subjects. PMID- 26100215 TI - Chest Pain After Percutaneous Coronary Intervention: More Than Meets the Eye. PMID- 26100214 TI - WNT5A inhibits hepatocyte proliferation and concludes beta-catenin signaling in liver regeneration. AB - Activation of Wnt/beta-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased beta-catenin-T-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in beta-catenin-T-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of beta-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses beta-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. PMID- 26100216 TI - [Palpebral conjunctivitis and preauricular adenopathy: Parinaud's oculoglandular syndrome]. PMID- 26100217 TI - [Prevalence study of the genetic markers associated with slow progression of human inmunodefiency virus type 1 in the Galician population (Northwest of Spain)]. AB - INTRODUCTION: The deletion in the CCR5 gene (CCR5Delta32), the HLA-B*27:05, and polymorphisms rs2395029 and rs9264942 have been associated with slower progression of HIV-1. METHODS: An analysis was performed on 408 patients on follow-up. The analysis of viral load, CD4+ Tlymphocytes and other clinical variables since the diagnosis of the infection were collected. RESULTS: The prevalence of the genetic markers rs9264942, CCR5wt/Delta32, rs2395029, HLA B*27:05 was 17.9%, 11.5%, 7.6%, and 6.4%, respectively. Of all the patients, 354 were classified as progressors and 46 as long-term non-progressors (LTNPs). Except for the HLA-B*27:05 allele, other genetic markers were associated with slower progression: CCR5wt/Delta32 (P=.011) and SNPs rs2395029 and rs9264942 (P<.0001), as well as their association (P<.0001). CONCLUSION: The prevalence of the HLA-B*57:01 allele was higher than described nationally. No association could be found between the HLA-B*27:05 allele and the presence of slower disease progression. PMID- 26100218 TI - Systems analysis of gene ontology and biological pathways involved in post myocardial infarction responses. AB - BACKGROUND: Pathway analysis has been widely used to gain insight into essential mechanisms of the response to myocardial infarction (MI). Currently, there exist multiple pathway databases that organize molecular datasets and manually curate pathway maps for biological interpretation at varying forms of organization. However, inconsistencies among different databases in pathway descriptions, frequently due to conflicting results in the literature, can generate incorrect interpretations. Furthermore, although pathway analysis software provides detailed images of interactions among molecules, it does not exhibit how pathways interact with one another or with other biological processes under specific conditions. METHODS: We propose a novel method to standardize descriptions of enriched pathways for a set of genes/proteins using Gene Ontology terms. We used this method to examine the relationships among pathways and biological processes for a set of condition-specific genes/proteins, represented as a functional biological pathway-process network. We applied this algorithm to a set of 613 MI specific proteins we previously identified. RESULTS: A total of 96 pathways from Biocarta, KEGG, and Reactome, and 448 Gene Ontology Biological Processes were enriched with these 613 proteins. The pathways were represented as Boolean functions of biological processes, delivering an interactive scheme to organize enriched information with an emphasis on involvement of biological processes in pathways. We extracted a network focusing on MI to demonstrate that tyrosine phosphorylation of Signal Transducer and Activator of Transcription (STAT) protein, positive regulation of collagen metabolic process, coagulation, and positive/negative regulation of blood coagulation have immediate impacts on the MI response. CONCLUSIONS: Our method organized biological processes and pathways in an unbiased approach to provide an intuitive way to identify biological properties of pathways under specific conditions. Pathways from different databases have similar descriptions yet diverse biological processes, indicating variation in their ability to share similar functional characteristics. The coverages of pathways can be expanded with the incorporation of more biological processes, predicting involvement of protein members in pathways. Further, detailed analyses of the functional biological pathway-process network will allow researchers and scientists to explore critical routes in biological systems in the progression of disease. PMID- 26100219 TI - Latent progenitor cells as potential regulators for tympanic membrane regeneration. AB - Tympanic membrane (TM) perforation, in particular chronic otitis media, is one of the most common clinical problems in the world and can present with sensorineural healing loss. Here, we explored an approach for TM regeneration where the latent progenitor or stem cells within TM epithelial layers may play an important regulatory role. We showed that potential TM stem cells present highly positive staining for epithelial stem cell markers in all areas of normal TM tissue. Additionally, they are present at high levels in perforated TMs, especially in proximity to the holes, regardless of acute or chronic status, suggesting that TM stem cells may be a potential factor for TM regeneration. Our study suggests that latent TM stem cells could be potential regulators of regeneration, which provides a new insight into this clinically important process and a potential target for new therapies for chronic otitis media and other eardrum injuries. PMID- 26100220 TI - Where Are We Heading in Nanotechnology Environmental Health and Safety and Materials Characterization? PMID- 26100222 TI - Comment on "Protein Corona Fingerprinting Predicts the Cellular Interaction of Gold and Silver Nanoparticles". PMID- 26100224 TI - Cytotoxicity of the mycotoxins deoxynivalenol and ochratoxin A on Caco-2 cell line in presence of resveratrol. AB - Exposure to mycotoxins through dietary food intake involves a highly complex scenario where co-contamination of different mycotoxins has been frequently demonstrated. On the other hand, the effect of the interaction of mycotoxins with other generally considered beneficial food components, as the antioxidants, has been scarcely studied. The main goal of the present work was to assess the cytotoxic effects on Caco-2 cells of the mycotoxins deoxynivalenol (DON) and ochratoxin A (OTA), alone or combined, and to explore potential protective effects of resveratrol (RES), an antioxidant frequently found in wine. In parallel, reactive oxygen species (ROS) production has also been studied as a first approach to understand the underlying mechanism of cytotoxicity. Results indicate a higher toxic effect of the mycotoxins when they are co-exposed. This increase in cytotoxicity was not accompanied by an increase in ROS production. The co-exposure of OTA or DON with RES did not result in a decrease in cytotoxicity; on the contrary, it resulted in increased cytotoxicity not associated with an increase in ROS production. PMID- 26100223 TI - Soluble extracellular Klotho decreases sensitivity to cigarette smoke induced cell death in human lung epithelial cells. AB - Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death in the US and is associated with an abnormal inflammatory response to cigarette smoke (CS). Exposure to CS induces oxidative stress and can result in cellular senescence in the lung. Cellular senescence can then lead to decreased proliferation of epithelial cells, the destruction of alveolar structure and pulmonary emphysema. The anti-aging gene, klotho, encodes a membrane bound protein that has been shown to be a key regulator of oxidative stress and cellular senescence. In this study the role of Klotho (KL) with regard to oxidative stress and cellular senescence was investigated in human pulmonary epithelial cells exposed to cigarette smoke. Individual clones that stably overexpress Klotho were generated through retroviral transfection and geneticin selection. Klotho overexpression was confirmed through RT-qPCR, Western blotting and ELISA. Compared to control cells, constitutive Klotho overexpression resulted in decreased sensitivity to cigarette smoke induced cell death in vitro via a reduction of reactive oxygen species and a decrease in the expression of p21. Our results suggest that increasing Klotho level in pulmonary epithelial cells may be a promising strategy to reduce cellular senescence and mitigate the risk for the development of COPD. PMID- 26100225 TI - A superfusion apparatus for ex vivo human eye irritation investigations. AB - A superfusion apparatus (SA) was developed to maintain isolated human corneas ex vivo under conditions which mimic the natural eye environment in vivo, including controlled temperature, tear flow and intraocular pressure. The SA was designed, developed and tested for use in ophthalmic pre-clinical research and to test new pharmaceutical formulations. Corneas undergo an equilibration process in the new physiological environment for one day. The test was then initiated by the application of the test substance, incubation, and temporal assessment of corneal damage using various parameters. The effects of mild and severe irritant concentrations of NaOH (2% and 8%, respectively) on corneal opacity, swelling and epithelial integrity were studied, and the inflammatory status assessed using F4/80 and MPO as macrophages and neutrophils markers, respectively. The SA was then used to test new artificial tear formulations supplemented with silver ions as an active constituent, showing different degrees of inflammatory responses as indicated by the migration of MPO and F4/80 positive cells towards the epithelium. The human cornea superfusion apparatus was proposed as a model for acute eye irritation research. PMID- 26100226 TI - Inhibition of human cytochrome P450 enzymes by licochalcone A, a naturally occurring constituent of licorice. AB - Licochalcone A (LCA) is a major bioactive compound in traditional Chinese herbal liquorice that possesses multiple pharmacological activities. However, the effects of the potential herb-drug interactions (HDIs) between LCA and therapeutic drugs on the inhibition of human cytochrome P450 (CYP) enzymes remain unclear. In the present study, the inhibitory effects of LCA on seven major human CYP isoforms, including CYP1A2, 2D6, 2E1, 2C19, 2C8, 2C9 and 3A4, were investigated in human liver microsomes (HLMs). The results demonstrated that LCA significantly inhibited the activities of CYP1A2, 2C19, 2C8, 2C9 and 3A4 and exhibited weak inhibitory effects on CYP2E1 and CYP2D6. Dixon and Lineweaver-Burk plots revealed that the inhibition types of LCA against CYP1A2, 2C9, 2C19 and 2C8 were best fit as mixed-type inhibitions, while LCA was a competitive inhibitor towards CYP3A4. The inhibition kinetic parameters (K(i)) were calculated to be 1.02 MUM, 0.17 MUM, 3.89 MUM 0.89 MUM, and 2.29 MUM, for CYP1A2, 2C9, 2C19, 2C8, and 3A4, respectively. Furthermore, the areas under the plasma concentration-time curves (AUCs) of several drugs that are primarily metabolized by CYPs were estimated to increase by 2-398% in the presence of LCA, which suggested that LCA exhibited high HDI potentials via CYP inhibition. These data are significant for the clinical applications of LCA-containing herbs. PMID- 26100227 TI - Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis. AB - 1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 MUM of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a |fold change| of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NFkappaB and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPARalpha/gamma/delta were predicted to be inhibited. In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure. PMID- 26100228 TI - Three infants with rotavirus gastroenteritis complicated by severe gastrointestinal bleeding. AB - Rotavirus gastroenteritis causes substantial morbidity and mortality worldwide in children. We report three infants with rotavirus gastroenteritis complicated by various severity of gastrointestinal bleeding. Two patients (cases 1 and 2) recovered completely without any specific treatments. One patient (case 3) died despite extensive treatments including a red blood cell transfusion and endoscopic hemostatic therapy. Rotavirus genotypes G1P[8] and G9P[8] were detected in cases 2 and 3, respectively. Rotavirus antigenemia levels were not high at the onset of melena, suggesting that systemic rotaviral infection does not play an important role in causing melena. PMID- 26100229 TI - A Randomized, Open-Label Phase II Trial of Volasertib as Monotherapy and in Combination With Standard-Dose Pemetrexed Compared With Pemetrexed Monotherapy in Second-Line Treatment for Non-Small-Cell Lung Cancer. AB - Second-line therapy options that improve survival for patients with advanced non small-cell lung cancer (NSCLC) are needed. This randomized, phase II trial (n [ 143) investigated volasertib monotherapy or in combination with pemetrexed compared with pemetrexed monotherapy in patients with NSCLC whose disease had progressed after previous platinum-based chemotherapy. The combination of volasertib with pemetrexed did not improve efficacy compared with pemetrexed monotherapy. INTRODUCTION: Volasertib is a potent, selective, cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase. In this study we compared volasertib, volasertib with pemetrexed, and pemetrexed alone in patients with advanced non-small-cell lung cancer (NSCLC) whose disease progressed after first-line platinum-based chemotherapy. PATIENTS AND METHODS: A run-in phase (n = 12) was used to determine whether volasertib could be combined in full dose with pemetrexed 500 mg/m(2). Subsequent patients were randomized to volasertib (n = 37), volasertib with pemetrexed (n = 47), or pemetrexed (n = 47) administered on day 1 every 21 days. The primary end point was progression-free survival (PFS); secondary end points included objective response rate and pharmacokinetics. RESULTS: Volasertib 300 mg was chosen for the randomized phase. Recruitment to single-agent volasertib was stopped early because of lack of efficacy. Median PFS was 5.3 months with pemetrexed compared with 3.3 months with volasertib with pemetrexed (hazard ratio [HR], 1.141; 95% confidence interval [CI], 0.73-1.771) and 1.4 months with volasertib (HR, 2.045; 95% CI, 1.27-3.292). ORRs were 10.6% with pemetrexed, 21.3% for volasertib with pemetrexed, and 8.1% with volasertib. The most common all-grade related adverse events (pemetrexed/volasertib with pemetrexed/volasertib) were: fatigue (28 [61%]/27 [59%]/11 [31%]), nausea (21 [46%]/19 [41%]/0 [0%]), decreased apetite (14 [31%]/13 [28%]/2 [6%]), neutropenia (4 [9%]/8 [17%]/9 [25%]), rash (9 [20%]/8 [17%]/2 [6%]), vomiting (6 [13%]/13 [28%]/0 [0%]), and diarrhea (8 [17%]/11 [24%]/0 [0%]). Pharmacokinetics analyses showed no drug-drug interactions between volasertib and pemetrexed. CONCLUSION: For treatment in the second-line for advanced or metastatic NSCLC, the combination of volasertib with standard pemetrexed did not increase toxicity significantly but also did not improve efficacy compared with single-agent pemetrexed. PMID- 26100230 TI - Neuroprosthetic technologies to augment the impact of neurorehabilitation after spinal cord injury. AB - Spinal cord injury leads to a range of disabilities, including limitations in locomotor activity, that seriously diminish the patients' autonomy and quality of life. Electrochemical neuromodulation therapies, robot-assisted rehabilitation and willpower-based training paradigms restored supraspinal control of locomotion in rodent models of severe spinal cord injury. This treatment promoted extensive and ubiquitous remodeling of spared circuits and residual neural pathways. In four chronic paraplegic individuals, electrical neuromodulation of the spinal cord resulted in the immediate recovery of voluntary leg movements, suggesting that the therapeutic concepts developed in rodent models may also apply to humans. Here, we briefly review previous work, summarize current developments, and highlight impediments to translate these interventions into medical practice to improve functional recovery of spinal-cord-injured individuals. PMID- 26100231 TI - RING1B O-GlcNAcylation regulates gene targeting of polycomb repressive complex 1 in human embryonic stem cells. AB - O-linked-N-acetylglucosamine (O-GlcNAc) post-translationally modifies and regulates thousands of proteins involved in various cellular mechanisms. Recently, O-GlcNAc has been linked to human embryonic stem cells (hESC) differentiation, however the identity and function of O-GlcNAc proteins regulating hESC remain unknown. Here, we firstly identified O-GlcNAc modified human stem cell regulators such as hnRNP K, HP1gamma, and especially RING1B/RNF2. Thereafter, we focused our work on RING1B which is the catalytic subunit of the polycomb repressive complex 1 (PRC1) a major epigenetic repressor essential for pluripotency maintenance and differentiation. By point-mutation, we show that T(250)/S(251) and S(278) RING1B residues are bearing O-GlcNAc, and that T(250)/S(251) O-GlcNAcylation decreases during differentiation. O-GlcNAc seems to regulate RING1B-DNA binding as suggested by our ChIP-sequencing results. Non-O GlcNAcylated RING1B is found to be enriched near cell cycle genes whereas O GlcNAcylated RING1B seems preferentially enriched near neuronal genes. Our data suggest that during hESC differentiation, the decrease of RING1B O-GlcNAcylation might enable PRC1 to switch its target to induce neuron differentiation. Overall, we demonstrate that O-GlcNAc modifies and regulates an essential epigenetic tool, RING1B, which may contribute to hESC pluripotency maintenance and differentiation. PMID- 26100232 TI - Pancreatic duct glands (PDGs) are a progenitor compartment responsible for pancreatic ductal epithelial repair. AB - Pancreatic duct glands (PDGs) have molecular features known to mark stem cell niches, but their function remains to be determined. To investigate the role of PDGs as a progenitor niche, PDGs were analyzed in both humans and mice. Cells were characterized by immunohistochemistry and microarray analysis. In vivo proliferative activity and migration of PDG cells were evaluated using a BrdU tag and-chase strategy in a mouse model of pancreatitis. In vitro migration assays were used to determine the role of trefoil factor (TFF) -1 and 2 in cell migration. Proliferative activity in the pancreatic epithelium in response to inflammatory injury is identified principally within the PDG compartment. These proliferating cells then migrate out of the PDG compartment to populate the pancreatic duct. Most of the pancreatic epithelial migration occurs within 5days and relies, in part, on TFF-1 and -2. After migration, PDG cells lose their PDG specific markers and gain a more mature pancreatic ductal phenotype. Expression analysis of the PDG epithelium reveals enrichment of embryonic and stem cell pathways. These results suggest that PDGs are an epithelial progenitor compartment that gives rise to mature differentiated progeny that migrate to the pancreatic duct. Thus PDGs are a progenitor niche important for pancreatic epithelial regeneration. PMID- 26100234 TI - A fourier transform infrared spectroscopy (FTIR) based assay for Candida parapsilosis ATCC 7330 mediated oxidation of aryl alcohols. AB - We present an FTIR based assay to monitor the whole cell mediated oxidation of aryl alcohols by measuring the characteristic IR absorption of the hydroxyl group [OH] of the substrate and the carbonyl group [CO] of the corresponding oxidized product. This method expedites the analysis of whole cell mediated catalysis which is usually done by GC and/or HPLC. The FTIR assay had linearity with R(2)>=0.980 and sensitivity up to 10MUM. The accuracy and precision of FTIR assay was found >=81% and >=94%, respectively. This assay was validated by GC which exhibited >=82% accuracy and >=79% precision. The time of analysis taken by this assay was 2-3min per sample in comparison with 20-40min by GC. PMID- 26100233 TI - Generation of human pluripotent stem cell reporter lines for the isolation of and reporting on astrocytes generated from ventral midbrain and ventral spinal cord neural progenitors. AB - Astrocytes play a critical role during the development and the maintenance of the CNS in health and disease. Yet, their lack of accessibility from fetuses and from the brain of diseased patients has hindered our understanding of their full implication in developmental and pathogenic processes. Human pluripotent stem cells (PSCs) are an alternative source to obtain large quantities of astrocytes in vitro, for mechanistic studies of development and disease. However, these studies often require highly pure populations of astrocytes, which are not always achieved, depending on the PSC lines and protocols used. Here, we describe the generation and characterization of human PSC reporter lines expressing TagRFP driven by the ABC1D region of the human GFAP promoter, as new cellular model for generating homogenous population of astrocytes generated from CNS regionally defined PSC-derived neural progenitors. GFA(ABC1D)::TagRFP-expressing astrocytes can be purified by fluorescent-activated cell sorting and maintain a bright expression for several additional weeks. These express canonical astrocyte markers NF1A, S100beta, CX43, GLAST, GS and CD44. These new cellular models, from which highly pure populations of fluorescence-expressing astrocytes can be obtained, provide a new platform for studies where pure or fluorescently labeled astrocyte populations are necessary, for example to assess pro-inflammatory cytokine and chemokine release in response to specific treatment, and uptake and degradation of fluorescently labeled pathogenic proteins, as reported in this study. PMID- 26100235 TI - Complete genome sequence of Bacillus thuringiensis YC-10, a novel active strain against plant-parasitic nematodes. AB - Bacillus thuringiensis is an important microbial biopesticide for controlling agricultural pests by the production of toxic parasporal crystals proteins.Here,we report the finished annotated genome sequence of B. thuringiensis YC-10,which is highly toxic to nematodes.The complete genome sequence consists of a circular chromosome and nine circular plasmids,which the biggest plasmid harbors six parasporal crystals proteins genes consisting of cry1Aa, cry1Ac, cry1Ia, cry2Aa, cry2Ab and cryB1. The crystals proteins of Cry1Ia and Cry1Aa have high nematicidal activity against Meloidogyne incognita. PMID- 26100236 TI - A novel Na(+)(K(+))/H(+) antiporter plays an important role in the growth of Acetobacter tropicalis SKU1100 at high temperatures via regulation of cation and pH homeostasis. AB - A gene encoding a putative Na(+)/H(+) antiporter was previously proposed to be involved in the thermotolerance mechanism of Acetobacter tropicalis SKU 1100. The results of this study show that disruption of this antiporter gene impaired growth at high temperatures with an external pH>6.5. The growth impairment at high temperatures was much more severe in the absence of Na(+) (with only the presence of K(+)); under these conditions, cells failed to grow even at 30 degrees C and neutral to alkaline pH values, suggesting that this protein is also important for K(+) tolerance. Functional analysis with inside-out membrane vesicles from wild type and mutant strains indicated that the antiporter, At NhaK2 operates as an alkali cation/proton antiporter for ions such as Na(+), K(+), Li(+), and Rb(+) at acidic to neutral pH values (6.5-7.5). The membrane vesicles were also shown to contain a distinct pH-dependent Na(+)(specific)/H(+) antiporter(s) that might function at alkaline pH values. In addition, phylogenetic analysis showed that At-NhaK2 is a novel type of Na(+)/H(+) antiporter belonging to a phylogenetically distinct new clade. These data demonstrate that At-NhaK2 functions as a Na(+)(K(+))/H(+) antiporter and is essential for K(+) and pH homeostasis during the growth of A. tropicalis SKU1100, especially at higher temperatures. PMID- 26100237 TI - Lysosomes are involved in induction of steroidogenic acute regulatory protein (StAR) gene expression and progesterone synthesis through low-density lipoprotein in cultured bovine granulosa cells. AB - Progesterone is an important steroid hormone in the regulation of the bovine estrous cycle. The steroidogenic acute regulatory protein (StAR) is an indispensable component for transporting cholesterol to the inner mitochondrial membrane, which is one of the rate-limiting steps for progesterone synthesis. Low density lipoprotein (LDL) supplies cholesterol precursors for progesterone formation, and the lysosomal degradation pathway of LDL is essential for progesterone biosynthesis in granulosa cells after ovulation. However, it is currently unknown how LDL and lysosomes coordinate the expression of the StAR gene and progesterone production in bovine granulosa cells. Here, we investigated the role of lysosomes in LDL-treated bovine granulosa cells. Our results reported that LDL induced expression of StAR messenger RNA and protein as well as expression of cholesterol side-chain cleavage cytochrome P-450 (CYP11A1) messenger RNA and progesterone production in cultured bovine granulosa cells. The number of lysosomes in the granulosa cells was also significantly increased by LDL; whereas the lysosomal inhibitor, chloroquine, strikingly abolished these LDL induced effects. Our results indicate that LDL promotes StAR expression, synthesis of progesterone, and formation of lysosomes in bovine granulosa cells, and lysosomes participate in the process by releasing free cholesterol from hydrolyzed LDL. PMID- 26100238 TI - Fabrication of nanoscale Ga balls via a Coulomb explosion of microscale silica covered Ga balls by TEM electron-beam irradiation. AB - Nanoscale Ga particles down to 5 nm were fabricated by an explosion via an in situ electron-beam irradiation on microscale silica-covered Ga balls in a transmission electron microscope. The explosion is confirmed to be a Coulomb explosion because it occurs on the surface rather than in the whole body of the insulating silica-covered Ga micro-balls, and on the pure Ga nano-balls on the edge of carbon film. The ejected particles in the explosion increase their sizes with increasing irradiation time until the stop of the explosion, but decrease their sizes with increasing distance from the original ball. The Coulomb explosion suggests a novel method to fabricate nanoscale metal particles with low melting point. PMID- 26100239 TI - Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment. AB - The bioactive lipid prostaglandin E2 (PGE2) is involved in several steps of carcinogenesis in some of the most common cancers, e.g. colon cancer, lung cancer, prostate cancer and breast cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) that target cyclooxygenase (COX) activity, the first step of the PGE2 biosynthesis, has been found to reduce the incidence of colon cancer. Due to severe adverse effects on the gastrointestinal tract and the cardiovascular system, their use as chemopreventing agent has been hampered. Genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme responsible for the second step of the PGE2 biosynthesis, has resulted in reduced tumor progression in mouse models of colon cancer. Inhibition of mPGES-1 would potentially be beneficial to a great number of patients without the side effects associated with long-term treatment with traditional NSAIDs. PMID- 26100240 TI - Multilocus Sequence Types of Campylobacter jejuni Isolates from Different Sources in Eastern China. AB - Campylobacter jejuni is a major food-borne pathogen that causes human gastroenteritis in many developed countries. In our study, we applied multilocus sequence typing (MLST) technology to 167 C. jejuni isolates from diverse sources in Eastern China to examine their genetic diversity. MLST defined 94 sequence types (STs) belonging to 18 clonal complexes (CCs). Forty-five STs from 60 isolates (36%) and 22 alleles have not been previously documented in an international database. One hundred and two isolates, accounting for 61.1% of all isolates, belonged to eight clonal complexes. The eight major CCs were also the most common complexes from different sources. The most common ST type of isolates from human and food was ST-353. The dominant ST type in chicken and foods was ST 354. Among 21 STs that contained two or more different sources isolates, 15 STs contained human isolates and isolates from other sources, suggesting that potentially pathogenic strains are not restricted to specific lineages. PMID- 26100241 TI - Phenotypic and Molecular Characterization of Leptospira interrogans Isolated from Canis familiaris in Southern Brazil. AB - Leptospirosis is a zoonotic disease caused by pathogenic spirochetes from the genus Leptospira, which includes 20 species and more than 300 serovars. Canines are important hosts of pathogenic leptospires and can transmit the pathogen to humans via infected urine. Here, we report the phenotypic and molecular characterization of Leptospira interrogans isolated from Canis familiaris in Southern Brazil. The isolated strain was characterized by variable-number tandem repeats analysis as L. interrogans, serogroup Icterohaemorrhagiae. In addition, the isolate was recognized by antibodies from human and canine serum samples previously tested by microscopic agglutination test. Ultimately, the expression of membrane-associated antigens (LipL32 and leptospiral immunoglobulin-like proteins) from pathogenic leptospires using monoclonal antibodies was detected by indirect immunofluorescence assay. In conclusion, identification of new strains of Leptospira can help in the diagnosis and control of leptospirosis. PMID- 26100242 TI - Improvements in bimanual hand function after baby-CIMT in two-year old children with unilateral cerebral palsy: A retrospective study. AB - The common assumption that early-onset intensive intervention positively affects motor development has rarely been investigated for hand function in children with unilateral cerebral palsy (CP). This retrospective study explored the possible impact of baby constraint-induced movement therapy (baby-CIMT) on hand function at two years of age. We hypothesized that baby-CIMT in the first year of life would lead to better bimanual hand use at two years of age than would not receiving baby-CIMT. The Assisting Hand Assessment (AHA) was administered at age 21 months (SD 2.4 months) in 72 children with unilateral CP, 31 of who received baby-CIMT. When dividing the children into four functional levels based on AHA, the proportional distribution differed between the groups in favour of baby-CIMT. Logistic regression analysis indicated that children in the baby-CIMT group were more likely than were children in the no baby-CIMT group to have a high functional level, even when controlling for the effect of brain lesion type (OR 5.83, 95% CI 1.44-23.56, p = 0.001). However, no difference was found between groups in the odds of having a very low functional level (OR 0.31, 95% CI 0.08 1.17, p = 0.084). The result shows that baby-CIMT at early age can have a positive effect. Children who received baby-CIMT were six times more likely to have a high functional level at two years of age than were children in the no baby-CIMT group. PMID- 26100243 TI - Hormone therapy and cardiovascular disease - are we back to the beginning? PMID- 26100244 TI - Persistent denial of undeniable bias. PMID- 26100245 TI - Large vessel area of the optic nerve head, measured with laser speckle flowgraphy, is significantly reduced in eyes with preperimetric glaucoma. PMID- 26100246 TI - The puzzling first-order phase transition in water-glycerol mixtures. AB - Over the last decade, discussions on a possible liquid-liquid transition (LLT) have strongly intensified. The LLT proposed by several authors focused mostly on explaining the anomalous properties of water in a deeply supercooled state. However, there have been no direct experimental observations yet of LLT in bulk water in the so-called 'no man's land', where water exists only in the crystalline states. Recently, a novel experimental strategy to detect LLT in water has been employed using water-glycerol (W-G) mixtures, because glycerol can generate a strong hindrance for water crystallization. As a result, the observed first-order phase transition at a concentration of glycerol around cg~ 20 mol% was ascribed to the LLT. Here we show unambiguously that the first order phase transition in W-G mixtures is caused by the ice formation. We provide additional dielectric measurements, applying specific annealing temperature protocols in order to reinforce this conclusion. We also provide an explanation, why such a phase transition occurs only in the narrow glycerol concentration range. These results clearly demonstrate the danger of analysis of phase-separating liquids to gain better insights into water dynamics. These liquids have complex phase behavior that is affected by temperature, phase stability and segregation, viscosity and nucleation, and finally by crystallization, that might lead to significant misinterpretations. PMID- 26100247 TI - Temperature-induced shifts in hibernation behavior in experimental amphibian populations. AB - Phenological shifts are primary responses of species to recent climate change. Such changes might lead to temporal mismatches in food webs and exacerbate species vulnerability. Yet insights into this phenomenon through experimental approaches are still scarce, especially in amphibians, which are particularly sensitive to changing thermal environments. Here, under controlled warming conditions, we report a critical, but poorly studied, life-cycle stage (i.e., hibernation) in frogs inhabiting subtropical latitudes. Using outdoor mesocosm experiments, we examined the effects of temperature (ambient vs. + ~2.2/2.4 degrees C of pre-/post-hibernation warming) and food availability (normal vs. 1/3 food) on the date of entrance into/emergence from hibernation in Pelophylax nigromaculatus. We found temperature was the major factor determining the hibernation period, which showed a significant shortening under experimental warming (6-8 days), with delays in autumn and advances in spring. Moreover, the timing of hibernation was not affected by food availability, whereas sex and, particularly, age were key factors in the species' phenological responses. Specifically, male individuals emerged from hibernation earlier, while older individuals also entered and emerged from hibernation earlier. We believe that this study provides some of the first experimental evidence for the effect of climate warming on the timing of amphibian hibernation. PMID- 26100248 TI - Comparison of carotid atherosclerotic plaque characteristics between patients with first-time and recurrent acute ischaemic stroke using B-mode ultrasound. AB - OBJECTIVES: The differences between initial and recurrent stroke plaques are not defined. Hence, a nested case-control study was conducted to evaluate the association of stroke recurrence with the echogenic characteristics of carotid plaques in patients with ischaemic stroke. METHODS: One hundred and four patients with 1-year recurrent acute ischaemic stroke were enrolled and compared with 104 control patients (first-time ischaemic stroke) matched for age, gender, stroke severity and treatment allocation. Based on the Mannheim Carotid Intima-Media Thickness Consensus (2004-2006), the number of carotid plaques and echogenicity between the two groups of patients were compared. RESULTS: As compared to patients with first-time stroke, those with recurrent stroke showed significantly higher prevalence of heart disease (13.46 vs 28.85%, P = 0.0066) and presence of intracranial stenosis (55.77 vs 89.90%, P < 0.0001). During the 1-year follow-up, patients with recurrent stroke had a significantly higher rate of unstable plaques (80.41%) than patients with first-time stroke (64.21%, P = 0.036). Also, patients with recurrent stroke had a significantly larger number of plaques than patients with first-time stroke (P = 0.0152). Multivariate conditional logistic regression analysis (after adjustment for heart disease and intracranial stenosis) identified an association between 1-year stroke recurrence and the presence of unstable plaques (hazard ratio 3.077; 95% CI: 1.133-8.355). CONCLUSION: Stroke recurrence is related to advanced atherosclerosis defined by carotid plaque and its characteristics. PMID- 26100249 TI - Curcumin inhibits human cytomegalovirus by downregulating heat shock protein 90. AB - Curcumin is a traditional Chinese medicine extracted from the rhizome of the herb Curcuma longa, which exhibits anti-human cytomegalovirus (HCMV) activity, however, the underlying mechanism remains to be elucidated. The present study reported that the pharmacogenomics of curcumin are similar to that of the antiviral drug, geldanamycin, which targets heat shock protein 90 (Hsp90). Comparative analysis of 3,000 clinical drugs demonstrated that curcumin had a positive association with the gene expression profiles of several drugs, among which the pharmacogenomics of the antiviral drug, geldanamycin, were most similar to that of curcumin. Molecular docking simulation analysis revealed that curcumin fit well in the binding pocket of Hsp90, with hydrogen bonds, hydrophobic interactions and conjugation to maintain adhesion. Consistently, HCMV infection of human embryonic lung fibroblast cells resulted in increased expression of Hsp90alpha, which was significantly inhibited by treatment with curcumin. These findings suggested that targeting Hsp90 contributed to the anti-HCMV activity of curcumin. PMID- 26100250 TI - Detection of selection signatures in Piemontese and Marchigiana cattle, two breeds with similar production aptitudes but different selection histories. AB - BACKGROUND: Domestication and selection are processes that alter the pattern of within- and between-population genetic variability. They can be investigated at the genomic level by tracing the so-called selection signatures. Recently, sequence polymorphisms at the genome-wide level have been investigated in a wide range of animals. A common approach to detect selection signatures is to compare breeds that have been selected for different breeding goals (i.e. dairy and beef cattle). However, genetic variations in different breeds with similar production aptitudes and similar phenotypes can be related to differences in their selection history. METHODS: In this study, we investigated selection signatures between two Italian beef cattle breeds, Piemontese and Marchigiana, using genotyping data that was obtained with the Illumina BovineSNP50 BeadChip. The comparison was based on the fixation index (Fst), combined with a locally weighted scatterplot smoothing (LOWESS) regression and a control chart approach. In addition, analyses of Fst were carried out to confirm candidate genes. In particular, data were processed using the varLD method, which compares the regional variation of linkage disequilibrium between populations. RESULTS: Genome scans confirmed the presence of selective sweeps in the genomic regions that harbour candidate genes that are known to affect productive traits in cattle such as DGAT1, ABCG2, CAPN3, MSTN and FTO. In addition, several new putative candidate genes (for example ALAS1, ABCB8, ACADS and SOD1) were detected. CONCLUSIONS: This study provided evidence on the different selection histories of two cattle breeds and the usefulness of genomic scans to detect selective sweeps even in cattle breeds that are bred for similar production aptitudes. PMID- 26100251 TI - Isolation and full-length genome analysis of mosquito-borne Manzanilla virus from Yunnan Province, China. AB - BACKGROUND: There have been four strains on Manzanilla virus (MANV) identified to date. Here, we identify a novel MANV strain (DHL10M107) isolated from Culex tritaeniorhynchus Giles mosquitoes from Ruili city, Dehong prefecture, Yunnan Province, in the People's Republic of China. RESULTS: The DHL10M107 L, M and S genes were sequenced at the nucleotide and deduced amino acid levels. The L, M and S gene sequences of DHL10M107 clustered with the MANV strains VN04-2108, TRVL3587, SA An 4165, and AV 782. DHL10M107 was most closely related to VN04 2108. Nucleotide homology ranged between 96 and 99% between DHL10M107 and VN04 2108. In terms of amino acid homology, all of the amino acid differences were in the L (96.3% homologous) and M (97.7% homologous) fragments. CONCLUSIONS: DHL10M107 is likely a MANV isolated from mosquitos in the Yunnan Province. This is the first reported isolation of MANV in mainland China. PMID- 26100252 TI - Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. AB - Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected alpha smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts. PMID- 26100253 TI - Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study. AB - Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34 1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers. PMID- 26100254 TI - Does Tourniquet Use in TKA Affect Recovery of Lower Extremity Strength and Function? A Randomized Trial. AB - BACKGROUND: Tourniquet use during total knee arthroplasty (TKA) improves visibility and reduces intraoperative blood loss. However, tourniquet use may also have a negative impact on early recovery of muscle strength and lower extremity function after TKA. QUESTIONS/PURPOSES: The purpose of this study was (1) to determine whether tourniquet use affects recovery of quadriceps strength (primary outcome) during the first 3 postoperative months; and (2) to examine the effects of tourniquet application on secondary outcomes: voluntary quadriceps activation, hamstring strength, unilateral limb balance as well as the effect on operative time and blood loss. METHODS: Twenty-eight patients (mean age 62 +/- 6 years; 16 men) undergoing same-day bilateral TKA (56 lower extremities) were enrolled in a prospective, randomized study. Subjects were randomized to receive a tourniquet-assisted knee arthroplasty on one lower extremity while the contralateral limb underwent knee arthroplasty without extended tourniquet use. In the former group, the tourniquet was inflated just before the incision was made and released after cementation; in the latter group, a tourniquet was not used (10 of 28 [36%]) or inflated only during component cementation (18 of 28 [64%]). The choice of no tourniquet or use just during cementation was based on surgeon choice, because some surgeons felt a tourniquet during cementation was necessary to achieve a dry surgical field to maximize cement fixation. A median parapatellar approach and the identical posterior-stabilized TKA design were used by all four fellowship-trained knee surgeons involved. Isometric quadriceps strength, hamstring strength, voluntary quadriceps activation, and unilateral balance were assessed preoperatively, 3 weeks, and 3 months after bilateral knee arthroplasty. Other factors, including pain, range of motion, and lower extremity girth, were assessed for descriptive purposes at each of these time points as well as on the second postoperative day. RESULTS: Quadriceps strength was slightly lower in the tourniquet group compared with the no-tourniquet group (group difference = 11.27 Nm [95% confidence interval {CI}, 2.33-20.20]; p = 0.01), and these differences persisted at 3 months after surgery (group difference = 9.48 Nm [95% CI, 0.43-18.54]; p = 0.03). Hamstring strength did not differ between groups at any time point nor did measures of quadriceps voluntary activation or measures of unilateral balance ability. There was less estimated intraoperative blood loss in the tourniquet group (84 +/- 26 mL) than in the no tourniquet group (156 +/- 63 mL) (group difference = -74 mL [95% CI, -100 to 49]; p < 0.001). However, there was no difference in total blood loss between the groups (group difference = -136 mL [95% CI, -318 to 45]; p = 0.13). CONCLUSIONS: Patients who underwent TKA using a tourniquet had diminished quadriceps strength during the first 3 months after TKA, the clinical significance of which is unclear. Future studies may be warranted to examine the effects of tourniquet use on long-term strength and functional outcomes. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 26100255 TI - Are There Long-term Benefits to Cementing the Metaphyseal Stem in Hip Resurfacing? AB - BACKGROUND: Cementing the metaphyseal stem during hip resurfacing surgery improves the initial fixation of the femoral component. However, there may be long-term detrimental effects such as stress shielding or an increased risk of thermal necrosis associated with this technique. QUESTIONS/PURPOSES: We compared (1) long-term survivorship free from radiographic femoral failure, (2) validated pain scores, and (3) radiographic evidence of component fixation between hips resurfaced with a cemented metaphyseal stem and hips resurfaced with the metaphyseal stem left uncemented. METHODS: We retrospectively selected all the patients who had undergone bilateral hip resurfacing with an uncemented metaphyseal stem on one side, a cemented metaphyseal stem on the other side, and had both surgeries performed between July 1998 and February 2005. Forty-three patients matched these inclusion criteria. During that period, the indications for cementing the stem evolved in the practice of the senior author (HCA), passing through four phases; initially, only hips with large femoral defects had a cemented stem, then all stems were cemented, then all stems were left uncemented. Finally, stems were cemented for patients receiving small femoral components (< 48 mm) or having large femoral defects (or both). Of the 43 cemented stems, two, 13, 0, and 28 came from each of those four periods. All 43 patients had complete followup at a minimum of 9 years (mean, 143 +/- 21 months for the uncemented stems; and 135 +/- 22 months for the cemented stems; p = 0.088). Survivorship analyses were performed with Kaplan-Meier and Cox proportional hazards ratios using radiographic failure of the femoral component as the endpoint. Pain was assessed with University of California Los Angeles (UCLA) pain scores, and radiographic femoral failure was defined as complete radiolucency around the metaphyseal stem or gross migration of the femoral component. RESULTS: There were four failures of the femoral component in the press-fit stem group while the cemented stem group had no femoral failures (p = 0.0471). With the numbers available, we found no differences between the two groups regarding pain relief or radiographic appearance other than in patients whose components developed loosening. CONCLUSIONS: Cementing the metaphyseal stem improves long-term implant survival and does not alter long-term pain relief or the radiographic appearance of the proximal femur as had been a concern based on the results of finite element studies. We believe that patients with small component sizes and large femoral head defects have more to gain from the use of this technique which adds surface area for fixation, and there is no clinical downside to cementing the stem in patients with large component sizes. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26100257 TI - Letter to the Editor: Editor's Spotlight/Take 5: Most American Academy of Orthopaedic Surgeons' Online Patient Education Material Exceeds Average Patient Reading Level. PMID- 26100256 TI - Can Good Infection Control Be Obtained in One-stage Exchange of the Infected TKA to a Rotating Hinge Design? 10-year Results. AB - BACKGROUND: Prosthetic joint infection (PJI) occurs in 1% to 2% of total knee arthroplasties (TKAs). Although two-stage exchange is the preferred management method of patients with chronic PJI in TKA in North America, one-stage exchange is an alternative treatment method, but long-term studies of this approach have not been conducted. QUESTIONS/PURPOSES: We reviewed our minimum 9-year results of 70 patients who underwent one-stage exchange arthroplasty with a rotating hinge design to determine: (1) What was the proportion of patients free of infection? (2) What was the patient rate of survival free of any reoperation? (3) What were the clinical outcomes as measured by Hospital for Special Surgery scores? (4) What proportion of patients developed radiographic evidence of loosening? METHODS: All one-stage revision TKAs for infection between January 1 and December 31, 2002, with a minimum 9-year followup (mean, 10 years; range, 9-11 years), in which patients had been seen within the last 1 year, were included in this retrospective review. During that period, 11 patients with infected TKAs were treated with other approaches (including two-stage approaches in eight); the general indication for one-stage revision was the diagnosis of PJI with a known causative organism. Exclusion criteria were culture-negative preoperative aspiration, known allergy to local antibiotics or bone cement, or cases in which radical debridement was impossible as a result of the involvement of important anatomical structures. Eighty-one patients with PJI were seen during this period; 70 underwent one-stage exchange using our strict protocol and were reimplanted with a rotating hinge TKA. Eleven patients (15.7%) were lost to followup. Hospital for Special Surgery scores were recorded and all radiographs were evaluated for prosthetic loosening. Failure was defined as revision surgery for infection or any other cause. RESULTS: Our 10-year infection-free survival was 93% (mean, 4.1; 95% confidence interval [CI], 89%-96%; p < 0.007); and the patient 10-year survival rate free of revision for other causes was 91% (mean, 5.2; 95% CI, 86%-95%; p < 0.002). Mean Hospital for Special Surgery knee score at last followup was 69.6 (+/- 22.5 SD; range, 22-100) and the mean improvement in Hospital for Special Surgery knee score from preoperative to most recent followup was 35 (+/- 24.2 SD; range, 13-99). Evidence of radiographic loosening was seen in 11 patients at last followup, whereby in six patients, there was need for revision surgery. CONCLUSIONS: Our study results showed an overall infection control rate of 93% and good clinical results using our one-stage approach, which combines aggressive debridement of the collateral ligaments and posterior capsule with a rotating hinge implant. These results are comparable with two-stage techniques at a followup of 10 years; further research into one-stage exchange techniques for PJI in TKA appears warranted. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26100258 TI - Editorial Comment: 2014 Annual Meeting of the Limb Lengthening and Reconstruction Society. PMID- 26100259 TI - CORR Insights((r)): What is the Best Clinical Test for Assessment of the Teres Minor in Massive Rotator Cuff Tears? PMID- 26100260 TI - Circumferential stent fracture repaired using a covered stent in a 42-year-old man with coarctation of the aorta. AB - We present a case of circumferential fracture of aortic coarctation stent with severe re-stentosis presenting 16 years after initial stent implantation with end stage renal disease. The patient was treated with a covered stent using the stent in-stent technique. The use of an ultra-high-pressure balloon was proved necessary to overcome the tight, non-compliant stenosis. PMID- 26100261 TI - Chemoenzymatic synthesis of alpha-dystroglycan core M1 O-mannose glycans. AB - The diversity-oriented chemoenzymatic synthesis of alpha-dystroglycan (alpha-DG) core M1 O-mannose glycans has been achieved via a three-step sequential one-pot multienzyme (OPME) glycosylation of a chemically prepared disaccharyl serine intermediate. The high flexibility and efficiency of this chemoenzymatic strategy was demonstrated for the synthesis of three more complex core M1 O-mannose glycans for the first time along with three previously reported core M1 structures. PMID- 26100262 TI - CKA2 functions in H2O2-induced apoptosis and high-temperature stress tolerance by regulating NO accumulation in yeast. AB - Nitric oxide (NO) plays key roles in yeast responses to various environmental factors, such as H2O2 and high temperature. However, the gene encoding NO synthase (NOS) in yeast has not yet been identified, and the mechanism underlying the regulation of NOS-like activity is poorly understood. Here, we report on the involvement of CKA2 in H2O2-induced yeast apoptosis and yeast high-temperature stress tolerance. Our results showed that although Deltacka2 mutant had reduced NO accumulation with decreased apoptosis after H2O2 exposure, treatment with a NO donor, sodium nitroprusside, resulted in similar survival rate of Deltacka2 mutant compared to that of wild-type yeast when subjected to H2O2 stress. This finding occurred because H2O2-enhanced NOS-like activity in wild-type yeast was significantly repressed in Deltacka2. Our additional experiments indicated that both high-temperature-enhanced NO accumulation and NOS-like activity were also suppressed in Deltacka2, leading to the hypersensitivity of the mutant to high temperature in terms of changes in survival rate. Thus, our results showed that CKA2 functioned in H2O2-induced apoptosis and high-temperature stress tolerance by regulating NOS-like-dependent NO accumulation in yeast. PMID- 26100263 TI - High-throughput transformation method for Yarrowia lipolytica mutant library screening. AB - As a microorganism of major biotechnological importance, the oleaginous yeast Yarrowia lipolytica is subjected to intensive genetic engineering and functional genomic analysis. Future advancements in this area, however, require a system that will generate a large collection of mutants for high-throughput screening. Here, we report a rapid and efficient method for high-throughput transformation of Y. lipolytica in 96-well plates. We developed plasmids and strains for the large-scale screening of overexpression mutant strains, using Gateway(r) vectors that were adapted for specific locus integration in Y. lipolytica. As an example, a collection of mutants that overexpressed the alkaline extracellular protease (AEP) was obtained in a single transformation experiment. The platform strain that we developed to receive the overexpression cassette was designed to constitutively express a fluorescent protein as a convenient growth reporter for screening in non-translucid media. An example of growth comparison in skim milk based medium between AEP overexpression and deletion mutants is provided. PMID- 26100264 TI - Comparison of redox and gene expression changes during vegetative/generative transition in the crowns and leaves of chromosome 5A substitution lines of wheat under low-temperature condition. AB - The aim of our experiments was to investigate the effect of chromosome 5A on the thiol-dependent redox environment and on the transcription of cold- and vernalization-related genes during the vegetative/generative transition in crowns and leaves of wheat. Chinese Spring, a moderately freezing-tolerant variety, and its more and less tolerant substitution lines - [CS(Ch5A)] and [CS(Tsp5A)], respectively - with different combinations of vernalization alleles were compared. At low temperature, the amount of cystine and glutathione disulphide and the related redox potentials increased in the crowns but not in the leaves. In the crowns of the substitution lines, the concentration and redox state of thiols were different only at the vegetative and double ridge (start of the generative transition) stages. The expression of the vernalization-related VRN1 gene increased significantly during the transition both in the crowns and leaves. The transcription of the freezing tolerance-related CBF14, COR14b and COR39 genes markedly increased in both organs after 2 weeks at 4 degrees C when the seedlings were still in the vegetative stage. This increment was greater in CS(Ch5A) than in CS(Tsp5A). The Ch5A chromosome in CS genetic background enhanced the expression of CBF regulon even in the generative phase in crown that is the key organ for overwintering and freezing tolerance. At certain developmental stages, both the thiol and the transcript levels differed significantly in the two substitution lines. PMID- 26100267 TI - Exploring Spanish health social media for detecting drug effects. AB - BACKGROUND: Adverse Drug reactions (ADR) cause a high number of deaths among hospitalized patients in developed countries. Major drug agencies have devoted a great interest in the early detection of ADRs due to their high incidence and increasing health care costs. Reporting systems are available in order for both healthcare professionals and patients to alert about possible ADRs. However, several studies have shown that these adverse events are underestimated. Our hypothesis is that health social networks could be a significant information source for the early detection of ADRs as well as of new drug indications. METHODS: In this work we present a system for detecting drug effects (which include both adverse drug reactions as well as drug indications) from user posts extracted from a Spanish health forum. Texts were processed using MeaningCloud, a multilingual text analysis engine, to identify drugs and effects. In addition, we developed the first Spanish database storing drugs as well as their effects automatically built from drug package inserts gathered from online websites. We then applied a distant-supervision method using the database on a collection of 84,000 messages in order to extract the relations between drugs and their effects. To classify the relation instances, we used a kernel method based only on shallow linguistic information of the sentences. RESULTS: Regarding Relation Extraction of drugs and their effects, the distant supervision approach achieved a recall of 0.59 and a precision of 0.48. CONCLUSIONS: The task of extracting relations between drugs and their effects from social media is a complex challenge due to the characteristics of social media texts. These texts, typically posts or tweets, usually contain many grammatical errors and spelling mistakes. Moreover, patients use lay terminology to refer to diseases, symptoms and indications that is not usually included in lexical resources in languages other than English. PMID- 26100265 TI - Immune response of healthy horses to DNA constructs formulated with a cationic lipid transfection reagent. AB - BACKGROUND: Deoxyribonucleic acid (DNA) vaccines are used for experimental immunotherapy of equine melanoma. The injection of complexed linear DNA encoding interleukin (IL)-12/IL-18 induced partial tumour remission in a clinical study including 27 grey horses. To date, the detailed mechanism of the anti-tumour effect of this treatment is unknown. RESULTS: In the present study, the clinical and cellular responses of 24 healthy horses were monitored over 72 h after simultaneous intradermal and intramuscular application of equine IL-12/IL-18 DNA (complexed with a transfection reagent) or comparative substances (transfection reagent only, nonsense DNA, nonsense DNA depleted of CG). Although the strongest effect was observed in horses treated with expressing DNA, horses in all groups treated with DNA showed systemic responses. In these horses treated with DNA, rectal temperatures were elevated after treatment and serum amyloid A increased. Total leukocyte and neutrophil counts increased, while lymphocyte numbers decreased. The secretion of tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) from peripheral mononuclear blood cells ex vivo increased after treatments with DNA, while IL-10 secretion decreased. Horses treated with DNA had significantly higher myeloid cell numbers and chemokine (C-X C motif) ligand (CXCL)-10 expression in skin samples at the intradermal injection sites compared to horses treated with transfection reagent only, suggesting an inflammatory response to DNA treatment. In horses treated with expressing DNA, however, local CXCL-10 expression was highest and immunohistochemistry revealed more intradermal IL-12-positive cells when compared to the other treatment groups. In contrast to non-grey horses, grey horses showed fewer effects of DNA treatments on blood lymphocyte counts, TNFalpha secretion and myeloid cell infiltration in the dermis. CONCLUSION: Treatment with complexed linear DNA constructs induced an inflammatory response independent of the coding sequence and of CG motif content. Expressing IL-12/IL-18 DNA locally induces expression of the downstream mediator CXCL-10. The grey horses included appeared to display an attenuated immune response to DNA treatment, although grey horses bearing melanoma responded to this treatment with moderate tumour remission in a preceding study. Whether the different immunological reactivity compared to other horses may contributes to the melanoma susceptibility of grey horses remains to be elucidated. PMID- 26100266 TI - Regional pressure and temperature variations across the injured human brain: comparisons between paired intraparenchymal and ventricular measurements. AB - INTRODUCTION: Intraparenchymal, multimodality sensors are commonly used in the management of patients with severe traumatic brain injury (TBI). The 'gold standard', based on accuracy, reliability and cost for intracranial pressure (ICP) monitoring is within the cerebral ventricle (external strain gauge). There are no standards yet for intracerebral temperature monitoring and little is known of temperature differences between brain tissue and ventricle. The aim of the study therefore was to determine pressure and temperature differences at intraparenchymal and ventricular sites during five days of continuous neuromonitoring. METHODS: Patients with severe TBI requiring emergency surgery. INCLUSION CRITERIA: patients who required ICP monitoring were eligible for recruitment. Two intracerebral probe types were used: a) intraventricular, dual parameter sensor (measuring pressure, temperature) with inbuilt catheter for CSF drainage: b) multiparameter intraparenchymal sensor measuring pressure, temperature and oxygen partial pressure. All sensors were inserted during surgery and under aseptic conditions. RESULTS: Seventeen patients, 12 undergoing neurosurgery (decompressive craniectomy n = 8, craniotomy n = 4) aged 21-78 years were studied. Agreement of measures for 9540 brain tissue-ventricular temperature 'pairs' and 10,291 brain tissue-ventricular pressure 'pairs' were determined using mixed model to compare mean temperature and pressure for longitudinal data. There was no significant overall difference for mean temperature (p = 0.92) or mean pressure readings (p = 0.379) between tissue and ventricular sites. With 95.8 % of paired temperature readings within 2SD (-0.4 to 0.4 degrees C) differences in temperature between brain tissue and ventricle were clinically insignificant. For pressure, 93.5 % of readings pairs fell within the 2SD range ( 9.4756 to 7.8112 mmHg). However, for individual patients, agreement for mean tissue-ventricular pressure differences was poor on occasions. CONCLUSIONS: There is good overall agreement between paired temperature measurements obtained from deep white matter and brain ventricle in patients with and without early neurosurgery. For paired ICP measurements, 93.5 % of readings were within 2SD of mean difference. Whilst the majority of paired readings were comparable (within 10 mmHg) clinically relevant tissue-ventricular dissociations were noted. Further work is required to unravel the events responsible for short intervals of pressure dissociation before tissue pressure readings can be definitively accepted as a reliable surrogate for ventricular pressure. PMID- 26100269 TI - Laser directed writing of flat lenses on buckypaper. AB - Laser directed patterning of carbon nanotubes-based buckypaper for producing a diffractive optical device is presented here. Using a laser ablation method the buckypaper was patterned into a binary Fresnel zone plate lens. Computational modelling was performed which revealed excellent focusing performance of the lens for both visible and THz radiations. SEM and Raman measurements of the lens were studied to analyse the laser-material interaction. The focusing properties of the lens were characterized and a good agreement with the simulations was achieved. Hence, we exploited a new way to fabricate thin flat lens. The one-step fabrication process is economical, convenient and has great potential for industrial scale up. PMID- 26100268 TI - Ethnic differences in medicinal plant use among University students: a cross sectional survey of self-reported medicinal plant use at two Midwest Universities. AB - BACKGROUND: Numerous surveys of medicinal plant use among college students abound, but none compare use between students enrolled in two different Universities with significantly different ethnic compositions. The objective of this study is to compare medicinal plant use between two different ethnic college populations and explore differences between student medicinal plant users and non users for comparison with previous research. METHODS: Students (n = 721) at a large research university (n = 498) and a Pan-Tribal University for Native Americans (n = 233) completed surveys in October 2011 to assess past year medicinal plant use. The Mann-Whitney U test, Chi Square test, and General Linear Model were used to compare demographics and self-reported use of medicinal plants among students at both Universities and between past year users and non-users. RESULTS: Over 23% of university students surveyed reported past year medicinal plant use. Users were more likely to use commercial tobacco products and to report poorer health than non-users. While Native American student medicinal plant users reported significantly higher rates of commercial tobacco use, lower self-assessment of health, and less use of prescription medicine than non-Native users, no significant differences in prevalence of medicinal plant use were found between University student populations. CONCLUSIONS: Results are consistent with preexisting data showing higher rates of medicinal plant use among college students compared to the larger US population of adults and demonstrate previously documented health disparities in Native American populations compared to non-Native Americans. PMID- 26100270 TI - MAGE-A3: an immunogenic target used in clinical practice. AB - Melanoma antigen family A, 3 (MAGE-A3) is a cancer-testis antigen whose expression has been demonstrated in a wide array of malignancies including melanoma, brain, breast, lung and ovarian cancer. In addition, its ability to elicit spontaneous humoral and cellular immune responses has been shown in cancer patients. As antigen-specific immune responses can be stimulated by immunization with MAGE-A3, several clinical trials have used MAGE-A3 vaccines to observe clinical responses. The frequent expressions of this antigen in various tumors and its immunogenicity in cancer patients have led to application of this antigen in cancer immunotherapy. However, the results of recent clinical trials indicate that there is a need for research in the vaccine design, adjuvant selection as well as patient selection criteria. PMID- 26100271 TI - Rindopepimut vaccine and bevacizumab combination therapy: improving survival rates in relapsed glioblastoma patients? PMID- 26100272 TI - IL-25 as a potential therapeutic target in allergic asthma. PMID- 26100273 TI - Recent advances in multidisciplinary approach for rectal cancer. AB - Surgery is a major treatment option for rectal cancer, and total mesorectal excision has been demonstrated to be advantageous in terms of oncological outcome and thus has been the standard surgical approach. Radiotherapy before or after radical surgery is the optimal treatment to control local recurrence of advanced rectal cancer. To date, in many countries, the combination of neoadjuvant concurrent chemotherapy and radiotherapy is considered the standard therapy. A more recent interest in neoadjuvant therapy has been the use of oxaliplatin or targeted agents for neoadjuvant chemoradiotherapy. However, despite many trials of oxaliplatin and targeted agents, 5-FU-based concurrent chemoradiotherapy has remained the only standard treatment option. Postoperative adjuvant chemotherapy with neoadjuvant chemoradiotherapy or induction chemotherapy with neoadjuvant chemoradiotherapy may further improve patient survival, as some clinical studies recently indicated. In Japan, neoadjuvant therapy is not the standard treatment method, because surgery with lateral lymph node dissection is usually performed and this type of surgery may reduce recurrence rate as does radiation therapy. The phase III study to evaluate the oncological effect of the Japanese standard operation (mesorectal excision, ME) with lateral lymph node dissection in comparison with ME alone for clinical stage II and III lower rectal cancer is currently ongoing. PMID- 26100274 TI - Palbociclib for the Treatment of Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. AB - Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 that acts by reducing phosphorylation of the tumor suppressor gene retinoblastoma. When added to the aromatase inhibitor letrozole in a randomized phase II trial for first-line therapy of estrogen receptor-positive, HER2-negative metastatic breast cancer, palbociclib significantly increased progression-free survival compared with letrozole alone [palbociclib + letrozole: 20.2 months; 95% confidence interval (CI), 13.8-27.5; letrozole: 10.2 months; 95% CI, 5.7-12.6; HR, 0.49; 95% CI, 0.32-0.75; P = 0.0004]. On the basis of these results, the drug was recently granted accelerated approval by the FDA, and confirmatory studies are ongoing. Because this drug has a rational target in an oncologic pathway, concurrent biomarker development is of interest. In breast cancer, the most useful predictive biomarkers identified thus far are estrogen receptor and HER2 receptor status, although additional studies are ongoing. In this article, we review the development of palbociclib and its use in treatment of hormone receptor-positive metastatic breast cancer in the context of other FDA-approved agents in this setting. PMID- 26100275 TI - MicroRNA-374b Suppresses Proliferation and Promotes Apoptosis in T-cell Lymphoblastic Lymphoma by Repressing AKT1 and Wnt-16. AB - PURPOSE: Deregulation of microRNA (miRNA) has been extensively investigated in both Hodgkin and non-Hodgkin lymphomas (NHL); however, little is known about the roles of miRNAs in T-cell lymphoblastic lymphoma (T-LBL). The aim of the present study was to investigate the potential roles of miR-374b in the development and treatment of T-LBL. EXPERIMENTAL DESIGN: MiRCURY LNA array was used to generate a miRNA-expressing profile. Real-time quantitative PCR and immunohistochemistry (IHC) were applied to detect the expression of miR-374b, AKT1, and Wnt16 in T-LBL samples. The dual-luciferase reporter assay was conducted to confirm target associations of miR-374b. The tumor-suppressive effect of miR-374b was determined by both in vitro and in vivo studies. RESULTS: The expression of 380 miRNAs was evaluated in five human T-LBL tissues and five infantile thymus samples by microRNA microarrays. Downregulation of miR-374b was frequently detected in primary T-LBL tissues, which was significantly associated with worse overall survival and increased risk of recurrence of the 58 patients enrolled in this study. miR-374b suppressed T-LBL cell proliferation in vitro and in vivo and sensitized cells to serum starvation- and chemotherapeutic agent-induced apoptosis. Furthermore, we characterized two AKT pathway-associated molecules, AKT1 and Wnt16, as direct targets of miR-374b. Consistently, in T-LBL patient tissues, AKT1 and Wnt16 expression was inversely correlated with miR-374b levels, and was an independent predictor of recurrence and survival. CONCLUSIONS: Our data highlight the molecular etiology and clinical significance of miR-374b in T LBL. Targeting miR-374b may represent a new therapeutic strategy to improve therapy and survival for T-LBL patients. PMID- 26100277 TI - Letter to the Editor concerning "Continuous wound infusion of ropivacaine for the control of pain after thoracolumbar spinal surgery: a randomized clinical trial" (by B. Xu, et al. (2015) Eur Spine J; 24: doi 10.1007/s00586-015-3979-x). PMID- 26100276 TI - Previous experiences and emotional baggage as barriers to lifestyle change - a qualitative study of Norwegian Healthy Life Centre participants. AB - BACKGROUND: Changing lifestyle is challenging and difficult. The Norwegian Directorate of Health recommends that all municipalities establish Healthy Life Centres targeted to people with lifestyle issues. Little is known about the background, experiences and reflections of participants. More information is needed about participants to shape effective lifestyle interventions with lasting effect. This study explores how participants in a lifestyle intervention programme describe previous life experiences in relation to changing lifestyle. METHODS: Semi-structured qualitative in-depth interviews were performed with 23 participants (16 women and 7 men) aged 18 - 70 years. The data were analysed using systematic text condensation searching for issues describing participants' responses, and looking for the essence, aiming to share the basis of life-world experiences as valid knowledge. RESULTS: Participants identified two main themes: being stuck in old habits, and being burdened with emotional baggage from their previous negative experiences. Participants expressed a wish to change their lifestyles, but were unable to act in accordance with the health knowledge they possessed. Previous experiences with lifestyle change kept them from initiating attempts without professional assistance. Participants also described being burdened by an emotional baggage with problems from childhood and/or with family, work and social life issues. Respondents said that they felt that emotional baggage was an important explanation for why they were stuck in old habits and that conversely, being stuck in old habits added load to their already emotional baggage and made it heavier. CONCLUSIONS: Behavioural change can be hard to perform as psychological distress from life baggage can influence the ability to change. The study participants' experience of being stuck in old habits and having substantial emotional baggage raises questions as to whether or not Healthy Life Centres are able to help participants who need to make a lifestyle change. PMID- 26100278 TI - Disappearance of lung adenocarcinoma after total en bloc spondylectomy using frozen tumor-bearing vertebra for reconstruction. AB - PURPOSE: Total en bloc spondylectomy (TES) is a surgical procedure performed to achieve complete resection of an aggressive benign spinal tumor or a malignant spinal tumor. When reconstructing the spine after resection, we have been using liquid nitrogen-frozen resected spine bearing tumor as a bone graft, expecting an immunological response to tumor-specific antigen(s). The purpose of this article is to report a successful treatment case of lung adenocarcinoma metastasis with TES and this cryotherapy. METHODS: A 59-year-old male presented with rapid progression of neurological deterioration of the lower limbs due to a spinal metastasis from T8 to T10. The primary lung adenocarcinoma had already been excised under thoracoscopy. The patient underwent TES with reconstruction using frozen tumor-bearing vertebra for the bone graft. RESULTS: One month after surgery, a new nodule appeared at the right middle lobe of the lung. However, we carried out no biopsy of the newly emerged nodule and the patient received no adjuvant chemotherapy or radiotherapy. Six months after surgery, the tumor vanished. No local recurrence or metastasis of the tumor has been observed until now. CONCLUSIONS: TES with a liquid nitrogen-frozen tumor specimen could be a promising therapeutic option for cancer patients with spine metastasis. PMID- 26100279 TI - Individual characteristics of reliable lumbar coupling motions. AB - INTRODUCTION: Coupling motions (CMs) are the motions occurring in different directions around the primary motion. As low back pain (LBP) is known to be associated with lumbar CMs, some studies measured lumbar CMs using the microelectromechanical system inertial measurement unit (MEMS-IMU) because of its low cost and small size. This study aimed to examine the reliability of lumbar CM measurements using the MEMS-IMU and to classify the individual characteristics of lumbar CMs. METHODS: MEMS-IMUs were attached to the two lumbar points (L1, L5) of 19 male volunteers (age, 24.3 +/- 1.2 years). Following an instructional video and audio recording, they conducted the six lumbar movements three times: flexion and extension, left and right lateral bending, and left and right rotation. The six lumbar movements were repeated after 1 h. Raw data were transformed into angle data using MATLAB. Intraclass correlation coefficients (ICCs) were calculated to evaluate intratest repeatability and test-retest reliability. Finally, angle data were analyzed to examine whether individual characteristics of lumbar CMs could be identified. RESULTS: Lumbar CM measurements showed fair to good or excellent intratest repeatability and test-retest reliability, ranging from 0.669 to 0.997 of the ICCs. All lumbar CMs could be categorized into six types, and flexion and extension CMs were more prominent than other CMs. CONCLUSIONS: Lumbar CM measurements obtained using the MEMS-IMU are reliable, and identifying the individual variations of lumbar CMs may be helpful for alleviating chronic or recurrent LBP. PMID- 26100280 TI - Reshaping the protein folding pathway by osmolyte via its effects on the folding intermediates. AB - It is now well established that the protein folding reaction proceeds via accumulation of various intermediate states. Osmolytes, besides their role in protein stabilization, have also been shown to possess the ability of inducing tremendous affects on these protein folding intermediates, reshape the folding pathway and the energy landscape. The present article describes the advances made so far in understanding the effects of organic osmolytes on the folding intermediates and pathways. The ability of osmolytes to rescue disease causing mutations in proteins by inducing proper folding into functionally active form is also discussed. Finally, some future directions are described. PMID- 26100281 TI - Neurotrophin Propeptides: Biological Functions and Molecular Mechanisms. AB - Neurotrophins constitute a family of growth factors that play a key role in the regulation of the development and function of the central and peripheral nervous systems. A common feature of all the neurotrophins is their synthesis in cells as long precursors (pre-pro-neurotrophins) that contain an N-terminal signal peptide, a following propeptide and the mature neurotrophin. Although the signal peptide functions have been well studied, the role of neurotrophin propeptides is not so clear. Here, we briefly summarize the biochemistry of neurotrophin propeptides, including their role as folding-assistants for the mature factor and their role in processing and in secretion of neurotrophins. In the main part of the review we summarize our current state of knowledge of the biological activity of neurotrophin propeptides, their possible mechanisms of action, and their potential influence on the activity of the mature neurotrophins. PMID- 26100282 TI - Structural and functional characterization of the proteins responsible for N6 methyladenosine modification and recognition. AB - More than 100 types of RNA modifications have been identified so far, which are involved in a variety of cellular processes. N6-methyladenosine (m6A), as one most abundant RNA modification, is found in several RNA species, and mainly located in the stop codons, long internal exons as well as 3'UTR. It was reported that m6A modification is preferred after G in the conserved sequence RRm6ACH (R = A/G and H = A/C/U). There are two families of enzymes responsible for maintaining the balance of m6A methylation: RNA methyltransferases and demethylases, which add and remove methyl marks from RNA, respectively. METTL3 complex, the m6A RNA methyltransferase, has been identified, and two kinds of demethylases are characterized thus far, including Fat mass and obesity-associated protein (FTO) and alkylation protein AlkB homolog 5 (ALKBH5). Besides the "writers" and "erasers" for m6A, m6A specific recognizing protein, such as the YTH domain, also has attracted significant attention. Herein, we will focus on the recent progress in understanding biological/biochemical functions and structures of proteins responsible for the m6A RNA modification and recognition. Detailed analysis of these important proteins will guide us in designing target-specific small molecule chemical probes and inhibitors. PMID- 26100283 TI - Reversible and Irreversible Aggregation of Proteins from the FET Family: Influence of Repeats in Protein Chain on Its Aggregation Capacity. AB - The discovery of protein chain regions responsible for protein aggregation is an important result of studying of the molecular mechanisms of prion diseases and different proteinopathies associated with the formation of pathological aggregations through the prion mechanism. The ability to control aggregation of proteins could be an important tool in the arsenal of the drug development. Here we demonstrate, on an example of RNA-binding proteins of the FET family from six animal species (human, gorilla, pig, mouse, chicken, zebra fish), the possible role of repeats within the disordered regions. For these proteins, different repeats are revealed in the prion-like (N-terminal disordered) domains, and in the C-terminal disordered regions, predicted using bioinformatics methods. Moreover, we have found that in more complex organisms the number of repeats is increased. It can be hypothesized that the presence of a large number of repeats in the disordered regions in the proteins of the FET-family could both modulate and accelerate the formation of a dynamic cross-beta structure, and pathological aggregates. PMID- 26100284 TI - The Phytoestrogen Genistein Affects Breast Cancer Cells Treatment Depending on the ERalpha/ERbeta Ratio. AB - Genistein (GEN) is a phytoestrogen found in soybeans. GEN exerts its functions through its interaction with the estrogen receptors (ER), ERalpha and ERbeta, and we previously reported that the ERalpha/ERbeta ratio is an important factor to consider in GEN-treated breast cancer cells. The aim of this study was to investigate the effects of GEN in breast cancer cells with different ERalpha/ERbeta ratio: MCF-7 (high ratio), T47D (low ratio), and MCF-7 overexpressing ERbeta (MCF7 + ERbeta) treated with cisplatin (CDDP), paclitaxel (PTX) or tamoxifen (TAM). Cell viability, ROS production, autophagy, apoptosis, antioxidant enzymes protein levels, and cell cycle were analyzed. GEN treatment provoked an increase in cell viability in MCF-7 cells and in the antioxidant enzymes protein levels in combination with the cytotoxic agents, decreasing ROS production (CDDP + GEN and TAM+GEN) and autophagy (TAM + GEN) or apoptosis (CDDP + GEN and TAM + GEN). Moreover GEN treatment enhanced the cell cycle S phase entry in CDDP+GEN- and TAM + GEN-treated MCF-7 cells and, in the case of CDDP + GEN, increased the proportion of cells in the G2/M phase and decreased it in the subG0 /G1 phase. Otherwise, in the T47D and MCF7 + ERbeta cells the combination of GEN with cytotoxic treatments did not cause significant changes in these parameters, even TAM + GEN-treated T47D cells showed less cell viability due to an increment in the autophagy. In conclusion, GEN consumption may be counterproductive in those patients receiving anticancer treatment with a high ERalpha/ERbeta ratio diagnosed breast cancer and it could be harmless or even beneficial in those patients with a lower ERalpha/ERbeta ratio breast cancer cells. PMID- 26100286 TI - ? PMID- 26100285 TI - Cost-Value Analysis and the SAVE: A Work in Progress, But an Option for Localised Decision Making? AB - BACKGROUND: Cost-value analysis aims to address the limitations of the quality adjusted life-year (QALY) by incorporating the strength of public concerns for fairness in the allocation of scarce health care resources. To date, the measurement of value has focused on equity weights to reflect societal preferences for the allocation of QALY gains. Another approach is to use a non QALY-based measure of value, such as an outcome 'equivalent to saving the life of a young person' (a SAVE). OBJECTIVE: This paper assesses the feasibility and validity of using the SAVE as a measure of value for the economic evaluation of health care technologies. METHODS: A web-based person trade-off (PTO) survey was designed and implemented to estimate equivalent SAVEs for outcome events associated with the progression and treatment of early-stage breast cancer. The estimated equivalent SAVEs were applied to the outputs of an existing decision analytic model for early breast cancer. RESULTS: The web-based PTO survey was undertaken by 1094 respondents. Validation tests showed that 68 % of eligible responses revealed consistent ordering of responses and 32 % displayed ordinal transitivity, while 37 % of respondents showing consistency and ordinal transitivity approached cardinal transitivity. Using consistent and ordinally transitive responses, the mean incremental cost per SAVE gained was L 3.72 million. CONCLUSION: Further research is required to improve the validity of the SAVE, which may include a simpler web-based survey format or a face-to-face format to facilitate more informed responses. A validated method for estimating equivalent SAVEs is unlikely to replace the QALY as the globally preferred measure of outcome, but the SAVE may provide a useful alternative for localized decision makers with relatively small, constrained budgets-for example, in programme budgeting and marginal analysis. PMID- 26100287 TI - ? PMID- 26100288 TI - [Self-neglect in housing]. AB - Self-neglect in housing has attracted growing interest from health and social care professionals over recent years. A complex issue, lying somewhere between a psychopathology and a lifestyle choice, between a private disorder and one which has consequences on the immediate environment, its clinical approach requires us to reconsider our practices to bring into being the message potential in the housing of the person presenting self-neglect. PMID- 26100290 TI - [Senses and crumbs: psychosis and self-neglect at home]. AB - What care can be given in cases of self-neglect? How can one be a good caregiver when one's senses and values are assaulted by the complete lack of hygiene? What is the bestway to help a patient who is used to living independently, when their health is under threat? What approach should be taken in order to rehabilitate their living place? A clinical illustration. PMID- 26100289 TI - [Psychosocial approach to Diogenes syndrome]. AB - Abnormal hoarding of random items in the home associated with severe self-neglect and neglect of one's environment, Diogenes syndrome is transnosographic. It can affect all social classes, people without any diagnosed mental health condition or patients with psychosis or dementia, over 60s and young people. It is conveyed by self-exclusion at home, a "poor precarity" which leads to a loss of the ability to trust others and ask for help. PMID- 26100291 TI - [Old age: knowing what self-neglect is]. AB - The issue of self-neglect in the elderly concerns society as well as caregivers who, in their practice, are ill at ease and frequently disorientated when faced with this behaviour which hampers the care approach. Here more than elsewhere, the choices of the people in question seem to collide with the care objectives, in such a way that it is important to remain curious in the face of what appears to be the height of incuriosity. PMID- 26100293 TI - [Self-neglect as a sign of decompensation]. AB - A lack of hygiene to which the patient appears indifferent, self-neglect can be a sign of the decompensation of a mental pathology. This article presents the case of a patient who, after several months of stabilisation and a return home to a relatively clean environment, reactivates a delusion of persecution. PMID- 26100292 TI - [Psymobile and the phenomenon of the hikikomori]. AB - By its very nature, the Psymobile team is often called on to visit young adults who remain confined at home but who have no diagnosed psychiatric conditions. The team has consequently become interested in the Japanese concept of hikikomori, a notion which appeared in the 1990s and which has since spread across the world. This concept still arouses some amount of discussion regarding its aetiology, its precise definition and its relevance outside Japan. PMID- 26100294 TI - [Art-therapy in anorexia: the mediative elements?]. AB - Art does not have any inherent curative property; it is used as a therapeutic medium. Three mediative elements, depending on their specificities, have a role to play in the intrapsychic and interpersonal transformation of the patient: the creation the art-therapist and the group of participants. This article looks at the different components of art-therapy used in the treatment of anorexia. PMID- 26100295 TI - ? PMID- 26100296 TI - Visceral adipose tissue measured by computed tomography and high-grade prostate cancer after radical prostatectomy. AB - We assessed the association between obesity measurements including visceral adipose tissue (VAT), measured by computed tomography, and the risk of high-grade prostate cancer after radical prostatectomy. We investigated 296 patients who were diagnosed with prostate cancer and underwent radical prostatectomy. Data extracted from medical records included age, body mass index (BMI), VAT, pretreatment prostate-specific antigen (PSA) levels and Gleason score (GS). We performed logistic regression to examine the association between indicators of obesity and a higher GS (?4+3). Among the 296 patients, 107 (36%) had a higher GS. After controlling for age and PSA, BMI was not associated with GS (odds ratio, OR=1.039, 95% confidence interval, CI=0.943-1.145; P=0.437). BMI had different effects on GS depending on VAT. When the data were stratified by the median VAT value, a higher BMI was significantly associated with a higher GS in patients with VAT?130.5 cm2 (OR=1.218, 95% CI=1.028-1.443; P=0.022), but not in those with VAT<130.5 cm2 (OR=0.912, 95% CI=0.783-1.062; P=0.236). A higher BMI was associated with an increased risk of high-grade cancer only in patients with more VAT. PMID- 26100297 TI - Using the electronic medical record to refer women taking category D or X medications for teratogen and contraceptive counseling. AB - BACKGROUND: Women taking teratogens may not receive teratogen and contraceptive counseling. The objective of this study is to explore the feasibility of an electronic medical record (EMR) alert and referral system to improve teratogen and contraceptive counseling. METHODS: We conducted a descriptive study in an academic outpatient setting to evaluate the feasibility of an EMR alert and referral system. Reproductive age women taking category D or X medications seen in family medicine clinics were referred by means of an EMR alert for teratogen and contraceptive counseling. A subset of these women consented to follow-up surveys assessing contraceptive usage before counseling, intended contraceptive method after counseling and satisfaction with the counseling. Participants were contacted at 1 and 3 months to assess contraceptive usage. RESULTS: A total of 354 women were prescribed category D or X medications by clinicians who received the EMR alert, 170 women were referred, 59 women received counseling, and 33 participants enrolled in the study. One participant did not use any contraception. Among the 32 participants using contraception, 12 (37.5%) used oral contraceptives, 11 (34.4%) used condoms, 3 (9.4%) used withdrawal, 3 (9.4%) used intrauterine devices, 2 (6.3%) used contraceptive rings, and 1 (3.1%) used the diaphragm. After counseling, one-third of participants were considering more effective contraception. Almost all participants strongly agreed or agreed that the counseling was helpful. CONCLUSION: Creating an EMR alert and referral system for women prescribed category X or D medications is feasible. Counseling on teratogen exposure and contraception may improve the acceptability of more effective contraception. PMID- 26100298 TI - Uterine artery embolization by use of porous gelatin particles for symptomatic uterine leiomyomas: comparison with hand-cut gelatin sponge particles. AB - PURPOSE: To evaluate the results of uterine artery embolization (UAE) for symptomatic uterine leiomyoma by use of porous gelatin particles (PGP) in comparison with conventional hand-cut gelatin sponge particles. MATERIALS AND METHODS: One hundred and fifteen consecutive patients who had undergone UAE were retrospectively assessed. The first 64 patients were treated with hand-cut gelatin sponge and the last 51 with PGP. Extent of infarction, volume reduction of the dominant leiomyoma on magnetic resonance (MR) imaging, and change in symptoms were assessed. RESULTS: UAE was successfully performed for all patients. No major complications were observed. MR images one month after UAE showed that the mean extent of infarction of the dominant leiomyoma was 97 % for patients treated with PGP and 96 % for those treated with hand-cut gelatin sponge. Volume reductions of the dominant leiomyoma after 3, 6, 12, and 24 months were, respectively, 45, 56, 62, and 66 % for use of PGP and 45, 57, 63, and 68 % for use of hand-cut gelatin sponge. Symptoms including heavy menstrual bleeding, heavy menstrual pain, and abdominal heaviness had improved by 95-100 % at 12 months. There was no difference between the two groups. CONCLUSION: UAE with PGP is safe, and as effective as conventional gelatin sponge particles. PMID- 26100300 TI - Third Congress of Physiological Sciences of Serbia with international participation (October 29-31, 2014, Belgrade, Serbia) (Report). PMID- 26100299 TI - Long-term clinical outcomes of combined BPTB ACL reconstruction and popliteus tendon plasty. AB - PURPOSE: A deficiency of posterolateral structures significantly increases the varus load on the ACL, while a chronic ACL lesion, the increased tibial rotation and the repetitive non-physiological knee motion, could affect and damage the integrity of the popliteus tendon. Therefore, the aim of the present study was to report the very long clinical outcomes of a combined single-bundle BPTB ACL reconstruction and popliteus plasty according to Bousquets technique, for the treatment of combined chronic anterior and posterolateral laxities. METHODS: Fifteen patients that underwent combined ACL reconstruction and popliteal plasty according to Bousquets technique were available at mean 26.8 +/- 1.0 years (range 25.4-28.0 years). All the patients were evaluated clinically and 13 by means of KT-1000 Arthrometer as well. Subjective evaluation was performed with the subjective IKDC, WOMAC and a 0-10 VAS for pain scales. RESULTS: At clinical evaluation, 10 patients (67 %) presented a negative anterior drawer test; Lachman test was negative in nine patients (60 %); the varus stress test was negative in eight (53 %); and the dial test was negative in all but one patient (93 %). Only two patients (15 %) presented a side-to-side difference >5 mm at the instrumented laxity evaluation. CONCLUSION: The combined single-bundle BPTB ACL reconstruction and popliteal plasty according to Bousquets technique were able to produce very good long-term results, in terms of knee stability, subjective outcomes, functional results and return to sport activity, in case of chronic anterior and posterolateral laxities. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 26100301 TI - Application of atomic force microscopy for investigation of Na(+),K(+)-ATPase signal-transducing function. AB - The Young's modulus of 10-12-day-old chick embryos' sensory neurons cultivated in dissociated cell culture was measured using a PeakForce Quantitative Nanomechanical Mapping atomic force microscopy. The native cells were tested in control experiments and after application of ouabain. At low "endogenous" concentration of 10-10 M, ouabain tended to increase the rigidity of sensory neurons. We hypothesize that this trend resulted from activation of Na+,K+-ATPase signal-transducing function. PMID- 26100302 TI - Positive effects of naringenin on near-surface membrane fluidity in human erythrocytes. AB - PURPOSE: Deformability/rheologic behavior of erythrocytes are related to near surface membrane fluidity. Specific agents can increase erythrocyte membrane fluidity in order to adjust hemodynamics in cardiovascular diseases. Grapefruit flavanone naringenin has been proposed for potential use in an alternative therapy of cardiovascular conditions. In respect to this, we assessed here effects of two nutritionally relevant concentrations of naringenin (0.1 and 1 MUg/ml) on near-surface membrane fluidity in human erythrocytes. METHODS: We used electron paramagnetic resonance spectroscopy and fatty acid spin probes (5-DS and 7-DS), the spectra of which are dependent on membrane fluidity. RESULTS: The results showed a significant (p = 0.029) increase of membrane fluidity near the hydrophilic surface in erythrocytes treated with higher concentration of naringenin. In the deeper layer, just below the erythrocyte membrane phospholipid heads, both lower and higher concentration of naringenin significantly increased membrane fluidity (p = 0.036 and p = 0.028, respectively). CONCLUSIONS: These data document the positive and dose dependent effect of naringenin on near surface membrane fluidity in human erythrocytes, recommending its use in the cardiovascular conditions characterized by disturbed hemodynamics. PMID- 26100303 TI - Organotypic tissue culture investigation of homocysteine thiolactone cardiotoxic effect. AB - Homocysteine thiolactone was demonstrated to inhibit the growth of 10-12-day-old chicken embryo cardiac tissue explants at 7 * 10-9 -1 * 10-3 M concentrations in a dose-dependent manner. The maximal cardiotoxic effect of homocysteine thiolactone was detected at 1 * 10-3 M, which corresponds to severe hyperhomocysteinemia. The results of experiments on culturing of cardiac tissue explants in the medium containing homocysteine thiolactone (1 * 10-3 M) and ouabain at concentrations regulating the signal-transducing (1 * 10-10 M) and pumping (1 * 10-8 M) functions of Na+,K+ -ATPase indicate that the cardiotoxic effect of homocysteine thiolactone is supposed to result from inhibition of the Na+,K+ -ATPase pumping function. PMID- 26100305 TI - The effect of subchronic supplementation with folic acid on homocysteine induced seizures. AB - Influence of folic acid on the CNS is still unclear. Folate has a neuroprotective effect, while on the other hand excess folate can exacerbate seizures in epileptics. The aim of the present study was to examine the effect of subchronic administration of folic acid on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone induced seizures in adult rats. The activity of Na+/K+-ATPase and Mg2+-ATPase in different brain regions was investigated. Adult male Wistar rats were divided into groups: 1. Controls (C, 0.9% NaCl); 2. DL homocysteine-thiolactone 8.0 mmol/kg (H); 3. Subchronic supplementation with folic acid 5 mg/kg for 7 days (F) and 4. Subchronic supplementation with F + single dose of H (FH). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. For EEG recordings, three gold-plated recording electrodes were implanted into the skull. Subchronic supplementation with folic acid did not affect seizure incidence, median number of seizure episodes and severity in FH, comparison with H (p > 0.05). The majority of seizure episodes in all groups were of grade 2. There were no significant differences in lethal outcomes at 24 h upon H injection in the FH vs. H group. The activity of Na+/K+-ATPase and Mg2+-ATPase was significantly increased in almost all examined structures in the FH vs. H group. Subchronic folic acid administration did not exacerbate H induced seizures and completely recovered the activity of ATPases. PMID- 26100304 TI - Iron concentrations in atherosclerotic plaque and serum in patients with carotid atherosclerosis. AB - The aim of this study was to investigate the iron concentrations in serum and carotid plaque in patients with different morphology of carotid atherosclerotic plaque and compared with other metal ions. Carotid endarterectomy due to the significant atherosclerotic stenosis was performed in 91 patients. Control group consisted of 27 patients, without carotid atherosclerosis. Atherosclerotic plaques were divided into four morphological groups, according to ultrasonic and intraoperative characteristics. Iron, copper and zinc concentration in plaque, carotid artery and serum were measured by spectrophotometry. Serum iron concentrations were higher in patients with hemorrhagic plaques in comparison to the control group (4.7 MUmol/l +/- 1.2 vs. 2.1 MUmol/l +/- 0.8, p < 0.05). Iron concentrations were higher in patients with hemorrhagic plaques in comparison to fibrolipid plaques (72.1 +/- 14.3 MUg/g vs. 39.3 +/- 22.9 MUg/g; p < 0.05). Negative significant correlation was found for zinc in serum and plaque iron concentration in patients (p < 0.05). We also demonstrated positive significant correlation for copper and iron in serum (p < 0.05). The data obtained in the current study are consistent with the hypothesis that high iron levels may contribute to atherosclerosis and its complications as factors in a multifactorial disease. PMID- 26100306 TI - Mechanisms to dyspnoea and dynamic hyperinflation related exercise intolerance in COPD. AB - Expiratory flow limitation can develop in parallel with the progression of COPD, and as a consequence, dynamic hyperinflation and lung mechanical abnormalities can develop. Dynamic hyperinflation can cause increased breathlessness and reduction in exercise tolerance. Achievement of critical inspiratory reserve volume is one of the main factors in exercise intolerance. Obesity has specific lung mechanical effects. There is also a difference concerning gender and dyspnoea. Increased nerve activity is characteristic in hyperinflation. Bronchodilator therapy, lung volume reduction surgery, endurance training at submaximal intensity, and heliox or oxygen breathing can decrease the degree of dynamic hyperinflation. PMID- 26100307 TI - Assessment of heat provocation tests on the human gingiva: the effect of periodontal disease and smoking. AB - Periodontal inflammation is associated with morphological changes in the blood vessels which may influence the regulation of gingival blood flow (GBF). Our aim was to adapt the heat provocation test to the human gingiva to assess vascular reactivity in periodontal inflammation. METHOD: GBF was recorded by Laser Doppler Flowmetry before and after heat provocation in healthy volunteers (n = 50). Heat was generated either by warm saline or a halogen lamp. The latter method was also utilized for a heat test in non-smoking and smoking patients with periodontal inflammation. The circulatory parameters were correlated to the inflammatory marker, i.e. gingival crevicular fluid (GCF) production measured by Periotron. RESULTS: Local application of heat caused a rapid, significant and transient increase in GBF regardless of the method used. The increase in the speed and not in the concentration of moving blood cells was responsible for increased GBF. Higher GCF values were correlated with increased peak flow, flux pulse amplitude and faster restoration of GBF after the test in non-smokers, but not in smokers. CONCLUSIONS: The heat test could be a valuable tool to check the vascular reactivity of gingival vessels. Moderate periodontal inflammation may facilitate gingival vascular responsiveness which can be suppressed by smoking. PMID- 26100308 TI - Coherence between tissue oxygen indexes in vastus lateralis and gastrocnemius in repetition of impulse exercise with high intensity. AB - The purpose of this study was to determine whether tissue oxygen indices (TOIs) in two muscle groups oscillated and were synchronized in repetition of impulse exercise with high intensity. Five impulse exercises of 400 watts for 10 s were repeated with intervals of 6 min. During this period, TOI was determined by near infrared spectroscopy in the vastus lateralis and gastrocnemius muscles. TOIs in the two muscles oscillated at rest. The TOIs rapidly decreased during each impulse exercise and then recovered and overshot after each impulse. The TOIs oscillated during each interval period. During this test period, coherent and phase differences were determined. There was high coherence between TOIs in the two muscles with a peak value at 0.019 Hz. There was a phase difference of -45 +/ 32.4 degrees between TOIs in the two muscles. This phase difference corresponded to about 6 s in time scale. It seemed from this time delay that impulse exercise was not a trigger factor for the starting point of TOIs in the two muscles. It has been concluded that TOIs oscillate and are synchronized between two muscles in repetition of impulse exercise with high intensity. PMID- 26100309 TI - Correlations between three-dimensional speckle-tracking echocardiography-derived left atrial functional parameters and aortic stiffness in healthy subjects - Results from the MAGYAR-Healthy Study. AB - Left atrial (LA) distension has been demonstrated to be linked with aortic stiffness in different patient populations. Three-dimensional (3D) speckle tracking echocardiography (STE) seems to be a promising tool for volumetric and functional evaluation of the LA. The aim of the present study was to determine whether correlations exist between 3DSTE-derived LA volume-based and strain parameters characterizing all phasic functions of the LA and echocardiographic aortic elastic properties in healthy subjects. The study included 19 healthy volunteers (mean age: 37.9 +/- 11.4 years, 11 men) who had undergone complete two dimensional (2D) Doppler transthoracic echocardiography extended with the assessment of aortic elastic properties and 3DSTE. RESULTS: None of LA volumes correlated with echocardiographic aortic elastic properties. Active atrial stroke volume correlated with aortic stiffness index (ASI, r = 0.45, p = 0.05). None of other volume-based functional properties significantly correlated with aortic stiffness parameters. Global peak 3D strain correlated with aortic strain (r = 0.46, p = 0.05). global radial pre-atrial contraction strain correlated with ASI (r = -0.49, p = 0.04) and AS (r = -0.50, p = 0.04). CONCLUSIONS: Correlations exist between 3DSTE-derived LA functional parameters and eschocardiographic aortic elastic properties in healthy subjects. PMID- 26100310 TI - Prediction of myocardial tissue loss by quantitative densitometric myocardial blush parameters following ST-elevation myocardial infarction. AB - Tissue level myocardial perfusion is one of the most important prognostic factors after successful recanalisation of the occluded coronary artery in patients suffering acute ST elevation myocardial infarction (STEMI). The primary objective of the present study was to examine the relationship between videodensitometric myocardial perfusion parameters as assessed on coronary angiograms directly following successful recanalization therapy and magnetic resonance imaging (MRI) derived myocardial tissue loss late after STEMI. The study comprised 29 STEMI patients. Videodensitometric parameter G(max)/T(max) was calculated to characterize myocardial perfusion, derived from the plateau of grey-level intensity (G(max)), divided by the time-to-peak intensity (Tmax). Myocardial loss index (MLI) was assessed by cardiac MRI following 376 +/- 254 days after PCI. RESULTS: Significant correlations could be demonstrated between MLI and G(max) (r = 0.36, p = 0.05) and G(max)/T(max) (r = 0.40, p = 0.03) using vessel masking. Using receiver operating characteristic curve analysis, G(max)/T(max) < 2.17 predicted best MLI = 0.3, 0.4, 0.5 and 0.6 with good sensitivity and specificity data, while G(max)/T(max) < 3.25 proved to have a prognostic role in the prediction of MLI = 0.7. CONCLUSIONS: Selective myocardial tissue level perfusion quantitative measurement method is feasible and can serve as a good predictor of myocardial tissue loss following STEMI and revascularization therapy. PMID- 26100311 TI - Altered mitochondrial response to activation of T-cells in neonate. AB - Mitochondrial functions have a major impact on T-cell functionality. In this study we characterized whether mitochondrial function in the neonatal T-cells differs from that in the adult T-cells during short T-cell activation. METHODS: We used flow cytometry methods to test mitochondrial mass and to monitor mitochondrial Ca2+ levels, mitochondrial potential and superoxide generation in parallel with cytoplasmic Ca2+ levels during phythohaemagglutinine-induced activation of CD4+ and CD8+ T-cells of 12 term neonates and 11 healthy adults. RESULTS: Baseline mitochondrial mass of CD4+ and CD8+ cells was lower in the neonate than in the adult. In comparison with the adult, neonatal resting CD4+ T cells had lower cytoplasmic Ca2+ levels and this was associated with normal activation induced Ca2+-response. During short-term activation cytoplasmic Ca2+ response was lower in neonatal than in adult CD8+ T-cells. Mitochondrial Ca2+ uptake was increased in CD4+ neonatal T cells while it decreased in CD8+ T-cells. Mitochondrial depolarization was increased in CD4+ and decreased in CD8+ neonatal T-cells compared to adults. Superoxide generation was higher and equal in neonatal CD4+ and CD8+ cells, respectively, compared to the adult ones. CONCLUSION: Our data suggest that neonatal T-cells exhibit marked differences in mitochondrial function and superoxide generation compared to adult T-cells. PMID- 26100312 TI - Prevalence of physiological and pathological electrocardiographic findings in Hungarian athletes. AB - In Hungary, ECG is a keystone of routine athletic screening. Its significance is based on simplicity, quickness and high informative value as well as the fact that appearance of pathological ECG signs can precede the formation of structural heart diseases. During screening of healthy athletes, we studied the incidence of athletic ECG changes and pathological ECG abnormalities. METHODS: We performed detailed analysis of 12-lead ECG recordings of asymptomatic elite, non-elite and master athletes and controls. RESULTS: 227 athletes (male: 180, age: 27.2 +/- 8.7 years) and 89 controls (male: 57, age: 28.1 +/- 6.8 years) were examined. Benign ECG signs: sinus bradycardia, early repolarization and isolated Voltage criteria of left ventricular hypertrophy were common and more often in athletes compared to controls. Potentially pathological ECG signs: ST- (6.6% vs. 1.1%, p < 0.05) and T-wave (15.0% vs. 5.6%, p < 0.05) changes and signs of pathological left ventricular hypertrophy (5.3% vs. 0%, p < 0.05) occurred more frequently in athletes compared to controls. CONCLUSIONS: Signs of pathological left ventricular hypertrophy and repolarization abnormalities are more often in athletes. No structural heart disease could be verified in the background of the disorders. However, athletes having pathological ECG should be kept under tight cardiology control. Exact definition and widespread knowledge of pathological ECG changes is essential in early recognition of high risk athletes. PMID- 26100313 TI - Estrogenic regulation of bicarbonate transporters from SLC4 family in rat Sertoli cells. AB - The formation of competent spermatozoa is a complex event that depends on the establishment of adequate environments throughout the male reproductive tract. Bicarbonate is essential not only to ionic homeostasis but also to pH maintenance along the male reproductive tract. Previous studies support an association of high 17beta-estradiol (E2) levels with modulation of specific ion transporters expression. Herein we determined the effect of E2 on the expression/functionality of SLC4 family bicarbonate transporters in rat Sertoli cells (SCs). All studied transporters [anion exchanger 2 (AE2), Na(+)-driven Cl(-)/HCO3 (-) exchanger (NDCBE), electrogenic Na(+)/HCO3 (-) co-transporters (NBCe1), and electroneutral Na(+)/HCO3 (-) co-transporters (NBCn1)] were identified in SCs, being AE2 and NBCn1 the most abundant. In E2-treated cells (100 nM), increases in AE2 and NBCn1 protein levels were observed, as well as altered transcellular transport. E2 treated SCs presented a significant perturbation of ATP-induced short-circuit current. This alteration was concurrent with augmented AE2 and NBCn1 levels. Overall, we report a relation between increased E2 levels and the expression/function of AE2 and NBCn1 in rat SCs, providing new evidence on the mechanisms by which E2 can regulate SCs physiology and consequently spermatogenesis, with direct influence on male reproductive potential. PMID- 26100314 TI - Effects of ageing on metabolite and oxidant concentrations in different regions of rat kidney under normal and stress conditions. AB - Metabolic and oxidative stresses have been implicated in ageing and the pathogenesis of chronic kidney disease. In this study, we investigated the glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and lactate concentrations in different kidney regions under control conditions and after exposure to oxidative stress invoked by 0.2 mM H2O2. Slices of superficial cortex, outer or inner medulla were dissected from kidneys of male Wistar rats of 5-, 12-, 36- and 60-week old. Samples were incubated for 30 min +/- 0.2 mM H2O2 prior to homogenisation and centrifugation. The concentrations of GSH, TBARS and lactate were measured by colorimetry. Each metabolite showed a distinctive pattern. For GSH, this was 12 weeks > 36 weeks > 60 weeks and 5 weeks with the highest concentration measured in the superficial cortex at 12 weeks. For TBARS and lactate, the pattern was for the lowest concentration at 12 weeks and the highest at 60 and 5 weeks. The highest lactate and TBARS concentrations were measured under oxidative stress conditions, particularly at 5 and 60 weeks. These results suggest that GSH in different kidney regions peaks at maturity and then reduces with increasing age. PMID- 26100315 TI - Immunomodulatory properties of the IL-6 cytokine family in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic disabling autoimmune disease of the central nervous system. The interleukin (IL)-6 cytokine family plays a crucial role in regulating the immune response in MS. All members of the IL-6 family share the common signal-transducing receptor protein, glycoprotein 130. Although the intracellular signaling of these cytokines seems to be largely overlapping, they have diverse and contrasting effects on the immune response. This review focuses on the effects of the family members IL-6, leukemia inhibitory factor, oncostatin M, and IL-11 on immune cell subsets and how these effects relate to the pathogenesis of MS. Finally, we propose possible avenues to modulate these family members for future MS therapy. PMID- 26100316 TI - The course and distribution of the infra patellar nerve in relation to ACL reconstruction. AB - INTRODUCTION: A common complication after ACL (anterior cruciate ligament reconstruction) is injury to the infra-patellar branch of the saphenous nerve (IPBSN). Very little about its origin and course of this nerve has been described. The aim of this study was to understand the course of IPBSN in relation to surgery around the knee. MATERIALS AND METHOD: The course of the nerve was dissected and traced in 25 knees from 14 cadaveric knees (10 males; four females). An incision was made posterior to the medial condyle of the tibia and continued deeper towards the saphenous nerve which is located under the sartorius muscle. The saphenous nerve branch was then followed to distally supply the anterior leg (IPBSN). The relationship of saphenous nerve and IPBSN to each other and the hamstrings were recorded. RESULTS: Four paths of IPBSN, in relation to the sartorius muscle, were identified: (1) posterior--inferior posterior border of the muscle, (2) transmuscular--penetrating through the muscle, (3) anterior--anterior border of the muscle, (4) posterior patellar--posterior of the muscle at the level of the patellar bone and (5) combined. The posterior pathway of IPSBN was the most common (57%) and had the closest proximity to the tendons of semitendinosus and gracilis muscles. The terminal branches of the IPSBN crossed over the patellar tendon in every dissection. CONCLUSIONS: A posterior path IPBSN is more prone to damage during a tendon harvest due to its proximity to the gracilis and semitendinosus muscle tendons. PMID- 26100317 TI - Comprehensive assessment of patellar morphology using computed tomography-based three-dimensional computer models. AB - BACKGROUND: The objectives of this study were to assess patellar morphology using computed tomography-based three-dimensional computer models and to determine the utility of the subchondral method for patellar resection in total knee arthroplasty (TKA). METHODS: Overall, 120 subjects (60 males, 60 females) from 20 to 50 years old were included. Computer tomography images were used to construct 3D computer models of 240 knees. An anthropometric analysis of variance was used with the models to detect differences between the sides, age groups, and genders. RESULTS: Based on the available numbers, there were significant gender differences in the patellar length, width, and thickness even with strict control for the height and weight of the patients. The average patellar width/thickness ratio was 1.95, regardless of gender, and there was a good correlation between the patellar width and thickness (male: r=0.68, p<0.01; female: r=0.75, p<0.01). After using the subchondral method to virtually resect the patellae, the mean thickness for males and female was 14.0mm and 12.3mm, respectively. The proportion of the residual bony thickness that was less than 12 mm was 5.83% (seven cases) in the male group and up to 42.5% (51 cases) in the female group. There was excellent intra-observer reliability and inter-observer reliability regarding the dimensional measurements in this study. CONCLUSIONS: A robust method of measuring and virtually resecting the patella was established. The anthropometric dimensions of this study could provide basic data for guiding surgical management of the patella in TKA and are useful in designing patellar implants. CLINICAL RELEVANCE: The anthropometric patellar information is essential for surgeons to perform patellar resurfacing in TKA. PMID- 26100319 TI - Protection of Lactobacillus acidophilus NRRL-B 4495 under in vitro gastrointestinal conditions with whey protein/pullulan microcapsules. AB - In this research, whey protein/pullulan (WP/pullulan) microcapsules were developed in order to assess its protective effect on the viability of Lactobacillus acidophilus NRRL-B 4495 under in vitro gastrointestinal conditions. Results demonstrated that WP/pullulan microencapsulated cells exhibited significantly (p <= 0.05) higher resistance to simulated gastric acid and bile salt. Pullulan incorporation into protein wall matrix resulted in improved survival as compared to free cells after 3 h incubation in simulated gastric solution. Moreover WP/pullulan microcapsules were found to release over 70% of encapsulated L. acidophilus NRRL-B 4495 cells within 1 h. The effect of encapsulation during refrigerated storage was also studied. Free bacteria exhibited 3.96 log reduction while, WP/pullulan encapsulated bacteria showed 1.64 log reduction after 4 weeks of storage. PMID- 26100318 TI - New compounds, nanaomycin F and G, discovered by physicochemical screening from a culture broth of Streptomyces rosa subsp. notoensis OS-3966. AB - Two new compounds, nanaomycin F and G, were isolated by physicochemical screening method from cultured broth of Streptomyces rosa subsp. notoensis OS-3966, which is known to produce nanaomycin A, B, C, D, and E. Nanaomycin F is a new nanaomycin analog, a 4a-hydroxyl analog of nanaomycin B. Nanaomycin G has a unique skeleton with 1-indanone infused with a tetrahydropyran ring. Nanaomycin A possesses broad antimicrobial activity but nanaomycin F and G demonstrated no bioactivity against all bacteria and fungi tested in this study. In addition, in both nanaomycin F and G, the production of superoxide radicals was majorly decreased in comparison to nanaomycin A. It was considered that the antimicrobial properties were lost as a result of the decrease in production of the superoxide radicals. PMID- 26100320 TI - Simple and efficient isolation of cordycepin from culture broth of a Cordyceps militaris mutant. AB - Isolation of cordycepin from the culture broth of Cordyceps militaris mutant was investigated. Based on the solubility curve, three crystallizing processes, temperature shift (process I), pH shift (process II), and pH shift followed by temperature shift (process III) were carried out. Process III was the most promising method regarding both purity and yield. PMID- 26100322 TI - The isolation and characterization of the novel chlorothalonil-degrading strain Paracoccus sp. XF-3 and the cloning of the chd gene. AB - Chlorothalonil (CTN) is one of the most widely used fungicides and is often detected in the environment. Here, we report the isolation and characterization of a novel CTN-degrading bacterial strain XF-3 from long-term CTN-contaminated sites and identify it as a strain of the Paracoccus sp. The isolate could utilise CTN as the sole source of carbon and energy for growth. The optimal pH and temperature for degradation by XF-3 were 7.0 and 30 degrees C, respectively. The CTN degradation gene was cloned by PCR. Although the results of a BLAST sequence search indicated that this gene has a 99% similarity with chd (a gene encoding the CTN hydrolytic dehalogenase), its hydrolytic efficiency for CTN was slightly greater than the chd from strain CTN-3. This is the first report of this gene from the genus Paracoccus. Therefore, there is a practical significance and a potential value of the isolated novel strain, XF-3. PMID- 26100321 TI - Effects of recombinant lycopene dietary supplement on the egg quality and blood characteristics of laying quails. AB - This study was conducted to determine the effect of dietary supplement of bacterial lycopene (BL) produced by Escherichia coli on the egg quality and blood characteristics of laying quails. The antioxidant activity measurement showed that BL exhibited 100% 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging capacity at a concentration of 4.65 MUg/ml, which was more effective than butylated hydroxytoluene (BHT) and commercial lycopene (CL). Moreover, seven dietary groups of laying quails consisting of 10 100-day-old quails (Coturnix coturnix japonica) each were fed with the basal diet supplemented with BL, CL or canthaxanthin (CA) for 4 weeks. Consequently, the triglyceride content of yolk was significantly lower in the group with BL and CL supplement. The serum malondialdehyde (MDA) level of the BL- and CA-supplemented groups at 18 mg/kg was lower than the control group. In conclusion, BL has a high antioxidant activity and is promising as a feed additive in the diet of laying quails. PMID- 26100323 TI - Application of lead isotopic methods to the study of the anthropogenic lead provenance in Spanish overbank floodplain deposits. AB - Changes in the principal sources of Pb in overbank sediment profiles have been documented for two Spanish areas by using Pb isotopes and Pb concentrations. These locations (Madrid and Tinto-Odiel basin) represent two of the most contaminated regions in Spain. The Community of Madrid is characterized by heavy industrial and urban activity, focused mainly in Madrid City. The Tinto-Odiel basin drains the Iberian Pyrite Belt, which hosts many polymetallic massive sulphides and is heavily affected by mining activities in their headwaters. It has been proven that the influence of anthropogenic activity is reflected in these overbank deposits by variations in Pb concentrations that, in general, correlate with shifts in the (206)Pb/(207)Pb ratio. Rivas profile (downstream of Madrid) was found to be the most anthropogenically influenced site. The sediments within this profile which were recently deposited (170 +/- 40 years BP) have the least radiogenic signatures. (206)Pb/(207)Pb ratios ranged between 1.1763 and 1.1876 indicating significant contributions of anthropogenic Pb. In contrast, profiles upstream of Madrid possess an average (206)Pb/(207)Pb ratio of 1.2272. It is difficult to clearly identify the most prominent source as the sediments appear to be characterized by an input from several sources. The floodplain profiles in the Tinto-Odiel basin exhibit uniform (206)Pb/(207)Pb ratios ranging from 1.1627 (Odiel river) to 1.1665 (Tinto river). These ratios are similar to the ones possessed by sulphide ores in the area and differ from the ratios of other nonmineralized formations in the basin, indicating that mining activities are the primary, if not sole, source of Pb to the sediments. PMID- 26100324 TI - High soil and groundwater arsenic levels induce high body arsenic loads, health risk and potential anemia for inhabitants of northeastern Iran. AB - Arsenic bioavailability in rock, soil and water resources is notoriously hazardous. Geogenic arsenic enters the body and adversely affects many biochemical processes in animals and humans, posing risk to public health. Chelpu is located in NE Iran, where realgar, orpiment and pyrite mineralization is the source of arsenic in the macroenvironment. Using cluster random sampling strategy eight rocks, 23 soils, 12 drinking water resources, 36 human urine and hair samples and 15 adult sheep urine and wool samples in several large-scale herds in the area were randomly taken for quantification of arsenic in rock/soil/water, wool/hair/urine. Arsenic levels in rock/soil/water and wool/hair/urine were measured using inductively coupled plasma spectroscopy and atomic absorption spectrophotometry, respectively. While arsenic levels in rocks, soils and water resources hazardously ranged 9.40-25,873.3 mg kg(-1), 7.10-1448.80 mg kg(-1) and 12-606 MUg L(-1), respectively, arsenic concentrations in humans' hair and urine and sheep's wool and urine varied from 0.37-1.37 MUg g(-1) and 9-271.4 MUg L(-1) and 0.3-3.11 MUg g(-1) and 29.1-1015 MUg L(-1), respectively. Local sheep and human were widely sick and slightly anemic. Hematological examination of the inhabitants revealed that geogenic arsenic could harm blood cells, potentially resulting in many other hematoimmunological disorders including cancer. The findings warn widespread exposure of animals and human in this agroecologically and geopolitically important region (i.e., its proximity with Afghanistan, Pakistan and Turkmenistan) and give a clue on how arsenic could induce infectious and non-infectious diseases in highly exposed human/animals. PMID- 26100325 TI - Chemically modified biochar produced from conocarpus waste increases NO3 removal from aqueous solutions. AB - Biochar has emerged as a universal sorbent for the removal of contaminants from water and soil. However, its efficiency is lower than that of commercially available sorbents. Engineering biochar by chemical modification may improve its sorption efficiency. In this study, conocarpus green waste was chemically modified with magnesium and iron oxides and then subjected to thermal pyrolysis to produce biochar. These chemically modified biochars were tested for NO3 removal efficiency from aqueous solutions in batch sorption isothermal and kinetic experiments. The results revealed that MgO-biochar outperformed other biochars with a maximum NO3 sorption capacity of 45.36 mmol kg(-1) predicted by the Langmuir sorption model. The kinetics data were well described by the Type 1 pseudo-second-order model, indicating chemisorption as the dominating mechanism of NO3 sorption onto biochars. Greater efficiency of MgO-biochar was related to its high specific surface area (391.8 m(2) g(-1)) and formation of strong ionic complexes with NO3. At an initial pH of 2, more than 89 % NO3 removal efficiency was observed for all of the biochars. We conclude that chemical modification can alter the surface chemistry of biochar, thereby leading to enhanced sorption capacity compared with simple biochar. PMID- 26100326 TI - Radon in indoor air of primary schools: determinant factors, their variability and effective dose. AB - Radon is a radioactive gas, abundant in granitic areas, such as in the city of Porto at the north-east of Portugal. This gas is a recognized carcinogenic agent, being appointed by the World Health Organization as the leading cause of lung cancer after smoking. The aim of this preliminary survey was to determine indoor radon concentrations in public primary schools, to analyse the main factors influencing their indoor concentration levels and to estimate the effective dose in students and teachers in primary schools. Radon concentrations were measured in 45 classrooms from 13 public primary schools located in Porto, using CR-39 passive radon detectors for about 2-month period. In all schools, radon concentrations ranged from 56 to 889 Bq/m(3) (mean = 197 Bq/m(3)). The results showed that the limit of 100 Bq/m(3) established by WHO IAQ guidelines was exceeded in 92 % of the measurements, as well as 8 % of the measurements exceeded the limit of 400 Bq/m(3) established by the national legislation. Moreover, the mean annual effective dose was calculated as 1.25 mSv/y (ranging between 0.58 and 3.07 mSv/y), which is below the action level (3-10 mSv). The considerable variability of radon concentration observed between and within floors indicates a need to monitor concentrations in several rooms for each floor. A single radon detector for each room can be used, provided that the measurement error is considerably lower than variability of radon concentration between rooms. The results of the present survey will provide useful baseline data for adopting safety measures and dealing effectively with radiation emergencies. In particular, radon remediation techniques should be used in buildings located in the highest radon risk areas of Portugal. The results obtained in the current study concerning radon levels and their variations will be useful to optimize the design of future research surveys. PMID- 26100328 TI - Commentary on "Racial variation in the quality of surgical care for bladder cancer." Barocas DA, Alvarez J, Koyama T, Anderson CB, Gray DT, Fowke JH, You C, Chang SS, Cookson MS, Smith JA Jr, Penson DF, Department of Urologic Surgery, Vanderbilt University, Nashville, Tennessee; Center for Surgical Quality and Outcomes Research, Vanderbilt University, Nashville, Tennessee.: Cancer. 2014 Apr 1;120(7):1018-25. doi:10.1002/cncr.28520. [Epub 2013 Dec 11]. AB - BACKGROUND: Differences in quality of care may contribute to racial variation in outcomes of bladder cancer (BCa). Quality indicators in patients undergoing surgery for BCa include the use of high-volume surgeons and high-volume hospitals, and, when clinically indicated, receipt of pelvic lymphadenectomy, receipt of continent urinary diversion, and undergoing radical cystectomy instead of partial cystectomy. The authors compared these quality indicators as well as adverse perioperative outcomes in black patients and white patients with BCa. METHODS: The Healthcare Cost and Utilization Project State Inpatient Databases for New York, Florida, and Maryland (1996-2009) were used, because they consistently included race, surgeon, and hospital identifiers. Quality indicators were compared across racial groups using regression models adjusting for age, sex, Elixhauser comorbidity sum, insurance, state, and year of surgery, accounting for clustering within hospital. RESULTS: Black patients were treated more often by lower volume surgeons and hospitals, they had significantly lower receipt of pelvic lymphadenectomy and continent diversion, and they experienced higher rates of adverse outcomes compared with white patients. These associations remained significant for black patients who received treatment from surgeons and at hospitals in the top volume decile. CONCLUSIONS: Black patients with BCa had lower use of experienced providers and institutions for BCa surgery. In addition, the quality of care for black patients was lower than that for whites even if they received treatment in a high-volume setting. This gap in quality of care requires further investigation. PMID- 26100327 TI - Magnetic Resonance Imaging-Ultrasound Fusion Targeted Prostate Biopsy in a Consecutive Cohort of Men with No Previous Biopsy: Reduction of Over Detection through Improved Risk Stratification. AB - PURPOSE: MRF-TB (magnetic resonance imaging-ultrasound fusion targeted prostate biopsy) may improve the detection of prostate cancer in men presenting for prostate biopsy. We report clinical outcomes of 12-core systematic biopsy and MRF TB in men who presented for primary biopsy and further describe pathological characteristics of cancers detected by systematic biopsy and not by MRF-TB. MATERIALS AND METHODS: Clinical outcomes of 452 consecutive men who underwent prebiopsy multiparametric magnetic resonance imaging followed by MRF-TB and systematic biopsy at our institution between June 2012 and June 2015 were captured in an institutional review board approved database. Clinical characteristics, biopsy results and magnetic resonance imaging suspicion scores were queried from the database. RESULTS: Prostate cancer was detected in 207 of 382 men (54.2%) with a mean+/-SD age of 64+/-8.5 years and mean+/-SEM prostate specific antigen 6.8+/-0.3 ng/ml who met study inclusion criteria. The cancer detection rate of systematic biopsy and MRF-TB was 49.2% and 43.5%, respectively (p=0.006). MRF-TB detected more Gleason score 7 or greater cancers than systematic biopsy (117 of 132 or 88.6% vs 102 of 132 or 77.3%, p=0.037). Of 41 cancers detected by systematic biopsy but not by MRF-TB 34 (82.9%) demonstrated Gleason 6 disease, and 26 (63.4%) and 34 (82.9%) were clinically insignificant by Epstein criteria and a UCSF CAPRA (University of California-San Francisco-Cancer of the Prostate Risk Assessment) score of 2 or less, respectively. CONCLUSIONS: In men presenting for primary prostate biopsy MRF-TB detects more high grade cancers than systematic biopsy. Most cancers detected by systematic biopsy and not by MRF-TB are at clinically low risk. Prebiopsy magnetic resonance imaging followed by MRF-TB decreases the detection of low risk cancers while significantly improving the detection and risk stratification of high grade disease. PMID- 26100329 TI - [Patient's care and management of dyslipidemia at discharge after an acute coronary syndrome in the clinical practice in Spain: The SINCOPA study]. AB - INTRODUCTION: European guidelines acknowledge that patients with an acute coronary syndrome (ACS) should have LDLc levels below 70mg/dL or reduced a 50% respect to their basal levels. However, some studies demonstrated that this goal is achieved in a small number of patients. The aim of this study was to determine how cardiologists (MC) and primary care specialist (GPs) from Spain manage LDLc in ACS patients during their daily practice. METHODS: An observational, cross sectional, multicentric study was conducted. Information about daily practice was obtained from 291 MC and 564 GPs across Spain. RESULTS: 68% of MC and 67% of GPs considered ACS patients to be high-risk. Most consider the cLDL targets based on European guidelines. The statins most widely used for MC are atorvastatin and rosuvastatina and for GPs are atorvastatin and simvastatin. 66.4% of GPs follow the prescription of MC. 42% of MC and 19.9% of GPs considered that 75-100% of their patients achieved the LDLc target. The main reason of not achieving this target was lack of treatment adherence. CONCLUSIONS: The lack of adherence and poor perception of real LDLc control may contribute to the failure in achieving lipid targets in ACS patients. PMID- 26100330 TI - Universal far-from-equilibrium dynamics of a holographic superconductor. AB - Symmetry-breaking phase transitions are an example of non-equilibrium processes that require real-time treatment, a major challenge in strongly coupled systems without long-lived quasiparticles. Holographic duality provides such an approach by mapping strongly coupled field theories in D dimensions into weakly coupled quantum gravity in D+1 anti-de Sitter spacetime. Here we use holographic duality to study the formation of topological defects-winding numbers-in the course of a superconducting transition in a strongly coupled theory in a 1D ring. When the system undergoes the transition on a given quench time, the condensate builds up with a delay that can be deduced using the Kibble-Zurek mechanism from the quench time and the universality class of the theory, as determined from the quasinormal mode spectrum of the dual model. Typical winding numbers deposited in the ring exhibit a universal fractional power law dependence on the quench time, also predicted by the Kibble-Zurek Mechanism. PMID- 26100331 TI - Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1. AB - Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot Marie-Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways. PMID- 26100332 TI - Influencing factors of immediate angiographic results in intracranial aneurysms patients after endovascular treatment. AB - The purpose of this study was to analyze influencing factors associated with immediate angiographic results in intracranial aneurysms patients after endovascular treatment (EVT), providing theoretical evidence and guidance for clinical treatment of intracranial aneurysms. Totally 529 patients met the inclusive criteria, consisting of 338 males and 191 females. Gender; age; history of hypertension, diabetes, and smoking; intracranial atherosclerosis; rupture status, size and location, features of aneurysmal neck, shapes; vasospasm; treatment modality; and degree of aneurysm occlusion were all carefully and completely recorded. All data were investigated in univariate and multivariate logistic regression model to determine whether they were correlated with the degree of aneurysm occlusion. According to aneurysm size, aneurysms were classified as micro-miniature, miniature, and large aneurysms. There were 451 narrow-neck aneurysms and 78 wide-neck aneurysms. Totally 417 were regular and 112 were irregular. And 125 were un-ruptured aneurysms; 404 were ruptured aneurysms. The modalities of treatment were as follows: embolization with coil (n = 415), stent-assisted coil embolization (n = 89), and balloon-assisted coil embolization (n = 25). Univariate analysis showed that aneurysm size, feature of aneurysm neck, shape, and rupture status might affect the immediate occlusion after EVT. Multivariate logistic regression analysis indicated that ruptured aneurysm, tiny aneurysm, and wide-neck aneurysm were independent influencing factors of complete occlusion of intracranial aneurysm. Aneurysm rupture status, size, feature of aneurysmal neck, and shape might be the independent influencing factors of immediate angiographic results in intracranial aneurysm patients after EVT. Un-ruptured, micro-miniature, narrow-neck, and regular-shaped aneurysms were more probable to be occluded completely. PMID- 26100334 TI - The role of the NG2 proteoglycan in OPC and CNS network function. AB - In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by alpha- and gamma-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only). PMID- 26100333 TI - Effects of co-administration of 2-arachidonylglycerol (2-AG) and a selective u opioid receptor agonist into the nucleus accumbens on high-fat feeding behaviors in the rat. AB - Previous research has demonstrated that the nucleus accumbens is a site where opioids and cannabinoids interact to alter feeding behavior. However, the influence of the endocannabinoid 2-arachidonylglycerol (2-AG) on the well characterized model of intra-accumbens opioid driven high-fat feeding behavior has not been explored. The present experiments examined high-fat feeding associated behaviors produced by the interaction of 2-AG and the MU-opioid receptor agonist DAla(2),N,Me-Phe(4),Gly-ol(5)-enkaphalin (DAMGO) administered into the nucleus accumbens. Sprague-Dawley rats were implanted with bilateral cannulae aimed at the nucleus accumbens and were co-administered both a sub threshold dose of 2-AG (0 or 0.25 MUg/0.5 MUl/side) and DAMGO (0, 0.025 MUg or 0.25 MUg/0.5 MUl/side) in all dose combinations, and in a counterbalanced order. Animals were then immediately allowed a 2h-unrestricted access period to a palatable high-fat diet. Consumption, number and duration of food hopper entries, and locomotor activity were all monitored. DAMGO treatment led to an increase in multiple behaviors, including consumption, duration of food hopper entry, and locomotor activity. However, combined intra-accumbens administration of DAMGO and a subthreshold dose of 2-AG led to a significant increase in number of food hopper entries and locomotor activity, compared to DAMGO by itself. The results confirm that intra-accumbens administration of subthreshold dose of the endogenous cannabinoid 2-AG increases the DAMGO-induced approach and locomotor behaviors associated with high-fat feeding. PMID- 26100336 TI - Effects of propofol and sevoflurane on aquaporin-4 and aquaporin-9 expression in patients performed gliomas resection. AB - Post-operative cerebral edema is a threat for patients performed gliomas resection. Some studies have shown that general anesthesia drugs, such as, propofol had neuroprotective effect. Aquaporin-4 (AQP4) and Aquaporin-9 (AQP9) play an important role in maintaining brain water homeostasis under various conditions. The aim of this study was to compare the effect of propofol or sevoflurane on expression of AQP4 and AQP9 in patients performed gliomas resection. 30 patients performed gliomas resection were included in this study. The patients were randomly divided into two groups: propofol group and sevoflurane group. Fresh human gliomas specimens were obtained and hematoxylin eosin (HE) staining, immunohistochemical staining and Western blot analysis were used for observation of the expression of AQP4 and AQP9. The immunohistochemical staining of the sections showed that the percentage of AQP4 positive cells in the propofol group (14.3+/-4.61%) was significantly lower than that in sevoflurane group (37.3+/-10.01%) (n=15, P<0.05). There was no significant difference in the percentage of AQP9 positive cells in propofol group and sevoflurane group (25.8+/ 2.67 versus 28.1+/-7.81%, n=15, P>0.05). Western blot analysis confirmed the immunohistochemistry results. AQP4 protein level in propofol group was significantly lower than that in sevoflurane group (1.4+/-0.13 versus 1.7+/-0.12, P<0.05). Western blot analysis did not show any difference of expression of AQP9 protein between the propofol group and sevoflurane group (2.0+/-0.13 versus 2.1+/ 0.13, P>0.05, n=6). AQP4 expression was lower in patients of propofol group than that in sevoflurane group. Our results suggested that propofol could inhibit the expression of AQP4. PMID- 26100335 TI - Chronic intermittent ethanol induced axon and myelin degeneration is attenuated by calpain inhibition. AB - Chronic alcohol consumption causes multifaceted damage to the central nervous system (CNS), underlying mechanisms of which are gradually being unraveled. In our previous studies, activation of calpain, a calcium-activated neutral protease has been found to cause detrimental alterations in spinal motor neurons following ethanol (EtOH) exposure in vitro. However, it is not known whether calpain plays a pivotal role in chronic EtOH exposure-induced structural damage to CNS in vivo. To test the possible involvement of calpain in EtOH-associated neurodegenerative mechanisms the present investigation was conducted in a well-established mouse model of alcohol dependence - chronic intermittent EtOH (CIE) exposure and withdrawal. Our studies indicated significant loss of axonal proteins (neurofilament light and heavy, 50-60%), myelin proteins (myelin basic protein, 20-40% proteolipid protein, 25%) and enzyme (2', 3'-cyclic-nucleotide 3' phosphodiesterase, 21-55%) following CIE in multiple regions of brain including hippocampus, corpus callosum, cerebellum, and importantly in spinal cord. These CIE-induced deleterious effects escalated after withdrawal in each CNS region tested. Increased expression and activity of calpain along with enhanced ratio of active calpain to calpastatin (sole endogenous inhibitor) was observed after withdrawal compared to EtOH exposure. Pharmacological inhibition of calpain with calpeptin (25 MUg/kg) prior to each EtOH vapor inhalation significantly attenuated damage to axons and myelin as demonstrated by immuno-profiles of axonal and myelin proteins, and Luxol Fast Blue staining. Calpain inhibition significantly protected the ultrastructural integrity of axons and myelin compared to control as confirmed by electron microscopy. Together, these findings confirm CIE exposure and withdrawal induced structural alterations in axons and myelin, predominantly after withdrawal and corroborate calpain inhibition as a potential protective strategy against EtOH associated CNS degeneration. PMID- 26100339 TI - A fixed-links modeling approach to assess individual differences in the attentional blink: Analysis of behavioral and psychophysiological data. AB - The attentional blink (AB) is a fundamental limitation of the ability to select relevant information from irrelevant information. It can be observed with the detection rate in an AB task as well as with the corresponding P300 amplitude of the event-related potential. In previous research, however, correlations between these two levels of observation were weak and rather inconsistent. A possible explanation of this finding might be that multiple processes underlie the AB and, thus, obscure a possible relationship between AB-related detection rate and the corresponding P300 amplitude. The present study investigated this assumption by applying a fixed-links modeling approach to represent behavioral individual differences in the AB as a latent variable. Concurrently, this approach enabled us to control for additional sources of variance in AB performance by deriving two additional latent variables. The correlation between the latent variable reflecting behavioral individual differences in AB magnitude and a corresponding latent variable derived from the P300 amplitude was high (r=.70). Furthermore, this correlation was considerably stronger than the correlations of other behavioral measures of the AB magnitude with their psychophysiological counterparts (all rs<.40). Our findings clearly indicate that the systematic disentangling of various sources of variance by utilizing the fixed-links modeling approach is a promising tool to investigate behavioral individual differences in the AB and possible psychophysiological correlates of these individual differences. PMID- 26100338 TI - Striatal patch compartment lesions reduce stereotypy following repeated cocaine administration. AB - Stereotypy can be characterized as inflexible, repetitive behaviors that occur following repeated exposure to psychostimulants, such as cocaine (COC). Stereotypy may be related to preferential activation of the patch (striosome) compartment of striatum, as enhanced relative activation of the patch compartment has been shown to positively correlate with the emergence of stereotypy following repeated psychostimulant treatment. However, the specific contribution of the patch compartment to COC-induced stereotypy following repeated exposure is unknown. To elucidate the involvement of the patch compartment to the development of stereotypy following repeated COC exposure, we determined if destruction of this sub-region altered COC-induced behaviors. The neurons of the patch compartment were ablated by bilateral infusion of the neurotoxin dermorphin saporin (DERM-SAP; 17 ng/MUl) into the striatum. Animals were allowed to recover for eight days following the infusion, and then were given daily injections of COC (25mg/kg) or saline for one week, followed by a weeklong drug-free period. Animals were then given a challenge dose of saline or COC, observed for 2h in activity chambers and sacrificed. The number of mu-labeled patches in the striatum were reduced by DERM-SAP pretreatment. In COC-treated animals DERM-SAP pretreatment significantly reduced the immobilization and intensity of stereotypy but increased locomotor activity. DERM-SAP pretreatment attenuated COC-induced c Fos expression in the patch compartment, while enhancing COC-induced c-Fos expression in the matrix compartment. These data indicate that the patch compartment contributes to repetitive behavior and suggests that alterations in activity in the patch vs matrix compartments may underlie to this phenomenon. PMID- 26100340 TI - Reality of a Vaccine in the Prevention and Treatment of Atherosclerosis. AB - Atherosclerosis together with multiple sclerosis, psoriasis and rheumatoid arthritis can be used as examples of chronic inflammatory diseases associated with multifactorial components that evolve over the years. Nevertheless, an important difference between these diseases relies on the fact that atherosclerosis develops from early ages where inflammation dominates the very beginning of the disease. This review highlights the inflammatory nature of atherosclerosis and the role the immune system plays in the process of atherogenesis. Although treatment of atherosclerosis has been for years based on lipid-lowering therapies reducing a series of risk factors, the degree of success has been only limited because cardiovascular complications related to the evolution of atherosclerotic lesions continue to appear in the population worldwide. In this sense, alternative treatments for atherosclerosis have come into play where both innate and adaptive immunity have been proposed to modulate atherosclerosis-associated inflammatory phenomena. When tested for their atheroprotective properties, several immunogens have been studied through passive and active immunization with good results and, therefore, the strategy through vaccination to control the disease has been made possible. Many experimental pre clinical studies demonstrating proof of concept that vaccination using DNA and protein with an effective use of adjuvants and the optimal route of administration now provide a tangible new therapeutic approach that sets the stage for several of these vaccines to be tested in large, randomized, long-term clinical studies. A vaccine ready for human use will only be accomplished through the close association between academia, regulatory government organizations and private industry, allowing the reality of a simple and successful therapy to reduce atherosclerosis and its severe clinical complications. PMID- 26100337 TI - Facilitated glutamate release at Schaffer collateral to CA1 synapses has access to an exclusive population of NMDA receptors. AB - In order to explore short-term facilitation of the Schaffer collateral to CA1 synapse in mouse hippocampal brain slices, we measured the time course of the decay of the peak amplitude of successive EPSCs during progressive MK-801 dependent block (PMDB) of NMDAR responses to paired (R1 and R2) stimuli. We made the unexpected observation that the R2 response exhibited a slower PMDB decay constant than that of the R1 response. This indicated that the facilitated R2 response engages release sites with NMDARs that are protected from opening and consequent MK-801 block during the basal R1 response. We then utilized conditions that affect synaptic glutamate distribution to dissect the components of the distinct PMDB decay constants of the first and second of paired pulses. While extra-synaptic NMDARs and glutamate transporters appear to play only minor roles in the differences of the PMDB decay constant, we showed important roles for the R1 response itself and for glutamate diffusion in determining the PMDB decay constant of R2. We used a simple computational model with realistic parameters that allowed us to predict the time course of R2 decay based on the R1 decay time course. PMID- 26100341 TI - The normative authority of the World Health Organization. AB - The World Health Organization (WHO) was born after the devastation of World War II, as a normative agency endowed with unprecedented constitutional powers. But even as it has achieved stunning successes, such as the eradication of smallpox, it has failed to live up to the exalted expectations of the postwar health and human rights movement - exemplified most recently by its inadequate response to the Ebola epidemic. Our aim is to offer innovative ideas for restoring the Organization to its leadership position by exercising its normative authority, even as it faces a crowded and often chaotic global health architecture. Before doing so, it will be helpful to summarize the main tensions the Organization faces in today's global health landscape. PMID- 26100342 TI - Direct imaging of biological sulfur dioxide derivatives in vivo using a two photon phosphorescent probe. AB - Sulfur dioxide (SO2) and its derivatives sulfite and bisulfite play important roles in biological systems. However, in vivo detection of sulfite/bisulfite remains challenging. In this study, we developed a dinuclear Ir(III) complex (Ir4) as a two-photon phosphorescent probe for sulfite and bisulfite. Ir4 selectively and rapidly responded, with high sensitivity, to sulfite/bisulfite over other bio-related ions and molecules. One-photon and two-photon microscopy images revealed that Ir4 preferentially targeted mitochondria and was capable of imaging biological sulfite/bisulfite levels in vitro and in vivo. In situ sulfite generation in Caenorhabditis elegans was visualized by two-photon excitation real time imaging. Finally, Ir4 was employed to monitor sulfite distribution in rat brain and other tissues. This study is the first report of the direct visualization of SO2 derivatives in vivo. These results provide new insights into the biological importance of SO2. PMID- 26100344 TI - Microstructured dextran hydrogels for burst-free sustained release of PEGylated protein drugs. AB - Hydrogels have gained significant attention as ideal delivery vehicles for protein drugs. However, the use of hydrogels for protein delivery has been restricted because their porous structures inevitably cause a premature leakage of encapsulated proteins. Here, we report a simple yet effective approach to regulate the protein release kinetics of hydrogels through the creation of microstructures, which serve as a reservoir, releasing their payloads in a controlled manner. Microstructured dextran hydrogels enable burst-free sustained release of PEGylated interferon over 3 months without compromising its bioactivity. These hydrogels substantially extend the circulation half-life of PEGylated interferon, allowing for less frequent dosing in a humanized mouse model of hepatitis C. The present approach opens up possibilities for the development of sustained protein delivery systems for a broad range of pharmaceutical and biomedical applications. PMID- 26100343 TI - Simple coating with fibronectin fragment enhances stainless steel screw osseointegration in healthy and osteoporotic rats. AB - Metal implants are widely used to provide structural support and stability in current surgical treatments for bone fractures, spinal fusions, and joint arthroplasties as well as craniofacial and dental applications. Early implant bone mechanical fixation is an important requirement for the successful performance of such implants. However, adequate osseointegration has been difficult to achieve especially in challenging disease states like osteoporosis due to reduced bone mass and strength. Here, we present a simple coating strategy based on passive adsorption of FN7-10, a recombinant fragment of human fibronectin encompassing the major cell adhesive, integrin-binding site, onto 316 grade stainless steel (SS). FN7-10 coating on SS surfaces promoted alpha5beta1 integrin-dependent adhesion and osteogenic differentiation of human mesenchymal stem cells. FN7-10-coated SS screws increased bone-implant mechanical fixation compared to uncoated screws by 30% and 45% at 1 and 3 months, respectively, in healthy rats. Importantly, FN7-10 coating significantly enhanced bone-screw fixation by 57% and 32% at 1 and 3 months, respectively, and bone-implant ingrowth by 30% at 3 months compared to uncoated screws in osteoporotic rats. These coatings are easy to apply intra-operatively, even to implants with complex geometries and structures, facilitating the potential for rapid translation to clinical settings. PMID- 26100345 TI - Regeneration inducers in limb regeneration. AB - Limb regeneration ability, which can be observed in amphibians, has been investigated as a representative phenomenon of organ regeneration. Recently, an alternative experimental system called the accessory limb model was developed to investigate early regulation of amphibian limb regeneration. The accessory limb model contributed to identification of limb regeneration inducers in urodele amphibians. Furthermore, the accessory limb model may be applied to other species to explore universality of regeneration mechanisms. This review aims to connect the insights recently gained to emboss universality of regeneration mechanisms among species. The defined molecules (BMP7 (or2) + FGF2 + FGF8) can transform skin wound healing to organ (limb) regeneration responses. The same molecules can initiate regeneration responses in some species. PMID- 26100346 TI - Conversion from Two Types of Wide QRS Complex Tachycardia to Narrow QRS Complex Tachycardia: What Are the Mechanisms? PMID- 26100347 TI - Organizing pneumonia components in non-specific interstitial pneumonia (NSIP): a clinicopathological study of 33 NSIP cases. AB - AIMS: To review the clinical, radiological and pathological features of non specific interstitial pneumonia (NSIP), mainly to characterize organizing pneumonia (OP) components in NSIP. METHODS AND RESULTS: Lung biopsy samples from 33 NSIP patients were collected over a period of 10 years. Microscopic analysis revealed that 13 cases showed a cellular pattern and 20 showed a mixed/fibrosing pattern. OP components were detected in 26 cases (13 with a cellular pattern; 13 with a mixed/fibrosing pattern), and were found to constitute a median proportion of 9% (range, 1-40%) of the affected tissues. In nine cellular and four mixed/fibrosing NSIP cases, the OP components accounted for >=10%. A proportion of >=20% was found in only five cellular pattern cases. Twenty-nine patients were followed up: 17 showed improvements, five were stabilized, and seven showed progression. CONCLUSIONS: OP components are common basic lesions in NSIP cases, although their proportion in cellular and mixed/fibrosing pattern cases varies substantially between patients. OP components do not impact on prognosis, even when they constitute >=20% of the affected tissue. Thus, a high level of OP components does not exclude a diagnosis of NSIP in cases that otherwise show pathological and radiological findings characteristic of NSIP. PMID- 26100348 TI - Anxiety and depression after failure of assisted reproductive treatment among patients experiencing infertility. AB - OBJECTIVE: To investigate the impact of the number of previous infertility treatment failures on anxiety and depression. METHODS: In a cross-sectional study, individuals (men and women, but not couples) aged at least 18 years who had a history of infertility and could read and write in Persian were enrolled at the Royan Institute, Tehran, Iran, between November 1, 2013, and February 28, 2014. Participants provided demographic and infertility information and completed the Persian version of the Hospital Anxiety and Depression Scale (HADS). RESULTS: Overall, 330 patients (122 men, 208 women) were included. Mean scores on the HADS anxiety and depression subscales (HADS-A and HADS-D) were 8.40+/-4.51 and 5.95+/ 3.54, respectively. In multiple regression analysis, mean HADS-A scores were significantly higher for patients with one treatment failure (9.57+/-4.58) than for those without a history of treatment (7.79+/-4.13; P=0.003). HADS-D scores were significantly higher for patients with two failures (6.92+/-3.69) than for those with no previous treatment (5.59+/-3.79; P=0.019). CONCLUSION: Patients with infertility have increased depression and anxiety after infertility treatment failure. Counseling or treatment for these potential psychological effects should be considered after infertility treatment failure. PMID- 26100349 TI - Tiotropium and Salmeterol in COPD Patients at Risk of Exacerbations: A Post Hoc Analysis from POET-COPD((r)). AB - INTRODUCTION: Among patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events. The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known. METHODS: A post hoc analysis of patients at low (<=1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (>=2 exacerbations [oral steroids/antibiotics requirement] or >=1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD((r))) database. RESULTS: Compared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76-0.92; p = 0.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81-0.99; p = 0.0383) in patients at high exacerbation risk. With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80-1.00; p = 0.0478). For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol. With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71-1.07; p = 0.1968). DISCUSSION: This analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk. FUNDING: Boehringer Ingelheim and Pfizer. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00563381. PMID- 26100350 TI - Plume Characteristics of Two HFA-Driven Inhaled Corticosteroid/Long-Acting Beta2 Agonist Combination Pressurized Metered-Dose Inhalers. AB - INTRODUCTION: New inhalers propelled by hydrofluoroalkanes (HFAs) have improved plume characteristics: higher fine particle fraction, and warmer plumes with reduced force and velocity. Together, this may avoid reflex interruption of inhalation and improve lung deposition of the inhaled drugs. However, even with HFA-propelled pressurized metered-dose inhalers (pMDIs), there are notable differences in device properties. Here we compared the duration, velocity, force, and temperature of two inhaled corticosteroid/long-acting beta2-agonist combination therapies, administered via HFA pMDIs: fluticasone propionate/formoterol 125/5 ug (FP/FORM; flutiform((r))) and fluticasone propionate/salmeterol 125/25 ug (FP/SAL; Seretide((r)) Evohaler((r))). METHODS: Inhalers were fired into ambient air. Plume duration and velocity were recorded with a high-speed camera and a pulsed laser light source. A copper disc attached to a sensitive load cell measured the plume force at various distances from the device. A thermal imaging video camera recorded impaction temperature in line with the device. RESULTS: The average plume duration for FP/FORM was longer than that of FP/SAL: 168.3 vs. 114.0 ms, respectively. The mean maximum plume velocities observed at 95 mm (the approximate distance between mouthpiece and throat) was consistently slower for FP/FORM (10.08 m/s) compared to FP/SAL (15.55 m/s). FP/FORM had a slower velocity at the outset, remaining relatively constant before declining steadily over the plume duration. The force of the FP/SAL plume was greater than that of FP/FORM at all distances: maximum force for FP/FORM was 138.2 vs. 278.9 mN for FP/SAL. The minimum impaction temperature was +5.9 degrees C for FP/FORM and -37.8 degrees C for FP/SAL; this difference became less pronounced over distance. CONCLUSION: There were substantial differences between the plumes of the two pMDIs. FP/FORM was warmer, less forceful, had a longer plume duration and slower maximal velocity. These plume characteristics of FP/FORM may lead to improved lung deposition. FUNDING: Mundipharma Research Limited, Cambridge, UK. PMID- 26100351 TI - Effects of reading proficiency on embedded stem priming in primary school children. AB - Prior evidence from masked morphological priming has revealed conflicting findings regarding the acquisition of morpho-orthographic segmentation mechanisms in developing readers. Here, we examined changes in masked morphological priming across grade within a large sample of French primary school children (n = 191, Grades 2-5) and how these effects are modulated by individual differences in reading proficiency, spelling proficiency, and morphological awareness. Target words were preceded by either (a) a suffixed word prime (e.g., tristesse-TRISTE), (b) a suffixed nonword prime (e.g., tristerie-TRISTE), (c) a non-suffixed nonword prime (e.g., tristald-TRISTE), or (d) an unrelated prime (e.g., direction-TRISTE) using very short prime durations (50 ms). Moreover, a frequency manipulation was included for suffixes and non-suffixes. The results revealed robust suffixed word priming across all children independent of grade and proficiency. On the other hand, priming in the suffixed and non-suffixed nonword conditions was modulated by reading proficiency, with high-proficiency children showing facilitation and low-proficiency children showing inhibition. The effects of suffix and non-suffix frequency were modulated by grade, with decreasing effects as grade increased. None of the observed priming effects were modulated by grade, spelling proficiency, or morphological awareness. The results suggest that reading proficiency is an important predictor for embedded stem activation mechanisms in primary school children, which we discuss in the context of recent theories of morphological processing. PMID- 26100353 TI - Formation and functionality of self-assembled whey protein microgels. AB - Whey proteins spontaneously form spherical particles when heated in aqueous solutions at conditions where their net charge density is below a critical value. The particles are microgels consisting of a hydrated crosslinked network of proteins with a diameter between 100nm and 1MUm. Stable suspensions of these microgels can be formed in a narrow range of conditions when the protein charge density is low enough to induce their formation, but high enough to inhibit further association into larger clusters or macroscopic gels. The formation of microgels and their application to stabilize emulsions and foams; form core-shell particles; form gels; or modify the texture of polysaccharide solutions and gels are reviewed. PMID- 26100352 TI - Co-modulation analysis of gene regulation in breast cancer reveals complex interplay between ESR1 and ERBB2 genes. AB - BACKGROUND: Gene regulation is dynamic across cellular conditions and disease subtypes. From the aspect of regulation under modulation, regulation strength between a pair of genes can be modulated by (dependent on) expression abundance of another gene (modulator gene). Previous studies have demonstrated the involvement of genes modulated by single modulator genes in cancers, including breast cancer. However, analysis of multi-modulator co-modulation that can further delineate the landscape of complex gene regulation is, to our knowledge, unexplored previously. In the present study we aim to explore the joint effects of multiple modulator genes in modulating global gene regulation and dissect the biological functions in breast cancer. RESULTS: To carry out the analysis, we proposed the Covariability-based Multiple Regression (CoMRe) method. The method is mainly built on a multiple regression model that takes expression levels of multiple modulators as inputs and regulation strength between genes as output. Pairs of genes were divided into groups based on their co-modulation patterns. Analyzing gene expression profiles from 286 breast cancer patients, CoMRe investigated ten candidate modulator genes that interacted and jointly determined global gene regulation. Among the candidate modulators, ESR1, ERBB2, and ADAM12 were found modulating the most numbers of gene pairs. The largest group of gene pairs was composed of ones that were modulated by merely ESR1. Functional annotation revealed that the group was significantly related to tumorigenesis and estrogen signaling in breast cancer. ESR1-ERBB2 co-modulation was the largest group modulated by more than one modulators. Similarly, the group was functionally associated with hormone stimulus, suggesting that functions of the two modulators are performed, at least partially, through modulation. The findings were validated in majorities of patients (> 99%) of two independent breast cancer datasets. CONCLUSIONS: We have showed CoMRe is a robust method to discover critical modulators in gene regulatory networks, and it is capable of achieving reproducible and biologically meaningful results. Our data reveal that gene regulatory networks modulated by single modulator or co-modulated by multiple modulators play important roles in breast cancer. Findings of this report illuminate complex and dynamic gene regulation under modulation and its involvement in breast cancer. PMID- 26100354 TI - Quantifying the Number of Discriminable Coincident Dendritic Input Patterns through Dendritic Tree Morphology. AB - Current developments in neuronal physiology are unveiling novel roles for dendrites. Experiments have shown mechanisms of non-linear synaptic NMDA dependent activations, able to discriminate input patterns through the waveforms of the excitatory postsynaptic potentials. Contextually, the synaptic clustering of inputs is the principal cellular strategy to separate groups of common correlated inputs. Dendritic branches appear to work as independent discriminating units of inputs potentially reflecting an extraordinary repertoire of pattern memories. However, it is unclear how these observations could impact our comprehension of the structural correlates of memory at the cellular level. This work investigates the discrimination capabilities of neurons through computational biophysical models to extract a predicting law for the dendritic input discrimination capability (M). By this rule we compared neurons from a neuron reconstruction repository (neuromorpho.org). Comparisons showed that primate neurons were not supported by an equivalent M preeminence and that M is not uniformly distributed among neuron types. Remarkably, neocortical neurons had substantially less memory capacity in comparison to those from non-cortical regions. In conclusion, the proposed rule predicts the inherent neuronal spatial memory gathering potentially relevant anatomical and evolutionary considerations about the brain cytoarchitecture. PMID- 26100355 TI - Imaging of Traumatic Diaphragmatic Rupture: Evaluation of Diagnostic Accuracy at a Level 1 Trauma Centre. AB - PURPOSE: Traumatic diaphragmatic rupture (TDR) is an uncommon injury that can be associated with significant morbidity if not detected and treated in a timely manner. The purpose of our study was to evaluate the diagnostic accuracy of 64 slice multidetector computed tomography (64-MDCT) for the detection of TDR in patients at our level 1 trauma centre. METHODS: We used our hospital's trauma registry to identify patients with a diagnosis of TDR from January 1, 2008, to December 31, 2012. Only patients with a 64-MDCT scan at presentation who subsequently underwent laparotomy/laparoscopy were included in the study cohort. Using surgical findings as the gold standard, the accuracy of the prospective radiology reports was analyzed. RESULTS: Of the 3225 trauma patients who presented to our institution, 38 (1.2%) had a TDR. Fourteen of the 38 were excluded as they did not have MDCT before surgery. The study cohort consisted of 20 males and 4 females with a median age of 34.5 years and a median Injury Severity Score (ISS90) of 26. Fifteen had blunt trauma while 9 had a penetrating injury. The overall sensitivity of the radiology reports was 66.7% (95% confidence interval [CI]: 46.7%-82.0%), specificity was 100% (95% CI: 94.1% 100%), positive predictive value was 100% (95% CI: 80.6%-100%), negative predictive value was 88.4% (95% CI: 78.8%-94.0%), and accuracy was 90.6% (95% CI: 82.5%-95.2%). However, only 3 of 9 patients with penetrating injury had a correct preoperative diagnosis. Two of the 6 missed penetrating trauma cases had only indirect signs of injury. CONCLUSIONS: The detection of TDR in trauma patients on 64-MDCT can be improved, especially in patients presenting with penetrating injury. A careful search for subtle diaphragmatic defects and indirect evidence of injury is important to avoid missing the diagnosis. PMID- 26100357 TI - GAA triplet-repeats cause nucleosome depletion in the human genome. AB - Although there have been many investigations into how trinucleotide repeats affect nucleosome formation and local chromatin structure, the nucleosome positioning of GAA triplet-repeats in the human genome has remained elusive. In this work, the nucleosome occupancy around GAA triplet-repeats across the human genome was computed statistically. The results showed a nucleosome-depleted region in the vicinity of GAA triplet-repeats in activated and resting CD4(+) T cells. Furthermore, the A-tract was frequently adjacent to the upstream region of GAA triplet-repeats and could enhance the depletion surrounding GAA triplet repeats. In vitro chromatin reconstitution assays with GAA-containing plasmids also demonstrated that the inserted GAA triplet-repeats destabilized the ability of recombinant plasmids to assemble nucleosomes. Our results suggested that GAA triplet-repeats have lower affinity to histones and can change local nucleosome positioning. These findings may be helpful for understanding the mechanism of Friedreich's ataxia, which is associated with GAA triplet-repeats at the chromatin level. PMID- 26100356 TI - Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. AB - Ipilimumab is a promising novel immunotherapy agent and is associated with a variety of immune-related adverse events (irAE). The purpose of this study was to investigate the manifestations of irAEs on body imaging in patients with advanced melanoma treated with ipilimumab. One-hundred forty-seven patients with advanced melanoma (59 women, 88 men; median age, 64.5 years) treated with ipilimumab were studied. All patients had the baseline and at least one follow-up chest/abdomen/pelvis CT or PET/CT during therapy, which were reviewed by a consensus of two radiologists blinded to the clinical data. Findings indicative of individual types of irAEs were assessed, including thyroiditis, sarcoid-like lymphadenopathy, pneumonitis, hepatitis, pancreatitis, and colitis. Among the 147 patients, 46 (31%) had radiologically identified irAEs. The time interval from the initiation of therapy to the development of irAEs was less than 3 months in 76% (35 of 46) of the patients (range, 0.2-9.1 months). Clinical characteristics did not differ between patients with and without irAEs (P > 0.18). Among the individual types of irAEs, colitis was most common (n = 28; 19%), followed by sarcoid-like lymphadenopathy (n = 8; 5%) and pneumonitis (n = 8; 5%). Hepatitis (n = 3), thyroiditis (n = 2), and pancreatitis (n = 1) were less common. The resolution of irAEs was noted in 32 of 36 patients (89%) with further follow-up scans, with a median time of 2.3 months after the detection of irAE. In conclusion, irAEs were noted on body imaging in 31% of patients with melanoma treated with ipilimumab. Colitis was the most common, followed by sarcoid-like lymphadenopathy and pneumonitis. The results call for an increased awareness of irAEs, given the expanding role of cancer immunotherapy. PMID- 26100358 TI - Recent advances in functional assays of transcriptional enhancers. AB - In this special edition of Genomics, we present reviews of the current state of the field in identifying and functionally understanding transcriptional enhancers in cells and developing tissues. Typically several enhancers coordinate the expression of an individual target gene, each controlling that gene's expression in specific cell types at specific times. Until recently, identifying each gene's enhancers had been challenging because enhancers do not occupy prescribed locations relative to their target genes. Recently there have been powerful advances in DNA sequencing and other technologies that make it possible to identify the majority of enhancers in virtually any cell type of interest. The reviews in this edition of Genomics highlight some of these new and powerful approaches. PMID- 26100359 TI - Childhood asthma biomarkers: present knowledge and future steps. AB - Asthma represents the most common chronic respiratory disease of childhood. Its current standard diagnosis relies on patient history of symptoms and confirmed expiratory airflow limitation. Nevertheless, the spectrum of asthma in clinical presentation is broad, and both symptoms and lung function may not always reflect the underlying airway inflammation, which can be determined by different pathogenetic mechanisms. For these reasons, the identification of objective biomarkers of asthma, which may guide diagnosis, phenotyping, management and treatment is of great clinical utility and might have a role in the development of personalized therapy. The availability of non-invasive methods to study and monitor disease inflammation is of relevance especially in childhood asthma. In this sense, a promising role might be played by the measurement of exhaled biomarkers, such as exhaled nitric oxide (FE(NO)) and molecules in exhaled breath condensate (EBC). Furthermore, recent studies have shown encouraging results with the application of the novel metabolomic approach to the study of exhaled biomarkers. In this paper the existing knowledge in the field of asthma biomarkers, with a special focus on exhaled biomarkers, will be highlighted. PMID- 26100360 TI - Choosing death in depression: a commentary on 'Treatment-resistant major depressive disorder and assisted dying'. PMID- 26100361 TI - The ethics of placebo treatments in clinical practice: a reply to Glackin. AB - In 'Placebo treatments, informed consent, and "the grip of a false picture"' Shane Nicholas Glackin argues that if a physician offers a patient an inert placebo with the following disclosure, this is compatible with informed consent and is not deceptive: 'I would like to offer you a pill which I believe can help lessen your suffering. I do not know exactly how it works. I have other pills to offer whose mechanism is clearer, but I am not sure that they will work better for you, and they may also entail more serious side effects'. According to Glackin, telling patients that the recommended treatment is an inert placebo is providing incidental information, analogous to telling a patient the chemical details of an active drug. He argues that this information would influence a patient's decision only if she was 'in the grip of a false picture' that inert drugs do not have physical effects on patients' bodies. We contend that this disclosure typically is incompatible with informed consent and typically is deceptive. We give an example of a transparent placebo disclosure, that is, a disclosure that is compatible with informed consent and is not deceptive. PMID- 26100362 TI - Addressing polarisation in science. AB - Ploug and Holm argue that polarisation in scientific communities can generate conflicts of interest for individual researchers. Their proposed solution to this problem is that authors should self-report whether they are polarised on conflict of interest disclosure forms. I argue that this is unlikely to work. This is because any author with the self-awareness and integrity to identify herself as polarised would be unlikely to conduct polarised research to begin with. Instead, I suggest that it is the role of (associate-level) editors of journals to detect and report on polarisation. One consequence of this view is that they need to be sufficiently familiar with the field of research they are evaluating to know whether polarisation is at stake. PMID- 26100363 TI - Benefits and drawbacks of molecular techniques for diagnosis of viral respiratory infections. Experience with two multiplex PCR assays. AB - Molecular techniques have represented a major step forward in the diagnosis of viral respiratory infections. They are considered highly sensitive and specific compared to conventional techniques. In this study two nucleic acid amplification tests (NAATs) were compared to conventional methods (immunofluorescence and viral culture). The aim of this work was to discuss the clinical interpretation of the results obtained by NAATs on the basis of the two-decade experience of our group and the literature. Eighty nasopharyngeal aspirates were collected from children under six years attended for acute respiratory illness at the pediatric emergency room of a third level Hospital. Both NAATs tested (Seeplex((r)) and Clart((r))) showed an overall higher performance regarding sensitivity (76% and 90%, respectively). Compared to Seeplex((r)), the Clart((r)) system tripled the number of multiple detections (8 by Seeplex((r)) vs. 25 by Clart((r))). In some specimens both NAATs detected different viruses. Given these discrepancies and the fact that detection of viral nucleic acids is not necessarily related to the current clinical syndrome, the interpretation of molecular results may not always be so straightforward. The pros and cons of NAATs should always be taken into account when giving a result. PMID- 26100364 TI - Patterns of care and survival after a cancer of unknown primary (CUP) diagnosis: A population-based nested cohort study in Australian Government Department of Veterans' Affairs clients. AB - BACKGROUND: Little is known about patterns of care after a cancer of unknown primary (CUP) diagnosis. METHODS: We performed a retrospective cohort study to describe and compare the treatment, health service use and survival of patients with CUP and metastatic cancer of known primary among 143,956 Australian Government Department of Veterans' Affairs clients, 2004-2007. We randomly matched clients with CUP (C809; n=252) with clients with a first diagnosis of metastatic solid cancer of known primary (n=980). We ascertained health services from the month of diagnosis up to 2 months post-diagnosis for consultations, hospitalizations and emergency department visits, and up to 1 year for treatment. We compared cancer treatments using conditional logistic regression; consultation rates using negative binomial regression; and survival using stratified Cox regression. RESULTS: 30% of CUP patients and 70% of patients with known primary received cancer treatment and the median survival was 37 days and 310 days respectively. CUP patients received fewer cancer medicines (odds ratio (OR)=0.54, 95% confidence interval (CI) 0.33-0.89) and less cancer-related surgery (OR=0.25, 95% CI 0.15-0.41); males with CUP received more radiation therapy (OR=2.88, 95% CI 1.69-4.91). CUP patients had more primary care consultations (incidence rate ratio (IRR)=1.25, 95% CI 1.11-1.41), emergency department visits (IRR=1.86, 95% CI 1.50-2.31) and hospitalizations (IRR=1.18, 95% CI 1.03-1.35), and a higher risk of death within 30 days (hazard ratio=3.30, 95% CI 1.69-6.44). CONCLUSIONS: Patients with CUP receive less treatment but use more health services, which may reflect underlying patient and disease characteristics. PMID- 26100365 TI - Survival and PSA-markers for mortality and metastasis in nonmetastatic prostate cancer treated with androgen deprivation therapy. AB - BACKGROUND: Few studies have examined the risk of developing castration-resistant prostate cancer (CRPC), metastasis, and mortality among nonmetastatic prostate cancer (M0-PC) patients treated with androgen deprivation therapy (ADT). We estimated the incidence of these outcomes among M0-PC patients on ADT and identified prostate-specific antigen (PSA) based biomarkers for mortality and metastasis. METHODS: This population-based cohort study included all nonmetastatic prostate cancer patients in Northern and Central Denmark Regions during 1997-2010, identified through registry data. Primary outcomes were metastasis, overall survival, and bone metastasis-free survival (BMFS). We estimated relative risks (RR) associated with PSA and PSA doubling-time (PSA-DT), measured as time-varying variables beginning at ADT treatment start. RESULTS: We included 2494 M0-PC patients treated with ADT, of whom 1617 (80%) developed CRPC during follow-up. One-fourth of the patients developed metastases within 5 years; bone metastases (BM) accounted for 81% of all metastases. Median survival time was 4.4 years. Compared with PSA <8 ng/mL, PSA >=8 ng/mL was associated with an adjusted RR of 14.0 (95% confidence interval [CI]: 10.2, 19.0) for BM, 4.4 (CI: 3.9, 5.0) for all-cause mortality, and RR of 4.8 (CI: 4.3, 5.4) for the inverse of BMFS. PSA-DT <=6 months was associated with an adjusted RR of 7.6 (95% CI: 6.1, 9.5) for BM, RR of 5.9 (CI: 5.2, 6.6) for all-cause mortality, and RR 6.6 (CI: 5.9, 7.4) for the inverse of BMFS. CONCLUSIONS: PSA >=8 ng/mL and PSA-DT <=6 months are strong predictors of mortality and bone metastasis. The poor prognosis observed in this study may reflect inclusion of patients with severe prostate cancer by requiring repeated PSA measurements. PMID- 26100367 TI - Novel VN/C nanocomposites as methanol-tolerant oxygen reduction electrocatalyst in alkaline electrolyte. AB - A novel VN/C nanostructure consisting of VN nanoparticles and graphite-dominant carbon layers is synthesized by nitridation of V2O5 using melamine as reductant under inert atmosphere. High crystalline VN nanoparticles are observed to be uniformly distributed in carbon layers with an average size of ca13.45 nm. Moreover, the electrocatalytic performance of VN/C towards oxygen reduction reaction (ORR) in alkaline electrolyte is fascinating. The results show that VN/C has a considerable ORR activity, including a 75 percent value of the diffusion limited current density and a 0.11 V smaller value about the onset potential with respect to Pt/C catalyst. Moreover, the excellent methanol-tolerance performance of VN/C has also been verified with 3 M methanol. Combined with the competitive prices, this VN/C nanocomposite can serve as an appropriate non-precious methanol tolerant ORR catalyst for alkaline fuel cells. PMID- 26100366 TI - Water-based preparation of spider silk films as drug delivery matrices. AB - The main focus of this work was to obtain a drug delivery matrix characterized by biocompatibility, water insolubility and good mechanical properties. Moreover the preparation process has to be compatible with protein encapsulation and the obtained matrix should be able to sustain release a model protein. Spider silk proteins represent exceptional natural polymers due to their mechanical properties in combination with biocompatibility. As both hydrophobic and slowly biodegrading biopolymers, recombinant spider silk proteins fulfill the required properties for a drug delivery system. In this work, we present the preparation of eADF4(C16) films as drug delivery matrices without the use of any organic solvent. Water-based spider silk films were characterized in terms of protein secondary structure, thermal stability, zeta-potential, solubility, mechanical properties, and water absorption and desorption. Additionally, this study includes an evaluation of their application as a drug delivery system for both small molecular weight drugs and high molecular weight molecules such as proteins. Our investigation focused on possible improvements in the film's mechanical properties including plasticizers in the film matrix. Furthermore, different film designs were prepared, such as: monolayer, coated monolayer, multilayer (sandwich), and coated multilayer. The release of the model protein BSA from these new systems was studied. Results indicated that spider silk films are a promising protein drug delivery matrix, capable of releasing the model protein over 90 days with a release profile close to zero order kinetic. Such films could be used for several pharmaceutical and medical purposes, especially when mechanical strength of a drug eluting matrix is of high importance. PMID- 26100368 TI - Hepatitis: After HCV cure, HBV cure? AB - Current treatments efficiently control chronic HBV infection but they do not lead to its elimination. Now, Ebert and colleagues have shown that cellular inhibitor of apoptosis proteins (cIAPs) prevent TNF-mediated killing of infected hepatocytes and that cIAP antagonists might lead to HBV cure by promoting death of infected cells. PMID- 26100370 TI - NAFLD: Sugary drinks and fatty liver--a bitter-sweet relationship. PMID- 26100371 TI - IBD: Lactococcus lactis alleviates oxidative stress and colitis in mice. PMID- 26100369 TI - Coeliac disease and gluten-related disorders in childhood. AB - Gluten-related disorders such as coeliac disease, wheat allergy and noncoeliac gluten sensitivity are increasingly being diagnosed in children. Coeliac disease occurs frequently, affecting 1-3% of the Western population. The condition manifests at a very young age, more so in girls, and is related to the HLA genotype. Coeliac disease might be considered a public health problem and, as primary prevention is not possible, the debate on mass screening should be reopened. Wheat proteins, including gluten, are responsible for one of the most common food allergies in children: wheat allergy. Unlike coeliac disease and wheat allergy, noncoeliac gluten sensitivity is an unclear and controversial entity. These three gluten-related disorders are treated with a gluten-free diet. In coeliac disease, the diet should be strictly followed, whereas wheat allergy only requires wheat elimination and in noncoeliac gluten sensitivity occasional trials of gluten reintroduction can be done. A good diagnostic work-up is important for gluten-related disorders in childhood to avoid unnecessary restrictive diets in children. In this Review, we provide an overview of the pathogenesis, diagnosis and management of the most common gluten-related disorders in children. PMID- 26100372 TI - Infection prevention and control in Europe - the picture in the mosaic. PMID- 26100373 TI - Incidence and species distribution of candidaemia in Asia: a laboratory-based surveillance study. AB - The epidemiology of candidaemia varies between hospitals and geographic regions. Although there are many studies from Asia, a large-scale cross-sectional study across Asia has not been performed. We conducted a 12-month, laboratory-based surveillance of candidaemia at 25 hospitals from China, Hong Kong, India, Singapore, Taiwan and Thailand. The incidence and species distribution of candidaemia were determined. There were 1601 episodes of candidaemia among 1.2 million discharges. The overall incidence was 1.22 episodes per 1000 discharges and varied among the hospitals (range 0.16-4.53 per 1000 discharges) and countries (range 0.25-2.93 per 1000 discharges). The number of Candida blood isolates and the total number of fungal isolates were highly correlated among the six countries (R2 = 0.87) and 25 hospitals (R2 = 0.77). There was a moderate correlation between incidence of candidaemia and the intensive care unit (ICU)/total bed ratio (R2 = 0.47), although ICUs contributed to only 23% of candidaemia cases. Of 1910 blood isolates evaluated, Candida albicans was most frequently isolated (41.3%), followed by Candida tropicalis (25.4%), Candida glabrata (13.9%) and Candida parapsilosis (12.1%). The proportion of C. tropicalis among blood isolates was higher in haemato-oncology wards than others wards (33.7% versus 24.5%, p 0.0058) and was more likely to be isolated from tropical countries than other Asian countries (46.2% versus 18.9%, p 0.04). In conclusion, the ICU settings contribute, at least in part, to the incidence variation among hospitals. The species distribution is different from Western countries. Both geographic and healthcare factors contribute to the variation of species distribution. PMID- 26100374 TI - Human bocavirus infection as a cause of severe acute respiratory tract infection in children. AB - In 2005 human bocavirus (HBoV) was discovered in respiratory tract samples of children. The role of HBoV as the single causative agent for respiratory tract infections remains unclear. Detection of HBoV in children with respiratory disease is frequently in combination with other viruses or bacteria. We set up an algorithm to study whether HBoV alone can cause severe acute respiratory tract infection (SARI) in children. The algorithm was developed to exclude cases with no other likely cause than HBoV for the need for admission to the paediatric intensive care unit (PICU) with SARI. We searched for other viruses by next generation sequencing (NGS) in these cases and studied their HBoV viral loads. To benchmark our algorithm, the same was applied to respiratory syncytial virus (RSV)-positive patients. From our total group of 990 patients who tested positive for a respiratory virus by means of RT-PCR, HBoV and RSV were detected in 178 and 366 children admitted to our hospital. Forty-nine HBoV-positive patients and 72 RSV-positive patients were admitted to the PICU. We found seven single HBoV infected cases with SARI admitted to PICU (7/49, 14%). They had no other detectable virus by NGS. They had much higher HBoV loads than other patients positive for HBoV. We identified 14 RSV-infected SARI patients with a single RSV infection (14/72, 19%). We conclude that our study provides strong support that HBoV can cause SARI in children in the absence of viral and bacterial co infections. PMID- 26100375 TI - Dermatitis by Dermatophilus congolensis. PMID- 26100376 TI - Geometric analysis of the Goldbeter minimal model for the embryonic cell cycle. AB - A minimal model describing the embryonic cell division cycle at the molecular level in eukaryotes is analyzed mathematically. It is known from numerical simulations that the corresponding three-dimensional system of ODEs has periodic solutions in certain parameter regimes. We prove the existence of a stable limit cycle and provide a detailed description on how the limit cycle is generated. The limit cycle corresponds to a relaxation oscillation of an auxiliary system, which is singularly perturbed and has the same orbits as the original model. The singular perturbation character of the auxiliary problem is caused by the occurrence of small Michaelis constants in the model. Essential pieces of the limit cycle of the auxiliary problem consist of segments of slow motion close to several branches of a two dimensional critical manifold which are connected by fast jumps. In addition, a new phenomenon of exchange of stability occurs at lines, where the branches of the two-dimensional critical manifold intersect. This novel type of relaxation oscillations is studied by combining standard results from geometric singular perturbation with several suitable blow-up transformations. PMID- 26100377 TI - Integrative Cancer Therapies. In This Issue. PMID- 26100378 TI - Transient Receptor Potential Channel and Interleukin-17A Involvement in LTTL Gel Inhibition of Bone Cancer Pain in a Rat Model. AB - Cancer pain management is a challenge for which Chinese herbal medicine might be useful. To study the spinal mechanisms of the Chinese medicated gel Long-Teng Tong-Luo (LTTL), a 7-herb compound, on bone cancer pain, a bone cancer pain model was made by inoculating the tibias of female rats with Walker 256 cells. LTTL gel or inert gel, 0.5 g/cm(2)/d, was applied to the skin of tumor-bearing tibias for 21 days beginning a day after the inoculation. Mechanical threshold and paw withdrawal latency to thermal stimulation was measured. Transient receptor potential (TRP) cation channels in lumbar dorsal root ganglia (DRG) were immunostained and counted, and lumbar spinal cord interleukin-17A (IL-17A) was measured with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. TRP antagonists and interleukin (IL)-17A antibodies were intrathecally administered to determine their effects on bone cancer pain. The gel significantly (P < .05) alleviated cancer-induced mechanical allodynia and thermal hyperalgesia and inhibited cancer-enhanced expression of IL-17A in spinal astrocytes and the TRP subfamily members V1, A1, and V4 in lumbar DRG. Intrathecal TRP antagonists at 10 ug significantly (P < .05) attenuated mechanical allodynia, thermal hyperalgesia, and IL-17A expression, indicating that TRP channels facilitate spinal IL-17 expression and cancer pain. IL-17A antibodies inhibited cancer pain, suggesting that IL-17A promotes such pain. The data show that LTTL gel inhibits cancer pain, and this might be accounted for by the decrease in expression of DRG TRP channels and spinal astrocyte IL-17A. PMID- 26100379 TI - Dynamic role of adult-born dentate granule cells in memory processing. AB - Throughout the adult life of all mammals including humans, new neurons are incorporated to the dentate gyrus of the hippocampus. During a critical window that lasts about two weeks, adult-born immature neurons are more excitable and plastic than mature ones, and they respond to a wider range of inputs. In apparent contradiction, new neurons have been shown to be crucial to solve behavioral tasks that involve the discrimination of very similar situations, which would instead require high input specificity. We propose that immature neurons are initially unspecific because their task is to identify novel elements inside a high dimensional input space. With maturation, they would specialize to represent details of these novel inputs, favoring discrimination. PMID- 26100380 TI - Comparing the ocular surface effects of topical vancomycin and linezolid for treating bacterial keratitis. AB - BACKGROUND: Vancomycin is the gold standard in combination therapy for severe and resistant gram-positive keratitis and in particular for Methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to report the ocular surface toxicity and scoring in patients whose treatment shifted to topical linezolid/ceftazidime from topical vancomycin/ceftazidime due to their vancomycin intolerance. METHODS: A retrospective, interventional case series of bacterial keratitis was treated with topical linezolid (one drop of 0.2% solution per eye), administered hourly until epithelization and then gradually decreased. The number and extent of punctate epithelial erosions were noted across the entire surface of the cornea. Ocular discomfort was assessed by means of (a) patient-reported pain upon instillation of the medication (vancomycin/linezolid), (b) reported burning sensation between doses and (c) reported foreign-body sensation. No ocular surface toxicity related to linezolid use was noted. Patients were followed for at least 2 months after treatment between April and December 2013. RESULTS: Of the seven patients included in the study (age range: 2 88 years; five females, two males), complete epithelization and resolution was achieved in five patients. One patient was treated with linezolid after penetrating keratoplasty. The second culture of another patient with impending perforation despite linezolid/ceftazidime therapy yielded Fusarium spp., so he underwent tectonic keratoplasty. The mean ocular surface score was 9.4 +/- 1.6 during vancomycin treatment and 5.9 +/- 1.3 during linezolid treatment after discontinuation of vancomycin. The topical linezolid score was significantly lower (p = 0.027). CONCLUSIONS: Topical linezolid may be better tolerated, according to the mean ocular surface score, than topical vancomycin by some patients and can be considered an alternative for patients who do not well tolerate vancomycin. PMID- 26100381 TI - Plant domestication slows pest evolution. AB - Agricultural practices such as breeding resistant varieties and pesticide use can cause rapid evolution of pest species, but it remains unknown how plant domestication itself impacts pest contemporary evolution. Using experimental evolution on a comparative phylogenetic scale, we compared the evolutionary dynamics of a globally important economic pest - the green peach aphid (Myzus persicae) - growing on 34 plant taxa, represented by 17 crop species and their wild relatives. Domestication slowed aphid evolution by 13.5%, maintained 10.4% greater aphid genotypic diversity and 5.6% higher genotypic richness. The direction of evolution (i.e. which genotypes increased in frequency) differed among independent domestication events but was correlated with specific plant traits. Individual-based simulation models suggested that domestication affects aphid evolution directly by reducing the strength of selection and indirectly by increasing aphid density and thus weakening genetic drift. Our results suggest that phenotypic changes during domestication can alter pest evolutionary dynamics. PMID- 26100382 TI - Nonlinear optical response of photochromic azobenzene-functionalized self assembled monolayers. AB - The combination of photochromic and nonlinear optical (NLO) properties of azobenzene-functionalized self-assembled monolayers (SAMs) constitutes an intriguing step towards novel photonic and optoelectronic devices. By utilizing the second-order NLO process of second harmonic generation (SHG), supported by density-functional theory and correlated wave function method calculations, we demonstrate that the photochromic interface provides the necessary prerequisites en route towards possible future technical applications: we find a high NLO contrast on the order of 16% between the switching states. These are furthermore accessible reversibly and with high efficiencies in terms of cross sections on the order of 10(-18) cm(2) for both photoisomerization reactions, i.e., drivable by means of low-power LED light sources. Finally, both photostationary states (PSSs) are thermally stable at ambient conditions. PMID- 26100383 TI - Constructal thermodynamics combined with infrared experiments to evaluate temperature differences in cells. AB - The aim of this work was to evaluate differences in energy flows between normal and immortalized cells when these distinct biological systems are exposed to environmental stimulation. These differences were considered using a constructal thermodynamic approach, and were subsequently verified experimentally. The application of constructal law to cell analysis led to the conclusion that temperature differences between cells with distinct behaviour can be amplified by interaction between cells and external fields. Experimental validation of the principle was carried out on two cellular models exposed to electromagnetic fields. By infrared thermography we were able to assess small changes in heat dissipation measured as a variation in cell internal energy. The experimental data thus obtained are in agreement with the theoretical calculation, because they show a different thermal dispersion pattern when normal and immortalized cells are exposed to electromagnetic fields. By using two methods that support and validate each other, we have demonstrated that the cell/environment interaction can be exploited to enhance cell behavior differences, in particular heat dissipation. We propose infrared thermography as a technique effective in discriminating distinct patterns of thermal dispersion and therefore able to distinguish a normal phenotype from a transformed one. PMID- 26100384 TI - Mesenchymal Stromal Cell Therapy in MDR/XDR Tuberculosis: A Concise Review. AB - Multi-drug-resistant (MDR) tuberculosis is a major public health problem worldwide. Drug resistance arises due to non-compliance of antibiotic therapy. Herein, we explored the therapeutic options available ranging from conservative treatment approaches to alternate adjunct therapies such as mesenchymal stromal cell (MSC) therapy interventions. It is attractive to understand the scientific rationale of using cells as drugs, in particular mesenchymal stem/stromal cells. The review dwells and attempts to analyze the mechanistic approaches of the current treatment modalities to modern therapies. MSCs have demonstrated profound capacity to regenerate and repair. They appear to modulate that the activities of dendritic cells regulate T cells, both in vivo and in vitro. While there seems to be some benefit of such therapies, its use warrants further research. The merits and de-merits of autologous therapy/allogeneic therapy are ill understood. The challenges of requirement of large number of cells for infusion, the route of administration, choice of timing are complex issues that need to be addressed. Furthermore, the host immune responses, environmental factors and epigenetic mechanisms compound the problem. Although, clinical studies are being performed using autologous MSCs in different inflammatory models, it is important that such an intervention should be based on sound scientific rationale. The current review examines the immunomodulatory properties of MSCs, its interactions with other cell types, in assessing the basis for autologous/allogeneic cell-based therapies in the treatment of XDR/MDR tuberculosis. PMID- 26100385 TI - Serum CXCL12 levels are associated with stroke severity and lesion volumes in stroke patients. AB - OBJECTIVE: Previous studies had shown that CXC chemokine ligand-12 (CXCL12) might play a significant role in stroke. The aim of this study was to test the serum baseline CXCL12 levels in Chinese patients with acute ischemic stroke (AIS). METHODS: All consecutive patients with first-ever AIS from January 2013 to June 2014 were recruited to participate in the study. CXCL12 and National Institutes of Health Stroke Scale were measured at the time of admission. Logistic regression analysis was used to evaluate the risk of stroke according to serum CXCL12 levels. Receiver operating characteristic (ROC) curve was used to evaluate the accuracy of serum CXCL12 in diagnosing stroke. RESULTS: From 306 screened patients, a total of 239 patients with first-ever AIS were included in this study. The results indicated that the serum CXCL12 levels were significantly higher in AIS patients as compared to normal controls (P < 0.0001). Serum CXCL12 were positively correlated with infarct volume(r = 0.307, P < 0.0001) and stroke severity(r = 0.288, P < 0.0001). After adjusting for all other possible covariates, CXCL12 was a stroke predictor with an adjusted OR of 2.047 [95% confidence interval (CI), 1.781-2.352; P < 0.0001]. Based on the ROC curve, the optimal cutoff value of serum CXCL12 levels as an indicator for auxiliary diagnosis of AIS was projected to be 3.4 ng/ml, which yielded a sensitivity of 87.9% and a specificity of 72.0%, with the area under the curve at 0.902 (95% CI, 0.875-0.929). CONCLUSION: Our study demonstrated that serum CXCL12 levels increased significantly following AIS, and these changes in serum CXCL12 were positively correlated with infarct volume and stroke severity in Chinese sample. PMID- 26100386 TI - Characterisation of a Recombinant Patchoulol Synthase Variant for Biocatalytic Production of Terpenes. AB - The patchoulol synthase (PTS) is a multi-product sesquiterpene synthases which is the central enzyme for biosynthesis of patchouli essential oil in the patchouli plant. Sesquiterpene synthases catalyse the formation of various complex carbon backbones difficult to approach by organic synthesis. Here, we report the characterisation of a recombinant patchoulol synthase complementary DNA (cDNA) variant (PTS var. 1), exhibiting significant amino acid exchanges compared to the native PTS. The product spectrum using the natural substrate E,E-farnesyl diphosphate (FDP) as well as terpenoid products resulting from conversions employing alternative substrates was analysed by GC-MS. In respect to a potential use as a biocatalyst, important enzymatic parameters such as the optimal reaction conditions, kinetic behaviour and the product selectivity were studied as well. Adjusting the reaction conditions, an increased patchoulol ratio in the recombinant essential oil was achieved. Nevertheless, the ratio remained lower than in plant-derived patchouli oil. As alternative substrates, several prenyl diposphates were accepted and converted in numerous compounds by the PTS var. 1, revealing its great biocatalytic potential. PMID- 26100387 TI - Green Synthesis of Silver Nano-particles by Macrococcus bovicus and Its Immobilization onto Montmorillonite Clay for Antimicrobial Functionality. AB - Macrococcus bovicus was locally isolated from soil and used in the green synthesis of nano-scaling silver (NSAg). It was immobilized on a sodic montmorillonite clay (MMT1) and cetyltrimethylammonium bromide-modified montmorillonite (MMT2) which was also calcined at 300 degrees C (MMT3). The NSAg clays were characterized by X-ray fluorescence, Fourier transform infrared spectra, X-ray diffractometry, surface area measurement, UV-Vis spectrometry, scanning electron microscope, transmission electron microscope and thermogravimetric analysis. NSAg was confirmed to be included in the interparticular cavities of the clay sheets and its mechanical stability was evidenced. The antimicrobial activity of the NSAg-modified clays was investigated against Staphylococcus aureus, Escherichia coli and Candida albicans using the cup plate and the plate count techniques. The antimicrobial activity of the NSAg clays was confirmed and attributed to the caging of NSAg in MMT cavities. MMT3 was found to inhibit the microbial growth to as high as 65 % as observed from the plate count method. Graphical Abstract Scheme of the biosynthesis of nano-scaling Ag and its immobilization and antimicrobial application. PMID- 26100388 TI - Bridging Between Proline Structure, Functions, Metabolism, and Involvement in Organism Physiology. AB - Much is now known about proline multifunctionality and metabolism; some aspects of its biological functions are still unclear. Here, we discuss some cases in the proline, structure, definition, metabolism, compartmentalization, accumulation, plausible functions and also its implication in homeostasis and organism physiology. Indeed, we report the role of proline in cellular homeostasis, including redox balance and energy status and their implication as biocatalyst for aldolase activity. Proline can act as a signaling molecule to modulate mitochondrial functions, influence cell proliferation or cell death, and trigger specific gene expression, which can be essential for plant recovery from stresses. Although, the regulation and the function of proline accumulation, during abiotic stresses, are not yet completely understood. The engineering of proline metabolism could lead to new opportunities to improve plant tolerance against environmental stresses. This atypical amino acid has a potential role in the toxicity during growth of some microorganism, vegetal, and mammalian species. Furthermore, we note that the purpose through the work is to provide a rich, concise, and mostly cohesive source on proline, considered as a platform and an anchor between several disciplines and biological functions. PMID- 26100389 TI - Effect of Light Intensity and Photoperiod on Growth and Biochemical Composition of a Local Isolate of Nostoc calcicola. AB - A study was conducted to investigate the effect of light intensity (21, 42, and 63 MUmol photons m(-2) s(-1)) and photoperiod (8:16, 12:12, and 16:8 h light/dark) on the biomass production and its biochemical composition (total carotenoids, chlorophyll a, phycoerythrin (PE), phycocyanin (PC) and allophycocyanin (APC), total protein, and carbohydrates) of a local isolate of Nostoc calcicola. The results revealed that N. calcicola prefers dim light; however, the most of the levels of light intensity and photoperiod investigated did not have a significant impact on biomass production. Increasing light intensity biomass content of chlorophyll a, PE, PC, APC, and total protein decreased, while total carotenoids and carbohydrate increased. The same behavior was observed also when light duration (photoperiod) increased. The interaction effect of increasing light intensity and photoperiod resulted in an increase of carbohydrate and total carotenoids, and to the decrease of chlorophyll a, PE, PC, APC, and total protein content. The results indicate that varying the light regime, it is capable to manipulate the biochemical composition of the local isolate of N. calcicola, producing either valuable phycobiliproteins or proteins under low light intensity and shorter photoperiods, or producing carbohydrates and carotenoids under higher light intensities and longer photoperiods. PMID- 26100391 TI - KO(t)Bu-mediated annulation of acetonitrile with aldehyde: synthesis of substituted dihydropyridin-2(1H)-ones, pyridin-2(1H)-ones, and thiopyridin-2(1H) ones. AB - The KO(t)Bu-mediated annulation of acetonitrile with aldehyde was observed, in which the cleavage of four C(sp(3))-H bonds occurred and a total of eight new bonds were formed during the synthesis of substituted dihydropyridinones in the presence of peroxide. Furthermore, dihydropyridinones have been transformed into pyridinones using KO(t)Bu in DMSO. PMID- 26100390 TI - A simple method to separate base population and segregation effects in genomic relationship matrices. AB - BACKGROUND: Genomic selection and estimation of genomic breeding values (GBV) are widely used in cattle and plant breeding. Several studies have attempted to detect population subdivision by investigating the structure of the genomic relationship matrix G. However, the question of how these effects influence GBV estimation using genomic best linear unbiased prediction (GBLUP) has received little attention. METHODS: We propose a simple method to decompose G into two independent covariance matrices, one describing the covariance that results from systematic differences in allele frequencies between groups at the pedigree base (G A (*) ) and the other describing genomic relationships (G S) corrected for these differences. Using this decomposition and Fst statistics, we examined whether observed genetic distances between genotyped subgroups within populations resulted from the heterogeneous genetic structure present at the base of the pedigree and/or from breed divergence. Using this decomposition, we tested three models in a forward prediction validation scenario on six traits using Brown Swiss and dual-purpose Fleckvieh cattle data. Model 0 (M0) used both components and is equivalent to the model using the standard G-matrix. Model 1 (M1) used G S only and model 2 (M2), an extension of M1, included a fixed genetic group effect. Moreover, we analyzed the matrix of contributions of each base group (Q) and estimated the effects and prediction errors of each base group using M0 and M1. RESULTS: The proposed decomposition of G helped to examine the relative importance of the effects of base groups and segregation in a given population. We found significant differences between the effects of base groups for each breed. In forward prediction, differences between models in terms of validation reliability of estimated direct genomic values were small but predictive power was consistently lowest for M1. The relative advantage of M0 or M2 in prediction depended on breed, trait and genetic composition of the validation group. Our approach presents a general analogy with the use of genetic groups in conventional animal models and provides proof that standard GBLUP using G yields solutions equivalent to M0, where base groups are considered as correlated random effects within the additive genetic variance assigned to the genetic base. PMID- 26100392 TI - Medical and Disaster Preparedness of US Marathons. AB - BACKGROUND: Despite the events that occurred at the 2013 Boston Marathon (Boston, Massachusetts USA), there are currently no evidence-based guidelines or published data regarding medical and disaster preparedness of marathon races in the United States. Purpose To determine the current state of medical disaster preparedness of marathons in the US and to identify potential areas for improvement. METHODS: A cross-sectional, questionnaire-based study was conducted from January through May of 2014. The questionnaire was distributed to race directors of US road and trail marathons, as identified by a comprehensive internet database. RESULTS: One hundred twenty-three questionnaires were available for analysis (19% usable response rate). Marathon races from all major regions of the US were represented. Runner medical information was not listed on race bibs in 53% of races. Only 45% of races held group training and planning sessions prior to race day. Automated external defibrillators (AEDs) were immediately available on 50% of courses, and medications such as albuterol (30%), oxygen (33%), and IV fluids (34%) were available less frequently. Regarding medical emergencies, 55% of races did not have protocols for the assessment of dehydration, asthma, chest pain, syncope, or exercise-induced cramping. With regard to disaster preparedness, 50% of races did not have protocols for the management of disasters, and 21% did not provide security personnel at start/finish lines, aid stations, road crossings, and drop bag locations. CONCLUSIONS: Areas for improvement in the preparedness of US marathons were identified, such as including printed medical information on race bibs, increasing pre-race training and planning sessions for volunteers, ensuring the immediate availability of certain emergency equipment and medications, and developing written protocols for specific emergencies and disasters. PMID- 26100393 TI - Ovarian hyperstimulation syndrome: a clinical report on 4894 consecutive ART treatment cycles. AB - BACKGROUND: Although a large number of studies have been dedicated to ovarian hyperstimulation syndrome (OHSS) none gave full embryological and clinical outcomes comparing oocyte trigger with human chorionic gonadotrophin (HCG) versus with a gonadotrophin-releasing hormone (GnRH) agonist (Buserelin) in cases with suspicious OHSS. The aim of the present study was thus to analyze 4894 consecutive assisted reproductive treatment cycles to undercover associated risk factors for development of OHSS, and the effects of the use of Buserelin as ovulation trigger on embryological and clinical outcomes. METHODS: In the 51 cases that developed OHSS, ovulation trigger was performed with HCG as indicators were not suspicious for OHSS. These were compared against two types of groups: 71 cases where Buserelin was used for ovulation induction due to suspicious development of OHSS; and those remaining 4772 cases where ovulation trigger was currently performed with HCG (control). RESULTS: Of the cases treated with Buserelin the oocyte maturation rate and the ongoing pregnancy rate were significantly lower, with higher rates of ectopic pregnancy and newborn malformations, but none developed OHSS. Of the OHSS cases, 23 needed hospitalization, with no major complications. CONCLUSIONS: Young age, lower time of infertility, lower basal follicle stimulating hormone levels, higher number of cases with female factor and polycystic ovarian syndrome, high number of follicles and higher estradiol concentrations were the risk factors found associated with OHSS. Cases with OHSS also presented higher follicle count but the estradiol levels were within the normal range. It thus remains to develop more strict criteria to avoid all cases with OHSS. PMID- 26100394 TI - Hepatitis B virus peptide inhibitors: solution structures and interactions with the viral capsid. AB - Hepatitis B virus (HBV) infection remains a health problem globally despite the availability of effective vaccines. In the assembly of the infectious virion, both the preS and S regions of the HBV large surface antigen (L-HBsAg) interact synergistically with the viral core antigen (HBcAg). Peptides preS and S based on the L-HBsAg were demonstrated as potential inhibitors to block the viral assembly. Therefore, the objectives of this study were to determine the solution structures of these peptides and study their interactions with HBcAg. The solution structures of these peptides were solved using (1)H, (13)C, and (15)N NMR spectroscopy. Peptide preS has several structured regions of beta-turns at Ser7-Pro8-Pro9, Arg11-Thr12-Thr13 and Ser22-Thr23-Thr24 sequences whereas peptide S has only one structured region observed at Ser3-Asn4-His5. Both peptides contain bend-like structures surrounding the turn structures. Docking studies revealed that both peptides interacted with the immunodominant region of HBcAg located at the tip of the viral capsid spikes. Saturation Transfer Difference (STD) NMR experiments identified several aromatic residues in peptides preS and S that interact with HBcAg. This study provides insights into the contact regions of L-HBsAg and HBcAg at atomic resolution which can be used to design antiviral agents that inhibit HBV morphogenesis. PMID- 26100395 TI - Characterization of Novel Fusaricidins Produced by Paenibacillus polymyxa-M1 Using MALDI-TOF Mass Spectrometry. AB - Paenibacillus polymyxa-M1 is a potent producer of bioactive compounds, such as lipopeptides, polyketides, and lantibiotics of biotechnological and medical interest. Genome sequencing revealed nine gene clusters for nonribosomal biosynthesis of such agents. Here we report on the investigation of the fusaricidins, a complex of cyclic lipopeptides containing 15-guanidino-3 hydroxypentadecanoic acid (GHPD) as fatty acid component by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). More than 20 variants of these compounds were detected and characterized in detail. Mass spectrometric sequence analysis was performed by MALDI-LIFT-TOF/TOF fragment analysis. The obtained product ion spectra show a specific processing in the fatty acid part. GHPD is cleaved between the alpha- and beta-position yielding two fragments a and b, one bearing the end-standing guanidine group and another one comprising the residual two C-atoms of GHPD with the attached peptide moiety. The complete sequence of all fusaricidins was derived from sets of bn- and yn ions. The fusaricidin complex can be divided into four lipopeptide families, three of them showing variations of the amino acid in position 3, Val or Ile for the first and Tyr or Phe for families 2 and 3, respectively. A collection of novel fusaricidins was detected differing from those of families 1-3 by an additional residue of 71 Da (family 4). LIFT-TOF/TOF fragment spectra of these species imply that in their peptide moiety, an Ala-residue is attached by an ester bond to the free hydroxyl group of Thr4. More than 10 novel fusaricidins were characterized mass spectrometrically. PMID- 26100396 TI - Switching from imiglucerase to miglustat for the treatment of French patients with Gaucher disease type 1: a case series. AB - INTRODUCTION: Gaucher disease is caused by a deficiency of the enzyme beta glucocerebrosidase. Treatment with enzyme replacement therapy has been available for the past two decades but, although effective, enzyme replacement therapy can be delivered only by intravenous infusion every other week. The oral substrate reduction therapy miglustat (Zavesca(r)) has been available in Europe since 2002 for the treatment of patients with mild or moderate Gaucher disease type 1 for whom enzyme replacement therapy is unsuitable or not a therapeutic option. There are few published real-world data on the use of miglustat as a maintenance therapy in Gaucher disease type 1 patients switched from previous enzyme replacement therapy. We report a case series of three patients who were switched from long-term enzyme replacement therapy to miglustat for various reasons. CASE PRESENTATION: All three patients were Caucasian and had confirmed Gaucher disease type 1. An 80-year-old man requested a switch to oral miglustat therapy in preference to ongoing intravenous enzyme replacement therapy, a 57-year-old woman was commenced on miglustat due to a shortage of imiglucerase, and a 56-year-old woman was switched from previous enzyme replacement therapy due to allergic reactions to intravenous infusions. Hematological disease parameters were stable in each patient on previous enzyme replacement therapy. Two patients continue to be treated with miglustat, having shown good tolerability and stable core disease parameters for approximately 4 years. One patient, who was also stable during 7 years of therapy, eventually discontinued miglustat as a precaution because he developed peripheral neuropathy of as yet unknown origin. CONCLUSIONS: Overall, our experience indicates that miglustat can be used as maintenance therapy for Gaucher disease type 1 after initial enzyme replacement therapy, but the selection of patients to whom this approach should be applied should be made after careful consideration of all disease parameters. PMID- 26100398 TI - Patient Classification Systems International 2014 - Patient information for better choice: abstracts. PMID- 26100397 TI - Immunotoxicity induced in mice by subacute exposure to berberine. AB - The immunotoxic effects of the isoquinoline alkaloid berberine (BBR) were investigated in Balb/c mice. Here, BBR was administered daily by intraperitoneal injection at doses of 5 and 10 mg/kg for 14 days. Following the exposure, host spleen weight, cellularity and histopathology, as well as delayed-type hypersensitivity (DTH) responses, hemagglutination titers (HA), spleen cell subtype profiles, splenocyte cytokine production and lymphocyte proliferation were studied in all of the test groups of animals. The results showed that the high dose of BBR (10 mg/kg) could suppress both cellular and humoral immune functions in the treated hosts. BBR at 5 mg/kg only appeared to impact on DTH responses and lymphoproliferation. Based on the finding here, it would seem that BBR has effective immunosuppressive properties. Mechanistic studies are required to determine exactly how this material is acting to impart many of the immunotoxic effects demonstrated here. At the same time, further research should also be performed on BBR to further develop its potential use as an effective immunosuppressant or co-adjuvant for the treatment of diseases caused by an exaggerated or unwanted immune response. PMID- 26100399 TI - Time-dependent risk factors associated with the decline of estimated GFR in CKD patients. AB - BACKGROUND: Targeting the modifiable risk factors may help halt the progression of CKD, thus risk factor analysis is better performed using the parameters in the follow-up. This study aimed to examine the time-dependent risk factors for CKD progression using time-averaged values and to investigate the characteristics of rapid progression group. METHODS: This is a retrospective cohort study enrolling 770 patients of CKD stage 3-4. Time-dependent parameters were calculated as time averaged values by a trapezoidal rule. % decline of estimated GFR (eGFR) per year from entry was divided to three groups: <10% (stable), 10-25% (moderate progression), and >=25% (rapid progression). Multivariate regression analyses were employed for the baseline and the time-averaged datasets. RESULTS: eGFR decline was 2.83 +/- 4.04 mL/min/1.73 m(2)/year (8.8 +/- 12.9 %) in male and 1.66 +/- 3.23 mL/min/1.73 m(2)/year (5.4 +/- 11.0%) in female (p < 0.001). % decline of eGFR was associated with male, proteinuria, phosphorus, and systolic blood pressure as risk factors and with age, albumin, and hemoglobin as protective factors using either dataset. Baseline eGFR and diabetic nephropathy appeared in the baseline dataset, while uric acid appeared in the time-averaged dataset. The rapid progression group was associated with proteinuria, phosphorus, albumin, and hemoglobin in the follow-up. CONCLUSION: These results suggest that time-averaged values provide insightful clinical guide in targeting the risk factors. Rapid decline of eGFR is strongly associated with hyperphosphatemia, proteinuria, and anemia indicating that these risk factors should be intervened in the follow-up of CKD. PMID- 26100401 TI - High grade cervical lesions decline in young US women. PMID- 26100400 TI - A cross-sectional study of high-risk human papillomavirus clustering and cervical outcomes in HIV-infected women in Rio de Janeiro, Brazil. AB - BACKGROUND: In Brazil, the rate of cervical cancer remains high despite the availability of screening programs. With ongoing vaccine development and implementation, information on the prevalence of specific HPV types is needed, particularly among high-risk populations, such as HIV-infected women. METHODS: We performed a study of HIV-infected women in Rio de Janeiro, Brazil, who underwent cervical HPV genotype testing between 2005-2013. We examined the prevalence of high-risk HPV types and the patterns of high-risk HPV type clustering. Using logarithmic binomial regression, we estimated the risk of abnormal cytology by HPV genotype result. RESULTS: Of the 562 women included, 498 (89 %) had at least one HPV type detected. 364 women (65 %) had at least one high-risk HPV type detected and 181 (32 %) had more than one high-risk type detected. HPV 58 was the most frequent HPV type detected overall (prevalence 19.8 % [95 % confidence interval 16.4-23.1]), followed by HPV 53 (prevalence 15.5 % [12.5-18.5]) and HPV 16 (prevalence 13 % [10.2-15.8]). Women infected with more than one high-risk HPV type were younger, had lower CD4+ lymphocyte counts, and were more likely to be infected with HPV 16 or 18. In adjusted analyses, presence of more than one high risk HPV type was associated with a two-fold increased risk of abnormal cytology after adjusting for presence of individual high-risk type, age, and CD4+ lymphocyte count (adjusted prevalence ratios 1.88-2.07, all p <0.001). No single high-risk HPV type was statistically associated with abnormal cytology after adjusting for the presence of more than one high-risk HPV type. CONCLUSIONS: In the largest study of cervical HPV genotypes among HIV-infected women in Latin America, infection by high-risk HPV types other than 16 or 18 and infection by more than one high-risk HPV types were common. Infection by more than one high risk type was more strongly associated with abnormal cervical cytology than any individual high-risk HPV type, highlighting the need for multi-valent HPV vaccines. PMID- 26100402 TI - Genetic variability of hepatitis B virus in Uruguay: D/F, A/F genotype recombinants. AB - Hepatitis B virus (HBV) infection is a serious global health problem. Approximately 2 billion people worldwide have been infected, and approximately 350 million individuals currently suffer from HBV-induced chronic liver infection, which causes 600,000 deaths annually from chronic hepatitis, cirrhosis and hepatocellular carcinoma. HBV is classified in eight genotypes (A-H), and two more have been proposed (I-J). In this paper, complete genome sequences of nine Uruguayan HBV are reported. Five samples belong to genotype F1b and one to genotype A2. Three HBV recombinants were detected: A1/F1b, A2/F1b and D3/F1b. The following mutations were detected: a G1896A substitution, a 33-nucleotide deletion from position 2896 to 2928 in the Pre-S1 region involving Pre-S1 residues 3-13, a 33-nt deletion in the Pre-S1 region involving nt 2913-2945 and Pre-S1 residues 9-19. More F genotypes strains than expected were detected in this study, supporting the hypothesis that there are more people of indigenous origin than declared in our population. Also, one third of the samples analyzed were recombinants. This cannot be explained by the low HBV prevalence in Uruguay, but a high HBV infection rate in drug addicts and dialysis patients could act in favor of multiple-genotype HBV infections that could lead to recombination. PMID- 26100403 TI - Immunoprophylactic effect of chicken egg yolk antibody (IgY) against a recombinant S1 domain of the porcine epidemic diarrhea virus spike protein in piglets. AB - Porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric pathogen of swine causing high mortality rates in piglets. PEDV outbreaks have occurred continuously in most swine-producing Asian countries and have recently emerged in the United States, leading to large economic losses for both the Asian and US pig industries. The spike (S) protein of PEDV consists of the S1 and S2 domains, responsible for virus binding and fusion, respectively. The involvement of the S1 domain in specific high-affinity interactions with the cellular receptor and induction of neutralizing antibodies in the natural host makes it a logical target for the development of effective vaccines and therapeutics against PEDV. Passive immunization by oral administration of egg yolk antibodies (IgY) obtained from immunized chickens provides an alternative source of specific antibodies for the prevention and treatment of PEDV in newborn piglets. In this study, we produced an IgY against the PEDV S1 protein and investigated its immunoprophylactic effect in neonatal piglets. A codon-optimized PEDV S1 gene consisting of amino acid residues 25-749 was synthesized and used to establish a stable porcine cell line constitutively expressing a recombinant PEDV S1 protein containing the chicken immunoglobulin Fc fragment at its C-terminus. The purified recombinant S1 protein was found to mediate potent immune responses in immunized hens. We next tested the ability of oral passive immunization with anti-PEDV S1 IgY to protect piglets against PEDV. Specific chicken IgY against the S1 protein was orally administered to neonatal piglets, and their responses subsequent to a virulent PEDV challenge were monitored. The results showed that oral administration of anti-PEDV S1 IgY efficiently protects neonatal piglets against PEDV, suggesting its potential as a prophylactic or therapeutic agent against acute PEDV infection. PMID- 26100404 TI - Molecular characterization of a new human echovirus 11 isolate associated with severe hand, foot and mouth disease in Yunnan, China, in 2010. AB - Human echovirus 11 (E-11), a member of the species Enterovirus B, frequently causes aseptic meningitis and hand, foot and mouth disease (HFMD). We determined the complete genome sequence of strain 520K/YN/CHN/2010, isolated from a subject with HFMD and aseptic meningitis in Yunnan Province, China, in 2010. The strain shared 78.8% and 81.1% nucleotide sequence similarity with prototype strain Gregory in the complete VP1 gene and the complete genome, respectively. Only the VP2-VP3-VP1 genome region of 520K/YN/CHN/2010 was similar to that of the E-11 strain; the other genome regions were most similar to those of other members of the species Enterovirus B. Using phylogenetic analysis and sequence comparisons of the complete VP1 gene, E-11 strains could be divided into five genogroups, and the 520K/YN/CHN/2010 strain was found to belong to genogroup A. Recombination analysis showed evidence of recombination with other member of the species Enterovirus B, especially the E-9 strain MSH/KM812/2010. Persistent surveillance of HFMD pathogens might help predict potential emerging viruses and related disease outbreaks. PMID- 26100405 TI - Spatial distribution of Brucella antibodies with reference to indigenous cattle populations among contrasting agro-ecological zones of Uganda. AB - Indigenous cattle populations exhibit various degrees of agro-ecological fitness and provide desirable opportunities for investments to improve sustainable production for better rural small-scale farmers' incomes globally. However, they could be a source of infection to their attendants and other susceptible livestock if their brucellosis status remains unknown. This study investigated the spatial distribution of Brucella antibodies among indigenous cattle populations in Uganda. Sera from a total of 925 indigenous cattle (410 Ankole Bos taurus indicus, 50 Nganda and 465 East African Shorthorn Zebu (EASZ) - B. indicus) obtained randomly from 209 herds spread throughout Uganda were sequentially analysed for Brucella antibodies using the indirect (I) and competitive (C) enzyme linked Immuno-sorbent assays (ELISA). Recent incidences of abortion within the previous 12 months and routine hygienic practices during parturition were explored for public health risks. Brucella antibodies occurred in approximately 8.64% (80/925) and 28.70% (95% CI: 22.52, 34.89) of the sampled individual cattle and herds, respectively. Findings have shown that Ankole and EASZ cattle had similar seroprevalences. Indigenous cattle from the different study agro-ecological zones (AEZs) exhibited varying seroprevalences ranging from approximately 1.78% (95% CI: 0, 5.29) to 19.67% (95% CI: 8.99, 30.35) in the Lake Victoria Crescent (LVC) and North Eastern Drylands (NED) respectively. Significantly higher odds for Brucella antibodies occurred in the NED (OR: 3.40, 95% CI: 1.34, 8.57, p=0.01) inhabited by EASZ cattle compared to the KP (reference category) AEZ. Recent incidences of abortions within the previous 12 months were significantly (p<0.001) associated with seropositive herds. These findings add critical evidence to existing information on the widespread occurrence of brucellosis among indigenous cattle populations in Uganda and could guide allocation of meagre resources for awareness creation. And deployment of control strategies including culling of older cattle and those which have aborted during advanced gestation, enforcement of hygiene practices and mass vaccination. PMID- 26100406 TI - Randomized comparison of next-generation sequencing and array comparative genomic hybridization for preimplantation genetic screening: a pilot study. AB - BACKGROUND: Recent advances in next-generation sequencing (NGS) have provided new methods for preimplantation genetic screening (PGS) of human embryos from in vitro fertilization (IVF) cycles. However, there is still limited information about clinical applications of NGS in IVF and PGS (IVF-PGS) treatments. The present study aimed to investigate the effects of NGS screening on clinical pregnancy and implantation outcomes for PGS patients in comparison to array comparative genomic hybridization (aCGH) screening. METHODS: This study was performed in two phases. Phase I study evaluated the accuracy of NGS for aneuploidy screening in comparison to aCGH. Whole-genome amplification (WGA) products (n = 164) derived from previous IVF-PGS cycles (n = 38) were retrospectively analyzed with NGS. The NGS results were then compared with those of aCGH. Phase II study further compared clinical pregnancy and implantation outcomes between NGS and aCGH for IVF-PGS patients. A total of 172 patients at mean age 35.2 +/- 3.5 years were randomized into two groups: 1) NGS (Group A): patients (n = 86) had embryos screened with NGS and 2) aCGH (Group B): patients (n = 86) had embryos screened with aCGH. For both groups, blastocysts were vitrified after trophectoderm biopsy. One to two euploid blastocysts were thawed and transferred to individual patients primarily based on the PGS results. Ongoing pregnancy and implantation rates were compared between the two study groups. RESULTS: NGS detected all types of aneuploidies of human blastocysts accurately and provided a 100 % 24-chromosome diagnosis consistency with the highly validated aCGH method. Moreover, NGS screening identified euploid blastocysts for transfer and resulted in similarly high ongoing pregnancy rates for PGS patients compared to aCGH screening (74.7 % vs. 69.2 %, respectively, p >0.05). The observed implantation rates were also comparable between the NGS and aCGH groups (70.5 % vs. 66.2 %, respectively, p >0.05). CONCLUSIONS: While NGS screening has been recently introduced to assist IVF patients, this is the first randomized clinical study on the efficiency of NGS for preimplantation genetic screening in comparison to aCGH. With the observed high accuracy of 24-chromosome diagnosis and the resulting high ongoing pregnancy and implantation rates, NGS has demonstrated an efficient, robust high-throughput technology for PGS. PMID- 26100407 TI - FOXM1 binds directly to non-consensus sequences in the human genome. AB - BACKGROUND: The Forkhead (FKH) transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in most types of cancer. FOXM1, similar to other FKH factors, binds to a canonical FKH motif in vitro. However, genome-wide mapping studies in different cell lines have shown a lack of enrichment of the FKH motif, suggesting an alternative mode of chromatin recruitment. We have investigated the role of direct versus indirect DNA binding in FOXM1 recruitment by performing ChIP-seq with wild-type and DNA binding deficient FOXM1. RESULTS: An in vitro fluorescence polarization assay identified point mutations in the DNA binding domain of FOXM1 that inhibit binding to a FKH consensus sequence. Cell lines expressing either wild-type or DNA binding deficient GFP-tagged FOXM1 were used for genome-wide mapping studies comparing the distribution of the DNA binding deficient protein to the wild-type. This shows that interaction of the FOXM1 DNA binding domain with target DNA is essential for recruitment. Moreover, analysis of the protein interactome of wild-type versus DNA binding deficient FOXM1 shows that the reduced recruitment is not due to inhibition of protein protein interactions. CONCLUSIONS: A functional DNA binding domain is essential for FOXM1 chromatin recruitment. Even in FOXM1 mutants with almost complete loss of binding, the protein-protein interactions and pattern of phosphorylation are largely unaffected. These results strongly support a model whereby FOXM1 is specifically recruited to chromatin through co-factor interactions by binding directly to non-canonical DNA sequences. PMID- 26100408 TI - Vanda roxburghii chloroform extract as a potential source of polyphenols with antioxidant and cholinesterase inhibitory activities: identification of a strong phenolic antioxidant. AB - BACKGROUND: Alzheimer's disease (AD) is a progressively developing neurodegenerative disorder of the brain in the elderly people. Vanda roxburghii Rbr. root has been used traditionally in Bangladesh as tonic to brain and in the treatment of nervous system disorders including AD. Therefore, we aimed to investigate the cholinesterase inhibitory activities and antioxidant properties of the extracts from V. roxburghii. METHODS: The crude methanol extract from the roots of plant was sequentially fractionated with petroleum ether, chloroform, ethylacetate and water to yield their corresponding extracts. The extracts were assessed for acetylcholinesterase and butyrylcholinesterase inhibitory activity by modified Ellman method and antioxidant property by several assays including ferric reducing antioxidant power, scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and hydroxyl radical, and inhibition of lipid peroxidation. Endogenous substances in the extracts were analyzed by the standard phytochemical methods and active compound was isolated by the chromatographic methods. RESULTS: Chloroform extract was shown to demonstrate strong ferric-reducing antioxidant power and scavenging activity against DPPH and hydroxyl free radicals when compared with the other extracts and the reference standard catechin. The antioxidant effect was further verified by inhibition of lipid peroxidation in rat brain homogenates. Likewise, the chloroform extract exhibited the highest inhibition against both the acetylcholinesterase and butyrylcholinesterase enzymes with IC50 values of 221.13 and 82.51 MUg/ml, respectively. Phytochemical screening revealed a large amount of phenolics and flavonoids in the chloroform extract. Bioactivity guided separation techniques led to the isolation of a strong antioxidant from the chloroform extract and its structure was determined as gigantol on the basis of spectral studies. CONCLUSION: These results suggest that the chloroform extract of V. roxburghii, possibly due to its phenolic compounds, exert potential antioxidant and cholinesterase inhibitory activities, which may be useful in the treatment of AD. PMID- 26100409 TI - The Rise and Fall of TRP-N, an Ancient Family of Mechanogated Ion Channels, in Metazoa. AB - Mechanoreception, the sensing of mechanical forces, is an ancient means of orientation and communication and tightly linked to the evolution of motile animals. In flies, the transient-receptor-potential N protein (TRP-N) was found to be a cilia-associated mechanoreceptor. TRP-N belongs to a large and diverse family of ion channels. Its unusually long N-terminal repeat of 28 ankyrin domains presumably acts as the gating spring by which mechanical energy induces channel gating. We analyzed the evolutionary origins and possible diversification of TRP-N. Using a custom-made set of highly discriminative sequence profiles we scanned a representative set of metazoan genomes and subsequently corrected several gene models. We find that, contrary to other ion channel families, TRP-N is remarkably conserved in its domain arrangements and copy number (1) in all Bilateria except for amniotes, even in the wake of several whole-genome duplications. TRP-N is absent in Porifera but present in Ctenophora and Placozoa. Exceptional multiplications of TRP-N occurred in Cnidaria, independently along the Hydra and the Nematostella lineage. Molecular signals of subfunctionalization can be attributed to different mechanisms of activation of the gating spring. In Hydra this is further supported by in situ hybridization and immune staining, suggesting that at least three paralogs adapted to nematocyte discharge, which is key for predation and defense. We propose that these new candidate proteins help explain the sensory complexity of Cnidaria which has been previously observed but so far has lacked a molecular underpinning. Also, the ancient appearance of TRP-N supports a common origin of important components of the nervous systems in Ctenophores, Cnidaria, and Bilateria. PMID- 26100410 TI - Angiotensin II Receptor Blocker Neprilysin Inhibitor (ARNI): New Avenues in Cardiovascular Therapy. AB - The burden of cardiovascular disease (CVD) is continuously and progressively raising worldwide. Essential hypertension is a major driver of cardiovascular events, including coronary artery disease, myocardial infarction, ischemic stroke and congestive heart failure. This latter may represent the final common pathway of different cardiovascular diseases, and it is often mediated by progressive uncontrolled hypertension. Despite solid advantages derived from effective and sustained blood pressure control, and the widespread availability of effective antihypertensive medications, the vast majority of the more than 1 billion hypertensive patients worldwide continue to have uncontrolled hypertension. Among various factors that may be involved, the abnormal activation of neurohormonal systems is one consistent feature throughout the continuum of cardiovascular diseases. These systems may initiate biologically meaningful "injury responses". However, their sustained chronic overactivity often may induce and maintain the progression from hypertension towards congestive heart failure. The renin angiotensin-aldosteron system, the sympathetic nervous system and the endothelin system are major neurohormonal stressor systems that are not only able to elevate blood pressure levels by retaining water and sodium, but also to play a role in the pathophysiology of cardiovascular diseases. More recently, the angiotensin receptor neprilysin inhibitor (ARNI) represents a favourable approach to inhibit neutral endopeptidase (NEP) and suppress the RAAS via blockade of the AT1 receptors, without the increased risk of angioedema. LCZ696, the first-in-class ARNI, has already demonstrated BP lowering efficacy in patients with hypertension, in particular with respect to systolic blood pressure levels, improved cardiac biomarkers, cardiac remodelling and prognosis in patients with heart failure. This manuscript will briefly overview the main pathophysiological and therapeutic aspects of ARNI in the clinical management of hypertension and heart failure. PMID- 26100411 TI - Single-taxon field measurements of bacterial gene regulation controlling DMSP fate. PMID- 26100414 TI - Erratum to: Intraoperative detection of viable bone with fluorescence imaging using Visually Enhanced Lesion Scope in patients with bisphosphonate-related osteonecrosis of the jaw: clinical and pathological evaluation. PMID- 26100413 TI - A phase IV, two-armed, randomized, cross-over study comparing compliance with once-a-month administration of vitamin D3 to compliance with daily administration of a fixed-dose combination of vitamin D3 and calcium during two 6-month periods. AB - In a randomized, cross-over study, once monthly administration of vitamin D3 was preferred over a once daily administration of a fixed-dose combination of vitamin D3 and calcium, with a better compliance but without any significant difference in the increase in vitamin D levels. INTRODUCTION: The aim of the present study was to compare a once-monthly administration of vitamin D3 to a daily administration of a fixed-dose combination of vitamin D3 and calcium during two treatment periods of 6 months. METHODS: One hundred volunteers aged 50 years old or older were randomized to receive either one drinkable ampoule containing 25,000 IU vitamin D3 (D-Cure(r), SMB) once monthly (group VD) or one chewable tablet containing 1000 mg calcium carbonate + 800 IU vitamin D3 (Steovit Forte(r), Takeda) once daily (group VDCa) during 6 months. After the first 6 months of treatment, the groups were reversed according to the randomized cross over design. Treatment compliance (i.e. the primary outcome), preference, acceptability and vitamin D levels and adverse events were all collected. RESULTS: For the two periods, the patients had a significantly higher compliance in the VD group than in the VDCa group (p < 0.0001). During the study, 50 (56.8 %) patients preferred the VD treatment, 16 (18.2 %) patients preferred the VDCa, and for 22 (25.0 %) patients, neither treatment was preferred. At the end of the first 6 months of treatment, the mean (SD) increase of 25(OH)D was 6.57 ng/mL (8.19) in the VD group and 3.88 ng/mL (10.0) in the VDCa group (p = 0.16 between groups). CONCLUSION: In this study, a once-monthly administration of vitamin D3 was preferred over a once-daily administration of a fixed-dose combination of vitamin D3 and calcium, with a better compliance but without any significant difference in the increase in vitamin D levels. PMID- 26100415 TI - Erratum to: Milk fortified with vitamin D could reduce the prevalence of vitamin D deficiency among Japanese female college students. PMID- 26100412 TI - The calcium-sensing receptor in bone metabolism: from bench to bedside and back. AB - The calcium-sensing receptor (CaSR), a key player in the maintenance of calcium homeostasis, can influence bone modeling and remodeling by directly acting on bone cells, as demonstrated by in vivo and in vitro evidence. The modulation of CaSR signaling can play a role in bone anabolism. INTRODUCTION: The calcium sensing receptor (CaSR) is a key player in the maintenance of calcium homeostasis through the regulation of PTH secretion and calcium homeostasis, thus indirectly influencing bone metabolism. In addition to this role, in vitro and in vivo evidence points to direct effects of CaSR in bone modeling and remodeling. In addition, the activation of the CaSR is one of the anabolic mechanisms implicated in the action of strontium ranelate, to reduce fracture risk. METHODS: This review is based upon the acquisition of data from a PubMed enquiry using the terms "calcium sensing receptor," "CaSR" AND "bone remodeling," "bone modeling," "bone turnover," "osteoblast," "osteoclast," "osteocyte," "chondrocyte," "bone marrow," "calcilytics," "calcimimetics," "strontium," "osteoporosis," "skeletal homeostasis," and "bone metabolism." RESULTS: A fully functional CaSR is expressed in osteoblasts and osteoclasts, so that these cells are able to sense changes in the extracellular calcium and as a result modulate their behavior. CaSR agonists (calcimimetics) or antagonists (calcilytics) have the potential to indirectly influence skeletal homeostasis through the modulation of PTH secretion by the parathyroid glands. The bone anabolic effect of strontium ranelate, a divalent cation used as a treatment for postmenopausal and male osteoporosis, might be explained, at least in part, by the activation of CaSR in bone cells. CONCLUSIONS: Calcium released in the bone microenvironment during remodeling is a major factor in regulating bone cells. Osteoblast and osteoclast proliferation, differentiation, and apoptosis are influenced by local extracellular calcium concentration. Thus, the calcium-sensing properties of skeletal cells can be exploited in order to modulate bone turnover and can explain the bone anabolic effects of agents developed and employed to revert osteoporosis. PMID- 26100416 TI - The Impact of Sports Cardiology on the Practice of Primary Care Sports Medicine: Where Were We, Where Are We, Where Are We Headed? AB - This article is a commentary on the role of sports cardiologists in the athletic arena and the beneficial impact they offer sports medicine in the comprehensive care of competitive athletes. The focus is a dialogue on current recommendations for primary prevention of sudden cardiac arrest (SCA), incorporating elements of the preparticipation evaluation and continuing care of athletes with diagnosed heart disease (HD). The feasibility and potential advantages of implementing well designed preparticipation cardiovascular screening programs and the role of sports cardiologists to educate primary care team physicians on secondary prevention of SCA and proper treatment of underlying HD are discussed. PMID- 26100417 TI - The Cardiovascular Physiology of Sports and Exercise. AB - Athletes represent the extremes of human performance. Many of their remarkable abilities stem from a cardiovascular system that has adapted to meet the metabolic needs of exercising muscle. A large and compliant heart is a hallmark feature of athletes who engage in highly aerobic events. Despite high fitness levels, athletes may present with symptoms that limit performance. Understanding and dissecting these limitations requires a strong background in sports science and the factors that determine sports capabilities. This article reviews the basic principles of exercise physiology, cardiovascular adaptations unique to the "athlete's heart," and the utility of exercise testing in athletes. PMID- 26100418 TI - Cardiovascular Adaptation and Remodeling to Rigorous Athletic Training. AB - Exercise-induced cardiac remodeling is a complex process by which the cardinal hemodynamic stresses of pressure and volume lead to a host of structural or functional adaptations. In aggregate, the constellation of changes that accompany this process serve to facilitate athletic performance by minimizing the cardiac work inherent in athletic activity. Although several key determinants of athletic cardiac adaptation have been described, observed variability across athlete cohorts remains an incompletely understood area. Ongoing and future work are required to further understand this process and ultimately to determine where the boundary lies between adaptive physiology and maladaptive disease. PMID- 26100419 TI - The Electrocardiogram in Highly Trained Athletes. AB - Regular intensive exercise is associated with a constellation of several structural and functional adaptations within the heart that permit the generation of a large and sustained increase in cardiac output and/or increase in blood pressure. The magnitude with which these markers of physiological remodeling manifest on the surface electrocardiogram is governed by several factors and some athletes show electrical and structural changes that overlap with those observed in cardiomyopathy and in ion channel diseases, which are recognized causes of sudden cardiac death in young athletes. This article provides a critical appraisal of the athlete's ECG. PMID- 26100420 TI - Advanced Imaging of Athletes: Added Value of Coronary Computed Tomography and Cardiac Magnetic Resonance Imaging. AB - Cardiac magnetic resonance imaging and cardiac computed tomographic angiography have become important parts of the armamentarium for noninvasive diagnosis of cardiovascular disease. Emerging technologies have produced faster imaging, lower radiation dose, improved spatial and temporal resolution, as well as a wealth of prognostic data to support usage. Investigating true pathologic disease as well as distinguishing normal from potentially dangerous is now increasingly more routine for the cardiologist in practice. This article investigates how advanced imaging technologies can assist the clinician when evaluating all athletes for pathologic disease that may put them at risk. PMID- 26100421 TI - Cardiovascular Concerns in Water Sports. AB - The cardiac effects of aquatic sports have increased in interest with the experience of cardiac responses to swimming and diving. The syndrome of swimming induced pulmonary edema is likely caused by a combination of central blood shifts, sudden onset of high exercise demands, and impaired diastolic relaxation of the left ventricle. Divers also develop venous gas emboli caused by nitrogen supersaturation in blood and tissues during ascent from depth. The physiology and physics of water immersion and diving are unique. Knowledge of pressure effects, gas solubility, and changes in gas volumes with depth is needed to understand the disorders related to these activities. PMID- 26100422 TI - Diseases of the Aorta in Elite Athletes. AB - Sudden cardiovascular deaths in athletes are rare and only a fraction are due to aortic events. There has been concern that the hemodynamic load during exercise may lead to aortic dilation, but aortic dimensions in endurance and strength trained athletes are only slightly larger than those in sedentary comparison subjects. The presence of a bicuspid aortic valve without significant valvular dysfunction and normal aortic dimensions should not influence eligibility to practice sport. Patients with genetic syndromes associated with aortopathy generally should be restricted from vigorous sports participation. This article reviews the diagnosis and management of diseases of the aorta in athletes. PMID- 26100424 TI - Sports and Exercise in Athletes with Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease and one of the most common causes of sudden cardiac death (SCD). Current guidelines restrict the participation of patients with HCM in competitive sports, limiting the health benefits of exercise. However, many individuals with HCM have safely participated in sports, with a low incidence of SCD. Improved stratification of patients and desired activity may allow most individuals with HCM to engage in physical activity safely. Therefore, physicians should create an individualized approach in guiding each patient with HCM eager to enjoy the benefits of physical activity in a safe manner. PMID- 26100425 TI - Legal and Ethical Issues in the Cardiovascular Care of Elite Athletes. AB - This article presents an overview of the legal and ethical issues in the cardiovascular care of elite athletes. An important distinction between the assessment and care of elite athletes and the general population necessitates an understanding of the applicable legal standard and the limitation of potential exposures. Important recommendations and pertinent case law is presented that can assist the medical provider in comprehending important considerations with regard to preparticipation evaluations, return-to-play decisions, and second opinions in elite athletes. PMID- 26100426 TI - Something Old, Something New: Using Family History and Genetic Testing to Diagnose and Manage Athletes with Inherited Cardiovascular Disease. AB - A primary objective of the preparticipation physical examination is to identify athletes at increased risk for sudden cardiac arrest (SCA). Review of an athlete's family history may identify those at risk for SCA. Genetic testing for inherited cardiovascular disease has emerged as a valuable addition to the repertoire of cardiologists facing the decision of clearing athletes with concerning clinical signs and/or family histories. Genetic testing may lead to various outcomes for an athlete including: reassurance, diagnosis in those with borderline clinical features, finding disease predisposition prior to the onset of clinical signs (ie, genotype-positive/phenotype-negative), or continued uncertainty. PMID- 26100423 TI - Athletes with Implantable Cardioverter Defibrillators. AB - Athletes with an implantable cardioverter defibrillator (ICD) represent a diverse group of individuals who may be at an increased risk of sudden cardiac death when engaging in vigorous physical activity. Therefore, they are excluded by the current guidelines from participating in most competitive sports except those classified as low intensity, such as bowling and golf. The lack of substantial data on the natural history of the cardiac diseases affecting these athletes as well as the unknown efficacy of ICDs in terminating life-threatening arrhythmias occurring during intense exercise has resulted in the restrictive nature of these now decade old guidelines. PMID- 26100427 TI - How to Practice Sports Cardiology: A Cardiology Perspective. AB - The rigorous cardiovascular (CV) demands of sport, combined with training-related cardiac adaptations, render the athlete a truly unique CV patient and sports cardiology a truly unique discipline. Cardiologists are advised to adopt a systematic approach to the CV evaluation of athletes, taking into consideration the individual sports culture, sports-specific CV demands, CV adaptations and their appearance on cardiac testing, any existing or potential interaction of the heart with the internal and external sports environment, short- and long-term CV risks, and potential effect of performance-enhancing agents and antidoping regulations. This article outlines the systematic approach, provides a detailed example, and outlines contemporary sports cardiology core competencies. PMID- 26100428 TI - The Management of Athletes with Congenital Heart Disease. AB - Although rare, sudden cardiac death (SCD) is devastating to families and communities. Screening of athletes prior to sports participation by trained professionals is useful in identifying individuals who carry known risk factors for SCD. Inclusive in this population are those athletes with congenital heart disease. Sports medicine specialists should be able to identify those at risk for adverse events surrounding vigorous activity and direct appropriate evaluation by the specialist (ie, cardiologist) as deemed appropriate. Equally importantly, they should be able to coach individuals in order to improve performance and quality of life with exercise in a safe environment. PMID- 26100429 TI - The Historical Perspective of Athletic Sudden Death. AB - Since antiquity, the athlete has been elevated to a heroic status both within small communities and at the international level. Although numerous population studies have estimated athletic sudden death to be a rare event, the consequences resonate far beyond those directly affected. Sports cardiology has evolved as a result of these tragedies, which highlighted a need for safer play and more programmatic protection of the athlete in play. In this article, athletic sudden death is analyzed from a historical and literary perspective and the development of modern initiatives to protect athletes from sudden death is reviewed. PMID- 26100430 TI - Foreword. Sports Cardiology. PMID- 26100431 TI - Sports Cardiology: A Discipline Emerged. PMID- 26100432 TI - Weight Gain and Metabolic Changes During Treatment with Antipsychotics and Antidepressants. AB - Weight gain and metabolic disturbances are common side effects during psychopharmacological treatment with specific antipsychotics and antidepressants. The antipsychotics clozapine and olanzapine, and antidepressants tricyclics and mirtazapine have a high risk of inducing weight gain. Recently discovered pathophysiological mechanisms include antihistaminergic effects, activation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK), modulation of hormonal signaling of ghrelin and leptin, changes in the production of cytokines such as tumor necrosis factor-alpha (TNF)-alpha and adipokines such as adiponektin, and the impact of genes, in particular the melanocortin 4 receptor (MC4R), serotonin 2C receptor (HTR2C), leptin, neuropeptide Y (NPY) and cannabinoid receptor 1 (CNR1) genes. Metabolic changes associated with weight gain include disturbances of glucose and lipid metabolism. Clozapine and olanzapine may, in addition to mechanisms resulting from weight gain, impair glucose metabolism by blockade of the muscarinic M3 receptor (M3R). Antidepressants associated with weight gain appear to have fewer unfavourable effects on glucose and lipid metabolism than the second-generation antipsychotics clozapine and olanzapine. To assess the risk of weight gain and its consequences for the patient's health, assessing body weight changes and metabolic monitoring in the first week of treatment as well as in long-term treatment is recommended. PMID- 26100433 TI - Controlled Synthesis of Ultrathin Lanthanide Oxide Nanosheets and Their Promising pH-Controlled Anticancer Drug Delivery. AB - Various lanthanide oxides (Sm2 O3 and Gd2 O3 ) nanostructures were synthesized by a facile hydrothermal method. The loss of surfactants on the nanocrystals surface, followed by the resultant assembly is responsible for the formation of ultrathin nanosheets. Owing to strong surface effects, the different morphologies of the Sm2 O3 :5 % Eu and Gd2 O3 :5 % Eu nanocrystals present unique photoluminescence properties. As a proof-of-concept application, the as-obtained Sm2 O3 and Gd2 O3 ultrathin nanosheets exhibit promising pH-controlled anticancer drug-delivery behavior. PMID- 26100435 TI - Normative approaches and activism in global bioethics. PMID- 26100436 TI - Molecular detection of Bartonella clarridgeiae in domestic cats from Midwest Brazil. PMID- 26100437 TI - Validation and clinical application of a nested PCR for paracoccidioidomycosis diagnosis in clinical samples from Colombian patients. AB - Paracoccidioidomycosis is a systemic and endemic mycosis, restricted to tropical and subtropical areas of Latin America. The infection is caused by the thermal dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii. The diagnosis of paracoccidioidomycosis is usually performed by microscopic examination, culture and immunodiagnostic tests to respiratory specimens, body fluids and/or biopsies; however these methods require laboratory personnel with experience and several days to produce a result. In the present study, we have validated and evaluated a nested PCR assay targeting the gene encoding the Paracoccidioides gp43 membrane protein in 191 clinical samples: 115 samples from patients with proven infections other than paracoccidioidomycosis, 51 samples as negative controls, and 25 samples from patients diagnosed with paracoccidioidomycosis. Additionally, the specificity of the nested PCR assay was also evaluated using purified DNA isolated from cultures of different microorganisms (n=35) previously identified by culture and/or sequencing. The results showed that in our hands, this nested PCR assay for gp43 protein showed specificity and sensitivity rates of 100%. The optimized nested PCR conditions in our laboratory allowed detection down to 1fg of P. brasiliensis DNA. PMID- 26100438 TI - Early predictive efficacy of core antigen on antiviral outcomes in genotype 1 hepatitis C virus infected patients. AB - Response-guided therapy is of limited use in developing countries because hepatitis C virus RNA detection by sensitive molecular methods is time- and labor consuming and expensive. We evaluated early predictive efficacy of serum hepatitis C virus core antigen kinetics on sustained virologic response in patients with genotype 1 hepatitis C virus during pegylated interferon plus ribavirin treatment. For 478 patients recruited, hepatitis C virus RNAs were detected at baseline, and at weeks 4, 12, 24, 48, and 72 using Cobas TaqMan. Architect hepatitis C virus core antigen was performed at baseline, and weeks 4 and 12. Predictive values of hepatitis C virus core antigen on sustained virologic response were compared to hepatitis C virus RNA. In the first 12 weeks after treatment initiation the dynamic patterns of serum hepatitis C virus core antigen and hepatitis C virus RNA levels were similar in sustained virologic response, relapse, and null response patients groups. Although areas under the receiver operating characteristics curves of hepatitis C virus core antigen were lower than those of hepatitis C virus RNA at the same time points, modeling analysis showed that undetectable hepatitis C virus core antigen (rapid virological response based on hepatitis C virus core antigen) had similar positive predictive value on sustained virologic response to hepatitis C virus RNA at week 4 (90.4% vs 93.3%), and hepatitis C virus core antigen decrease greater than 1log10IU/mL (early virological response based on hepatitis C virus core antigen) had similar negative predictive value to hepatitis C virus RNA at week 12 (94.1% vs 95.2%). Analysis on the validation group demonstrated a positive predictive value of 97.5% in rapid virological response based on hepatitis C virus core antigen and a negative predictive value of 100% in early virological response based on hepatitis C virus core antigen. In conclusion, hepatitis C virus core antigen is comparable to hepatitis C virus RNA in predicting sustained virologic response of chronic genotype 1 hepatitis C virus infected patients, and can be used to guide anti-hepatitis C virus treatment, especially in resource-limited areas. PMID- 26100439 TI - Effect of mitochondrial stress on systemic metabolism. AB - In our studies investigating the role of autophagy in systemic metabolism, we found that mitochondrial dysfunction due to autophagy deficiency in insulin target tissues, such as skeletal muscle or liver, leads to the induction of fibroblast growth factor (FGF)21 as a mitokine and protection against obesity and insulin resistance. In the following studies, we observed that metformin, one of the most widely used antidiabetic medications, induces mitochondrial stress and induces FGF21 through a PERK-eIF2alpha-ATF4 pathway, which may contribute to the antidiabetic effect of metformin. Amino acid deprivation also induced ATF4 and FGF21, while the role of mitochondrial dysfunction in this condition is not yet clear. These results suggest the possibility that mitochondrial stress inducing an integrated stress response can induce a mitokine response and affect systemic metabolism in a non-cell-autonomous manner, in addition to the well-recognized cell-autonomous role of mitochondrial function in metabolism. PMID- 26100440 TI - Design, synthesis and preliminary biological evaluation of indoline-2,3-dione derivatives as novel HDAC inhibitors. AB - Histone deacetylases (HDACs) are zinc-dependent or NAD(+) dependent enzymes and play a critical role in the process of tumor development. Herein a series of indoline-2,3-dione derivatives have been designed and synthesized as potential HDACs inhibitors. The preliminary biological evaluation showed that most compounds synthesized have exhibited moderate Hela cell nuclear extract inhibitory activities, among which compound 25a (IC50=10.13 nM) has shown the best efficacy. The anti-proliferative activities of some of these compounds were also discussed. PMID- 26100441 TI - Orally active ghrelin receptor inverse agonists and their actions on a rat obesity model. AB - A series of 2-alkylamino nicotinamide analogs was prepared as orally active ghrelin receptor (ghrelinR) inverse agonists. Starting from compound 1, oral bioavailability was improved by modifying metabolically unstable sites and reducing molecular weight. Brain-permeable compound 33 and compound 24 with low brain permeability were tested in rat models of obesity; 30 mg/kg of compound 33 suppressed weight gain. PK/PD analysis revealed that the anti-obesity effect of ghrelinR inverse agonists depends on their brain concentrations. PMID- 26100442 TI - Discovery of novel, potent, selective and cellular active ADC type PTP1B inhibitors via fragment-docking-oriented de novel design. AB - Fragment-docking-oriented de novel design for both the catalytic site and the C phosphotyrosine binding site led to the discovery of novel scaffold and chemical easy N-(2,5-diethoxy-phenyl)-methanesulfonamide based phosphotyrosine mimetics that when incorporated into ureas are high potent and selective inhibitors of protein tyrosine phosphatase 1B. Among them, compound 15 was shown to be the most potent PTP1B inhibitor with great selectivity over the highly homologous T-cell protein tyrosine phosphatase. PMID- 26100443 TI - Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time dependent inhibition and phototoxic liabilities. AB - Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6 difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3 (trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3 dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8 nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO-LUMO gap hypothesis during the course of optimization efforts. PMID- 26100444 TI - Subjective perception of sleepiness in a driving simulator is different from that in the Maintenance of Wakefulness Test. AB - OBJECTIVE: To test whether sleep-deprived, healthy subjects who do not always signal spontaneously perceived sleepiness (SPS) before falling asleep during the Maintenance of Wakefulness Test (MWT) would do so in a driving simulator. METHODS: Twenty-four healthy subjects (20-26 years old) underwent a MWT for 40 min and a driving simulator test for 1 h, before and after one night of sleep deprivation. Standard electroencephalography, electrooculography, submental electromyography, and face videography were recorded simultaneously to score wakefulness and sleep. Subjects were instructed to signal SPS as soon as they subjectively felt sleepy and to try to stay awake for as long as possible in every test. They were rewarded for both "appropriate" perception of SPS and staying awake for as long as possible. RESULTS: After sleep deprivation, seven subjects (29%) did not signal SPS before falling asleep in the MWT, but all subjects signalled SPS before falling asleep in the driving simulator (p <0.004). CONCLUSIONS: The previous results of an "inaccurate" SPS in the MWT were confirmed, and a perfect SPS was shown in the driving simulator. It was hypothesised that SPS is more accurate for tasks involving continuous feedback of performance, such as driving, compared to the less active situation of the MWT. Spontaneously perceived sleepiness in the MWT cannot be used to judge sleepiness perception while driving. Further studies are needed to define the accuracy of SPS in working tasks or occupations with minimal or no performance feedback. PMID- 26100445 TI - Calcium and aluminum cycling in a temperate broadleaved deciduous forest of the eastern USA: relative impacts of tree species, canopy state, and flux type. AB - Ca/Al molar ratios are commonly used to assess the extent of aluminum stress in forests. This is among the first studies to quantify Ca/Al molar ratios for stemflow. Ca/Al molar ratios in bulk precipitation, throughfall, stemflow, litter leachate, near-trunk soil solution, and soil water were quantified for a deciduous forest in northeastern MD, USA. Data were collected over a 3-year period. The Ca/Al molar ratios in this study were above the threshold for aluminum stress (<1). Fagus grandifolia Ehrh. (American beech) had a median annual stemflow Ca/Al molar ratio of 15.7, with the leafed and leafless values of 12.4 and 19.2, respectively. The corresponding Ca/Al molar ratios for Liriodendron tulipifera L. (yellow poplar) were 11.9 at the annual time scale and 11.9 and 13.6 for leafed and leafless periods, respectively. Bayesian statistical analysis showed no significant effect of canopy state (leafed, leafless) on Ca/Al molar ratios. DOC was consistently an important predictor of calcium, aluminum, and Ca/Al ratios. pH was occasionally an important predictor of calcium and aluminum concentrations, but was not a good predictor of Ca/Al ratio in any of the best-fit models (of >500 examined). This study supplies new data on Ca/Al molar ratios for stemflow from two common deciduous tree species. Future work should examine Ca/Al molar ratios in stemflow of other species and examine both inorganic and organic aluminum species to better gauge the potential for, and understand the dynamics of, aluminum toxicity in the proximal area around tree boles. PMID- 26100446 TI - Glutamatergic regulation of brain histamine neurons: In vivo microdialysis and electrophysiology studies in the rat. AB - The interactions between the glutamatergic and the histaminergic systems in the brain are not fully understood. Here we studied histamine release in the medial prefrontal cortex and the posterior hypothalamus-tuberomamillary nucleus (PH-TMN) using in vivo microdialysis and electrophysiological recordings of histaminergc neurons in the PH-TMN in vivo to further address the mechanistic details of these interactions. We demonstrated that histaminergic activity was regulated by group II metabotropic glutamate receptors (mGluR 2 and 3) using systemic dosing with mGluR 2/3 agonist and antagonists and an mGluR 2 positive allosteric modulator. These interactions likely occur via direct modulation of glutamate release in the PH-TMN. The importance of circadian rhythm for histamine release was also shown using microdialysis studies with mGluR 2/3 compounds under light and dark conditions. Based on histamine release studies with NMDA and ketamine, we propose the existence of two sub-populations of NMDA receptors where one subtype is located on histaminergic cell bodies in the PH-TMN and the second on GABA-ergic neurons projecting to the PH-TMN. These subpopulations could be distinguished based on function, notably opposing actions were seen on histamine release in the medial prefrontal cortex of the rat. In summary, this paper provides evidence that the histaminergic system is closely regulated by glutamate neurons in multiple ways. In addition, this interaction depends to a great extent on the activity state of the subject. PMID- 26100447 TI - Editor's choice - thirty day outcomes and costs of fenestrated and branched stent grafts versus open repair for complex aortic aneurysms. AB - OBJECTIVE: To compare 30 day outcomes and costs of fenestrated and branched stent grafts (f/b EVAR) and open surgery (OSR) for the treatment of complex abdominal aortic aneurysms (AAA) and thoraco-abdominal aortic aneurysms (TAAA). METHODS: The multicenter prospective registry WINDOW was set up to evaluate f/b EVAR in high risk patients with para/juxtarenal AAA, and infradiaphragmatic and supradiaphragmatic TAAA. A control group of patients treated by OSR was extracted from the national hospital discharge database. The primary endpoint was 30 day mortality. Secondary endpoints included severe complications, length of stay, and costs. Mortality was assessed by survival analysis and uni/multivariate Cox regression analyses using pre- and post-operative characteristics. Bootstrap methods were used to estimate the cost-effectiveness of f/b EVAR versus OSR. RESULTS: Two hundred and sixty eight cases and 1,678 controls were included. There was no difference in 30 day mortality (6.7% vs. 5.4%, p = 0.40), but costs were higher with f/b EVAR (?38,212 vs. ?16,497, p < .001). After group stratification, mortality was similar with both treatments for para/juxtarenal AAA (4.3% vs. 5.8%, p = .26) and supradiaphragmatic TAAA (11.9% vs. 19.7%, p = .70), and higher with f/b EVAR for infradiaphragmatic TAAA (11.9% vs. 4.0%, p = .010). Costs were higher with f/b EVAR for para/juxtarenal AAA (?34,425 vs. ?14,907, p < .0001) and infradiaphragmatic TAAA (?37,927 vs. ?17,530, p < .0001), but not different for supradiaphragmatic TAAA (?54,710 vs. ?44,163, p = .18). CONCLUSION: f/b EVAR does not appear justified for patients with para/juxtarenal AAA and infradiaphragmatic TAAA fit for OSR but may be an attractive option for patients with para/juxtarenal AAA not eligible for surgery and patients with supradiaphragmatic TAAA. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov/ct2/show/NCT01168037; identifier: NCT01168037 (WINDOW registry). PMID- 26100448 TI - Do blood constituents in varicose veins differ from the systemic blood constituents? AB - OBJECTIVE: Varicose veins represent one of the most frequent vascular diseases and are in most cases benign. However, advanced disease is frequently associated with complications such as chronic venous insufficiency and superficial vein thrombosis. The pathogenic mechanisms are not well understood. Besides increased venous pressure, it is suggested that local blood constituents trigger various mechanisms responsible for the progression of the disease and its complications. DESIGN: The aim of this study was to investigate the changes in the blood in varicose veins and to compare them with the systemic markers of inflammation and endothelial damage. MATERIALS AND METHODS: Forty patients with primary varicose veins were included in the study. Most patients were class C2. Blood samples were taken from the leg from the tortuous and dilated varicose tributaries of the great saphenous vein and from the cubital vein. RESULTS: The values of basic hematologic tests were comparable between blood samples (varicose vs. systemic). In varicose veins, the following parameters were significantly increased in comparison with systemic blood: hsCRP (3.12 +/- 2.18 mg/L vs. 2.04 +/- 2.21 mg/L, p = .04), IL-6 (3.54 +/- 2.59 pg/mL vs. 2.25 +/- 1.27 pg/mL, p = .008), vWF (118.4 +/- 27% vs. 83.2 +/- 22%, p < .05). D-dimer, in samples taken from the leg varicose veins, was also significantly higher than in the systemic blood (104.3 +/- 9.3 ng/mL vs. 89.5 +/- 8.3 ng/mL, p = .039). CONCLUSIONS: Some inflammatory markers and indicators of endothelial dysfunction are increased in varicose vein blood. This is most probably the consequence of deteriorated blood flow in dilated and tortuous superficial veins, and increased venous pressure. Damage to the venous wall, which causes a chronic inflammatory response, together with the procoagulant properties of local blood may promote further progression of the disease and thrombotic complications. PMID- 26100449 TI - Modified Petticoat Technique with Pre-placement of a Distal Bare Stent Improves Early Aortic Remodeling after Complicated Acute Stanford Type B Aortic Dissection. AB - OBJECTIVE: This study evaluates the safety and efficacy of pre-placement of a distal bare stent as an adjunct to thoracic endovascular aortic repair (TEVAR) in the setting of complicated acute Stanford type B aortic dissection (cTBAD). METHODS: The records of all patients diagnosed with cTBAD at the institution between 2010 and 2013 were reviewed. Indications for the pre-placement of a distal bare stent included symptomatic malperfusion and/or radiological evidence of true lumen collapse. Computed tomography angiography was performed post operatively to assess aortic remodeling. RESULTS: 148 patients were treated for cTBAD: 113 patients (76.4%) were treated with standard TEVAR and 35 (23.6%) were treated by combined proximal TEVAR with pre-placement of an adjunctive distal bare stent. Primary technical success was 95.9%. The 30 day mortality rate was 4.1% and was not different between groups. The 30 day morbidity included transient renal failure (10.1%), endoleak (7.4%), and paraplegia (2.7%), and was not different between groups. The mean follow up was 10 months (range 2-12 months). No late stent complications were observed; patients with an adjunctive bare stent had less distal re-dissection (0% vs. 15%; p = .01) and fewer endovascular re-interventions (5.7% vs. 20.4%; p = .04). At 1 year, patients treated with TEVAR and an adjunctive distal bare stent had increased true lumen volume (166 vs. 110 mL; p = .022), decreased false lumen volume (60 vs. 90 mL; p = .043), and increased complete false lumen thrombosis in the thoracic (76.5% vs. 29.5%; p < .001) and abdominal (20.6% vs. 3.8%; p = .002) segments. CONCLUSIONS: Combined pre-placement of a distal bare stent as an adjunct to proximal TEVAR to treat cTBAD restricts oversizing of the distal stent graft, reducing the potential for distal true lumen collapse and visceral malperfusion, and improving remodeling of the dissected thoracic aorta. Long-term follow up and prospective studies are needed to assess the overall effectiveness of this treatment strategy. PMID- 26100450 TI - F-EVAR does not Impair Renal Function more than Open Surgery for Juxtarenal Aortic Aneurysms: Single Centre Results. AB - OBJECTIVE: To compare the results of elective open surgical repair (OSR) and total endovascular repair of juxtarenal aortic aneurysms (JAA), with either the Cook Zenith or the Vascutek Anaconda fenestrated stent grafts (F-EVAR) in a university hospital setting. PATIENTS AND METHODS: Between April 1999 and July 2014, of 926 patients with an abdominal aortic aneurysm, 69 were juxtarenal, where 34 had an elective OSR and 35 had F-EVAR. A post-operative rise of baseline creatinine by >50% and/or deterioration of estimated glomerular filtration rate by 25% were defined as renal failure. RESULTS: The demographics of the patients were similar except for heart insufficiency, peripheral arterial disease, and pre existing renal artery stenosis (p < .05). Median aneurysm diameters were 57 mm (range 50-80 mm) and 56 mm (range 36-64 mm) (p = .194), respectively, and the median pre-operative serum creatinine levels were 94 MUmol/L (range 65-286 MUmol/L) and 96 MUmol/L (range 57-333 MUmol/L) (p = .871) with median estimated glomerular filtration rate of 68 mL/min (range 21-117 mL/min) and 70 mL/min (range 18-114 mL/min) (p = .308) in the open and endovascular groups, respectively. The technical success (OSR versus F-EVAR) was 100% versus 94.3% with complete exclusion of the aneurysms in all cases. Median procedure time was 171 versus 188 min. During median in hospital stay of 11 versus 7 days (p = .05), mortality was 0 versus 2.9% and new onset of post-operative renal insufficiency was detected in 26.5% versus 8.5% patients (p = .05), although with 11.8% versus 5.7% being persistent (p = .428). During follow up, statistically similar new (late or persistent post-operative) renal insufficiency was detected in 14.7% versus 8.8% with dialysis in 3% of patients in each group with similar mortality within the 24 months. CONCLUSIONS: This retrospective analysis demonstrates that OSR might be combined with more acute post-operative renal impairment than F-EVAR for JAA, but with similar intermediate term procedure related mortality and renal outcomes. PMID- 26100451 TI - Early aqueous activity on the ordinary and carbonaceous chondrite parent bodies recorded by fayalite. AB - Chronology of aqueous activity on chondrite parent bodies constrains their accretion times and thermal histories. Radiometric (53)Mn-(53)Cr dating has been successfully applied to aqueously formed carbonates in CM carbonaceous chondrites. Owing to the absence of carbonates in ordinary (H, L and LL), and CV and CO carbonaceous chondrites, and the lack of proper standards, there are no reliable ages of aqueous activity on their parent bodies. Here we report the first (53)Mn-(53)Cr ages of aqueously formed fayalite in the L3 chondrite Elephant Moraine 90161 as Myr after calcium-aluminium-rich inclusions (CAIs), the oldest Solar System solids. In addition, measurements using our synthesized fayalite standard show that fayalite in the CV3 chondrite Asuka 881317 and CO3 like chondrite MacAlpine Hills 88107 formed and Myr after CAIs, respectively. Thermal modelling, combined with the inferred conditions (temperature and water/rock ratio) and (53)Mn-(53)Cr ages of aqueous alteration, suggests accretion of the L, CV and CO parent bodies ~1.8-2.5 Myr after CAIs. PMID- 26100452 TI - Influence of macular oedema on the measurement of macular pigment optical density. AB - INTRODUCTION: The purpose of this study was to determine macular pigment optical density (MPOD) in patients with macular degeneration as well as in patients with non-proliferative diabetic retinopathy. METHODS: Fifty-one phakic patients with either age-related macular degeneration (60 eyes of 30 patients; average age, 70.9 years) or non-proliferative diabetic retinopathy (42 eyes of 21 patients; average age, 61.7 years) were included in this cross-sectional study. Within the groups, patients were divided into those suffering from macular oedema and those with no oedema. An intra-subject comparison between eyes was carried out in both groups. Data were investigated on the basis of the coefficient of determination (R (2)). Macular pigment optical density was measured by fundus reflectometry using the one-wavelength reflection method (Visucam 500; Carl Zeiss Meditec AG, Jena, Germany), in conformity with the method described by Schweitzer et al. (2010). We evaluated the maximum optical density in the measurement area (max OD) and the average optical density across the reference area in the measurement area (mean OD). Specifically, the influence of macular oedema on macular pigment optical density was examined. The subsequent measurement of retinal thickness was carried out by spectral-domain optical coherence tomography (Spectralis SD-OCT, Heidelberg Engineering GmbH, Heidelberg, Germany). RESULTS: The current study included two groups. The first group consisted of patients with non-proliferative diabetic retinopathy, as follows: no macular oedema on either side (max OD: R (2) = 43.2 %, p = 0.16; mean OD: R (2) = 68.7 %, p = 0.04); one-sided macular oedema (max OD: R(2) = 16 %, p = 0.60; mean OD: R(2) = 100 %, p = 0.04); or macular oedema in both eyes (max OD: R(2) = 79.7 %, p < 0.01; mean OD: R(2) = 81.4 %, p < 0.01). The second group comprised patients with age-related macular degeneration (AMD), as follows: non-exudative changes on both sides (max OD: R(2) = 64.0 %, p = 0.20; mean OD: R (2) = 16 %, p = 0.60); one-sided exudative macular changes (max OD: R (2) = 50.6 %, p < 0.01; mean OD: R (2) = 20.8 %, p = 0.04); or exudative macular degeneration on both sides (max OD: 3 R (2) = 6.0 %, p = 0.29; mean OD: R (2)= 81.0 %, p = 0.04). The data available presented a correlation of MPOD values of both eyes of an individual within the groups investigated. In this respect, the data of the partner eyes within the group of patients with diabetic retinopathy were more highly correlated with each other than the values of both eyes of patients suffering from age-related macular degeneration. CONCLUSIONS: The present study showed that macular oedema did not seem to have an influence on a valid measurement of MPOD by one-wavelength fundus reflectometry. Thus, meaningful data could also be obtained on patients with exudative retinal changes. PMID- 26100453 TI - A morphological study of amblyopic eyes in children failing to achieve normal visual acuity after electronically monitored long-term occlusion treatment. AB - PURPOSE: To search for morphological abnormalities in compliant unilaterally amblyopic children with poor occlusion treatment outcomes, for the first time with electronically recorded patching dosage. We included school children with remaining interocular logMAR (logarithm of the minimum angle of resolution) difference >= 0.3 after patching time of more than 22 months and 1300 h total in a previous prospective study. METHODS: Six patients with a mean age of 11.19 years were included. Four patients had anisometropic amblyopia and two patients had a mixed strabismic and anisometropic amblyopia. Best-corrected visual acuity, cycloplegic refraction, dilated fundus examination, optic disc morphology and macular thickness using optical coherence tomography (OCT), retinal visual acuity, color perception, and the presence of a relative afferent pupillary defect (RAPD) were assessed. Paired t tests were performed to compare optic disc values and macular thickness of the amblyopic eyes to those of the fellow eyes. RESULTS: Average (+/- SD) logMAR VA in the amblyopic eyes was 0.42 (+/-0.23) with a remaining average interocular difference (IOD) of 0.51 (+/- 0.23), despite electronically monitored occlusion treatment of more than 1300 h. All patients presented with hyperopia and a significantly different mean spherical equivalent of + 4.73 (+/- 2.73) D in the amblyopic eye compared with the fellow eye (p = 0.02). A statistically significant difference in macular thickness was found between amblyopic and fellow eyes, with amblyopic eyes having an increased average thickness (p = 0.0062) and total volume (p = 0.0091) of the macula. One patient had familial hereditary primary macrodisc in both eyes. CONCLUSIONS: Our results provide evidence that average macular thickness and total macular volume tended to be increased among these compliant amblyopic children with unsatisfactory occlusion treatment outcomes. Further studies are warranted to evaluate whether morphological changes may have an impact on the effectiveness of amblyopia treatment. Moreover, our findings suggest that greater magnitude of hyperopia and anisometropia as well as older age may be risk factors associated with a poor visual acuity outcome among compliant amblyopic children. PMID- 26100454 TI - Partial volumes of cholesterol and monounsaturated diacylphosphatidylcholines in mixed bilayers. AB - Dispersions of multilamellar liposomes prepared from monounsaturated diacylphosphatidylcholines having 18-24 carbons and from varying amounts of cholesterol were studied by densitometry. Ideal mixing of the studied phosphatidylcholines with cholesterol in the fluid phase was observed. The temperature dependence of partial volumes of both phosphatidylcholines and cholesterol was determined. A slight decrease in the partial volume of cholesterol with the lengthening of the acyl chain of the host phosphatidylcholine was observed. By measuring the density of multilamellar liposomes of dinervonoylposphatidylcholine and cholesterol below the main phase transition temperature, the phase boundary between the solid ordered phase and the area of coexistence of the solid ordered and liquid ordered phases was detected. PMID- 26100455 TI - Negative mental imagery in public speaking anxiety: Forming cognitive resistance by taxing visuospatial working memory. AB - BACKGROUND AND OBJECTIVES: This study sought to reconcile two lines of research. Previous studies have identified a prevalent and causal role of negative imagery in social phobia and public speaking anxiety; others have demonstrated that lateral eye movements during visualisation of imagery reduce its vividness, most likely by loading the visuospatial sketchpad of working memory. It was hypothesised that using eye movements to reduce the intensity of negative imagery associated with public speaking may reduce anxiety resulting from imagining a public speaking scenario compared to an auditory control task. METHODS: Forty undergraduate students scoring high in anxiety on the Personal Report of Confidence as a Speaker scale took part. A semi-structured interview established an image that represented the participant's public speaking anxiety, which was then visualised during an eye movement task or a matched auditory task. Reactions to imagining a hypothetical but realistic public speaking scenario were measured. RESULTS: As hypothesised, representative imagery was established and reduced in vividness more effectively by the eye movement task than the auditory task. The public speaking scenario was then visualised less vividly and generated less anxiety when imagined after performing the eye movement task than after the auditory task. LIMITATIONS: Self-report measures and a hypothetical scenario rather than actual public speaking were used. Replication is required in larger as well as clinical samples. CONCLUSIONS: Visuospatial working memory tasks may preferentially reduce anxiety associated with personal images of feared events, and thus provide cognitive resistance which reduces emotional reactions to imagined, and potentially real-life future stressful experiences. PMID- 26100456 TI - [Some comments to the letter "Controversy to use icatibant for prophylaxis in angioedema"]. PMID- 26100457 TI - Outcome and treatment of elderly patients with ANCA-associated vasculitis. AB - BACKGROUND AND OBJECTIVES: ANCA-associated vasculitis is commonly found in elderly patients, but there are few data concerning outcome and treatment in the highest age groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Consecutive patients (N=151) presenting between 1997 and 2009 were retrospectively included from local registries in six centers in Sweden, the United Kingdom, and the Czech Republic if diagnosed with microscopic polyangiitis or granulomatosis with polyangiitis at age >=75 years during the study period. Patients were followed until 2 years from diagnosis or death. Data on survival and renal function were analyzed with respect to age, sex, ANCA specificity, renal function, C-reactive protein, comorbidities, and Birmingham Vasculitis Activity Score at diagnosis as well as treatment during the first month. RESULTS: Median follow-up was 730 days (interquartile range, 244-730). Overall 1-year survival was 71.5% and 2-year survival was 64.6%. Older age, higher creatinine, and lower Birmingham Vasculitis Activity Score were associated with higher mortality in multivariable analysis. Patients who were not treated with standard immunosuppressive therapy had significantly worse survival. Renal survival was 74.8% at 1 year. No new cases of ESRD occurred during the second year. High creatinine at diagnosis was the only significant predictor of renal survival in multivariable analysis. CONCLUSIONS: ANCA-associated vasculitis is a disease with substantial mortality and morbidity among elderly patients. This study showed a better prognosis for those who received immunosuppressive treatment and those who were diagnosed before having developed advanced renal insufficiency. PMID- 26100458 TI - Treating elderly patients with ANCA-associated vasculitis. PMID- 26100459 TI - Coauthorship and 'soft colonialism'. PMID- 26100462 TI - RN4CAST@IT: why is it important for Italy to take part in the RN4CAST project? PMID- 26100463 TI - EMG and force production of the flexor hallucis longus muscle in isometric plantarflexion and the push-off phase of walking. AB - Large forces are generated under the big toe in the push-off phase of walking. The largest flexor muscle of the big toe is the flexor hallucis longus (FHL), which likely contributes substantially to these forces. This study examined FHL function at different levels of isometric plantarflexion torque and in the push off phase at different speeds of walking. FHL and calf muscle activity were measured with surface EMG and plantar pressure was recorded with pressure insoles. FHL activity was compared to the activity of the calf muscles. Force and impulse values were calculated under the big toe, and were compared to the entire pressed area of the insole to determine the relative contribution of big toe flexion forces to the ground reaction force. FHL activity increased with increasing plantarflexion torque level (F=2.8, P=0.024) and with increasing walking speed (F=11.608, P<0.001). No differences were observed in the relative contribution of the force under the big toe to the entire sole between different plantarflexion torque levels (F=0.836, P=0.529). On the contrary, in the push-off phase of walking, peak force under the big toe increased at a higher rate than force under the other areas of the plantar surface (F=3.801, P=0.018), implying a greater relative contribution to total force at faster speeds. Moreover, substantial differences were found between isometric plantarflexion and walking concerning FHL activity relative to that of the calf muscles, highlighting the task-dependant behaviour of FHL. PMID- 26100464 TI - A phenomenological contact model: Understanding the graft-tunnel interaction in anterior cruciate ligament reconstructive surgery. AB - In this paper, we sought to expand the fidelity of a validated model of the anterior cruciate ligament reconstruction (ACL-R) procedure by incorporating a stick-slip contact model with linear pressure-overclosure relationship at the interface. The suggested model is characterized by three unknown parameters, friction coefficient, shear stress softening and contact stiffness. In the absence of any isolated experiments exploring the graft-tunnel interactions during an aggregate joint load, the calibration data used in this study are derived from a reported biomechanical study. A Bayesian calibration procedure was employed to find the unknown probability distribution function (PDF) of these contact parameters. Initially, the response surface approximations of the predicted graft forces from laxity test simulations was adopted to estimate the likelihood of noisy experimental data reported in the literature. Then, the wide domain of contact parameters was sampled sequentially based on the Marcov Chain Monte Carlo (MCMC) method with acceptance-rejection criteria to search for population of samples in significantly narrower domain of unknown parameters that are associated with the highest occurrence likelihood of noisy experimental data. Our simulations with calibrated contact parameters indicate that pre-tensioning applied at 30 degrees of flexion leads to larger graft force after the joint is fully extended compared to the graft force when the same pre-tensioning force is applied at full extension. Moreover, regardless of the pre-tensioning force, the graft-tunnel contact pressure is larger when the fixation of the graft is performed at full extension, increasing with the pre-tensioning force. PMID- 26100465 TI - Electronic cigarettes: The nicotyrine hypothesis. AB - There are conflicting reports about the efficacy of electronic cigarettes (e cigs) as nicotine delivery devices and smoking cessation products. In addition, smokers' responses to some nicotine dependence questions often change as they transition to exclusive e-cig use. Nicotyrine may explain these observations. Nicotyrine forms by the gradual oxidation of nicotine in e-liquids exposed to air. E-cigs aerosolize nicotyrine along with nicotine. Nicotyrine inhibits the cytochrome P450 2A family of enzymes (CYP2A) in airways and liver. These enzymes metabolize nicotine to cotinine, and then cotinine to trans 3-hydroxycotinine. In humans, nicotine is metabolized primarily by hepatic CYP2A6. We propose that e cig users (vapers) achieve measurable serum nicotine levels when they inhale nicotine and nicotyrine together, because nicotyrine reversibly inhibits nicotine metabolism by CYP2A13 in airways. Consuming nicotyrine by any route should irreversibly inhibit hepatic CYP2A6. When CYP2A6 is substantially inhibited, nicotine clearance is delayed and nicotine withdrawal symptoms are attenuated. Small, relatively infrequent nicotine doses can then sustain satisfying nicotine levels. This theory has numerous implications for e-cig research and tobacco control. Behavioral and pharmacokinetic e-cig studies should be interpreted with attention to likely levels of nicotyrine delivery: e-cig studies may need to routinely measure nicotyrine exposure, assess CYP2A6 activity, confirm nicotine delivery, or deliberately compare unoxidized and oxidized e-liquids. The risks of nicotyrine exposure include impaired clearance of all CYP2A substrates and any effects of the metabolic products of nicotyrine. CYP2A inhibitors like nicotyrine may be useful for future smoking cessation therapy. PMID- 26100466 TI - Burning Graphene Layer-by-Layer. AB - Graphene, in single layer or multi-layer forms, holds great promise for future electronics and high-temperature applications. Resistance to oxidation, an important property for high-temperature applications, has not yet been extensively investigated. Controlled thinning of multi-layer graphene (MLG), e.g., by plasma or laser processing is another challenge, since the existing methods produce non-uniform thinning or introduce undesirable defects in the basal plane. We report here that heating to extremely high temperatures (exceeding 2000 K) and controllable layer-by-layer burning (thinning) can be achieved by low-power laser processing of suspended high-quality MLG in air in "cold-wall" reactor configuration. In contrast, localized laser heating of supported samples results in non-uniform graphene burning at much higher rates. Fully atomistic molecular dynamics simulations were also performed to reveal details of oxidation mechanisms leading to uniform layer-by-layer graphene gasification. The extraordinary resistance of MLG to oxidation paves the way to novel high-temperature applications as continuum light source or scaffolding material. PMID- 26100467 TI - Reply to: "Serotype transition in invasive pneumococcal infection in postvaccine era". PMID- 26100468 TI - The impact of multidisciplinary rehabilitation on the quality of life of hemodialysis patients in Iran. AB - BACKGROUND/PURPOSE: Hemodialysis contributes to changes in lifestyle and the health status of patients. The aim of this study was to evaluate the impact of participatory rehabilitation on the quality of life of patients. METHODS: This quasi-experimental before and after study was conducted on 30 patients in the hemodialysis center at Hazrat-e-Rasoul Hospital in Javanrood during 2013. The rehabilitation program was executed with participation of experts in the fields of nursing, physiotherapy, and clinical psychology for 8 weeks. The instrument used for data collection was the hemodialysis version of Ferrans and Powers Quality of Life Index (QLI) which was completed by the research assistant by interview before and after the rehabilitation program. RESULTS: The mean age of patients was 55.8 +/- 14.3 years, 60% were male, and 93.3% were married. The average duration of hemodialysis was 3 +/- 2.4 years. The quality of life score of all patients before the intervention was between 10 and 19 (moderate level), which after intervention, improved to a good level in half of the patients (p < 0.001). CONCLUSION: Rehabilitation programs improve the quality of life of hemodialysis patients. By this finding, implementation of rehabilitation programs is recommended in hemodialysis centers with participation of experts from different fields including nurses, physiotherapists, and clinical psychologists. PMID- 26100470 TI - Cobalt to Chromium Ratio is Not a Key Marker for Adverse Local Tissue Reaction (ALTR) in Metal on Metal Hips. AB - The diagnosis of adverse local tissue reaction (ALTR) after metal-on-metal total hip arthroplasty (MoMTHA) presents a significant challenge. No single biomarker is specific for ALTR. The purpose of this study was to determine if the ratio of cobalt to chromium ions is useful for diagnosing ALTR in MoMTHA. In 89 bearing related revision THAs, preoperative cobalt and chromium ion levels were compared to an intraoperative soft tissue damage grading scale. The average cobalt to chromium ratio was 2.96 (0-20). There was no correlation between the tissue scale and the cobalt to chromium ratio (R=0.095; P=0.41). Many variables affecting ion production/excretion mitigate the use of the ion ratio. The cobalt to chromium ratio is not a predictive biomarker for ALTR in MoMTHA. PMID- 26100469 TI - Multiple signatures of a disease in potential biomarker space: Getting the signatures consensus and identification of novel biomarkers. AB - BACKGROUND: The lack of consensus among reported gene signature subsets (GSSs) in multi-gene biomarker discovery studies is often a concern for researchers and clinicians. Subsequently, it discourages larger scale prospective studies, prevents the translation of such knowledge into a practical clinical setting and ultimately hinders the progress of the field of biomarker-based disease classification, prognosis and prediction. METHODS: We define all "gene identificators" (gIDs) as constituents of the entire potential disease biomarker space. For each gID in a GSS of interest ("tested GSS"/tGSS), our method counts the empirical frequency of gID co-occurrences/overlaps in other reference GSSs (rGSSs) and compares it with the expected frequency generated via implementation of a randomized sampling procedure. Comparison of the empirical frequency distribution (EFD) with the expected background frequency distribution (BFD) allows dichotomization of statistically novel (SN) and common (SC) gIDs within the tGSS. RESULTS: We identify SN or SC biomarkers for tGSSs obtained from previous studies of high-grade serous ovarian cancer (HG-SOC) and breast cancer (BC). For each tGSS, the EFD of gID co-occurrences/overlaps with other rGSSs is characterized by scale and context-dependent Pareto-like frequency distribution function. Our results indicate that while independently there is little overlap between our tGSS with individual rGSSs, comparison of the EFD with BFD suggests that beyond a confidence threshold, tested gIDs become more common in rGSSs than expected. This validates the use of our tGSS as individual or combined prognostic factors. Our method identifies SN and SC genes of a 36-gene prognostic signature that stratify HG-SOC patients into subgroups with low, intermediate or high-risk of the disease outcome. Using 70 BC rGSSs, the method also predicted SN and SC BC prognostic genes from the tested obesity and IGF1 pathway GSSs. CONCLUSIONS: Our method provides a strategy that identify/predict within a tGSS of interest, gID subsets that are either SN or SC when compared to other rGSSs. Practically, our results suggest that there is a stronger association of the IGF1 signature genes with the 70 BC rGSSs, than for the obesity-associated signature. Furthermore, both SC and SN genes, in both signatures could be considered as perspective prognostic biomarkers of BCs that stratify the patients onto low or high risks of cancer development. PMID- 26100471 TI - A Heritable Predisposition to Osteoarthritis of the Hip. AB - Using THA as a proxy for underlying osteoarthritis, we describe population-based familial clustering of osteoarthritis of the hip. The GIF test for excess relatedness on 1049 patients that underwent THA (and do not have a diagnostic code for other conditions leading to THA) showed excess relatedness (P<0.001). Even when close relationships were ignored (closer than third-degree relationships), excess relatedness was observed (P=0.020). Relative risk was elevated in first-degree (RR 2.59; 95% CI 1.84-3.53, P=2.0e(-7)), second-degree (RR 1.66; 95% CI 1.11-2.39; P=0.0075) and third-degree relatives (RR 1.46; 95% CI 1.17-1.81; P=5.7e(-4)). Excess relatedness of individuals who had undergone THA for osteoarthritis and elevated risks to both near and distant relatives were observed. PMID- 26100472 TI - Are Revisions of Unicompartmental Knee Arthroplasties More Like a Primary or Revision TKA? AB - If revision is required, most unicompartmental arhroplasties (UKAs) are converted to total knee arthroplasties (TKAs) and conflicting results regarding surgical complexity and outcome have been reported in publications. 48 UKAs converted to a TKA between 1998 and 2009 were matched based on age, gender, and body mass index, pre-operative Knee Society Score, length of follow-up, and date of the index surgery to 48 primary TKAs and 48 revision TKAs. Surgical characteristics, clinical outcomes, and complications were compared at a mean follow-up of 7 +/- 4 years. Even if a revision of UKA is technically less demanding than a revision TKA, functional scores, quality of life, complications and survival rate after revision UKA are more comparable to a revision than primary TKA. PMID- 26100473 TI - Long-Term Survivorship and Clinical Outcomes Following Total Knee Arthroplasty. AB - Total knee arthroplasty (TKA) is one of the most successful commonly performed orthopedic procedures; as such, the purpose was to assess the long-term outcomes and survivorship of primary TKAs with a dual-radius prosthesis. We evaluated 125 patients (145-knees), with a mean age of 63 years (37-90 years) for a mean 11 year follow-up (10-13 years). Outcomes were assessed with KSS, UCLA, SF-36, satisfaction scores, and aseptic survivorship analysis. At 10-year follow-up, the UCLA (6-points), KSS objective (84-points) and functional (73-points), SF-36 physical (41-points) and mental (51-points), and patient satisfaction (14-points) scores were reported to be good to excellent. The 10-year Kaplan-Meier survivorship rate was 99%; one TKA demonstrated radiographic loosening. At a minimum 10-year follow-up, this device demonstrated satisfactory outcomes and outstanding aseptic-survivorship rates. PMID- 26100474 TI - Is Electrocautery of Patella Useful in Patella Non-Resurfacing Total Knee Arthroplasty?: A Prospective Randomized Controlled Study. AB - There is controversy over the need for electrocauterization of the patella in non resurfacing total knee arthroplasty (TKA). We investigated whether this procedure is beneficial through a prospective randomized controlled trial. Fifty patients who underwent electrocautery were compared with 50 patients who did not undergo this procedure. We determined cartilage status, preoperative and postoperative American Knee Society (AKS) score, the Western Ontario and McMaster Universities score (WOMAC) and the Patellofemoral (PF) scores for a minimum of 5 years. The two groups did not differ significantly in demographics, intraoperative cartilage status, or preoperative or postoperative outcomes. No complications were detected in either group. We found no benefits of electrocautery of the patella in patellar non-resurfacing TKA up to 5 years. PMID- 26100475 TI - The Use of Trabecular Metal Cones in Complex Primary and Revision Total Knee Arthroplasty. AB - Trabecular metal cones are one option for treating osseous defects during TKA. A total of 83 consecutive TKAs utilizing cones with an average of 40 months follow up were reviewed. There were 24 males and 59 females, with an average age of 69 years old. Four were complex primary and 79 were revision procedures. Of 83 patients, 10 (12%) required repeat revision surgery (8 infections, one periprosthetic fracture, one aseptic loosening) and overall, 37 of 83 patients (45%) experienced at least one complication. Of 73 unrevised knees, 72 (99%) demonstrated radiographic evidence of osseointegration. Despite a high complication rate in this population, trabecular metal cones represent an attractive option for managing bone loss in complex primary and revision TKA with a high rate of osseointegration. PMID- 26100476 TI - [What limits do we have for children today?]. PMID- 26100477 TI - [Childhood epilepsy. Necessary care from multiple competencies]. PMID- 26100479 TI - [Objectives and practical aspects of antiepileptic medication]. AB - Antiepileptics are a group of drugs with various pharmacological properties and mechanisms of action. They are grouped together due to the fact that they are used to treat epilepsy. There are around twenty molecules in this group. Particular care needs to be taken when prescribing them for children as they carry risks. PMID- 26100478 TI - [Clinical presentations, etiologies and prognosis of epilepsy in children]. AB - Epilepsy in children is a neurological pathology with very diverse clinical forms and aetiologies. An electroencephalogram is essential for guiding the diagnosis, completed when indicated with imaging examinations. The treatment aims to control the seizures and takes into account the quality of the child's life. Regular follow-up must be provided by a paediatric neurologist specialised in epilepsy. PMID- 26100480 TI - [Surgical management of epilepsy]. AB - Epilepsy surgery raises hopes, but still remains reserved for a small number of cases of epilepsy resistant to medical treatments. It requires the involvement of multidisciplinary medical and allied health teams with expertise in this field. From the patient's admission through to their discharge, the nurse and the electroencephalogram technician have an essential role to play. PMID- 26100481 TI - [The role of the nurse in the patient education of young epileptic patients]. AB - An epileptic seizure in a child is a major source of anxiety and turns the family's everyday life upside down. Through therapeutic education, the nurse guides the families towards the autonomous management of the seizures, antiepileptic treatments, adaptations to daily life and potential comorbidities. PMID- 26100482 TI - [Experience of a chronic condition and psychological support of the child with epilepsy]. AB - Epilepsy is a chronic condition with extremely variable consequences in children and can disrupt their development. Children who have epilepsy can present cognitive, behavioural and psychological disorders. The psychological follow-up forms part of a global care management of the child and their family, enabling everyone to express their own experience of the condition. This support helps them to develop strategies to face up to epilepsy and preserve their quality of life. PMID- 26100483 TI - [The psychosocial challenges of epilepsy and the role of the clinical nurse specialist]. AB - Epilepsy in children is a complex disease with significant psychosocial consequences for the child and their family. The intervention of a multidisciplinary team enables the care to be adapted and provides support for the families. At Sainte-Justine Hospital in Montreal, Canada, the nurse clinician specialised in epilepsy plays a key role in this team. PMID- 26100484 TI - [Social and cultural representations in epilepsy awareness]. AB - Representations relating to epilepsy have evolved over the centuries, but the manifestations of epilepsy awaken archaic images linked to death, violence and disgust. Indeed, the generalised epileptic seizure symbolises a rupture with the surrounding environment, "informs it", through the loss of social codes which it causes. The social and cultural context, as well as medical knowledge, influences the representations of the disease. As a result, popular knowledge is founded on the social and cultural representations of a given era, in a given society. PMID- 26100485 TI - [Draw me a donation, ethical reflection with children in pediatrics]. AB - An organ and tissue removal coordination department organised a drawing competition for the children in the paediatric unit, on the theme: "Donation, passing on the baton". This ethical reflection combining respect for the children, interaction with the parents and multi-disciplinary collaboration provided an opportunity for exchanges on the topic of organ donation and encouraged a different approach on the part of the medical team. PMID- 26100486 TI - [The infant's body in movement and the professional's perspective]. AB - The observation of the young infant, and in particular the movements of their body, provides the basis for understanding their psychological construction. The psychoanalytical perspective of the infant's behaviour is very valuable for early childhood professionals. It guides their actions in providing containment and reassuring support. PMID- 26100487 TI - Respiratory infection with a bacterial pathogen attenuates CNS autoimmunity through IL-10 induction. AB - Infection with viral or bacterial pathogens has been linked with the development of multiple sclerosis (MS), while infection with helminth parasites has been associated protection against MS and other autoimmune diseases. Here we have used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the effect of infection with the respiratory pathogen Bordetella pertussis infection on development of CNS inflammation. The data demonstrate that infection of mice with B. pertussis significantly attenuates the clinical course of EAE induced by active immunization or cell transfer. This was reflected in a significant reduction in VLA-4 and LFA-1 expression on T cells and infiltration of IL-17(+), IFN-gamma(+) and IFN-gamma(+)IL-17(+) CD4 T cells into the CNS. Infection with B. pertussis induced IL-10 production from dendritic cells in vitro and enhanced the frequency of IL-10-producing CD25(-)Foxp3(+/-) CD4(+) T cells in vivo. Furthermore, the suppressive effects of B. pertussis infection on EAE were lost in IL-10(-/-) mice. Our findings demonstrate that a bacterial infection of the respiratory tract can attenuate EAE by promoting production of the anti-inflammatory cytokine IL-10 that may suppress licensing of autoaggressive T cells in the lungs, thereby preventing their migration into the CNS. PMID- 26100489 TI - Inflammation and metabolic changes in first episode psychosis: preliminary results from a longitudinal study. AB - Metabolic abnormalities are commonly observed in patients with psychosis, and may confer greater risk of developing cardiovascular disease later in life. Such abnormalities are associated with inflammation in the general population, and there is increasing evidence for elevated inflammation in patients with first episode psychosis (FEP). The aim of this preliminary study is to examine the effect of changes in inflammation, as measured by high-sensitivity C-reactive protein (hsCRP), on metabolic changes in a three-month longitudinal study in a FEP sample. Fifty-three FEP patients from in- and out-patient services in South London, England, were included in this longitudinal study. Social and clinical data were collected, and fasting blood samples and anthropometric measurements (weight, Body Mass Index (BMI), lipid profile and gluco-metabolic parameters) were obtained at baseline and at three-month follow-up. Correlation analyses showed that those with increases in hsCRP over the three-month period also had increases in triglyceride levels (r=0.49, p=0.02). No association was observed with other lipid profile, or gluco-metabolic parameters, across the whole sample. Increases in weight and BMI were also associated with increases in triglyceride levels (r=0.33, p=0.02; and r=0.31, p=0.03, respectively); however, a multiple linear regression analysis found that the effects of inflammation on triglycerides were independent from the effect of changes in weight, and from the baseline inflammatory state. Our preliminary findings suggest that those patients experiencing greater increases in inflammation early on in the course of their illness may be at greater risk of developing short-term metabolic abnormalities, in particular dyslipidaemia, independent of weight-gain. Future work should investigate the use of inflammatory markers to identify patients in greater need of physical health interventions. PMID- 26100488 TI - Stress exacerbates neuron loss and microglia proliferation in a rat model of excitotoxic lower motor neuron injury. AB - All individuals experience stress and hormones (e.g., glucocorticoids/GCs) released during stressful events can affect the structure and function of neurons. These effects of stress are best characterized for brain neurons; however, the mechanisms controlling the expression and binding affinity of glucocorticoid receptors in the spinal cord are different than those in the brain. Accordingly, whether stress exerts unique effects on spinal cord neurons, especially in the context of pathology, is unknown. Using a controlled model of focal excitotoxic lower motor neuron injury in rats, we examined the effects of acute or chronic variable stress on spinal cord motor neuron survival and glial activation. New data indicate that stress exacerbates excitotoxic spinal cord motor neuron loss and associated activation of microglia. In contrast, hypertrophy and hyperplasia of astrocytes and NG2+ glia were unaffected or were modestly suppressed by stress. Although excitotoxic lesions cause significant motor neuron loss and stress exacerbates this pathology, overt functional impairment did not develop in the relevant forelimb up to one week post-lesion. These data indicate that stress is a disease-modifying factor capable of altering neuron and glial responses to pathological challenges in the spinal cord. PMID- 26100490 TI - Comparison of the conventional multiplex RT-PCR, real time RT-PCR and Luminex xTAG(r) RVP fast assay for the detection of respiratory viruses. AB - Detection of respiratory viruses using polymerase chain reaction (PCR) is sensitive, specific and cost effective, having huge potential for patient management. In this study, the performance of an in-house developed conventional multiplex RT-PCR (mRT-PCR), real time RT-PCR (rtRT-PCR) and Luminex xTAG((r)) RVP fast assay (Luminex Diagnostics, Toronto, Canada) for the detection of respiratory viruses was compared. A total 310 respiratory clinical specimens predominantly from pediatric patients, referred for diagnosis of influenza A/H1N1pdm09 from August 2009 to March 2011 were tested to determine performance characteristic of the three methods. A total 193 (62.2%) samples were detected positive for one or more viruses by mRT-PCR, 175 (56.4%) samples by real time monoplex RT-PCR, and 138 (44.5%) samples by xTAG((r)) RVP fast assay. The overall sensitivity of mRT-PCR was 96.9% (95% CI: 93.5, 98.8), rtRT-PCR 87.9% (95% CI: 82.5, 92.1) and xTAG((r)) RVP fast was 68.3% (95% CI: 61.4, 74.6). Rhinovirus was detected most commonly followed by respiratory syncytial virus group B and influenza A/H1N1pdm09. The monoplex real time RT-PCR and in-house developed mRT PCR are more sensitive, specific and cost effective than the xTAG((r)) RVP fast assay. PMID- 26100491 TI - Innovative Varied-Fidelity Simulation Mobile Teaching Cart and Education Project. AB - The use of a varied-fidelity simulation mobile teaching cart is a teaching tool that offers unique advantages in the acute care setting. The cart is used to demonstrate the use of patient monitoring devices, and there are a variety of software tools available with the monitoring technology to ensure that the outputs, including electrocardiographic waves, are analyzed appropriately by nursing staff using this varied-fidelity simulation mobile teaching cart. Bringing varied-fidelity simulation to the nurses' work area is a unique application setting. PMID- 26100492 TI - Infection with Ehrlichia canis and Anaplasma platys (Rickettsiales: Anaplasmataceae) in two lineages of Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) from Argentina. AB - Natural infection with Ehrlichia canis and Anaplasma platys in ticks belonging to the tropical and temperate lineages of Rhipicephalus sanguineus sensu lato from Argentina was evaluated. Samples were tested for Ehrlichia canis infection by PCR assays using 16S rRNA, dsb and p28 gene, while detection of A. platys was performed with 16S rRNA and groESL gene. The assignment of the ticks to each lineage was corroborated with 16S rDNA sequences. All ticks infected with E. canis and A. platys belonged to the tropical lineage. These results constitute the first record of E. canis infection in R. sanguineus s.l ticks from Argentina. No ticks from the temperate lineage were found to be infected with E. canis, coinciding with previous studies performed in Argentina and Uruguay where E. canis infection was not detected in R. sanguineus s.l from the temperate lineage. Because the presence of the tropical lineage of R. sanguineus s.l has been documented in tropical areas of northern Argentina between 22 degrees and 24 degrees of south latitude, the findings of this work indicate that transmission of E. canis and A. platys to dogs by R. sanguineus s.l probably occurs along this region. PMID- 26100493 TI - How far north are migrant birds transporting the tick Ixodes scapularis in Canada? Insights from stable hydrogen isotope analyses of feathers. AB - Lyme disease is emerging in Canada because of northward range expansion of the tick vector Ixodes scapularis. It is hypothesised that I. scapularis feeding on passerine birds migrating north in spring are important in founding new I. scapularis populations leading to northward range expansion. However, there are no studies on how far north I. scapularis may be carried, only inferences from passive tick surveillance. We used stable hydrogen isotope (delta(2)H) analysis of rectrices collected from northward migrating, I. scapularis-carrying, passerine birds captured in Canada to estimate how far north I. scapularis may be carried. Rectrices are usually grown close to breeding sites and their delta(2)H values reflect those in the environment, which vary strongly with latitude in North America. Passerines usually return to their breeding or natal sites so delta(2)H values of rectrices of northward migrating birds can identify the likely latitudinal bands of their intended destinations. In 2006 we analysed delta(2)H from rectrices of 73 I. scapularis-carrying birds captured at five migration monitoring stations, mainly from southern Ontario. Values of delta(2)H ranged from -33 to -1240/00, suggesting 19/71 (26.7%) birds were destined for latitude band B (the most southerly part of Ontario), 40/71 (56.3%) birds were destined for band C (which extends from southern Ontario, Quebec and the Maritimes to southern James Bay) and 12/71 (16.9%) birds were destined for bands D and E (which extend from northern Ontario and Quebec into the southern Canadian Arctic). This indicates that many I. scapularis-carrying migratory birds in spring have destinations far north in Canada, including some farther north than the current region of climatic suitability for I. scapularis. These findings support the hypothesis that I. scapularis may continue to be spread north by spring migrating passerines. Some thrush species may be particularly implicated in far northward dispersion of I. scapularis. PMID- 26100494 TI - Reassortment and distinct evolutionary dynamics of Rift Valley Fever virus genomic segments. AB - Rift Valley Fever virus (RVFV) is a member of Bunyaviridae family that causes a febrile disease affecting mainly ruminants and occasionally humans in Africa, with symptoms that range from mid to severe. RVFV has a tri-segmented ssRNA genome that permits reassortment and could generate more virulent strains. In this study, we reveal the importance of reassortment for RVFV evolution using viral gene genealogy inference and phylodynamics. We uncovered seven events of reassortment that originated RVFV lineages with discordant origins among segments. Moreover, we also found that despite similar selection regimens, the three segments have distinct evolutionary dynamics; the longer segment L evolves at a significant lower rate. Episodes of discordance between population size estimates per segment also coincided with reassortment dating. Our results show that RVFV segments are decoupled enough to have distinct demographic histories and to evolve under different molecular rates. PMID- 26100497 TI - HCV targeting of patients with cirrhosis. AB - Interferon (IFN)-free treatments are now the treatment of choice for patients with chronic hepatitis C. Previously difficult to treat patients by IFN containing treatments can now be treated safely by IFN-free therapies. More than 90% of hepatitis C genotype 1 and 4 patients with compensated cirrhosis or after orthotopic liver transplantation (OLT) can be cured by sofosbuvir combined with simeprevir, daclatasvir or ledipasvir, or by the paritaprevir/ritona vir/ombitasvir/+/-dasabuvir (3D) combination. Addition of ribavirin confers to a minimal, if any, benefit to increase SVR. The need for ribavirin is controversial and remains to be studied. The optimal length of treatment is still unknown, and an individual approach may be needed. Most patients require only 12weeks of therapy. The safety of these drugs is not fully explored in patients with decompensated cirrhosis (Child-Pugh C), who should not be treated with protease inhibitors. In cirrhosis hepatitis C virus eradication does not necessarily mean a cure of the disease and patients regularly require follow-up. Drug-drug interactions with immunosuppressant in patients after OLT are easier to manage but still require attention. Better drugs are needed for genotype 3 patients. PMID- 26100495 TI - The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: A 12-year prospective cohort study. AB - BACKGROUND & AIMS: Esophageal varices (EV) are a marker of disease severity in compensated cirrhosis due to hepatitis B virus (HBV) which predicts also the risk of hepatocellular carcinoma (HCC), clinical decompensation and anticipated liver related death. The dynamics and prognostic significance of EV in patients under long-term HBV suppression by nucleos(t)ide analogs (NUC), are poorly known. METHODS: A standardized protocol (Baveno) including 414 upper gastrointestinal (GI) endoscopies was applied to 107 HBeAg-negative compensated cirrhotic patients (93% Child-Pugh A) during a median of 12 (range 2 to 17) years of NUC therapy. Patients who initially started on lamivudine (LMV) and then developed resistance (LMV-R), were rescued by early administration of adefovir, or were switched to tenofovir. Surveillance included serum HBV DNA every three months and abdominal ultrasound every six months. RESULTS: Twenty-seven patients had baseline F1 EV which regressed in 18, remained unchanged in eight and progressed in one patient; the 12-year cumulative incidence of EV regression was 83% (95% CI: 52-92%). De novo F1/F2 EV developed in 6/80 patients with a 12-year cumulative incidence of 10% (95% CI: 5-20%). Six of seven patients with de novo varices or progression of pre-existing varices had either a clinical breakthrough due to LMV-R and/or developed a HCC. No bleedings from ruptured EV occurred, 12 patients died (9 HCC) and 15 were transplanted (13 HCC): the 12-year cumulative incidence of HCC and overall survival was 33% (95% CI: 24-42%) and 76% (95% CI: 67-83%), respectively. CONCLUSIONS: Long-term pharmacological suppression of HBV in HBeAg-seronegative patients with compensated cirrhosis leads to a significant regression of pre existing EV accompanied by a negligible risk of developing de novo EV. PMID- 26100496 TI - Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. AB - BACKGROUND & AIMS: The inflammasome is a well-characterized inducer of inflammation in alcoholic steatohepatitis (ASH). Inflammasome activation requires two signals for mature interleukin (IL)-1beta production. Here we asked whether metabolic danger signals trigger inflammasome activation in ASH. METHODS: Wild type mice, ATP receptor 2x7 (P2rx7)-KO mice, or mice overexpressing uricase were fed Lieber-DeCarli ethanol or control diet. We also implemented a pharmacological approach in which mice were treated with probenecid or allopurinol. RESULTS: The sterile danger signals, ATP and uric acid, were increased in the serum and liver of alcohol-fed mice. Depletion of uric acid or ATP, or lack of ATP signaling attenuated ASH and prevented inflammasome activation and its major downstream cytokine, IL-1beta. Pharmacological depletion of uric acid with allopurinol provided significant protection from alcohol-induced inflammatory response, steatosis and liver damage, and additional protection was achieved in mice treated with probenecid, which depletes uric acid and blocks ATP-induced P2rx7 signaling. We found that alcohol-damaged hepatocytes released uric acid and ATP in vivo and in vitro and that these sterile danger signals activated the inflammasome in LPS-exposed liver mononuclear cells. CONCLUSIONS: Our data indicate that the second signal in inflammasome activation and IL-1beta production in ASH results from the endogenous danger signals, uric acid and ATP. Inhibition of signaling triggered by uric acid and ATP may have therapeutic implications in ASH. PMID- 26100498 TI - Surveillance for hepatocellular carcinoma is associated with increased survival: Results from a large cohort in the Netherlands. AB - BACKGROUND & AIMS: Effectiveness of surveillance for hepatocellular carcinoma is controversial. We here explore its effects in "real life" clinical practice. METHODS: Patients with hepatocellular carcinoma diagnosed in the period 2005-2012 in five Dutch academic centers were evaluated. Surveillance was defined as ?2 screening tests during three preceding years and at least one radiologic imaging test within 18 months before diagnosis. RESULTS: 295 (27%) of 1074 cases underwent surveillance. Median time interval between last negative radiologic imaging and hepatocellular carcinoma diagnosis was 7.5 months. In the surveillance group, cirrhosis (97% vs. 60%, p<0.001) and viral hepatitis were more frequent, and non-alcoholic fatty liver disease or absence of risk factors less frequent. In case of surveillance, tumor size was significantly smaller (2.7 vs. 6.0 cm), with lower alpha-fetoprotein levels (16 vs. 44 MUg/L), earlier tumor stage (BCLC 0 and A combined: 61% vs. 21%) and resection/transplantation (34% vs. 25%) or radiofrequency ablation (23% vs. 7%) more often applied, with significantly higher 1-, 3-, and 5-year survival rates. Survival benefit by surveillance remained significant after adjustment for lead-time bias based on assumed tumor doubling time of 90 days, but not with doubling time of ?120 days. In multivariate analysis, surveillance was an independent predictor for mortality (for interval ?9 respectively >9 months: adjusted HRs 0.51 and 0.50, 95% confidence intervals: 0.39-0.67 and 0.37-0.69). CONCLUSIONS: Surveillance for hepatocellular carcinoma was associated with smaller tumor size, earlier tumor stage, with an impact on therapeutic strategy and was an independent predictor of survival. PMID- 26100503 TI - Epidemiology: Global Burden of Disease Study 2013 reports that disability caused by CKD is increasing worldwide. PMID- 26100505 TI - Podocyte biology: Age-associated changes in podocytes linked to FGGS. PMID- 26100506 TI - [Incidental finding of a cardiac paraganglioma]. AB - Cardiac paragangliomas are extremely rare neoplasms with an incidence of 1% of all cardiac tumors and can be completely asymptomatic, therefore, diagnosis is difficult. This article reports the case of an 18-year-old man with a heart murmur detected during a routine physical examination. Echocardiography revealed a heart tumor measuring 7 cm in size in the right atrium. Due to the tumor size and the threat of tricuspid valve insufficiency, tumor resection was performed. The histopathological examination revealed a cardiac paraganglioma with positive reactions of the tumor cells for chromogranin A, synaptophysin and CD56. Differentiating a primary cardiac paraganglioma from other more common cardiac tumors and particularly from metastases of neuroendocrine neoplasms from other locations is essential not only for the further clinical treatment but also for the prognosis of the patient. PMID- 26100504 TI - The effects of environmental chemicals on renal function. AB - The global incidence of chronic kidney disease (CKD) is increasing among individuals of all ages. Despite advances in proteomics, genomics and metabolomics, there remains a lack of safe and effective drugs to reverse or stabilize renal function in patients with glomerular or tubulointerstitial causes of CKD. Consequently, modifiable risk factors that are associated with a progressive decline in kidney function need to be identified. Numerous reports have documented the adverse effects that occur in response to graded exposure to a wide range of environmental chemicals. This Review summarizes the effects of such chemicals on four aspects of cardiorenal function: albuminuria, glomerular filtration rate, blood pressure and serum uric acid concentration. We focus on compounds that individuals are likely to be exposed to as a consequence of normal consumer activities or medical treatment, namely phthalates, bisphenol A, polyfluorinated alkyl acids, dioxins and furans, polycyclic aromatic hydrocarbons and polychlorinated biphenyls. Environmental exposure to these chemicals during everyday life could have adverse consequences on renal function and might contribute to progressive cumulative renal injury over a lifetime. Regulatory efforts should be made to limit individual exposure to environmental chemicals in an attempt to reduce the incidence of cardiorenal disease. PMID- 26100508 TI - The impact of care on family and health-related quality of life of parents with chronically ill and disabled children. AB - PURPOSE: Parents of disabled and/or chronically ill children are more vulnerable regarding their health compared to parents of healthy children. This study examines how far the burden of care is associated with health-related quality of life (QoL) in parents, across different illnesses and disabilities. Moreover, it is unclear whether and to which extent familial resources can explain the association between parents' care burden and health. METHOD: Data stem from a survey with the German Children's Network, a self-help umbrella organization of parents and families of chronically ill and disabled children. Data collection was conducted nationwide with a standardized online questionnaire, which included children's diagnoses and severity, burden of care, family and socioeconomic status, health-related QoL (SF-12) and family impact (Impact on Family Scale, IFS). 1567 parents participated. RESULTS: A higher burden of care is associated with higher risks for poor health-related QoL. Especially, social impact and financial burden, which are both associated with care, can help to explain these associations. CONCLUSIONS: Future interventions should focus not only on the affected child but also on the whole family system and its social integration, as this seems likely to relief parents from burden of care. Therefore, a sustainable cooperation of health care institutions and professionals with self-help groups and parental initiatives is recommended. Implications for Rehabilitation Parents of disabled and chronically ill children are a vulnerable group regarding their health-related quality of life. A higher burden of care is associated with less social contacts, higher financial burden and higher help-needs in the household, which significantly contribute to higher health risks. Rehabilitation should take these constraints into account and put a stronger focus on the family of disabled and chronically ill children to support their inclusion. A sustainable and formally anchored collaboration with self-help and patient groups is recommended. PMID- 26100507 TI - The Relationship Between Sexual Minority Stigma and Sexual Health Risk Behaviors Among HIV-Positive Older Gay and Bisexual Men. AB - This study investigates how internalized sexual minority stigma and enacted sexual minority stigma in health care settings are associated with sexual health risk behaviors (SRBs) and the mediating role of infrequent routine health care and perceived stress among older gay and bisexual (G/B) men living with HIV disease. Survey responses from 135 sexually active older G/B men living with HIV were analyzed using hierarchical linear regression models. Results indicate that one fifth of G/B older adult men living with HIV are engaged in multiple SRBs. Internalized sexual minority stigma and enacted sexual minority stigma in health care settings are significantly associated with SRBs. The relationship between internalized sexual minority stigma and SRBs are mediated by infrequent routine health care and elevated levels of perceived stress. Improved primary and secondary prevention strategies are needed for the growing number of sexually active older G/B men. PMID- 26100509 TI - Evidence for horizontal transfer of mitochondrial DNA to the plastid genome in a bamboo genus. AB - In flowering plants, three genomes (nuclear, mitochondrial, and plastid) coexist and intracellular horizontal transfer of DNA is prevalent, especially from the plastid to the mitochondrion genome. However, the plastid genomes are generally conserved in evolution and have long been considered immune to foreign DNA. Recently, the opposite direction of DNA transfer from the mitochondrial to the plastid genome has been reported in two eudicot lineages. Here we sequenced 6 plastid genomes of bamboos, three of which are neotropical woody species and three are herbaceous ones. Several unusual features were found, including the duplication of trnT-GGU and loss of one copy of rps19 due to contraction of inverted repeats (IRs). The most intriguing was the ~2.7 kb insertion in the plastid IR regions in the three herbaceous bamboos. Furthermore, the insertion was documented to be horizontally transferred from the mitochondrial to the plastid genome. Our study provided evidence of the mitochondrial-to-plastid DNA transfer in the monocots, demonstrating again that this rare event does occur in other angiosperm lineages. However, the mechanism underlying the transfer remains obscure, and more studies in other plants may elucidate it in the future. PMID- 26100510 TI - Interleukin-1 receptor antagonist deficiency with a novel mutation; late onset and successful treatment with canakinumab: a case report. AB - INTRODUCTION: Interleukin-1 receptor antagonist deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. The underlying genetic abnormality involves a recessive mutation in IL1RN, which encodes interleukin-1 receptor antagonist. In this case report, we describe a case of a 12-year-old Turkish girl who initially was presented at 1 year of age, older than previously reported children with interleukin-1 receptor antagonist deficiency, and with a novel mutation, p.R26X, in ILR1N. CASE PRESENTATION: Our patient developed pustular cutaneous lesions at 1 year of age. At the age of 12 years, she was hospitalized for arthralgia of her knees, elbows, and ankles and arthritis of the left knee, with simultaneous pustular cutaneous lesions. She was admitted to the intensive care unit because of septicemia and respiratory insufficiency during follow-up. A skin biopsy of hyperpigmented lesions demonstrated neutrophil infiltration in the epidermis and subepidermal pustular dermatosis. Interleukin-1 receptor antagonist deficiency was suspected, and genetic analysis revealed a homozygous mutation (p.R26X) in IL1RN, which led to a diagnosis of interleukin-1 receptor antagonist deficiency. Treatment with canakinumab (recombinant human anti-human interleukin-1beta monoclonal antibody) 150 mg subcutaneously once every 6 weeks was initiated. Our patient did not experience further cutaneous lesions or arthritis. Her post treatment inflammatory markers were normal; she gained weight; and she was able to walk independently. CONCLUSIONS: In this case report, we describe a patient with interleukin-1 receptor antagonist deficiency who responded excellently to canakinumab treatment. We believe more awareness is warranted for interleukin-1 receptor antagonist deficiency in children. It is possible that the mutation in our patient was a founder mutation that may lead to diagnosis of additional cases in Turkey. PMID- 26100511 TI - Structure, reliability, and validity of the revised child anxiety and depression scale (RCADS) in a multi-ethnic urban sample of Dutch children. AB - BACKGROUND: Although anxiety and, to a lesser extent, depression are highly prevalent in children, these problems are, difficult to identify. The Revised Anxiety and Depression Scale (RCADS) assesses self-reported symptoms of anxiety and depression in youth. METHODS: The present study examined the factor structure, internal consistency, short-term stability, and validity including sensitivity to change of the RCADS in a multi-ethnic urban sample of 3636 Dutch children aged 8 to 13 years old. RESULTS: Results indicate that the RCADS is a reliable and valid instrument. The original 6-factor structure was replicated to a fair extent in the present study (RMSEA = 0.048) and internal consistency was good (alphas = 0.70-0.96). ICCs for short-term stability were 0.76 to 0.86. Girls and children who indicated wishing to participate in a program targeting anxiety and depression had higher RCADS scores. Sensitivity to change analyses showed that the RCADS can detect changes in anxiety and depression symptoms in children who participated in a preventive intervention. The study showed low agreement between teacher and self-reported internalizing problems, even for children scoring above the 90(th) percentile of the RCADS, indicating a high level of problems, emphasizing the need to also take child reports into account when screening for anxiety and depression in children. CONCLUSION: This study shows that the RCADS can yield reliable data on a diversity of anxiety disorders and depression in urban children aged 8-13 from very diverse ethnic backgrounds. TRIAL REGISTRATION: Netherlands Trial Register: NTR2397 . Registered 30 June 2010. PMID- 26100512 TI - First-principles assessment of hole transport in pure and Li-doped NiO. AB - Alloying nickel oxide (NiO) with lithium oxide (Li2O) at high Li concentrations may reduce NiO's band gap and expand its use as a light absorber in photocatalytic and tandem dye-sensitized solar cell technologies. In this work, we evaluate the viability of this alloy as a p-type hole transport material. We use embedded cluster models, along with unrestricted Hartree-Fock and complete active space self-consistent field theories, to study the impact of alloying on polaronic transport of holes. Our calculated energy barrier for hole transfer in undoped NiO is in excellent agreement with the experimental value of ~0.1 eV. We predict that hole transport in NiO is anisotropic and mostly confined parallel to the (111) ferromagnetic planes. Applying the same model to Li-doped NiO indicates that isolated Li ions do not introduce free holes into NiO samples. However, free holes can be created in the homogeneous Li0.125Ni0.875O alloy, in which the Li concentration is very high. Our kinetic Monte Carlo calculations show that hole mobility in this alloy is lower than in undoped NiO. However, the additional free holes and the predicted lower band gap of Li0.125Ni0.875O should increase hole conductivity compared to NiO upon alloy formation. Therefore, Li0.125Ni0.875O alloys have potential for use as a hole transporter, as well as a sunlight absorber, in a variety of solar energy applications. PMID- 26100513 TI - The lung communication network. AB - The different types of cells in the lung, from the conducting airway epithelium to the alveolar epithelium and the pulmonary vasculature, are interconnected by gap junctions. The specific profile of gap junction proteins, the connexins, expressed in these different cell types forms compartments of intercellular communication that can be further shaped by the release of extracellular nucleotides via pannexin1 channels. In this review, we focus on the physiology of connexins and pannexins and describe how this lung communication network modulates lung function and host defenses in conductive and respiratory airways. PMID- 26100515 TI - Connexins and pannexins in the immune system and lymphatic organs. AB - Connexin43 and pannexin1 are found in immune cells. While gap junctional communication has been demonstrated between immune cells, hemichannels have been implicated in many cellular functions. Among the functions involved as being connexin dependent and pannexin dependent are cell migration, phagocytosis, antigen presentation, T-cell reactivity and B-cell responses. Surprisingly, many of these connexin-related and pannexin-related functions are not recapitulated in in vivo models. This is leading to a reevaluation of the role of these proteins in immune function. PMID- 26100514 TI - Physiological roles of connexins and pannexins in reproductive organs. AB - Reproductive organs are complex and well-structured tissues essential to perpetuate the species. In mammals, the male and female reproductive organs vary on their organization, morphology and function. Connectivity between cells in such tissues plays pivotal roles in organogenesis and tissue functions through the regulation of cellular proliferation, migration, differentiation and apoptosis. Connexins and pannexins can be seen as major regulators of these physiological processes. In the present review, we assembled several lines of evidence demonstrating that these two families of proteins are essential for male and female reproduction. PMID- 26100517 TI - The impact of read length on quantification of differentially expressed genes and splice junction detection. AB - BACKGROUND: The initial next-generation sequencing technologies produced reads of 25 or 36 bp, and only from a single-end of the library sequence. Currently, it is possible to reliably produce 300 bp paired-end sequences for RNA expression analysis. While read lengths have consistently increased, people have assumed that longer reads are more informative and that paired-end reads produce better results than single-end reads. We used paired-end 101 bp reads and trimmed them to simulate different read lengths, and also separated the pairs to produce single-end reads. For each read length and paired status, we evaluated differential expression levels between two standard samples and compared the results to those obtained by qPCR. RESULTS: We found that, with the exception of 25 bp reads, there is little difference for the detection of differential expression regardless of the read length. Once single-end reads are at a length of 50 bp, the results do not change substantially for any level up to, and including, 100 bp paired-end. However, splice junction detection significantly improves as the read length increases with 100 bp paired-end showing the best performance. We performed the same analysis on two ENCODE samples and found consistent results confirming that our conclusions have broad application. CONCLUSIONS: A researcher could save substantial resources by using 50 bp single end reads for differential expression analysis instead of using longer reads. However, splicing detection is unquestionably improved by paired-end and longer reads. Therefore, an appropriate read length should be used based on the final goal of the study. PMID- 26100519 TI - Rhenium-catalyzed C-H aminocarbonylation of azobenzenes with isocyanates. AB - The first C-H aminocarbonylation of azobenzenes with isocyanates is achieved by using rhenium-catalysis, which provides an expedient and atom-economical access to varied o-azobenzamides from readily available starting materials. The reaction efficiency can be enhanced by the catalytic use of sodium acetate via accelerated C-H bond activation. PMID- 26100518 TI - N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting. AB - BACKGROUND: The epidermis forms a critical barrier that is maintained by orchestrated programs of proliferation, differentiation, and cell death. Gene mutations that disturb this turnover process may cause skin diseases. Human GASDERMIN A (GSDMA) is frequently silenced in gastric cancer cell lines and its overexpression has been reported to induce apoptosis. GSDMA has also been linked with airway hyperresponsiveness in genetic association studies. The function of GSDMA in the skin was deduced by dominant mutations in mouse gasdermin A3 (Gsdma3), which caused skin inflammation and hair loss. However, the mechanism for the autosomal dominance of Gsdma3 mutations and the mode of Gsdma3's action remain unanswered. RESULTS: We demonstrated a novel function of Gsdma3 in modulating mitochondrial oxidative stress. We showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 associates with Hsp90 and is delivered to mitochondrial via mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and causes increased production of mitochondrial reactive oxygen species (ROS), dissipation of mitochondrial membrane potential, and mitochondrial permeability transition (MPT). Overexpression of the C-terminal domain of Gsdma3 as well as pharmacological interventions of mitochondrial translocation, ROS production, and MPT pore opening alleviate the cell death induced by Gsdma3 mutants. CONCLUSIONS: Our results indicate that the genetic mutations in the C-terminal domain of Gsdma3 are gain-of-function mutations which unmask the N-terminal functional domain of Gsdma3. Gsdma3 regulates mitochondrial oxidative stress through mitochondrial targeting. Since mitochondrial ROS has been shown to promote epidermal differentiation, we hypothesize that Gsdma3 regulates context-dependent response of keratinocytes to differentiation and cell death signals by impinging on mitochondria. PMID- 26100516 TI - Beyond vascular inflammation--recent advances in understanding atherosclerosis. AB - Atherosclerosis is the most life-threatening pathology worldwide. Its major clinical complications, stroke, myocardial infarction, and heart failure, are on the rise in many regions of the world--despite considerable progress in understanding cause, progression, and consequences of atherosclerosis. Originally perceived as a lipid-storage disease of the arterial wall (Die cellularpathologie in ihrer begrundung auf physiologische und pathologische gewebelehre. August Hirschwald Verlag Berlin, [1871]), atherosclerosis was recognized as a chronic inflammatory disease in 1986 (New Engl J Med 314:488-500, 1986). The presence of lymphocytes in atherosclerotic lesions suggested autoimmune processes in the vessel wall (Clin Exp Immunol 64:261-268, 1986). Since the advent of suitable mouse models of atherosclerosis (Science 258:468-471, 1992; Cell 71:343-353, 1992; J Clin Invest 92:883-893, 1993) and the development of flow cytometry to define the cellular infiltrate in atherosclerotic lesions (J Exp Med 203:1273 1282, 2006), the origin, lineage, phenotype, and function of distinct inflammatory cells that trigger or inhibit the inflammatory response in the atherosclerotic plaque have been studied. Multiphoton microscopy recently enabled direct visualization of antigen-specific interactions between T cells and antigen presenting cells in the vessel wall (J Clin Invest 122:3114-3126, 2012). Vascular immunology is now emerging as a new field, providing evidence for protective as well as damaging autoimmune responses (Int Immunol 25:615-622, 2013). Manipulating inflammation and autoimmunity both hold promise for new therapeutic strategies in cardiovascular disease. Ongoing work (J Clin Invest 123:27-36, 2013; Front Immunol 2013; Semin Immunol 31:95-101, 2009) suggests that it may be possible to develop antigen-specific immunomodulatory prevention and therapy-a vaccine against atherosclerosis. PMID- 26100520 TI - Effect of Combined Treatment with Ursolic Acid and Resveratrol on Skin Tumor Promotion by 12-O-Tetradecanoylphorbol-13-Acetate. AB - In this study, the effects of combining ursolic acid + resveratrol, for possible combined inhibitory effects on skin tumor promotion, were evaluated. Ursolic acid, resveratrol, and the combination of ursolic acid + resveratrol were applied topically prior to 12-O-tetracanoylphorbol-13-acetate (TPA) treatment on mouse skin to examine their effect on TPA-induced signaling pathways, epidermal hyperproliferation, skin inflammation, inflammatory gene expression, and skin tumor promotion. The combination of ursolic acid + resveratrol produced a greater inhibition of TPA-induced epidermal hyperproliferation. The combination of ursolic acid + resveratrol inhibited TPA-induced signaling pathways, including EGFR, STAT3, Src, Akt, Cox-2, Fas, NF-kappaB, p38 MAPK, c-Jun, and JNK1/2 while increasing levels of tumor suppressors, such as p21 and PDCD4, to a greater extent compared with the groups treated with the individual compounds. Ursolic acid + resveratrol also induced a dramatic increase of p-AMPK-alpha(Thr172). Combined treatment with ursolic acid + resveratrol resulted in a greater inhibition of expression of proinflammatory cytokines, including Il1a, Il1b, and Il22. Furthermore, NF-kappaB, Egr-1, and AP-1 DNA binding activities after TPA treatment were dramatically decreased by the combination of ursolic acid + resveratrol. Treatment with ursolic acid + resveratrol during skin tumor promotion with TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the greater ability of the combination of ursolic acid + resveratrol to inhibit skin tumor promotion was due to the greater inhibitory effects on growth factor and inflammatory signaling, skin inflammation, and epidermal hyperproliferation induced by TPA treatment. PMID- 26100521 TI - Omega-3-Acid Ethyl Esters Block the Protumorigenic Effects of Obesity in Mouse Models of Postmenopausal Basal-like and Claudin-Low Breast Cancer. AB - Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.025%, resulting in blood levels of EPA and DHA comparable with women taking Lovaza 4 g/d) for 6 weeks. All mice were then orthotopically injected with Wnt-1 cells (a BL tumor cell suspension derived from MMTV-Wnt-1 transgenic mouse mammary tumors) or M-Wnt cells (a CL tumor cell line cloned from the Wnt-1 tumor cell suspension). Mice were killed when tumors were 1 cm in diameter. EPA+DHA supplementation did not significantly affect Wnt-1 or M-Wnt mammary tumor growth in normoweight control mice. However, EPA+DHA supplementation in DIO mice reduced growth of Wnt-1 and M-Wnt tumors; reduced leptin:adiponectin ratio and proinflammatory eicosanoids in the serum; improved insulin sensitivity; and decreased tumoral expression of COX-2 and phospho-p65. Thus, EPA+DHA supplementation in mouse models of postmenopausal BL and CL breast cancer offsets many of the protumorigenic effects of obesity. These preclinical findings, in combination with results from parallel biomarker studies in women, suggest that EPA+DHA supplementation may reduce the burden of BL and CL breast cancer in obese women. PMID- 26100523 TI - Role of Prophylactic Bilateral Tonsillectomy as a Cancer Preventive Strategy. AB - The rate of vaccination against human papillomavirus (HPV) among adolescent girls and boys over the past few years has been stagnant in spite of the increase in incidence of HPV-positive oropharyngeal (OPX) squamous cell carcinoma (SCC). The indirect relationship between HPV cancer incidence and preventive vaccination poses a public health concern and has caused clinicians to search for other methods toward eradicating the ongoing oropharyngeal carcinoma epidemic. This alarming increase in OPX is motivating a search for therapeutic prevention strategies, including biomarker discovery, risk assessment, therapeutic vaccines, immunotherapy, and surgery. The current Danish Cancer Registry study by Fakhry and colleagues (in this issue) is the first to investigate the impact of prior tonsillectomy on the development of HPV OPX. They report that remote tonsillectomy resulted in a decreased incidence of tonsillar SCC. While thought provoking, this study has a small sample size. Also, tonsillectomy does not address all anatomic sites at risk; there is lack of well-defined precancerous lesions or biomarkers to identify high-risk patients, and cost and morbidity make it impractical to justify prophylactic tonsillectomy as a cancer preventive strategy at present. The provocative clinical signal reported in this study supports further research and strategies that employ surgery when the technology and epidemiology can reliably be used to identify high-risk subjects. PMID- 26100522 TI - Impact of Short-term 1,25-Dihydroxyvitamin D3 on the Chemopreventive Efficacy of Erlotinib against Oral Cancer. AB - Activation of the epidermal growth factor receptor (EGFR) pathway is an early event in head and neck carcinogenesis. As a result, targeting EGFR for chemoprevention of head and neck squamous cell carcinomas (HNSCC) has received considerable attention. In the present study, we examined the impact of 1,25(OH)2D3, the active metabolite of the nutritional supplement vitamin D on the chemopreventive efficacy of the EGFR inhibitor, erlotinib, against HNSCC. Experimental studies were conducted in patient-derived xenografts (PDX) and the 4 nitroquinoline-1-oxide (4NQO) carcinogen-induced model of HNSCC. Short-term treatment (4 weeks) of PDX-bearing mice with 1,25(OH)2D3 and erlotinib resulted in significant inhibition of tumor growth. Noninvasive MRI enabled longitudinal monitoring of disease progression in the 4NQO model with 100% of control animals showing evidence of neoplastic lesions by 24 weeks. Among the experimental groups, animals treated with the combination regimen showed the greatest reduction in tumor incidence and volume (P < 0.05). Combination treatment was well tolerated and was not associated with any significant change in body weight. Histopathologic assessment revealed a significant reduction in the degree of dysplasia with combination treatment. Immunoblot analysis of whole tongue extracts showed downregulation of phospho-EGFR and phospho-Akt with the combination regimen. These results highlight the potential of 1,25(OH)2D3 to augment the efficacy of erlotinib against HNSCC. Further optimization of schedule and sequence of this combination regimen along with investigation into the activity of less calcemic analogues or dietary vitamin D is essential to fully realize the potential of this approach. PMID- 26100524 TI - Individual differences in learning predict the return of fear. AB - Using a laboratory analogue of learned fear (Pavlovian fear conditioning), we show that there is substantial heterogeneity across individuals in spontaneous recovery of fear following extinction training. We propose that this heterogeneity might stem from qualitative individual differences in the nature of extinction learning. Whereas some individuals tend to form a new memory during extinction, leaving their fear memory intact, others update the original threat association with new safety information, effectively unlearning the fear memory. We formalize this account in a computational model of fear learning and show that individuals who, according to the model, are more likely to form new extinction memories tend to show greater spontaneous recovery compared to individuals who appear to only update a single memory. This qualitative variation in fear and extinction learning may have important implications for understanding vulnerability and resilience to fear-related psychiatric disorders. PMID- 26100525 TI - Comparing the context specificity of extinction and latent inhibition. AB - Exposure to a cue alone either before (i.e., latent inhibition treatment) or after (i.e., extinction) the cue is paired with an unconditioned stimulus results in attenuated conditioned responding to the cue. Here we report two experiments in which potential parallels between the context specificity of the effects of extinction and latent inhibition treatments were directly compared in a lick suppression preparation with rats. The reversed ordering of conditioning and nonreinforcement in extinction and latent inhibition designs allowed us to examine the effect of training order on the context specificity of what is learned given phasic reinforcement and nonreinforcement of a target cue. Experiment 1 revealed that when conditioned-stimulus (CS) conditioning and CS nonreinforcement were administered in the same context, both extinction and latent inhibition treatments had reduced impacts on test performance, relative to excitatory conditioning when testing occurred outside the treatment context. Similarly, Experiment 2 showed that when conditioning was administered in one context and nonreinforcement was administered in a second context, the effects of both extinction and latent inhibition treatments were attenuated when testing occurred in a neutral context, relative to the context in which the CS was nonreinforced. The observed context specificity of extinction and latent inhibition treatments has been previously reported in both cases, but not in a single experiment under otherwise identical conditions. The results of the two experiments convergently suggest that memory of nonreinforcement becomes context dependent after a cue is both reinforced and nonreinforced, independent of the order of training. PMID- 26100527 TI - Regulators seize 6.2 million doses of illegally traded medicines in UK. PMID- 26100526 TI - Voriconazole: a novel treatment option for cryptococcal meningitis. AB - BACKGROUND: Cryptococcal meningitis (CM) is a relatively common opportunistic infection in patients with human immunodeficiency virus (HIV) infection and can also occur in patients with no underlying disease. The aim of this study was to evaluate the clinical manifestations, laboratory findings, diagnosis and misdiagnosis, treatment, and prognosis of CM at a tertiary care hospital. METHODS: We performed a retrospective study of 55 patients at a tertiary care hospital from January 1, 1992 to December 31, 2013. All the patients had a definite diagnosis based on etiology. RESULTS: All 55 patients had a positive cerebrospinal fluid (CSF) India ink staining result. The predominant change observed on magnetic resonance imaging (MRI) was leptomeningeal liner enhancement, which is also called 'lumbriciform-enhancing.' Only 15 patients were first diagnosed with CM, indicating a misdiagnosis rate of 72.7%. At the follow up end point, 8 patients were cured, 33 had improved, and 14 had died. The overall response rate was 74.5%. The voriconazole group had a response rate of 100%, which was significantly higher than the other two groups. CONCLUSIONS: Most CM patients in China were previously healthy without any potential risk factors. CM was easily misdiagnosed due to the lack of specificity of early clinical symptoms. Repeated CSF India ink staining should be performed to identify the pathogen. Voriconazole could be administered to the patients with CM, especially to patients who had a treatment failure with amphotericin B alone or accompanied by fluconazole. PMID- 26100528 TI - Sexual Cognitions in Victims of Childhood and Adolescence/Adulthood Sexual Abuse. AB - This study explored the relationship between 1) child sexual abuse (CSA), adolescent/adult sexual abuse (AASA), and both (CSA+AASA), and 2) the frequency of positive and negative sexual cognitions according to their content -intimate, exploratory, dominance, submission, and impersonal- in men and women. We also analyzed the severity of the sexual contact of individuals who had experienced AASA. We assessed a Spanish sample of 228 men and 333 women, aged between 18 and 50 years old. In the sample, 341 individuals reported having experienced some type of sexual victimization (victims group), while 220 individuals reported no victimization (non-victims group). Overall, sexual victims reported a higher frequency of positive sexual cognitions compared to non-victims, particularly when they had experienced CSA+AASA and the severity of the sexual contact was greater. Men and women who had experienced abuse reported a higher frequency of exploratory cognitions (p < .01). Male victims reported more cognitions of submission (p < .01), whereas female victims reported more cognitions of dominance (p < .05), which indicates lack of congruence with traditional gender roles. Finally, only intimate cognitions (p < .001) were experienced as negative by male victims. We discuss the relevance of the findings for therapeutic interventions with sexual abuse victims. PMID- 26100529 TI - Oxidative Stress and Adult Neurogenesis. AB - There is a growing evidence that adult neurogenesis is critical for brain function. The reactive oxygen species (ROS) is accumulated during adult neurogenesis as a physiological mechanism; while ROS overload impairs adult neurogenesis during ageing, neuroinflammation and neurodegeneration. Here we propose that targeting oxidative stress provides a novel way to regulate adult neurogenesis and manage different brain diseases. PMID- 26100530 TI - Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1. AB - OBJECTIVE: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). METHODS: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. RESULTS: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche. CONCLUSIONS: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations. PMID- 26100531 TI - The mean platelet volume and neutrophil to lymphocyte ratio in obese and lean patients with polycystic ovary syndrome. AB - PURPOSE: Mean platelet volume (MPV) and neutrophil to lymphocyte ratio (NLR) are the new markers of the detection of inflammation. Our aim is to investigate MPV and NLR in lean and obese patients with polycystic ovary syndrome (PCOS). METHODS: This study was designed to investigate MPV, NLR, and high-sensitive C reactive protein (hsCRP) levels in 25 obese patients with PCOS and 16 lean patients with PCOS, and our study group was matched with 16 obese and 14 non obese controls, respectively. RESULTS: PCOS group had higher MPV, NLR, neutrophil count, neutrophil to total leucocyte ratio, basophil count, waist circumference (WC), insulin, glucose, and HOMA-IR rates than those of controls. hsCRP levels were similar in both groups. Subgroup analyses revealed that obese PCOS group had higher insulin and HOMA-IR levels, compared to those of controls. In this subgroup, total leucocyte counts, MPV, and hsCRP levels were similar. On the other hand, lean PCOS group had higher WC, NLR, MPV, and basophil count than controls. In correlation analysis, hsCRP was positively correlated with body mass index (BMI), WC, total leucocyte count, neutrophil count, while negatively correlated with lymphocyte ratio. Although leucocyte count was positively correlated with BMI, MPV was negatively correlated with BMI, total leucocyte, platelet, and neutrophil counts. NLR was positively correlated with HOMA-IR, hsCRP, BMI, WC, and insulin. CONCLUSION: Our study demonstrated that MPV and NLR levels are increased despite similar hsCRP levels in patients with PCOS. However, we failed to demonstrate these differences in obese PCOS patients. Further studies with larger sample size are required to determine the significance of BMI in the inflammation of PCOS patients. PMID- 26100533 TI - Divergent Approach to a Family of Tyrosine-Derived Ru-Alkylidene Olefin Metathesis Catalysts. AB - A simple and generic approach to access a new family of Ru-alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second generation Hoveyda-Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions. PMID- 26100532 TI - Suppression of acute pancreatitis by L-lysine in mice. AB - BACKGROUND: Acute pancreatitis is an inflammatory disease caused by several factors such as viral infection, drugs, and diagnostic endoscopy. The aim of this study was to evaluate the potential protective or therapeutic effects of L-lysine on pancreatitis induced by L-arginine in mice. METHODS: Four groups of mice (10 in each group) were assessed. Group I was the control. Animals in groups II-IV were injected intraperitoneally with L-arginine hydrochloride (400 mg/kg body weight [bw]) for 3 days. Group III animals were orally pre-treated with L-lysine (10 mg/kg bw), whereas group IV animals were orally post-treated with L-lysine (10 mg/kg bw). Serum samples were subjected to amylase, lipase, transaminase, and interleukin-6 (IL-6) assays. The pancreas was excised to measure the levels of malondialdehyde, nitric oxide, catalase, superoxide dismutase, reduced glutathione, and glutathione peroxidase. RESULTS: Pre- or post-treatment with L lysine led to significant decreases in the levels of malondialdehyde and nitric oxide, while significant enhancement was observed in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and glutathione (p < 0.001). However, the treatment potential of L-lysine was better as a protective agent than a therapeutic agent. CONCLUSIONS: L-lysine treatment attenuates pancreatic tissue injury induced by L-arginine by inhibiting the release of the inflammatory cytokine IL-6 and enhance antioxidant activity. These effects may involve upregulation of anti-inflammatory factors and subsequent downregulation of IL6. PMID- 26100534 TI - Immunophenotype of normal vs. myeloma plasma cells: Toward antibody panel specifications for MRD detection in multiple myeloma. AB - In recent years, several studies on large series of multiple myeloma (MM) patients have demonstrated the clinical utility of flow cytometry monitoring of minimal residual disease (flow-MRD) in bone marrow (BM), for improved assessment of response to therapy and prognostication. However, disturbing levels of variability exist regarding the specific protocols and antibody panels used in individual laboratories. Overall, consensus exists about the utility of combined assessment of CD38 and CD138 for the identification of BM plasma cells (PC); in contrast, more heterogeneous lists of markers are used to further distinguish between normal/reactive PCs and myeloma PCs in the MRD settings. Among the later markers, CD19, CD45, CD27, and CD81, together with CD56, CD117, CD200, and CD307, have emerged as particularly informative; however, no single marker provides enough specificity for clear discrimination between clonal PCs and normal PCs. Accordingly, multivariate analyses of single PCs from large series of normal/reactive vs. myeloma BM samples have shown that combined assessment of CD138 and CD38, together with CD45, CD19, CD56, CD27, CD81, and CD117 would be ideally suited for MRD monitoring in virtually every MM patient. However, the specific antibody clones, fluorochrome conjugates and sources of the individual markers determines its optimal (vs. suboptimal or poor) performance in an eight color staining. Assessment of clonality, via additional cytoplasmic immunoglobulin (CyIg) kappa vs. CyIglambda evaluation, may contribute to further establish the normal/reactive vs. clonal nature of small suspicious PC populations at high sensitivity levels, provided that enough cells are evaluated. PMID- 26100535 TI - Analysis of bolus formation in micropipette ejection systems. AB - The ejection of drugs from micropipettes is practiced frequently in biomedical research and clinical studies however, little is known about the dynamics of this process. The fundamentals of disperse fluid injection via a capillary into an ambient immiscible fluid have been investigated extensively. Here, we experimentally investigate the bolus formation in micropipette ejection systems, where the injection and ambient fluid are the same. We experimentally measure the temporal evolution of the bolus formation in the same fluid. There are three different bolus formation mechanisms that arise from different Re t regimes: a) a nearly spherical bolus, b) a pear-like bolus, and c) a large distortion or axial jet. We examine the scaled dimensions of the bolus, R b/D t, L b/D t, H/D t, and alpha, as a function of the dimensionless parameters such as tip Reynolds number, Re t, dimensionless value of g/(D t (.) V t), the dimensionless time, tV t/D t, and the distance between the edge of the micropipette and the free surface, D/D t. The bolus radius for 0.2 < Re t < 30 grows according to t (1/2) in the entire time range, which allows us to estimate the time for complete bolus formation. PMID- 26100536 TI - Gene expression in major depressive disorder. PMID- 26100537 TI - L-type Ca2+ channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory. AB - Drug addiction is driven, in part, by powerful and enduring memories of sensory cues associated with drug intake. As such, relapse to drug use during abstinence is frequently triggered by an encounter with drug-associated cues, including the drug itself. L-type Ca(2+) channels (LTCCs) are known to regulate different forms of synaptic plasticity, the major neural substrate for learning and memory, in various brain areas. Long-term potentiation (LTP) of NMDA receptor (NMDAR) mediated glutamatergic transmission in the ventral tegmental area (VTA) may contribute to the increased motivational valence of drug-associated cues triggering relapse. In this study, using rat brain slices, we found that isradipine, a general LTCC antagonist used as antihypertensive medication, not only blocks the induction of NMDAR LTP but also promotes the reversal of previously induced LTP in the VTA. In behaving rats, isradipine injected into the VTA suppressed the acquisition of cocaine-paired contextual cue memory assessed using a conditioned place preference (CPP) paradigm. Furthermore, administration of isradipine or a CaV1.3 subtype-selective LTCC antagonist (systemic or intra VTA) before a single extinction or reinstatement session, while having no immediate effect at the time of administration, abolished previously acquired cocaine and alcohol (ethanol) CPP on subsequent days. Notably, CPP thus extinguished cannot be reinstated by drug re-exposure, even after 2 weeks of withdrawal. These results suggest that LTCC blockade during exposure to drug associated cues may cause unlearning of the increased valence of those cues, presumably via reversal of glutamatergic synaptic plasticity in the VTA. PMID- 26100538 TI - Huntington's disease cerebrospinal fluid seeds aggregation of mutant huntingtin. AB - Huntington's disease (HD), a progressive neurodegenerative disease, is caused by an expanded CAG triplet repeat producing a mutant huntingtin protein (mHTT) with a polyglutamine-repeat expansion. Onset of symptoms in mutant huntingtin gene carrying individuals remains unpredictable. We report that synthetic polyglutamine oligomers and cerebrospinal fluid (CSF) from BACHD transgenic rats and from human HD subjects can seed mutant huntingtin aggregation in a cell model and its cell lysate. Our studies demonstrate that seeding requires the mutant huntingtin template and may reflect an underlying prion-like protein propagation mechanism. Light and cryo-electron microscopy show that synthetic seeds nucleate and enhance mutant huntingtin aggregation. This seeding assay distinguishes HD subjects from healthy and non-HD dementia controls without overlap (blinded samples). Ultimately, this seeding property in HD patient CSF may form the basis of a molecular biomarker assay to monitor HD and evaluate therapies that target mHTT. PMID- 26100540 TI - Facial skin physiology recovery kinetics during 180 min post-washing with a cleanser. AB - BACKGROUND/PURPOSE: Facial cleansing is important to clean and exfoliate the skin while maintaining optimal physiologic function. However, there is insufficient data on the very early stage of skin change after applying soap or cleansing foam. We investigated the recovery kinetics of facial skin physiology during 180 min after exposure to the cleanser. METHODS: For the study, 22 Korean female subjects with normal and dry to oily skin type were recruited in this study. Study subjects were required to have face washing done within the 12 hours prior to visiting the research center, with only toner, lotion, or cream applied. The next day, the subjects visited the research center without face washing. We evaluated the skin hydration (Corneometer((r)) CM 825), sebum (Sebumeter((r)) SM 815), transepidermal water loss (Tewameter((r)) TM 300), and pH (Skin-pH Meter((r)) PH 905) to define recovery kinetics of facial skin physiology during 180 min exposure post-cleansing. RESULTS: Skin hydration, sebum, and TEWL were significantly decreased at 20 min after washing, as compared to the baseline (P < 0.05). And skin hydration returned at 40 min, and skin sebum and TEWL returned at 120 min after washing. However, skin pH did not show significant differences at all times points. CONCLUSIONS: This study indicated that each of the skin parameters was restored at defined time points post-cleansing. Our result could be a useful reference to set the resting time in the estimation of skin bioengineering parameters. PMID- 26100539 TI - Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration. AB - Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, ~80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive-like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant-like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies. PMID- 26100541 TI - Vasopressin signaling at brain level controls stress hormone release: the vasopressin-deficient Brattleboro rat as a model. AB - The nonapeptide arginine vasopressin (AVP) has long been suggested to play an important role as a secretagogue for triggering the activity of the endocrine stress response. Most recent studies employed mutant mice for analyzing the importance of AVP for endocrine regulation under stress. However, it is difficult to compare and draw overall conclusions from all these studies as mixing the genetic material from different mouse strains has consequences on the individual's stress response. Moreover, mice are not ideal subjects for several experimental procedures. Therefore, to get more insight, we used a rather old mutant rat model: the AVP-deficient Brattleboro rat. The present short review is aimed at providing the most interesting results of these studies within the last 8 years that allowed gaining new insights in the potential signal function of AVP in stress and endocrine regulation. PMID- 26100547 TI - A cationic cysteine-hydrazide as an enrichment tool for the mass spectrometric characterization of bacterial free oligosaccharides. AB - In Campylobacterales and related epsilon-proteobacteria with N-linked glycosylation (NLG) pathways, free oligosaccharides (fOS) are released into the periplasmic space from lipid-linked precursors by the bacterial oligosaccharyltransferase (PglB). This hydrolysis results in the same molecular structure as the oligosaccharide that is transferred to a protein to be glycosylated. This allowed for the general elucidation of the fOS-branched structures and monosaccharides from a number of species using standard enrichment and mass spectrometry methods. To aid characterization of fOS, hydrazide chemistry has often been used for chemical modification of the reducing part of oligosaccharides resulting in better selectivity and sensitivity in mass spectrometry; however, the removal of the unreacted reagents used for the modification often causes the loss of the sample. Here, we develop a more robust method for fOS purification and characterize glycostructures using complementary tandem mass spectrometry (MS/MS) analysis. A cationic cysteine hydrazide derivative was synthesized to selectively isolate fOS from periplasmic fractions of bacteria. The cysteine hydrazide nicotinamide (Cyhn) probe possesses both thiol and cationic moieties. The former enables reversible conjugation to a thiol activated solid support, while the latter improves the ionization signal during MS analysis. This enrichment was validated on the well-studied Campylobacter jejuni by identifying fOS from the periplasmic extracts. Using complementary MS/MS analysis, we approximated data of a known structure of the fOS from Campylobacter concisus. This versatile enrichment technique allows for the exploration of a diversity of protein glycosylation pathways. PMID- 26100548 TI - Development of a mass-spectrometry-based lipidomics platform for the profiling of phospholipids and sphingolipids in brain tissues. AB - This article describes the development of a lipidomic platform consisting of a 4000 QTRAP mass spectrometer and a self-installed sample inlet system to indentify and quantify 12 phospholipid and five sphingolipid classes from lipid rich brain tissues of mouse, duck, and salmon. The total mass spectrometry analysis time per sample was 30 min, including 14 min for direct infusion for phospholipids and sulfatide in precursor ion scanning mode or neutral loss scanning mode, and 16 min for liquid-chromatographic separation of ceramide, sphingomyelin, monohexosylceramide, and dihexosylceramide in multiple reaction monitoring mode. The method was fully validated in terms of linearity, detectability, recovery, and repeatability, with satisfactory results for all targets. We individually quantified 307, 308, and 330 lipid species from 17 lipid subclasses, and obtained total amounts of 57.2, 61.7, and 53.1 mg/g wet brain for mouse, duck, and salmon tissues, respectively. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and sphingomyelin were the major lipids in all the brain samples, whereas phosphatidylinositol occurred at a relatively higher level in the salmon sample. For phospholipids, sphingolipids, and minor lysophospholipids, differences in the identity of the molecular species, their distributions, and their relative amounts as well as the contribution of each lipid subclass to the whole polar lipidome were found. Palmitic acid (16:0), stearic acid (18:0), lignoceric acid (24:0), oleic acid (18:1), nervonic acid (24:1), arachidonic acid (20:4), and docosahexaenoic acid (22:6) were found as the main saturated, monounsaturated, and polyunsaturated fatty acids in samples from the different species, but eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) were more abundant in the salmon brain sample. The results are in good agreement with those in previous reports obtained from the relevant tissues, providing a reliable basis that could be extended to clinical research and resource evaluation. Graphical Abstract Methodology for phospholipids and sphingolipids profiling in brain tissues. PMID- 26100546 TI - A prospective multicenter study of venous thromboembolism in patients with newly diagnosed high-grade glioma: hazard rate and risk factors. AB - Venous thromboembolism (VTE) is a common complication in patients with high-grade gliomas. The purpose of this prospective multicenter study was to determine the hazard rate of first symptomatic VTE in newly-diagnosed glioma patients and identify clinical and laboratory risk factors. On enrollment, demographic and clinical information were recorded and a comprehensive coagulation evaluation was performed. Patients were followed until death. The study end point was objectively-documented symptomatic VTE. One hundred seven patients were enrolled with a median age of 57 years (range 29-85) between June 2005 and April 2008. Ninety-one (85 %) had glioblastoma multiforme (GBM). During an average survival of 17.7 months, 26 patients (24 %) (95 % CI 17-34 %) developed VTE (hazard rate 0.15 per person-year) and 94 patients (88 %) died. Median time to VTE was 14.2 weeks post-operation (range 3-126). Patients with an initial tumor biopsy were 3.0 fold more likely to suffer VTE (p = 0.02). Patients with an elevated factor VIII activity (>147 %) were 2.1-fold more likely to develop VTE. ABO blood group, D dimer and thrombin generation were not associated with VTE. No fatal VTE occurred. VTE is a common complication in patients with newly-diagnosed high grade gliomas, particularly in the first six months after diagnosis. Patients with an initial tumor biopsy and elevated factor VIII levels are at increased risk. However, VTE was not judged to be primarily responsible for any patient deaths. Therefore, outpatient primary VTE prophylaxis remains investigational until more effective primary prophylaxis strategies and therapies for glioma are identified. PMID- 26100549 TI - Electrochemiluminescence DNA sensor array for multiplex detection of biowarfare agents. AB - Development of a fully automated electrochemiluminescence (ECL) DNA assay for multiplex detection of six biowarfare agents is described. Aminated-DNA capture probes were covalently immobilised on activated-carbon electrodes and subsequently hybridised to target strands. Detection was achieved via a sandwich type assay after Ru(bpy)3(2+)-labelled reporter probes were hybridised to the formed probe-target complexes. The assay was performed in an automated microsystem in a custom designed ECL detection box with integrated fluidics, electronics,and movable photomultiplier detector. The obtained limits of detection were 0.6-1.2 nmol L(-1) for six targets ranging from 50 to 122 base pairs in size, with linear range 1-15 nmol L(-1). Non-specific adsorption and cross-reactivity were very low. Detection of six targets on a single chip was achieved with subnanomolar detection limits. PMID- 26100550 TI - Development and validation of a method for mercury determination in seawater for the process control of a candidate certified reference material. AB - A simple, robust and reliable method for mercury determination in seawater matrices based on the combination of cold vapour generation and inductively coupled plasma mass spectrometry (CV-ICP-MS) and its complete in-house validation are described. The method validation covers parameters such as linearity, limit of detection (LOD), limit of quantification (LOQ), trueness, repeatability, intermediate precision and robustness. A calibration curve covering the whole working range was achieved with coefficients of determination typically higher than 0.9992. The repeatability of the method (RSDrep) was 0.5 %, and the intermediate precision was 2.3 % at the target mass fraction of 20 ng/kg. Moreover, the method was robust with respect to the salinity of the seawater. The limit of quantification was 2.7 ng/kg, which corresponds to 13.5 % of the target mass fraction in the future certified reference material (20 ng/kg). An uncertainty budget for the measurement of mercury in seawater has been established. The relative expanded (k = 2) combined uncertainty is 6 %. The performance of the validated method was demonstrated by generating results for process control and a homogeneity study for the production of a candidate certified reference material. PMID- 26100551 TI - Authors' response to "Difficult to wean patients". PMID- 26100552 TI - Influence of the Base on Pd@MIL-101-NH2 (Cr) as Catalyst for the Suzuki-Miyaura Cross-Coupling Reaction. AB - The chemical stability of metal-organic frameworks (MOFs) is a major factor preventing their use in industrial processes. Herein, it is shown that judicious choice of the base for the Suzuki-Miyaura cross-coupling reaction can avoid decomposition of the MOF catalyst Pd@MIL-101-NH2 (Cr). Four bases were compared for the reaction: K2 CO3 , KF, Cs2 CO3 and CsF. The carbonates were the most active and achieved excellent yields in shorter reaction times than the fluorides. However, powder XRD and N2 sorption measurements showed that the MOF catalyst was degraded when carbonates were used but remained crystalline and porous with the fluorides. XANES measurements revealed that the trimeric chromium cluster of Pd@MIL-101-NH2 (Cr) is still present in the degraded MOF. In addition, the different countercations of the base significantly affected the catalytic activity of the material. TEM revealed that after several catalytic runs many of the Pd nanoparticles (NPs) had migrated to the external surface of the MOF particles and formed larger aggregates. The Pd NPs were larger after catalysis with caesium bases compared to potassium bases. PMID- 26100553 TI - Pathophysiological mechanisms of exercise-induced anaphylaxis: an EAACI position statement. AB - This document is the result of a consensus on the mechanisms of exercise-induced anaphylaxis (EIAn), an unpredictable and potentially fatal syndrome. A multidisciplinary panel of experts including exercise physiologists, allergists, lung physicians, paediatricians and a biostatistician reached the given consensus. Exercise-induced anaphylaxis (EIAn) describes a rare and potentially fatal syndrome in which anaphylaxis occurs in conjunction with exercise. The pathophysiological mechanisms underlying EIAn have not yet been elucidated although a number of hypotheses have been proposed. This review evaluates the validity of each of the popular theories in relation to exercise physiology and immunology. On the basis of this evidence, it is concluded that proposed mechanisms lack validity, and it is recommended that a global research network is developed with a common approach to the diagnosis and treatment of EIAn in order to gain sufficient power for scientific evaluation. PMID- 26100554 TI - Preparation and Transport Performances of High-Density, Aligned Carbon Nanotube Membranes. AB - We report a simple and effective method for the preparation of high-density and aligned carbon nanotube (CNT) membranes. The CNT arrays were prepared by water assisted chemical vapor deposition (CVD) and were subsequently pushed over and stacked into dense membranes by mechanical rolling. It was demonstrated that various gases and liquids, including H2, He, N2, O2, Ar, water, ethanol, hexane, and kerosene, could effectively pass through the aligned carbon nanotube membranes. The membranes exhibited different selections on different gases, indicating that there was a separation potential for the gas mixtures. The selectivities (H2 relative to other gases) of H2/He, H2/N2, H2/O2, and H2/Ar were found to be lower than that of the ideal Knudsen model. For pure water, the permeability was measured to be 3.23 +/- 0.05 ml.min(-1).cm(-2) at 1 atm, indicating that the CNT membranes were promising for applications in liquid filtration and separation. PMID- 26100555 TI - Controlled growth of Si-based heterostructure nanowires and their structural and electrical properties. AB - Ni-catalyzed Si-based heterostructure nanowires grown on crystal Si substrates by hot-wire chemical vapor deposition (HWCVD) were studied. The nanowires which included NiSi nanowires, NiSi/Si core-shell nanowires, and NiSi/SiC core-shell nanowires were grown by varying the filament temperature T f from 1150 to 1850 degrees C. At a T f of 1450 degrees C, the heterostructure nanowires were formed by crystalline NiSi and crystalline Si that were attributed to the core and shell of the nanowires, respectively. The morphology of the nanowires showed significant changes with the increase in the filament temperature to 1850 degrees C. Moreover, the effect of hydrogen heat transfer from the filament temperature demonstrated significant phase changes from NiSi to Ni2Si with increase in the filament temperature. The increased filament temperature also enhanced reactions in the gas phase thus generating more SiC clusters and consequently formed the NiSi/SiC heterostructure core-shell nanowires at T f of 1850 degrees C. This paper discusses the role of filament temperatures on the growth and constituted phase change of the nanowires as well as their electrical characteristics. PMID- 26100556 TI - Genetic mutations in SPINK1, CFTR, CTRC genes in acute pancreatitis. AB - BACKGROUND: Explanation of the ultimate causes of acute and chronic pancreatitis is challenging. Hence, it is necessary to seek various etiological factors, including genetic mutations that may be of importance in triggering recurrence and progression of acute to chronic pancreatitis. The aim of this study was to determine the frequency of genetic mutations in patients with acute pancreatitis and to investigate their relationship with the etiology and clinical course. METHODS: The study included 221 patients treated for acute pancreatitis and 345 healthy subjects as a control group. Peripheral blood samples were collected from each study participant and genomic DNA was isolated. Genotyping of common mutations in the SPINK1 (p.N34S and p.P55S) and CTRC (p.I259V, p.V235I, p.K247_R254del, p.E225A) genes was performed using the high-resolution melting method. Mutations in the CFTR p.F508del (delF508_CTT) were genotyped using allele specific amplification polymerase chain reaction. All detected mutations were confirmed with direct capillary DNA sequencing. RESULTS: Mutations in SPINK 1, CFTR and CTRC were detected in 6.3%, 2.3% and 1.8% of patients with acute pancreatitis versus 3.2%, 3.8% and 1.2% of volunteers in the control group. No relationship was found between the detected mutations and severity of acute pancreatitis: mild acute pancreatitis, mutation of CFTR in 4 (2.8%) and CTRC in 2 (1.4%) patients; severe acute pancreatitis, mutation of CFTR and CTRC in 1 (2.6%) case each. The SPINK1 mutation was significantly more frequent in 8 (10.4%) severe cases than in 6 (4.2%) mild cases (P < 0.05), and was observed in 5/70 (7.1%) patients with alcohol-related AP, 5/81 (6.2%) with biliary AP, and 4/63 (6.3%) in those without any established cause of the disease. CONCLUSIONS: Mutation p.N34S in SPINK1 may predispose patients to acute pancreatitis, especially in those abusing alcohol, and may promote a more severe course of the disease. PMID- 26100557 TI - Effects of short-chain fructooligosaccharides (scFOS) and rearing temperature on growth performance and hepatic intermediary metabolism in gilthead sea bream (Sparus aurata) juveniles. AB - The effect of dietary short-chain fructooligosaccharides (scFOS) incorporation on growth, feed utilization, body composition, plasmatic metabolites and liver activity of key enzymes of lipogenic and amino acid catabolic pathways was evaluated in gilthead sea bream reared at 18 and 25 degrees C. Four practical diets containing plant ingredients and fish meal (50:50) as protein sources and supplemented with 0, 0.1, 0.25 and 0.5 % scFOS were fed to triplicate groups of fish for 8 weeks. Growth performance, feed efficiency and nitrogen retention were higher at 25 degrees C. In fish reared at 18 degrees C, there was a positive correlation between dietary scFOS concentration and growth. At 18 degrees C, liver glycogen was higher in fish fed the control diet, while at 25 degrees C it was higher in fish fed the 0.5 % scFOS diet. Plasma cholesterol LDL was lower in fish fed 0.25 % scFOS diet, and in fish reared at 18 degrees C plasma glucose was higher in fish fed the 0.1 % scFOS diet. Glucose 6-phosphate dehydrogenase, fatty acid synthetase and aspartate aminotransferase (ASAT) activities were higher in fish reared at 18 degrees C, whereas alanine aminotransferase activity was higher in fish reared at 25 degrees C. scFOS affected ASAT activity, which was lower in fish fed 0.25 % scFOS diet. Although, scFOS seemed to have no major effects on gilthead sea bream metabolism, the positive correlation between dietary prebiotic incorporation and growth at 18 degrees C indicates a beneficial effect of scFOS in fish reared at low temperatures. PMID- 26100558 TI - Impacts of Particulate Air Pollution on Asthma: Current Understanding and Future Perspectives. AB - The impacts of air pollution on human health and disease have been attracting attention, especially in industrialized countries and areas with heavy traffic burdens. Fine particulate matters (PMs) are considered as an important air pollutant, since it was reported that there was a significant relationship between PM2.5 levels and mortality by cohort studies in 1990s. Epidemiological and toxicological studies have strongly suggested a causative relationship between fine particulate air pollution and increased incidence as well as exacerbations of asthma, and other respiratory disorders. Recent advances in research have elucidated that PMs primarily and secondarily induce oxidative stresses which result both in pro- and antiinflammatory activities. It has been demonstrated that gene polymorphisms of antioxidant enzymes might change responses to particulate air pollution exposures. To prevent health hazardous effects of particles, it is crucial to screen susceptible subpopulations and establish chemoprevention strategies in the world. Novel techniques and modalities are patented for future progress on better control of air pollution. PMID- 26100559 TI - Brain regional networks active during the mismatch negativity vary with paradigm. AB - We used independent component analysis (ICA) of high-density EEG recordings coupled with single dipole fitting to identify the dominant brain regions active during the MMN in two different versions of a passive oddball paradigm: a simple, monotic, frequency-deviant paradigm and a more complex, dichotic, frequency deviant paradigm with deviants occurring in either ear alone or in both ears at the same time. In both paradigms we found brain regional sources in the temporal and frontal cortices active during the MMN period, consistent with some previous studies. In the simpler paradigm, the scalp-potential variance during the earlier (70-120 ms) MMN was mostly accounted for by a wide array of temporal, frontal, and parietal sources. In the more complex paradigm, however, a generator in the prefrontal cortex accounted for a substantial amount of the variance of the scalp potential during the somewhat later MMN period (120-200 ms). These findings are consistent with a more nuanced view of the MMN and its generators than has been held in the past. PMID- 26100560 TI - The neural speed of familiar face recognition. AB - Rapidly recognizing familiar people from their faces appears critical for social interactions (e.g., to differentiate friend from foe). However, the actual speed at which the human brain can distinguish familiar from unknown faces still remains debated. In particular, it is not clear whether familiarity can be extracted from rapid face individualization or if it requires additional time consuming processing. We recorded scalp EEG activity in 28 subjects performing a go/no-go, famous/non-famous, unrepeated, face recognition task. Speed constraints were used to encourage subjects to use the earliest familiarity information available. Event related potential (ERP) analyses show that both the N170 and the N250 components were modulated by familiarity. The N170 modulation was related to behaviour: subjects presenting the strongest N170 modulation were also faster but less accurate than those who only showed weak N170 modulation. A complementary Multi-Variate Pattern Analysis (MVPA) confirmed ERP results and provided some more insights into the dynamics of face recognition as the N170 differential effect appeared to be related to a first transitory phase (transitory bump of decoding power) starting at around 140 ms, which returned to baseline afterwards. This bump of activity was henceforth followed by an increase of decoding power starting around 200 ms after stimulus onset. Overall, our results suggest that rather than a simple single-process, familiarity for faces may rely on a cascade of neural processes, including a coarse and fast stage starting at 140 ms and a more refined but slower stage occurring after 200 ms. PMID- 26100561 TI - The contribution of dynamic visual cues to audiovisual speech perception. AB - Seeing a speaker's facial gestures can significantly improve speech comprehension, especially in noisy environments. However, the nature of the visual information from the speaker's facial movements that is relevant for this enhancement is still unclear. Like auditory speech signals, visual speech signals unfold over time and contain both dynamic configural information and luminance defined local motion cues; two information sources that are thought to engage anatomically and functionally separate visual systems. Whereas, some past studies have highlighted the importance of local, luminance-defined motion cues in audiovisual speech perception, the contribution of dynamic configural information signalling changes in form over time has not yet been assessed. We therefore attempted to single out the contribution of dynamic configural information to audiovisual speech processing. To this aim, we measured word identification performance in noise using unimodal auditory stimuli, and with audiovisual stimuli. In the audiovisual condition, speaking faces were presented as point light displays achieved via motion capture of the original talker. Point light displays could be isoluminant, to minimise the contribution of effective luminance-defined local motion information, or with added luminance contrast, allowing the combined effect of dynamic configural cues and local motion cues. Audiovisual enhancement was found in both the isoluminant and contrast-based luminance conditions compared to an auditory-only condition, demonstrating, for the first time the specific contribution of dynamic configural cues to audiovisual speech improvement. These findings imply that globally processed changes in a speaker's facial shape contribute significantly towards the perception of articulatory gestures and the analysis of audiovisual speech. PMID- 26100562 TI - Reprint of: Transcranial direct current stimulation (tDCS) - Application in neuropsychology. AB - Non-invasive brain stimulation is a versatile tool to modulate psychological processes via alterations of brain activity, and excitability. It is applied to explore the physiological basis of cognition and behavior, as well as to reduce clinical symptoms in neurological and psychiatric diseases. Neuromodulatory brain stimulation via transcranial direct currents (tDCS) has gained increased attention recently. In this review we will describe physiological mechanisms of action of tDCS, and summarize its application to modulate psychological processes in healthy humans and neuropsychiatric diseases. Furthermore, beyond giving an overview of the state of the art of tDCS, including limitations, we will outline future directions of research in this relatively young scientific field. PMID- 26100563 TI - A unilateral medial frontal cortical lesion impairs trial and error learning without visual control. AB - There is considerable debate regarding the involvement of the medial frontal cortex in motor and cognitive functions. Recent neuroimaging data suggest a fundamental underlying process that links the motor and cognitive roles of the mid-cingulate cortex (MCC), namely the processing of feedback during trial and error learning in the cingulate motor region that is related to the modality of the feedback. These data suggest that the specific motor context of a task may be a critical determinant of how its outcome is processed in the MCC. We assessed a patient before and after surgery for brain tumour removal in the medial frontal cortex, and a group of matched control subjects. Subjects had to find by trial and error the stimulus associated with the correct feedback amongst four or five similar stimuli. Subjects performed the task in two different visuo-motor contexts: with the response pad and hand visible and with no sight of either pad or hand. The patient showed a selective impairment in this task relative to control subjects in the hardest conditions and the impairment was most marked when the response pad and the hand were not visible. The results support a specific role of the medial frontal cortex in the construction of a sensorimotor representation of choices and related feedback by encoding the contingency between an efference copy of the action and its outcome. PMID- 26100564 TI - Effects of non-invasive brain stimulation on attention: Current debates, cognitive studies and novel clinical applications. PMID- 26100565 TI - Hypogammaglobulinemia and impaired antibody response in a child with chromosome 2p15-16.1 microdeletion syndrome. PMID- 26100566 TI - Arbitrary lattice symmetries via block copolymer nanomeshes. AB - Self-assembly of block copolymers is a powerful motif for spontaneously forming well-defined nanostructures over macroscopic areas. Yet, the inherent energy minimization criteria of self-assembly give rise to a limited library of structures; diblock copolymers naturally form spheres on a cubic lattice, hexagonally packed cylinders and alternating lamellae. Here, we demonstrate multicomponent nanomeshes with any desired lattice symmetry. We exploit photothermal annealing to rapidly order and align block copolymer phases over macroscopic areas, combined with conversion of the self-assembled organic phase into inorganic replicas. Repeated photothermal processing independently aligns successive layers, providing full control of the size, symmetry and composition of the nanoscale unit cell. We construct a variety of symmetries, most of which are not natively formed by block copolymers, including squares, rhombuses, rectangles and triangles. In fact, we demonstrate all possible two-dimensional Bravais lattices. Finally, we elucidate the influence of nanostructure on the electrical and optical properties of nanomeshes. PMID- 26100567 TI - Volume of blood loss during surgery for colon cancer is a risk determinant for future small bowel obstruction caused by recurrence--a population-based epidemiological study. AB - PURPOSE: Small bowel obstruction (SBO) is a serious late complication after abdominal surgery. The pathogenesis of intra-abdominal adhesions has been extensively studied and reviewed, but the cascade of mechanisms involved is still not understood. The objective was to test the hypothesis that increasing volume of blood loss during surgery for colon cancer increases the risk for future SBO, mainly due to adhesions. METHODS: Data were retrieved from the Regional Quality Register for all patients undergoing locally radical surgery for colon cancer 1997-2003 (n = 3 554) and matched with the Swedish National Patient Register data on surgery and admission for SBO. Records were reviewed to determine the etiology of surgery for SBO. Uni- and multivariate Cox analyses were used. RESULTS: One hundred ten patients (3.1 %) underwent surgery for SBO >30 days after the index operation. Blood loss >=250 ml was an independent risk factor for surgery for SBO due to recurrence (HR 2.20; 95 % CI 1.12-4.31). Amount of blood loss did not affect the risk for surgery for SBO due to adhesions. Furthermore, blood loss of >=250 ml increased the risk for hospital admission for SBO not requiring surgery. CONCLUSIONS: Blood loss >=250 ml during surgery for colon cancer is an independent risk factor for later surgery for SBO caused by tumor recurrence, not by adhesions. PMID- 26100568 TI - Central obesity is an independent risk factor for microalbuminuria in both the general Korean women and nondiabetic nonhypertensive subpopulation: Association of microalbuminuria and metabolic syndrome from the Korea National Health and Nutrition Examination Survey 2011-2012. AB - BACKGROUND: We investigated the major contributing component of metabolic syndrome (MetS) that results in microalbuminuria (MAU) in the general population as well as in nondiabetic nonhypertensive subjects. METHODS: The study population consisted of a total of 9961 subjects (4429 men and 5532 women) who participated in the Korea National Health and Nutrition Examination Surveys conducted in 2011 and 2012. MAU was defined as a urine albumin-to-creatinine ratio of >3.39mg/mmol. After analyzing the contribution of each five MetS components for the presence of MAU with adjustment for other risk factors in the total population, we further examined the contribution of these components to MAU in the nondiabetic nonhypertensive subpopulation. RESULTS: The most significantly associated factors for MAU in both genders were high blood pressure, followed by impaired fasting glucose, and high triglycerides. In addition, central obesity contributed significantly to MAU only in women. For the nondiabetic nonhypertensive subpopulation, high blood pressure in both genders and central obesity in women were important risk factors for MAU. We suggest two possible hypotheses for the gender different phenomenon. CONCLUSIONS: Central obesity was an independent risk factor for MAU in the general Korean women as well as in the nondiabetic nonhypertensive women. PMID- 26100570 TI - Heritability of heterozygosity offers a new way of understanding why dominant gene action contributes to additive genetic variance. AB - Whenever allele frequencies are unequal, nonadditive gene action contributes to additive genetic variance and therefore the resemblance between parents and offspring. The reason for this has not been easy to understand. Here, we present a new single-locus decomposition of additive genetic variance that may give greater intuition about this important result. We show that the contribution of dominant gene action to parent-offspring resemblance only depends on the degree to which the heterozygosity of parents and offspring covary. Thus, dominant gene action only contributes to additive genetic variance when heterozygosity is heritable. Under most circumstances this is the case because individuals with rare alleles are more likely to be heterozygous, and because they pass rare alleles to their offspring they also tend to have heterozygous offspring. When segregating alleles are at equal frequency there are no rare alleles, the heterozygosities of parents and offspring are uncorrelated and dominant gene action does not contribute to additive genetic variance. PMID- 26100569 TI - Risk factors for wound morbidity after open retromuscular (sublay) hernia repair. AB - BACKGROUND: Retrorectus repairs (RR) of abdominal wall hernias are growing in popularity, yet wound morbidity and predictors in this context have been characterized poorly. Models aimed at predicting wound morbidity typically do not control for technique and/or location of mesh. Our aim was to describe wound morbidity and risk factors specifically in the context of RR hernia repair. Our hypothesis was that the incidence of wound morbidity with mesh sublay would be less than predicted by a model that does not control for mesh position. METHODS: Consecutive RR hernia repairs with at least a 90-day follow-up were identified in our prospective database and analyzed. The primary outcome measures were the incidence of surgical-site occurrence (SSO) and surgical-site infection (SSI) via modern, standardized definitions. For predictors of SSO, statistical analysis was performed with univariate analysis, chi(2), and logistic regression as well as multivariate regression. RESULTS: A total of 306 patients met the inclusion criteria. Eighty-four SSOs identified in 72 (23.5%) patients included 48 (15.7%) SSIs, 14 (4.6%) instances of wound cellulitis, 12 (3.9%) skin dehiscences, 6 (2.0%) seromas, and 4 (1.3%) hematomas but no instances of mesh excision or fistula formation. Treatment entailed antibiotics alone in 30 patients, 14 bedside drainage procedures, 9 radiographically assisted drainage procedures, and 10 returns to the operating room for debridement. After multivariate analysis, diabetes (OR 2.41), hernia width >20 cm (OR 2.49), and use of biologic mesh (OR 2.93) were statistically associated with the development of a SSO (P < .05). Notably, the mere presence of contamination was not independently associated with wound morbidity (OR 1.83, P = .11). SSO and SSI rates anticipated by a recent risk prediction model were 50-80% and 17-83%, respectively, compared with our actual rates of 20-46% and 7-32%. CONCLUSION: Based on a large cohort of patients, we identified factors contributing to SSOs specifically for RR hernia repairs. Paradoxically, biologic mesh was an independent predictor of wound morbidity. The development of clinically important mesh complications and rates of wound morbidity less than anticipated by recent predictive models suggest that the retromuscular (sublay) mesh position may be more advantageous. PMID- 26100571 TI - Heart disease in patients with osteogenesis imperfecta - A systematic review. AB - INTRODUCTION: Osteogenesis imperfecta (OI) is a rare, inherited systemic connective tissue disease that causes decreased bioavailability of collagen type 1. Collagen type 1 is the most abundant connective tissue in the body and a key part of many organs. While the bone phenotype in OI is well described, less is known about the effects of decreased collagen on other organs. In the heart, collagen type 1 is present in the heart valves, chordae tendineae, annuli fibrosi and the interventricular septum. It is thus likely that the heart is affected in OI. OBJECTIVES: The aim of this systematic literature review was to investigate whether patients with OI have an increased risk of cardiovascular disease compared to healthy adults. DATA SOURCES: PubMed, Embase and key scientific meetings were searched for publications fulfilling the inclusion criteria. STUDY SELECTION: Studies were selected if at least one patient with OI was described as having cardiovascular disease. The articles should be written in English, French, Italian, Spanish, German, Norwegian or Danish or have an English abstract. DATA EXTRACTION: Data were extracted by HA, FTJ and LF using a predefined protocol. RESULTS: A total of 68 studies were included in the review, comprising 51 case reports, 8 small case series (n<10 patients), 4 large case series (n >= 10 patients) and 5 cross-sectional studies comparing patients and controls. Together, the papers comprised 499 patients and covered 45 years of medical literature. The most commonly reported heart diseases amongst the patients with OI were valvulopathies and increased aortic diameter. Findings in the large case series and the cross-sectional studies were broadly similar to each other. CONCLUSION: The findings support the hypothesis that patients with OI have increased risk of heart disease compared to healthy controls. It is biologically plausible that patients with OI may have an increased risk of developing heart disease, and valve disease in particular. PMID- 26100572 TI - Comparative effectiveness of a bioengineered living cellular construct vs. a dehydrated human amniotic membrane allograft for the treatment of diabetic foot ulcers in a real world setting. AB - We evaluated the comparative effectiveness of a bioengineered living cellular construct (BLCC) and a dehydrated human amnion/chorion membrane allograft (dHACM) for the treatment of diabetic foot ulcers (DFUs). Using a wound care-specific electronic medical record database, we assessed real-world outcomes in 218 patients with 226 DFUs receiving treatment in 2014 at 99 wound care centers. The analysis included DFUs >=1 and <25 cm2 with duration <=1 year and area reduction <=20% in 14 days prior to treatment (N=163, BLCC; N=63, dHACM). The average baseline areas and durations were 6.0 cm2 and 4.4 months for BLCC and 5.2 cm2 and 4.6 months for dHACM, respectively. Patients treated with dHACM had more applications compared to those treated with BLCC (median 3.0 vs. 2.0) (p=0.003). A Cox model adjusted for key covariates including area and duration found the median time to closure for BLCC was 13.3 weeks compared to 26 weeks for dHACM, and the proportion of wounds healed were significantly higher for BLCC by 12 weeks (48% vs. 28%) and 24 weeks (72% vs. 47%) (p=0.01). Treatment with a bioengineered living cellular technology increased the probability of healing by 97% compared with a dehydrated amniotic membrane (hazard ratio = 1.97 [95% confidence interval 1.17, 3.33], p=0.01). PMID- 26100573 TI - Using the Care Dependency Scale for identifying patients at risk for pressure ulcer. AB - AIM: The aim of this study was to evaluate risk screening for pressure ulcer by using the Care Dependency Scale (CDS) for patients receiving home care or admitted to a residential or nursing home in the Netherlands. BACKGROUND: Pressure ulcer is a serious and persistent problem for patients throughout the Western world. Pressure ulcer is among the most common adverse events in nursing practice and when a pressure ulcer occurs it has many consequences for patients and healthcare professionals. DESIGN: Cross-sectional design. METHODS: The convenience sample consisted of 13,633 study participants, of whom 2639 received home care from 15 organisations, 4077 were patients from 67 residential homes and 6917 were admitted in 105 nursing homes. Data were taken from the Dutch National Prevalence Survey of Care Problems that was carried out in April 2012 in Dutch healthcare settings. RESULTS: For the three settings, cut-off points above 80% sensitivity were established, while in the residential home sample an almost 60% combined specificity score was identified. The CDS items 'Body posture' (home care), 'Getting dressed and undressed' (residential homes) and 'Mobility' (nursing homes) were the most significant variables which affect PU. CONCLUSIONS: The CDS is able to distinguish between patients at risk for pressure ulcer development and those not at risk in both home care and residential care settings. In nursing homes, the usefulness of the CDS for pressure ulcer detection is limited. PMID- 26100574 TI - Travelling-wave ion mobility time-of-flight mass spectrometry as an alternative strategy for screening of multi-class pesticides in fruits and vegetables. AB - This paper reports a novel approach to screening multi-class pesticides by ion mobility time-of-flight mass spectrometry detection. Nitrogen was selected as mobility gas. After optimization of the different ion mobility parameters, determination of matrix effect on the drift times was conducted using different matrix extracts. The results showed that drift time values are not influenced by the matrix and also are independent of the concentration within the working range for 100 pesticides tested, making drift time a powerful additional identification tool. Based on statistics, 2% variation criteria provides a good fit for all the pesticides targeted, and could be considered as a maximum acceptable criteria associated with the drift time parameter for identification purpose. This 2% value is in agreement with already reported criteria, for instance, for GC or LC retention time in European documents. Finally, the well-known feature of mobility to separate complex mixtures was also tested to obtain purified extracted mass spectra of pesticides present in fruit extract. PMID- 26100575 TI - Comprehensive thin layer chromatography*gas chromatography using headspace sampling modulation-A case study on fatty acid composition analysis. AB - The recently developed comprehensive TLC*GC technique using headspace sampling is presented. The main advantage of this approach, as demonstrated in lipid analysis, is the possibility to include a transesterification step of glycerides into fatty acid methyl ester derivatives (FAME) because no particular constraints in terms of operational time between TLC and GC are present. Besides being a relatively low-cost solution, TLC*GC by means of headspace sampling provides many benefits in terms of flexibility of separation conditions and modulation sampling width. The technique provides over two orders of magnitude of linear range with TLC sample loads of about 1mg with good reproducibility and accuracy, as demonstrated by multiple headspace extraction (MHE) tests. The technique is a viable alternative to the established but more expensive HPLC*GC technique. The useful range of TLC*GC in terms of analyte volatility can be further extended with a future development of devices based on thermal desorption. PMID- 26100576 TI - Potential of bacteriocin-producing lactic acid bacteria for safety improvements of traditional Thai fermented meat and human health. AB - Lactic acid bacteria (LAB) are very important in converting of agricultural products into safe, delicious and shelf stable foods for human consumption. The preservative activity of LAB in foods is mainly attributed to the production of anti-microbial metabolites such as organic acids and bacteriocins which enables them to grow and control the growth of pathogens and spoilage microorganisms. Besides ensuring safety, bacteriocin-producing LAB with their probiotic potentials could also be emerging as a means to develop functional meat products with desirable health benefits. Nevertheless, to be qualified as a candidate probiotic culture, other prerequisite probiotic properties of bacteriocin producing LAB have to be assessed according to regulatory guidelines for probiotics. Nham is an indigenous fermented sausage of Thailand that has gained popularity and acceptance among Thais. Since Nham is made from raw meat and is usually consumed without cooking, risks due to undesirable microorganisms such as Salmonella spp., Staphylococcus aureus, and Listeria monocytogenes, are frequently observed. With an ultimate goal to produce safer and healthier product, our research attempts on the development of a variety of new Nham products are discussed. PMID- 26100577 TI - First direct evidence of sedimentary carbonate recycling in subduction-related xenoliths. AB - Carbon in rocks and its rate of exchange with the exosphere is the least understood part of the carbon cycle. The amount of carbonate subducted as sediments and ocean crust is poorly known, but essential to mass balance the cycle. We describe carbonatite melt pockets in mantle peridotite xenoliths from Dalihu (northern China), which provide firsthand evidence for the recycling of carbonate sediments within the subduction system. These pockets retain the low trace element contents and delta(18)OSMOW = 21.1 +/- 0.3 of argillaceous carbonate sediments, representing wholesale melting of carbonates instead of filtered recycling of carbon by redox freezing and melting. They also contain microscopic diamonds, partly transformed to graphite, indicating that depths >120 km were reached, as well as a bizarre mixture of carbides and metal alloys indicative of extremely reducing conditions. Subducted carbonates form diapirs that move rapidly upwards through the mantle wedge, reacting with peridotite, assimilating silicate minerals and releasing CO2, thus promoting their rapid emplacement. The assimilation process produces very local disequilibrium and divergent redox conditions that result in carbides and metal alloys, which help to interpret other occurrences of rock exhumed from ultra-deep conditions. PMID- 26100578 TI - Minimizing the radiation dose of CT attenuation correction while improving image quality: The case for innovation. PMID- 26100579 TI - Predicting and exploring network components involved in pathogenesis in the malaria parasite via novel subnetwork alignments. AB - BACKGROUND: Malaria is a major health threat, affecting over 40% of the world's population. The latest report released by the World Health Organization estimated about 207 million cases of malaria infection, and about 627,000 deaths in 2012 alone. During the past decade, new therapeutic targets have been identified and are at various stages of characterization, thanks to the emerging omics-based technologies. However, the mechanism of malaria pathogenesis remains largely unknown. In this paper, we employ a novel neighborhood subnetwork alignment approach to identify network components that are potentially involved in pathogenesis. RESULTS: Our module-based subnetwork alignment approach identified 24 functional homologs of pathogenesis-related proteins in the malaria parasite P. falciparum, using the protein-protein interaction networks in Escherichia coli as references. Eighteen out of these 24 proteins are associated with 418 other proteins that are related to DNA replication, transcriptional regulation, translation, signaling, metabolism, cell cycle regulation, as well as cytoadherence and entry to the host. CONCLUSIONS: The subnetwork alignments and subsequent protein-protein association network mining predicted a group of malarial proteins that may be involved in parasite development and parasite-host interaction, opening a new systems-level view of parasite pathogenesis and virulence. PMID- 26100580 TI - Discovery and characterization of long intergenic non-coding RNAs (lincRNA) module biomarkers in prostate cancer: an integrative analysis of RNA-Seq data. AB - BACKGROUND: Prostate cancer (PCa) is a leading cause of cancer-related death of men worldwide. There is an urgent need to develop novel biomarkers for PCa prognosis and diagnosis in the post prostate-specific antigen era. Long intergenic noncoding RNAs (lincRNAs) play essential roles in many physiological processes and can serve as alternative biomarkers for prostate cancer, but there has been no systematic investigation of lincRNAs in PCa yet. RESULTS: Nine lincRNA co-expression modules were identified from PCa RNA-Seq data. The association between the principle component of each module and the PCa phenotype was examined by calculating the Pearson's correlation coefficients. Three modules (M1, M3, and M5) were found associated with PCa. Two modules (M3 and M5) were significantly enriched with lincRNAs, and one of them, M3, may be used as a lincRNA module-biomarker for PCa diagnosis. This module includes seven essential lincRNAs: TCONS_l2_00001418, TCONS_l2_00008237, TCONS_l2_00011130, TCONS_l2_00013175, TCONS_l2_00022611, TCONS_l2_00022670 and linc-PXN-1. The clustering analysis and microRNA enrichment analysis further confirmed our findings. CONCLUSION: The correlation between lincRNAs and protein-coding genes is helpful for further exploration of functional mechanisms of lincRNAs in PCa. This study provides some important insights into the roles of lincRNAs in PCa and suggests a few lincRNAs as candidate biomarkers for PCa diagnosis and prognosis. PMID- 26100581 TI - A pilot study of audiovisual family meetings in the intensive care unit. AB - PURPOSE: We hypothesized that virtual family meetings in the intensive care unit with conference calling or Skype videoconferencing would result in increased family member satisfaction and more efficient decision making. METHODS: This is a prospective, nonblinded, nonrandomized pilot study. A 6-question survey was completed by family members after family meetings, some of which used conference calling or Skype by choice. Overall, 29 (33%) of the completed surveys came from audiovisual family meetings vs 59 (67%) from control meetings. RESULTS: The survey data were analyzed using hierarchical linear modeling, which did not find any significant group differences between satisfaction with the audiovisual meetings vs controls. There was no association between the audiovisual intervention and withdrawal of care (P = .682) or overall hospital length of stay (z = 0.885, P = .376). CONCLUSIONS: Although we do not report benefit from an audiovisual intervention, these results are preliminary and heavily influenced by notable limitations to the study. Given that the intervention was feasible in this pilot study, audiovisual and social media intervention strategies warrant additional investigation given their unique ability to facilitate communication among family members in the intensive care unit. PMID- 26100582 TI - Outcomes and prognostic factors in patients with prolonged acute mechanical ventilation: A single-center study in Korea. AB - PURPOSE: The purpose of the study is to evaluate outcomes and objective parameters related to poor prognosis in patients who were defined as prolonged acute mechanical ventilation (PAMV; ventilator care >=96 hours) in the medical intensive care unit of a university-affiliated tertiary care hospital in Korea. MATERIAL AND METHODS: We analyzed retrospectively clinical data gathered from the medical records on day 4 of MV between 2008 and 2013. In total, 311 were categorized as PAMV. RESULTS: Their median age was 67 years (range, 18-93 years), and 71.7% were male. The 28-day mortality rate after intensive care unit admission was 34.7%. Four variables on day 4 of mechanical ventilation (need for neuromuscular blockers [hazard ratio {HR}, 2.432; 95% confidence interval, 1.337 4.422], need for vasopressors [HR, 2.312; 95% confidence interval, 1.258-4.248], need for hemodialyses [HR, 1.913; 95% confidence interval, 1.018-3.595], and body mass index <=21 kg/m(2) [HR, 1.827; 95% confidence interval, 1.015-3.288]) were independent factors associated with mortality based on a Cox proportional hazards model. As the number of these prognostic factors increased, the survival rate decreased. CONCLUSIONS: Four clinical factors (body mass index <=21, requirement for neuromuscular blockers, vasopressors, and hemodialysis) on day 4 of mechanical ventilation were associated with 28-day mortality in PAMV patients. PMID- 26100583 TI - Iodide-Responsive Cu-Au Nanoparticle-Based Colorimetric Platform for Ultrasensitive Detection of Target Cancer Cells. AB - Colorimetric analysis is promising in developing facile, fast, and point-of-care cancer diagnosis techniques, but the existing colorimetric cancer cell assays remain problematic because of dissatisfactory sensitivity as well as complex probe design or synthesis. To solve the problem, we here present a novel colorimetric analytical strategy based on iodide-responsive Cu-Au nanoparticles (Cu-Au NPs) combined with the iodide-catalyzed H2O2-TMB (3,3,5,5 tetramethylbenzidine) reaction system. In this strategy, bimetallic Cu-Au NPs prepared with an irregular shape and a diameter of ~15 nm could chemically absorb iodide, thus indirectly inducing colorimetric signal variation of the H2O2-TMB system. By further utilizing its property of easy biomolecule modification, a versatile colorimetric platform was constructed for detection of any target that could cause the change of Cu-Au NPs concentration via molecular recognition. As proof of concept, an analysis of human leukemia CCRF-CEM cells was performed using aptamer Sgc8c-modified Cu-Au NPs as the colorimetric probe. Results showed that Sgc8c-modified Cu-Au NPs successfully achieved a simple, label-free, cost effective, visualized, selective, and ultrasensitive detection of cancer cells with a linear range from 50 to 500 cells/mL and a detection limit of 5 cells in 100 MUL of binding buffer. Moreover, feasibility was demonstrated for cancer cell analysis in diluted serum samples. The iodide-responsive Cu-Au NP-based colorimetric strategy might not only afford a new design pattern for developing cancer cell assays but also greatly extend the application of the iodide catalyzed colorimetric system. PMID- 26100584 TI - Clinical Comparison With Short-Term Follow-Up of Bioresorbable Vascular Scaffold Versus Everolimus-Eluting Stent in Primary Percutaneous Coronary Interventions. AB - Objective of this study was to assess the clinical performance of bioresorbable vascular scaffold (BVS) compared to everolimus-eluting stent (EES) in subjects with ST-segment elevation myocardial infarction (STEMI). We included all consecutive patients with STEMI who underwent percutaneous coronary intervention (PCI) with BVS implantation in centers participating to the Italian ABSORB Prospective Registry (BVS-RAI) and PCI with EES in the same centers during the same period. The 2 groups were compared. The primary end point was patient oriented composite end point (POCE) including cardiac death, myocardial infarction, and target lesion revascularization (TLR) at the longest available follow-up. BVS or EES thrombosis at follow-up was also evaluated. Of the 563 patients with STEMI included, 122 received BVS and 441 EES. Procedural success was obtained in 549 (97.5%) cases without significant differences between the 2 groups (BVS 99.3% vs EES 97.0%, p = 0.2). At a median of 220-day (interquartile range 178 to 369) follow-up, no significant differences were observed in terms of POCE (BVS 4.9% vs EES 7.0%, p = 0.4); death (BVS 0.8%, EES 2.0%, p = 0.4), MI (BVS 4.1%, EES 2.0%, p = 0.2), TLR (BVS 4.1%, EES 4.5%, p = 0.8), device thrombosis (BVS 2.5%, EES 1.4%, p = 0.4). All TLR cases were successfully managed with re-PCI in both groups. A propensity matching of the study populations showed no significant differences regarding POCE at the longest available follow-up (odds ratio 0.53, 0.1 to 4.3). In conclusion, in this direct prospective comparison, BVS was associated with similar clinical results compared to EES in the STEMI setting. Larger and adequately powered randomized trials are needed to fully assess the potential clinical benefit of BVS versus the current standard of care in patients with STEMI. PMID- 26100586 TI - Risk of Systemic Hypertension and Cerebrovascular Accident in Patients With Aortic Coarctation Aged <60 Years (from a National Database Study). AB - Patients with coarctation of the aorta (CoA) may develop hypertension and cerebrovascular accident (CVA) late after intervention, but the risk is still unclear. Therefore, we studied the epidemiologic profile from a general population aged <60 years to assess the relative risk. Our study population consisted of 126,943 patients with congenital heart disease (CHD) derived from Taiwan's National Health Insurance database from 2000 to 2010 (population 22,765,535). There were 2,295 patients with CoA (50.3% men) (prevalence: 0.116/1000). Associated cardiac lesions in 44% of the patients with CoA included ventricular septal defect (VSD; 23.3%), patent ductus arteriosus (7.5%), atrial septal defect (9.0%), and so forth. Hypertension occurred in 190 patients (8.3%) and was related to age, without associated VSD (odds ratio [OR] 5.90, 95% confidence interval [CI] 2.12 to 16.39, p = 0.001) and male gender (OR 1.59, 95% CI 1.09 to 2.30, p = 0.015). The incidence of hypertension increased rapidly in the young adulthood and was 1.36% in pediatric age group and 28.9% and 45.7% in age group 20 to 29 and 30 to 39, respectively. CVA occurred in 29 patients (1.67%), and the coexisting hypertension was the single predictor (OR 3.19, 95% CI 1.13 to 9.00, p = 0.029). Furthermore, in all patients with CHD, CoA was an independent risk factor for hypertension (OR 15.65, 95% CI 12.44 to 19.68, p <0.001) and CVA (OR 6.55, 95% CI 4.41 to 9.74, p <0.001). Comparing with non-CoA CHD patients, patients with CoA, particularly men, adult, and patients without VSD, have high risk of hypertension, which would further increase the risk of CVA. Early recognition and timely intervention for the hypertension in patients with CoA is mandatory. PMID- 26100585 TI - Impact of Hospital Volume on Outcomes of Lower Extremity Endovascular Interventions (Insights from the Nationwide Inpatient Sample [2006 to 2011]). AB - Our primary objective was to study postprocedural outcomes and hospitalization costs after peripheral endovascular interventions and the multivariate predictors affecting the outcomes with emphasis on hospital volume. The study cohort was derived from Healthcare Cost and Utilization Project Nationwide Inpatient Sample database (2006 to 2011). Peripheral endovascular interventions were identified using appropriate International Classification of Diseases, Ninth Revision diagnostic and procedural codes. Annual institutional volumes were calculated using unique identification numbers and then divided into quartiles. Two-level hierarchical multivariate mixed models were created. The primary outcome was inhospital mortality; secondary outcome was a composite of inhospital mortality and postprocedural complications. Amputation rates and hospitalization costs were also assessed. Multivariate analysis (odds ratio, 95% confidence interval, p value) revealed age (1.46, 1.37 to 1.55, p <0.001), female gender (1.28, 1.12 to 1.46, p <0.001), baseline co-morbidity status as depicted by a greater Charlson co-morbidity index score (>=2: 4.32, 3.45 to 5.40, p <0.001), emergent or urgent admissions(2.48, 2.14 to 2.88, p <0.001), and weekend admissions (1.53, 1.26 to 1.86, p <0.001) to be significant predictors of primary outcome. An increasing hospital volume quartile was independently predictive of improved primary (0.65, 0.52 to 0.82, p <0.001 for the fourth quartile) and secondary (0.85, 0.73 to 0.97, 0.02 for the fourth quartile) outcomes and lower amputation rates (0.52, 0.45 to 0.61, p <0.001). A significant reduction hospitalization costs ($-3,889, 5,318 to -2,459, p <0.001) was also seen in high volume centers. In conclusion, a greater hospital procedural volume is associated with superior outcomes after peripheral endovascular interventions in terms of inhospital mortality, complications, and hospitalization costs. PMID- 26100587 TI - Intravascular Ultrasonic Imaging of Coronary Arterial Remodeling in Heart Transplant Recipients. AB - The purpose of this study was to evaluate long-term changes of transplant coronary arteries, including vessel, plaque, and lumen areas. There are limited long-term data on vessel remodeling after heart transplantation. We analyzed serial intravascular ultrasound images of the left anterior descending coronary artery (LAD) in 54 heart transplantation recipients. Nine patients (16.7%) had a history of rejection. Proximal left anterior descending artery segments were matched among time points, a >=20-mm long segment was analyzed every 1 mm, and results were normalized for analysis length and reported as mm(3)/mm. During follow-up, vessel area decreased (-0.48 +/- 1.3 mm(3)/mm/year), and plaque area did not change (-0.01 +/- 0.47 mm(3)/mm/year). As a result, lumen area decreased (-0.52 +/- 1.34 mm(3)/mm/year). The change in mean lumen area was well correlated to the change in mean vessel area (r = 0.94, p <0.01) but not to the change in mean plaque area (r = -0.27, p = 0.05). In conclusion, lumen loss occurred during long-term follow-up of patients who underwent heart transplantation, primarily secondary to negative remodeling (decrease in vessel dimensions). PMID- 26100588 TI - Utility of Routine Exercise Testing to Detect Rate-Related QRS Widening in Patients Without Structural Heart Disease on Class Ic Antiarrhythmic Agents (Flecainide and Propafenone). AB - Class Ic antiarrhythmic agents are effective in the treatment of various atrial tachyarrhythmias. They are known to cause rate-related QRS widening in the presence of structural heart disease, which can lead to life-threatening arrhythmias. The role of routine exercise electrocardiography in patients without structural heart disease is unknown. All patients initiated on class Ic antiarrhythmic agents and who had exercise electrocardiography performed from June 2009 to June 2013 were included. Symptom-limited treadmill electrocardiography was performed to detect significant QRS widening at peak exercise (defined as an increase of >25% of baseline QRS). Fifty-six patients were included in the study. All patients were screened for structural heart disease before initiation of the medication. Significant QRS widening and atrial tachycardia occurred in a single patient, which terminated with cessation of exercise. This patient had a history of tachycardia-mediated cardiomyopathy with normalization of ejection fraction 3 years before being placed on flecainide. In conclusion, routine exercise testing to detect QRS widening is not warranted in patients with no structural heart disease. PMID- 26100589 TI - National Trends in Hospitalizations for Patients With Single-Ventricle Anatomy. AB - Patients with single-ventricle (SV) anatomy now live to adulthood. Little is known about the cost of care and outcomes for patients with SV anatomy, especially those who develop heart failure (HF) cared for in adult hospitals in the United States. We analyzed the Nationwide Inpatient Sample from 2000 to 2011 for patients >14 years admitted to adult hospitals with the International Classifications of Diseases, Ninth Revision, codes for SV anatomy. Demographics, outcomes, co-morbidities, and cost were assessed. From 2000 to 2011, the number of SV admissions was stable with a trend toward increased cost per admission over time. Coexistent hypertension, obesity, and liver, pulmonary, and renal diseases significantly increased over time. The most common reason for admission was atrial arrhythmia followed by HF. Patients with SV with HF had significantly higher inhospital mortality, length of stay, and more medical co-morbidities than those with SV and without HF. In conclusion, the cohort of patients with SV admitted to adult hospitals has changed in the modern era. Patients with SV have medical co-morbidities including renal and liver diseases, hypertension, and obesity at a surprisingly young age. Aggressive and proactive management of HF and arrhythmia may reduce cost of care for this challenging population. Patients with SV with HF have particularly high mortality, more medical co-morbidities, and increased cost of care and deserve more focused attention to improve outcomes. PMID- 26100590 TI - A Rare Case of Acroangiodermatitis Associated with a Congenital Arteriovenous Malformation (Stewart-Bluefarb Syndrome) in a Young Veteran: Case Report and Review of the Literature. AB - Acroangiodermatitis (AD) is a rare angioproliferative disease manifesting with cutaneous lesions clinically similar to Kaposi's sarcoma. AD is a benign hyperplasia of preexisting vasculature and may be associated with acquired or congenital arteriovenous malformations (AVM), or severe chronic venous insufficiency (because of hypostasis, elevated venous pressure, arteriovenous shunting). Stewart-Bluefarb syndrome is the rare syndrome in which AD is associated with a congenital AVM. We present the case of a young veteran with a painful, chronic nonhealing ulcer and ipsilateral popliteal artery occlusion likely because of trauma, who elected transmetatarsal amputation for symptomatic relief. A 24-year-old male veteran presented with a 5-year history of a nonhealing dorsal left foot ulcer, resulting from a training exercise injury. He ultimately developed osteomyelitis requiring antibiotics, frequent debridements, multiple trials of unsuccessful skin substitute grafting, and severe unremitting pain. He noted a remote history of left digital deformities treated surgically as a child, and an AVM, previously endovascularly treated at an outside facility. Arterial duplex revealed somewhat dampened left popliteal, posterior tibial (PT), and dorsalis pedis (DP) artery signals with arterial brachial index of 1.0. CT angiography showed occlusion of the proximal to mid popliteal artery with significant calcifications felt initially to be a result of prior trauma. Pedal pulses were palpable and transcutaneous oxygen measurements revealed adequate oxygenation. Because of unremitting pain, the patient opted for amputation. Pathology revealed vascular proliferation consistent with AD. This case illustrates an unusual diagnosis of acroangiodermatitis, and a rare syndrome when associated with his underlying AVM (Stewart-Bluefarb syndrome). This resulted in a painful, chronic ulcer and was further complicated by trauma-related arterial occlusive disease. AD disease can hinder wound healing even in the presence of clinically evident blood flow. Although rare, such unusual diagnoses should be entertained particularly in the unusually young vascular surgical patient. PMID- 26100591 TI - Rhinovirus-C detection in children presenting with acute respiratory infection to hospital in Brazil. AB - Human rhinovirus (RV) is a common cause of acute respiratory infection (ARI) in children. We aimed to characterize the clinical and demographic features associated with different RV species detected in children attending hospital with ARI, from low-income families in North-east Brazil. Nasopharyngeal aspirates were collected from 630 children <5 years with ARI. Clinical diagnosis and disease severity were also recorded. Samples were analyzed by multiplex PCR for 18 viral and atypical bacterial pathogens; RV positive samples underwent partial sequencing to determine species and type. RV was the fourth commonest pathogen accounting for 18.7% of pathogens detected. RV was commonly detected in children with bronchiolitis, pneumonia, and asthma/episodic viral wheeze (EVW). Species and type were assigned in 112 cases (73% RV-A; 27% RV-C; 0% RV-B). Generally, there were no differences in clinical or demographic characteristics between those infected with RV-A and RV-C. However, in children with asthma/EVW, RV-C was detected relatively more frequently than RV-A (23% vs. 5%; P = 0.04). Our findings highlight RV as a potentially important pathogen in this setting. Generally, clinical and demographic features were similar in children in whom RV A and C species were detected. However, RV-C was more frequently found in children with asthma/EVW than RV-A. PMID- 26100592 TI - [Effect of breastfeeding on obesity of schoolchildren: influence of maternal education]. AB - OBJECTIVE: To evaluate the association between duration of breastfeeding (BF) and obesity in schoolchildren of Florianopolis (SC), and the role of possible effect modifiers. METHODS: Cross-sectional study with a random sample of 2,826 schoolchildren (7-14 years). Weight and height were measured according to standardized procedures. Data concerning BF and sociodemographic variables were obtained from a questionnaire sent to parents/guardians. Children's nutritional status was evaluated by BMI-for-age z-score for gender (WHO reference curves). Adjusted analyses were performed through logistic regression, considering a possible interaction among variables. RESULTS: Prevalence of obesity was 8.6% (95% CI: 7.6-9.7%) and 55.7% (95% CI: 53.8-57.6%) received breastmilk for >=6 months. BF was not associated with obesity, even in the adjusted analysis. Stratified analysis according to maternal schooling showed that, in children aged 7-10 years and children whose mothers had 0-8 years of schooling, the chance of obesity was lower among those breastfeed for >1 month, especially among those who received breastmilk for 1-5 months (OR=0.22; 95% CI 0.08-0.62). Among children of women with higher educational level (>8 years), the chance of obesity was 44% lower in those who were breastfed for >12 months (p-value for interaction <0.01). This interaction was not found in older children (11-14 years). CONCLUSIONS: Among children of women with lower schooling, BF for any period longer than 1 month is protective against obesity; however, for a higher maternal schooling, BF for less than 12 months increases the odds of obesity. PMID- 26100593 TI - [Prevalence of vitamin D deficiency and associated factors in women and newborns in the immediate postpartum period]. AB - OBJECTIVE: To assess the prevalence of vitamin D deficiency and its associated factors in women and their newborns in the postpartum period. METHODS: This cross sectional study evaluated vitamin D deficiency/insufficiency in 226 women and their newborns in Vicosa (Minas Gerais, BR) between December 2011 and November 2012. Cord blood and venous maternal blood were collected to evaluate the following biochemical parameters: vitamin D, alkaline phosphatase, calcium, phosphorus and parathyroid hormone. Poisson regression analysis, with a confidence interval of 95% was applied to assess vitamin D deficiency and its associated factors. Multiple linear regression analysis was performed to identify factors associated with 25(OH)D deficiency in the newborns and women from the study. The criteria for variable inclusion in the multiple linear regression model was the association with the dependent variable in the simple linear regression analysis, considering p<0.20. Significance level was alpha<5%. RESULTS: From 226 women included, 200 (88.5%) were 20 to 44 years old; the median age was 28 years. Deficient/insufficient levels of vitamin D were found in 192 (85%) women and in 182 (80.5%) neonates. The maternal 25(OH)D and alkaline phosphatase levels were independently associated with vitamin D deficiency in infants. CONCLUSIONS: This study identified a high prevalence of vitamin D deficiency and insufficiency in women and newborns and the association between maternal nutritional status of vitamin D and their infants' vitamin D status. PMID- 26100594 TI - [Pathologic aerophagia: a rare cause of chronic abdominal distension]. AB - OBJECTIVE: To describe an adolescent with pathologic aerophagia, a rare condition caused by excessive and inappropriate swallowing of air and to review its treatment and differential diagnoses. CASE DESCRIPTION: An 11 year-old mentally impaired blind girl presenting serious behavior problems and severe developmental delay with abdominal distension from the last 8 months. Her past history included a Nissen fundoplication. Abdominal CT and abdominal radiographs showed diffuse gas distension of the small bowel and colon. Hirschsprung's disease was excluded. The distention was minimal at the moment the child awoke and maximal at evening, and persisted after control of constipation. Audible repetitive and frequent movements of air swallowing were observed. The diagnosis of pathologic aerophagia associated to obsessive compulsive disorder and developmental delay was made, but pharmacological treatment was unsuccessful. The patient was submitted to an endoscopic gastrostomy, permanently opened and elevated relative to the stomach. The distention was resolved, while maintaining oral nutrition COMMENTS: Pathologic aerophagia is a rare self-limiting condition in normal children exposed to high levels of stress and may be a persisting problem in children with psychiatric or neurologic disease. In this last group, the disease may cause serious complications. Pharmacological and behavioral treatments are ill-defined. Severe cases may demand surgical strategies, mainly decompressive gastrostomy. PMID- 26100595 TI - Nicotine-induced cellular stresses and autophagy in human cancer colon cells: A supportive effect on cell homeostasis via up-regulation of Cox-2 and PGE(2) production. AB - Nicotine, one of the active components in cigarette smoke, has been described to contribute to the protective effect of smoking in ulcerative colitis (UC) patients. Furthermore, the nicotinic acetylcholine receptor alpha7 subunit (alpha7nAChR) expressed on immune cells, is an essential regulator of inflammation. As intestinal epithelial cells also express alpha7nAChR, we investigated how nicotine could participate in the homeostasis of intestinal epithelial cells. First, using the human adenocarcinoma cell line HT-29, we revealed that nicotine, which triggers an influx of extracellular Ca(2+) following alpha7nAChR stimulation, induces mitochondrial reactive oxygen species (ROS) production associated with a disruption of the mitochondrial membrane potential and endoplasmic reticulum stress. This results in caspase-3 activation, which in turn induces apoptosis. Additionally, we have shown that nicotine induces a PI3-K dependent up-regulation of cyclooxygenase-2 (Cox-2) expression and prostaglandin E2 (PGE2) production. In this context, we suggest that this key mediator participates in the cytoprotective effects of nicotine against apoptosis by stimulating autophagy in colon cancer cells. Our results provide new insight into one potential mechanism by which nicotine could protect from UC and suggest an anti-inflammatory role for the cholinergic pathway at the epithelial cell level. PMID- 26100596 TI - Epigenetic regulation in the carcinogenesis of cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a malignancy arising from the epithelial cells lining the biliary tract. Despite the existence of variation in incidence and etiology worldwide, its incidence is increasing globally in the past few decades. Surgery is the only curative treatment option for a minority of patients presented with early disease; while moderate effective chemotherapy remains the standard care for patients with locally advanced or metastatic diseases. In this article, we briefly review the molecular alterations that have been described in CCAs focusing on the role of epigenetic modification, including promoter methylation inactivation, histone modification and microRNA, in the carcinogenesis and progression of CCAs. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 26100597 TI - Realization of Multi-Stable Ground States in a Nematic Liquid Crystal by Surface and Electric Field Modification. AB - Owing to the significant price drop of liquid crystal displays (LCDs) and the efforts to save natural resources, LCDs are even replacing paper to display static images such as price tags and advertising boards. Because of a growing market demand on such devices, the LCD that can be of numerous surface alignments of directors as its ground state, the so-called multi-stable LCD, comes into the limelight due to the great potential for low power consumption. However, the multi-stable LCD with industrial feasibility has not yet been successfully performed. In this paper, we propose a simple and novel configuration for the multi-stable LCD. We demonstrate experimentally and theoretically that a battery of stable surface alignments can be achieved by the field-induced surface dragging effect on an aligning layer with a weak surface anchoring. The simplicity and stability of the proposed system suggest that it is suitable for the multi-stable LCDs to display static images with low power consumption and thus opens applications in various fields. PMID- 26100598 TI - Left Atrial Appendage Occlusion With the New AmuletTM Device: Feasibility, Safety and Short-term Efficacy. PMID- 26100599 TI - Editorial. Convenience Foods: Schopping, Cooking & Eating. PMID- 26100600 TI - Thioflavin T templates amyloid beta(1-40) conformation and aggregation pathway. AB - Abeta(1-40) peptide supramolecular assembly and fibril formation processes are widely recognized to have direct implications in the progression of Alzheimer's disease. The molecular basis of this biological process is still unknown and there is a strong need of developing effective strategies to control the occurring events. To this purpose the exploitation of small molecules interacting with Abeta aggregation represents one of the possible routes. Moreover, the use specific labeling has represented so far one of the most common and effective methods to investigate such a process. This possibility in turn rests on the reliability of the probe/labels involved. Here we present evidences of the effect of Thioflavin T (ThT), a worldwide used fluorescent dye to monitor amyloid growth, on the Abeta(1-40) conformation, stability and aggregation. By combining experimental information and Molecular Dynamics simulation results, we show that the presence of ThT in solution affects peptide conformation inducing peculiar supramolecular association. In particular ThT interactions with specific Abeta(1 40) residues promote a rigid partially-folded conformation which shifts the balance between different species in solution toward a more aggregation-prone ensemble of peptides, leading to aggregation. Our findings suggest ways for developing strategies to reverse and block aggregation or to stimulate supramolecular assembly and consequently reduce the presence of transient oligomers. This investigation underlines the need of developing label-free techniques for unbiased quantitative studies of Abeta(1-40) aggregation processes. PMID- 26100601 TI - The International Symposium on Fungal Stress: ISFUS. AB - Fungi play central roles in many biological processes, influencing soil fertility, decomposition, cycling of minerals, and organic matter, plant health, and nutrition. They produce a wide spectrum of molecules, which are exploited in a range of industrial processes to manufacture foods, food preservatives, flavoring agents, and other useful biological products. Fungi can also be used as biological control agents of microbial pathogens, nematodes or insect pests, and affect plant growth, stress tolerance, and nutrient acquisition. Successful exploitation of fungi requires better understanding of the mechanisms that fungi use to cope with stress as well as the way in which they mediate stress tolerance in other organisms. It is against this backdrop that a scientific meeting on fungal stress was held in Sao Jose dos Campos, Brazil, in October 2014. The meeting, hosted by Drauzio E. N. Rangel and Alene E. Alder-Rangel, and supported by the Sao Paulo Research Foundation (FAPESP), brought together more than 30 young, mid-career, and highly accomplished scientists from ten different countries. Here we summarize the highlights of the meeting. PMID- 26100602 TI - The influence of action-outcome delay and arousal on sense of agency and the intentional binding effect. AB - The sense of agency refers to the feeling of being able to initiate and control events through one's actions. The "intentional binding" effect (Haggard, Clark, & Kalogeras, 2002), refers to a subjective compression of the temporal interval between actions and their effects. The present study examined the influence of action-outcome delays and arousal on both the subjective judgment of agency and the intentional binding effect. In the experiment, participants pressed a key to trigger a central square to jump after various delays. A red central square was used in the high-arousal condition. Results showed that a longer interval between actions and their effects was associated with a lower sense of agency but a stronger intentional binding effect. Furthermore, although arousal enhanced the intentional binding effect, it did not influence the judgment of agency. PMID- 26100603 TI - The 'cephalosporin era' of triazole therapy: isavuconazole, a welcomed newcomer for the treatment of invasive fungal infections. AB - INTRODUCTION: Invasive fungal infections remain frequent life-threatening complications in immunocompromised patients. Each of the currently available antifungals has limitations in terms of pharmacokinetic and pharmacodynamic profile, spectrum of efficacy, and tolerability. Isavuconazole (ISA) is a new generation, broad-spectrum triazole that has a favorable spectrum of efficacy and is available in both intravenous and oral forms. Recent Phase III clinical studies showed that ISA had comparable efficacy to voriconazole for the treatment of a variety of mould infections. AREAS COVERED: This review summarizes the literature on the use of ISA. PubMed was searched for publications in English from 2006 to December 2014 using the terms 'ISA', 'BAL4815', and 'BAL 8557'. Relevant publications were reviewed and reference lists were examined for further publications. Conference abstracts from the meeting during 2013 - 2014 were also reviewed. EXPERT OPINION: ISA is a new broad spectrum triazole antifungal for the treatment of invasive fungal disease available as oral and intravenous formulations, and the ability to be administered as a once-daily regimen. ISA has broad-spectrum in vitro activity, favorable pharmacokinetic profile, and good tolerability. ISA may be considered for primary treatment for a vast variety of invasive fungal infections. Further study of ISA given as prophylaxis, combination, or salvage therapy is warranted. PMID- 26100604 TI - Tailoring low-dimensional structures of bismuth on monolayer epitaxial graphene. AB - To improve graphene-based multifunctional devices at nanoscale, a stepwise and controllable fabrication procedure must be elucidated. Here, a series of structural transition of bismuth (Bi) adatoms, adsorbed on monolayer epitaxial graphene (MEG), is explored at room temperature. Bi adatoms undergo a structural transition from one-dimensional (1D) linear structures to two-dimensional (2D) triangular islands and such 2D growth mode is affected by the corrugated substrate. Upon Bi deposition, a little charge transfer occurs and a characteristic peak can be observed in the tunneling spectrum, reflecting the distinctive electronic structure of the Bi adatoms. When annealed to ~500 K, 2D triangular Bi islands aggregate into Bi nanoclusters (NCs) of uniform size. A well-controlled fabrication method is thus demonstrated. The approaches adopted herein provide perspectives for fabricating and characterizing periodic networks on MEG and related systems, which are useful in realizing graphene-based electronic, energy, sensor and spintronic devices. PMID- 26100606 TI - Quantum dynamics of polyatomic dissociative chemisorption on transition metal surfaces: mode specificity and bond selectivity. AB - Dissociative chemisorption is the initial and often rate-limiting step in many heterogeneous processes. As a result, an in-depth understanding of the reaction dynamics of such processes is of great importance for the establishment of a predictive model of heterogeneous catalysis. Overwhelming experimental evidence has suggested that these processes have a non-statistical nature and excitations in various reactant modes have a significant impact on reactivity. A comprehensive characterization of the reaction dynamics requires a quantum mechanical treatment on a global potential energy surface. In this review, we summarize recent progress in constructing high-dimensional potential energy surfaces for polyatomic molecules interacting with transition metal surfaces based on the plane-wave density functional theory and in quantum dynamical studies of dissociative chemisorption on these potential energy surfaces. A special focus is placed on the mode specificity and bond selectivity in these gas surface collisional processes, and their rationalization in terms of the recently proposed Sudden Vector Projection model. PMID- 26100605 TI - Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds. AB - BACKGROUND: The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. RESULTS: We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. CONCLUSIONS: We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals. PMID- 26100607 TI - Community-wide promotion of physical activity in middle-aged and older Japanese: a 3-year evaluation of a cluster randomized trial. AB - BACKGROUND: Promotion of physical activity (PA) is a key strategy to prevent non communicable diseases. However, evidence on the effectiveness of community-wide interventions (CWIs) for promoting PA is limited. PURPOSE: To evaluate the effectiveness of a 3-year CWI for promoting PA in middle-aged and older adults compared with usual public health services. This study is an extension to an original 1-year investigation study. DESIGN: Cluster randomized controlled trial with community as unit of randomization and individual as unit of analysis. SETTING/PARTICIPANTS: 12 communities in Unnan, Japan were randomly allocated to the intervention (9) or the control (3). Additionally intervention communities were randomly allocated to aerobic activity promotion (Group A), flexibility and muscle-strengthening activities promotion (Group FM), or aerobic, flexibility, and muscle-strengthening activities promotion (Group AFM), each consisting of three communities. Randomly-sampled 4414 residents aged 40 to 79 years responded to the baseline survey (74%), and were analyzed in 2013-2014. INTERVENTION: A 3 year CWI based on social marketing, to promote PA from 2009 to 2012. MAIN OUTCOME MEASURES: The primary outcome was a change in regular aerobic, flexibility, and/or muscle-strengthening activities, defined by (1) engaging in 150 mins/week or more of walking, (2) engaging in daily flexibility activity, or (3) engaging 2 or more days/week in muscle-strengthening activities, evaluated at the individual level. Secondary outcomes were changes in specific types of PA and musculoskeletal pain. Outcomes were measured at baseline and at 1 and 3 years (2009, 2010, and 2012). RESULTS: The CWI did not significantly increase the proportion of adults who reached recommended levels of aerobic, flexibility, and/or muscle-strengthening activities (adjusted change difference = 1.6% [95% CI: -3.5, 6.6]). In the subgroup analysis, compared to the controls, adults doing flexibility activity daily significantly increased in Group FM (6.3% [95% CI: 1.9, 10.7]). In Group A and AFM for PA outcomes and in all groups for pain outcomes, there was no significant change compared to controls. CONCLUSIONS: The CWI did not achieve significant increase in the proportion of adults who reached recommended PA levels. However, it might be effective in promoting flexibility activity in middle-aged and older Japanese. TRIAL REGISTRATION: UMIN-CTR UMIN000002683 . PMID- 26100608 TI - Maternal immunity enhances systemic recall immune responses upon oral immunization of piglets with F4 fimbriae. AB - F4 enterotoxigenic Escherichia coli (ETEC) cause diarrhoea and mortality in piglets leading to severe economic losses. Oral immunization of piglets with F4 fimbriae induces a protective intestinal immune response evidenced by an F4 specific serum and intestinal IgA response. However, successful oral immunization of pigs with F4 fimbriae in the presence of maternal immunity has not been demonstrated yet. In the present study we aimed to evaluate the effect of maternal immunity on the induction of a systemic immune response upon oral immunization of piglets. Whereas F4-specific IgG and IgA could be induced by oral immunization of pigs without maternal antibodies and by intramuscular immunization of pigs with maternal antibodies, no such response was seen in the orally immunized animals with maternal antibodies. Since maternal antibodies can mask an antibody response, we also looked by ELIspot assays for circulating F4 specific antibody secreting cells (ASCs). Enumerating the F4-specific ASCs within the circulating peripheral blood mononuclear cells, and the number of F4-specific IgA ASCs within the circulating IgA(+) B-cells revealed an F4-specific immune response in the orally immunized animals with maternal antibodies. Interestingly, results suggest a more robust IgA booster response by oral immunization of pigs with than without maternal antibodies. These results demonstrate that oral immunization of piglets with F4-specific maternal antibodies is feasible and that these maternal antibodies seem to enhance the secondary systemic immune response. Furthermore, our ELIspot assay on enriched IgA(+) B-cells could be used as a screening procedure to optimize mucosal immunization protocols in pigs with maternal immunity. PMID- 26100609 TI - Composite bottlebrush mechanics: alpha-internexin fine-tunes neurofilament network properties. AB - Neuronal cytoplasmic intermediate filaments are principal structural and mechanical elements of the axon. Their expression during embryonic development follows a differential pattern, while their unregulated expression is correlated to neurodegenerative diseases. The largest neurofilament proteins of medium (NF M) and high molecular weight (NF-H) were shown to modulate the axonal architecture and inter-filament spacing. However, the individual roles of the remaining alpha-internexin (alpha-Inx) and neurofilament of low molecular weight (NF-L) proteins in composite filaments remained elusive. In contrast to previous predictions, we show that when co-assembled with NF-M, the shortest and the least charged alpha-Inx protein increases inter-filament spacing. These findings suggest a novel structural explanation for the expression pattern of neurofilament proteins during embryonic development. We explain our results by an analysis of ionic cross-links between the disordered polyampholytic C-terminal tails and suggest that a collapsed conformation of the alpha-Inx tail domain interferes with tail cross-linking near the filament backbone. PMID- 26100610 TI - Psychiatric pharmacists' perception on the use of pharmacogenomic testing in the mental health population. AB - AIM: Pharmacogenomics could play a role in improving patient care, reducing adverse drug reactions and overall healthcare costs. However, whether it is utilized may be determined by how it is perceived by healthcare professionals, including pharmacists. METHODS: A cross-sectional web-based survey evaluated psychiatric pharmacists' use, knowledge and perception of the effectiveness of such testing. RESULTS: Among participants, 80% worked at sites not offering pharmacogenomic testing, mostly due to a lack of funding. About 36% of pharmacists considered themselves more knowledgeable and 47% considered themselves less knowledgeable about pharmacogenomic testing; however, most agreed on the potential usefulness of testing. CONCLUSION: Among psychiatric pharmacists, the use of pharmacogenomics appears underappreciated due to factors such as lack of availability and understanding of testing. Original submitted 26 November 2014; Revision submitted 13 February 2015. PMID- 26100611 TI - The effects of parental components in a trauma-focused cognitive behavioral based therapy for children exposed to interparental violence: study protocol for a randomized controlled trial. AB - BACKGROUND: Interparental violence is both common and harmful and impacts children's lives directly and indirectly. Direct effects refer to affective, behavioral, and cognitive responses to interparental violence and psychosocial adjustment. Indirect effects refer to deteriorated parental availability and parent-child interaction. Standard Trauma Focused Cognitive Behavioral Therapy may be insufficient for children traumatized by exposure to interparental violence, given the pervasive impact of interparental violence on the family system. HORIZON is a trauma focused cognitive behavioral therapy based group program with the added component of a preparatory parenting program aimed at improving parental availability; and the added component of parent-child sessions to improve parent-child interaction. METHODS/DESIGN: This is a multicenter, multi informant and multi-method randomized clinical trial study with a 2 by 2 factorial experimental design. Participants (N = 100) are children (4-12 years), and their parents, who have been exposed to interparental violence. The main aim of the study is to test the effects of two parental components as an addition to a trauma focused cognitive behavioral based group therapy for reducing children's symptoms. Primary outcome measures are posttraumatic stress symptoms, and internalizing and externalizing problems in children. The secondary aim of the study is to test the effect of the two added components on adjustment problems in children and to test whether enhanced effects can be explained by changes in children's responses towards experienced violence, in parental availability, and in quality of parent-child interaction. To address this secondary aim, the main parameters are observational and questionnaire measures of parental availability, parent-child relationship variables, children's adjustment problems and children's responses to interparental violence. Data are collected three times: before and after the program and six months later. Both intention-to-treat and completer analyses will be done. DISCUSSION: The current study will enhance our understanding of the efficacy interparental violence-related parental components added to trauma focused cognitive behavioral group program for children who have been exposed to IPV. It will illuminate mechanisms underlying change by considering multiple dimensions of child responses, parenting variables and identify selection criteria for participation in treatment. TRIAL REGISTRATION: Netherlands Trial Register NTR4015 . Registered 4th of June, 2013. PMID- 26100612 TI - Adaptations for nocturnal and diurnal vision in the hawkmoth lamina. AB - Animals use vision over a wide range of light intensities, from dim starlight to bright sunshine. For animals active in very dim light the visual system is challenged by several sources of visual noise. Adaptations in the eyes, as well as in the neural circuitry, have evolved to suppress the noise and enhance the visual signal, thereby improving vision in dim light. Among neural adaptations, spatial summation of visual signals from neighboring processing units is suggested to increase the reliability of signal detection and thus visual sensitivity. In insects, the likely neural candidates for carrying out spatial summation are the lamina monopolar cells (LMCs) of the first visual processing area of the insect brain (the lamina). We have classified LMCs in three species of hawkmoths with considerably different activity periods but very similar ecology-the diurnal Macroglossum stellatarum, the nocturnal Deilephila elpenor and the crepuscular-nocturnal Manduca sexta. Using this classification, we investigated the anatomical adaptations of hawkmoth LMCs suited for spatial summation. We found that specific types of LMCs have dendrites extending to significantly more neighboring cartridges in the two nocturnal and crepuscular species than in the diurnal species, making these LMC types strong candidates for spatial summation. Moreover, while the absolute number of cartridges visited by the LMCs differed between the two dim-light species, their dendritic extents were very similar in terms of visual angle, possibly indicating a limiting spatial acuity. The overall size of the lamina neuropil did not correlate with the size of its LMCs. PMID- 26100614 TI - A poroelastic model coupled to a fluid network with applications in lung modelling. AB - We develop a lung ventilation model based on a continuum poroelastic representation of lung parenchyma that is strongly coupled to a pipe network representation of the airway tree. The continuous system of equations is discretized using a low-order stabilised finite element method. The framework is applied to a realistic lung anatomical model derived from computed tomography data and an artificially generated airway tree to model the conducting airway region. Numerical simulations produce physiologically realistic solutions and demonstrate the effect of airway constriction and reduced tissue elasticity on ventilation, tissue stress and alveolar pressure distribution. The key advantage of the model is the ability to provide insight into the mutual dependence between ventilation and deformation. This is essential when studying lung diseases, such as chronic obstructive pulmonary disease and pulmonary fibrosis. Thus the model can be used to form a better understanding of integrated lung mechanics in both the healthy and diseased states. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26100613 TI - Cross-cultural gene- environment interactions in depression, post-traumatic stress disorder, and the cortisol awakening response: FKBP5 polymorphisms and childhood trauma in South Asia. AB - Despite increased attention to global mental health, psychiatric genetic research has been dominated by studies in high-income countries, especially with populations of European descent. The objective of this study was to assess single nucleotide polymorphisms (SNPs) in the FKBP5 gene in a population living in South Asia. Among adults in Nepal, depression was assessed with the Beck Depression Inventory (BDI), post-traumatic stress disorder (PTSD) with the PTSD Checklist Civilian Version (PCL-C), and childhood maltreatment with the Childhood Trauma Questionnaire (CTQ). FKBP5 SNPs were genotyped for 682 participants. Cortisol awakening response (CAR) was assessed in a subsample of 118 participants over 3 days. The FKBP5 tag-SNP rs9296158 showed a main effect on depressive symptoms (p = 0.03). Interaction of rs9296158 and childhood maltreatment predicted adult depressive symptoms (p = 0.02) but not PTSD. Childhood maltreatment associated with endocrine response in individuals homozygous for the A allele, demonstrated by a negative CAR and overall hypocortisolaemia in the rs9296158 AA genotype and childhood maltreatment group (p < 0.001). This study replicated findings related to FKBP5 and depression but not PTSD. Gene-environment studies should take differences in prevalence and cultural significance of phenotypes and exposures into account when interpreting cross-cultural findings. PMID- 26100615 TI - In vivo imaging of endogenous enzyme activities using luminescent 1,2-dioxetane compounds. AB - BACKGROUND: Here we present a non-invasive imaging method for visualizing endogenous enzyme activities in living animals. This optical imaging method is based on an energy transfer principle termed chemically initiated electron exchange luminescence (CIEEL). The light energy is provided by enzymatic activation of metastable 1,2-dioxetane substrates, whose protective groups are removed by hydrolytic enzymes such as beta-galactosidase and alkaline phosphatase. In the presence of a nearby fluorescent recipient, the chemical energy within the activated substrate is then transferred via formation of a charge-transfer complex with the fluorophore, a mechanism closely related to glow stick chemistry. RESULTS: Efficient CIEEL energy transfer requires close proximity between the trigger enzyme and the fluorescent recipient. Using cells stained with fluorescent dialkylcarbocyanines as the energy recipients, we demonstrated CIEEL imaging of cellular beta-galactosidase or alkaline phosphatase activity. In living animals, we used a similar approach to non-invasively image alkaline phosphatase activity in the peritoneal cavity. CONCLUSIONS: In this report, we provide proof-of-concept for CIEEL imaging of in vivo enzymatic activity. In addition, we demonstrate the use of CIEEL energy transfer for visualizing elevated alkaline phosphatase activity associated with tissue inflammation in living animals. PMID- 26100616 TI - Physical activity level is associated with fasting plasma glucose among women aged 35-55 without diabetes in Shandong, China. PMID- 26100617 TI - The influence of parental encouragement and caring about healthy eating on children's diet quality and body weights. AB - OBJECTIVE: In order to mitigate childhood obesity, evidence on what influences children's health behaviours is needed to inform new health promotion strategies. The present study investigated the association between parental practices and their child's diet and body weight status. DESIGN: Grade 5 students and their parents completed health surveys. Parents were asked how much they 'encourage their child to eat healthy foods' and how much they 'personally care about healthy eating'. Children's diet quality and vegetable and fruit intake were assessed using an FFQ. Children's heights and weights were measured to determine body weight status. Mixed-effects regression models were used to determine the influence of parental responses on the outcomes of interest. SETTING: Elementary schools across the province of Alberta, Canada. SUBJECTS: Grade 5 students (aged 10 and 11 years; n 8388) and their parent(s). RESULTS: Most parents reported caring about healthy eating and encouraging their child to eat healthy foods at least quite a lot. Children whose parents who cared or encouraged 'very much' compared with 'quite a lot' were more likely have better diet quality and were less likely to be overweight. Children whose parents both cared and encouraged 'very much' compared with 'quite a lot' scored an average of 2.06 points higher on the diet quality index (beta=2.06; 95 % CI 1.45, 2.66). CONCLUSIONS: Health promotion strategies that aim for a high level of parental interest and encouragement of their children to eat healthy foods may improve diet quality and prevent overweight among children. PMID- 26100618 TI - Cutaneous Manifestations in Dermatomyositis: Key Clinical and Serological Features-a Comprehensive Review. AB - Dermatomyositis (DM) is a common idiopathic inflammatory myopathy. The pathogenesis is considered to be microangiopathy affecting skin and muscle. The cutaneous manifestations of DM are the most important aspect of this disease, and their correct evaluation is important for early diagnosis. The skin signs are various: Some are pathognomonic or highly characteristic, and others are compatible with DM. Recently, DM has been categorized into several disease subsets based on the various autoantibodies present in patients. Sometimes, characteristic cutaneous manifestations are strongly associated with the presence of specific autoantibodies. For example, anti-Mi-2 antibody is associated with the classic features of DM, including heliotrope rash, Gottron's papules, the V neck sign, the shawl sign, cuticular overgrowth, and photosensitivity. Frequent cutaneous features in anti-transcriptional intermediary factor 1 gamma (TIF1gamma)-positive patients are diffuse photoerythema, including "dusky red face," while skin ulcerations, palmar papules (inverse Gottron), diffuse hair loss, panniculitis, and oral pain and/or ulcers are sometimes associated with anti-melanoma differentiation-associated gene 5 product (MDA5) antibody. Here, we review important cutaneous manifestations seen in patients with DM, and we examine the relationship between the skin changes and myositis-associated autoantibodies. Correct evaluation of cutaneous manifestations and myositis associated autoantibodies should help the clinician in the early diagnosis of DM, for a quick recognition of cutaneous signs that may be the symptom of onset before muscle inflammation. PMID- 26100619 TI - Risk Stratification in Older Patients With Acute Myocardial Infarction: Physicians' Perspectives. AB - OBJECTIVE: Risk stratification models support clinical decision making in acute myocardial infarction (AMI) care. Existing models were developed using data from younger populations, potentially limiting accuracy and relevance in older adults. We describe physician-perceived risk factors, views of existing models, and preferences for future model development in older adults. METHOD: Qualitative study using semi-structured telephone interviews and the constant comparative method. RESULTS: Twenty-two physicians from 14 institutions completed the interviews. Median age was 37, and median years of clinical experience was 11.5. Perceived predictors included cardiovascular, comorbid, functional, and social risk factors. Physicians viewed models as easy to use, yet neither inclusive of risk factors nor predictive of non-mortality outcomes germane to clinical decision making in older adults. Ideal models included multidimensional risk domains and operational requirements. DISCUSSION: Physicians reported limitations of available risk models when applied to older adults with AMI. New models are needed to guide AMI treatment in this population. PMID- 26100620 TI - Understanding Rural-Urban Differences in Depressive Symptoms Among Older Adults in China. AB - OBJECTIVE: Studies have reported that rural elders in China have higher levels of depression than their urban peers. We aimed to examine the extent to which four sets of factors (socioeconomic status [SES], health care access, health status, and social support and participation) account for such rural-urban differences. METHOD: Cross-sectional data from the 2011 China Health and Retirement Longitudinal Study were analyzed. A representative sample (N = 5,103) of older Chinese (age 60+) was included. Depressive symptoms were measured by the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10). Multilevel linear regression was conducted. RESULTS: Rural elders had more depressive symptoms than urban elders. When SES at the individual, household, and community level was simultaneously controlled, the rural-urban difference lost its statistical significance. Health status, social support, and social participation accounted for some, whereas health care access explained almost none, of the rural-urban difference. DISCUSSION: Results suggest that SES is the predominant factor accounting for the rural-urban depression gap in China. PMID- 26100621 TI - Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4 hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor alpha (FXRalpha) in Stabilizing the Homodimerization of the Receptor. AB - Farnesoid X receptor alpha (FXRalpha) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRalpha (hFXRalpha), and the crystal structure of hFXRalpha ligand binding domain (hFXRalpha-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRalpha-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRalpha target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRalpha-LBD.NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research. PMID- 26100622 TI - STAT3 Protein Regulates Vascular Smooth Muscle Cell Phenotypic Switch by Interaction with Myocardin. AB - The JAK-STAT3 signaling pathway is one of the critical pathways regulating cell proliferation, differentiation, and apoptosis. Myocardin is regarded as a key mediator for the change of smooth muscle phenotypes. However, the relationship between STAT3 and myocardin in the vascular smooth muscle cell (VSMC) phenotypic switch has not been investigated. The goal of this study was to investigate the molecular mechanism by which STAT3 affects the myocardin-regulated VSMC phenotypic switch. Data presented in this study demonstrated that STAT3 was rapidly up-regulated after stimulation with VEGF. Inhibition of the STAT3 activation process impaired VSMC proliferation and enhanced the expression of VSMC contractile genes by increasing serum-response factor binding to the CArG containing regions of VSMC-specific contractile genes. In contrast, the interaction between serum-response factor and its co-activator myocardin was reduced by overexpression of STAT3. In addition, treated VEGF inhibited the transcription activity of myocardin, and overexpression of STAT3 inhibited myocardin-induced up-regulation of VSMC contractile phenotype-specific genes. Although myocardin and STAT3 are negatively correlated, interestingly, both of them can enhance the expression of VEGF, suggesting a feedback loop to regulate the VSMC phenotypic switch. Taken together, these results indicate that the JAK STAT3 signaling pathway plays a key role in controlling the phenotypic switch of VSMCs through the interactions between STAT3 and myocardin by various coordinated gene regulation pathways and feedback loops. PMID- 26100623 TI - Molecular Determinants for the Inactivation of the Retinoblastoma Tumor Suppressor by the Viral Cyclin-dependent Kinase UL97. AB - The retinoblastoma (Rb) tumor suppressor restricts cell cycle progression by repressing E2F-responsive transcription. Cellular cyclin-dependent kinase (CDK) mediated Rb inactivation through phosphorylation disrupts Rb-E2F complexes, stimulating transcription. The human cytomegalovirus (HCMV) UL97 protein is a viral CDK (v-CDK) that phosphorylates Rb. Here we show that UL97 phosphorylates 11 of the 16 consensus CDK sites in Rb. A cleft within Rb accommodates peptides with the amino acid sequence LXCXE. UL97 contains three such motifs. We determined that the first LXCXE motif (L1) of UL97 and the Rb cleft enhance UL97 mediated Rb phosphorylation. A UL97 mutant with a non-functional L1 motif (UL97 L1m) displayed significantly reduced Rb phosphorylation at multiple sites. Curiously, however, it efficiently disrupted Rb-E2F complexes but failed to relieve Rb-mediated repression of E2F reporter constructs. The HCMV immediate early 1 protein cooperated with UL97-L1m to inactivate Rb in transfection assays, likely indicating that cells infected with a UL97-L1m mutant virus show no defects in growth or E2F-responsive gene expression because of redundant viral mechanisms to inactivate Rb. Our data suggest that UL97 possesses a mechanism to elicit E2F-dependent gene expression distinct from disruption of Rb-E2F complexes and dependent upon both the L1 motif of UL97 and the cleft region of Rb. PMID- 26100624 TI - Dimerization Domain of Retinal Membrane Guanylyl Cyclase 1 (RetGC1) Is an Essential Part of Guanylyl Cyclase-activating Protein (GCAP) Binding Interface. AB - The photoreceptor-specific proteins guanylyl cyclase-activating proteins (GCAPs) bind and regulate retinal membrane guanylyl cyclase 1 (RetGC1) but not natriuretic peptide receptor A (NPRA). Study of RetGC1 regulation in vitro and its association with fluorescently tagged GCAP in transfected cells showed that R822P substitution in the cyclase dimerization domain causing congenital early onset blindness disrupted RetGC1 ability to bind GCAP but did not eliminate its affinity for another photoreceptor-specific protein, retinal degeneration 3 (RD3). Likewise, the presence of the NPRA dimerization domain in RetGC1/NPRA chimera specifically disabled binding of GCAPs but not of RD3. In subsequent mapping using hybrid dimerization domains in RetGC1/NPRA chimera, multiple RetGC1 specific residues contributed to GCAP binding by the cyclase, but the region around Met(823) was the most crucial. Either positively or negatively charged residues in that position completely blocked GCAP1 and GCAP2 but not RD3 binding similarly to the disease-causing mutation in the neighboring Arg(822). The specificity of GCAP binding imparted by RetGC1 dimerization domain was not directly related to promoting dimerization of the cyclase. The probability of coiled coil dimer formation computed for RetGC1/NPRA chimeras, even those incapable of binding GCAP, remained high, and functional complementation tests showed that the RetGC1 active site, which requires dimerization of the cyclase, was formed even when Met(823) or Arg(822) was mutated. These results directly demonstrate that the interface for GCAP binding on RetGC1 requires not only the kinase homology region but also directly involves the dimerization domain and especially its portion containing Arg(822) and Met(823). PMID- 26100625 TI - A Catalase-related Hemoprotein in Coral Is Specialized for Synthesis of Short chain Aldehydes: DISCOVERY OF P450-TYPE HYDROPEROXIDE LYASE ACTIVITY IN A CATALASE. AB - In corals a catalase-lipoxygenase fusion protein transforms arachidonic acid to the allene oxide 8R,9-epoxy-5,9,11,14-eicosatetraenoic acid from which arise cyclopentenones such as the prostanoid-related clavulones. Recently we cloned two catalase-lipoxygenase fusion protein genes (a and b) from the coral Capnella imbricata, form a being an allene oxide synthase and form b giving uncharacterized polar products (Lohelaid, H., Teder, T., Toldsepp, K., Ekins, M., and Samel, N. (2014) PloS ONE 9, e89215). Here, using HPLC-UV, LC-MS, and NMR methods, we identify a novel activity of fusion protein b, establishing its role in cleaving the lipoxygenase product 8R-hydroperoxy-eicosatetraenoic acid into the short-chain aldehydes (5Z)-8-oxo-octenoic acid and (3Z,6Z)-dodecadienal; these primary products readily isomerize in an aqueous medium to the corresponding 6E- and 2E,6Z derivatives. This type of enzymatic cleavage, splitting the carbon chain within the conjugated diene of the hydroperoxide substrate, is known only in plant cytochrome P450 hydroperoxide lyases. In mechanistic studies using (18)O-labeled substrate and incubations in H2(18)O, we established synthesis of the C8-oxo acid and C12 aldehyde with the retention of the hydroperoxy oxygens, consistent with synthesis of a short-lived hemiacetal intermediate that breaks down spontaneously into the two aldehydes. Taken together with our initial studies indicating differing gene regulation of the allene oxide synthase and the newly identified catalase-related hydroperoxide lyase and given the role of aldehydes in plant defense, this work uncovers a potential pathway in coral stress signaling and a novel enzymatic activity in the animal kingdom. PMID- 26100626 TI - TGFbeta-activated Kinase 1 (TAK1) Inhibition by 5Z-7-Oxozeaenol Attenuates Early Brain Injury after Experimental Subarachnoid Hemorrhage. AB - Accumulating evidence suggests that activation of mitogen-activated protein kinases (MAPKs) and nuclear factor NF-kappaB exacerbates early brain injury (EBI) following subarachnoid hemorrhage (SAH) by provoking proapoptotic and proinflammatory cellular signaling. Here we evaluate the role of TGFbeta activated kinase 1 (TAK1), a critical regulator of the NF-kappaB and MAPK pathways, in early brain injury following SAH. Although the expression level of TAK1 did not present significant alternation in the basal temporal lobe after SAH, the expression of phosphorylated TAK1 (Thr-187, p-TAK1) showed a substantial increase 24 h post-SAH. Intracerebroventricular injection of a selective TAK1 inhibitor (10 min post-SAH), 5Z-7-oxozeaenol (OZ), significantly reduced the levels of TAK1 and p-TAK1 at 24 h post-SAH. Involvement of MAPKs and NF-kappaB signaling pathways was revealed that OZ inhibited SAH-induced phosphorylation of p38 and JNK, the nuclear translocation of NF-kappaB p65, and degradation of IkappaBalpha. Furthermore, OZ administration diminished the SAH-induced apoptosis and EBI. As a result, neurological deficits caused by SAH were reversed. Our findings suggest that TAK1 inhibition confers marked neuroprotection against EBI following SAH. Therefore, TAK1 might be a promising new molecular target for the treatment of SAH. PMID- 26100627 TI - Novel Allosteric Modulators of G Protein-coupled Receptors. AB - G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization. PMID- 26100628 TI - From G Protein-coupled Receptor Structure Resolution to Rational Drug Design. AB - A number of recent technical solutions have led to significant advances in G protein-coupled receptor (GPCR) structural biology. Apart from a detailed mechanistic view of receptor activation, the new structures have revealed novel ligand binding sites. Together, these insights provide avenues for rational drug design to modulate the activities of these important drug targets. The application of structural data to GPCR drug discovery ushers in an exciting era with the potential to improve existing drugs and discover new ones. In this review, we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient findings from structures that are relevant to drug discovery. Finally, we outline some of the approaches used in GPCR structure based drug design. PMID- 26100629 TI - Integrated Approaches for Genome-wide Interrogation of the Druggable Non olfactory G Protein-coupled Receptor Superfamily. AB - G-protein-coupled receptors (GPCRs) are frequent and fruitful targets for drug discovery and development, as well as being off-targets for the side effects of a variety of medications. Much of the druggable non-olfactory human GPCR-ome remains under-interrogated, and we present here various approaches that we and others have used to shine light into these previously dark corners of the human genome. PMID- 26100630 TI - A Cytotoxic Antibody Recognizing Lacto-N-fucopentaose I (LNFP I) on Human Induced Pluripotent Stem (hiPS) Cells. AB - We have generated a mouse monoclonal antibody (R-17F, IgG1 subtype) specific to human induced pluripotent stem (hiPS)/embryonic stem (ES) cells by using a hiPS cell line as an antigen. Triple-color confocal immunostaining images of hiPS cells with R-17F indicated that the R-17F epitope was expressed exclusively and intensively on the cell membranes of hiPS cells and co-localized partially with those of SSEA-4 and SSEA-3. Lines of evidence suggested that the predominant part of the R-17F epitope was a glycolipid. Upon TLC blot of total lipid extracts from hiPS cells with R-17F, one major R-17F-positive band was observed at a slow migration position close to that of anti-blood group H1(O) antigen. MALDI-TOF-MS and MS(n) analyses of the purified antigen indicated that the presumptive structure of the R-17F antigen was Fuc-Hex-HexNAc-Hex-Hex-Cer. Glycan microarray analysis involving 13 different synthetic oligosaccharides indicated that R-17F bound selectively to LNFP I (Fucalpha1-2Galbeta1-3GlcNAcbeta1-3Galbeta1-4Glc). A critical role of the terminal Fucalpha1-2 residue was confirmed by the selective disappearance of R-17F binding to the purified antigen upon alpha1-2 fucosidase digestion. Most interestingly, R-17F, when added to hiPS/ES cell suspensions, exhibited potent dose-dependent cytotoxicity. The cytotoxic effect was augmented markedly upon the addition of the secondary antibody (goat anti-mouse IgG1 antibody). R-17F may be beneficial for safer regenerative medicine by eliminating residual undifferentiated hiPS cells in hiPS-derived regenerative tissues, which are considered to be a strong risk factor for carcinogenesis. PMID- 26100631 TI - Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling. AB - We recently described the induction of noncanonical IL-1beta processing via caspase-8 recruited to ripoptosome signaling platforms in myeloid leukocytes. Here, we demonstrate that activated NLRP3.ASC inflammasomes recruit caspase-8 to drive IL-1beta processing in murine bone marrow-derived dendritic cells (BMDC) independent of caspase-1 and -11. Sustained stimulation (>2 h) of LPS-primed caspase-1-deficient (Casp1/11(-/-)) BMDC with the canonical NLRP3 inflammasome agonist nigericin results in release of bioactive IL-1beta in conjunction with robust caspase-8 activation. This IL-1beta processing and caspase-8 activation do not proceed in Nlrp3(-/-) or Asc(-/-) BMDC and are suppressed by pharmacological inhibition of caspase-8, indicating that caspase-8 can act as a direct IL-1beta converting enzyme during NLRP3 inflammasome activation. In contrast to the rapid caspase-1-mediated death of wild type (WT) BMDC via NLRP3-dependent pyroptosis, nigericin-stimulated Casp1/11(-/-) BMDC exhibit markedly delayed cell death via NLRP3-dependent apoptosis. Biochemical analyses of WT and Casp1/11(-/-) BMDC indicated that caspase-8 is proteolytically processed within detergent-insoluble ASC-enriched protein complexes prior to extracellular export during nigericin treatment. Although nigericin-stimulated caspase-1 activation and activity are only modestly attenuated in caspase-8-deficient (Casp8(-/-)Rip3(-/-)) BMDC, these cells do not exhibit the rapid loss of viability of WT cells. These results support a contribution of caspase-8 to both IL-1beta production and regulated death signaling via NLRP3 inflammasomes. In the absence of caspase-1, NLRP3 inflammasomes directly utilize caspase-8 as both a pro-apoptotic initiator and major IL-1beta-converting protease. In the presence of caspase-1, caspase-8 acts as a positive modulator of the NLRP3-dependent caspase-1 signaling cascades that drive both IL-1beta production and pyroptotic death. PMID- 26100632 TI - Autophagy-Lysosome Pathway in Renal Tubular Epithelial Cells Is Disrupted by Advanced Glycation End Products in Diabetic Nephropathy. AB - It has been suggested that autophagy protects renal tubular epithelial cells (TECs) from injury in diabetic nephropathy (DN). However, the manner in which the autophagy-lysosome pathway is changed in this state remains unclear. In this study of DN, we investigated the autophagic activity and lysosomal alterations in vivo and in vitro. We found that autophagic vacuoles and SQSTM1-positive proteins accumulated in TECs from patients with DN and in human renal tubular epithelial cell line (HK-2 cells) treated with advanced glycation end products (AGEs), the important factors that involved in the pathogenesis of DN. In HK-2 cells, exposure to AGEs caused a significant increase in autophagosomes but a marked decrease in autolysosomes, and the lysosomal turnover of LC3-II was not observed, although LC3-II puncta were co-localized with the irregular lysosomal-associated membrane protein1 granules after AGEs treatment. Furthermore, lysosomal membrane permeabilization was triggered by AGEs, which likely resulted in a decrease in the enzymatic activities of cathepsin B and cathepsin L, the defective acidification of lysosomes, and suppression of the lysosomal degradation of DQ ovalbumin. Oxidative stress evoked by AGEs-receptor for AGE interaction likely played an important role in the lysosomal dysfunction. Additionally, ubiquitinated proteins were co-localized with SQSTM1-positive puncta and accumulated in HK-2 cells after exposure to AGEs, indicating blocked degradation of SQSTM1-positive and ubiquitinated aggregates. Taken together, the results show that lysosomal membrane permeabilization and lysosomal dysfunction are triggered by AGEs, which induce autophagic inactivation in TECs from patients with DN. Disruption of the autophagy-lysosome pathway should be focused when studying the mechanisms underlying DN. PMID- 26100633 TI - Transcriptional Regulation of the Sodium-activated Potassium Channel SLICK (KCNT2) Promoter by Nuclear Factor-kappaB. AB - Although recent studies have shown the sodium-activated potassium channel SLACK (KCNT1) can contribute to neuronal excitability, there remains little information on the physiological role of the closely related SLICK (KCNT2) channel. Activation of SLICK channels may be important during pathological states such as ischemia, in which an increase in intracellular sodium and chloride can perturb membrane potential and ion homeostasis. We have identified two NFkappaB-binding sites within the promoter region of the human SLICK (KCNT2) and orthologous rat Slick (Kcnt2) genes, suggesting that conditions in which NFkappaB transcriptional activity is elevated promote expression of this channel. NFkappaB binding to the rat Slick promoter was confirmed in vivo by ChIP analyses, and NFkappaB was found differentially bound to the two sites. We verified NFkappaB transcriptional regulation of SLICK/Slick by mutational analyses and studying gene expression by luciferase assay in P19 cells, where NFkappaB is constitutively active. For the rat gene, activation of the Slick promoter was found to be additive in single NFkappaB mutations and synergistic in double mutations. Unexpectedly, for the human gene, NFkappaB exhibited cooperativity in activating the SLICK promoter. The human SLICK promoter constructs were then tested under hypoxic conditions in PC-12 cells, where NFkappaB is not active. Only under hypoxic conditions could luciferase activity be detected; the double NFkappaB mutant construct failed to exhibit activity. Transcriptional regulation of Slick by NFkappaB was verified in primary neurons. The Slick transcript decreased 24 h after NFkappaB inhibition. Our data show SLICK expression is predominantly under the control of NFkappaB. Because neuronal NFkappaB activation occurs during stressful stimuli such as hypoxia and injury, our findings suggest that SLICK is a neuroprotective gene. PMID- 26100634 TI - Bacteria May Cope Differently from Similar Membrane Damage Caused by the Australian Tree Frog Antimicrobial Peptide Maculatin 1.1. AB - Maculatin 1.1 (Mac1) is an antimicrobial peptide from the skin of Australian tree frogs and is known to possess selectivity toward Gram-positive bacteria. Although Mac1 has membrane disrupting activity, it is not known how Mac1 selectively targets Gram-positive over Gram-negative bacteria. The interaction of Mac1 with Escherichia coli, Staphylococcus aureus, and human red blood cells (hRBC) and with their mimetic model membranes is here reported. The peptide showed a 16-fold greater growth inhibition activity against S. aureus (4 MUM) than against E. coli (64 MUM) and an intermediate cytotoxicity against hRBC (30 MUM). Surprisingly, Sytox Green uptake monitored by flow cytometry showed that Mac1 compromised both bacterial membranes with similar efficiency at ~20-fold lower concentration than the reported minimum inhibition concentration against S. aureus. Mac1 also reduced the negative potential of S. aureus and E. coli membrane with similar efficacy. Furthermore, liposomes mimicking the cell membrane of S. aureus (POPG/TOCL) and E. coli (POPE/POPG) were lysed at similar concentrations, whereas hRBC-like vesicles (POPC/SM/Chol) remained mostly intact in the presence of Mac1. Remarkably, when POPG/TOCL and POPE/POPG liposomes were co-incubated, Mac1 did not induce leakage from POPE/POPG liposomes, suggesting a preference toward POPG/TOCL membranes that was supported by surface plasma resonance assays. Interestingly, circular dichroism spectroscopy showed a similar helical conformation in the presence of the anionic liposomes but not the hRBC mimics. Overall, the study showed that Mac1 disrupts bacterial membranes in a similar fashion before cell death events and would preferentially target S. aureus over E. coli or hRBC membranes. PMID- 26100635 TI - Lipopolysaccharide Phosphorylation by the WaaY Kinase Affects the Susceptibility of Escherichia coli to the Human Antimicrobial Peptide LL-37. AB - The human cathelicidin LL-37 is a multifunctional host defense peptide with immunomodulatory and antimicrobial roles. It kills bacteria primarily by altering membrane barrier properties, although the exact sequence of events leading to cell lysis has not yet been completely elucidated. Random insertion mutagenesis allowed isolation of Escherichia coli mutants with altered susceptibility to LL 37, pointing to factors potentially relevant to its activity. Among these, inactivation of the waaY gene, encoding a kinase responsible for heptose II phosphorylation in the LPS inner core, leads to a phenotype with decreased susceptibility to LL-37, stemming from a reduced amount of peptide binding to the surface of the cells, and a diminished capacity to lyse membranes. This points to a specific role of the LPS inner core in guiding LL-37 to the surface of Gram negative bacteria. Although electrostatic interactions are clearly relevant, the susceptibility of the waaY mutant to other cationic helical cathelicidins was unaffected, indicating that particular structural features or LL-37 play a role in this interaction. PMID- 26100637 TI - Hypertension-causing Mutations in Cullin3 Protein Impair RhoA Protein Ubiquitination and Augment the Association with Substrate Adaptors. AB - Cullin-Ring ubiquitin ligases regulate protein turnover by promoting the ubiquitination of substrate proteins, targeting them for proteasomal degradation. It has been shown previously that mutations in Cullin3 (Cul3) causing deletion of 57 amino acids encoded by exon 9 (Cul3Delta9) cause hypertension. Moreover, RhoA activity contributes to vascular constriction and hypertension. We show that ubiquitination and degradation of RhoA is dependent on Cul3 in HEK293T cells in which Cul3 expression is ablated by either siRNA or by CRISPR-Cas9 genome editing. The latter was used to generate a Cul3-null cell line (HEK293T(Cul3KO)). When expressed in these cells, Cul3Delta9 supported reduced ubiquitin ligase activity toward RhoA compared with equivalent levels of wild-type Cul3 (Cul3WT). Consistent with its reduced activity, binding of Cul3Delta9 to the E3 ubiquitin ligase Rbx1 and neddylation of Cul3Delta9 were impaired significantly compared with Cul3WT. Conversely, Cul3Delta9 bound to substrate adaptor proteins more efficiently than Cul3WT. Cul3Delta9 also forms unstable dimers with Cul3WT, disrupting dimers of Cul3WT complexes that are required for efficient ubiquitination of some substrates. Indeed, coexpression of Cul3WT and Cul3Delta9 in HEK293T(Cul3KO) cells resulted in a decrease in the active form of Cul3WT. We conclude that Cul3Delta9-associated ubiquitin ligase activity toward RhoA is impaired and suggest that Cul3Delta9 mutations may act dominantly by sequestering substrate adaptors and disrupting Cul3WT complexes. PMID- 26100638 TI - A Polybasic Plasma Membrane Binding Motif in the I-II Linker Stabilizes Voltage gated CaV1.2 Calcium Channel Function. AB - L-type voltage-gated Ca(2+) channels (LTCCs) regulate many physiological functions like muscle contraction, hormone secretion, gene expression, and neuronal excitability. Their activity is strictly controlled by various molecular mechanisms. The pore-forming alpha1-subunit comprises four repeated domains (I IV), each connected via an intracellular linker. Here we identified a polybasic plasma membrane binding motif, consisting of four arginines, within the I-II linker of all LTCCs. The primary structure of this motif is similar to polybasic clusters known to interact with polyphosphoinositides identified in other ion channels. We used de novo molecular modeling to predict the conformation of this polybasic motif, immunofluorescence microscopy and live cell imaging to investigate the interaction with the plasma membrane, and electrophysiology to study its role for Cav1.2 channel function. According to our models, this polybasic motif of the I-II linker forms a straight alpha-helix, with the positive charges facing the lipid phosphates of the inner leaflet of the plasma membrane. Membrane binding of the I-II linker could be reversed after phospholipase C activation, causing polyphosphoinositide breakdown, and was accelerated by elevated intracellular Ca(2+) levels. This indicates the involvement of negatively charged phospholipids in the plasma membrane targeting of the linker. Neutralization of four arginine residues eliminated plasma membrane binding. Patch clamp recordings revealed facilitated opening of Cav1.2 channels containing these mutations, weaker inhibition by phospholipase C activation, and reduced expression of channels (as quantified by ON-gating charge) at the plasma membrane. Our data provide new evidence for a membrane binding motif within the I-II linker of LTCC alpha1-subunits essential for stabilizing normal Ca(2+) channel function. PMID- 26100636 TI - Inhibition of N-Methyl-D-aspartate-induced Retinal Neuronal Death by Polyarginine Peptides Is Linked to the Attenuation of Stress-induced Hyperpolarization of the Inner Mitochondrial Membrane Potential. AB - It is widely accepted that overactivation of NMDA receptors, resulting in calcium overload and consequent mitochondrial dysfunction in retinal ganglion neurons, plays a significant role in promoting neurodegenerative disorders such as glaucoma. Calcium has been shown to initiate a transient hyperpolarization of the mitochondrial membrane potential triggering a burst of reactive oxygen species leading to apoptosis. Strategies that enhance cell survival signaling pathways aimed at preventing this adverse hyperpolarization of the mitochondrial membrane potential may provide a novel therapeutic intervention in retinal disease. In the retina, brain-derived neurotrophic factor has been shown to be neuroprotective, and our group previously reported a PSD-95/PDZ-binding cyclic peptide (CN2097) that augments brain-derived neurotrophic factor-induced pro-survival signaling. Here, we examined the neuroprotective properties of CN2097 using an established retinal in vivo NMDA toxicity model. CN2097 completely attenuated NMDA-induced caspase 3-dependent and -independent cell death and PARP-1 activation pathways, blocked necrosis, and fully prevented the loss of long term ganglion cell viability. Although neuroprotection was partially dependent upon CN2097 binding to the PDZ domain of PSD-95, our results show that the polyarginine-rich transport moiety C-R(7), linked to the PDZ-PSD-95-binding cyclic peptide, was sufficient to mediate short and long term protection via a mitochondrial targeting mechanism. C-R(7) localized to mitochondria and was found to reduce mitochondrial respiration, mitochondrial membrane hyperpolarization, and the generation of reactive oxygen species, promoting survival of retinal neurons. PMID- 26100639 TI - Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt mediated Increase in AMPKSer-485 Phosphorylation. AB - Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including obesity, diabetes, and dyslipidemia, and insulin resistance (IR) is the central feature of MetS. Recent studies suggest that MetS is a risk factor for Alzheimer disease (AD). AMP-activated kinase (AMPK) is an evolutionarily conserved fuel sensing enzyme and a key player in regulating energy metabolism. In this report, we examined the role of IR on the regulation of AMPK phosphorylation and AMPK mediated Tau phosphorylation. We found that AMPK(Ser-485), but not AMPK(Thr-172), phosphorylation is increased in the cortex of db/db and high fat diet-fed obese mice, two mouse models of IR. In vitro, treatment of human cortical stem cell line (HK-5320) and primary mouse embryonic cortical neurons with the AMPK activator, 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), induced AMPK phosphorylation at both Thr-172 and Ser-485. AMPK activation also triggered Tau dephosphorylation. When IR was mimicked in vitro by chronically treating the cells with insulin, AICAR specifically induced AMPK(Ser-485), but not AMPK(Thr-172), hyperphosphorylation whereas AICAR-induced Tau dephosphorylation was inhibited. IR also resulted in the overactivation of Akt by AICAR treatment; however, preventing Akt overactivation during IR prevented AMPK(Ser-485) hyperphosphorylation and restored AMPK-mediated Tau dephosphorylation. Transfection of AMPK(S485A) mutant caused similar results. Therefore, our results suggest the following mechanism for the adverse effect of IR on AD pathology: IR -> chronic overactivation of Akt -> AMPK(Ser-485) hyperphosphorylation -> inhibition of AMPK-mediated Tau dephosphorylation. Together, our results show for the first time a possible contribution of IR induced AMPK(Ser-485) phosphorylation to the increased risk of AD in obesity and diabetes. PMID- 26100640 TI - Insulin pump therapy, multiple daily injections, and cardiovascular mortality in 18,168 people with type 1 diabetes: observational study. AB - OBJECTIVE: To investigate the long term effects of continuous subcutaneous insulin infusion (insulin pump therapy) on cardiovascular diseases and mortality in people with type 1 diabetes. DESIGN: Observational study. SETTING: Swedish National Diabetes Register, Sweden 2005-12. PARTICIPANTS: 18,168 people with type 1 diabetes, 2441 using insulin pump therapy and 15,727 using multiple daily insulin injections. MAIN OUTCOME MEASURES: Cox regression analysis was used to estimate hazard ratios for the outcomes, with stratification of propensity scores including clinical characteristics, risk factors for cardiovascular disease, treatments, and previous diseases. RESULTS: Follow-up was for a mean of 6.8 years until December 2012, with 114,135 person years. With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in >80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association. CONCLUSION: Among people with type 1 diabetes use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections. PMID- 26100641 TI - Comparison of magnesium alloys and poly-l-lactide screws as degradable implants in a canine fracture model. AB - The aims of this study were to evaluate in vivo the biological responses to implants composed of biodegradable anodized WE43 (containing magnesium yttrium, rare earth elements and zirconium; Elektron SynerMag(r)) magnesium alloy, monolithic WE43 magnesium alloy and poly-l-lactic acid (PLLA), which are commonly used materials in clinic settings, and to evaluate the effectiveness of the materials as bone screws. The effectiveness of the magnesium alloy implants in osteosynthesis was evaluated using a bone fracture model involving the tibia of beagle dogs. For the monolithic WE43 implants, radiological, and histological evaluation revealed that bone trabeculae around the implanted monolithic WE43 decreased because of an inflammatory response. However, there was no damage due to hydrogen gas or inflammatory response in the bone tissue around the anodized WE43 implants. After 4 weeks, all the PLLA implants (n = 3) had broken but the WE43 implants had not (n = 6). These results suggest that the WE43 implants had sufficient strength to fix bone fractures at load-bearing sites in orthopedic and oral maxillofacial surgery. Therefore, these biodegradable magnesium alloys are good candidates for replacing biodegradable polymers. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1282-1289, 2016. PMID- 26100642 TI - Nanoscale alterations of corneocytes indicate skin disease. AB - BACKGROUND: The skin barrier protects the organism against exogenous stressors and simultaneously prevents excessive water loss. While the delicate regulation of skin barrier is not completely understood, morphological and histological evaluation remain key features of clinical investigations. Here, we extended the phenotypic perspective down to the nanoscale. METHODS: Corneocyte samples were obtained non-invasively by a standard tape stripping procedure from 21 indviduals. Scanning electron (SEM) and atomic force microcopy (AFM) were used to record nanoscale topography. Circular nano-objects were identified and these were quantitated through computer vision. RESULTS: Typical dimensions of 273 nm height and 305 nm width. We showed that their density does not correlate to age or pigmentation in healthy subjects, but that they were clearly elevated in corneocytes from patients with atopic dermatitis, a common inflammatory skin condition. CONCLUSION: The presence of these corneocyte-nanostructures might be used as a diagnostic parameter for skin disorders - even in cases below a clinical threshold. PMID- 26100643 TI - Hydrogen bonding of the dissociated histidine ligand is not required for formation of a proximal NO adduct in cytochrome c'. AB - Cytochromes c', that occur in methanotrophic, denitrifying and photosynthetic bacteria, form unusual proximal penta-coordinate NO complexes via a hexa coordinate distal NO intermediate. Their NO binding properties are similar to those of the eukaryotic NO sensor, soluble guanylate cyclase, for which they provide a valuable structural model. Previous studies suggested that hydrogen bonding between the displaced proximal histidine (His120) ligand (following its dissociation from heme due to trans effects from the distally bound NO) and a conserved aspartate residue (Asp121) could play a key role in allowing proximal NO binding to occur. We have characterized three variants of Alcaligenes xylosoxidans cytochrome c' (AXCP) where Asp121 has been replaced by Ala, Ile and Gln, respectively. In all variants, hydrogen bonding between residue 121 and His120 is abolished yet 5-coordinate proximal NO species are still formed. Our data therefore demonstrate that the His120-Asp121 bond is not essential for proximal NO binding although it likely provides an energy minimum for the displaced His ligand. All variants have altered proximal pocket structure relative to native AXCP. PMID- 26100648 TI - Transcription factors GATA4 and TBX5 promote cardiomyogenic differentiation of rat bone marrow mesenchymal stromal cells. AB - Bone marrow mesenchymal stromal cells (BMSCs) have potential applications in cell and gene therapies for cardiac disease. The cardiac-specific transcription factors GATA-binding protein 4 (GATA4) and T-Box protein 5 (TBX5) are considered to be pivotal in cardiogenesis. The aim of this study was to investigate the effects of GATA4 and TBX5 on cardiomyogenic differentiation of BMSCs. The BMSCs were initially isolated and identified. Vectors harboring cardiac transcription factor genes GATA4 and TBX5 or empty vectors were transferred into BMSCs. Cardiomyogenic cells differentiated from BMSCs were identified by expression of cardiac-specific markers including cardiac troponin T, connexin 43, beta-myosin heavy chain, and myosin light chain-2 using immunocytochemical staining, western blotting, and quantitative real-time PCR. The ultrastructures of the differentiated cells were examined by transmission electron microscopy, which were similar to those of fetal cardiomyocytes. The differentiated cells exhibited L-type calcium current activities reflective of the electrophysiological characteristics of cardiomyocytes. These findings indicate that exogenous expression of cardiac-specific transcription factors GATA4 and TBX5 enhance cardiomyogenic differentiation of BMSCs. PMID- 26100650 TI - Pharmacologic Options for the Treatment of Sarcopenia. AB - Sarcopenia is now clinically defined as a loss of muscle mass coupled with functional deterioration (either walking speed or distance or grip strength). Based on the FRAX studies suggesting that the questions without bone mineral density can be used to screen for osteoporosis, there is now a valid simple questionnaire to screen for sarcopenia, i.e., the SARC-F. Numerous factors have been implicated in the pathophysiology of sarcopenia. These include genetic factors, mitochondrial defects, decreased anabolic hormones (e.g., testosterone, vitamin D, growth hormone and insulin growth hormone-1), inflammatory cytokine excess, insulin resistance, decreased protein intake and activity, poor blood flow to muscle and deficiency of growth derived factor-11. Over the last decade, there has been a remarkable increase in our understanding of the molecular biology of muscle, resulting in a marked increase in potential future targets for the treatment of sarcopenia. At present, resistance exercise, protein supplementation, and vitamin D have been established as the basic treatment of sarcopenia. High-dose testosterone increases muscle power and function, but has a number of potentially limiting side effects. Other drugs in clinical development include selective androgen receptor molecules, ghrelin agonists, myostatin antibodies, activin IIR antagonists, angiotensin converting enzyme inhibitors, beta antagonists, and fast skeletal muscle troponin activators. As sarcopenia is a major predictor of frailty, hip fracture, disability, and mortality in older persons, the development of drugs to treat it is eagerly awaited. PMID- 26100649 TI - Synthesis of a Novel Nitronyl Nitroxide Radical and Determination of its Protective Effects Against Infrasound-Induced Injury. AB - Infrasound causes functional disorders and structural injury to the central nervous system. However, few anti-infrasound drugs exist, and they are inefficient. Nitronyl nitroxide radicals have been reported to be good antioxidants that act as superoxide dismutase mimics and directly react with reactive oxygen species, such as .OH, H2O2, and O 2 (?) -. Our previous research showed that the nitronyl nitroxide radical L-NNNBP has good protective effects against beta-amyloid deposition and memory deficits in an AD rat model of APP/PS1. The objective of the present study was to find a new group of anti infrasound drugs and determine the underlying pharmacological actions of nitronyl nitroxide radicals against infrasound-induced neuronal impairment in vivo. We synthesized a new stable nitronyl nitroxide radical, NRbt, and characterized its crystal structure. The results of the anti-oxidative damage effects of NRbt and the positive control drug tempol showed that they could significantly increase the SOD activity, CAT activity and GSH level and decrease the MDA level in rat hippocampi compared with infrasound exposure without pretreatment. Moreover, the ability of NRbt to regulate the activity or level of these biochemical markers was better than that of tempol. Our results showed that both NRbt and tempol significantly protected against the learning and memory impairments induced by infrasound exposure in a Morris water maze, but there were no significant differences in the path length or escape latency between the rats in the tempol group and the three NRbt groups (P > 0.05). In addition, the infrasound-induced neuronal apoptosis in rat hippocampi was significantly suppressed by NRbt and tempol. The results demonstrated that compared with the infrasound exposure group, the expression of Bcl-2 was up-regulated and the expressions of Bax and caspase-3 were down-regulated in rats pretreated with NRbt (40 mg/kg) or tempol (40 mg/kg). These results showed that the newly synthesized nitronyl nitroxide radical, NRbt, may be an effective anti-infrasound drug because of its capacity to inhibit the oxidative damage of free radicals induced by infrasound exposure. PMID- 26100651 TI - Abnormal Bone Mechanical and Structural Properties in Adolescent Idiopathic Scoliosis: A Study with Finite Element Analysis and Structural Model Index. AB - Previous studies found adolescent idiopathic scoliosis (AIS) is associated with low bone mineral density (BMD) and abnormal bone quality, whilst the association between AIS and their bone strength is unknown. From high-resolution peripheral quantitative computed tomography-generated images, bone mechanical properties can be evaluated with finite element analysis (FEA), and trabecular rod-plate configuration related to trabecular bone strength can be quantified by structure model index (SMI). This study aimed to compare trabecular configuration and bone mechanical properties between AIS and the controls. 95 AIS girls aged 12-14 years and 97 age- and gender-matched normal controls were recruited. Bilateral femoral necks and non-dominant distal radius were scanned by dual-energy X-ray absorptiometry for areal BMD and HR-pQCT for SMI and FEA, respectively. Subjects were further classified into osteopenic and non-osteopenic group based on their areal BMD. Bone mechanical properties (stiffness, failure load and apparent modulus) were calculated using FEA. Linear regression model was used for controlling age, physical activity and calcium intake. AIS was associated with lower failure load and apparent modulus after adjusting for age, whereas AIS was associated with lower apparent modulus after adjusting for all confounders. Osteopenic AIS was associated with more rod-like trabeculae when compared with non-osteopenic AIS, whereas no difference was detected between osteopenic and non osteopenic controls. This might be the result of abnormal regulation and modulation of bone metabolism and bone modelling and remodelling in AIS which will warrant future studies with a longitudinal design to determine the significance of micro-architectural abnormalities in AIS. PMID- 26100652 TI - Updated recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer. AB - Prostate cancer is the most prevalent male urogenital malignancy. Approximately 30% of patients with prostate cancer will develop advanced disease. Androgen deprivation therapy achieves disease control in about 90% of these patients, but the majority of them will eventually develop progressive disease, a status called castration-resistant prostate carcinoma (CRPC). However, in recent years, several new therapy strategies, such as immunotherapy, hormonal manipulations, chemotherapy agents and some bone-targeted therapies, have demonstrated an improvement in terms of overall survival in controlled trials. In 2012, the Spanish Oncology Genitourinary Group (SOGUG) published its recommendations for the treatment of patients with CRPC. Due to the recent appearance of important new data and the complexity of decision-making in this field, SOGUG herein provides updated recommendations for the treatment of patients with metastatic prostate cancer. PMID- 26100653 TI - The role of ABC transporters in ovarian cancer progression and chemoresistance. AB - Over 80% of ovarian cancer patients develop chemoresistance which results in a lethal course of the disease. A well-established cause of chemoresistance involves the family of ATP-binding cassette transporters, or ABC transporters that transport a wide range of substrates including metabolic products, nutrients, lipids, and drugs across extra- and intra-cellular membranes. Expressions of various ABC transporters, shown to reduce the intracellular accumulation of chemotherapy drugs, are increased following chemotherapy and impact on ovarian cancer survival. Although clinical trials to date using ABC transporter inhibitors have been disappointing, ABC transporter inhibition remains an attractive potential adjuvant to chemotherapy. A greater understanding of their physiological functions and role in ovarian cancer chemoresistance will be important for the development of more effective targeted therapies. This article will review the role of the ABC transporter family in ovarian cancer progression and chemoresistance as well as the clinical attempts used to date to reverse chemoresistance. PMID- 26100654 TI - Photoregulation of alpha-Chymotrypsin Activity by Spiropyran-Based Inhibitors in Solution and Attached to an Optical Fiber. AB - Here the synthesis and characterization of a new class of spiropyran-based protease inhibitor is reported that can be reversibly photoswitched between an active spiropyran (SP) isomer and a less active merocyanine (MC) isomer upon irradiation with UV and visible light, respectively, both in solution and on a surface of a microstructured optical fiber (MOF). The most potent inhibitor in the series (SP-3 b) has a C-terminal phenylalanyl-based alpha-ketoester group and inhibits alpha-chymotrypsin with a Ki of 115 nM. An analogue containing a C terminal Weinreb amide (SP-2 d) demonstrated excellent stability and photoswitching in solution and was attached to the surface of a MOF. The SP isomer of Weinreb amide 2 d is a competitive reversible inhibitor in solution and also on fiber, while the corresponding MC isomer was significantly less active in both media. The ability of this new class of spiropyran-based protease inhibitor to modulate enzyme activity on a MOF paves the way for sensing applications. PMID- 26100655 TI - Eating Disorders in Adolescents with Celiac Disease: Influence of Personality Characteristics and Coping. AB - OBJECTIVES: Patients suffering from celiac disease (CD) have a higher risk of developing disturbed eating behaviour. METHOD: In a multi-centre study, 259 female adolescents with CD and without a chronic condition were analysed regarding their eating disorder (ED) status, depression, personality, coping strategies and quality of life. RESULTS: Patients with CD and comorbid EDs were older and more often non-compliant with their diet and had a higher body mass index (BMI) and higher levels of depression. Differences in personality features disappear when controlling for age and depression. Higher ill-being and lower joy in life were reported by patients with CD and ED compared with patients without EDs, even when controlling for age and depression levels. No differences between patients (with CD) with and without EDs in coping strategies were found. BMI and lower self-directedness predicted ED status. CONCLUSIONS: Early identification of EDs in patients with CD is suggested and should include BMI and personality factors. PMID- 26100656 TI - Cytocompatibility of Biodentine using a three-dimensional cell culture model. AB - AIM: To evaluate the cytotoxic effects of Biodentine, using a three-dimensional (3D) cell culture associated with an in situ root-end filling experimental model. White mineral trioxide aggregate (MTA) and zinc oxide cement were used as reference for comparison. IL-1alpha and TNF-alpha cytokine production were also evaluated. METHODOLOGY: The root canals of 24 human maxillary incisor teeth were prepared using a single-file reciprocating technique. After root filling, a 3-mm root-end resection was performed and 3 mm of gutta-percha was removed from the canal. The teeth were randomly distributed to receive one of the following root end filling materials: Biodentine, white MTA or zinc oxide cement (positive control group). In the negative control group, the root canal was not retro filled. The cytocompatibility of the materials was evaluated using the methyl thiazol-diphenyl-tetrazolium (MTT) assay in an in situ root-end filling experimental model. Balb/c 3T3 fibroblasts, cultured in rat tail collagen type I 3D scaffold, were exposed to the root apex for 24 h, and cell viability was measured by means of reduction MTT salt. IL-1alpha and TNF-alpha production were analysed using enzyme-linked immunosorbent assay. One-way analysis of variance was performed and, when the F-ratios were significant, data were compared by Duncan's multiple-range test. The alpha-type error was set at 0.05. RESULTS: Biodentine and MTA groups had similar cell activity to the negative control group (P > 0.05), indicating low cytotoxicity for both materials. The stronger cytotoxicity effect was identified on the zinc oxide cement (P < 0.05). Zinc oxide cement caused a significant up-regulation in IL-1alpha and TNF-alpha (P < 0.05). No significant differences amongst MTA, Biodentine and the negative control group were observed for TNF-alpha (P > 0.05); however, both MTA and Biodentine were associated with overproduction of IL-1alpha when compared to the control group (P < 0.05). CONCLUSIONS: Biodentine and MTA had similar cytocompatibility in a 3D cell culture model associated with an in situ root-end filling model. The methodology could be used as an alternative to assess the cytocompatibility of endodontic cements because it is more closely related to the in vivo situation. PMID- 26100657 TI - Neuroimaging as a biomarker in symptom validity and performance validity testing. AB - How neuropsychological assessment findings are deemed valid has been a topic of numerous articles but few have addressed any role that neuroimaging studies could provide. Within military and various clinical samples of individuals undergoing neuropsychological evaluations, high levels of failure on measures of symptom validity testing (SVT) and/or performance validity testing (PVT) have been reported. Where 'failure' is defined as a below cut-score performance on some pre determined set-point on a SVT/PVT measure, are such failures always indicative of invalid test findings or are there other explanations, especially based on informative neuroimaging findings? This review starts with the premise that even though the SVT/PVT task is designed to be simple and easy to perform, it nonetheless requires intact frontoparietal attention, working memory and task engagement (motivation) networks. If there is damage or pathology within any aspect of these networks as demonstrated by neuroimaging findings, the patient may perform below the cut-point as a result of the underlying damage or pathophysiology. The argument is made that neuroimaging findings should be considered as to where SVT/PVT cut-points are established and there should be much greater flexibility in SVT/PVT measures based on other personal, demographic and neuroimaging information. Several case studies are used to demonstrate these points. PMID- 26100658 TI - Grey matter correlates of susceptibility to scams in community-dwelling older adults. AB - Susceptibility to scams is a significant issue among older adults, even among those with intact cognition. Age-related changes in brain macrostructure may be associated with susceptibility to scams; however, this has yet to be explored. Based on previous work implicating frontal and temporal lobe functioning as important in decision making, we tested the hypothesis that susceptibility to scams is associated with smaller grey matter volume in frontal and temporal lobe regions in a large community-dwelling cohort of non-demented older adults. Participants (N = 327, mean age = 81.55, mean education = 15.30, 78.9 % female) completed a self-report measure used to assess susceptibility to scams and an MRI brain scan. Results indicated an inverse association between overall grey matter and susceptibility to scams in models adjusted for age, education, and sex; and in models further adjusted for cognitive function. No significant associations were observed for white matter, cerebrospinal fluid, or total brain volume. Models adjusted for age, education, and sex revealed seven clusters showing smaller grey matter in the right parahippocampal/hippocampal/fusiform, left middle temporal, left orbitofrontal, right ventromedial prefrontal, right middle temporal, right precuneus, and right dorsolateral prefrontal regions. In models further adjusted for cognitive function, results revealed three significant clusters showing smaller grey matter in the right parahippocampal/hippocampal/fusiform, right hippocampal, and right middle temporal regions. Lower grey matter concentration in specific brain regions may be associated with susceptibility to scams, even after adjusting for cognitive ability. Future research is needed to determine whether grey matter reductions in these regions may be a biomarker for susceptibility to scams in old age. PMID- 26100659 TI - Quality assessment of the guidelines on cystic neoplasms of the pancreas. AB - BACKGROUND: Though cystic pancreatic neoplasms (CPNs) are being increasingly detected, their evaluation and management are still debated and have lead to publication of multiple guidelines for diagnostic work-up, indications for resection, and non-operative management with follow-up strategies of CPNs. AIMS: To analyze available guidelines in order to evaluate their overall quality and clinical applicability, indications for surgical resection and its extent, modalities and timing of follow-up when non-operative management is indicated. METHODS: After a systematic search of the English literature, we selected eight guidelines for assessment according to the Appraisal of Guidelines, Research and Evaluation in Europe (AGREE) II instrument. RESULTS: One guideline received the lower AGREE score regarding the "scope and purpose", "rigor of development" and "clarity and presentation" domains, whereas one received the best score for "stakeholder involvement" domain. No differences were found among different guidelines regarding the "applicability". The overall quality assessment score showed that only two guidelines were significantly lower than the others. According to the practical utilization recommendation score, four guidelines were considered as having full applicability in clinical practice. CONCLUSION: Existing guidelines provide adequate guidance, at least with the present knowledge, for the management of cystic pancreatic lesions; however, not any one was satisfactory to all aspects related to the management of CPN. An update of the existing guidelines should be considered if and when more evidence-based data are available. PMID- 26100660 TI - Calcium signaling and secretion in cholangiocytes. AB - Alcoholic hepatitis affects up to one-third of individuals who abuse alcohol and can be associated with high mortality. Although this disorder is characterized by hepatocellular damage, steatosis and neutrophil infiltration, recent evidence suggests that cholestasis or impaired bile secretion may be a frequent occurrence as well. Bile secretion results from the concerted activity of hepatocytes and cholangiocytes, the epithelial cells that line the bile ducts. Hepatocytes secrete bile acids and conjugated products into the bile canaliculi, which then are modified by cholangiocytes through secretion of bicarbonate and water to give rise to the final secreted bile. Here the molecular mechanisms regulating bile secretion in cholangiocytes are reviewed. Moreover, we discuss how the expression of intracellular Ca(2+) channels might be regulated in cholangiocytes, plus evidence that components of the Ca(2+) signaling machinery are altered in a range of cholestatic diseases of the bile ducts. PMID- 26100661 TI - Shaping the oral mycobiota: interactions of opportunistic fungi with oral bacteria and the host. AB - The oral mycobiota is an important component of the oral microbiota that has only recently received increased attention. The diversity and complexity of the oral mycobiota in healthy humans is greater than any other body site. Dysbiotic imbalance of indigenous fungal communities in immunosuppressed hosts has been proposed to lead to oropharyngeal fungal infections. As in other body sites, to survive and thrive in the oral cavity fungi have to maintain mutually beneficial relationships with the resident bacterial microbiota and the host. Here we review our current understanding of the composition of the oral mycobiota and how it may be influenced by oral commensal bacteria and the host environment. PMID- 26100662 TI - Compensation for Blood Plasma Donation as a Distinctive Ethical Hazard: Reformulating the Commodification Objection. AB - In this essay, I argue that the Commodification Objection (suitably redescribed), locates a phenomenon of real moral significance. In defending the Commodification Objection, I review three common criticisms of it, which claim firstly, that commodification doesn't always lead to instrumentalization; secondly, that commodification isn't the only route to such an outcome; and finally, that the Commodification Objection applies only to persons, and human organs (and, therefore, blood products) are not persons. In response, I conclude that (i) moral significance does not require that an undesirable outcome be a necessary consequence of the phenomenon under examination; (ii) the relative likelihood of an undesirable mode of regard arising provides a morally-relevant distinguishing marker for assessing the comparative moral status of social institutions and arrangements; and (iii) sales in blood products (and human organs more generally) are sufficiently distinct from sales of everyday artefacts and sufficiently close to personhood to provide genuine grounds for concern. Accordingly, criticisms of the Commodification Objection do not provide grounds for rejecting the claim that human organ sales in general and compensation for blood plasma donation in particular can have morally pernicious 'commodificatory effects' upon our attitudes, for what human organ sales provide is a distinctive ethical hazard. PMID- 26100663 TI - A sleep-inducing peptide from the venom of the Indian cone snail Conus araneosus. AB - The marine snail Conus araneosus has unusual significance due to its confined distribution to coastal regions of southeast India and Sri Lanka. Due to its relative scarceness, this species has been poorly studied. In this work, we characterized the venom of C. araneosus to identify new venom peptides. We identified 14 novel compounds. We determined amino acid sequences from chemically modified and unmodified crude venom using liquid chromatography-electrospray ionization mass spectrometry and matrix assisted laser desorption ionization time of-flight mass spectrometry. Ten sequences showed six Cys residues arranged in a pattern that is most commonly associated with the M-superfamily of conotoxins. Four other sequences had four Cys residues in a pattern that is most commonly associated with the T-superfamily of conotoxins. The post-translationally modified residue (pyroglutamate) was determined at the N-terminus of two sequences, ar3h and ar3i respectively. In addition, two sequences, ar3g and ar3h were C-terminally amidated. At a dose of 2 nmol, peptide ar3j elicited sleep when injected intraperitoneally into mice. To our knowledge, this is the first report of a peptide from a molluscivorous cone snail with sleep-inducing effects in mice. The novel peptides characterized herein extend the repertoire of unique peptides derived from cone snails and may add value to the therapeutic promise of conotoxins. PMID- 26100664 TI - Lachesis stenophrys venom reduces the equine antibody response towards Bothrops asper venom used as co-immunogen in the production of polyspecific snake antivenom. AB - The anti-bothropic activity of an antivenom prepared from the plasma of horses immunized with Bothrops asper venom (anti-B antivenom) was compared with a similar formulation produced from the plasma of horses immunized with a mixture of B. asper and Lachesis stenophrys venoms (anti-BL antivenom). Likewise, a comparison between the anti-lachesic activity of the anti-BL antivenom and a similar formulation prepared from horses immunized only with L. stenophrys venom (anti-L antivenom) was performed. The anti-BL antivenom had lower concentration of anti-bothropic antibodies than the anti-B antivenom. This difference was associated to a lower response towards all components of B. asper venom, but particularly towards some D49-phospholipases A2 (PLA2s) and PIII metalloproteinases. Consequently, the anti-BL antivenom was less effective neutralizing lethal, coagulant, defibrinogenating, PLA2, and myotoxic activities of B. asper venom. On the other hand, anti-BL and anti-L antivenoms showed similar concentration of anti-lachesic antibodies, and similar capacity to recognize the HPLC fractions of L. stenophrys venom and to neutralize lethal, coagulant, proteolytic, hemorrhagic, PLA2 and myotoxic activities induced by this venom. It is concluded that, when used as co-immunogens, the venom of L. stenophrys reduces the antibody response towards B. asper venom, whereas the latter does not affect the anti-lachesic response. PMID- 26100665 TI - Purification and characterization of two high molecular mass snake venom metalloproteinases (P-III SVMPs), named SV-PAD-2 and HR-Ele-1, from the venom of Protobothrops elegans (Sakishima-habu). AB - We herein identified two high molecular mass metalloproteinases, named SV-PAD-2 and HR-Ele-1, in the venom of Protobothrops elegans. HR-Ele-1 appeared as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) regard under reducing and non-reducing conditions, and the molecular mass of this protease was approximately 60 kDa under reducing conditions. On the other hand, the molecular masses of SV-PAD-2 on SDS-PAGE were 110 kDa under the non reducing condition and 52 kDa under the reducing condition. These SVMPs exhibited fibrinogenolytic and enzymatic activities against synthetic substrates for matrix metalloproteinases (MMPs) and the insulin B-chain, and were both inhibited by EDTA. SV-PAD-2 inhibited ADP- and collagen-induced platelet aggregation, with IC50 values of 240 nM and 185 nM, respectively. HR-Ele-1 exhibited hemorrhagic activity, and its minimum hemorrhagic dose (MHD) was 0.05 MUg in the guinea pig. PMID- 26100666 TI - Mast cells and histamine play an important role in edema and leukocyte recruitment induced by Potamotrygon motoro stingray venom in mice. AB - This work aimed to investigate mechanisms underlying the inflammatory response caused by Potamotrygon motoro stingray venom (PmV) in mouse paws. Pre-treatment of animals with a mast cell degranulation inhibitor (cromolyn) diminished edema (62% of inhibition) and leukocyte influx into the site of PmV injection. Promethazine (histamine type 1 receptor antagonist) or thioperamide (histamine type 3 and 4 receptor antagonist) also decreased edema (up to 30%) and leukocyte numbers, mainly neutrophils (40-50 %). Cimetidine (histamine type 2 receptor antagonist) had no effect on PmV-induced inflammation. In the RBL-2H3 lineage of mast cells, PmV caused proper cell activation, in a dose-dependent manner, with release of PGD2 and PGE2. In addition, the role of COXs products on PmV inflammatory response was evaluated. Indomethacin (COX-1/COX-2 inhibitor) or etoricoxib (COX-2 inhibitor) partially diminished edema (around 20%) in PmV injected mice. Indomethacin, but not etoricoxib, modulated neutrophil influx into the site of venom injection. In conclusion, mast cell degranulation and histamine, besides COXs products, play an important role in PmV-induced reaction. Since PmV mechanism of action remains unknown, hindering accurate treatment, clinical studies can be performed to validate the prescription of antihistaminic drugs, besides NSAIDs, to patients injured by freshwater stingrays. PMID- 26100667 TI - Production of (15)N-labeled alpha-amanitin in Galerina marginata. AB - alpha-Amanitin is the major causal constituent of deadly Amanita mushrooms that account for the majority of fatal mushroom poisonings worldwide. It is also an important biochemical tool for the study of its target, RNA polymerase II. The commercial supply of this bicyclic peptide comes from Amanita phalloides, the death cap mushroom, which is collected from the wild. Isotopically labeled amanitin could be useful for clinical and forensic applications, but alpha amanitin has not been chemically synthesized and A. phalloides cannot be cultured on artificial medium. Using Galerina marginata, an unrelated saprotrophic mushroom that grows and produces alpha-amanitin in culture, we describe a method for producing (15)N-labeled alpha-amanitin using growth media containing (15)N as sole nitrogen source. A key to success was preparing (15)N-enriched yeast extract via a novel method designated "glass bead-assisted maturation." In the presence of the labeled yeast extract and (15)N-NH4Cl, alpha-amanitin was produced with >97% isotope enrichment. The labeled product was confirmed by HPLC, high resolution mass spectrometry, and NMR. PMID- 26100669 TI - Massive mesenteric panniculitis due to fibromuscular dysplasia of the inferior mesenteric artery: a case report. AB - BACKGROUND: Fibromuscular dysplasia (FMD) is a nonatheromatous, noninflammatory arterial disorder of unknown etiology resulting in vessel stenosis and/or aneurysm formation. The renal and cephalocervical (mainly carotid arteries) arterial beds are classically involved; involvement of visceral arteries is rare. Mesenteric panniculitis (MP) is an inflammatory process of mesenteric fat considered to be of unknown etiology. The majority of cases involve the small bowel mesentery; colorectal MP is rare. To our knowledge, no example of MP due to FMD has been described. CASE PRESENTATION: A 52 year old man presented with steadily worsening lower abdominal pain. Investigation revealed ischemic rectosigmoid mucosa associated with a large mesenteric mass of unknown nature. Angiography showed the disease was limited to the distribution of the inferior mesenteric artery. Subsequent symptoms of large bowel obstruction necessitated a left hemicolectomy. Pathologic examination showed bowel wall necrosis and massive panniculitis of the rectosigmoid due to FMD. Subsequent angiographic imaging of other vascular beds was negative. CONCLUSIONS: Several features of this case are noteworthy: FMD limited to the inferior mesenteric artery has not been previously reported, FMD has not previously been implicated as a cause of MP, and the massive extent of panniculitis. An accompanying literature review of cases of visceral FMD, traditionally believed to almost exclusively affect females, highlights a greater than anticipated number of males (33%), and a gender difference regarding concomitant involvement of cephalocervical and/or renal vascular beds (32% in males versus 80% in females). The latter observation may have implications regarding the value of radiologic screening of other vascular beds, particularly in asymptomatic males, in patients presenting with visceral artery FMD. PMID- 26100668 TI - Aquaporin-3-mediated hydrogen peroxide transport is required for NF-kappaB signalling in keratinocytes and development of psoriasis. AB - Aquaporin 3 (AQP3), a water/glycerol channel protein, has been found to transport hydrogen peroxide (H2O2). Here, we show that H2O2, imported via AQP3, is involved in nuclear factor-kappaB (NF-kappaB) signalling in keratinocytes and in the pathogenesis of psoriasis. IL-23-mediated induction of psoriasis is reduced in AQP3 knockout mice (AQP3(-/-)), and is accompanied by impaired NF-kappaB activation and intracellular H2O2 accumulation. In primary keratinocyte cultures, cellular import of H2O2 produced by membrane NADPH oxidase 2 (Nox2) in response to TNF-alpha is facilitated by AQP3 and required for NF-kappaB activation by regulation of protein phosphatase 2A. As AQP3 associates with Nox2, we propose that this interplay constitutes H2O2-mediated signalling in response to TNF-alpha stimulation. Collectively, these data indicate that AQP3-facilitated H2O2 transport is required for NF-kappaB activation in keratinocytes in the development of psoriasis. PMID- 26100670 TI - Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf DAPK Complex by Raf Inhibitor Combination Therapy. AB - Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf(S338)) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK(S308)), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF(C-Raf-/-) or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK(S308), this drug target interaction compromised the mitochondrial targeting effect of the N terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf(S338) and pDAPK(S308) translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK(S308) to DAPK. PP2A then dissociated from the C-Raf DAPK complex and induced profound cancer cell death. Increased pDAPK(S308) modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK(S308) may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. PMID- 26100671 TI - Tumor-Specific Effector CD8+ T Cells That Can Establish Immunological Memory in Humans after Adoptive Transfer Are Marked by Expression of IL7 Receptor and c myc. AB - The optimal T-cell attributes for adoptive cancer immunotherapy are unclear. Recent clinical trials of ex vivo-expanded tumor-infiltrating lymphocytes indicated that differentiated T effector cells can elicit durable antitumor responses in some patients with cancer, with their antitumor activity tightly correlated with their persistence in the host. Thus, there is great interest in the definition of intrinsic biomarkers that can predict the conversion of short lived tumor antigen-specific T effector cells into long-lived T memory cells. Long-term persistence of ex vivo-expanded tumor-specific CD8+ T effector clones has been reported in refractory metastatic melanoma patients after adoptive T cell transfer. By using highly homogeneous clone populations from these preparations, we performed a comparative transcriptional profiling to define preinfusion molecular attributes that can be ascribed to an effector-to-memory transition. Through this route, we discovered that preinfusion T-cell clones that expressed the IL7 receptor (IL7R) and c-myc were more likely to persist longer after adoptive transfer to patients. The predictive value of these two biomarkers was strengthened by using IL7R protein, IL7-induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor-specific T effector clones capable of engraftment into immunodeficient mice. Overall, our findings reveal IL7R and c-myc expression as intrinsic biomarkers that can predict the fate of CD8+ T effector cells after adoptive transfer. PMID- 26100672 TI - CASC15-S Is a Tumor Suppressor lncRNA at the 6p22 Neuroblastoma Susceptibility Locus. AB - Chromosome 6p22 was identified recently as a neuroblastoma susceptibility locus, but its mechanistic contributions to tumorigenesis are as yet undefined. Here we report that the most highly significant single-nucleotide polymorphism (SNP) associations reside within CASC15, a long noncoding RNA that we define as a tumor suppressor at 6p22. Low-level expression of a short CASC15 isoform (CASC15-S) associated highly with advanced neuroblastoma and poor patient survival. In human neuroblastoma cells, attenuating CASC15-S increased cellular growth and migratory capacity. Gene expression analysis revealed downregulation of neuroblastoma specific markers in cells with attenuated CASC15-S, with concomitant increases in cell adhesion and extracellular matrix transcripts. Altogether, our results point to CASC15-S as a mediator of neural growth and differentiation, which impacts neuroblastoma initiation and progression. PMID- 26100673 TI - A structural model for facultative anion channels in an oligomeric membrane protein: the yeast TRK (K(+)) system. AB - TRK transporters, a class of proteins which generally carry out the bulk of K(+) accumulation in plants, fungi, and bacteria, mediate ion currents driven by the large membrane voltages (-150 to -250 mV) common to non-animal cells. Bacterial TRK proteins resemble K(+) channels in their primary sequence, crystallize as membrane dimers having intramolecular K(+)-channel-like folding, and complex with a cytoplasmic collar formed of four RCK domains (Nature 471:336, 2011; Ibid 496:324, 2013). Fungal TRK proteins appear simpler in form than the bacterial members, but do possess two special features: a large built-in regulatory domain, and a highly conserved pair of transmembrane helices (TM7 and TM8, ahead of the C terminus), which were postulated to facilitate intramembranal oligomerization (Biophys. J. 77:789, 1999; FEMS Yeast Res. 9:278, 2009). A surprising associated functional process in the fungal proteins which have been explored (Saccharomyces, Candida, and Neurospora) is facilitation of channel-like chloride efflux. That process is suppressed by osmoprotective agents, appears to involve hydrophobic gating, and strongly resembles conduction by Cys-loop ligand-gated anion channels. And it leads to a rather general hypothesis: that the thermodynamic tendency for hydrophobic or amphipathic transmembrane helices to self-organize into oligomers can create novel ionic pathways through biological membranes: fundamental hydrophobic nanopores, pathways of low selectivity governed by the chaotropic behavior of individual ionic species and under the strong influence of membrane voltage. PMID- 26100675 TI - Long-term temporal variability of the radon-222 exhalation flux from a landform covered by low uranium grade waste rock. AB - Radon-222 exhalation flux densities from two different substrates of several metres thickness, waste rock and waste rock mixed with approximately 30% lateritic material, were measured over a period of five years in the wet-dry tropics of Northern Australia. Fourteen measurement campaigns using activated charcoal canisters (n > 1000) covered both dry and wet seasons and showed differences in seasonal and long term trends of the (222)Rn exhalation flux densities normalised to the (226)Ra activity concentrations of the substrate. Dry season (222)Rn exhalation was generally higher for the mixed substrate, due to the larger fraction of fines. Seasonality established within the first year of landform construction on the mixed substrate, due to the higher water holding capacity of the lateritic material. In contrast, waste rock only shows no seasonality until years four and five after construction, when average normalised dry season (222)Rn exhalation flux densities from waste rock increase to values (0.47 +/- 0.06 mBq m(-2) s(-1) per Bq kg(-1)) similar to the mixed substrate (0.64 +/- 0.08 mBq m(-2) s(-1) per Bq kg(-1)), likely due to an increase in fines from rapid weathering of the schistose waste rock. Volumetric water content has been used to parametrize relative (222)Rn exhalation and we determined that wet season (222)Rn exhalation is about 40% of the dry season exhalation. PMID- 26100674 TI - Ca(2+) clearance by plasmalemmal NCLX, Li(+)-permeable Na(+)/Ca(2+) exchanger, is required for the sustained exocytosis in rat insulinoma INS-1 cells. AB - Na(+)/Ca(2+) exchangers are key players for Ca(2+) clearance in pancreatic beta cells, but their molecular determinants and roles in insulin secretion are not fully understood. In the present study, we newly discovered that the Li(+) permeable Na(+)/Ca(2+) exchangers (NCLX), which were known as mitochondrial Na(+)/Ca(2+) exchangers, contributed to the Na(+)-dependent Ca(2+) movement across the plasma membrane in rat INS-1 insulinoma cells. Na(+)/Ca(2+) exchange activity by NCLX was comparable to that by the Na(+)/Ca(2+) exchanger, NCX. We also confirmed the presence of NCLX proteins on the plasma membrane using immunocytochemistry and cell surface biotinylation experiments. We further investigated the role of NCLX on exocytosis function by measuring the capacitance increase in response to repetitive depolarization. Small interfering (si)RNA mediated downregulation of NCLX did not affect the initial exocytosis, but significantly suppressed sustained exocytosis and recovery of exocytosis. XIP (NCX inhibitory peptide) or Na(+) replacement for inhibiting Na(+)-dependent Ca(2+) clearance also selectively suppressed sustained exocytosis. Consistent with the idea that sustained exocytosis requires ATP-dependent vesicle recruitment, mitochondrial function, assessed by mitochondrial membrane potential (DeltaPsi), was impaired by siNCLX or XIP. However, depolarization-induced exocytosis was hardly affected by changes in intracellular Na(+) concentration, suggesting a negligible contribution of mitochondrial Na(+)/Ca(2+) exchanger. Taken together, our data indicate that Na(+)/Ca(2+) exchanger-mediated Ca(2+) clearance mediated by NCLX and NCX is crucial for optimizing mitochondrial function, which in turn contributes to vesicle recruitment for sustained exocytosis in pancreatic beta-cells. PMID- 26100676 TI - Protective effect of cholesterol-loaded cyclodextrin pretreatment against hydrogen peroxide induced oxidative damage in ram sperm. AB - Three experiments were conducted to determine the protective effect of cholesterol-loaded cyclodextrin (CLC) against hydrogen peroxide (H2O2) or cryo induced damage in ram sperm. In Experiment 1, the fresh ejaculates were either treated with CLC or remained untreated. Both CLC treated and untreated samples were then incubated with 0, 250 or 500 MUM H2O2 at 35 degrees C for 12 h. After incubation period of 12 h, the motility, viability and membrane integrity remained higher in CLC treated sperm even in the presence of 250 or 500 MUM H2O2. The H2O2 treatment affected all the sperm parameters adversely (P<0.05). However, compared to CLC untreated counterpart, the motility, viability and membrane integrity remained higher (P<0.05) in treated sperm, even in the presence of 250 or 500 MUM H2O2 during 12 h of incubation. In Experiment 2, semen was cryopreserved in the presence or absence of CLC. The post-thaw results revealed that CLC treated sperm has higher (P<0.05) motility, viability and membrane integrity compared to the control. In Experiment 3, lipid peroxidation levels were assessed by determining malondialdehyde (MDA) concentrations during the H2O2 induced oxidative stress in CLC treated and untreated sperm. However, no difference (P>0.05) in MDA level was observed among the groups at any stage of incubation. In conclusion, the CLC incorporation in ram sperm membrane may protects it against H2O2 or cryo-induced oxidative damage. The cryoprotective influence of CLC on ram sperm might be resulted from, at least partly, its antioxidative property. PMID- 26100677 TI - Individual contributions of visceral fat and total body fat to subclinical atherosclerosis: The NEO study. AB - BACKGROUND: Both overall and abdominal adiposity are established risk factors for cardiovascular disease. Visceral adipose tissue (VAT) and total body fat (TBF) are strongly correlated and previous studies did not make this distinction. OBJECTIVE: We aimed to distinguish individual contributions of TBF, VAT, and the ratio of VAT to abdominal subcutaneous adipose tissue (VAT/SAT) to subclinical atherosclerosis in men and women. METHODS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, we assessed VAT and SAT with magnetic resonance imaging, TBF with bio-electrical impendence analysis, and carotid Intima-Media Thickness (cIMT) with ultrasound. We performed linear regression analyses of standardized values of TBF, VAT, VAT/SAT with cIMT. We adjusted the models for confounding factors (age, sex, ethnicity, education, smoking, alcohol, physical activity), and either for VAT or TBF. RESULTS: This analysis included 2451 participants, 53% men with mean (SD) cIMT of 615 (91)MUm. After adjustment for confounding factors, the difference in cIMT (95% CI) per SD in VAT was 14 (8,21)MUm in men and 18 (13,24)MUm in women. After adjustment for TBF, this attenuated to 5 (-3,13)MUm in men and 13 (5,20)MUm in women. In the full model, differences in cIMT (95% CI) per SD of TBF were 14 (6,22)MUm in men and 8 (0,16)MUm in women, and per SD of VAT/SAT were 7 (-1,15)MUm and 9 (3,16)MUm respectively. CONCLUSIONS: In this population-based study, VAT contributed beyond overall adiposity to subclinical atherosclerosis, particularly in women. This implies a specific role of VAT in the early development of atherosclerosis. PMID- 26100678 TI - Interaction between periodontal disease and atherosclerotic vascular disease- Fact or fiction? AB - C-reactive protein (CRP) level is associated with the 10-year risk of an atherosclerotic vascular disease (ASVD), suggesting presence of systemic inflammation probably long before ASVD is present. Where, however, does this systemic inflammation come from? One active area of research has been the study of dental infection and various forms of periodontal disease (PD), both of which are highly prevalent in populations at risk for ASVD. Recent data show that ASVD and PD interact with each other via systemic release of specific pro- and anti inflammatory cytokines, small signal molecules and enzymes which modulate initiation and progression of the chronic inflammatory reaction involved in both diseases. In addition, periodontal pathogens were identified within atherosclerotic lesions and thrombi isolated from myocardial infarction patients. LDL cholesterol, a strong risk factor for ASVD, is also associated with PD; and statins, used to treat ASVD, are also active to prevent or reduce PD. Finally, there is growing evidence for common genetic susceptibility factors involved in both diseases. These findings support commonalities with respect to the pathogenic mechanisms involved in both inflammatory diseases. Conversely, a causative relationship cannot yet be concluded in the absence of data from large longitudinal cohort and randomized controlled intervention trials. PMID- 26100679 TI - TRIF adaptor signaling is important in abdominal aortic aneurysm formation. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-beta (TRIF), could inhibit the inflammatory response and AAA development in mice. RESULTS: In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/ )Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE( /-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE( /-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P < 0.05), CD11b (P < 0.05), and TNF-alpha (P < 0.05) and the protease gene MMP-12 (P < 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII. CONCLUSION: Our results suggest that signaling through TRIF is important for the inflammatory response of AngII induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation. PMID- 26100680 TI - Psychological stress impairs ischemia-induced neovascularization: Protective effect of fluoxetine. AB - BACKGROUND: Psychological stress (PS) has been associated with the development of cardiovascular diseases and adverse long-term outcomes after ischemic events. However, the precise mechanisms involved are not completely understood. Here we investigated the effect of PS on ischemia-induced neovascularization, and the potential therapeutic effect of fluoxetine in this condition. METHODS AND RESULTS: Balb/c mice were subjected or not to chronic restraint stress. After 3 weeks, hindlimb ischemia was surgically induced by femoral artery removal. We found that blood flow recovery was significantly impaired in mice exposed to PS compared to controls (Doppler flow ratio (DFR) 0.61 +/- 0.07 vs. 0.80 +/- 0.07, p < 0.05). At the microvascular level, capillary density was significantly reduced in ischemic muscles of mice exposed to PS (38 +/- 1 vs. 74 +/- 3 capillaries per field, p < 0.001). This correlated with increased oxidative stress levels and reduced expression of VEGF and VEGF signalling molecules (p44/p42 MAPK, Akt) in ischemic muscles. We found that the number of pro-angiogenic cells (PACs) was significantly reduced in mice exposed to PS. In addition, oxidative stress levels (DCF-DA, DHE) were increased in PACs isolated from mice exposed to PS, and this was associated with impaired PAC functional activities (migration, adhesion, and integration into tubules). Importantly, treatment of mice exposed to PS with the selective serotonin reuptake inhibitor (SSRI) fluoxetine improved all the angiogenic parameters, and completely rescued PS-induced impairment of neovascularization. CONCLUSION: PS impairs ischemia-induced neovascularization. Potential mechanisms involved include reduced activation of the VEGF pathway in ischemic tissues, increased oxidative stress levels and reduced number and functional activities of PACs. Our results suggest that fluoxetine may represent a novel therapeutic strategy to improve neovascularization and reduce ischemia in patients suffering from cardiovascular diseases and exposed to PS. PMID- 26100681 TI - A Forward Genetic Screen for Suppressors of Somatic P Granules in Caenorhabditis elegans. AB - In Caenorhabditis elegans, germline expression programs are actively repressed in somatic tissue by components of the synMuv (synthetic multi-vulva) B chromatin remodeling complex, which include homologs of tumor suppressors Retinoblastoma (Rb/LIN-35) and Malignant Brain Tumor (MBT/LIN-61). However, the full scope of pathways that suppress germline expression in the soma is unknown. To address this, we performed a mutagenesis and screened for somatic expression of GFP tagged PGL-1, a core P-granule nucleating protein. Eight alleles were isolated from 4000 haploid genomes. Five of these alleles exhibit a synMuv phenotype, whereas the remaining three were identified as hypomorphic alleles of known synMuv B genes, lin-13 and dpl-1. These findings suggest that most suppressors of germline programs in the soma of C. elegans are either required for viability or function through synMuv B chromatin regulation. PMID- 26100682 TI - The potential of 3-dimensional construct engineered from poly(lactic-co-glycolic acid)/fibrin hybrid scaffold seeded with bone marrow mesenchymal stem cells for in vitro cartilage tissue engineering. AB - Articular cartilage is well known for its simple uniqueness of avascular and aneural structure that has limited capacity to heal itself when injured. The use of three dimensional construct in tissue engineering holds great potential in regenerating cartilage defects. This study evaluated the in vitro cartilaginous tissue formation using rabbit's bone marrow mesenchymal stem cells (BMSCs)-seeded onto poly(lactic-co-glycolic acid) PLGA/fibrin and PLGA scaffolds. The in vitro cartilaginous engineered constructs were evaluated by gross inspection, histology, cell proliferation, gene expression and sulphated glycosaminoglycan (sGAG) production at week 1, 2 and 3. After 3 weeks of culture, the PLGA/fibrin construct demonstrated gross features similar to the native tissue with smooth, firm and glistening appearance, superior histoarchitectural and better cartilaginous extracellular matrix compound in concert with the positive glycosaminoglycan accumulation on Alcian blue. Significantly higher cell proliferation in PLGA/fibrin construct was noted at day-7, day-14 and day-21 (p<0.05 respectively). Both constructs expressed the accumulation of collagen type II, collagen type IX, aggrecan and sox9, showed down-regulation of collagen type I as well as produced relative sGAG content with PLGA/fibrin construct exhibited better gene expression in all profiles and showed significantly higher relative sGAG content at each time point (p<0.05). This study suggested that with optimum in vitro manipulation, PLGA/fibrin when seeded with pluripotent non committed BMSCs has the capability to differentiate into chondrogenic lineage and may serve as a prospective construct to be developed as functional tissue engineered cartilage. PMID- 26100683 TI - Association of Interleukin-10 promoter polymorphisms with neurosyphilis. AB - Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine. Increased production of IL-10 has been found in late syphilis, presumably creating favorable conditions for bacteria persistence. Single-nucleotide polymorphisms (SNPs) within the promoter of IL-10 gene have been found to influence IL-10 production. We investigated whether SNPs in the IL-10 gene promoter are associated with cerebrospinal fluid (CSF) levels of IL-10 and neurosyphilis. Polymorphisms in the gene for IL-10 (G->A mutation at the position -1084 and C->A mutation at the position -592) were sought in 35 patients with syphilis and 24 healthy volunteers. CSF examination (i.e. routine laboratory tests and IL-10 levels) was performed in all syphilis patients. Neurosyphilis was defined as reactive CSF VDRL test or CSF white blood cells?5/MUL and CSF protein concentration?45mg/dL. Overall, 31% of patients with syphilis had neurosyphilis. CSF IL-10 levels were significantly higher in patients with neurosyphilis when compared to those with syphilis but not neurosyphilis. -1082 GG and -592 CC genotypes were significantly associated with higher CSF IL-10 levels. Moreover, these genotypes were found to be more frequent in individuals with neurosyphilis in comparison to those without neurosyphilis. Anti-inflammatory immune response seems to be important in pathogenesis of neurosyphilis. Our data suggest that host-related factors, such as SNPs of immune regulatory genes may influence the susceptibility to neurosyphilis. PMID- 26100684 TI - The Experience Sampling Method--a new digital tool for momentary symptom assessment in IBS: an exploratory study. AB - BACKGROUND: Retrospective questionnaires are frequently used for symptom assessment in irritable bowel syndrome (IBS) patients, but are influenced by recall bias and circumstantial and psychological factors. These limitations may be overcome by random, repeated, momentary assessment during the day, using electronic Experience Sampling Methodology (ESM). Therefore, we compared symptom assessment by ESM to retrospective paper questionnaires in IBS patients. METHODS: Twenty-six IBS patients (Rome III) were included, of which 16 were diagnosed with panic disorder (DSM-IV-TR). Patients scored symptoms using end-of-day diaries during 14 days and the gastrointestinal symptom rating scale (GSRS) once. ESM was used on seven consecutive days during the same time period. KEY RESULTS: End-of day diary abdominal pain scores were 0.4 (SE 0.1, p < 0.001) point higher (on a 1 to-5-point scale) compared to corresponding ESM mean-scores in IBS patients. The difference was even more pronounced for upper abdominal pain scores assessed by the GSRS (4.77 +/- 1.50) compared to ESM mean-scores (2.44 +/- 1.30, p < 0.001), both on 1-to-7-point scale. For flatulence, comparable results were found. Nausea and belching scores showed small, but significant differences between end-of-day diary and ESM. All tested symptoms were scored higher on GSRS compared to ESM mean-scores (p < 0.01). Affective comorbidity did not influence differences in pain reporting between methods. CONCLUSIONS & INFERENCES: IBS patients report higher scores for abdominal pain in retrospective questionnaires compared to ESM, with a tendency to report peak rather than average pain scores. ESM can provide more insight in symptom course and potential triggers, and may lead to a better understanding of IBS symptomatology. PMID- 26100685 TI - Prevention of Serum Albumin Glycation/Fibrillation by beta-Cyclodextrin Functionalized Magnetic Nanoparticles. AB - Nowadays, glycation induced protein aggregation and related opposing strategies have received much attention. We present the effect of functionalized magnetic core-shell nanoparticles of Fe3O4 (MNPs) with beta-cyclodextrin (beta-CD) on the aggregation/fibrillation of bovine serum albumin (BSA) under diabetic condition known as amyloidogenesis. To confirm the beta-CD conjugation on MNP, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM) methods were applied. Moreover, spectrofluorimetry and spectropolarimetry were utilized to analyze the effect of beta-CD/Fe3O4 MNPs on the aggregation and amyloidogenesis of BSA through glycation. The BSA amyloidogenesis was significantly inhibited by interfering beta-CD-MNPs that may present the possible diagnostic and preventive applications against the degenerative effects of protein glycation/fibrillation under diabetes. PMID- 26100686 TI - Unfolding and Refolding Study of a Large Dimeric Protein beta-Glucosidase from Almond Monitored by Fluorescence Spectroscopy. AB - In our present investigation, the unfolding and refolding of beta-glucosidase (BGL-Al) from sweet almond was investigated using tryptophan (Trp) fluorescence spectroscopy. When the unfolding of BGL-Al was induced by guanidium chloride (GdnHCl) and monitored using biological activity as well as Trp fluorescence spectroscopic measurement, we observed that the denaturation of BGL-Al could be easily induced by low concentration of GdnHCl and the enzyme was completely inactivated at 1.0 M GdnHCl. Higher unfolding in the presence of reducing agent revealed that the protein perhaps containing multiple di-sulfide bonds indicating a reason of high stability against unfolding by GdnHCl. Refolding results suggested that the protein refolded with high yield from 1 M GdnHCl denatured state, however, refolded with negligible yield from completely unfolded state. The kinetic studies of BGL-Al refolding unravel a two phase refolding process with calculated t1/2 (refolding half time) of 1.8 and 33 min, respectively. When 8-Anilino-1-naphthalenesulfonic acid (ANS) was used as extrinsic fluorophore, we found that the surface hydrophobicity of BGL-Al was continuously decreased during GdnHCl-mediated unfolding. The surface hydrophobicity of the protein was calculated to be as high as 128.32. Acrylamide quenching study demonstrated that Trp residues of BGL-Al are mostly and hence they must be located either on the surface or in the crevices accessible by quenchers. PMID- 26100687 TI - Recapturing the Correlated Motions of Protein Using Coarse- Grained Models. AB - Long-range interactions and allostery are important for many biological processes. Increasing numbers of studies, both experimental and computational, show that internal dynamics may play an important role in such behaviors. Investigating the dynamical effects of proteins, how- ever, is a challenging problem using all-atom molecular dynamics because of the length-scales and timescales involved. As a result, coarse-grained models are often implemented. Herein, we use three well-defined coarse-grained models: Go, Martini and Cafemol, and a small model protein Eglin C, which is readily studied via all-atom molecular dynamics, to examine if these coarse grained models can explore the dynamics of Eglin C accurately as well as to see how these models respond to mutations. We found that all three models can recapture the dynamics of Eglin C to a significant extent - where we focus on root-mean square fluctuations and correlated motions as dynamical measures - but that the Cafemol and Go models are superior. The best agreement with all-atom simulations is for structured regions of Eglin C. PMID- 26100688 TI - Assessing the influence of artificially constructed channels in the growth of afforested black mangrove (Avicennia germinans) within an arid coastal region. AB - Hypersaline conditions are common in sub-tropical latitudes where freshwater availability is seasonal. Hence, hydroperiod plays a crucial role in providing a suitable area for the establishment of new mangrove seedlings. The purpose of this study was to assess the function of hydrological change and irradiance in the growth of afforested black mangrove (Avicennia germinans) along the upper saltpan area by creating six channels of 1 m wide by 0.3 deep and 30 m length. All channels were constructed perpendicular to the main coastline of the Urias lagoon, Pacific coast of Mexico. Seedlings of black mangrove were planted along four of the channels. After ten months, the pore-water salinity concentration within the six channels was reduced by half. Results indicate that there were no significant differences (P > 0.05) in mangrove survival among the channels. However, the optimal growth of black mangroves was near the channels edge. The growth of mangrove seedlings planted under 50% of solar attenuation was 10 times higher as compared to mangroves under direct sunlight. This study shows the feasibility of using channels to enhance tidal flow and decrease hypersaline conditions for future afforestation endeavors in arid coastlines. PMID- 26100689 TI - N2O emissions and nitrogen transformation during windrow composting of dairy manure. AB - Windrow composting involves piling and regularly turning organic wastes in long rows, being in the succession of static standing periods between two consecutive pile turnings as well as a period of pile turning. N2O emissions and N transformation were investigated during the processes of windrow composting. In contrast to the conventional understanding, we observed that N2O concentrations inside compost materials were significantly higher after pile turning (APT) than before pile turning (BPT). Pile turning triggered a burst of N2O production rather than simple gaseous N2O escape from the stirred compost. Denitrification was the dominant pathway in pile turning because the observed [Formula: see text] and [Formula: see text] concentrations were significantly lower APT compared to BPT. The sudden exposure of O2 severely inhibited N2O reductase, which can block the transformation of N2O to N2 and thus caused an increase of N2O emission. As the [Formula: see text] and [Formula: see text] concentrations rose during the following 48 standing hours, nitrification dominated N transformation and did not cause an increase of surface N2O emissions. Thus, pile turning resulted in a dramatic conversion of N transformation and strongly influenced its flux size. It was also found that high [Formula: see text] was accumulated in the compost and had a strong correlation with N2O emissions. Practical methods regulating nitrite and the frequency of pile turning would be useful to mitigate N2O emissions in manure composting. PMID- 26100690 TI - Pectus excavatum: Benefit of randomization. AB - BACKGROUND: Minimally invasive bar repair for pectus patients produces substantial pain which dictates the post-operative hospital course. We have data from 2 randomized trials comparing epidural catheter placement to patient controlled analgesia. The purpose of this study was to compare the outcomes of patients who were enrolled in the trials to those that did not participate in the trials. METHODS: A retrospective chart review was performed on patients not enrolled in the trials to compare to the prospective datasets from October 2006 to June 2014. Perioperative outcomes were examined. RESULTS: There were 135 patients in a study protocol (IS) and 195 patients that were not enrolled in a study (OS). Comparing the entire IS and OS groups, length of stay was less in the IS group, as was time to regular diet. Average pain scores, operative time and complication rates were not significantly different between the groups. Of the IS patients a significantly lower number of patients had epidural failure, requiring substitution of a PCA for pain control. CONCLUSIONS: There are benefits derived from participating in our randomized trials comparing epidural to patient controlled analgesia after bar placement for pectus excavatum regardless of which arm is utilized. PMID- 26100691 TI - The first 100 infant thoracoscopic lobectomies: Observations through the learning curve and comparison to open lobectomy. AB - OBJECTIVE: The objective of the study is to describe our initial 100 attempted infant thoracoscopic lobectomies for asymptomatic, prenatally diagnosed lung lesions, and compare the results to contemporaneous age-matched patients undergoing open lobectomy. BACKGROUND: Infant thoracoscopic lobectomy is a technically challenging procedure, which has only gained acceptance worldwide in recent years. METHODS: This is a retrospective review of all patients undergoing thoracoscopic or open lung lobectomy between March 2005 and January 2014. Included were all asymptomatic infants younger than 4months. Excluded were patients undergoing emergent lobectomy and patients with isolated extralobar bronchopulmonary sequestrations. RESULTS: A total of 100 attempted thoracoscopic lobectomies were compared with 188 open lobectomies. In the thoracoscopic group, mean age and weight at surgery were 7.3weeks and 4.8kg, mean operative time was 185minutes, and mean hospital stay was 3days. Twelve cases were converted to open (12%). Ten conversions occurred within the first third of the series and none in the last third. There were no mortalities. There were no differences between the thoracoscopic and open groups in perioperative complications or hospital stay. There was a significant difference in the operative time: 111minutes vs. 185minutes (open vs. thoracoscopic; p<0.001). There was a higher mean end-tidal carbon dioxide (ETCO2) and lower mean peripheral capillary oxygen saturation (SpO2) in the thoracoscopic group versus the open group (51.7 versus 38.6mmHg and 97.5 versus 99.1%, respectively). CONCLUSION: In high volume centers, the learning curve of thoracoscopic lobectomy can be overcome and the procedure can be performed with equivalent outcomes and, in our opinion, superior cosmetic results to open lobectomy. PMID- 26100692 TI - Ultrasonography-guided central venous port placement with subclavian vein access in pediatric oncology patients. AB - BACKGROUND/PURPOSE: To evaluate the technical success and complications of image guided central venous port (CVP) placement with subclavian vein (SCV) access in pediatric oncology population. MATERIALS AND METHODS: Ninety-two children (52 boys, 40 girls; mean age, 8.5 years) underwent CVP implantation under local anesthesia with conscious sedation. SCV access was firstly attempted under ultrasonographic guidance and CVP implantation was performed under fluoroscopic guidance. Technical success, peri-procedural (<24h) complication, and post procedural (>24h) complication were assessed. RESULTS: In total, 102 CVPs were implanted in 92 children with a mean catheter time of 364 days (total, 38,224 days; range, 14-1911 days). In three small children, conversion of SCV access to internal jugular vein access yielded a primary technical success rate of 97.1% and overall technical success rate of 100%. Three minor peri-procedural complications were observed (2.9%) and seven post-procedural infectious complications occurred (infection rate, 6.7%; 0.18/1000 catheter days). No pneumothorax, catheter malposition, venous thrombosis, or mortality occurred. CONCLUSION: Image-guided CVP placement with SCV access in a pediatric population was performed with high technical success and low complication rate without general anesthesia. This procedure can be taken into account as a choice of procedure when internal jugular venous access is not possible. PMID- 26100693 TI - Complete sequence of the multidrug-resistant IncL/M plasmid pIMP-HB623 Cocarrying bla IMP-34 and fosC2 in an Enterobacter cloacae strain associated with medical travel to China. PMID- 26100694 TI - A novel point mutation promotes growth phase-dependent daptomycin tolerance in Staphylococcus aureus. AB - Recalcitrance of genetically susceptible bacteria to antibiotic killing is a hallmark of bacterial drug tolerance. This phenomenon is prevalent in biofilms, persisters, and also planktonic cells and is associated with chronic or relapsing infections with pathogens such as Staphylococcus aureus. Here we report the in vitro evolution of an S. aureus strain that exhibits a high degree of nonsusceptibility to daptomycin as a result of cyclic challenges with bactericidal concentrations of the drug. This phenotype was attributed to stationary growth phase-dependent drug tolerance and was clearly distinguished from resistance. The underlying genetic basis was revealed to be an adaptive point mutation in the putative inorganic phosphate (Pi) transporter gene pitA. Drug tolerance caused by this allele, termed pitA6, was abrogated when the upstream gene pitR was inactivated. Enhanced tolerance toward daptomycin, as well as the acyldepsipeptide antibiotic ADEP4 and various combinations of other drugs, was accompanied by elevated intracellular concentrations of Pi and polyphosphate, which may reversibly interfere with critical cellular functions. The evolved strain displayed increased rates of survival within human endothelial cells, demonstrating the correlation of intracellular persistence and drug tolerance. These findings will be useful for further investigations of S. aureus drug tolerance, toward the development of additional antipersister compounds and strategies. PMID- 26100695 TI - Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824 resistant mutants of Mycobacterium tuberculosis. AB - Alleviating the burden of tuberculosis (TB) requires an understanding of the genetic basis that determines the emergence of drug-resistant mutants. PA-824 (pretomanid) is a bicyclic nitroimidazole class compound presently undergoing the phase III STAND clinical trial, despite lacking identifiable genetic markers for drug-specific resistant Mycobacterium tuberculosis. In the present study, we aimed to characterize the genetic polymorphisms of spontaneously generated PA-824 resistant mutant strains by surveying drug metabolism genes for potential mutations. Of the 183 independently selected PA-824-resistant M. tuberculosis mutants, 83% harbored a single mutation in one of five nonessential genes associated with either PA-824 prodrug activation (ddn, 29%; fgd1, 7%) or the tangential F420 biosynthetic pathway (fbiA, 19%; fbiB, 2%; fbiC, 26%). Crystal structure analysis indicated that identified mutations were specifically located within the protein catalytic domain that would hinder the activity of the enzymes required for prodrug activation. This systematic analysis conducted of genotypes resistant to PA-824 may contribute to future efforts in monitoring clinical strain susceptibility with this new drug therapy. PMID- 26100696 TI - AbaR-type genomic islands in non-baumannii Acinetobacter species isolates from South Korea. AB - To investigate the presence and structure of AbaR-type genomic islands (GIs) in non-Acinetobacter baumannii isolates, a total of 155 non-baumannii Acinetobacter isolates from a South Korean hospital were analyzed. GIs were found in three Acinetobacter nosocomialis and two Acinetobacter seifertii isolates. Their structures were similar to those in A. baumannii isolates from Asian countries, including South Korea. The existence of AbaR-type GIs in non-baumannii Acinetobacter isolates is believed to be due to interspecies transfer of GI. PMID- 26100697 TI - Prolonged entecavir therapy is not effective for HBeAg seroconversion in treatment-naive chronic hepatitis B patients with a partial virological response. AB - The aims of this study were to investigate the efficacy of prolonged entecavir (ETV) therapy in treatment-naive chronic hepatitis B (CHB) patients and to determine whether continuous ETV therapy is feasible to achieve HBeAg seroconversion, particularly in patients with partial virological response (PVR). A total of 142 treatment-naive patients with CHB were enrolled. The mean duration of treatment was 65 (range, 26 to 90) months, and 86 patients (60.6%) were HBeAg positive. PVR was defined as detectable hepatitis B virus (HBV) DNA (>116 copies/ml) at year 1. The cumulative incidence of virological response (VR) increased from 54.9% at year 1 to 98.2% at year 7. HBeAg positivity (odds ratio [OR], 4.146; P = 0.001) and initial alanine aminotransferase (ALT) (OR, 0.997; P = 0.004) were independent risk factors for PVR. Among the 64 patients with PVR, 47 patients (73.4%) achieved VR within 4 years after prolonged ETV therapy without treatment adaptation. Three patients (2.1%) experienced virological breakthrough and HBV variants with genotypic resistance. The cumulative rate of HBeAg seroconversion was significantly higher in the patients with VR than in the patients with PVR (P = 0.018). None of the PVR patients with HBV DNA at >=5,000 copies/ml at year 1 ever experienced HBeAg seroconversion. Multivariate analysis identified VR at year 1 as the only determinant of HBeAg seroconversion (hazard ratio [HR], 3.009; P = 0.010). In conclusion, although there were patients with PVR, prolonged ETV therapy showed excellent VR, with only 2.1% emergence of viral resistance during a 7-year follow-up. However, to achieve HBeAg seroconversion, drug modification is needed for HBeAg-positive patients with PVR (especially those with HBV DNA at >=5,000 copies/ml at year 1). PMID- 26100698 TI - In vitro activities of a wide panel of antifungal drugs against various Scopulariopsis and Microascus species. AB - The in vitro activities of 11 antifungal drugs against 68 Scopulariopsis and Microascus strains were investigated. Amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole, and ciclopirox showed no or poor antifungal effect. The best activities were exhibited by terbinafine and caspofungin, where the MIC and MEC (minimal effective concentration) ranges were 0.0313 to >16 MUg/ml and 0.125 to 16 MUg/ml, respectively. The MIC and MEC modes were both 1 ug/ml for terbinafine and caspofungin; the MIC50 and MEC50 were 1 ug/ml for both drugs, whereas the MIC90 and MEC90 were 4 ug/ml and 16 ug/ml, respectively. PMID- 26100699 TI - Correlation between GyrA substitutions and ofloxacin, levofloxacin, and moxifloxacin cross-resistance in Mycobacterium tuberculosis. AB - The newer fluoroquinolones moxifloxacin (MXF) and levofloxacin (LVX) are becoming more common components of tuberculosis (TB) treatment regimens. However, the critical concentrations for testing susceptibility of Mycobacterium tuberculosis to MXF and LVX are not yet well established. Additionally, the degree of cross resistance between ofloxacin (OFX) and these newer fluoroquinolones has not been thoroughly investigated. In this study, the MICs for MXF and LVX and susceptibility to the critical concentration of OFX were determined using the agar proportion method for 133 isolates of M. tuberculosis. Most isolates resistant to OFX had LVX MICs of >1 MUg/ml and MXF MICs of >0.5 MUg/ml. The presence of mutations within the gyrA quinolone resistance-determining regions (QRDR) correlated well with increased MICs, and the level of LVX and MXF resistance was dependent on the specific gyrA mutation present. Substitutions Ala90Val, Asp94Ala, and Asp94Tyr resulted in low-level MXF resistance (MICs were >0.5 but <=2 MUg/ml), while other mutations led to MXF MICs of >2 MUg/ml. Based on these results, a critical concentration of 1 MUg/ml is suggested for LVX and 0.5 MUg/ml for MXF drug susceptibility testing by agar proportion with reflex testing for MXF at 2 MUg/ml. PMID- 26100700 TI - Innate inflammatory response and immunopharmacologic activity of micafungin, caspofungin, and voriconazole against wild-type and FKS mutant Candida glabrata isolates. AB - The direct or indirect interactions that antifungals have with the host immune response may play a significant role in defining their activity in vivo. However, the impact that acquired antifungal resistance has on the immunopharmacologic activity of antifungals is not well described. We assessed the immunopharmacologic activity of caspofungin, micafungin, and voriconazole among isolates of Candida glabrata with or without FKS-mediated echinocandin resistance. Clinical bloodstream isolates of C. glabrata from patients who did (n = 5) or did not (n = 3) develop persistent candidemia and who did (n = 2) or did not (n = 11) harbor FKS gene mutations were included. A cell-based assay was used to compare differences in macrophage activation among isolates when grown in the presence or absence of subinhibitory concentrations of caspofungin, micafungin, or voriconazole. In the absence of antifungals, macrophage activation was significantly lower for index C. glabrata isolates obtained from persistent candidemia patients than for those from nonpersistent patients (33% versus 79% increase over negative controls, respectively; P < 0.01). Growth of isolates possessing wild-type FKS genes in subinhibitory concentrations of micafungin or caspofungin, but not voriconazole, significantly increased macrophage inflammatory responses compared to untreated controls (1.25- to 2.75-fold increase, P < 0.01). For isolates harboring the FKS2 hot spot 1 (HS1) S663P mutation, however, a significant increase was observed only with micafungin treatment (1.75-fold increase versus negative control, P < 0.01). Macrophage activation correlated with the level of unmasking of beta-glucan in the cell wall. The diminished macrophage inflammatory response to isolates that caused persistent candidemia and differential immunopharmacologic activity of echinocandins among FKS mutants suggest that certain strains of C. glabrata may have a higher propensity for immunoevasion and development of antifungal resistance during treatment. PMID- 26100701 TI - Transcription factor ADS-4 regulates adaptive responses and resistance to antifungal azole stress. AB - Azoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungal drug sensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription of ads-4 in Neurospora crassa cells increased when they were subjected to ketoconazole treatment, whereas the deletion of ads-4 resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression of ads-4 increased resistance to fluconazole and ketoconazole in N. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress in N. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of the ads-4-homologous gene Afads-4 in Aspergillus fumigatus caused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs. PMID- 26100702 TI - Differences in antibiotic-induced oxidative stress responses between laboratory and clinical isolates of Streptococcus pneumoniae. AB - Oxidants were shown to contribute to the lethality of bactericidal antibiotics in different bacterial species, including the laboratory strain Streptococcus pneumoniae R6. Resistance to penicillin among S. pneumoniae R6 mutants was further shown to protect against the induction of oxidants upon exposure to unrelated bactericidal compounds. In the work described here, we expanded on these results by studying the accumulation of reactive oxygen species in the context of antibiotic sensitivity and resistance by including S. pneumoniae clinical isolates. In S. pneumoniae R6, penicillin, ciprofloxacin, and kanamycin but not the bacteriostatic linezolid, erythromycin, or tetracycline induced the accumulation of reactive oxygen species. For the three bactericidal compounds, resistance to a single molecule prevented the accumulation of oxidants upon exposure to unrelated bactericidal antibiotics, and this was accompanied by a reduced lethality. This phenomenon does not involve target site mutations but most likely implicates additional mutations occurring early during the selection of resistance to increase survival while more efficient resistance mechanisms are being selected or acquired. Bactericidal antibiotics also induced oxidants in sensitive S. pneumoniae clinical isolates. The importance of oxidants in the lethality of bactericidal antibiotics was less clear than for S. pneumoniae R6, however, since ciprofloxacin induced oxidants even in ciprofloxacin-resistant S. pneumoniae clinical isolates. Our results provide a clear example of the complex nature of the mode of action of antibiotics. The adaptive approach to oxidative stress of S. pneumoniae is peculiar, and a better understanding of the mechanism implicated in response to oxidative injury should also help clarify the role of oxidants induced by antibiotics. PMID- 26100703 TI - Variation in resistance traits, phylogenetic backgrounds, and virulence genotypes among Escherichia coli clinical isolates from adjacent hospital campuses serving distinct patient populations. AB - Escherichia coli sequence type 13 (ST131), an emergent cause of multidrug resistant extraintestinal infections, has important phylogenetic subsets, notably the H30 and H30Rx subclones, with distinctive resistance profiles and, possibly, clinical associations. To clarify the local prevalence of these ST131 subclones and their associations with antimicrobial resistance, ecological source, and virulence traits, we extensively characterized 233 consecutive E. coli clinical isolates (July and August 2013) from the University of Minnesota Medical Center Fairview Infectious Diseases and Diagnostic Laboratory, Minneapolis, MN, which serves three adjacent facilities (a children's hospital and low- and high-acuity adult facilities). ST131 accounted for 26% of the study isolates (more than any other clonal group), was distributed similarly by facility, and was closely associated with ciprofloxacin resistance and extended-spectrum beta-lactamase (ESBL) production. The H30 and H30Rx subclones accounted for most ST131 isolates and for the association of ST131 with fluoroquinolone resistance and ESBL production. Unlike ST131 per se, these subclones were distributed differentially by hospital, being most prevalent at the high-acuity adult facility and were absent from the children's hospital. The virulence gene profiles of ST131 and its subclones were distinctive and more extensive than those of other fluoroquinolone resistant or ESBL-producing isolates. Within ST131, bla CTX-M-15 was confined to H30Rx isolates and other bla CTX-M variants to non-Rx H30 isolates. Pulsed-field gel electrophoresis documented a predominance of globally distributed pulsotypes and no local outbreak pattern. These findings help clarify the epidemiology, ecology, and bacterial correlates of the H30 and H30Rx ST131 subclones by documenting a high overall prevalence but significant segregation by facility, strong associations with fluoroquinolone resistance and specific ESBL variants, and distinctive virulence gene associations that may confer fitness advantages over other resistant E. coli. PMID- 26100704 TI - Surveillance and characterization of carbapenemase-producing Klebsiella pneumoniae recovered from patient stool samples at a tertiary care medical center. PMID- 26100705 TI - Case-control study of the risk factors for acquisition of Pseudomonas and Proteus species during tigecycline therapy. AB - Tigecycline is an important agent in clinical practice because of its broad spectrum activity. However, it has no activity against Pseudomonas or Proteus species. We conducted a case-control study to analyze risk factors for the acquisition of Pseudomonas or Proteus spp. during tigecycline therapy. Placement of suction drainage at infected wound sites, ICU stay, and neurologic disease were identified as independent risk factors for the acquisition of Pseudomonas and Proteus spp. PMID- 26100706 TI - Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model. AB - Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrug-resistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the dose-ranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC = 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (r(2) = 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1- and 2 log10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study. PMID- 26100707 TI - An in vitro combined antibiotic-antibody treatment eliminates toxicity from Shiga toxin-producing Escherichia coli. AB - Treating Shiga toxin-producing Escherichia coli (STEC) gastrointestinal infections is difficult. The utility of antibiotics for STEC treatment is controversial, since antibiotic resistance among STEC isolates is widespread and certain antibiotics dramatically increase the expression of Shiga toxins (Stxs), which are some of the most important virulence factors in STEC. Stxs contribute to life-threatening hemolytic uremic syndrome (HUS), which develops in considerable proportions of patients with STEC infections. Understanding the antibiotic resistance profiles of STEC isolates and the Stx induction potential of promising antibiotics is essential for evaluating any antibiotic treatment of STEC. In this study, 42 O157:H7 or non-O157 STEC isolates (including the "big six" serotypes) were evaluated for their resistance against 22 antibiotics by using an antibiotic array. Tigecycline inhibited the growth of all of the tested STEC isolates and also inhibited the production of Stxs (Stx2 in particular). In combination with neutralizing antibodies to Stx1 and Stx2, the tigecycline antibody treatment fully protected Vero cells from Stx toxicity, even when the STEC bacteria and the Vero cells were cultured together. The combination of an antibiotic such as tigecycline with neutralizing antibodies presents a promising strategy for future STEC treatments. PMID- 26100708 TI - Multicenter retrospective study of cefmetazole and flomoxef for treatment of extended-spectrum-beta-lactamase-producing Escherichia coli bacteremia. AB - The efficacy of cefmetazole and flomoxef (CF) for the treatment of patients with extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) bacteremia (ESBL-CF group) was compared with that of carbapenem treatment for ESBL-EC patients (ESBL-carbapenem group) and with that of CF treatment in patients with non-ESBL-EC bacteremia (non-ESBL-CF group). Adult patients treated for E. coli bacteremia in four hospitals were retrospectively evaluated. The 30-day mortality rates in patients belonging to the ESBL-CF, ESBL-carbapenem, and non-ESBL-CF groups were compared as 2 (empirical and definitive therapy) cohorts. The adjusted hazard ratios (aHRs) for mortality were calculated using Cox regression models with weighting according to the inverse probability of propensity scores for receiving CF or carbapenem treatment. The empirical-therapy cohort included 104 patients (ESBL-CF, 26; ESBL-carbapenem, 45; non-ESBL-CF, 33), and the definitive-therapy cohort included 133 patients (ESBL-CF, 59; ESBL-carbapenem, 54; non-ESBL-CF, 20). The crude 30-day mortality rates for patients in the ESBL CF, ESBL-carbapenem, and non-ESBL-CF groups were, respectively, 7.7%, 8.9%, and 3.0% in the empirical-therapy cohort and 5.1%, 9.3%, and 5.0% in the definitve therapy cohort. In patients without hematological malignancy and neutropenia, CF treatment for ESBL-EC patients was not associated with mortality compared with carbapenem treatment (empirical-therapy cohort: aHR, 0.87; 95% confidence interval [CI], 0.11 to 6.52; definitive therapy cohort: aHR, 1.04; CI, 0.24 to 4.49). CF therapy may represent an effective alternative to carbapenem treatment for patients with ESBL-EC bacteremia for empirical and definitive therapy in adult patients who do not have hematological malignancy and neutropenia. PMID- 26100709 TI - The times they are a-changin': carbapenems for extended-spectrum-beta-lactamase producing bacteria. AB - Several antimicrobial agents are being investigated as alternatives to carbapenems in the treatment of infections caused by ESBL-producing Enterobacteriaceae, which may be useful in avoiding overuse of carbapenems in the context of recent global spread of carbapenem-resistant Enterobacteriaceae. The most promising candidates for invasive infections so far are beta-lactam/beta lactamase inhibitor combinations and cephamycins. PMID- 26100710 TI - Characterization of epidemic IncI1-Igamma plasmids harboring ambler class A and C genes in Escherichia coli and Salmonella enterica from animals and humans. AB - The aim of the study was to identify the plasmid-encoded factors contributing to the emergence and spread of epidemic IncI1-Igamma plasmids obtained from Escherichia coli and Salmonella enterica isolates from animal and human reservoirs. For this, 251 IncI1-Igamma plasmids carrying various extended spectrum beta-lactamase (ESBL) or AmpC beta-lactamase genes were compared using plasmid multilocus sequence typing (pMLST). Thirty-two of these plasmids belonging to different pMLST types were sequenced using Roche 454 and Illumina platforms. Epidemic IncI1-Igamma plasmids could be assigned to various dominant clades, whereas rarely detected plasmids clustered together as a distinct clade. Similar phylogenetic trees were obtained using only the plasmid backbone sequences, showing that the differences observed between the plasmids belonging to distinct clades resulted mainly from differences between their backbone sequences. Plasmids belonging to the various clades differed particularly in the presence/absence of genes encoding partitioning and addiction systems, which contribute to stable inheritance during cell division and plasmid maintenance. Despite this, plasmids belonging to the various phylogenetic clades also showed marked resistance gene associations, indicating the circulation of successful plasmid-gene combinations. The variation in traY and excA genes found in IncI1 Igamma plasmids is conserved within pMLST sequence types and plays a role in incompatibility, although functional study is needed to elucidate the role of these genes in plasmid epidemiology. PMID- 26100711 TI - Resistance analysis of baseline and treatment-emergent variants in hepatitis C virus genotype 1 in the AVIATOR study with paritaprevir-ritonavir, ombitasvir, and dasabuvir. AB - AVIATOR, a phase 2 clinical trial, evaluated ritonavir-boosted paritaprevir (a protease inhibitor), ombitasvir (an NS5A inhibitor), and dasabuvir (a nonnucleoside polymerase inhibitor) (the three-drug [3D] regimen) with or without ribavirin (RBV) for 8, 12, or 24 weeks in 406 HCV genotype 1 (GT1)-infected patients. The rate of sustained virologic response 24 weeks after treatment ranged from 88% to 100% across the arms of the 3D regimen with or without RBV; 20 GT1a-infected patients and 1 GT1b-infected patient experienced virologic failure (5.2%). Baseline resistance-conferring variants in NS3 were rare. M28V in GT1a and Y93H in GT1b were the most prevalent preexisting variants in NS5A, and C316N in GT1b and S556G in both GT1a and GT1b were the most prevalent variants in NS5B. Interestingly, all the GT1a sequences encoding M28V in NS5A were from the United States, while GT1b sequences encoding C316N and S556G in NS5B were predominant in the European Union. Variants preexisting at baseline had no significant impact on treatment outcome. The most prevalent treatment-emergent resistance-associated variants (RAVs) in GT1a were R155K and D168V in NS3, M28T and Q30R in NS5A, and S556G in NS5B. The single GT1b-infected patient experiencing virologic failure had no RAVs in any target. A paritaprevir-ritonavir dose of 150/100 mg was more efficacious in suppressing R155K in NS3 than a 100/100-mg dose. In patients who failed after receiving 12 or more weeks of treatment, RAVs were selected in all 3 targets, while most patients who relapsed after 8 weeks of treatment did so without any detectable RAVs. Results from this study guided the selection of the optimal treatment regimen, treatment duration, and paritaprevir dose for further development of the 3D regimen. (This study has been registered at ClinicalTrials.gov under registration number NCT01464827.). PMID- 26100712 TI - In vitro selection of ceftazidime-avibactam resistance in Enterobacteriaceae with KPC-3 carbapenemase. AB - Ceftazidime-avibactam is active against most Enterobacteriaceae isolates with KPC carbapenemases. We investigated whether this activity could be compromised by mutation. Single-step and multistep selections were attempted using ceftazidime avibactam (avibactam fixed at 1 or 4 MUg/ml) versus two strains each of Enterobacter cloacae and Klebsiella pneumoniae, all with the KPC-3 enzyme. Mutant bla KPC alleles were sequenced, and their parentage was confirmed by typing. Ceftazidime-avibactam selected mutants at up to 16* MIC, with frequencies of ca. 10(-9). This contrasted with previous experience for ceftaroline-avibactam, where mutant frequencies under similar conditions were <10(-9). The MICs of ceftazidime with 1 MUg/ml avibactam for the ceftazidime-avibactam-selected mutants rose from 1 to 8 MUg/ml to 16 to >256 MUg/ml and those of ceftazidime with 4 MUg/ml avibactam from 0.25 to 1 MUg/ml to 4 to 128 MUg/ml; ceftaroline-avibactam MICs rose less, typically from 0.5 to 1 MUg/ml to 1 to 8 MUg/ml. The MICs of carbapenems and cephalosporins except ceftazidime and piperacillin-tazobactam were reduced for many mutants. Sequencing of blaKPC revealed point and insertion changes in 12/13 mutants investigated, representing all four parents; one mutant lacked bla KPC changes and possibly had reduced permeability. Amino acid changes commonly involved Omega loop alterations or 1 to 6 amino acid insertions immediately C-terminal to this loop. The most frequent change, seen in four mutants from three strains, was Asp179Tyr, replacing a residue that ordinarily forms a salt bridge to stabilize the Omega loop. Since ceftaroline-avibactam was less affected than ceftazidime-avibactam, we postulate that these mutations increase ceftazidimase specificity rather than conferring avibactam resistance. The clinical relevance remains uncertain. PMID- 26100713 TI - Characterization of IncI1 sequence type 71 epidemic plasmid lineage responsible for the recent dissemination of CTX-M-65 extended-spectrum beta-lactamase in the Bolivian Chaco region. AB - During the last decade, a significant diffusion of CTX-M-type extended-spectrum beta-lactamases (ESBLs) was observed in commensal Escherichia coli from healthy children in the Bolivian Chaco region, with initial dissemination of CTX-M-2, which was then replaced by CTX-M-15 and CTX-M-65. In this work, we demonstrate that the widespread dissemination of CTX-M-65 observed in this context was related to the polyclonal spreading of an IncI1 sequence type 71 (ST71) epidemic plasmid lineage. The structure of the epidemic plasmid population was characterized by complete sequencing of four representatives and PCR mapping of the remainder (n = 16). Sequence analysis showed identical plasmid backbones (similar to that of the reference IncI1 plasmid, R64) and a multiresistance region (MRR), which underwent local microevolution. The MRR harbored genes responsible for resistance to beta-lactams, aminoglycosides, florfenicol, and fosfomycin (with microevolution mainly consisting of deletion events of resistance modules). The bla CTX-M-65 module harbored by the IncI1 ST71 epidemic plasmid was apparently derived from IncN-type plasmids, likely via IS26-mediated mobilization. The plasmid could be transferred by conjugation to several different enterobacterial species (Escherichia coli, Cronobacter sakazakii, Enterobacter cloacae, Klebsiella oxytoca, Klebsiella pneumoniae, and Salmonella enterica) and was stably maintained without selective pressure in these species, with the exception of K. oxytoca and S. enterica. Fitness assays performed in E. coli recipients demonstrated that the presence of the epidemic plasmid was apparently not associated with a significant biological cost. PMID- 26100714 TI - Pseudomonas aeruginosa high-level resistance to polymyxins and other antimicrobial peptides requires cprA, a gene that is disrupted in the PAO1 strain. AB - The arn locus, found in many Gram-negative bacterial pathogens, mediates resistance to polymyxins and other cationic antimicrobial peptides through 4 amino-l-arabinose modification of the lipid A moiety of lipopolysaccharide. In Pseudomonas aeruginosa, several two-component regulatory systems (TCSs) control the arn locus, which is necessary but not sufficient for these resistance phenotypes. A previous transposon mutagenesis screen to identify additional polymyxin resistance genes that these systems regulate implicated an open reading frame designated PA1559 in the genome of the P. aeruginosa PAO1 strain. Resequencing of this chromosomal region and bioinformatics analysis for a variety of P. aeruginosa strains revealed that in the sequenced PAO1 strain, a guanine deletion at the end of PA1559 results in a frameshift and truncation of a full length open reading frame that also encompasses PA1560 in non-PAO1 strains, such as P. aeruginosa PAK. Deletion analysis in the PAK strain showed that this full length open reading frame, designated cprA, is necessary for polymyxin resistance conferred by activating mutations in the PhoPQ, PmrAB, and CprRS TCSs. The cprA gene was also required for PmrAB-mediated resistance to other cationic antimicrobial peptides in the PAK strain. Repair of the mutated cprA allele in the PAO1 strain restored polymyxin resistance conferred by an activating TCS mutation. The deletion of cprA did not affect the arn-mediated lipid A modification, indicating that the CprA protein is necessary for a different aspect of polymyxin resistance. This protein has a domain structure with a strong similarity to the extended short-chain dehydrogenase/reductase family that comprises isomerases, lyases, and oxidoreductases. These results suggest a new avenue through which to pursue targeted inhibition of polymyxin resistance. PMID- 26100715 TI - A drug-disease model describing the effect of oseltamivir neuraminidase inhibition on influenza virus progression. AB - A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate beta, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate delta, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75 mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (beta) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation. PMID- 26100716 TI - Interactions between QnrB, QnrB mutants, and DNA gyrase. AB - Plasmid-encoded protein QnrB1 protects DNA gyrase from ciprofloxacin inhibition. Using a bacterial two-hybrid system, we evaluated the physical interactions between wild-type and mutant QnrB1, the GyrA and GyrB gyrase subunits, and a GyrBA fusion protein. The interaction of QnrB1 with GyrB and GyrBA was approximately 10-fold higher than that with GyrA, suggesting that domains of GyrB are important for stabilizing QnrB1 interaction with the holoenzyme. Sub-MICs of ciprofloxacin or nalidixic acid reduced the interactions between QnrB1 and GyrA or GyrBA but produced no reduction in the interaction with GyrB or a quinolone resistant GyrA:S83L (GyrA with S83L substitution) mutant, suggesting that quinolones and QnrB1 compete for binding to gyrase. Of QnrB1 mutants that reduced quinolone resistance, deletions in the C or N terminus of QnrB1 resulted in a marked decrease in interactions with GyrA but limited or no effect on interactions with GyrB and an intermediate effect on interactions with GyrBA. While deletion of loop B and both loops moderately reduced the interaction signal with GyrA, deletion of loop A resulted in only a small reduction in the interaction with GyrB. The loop A deletion also caused a substantial reduction in interaction with GyrBA, with little effect of loop B and dual-loop deletions. Single-amino-acid loop mutations had little effect on physical interactions except for a Delta105I mutant. Therefore, loops A and B may play key roles in the proper positioning of QnrB1 rather than as determinants of the physical interaction of QnrB1 with gyrase. PMID- 26100717 TI - A predictive machine learning approach for microstructure optimization and materials design. AB - This paper addresses an important materials engineering question: How can one identify the complete space (or as much of it as possible) of microstructures that are theoretically predicted to yield the desired combination of properties demanded by a selected application? We present a problem involving design of magnetoelastic Fe-Ga alloy microstructure for enhanced elastic, plastic and magnetostrictive properties. While theoretical models for computing properties given the microstructure are known for this alloy, inversion of these relationships to obtain microstructures that lead to desired properties is challenging, primarily due to the high dimensionality of microstructure space, multi-objective design requirement and non-uniqueness of solutions. These challenges render traditional search-based optimization methods incompetent in terms of both searching efficiency and result optimality. In this paper, a route to address these challenges using a machine learning methodology is proposed. A systematic framework consisting of random data generation, feature selection and classification algorithms is developed. Experiments with five design problems that involve identification of microstructures that satisfy both linear and nonlinear property constraints show that our framework outperforms traditional optimization methods with the average running time reduced by as much as 80% and with optimality that would not be achieved otherwise. PMID- 26100718 TI - Detection and Genetic Analysis of Noroviruses and Sapoviruses in Sea Snail. AB - An outbreak of acute gastroenteritis occurred at a restaurant in Yokohama in December 2011. Because many of the customers had consumed raw sea snail, sea snail was suspected to be the source of this outbreak. To determine whether sea snail contains Norovirus (NoV) or Sapovirus (SaV), we analyzed 27 sea snail samples collected over 5 months (May, June, August, October, and December 2012) and 59.3% were positive for NoV and/or SaV. The levels of NoV ranged from 1.5 * 10(3) to 1.5 * 10(5) copies/g tissue, and those of SaV from 1.5 * 10(2) to 1.3 * 10(3) copies/g tissue. The highest levels were observed in sea snails collected in December. A phylogenetic analysis of the NoVs showed that the viral strains were NoV genotypes GI.4, GI.6, GII.4, GII.12, GII.13, and GII.14, and the SaV strains were genotypes GI.2 and GI.3. The NoV GII.4 Sydney 2012 variants were only detected in December. This variant was a major source of gastroenteritis in Japan in the winter of 2012/2013. In contrast, the NoV GII.4 strains detected in May and June 2012 were not the Sydney 2012 variant. This study demonstrates that sea snail contains multiple genogroups and genotypes of NoV and SaV strains. We conclude that the sea snail presents a risk of gastroenteritis when consumed raw. PMID- 26100719 TI - A randomized controlled trial of the feasibility and preliminary efficacy of a texting intervention on medication adherence in adults prescribed oral anti cancer agents: study protocol. AB - AIM: The aim of this study was to report a study protocol that examines feasibility, preliminary efficacy and satisfaction of a text message intervention on the outcome of medication adherence in adult patients prescribed oral anti cancer agents. BACKGROUND: Administration of oral anti-cancer agents occurs in the home setting, requiring patients to self-manage the regimen as prescribed. However, many barriers to medication adherence exist: regimens are often complex, with cycling of two or more medications; side effects of treatment; most cancer patients are older with comorbid conditions and competing demands; and cognitive decline and forgetfulness may occur. Research indicates patients miss nearly one third of the prescribed oral anti-cancer agent dosages. Text message interventions have been shown to improve medication adherence in chronic conditions other than cancer. However, a majority of those patients were less than 50 years of age and most cancer patients are diagnosed later in life. DESIGN: A two-group randomized controlled trial with repeated measures. METHODS: Seventy-five adult patients newly prescribed an oral anti-cancer agent will be recruited (project funded in April 2013) from community cancer centres and a specialty pharmacy. Participants will be randomized to either a control group (n = 25; usual care) or an intervention group (n = 50; usual care plus text messages timed to medication regimen). Outcome measures include: medication adherence, feasibility and satisfaction with the intervention. Data will be collected over 8 weeks: baseline, weekly and exit. DISCUSSION: Standardized text message intervention protocol and detailed study procedures have been developed in this study to improve medication adherence. PMID- 26100720 TI - A weighted and integrated drug-target interactome: drug repurposing for schizophrenia as a use case. AB - BACKGROUND: Computational pharmacology can uniquely address some issues in the process of drug development by providing a macroscopic view and a deeper understanding of drug action. Specifically, network-assisted approach is promising for the inference of drug repurposing. However, the drug-target associations coming from different sources and various assays have much noise, leading to an inflation of the inference errors. To reduce the inference errors, it is necessary and critical to create a comprehensive and weighted data set of drug-target associations. RESULTS: In this study, we created a weighted and integrated drug-target interactome (WinDTome) to provide a comprehensive resource of drug-target associations for computational pharmacology. We first collected drug-target interactions from six commonly used drug-target centered data sources including DrugBank, KEGG, TTD, MATADOR, PDSP K(i) Database, and BindingDB. Then, we employed the record linkage method to normalize drugs and targets to the unique identifiers by utilizing the public data sources including PubChem, Entrez Gene, and UniProt. To assess the reliability of the drug-target associations, we assigned two scores (Score_S and Score_R) to each drug-target association based on their data sources and publication references. Consequently, the WinDTome contains 546,196 drug-target associations among 303,018 compounds and 4,113 genes. To assess the application of the WinDTome, we designed a network-based approach for drug repurposing using mental disorder schizophrenia (SCZ) as a case. Starting from 41 known SCZ drugs and their targets, we inferred a total of 264 potential SCZ drugs through the associations of drug-target with Score_S higher than two in WinDTome and human protein-protein interactions. Among the 264 SCZ-related drugs, 39 drugs have been investigated in clinical trials for SCZ treatment and 74 drugs for the treatment of other mental disorders, respectively. Compared with the results using other Score_S cutoff values, single data source, or the data from STITCH, the inference of 264 SCZ-related drugs had the highest performance. CONCLUSIONS: The WinDTome generated in this study contains comprehensive drug-target associations with confidence scores. Its application to the SCZ drug repurposing demonstrated that the WinDTome is promising to serve as a useful resource for drug repurposing. PMID- 26100721 TI - Enzymatic Hydrogelation-Induced Fluorescence Turn-Off for Sensing Alkaline Phosphatase in Vitro and in Living Cells. AB - Alkaline phosphatase (ALP)-catalyzed hydrogelation has been extensively explored and found wide applications. Spectroscopic and electrochemical approaches are commonly employed for the detection of ALP activity. Herein, by rational design of a fluorescence probe Fmoc-K(FITC)FFYp (P1) (where FITC is fluorescein), we incorporated sol-gel transition with fluorescence "turn-off" and developed a new method for quantitative sensing ALP activity in vitro and in living cells. Under the catalysis of ALP, P1 was converted to hydrogelator Fmoc-K(FITC)FFY (1) which self-assembles into nanofibers to form Gel I. Accompanying this sol-gel transition, the fluorescence emission of P1 was turned off. Our assay was employed to detect ALP activity over the range of 0-2.8 U/mL with a limit of detection (LOD) of 0.06 U/mL. ALP-inhibitor-treated cell imaging indicated that P1 could be applied for sensing ALP activity in living cells. Our method provides a new option for real time and quantitative sensing ALP activity in vitro and even in living cells. PMID- 26100722 TI - Burden of First and Recurrent Cardiovascular Events Among Patients With Hyperlipidemia. AB - BACKGROUND: Acute cardiovascular (CV) events have been evaluated in patients with specific comorbidities but have not focused on patients with hyperlipidemia or on the their long-term costs. OBJECTIVES: To evaluate incidence of CV events, costs, and resource utilization among patients with hyperlipidemia and baseline risk of CV disease (CVD). METHODS: Patients (age 18 to 64 years) diagnosed with hyperlipidemia or using lipid-modifying medications were identified from administrative claims. Patients were categorized into 3 cohorts based on pre index clinical characteristics-secondary prevention (SP; history of CV event, n = 15 613); high risk (HR; CVD, n = 47 600); and primary prevention (PP; no CV event history or CVD, n = 60 637)-and followed up to 2 years after the CV event. RESULTS: During follow-up, >=1 new CV event occurred in 43.0% of the SP cohort, 33.9% of HR, and 20.9% of PP; and >=3 new events occurred in 19.8% of the SP cohort, 12.9% of HR, and 5.5% of PP. Incremental total costs were $19 320 for SP, $20 003 for HR, and $17 650 for PP. Compared with patients with only 1 CV event, the mean 2-year cost was 30% higher in patients with 2 CV events and 48% higher in patients with 3 CV events. Only 50% of HR patients (with or without CV events) received statins. CONCLUSIONS: Patients with recurrent CV events had higher total health care costs during 24-month follow-up for each type of CV event. Total health care costs among patients with a CV event were higher for the initial as well as subsequent events. Statins and lipid-modifying medications were significantly underutilized in all cohorts, despite the presence of CVD. PMID- 26100723 TI - Shape matching algorithm to validate the tracing protocol of placental chorionic surface vessel networks. AB - Variability in placental chorionic surface vessel networks (PCSVNs) may mark developmental and functional changes in fetal health. Here we report a protocol of manually tracing PCSVNs from digital 2D images of post-delivery placentas and its validation by a shape matching method to compare the similarity between paint injected and unmanipulated (uninjected and deflated vessels) tracings of PCSVNs. We show that tracings of unmanipulated vessels produce networks that are very comparable to the networks obtained by tracing paint-injected PCSVNs. We suggest that manual tracings of unmanipulated PCSVNs can extract features of PCSVN growth and structure that may impact fetal wellbeing. PMID- 26100724 TI - Comparing catchment sediment fingerprinting procedures using an auto-evaluation approach with virtual sample mixtures. AB - Information on sediment sources in river catchments is required for effective sediment control strategies, to understand sediment, nutrient and pollutant transport, and for developing soil erosion management plans. Sediment fingerprinting procedures are employed to quantify sediment source contributions and have become a widely used tool. As fingerprinting procedures are naturally variable and locally dependant, there are different applications of the procedure. Here, the auto-evaluation of different fingerprinting procedures using virtual sample mixtures is proposed to support the selection of the fingerprinting procedure with the best capacity for source discrimination and apportionment. Surface samples from four land uses from a Central Spanish Pyrenean catchment were used i) as sources to generate the virtual sample mixtures and ii) to characterise the sources for the fingerprinting procedures. The auto-evaluation approach involved comparing fingerprinting procedures based on four optimum composite fingerprints selected by three statistical tests, three source characterisations (mean, median and corrected mean) and two types of objective functions for the mixing model. A total of 24 fingerprinting procedures were assessed by this new approach which were solved by Monte Carlo simulations and compared using the root mean squared error (RMSE) between known and assessed source ascriptions for the virtual sample mixtures. It was found that the source ascriptions with the highest accuracy were achieved using the corrected mean source characterisations for the composite fingerprints selected by the Kruskal Wallis H-test and principal components analysis. Based on the RMSE results, high goodness of fit (GOF) values were not always indicative of accurate source apportionment results, and care should be taken when using GOF to assess mixing model performance. The proposed approach to test different fingerprinting procedures using virtual sample mixtures provides an enhanced basis for selecting procedures that can deliver optimum source discrimination and apportionment. PMID- 26100725 TI - Deforestation and cultivation mobilize mercury from topsoil. AB - Terrestrial biomass and soils are a primary global reservoir of mercury (Hg) derived from natural and anthropogenic sources; however, relatively little is known about the fate and stability of Hg in the surface soil reservoir and its susceptibility to change as a result of deforestation and cultivation. In southwest Ohio, we measured Hg concentrations in soils of deciduous old- and new growth forests, as well as fallow grassland and agricultural soils that had once been forested to examine how, over decadal to century time scales, man-made deforestation and cultivation influence Hg mobility from temperate surface soils. Mercury concentrations in surficial soils were significantly greater in the old growth than new-growth forest, and both forest soils had greater Hg concentrations than cultivated and fallow fields. Differences in Hg:lead ratios between old-growth forest and agricultural topsoils suggest that about half of the Hg lost from deforested and cultivated Ohio soils may have been volatilized and the other half eroded. The estimated mobilization potential of Hg as a result of deforestation was 4.1 mg m(-2), which was proportional to mobilization potentials measured at multiple locations in the Amazon relative to concentrations in forested surface soils. Based on this relationship and an estimate of the global average of Hg concentrations in forested soils, we approximate that about 550 M mol of Hg has been mobilized globally from soil as a result of deforestation during the past two centuries. This estimate is comparable to, if not greater than, the amount of anthropogenic Hg hypothesized by others to have been sequestered by the soil reservoir since Industrialization. Our results suggest that deforestation and soil cultivation are significant anthropogenic processes that exacerbate Hg mobilization from soil and its cycling in the environment. PMID- 26100726 TI - Impact of trees on pollutant dispersion in street canyons: A numerical study of the annual average effects in Antwerp, Belgium. AB - Effects of vegetation on pollutant dispersion receive increased attention in attempts to reduce air pollutant concentration levels in the urban environment. In this study, we examine the influence of vegetation on the concentrations of traffic pollutants in urban street canyons using numerical simulations with the CFD code OpenFOAM. This CFD approach is validated against literature wind tunnel data of traffic pollutant dispersion in street canyons. The impact of trees is simulated for a variety of vegetation types and the full range of approaching wind directions at 15 degrees interval. All these results are combined using meteo statistics, including effects of seasonal leaf loss, to determine the annual average effect of trees in street canyons. This analysis is performed for two pollutants, elemental carbon (EC) and PM10, using background concentrations and emission strengths for the city of Antwerp, Belgium. The results show that due to the presence of trees the annual average pollutant concentrations increase with about 8% (range of 1% to 13%) for EC and with about 1.4% (range of 0.2 to 2.6%) for PM10. The study indicates that this annual effect is considerably smaller than earlier estimates which are generally based on a specific set of governing conditions (1 wind direction, full leafed trees and peak hour traffic emissions). PMID- 26100727 TI - Effects of day-of-week trends and vehicle types on PM2.5-bounded carbonaceous compositions. AB - Carbonaceous compositions of PM2.5 were measured in the heart of Bangkok from 17th November 2010 to 19th January 2012, and a data set of 94 samples was constructed. Effects of day-of-week trends and vehicle types on PM2.5-bound TC, OC, and EC were carefully investigated. In this study, OC was the most important contributor to the total PM2.5 mass concentration. The average PM2.5-bound OC content measured at CHAOS (18.8 +/- 9.18 MUg m(-3)) was approximately 11 times higher than at Chaumont, Switzerland (1.7 MUg m(-3)), but approximately five times lower than at Xi'an, China (93.0 MUg m(-3)). The application of diagnostic binary ratios of OC/EC and estimations of secondary organic carbon (SOC) coupled with autocorrelation plots (Box and Jenkins) highlight the enhanced impacts of traffic emissions, especially from diesel vehicles, on PM2.5-bound carbonaceous compositions on weekdays relative to weekends. Hierarchical cluster analysis (HCA) coupled with principal component analysis (PCA) underline the importance of diesel emissions as the primary contributors of carbonaceous aerosols, particularly during weekdays. PMID- 26100728 TI - Ultrasound coupled with Fenton oxidation pre-treatment of sludge to release organic carbon, nitrogen and phosphorus. AB - We focused on the effects of ultrasound and Fenton reagent in ultrasonic coupling Fenton oxidation (U + F) pre-treatment processes on the disintegration of wastewater treatment plant sludge. The results demonstrated that U + F treatment could significantly increase soluble COD, TOC, total N, proteins, total P and PO4(3-) concentrations in sludge supernatant. This method was more effective than ultrasonic (U) or Fenton oxidation (F) treatment alone. U + F treatment increased the soluble COD by 2.1- and 1.4-fold compared with U and F alone, respectively. U + F treatment increased the total N and P by 1.7- and 2.2-fold, respectively, compared with F alone. After U + F treatment, sludge showed a considerably finer particle size and looser microstructure based on scanning electron microscopy, and the highest OH signal intensity increased from 568.7 by F treatment to 1106.3 using electron spin resonance. This demonstrated that U+F treatment induces disintegration of sludge and release of organic carbon, nitrogen and phosphorus better. PMID- 26100729 TI - High sensitive multiresidue analysis of pharmaceuticals and antifungals in surface water using U-HPLC-Q-Exactive Orbitrap HRMS. Application to the Danube river basin on the Romanian territory. AB - The occurrence of 67 pharmaceutical and antifungal residues in the Danube river on the Romanian territory was studied by using solid-phase extraction (SPE) and LC-Q Exactive Orbitrap high resolution MS in both full scan (FS) MS and targeted MS/MS modes. A single-laboratory validation procedure was carried out for the determination of 67 compounds in FSMS mode evaluating selectivity, sensitivity, linearity, precision and accuracy. The method showed satisfactory analytical performance. The evaluation of the recovery concluded that 75% of the compounds show recoveries between 85 and 115% and 10% of the compounds show recoveries between 85% and 65%. The level of detection was lower than 5 ng l(-1) for 66% of the compounds, between 5 and 10 ng l(-1) for 22% and between 10 and 25 ng l(-1) for 14% of the compounds. The coefficients of determination R(2) were higher than 0.99 for 79% of the compounds, over a linearity range of 2.5-50 ng l(-1). Targeted MS/MS analysis, performed in addition to the full scan acquisition was used for confirmatory purpose. Twenty samples of Danube water and three of the main tributaries were collected in May, July, August and October 2014. Analysis of the selected water samples revealed the occurrence of 23 compounds such as diclofenac, carbamazepine, sulfamethoxazole, tylosin, indomethacin, ketoprofen, piroxicam, together with antifungals like thiabendazole, and carbendazim. Carbamazepine was detected in 17 samples, the maximum concentration being 40 ng l(-1). The highest concentration reached was 166 ng l(-1) for diclofenac. PMID- 26100730 TI - Metal exposure influences the melanin and carotenoid-based colorations in great tits. AB - Metals are naturally found in the environment but are also emitted through anthropogenic activities, raising some concerns about the potential deleterious effects of these elements on wildlife. The potential effects of metals on bird coloration have been the focus of several recent studies since animal colored signals often reflect the physiology of their bearers and are thus used by animals to assess the quality of another individual as a mate or competitor. These studies have shown that the melanin pigmentation seems to be positively associated and the carotenoid-based coloration negatively associated with metal exposure in wild birds. Although these studies have been very useful to show the associations between metal exposure and coloration, only few of them have actually quantified the levels of metal exposure at the individual level; always focusing on one or two of them. Here, we measured the concentrations of eight metals in great tits' feathers and then assessed how these levels of metals were associated with the carotenoid and melanin-based colorations. We found that the melanin pigmentation was positively associated with the copper concentration and negatively correlated with the chromium concentration in feathers. In addition, we have shown that the carotenoid-based coloration was negatively associated with the feather's mercury concentration. This study is the first one to identify some metals that might affect positively and negatively the deposition of melanin and carotenoid into the plumage of wild birds. PMID- 26100731 TI - Drip water electrical conductivity as an indicator of cave ventilation at the event scale. AB - The use of speleothems to reconstruct past climatic and environmental change through chemical proxies is becoming increasingly common. Speleothem chemistry is controlled by hydrological and atmospheric processes which vary over seasonal time scales. However, as many reconstructions using speleothem carbonate are now endeavouring to acquire information about precipitation and temperature dynamics at a scale that can capture short term hydrological events, our understanding of within cave processes must match this resolution. Monitoring within Cueva de Asiul (N. Spain) has identified rapid (hourly resolution) changes in drip water electrical conductivity (EC), which is regulated by the pCO2 in the cave air. Drip water EC is therefore controlled by different modes of cave ventilation. In Cueva de Asiul a combination of density differences, and external pressure changes control ventilation patterns. Density driven changes in cave ventilation occur on a diurnal scale at this site irrespective of season, driven by fluctuations in external temperature across the cave internal temperature threshold. As external temperatures drop below those within the cave low pCO2 external air enters the void, facilitating the deposition of speleothem carbonate and causing a reduction in measured drip water EC. Additionally, decreases in external pressure related to storm activity act as a secondary ventilation mechanism. Reductions in external air pressure cause a drop in cave air pressure, enhancing karst air draw down, increasing the pCO2 of the cave and therefore the EC measured within drip waters. EC thereby serves as a first order indicator of cave ventilation, regardless of changes in speleothem drip rates and karst hydrological conditions. High resolution monitoring of cave drip water electrical conductivity reveals the highly sensitive nature of ventilation dynamics within cave environments, and highlights the importance of this for understanding trace element incorporation into speleothem carbonate at the event scale. PMID- 26100732 TI - Investigating physiological, cellular and molecular effects in juvenile blue crab, Callinectus sapidus, exposed to field-collected sediments contaminated by oil from the Deepwater Horizon Incident. AB - Juvenile blue crabs, Callinectus sapidus, were exposed for 31 days to six different sediments collected within the Pass a Loutre State Wildlife Management Area approximately 6 months or 1.5 years post-capping of the Macondo-252 well head following the Deepwater Horizon (DWH) Incident. Based on forensic analysis to fingerprint for DWH oil, these sediments differed in their levels of DWH oil contamination, and included one reference sediment collected from a location with no detectable DWH oil present. The concentration of 50 individual parent and alkylation group polycyclic aromatic hydrocarbons (PAHs), saturated hydrocarbons (37 total), and total extractable hydrocarbons were determined in each sediment, as were biologically relevant metals, grain size distribution, percent total organic carbon, and percent total solids. Total concentrations of 50 PAHs (TPAH50) of initial treatment sediments ranged from 187 MUg kg(-1) (reference site) to 2,086,458 MUg kg(-1) (the highest DWH oil contaminated site). Multiple biological endpoints were measured including mortality, growth, and ecdysis. Additionally, early biomarkers of biological stress were examined in the hemolymph and hepatopancreas of crabs, including DNA damage (Comet assay) and expression of genes encoding Cu-metallothionein (CuMT), glutathione-S-transferase (GST), and manganese superoxide dismutase (MnSOD). Over the 31 day exposure, there were no treatment related mortalities in juvenile blue crabs. The overall growth and molting of the crabs were not substantially different between the various sediment exposures over the exposure period. Additionally, none of the early biomarkers of biological stress were correlated with PAH concentrations. Overall, juvenile blue crabs did not appear to be negatively impacted during the 31 day exposure by DWH oil contaminated sediments collected at least 6 months post-capping of the Macondo-252 well-head. PMID- 26100733 TI - Evaluation of disinfection by-product formation potential (DBPFP) during chlorination of two algae species--Blue-green Microcystis aeruginosa and diatom Cyclotella meneghiniana. AB - Microcystis aeruginosa (blue-green alga) commonly blooms in summer and Cyclotella meneghiniana (diatom) outbreaks in fall in the reservoirs that serve as drinking water sources in Southeast China. Herein, an evaluation of disinfection by product formation potential (DBPFP) from them during chlorination should be conducted. Five DBPs including trichloromethane (TCM), trichloronitromethane (TCNM), dichloroacetonitrile (DCAN), 1,1-dichloropropanone (1,1-DCP) and 1,1,1 trichloropropanone (1,1,1-TCP) were monitored. The formation potential of TCM and TCNM was enhanced with the increase of reaction time and chlorine dosage, whereas that of DCAN, 1,1-DCP and 1,1,1-TCP increased first and then fell with continuing reaction time. M. aeruginosa showed higher DBPFP than C. meneghiniana, the yield of DBPs varied with components of algal cells. The DBPFP order from components of M. aeruginosa was cell suspension (CS) ~ intracellular organic matter (IOM) > extracellular organic matter (EOM) > cell debris (CD), which indicated that IOM was the main DBP precursors for M. aeruginosa. The yields of DBPs from components of C. meneghiniana were in the order of CS>IOM~ CD ~ EOM, suggesting that three components made similar contributions to the total DBP formation. The amount of IOM with higher DBPFP leaked from both algae species increased with the chlorine dosage, indicating that chlorine dosage should be considered carefully in the treatment of eutrophic water for less destroying of the cell integrity. Though fluorescence substances contained in both algae species varied significantly, the soluble microbial products (SMPs) and aromatic protein-like substances were the main cellular components that contributed to DBP formation for both algae. PMID- 26100734 TI - Perfluorinated chemicals in blood serum of inhabitants in central Poland in relation to gender and age. AB - The goal of this paper is to determine concentrations of seven selected perfluoroalkylated substances (PFASs): perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorododecanoic acid (PFDoDA) in the blood serum of men and women of reproductive age from the central region of Poland. The relation between sex of tested subjects and the levels of compounds in blood serum of humans will also be considered and analysed as an element of the risk assessment. The study was made on the blood serum samples collected from 253 women and 176 men of reproductive age between 20 and 44 years from Warsaw and surrounding areas. Higher concentrations of five (PFOS, PFOA, PFNA, PFDA, PFUnDA) from among seven selected PFASs were observed in men in comparison to women from the same populations. Only the concentrations of PFHxS and PFDoDA were slightly higher in women than in men. These differences were statistically significant in all cases, except for PFUnDA. The hypothesis that the concentrations of said compounds increase with age of the test subjects, regardless of gender has not been confirmed. PMID- 26100735 TI - Formation of complexes between hematite nanoparticles and a non-conventional galactomannan gum. Toward a better understanding on interaction processes. AB - The physicochemical characteristics of hematite nanoparticles related to their size, surface area and reactivity make them useful for many applications, as well as suitable models to study aggregation kinetics. For several applications (such as remediation of contaminated groundwater) it is crucial to maintain the stability of hematite nanoparticle suspensions in order to assure their arrival to the target place. The use of biopolymers has been proposed as a suitable environmentally friendly option to avoid nanoparticle aggregation and assure their stability. The aim of the present work was to investigate the formation of complexes between hematite nanoparticles and a non-conventional galactomannan (vinal gum--VG) obtained from Prosopis ruscifolia in order to promote hematite nanoparticle coating with a green biopolymer. Zeta potential and size of hematite nanoparticles, VG dispersions and the stability of their mixtures were investigated, as well as the influence of the biopolymer concentration and preparation method. DLS and nanoparticle tracking analysis techniques were used for determining the size and the zeta-potential of the suspensions. VG showed a polydispersed size distribution (300-475 nm Z-average diameter, 0.65 Pdi) and a negative zeta potential (between -1 and -12 mV for pH2 and 12, respectively). The aggregation of hematite nanoparticles (3.3 mg/L) was induced by the addition of VG at lower concentrations than 2mg/L (pH5.5). On the other hand, hematite nanoparticles were stabilized at concentrations of VG higher than 2 mg/L. Several phenomena between hematite nanoparticles and VG were involved: steric effects, electrostatic interactions, charge neutralization, charge inversion and polymer bridging. The process of complexation between hematite nanoparticles and the biopolymer was strongly influenced by the preparation protocols. It was concluded that the aggregation, dispersion, and stability of hematite nanoparticles depended on biopolymer concentration and also on the way of preparation and initial physicochemical properties of the aqueous system. PMID- 26100736 TI - The current state of drug discovery and what it might take to improve drug discovery outcomes and approval successes. PMID- 26100737 TI - Transdermal delivery of antidiabetic drugs: formulation and delivery strategies. AB - Most oral antidiabetic drugs exhibit low oral bioavailability and need to be taken more than once daily owing to short half-lives, resulting in poor patient compliance. There is a necessity for improved drug delivery devices for antidiabetic agents because of the scale of their use and short-comings associated with their conventional dosage forms. This review presents an outline of transdermal research specifically in the area of antidiabetic drugs, showing that several transdermal approaches have been made to enhance delivery of these drugs via the skin barrier, significantly improving bioavailability as well as patient compliance. PMID- 26100738 TI - 2014 in review: FDA approval of new drugs. AB - The year 2014 witnessed the approval by the US Food and Drug Administration (FDA) of 42 new molecular entities (NMEs), which is well above recent averages. These molecules targeted a range of molecular pathways and clinical indications, although the latter was skewed toward hepatitis C virus (HCV) infection and diabetes. By contrast, a single drug was approved for cardiovascular diseases and none for neurological indications (excepting sleeping disorders). Of note is a continued trend toward consolidation because the net number of biotechnology companies has reached its lowest point in over 25 years, raising questions about sustainability. PMID- 26100739 TI - Contributions of wheat and maize residues to soil organic carbon under long-term rotation in north China. AB - Soil organic carbon (SOC) dynamics in agro-ecosystem is largely influenced by cropping. However, quantifying the contributions of various crops has been lacking. Here we employed a stable isotopic approach to evaluate the contributions of wheat and maize residues to SOC at three long-term experimental sites in north China. Soil samples were collected from 0-20, 20-40, 40-60, 60-80 and 80-100 cm after 13 and 20 years of wheat-maize rotation, and SOC and its stable (13)C composition were determined. Our data showed that the delta(13)C value of SOC varied, on average, from -22.10/00 in the 0-20 cm to -21.50/00 in the 80-100 cm. Carbon input through maize residues ranged from 35% to 68% whereas the contribution of maize residues to SOC (0-40 cm) ranged from 28% to 40%. Our analyses suggested that the retention coefficient was in the range of 8.0-13.6% for maize residues and 16.5-28.5% for wheat residues. The two-fold higher retention coefficient of wheat versus maize residues was due to the differences in the quality of residues and probably also in the temperature during the growing season. Our study highlighted the importance of crop management on carbon sequestration in agricultural lands. PMID- 26100740 TI - [Safety and efficacy of kyphoplasty in the treatment of tumoral disease of the spine]. AB - Vertebral fractures in oncology patients cause significant pain and disability, with decreased quality of life. The aim of the study is to assess the efficacy and safety of kyphoplasty in this type of vertebral fracture in the acute phase. MATERIALS AND METHODS: A retrospective study was conducted on 75 consecutive oncology patients with 122 acute vertebral fractures, who underwent bilateral balloon kyphoplasty, with a mean follow up of 11 months. RESULTS: Almost all (91%) of the patients improved their pain level. The mean improvement in the Visual Analogue Scale (VAS) was 4.28 points (preoperative value 7.49 [SD 1.19], postoperative 3.21 [SD 0.95]). Before surgery, 53% of patients needed major opioids (40 cases), and one month after surgery only 12% (9 patients) required them. Quality of life determined by the Karnofsky index improved from 60.2 (SD 10) to 80.7 (SD 12.1). Cement leaks were found in 5.7% (7 cases), all without neurological repercussions. New fractures appeared in 11 patients. This subgroup showed a slight worsening of the initially acquired clinical improvement. No neurological or pulmonary complications related to surgical technique were found. CONCLUSIONS: Kyphoplasty is an effective and safe for treating vertebral fractures in patients with cancer. LEVEL OF EVIDENCE: Level IV. PMID- 26100742 TI - Neuroimmunology: Uncovering the secrets of the 'brain drain'--the CNS lymphatic system is finally revealed. PMID- 26100741 TI - Mammalian touch catches up. AB - An assortment of touch receptors innervate the skin and encode different tactile features of the environment. Compared with invertebrate touch and other sensory systems, our understanding of the molecular and cellular underpinnings of mammalian touch lags behind. Two recent breakthroughs have accelerated progress. First, an arsenal of cell-type-specific molecular markers allowed the functional and anatomical properties of sensory neurons to be matched, thereby unraveling a cellular code for touch. Such markers have also revealed key roles of non neuronal cell types, such as Merkel cells and keratinocytes, in touch reception. Second, the discovery of Piezo genes as a new family of mechanically activated channels has fueled the discovery of molecular mechanisms that mediate and mechanotransduction in mammalian touch receptors. PMID- 26100743 TI - Epilepsy: Status epilepticus epidemiology--tracking a moving target. PMID- 26100751 TI - Dopa-responsive dystonia--clinical and genetic heterogeneity. AB - Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment. PMID- 26100750 TI - Interactions of the histamine and hypocretin systems in CNS disorders. AB - Histamine and hypocretin neurons are localized to the hypothalamus, a brain area critical to autonomic function and sleep. Narcolepsy type 1, also known as narcolepsy with cataplexy, is a neurological disorder characterized by excessive daytime sleepiness, impaired night-time sleep, cataplexy, sleep paralysis and short latency to rapid eye movement (REM) sleep after sleep onset. In narcolepsy, 90% of hypocretin neurons are lost; in addition, two groups reported in 2014 that the number of histamine neurons is increased by 64% or more in human patients with narcolepsy, suggesting involvement of histamine in the aetiology of this disorder. Here, we review the role of the histamine and hypocretin systems in sleep-wake modulation. Furthermore, we summarize the neuropathological changes to these two systems in narcolepsy and discuss the possibility that narcolepsy associated histamine abnormalities could mediate or result from the same processes that cause the hypocretin cell loss. We also review the changes in the hypocretin and histamine systems, and the associated sleep disruptions, in Parkinson disease, Alzheimer disease, Huntington disease and Tourette syndrome. Finally, we discuss novel therapeutic approaches for manipulation of the histamine system. PMID- 26100755 TI - Suppression of non-radiative surface recombination by N incorporation in GaAs/GaNAs core/shell nanowires. AB - III-V semiconductor nanowires (NWs) such as GaAs NWs form an interesting artificial materials system promising for applications in advanced optoelectronic and photonic devices, thanks to the advantages offered by the 1D architecture and the possibility to combine it with the main-stream silicon technology. Alloying of GaAs with nitrogen can further enhance performance and extend device functionality via band-structure and lattice engineering. However, due to a large surface-to-volume ratio, III-V NWs suffer from severe non-radiative carrier recombination at/near NWs surfaces that significantly degrades optical quality. Here we show that increasing nitrogen composition in novel GaAs/GaNAs core/shell NWs can strongly suppress the detrimental surface recombination. This conclusion is based on our experimental finding that lifetimes of photo-generated free excitons and free carriers increase with increasing N composition, as revealed from our time-resolved photoluminescence (PL) studies. This is accompanied by a sizable enhancement in the PL intensity of the GaAs/GaNAs core/shell NWs at room temperature. The observed N-induced suppression of the surface recombination is concluded to be a result of an N-induced modification of the surface states that are responsible for the nonradiative recombination. Our results, therefore, demonstrate the great potential of incorporating GaNAs in III-V NWs to achieve efficient nano-scale light emitters. PMID- 26100756 TI - [Osteotomies in children and adolescents]. PMID- 26100757 TI - Microdynamics and arrest of coarsening during spinodal decomposition in thermoreversible colloidal gels. AB - Coarsening and kinetic arrest of colloidal systems undergoing spinodal decomposition (SD) is a conserved motif for forming hierarchical, bicontinuous structures. Although the thermodynamic origins of SD in colloids are widely known, the microstructural processes responsible for its coarsening and associated dynamics en route to arrest remain elusive. To better elucidate the underlying large-scale microdynamical processes, we study a colloidal system with moderate-range attractions which displays characteristic features of arrested SD, and study its dynamics during coarsening through a combination of differential dynamic microscopy and real-space tracking. Using these recently developed imaging techniques, we reveal directly that the coarsening arises from collective dynamics of dense domains, which undergo slow, intermittent, and ballistic motion. These collective motions indicate interfacial effects to be the driving force of coarsening. The nature of the gelation enables control of the arrested length scale of coarsening by the depths of quenching into the spinodal regime, which we demonstrate to provide an effective means to control the elasticity of colloidal gels. PMID- 26100754 TI - Is early-life iron exposure critical in neurodegeneration? AB - The effects of iron deficiency are well documented, but relatively little is known about the long-term implications of iron overload during development. High levels of redox-active iron in the brain have been associated with neurodegenerative disorders, most notably Parkinson disease, yet a gradual increase in brain iron seems to be a feature of normal ageing. Increased brain iron levels might result from intake of infant formula that is excessively fortified with iron, thereby altering the trajectory of brain iron uptake and amplifying the risk of iron-associated neurodegeneration in later life. In this Perspectives article, we discuss the potential long-term implications of excessive iron intake in early life, propose the analysis of iron deposits in teeth as a method for retrospective determination of iron exposure during critical developmental windows, and call for evidence-based optimization of the chemical composition of infant dietary supplements. PMID- 26100758 TI - Investigating effects of hydroxypropyl methylcellulose (HPMC) molecular weight grades on lag time of press-coated ethylcellulose tablets. AB - The research undertaken exemplifies the effects of hydroxypropyl methylcellulose (HPMC) molecular weight (MW) grades of on lag time of press-coated ethylcellulose (EC) tablets. The formulation comprised an immediate release core (containing prednisone as a model drug) surrounded by compression coating with variegated EC HPMC blends. Five selected HPMC grades (E5, E15, E50, K100LV and K4M) were explored at three different concentrations (10% w/w, 20% w/w and 30% w/w in outer coat) to understand their effects on lag time and drug release. In vitro drug release testing demonstrated that, with increase in concentration of E5 and E15, up to 30% w/w, the mean lag time decreased progressively; whereas with remaining grades, the mean lag time initially decreased up to 20% w/w level and thereafter increased for 30% w/w level. Importantly, with increase in HPMC concentration in the outer coat, the variability in lag time (%RSD; n = 6) was decreased for each of E5, E15 and E50, whereas increased for K100LV and K4M. In general, the variability in lag time was increased with increase in HPMC MW at studied concentration levels. Markedly, tablets with 30% w/w K4M in outer coat exhibited slight premature release (before the rupture of outer coat) along with high variability in lag time. Overall, the study concluded that low MW HPMCs (E5, E15 and E50) were found rather efficient than higher MW HPMCs for developing robust EC-based press-coated pulsatile release formulations where precise lag time followed by sharp burst release is desired. PMID- 26100759 TI - Sex, social status, and CRF receptor densities in naked mole-rats. AB - Naked mole-rats (Heterocephalus glaber) live in groups that are notable for their large size and caste structure, with breeding monopolized by a single female and a small number of males. Recent studies have demonstrated substantial differences between the brains of breeders and subordinates induced by changes in social standing. Corticotropin-releasing factor (CRF) receptors-which bind the hormone CRF as well as related peptides-are important regulators of stress and anxiety, and are emerging as factors affecting social behavior. We conducted autoradiographic analyses of CRF1 and CRF2 receptor binding densities in female and male naked mole-rats varying in breeding status. Both globally and in specific brain regions, CRF1 receptor densities varied with breeding status. CRF1 receptor densities were higher in subordinates across brain regions, and particularly in the piriform cortex and cortical amygdala. Sex differences were present in CRF2 receptor binding densities, as is the case in multiple vole species. CRF2 receptor densities were higher in females, both globally and in the cortical amygdala and lateral amygdalar nucleus. These results provide novel insights into the neurobiology of social hierarchy in naked mole-rats, and add to a growing body of work that links changes in the CRF system with social behavior. PMID- 26100760 TI - Mycobacterial glycolipids di-O-acylated trehalose and tri-O-acylated trehalose downregulate inducible nitric oxide synthase and nitric oxide production in macrophages. AB - BACKGROUND: Tuberculosis (TB) remains a serious human health problem that affects millions of people in the world. Understanding the biology of Mycobacterium tuberculosis (Mtb) is essential for tackling this devastating disease. Mtb possesses a very complex cell envelope containing a variety of lipid components that participate in the establishment of the infection. We have previously demonstrated that di-O-acylated trehalose (DAT), a non-covalently linked cell wall glycolipid, inhibits the proliferation of T lymphocytes and the production of cytokines. RESULTS: In this work we show that DAT and the closely related tri O-acylated trehalose (TAT) inhibits nitric oxide (NO) production and the inducible nitric oxide synthase (iNOS) expression in macrophages (MO). CONCLUSIONS: These findings show that DAT and TAT are cell-wall located virulence factors that downregulate an important effector of the immune response against mycobacteria. PMID- 26100761 TI - The effect of chart speed on fetal monitor interpretation. AB - OBJECTIVE: Electronic fetal heart monitor chart speeds vary between countries, and it is unclear whether differing chart speeds affect physician tracing interpretation. METHODS: Twenty-minute segments of 19 tracings were displayed on both 1 and 3 cm/min strips and interpreted by 14 physicians at the particular speed they were accustomed to reading. Interpretations of tracing characteristics were compared between groups using free margin kappa, a measure of interobserver agreement. RESULTS: Compared to 3 cm/min tracings, 1 cm/min tracings were significantly more often identified as having absent than minimal variability, and minimal than moderate variability. Accelerations were significantly more often identified in 1 versus 3 cm/min strips. There were no significant differences between groups with respect to baseline fetal heart rate, prolonged or repetitive decelerations, or American College of Obstetricians and Gynecologists tracing category. Neither chart speed had substantial interobserver agreement in tracing variables; however, agreement was consistently higher in 3 versus 1 cm/min tracings (all p < 0.05). CONCLUSIONS: Tracing interpretation is significantly affected by fetal monitor chart speed with regards to variability, acceleration and deceleration. Further studies are required to determine if differences in chart speed interpretation affect clinical management. PMID- 26100762 TI - Prediction of gestational diabetes mellitus by first trimester serum secreted frizzle-related protein-5 levels. AB - OBJECTIVE: The main aim of this study was to investigate the first trimester maternal serum secreted frizzle-related protein-5 (Sfrp-5) levels and to evaluate the predictive value on the subsequently developed gestational diabetes mellitus (GDM). METHODS: A total of 40 pregnant women who subsequently developed GDM and 44 age- and pre-pregnancy BMI-matched healthy pregnant women were enrolled in this prospective case-control study. First trimester serum Sfrp-5 levels were evaluated to determine if there is an association with the onset of GDM, by using logistic regression analysis. RESULTS: Decreased first trimester serum Sfrp-5 levels (OR = 14.332, 95%CI: 4.166-49.301, p < 0.001) were found to be significantly associated with the increased risk of GDM. There were no statistically significant differences in serum Sfrp-5 levels between the diet- and insulin-treated GDM groups and also serum Sfrp-5 levels were not found to be predictive for adverse perinatal outcomes (p > 0.05). CONCLUSIONS: Decreased first trimester serum Sfrp-5 levels are significantly associated with the increased risk of GDM. PMID- 26100763 TI - A comparison of two techniques of uterine closure in caesarean section. AB - OBJECTIVE: To compare the results of two different techniques of uterine closure in caesarean section operations in which assistant surgeons participated. METHODS: A total of 765 patients were separated into two groups.In Group1(n = 380), the assistant surgeon, while pulling the suture in a caudal direction with the left hand, held the uterine wall from the joined site with the right hand to prevent upward tension of tissue. In Group 2 (n = 385), the suture was placed by the assistant surgeon by pulling it in the cephalic direction with the right hand. These two techniques were evaluated in respect of the postoperative decrease in haemoglobin level ,the need for additional sutures and operative outcomes. RESULTS: The need for additional sutures was determined as statistically high in Group 2 at mean 0.5 +/- 0.6 compared to mean 0.2 +/- 0.5 in Group1 (p < 0.001). The mean operating time was determined as statistically significantly longer in Group 2 (Group1, 38.0 +/- 5.6 mins and Group2, 41.3 +/- 4.3 mins) (p < 0.001). The postoperative decrease in hb was statistically significantly greater in Group 2 (Group1, 1.1 +/- 0.4, Group2, 1.2 +/- 0.4) (p = 0.002). CONCLUSION: The cephalic direction placement of the suture with the right hand of the assistant surgeon in uterine closure leads to bleeding due to tissue cuts in the lower wound lip and thereby creating a need for additional sutures. Therefore, the suture should be placed in a caudal direction with the left hand. PMID- 26100764 TI - A benchmark study of numerical schemes for one-dimensional arterial blood flow modelling. AB - Haemodynamical simulations using one-dimensional (1D) computational models exhibit many of the features of the systemic circulation under normal and diseased conditions. Recent interest in verifying 1D numerical schemes has led to the development of alternative experimental setups and the use of three dimensional numerical models to acquire data not easily measured in vivo. In most studies to date, only one particular 1D scheme is tested. In this paper, we present a systematic comparison of six commonly used numerical schemes for 1D blood flow modelling: discontinuous Galerkin, locally conservative Galerkin, Galerkin least-squares finite element method, finite volume method, finite difference MacCormack method and a simplified trapezium rule method. Comparisons are made in a series of six benchmark test cases with an increasing degree of complexity. The accuracy of the numerical schemes is assessed by comparison with theoretical results, three-dimensional numerical data in compatible domains with distensible walls or experimental data in a network of silicone tubes. Results show a good agreement among all numerical schemes and their ability to capture the main features of pressure, flow and area waveforms in large arteries. All the information used in this study, including the input data for all benchmark cases, experimental data where available and numerical solutions for each scheme, is made publicly available online, providing a comprehensive reference data set to support the development of 1D models and numerical schemes. PMID- 26100765 TI - Dangers and uses of cross-correlation in analyzing time series in perception, performance, movement, and neuroscience: The importance of constructing transfer function autoregressive models. AB - Many articles on perception, performance, psychophysiology, and neuroscience seek to relate pairs of time series through assessments of their cross-correlations. Most such series are individually autocorrelated: they do not comprise independent values. Given this situation, an unfounded reliance is often placed on cross-correlation as an indicator of relationships (e.g., referent vs. response, leading vs. following). Such cross-correlations can indicate spurious relationships, because of autocorrelation. Given these dangers, we here simulated how and why such spurious conclusions can arise, to provide an approach to resolving them. We show that when multiple pairs of series are aggregated in several different ways for a cross-correlation analysis, problems remain. Finally, even a genuine cross-correlation function does not answer key motivating questions, such as whether there are likely causal relationships between the series. Thus, we illustrate how to obtain a transfer function describing such relationships, informed by any genuine cross-correlations. We illustrate the confounds and the meaningful transfer functions by two concrete examples, one each in perception and performance, together with key elements of the R software code needed. The approach involves autocorrelation functions, the establishment of stationarity, prewhitening, the determination of cross-correlation functions, the assessment of Granger causality, and autoregressive model development. Autocorrelation also limits the interpretability of other measures of possible relationships between pairs of time series, such as mutual information. We emphasize that further complexity may be required as the appropriate analysis is pursued fully, and that causal intervention experiments will likely also be needed. PMID- 26100766 TI - Performance impact of stop lists and morphological decomposition on word-word corpus-based semantic space models. AB - Corpus-based semantic space models, which primarily rely on lexical co-occurrence statistics, have proven effective in modeling and predicting human behavior in a number of experimental paradigms that explore semantic memory representation. The most widely studied extant models, however, are strongly influenced by orthographic word frequency (e.g., Shaoul & Westbury, Behavior Research Methods, 38, 190-195, 2006). This has the implication that high-frequency closed-class words can potentially bias co-occurrence statistics. Because these closed-class words are purported to carry primarily syntactic, rather than semantic, information, the performance of corpus-based semantic space models may be improved by excluding closed-class words (using stop lists) from co-occurrence statistics, while retaining their syntactic information through other means (e.g., part-of-speech tagging and/or affixes from inflected word forms). Additionally, very little work has been done to explore the effect of employing morphological decomposition on the inflected forms of words in corpora prior to compiling co-occurrence statistics, despite (controversial) evidence that humans perform early morphological decomposition in semantic processing. In this study, we explored the impact of these factors on corpus-based semantic space models. From this study, morphological decomposition appears to significantly improve performance in word-word co-occurrence semantic space models, providing some support for the claim that sublexical information-specifically, word morphology plays a role in lexical semantic processing. An overall decrease in performance was observed in models employing stop lists (e.g., excluding closed-class words). Furthermore, we found some evidence that weakens the claim that closed-class words supply primarily syntactic information in word-word co-occurrence semantic space models. PMID- 26100767 TI - Elucidating the evolution of hominid dentition in the age of phenomics, modularity, and quantitative genetics. AB - An organism's anatomy is the result of millions of years of interplay between DNA sequence, developmental processes, the environment, and evolutionary forces. The anatomical sciences are consequently highly integrative and interdisciplinary. That said, reaching across all of the relevant disciplines can be a daunting task because scientific publications are produced today at an astounding rate. This manuscript brings together insights from the quantitative genetic analysis of dental variation into the study of human evolutionary odontology within the context of genomics, genetic modularity, and phenomics. It primarily advocates the use of quantitative genetics to not only identify QTLs, but also to assess the patterns of genetic covariance that underlie phenotypic covariance, thereby enabling us to conceptualize phenotypic variation as a reflection of the underlying genetic mechanisms. By highlighting three phenotypes of importance within the study of human evolution (patterning of the dental arcade, enamel thickness, and taurodontism), it is demonstrated how an integrated consideration of quantitative genetics, genomic analyses, and paleontology can bring us to more detailed hypotheses about the evolution of the hominid clade. PMID- 26100768 TI - Lobodontia: Genetic entity with specific pattern of dental dysmorphology. AB - A characteristic pattern of dental anomalies including cone-shaped premolars, multitubercular molar crowns, pyramidal molar roots with single root canals, shovel-shaped incisors with palatal invaginations and hypodontia usually described as lobodontia was recognised as a separate entity. Only a few family reports on this condition have been published until now. The prevalence of the condition is estimated to be less than 1:1000,000. In the present paper we tried to delineate and clarify some additional aspects of this rare genetic entity in three families with 17 affected members. This represents the largest number of cases recorded since now. The analyses of dental morphology, crown-size profile patterns, pedigree analyses, and analyses of digitopalmar dermatoglyphics were performed in 7 examined patients. Crown-size profile pattern was calculated for seven patients and compared with standards for the Croatian population. The most striking features of the condition are conical premolars, tritubercular canines, single pyramidal molar roots, multitubercular molar crowns and invaginated upper incisors. A considerable reduction of crown-size was observed for all premolars, particularly in mandible. The alveolar process in the premolar region was hypoplastic and thin in all patients studied. Gender ratio of affected individuals was approximately M1:F1. Our data suggest that the prevalence of this condition is less than 1:300,000 in the Croatian population, which is considerably higher than previously reported in the literature. The analysis of the anomaly in all the families showed a slight variability in the clinical picture and autosomal dominant (AD) mode of inheritance. It could be concluded that this rare condition described as lobodontia represents a true genetic entity which follows AD mode of inheritance and displays variability in its expression. PMID- 26100769 TI - Cervical spine injury in dismounted improvised explosive device trauma. AB - BACKGROUND: The injury pattern from improvised explosive device (IED) trauma is different if the target is in a vehicle (mounted) or on foot (dismounted). Combat and civilian first response protocols require the placement of a cervical collar on all victims of a blast injury. METHODS: We searched the Joint Theatre Trauma Registry (JTTR) and the Role 3 Hospital, Kandahar Airfield (KAF) database from Mar. 1, 2008, to May 31, 2011. We collected data on cervical fracture; head injury; traumatic amputation; initial blood pressure, pulse, injury severity score (ISS), Glasgow Coma Scale (GCS) score and base excess; and patient demographic information. RESULTS: The concordance rate between JTTR and KAF databases was 98%. Of the 15 693 admissions in JTTR, 326 patients with dismounted IED injuries were located. The rate of cervical collar prehospital placement was 7.6%. Cervical fractures were found in 19 (5.8%) dismounted IED victims, but only 4 (1.2%) were considered radiographically unstable. None of these 19 patients had prehospital placement of a collar. Patients with cervical spine fractures were more severely injured than those without (ISS 18.2 v. 13.4; GCS 10.1 v. 12.5). Patients with head injuries had significantly higher risk of cervical spine injury than those with no head injury recorded (13.6% v. 3.9%). No differences in frequency of cervical spine injury were found between patients who had associated traumatic amputations and those who did not (5.4% v. 6.0%). CONCLUSION: Dismounted IED is a mechanism of injury associated with a low risk for cervical spine trauma. A selective protocol for cervical collar placement on victims of dismounted IED blasts is possible and may be more amenable to combat situations. PMID- 26100770 TI - Blunt splenic injury and severe brain injury: a decision analysis and implications for care. AB - BACKGROUND: The initial nonoperative management (NOM) of blunt splenic injuries in hemodynamically stable patients is common. In soldiers who experience blunt splenic injuries with concomitant severe brain injury while on deployment, however, NOM may put the injured soldier at risk for secondary brain injury from prolonged hypotension. METHODS: We conducted a decision analysis using a Markov process to evaluate 2 strategies for managing hemodynamically stable patients with blunt splenic injuries and severe brain injury--immediate splenectomy and NOM--in the setting of a field hospital with surgical capability but no angiography capabilities. We considered the base case of a 40-year-old man with a life expectancy of 78 years who experienced blunt trauma resulting in a severe traumatic brain injury and an isolated splenic injury with an estimated failure rate of NOM of 19.6%. The primary outcome measured was life expectancy. We assumed that failure of NOM would occur in the setting of a prolonged casualty evacuation, where surgical capability was not present. RESULTS: Immediate splenectomy was the slightly more effective strategy, resulting in a very modest increase in overall survival compared with NOM. Immediate splenectomy yielded a survival benefit of only 0.4 years over NOM. CONCLUSION: In terms of overall survival, we would not recommend splenectomy unless the estimated failure rate of NOM exceeded 20%, which corresponds to an American Association for the Surgery of Trauma grade III splenic injury. For military patients for whom angiography may not be available at the field hospital and who require prolonged evacuation, immediate splenectomy should be considered for grade III-V injuries in the presence of severe brain injury. PMID- 26100771 TI - Needle thoracostomy for tension pneumothorax: the Israeli Defense Forces experience. AB - BACKGROUND: Point of injury needle thoracostomy (NT) for tension pneumothorax is potentially lifesaving. Recent data raised concerns regarding the efficacy of conventional NT devices. Owing to these considerations, the Israeli Defense Forces Medical Corps (IDF-MC) recently introduced a longer, wider, more durable catheter for the performance of rapid chest decompression. The present series represents the IDF-MC experience with chest decompression by NT. METHODS: We reviewed the IDF trauma registry from January 1997 to October 2012 to identify all cases in which NT was attempted. RESULTS: During the study period a total of 111 patients underwent chest decompression by NT. Most casualties (54%) were wounded as a result of gunshot wounds (GSW); motor vehicle accidents (MVAs) were the second leading cause (16%). Most (79%) NTs were performed at the point of injury, while the rest were performed during evacuation by ambulance or helicopter (13% and 4%, respectively). Decreased breath sounds on the affected side were one of the most frequent clinical indications for NT, recorded in 28% of cases. Decreased breath sounds were more common in surviving than in nonsurviving patients. (37% v. 19%, p < 0.001). A chest tube was installed on the field in 35 patients (32%), all after NT. CONCLUSION: Standard NT has a high failure rate on the battlefield. Alternative measures for chest decompression, such as the Vygon catheter, appear to be a feasible alternative to conventional NT. PMID- 26100772 TI - Current use of live tissue training in trauma: a descriptive systematic review. AB - BACKGROUND: Growing public concern for animal welfare, advances in computerized simulation and economic barriers have drawn a critical eye to the use of live tissue training (LTT) in trauma skills acquisition. As a consequence, other simulation methods have replaced LTT, for example, in the Advanced Trauma Life Support (ATLS) course. Owing to the lack of clear conclusions in the literature, we conducted a systematic review to determine the value of LTT alone and in comparison to other simulation methods in trauma. METHODS: We performed a systematic review of the literature considering observational studies and randomized controlled trials (RCTs) that examined LTT in trauma exclusively or compared with other simulation methods. Independently and in duplicate, we adjudicated studies for inclusion and data abstraction. We assessed the quality and risk of bias. RESULTS: Twelve studies met our inclusion criteria: 2 RCTs and 10 prospective cohort studies. Eight and 4 studies were performed in the military and in the civilian settings, respectively. Anesthetized swine were used in 8 studies and goats in 1. The cohort studies involved LTT alone. Different adjunctive training modalities were included: mannequins in 6 studies, cadavers in 2, computer simulation in 1, video presentations in 2 and wound moulage scenarios in 1. The overall methodological quality was moderate as per the Newcastle-Ottawa score (mean 6.0 +/- 0, possible range 1-9). The 2 RCTs did not demonstrate adequate random sequence generation and allocation concealment. CONCLUSION: There is limited evidence that other types of simulation are better than LTT. Data on training effects of LTT versus other simulations on outcomes are lacking. PMID- 26100773 TI - Acute nontraumatic general surgical conditions on a combat deployment. AB - BACKGROUND: Literature is lacking on acute surgical problems that may be encountered on military deployment; even less has been written on whether or not any of these surgical problems could have been avoided with more focused predeployment screening. We sought to determine the burden of illness attributable to acute nontraumatic general surgical problems while on deployment and to identify areas where more rigorous predeployment screening could be implemented to decrease surgical resource use for nontraumatic problems. METHODS: We studied all Canadian Armed Forces (CAF) members deployed to Afghanistan between Feb. 7, 2006, and June 30, 2011, who required treatment for a nontraumatic general surgical condition. RESULTS: During the study period 28 990 CAF personnel deployed to Afghanistan; 373 (1.28%) were repatriated because of disease and 100 (0.34%) developed an acute general surgical condition. Among those who developed an acute surgical illness, 42 were combat personnel (42%) and 58 were support personnel (58%). Urologic diagnoses (n = 34) were the most frequent acute surgical conditions, followed by acute appendicitis (n = 18) and hernias (n = 12). We identified 5 areas where intensified predeployment screening could have potentially decreased the incidence of in-theatre acute surgical illness. CONCLUSION: Our findings suggest that there is a significant acute care surgery element encountered on combat deployment, and surgeons tasked with caring for this population should be prepared to treat these patients. PMID- 26100774 TI - Factors affecting mortality of pediatric trauma patients encountered in Kandahar, Afghanistan. AB - BACKGROUND: The North Atlantic Treaty Organization (NATO) Role 3 Multinational Medical Unit (R3-MMU) is a tertiary care trauma facility that receives casualties, both coalition and civilian, and provides humanitarian medical assistance when able to the Kandahar province in southern Afghanistan. We examined the cohort of pediatric patients evaluated at the facility during a 16 month period to determine the characteristics and care requirements of this unique patient population. METHODS: A database of Afghan patients younger than 18 years of age admitted to the NATO R3-MMU between January 2010 and April 2011 was developed from the Joint Theatre Trauma Registry. This patient cohort was analyzed to determine demographics, injury mechanism, injury severity, resource utilization and factors associated with mortality. RESULTS: A total of 263 children were admitted to the NATO R3-MMU during the study period, representing 12% of all trauma admissions during this time period. The median age was 9 years (range 3 mo-17 yr) with a predominance of male patients (82%). Battle-related trauma was responsible for 62% of admissions, with explosive blast injury constituting the predominant mechanism (42%). The average injury severity score was 12.3 +/- 9.3. Overall mortality was 8%. Factors associated with increased risk of death included admission acidosis, coagulopathy, hypothermia and female sex. CONCLUSION: Children represent a significant proportion of traumatic injuries encountered in a modern war zone; many of them are critically injured. Organizations that provide health care in such environments should be prepared to care for this patient population where their mandates and facilities allow for it. PMID- 26100775 TI - The Canadian Armed Forces medical response to Typhoon Haiyan. AB - BACKGROUND: In the setting of international disaster response, an important challenge is determining when it is appropriate to withdraw deployed assets as the acute disaster response transitions to recovery and rebuilding. We describe our experience with realtime data collection during our medical response to Typhoon Haiyan as a means to guide military aid mission parameters. METHODS: The operational medical headquarters prospectively developed a database for use in this mission. Mobile medical teams (MMTs) were deployed to provide primary care, and the nurse designated to each MMT was responsible for entering and transmitting data daily to the medical headquarters. Data collected included the MMT location, basic patient demographics, the primary reason for the encounter and any treatment provided. These encounters were then classified as disaster, acute or chronic. RESULTS: Between Nov. 16 and Dec. 16, 2013, medical care was provided to 6596 local nationals; 238 (3.6%) had disaster-related illness or injury, 4321 (65.5%) had acute postdisaster medical conditions and 2037 (30.9%) sought medical care for chronic conditions. Of the 257 patients with traumatic injuries, 28 (11%) had disaster-related injuries and 214 (83%) had acute injuries that occurred postdisaster. CONCLUSION: The data collected during the mission to the Phillippines was compiled with performance metrics from the other Disaster Assistance Response Team components to help advise the Canadian government regarding mission duration. We recommended that data collection continue on all future missions and be modified to provide further information to larger disaster coordination teams, such as the United Nations Office for the Coordination of Humanitarian Affairs. PMID- 26100776 TI - Fresh whole blood transfusion capability for Special Operations Forces. AB - Fresh whole blood (FWB) transfusion is an option for providing volume and oxygen carrying capacity to bleeding Special Operations soldiers who are injured in an austere environment and who are far from a regular blood bank. Retrospective data from recent conflicts in Iraq and Afghanistan show an association between the use of FWB and survival. We reviewed the literature to document the issues surrounding FWB transfusion to Special Operations soldiers in the austere environment and surveyed the literature regarding best practice guidelines for and patient outcomes after FWB transfusions. Most literature regarding FWB transfusion is retrospective or historical. There is limited prospective evidence currently to change transfusion practice in tertiary care facilities, but FWB remains an option in the austere setting. PMID- 26100777 TI - The Canadian Armed Forces Supplement on Military Medicine: Caring for the Wounded in the Future. Foreword. PMID- 26100779 TI - Introduction. PMID- 26100781 TI - In memoriam--Erin Savage, MD, CCFP(EM) Lieutenant Colonel, Royal Canadian Medical Service. AB - This supplement is dedicated to the memory of Lieutenant Colonel Erin Savage. Erin passed away peacefully on Nov. 7, 2014, surrounded by loving family and friends in Ottawa, Ont., after a lengthy battle with breast cancer. PMID- 26100782 TI - The need for a robust 24/7 subspecialty "clearing house" response for telementored trauma care. AB - Traumatic injury is increasing in importance in all settings and environments worldwide. Many preventable deaths are from conditions that are common and treatable. However, as potentially lethal injuries often induce progressive and frequently irreversible physiologic decline, the timing of interventions is critical. Invasive treatments may need to be offered by prehospital care providers who lack extensive training and practice. Telementoring allows experienced experts to guide less experienced providers remotely using information technology (IT). Early experience has shown that these techniques are practical and considered valuable. Their translation to regular practice, however, will require the immediate availability of appropriately trained remote experts willing to serve as mentors. Acute care trauma specialists are acclimatized to responding to out-of-hospital consultations and assuming overall responsibility for critical physiology and transport and may serve as the backbone of such a national/ international call response initiative. PMID- 26100783 TI - Technical innovations that may facilitate real-time telementoring of damage control surgery in austere environments: a proof of concept comparative evaluation of the importance of surgical experience, telepresence, gravity and mentoring in the conduct of damage control laparotomies. AB - Bleeding to death is the most preventable cause of posttraumatic death worldwide. Despite the fact that many of these deaths are anatomically salvageable with relatively basic surgical interventions, they remain lethal in actuality in prehospital environments when no facilities and skills exist to contemplate undertaking basic damage control surgery (DCS). With better attention to prehospital control of extremity hemorrhage, intracavitary bleeding (especially intraperitoneal) remains beyond the scope of prehospital providers. However, recent revolutions in the informatics and techniques of telementoring (TMT), DCS and highly realistic accelerated training of motivated first responders suggests that basic lifesaving DCS may have applicability to save bleeding patients in austere environments previously considered unsalvageable. Especially with informatic advances, any provider with Internet connectivity can potentially be supported by highly proficient specialists with content expertise in the index problem. This unprecedented TMT support may allow highly motivated but inexperienced personnel to provide advanced surgical interventions in extreme environments in many austere locations both on and above the planet. PMID- 26100784 TI - Advances in damage control resuscitation and surgery: implications on the organization of future military field forces. AB - Medical support to deployed field forces is increasingly becoming a shared responsibility among allied nations. National military medical planners face several key challenges, including fiscal restraints, raised expectations of standards of care in the field and a shortage of appropriately trained specialists. Even so, medical services are now in high demand, and the availability of medical support may become the limiting factor that determines how and where combat units can deploy. The influence of medical factors on operational decisions is therefore leading to an increasing requirement for multinational medical solutions. Nations must agree on the common standards that govern the care of the wounded. These standards will always need to take into account increased public expectations regarding the quality of care. The purpose of this article is to both review North Atlantic Treaty Organization (NATO) policies that govern multinational medical missions and to discuss how recent scientific advances in prehospital battlefield care, damage control resuscitation and damage control surgery may inform how countries within NATO choose to organize and deploy their field forces in the future. PMID- 26100785 TI - Medical mentorship in Afghanistan: How are military mentors perceived by Afghan health care providers? AB - BACKGROUND: Previous work has been published on the experiences of high-resource setting physicians mentoring in low-resource environments. However, not much is known about what mentees think about their First World mentors. We had the opportunity to explore this question in an Afghan Army Hospital, and we believe this is the first time this has been studied. METHODS: We conducted a pilot cross sectional survey of Afghan health care providers evaluating their Canadian mentors. We created a culturally appropriate 19- question survey with 5-point Likert scores that was then translated into the local Afghan language. The survey questions were based on domains of Royal College of Physicians and Surgeons of Canada's CanMEDS criteria. RESULTS: The survey response rate was 90% (36 of 40). The respondents included 13 physicians, 21 nurses and 2 other health care professionals. Overall, most of the Afghan health care workers felt that working with mentors from high-resource settings was a positive experience (median 4.0, interquartile range [IQR] 4-4), according to CanMEDS domains. However, respondents indicated that the mentors were reliant on medical technology for diagnosis (median 5.0, IQR 4-5) and failed to consider the limited resources available in Afghanistan. CONCLUSION: The overall impression of Afghan health care providers was that mentors are appropriate and helpful. CanMEDS can be used as a framework to evaluate mentors in low-resource conflict environments. PMID- 26100786 TI - Levels of regulatory T cells CD69(+)NKG2D(+)IL-10(+) are increased in patients with autoimmune thyroid disorders. AB - Regulatory T (Treg) cells play an important role in the pathogenesis of autoimmune thyroid disorders (AITD). New subsets of CD4(+)CD69(+) and CD4(+)NKG2D(+) T lymphocytes that behave as regulatory cells have been recently reported. The role of these immunoregulatory lymphocytes has not been previously explored in AITD. We analyzed by multi-parametric flow cytometry different Treg cell subsets in peripheral blood from 32 patients with AITD and 19 controls, and in thyroid tissue from seven patients. The suppressive activity was measured by an assay of inhibition of lymphocyte activation. We found a significant increased percentage of CD4(+)CD69(+)IL-10(+), CD4(+)CD69(+)NKG2D(+), and CD4(+)CD69(+)IL 10(+)NKG2D(+) cells, in peripheral blood from GD patients compared to controls. The increase in CD4(+)CD69(+)IL-10(+) and CD4(+)CD69(+)IL-10(+)NKG2D(+) T cells was especially remarkable in patients with active Graves' ophthalmopathy (GO), and a significant positive correlation between GO activity and CD4(+)CD69(+)IL 10(+) or CD4(+)CD69(+)IL-10(+)NKG2D(+) cells was also found. In addition, these cells were increased in patients with a more severe and/or prolonged disease. Thyroid from AITD patients showed an increased proportion of CD69(+) regulatory T cells subpopulations compared to autologous peripheral blood. The presence of CD69(+), NKG2D(+), and IL-10(+) cells was confirmed by immunofluorescence microscopy. In vitro functional assays showed that CD69(+) Treg cells exerted an important suppressive effect on the activation of T effector cells in controls, but not in AITD patients. Our findings suggest that the levels of CD69(+) regulatory lymphocytes are increased in AITD patients, but they are apparently unable to down-modulate the autoimmune response and tissue damage. PMID- 26100787 TI - Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes. AB - Decreases in serum testosterone concentrations in aging men are associated with metabolic disorders. Testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available. This study was designed to determine the effects of testosterone on glucose uptake in adipocytes. Glucose uptake was assessed with 2 [(3)H] deoxyglucose in 3T3-L1 adipocytes. GLUT4 translocation was evaluated in plasma membrane (PM) sheets and PM fractions by immunofluorescence and immunoblotting, respectively. Activation of GLUT4 translocation-related protein kinases, including Akt, AMPK, LKB1, CaMKI, CaMKII, and Cbl was followed by immunoblotting. Expression levels of androgen receptor (AR) mRNA and AR translocation to the PM were assessed by real-time RT-PCR and immunoblotting, respectively. The results showed that both high-dose (100 nM) testosterone and testosterone-BSA increased glucose uptake and GLUT4 translocation to the PM, independently of the intracellular AR. Testosterone and testosterone-BSA stimulated the phosphorylation of AMPK, LKB1, and CaMKII. The knockdown of LKB1 by siRNA attenuated testosterone- and testosterone-BSA-stimulated AMPK phosphorylation and glucose uptake. These results indicate that high-dose testosterone and testosterone-BSA increase GLUT4-dependent glucose uptake in 3T3 L1 adipocytes by inducing the LKB1/AMPK signaling pathway. PMID- 26100789 TI - Increased risk of thyroid autoimmunity in rheumatoid arthritis. PMID- 26100788 TI - Subjects with isolated GH deficiency due to a null GHRHR mutation eat proportionally more, but healthier than controls. AB - The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G->A) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO. PMID- 26100790 TI - 'Language is the source of misunderstandings'--impact of terminology on public perceptions of health promotion messages. AB - BACKGROUND: The high level of premature death due to non-communicable diseases has been associated with unhealthful lifestyles, including poor diet. The effectiveness of public health strategies designed to promote health via messages focusing on food and diets depends largely on the perception of the messages by the public. The aim of this study was to explore public perceptions of language commonly used to communicate concepts linking health, food and the diet. METHODS: This study is a qualitative and semi-quantitative cross-sectional survey exploring public perceptions of terms used to improve eating habits within public health strategies. We recruited adults with no background in nutrition or health care, from May to July 2013, from urban areas of varying deprivation (n = 12) in Glasgow and Edinburgh, UK. Four key prompt-terms used to convey the idea of improving health through diet were selected for testing: Healthy Eating, Eating for Health, Balanced Diet and Nutritional Balance. Consumer understanding of these terms was explored using mixed-methods, including qualitative focus groups (n = 17) and an interviewer-led word-association exercise (n = 270). RESULTS: The word-association exercise produced 1,386 individual responses from the four prompt-terms, with 130 unique responses associated with a single term. Cluster analysis revealed 16 key themes, with responses affected by prompt-term used, age, gender and socio-economic status. Healthy Eating was associated with foods considered 'healthy' (p <0.05); Eating for Health and Balanced Diet with negative connotations of foods to avoid (both p <0.001) and Nutritional Balance with the benefits of eating healthily (p <0.01). Focus groups revealed clear differences in perceptions: Eating for Health = positive action one takes to manage existing medical conditions, Healthy Eating = passive aspirational term associated with weight management, Balanced Diet = old fashioned, also dieting for weight loss, Nutritional Balance = maximising physical performance. Food suppliers use Healthy Eating terminology to promote weight management products. Focus group participants welcomed product reformulation to enhance food health properties as a strategy to overcome desensitisation to health-messages. CONCLUSIONS: Public perceptions of messages communicating concepts linking health, food and the diet are influenced by terminology, resulting in confusion. To increase individual commitment to change eating habits in the long term, public health campaigns need strengthening, potentially by investing in tailored approaches to meet the needs of defined groups of consumers. PMID- 26100792 TI - Chemical doublespeak. PMID- 26100791 TI - Theoretical Studies of Interactions between O-Phosphorylated and Standard Amino Acid Side-Chain Models in Water. AB - Phosphorylation is a common post-translational modification of the amino-acid side chains (serine, tyrosine, and threonine) that contain hydroxyl groups. The transfer of the negatively charged phosphate group from an ATP molecule to such amino-acid side chains leads to changes in the local conformations of proteins and the pattern of interactions with other amino-acid side-chains. A convenient characteristic of the side chain-side chain interactions in the context of an aqueous environment is the potential of mean force (PMF) in water. A series of umbrella-sampling molecular dynamic (MD) simulations with the AMBER force field were carried out for pairs of O-phosphorylated serine (pSer), threonine (pThr), and tyrosine, (pTyr) with natural amino acids in a TIP3P water model as a solvent at 298 K. The weighted-histogram analysis method was used to calculate the four dimensional potentials of mean force. The results demonstrate that the positions and depths of the contact minima and the positions and heights of the desolvation maxima, including their dependence on the relative orientation depend on the character of the interacting pairs. More distinct minima are observed for oppositely charged pairs such as, e.g., O-phosphorylated side-chains and positively charged ones, such as the side-chains of lysine and arginine. PMID- 26100798 TI - Bioorthogonal catalysis: Rise of the nanobots. PMID- 26100799 TI - Stereoselective synthesis: Molecular editing of carbohydrates. PMID- 26100800 TI - Analytical chemistry: Clamping down on cancer detection. PMID- 26100801 TI - Nano-plasmonics: Chirality transfer takes a jump. PMID- 26100802 TI - Simulation-guided DNA probe design for consistently ultraspecific hybridization. AB - Hybridization of complementary sequences is one of the central tenets of nucleic acid chemistry; however, the unintended binding of closely related sequences limits the accuracy of hybridization-based approaches to analysing nucleic acids. Thermodynamics-guided probe design and empirical optimization of the reaction conditions have been used to enable the discrimination of single-nucleotide variants, but typically these approaches provide only an approximately 25-fold difference in binding affinity. Here we show that simulations of the binding kinetics are both necessary and sufficient to design nucleic acid probe systems with consistently high specificity as they enable the discovery of an optimal combination of thermodynamic parameters. Simulation-guided probe systems designed against 44 sequences of different target single-nucleotide variants showed between a 200- and 3,000-fold (median 890) higher binding affinity than their corresponding wild-type sequences. As a demonstration of the usefulness of this simulation-guided design approach, we developed probes that, in combination with PCR amplification, detect low concentrations of variant alleles (1%) in human genomic DNA. PMID- 26100804 TI - Roaming-mediated ultrafast isomerization of geminal tri-bromides in the gas and liquid phases. AB - 'Roaming' is a new and unusual class of reaction mechanism that has recently been discovered in unimolecular dissociation reactions of isolated molecules in the gas phase. It is characterized by frustrated bond cleavage, after which the two incipient fragments 'roam' on a flat region of the potential energy surface before reacting with one another. Here, we provide evidence that supports roaming in the liquid phase. We are now able to explain previous solution-phase experiments by comparing them with new ultrafast transient absorption data showing the photoisomerization of gas-phase CHBr3. We see that, upon S0-S1 excitation, gas-phase CHBr3 isomerizes within 100 fs into the BrHCBr-Br species, which is identical to what has been observed in solution. Similar sub-100 fs isomerization is now also observed for BBr3 and PBr3 in solution upon S1 excitation. Quantum chemical simulations of XBr3 (X = B, P or CH) suggest that photochemical reactivity in all three cases studied is governed by S1/S0 conical intersections and can best be described as occurring through roaming-mediated pathways. PMID- 26100803 TI - Selective, rapid and optically switchable regulation of protein function in live mammalian cells. AB - The rapid and selective regulation of a target protein within living cells that contain closely related family members is an outstanding challenge. Here we introduce genetically directed bioorthogonal ligand tethering (BOLT) and demonstrate selective inhibition (iBOLT) of protein function. In iBOLT, inhibitor conjugate/target protein pairs are created where the target protein contains a genetically encoded unnatural amino acid with bioorthogonal reactivity and the inhibitor conjugate contains a complementary bioorthogonal group. iBOLT enables the first rapid and specific inhibition of MEK isozymes, and introducing photoisomerizable linkers in the inhibitor conjugate enables reversible, optical regulation of protein activity (photo-BOLT) in live mammalian cells. We demonstrate that a pan kinase inhibitor conjugate allows selective and rapid inhibition of the lymphocyte specific kinase, indicating the modularity and scalability of BOLT. We anticipate that BOLT will enable the rapid and selective regulation of diverse proteins for which no selective small-molecule ligands exist. PMID- 26100805 TI - An electrochemical clamp assay for direct, rapid analysis of circulating nucleic acids in serum. AB - The analysis of cell-free nucleic acids (cfNAs), which are present at significant levels in the blood of cancer patients, can reveal the mutational spectrum of a tumour without the need for invasive sampling of the tissue. However, this requires differentiation between the nucleic acids that originate from healthy cells and the mutated sequences shed by tumour cells. Here we report an electrochemical clamp assay that directly detects mutated sequences in patient serum. This is the first successful detection of cfNAs without the need for enzymatic amplification, a step that normally requires extensive sample processing and is prone to interference. The new chip-based assay reads out the presence of mutations within 15 minutes using a collection of oligonucleotides that sequester closely related sequences in solution, and thus allow only the mutated sequence to bind to a chip-based sensor. We demonstrate excellent levels of sensitivity and specificity and show that the clamp assay accurately detects mutated sequences in a collection of samples taken from lung cancer and melanoma patients. PMID- 26100806 TI - Chemoselective conversion of biologically sourced polyols into chiral synthons. AB - Crude oil currently provides much of the world's energy, but it is also the source of many feedstock chemicals. Methodology for the conversion of biomass into useful chemicals has often focused on either complete deoxygenation or the production of high-volume platform chemicals. Here, we describe the chemoselective partial reduction of silyl-protected C6O6-derived polyols to produce a diverse set of oxygen-functionalized chiral synthons. The combination of B(C6F5)3 and a tertiary silane efficiently generates a reactive equivalent of an electrophilic silylium ion (R3Si(+)) and a hydride (H(-)) reducing agent. The mechanism of oxygen loss does not involve a dehydrative elimination and thus avoids ablation of stereochemistry. Neighbouring group participation and the formation of cyclic intermediates is key to achieving selectivity in these reactions and, where both primary and secondary C-O bonds are present, the mechanism allows further control. The method provides--in one or two synthetic steps--highly improved syntheses of many C6On synthons as well as several previously undescribed products. PMID- 26100807 TI - Triamidoamine uranium(IV)-arsenic complexes containing one-, two- and threefold U As bonding interactions. AB - To further our fundamental understanding of the nature and extent of covalency in uranium-ligand bonding, and the benefits that this may have for the design of new ligands for nuclear waste separation, there is burgeoning interest in the nature of uranium complexes with soft- and multiple-bond-donor ligands. Despite this, there have so far been no examples of structurally authenticated molecular uranium-arsenic bonds under ambient conditions. Here, we report molecular uranium(IV)-arsenic complexes featuring formal single, double and triple U-As bonding interactions. Compound formulations are supported by a range of characterization techniques, and theoretical calculations suggest the presence of polarized covalent one-, two- and threefold bonding interactions between uranium and arsenic in parent arsenide [U-AsH2], terminal arsinidene [U=AsH] and arsenido [U=AsK2] complexes, respectively. These studies inform our understanding of the bonding of actinides with soft donor ligands and may be of use in future ligand design in this area. PMID- 26100808 TI - Through-space transfer of chiral information mediated by a plasmonic nanomaterial. AB - The ability to detect chirality gives stereochemically attuned nanosensors the potential to revolutionize the study of biomolecular processes. Such devices may structurally characterize the mechanisms of protein-ligand binding, the intermediates of amyloidogenic diseases and the effects of phosphorylation and glycosylation. We demonstrate that single nanoparticle plasmonic reporters, or nanotags, can enable a stereochemical response to be transmitted from a chiral analyte to an achiral benzotriazole dye molecule in the vicinity of a plasmon resonance from an achiral metallic nanostructure. The transfer of chirality was verified by the measurement of mirror image surface enhanced resonance Raman optical activity spectra for the two enantiomers of both ribose and tryptophan. Computational modelling confirms these observations and reveals the novel chirality transfer mechanism responsible. This is the first report of colloidal metal nanoparticles in the form of single plasmonic substrates displaying an intrinsic chiral sensitivity once attached to a chiral molecule. PMID- 26100809 TI - Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle embedded transition metal catalysts. AB - Bioorthogonal catalysis broadens the functional possibilities of intracellular chemistry. Effective delivery and regulation of synthetic catalytic systems in cells are challenging due to the complex intracellular environment and catalyst instability. Here, we report the fabrication of protein-sized bioorthogonal nanozymes through the encapsulation of hydrophobic transition metal catalysts into the monolayer of water-soluble gold nanoparticles. The activity of these catalysts can be reversibly controlled by binding a supramolecular cucurbit[7]uril 'gate-keeper' onto the monolayer surface, providing a biomimetic control mechanism that mimics the allosteric regulation of enzymes. The potential of this gated nanozyme for use in imaging and therapeutic applications was demonstrated through triggered cleavage of allylcarbamates for pro-fluorophore activation and propargyl groups for prodrug activation inside living cells. PMID- 26100810 TI - An eight-step gram-scale synthesis of (-)-jiadifenolide. AB - Development of a biologically active secondary metabolite into a useful medicine requires continuous access to meaningful quantities of material. Although any chemical synthesis is broadly useful for its versatility, identification of a synthesis route that can be economically scaled represents a greater challenge. Here we report a concise synthesis of the neurotrophic trace metabolite (-) jiadifenolide and its production on a gram-scale. The brevity of the route and the structural similarity of a key intermediate to many potent Illicium terpenes make chemical synthesis the unquestionable method for accessing and modifying these potential therapeutics. PMID- 26100811 TI - Corrigendum: Orthogonal tandem catalysis. PMID- 26100812 TI - Toxic thallium. PMID- 26100813 TI - Invasive urothelial carcinoma exhibiting basal cell immunohistochemical markers: A variant of urothelial carcinoma associated with aggressive features. AB - We characterize invasive urothelial carcinoma (UC) exhibiting urothelial basal cell immunohistochemical markers. Consecutive invasive UCs were immunostained with CK20 and urothelial basal cell markers, cytokeratin 5 (CK5)/CD44. Immunostaining for CK5 and CD44 was scored as follows: positive for staining of more than 25% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity. Invasive urothelial carcinoma (UC) exhibiting positive CK5/CD44 staining was designated as basal-like UC (BUC). In this study, of 251 invasive UC (pT1 in 57% and pT2-4 in 43%), BUC accounted for 40% of cases (accounting for most pT2-4 UC) and often presented as non-papillary UC without previous history of UC. In addition, BUC exhibited uniform nuclei with lesser degree of atypia than non BUC and decreased or negative cytokeratin 20 reactivity. Nested and microcystic variants of UC immunohistochemically stained as BUCs. Invasive non BUCs were often papillary with marked cytologic atypia and pleomorphism, and accounted for most pT1 UC. The rates of perivesical invasion, lymph node and distant metastases were higher for BUC than non-BUC. All nine cases with absent/minimal residual in situ UC in 102 radical cystectomy specimens were from invasive non-BUC. BUC is distinguished from non-BUC due to this aggressive behavior, distinct immunohistochemical profile, and predominant non-papillary architecture. Our findings are consistent with recent studies identifying a subtype of muscle-invasive UC with molecular expression of basal cell and luminal cell molecular profiles. Our study further supports categorizing invasive UCs into these subtypes with different biological behaviors, possibly contributing to better therapeutic strategies. PMID- 26100814 TI - A genome-wide systems analysis reveals strong link between colorectal cancer and trimethylamine N-oxide (TMAO), a gut microbial metabolite of dietary meat and fat. AB - BACKGROUND: Dietary intakes of red meat and fat are established risk factors for both colorectal cancer (CRC) and cardiovascular disease (CVDs). Recent studies have shown a mechanistic link between TMAO, an intestinal microbial metabolite of red meat and fat, and risk of CVDs. Data linking TMAO directly to CRC is, however, lacking. Here, we present an unbiased data-driven network-based systems approach to uncover a potential genetic relationship between TMAO and CRC. MATERIALS AND METHODS: We constructed two different epigenetic interaction networks (EINs) using chemical-gene, disease-gene and protein-protein interaction data from multiple large-scale data resources. We developed a network-based ranking algorithm to ascertain TMAO-related diseases from EINs. We systematically analyzed disease categories among TMAO-related diseases at different ranking cutoffs. We then determined which genetic pathways were associated with both TMAO and CRC. RESULTS: We show that CVDs and their major risk factors were ranked highly among TMAO-related diseases, confirming the newly discovered mechanistic link between CVDs and TMAO, and thus validating our algorithms. CRC was ranked highly among TMAO-related disease retrieved from both EINs (top 0.02%, #1 out of 4,372 diseases retrieved based on Mendelian genetics and top 10.9% among 882 diseases based on genome-wide association genetics), providing strong supporting evidence for our hypothesis that TMAO is genetically related to CRC. We have also identified putative genetic pathways that may link TMAO to CRC, which warrants further investigation. Through systematic disease enrichment analysis, we also demonstrated that TMAO is related to metabolic syndromes and cancers in general. CONCLUSIONS: Our genome-wide analysis demonstrates that systems approaches to studying the epigenetic interactions among diet, microbiome metabolisms, and disease genetics hold promise for understanding disease pathogenesis. Our results show that TMAO is genetically associated with CRC. This study suggests that TMAO may be an important intermediate marker linking dietary meat and fat and gut microbiota metabolism to risk of CRC, underscoring opportunities for the development of new gut microbiome-dependent diagnostic tests and therapeutics for CRC. PMID- 26100815 TI - Peripheral inflammation increases seizure susceptibility via the induction of neuroinflammation and oxidative stress in the hippocampus. AB - BACKGROUND: Neuroinflammation with activation of microglia and production of proinflammatory cytokines in the brain plays an active role in epileptic disorders. Brain oxidative stress has also been implicated in the pathogenesis of epilepsy. Damage in the hippocampus is associated with temporal lobe epilepsy, a common form of epilepsy in human. Peripheral inflammation may exacerbate neuroinflammation and brain oxidative stress. This study examined the impact of peripheral inflammation on seizure susceptibility and the involvement of neuroinflammation and oxidative stress in the hippocampus. RESULTS: In male, adult Sprague-Dawley rats, peripheral inflammation was induced by the infusion of Escherichia coli lipopolysaccharide (LPS, 2.5 mg/kg/day) into the peritoneal cavity for 7 days via an osmotic minipump. Pharmacological agents were delivered via intracerebroventricular (i.c.v.) infusion with an osmotic minipump. The level of cytokine in plasma or hippocampus was analyzed by ELISA. Redox-related protein expression in hippocampus was evaluated by Western blot. Seizure susceptibility was tested by intraperitoneal (i.p.) injection of kainic acid (KA, 10 mg/kg). We found that i.p. infusion of LPS for 7 days induced peripheral inflammation characterized by the increases in plasma levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). This is associated with a significant increase in number of the activated microglia (Iba 1(+) cells), enhanced production of proinflammatory cytokines (including IL 1beta, IL-6 and TNF-alpha), and tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus. These cellular and molecular responses to peripheral inflammation were notably blunted by i.c.v. infusion of a cycloxygenase-2 inhibitor, NS398 (5 MUg/MUl/h). The i.c.v. infusion of tempol (2.5 MUg/MUl/h), a reactive oxygen species scavenger, protected the hippocampus from oxidative damage with no apparent effect on microglia activation or cytokine production after peripheral inflammation. In the KA-induced seizure model, i.c.v. infusion of both NS398 and tempol ameliorated the increase in seizure susceptibility in animals succumbed to the LPS-induced peripheral inflammation. CONCLUSIONS: Together these results indicated that LPS-induced peripheral inflammation evoked neuroinflammation and the subsequent oxidative stress in the hippocampus, resulting in the increase in KA-induced seizure susceptibility. Moreover, protection from neuroinflammation and oxidative stress in the hippocampus exerted beneficial effect on seizure susceptibility following peripheral inflammation. PMID- 26100817 TI - Parathyroid Carcinoma: Is It Time for Change? PMID- 26100816 TI - Integrating Chemotherapy into the Management of Oligometastatic Colorectal Cancer: Evidence-Based Approach Using Clinical Trial Findings. AB - BACKGROUND: This study used case reports to review the role of systemic chemotherapy in oligometastatic colorectal cancer (CRC) and to suggest ways to integrate clinical research findings into the interdisciplinary management of this potentially curable subset of patients. METHODS: This educational review discusses the role of chemotherapy in the management of oligometastatic metastatic CRC. RESULTS: In initially resectable oligometastatic CRC, the goal of chemotherapy is to eradicate micrometastatic disease. Perioperative 5 fluorouracil and oxaliplatin together with surgical resection can result in 5 year survival rates as high as 57 %. With the development of increasingly successful chemotherapy regimens, attention is being paid to chemotherapy used to convert patients with initially unresectable metastasis to patients with a chance of surgical cure. The choice of chemotherapy regimen requires consideration of the goals for therapy and assessment of both tumor- and patient-specific factors. CONCLUSION: This report discusses the choice and timing of chemotherapy in patients with initially resectable and borderline resectable metastatic CRC. Coordinated multidisciplinary care of such patients can optimize survival outcomes and result in cure for patients with this otherwise lethal disease. PMID- 26100818 TI - Multimodality Treatment of T4 Gastric Cancer in the United States: Utilization Trends and Impact on Survival. AB - BACKGROUND: National guidelines advocate use of multimodality therapy (MMT) for treatment of T4 gastric cancer (T4GC). Prior studies demonstrate poor compliance with these guidelines. We sought to assess treatment trends and association between different treatment approaches and overall survival (OS) in a large cohort of U.S. METHODS: Patients diagnosed with clinical T4 gastric adenocarcinoma were selected from the National Cancer Data Base (1998-2011). Temporal trends, risk factors associated with failure to receive treatment, and effect of treatments on OS were assessed. RESULTS: Of 4369 patients with T4GC, only 15 % (n = 652) received MMT. Treatment with MMT increased over time, and was utilized in 25 % of patients after 2006. Older age, African American race, nonprivate insurance, proximal tumor location, and clinical node-negative disease were associated with failure to receive surgery; older age, female sex, poorly differentiated tumor grade, clinical node-negative disease, and prolonged postoperative length of stay were associated with failure to complete MMT in patients who underwent surgical resection. Median OS was longest in patients receiving MMT (19.2 months), and was similarly poor in patients undergoing surgical resection (9.0 months) or nonsurgical therapy (8.3 months; p < 0.001). Median OS was longer in patients receiving neoadjuvant therapy compared to patients receiving adjuvant therapy (27.8 vs. 16.6 months; p = 0.004). CONCLUSIONS: Treatment with neoadjuvant MMT is increasing and is associated with prolonged survival. Surgery alone and chemotherapy with or without radiotherapy without resection are associated with similarly poor outcomes. Appropriate treatment sequencing may facilitate delivery of MMT and improve outcomes in patients with T4GC. PMID- 26100819 TI - Mitomycin C Pharmacokinetics as Predictor of Severe Neutropenia in Hyperthermic Intraperitoneal Therapy. AB - BACKGROUND: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an approach to overcome peritoneal carcinomatosis from colorectal adenocarcinoma. Mitomycin C (MMC) is frequently used but not devoid of toxicity, of which the most common and feared is neutropenia. Our study explores the clinical and surgical risk factors of neutropenia and a possible link between MMC pharmacokinetics and neutropenia as HIPEC's supervention. METHODS: A total of 45 patients undergoing CRS-HIPEC for peritoneal carcinomatosis of colorectal origin between 2004 and 2010 were followed. For each patient, MMC was measured in plasma at different times during HIPEC and the area under the MMC concentration-time curve (MMC-AUC) was calculated. RESULTS: The incidence of neutropenia was 40 %. No demographic, clinical, or surgical factors increased the risk of neutropenia. However, we found that the occurrence of neutropenia and its gravity increased in direct correlation with an increase in MMC plasma concentration 30 min (T30) and 45 min (T45) after the start of HIPEC. The same correlation was observed between the MMC AUC and the risk of neutropenia. CONCLUSIONS: Neutropenia is a frequent complication associated with MMC-HIPEC. The results of our study indicate the feasibility and the potential benefit of a protocol including the MMC dosage at T30 after the start of HIPEC. A threshold of 572 ug/L gives a predictive sensitivity of 86 % and a specificity of 80 %. These results must be considered in the management of patients undergoing MMC-HIPEC in order to place high-risk patients under neutropenic monitoring while the other patients can undergo simple hematological monitoring. PMID- 26100824 TI - The effect of varenicline on Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio in healthy smokers and nonsmokers. AB - BACKGROUND: Varenicline could affect the T wave and QT interval. The interval from the peak to the end of the electrocardiographic (ECG) T wave (Tp-e) may correspond to the transmural dispersion of repolarization, and increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. In this study, we assessed the effects of varenicline on Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio. METHODS: Thirty healthy volunteers (15 healthy non smokers [NS] and 15 healthy smokers [S]) were included in the randomized, double blind, placebo-controlled, crossover study. Varenicline (2 mg single dose) or placebo was administered in two different testing sessions (5 days after the first period, performed the second period). Tp-e interval, Tp-e/QT ratio and Tp e/QTc ratio were assessed in the supine position and during handgrip exercise before and after the participants were given placebo or varenicline. Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were calculated from continuous ECG recordings and averages were used in the final analysis. RESULT: There were no statistically significant differences among any of the Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio before and after placebo administration in both groups (S and NS). In the S group, Tp-e and QTc interval, and Tp-e/QT and Tp-e/QTc ratio were significantly increased after varenicline administration (Tp-e: 64.28 +/- 8.78 vs. 70.42 +/- +/- 13.12; p = 0.02, QTc: 409.57 +/- 28.17 vs. 425.28 +/- 32.79; p = 0.02, Tp-e/QT: 0.18 +/- 0.02 vs. 0.19 +/- 0.03; p = 0.04, Tp-e/QTc: 0.17 +/- 0.02 vs. 0.19 +/- 0.02; p = 001) but these parameters were not changed in the NS group. CONCLUSIONS: Tp-e and QTc interval, and Tpe/QT and Tpe/QTc ratio were increased after varenicline administration in smokers. PMID- 26100820 TI - Multibracket appliance: impression defaults and their reduction by blocking-out a three-dimensional study. AB - OBJECTIVES: This study examines accuracy of dental impressions and following plaster models taken during treatment with fixed appliances. MATERIALS AND METHODS: A maxillary typodont was provided with brackets. Three examiners took impressions three times each of the variants: brackets only, archwire fixed by alastics, ligatures or Kobayashi-hooks, and brackets and archwire covered completely or just on the gingival side by protection or impression wax. Casts were scanned using Activity102((r)). Virtual models were compared to the scan of the typodont using Comparison((r)). Differences were measured and descriptively analyzed. Estimated means with 95% confidence intervals were computed. Significance was assessed using linear mixed models. RESULTS: While pyramidal reference blocks had a mean difference of 0.019 mm (95% CI = 0.017-0.021 mm) to the master model, teeth without attachments showed 0.097 mm (95% CI = 0.082-0.111 mm), and teeth with brackets 0.169 mm (95% CI = 0.156-0.182 mm) (p < 0.001). Smallest mean was found when using protection wax only on the gingival bracket side (0.152 mm (95% CI = 0.113-0.192 mm)). Incisors deviated most (0.258 mm (95 % CI = 0.239-0.277 mm)). CONCLUSIONS: Teeth with brackets make impressions more inaccurate because of undercuts. Removing the archwire before taking the impression or covering the brackets on the gingival side shows tendencies toward better precision. CLINICAL RELEVANCE: Taking impressions during treatment with fixed appliances, some inaccuracy has to be taken into account. PMID- 26100825 TI - Evaluation of the impact of warfarin time in therapeutic range on outcomes of patients with atrial fibrillation in Turkey: perspectives from the observational, prospective WATER Registry. AB - BACKGROUND: Warfarin is highly efficacious in reducing stroke risk in patients with atrial fibrillation (AF). However, its safety and efficacy in stroke prevention is markedly influenced by its time in therapeutic range (TTR). The quality of anticoagulant therapy varies considerably among countries. Representative data concerning the quality of anticoagulant therapy and its effects on clinical outcomes in Turkey are lacking. METHODS: Warfarin in Therapeutic Range (WATER) registry is a prospective, observational study which followed 572 AF patients (mean age 67.3 +/- 12 years; females 60%; 71% non valvular AF) treated with warfarin. RESULTS: At a median of 22-month follow-up, the mean TTR value was 42.3 +/- 18% (median: 40%) for the whole population and lower in non-valvular AF su group than valvular AF subgroup (40.3 +/- 18 vs. 46.9 +/- 19, respectively, p < 0.001). Death, cardiac hospital-ization and minor bleeding rates were higher in the group with TTR value < 40% than the group with > 40% (3.4% vs. 5.9%; 28.6% vs. 35.4%; 36.5% vs. 41.7%, respectively, all of them p < 0.001). A correlation analysis showed a negative correlation between age and TTR value (r = -0.178, p < 0.001). Mean CHA2DS2VASc score was 3.63 +/- 1.5 and mean HASBLED score was 2.38 +/- 1.01 in the non-valvular AF group. A negative correlation was observed between TTR levels and CHA2DS2VASc score. CONCLUSIONS: WATER provides insight into the anticoagulation control status of AF patients in Turkey. The quality of anticoagulation was poor. Strategies should be undertaken by clinicians and patients to improve TTR. New oral anticoagulant agents may be perfect alternatives for non-valvular AF patients. PMID- 26100826 TI - Readmissions and repeat procedures after catheter ablation for atrial fibrillation. AB - BACKGROUND: The aim of this study was to assess the frequency of all-cause rehospitalization and due to atrial fibrillation/flutter (AF/AFl), repeat ablation of AF/AFl, mortality within 30 days and 1-year follow-up in patients after AF/AFl ablation procedure. METHODS: Using data from the National Health Fund we identified a database comprising 2,022 patients who underwent AF/AFl ablation between January, 2012 and December, 2012 in Poland. The primary endpoint was readmission to hospital with discharge diagnosis AF/AFl. The secondary endpoints included: repeat AF/AFl ablation, cardiovascular hospitalization, all cause hospitalization, all-cause mortality assessed in 30-day and 1-year time frame. RESULTS: The mean age was 58.6 +/- 10.9 years (66.8% male). The mean time of the index ablation hospitalization was 3.8 +/- 2.6 days. After discharge, 123 (6.1%) and 540 (26.7%) patients were hospitalized because of AF/AFl within 30 days and 1 year, respectively. During 1-year follow-up, 192 (9.5%) patients underwent subsequent AF/AFl ablations. The patients that underwent the second ablation were younger (56.6 +/- 11.0 vs. 59.1 +/- 10.8; p = 0.019) and the time of the index hospitalization was shorter (3.75 +/- 2.16 vs. 4.45 +/- 3.26; p = 0.03). Within 30 days 194 (9.6%) patients were hospitalized and 747 (36.9%) in 1 year follow-up. All-cause mortality was 0.1% and 1.4% in 30-day and 1-year follow up, respectively. In a 1-year follow-up patients hospitalized from AF/AFl recurrence were more frequently hospitalized due to cardiovascular diseases other than AF/AFl (9.6% vs. 6.7%; p = 0.026), especially due to hypertension (2.9% vs. 0.7%; p < 0.001). CONCLUSIONS: Over 1 out of 4 patients who underwent AF/AFl ablation were hospitalized due to arrhythmia recurrence in 1 year. PMID- 26100827 TI - Could an analysis of mean corpuscular volume help to improve risk stratification in non-anemic patients with acute myocardial infarction? AB - BACKGROUND: Nowadays, when the majority of patients with acute myocardial infarction (AMI) are treated with primary percutaneous coronary intervention and modern pharmacotherapy, risk stratification becomes a challenge. Simple and easily accessible parameters that would help in a better determination of prognosis are needed. The aim of the study was to estimate the prevalence of high mean corpuscular volume (MCV, defined as MCV > 92 fL) and to establish its prognostic value in non-anemic patients with AMI. METHODS: We retrospectively analyzed the data of 248 consecutive non-anemic patients hospitalized due to AMI (median age: 65 [59-76] years, men: 63%, ST segment elevation myocardial infarction: 31%, and median left ventricular ejection fraction [LVEF]: 50%). RESULTS: The prevalence of high MCV was 39 +/- 6% (+/- 95% confidence interval) in the entire AMI population. High MCV was more prevalent in males, patients with low body mass index, non-diabetics and cigarette smokers (all p < 0.05). During the 180-day follow-up, there were 38 (15%) events, defined as another AMI or death. In a multivariable Cox proportional hazard model, female gender (p < 0.01), low LVEF (p < 0.001), previous AMI (p < 0.05), arterial hypertension (p < 0.05), and high MCV (p < 0.001) were prognosticators of pre-defined events. CONCLUSIONS: In non-anemic patients with AMI, high MCV is an independent prognostic factor of poor outcome defined as another AMI or death. PMID- 26100828 TI - Severe aortic stenosis with preserved ejection fraction and evidence of impairment in structure, myocardial strain and ventricular function: A new contribution to clinical decision making. AB - BACKGROUND: Left ventricular ejection fraction (LVEF) is among the parameters that are usually employed to define surgical timing of severe aortic stenosis (AS). Our hypothesis states that even when their LVEF is preserved, patients with severe symptomatic AS have impaired myocardial structure and function, and such impairment is related to the deleterious progression of left ventricular hypertrophy (LVH) from the compensated to the decompensated stage, as shown by the changes in diastolic function and the increase in left ventricular end diastolic pressure (LVEDP). METHODS AND RESULTS: A total of 26 patients with severe AS and LVEF > 50% referred for aortic valve replacement underwent catheterization, echocardiography and an intraoperative biopsy. Patients with severe symptomatic AS were classified as: group 1 (G1; compensated LVH, LVEDP < 15 mm Hg without coronary artery disease [CAD], n = 7), group 2a (G2a, decompensated LVH, without CAD, n = 7), and group 2b (G2b, decompensated LVH with CAD, n = 12). Differences were seen in the following: myocyte area [um2]: G1: 328 +/- 66, G2a: 376 +/- 22, G2b: 385 +/- 13, p < 0.01; collagen volume [%]: G1: 4.77 +/- 1.27, G2a: 8.40 +/- 1.27, G2b: 11.05 +/- 3.08, p < 0.01; LVEDP normalized by diastolic diameter [mm Hg/mm]: G1: 0.27 +/- 0.01, G2a: 0.39 +/- 0.06, G2b: 0.44 +/- 0.11, p < 0.02; +dP/dtmax/LVEDP [mm Hg/s/mm Hg]: G1: 176 +/- 45, G2a: 89.6 +/ 20, G2b: 113.1 +/- 41, p < 0.01; two-dimensional peak systolic longitudinal strain [%]: G1: -17.7 +/- 4.75, G2a: -13.4 +/- 3.04, G2b: -13.5 +/- 3.13, p < 0.05. CONCLUSIONS: Patients with severe symptomatic AS and preserved ejection fraction who develop decompensated LVH characterized by increased LVEDP, exhibit an abnormal myocardial structure and diastolic and systolic impairment. PMID- 26100830 TI - Left atrial mechanical function and stiffness in patients with atrial septal aneurysm: a speckle tracking study. AB - BACKGROUND: Atrial septal aneurysm (ASA) is a risk factor for arterial embolism. Atrial dysfunction and atrial arrhythmia, such as atrial fibrillation, might represent a mechanism for arterial embolism in such patients. Speckle tracking echocardiography (STE) is a novel and promising tool for detecting early changes in left atrial (LA) myocardial dysfunction. The aim of the study was to evaluate LA mechanical function and stiffness in ASA patients by 2-dimensional STE strain parameters. METHODS: Thirty-four ASA patients (44.2 +/- 12.3 years, 15 male) were studied, using a STE, and were compared with 31 age, gender, and left ventricular (LV) mass-matched controls (41.8 +/- +/- 11.5 years, 14 male). LA volume indices, mitral annular velocities, and global longitudinal LA strain were measured. The ratio of E/e' to LA strain was used as an index of LA stiffness. RESULTS: Patients with ASA showed increased LA volume indices and decreased LA global strain (25.3 +/- 5.2 vs. 42.1 +/- 8.7, p < 0.001). LA stiffness was increased in patients with ASA compared to the control subjects (0.41 +/- 0.15 vs. 0.14 +/- 0.05, p < 0.001), and LA strain and stiffness were related with LA volume indices. CONCLUSIONS: Patients with ASA have decreased LA global strain and increased stiffness, in comparison with those of the control subjects. LA strain and stiffness were significantly related with LA volume indices. LA stiffness and strain can be used for the assessment of LA function in patients with ASA. PMID- 26100829 TI - Survival after alcohol septal ablation versus conservative therapy in obstructive hypertrophic cardiomyopathy. AB - BACKGROUND: The impact of alcohol septal ablation (ASA) on the survival of patients with drug-refractory obstructive hypertrophic cardiomyopathy (HCM) remains unresolved. The aim of this study was to compare survival after ASA vs. conservative therapy. METHODS: We studied a consecutive cohort of 274 patients with severe drug-refractory obstructive HCM, 229 in ASA group and 45 in conservative group. The primary endpoint was a composite of all-cause mortality and aborted cardiac arrest. RESULTS: With a median follow-up of 4.3 years, primary endpoint occurred in 13 (5.7%) patients in the ASA group, and 8 (17.8%) patients in the conservative group. The 5- and 10-year survival free from primary endpoint of the ASA group (94.5% and 93.0%, respectively) was significantly better than that of the conservative group (78.3% and 72.2%, respectively, log rank p = 0.009). Independent determinants of primary endpoint were ASA therapy (hazard ratio [HR] 0.22; 95% confidence interval [CI] 0.08-0.60; p = 0.003) and maximal septal thickness (HR 1.14; 95% CI 1.03-1.27; p = 0.011). CONCLUSIONS: In patients with severe drug-refractory obstructive HCM, survival after ASA is favorable and better than that of conservative therapy. ASA seems to improve survival. PMID- 26100831 TI - Serum copeptin level can be a helpful biomarker in evaluation of myocardial perfusion scintigraphy results. AB - BACKGROUND: Myocardial perfusion scintigraphy (MPS) is a well-established diagnostic tool. The sensitivity and specificity of single photon emission computed tomography (SPECT) MPS to detect significant coronary lesion were 86% and 74%, respectively. The aim of this study was to examine the role of serum copeptin in evaluation of MPS. METHODS: Sixty-two consecutive patients underwent both SPECT MPS using 99mTc-sestamibi and transthoracic echocardiography were enrolled prospectively. Age, gender, height, weight, presence of cardiovascular risk factors were recorded. Exercise treadmill test (ETT) with modified Bruce protocol was used to induce coronary ischemia during MPS. While performing MPS, blood samples for serum copeptin level were drawn three times at pre-exercise, at the peak of ETT, and 6 h after ETT, respectively. The patients were enrolled into three groups according to MPS results (normal, equivocal and ischemia). RESULTS: The study included 62 patients (23 with normal, 20 with equivocal, 19 with ischemia on MPS). Pre-, peak-, and post-exercise B-type natriuretic peptide and troponin I values were similar across the groups (p > 0.05 for all comparisons). Serum copeptin values for pre- and peak-exercise were similar among all groups (p = 0.883 and p = 0.089). Post-exercise copeptin values of the normal and equivocal groups were similar (p = 0.661, z = -0.438) while that of the ischemia group was significantly higher than both the normal (p < 0.001) and equivocal group (p < 0.001). CONCLUSIONS: Serum copeptin was found to be increasing significantly in case of ischemia on MPS. It may be used in differentiation of equivocal results from false positive results. PMID- 26100832 TI - Dietary supplement consumption among cardiac patients admitted to internal medicine and cardiac wards. AB - BACKGROUND: Dietary supplements may have adverse effects and potentially interact with conventional medications. They are perceived as "natural" products, free of side effects with no need for medical consultation. Little is known about consumption of dietary supplements by patients with cardiac diseases. The objective of this study was to investigate dietary supplement consumption among cardiac patients admitted to internal and cardiology wards. Potential drug dietary supplement interactions were also assessed. METHODS: During a period of 6 months, patients with cardiac disease hospitalized in the Internal Medicine and Cardiology Wards at Assaf Harofeh Medical Center were evaluated regarding their dietary supplement consumption. A literature survey examining possible drug supplement interaction was performed. RESULTS: Out of 149 cardiac patients, 45% were dietary supplement consumers. Patients ad-mitted to the Internal Medicine Wards consumed more dietary supplements than those admit-ted to the Cardiology Division. Dietary supplement consumption was associated with older age (OR = 1.05, p = 0.022), female gender (OR = 2.94, p = 0.014) and routine physical activity (OR = 3.15, p = 0.007). Diabetes mellitus (OR = 2.68, p = 0.020), hematological diseases (OR = 13.29, p = 0.022), and the use of anti-diabetic medications (OR = 4.28, p = 0.001) were independently associated with dietary supplement intake. Sixteen potential moderate interactions between prescribed medications and dietary supplements were found. CONCLUSIONS: Consumption of dietary supplements is common among cardiac patients. It is more common in those admitted to Internal Medicine Departments than in those admitted to the Cardiology Wards. Due to the risk of various drug-supplement interactions consumed by patients with cardiac diseases, there is a need to increase awareness and knowledge among medical staff regarding the intake of dietary supplements. PMID- 26100833 TI - Current status of the development of Ras inhibitors. AB - Despite the importance of ras as driver genes in many cancers, clinically effective anti-cancer drugs targeting their products, Ras, have been unavailable so far, which was in part ascribable to the apparently 'undruggable' nature of their tertiary structures. Nonetheless, recent studies in academia and industry have identified novel surface pockets accepting small-molecule ligands in both their active GTP-bound and inactive GDP-bound forms (Ras*GTP and Ras*GDP, respectively), which has led to a surge of investigations into the discovery of Ras-specific inhibitors particularly by utilizing their structural information for structure-based drug design (SBDD). We have been developing Ras inhibitors by SBDD targeting a novel conformation of Ras*GTP called state 1, possessing 'druggable' surface pockets, which emerges from the conformational dynamics. In this article, we will survey Ras functions from the structural biological point of view and summarize the current status of the development of Ras inhibitors including our own. PMID- 26100834 TI - Most women with early stage breast cancer are tested for metastases despite advice against it, study finds. PMID- 26100835 TI - Puzzle-based versus traditional lecture: comparing the effects of pedagogy on academic performance in an undergraduate human anatomy and physiology II lab. AB - BACKGROUND: A traditional lecture-based pedagogy conveys information and content while lacking sufficient development of critical thinking skills and problem solving. A puzzle-based pedagogy creates a broader contextual framework, and fosters critical thinking as well as logical reasoning skills that can then be used to improve a student's performance on content specific assessments. This paper describes a pedagogical comparison of traditional lecture-based teaching and puzzle-based teaching in a Human Anatomy and Physiology II Lab. METHODS: Using a single subject/cross-over design half of the students from seven sections of the course were taught using one type of pedagogy for the first half of the semester, and then taught with a different pedagogy for the second half of the semester. The other half of the students were taught the same material but with the order of the pedagogies reversed. Students' performance on quizzes and exams specific to the course, and in-class assignments specific to this study were assessed for: learning outcomes (the ability to form the correct conclusion or recall specific information), and authentic academic performance as described by (Am J Educ 104:280-312, 1996). RESULTS: Our findings suggest a significant improvement in students' performance on standard course specific assessments using a puzzle-based pedagogy versus a traditional lecture-based teaching style. Quiz and test scores for students improved by 2.1 and 0.4% respectively in the puzzle-based pedagogy, versus the traditional lecture-based teaching. Additionally, the assessments of authentic academic performance may only effectively measure a broader conceptual understanding in a limited set of contexts, and not in the context of a Human Anatomy and Physiology II Lab. CONCLUSION: In conclusion, a puzzle-based pedagogy, when compared to traditional lecture-based teaching, can effectively enhance the performance of students on standard course specific assessments, even when the assessments only test a limited conceptual understanding of the material. PMID- 26100837 TI - Discovery opens new approaches to neurological diseases. PMID- 26100836 TI - The role of the pharmacist in the selection and use of over-the-counter proton pump inhibitors. AB - BACKGROUND: Heartburn and other symptoms of gastro-oesophageal reflux occur in ~30% of survey respondents in multiple countries worldwide. Heartburn and acid regurgitation are common complaints in the pharmacy, where patients frequently seek relief through medication and advice. The growing number of proton-pump inhibitors available in the over-the-counter setting provides an efficacious choice to patients experiencing frequent heartburn. Pharmacists can assist patients in their treatment decisions whilst inquiring about alarm symptoms that should prompt a physician referral. Aim of the review Provide pharmacists with a review of current clinical research and expert guidelines on use of over-the counter proton-pump inhibitors. METHODS: This narrative review was conducted to identify publications relevant to the following themes: overview of available treatments for frequent episodes of heartburn/acid regurgitation; treatment algorithms providing guidance on when to use over-the-counter proton-pump inhibitors; and the role of the pharmacist in the use of over-the-counter proton pump inhibitors. RESULTS: Frequent symptoms of acid reflux, such as heartburn and acid regurgitation, can interfere substantially with daily life activities. Proton-pump inhibitors are the most efficacious treatment for frequent reflux symptoms and are recommended as an appropriate initial treatment in uncomplicated cases. Proton-pump inhibitors have varying pharmacokinetics and pharmacodynamics across the class; 20 mg esomeprazole has higher bioavailability and exposure than over-the-counter omeprazole, for example. However, differences in clinical efficacy for symptom relief have not been demonstrated. The safety and tolerability of proton-pump inhibitors have been well established in clinical trial and post-marketing settings, and use of a short regimen is associated with a very low likelihood of missing a more serious condition. Pharmacists can assist patients with accurate self-diagnosis by asking short, simple questions to characterize the nature, severity, and frequency of symptoms. Additionally, pharmacists can inquire about alarm symptoms that should prompt referral to a physician. Pharmacists should inform those patients for whom over-the-counter proton-pump inhibitors are appropriate on their proper use. CONCLUSION: Over-the counter proton-pump inhibitors have a valuable role in the treatment of frequent heartburn. Pharmacists have the opportunity to guide patients through selection of the best treatment option for their symptoms. PMID- 26100838 TI - Inferior vena cava filters. PMID- 26100839 TI - Chronic necrotizing pulmonary aspergillosis in a patient with diabetes and marijuana use. PMID- 26100840 TI - First physical. PMID- 26100842 TI - Investigations for patients with early-stage breast cancer: oversetting the stage. PMID- 26100841 TI - Imaging for distant metastases in women with early-stage breast cancer: a population-based cohort study. AB - BACKGROUND: Practice guidelines recommend that imaging to detect metastatic disease not be performed in the majority of patients with early-stage breast cancer who are asymptomatic. We aimed to determine whether practice patterns in Ontario conform with these recommendations. METHODS: We used provincial registry data to identify a population-based cohort of Ontario women in whom early-stage, operable breast cancer was diagnosed between 2007 and 2012. We then determined whether imaging of the skeleton, thorax, and abdomen or pelvis had been performed within 3 months of tissue diagnosis. We calculated rates of confirmatory imaging of the same body site. RESULTS: Of 26,547 patients with early-stage disease, 22,811 (85.9%) had at least one imaging test, and a total of 83,249 imaging tests were performed (mean of 3.7 imaging tests per patient imaged). Among patients with pathologic stage I and II disease, imaging was performed in 79.6% (10,921/13,724) and 92.7% (11,882/12,823) of cases, respectively. Of all imaging tests, 19,784 (23.8%) were classified as confirmatory investigations. Imaging was more likely for patients who were younger, had greater comorbidity, had tumours of higher grade or stage or had undergone preoperative breast ultrasonography, mastectomy or surgery in the community setting. INTERPRETATION: Despite recommendations from multiple international guidelines, most Ontario women with early-stage breast cancer underwent imaging to detect distant metastases. Inappropriate imaging in asymptomatic patients with early-stage disease is costly and may lead to harm. The use of population datasets will allow investigators to evaluate whether or not strategies to implement practice guidelines lead to meaningful and sustained change in physician practice. PMID- 26100843 TI - New owner, but "business as usual" for CMAJ. PMID- 26100844 TI - Is withholding clinical trial results "research misconduct"? PMID- 26100846 TI - Rx for data-rich, access-poor researchers. PMID- 26100847 TI - Rh(III) -catalyzed C(sp(3))-H bond activation by an external base metalation/deprotonation mechanism: a theoretical study. AB - The C(sp(3) )?H bond activation of 8-methylquinoline followed by alkyne insertion catalyzed by a Rh(III) complex has been studied by using density functional theory (DFT) calculations. Contrary to common belief, the C?H bond activation of methylquinoline does not occur by the traditional intramolecular concerted metalation/deprotonation (CMD) mechanism but by an external base CMD mechanism. The use of free acetate or copper(II) acetate as base permits the C?H activation step, as observed experimentally. However, the following insertion is possible only if copper(II) acetate is used. The insertion followed by metathesis occurs via a cationic Rh(III) complex and is irreversible, which ensures the efficiency of the entire process. Therefore the use of copper is crucial for completing the catalytic cycle. The present work should help to rationalize the origins of the experimental results described in the literature. PMID- 26100848 TI - Diallyl disulfide inhibits TNFalpha induced CCL2 release through MAPK/ERK and NF Kappa-B signaling. AB - TNFalpha receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NFkappaB and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNFalpha induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNFalpha mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNFalpha initiates a rise in NFkappaB mRNA, which is not reversed by DADS. However, TNFalpha induced heightened expression of IKKepsilon and phosphorylated ERK. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNFalpha was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNFalpha invoked CCL2 production primarily through reduction of IKKepsilon and phosphorylated-ERK, thereby impairing MAPK/ERK, and NFkappaB pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNFalpha surface receptors. PMID- 26100850 TI - One-session root canal treatment with antimicrobial photodynamic therapy (aPDT): an in vivo study. AB - AIM: To evaluate the response of the apical and periapical tissues of dog teeth with apical periodontitis after one-session root canal treatment with and without antimicrobial photodynamic therapy (aPDT) compared with the use of an intracanal dressing. METHODOLOGY: Sixty root canals with an induced periapical lesion were instrumented and assigned to three groups: I, two-session root canal treatment using antibacterial dressing with calcium hydroxide-based paste; II, one-session root canal treatment using aPDT; and III, one-session root canal treatment in which the root canals were filled immediately after biomechanical preparation. The animals were euthanized after a 90-day experimental period. The maxillas and mandibles with teeth were submitted to histotechnical processing and haematoxylin eosin staining. Descriptive microscopic analysis of the apical and periapical region characteristics was performed, as well as morphometric assessment of the periapical lesion areas in fluorescence microscopy. Quantitative data were analysed statistically by the nonparametric Kruskal-Wallis test and Dunn's post test (alpha = 0.05). RESULTS: Group I was characterized by progressive repair, with the presence of fibres, cells and blood vessels. Group II had periodontal ligaments with the presence of collagen fibres and residual inflammatory cells. Group III had a dense inflammatory infiltrate with extensive oedematous areas and fibrillar dissociation, suggesting a persistent inflammatory and resorptive condition. Regarding periapical lesion size, group I had significantly smaller lesions (P < 0.05) than groups II and III, which did not differ significantly from each other. CONCLUSION: Two-session root canal treatment using a calcium hydroxide-based dressing was associated with significantly smaller periapical lesions at 90 days and characterized by progressive repair. PMID- 26100849 TI - Regulation of Voltage-Gated K+ Channel Kv1.5 by the Janus Kinase JAK3. AB - The tyrosine kinase Janus kinase 3 (JAK3) participates in the regulation of cell proliferation and apoptosis. The kinase further influences ion channels and transport proteins. The present study explored whether JAK3 contributes to the regulation of the voltage-gated K(+) channel Kv1.5, which participates in the regulation of diverse functions including atrial cardiac action potential and tumor cell proliferation. To this end, cRNA encoding Kv1.5 was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild-type JAK3, constitutively active (A568V)JAK3, or inactive (K851A)JAK3. Voltage-gated K(+) channel activity was measured utilizing dual electrode voltage clamp, and Kv1.5 channel protein abundance in the cell membrane was quantified utilizing chemiluminescence of Kv1.5 containing an extracellular hemagglutinin epitope (Kv1.5-HA). As a result, Kv1.5 activity and Kv1.5-HA protein abundance were significantly decreased by wild-type JAK3 and (A568V)JAK3, but not by (K851A)JAK3. Inhibition of Kv1.5 protein insertion into the cell membrane by brefeldin A (5 MUM) resulted in a decline of the voltage-gated current, which was similar in the absence and presence of (A568V)JAK3, suggesting that (A568V)JAK3 did not accelerate Kv1.5 protein retrieval from the cell membrane. A 24 h treatment with ouabain (100 uM) significantly decreased the voltage-gated current in oocytes expressing Kv1.5 without or with (A568V)JAK3 and dissipated the difference between oocytes expressing Kv1.5 alone and oocytes expressing Kv1.5 with (A568V)JAK3. In conclusion, JAK3 contributes to the regulation of membrane Kv1.5 protein abundance and activity, an effect sensitive to ouabain and thus possibly involving Na(+)/K(+) ATPase activity. PMID- 26100851 TI - Female Autism Phenotypes Investigated at Different Levels of Language and Developmental Abilities. AB - This study investigated the differences in clinical symptoms between females and males with autism spectrum disorder (ASD) across three verbal ability groups (nonverbal, phrase and fluent speech), based on which Autism Diagnostic Observation Schedule module was administered to 5723 individuals in four research datasets. In the Simons Simplex Collection and Autism Treatment Network, females with ASD and phrase or fluent speech had lower cognitive, adaptive, and social abilities than males. In the Autism Genetics Resource Exchange and the Autism Consortium, females with phrase or fluent speech had similar or better adaptive and social abilities than males. Females who were nonverbal had similar cognitive, adaptive, and social abilities as males. Population-based longitudinal studies of verbally fluent females with ASD are needed. PMID- 26100853 TI - Special issue of 13th Chinese International Peptide Symposium. PMID- 26100852 TI - Mothers' Parenting Behaviors in Families of School-Aged Children with Autism Spectrum Disorder: An Observational and Questionnaire Study. AB - Although parents of children with ASD face specific challenges in parenting, only a few studies have empirically investigated parenting behaviors among these parents. The current study examined differences in parenting behaviors between mothers of school-aged children with ASD (n = 30) and mothers of typically developing children (n = 39), using both an observational measure and a self report questionnaire. Results indicated that mothers of children with ASD obtained significantly lower scores on Sensitivity and Provision of structure as measured during the observation. They reported significantly higher scores on Material rewarding and Adapting the environment on the questionnaire. When controlling for parenting stress, the group differences on Sensitivity and Material rewarding did not remain significant. PMID- 26100854 TI - Role of peptide self-assembly in antimicrobial peptides. AB - Antimicrobial peptides (AMPs) are considered as potential antibiotic substitutes because of their potent activities. Previous studies mainly focused on the effects of peptide charges and secondary structures, but the self-assembly of AMPs was neglected. As more and more researchers notice the roles of peptide self assembly in AMPs, it has been considered as another important property. In this review, we will discuss the influences of peptide self-assembly on the activity and mode of action, and some specific features it introduces to the AMPs, such as particular responsiveness, improved cell selectivity and stability and sustained release. In addition, some methods to design self-assembling AMPs are primarily discussed. With further understanding about the self-assembling regularity, design of particular self-assembling AMPs will be very helpful for their applications, especially in the fields of drug delivery and biomedical engineering. PMID- 26100855 TI - Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase. AB - In the tyrosine kinase inhibitor (TKI) era, imatinib is the first-line therapy for patients with chronic myeloid leukemia (CML) in chronic or accelerated phase. Although second-generation TKIs (TKI2), including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 (n = 33) and allo-HSCT (n = 60) groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 (36.7%), 35 (58.3%), and 3 (10%) patients underwent allo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients (100%) achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate (42.9% vs. 86.4%, P = 0.002), 5-year event-free survival rate (14.3% vs. 76.1%, P < 0.001), and 5-year progression-free survival (28.6% vs. 78.1%, P < 0.001) than those in the allo-HSCT group. Multivariate analysis showed that male sex and TKI2 therapy were predictors of poor overall survival, whereas hemoglobin < 100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult patients with CML in accelerated phase. PMID- 26100856 TI - Gluteal muscle function and size in swimmers. AB - OBJECTIVES: To compare the gluteus medius and minimus segments size and activity in swimmers versus non-swimmers. DESIGN: Case matched-control cross-sectional study. METHODS: The three segments of gluteus medius (anterior, middle and posterior) and two segments of gluteus minimus (anterior and posterior) were evaluated using electromyography and magnetic resonance imaging in 15 swimmers (7 elite and 8 non-elite) and 15 gender- and aged-matched controls. For each muscle segment, values were obtained for peak amplitude, average amplitude, and time to peak from each phase of the gait cycle (0-20%, 20-60%, and total stance). RESULTS: The pattern of anterior gluteus minimus EMG activity in swimmers demonstrated additional activity early in the gait cycle when compared with controls. The segmental differences between anterior and posterior gluteus minimus during gait identified in the control group were not present in the swimmers. Overall, there were no significant differences in the gluteus medius EMG characteristics between groups and muscle size was not significantly different between groups for any of the hip abductor muscles. CONCLUSIONS: The preliminary evidence of non-segmental differences within the gluteus minimus of swimmers (as opposed to non-swimmers) might implicate reduced-gravity environments in contributing to subsequent changes in deep stabiliser muscles. Such changes might predispose the athlete to a greater risk of lower limb injury during weight bearing activities. PMID- 26100857 TI - A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, but its underlying mechanism is poorly understood. Here we show that hepatocyte nuclear factor 4alpha (HNF4alpha), a liver-enriched nuclear hormone receptor, is markedly inhibited, whereas miR-34a is highly induced in patients with non-alcoholic steatohepatitis, diabetic mice and mice fed a high-fat diet. miR-34a is essential for HNF4alpha expression and regulates triglyceride accumulation in human and murine hepatocytes. miR-34a inhibits very low-density lipoprotein secretion and promotes liver steatosis and hypolipidemia in an HNF4alpha-dependent manner. As a result, increased miR-34a or reduced HNF4alpha expression in the liver attenuates the development of atherosclerosis in Apoe(-/ ) or Ldlr(-/-) mice. These data indicate that the miR-34a-HNF4alpha pathway is activated under common conditions of metabolic stress and may have a role in the pathogenesis of NAFLD and in regulating plasma lipoprotein metabolism. Targeting this pathway may represent a novel approach for the treatment of NAFLD. PMID- 26100859 TI - Abomasal displacement in dairy cattle: A hereditary disease? PMID- 26100858 TI - TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer. AB - OBJECTIVE: The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. METHODS: From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. RESULTS: Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. CONCLUSIONS: These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC. PMID- 26100860 TI - Horsemanship, dogmanship and humanship. PMID- 26100861 TI - Association between FOXE1 and non-syndromic orofacial clefts in a northeastern Chinese population. AB - Non-syndromic orofacial clefts are among the most common congenital defects, and several reports have shown that the FOXE1 gene has strong associations with them. To find out if the gene was a risk factor we used a case-control and family-based analysis, and recruited 230 patients with non-syndromic oral clefts including 179 with non-syndromic cleft lip with or without cleft palate, and 51 with non syndromic cleft palate alone, their parents (166 mothers and 161 fathers, including 135 complete trios), and 180 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to genotype the 2 most strongly associated markers (rs4460498 and rs3758249) in FOXE1, and case-control and family-based associations were analysed. In the case control analyses we found a significant association with non-syndromic cleft lip and palate in rs4460498 (p=0.009) and rs3758249 (p=0.014), but no association in patients with cleft palate alone. For rs4460498 in FOXE1, the odds ratio (OR) for cases with CC homozygotes compared with TC+CC genotypes was 1.813 (95% CI 1.176 to 2.796), and for rs3758249 in FOXE1, the OR for cases with GG homozygotes compared with those with AG+AA genotypes was 0.561 (95%CI 0.371 to 0.848). The results of transmission-disequilibrium tests for rs4460698 and rs3758249 for non syndromic orofacial clefts were p=0.003, OR=2.781 (95% CI 1.414 to 5.469) and p=0.001, OR=2.552 (95%CI 1.574 to 4.138), respectively. This suggests that FOXE1 (rs4460498 and rs3758249) is strongly associated with non-syndromic cleft lip and palate in populations in northeast China, and further study between FOXE1 and non syndromic orofacial clefts is necessary. PMID- 26100863 TI - Swimming muscles power suction feeding in largemouth bass. AB - Most aquatic vertebrates use suction to capture food, relying on rapid expansion of the mouth cavity to accelerate water and food into the mouth. In ray-finned fishes, mouth expansion is both fast and forceful, and therefore requires considerable power. However, the cranial muscles of these fishes are relatively small and may not be able to produce enough power for suction expansion. The axial swimming muscles of these fishes also attach to the feeding apparatus and have the potential to generate mouth expansion. Because of their large size, these axial muscles could contribute substantial power to suction feeding. To determine whether suction feeding is powered primarily by axial muscles, we measured the power required for suction expansion in largemouth bass and compared it to the power capacities of the axial and cranial muscles. Using X-ray reconstruction of moving morphology (XROMM), we generated 3D animations of the mouth skeleton and created a dynamic digital endocast to measure the rate of mouth volume expansion. This time-resolved expansion rate was combined with intraoral pressure recordings to calculate the instantaneous power required for suction feeding. Peak expansion powers for all but the weakest strikes far exceeded the maximum power capacity of the cranial muscles. The axial muscles did not merely contribute but were the primary source of suction expansion power and generated up to 95% of peak expansion power. The recruitment of axial muscle power may have been crucial for the evolution of high-power suction feeding in ray-finned fishes. PMID- 26100862 TI - DNA damage during the G0/G1 phase triggers RNA-templated, Cockayne syndrome B dependent homologous recombination. AB - Damage repair mechanisms at transcriptionally active sites during the G0/G1 phase are largely unknown. To elucidate these mechanisms, we introduced genome site specific oxidative DNA damage and determined the role of transcription in repair factor assembly. We find that KU and NBS1 are recruited to damage sites independent of transcription. However, assembly of RPA1, RAD51C, RAD51, and RAD52 at such sites is strictly governed by active transcription and requires both wild type Cockayne syndrome protein B (CSB) function and the presence of RNA in the G0/G1 phase. We show that the ATPase activity of CSB is indispensable for loading and binding of the recombination factors. CSB counters radiation-induced DNA damage in both cells and zebrafish models. Taken together, our results have uncovered a novel, RNA-based recombination mechanism by which CSB protects genome stability from strand breaks at transcriptionally active sites and may provide insight into the clinical manifestations of Cockayne syndrome. PMID- 26100864 TI - Osmotic stress induces phosphorylation of histone H3 at threonine 3 in pericentromeric regions of Arabidopsis thaliana. AB - Histone phosphorylation plays key roles in stress-induced transcriptional reprogramming in metazoans but its function(s) in land plants has remained relatively unexplored. Here we report that an Arabidopsis mutant defective in At3g03940 and At5g18190, encoding closely related Ser/Thr protein kinases, shows pleiotropic phenotypes including dwarfism and hypersensitivity to osmotic/salt stress. The double mutant has reduced global levels of phosphorylated histone H3 threonine 3 (H3T3ph), which are not enhanced, unlike the response in the wild type, by drought-like treatments. Genome-wide analyses revealed increased H3T3ph, slight enhancement in trimethylated histone H3 lysine 4 (H3K4me3), and a modest decrease in histone H3 occupancy in pericentromeric/knob regions of wild-type plants under osmotic stress. However, despite these changes in heterochromatin, transposons and repeats remained transcriptionally repressed. In contrast, this reorganization of heterochromatin was mostly absent in the double mutant, which exhibited lower H3T3ph levels in pericentromeric regions even under normal environmental conditions. Interestingly, within actively transcribed protein coding genes, H3T3ph density was minimal in 5' genic regions, coincidental with a peak of H3K4me3 accumulation. This pattern was not affected in the double mutant, implying the existence of additional H3T3 protein kinases in Arabidopsis. Our results suggest that At3g03940 and At5g18190 are involved in the phosphorylation of H3T3 in pericentromeric/knob regions and that this repressive epigenetic mark may be important for maintaining proper heterochromatic organization and, possibly, chromosome function(s). PMID- 26100865 TI - Individual olfactory perception reveals meaningful nonolfactory genetic information. AB - Each person expresses a potentially unique subset of ~ 400 different olfactory receptor subtypes. Given that the receptors we express partially determine the odors we smell, it follows that each person may have a unique nose; to capture this, we devised a sensitive test of olfactory perception we termed the "olfactory fingerprint." Olfactory fingerprints relied on matrices of perceived odorant similarity derived from descriptors applied to the odorants. We initially fingerprinted 89 individuals using 28 odors and 54 descriptors. We found that each person had a unique olfactory fingerprint (P < 10(-10)), which was odor specific but descriptor independent. We could identify individuals from this pool using randomly selected sets of 7 odors and 11 descriptors alone. Extrapolating from this data, we determined that using 34 odors and 35 descriptors we could individually identify each of the 7 billion people on earth. Olfactory perception, however, fluctuates over time, calling into question our proposed perceptual readout of presumably stable genetic makeup. To test whether fingerprints remain informative despite this temporal fluctuation, building on the linkage between olfactory receptors and HLA, we hypothesized that olfactory perception may relate to HLA. We obtained olfactory fingerprints and HLA typing for 130 individuals, and found that olfactory fingerprint matching using only four odorants was significantly related to HLA matching (P < 10(-4)), such that olfactory fingerprints can save 32% of HLA tests in a population screen (P < 10( 6)). In conclusion, a precise measure of olfactory perception reveals meaningful nonolfactory genetic information. PMID- 26100866 TI - Pathways to dewetting in hydrophobic confinement. AB - Liquid water can become metastable with respect to its vapor in hydrophobic confinement. The resulting dewetting transitions are often impeded by large kinetic barriers. According to macroscopic theory, such barriers arise from the free energy required to nucleate a critical vapor tube that spans the region between two hydrophobic surfaces--tubes with smaller radii collapse, whereas larger ones grow to dry the entire confined region. Using extensive molecular simulations of water between two nanoscopic hydrophobic surfaces, in conjunction with advanced sampling techniques, here we show that for intersurface separations that thermodynamically favor dewetting, the barrier to dewetting does not correspond to the formation of a (classical) critical vapor tube. Instead, it corresponds to an abrupt transition from an isolated cavity adjacent to one of the confining surfaces to a gap-spanning vapor tube that is already larger than the critical vapor tube anticipated by macroscopic theory. Correspondingly, the barrier to dewetting is also smaller than the classical expectation. We show that the peculiar nature of water density fluctuations adjacent to extended hydrophobic surfaces--namely, the enhanced likelihood of observing low-density fluctuations relative to Gaussian statistics--facilitates this nonclassical behavior. By stabilizing isolated cavities relative to vapor tubes, enhanced water density fluctuations thus stabilize novel pathways, which circumvent the classical barriers and offer diminished resistance to dewetting. Our results thus suggest a key role for fluctuations in speeding up the kinetics of numerous phenomena ranging from Cassie-Wenzel transitions on superhydrophobic surfaces, to hydrophobically driven biomolecular folding and assembly. PMID- 26100867 TI - Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial. AB - HIV-1-specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case-control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-gamma enzyme-linked immunospot (ELISpot) assay. IFN-gamma responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1-negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19-0.66 and HR = 0.52, 95% CI = 0.28 0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-gamma secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1-specific T cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes. PMID- 26100868 TI - Theta-gamma coordination between anterior cingulate and prefrontal cortex indexes correct attention shifts. AB - Anterior cingulate and lateral prefrontal cortex (ACC/PFC) are believed to coordinate activity to flexibly prioritize the processing of goal-relevant over irrelevant information. This between-area coordination may be realized by common low-frequency excitability changes synchronizing segregated high-frequency activations. We tested this coordination hypothesis by recording in macaque ACC/PFC during the covert utilization of attention cues. We found robust increases of 5-10 Hz (theta) to 35-55 Hz (gamma) phase-amplitude correlation between ACC and PFC during successful attention shifts but not before errors. Cortical sites providing theta phases (i) showed a prominent cue-induced phase reset, (ii) were more likely in ACC than PFC, and (iii) hosted neurons with burst firing events that synchronized to distant gamma activity. These findings suggest that interareal theta-gamma correlations could follow mechanistically from a cue triggered reactivation of rule memory that synchronizes theta across ACC/PFC. PMID- 26100869 TI - Structural and functional insights into Escherichia coli alpha2-macroglobulin endopeptidase snap-trap inhibition. AB - The survival of commensal bacteria requires them to evade host peptidases. Gram negative bacteria from the human gut microbiome encode a relative of the human endopeptidase inhibitor, alpha2-macroglobulin (alpha2M). Escherichia coli alpha2M (ECAM) is a ~ 180-kDa multidomain membrane-anchored pan-peptidase inhibitor, which is cleaved by host endopeptidases in an accessible bait region. Structural studies by electron microscopy and crystallography reveal that this cleavage causes major structural rearrangement of more than half the 13-domain structure from a native to a compact induced form. It also exposes a reactive thioester bond, which covalently traps the peptidase. Subsequently, peptidase-laden ECAM is shed from the membrane and may dimerize. Trapped peptidases are still active except against very large substrates, so inhibition potentially prevents damage of large cell envelope components, but not host digestion. Mechanistically, these results document a novel monomeric "snap trap." PMID- 26100870 TI - Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan. AB - Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylation-deaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant. PMID- 26100871 TI - Genetic and epigenetic architecture of sex-biased expression in the jewel wasps Nasonia vitripennis and giraulti. AB - There is extraordinary diversity in sexual dimorphism (SD) among animals, but little is known about its epigenetic basis. To study the epigenetic architecture of SD in a haplodiploid system, we performed RNA-seq and whole-genome bisulfite sequencing of adult females and males from two closely related parasitoid wasps, Nasonia vitripennis and Nasonia giraulti. More than 75% of expressed genes displayed significantly sex-biased expression. As a consequence, expression profiles are more similar between species within each sex than between sexes within each species. Furthermore, extremely male- and female-biased genes are enriched for totally different functional categories: male-biased genes for key enzymes in sex-pheromone synthesis and female-biased genes for genes involved in epigenetic regulation of gene expression. Remarkably, just 70 highly expressed, extremely male-biased genes account for 10% of all transcripts in adult males. Unlike expression profiles, DNA methylomes are highly similar between sexes within species, with no consistent sex differences in methylation found. Therefore, methylation changes cannot explain the extensive level of sex-biased gene expression observed. Female-biased genes have smaller sequence divergence between species, higher conservation to other hymenopterans, and a broader expression range across development. Overall, female-biased genes have been recruited from genes with more conserved and broadly expressing "house-keeping" functions, whereas male-biased genes are more recently evolved and are predominately testis specific. In summary, Nasonia accomplish a striking degree of sex-biased expression without sex chromosomes or epigenetic differences in methylation. We propose that methylation provides a general signal for constitutive gene expression, whereas other sex-specific signals cause sex-biased gene expression. PMID- 26100872 TI - The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. AB - Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin based mechanisms repress ERVs in cells of embryonic origin (histone methylation dominant) vs. more differentiated cells (DNA methylation dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, on loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory elements. These findings have important implications for genome stability in somatic cells, as well as the interface between epigenetic repression and viral latency. PMID- 26100873 TI - Developed turbulence and nonlinear amplification of magnetic fields in laboratory and astrophysical plasmas. AB - The visible matter in the universe is turbulent and magnetized. Turbulence in galaxy clusters is produced by mergers and by jets of the central galaxies and believed responsible for the amplification of magnetic fields. We report on experiments looking at the collision of two laser-produced plasma clouds, mimicking, in the laboratory, a cluster merger event. By measuring the spectrum of the density fluctuations, we infer developed, Kolmogorov-like turbulence. From spectral line broadening, we estimate a level of turbulence consistent with turbulent heating balancing radiative cooling, as it likely does in galaxy clusters. We show that the magnetic field is amplified by turbulent motions, reaching a nonlinear regime that is a precursor to turbulent dynamo. Thus, our experiment provides a promising platform for understanding the structure of turbulence and the amplification of magnetic fields in the universe. PMID- 26100874 TI - Early procurement of scarlet macaws and the emergence of social complexity in Chaco Canyon, NM. AB - High-precision accelerator mass spectrometer (AMS) (14)C dates of scarlet macaw (Ara macao) skeletal remains provide the first direct evidence from Chaco Canyon in northwestern New Mexico that these Neotropical birds were procured from Mesoamerica by Pueblo people as early as ~ A.D. 900-975. Chaco was a prominent prehistoric Pueblo center with a dense concentration of multistoried great houses constructed from the 9th through early 12th centuries. At the best known great house of Pueblo Bonito, unusual burial crypts and significant quantities of exotic and symbolically important materials, including scarlet macaws, turquoise, marine shell, and cacao, suggest societal complexity unprecedented elsewhere in the Puebloan world. Scarlet macaws are known markers of social and political status among the Pueblos. New AMS (14)C-dated scarlet macaw remains from Pueblo Bonito demonstrate that these birds were acquired persistently from Mesoamerica between A.D. 900 and 1150. Most of the macaws date before the hypothesized apogeal Chacoan period (A.D. 1040-1110) to which they are commonly attributed. The 10th century acquisition of these birds is consistent with the hypothesis that more formalized status hierarchies developed with significant connections to Mesoamerica before the post-A.D. 1040 architectural florescence in Chaco Canyon. PMID- 26100876 TI - Effect of salt on the H-bond symmetrization in ice. AB - The richness of the phase diagram of water reduces drastically at very high pressures where only two molecular phases, proton-disordered ice VII and proton ordered ice VIII, are known. Both phases transform to the centered hydrogen bond atomic phase ice X above about 60 GPa, i.e., at pressures experienced in the interior of large ice bodies in the universe, such as Saturn and Neptune, where nonmolecular ice is thought to be the most abundant phase of water. In this work, we investigate, by Raman spectroscopy up to megabar pressures and ab initio simulations, how the transformation of ice VII in ice X is affected by the presence of salt inclusions in the ice lattice. Considerable amounts of salt can be included in ice VII structure under pressure via rock-ice interaction at depth and processes occurring during planetary accretion. Our study reveals that the presence of salt hinders proton order and hydrogen bond symmetrization, and pushes ice VII to ice X transformation to higher and higher pressures as the concentration of salt is increased. PMID- 26100875 TI - Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex. AB - The bHLH transcription factors SHARP1 and SHARP2 are partially redundant modulators of the circadian system. SHARP1/DEC2 has been shown to control sleep length in humans and sleep architecture is also altered in double mutant mice (S1/2(-/-)). Because of the importance of sleep for memory consolidation, we investigated the role of SHARP1 and SHARP2 in cognitive processing. S1/2(-/-) mice show enhanced cortex (Cx)-dependent remote fear memory formation as well as improved reversal learning, but do not display alterations in hippocampus (Hi) dependent recent fear memory formation. SHARP1 and SHARP2 single null mutants do not display any cognitive phenotype supporting functional redundancy of both factors. Molecular and biochemical analyses revealed elevated insulin-related growth factor 2 (IGF2) signaling and increased phosphorylation of MAPK and S6 in the Cx but not the Hi of S1/2(-/-) mice. No changes were detected in single mutants. Moreover, adeno-associated virus type 2-mediated IGF2 overexpression in the anterior cingulate cortex enhanced remote fear memory formation and the analysis of forebrain-specific double null mutants of the Insulin and IGF1 receptors revealed their essential function for memory formation. Impaired fear memory formation in aged S1/2(-/-) mice indicates that elevated IGF2 signaling in the long term, however, has a negative impact on cognitive processing. In summary, we conclude that the bHLH transcription factors SHARP1 and SHARP2 are involved in cognitive processing by controlling Igf2 expression and associated signaling cascades. Our analyses provide evidence that the control of sleep and memory consolidation may share common molecular mechanisms. PMID- 26100877 TI - N-linked glycosylation of protease-activated receptor-1 at extracellular loop 2 regulates G-protein signaling bias. AB - Protease-activated receptor-1 (PAR1) is a G-protein-coupled receptor (GPCR) for the coagulant protease thrombin. Similar to other GPCRs, PAR1 is promiscuous and couples to multiple heterotrimeric G-protein subtypes in the same cell and promotes diverse cellular responses. The molecular mechanism by which activation of a given GPCR with the same ligand permits coupling to multiple G-protein subtypes is unclear. Here, we report that N-linked glycosylation of PAR1 at extracellular loop 2 (ECL2) controls G12/13 versus Gq coupling specificity in response to thrombin stimulation. A PAR1 mutant deficient in glycosylation at ECL2 was more effective at stimulating Gq-mediated phosphoinositide signaling compared with glycosylated wildtype receptor. In contrast, wildtype PAR1 displayed a greater efficacy at G12/13-dependent RhoA activation compared with mutant receptor lacking glycosylation at ECL2. Endogenous PAR1 rendered deficient in glycosylation using tunicamycin, a glycoprotein synthesis inhibitor, also exhibited increased PI signaling and diminished RhoA activation opposite to native receptor. Remarkably, PAR1 wildtype and glycosylation-deficient mutant were equally effective at coupling to Gi and beta-arrestin-1. Consistent with preferential G12/13 coupling, thrombin-stimulated PAR1 wildtype strongly induced RhoA-mediated stress fiber formation compared with mutant receptor. In striking contrast, glycosylation-deficient PAR1 was more effective at increasing cellular proliferation, associated with Gq signaling, than wildtype receptor. These studies suggest that N-linked glycosylation at ECL2 contributes to the stabilization of an active PAR1 state that preferentially couples to G12/13 versus Gq and defines a previously unidentified function for N-linked glycosylation of GPCRs in regulating G-protein signaling bias. PMID- 26100878 TI - A self-lysis pathway that enhances the virulence of a pathogenic bacterium. AB - In mammalian cells, programmed cell death (PCD) plays important roles in development, in the removal of damaged cells, and in fighting bacterial infections. Although widespread among multicellular organisms, there are relatively few documented instances of PCD in bacteria. Here we describe a potential PCD pathway in Pseudomonas aeruginosa that enhances the ability of the bacterium to cause disease in a lung infection model. Activation of the system can occur in a subset of cells in response to DNA damage through cleavage of an essential transcription regulator we call AlpR. Cleavage of AlpR triggers a cell lysis program through de-repression of the alpA gene, which encodes a positive regulator that activates expression of the alpBCDE lysis cassette. Although this is lethal to the individual cell in which it occurs, we find it benefits the population as a whole during infection of a mammalian host. Thus, host and pathogen each may use PCD as a survival-promoting strategy. We suggest that activation of the Alp cell lysis pathway is a disease-enhancing response to bacterial DNA damage inflicted by the host immune system. PMID- 26100879 TI - QnAs with James J. Collins. PMID- 26100880 TI - Human population dynamics in Europe over the Last Glacial Maximum. AB - The severe cooling and the expansion of the ice sheets during the Last Glacial Maximum (LGM), 27,000-19,000 y ago (27-19 ky ago) had a major impact on plant and animal populations, including humans. Changes in human population size and range have affected our genetic evolution, and recent modeling efforts have reaffirmed the importance of population dynamics in cultural and linguistic evolution, as well. However, in the absence of historical records, estimating past population levels has remained difficult. Here we show that it is possible to model spatially explicit human population dynamics from the pre-LGM at 30 ky ago through the LGM to the Late Glacial in Europe by using climate envelope modeling tools and modern ethnographic datasets to construct a population calibration model. The simulated range and size of the human population correspond significantly with spatiotemporal patterns in the archaeological data, suggesting that climate was a major driver of population dynamics 30-13 ky ago. The simulated population size declined from about 330,000 people at 30 ky ago to a minimum of 130,000 people at 23 ky ago. The Late Glacial population growth was fastest during Greenland interstadial 1, and by 13 ky ago, there were almost 410,000 people in Europe. Even during the coldest part of the LGM, the climatically suitable area for human habitation remained unfragmented and covered 36% of Europe. PMID- 26100881 TI - Integrated, systems metabolic picture of acetone-butanol-ethanol fermentation by Clostridium acetobutylicum. AB - Microbial metabolism involves complex, system-level processes implemented via the orchestration of metabolic reactions, gene regulation, and environmental cues. One canonical example of such processes is acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum, during which cells convert carbon sources to organic acids that are later reassimilated to produce solvents as a strategy for cellular survival. The complexity and systems nature of the process have been largely underappreciated, rendering challenges in understanding and optimizing solvent production. Here, we present a system-level computational framework for ABE fermentation that combines metabolic reactions, gene regulation, and environmental cues. We developed the framework by decomposing the entire system into three modules, building each module separately, and then assembling them back into an integrated system. During the model construction, a bottom-up approach was used to link molecular events at the single-cell level into the events at the population level. The integrated model was able to successfully reproduce ABE fermentations of the WT C. acetobutylicum (ATCC 824), as well as its mutants, using data obtained from our own experiments and from literature. Furthermore, the model confers successful predictions of the fermentations with various network perturbations across metabolic, genetic, and environmental aspects. From foundation to applications, the framework advances our understanding of complex clostridial metabolism and physiology and also facilitates the development of systems engineering strategies for the production of advanced biofuels. PMID- 26100882 TI - Paternal allelic mutation at the Kcnq1 locus reduces pancreatic beta-cell mass by epigenetic modification of Cdkn1c. AB - Genetic factors are important determinants of the onset and progression of diabetes mellitus. Numerous susceptibility genes for type 2 diabetes, including potassium voltage-gated channel, KQT-like subfamily Q, member1 (KCNQ1), have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, the possible effects of the parent of origin for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at the Kcnq1 locus reduces pancreatic beta-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNA KCNQ1 overlapping transcript1 (Kcnq1ot1) is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression as well as the increased expression of cyclin-dependent kinase inhibitor 1C (Cdkn1c), an imprinted gene that encodes a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification at the Cdkn1c promoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that the Kcnq1 genomic region directly regulates pancreatic beta-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus. PMID- 26100883 TI - The butterfly plant arms-race escalated by gene and genome duplications. AB - Coevolutionary interactions are thought to have spurred the evolution of key innovations and driven the diversification of much of life on Earth. However, the genetic and evolutionary basis of the innovations that facilitate such interactions remains poorly understood. We examined the coevolutionary interactions between plants (Brassicales) and butterflies (Pieridae), and uncovered evidence for an escalating evolutionary arms-race. Although gradual changes in trait complexity appear to have been facilitated by allelic turnover, key innovations are associated with gene and genome duplications. Furthermore, we show that the origins of both chemical defenses and of molecular counter adaptations were associated with shifts in diversification rates during the arms race. These findings provide an important connection between the origins of biodiversity, coevolution, and the role of gene and genome duplications as a substrate for novel traits. PMID- 26100884 TI - Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1 deficient metaplastic breast cancer. AB - Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics. PMID- 26100885 TI - Miniaturized mitogenome of the parasitic plant Viscum scurruloideum is extremely divergent and dynamic and has lost all nad genes. AB - Despite the enormous diversity among parasitic angiosperms in form and structure, life-history strategies, and plastid genomes, little is known about the diversity of their mitogenomes. We report the sequence of the wonderfully bizarre mitogenome of the hemiparasitic aerial mistletoe Viscum scurruloideum. This genome is only 66 kb in size, making it the smallest known angiosperm mitogenome by a factor of more than three and the smallest land plant mitogenome. Accompanying this size reduction is exceptional reduction of gene content. Much of this reduction arises from the unexpected loss of respiratory complex I (NADH dehydrogenase), universally present in all 300+ other angiosperms examined, where it is encoded by nine mitochondrial and many nuclear nad genes. Loss of complex I in a multicellular organism is unprecedented. We explore the potential relationship between this loss in Viscum and its parasitic lifestyle. Despite its small size, the Viscum mitogenome is unusually rich in recombinationally active repeats, possessing unparalleled levels of predicted sublimons resulting from recombination across short repeats. Many mitochondrial gene products exhibit extraordinary levels of divergence in Viscum, indicative of highly relaxed if not positive selection. In addition, all Viscum mitochondrial protein genes have experienced a dramatic acceleration in synonymous substitution rates, consistent with the hypothesis of genomic streamlining in response to a high mutation rate but completely opposite to the pattern seen for the high-rate but enormous mitogenomes of Silene. In sum, the Viscum mitogenome possesses a unique constellation of extremely unusual features, a subset of which may be related to its parasitic lifestyle. PMID- 26100887 TI - Statistical learning and selective inference. AB - We describe the problem of "selective inference." This addresses the following challenge: Having mined a set of data to find potential associations, how do we properly assess the strength of these associations? The fact that we have "cherry picked"--searched for the strongest associations--means that we must set a higher bar for declaring significant the associations that we see. This challenge becomes more important in the era of big data and complex statistical modeling. The cherry tree (dataset) can be very large and the tools for cherry picking (statistical learning methods) are now very sophisticated. We describe some recent new developments in selective inference and illustrate their use in forward stepwise regression, the lasso, and principal components analysis. PMID- 26100886 TI - Environmental CO2 inhibits Caenorhabditis elegans egg-laying by modulating olfactory neurons and evokes widespread changes in neural activity. AB - Carbon dioxide (CO2) gradients are ubiquitous and provide animals with information about their environment, such as the potential presence of prey or predators. The nematode Caenorhabditis elegans avoids elevated CO2, and previous work identified three neuron pairs called "BAG," "AFD," and "ASE" that respond to CO2 stimuli. Using in vivo Ca(2+) imaging and behavioral analysis, we show that C. elegans can detect CO2 independently of these sensory pathways. Many of the C. elegans sensory neurons we examined, including the AWC olfactory neurons, the ASJ and ASK gustatory neurons, and the ASH and ADL nociceptors, respond to a rise in CO2 with a rise in Ca(2+). In contrast, glial sheath cells harboring the sensory endings of C. elegans' major chemosensory neurons exhibit strong and sustained decreases in Ca(2+) in response to high CO2. Some of these CO2 responses appear to be cell intrinsic. Worms therefore may couple detection of CO2 to that of other cues at the earliest stages of sensory processing. We show that C. elegans persistently suppresses oviposition at high CO2. Hermaphrodite-specific neurons (HSNs), the executive neurons driving egg-laying, are tonically inhibited when CO2 is elevated. CO2 modulates the egg-laying system partly through the AWC olfactory neurons: High CO2 tonically activates AWC by a cGMP-dependent mechanism, and AWC output inhibits the HSNs. Our work shows that CO2 is a more complex sensory cue for C. elegans than previously thought, both in terms of behavior and neural circuitry. PMID- 26100888 TI - Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer. AB - Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain. PMID- 26100890 TI - The self-control consequences of political ideology. AB - Evidence from three studies reveals a critical difference in self-control as a function of political ideology. Specifically, greater endorsement of political conservatism (versus liberalism) was associated with greater attention regulation and task persistence. Moreover, this relationship is shown to stem from varying beliefs in freewill; specifically, the association between political ideology and self-control is mediated by differences in the extent to which belief in freewill is endorsed, is independent of task performance or motivation, and is reversed when freewill is perceived to impede (rather than enhance) self-control. Collectively, these findings offer insight into the self-control consequences of political ideology by detailing conditions under which conservatives and liberals are better suited to engage in self-control and outlining the role of freewill beliefs in determining these conditions. PMID- 26100889 TI - Assessing niche width of endothermic fish from genes to ecosystem. AB - Endothermy in vertebrates has been postulated to confer physiological and ecological advantages. In endothermic fish, niche expansion into cooler waters is correlated with specific physiological traits and is hypothesized to lead to greater foraging success and increased fitness. Using the seasonal co-occurrence of three tuna species in the eastern Pacific Ocean as a model system, we used cardiac gene expression data (as a proxy for thermal tolerance to low temperatures), archival tag data, and diet analyses to examine the vertical niche expansion hypothesis for endothermy in situ. Yellowfin, albacore, and Pacific bluefin tuna (PBFT) in the California Current system used more surface, mesopelagic, and deep waters, respectively. Expression of cardiac genes for calcium cycling increased in PBFT and coincided with broader vertical and thermal niche utilization. However, the PBFT diet was less diverse and focused on energy rich forage fishes but did not show the greatest energy gains. Ecosystem-based management strategies for tunas should thus consider species-specific differences in physiology and foraging specialization. PMID- 26100891 TI - Climate-driven diversity loss in a grassland community. AB - Local ecological communities represent the scale at which species coexist and share resources, and at which diversity has been experimentally shown to underlie stability, productivity, invasion resistance, and other desirable community properties. Globally, community diversity shows a mixture of increases and decreases over recent decades, and these changes have relatively seldom been linked to climatic trends. In a heterogeneous California grassland, we documented declining plant diversity from 2000 to 2014 at both the local community (5 m(2)) and landscape (27 km(2)) scales, across multiple functional groups and soil environments. Communities became particularly poorer in native annual forbs, which are present as small seedlings in midwinter; within native annual forbs, community composition changed toward lower representation of species with a trait indicating drought intolerance (high specific leaf area). Time series models linked diversity decline to the significant decrease in midwinter precipitation. Livestock grazing history, fire, succession, N deposition, and increases in exotic species could be ruled out as contributing causes. This finding is among the first demonstrations to our knowledge of climate-driven directional loss of species diversity in ecological communities in a natural (nonexperimental) setting. Such diversity losses, which may also foreshadow larger-scale extinctions, may be especially likely in semiarid regions that are undergoing climatic trends toward higher aridity and lower productivity. PMID- 26100892 TI - Genetic architecture of natural variation in Drosophila melanogaster aggressive behavior. AB - Aggression is an evolutionarily conserved complex behavior essential for survival and the organization of social hierarchies. With the exception of genetic variants associated with bioamine signaling, which have been implicated in aggression in many species, the genetic basis of natural variation in aggression is largely unknown. Drosophila melanogaster is a favorable model system for exploring the genetic basis of natural variation in aggression. Here, we performed genome-wide association analyses using the inbred, sequenced lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and replicate advanced intercross populations derived from the most and least aggressive DGRP lines. We identified genes that have been previously implicated in aggressive behavior as well as many novel loci, including gustatory receptor 63a (Gr63a), which encodes a subunit of the receptor for CO2, and genes associated with development and function of the nervous system. Although genes from the two association analyses were largely nonoverlapping, they mapped onto a genetic interaction network inferred from an analysis of pairwise epistasis in the DGRP. We used mutations and RNAi knock-down alleles to functionally validate 79% of the candidate genes and 75% of the candidate epistatic interactions tested. Epistasis for aggressive behavior causes cryptic genetic variation in the DGRP that is revealed by changing allele frequencies in the outbred populations derived from extreme DGRP lines. This phenomenon may pertain to other fitness traits and species, with implications for evolution, applied breeding, and human genetics. PMID- 26100893 TI - An eIF2alpha-binding motif in protein phosphatase 1 subunit GADD34 and its viral orthologs is required to promote dephosphorylation of eIF2alpha. AB - Transient protein synthesis inhibition, mediated by phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha), is an important protective mechanism cells use during stress conditions. Following relief of the stress, the growth arrest and DNA damage-inducible protein GADD34 associates with the broadly acting serine/threonine protein phosphatase 1 (PP1) to dephosphorylate eIF2alpha. Whereas the PP1-binding motif on GADD34 has been defined, it remains to be determined how GADD34 directs PP1 to specifically dephosphorylate eIF2alpha. In this report, we map a novel eIF2alpha-binding motif to the C terminus of GADD34 in a region distinct from where PP1 binds to GADD34. This motif is characterized by the consensus sequence Rx[Gnl]x(1 2)Wxxx[Arlv]x[Dn][Rg]xRFxx[Rlvk][Ivc], where capital letters are preferred and x is any residue. Point mutations altering the eIF2alpha-binding motif impair the ability of GADD34 to interact with eIF2alpha, promote eIF2alpha dephosphorylation, and suppress PKR toxicity in yeast. Interestingly, this eIF2alpha-docking motif is conserved among viral orthologs of GADD34, and is necessary for the proteins produced by African swine fever virus, Canarypox virus, and Herpes simplex virus to promote eIF2alpha dephosphorylation. Taken together, these data indicate that GADD34 and its viral orthologs direct specific dephosphorylation of eIF2alpha by interacting with both PP1 and eIF2alpha through independent binding motifs. PMID- 26100895 TI - Synaptic clusters function as odor operators in the olfactory bulb. AB - How the olfactory bulb organizes and processes odor inputs through fundamental operations of its microcircuits is largely unknown. To gain new insight we focus on odor-activated synaptic clusters related to individual glomeruli, which we call glomerular units. Using a 3D model of mitral and granule cell interactions supported by experimental findings, combined with a matrix-based representation of glomerular operations, we identify the mechanisms for forming one or more glomerular units in response to a given odor, how and to what extent the glomerular units interfere or interact with each other during learning, their computational role within the olfactory bulb microcircuit, and how their actions can be formalized into a theoretical framework in which the olfactory bulb can be considered to contain "odor operators" unique to each individual. The results provide new and specific theoretical and experimentally testable predictions. PMID- 26100896 TI - QnAs with Robert Tibshirani. PMID- 26100894 TI - Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae, an urgent threat to public health. AB - Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats. PMID- 26100897 TI - Adolescent impatience decreases with increased frontostriatal connectivity. AB - Adolescence is a developmental period associated with an increase in impulsivity. Impulsivity is a multidimensional construct, and in this study we focus on one of the underlying components: impatience. Impatience can result from (i) disregard of future outcomes and/or (ii) oversensitivity to immediate rewards, but it is not known which of these evaluative processes underlie developmental changes. To distinguish between these two causes, we investigated developmental changes in the structural and functional connectivity of different frontostriatal tracts. We report that adolescents were more impatient on an intertemporal choice task and reported less future orientation, but not more present hedonism, than young adults. Developmental increases in structural connectivity strength in the right dorsolateral prefrontal tract were related to increased negative functional coupling with the striatum and an age-related decrease in discount rates. Our results suggest that mainly increased control, and the integration of future oriented thought, drives the reduction in impatience across adolescence. PMID- 26100898 TI - Antibiotic efficacy is linked to bacterial cellular respiration. AB - Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes--the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy. PMID- 26100899 TI - Generating new prions by targeted mutation or segment duplication. AB - Yeasts contain various protein-based genetic elements, termed prions, that result from the structural conversion of proteins into self-propagating amyloid forms. Most yeast prion proteins contain glutamine/asparagine (Q/N)-rich prion domains that drive prion activity. Here, we explore two mechanisms by which new prion domains could evolve. First, it has been proposed that mutation and natural selection will tend to result in proteins with aggregation propensities just low enough to function under physiological conditions and thus that a small number of mutations are often sufficient to cause aggregation. We hypothesized that if the ability to form prion aggregates was a sufficiently generic feature of Q/N-rich domains, many nonprion Q/N-rich domains might similarly have aggregation propensities on the edge of prion formation. Indeed, we tested four yeast Q/N rich domains that had no detectable aggregation activity; in each case, a small number of rationally designed mutations were sufficient to cause the proteins to aggregate and, for two of the domains, to create prion activity. Second, oligopeptide repeats are found in multiple prion proteins, and expansion of these repeats increases prion activity. However, it is unclear whether the effects of repeat expansion are unique to these specific sequences or are a generic result of adding additional aggregation-prone segments into a protein domain. We found that within nonprion Q/N-rich domains, repeating aggregation-prone segments in tandem was sufficient to create prion activity. Duplication of DNA elements is a common source of genetic variation and may provide a simple mechanism to rapidly evolve prion activity. PMID- 26100900 TI - Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. AB - A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2 nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy. PMID- 26100901 TI - Structural insights into the recognition of cisplatin and AAF-dG lesion by Rad14 (XPA). AB - Nucleotide excision repair (NER) is responsible for the removal of a large variety of structurally diverse DNA lesions. Mutations of the involved proteins cause the xeroderma pigmentosum (XP) cancer predisposition syndrome. Although the general mechanism of the NER process is well studied, the function of the XPA protein, which is of central importance for successful NER, has remained enigmatic. It is known, that XPA binds kinked DNA structures and that it interacts also with DNA duplexes containing certain lesions, but the mechanism of interactions is unknown. Here we present two crystal structures of the DNA binding domain (DBD) of the yeast XPA homolog Rad14 bound to DNA with either a cisplatin lesion (1,2-GG) or an acetylaminofluorene adduct (AAF-dG). In the structures, we see that two Rad14 molecules bind to the duplex, which induces DNA melting of the duplex remote from the lesion. Each monomer interrogates the duplex with a beta-hairpin, which creates a 13mer duplex recognition motif additionally characterized by a sharp 70 degrees DNA kink at the position of the lesion. Although the 1,2-GG lesion stabilizes the kink due to the covalent fixation of the crosslinked dG bases at a 90 degrees angle, the AAF-dG fully intercalates into the duplex to stabilize the kinked structure. PMID- 26100902 TI - RNA ligation in neurons by RtcB inhibits axon regeneration. AB - Activity of the RNA ligase RtcB has only two known functions: tRNA ligation after intron removal and XBP1 mRNA ligation during activation of the unfolded protein response. Here, we show that RtcB acts in neurons to inhibit axon regeneration after nerve injury. This function of RtcB is independent of its basal activities in tRNA ligation and the unfolded protein response. Furthermore, inhibition of axon regeneration is independent of the RtcB cofactor archease. Finally, RtcB is enriched at axon termini after nerve injury. Our data indicate that neurons have co-opted an ancient RNA modification mechanism to regulate specific and dynamic functions and identify neuronal RtcB activity as a critical regulator of neuronal growth potential. PMID- 26100903 TI - Single-molecule imaging of Hedgehog pathway protein Smoothened in primary cilia reveals binding events regulated by Patched1. AB - Accumulation of the signaling protein Smoothened (Smo) in the membrane of primary cilia is an essential step in Hedgehog (Hh) signal transduction, yet the molecular mechanisms of Smo movement and localization are poorly understood. Using ultrasensitive single-molecule tracking with high spatial/temporal precision (30 nm/10 ms), we discovered that binding events disrupt the primarily diffusive movement of Smo in cilia at an array of sites near the base. The affinity of Smo for these binding sites was modulated by the Hh pathway activation state. Activation, by either a ligand or genetic loss of the negatively acting Hh receptor Patched-1 (Ptch), reduced the affinity and frequency of Smo binding at the base. Our findings quantify activation-dependent changes in Smo dynamics in cilia and highlight a previously unknown step in Hh pathway activation. PMID- 26100904 TI - Solid-liquid critical behavior of water in nanopores. AB - Nanoconfined liquid water can transform into low-dimensional ices whose crystalline structures are dissimilar to any bulk ices and whose melting point may significantly rise with reducing the pore size, as revealed by computer simulation and confirmed by experiment. One of the intriguing, and as yet unresolved, questions concerns the observation that the liquid water may transform into a low-dimensional ice either via a first-order phase change or without any discontinuity in thermodynamic and dynamic properties, which suggests the existence of solid-liquid critical points in this class of nanoconfined systems. Here we explore the phase behavior of a model of water in carbon nanotubes in the temperature-pressure-diameter space by molecular dynamics simulation and provide unambiguous evidence to support solid-liquid critical phenomena of nanoconfined water. Solid-liquid first-order phase boundaries are determined by tracing spontaneous phase separation at various temperatures. All of the boundaries eventually cease to exist at the critical points and there appear loci of response function maxima, or the Widom lines, extending to the supercritical region. The finite-size scaling analysis of the density distribution supports the presence of both first-order and continuous phase changes between solid and liquid. At around the Widom line, there are microscopic domains of two phases, and continuous solid-liquid phase changes occur in such a way that the domains of one phase grow and those of the other evanesce as the thermodynamic state departs from the Widom line. PMID- 26100905 TI - Relationship between thermoelectric figure of merit and energy conversion efficiency. AB - The formula for maximum efficiency (etamax) of heat conversion into electricity by a thermoelectric device in terms of the dimensionless figure of merit (ZT) has been widely used to assess the desirability of thermoelectric materials for devices. Unfortunately, the etamax values vary greatly depending on how the average ZT values are used, raising questions about the applicability of ZT in the case of a large temperature difference between the hot and cold sides due to the neglect of the temperature dependences of the material properties that affect ZT. To avoid the complex numerical simulation that gives accurate efficiency, we have defined an engineering dimensionless figure of merit (ZT)eng and an engineering power factor (PF)eng as functions of the temperature difference between the cold and hot sides to predict reliably and accurately the practical conversion efficiency and output power, respectively, overcoming the reporting of unrealistic efficiency using average ZT values. PMID- 26100906 TI - Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar. AB - Experimental and computational folding studies of Proteins L & G and NuG2 typically find that sequence differences determine which of the two hairpins is formed in the transition state ensemble (TSE). However, our recent work on Protein L finds that its TSE contains both hairpins, compelling a reassessment of the influence of sequence on the folding behavior of the other two homologs. We characterize the TSEs for Protein G and NuG2b, a triple mutant of NuG2, using psi analysis, a method for identifying contacts in the TSE. All three homologs are found to share a common and near-native TSE topology with interactions between all four strands. However, the helical content varies in the TSE, being largely absent in Proteins G & L but partially present in NuG2b. The variability likely arises from competing propensities for the formation of nonnative beta turns in the naturally occurring proteins, as observed in our TerItFix folding algorithm. All-atom folding simulations of NuG2b recapitulate the observed TSEs with four strands for 5 of 27 transition paths [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517-520]. Our data support the view that homologous proteins have similar folding mechanisms, even when nonnative interactions are present in the transition state. These findings emphasize the ongoing challenge of accurately characterizing and predicting TSEs, even for relatively simple proteins. PMID- 26100908 TI - Cooperative strings and glassy interfaces. AB - We introduce a minimal theory of glass formation based on the ideas of molecular crowding and resultant string-like cooperative rearrangement, and address the effects of free interfaces. In the bulk case, we obtain a scaling expression for the number of particles taking part in cooperative strings, and we recover the Adam-Gibbs description of glassy dynamics. Then, by including thermal dilatation, the Vogel-Fulcher-Tammann relation is derived. Moreover, the random and string like characters of the cooperative rearrangement allow us to predict a temperature-dependent expression for the cooperative length xi of bulk relaxation. Finally, we explore the influence of sample boundaries when the system size becomes comparable to xi. The theory is in agreement with measurements of the glass-transition temperature of thin polymer films, and allows quantification of the temperature-dependent thickness hm of the interfacial mobile layer. PMID- 26100907 TI - A structural, functional, and computational analysis suggests pore flexibility as the base for the poor selectivity of CNG channels. AB - Cyclic nucleotide-gated (CNG) ion channels, despite a significant homology with the highly selective K(+) channels, do not discriminate among monovalent alkali cations and are permeable also to several organic cations. We combined electrophysiology, molecular dynamics (MD) simulations, and X-ray crystallography to demonstrate that the pore of CNG channels is highly flexible. When a CNG mimic is crystallized in the presence of a variety of monovalent cations, including Na(+), Cs(+), and dimethylammonium (DMA(+)), the side chain of Glu66 in the selectivity filter shows multiple conformations and the diameter of the pore changes significantly. MD simulations indicate that Glu66 and the prolines in the outer vestibule undergo large fluctuations, which are modulated by the ionic species and the voltage. This flexibility underlies the coupling between gating and permeation and the poor ionic selectivity of CNG channels. PMID- 26100909 TI - BEND3 represses rDNA transcription by stabilizing a NoRC component via USP21 deubiquitinase. AB - Ribosome biogenesis dictates the translational capacity of cells. Several mechanisms establish and maintain transcriptional output from eukaryotic ribosomal DNA (rDNA) loci. rDNA silencing is one such mechanism that ensures the inactivity and hence the maintenance of a silenced state of a subset of rRNA gene copies. Whereas oncogenic agents stimulate rRNA gene transcription, tumor suppressors decrease rRNA gene transcription. We demonstrate in mammalian cells that BANP, E5R, and Nac1 (BEN) domain 3 (BEND3), a quadruple BEN domain containing protein, localizes in nucleoli and binds to ribosomal RNA gene promoters to help repress rRNA genes. Loss of BEND3 increases histone H3K4 trimethylation and, correspondingly, decreases rDNA promoter DNA methylation, consistent with a role for BEND3 in rDNA silencing. BEND3 associates with the nucleolar-remodeling complex (NoRC), and SUMOylated BEND3 stabilizes NoRC component TTF-1-interacting protein 5 via association with ubiquitin specific protease 21 (USP21) debiquitinase. Our results provide mechanistic insights into how the novel rDNA transcription repressor BEND3 acts together with NoRC to actively coordinate the establishment of rDNA silencing. PMID- 26100910 TI - DNA polymerase from temperate phage Bam35 is endowed with processive polymerization and abasic sites translesion synthesis capacity. AB - DNA polymerases (DNAPs) responsible for genome replication are highly faithful enzymes that nonetheless cannot deal with damaged DNA. In contrast, translesion synthesis (TLS) DNAPs are suitable for replicating modified template bases, although resulting in very low-fidelity products. Here we report the biochemical characterization of the temperate bacteriophage Bam35 DNA polymerase (B35DNAP), which belongs to the protein-primed subgroup of family B DNAPs, along with phage Phi29 and other viral and mobile element polymerases. B35DNAP is a highly faithful DNAP that can couple strand displacement to processive DNA synthesis. These properties allow it to perform multiple displacement amplification of plasmid DNA with a very low error rate. Despite its fidelity and proofreading activity, B35DNAP was able to successfully perform abasic site TLS without template realignment and inserting preferably an A opposite the abasic site (A rule). Moreover, deletion of the TPR2 subdomain, required for processivity, impaired primer extension beyond the abasic site. Taken together, these findings suggest that B35DNAP may perform faithful and processive genome replication in vivo and, when required, TLS of abasic sites. PMID- 26100911 TI - Disruption of prostaglandin E2 receptor EP4 impairs urinary concentration via decreasing aquaporin 2 in renal collecting ducts. AB - The antidiuretic hormone arginine vasopressin is a systemic effector in urinary concentration. However, increasing evidence suggests that other locally produced factors may also play an important role in the regulation of water reabsorption in renal collecting ducts. Recently, prostaglandin E2 (PGE2) receptor EP4 has emerged as a potential therapeutic target for the treatment of nephrogenic diabetes insipidus, but the underlying mechanism is unknown. To evaluate the role of EP4 in regulating water homeostasis, mice with renal tubule-specific knockout of EP4 (Ksp-EP4(-/-)) and collecting duct-specific knockout of EP4 (AQP2-EP4(-/ )) were generated using the Cre-loxP recombination system. Urine concentrating defect was observed in both Ksp-EP4(-/-) and AQP2-EP4(-/-) mice. Decreased aquaporin 2 (AQP2) abundance and apical membrane targeting in renal collecting ducts were evident in Ksp-EP4(-/-) mice. In vitro studies demonstrated that AQP2 mRNA and protein levels were significantly up-regulated in mouse primary inner medullary collecting duct (IMCD) cells after pharmacological activation or adenovirus-mediated overexpression of EP4 in a cAMP/cAMP-response element binding protein-dependent manner. In addition, EP4 activation or overexpression also increased AQP2 membrane accumulation in a mouse IMCD cell line (IMCD3) stably transfected with the AQP2 gene, mainly through the cAMP/protein kinase A and extracellular signal-regulated kinase pathways. In summary, the EP4 receptor in renal collecting ducts plays an important role in regulating urinary concentration under physiological conditions. The ability of EP4 to promote AQP2 membrane targeting and increase AQP2 abundance makes it a potential therapeutic target for the treatment of clinical disorders including acquired and congenital diabetes insipidus. PMID- 26100913 TI - Top-down control of the phase of alpha-band oscillations as a mechanism for temporal prediction. AB - The physiological state of the brain before an incoming stimulus has substantial consequences for subsequent behavior and neural processing. For example, the phase of ongoing posterior alpha-band oscillations (8-14 Hz) immediately before visual stimulation has been shown to predict perceptual outcomes and downstream neural activity. Although this phenomenon suggests that these oscillations may phasically route information through functional networks, many accounts treat these periodic effects as a consequence of ongoing activity that is independent of behavioral strategy. Here, we investigated whether alpha-band phase can be guided by top-down control in a temporal cueing task. When participants were provided with cues predictive of the moment of visual target onset, discrimination accuracy improved and targets were more frequently reported as consciously seen, relative to unpredictive cues. This effect was accompanied by a significant shift in the phase of alpha-band oscillations, before target onset, toward each participant's optimal phase for stimulus discrimination. These findings provide direct evidence that forming predictions about when a stimulus will appear can bias the phase of ongoing alpha-band oscillations toward an optimal phase for visual processing, and may thus serve as a mechanism for the top-down control of visual processing guided by temporal predictions. PMID- 26100914 TI - Self-reproducing catalyst drives repeated phospholipid synthesis and membrane growth. AB - Cell membranes are dynamic structures found in all living organisms. There have been numerous constructs that model phospholipid membranes. However, unlike natural membranes, these biomimetic systems cannot sustain growth owing to an inability to replenish phospholipid-synthesizing catalysts. Here we report on the design and synthesis of artificial membranes embedded with synthetic, self reproducing catalysts capable of perpetuating phospholipid bilayer formation. Replacing the complex biochemical pathways used in nature with an autocatalyst that also drives lipid synthesis leads to the continual formation of triazole phospholipids and membrane-bound oligotriazole catalysts from simpler starting materials. In addition to continual phospholipid synthesis and vesicle growth, the synthetic membranes are capable of remodeling their physical composition in response to changes in the environment by preferentially incorporating specific precursors. These results demonstrate that complex membranes capable of indefinite self-synthesis can emerge when supplied with simpler chemical building blocks. PMID- 26100912 TI - Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1. AB - G protein-coupled receptors (GPCRs) are surprisingly flexible molecules that can do much more than simply turn on G proteins. Some even exhibit biased signaling, wherein the same receptor preferentially activates different G-protein or arrestin signaling pathways depending on the type of ligand bound. Why this behavior occurs is still unclear, but it can happen with both traditional ligands and ligands that bind allosterically outside the orthosteric receptor binding pocket. Here, we looked for structural mechanisms underlying these phenomena in the marijuana receptor CB1. Our work focused on the allosteric ligand Org 27569, which has an unusual effect on CB1-it simultaneously increases agonist binding, decreases G--protein activation, and induces biased signaling. Using classical pharmacological binding studies, we find that Org 27569 binds to a unique allosteric site on CB1 and show that it can act alone (without need for agonist cobinding). Through mutagenesis studies, we find that the ability of Org 27569 to bind is related to how much receptor is in an active conformation that can couple with G protein. Using these data, we estimated the energy differences between the inactive and active states. Finally, site-directed fluorescence labeling studies show the CB1 structure stabilized by Org 27569 is different and unique from that stabilized by antagonist or agonist. Specifically, transmembrane helix 6 (TM6) movements associated with G-protein activation are blocked, but at the same time, helix 8/TM7 movements are enhanced, suggesting a possible mechanism for the ability of Org 27569 to induce biased signaling. PMID- 26100915 TI - Structure and function of the mammalian middle ear. II: Inferring function from structure. AB - Anatomists and zoologists who study middle ear morphology are often interested to know what the structure of an ear can reveal about the auditory acuity and hearing range of the animal in question. This paper represents an introduction to middle ear function targetted towards biological scientists with little experience in the field of auditory acoustics. Simple models of impedance matching are first described, based on the familiar concepts of the area and lever ratios of the middle ear. However, using the Mongolian gerbil Meriones unguiculatus as a test case, it is shown that the predictions made by such 'ideal transformer' models are generally not consistent with measurements derived from recent experimental studies. Electrical analogue models represent a better way to understand some of the complex, frequency-dependent responses of the middle ear: these have been used to model the effects of middle ear subcavities, and the possible function of the auditory ossicles as a transmission line. The concepts behind such models are explained here, again aimed at those with little background knowledge. Functional inferences based on middle ear anatomy are more likely to be valid at low frequencies. Acoustic impedance at low frequencies is dominated by compliance; expanded middle ear cavities, found in small desert mammals including gerbils, jerboas and the sengi Macroscelides, are expected to improve low-frequency sound transmission, as long as the ossicular system is not too stiff. PMID- 26100916 TI - In malignant cartilagenous tumors, immunohistochemical expression of procollagen PC1CP peptide is higher and that of PC2CP lower than in benign cartilaginous lesions. AB - Few studies on oncogenesis of chondrosarcoma (CS) are available in the literature. Our previously published experimental evidence suggests that while the C-propeptide of procollagen Ialpha1 (PC1CP), a component of cartilage, favors tumor progression, the C-propeptide of procollagen IIalpha1 (PC2CP) exerts antitumor properties. In this study, we analyzed expression of PC1CP and PC2CP by immunohistochemistry in a series of enchondromas and CS. Our retrospective series consisted of 88 cases, including 43 CSs, 34 enchondromas and 11 nontumor samples. Immunohistochemical staining for PC1CP and PC2CP was evaluated in the cytoplasm and in the extracellular matrix (ECM). Diffuse staining for PC1CP in ECM was significantly more frequent in tumor than in nontumor samples (32 % vs. 0 %; p = 0.03), and in CSs than in enchondromas (44 vs. 18 %; p = 0.02). ECM semiquantitative score was higher in tumors than in nontumor samples (p < 0.005) and higher in CSs than in enchondromas (p = 0.05). Staining for PC2CP in ECM was more frequently found in enchondromas than in CSs (59 vs. 33 %; p = 0.02). ECM semiquantitative score was higher in enchondromas than in CSs (p = 0.02). Diffuse staining for PC1CP in combination with absence of staining for PC2CP had 94 % specificity for CS but with a sensitivity of only 35 %. Expression of neither PC1CP nor PC2CP correlated with recurrence-free survival or occurrence of metastases. In conclusion, we show that the expression of PC1CP is higher and that of PC2CP lower in malignant cartilaginous tumors. These results support an oncogenic role of PC1CP and anti-oncogenic property of PC2CP in cartilaginous tumors. PMID- 26100917 TI - Endocardial Brg1 disruption illustrates the developmental origins of semilunar valve disease. AB - The formation of intricately organized aortic and pulmonic valves from primitive endocardial cushions of the outflow tract is a remarkable accomplishment of embryonic development. While not always initially pathologic, developmental semilunar valve (SLV) defects, including bicuspid aortic valve, frequently progress to a disease state in adults requiring valve replacement surgery. Disrupted embryonic growth, differentiation, and patterning events that "trigger" SLV disease are coordinated by gene expression changes in endocardial, myocardial, and cushion mesenchymal cells. We explored roles of chromatin regulation in valve gene regulatory networks by conditional inactivation of the Brg1-associated factor (BAF) chromatin remodeling complex in the endocardial lineage. Endocardial Brg1-deficient mouse embryos develop thickened and disorganized SLV cusps that frequently become bicuspid and myxomatous, including in surviving adults. These SLV disease-like phenotypes originate from deficient endocardial-to-mesenchymal transformation (EMT) in the proximal outflow tract (pOFT) cushions. The missing cells are replaced by compensating neural crest or other non-EMT-derived mesenchyme. However, these cells are incompetent to fully pattern the valve interstitium into distinct regions with specialized extracellular matrices. Transcriptomics reveal genes that may promote growth and patterning of SLVs and/or serve as disease-state biomarkers. Mechanistic studies of SLV disease genes should distinguish between disease origins and progression; the latter may reflect secondary responses to a disrupted developmental system. PMID- 26100918 TI - Molecular asymmetry in the 8-cell stage Xenopus tropicalis embryo described by single blastomere transcript sequencing. AB - Correct development of the vertebrate body plan requires the early definition of two asymmetric, perpendicular axes. The first axis is established during oocyte maturation, and the second is established by symmetry breaking shortly after fertilization. The physical processes generating the second asymmetric, or dorsal ventral, axis are well understood, but the specific molecular determinants, presumed to be maternal gene products, are poorly characterized. Whilst enrichment of maternal mRNAs at the animal and vegetal poles in both the oocyte and the early embryo has been studied, little is known about the distribution of maternal mRNAs along either the dorsal-ventral or left-right axes during the early cleavage stages. Here we report an unbiased analysis of the distribution of maternal mRNA on all axes of the Xenopus tropicalis 8-cell stage embryo, based on sequencing of single blastomeres whose positions within the embryo are known. Analysis of pooled data from complete sets of blastomeres from four embryos has identified 908 mRNAs enriched in either the animal or vegetal blastomeres, of which 793 are not previously reported as enriched. In contrast, we find no evidence for asymmetric distribution along either the dorsal-ventral or left right axes. We confirm that animal pole enrichment is on average distinctly lower than vegetal pole enrichment, and that considerable variation is found between reported enrichment levels in different studies. We use publicly available data to show that there is a significant association between genes with human disease annotation and enrichment at the animal pole. Mutations in the human ortholog of the most animally enriched novel gene, Slc35d1, are causative for Schneckenbecken dysplasia, and we show that a similar phenotype is produced by depletion of the orthologous protein in Xenopus embryos. PMID- 26100920 TI - Can we use peripheral tissue biopsies to diagnose Parkinson's disease? A review of the literature. AB - Phosphorylated alpha-synuclein (phosalphaSYN) containing inclusions in neurons (Lewy bodies, LB) and nerve terminals (Lewy neurites, LN), the pathological hallmark of Parkinson's disease (PD), are not confined to the central nervous system, but have also been reported in peripheral tissues. However, the usefulness of alphaSYN/phosalphaSYN detection in tissues accessible to biopsies as a reliable biomarker for prodromal PD remains unclear. A systematic review of studies using biopsies of skin, olfactory and gastrointestinal (GI) tissues was conducted to evaluate the sensitivity and specificity of both alphaSYN and phosalphaSYN staining in PD patients. Data analysis was hampered by the diversity of the methods used, e.g. choice of biopsy sites, tissue processing, staining protocols and evaluation of the findings. Tissue obtained from GI tract/salivary glands (13 post-mortem, 13 in vivo studies) yielded the highest overall sensitivity and specificity compared to skin (three post-mortem, eight in vivo studies) and olfactory mucosa/bulb (six post-mortem studies, one in vivo study). In contrast to phosalphaSYN, alphaSYN was more consistently detectable in peripheral tissues of healthy controls. GI tract/salivary glands appear to be the most promising candidate tissue for peripheral biopsy-taking. phosalphaSYN is considered as the marker of choice to delineate pathological aggregates from normal alphaSYN regularly found in peripheral neural tissues. However, the sensitivity and specificity of phosalphaSYN are not yet acceptable for using phosalphaSYN as a reliable peripheral biomarker for PD in clinical routine. Further refinement regarding the interpretation of the peripheral alphaSYN/phosalphaSYN burden and the phenotypical definition of peripheral LB/LN is needed to optimize screening methods for prodromal PD. PMID- 26100919 TI - Family impact of Rotavirus Gastroenteritis in Taiwan and Vietnam: an Ethnographic Study. AB - BACKGROUND: Prior to the introduction of rotavirus vaccines, rotavirus was the leading cause of severe gastroenteritis in infants and young children, and it continues to be the leading cause in countries without vaccination programs. Rotavirus gastroenteritis results in substantial economic burden and has a pronounced effect on the family of those who are ill. Both in Taiwan and in Vietnam, rotavirus illness is viewed as a priority disease. This study assessed, in Taiwan and Vietnam, the impact of rotavirus gastroenteritis on the family among a group of parents whose children had recently been hospitalized for this illness. METHODS: In the first half of 2013, parents of children who had been hospitalized due to rotavirus infection were recruited from hospitals in Taiwan (n = 12) and Vietnam (n = 22), and participated in focus group sessions or in depth ethnographic interviews. RESULTS: In both countries, the results point to a substantial burden on the parents concerning emotions and logistics of daily tasks, and to considerable disruptions of the family routine. Taiwanese parents reported satisfaction with the health care system, a great deal of effort to suppress emotions, a fair amount of knowledge about rotavirus, and little extra costs related to the illness. On the other hand, parents in Vietnam expressed concern about the emotional well-being of and the health care treatments for their children, were less knowledgeable regarding rotavirus infection, and experienced a substantial financial burden due to indirect costs that were related to accessing treatment. CONCLUSIONS: Families in Taiwan and Vietnam suffer from a considerable economic and emotional burden related to rotavirus gastroenteritis. One way to substantially reduce this burden is to provide universal and affordable rotavirus vaccination to susceptible children, especially since cost-effectiveness studies have demonstrated that universal vaccination would be safe and efficacious against severe rotavirus gastroenteritis in these countries. PMID- 26100921 TI - Prospects for a globally effective HIV-1 vaccine. AB - A globally effective vaccine strategy must cope with the broad genetic diversity of HIV and contend with multiple transmission modalities. Understanding correlates of protection and the role of diversity in limiting protective vaccines with those correlates is key. RV144 was the first HIV-1 vaccine trial to demonstrate efficacy against HIV-1 infection. A correlates analysis compared vaccine-induced immune responses in vaccinated-infected and vaccinated-uninfected volunteers suggested that IgG specific for the V1V2 region of gp120 was associated with reduced risk of HIV-1 infection and that plasma Env IgA was directly correlated with infection risk. RV144 and recent NHP challenge studies suggest that Env is essential and perhaps sufficient to induce protective antibody responses against mucosally acquired HIV-1. Whether RV144 immune correlates can apply to different HIV vaccines, to populations with different modes and intensity of transmission, or to divergent HIV-1 subtypes remains unknown. Newer prime-boost mosaic and conserved sequence immunization strategies aiming at inducing immune responses of greater breadth and depth as well as the development of immunogens inducing broadly neutralizing antibodies should be actively pursued. Efficacy trials are now planned in heterosexual populations in southern Africa and MSM in Thailand. Although NHP challenge studies may guide vaccine development, human efficacy trials remain key to answer the critical questions leading to the development of a global HIV-1 vaccine for licensure. PMID- 26100922 TI - Safety and efficacy of a new octavalent combined Erysipelas, Parvo and Leptospira vaccine in gilts against Leptospira interrogans serovar Pomona associated disease and foetal death. AB - The safety and protective efficacy of a new octavalent combination vaccine containing inactivated Erysipelothrix rhusiopathiae, Parvovirus, and Leptospira interrogans (sensu lato) serogroups Canicola, Icterohaemorrhagiae, Australis (Bratislava), Grippotyphosa, Pomona and Tarassovi - Porcilis((r)) Ery+Parvo+Lepto - was evaluated in laboratory studies and under field conditions. The safety (2* overdose and repeated dose) was tested in 26 gilts. In this study, neither vaccine related temperature increase nor other systemic reactions were observed after intramuscular vaccination. No local reactions were observed except for one animal that had a small local reaction (2cm diameter) that lasted for 5 days after the third vaccination. Efficacy was tested in 40 gilts. A group of 20 gilts was vaccinated at 20 and 24 weeks of age with Porcilis((r)) Ery+Parvo+Lepto and a group of 20 age- and source-matched animals served as the control group. The gilts were inseminated at 41 weeks or 66 weeks of age and were challenged with serovar Pomona 10 weeks after insemination, corresponding to 6 months (n=2*10) and 12 months (n=2*10) after the last vaccination. After both the 6- and 12-month challenges the control animals developed clinical signs (fever, lethargy and anorexia) and leptospiraemia as determined by positive blood culture. In addition, both the 6- and 12-month challenges resulted in death of 21% and 27% of the total number of foetuses in the control groups, respectively. Clinical signs and leptospiraemia were statistically significantly lower in vaccinated gilts after both the 6- and 12-month challenges. In addition, foetal death was statistically significantly lower (3% and 2%, respectively) in vaccinated gilts after both the 6- and 12 month challenges. The vaccine was tested further under field conditions on a Portuguese farm with a history of an increasing abortion rate associated with a Leptospira serovar Pomona infection (confirmed by PCR and serology). This study was designed as an observational-longitudinal field study. At the start of the study, all breeding sows and replacement gilts on the farm were vaccinated twice with Porcilis((r)) Ery+Parvo+Lepto at an interval of 4 weeks. Starting six months after the primary vaccination schedule, the animals were re-vaccinated during the second week of every subsequent lactation. New replacement gilts were vaccinated using the same schedule. After vaccination, the abortion rate reduced rapidly from 12.6% in winter months of 2012 (December 2011 to March 2012) to 0.5% in winter months of 2013, a statistical significant decrease of 96%. The total number of abortions on the farm decreased from 55 in 2012 to 6 in 2013. Thereafter, the abortion rate remained stable and in the period December 2013 to April 2014 was still low (0.6%). In conclusion, the present studies demonstrate that the octavalent Porcilis((r)) Ery+Parvo+Lepto vaccine can be safely used in gilts and sows and induces significant protection, for the duration of at least one year, against serovar Pomona induced clinical signs, leptospiraemia and foetal death. Protection against Pomona associated reproductive failure was confirmed under field conditions where a significant reduction in abortion rate was observed. PMID- 26100923 TI - AS03-adjuvanted H7N1 detergent-split virion vaccine is highly immunogenic in unprimed mice and induces cross-reactive antibodies to emerged H7N9 and additional H7 subtypes. AB - Avian H7 is one of several influenza A virus subtypes that have the potential to cause pandemics. Herein we describe preclinical results following administration of an investigational H7N1 inactivated detergent-split virion vaccine adjuvanted with the AS03 Adjuvant System. The adjuvanted H7N1 vaccine was highly immunogenic compared to the non-adjuvanted H7N1 vaccine in unprimed mice with less than 100ng of hemagglutinin antigen per dose. In addition, compared to the non-adjuvanted vaccine, the AS03-adjuvanted H7N1 vaccine also induced robust HI and VN antibody responses that cross-reacted with other H7 subtypes, including recently emerged H7N9 virus. These H7 data from the preclinical mouse model add to the existing H5 data to suggest that AS03 adjuvant technology may be generally effective for formulating antigen-sparing detergent-split virion vaccines against intrinsically sub-immunogenic avian influenza A virus subtypes. PMID- 26100926 TI - WHO consultation on Respiratory Syncytial Virus Vaccine Development Report from a World Health Organization Meeting held on 23-24 March 2015. AB - Respiratory syncytial virus (RSV) is a globally prevalent cause of lower respiratory infection in neonates and infants. Despite its disease burden, a safe and effective RSV vaccine has remained elusive. In recent years, improved understanding of RSV biology and innovations in immunogen design has resulted in the advancement of multiple vaccine candidates into the clinical development pipeline. Given the growing number of vaccines in clinical trials, the rapid pace at which they are being tested, and the likelihood that an RSV vaccine will reach the commercial market in the next 5-10 years, consensus and guidance on clinical development pathways and licensure routes are needed now, before large-scale efficacy trials commence. In pursuit of this aim, the World Health Organization convened the first RSV vaccine consultation in 15 years on the 23rd and 24th of March, 2015 in Geneva, Switzerland. The meeting's primary objective was to provide guidance on clinical endpoints and development pathways for vaccine trials with a focus on considerations of low- and middle-income countries. Meeting participants reached consensus on candidate case definitions for RSV disease, considerations for clinical efficacy endpoints, and the clinical development pathway for active and passive immunization trials in maternal and pediatric populations. The strategic focus of this meeting was on the development of high quality, safe and efficacious RSV preventive interventions for global use and included: (1) maternal/passive immunization to prevent RSV disease in infants less than 6 months; (2) pediatric immunization to prevent RSV disease in infants and young children once protection afforded by maternal immunization wanes. PMID- 26100924 TI - Immunogenicity and safety of an E. coli-produced bivalent human papillomavirus (type 16 and 18) vaccine: A randomized controlled phase 2 clinical trial. AB - BACKGROUND: This study aimed to investigate the dosage, immunogenicity and safety profile of a novel human papillomavirus (HPV) types 16 and 18 bivalent vaccine produced by E. coli. METHODS: This randomized, double-blinded, controlled phase 2 trial enrolled women aged 18-25 years in China. Totally 1600 eligible participants were randomized to receive 90MUg, 60MUg, or 30MUg of the recombinant HPV 16/18 bivalent vaccine or the control hepatitis B vaccine on a 0, 1 and 6 month schedule. The designated doses are the combined micrograms of HPV16 and 18 VLPs with dose ratio of 2:1. The immunogenicity of the vaccines was assessed by measuring anti-HPV 16 and 18 neutralizing antibodies and total IgG antibodies. Safety of the vaccine was assessed. RESULTS: All but one of the seronegative participants who received 3 doses of the HPV vaccines seroconverted at month 7 for anti-HPV 16/18 neutralizing antibodies and IgG antibodies. For HPV 16, the geometric mean titers (GMTs) of the neutralizing antibodies were similar between the 60MUg (GMT=10,548) and 90MUg (GMT=12,505) HPV vaccine groups and were significantly higher than those in the 30MUg (GMT=7596) group. For HPV 18, the GMTs of the neutralizing antibodies were similar among the 3 groups. The HPV vaccine was well tolerated. No vaccine-associated serious adverse events were identified. CONCLUSION: The prokaryotic-expressed HPV vaccine is safe and immunogenic in women aged 18-25 years. The 60MUg dosage formulation was selected for further investigation for efficacy. CLINICAL TRIALS REGISTRATION: NCT01356823. PMID- 26100925 TI - Salivary antibody levels in adolescents in response to a meningococcal serogroup C conjugate booster vaccination nine years after priming: systemically induced local immunity and saliva as potential surveillance tool. AB - BACKGROUND: In several countries large-scale immunization of children and young adults with Meningococcal serogroup C (MenC) conjugate vaccines has induced long standing herd protection. Salivary antibodies may play an important role in mucosal protection against meningococcal acquisition and carriage. AIM: To investigate antibody levels in (pre)adolescents primed 9 years earlier with a single dose of MenC-polysaccharide tetanus toxoid conjugated (MenC-TT) vaccine and the response to a booster vaccination, with special focus on age-related differences and the relation between salivary and serum antibody levels. METHODS: Nine years after priming, healthy 10- (n=91), 12- (n=91) and 15-year-olds (n=86) received a MenC-TT booster vaccination. Saliva and serum samples were collected prior to and 1 month and 1 year after vaccination. MenC-polysaccharide(MenC-PS) specific antibody levels were measured using a fluorescent-bead-based multiplex immunoassay. RESULTS: Before the booster, MenC-PS-specific IgG and IgA levels in saliva and serum were low and correlated with age at priming. The booster induced a marked increase in salivary MenC-PS-specific IgG (>200-fold), but also in IgA (~10-fold). One year after the booster, salivary IgG and IgA had remained above pre-booster levels in all age groups (~20-fold and ~3-fold, respectively), with persistence of highest levels in the 15-year-olds. MenC-PS-specific IgG and IgA levels in saliva strongly correlated with the levels in serum. CONCLUSION: Parenteral MenC-TT booster vaccination induces a clear increase in salivary MenC PS-specific IgG and IgA levels and persistence of highest levels correlates with age. The strong correlation between serum and salivary antibody levels indicate that saliva may offer an easy and reliable tool for future antibody surveillance. PMID- 26100927 TI - Influenza bivalent vaccine comprising recombinant H3 hemagglutinin (HA) and H1 HA containing replaced H3 hemagglutinin transmembrane domain exhibited improved heterosubtypic protection immunity in mice. AB - Influenza caused by infection of influenza viruses is still a leading cause of morbidity and mortality in human. Vaccination is the main defense against influenza virus, but current influenza trivalent or quatrivalent vaccines (TIV/QIV) would lose their effectiveness when vaccine strains are mismatched with circulating strains. Our early study showed that recombinant influenza Hx-TM HA proteins containing H3 HA transmembrane domain(TM) had improved immunogenicity and heterosubtypic protection over corresponding wild-type Hx-WT HA proteins. In present study, bivalent vaccines containing H3-WT+Hx-TM were investigated for their immune responses and heterosubtypic protection immunities. The data showed that the bivalent vaccines containing H3-WT and H5-TM or H1-TM had improved immune responses and heterosubtypic protection over the bivalent vaccines containing H3-WT and H5-WT or H1-WT respectively. These results demonstrated that the improved immune responses and heterosubtypic protection of Hx-TM HA proteins could be translated into bivalent vaccines, suggesting a feasible strategy of improving the immune responses and heterosubtypic protection of influenza multivalent vaccines such as TIV and QIV. PMID- 26100929 TI - Comparison of the marginal fit of lithium disilicate crowns fabricated with CAD/CAM technology by using conventional impressions and two intraoral digital scanners. AB - STATEMENT OF PROBLEM: Conventional impression materials and techniques have been used successfully to fabricate fixed restorations. Recently, digital pathways have been developed, but insufficient data are available regarding their marginal accuracy. PURPOSE: The purpose of this in vitro study was to compare the marginal gap discrepancy of lithium disilicate single crowns fabricated with computer aided design and computer-aided manufacturing (CAD/CAM) technology by using both conventional and 2 digital impression techniques. MATERIAL AND METHODS: One typodont maxillary right central incisor was prepared for a ceramic crown. Ten impressions were made by using each method: conventional with polyvinyl siloxane impression material, Lava COS (3M ESPE), and iTero (Cadent) intraoral scanning devices. Lithium disilicate (e.max CAD) crowns were fabricated with CAD/CAM technology, and the marginal gap was measured for each specimen at 4 points under magnification with a stereomicroscope. The mean measurement for each location and overall mean gap size by group were calculated. Statistically significant differences among the impression techniques were tested with F and t tests (alpha=.05). RESULTS: The average (+/-SD) gap for the conventional impression group was 112.3 (+/-35.3) MUm. The digital impression groups had similar average gap sizes; the Lava group was 89.8 (+/-25.4) MUm, and the iTero group was 89.6 (+/-30.1) MUm. No statistically significant difference was found in the effects among impression techniques (P=.185) CONCLUSIONS: Within the limitations of this study, digital and conventional impressions were found to produce crowns with similar marginal accuracy. PMID- 26100928 TI - Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. AB - OBJECTIVE: Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with body fat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between faecal A. muciniphila abundance, faecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR). DESIGN: The intervention consisted of a 6-week CR period followed by a 6-week weight stabilisation diet in overweight and obese adults (N=49, including 41 women). Faecal A. muciniphila abundance, faecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and weight stabilisation. RESULTS: At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. These participants also experienced a reduction in A. muciniphila abundance, but it remained significantly higher than in individuals with lower baseline abundance. A. muciniphila was associated with microbial species known to be related to health. CONCLUSIONS: A. muciniphila is associated with a healthier metabolic status and better clinical outcomes after CR in overweight/obese adults. The interaction between gut microbiota ecology and A. muciniphila warrants further investigation. TRIAL REGISTRATION NUMBER: NCT01314690. PMID- 26100930 TI - Technique to retrieve implant abutment fragments. AB - This clinical report describes the fractured hexagonal part of an implant abutment. The initial clinical sign was a loose abutment screw. Upon further clinical evaluation, the abutment was seen to have fractured and had wedged inside the implant body. Because the implant was a bone-level internal conical connection system, access and visibility were limited. A simple and economical technique with modified round-tip scissors was used to retrieve the fractured titanium abutment. PMID- 26100931 TI - Environmental microbiology for public health--capturing international developments in the field. PMID- 26100932 TI - Capturing prokaryotic dark matter genomes. AB - Prokaryotes are the most diverse and abundant cellular life forms on Earth. Most of them, identified by indirect molecular approaches, belong to microbial dark matter. The advent of metagenomic and single-cell genomic approaches has highlighted the metabolic capabilities of numerous members of this dark matter through genome reconstruction. Thus, linking functions back to the species has revolutionized our understanding of how ecosystem function is sustained by the microbial world. This review will present discoveries acquired through the illumination of prokaryotic dark matter genomes by these innovative approaches. PMID- 26100933 TI - Diversity in the antibacterial potential of probiotic cultures Bacillus licheniformis MCC2514 and Bacillus licheniformis MCC2512. AB - The aim of the present study was to investigate the characteristic diversity and stability of antimicrobial compounds produced by two probiotic strains of Bacillus licheniformis (MCC2514 and MCC2512). Antimicrobial compounds from the two strains notably varied, related to stability and potency. The inhibitory spectrum of B. licheniformis MCC2512 was higher than MCC2514, but, related to the effect on Micrococcus luteus ATCC9341, MCC2514 (LD50 = 450 AU ml(-1)) was more potent than MCC2512 (LD50 = 750 AU ml(-1)). The compounds were thermo-resistant and stable at a wide range of pH and exhibited considerable resistance to digestive enzymes and bile salts (anionic biological detergents), contributing to their appropriate application in various food systems. The isolate B. licheniformis MCC2512 gave a positive response to Bacillus subtilis-based biosensors BSF2470 and BS168.BS2, confirming the mode of action on the cell wall and subtilin-type, respectively. For B. licheniformis MCC2514, the mode of action was characterized by constructing B. subtilis reporters that interfered in five major biosynthetic pathways, i.e., biosynthesis of DNA, RNA, protein, the cell wall and fatty acids. B. licheniformis MCC2514 responded to the yvgS reporter, indicating it as an RNA synthesis inhibitor. Overall, the investigation reveals variability of the antimicrobial compounds from B. licheniformis of different origins and for their possible application as biopreservative agents. PMID- 26100934 TI - Ag2CO3/UiO-66(Zr) composite with enhanced visible-light promoted photocatalytic activity for dye degradation. AB - Because of their excellent properties, metal-organic frameworks (MOFs) are considered as ideal materials for the development of visible-light photocatalyst. Particularly, although increasing research interests have been put on MOF based photocatalysts, the MOF supported Ag2CO3 as photocatalyst has not been reported in the field of water treatment. In this study, a zirconium based MOF, UiO-66, was incorporated with Ag2CO3 through a convenient solution method and used for visible-light prompted dye degradation. Compared to the mixture of pristine UiO 66 and Ag2CO3, the developed Ag2CO3/UiO-66 composite exhibited enhanced photocatalytic activity to the degradation of rhodamine B (RhB) under visible light irradiation. It was supposed that the participation of UiO-66 during the synthesis of Ag2CO3 was crucial for such improvement. In addition, the Ag2CO3/UiO 66 composite demonstrated good structural stability after the degradation experiment, and most of its photocatalytic activity was still preserved after the recycle test. Moreover, the photocatalytic mechanism of the Ag2CO3/UiO-66 composite was investigated and a possible pathway of RhB degradation was also proposed. PMID- 26100935 TI - Stabilization and separation of heavy metals in incineration fly ash during the hydrothermal treatment process. AB - In the paper, hydrothermal treatment (HT) of MSWI fly ashes was performed to stabilize and separate heavy metals. Influences of pre-treatment, types of ferric and/or ferrous additives, and subsequent heavy metal stabilization procedure by adding phosphate were investigated. The chemical stability of hydrothermal products was examined by solid waste extraction procedure with acetic acid buffer solution. Mineralogical investigation of selected hydrothermal product was carried out by XRD. FEGE SEM- -EDX was used to study the morphology and surface compositions of the ash particles. Experimental results revealed that HT process facilitated heavy metal exposure to leaching solution. FEGE SEM-EDX images revealed that fly ash particles were re-organized during hydrothermal process and that the minerals with special shapes and containing high levels of heavy metals were formed. A mild acid washing treatment with final pH around 6.20 could remove soluble heavy metals. Therefore, it may be a proper pre- or post-treatment method for fly ash particles for the purpose of reducing heavy metal contents. For the purpose of stabilizing heavy metals, the addition of ferric/ferrous salts in the HT process or phosphate stabilization after HT is recommended. The HT process may be applied to realize the environmentally sound management of MSWI fly ash or to recover and utilize MSWI fly ash. PMID- 26100936 TI - Judging the Probability of Hypotheses Versus the Impact of Evidence: Which Form of Inductive Inference Is More Accurate and Time-Consistent? AB - Inductive reasoning requires exploiting links between evidence and hypotheses. This can be done focusing either on the posterior probability of the hypothesis when updated on the new evidence or on the impact of the new evidence on the credibility of the hypothesis. But are these two cognitive representations equally reliable? This study investigates this question by comparing probability and impact judgments on the same experimental materials. The results indicate that impact judgments are more consistent in time and more accurate than probability judgments. Impact judgments also predict the direction of errors in probability judgments. These findings suggest that human inductive reasoning relies more on estimating evidential impact than on posterior probability. PMID- 26100937 TI - Corrigendum to "Superparamagnetic PLGA-iron oxide microcapsules for dual-modality US/MR imaging and high intensity focused US breast cancer ablation" [Biomaterials 33 (2012) 5854-5864]. PMID- 26100938 TI - Reply to Letter: 'Re: Education for cardiac arrest - Treatment or prevention?'. PMID- 26100939 TI - Automatic mechanical chest compressions during cardiopulmonary resuscitation: What is the evidence for its use? PMID- 26100940 TI - Re: Education for cardiac arrest - Treatment or prevention? PMID- 26100941 TI - Education for cardiac arrest - Prevention AND treatment. PMID- 26100942 TI - Reply to Letter: 'Re: Education for cardiac arrest - Prevention and treatment'. PMID- 26100943 TI - Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737. AB - PURPOSE: BAG3 is overexpressed in several malignancies and mediates a non canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. METHODS: Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (-)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. RESULTS: Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. CONCLUSION: Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer. PMID- 26100944 TI - Real-time cancer diagnosis during prostate biopsy: ex vivo evaluation of full field optical coherence tomography (FFOCT) imaging on biopsy cores. AB - OBJECTIVES: To evaluate the diagnostic accuracy (Acc) of full-field optical coherence tomography (FFOCT) for cancer detection on prostate biopsy. MATERIALS AND METHODS: Thirty-eight consecutive patients with elevated PSA and/or suspicious digital rectal examination were prospectively included. For each patient, 1-10 cores were randomly selected and imaged with FFOCT immediately after sampling. The images obtained were de-identified and analyzed by three pathologists blinded to the results of pathological evaluation. The overall average Acc was measured, as well as sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV and NPV). The Acc learning curve was assessed by multivariate logistic regression, and inter-reader concordance was assessed by Kappa index. RESULTS: One hundred and nineteen cores were imaged. Of them, 40 (33.6%) were involved with cancer. The overall average Acc of FFOCT for cancer detection was of 70.6%. Se, Sp, PPV, and NPV were of 63, 74, 55.5, and 80%, respectively. A substantial agreement was observed among pathologists (kappa = 0.6, p < 0.001). On multivariate analysis, Acc was associated with the number of previously interpreted cases, with a predicted Acc of 82% at the end of learning curve. The overall average accuracy for high Gleason score (>3 + 3) determination was of 72%, although results were limited by the small amount of cases. CONCLUSIONS: FFOCT of prostate biopsy cores may provide a diagnostic accuracy greater than 80%, with a good reliability and a high NPV. TAKE HOME MESSAGE: "Full-field optical coherence tomography is a novel imaging modality that could have a potential value in real-time diagnosis of prostate cancer during prostate biopsy procedures." PMID- 26100945 TI - Intraoperative frozen section monitoring during nerve-sparing radical prostatectomy: evaluation of partial secondary resection of neurovascular bundles and its effect on oncologic and functional outcome. AB - PURPOSE: Intraoperative frozen sections (IFS) of the prostate have demonstrated to be effective in reducing positive surgical margins (PSM) and biochemical recurrence (BCR). The aim of this study was to assess partial secondary resection of neurovascular bundles (NVB) and report for the first time corresponding functional results. METHODS: A total of 500 consecutive patients were included in this prospective series. All patients underwent open nerve-sparing radical prostatectomy. Intraoperatively, both posterolateral aspects of the prostate were sent for IFS. In case of PSM, additional tissue was partly resected from the prostatic bed along the NVB. BCR was the oncologic endpoint (PSA >= 0.2 ng/ml). The impact of IFS on PSM and BCR-free survival, and the effect of secondary partial resection of NVB on continence and erectile function (EF) recovery were analyzed by Kaplan-Meier analyses. RESULTS: Twenty-nine patients were excluded because of neoadjuvant treatment/lymph node positive disease. PSM were detected in 137/471 patients (29.1%). After secondary resection, 127/137 patients (92.7%) converted to definitive negative surgical margins (NSM). Out of 137 patients, ten (7.3%) showed persistent PSM. False-negative rate was 3.3% (11/334). Out of 471 patients, two (0.4%) showed PSM outside the IFS area. Overall, final PSM rate was 4.9% (23/471). Five-year BCR-free survival did not differ significantly in patients with primarily and converted NSM. Continence and EF recovery after 12 months were 95.8 versus 94.3%, and 65.7 versus 56.1%, respectively (all p > 0.05). CONCLUSION: IFS are highly effective in reducing PSM and avoiding compromised oncologic outcome. Partial secondary resection of the NVB ensures ns status and consequently preserves continence and EF. PMID- 26100946 TI - Androgen receptor aberrations in the era of abiraterone and enzalutamide. AB - Prostate cancer is the most prevalent non-skin cancer and the second leading cause of cancer death in men of the western world. As growth and differentiation of prostate cancer largely depend on androgens, inhibition of the androgen/androgen receptor signaling axis is the main treatment for locally advanced and/or metastatic tumors. Although first-line androgen deprivation therapies like chemical/surgical castration and/or administration of anti androgens are able to control the disease for several years, prostate cancer almost invariably recurs as castration-resistant prostate cancer. This stage of the disease is characterized by a sustained AR-signaling despite castrate levels of circulating androgens. Various molecular mechanisms were shown to induce castration resistance. This review will discuss the most recent and relevant experimental findings on AR-signaling in castration-resistant prostate cancer in order to provide a comprehensive interpretation of the clinical behavior of this tumor entity following treatments with abiraterone, enzalutamide, ARN-509 or taxanes. PMID- 26100947 TI - CaMKII regulates intracellular Ca2+ dynamics in native endothelial cells. AB - Localized endothelial Ca(2+) signalling, such as Ca(2+) pulsars, can modulate the contractile state of the underlying vascular smooth muscle cell through specific endothelial targets. In addition to K(Ca)3.1 as a target, Ca(2+) pulsars, an IP3R dependent pulsatile Ca(2+) release from the endoplasmic reticulum (ER) could activate a frequency-sensitive Ca(2+)-dependent kinase such as CaMKII. In the absence of extracellular Ca(2+), acetylcholine increased endothelial CaMKII phosphorylation and activation, thereby suggesting CaMKII activation independently of Ca(2+) influx. Herein, a reciprocal relation where CaMKII controls endothelial Ca(2+) dynamics has been investigated in mesenteric arteries. Both CaMKIIalpha and beta isoforms have been identified in endothelial cells and close proximity (<40 nm) suggests their association in heteromultimers. Intracellular Ca(2+) monitoring with high speed confocal microscopy then showed that inhibition of CaMKII with KN-93 significantly increased the population of Ca(2+) pulsars active sites (+89%), suggesting CaMKII as a major regulator of Ca(2+) pulsars in native endothelium. Mechanistic insights were then sought through the elucidation of the impact of CaMKII on ER Ca(2+) store. ER Ca(2+) emptying was accelerated by CaMKII inhibition and ER Ca(2+) content was assessed using ionomycin. Exposure to KN-93 strongly diminished ER Ca(2+) content (-61%) by relieving CaMKII-dependent inhibition of IP3 receptors (IP3R). Moreover, in situ proximity ligation assay suggested CaMKII-IP3R promiscuity, essential condition for a protein-protein interaction. Interestingly, segregation of IP3R within myoendothelial projection (MEP) appears to be isoform-specific. Hence, only IP3R type 1 and type 2 are detected within fenestrations of the internal elastic lamina, sites of MEP, whilst type 3 is absent from these structures. In summary, CaMKII seems to act as a Ca(2+)-sensitive switch of a negative feedback loop regulating endothelial Ca(2+) homeostasis, including Ca(2+) pulsars. PMID- 26100949 TI - Water-Soluble Dried Blood Spot in Protein Analysis: A Proof-of-Concept Study. AB - In the present work human chorionic gonadotropin (hCG) was used as a model protein in a proof-of-concept study combining water-soluble dried blood spot (DBS) material in liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based protein analysis. A water-soluble material consisting of commercially available carboxymethyl cellulose (CMC) was evaluated as sampling material for this purpose. The material dissolved readily at physiological pH. Different sample preparation methods were evaluated, and in the final method, 15 MUL of whole blood was deposited and dried on CMC before the whole spot was dissolved prior to cleanup by immunoaffinity extraction, tryptic digest, and preconcentration by solid-phase extraction (SPE). The results indicated complete dissolution of hCG from the spots, acceptable limit of detection (LOD) (0.1 IU/mL), linearity (R(2) = 0.959), accuracy (16%), and precision (<=22%). Long-term stability (45 days) of hCG in dried spots at reduced temperatures (<=8 degrees C) was also demonstrated. The analyte recovery was comparable to the commercially available nonsolvable cellulose material (FTA DMPK-C card). PMID- 26100948 TI - Both RyRs and TPCs are required for NAADP-induced intracellular Ca2+ release. AB - Intracellular Ca(2+) release is mostly mediated by inositol trisphosphate, but intracellular cyclic-ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are important messengers in many systems. Whereas cADPR generally activates type 2 ryanodine receptors (RyR2s), the NAADP-activated Ca(2+) release mechanism is less clear. Using knockouts and antibodies against RyRs and Two-Pore Channels (TPCs), we have compared their relative importance for NAADP-induced Ca(2+) release from two-photon permeabilized pancreatic acinar cells. In these cells, cholecystokinin-elicited Ca(2+) release is mediated by NAADP. TPC2-KO reduced NAADP-induced Ca(2+) release by 64%, but the combination of TPC2-KO and an antibody against TPC1, significantly reduced Ca(2+) release by 86% (64% vs. 86%, p<0.0002). In RyR3-KO, NAADP-evoked Ca(2+) release reduced by ~50% but, when combined with antibodies against RyR1, responses were 90% inhibited. Antibodies against RyR2 had practically no effect on NAADP-evoked Ca(2+) release, but reduced release in response to cADPR by 55%. Antibodies to RyR1 inhibited NAADP-induced Ca(2+) liberation by 81%, but only reduced cADPR responses by 30%. We conclude that full NAADP-mediated Ca(2+) release requires both TPCs and RyRs. The sequence of relative importance for NAADP-elicited Ca(2+) release from the all stores is RyR1>TPC2>RyR3>TPC1>>RyR2. However, when assessing NAADP-induced Ca(2+) release solely from the acidic stores (granules/endosomes/lysosomes), antibodies against TPC2 and TPC1 virtually abolished the Ca(2+) liberation as did antibodies against RyR1 and RyR3. Our results indicate that the primary, but very small, NAADP-elicited Ca(2+) release via TPCs from endosomes/lysosomes triggers the detectable Ca(2+)-induced Ca(2+) release via RyR1 and RyR3 occurring from the granules and the ER. PMID- 26100950 TI - Complete Mitochondrial genome of an equine intestinal parasite, Triodontophorus brevicauda (Chromadorea: Strongylidae): the first characterization within the genus. AB - The complete mitochondrial (mt) genome sequence of Triodontophorus brevicauda, an intestinal equine nematode parasite was determined for the first time. The circular T. brevicauda mt genome is 14,305 bp in length and contains 36 genes, of which 12 code for protein, 22 for transfer RNA, and two for ribosomal RNA, and lacks atp8 mtDNA gene. Phylogenetic analysis based on the concatenated amino acid sequence of the 12 protein-coding genes was performed using three different tree building methods. The Strongyloidea cluster divides into two large branches, and each nematode family included in our study forms an independent clade, though paraphyly confounds the issue at some nodes. T. brevicauda clusters together with Cylicocyclus insignis with high statistical support. The mtDNA data in this study not only provide a new mtDNA resource for phylogeny, but also become a novel and useful genetic marker for further studies on the identification, population genetics, and molecular epidemiology of the genus Triodontophorus in equine. PMID- 26100952 TI - Rice seed for delivery of vaccines to gut mucosal immune tissues. AB - Gut-associated lymphoid tissue (GALT) is the biggest lymphoid organ in the body. It plays a role in robust immune responses against invading pathogens while maintaining immune tolerance against nonpathogenic antigens such as foods. Oral vaccination can induce mucosal and systemic antigen-specific immune reactions and has several advantages including ease of administration, no requirement for purification and ease of scale-up of antigen. Thus far, taking advantage of these properties, various plant-based oral vaccines have been developed. Seeds provide a superior production platform over other plant tissues for oral vaccines; they offer a suitable delivery vehicle to GALT due to their high stability at room temperature, ample and stable deposition space, high expression level, and protection from digestive enzymes in gut. A rice seed production system for oral vaccines was established by combining stable deposition in protein bodies or protein storage vacuoles and enhanced endosperm-specific expression. Various types of rice-based oral vaccines for infectious and allergic diseases were generated. Efficacy of these rice-based vaccines was evaluated in animal models. PMID- 26100953 TI - Vector analysis after toric intraocular lens implantation to correct astigmatism. PMID- 26100954 TI - Glistenings 9 years after phacoemulsification in hydrophobic and hydrophilic acrylic intraocular lenses. AB - PURPOSE: To compare the development of glistenings after implantation of a hydrophobic acrylic intraocular lens (IOL) (AcrySof SA60AT) and a hydrophilic IOL (BL27) and evaluate the effect on corrected distance visual acuity (CDVA) and contrast sensitivity 9 years postoperatively. SETTING: St. Erik Eye Hospital, Stockholm, Sweden. DESIGN: Prospective randomized clinical trial. METHODS: One of 3 experienced cataract surgeons performed standard phacoemulsification in 1 eye of each patient. The patients were randomized to implantation of a hydrophobic acrylic IOL or a hydrophilic acrylic IOL. Both IOLs had sharp posterior edges. The CDVA and contrast sensitivity were measured 9 years postoperatively. Scheimpflug images of the IOLs were obtained to analyze glistenings, which were graded subjectively at the slitlamp and quantified objectively with digital image analysis using computer software. RESULTS: Seventy-eight of the 120 patients were available for the 9-year follow-up examination. Patients with the hydrophilic IOL had statistically significantly fewer glistenings (P < .001). The development of glistenings was not correlated with IOL power, CDVA, or contrast sensitivity. CONCLUSIONS: After 9 years, the hydrophobic IOL developed more glistenings than the hydrophilic IOL. Glistenings did not affect CDVA or contrast sensitivity. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 26100956 TI - Capsule-splitting phenomenon during capsulorhexis in pseudoexfoliation. AB - We present the case of a 78-year-old white woman with a 2+ nuclear sclerotic cataract and pseudoexfoliation syndrome who had cataract extraction with intraocular lens implantation. The initial continuous curvilinear capsulorhexis (CCC) was performed with a cystotome. Due to unusual tearing characteristics, there was concern that the anterior flap was pseudoexfoliative material instead of the lens capsule. Trypan blue was instilled in the anterior chamber, and the staining pattern indicated that the anterior capsule flap had failed to fold on itself initially. A CCC was initiated in the reverse direction and completed without complication. This case illustrates the importance of recognizing the potential for the capsule-splitting phenomenon when performing a CCC in patients with pseudoexfoliation and the important role for capsule staining in these patients. PMID- 26100955 TI - Frequency of pseudoexfoliation among patients scheduled for cataract surgery. AB - PURPOSE: To assess the frequency of pseudoexfoliation syndrome (PXF) in patients scheduled for cataract surgery and to evaluate its association with pupil dilation, lens nucleus hardness, intraocular pressure (IOP), glaucoma, age, and sex. SETTING: Ourense University Hospital, Ourense, Spain. DESIGN: Cross sectional study. METHODS: This study evaluated eyes scheduled for cataract surgery between January 2013 and July 2013. Pseudoexfoliation was diagnosed in phakic eyes that showed central and/or peripheral white deposits on the lens surface, pupillary margin, or both. Dilated pupils were evaluated with a portable pupil chart. Nucleus hardness was assessed according to the Lens Opacities Classification System III. Diagnosis of glaucoma was based on International Society Geographical and Epidemiological Ophthalmology criteria. RESULTS: Of the 1763 eyes (1093 patients) evaluated, 381 (21.6%) were diagnosed with PXF. The frequency of PXF increased with age from 6.0% in people between 50 year and 60 years to 31.66% in those older than 80 years. In PXF eyes, nuclear cataracts were significantly harder than in non-PXF eyes (P < .001). The mean IOP was significantly higher in PXF eyes than in non-PXF eyes (P = .002). The frequency of glaucoma was higher in PXF eyes (17.4%) than in non-PXF eyes (9.4%), with a statistically significant difference (P < .001). In PXF eyes, the pupil was significantly smaller than in non-PXF eyes (P < .001). CONCLUSIONS: The frequency of PXF was high in the study population and increased with age. Eyes with PXF were associated with significantly harder nuclear cataracts, smaller pupils, and glaucoma. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26100957 TI - Long-term observation of surface light scattering in a foldable acrylic intraocular lens. AB - PURPOSE: To observe time-course changes in surface light scattering after Acrysof intraocular lens (IOL) implantation over 6 years postoperatively and its influence on visual function. SETTING: Miyata Eye Hospital, Miyakonojo, Miyazaki, Japan. DESIGN: Retrospective comparative case series. METHODS: Clinical records of eyes that had implantation of an Acrysof IOL (Group 1) or another IOL model (AR40 or Clariflex) (Group 2) were evaluated. Postoperative examinations including light scattering on the anterior surface of the IOL, corrected distance visual acuity (CDVA), and contrast sensitivity were performed 1 month and 3 years postoperatively. The same examinations were performed over the extended postoperative period, allowing analysis of time-course changes in surface light scattering and visual function. RESULTS: The study evaluated 24 eyes, 14 in Group 1 and 10 in Group 2. The mean time to the last postoperative examination was 8.4 years +/- 1.0 (SD) (range 6.5 to 10 years). Surface light scattering in Group 1 increased, even after 3 years, at a rate of 12.02 computer-compatible tapes per year. Scattering did not increase in Group 2. The CDVA remained unchanged 3 to 6 or more years postoperatively in both groups. There was no difference in contrast sensitivity between the 2 groups 6 or more years postoperatively. CONCLUSION: Surface light scattering increased in Group 1, even after 3 years postoperatively; however, it did not affect visual function. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26100958 TI - Impact of micropulsed ultrasound power settings on the efficiency and chatter associated with lens-fragment removal. AB - PURPOSE: To determine the optimum power settings in micropulsed ultrasound (US). SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Pig lenses hardened to be comparable to dense human cataracts were cut into 2.0 mm cubes and removed using micropulsed longitudinal US with previously optimized settings (6 milliseconds on and 6 milliseconds off and using a 0.9 mm 30-degree beveled bent phaco tip). The aspiration was set at 40 mL/min and the vacuum level at 550 mm Hg. Twenty lens cubes were tested with the power set from 10% to 100% in increments of 10%. Primary outcome measures were efficiency time (time to lens removal) and chatter (number of times the lens fragment visibly bounced off the tip). RESULTS: Efficiency time decreased with increasing power. There was a correlation between power and efficiency time (R(2) = 0.41, P = .046), which was more substantial between 30% and 100% power (R(2) = 0.71, P = .004). The mean number of chatter events did not differ significantly between power settings (R(2) = 0.012, P = .1195). CONCLUSIONS: There was a 5-fold increase in efficiency between 10% power and 20% power, which likely indicates that there is a minimum power threshold for efficient breakup of the lens. Between 20% and 100% power, there was a linear, strong, and statistically significant improvement in efficiency in these lens fragments. In addition, with micropulsed US there was little chatter or microchatter throughout the power range. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26100959 TI - Calcification of hydrophilic acrylic intraocular lenses associated with intracameral air injection following DMEK. AB - We present 2 cases of localized calcification on the anterior surface/subsurface of hydrophilic acrylic intraocular lenses (IOLs) following procedures involving intracameral injection of air. Although this phenomenon has been reported in hydrophilic acrylic IOLs, to our knowledge it has not been reported in the IOLs described in our cases, one a sulcus-fixated supplementary IOL and the other a hydrophilic acrylic IOL with a hydrophobic surface. Centralized opacity of the IOLs was first noted months after Descemet membrane endothelial keratoplasty had been performed in both cases; explantation was required. Laboratory analysis of the IOLs confirmed calcification of the anterior surfaces in a localized pattern in the area of the capsulorhexis or pupil. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26100960 TI - Association between corneal hysteresis and the magnitude of intraocular pressure decrease after cataract surgery. AB - PURPOSE: To evaluate the relationship between baseline corneal hysteresis (CH) and the change in intraocular pressure (IOP) before and after cataract extraction in patients without glaucoma. SETTING: Private practice, New York City, New York, USA. DESIGN: Retrospective cohort study. METHODS: Charts of consecutive patients who had phacoemulsification cataract extraction with posterior chamber intraocular lens implantation were analyzed. All included patients had preoperative and postoperative measurements with the Ocular Response Analyzer 2 to 4 months and 10 to 12 months postoperatively. Data collected included age, baseline CH, baseline central corneal thickness (CCT), and IOP. RESULTS: Thirty nine (65 eyes) of the 230 patients met the inclusion criteria. The mean patient age was 70.8 years +/- 8.6 (SD). The mean preoperative, 2- to 4-month and 10- to 12- month postoperative IOP values were 14.8 +/- 3.5 mm Hg, 11.9 +/- 3.4 mm Hg, and 12.6 +/- 3.1 mm Hg, respectively (P < .05 for comparisons with preoperative IOP). The baseline CH was not predictive of the IOP reduction at 2 to 4 months (beta = -0.3; 95% confidence interval [CI], -0.7 to 0.01; P = .06). However, the baseline CH (but not the baseline CCT) was statistically associated with the magnitude of IOP reduction at 10 to 12 months when controlling for patient age (beta = -0.5; 95% CI, -0.8 to -0.1; P = .01). CONCLUSION: A low baseline CH was associated with a larger magnitude of IOP reduction after cataract extraction. FINANCIAL DISCLOSURE: Dr. Radcliffe is a consultant to Reichert Technologies and Glaukos Corp.; a consultant to and speaker for Allergan, Inc., Alcon Laboratories, Inc., Iridex Corp., Merge Healthcare, Carl Zeiss Meditec AG; and a speaker for Merck Pharmaceuticals. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 26100961 TI - New intrastromal corneal reshaping procedure using high-intensity femtosecond laser pulses. AB - A minimally invasive keratorefractive procedure using high-intensity, low-energy femtosecond laser pulses to perform intrastromal ablation is described. Because of the low pulse energy and the ultrashort duration, tissue in the corneal stroma can be ablated with almost no heat or shockwave generation. This technique obviates the need for the laser in situ keratomileusis (LASIK) flap but retains the advantages of the LASIK procedure. In the technique, a series of femtosecond laser pulses create temporary microchannels in the stroma, oriented perpendicular to the eye's optical axis. After the microchannels are created, a second series of femtosecond pulses directly ablate the desired amount of stromal tissue in a controlled fashion. The ablated material is ejected from the microchannels so the surface layer above the ablated regions collapses, with a consequent change in the refractive power of the cornea. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 26100962 TI - MOF crystal growth: UV resonance Raman investigation of metal-ligand binding in solution and accelerated crystal growth methods. AB - Determining the mechanism of metal-organic framework (MOF) crystal growth is important for the development of more efficient and reliable synthetic methods. Resonance Raman spectroscopy has been used for the first time to detect interactions in solution between metal ions and bridging ligands as MOFs form. UV excitation (229 nm) produced strong resonance enhancement of 4,4'-bipyridine (bpy) vibrational bands and showed that soluble Co(2+)-bpy species formed in solution prior to the growth of MOF crystals from bpy and Co(NO3)2. The results of the Raman experiments informed the development of faster methods for synthesizing [Co2(bpy)3(NO3)4]n 2D bilayer and [Co(bpy)(NO3)2(H2O)2]n 1D chain MOFs. PMID- 26100963 TI - Linear correlation between the number of olfactory sensory neurons expressing a given mouse odorant receptor gene and the total volume of the corresponding glomeruli in the olfactory bulb. AB - Chemosensory specificity in the main olfactory system of the mouse relies on the expression of ~1,100 odorant receptor (OR) genes across millions of olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE), and on the coalescence of OSN axons into ~3,600 glomeruli in the olfactory bulb. A traditional approach for visualizing OSNs and their axons consists of tagging an OR gene genetically with an axonal marker that is cotranslated with the OR by virtue of an internal ribosome entry site (IRES). Here we report full cell counts for 15 gene-targeted strains of the OR-IRES-marker design coexpressing a fluorescent protein. These strains represent 11 targeted OR genes, a 1% sample of the OR gene repertoire. We took an empirical, "count every cell" strategy: we counted all fluorescent cell profiles with a nuclear profile within the cytoplasm, on all serial coronal sections under a confocal microscope, a total of 685,673 cells in 56 mice at postnatal day 21. We then applied a strain-specific Abercrombie correction to these OSN counts in order to obtain a closer approximation of the true OSN numbers. We found a 17-fold range in the average (corrected) OSN number across these 11 OR genes. In the same series of coronal sections, we then determined the total volume of the glomeruli (TGV) formed by coalescence of the fluorescent axons. We found a strong linear correlation between OSN number and TGV, suggesting that TGV can be used as a surrogate measurement for estimating OSN numbers in these gene-targeted strains. PMID- 26100964 TI - Genome-wide Association Study on Platinum-induced Hepatotoxicity in Non-Small Cell Lung Cancer Patients. AB - Platinum-based chemotherapy has been shown to improve the survival of advanced non-small cell lung cancer (NSCLC) patients; the platinum-induced toxicity severely impedes the success of chemotherapy. Genetic variations, such as single nucleotide polymorphisms (SNPs), may contribute to patients' responses to the platinum-based chemotherapy. To identify SNPs that modify the risk of hepatotoxicity in NSCLC patients receiving platinum-based chemotherapy, we performed a genome-wide association scan in 334 subjects followed by a replication study among 375 subjects. Consistent associations with platinum induced hepatotoxicity risk was identified for SNP rs2838566 located at 21q22.3, as the minor A allele could significantly increase the risk of liver injury (OR = 3.78, 95%CI = 1.99-7.19, P = 4.90 * 10(-5) for GWAS scan, OR = 1.89, 95%CI = 1.03 3.46, P = 0.039 for replication, and OR = 2.56, 95%CI = 1.65-3.95, P = 2.55 * 10( 5) for pooled population). These results suggested that genetic variants at 21q22.3 may contribute to the susceptibility of platinum-induced hepatotoxicity in NSCLC patients. PMID- 26100965 TI - PSA bounce after 125I-brachytherapy for prostate cancer as a favorable prognosticator. AB - BACKGROUND: Permanent low-dose-rate brachytherapy (BT) with iodine 125 is an established curative treatment for localized prostate cancer. After treatment, prostate-specific antigen (PSA) kinetics may show a transient rise (PSA bounce). Our aim was to investigate the association of PSA bounce with biochemical control. PATIENTS AND METHODS: Patients treated with BT in Switzerland were registered in a prospective database. Only patients with a follow-up of at least 2 years were included in our analysis. Clinical follow-up and PSA measurements were assessed after 1.5, 3, 6, and 12 months, and annually thereafter. If PSA increased, additional follow-up visits were scheduled. Cases of PSA bounce were defined as a rise of at least 0.2 ng/ml above the initial PSA nadir with a subsequent decline to or below the initial nadir without treatment. Biochemical failure was defined as a rise to nadir + 2 ng/ml. RESULTS: Between March 2001 and November 2010, 713 patients with prostate cancer undergoing BT with at least 2 years of follow-up were registered. Median follow-up time was 41 months. Biochemical failure occurred in 28 patients (3.9 %). PSA bounce occurred in 173 (24.3 %) patients; only three (1.7 %) patients with PSA bounce developed biochemical failure, in contrast to 25 (4.6 %) patients without previous bounce (p < 0.05). The median time to bounce was 12 months, the median time to biochemical failure was 30 months. The median bounce increase was 0.78 ng/ml. Twenty-eight patients with bounce (16.5 %) had a transient PSA rise of + 2 ng/ml above the nadir. CONCLUSION: In most cases, an early increase in PSA after BT indicates PSA bounce and is associated with a lower risk of biochemical failure. PMID- 26100966 TI - The Norwegian General Practice--Nursing Home criteria (NORGEP-NH) for potentially inappropriate medication use: A web-based Delphi study. AB - OBJECTIVE: To develop a set of explicit criteria for pharmacologically inappropriate medication use in nursing homes. DESIGN: In an expert panel, a three-round Delphi consensus process was conducted via survey software. SETTING: Norway. SUBJECTS: Altogether 80 participants - specialists in geriatrics or clinical pharmacology, physicians in nursing homes and experienced pharmacists - agreed to participate in the survey. Of these, 62 completed the first round, and 49 panellists completed all three rounds (75.4% of those ultimately entering the survey). MAIN OUTCOME MEASURES: The authors developed a list of 27 criteria based on the Norwegian General Practice (NORGEP) criteria, literature, and clinical experience. The main outcome measure was the panellists' evaluation of the clinical relevance of each suggested criterion on a digital Likert scale from 1 (no clinical relevance) to 10. In the first round panellists could also suggest new criteria to be included in the process. For each criterion, degree of consensus was based on the average Likert score and corresponding standard deviation (SD). RESULTS: A list of 34 explicit criteria for potentially inappropriate medication use in nursing homes was developed through a three-round web-based Delphi consensus process. Degree of consensus increased with each round. No criterion was voted out. Suggestions from the panel led to the inclusion of seven additional criteria in round two. IMPLICATIONS: The NORGEP-NH list may serve as a tool in the prescribing process and in medication list reviews and may also be used in quality assessment and for research purposes. PMID- 26100967 TI - Linear microrheology with optical tweezers of living cells 'is not an option'! AB - Optical tweezers have been successfully adopted as exceptionally sensitive transducers for microrheology studies of complex fluids. Despite the general trend, in this article I explain why a similar approach should not be adopted for microrheology studies of living cells. This conclusion is acheived on the basis of statistical mechanics principles that indicate the unsuitability of optical tweezers for such purpose. PMID- 26100968 TI - An update on pleuro-pulmonary cytopathology: Part i: Cytological diagnosis of mesothelioma and molecular cytology of lung cancer with an historical perspective. PMID- 26100969 TI - Guidelines for the cytopathologic diagnosis of epithelioid and mixed-type malignant mesothelioma: Complementary Statement from the International Mesothelioma Interest Group, Also Endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. AB - OBJECTIVE: To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma. DATA SOURCES: Cytopathologists with an interest in the field involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC) contributed to this update. Reference material includes peer-reviewed publications and textbooks. RATIONALE: This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in Cape Town. PMID- 26100970 TI - Tunable room-temperature ferromagnet using an iron-oxide and graphene oxide nanocomposite. AB - Magnetic materials have found wide application ranging from electronics and memories to medicine. Essential to these advances is the control of the magnetic order. To date, most room-temperature applications have a fixed magnetic moment whose orientation is manipulated for functionality. Here we demonstrate an iron oxide and graphene oxide nanocomposite based device that acts as a tunable ferromagnet at room temperature. Not only can we tune its transition temperature in a wide range of temperatures around room temperature, but the magnetization can also be tuned from zero to 0.011 A m(2)/kg through an initialization process with two readily accessible knobs (magnetic field and electric current), after which the system retains its magnetic properties semi-permanently until the next initialization process. We construct a theoretical model to illustrate that this tunability originates from an indirect exchange interaction mediated by spin imbalanced electrons inside the nanocomposite. PMID- 26100971 TI - Osteoarthritis: Replacing the meniscus to prevent knee OA--fact or fiction? PMID- 26100972 TI - Rheumatoid arthritis: First-in-human phase I trial of DC immunotherapy for early RA. PMID- 26100973 TI - Characterization and identification of the xylanolytic enzymes from Aspergillus fumigatus Z5. AB - BACKGROUND: Plant biomass, the most abundant natural material on earth, represents a vast source of food and energy in nature. As the main component of plant biomass, xylan is a complex polysaccharide comprising a linear beta(1,4) linked backbone of xylosyl residues substituted by acetyl, arabinosyl, glucuronysyl and 4-O-methylglucuronycyl residues. RESULTS: Aspergillus fumigatus Z5 is an efficient plant biomass depolymerization fungus. In this study, its crude xylanolytic enzymes were characterized and identified by two-dimensional gel electrophoresis (2-DE). The optimal temperature for the crude xylanases was close to 60 degrees C, the highest xylanase activity was achieved at pH ranged from 3 to 6, and the crude xylanases also showed a very broad region of pH (3-11) stability. The maximal xylanase activity of 21.45 U . ml(-1) was observed in the fourth day of cultivation at 50 degrees C and 150 rpm with 2 % xylan as the sole carbon source. Zymogram analysis indicated that there were more than seven secreted proteins with xylanase activity. In the crude enzyme, two major endoxylanases, five cellulases and several associated enzymes were identified to be involved in the hydrolysis of polysaccharides. Of the total 13 xylanase genes in the Z5 genome, 11 were observed using q-PCR to be induced by xylan, one of which, An endo-1,4-beta-xylanase with a low secretion level, was also expressed and characterized. The final hydrolysis products of xylan by crude enzyme mainly consisted of xylobiose. CONCLUSIONS: This study provides a comprehensive understanding of the depolymerization of xylan by Z5 and will help to design enzymatic strategies for plant biomass utilization. PMID- 26100974 TI - Extrinsic compression of the left main coronary artery by a contained aortic annular rupture following trans-catheter aortic valve implantation. AB - We present a case of an 83-year-old female who suffered from annular rupture with contained hematoma immediately after trans-apical implantation of balloon expandable Sapien valve. The patient developed acute cardiogenic shock which resulted from an extrinsic compression of the left main coronary artery. We report the successful management of this complication. PMID- 26100975 TI - Registro Absorb Italiano (BVS-RAI): an investigators-owned and -directed, open, prospective registry of consecutive patients treated with the AbsorbTM BVS: study design. AB - BACKGROUND: The AbsorbTM BVS is a bioresorbable, everolimus-eluting scaffold approved and marketed for coronary use. Published data on long-term results after treatment are limited to a small number of patients, most of them with elective PCI of simple lesions. The importance of scaffold resorption is variably appreciated among cardiologists, and indications for use from health technology assessment bodies or guidelines are missing. Instruments are needed to collect, share and assess the experience being accumulated with this new device in several centres. METHODS/DESIGN: The BVS-RAI Registry is a spontaneous initiative of a group of Italian interventional cardiologists in cooperation with Centro di Ricerche Farmacologiche e Biomediche "Mario Negri" Institute, and is not recipient of funding or benefits originating from the BVS manufacturer. It is a prospective registry with 5-year follow-up of all consecutive patients who have undergone successful implantation of 1 or more coronary BVS following the indications, techniques and protocols used in each of the participating institutions. Outcome measures are BVS target lesion failure within one year and device-oriented major adverse cardiac events within 5years. The registry started in October 2012 and will extend enrolment throughout 2015, with the aim to include about 1000 patients. ClinicalTrials.gov identifier is CT02298413. CONCLUSIONS: The BVS-RAI Registry will contribute observational knowledge on the long-term safety and efficacy of the AbsorbTM BVS as used in a number of Italian interventional centres in a broad spectrum of settings. Unrewarded and undirected consecutive patient enrolments are key-features of this observation, which is therefore likely to reflect common clinical practice in those centres. PMID- 26100976 TI - Stress distribution in bone simulation model with pre-angled implants. AB - The aim of this study was evaluate the biomechanical behaviour of prostheses screwed into conventional (0 degrees angulation) and pre-angled experimental (8, 12 and 20 degrees ) external hexagon implants (13 * 4 mm) by photoelastic analysis. Eight casts were made in photoelastic resin. Casts were divided into groups of single crowns or three combined elements. Each unit was positioned in a circular polariscope. By using a universal testing machine, 100 N loads were applied in the axial and oblique (45 degrees ) directions to fixed points on the occlusal surfaces of the crowns. Generated stresses were recorded photographically and analysed qualitatively in a graphics program. In single element prostheses, the number of high-stress fringes increased with increasing implant angle. However, in three-element prostheses, there was no difference in the stress distribution with implant angle, except for the 12 degrees implant that had a higher degree of stress. For the other groups pre-angulation of the implant increases the concentration and intensity of stresses for single prosthesis and has similar stress distribution in three-element fixed prostheses. PMID- 26100977 TI - Enhanced Evaporation Strength through Fast Water Permeation in Graphene-Oxide Deposition. AB - The unique characteristic of fast water permeation in laminated graphene oxide (GO) sheets has facilitated the development of ultrathin and ultrafast nanofiltration membranes. Here we report the application of fast water permeation property of immersed GO deposition for enhancing the performance of a GO/water nanofluid charged two-phase closed thermosyphon (TPCT). By benchmarking its performance against a silver oxide/water nanofluid charged TPCT, the enhancement of evaporation strength is found to be essentially attributed to the fast water permeation property of GO deposition instead of the enhanced surface wettability of the deposited layer. The expansion of interlayer distance between the graphitic planes of GO deposited layer enables intercalation of bilayer water for fast water permeation. The capillary force attributed to the frictionless interaction between the atomically smooth, hydrophobic carbon structures and the well-ordered hydrogen bonds of water molecules is sufficiently strong to overcome the gravitational force. As a result, a thin water film is formed on the GO deposited layers, inducing filmwise evaporation which is more effective than its interfacial counterpart, appreciably enhanced the overall performance of TPCT. This study paves the way for a promising start of employing the fast water permeation property of GO in thermal applications. PMID- 26100978 TI - The Human Epidermal Antimicrobial Barrier: Current Knowledge, Clinical Relevance and Therapeutic Implications. AB - Most of the defensive functions of the human skin are localized to the stratum corneum (SC), the outermost layer of the epidermis consisting of several layers of cornified keratinocytes embedded in a lipid matrix. Included in the armamentarium of the epidermal barrier against microbial invasion are surface pH, SC lipids, specialized antimicrobial peptides such as defensins and cathelicidins, enzymes and enzyme inhibitors, chemokines, and epidermal Toll-like receptors. Multiple epidermal defensive mechanisms are co-localized, coregulated, and intertwined. The purpose of this review is to discuss patents and to describe the current knowledge that concerns the role of the epidermis as an antimicrobial barrier, outlining potential clinical and therapeutic implications. PMID- 26100979 TI - Antiseptic Resistance in Methicillin Sensitive and Methicillin Resistant Staphylococcus aureus Isolates from Some Major Hospitals, Iran. AB - BACKGROUND: Extensive use of antibiotics and biocide in treatment of patients and cleaning of surfaces and medical equipment has led to the emergence of resistant microorganisms. The current research goals to determine the antiseptics Minimum Inhibitory Concentration value in Staphylococcus aureus (methicillin -resistant Staphylococcus aureus and methicillin sensitive Staphylococcus aureus) isolates from some major hospitals in Iran and to detect qacA/B, norA , smr and blaZ genes. METHODS: Two hundred isolates of S. aureus including 100 MRSA and 100 MSSA clinical isolates were collected from 4 hospitals in the west of Iran during period 2012 to 2013. Detection of disinfectant resistant genes (qac A/B, smr and norA), antimicrobial resistance genes (mecA and blaZ) and SCCmec typing of MRSA isolates was performed by PCR. RESULTS: MIC of chlorhexidine digluconate (CHX) in 70% of MRSA and 30% of MSSA strains was 8-16 ug/ml. High level of MIC of citrimide (>2 ug/ml) in MRSA and MSSA isolates was 20% and 5% , respectively. MIC of benzalkonium chloride (BC) in 80% of MRSA and 83% of MSSA isolates was less than 2 ug/ml; only 9% of MRSA had MIC higher than 2 ug/ml. Frequency of antiseptic and antibiotic resistance genes norA, blaZ and qacA/B in MRSA isolates were 83%, 98% and 9%, respectively; while this value for MSSA isolates were 62%, 8% and 0%, respectively. The smr gene was not detected in both MRSA and MSSA isolates. In all biocides high MIC were observed in SCCmec type III and IVc. High frequency of qacA/B gene was found in SCCmec type III,Vc and IVb, which were 66.6% ,22% and 11.1% respectively. CONCLUSION: We found SCCmec types III, Vc was related to high MIC of biocide in MRSA isolates. PMID- 26100980 TI - High-mobility group box 1 in multiple sclerosis. AB - This study is one in series determining the potential of RAGE axis (receptor for advanced glycation end products, isoforms, ligands) as a biomarker in multiple sclerosis (MS). We evaluated serum levels of RAGE ligand, the high-mobility group box (HMGB)1 in MS patients, and assessed the correlation between HMGB1 serum levels and the use of disease-modifying drugs (DMDs), and between HMGB1 serum levels and indicators of MS disease severity. HMGB1 serum levels were compared between 96 (23 males) MS patients and 34 age- and gender-matched healthy controls (HCs) using enzyme-linked immunosorbent assays. DMD-naive MS patients had significantly higher HMGB1 serum levels compared with DMD-treated (P = 0.04) and compared with HCs (P = 0.01). HMGB1 serum levels were not significantly different between total MS patients (DMD-naive plus DMD-treated) and HCs (P = 0.09). DMD naive MS patients in clinical relapse tended to have lower HMGB1 serum levels than clinically stable RRMS patients (P = 0.07). HMGB1 serum levels showed 0.65 area under the curve (95 % CI 0.55-0.95) sensitivity/specificity for MS clinical relapse. The role of HMGB1 in MS disease pathology and DMD modulation of this protein warrant further investigations. PMID- 26100981 TI - For Better or Worse: The Health Implications of Marriage Separation Due to Migration in Rural China. AB - Massive rural-to-urban migration in China has led to spatial separation of millions of married couples. In this article, we examine the question of whether the well-documented health benefits of marriage extend to left-behind individuals in rural China who are spatially separated from their spouses. Using longitudinal data that span 16 years (China Health and Nutrition Survey 1991, 1993, 1997, 2000, 2004, 2006), we compare the self-reported health trajectories of adults across different marital statuses while taking into account the physical location of their spouses. Our results suggest a clear health disadvantage of married individuals whose spouses are absent compared with those whose spouses are living in the same household. Further, longer spousal absence is more harmful to an individual's health. Finally, spousal absence and longer physical separation from their spouses induce stronger health deficits for married men than for married women, suggesting that a gendered process is at work. PMID- 26100982 TI - Gender, Power, and Emigration From Mexico. AB - The prevailing model of migration in developing countries conceives of a risk diversifying household in which members act as a single entity when making migration decisions. Ethnographic studies challenge this model by documenting gender hierarchy in family decisions and arguing that, in many contexts, men and women have differing views on the value of migration. We assess these perspectives using longitudinal survey data from Mexico. We show that Mexican households are heterogeneous in terms of women's decision-making authority and control over resources, and this variation predicts the subsequent emigration of their male partners to the United States. We then use data from a policy experiment to demonstrate that an exogenous increase in a woman's control over household resources decreases the probability that her spouse migrates. Our findings support the presence of important gender differences in how migration is valued. They also suggest that women's role in these decisions is inadvertently underrepresented in studies of migrant families. Staying is also a migration decision, and it is more likely in homes in which women have greater authority. From a policy perspective, the results suggest that Mexican migration is influenced not only by increases in household resources but also by which members of the household control them. PMID- 26100983 TI - Education and Lifetime Earnings in the United States. AB - Differences in lifetime earnings by educational attainment have been of great research and policy interest. Although a large literature examines earnings differences by educational attainment, research on lifetime earnings--which refers to total accumulated earnings from entry into the labor market until retirement--remains limited because of the paucity of adequate data. Using data that match respondents in the Survey of Income and Program Participation to their longitudinal tax earnings as recorded by the Social Security Administration, we estimate the 50-year work career effects of education on lifetime earnings for men and women. By overcoming the purely synthetic cohort approach, our results provide a more realistic appraisal of actual patterns of lifetime earnings. Detailed estimates are provided for gross lifetime earnings by education; net lifetime earnings after controlling for covariates associated with the probability of obtaining a bachelor's degree; and the net present 50-year lifetime value of education at age 20. In addition, we provide estimates that include individuals with zero earnings and disability. We also assess the adequacy of the purely synthetic cohort approach, which uses age differences in earnings observed in cross-sectional surveys to approximate lifetime earnings. Overall, our results confirm the persistent positive effects of higher education on earnings over different stages of the work career and over a lifetime, but also reveal notably smaller net effects on lifetime earnings compared with previously reported estimates. We discuss the implications of these and other findings. PMID- 26100984 TI - Dysregulated transcription across diverse cancer types reveals the importance of RNA-binding protein in carcinogenesis. AB - BACKGROUND: It is well known that carcinogenesis is in part dictated by dysregulated transcription events and signal pathways. Large-scale transcriptional profiling studies in each cancer type have reported aberrant gene expression associated with cancer development. However, common and specific patterns altered across cancer types, especially the contribution of transcriptional and post-transcriptional regulators, are rarely explored. RESULTS: Using transcriptional profiles from matched tumor and normal samples in the Cancer Genome Atlas pan-cancer dataset, we performed a comprehensive analysis on the altered expression across 9 cancer types, focusing on transcriptional and post-transcriptional regulators and cancer-related genes. As we expected, the transcription of cancer-related genes was significantly deregulated in tumor vs. normal across all cancer types. Surprisingly, the expression of RNA-binding proteins (RBPs), master regulators of post-transcriptional gene expression, was also significantly changed across most studied cancer types. Although the expression of RBPs was not as strongly deregulated as cancer-related genes, their direct interaction partners are enriched by cancer-related genes, suggesting the cascade regulation effect of RBPs. Integrating genetic and epigenetic profiles found that deregulated RBPs were frequently caused by genetic rather than epigenetic alterations. Furthermore, tissue-specific genes were under-expressed in tumor vs. normal across all cancer types except prostate cancer. CONCLUSIONS: Dysregulated transcription across cancer types reveals the importance of RBPs in carcinogenesis. The aberrant expression of RBPs is caused by genetic alterations and spreads their effect to cancer-related genes. In addition, disruption of tissue-specific genes contributes to the corresponding cancer pathology. PMID- 26100986 TI - Ulnar Nerve Repair With Simultaneous Metacarpophalangeal Joint Capsulorrhaphy and Pulley Advancement. AB - PURPOSE: To evaluate the validity of performing a static anti-claw procedure (metacarpophalangeal joint volar capsulorrhaphy and A1 and A2 pulley release) at the time of ulnar nerve repair for acute or chronic lacerations to prevent development of claw hand deformity and disability or to correct them. METHODS: We present a case series of 14 patients for whom metacarpophalangeal joint capsulorrhaphy and pulley advancement were done at the time of ulnar nerve management. Direct nerve repair was performed in 10 patients, nerve grafting in 2, neurolysis in 1, and combined direct repair and anterior interosseous nerve transfer in 1. Outcome measurements included assessment of claw hand correction and sequence of phalangeal flexion according to modified evaluation criteria of Brand and motor recovery of ulnar nerve function using the British Medical Research Council (MRC) scale. RESULTS: Average follow-up was 39 months. At 3 months, 12 patients had good and 2 had fair claw hand correction. At 6 months, 2 patients had excellent, 10 patients had good, and 2 patients had fair correction. At final follow-up, 13 patients had good to excellent correction and 1 had fair correction. Motor recovery of the intrinsic muscles was rated from 2 to 5 according to the MRC scale. CONCLUSIONS: This technique is simple and effective. It acts as an internal orthosis during recovery of sufficient strength of the intrinsic muscles. In cases of incomplete recovery of the intrinsic muscles (up to MRC grade 2), it may eliminate the need for secondary surgery to correct a claw hand deformity. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26100987 TI - Delivering Healthcare Services in Resource Constraint Countries Like Pakistan: Sustainable Options. PMID- 26100985 TI - The use of a dietary quality score as a predictor of childhood overweight and obesity. AB - BACKGROUND: The use of dietary quality scores/indices to describe diet quality in children has increased in the past decade. However, to date, few studies have focused on the use of these scores on disease outcomes such as childhood obesity and most are developed from detailed dietary assessments. Therefore, the aims of this study were: firstly to construct a diet quality score (DQS) from a brief dietary assessment tool; secondly to examine the association between diet quality and childhood overweight or obesity; thirdly we also aim to examine the associations between individual DQS components and childhood overweight or obesity. METHODS: A secondary analysis of cross sectional data of a sample of 8,568 9-year-old children and their families as part of the Growing Up in Ireland (GUI) study. Subjects were drawn from a probability proportionate to size sampling of primary schools throughout Ireland over the school year 2007-2008. Height and weight were measured by trained researchers using standardised methods and BMI was classified using the International Obesity Taskforce cut-points. The DQS (un-weighted) was developed using a 20-item, parent reported, food frequency questionnaire of foods consumed over the past 24 h. Adjusted odds ratios for overweight and obesity were examined by DQS quintile, using the first quintile (highest diet quality) as the reference category. RESULTS: The prevalence of normal weight, overweight and obese was 75, 19 and 6% respectively. DQS ranged from -5 to 25, higher scores indicated higher diet quality in the continuous score. In analyses adjusted for gender, parent's education, physical activity and T.V. viewing, child obesity but not overweight was significantly associated with poor diet quality: OR of 1.56 (95% CI 1.02 2.38) in the 5th compared to the 1st DQS quintile. Findings from individual food items were inconsistent. CONCLUSIONS: The findings suggest that diet quality may be an important factor in childhood obesity. A simple DQS developed from a short dietary assessment tool is significantly associated with childhood obesity. PMID- 26100988 TI - Serum Ischemia-Modified Albumin Levels in Experimental Model of Acute Pancreatitis. AB - OBJECTIVE: To establish whether the Ischemia-Modified Albumin (IMA), a new parameter of oxidative stress, has diagnostic role in experimental acute pancreatitis. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Experimental Animal Center, Canakkale Onsekiz Mart University, Canakkale, Turkey, from May to September 2013. METHODOLOGY: Sixteen Sprague-Dawley rats were randomly divided into two groups (n=8 each): Sham and AP groups. AP was induced by ligation of pancreatic duct. Serum IMA, amylase, lipase, AST, ALT and CRP were determined. The severity of pancreatitis was scored by a blinded pathologist under microscope. RESULTS: Serum IMA levels in the AP group increased significantly compared with the control group (p < 0.05). There was also a strong positive correlation between amylase and IMA levels. CONCLUSION: The present study showed in a rodent model that serum IMA might serve as an additional marker to monitor inflammation during pancreatitis. PMID- 26100990 TI - Clinical Indications and Adverse Reactions of Platelet Apheresis. AB - OBJECTIVE: To determine the clinical indications and adverse reactions of platelet apheresis procedure. STUDY DESIGN: Cross-sectional, observational study. PLACE AND DURATION OF STUDY: Blood Bank of Pakistan Atomic Energy Commission General Hospital, Islamabad, from January 2010 to December 2014. METHODOLOGY: Indications and adverse reaction verified for 200 consecutive platelet apheresis donations performed for 125 patients was included in this study. Data was analysed for descriptive variables using SPSS version 16. RESULTS: Donor deferral rate in the study was 63.83%. All the donors were males (100%) and replacement donors. Most prevalent blood type was B-positive (n=63, 31.5%), followed by O positive (n=59, 29.5%). Rh negative groups constituted 13.5% (n=27) of all the donors. Average age of platelet apheresis donors was 28.56 +/- 5.77 years. Maximum numbers of donors were in age range 20 - 30 years. Average weight of the donors was 73.96 +/- 11.96 kg. Mean pre-procedure platelet count of donors was 268,000/uL. The postprocedure average platelet count was approximately 200,000/uL. The mean duration of a platelet apheresis session was 78.27 +/- 26.07 minutes. Average volume of the final product was 412.53 +/- 45.33 ml. Average volume of anti-coagulant acid citrate dextrose used per procedure was 300 +/- 40 ml, 245 ml returned to donor along with returned blood while 55 ml used as anticoagulant in final concentrate. Of total 200, two (1%) final products were contaminated with red cells. Three (1.5%) products were not issued and finally expired. Of the 125 patients for which plateletpheresis procedures were performed, 54 (43.2%) patients were males and 71 (56.8%) were females (M: F=0.76:1). Six donors (3%) had adverse events: three donors (1.5%) had mild reactions, two (1%) moderate reaction, and one donor (0.5%) developing hematoma. None had severe or life-threatening reactions. CONCLUSION: Plateletpheresis procedure is relatively safe and forms an important adjuvant to blood bank inventory. PMID- 26100989 TI - Multidetector CT Patterns of Peritoneal Involvement in Patients with Abdominopelvic Malignancies. AB - OBJECTIVE: To determine the patterns of peritoneal involvement in patients with abdominopelvic malignancies. STUDY DESIGN: Retrospective observational study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, Pakistan, from May 2004 to May 2012. METHODOLOGY: Two hundred and three patients with histopathologically proven abdominopelvic malignancies with peritoneal involvement who underwent contrast-enhanced CT abdomen and pelvis were identified through electronic data base system and were included in this study after ethical committee approval. Peritoneal disease pattern, predominant sites of involvement and associated findings of ascites, lymph nodes and metastasis were assessed. Patients with tuberculosis and lymphoproliferative disorders were excluded. RESULTS: The malignancies showing peritoneal involvement, in decreasing order of frequency, were ovarian cancer (n=118), colorectal cancer (n=45), pancreatic cancer (n=11), gastric cancer (n=7), endometrial cancer (n=6), gallbladder/ cholangio-carcinoma and hepatocellular cancer (n=5 each), cervical cancer (n=3), renal cell carcinoma (n=2) and transitional cell urinary bladder cancer (n=1). The most common pattern of peritoneal involvement was mixed in 79 patients (39%), omental caking in 74 patients (37%) and nodular deposits in 50 patients (24%). The most common sites of peritoneal involvement were pelvic peritoneum followed by greater omentum. CONCLUSION: Peritoneal involvement is the commonest with ovarian and colorectal carcinoma. Mixed pattern of peritoneal disease was most frequently seen in these patients followed by omental caking and nodular peritoneal deposits. PMID- 26100991 TI - Antigen Expression on Blast Cells and Hematological Parameters at Presentation in Acute Lymphoblastic Leukemia Patients. AB - OBJECTIVE: To analyze the expression of various antigens on the leukemic blasts and to determine the hematological parameters, in Acute Lymphoblastic Leukemia (ALL) patients at presentation. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: King Edward Medical University, Lahore and Hameed Latif Hospital, Lahore, from February 2013 to March 2014. METHODOLOGY: A total of 50 newly diagnosed and untreated patients of ALL were selected from Mayo Hospital and Hameed Latif Hospital. These patients included both genders and all age groups. Hemoglobin, total leukocyte count and platelet count were determined on hematology analyser-Sysmex-Kx-2I. Blast cell percentage was estimated on Giemsa stained blood smears. Immunophenotyping was done on bone marrow samples by 5 colour flowcytometery on Beckman Coulter Navious Flowcytometer. An acute leukemia panel of 23 antibodies was used. The data was entered and analyzed in SPSS version 22. RESULTS: Of the 50 ALL patients, 36 (72%) were B-ALL and 14 (28%) T ALL. There were 18 (36%) children and 32 (64%) adults. T-ALL included 22% of the childhood and 31% of the adult cases. Immunophenotypic analysis showed that CD19, CD79a and CD20 were B-lineage specific markers whereas cCD3, CD3 and CD5 were T lineage specific. CD10 was the most sensitive marker for B-ALL and CD7 was the most sensitive marker of T-ALL. TdT was expressed in 92% B-ALL and 71% T-ALL cases, CD34 in 58% and 43% cases and CD45 in 83% and 100% respectively. High leukocyte count (> 50 x 109/L) was present in 58% cases. Hemoglobin was < 10 g/dl in 74% patients and platelet count was below 20 x 109/Lin 12% patients. Leukocyte count, hemoglobin, platelet count and blast cell % did not show a significant difference in the two ALL immunotypes. CONCLUSION: The frequency of T-ALL is higher in childhood as well as adult ALL in our population compared to the Western literature. Antigenic expression of the blast cells also shows some interesting differences. A large number of our patients present with high leukocyte count which is a known factor associated with poor prognosis. PMID- 26100992 TI - Spectrum of Histopathological Findings in Live Donor Liver Graft Biopsies. AB - OBJECTIVE: To study the spectrum of histopathological findings in live donor liver graft biopsies. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Histopathology Department, Shifa International Hospital, Islamabad, from January 2011 to March 2014. METHODOLOGY: The biopsies were received in formalin and routinely processed. The changes encountered were divided into three categories: (i) new-onset post liver transplantation (LT) complications (early and late), (ii) acute rejection and (iii) recurrence of original disease. Banff schema 1997 of rejection activity index (RAI), modified histological activity index (mHAI) and recent literature were utilized for evaluation. The results were finalized in the light of clinical details along with relevant laboratory investigations and radiological findings. RESULTS: Seventy eight percutaneous hepatic graft biopsies of 59 patients were evaluated. Among them, findings noticed in descending order of frequencies were Acute Cellular Rejection (ACR) in 37% (n=30), recurrent hepatitis C (HCV) in 22% (n=18), cholestasis/ductular proliferation in 27% (n=22), ischemic/reperfusion injury in 9.8% (n=8) and drug-induced liver injury in 3.7% (n=3). In the first six months post LT, ACR was the commonest cause of graft dysfunction, while recurrent HCV was noticed to be predominant reason after 6 months. CONCLUSION: In this study, ACR was the most frequent finding in graft biopsies, followed by recurrent HCV. However, in first six months, ACR is the commonest histopathological finding while recurrent HCV was more frequently documented after 6 months. PMID- 26100993 TI - Rapid Mycobacterium tuberculosis DNA Detection on Fine Needle Aspirates from Extra Pulmonary Lymph Nodes. AB - OBJECTIVE: To evaluate the diagnostic efficacy of two rapid methods i.e. Mycobacterium tuberculosis (MTB) Polymerase Chain Reaction (PCR) on Fine Needle Aspiration (FNA) samples by comparing with cytology of respective site sample. STUDY DESIGN: Cross-sectional comparative study. PLACE AND DURATION OF STUDY: Department of Microbiology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan, from July 2010 through November 2013. METHODOLOGY: A total of 105 extra pulmonary lymph nodes aspirates obtained through fine needle aspiration were processed. Cytology and PCR were done on each specimen. Cytology was taken as gold standard. RESULTS: Out of the total 105 samples, 71 (67.6%) were positive for the MTB PCR while 34 (32.4%) showed negative status. According to FNA cytology (FNAC) results, 72 (68.6%) cases were positive for the disease while 33 (31.4%) were negative. Sensitivity of PCR was 90.3%, specificity 81.8%, positive predictive value (PPV) 91.5%, negative predictive value (NPV) 79.4%, with diagnostic accuracy of 87.6%. Area under the curve was 0.860 (p < 0.001). CONCLUSION: PCR is a sensitive tool for detection of MTB on FNA samples from EPTB cases. The results are available within few hours which is helpful for the clinicians to initiate therapy. PMID- 26100994 TI - Cytomorphology Versus Conventional Microbiological Tests in the Diagnosis of Tuberculous Lymphadenitis. AB - OBJECTIVE: To determine the accuracy of Fine Needle Aspiration Cytology (FNAC) in the diagnosis of tuberculous lymphadenitis. STUDY DESIGN: Comparative cross sectional study. PLACE AND DURATION OF STUDY: Department of Pathology, Khalifa Gul Nawaz Teaching Hospital (KGNTH), Bannu, from September 2012 to March 2013. METHODOLOGY: FNAC of enlarged lymph nodes was performed in the Department of Pathology, KGNTH, Bannu. Smears of the aspirates were examined under light microscope after staining with Haematoxylin and Eosin (H & E) stains. In cases of chronic lymphadenitis, the smears were stained with Ziehl-Neelsen (ZN) stain for Acid Fast Bacilli (AFB). If no AFB was visualized, the aspirate was subjected to culture on Lowenstein Jensen (LJ) medium for yield of AFB. The results were analyzed by Microsoft Excel software. RESULTS: Chronic granulomatous lymphadenitis was found in 110 (46.81%) out of 235 cases. AFB were seen in aspirates of 43/110 (39.09%) cases by direct microscopy. Among the remaining 67 aspirates subjected to LJ medium, only 07 (10.45%) yielded growth of AFB. Smears of 4/15 (3.6%), 13/47 (11.7%) and 33/48 (29.7%) cases with haemorrhagic, inflammatory and caseous background respectively, were confirmed by conventional microbiologic tests. Out of 125 nongranulomatous lymphadenitis cases only 05 were confirmed to be due to tuberculosis by direct microscopy while culture was not positive in any case. Thus accuracy of FNAC was 72.34%. CONCLUSION: FNAC has a good accuracy in diagnosing tuberculous lymphadenopathy. PMID- 26100995 TI - In Vitro Evaluation of Linezolid and Meropenem Against Clinical Isolates of Multi Drug Resistant Tuberculosis By Mycobacterial Growth Indicator Tube (MGIT) 960. AB - OBJECTIVE: To evaluate the in vitro effectiveness of multiple breakpoint concentrations of newer antituberculosis agents (Linezolid and Meropenem) against Multi Drug-Resistant Tuberculosis (MDR-TB) isolates. STUDY DESIGN: A descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Microbiology Department, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from September 2011 to August 2013. METHODOLOGY: A total of 100 MDR-TB isolates recovered during the study period were subjected to susceptibility testing against multiple breakpoint concentrations of Linezolid (LZD) and Meropenem (MER). The breakpoint concentration used for LZD were 0.5, 1.0 and 2.0 ug/ml, while for MER were 4.0, 8.0 and 16 ug/ml. Mycobacterial Growth Indicator Tube (MGIT) 960 system was used to carry out drug susceptibility testing as per recommended protocol. RESULTS: At break point concentration of 0.5 ug/ml, 80 out of 100 (80%) MDR-TB isolates were susceptible to LZD while at breakpoint concentration of 1.0 ug/ml and 2.0 ug/ml, 96/100, (96%) of MDR-TB isolates were susceptible. For MER, at breakpoint concentrations of 4.0 ug/ml no MDR-TB isolate was susceptible, while at 8.0 ug/ml 3/100, (3%) and at 16.0 ug/ml 11/100, (11%) of MDR-TB isolates were susceptible. CONCLUSION: LZD was found to have excellent in vitro efficacy as 96% of MDR-TB isolates were susceptible at breakpoint concentration of 1.0 ug/ml or more. In case of MER it was found that in vitro susceptibility improved as the break point concentrations were increased. PMID- 26100996 TI - Dandy-Walker Malformation: A Clinical and Surgical Outcome Analysis. AB - OBJECTIVE: To determine the clinical presentations, complications and mortality in patients with Dandy-Walker Malformation (DWM) after surgery i.e., shunt with y connector. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Neurosurgery Ward, JPMC, Karachi, from January 2009 to December 2013. METHODOLOGY: Cases of DWM, with associated hydrocephalus, further confirmed on CT scan of brain, were admitted through OPD. Those who were previously operated, those with other associated co-morbid or anomalies were excluded from this study. Combined drainage of the ventricular system and posterior fossa cyst, via dual shunt i.e. cystoperitoneal and ventriculoperitoneal shunt with y-connector was performed in all patients. Complications and mortality after surgical intervention in these patients were noted upto one month after surgery. The data analysis for descriptive statistics was done on SPSS version 20. RESULTS: In this study of 70 patients, majority of the patients were female aged between 1 - 2 years. Hydrocephalus was the predominant symptom as being present in all patients, followed by cerebellar signs in 60 (86%), and other in 5 (7.14%) patients. Complications of surgery were infection and shunt fracture dislocation in 7 (10%) each, malpositioning and shunt blockage in 6 (8.5%) each within one month of surgery, intracranial haemorrhage in 5 (7.14%) patients. Only one patient (1.42%) expired after surgical intervention. CONCLUSION: In DWM, the commonest presentation is that of hydrocephalus. Shunt malfunction and infection are the commonest complication after shunting. Dual shunt with y-connector has the lowest mortality when compared with other methods for treatment of shunt with y connector. PMID- 26100997 TI - Effect of Sleep/Wake Cycle on Autonomic Regulation. AB - OBJECTIVE: To evaluate the association between irregular sleep/wake cycle in shift workers and autonomic regulation. STUDY DESIGN: Cross-sectional, analytical study. PLACE AND DURATION OF STUDY: Dow University Hospital, Karachi, from August to November 2013. METHODOLOGY: All healthcare providers working in rotating shifts making a total (n=104) were included. Instrument was an integrated questionnaire applied to assess autonomic regulation, taken from Kroz et al. on scoring criteria, ranging from 18 - 54, where higher rating signifies strong autonomic regulation, indicating a stable Autonomic Nervous System (ANS) and vice versa. Participants were interviewed and their response was recorded by the investigator. Influence of sleep misalignment was measured quantitatively to extract index of autonomic activity. RESULTS: There was a reduced trend in autonomic strength amongst shift workers. The mean score obtained on the Autonomic Scale was 37.8 +/- 5.9. CONCLUSION: Circadian misalignment has an injurious influence on ANS which might be valuable in controlling autonomic dysfunction that leads to fatal triggers in rotating shift workers. PMID- 26100998 TI - Delayed Single Stage Perineal Posterior Urethroplasty. AB - OBJECTIVE: To determine the delayed single stage perineal posterior urethroplasty for treatment of posterior urethral stricture/distraction defect. STUDY DESIGN: Descriptive case series. PLACE AND DURATION OF STUDY: Department of Urology, Jinnah Postgraduate Medical Centre, Karachi, from January 2009 to December 2011. METHODOLOGY: Patients were selected for delayed single stage perineal posterior urethroplasty for treatment of posterior urethral stricture / distraction defect. All were initially suprapubically catheterized followed by definitive surgery after at least 3 months. RESULTS: Thirty male patients were analyzed with a mean follow-up of 10 months, 2 patients were excluded as they developed failure in first 3 months postoperatively. Mean patient's age was 26.25 +/- 7.9 years. On follow-up, 7 patients (23.3%) experienced recurrent stricture during first 10 months. Five (16.6%) patients were treated successfully with single direct visual internal urethrotomy. Two patients (6.6%) had more than one direct visual internal urethrotomy and considered failed. Re-do perineal urethroplasty was eventually performed. The overall success rate was 93.3% with permissive criteria allowing single direct visual internal urethrotomy and 76.6% with strict criteria allowing no more procedures postoperatively. CONCLUSION: Posterior anastomotic urethroplasty offers excellent long-term results to patients with posterior urethral trauma and distraction defect even after multiple prior procedures. PMID- 26100999 TI - Tuberculosis and Crohn's Disease Revisited. AB - Crohn's Disease (CD) and Intestinal Tuberculosis (ITB) share confusingly similar clinical, endoscopic, radiological and pathological manifestations. There is no simple test for differentiating ITB from CD. Although there are a number of sensitive and specific parameters for distinguishing between CD and ITB, the differential diagnosis still remains challenging and both clinical suspicion and appropriate clinical and laboratory studies are required to establish the diagnosis. Correct diagnosis is crucial because the therapy strategies of the two diseases are dramatically different. Treatment of ITB with immunosuppressive agents would lead to worsening of the patients' condition. Likewise, unnecessary antituberculosis therapy would delay the treatment of CD. Another important consideration is the risk of reactivation TB in patients with inflammatory bowel diseases which has been significantly increased following the widespread use of anti-Tumor Necrosis Factor Alpha (TNF-alpha) therapy. The majority of reactivation cases are extrapulmonary or disseminated TB. And it is widely recommended that patients with IBD who are to receive TNF inhibitor therapy should be screened for evidence of latent TB. This paper mainly reviews current literature on differential diagnosis between CD and ITB, and summarizes strategies to reduce the TB risk among candidates for TNF antagonist therapy in this specific patient population. PMID- 26101000 TI - Biodegradable Synthetic Polyurethane Foam Nasal Packing After Septoplasty. AB - OBJECTIVE: To determine the usefulness of biodegradable Synthetic Polyurethane Foam (SPF) nasal packing as an adjunct to day-case septoplasty. STUDY DESIGN: Comparative, observational case series. PLACE AND DURATION OF STUDY: Aberdeen Royal Infirmary, University of Aberdeen, Scotland, UK, in the year 2011. METHODOLOGY: One-hundred consecutive patients who underwent septoplasty and received SPF packing in 2010 were prospectively audited while one-hundred consecutive patients undergoing septoplasty in the year 2000 were studied retrospectively. Data collected include demographics, type of operation and duration of hospital stay. Excel and SPSS were used for data collection and analysis. RESULTS: In the year 2000, the average age of the patients was 40.6 years. There were 37 females and 63 males. One patient returned home the same day, 22 stayed one night, 69 spent two nights and 8 stayed more than two nights in hospital for their operation. The average length of stay was 1.84 nights. In 2010, the average age of patients was 37.86 years, with 31 patients being female and 69 male. All patients in this cohort received SPF packing postoperatively. Seventy-three patients went home the same day, 24 patients stayed one night and 3 patients spent two nights in hospital for their operation. Average length of hospital stay was 0.3 nights. Results were statistically significant (p < 0.001). CONCLUSION: SPF was a useful nasal packing option after septoplasty and inferior turbinate surgery, which enabled the surgeons to carry out this surgery safely as a day-case procedure. PMID- 26101001 TI - Expanded Outcomes Framework for Effective CME - The Way Forward for Pakistan. AB - Continuing Medical Education (CME) providers recognize the importance to plan educational activities that focus to improving and assessing knowledge, competency and performance outcomes rather than on attendance and satisfaction. This perspective proposes using an expanded outcomes framework for planning and assessing CME. The expanded outcomes framework supports backward planning, that starts with the population health outcomes (level 7) and moves backward, to providing continuing education for physicians that may result in improved outcomes. We the authors recognize the complexity of this framework, the recently evolved CME system in Pakistan, and the limited resources; and therefore, we suggest that planning and assessment should begin at level 3, physician knowledge. Thus, be mindful of the end and the scope of this framework that is associated and leads toward the improvement of population health outcomes. PMID- 26101002 TI - Applicability of the New ESPGHAN Guidelines for Diagnosing Coeliac Disease in Children from Resource Limited Countries. AB - Coeliac Disease (CD) is an immune-mediated systemic disorder elicited by the ingestion of gluten. Small-bowel biopsies and histology has been the gold standard for diagnosing CD. The modified ESPGHAN guidelines recommend that in symptomatic children with anti-tissue-Transglutaminase (tTG) titre of > 10 times Upper-Limit-of-Normal (ULN), diagnosis of CD can be made without small-bowel biopsies. However, positive HLA-DQ2/DQ8 serotype and anti-Endomysial Antibodies (EMA) are necessary. Studies from resource-limited countries have demonstrated applicability of the ESPGHAN guidelines for serological diagnosis of CD. CD should not be diagnosed on the basis of a single high tTG-titre. Small-bowel biopsies are necessary for diagnosing CD in asymptomatic children and those with tTG-titre < 10 x ULN. Management of CD needs lifelong gluten free diet. PMID- 26101003 TI - Carcinomatous Meningitis: A Rare Complication of Pancreatic Adenocarcinoma. AB - Carcinomatous Meningitis (CM) is a relatively uncommon metastatic complication of systemic solid tumors. The condition is mostly diagnosed by presence of malignant cells in the cerebrospinal fluid. The prognosis of the condition is generally poor. CM very rarely complicates pancreatic cancers and very few cases have been reported in the literature. We present a case of a 58-year old female patient operated for pancreatic head carcinoma. She made an immediate uneventful recovery after her pancreatico-duodenectomy. She presented 3 weeks post-surgery with acute confusional state and was diagnosed as a case of CM. PMID- 26101004 TI - Schwannoma of Nasal Inferior Turbinate in Young Male: A Rare Occurrence. AB - A12-year old boy presented to the ENT Department of Abbasi Shaheed Hospital, Karachi, with a one year history of progressively increasing unilateral right sided nasal obstruction. He denied any other symptoms like that of rhinorrhea, epistaxis, facial pain, headache and any history of nasal trauma. After routine clinical examination, CT scan nose/PNS with contrast was advised and subsequently biopsy was done that revealed the mass to be as schwannoma. This was then removed via a lateral rhinotomy approach and the postoperative specimen again revealed the same. The boy was followed for 1-year and no recurrence is seen. He is still in the follow-up phase. PMID- 26101005 TI - Methylmalonic Acidemia. AB - Methylmalonic Acidemia (MMA) is an inborn error of metabolism that results in accumulation of methylmalonic acid in blood and increased excretion in urine. The effects of MMA vary from mild to life threatening and it usually presents in early infancy. Affected infants can have vomiting, dehydration, hypotonia, developmental delay and failure to thrive. The emergency treatment of the newborn with MMA mainly comprises rehydration and promotion of anabolism, followed by long-term dietary management by both the restriction of precursor amino acids using a low protein diet and avoidance of prolonged fasting. Prognosis depends on the type of MMA and whether the condition is well controlled in general and during episodes of metabolic decompensation. We report here the presentation and management of a 2-year boy with MMA who failed to achieve expected milestones for age. To the best of our knowledge, only one case of MMA has been reported from Pakistan. PMID- 26101006 TI - Per Oral Bleeding: Rare Presentation of Gardner-Diamond Syndrome. AB - A10-year boy presented with spontaneous episodes of oral bleeding for the last 6 months. Detailed ENT examination showed no pathology, bleeding profile was normal, endoscopy and dental examination also did not reveal any abnormality. Child abuse or malingering was also ruled out. Initially the child was managed with platelet transfusion and fresh frozen plasma and then put on follow-up treatment with antifibrinolytics, Vitamin C but the episodes became recurrent. Psychiatric evaluation revealed that child was suffering from depression. Antidepressants were prescribed by the psychiatrist that not only cured the depression with time but also the bleeding episodes which were actually related to child's depression (Gardner-Diamond syndrome or psychogenic purpura). This is a diagnosis by exclusion where the patients bleed due to dysregulated steroid secretion secondary to stress; resulting in development of sensitization to RBC membrane, and dysregulated fibrinolytic system activity. PMID- 26101007 TI - Histomorphological Spectrum of Papillary Carcinoma of Thyroid in Oman. AB - Thyroid cancer is the commonest endocrine malignancy and is the second most common cancer affecting young females in Oman. The diagnosis of Papillary Thyroid Carcinoma (PTC) is based primarily on histologic architecture and nuclear morphology in routine Haematoxilin and Eosin (H & E) stained slides. Whenever in doubt, immunohistochemistry may be helpful. This retrospective study included 115 cases of PTC diagnosed at a tertiary care center in Oman over 10 years period, from 2001 to 2010. Slides and blocks of these cases were retrieved from the pathology laboratory. Ninety five (95) were females and 20 were males. Papillary Thyroid Carcinoma (PTC) was most commonly seen in the 20 - 50 years of age. The commonest morphologic variant seen in this population was classical papillary variant in 44/115 (38%) followed by papillary micro-carcinoma (n=30/115, 26%) and follicular variant of papillary carcinoma (n=18/115, 15.6%). Out of the 30 micro carcinoma cases, 18 were diagnosed incidentally in thyroids operated for multi nodular goiter. Immunohistochemical marker CK-19 was positive in 29/31, HBME-1 and HMW-CK in 15/15 cases; CEA was in one case where it was reported negative. Immunohistochemical stains were useful in cases with atypical /doubtful morphology. PMID- 26101008 TI - Thyroxine Replacement in Patients on Parenteral Nutrition: A Clinical Conundrum. PMID- 26101009 TI - Concomitant Congenital Trigger Thumb and Thumb Aplasia. PMID- 26101010 TI - Assessing and Treating Early Onset Schizophrenia at Schools. PMID- 26101011 TI - Comment on the Management of Thyroid Nodules: An Optimum Approach. PMID- 26101012 TI - The initial steps of operating room emergency checklist. PMID- 26101013 TI - Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer. AB - OBJECTIVES: To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). MATERIALS AND METHODS: Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. RESULTS: 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2 4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. CONCLUSION: HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management. PMID- 26101014 TI - Silencing of miR-137 by aberrant promoter hypermethylation in surgically resected lung cancer. AB - BACKGROUND: Recent studies demonstrated that miR-137 is downregulated in various tumors, and that it functions as a tumor suppressor. miR-137 could be silenced by its aberrant promoter hypermethylation. The purpose of this study was to investigate the significance of MIR137 promoter methylation on its expression in lung cancer. METHODS: Lung cancer cell lines were treated with either a DNA methyltransferase inhibitor (5-azacytidine, AZA) and/or an HDAC inhibitor (trichostatin A, TSA) to determine whether miR-137 expression was reactivated. Paired lung tumor and adjacent non-tumor lung tissues were obtained (n=50). Quantitative methylation-specific PCR and bisulfite sequencing were used to analyze the methylation status of MIR137, and real-time RT-PCR was performed to analyze miR-137 expression. RESULTS: miR-137 was reactivated by treatment with either AZA and/or TSA in lung cancer cell lines. Methylation-specific PCR showed increased MIR137 promoter methylation in lung tumors compared with adjacent non tumor tissues, which was further validated by bisulfite sequencing. The expression of miR-137 was downregulated significantly in lung tumors, which was correlated with level of MIR137 promoter methylation inversely. CONCLUSIONS: miR 137 downregulation was related to its promoter hypermethylation in lung cancer. Further studies are needed to assess its value as a prognostic factor and potential therapeutic applications in lung cancer. PMID- 26101016 TI - Isolation, characterization, and survival strategies of Thermotoga sp. strain PD524, a hyperthermophile from a hot spring in Northern Thailand. AB - A hyperthermophilic Thermotoga sp. strain PD524 was isolated from a hot spring in Northern Thailand. Cells were long-curved rods (0.5-0.6 * 2.5-10 MUm) surrounded by a typical outer membrane toga. Strain PD524 is aero-tolerant at 4 degrees C but is aero-sensitive at 80 degrees C. A heat resistant subpopulation was observed in late-stationary phase. Cells from late-stationary phase were revealed remarkably less sensitive to 0.001 % SDS treatment than cells from exponential phase. The temperature range for growth was 70-85 degrees C (opt. temp. 80 degrees C), pH range was 6-8.5 (opt. pH 7.5-8.0), and NaCl range of 0 to <10 g/L (opt. 0.5 g/L). Glucose, sucrose, maltose, fructose, xylose, mannose, arabinose, trehalose, starch, and cellobiose were utilized as growth substrates. Growth was inhibited by S(o). Growth yield was stimulated by SO 4 (=) but not by S2O 3 (=) and NO3 (-). Analysis of 16S rRNA gene sequence (KF164213) of strain PD524 revealed closest similarity (96 %) to Thermotoga maritima MSB8(T), T. neapolitana NES(T), T. petrophila RKU-1(T), and T. naphthophila RKU-10(T). PMID- 26101015 TI - Microbial diversity and adaptation to high hydrostatic pressure in deep-sea hydrothermal vents prokaryotes. AB - Prokaryotes inhabiting in the deep sea vent ecosystem will thus experience harsh conditions of temperature, pH, salinity or high hydrostatic pressure (HHP) stress. Among the fifty-two piezophilic and piezotolerant prokaryotes isolated so far from different deep-sea environments, only fifteen (four Bacteria and eleven Archaea) that are true hyper/thermophiles and piezophiles have been isolated from deep-sea hydrothermal vents; these belong mainly to the Thermococcales order. Different strategies are used by microorganisms to thrive in deep-sea hydrothermal vents in which "extreme" physico-chemical conditions prevail and where non-adapted organisms cannot live, or even survive. HHP is known to impact the structure of several cellular components and functions, such as membrane fluidity, protein activity and structure. Physically the impact of pressure resembles a lowering of temperature, since it reinforces the structure of certain molecules, such as membrane lipids, and an increase in temperature, since it will also destabilize other structures, such as proteins. However, universal molecular signatures of HHP adaptation are not yet known and are still to be deciphered. PMID- 26101019 TI - Selection of cholesterol esterase aptamers using a dual-partitioning approach. AB - Non-systematic evolution of ligands by exponential enrichment and other capillary based methods have grown in popularity for selection of aptamers since they provide a fast and efficient partitioning method when compared to classical techniques. Despite promising developments in these techniques, a major obstacle needs to be overcome for capillary-based selections to be widely accepted. Due to the small injection volumes associated with CE, only a small proportion of the nucleic acid library can be partitioned at any one time. In this paper, we propose a new two-step method for the selection of aptamers which firstly incorporates a nitrocellulose membrane filter followed by CE. This technique allows for nonbinding sequences to be eliminated, reducing the library size before subsequent capillary-based partitioning, while still reducing the time taken for aptamers to be selected. We demonstrated this technique on the selection of aptamers for cholesterol esterase and the highest binding truncated aptamer CES 4T displayed a K(D) of 203 +/- 14 nM. In addition, an increase in the number of sequences partitioned was estimated using spectrophotometry and capillary injection volumes. The results suggested that for successful selection a two-step approach is needed. This hybrid technique could be used to select aptamers that bind to targets both in solution and immobilized onto a stationary phase, allowing the aptamers to be used in different binding environments. PMID- 26101017 TI - Characterization of recombinant glutathione reductase from the psychrophilic Antarctic bacterium Colwellia psychrerythraea. AB - Glutathione reductases catalyze the reduction of oxidized glutathione (glutathione disulfide, GSSG) using NADPH as the substrate to produce reduced glutathione (GSH), which is an important antioxidant molecule that helps maintain the proper reducing environment of the cell. A recombinant form of glutathione reductase from Colwellia psychrerythraea, a marine psychrophilic bacterium, has been biochemically characterized to determine its molecular and enzymatic properties. C. psychrerythraea glutathione reductase was shown to be a homodimer with a molecular weight of 48.7 kDa using SDS-PAGE, MALDI-TOF mass spectrometry and gel filtration. The C. psychrerythraea glutathione reductase sequence shows significant homology to that of Escherichia coli glutathione reductase (66 % identity), and it possesses the FAD and NADPH binding motifs, as well as absorption spectrum features which are characteristic of flavoenzymes such as glutathione reductase. The psychrophilic C. psychrerythraea glutathione reductase exhibits higher k cat and k cat/K m at lower temperatures (4 degrees C) compared to mesophilic Baker's yeast glutathione reductase. However, C. psychrerythraea glutathione reductase was able to complement an E. coli glutathione reductase deletion strain in oxidative stress growth assays, demonstrating the functionality of C. psychrerythraea glutathione reductase over a broad temperature range, which suggests its potential utility as an antioxidant enzyme in heterologous systems. PMID- 26101020 TI - New diagnostic pathways urgently needed. Protocol of PET Guidance I pilot study: positron emission tomography in suspected cardiac implantable electronic device related infection. AB - BACKGROUND: Cardiovascular implantable electronic device (CIED) infection is a complication of increasing incidence. We present a protocol of an observational case control clinical trial "Positron Emission Tomography Combined With Computed Tomography (PET CT) in Suspected Cardiac Implantable Electronic Device Infection, a Pilot Study - PET Guidance I" (NCT02196753). AIM: The aim of this observational clinical trial is to assess and standardise diagnostic algorithms for CIED infections (lead-dependent infective endocarditis, generator pocket infection, fever of unknown origin) with PET CT in Poland. METHODS AND RESULTS: Study group will consist of 20 patients with initial diagnosis of CIED-related infection paired with a control group of 20 patients with implanted CIEDs, who underwent PET CT due to other non-infectious indications and have no data for infectious process in follow-up. All patients included in the study will undergo standard diagnostic pro-cess. Conventional/standard diagnostic and therapeutic process will consist of: medical interview, physical examination, laboratory tests, blood cultures; imaging studies: echocardiography: transthoracic (TTE), and, if there are no contraindications transoesophageal, computed tomography scan for pulmonary embolism if indicated; if there are abnormalities in other systems, decisions concerning further diagnostics will be made at the physician's discretion. As well as standard diagnostic procedures, patients will undergo whole body PET CT scan to localise infection or inflammation. Diagnosis and therapeutic decision will be obtained from the Study Committee. Follow-up will be held within six months with control visits at three and six months. During each follow-up visit, all patients will undergo laboratory tests, two blood cultures collected 1 h apart, and TTE. In case of actual clinical suspicion of infective endocarditis or local generator pocket infection, patients will be referred for further diagnostics. Endpoints for the results assessment - primary endpoints are to standardise PET CT in the diagnostic process: sensitivity, specificity, positive predictive value, and negative predictive value of the diagnosis made by PET CT; secondary endpoints are: assessment of usefulness of PET CT for detection of remote infective complications (metastatic abscesses, infected pulmonary emboli), incidence of particular localisations of infection, influence of PET CT on therapeutic decision: confirmation or change of decision based on PET CT, safety and complications of diagnostic process of CIED-related infections with PET CT. CONCLUSIONS: Evaluation of PET CT use for device-related infections in a case control study may be conclusive and improve diagnostic pathway. PMID- 26101021 TI - Predictors of one-year outcome in patients hospitalised for heart failure: results from the Polish part of the Heart Failure Pilot Survey of the European Society of Cardiology. AB - BACKGROUND: Over the last few decades, the incidence and prevalence of chronic heart failure (HF) have been constantly increasing. AIM: To identify predictors of one-year mortality and hospital readmissions in patients discharged after hospitalisation for HF. METHODS: The study included Polish patients who agreed to participate in the Heart Failure Pilot Survey of the European Society of Cardiology and were followed for 12 months. The primary endpoint was all-cause death at 12 months. The secondary endpoint was a composite of all-cause death and readmission for cardiac causes at 12 months. RESULTS: The final analysis included 629 patients. The primary end point occurred in 68 of 629 patients (10.8%). In multivariate analysis, independent predictors of one-year mortality were: higher New York Heart Association (NYHA) class at admission (odds ratio [OR] 1.90; 95% confidence interval [CI] 1.01-3.59; p = 0.0478), inotropic support during hospitalisation (OR 3.95; 95% CI 1.49-10.47; p = 0.0056), and lower glomerular filtration rate at discharge (OR 0.978; 95% CI 0.961-0.995; p = 0.0117). The secondary endpoint occurred in 278 of 503 patients (55.3%). In multivariate analysis, predictors of secondary endpoint were a history of previous coronary revascularisation (OR 2.403; 95% CI 1.221-4.701; p = 0.002) and inotropic support during hospitalisation (OR 2.521; 95% CI 1.062-5.651; p = 0.009). CONCLUSIONS: Patients discharged after hospitalisation for HF remained at high risk of death and hospital readmission. A previous history of coronary revascularisation, decreased renal function, and worse clinical status at admission with the need for inotropic support were predictors of one-year outcome in Polish patients hospitalised for HF. PMID- 26101022 TI - Renal resistive index in patients with true resistant hypertension: results from the RESIST-POL study. AB - BACKGROUND: Increased ultrasound Doppler renal resistive index (RRI) is a marker of atherosclerotic and hypertensive organ damage both at renal and systemic level. AIM: To evaluate RRI in patients with true resistant hypertension (TRHT) in the RESIST-POL study. METHODS: From 204 patients diagnosed with TRHT in the RESIST-POL study, 151 patients (90 male, 61 female, mean age: 47.7 +/- 10.4, range: 19-65 years) without secondary hypertension were included into the analysis. All patients were characterised by estimated glomerular filtration rate > 60 mL/min/1.73 m2 and no history of diabetes prior to the study. As a control group we included 50 age- and gender-matched patients (35 male, 15 female, mean age: 46.8 +/- 10.4, range: 19-65 years) with primary well-controlled hypertension. The groups also did not differ in respect to the number of years of known history of hypertension. The RRIs were evaluated on the basis of the Doppler ultrasound examination. Increased RRI was defined as >= 0.7. RESULTS: Both groups did not differ in terms of renal function. Patients with TRHT were characterised by higher RRI as compared with the group with well-controlled hypertension (0.62 +/- 0.05 vs. 0.60 +/- 0.05, p < 0.05). In the TRHT group RRI correlated significantly with age, clinic and ambulatory blood pressure measurement, diastolic blood pressure (DBP) levels, as well as with clinic pulse pressure (PP) (r = 0.297; p = 0.001), with daytime (r = 0.355; p < 0.001) and nighttime (r = 0.313; p < 0.001) PP, and with fasting glucose concentration (r = 0.215; p = 0.008) and E/E' ratio (r = 0.289; p = 0.001) on echocardiography. RRI values were significantly higher in TRHT patients with newly diagnosed diabetes as compared with TRHT patients without diabetes (0.65 +/- 0.05 vs. 0.62 +/- 0.05, p = 0.022). Age, daytime DBP, daytime PP, and E/E' ratio but not fasting glucose concentration correlated independently with RRI in the model. Among patients with TRHT, patients with increased RRI were characterised by older age (52.2 +/- 4.9 vs. 47.3 +/- 10.6 years, p = 0.012), higher body mass index (32.8 +/- 6.0 vs. 29.7 +/- 4.5 kg/m2, p = 0.034), as well as lower daytime and nighttime DBP values and lower daytime and nighttime heart rate, as compared to patients with RRI < 0.7. The TRHT patients with increased RRI as compared to patients with RRI < 0.7 were characterised also by higher daytime and nighttime PP. Both groups did not differ in respect of renal function. CONCLUSIONS: Our study showed that the patients with TRHT were characterised by significantly higher RRI values as compared to the subjects with well-controlled hypertension. It may also be suggested that in the subjects with TRHT renal vascular resistance is related to blood pressure values, selected echocardiographic abnormalities, and some surrogate markers for metabolic and cardiovascular events, including fasting glucose plasma concentration and PP, respectively. PMID- 26101023 TI - Heart failure is the strongest predictor of acute kidney injury in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction. AB - BACKGROUND: ST elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PCI) are at higher risk of acute kidney injury (AKI) than patients undergoing PCI in stable clinical conditions. This fact suggests that mechanisms other than contrast nephrotoxicity are involved. AIM: To evaluate the incidence, risk factors, and consequences of AKI in patients undergoing primary PCI for STEMI in current daily practice. METHODS: Analysis of all consecutive patients who underwent primary PCI over a one-year period. AKI was defined as an increase in serum creatinine >= 50% or 26.5 MUmol/L (AKIN criteria) from the baseline within 48 h. RESULTS: A total of 202 patients were included. AKI occurred in 25 (12.4%) subjects. Baseline characteristics and in-hospital complications of the patients with and without AKI did not differ significantly except for age (69 +/- 13 vs. 62 +/- 12; p = 0.003), female gender (48.0% vs. 26.6%; p = 0.035), hypertension (88.0% vs. 62.7%; p = 0.013), left ventricular ejection fraction (40% +/- 12% vs. 49% +/- 14%; p = 0.002), cardiogenic shock (44.0% vs. 5.1%; p < 0.0001), use of intravenous diuretics (76.0% vs. 26.0%; p < 0.0001), ventricular arrhythmias (24.0% vs. 3.4%; p = 0.001), and in-hospital mortality (24.0% vs. 3.4%; p = 0.001). In multivariate analysis heart failure remained the only independent correlate of AKI. CONCLUSIONS: AKI was an frequent and serious complication of STEMI in patients treated by primary PCI. Heart failure was the strongest predictor of AKI. Other risk factors including contrast medium volume, baseline renal function, diabetes, and age failed to predict AKI. PMID- 26101024 TI - Depression and anxiety in patients with coronary artery disease, measured by means of self-report measures and clinician-rated instrument. AB - BACKGROUND: The presence of depression symptomatology significantly deteriorates the prognosis for the patient. There are many instruments developed to measure depression and anxiety in clinical trials; however, the suitability of the specific scale for screening these disorders in cardiovascular patients is debatable. The aim of current study is to verify which of the major assessment instruments is the most relevant for the screening evaluation of depression and anxiety in patients with cardiovascular system diseases. AIM: The sample studied consisted of 120 patients with stable coronary artery disease (CAD). They did not display serious psychiatric or somatic disorders. METHODS: To assess depressive and anxiety symptoms we used self-reporting measures (BDI-II, HADS, SSAI/STAI, and PHQ), the results of which were compared to results obtained on the basis of a clinician-rating instrument (HRSD). RESULTS: We found that depressive symptoms assessed on the basis of HRSD, BDI-II, and PHQ-9 were equivalent in results, while the results obtained in HADS-D were significantly lower. Anxiety symptoms were found at approximate levels in HADS, SSAI, and GAD-7. The assessment of somatic symptoms in patients with CAD indicates that 87.5% of the subjects reported somatic symptoms of various intensity. CONCLUSIONS: Screening assessment of depression in patients with CAD gives different results depending on the tool used. We found that HADS significantly underestimates the percentage of patients with symptoms of depression in patients with CAD. Assessing anxiety symptoms with the aid of HADS gave outcomes close to the results gained by use of other tools. PMID- 26101025 TI - Prediction of high risk of non-adherence to antiplatelet treatment. AB - BACKGROUND: Dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel is the standard of care for secondary prevention. Premature discontinuation of clopidogrel is associated with an increased risk of myocardial infarction (MI) or death, and greater health care expenditure. AIM: To develop an objective method for identification of patients with high risk of non-adherence to clopidogrel after MI. METHODS: A total of 189 patients were enrolled into a prospective, observational, single-centre study with a nine-month follow-up. Patients received a 600-mg loading dose and 75-mg maintenance dose of clopidogrel in combination with ASA doses of 300 mg and 75 mg, respectively. Adenosine diposphate-induced platelet aggregation (ADP-PA) was assessed during baseline hospitalisation and at three, six, and nine months after discharge. Adherence to medication with clopidogrel was defined as the proportion of drug availability based on data from the National Health Fund regarding prescribed drug purchases. Adherence was arbitrarily judged adequate when the proportion exceeded 80%. RESULTS: According to our hypothesis, ADP-PA in non-adherent patients should be higher at follow-up visits (at least once) as compared with measurement at hospitalisation. Based on the ROC curve analysis, the optimal cut-off point equal to 4 U was defined (p < 0.0001, 95% CI 0.562-0.654; sensitivity: 60.6%, specificity: 57.1%, positive predictive value: 63.3%, negative predictive value: 54.2%). The prevalence of true adherence to medication in groups of high and low probability of adherence defined according to developed criteria amounted 60 (50.8%) and 23 (32.4%) cases, respectively (p = 0.01). CONCLUSIONS: The newly developed method of objective identification of patients with high risk of non adherence to clopidogrel after MI is easily applicable and cheap, and, despite relatively low sensitivity and specificity, it efficiently differentiates patients with regard to clinical end-points during follow-up. PMID- 26101026 TI - Comparison of patient comfort after coronary angiography by standard arterial access approaches. AB - BACKGROUND: Radial access during coronary angiography has become an increasingly popular alternative to femoral access. The procedural outcomes and complications of these two approaches have been thoroughly evaluated; however, no studies have focused exclusively on the postprocedural quality of life of patients. AIM: To determine and compare both methods from the patient's point of view. METHODS: Data were gathered from 165 consecutive patients scheduled for elective coronary angiography (from October 2011 to June 2012). The choice of the access site was left at operator's discretion. Femoral and radial groups consisted of 91 and 74 patients, respectively. Quality of life was assessed by the Short Form of the McGill Questionnaire and a self-designed questionnaire (Questionnaire II) consisting of eight questions evaluating the procedure-specific aspects of recovery time. After three months from index hospitalisation post-discharge interviews were conducted using a modified version of Questionnaire II with an additional two questions. RESULTS: Patients from the transfemoral approach group characterised their pain (according to McGill Questionnaire) more often as aching (mean value +/- SD: 0.84 +/- 1.2 vs. 0.21 +/- 0.6; p = 0.003), heavy (0.29 vs. 0.027; p = 0.02), and exhausting (0.22 +/- 0.7 vs. 0.07 +/- 0.2; p = 0.037). Moreover, in Questionnaire II they indicated tenderness of the puncture site (0.42 +/- 0.8 vs. 0.23 +/- 0.07; p = 0.00004) more frequently. CONCLUSIONS: The quality of life of patients who underwent coronary angiography from radial access was remarkably better in terms of pain characteristic and overall discomfort. PMID- 26101027 TI - Electrocardiographic markers of left ventricular systolic dysfunction in patients with left bundle branch block. AB - BACKGROUND: Although some patients with left bundle branch block (LBBB) have structural heart diseases, some patients with LBBB have "normal hearts". The electrocardiography (ECG) criteria of LBBB in reduced left ventricular ejection fraction (LVEF) have not been defined completely. AIM: The main purpose of this study was to differentiate patients with reduced LVEF from patients with normal left ventricular systolic function simply by analysing 12-lead ECG. METHODS: Subjects admitted to our hospital with LBBB in their ECG were included in the study. The patients were categorised according to their left ventricular systolic function as group 1 (LVEF >= 50%) and group 2 (LVEF < 50%). Duration of the QRS complex, residual conduction of left bundle branch, and concordance/discordance of T waves in leads V5, V6, or D1 were recorded. The ECG findings of the two groups were compared. RESULTS: One hundred consecutive patients with LBBB were included in the study (male/female: 56/44, age: 66 +/- 15 years). In the whole group, there were 35 patients with normal left ventricular systolic function (LVEF >= 50%), and 65 patients had LVEF below 50%. 80% of male patients with LBBB and 45% of female patients with LBBB had their LVEF below 50% (p < 0.001). Mean QRS durations of group 1 and group 2 were 132 +/- 10 ms vs. 152 +/- 22 ms, respectively (p < 0.001). The QRS duration of 140 ms was found to be the cut-off value to differentiate group 1 from group 2, with sensitivity and specificity of 72% and 75%, respectively. Twenty-one per cent of patients in group 1 and 69% in group 2 had discordant LBBB (p < 0.001). Residual conduction of left bundle branch was more frequent in group 2 (29% in group 1 vs. 52% in group 2, p = 0.03). CONCLUSIONS: Male gender, QRS duration greater than 140 ms, discordant LBBB, and residual conduction in the left bundle branch seem to be markers of reduced LVEF in patients with LBBB. PMID- 26101029 TI - Coupled Simulation of Heart Valves: Applications to Clinical Practice. AB - The last few decades have seen great advances in the understanding of heart valves, and consequently, in the development of novel treatment modalities and surgical procedures for valves afflicted by disease. This is due in part to the profound advancements in computing technology and noninvasive medical imaging techniques that have made it possible to numerically model the complex heart valve systems characterized by distinct features at different length scales and various interacting processes. In this article, we highlight the importance of explicitly coupling these multiple scales and diverse processes to accurately simulate the true behavior of the heart valves, in health and disease. We examine some of the computational modeling studies that have a direct consequence on clinical practice. PMID- 26101028 TI - Prognosis in children with pulmonary arterial hypertension: 10-year single centre experience. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare progressive disease of the pulmonary arterioles with an unfavourable prognosis. AIM: To evaluate survival and prognostic factors in patients with PAH diagnosed and treated at a single centre in the years 2004-2013. METHODS: The study included 55 children (33 girls; 66%, 22 boys; 33%), with an average age 6.2 +/- 6.0 years, with idiopathic PAH - n = 23 (42%), PAH associated with systemic-to-pulmonary shunts - n = 17 (31%), and PAH after corrective cardiac surgery - n = 15 (27%). Forty-seven of them (87%) were treated with advanced therapy. RESULTS: During the follow-up with an average time of 5.6 +/- 4.7 years 15 (27.3%) children died. The one-, three-, five-, and ten-year survival was, respectively, 83.1%, 77.1%, 70.7%, and 65.2%. The analysis of the survival curves revealed a better prognosis in patients with baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) level < 605 pg/mL (p = 0.024) and a higher probability of survival of three and five years in children at baseline I/II World Health Organisation functional class (WHO-FC). The higher risk of death was associated with a higher pressure in the right atrium (HR 1.23, p < 0.01) and higher pulmonary resistance (HR 1.1, p < 0.01), whereas no history of syncope had a better prognosis (HR 0.31, p = 0.03). CONCLUSIONS: Survival in the study group was comparable to the currently published register data. Mortality risk factors were connected with the severity of the disease at diagnosis. PMID- 26101030 TI - Modeling of Experimental Atherosclerotic Plaque Delamination. AB - A cohesive zone model (CZM) approach is applied to simulate atherosclerotic plaque delamination experiments in mouse abdominal aorta specimens. A three dimensional finite element model is developed for the experiments. The aortic wall is treated as a fiber-reinforced, highly deformable, incompressible material, and the Holzapfel-Gasser-Ogden (HGO) model is adopted for the aortic bulk material behavior. Cohesive elements are placed along the plaque-media interface along which delamination occurs. The 3D specimen geometry is created based on images from the experiments and certain simplifying approximations. A set of HGO and CZM parameter values is determined based on values suggested in the literature and through matching simulation predictions of the load vs. load point displacement curve with experimental measurements for one loading delamination-unloading cycle. Using this set of parameter values, simulation predictions for four other loading-delamination-unloading cycles are obtained, which show good agreement with experimental measurements. The findings of the current study demonstrate the applicability of the CZM approach in arterial tissue failure simulations. PMID- 26101031 TI - Nitinol Stent Oversizing in Patients Undergoing Popliteal Artery Revascularization: A Finite Element Study. AB - Nitinol stent oversizing is frequently performed in peripheral arteries to ensure a desirable lumen gain. However, the clinical effect of mis-sizing remains controversial. The goal of this study was to provide a better understanding of the structural and hemodynamic effects of Nitinol stent oversizing. Five patient specific numerical models of non-calcified popliteal arteries were developed to simulate the deployment of Nitinol stents with oversizing ratios ranging from 1.1 to 1.8. In addition to arterial biomechanics, computational fluid dynamics methods were adopted to simulate the physiological blood flow inside the stented arteries. Results showed that stent oversizing led to a limited increase in the acute lumen gain, albeit at the cost of a significant increase in arterial wall stresses. Furthermore, localized areas affected by low Wall Shear Stress increased with higher oversizing ratios. Stents were also negatively impacted by the procedure as their fatigue safety factors gradually decreased with oversizing. These adverse effects to both the artery walls and stents may create circumstances for restenosis. Although the ideal oversizing ratio is stent specific, this study showed that Nitinol stent oversizing has a very small impact on the immediate lumen gain, which contradicts the clinical motivations of the procedure. PMID- 26101032 TI - Computational Models of the Foot and Ankle for Pathomechanics and Clinical Applications: A Review. AB - Complementary to experimental studies, computational biomechanics has become useful tool for the understanding of human foot biomechanics and pathomechanics. Its findings have been widely used for the evaluation of the effectiveness of surgical and conservative interventions. These models, however, were developed with a wide range of variations in terms of simplifications and assumptions on the representation of geometrical structures and material properties, as well as boundary and loading conditions. These variations may create differences in prediction accuracy, and restrict practical and clinical applications. This paper reviews the state-of-the-art technologies and challenges in computational model development, focusing on foot problem-specific models for the assessment of the effectiveness and accessibility of clinical treatments. The computational models have provided valuable biomechanical information for clinical applications but further investigations come with many challenges in terms of detailed and patient specific models, accurate representations of tissue properties, and boundary and loading conditions. Multi-scale computational models are expected to be an efficient platform to fully address the biomechanical and biological concerns. PMID- 26101033 TI - Computational Patient Avatars for Surgery Planning. AB - In this paper a new method is described for the generation of computational patient avatars for surgery planning. By "patient avatar" a computational, patient-specific, model of the patient is meant, that should be able to provide the surgeon with an adequate response under real-time restrictions, possibly including haptic response. The method is based on the use of computational vademecums (F. Chinesta et al., PGD-based computational vademecum for efficient design, optimization and control. Arch. Comput. Methods Eng. 20(1):31-59, 2013), that are properly interpolated so as to generate a patient-specific model. It is highlighted how the interpolation of shapes needs for a specialized technique, since a direct interpolation of biological shapes would produce, in general, non physiological shapes. To this end a manifold learning technique is employed, that allows for a proper interpolation that provides very accurate results in describing patient-specific organ geometries. These interpolated vademecums thus give rise to very accurate patient avatars able to run at kHz feedback rates, enabling not only visual, but also haptic response to the surgeon. PMID- 26101034 TI - AView: An Image-based Clinical Computational Tool for Intracranial Aneurysm Flow Visualization and Clinical Management. AB - Intracranial aneurysms (IAs) occur in around 3% of the entire population. IA rupture is responsible for the most devastating type of hemorrhagic strokes, with high fatality and disability rates as well as healthcare costs. With increasing detection of unruptured aneurysms, clinicians are routinely faced with the dilemma whether to treat IA patients and how to best treat them. Hemodynamic and morphological characteristics are increasingly considered in aneurysm rupture risk assessment and treatment planning, but currently no computational tools allow routine integration of flow visualization and quantitation of these parameters in clinical workflow. In this paper, we introduce AView, a prototype of a clinician-oriented, integrated computation tool for aneurysm hemodynamics, morphology, and risk and data management to aid in treatment decisions and treatment planning in or near the procedure room. Specifically, we describe how we have designed the AView structure from the end-user's point of view, performed a pilot study and gathered clinical feedback. The positive results demonstrate AView's potential clinical value on enhancing aneurysm treatment decision and treatment planning. PMID- 26101035 TI - siRNA Delivery Impedes the Temporal Expression of Cytokine-Activated VCAM1 on Endothelial Cells. AB - Leukocyte recruitment plays a key role in chronic inflammatory diseases such as cardiovascular disease, rheumatoid arthritis, and cancer. Leukocyte rolling and arrest are mediated in part by the temporally-regulated surface expression of vascular cell adhesion molecule-1 (VCAM1) on endothelial cells (ECs). In this paper, we engineered a pH-responsive vehicle comprised of 30 mol% dimethylaminoethyl methacrylate (30D) and 70 mol% hydroxyethyl methacrylate (70H) to encapsulate, protect, and deliver VCAM1 small interfering RNA (siRNA). The ability of siRNA to reduce VCAM1 gene expression is in direct opposition to its activation by cytokines. At 12 h post-activation, VCAM1 gene knockdown was 90.1 +/- 7.5% when delivered via 30D/70H nanoparticles, which was on par with a leading commercial transfection agent. This translated into a 68.8 +/- 6.7% reduction in the surface density of VCAM1 on cytokine-activated ECs. The pH responsive delivery of VCAM1 siRNA efficiently reduced temporal surface protein expression, which may be used to avert leukocyte recruitment. PMID- 26101036 TI - Computational Biomechanics in Thoracic Aortic Dissection: Today's Approaches and Tomorrow's Opportunities. AB - Dissection of an artery is characterised by the separation of the layers of the arterial wall causing blood to flow within the wall. The incidence rates of thoracic aortic dissection (AoD) are increasing, despite falls in virtually all other manifestations of cardiovascular disease, including abdominal aortic aneurysm (AAA). Dissections involving the ascending aorta (Type A) are a medical emergency and require urgent surgical repair. However, dissections of the descending aorta (Type B) are less lethal and require different clinical management whereby the patient may not be offered surgery unless complicating factors are present. But how do we tell if a patient will develop a complication later on? Currently, there is no consensus and the evidence base is limited. There is an opportunity for computational biomechanics to help clinicians decide as to which cases to repair and which to manage with blood pressure control. In this review article, we look at AoD from both the clinical and biomechanical perspective and discuss some of the recent computational studies of both Type A and B AoD. We then focus more on Type B where the real opportunity for patient specific modelling exists. Finally, we look ahead at some of the promising areas of research that may help clinicians improve the decision-making process surrounding Type B AoD. PMID- 26101037 TI - Photoinactivation of Photosystem II in wild-type and chlorophyll b-less barley leaves: which mechanism dominates depends on experimental circumstances. AB - Action spectra of photoinactivation of Photosystem II (PS II) in wild-type and chlorophyll b-less barley leaf segments were obtained. Photoinactivation of PS II was monitored by the delivery of electrons from PS II to PS I following single turnover flashes superimposed on continuous far-red light, the time course of photoinactivation yielding a rate coefficient k i. Susceptibility of PS II to photoinactivation was quantified as the ratio of k i to the moderate irradiance (I) of light at each selected wavelength. k i/I was very much higher in blue light than in red light. The experimental conditions permitted little excess light energy absorbed by chlorophyll (not utilized in photochemical conversion or dissipated in controlled photoprotection) that could lead to photoinactivation of PS II. Therefore, direct absorption of light by Mn in PS II, rather than by chlorophyll, was more likely to have initiated the much more severe photoinactivation in blue light than in red light. Mutant leaves were ca. 1.5 fold more susceptible to photoinactivation than the wild type. Neither the excess energy mechanism nor the Mn mechanism can explain this difference. Instead, the much lower chlorophyll content of mutant leaves could have exerted an exacerbating effect, possibly partly due to less mutual shading of chloroplasts in the mutant leaves. In general, which mechanism dominates depends on the experimental conditions. PMID- 26101039 TI - Total Synthesis and Structural Reassignment of Lyngbyaloside C Highlighted by Intermolecular Ketene Esterification. AB - Lyngbyaloside C, a classic macrolide, isolated from Lyngbya bouilloni, has shown moderate anticancer activity against several cancer cell lines. Here, we report the first total synthesis and stereochemical configuration reassignment of lyngbyaloside C. The synthesis highlights a one-pot intermolecular ketene esterification reaction to form the crucial tertiary ester and tetrahydropyran. In addition, a novel and concise synthetic pathway towards the 1,3-syn secondary, tertiary diol fragment is described using a regio- and stereospecific electrophilic ether transfer reaction. PMID- 26101038 TI - BEWARE: Body awareness training in the treatment of wearing-off related anxiety in patients with Parkinson's disease: study protocol for a randomized controlled trial. AB - BACKGROUND: The wearing-off phenomenon in patients with Parkinson's disease (PD) is a complication of prolonged levodopa usage. During this phenomenon, motor symptoms such as rigidity and freezing re-emerge. This is often accompanied by non-motor symptoms, including anxiety, the so-called wearing-off related anxiety (WRA). Current treatment options are limited and typically focus on either the physical or mental aspects of wearing-off. An integrated approach seems warranted in order to optimally address the complex reciprocal interactions between these aspects. Also, because wearing-off is eventually inescapable, treatment needs to focus on coping, acceptance, and self-efficacy. We therefore developed an integrated body awareness intervention, combining principles from physical therapy with acceptance and commitment therapy to teach patients to deal with WRA. This study will investigate whether this new intervention, named BEWARE, is more effective than treatment as usual in increasing self-efficacy. METHODS/DESIGN: This is a single-blinded randomized controlled trial in 36 PD patients who experience WRA. Subjects will be recruited from the outpatient clinic for movement disorders of the VU University Medical Center. After providing written informed consent, patients will be randomly assigned to an experimental (BEWARE) or treatment-as-usual (physical therapy) group. Clinical assessments will be performed prior to the intervention, directly after the 6 week intervention period, and at 3-month naturalistic follow-up by a blinded investigator not involved in the study. The primary outcome measure is self efficacy, and secondary outcomes focus on mobility, daily functioning, anxiety, and quality of life. DISCUSSION: Because wearing-off is an inevitable consequence of levodopa therapy and current treatment options are insufficient, a multidisciplinary intervention that addresses both physical and mental aspects of wearing-off in PD may foster additional benefits for treating WRA in PD patients over mono-disciplinary care alone. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02054845. Date of registration: 30 January 2014. PMID- 26101040 TI - Multi-metals Measured at Sediment-Water Interface (SWI) by Diffusive Gradients in Thin Films (DGT) Technique for Geochemical Research. AB - Diffusive gradients in thin films (DGT) technique was used to determine pore water profile and to assess remobilization character of metals at sediment/water interface. The remobilization of Mn was due to redox reaction in profile, which engendered two large peaks: one with DGT concentration of 1355 ug L(-1) at depth of -4.75 cm in sediment and the other with DGT concentration of 1040 ug L(-1) at depth of -3.25 cm in sediment pore water. Fe reduction zone had a large peak of Fe (3209 ug L(-1)) at depth of -4.75 cm in sediment. Fe DGT-profile also indicated the little peaks and low values of dissolved Fe concentration in Fe reduction/S-reduction boundary zone in sediment. Detailed correspondence of trace metals with Fe or Mn features in DGT-profiles suggested that their release is related to the reductive dissolution of Fe- or Mn-oxide. PMID- 26101041 TI - Comparative evaluation of cyclic fatigue resistance of D-RaCe and ProTaper retreatment instruments in curved artificial canals. AB - AIM: To compare the cyclic fatigue resistance of D-RaCe and ProTaper rotary nickel-titanium (NiTi) retreatment files when used in curved artificial canals. METHODOLOGY: A total of 120 new D-RaCe DR2 and ProTaper D3 retreatment files were tested in stainless steel artificial canals having 45 degrees and 60 degrees angles of curvature. Thirty instruments of each of the file systems were tested in both angles of curvature (n = 30). The retreatment instruments were rotated until fracture to calculate the number of cycles to failure. The length of each fractured fragment was recorded. Data were analysed by independent sample t-test. Fractured surfaces of the instruments were analysed by scanning electron microscopy. RESULTS: In the canal with 45 degrees angle of curvature, no significant difference was observed between the retreatment systems (P > 0.05); on the other hand, in the canal with 60 degrees angle of curvature, D-RaCe DR2 instruments had greater cyclic fatigue resistance than ProTaper D3 (P < 0.05). No difference was observed between the retreatment instruments regarding the lengths of fractured fragments (P > 0.05). The fracture surfaces of the instruments had morphologic characteristics of ductile fracture. CONCLUSIONS: D-RaCe DR2 instrument exhibited greater cyclic fatigue resistance than ProTaper D3 only in root canals with 60 degrees angle of curvature. PMID- 26101042 TI - The economics of tobacco control (Part 2): evidence from the ITC Project. PMID- 26101043 TI - Trends and socioeconomic differences in roll-your-own tobacco use: findings from the ITC Europe Surveys. AB - OBJECTIVES: To examine if exclusive Roll-Your-Own (RYO) tobacco use relative to factory-made (FM) cigarette use has been rising over time, to determine the extent to which economic motives and perceptions that RYO cigarettes are less harmful act as primary motivations for use, and to examine the association of income and education with the level of RYO tobacco use among smokers in four European countries. METHODS: Data were obtained from the International Tobacco Control (ITC) Europe Surveys, and a cohort sample of 7070 smokers from the Netherlands, Germany, France and UK were interviewed between June 2006 and December 2012. Generalised estimating equations (GEE) were used to assess trends in RYO use, and whether RYO consumption varied by socioeconomic variables. RESULTS: Exclusive RYO use over the study period has increased significantly in the UK from 26.4% in 2007 to 32.7% in 2010 (p<0.001); France from 12.2% in 2006 to 19.1% in 2012 (p<0.001); and Germany from 12.7% in 2007 to 18.6% in 2011 (p=0.031), with increased borderline significantly in the Netherlands (31.7% to 34.3%, p=0.052), from 2008 to 2010. Over three-quarters of users in each of the study countries indicated that lower price was a reason why they smoked RYO. Just over a fourth of smokers in the UK, less than a fifth in France, and around a tenth in Germany and the Netherlands believed that RYO is healthier. Compared with exclusive FM users, exclusive RYO users were more likely to have lower incomes and lower education. CONCLUSIONS: Effective tobacco tax regulation is needed in the European Union and elsewhere to eliminate or reduce the price advantage of RYO tobacco. Additional health messages are also required to correct the misperception that RYO tobacco is healthier than FM cigarettes. PMID- 26101044 TI - What cigarette price is required for smokers to attempt to quit smoking? Findings from the ITC Korea Waves 2 and 3 Survey. AB - OBJECTIVES: We assess the cigarette price that would motivate smokers to quit. We also explore the factors associated with the required price, including exposures to non-tax tobacco control policies. METHODS: Cross-sectional analysis was conducted on data from 1257 male smokers, who participated in either Wave 2 or 3 of the ITC Korea Survey. Information was obtained on what cigarette price per pack would make them try to quit ('price to quit'). Tobit regression on log transformed price and logistic regression on non-quitting were conducted to identify associated factors. RESULTS: The median price to quit was KRW5854 (US$5.31)/pack, given the current price of KRW2500 (US$2.27)/pack. Younger age, higher education, lack of concern about the health effects of smoking, lack of quit attempts and more cigarettes consumed per day were related to a higher price needed for a quit attempt. Exposures to combinations of non-tax policies were significantly associated with lower price levels to be motivated to quit. CONCLUSIONS: Considering the large price increase required for quit attempts, tax policy needs to be combined with other policies, particularly for certain groups, such as heavy smokers. Strengthening non-tax policies is likely to facilitate greater responsiveness to tax policy. PMID- 26101046 TI - BMA annual meeting: BMA will lobby government over purchaser-provider split. PMID- 26101047 TI - Increased Belching After Sleeve Gastrectomy. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) is considered to be an effective procedure for patients with morbid obesity. Belching is frequently reported after this procedure, but it has not been well studied in the bariatric population. This study aims to assess the changes in belching before and after sleeve gastrectomy, as measured with impedance monitoring. METHODS: In a prospective study, patients underwent 24-h pH-impedance monitoring before and 3 months after LSG. Using this technique, belches can be identified. Preoperative and postoperative upper gastrointestinal symptoms were assessed using the Reflux Disease Questionnaire (RDQ). RESULTS: Fifteen patients (1 M/14 F, mean age 42.2 +/- 11.0 years, mean weight 134.5 +/- 21.1 kg, mean BMI 46.4 +/- 6.0 kg/m(2)) participated in this study. Belching occurred significantly more often after LSG, with an increase in symptom score from 2.9 +/- 2.6 before to 5.3 +/- 3.5 3 months after LSG (p = 0.04). The total number of gastric belches increased from 29.7 +/- 11.7 before to 59.5 +/- 38.3/24 h 3 months after LSG (p = 0.03). The total number of supragastric belches did not change after LSG. The number of swallows decreased from 746.9 +/- 302.4 before to 555.7 +/- 172.5 3 months after the procedure (p = 0.03). The number of air swallows tended to decrease (p = 0.08). Esophageal acid exposure increased significantly, from 3.7 +/- 2.9 % before to 12.6 +/- 10.5 % after LSG (p = 0.01). CONCLUSION: Subjectively (as reported by patients) and objectively (as measured by impedance monitoring), an increase in gastric belches is seen after LSG, while the number of (air) swallows tends to decrease after the procedure and the incidence of supragastric belches remains constant. The altered anatomy as well as increased gastroesophageal reflux after LSG may play a role in the increase of belching. PMID- 26101048 TI - Analysis of Causes and Risk Factors for Hospital Readmission After Roux-en-Y Gastric Bypass. AB - BACKGROUND: Identification of causes and preventable triggers for hospital readmission after bariatric surgery is very important to implement strategies for surgical outcome optimization. The aim of the study was to analyze our readmissions after a Roux-en-Y gastric bypass (RYGB). PATIENTS AND METHODS: From our prospectively constructed database, patients who were readmitted to the hospital within the following 30 and 90 days after discharge were analyzed. Hospital charts were reviewed to determine the cause of readmission and the outcome. Potential risk factors for readmission were statistically analyzed. RESULTS: Between June 2004 and November 2013, 657 patients underwent a primary RYGB and 100 revisions. There were 442 (58%) females and 315 (42%) males with a mean age of 40.1 +/- 11.5 years and a mean BMI of 42.4 +/- 6.5 Kg/m(2). Comorbidities were present in 441 (58.2%) patients. Operations were completed laparoscopically in 741 (97.8%) patients. Mean hospital stay after the RYGB was 2.5 +/- 1.6 days. The 30-day and 90-day readmission rate was 2.6 and 4.58%, respectively. Most common causes for readmission at 30 days were gastrointestinal bleeding in 30%, lung disease in 15%, and food intolerance in 15%. At 90 days, they were stricture of the gastrojejunostomy in 20%, gastrointestinal bleeding in 13.3%, and nephrolithiasis in 13.3%. Open surgery and previous upper abdominal surgery were significant risk factors for 90-day readmission. CONCLUSION: Our readmission rate after RYGB was low. Most common causes for readmission were upper gastrointestinal bleeding and food intolerance. Associated risk factors were open surgery and previous upper abdominal surgery. PMID- 26101049 TI - Severe Intellectual Disability: Systematic Review of the Prevalence and Nature of Presentation of Unipolar Depression. AB - BACKGROUND: The diagnosis of depression in severe and profound intellectual disability is challenging. Without adequate skills in verbal self-expression, standardized diagnostic criteria cannot be used with confidence. The purpose of this systematic review was to investigate the assessment and diagnosis of unipolar depression in severe and profound intellectual disability. The review aimed to examine the methods used to assess for depression. The secondary aim was to explore the frequency and symptoms of depression. METHODS: The PRISMA (2009) Checklist for systematic review was followed, and a search of electronic databases was undertaken. Nine studies were included in the qualitative synthesis from over 2000 records identified. RESULTS: The quality of the studies was assessed and scored, with a wide range of results. Individual studies scored between 2 and 7 of a maximum possible score of 8. The diagnostic tools utilized by each of the studies were assessed and compared. CONCLUSIONS: In terms of the methods used to assess for depression, results were varied. This was due to the heterogeneous nature of the individual study designs. The Aberrant Behaviour Checklist consistently showed promise, in particular when combined with other instruments or clinical examination. Qualitative analysis of the selected studies has shown a wide variation in the quality of primary research in this field, with more required to make firm conclusions regarding the diagnosis, frequency and presentation of depression in severe and profound intellectual disability. PMID- 26101050 TI - Meta-analysis of the association of AhR Arg554Lys, AhRR Pro185Ala, and ARNT Val189Val polymorphisms and endometriosis risk in Asians. AB - PURPOSE: Several studies have suggested an association between the polymorphisms AhR Arg554Lys, AhRR Pro185Ala, and ARNT Val189Val and endometriosis, but results have been inconclusive. The aim of the present study was to assess these associations by meta-analysis. METHODS: Eligible literatures were retrieved from PubMed, ISI Web of Science, Elsevier Science Direct, and several Chinese databases. The pooled odds ratios (ORs) and the corresponding 95 % confidence intervals (CIs) were calculated with a random or fixed-effect model. RESULTS: A total of six eligible studies were included. Regarding the AhR Arg554Lys and ARNT Val189Val polymorphisms, no obvious associations were found in either overall analysis or subgroup analysis based on the country, source of control, sample size, and genotyping method. For the AhRR Pro185Ala polymorphism, overall results suggested a marginal association with endometriosis susceptibility under the dominant model (OR = 1.65, 95 % CI = 1.00-2.72). Furthermore, a significantly increased risk for endometriosis was found in the subgroups which used the TaqMan method for genotype analysis or had a sample size >=200. CONCLUSIONS: This meta analysis suggested that the polymorphisms of AhR Arg554Lys and ARNT Val189Val are not associated with endometriosis, while the AhRR Pro185Ala polymorphism may be associated with endometriosis risk. However, further case-control studies with larger sample sizes are needed to confirm our results. PMID- 26101051 TI - Spatial and temporal imaging of long-range charge transport in perovskite thin films by ultrafast microscopy. AB - Charge carrier diffusion coefficient and length are important physical parameters for semiconducting materials. Long-range carrier diffusion in perovskite thin films has led to remarkable solar cell efficiencies; however, spatial and temporal mechanisms of charge transport remain unclear. Here we present a direct measurement of carrier transport in space and in time by mapping carrier density with simultaneous ultrafast time resolution and ~50-nm spatial precision in perovskite thin films using transient absorption microscopy. These results directly visualize long-range carrier transport of ~220 nm in 2 ns for solution processed polycrystalline CH3NH3PbI3 thin films. Variations of the carrier diffusion coefficient at the MUm length scale have been observed with values ranging between 0.05 and 0.08 cm(2) s(-1). The spatially and temporally resolved measurements reported here underscore the importance of the local morphology and establish an important first step towards discerning the underlying transport properties of perovskite materials. PMID- 26101052 TI - Association between resting heart rate and cardiovascular risk factors in adolescents. AB - This cross-sectional study was performed in 2011 and included 4619 Brazilian adolescents (14-19 years old) to analyze the association between elevated resting heart rate (RHR) and cardiovascular risk factors in boys and girls. RHR and blood pressure were measured using an oscillometric monitor. Overweight was assessed by body mass index and abdominal obesity by waist circumference. Physical activity levels and sedentary behaviors were obtained using a questionnaire. The effect of clustering of cardiovascular risk factors on RHR was analyzed. For boys, abdominal obesity (b = 0.106, p = 0.003), high sedentary behavior (b = 0.099, b < 0.001), physical inactivity (b = 0.049, p = 0.034), and high blood pressure (b = 0.160, p < 0.001) were associated with RHR, whereas for girls, only high blood pressure was associated with RHR (b = 0.259, p < 0.001), after adjustment for age, period of the day, and other cardiovascular risk factors. Boys with five risk factors presented significantly higher (p < 0.05) RHR values (82.5 +/- 13.4 beats min(-1)) than those for boys without any cardiovascular risk factors (68.8 +/- 10.4 beats min(-1)). The girls with five risk factors presented a mean RHR value of 89.8 +/- 9.9 beats min(-1) that was higher (p < 0.05) than that for girls who had no risk factors (79.6 +/- 10.9 beats min(-1)). CONCLUSIONS: Our study demonstrated that while RHR was associated with cardiovascular risk factors in both sexes, the clustering of risk factors amplified the elevation of RHR in a gender-dependent fashion. WHAT IS KNOWN: * Resting heart rate is a marker of cardiovascular disease and mortality in adults and associated with risk factor such as higher levels of blood pressure, triglycerides, glucose, and obesity in children and adolescents. WHAT IS NEW: * The data from the current study suggest that the risk factor clustering is associated with elevated resting heart rate in adolescents and that the clustering of risk factors amplifies the elevation of resting heart rate in a gender-dependent fashion. PMID- 26101053 TI - Laparoscopic-assisted percutaneous endoscopic gastrostomy in two patients who failed percutaneous endoscopic gastrostomy. AB - INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is a common procedure to obtain a feeding tube. However, this technique might imply several difficulties and complications. The inability to transilluminate the abdominal wall may occur frequently, especially in obese or multi-operated patients. With the emergence of minimally invasive surgery, laparoscopic-assisted percutaneous endoscopic gastrostomy (LAPEG) might provide a safe and efficient alternative. PRESENTATION OF CASES: We report hereby two cases of patients having undergone LAPEG in our institution. Conventional PEGs were deemed impossible because of the absence of transillumination and motivated a surgical approach. Two obese patients with a Body Mass Index (BMI) of 31 and 45kg/m(2) respectively presented neurological condition (stroke and Parkinson's disease) requiring a feeding tube. While a PEG was unsuccessful (impossibility to transilluminate), a LAPEG was attempted. The procedure and the recovery were uneventful. DISCUSSION: There are different techniques for gastrostomy tube placement: open gastrostomy, PEG and radiologic procedure. The PEG is associated with a significant risk of bowel perforation. LAPEG seems to be an interesting option in order to avoid an open gastrostomy in patients in whom a PEG cannot be performed. This is especially true in obese patients, where a transillumination cannot be performed. It offers an endoscopic view of the stomach simultaneously to the laparoscopic approach that allows a potential decrease of major complications. CONCLUSION: While the literature reports mainly pediatric cases, we present herein two successful LAPEG in adult obese patients. In case of impossibility to perform PEG, this technique allows a safe direct visualization of the stomach and other adjacent organs. PMID- 26101054 TI - Mucoepidermoid carcinoma in a thyroglossal duct remnant. AB - INTRODUCTION: Thyroglossal duct cysts (TDC) are common midline neck swellings resulting from embryological remnants of the thyroglossal duct. They often contain ectopic thyroid tissue and malignant transformation has been reported, most commonly to papillary thyroid carcinoma. Mucoepidermoid carcinoma (MEC) usually occurs in the salivary glands and only rarely in the thyroid. This is the first case of a MEC occurring within a thyroglossal duct remnant. PRESENTATION OF A CASE: A 73 year old lady presented with a thyroglossal duct cyst. She declined surgical excision, as she was adamant she wanted to avoid surgery. The neck mass rapidly enlarged at two years following initial diagnosis. Fine needle aspiration cytology was suspicious for carcinoma. She underwent total thyroidectomy and selective central compartment neck dissection with adjuvant radiotherapy. She remains alive and well two years post treatment. DISCUSSION: Mucoepidermoid carcinoma is the most common malignant neoplasm of salivary glands, although it has rarely been reported in diverse locations including the thyroid, lung and pancreas. To the best of our knowledge, this is the first reported case of mucoepidermoid carcinoma arising from a thyroglossal duct remnant. CONCLUSION: This case adds weight to the literature favouring surgical excision of thyroglossal duct remnants due to the risk of malignant transformation. PMID- 26101056 TI - Facial nerve palsy, Kawasaki disease, and coronary artery aneurysm. AB - Kawasaki disease is rarely complicated by cranial nerve VII palsy. This report describes a 15-month-old female presenting with 3 days of fever, irritability, and rash who was subsequently diagnosed with Kawasaki disease and treated with intravenous immunoglobulin. She was found to have mild coronary artery ectasia and developed an acute, transient, left-sided facial palsy on the sixth day of illness. Repeat echocardiography demonstrated worsening aneurysm and intravenous methylprednisolone was added to her treatment regimen. At 1 and 3 months post discharge, echocardiography demonstrated resolution of her coronary aneurysm. This case makes 41 total described in the literature. Patients tend to be under 12-months-old and there is a higher association with coronary artery aneurysm in such patients compared to those without facial palsy who never even received treatment. Kawasaki disease associated with facial palsy may indicate increased inflammatory burden and patients may require additional anti-inflammatory agents and more vigilant echocardiography. PMID- 26101055 TI - The influence of task complexity on knee joint kinetics following ACL reconstruction. AB - BACKGROUND: Previous research indicates that subjects with anterior cruciate ligament reconstruction exhibit abnormal knee joint movement patterns during functional activities like walking. While the sagittal plane mechanics have been studied extensively, less is known about the secondary planes, specifically with regard to more demanding tasks. This study explored the influence of task complexity on functional joint mechanics in the context of graft-specific surgeries. METHODS: In 25 participants (10 hamstring tendon graft, 6 patellar tendon graft, 9 matched controls), three-dimensional joint torques were calculated using a standard inverse dynamics approach during level walking and stair descent. The stair descent task was separated into two functionally different sub-tasks-step-to-floor and step-to-step. The differences in external knee moment profiles were compared between groups; paired differences between the reconstructed and non-reconstructed knees were also assessed. FINDINGS: The reconstructed knees, irrespective of graft type, typically exhibited significantly lower peak knee flexion moments compared to control knees during stair descent, with the differences more pronounced in the step-to-step task. Frontal plane adduction torque deficits were graft specific and limited to the hamstring tendon knees during the step-to-step task. Internal rotation torque deficits were also primarily limited to the hamstring tendon graft group during stair descent. Collectively, these results suggest that task complexity was a primary driver of differences in joint mechanics between anterior cruciate ligament reconstructed individuals and controls, and such differences were more pronounced in individuals with hamstring tendon grafts. INTERPRETATION: The mechanical environment experienced in the cartilage during repetitive, cyclical tasks such as walking and other activities of daily living has been argued to contribute to the development of degenerative changes to the joint and ultimately osteoarthritis. Given the task-specific and graft-specific differences in joint mechanics detected in this study, care should be taken during the rehabilitation process to mitigate these changes. PMID- 26101057 TI - Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure. AB - The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long-term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization was also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals were observed for the 2.5 and 10.0mg/kg MPD exposed groups. For 2.5mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and oppositely at ED10 MPD rechallenge. While the behaviorally sensitized animals in general increased in their percentage change of firing rats were observed following acute 10.0mg/kg MPD and the behaviorally sensitized 10.0mg/kg MPD animals and a robust increase in neuronal firing rates at ED1 and ED10 rechallenge. These results suggest the need to first individually analyze animal behavioral activity, and then to evaluate the neuronal responses to the drug based on the animals behavioral response to chronic MPD exposure. PMID- 26101058 TI - Testing predator-prey theory using broad-scale manipulations and independent validation. AB - A robust test of ecological theory is to gauge the predictive accuracy of general relationships parameterized from multiple systems but applied to a new area. To address this goal, we used an ecosystem-level experiment to test predator-prey theory by manipulating prey abundance to determine whether predation was density dependent, density independent, compensatory or depensatory (inversely density dependent) on prey populations. Understanding the nature of predation is of primary importance in community ecology because it establishes whether predation has little effect on prey abundance (compensatory), whether it promotes coexistence (density dependent) and reduces the equilibrium of prey (density independent) or whether it can be destabilizing (depensatory). We used theoretical predictions consisting of functional and numerical equations parameterized independently from meta-analyses on wolves (Canis lupus) and moose (Alces alces), but applied to our specific wolf-moose system. Predictions were tested by experimentally reducing moose abundance across 6500 km(2) as a novel way of evaluating the nature of predation. Depensatory predation of wolves on moose was the best explanation of the population dynamic - a mechanism that has been hypothesized to occur but has rarely been evaluated. Adding locally obtained kill rates and numerical estimates to the independent data provided no benefit to model predictions, suggesting that the theory was robust to local variation. These findings have critical implications for any organism that is preyed upon but that also has, or will be, subject to increased human exploitation or perturbations from environmental change. If depensatory predation is not accounted for in harvest models, predicted yields will be excessive and lead to further population decline. PMID- 26101059 TI - Sustained wash-resistant receptor activation responses of GPR119 agonists. AB - G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses. PMID- 26101060 TI - Screening of central functions of amino acids and their metabolites for sedative and hypnotic effects using chick models. AB - The chick has a practical advantage in the screening process in that chicks require only small quantities of drugs. The chick separation stress paradigm has traditionally been recognized as a valid form of anxiolytic screening. Further, chick behavior involving standing motionless with eyes closed or sitting motionless with head drooped is nearly always associated with electrophysiological sleep. When centrally administered, some DNA-encoded L-alpha amino acids, as well as some DNA-non-encoded amino acids, such as metabolites of L-alpha-amino acids, D-amino acid and beta-amino acid, have shown sedative and/or hypnotic effects in chicks. The effects of some of these amino acids have subsequently been confirmed in humans. In conclusion, the chick model is convenient and useful for screening central functions of amino acids and their metabolites for hypnosis and sedation. PMID- 26101061 TI - Carbon monoxide-releasing molecule-3 suppresses Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-1beta in murine macrophages. AB - This study was performed to analyze the effect of carbon monoxide (CO)-releasing molecule-3 (CORM-3) in alleviating the production of proinflammatory mediators in macrophages treated with lipopolysaccharide (LPS) from Prevotella intermedia, a pathogen associated with periodontal disease, and its possible mechanisms of action. LPS was isolated using the hot phenol-water method. Culture supernatants were assayed for nitric oxide (NO) and interleukin-1beta (IL-1beta). Gene expression was quantified by real-time PCR, and protein expression by immunoblotting. DNA-binding activities of NF-kappaB subunits were determined using an ELISA-based kit. CORM-3 suppressed the production of inducible NO synthase (iNOS)-derived NO and IL-1beta at both gene transcription and translation levels in P. intermedia LPS-activated RAW264.7 cells. CORM-3 enhanced heme oxygenase-1 (HO-1) expression in cells stimulated with P. intermedia LPS, and inhibition of HO-1 activity by SnPP notably reversed the suppressive effect of CORM-3 on LPS-induced production of NO. LPS-induced phosphorylation of p38 and JNK was not affected by CORM-3. CORM-3 did not influence P. intermedia LPS induced degradation of IkappaB-alpha. Instead, nuclear translocation of NF-kappaB p65 and p50 subunits was blocked by CORM-3 in LPS-treated cells. In addition, CORM-3 reduced LPS-induced p65 and p50 binding to DNA. Besides, CORM-3 significantly suppressed P. intermedia LPS-induced phosphorylation of STAT1. Overall, this study indicates that CORM-3 suppresses the production of NO and IL 1beta in P. intermedia LPS-activated murine macrophages via HO-1 induction and inhibition of NF-kappaB and STAT1 pathways. The modulation of host inflammatory response by CORM-3 would be an attractive therapeutic approach to attenuate the progression of periodontal disease. PMID- 26101062 TI - 6-Shogaol induces cell cycle arrest and apoptosis in human hepatoma cells through pleiotropic mechanisms. AB - Shogaols are a group of the active constituents of ginger that have been identified to have various biological activities. The aim of the current study was to investigate the antitumor activity of 6-shogaol in hepatocellular carcinoma (HCC) and the possible involvement of reactive oxygen species as a putative mechanism of action. HCC cell lines, HepG2 and Huh-7, were used to study the in vitro anti-cancer activity of 6-shogaol via the application of various molecular biology techniques. Results showed that 6-shogaol effectively inhibited the cell viability, caused cell cycle arrest at G2/M phase and induced apoptosis in HCC cells as indicated by MTT assay, DAPI nuclear staining, annexin V assay, cell cycle analysis, and activation of caspase-3. Western blot analysis revealed the ability of 6-shogaol to target cancer survival signaling pathways mediated by mitogen-activated protein kinase (MAPK), 5' AMP-activated protein kinase (AMPK) and Akt. In addition, 6-Shogaol induced alteration of cyclin proteins expression and caused cleavage of protein kinase C delta. Furthermore, 6-Shogaol was able to induce the production of reactive oxygen species and endoplasmic reticulum (ER) stress-associated proteins and the consequent activation of autophagy in HepG2 cells. Taken together, the current study highlights evidences that 6-shogaol induces apoptosis, modulates cyclins expression and targets cancer survival signaling pathways in HCC cell lines, at least in part, via the production of reactive oxygen species. These findings support 6-shogaol's clinical promise as a potential candidate for HCC therapy. PMID- 26101064 TI - Elevated level of nitric oxide mediates the anti-depressant effect of rubidium chloride in mice. AB - Rubidium has been used to treat psychiatric conditions including depression. We examined the antidepressant activity of rubidium chloride (RbCl) in male mice and the possible interference of nitric oxide (NO) in this effect. Mouse forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant-like effect of RbCl. These drugs were used in this study: N(G)-l arginine methyl ester (l-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, 7-Nitroindazole and aminoguanidine, selective neuronal and inducible NOS inhibitors, respectively, and l-arginine, an NO precursor. We studied the changes of serum and hippocampus nitrite level after different treatments. RbCl (30mg/kg), when administered 60min before the tests, significantly reduced the immobility time. Non-effective doses of l-NAME (10mg/kg) and aminoguanidine (50mg/kg), co-administered with the effective dose of RbCl (30mg/kg), reversed the anti-immobility effect of RbCl, while 7-NI (25mg/kg) could not prevent the diminishing effect of RbCl on immobility time. Moreover, co-administration of non effective doses of l-arginine (750mg/kg) and RbCl (10mg/kg) decreased the immobility time. None of the mentioned treatments altered the locomotor activity of mice in open-field test. Nitrite level was significantly increased in serum and hippocampus of animals after RbCl (30mg/kg) administration and this nitrite level elevation was reversed by non-effective dose of l-NAME and aminoguanidine, but not 7-NI. Our data for the first time reveal the role of NO pathway in the antidepressant-like activity of RbCl, concluding that this effect results from elevation of NO through involvement of iNOS in mice. PMID- 26101063 TI - Fisetin regulates TPA-induced breast cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways. AB - Invasion and metastasis are among the main causes of death in patients with malignant tumors. Fisetin (3,3',4',7-tetrahydroxyflavone), a natural flavonoid found in the smoke tree (Cotinus coggygria), is known to have antimetastatic effects on prostate and lung cancers; however, the effect of fisetin on breast cancer metastasis is unknown. The aim of this study was to determine the anti invasive activity of fisetin in human breast cancer cells. Matrix metalloproteinase (MMP)-9 is a major component facilitating the invasion of many cancer tumor cell types, and thus the inhibitory effect of fisetin on MMP-9 expression in 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated human breast cancer cells was investigated in this study. Fisetin significantly attenuated TPA induced cell invasion in MCF-7 human breast cancer cells, and was found to inhibit the activation of the PKCalpha/ROS/ERK1/2 and p38 MAPK signaling pathways. This effect was furthermore associated with reduced NF-kappaB activation, suggesting that the anti-invasive effect of fisetin on MCF-7 cells may result from inhibited TPA activation of NF-kappaB and reduced TPA activation of PKCalpha/ROS/ERK1/2 and p38 MAPK signals, ultimately leading to the downregulation of MMP-9 expression. Our findings indicate the role of fisetin in MCF-7 cell invasion, and clarify the underlying molecular mechanisms of this role, suggesting fisetin as a potential chemopreventive agent for breast cancer metastasis. PMID- 26101065 TI - Midkine proteins in cardio-vascular disease. Where do we come from and where are we heading to? AB - Midkine is a recently identified new growth factor/cytokine with pleiotropic functions in the human organism. First discovered in the late eighties, midkines have now become the subject of numerous studies in cardiovascular, neurologic, renal diseases and also various types of cancers. We summarize here the most important functions of midkine in cardiovascular diseases, emphasizing its role in inflammation and its antiapoptotic and proangiogenetic effects. Midkine has multiple roles in the organism, with the specific feature of being either beneficial or harmful depending on which tissue it acts on. Even though midkine has been shown to have cardiac protective effects against acute ischemia/reperfusion injury and to inhibit cardiac remodeling, it also promotes intimal hyperplasia and vascular stenosis. As such, different therapeutic strategies are currently being evaluated, consisting of administering either midkine proteins or midkine inhibitors depending on the desired outcome. More data is gathering to suggest that these novel therapies could become an adjunctive to standard cardiovascular therapy. Nonetheless, much is still to be learned about midkine. The encouraging results up till now require further studying in order to fully understand the complete profile of its mechanism of action and the clinical safety and efficacy of novel therapeutic opportunities offered by midkine molecular targeting. PMID- 26101066 TI - Contrasting cardiovascular properties of the u-opioid agonists morphine and methadone in the rat. AB - Morphine and methadone share the property of MU-opioid receptor agonism yet have markedly different cardiovascular actions suggesting additional properties are at play. We investigated the i.v. dose-response relationships of the opioids on cardiovascular metameters in anaesthetised rats in the absence or presence of H1- and H2-receptor antagonism and the MU-opioid antagonist naloxone. In vitro tissue assays were employed to define more clearly cardiac and vascular mechanisms of action. Morphine (9, 30, 90mg/kg i.v.) decreased heart rate (HR) and mean arterial pressure (MAP) - responses that were blocked by naloxone pretreatment (10mg/kg i.v.). In contrast, methadone (3, 10, 30mg/kg i.v.) caused dramatic short-lived (1-3min) bradycardia, hypotension and lengthening of the QT interval before stabilising 5min after i.v. dosing. Only the steady-state responses of HR and MAP were blocked by naloxone. Mepyramine (10mg/kg i.v.) and cimetidine (100mg/kg i.v.) also blocked the naloxone-sensitive components. In isolated small mesenteric arteries precontracted by K(+) 62mM or endothelin-1, methadone (1 30MUM) relaxed vessels while morphine (1-100MUM) had no effect. Pretreatment with naloxone (10MUM), indomethacin (30MUM) or nitro-l-arginine (100MUM) did not affect the relaxation to methadone. In rat isolated left atria, morphine and methadone inhibited inotropic responses at high concentrations (100MUM). In rat papillary muscle and right atria, methadone was more than 30 times more potent at lengthening the refractory period and slowing the atrial rate than morphine. We conclude that methadone is a potent vasodilator agent, possibly through blocking L-type calcium channels. PMID- 26101067 TI - Galectin-3 and post-myocardial infarction cardiac remodeling. AB - This review summarizes the current literature regarding the involvement and the putative role(s) of galectin-3 in post-myocardial infarction cardiac remodeling. Post-myocardial infarction remodeling is characterized by acute loss of myocardium, which leads to structural and biomechanical changes in order to preserve cardiac function. A hallmark herein is fibrosis formation, both in the early and late phase following acute myocardial infarction. Galectin-3, a beta galactoside-binding lectin, which is a shared factor in fibrosis formation in multiple organs, has an established role in cardiac fibrosis in the setting of pressure overload, neuro-endocrine activation and hypertension, but its role in post- myocardial infarction remodeling has received less attention. However, accumulative experimental studies have shown that myocardial galectin-3 expression is upregulated after myocardial infarction, both on mRNA and protein level. This already occurs shortly after myocardial infarction in the infarcted and border zone area, and also at a later stage in the spared myocardium, contributing to tissue repair and fibrosis. This is associated with typical aspects of fibrosis formation, such as apposition of matricellular proteins and increased factors of collagen turnover. Interestingly, myocardial fibrosis in experimental post-myocardial infarction cardiac remodeling could be attenuated by galectin-3 inhibition. In clinical studies, circulating galectin-3 levels have been shown to identify patients at risk for new-onset heart failure and atrial fibrillation. Circulating galectin-3 levels also predict progressive left ventricular dilatation after myocardial infarction. From literature we conclude that galectin-3 is an active player in cardiac remodeling after myocardial infarction. Future studies should focus on the dynamics of galectin-3 activation after myocardial infarction, and study the possibilities to target galectin-3. PMID- 26101068 TI - TRAM-Derived Decoy Peptides inhibits the inflammatory response in mouse mammary epithelial cells and a mastitis model in mice. AB - It has been proved that TRAM-Derived Decoy peptides have anti-inflammatory properties. In this study, we synthesized a TRAM-Derived decoy peptide (TM6), belongs to TRAM TIR domain, of which sequence is "N"-RQIKIWFQNRRMKWK, KENFLRDTWCNFQFY-"C" and evaluated the effects of TM6 on lipopolysaccharide induced mastitis in mice. In vivo, LPS-induced mice mastitis model was established by injection of LPS through the duct of mammary gland. TM6 was injected 1h before or after LPS treatment. In vitro, primary mouse mammary epithelial cells were used to investigate the effects of TM6 on LPS-induced inflammatory responses. The results showed that TM6 inhibited LPS-induced mammary gland histopathologic changes, MPO activity, and TNF-alpha, IL-1beta and IL-6 production in mice. In vitro, TM6 significantly inhibited LPS-induced TNF-alpha and IL-6 production, as well as NF-kappaB and MAPKs activation. In conclusion, this study demonstrated that TM6 had protective effects on LPS-mastitis and may be a promising therapeutic reagent for mastitis treatment. PMID- 26101069 TI - Amitifadine, a triple monoamine re-uptake inhibitor, reduces nicotine self administration in female rats. AB - A wider diversity of drug treatments to aid smoking cessation is needed to help tailor the most efficacious treatment for different types of smokers. This study was conducted to determine whether amitifadine, which inhibits re-uptake of dopamine, norepinephrine and serotonin, would decrease nicotine self administration at doses that do not cause adverse side effects. Adult female Sprague-Dawley rats were trained to self-administer nicotine intravenous (IV) and were given acute doses of amitifadine in a repeated measures counterbalanced design. Effects of amitifadine on locomotor activity and food motivated responding were also evaluated. Chronic amitifadine effects were also examined. The 30 mg/kg amitifadine dose significantly reduced nicotine self-administration. The 5 and 10 mg/kg doses reduced nicotine self-administration during the first 15 min of the session when the greatest amount of nicotine was self-administered. The 30 mg/kg amitifadine dose, but not the lower doses caused a significant reduction in locomotor activity averaged over the one-hour session and reduced food motivated responding. The 10 mg/kg dose caused hypoactivity at the beginning of the session, but 5 mg/kg did not cause any hypoactivity. The effects of chronic amitifadine treatment (10 mg/kg) over the course of 15 sessions was also determined. Amitifadine caused a significant reduction in nicotine self administration, which was not seen to diminish over two consecutive weeks of treatment and a week after enforced abstinence. Amitifadine significantly reduced nicotine self-administration. This prompts further research to determine if amitifadine might be an effective treatment for smoking cessation. PMID- 26101071 TI - Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis. PMID- 26101070 TI - Deferoxamine modulates cytokines and growth factors to accelerate cutaneous wound healing in diabetic rats. AB - Deferoxamine has shown cutaneous wound healing potential by increased neovascularization. We hypothesized that topically applied deferoxamine facilitates wound healing in diabetic rats by modulating important cytokines and growth factors that take part in healing processes in a time-dependent manner. Diabetes was induced in male Wistar rats by streptozotocin and wound was created under pentobarbitone anesthesia. The diabetic rats were divided into two groups, of which one (control) was treated with ointment base and other with deferoxamine ointment (0.1%). Wound closure measurement and tissue collection were done on days 3, 7, 14 and 19 post-wounding. The relative expressions of hypoxia-inducible factor 1-alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), stromal cell-derived factor 1-alpha (SDF-1alpha), transforming growth factor beta 1 (TGF beta1), tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP 9), interleukin-1 beta (IL-1beta) and interleukin-10 (IL-10) mRNA and proteins were determined in the wound tissues. CD-31 staining and collagen content were evaluated by immunohistochemistry and picrosirius red staining, respectively. Histological changes were assessed by H&E staining. The per cent wound closure was significantly higher from day 7 onwards in deferoxamine-treated rats. HIF 1alpha, VEGF, SDF-1alpha, TGF-beta1, IL-10 mRNA and their protein levels were significantly higher on days 3, 7 and 14 in deferoxamine-treated rats. The mRNA expression and protein levels of TNF-alpha, MMP-9 and IL-1beta were progressively and markedly reduced in deferoxamine-treated rats. The collagen deposition and formation of blood vessels were greater in deferoxamine-treated rats. It is suggested that topical application of deferoxamine ointment might be useful in cutaneous wound healing in diabetic patients. PMID- 26101073 TI - Nerve Gap Reconstruction. PMID- 26101074 TI - Antibiotic Prescribing Habits of Oral and Maxillofacial Surgeons in Conjunction With Routine Dental Implant Placement. AB - PURPOSE: Although various prophylactic systemic antibiotic regimens have been suggested to minimize failure after dental implant placement, the role of antibiotics in implant dentistry is still controversial. The purpose of the present survey was to determine the current antibiotic prescribing habits of oral and maxillofacial surgeons in conjunction with routine dental implant placement to determine whether any consensus has been reached among such practitioners. MATERIALS AND METHODS: An electronic survey was sent by electronic mail to all members of the American College of Oral and Maxillofacial Surgeons. The questions asked were related to whether antibiotics were routinely prescribed either pre- or postoperatively during routine dental implant placement, and, if so, what antibiotics, dosage, frequency, and duration were used. The survey participants were also asked to specify whether they were in solo private practice, group private practice, academia, military, or "other." The results were tabulated and analyzed using SAS software. Descriptive statistics and chi(2) analyses were used. RESULTS: A total of 217 members responded to the survey. Overall, 112 of 217 (51.6%) prescribed antibiotics preoperatively (95% confidence interval [CI] 50.0 to 58.2%) and 152 of 213 (71.4%) prescribed antibiotics postoperatively (95% CI 65.0 to 77.0%) during routine dental implant placement. Also, 72 (34%) indicated that they prescribed antibiotics both pre- and postoperatively. The most common preoperative regimen used was amoxicillin 2 g given 1 hour before the procedure (32%, n = 36). The most common postoperative regimen used was amoxicillin 500 mg 3 times daily for 5 days (53%, n = 81). CONCLUSIONS: We found no consensus among oral and maxillofacial surgeons regarding the use of antibiotics in association with routine dental implant placement, the type of regimen to use, or whether such use is even effective in preventing early implant loss. Furthermore, most of the antibiotic regimens being used are not in accordance with the recommendations current in the published data. PMID- 26101072 TI - Regional beta-amyloid burden does not correlate with cognitive or language deficits in Alzheimer's disease presenting as aphasia. AB - BACKGROUND AND PURPOSE: A subset of patients with Alzheimer's disease (AD) present with early and prominent language impairment (aphasic AD). Our previous study demonstrated an association between global beta-amyloid burden measured on [(11)C] Pittsburgh compound B (PiB) positron emission tomography and general cognitive impairment, but not with aphasia, in such subjects. As a follow-up, whether there is any association between regional beta-amyloid burden, atrophy on magnetic resonance imaging (MRI) and global cognitive impairment, aphasia or other cognitive and functional impairment in aphasic AD is assessed. METHODS: Forty-four aphasic AD subjects who underwent PiB scanning and volumetric MRI and were determined to be positive for beta-amyloid deposition were analyzed. All had completed detailed neurological, neuropsychological and language batteries. Spearman's rank-order correlation was utilized to assess for associations. RESULTS: Greater visuospatial impairment was associated with increased beta amyloid burden in the primary visual cortex (P = 0.001). Although there were many trends for associations between neurocognitive and language deficits and regional beta-amyloid burden, there were no strong associations that survived correction for multiple comparisons. However, neurocognitive and language impairment in these subjects strongly correlated with the degree of left lateral temporal and inferior parietal atrophy (P < 0.004). CONCLUSIONS: The findings from this study suggest a close relation between the severity of regional atrophy and cognitive and language impairment, but argue against a strong association between regional beta-amyloid burden and such deficits in aphasic AD subjects. Hence, other pathological factors may be driving the previously identified association between global beta-amyloid deposition and general cognitive impairment in aphasic AD. PMID- 26101075 TI - STAM2, a member of the endosome-associated complex ESCRT-0 is highly expressed in neurons. AB - STAM2 (signal transducing adaptor molecule 2), a subunit of the ESCRT-0 complex, is an endosomal protein acting as a regulator of receptor signaling and trafficking. To analyze STAM2 in the nervous system, its gene expression and protein localization in the mouse brain were identified using three methods: mRNA in situ hybridization, immunohistochemistry, and via lacZ reporter in frame with Stam2 gene using the gene trap mouse line Stam2(Gt1Gaj). STAM2 intracellular localization was analyzed by subcellular fractionation and co-immunofluorescence using confocal microscopy. Stam2 was strongly expressed in the cerebral and cerebellar cortex, hippocampal formation, olfactory bulb, and medial habenula. The majority of STAM2-positive cells co-stained with the neuronal markers. In neurons STAM2 was found in the early endosomes and also in the nucleus. The other members of the ESCRT-0 complex co-localized with STAM2 in the cytoplasm, but they were not present in the nucleus. The newly identified neuron-specific nuclear localization of STAM2, together with its high expression in the brain indicated that STAM2 might have a specific function in the mouse nervous system. PMID- 26101076 TI - Anaemia prevalence may be reduced among countries that fortify flour. AB - The effectiveness of flour fortification in reducing anaemia prevalence is equivocal. The goal was to utilise the existing national-level data to assess whether anaemia in non-pregnant women was reduced after countries began fortifying wheat flour, alone or in combination with maize flour, with at least Fe, folic acid, vitamin A or vitamin B12. Nationally representative anaemia data were identified through Demographic and Health Survey reports, the WHO Vitamin and Mineral Nutrition Information System database and other national-level nutrition surveys. Countries with at least two anaemia surveys were considered for inclusion. Within countries, surveys were excluded if altitude was not consistently adjusted for, or if the blood-draw site (e.g. capillary or venous) or Hb quantification method (e.g. HemoCue or Cyanmethaemoglobin) differed. Anaemia prevalence was modelled for countries that had pre- and post fortification data (n 12) and for countries that never fortified flour (n 20) using logistic regression models that controlled for time effects, human development index (HDI) and endemic malaria. After adjusting for HDI and malaria, each year of fortification was associated with a 2.4% reduction in the odds of anaemia prevalence (PR 0.976, 95% CI 0.975, 0.978). Among countries that never fortified, no reduction in the odds of anaemia prevalence over time was observed (PR 0.999, 95% CI 0.997, 1.002). Among both fortification and non-fortification countries, HDI and malaria were significantly associated with anaemia (P,0.001). Although this type of evidence precludes a definitive conclusion, results suggest that after controlling for time effects, HDI and endemic malaria, anaemia prevalence has decreased significantly in countries that fortify flour with micronutrients, while remaining unchanged in countries that do not. PMID- 26101077 TI - Association of exposure to neighborhood drug activity, neurobehavioral traits, and marijuana use among at-risk African American females. AB - INTRODUCTION: Theories of relative deprivation suggest African Americans in disadvantaged communities are at increased risk for drug use. This increased risk may be due, in part, to exposure to drugs and drug subcultures. Given the significance of the prefrontal cortex (PFC) functioning in yielding behavior that is strategically guided rather than reactive to environmental demands, it is important to examine the relationship between PFC functioning, neighborhood drug activity and substance use among African Americans residing in high risk communities. METHODS: A sample of 120 young adult African American females was recruited from high-risk neighborhoods. Each completed the modified version of the neighborhood environment scale, a neurobehavioral assessment designed to measure apathy, behavioral disinhibition and executive dysfunction, and provided a urine sample that was tested for the presence of psychoactive drugs. RESULTS: Logistic regression analyses indicated that females with higher scores on behavioral disinhibition were 2.6 times more likely to test positive for marijuana (95%CI = 1.02, 6.57). Neither apathy nor executive dysfunction was related to marijuana use. No relationship emerged between neighborhood drug activity and marijuana use. CONCLUSIONS: Among the neurobehavioral traits considered only behavioral disinhibition was associated with marijuana use, suggesting that different neurobehavioral domains may be uniquely related to marijuana use. For females living in high risk environments, the extent to which they are able to control impulses may provide some protection against marijuana use. Future studies focused on the moderating effects of behavioral disinhibition on the association of exposure to risk environments and marijuana use may prove beneficial. Further, the study adds to the small base of literature supporting the Frontal Systems Behavior Scale as a brief assessment to evaluate frontally mediated neurobehavioral traits relevant to substance use. However, future studies aimed at examining the influence of neighborhood drug activity might benefit from more precise measures of exposure to neighborhood drug activity. More research to replicate and expand on the present findings is warranted. PMID- 26101078 TI - Drinking patterns of alcohol intoxicated adolescents in the emergency department: A latent class analysis. AB - INTRODUCTION: The increasing number of children and adolescents in need of emergency medical treatment following acute alcohol intoxication has been a major public health concern in Europe in recent years. However, little is known about drinking habits and associated risks in this population. To our knowledge, this is the first study to examine drinking patterns and associated risks in adolescent emergency department patients following alcohol intoxication. The aim of this study is to establish a classification system for admitted adolescents METHODS: Latent class analysis was used to identify subgroups of adolescents with distinct patterns of habitual drinking as defined by the quantity of consumed alcohol on a typical drinking occasion, frequency of binge drinking and drunkenness, alcohol-related problems, prior alcohol-related hospitalizations and alcohol-related risk behaviors. Subgroup characteristics were examined with regard to sociodemographics, other substance use and psychosocial problems using analysis of variance (ANOVA) and chi-square tests. RESULTS: A total of 316 adolescents aged 12-17 treated in 6 urban emergency departments in Germany were analyzed. Five classes of drinking patterns were identified: one class representing low-risk drinking (class 1 "low-risk" (61.2%)), two classes representing risky drinking (class 2 "moderate-risk" (5.7%) and class 3 "frequent drunk" (15.8%)), as well as two classes representing high-risk drinking (class 4 "alcohol-related problems" (11.4%) and class 5 "excessive drinking" (5.1%)). Membership of classes 4 and 5 was associated with the most severe psychosocial problems, especially with regard to aggressive-dissocial behaviors. The CRAFFT-d and brief RAPI screening tools allowed identifying the two risky drinking classes and two high-risk drinking classes. CONCLUSIONS: Our findings provide the first in-depth analysis of habitual drinking in this study population and may help practitioners to better tailor interventions to patients' needs by using the identified classes as a form of classification system for admitted adolescents. PMID- 26101079 TI - Emotional reactions to alcohol-related words: Differences between low- and high risk drinkers. AB - INTRODUCTION: Research that has examined responses to alcohol-related words in drinkers has mostly linked such responses to memory, attentional, and perceptual bias. However, studies of emotional processing in alcoholics have not received much attention. The main goal of the present study was to identify the features and differences of emotional responses to alcohol-related words in low- and high risk drinkers. METHOD: A total of 149 low-risk drinkers and 125 high-risk drinkers evaluated five alcohol-related words and 15 words from the Affective Norms for English Words in the dimensions of valence, arousal, and dominance using the Self-Assessment Manikin. RESULTS: The results indicated that high-risk drinkers evaluated alcohol-related words as more appetitive and arousing. CONCLUSION: These results, together with findings in the attention and memory research literature, suggest that alcohol-related words can serve as conditioned cues in alcohol consumption. PMID- 26101080 TI - The evolution of Campylobacter jejuni and Campylobacter coli. AB - The global significance of Campylobacter jejuni and Campylobacter coli as gastrointestinal human pathogens has motivated numerous studies to characterize their population biology and evolution. These bacteria are a common component of the intestinal microbiota of numerous bird and mammal species and cause disease in humans, typically via consumption of contaminated meat products, especially poultry meat. Sequence-based molecular typing methods, such as multilocus sequence typing (MLST) and whole genome sequencing (WGS), have been instructive for understanding the epidemiology and evolution of these bacteria and how phenotypic variation relates to the high degree of genetic structuring in C. coli and C. jejuni populations. Here, we describe aspects of the relatively short history of coevolution between humans and pathogenic Campylobacter, by reviewing research investigating how mutation and lateral or horizontal gene transfer (LGT or HGT, respectively) interact to create the observed population structure. These genetic changes occur in a complex fitness landscape with divergent ecologies, including multiple host species, which can lead to rapid adaptation, for example, through frame-shift mutations that alter gene expression or the acquisition of novel genetic elements by HGT. Recombination is a particularly strong evolutionary force in Campylobacter, leading to the emergence of new lineages and even large-scale genome-wide interspecies introgression between C. jejuni and C. coli. The increasing availability of large genome datasets is enhancing understanding of Campylobacter evolution through the application of methods, such as genome-wide association studies, but MLST-derived clonal complex designations remain a useful method for describing population structure. PMID- 26101081 TI - Oligodendrocytes: Myelination and Axonal Support. AB - Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons. PMID- 26101082 TI - A case report of avian influenza H7N9 killing a young doctor in Shanghai, China. AB - BACKGROUND: The novel avian influenza H7N9 virus has caused severe diseases in humans in eastern China since the spring of 2013. On January 18(th) 2014, a doctor working in the emergency department of a hospital in Shanghai died of H7N9 virus infection. To understand possible reasons to explain this world's first fatal H7N9 case of a health care worker (HCW), we summarize the clinical presentation, epidemiological investigations, laboratory results, and prevention and control policies and make important recommendations to hospital-related workers. CASE PRESENTATION: The patient was a 31-year-old male Chinese surgeon who was obese and had a five-year history of hypertension and suspected diabetes. On January 11(th) 2014, he showed symptoms of an influenza-like illness. Four days later, his illness rapidly progressed with bilateral pulmonary infiltration, hypoxia and lymphopenia. On January 17th, the case had a high fever, productive cough, chest tightness and shortness of breath, so that he was administered with oseltamivir, glucocorticoid, immunoglobulin, and broad-spectrum antibiotic therapy. The case died in the early morning of next day after invasive ventilation. He had no contact with poultry nor had he visited live-poultry markets (LPMs), where positive rates of H7N9 were 14.6 % and 18.5 %. Before his illness, he cared for three febrile patients and had indirect contact with one severe pneumonia patient. Follow-up with 35 close contacts identified two HCWs who had worked also in emergency department but had not worn masks were anti-H7N9 positive. Viral sequence identity percentages between the patient and two LPM H7N9 isolates were fewer than between the patient and another human case in shanghai in January of 2014. CONCLUSIONS: Important reasons for the patient's death might include late treatment with oseltamivir, and the infected H7N9 virus carrying both mammalian-adapted signature (HA-Q226L) and aerosol transmissibility (PB2-D701N). The LPM he passed every day was an unlikely source of his infection, but a contaminated environment, or an unidentified mild/asymptomatic H7N9 carrier were more probable. We advocate rigorous standard operating procedures for infection control practices in hospital settings and evaluations thereafter. PMID- 26101083 TI - Comparison of disinfectant efficacy when using high-volume directed mist application of accelerated hydrogen peroxide and peroxymonosulfate disinfectants in a large animal hospital. AB - REASONS FOR PERFORMING STUDY: Effective decontamination of animal holding environments is critical for providing high quality patient care and maintaining a safe working environment. Disinfection of animal holding environments is a significant challenge during times of epidemic disease. OBJECTIVES: The purpose of this study was to evaluate the disinfectant efficacy of 3 strategies for high volume directed mist application of accelerated hydrogen peroxide and peroxymonosulfate disinfectants; 4.25% accelerated hydrogen peroxide (Accel((r)) ; AHP) at a 1:16 dilution and single and double applications of 2% peroxymonosulfate solution (Virkon-S((r)) ; VIR-1 and VIR-2) for decontamination of a large animal hospital environment. STUDY DESIGN: Experiment. METHODS: After cleaning and disinfection of the hospital environment, transparencies experimentally contaminated with known concentrations of Staphylococcus aureus, Salmonella enterica and Pseudomonas aeruginosa were placed on vertical surfaces. Disinfectant solution was applied by directed mist application and, after 30 min of contact time, transparencies were collected and individually placed into tubes containing 10 ml Dey-Engley broth. The process was repeated for each disinfectant. Tenfold dilutions of each sample were plated onto tryptic soy blood agar with 5% sheep blood. Bacterial counts from transparencies exposed to disinfectants were compared with counts from control transparencies (unexposed to disinfectants) to evaluate reduction in colony forming units. RESULTS: The least squares mean reduction (log10 ) in colony forming units (CFUs) for S. aureus and P. aeruginosa was 1.5-2.5 logs and approximately 0.8-1.0 logs for S. enterica. Reductions were generally largest for VIR-2 and smallest for AHP, although these differences were not all statistically significant and the magnitude of differences may not be clinically relevant. CONCLUSIONS: For the organisms evaluated, all 3 disinfectants applied as a directed mist were effective at reducing CFUs in a veterinary hospital environment. Effective disinfection using this method of application is dependent on adequate cleaning prior to application, and use of adequate volumes of disinfectant. PMID- 26101084 TI - Exposure to phthalates, bisphenol A and metals in pregnancy and the association with impaired glucose tolerance and gestational diabetes mellitus: The MIREC study. AB - BACKGROUND: Studies from several countries report increases in rates of gestational diabetes mellitus (GDM) over recent decades. Exposure to environmental chemicals could contribute to this trend. OBJECTIVES: To determine the associations between plasticisers and metals measured in early pregnancy with impaired glucose tolerance (IGT) and GDM in a Canadian pregnancy cohort. METHODS: Women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study were included if they had a singleton delivery and did not have pre existing diabetes. Eleven phthalate metabolites and total bisphenol A (BPA) were measured in first-trimester urine samples, and four metals (lead, cadmium, mercury and arsenic) were measured in first-trimester blood samples. IGT and GDM were assessed in accordance with standard guidelines by chart review. Chemical concentrations were grouped by quartiles, and associations with outcomes were examined using logistic regression with adjustment for maternal age, race, pre pregnancy BMI, and education. Restricted cubic spline analysis was performed to help assess linearity and nature of any dose-response relationships. RESULTS: Of 2001 women recruited into the MIREC cohort, 1274 met the inclusion criteria and had outcome data and biomonitoring data measured for at least one of the chemicals we examined. Elevated odds of GDM were observed in the highest quartile of arsenic exposure (OR = 3.7, 95% CI = 1.4-9.6) in the adjusted analyses. A significant dose-response relationship was observed in a cubic spline model between arsenic and odds of GDM (p < 0.01). No statistically significant associations were observed between phthalates or BPA or other metals with IGT or GDM. CONCLUSIONS: Our findings add to the growing body of evidence supporting the role of maternal arsenic exposure as a risk factor for gestational diabetes. PMID- 26101085 TI - Machine learning for toxicity characterization of organic chemical emissions using USEtox database: Learning the structure of the input space. AB - Toxicity characterization of chemical emissions in Life Cycle Assessment (LCA) is a complex task which usually proceeds via multimedia (fate, exposure and effect) models attached to models of dose-response relationships to assess the effects on target. Different models and approaches do exist, but all require a vast amount of data on the properties of the chemical compounds being assessed, which are hard to collect or hardly publicly available (especially for thousands of less common or newly developed chemicals), therefore hampering in practice the assessment in LCA. An example is USEtox, a consensual model for the characterization of human toxicity and freshwater ecotoxicity. This paper places itself in a line of research aiming at providing a methodology to reduce the number of input parameters necessary to run multimedia fate models, focusing in particular to the application of the USEtox toxicity model. By focusing on USEtox, in this paper two main goals are pursued: 1) performing an extensive exploratory analysis (using dimensionality reduction techniques) of the input space constituted by the substance-specific properties at the aim of detecting particular patterns in the data manifold and estimating the dimension of the subspace in which the data manifold actually lies; and 2) exploring the application of a set of linear models, based on partial least squares (PLS) regression, as well as a nonlinear model (general regression neural network- GRNN) in the seek for an automatic selection strategy of the most informative variables according to the modelled output (USEtox factor). After extensive analysis, the intrinsic dimension of the input manifold has been identified between three and four. The variables selected as most informative may vary according to the output modelled and the model used, but for the toxicity factors modelled in this paper the input variables selected as most informative are coherent with prior expectations based on scientific knowledge of toxicity factors modelling. Thus the outcomes of the analysis are promising for the future application of the approach to other portions of the model, affected by important data gaps, e.g., to the calculation of human health effect factors. PMID- 26101086 TI - Mentoring during anesthesia residency training: challenges and opportunities. PMID- 26101087 TI - So... why do you want to become an anesthesiologist? PMID- 26101088 TI - Independent effects of eye gaze and spatial attention on the processing of tactile events: Evidence from event-related potentials. AB - Directing one's gaze at a body part reduces detection speed and enhances the processing of tactile stimuli presented at the gazed location. Given the close links between spatial attention and the oculomotor system it is possible that these gaze- dependent modulations of touch are mediated by attentional mechanisms. To investigate this possibility, gaze direction and sustained tactile attention were orthogonally manipulated in the present study. Participants covertly attended to one hand to perform a tactile target-nontarget discrimination while they gazed at the same or opposite hand. Spatial attention resulted in enhancements of the somatosensory P100 and Nd components. In contrast, gaze resulted in modulations of the N140 component with more positive ERPs for gazed than non gazed stimuli. This dissociation in the pattern and timing of the effects of gaze and attention on somatosensory processing reveals that gaze and attention have independent effects on touch. PMID- 26101090 TI - Mechanistic Insights into R776H Mediated Activation of Epidermal Growth Factor Receptor Kinase. AB - The epidermal growth factor receptor (EGFR) kinase is activated by a variety of mutations in human cancers. R776H is one such recurrent mutation (R752H in another numbering system) in the alphaC-beta4 loop of the tyrosine kinase domain that activates EGFR in the absence of the activating EGF ligand. However, the mechanistic details of how R776H contributes to kinase activation are not well understood. Here using cell-based cotransfection assays, we show that the R776H mutation activates EGFR in a dimerization-dependent manner by preferentially adopting the acceptor position in the asymmetric dimer. The acceptor function, but not the donor function, is enhanced for the R776H mutant, supporting the "superacceptor" hypothesis proposed for oncogenic mutations in EGFR. We also find that phosphorylation of monomeric EGFR is increased by R776H mutation, providing insights into EGFR lateral phosphorylation and oligomerization. On the basis of molecular modeling and molecular dynamics simulation, we propose a model in which loss of key autoinhibitory alphaC-helix capping interaction and alteration of coconserved cis regulatory interactions between the kinase domain and the flanking regulatory segments contribute to mutational activation. Since the R776 equivalent position is mutated in ErbB2 and ErbB4, our studies have implications for understanding kinase mutational activation in other ErbB family members as well. PMID- 26101089 TI - Thermosensation and longevity. AB - Temperature has profound effects on behavior and aging in both poikilotherms and homeotherms. To thrive under the ever fluctuating environmental temperatures, animals have evolved sophisticated mechanisms to sense and adapt to temperature changes. Animals sense temperature through various molecular thermosensors, such as thermosensitive transient receptor potential (TRP) channels expressed in neurons, keratinocytes, and intestine. These evolutionarily conserved thermosensitive TRP channels feature distinct activation thresholds, thereby covering a wide spectrum of ambient temperature. Temperature changes trigger complex thermosensory behaviors. Due to the simplicity of the nervous system in model organisms such as Caenorhabditis elegans and Drosophila, the mechanisms of thermosensory behaviors in these species have been extensively studied at the circuit and molecular levels. While much is known about temperature regulation of behavior, it remains largely unclear how temperature affects aging. Recent studies in C. elegans demonstrate that temperature modulation of longevity is not simply a passive thermodynamic phenomenon as suggested by the rate-of-living theory, but rather a process that is actively regulated by genes, including those encoding thermosensitive TRP channels. In this review, we discuss our current understanding of thermosensation and its role in aging. PMID- 26101091 TI - Role of percutaneous mitral valve repair in the contemporary management of mitral regurgitation. AB - Percutaneous mitral valve (MV) repair has been performed in over 20,000 patients worldwide. As clinical experience in this technique grows indications for its use are being defined. Mitral regurgitation (MR) encompasses a complex heterogeneous group and its treatment is governed by determining a clear understanding of the underlying aetiology. Surgical MV repair remains the gold standard therapy for severe MR. However in select groups of high-risk surgical patients, a percutaneous approach to MV repair is establishing its role. This review gives an overview of the published data in percutaneous MV repair and its impact on the contemporary management of MR. PMID- 26101092 TI - Interleukin-18 for predicting the development of macrophage activation syndrome in systemic juvenile idiopathic arthritis. AB - To assess the role of IL-6/IL-18 in the pathogenesis of systemic juvenile idiopathic arthritis (s-JIA) and to investigate the clinical significance of serum IL-18 levels for predicting macrophage activation syndrome (MAS) development, we measured the serum IL-6/IL-18 levels in 76s-JIA patients, including 15 with MAS, and compared them with the clinical features. We identified 2 distinct subsets on the basis of serum IL-6/IL-18 levels. The IL-18 dominant subset had more patients who developed MAS. Serum IL-18 levels during active phase in patients with MAS were significantly higher than those without MAS. The cutoff value of serum IL-18 levels for predicting MAS development was 47750 pg/ml. The patients with IL-18 dominant subset at their disease onset were significantly more likely to develop MAS after TCZ therapy started. IL-18 might have a key role in the pathogenesis of MAS. Serum IL-18 levels >47750 pg/ml might be useful to predict MAS development. PMID- 26101095 TI - Novel Magnetic Resonance Imaging Findings in Children With Intracranial Hypertension. AB - BACKGROUND: Increased intracranial hypertension is defined as elevated intracranial pressure with absence of hydrocephalus, vascular or structural abnormalities, and normal cerebrospinal fluid content. Magnetic resonance imaging abnormalities of the optic nerve and sheath that have been described in adults include increased nerve tortuosity, flattening in posterior aspect of globe, intraocular protrusion of the optic nerve, and enlarged optic nerve sheath. PURPOSE: We evaluated accuracy of those proposed markers on magnetic resonance imaging in children with increased intracranial hypertension that are described in adults. MATERIALS AND METHODS: Eleven patients between 3 and 15 years of age with intracranial hypertension were selected for re-evaluation of magnetic resonance imaging that had been previously described as normal to determine the presence of: (1) increased tortuosity and elongation of the optic nerve; (2) enlargement of the optic nerve sheath on axial and coronal T2 so called by us "target sign" and postcontrast T1 sequences; (3) flattening in posterior aspect of the globe; and (4) intraocular protrusion of the optic nerve head. RESULTS: Of the 11 patients, tortuosity of the optic nerve (10/11, 90.9%) and enlarged optic nerve sheath--target sign (7/11, 63.6%)--were the most common findings. Flattening in the posterior aspect of globe (5/11, 45.5%) and intraocular protrusion (3/11, 27.3%) were also detected as a novel magnetic resonance imaging findings. CONCLUSION: Magnetic resonance imaging findings of the optic nerve and sheath include valuable signs of intracranial hypertension not only in adults but also in children. This is the first detailed analysis of the magnetic resonance imaging findings in children with increased intracranial hypertension. PMID- 26101096 TI - Super-Charged Pedicled Jejunal Interposition Performance Compares Favorably With a Gastric Conduit After Esophagectomy. AB - BACKGROUND: A variety of conduits can be utilized for esophageal reconstruction, but their postoperative function remains unknown. The objective of our study was to compare functional performance of super-charged pedicled jejunal (SPJ) to gastric conduits using a novel conduit assessment tool. METHODS: Patients who underwent esophageal reconstruction between January 1, 2009 and December 31, 2013 were asked to complete questionnaires measuring postoperative functional outcomes. Conduit emptying and postoperative variables were recorded. Statistical analysis was performed using the Mann-Whitney U test and Fisher exact test for crosstabs. RESULTS: Forty-five of the 94 esophageal reconstruction patients (48%) were alive, had either a gastric conduit or SPJ reconstruction, and completed the questionnaire. The mean age was 60.6 +/- 12.5 years, 69% were male, and the majority of patients had cancer (87%). While the majority of the gastric patients underwent an oncologic resection for adenocarcinoma (65%), 50% of SPJ patients had undergone a previous resection (p = 0.008). The average time after surgery for last conduit assessment was 15 +/- 13 months for the gastric conduit group and 17 +/- 12 months for the SPJ group (p = 0.315). The average reflux, dumping, dysphagia, stricture, conduit emptying, and Zubrod scores were low and similar between groups: reflux 1.7 +/- 1.9 for gastric conduit and 0.7 +/- 1.3 for SPJ; dumping 0.97 +/- 1.2 and 0.93 +/- 1.1; dysphagia 0.60 +/- 0.72 and 0.79 +/- 0.89; stricture 0.7 +/- 1.4 and 0.38 +/- 0.96; conduit emptying 0.46 +/- 0.93 and 0.33 +/- 0.88; and Zubrod 0.84 +/- 0.64 and 1.21 +/- 0.8, respectively. The SPJ patients had a higher pain score (7.0 +/- 3.2 vs 2.4 +/- 2.4, p = 0.043). CONCLUSIONS: Super-charged pedicled jejunal interposition performance is comparable with a gastric conduit after esophagectomy according to a novel, comprehensive conduit assessment tool. PMID- 26101093 TI - Publisher's Note:Abstraction for data integration:Fusing mammalian molecular, cellular and phenotype big datasets for better knowledge extraction. PMID- 26101097 TI - Is Medical Student Interest in Cardiothoracic Surgery Maintained After Receiving Scholarship Awards? AB - BACKGROUND: Medical student exposure to cardiothoracic surgery has been facilitated by many scholarship opportunities. This study reviews the long-term interest of students at our institution who have received such support. METHODS: After the first or second year of medical school, participants were selected to receive scholarships for clinical or research activities in cardiothoracic surgery ranging from 4 to 8 weeks in duration. These were funded by the American Association for Thoracic Surgery, Society of Thoracic Surgeons, Southern Thoracic Surgical Association, or a private family donor. Over time, each student's scholarship type, current interest in cardiothoracic surgery, and current education or career status was prospectively monitored in an institutional database. RESULTS: Since 1999, 45 students received scholarships. Eight (18%) were funded by the American Association for Thoracic Surgery, two (4%) by The Society of Thoracic Surgeons one (2%) by the Southern Thoracic Surgical Association, and 34 (76%) by private donors. The median follow-up of graduated students is 7 years. Of the 20 (44%) with an active current interest in cardiothoracic surgery, 2 are faculty, 1 is a fellow, 1 is in an integrated 6 year program, 11 are in general surgery residency and are planning to apply to cardiothoracic surgery fellowship, and the remaining 5 are in medical school and planning a cardiothoracic surgery career. Of all former medical students who received cardiothoracic surgery research scholarships and who have now made a career choice, 17.4% chose cardiothoracic surgery. CONCLUSIONS: More than one third of medical students who received scholarships in cardiothoracic surgery maintained their interest over time, and more than half maintained interest in a surgical field. Although long-term data are scarce, it remains critical to foster mentoring relationships with students over time to guide their career choices. PMID- 26101099 TI - Power generating reflective-type liquid crystal displays using a reflective polariser and a polymer solar cell. AB - We herein report the results of a study of a power generating reflective-type liquid crystal display (LCD), composed of a 90 degrees twisted nematic (TN) LC cell attached to the top of a light-absorbing polymer solar cell (PSC), i.e., a Solar-LCD. The PSC consisted of a polymer bulk-heterojunction photovoltaic (PV) layer of poly[[9-(1-octylnonyl)-9H-carbazole-2,7-diyl]-2,5-thiophenediyl-2,1,3 benzothiadiazole-4,7-diyl-2,5-thiophenediyl] and [6,6]-phenyl C71 butyric acid methyl ester (PCDTBT:PCBM70), and showed a high power conversion efficiency of about 5%. In order to improve the visibility of the Solar-LCD, between the TN-LC and the PV cells we inserted a reflective polariser of a giant birefringent optical (GBO) film. The reflectivity from the Solar-LCD was observed to be considerably increased by more than 13-15% under illumination by visible light. The Solar-LCD also exhibited a significantly improved contrast ratio of more than 17-19. We believe there is a clear case for using such Solar-LCDs in new power generating reflective-type displays; taken as a whole these results also demonstrate the possibility of their application in a number of energy-harvesting opto-electrical display devices. PMID- 26101098 TI - Individual differences in cortical connections of somatosensory cortex are associated with parental rearing style in prairie voles (Microtus ochrogaster). AB - Early-life sensory experiences have a profound effect on brain organization, connectivity, and subsequent behavior. In most mammals, the earliest sensory inputs are delivered to the developing brain through tactile contact with the parents, especially the mother. Prairie voles (Microtus ochrogaster) are monogamous and, like humans, are biparental. Within the normal prairie vole population, both the type and the amount of interactions, particularly tactile contact, that parents have with their offspring vary. The question is whether these early and pervasive differences in tactile stimulation and social experience between parent and offspring are manifest in differences in cortical organization and connectivity. To address this question, we examined the cortical and callosal connections of the primary somatosensory area (S1) in high-contact (HC) and low-contact (LC) offspring using neuroanatomical tracing techniques. Injection sites within S1 were matched so that direct comparisons between these two groups could be made. We observed several important differences between these groups. The first was that HC offspring had a greater density of intrinsic connections within S1 compared with LC offspring. Additionally, HC offspring had a more restricted pattern of ipsilateral connections, whereas LC offspring had dense connections with areas of parietal and frontal cortex that were more widespread. Finally, LC offspring had a broader distribution of callosal connections than HC offspring and a significantly higher percentage of labeled callosal neurons. This study is the first to examine individual differences in cortical connections and suggests that individual differences in cortical connections may be related to natural differences in parental rearing styles associated with tactile contact. PMID- 26101100 TI - Cysteine induces longitudinal bone growth in mice by upregulating IGF-I. AB - Cysteine (Cys) is known to exert various effects, such as antioxidant, antipancreatitic and antidiabetic effects. However, the effects of Cys on longitudinal bone growth have not been elucidate to date. Thus, the aim of the present study was to evaluate the effects of Cys on bone growth. Growth-plate thickness and bone parameters, such as bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), connectivity density (Conn.D) and total porosity were analyzed by means of micro-computed tomography (MUCT). The levels of serum insulin-like growth factor-I (IGF-I) were measured by enzyme-linked immunosorbent assay (ELISA). Hepatic IGF-I mRNA expression was analyzed by quantitative polymerase chain reaction (qPCR). The phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) was investigated by western blot analysis. Our results revealed that Cys increased IGF-I mRNA expression in HepG2 cells. The thickness of the growth plates was increased following treatment with Cys. Moreover, BV/TV, Tb.Th, TbN, Conn.D and total porosity were improved following treatment with Cys. Hepatic IGF I mRNA expression and serum IGF-I levels were increased by Cys. The levels of phosphorylated JAK2 and STAT5 were elevated by Cys. The findings of our study indicate that Cys increases the thickness of growth plates through the upregulation of IGF-I, which results from the phosphorylation of JAK2-STAT5. Thus, our data suggest that Cys may have potential for use as a growth-promoting agent. PMID- 26101101 TI - Recovery of kraft lignin from pulping wastewater via emulsion liquid membrane process. AB - Kraft lignin (KL) is a renewable source of many valuable intermediate biochemical products currently derived from petroleum. An excessive of lignin comes from pulping wastewater caused an adverse pollution problems hence affecting human and aquatic life. A comprehensive study pertaining to emulsion liquid membrane (ELM) extraction of lignin from pulping wastewater was presented. ELM formulation contains Aliquat 336 as carrier, kerosene as diluent, sodium bicarbonate (NaHCO3 ) as stripping agent and Span 80 as surfactant. The emulsion stability was investigated at different surfactant concentrations, homogenizer speed and emulsification time. Modifier (2-ethyl-1-hexanol) was added to avoid segregation of third phase while improving the emulsion stability. At optimum conditions, 95% and 56% of lignin were extracted and recovered, respectively at 10 min of extraction time, 0.007 M of Aliquat 336, 0.1 M of NaHCO3 and 1:5 of treat ratio. Additional of modifier was contributed to highest recovery up to 98%. The ELM process was found to be equally feasible and quite effective in the recovery of KL from real pulping wastewater. Therefore, ELM process provides a promising alternative technology to recover KL from pulping wastewater while solving the environmental problems simultaneously. PMID- 26101103 TI - Lining up against epilepsy: We are all in this fight together. PMID- 26101102 TI - Ionizing air affects influenza virus infectivity and prevents airborne transmission. AB - By the use of a modified ionizer device we describe effective prevention of airborne transmitted influenza A (strain Panama 99) virus infection between animals and inactivation of virus (>97%). Active ionizer prevented 100% (4/4) of guinea pigs from infection. Moreover, the device effectively captured airborne transmitted calicivirus, rotavirus and influenza virus, with recovery rates up to 21% after 40 min in a 19 m(3) room. The ionizer generates negative ions, rendering airborne particles/aerosol droplets negatively charged and electrostatically attracts them to a positively charged collector plate. Trapped viruses are then identified by reverse transcription quantitative real-time PCR. The device enables unique possibilities for rapid and simple removal of virus from air and offers possibilities to simultaneously identify and prevent airborne transmission of viruses. PMID- 26101104 TI - Hypothesis: CeM-PAG GABAergic circuits may be implicated in sudden unexpected death in epilepsy by melanocortinergic signaling. PMID- 26101105 TI - The understanding of patients with epilepsy with regard to how their disease is managed: The role of health professionals. PMID- 26101106 TI - Reduced Pumilio-2 expression in patients with temporal lobe epilepsy and in the lithium-pilocarpine induced epilepsy rat model. AB - OBJECTIVE: Drosophila Pumilio (Pum), a homolog of mammalian Pum2, plays an important role in translational regulation in the central nervous system (CNS), particularly for dendrite outgrowth and neuronal excitability. We investigated the expression pattern and cellular distribution of Pum2 in patients with drug refractory temporal lobe epilepsy (TLE) and rats with lithium chloride pilocarpine-induced epilepsy. METHODS: Real-time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, and double-labeled immunofluorescence were utilized to determine the expression level and distribution of Pum2 in temporal neocortex tissues from patients with intractable TLE (n=20) and patients with severe head trauma (n=20) in addition to the hippocampus and adjacent cortex of rats with lithium chloride-pilocarpine-induced TLE and controls. RESULTS: Pum2 was expressed in the cell bodies and dendrites of neurons but did not colocalize with glial fibrillary acidic protein-positive astrocytes or propidium iodide (PI) in nuclei. The expression of Pum2 was significantly reduced in patients and rats with TLE in comparison to controls (P<0.05). CONCLUSION: Pum2 expression was less in patients with TLE and a rodent model of epilepsy, suggesting that decreased expression of Pum2 may be involved in the pathogenesis of TLE. PMID- 26101107 TI - Infection: Catheter-associated UTIs can be controlled with simple interventions. PMID- 26101109 TI - BPH: Go with the Flowens(TM)--cranberry powder improves male LUTS in double blind, placebo-controlled trial. PMID- 26101110 TI - Prostate cancer: High-dose-rate brachytherapy as monotherapy in prostate cancer. PMID- 26101111 TI - Light-Triggered Disruption of PAG-Based Amphiphilic Random Copolymer Micelles. AB - The amphiphilic random copolymer of P(NVP-co-NHPSS) with photocleavable N-O sulfonate side groups has been prepared to investigate the light-triggered disruption of copolymer micelles. Methods of absorption and emission spectra, solution transmittance, dynamic light scattering (DLS), and transmission electron microscopy (TEM) were applied. It was found that P(NVP-co-NHPSS) could form polymeric nanoaggregates in aqueous solution. And the photocleavage of the N-O bond within copolymer micelles upon 365 nm UV light could be conveniently controlled by changing the irradiation intensity, leading to the disruption of copolymer micelles and the photocontrolled release of Nile red encapsulation. And by encapsulating NaLuF4:Gd/Yb/Tm UCNPs inside copolymer micelles, the response of the photocleavable N-O bond to the 980 nm laser was much weaker than the response to 365 nm light; however, the photocontrolled release of Nile red could still be effectively triggered by the NIR light of the 980 nm laser. PMID- 26101112 TI - Issue conflation leads to dietary confusion. PMID- 26101113 TI - Sudden unexpected death in infancy (SUDI) in New Zealand: discussion over the last 5 years and where to from here? PMID- 26101108 TI - Adverse effects of common medications on male fertility. AB - An increasing number of patients require long-term medication regimens at a young age, but the adverse effects of medications on male reproduction are often inadequately considered, recognized and investigated. Medications can affect male reproduction through central hormonal effects, direct gonadotoxic effects, effects on sperm function or on sexual function. For example, exogenous testosterone inhibits spermatogenesis through central suppression of the hypothalamic-pituitary-gonadal hormonal axis. 5alpha-reductase inhibitors can impair sexual function, decrease semen volume and negatively affect sperm parameters, depending on dose and treatment duration. alpha-Blockers might decrease seminal emission and cause retrograde ejaculation, depending on the receptor specificity and dose of the agent. Phosphodiesterase inhibitors seem to have variable effects based on the isoform inhibited and evidence is conflicting. Antihypertensive and psychotropic agents can affect sperm, sexual function and hormonal parameters. For antibiotics, the literature on effects on sperm and sperm function is limited and dated. Many chemotherapeutic agents have a direct gonadotoxic effect, depending on agents used, dosing and number of treatment cycles. Overall, many medications commonly used in urology can have effects on male fertility (mostly reversible) but conclusive evidence in humans is often limited. Men should be counselled appropriately about potential drug-related adverse effects on their fertility. PMID- 26101114 TI - The wahakura: a qualitative study of the flax bassinet as a sleep location for New Zealand Maori infants. AB - AIMS: The wahakura (flax bassinet) is presently being distributed as a safe infant sleeping device amongst New Zealand Maori, where sudden unexpected deaths in infancy (SUDI) rates are high. It is promoted as mitigating bedsharing risk by providing a separate infant sleeping surface. This study aimed to understand exactly what factors determine the apparent acceptability of the wahakura as an infant sleeping device to Maori mothers and other key Maori community stakeholders. METHODS: The qualitative study used face-to-face, semi-structured interviews, following Maori cultural protocols, to explore the experiences and views of 12 Maori mothers and 10 key informants who had wahakura experience. We employed purposeful sampling of participants and thematic analysis of data. RESULTS: The practical appeal of the wahakura related to its portability, the enabling of bedsharing and easier breastfeeding. Considerable cultural and spiritual appeal was related to its native flax composition and traditional origin. Health professionals found it useful to engage Maori women antenatally. CONCLUSIONS: The study affirmed the acceptance of the wahakura as a culturally initiated endeavour, meaningfully engaging Maori mothers and families in SUDI risk mitigation. It has the potential to capitalise on the benefits of bedsharing to enhance infant wellbeing while also safeguarding them from harm. PMID- 26101115 TI - Token monetary incentives improve mail survey response rates and participant retention: results from a large randomised prospective study of mid-age New Zealand women. AB - AIM: To examine if a small token monetary incentive (NZ$5) increases mail survey response rates and participant retention of 40-50 year old New Zealand women. METHOD: In 2009, 2500 women were randomly selected from the New Zealand electoral rolls for a prospective study investigating factors related to the prevention of weight gain. At baseline, 400 women were randomly assigned to receive NZ$5 with the initial survey mail-out in addition to nonmonetary gifts to encourage participation (pen, tea bag, entry in lottery draw) received by all women. At 2 years, 400 women (200 received NZ$5 at baseline and 200 had not) were randomly assigned to receive the same token monetary incentive. At 3 years, all women identifying as an ethnic minority (n=234) and 300 randomly selected women of other ethnicities received the token monetary incentive with the initial mail out. RESULTS: The baseline response rate for women who received NZ$5 was significantly higher than for women who did not (76% vs 64%, p<0.001). At 2 years, retention rate for all women who received NZ$5 was significantly higher than for women who did not (88% vs 80%, p<0.001). At 3 years, among those women not identifying as an ethnic minority, the retention rate for those who received NZ$5 was significantly higher than for those who did not (84% vs 77%, p=0.014). CONCLUSION: Inclusion of a small token monetary incentive significantly increases mail survey response rates and participant retention in mid-age New Zealand women. PMID- 26101116 TI - Retrieval rates of inferior vena cava (IVC) filters: are we retrieving enough? AB - AIM: The aim of this study was to document retrieval rates of IVC filters in a single tertiary centre, before and after implementation of an IVC filter pathway, and to identify factors that may affect retrieval rates. METHOD: This was a two phase study. In Phase 1, rates of IVC filter retrieval were collected retrospectively from June 2010 to June 2012. During Phase 2 an IVC filter pathway was developed and prospective data was collected from July 2012 to June 2014. Univariate analysis and Kaplan-Meier estimates were performed to determine the rate of IVC filter retrieval and to analyse factors contributing to retrieval rates. RESULTS: 95 patients (39 Phase 1; 56 Phase 2) had an IVC filter inserted over a 4 year period. In Phase 1, of those eligible to have their filter removed, the 12-month retrieval rate was 63%, this improved to 100% in Phase 2. Following implementation of the IVC filter pathway (Phase 2) no patients were lost to follow-up. CONCLUSION: We have improved the rate of IVC filter retrieval in our institution by development of an IVC filter pathway. Rates of optional IVC filter retrieval in our experience are now higher than previously published figures. PMID- 26101117 TI - CT pulmonary angiography and pulmonary embolism following 5809 primary joint arthroplasties. AB - AIM: Controversy surrounds prevention, detection and clinical relevance of pulmonary embolism (PE) following arthroplasty in orthopaedic patients. We aimed to review the rates of computer tomography pulmonary angiography (CTPA), PE and fatal PE following total joint replacement. METHOD: Mixed retrospective/prospective review of CTPA requests and PE incidence amongst patients undergoing primary knee and hip arthroplasty. RESULTS: The overall PE rate was 112/5809 (1.93%): 38/3473 (1.1%) and 74/2336 (3.5%) following total hip arthroplasty (THA) and total knee arthroplasty (TKA), respectively. Two deaths from PE occurred, both after TKA, a procedural mortality rate of 0.086%; the overall mortality rate was 0.034%. The rate of CTPA requests increased for the initial 7 years as did the rate of PE, in the last 2 years both rates fell. CONCLUSION: The findings are discussed in context of published data and with reference to studies suggesting the high sensitivity of CTPA may over diagnose clinically significant PE following arthroplasty if ordered without a robust method of determining the pre-test probability. PMID- 26101118 TI - The measurement of New Zealand health care. AB - The effective and economical measurement of the quality and safety of health and disability services in New Zealand is of signal importance. The Health Quality and Safety Commission has overseen the introduction of an architecture of interacting measures. These include quality and safety indicators, or QSIs, which are whole-system measures; quality and safety markers, or QSMs, which are targeted measures of quality and safety interventions comprising process and outcome measures in sets; and the New Zealand Atlas of Healthcare Variation, which illustrates the differences in the health care received in different regions and by different groups of patients within New Zealand. PMID- 26101119 TI - Reversible hypertensive encephalomyelopathy - the spinal variant of the posterior reversible encephalopathy syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is characterised clinically by encephalopathy, headache, visual disturbance and/or focal neurological symptoms. Bilateral cerebral oedema on T2 MRI sequences within the posterior cerebral white matter is the radiological hallmark, although involvement of the frontal lobe, basal ganglia and brainstem can occur. PRES with spinal cord involvement has been rarely reported and is under-recognised due to lack of myelopathic features in nearly half of the reported cases. We report a patient with PRES with spinal cord involvement and review the literature. PMID- 26101120 TI - Medical image. Primary Raynaud's phenomenon. PMID- 26101121 TI - Chewing the saturated fat: we still shouldn't. PMID- 26101122 TI - HPV immunisation research. PMID- 26101123 TI - Menstrual dysfunction and hysterectomy rates in women up to 10 years post-tubal ligation in Counties Manukau District Heath Board. PMID- 26101124 TI - The New Zealand Register of Exercise Professionals (NZ REPs). PMID- 26101125 TI - Incidence of motor neurone disease in Hawke's Bay and Gisborne/East Coast. PMID- 26101126 TI - Wells score, D-dimer testing and computer tomographic pulmonary angiography appropriateness in the Auckland Hospital Adult Emergency Department. PMID- 26101127 TI - Realignment of tobacco control services-will it be sufficient to achieve the nation's Smokefree 2025 Goal? PMID- 26101128 TI - Effects of new biomimetic regenerating agents on corneal wound healing in an experimental model of post-surgical corneal ulcers. AB - OBJECTIVE: The purpose of this study is to assess the effectiveness of the topical application of cacicol regenerating agent (RGTA) in an experimental model of corneal ulcer after photorefractive keratectomy (PRK) in mice. METHODS: Mice were subjected to PRK surgery with a 2.0mm ablation zone on the central cornea and 45mm of depth on a VISX Star S2 excimer laser. Corneas were treated topically with cacicol drops 1hour and 48hours after injury. Control groups received balanced salt solution (BSS) in the same dosage. Clinical and histopathological events were evaluated at 1, 2, 3 and 7 days after surgery. Sections obtained through the central region of the corneas were used to analyze the histopathological events of injured and healed corneas. alphaSMA (myofibroblast transformation), E cadherin (assembly of epithelial cells) and neuronal class III beta-tubulin (innervation) were performed. RESULTS: Corneas treated topically with cacicol for 7 days showed a greater degree of transparency compared to controls. cacicol treated corneas showed improved epithelial cytoarchitecture. Analysis of alphaSMA profiles in the stroma showed that cacicol reduced or delayed the presence of myofibroblasts in the stroma compared to BSS (P<0.001). Finally, a putative neuroregenerative effect of cacicol was found in corneas subjected to an experimental PRK lesion. In some cases some interindividual variability could be observed due to the design of the experimental model. This is a limitation to consider, despite the statistical significance of the data. CONCLUSIONS: In a model of laser induced surgical lesions in the cornea, topical application of an RGTA (i.e. cacicol) could be involved in avoiding myofibroblast scarring formation and promoting nerve regeneration. PMID- 26101129 TI - [Cancer in ectopic breast tissue]. AB - Two different forms of ectopic breast tissue exist in human beings: supernumerary and aberrant. Both forms are usually seen alongside the milk lines, which extend from the upper limbs to the inguinal region where they give rise to mammary glands, areolas and nipples. Although ectopic- and orthotopic breast tissue are placed in different areas of the body, they still share the same ability to undergo pathological degeneration. The focus of this case report is to shed light on this unusual form of breast cancer, and raise the level of awareness in cases with lumps located in the milk lines. PMID- 26101130 TI - [Benign paroxysmal positional vertigo in children after head trauma]. AB - We present an eight-year-old boy with benign paroxysmal positional vertigo (BPPV) after a head trauma, successfully treated with Epley's manoeuvre. BPPV is a common cause of vestibular vertigo in adults, but it is rarely seen in children. Diagnostic work-up is challenging as children often lack the ability to describe their symptoms accurately and to cooperate in clinical examination. The diagnosis should be suspected in children with a relevant medical history and verified by positional testing. BPPV of childhood is treated with otolith repositioning manoeuvres, and the prognosis is good. PMID- 26101131 TI - [Stiff person syndrome is a rare autoimmune disorder]. AB - Atypical symptoms raise classical diagnostic dilemmas of somatic versus functional disease. The challenge is greater when the condition is less frequent. Illustrating this issue is a case of stiff person syndrome (SPS) where a 46-year old man was admitted with lower back and hip pain and stiffness of the musculature of the lower extremities resulting in stooped gait. Stiffness was absent while sleeping. Thorough clinical examination and tests were unable to explain the symptomology until suspicion of SPS was raised, supported by high levels of glutamic acid decarboxylase antibodies. PMID- 26101132 TI - [Myocardial injury and infarction is an overlooked complication after non-cardiac surgery]. AB - Annually, several million patients undergoing non-cardiac surgery develop myocardial injury or a myocardial infarction in the perioperative period. This frequent complication is associated with a high mortality. Despite an increasing focus on the issue the pathophysiology and the treatment of perioperative myocardial injury and infarction still remains partly unclear. Recently a new risk stratification tool was developed, which allows physicians to identify patients at risk. This review offers insight into the prevalence, pathophysiology, diagnostics, risk stratification and treatment of perioperative myocardial injury and infarction. PMID- 26101133 TI - [Persisting upper cervical pain as sole symptom by unstable fractures in the cervical spine]. AB - Upper cervical spine fractures can be caused by very low-energy traumas, and the clinical presentation can vary from mild neck pain to paraplegia and ultimately to death. The most common cause of these fractures is trauma but degenerative and pathologic aetiology is also seen. Upper cervical spine fractures can be difficult to diagnose because of lack of symptoms. Two case stories describe neck pain as the only symptom to severe and unstable cervical fracture and highlight the importance of an accurate history, thorough physical examination and relevant radiological investigation. PMID- 26101134 TI - [Patients in need for major lower extremity amputations are a challenge]. AB - Major lower extremity amputations based on end-stage chronic leg ischaemia or diabetic ulcers with infection are relatively common orthopaedic procedures. Patients are usually evaluated for the possibility of lower extremity revascularisation. Those who are not fit for vascular surgery are transferred to an orthopaedic department for amputation. These patients are a big challenge as they are by definition multi-morbid individuals, who have to undergo major surgery. The high mortality rate in this population warrants new approaches, including optimised multidisciplinary regimes. PMID- 26101135 TI - Ginger extract prevents high-fat diet-induced obesity in mice via activation of the peroxisome proliferator-activated receptor delta pathway. AB - The initiation of obesity entails an imbalance wherein energy intake exceeds expenditure. Obesity is increasing in prevalence and is now a worldwide health problem. Food-derived peroxisome proliferator-activated receptor delta (PPARdelta) stimulators represent potential treatment options for obesity. Ginger (Zingiber officinale Roscoe) was previously shown to regulate the PPARgamma signaling pathway in adipocytes. In this study, we investigated the antiobesity effects of ginger in vivo and the mechanism of action in vitro. Energy expenditure was increased, and diet-induced obesity was attenuated in C57BL/6J mice treated with dietary ginger extract (GE). GE also increased the number of Type I muscle fibers, improved running endurance capacity and upregulated PPARdelta-targeted gene expression in skeletal muscle and the liver. 6-Shogaol and 6-gingerol acted as specific PPARdelta ligands and stimulated PPARdelta dependent gene expression in cultured human skeletal muscle myotubes. An analysis of cellular respiration revealed that pretreating cultured skeletal muscle myotubes with GE increased palmitate-induced oxygen consumption rate, which suggested an increase in cellular fatty acid catabolism. These results demonstrated that sustained activation of the PPARdelta pathway with GE attenuated diet-induced obesity and improved exercise endurance capacity by increasing skeletal muscle fat catabolism. 6-Shogaol and 6-gingerol may be responsible for the regulatory effects of dietary ginger on PPARdelta signaling. PMID- 26101136 TI - Metallic High-Angle Grain Boundaries in Monolayer Polycrystalline WS2. PMID- 26101138 TI - Lactate and short chain fatty acids produced by microbial fermentation downregulate proinflammatory responses in intestinal epithelial cells and myeloid cells. AB - The use of short chain fatty acids to modulate gastrointestinal inflammatory conditions such as ulcerative colitis has produced encouraging results either in animal models or also in clinical trials. Identifying the key cellular and molecular targets of this activity will contribute to establish the appropriate combinations/targeting strategies to maximize the efficacy of anti-inflammatory interventions. In the present work, we evaluated in vitro the interaction of lactate, acetate, propionate and butyrate on cells relevant for innate immune response of the gastrointestinal tract. All molecules tested regulate the production of proinflammatory cytokines by TLR-4 and TLR-5 activated intestinal epithelial cells in a dose response manner. Furthermore SCFAs and lactate modulate cytokine secretion of TLR-activated bone marrow derived macrophages and also TLR-dependent CD40 upregulation in bone marrow derived dendritic in a dose dependent manner. Butyrate and propionate have been effective at concentrations of 1 to 5mM whereas acetate and lactate produced modulatory effects at concentrations higher than 20-50mM in different assays. Our results indicate that in concentrations similar to found in large bowel lumen, all SCFAs tested and lactate can modulate activity of relevant sentinel cell types activated by TLR signals. Modulatory activity was not inhibited by pertussis toxin treatment indicating that the effects are not related to Gi signaling. The use of these molecules in combined or separately as intervention strategy in conditions where epithelial or myeloid cells are main triggers of the inflammatory situation seems appropriate. PMID- 26101137 TI - Therapeutic control of complement activation at the level of the central component C3. AB - The increasing recognition of the complement system's association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the complement response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 activation may offer a powerful opportunity to interfere with or even prevent complement-driven pathologies, the development of C3 inhibitors has often been accompanied by concerns regarding the safety and feasibility of this approach. Although no C3-targeted inhibitors have thus far been approved for clinical use, several promising concepts and candidates have emerged in recent years. At the same time, experiences from preclinical development and clinical trials are slowly providing a more detailed picture of therapeutic complement inhibition at the level of C3. This review highlights the current therapeutic strategies to control C3 activation and discusses the possibilities and challenges on the road to bringing C3-targeted therapeutics to the clinic. PMID- 26101139 TI - Candida albicans up-regulates the Fas-L expression in liver Natural Killer and Natural Killer T cells. AB - After Candida albicans arrival to the liver, the local production of proinflammatory cytokines and the expanded intrahepatic lymphocytes (IHL) can be either beneficial or detrimental to the host. Herein we explored the balance between protective inflammatory reaction and liver damage, focusing our study on the contribution of TNF-alpha and Fas-Fas-L pathways in the hepatocellular apoptosis associated to C. albicans infection. A robust tissue reaction and a progressive increase of IL-1beta, IL-6 and TNF-alpha were observed in infected animals. Blocking the biological activity of TNF-alpha did not modify the number of apoptotic cells observed in C. albicans infected animals. Fas-L molecule was up regulated on purified hepatic mononuclear cells and its expression progressed with the infection. In the IHL compartment, the absolute number of Fas-L+ NK and NKT cells increased on days 1 and 3 of the infection. C. albicans was also able to up regulate Fas-L expression in normal liver NK and NKT cells after in vitro contact. The innate receptor TLR2 was involved in this phenomenon. In the interplay between host factors and evasion strategies exploited by pathogens, the mechanism supported here could represent an additional way that allows this fungus to circumvent protective immune responses in the liver. PMID- 26101140 TI - Capillary electrophoresis for fast detection of heterogeneous population in colistin-resistant Gram-negative bacteria. AB - It has been shown that diverse strains of bacteria can be separated according to their characteristic surface properties by means of CE. We employed here this analytical technique to the study of colistin-resistance in Gram-negative bacteria, which involves the selection of mutants with modified outer membrane composition resulting in changes of surface cell properties. In the same way as with molecular entities, we performed firstly the validation of an ITP-based CE method for three common pathogenic Gram-negative bacteria namely Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Secondly, we compared the electrophoretic profiles of bacterial samples from a colistin-susceptible clinical isolate of K. pneumoniae and from the corresponding colistin-resistant derivative. By a simple CE run taking a few minutes, the coexistence of several bacterial subpopulations in the colistin-resistant derivative was clearly evidenced. This work encourages further research that would allow applications of CE in clinical laboratory for a daily monitoring of bacterial population in cared patients when "last-chance" colistin treatment is initiated against multidrug resistant bacteria. PMID- 26101142 TI - Consumption of Argan Oil Improves Anti-Oxidant and Lipid Status in Hemodialysis Patients. AB - OBJECTIVE: Virgin Argan oil (VAO) is of interest in oxidative stress and lipid profile because of its fat composition and antioxidant compounds. We investigated the effect of VAO consumption on lipid profile and antioxidant status in hemodialysis patients after a 4-week period of consumption. METHODS: In a crossover, controlled trial, 37 patients (18 men, 19 women) with end-stage renal disease on maintenance hemodialysis, were randomly assigned to a 4-week VAO diet. Fasting plasma lipids, vitamin E and oxidized LDL (ox-LDL) were analyzed. Malondialdehyde (MDA) was determined before and after hemodialysis session. RESULTS: There was no significant change in serum total cholesterol and ox-LDL. However, VAO consumption decreased the levels of triglyceride (p = 0.03), total cholesterol (p = 0.02) and low-density lipoprotein (p = 0.03) and increased the levels of high-density lipoprotein (p = 0.01). Plasma vitamin E contents significantly increased from baseline only in VAO-group (p < 0.001). Hemodialysis session increased MDA levels, but the increase in VAO group was less than in control group. CONCLUSION: VAO consumption improved lipid profile and oxidative stress status in hemodialysis patients. PMID- 26101141 TI - Ambulatory and diary methods can facilitate the measurement of patient-reported outcomes. AB - PURPOSE: Ambulatory and diary methods of self-reported symptoms and well-being have received increasing interest in recent years. These methods are a valuable addition to traditional strategies for the assessment of patient-reported outcomes (PROs) in that they capture patients' recent symptom experiences repeatedly in their natural environments. In this article, we review ways that incorporating diary methods into PRO measurement can facilitate research on quality of life. METHODS: Several diary methods are currently available, and they include "real-time" (Ecological Momentary Assessment) and "near-real-time" (end of-day assessments, Day Reconstruction Method) formats. We identify the key benefits of these methods for PRO research. RESULTS: (1) In validity testing, diary assessments can serve as a standard for evaluating the ecological validity and for identifying recall biases of PRO instruments with longer-term recall formats. (2) In research and clinical settings, diaries have the ability to closely capture variations and dynamic changes in quality of life that are difficult or not possible to obtain from traditional PRO assessments. (3) In test construction, repeated diary assessments can expand understanding of the measurement characteristics (e.g., reliability, dimensionality) of PROs in that parameters for differences between people can be compared with those for variation within people. CONCLUSIONS: Diary assessment strategies can enrich the repertoire of PRO assessment tools and enhance the measurement of patients' quality of life. PMID- 26101143 TI - Stem cell-based pulp tissue engineering: variables enrolled in translation from the bench to the bedside, a systematic review of literature. AB - Stem cell-based therapy (SC-BT) is emerging as an alternative for endodontic therapies. The interaction between stem cells and scaffolds plays a crucial role in the generation of a 'friendly cell' microenvironment. The aim of this systematic review was to explore techniques applied to regenerate the pulp dentine complex tissue using SC-BT. An electronic search into the SciVerse Scopus (SS), ISI Web Science (IWS) and Entrez PubMed (EP) using specific keywords was performed. Specific inclusion and exclusion criteria were predetermined. The search yielded papers, out of which full-text papers were included in the final analyses. Data extraction pooled the results in four main topics: (a) influence of the chemical properties of the scaffolds over cell behaviour; (b) influence of the physical characteristics of scaffolds over cell behaviour; (c) strategies applied to improve the stem cell/scaffold interface; and (d) influence of cue microenvironment on stem cell differentiation towards odontoblast-like cells and pulp-like tissue formation. The relationship between the scaffolds, the environment and the growth factors released from dentine are critical for de novo pulp tissue regeneration. The preconditioning of dentine walls with ethylenediaminetetraacetic acid (EDTA) was imperative for successful pulp-dentine complex regeneration. An analyses of the grouped results revealed that pulp regeneration was an attainable goal. PMID- 26101144 TI - BMA annual meeting: Doctors fear that devolving health spending in Manchester will lead to cuts. PMID- 26101145 TI - Prenylated flavanone derivatives isolated from Erythrina addisoniae are potent inducers of apoptotic cell death. AB - Extracts of Erythrina addisoniae are frequently used in the traditional medicine of Western Africa, but insufficient information about active compounds is available. From the stem bark of E. addisoniae, three (1, 2, 4) and three known (3, 5, 6) flavanones were isolated: addisoniaflavanones I and II, containing either a 2",3"-epoxyprenyl moiety (1) or a 2",3"-dihydroxyprenyl moiety (2) were shown to be highly toxic (MTT assay: EC50 values of 5.25+/-0.7 and 8.5+/-1.3 MUM, respectively) to H4IIE hepatoma cells. The cytotoxic potential of the other isolated flavanones was weaker (range of EC50 values between 15 and >100 MUM). Toxic effects of addisoniaflavanone I and II were detectable after 3h (MTT assay). Both compounds induced an apoptotic cell death (caspase-3/7 activation, nuclear fragmentation) in the hepatoma cells and, at high concentrations, also necrosis (membrane disruption: ethidium bromide staining). Formation of DNA strand breaks was not detectable after incubation with these compounds (comet assay). In conclusion, the prenylated flavanones addisoniaflavanones I and II may be of interest for pharmacological purposes due to their high cytotoxic and pro apoptotic potential against hepatoma cells. PMID- 26101146 TI - Sesquiterpenes, flavonoids, shikimic acid derivatives and pyrrolizidine alkaloids from Senecio kingii Hook. AB - Twenty-four compounds including eleven eremophilanolides (1-11), one eremophilane (13), five shikimic acid derivatives (14-18), six flavonoids (19-24), and the macrocyclic unsaturated pyrrolizidine alkaloid integerrimine (25) were isolated from Senecio kingii, an endemic species from the Magallanes Region (Chile). Compounds 3, 5, 6, 8-11 and 13-18 have not been previously reported as natural products. Their molecular structures were determined by NMR spectroscopic analysis and comparison with published NMR data. An X-ray-analysis of compound 3 has been performed. Their insecticidal and antifungal activities were tested, being compound 3 the strongest insect antifeedant. Compounds 6, 9 and 18 were moderate antifungals. PMID- 26101147 TI - Novel stilbenoids, including cannabispiradienone glycosides, from Tragopogon tommasinii (Asteraceae, Cichorieae) and their potential anti-inflammatory activity. AB - A phytochemical investigation of Tragopogon tommasinii Sch.Bip. (Asteraceae, Cichorieae) yielded a total of 21 natural products, two simple phenolic acids (4 hydroxybenzoic acid and p-coumaric acid), four caffeic acid derivatives (chlorogenic acid, 3-O-caffeoylquinic acid, 3,5-O-dicaffeoylquinic acid, and 4,5 O-dicaffeoylquinic acid), six flavonoids (luteolin, luteolin 7-O-glucoside, vitexin, orientin, quercetin 3-O-glucoside, and isorhamnetin 3-O-glucoside), three simple bibenzyls [2-carboxyl-5-hydroxy-3-methoxy-4'-beta-glucopyranosyl oxybibenzyl, 3-caffeoyl-(9->5)-beta-apiosyl-(1->6)-beta-glucopyranosyloxy-5,4' dihydroxy-3'-methoxybibenzyl, 3-caffeoyl-(9->5)-beta-apiosyl-(1->6)-beta glucopyranosyloxy-4'-dihydroxy-5,3'-dimethoxybibenzyl], three phtalides [3-(4 beta-glucopyranosyloxybenzyl)-7-hydroxy-5-methoxyphtalide, 7-beta glucopyranosyloxy-(S)-3-(4-hydroxybenzyl)-5-methoxyphtalide, and 7-(1->6)-alpha rhamnosyl-beta-glucopyranosyloxy-(S)-3-(4-hydroxybenzyl)-5-methoxyphtalide], two cannabispiradienone derivatives [3-O-beta glucopyranosyldemethoxycannabispiradienone and 3-caffeoyl-(9->5)-beta-apiosyl-(1 >6)-beta-glucopyranosyloxydemethoxycannabispiradienone], and tetra-N-coumaroyl spermine. The three bibenzyls, the latter two benzylphthalides, and both cannabispiradienone derivatives represent new natural compounds and all compounds, except the caffeic acid derivatives and the flavonoids were new for T. tommasinii. The structures were established by HR mass spectrometry, extensive 1D and 2D NMR spectroscopy, and CD spectroscopy. Moreover, the potential anti inflammatory activities of the new compounds were assayed using human neutrophils and their production of IL-1b, IL-8, TNF-alpha and MMP-9 as well as the expression of TLR-4, respectively. PMID- 26101148 TI - Plant betalains: Chemistry and biochemistry. AB - Betalains are vacuolar pigments composed of a nitrogenous core structure, betalamic acid [4-(2-oxoethylidene)-1,2,3,4-tetrahydropyridine-2,6-dicarboxylic acid]. Betalamic acid condenses with imino compounds (cyclo-l-3,4-dihydroxy phenylalanine/its glucosyl derivatives), or amino acids/derivatives to form variety of betacyanins (violet) and betaxanthins (yellow), respectively. About 75 betalains have been structurally unambiguously identified from plants of about 17 families (known till date) out of 34 families under the order Caryophyllales, wherein they serve as chemosystematic markers. In this review, all the identified betalain structures are presented with relevant discussion. Also, an estimated annual production potential of betalains has been computed for the first time. In addition, mutual exclusiveness of anthocyanins and betalains has been discussed in the wake of new evidences. An inclusive list of betalain-accumulating plants reported so far has been presented here to highlight pigment occurrence and accumulation pattern. Betalain synthesis starts with hydroxylation of tyrosine to DOPA, and subsequent cleavage of aromatic ring of DOPA resulting to betalamic acid formation. This pathway consists of two key enzymes namely, bifunctional tyrosinase (hydroxylation and oxidation) and DOPA dioxygenase (O2-dependent aromatic ring cleavage). Various spontaneous cyclisation, condensation and glucosylation steps complement the extended pathway, which has been presented here comprehensively. The biosynthesis is affected by various ecophysiological factors including biotic and abiotic elicitors that can be manipulated to increase pigment production for commercial scale extraction. Betalains are completely safe to consume, and contribute to health. PMID- 26101149 TI - Response to Nakao et al. - is Echinococcus intermedius a valid species? PMID- 26101150 TI - Is Echinococcus intermedius a valid species? PMID- 26101151 TI - Vitamin D intake associates with insulin resistance in type 2 diabetes, but not in latent autoimmune diabetes in adults. AB - This study aimed to evaluate the relationship between vitamin D (vitD) intake and serum concentrations and insulin secretion (assessed by C-peptide serum concentration)/insulin resistance (determined by estimated glucose disposal rate [eGDR]) in patients with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2DM). C-peptide, serum vitD, lipid profile, insulin, glucose, and glycosylated hemoglobin (HbA1c) were assessed; vitD intake was determined; and eGDR was calculated. Groups were compared using the Student t or Mann-Whitney U test. Correlations were performed between insulin secretion, insulin resistance, and vitD, and linear regression models were adjusted for confounding variables. Of 107 patients included, age was 55.3 +/- 11.84 years old, and time since diabetes diagnosis was 13.23 +/- 5.96 years. There were significant intergroup differences in age, body mass index (BMI), hip measurements, glucose, and HbA1c. The correlation between vitD intake and C-peptide for the whole group was significant (r = 0.213; P = .032) as well as for vitD deficiency/sufficiency in T2DM (P = .042), whereas neither was significant in eGDR. After adjustment for age, HbA1c, disease progression, physical activity, solar exposure, sex, and BMI, vitD intake was only significant in T2DM (P = .028). In serum vitD, only the correlation between eGDR and vitD in T2DM was significant and intragroup when comparing vitD sufficiency. After adjustments, significance was lost. Patients with LADA had lower intake of vitD, poorer metabolic control, lower BMI, and younger age compared to T2DM patients. There was no association between serum vitD or vitD intake and insulin secretion when analyzed by group, although vitD intake was associated with insulin resistance in T2DM, but not LADA. PMID- 26101152 TI - Stereochemical Communication within a Chiral Ion Pair Catalyst. AB - Ionic interactions are increasingly appreciated as a key, asymmetry-inducing factor in enantioselective catalytic transformations, including those involving Bronsted acid or base catalysis, phase-transfer catalysis, and related processes. However, a detailed understanding of these interactions is often lacking. Herein, we show how an enantiopure anion enforces a chiral conformation onto a catalytically relevant achiral cation. Specifically, we use vibrational circular dichroism (VCD) spectroscopy to monitor the transmission of stereochemical information from a chiral phosphate anion to a flexible manganese(III)-salen cation. We show that VCD can be used to study solvent effects and that the obtained chiroptical data directly and quantitatively correlate with the experimentally observed enantioselectivity in an asymmetric olefin epoxidation reaction. PMID- 26101154 TI - Pseudohyperplastic prostate carcinoma: histologic patterns and differential diagnosis. AB - The similarity between some carcinomas and many benign glandular proliferations has been mentioned in the literature for decades. The description of the main histologic features of pseudohyperplastic carcinoma has been very useful in avoiding errors of interpretation, particularly false-negative results. In recent years, we have found some histologic variants of this neoplasm that have not been mentioned previously. In order to classify the different histologic growth patterns and comment on their differential diagnosis, we reviewed the architectural and cytologic features of 34 cases of pseudohyperplastic adenocarcinoma in 2 radical prostatectomies, 4 transurethral resections, and 28 needle biopsies. Growth patterns most commonly observed included nodular, complex, and mixed (nodular and complex) patterns. Other less frequent histologic varieties included adenosis-like pattern, prostatic intraepithelial neoplasia like pattern, pseudohyperplastic adenocarcinoma with xanthomatous features, and limited pseudohyperplastic adenocarcinoma. Frequent changes in neoplastic glands included papillary infoldings, large/cystic glands, and branching. Criteria associated with malignancy include nuclear enlargement (92%), apparent nucleoli (85%), pink amorphous secretions (78%), and transition to small acinar carcinoma (70%). However, in some biopsies, nuclear atypia was little apparent. Fifteen of the 34 cases were misdiagnosed as benign and 5 as other malignant neoplasms, and included the following diagnoses: hyperplastic nodules (11), prostatic adenosis (2), diffuse adenosis of the peripheral zone (1), benign cystic glands (1), and less frequently other malignant tumors including xanthomatous carcinoma (2), low grade prostatic adenocarcinoma (2), and atrophic carcinoma (1). It is important to recognize the different growth patterns of this neoplasm in order to avoid an underdiagnosis of malignancy. PMID- 26101153 TI - Zic1 controls placode progenitor formation non-cell autonomously by regulating retinoic acid production and transport. AB - All cranial placode progenitors arise from a common precursor field anterior to the neural plate, the pre-placodal region (PPR). We showed that transcription factor Zic1, expressed at the anterior neural plate, is necessary and sufficient to promote placode fate. Here we reveal the non-cell autonomous activity of Zic1 and implicate retinoic acid (RA) signalling as a key player in cranial placode progenitor specification. In a screen for genes activated by Zic1, we identify several factors involved in RA metabolism and function. Among them we show that retinaldehyde dehydrogenase 2 (RALDH2) and lipocalin-type prostaglandin D2 synthase (LPGDS), which, respectively, regulate the synthesis and transport of RA, directly participate in the establishment of the PPR. We propose that RALDH2 and LPGDS induction by Zic1 at the anterior neural plate allows for the localized production and transport of RA, which in turn activates a cranial placode developmental programme in neighbouring cells. PMID- 26101155 TI - Photoinitiated hydrothiolation of pyranoid exo-glycals: the d-galacto and d-xylo cases. AB - Radical-mediated addition reactions of thiols to O-peracetylated exo-galactal and exo-xylal with 2,2-dimethoxy-2-phenylacetophenone as the photoinitiator resulted in high yielding formation of the corresponding beta-d-glycopyranosylmethyl sulfide derivatives (2,6-anhydro-1-deoxy-1-S-substituted-1-thio-alditols) with exclusive regio- and very high stereoselectivity, including disaccharide mimicks with Gly-CH2-S-Gly scaffolds. PMID- 26101156 TI - JAZF1 promotes proliferation of C2C12 cells, but retards their myogenic differentiation through transcriptional repression of MEF2C and MRF4-Implications for the role of Jazf1 variants in oncogenesis and type 2 diabetes. AB - Single-nucleotide polymorphisms associated with type 2 diabetes (T2D) have been identified in Jazf1, which is also involved in the oncogenesis of endometrial stromal tumors. To understand how Jazf1 variants confer a risk of tumorigenesis and T2D, we explored the functional roles of JAZF1 and searched for JAZF1 target genes in myogenic C2C12 cells. Consistent with an increase of Jazf1 transcripts during myoblast proliferation and their decrease during myogenic differentiation in regenerating skeletal muscle, JAZF1 overexpression promoted cell proliferation, whereas it retarded myogenic differentiation. Examination of myogenic genes revealed that JAZF1 overexpression transcriptionally repressed MEF2C and MRF4 and their downstream genes. AMP deaminase1 (AMPD1) was identified as a candidate for JAZF1 target by gene array analysis. However, promoter assays of Ampd1 demonstrated that mutation of the putative binding site for the TR4/JAZF1 complex did not alleviate the repressive effects of JAZF1 on promoter activity. Instead, JAZF1-mediated repression of Ampd1 occurred through the MEF2 binding site and E-box within the Ampd1 proximal regulatory elements. Consistently, MEF2C and MRF4 expression enhanced Ampd1 promoter activity. AMPD1 overexpression and JAZF1 downregulation impaired AMPK phosphorylation, while JAZF1 overexpression also reduced it. Collectively, these results suggest that aberrant JAZF1 expression contributes to the oncogenesis and T2D pathogenesis. PMID- 26101157 TI - Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL. AB - Multidrug resistance (MDR) has been associated with expression of ABC transporter genes including P-glycoprotein (Pgp, MDR1, ABCB1). However, deregulation of apoptotic pathways also renders cells resistant to chemotherapy. To discover apoptosis-related genes affected by Pgp expression, we used the HeLa MDR-off system. We found that using doxycycline to control Pgp expression has a significant advantage over tetracycline, in that doxycycline caused less endogenous gene expression modification/perturbation, and was more potent than tetracycline in suppressing Pgp expression. Cells overexpressing Pgp have lower TNFSF10 (TRAIL) expression than their parental cells. Controlled downregulation of Pgp increased endogenous TRAIL protein expression. Also, ectopic overexpression of TRAIL in Pgp-positive cells was associated with a reduction in Pgp levels. However, cells expressing a functionally defective mutant Pgp showed an increase in TRAIL expression, suggesting that Pgp function is required for TRAIL suppression. Cells in which Pgp is knocked down by upregulation of TRAIL expression are less susceptible to TRAIL ligand (sTRAIL)-induced apoptosis. Our findings reveal an inverse correlation between functional Pgp and endogenous TRAIL expression. Pgp function plays an important role in the TRAIL-mediated apoptosis pathway by regulating endogenous TRAIL expression and the TRAIL mediated apoptosis pathway in MDR cancer cells. PMID- 26101158 TI - 4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide - A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation. AB - Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5 diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate. PMID- 26101160 TI - Multilineage dysplasia as assessed by immunophenotype has no impact on clinical biological features and outcome of NPM1-mutated acute myeloid leukemia. AB - The presence of multilineage dysplasia (MLD) by morphology at diagnosis in acute myeloid leukemia (AML) defines a separate subset in the World Health Organization classification with still-debated prognostic value. A major controversy concerns MLD's role in NPM1-mutated (NPM1+) AML, which correlates with good prognosis. We used flow cytometry (FC), an emerging technique for assessing dysplasia, to investigate MLD in NPM1+ AML by an immunophenotypic score (IPS), a technique previously adopted in myelodysplastic syndrome. Eighty-five intensively treated NPM1+ AML cases were studied. Patients were grouped according to the combination of data in maturing cell compartments. FC-assessed dysplasia showed a significant correlation with morphology-assessed dysplasia, showing the efficacy of this method in highlighting dysplasia in AML. Except for MLD, IPS did not influence any patient- or disease-related characteristics at diagnosis. Furthermore, IPS did not influence complete remission rate, disease-free survival, or overall survival. By investigating NPM1 status on separated cell compartments, we established a correlation between FC-assessed MLD and belonging to AML clone. This study shows that dysplasia evaluated by immunophenotype has no impact on clinical-biological characteristics or on outcome of NPM1+ AML. Dysplasia is part of the spectrum of NPM1+ AML, and the prognostic stratification of this category of patients should not be based upon it. PMID- 26101159 TI - Angiotensin-(1-7) counteracts angiotensin II-induced dysfunction in cerebral endothelial cells via modulating Nox2/ROS and PI3K/NO pathways. AB - Angiotensin (Ang) II, the main effector of the renin-angiotensin system, has been implicated in the pathogenesis of vascular diseases. Ang-(1-7) binds to the G protein-coupled Mas receptor (MasR) and can exert vasoprotective effects. We investigated the effects and underlying mechanisms of Ang-(1-7) on Ang II-induced dysfunction and oxidative stress in human brain microvascular endothelial cells (HbmECs). The pro-apoptotic activity, reactive oxygen species (ROS) and nitric oxide (NO) productions in HbmECs were measured. The protein expressions of nicotinamide adenine dinucleotide phosphate oxidase 2 (Nox2), serine/threonine kinase (Akt), endothelial nitric oxide synthase (eNOS) and their phosphorylated forms (p-Akt and p-eNOS) were examined by western blot. MasR antagonist and phosphatidylinositol-3-kinase (PI3K) inhibitor were used for receptor/pathway verification. We found that Ang-(1-7) suppressed Ang II-induced pro-apoptotic activity, ROS over-production and NO reduction in HbmECs, which were abolished by MasR antagonist. In addition, Ang-(1-7) down-regulated the expression of Nox2, and up-regulated the ratios of p-Akt/Akt and its downstream p-eNOS/eNOS in HbmECs. Exposure to PI3K inhibitor partially abrogated Ang-(1-7)-mediated protective effects in HbmECs. Our data suggests that Ang-(1-7)/MasR axis protects HbmECs from Ang II-induced dysfunction and oxidative stress via inhibition of Nox2/ROS and activation of PI3K/NO pathways. PMID- 26101161 TI - Molecular basis and clinical significance of genetic aberrations in B-cell precursor acute lymphoblastic leukemia. AB - B-Cell precursor acute lymphoblastic leukemia (BCP-ALL) arises from recurrent genetic insults that block precursor B-cell differentiation and drive aberrant proliferation and cell survival. Risk-adapted intensive chemotherapy is effective in curing the majority of children with BCP-ALL (>85%), but some children, not considered "high risk" and treated accordingly, experience a hematologic relapse. Moreover, survival rates in adults are significantly lower (~40%) than those in children. Recent developments in genomewide genetic analysis have provided a wide range of chromosomal and genomic abnormalities characterizing BCP-ALL, several of which are associated with patient outcome. These findings provide an opportunity to adapt risk stratification and treatment schedules and to identify new druggable targets. In this review, we discuss the established and novel genetic alterations in BCP-ALL, their molecular background, and their potential use in risk stratification and treatment of BCP-ALL. PMID- 26101163 TI - Melatonin attenuates hepatic ischemia through mitogen-activated protein kinase signaling. AB - BACKGROUND: Melatonin exerts a protective effect during hepatic ischemia reperfusion (I/R) injury through modulation of the apoptotic cell death program. Mitogen-activated protein kinases mediate various intracellular processes such as cell differentiation, survival, and death. This study investigated whether melatonin exerts a protective effect through the activation of Raf-MEK-ERK and its downstream targets, including 90 ribosomal S6 kinase (p90RSK) and Bad, during hepatic I/R damage. METHODS: Hepatic ischemia was induced in mice by occlusion of the hepatic artery, portal vein, and bile duct. Adult mice were subjected to 1 h of hepatic ischemia and 3 h of reperfusion. Vehicle or melatonin (10 mg/kg, intraperitoneal) was injected 15 min before ischemia and just before reperfusion. Serum aspartate aminotransferase and alanine aminotransferase levels were measured, and terminal deoxynucleotidyl transferase dUTP nick-end labeling histochemistry was performed. Moreover, Western blot and immunoprecipitation analyses were performed. RESULTS: Melatonin treatment attenuated hepatic I/R induced increases in alanine aminotransferase and aspartate aminotransferase levels and also ameliorated hepatic injury-induced pathologic lesions and increases of positive terminal deoxynucleotidyl transferase dUTP nick-end labeling staining in hepatic tissues. Hepatic I/R injury induced decreases in the phosphorylation of Raf-1, MEK1/2, and extracellular-regulated kinase (ERK)1/2, whereas melatonin attenuated decreases in these phosphorylation levels. Moreover, melatonin prevented the injury-induced decreases in phosphorylation of downstream targets, p90RSK and Bad. Immunoprecipitation analysis showed that the interaction between phospho-Bad and 14-3-3 was decreased in vehicle-treated animals, while melatonin prevented this decrease. Melatonin also attenuated the injury-induced increase in cleaved caspase-3. In cultured hepatocytes, melatonin treatment prevented the hydrogen peroxide-induced cell death and decrease in phosphorylation of ERK1/2. Moreover, blocking MEK by PD98059 attenuated the effect of melatonin. CONCLUSIONS: These data suggest that melatonin protects hepatic cells against hepatic I/R damage through the activation of the Raf-MEK ERK cascade and phosphorylation of its downstream targets. PMID- 26101162 TI - CRISPR-mediated genotypic and phenotypic correction of a chronic granulomatous disease mutation in human iPS cells. AB - Chronic granulomatous disease (CGD) is a rare genetic disease characterized by severe and persistent childhood infections. It is caused by the lack of an antipathogen oxidative burst, normally performed by phagocytic cells to contain and clear bacterial and fungal growth. Restoration of immune function can be achieved with heterologous bone marrow transplantation; however, autologous bone marrow transplantation would be a preferable option. Thus, a method is required to recapitulate the function of the diseased gene within the patient's own cells. Gene therapy approaches for CGD have employed randomly integrating viruses with concomitant issues of insertional mutagenesis, inaccurate gene dosage, and gene silencing. Here, we explore the potential of the recently described clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 site-specific nuclease system to encourage repair of the endogenous gene by enhancing the levels of homologous recombination. Using induced pluripotent stem cells derived from a CGD patient containing a single intronic mutation in the CYBB gene, we show that footprintless gene editing is a viable option to correct disease mutations. Gene correction results in restoration of oxidative burst function in iPS-derived phagocytes by reintroduction of a previously skipped exon in the cytochrome b-245 heavy chain (CYBB) protein. This study provides proof-of principle for a gene therapy approach to CGD treatment using CRISPR-Cas9. PMID- 26101164 TI - Stability of temperament in South Korean infants from 6 to 12 to 18 months: Moderation by age, gender, and birth order. PMID- 26101165 TI - Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models. AB - Human pluripotent stem cells (PSCs) have the capacity to revolutionize medicine by allowing the generation of functional cell types such as neurons for cell replacement therapy. However, the more immediate impact of PSCs on treatment of Alzheimer's disease (AD) will be through improved human AD model systems for mechanistic studies and therapeutic screening. This review will first briefly discuss different types of PSCs and genome-editing techniques that can be used to modify PSCs for disease modeling or for personalized medicine. This will be followed by a more in depth analysis of current AD iPSC models and a discussion of the need for more complex multicellular models, including cell types such as microglia. It will finish with a discussion on current clinical trials using PSC derived cells and the long-term potential of such strategies for treating AD. PMID- 26101170 TI - Effect of overcuffing on the accuracy of oscillometric blood pressure measurements. AB - Overcuffing (using too large a blood pressure [BP] cuff), is known to artificially lower auscultatory BP measurements; however, its effect on oscillometric readings is unclear. The possibility that overcuffing biases oscillometric readings is currently widely disregarded. We sought to confirm that overcuffing lowers auscultatory readings and to assess its effect on oscillometric measurements. Community-dwelling adults (aged >=18 years) with arm circumferences within the standard range of 25-32 cm were recruited. Using primarily the International Standards Organization 2009 protocol, we compared the standard Baum adult (25-35 cm) to the large adult (33-47 cm) cuff. The standard cuff was considered the "reference standard." In Phase I, auscultatory measurements were performed by two trained observers. In Phase II, oscillometric measurements were performed. Each phase was analyzed independently using paired t tests and by generating Bland-Altman plots. Of 108 participants, 87 contributed data for Phase I, 85 for Phase II, and 69 were common to both phases. Phase I mean age was 38.0 +/- 18.5 years, mean arm circumference was 28.0 +/- 1.9 cm, and 21% had a past hypertension. The Phase I results confirmed that overcuffing reduced auscultatory BP measurements by 3.6 +/- 5.1/2.8 +/- 4.0 mm Hg (P-values <.0001 for both). For Phase II, mean age was 39.3 +/- 18.3 years, mean arm circumference was 28.0 +/- 1.9 cm, and 22% had past hypertension. Mean BPs were 112.2 +/- 13.1/67.8 +/- 7.3 mm Hg for the large cuff and 117.8 +/- 13.3/71.2 +/- 7.1 mm Hg for the standard cuff (5.5 +/- 5.9/3.4 +/- 5.2 mm Hg lower with the large cuff; P-values <.0001).Overcuffing leads to a clinically important downward bias in oscillometric measurements. An upper size limits for oscillometric cuffs should be specified. PMID- 26101171 TI - Uric acid levels within the normal range predict increased risk of hypertension: a cohort study. AB - There are data describing that cardiovascular risks related to serum uric acid (SUA) levels may begin below the current diagnostic level for hyperuricemia. Values from 5.2 to 6.0 mg/dL were positively associated with higher cardiovascular risk. The risk associated with lower SUA levels has not been fully assessed in healthy adults. The purpose of this study was to evaluate whether normal SUA levels, even below 5-6 mg/dL, might be related to an increased risk of hypertension, compared with low-normal SUA. This cohort study was conducted in an outpatient setting: all clinics of the largest Health Maintenance Organization in Israel, in a national distribution. A total of 118,920 healthy adults (40-70 years old), who had SUA levels screened during 2002, were eligible for the study. They were stratified according to baseline SUA, and were followed for 10 years. The study endpoint was any new diagnosis of hypertension during the study period (until December 31, 2011). During 10 years of follow-up (2002-2011), 28,436 examinees developed hypertension (23.9%). Compared with the pre-defined SUA reference values (2-3 mg/dL), women with SUA within the normal range had a gradual, increased risk of developing new-onset hypertension, starting at values as low as 3-4 mg/dL (adjusted odds ratio, 1.15; 95% confidence interval, 1.01 1.30). Women with SUA 5-6 mg/dL, still accepted as normouricemia, had a 66% increased risk of developing hypertension. Younger women (ages 40-50 years at baseline) in a similar SUA subgroup (5-6 mg/dL) had an even higher risk (odds ratio, 2.25; 95% confidence interval, 1.96-2.60). Similar results were seen among men. The possibility of subtle confounders exists, despite extensive adjustment. SUA within the normal range is associated with new-onset hypertension among healthy adults, compared with once very common low-normal range values. Further study is warranted to determine new cutoffs of hypo-, normo-, and hyperuricemia, which might be far lower than current scales. PMID- 26101172 TI - A mechanism for mineralocortcoid participation in renal disease and heart failure. AB - Various forms of chronic renal disease as well as congestive heart failure progress irrespective of currently available supportive care. Clinical evidence indicates that blockade of the renin-angiotensin system and/or mineralocorticoid inhibition are partially effective. Recently, it was suggested that the initiation of feed-forward intracrine loops such as renin-angiotensin system up regulation can explain the progression of disease in the face of the control of initiating factors such as high glucose or hypertension. Here, these notions are expanded to include a potential interaction of mineralocorticoid activity with intracrine renin-angiotensin system up-regulation. In addition to suggesting therapeutic interventions, these observations lead to an expanded view of intracrine physiology. PMID- 26101173 TI - Selective colors reflection from stratified aragonite calcium carbonate plates of mollusk shells. AB - An interaction between the incident light and the structural architecture within the shell of Asian green mussel (Perna viridis) induces observable pearlescent colors. In this paper, we investigate the influence of the structural architecture on the expressed colors. After a removal of the organic binder, small flakes from crushed shells show vivid rainbow reflection under an optical microscope. An individual flake expresses vivid color under a bright-field illumination while become transparent under a dark-field illumination. The expressed colors of the aragonite flakes are directly associated with its structural architecture. The flakes with aragonite thickness of 256, 310, and 353 nm, respectively, appear blue, green, and red under an optical microscope. The spectral simulation corroborates the experimentally observed optical effects as the flakes with thicker aragonite layers selectively reflected color with longer wavelengths. Flakes with multiple aragonite thicknesses expressed multi-color as the upper aragonite layers allow reflected colors from the lower layers to be observed. PMID- 26101174 TI - Effects of Food Intake on the Relative Bioavailability of Amifampridine Phosphate Salt in Healthy Adults. AB - PURPOSE: Amifampridine (3,4-diaminopyridine) has been approved in the European Union for the treatment of Lambert-Eaton myasthenic syndrome. Amifampridine has a narrow therapeutic index, and supratherapeutic exposure has been associated with dose-dependent adverse events, including an increased risk for seizure. This study assessed the effect of food on the relative bioavailability of amifampridine in healthy subjects and informed on conditions that can alter exposure. METHODS: This randomized, open-labeled, 2-treatment, 2-period crossover study enrolled 47 healthy male and female subjects. Subjects were randomly assigned to receive 2 single oral doses of amifampridine phosphate salt (20 mg base equivalents per dose) under fed or fasted conditions separated by a washout period. Blood and urine samples for pharmacokinetic analyses were taken before and after dosing. Plasma concentrations of amifampridine and an inactive 3-N acetyl metabolite were determined. The relative bioavailability values of amifampridine and metabolite were assessed based on the plasma PK parameters AUC0 infinity, AUC0-t, and Cmax in the fed and fasted states using noncompartmental pharmacokinetic analysis. Parent drug and metabolite excretion were calculated from urinary concentrations. A food effect on bioavailability would be established if the 90% CI of the ratio of population geometric mean value of AUC0 infinity, AUC0-t, or Cmax between fed and fasted administration was not within the bioequivalence range of 80% to 125%. Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use. FINDINGS: Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed. IMPLICATIONS: At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13. PMID- 26101176 TI - The association between unequal parental treatment and the sibling relationship in Finland: The difference between full and half-siblings. AB - Studies have shown that unequal parental treatment is associated with relationship quality between siblings. However, it is unclear how it affects the relationship between full and half-siblings. Using data from the Generational Transmissions in Finland project (n = 1,537 younger adults), we study whether those who have half-siblings perceive more unequal parental treatment than those who have full siblings only. In addition, we study how unequal parental treatment is associated with sibling relationship between full, maternal, and paternal half siblings. First, we found that individuals who have maternal and/or paternal half siblings are more likely to have encountered unequal maternal treatment than individuals who have full siblings only. Second, we found that unequal parental treatment impairs full as well as maternal and paternal half-sibling relations in adulthood. Third, unequal parental treatment mediates the effect of genetic relatedness on sibling relations in the case of maternal half-siblings, but not in the case of paternal half-siblings. After controlling for unequal parental treatment, the quality of maternal half-sibling relationships did not differ from that of full siblings, whereas the quality of paternal half-sibling relationships still did. Fourth, the qualitative comments (n = 206) from the same population reveal that unequal parental treatment presents itself several ways, such as differential financial, emotional, or practical support. PMID- 26101175 TI - Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Single- and multiple-dose Once-daily Empagliflozin, a Sodium Glucose Cotransporter 2 Inhibitor, in Chinese Patients With Type 2 Diabetes Mellitus. AB - PURPOSE: The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties and tolerability of the oral once-daily sodium glucose cotransporter 2 inhibitor empagliflozin, given in single and multiple 10 and 25 mg doses in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: In a double-blind, placebo-controlled, parallel-group study, Chinese patients with T2DM were randomly assigned to receive a single dose of empagliflozin 10 or 25 mg or placebo on day 1 and once daily on days 3 to 9. FINDINGS: A total of 24 patients were enrolled (14 men, 10 women; median age, 53.5 years; empagliflozin 10 mg, n = 9; empagliflozin 25 mg, n = 9; and placebo, n = 6). After both single- and multiple-dose administration, empagliflozin 10 and 25 mg were rapidly absorbed, reaching peak plasma concentrations within 1 to 1.5 hours (median), with plasma levels declining biphasically. Empagliflozin exposure increased roughly dose proportionally between 10 and 25 mg. Mean terminal elimination half life values at steady state were 13.9 and 12.1 hours with empagliflozin 10 and 25 mg, respectively. Mean (SD) changes from baseline in 24-hour urinary glucose excretion (UGE) on day 1 were +87.7 (22.9) and +82.8 (18.8) g with empagliflozin 10 and 25 mg, respectively, compared with -1.0 (2.8) g with placebo, and on day 9 were +95.8 (24.1), +82.6 (34.8) g with empagliflozin 10 and 25 mg, respectively, compared with -4.1 (6.4) g with placebo. Mean (SD) changes from baseline in fasting plasma glucose (FPG) on day 2 were -18.7 (17.2) mg/dL and -25.8 (19.6) mg/dL with empagliflozin 10 and 25 mg, respectively, compared with -4.2 (15.2) mg/dL with placebo, and on day 9, were -25.6 (20.7) mg/dL and -31.4 (26.9) mg/dL with empagliflozin 10 and 25 mg, respectively, compared to -3.7 (7.5) mg/dL with placebo. On day 10, mean changes in weight were -1.1, -1.6, and +0.5 kg with empagliflozin 10 and 25 mg and placebo, respectively. Overall, empagliflozin 10 and 25 mg had safety profiles similar to that of placebo. There were no reports of hypoglycemia, urinary tract infections, or genital infections. IMPLICATIONS: Results with single and multiple doses of empagliflozin 10 and 25 mg suggest linear pharmacokinetic properties in Chinese patients with T2DM, with a safety profile similar to that of placebo. Empagliflozin treatment was associated with increases in UGE and reductions in FPG compared with placebo. ClinicalTrials.gov identifier: NCT01316341. PMID- 26101177 TI - Influence of thermodynamic properties of a thermo-acoustic emitter on the efficiency of thermal airborne ultrasound generation. AB - In this work we experimentally verify the theoretical prediction of the recently published Energy Density Fluctuation Model (EDF-model) of thermo-acoustic sound generation. Particularly, we investigate experimentally the influence of thermal inertia of an electrically conductive film on the efficiency of thermal airborne ultrasound generation predicted by the EDF-model. Unlike widely used theories, the EDF-model predicts that the thermal inertia of the electrically conductive film is a frequency-dependent parameter. Its influence grows non-linearly with the increase of excitation frequency and reduces the efficiency of the ultrasound generation. Thus, this parameter is the major limiting factor for the efficient thermal airborne ultrasound generation in the MHz-range. To verify this theoretical prediction experimentally, five thermo-acoustic emitter samples consisting of Indium-Tin-Oxide (ITO) coatings of different thicknesses (from 65 nm to 1.44 MUm) on quartz glass substrates were tested for airborne ultrasound generation in a frequency range from 10 kHz to 800 kHz. For the measurement of thermally generated sound pressures a laser Doppler vibrometer combined with a 12 MUm thin polyethylene foil was used as the sound pressure detector. All tested thermo-acoustic emitter samples showed a resonance-free frequency response in the entire tested frequency range. The thermal inertia of the heat producing film acts as a low-pass filter and reduces the generated sound pressure with the increasing excitation frequency and the ITO film thickness. The difference of generated sound pressure levels for samples with 65 nm and 1.44 MUm thickness is in the order of about 6 dB at 50 kHz and of about 12 dB at 500 kHz. A comparison of sound pressure levels measured experimentally and those predicted by the EDF model shows for all tested emitter samples a relative error of less than +/-6%. Thus, experimental results confirm the prediction of the EDF-model and show that the model can be applied for design and optimization of thermo-acoustic airborne ultrasound emitters. PMID- 26101179 TI - A non-randomized clinical trial to assess the impact of nonrigid, inelastic corsets on spine function in low back pain participants and asymptomatic controls. AB - BACKGROUND CONTEXT: Although previous studies suggest braces/corsets can reduce acute pain, no prior study has assessed back function after bracing with both self-reported and objective measures. Use of both self-reported and objective measures of spine function together may be important given evidence they assess unique aspects of function. PURPOSE: The aim was to assess both self-reported and objective measures of spinal function before, and after, use of a nonrigid, inelastic lumbar brace. STUDY DESIGN/SETTING: This was a non-randomized clinical trial. PATIENT SAMPLE: The sample included acute low back pain (LBP) participants and asymptomatic controls. OUTCOME MEASURES: Oswestry Disability Index (ODI), spinal stiffness, and muscle endurance were the outcome measures. METHODS: Three groups were studied: -LBP/-Brace (n=19), -LBP/+Brace (n=18), and +LBP/+Brace (n=17). Both groups of braced participants were instructed to wear the brace continually for 2 weeks with the exception of bedroom and bathroom activities. Before and after the 2-week period, three measures of spinal function were performed: spinal stiffness via motorized indentation of the L3 spinous process, a modified Sorensen test (timed lumbar extension against gravity), and the ODI. Repeated measures analyses of variance were conducted for all three outcomes. RESULTS: Among the groups, ODI scores decreased significantly for the +LBP/+Brace group (p<.001) compared with the other two groups. The +LBP/+Brace mean ODI score decreased 3.71 points (95% confidence interval [CI] 2.01-5.40) compared with the LBP/-Brace group and decreased 3.48 points (95% CI 1.77-5.20) compared with the LBP/+Brace group. Change scores for the Sorensen test were significantly increased in the +LBP/+Brace group (p=.037) compared with the -LBP/-Brace group (22.47s 95% CI 8.14-36.80). Spinal stiffness did not change significantly between groups. CONCLUSIONS: This study demonstrates that lumbar function assessed by self-reported and objective measures does not worsen when nonrigid, inelastic bracing is used for short periods of time for those with, or without, back pain. These data add to the existing literature that suggests short-term use of nonrigid, inelastic bracing for acute LBP does not decrease spinal function when measured separately with subjective or objective tools. PMID- 26101182 TI - Correction: Facile synthesis of phosphine free ultra-small PbSe nanocrystals and their light harvesting studies in ETA solar cells. PMID- 26101180 TI - Evolution of posterior parietal cortex and parietal-frontal networks for specific actions in primates. AB - Posterior parietal cortex (PPC) is an extensive region of the human brain that develops relatively late and is proportionally large compared with that of monkeys and prosimian primates. Our ongoing comparative studies have led to several conclusions about the evolution of this posterior parietal region. In early placental mammals, PPC likely was a small multisensory region much like PPC of extant rodents and tree shrews. In early primates, PPC likely resembled that of prosimian galagos, in which caudal PPC (PPCc) is visual and rostral PPC (PPCr) has eight or more multisensory domains where electrical stimulation evokes different complex motor behaviors, including reaching, hand-to-mouth, looking, protecting the face or body, and grasping. These evoked behaviors depend on connections with functionally matched domains in premotor cortex (PMC) and motor cortex (M1). Domains in each region compete with each other, and a serial arrangement of domains allows different factors to influence motor outcomes successively. Similar arrangements of domains have been retained in New and Old World monkeys, and humans appear to have at least some of these domains. The great expansion and prolonged development of PPC in humans suggest the addition of functionally distinct territories. We propose that, across primates, PMC and M1 domains are second and third levels in a number of parallel, interacting networks for mediating and selecting one type of action over others. PMID- 26101181 TI - Amniotic fluid stem cells provide considerable advantages in epidermal regeneration: B7H4 creates a moderate inflammation microenvironment to promote wound repair. AB - The current treatments for severe skin injury all involve skin grafting. However, there is a worldwide shortage of donor skin tissue. In this study, we examined the advantages of using human amniotic fluid stem (hAFS) cells in skin wound healing. In vitro, hAFS cells differentiate into keratinocytes (termed hAFS-K). Like keratinocytes, hAFS-K cells express the markers K5, K14, K10 and involucrin; display typical cellular structure, including a tonofibril-rich cytoplasm; and construct a completely pluristratified epithelium in 3D culture. In vivo, in a mouse excisional wound model, GFP-positive hAFS cells participate in wound repair. Co-localization of GFP/K14 and GFP/K10 in the repaired epidermis demonstrated that hAFS cells can differentiate into keratinocytes. Real-time PCR results confirmed that hAFS cells can initiate and promote early-stage repair of skin damage. During wound repair, hAFS cells did not directly secrete repair related factors, such as bFGF, VEGF, CXCL12, TGF-beta1 and KGF, and provided a moderate inflammation reaction with lower expression of IL-1beta, IL-6, TNF alpha, Cox2 and Mac3. In hAFS cells, the negative co-stimulatory molecule B7H4 regulates low immunogenicity, which can provide a modest inflammatory reaction microenvironment for wound repair. Furthermore, with their uniquely high proliferation rate, hAFS cells offer a promising alternative for epidermal regeneration. PMID- 26101183 TI - Puerarin attenuates glucocorticoid-induced apoptosis of hFOB1.19 cells through the JNK- and Akt-mediated mitochondrial apoptotic pathways. AB - Puerarin is an active component of Pueraria lobata, which is a commonly used Chinese herbal medicine for the treatment of osteoporosis. The present study aimed to evaluate the osteoprotective effect of puerarin on glucocorticoid (GC) induced apoptosis of osteoblasts in vitro. The effects of puerarin on dexamethasone (DEX)-induced cell apoptosis were assessed using enzyme-linked immunosorbent assay and a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and found that the viability of hFOB1.19 cells was significantly increased following exposure to between 10(-6) and 10(-10) M puerarin, with a maximal anti-apoptotic effect at a concentration of 10(-8) M. In addition, compared with the control group, puerarin upregulated the transcription and protein levels of B-cell lymphoma-2 and downregulated B-cell-associated X protein in the hFOB1.19 cells. Puerarin attenuated the DEX-induced release of cytochrome c and cleavage of caspase-3, and treatment with puerarin inhibited the c-Jun N terminal kinase (JNK) pathway and activated the phosphoinositide 3-kinase (PI3K)/Akt pathway in the hFOB1.19 cells. Furthermore, the Akt inhibitor, LY294002, partly eliminated the protective effect of puerarin on DEX-induced apoptosis, and puerarin combined with the JNK inhibitor, SP600125, suppressed DEX induced apoptosis to a lesser extent than in the cells treated with SP600125 alone. These results suggested that the JNK and PI3K/Akt signaling pathways mediate the inhibitory effects of puerarin on apoptosis in the hFOB1.19 cells. In conclusion, puerarin prevented DEX-induced apoptosis of hFOB1.19 cells via inhibition of the JNK pathway and activation of the PI3K/Akt signaling pathway in the cells, dependent on the mitochondrial apoptotic pathway. These results support puerarin as a promising target in the treatment of GC-induced osteoporosis. PMID- 26101184 TI - Effect of papain-based gel on type I collagen--spectroscopy applied for microstructural analysis. AB - Considering the improvement of biomaterials that facilitate atraumatic restorative techniques in dentistry, a papain-based gel can be used in the chemomechanical removal of decayed dental tissue. However, there is no information regarding the influence of this gel on the structure of sound collagen. The aim of the present study was to investigate the adsorption of a papain-based gel (Papacarie(TM)) to collagen and determine collagen integrity after treatment. A pilot study was first performed with 10 samples of type I collagen membrane obtained from bovine Achilles deep tendon to compare the influence of hydration (Milli-Q water) on infrared bands of collagen. In a further experiment, 10 samples of type I collagen membrane were used to evaluate the effects of Papacarie(TM) on the collagen microstructure. All analyses were performed using the attenuated total reflectance technique of Fourier transform infrared (ATR-FTIR). The results demonstrated that the application of Papacarie(TM) does not lead to the degradation of collagen and this product can be safely used in minimally invasive dentistry. As the integrity of sound collagen is preserved after the application of the papain-based gel, this product is indicated for the selective removal of infected dentin, leaving the affected dentin intact and capable of re-mineralization. PMID- 26101186 TI - Intrinsic Levy behaviour in organisms--searching for a mechanism: Comment on "Liberating Levy walk research from the shackles of optimal foraging" by A.M. Reynolds. PMID- 26101185 TI - A novel endo-beta-N-acetylglucosaminidase releases specific N-glycans depending on different reaction conditions. AB - Milk glycoproteins are involved in different functions and contribute to different cellular processes, including adhesion and signaling, and shape the development of the infant microbiome. Methods have been developed to study the complexities of milk protein glycosylation and understand the role of N-glycans in protein functionality. Endo-beta-N-acetylglucosaminidase (EndoBI-1) isolated from Bifidobacterium longum subsp. infantis ATCC 15697 is a recently isolated heat-stable enzyme that cleaves the N-N'-diacetyl chitobiose moiety found in the N-glycan core. The effects of different processing conditions (pH, temperature, reaction time, and enzyme/protein ratio) were evaluated for their ability to change EndoBI-1 activity on bovine colostrum whey glycoproteins using advanced mass spectrometry. This study shows that EndoBI-1 is able to cleave a high diversity of N-glycan structures. Nano-LC-Chip-Q-TOF MS data also revealed that different reaction conditions resulted in different N-glycan compositions released, thus modifying the relative abundance of N-glycan types. In general, more sialylated N-glycans were released at lower temperatures and pH values. These results demonstrated that EndoBI-1 is able to release a wide variety of N glycans, whose compositions can be selectively manipulated using different processing conditions. PMID- 26101187 TI - Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study. AB - BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7 10). PMID- 26101188 TI - Epoprostenol Therapy for Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure caused by pulmonary vasoconstriction and vascular remodeling, which leads to right heart failure and death. Epoprostenol (prostaglandin I2) has a potent short-acting vasodilator property, and intravenous continuous epoprostenol is therefore used for treatment of PAH. Here we review evidence for the usefulness of intravenous continuous epoprostenol therapy in patients with PAH. Epoprostenol therapy is effective in idiopathic PAH patients and in patients with PAH associated with connective tissue disease, portal hypertension or congenital heart diseases, but it is not effective in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. High-dose epoprostenol therapy markedly improved hemodynamics in some patients with PAH, possibly due to reverse remodeling of pulmonary arteries. This therapy has several side effects and complications such as headache, hypotension and catheter related infections. Intravenous continuous epoprostenol is an effective treatment, but there are still some problems to be resolved. PMID- 26101189 TI - Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis. AB - A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patients' hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis. PMID- 26101190 TI - Eosinophil Cationic Protein Shows Survival Effect on H9c2 Cardiac Myoblast Cells with Enhanced Phosphorylation of ERK and Akt/GSK-3beta under Oxidative Stress. AB - Eosinophil cationic protein (ECP) is well known as a cationic protein contained in the basic granules of activated eosinophils. Recent studies have reported that ECP exhibits novel activities on various types of cells, including rat neonatal cardiomyocytes. Here we evaluated the effects of ECP on rat cardiac myoblast H9c2 cells. Our results showed that ECP enhanced the survival of the cells, in part by promoting the ERK and Akt/GSK-3beta signaling pathways. ECP attenuated the cytotoxic effects of H2O2 on H9c2 cells as well as the production of reactive oxygen species, the number of apoptotic cells and caspase 3/7 activity in the cells. In conclusion, ECP activated the ERK and Akt/GSK-3beta pathways, resulting in anti-oxidative effects on H9c2 cells that attenuated apoptosis. PMID- 26101191 TI - Knowledge and Attitudes toward Non-invasive Prenatal Testing among Pregnant Japanese Women. AB - To assess the knowledge and attitudes of pregnant Japanese women regarding non invasive prenatal testing (NIPT). Between March and June 2013, 557 pregnant women in the Hyogo and Hiroshima Prefectures were surveyed using an anonymous, self completed questionnaire. A total of 91.9% respondents (512/557) stated that they "agree" or "conditionally agree" with NIPT implementation in Japan. Approximately 28.5% of respondents stated that they knew that the accuracy of a positive NIPT result can be affected by mother's age and background, while 34.5% of respondents stated that it was necessary for pregnant women with a positive result to undergo fetal chromosome diagnosis using amniocentesis;both percentages were low. Additionally, 92.3% of respondents would "like a detailed explanation of the test," 65.1% of them would "like psychological support if the NIPT test results came back positive," and 5.7% would terminate the pregnancy if the NIPT test results came back positive without undergoing fetal chromosome diagnosis via amniocentesis. Although a high proportion of pregnant Japanese women agreed with the introduction of NIPT into Japanese obstetrical care, there was insufficient knowledge regarding the test. It is necessary for women undergoing NIPT to be provided sufficient information and psychological support. PMID- 26101192 TI - Dynamic Finite Element Analysis of Impulsive Stress Waves Propagating from the Greater Trochanter of the Femur by a Sideways Fall. AB - Fall accidents are a common cause of femoral fracture in the elderly. The greater trochanter of the femur is often subjected to impact loading by a sideways fall, and thus it is worth studying the impulsive stress waves propagating in the femur. In this study, the impulsive stress was analyzed by the dynamic finite element method using a 3-dimensional model of the femur, and the influence of the fall configuration on the stress was discussed. The stress was concentrated around the femoral neck during the propagation of the stress wave, and the tensile maximum principal stress changed into compressive minimum principle stress on the anterior and medial sides of the neck. On the other hand, the compressive minimum principal stress changed into tensile maximum principle stress on the lateral side of the neck. The largest maximum principal stress during the impact loading was always larger in the neck than in the impact region. The largest absolute value of the minimum principal stress was found in the neck or the impact region depending on the fall configuration. The largest absolute values of the maximum and minimum principal stress were nearly equal, indicating that the bone fracture due to the tensile stress may occur around the femoral neck. PMID- 26101193 TI - Prone-Position Thoracoscopic Ligation of the Thoracic Duct for Chyle Leak Following Radical Neck Dissection in a Patient with a Right Aortic Arch. AB - A chyle leak can occur as a complication after neck or chest surgery. Such a leak prolongs the hospital stay and is sometimes life-threatening. The treatment options are conservative management, interventional radiologic embolization, and surgery. Thoracoscopic ligation of the thoracic duct has emerged as a promising and definitive treatment. The case of a 65-year-old Japanese male patient with a rare congenital right aortic arch (typeIIIB1 of Edward's classification) and a severe chyle leak that occurred after a total pharyngolaryngo-esophagectomy (TPLE) is described. The chyle leak was successfully managed by thoracoscopic ligation of the thoracic duct via a left-side approach with the patient in the prone position. PMID- 26101194 TI - Maxillary Advancement for Unilateral Crossbite in a Patient with Sleep Apnea Syndrome. AB - This article reports the case of a 44-year-old male with skeletal Class III, Angle Class III malocclusion and unilateral crossbite with concerns about obstructive sleep apnea syndrome (OSAS), esthetics and functional problems. To correct the skeletal deformities, the maxilla was anteriorly repositioned by employing LeFort I osteotomy following pre-surgical orthodontic treatment, because a mandibular setback might induce disordered breathing and cause OSAS. After active treatment for 13 months, satisfactory occlusion was achieved and an acceptable facial and oral profile was obtained. In addition, the apnea hypopnea index (AHI) decreased from 18.8 preoperatively to 10.6 postoperatively. Furthermore, after a follow-up period of 7 months, the AHI again significantly decreased from 10.6 to 6.2. In conclusion, surgical advancement of the maxilla using LeFort I osteotomy has proven to be useful in patients with this kind of skeletal malocclusion, while preventing a worsening of the OSAS. PMID- 26101195 TI - Pure Choriocarcinoma of the Ovary in Silver-Russell Syndrome. AB - Pure ovarian choriocarcinoma is an extremely rare malignancy that can be gestational or non-gestational in origin. Silver-Russell syndrome (SRS) is a rare congenital developmental disorder characterized by pre- and postnatal growth failure, relative macrocephaly, a triangular face, hemihypotrophy, and fifth finger clinodactyly. We report a rare case of pure ovarian choriocarcinoma occurring in a 19-year-old woman with SRS. Following surgery, multiple chemotherapy courses were effective and she was free of disease at the 10-month follow-up. PMID- 26101196 TI - Clinical Image: Dieulafoy's lesion: A case report. PMID- 26101199 TI - Boosting methane generation by co-digestion of sludge with fruit and vegetable waste: Internal environment of digester and methanogenic pathway. AB - The effects of anaerobic co-digestion of waste-mixed sludge with fruit and vegetable waste (FVW) on the methane generation of a mesophilic digester was investigated. Organic loading rates (OLR) were 1.46kgVS/m(3)day, 2.1kgVS/m(3)day and 2.8kgVS/m(3)day. Increase in the OLR due to FVW co-digestion caused modification of the internal environment of the digester, mainly in terms of N NH4 (mg/L). Corresponding microbial populations were investigated by metagenomic high-throughput sequencing. Maximum specific bio-methane generation of 435 NLCH4 per kgVS feed was achieved for an OLR of 2.1kgVS/m(3)day, which corresponded to a biomethane generation per kgVS removed of about 1700 NLCH4. In these conditions the methanogenic pathway was dominated by aceticlastic Methanosaeta and hydrogenotrophic/aceticlastic Methanoscarcinae. Ammonia concentration in the digester resulted a key parameter for enhancing syntrophic acetate oxidation, enabling a balanced aceticlastic and hydrogenotrophic/aceticlastic methanogenic pathway. PMID- 26101200 TI - Effect of temperature on methane production from field-scale anaerobic digesters treating dairy manure. AB - Temperature is a critical factor affecting anaerobic digestion because it influences both system heating requirements and methane production. Temperatures of 35-37 degrees C are typically suggested for manure digestion. In temperate climates, digesters require a considerable amount of additional heat energy to maintain temperatures at these levels. In this study, the effects of lower digestion temperatures (22 and 28 degrees C), on the methane production from dairy digesters were evaluated and compared with 35 degrees C using duplicate replicates of field-scale (FS) digesters with a 17-day hydraulic retention time. After acclimation, the FS digesters were operated for 12weeks using solids separated manure at an organic loading rate (OLR) of 1.4kgVSm(-3)d(-1) and then for 8weeks using separated manure amended with manure solids at an OLR of 2.6kgVSm(-3)d(-1). Methane production values of the FS digesters at 22 and 28 degrees C were about 70% and 87%, respectively, of the values from FS digesters at 35 degrees C. The results suggest that anaerobic digesters treating dairy manure at 28 degrees C were nearly as efficient as digesters operated at 35 degrees C, with 70% of total methane achievable at 22 degrees C. These results are relevant to small farms interested in anaerobic digestion for methane reduction without heat recovery from generators or for methane recovery from covered lagoon digesters. PMID- 26101197 TI - Novel epigenetic determinants of type 2 diabetes in Mexican-American families. AB - Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D. PMID- 26101201 TI - Microchip with an open tubular immobilized ph gradient for UV whole column imaging detection. AB - This study reports a new method for establishing an open tubular IPG in a microchip coupled with a whole column image detection (WCID) system for protein separation applications. This method allows a wider range of immobilized pH (2.6 9.5) to be established in a PDMS/quartz channel by controlling the diffusion of acidic and basic polymer solutions into the channel through well-designed channel dimensions. The developed pH gradient was experimentally validated by performing the separation of a mixture of standard pI markers. It was further validated by the separation of the hemoglobin control AFSC sample. This method is advantageous over existing IPG methods because it has a wider range of pH and maintains the open tubular feature that matches the UV WCID to improve the sensitivity. PMID- 26101202 TI - Shape-Persistent, Sterically Crowded Star Mesogens: From Exceptional Columnar Dimer Stacks to Supermesogens. AB - Hexasubstituted C3 -symmetric benzenes with three oligophenylenevinylene (OPV) arms and three pyridyl or phenyl substituents are shape-persistent star mesogens that are sterically crowded in the center. Such molecular structures possess large void spaces between their arms, which have to be filled in condensed phases. For the neat materials, this is accomplished by an exceptional formation of dimers and short-range helical packing in columnar mesophases. The mesophase is thermodynamically stable for the pyridyl compound. Only this derivative forms filled star-shaped supermesogens in the presence of various carboxylic acids. The latter do not arrange as dimers, but as monomers along the columnar stacks. In this liquid crystal (LC) phase, the guests are completely enclosed by the hosts. Therefore, the host can be regarded as a new LC endoreceptor, which allows the design of columnar functional structures in the future. PMID- 26101198 TI - Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson's disease. AB - In the past few years, there have been a large number of genes identified that contribute to the lifetime risk of Parkinson's disease (PD). Some genes follow a Mendelian inheritance pattern, but others are risk factors for apparently sporadic PD. Here, we will focus on those genes nominated by genome-wide association studies (GWAS) in sporadic PD, with a particular emphasis on genes that overlap between familial and sporadic disease such as those encoding a synuclein (SNCA), tau (MAPT), and leucine-rich repeat kinase 2 (LRRK2). We will advance the view that there are likely relationships between these genes that map not only to neuronal processes, but also to neuroinflammation. We will particularly discuss evidence for a role of PD proteins in microglial activation and regulation of the autophagy-lysosome system that is dependent on microtubule transport in neurons. Thus, there are at least two non-mutually exclusive pathways that include both non-cell-autonomous and cell-autonomous mechanisms in the PD brain. Collectively, these data have highlighted the amount of progress made in understanding PD and suggest ways forward to further dissect this disorder. PMID- 26101203 TI - Phthalate exposure and childrens neurodevelopment: A systematic review. AB - BACKGROUND: Emerging evidence from observational studies suggests that prenatal exposure to phthalates affects neurodevelopment in children. OBJECTIVE: To conduct a systematic review of the existing literature on the association between urinary phthalate concentrations and children's neurodevelopment. METHODS: We searched electronic bibliographic databases (MEDLINE, PubMed, EMBASE, PsycINFO, CINAHL, Global Health, CAB abstracts, and ERIC) (1910 to February 21st, 2014); reference lists of included articles, and conference abstracts (American Psychiatric Association, American Academy of Neurology, and Pediatric Academic Societies). Two independent reviewers screened abstracts and extracted data. We included original studies reporting on the association between prenatal or childhood urinary phthalate metabolites, and cognitive and behavioral outcomes (e.g., IQ scores, BASC-2 scores or equivalent) in children 0-12 years of age. RESULTS: Of 2804 abstracts screened, 11 original articles met our criteria for inclusion. CONCLUSIONS: A systematic review of the literature supports the contention that prenatal exposure phthalates is associated with adverse cognitive and behavioral outcomes in children, including lower IQ, and problems with attention, hyperactivity, and poorer social communication. Further research characterizing the associations between specific phthalate metabolites and children's neurodevelopmental outcomes is needed to support the development of mitigation strategies and enhance the development of appropriate health policy. PMID- 26101205 TI - Protecting Traditional Knowledge Related to Biological Resources: Is Scientific Research Going to Become More Bureaucratized? AB - For the past several decades, there has been a world debate on the need for protecting traditional knowledge. A global treaty appears to be a distant reality. Of more immediate concern are the steps taken by the global community to protect access to biological resources in the name of protecting traditional knowledge. The Indian experience with implementing the Convention on Biological Diversity has created substantial legal uncertainty in collaborative scientific research between Indians and foreigners apart from bureaucratizing the entire process of scientific research, especially with regard to filing of applications for intellectual property rights. The issue therefore is whether the world needs to better balance the needs of the scientific community with the rights of those who have access to traditional knowledge. PMID- 26101207 TI - Experts disagree over necessity of hepatitis E vaccine in Nepal. PMID- 26101206 TI - Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis. AB - Retinoschisis is an X-linked recessive genetic disease that leads to vision loss in males. X-linked retinoschisis (XLRS) typically affects young males; however, progressive vision loss continues throughout life. Although discovered in 1898 by Haas in two brothers, the underlying biology leading to blindness has become apparent only in the last 15 years with the advancement of human genetic analyses, generation of XLRS animal models, and the development of ocular monitoring methods such as the electroretinogram and optical coherence tomography. It is now recognized that retinoschisis results from cyst formations within the retinal layers that interrupt normal visual neurosignaling and compromise structural integrity. Mutations in the human retinoschisin gene have been correlated with disease severity of the human XLRS phenotype. Introduction of a normal human retinoschisin cDNA into retinoschisin knockout mice restores retinal structure and improves neural function, providing proof-of-concept that gene replacement therapy is a plausible treatment for XLRS. PMID- 26101204 TI - Glutamatergic Mechanisms Associated with Seizures and Epilepsy. AB - Epilepsy is broadly characterized by aberrant neuronal excitability. Glutamate is the predominant excitatory neurotransmitter in the adult mammalian brain; thus, much of past epilepsy research has attempted to understand the role of glutamate in seizures and epilepsy. Seizures induce elevations in extracellular glutamate, which then contribute to excitotoxic damage. Chronic seizures can alter neuronal and glial expression of glutamate receptors and uptake transporters, further contributing to epileptogenesis. Evidence points to a shared glutamate pathology for epilepsy and other central nervous system (CNS) disorders, including depression, which is often a comorbidity of epilepsy. Therapies that target glutamatergic neurotransmission are available, but many have met with difficulty because of untoward adverse effects. Better understanding of this system has generated novel therapeutic targets that directly and indirectly modulate glutamatergic signaling. Thus, future efforts to manage the epileptic patient with glutamatergic-centric treatments now hold greater potential. PMID- 26101209 TI - Proposed 7.4% cut in public health budget threatens antismoking and antiobesity initiatives, leader says. PMID- 26101208 TI - Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development. AB - Rapidly proliferating tumors attempt to meet the demands for nucleotide biosynthesis by upregulating folate pathways that provide the building blocks for pyrimidine and purine biosynthesis. In particular, the key role of mitochondrial folate enzymes in providing formate for de novo purine synthesis and for providing the one-carbon moiety for thymidylate synthesis has been recognized in recent studies. We have shown a significant correlation between the upregulation of the mitochondrial folate enzymes, high proliferation rates, and sensitivity to the folate antagonist methotrexate (MTX). Burkitt lymphoma and diffuse large-cell lymphoma tumor specimens have the highest levels of mitochondrial folate enzyme expression and are known to be sensitive to treatment with MTX. A key enzyme upregulated in rapidly proliferating tumors but not in normal adult cells is the mitochondrial enzyme methylenetetrahydrofolate dehydrogenase (MTHFD2). This perspective outlines the rationale for specific targeting of MTHFD2 and compares known and generated crystal structures of MTHFD2 and closely related enzymes as a molecular basis for developing therapeutic agents against MTHFD2. Importantly, the development of selective inhibitors of mitochondrial methylenetetrahydrofolate dehydrogenase is expected to have substantial activity, and this perspective supports the investigation and development of MTHFD2 inhibitors for anticancer therapy. PMID- 26101210 TI - The Writing Performance of Elementary Students Receiving Strategic and Interactive Writing Instruction. AB - Strategic and Interactive Writing Instruction (SIWI) has led to improved writing and language outcomes among deaf and hard of hearing (DHH) middle grades students. The purpose of this study was to examine the effects of SIWI on the written expression of DHH elementary students across recount/personal narrative, information report, and persuasive genres. Five multiple-probe case studies demonstrate a relationship between implementation of SIWI and improvements in genre-related writing performance. The effect of instruction was most immediately demonstrated with information reports and persuasive writing, whereas several sessions of recount instruction were needed for students to satisfy performance criteria. Additionally, pre- and post-data from a larger group of students (N = 31) were compared. Wilcoxon signed-rank test statistics were statistically significant for each genre with medium to high effect sizes. Data suggest SIWI as a promising practice with elementary students, and comments regarding further development and research are provided. PMID- 26101211 TI - What Shapes Adolescents' Future Perceptions? The Effects of Hearing Loss, Social Affiliation, and Career Self-Efficacy. AB - The current study examined the contribution of hearing loss, social affiliation, and career self-efficacy to adolescents' future perceptions. Participants were 191 11th and 12th grade students: 60 who were deaf, 36 who were deaf or hard of hearing, and 95 who were hearing. They completed the Future Perceptions Scale, the Career Decision-Making Self-Efficacy (CDMSE) Scale, and the Self-Efficacy for the Management of Work-Family Conflict Scale. Results indicated that participants who were deaf reported significantly higher levels of future clarity and intensity than the other groups. However, no significant differences were found in career self-efficacy. Hearing status and affiliation and the efficacy to manage future conflict between work and family roles were significant predictors of participants' future clarity. CDMSE was a significant predictor of future planning. Implications for theory and practice are discussed. PMID- 26101212 TI - Margaret McCartney: Medicine is a bit of a giggle. PMID- 26101213 TI - Elena Gracheva: Ion channels run hot and cold. PMID- 26101214 TI - The first buds of Cdc42. PMID- 26101215 TI - The unpredictability of prolonged activation of stress response pathways. AB - In response to stress, cellular compartments activate signaling pathways that mediate transcriptional programs to promote survival and reestablish homeostasis. Manipulation of the magnitude and duration of the activation of stress responses has been proposed as a strategy to prevent or repair the damage associated with aging or degenerative diseases. However, as these pathways likely evolved to respond specifically to transient perturbations, the unpredictability of prolonged activation should be considered. PMID- 26101216 TI - GMFbeta controls branched actin content and lamellipodial retraction in fibroblasts. AB - The lamellipodium is an important structure for cell migration containing branched actin nucleated via the Arp2/3 complex. The formation of branched actin is relatively well studied, but less is known about its disassembly and how this influences migration. GMF is implicated in both Arp2/3 debranching and inhibition of Arp2/3 activation. Modulation of GMFbeta, a ubiquitous GMF isoform, by depletion or overexpression resulted in changes in lamellipodial dynamics, branched actin content, and migration. Acute pharmacological inhibition of Arp2/3 by CK-666, coupled to quantitative live-cell imaging of the complex, showed that depletion of GMFbeta decreased the rate of branched actin disassembly. These data, along with mutagenesis studies, suggest that debranching (not inhibition of Arp2/3 activation) is a primary activity of GMFbeta in vivo. Furthermore, depletion or overexpression of GMFbeta disrupted the ability of cells to directionally migrate to a gradient of fibronectin (haptotaxis). These data suggest that debranching by GMFbeta plays an important role in branched actin regulation, lamellipodial dynamics, and directional migration. PMID- 26101217 TI - Centromere protein F includes two sites that couple efficiently to depolymerizing microtubules. AB - Firm attachments between kinetochores and dynamic spindle microtubules (MTs) are important for accurate chromosome segregation. Centromere protein F (CENP-F) has been shown to include two MT-binding domains, so it may participate in this key mitotic process. Here, we show that the N-terminal MT-binding domain of CENP-F prefers curled oligomers of tubulin relative to MT walls by approximately fivefold, suggesting that it may contribute to the firm bonds between kinetochores and the flared plus ends of dynamic MTs. A polypeptide from CENP-F's C terminus also bound MTs, and either protein fragment diffused on a stable MT wall. They also followed the ends of dynamic MTs as they shortened. When either fragment was coupled to a microbead, the force it could transduce from a shortening MT averaged 3-5 pN but could exceed 10 pN, identifying CENP-F as a highly effective coupler to shortening MTs. PMID- 26101218 TI - Pheromone-encoding mRNA is transported to the yeast mating projection by specific RNP granules. AB - Association of messenger RNAs with large complexes such as processing bodies (PBs) plays a pivotal role in regulating their translation and decay. Little is known about other possible functions of these assemblies. Exposure of haploid yeast cells, carrying mating type "a," to "alpha pheromone" stimulates polarized growth resulting in a "shmoo" projection; it also induces synthesis of "a pheromone," encoded by MFA2. In this paper, we show that, in response to alpha pheromone, MFA2 mRNA is assembled with two types of granules; both contain some canonical PB proteins, yet they differ in size, localization, motility, and sensitivity to cycloheximide. Remarkably, one type is involved in mRNA transport to the tip of the shmoo, whereas the other-in local translation in the shmoo. Normal assembly of these granules is critical for their movement, localization, and for mating. Thus, MFA2 mRNAs are transported to the shmoo tip, in complex with PB-like particles, where they are locally translated. PMID- 26101219 TI - Binding of STIL to Plk4 activates kinase activity to promote centriole assembly. AB - Centriole duplication occurs once per cell cycle in order to maintain control of centrosome number and ensure genome integrity. Polo-like kinase 4 (Plk4) is a master regulator of centriole biogenesis, but how its activity is regulated to control centriole assembly is unclear. Here we used gene editing in human cells to create a chemical genetic system in which endogenous Plk4 can be specifically inhibited using a cell-permeable ATP analogue. Using this system, we demonstrate that STIL localization to the centriole requires continued Plk4 activity. Most importantly, we show that direct binding of STIL activates Plk4 by promoting self phosphorylation of the activation loop of the kinase. Plk4 subsequently phosphorylates STIL to promote centriole assembly in two steps. First, Plk4 activity promotes the recruitment of STIL to the centriole. Second, Plk4 primes the direct binding of STIL to the C terminus of SAS6. Our findings uncover a molecular basis for the timing of Plk4 activation through the cell cycle regulated accumulation of STIL. PMID- 26101220 TI - Calcium release through P2X4 activates calmodulin to promote endolysosomal membrane fusion. AB - Intra-endolysosomal Ca(2+) release is required for endolysosomal membrane fusion with intracellular organelles. However, the molecular mechanisms for intra endolysosomal Ca(2+) release and the downstream Ca(2+) targets involved in the fusion remain elusive. Previously, we demonstrated that endolysosomal P2X4 forms channels activated by luminal adenosine triphosphate in a pH-dependent manner. In this paper, we show that overexpression of P2X4, as well as increasing endolysosomal P2X4 activity by alkalinization of endolysosome lumen, promoted vacuole enlargement in cells and endolysosome fusion in a cell-free assay. These effects were prevented by inhibiting P2X4, expressing a dominant-negative P2X4 mutant, and disrupting the P2X4 gene. We further show that P2X4 and calmodulin (CaM) form a complex at endolysosomal membrane where P2X4 activation recruits CaM to promote fusion and vacuolation in a Ca(2+)-dependent fashion. Moreover, P2X4 activation-triggered fusion and vacuolation were suppressed by inhibiting CaM. Our data thus suggest a new molecular mechanism for endolysosomal membrane fusion involving P2X4-mediated endolysosomal Ca(2+) release and subsequent CaM activation. PMID- 26101221 TI - Kinase-interacting substrate screening is a novel method to identify kinase substrates. AB - Protein kinases play pivotal roles in numerous cellular functions; however, the specific substrates of each protein kinase have not been fully elucidated. We have developed a novel method called kinase-interacting substrate screening (KISS). Using this method, 356 phosphorylation sites of 140 proteins were identified as candidate substrates for Rho-associated kinase (Rho-kinase/ROCK2), including known substrates. The KISS method was also applied to additional kinases, including PKA, MAPK1, CDK5, CaMK1, PAK7, PKN, LYN, and FYN, and a lot of candidate substrates and their phosphorylation sites were determined, most of which have not been reported previously. Among the candidate substrates for Rho kinase, several functional clusters were identified, including the polarity associated proteins, such as Scrib. We found that Scrib plays a crucial role in the regulation of subcellular contractility by assembling into a ternary complex with Rho-kinase and Shroom2 in a phosphorylation-dependent manner. We propose that the KISS method is a comprehensive and useful substrate screen for various kinases. PMID- 26101223 TI - Drug overdose has become leading cause of death from injury in US. PMID- 26101224 TI - The Presystemic Interplay between Gut Microbiota and Orally Administered Calycosin-7-O-beta-D-Glucoside. AB - Presystemic interactions with gut microbiota might play important roles in the holistic action of herbal medicines in their traditional oral applications. However, research interests usually focus on biologic activities of the in vivo available herb-derived components and their exposure in circulation. In this study, we illustrated the importance of studying the presystemic interplay with gut microbiota for understanding the holistic actions of medicinal herbs by using calycosin-7-O-beta-D-glucoside (C7G), the most abundant flavonoid and chemical marker in Astragali Radix, as a model compound. When C7G was orally administrated to rats, calycosin-3'-O-glucuronide (G2) was the major circulating component in the blood together with a minor calycosin but not C7G. Rat gut microbiota hydrolyzed C7G in vitro rapidly and produced its aglycone calycosin. Calycosin exhibited higher permeability than C7G and further underwent extensive glucuronidation to yield 3'-glucuronide as the dominant metabolite. Bioactivity assays revealed that G2 exhibited similar or more potent proangiogenic effects than calycosin in human umbilical vein endothelial cells in vitro and in the vascular endothelial growth factor receptor tyrosine kinase inhibitor II-induced blood vessel loss model in zebrafish. More interestingly, the incubation of C7G with gut microbiota from both normal and colitic rats showed a probiotics-like effect through stimulating the growth of the beneficial bacteria Lactobacillus and Bifidobacterium. In conclusion, C7G interacts reciprocally with gut microbiota after oral dosing, which makes it not only an angiogenic prodrug but also a modulator of gut microbiota. PMID- 26101222 TI - Targeted Inhibition of Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Sensitizes Pancreatic Cancer Cells to Doxorubicin without Exacerbating Cardiac Toxicity. AB - Pancreatic cancer has the lowest 5-year survival rate of all major cancers despite decades of effort to design and implement novel, more effective treatment options. In this study, we tested whether the dual phosphoinositide 3 kinase/mechanistic target of rapamycin inhibitor BEZ235 (BEZ) potentiates the antitumor effects of doxorubicin (DOX) against pancreatic cancer. Cotreatment of BEZ235 with DOX resulted in dose-dependent inhibition of the phosphoinositide 3 kinase/mechanistic target of rapamycin survival pathway, which corresponded with an increase in poly ADP ribose polymerase cleavage. Moreover, BEZ cotreatment significantly improved the effects of DOX toward both cell viability and cell death in part through reduced Bcl-2 expression and increased expression of the shorter, more cytotoxic forms of BIM. BEZ also facilitated intracellular accumulation of DOX, which led to enhanced DNA damage and reactive oxygen species generation. Furthermore, BEZ in combination with gemcitabine reduced MiaPaca2 cell proliferation but failed to increase reactive oxygen species generation or BIM expression, resulting in reduced necrosis and apoptosis. Treatment with BEZ and DOX in mice bearing tumor xenographs significantly repressed tumor growth as compared with BEZ, DOX, or gemcitabine. Additionally, in contrast to the enhanced expression seen in MiaPaca2 cells, BEZ and DOX cotreatment reduced BIM expression in H9C2 cardiomyocytes. Also, the Bcl-2/Bax ratio was increased, which was associated with a reduction in cell death. In vivo echocardiography showed decreased cardiac function with DOX treatment, which was not improved by combination treatment with BEZ. Thus, we propose that combining BEZ with DOX would be a better option for patients than current standard of care by providing a more effective tumor response without the associated increase in toxicity. PMID- 26101225 TI - Intracellular Catabolism of an Antibody Drug Conjugate with a Noncleavable Linker. AB - Antibody drug conjugates are emerging as a powerful class of antitumor agents with efficacy across a range of cancers; therefore, understanding the disposition of this class of therapeutic is crucial. Reported here is a method of enriching a specific organelle (lysosome) to understand the catabolism of an anti-CD70 Ab-MCC DM1, an antibody drug conjugate with a noncleavable linker. With such techniques a higher degree of concentration-activity relationship can be established for in vitro cell lines; this can aid in understanding the resultant catabolite concentrations necessary to exert activity. PMID- 26101227 TI - Correction of iron deficiency anaemia using IV CosmoFer in CKD patients with asthma: a prospective study. AB - BACKGROUND: Intravenous (IV) iron is commonly used for correcting iron deficiency anaemia in patients with chronic kidney disease (CKD). There remains a concern for its use in patients with asthma as it may trigger an acute exacerbation. Pre treatment with a single dose of parenteral hydrocortisone may obviate this risk. METHOD: We carried out a prospective study of known asthmatic patients with CKD requiring single-dose iron repletion therapy. We analysed the efficacy and safety of IV CosmoFer (low molecular weight iron dextran). Twenty non-dialysis CKD patients with iron deficiency anaemia and a history of asthma were enrolled. Severity of asthma and level of control were recorded as per British Thoracic Society Guidelines and Royal Collage of Physician questionnaire, respectively. All patients received IV hydrocortisone 30 min before the test dose of CosmoFer followed by the remaining total dose. Patients were monitored for adverse reactions. Haemoglobin, serum ferritin levels and estimated glomerular filtration rate were measured pre and 6-weeks post-infusion. All patients were followed up until 6 weeks to assess the control of their asthma. RESULTS: All 20 patients completed the study. No patient experienced acute hypersensitivity or infusion reactions. At 6 weeks follow-up, no patient reported worsening of their asthma. There was an increase in mean haemoglobin from 10.1 to 11.1 g/dl and mean ferritin from 93.5 to 302.6 ng/ml. CONCLUSIONS: This study demonstrates that IV CosmoFer may be administered safely in asthmatics by administering a single 50 mg dose of hydrocortisone pre-infusion. PMID- 26101226 TI - Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. AB - OBJECTIVE: To compare the clinical efficacy and bioequivalence of generic immunosuppressive drugs in patients with solid organ transplants. DESIGN: Systematic review and meta-analysis of all studies comparing generic with innovator immunosuppressive drugs. DATA SOURCES: Medline and Embase from 1980 to September 2014. REVIEW METHODS: A literature search was performed for all studies comparing a generic to an innovator immunosuppressive drug in solid organ transplantation. Two reviewers independently extracted data and assessed quality of studies. Meta-analyses of prespecified outcomes were performed when deemed appropriate. Outcomes included patient survival, allograft survival, acute rejection, adverse events and bioequivalence. RESULTS: 1679 citations were screened, of which 50 studies met eligibility criteria (17 randomized trials, 15 non-randomized interventional studies, and 18 observational studies). Generics were compared with Neoral (cyclosporine) (32 studies), Prograf (tacrolimus) (12 studies), and Cellcept (mycophenolate mofetil) (six studies). Pooled analysis of randomized controlled trials in patients with kidney transplants that reported bioequivalence criteria showed that Neoral (two studies) and Prograf (three studies) were not bioequivalent with generic preparations according to criteria of the European Medicines Agency. The single Cellcept trial also did not meet bioequivalence. Acute rejection was rare but did not differ between groups. For Neoral, the pooled Peto odds ratio was 1.23 (95% confidence interval 0.64 to 2.36) for kidney randomized controlled trials and 0.66 (0.40 to 1.08) for observational studies. For kidney observational studies, the pooled Peto odds ratios were 0.98 (0.37 to 2.60) for Prograf and 0.49 (0.09 to 2.56) for Cellcept. Meta-analyses for non-renal solid organ transplants were not performed because of a lack of data.There were insufficient data reported on patient or graft survival. Pooling of results was limited by inconsistent study methods and reporting of outcomes. Many studies did not report standard criteria used to determine bioequivalence. While rates of acute rejection seemed similar and were relatively rare, few studies were designed to properly compare clinical outcomes. Most studies had short follow-up times and included stable patients without a history of rejection. CONCLUSIONS: High quality data showing bioequivalence and clinical efficacy of generic immunosuppressive drugs in patients with transplants are lacking. Given the serious consequences of rejection and allograft failure, well designed studies on bioequivalence and safety of generic immunosuppression in transplant recipients are needed. PMID- 26101228 TI - Contrast media induced transient cortical blindness. PMID- 26101229 TI - Are generic immunosuppressants safe and effective? PMID- 26101230 TI - Interconnected Networks. PMID- 26101231 TI - Leading with a Consistency of Purpose. PMID- 26101232 TI - Addressing Oral Health Inequalities in the Africa and Middle East Region. PMID- 26101235 TI - Comparative Risk Assessment of Formulation Changes in Generic Drug Products: A Pharmacology/Toxicology Perspective. AB - This review highlights general toxicology concerns caused by formulation differences between generic and innovator drugs. It underscores the importance of a scientific, clinically oriented, evidence-based comparative safety evaluation procedure for generic drugs and discusses representative case studies from a pharmacology-toxicology perspective. For consideration by generic drug industry stakeholders, this article provides an overview of comparative risk assessments for generic drug products. PMID- 26101236 TI - Corrigendum: Gene Expression in Liver Injury Caused by Long-Term Exposure to Titanium Dioxide Nanoparticles in Mice. PMID- 26101237 TI - Serum and urinary cystatin C in cats with feline immunodeficiency virus infection and cats with hyperthyroidism. AB - OBJECTIVES: The objective of this study was to investigate serum cystatin C (sCysC) and urinary cystatin C (uCysC) in cats with hyperthyroidism and cats with feline immunodeficiency virus (FIV). METHODS: Thirty cats with FIV, 26 hyperthyroid cats and 28 healthy cats were included. sCysC and uCysC:creatinine (uCysC/uCr) ratio were measured with a human particle-enhanced nephelometric immunoassay, previously validated for feline CysC measurement. Routine renal variables (serum creatinine [sCr], urine specific gravity, urinary protein:creatinine ratio [UPC]) were also measured in the three groups. RESULTS: Cats with hyperthyroidism had significantly higher sCysC and higher uCysC/uCr ratio, lower sCr and a higher UPC than healthy cats. Cats with FIV infection did not show a significantly higher sCysC concentration but had a significantly higher sCr and UPC than healthy cats. uCysC could be detected in only four of them. CONCLUSIONS AND RELEVANCE: This study demonstrated that sCysC is increased in cats with hyperthyroidism, in contrast with sCr, but not in cats with FIV. Many hyperthyroid cats, but only four cats with FIV, had an elevated uCysC/uCr ratio. Further studies may reveal if uCysC might be a valuable marker for tubular dysfunction in cats. PMID- 26101238 TI - Stress in owned cats: behavioural changes and welfare implications. AB - Domestic cats are exposed to a variety of stressful stimuli, which may have a negative effect on the cats' welfare and trigger a number of behavioural changes. Some of the stressors most commonly encountered by cats include changes in environment, inter-cat conflict, a poor human-cat relationship and the cat's inability to perform highly motivated behaviour patterns. Stress is very likely to reduce feed intake, and stress-related anorexia may contribute to the development of potentially serious medical conditions. Stress also increases the risk of cats showing urine marking and some forms of aggression, including redirected aggression. A number of compulsive disorders such as over-grooming may also develop as a consequence of stressful environments. Some of the main strategies to prevent or reduce stress-related behavioural problems in cats are environmental enrichment, appropriate management techniques to introduce unfamiliar cats to each other and the use of the synthetic analogue of the feline facial pheromone. As the stress response in cats depends, to a large extent, on the temperament of the animal, breeding and husbandry strategies that contribute to the cat developing a well-balanced temperament are also very useful. PMID- 26101239 TI - Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors <= 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. AB - PURPOSE: We compared efficacy of trastuzumab versus no trastuzumab in patients with small (<= 2 cm) human epidermal growth factor receptor 2 (HER2) -positive breast cancer treated in randomized trials. METHODS: A meta-analysis was conducted using data from five of the six adjuvant trastuzumab trials. Efficacy end points were disease-free survival (DFS) and overall survival (OS). Separate analyses were prospectively planned for hormone receptor (HR) -positive and HR negative cohorts. Random effect models and Yusuf-Peto fixed effects models assessed the impact of heterogeneity on baseline hazards and treatment effects across studies. Peto-Pike cumulative incidence estimates were stratified by study and nodal status. RESULTS: Median follow-up time was 8 years. For 2,263 patients with HR-positive disease, 8-year cumulative incidence rates comparing trastuzumab versus no trastuzumab were 17.3% versus 24.3% (P < .001) for DFS and 7.8% versus 11.6% (P = .005) for OS, respectively; for 1,092 HR-positive patients with zero or one positive lymph nodes, results were 12.7% versus 19.4% (P = .005) for DFS and 5.3% versus 7.4% (P = .12) for OS, respectively. For 1,957 patients with HR negative disease, 8-year cumulative incidence rates were 24.0% versus 33.4% (P < .001) for DFS and 12.4% versus 21.2% (P < .001) for OS, respectively; for 1,040 HR-negative patients with zero or one positive lymph nodes, results were 20.4% versus 26.3% (P = .05) for DFS and 8.2% versus 12.2% (P = .084) for OS, respectively. CONCLUSION: Women with HER2-positive tumors <= 2 cm in the randomized trastuzumab trials derived substantial DFS and OS benefit from adjuvant trastuzumab. Trastuzumab-treated patients with HR-positive disease and <= one positive lymph node may be candidates for trials assessing less aggressive treatment approaches. PMID- 26101240 TI - Postoperative Radiation Therapy Is Associated With Improved Overall Survival in Incompletely Resected Stage II and III Non-Small-Cell Lung Cancer. AB - PURPOSE: To review trends in the use of postoperative radiotherapy (PORT) for stage II and III incompletely resected non-small-cell lung cancer (NSCLC) and evaluate the association between PORT and survival in such patients. PATIENTS AND METHODS: We identified patients with pathologic stage N0-2, overall American Joint Committee on Cancer stage II or III NSCLC within the National Cancer Data Base who had undergone a lobectomy or pneumonectomy with positive surgical margins. Only patients coded as receiving external-beam PORT at 50 to 74 Gy or observation were included. To account for perioperative mortality, we excluded patients who survived less than 4 months after diagnosis. Multivariable logistic regression was used to determine factors associated with PORT receipt. Cox proportional hazards regression was performed for multivariable analyses of overall survival. RESULTS: Among 3,395 included patients, 1,207 (35.6%) received PORT. Predictors for the use of PORT among this patient population included age less than 60 years, treatment in a nonacademic facility, earlier year of diagnosis, decreased travel distance, lower nodal stage, and chemotherapy receipt. On multivariable analysis adjusting for demographic and clinicopathologic covariates, PORT (hazard ratio, 0.80; 95% CI, 0.70 to 092) was associated with improved survival. Subset analysis by nodal stage showed that PORT improved survival across all nodal stages. CONCLUSION: PORT is associated with improved overall survival in patients with incompletely resected stage II or III N0-2 NSCLC. The use of PORT for this population in more recent years has been declining. In the absence of randomized trials evaluating PORT utilization for this patient population, our findings strongly support the delivery of PORT in patients with incompletely resected NSCLC. PMID- 26101241 TI - More Options for Fertility Preservation for Patients With Cancer. PMID- 26101242 TI - Genotype Versus Phenotype: The Yin and Yang of Germline TP53 Mutations in Li Fraumeni Syndrome. PMID- 26101243 TI - Optimizing Adjuvant Taxanes in Early Breast Cancer. PMID- 26101244 TI - Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study. AB - PURPOSE: This phase II trial evaluated the effect of neoadjuvant chemotherapy with or without second-look surgery before craniospinal irradiation on response rates and survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors. PATIENTS AND METHODS: Induction chemotherapy consisted of six cycles of carboplatin/etoposide alternating with ifosfamide/etoposide. Patients demonstrating less than complete response after induction chemotherapy were encouraged to undergo second-look surgery. Patients who did not achieve complete response or partial response after chemotherapy with or without second-look surgery proceeded to high-dose chemotherapy with thiotepa and etoposide and autologous peripheral blood stem-cell rescue before craniospinal irradiation. RESULTS: The study included 102 patients treated between January 2004 and July 2008. Median age was 12 years, and 76% were male; 53.9% had pineal region masses, and 23.5% had suprasellar lesions. Sixty-nine percent of patients achieved complete response or partial response with neoadjuvant chemotherapy. At 5 years, event-free survival was 84% +/- 4% (SE) and overall survival was 93% +/- 3%. During the median follow-up of 5.1 years, 16 patients recurred or progressed, with seven deaths after relapse. No deaths were attributed to therapy-related toxicity. Relapse occurred at the site of primary disease in 10 patients, at a distant site in three patients, or both in one patient. In two patients, progression was detected by marker increase alone. Increased serum alpha fetoprotein was a negative prognostic variable. Histologic subtype and increase of beta-human chorionic gonadotropin were not significantly correlated with worse outcomes. CONCLUSION: Neoadjuvant chemotherapy with or without second-look surgery achieved high response rates contributing to excellent survival outcomes in children with newly diagnosed non-germinomatous germ cell tumors. This regimen should be included as a backbone for further studies. PMID- 26101245 TI - Impact of Bleomycin and Vincristine Dose Reductions in Patients With Advanced Hodgkin Lymphoma Treated With BEACOPP: An Analysis of the German Hodgkin Study Group HD12 and HD15 Trials. AB - PURPOSE: The role of bleomycin and vincristine in the treatment of patients with advanced Hodgkin lymphoma (HL) is unclear, and the impact of dose reductions of these drugs on outcome and tolerability has not been systematically assessed. Because both drugs can cause significant toxicity and are frequently discontinued, we performed an analysis of patients with HL treated with BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) in the German Hodgkin Study Group HD12 and HD15 trials. PATIENTS AND METHODS: Characteristics and outcome of patients were analyzed with respect to discontinuation of bleomycin and/or vincristine. RESULTS: With 3,309 patients with HL analyzed, bleomycin was discontinued in 17.6% and vincristine in 32.6%. A total of 157 patients (4.7%) received <= four cycles of bleomycin, and 218 (6.6%) received <= three cycles of vincristine; these were compared with patients receiving > four cycles of bleomycin or > three cycles of vincristine, respectively. After a median follow-up of 59 and 67 months for progression-free survival (PFS) and overall survival (OS), respectively, there was no significant difference in PFS or OS in patients receiving <= or > four cycles of bleomycin (5 year PFS difference, 1.7%; 95% CI, -4.2% to 7.6%; 5-year OS difference, 1.5%; 95% CI, -2.6% to 5.5%). Similarly, there was no significant difference in patients receiving <= or > three cycles of vincristine (5-year PFS difference, -1.3%; 95% CI, -5.6% to 3.1%; 5-year OS difference, -0.1%; 95% CI, -3.1% to 2.9%). CONCLUSION: Bleomycin and vincristine discontinuation because of drug-specific adverse effects does not affect the efficacy of treatment in this setting. PMID- 26101246 TI - Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study. AB - PURPOSE: Peripheral T-cell lymphomas (PTCLs) represent a diverse group of non Hodgkin lymphomas with a poor prognosis and no accepted standard of care for patients with relapsed or refractory disease. This study evaluated the efficacy and tolerability of belinostat, a novel histone deacetylase inhibitor, as a single agent in relapsed or refractory PTCL. PATIENTS AND METHODS: Patients with confirmed PTCL who experienced progression after >= one prior therapy received belinostat 1,000 mg/m(2) as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary end point was overall response rate. Secondary end points included duration of response (DoR) and progression-free and overall survival. RESULTS: A total of 129 patients were enrolled, with a median of two prior systemic therapies. Overall response rate in the 120 evaluable patients was 25.8% (31 of 120), including 13 complete (10.8%) and 18 partial responses (15%). Median DoR by International Working Group criteria was 13.6 months, with the longest ongoing patient at >= 36 months. Median progression-free and overall survival were 1.6 and 7.9 months, respectively. Twelve of the enrolled patients underwent stem-cell transplantation after belinostat monotherapy. The most common grade 3 to 4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia (6.2%). CONCLUSION: Monotherapy with belinostat produced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across the major subtypes, irrespective of number or type of prior therapies. These results have led to US Food and Drug Administration approval of belinostat for this indication. PMID- 26101247 TI - Fertility Preservation Success Subsequent to Concurrent Aromatase Inhibitor Treatment and Ovarian Stimulation in Women With Breast Cancer. AB - PURPOSE: We have previously reported an approach to ovarian stimulation for the purpose of fertility preservation (FP) in women with breast cancer via embryo freezing with the concurrent use of letrozole. The aim of this study was to provide the pregnancy and FP outcomes when embryos generated with the same protocol are used. PATIENTS AND METHODS: In all, 131 women with stage <= 3 breast cancer underwent ovarian stimulation and received concurrent letrozole 5 mg per day before receiving adjuvant chemotherapy and cryopreserving embryos. RESULTS: Thirty-three of the 131 women underwent 40 attempts to transfer embryos to their own uterus (n = 18) or via the use of a gestational carrier (n = 22) at a mean age of 41.5 +/- 4.3 years with a median 5.25 years after embryo cryopreservation. The overall live birth rate per embryo transfer was similar to the US national mean among infertile women of a similar age undergoing in vitro fertilization embryo transfer (45.0 v 38.2; P = .2). Seven (38.8%) of the 18 pregnancies were twins with no higher-order pregnancies being encountered. No fetal anomalies or malformations were reported in 25 children after a mean follow-up of 40.4 +/- 26.4 months. Seventeen of the 33 women attempting pregnancy had at least one child, translating into an FP rate of 51.5% per attempting woman. CONCLUSION: Embryo cryopreservation after ovarian stimulation with the letrozole and follicle stimulating hormone protocol preserves fertility in women with breast cancer and results in pregnancy rates comparable to those expected in a noncancer population undergoing in vitro fertilization. PMID- 26101248 TI - American Society of Clinical Oncology Statement: A Conceptual Framework to Assess the Value of Cancer Treatment Options. PMID- 26101249 TI - Ribosomal protein L10(L12)4 autoregulates expression of the Bacillus subtilis rplJL operon by a transcription attenuation mechanism. AB - Ribosomal protein genes are often controlled by autoregulatory mechanisms in which a protein encoded in the operon can either bind to newly synthesized rRNA during rapid growth or to a similar target in its mRNA during poor growth conditions. The rplJL operon encodes the ribosomal L10(L12)4 complex. In Escherichia coli L10(L12)4 represses its translation by binding to the rplJL leader transcript. We identified three RNA structures in the Bacillus subtilis rplJL leader transcript that function as an anti-antiterminator, antiterminator or intrinsic terminator. Expression studies with transcriptional and translational fusions indicated that L10(L12)4 represses rplJL expression at the transcriptional level. RNA binding studies demonstrated that L10(L12)4 stabilizes the anti-antiterminator structure, while in vitro transcription results indicated that L10(L12)4 promotes termination. Disruption of anti-antiterminator, antiterminator or terminator function by competitor oligonucleotides in vitro and by mutations in vivo demonstrated that each structure functions as predicted. Thus, rplJL expression is regulated by an autogenous transcription attenuation mechanism in which L10(L12)4 binding to the anti-antiterminator structure promotes termination. We also found that translation of a leader peptide increases rplJL expression, presumably by inhibiting Rho-dependent termination. Thus, the rplJL operon of B. subtilis is regulated by transcription attenuation and antitermination mechanisms. PMID- 26101250 TI - BioJazz: in silico evolution of cellular networks with unbounded complexity using rule-based modeling. AB - Systems biologists aim to decipher the structure and dynamics of signaling and regulatory networks underpinning cellular responses; synthetic biologists can use this insight to alter existing networks or engineer de novo ones. Both tasks will benefit from an understanding of which structural and dynamic features of networks can emerge from evolutionary processes, through which intermediary steps these arise, and whether they embody general design principles. As natural evolution at the level of network dynamics is difficult to study, in silico evolution of network models can provide important insights. However, current tools used for in silico evolution of network dynamics are limited to ad hoc computer simulations and models. Here we introduce BioJazz, an extendable, user friendly tool for simulating the evolution of dynamic biochemical networks. Unlike previous tools for in silico evolution, BioJazz allows for the evolution of cellular networks with unbounded complexity by combining rule-based modeling with an encoding of networks that is akin to a genome. We show that BioJazz can be used to implement biologically realistic selective pressures and allows exploration of the space of network architectures and dynamics that implement prescribed physiological functions. BioJazz is provided as an open-source tool to facilitate its further development and use. Source code and user manuals are available at: http://oss-lab.github.io/biojazz and http://osslab.lifesci.warwick.ac.uk/BioJazz.aspx. PMID- 26101251 TI - FKBP51 employs both scaffold and isomerase functions to promote NF-kappaB activation in melanoma. AB - Melanoma is the most aggressive skin cancer; its prognosis, particularly in advanced stages, is disappointing largely due to the resistance to conventional anticancer treatments and high metastatic potential. NF-kappaB constitutive activation is a major factor for the apoptosis resistance of melanoma. Several studies suggest a role for the immunophilin FKBP51 in NF-kappaB activation, but the underlying mechanism is still unknown. In the present study, we demonstrate that FKBP51 physically interacts with IKK subunits, and facilitates IKK complex assembly. FKBP51-knockdown inhibits the binding of IKKgamma to the IKK catalytic subunits, IKK-alpha and -beta, and attenuates the IKK catalytic activity. Using FK506, an inhibitor of the FKBP51 isomerase activity, we found that the IKK regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Interestingly, both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKgamma, whereas only the TPR domain is involved in interactions with IKKalpha and beta. Collectively, these results suggest that FKBP51 promotes NF-kappaB activation by serving as an IKK scaffold as well as an isomerase. Our findings have profound implications for designing novel melanoma therapies based on modulation of FKBP51. PMID- 26101252 TI - Multiplexed highly-accurate DNA sequencing of closely-related HIV-1 variants using continuous long reads from single molecule, real-time sequencing. AB - Single Molecule, Real-Time (SMRT) Sequencing (Pacific Biosciences, Menlo Park, CA, USA) provides the longest continuous DNA sequencing reads currently available. However, the relatively high error rate in the raw read data requires novel analysis methods to deconvolute sequences derived from complex samples. Here, we present a workflow of novel computer algorithms able to reconstruct viral variant genomes present in mixtures with an accuracy of >QV50. This approach relies exclusively on Continuous Long Reads (CLR), which are the raw reads generated during SMRT Sequencing. We successfully implement this workflow for simultaneous sequencing of mixtures containing up to forty different >9 kb HIV-1 full genomes. This was achieved using a single SMRT Cell for each mixture and desktop computing power. This novel approach opens the possibility of solving complex sequencing tasks that currently lack a solution. PMID- 26101253 TI - Structural and biochemical studies of the distinct activity profiles of Rai1 enzymes. AB - Recent studies showed that Rai1 and its homologs are a crucial component of the mRNA 5'-end capping quality control mechanism. They can possess RNA 5'-end pyrophosphohydrolase (PPH), decapping, and 5'-3' exonuclease (toward 5' monophosphate RNA) activities, which help to degrade mRNAs with incomplete 5'-end capping. A single active site in the enzyme supports these apparently distinct activities. However, each Rai1 protein studied so far has a unique set of activities, and the molecular basis for these differences are not known. Here, we have characterized the highly diverse activity profiles of Rai1 homologs from a collection of fungal organisms and identified a new activity for these enzymes, 5'-end triphosphonucleotide hydrolase (TPH) instead of PPH activity. Crystal structures of two of these enzymes bound to RNA oligonucleotides reveal differences in the RNA binding modes. Structure-based mutations of these enzymes, changing residues that contact the RNA but are poorly conserved, have substantial effects on their activity, providing a framework to begin to understand the molecular basis for the different activity profiles. PMID- 26101254 TI - The de-ubiquitylating enzymes USP26 and USP37 regulate homologous recombination by counteracting RAP80. AB - The faithful repair of DNA double-strand breaks (DSBs) is essential to safeguard genome stability. DSBs elicit a signaling cascade involving the E3 ubiquitin ligases RNF8/RNF168 and the ubiquitin-dependent assembly of the BRCA1-Abraxas RAP80-MERIT40 complex. The association of BRCA1 with ubiquitin conjugates through RAP80 is known to be inhibitory to DSB repair by homologous recombination (HR). However, the precise regulation of this mechanism remains poorly understood. Through genetic screens we identified USP26 and USP37 as key de-ubiquitylating enzymes (DUBs) that limit the repressive impact of RNF8/RNF168 on HR. Both DUBs are recruited to DSBs where they actively remove RNF168-induced ubiquitin conjugates. Depletion of USP26 or USP37 disrupts the execution of HR and this effect is alleviated by the simultaneous depletion of RAP80. We demonstrate that USP26 and USP37 prevent excessive spreading of RAP80-BRCA1 from DSBs. On the other hand, we also found that USP26 and USP37 promote the efficient association of BRCA1 with PALB2. This suggests that these DUBs limit the ubiquitin-dependent sequestration of BRCA1 via the BRCA1-Abraxas-RAP80-MERIT40 complex, while promoting complex formation and cooperation of BRCA1 with PALB2-BRCA2-RAD51 during HR. These findings reveal a novel ubiquitin-dependent mechanism that regulates distinct BRCA1-containing complexes for efficient repair of DSBs by HR. PMID- 26101255 TI - microRNAs and the evolution of complex multicellularity: identification of a large, diverse complement of microRNAs in the brown alga Ectocarpus. AB - There is currently convincing evidence that microRNAs have evolved independently in at least six different eukaryotic lineages: animals, land plants, chlorophyte green algae, demosponges, slime molds and brown algae. MicroRNAs from different lineages are not homologous but some structural features are strongly conserved across the eukaryotic tree allowing the application of stringent criteria to identify novel microRNA loci. A large set of 63 microRNA families was identified in the brown alga Ectocarpus based on mapping of RNA-seq data and nine microRNAs were confirmed by northern blotting. The Ectocarpus microRNAs are highly diverse at the sequence level with few multi-gene families, and do not tend to occur in clusters but exhibit some highly conserved structural features such as the presence of a uracil at the first residue. No homologues of Ectocarpus microRNAs were found in other stramenopile genomes indicating that they emerged late in stramenopile evolution and are perhaps specific to the brown algae. The large number of microRNA loci in Ectocarpus is consistent with the developmental complexity of many brown algal species and supports a proposed link between the emergence and expansion of microRNA regulatory systems and the evolution of complex multicellularity. PMID- 26101256 TI - Induced folding in RNA recognition by Arabidopsis thaliana DCL1. AB - DCL1 is the ribonuclease that carries out miRNA biogenesis in plants. The enzyme has two tandem double stranded RNA binding domains (dsRBDs) in its C-terminus. Here we show that the first of these domains binds precursor RNA fragments when isolated and cooperates with the second domain in the recognition of substrate RNA. Remarkably, despite showing RNA binding activity, this domain is intrinsically disordered. We found that it acquires a folded conformation when bound to its substrate, being the first report of a complete dsRBD folding upon binding. The free unfolded form shows tendency to adopt folded conformations, and goes through an unfolded bound state prior to the folding event. The significance of these results is discussed by comparison with the behavior of other dsRBDs. PMID- 26101257 TI - SAMHD1 is a single-stranded nucleic acid binding protein with no active site associated nuclease activity. AB - The HIV-1 restriction factor SAMHD1 is a tetrameric enzyme activated by guanine nucleotides with dNTP triphosphate hydrolase activity (dNTPase). In addition to this established activity, there have been a series of conflicting reports as to whether the enzyme also possesses single-stranded DNA and/or RNA 3'-5' exonuclease activity. SAMHD1 was purified using three chromatography steps, over which the DNase activity was largely separated from the dNTPase activity, but the RNase activity persisted. Surprisingly, we found that catalytic and nucleotide activator site mutants of SAMHD1 with no dNTPase activity retained the exonuclease activities. Thus, the exonuclease activity cannot be associated with any known dNTP binding site. Monomeric SAMHD1 was found to bind preferentially to single-stranded RNA, while the tetrameric form required for dNTPase action bound weakly. ssRNA binding, but not ssDNA, induces higher-order oligomeric states that are distinct from the tetrameric form that binds dNTPs. We conclude that the trace exonuclease activities detected in SAMHD1 preparations arise from persistent contaminants that co-purify with SAMHD1 and not from the HD active site. An in vivo model is suggested where SAMHD1 alternates between the mutually exclusive functions of ssRNA binding and dNTP hydrolysis depending on dNTP pool levels and the presence of viral ssRNA. PMID- 26101258 TI - Ca2+ enrichment in culture medium potentiates effect of oligonucleotides. AB - Antisense and RNAi-related oligonucleotides have gained attention as laboratory tools and therapeutic agents based on their ability to manipulate biological events in vitro and in vivo. We show that Ca(2+) enrichment of medium (CEM) potentiates the in vitro activity of multiple types of oligonucleotides, independent of their net charge and modifications, in various cells. In addition, CEM reflects in vivo silencing activity more consistently than conventional transfection methods. Microscopic analysis reveals that CEM provides a subcellular localization pattern of oligonucleotides resembling that obtained by unassisted transfection, but with quantitative improvement. Highly monodispersed nanoparticles ~100 nm in size are found in Ca(2+)-enriched serum-containing medium regardless of the presence or absence of oligonucleotides. Transmission electron microscopy analysis reveals that the 100-nm particles are in fact an ensemble of much smaller nanoparticles (phi ~ 15 nm). The presence of these nanoparticles is critical for the efficient uptake of various oligonucleotides. In contrast, CEM is ineffective for plasmids, which are readily transfected via the conventional calcium phosphate method. Collectively, CEM enables a more accurate prediction of the systemic activity of therapeutic oligonucleotides, while enhancing the broad usability of oligonucleotides in the laboratory. PMID- 26101260 TI - ECHO-liveFISH: in vivo RNA labeling reveals dynamic regulation of nuclear RNA foci in living tissues. AB - Elucidating the dynamic organization of nuclear RNA foci is important for understanding and manipulating these functional sites of gene expression in both physiological and pathological states. However, such studies have been difficult to establish in vivo as a result of the absence of suitable RNA imaging methods. Here, we describe a high-resolution fluorescence RNA imaging method, ECHO liveFISH, to label endogenous nuclear RNA in living mice and chicks. Upon in vivo electroporation, exciton-controlled sequence-specific oligonucleotide probes revealed focally concentrated endogenous 28S rRNA and U3 snoRNA at nucleoli and poly(A) RNA at nuclear speckles. Time-lapse imaging reveals steady-state stability of these RNA foci and dynamic dissipation of 28S rRNA concentrations upon polymerase I inhibition in native brain tissue. Confirming the validity of this technique in a physiological context, the in vivo RNA labeling did not interfere with the function of target RNA nor cause noticeable cytotoxicity or perturbation of cellular behavior. PMID- 26101259 TI - Post-translational environmental switch of RadA activity by extein-intein interactions in protein splicing. AB - Post-translational control based on an environmentally sensitive intervening intein sequence is described. Inteins are invasive genetic elements that self splice at the protein level from the flanking host protein, the exteins. Here we show in Escherichia coli and in vitro that splicing of the RadA intein located in the ATPase domain of the hyperthermophilic archaeon Pyrococcus horikoshii is strongly regulated by the native exteins, which lock the intein in an inactive state. High temperature or solution conditions can unlock the intein for full activity, as can remote extein point mutations. Notably, this splicing trap occurs through interactions between distant residues in the native exteins and the intein, in three-dimensional space. The exteins might thereby serve as an environmental sensor, releasing the intein for full activity only at optimal growth conditions for the native organism, while sparing ATP consumption under conditions of cold-shock. This partnership between the intein and its exteins, which implies coevolution of the parasitic intein and its host protein may provide a novel means of post-translational control. PMID- 26101262 TI - Dermcidin: a skeletal muscle myokine modulating cardiomyocyte survival and infarct size after coronary artery ligation. AB - AIMS: Coronary artery disease is the leading cause of death in western countries, and its association with lower extremity peripheral artery disease (LE-PAD) represents an independent predictor of worse outcome. However, the molecular mechanisms underlying these effects are currently unknown. METHODS AND RESULTS: To investigate these processes, we used in vitro approaches and several mouse models: (i) unilateral limb ischaemia by left common femoral artery ligation [peripheral ischaemia (PI), n = 38]; (ii) myocardial infarction by permanent ligation of the left descending coronary artery (MI, n = 40); (iii) MI after 5 weeks of limb ischaemia (PI + MI, n = 44); (iv) sham operation (SHAM, n = 20). Compared with MI, PI + MI hearts were characterized by a significant increase in cardiomyocyte apoptosis, larger infarct areas, and decreased cardiac function. By using a proteomic approach, we identified a ? 8 kDa circulating peptide, Dermcidin (DCD), secreted by ischaemic skeletal muscles, enhancing cardiomyocytes apoptosis under hypoxic conditions and infarct size after permanent coronary artery ligation. siRNA interference experiments to reduce DCD circulating levels significantly reduced infarct size and ameliorated cardiac function after MI. CONCLUSION: Our data demonstrate that chronic limb ischaemia activates detrimental pathways in the ischaemic heart through humoral mechanisms of remote organ crosstalk. Thus, DCD may represent a novel important myokine modulating cardiomyocyte survival and function. PMID- 26101261 TI - Transcription blockage by stable H-DNA analogs in vitro. AB - DNA sequences that can form unusual secondary structures are implicated in regulating gene expression and causing genomic instability. H-palindromes are an important class of such DNA sequences that can form an intramolecular triplex structure, H-DNA. Within an H-palindrome, the H-DNA and canonical B-DNA are in a dynamic equilibrium that shifts toward H-DNA with increased negative supercoiling. The interplay between H- and B-DNA and the fact that the process of transcription affects supercoiling makes it difficult to elucidate the effects of H-DNA upon transcription. We constructed a stable structural analog of H-DNA that cannot flip into B-DNA, and studied the effects of this structure on transcription by T7 RNA polymerase in vitro. We found multiple transcription blockage sites adjacent to and within sequences engaged in this triplex structure. Triplex-mediated transcription blockage varied significantly with changes in ambient conditions: it was exacerbated in the presence of Mn(2+) or by increased concentrations of K(+) and Li(+). Analysis of the detailed pattern of the blockage suggests that RNA polymerase is sterically hindered by H-DNA and has difficulties in unwinding triplex DNA. The implications of these findings for the biological roles of triple-stranded DNA structures are discussed. PMID- 26101263 TI - Modulation of sympathetic activity and heart rate variability by ivabradine. AB - AIMS: Bradycardic agents are currently used in the treatment of angina and heart failure; direct information on their effects on cardiac sympathetic nerve activity (SNA) may be relevant to their chronic use. The present study evaluates the effect of pacemaker inhibition on SNA; direct nerve recordings and indirect autonomic indexes are compared. METHODS AND RESULTS: Experiments were performed in 18 anaesthetized rats. SNA (direct nerve recording) and heart rate variability (HRV) indexes were evaluated in parallel. All parameters were recorded 10 min before to 60 min after administration of the If blocker ivabradine (IVA; 2 mg/kg, i.v.; n = 8) or vehicle (VEH; n = 5). IVA-induced RR interval (RR) prolongation (at 60 min +15.0 +/- 7.1%, P < 0.01) was associated with decreased diastolic arterial pressure (DAP; -17.3 +/- 8.4%, P < 0.05) and increased SNA (+51.1 +/- 12.3%, P < 0.05). These effects were accompanied by increased RR variance (RRsigma(2)), which showed strong positive correlation with RR. Frequency-domain HRV indexes (in normalized units) were unchanged by IVA. After baroreceptor reflexes had been eliminated by sino-aortic denervation (n = 5), similar IVA induced RR prolongation (at 60 min +14.3 +/- 5.9%, NS vs. intact) was associated with a larger DAP reduction (-30.9 +/- 4.1%, P < 0.05 vs. intact), but failed to affect SNA. CONCLUSIONS: (i) IVA-induced bradycardia was associated with increased SNA, resulting from baroreceptor unloading; if this applied to chronic IVA use in humans, it would be of relevance for therapeutic use of the drug. (ii) Whenever mean HR is concomitantly changed, time-domain HRV indexes should not be unequivocally interpreted in terms of autonomic balance. PMID- 26101264 TI - Mitochondrial complex I defect and increased fatty acid oxidation enhance protein lysine acetylation in the diabetic heart. AB - AIMS: Cardiomyopathy is a major complication of diabetes. Our study was aimed to identify the sites of mitochondrial dysfunction and delineate its consequences on mitochondrial metabolism in a model of type 1 diabetes. METHODS AND RESULTS: Diabetes was induced by streptozotocin injection to male Lewis rats. We found a decrease in mitochondrial biogenesis pathway and electron transport chain complex assembly that targets Complex I. Oxidation of Complex II and long-chain fatty acid substrates support the electron leak and superoxide production. Mitochondrial defects do not limit fatty acid oxidation as the heart's preferred energy source indicating that the diabetic heart has a significant reserve in Complex I- and II-supported ATP production. Both mitochondrial fatty acid oxidation and Complex I defect are responsible for increased protein lysine acetylation despite an unchanged amount of the NAD(+)-dependent mitochondrial deacetylase sirt3. We quantitatively analysed mitochondrial lysine acetylation post-translational modifications and identified that the extent of lysine acetylation on 54 sites in 22 mitochondrial proteins is higher in diabetes compared with the same sites in the control. The increased lysine acetylation of the mitochondrial trifunctional protein subunit alpha may be responsible for the increased fatty acid oxidation in the diabetic heart. CONCLUSION: We identified the specific defective sites in the electron transport chain responsible for the decreased mitochondrial oxidative phosphorylation in the diabetic heart. Mitochondrial protein lysine acetylation is the common consequence of both increased fatty acid oxidation and mitochondrial Complex I defect, and may be responsible for the metabolic inflexibility of the diabetic heart. PMID- 26101265 TI - Identification of phenotypically and functionally heterogeneous mouse mucosal associated invariant T cells using MR1 tetramers. AB - Studies on the biology of mucosal-associated invariant T cells (MAIT cells) in mice have been hampered by a lack of specific reagents. Using MR1-antigen (Ag) tetramers that specifically bind to the MR1-restricted MAIT T cell receptors (TCRs), we demonstrate that MAIT cells are detectable in a broad range of tissues in C57BL/6 and BALB/c mice. These cells include CD4(-)CD8(-), CD4(-)CD8(+), and CD4(+)CD8(-) subsets, and their frequency varies in a tissue- and strain-specific manner. Mouse MAIT cells have a CD44(hi)CD62L(lo) memory phenotype and produce high levels of IL-17A, whereas other cytokines, including IFN-gamma, IL-4, IL-10, IL-13, and GM-CSF, are produced at low to moderate levels. Consistent with high IL-17A production, most MAIT cells express high levels of retinoic acid-related orphan receptor gammat (RORgammat), whereas RORgammat(lo) MAIT cells predominantly express T-bet and produce IFN-gamma. Most MAIT cells express the promyelocytic leukemia zinc finger (PLZF) transcription factor, and their development is largely PLZF dependent. These observations contrast with previous reports that MAIT cells from Valpha19 TCR transgenic mice are PLZF(-) and express a naive CD44(lo) phenotype. Accordingly, MAIT cells from normal mice more closely resemble human MAIT cells than previously appreciated, and this provides the foundation for further investigations of these cells in health and disease. PMID- 26101266 TI - Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration. AB - CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals during this process remains unknown. We show that during TEM, endothelial cell (EC) CD99 activates protein kinase A (PKA) via a signaling complex formed with the lysine-rich juxtamembrane cytoplasmic tail of CD99, the A kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC). PKA then stimulates membrane trafficking from the lateral border recycling compartment to sites of TEM, facilitating the passage of leukocytes across the endothelium. Pharmacologic or genetic inhibition of EC sAC or PKA, like CD99 blockade, arrests neutrophils and monocytes partway through EC junctions, in vitro and in vivo, without affecting leukocyte adhesion or the expression of relevant cellular adhesion molecules. This is the first description of the CD99 signaling pathway in TEM as well as the first demonstration of a role for sAC in leukocyte TEM. PMID- 26101268 TI - Solitaire FR revascularization device 4*40: safety study and effectiveness in preclinical models. AB - Recent randomized clinical trials have shown the benefit of stent retrievers for endovascular intervention in patients with acute ischemic stroke. The Solitaire 2 FR 4*40 device was developed to address longer clots as well as procedural difficulties. This study was undertaken to evaluate the safety of the new device in a swine model at 0, 30, and 90 days as well as its in vitro effectiveness. There were no significant differences in the overall animal health, tissue injury, hemorrhagic or thrombogenic events related to device usage. Based on the comparison at multiple time points, the Solitaire 2 4*40 device was similar in safety and usability to the Solitaire 2 4*20 device. Due to the additional length of the device, the Solitaire 2 4*40 device may in fact provide a number of additional technical benefits in the neurothrombectomy treatment of ischemic stroke. PMID- 26101269 TI - Intra-DIC (distal intracranial catheter) deployment of the Pipeline embolization device: a novel rescue strategy for failed device expansion. AB - BACKGROUND: The Pipeline embolization device (PED) is a braided flow diverter that requires a combination of meticulous maneuvers to assure proper device opening and expansion. Mechanical, anatomical, or technical challenges can result in a partially deployed PED with failed expansion. OBJECTIVE: To present a new alternative method of PED deployment using the Navien distal intracranial catheter (DIC) as a salvage maneuver for cases where PED opening fails with standard techniques. METHODS: We retrospectively reviewed a prospective, single center aneurysm database to identify all patients who underwent endovascular treatment of intracranial aneurysms using the PED with the Navien distal intracranial catheter access platform. Cases requiring PED deployment within the Navien catheter were reviewed. Data was collected for patient demographics, aneurysm characteristics, and technical details of the interventional procedure. RESULTS: Eleven PED neurointerventions requiring intra-Navien PED deployment to fully open the PED were identified. Mean patient age was 55.5+/-9.9 years (range 37-76 years). Mean aneurysm size was 12.5 mm+/-4.9 mm (range 2-42 mm). All aneurysms were located in the anterior circulation (anterior cerebral artery, n=1; supraclinoid, n=1; ophthalmic/paraophthalmic, n=6; cavernous, n=3; petrocervical, n=1). Mean fluoroscopy time was 67.1+/-20.5 min. The intra-Navien technique was used to open the proximal PED (n=7) and the mid-portion (n=4). Post processing of the PED with a balloon was used in six cases. CONCLUSIONS: When a partially deployed PED remains constrained despite exhaustion of standard maneuvers to facilitate opening, the technique of intra-Navien PED deployment is a valuable rescue strategy. This new alternative method of PED deployment can be used to open a stretched device with successful completion of the PED implantation. PMID- 26101267 TI - Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. AB - Autophagy is a conserved process that uses double-membrane vesicles to deliver cytoplasmic contents to lysosomes for degradation. Although autophagy may impact many facets of human biology and disease, in this review we focus on the ability of autophagy to protect against certain neurodegenerative and infectious diseases. Autophagy enhances the clearance of toxic, cytoplasmic, aggregate-prone proteins and infectious agents. The beneficial roles of autophagy can now be extended to supporting cell survival and regulating inflammation. Autophagic control of inflammation is one area where autophagy may have similar benefits for both infectious and neurodegenerative diseases beyond direct removal of the pathogenic agents. Preclinical data supporting the potential therapeutic utility of autophagy modulation in such conditions is accumulating. PMID- 26101270 TI - Detection of Entebbe Bat Virus After 54 Years. AB - Entebbe bat virus (ENTV; Flaviviridae: Flavivirus), closely related to yellow fever virus, was first isolated from a little free-tailed bat (Chaerephon pumilus) in Uganda in 1957, but was not detected after that initial isolation. In 2011, we isolated ENTV from a little free-tailed bat captured from the attic of a house near where it had originally been found. Infectious virus was recovered from the spleen and lung, and the viral RNA was sequenced and compared with that of the original isolate. Across the polypeptide sequence, there were 76 amino acid substitutions, resulting in 97.8% identity at the amino acid level between the 1957 and 2011 isolates. Further study of this virus would provide valuable insights into the ecological and genetic factors governing the evolution and transmission of bat- and mosquito-borne flaviviruses. PMID- 26101271 TI - Clinical Features of Imported Loiasis: A Case Series from the Hospital for Tropical Diseases, London. AB - We retrospectively analyzed the background, clinical features, and treatment response of 50 cases of imported loiasis who presented between 2000 and 2014 to the Hospital for Tropical Diseases (HTD), London, United Kingdom. Of them, 29 were migrants from, and 21 were visitors to, countries where the disease is endemic. Clinical features differed between these groups. Migrants experienced fewer Calabar swellings (odds ratio [OR] = 0.12), more eye worm (OR = 3.4), more microfilaremia (OR = 3.5), lower filarial antibody levels, and lower eosinophil counts (P < 0.05 for all tests). Among 46 patients who were started on treatment at HTD, 33 (72%) received diethylcarbamazine (DEC) monotherapy as first-line treatment, and among 26 patients who were followed up after treatment, seven (27%) needed a second course of treatment. There were 46 courses of treatment with DEC, and 20 (43%) of them had reactions. All patients with microfilaremia > 3,000 microfilariae/mL and all those with an elevated C-reactive protein (CRP) (>= 5 mg/L) before treatment had reactions (P = 0.10 and P = 0.01, respectively). These data suggest that monotherapy with DEC may not be the optimal treatment for patients with loiasis, particularly for those with a high microfilarial load. PMID- 26101272 TI - Detection of Zika Virus Infection in Thailand, 2012-2014. AB - Zika virus (ZIKV) is an emerging mosquito-borne pathogen with reported cases in Africa, Asia, and large outbreaks in the Pacific. No autochthonous ZIKV infections have been confirmed in Thailand. However, there have been several cases reported in travelers returning from Thailand. Here we report seven cases of acute ZIKV infection in Thai residents across the country confirmed by molecular or serological testing including sequence data. These endemic cases, combined with previous reports in travelers, provide evidence that ZIKV is widespread throughout Thailand. PMID- 26101273 TI - Hemoglobin E and Glucose-6-Phosphate Dehydrogenase Deficiency and Plasmodium falciparum Malaria in the Chittagong Hill Districts of Bangladesh. AB - Hemoglobin E is largely confined to south and southeast Asia. The association between hemoglobin E (HbE) and malaria is less clear than that of hemoglobin S and C. As part of a malaria study in the Chittagong Hill Districts of Bangladesh, an initial random sample of 202 individuals showed that 39% and 49% of Marma and Khyang ethnic groups, respectively, were positive for either heterozygous or homozygous hemoglobin E. In this group, 6.4% were also found to be severely deficient and 35% mildly deficient for glucose-6-phosphate dehydrogenase (G6PD). In a separate Plasmodium falciparum malaria case-uninfected control study, the odds of having homozygous hemoglobin E (HbEE) compared with normal hemoglobin (HbAA) were higher among malaria cases detected by passive surveillance than age and location matched uninfected controls (odds ratio [OR] = 5.0, 95% confidence interval [CI] = 1.07-46.93). The odds of heterozygous hemoglobin E (HbAE) compared with HbAA were similar between malaria cases and uninfected controls (OR = 0.71, 95% CI = 0.42-1.19). No association by hemoglobin type was found in the initial parasite density or the proportion parasite negative after 2 days of artemether/lumefantrine treatment. HbEE, but not HbAE status was associated with increased passive case detection of malaria. PMID- 26101274 TI - Molecular Detection of the Carriage Rate of Four Intestinal Protozoa with Real Time Polymerase Chain Reaction: Possible Overdiagnosis of Entamoeba histolytica in Nigeria. AB - Diarrhea remains the second largest killer of children worldwide, and Nigeria ranks number two on the list of global deaths attributable to diarrhea. Meanwhile, prevalence studies on potentially diarrheagenic protozoa in asymptomatic carriers using molecular detection methods remain scarce in sub Saharan countries. To overcome sensitivity issues related to microscopic detection and identification of cysts in stool concentrates, real-time polymerase chain reaction (PCR) was used to analyze genomic DNAs extracted from stool samples from 199 healthy school children for Entamoeba histolytica, E. dispar, Giardia intestinalis, and Cryptosporidium. Questionnaires were administered for epidemiological data collection. E. histolytica was not detected in any of the samples, whereas Giardia (37.2%), E. dispar (18.6%), and Cryptosporidium (1%) were found. Most of the children sourced their drinking water from community wells (91%), while the majority disposed of feces in the bush (81.9%). Our study is the first to use real-time PCR to evaluate the epidemiology of E. histolytica, Giardia, and Cryptosporidium in Nigeria where previous studies using traditional diagnostic techniques have suggested higher and lower carriage rates of E. histolytica and Giardia, respectively. It is also the first study to accurately identify the prevalence of common potentially diarrheagenic protozoa in asymptomatic carriers in sub-Saharan Africa. PMID- 26101275 TI - Strong Association Between Human and Animal Brucella Seropositivity in a Linked Study in Kenya, 2012-2013. AB - Brucellosis is a common bacterial zoonotic infection but data on the prevalence among humans and animals is limited in Kenya. A cross-sectional survey was conducted in three counties practicing different livestock production systems to simultaneously assess the seroprevalence of, and risk factors for brucellosis among humans and their livestock (cattle, sheep, camels, and goats). A two-stage cluster sampling method with random selection of sublocations and households was conducted. Blood samples were collected from humans and animals and tested for Brucella immunoglobulin G (IgG) antibodies. Human and animal individual seroprevalence was 16% and 8%, respectively. Household and herd seroprevalence ranged from 5% to 73% and 6% to 68%, respectively. There was a 6-fold odds of human seropositivity in households with a seropositive animal compared with those without. Risk factors for human seropositivity included regular ingestion of raw milk (adjusted odds ratio [aOR] = 3.5, 95% confidence interval [CI] = 2.8-4.4), exposure to goats (herding, milking, and feeding) (aOR = 3.1, 95% CI = 2.5-3.8), and handling of animal hides (aOR = 1.8, 95% CI = 1.5-2.2). Attaining at least high school education and above was a protective factor for human seropositivity (aOR = 0.3, 95% CI = 0.3-0.4). This linked study provides evidence of a strong association between human and animal seropositivity at the household level. PMID- 26101277 TI - Time to think differently: catalysing a paradigm shift in forensic science. PMID- 26101276 TI - Insights Into Circulating Cytokine Dynamics During Pregnancy in HIV-Infected Beninese Exposed to Plasmodium falciparum Malaria. AB - We investigated the circulating plasma levels of Th1- (Interleukin-2 [IL-2], tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma]) and Th2 type (IL-4, IL-5, IL-10) cytokines in human immunodeficiency virus (HIV)-infected pregnant women living in a malaria-endemic area. We analyzed samples from 200 pregnant women included in the prevention of pregnancy-associated malaria in HIV infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) clinical trial who were followed until delivery. Cytokine concentrations were measured by flow cytometry-based multiplex bead array. Significantly elevated levels of IL-10 and lower levels of TNF-alpha were observed at delivery compared with inclusion (P = 0.005). At inclusion, the presence of circulating IFN-gamma, a higher CD4(+) T cell count and having initiated intermittent preventive treatment of malaria with sulfadoxine pyrimethamine (SP-IPTp) were all associated with a lower likelihood of Plasmodium falciparum infection. At delivery, the inverse relationship between the presence of infection and circulating IFN-gamma persisted, although there was a positive association between the likelihood of infection and the presence of circulating TNF-alpha. Initiation of antiretroviral therapy was associated with elevated IL-5 production. Consistent with our own and others' observations in HIV seronegative subjects, this study shows circulating IL-10 to be a marker of infection with P. falciparum during pregnancy even in HIV infected women, although plasma IFN-gamma may be a marker of anti-malarial protection in such women. PMID- 26101278 TI - The future of forensic DNA analysis. AB - The author's thoughts and opinions on where the field of forensic DNA testing is headed for the next decade are provided in the context of where the field has come over the past 30 years. Similar to the Olympic motto of 'faster, higher, stronger', forensic DNA protocols can be expected to become more rapid and sensitive and provide stronger investigative potential. New short tandem repeat (STR) loci have expanded the core set of genetic markers used for human identification in Europe and the USA. Rapid DNA testing is on the verge of enabling new applications. Next-generation sequencing has the potential to provide greater depth of coverage for information on STR alleles. Familial DNA searching has expanded capabilities of DNA databases in parts of the world where it is allowed. Challenges and opportunities that will impact the future of forensic DNA are explored including the need for education and training to improve interpretation of complex DNA profiles. PMID- 26101279 TI - Imaging and virtual autopsy: looking back and forward. AB - In order to create a three-dimensional (3D) documentation of findings which can be reassessed if necessary by other experts, the research project 'Virtopsy(r)' was launched in the late 1990s. This project combined autopsy results with forensic imaging in the form of computed tomography, magnetic resonance tomography and 3D surface scanning. The success of this project eventually succeeded in convincing the courts in Switzerland to accept these novel methods as evidence. As opposition towards autopsies has grown over the last decades, Virtopsy also strives to find and elaborate additional methods which can answer the main forensic questions without autopsy. These methods comprise post-mortem angiography for illustration of the vascular bed and image-guided tissue and fluid sampling for histological, toxicological and microbiological examinations. Based on the promising results, post-mortem imaging, especially with 3D surface scanning, has meanwhile also been applied to living victims of assault, who have suffered patterned injuries due to bites, blows with objects, etc. In our opinion, forensic imaging is an objective method which offers the possibility for a reassessment of the findings by other experts, even after burial or cremation of the corpse, or healing of the injuries in living victims, thus leading to a greater security in court. PMID- 26101280 TI - Bridging the gap: from biometrics to forensics. AB - Biometric recognition, or simply biometrics, refers to automated recognition of individuals based on their behavioural and biological characteristics. The success of fingerprints in forensic science and law enforcement applications, coupled with growing concerns related to border control, financial fraud and cyber security, has generated a huge interest in using fingerprints, as well as other biological traits, for automated person recognition. It is, therefore, not surprising to see biometrics permeating various segments of our society. Applications include smartphone security, mobile payment, border crossing, national civil registry and access to restricted facilities. Despite these successful deployments in various fields, there are several existing challenges and new opportunities for person recognition using biometrics. In particular, when biometric data is acquired in an unconstrained environment or if the subject is uncooperative, the quality of the ensuing biometric data may not be amenable for automated person recognition. This is particularly true in crime-scene investigations, where the biological evidence gleaned from a scene may be of poor quality. In this article, we first discuss how biometrics evolved from forensic science and how its focus is shifting back to its origin in order to address some challenging problems. Next, we enumerate the similarities and differences between biometrics and forensics. We then present some applications where the principles of biometrics are being successfully leveraged into forensics in order to solve critical problems in the law enforcement domain. Finally, we discuss new collaborative opportunities for researchers in biometrics and forensics, in order to address hitherto unsolved problems that can benefit society at large. PMID- 26101281 TI - Cognitive neuroscience in forensic science: understanding and utilizing the human element. AB - The human element plays a critical role in forensic science. It is not limited only to issues relating to forensic decision-making, such as bias, but also relates to most aspects of forensic work (some of which even take place before a crime is ever committed or long after the verification of the forensic conclusion). In this paper, I explicate many aspects of forensic work that involve the human element and therefore show the relevance (and potential contribution) of cognitive neuroscience to forensic science. The 10 aspects covered in this paper are proactive forensic science, selection during recruitment, training, crime scene investigation, forensic decision-making, verification and conflict resolution, reporting, the role of the forensic examiner, presentation in court and judicial decisions. As the forensic community is taking on the challenges introduced by the realization that the human element is critical for forensic work, new opportunities emerge that allow for considerable improvement and enhancement of the forensic science endeavour. PMID- 26101282 TI - Paradigms of forensic science and legal process: a critical diagnosis. AB - This article reconsiders the relationship between criminal adjudication and forensic expertise in the light of 'new paradigms' of forensic practice and recent law reform. It briefly summarizes conventional wisdom on the typical shortcomings of forensic science and other expert evidence, as a springboard for a more searching critical diagnosis of longstanding maladies. The fundamentally jurisdictional nature of law is emphasized, and some implications for expert testimony noted. English law's traditionally adversarial model of criminal procedure is then reassessed, taking account of a proper understanding of its normative structure and modern development, and drawing on comparative legal research and theorizing to obtain a more rounded second opinion. In conclusion, some avenues for intelligent prescription are canvassed, highlighting the importance of promoting and facilitating effective communication between experts, lawyers and courts, and prioritizing modest practical remedies over radical surgery. PMID- 26101283 TI - The legal framework for more robust forensic science evidence. PMID- 26101284 TI - Fingerprint identification: advances since the 2009 National Research Council report. AB - This paper will discuss the major developments in the area of fingerprint identification that followed the publication of the National Research Council (NRC, of the US National Academies of Sciences) report in 2009 entitled: Strengthening Forensic Science in the United States: A Path Forward. The report portrayed an image of a field of expertise used for decades without the necessary scientific research-based underpinning. The advances since the report and the needs in selected areas of fingerprinting will be detailed. It includes the measurement of the accuracy, reliability, repeatability and reproducibility of the conclusions offered by fingerprint experts. The paper will also pay attention to the development of statistical models allowing assessment of fingerprint comparisons. As a corollary of these developments, the next challenge is to reconcile a traditional practice dominated by deterministic conclusions with the probabilistic logic of any statistical model. There is a call for greater candour and fingerprint experts will need to communicate differently on the strengths and limitations of their findings. Their testimony will have to go beyond the blunt assertion of the uniqueness of fingerprints or the opinion delivered ispe dixit. PMID- 26101285 TI - The end of the (forensic science) world as we know it? The example of trace evidence. AB - The dominant conception of forensic science as a patchwork of disciplines primarily assisting the criminal justice system (i.e. forensics) is in crisis or at least shows a series of anomalies and serious limitations. In recent years, symptoms of the crisis have been discussed in a number of reports by various commentators, without a doubt epitomized by the 2009 report by the US National Academies of Sciences (NAS 2009 Strengthening forensic science in the United States: a path forward). Although needed, but viewed as the solution to these drawbacks, the almost generalized adoption of stricter business models in forensic science casework compounded with ever-increasing normative and compliance processes not only place additional pressures on a discipline that already appears in difficulty, but also induce more fragmentation of the different forensic science tasks, a tenet many times denounced by the same NAS report and other similar reviews. One may ask whether these issues are not simply the result of an unfit paradigm. If this is the case, the current problems faced by forensic science may indicate future significant changes for the discipline. To facilitate broader discussion this presentation focuses on trace evidence, an area that is seminal to forensic science both for epistemological and historical reasons. There is, however, little doubt that this area is currently under siege worldwide. Current and future challenges faced by trace evidence are discussed along with some possible answers. The current situation ultimately presents some significant opportunities to re-invent not only trace evidence but also forensic science. Ultimately, a distinctive, more robust and more reliable science may emerge through rethinking the forensics paradigm built on specialisms, revisiting fundamental forensic science principles and adapting them to the twenty-first century. PMID- 26101286 TI - Integrating research into operational practice. AB - Research and development can be classified into three categories: technology adoption, technology extension, and knowledge and technology creation. In general, technology adoption is embedded in operational forensic science laboratory practice but the latter two categories require partnerships with industry and/or academia both to conduct the research and implement the outcomes. In a 2012 survey, Australian and New Zealand forensic science laboratories identified a number of 'roadblocks' to undertaking research and operationalizing research outcomes. These included insufficient time and funding, a lack of in house research experience and the absence of a tangible research culture. Allied to this is that, increasingly, forensic science research is conducted in a 'commercial in confidence' environment and the outcomes are not readily or cost effectively available to be integrated into operational forensic science laboratories. The paper is predominantly reflective of the current situation in Australia and New Zealand. PMID- 26101287 TI - Advances in the use of odour as forensic evidence through optimizing and standardizing instruments and canines. AB - This paper explores the advances made in identifying trace amounts of volatile organic compounds (VOCs) that originate from forensic specimens, such as drugs, explosives, live human scent and the scent of death, as well as the probative value for detecting such odours. The ability to locate and identify the VOCs liberated from or left by forensic substances is of increasing importance to criminal investigations as it can indicate the presence of contraband and/or associate an individual to a particular location or object. Although instruments have improved significantly in recent decades-with sensitivities now rivalling that of biological detectors-it is widely recognized that canines are generally still more superior for the detection of odourants due to their speed, versatility, ruggedness and discriminating power. Through advancements in the detection of VOCs, as well as increased standardization efforts for instruments and canines, the reliability of odour as evidence has continuously improved and is likely to continue to do so. Moreover, several legal cases in which this novel form of evidence has been accepted into US courts of law are discussed. As the development and implementation of best practice guidelines for canines and instruments increase, their reliability in detecting VOCs of interest should continue to improve, expanding the use of odour as an acceptable form of forensic evidence. PMID- 26101288 TI - The logical foundations of forensic science: towards reliable knowledge. AB - The generation of observations is a technical process and the advances that have been made in forensic science techniques over the last 50 years have been staggering. But science is about reasoning-about making sense from observations. For the forensic scientist, this is the challenge of interpreting a pattern of observations within the context of a legal trial. Here too, there have been major advances over recent years and there is a broad consensus among serious thinkers, both scientific and legal, that the logical framework is furnished by Bayesian inference (Aitken et al. Fundamentals of Probability and Statistical Evidence in Criminal Proceedings). This paper shows how the paradigm has matured, centred on the notion of the balanced scientist. Progress through the courts has not been always smooth and difficulties arising from recent judgments are discussed. Nevertheless, the future holds exciting prospects, in particular the opportunities for managing and calibrating the knowledge of the forensic scientists who assign the probabilities that are at the foundation of logical inference in the courtroom. PMID- 26101290 TI - New psychoactive substances: catalysing a shift in forensic science practice? AB - The analysis of substances of abuse remains one of the most matured areas in forensic science with a strong scientific basis, namely analytical chemistry. The current evolving drug markets, characterized by the global emergence of new psychoactive substances (NPS) and the need for forensic scientists to identify an unprecedented and ever-increasing number of NPS, presents a unique challenge to this discipline. This article looks at the current situation with NPS at the global level, and the challenges posed to the otherwise technically robust forensic science discipline of analysis of substances of abuse. It discusses the preparedness of forensic science to deal with the current situation and identifies the need for a shift in forensic science practice, especially one which embraces research and looks beyond normal casework in order to provide the much needed data for developing effective policy responses to the NPS problem. PMID- 26101289 TI - The interface between forensic science and technology: how technology could cause a paradigm shift in the role of forensic institutes in the criminal justice system. AB - In this paper, the importance of modern technology in forensic investigations is discussed. Recent technological developments are creating new possibilities to perform robust scientific measurements and studies outside the controlled laboratory environment. The benefits of real-time, on-site forensic investigations are manifold and such technology has the potential to strongly increase the speed and efficacy of the criminal justice system. However, such benefits are only realized when quality can be guaranteed at all times and findings can be used as forensic evidence in court. At the Netherlands Forensic Institute, innovation efforts are currently undertaken to develop integrated forensic platform solutions that allow for the forensic investigation of human biological traces, the chemical identification of illicit drugs and the study of large amounts of digital evidence. These platforms enable field investigations, yield robust and validated evidence and allow for forensic intelligence and targeted use of expert capacity at the forensic institutes. This technological revolution in forensic science could ultimately lead to a paradigm shift in which a new role of the forensic expert emerges as developer and custodian of integrated forensic platforms. PMID- 26101291 TI - Science in the court: pitfalls, challenges and solutions. AB - We are at a critical juncture for the forensic sciences. A number of high-profile reports and a growing body of literature question and critically reflect on core issues pertaining to the methodologies informing forensic science and their effective use within the criminal justice system. We argue for the need for an improved association and outline key areas that require attention from practitioners operating within the fields of both forensic science and law. PMID- 26101292 TI - An investigation of the disparity in estimates of microfilaraemia and antigenaemia in lymphatic filariasis surveys. AB - BACKGROUND: The diagnosis of lymphatic filariasis (LF) is based typically on either microfilaraemia as assessed by microscopy or filarial antigenaemia using an immuno-chromatographic test. While it is known that estimates of antigenaemia are generally higher than estimates of microfilaraemia, the extent of the difference is not known. METHODS: This paper presents the results of an extensive literature search for surveys that estimated both microfilaraemia and antigenaemia in order to better understand the disparity between the two measures. RESULTS AND CONCLUSIONS: In some settings there was a very large disparity, up to 40-70%, between estimates of microfilaraemia and antigenaemia. Regression analysis was unable to identify any predictable relationship between the two measures. The implications of findings for risk mapping and surveillance of LF are discussed. PMID- 26101293 TI - A Single Controlled Exposure to Secondhand Smoke May Not Alter Thrombogenesis or Trigger Platelet Activation. AB - INTRODUCTION: Chronic secondhand smoke (SHS) exposure increases cardiovascular events, particularly acute thrombotic events. There are little human data on acute SHS exposure. The aim of this study was to determine whether a single controlled exposure of humans to SHS increased thrombogenesis. METHODS: After 6-8 hours fast, subjects (n = 50) were exposed to constant dose SHS (particulate level of 500 MUg/m(3)) for 120 minutes in a temperature-regulated and ventilated, simulated bar environment. Blood was drawn before and immediately after SHS exposure for thromboelastography (TEG) and flow cytometry. Maximum clot strength (MA) was measured using TEG and platelet leukocyte aggregates (LPA) were measured as an index of platelet activation. Anti-CD 14 antibodies were used as leukocyte markers and anti-CD 41 antibodies as platelet markers for cytometry. Data were analyzed using students' t test for paired samples. RESULTS: There was no effect of acute exposure to SHS on platelet activation or thrombogenesis. Also, intra group (smokers [n = 19] and nonsmokers [n = 31]) comparisons of LPA and TEG parameters did not show changes with SHS exposure. CONCLUSIONS: While there are abundant data showing enhanced thrombogenesis and platelet activation following repeated exposure to SHS, our study suggests that a single exposure does not appear to significantly alter thrombin kinetics nor result in platelet activation. The effects of SHS on thrombogenesis might be nonlinear. PMID- 26101294 TI - Diagnostic accuracy of porcine acute phase proteins in meat juice for detecting disease at abattoir. AB - The aim of this work was to evaluate whether acute phase protein (APP) determinations could assist Official Veterinarians carrying out work in slaughterhouses. To test this hypothesis, the diagnostic accuracy of APP determinations in meat juice of pigs was analysed to differentiate between healthy and diseased pigs. One hundred and one pigs of two different origins were classified into two groups according to their health status (healthy and diseased pigs), which was determined by a veterinary clinical examination on the farm. To assess the pigs' immune status, against the main porcine diseases, serological analyses were monitored. A general idea of the degree of disease coverage was analysed by examining organ lesions postmortem. Haptoglobin (Hp) and C reactive protein (CRP) were measured in meat juice samples. 72.13 per cent of pigs appeared to be seropositive for the porcine respiratory and reproductive syndrome virus, and almost 86.2 per cent of them had concomitant infections with other pathogens, such as Porcine circovirus type 2 or Swine influenza virus. Median Hp and CRP concentrations were significantly higher in diseased animals at different stages of the production chain, when compared with levels found in healthy finishing pigs (P<0.0001). Receiver operating characteristic analysis showed the highest sensitivity-specificity pairs, nearly 80-90 per cent, at cut-off levels of 83 and 10 ug/ml for Hp and CRP determinations, respectively, with high AUCs 0.9. This cut-off could be useful for veterinary inspections at the time of slaughter, to differentiate between the carcase of a healthy animal and the carcase of an animal suffering from a systemic disease, which should be completely condemned. PMID- 26101295 TI - Working hours and mental health in Australia: evidence from an Australian population-based cohort, 2001-2012. AB - OBJECTIVES: This paper assesses the impact of working less than or more than standard full-time hours on mental health, as well as possible differences in this relationship by gender and skill level. METHODS: The study design was a longitudinal cohort with 12 annual waves of data collection over the period 2001 2012, yielding a sample of 90,637 observations from 18,420 people. Fixed effects within-person regression was used to control for time invariant confounding. The Mental Component Summary of the Short Form 36 (SF-36) measure was used as the primary outcome measure. Working hours over the preceding year was measured in five categories with standard full-time hours (35-40 h/week) as the reference. RESULTS: Results indicated that when respondents were working 49-59 h (-0.52, 95% CI -0.74 to -0.29, p<0.001) and 60 h or more (-0.47, 95% CI -0.77 to -0.16, p=0.003) they had worse mental health than when they were working 35-40 h/week (reference). The difference in mental health when working 49-59 h was greater for women than for men. There were greater declines in mental health in relation to longer working hours among persons in higher compared to lower occupational skill levels. CONCLUSIONS: Study results suggest the need for employers and governments to regulate working hours to reduce the burden of mental ill health in the working population. PMID- 26101297 TI - Neuro-Behcet's disease mimicking a cranial tumour. AB - Behcet's disease affects many systems and has been described as a multisystem disorder. In Behcet's disease, neurological involvement is responsible for morbidity and mortality, and can sometimes mimic other neurological disorders. We present a case of neuro-Behcet's disease that mimicked a cranial tumour. PMID- 26101298 TI - Correction. PMID- 26101299 TI - Alcohol use disorder due to social isolation after a nuclear disaster in Fukushima. AB - It is well-known that a nuclear disaster causes health problems including cancer, however, information on mental disorders linked to a nuclear disaster is limited. On 11 March 2011, there was a serious nuclear power plant accident in Fukushima, Japan. Subsequently, in October 2012, a 78-year-old man living 31 km from the plant was admitted to the hospital with head trauma. This was his third physical trauma since the nuclear accident. A thorough interview revealed that his alcohol intake had increased after the disaster, suggesting that his injuries might be related to alcohol use. The diagnosis of alcohol use disorder was established based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. He had been exposed to social isolation after evacuation of his neighbourhood. Using education and intervention, he was successfully treated. We should recognise that a nuclear disaster might cause social isolation among the elderly, leading to mental disorders and alcohol use disorder. Early diagnosis and intervention might be beneficial for individuals presenting the above symptoms. PMID- 26101300 TI - Squamous cell carcinoma of unknown origin metastasising to the right atrium causing acute heart failure. AB - We describe a case of metastasis to the heart, which was initially suspected to be a myxoma, causing acute right heart failure. Emergency surgery was carried out by opening the right atrium and superior vena cava, and debulking the tumour in a piecemeal fashion, providing temporary relief of symptoms. The histology showed this to be metastatic squamous cell carcinoma possibly of head and neck origin. This is extremely rare, with few published cases. Full endoscopic and CT, including positron emission tomography CT, investigation of the head and neck was performed with no primary findings. Only two such cases of squamous cell carcinoma of unknown origin metastasising to the heart have been described, and, in both cases, the patients died within several weeks of diagnosis. This patient remains alive 2 months postoperatively and is receiving radiotherapy to the chest, but his prognosis remains poor. PMID- 26101301 TI - Cervicofacial subcutaneous emphysema in a 4-year-old boy. PMID- 26101302 TI - Radiological features of tension pneumoperitoneum. PMID- 26101303 TI - Bimodal assessment to facilitate accurate mediastinal repositioning following pneumonectomy. PMID- 26101304 TI - The Contribution of Experiential Wisdom to the Development of the Mental Health Professional Discourse. PMID- 26101307 TI - Ten years' work on prevention of feline infectious disease. PMID- 26101305 TI - Neurocognition and Duration of Psychosis: A 10-year Follow-up of First-Episode Patients. AB - A substantial proportion of schizophrenia-spectrum patients exhibit a cognitive impairment at illness onset. However, the long-term course of neurocognition and a possible neurotoxic effect of time spent in active psychosis, is a topic of controversy. Furthermore, it is of importance to find out what predicts the long term course of neurocognition. Duration of untreated psychosis (DUP), accumulated time in psychosis the first year after start of treatment, relapse rates and symptoms are potential predictors of the long-term course. In this study, 261 first-episode psychosis patients were assessed neuropsychologically on one or more occasions. Patients were tested after remission of psychotic symptoms and reassessed 1, 2, 5, and 10 years after inclusion. The neurocognitive battery consisted of California Verbal Learning Test, Wisconsin Card Sorting Test, Controlled Oral Word Association Task, Trail Making A and B, and Finger Tapping. We calculated a composite score by adding the z-scores of 4 tests that were only moderately inter-correlated, not including Finger Tapping. Data were analyzed by a linear mixed model. The composite score was stable over 10 years. No significant relationship between psychosis before (DUP) or after start of treatment and the composite score was found, providing no support for the neurotoxicity hypothesis, and indicating that psychosis before start of treatment has no significant impact on the course and outcome in psychosis. We found no association between symptoms and the neurocognitive trajectory. Stable remission during the first year predicted neurocognitive functioning, suggesting that the early clinical course is a good predictor for the long-term course. PMID- 26101306 TI - Efficacy of a Telehealth Intervention on Colonoscopy Uptake When Cost Is a Barrier: The Family CARE Cluster Randomized Controlled Trial. AB - BACKGROUND: We tested the efficacy of a remote tailored intervention Tele-Cancer Risk Assessment and Evaluation (TeleCARE) compared with a mailed educational brochure for improving colonoscopy uptake among at-risk relatives of colorectal cancer patients and examined subgroup differences based on participant reported cost barriers. METHODS: Family members of colorectal cancer patients who were not up-to-date with colonoscopy were randomly assigned as family units to TeleCARE (N = 232) or an educational brochure (N = 249). At the 9-month follow-up, a cost resource letter listing resources for free or reduced-cost colonoscopy was mailed to participants who had reported cost barriers and remained nonadherent. Rates of medically verified colonoscopy at the 15-month follow-up were compared on the basis of group assignment and within group stratification by cost barriers. RESULTS: In intent-to-treat analysis, 42.7% of participants in TeleCARE and 24.1% of participants in the educational brochure group had a medically verified colonoscopy [OR, 2.37; 95% confidence interval (CI) 1.59-3.52]. Cost was identified as a barrier in both groups (TeleCARE = 62.5%; educational brochure = 57.0%). When cost was not a barrier, the TeleCARE group was almost four times as likely as the comparison to have a colonoscopy (OR, 3.66; 95% CI, 1.85-7.24). The intervention was efficacious among those who reported cost barriers; the TeleCARE group was nearly twice as likely to have a colonoscopy (OR, 1.99; 95% CI, 1.12 3.52). CONCLUSIONS: TeleCARE increased colonoscopy regardless of cost barriers. IMPACT: Remote interventions may bolster screening colonoscopy regardless of cost barriers and be more efficacious when cost barriers are absent. PMID- 26101308 TI - Something old, something new: Update of the 2009 and 2013 ABCD guidelines on prevention and management of feline infectious diseases. AB - OVERVIEW: The ABCD has published 34 guidelines in two Special Issues of the Journal of Feline Medicine and Surgery (JFMS): the first in July 2009 (Volume 11, Issue 7, pages 527-620) and the second in July 2013 (Volume 15, Issue 7, pages 528-652). The present article contains updates and new information on 18 of these (17 disease guidelines and one special article 'Prevention of infectious diseases in cat shelters'). For detailed information, readers are referred to the guidelines published in the above-mentioned JFMS Special Issues. PMID- 26101309 TI - Matrix vaccination guidelines: 2015 ABCD recommendations for indoor/outdoor cats, rescue shelter cats and breeding catteries. AB - OVERVIEW: In 2013, the ABCD published 'Matrix vaccination guidelines: ABCD recommendations for indoor/outdoor cats, rescue shelter cats and breeding catteries' in a Special Issue of the Journal of Feline Medicine and Surgery (Volume 15, Issue 7, pages 540-544). The ABCD's vaccination recommendations were presented in tabulated form, taking into account that there is no universal vaccination protocol for all cats. To support the veterinarian's decision making, recommendations for four lifestyles were made: for cats with outdoors access, cats kept solely indoors, rescue shelter cats and cats in breeding catteries. This update article follows the same approach, offering current and, where relevant, expanded recommendations. PMID- 26101310 TI - Blood transfusion in cats: ABCD guidelines for minimising risks of infectious iatrogenic complications. AB - OVERVIEW: The availability of blood components has increased the number of indications for transfusing cats, and fresh whole blood is readily accessible to clinicians because it can be taken from in-house donor cats or 'volunteer' feline blood donors. A certain amount of risk remains to the recipient cat, as immediate or delayed adverse reactions can occur during or after transfusion, related to immunemediated mechanisms. This article, however, focuses on adverse events caused by infectious agents, which may originate either from contamination of blood following incorrect collection, storage or transfusion, or from transfusion of contaminated blood obtained from an infected donor. PREVENTION OF BLOOD CONTAMINATION: In cats, blood cannot be collected through a closed system and, therefore, collection of donor blood requires a multi-step manipulation of syringes and other devices. It is crucial that each step of the procedure is performed under the strictest aseptic conditions and that bacterial contamination of blood bags is prevented, as bacterial endotoxins can cause an immediate febrile reaction or even fatal shock in the recipient cat. PREVENTION OF DISEASE TRANSMISSION: With a view to preventing transmission of blood-borne infectious diseases, the American College of Veterinary Internal Medicine has adopted basic criteria for selecting pathogens to be tested for in donor pets. The worldwide core screening panel for donor cats includes feline leukaemia virus, feline immunodeficiency virus, Bartonella species and feline haemoplasma. The list should be adapted to the local epidemiological situation concerning other vector borne feline infections. The most practical, rapid and inexpensive measure to reduce transfusion risk is to check the risk profile of donor cats on the basis of a written questionnaire. Blood transfusion can never, however, be considered entirely safe. PMID- 26101311 TI - Disinfectant choices in veterinary practices, shelters and households: ABCD guidelines on safe and effective disinfection for feline environments. AB - OVERVIEW: Regardless of whether a pathogen is viral, bacterial, parasitic, fungal or an emerging unknown, the mainstay of infectious disease control is hygiene, and the cornerstone of good hygiene is effective disinfection. CHALLENGES AND CURRENT CHOICES: Certain pathogens present a challenge to kill effectively: parvovirus, protozoal oocysts, mycobacteria, bacterial spores and prions resist most disinfectants but can be eliminated through heat, especially steam, which will kill protozoal oocysts. Heat is the safest and most effective disinfectant, but cannot be universally applied. Temperatures in washing machines and dishwashers should be at least 60 degrees C to eliminate pathogenic spores and resistant viruses. Enveloped viruses are susceptible to most disinfectants; of the non-enveloped viruses, parvovirus is recognised as being the most difficult to eradicate. Sodium hypochlorite is recommended for many applications: cleaning of floors, laundry, food preparation surfaces and utensils. Skin scrubs and rubs containing alcohols are more effective than those containing chlorhexidine, and less subject to contamination. DISINFECTANTS TO AVOID: Deficiency of the enzyme UDP-glucuronosyl transferase renders the cat susceptible to the toxic effects of phenol-based disinfectants (including many essential oils), so these should be avoided in feline environments. Quaternary ammonium compounds (eg, benzalkonium chloride) are also probably best avoided. THE FUTURE: Veterinary disinfection approaches in the future may include use of ultraviolet radiation and, increasingly, silver. PMID- 26101312 TI - Feline injection-site sarcoma: ABCD guidelines on prevention and management. AB - OVERVIEW: In cats, the most serious of adverse effects following vaccination is the occurrence of invasive sarcomas (mostly fibrosarcomas): so-called 'feline injection-site sarcomas' (FISSs). These develop at sites of previous vaccination or injection. They have characteristics that are distinct from those of fibrosarcomas in other areas and behave more aggressively. The rate of metastasis ranges from 10-28%. PATHOGENESIS: The pathogenesis of these sarcomas is not yet definitively explained. However, chronic inflammatory reactions are considered the trigger for subsequent malignant transformation. Injections of long-acting drugs (such as glucocorticoids, and others) have been associated with sarcoma formation. Adjuvanted vaccines induce intense local inflammation and seem therefore to be particularly linked to the development of FISS. The risk is lower for modified-live and recombinant vaccines, but no vaccine is risk-free. TREATMENT AND PREVENTION: Aggressive, radical excision is required to avoid tumour recurrence. The prognosis improves if additional radiotherapy and/or immunotherapy (such as recombinant feline IL-2) are used. For prevention, administration of any irritating substance should be avoided. Vaccination should be performed as often as necessary, but as infrequently as possible. Non adjuvanted, modified-live or recombinant vaccines should be selected in preference to adjuvanted vaccines. Injections should be given at sites at which surgery would likely lead to a complete cure; the interscapular region should generally be avoided. Post-vaccination monitoring should be performed. PMID- 26101313 TI - Borna disease virus infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Borna disease virus (BDV) has a broad host range, affecting primarily horses and sheep, but also cattle, ostriches, cats and dogs. In cats, BDV may cause a non-suppurative meningoencephalomyelitis ('staggering disease'). INFECTION: The mode of transmission is not completely elucidated. Direct and indirect virus transmission is postulated, but BDV is not readily transmitted between cats. Vectors such as ticks may play a role and shrews have been identified as a potential reservoir host. Access to forested areas has been reported to be an important risk factor for staggering disease. DISEASE SIGNS: It is postulated that BDV may infect nerve endings in the oropharynx and spread via olfactory nerve cells to the central nervous system. A strong T-cell response may contribute to the development of clinical disease. Affected cats develop gait disturbances, ataxia, pain in the lower back and behavioural changes. DIAGNOSIS: For diagnostic purposes, detection of viral RNA by reverse transcription PCR in samples collected from cats with clinical signs of Borna disease can be considered diagnostic. Serology is of little value; cats without signs of Borna disease may be seropositive and yet not every cat with BDV infection has detectable levels of antibodies. HUMAN INFECTION: A hypothesis that BDV infection may be involved in the development of selected neurological disorders in man could not be confirmed. A research group within the German Robert Koch Institute studied the potential health threat of BDV to humans and concluded that BDV was not involved in the aetiology of human psychiatric diseases. PMID- 26101314 TI - West Nile virus infection in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: West Nile virus (WNV) is a zoonotic mosquito-borne virus with a broad host range that infects mainly birds and mosquitos, but also mammals (including humans), reptiles, amphibians and ticks. It is maintained in a bird-mosquito-bird transmission cycle. The most important vectors are bird-feeding mosquitos of the Culex genus; maintenance and amplification mainly involve passerine birds. WNV can cause disease in humans, horses and several species of birds following infection of the central nervous system. INFECTION IN CATS: Cats can also be infected through mosquito bites, and by eating infected small mammals and probably also birds. Although seroprevalence in cats can be high in endemic areas, clinical disease and mortality are rarely reported. If a cat is suspected of clinical signs due to an acute WNV infection, symptomatic treatment is indicated. PMID- 26101315 TI - Streptococcal infections in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Streptococcus canis is most prevalent in cats, but recently S equi subsp zooepidemicus has been recognised as an emerging feline pathogen. S CANIS INFECTION: S canis is considered part of the commensal mucosal microflora of the oral cavity, upper respiratory tract, genital organs and perianal region in cats. The prevalence of infection is higher in cats housed in groups; and, for example, there may be a high rate of vaginal carriage in young queens in breeding catteries. A wide spectrum of clinical disease is seen, encompassing neonatal septicaemia, upper respiratory tract disease, abscesses, pneumonia, osteomyelitis, polyarthritis, urogenital infections, septicaemia, sinusitis and meningitis. S EQUI SUBSP ZOOEPIDEMICUS INFECTION: S equi subsp zooepidemicus is found in a wide range of species including cats. It was traditionally assumed that this bacterium played no role in disease of cats, but it is now considered a cause of respiratory disease with bronchopneumonia and pneumonia, as well as meningoencephalitis, often with a fatal course. Close confinement of cats, such as in shelters, appears to be a major risk factor. As horses are common carriers of this bacterium, contact with horses is a potential source of infection. Additionally, the possibility of indirect transmission needs to be considered. DIAGNOSIS: Streptococci can be detected by conventional culture techniques from swabs, bronchoalveolar lavage fluid or organ samples. Also real-time PCR can be used, and is more sensitive than culture. TREATMENT: In suspected cases, treatment with broad-spectrum antibiotics should be initiated as soon as possible and, if appropriate, adapted to the results of culture and sensitivity tests. PMID- 26101316 TI - Lungworm disease in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Cardiopulmonary nematodes are emerging parasites of cats in Europe. A number of helminth parasites may be involved. The most prevalent lungworm in domestic cats is Aelurostrongylus abstrusus. Oslerus rostratus and Troglostrongylus species are found mainly in wild cats. The trichurid Capillaria aerophila has a low host specificity and is not uncommon in cats. Additionally the lung flukes Paragonimus species are reported in many species outside of Europe, including cats. CLINICAL SIGNS: Lungworm infections may be asymptomatic, or cause mild to severe respiratory signs, dependent on the worm species and burden; mixed infections are observed. Kittens can be vertically infected and may develop a more severe disease. Affected cats show a productive cough, mucopurulent nasal discharge, tachypnoea, dyspnoea and, in severe cases, respiratory failure and death. MANAGEMENT: Early diagnosis and treatment greatly improves the prognosis. First-stage larvae can be easily detected in fresh faecal samples; the Baermann migration method is the enrichment technique of choice, but takes 24 h. Lungworm larvae can be found in tracheal swabs and bronchoalveolar lavage fluid, but with less sensitivity than in faeces. Molecular methods have been developed that exhibit high specificity and sensitivity, and allow diagnosis in the prepatent phase. Treatment options include fenbendazole paste, milbemycin oxime/praziquantel and various spot-on formulations. Severe cases should receive prompt medical care in an intensive care unit. PREVENTION: Avoiding predation is at present the only preventive measure for pulmonary worms with indirect life cycles. ZOONOTIC RISK: C aerophila has zoonotic potential, causing severe pulmonary disease in humans. Some Paragonimus species are also of zoonotic concern. PMID- 26101318 TI - Hepatozoonosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Hepatozoonosis of domestic cats has been reported in several countries, mainly as a subclinical infection. DISEASE AGENT: Infection has been described mostly in areas where canine infection is present and, in recent years, Hepatozoon felis has been identified as a distinct species by molecular techniques. The vector for feline hepatozoonosis remains unknown and the pathogenesis has not been elucidated. INFECTION IN CATS: Feline hepatozoonosis is mainly a subclinical infection and few cases have been reported with clinical signs. The diagnosis of hepatozoonosis in cats can be made by observation of parasite gamonts in blood smears, parasite meronts in muscles by histopathology, and detection of parasite DNA in blood and tissue by PCR. DISEASE MANAGEMENT: The treatment of choice is not known, but single cases have been treated with doxycycline or oxytetracycline and primaquine. Although the mode of transmission and the type of vector is not known, preventive treatment against blood-sucking vectors (fleas and ticks) is advised. PMID- 26101317 TI - Cytauxzoonosis in cats: ABCD guidelines on prevention and management. AB - OVERVIEW: Cytauxzoon species are apicomplexan haemoparasites, which may cause severe disease in domestic cats, as well as lions and tigers. For many years, cytauxzoonosis in domestic cats was only reported in North and South America, but in recent years the infection has also been seen in Europe (Spain, France and Italy). INFECTION: Cytauxzoon felis is the main species; it occurs as numerous different strains or genotypes and is transmitted via ticks. Therefore, the disease shows a seasonal incidence from spring to early autumn and affects primarily cats with outdoor access in areas where tick vectors are prevalent. Domestic cats may experience subclinical infection and may also act as reservoirs. CLINICAL SIGNS: Cytauxzoonosis caused by C felis in the USA is an acute or peracute severe febrile disease with non-specific signs. Haemolytic anaemia occurs frequently; in some cats neurological signs may occur in late stages. The Cytauxzoon species identified in Europe differ from C felis that causes disease in the USA and are probably less virulent. The majority of infected cats have been healthy; in some cases anaemia was found, but disease as it occurs in the USA has not been reported to date. DIAGNOSIS: Diagnosis is usually obtained by Cytauxzoon detection in blood smears and/or fine-needle aspirates from the liver, spleen and lymph nodes. PCR assays are able to detect low levels of parasitaemia and may be used for confirmation. TREATMENT: Currently a combination of the antiprotozoal drugs atovaquone and azithromycin is the treatment of choice. Concurrent supportive and critical care treatment is extremely important to improve the prognosis. Cats that survive the infection may become chronic carriers for life. PREVENTION: Cats with outdoor access in endemic areas should receive effective tick treatment. PMID- 26101320 TI - TLR3-Mediated CD8+ Dendritic Cell Activation Is Coupled with Establishment of a Cell-Intrinsic Antiviral State. AB - Because of their unique capacity to cross-present Ags to CD8(+) T cells, mouse lymphoid tissue-resident CD8(+) dendritic cells (DCs) and their migratory counterparts are critical for priming antiviral T cell responses. High expression of the dsRNA sensor TLR3 is a distinctive feature of these cross-presenting DC subsets. TLR3 engagement in CD8(+) DCs promotes cross-presentation and the acquisition of effector functions required for driving antiviral T cell responses. In this study, we performed a comprehensive analysis of the TLR3 induced antiviral program and cell-autonomous immunity in CD8(+) DC lines and primary CD8(+) DCs. We found that TLR3-ligand polyinosinic-polycytidylic acid and human rhinovirus infection induced a potent antiviral protection against Sendai and vesicular stomatitis virus in a TLR3 and type I IFN receptor-dependent manner. Polyinosinic-polycytidylic acid-induced antiviral genes were identified by mass spectrometry-based proteomics and transcriptomics in the CD8(+) DC line. Nanostring nCounter experiments confirmed that these antiviral genes were induced by TLR3 engagement in primary CD8(+) DCs, and indicated that many are secondary TLR3-response genes requiring autocrine IFN-beta stimulation. TLR3-activation thus establishes a type I IFN-dependent antiviral program in a DC subtype playing crucial roles in priming adaptive antiviral immune responses. This mechanism is likely to shield the priming of antiviral responses against inhibition or abrogation by the viral infection. It could be particularly relevant for viruses detected mainly by TLR3, which may not trigger type I IFN production by DCs that lack TLR3, such as plasmacytoid DCs or CD8(-) DCs. PMID- 26101322 TI - Targeting Antigen to Clec9A Primes Follicular Th Cell Memory Responses Capable of Robust Recall. AB - Targeting Ags to dendritic cell (DC) surface receptors can induce a variety of responses depending on the DC type targeted, the receptor targeted, and the adjuvant used. Clec9A (DNGR-1), which is expressed by CD8(+) DCs, has been shown to bind F-actin exposed on damaged cells. Targeting Ag to this receptor in mice and nonhuman primates induces strong humoral immunity even in the absence of adjuvant, a process seen for a few select DC receptors. In contrast with other receptors, however, targeting Clec9A induces long-lived, affinity-matured Ab responses that are associated with efficient CD4(+) T cell responses shown to possess properties of follicular Th cells (TFH). In this article, we provide definitive evidence that Clec9A targeting promotes the development of TFH by showing that responding CD4 T cells express CXCR5, PD1, the TFH transcription factor Bcl6, and the cytokine IL-21, and that these cells localize to germinal centers. Furthermore, we extend studies from the model Ag OVA to the viral Ag glycoprotein D of HSV-1 and examine the capacity of primed TFH to form functional memory. We show that targeting glycoprotein D to Clec9A even in the absence of adjuvant induced long-lived memory CXCR5(+) PD1(hi) CD4(+) T cells that proliferated extensively upon secondary challenge and rapidly developed into effector TFH. This was associated with enhanced germinal center B cell responses and accelerated Ab production. Our study indicates that targeting Ags to Clec9A in the absence of adjuvant routinely generates TFH responses that form long-lived memory capable of robust secondary TFH responses. PMID- 26101321 TI - Domain-Specific and Stage-Intrinsic Changes in Tcrb Conformation during Thymocyte Development. AB - Considerable cross-talk exists between mechanisms controlling genome architecture and gene expression. AgR loci are excellent models for these processes because they are regulated at both conformational and transcriptional levels to facilitate their assembly by V(D)J recombination. Upon commitment to the double negative stage of T cell development, Tcrb adopts a compact conformation that promotes long-range recombination between Vbeta gene segments (Trbvs) and their DbetaJbeta targets. Formation of a functional VbetaDbetaJbeta join signals for robust proliferation of double-negative thymocytes and their differentiation into double-positive (DP) cells, where Trbv recombination is squelched (allelic exclusion). DP differentiation also is accompanied by decontraction of Tcrb, which has been thought to separate the entire Trbv cluster from DbetaJbeta segments (spatial segregation-based model for allelic exclusion). However, DP cells also repress transcription of unrearranged Trbvs, which may contribute to allelic exclusion. We performed a more detailed study of developmental changes in Tcrb topology and found that only the most distal portion of the Trbv cluster separates from DbetaJbeta segments in DP thymocytes, leaving most Trbvs spatially available for rearrangement. Preferential dissociation of distal Trbvs is independent of robust proliferation or changes in transcription, chromatin, or architectural factors, which are coordinately regulated across the entire Trbv cluster. Segregation of distal Trbvs also occurs on alleles harboring a functional VbetaDbetaJbeta join, suggesting that this process is independent of rearrangement status and is DP intrinsic. Our finding that most Trbvs remain associated with DbetaJbeta targets in DP cells revises allelic exclusion models from their current conformation-dominant to a transcription-dominant formulation. PMID- 26101323 TI - TLR8 Senses Bacterial RNA in Human Monocytes and Plays a Nonredundant Role for Recognition of Streptococcus pyogenes. AB - Microbial nucleic acids constitute an important group of pathogen-associated molecular patterns (PAMPs) that efficiently trigger innate immune activation. In mice, TLR13 has recently been identified to sense a highly conserved region within bacterial 23S rRNA. However, TLR13 is not expressed in humans, and the identity of its human homolog remains elusive. Moreover, the contribution of bacterial RNA to the induction of innate immune responses against entire bacteria is still insufficiently defined. In the current study, we show that human monocytes respond to bacterial RNA with secretion of IL-6, TNF, and IFN-beta, which is critically dependent on lysosomal maturation. Using small interfering RNA and overexpression, we unambiguously identify TLR8 as receptor for bacterial RNA in primary human monocyte-derived macrophages. We further demonstrate that the sequence motif sensed by TLR8 is clearly distinct from that recognized by TLR13. Moreover, TLR8-dependent detection of bacterial RNA was critical for triggering monocyte activation in response to infection with Streptococcus pyogenes. Bacterial RNA within streptococci was also a dominant stimulus for murine immune cells, highlighting the physiological relevance of RNA sensing in defense of infections. PMID- 26101324 TI - Definition of a Novel Pathway Centered on Lysophosphatidic Acid To Recruit Monocytes during the Resolution Phase of Tissue Inflammation. AB - Blood-derived monocytes remove apoptotic cells and terminate inflammation in settings as diverse as atherosclerosis and Alzheimer's disease. They express high levels of the proresolving receptor ALX/FPR2, which is activated by the protein annexin A1 (ANXA1), found in high abundance in inflammatory exudates. Using primary human blood monocytes from healthy donors, we identified ANXA1 as a potent CD14(+)CD16(-) monocyte chemoattractant, acting via ALX/FPR2. Downstream signaling pathway analysis revealed the p38 MAPK-mediated activation of a calcium independent phospholipase A2 with resultant synthesis of lysophosphatidic acid (LPA) driving chemotaxis through LPA receptor 2 and actin cytoskeletal mobilization. In vivo experiments confirmed ANXA1 as an independent phospholipase A2-dependent monocyte recruiter; congruently, monocyte recruitment was significantly impaired during ongoing zymosan-induced inflammation in AnxA1(-/-) or alx/fpr2/3(-/-) mice. Using a dorsal air-pouch model, passive transfer of apoptotic neutrophils between AnxA1(-/-) and wild-type mice identified effete neutrophils as the primary source of soluble ANXA1 in inflammatory resolution. Together, these data elucidate a novel proresolving network centered on ANXA1 and LPA generation and identify previously unappreciated determinants of ANXA1 and ALX/FPR2 signaling in monocytes. PMID- 26101325 TI - Cross-Talk between Shp1 and PIPKIgamma Controls Leukocyte Recruitment. AB - Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. However, overwhelming activation and accumulation of neutrophils in the tissue may cause tissue damage and autoimmunity due to the release of cytokines, oxidants, and proteases. Neutrophil adhesion in acute inflammation is initiated by activation of alphaLbeta2 (LFA-1), which can be induced by rolling on E selectin (slowly) or by exposure to the chemokine CXCL1 (rapidly). Despite the clinical importance, cell-intrinsic molecular mechanisms of negative regulation of integrin adhesiveness and neutrophil recruitment are poorly understood. Mice deficient in the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 1 (Shp1) show increased leukocyte adhesion, but the interpretation of these data is limited by the severe global phenotype of these mice. In this study, we used mice with global and myeloid-restricted deletion of Shp1 to study neutrophil arrest, adhesion, crawling, and transendothelial migration in vitro and in vivo. Shp1 deficiency results in increased neutrophil adhesion in vivo; however, neutrophil crawling, transmigration, and chemotaxis were reduced in these mice. Mechanistically, Shp1 binds and controls PIPKIgamma activity and, thereby, modulates phosphatidylinositol (4,5)-bisphosphate levels and adhesion. Thus, Shp1 is involved in the deactivation of integrins and regulation of neutrophil recruitment into inflamed tissue. PMID- 26101326 TI - Neonatal CD71+ Erythroid Cells Do Not Modify Murine Sepsis Mortality. AB - Sepsis is a major cause of neonatal mortality and morbidity worldwide. A recent report suggested that murine neonatal host defense against infection could be compromised by immunosuppressive CD71(+) erythroid splenocytes. We examined the impact of CD71(+) erythroid splenocytes on murine neonatal mortality to endotoxin challenge or polymicrobial sepsis and characterized circulating CD71(+) erythroid (CD235a(+)) cells in human neonates. Adoptive transfer or an Ab-mediated reduction in neonatal CD71(+) erythroid splenocytes did not alter murine neonatal survival to endotoxin challenge or polymicrobial sepsis challenge. Ex vivo immunosuppression of stimulated adult CD11b(+) cells was not limited to neonatal splenocytes; it also occurred with adult and neonatal bone marrow. Animals treated with anti-CD71 Ab showed reduced splenic bacterial load following bacterial challenge compared with isotype-treated mice. However, adoptive transfer of enriched CD71(+) erythroid splenocytes to CD71(+)-reduced animals did not reduce bacterial clearance. Human CD71(+)CD235a(+) cells were common among cord blood mononuclear cells and were shown to be reticulocytes. In summary, a lack of effect on murine survival to polymicrobial sepsis following adoptive transfer or diminution of CD71(+) erythroid splenocytes under these experimental conditions suggests that the impact of these cells on neonatal infection risk and progression may be limited. An unanticipated immune priming effect of anti-CD71 Ab treatment, rather than a reduction in immunosuppressive CD71(+) erythroid splenocytes, was likely responsible for the reported enhanced bacterial clearance. In humans, the well-described rapid decrease in circulating reticulocytes after birth suggests that they may have a limited role in reducing inflammation secondary to microbial colonization. PMID- 26101327 TI - MALDI-mass spectrometry imaging identifies vitronectin as a common constituent of amyloid deposits. AB - Amyloids are pathological intra- and extracellular fibrillar aggregates of polypeptides with a cross-beta-sheet structure and characteristic tinctorial properties. The amyloid deposits commonly enclose several non-fibrillar components of the extracellular matrix. Their potential to regulate the formation and aggregation process of amyloid fibrils is still poorly understood. For a better understanding of the role of the extracellular matrix in amyloidosis, it is essential to gain deeper insights into the composition of amyloid deposits. Here, we utilized matrix-assisted laser desorption and ionization mass spectrometry imaging to identify extracellular matrix compounds in amyloid deposits. Using this technique, we identified and determined the spatial distribution of vitronectin within AApoAI-, ALlambda-, ATTR- and AIns amyloid deposits and, using immunohistochemistry, validated the spatial overlap of vitronectin with amyloids in 175 cases with diverse types of amyloid in several different tissues. PMID- 26101328 TI - The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation. AB - The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation. However, the role of PU.1 in alternatively activated macrophage (AAM) and asthmatic inflammation has yet been investigated. Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation. In response to the challenge of DRA (dust mite, ragweed, and Aspergillus) allergens, conditional PU.1-deficient (PU/ER(T)(+/-)) mice displayed attenuated allergic airway inflammation, including decreased alveolar eosinophil infiltration and reduced production of IgE, which were associated with decreased mucous glands and goblet cell hyperplasia. The reduced asthmatic inflammation in PU/ER(T)(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type (WT) macrophages. Moreover, after treating PU/ER(T)(+/-) mice with tamoxifen to rescue PU.1 function, the allergic asthmatic inflammation was significantly restored. In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3 (Ym-1) and resistin-like molecule alpha 1 (Fizz-1), two specific markers of AAM polarization. In addition, PU.1 expression in macrophages was inducible in response to IL-4 challenge, which was associated with phosphorylation of signal transducer and activator of transcription 6 (STAT6). Furthermore, DRA challenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)(+/-) mice compared with WT mice. These data, all together, indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation. PMID- 26101329 TI - Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism. AB - BACKGROUND: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. METHODS: Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu). RESULTS: The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional beta cells. Whole exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. CONCLUSIONS: Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without beta cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life. PMID- 26101330 TI - Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. AB - INTRODUCTION: Lynch syndrome is known to cause an increased risk of malignancies, including bowel and endometrial cancers. However, the risk of breast cancer associated with mutations in the mismatch repair (MMR) genes that cause Lynch syndrome is still unclear. MATERIALS AND METHODS: This study assesses the cumulative risk of breast cancer in 106 MLH1 and 118 MSH2 families. Families were referred on the basis of clinical criteria. Pedigree information was obtained, and tumour immunohistochemistry and microsatellite testing performed. Appropriate patients underwent sequencing and multiple ligation dependent probe amplification of all relevant exons of the MMR genes. Kaplan-Meier analysis of cumulative lifetime risk of breast cancer was made combining proven mutation carriers and their first-degree female relatives. RESULTS: After allocation of mutation status, the cumulative risk of breast cancer to 70 years in MLH1 carriers was 18.6% (95% CI 11.3 to 25.9)). This is significantly higher than the cumulative risk for MSH2 which was 11.2% (95% CI 1.4 to 21.0) to age 70 years (p=0.014). The UK population risk is 7.5%-8% at the age of 70 years. Prospective analysis identified six breast cancers in 1120 years of follow-up with an OR of 3.41 (95% CI 1.53 to 7.59). DISCUSSIONS: Female MLH1 carriers would appear to be at moderate risk of breast cancer and should be considered for breast screening at ages earlier than national screening programmes. PMID- 26101332 TI - Neurocognitive Impairment as One Facet of Cancer-Related Sickness Behavior Symptoms. PMID- 26101331 TI - Inflammatory Biomarkers, Comorbidity, and Neurocognition in Women With Newly Diagnosed Breast Cancer. AB - BACKGROUND: Neurocognitive dysfunction is reported in women with breast cancer even prior to receipt of adjuvant therapy; however, there is little understanding of underlying mechanisms. We tested the hypothesis that pretreatment neurocognitive dysfunction in newly diagnosed patients is related to immunological activation, as indexed by pro-inflammatory cytokines. METHODS: One hundred seventy-four postmenopausal patients with newly diagnosed breast cancer underwent a comprehensive neuropsychological evaluation (assessment of cognitive function, mood, and fatigue) and measurement of key cytokine levels prior to surgery. Age-matched control participants without cancer were evaluated concurrently. Multivariable regression analyses examined the contribution of circulating Interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra), and soluble TNF receptor type two (sTNF-RII) in predicting neurocognitive performance in patients after controlling for key factors thought to impact functioning. All tests of statistical significance were two-sided. RESULTS: Memory performance was statistically significantly reduced, in patients compared with controls (P = .02). Of the three cytokines measured, only IL-1ra was statistically significantly elevated in cancer patients when compared with control participants (mean +/- SD, 375 +/- 239 pg/mL vs 291 +/- 169 pg/mL, P = .007). After controlling for age, education, race, mood, fatigue, body mass index, and comorbidity, cytokines independently explained 6.0% of the total variance in memory performance (P = .01) in cancer patients but not control participants, with higher sTNF-RII associated with worse functioning. Exploratory analyses found that comorbidity statistically significantly explained variance in processing speed and executive functioning (P = .03 and P = .03, respectively). CONCLUSION: An association of TNF with memory, previously reported in patients after exposure to chemotherapy, was found prior to initiation of any treatment, including surgery. This association requires further investigation as sTNF-RII was not higher in cancer patients relative to control participants. PMID- 26101333 TI - Oral Health Inequalities in Africa and the Middle East. PMID- 26101334 TI - Reducing Inequalities in Oral Health in the Africa and Middle East Region. AB - Dentistry is facing many serious challenges and threats. Addressing them will require major changes in strategy. This work outlines the extent of dental disease in the Africa and Middle East Region (AMER) and suggests strategies to reduce inequalities in oral health. The main oral health challenges in the AMER relate to controlling the relentless increase in caries with age. A very conservative estimate of population caries levels suggests that a 5-fold increase in dental personnel would be required just to treat current levels of caries. Hence, we argue that current approaches to control caries in the AMER are both ineffective and unaffordable, and a new model to promote oral health is needed. Unless determinants of noncommunicable diseases are addressed and access to evidence-based minimal intervention dental care is improved, the burden of dental disease will persist. The new oral health promotion model calls for an integrated intersectoral common risk factor approach, namely, "oral health in all policies" (OHiAP). An OHiAP framework will initiate high-level policy initiatives and intersectoral partnerships. Oral health professionals have an important advocacy role in securing the fundamental changes in health strategy needed to control the growing, unjust, and unaffordable burden of oral disease. PMID- 26101335 TI - Prevalence and Severity of Oral Diseases in the Africa and Middle East Region. AB - This review aims to determine the prevalence and severity of oral health diseases in the Africa and Middle East region (AMER). The profile of oral diseases is not homogeneous across the AMER. There are large disparities between groups. Reliable data are scarce. The prevalence and severity of oral diseases appear to be increasing in the African region, as does associated morbidity. There are substantial differences in inequalities in oral health. Dental caries prevalence is less severe in most African countries than in developed countries, but the high rate of untreated caries reflects the limited resources available and difficulties of access and affordability to essential oral health care services. The prevalence of gingival inflammation is very high in all age groups in several African countries. The prevalence of maxillofacial trauma has increased in many countries, with a wide variation of the incidence and high prevalence of traumatic dental injuries in primary and permanent teeth. Orofacial clefts are among the most common birth defects. Annual incidence of oral cancer is estimated as 25 cases per 100,000 people in Africa. Noma is a major public health problem for the Middle East and North African (MENA) region. Data about human immunodeficiency virus/AIDS are limited, particularly in the MENA region. According to the World Health Organization Regional Committee for Africa report, some fundamental key basic knowledge gaps need to be underlined. They include inequalities in oral health, low priority for oral health, lack of adequate funding, inadequate dental student training, obstacles to medical and dental research, and poor databases. There are very few effective public prevention and oral health promotion programs in the AMER. Universal health coverage is not achievable without scientific research on the effectiveness of health promotion interventions. PMID- 26101336 TI - Oral Health Inequalities between Rural and Urban Populations of the African and Middle East Region. AB - Although there have been major improvements in oral health, with remarkable advances in the prevention and management of oral diseases, globally, inequalities persist between urban and rural communities. These inequalities exist in the distribution of oral health services, accessibility, utilization, treatment outcomes, oral health knowledge and practices, health insurance coverage, oral health-related quality of life, and prevalence of oral diseases, among others. People living in rural areas are likely to be poorer, be less health literate, have more caries, have fewer teeth, have no health insurance coverage, and have less money to spend on dental care than persons living in urban areas. Rural areas are often associated with lower education levels, which in turn have been found to be related to lower levels of health literacy and poor use of health care services. These factors have an impact on oral health care, service delivery, and research. Hence, unmet dental care remains one of the most urgent health care needs in these communities. We highlight some of the conceptual issues relating to urban-rural inequalities in oral health, especially in the African and Middle East Region (AMER). Actions to reduce oral health inequalities and ameliorate rural-urban disparity are necessary both within the health sector and the wider policy environment. Recommended actions include population-specific oral health promotion programs, measures aimed at increasing access to oral health services in rural areas, integration of oral health into existing primary health care services, and support for research aimed at informing policy on the social determinants of health. Concerted efforts must be made by all stakeholders (governments, health care workforce, organizations, and communities) to reduce disparities and improve oral health outcomes in underserved populations. PMID- 26101337 TI - Determinants of Oral Diseases in the African and Middle East Region. AB - Oral health policies must be developed that emphasize the role of social determinants in health and oral diseases. The aim of this report is to review literature on determinants of oral diseases and apply the concepts to promoting oral health in the African countries in the African and Middle East region (AMER). Structural and proximal determinants of oral diseases are common to those affected by other noncommunicable diseases (NCDs). Oral diseases are also heavily affected by issues of politics, poor health behaviors, underdeveloped health systems, and low oral health literacy. Wide-scale poverty exists in populations in the AMER. Oral health promotion and preventive oral health programs should therefore be integrated with those for general health and use the common risk factor approach (CRFA). Attempts should be made to improve the daily living conditions and reduce the incline of the social gradient. Oral health practitioners should use the CRFA when dealing with determinants of oral diseases and in the design of preventive oral health programs. The detrimental effects of the social determinants of health may be ameliorated by involving both the individual and community. Interventions in health promotion programs in the AMER need more research on the epidemiology of oral diseases and the role played by the social determinants of oral diseases, especially with regard to poverty. The high levels of poverty and low gross domestic product in most countries in the African region make it difficult to fund high-quality, affordable, accessible oral health services. PMID- 26101338 TI - Capacity Building and Financing Oral Health in the African and Middle East Region. AB - Many low- and middle-income countries do not yet have policies to implement effective oral health programs. A reason is lack of human and financial resources. Gaps between resource needs and available health funding are widening. By building capacity, countries aim to improve oral health through actions by oral health care personnel and oral health care organizations and their communities. Capacity building involves achieving measurable and sustainable results in training, research, and provision of care. Actions include advancement of knowledge, attitudes and skills, expansion of support, and development of cohesiveness and partnerships. The aim of this critical review is to review existing knowledge and identify gaps and variations between and within different income levels in relation to the capacity building and financing oral health in the African and Middle East region (AMER). A second aim is to formulate research priorities and outline a research agenda for capacity building and financing to improve oral health and reduce oral health inequalities in the AMER. The article focuses on capacity building for oral health and oral health financing in the AMER of the IADR. In many communities in the AMER, there are clear and widening gaps between the dental needs and the existing capacity to meet these needs in terms of financial and human resources. Concerted efforts are required to improve access to oral health care through appropriate financing mechanisms, innovative health insurance schemes, and donor support and move toward universal oral health care coverage to reduce social inequality in the region. It is necessary to build capacity and incentivize the workforce to render evidence-based services as well as accessing funds to conduct research on equity and social determinants of oral health while promoting community engagement and a multidisciplinary approach. PMID- 26101339 TI - Strategies for Oral Health Research in Africa and the Middle Eastern Region. AB - The highest burden of diseases worldwide is in low- and middle-income countries, but due to lack of capacity and inadequate infrastructure, research output from these countries is unable to address existing and emerging challenges in health care. Oral health research has particularly been hampered by low prioritization, resulting in insufficient development of this sector. There is an urgent need for research correlating oral health to upstream social and environmental determinants and promoting the common risk factor approach for prevention of noncommunicable diseases. Population-wide preventive measures for oral health care are more effective than purely curative approaches, especially for vulnerable groups who have limited access to information and appropriate health care. This article identifies priorities and proposes strategies for researchers, stakeholders, and policy makers for the initiation and sustenance of appropriate oral health care research. The proposed interventions are intended to promote collaboration, capacity building, and health advocacy. Local ownership in multinational research projects in low- and middle-income countries, complemented by skills transfer from high-income countries, is encouraged to ensure that regional health needs are addressed. Emphasis is placed on a shift toward translational research that has a direct impact on oral health care systems. PMID- 26101340 TI - New clues towards solving the mystery of endothelin and blood pressure regulation. PMID- 26101341 TI - Remodeling of Afferent Arterioles From Mice With Oxidative Stress Does Not Account for Increased Contractility but Does Limit Excessive Wall Stress. AB - Because superoxide dismutase (SOD) knockout enhances arteriolar remodeling and contractility, we hypothesized that remodeling enhances contractility. In the isolated and perfused renal afferent arterioles from SOD wild type (+/+) and gene deleted mice, contractility was assessed from reductions in luminal diameter with perfusion pressure from 40 to 80 mm Hg (myogenic responses) or angiotensin II (10(-6) mol/L), remodeling from media:lumen area ratio, superoxide (O2 (.-)) and hydrogen peroxide (H2O2) from fluorescence microscopy, and wall stress from wall tension/wall thickness. Compared with +/+ strains, arterioles from SOD1-/-, SOD2+/-, and SOD3-/- mice developed significantly (P<0.05) more O2 (.-) with perfusion pressure and angiotensin II and significantly increased myogenic responses (SOD1-/-: -20.7+/-2.2% versus -12.7+/-1.6%; SOD2+/-: -7.4+/-1.3% versus -12.6+/-1.4%; and SOD3-/-: -9.1+/-1.9% versus -15.8+/-2.2%) and angiotensin II contractions and ~2-fold increased media:lumen ratios. Media:lumen ratios correlated with myogenic responses (r(2) =0.23; P<0.01), angiotensin II contractions (r(2)=0.57; P<0.0001), and active wall tension (r(2) =0.19; P<0.01), but not with active wall stress (r(2)=0.08; NS). Differences in myogenic responses among SOD3 mice were abolished by bath addition of SOD and were increased 3 days after inducing SOD3 knockout (-26.9+/-1.7% versus -20.1+/-0.7%; P<0.05), despite unchanged media:lumen ratios (2.01+/-0.09 versus 2.02+/-0.03; NS). We conclude that cytosolic, mitochondrial, or extracellular O2 (.-) enhance afferent arteriolar contractility and remodeling. Although remodeling does not enhance contractility, it does prevent the potentially damaging effects of increased wall stress. PMID- 26101343 TI - Exacerbating Pressure Overload-Induced Cardiac Hypertrophy: Novel Role of Adaptor Molecule Src Homology 2-B3. AB - The adaptor protein Src homology 2-B3 (SH2B3), which belongs to a subfamily of Src homology 2 proteins, is a broad inhibitor of growth factors and cytokine signaling in hematopoietic cells. However, the role of SH2B3 in nonhematopoietic systems, particularly cardiomyocytes, has not been defined. In this study, we observed noticeable increase in SH2B3 protein expression during pathological cardiac remodeling in both humans and rodents. Follow-up in vitro gain- and loss of-function studies suggested that SH2B3 promotes the cardiomyocyte hypertrophy response. Consistent with the cell phenotype, SH2B3 knockout (SH2B3(-/-)) mice exhibited attenuated cardiac remodeling with preserved cardiac function after chronic pressure overload. Conversely, cardiac-specific SH2B3 overexpression aggravated pressure overload-triggered cardiac hypertrophy, fibrosis, and dysfunction. Mechanistically, SH2B3 accelerates and exacerbates cardiac remodeling through the activation of focal adhesion kinase, which, in turn, activates the prohypertrophic downstream phosphoinositide 3-kinase-AKT-mammalian target of rapamycin/glycogen synthase kinase 3beta signaling pathway. Finally, we generated a novel SH2B3 knockout rat line and further confirmed the protective effects of SH2B3 deficiency on cardiac remodeling across species. Collectively, our data indicate that SH2B3 functions as a novel and effective modulator of cardiac remodeling and failure. PMID- 26101342 TI - Activation of central PPAR-gamma attenuates angiotensin II-induced hypertension. AB - Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-gamma in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-gamma might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR gamma agonist pioglitazone (3 nmol/h) or the PPAR-gamma antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-gamma mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-gamma DNA binding activity was reduced. mRNA for interleukin-1beta, tumor necrosis factor alpha, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-gamma mRNA and PPAR-gamma DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-gamma to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID- 26101344 TI - Short-Term Blood Pressure Variability Relates to the Presence of Subclinical Brain Small Vessel Disease in Primary Hypertension. AB - Blood pressure (BP) variability is associated with stroke risk, but less is known about subclinical cerebral small vessel disease (CSVD). We aimed to determine whether CSVD relates to short-term BP variability independently of BP levels and also, whether they improve CSVD discrimination beyond clinical variables and office BP levels. This was a cohort study on asymptomatic hypertensives who underwent brain magnetic resonance imaging and 24-hour ambulatory BP monitoring. Office and average 24-hour, daytime and nighttime BP levels, and several metrics of BP variability (SD, weighted SD, coefficient of variation, and average real variability [ARV]) were calculated. Definition of CSVD was based on the presence of lacunar infarcts and white matter hyperintensity grades. Multivariate analysis and integrated discrimination improvement were performed to assess whether BP variability and levels were independently associated with CSVD and improved its discrimination. Four hundred eighty-seven individuals participated (median age, 64; 47% women). CSVD was identified in 18.9%, related to age, male sex, diabetes mellitus, use of treatment, ambulatory BP monitoring-defined BP levels, and ARV of systolic BP at any period. The highest prevalence (33.7%) was found in subjects with both 24-hour BP levels and ARV elevated. BP levels at any period and ARV (24 hours and nocturnal) emerged as independent predictors of CSVD, and discrimination was incrementally improved although not to a clinically significant extent (integrated discrimination improvement, 5.31%, 5.17% to 5.4%). Ambulatory BP monitoring-defined BP levels and ARV of systolic BP relate to subclinical CSVD in hypertensive individuals. PMID- 26101345 TI - Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure. AB - The mammalian target of rapamycin complex 2 (mTORC2) contains the essential protein RICTOR and is activated by growth factors. mTORC2 in adipose tissue contributes to the regulation of glucose and lipid metabolism. In the perivascular adipose tissue, mTORC2 ensures normal vascular reactivity by controlling expression of inflammatory molecules. To assess whether RICTOR/mTORC2 contributes to blood pressure regulation, we applied a radiotelemetry approach in control and Rictor knockout (Rictor(aP2KO)) mice generated using adipocyte protein-2 gene promoter-driven CRE recombinase expression to delete Rictor. The 24-hour mean arterial pressure was increased in Rictor(aP2KO) mice, and the physiological decline in mean arterial pressure during the dark period was impaired. In parallel, heart rate and locomotor activity were elevated during the dark period with a pattern similar to blood pressure changes. This phenotype was associated with mild cardiomyocyte hypertrophy, decreased cardiac natriuretic peptides, and their receptor expression in adipocytes. Moreover, clock gene expression was reduced or phase-shifted in perivascular adipose tissue. No differences in clock gene expression were observed in the master clock suprachiasmatic nucleus, although Rictor gene expression was also lower in brain of Rictor(aP2KO) mice. Thus, this study highlights the importance of RICTOR/mTORC2 for interactions between vasculature, adipocytes, and brain to tune physiological outcomes, such as blood pressure and locomotor activity. PMID- 26101346 TI - Inducible human endothelin-1 overexpression in endothelium raises blood pressure via endothelin type A receptors. AB - The mechanisms of blood pressure regulation by endothelin-1 produced by endothelial cells are complex and still unclear. Transgenic mice with endothelium restricted human endothelin-1 (EDN1) overexpression presented vascular damage but no significant change in blood pressure, which could be because of adaptation to life-long exposure to elevated endothelin-1 levels. We now generated a tamoxifen inducible endothelium-restricted EDN1 overexpressing transgenic mouse (ieET-1) using Cre/loxP technology. Sixteen days after tamoxifen treatment, ieET-1 mice presented >=10-fold increase in plasma endothelin-1 (P<0.01) and >=20 mm Hg elevation in systolic blood pressure (P<0.01), which could be reversed by atrasentan (P<0.05). Endothelin-1 overexpression did not cause vascular or kidney injury or changes in kidney perfusion or function. However, endothelin type A and B receptor expression was differentially regulated in the mesenteric arteries and the kidney. Our results demonstrate using this ieET-1 mouse model that 21 days of induction of endothelin-1 overexpression caused endothelin-1-dependent elevated blood pressure mediated by endothelin type A receptors. PMID- 26101347 TI - Maintaining Balance Under Pressure: Integrated Regulation of Renal Transporters During Hypertension. PMID- 26101349 TI - Pediatric Palliative Care Pilot Curriculum: Impact of "Pain Cards" on Resident Education. AB - BACKGROUND: Prior research has shown that less than 40% of pediatric program directors believe their graduating residents competent in palliative care. While many curricula have been developed to address this need, few have demonstrated improved comfort and/or knowledge with palliative care principles. The purpose of this study was to test a pocket card educational intervention regarding resident knowledge and comfort with palliative care principles. METHODS: Pocket reference cards were created to deliver fundamentals of pediatric palliative care to resident learners; didactics and case studies emphasized principles on the cards. Self-reported comfort and objective knowledge were measured before and after the curriculum among residents. RESULTS: Of 32 post-graduate year 2 (PGY2) residents, 23 (72%) completed the pre-test survey. The post-test was completed by 14 PGY2 residents (44%) and 16 of 39 PGY3/4 residents (41%). There was improvement in comfort with communication, as well as pain and symptom management among the residents. Knowledge of palliative care principles improved in part, with only a few survey questions reaching statistical significance. 100% of respondents recommended the cards be provided to their colleagues. CONCLUSION: This longitudinal curriculum, designed specifically for pediatric residents, was built into an existing training program and proved to be popular, feasible, and effective at improving comfort with basic palliative care principles. PMID- 26101348 TI - Oral Contraceptive Use, Muscle Sympathetic Nerve Activity, and Systemic Hemodynamics in Young Women. AB - Endogenous female sex hormones influence muscle sympathetic nerve activity (MSNA), a regulator of arterial blood pressure and important factor in hypertension development. Although ~80% of American women report using hormonal contraceptives sometime during their life, the influence of combined oral contraceptives (OCs) on MSNA and systemic hemodynamics remains equivocal. The goal of this study was to determine whether women taking OCs have altered MSNA and hemodynamics (cardiac output and total peripheral resistance) at rest during the placebo phase of OC use compared with women with natural menstrual cycles during the early follicular phase. We retrospectively analyzed data from studies in which healthy, premenopausal women (aged 18-35 years) participated. We collected MSNA values at rest and hemodynamic measurements in women taking OCs (n=53; 25+/-4 years) and women with natural menstrual cycles (n=74; 25+/-4 years). Blood pressure was higher in women taking OCs versus those with natural menstrual cycles (mean arterial pressure, 89+/-1 versus 85+/-1 mm Hg, respectively; P=0.01), although MSNA was similar in both groups (MSNA burst incidence, 16+/-1 versus 18+/-1 bursts/100 heartbeats, respectively; P=0.19). In a subset of women in which detailed hemodynamic data were available, those taking OCs (n=33) had similar cardiac output (4.9+/-0.2 versus 4.7+/-0.2 L/min, respectively; P=0.47) and total peripheral resistance (19.2+/-0.8 versus 20.0+/ 0.9 U, respectively; P=0.51) as women with natural menstrual cycles (n=22). In conclusion, women taking OCs have higher resting blood pressure and similar MSNA and hemodynamics during the placebo phase of OC use when compared with naturally menstruating women in the early follicular phase. PMID- 26101350 TI - Contribution of NADPH oxidase to the establishment of hippocampal neuronal polarity in culture. AB - Reactive oxygen species (ROS) produced by the NADPH oxidase (NOX) complex play important physiological and pathological roles in neurotransmission and neurodegeneration, respectively. However, the contribution of ROS to the molecular mechanisms involved in neuronal polarity and axon elongation is not well understood. In this work, we found that loss of NOX complex function altered neuronal polarization and decreased axonal length by a mechanism that involves actin cytoskeleton dynamics. These results indicate that physiological levels of ROS produced by the NOX complex modulate hippocampal neuronal polarity and axonal growth in vitro. PMID- 26101351 TI - Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface. AB - The neural cell adhesion molecule (NCAM, also known as NCAM1) is important during neural development, because it contributes to neurite outgrowth in response to its ligands at the cell surface. In the adult brain, NCAM is involved in regulating synaptic plasticity. The molecular mechanisms underlying delivery of NCAM to the neuronal cell surface remain poorly understood. We used a protein macroarray and identified the kinesin light chain 1 (KLC1), a component of the kinesin-1 motor protein, as a binding partner of the intracellular domains of the two transmembrane isoforms of NCAM, NCAM140 and NCAM180. KLC1 binds to amino acids CGKAGPGA within the intracellular domain of NCAM and colocalizes with kinesin-1 in the Golgi compartment. Delivery of NCAM180 to the cell surface is increased in CHO cells and neurons co-transfected with kinesin-1. We further demonstrate that the p21-activated kinase 1 (PAK1) competes with KLC1 for binding to the intracellular domain of NCAM and contributes to the regulation of the membrane insertion of NCAM. Our results indicate that NCAM is delivered to the cell surface through a kinesin-1-mediated transport mechanism in a PAK1-dependent manner. PMID- 26101354 TI - Correction. To lower or not to lower? Making sense of the latest research on intensive glycaemic control and cardiovascular outcomes. PMID- 26101352 TI - Analysis of ER-mitochondria contacts using correlative fluorescence microscopy and soft X-ray tomography of mammalian cells. AB - Mitochondrial fission is important for organelle transport, quality control and apoptosis. Changes to the fission process can result in a wide variety of neurological diseases. In mammals, mitochondrial fission is executed by the GTPase dynamin-related protein 1 (Drp1; encoded by DNM1L), which oligomerizes around mitochondria and constricts the organelle. The mitochondrial outer membrane proteins Mff, MiD49 (encoded by MIEF2) and MiD51 (encoded by MIEF1) are involved in mitochondrial fission by recruiting Drp1 from the cytosol to the organelle surface. In addition, endoplasmic reticulum (ER) tubules have been shown to wrap around and constrict mitochondria before a fission event. Up to now, the presence of MiD49 and MiD51 at ER-mitochondrial division foci has not been established. Here, we combine confocal live-cell imaging with correlative cryogenic fluorescence microscopy and soft x-ray tomography to link MiD49 and MiD51 to the involvement of the ER in mitochondrial fission. We gain further insight into this complex process and characterize the 3D structure of ER mitochondria contact sites. PMID- 26101353 TI - gamma-SNAP stimulates disassembly of endosomal SNARE complexes and regulates endocytic trafficking pathways. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) that reside in the target membranes and transport vesicles assemble into specific SNARE complexes to drive membrane fusion. N-ethylmaleimide-sensitive factor (NSF) and its attachment protein, alpha-SNAP (encoded by NAPA), catalyze disassembly of the SNARE complexes in the secretory and endocytic pathways to recycle them for the next round of fusion events. gamma-SNAP (encoded by NAPG) is a SNAP isoform, but its function in SNARE-mediated membrane trafficking remains unknown. Here, we show that gamma-SNAP regulates the endosomal trafficking of epidermal growth factor (EGF) receptor (EGFR) and transferrin. Immunoprecipitation and mass spectrometry analyses revealed that gamma-SNAP interacts with a limited range of SNAREs, including endosomal ones. gamma-SNAP, as well as alpha-SNAP, mediated the disassembly of endosomal syntaxin-7-containing SNARE complexes. Overexpression and small interfering (si)RNA-mediated depletion of gamma-SNAP changed the morphologies and intracellular distributions of endosomes. Moreover, the depletion partially suppressed the exit of EGFR and transferrin from EEA1 positive early endosomes to delay their degradation and uptake. Taken together, our findings suggest that gamma-SNAP is a unique SNAP that functions in a limited range of organelles - including endosomes - and their trafficking pathways. PMID- 26101355 TI - Therapeutic Drug Monitoring in Neonatal HSV Infection on Continuous Renal Replacement Therapy. AB - Optimal acyclovir dosing under continuous renal replacement therapy (CRRT) in neonates is unknown. We monitored serum acyclovir levels and herpes simplex virus 1 (HSV-1) DNA levels in a neonate with disseminated HSV-1 infection and renal failure undergoing CRRT. A full-term, 5-day-old female presented with a 2-day history of lethargy and fever. She developed fulminant hepatitis and was diagnosed with HSV-1 infection by real-time polymerase chain reaction. Acyclovir was initiated at 60 mg/kg/day, which was lowered to 20 mg/kg/day because of development of renal failure. She was placed on continuous hemodialysis. Acyclovir dosing was adjusted according to serum acyclovir levels, and HSV-1 viral load was sequentially monitored. Semiquantification of serum HSV-1 levels was performed by real-time polymerase chain reaction. Acyclovir levels were measured by using liquid chromatography-tandem mass spectrometry. Acyclovir was administered at 20 mg/kg intravenously over 1 hour; peak concentration was 18.9 MUg/mL. The half-life of acyclovir was estimated to be 2 to 3 h. Viral load remained high during dosing every 24 hours, with a decline of 0.17 log copies/24 hours. Acyclovir dosing was changed to 20 mg/kg/dose every 8 hours, with an average viral load decline of 0.44 log copies/24 hours. Despite the guideline recommendation of 24-hour redosing, acyclovir was dialyzed at a rate that resulted in suboptimal treatment. Individual therapeutic drug monitoring for acyclovir and dosing adjustment may be required to optimize therapy for patients undergoing CRRT. PMID- 26101357 TI - Comparative Effectiveness Research Through a Collaborative Electronic Reporting Consortium. AB - The United States lacks a system to use routinely collected electronic health record (EHR) clinical data to conduct comparative effectiveness research (CER) on pediatric drug therapeutics and other child health topics. This Special Article describes the creation and details of a network of EHR networks devised to use clinical data in EHRs for conducting CER, led by the American Academy of Pediatrics Pediatric Research in Office Settings (PROS). To achieve this goal, PROS has linked data from its own EHR-based "ePROS" network with data from independent practices and health systems across the United States. Beginning with 4 of proof-of-concept retrospective CER studies on psychotropic and asthma medication use and side effects with a planned full-scale prospective CER study on treatment of pediatric hypertension, the Comparative Effectiveness Research Through Collaborative Electronic Reporting (CER(2)) collaborators are developing a platform to advance the methodology of pediatric pharmacoepidemiology. CER(2) will provide a resource for future CER studies in pediatric drug therapeutics and other child health topics. This article outlines the vision for and present composition of this network, governance, and challenges and opportunities for using the network to advance child health and health care. The goal of this network is to engage child health researchers from around the United States in participating in collaborative research using the CER(2) database. PMID- 26101356 TI - Antibiotic Choice for Children Hospitalized With Pneumonia and Adherence to National Guidelines. AB - INTRODUCTION: The 2011 national guidelines for the management of childhood community-acquired pneumonia (CAP) recommended narrow-spectrum antibiotics (eg, ampicillin) for most children hospitalized with CAP. We assessed the impact of these guidelines on antibiotic prescribing at 3 children's hospitals. METHODS: Children hospitalized with clinical and radiographic CAP were enrolled from January 1, 2010, through June 30, 2012, at 3 hospitals in Tennessee and Utah as part of the Centers for Disease Control and Prevention Etiology of Pneumonia in the Community study. Antibiotic selection was determined by the treating provider. The impact of the guidelines and hospital-level implementation efforts was determined by assessing the monthly percentage of enrolled children receiving third-generation cephalosporins or penicillin/ampicillin. Segmented linear regression was used to compare observed antibiotic selection in the postguideline period with expected antibiotic use projected from preguideline months. RESULTS: Overall, 2121 children were included. During the preguideline period, 52.8% (interquartile range 47.8-56.6) of children with CAP received third-generation cephalosporins, whereas 2.7% (2.1, 7.0) received penicillin/ampicillin. By 9 months postguidelines, third-generation cephalosporin use declined (absolute difference -12.4% [95% confidence interval -19.8% to -5.1%]), whereas penicillin/ampicillin use increased (absolute difference 11.3% [4.3%-18.3%]). The most substantial changes were noted at those institutions that implemented guideline-related dissemination activities. CONCLUSIONS: After publication of national guidelines, third-generation cephalosporin use declined and penicillin/ampicillin use increased among children hospitalized with CAP. Changes were more apparent among those institutions that proactively disseminated the guidelines, suggesting that targeted, hospital-based efforts are important for timely implementation of guideline recommendations. PMID- 26101358 TI - Systematic Review on Intensive Interdisciplinary Pain Treatment of Children With Chronic Pain. AB - BACKGROUND AND OBJECTIVE: Pediatric debilitating chronic pain is a severe health problem, often requiring complex interventions such as intensive interdisciplinary pain treatment (IIPT). Research is lacking regarding the effectiveness of IIPT for children. The objective was to systematically review studies evaluating the effects of IIPT. METHODS: Cochrane, Medline/Ovid, PsycInfo/OVID, PubMed, PubPsych, and Web of Science were searched. Studies were included if (1) treatment was coordinated by >=3 health professionals, (2) treatment occurred within an inpatient/day hospital setting, (3) patients were <22 years, (4) patients experienced debilitating chronic pain, (5) the study was published in English, and (6) the study had >=10 participants at posttreatment. The child's pain condition, characteristics of the IIPT, and 5 outcome domains (pain intensity, disability, school functioning, anxiety, depressive symptoms) were extracted at baseline, posttreatment, and follow-up. RESULTS: One randomized controlled trial and 9 nonrandomized treatment studies were identified and a meta analysis was conducted separately on pain intensity, disability, and depressive symptoms revealing positive treatment effects. At posttreatment, there were large improvements for disability, and small to moderate improvements for pain intensity and depressive symptoms. The positive effects were maintained at short term follow-up. Findings demonstrated extreme heterogeneity. CONCLUSIONS: Effects in nonrandomized treatment studies cannot be attributed to IIPT alone. Because of substantial heterogeneity in measures for school functioning and anxiety, meta analyses could not be computed. There is preliminary evidence for positive treatment effects of IIPT, but the small number of studies and their methodological weaknesses suggest a need for more research on IIPTs for children. PMID- 26101359 TI - Critical Elements in the Medical Evaluation of Suspected Child Physical Abuse. AB - BACKGROUND: Previous research has described variability in medical evaluation of suspected abuse. The objective of this study was to identify, through expert consensus, required and highly recommended elements of a child abuse pediatrics (CAP) evaluation for 3 common presentations of suspected physical abuse in children aged 0 to 60 months. METHODS: Twenty-eight CAPs recruited from 2 national organizations formed the expert panel for this modified Delphi Process. An initial survey was developed for each presentation based on demographics, history of present illness, past medical, family and social history, laboratory, radiology, and consultation elements present in at least 10% of CAP consultations collected for a larger study. CAPs ranked each element on a 9-point scale then reviewed and discussed summary results through a project blog over 3 rounds. Required and highly recommended elements were defined as elements ranked as 9 and 8, respectively, by >=75% of experts after the final round. RESULTS: From 96 elements in the initial surveys, experts identified 30 Required elements and 37 Highly Recommended elements for CAP evaluation of intracranial hemorrhage, 21 Required and 33 Highly Recommended elements for CAP evaluation of long bone fracture, and 18 Required and 16 Highly Recommended elements for CAP evaluation of isolated skull fracture. CONCLUSIONS: This guideline reflects expert consensus and provides a starting point for development of child abuse assessment protocols for quality improvement or research. Additional research is required to determine whether this guideline can reduce variability and/or improve reliability in the evaluation and diagnosis of child physical abuse. PMID- 26101360 TI - Weight Growth Velocity and Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000-2013. AB - BACKGROUND: Very low birth weight infants often gain weight poorly and demonstrate growth failure during the initial hospitalization. Although many of the major morbidities experienced by these infants during their initial NICU stays have decreased in recent years, it is unclear whether growth has improved. METHODS: We studied 362 833 infants weighing 501 to 1500 g without major birth defects born from 2000 to 2013 and who were hospitalized for 15 to 175 days at 736 North American hospitals in the Vermont Oxford Network. Average growth velocity (GV; g/kg per day) was computed by using a 2-point exponential model on the basis of birth weight and discharge weight. Postnatal growth failure and severe postnatal growth failure were defined as a discharge weight less than the 10th and third percentiles for postmenstrual age, respectively. RESULTS: From 2000 to 2013, average GV increased from 11.8 to 12.9 g/kg per day. Postnatal growth failure decreased from 64.5% to 50.3% and severe postnatal growth failure from 39.8% to 27.5%. The interquartile ranges for the hospitals participating in 2013 were as follows: GV, 12.3 to 13.4 g/kg per day; postnatal growth failure, 41.1% to 61.7%; and severe postnatal growth failure, 19.4% to 36.0%. Adjusted and unadjusted estimates were nearly identical. CONCLUSIONS: For infants weighing 501 to 1500 g at birth, average GV increased and the percentage with postnatal growth failure decreased. However, in 2013, half of these infants still demonstrated postnatal growth failure and one-quarter demonstrated severe postnatal growth failure. PMID- 26101361 TI - Association of National Guidelines With Tonsillectomy Perioperative Care and Outcomes. AB - OBJECTIVE: To investigate the association of the 2011 American Academy of Otolaryngology Head and Neck Surgery guidelines with perioperative care processes and outcomes in children undergoing tonsillectomy. METHODS: We conducted a retrospective cohort study of otherwise healthy children undergoing tonsillectomy between January 2009 and January 2013 at 29 US children's hospitals participating in the Pediatric Health Information System. We measured evidence-based processes suggested by the guidelines (perioperative dexamethasone and no antibiotic use) and outcomes (30-day tonsillectomy complication-related revisits). We analyzed rates aggregated over the preguideline and postguideline periods and then by month over time by using interrupted time series. RESULTS: Of 111,813 children who underwent tonsillectomy, 54,043 and 57,770 did so in the preguideline and postguideline periods, respectively. Dexamethasone use increased from 74.6% to 77.4% (P < .001) in the preguideline to postguideline period, as did its rate of change in use (percentage change per month, -0.02% to 0.29%; P < .001). Antibiotic use decreased from 34.7% to 21.8% (P < .001), as did its rate of change in use (percentage change per month, -0.17% to -0.56%; P < .001). Revisits for bleeding remained stable; however, total revisits to the hospital for tonsillectomy complications increased from 8.2% to 9.0% (P < .001) because of an increase in revisits for pain. Hospital-level results were similar. CONCLUSIONS: The guidelines were associated with some improvement in evidence-based perioperative care processes but no improvement in outcomes. Dexamethasone use increased slightly, and antibiotic use decreased substantially. Revisits for tonsillectomy-related complications increased modestly over time because of revisits for pain. PMID- 26101362 TI - Adolescent Health and Adult Education and Employment: A Systematic Review. AB - OBJECTIVE: Poor health in adolescence has the potential to disrupt education and employment pathways. This study is the first systematic review of the literature examining education and employment outcomes in adulthood of poor adolescent mental and physical health. METHODS: We conducted searches using a standardized search protocol in 8 electronic databases: PsycINFO, Medline, Embase, ERIC, British Education Index, Australian Education Index, Social Sciences Citation Index, and CINAHL Plus. We identified studies that longitudinally compared adult education and employment outcomes of those with an adolescent chronic condition of clinical severity with healthy controls. We conducted meta-analyses using odds ratios (for dichotomous variables) and Cohen's d (for continuous variables) as our main summary statistics. RESULTS: We identified 27 studies incorporating 70 relevant analyses. Our meta-analyses suggested that overall, poor health in adolescence was associated with poorer education and employment outcomes in adulthood. However, evidence was much stronger for mental health conditions than for physical health conditions, for which less evidence was available and mixed findings emerged. Compared with mental health conditions, we identified few studies investigating the long-term outcomes of physical health conditions. Age and follow-up times varied considerably across our studies, which potentially resulted in some heterogeneity in effect sizes. The majority of included studies were conducted in the United States, raising questions about the generalizability of the results internationally. CONCLUSIONS: Health in adolescence contributes to adult attainment and life chances. The results suggest that investment in health may improve life chances and that policy interventions may improve outcomes for those with adolescent chronic conditions. PMID- 26101363 TI - Quality Improvement Effort to Reduce Cranial CTs for Children With Minor Blunt Head Trauma. AB - OBJECTIVE: Blunt head trauma is a common injury in children, although it rarely requires surgical intervention. Cranial computed tomography (CT) is the reference standard for the diagnosis of traumatic brain injury but has been associated with increased lifetime malignancy risk. We implemented a multifaceted quality improvement initiative to decrease the use of cranial CT for children with minor head injuries. METHODS: We designed and implemented a quality improvement effort that included an evidence-based guideline as well as individual feedback for children aged 0 to 21 years who present to the emergency department (ED) for evaluation of minor blunt head trauma. Our primary outcome was cranial CT rate, and our balancing measure was any return to the ED within 72 hours that required hospitalization. We used statistical process control methodology to measure cranial CT rates over time. RESULTS: We included 6851 ED visits of which 4242 (62%) occurred in the post-guideline implementation period. From a baseline CT rate of 21%, we observed an absolute reduction of 6% in cranial CT rate (95% confidence interval 3% to 9%) after initial guideline implementation and an additional absolute reduction of 6% (95% confidence interval 4% to 8%) after initiation of individual provider feedback. No children discharged from the ED required admission within 72 hours of initial evaluation. CONCLUSIONS: An ED quality improvement effort that included an evidence-based guideline as well as individual provider feedback was associated with a reduction in cranial CT rates without an increase in missed significant head injuries. PMID- 26101364 TI - Mycophenolate Mofetil Following Rituximab in Children With Steroid-Resistant Nephrotic Syndrome. AB - BACKGROUND: Rituximab is being increasingly used in children with idiopathic nephrotic syndrome resistant to standard treatments. In spite of good initial response, rituximab responders always remain prone to further relapse, necessitating either repeat course of rituximab or addition of another steroid sparing immunosuppressant. METHODS: A retrospective analysis of baseline clinico pathologic presentation and treatment outcome (complete remission, partial remission, or no response) was performed among 24 children with refractory idiopathic SRNS over a follow-up period of 24 months. Children received 2 to 4 rituximab infusions (375 mg/m(2) weekly) depending on circulating B-cell level. At 3-month follow-up, a second course of rituximab was administered (if >5 B cells/mm(3)) along with MMF (1200 mg/m(2) per day) maintenance therapy. RESULTS: Of 24 patients, 54% (13/24) and 46% (11/24) had minimal change disease and focal segmental glomerulosclerosis, respectively, on renal histopathology. After the first course of rituximab, 21% (5/24) of children achieved complete remission; however, most (4/5) of them relapsed again at a median interval of 53 (interquartile range 46-72) days. Depending on response to the first course of rituximab, MMF was started on 15 children at 3 months. After 6 months, 67% (10/15) of children on MMF achieved complete remission and 33% (5/15) remained at partial remission. At 24 months overall, 25% (6/24) and 42% (10/24) of children were in complete remission and partial remission, respectively; 33% (5/15) of children continued sustained complete remission after postrituximab-MMF maintenance therapy in comparison with no sustained complete remission with rituximab alone at 24 months (P < .001). CONCLUSIONS: MMF may be an effective and safe maintenance therapy to consider as an additive immunosuppressant after induction with rituximab in maintaining remission among children with refractory SRNS. PMID- 26101365 TI - Case Report: Intravenous and Oral Pyridoxine Trial for Diagnosis of Pyridoxine Dependent Epilepsy. AB - Pyridoxine-dependent epilepsy is a rare, autosomal recessive, treatable cause of neonatal seizures. Genetic testing can confirm mutations in the ALDH7A1 gene, which encodes antiquitin. To avoid delays in initiating treatment while awaiting confirmatory genetic testing, it is recommended that all neonates with unexplained seizures should receive trial of intravenous (IV) pyridoxine to assess for responsiveness. However, oral pyridoxine is not commonly continued in the absence of the typical EEG changes. Two cases are presented that highlight the potential inadequacy of this single-step approach. One neonate ultimately diagnosed with pyridoxine-dependent seizures had no EEG changes after administration of IV pyridoxine. In contrast, another neonate who did not have this diagnosis had profound EEG changes after pyridoxine administration. We present 2 cases that highlight the difficulties in using initial EEG response to IV pyridoxine in establishing a diagnosis of pyridoxine-dependent seizures in the neonate. Given the availability of biochemical markers and gene testing, we suggest that oral pyridoxine treatment should be continued until biochemical and/or genetic testing has confirmed the presence or absence of pyridoxine dependent epilepsy. PMID- 26101366 TI - Immunogenicity and Safety of a 9-Valent HPV Vaccine. AB - OBJECTIVES: Prophylactic vaccination of youngwomen aged 16 to 26 years with the 9 valent (6/11/16/18/31/33/45/52/58) human papillomavirus (HPV) virus-like particle (9vHPV) vaccine prevents infection and disease. We conducted a noninferiority immunogenicity study to bridge the findings in young women to girls and boys aged 9 to 15 years. METHODS: Subjects (N = 3066) received a 3-dose regimen of 9vHPV vaccine administered at day 1, month 2, and month 6. Anti-HPV serologic assays were performed at day 1 and month 7. Noninferiority required that the lower bound of 2-sided 95% confidence intervals of geometric mean titer ratios (boys:young women or girls:young women) be >0.67 for each HPV type. Systemic and injection site adverse experiences (AEs) and serious AEs were monitored. RESULTS: At 4 weeks after dose 3, >99% of girls, boys, and young women seroconverted for each vaccine HPV type. Increases in geometric mean titers to HPV types 6/11/16/18/31/33/45/52/58 were elicited in all vaccine groups. Responses in girls and boys were noninferior to those of young women. Persistence of anti-HPV responses was demonstrated through 2.5 years after dose 3. Administration of the 9vHPV vaccine was generally well tolerated. A lower proportion of girls (81.9%) and boys (72.8%) than young women (85.4%) reported injection-site AEs, most of which were mild to moderate in intensity. CONCLUSIONS: These data support bridging the efficacy findings with 9vHPV vaccine in young women 16 to 26 years of age to girls and boys 9 to 15 years of age and implementing gender-neutral HPV vaccination programs in preadolescents and adolescents. PMID- 26101367 TI - Increased Glycated Hemoglobin Level is Associated With SYNTAX Score II in Patients With Type 2 Diabetes Mellitus. AB - SYNTAX score II (SS II) uses 2 anatomical and 6 clinical variables for the prediction of mortality after coronary artery bypass graft and percutaneous coronary intervention. The aim of this study was to investigate the relationship between glycated hemoglobin (HbA1c), fasting blood glucose (FBG), postprandial glucose (PPG), and SYNTAX Score (SS) and SS II in patients with type 2 diabetes mellitus and coronary artery disease (CAD). We enrolled 215 consecutive diabetic patients with stable angina pectoris who underwent coronary angiography. The SS II was calculated using a nomogram that was based on the findings of a previous study. There was a moderate correlation between HbA1c and SS (r = .396, P < .001), but there was a good correlation between HbA1c and SS II (r = .535, P < .001). There was also a weak correlation between FBG (r = .270, P = .001), PPG (r = .177, P = .027), and SS, but there was a weak-moderate correlation between FBG (r = .341, P < .001), PPG (r = .256, P = .001), and SS II. A better correlation has been detected between HbA1c and SS II compared to the correlation between HbA1c and SS. PMID- 26101368 TI - Platelet to Lymphocyte Ratio as a Prognostic Marker of In-Hospital and Long-Term Major Adverse Cardiovascular Events in ST-Segment Elevation Myocardial Infarction. AB - We assessed the prognostic value of the platelet to lymphocyte ratio (PLR) on in hospital and long-term major adverse cardiovascular events (MACEs) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI) in a large prospective study. Patients (n = 1938) admitted with acute STEMI within 12 hours of symptom onset and who underwent pPCI between January 2010 and January 2015 were followed up for 31.6 +/ 16.2 months. During the in-hospital and long-term follow-up period, MACE, the prevalence of stent thrombosis, nonfatal myocardial infarction, and mortality were higher in the third PLR tertile group. A PLR in the third tertile had 2.4 fold increased risk of in-hospital MACE and 2.8-fold risk of long-term MACE. The PLR was significantly and positively correlated with peak creatine kinase MB (CK MB) levels (r = 0.562, P < .001) and Gensini score (r = 0.408, P < .001). Kaplan Meier analysis of long-term MACE-free survival revealed a higher occurrence of MACE in the third PLR tertile group compared to the other tertiles. In conclusion, the PLR may be a marker of inflammatory and prothrombotic status and predicted in-hospital and long-term MACE in a population with STEMI. PMID- 26101369 TI - Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: Which Regimen and for How Long? PMID- 26101370 TI - Is surgery necessary for 'mild' or 'asymptomatic' hyperparathyroidism? AB - A large majority of the currently diagnosed patients with hyperparathyroidism (PHPT) are mild or asymptomatic, mainly women after menopause. Following the debate held at the 16th European Congress of Endocrinology in Wroclaw (Poland) from May 3-7, 2014, arguments are here presented by a surgeon and a medical practitioner considering these situations rather have to profit from surgery, or simply from survey. For the trained endocrine surgeon, it is evident that parathyroidectomy confirms the diagnosis and undoubtedly reduces the discomfort felt by certain patients, prevents all risks of complications, removes patients and medical teams from the monitoring and represents a real individual financial benefit. On the other hand, the medical practitioner considers that mild or asymptomatic PHPT is commonly stable, and very rare are the subjects at risk of complications, particularly of fractures; prevention of vascular and metabolic disorders, nephrolithiasis and bone rarefaction justify regular physical exercise, a safe alimentation, a sufficient calcium and high water intake, the correction of the frequent deficit in vitamin D; finally has also to be considered the impossibility to refer to specialized (endocrine) surgeons, the enormous cohort of subjects more than 50 years with 'mild' or 'asymptomatic' PHPT. The surgeon and the medical practitioner agree to consider that in patients with 'mild' or 'asymptomatic' disease, there is no place for medical treatments, in particular calcimimetics and bisphophonates. Both agree that further studies are needed to clarify the long-term prognosis of operated and non-operated PHPT in term of fractures, cardiovascular risk and mortality. Individual and collective cost/benefit ratios of surgery or survey are also still imperfectly evaluated. PMID- 26101371 TI - Prevalence of subnormal testosterone concentrations in men with type 2 diabetes and chronic kidney disease. AB - BACKGROUND: One-third of men with type 2 diabetes have subnormal testosterone concentrations along with inappropriately normal LH and FSH concentrations. It is not known if the presence of renal insufficiency affects free testosterone concentrations in men with type 2 diabetes. HYPOTHESIS: We hypothesized that type 2 diabetic men with chronic renal disease (CKD; estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2)) have lower free testosterone concentrations than men with normal renal function (eGFR >= 60 ml/min per 1.73 m(2)). STUDY DESIGN AND SETTING: This is a retrospective chart review of patients attending diabetes and nephrology clinics. Men with type 2 diabetes who had the following information available were included in the study: testosterone (total and free) done by LC/MS-MS followed by equilibrium dialysis, sex hormone binding globulin, LH, FSH and prolactin concentrations. PARTICIPANTS: We present data on T and gonadotropin concentrations in 111 men with type 2 diabetes and CKD (stages 3-5) and 182 type 2 diabetic men without CKD. RESULTS: The prevalence of subnormal free testosterone concentrations was higher in men with type 2 diabetes and CKD as compared to those without CKD (66% vs 37%, P < 0.001). Men with CKD had a higher prevalence of hypergonadotropic hypogonadism (26% vs 5%, P < 0.001) but not of hypogonadotropic hypogonadism (HH; 40% vs 32%, P = 0.22). There was an increase in the prevalence of hypergonadotropic hypogonadism with decreasing eGFR. Fifty-two percent of men with renal failure (CKD stage 5) had hypergonadotropic hypogonadism and 25% had HH. In men with CKD, the hemoglobin concentrations were lower in those with subnormal free T concentrations as compared to men with normal free T concentrations (119 +/- 19 vs 128 +/- 19 g/l, P = 0.04). CONCLUSIONS: Two-thirds of men with type 2 diabetes and CKD have subnormal free T concentrations. The hypogonadism associated with CKD is predominantly hypergonadotropic. PMID- 26101373 TI - The deadly bite of Salmonella Typhi. PMID- 26101372 TI - TRIM5alpha requires Ube2W to anchor Lys63-linked ubiquitin chains and restrict reverse transcription. AB - TRIM5alpha is an antiviral, cytoplasmic, E3 ubiquitin (Ub) ligase that assembles on incoming retroviral capsids and induces their premature dissociation. It inhibits reverse transcription of the viral genome and can also synthesize unanchored polyubiquitin (polyUb) chains to stimulate innate immune responses. Here, we show that TRIM5alpha employs the E2 Ub-conjugating enzyme Ube2W to anchor the Lys63-linked polyUb chains in a process of TRIM5alpha auto ubiquitination. Chain anchoring is initiated, in cells and in vitro, through Ube2W-catalyzed monoubiquitination of TRIM5alpha. This modification serves as a substrate for the elongation of anchored Lys63-linked polyUb chains, catalyzed by the heterodimeric E2 enzyme Ube2N/Ube2V2. Ube2W targets multiple TRIM5alpha internal lysines with Ub especially lysines 45 and 50, rather than modifying the N-terminal amino group, which is instead alphaN-acetylated in cells. E2 depletion or Ub mutation inhibits TRIM5alpha ubiquitination in cells and restores restricted viral reverse transcription, but not infection. Our data indicate that the stepwise formation of anchored Lys63-linked polyUb is a critical early step in the TRIM5alpha restriction mechanism and identify the E2 Ub-conjugating cofactors involved. PMID- 26101374 TI - Chronic cortisol and the regulation of food intake and the endocrine growth axis in rainbow trout. AB - To gain a better understanding of the mechanisms by which cortisol suppresses growth during chronic stress in fish, we characterized the effects of chronic cortisol on food intake, mass gain, the expression of appetite-regulating factors, and the activity of the GH/IGF axis. Fish given osmotic pumps that maintained plasma cortisol levels at ~70 or 116 ng/ml for 34 days were sampled 14, 28 and 42 days post-implantation. Relative to shams, the cortisol treatments reduced food intake by 40-60% and elicited marked increases in liver leptin (lep a1) and brain preoptic area (POA) corticotropin-releasing factor (crf) mRNA levels. The cortisol treatments also elicited 40-80% reductions in mass gain associated with increases in pituitary gh, liver gh receptor (ghr), liver igfI and igf binding protein (igfbp)-1 and -2 mRNA levels, reduced plasma GH and no change in plasma IGF1. During recovery, while plasma GH and pituitary gh, liver ghr and igfI gene expression did not differ between treatments, the high cortisol treated fish had lower plasma IGF1 and elevated liver igfbp1 mRNA levels. Finally, the cortisol-treated fish had higher plasma glucose levels, reduced liver glycogen and lipid reserves, and muscle lipid content. Thus, our findings suggest that the growth-suppressing effects of chronic cortisol in rainbow trout result from reduced food intake mediated at least in part by increases in liver lep-a1 and POA crf mRNA, from sustained increases in hepatic igfbp1 expression that reduce the growth-promoting actions of the GH/IGF axis, and from a mobilization of energy reserves. PMID- 26101375 TI - 60 YEARS OF NEUROENDOCRINOLOGY: Regulation of mammalian neuroendocrine physiology and rhythms by melatonin. AB - The isolation of melatonin was first reported in 1958. Since the demonstration that pineal melatonin synthesis reflects both daily and seasonal time, melatonin has become a key element of chronobiology research. In mammals, pineal melatonin is essential for transducing day-length information into seasonal physiological responses. Due to its lipophilic nature, melatonin is able to cross the placenta and is believed to regulate multiple aspects of perinatal physiology. The endogenous daily melatonin rhythm is also likely to play a role in the maintenance of synchrony between circadian clocks throughout the adult body. Pharmacological doses of melatonin are effective in resetting circadian rhythms if taken at an appropriate time of day, and can acutely regulate factors such as body temperature and alertness, especially when taken during the day. Despite the extensive literature on melatonin physiology, some key questions remain unanswered. In particular, the amplitude of melatonin rhythms has been recently associated with diseases such as type 2 diabetes mellitus but understanding of the physiological significance of melatonin rhythm amplitude remains poorly understood. PMID- 26101376 TI - 60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary-thyroid axis. AB - This review presents the findings that led to the discovery of TRH and the understanding of the central mechanisms which control hypothalamus-pituitary thyroid axis (HPT) activity. The earliest studies on thyroid physiology are now dated a century ago when basal metabolic rate was associated with thyroid status. It took over 50 years to identify the key elements involved in the HPT axis. Thyroid hormones (TH: T4 and T3) were characterized first, followed by the semi purification of TSH whose later characterization paralleled that of TRH. Studies on the effects of TH became possible with the availability of synthetic hormones. DNA recombinant techniques facilitated the identification of all the elements involved in the HPT axis, including their mode of regulation. Hypophysiotropic TRH neurons, which control the pituitary-thyroid axis, were identified among other hypothalamic neurons which express TRH. Three different deiodinases were recognized in various tissues, as well as their involvement in cell-specific modulation of T3 concentration. The role of tanycytes in setting TRH levels due to the activity of deiodinase type 2 and the TRH-degrading ectoenzyme was unraveled. TH-feedback effects occur at different levels, including TRH and TSH synthesis and release, deiodinase activity, pituitary TRH-receptor and TRH degradation. The activity of TRH neurons is regulated by nutritional status through neurons of the arcuate nucleus, which sense metabolic signals such as circulating leptin levels. Trh expression and the HPT axis are activated by energy demanding situations, such as cold and exercise, whereas it is inhibited by negative energy balance situations such as fasting, inflammation or chronic stress. New approaches are being used to understand the activity of TRHergic neurons within metabolic circuits. PMID- 26101378 TI - BVA renews call for labelling of non-stun meat. PMID- 26101379 TI - BSE suspected in a cow in Ireland. PMID- 26101380 TI - New FVE board appointed. PMID- 26101381 TI - Welfare implications of signing horses out of the food chain. PMID- 26101382 TI - FSA welcomes retailers' efforts to reduce Campylobacter on chickens. PMID- 26101383 TI - Dog bites: a complex public health issue. PMID- 26101384 TI - Kennel Club launches resource to help schools teach safety around dogs. PMID- 26101377 TI - 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis. AB - The hypothalamic control of prolactin secretion is different from other anterior pituitary hormones, in that it is predominantly inhibitory, by means of dopamine from the tuberoinfundibular dopamine neurons. In addition, prolactin does not have an endocrine target tissue, and therefore lacks the classical feedback pathway to regulate its secretion. Instead, it is regulated by short loop feedback, whereby prolactin itself acts in the brain to stimulate production of dopamine and thereby inhibit its own secretion. Finally, despite its relatively simple name, prolactin has a broad range of functions in the body, in addition to its defining role in promoting lactation. As such, the hypothalamo-prolactin axis has many characteristics that are quite distinct from other hypothalamo-pituitary systems. This review will provide a brief overview of our current understanding of the neuroendocrine control of prolactin secretion, in particular focusing on the plasticity evident in this system, which keeps prolactin secretion at low levels most of the time, but enables extended periods of hyperprolactinemia when necessary for lactation. Key prolactin functions beyond milk production will be discussed, particularly focusing on the role of prolactin in inducing adaptive responses in multiple different systems to facilitate lactation, and the consequences if prolactin action is impaired. A feature of this pleiotropic activity is that functions that may be adaptive in the lactating state might be maladaptive if prolactin levels are elevated inappropriately. Overall, my goal is to give a flavour of both the history and current state of the field of prolactin neuroendocrinology, and identify some exciting new areas of research development. PMID- 26101385 TI - Ensuring successful translocation of wild animals. PMID- 26101386 TI - Academic standards and quality of learning confirmed at the RVC. PMID- 26101387 TI - Gaining practical experience abroad. PMID- 26101388 TI - Safeguarding the role of the vet in sheep farming. PMID- 26101389 TI - PCV type 2-associated fetopathy in pigs. PMID- 26101390 TI - Do codes of conduct matter? PMID- 26101391 TI - Recognised veterinary practice and clinical trials. PMID- 26101392 TI - Mental health and seeking help. PMID- 26101393 TI - Guidelines and training for ram prebreeding examinations. PMID- 26101394 TI - Learning from teaching overseas. PMID- 26101395 TI - Diary of a poultry intern. PMID- 26101396 TI - Severe mental illness trumps PCL-R and HCR-20: Commentary on Simpson et al. PMID- 26101397 TI - Clozapine in the community: Improved access or risky free-for-all? PMID- 26101398 TI - RDoC: We should look before we leap. PMID- 26101399 TI - Using aripiprazole to treat new-onset hyperprolactinemia-related delusion of pregnancy. PMID- 26101400 TI - Perceptions of dental undergraduates in India of a clinical induction program. AB - This study aimed to investigate undergraduate students' perceptions of the clinical induction program for dental undergraduates conducted at the DMIMS Deemed University, Sawangi-Meghe, India. Seventy-four third-year dental students who entered the clinical phase of the dental program in 2012 and attended all sessions of the clinical induction program were enrolled in this study. The students' perceptions of the clinical induction program were assessed through a Likert-scale questionnaire, focus group discussions, and individual interviews. Seventy-two students (97.3%) responded positively about the program, evaluating it as successful and making a few suggestions. Fifty-four students (73.0%) stated that the clinical tours and visits to the departments were the best feature of the program. Nine students (12.2%) suggested that the program should include interaction with their immediate seniors and that interactive activities should be included in the program. The induction program may help students become acclimated during the first few days of being introduced into the clinical phase of their education. It is crucial to ensure that students do not develop a negative attitude towards their educational program by facilitating their smooth transition to the clinical phase. PMID- 26101401 TI - External and internal factors influencing self-directed online learning of physiotherapy undergraduate students in Sweden: a qualitative study. AB - PURPOSE: Online courses have become common in health sciences education. This learning environment can be designed using different approaches to support student learning. To further develop online environment, it is important to understand how students perceive working and learning online. The aim of this study is to identify aspects influencing students' learning processes and their adaptation to self-directed learning online. METHODS: Thirty-four physiotherapy students with a mean age of 25 years (range, 21 to 34 years) participated. Qualitative content analysis and triangulation was used when investigating the students' self-reflections, written during a five week self-directed, problem oriented online course. RESULTS: Two categories emerged: 'the influence of the structured framework' and 'communication and interaction with teachers and peers.' The learning processes were influenced by external factors, e.g., a clear structure including a transparent alignment of assignments and assessment. Important challenges to over-come were primarily internal factors, e.g., low self efficacy, difficulties to plan the work effectively and adapting to a new environment. CONCLUSION: The analyses reflected important perspectives targeting areas which enable further course development. The influences of external and internal factors on learning strategies and self-efficacy are important aspects to consider when designing online courses. Factors such as pedagogical design, clarity of purpose, goals, and guidelines were important as well as continuous opportunities for communication and collaboration. Further studies are needed to understand and scaffold the motivational factors among students with low self efficacy. PMID- 26101402 TI - A comparison of the effectiveness of the team-based learning readiness assessments completed at home to those completed in class. AB - PURPOSE: The readiness assurance process (RAP) of team-based learning (TBL) is an important element that ensures that students come prepared to learn. However, the RAP can use a significant amount of class time which could otherwise be used for application exercises. The authors administered the TBL-associated RAP in class or individual readiness assurance tests (iRATs) at home to compare medical student performance and learning preference for physiology content. METHODS: Using cross-over study design, the first year medical student TBL teams were divided into two groups. One group was administered iRATs and group readiness assurance tests (gRATs) consisting of physiology questions during scheduled class time. The other group was administered the same iRAT questions at home, and did not complete a gRAT. To compare effectiveness of the two administration methods, both groups completed the same 12-question physiology assessment during dedicated class time. Four weeks later, the entire process was repeated, with each group administered the RAP using the opposite method. RESULTS: The performance on the physiology assessment after at-home administration of the iRAT was equivalent to performance after traditional in-class administration of the RAP. In addition, a majority of students preferred the at-home method of administration and reported that the at-home method was more effective in helping them learn course content. CONCLUSION: The at-home administration of the iRAT proved effective. The at-home administration method is a promising alternative to conventional iRATs and gRATs with the goal of preserving valuable in-class time for TBL application exercises. PMID- 26101403 TI - Proposal of a linear rather than hierarchical evaluation of educational initiatives: the 7Is framework. AB - Extensive resources are expended attempting to change clinical practice; however, determining the effects of these interventions can be challenging. Traditionally, frameworks to examine the impact of educational interventions have been hierarchical in their approach. In this article, existing frameworks to examine medical education initiatives are reviewed and a novel '7Is framework' discussed. This framework contains seven linearly sequenced domains: interaction, interface, instruction, ideation, integration, implementation, and improvement. The 7Is framework enables the conceptualization of the various effects of an intervention, promoting the development of a set of valid and specific outcome measures, ultimately leading to more robust evaluation. PMID- 26101404 TI - Teamwork education improves trauma team performance in undergraduate health professional students. AB - PURPOSE: Effective trauma resuscitation requires efficient and coordinated care from a team of providers; however, providers are rarely instructed on how to be effective members of trauma teams. Team-based learning using Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) has been shown to improve team dynamics among practicing professionals, including physicians and nurses. The impact of TeamSTEPPS on students being trained in trauma management in an undergraduate health professional program is currently unknown. We sought to determine the impact of TeamSTEPPS on team dynamics among undergraduate students being trained in trauma resuscitation. METHODS: We enrolled teams of undergraduate health professional students from four programs: nursing, physician assistant, radiologic science, and respiratory care. After completing an online training on trauma resuscitation principles, the participants completed a trauma resuscitation scenario. The participants then received teamwork training using TeamSTEPPS and completed a second trauma resuscitation scenario identical to the first. All resuscitations were recorded and scored offline by two blinded research assistants using both the Team Emergency Assessment Measure (TEAM) and Trauma Team Performance Observation Tool (TPOT) scoring systems. Pre-test and post-test TEAM and TPOT scores were compared. RESULTS: We enrolled a total of 48 students in 12 teams. Team leadership, situational monitoring, and overall communication improved with TeamSTEPPS training (P=0.04, P=0.02, and P=0.03, respectively), as assessed by the TPOT scoring system. TeamSTEPPS also improved the team's ability to prioritize tasks and work together to complete tasks in a rapid manner (P<0.01 and P=0.02, respectively) as measured by TEAM. CONCLUSIONS: Incorporating TeamSTEPPS into trauma team education leads to improved TEAM and TPOT scores among undergraduate health professionals. PMID- 26101405 TI - Innovation in the field of medical-conference-based education: a new marketplace. PMID- 26101406 TI - Should we be looking for and treating isolated calf vein thrombosis? AB - Management of isolated calf deep vein thrombosis is an area of significant international debate and variable clinical practice. Both therapeutic anticoagulation and conservative management carry risk. As clinical care of suspected and confirmed venous thromboembolic disease increasingly becomes the remit of emergency medicine, complex decisions are left to practising clinicians at the front door. We aim to provide a contemporary overview of recent evidence on this topic and associated challenges facing clinicians. Given the lack of high level evidence, we present this work as a narrative review, based on structured literature review and expert opinion. A decision to manage calf thrombosis is principally dependent on the risk of complications without treatment balanced against the risks of therapeutic anticoagulation. Estimates of the former risks taken from systematic review, meta-analysis, observational cohort and recent pilot trial evidence include proximal propagation 7%-10%, pulmonary embolism 2% 3% and death <1%. Fatal bleeding with therapeutic anticoagulation stands at <0.5%, and major bleeding at approximately 2%. Estimates of haemorrhagic risk are based on robust data from large prospective management studies of venous thromboembolic disease; the risks of untreated calf deep vein thrombosis are based on small cohorts and therefore less exact. Pending further trial evidence, these risks should be discussed with patients openly, in the context of personal preference and shared decision-making. Anticoagulation may maximally benefit those patients with extensive and/or symptomatic disease or those with higher risk for complication (unprovoked, cancer-associated or pregnancy). PMID- 26101408 TI - Taking the long view on the ecological effects of plant invasions. PMID- 26101409 TI - Mechanisms for the evolution of complex and diversely elaborated sepals in Iris identified by comparative analysis of developmental sequences. AB - PREMISE OF THE STUDY: Crested sepals, which have evolved at least five times in Iris, are adaxially elaborated with a sinuous and/or uneven median structure (crest) along the proximal-distal axis and sometimes with various lateral structures (ridges, crests, and linear protuberances) flanking the median crest. These structural elaborations are complex yet diverse in form, providing a good opportunity to investigate developmental mechanisms for the diversification of reproductive lateral organs. METHODS: Morphologies of the median and lateral structures at different developmental stages from selected crested sepals representing the major types of structural elaborations were recorded using scanning electron microscopy and light microscopy. Developmental (morphogenetic) events that contribute to changes in shape (e.g., sinuousness, unevenness) between consecutive stages were recorded. Developmental sequences-trajectories that consist of a series of developmental events-were compared in a phylogenetic context. KEY RESULTS: Three developmental events (development of outgrowths, greater expansion of the upper zone, and greater expansion of the lower zone), are shared across lineages, occur in the same developmental sequences, and are responsible for the changes in shape during the development of diverse structural elaborations. In addition, two novel developmental events and the development of trichomes on elaborate structures were observed within the core-crested clade. CONCLUSIONS: Developmental sequences are conserved across independently evolved crested lineages. Heterochronic and heterotopic shifts of developmental events play the major role in the diversification of elaborations of crested sepals in Iris. The evolution of novel developmental events and the development of trichomes also contribute to the diversity. PMID- 26101410 TI - Foliar secretory structures in Crotoneae (Euphorbiaceae): Diversity, anatomy, and evolutionary significance. AB - PREMISE OF THE STUDY: Phylogenetic and morphological studies have helped clarify the systematics of large and complex groups such as the tribe Crotoneae (Euphorbiaceae). However, very little is known about the diversity, structure, and function of anatomical features in this tribe. Crotoneae comprises the species-rich pantropical genus Croton and six small neotropical genera. Here we characterized the anatomy of leaf secretory structures in members of this tribe and explored their function and evolutionary significance. METHODS: Young and mature leaves of 26 species were studied using standard anatomical light microscopy techniques. Three sections of Croton and one representative of Brasiliocroton and Astraea were sampled. KEY RESULTS: We identified five types of secretory structures: laticifers, colleters, extrafloral nectaries, idioblasts, and secretory trichomes. Laticifers were present in all species studied except Croton alabamensis, which instead presented secretory parenchyma cells. Articulated laticifers are reported in Crotoneae for the first time. Colleters of the standard type were observed in the majority of the sampled taxa. Extrafloral nectaries were present in section Cleodora and in B. mamoninha, but absent in section Lamprocroton and Astraea lobata. Idioblasts were spread throughout the palisade and/or spongy parenchyma in most of the studied species. Secretory trichomes were restricted to Lamprocroton except for C. imbricatus. CONCLUSIONS: This study revealed a high diversity of secretory structures, including novel ones, in one of the largest clades of Euphorbiaceae. Our results are promising for investigations on the anatomical and ecophysiological bases of species diversification within Euphorbiaceae. PMID- 26101411 TI - Developmental morphology of flattened shoots in Dalzellia ubonensis and Indodalzellia gracilis with implications for the evolution of diversified shoot morphologies in the subfamily Tristichoideae (Podostemaceae). AB - PREMISE OF THE STUDY: Podostemaceae is a unique family of aquatic angiosperms that grow in swift-running water on rock surfaces in the tropics. Their plant bodies show a remarkable adaptation: the main plant body is mostly creeping or flattened, or in extreme cases foliose, functioning as an adhering and photosynthetic organ. In the subfamily Podostemoideae, the root is foliose, whereas in the subfamily Tristichoideae, the shoot is foliose. An evolutionary scenario for the foliose root has already been proposed, but that for the foliose shoot remains to be addressed. METHODS: Shoots of Indodalzellia gracilis and Dalzellia ubonensis (subfamily Tristichoideae) were observed using light microscopy and scanning electron microscopy. Gene expression patterns of orthologs of marker genes for the shoot apical meristem, i.e., SHOOT MERISTEMLESS and WUSCHEL, in D. ubonensis were analyzed. KEY RESULTS: When very young, the phyllotaxis is tristichous in both genera: a set of one dorsal and two marginal leaves forms. When the shoot branches, extra-axillary buds of two subsequent marginal leaves form as new (lateral) shoots, and the original shoot stops growing; this growth pattern is called sympodial branching. Due to zonal growth in the common zone just below the original and lateral shoot apices, flattened or foliose shoots result. The expression patterns of DuSTM and DuWUS in the shoot apices of Dalzellia were similar to those published for Terniopsis. CONCLUSIONS: The foliose shoots of Indodalzellia and Dalzellia evolved as a result of congenital fusion among several original and lateral branches, each of which grows separately in other Tristichoideae. PMID- 26101412 TI - Lack of divergence in seed ecology of two Amphicarpaea (Fabaceae) species disjunct between eastern Asia and eastern North America. AB - PREMISE OF THE STUDY: Many congeneric species are disjunct between eastern Asia and eastern North America. No previous study has compared the seed biology of closely related disjunct taxa of legumes or of a diaspore-heteromorphic species. Our objective was to compare seed dormancy in two such sister species in the genus Amphicarpaea (Fabaceae). METHODS: We investigated the ecology and ecophysiology of aerial and subterranean seeds of the amphicarpic species Amphicarpaea edgeworthii from China and compared the results to those published for its sister species A. bracteata from eastern North America. KEY RESULTS: The seed coat of aerial seeds of A. edgeworthii is well developed, whereas the seed coat of subterranean seeds is not. Aerial seeds have combinational dormancy (physical dormancy [PY] + physiological dormancy [PD]) broken by scarification followed by cold stratification or by after-ripening and scarification; whereas subterranean seeds have PD broken by cold stratification. Aerial seeds formed a persistent soil seed bank, and subterranean seeds a transient soil seed bank. Aerial seeds of A. bracteata also have PY+PD and subterranean seeds PD. Subterranean seeds of both species are desiccation intolerant. CONCLUSION: Dormancy in neither aerial nor subterranean seeds of both species has diverged over geological time. Compared to subterranean seeds, aerial seeds of both species dispersed over longer distances. Seed dispersal ability and degree of dormancy of neither species fits the high-risk/low-risk (H-H/L-L) strategy found in many diaspore-dimorphic species. Rather, both species have an H-L/L-H strategy for these two life history traits. PMID- 26101413 TI - Conservation biogeography of the Cerrado's wild edible plants under climate change: Linking biotic stability with agricultural expansion. AB - REMISE OF THE STUDY: Wild edible plants (WEPs) have an important cultural and economic role in human population worldwide. Human impacts are quickly converting natural habitats in agricultural, cattle ranch, and urbanized lands, putting native species on peril of risk of extinction, including some WEPs. Moreover, global climate changes also can pose another threat to species persistency. Here, we established conservation priorities for the Cerrado, a neotropical region in South America with high levels of plant endemism and vulnerability, aiming to assure long-term persistency of 16 most important WEPs. We evaluated these conservation priorities using a conservation biogeography framework using ecological patterns and process at a biogeographical scale to deal with species conservation features. METHODS: We built ecological niche models for 16 WEPs from Cerrado in the neotropics using climate models for preindustrial, past (Last Glacial Maximum) and future (year 2080) time periods to establish climatically stable areas through time, finding refugias for these WEPs. We used a spatial prioritization algorithm based on the spatial pattern of irreplaceability across the neotropics, aiming to ensure the persistence of at least 25% of range size in climatically stable areas for each WEP, using agricultural models as constraints. KEY RESULTS: The Southeast Cerrado was the most biotically stable and irreplaceable region for the WEPs compared with other areas across the neotropics. CONCLUSIONS: Our findings strongly suggest that the Southeast Cerrado should be considered a conservation priority, with new protected areas to be sustainably managed and restored, to guarantee the supply of cultural and ecosystem services provided from the Cerrado's WEPs. PMID- 26101414 TI - Geographic variation in shoot traits and branching intensity in relation to leaf size in Fagus crenata: A common garden experiment. AB - PREMISE OF THE STUDY: Differences in leaf size are expected to be coordinated with various shoot traits and branching intensity because these relationships will influence light capture efficiency, water use, and biomechanics. Previous studies have mainly focused on interspecific patterns of these trait relationships, but not on intraspecific patterns at the geographic scale. We investigated intraspecific variation in shoot traits and branching intensity of Fagus crenata in Japan. METHODS: Allometric relationships between the traits of current-year shoots and branching intensity per branch unit of 1-m length on the main axis (BI) and its coordination with latitude were investigated using trees from 10 provenances in a common garden. KEY RESULTS: Individual trees originating from lower latitudes have smaller leaves with greater leaf mass per area and nitrogen content per area, greater Huber value (stem cross-sectional area per total leaf area [ATL]) of current-year shoots, and greater BI. Notably, the slope of the log-log relationship between BI and ATL was close to -1.0 across the trees from different source sites, implying that branching in this species occurs to control leaf area. CONCLUSIONS: Shoot traits and branching intensity were apparently coordinated with leaf size to control leaf area deployment in this species. Such patterns probably reflect differences in competition for hydraulic conductance among nearby shoots within crowns, as a consequence of different meteorological conditions across the source sites. PMID- 26101416 TI - Floral cost vs. floral display: Insights from the megadiverse Myrtales suggest that energetically expensive floral parts are less phylogenetically constrained. AB - PREMISE OF THE STUDY: Floral display describes the effect of flower size combined with the number of flowers per inflorescence. There is strong evidence that a floral-display trade-off operates under energetic constraint, with few-flowered inflorescences likely to have larger flowers than many-flowered inflorescences. Flower size can be estimated by different variables; thus, we propose that the variable for flower size that is most highly (negatively) correlated with the number of flowers per inflorescence will also be the best estimate of floral cost. Ranking the correlation with the phylogenetic signal of the variable can provide additional insight into the evolution of floral display. METHODS: The Myrtales were chosen as a model order based on age, worldwide distribution, and diversity of reproductive strategies. Ninety-nine species representing all families and one quarter of generic diversity across its geographic and ecological range were sampled to reconstruct a phylogeny based on rbcL and ndhF sequences. Correlation coefficients were calculated for flower size variables vs. the number of flowers per inflorescence. Phylogenetic signal was measured for all variables and for floral display. KEY RESULTS: Flowers per inflorescence showed significant negative correlation with the following flower size variables (weakest to strongest): filament length < anther size < flower depth < flower diameter. As the correlation of each character with number of flowers per inflorescence rose (suggesting increased cost), the values for phylogenetic signal diminished (suggesting less constraint). CONCLUSIONS: We conclude that energetically costly floral characters appear to be less phylogenetically constrained, while low-cost floral characters maintain higher levels of phylogenetic inertia. PMID- 26101415 TI - Resolving relationships within the palm subfamily Arecoideae (Arecaceae) using plastid sequences derived from next-generation sequencing. AB - PREMISE OF THE STUDY: Several studies have incorporated molecular and morphological data to study the phylogeny of the palms (Arecaceae), but some relationships within the family remain ambiguous-particularly those within Arecoideae, the most diverse subfamily including coconut and oil palm. Here, two next-generation, targeted plastid-enrichment methods were compared and used to elucidate Arecoideae phylogeny. METHODS: Next-generation sequencing techniques were used to generate a plastid genome data set. Long range PCR and hybrid gene capture were used to enrich for chloroplast targets. Ten taxa were enriched using both methods for comparison. Chloroplast sequence data were generated for 31 representatives of the 14 Arecoideae tribes and five outgroup taxa. The phylogeny was reconstructed using maximum likelihood, maximum parsimony, and Bayesian analyses. KEY RESULTS: Long range PCR and hybrid gene capture both enriched the plastid genome and provided similar sequencing coverage. Subfamily Arecoideae was resolved as monophyletic with tribe Chamaedoreeae as the earliest-diverging lineage, implying that the development of flowers in triads defines a synapomorphy for the Arecoideae clade excluding Chamaedoreeae. Three major clades within this group were recovered: Roystoneeae/Reinhardtieae/Cocoseae (RRC), Areceae/Euterpeae/Geonomateae/Leopoldinieae/Manicarieae/Pelagodoxeae (core arecoids), and Podococceae/Oranieae/Sclerospermeae (POS). An Areceae + Euterpeae clade was resolved within the core arecoids. The POS clade was sister to a RRC + core arecoids clade, implying a shared ancestral area in South America for these three clades. CONCLUSIONS: The plastome phylogeny recovered here provides robust resolution of previously ambiguous studies and new insights into palm evolution. PMID- 26101417 TI - Species tree estimation of diploid Helianthus (Asteraceae) using target enrichment. AB - PREMISE OF THE STUDY: The sunflower genus Helianthus has long been recognized as economically significant, containing species of agricultural and horticultural importance. Additionally, this genus displays a large range of phenotypic and genetic variation, making Helianthus a useful system for studying evolutionary and ecological processes. Here we present the most robust Helianthus phylogeny to date, laying the foundation for future studies of this genus. METHODS: We used a target enrichment approach across 37 diploid Helianthus species/subspecies with a total of 103 accessions. This technique garnered 170 genes used for both coalescent and concatenation analyses. The resulting phylogeny was additionally used to examine the evolution of life history and growth form across the genus. KEY RESULTS: Coalescent and concatenation approaches were largely congruent, resolving a large annual clade and two large perennial clades. However, several relationships deeper within the phylogeny were more weakly supported and incongruent among analyses including the placement of H. agrestis, H. cusickii, H. gracilentus, H. mollis, and H. occidentalis. CONCLUSIONS: The current phylogeny supports three major clades including a large annual clade, a southeastern perennial clade, and another clade of primarily large-statured perennials. Relationships among taxa are more consistent with early phylogenies of the genus using morphological and crossing data than recent efforts using single genes, which highlight the difficulties of phylogenetic estimation in genera known for reticulate evolution. Additionally, conflict and low support at the base of the perennial clades may suggest a rapid radiation and/or ancient introgression within the genus. PMID- 26101418 TI - Assessing the evolutionary history of the class Synurophyceae (Heterokonta) using molecular, morphometric, and paleobiological approaches. AB - PREMISE OF THE STUDY: Heterokont algae of the class Synurophyceae, characterized by distinctive siliceous scales that cover the surface of the cell, are ecologically important in inland waters, yet their evolutionary history remains enigmatic. We explore phylogenetic relationships within this group of algae relative to geologic time, with a focus on evolution of siliceous components. METHODS: We combined an expansive five-gene and time-calibrated molecular phylogeny of synurophyte algae with an extensive array of fossil specimens from the middle Eocene to infer evolutionary trends within the group. KEY RESULTS: The group originated in the Jurassic approximately 157 million years ago (Ma), with the keystone genera Mallomonas and Synura diverging during the Early Cretaceous at 130 Ma. Mallomonas further splits into two major subclades, signaling the evolution of the V-rib believed to aid in the spacing and organization of scales on the cell covering. Synura also diverges into two primary subclades, separating taxa with forward-projecting spines on the scale from those with a keel positioned on the scale proper. Approximately one third of the fossil species are extinct, whereas the remaining taxa are linked to modern congeners. CONCLUSIONS: The taxonomy of synurophytes, which relies extensively on the morphology of the siliceous components, is largely congruent with molecular analyses. Scales of extinct synurophytes were significantly larger than those of modern taxa and may have played a role in their demise. In contrast, many fossil species linked to modern lineages were smaller in the middle Eocene, possibly reflecting growth in the greenhouse climatic state that characterized this geologic interval. PMID- 26101419 TI - Middle Jurassic evidence for the origin of Cupressaceae: A paleobotanical context for the roles of regulatory genetics and development in the evolution of conifer seed cones. AB - PREMISE OF THE STUDY: Triassic and Jurassic fossils record structural changes in conifer seed cones through time, provide the earliest evidence for crown-group conifer clades, and further clarify sister-group relationships of modern conifer families. A new and distinct seed-cone from the Isle of Skye in western Scotland provides the oldest detailed evidence for the ancestral morphology of the phylogenetically contentious family Cupressaceae. METHODS: A single isolated cone was prepared as serial sections by the cellulose acetate peel technique, mounted on microscope slides, and viewed and photographed using transmitted light. The three-dimensional structure of the cone was first reconstructed from the serial sections and then refined through imaging with x-ray microtomography. KEY RESULTS: Scitistrobus duncaanensis, gen. et sp. nov., is a 7.5 mm-diameter cylindrical seed cone with helically arranged bract-scale complexes in which three scale tips separate from a large bract, each tip bearing one adaxial seed. Seeds are near-inverted, show 180 degrees rotational symmetry, and have a diminutive wing in the major plane. CONCLUSIONS: Scitistrobus duncaanensis extends the fossil record for anatomically preserved seed cones of the Cupressaceae backward from the Upper Jurassic to the Aalenian Stage of the Middle Jurassic. The cone displays a previously unknown combination of characters that we regard as diagnostic for seed cones of early-divergent Cupressaceae and helps to clarify the sequence of structural changes that occurred during the transition from ancestral voltzialean conifers to morphologically recognizable Cupressaceae. Hypotheses of homology underpinning such transformational series can be tested by ongoing reciprocal illumination between the morphology of fossil taxa and the morphogenesis and developmental genetics of their extant crown-group relatives. PMID- 26101420 TI - Seasonal changes in physiological performance in wild Clarkia xantiana populations: Implications for the evolution of a compressed life cycle and self fertilization. AB - PREMISE OF THE STUDY: One explanation for the evolution of selfing, the drought escape hypothesis, proposes that self-fertilization may evolve under conditions of intensifying seasonal drought as part of a suite of traits that enable plants to accelerate the completion of their life cycle, thereby escaping late-season drought. Here, we test two fundamental assumptions of this hypothesis in Clarkia xantiana: (1) that a seasonal decline in precipitation causes an increase in drought stress and (2) that this results in changes in physiological performance, reflecting these deteriorating conditions. METHODS: We examined seasonal and interannual variation in abiotic environmental conditions (estimated by ambient temperature, relative humidity, predawn leaf water potentials, and carbon isotope ratios) and physiological traits (photosynthesis, conductance, transpiration, instantaneous water-use efficiency, ascorbate peroxidase and glutathione reductase activities, quantum yield of photosystem II, PSII potential efficiency) in field populations of C. xantiana in 2009 and 2010. KEY RESULTS: In both years, plants experienced intensifying drought across the growing season. Gas exchange rates decreased over the growing season and were lower in 2009 (a relatively dry year) than in 2010, suggesting that the temporal changes from early to late spring were directly linked to the deteriorating environmental conditions. CONCLUSIONS: Seasonal declines in transpiration rate may have increased survival by protecting plants from desiccation. Concomitant declines in photosynthetic rate likely reduced the availability of resources for seed production late in the season. Thus, the physiological patterns observed are consistent with the conditions required for the drought escape hypothesis. PMID- 26101421 TI - Population genetic variation, geographic structure, and multiple origins of autopolyploidy in Galax urceolata. AB - PREMISE OF THE STUDY: Whereas population genetic studies have examined allopolyploids, comparable studies of naturally occurring autopolyploids remain rare. To address fundamental questions regarding autopolyploidy, we undertook a detailed population genetic study of one of the classic examples of autopolyploidy, Galax urceolata (Diapensiaceae), which comprises diploid, triploid, and autotetraploid cytotypes. Galax is endemic to the Appalachian Mountains, the adjacent piedmont, sandhills, and coastal plain and represents perhaps the most widely known example of autopolyploidy in nature. METHODS: Flow cytometry was used to diagnose ploidal level of ~1000 individuals across 71 populations. We used 10 microsatellite markers to examine genetic variation across the geographic range of Galax and assessed multiple origins though comparisons of diploid, triploid, and tetraploid accessions using multiple analytical approaches. KEY RESULTS: Tetraploids had higher levels of heterozygosity than diploids did. Genetic variation in diploid and tetraploid Galax is geographically structured among the ecoregions of the southeastern United States. Autotetraploidy in Galax urceolata has occurred independently at least 46 times, with triploidy having occurred a minimum of 31 times. CONCLUSIONS: Genetic differentiation among ecoregions suggests historical patterns of local adaptation. The numerous independent origins of tetraploid Galax reported here are among the highest frequencies of independent polyploidizations ever reported for any polyploid (auto- or allopolyploid). PMID- 26101422 TI - Lack of early inbreeding depression and distribution of selfing rates in the neotropical emergent tree Ceiba pentandra: Assessment from several reproductive events. AB - PREMISE OF THE STUDY: Selfing and mixed mating systems are prevalent in many flowering plants. Purging of genetic load can occur in these species, reducing negative effects of selfing. Long-term studies of the temporal and spatial variation of selfing rates and inbreeding depression at the individual level are necessary to understand the forces that maintain selfing as a mating strategy in these species. METHODOLOGY: We used microsatellites to estimate selfing rates in seeds and seedlings over 6 years in a population of Ceiba pentandra in southwestern Costa Rica. We studied the correlation of selfing with early seedling vigor variables to test for inbreeding depression. KEY RESULTS: Selfing rates varied widely among maternal trees. However, we found high consistency of selfing rates for individuals among years. Selfing rate did not influence early fitness traits, suggesting a lack of inbreeding depression at this stage. Maternal effects were a predominant source of variation for early vigor variables. CONCLUSIONS: Variability in selfing rates among trees may be partly explained by genetic variation in a late-acting self-incompatibility system or low, early-acting genetic load in some individuals. This population did not show evidence of early inbreeding depression in traits related to seed vigor probably from complete or partial purging as a result of repeated selfing of a fraction of the population or from strong maternal effects. Expression of genetic load at later developmental stages or in more stressful natural conditions may explain differences in inbreeding levels between seeds and adults. PMID- 26101424 TI - Correction to "Comparative analysis of complete chloroplast genome sequence and inversion variation in Lasthenia burkei (Madieae, Asteraceae)". PMID- 26101423 TI - The Tetramerium lineage (Acanthaceae: Justicieae) does not support the Pleistocene Arc hypothesis for South American seasonally dry forests. AB - PREMISE OF THE STUDY: The Tetramerium lineage (Acanthaceae) presents a striking ecological structuring in South America, with groups concentrated in moist forests or in seasonally dry forests. In this study, we investigate the circumscription and relationships of the South American genera as a basis for better understanding historic interactions between dry and moist biomes in the Neotropics. METHODS: We dated the ancestral distribution of the Tetramerium lineage based on one nuclear and four plastid DNA regions. Maximum parsimony, maximum likelihood, and Bayesian inference analyses were performed for this study using 104 terminals. Phylogenetic divergences were dated using a relaxed molecular clock approach and ancestral distributions obtained from dispersal vicariance analyses. KEY RESULTS: The genera Pachystachys, Schaueria, and Thyrsacanthus are nonmonophyletic. A dry forest lineage dispersed from North America to South America and reached the southwestern part of the continent between the end of the Miocene and beginning of the Pleistocene. This period coincides with the segregation between Amazonian and Atlantic moist forests that established the geographic structure currently found in the group. CONCLUSIONS: The South American genera Pachystachys, Schaueria, and Thyrsacanthus need to be recircumscribed. The congruence among biogeographical events found for the Tetramerium lineage suggests that the dry forest centers currently dispersed throughout South America are relatively old remnants, probably isolated since the Neogene, much earlier than the Last Glacial Maximum postulated by the Pleistocene Arc hypothesis. In addition to exploring the Pleistocene Arc hypothesis, this research also informs evolution in a lineage with numerous geographically restricted and threatened species. PMID- 26101425 TI - Reclassification of C4d-Positive Endomyocardial Biopsy (EMB) According to New International Society for Heart and Lung Transplantation (ISHLT) 2013 Categories for Reporting Pathologic Antibody-Mediated Rejection (pAMR): Preliminary Data from a Polish Single-Center Study. AB - BACKGROUND: The International Society for Heart and Lung Transplantation (ISHLT) has recently proposed a new protocol for reporting pathologic diagnosis of antibody-mediated rejection (pAMR). The new criteria precisely defined antibody panels and morphologic features indicative of AMR. The aim of this study was to reclassify endomyocardial biopsy specimens (EMBs) that had previously been classified as C4d-positive (AMR1) according to the former ISHLT 2004 protocol and to verify whether the new, stricter criteria have any impact on number of AMR diagnosis. MATERIAL AND METHODS: We retrospectively analyzed 1374 EMBs from 212 patients who underwent heart transplantation in the years 2001-2013 and who were diagnosed at the Department of Pathology, The Children's Memorial Health Institute. Recorded data were: histopathologic features indicative of AMR (endothelial swelling, interstitial edema, intracapillary macrophages and leucocytes); C4d stain patterns, and presence of cellular rejection (ACR) or Quilty effect in any biopsy. All EMBs were reevaluated according to new ISHLT 2013 criteria and pAMR was specified. RESULTS: There were 77 EMBs from 46 (21.69%) patients that were initially diagnosed as AMR1 based on any C4d-positive stain. After reclassification according to ISHLT 2013: 22 (28.57%) EMBs were evaluated as pAMR 1(H+); 14 (18.18%) EMBs were pAMR 1(I+); 13 (16.88%) EMBs were pAMR 2, and 28 (36.36%) EMBs were pAMR0. Endothelial swelling was observed in 45 (58.44%) EMBs; interstitial edema in 32 (41.55%) EMBs, and intracapillary activated mononuclear cells in 26 (33.77%) EMBs. Then, all 1374 EMBs from 212 patients were reclassified and we noticed that pAMR1H+ was found in 95 (44.81%) patients; pAMR1I+ in 12 (5.66%) patients; pAMR2 in 8 (3.77%) patients; pAMR0 in 95 (45.75%) in patients, and pAMR3 was not present. CONCLUSIONS: New, more restrictive ISHLT 2013 criteria for reporting pathologic antibody-mediated rejection (pAMR) decrease number of AMR diagnosis in a selected Polish population, but they increase number of silent/sub-silent AMR diagnoses. PMID- 26101426 TI - Treatment of mCRPC in the AR-axis-targeted therapy-resistant state. AB - BACKGROUND: The increased use of the androgen receptor axis-targeted (ARAT) agents abiraterone and enzalutamide in first- and second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) has improved patient outcomes, but resistance to these agents is inevitable. Early identification of patients with primary or secondary resistance to ARAT therapy is of increasing clinical concern. DESIGN: PubMed and conference proceedings were searched for studies of agents used after progression on abiraterone or enzalutamide. The key search terms (or aliases) used a combination of mCRPC and abiraterone or enzalutamide, and results were limited to clinical trials and comparative or validation studies. RESULTS AND CONCLUSION: This systematic review assembles current evidence and provides an approach to treatment using available clinical factors. Issues of patient selection, use of laboratory and clinical biomarkers to identify patients at risk of poor outcomes, and the timing and sequencing of available treatment options are addressed. Our findings reveal a lack of high level evidence regarding predictive factors and treatment of patients with resistance to ARAT therapy, and a need for further research in this area. In the meantime, we suggest practical strategies to guide management of ARAT treatment resistant patients based on available data. PMID- 26101427 TI - Vitamin B12 Deficiency and Elevated Folate Levels: An Unusual Cause of Generalized Tonic-Clonic Seizure. AB - BACKGROUND: Vitamin B12 deficiency leads to abnormal myelination or demyelination, resulting in sub-acute combined degeneration, peripheral neuropathy, and psychiatric problems, including delusions, hallucinations, cognitive changes, depression, and dementia. Vitamin B12 deficiency also leads to brain shrinkage and neurodegenerative disorders. CASE REPORT: We report the case of a 49-year-old man presenting with new-onset seizures one and a half years following subtotal gastrectomy due to stage IV gastric adenocarcinoma. The patient did not have any history of head injury. Laboratory tests were negative for any metabolic derangements. There were no signs of infection. MRI brain and EEG were normal and there were no changes in medications. CONCLUSIONS: In case of unexplained new-onset seizures, patients should be tested for vitamin B12 and folic acid levels and these should be done as part of the initial work-up. PMID- 26101429 TI - Significance of routine cerebrospinal fluid analysis in subarachnoid hemorrhage. AB - BACKGROUND: The aim of this paper was to determine the diagnostic value of cerebrospinal fluid (CSF) analysis in the setting of aneurysmal subarachnoid hemorrhage (aSAH), hypothesizing that CSF analysis is only critical in confirming suspected infection and may be useful in predicting and/or detecting delayed cerebral ischemia (DCI). METHODS: Retrospective review of consecutive adult patients diagnosed with aSAH from 1/2000 to 12/2013 at Mayo Clinic, Rochester, MN, USA with cerebral aneurysm(s) identified by vascular imaging, and CSF drawn within 14 days of the date of hemorrhage. RESULTS: We identified 741 patients during the study period, 167 met inclusion criteria and 356 samples were collected. First Median CSF samples were taken 5 (4-8) days postbleed. Multiple samples were taken in 94 (54.5%) patients and the mean number of samples per patient was 2.1. Ventriculitis, confirmed by growth of organism from CSF culture was present in 2 (1.2%) patients and one patient (0.6%) developed meningitis. CSF WBC count remained elevated throughout the 14 days, even when corrected for red blood cell count (RBC). Peak CSF RBCs occurred 2-4 days post bleed, and then gradually normalized. Maximum CSF RBCs did not correlate with modified Fisher grades (P=0.422). Delayed cerebral ischemia (DCI) was present in 86 (51.5%) patients and there was no difference in the CSF profile of patients with DCI compared with those without. CONCLUSIONS: Routine CSF sampling for cell count and chemistry in the setting of temporary diversion following aSAH appears to have little clinical benefit beyond the evaluation for infection. PMID- 26101428 TI - Relationships between Depressive Symptoms and Endothelial Function Among Outpatients of a General Hospital in China. AB - BACKGROUND: This study aimed to investigate the endothelial function by reactive hyperemia index (RHI) in patients with depression, subjects recovering from depression, and subjects without a history of depression. MATERIAL AND METHODS: Outpatients were recruited from a general hospital in China; 62 patients diagnosed with depression and the 17-item Hamilton Rating Scale for Depression (HAMD17) total scores >=17 were enrolled as the depression group, 62 patients with a history of depression, discontinuation of antidepressants therapy at least 3 months ago, and HAMD17 <=7 were recruited as remission group, and 62 subjects without a history of depression served as the control group (HAMD17 <=7). RESULTS: The mean RHI was 1.93, 2.34, and 2.19 in depression, control, and remission groups, respectively, showing a significant difference among the 3 groups (P=0.0004). In addition, a marked difference in RHI was found between depression and control groups (P=0.0003) and between depression and remission groups (P=0.0270). However, there was no significant difference between remission and control groups (P=0.3363). CONCLUSIONS: There is a relationship between depression and endothelial dysfunction in outpatients from a general hospital in China. The improvement of depression is synchronous with the improvement of endothelial function. PMID- 26101430 TI - Prognostic value of Positron Emission Tomography/Computed Tomography in patients with Lymphoma treated with autologous stem cell transplantation (ASCT) for relapsed/refractory or high risk disease. AB - AIM: Positron Emission Tomography/Computed Tomography (PET/CT scan) has increasingly been used for management of lymphoma, however few and conflicting data have been provided in the setting of high dose therapy with autologous stem cell transplantation (ASCT) so far. METHODS: We retrospectively evaluated the outcome of 47 NHL patients who underwent ASCT for relapsed/refractory disease or high risk disease or partial response after first line treatment, with the aim of testing sensitivity, specificity, positive and negative prognostic value of PET/CT performed before and after ASCT. RESULTS: In our experience pre ASCT PET/CT predicts outcome of Non Hodgkin's Lymphoma patients with chemosensitive relapse, whereas post ASCT-PET showed a better prognostic value for relapsed disease. CONCLUSIONS: Results of our study, if confirmed by studies on a larger scale, could significantly contribute to design future trials and optimise the management of lymphoma patients. PMID- 26101431 TI - Optimal management of polycystic ovary syndrome in adolescence. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of reproduction and metabolism, which emerges at puberty, and is characterised by a wide spectrum of signs and symptoms of hyperandrogenism, anovulation, hyperinsulinaemia and associated comorbidities. Unlike adult PCOS, there are no agreed-upon diagnostic criteria for adolescent PCOS, but hyperandrogenaemia remains the sine qua non for its diagnosis. Many adolescent girls with PCOS are overweight/obese, and have a heightened risk for comorbidities such as dysglycaemia, dyslipidaemia, fatty liver disease, sleep apnoea and cardiovascular disease. Therefore, early and accurate diagnosis is essential for implementation of appropriate treatment and management. Available treatments include lifestyle modifications, hormonal contraceptives and insulin sensitisers. However, there are limited data on the best treatment modalities in adolescents. The objective of this review is to describe the clinical manifestations of PCOS in adolescents and the appropriate diagnostic work-up. The optimal treatment modalities based on a review of the available adult and adolescent literature will be discussed. PMID- 26101433 TI - Editorial: Technology and Hand surgery. PMID- 26101432 TI - Correlation of maternal abuse during pregnancy with infant temperament and development. AB - OBJECTIVE: To investigate the effects of domestic violence (DV) against pregnant women on their infant's development in China. DESIGN: 247 mothers were interviewed using the Chinese version of the Abuse Assessment Screen, and all participants underwent postnatal assessment with the Edinburgh Postpartum Depression Scale (EDPS). Plasma glutamate (Glu), gamma-aminobutyric acid (GABA) and cortisol levels of the neonates were measured. After a 10-month follow-up, the infants were assessed using the Revised Infant Temperament Questionnaire (RITQ) and Bayley Scales of Infant Development (BSID). RESULTS: 86 infants of abused mothers (DV group) and 137 infants of non-abused mothers (non-DV group) completed the 10-month follow-up. Neonate levels of plasma Glu, GABA and cortisol were significantly higher in the DV group than in the non-DV group. Scores for the temperament factors, rhythmicity, approach/withdrawal, mood, distractibility and persistence, of the RITQ were rated significantly higher, and results for the Psychomotor Development Index (PDI) of the BSID were significantly lower in the DV group than in the non-DV group at 10 months. After adjustment for the EPDS as a covariate, only distractibility of the RITQ showed a statistically significant difference between the two groups. In correlation analysis, infant mood correlated significantly with levels of plasma Glu (beta=0.2345) and GABA (beta=0.2554), whether or not the EPDS scores were adjusted. Infant persistence and threshold of stimuli scores did not correlate significantly with DV during pregnancy after adjustment for the EPDS. CONCLUSIONS: DV against pregnant women may be associated with impaired temperament and development in their infants. PMID- 26101434 TI - Commentary on Anatomical and histomorphometric observations on the transfer of the anterior interosseous nerve to the deep branch of the ulnar nerve. T. L. Schenck, J. Stewart, S. Lin, M. Aichler, H.-G. Machens and R. E. Giunta. J Hand Surg Eur. 2015, 40: 591-6. PMID- 26101435 TI - Commentary on Enhanced early sensory outcome after nerve repair as a result of immediate post-operative re-learning: a randomized controlled trial. B. Rosen, P. Vikstrom, S. Turner, D. A. McGrouther, R. W. Selles, T. A. R. Schreuders and A. Bjorkman. J Hand Surg Eur. 2015, 40: 598-606. PMID- 26101436 TI - Robert Robins (1923-2015). PMID- 26101439 TI - Forgiveness Reduces Anger in a School Bullying Context. AB - Forgiveness has been shown to be a helpful strategy for victims of many different forms of abuse and trauma. It has also been theoretically linked to positive outcomes for victims of bullying. However, it has never been experimentally manipulated in a school bullying context. This research investigates an experimental manipulation providing children with response advice following a bullying incident. Children read hypothetical physical and verbal bullying scenarios, followed by advice from a friend to either respond with forgiveness, avoidance, or revenge, in a within-subjects repeated measures design. One hundred eighty-four children aged 11 to 15 from private schools in Sydney participated in this study. Results indicated that advice to forgive the perpetrator led to significantly less anger than advice to either avoid or exact revenge. Avoidance was the most likely advice to be followed by students and the most likely to result in ignoring the bullying and developing empathy for their abuser. However, it also resulted in interpretations of the bullying as being more serious. Forgiveness is suggested as an effective coping response for ameliorating the affective aggressive states of victimized youth, with further exploration needed regarding the interplay between the avoidance and forgiveness processes. PMID- 26101440 TI - Ages of legal importance: Implications in relation to birth registration and age assessment practices. AB - Assessment of age is a common procedure routinely conducted in many countries following birth date disputes, particularly following asylum claims and criminal offenses. UNICEF reports that only 65% of children in the world were registered, and the numbers of children who possess an authentic birth certificate were significantly lower than those registered. Legally important ages can be categorized into defined age ranges that vary among different countries. Recently, following an increase in the number of age-specific crimes, many countries have revised their legally important ages. This article is intended to report the most recent data on the ages of legal importance in the major countries of the world and implicate its relevance to birth registration and age assessment practices. PMID- 26101441 TI - Child homicide or natural death? A case report of unexpected death of unusual asymptomatic acute laryngotracheobronchitis. AB - Cases involving the unexpected deaths of children are always a concern for the police and medical examiners alike. In particular, unexpected deaths due to asphyxia without obvious injuries sometimes make decisions regarding the manner of death more difficult. In the present case, a 2-year-old boy was found dead at home, and his mother was initially believed to have killed him. A complete autopsy and forensic investigation were performed, and no injuries were found on the body; however, marked laryngeal edema was observed. Histology showed extensive inflammatory infiltration of the mucosa and submucosa of the larynx, trachea, and bronchi. The cause of death was given as respiratory failure due to acute laryngotracheobronchitis; thus, the manner of death was natural. This case helps to remind the forensic community to keep an open mind and consider a broad differential diagnosis when approaching a case rather than jumping to a conclusion based solely on a preliminary investigation. PMID- 26101442 TI - Cut-throat wounds: Suicidal and homicidal-two case reports and review of literature. AB - Cut-throat wounds are a well-recognized method of homicide, are less commonly used in suicides and are rarely accidental. The forensic pathologist has a very challenging and important task when commenting on the manner of infliction of such wounds when such a case is presented with no proper history or witnesses. We present two cases of cut-throat wounds, one suicide and one homicide, to show the differences between the pattern of wounds. We highlight the differences between the two cases in relation to other external injuries, the circumstances in which the bodies were found and other factors. We intend to update the literature regarding this topic in reference to our cases. We also hope that our presentation will be beneficial to doctors performing autopsies on such cases, so as to distinguish the manner of cut-throat wounds in equivocal cases of death. PMID- 26101443 TI - Child maltreatment and neglect, or poverty and ignorance: An old case from the museum. AB - We present an old case, from the year 1928, of a girl who, as an 18-month-old, had ingested a small amount of lye, and over time oesophageal stenosis had developed. However, her parents had not taken her to hospital until 4 months after the event, after an episode of bloody vomiting. She spent the remaining time of her life in the hospital, where she died as a 3-year-old. Her parents did not visit once during that time. After the autopsy, the opinion about the cause and mechanism of death had five steps: the immediate cause of death was purulent pneumonia, which was a complication of small pox and severe undernourishment; the severe undernourishment was the consequence of a narrowed part of the oesophagus; this developed due to the ingestion of the corrosive agent; and it remained uncertain whether the ingestion of the corrosive agent was accidental or homicidal in manner. The presented case could be an example of possible child maltreatment and neglect in rural parts of society, from almost 90 year ago; at the time these cases were not recognized and treated as they would be today. This is also an example of how the forensic pathologist, via the conclusion about the cause of death, highlighted the parents' carelessness and neglect of the child. PMID- 26101444 TI - Skin wounds vitality markers in forensic pathology: An updated review. AB - Wound age evaluation is one of the most challenging issues in forensic pathology. In the first minutes or hours, standard histological examination may not determine whether the wound was inflicted in the pre- or post-mortem period. While red blood cell infiltration is classically considered as a sign of vital reaction, several studies have shown that extravasation of blood cells may also occur after death and cannot be used as a reliable marker in the diagnosis of wound vitality. Numerous studies about wound vitality are available in the literature. They have evaluated markers involved in coagulation or inflammation, using various methods such as enzymology, molecular biology or immunohistochemistry. In this update, we first introduce some methodological principles. Then, we review the main studies available in the literature. Immunohistochemistry seems to be the most valuable method, given its easy application and the possibility to analyse the localization of the molecules of interest. Some markers are promising, such as CD15, TNFalpha, IL-6, IL-1beta, TGFalpha or TGFbeta1. Prior to their application in daily practice, these early results need to be confirmed with other studies, conducted by independent teams and integrating multiple controls. Most notably, the antibodies have to be tested in numerous post-mortem wounds. Indeed, a critical risk of overexpression in post mortem wounds is present. Some promising markers have been later invalidated because of post-mortem false positivity. Finally, optimal sensitivity and specificity values could probably be reached by combining several markers, validated by large groups of pre- and post-mortem wounds. PMID- 26101445 TI - Power Versus Affiliation in Political Ideology: Robust Linguistic Evidence for Distinct Motivation-Related Signatures. AB - Posited motivational differences between liberals and conservatives have historically been controversial. This motivational interface has recently been bridged, but the vast majority of studies have used self-reports of values or motivation. Instead, the present four studies investigated whether two classic social motive themes--power and affiliation--vary by political ideology in objective linguistic analysis terms. Study 1 found that posts to liberal chat rooms scored higher in standardized affiliation than power, whereas the reverse was true of posts to conservative chat rooms. Study 2 replicated this pattern in the context of materials posted to liberal versus conservative political news websites. Studies 3 and 4, finally, replicated a similar interactive (ideology by motive type) pattern in State of the State and State of the Union addresses. Differences in political ideology, these results suggest, are marked by, and likely reflective of, mind-sets favoring affiliation (liberal) or power (conservative). PMID- 26101446 TI - Psychiatry has many frontiers. PMID- 26101447 TI - CONSORTing with scoundrels? The perils of trials by checklist. PMID- 26101448 TI - Do I have a self? (and other useful questions from Buddhist mindfulness). PMID- 26101449 TI - Deficits in metacognitive monitoring in mathematics assessments in learners with autism spectrum disorder. AB - Children and adults with autism spectrum disorder have been found to have deficits in metacognition that could impact upon their learning. This study explored metacognitive monitoring in 28 (23 males and 5 females) participants with autism spectrum disorder and 56 (16 males and 40 females) typically developing controls who were being educated at the same level. Participants were asked a series of mathematics questions. Based upon previous research, after each question they were asked two metacognitive questions: (1) whether they thought they had got the answer correct or not (or 'don't know') and (2) whether they meant to get the answer correct or not (or 'don't know'). Participants with autism spectrum disorder were significantly more likely than the typically developing group to erroneously think that they had got an incorrect answer correct. Having made an error, those with autism spectrum disorder were also significantly more likely to report that they had meant to make the error. Different patterns in the types of errors made were also identified between the two groups. Deficits in metacognition were identified for the autism spectrum disorder group in the learning of mathematics. This is consistent with metacognitive research from different contexts and the implications for supporting learning in autism spectrum disorder are discussed. PMID- 26101451 TI - Correction. PMID- 26101452 TI - College-Going Benefits of High School Sports Participation: Race and Gender Differences over Three Decades. AB - The long touted athlete advantage in college enrollment has been tempered by assertions that this advantage is actually due to characteristics that precede participation. Moreover, it remains unclear whether the benefits of sports extend into contemporary times, and apply equally to female and racial minority athletes. This study uses three nationally representative longitudinal datasets of students who were 10th graders in 1980, 1990, and 2002. We find that high school sports participation was positively associated with college enrollment, even with the utilization of propensity score modeling, for white boys and girls, black boys, and Latino boys and girls during the 1980s, 1990s, and 2000s. The most important gender and race differences include black female athletes' college going disadvantage in the 1980s and 1990s, and girls' persistently lower rates of high school sports participation than boys'. PMID- 26101454 TI - Introduction to Special Issue: The Retirement Career Phase across Cultures. AB - Increasingly, older workers in the United States remain in the workforce beyond retirement age, meaning the term "retirement" might include at least some form of workforce participation. Although the proportions of women and individuals from racial and ethnic minority groups working past the age of 65 has significantly increased (Wegman & McGee, 2004); few scholars have examined the retirement career phase from a multicultural perspective. This special issue will critically review vocational literature as well as provide specific recommendations for research and practice with the aim of helping scholars and practitioners conceptualize the current concerns older adults across cultures (e.g., women and racial/ethnic minorities, among others) face during retirement planning. PMID- 26101455 TI - Career and Retirement Theories: Relevance for Older Workers Across Cultures. AB - This paper reviews selected career development theories as well as theories specifically focused on retirement, with an emphasis on their application to retirement decisions and vocational behavior in multicultural populations. Theories are evaluated based on whether: (a) retirement was considered a stage of working life, (b) work satisfaction, motivation, and other work variables at retirement age were addressed, (c) work choices at retirement age were included, and (d) cultural and other minority status issues were either directly considered in the work/retirement decision or if the model could be reasonably applied to retirement across cultures. We provide specific recommendations for research and practice with the aim of helping practitioners and scholars conceptualize the current concerns older adults face in their working lives and during retirement planning. PMID- 26101453 TI - Epstein-Barr Virus Specific Antibody Response in Multiple Sclerosis Patients during 21 Months of Natalizumab Treatment. AB - Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. Natalizumab, a humanized anti-alpha4 integrin monoclonal antibody, is a highly effective treatment approved for MS. An association between MS and an exposure to Epstein-Barr Virus (EBV) sustained by the levels of antiviral capsid antigen (VCA) and anti-Epstein-Barr nuclear antigen-1 (EBNA-1) IgG has been described. Our goal was to verify the utility of EBV-specific IgG as a marker in Natalizumab treated MS. Twenty patients (17 female and 3 male) in treatment with Natalizumab were enrolled. Serum levels of anti-VCA and anti-EBNA 1 IgG were determined and expressed as arbitrary units (AU) before treatment and every three months for 21 months of therapy. Anti-VCA IgG levels were increased at the 15th month (235410 +/- 196712 AU) comparing with the 3rd (98146 +/- 47145 AU) and the 6th (109866 +/- 52270 AU) months of therapy (p < 0.05). No significant differences were found for serum anti-EBNA-1 IgG levels. Our data indicate that a transient, self-limited, EBV reactivation can occur in MS during Natalizumab therapy but our results do not support the use of serum EBV-specific antibody levels as biomarkers for monitoring therapeutic response to Natalizumab in the course of MS. PMID- 26101456 TI - Social Cognitive Career Theory, the Theory of Work Adjustment, and Work Satisfaction of Retirement-Age Adults. AB - Despite a recent increase in the number of adults who work past traditional retirement age, existing theories of vocational behavior have not yet received adequate empirical support. In a large sample of adults age 60-87, we evaluated the relationship between theorized predictors of work satisfaction proposed by Social Cognitive Career Theory (SCCT), work satisfaction as a predictor of continued work, as proposed by the Theory of Work adjustment (TWA), as well as the influence of reported experiences of discrimination on these relationships. While the results supported most of the predicted relationships, the effects of discrimination were stronger than the variables proposed by either SCCT or TWA for the present sample. PMID- 26101457 TI - Attentional Control and Intelligence: MRI Orbital Frontal Gray Matter and Neuropsychological Correlates. AB - Attentional control is a key function of working memory that is hypothesized to play an important role in psychometric intelligence. To test the neuropsychological underpinnings of this hypothesis, we examined full-scale IQ, as measured by the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), and attentional control, as measured by Trails B response time and Wisconsin Card Sorting (WCS) test perseverative errors in 78 healthy participants, 25 of whom also had available magnetic resonance imaging (MRI) gray matter volume studies of the orbital frontal cortex (OFC) parcellated into three regions: gyrus rectus, middle orbital gyrus, and lateral orbital gyrus. Hierarchical regression indicated that Trails B response time specifically explained 15.13% to 19.18% of the variation in IQ and WCS perseverative errors accounted for an additional 8.12% to 11.29% of the variance. Full-scale IQ correlated very strongly with right middle orbital gyrus gray matter volume (r = 0.610, p = 0.002), as did Trails B response time with left middle orbital gyrus gray matter volume (r = 0.608, p = 0.003). Trails B response time and right middle orbital gyrus gray matter volume jointly accounted for approximately 32.95% to 54.82% of the variance in IQ scores. These results provided evidence of the unique contributions of attentional control and OFC gray matter to intelligence. PMID- 26101458 TI - Behavioural and Cognitive-Behavioural Treatments of Parasomnias. AB - Parasomnias are unpleasant or undesirable behaviours or experiences that occur predominantly during or within close proximity to sleep. Pharmacological treatments of parasomnias are available, but their efficacy is established only for few disorders. Furthermore, most of these disorders tend spontaneously to remit with development. Nonpharmacological treatments therefore represent valid therapeutic choices. This paper reviews behavioural and cognitive-behavioural managements employed for parasomnias. Referring to the ICSD-3 nosology we consider, respectively, NREM parasomnias, REM parasomnias, and other parasomnias. Although the efficacy of some of these treatments is proved, in other cases their clinical evidence cannot be provided because of the small size of the samples. Due to the rarity of some parasomnias, further multicentric researches are needed in order to offer a more complete account of behavioural and cognitive behavioural treatments efficacy. PMID- 26101459 TI - T, B, and NKT Cells in Systemic Inflammation in Obstructive Sleep Apnoea. AB - BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) brings risk of serious complications. The study objective was to assess elements of the cellular immune response in the course of OSAS. METHODS: Peripheral blood (PB) lymphocytes: T, B, NK, NKT-like, Th, Tc, and HLA DR+ T cells were evaluated by flow cytometry of 48 OSA patients; the concentration of adiponectin, interleukin 1beta, and TNFalpha was measured by ELISA method. The OSA complication score was developed and used for statistical analysis. RESULTS: The proportion of B cells and Th/Tc ratio were significantly lower in the BP of OSA patients when compared with control subjects (median 7.9 versus 10.9%, 0.9 versus 1.5, p < 0.05). The proportion of Tc, NK, NKT-like, and HLADR positive T cells were elevated in OSA patients when compared with healthy subjects (36.4 versus 26.8, 15.5 versus 8.5, 5.7 versus 3.0, and 8.4 versus 4.5%, p < 0.05, resp.) and were more pronounced in patients with metabolic syndrome. The grade of OSA complication score correlated with systemic inflammation markers and the proportion of B cells. The value of adiponectin/BMI ratio correlated significantly with SpO2 (r = 0.31, p < 0.05), CRP (r = -0.35, p < 0.05), TNFalpha concentration (r = -0.36, p < 0.05), and proportion of B cells (r = 0.32, p < 0.05). CONCLUSION: Lymphocytes B, Tc, NK, NKT-like, and adiponectin are involved in systemic immune response in OSA patients possibly predisposing them to cardiovascular and metabolic complications. PMID- 26101460 TI - Harnessing the Therapeutic Potential of Th17 Cells. AB - Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORgammat while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon gamma (IFNgamma). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORgammat is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases. PMID- 26101461 TI - Changes in LDL Oxidative Status and Oxidative and Inflammatory Gene Expression after Red Wine Intake in Healthy People: A Randomized Trial. AB - Postprandial oxidative stress is characterized by an increased susceptibility of the organism towards oxidative damage after consumption of a meal rich in lipids and/or carbohydrates. Micronutrients modulate immune system and exert a protective action by reducing low density lipoproteins (LDL) oxidation via induction of antioxidant enzymes. We evaluated the gene expression of oxidative stress (HOSp), inflammasome (HIp), and human drug metabolism pathways (HDM) and ox-LDL level at baseline and after the intake of red wine naturally enriched with resveratrol (NPVRW), in association with or without a McDonald's meal (McDM). The ox-LDL levels significantly increase comparing baseline (B) versus McDM and decreased comparing McDM versus McDM + NPVRW (P <= 0.05). Percentages of significant genes expressed after each nutritional intervention were the following: (1) B versus McDM, 2.88% HOSp, 2.40% of HIp, and 3.37% of HDMp; (2) B versus McDM + NPVRW, 1.44% of HOSp, 4.81% of HIp, and 0.96% of HDMp; (3) McDM versus McDM + NPVRW, 2.40% of HOSp, 2.40% of HIp, and 5.77% of HDMp; (4) B versus NPVRW, 4.80% HOSp, 3.85% HIp, and 3.85% HDMp. NPVRW intake reduced postprandial ox-LDL and the expression of inflammation and oxidative stress related genes. Chronic studies on larger population are necessary before definitive conclusions. PMID- 26101462 TI - Modulation of Acid Sphingomyelinase in Melanoma Reprogrammes the Tumour Immune Microenvironment. AB - The inflammatory microenvironment induces tumours to acquire an aggressive and immunosuppressive behaviour. Since acid sphingomyelinase (A-SMase) downregulation in melanoma was shown to determine a malignant phenotype, we aimed here to elucidate the role of A-SMase in the regulation of tumour immunogenic microenvironment using in vivo melanoma models in which A-SMase was either downregulated or maintained at constitutively high levels. We found high levels of inflammatory factors in low A-SMase expressing tumours, which also displayed an immunosuppressive/protumoural microenvironment: high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs), as well as low levels of dendritic cells (DCs). In contrast, the restoration of A-SMase in melanoma cells not only reduced tumour growth and immunosuppression, but also induced a high recruitment at tumour site of effector immune cells with an antitumoural function. Indeed, we observed a poor homing of MDSCs and Tregs and the increased recruitment of CD8(+) and CD4(+) T lymphocytes as well as the infiltration of DCs and CD8(+)/CD44(high) T lymphocytes. This study demonstrates that change of A-SMase expression in cancer cells is sufficient per se to tune in vivo melanoma growth and that A-SMase levels modulate immune cells at tumour site. This may be taken into consideration in the setting of therapeutic strategies. PMID- 26101463 TI - beta Common Receptor Mediates Erythropoietin-Conferred Protection on OxLDL Induced Lipid Accumulation and Inflammation in Macrophages. AB - Erythropoietin (EPO), the key factor for erythropoiesis, also protects macrophage foam cells from lipid accumulation, yet the definitive mechanisms are not fully understood. beta common receptor (betaCR) plays a crucial role in the nonhematopoietic effects of EPO. In the current study, we investigated the role of betaCR in EPO-mediated protection in macrophages against oxidized low-density lipoprotein- (oxLDL-) induced deregulation of lipid metabolism and inflammation. Here, we show that betaCR expression was mainly in foamy macrophages of atherosclerotic aortas from apolipoprotein E-deficient mice. Results of confocal microscopy and immunoprecipitation analyses revealed that betaCR was colocalized and interacted with EPO receptor (EPOR) in macrophages. Inhibition of betaCR activation by neutralizing antibody or small interfering RNA (siRNA) abolished the EPO-conferred protection in oxLDL-induced lipid accumulation. Furthermore, EPO-promoted cholesterol efflux and upregulation of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 were prevented by pretreatment with betaCR neutralizing antibody or betaCR siRNA. Additionally, blockage of betaCR abrogated the EPO-conferred anti-inflammatory action on oxLDL-induced production of macrophage inflammatory protein-2. Collectively, our findings suggest that betaCR may play an important role in the beneficial effects of EPO against oxLDL elicited dysfunction of macrophage foam cells. PMID- 26101464 TI - Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. AB - Asthma represents a public health problem and traditionally is classified as an atopic disease, where the allergen can induce clinical airway inflammation, bronchial hyperresponsiveness, and reversible obstruction of airways. Studies have demonstrated the presence of T-helper 2 lymphocytes in the lung of patients with asthma. These cells are involved in cytokine production that regulates immunoglobulin synthesis. Recognizing that T cell interaction with antigens/allergens is key to the development of inflammatory diseases, the aim of this study is to evaluate the anti-inflammatory potential of cannabidiol (CBD) in this setting. Asthma was induced in 8-week-old Wistar rats by ovalbumin (OVA). In the last 2 days of OVA challenge animals received CBD (5 mg/kg, i.p.) and were killed 24 hours after. The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF alpha were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels. CBD seems to be a potential new drug to modulate inflammatory response in asthma. PMID- 26101465 TI - Role Analysis in Networks using Mixtures of Exponential Random Graph Models. AB - A novel and flexible framework for investigating the roles of actors within a network is introduced. Particular interest is in roles as defined by local network connectivity patterns, identified using the ego-networks extracted from the network. A mixture of Exponential-family Random Graph Models is developed for these ego-networks in order to cluster the nodes into roles. We refer to this model as the ego-ERGM. An Expectation-Maximization algorithm is developed to infer the unobserved cluster assignments and to estimate the mixture model parameters using a maximum pseudo-likelihood approximation. The flexibility and utility of the method are demonstrated on examples of simulated and real networks. PMID- 26101466 TI - Contributions of temporal segregation, oviposition choice, and non-additive effects of competitors to invasion success of Aedes japonicus (Diptera: Culicidae) in North America. AB - The mosquito Aedes japonicus (Diptera: Culicidae) has spread rapidly through North America since its introduction in the 1990s. The mechanisms underlying its establishment in container communities occupied by competitors Aedes triseriatus and Aedes albopictus are unclear. Possibilities include (A) temporal separation of A. japonicus from other Aedes, (B) oviposition avoidance by A. japonicus of sites containing heterospecific Aedes larvae, and (C) non-additive competitive effects in assemblages of multiple Aedes. Containers sampled throughout the summer in an oak-hickory forest near Eureka, MO showed peak abundance for A. japonicus occurring significantly earlier in the season than either of the other Aedes species. Despite this, A. japonicus co-occurred with one other Aedes species in 53 % of samples when present, and co-occurred with both other Aedes in 18 % of samples. In a field oviposition experiment, A. japonicus laid significantly more eggs in forest edge containers than in forest interior containers, but did not avoid containers with low or high densities of larvae of A. triseriatus, A. albopictus, or both, compared to containers without larvae. Interspecific competitive effects (measured as decrease in the index of performance, lambda') of A. triseriatus or A. albopictus alone on A. japonicus larvae were not evident at the densities used, but the effect of both Aedes combined was significantly negative and super-additive of effects of individual interspecific competitors. Thus, neither oviposition avoidance of competitors nor non-additive competitive effects contribute to the invasion success of A. japonicus in North America. Distinct seasonal phenology may reduce competitive interactions with resident Aedes. PMID- 26101467 TI - Only one health, and so many omics. AB - The development of new approaches based on wide profiling methods in studying biological and medical systems is bringing large amounts of data on a daily basis. The causes of complex diseases have been directed to the genome examination bringing formidable knowledge. We can study genome, but also proteome, exome, transcriptome, epigenome, metabolome, and newcomers too such as microbiome, connectome and exposome. The title of this editorial is paraphrasing the famous saying of Victor Schlichter from Buenos Aires children hospital in Argentina who said "How unfair! Only one health, and so many diseases". Today there is indeed a whole lot of omics. We think that we are lucky to have all the omics possible, but we also wanted to stress the importance of future holistic approach in integrating the knowledge omics has rewarded us. PMID- 26101471 TI - Second International Conference on Publication Ethics organized by Shiraz University of Medical Sciences (Shiraz - Iran December 4-5, 2014). PMID- 26101468 TI - Choosing wisely: practical considerations on treatment efficacy and safety of asthma in the elderly. AB - The prevalence of asthma in the most advanced ages is similar to that of younger ages. However, the concept that older individuals may suffer from allergic asthma has been largely denied in the past, and a common belief attributes to asthma the definition of "rare" disease. Indeed, asthma in the elderly is often underdiagnosed or diagnosed as COPD, thus leading to undertreatment of improper treatment. This is also due to the heterogeneity of clinical and functional presentations of geriatric asthma, including the partial loss of reversibility and the lower occurrence of the allergic component in this age range. The older asthmatic patients are also characterized the coexistence of comorbid conditions that, in conjunction with age-associated structural and functional changes of the lung, may contribute to complicate the management of asthma. The current review addresses the main issues related to the management of allergic asthma in the geriatric age. In particular, the paper aims at revising current pharmacological and non pharmacological treatments for allergic asthmatics of advanced ages, primarily focusing on their safety and efficacy, although most behaviors are an arbitrary extrapolation of what has been tested in young ages. In fact, age has always represented an exclusion criterion for eligibility to clinical trials. Experimental studies and real life observations specifically testing the efficacy and safety of therapeutic approaches in allergic asthma in the elderly are urgently needed. PMID- 26101469 TI - Identification of risk factors of severe hypersensitivity reactions in general anaesthesia. AB - BACKGROUND: Hypersensitivity reactions to anaesthetic agents are rare but often severe, with a mortality ranging from 4 to 9% in IgE-mediated events. Identification of the risk factors may contribute to limit the incidence of these reactions. The aim of our study was to search for possible risk factors of severe perioperative hypersensitivity reactions in our study population. METHODS: For this study we retrospectively reviewed data from 193 patients who experienced drug hypersensitivity reactions during general anaesthesia. The diagnostic protocol consisted of 1) history of the reaction, 2) measurement of serum baseline tryptase and specific IgE-assays for latex, beta-lactams and succinylcholine, 3) skin tests for the agents listed in the anaesthesia chart and for others likely to be safe for future use, latex, and others medications administered during the perioperative period (i.e. antibiotics), 4) subdivision of our patients on the basis of two criteria: a) grade of severity of clinical reactions according to the Ring and Messmer classification; b) results of skin tests and/or serum specific IgE-assays. RESULTS: One hundred of 193 patients had reactions of grade I, 32/193 patients had reactions of grade II, 55/193 patients had reactions of grade III and 6/193 patients had reactions of grade IV. A diagnosis of IgE-mediated reaction was established in 55 cases (28.50%); the most common causes were neuromuscular blocking agents, followed by latex and beta lactams. Severe reactions were associated with older age (p = 0.025), asthma (p = 0.042), history of hypertension (p = 0.001), intake of serum angiotensin converting enzyme inhibitor medication (p = 0.012) or serum angiotensin II antagonist (p = 0.033), higher levels of basal tryptase (p = 0.0211). Cardiovascular symptoms (p = 0.006) and history of hypersensitivity to antibiotics (p = 0.029) were more frequently reported in IgE-mediated reactions. CONCLUSIONS: We confirmed the relevance of several clinical features as risk factors for anaphylactic reactions induced by anaesthetic agents: older age, asthma, hypertension and antihypertensive drugs. We observed increased levels of serum basal tryptase in severe reactions: this finding may signify that this biomarker is useful for the identification of patients at risk. PMID- 26101470 TI - Contribution of Shellfish Consumption to Lower Mercury Health Risk for Residents in Northern Jiaozhou Bay, China. AB - Fish and marine mammal consumption are an important pathway for human exposure to mercury. The low mercury content in shellfish poses a low mercury health risk to people who consume shellfish. The objectives of this study are to detect mercury concentrations in different species of shellfish and to calculate the mercury health risk from shellfish consumption among traditional residents near northern Jiaozhou Bay. A total of 356 shellfish samples, which comprised 7 species from 5 different places in northern Jiaozhou Bay, were collected from April to June in 2012. The average mercury content in the collected shellfish ranged from 0.024 mg.kg(-1) to 0.452 mg.kg(-1). A total of 44 shellfish samples (12.36%) had mercury levels exceeding the national pollution-free aquatic products limit (0.3 mg.kg(-1)). Generally, the viscus had the highest mercury content among all parts of the shellfish. A positive correlation between mercury content and total weight/edible part weight was found in most species of the collected shellfish. The results showed that shellfish consumption resulted in the lower risk of mercury exposure to residents based on the calculation of daily intake (DI) and target hazard quotient (THQ). PMID- 26101472 TI - Diagnostic accuracy of Magnetic Resonance Imaging in assessment of Meniscal and ACL tear: Correlation with arthroscopy. AB - OBJECTIVE: To determine the diagnostic accuracy of magnetic resonance imaging (MRI) in injuries related to anterior cruciate ligament and menisci and compare its effectiveness with that of arthroscopy. METHODS: This retrospective cross sectional study was conducted in the department of Radiology & Medical Imaging of Dallah Hospital, Riyadh, Kingdom of Saudi Arabia from September 2012 to March 2014. Fifty four patients (including 30 men and 24 women) with internal derangement of knee referred from the orthopedic consulting clinics underwent MR imaging followed by arthroscopic evaluation. The presence of meniscal and ligamentous abnormality on the imaging was documented by two trained radiologist. Findings were later compared with arthroscopic findings. RESULTS: The sensitivity, specificity and accuracy of MR imaging for menisci and ACL injury were calculated: 100% sensitivity, 88.4% specificity, 90% positive predictive value, 100% negative predictive value, and 94.4% accuracy were noted for medial meniscal injury. Similarly, MR had sensitivity of 85.7%, specificity of 95%, positive predictive value of 85.7%, negative predictive value of 95%, and accuracy of 92.5% for lateral meniscal injuries. Likewise, anterior cruciate ligament had 91.6% sensitivity, 95.2% specificity, 84.6% positive predictive value, 97.5% negative predictive value, and 94.4% accuracy. CONCLUSION: MRI is extremely helpful in identifying meniscal and anterior cruciate ligaments tears. MR imaging has high negative predictive value making it better choice as screening tool compared to diagnostic arthroscopic evaluation in most patients with soft tissue trauma to knee. PMID- 26101473 TI - Single nucleotide polymorphisms of nucleotide excision repair and homologous recombination repair pathways and their role in the risk of osteosarcoma. AB - OBJECTIVE: To evaluate the influence of polymorphisms in nucleotide excision repair (NER) and homologous recombination repair (HRR) pathways on the development of osteosarcoma patients. METHODS: Genotypes of ERCC1 rs11615 and rs3212986, ERCC2 rs1799793 and rs13181, NBN rs709816 and rs1805794, RAD51 rs1801320, rs1801321 and rs12593359, and XRCC3 rs861539 were conducted by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. RESULTS: Total 148 osteosarcoma patients and 296 control subjects were collected from Taizhou First People's Hospital. Conditional logistic regression analyses found that individuals carrying with GA+AA genotype of ERCC2 rs1799793 and GC+CC genotype of NBN rs1805794 were significantly associated with increased risk of osteosarcoma, and the ORs(95%CI) were 1.58(1.03-2.41) and 2.66(1.73 4.08), respectively. We found that GA+AA genotype of ERCC2 rs1799793 or GC+CC genotype of NBN rs1805794 were associated with an increased risk of osteosarcoma in females, with ORs(95%CI) of 2.42(1.20-4.87) and 2.01(1.07-4.23), respectively. CONCLUSION: Our results suggest that ERCC2 rs1799793 and NBN rs1805794 polymorphisms were associated with an increased risk for osteosarcoma, which suggests that NER and HRR pathways modulate the risk of developing osteosarcoma. PMID- 26101474 TI - Differential immune cell densities in ductal carcinoma In-Situ and invasive breast cancer: Possible role of leukocytes in early stages of carcinogenesis. AB - OBJECTIVES: To investigate immune cell densities in pre-neoplastic (DCIS), cancer (IDC) and control breast tissues. METHODS: A total of four preneoplastic, 104 cancer and 104 control samples were analyzed. Morphological classification and prognostic scoring along with quantification of immune cells/mm(2) was performed. Data were entered and analyzed using SPSS version 16. Correlation of immune cell densities with various tumour sub-types was investigated using paired t-test and ANOVA. A p-value of <0.05 was considered as significant. RESULTS: Our data show increased infiltration of lymphocytes (mean lymphocytes = 287.6cells/mm(2)) as well as myelocytes (mean lymphocytes = 117.1cells/mm(2)) in pre-neoplastic tissues. This infiltration was significantly high compared to cancer (p value<0.001) as well as control tissues (p-value <0.001). Moreover, we report increased infiltration of lymphocytes in cancer tissues compared to controls (p value<0.001). There was no difference in lymphocyte densities within various tumour sub-types (all p-values >0.05). CONCLUSION: Leukocytes may play a role in early stages of breast carcinogenesis. PMID- 26101475 TI - Clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. AB - OBJECTIVE: To analyze the clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. METHODS: One hundred and eight tissue samples from the patients with endometrial cancer enrolled in our hospital from August 2011 to July 2014 were selected, including 60 normal tissue samples (normal group), 60 neoplastic tissue samples (neoplastic group) and 60 cancer tissue samples (cancer group). All the samples were subjected to immunohistochemical assay to detect the expressions of COX-2, GLUT-1 and VEGF. The clinical data were also investigated for correlation analysis. RESULTS: The positive rates of COX-2 in normal group, neoplastic group and cancer groups were 3.3%, 21.7% and 55.0% respectively. The positive rates of GLUT-1 in normal group, neoplastic group and cancer groups were 3.3%, 25.0% and 70.0% respectively. The positive rates of VEGF in normal group, neoplastic group and cancer groups were 1.7%, 23.3% and 63.3% respectively. With increasing stage of such cancer, decreasing degree of differentiation and lymphatic metastasis, the positive expression rates of COX-2, GLUT-1 and VEGF proteins were raised significantly (P<0.05). Spearman's correlation analysis showed that the expressions of COX-2 and GLUT-1 (r=0.207, P<0.05), COX-2 and VEGF (r=0.243, P<0.05), as well as GLUT-1 and VEGF (r=0.758, P<0.05) were positively correlated. CONCLUSION: COX-2, GLUT-1 and VEGF were highly prominent in endometrial cancer, especially in the patients with low degree of differentiation, late stage and metastasis. They functioned synergistically in the onset and progression of this cancer. PMID- 26101476 TI - Frequency of ICD-10 psychiatric diagnosis in children with intellectual disability in Lahore, Pakistan & Caregivers Perspective. AB - OBJECTIVE: Association between Intellectual disability (ID) and psychiatric disorders in children & adolescents is well established but there is a paucity of published studies from Pakistan on this topic. The main aim of the study was to assess the frequency of ICD-10 psychiatric diagnosis in the hospital outpatient sample of children with ID in Lahore, Pakistan as well as to find out which challenging behaviors, caregivers find difficult to manage in this setup. METHODS: Socio-demographic information was collected, Wechsler Intelligence Scale for Children-Revised & ICD-10 diagnostic criteria was used to assess children (age range 6 - 16 years) with suspected ID along with identification of behaviors found to be difficult to manage by caregivers. RESULTS: 150 children were assessed with mean age of 10.7 years (males 70 %). Majority (72%) had mild ID while 18.7% and 9.3% had moderate and severe ID respectively. Thirty percent of children met the criteria for any psychiatric diagnosis, the most common being Oppositional Defiant Disorder (14%) and Hyperkinetic Disorders (10%). Verbal and physical aggression, school difficulties, socialization problems, inappropriate behaviors (e.g. disinhibition), sleep & feeding difficulties were the significant areas identified by the caregivers as a cause of major concern. CONCLUSIONS: Significantly high prevalence of ICD-10 psychiatric diagnosis in children with ID was found in Lahore, Pakistan. Support services for these children should be responsive not only to the needs of the child, but also to the needs of the family. PMID- 26101477 TI - Impact of polymorphisms of the DNA repair gene XRCC1 and their role in the risk of prostate cancer. AB - OBJECTIVE: We conducted a case-control study to examine the role of XRCC1 codons 194 (Arg>Trp), 280 (Arg>His) and 399 (Arg>Gln) polymorphisms in the risk of prostate cancer. METHODS: This study included 572 consecutive primary prostate cancer patients and 572 controls between January 2011 and January 2014. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect XRCC1 codons 194 (Arg>Trp), 280 (Arg>His) and 399 (Arg>Gln) polymorphisms. RESULTS: Compared with the control subjects, the prostate cancer cases had a habit of cigarette smoking (chi(2)=18.13, P<0.001) and a family history of cancer (chi(2)=25.23, P<0.001). Conditional logistic regression analysis showed that the subjects carrying Trp/Trp genotype were more likely to greatly increase the prostate cancer when compared with Arg/Arg genotype, and the adjusted OR was 2.04(1.24-3.41). We did not find significant association between XRCC1 194 (Arg>Trp) polymorphism and clinical stage and Gleason score of prostate cancer (P>0.05). CONCLUSION: Our results show an increased risk for prostate cancer in individuals with XRCC1 194 (Arg>Trp) polymorphism, and a significant interaction between XRCC1 194 (Arg>Trp) polymorphism and tobacco smoking, alcohol drinking and family history of cancer. PMID- 26101478 TI - Scrub typhus associated hepatic dysfunction and abdominal CT findings. AB - OBJECTIVE: This retrospective study investigated abnormal hepatic dysfunction and abdominal computed tomography (CT) findings in scrub typhus. METHODS: Three hundred forty nine adult patients were diagnosed with scrub typhus. Ninety four underwent abdominal CT. The CT images were reviewed by the attending radiologist. Patient data of history, symptoms, signs, and results of laboratory tests were collected from the electronic medical records. RESULTS: In 349 patients with scrub typhus, elevation of aspartate aminotransferase (78.5%) and alanine aminotransferase (63.0%) were dominant compared to alkaline phosphatase (27.2%) and total bilirubin (16.1%). Abdominal CT findings of 94 patients were, in descending order of frequency, enlarged lymph node (53.2%), inhomogeneous enhancement of liver (47.9%), splenomegaly (46.8%), ascites (28.7%), low attenuation of periportal areas (27.7%), gallbladder wall thickening (17.0%), and splenic infarct (6.4%). Also, the level of aspartate aminotransferase tended to be elevated according to the number of CT findings (P= 0.028). CONCLUSIONS: We found that abdominal CT manifestations of scrub typhus with elevated aminotransferases were varied and not specific. However, knowledge of these findings may evoke the recognition of scrub typhus by clinicians in endemic areas. PMID- 26101479 TI - Effect of preemptive analgesia with intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor. AB - OBJECTIVE: To evaluate the efficacy of preemptive intravenous oxycodone in the patients undergoing laparoscopic resection of ovarian tumor. METHODS: Sixty ASA I or II patients undergoing elective laparoscopic resection of ovarian tumor were randomly allocated to one of two groups: Group O (n=30) received intravenous oxycodone (0.1 mg.kg(-1)) 10 minutes before surgery over 2 minutes, and Group N (n=30) received an equivalent volume of normal saline. All patients received a standardized general anesthesia. MBP and HR at the time of arrival of the operating room (T1), 5 min before pneumoperitoneum (T2), 5 minutes (T3), 10 minutes (T4), and 15 minutes after pneumoperitoneum (T5), and VAS scores at postoperative 2, 4, 8, 12 and 24 hour were recorded. The tramadol consumption and side effects in 24 h after surgery were recorded. RESULTS: VAS pain scores at 2, 4, 8 and 12 hour after operation were significantly lower in Group O (P<0.05). MBP and HR increased significantly due to pneumoperitoneum at T3, T4 and T5, compared with T1 and T2 within Group N, and were higher at T3, T4 and T5 in Group N than at the same time points in Group O. Tramadol consumption was statistically lower in Group O (P=0.0003). CONCLUSIONS: Preemptive intravenous oxycodone was an efficient and safe method to reduce intraoperative haemodynamic effect and postoperative pain. PMID- 26101480 TI - Malabsorption of iron as a cause of iron deficiency anemia in postmenopausal women. AB - OBJECTIVE: Malabsorption is one of the causes of iron deficiency anemia in postmenopausal women. The main objective of this study was to access the frequency of malabsorption in iron deficient anemic postmenopausal women. METHODS: A total of 123 postmenopausal women were enrolled in the study. Of these 123 women, 50 were included as 'control group' and 73 patients with comparable severity of anemia were the 'patient group'. Two tablets of ferrous sulfate (200 mg/tablet) along with one tablet of vitamin C (500 mg) were given to all participants. Serum iron levels were determined on samples collected from all participants before and after the administration of ferrous sulfate. Difference between before and after serum iron levels of normal and patients were compared. RESULTS: No change in serum iron between sample one and sample two represented malabsorption. Out of 73, 5 postmenopausal anemic patients showed no change in their serum iron level after the administration of ferrous sulfate. This study shows that frequency of malabsorption of iron in postmenopausal women is 6.8%. CONCLUSION: Malabsorption should be considered as a prevalent cause of iron deficiency anemia in postmenopausal women. It should be properly diagnosed and iron response should be monitored properly in postmenopausal women with IDA after oral iron therapy. If a postmenopausal woman does not show any response to oral iron therapy, she should be evaluated for iron loss (blood loss and/or malabsorption). Intravenous route should be used for the administration of iron in these patients. PMID- 26101481 TI - A comparison study on the clinical effects of foscarnet sodium injection and interferon on human immunodeficiency virus-infected patients complicated with herpes zoster. AB - OBJECTIVE: To compare the clinical effects of foscarnet sodium injection and interferon on human immunodeficiency virus (HIV)-infected patients complicated with herpes zoster. METHODS: Ninety HIV-infected patients complicated with herpes zoster were divided into a treatment group and a control group that were both treated routinely first. Then the control group and treatment group were administered with interferon and foscarnet sodium injection respectively for four consecutive weeks. RESULTS: After four weeks, the effective rates of the treatment and control groups were 95.6% and 80.0% respectively, which were significantly different (P < 0.05). The pain scores of the two groups were similar before treatment, but the scores of the treatment group were significantly lower than those of the control group two and four weeks after treatment (P < 0.05) as well as were significantly lower than those before treatment (P < 0.05). The numbers of CD4+ cells and the contents of IL-2 of both groups two and four weeks after treatment significantly exceeded those before treatment (P < 0.05), with significant inter-group differences also (P < 0.05). Two and four weeks after treatment, the treatment group scored significantly higher in physical activity, energy, sleep, social life and emotional reaction than the control group did (P < 0.05). CONCLUSIONS: HIV-infected patients are prone to being complicated with herpes zoster. Compared with interferon, foscarnet sodium injection better improves the clinical outcomes by effectively relieving pain and by regulating immune mediated inflammatory diseases, thus boosting the prognostic quality of life. PMID- 26101482 TI - Vaginal micronized progesterone capsule versus vaginal progesterone gel for lutheal support in normoresponder IVF/ICSI-ET cycles. AB - OBJECTIVE: To compare the outcomes of luteal phase support by micronized progesteron vaginal capsule 600mg/day and progesterone vaginal gel 180mg/day in the normoresponder IVF/ICSI-ET cycles of the patients down-regulated via GnRH agonist long protocol or fixed antagonist protocol below 40 years of age. METHODS: A total of 463 normoresponder cycles between January 2013 and December 2013 were retrospectively analyzed. Those with a BMI>28 kg/m(2), any kind of uterine, ovarian or adnexial pathology, any significant systemic, endocrine or metabolic disease or who were reported as azoospermia, were excluded from the study. The patients were grouped according to the usage of micronized progesterone vaginal capsule 600mg/day (Group 1) or progesterone vaginal gel 180mg/day (Group 2) as luteal phase support. Treatment cycle characteristics and pregnancy outcomes were compared between groups. RESULTS: Group-I included 220 cycles and group 2 included 243 cycles. Although the MII oocyte percentage among the total number of MII oocytes was significantly higher in Group-II (77.5% and 80.2%; p=0.034), positive beta-hCG (32.3% and 21.8%; p=0.015) and clinical pregnancy (27.3% and 17.7%; p=0.018) rates were significantly higher in Group-I. No difference was observed between groups regarding the ongoing pregnancy rates (23.2% and 17.3%; p=0.143). CONCLUSION: Micronized progesterone vaginal capsule 600mg daily used for luteal support in the IVF/ICSI-ET cycles was observed to significantly increase the biochemical and clinical pregnancy rates compared to progesterone vaginal gel 180mg daily. However, no difference was observed between two groups regarding ongoing pregnancy rates. PMID- 26101483 TI - Clinical outcomes of low-dose leflunomide for rheumatoid arthritis complicated with Hepatitis B virus carriage and safety observation. AB - OBJECTIVE: To study the clinical outcomes of low-dose leflunomide for rheumatoid arthritis (RA) complicated with hepatitis B virus (HBV) carriage and to observe the safety. METHODS: A total of 115 RA patients were divided into three groups according to the state of HBV. They were all given leflunomide to observe the clinical outcomes and whether HBV was activated. RESULTS: The indices (e.g. activity score) of all patients were significantly better after treatment than those before (P < 0.05), with 89.00% (92/115) of them reaching ACR20. Fourteen cases (12.2%) suffered from abnormal liver functions, and 5 cases who had HBV reactivation originated from the HBV carriage group. Neither the previous HBV infection group nor the infection-free group succumbed to HBV reactivation. The multiple regression model showed that the HBV reactivation risk of RA patients treated by leflunomide was increased by 30% by the basic state of hepatitis B as well as alanine transaminase level and swollen joint count before treatment. CONCLUSION: Leflunomide exerted satisfactory therapeutic effects on RA, but liver diseases, liver function, HBV-DNA load and the reactivation risks of carried HBV should be thoroughly checked and cautiously pondered. PMID- 26101484 TI - The prevalence of dyspepsia symptoms and its correlation with the quality of life among Qashqai Turkish migrating nomads in Fars Province, Southern Iran. AB - OBJECTIVES: To determine the prevalence of dyspepsia and its correlation with quality of life in Fars Qashqai Turkish migrating nomads from Southern Iran. METHODS: During 2010 we enrolled 397 Qashqai migrating nomads from Southern Iran who were 25 years of age or older. Participants completed a questionnaire that consisted of demographic factors, lifestyle data, gastrointestinal symptoms, and the Short-Form 36 Health Survey (SF-36) questionnaire. RESULTS: There was a 48% prevalence of dyspepsia symptoms among participants. The prevalence was higher among females, those less than 35 years of age, married participants, and those with a low body mass index (BMI). The correlation between dyspepsia and quality of life was significant. Dyspeptic patients were classified into ulcer-like (27.9%), dysmotility-like (26.2%), and unspecified (45.9%) groups. A significant correlation existed between dyspepsia symptoms and consumption of dairy products, drinking water and tea before and after meals, smoking, dysphagia, reflux, heartburn, and use of non-steroid anti-inflammatory drugs and acetaminophen. CONCLUSION: The high prevalence of dyspepsia in Qashqai nomads necessitates educational health programs for the migrating tribes in order to decrease prevalence of this disease. PMID- 26101485 TI - Prevalence and associated factors of Carpal Tunnel Syndrome (CTS) among medical laboratory staff at King Saud University Hospitals, KSA. AB - BACKGROUND AND OBJECTIVES: Carpal tunnel syndrome (CTS) is a group of symptoms resulting from local compression of the median nerve at the wrist leading to its subsequent functional impairment and local ischemia of the nerve. Our objective was to determine the prevalence and commonly reported symptoms of CTS in the laboratory workers of King Saud University (KSU) hospitals and to identify the associated variables with CTS. METHODS: This was a quantitative observational cross-sectional study which was conducted in KSU hospitals' laboratories with a total of 225 participants by using a standardized questionnaire known as " Boston Carpal Tunnel Questionnaire (BCTQ). Data Analysis was carried out by IBM SPSS Statistics software version 21.0. RESULTS: Out of the 225 participants, 57 were found to be severely symptomatic with a prevalence of 25.3%. Among the severely affected participants, females were more than males (58% > 42%) and the difference was statistically significant (p=0.045). Technicians affected (91.2%) were more than attendants (8.8%) and the difference was statistically significant (p=0.042). CONCLUSION: The prevalence of Carpal tunnel syndrome in KSU hospitals' medical laboratory staff (25.3%) was close to what was found in literature (21.5%). So laboratory workers are at risk of developing CTS, especially females and technicians with the dominant hand most likely to be affected. PMID- 26101486 TI - Comparing the effects of Osteoporosis Prevention Exercise Protocol (OPEP) versus walking in the prevention of osteoporosis in younger females. AB - OBJECTIVE: The aim of this work was to evaluate the effectiveness of Osteoporosis Prevention Exercise Protocol (OPEP) in younger females. METHODS: One hundred young female volunteers aged 20-30 were selected from IPM&R Dow University of Health Sciences. This was a comparative study in which 64 females participants were randomly assigned into two groups (32 in OPEP exercise group and 32 in walking group). The exercise session had three components 1) stretching 2) strengthening 3) high impact weight bearing exercises. Both interventional programs consisted of 3 sessions per week for twelve weeks under the supervision of physiotherapist. Pre and post intervention bone mass density (BMD) was measured on the lumbar spine (L1-L4), hip, femur, and distal forearm by using Dual-Energy X-ray Absorptiometry (DEXA) scan. RESULTS: After twelve weeks of intervention BMD was found to be statistically insignificant at hip, femur, lumbar spine and wrist (p > 0.05) comparing the post results in the OPEP and exercise group. Moreover BMD at hip, femur, lumbar spine and wrist was unaltered in both groups comparing the results of pre and post intervention. Though significant changes were observed in BMI in the OPEP exercise group (p value =0.010) mean +/- standard deviation pre and post found to be 20.2578 +/- 3.11123 and 21.0942 +/- 3.64203 but no variations in anthropometrics in walking group were found. CONCLUSION: The present study highlights the burden of osteopenia in younger females. The Osteoporosis Prevention Exercise Protocol formulated by author was not useful to bring any significant changes in BMD moreover it had no significant effects in comparison to walking group. However additional studies are needed to evaluate the efficacy of Osteoporosis Prevention Exercise Protocol on bone quality with long term effects. PMID- 26101487 TI - Antibiotic resistance pattern of Pseudomonas aeruginosa isolated from urine samples of Urinary Tract Infections patients in Karachi, Pakistan. AB - OBJECTIVE: The aim of this study was to evaluate the antibiotic resistance pattern of Psedomonas aeruginosa and its prevalence in patients with urinary tract infections (UTI) for effective treatment in a developing country like Pakistan. METHODS: This is an observational study conducted for a period of ten months which ended on December 2013 at the Dr. Essa Laboratory and Diagnostic Centre in Karachi. A total of 4668 urine samples of UTI patients were collected and standard microbiological techniques were performed to identify the organisms in urine cultures. Antibiotic susceptibility testing was performed by Kirby-Bauer technique for twenty five commonly used antimicrobials and then analyzed on SPSS version 17. RESULTS: P. aeruginosa was isolated in 254 cultures (5.4%). The most resistant drugs included Ceclor(100%) and Cefizox (100%) followed by Amoxil/Ampicillin (99.6%), Ceflixime (99.6%), Doxycycline (99.6%), Cefuroxime (99.2%), Cephradine (99.2%), Cotrimoxazole (99.2%), Nalidixic acid (98.8%), Pipemidic acid (98.6%) and Augmentin (97.6%). CONCLUSION: Emerging resistant strains of Pseudomonas aeruginosa are potentially linked to injudicious use of drugs leading to ineffective empirical therapy and in turn, appearance of even more resistant strains of the bacterium. Therefore, we recommend culture and sensitivity testing to determine the presence of P.aeruginosa prior to specific antimicrobial therapy. PMID- 26101488 TI - Comparison of therapeutic effects of anterior decompression and posterior decompression on thoracolumbar spine fracture complicated with spinal nerve injury. AB - OBJECTIVE: To compare the clinical therapeutic effects of anterior decompression and posterior decompression on thoracolumbar spine fracture (TSF) complicated with spinal nerve injury (SNI). METHODS: A total of 120 patients with TSF and SNI were selected and divided into a treatment group and a control group that were then treated by anterior decompression and posterior decompression respectively. The preoperative and postoperative motor scores, tactile scores, heights of injured vertebral body and Cobb's angles, as well as surgical times and intraoperative blood losses were recorded and compared. RESULTS: Before surgeries, the motor score, tactile score, height of injured vertebral body and Cobb's angle of the treatment group were similar to those of the control group (P>0.05). After surgeries, the values of the treatment group were significantly different from those of the control group (P<0.05). The two groups also had significantly different intraoperative blood losses and surgical times (P<0.05). CONCLUSION: Compared with posterior decompression, anterior decompression improved spinal cord function better and relived spinal cord compression more effectively with a more reasonable mechanics of internal fixation. Although this protocol caused more blood loss, the overall therapeutic effects were more satisfactory. PMID- 26101489 TI - Is rapid antibacterial susceptibility testing medium reliable for routine laboratory practices? AB - OBJECTIVE: Early detection of antibiotic susceptibility profile of the isolates has critical importance in terms of immediate beginning of the appropriate treatment and increasing of treatment success, such as meningitis, bacteriemia and sepsis. In the present study, it was aimed to compare the antibiotic susceptibility results of Quicolor (Salubris Inc., Massachusetts, USA) and standard disk diffusion method. METHODS: One hundred twenty three isolates were included in this study (80 Enterobacteriaceae, 15 Staphylococci and 28 nonfermentative Gram-negative bacteria). Antibiotic susceptibility in clinical isolates was evaluated using Mueller-Hinton (MH) agar and Quicolor (ES and NF) agar plates. RESULTS: For Enterobacteriaceae, frequency of total concordance, major error, and minor error between the tests were found as 96.8%, 0.8%, and 2.4%, respectively. For Staphylococci, frequency of total concordance, major error, and minor error among the tests were found as 95.7%, 3.5%, and 0.8%, respectively. For non fermentative bacteria, frequency of total concordance, major error, and minor error among the tests were found as 83.9%, 9.6%, and 6.4%, respectively. CONCLUSIONS: Quicolor media provided reliable susceptibility results in enteric bacteria and Staphylococci. However, further studies including higher number of nonfermentative bacteria are required to determine whether the chromogenic media are appropriate for this group of bacteria. PMID- 26101490 TI - Association between serum total testosterone and Body Mass Index in middle aged healthy men. AB - OBJECTIVE: To determine correlation of serum total testosterone with body mass index (BMI) and waist hip ratio (WHR) in healthy adult males. METHODS: A cross sectional study was conducted on 200 nonsmoker healthy males (aged 30-50 years) university employees. They were selected by convenience sampling technique after a detailed medical history and clinical examination including BMI and Waist Hip Ratio (WHR) calculation. Blood sampling was carried out to measure serum total testosterone (TT) using facilities of Chemiluminescence assay (CLIA) technique in Dow Chemical Laboratory. Independent sample T test was used for mean comparisons of BMI and WHR in between low and normal testosterone groups. (Subjects having < 9.7 nmol/L of total testosterone in blood were placed in low testosterone group and subjects having >= 9.7 nmol/L of total testosterone in blood were placed in normal testosterone group). Correlation of testosterone with BMI and WHR was analyzed by Pearson Correlation. RESULTS: Mean (+/- SD) age of the subjects included in this study was 38.7 (+/- 6.563) years mean (+/- SD) total testosterone was 15.92 (+/-6.322)nmol/L. The mean (+/- SD) BMI, and WHR were 24.95 (+/-3.828) kg/m(2) and 0.946 (+/-0.0474) respectively. Statistically significant differences were observed in the mean values of BMI and WHR for the two groups of testosterone. Significant inverse correlation of serum total testosterone with BMI(r = -0.311, p = 0.000) was recorded in this study. However testosterone was not significantly correlated with waist/hip ratio.(r = -0.126, p = 0.076). CONCLUSION: Middle age men working at DUHS who have low level of serum total testosterone are more obese than individuals with normal total testosterone level. PMID- 26101491 TI - Frequency of placenta previa in previously scarred and non scarred uterus. AB - OBJECTIVE: To determine the frequency of placenta Previa in patients coming to a tertiary care unit with previously scarred and non-scarred uterus. METHODS: A descriptive cross sectional study was carried on 114 cases who underwent caesarean sections (37 cases out of 645 cases with non scarred uterus and 77 cases from 721 cases with scarred uterus) in the department of obstetrics and gynecology Lady Willingdon Hospital from January 2008- December 2011. RESULTS: Most patients (47.36%) were between 26-30 years age group, presented with gestational age between 36-40 weeks (70.17%), were mostly G2-4, while frequency of placenta Previa in non-scarred uterus was 32.45% (37 cases), and frequency in previously scarred uterus was 67.54% (77 cases). Major degree Previa was found in 88 cases (77.19%). There were 5.70% cases of placenta Previa from non-scarred uteruses and 10.67% cases of placenta Previa (10.67%) from already scarred uteruses. Stratification revealed a higher trend of the morbidity with the increase in number of previous caesarean sections. CONCLUSION: A significantly higher frequency of placenta Previa was found among patients coming to a tertiary care hospital with previously scarred uterus. PMID- 26101492 TI - Investigation on the role of VEGF gene polymorphisms in the risk of osteosarcoma. AB - OBJECTIVE: The VEGF in low oxygen conditions are reported to prolong the survival of malignant cell, and thus this gene has a critical role in tumor growth and invasion as well as development of malignant tumor. We aimed to assess the association between the six common SNPs and the risk of osteosarcoma, and their association with environmental factors. METHODS: 176 subjects with osteosarcoma and 176 gender- and sex-matched healthy control individuals were enrolled into our study. The VEGF -2578C/A, -1156G/A, +1612G/A, +936C/T, -634G/C and -460T/C gene polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay according to manufacturer's instructions. RESULTS: By conditional logistic regression analysis, AA and CA+AA genotypes of VEGF -2578C/A were associated with significant increased risk of osteosarcoma compared with CC genotype, and the ORs(95%CI) were 2.32(1.18-4.60) and 1.68(1.07-2.64), respectively. Moreover, individuals with CC and TC+CC genotypes of VEGF-460T/C had significant increased risk of osteosarcoma compared with those carrying with the TT genotype, and ORs(95%CI) were 2.15(1.10-4.21) and 1.60(1.0-2.58), respectively. By stratified analysis, we did not find statistically significant associated between VEGF -2578C/A and -460T/C gene polymorphisms and cancer risk by stratification analysis. CONCLUSION: Our results suggested that VEGF -2578C/A and -460T/C gene polymorphisms may be association with an increased risk of osteosarcoma. PMID- 26101493 TI - Association of geographical distribution of air quality index and type 2 diabetes mellitus in Isfahan, Iran. AB - OBJECTIVES: Air pollution is a hazardous environmental problem with several adverse health effects including its impact on the development of chronic diseases as diabetes mellitus. This study aimed to investigate the association of geographical distribution of air quality index (AQI) and type 2 diabetes mellitus in an air-polluted city by using geographic information system (GIS). METHODS: This cross-sectional study was conducted in Isfahan, Iran. The records that have been registered from 2009 to 2012 in major referral public diabetes clinics were gathered; they included data of 1467 diabetic patients. Their living area was represented with spots in the city map. AQI data were also interpolated from monitoring stations spreading around the city. The GIS maps of air pollutants and diabetes were developed and the associations were determined. RESULTS: The density of diabetic population was higher in highly polluted areas compared with areas with the lower levels of air pollution. No significant correlation was documented between the distribution of diabetic patients and air pollution level throughout the city. CONCLUSION: Although the density of diabetic patients was higher in areas with higher air pollution, but the lack of association between AQI and the prevalence of diabetes might be because the air of different parts of the city was highly polluted, and we could not compare the prevalence of diabetes in areas with clean and polluted air. PMID- 26101494 TI - Cervical length versus vaginal PH in the second trimester as preterm birth predictor. AB - OBJECTIVE: To evaluate diagnostic value of vaginal pH and cervical length measurement in the second trimester of pregnancy as a preterm labor (PTL) predictor. METHODS: During a prospective cohort study 438 uncomplicated singleton pregnant women between 18 and 24 weeks of gestation were assessed regarding vaginal PH and cervical length. Vaginal pH was measured using Ph-indicator strips and cervical length was determined using transvaginal ultrasound. The cut-off values for vaginal PH and cervical length were defined as 5 and <30 mm respectively. RESULTS: Vaginal pH of 5 and above was found in 162/438 women (37%) while cervical length <30mm was found in 38/438 (8.7%). The incidence of PTL < 37 weeks was 87/438 (19.9%) while the incidence of early (PTL <34 weeks) was 51/438 (11.6%). Predictive value of higher vaginal PH was significantly more (31%) than vaginal PH<5 (13%) in predicting PTL. As a result, alkaline vaginal PH significantly increases the odds of preterm labor (OR=3.06). Shortened cervical length is better predictor of PTL than higher vaginal PH with positive predictive value of 71% and negative predictive value of 85%. Cervical length less than 30 mm nearly 14-fold increases odds of preterm birth (OR=13.9). CONCLUSION: Compared to alkaline vaginal PH, shortened cervical length has better value to predict PTL overall. However, regarding early or late PTL, vaginal PH is more accurate to predict late PTL, while cervical length measurement is more appropriate to predict early PTL (<34 weeks). PMID- 26101495 TI - Level of perioperative B-type natriuretic peptide associates with heart function after on-pump coronary artery bypass graft surgery on a beating heart. AB - OBJECTIVE: To explore the relationship of the perioperative B-type natriuretic peptide (BNP) level with heart function among patients undergoing on-pump coronary artery bypass graft surgery on a beating heart. METHODS: Total 90 patients expected to undergo coronary artery bypass graft surgery were selected and their left ventricular ejection fraction (LVEF) were examined before operation. Patients with LVEF greater than or equal to 50% were selected as the A group (n=46), and those less than 50% formed the B group (n=44). BNP levels of the patients were examined and its relationship with cardiac function was analyzed. RESULTS: BNP levels of group A was lower than that in group B pre-and post-operatively (until 7 days after the surgery), the difference is statistically significant (p<0.05). Pearson analysis showed that the BNP level was negatively correlated with the LVEF (r = 0.767, p< 0.05). The area under the Roc curve is 0.865. CONCLUSION: BNP level was negatively correlated with the LVEF. Perioperative BNP level can be used as the prediction for heart function of patients with on-pump coronary artery bypass graft surgery on a beating heart. PMID- 26101496 TI - Adverse fetomaternal outcome among pregnant overweight women. AB - OBJECTIVE: To compare the adverse fetometernal out come in overweight and normal weight pregnant women. METHODS: This comparative cohort study was conducted from 1(st) October 2010 to 30 September 2012. Total 200 gravid women 100 were overweight and 100 normal weight pregnant women with gestational age for 08-40 weeks were included. Women having BMI (25 - 29.9 Kg/m(2)) were measured overweight and included in group A and 100 women having normal BMI of 18.5 to 24.9 as controls were in-group B. Chi-square test was applied to compare the proportion of maternal and fetal outcomes. Significant P - value of < 0.05 was considered. RESULTS: The age range was between 30 to 45 years with mean age of 30+/-4.1 years in both groups. Overweight pregnant women had significantly high frequency of pre-eclampsia (27% versus 9% in controls), PIH (24% versus 8% in controls), gestational diabetes mellitus (22% versus 5% in controls), prolonged labour (4% versus 6% in controls), Caesarean section (44% versus 16% in controls), Wound infection (3% versus 2% in controls) and Postpartum Hemorrhage (5% versus 2% in controls). P-value < 0.001 was considered significance. Fetal complications in overweight pregnant women compared to controls i.e. Still birth (13% versus 2%), Early neonatal death (11% versus 1%), shoulder dystocia (5% versus 1%) and NICU admission (47% versus 10%). Results were statistically significant except shoulder dystocia. CONCLUSION: We conclude that the result of present study indicates obesity exerts deleterious effect, both on fetal and maternal outcome. PMID- 26101497 TI - Orofacial findings associated with obstructive sleep apnea in a group of Saudi Children. AB - OBJECTIVES: To evaluate orofacial and occlusion findings associated with obstructive sleep apnea (OSA) in a group of Saudi children. METHODS: The sample consisted of 30 OSA patients, and 30 age and gender matched, healthy control. The following facial and occlusal features were evaluated: frontal view, facial profile, mandibular angle, tongue size, dental midline to facial midline, upper to lower dental midline, overjet, overbite, anterior open bite, cross bite, scissors bite, palatal vault, maxillary and mandibular arch crowding and spacing, molar and canine relationship. RESULTS: Participants age ranged from 3 to 8 years. Study group had steeper mandibular angle, deeper palatal vault, and less spaced upper and lower arches. There was no statistically significant difference between the two examined groups regarding facial morphology, facial profile, midline, anterior openbite, tongue size, posterior crossbite, overjet or molar relationship. CONCLUSION: OSA children have a relatively different orofacial morphology compared with control children. OSA subjects had deeper palatal vault, steeper mandibular plane angle and less spaced upper and lower arches compared to control. PMID- 26101498 TI - Depression in Rheumatoid Arthritis and its relation to disease activity. AB - OBJECTIVES: To determine the level of depression in Rheumatoid Arthritis and its relationship with severity of Rheumatoid Arthritis. METHODS: This cross sectional analytical study was conducted from March 2014 to May 2014. Total 102 cases of Rheumatoid Arthritis (RA) diagnosed as per ACR (American College of Rheumatology) 1987 criteria were enrolled from Rheumatology Department, Fatima Memorial Hospital. Severity of Rheumatoid Arthritis was assessed by Health Assessment Questionnaire (HAQ) and disease activity score (DAS - 28) while severity of depression was measured by Beck Depression Inventory (BDI) scale II questionnaire. The relationship between depression and disease activity (severity) of Rheumatoid Arthritis was assessed by calculating correlation coefficient between depression, disease activity score (DAS 28) of Rheumatoid Arthritis and health assessment questionnaire (HAQ). RESULTS: Out of 102 patients, 77(75.5%) were females and 25(24.5%) males. The mean age of patients was 43.5+/- 11.9 years and the mean duration of disease was 7.8 +/- 5.5 years.71.5% of Rheumatoid Arthritis patients were found to have some degree of depression and this was directly related to the severity of disease. Moderate and severe depression were present in 23 (22.5%) and 19(18.6%) patients respectively. CONCLUSION: In this study, almost three-fourths of Rheumatoid Arthritis patients were found to have depression. There was a strong association between Rheumatoid Arthritis disease activity and the level of depression. So it is imperative for clinicians treating Rheumatoid Arthritis patients to screen them for co morbid depression and manage it accordingly. PMID- 26101499 TI - Study on relationships among deep vein thrombosis, homocysteine & related B group vitamins. AB - OBJECTIVES: Hyperhomocysteinemia has been considered as a potential risk factor for deep venous thrombosis (DVT) but it is still controversy. We aimed to evaluate the prevalence of hyperhomocysteinemia in patients with DVT. Our second objective was to document the prevalence of folate, Vitamin B6, and Vitamin B12 level in this patient population. METHODS: Sixty patients with DVT aged from 23 to 84 years, were assessed regarding demographic characteristics, serum levels of homocysteine, folate, vitamin B12, and vitamin B6. The diagnosis of DVT was based upon Wells scoring system and serum D-dimer level and confirmed by deep venous Doppler ultrasonography of the lower limbs. RESULTS: Mean serum homocysteine levels were found significantly higher in patients over the age of 40 years (10.81+/-4.26 umol/L vs 9.13+/-3.23 umol/L). Of all the patients, 9 patients had homocysteine level above the 15umol/L, 26 had folic acid level below 3 ng/ml, one had vitamin B12 level below 150 pmol/L, and two had vitamin B6 level below 30 nmol/L. In the hyperhomocysteinemic group, five patients had low folic acid level, one had low vitamin B12 level, and two had low vitamin B6 level. CONCLUSIONS: Hyperhomocysteinemia, in women older than 40 years, may be a risk factor for DVT. Folic acid deficiency may also influence serum homocysteine concentrations. Folate therapy may be offered to the patients with DVT. However further studies are required to clarify the underlying molecular mechanisms. PMID- 26101500 TI - Seroprevalence rate of Poliovirus antibodies among the Healthy and Protein Energy Malnutrition children. AB - OBJECTIVE: To study the association between Protein energy malnutrition and polio specific immunoglobulin G antibodies production among children in Gadap Town Karachi, Pakistan. METHODS: Comparative cross sectional survey conducted at fixed EPI center and Pediatric OPD of a tertiary care hospital Karachi. Children were selected by convenient sampling method during the period from 17 March to 17 May 2013. It was ensured that they must have received more than seven oral polio vaccine doses as eligibility criteria for the study. A total of 170 blood samples were collected and tested for the presence of polio-specific IgG antibodies using Poliomyelitis IgG ELISA Test Kit produced. RESULTS: Statistically significant relation was found between PEM and IgG antibodies production OR (P = 0.000). Overall Seroprevalence rate among the study population was 98.8%, PEM group 97.6% and healthy group 100%. CONCLUSION: The study demonstrated that there is a need to focus on the protein energy malnutrition among the children as an immunization strategy for the 100% seroprevalence rate in all population against polio in Pakistan. PMID- 26101501 TI - Postnatal depression among women availing maternal health services in a rural hospital in South India. AB - BACKGROUND AND OBJECTIVE: Postnatal depression, with an estimated prevalence of 13-19%, causes significant impairment of mental health among women worldwide and has long term consequences. However, more than half of all cases are not detected by healthcare providers. Screening for postnatal depression has not been given importance in maternal health programs in India. Our objective was to screen for postnatal depression among women attending a rural hospital in India, immediately postpartum and at 6-8 weeks post-delivery, and to study associated factors. METHODS: A cross sectional study was done on 123 postnatal women attending a rural maternity hospital in Karnataka, South India, of whom 74 women were interviewed within one week of childbirth, and 49 women at 6-8 weeks post delivery. The Edinburgh Postnatal Depression Scale was used to screen for postnatal depression. RESULTS: About 45.5% of the women screened positive for postnatal depression (44.6% of all subjects within one week of delivery and 46.9% at 6-8 weeks after delivery). Postnatal depression was significantly associated with mood swings during antenatal period, staying with the family of birth during pregnancy and away from their husbands, and was significantly higher among women who perceived their life as stressful and having a low self-esteem (P<0.05). CONCLUSIONS: This study found a high prevalence of postnatal depression in women in rural Karnataka. This underlines the need for incorporating screening for postnatal depression in the routine care of women during pregnancy and delivery. PMID- 26101502 TI - Environmental, urinary iodine status and prevalence of goitre among schoolchildren in a high altitude area of Saudi Arabia. AB - OBJECTIVE: This study aimed to assess the iodine deficiency, prevalence of goitre among schoolchildren and measuring environmental iodine in Taif city, Saudi Arabia. METHODS: A cross-sectional multistage cluster-sampling methodology was done on 1887 schoolchildren. Their urinary iodine concentration (UIC) and goitre prevalence was assessed. Blood level of triiodothyronin, thyroxine and thyroid stimulating-hormone was carried out for students with normal, mild; moderate and sever iodine deficiency. The iodine content of salt, water and soil was also assessed. RESULTS: Goitre prevalence was 7.4% and about 71% of the participants had UIC less than 100MUg/L. An inverse relationship between median UIC and the percent prevalence of goitre was found. The mean serum T3, T4 and TSH were 1.05ng/dL, 6.81ug/dL, and 5.69mIU/L, respectively. A significant positive correlation was found between the mean value of urinary iodine and the mean value of both T3 and T4. While a significant negative correlation between the mean value of urinary iodine and the mean value of TSH was also noted. CONCLUSIONS: The results revealed the presence of a potential public health problem of iodine deficiency among school going children in high altitude areas of Saudi Arabia. There is a need to monitor and evaluate the salt iodization process, and distribute adequately iodized salt in the affected areas. PMID- 26101504 TI - Evaluation of root canal morphology of maxillary molars using cone beam computed tomography. AB - OBJECTIVES: The success of endodontic treatment is based on cleaning and shaping of the root canals. The root canals have complex morphology and wide individual variations. The objective of this study was to analyze root canals morphology and existence of extra canals in maxillary molars in Saudi subpopulation. METHODS: Freshly extracted maxillary first molars (n=100) were included in this study. All teeth were examined for morphology of roots, root canals and apical foramen by Cone Beam Computed Tomography (CBCT). The root canals configuration was classified using Vertucci's classification. RESULTS: The majority of maxillary first molars (94%) were having three distinctly separated roots and 6% had four roots. Palatal and distobuccal roots were observed to contain one root canal (100%) and Vertucci's type I configuration. The mesiobuccal root had one (29.4%; type I) or two canals (70.6%; type II, III or IV). CONCLUSIONS: The occurrence of second canal in the mesiobuccal root of upper first molar is very much likely (>70%). The mesiobuccal roots are more likely to have Vertucci's type I or II configuration (>76%). The palatal and distobuccal roots always have a Vertucci's type I canal configuration. PMID- 26101503 TI - Comparison of primary coronary percutaneous coronary intervention between Diabetic Men and Women with acute myocardial infarction. AB - OBJECTIVE: This study aimed to explore the short-term efficacy and safety of primary percutaneous coronary intervention (PCI) in female diabetic patients complicated with acute myocardial infarction (AMI). METHODS: A total of 169 diabetic patients with AMI who underwent primary PCI were selected and divided into group A (52 females) and group B (117 males). The clinical data, characteristics of coronary artery lesions, lengths of hospital stay, and incidences of complications were then compared between two groups. RESULTS: The average age, history of hyperlipidemia, double branch lesions, triple branch lesions, and left main lesions were significantly higher in group A than in group B (P < 0.05). Smoking history, PCI history, and pre-infarction angina were distinctly lower in group A than in group B (P < 0.05). Thrombolysis in myocardial infarction 3 (TIMI3) flow and TIMI myocardial perfusion grade 3 (TMPG3) after PCI were markedly lower in group A than in group B (P < 0.001). Group A had a higher incidence of complications, such as severe arrhythmia, cardiac function Killip III/IV, cardiogenic shock, major, moderate and mild bleed event, as well as a 30-day mortality rate, compared with group B (P < 0.05). CONCLUSION: In summary, our study demonstrated that female diabetic patients with AMI had lower TIMI3 flow and TMPG3 following PCI than male patients, while there was higher incidence of complications and 30-day mortality rate. Therefore, more attention should be paid to the therapy of diabetic women with acute myocardial infarction as well as the control of risk factors. PMID- 26101505 TI - Diagnostic dilemmas in Intraductal papillomas of the breast - Experience at Sultan Qaboos University Hospital in the Sultanate of Oman. AB - OBJECTIVES: The aim of this retrospective study was to correlate the significance and accuracy of the colour of nipple discharge and breast ultrasound imaging in the diagnosis of intraductal papilloma. METHODS: This is a retrospective study of 34 patients who underwent 36 microdochectomies in Sultan Qaboos University Hospital (SQUH) in the Sultanate of Oman, over a 4 year period of January 2009 till December 2012. The confounders considered were patient age, physical examination findings, nipple discharge cytology result, ultrasound results and biopsy report following microdochectomy. Comparisons analysis, charts and graphs were made using the SPSS software (version 20). RESULTS: The mean age of the patients was 44(27-73) years old. Twenty-seven out 36 (75%) patients had presented with nipple discharge, 14 out 27 (52%) had blood stained nipple discharge and 13(48%) with coloured discharge (yellow, brown and green), 9 patients had no discharge. The final histopathology showed intraductal papilloma 13 (36%), duct ectasia 18(50%), DCIS 1 (2.7%), fibrocystic disease 3(8.3%) and LCIS 1(2.7%). Thirteen out of 36 had intraductal papilloma on final histopathology. The correlation between blood stained discharge and final histopathology of intraductal papilloma was insignificant (p=0.44). CONCLUSION: Nipple discharge is irrelevant to the diagnosis of intraductal papilloma. Spontaneous nipple discharge regardless of color is to be referred to breast surgeon and to be assessed with triple assessment. Surgery remains the mainstay of treatment. PMID- 26101506 TI - How frequently external ventricular drainage device should be changed in children with ventriculoperitonel shunt infection? AB - OBJECTIVE: The purpose of the presenting study was to determine how frequently external ventricular drainage (EVD) device should be changed in children with ventriculopertienal shunt (VPS) infection during prolonged intravenous antimicrobial therapy. METHODS: In this retrospective study, 25 children with VPS infection were evaluated between January 2012 and December 2013. In these children VPS was surgically removed and appropriate antimicrobial therapy was administered according to cerebrospinal culture results. Data noted about how frequently EVD device had been changed, the number of cells on direct observation of cerebrospinal fluid (CSF), glucose and protein levels of CSF, and CSF culture results were obtained from patients' records. RESULTS: Total 25 children were included in the study. The median age was three months (1 and 65 months). In 44% of children, Staphylococcus epidermidis was isolated. During treatment period, EVD catheter has changed one to six times. A total of 68 EVD catheters were changed in these patients. When the duration of ventriculostomy catheter and leukocyte count in CSF were evaluated on daily basis, leukocyte count was decreased 5 units per day in children whose catheter remained less than 10 days. However, in children whose catheter remained more than 10 days leukocyte count was decreased 2.21 units per day. CONCLUSIONS: In children with VPS infection, EVD device should be changed at every 10 days for the rapid resolution of the infection. PMID- 26101507 TI - Typhidot - A blessing or a menace. AB - OBJECTIVES: Typhoid remain an increasing problem in Third world countries like Pakistan. A reliable, easy and affordable rapid diagnostic test is a need for our clinicians, many of whom consider Typhidot to be promising. Typhidot has been used as the only tool to diagnose typhoid fever by general practitioners and consultants despite its low sensitivity and specificity causing misdiagnosis and treatment. We therefore conducted this study to evaluate the sensitivity and specificity of Typhidot in patients with fever. METHODS: A retrospective analysis of a total of 145 febrile patients was done. Blood culture and Typhidot along with other relevant investigations had been performed in each case. Sensitivity, specificity and the association of Typhidot to the diagnosis was found using SPSS v16.0. RESULTS: Out of 145 patients, 15(10.3%) had positive blood culture for Salmonella typhi, 7 (4.8%) had positive culture for salmonella paratyphi and 94(64.8%) had positive culture for other organisms. Twenty nine (20%) patients had negative culture results. Forty seven (32.4%) patients had only IgM positive on Typhidot, 7(4.8%) had both IgM and IgG positive and 91(62.8%) had both IgM and IgG negative. Amongst the 130 patients with diseases other than typhoid, 50(38.5%) showed a positive Typhidot result. Amongst the 15 patients with typhoid, 11(73.3%) showed a negative Typhidot result. The sensitivity of Typhidot was found to be 26.7% and the specificity was 61.5%. The Positive Predictive Value (PPV) was 7.4% and the Negative Predictive Value (NPV) was 87.9%. CONCLUSION: Even though Typhidot is rapid, easy and affordable, its use should be discouraged due to low sensitivity and specificity and insignificant (p=0.067) association to the disease. PMID- 26101508 TI - Association of breast arterial calcification and osteoporosis in Turkish women. AB - OBJECTIVE: Breast arterial calcification (BAC), medial calcific sclerosis of small to medium-sized muscular arteries, is a benign finding of mammographic evaluation. Previous studies have shown the relationships between BAC and systemic disorders such as cardiovascular disease, diabetes mellitus and hypertension. The aim of this study was to determine the association between reduced bone mineral density and BAC. METHODS: The study population consisted of 567 women who had both mammography and bone mineral density evaluation. BAC (+) and BAC (-) women were compared for age, body mass index, postmenopausal duration, number of deliveries, breastfeeding duration, DM, HT, lipid treatment, osteopenia, and osteoporosis. RESULTS: BAC was seen in mammographic evaluation of 179 women and 388 subjects without BAC accepted as the control group. There was a statistically significant relationship between age, postmenopausal duration, number of deliveries, history of DM, HT, lipid treatment and BAC. While the prevalence of osteopenia was higher in control group (52.8%), the rate of osteoporosis (48.7%) was higher in group with BAC. CONCLUSION: There was statistically significant relationship between BAC and osteoporosis in postmenopausal women. Determination of BAC in routine screening mammography might be helpful in both identifying women with risk of cardiovascular disease and osteoporosis. PMID- 26101509 TI - Consequences of traffic noise in residents of Karachi, Pakistan. AB - OBJECTIVE: To find out effect of road traffic noise on human beings in busy places of Karachi, working at these places and to compare its results with the previously done studies on this subject. METHODS: This prospective epidemiological study was designed to evaluate effects of Noise induced hearing Loss due to road traffic at different places (Gurumander, Tibet Centre, Marry Weather Tower) of Karachi. A sample of 125 cases were randomly selected who had noise exposure of 90 dB or above of their surroundings for more than 6 months. The study was conducted from October 1(st) 2013 to January 1(st) 2013. RESULTS: The minimum age was 18 years while maximum age was 47 years. The age group found most affected was from 23 years to 27 years. The males were 84% and females 16%. Subjects exposed to noise for more than 12 hours per day were 36.8%. Varying degree of hearing loss was evaluated in subjects where 17.6% were normal, 33.6% had mild hearing loss, 45.6% had moderate and 3.2% had moderately severe hearing loss. Traffic noise was found to bother 55.2% of subjects. CONCLUSION: Analysis of data indicates an enormous increase in noise levels as compared to previous studies. This study establishes that there exists a concrete direct link between NIHL and duration of exposure to noise above permissible levels. Traffic authorities should initiate measures to reduce the noise levels in the city particularly at more noisy places. PMID- 26101510 TI - Analysis of deep venous thrombosis after Gynecological surgery: A clinical study of 498 cases. AB - OBJECTIVES: To find out the clinical characteristics and risk factors for deep venous thrombosis (DVT) after gynecological surgery. METHODS: Four hundred and ninety-eight patients treated surgically in the department of gynecology of our hospital from July 2012 to May 2014 were reviewed retrospectively. The data including patient age, gender, medical history, hospital stay, anesthesia type, operation time, occupation type, operative or postoperative medicine, perioperative bleeding, postoperative activity time, mortality rate and so on, were collected. RESULTS: Among 498 patients, 58 were included in the thrombosis group, 423 patients in the non-thrombosis group and 17 patients were excluded. The incidence of deep venous thrombosis was 11.6%. In 58 cases with deep venous thrombosis, 6 cases developed pulmonary embolism and two patients died, the mortality rate for pulmonary embolism is 33.3%. In multivariate analysis, age, malignant tumor, cardiovascular comorbidity and postoperative hemostatics dose are independent risk factors, physical labour and minimally invasive surgery are protective factors for DVT. CONCLUSION: The patients with elder age, malignant tumor, cardiovascular comorbidity or large postoperative hemostatics dose should be paid high attention to and the minimally invasive surgery are optimal treatment in preventing DVT. PMID- 26101511 TI - Effect of course coordinator behavior and motivation on students' achievement: Results from five curriculum blocks of two undergraduate student cohorts at King Saud bin Abdulaziz University of Health Sciences. AB - OBJECTIVE: The purpose of the study was to assess the relationship between students' perception of course/block coordinators performance and attributes with students' assessment scores in respective courses. METHODS: This retrospective data based study was conducted at the College of Medicine, King Saud bin Abdulaziz University of Health Sciences (KSAU-HS). It was started in March 2013 and completed in June 2013 after the graduation of the fourth cohort. Exam score of 3(rd) and 4(th) cohort of students from the courses taught in the last two years of medical school were correlated with faculty and block evaluation done by the students. Scores from mid-block MCQs, portfolio scores, OSCEs and end-of block MCQs were obtained. RESULTS: The Mean scores of all the assessments for all five blocks were not significantly different for both batches. There was significant difference between block coordinators for students' score on portfolio, midterm exam and the final written exam. The students' Score in OSCE had significantly strong correlation with quality of station monitors, coverage of content and flow between stations. Student's perception of the commitment and motivation of the coordinator was strongly correlated with block organization, availability of clinical cases, performance of block coordinator, cooperation with students, and organization of clinical activities. CONCLUSIONS: Block coordinator's motivation and commitment affects quality of block organization and student's success. Faculty training programs should include block management competencies and components identified through self-determination theory for improving the intrinsic motivation for students success. PMID- 26101512 TI - Glomerular diseases outcome at one year in a tertiary care centre. AB - OBJECTIVES: To determine outcome in primary and secondary glomerular diseases at one year follow up. METHODS: Study design is observational cohort, done in out patient department, Dow Iinternational Medical College, DUHS. All information gathered on a proforma. All patients with dipstick positive proteinuria and clinical glomerular disease were included in study. Patients with no proteinuria were excluded so were patients with stage 5 CKD. Patients were followed for proteinuria and renal insufficiency at completion of one year follow up. Statistical analysis was done on SPSS version 16. RESULT: Total number of patients who completed one year follow up was 173. Mean age of patients was 51.67+ 10.16 (range 15 to 75 years). Ninety two (53.2%), were males and 81(46.8%) were females, ratio being 1.1: 1.0. Mean weight of our patients was 67.43+ 14.13 Kg, (35 to 107 kg). Commonest cause of glomerular disease in our patient was diabetic nephropathy which was seen in 94.2% patients. Commonest associated problem with glomerular disease was hypertension seen in 66.5% of patients. Four out of 173 patients had stage 5 CKD at end of follow up at one year while quantitativ proteinuria remained same at one year follow up. CONCLUSION: One year follow up is critical for patients with glomerular disease associated with stage 4 CKD as progression to end stage renal failure may be seen within one year in these patients. PMID- 26101513 TI - An overview of smoking practices in Pakistan. AB - Smoking remains a major player in morbidity and mortality worldwide. It is a matter of immense public health importance as single leading cause of preventable deaths. The aim of this study was to assess smoking practices that prevail across Pakistan & Attitude of people towards this issue. We conducted an extensive search on major databases as well as search of bibliography of published literature for studies assessing Attitudes and Practices of tobacco smoking that prevail across Pakistan. Data from available studies was abstracted and utilized in preparation of this manuscript. After screening of 613 articles, we were able to identify 22 studies matching our criteria for inclusion. Majority of studies reported adolescence as time of initiation. Average national prevalence was 21.6%. A significant portion of smokers comprised of females. The prevalence of smoking in healthcare professionals ranged from 32 - 37%. Passive smoking was a major contributor of tobacco exposure. Prevalence of 'Shisha' use was 33%. Smoking continues to be a major Public Health issue in Pakistan. The prevalence in healthcare professionals and adolescents is alarming. Adequate measures need to be taken to ensure its control. PMID- 26101514 TI - Steroid-induced ischemic bone necrosis of femoral head: Treatment strategies. AB - Fat hypertrophy, intravascular coagulation, and fat emboli are important risk factors of steroid-induced ischemic bone necrosis (SI-IBN) which may develop during the initial one year after commencing the use of steroids. This pathology is best studied by MRI, particularly for its staging. The cautious strategies such as low dose, oral route, short duration of steroid usage, use of steroid sparing agent, and alcohol avoidance should be followed as a traditional therapy. The objective of this review article was to recognize and evaluate various Treatment strategies for steroid-induced ischemic bone necrosis of femoral head. LITERATURE SEARCH: Various electronic databases including PubMed, Google and Cochrane library were comprehensively searched for articles on steroid-induced ischemic bone necrosis of femoral head and its treatment strategies. Ninety four articles were reviewed, examined and importantly appraised and the most appropriate 32 papers were used to write this review article. CONCLUSION: Bisphosphonates, alendronate, and hyperbaric oxygen (HBO) treatments have been reported to be effective against IBN. To recommend the regular use of bisphosphonate in IBN patients, more evidences with a larger number of patients are required to verify its therapeutic effectiveness. Core decompression, osteotomy, bone graft and tantalum rod are the surgical approaches for the management of IBN. Advance form of IBN (bone tissue collapse) is advised to be treated with arthroplasty which should be durable, particularly in young patients. PMID- 26101515 TI - A rare case of bilateral bronchial foreign body. AB - We present the case of a 7-year-old male patient with bilateral bronchial cocklebur fruit aspiration, which he sustained while playing. The patient presented with a triad of cough, wheezing, and decreased breath sounds (decreased in the right lung and absent in the left). These symptoms led to a diagnosis of bilateral bronchial foreign body, which was confirmed by computed tomography three-dimensional reconstruction of the bronchial tree. The patient was on the verge of death during operation but was ultimately rescued. Our therapeutic experience in treating this case of bilateral bronchial cocklebur fruit aspiration may provide a good reference for others. PMID- 26101516 TI - A rare case of paralysis in an endemic area. AB - Thyrotoxicosis mostly presents with tachycardia, tremor, weight loss and other hypermetabolism signs. However, there are other unusual signs of thyrotoxicosis such as paralysis. This unusual clinical presentation may postpone prompt diagnosis and treatment. In this case report, we present a 27-years-old woman, who presented with quadriparesis at the emergency department. PMID- 26101517 TI - Ebola Virus: The need to take some preventive measures. PMID- 26101518 TI - Use of Corticosteroids in the management of Idiopathic Pulmonary Haemosiderosis: Do we have enough evidence. AB - Idiopathic Pulmonary Haemosiderosis (IPH) is a rare disease commonly affecting the paediatric population with approximately 500 globally reported cases in the literature. The disease usually presentswith a symptom triad consisting of ferropenic anaemia, cough with haemoptysis and diffuse bilateral alveolar infiltrates. Therapeutic options for this disorder are not only limited but also not fully effective. Moreover, corticosteroids remain the mainstay of IPH treatment. This communication reviews the available evidence in support of corticosteriod usage in the treatment of IPH. We conclude that the use of corticosteroid in IPH treatment is unfathomed and demands further investigation. PMID- 26101519 TI - Publication Audit - a useful tool to evaluate progress and plan for the future. PMID- 26101520 TI - Inclusion of Neuropsychological Scores in Atrophy Models Improves Diagnostic Classification of Alzheimer's Disease and Mild Cognitive Impairment. AB - Brain atrophy in mild cognitive impairment (MCI) and Alzheimer's disease (AD) are difficult to demarcate to assess the progression of AD. This study presents a statistical framework on the basis of MRI volumes and neuropsychological scores. A feature selection technique using backward stepwise linear regression together with linear discriminant analysis is designed to classify cognitive normal (CN) subjects, early MCI (EMCI), late MCI (LMCI), and AD subjects in an exhaustive two group classification process. Results show a dominance of the neuropsychological parameters like MMSE and RAVLT. Cortical volumetric measures of the temporal, parietal, and cingulate regions are found to be significant classification factors. Moreover, an asymmetrical distribution of the volumetric measures across hemispheres is seen for CN versus EMCI and EMCI versus AD, showing dominance of the right hemisphere; whereas CN versus LMCI and EMCI versus LMCI show dominance of the left hemisphere. A 2-fold cross-validation showed an average accuracy of 93.9%, 90.8%, and 94.5%, for the CN versus AD, CN versus LMCI, and EMCI versus AD, respectively. The accuracy for groups that are difficult to differentiate like EMCI versus LMCI was 73.6%. With the inclusion of the neuropsychological scores, a significant improvement (24.59%) was obtained over using MRI measures alone. PMID- 26101521 TI - Cumulative Small Effect Genetic Markers and the Risk of Colorectal Cancer in Poland, Estonia, Lithuania, and Latvia. AB - The continued identification of new low-penetrance genetic variants for colorectal cancer (CRC) raises the question of their potential cumulative effect among compound carriers. We focused on 6 SNPs (rs380284, rs4464148, rs4779584, rs4939827, rs6983267, and rs10795668), already described as risk markers, and tested their possible independent and combined contribution to CRC predisposition. Material and Methods. DNA was collected and genotyped from 2330 unselected consecutive CRC cases and controls from Estonia (166 cases and controls), Latvia (81 cases and controls), Lithuania (123 cases and controls), and Poland (795 cases and controls). Results. Beyond individual effects, the analysis revealed statistically significant linear cumulative effects for these 6 markers for all samples except of the Latvian one (corrected P value = 0.018 for the Estonian, corrected P value = 0.0034 for the Lithuanian, and corrected P value = 0.0076 for the Polish sample). Conclusions. The significant linear cumulative effects demonstrated here support the idea of using sets of low-risk markers for delimiting new groups with high-risk of CRC in clinical practice that are not carriers of the usual CRC high-risk markers. PMID- 26101522 TI - Outcomes and Risk Factors Associated with Clostridium difficile Diarrhea in Hospitalized Adult Patients. AB - Background. The epidemiology of Clostridium difficile infection has changed over time. Therefore, it is essential to monitor the characteristics of patients at risk of infection and factors associated with poor prognosis. Objective. To evaluate factors associated with C. difficile infection and with poor prognosis in those with documented C. difficile colitis. Methods. A retrospective case control study of 75 patients with documented C. difficile colitis and 75 controls with hospital-acquired diarrhea of other causes. Stepwise multiple logistic regression was used to identify factors associated with C. difficile infection among patients with hospital-acquired diarrhea. Results. Previous antibiotic treatment (odds ratio (OR), 13.3; 95% confidence interval (CI), 1.40-126.90), abdominal distension (OR, 3.85; 95% CI, 1.35-10.98), and fecal leukocytes (OR, 8.79; 95% CI, 1.41-54.61) are considered as predictors of C. difficile colitis; anorexia was negatively associated with C. difficile infection (OR, 0.15; 95% CI, 0.03-0.66). Enteral tube feeding was independently associated with a composite outcome that included in-hospital mortality, intensive care unit admission, and treatment failure (OR, 3.75; 95%CI, 1.24-11.29). Conclusions. Previous antibiotic use and presence of fecal leukocytes in patients with hospital-acquired diarrhea are associated with C. difficile colitis and enteral tube support with complications associated with C. difficile colitis. PMID- 26101523 TI - Technical Feasibility of TachoSil Application on Esophageal Anastomoses. AB - Purpose. Sealing esophageal anastomoses with a sealant patch (TachoSil) containing human fibrinogen and thrombin may improve mechanical strength. The aim was to evaluate the technical feasibility of the application of a sealant patch in upper gastrointestinal surgery. Methods. In total 15 patients, 18-80 years old, undergoing thoracolaparoscopic esophagectomy with esophagogastrostomy or laparoscopic total gastrectomy with esophagojejunostomy was included. Different techniques of anastomotic TachoSil patch application were tested and recorded on video. Results. TachoSil was successfully applied to the esophagogastrostomy (n = 11) and to the esophagojejunostomy (n = 4). A median of 2 (1-6) attempts was necessary to reach successful application. The median duration was 7 (3-26) minutes before successful application was accomplished. The best technique in esophagectomy was the application of TachoSil with the use of 2 cellophane sheets. For total gastrectomy, the patch was folded into a harmonica shape and wrapped around the esophagojejunostomy. Although not significant, the number of attempts and time to success showed a decreasing trend along with the increased experience. Conclusion. Application of TachoSil as a sealant of esophageal anastomoses was technically feasible. Future studies may investigate the value of TachoSil application on the prevention of anastomotic leakage. PMID- 26101524 TI - Adjuvant Chemoradiation Therapy in Gastric Cancer: Critically Reviewing the Past and Visualizing the Next Step Forward. AB - Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches. PMID- 26101525 TI - Studying and Incorporating Efficiency into Gastrointestinal Endoscopy Centers. AB - Efficiency is defined as the use of resources in such a way as to maximize the production of goods and services. Improving efficiency has been the focus of management in many industries; however, it has not been until recently that incorporating efficiency models into healthcare has occurred. In particular, the study and development of improvement projects aimed at enhancing efficiency in GI have been growing rapidly in recent years. This focus on improving efficiency in GI has been spurred by the dramatic rise in the demand for endoscopic procedures as well as the rising number of insured patients requiring GI care coupled at the same time with limited resources in terms of staffing and space in endoscopy centers. This paper will critically review the history of efficiency in endoscopy centers, first by looking at other healthcare industries that have extensively studied and improved efficiency in their fields, examine a number of proposed efficiency metrics and benchmarks in endoscopy centers, and finally discuss opportunities where endoscopy centers could improve their efficiency. PMID- 26101526 TI - Intoxication by Cyanide in Pregnant Sows: Prenatal and Postnatal Evaluation. AB - Cyanide is a ubiquitous chemical in the environment and has been associated with many intoxication episodes; however, little is known about its potentially toxic effects on development. The aim of this study was to evaluate the effects of maternal exposure to potassium cyanide (KCN) during pregnancy on both sows and their offspring. Twenty-four pregnant sows were allocated into four groups that orally received different doses of KCN (0.0, 2.0, 4.0, and 6.0 mg/kg of body weight) from day 21 of pregnancy to term. The KCN-treated sows showed histological lesions in the CNS, thyroid follicle enlargement, thyroid epithelial thickening, colloid reabsorption changes, and vacuolar degeneration of the renal tubular epithelium. Sows treated with 4.0 mg/kg KCN showed an increase in the number of dead piglets at birth. Weaned piglets from all KCN-treated groups showed histological lesions in the thyroid glands with features similar to those found in their mothers. The exposure of pregnant sows to cyanide thus caused toxic effects in both mothers and piglets. We suggest that swine can serve as a useful animal model to assess the neurological, goitrogenic, and reproductive effects of cyanide toxicosis. PMID- 26101527 TI - Diabetes Mellitus 2014. PMID- 26101529 TI - Satellite Cells CD44 Positive Drive Muscle Regeneration in Osteoarthritis Patients. AB - Age-related bone diseases, such as osteoarthritis and osteoporosis, are strongly associated with sarcopenia and muscle fiber atrophy. In this study, we analyzed muscle biopsies in order to demonstrate that, in osteoarthritis patients, both osteophytes formation and regenerative properties of muscle stem cells are related to the same factors. In particular, thanks to immunohistochemistry, transmission electron microscopy, and immunogold labeling we investigated the role of BMP-2 in muscle stem cells activity. In patients with osteoarthritis both immunohistochemistry and transmission electron microscopy allowed us to note a higher number of CD44 positive satellite muscle cells forming syncytium. Moreover, the perinuclear and cytoplasmic expression of BMP-2 assessed by in situ molecular characterization of satellite cells syncytia suggest a very strict correlation between BMP-2 expression and muscle regeneration capability. Summing up, the higher BMP-2 expression in osteoarthritic patients could explain the increased bone mineral density as well as decreased muscle atrophy in osteoarthrosic patients. In conclusion, our results suggest that the control of physiological BMP-2 balance between bone and muscle tissues may be considered as a potential pharmacological target in bone-muscle related pathology. PMID- 26101528 TI - The Clinical Status of Stem Cell Therapy for Ischemic Cardiomyopathy. AB - Ischemic cardiomyopathy (ICM) is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ICM. Several stem cell types including cardiac-derived stem cells (CSCs), bone marrow-derived stem cells, mesenchymal stem cells (MSCs), skeletal myoblasts (SMs), and CD34(+) and CD 133(+) stem cells have been applied in clinical researches. The clinical effect produced by stem cell administration in ICM mainly depends on the transdifferentiation and paracrine effect. One important issue is that low survival and residential rate of transferred stem cells in the infracted myocardium blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ICM mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical condition, the particular microenvironment onto which the cells are delivered, and clinical condition remain to be addressed. Here we provide an overview of the pros and cons of these transferred cells and discuss the current state of their therapeutic potential. We believe that stem cell translation will be an ideal option for patients following ischemic heart disease in the future. PMID- 26101530 TI - Increased Body Mass Index during Therapy for Childhood Acute Lymphoblastic Leukemia: A Significant and Underestimated Complication. AB - Objective & Design. We undertook a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL) and treated with modern COG protocols (n = 80) to determine longitudinal changes in body mass index (BMI) and the prevalence of obesity compared with a healthy reference population. Results. At diagnosis, the majority of patients (77.5%) were in the healthy weight category. During treatment, increases in BMI z-scores were greater for females than males; the prevalence of obesity increased from 10.3% to 44.8% (P < 0.004) for females but remained relatively unchanged for males (9.8% to 13.7%, P = 0.7). Longitudinal analysis using linear mixed-effects identified associations between BMI z-scores and time-dependent interactions with sex (P = 0.0005), disease risk (P < 0.0001), age (P = 0.0001), and BMI z-score (P < 0.0001) at diagnosis and total dose of steroid during maintenance (P = 0.01). Predicted mean BMI z-scores at the end of therapy were greater for females with standard risk ALL irrespective of age at diagnosis and for males younger than 4 years of age at diagnosis with standard risk ALL. Conclusion. Females treated on standard risk protocols and younger males may be at greatest risk of becoming obese during treatment for ALL. These subgroups may benefit from intervention strategies to manage BMI during treatment for ALL. PMID- 26101531 TI - Thymoquinone Protects against Myocardial Ischemic Injury by Mitigating Oxidative Stress and Inflammation. AB - The present study was aimed at investigating the cardioprotective activity of thymoquinone (TMQ), an active principle of the herb, Nigella sativa, which is used for the management of various diseases. The present study examined the cardioprotective effect of TMQ in isoproterenol- (ISP-) induced myocardial infarction in rats. Myocardial infarction was induced by two subcutaneous injections of ISP (85 mg/kg) at an interval of 24 hr. TMQ (20 mg/kg) was administered orally for 21 days. ISP-treated rats showed depletion of antioxidants and marker enzymes from myocardium along with lipid peroxidation and enhanced levels of proinflammatory cytokines. ISP also induced histopathological alterations in myocardium. Treatment with TMQ prevented the depletion of endogenous antioxidants and myocyte injury marker enzymes and inhibited lipid peroxidation as well as reducing the levels of proinflammatory cytokines. TMQ pretreatment also reduced myonecrosis, edema, and infiltration of inflammatory cells and showed preservation of cardiomyocytes histoarchitecture. The present study results demonstrate that TMQ exerts cardioprotective effect by mitigating oxidative stress, augmenting endogenous antioxidants, and maintaining structural integrity. The results of the present study indicate that TMQ may serve as an excellent agent alone or as adjuvant to prevent the onset and progression of myocardial injury. PMID- 26101532 TI - In Vitro Antibacterial, Antifungal, Antibiofilm, Antioxidant, and Anticancer Properties of Isosteviol Isolated from Endangered Medicinal Plant Pittosporum tetraspermum. AB - This study aimed to investigate the in vitro antibacterial, antifungal, antibiofilm, antioxidant, and anticancer properties of isosteviol isolated from endangered medicinal plant Pittosporum tetraspermum. Pure compound was obtained and characterized by column chromatography followed by (1)H NMR, (13)C NMR, IR, and mass spectral analysis. The antimicrobial activities of the compound were assessed by the broth microdilution method and the antioxidant properties were determined using reducing ability assay, DPPH scavenging assay, hydroxyl radical scavenging activity, and superoxide radical scavenging assay. Anticancer study was evaluated by following MTT assay. Column purification and spectrocopical analysis lead to identifying isosteviol from the crude ethyl acetate extract. The compound exhibited significant activity against bacteria such as Staphylococcus epidermidis (125 ug/mL), Staphylococcus aureus (125 ug/mL), and Klebsiella pneumoniae (62.5 ug/mL). The MIC of the compound against Candida albicans, Aspergillus niger, and Trichophyton mentagrophytes was 62.5, 125, and 500 ug/mL, respectively. The compound showed comparatively better antibiofilm activity against E. coli, S. typhi, and P. aeruginosa. Furthermore, it exhibited good antioxidant properties. Anticancer properties of the compound against Vero and MCF7 cell lines were its advantage. Novel isosteviol would be useful to reduce the infectious diseases caused by pathogenic microorganisms or slow the progress of various oxidative stress-related diseases. PMID- 26101533 TI - Effects of a Dietary Supplement with Barley Sprout Extract on Blood Cholesterol Metabolism. AB - Objective. Barley sprout (Hordeum vulgare L.) contains 4.97% fat, 52.6% polysaccharide, and 34.1% protein along with a variety of vitamins, minerals, and polyphenolic compounds. Hexacosanol is one such compound from the barley leaf that might improve cholesterol metabolism by decreasing cholesterol synthesis. Method. Therefore, this study was conducted to investigate the effects of barley sprout extract on serum lipid metabolism in healthy volunteers (n = 51). Subjects were randomly divided into two groups: one group consumed a single capsule of barley leaf extract daily (n = 25, 42.48 +/- 13.58 years) and the other consumed placebo capsules (n = 26, 40.54 +/- 11.1 years) for 12 weeks. Results. After 12 weeks, total cholesterol and low-density lipoprotein- (LDL-) cholesterol were not lower in the barley sprout extract group compared to the placebo group (p = 0.415 and p = 0.351, resp.) and no differences in clinical or laboratory findings were observed between both groups. Conclusion. Our study failed to show significant lipid-lowering effects of barley sprout extract, possibly due to dosage, duration of therapy, and small sample size. Despite our nonsignificant findings, barley sprout has a possibility as a functional health food; therefore future research is needed. PMID- 26101534 TI - Partially Automated Method for Localizing Standardized Acupuncture Points on the Heads of Digital Human Models. AB - Having modernized imaging tools for precise positioning of acupuncture points over the human body where the traditional therapeutic method is applied is essential. For that reason, we suggest a more systematic positioning method that uses X-ray computer tomographic images to precisely position acupoints. Digital Korean human data were obtained to construct three-dimensional head-skin and skull surface models of six individuals. Depending on the method used to pinpoint the positions of the acupoints, every acupoint was classified into one of three types: anatomical points, proportional points, and morphological points. A computational algorithm and procedure were developed for partial automation of the positioning. The anatomical points were selected by using the structural characteristics of the skin surface and skull. The proportional points were calculated from the positions of the anatomical points. The morphological points were also calculated by using some control points related to the connections between the source and the target models. All the acupoints on the heads of the six individual were displayed on three-dimensional computer graphical image models. This method may be helpful for developing more accurate experimental designs and for providing more quantitative volumetric methods for performing analyses in acupuncture-related research. PMID- 26101535 TI - Herbal SGR Formula Prevents Acute Ethanol-Induced Liver Steatosis via Inhibition of Lipogenesis and Enhancement Fatty Acid Oxidation in Mice. AB - Our previous study indicated that herbal SGR formula partially attenuates ethanol induced fatty liver, but the underlying mechanisms remain unclear. In the present study, mice were pretreated with SGR (100 and 200 mg/kg/d bw) for 30 d before being exposed to ethanol (4.8 g/kg bw). The biochemical indices and histopathological changes were examined to evaluate the protective effects and to explore potential mechanisms by investigating the adiponectin, tumor necrosis factor-alpha (TNF-alpha), peroxisome proliferators-activated receptor-alpha (PPAR alpha), sterol regulatory element binding protein-1c (SREBP-1c), adenosine monophosphate-activated protein kinase (AMPK), and so forth. Results showed that SGR pretreatment markedly inhibited acute ethanol-induced liver steatosis, significantly reduced serum and hepatic triglyceride (TG) level, and improved classic histopathological changes. SGR suppressed the protein expression of hepatic SREBP-1c and TNF-alpha and increased adiponectin, PPAR-alpha, and AMPK phosphorylation in the liver. Meanwhile, acute toxicity tests showed that no death or toxic side effects within 14 days were observed upon oral administration of the extracts at a dose of 16 g/kg body wt. These results demonstrate that SGR could protect against acute alcohol-induced liver steatosis without any toxic side effects. Therefore, our studies provide novel molecular insights into the hepatoprotective effect of SGR formula, which may be exploited as a therapeutic agent for ethanol-induced hepatosteatosis. PMID- 26101536 TI - A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Duliang Soft Capsule in Patients with Chronic Daily Headache. AB - Objective. To investigate the efficacy and safety of traditional Chinese medicine Duliang soft capsule (DSC) in prophylactic treatment for patients with chronic daily headache (CDH). Methods. A multicenter, double-blind, randomized, placebo controlled clinical study was conducted at 18 Chinese clinical centers. The participants received either DSC or placebo for 4 weeks. The primary efficacy measure was headache-free rate (HFR) in a 4-week period between the pretreatment and posttreatment stages. The secondary efficacy measures were the decrease of headache days, the duration of headache attacks, the frequency of analgesic usage, quality of life, disability, and the headache severity (VAS scores). The accompanying symptoms and adverse events were also assessed. Results. Of 584 CDH patients assessed, 468 eligible patients were randomized. 338 patients received DSC, while 111 patients were assigned in the placebo group. Following treatment, there was a 16.56% difference in HFR favoring DSC over placebo (P < 0.01). Significant differences were also observed between DSC and placebo groups in the secondary measures. However, no statistical difference was found between the two groups in the associated symptoms. No severe adverse effects were observed in the study. Conclusions. DSC might be an effective and well-tolerated option for the prophylactic treatment of patients with CDH. PMID- 26101537 TI - The Effect of Channa striatus (Haruan) Extract on Pain and Wound Healing of Post Lower Segment Caesarean Section Women. AB - Channa striatus has been consumed for decades as a remedy to promote wound healing by women during postpartum period. The objectives of this study were to compare postoperative pain, wound healing based on wound evaluation scale (WES), wound cosmetic appearance based on visual analogue scale (VAS) scores and patient satisfaction score (PSS), and safety profiles between C. striatus group and placebo group after six weeks of lower segment caesarean section (LSCS) delivery. A randomised, double-blind, placebo-controlled study was conducted. Subjects were randomised in a ratio of 1 : 1 into either the C. striatus group (500 mg daily) or placebo group (500 mg of maltodextrin daily). 76 subjects were successfully randomised, with 38 in the C. striatus group and 35 in the placebo group. There were no significant differences in postoperative pain (p = 0.814) and WES (p = 0.160) between the C. striatus and placebo groups. However, VAS and PSS in the C. striatus group were significantly better compared with the placebo group (p = 0.014 and p < 0.001, resp.). The safety profiles showed no significant differences between the groups. In conclusion, six-week supplementation of 500 mg of C. striatus extract showed marked differences in wound cosmetic appearance and patient's satisfaction and is safe for human consumption. PMID- 26101538 TI - The Hepatoprotective Effect of Haoqin Qingdan Decoction against Liver Injury Induced by a Chemotherapeutic Drug Cyclophosphamide. AB - Haoqin Qingdan decoction (HQQD), a modern Chinese formula, has been widely used in Eastern Asia. Our study focuses on the hepatoprotective effect of HQQD against cyclophosphamide-induced hepatotoxicity. S180, a kind of ascites tumor cells, was used to establish S180-bearing mice, followed by the injection of cyclophosphamide (CP, 80 mg/kg) every other day for 5 times. HQQD was used intragastrically at the dose of 80 g/kg, 40 g/kg, and 20 g/kg twice a day for 12 days. HL-7702 hepatic cell line was incubated with HQQD-medicated serum. Then we detected the effects of HQQD on (i) tumor suppression; (ii) morphological examination; (iii) SOD, MDA, GSH, ALT, and AST; (iv) cleaved caspase-3 expression and (v) cellular viability. CP caused dramatic elevations of AST, ALT, and MDA, while HQQD notably attenuated these elevations. SOD and GSH were notably increased, which were efficiently attenuated by HQQD. CP injection significantly increased apoptosis by increasing cleaved caspase-3 expression, which was obviously inhibited by HQQD, accompanied by the improvement of cells viability. Histopathological examinations supported the above findings. Therefore, HQQD may protect liver tissue through attenuating oxidative stress and the caspase-3 dependent intrinsic apoptosis induced by CP, which suggests the potentially therapeutic effect of HQQD in the use of alkylating agent for cancer chemotherapy. PMID- 26101539 TI - Systems Pharmacology Dissecting Holistic Medicine for Treatment of Complex Diseases: An Example Using Cardiocerebrovascular Diseases Treated by TCM. AB - Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future. PMID- 26101540 TI - Correlation between CD117+ myeloma plasma cells and hematopoietic progenitor cells in different categories of patients. AB - BACKGROUND: Multiple myeloma (MM) is a neoplastic disorder of plasma cells interesting mainly the elderly. MM remains an incurable disease, mostly because of the strong interplay between clonal plasma cells (cPCs) and bone marrow (BM) microenvironment. Multiparameter flow cytometry (MFC) allows the simultaneous study of the cPC immunophenotype and alterations involving other cells in BM, but rarely these data are interpreted as connected. One exception to this habit are previous studies about relationship between CD117 cPC positivity and hematopoietic progenitor cell (HPC) distribution in newly diagnosed patients. Thus we were interested in verifying the distribution of BM CD34+ HPCs in healthy controls, and monoclonal gammopathy of undetermined significance (MGUS) patients and various categories of responding/relapsing MM subjects divided according to CD117 positivity. RESULTS: Our data completely agree with precedent reports as regards untreated patients. In the group with progression of disease, CD117- patients exhibited a lower CD34 + CD19-/CD34 + CD19+ ratio vs CD117+ subjects. Among CD117- cases, newly diagnosed patients exhibited differences in distribution of HPCs vs responding myeloma subjects and patients with progressive disease. These differences reached statistical significance comparing CD117- newly diagnosed with CD117- responding cases, as reflected by CD34 + CD19-/CD34 + CD19+ ratio. In turn, no differences emerged comparing CD117+ treated and untreated patients. CONCLUSIONS: We demonstrate that administration of treatment and depth of reached response/presence of relapse imply a distinct regulation in distribution of CD34+ HPC subsets in CD117- and CD117+ patients. These differences become evident comparing untreated and treated CD117- patients, but they are impossible to detect in CD117+ cases. PMID- 26101542 TI - Inducing Herd Immunity against Seasonal Influenza in Long-Term Care Facilities through Employee Vaccination Coverage: A Transmission Dynamics Model. AB - INTRODUCTION: Vaccinating healthcare workers (HCWs) in long-term care facilities (LTCFs) may effectively induce herd immunity and protect residents against influenza-related morbidity and mortality. We used influenza surveillance data from all LTCFs in New Mexico to validate a transmission dynamics model developed to investigate herd immunity induction. MATERIAL AND METHODS: We adjusted a previously published transmission dynamics model and used surveillance data from an active system among 76 LTCFs in New Mexico during 2006-2007 for model validation. We used a deterministic compartmental model with a stochastic component for transmission between residents and HCWs in each facility in order to simulate the random variation expected in such populations. RESULTS: When outbreaks were defined as a dichotomous variable, our model predicted that herd immunity could be induced. When defined as an attack rate, the model demonstrated a curvilinear trend, but insufficiently strong to induce herd immunity. The model was sensitive to changes in the contact parameter beta but was robust to changes in the visitor contact probability. CONCLUSIONS: These results further elucidate previous studies' findings that herd immunity may not be induced by vaccinating HCWs in LTCFs; however, increased influenza vaccination coverage among HCWs reduces the probability of influenza infection among residents. PMID- 26101541 TI - Sumo and the cellular stress response. AB - The ubiquitin family member Sumo has important functions in many cellular processes including DNA repair, transcription and cell division. Numerous studies have shown that Sumo is essential for maintaining cell homeostasis when the cell encounters endogenous or environmental stress, such as osmotic stress, hypoxia, heat shock, genotoxic stress, and nutrient stress. Regulation of transcription is a key component of the Sumo stress response, and multiple mechanisms have been described by which Sumo can regulate transcription. Although many individual substrates have been described that are sumoylated during the Sumo stress response, an emerging concept is modification of entire complexes or pathways by Sumo. This review focuses on the function and regulation of Sumo during the stress response. PMID- 26101543 TI - Inside of the Linear Relation between Dependent and Independent Variables. AB - Simple and multiple linear regression analyses are statistical methods used to investigate the link between activity/property of active compounds and the structural chemical features. One assumption of the linear regression is that the errors follow a normal distribution. This paper introduced a new approach to solving the simple linear regression in which no assumptions about the distribution of the errors are made. The proposed approach maximizes the probability of observing the event according to the random error. The use of the proposed approach is illustrated in ten classes of compounds with different activities or properties. The proposed method proved reliable and was showed to fit properly the observed data compared to the convenient approach of normal distribution of the errors. PMID- 26101544 TI - From Heuristic to Mathematical Modeling of Drugs Dissolution Profiles: Application of Artificial Neural Networks and Genetic Programming. AB - The purpose of this work was to develop a mathematical model of the drug dissolution (Q) from the solid lipid extrudates based on the empirical approach. Artificial neural networks (ANNs) and genetic programming (GP) tools were used. Sensitivity analysis of ANNs provided reduction of the original input vector. GP allowed creation of the mathematical equation in two major approaches: (1) direct modeling of Q versus extrudate diameter (d) and the time variable (t) and (2) indirect modeling through Weibull equation. ANNs provided also information about minimum achievable generalization error and the way to enhance the original dataset used for adjustment of the equations' parameters. Two inputs were found important for the drug dissolution: d and t. The extrudates length (L) was found not important. Both GP modeling approaches allowed creation of relatively simple equations with their predictive performance comparable to the ANNs (root mean squared error (RMSE) from 2.19 to 2.33). The direct mode of GP modeling of Q versus d and t resulted in the most robust model. The idea of how to combine ANNs and GP in order to escape ANNs' black-box drawback without losing their superior predictive performance was demonstrated. Open Source software was used to deliver the state-of-the-art models and modeling strategies. PMID- 26101545 TI - Optimized inorganic carbon regime for enhanced growth and lipid accumulation in Chlorella vulgaris. AB - BACKGROUND: Large-scale algal biofuel production has been limited, among other factors, by the availability of inorganic carbon in the culture medium at concentrations higher than achievable with atmospheric CO2. Life cycle analyses have concluded that costs associated with supplying CO2 to algal cultures are significant contributors to the overall energy consumption. RESULTS: A two-phase optimal growth and lipid accumulation scenario is presented, which (1) enhances the growth rate and (2) the triacylglyceride (TAG) accumulation rate in the oleaginous Chlorophyte Chlorella vulgaris strain UTEX 395, by growing the organism in the presence of low concentrations of NaHCO3 (5 mM) and controlling the pH of the system with a periodic gas sparge of 5 % CO2 (v/v). Once cultures reached the desired cell densities, which can be "fine-tuned" based on initial nutrient concentrations, cultures were switched to a lipid accumulation metabolism through the addition of 50 mM NaHCO3. This two-phase approach increased the specific growth rate of C. vulgaris by 69 % compared to cultures sparged continuously with 5 % CO2 (v/v); further, biomass productivity (g L(-1) day(-1)) was increased by 27 %. Total biodiesel potential [assessed as total fatty acid methyl ester (FAME) produced] was increased from 53.3 to 61 % (FAME biomass(-1)) under the optimized conditions; biodiesel productivity (g FAME L(-1) day(-1)) was increased by 7.7 %. A bicarbonate salt screen revealed that American Chemical Society (ACS) and industrial grade NaHCO3 induced the highest TAG accumulation (% w/w), whereas Na2CO3 did not induce significant TAG accumulation. NH4HCO3 had a negative effect on cell health presumably due to ammonia toxicity. The raw, unrefined form of trona, NaHCO3?Na2CO3 (sodium sesquicarbonate) induced TAG accumulation, albeit to a slightly lower extent than the more refined forms of sodium bicarbonate. CONCLUSIONS: The strategic addition of sodium bicarbonate was found to enhance growth and lipid accumulation rates in cultures of C. vulgaris, when compared to traditional culturing strategies, which rely on continuously sparging algal cultures with elevated concentrations of CO2(g). This work presents a two-phased, improved photoautotrophic growth and lipid accumulation approach, which may result in an overall increase in algal biofuel productivity. PMID- 26101546 TI - Precipitate obtained following membrane separation of hydrothermally pretreated rice straw liquid revealed by 2D NMR to have high lignin content. AB - BACKGROUND: Hydrothermal pretreatment of lignocellulosic biomass such as rice straw can dissolve part of the lignin and hemicellulose into a liquid fraction, thus facilitating enzyme accessibility to cellulose in bioethanol production process. Lignin is awaited to be recovered after hydrothermal pretreatment for utilization as value-added chemical, and lignin recovery also means removal of fermentation inhibitors. To recover lignin with high content from the liquid fraction, it is necessary to separate lignin and hemicellulose-derived polysaccharide. Therefore, the following processes were applied: membrane separation with nanofiltration (NF) and enzymatic hydrolysis by hemicellulase. To clarify lignin-concentrated fraction obtained during these processes, the fates of lignin and polysaccharide components were pursued by a solution NMR method and confirmed by compositional analysis of each fraction. RESULTS: After hydrothermal pretreatment of rice straw, the NF concentrate of the supernatant of liquid fraction was hydrolyzed by hemicellulase and the resulting black precipitate was recovered. In this black precipitate, the intensity of NMR spectra related to lignin aromatic regions increased and those related to polysaccharides decreased, compared to rice straw, the solid fraction after hydrothermal pretreatment, and the NF concentrate. The lignin content of the black precipitate was 65.8 %. Lignin in the black precipitate included 52.9 % of the acid-insoluble lignin and 19.4 % of the soluble lignin in the NF concentrate of supernatant of liquid fraction. CONCLUSION: A precipitate with high lignin content was obtained from supernatants of the liquid fraction. These results suggested that precipitation of lignin was enhanced from concentrated mixtures of lignin and hemicellulosic polysaccharides by hydrolyzing the polysaccharides. Precipitation of lignin can contribute to lignin recovery from lignocellulosic biomass and, at the same time, allow more efficient ethanol production in the subsequent fermentation process. PMID- 26101548 TI - Open Drug Discovery Toolkit (ODDT): a new open-source player in the drug discovery field. AB - BACKGROUND: There has been huge progress in the open cheminformatics field in both methods and software development. Unfortunately, there has been little effort to unite those methods and software into one package. We here describe the Open Drug Discovery Toolkit (ODDT), which aims to fulfill the need for comprehensive and open source drug discovery software. RESULTS: The Open Drug Discovery Toolkit was developed as a free and open source tool for both computer aided drug discovery (CADD) developers and researchers. ODDT reimplements many state-of-the-art methods, such as machine learning scoring functions (RF-Score and NNScore) and wraps other external software to ease the process of developing CADD pipelines. ODDT is an out-of-the-box solution designed to be easily customizable and extensible. Therefore, users are strongly encouraged to extend it and develop new methods. We here present three use cases for ODDT in common tasks in computer-aided drug discovery. CONCLUSION: Open Drug Discovery Toolkit is released on a permissive 3-clause BSD license for both academic and industrial use. ODDT's source code, additional examples and documentation are available on GitHub (https://github.com/oddt/oddt). PMID- 26101547 TI - Quantitative modeling of dose-response and drug combination based on pathway network. AB - BACKGROUND: Quantitative description of dose-response of a drug for complex systems is essential for treatment of diseases and drug discovery. Given the growth of large-scale biological data obtained by multi-level assays, computational modeling has become an important approach to understand the mechanism of drug action. However, due to complicated interactions between drugs and cellular targets, the prediction of drug efficacy is a challenge, especially for complex systems. And the biological systems can be regarded as networks, where nodes represent molecular entities (DNA, RNA, protein and small compound) and processes, edges represent the relationships between nodes. Thus we combine biological pathway-based network modeling and molecular docking to evaluate drug efficacy. RESULTS: Network efficiency (NE) and network flux (NF) are both global measures of the network connectivity. In this work, we used NE and NF to quantitatively evaluate the inhibitory effects of compounds against the lipopolysaccharide-induced production of prostaglandin E2. The edge values of the pathway network of this biological process were reset according to the Michaelis Menten equation, which used the binding constant and drug concentration to determine the degree of inhibition of the target protein in the pathway. The combination of NE and NF was adopted to evaluate the inhibitory effects. The dose response curve was sigmoid and the EC50 values of 5 compounds were in good agreement with experimental results (R(2) = 0.93). Moreover, we found that 2 drugs produced maximal synergism when they were combined according to the ratio between each EC50. CONCLUSIONS: This quantitative model has the ability to predict the dose-response relationships of single drug and drug combination in the context of the pathway network of biological process. These findings are valuable for the evaluation of drug efficacy and thus provide an effective approach for pathway network-based drug discovery. PMID- 26101549 TI - Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one. AB - A heterocyclic compound 1-propenyl-1,3-dihydro-benzimidazol-2-one was synthesized by a palladium-catalyzed rearrangement reaction. Anticancer activities were confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against Neura 2a (neuroblastoma cell), HEK 293 (kidney cancer) and MCF-7 (breast cancer) cell lines at low micromolar range. Furthermore, clear images from phase-contrast and fluorescence microscopes and confocal images unambiguously confirm the cancer cell death. The single X-ray crystal structure of the compound unambiguously proves the structure of the benzimidazolone compound. PMID- 26101550 TI - Design and activity of AP endonuclease-1 inhibitors. AB - Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE-1) is a critical component of base excision repair that excises abasic lesions created enzymatically by the action of DNA glycosylases on modified bases and non enzymatically by hydrolytic depurination/depyrimidination of nucleobases. Many anticancer drugs generate DNA adducts that are processed by base excision repair, and tumor resistance is frequently associated with enhanced APE-1 expression. Accordingly, APE-1 is a potential therapeutic target to treat cancer. Using computational approaches and the high resolution structure of APE-1, we developed a 5-point pharmacophore model for APE-1 small molecule inhibitors. One of the nM APE-1 inhibitors (AJAY-4) that was identified based on this model exhibited an overall median growth inhibition (GI50) of 4.19 MUM in the NCI-60 cell line panel. The mechanism of action is shown to be related to the buildup of abasic sites that cause PARP activation and PARP cleavage, and the activation of caspase 3 and caspase-7, which is consistent with cell death by apoptosis. In a drug combination growth inhibition screen conducted in 10 randomly selected NCI-60 cell lines and with 20 clinically used non-genotoxic anticancer drugs, a synergy was flagged in the SK-MEL-5 melanoma cell line exposed to combinations of vemurafenib, which targets melanoma cells with V600E mutated BRAF, and AJAY-4, our most potent APE-1 inhibitor. The synergy between AJAY-4 and vemurafenib was not observed in cell lines expressing wild-type B-Raf protein. This synergistic combination may provide a solution to the resistance that develops in tumors treated with B-Raf-targeting drugs. PMID- 26101551 TI - Prediction of protein targets of kinetin using in silico and in vitro methods: a case study on spinach seed germination mechanism. AB - Kinetin, a cytokinin which promotes seed germination by inhibiting the action of abscisic acid, is an important molecule known to trigger various molecular mechanisms by interacting with an array of proteins shown from experimental observations in various model organisms. We report here the prediction of most probable protein targets of kinetin from spinach proteome using in silico approaches. Inverse docking and ligand-based similarity search was performed using kinetin as molecule. The former method prioritized six spinach proteins, whereas the latter method provided a list of protein targets retrieved from several model organisms. The most probable protein targets were selected by comparing the rank list of docking and ligand similarity methods. Both of these methods prioritized chitinase as the most probable protein target (DeltaG pred = 5.064 kcal/mol) supported by the experimental structure of yeast chitinase 1 complex with kinetin (PDB: 2UY5) and Gliocladium roseum chitinase complex with 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (caffeine; 3G6M) which bears a 3D similarity of 0.43 with kinetin. An in vitro study to evaluate the effect of kinetin on spinach seed germination indicated that a very low concentration of kinetin (0.5 mg/l) did not show a significant effect compared to control in inducing seed germination process. Further, higher levels of kinetin (>0.5 mg/l) constituted an antagonist effect on spinach seed germination. It is anticipated that kinetin may have a molecular interaction with prioritized protein targets synthesized during the seed germination process and reduces growth. Thus, it appears that kinetin may not be a suitable hormone for enhancing spinach seed germination in vitro. PMID- 26101553 TI - JOCB Bulletin. PMID- 26101552 TI - Steroidal dihydrocarbothioic acid amido pyrazoles: synthesis, characterization, cytotoxicity and genotoxicity studies. AB - A new series of steroidal dihydrocarbothioic acid amido pyrazole analogues were synthesized, and after characterization, evaluation for cytotoxicity, comet assay and western blotting was carried out. The synthesis of these analogues is convenient and involves two steps, i.e. aldol condensation as first step followed by nucleophilic addition of thiosemicarbazide across alpha, beta-unsaturated carbonyl as a later step. Quantitative yields of more than 80 % are obtained in both the steps. After characterization by IR, (1)H NMR, (13)C NMR, MS and analytical data, all the compounds of both series were tested for cytotoxic activity against a panel of different human cancer cell lines by MTT assay, during which compound 3e, 3f, 4e, 4f and 4h are very potent especially against HepG2 and MCF-7 cancer cell lines. Cell cycle analysis depicted the cell death in S-phase while as annexin V-FITC/PI analysis showed that compounds effectively induce apoptosis. Apoptotic degradation of DNA of MCF-7 cells in the presence of different steroidal derivatives was analysed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). In western blotting analysis, the relative expressions of relevant apoptotic markers depicted an apoptosis by steroidal dihydropyrazole in MCF-7 cancer cells. PMID- 26101554 TI - State of emergency medicine in Rwanda 2015: an innovative trainee and trainer model. AB - The 1994 Rwandan war and genocide left more than 1 million people dead; millions displaced; and the country's economic, social, and health infrastructure destroyed. Despite remaining one of the poorest countries in the world, Rwanda has made remarkable gains in health, social, and economic development over the last 20 years, but modern emergency care has been slow to progress. Rwanda has recently established the Human Resources for Health program to rapidly build capacity in multiple sectors of its healthcare delivery system, including emergency medicine. This project involves multiple medical and surgical residencies, nursing programs, allied health professional trainings, and hospital administrative support. A real strength of the program is that trainers work with international faculty at Rwanda's referral hospital, but also as emergency medicine specialty trainers when returning to their respective district hospitals. Rwanda's first emergency medicine trainees are playing a unique and important role in the implementation of emergency care systems and education in the country's district hospitals. While there has been early vital progress in building emergency medicine's foundations in Rwanda, there remains much work to be done. This will be accomplished with careful planning and strong commitment from the country's healthcare and emergency medicine leaders. PMID- 26101556 TI - Youths' socialization to work and school within the family. AB - The present study tested a model of socialization to work in the family context and its implications as a lever for school engagement using a sample of 154 parent-youth dyads living in the United States. A path model was fitted to data. Findings revealed that parents' reported work experiences was aligned to youths' perception of their parents' success in the work domain. Also, a significant association was found between youth's perception of their parents' family success and youth's emotional and experiential conceptualizations of work. Furthermore, youth who viewed work as a positive experience were more likely to be engaged in schoolwork, both emotionally and cognitively. Implications for vocational guidance are discussed. PMID- 26101555 TI - Treatment of Acanthamoeba neurotrophic corneal ulcer with topical matrix therapy. AB - BACKGROUND: This study was done to evaluate the visual and anatomical outcomes of topical regenerating agents as a novel therapy for neutrophic corneal ulcer (NCU) secondary to acanthamoeba infection. FINDINGS: A 20-year-old woman with a history of contact lens wear was referred to our hospital for keratitis after responding poorly to conventional treatment. In vivo confocal microscopy images suggested acanthamoeba keratitis with double-walled cysts in the anterior corneal stroma. Acanthamoeba infection was confirmed by laboratory findings. She was started on 0.1 % propamidine and 0.02 % chlorhexidine drops every hour. The antibiotic and antifungal drops were stopped when bacterial and fungal cultures proved negative. A central neurotrophic corneal ulcers (NCU) appeared, and despite treatment with artificial tears, bandage contact lens, and autologous serum, the ulcer worsened and she was treated with topical CACICOL20 (1 drop every 2 days) for 8 weeks. The corneal defect was completely repaired in 3 weeks. The treatment was well tolerated, and no local or systemic side effects were noted. Visual acuity remained 20/400. Two months later, the defect was still closed and the patient continued with 0.1 % propamidine and 0.02 % chlorhexidine drops, bandage contact lens, artificial tears, and autologous serum. CONCLUSIONS: Topical regenerating agents interact with components of the extracellular matrix, binding matrix proteins and protecting them from proteolysis, restoring the matrix environment, and improving tissue healing. In this case, CALCICOL20 was effective for vision stabilization, wound healing, and was well tolerated for NCU secondary to acanthamoeba infection. PMID- 26101559 TI - Target (In)Validation: A Critical, Sometimes Unheralded, Role of Modern Medicinal Chemistry. AB - Small molecule drug discovery commonly ventures into previously unknown and unexplored target space. For such programs, an important role of medicinal chemistry is to generate molecules that enable the most reliable conclusions from a preclinical target validation/invalidation study. Multiple facets of chemistry that provide the most rigorous results for such an experiment are highlighted. PMID- 26101557 TI - Metallothionein-I/II Knockout Mice Aggravate Mitochondrial Superoxide Production and Peroxiredoxin 3 Expression in Thyroid after Excessive Iodide Exposure. AB - PURPOSE: We aim to figure out the effect of metallothioneins on iodide excess induced oxidative stress in the thyroid. METHODS: Eight-week-old MT-I/II knockout (MT-I/II KO) mice and background-matched wild-type (WT) mice were used. Mitochondrial superoxide production and peroxiredoxin (Prx) 3 expression were measured. RESULTS: In in vitro study, more significant increases in mitochondrial superoxide production and Prx 3 expression were detected in the MT-I/II KO groups. In in vivo study, significantly higher concentrations of urinary iodine level were detected in MT-I/II KO mice in 100 HI group. Compared to the NI group, there was no significant difference existing in serum thyroid hormones level in either groups (P > 0.05), while the mitochondrial superoxide production was significantly increased in 100 HI groups with significantly increased LDH activity and decreased relative cell viability. Compared to WT mice, more significant changes were detected in MT-I/II KO mice in 100 HI groups. No significant differences were detected between the NI group and 10 HI group in both the MT-I/II KO and WT mice groups (P > 0.05). CONCLUSIONS: Iodide excess in a thyroid without MT I/II protection may result in strong mitochondrial oxidative stress, which further leads to the damage of thyrocytes. PMID- 26101558 TI - Immunohistochemical Study of Nrf2-Antioxidant Response Element as Indicator of Oxidative Stress Induced by Cadmium in Developing Rats. AB - In developing animals, Cadmium (Cd) induces toxicity to many organs including brain. Reactive oxygen species (ROS) are often implicated in Cd-inducedtoxicity and it has been clearly demonstrated that oxidative stress interferes with the expression of genes as well as transcriptional factors such as Nrf2-dependent Antioxidant Response Element (Nrf2-ARE). Cd-generated oxidative stress and elevated Nrf2 activity have been reported in vitro and in situ cells. In this study we evaluated the morphological changes and the expression pattern of Nrf2 and correlated them with the Cd concentrations in different ages of developing rats in heart, lung, kidney, liver, and brain. The Cd content in different organs of rats treated with the metal was increased in all ages assayed. Comparatively, lower Cd brain levels were found in rats intoxicated at the age of 12 days, then pups treated at 5, 10, or 15 days old, at the same metal dose. No evident changes, as a consequence of cadmium exposure, were evident in the morphological analysis in any of the ages assayed. However, Nrf2-ARE immunoreactivity was observed in 15-day-old rats exposed to Cd. Our results support that fully developed blood-brain barrier is an important protector against Cd entrance to brain and that Nrf2 increased expression is a part of protective mechanism against cadmium-induced toxicity. PMID- 26101560 TI - Pyridinonaphthyridinone Inhibitors of Type 2 Methionine Aminopeptidase. PMID- 26101561 TI - Treatment of Cancer with NAMPT Inhibitors. PMID- 26101562 TI - Prostaglandin EP3 Receptor Antagonists May Provide Novel Treatment for Diabetes. PMID- 26101563 TI - Inhibition of Cathepsin K: A Novel and Promising Treatment for Osteoporosis. PMID- 26101565 TI - Selective Acetamidine-Based Nitric Oxide Synthase Inhibitors: Synthesis, Docking, and Biological Studies. AB - N-[(3-Aminomethyl)benzyl]acetamidine derivatives were synthesized and in vitro evaluated as inhibitors of the inducible isoform of nitric oxide synthase (iNOS). Because of the high potency of action and the excellent selectivity over the endothelial nitric oxide synthase (eNOS), compound 10 was ex vivo evaluated on isolated and perfused resistance arteries. The results confirm that compound 10 selectively inhibits the iNOS, without affecting the endothelial isoform. The outcome of the docking studies showed that the hydrophobic interaction is the driving force of the binding process, especially for iNOS, where the binding pocket is characterized by a significant lipophilic region. PMID- 26101564 TI - MLN8054 and Alisertib (MLN8237): Discovery of Selective Oral Aurora A Inhibitors. AB - The Aurora kinases are essential for cell mitosis, and the dysregulation of Aurora A and B have been linked to the etiology of human cancers. Investigational agents MLN8054 (8) and alisertib (MLN8237, 10) have been identified as high affinity, selective, orally bioavailable inhibitors of Aurora A that have advanced into human clinical trials. Alisertib (10) is currently being evaluated in multiple Phase II and III clinical trials in hematological malignancies and solid tumors. PMID- 26101566 TI - Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T Type Calcium Channel Blocker, ABT-639. AB - The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat. PMID- 26101567 TI - Generation of Broad-Spectrum Antifungal Drug Candidates from the Natural Product Compound Aureobasidin A. AB - The natural product aureobasidin A (AbA) is a potent, well-tolerated antifungal agent with robust efficacy in animals. Although native AbA is active against a number of fungi, it has little activity against Aspergillus fumigatus, an important human pathogen, and attempts to improve the activity against this organism by structural modifications have to date involved chemistries too complex for continued development. This report describes novel chemistry for the modification of AbA. The key step involves functionalization of the phenylalanine residues in the compound by iridium-catalyzed borylation. This is followed by displacement of the pinacol boron moiety to form the corresponding bromide or iodide and substitution by Suzuki biaryl coupling. The approach allows for synthesis of a truly wide range of derivatives and has produced compounds with A. fumigatus minimal inhibitory concentrations (MIC) of <0.5 MUg/mL. The approach is readily adaptable to large-scale synthesis and industrial production. PMID- 26101568 TI - Discovery and Optimization of Selective Nav1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain. AB - Voltage-gated sodium channels, in particular Nav1.8, can be targeted for the treatment of neuropathic and inflammatory pain. Herein, we described the optimization of Nav1.8 modulator series to deliver subtype selective, state, and use-dependent chemical matter that is efficacious in preclinical models of neuropathic and inflammatory pain. PMID- 26101569 TI - Aryl Pyrazoles as Potent Inhibitors of Arginine Methyltransferases: Identification of the First PRMT6 Tool Compound. AB - A novel aryl pyrazole series of arginine methyltransferase inhibitors has been identified. Synthesis of analogues within this series yielded the first potent, selective, small molecule PRMT6 inhibitor tool compound, EPZ020411. PRMT6 overexpression has been reported in several cancer types suggesting that inhibition of PRMT6 activity may have therapeutic utility. Identification of EPZ020411 provides the field with the first small molecule tool compound for target validation studies. EPZ020411 shows good bioavailability following subcutaneous dosing in rats making it a suitable tool for in vivo studies. PMID- 26101570 TI - Amino Acid Thioester Derivatives: A Highly Promising Scaffold for the Development of Metallo-beta-lactamase L1 Inhibitors. AB - In light of the biomedical significance of metallo-beta-lactamases (MbetaLs), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2.9 MUM and a K i value range of 0.11-0.95 MUM using cefazolin as substrate. Partial thioesters also showed effective inhibitory activities against NDM-1 and ImiS with an IC50 value range of 12-96 and 3.6-65 MUM, respectively. Also, all these thioesters increased susceptibility of E. coli cells expressing L1 to cefazolin, indicated by a 2-4-fold reduction in MIC of the antibiotic. Docking studies revealed potential binding modes of the two most potent L1 inhibitors to the active site in which the carboxylate group interacts with both Zn(II) ions and Ser221. This work introduces a highly promising scaffold for the development of metallo-beta-lactamase L1 inhibitors. PMID- 26101571 TI - Identification of Jumonji AT-Rich Interactive Domain 1A Inhibitors and Their Effect on Cancer Cells. AB - Jumonji AT-rich interactive domain 1A (JARID1A), one of the jumonji C domain containing histone demethylase (JHDM) family members, plays key roles in cancer cell proliferation and development of drug tolerance. Therefore, selective JARID1A inhibitors are potential anticancer agents. In this study, we searched for cell-active JARID1A inhibitors by screening hydroxamate compounds in our in house library and the structural optimization based on docking study of the hit compound to a homology model of JARID1A. As a result, we identified compound 6j, which selectively inhibits JARID1A over three other JHDM family members. Compound 7j, a prodrug form of compound 6j, induced a selective increase in the level of trimethylation of histone H3 lysine 4, a substrate of JARID1A. Furthermore, compound 7j synergistically enhanced A549 human lung cancer cell growth inhibition induced by vorinostat, a histone deacetylase inhibitor. These findings support the idea that JARID1A inhibitors have potential as anticancer agents. PMID- 26101572 TI - Synthesis, SAR, and Pharmacological Characterization of Brain Penetrant P2X7 Receptor Antagonists. AB - We describe the synthesis and SAR of 1,2,3-triazolopiperidines as a novel series of potent, brain penetrant P2X7 antagonists. Initial efforts yielded a series of potent human P2X7R antagonists with moderate to weak rodent potency, some CYP inhibition, poor metabolic stability, and low solubility. Further work in this series, which focused on the SAR of the N-linked heterocycle, not only increased the potency at the human P2X7R but also provided compounds with good potency at the rat P2X7R. These efforts eventually delivered a potent rat and human P2X7R antagonist with good physicochemical properties, an excellent pharmacokinetic profile, good partitioning into the CNS, and demonstrated in vivo target engagement after oral dosing. PMID- 26101573 TI - Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation. AB - IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituents were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation. PMID- 26101574 TI - Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4. AB - Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4 yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing. PMID- 26101575 TI - Structure-Activity Relationship Studies of 3-epi-Deoxynegamycin Derivatives as Potent Readthrough Drug Candidates. AB - (+)-Negamycin (1), a natural dipeptidic antibiotic bearing a hydrazide structure, exhibits a readthrough activity toward the nonsense mutation of the dystrophin gene and restores dystrophin expression in muscles of Duchenne muscular dystrophy model mdx mice. Herein to develop more potent readthrough compounds, we performed a structure-activity relationship (SAR) study of 3-epi-deoxynegamycin (2), which is also another natural readthrough compound with little antimicrobial activity, focusing on the main carbon chain length. We found that one carbon atom shorter derivative 9b shows a higher readthrough activity than 1 and 2. Further derivatization at the carboxylic acid part of 9b demonstrates that its meta chlorobenzyl ester derivative 17e, which has a higher ClogP value, exhibits a more potent readthrough activity than 9b. Interestingly, in the cell-free protein expression system, the readthrough activity of 17e drastically decreases compared to that in the cell-based assay. These results suggest that benzyl ester-type derivatives enhance the hydrophobicity and function as prodrugs to produce active compound 9b in living cell systems. PMID- 26101576 TI - Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. AB - A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line. PMID- 26101578 TI - Syntheses and Antibacterial Activity of N-Acylated Ciprofloxacin Derivatives Based on the Trimethyl Lock. AB - Several N-acyl ciprofloxacin quinone derivatives based on a trimethyl lock structure were synthesized, and their in vitro antibacterial activity against a panel of clinically relevant bacteria was evaluated. A few new analogues displayed enhanced activity against Gram-positive species compared to the parent drug. Additionally, studies of 8-Cip, which was the most potent compound tested, indicate that it may act through a dual-action mechanism. PMID- 26101577 TI - Dehydro-beta-proline Containing alpha4beta1 Integrin Antagonists: Stereochemical Recognition in Ligand-Receptor Interplay. AB - A novel class of dehydro-beta-proline-containing peptidomimetics, designed to be effective as alpha4beta1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-beta-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino derivative. The synthesized products showed to be effective and selective as alpha4beta1 integrin antagonists and displayed IC50 values in the nanomolar range in cell adhesion inhibition assays and in VCAM-1-induced phosphorylation of extracellular signal-regulated kinases. Significant activity was observed also toward the homologous integrin alpha4beta7, while they did not display any activity toward selected members of beta1, beta2, and beta3 families. A strong dependence on the stereochemistry of the heterocyclic central core could be observed. The great importance of alpha4beta1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compounds for therapeutic tools development. PMID- 26101579 TI - Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series. AB - To increase kinase selectivity in an aminopyrazole-based PAK1 inhibitor series, analogues were designed to interact with the PAK1 deep-front pocket pre-DFG residue Thr-406, a residue that is hydrophobic in most kinases. This goal was achieved by installing lactam head groups to the aminopyrazole hinge binding moiety. The corresponding analogues represent the most kinase selective ATP competitive Group I PAK inhibitors described to date. Hydrogen bonding with the Thr-406 side chain was demonstrated by X-ray crystallography, and inhibitory activities, particularly against kinases with hydrophobic pre-DFG residues, were mitigated. Leveraging hydrogen bonding side chain interactions with polar pre-DFG residues is unprecedented, and similar strategies should be applicable to other appropriate kinases. PMID- 26101580 TI - Synthesis and evaluation of [11C]PBD150, a radiolabeled glutaminyl cyclase inhibitor for the potential detection of Alzheimer's disease prior to amyloid beta aggregation. AB - The phenol of 1-(3-(1H-imidazol-1-yl)propyl)-3-(4-hydroxy-3 methoxyphenyl)thiourea was selectively carbon-11 labelled to generate [11C]PBD150 in 7.3% yield from [11C]methyl triflate (non-decay corrected; radiochemical purity >=95%, specific activity = 5.7 Ci/umol, n=5). Evaluation of [11C]PBD150 by small animal PET imaging (mouse and rat) determined it does not permeate the blood brain barrier, indicating previously described therapeutic effect in transgenic mice was likely not the result of inhibiting central nervous system glutaminyl cyclase. PMID- 26101581 TI - Intermolecular carbene S-H insertion catalysed by engineered myoglobin-based catalysts?. AB - The first example of a biocatalytic strategy for the synthesis of thioethers via an intermolecular carbene S-H insertion reaction is reported. Engineered variants of sperm whale myoglobin were found to efficiently catalyze this C-S bond forming transformation across a diverse set of aryl and alkyl mercaptan substrates and alpha-diazoester carbene donors, providing high conversions (60-99%) and high numbers of catalytic turnovers (1,100-5,400). Furthermore, the enantioselectivity of these biocatalysts could be tuned through mutation of amino acid residues within the distal pocket of the hemoprotein, leading to myoglobin variants capable of supporting asymmetric S-H insertions with up to 49% ee. Rearrangement experiments support a mechanism involving the formation of a sulfonium ylide generated upon attack of the thiol substrate to a heme-bound carbene intermediate. PMID- 26101582 TI - Par system components are asymmetrically localized in ectodermal epithelia, but not during early development in the sea anemone Nematostella vectensis. AB - BACKGROUND: The evolutionary origins of cell polarity in metazoan embryos are unclear. In most bilaterian animals, embryonic and cell polarity are set up during embryogenesis with the same molecules being utilized to regulate tissue polarity at different life stages. Atypical protein kinase C (aPKC), lethal giant larvae (Lgl), and Partitioning-defective (Par) proteins are conserved components of cellular polarization, and their role in establishing embryonic asymmetry and tissue polarity have been widely studied in model bilaterian groups. However, the deployment and role of these proteins in animals outside Bilateria has not been studied. We address this by characterizing the localization of different components of the Par system during early development of the sea anemone Nematostella vectensis, a member of the clade Cnidaria, the sister group to bilaterian animals. RESULTS: Immunostaining using specific N. vectensis antibodies and the overexpression of mRNA-reporter constructs show that components of the N. vectensis Par system (NvPar-1, NvPar-3, NvPar-6, NvaPKC, and NvLgl) distribute throughout the microtubule cytoskeleton of eggs and early embryos without clear polarization along any embryonic axis. However, they become asymmetrically distributed at later stages, when the embryo forms an ectodermal epithelial layer. NvLgl and NvPar-1 localize in the basolateral cortex, and NvaPKC, NvPar-6, and NvPar-3 at the apical zone of the cell in a manner seen in bilaterian animals. CONCLUSIONS: The cnidarian N. vectensis exhibits clear polarity at all stages of early embryonic development, which appears to be established independent of the Par system reported in many bilaterian embryos. However, in N. vectensis, using multiple immunohistochemical and fluorescently labeled markers in vivo, components of this system are deployed to organize epithelial cell polarity at later stages of development. This suggests that Par system proteins were co-opted to organize early embryonic cell polarity at the base of the Bilateria and that, therefore, different molecular mechanisms operate in early cnidarian embryogenesis. PMID- 26101584 TI - Saltman on solidarity. AB - Richard Saltman suggests that solidarity, a cherished notion at the heart of West European health care systems is being reconsidered in the light of today's austere economic conditions. Solidarity, he argues, has always been a flexible moral guideline, one that allows for policy responses, such as limitations on health benefits or increased out of pocket payments, that challenging fiscal conditions are said to demand. Here we consider what the basic elements in solidarity - universality, redistribution, and uniformity-- mean in health as compared to other social policy realms such as pensions. Traditionally, the commitment to solidarity said little about the contents of services, but the latter is perhaps subject to increasing scrutiny under the health policy microscope. Saltman is right to emphasize the conceptual and cross-national flexibility of solidarity, but the notion retains a solid and durable core that continues to give valuable direction to policymakers in search of acceptable strategies and structures for decision making. PMID- 26101583 TI - Association of aberrant DNA methylation in Apc(min/+) mice with the epithelial mesenchymal transition and Wnt/beta-catenin pathways: genome-wide analysis using MeDIP-seq. AB - BACKGROUND: Aberrant DNA methylation at the 5-carbon on cytosine residues (5mC) in CpG dinucleotides is probably the most extensively characterized epigenetic modification in colon cancer. It has been suggested that the loss of adenomatous polyposis coli (APC) function initiates tumorigenesis and that additional genetic and epigenetic events are involved in colon cancer progression. We aimed to study the genome-wide DNA methylation profiles of intestinal tumorigenesis in Apc(min/+) mice. RESULTS: Methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing was used to determine the global profile of DNA methylation changes in Apc(min/+) mice. DNA was extracted from adenomatous polyps from Apc(min/+) mice and from normal intestinal tissue from age-matched Apc(+/+) littermates, and the MeDIP-seq assay was performed. Ingenuity Pathway Analysis (IPA) software was used to analyze the data for gene interactions. A total of 17,265 differentially methylated regions (DMRs) displayed a >= 2-fold change (log2) in methylation in Apc(min/+) mice; among these DMRs, 9,078 (52.6 %) and 8,187 (47.4 %) exhibited increased and decreased methylation, respectively. Genes with altered methylation patterns were mainly mapped to networks and biological functions associated with cancer and gastrointestinal diseases. Among these networks, several canonical pathways, such as the epithelial-mesenchymal transition (EMT) and Wnt/beta-catenin pathways, were significantly associated with genome-wide methylation changes in polyps from Apc(min/+) mice. The identification of certain differentially methylated molecules in the EMT and Wnt/beta-catenin pathways, such as APC2 (adenomatosis polyposis coli 2), SFRP2 (secreted frizzled-related protein 2), and DKK3 (dickkopf-related protein 3), was consistent with previous publications. CONCLUSIONS: Our findings indicated that Apc(min/+) mice exhibited extensive aberrant DNA methylation that affected certain signaling pathways, such as the EMT and Wnt/beta-catenin pathways. The genome-wide DNA methylation profile of Apc(min/+) mice is informative for future studies investigating epigenetic gene regulation in colon tumorigenesis and the prevention of colon cancer. PMID- 26101585 TI - Assessment of sensitization to grape and wine allergens as possible causes of adverse reactions to wine: a pilot study. AB - BACKGROUND: In a recently performed survey with 4000 randomly selected persons, 68 (7.2 %) of 948 respondents reported intolerance and/or allergy-like symptoms to wine. The aim of this study was to analyze whether a real sensitization to wine proteins could be confirmed by diagnostic and/or immunological settings. FINDINGS: For this purpose, 19 subjects with self-reported intolerance to wine of the invited subjects and 10 controls without a history of intolerance participated in an allergological examination (skin prick test, ImmunoCAP for determination of specific IgE antibodies, CAST for testing basophil activation, ImmunoBlot for testing specificity of IgE-antibodies). For the allergological work-up red and white grapes, selected wines, and the purified lipid transfer protein (LTP), a known grape allergen, were used. 7 subjects showed evidence of IgE sensitization to wine or grape extracts, including one control. One participant with symptoms of intolerance showed a positive skin prick test to red grape, a positive ImmunoCAP to grape, a positive cellular antigen stimulation test (CAST) and inhibition of Western blot by removal of cross-reactive carbohydrate determinants (CCD). CONCLUSION: The presented study focused on the grape protein-related IgE-mediated cause of intolerance to wine (true allergy) and not on other wine components or fining agents (other forms of intolerance). A sensitization to grape and wine proteins was observed in our cohort. In one case, this reactivity could be explained by cross-reactivity to CCD. The results of this pilot study need to be validated in greater cohorts. PMID- 26101586 TI - The effect of Lameness before and during the breeding season on fertility in 10 pasture-based Irish dairy herds. AB - BACKGROUND: The effects of lameness on fertility have been documented frequently but few data are available from seasonally breeding, pasture-based herds (such as those used in Ireland) where cows are housed during the winter months but managed at pasture for the remainder of the year. This study determined the prevalence of lameness in a group of 786 cows in 10 pasture-based Irish dairy herds before, during and after the breeding season and assessed the relationship between lameness and the reproductive performance in these herds through serial locomotion scoring during the grazing period. RESULTS: Lameness prevalences of 11.6 % before, 14.6 % during and 11.6 % after the breeding season were found and these compared favourably to results from housed cattle and are similar to other studies carried out in grazing herds. A Cox proportional hazards model with locomotion score as time varying covariate was used. After controlling for the effect of farm, month of calving, body condition score at calving, body condition score loss after calving and economic breeding index, cows identified as lame during the study were less likely to become pregnant. Cows lame before the earliest serve date but no longer lame during the breeding season, cows becoming lame after the earliest serve date and cows identified lame both before and after this date were respectively 12 %, 35 % and 38 % less likely to become pregnant compared to cows never observed lame during the study. However, these findings were only significant for cows becoming lame after the earliest serve date and cows lame both before and after the start of breeding. CONCLUSIONS: This study found that the reproductive efficiency was significantly (p < 0.05) lower in cows becoming lame during the breeding season and cows lame before and during the breeding season compared to non-lame cows. Cows no longer lame during the breeding season had a lower Submission Rate to first serve within 3 weeks of earliest serve date. However, the Pregnancy Rate was not significantly (p > 0.05) lower in these animals compared to cows never diagnosed as lame. In addition to lameness status, nutritional status and genetics were found to influence the reproductive performance in pasture-based Irish dairy herds. PMID- 26101588 TI - Improving standards for reporting studies involving humans and experimental animals in the British Journal of Nutrition and in the Journal of Nutritional Science. PMID- 26101587 TI - A metabolomics approach used to profile plasma from portal-arterial pigs revealed differences between breads incurred by dietary fibre and protein contents. AB - A liquid chromatography-MS (LC-MS) metabolomics analysis of plasma from portal arterial catheterised pigs fed breads prepared with whole-grain rye or wheat flour with added concentrated arabinoxylan (AX) or beta-glucan (BG) was conducted. Comparison of the effects of concentrated fibres with whole grains has received little attention. Six female catheterised pigs were given two white wheat breads with wheat AX or oat BG, two rye breads with ground rye (GR) or intact rye kernels (RK), and a control white wheat bread (WF) on separate occasions in a randomised cross-over design. The amount of available carbohydrate was similar for the five breads but varied in the content of protein. Plasma was collected continuously for 4 h after feeding. Glucose levels in the portal vein were reduced postprandially in response to the AX, GR and RK breads that had high contents of AX compared with WF bread (P < 0.03). AX and RK breads further tended to decrease plasma levels of some lysophosphatidylcholine species (P <= 0.10). The abundance of amino acids in plasma correlated with the protein contents in the breads and leucine uptake significantly affected insulin secretion in the mesenteric artery. In conclusion, the present study revealed that concentrated AX in wheat bread had similar positive effects as whole-grain rye bread on glucose and lipid metabolism. PMID- 26101589 TI - Sugarcane fibre may prevents hairball formation in cats. AB - Hair ingested by licking during cat grooming can eventually coalesce into solid masses in cat gastrointestinal tract. It is believed that dietary fibre might reduce formation of these trichobezoars (hairballs). The effects of two insoluble fibre sources added to kibble diets were evaluated with respect to trichobezoar faecal excretion. Thirty-two cats and four diets were used in a randomised block design: a control diet without additional fibre, 10 % added sugarcane fibre, 20 % added sugarcane fibre or 10 % added cellulose. Animals were fed for 42 d and during three separate periods (days 15-17, 25-27 and 40-42), the cats were housed individually in metabolic cages and their faeces were totally collected. The faeces were evaluated and the trichobezoars were isolated and classified into small (<1 cm), medium (1.1-2 cm) or large (>2.1 cm). Means were evaluated by repeated measures ANOVA and contrasts (P < 0.05). Cats fed sugarcane fibre shown a linear reduction of small and medium trichobezoar excretion (number per cat per day; P = 0.004) as well as a reduction in trichobezoar mass excretion (mg per cat per day; P < 0.01). The control group showed increased faecal excretion of large trichobezoars (P = 0.003), which were not present in the high sugarcane fibre group (P < 0.006). No effect of cellulose was observed for any evaluated trait. Therefore, long fibres (sugarcane fibre) may cause greater peristaltic stimulation, increasing the propulsion of hair through the gut, but further research is needed to validate this mechanism. In conclusion, sugarcane fibre reduced faecal hairball elimination in cats, which may have clinical applications for the prevention of health problems related to trichobezoars. PMID- 26101590 TI - The effect of reducing dietary energy density via the addition of water to a dry diet, on body weight, energy intake and physical activity in adult neutered cats. AB - Increasingly domestic cats live in an overfeeding and underexercising environment where obesity is a major health concern. One strategy to aid healthy body weight maintenance is dietary energy dilution. Published data indicate that increasing dietary moisture content leads to a reduction in energy intake and increased activity. However, a number of different methodologies were employed in these studies and associated changes in physical activity have only been measured once. The aim of the present study was to determine the effect of diets of three different moisture contents offered in excess of energy requirements, on body weight, energy intake and physical activity in adult neutered cats. Sixty-nine adult cats randomised into three groups, received 100 % of their daily individual maintenance energy requirements (IMER) of dry diet or dry diet hydrated to 40 or 80 % total moisture content (tmc). Baseline activity, intake, body weight and body composition were measured. Following this baseline phase, the cats received the same diets at 200 % of daily IMER and the measurements repeated over the next 28 d. When offered the diets at 200 % IMER, cats fed the dry diet significantly increased body weight and percentage of body fat (P < 0.01), while those offered the hydrated diets did not (P > 0.01). The levels of physical activity in cats offered the hydrated 80 % tmc diet were significantly (P < 0.01) higher than those offered the dry or 40 % tmc diet. We suggest that dietary energy dilution by addition of water may be a useful strategy for healthy body weight maintenance in overfed cats. PMID- 26101591 TI - Faecal microbiota of domestic cats fed raw whole chicks v. an extruded chicken based diet. AB - Extruded cat foods differ greatly in macronutrient distribution compared with wild-type diets (i.e. small mammals, reptiles, birds and insects). Based on the literature, this variability likely impacts faecal microbial populations. A completely randomised design was utilised to test the impacts of two dietary treatments on faecal microbial populations: (1) chicken-based extruded diet (EXT; n 3 cats) and (2) raw 1-3-d-old chicks (CHI; n 5 cats). Cats were adapted to diets for 10 d. Bacterial DNA was isolated from faecal samples and amplicons of the 16S rRNA V4-V6 region were generated and analysed by 454 pyrosequencing. Faeces of cats fed CHI had greater (P < 0.05) proportions of the following bacterial genera: unidentified Lachnospiraceae (15 v. 5 %), Peptococcus (9 v. 3 %) and Pseudobutyrivibrio (4 v. 1 %). Faeces of cats fed EXT had greater (P < 0.05) proportions of Faecalibacterium (1.0 v. 0.2 %) and Succinivibrio (1.2 v. < 0.1 %). Five genera, including Lactobacillus and Bifidobacterium, were present in a majority of samples (two to three out of three) from cats fed EXT, but were not detected in the samples (zero of five) for cats fed CHI. These shifts in faecal bacterial populations compared with feeding a whole-prey diet may impact the functional capacities of the microbiota and its interaction with the host. Further research is warranted to determine the impacts of these shifts on long term health of domestic cats. PMID- 26101592 TI - Evaluation of the owner's perception in the use of homemade diets for the nutritional management of dogs. AB - Many dog owners see homemade diets as a way of increasing the bond with their pets, even though they may not have the convenience of commercial diets. Modifications of ingredients, quality and proportion might change the nutritional composition of the diet, generating nutritional imbalances. The present study evaluated how dog owners use and adhere to homemade diets prescribed by veterinary nutritionists over an extended period of time. Forty-six owners of dogs fed a homemade diet for at least 6 months were selected for the present study. Owners were invited to answer questions by first reading all possible answers and then selecting the one that best indicated their opinion. The results were evaluated through descriptive statistics. Thirty-five owners (76.1 %) found that the diets are easy to prepare. Fourteen owners (30.4 %) admitted to modifying the diets, 40 % did not adequately control the amount of provided ingredients, 73.9 % did not use the recommended amounts of soyabean oil and salt, and 34.8 % did not correctly use the vitamin, mineral or amino acid supplements. Twenty-six owners (56.5 %) reported that their dogs refused to eat at least one food item. All of these alterations make the nutritional composition of the diets unpredictable and likely nutritionally imbalanced. Although homemade diets could be a useful tool for the nutritional management of dogs with certain diseases, not all owners are able to appropriately use this type of diet and adhere to it for an extended period of time and this limitation needs to be considered when recommending the use of homemade diets. PMID- 26101593 TI - Evaluation of a performance enhancing supplement in American Foxhounds during eventing. AB - Enhancing performance through dietary measures is constantly sought as some supplements have shown modest performance enhancement in rodents and human subjects. To evaluate a proprietary dietary supplement, a study was undertaken to assess the effect of diet and exercise on blood physiological parameters during a tracking American Fox Hound field championship. Ten dogs were assigned to two different groups. Group A received a commercial kibble and Group B received the same diet with the addition of a supplement added to the dietary premix for 4 weeks before the field event. Blood was collected at rest, immediately following days 1 and 2 of the event and 48 h after day 2. Blood chemistry, complete blood cell counts and cortisol concentrations were analysed. Competition performance was also documented for all dogs using a points system for tracking events. Many chemistry parameters and blood cell counts changed significantly due to exercise. Differences between the dietary groups showed that Group B had significantly lower aspartate aminotransferase on days 1 and 2 of exercise and lower creatine kinase on day 2. Based on tracking scores, dogs in Group B out-performed dogs in Group A. This study suggests that endurance hunting dogs develop changes in serum markers of musculoskeletal integrity that might be mitigated by the addition of the supplement, resulting in better performance. Although intriguing, follow-up controlled studies are needed to ensure that the enhanced performance was not biased due to lack of randomisation. PMID- 26101594 TI - Long-term follow-up after weight management in obese cats. AB - Feline obesity is a prevalent medical disease and the main therapeutic strategy is dietary energy restriction. However, at present there are no data regarding long-term outcome in this species. The purpose of the present study was to investigate if, as in other species, some cats regain weight following successful weight loss, and to identify any influencing factors in a cohort of client-owned cats with naturally occurring obesity. Twenty-six cats were included, all of which had successfully completed a weight management programme. After weight loss, cats were periodically monitored. The median duration of follow-up was 954 d (72-2162 d). Ten cats (39 %) maintained their completion weight (+/-5 %), four (15 %) lost >5 % additional weight and 12 (46 %) gained >5 % weight. Seven of the rebounding cats (58 %) regained over 50 % of their original weight lost. Older cats were less likely to regain weight than younger cats (P = 0.024); with an approximately linear negative association between the cat's age and the amount of weight regained (Kendall's tau = -0.340, P = 0.016). Furthermore, cats whose energy intake during weight loss was greater were also more likely to regain weight (P = 0.023). When the characteristics of weight regain in cats were compared with those from a similar cohort of dogs, cats that rebounded were more likely to regain >50 % of the weight they had lost. These results suggest that weight regain, after successful weight loss, is common in obese cats, and that young cats (<7 years of age) are most at risk. PMID- 26101595 TI - Serum chemistry and electrolyte alterations in sled dogs before and after a 1600 km race: dietary sodium and hyponatraemia. AB - Sled dogs are known to develop numerous serum biochemical changes due to endurance exercise. Previous studies have suggested that mild hyponatraemia and hypokalaemia can develop during endurance racing. The aim of the present study was to determine if serum biochemical alterations are similar to previous reports, and if electrolyte alterations are still present with present feeding practices utilised by mushers. Serum chemistries were obtained from 26 Alaskan Huskies belonging to 3 different teams, before and after a 1600 km race. Meals and snacks were analysed via calculation to determine daily macronutrient and electrolyte intake. Numerous biochemical alterations were observed including significant differences in serum total protein, albumin, globulin, aspartate aminotransferase, creatine kinase, TAG, NEFA and urea nitrogen (P < 0.05). Serum electrolyte status revealed a mild, yet significant decrease in serum sodium (P = 0.002); and serum potassium was not significantly different (P = 0.566). Further examination of the sodium intake across the three teams revealed two teams with an average daily intake of approximately 8.5 g/dog/d (700 mg/4184 kJ) and the other team consuming 11.1 g/dog/d (1200 mg/4184 kJ). Regression analysis shows a significant modest positive correlation between serum sodium decrease and sodium intake per metabolic body weight of the dogs, as well as a modest positive correlation between sodium intake and serum potassium implicating the renin angiotensin aldosterone system as a major factor involved in sodium and potassium homoeostasis. These findings suggest that consumption of approximately 0.9 g/kg(0.75) (1.2 g/4184 kJ) of sodium per d may prevent exercise-induced decreases in sodium and potassium. PMID- 26101596 TI - Alterations to oxidative stress markers in dogs after a short-term stress during transport. AB - While methods to evaluate antioxidant capacity in animals exist, one problem with the models is induction of oxidative stress. It is necessary to promote a great enough challenge to induce measurable alterations to oxidative parameters while ensuring the protocol is compatible with animal welfare. The aim of the present study was to evaluate caged transport as a viable short-term stress that would significantly affect oxidative parameters. Twenty adult Beagle dogs, maintained on the same diet for 60 d prior to the transport, were included in the study. To simulate the stress, the dogs were housed in pairs in transport cages (1.0 m * 1.0 m * 1.5 m), placed on a truck coupled to a trailer and transported for a period of 15 min. Blood collection was performed immediately before and again 3 h after the transportation to evaluate oxidative parameters in blood serum, including thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), sequestration activity of the radical 2,2-diphenyl-1-picryl hydrazyl (DPPH*), protein carbonylation (PC), total sulfhydryl groups (SH), alpha tocopherol (alphaToc) and retinol (Ret). PC, SH and alphaToc were not significantly changed in the study; however, TBARS, TAC and DPPH increased, whereas Ret decreased after the transport. Although the lack of a control group of dogs not submitted to transport is a limitation to be considered, we conclude that the transport model is effective in inducing an antioxidant response in dogs and relevant blood parameters show sensitivity to this proposed model. PMID- 26101597 TI - Association of signalment parameters with activity of pet dogs. AB - Activity monitors are increasingly being used to quantify the activity of pet dogs. The aim of the present study was to investigate associations between signalment and activity of free-living pet dogs. Healthy pet dogs were recruited to wear an Actical activity monitor on their collars continuously for 2 weeks in their home environment. At least fifteen dogs were enrolled in each of the following weight ranges: <10, 10-20, 21-30, 31-40, >40 kg and their age, sex and reproductive status recorded. Each dog's intensity of activity for each minute of recording was classified using the total counts for that minute and our pre established cut-points. The percentage of time dogs spent in sedentary, light or moderate/vigorous activity each day was calculated. Median total daily activity counts and median percentages of time dogs spent in activities of differing intensity were used for the analysis. Associations between signalment characteristics and activity parameters were evaluated with the Mann-Whitney test, the Kruskal-Wallis test and Spearman rank correlations. Ninety-eight dogs were enrolled with >=17 dogs in each weight category. Time that dogs were sedentary correlated positively with age (r 0.50, uncorrected P < 0.001), while the median total daily activity count (r -0.47, uncorrected P < 0.001), time spent in light (r -0.46, uncorrected P < 0.001) and more vigorous activity (r 0.50, uncorrected P < 0.001) were negatively associated with age. No other significant associations between signalment and activity parameters were found. The lack of differences in activity across weight categories may reflect the impact of lifestyle negating any potential behavioural differences across breeds. PMID- 26101598 TI - Protein quality of insects as potential ingredients for dog and cat foods. AB - Insects have been proposed as a high-quality, efficient and sustainable dietary protein source. The present study evaluated the protein quality of a selection of insect species. Insect substrates were housefly pupae, adult house cricket, yellow mealworm larvae, lesser mealworm larvae, Morio worm larvae, black soldier fly larvae and pupae, six spot roach, death's head cockroach and Argentinean cockroach. Reference substrates were poultry meat meal, fish meal and soyabean meal. Substrates were analysed for DM, N, crude fat, ash and amino acid (AA) contents and for in vitro digestibility of organic matter (OM) and N. The nutrient composition, AA scores as well as in vitro OM and N digestibility varied considerably between insect substrates. For the AA score, the first limiting AA for most substrates was the combined requirement for Met and Cys. The pupae of the housefly and black soldier fly were high in protein and had high AA scores but were less digestible than other insect substrates. The protein content and AA score of house crickets were high and similar to that of fish meal; however, in vitro N digestibility was higher. The cockroaches were relatively high in protein but the indispensable AA contents, AA scores and the in vitro digestibility values were relatively low. In addition to the indices of protein quality, other aspects such as efficiency of conversion of organic side streams, feasibility of mass-production, product safety and pet owner perception are important for future dog and cat food application of insects as alternative protein source. PMID- 26101599 TI - Salmonellosis impacts the proportions of faecal microbial populations in domestic cats fed 1-3-d-old chicks. AB - There has been a recent increase in the feeding of unconventional diets, including whole-prey diets, to domestic pet cats. Our objective was to characterise faecal microbial populations of domestic cats fed whole and ground (6.35 mm grind) raw 1-3-d-old chicks (Rodent Pro). Faecal samples were collected from neutered male domestic cats (mean age = 5.7 years) fed these diet items in a crossover design. Bacterial DNA was isolated from faecal samples and amplicons of the 16S rRNA V4-V6 region were generated and analysed by 454 pyrosequencing. Faecal microbial populations of cats fed whole v. ground chicks did not differ. During the study, three cats presented with symptoms of infection (anorexia or diarrhoea) and tested clinically positive for Salmonella using a standard PCR method. The remaining cats tested negative. Data were analysed post hoc to test for differences in microbial populations due to clinical status. The predominant genera were Clostridium (9-30 %), unidentified Lachnospiraceae (10-28 %), Blautia (4-19 %), Peptococcus (2-19 %) and Fusobacterium (2-14 %). Faeces of cats testing clinically positive for Salmonella had higher (P <= 0.05) proportions of the genera Coprococcus (5.6 v. 0.4 %) and Escherichia (subgenera Shigella; 1.1 v. 0.3 %). Salmonella was not detected in faecal samples utilising the pyrosequencing method; however, there was a shift in microbial populations due to clinical status. The clinical symptoms reported herein may be not only due to the Salmonella itself, but also shifts in other gut microbial populations. PMID- 26101600 TI - Practical approach to determine apparent digestibility of canine diets. AB - A practical approach to determine apparent faecal digestibility using privately owned dogs may be a useful tool in evaluating differences in nutrient digestibility between dogs with various life stages. The aim was to develop a simple method that would suit such studies using the whitening agent titanium oxide (TiO2) as an indigestible marker. Forty privately owned, healthy male and female dogs of various breeds were included. Selection was based on an owner questionnaire. Means with their standard errors age and body weight (BW) of the dogs were 6.2 (0.6) years (range 1.0-13.0 years) and 22.3 (2.5) kg (range 5.0 43.2 kg), respectively. Owners were provided a commercial dry extruded diet supplemented with a commercially available TiO2 containing kibble (final dietary TiO2 content: 0.77 g/kg). Dogs were fed the diet for seven consecutive days at 480 kJ * BW(0.75). On day 7, owners were asked to collect all faeces during 24 h and store faeces at -20 degrees C. Faecal samples were analysed for DM, ash, N, crude fat (CF), crude fibre and Ti and gross energy (GE) and organic matter were calculated. Means with their standard errors apparent faecal digestibility of GE, DM, organic matter, N, CF and crude fibre was 83.7 (0.71), 77.4 (0.79), 83.0 (0.61), 77.7 (0.81), 94.3 (0.51) and 30.3 (4.85), respectively. No significant differences were observed in nutrient digestibility due to weight, age, sex or neuter status. The digestibility assay using a practical approach described here may be a promising tool to determine digestibility of dietary nutrients under free-living conditions. Owner compliance, however, is a potentially limiting factor. PMID- 26101601 TI - Comparison of the digestive efficiency of extruded diets fed to ferrets (Mustela putorius furo), dogs (Canis familiaris) and cats (Felis catus). AB - The digestive tract of ferrets is anatomically simple, with no caecum, ileocolic valve or external differentiation between the transition of ileum and colon. The species has a short large intestine that provides minor contributions to the digestive process. Aiming to better understand the digestibility efficiency of ferrets, the present study compared the digestibility of extruded diets with different amounts of macronutrients fed to dogs, cats and ferrets. Three formulations for cat maintenance were used (values in % of DM basis): high carbohydrate (HC; nitrogen-free extract (NFE) = 54 %, protein = 31 % and fat = 8 %); moderate carbohydrate (MC; NFE = 37 %, protein = 41 % and fat = 10 %); and low carbohydrate (LC; NFE = 19 %, protein = 46 % and fat = 23 %). Apparent total tract macronutrient digestibility was determined by the method of total collection of faeces. Results were compared by ANOVA, considering the diet and species effects and their interactions. Means were compared by the Tukey's test (P < 0.05). Dogs and cats presented similar food intakes, but ferrets consumed almost two times more food (g/kg body weight). Species * diet interactions were verified for apparent total tract digestibility (ATTD; P < 0.05). Ferrets presented lower DM digestibility than dogs and cats for all three diets (P < 0.05), lower NFE digestibility than dogs for the three diets and lower NFE digestibility than cats for the HC and LC diets (P < 0.05). For crude protein (CP), ferrets presented lower ATTD than dogs and cats (P < 0.05), whereas for fat, dogs and ferrets presented similar ATTD, and higher values than those presented by cats (P < 0.05). Kibble diets had a lower DM, CP and NFE digestibility when fed to ferrets compared with dogs and cats. Fat digestibility was similar between dogs and ferrets and higher than that for cats. PMID- 26101602 TI - Acute changes in blood metabolites and amino acid profile post-exercise in Foxhound dogs fed a high endurance formula. AB - Dogs participating in endurance exercise, including herding, hunting and racing have a greater energy requirement and may be more susceptible to nutrient depletion, electrolyte imbalance and metabolic stress. The objective of the present study was to investigate the acute response to unstructured mixed exercise in American Foxhounds fed a nutrient-fortified endurance diet. Thirty nine adult Foxhound dogs (median age: 5.0, range: 2-10 years and median body weight (BW): 36.4, range: 24.9-49.5 kg) were allotted to a standard performance diet (Control) or nutrient-fortified endurance diet for adult dogs (Test). Dogs were balanced by sex, age, BW and athletic performance between diets. All male dogs were intact, whereas all the female dogs were spayed. After 80 d on diet, blood samples were collected via jugular puncture at baseline (0 h), and at 3 and 25 h post-exercise (mean: 17.7 (sem 0.92) km run over 2-3 h). Plasma taurine concentration and complete amino acid (AA) profile, serum chemistry and creatine kinase were measured. Serum chemistry profile remained within normal ranges throughout the study. A significant (P < 0.05) diet by time interaction was observed for calcium, alkaline phosphatase and most AA. Plasma taurine and most essential AA were increased (P < 0.05) after exercise and remained greater (P < 0.05) in dogs fed the Test diet, including the branched-chain AA (isoleucine, leucine and valine). Creatine kinase increased (P = 0.01) after 3 h and returned to baseline after 25 h post-exercise, but was not altered by diet. These data indicate that dogs undergoing a moderate bout of exercise did not suffer from electrolyte imbalance, and that a nutrient-fortified diet resulted in greater plasma taurine and essential AA concentrations. PMID- 26101603 TI - Energy requirements for racing endurance sled dogs. AB - Endurance sled dogs have unique dietary energy requirements. At present, there is disparity in the literature regarding energy expenditure and thus energy requirements of these dogs. We sought to further elucidate energy requirements for endurance sled dogs under field conditions. Three sled dog teams completing the 2011 Yukon Quest volunteered to provide diet history. Nutritional content was evaluated and a mock meal was analysed for each team. Race data were obtained from www.yukonquest.com. Dogs were weighed at the start of the race in Whitehorse Yukon (WH), a mid-way checkpoint in Dawson Yukon (DS) and at the finish in Fairbanks Alaska. Data are average value per dog or per dog per d. Linear regression compared average weight loss to average kcal/dog consumed daily. Diets and feeding regimes were similar for all three teams. The average daily energy intake and nutrient content was similar for all diets. During leg one (WH to DS), team 1 gained weight overall, whereas the other two teams experienced weight loss. Linear regression revealed 37 638 kJ/dog/d (8995 kcal/dog/d) was required for weight maintenance. During leg two (DS to Fairbanks Alaska), average weights decreased for all three teams. The extrapolated kcal requirement was approximately 57 734 kJ/dog/d (13 799 kcal/dog/d). The carbohydrate contents of these diets also suggest that presumed fat intake for endurance sled dogs may be slightly less than previously thought. Finally, these data support the concept that dietary energy requirements vary substantially with additional variables such as load pulled, terrain and ambient temperature. PMID- 26101604 TI - Reactive lysine content in commercially available pet foods. AB - The Maillard reaction can occur during processing of pet foods. During this reaction, the epsilon-amino group of lysine reacts with reducing sugars to become unavailable for metabolism. The aim of the present study was to determine the reactive lysine (RL; the remaining available lysine) to total lysine (TL) ratio of commercial pet foods and to evaluate whether RL levels meet minimal lysine requirements (MLR). Sixty-seven extruded, canned and pelleted commercially available dog and cat foods for growth and maintenance were analysed for proximate nutrient composition, TL and RL. RL was expressed on a metabolisable energy basis and compared with the MLR for maintenance and growth. In dog foods, average RL:TL ratios were 0.87 (se 0.02) for extruded, 0.97 (se 0.02) for canned and 0.85 (se 0.01) for pelleted foods, with the lowest ratio of 0.77 in an extruded diet for growing dogs. In extruded and canned cat foods, the average ratio was 0.91 (se 0.02) and 0.90 (se 0.03), respectively, with the lowest ratio being 0.67 in an extruded diet for growing cats. Variation in the RL:TL ratio between and within processing type indicate that ingredients rather than processing might be the key factor influencing RL content in pet foods. Eight dry foods for growing dogs had RL contents between 96 and 138 % of MLR, indicating that RL has to be between 62 and 104 % digestible to meet the MLR. Considering the variability in RL digestibility, these foods could be at risk of not meeting the MLR for growing dogs. Ingredients and pet foods should be characterised with respect to the RL content and digestibility, to avoid limitations in the lysine supply to growing dogs. PMID- 26101605 TI - Prediction of crude protein digestibility of animal by-product meals for dogs by the protein solubility in pepsin method. AB - Animal by-product meals have large variability in crude protein (CP) content and digestibility. In vivo digestibility procedures are precise but laborious, and in vitro methods could be an alternative to evaluate and classify these ingredients. The present study reports prediction equations to estimate the CP digestibility of meat and bone meal (MBM) and poultry by-product meal (PM) using the protein solubility in pepsin method (PSP). Total tract CP digestibility of eight MBM and eight PM samples was determined in dogs by the substitution method. A basal diet was formulated for dog maintenance, and sixteen diets were produced by mixing 70 % of the basal diet and 30 % of each tested meal. Six dogs per diet were used to determine ingredient digestibility. In addition, PSP of the MBM and PM samples was determined using three pepsin concentrations: 0.02, 0.002 and 0.0002 %. The CP content of MBM and PM ranged from 39 to 46 % and 57 to 69 %, respectively, and their mean CP digestibility by dogs was 76 (2.4) and 85 (2.6) %, respectively. The pepsin concentration with higher Pearson correlation coefficients with the in vivo results were 0.0002 % for MBM (r 0.380; P = 0.008) and 0.02 % for PM (r 0.482; P = 0.005). The relationship between the in vivo and in vitro results was better explained by the following equations: CP digestibility of MBM = 61.7 + 0.2644 * PSP at 0.0002 % (P = 0.008; R (2) 0.126); and CP digestibility of PM = 54.1 + 0.3833 * PSP at 0.02 % (P = 0.005; R (2) 0.216). Although significant, the coefficients of determination were low, indicating that the models were weak and need to be used with caution. PMID- 26101606 TI - Post-castration variations in weight gain in a cohort of young adult male cats. AB - The predisposition of cats to gain weight following neutering is well established; however, there is little information about the distribution and range of post-neutering weight gains observed in cats under a controlled environment. This retrospective study investigated 6-month post-castration weight gain and distribution of percentage body weight (BW) change in a cohort of twenty, male domestic shorthair cats relative to a control group of intact cats. Cats were matched in age (2.0-2.6 years), husbandry conditions and consumed ad libitum the same dry maintenance diet for at least 3 months prior to and 6 months following castration. All cats were castrated within 48 h of each other. All cats gained weight after castration. Mean BW was 4.67 (sd 0.70) kg at the start of the study and 5.93 (sd 1.38) kg at the end of the study, with individual weight gain ranging 3-53 % at 6 months post-neutering. The pre-conception BW of the queens of each cat was compared with the pre- and post-neutering BW of their offspring. The pre-conception BW of the queens was significantly correlated with the offspring's initial BW (rho = 0.65, P = 0.01), final BW (rho = 0.67, P = 0.01) and percentage BW change (rho = 0.54, P = 0.04). A wide range of post-castration weight gains was observed among cats of similar backgrounds and housing conditions. Implementation of effective methods to control food consumption pre-conception and post-neutering may be a strategy for preventing obesity and obesity-related disorders in cats. PMID- 26101607 TI - The effects of feeding resistant starch on apparent total tract macronutrient digestibility, faecal characteristics and faecal fermentative end-products in healthy adult dogs. AB - The benefits of whole grain consumption have been studied in human subjects, but little research exists on their effects in dogs. The objective of the present study was to test the effects of resistant starch (RS) in the diet of healthy adult dogs. Twelve adult Miniature Schnauzer dogs (eight males, four females; mean age: 3.3 (1.6) years; mean body weight: 8.4 (1.2) kg; mean body condition score: D/ideal) were randomly allotted to one of three treatment groups, which consisted of different amounts of RS supplied in a biscuit format. Dogs received either 0, 10 or 20 g biscuits per d (estimated to be 0, 2.5 or 5 g RS per d) that were fed within their daily energetic allowance. A balanced Latin square design was used, with each treatment period lasting 21 d (days 0-17 adaptation; days 18 21 fresh and total faecal collection). All dogs were fed the same diet to maintain body weight throughout the study. Dogs fed 5 g RS per d had lower (P = 0.03) fat digestibility than dogs fed 0 gRS per d, but DM, organic matter and crude protein digestibilities were not affected. Faecal fermentative end products, including SCFA and branched-chain fatty acids, ammonia, phenols and indoles, and microbial populations were not affected. The minor changes observed in the present study suggest the RS doses provided to the dogs were too low. Further work is required to assess the dose of RS required to affect gut health. PMID- 26101608 TI - Amino acid content of selected plant, algae and insect species: a search for alternative protein sources for use in pet foods. AB - In response to global economic duress and heightened consumer awareness of nutrition and health, sustainable and natural ingredients are in demand. Identification of alternative sources of nitrogen and amino acids, including taurine, may help meet dietary requirements while fostering sustainability and natural feeding approaches. Twenty plants, eighteen marine algae and five insect species were analysed. All samples were freeze-dried, hydrolysed and filtered prior to amino acid analysis. Samples for amino acids were analysed in duplicate and averaged. Nitrogen was analysed and crude protein (CP) determined by calculation. With the exception of taurine concentration in soldier fly larvae, all insects exceeded both the National Research Council's canine and feline minimal requirements (MR) for growth of all essential amino acids (EAA) and CP. Although some plants and marine algal species exceeded the canine and feline MR for growth for EAA and CP, only very low concentrations of taurine were found in plants. Taurine concentration in insects was variable but high, with the greatest concentration found in ants (6.42 mg/g DM) and adult flesh flies (3.33 mg/g DM). Taurine was also high in some macroalgae, especially the red algal species: Mazaella spp. (4.11 mg/g DM), Porphyra spp. (1.22 mg/g DM) and Chondracanthus spp. (6.28 mg/g DM). Preliminary results suggest that insects and some marine algal species may be practical alternatives to traditional protein and supplemental taurine sources in pet foods. Safety, bioavailability, palatability and source variability of alternative items as food ingredients should be investigated prior to incorporation into canine and feline diets. PMID- 26101609 TI - A moderate fat, low-energy dry expanded diet reduces gain in body condition score when fed as part of a post neutering weight-control regimen in growing pet cats. AB - Neutering of cats has been associated with significant weight gain in the weeks following surgery. The present study aimed to evaluate the effectiveness of a moderate fat, low-energy dry expanded diet in reducing weight gain in growing pet cats when fed as part of a weight-control regimen over the 6 months post neutering. Cats in participating primary care veterinary hospitals were enrolled at neutering and assigned to receive one of the two dietary treatments based on the hospital of origin. Owners of cats in the treatment group were instructed to feed the trial diet at maintenance (324.7 kJ/kg BW(0.711) per d). Instructions for the control group were to feed the cat's regular diet according to the manufacturer's recommendations. Body weight and condition were evaluated by veterinarians at enrolment, 2-weeks, and 1-4 and 6 months after surgery. Body condition score (five-point scale) was compared between enrolment and each subsequent visit, controlling for enrolment age and sex. Percentage change in body weight was evaluated via multivariate mixed modelling to account for repeated measures. A total of 187 cats (eighty-seven females and 100 males) with a mean age of 5.2 (sd 0.8) months and mean weight of 2.8 (sd 0.6) kg from fifty one hospitals completed the trial. The odds of being scored as overweight were 4.1 times as great for cats in the control v. treatment groups (95 % CI 2.1, 8.2). Percentage change in body weight differed significantly with enrolment age (P = 0.007) and approached significance between diet groups (P = 0.08). Cats fed the trial diet had a significantly reduced incidence of overweight in the 6 months following neutering. PMID- 26101610 TI - Effect of age, gestation and lactation on faecal IgA and calprotectin concentrations in dogs. AB - Faecal calprotectin and IgA have been suggested as non-invasive markers of gut health. Faecal calprotectin is a marker of intestinal inflammation in adults, whereas IgA has been suggested as a marker of intestinal immunity. The purpose of the present study was to evaluate the effect of gestation, lactation and age on faecal concentrations of these biomarkers. Thirty puppies, nineteen pregnant or lactating bitches and eighty-nine healthy control adult dogs were included in the study. Faeces were collected from the fourth week of gestation until the eighth week of lactation in pregnant and lactating bitches, and between 4 and 9 weeks of age in puppies. Faeces from the eighty-nine healthy control adult dogs were also collected. Faecal calprotectin and IgA concentrations were measured. Faecal calprotectin concentrations in control dogs were significantly lower than faecal calprotectin concentrations in puppies between 4 and 6 weeks of age (P < 0.001) or between 7 and 9 weeks of age (P = 0.004). Puppies between 4 and 6 weeks of age had significantly higher faecal IgA concentrations compared with puppies between 7 and 9 weeks of age (P = 0.001). Bitches during their second month of lactation had significantly lower faecal IgA concentrations compared with their first month of lactation (P = 0.049). Faecal calprotectin and IgA have been suggested as non invasive and easily measured biomarkers of gut health in adults. However, the present study underlines that faecal IgA and calprotectin concentrations vary markedly depending of physiologic factors such as gestation, lactation and age. These factors need to be considered when these faecal biomarkers are used for evaluation of intestinal immunity or inflammation. PMID- 26101611 TI - Body condition of dogs fed diets containing soya hulls. AB - Obesity is a growing problem in dogs. Therefore, there is an increasing need of foods for obese dogs with high-fibre content to dilute energies and to reduce energy absorption. Soya hulls are cheap and are widely available as a fibre source. We aimed at evaluating the body condition of dogs fed diets containing 0 % soya hulls (0SH) or 16 % soya hulls (16SH) in replacement of maize. Twelve adult dogs, with 11.3 (se 1.6) kg average body weight (BW), 4.1 (se 0.1) years old and body condition score (BCS) between 4 and 7, were completely randomised assigned (six per treatment) and were fed the 0SH diet according to their maintenance energy requirements or the same amount in grams (g/kg BW(0.75)) of the 16SH diet once daily for 56 d. The animals were evaluated on days 0 and 57 for BW, BCS (1, very thin to 9, obese), subcutaneous fat thickness in the L7 vertebra using ultrasound (L7), canine BMI (CBMI) and body fat (BF). Data were analysed by the Student's t test and Kruskal-Wallis test (P < 0.05). The change (final - initial) in BW (-0.58 v. -0.49 kg), BCS (-1 v. -1), L7 (-2 v. 0.35 mm), CBMI (-0.85 v. -0.63 kg/m(2)) and BF (-5.0 v. -5.4 %) of dogs fed the 0SH and 16SH diets, respectively, were not different (P > 0.05). The 16SH diet, with 11.4 % restriction in metabolisable energy, did not change the BCS of adult dogs. Further studies evaluating the supply of soya hulls only to overweight/obese dogs should to be carried out, because these dogs may respond differently than the group evaluated, which had a BCS between 4 and 7 (ideal to overweight). PMID- 26101612 TI - Dietary gamma-linolenic acid supports arachidonic acid accretion and associated Delta-5 desaturase activity in feline uterine but not ovarian tissues. AB - Arachidonic acid (ARA) is essential in felines because conversion of dietary linoleic acid (LA) to ARA is rate-limited by low Delta6-desaturase. Dietary gamma linolenic acid (GLA) may serve as an ARA precursor by-passing this initial rate limiting step. This possibility was investigated using twenty-six adult female domestic shorthair cats divided into three groups and fed on complete and balanced diets containing high GLA (GL), high LA (HL) or low LA (LL, control) diets, for 300 d prior to ovariohysterectomy. Plasma was obtained 1-2 d before surgery and uterine, ovarian and associated adipose tissues were reserved for lipid analysis. Fatty acid profiles of the plasma phospholipid (PL) fractions and adipose lipids were performed. In the GL group, plasma and uterine tissue PL were significantly enriched in GLA, di-homo GLA (DGLA) and ARA compared with control. However, ovarian and adipose tissue PL were only enriched in DGLA. Enrichment of uterine tissues with DGLA and ARA probably supplies the essential eicosanoid precursors for reproduction when GLA is fed consistently with an active Delta5 desaturase in uterus. By contrast, this enzyme appears less active in ovary because ARA was not higher compared with control. Earlier reports concluded that ARA was not necessary for fertilisation (an ovarian function), but required for successful pregnancy and reproduction (a uterine function). Adipose tissue DGLA may be a reservoir for ARA synthesis by other tissues upon mobilisation. Dietary GLA may meet feline ARA requirements in the absence of an animal-based preformed source of ARA. PMID- 26101613 TI - Owner misperception of canine body condition persists despite use of a body condition score chart. AB - Canine obesity is a prevalent disease, but many owners are unaware of it, partly due to misperception of their dog's body shape. Body condition scoring (BCS) is a simple method of assessing body composition, but whether it can reduce owner misperception is unclear. Our aim was to determine the effect of a BCS system on owners' ability to estimate the body condition of their dog. Information from 110 dog owners attending three UK veterinary practices was gathered, by interview, between March and April 2013. First, owners were asked to determine their dog's body condition without guidance, and then reassess it using a five-point BCS chart. Most owners (85/110, 77 %) believed the chart to have improved their ability to estimate the condition of their dog correctly. However, only a weak agreement existed between owner estimates and those of the primary investigator, both with (kappa (kappa) = 0.28; P < 0.001) and without (kappa = 0.32; P < 0.001) the BCS chart. Furthermore, most owners incorrectly estimated their dog's body condition, both with (71/110; 64 %) and without (72/110; 65 %) the chart (P = 1.00), with underestimation being most common (with = 63/71, 89 %; without = 66/72, 92 %; P = 0.57). Owners of overweight dogs more commonly misperceived their dog's body condition, both with (BCS 1-3: 5/35, 14 %; BCS 4-5: 64/75, 85 %; P < 0.001) and without (BCS 1-3: 10/35, 28 %; BCS 4-5: 61/75, 81 %; P < 0.001) the BCS chart. Thus, use of a five-point BCS chart does not improve accuracy of owners' perception of their dog's body shape, despite the accompanying perception that it does. PMID- 26101614 TI - The impact of date palm fruits and their component polyphenols, on gut microbial ecology, bacterial metabolites and colon cancer cell proliferation. AB - The fruit of the date palm (Phoenix dactylifera L.) is a rich source of dietary fibre and polyphenols. We have investigated gut bacterial changes induced by the whole date fruit extract (digested date extract; DDE) and its polyphenol-rich extract (date polyphenol extract; DPE) using faecal, pH-controlled, mixed batch cultures mimicking the distal part of the human large intestine, and utilising an array of microbial group-specific 16S rRNA oligonucleotide probes. Fluorescence microscopic enumeration indicated that there was a significant increase in the growth of bifidobacteria in response to both treatments, whilst whole dates also increased bacteroides at 24 h and the total bacterial counts at later fermentation time points when compared with DPE alone. Bacterial metabolism of whole date fruit led to the production of SCFA, with acetate significantly increasing following bacterial incubation with DDE. In addition, the production of flavonoid aglycones (myricetin, luteolin, quercetin and apigenin) and the anthocyanidin petunidin in less than 1 h was also observed. Lastly, the potential of DDE, DPE and metabolites to inhibit Caco-2 cell growth was investigated, indicating that both were capable of potentially acting as antiproliferative agents in vitro, following a 48 h exposure. This potential to inhibit growth was reduced following fermentation. Together these data suggest that consumption of date fruits may enhance colon health by increasing beneficial bacterial growth and inhibiting the proliferation of colon cancer cells. This is an early suggestion that date intake by humans may aid in the maintenance of bowel health and even the reduction of colorectal cancer development. PMID- 26101615 TI - In vitro disappearance characteristics of selected categories of commercially available dog treats. AB - Pet owners desire treats with adequate nutritional profiles, functional benefits, long-lasting properties and an interactive nature. Therefore, it is pivotal to understand the digestion characteristics of treats produced by different processing methods and having variable nutritional composition. The objective of the present study was to measure in vitro disappearance characteristics of selected categories of commercially available treats. In vitro procedures developed by Boisen and Eggum in 1991 were modified to handle larger sample sizes. Treat samples were evaluated in triplicate. Following incubation, in vitro DM disappearance (DMD) was calculated. In vitro DMD of selected treats varied widely. For the gastric phase, DMD ranged from 6.9 to 88.8 %, whereas intestinal phase digestion resulted in a DMD range of 10.7-100.0 % (P < 0.05). Because of differences in treat composition and size, they were divided into six categories: Biscuit, Bone, Chew, Dental, Meat Product and Rawhide. In general, Bone was the least digestible treat category in both gastric and intestinal phases. Meat Product and Rawhide treats had a DMD of 71.5-100 % after the intestinal phase, whereas Biscuit had values above 93 %. Chew and Dental treats had a wide DMD range (54.5-100 %). Understanding the DMD of commercially available treats is important to verify their safety for consumption and potential digestibility once ingested. These data indicate wide variation in DMD among and within different treat categories. This information will assist pet food sale associates, pet owners and veterinarians to make more educated decisions when it relates to selection and recommendations about commercially available treats. Future work is needed to expand the knowledge on in vitro DMD and safety of treats and to further investigate their impact on in vivo DM digestibility once fed to dogs. PMID- 26101616 TI - Coffee and beverages are the major contributors to polyphenol consumption from food and beverages in Japanese middle-aged women. AB - Food and beverages rich in polyphenols have been shown to reduce the risk of non communicable diseases. The present study estimated polyphenol levels and consumption from food and beverages in Japanese women. Randomly recruited housewives living in the area around Tokyo (n 109; aged 21-56 years; Group 1) recorded all beverages and foods they ingested for 7 d, and the total polyphenol (TP) consumption was estimated based on the TP content of each item measured with a modified Folin-Ciocalteu method. For Group 1, TP was consumed at 841 (sd 403) mg/d (range 113-1759 mg/d), and beverages were a larger source of TP (79 %) than food (21 %). The largest single source of TP was coffee at 47 %, followed by green tea, black tea, chocolate, beer and soya sauce, at 16, 5.7, 3.3, 3.2 and 3.1 %, respectively. In terms of food groups, cereals/noodles, vegetables, fruits, beans and seeds, and seasonings (except for soya sauce) contributed 5.0, 4.0, 1.4, 1.8 and 2.4 %, respectively. Another group of housewives who consumed at least one cup of coffee per d were separately recruited (n 100; Group 2) in the same area. Their consumption of TP was higher at 1187 (sd 371) mg/d (range 440-2435 mg/d) than Group 1 (P < 0.001), and the difference mostly came from the coffee consumption. We conclude that not food but beverages, especially coffee, may be the major contributor to TP consumption in Japanese women. PMID- 26101617 TI - Tolerance and the effect of high doses of wheat bran extract, containing arabinoxylan-oligosaccharides, and oligofructose on faecal output: a double blind, randomised, placebo-controlled, cross-over trial. AB - Wheat bran extract (WBE) is a food-grade soluble fibre preparation that is highly enriched in arabinoxylan-oligosaccharides. In this placebo-controlled cross-over human intervention trial, tolerance to WBE as well as the effects of WBE on faecal parameters, including faecal output and bowel habits, were studied. After a 2-week run-in period, twenty healthy volunteers consumed WBE (15 g/d in the first week, 30 g/d in the second week), oligofructose (15 g/d in the first week, 30 g/d in the second week) and placebo (for 2 weeks) in a random order, with 2 week washout periods between each treatment period. Subjects collected a 72 h stool sample for analysis of faecal output, stool pH and stool moisture concentration. Additionally, the volunteers completed questionnaires scoring occurrence frequency and distress severity of eighteen gastrointestinal (GI) symptoms. An overall GI symptom measure was calculated to analyse the overall effect of WBE and oligofructose on GI symptoms. Intake of both 30 g/d WBE and 30 g/d oligofructose lowered stool pH, indicative of increased colonic fermentation, and increased stool moisture concentration as compared with placebo intake. Intake of 30 g/d oligofructose increased the overall GI symptom measure by 1.9 fold as compared with placebo intake. Intake of WBE at doses up to 30 g/d did not affect the overall GI symptom measure. WBE exerts beneficial effects on stool characteristics and is well tolerated at up to 30 g/d. Oligofructose exerts comparable beneficial effects on stool characteristics. However, intake of 30 g/d oligofructose appears to cause GI discomfort to some extent. PMID- 26101618 TI - Dietary patterns and physical inactivity, two contributing factors to the double burden of malnutrition among adults in Burkina Faso, West Africa. AB - A population-based cross-sectional study was carried out in the northern neighbourhoods of Ouagadougou (Burkina Faso), to examine the relationship of nutritional deficiencies and cardiometabolic risk factors (CMRF) with lifestyle in adults. We randomly selected 330 households stratified by income tertile. In each income stratum, 110 individuals aged 25-60 years and having lived in Ouagadougou for at least 6 months were randomly selected. We performed anthropometric, dietary intake and physical activity measurements, and blood sample collection. Cluster analysis of dietary intake identified two dietary patterns: 'urban' (29 % of subjects) and 'traditional' (71 %). The 'urban' cluster exhibited a higher intake of fat and sugar, whereas a higher intake of plant protein, complex carbohydrate and fibre was observed in the 'traditional' pattern. Female sex, low income and lack of education were associated with the 'traditional' cluster, as well as Fe and vitamin A deficiency. CMRF prevalence (abdominal obesity, hypertension, hyperglycaemia, dyslipidaemia) was similar in both clusters. Subjects in the 'traditional' cluster spent more time in physical activity and had less sedentary time than those in the 'urban' cluster. 'Traditional' dietary pattern, low income, female sex and sedentary time were significant contributing factors to the double burden of malnutrition. The rapid nutrition transition is reflected in this co-occurrence of CMRF and nutritional deficiencies. This stresses the need for prevention strategies addressing both ends of the nutrition spectrum. PMID- 26101619 TI - Relevance of dietary protein concentration and quality as risk factors for the formation of calcium oxalate stones in cats. AB - The role of dietary protein for the development of feline calcium oxalate (CaOx) uroliths has not been conclusively clarified. The present study evaluated the effects of a varying dietary protein concentration and quality on critical indices for the formation of CaOx uroliths. Three diets with a high protein quality (10-11 % greaves meal/diet) and a varying crude protein (CP) concentration (35, 44 and 57 % in DM) were compared. Additionally, the 57 % CP diet was compared with a fourth diet that had a similar CP concentration (55 % in DM), but a lower protein quality (34 % greaves meal/diet). The Ca and oxalate (Ox) concentrations were similar in all diets. A group of eight cats received the same diet at the same time. Each feeding period was divided into a 21 d adaptation period and a 7 d sampling period to collect urine. There were increases in urinary volume, urinary Ca concentrations, renal Ca and Ox excretion and urinary relative supersaturation (RSS) with CaOx with increasing dietary protein concentrations. Urinary pH ranged between 6.34 and 6.66 among all groups, with no unidirectional effect of dietary protein. Lower renal Ca excretion was observed when feeding the diet with the lower protein quality, however, the underlying mechanism needs further evaluation. In conclusion, although the observed higher urinary volume is beneficial, the increase in urinary Ca concentrations, renal Ca and Ox excretion and urinary RSS CaOx associated with a high-protein diet may be critical for the development of CaOx uroliths in cats. PMID- 26101621 TI - Lutein and cognition in children. PMID- 26101620 TI - Comparison of the GEM and the ECAL indirect calorimeters against the Deltatrac for measures of RMR and diet-induced thermogenesis. AB - The DeltatracTM II Metabolic Monitor (Datex-Ohmeda Inc.) is considered the standard reference machine in indirect calorimetry; however, it is no longer commercially available thus there is a need for new machines. The gas exchange measurement (GEM; GEM Nutrition Ltd) and the ECAL (Health Professional Solutions) are alternative measuring systems. The aim of this study was to compare the ECAL and GEM with Deltatrac for measures of RMR and the GEM to the Deltatrac for measures of diet-induced thermogenesis (DIT). Twenty healthy participants were tested on test day 1 (T1) and test day 2 (T2). RMR was measured in a randomised order for 30 min on the Deltatrac, the GEM and the ECAL. Following this, a 1553 kJ meal was consumed and DIT was measured on the Deltatrac and the GEM in alternating 15 min intervals for 4 h. The GEM reported consistently higher values than the Deltatrac for VO2, VCO2, RMR and fat oxidation (P < 0.005). The ECAL was significantly higher than the Deltatrac for measures of VO2, RMR, carbohydrate oxidation (T2) and respiratory quotient and fat oxidation (T1, T2) (P < 0.05). There were no significant differences within repeated RMR measures on the ECAL, the GEM or the Deltatrac. DIT measures were consistently higher on the GEM (T1) (P < 0.005); however, there were no significant differences between repeated measures. The findings suggest that while the GEM and the ECAL were not accurate alternatives to the Deltatrac, they may be reliable for repeated measures. PMID- 26101622 TI - Protection against canine parvovirus type 2 infection in puppies by colostrum derived antibodies. AB - During the first weeks of life puppies remain protected against canine parvovirus type 2 (CPV2) infection thanks to maternally derived antibodies (MDA) absorbed with colostrum after birth. The objective of the present study was to present the variability in CPV2-specific passive immune transfer and its consequences in puppies naturally exposed to the parvovirus. Seventy-nine puppies from one breeding kennel were included in the study at birth and followed until 56 d of age. Once per week the MDA titre for CPV2 specific antibodies was determined in blood. Viral excretion was also evaluated on a rectal swab by CPV2 PCR assay and puppies were weighed to determine growth rate. At 2 d of age, thirty-four out of seventy-nine puppies (43 %) had MDA <=1:160 (designed group A) and forty-five puppies (57 %) had greater MDA titres (designed group B). The level of absorbed maternal antibodies was shown to be associated with breed size and growth rate during the first 48 h of life. The MDA level declined with age in all cases; however, the proportion of puppies with the antibody level considered as protective against CPV2 infection was significantly higher in group B compared with A from day 2 until 42. Among all puppies surviving until 56 d of age, sixty seven out of seventy (95.7 %) underwent CPV2 infection. However, puppies from group A excreted CPV2 significantly earlier than puppies from group B. The present study demonstrates the link between passive immune transfer, in terms of level of specific MDA absorbed, and length of the protection period against parvovirus infection in weaning puppies. PMID- 26101623 TI - Seasonal differences in food and nutrient intakes among young children and their mothers in rural Burkina Faso. AB - It is important to understand and account for seasonal variation in food and nutrient intakes when planning interventions to combat micronutrient deficiencies in resource-poor settings. The objective of the present study was to quantify food and nutrient intakes and assess the adequacy of micronutrient intakes among young children and their mothers during the lean and post-harvest (PH) seasons in rural Burkina Faso. We quantified food intakes by 24-h recall in a representative sample of 480 children aged 36-59 months and their mothers in two provinces in Western Burkina Faso. We calculated the probability of adequacy (PA) of usual intakes of ten micronutrients and an overall mean PA (MPA). Seasonal changes in nutrient intakes and PA were assessed by mixed linear regression and non parametric tests, respectively. Energy intakes did not differ significantly between seasons for women or children, although the women's intakes were slightly higher in the PH season. Most of the micronutrient intakes were significantly higher in the PH season, with the exception of vitamin A which was lower and vitamin B12 and Zn which were similar across seasons. MPA increased significantly across seasons, from 0.26 to 0.37 for women and from 0.43 to 0.52 for children. PA of Ca, vitamin C, folate and vitamin B12 were very low. Staple grains and vegetables were major sources of micronutrients but intakes were not sufficient to meet nutrient needs for the majority of the subjects. Food-based strategies are needed to increase micronutrient intakes of women and children in Burkina Faso. PMID- 26101624 TI - Skipping breakfast leads to weight loss but also elevated cholesterol compared with consuming daily breakfasts of oat porridge or frosted cornflakes in overweight individuals: a randomised controlled trial. AB - Eating breakfast may reduce appetite, body weight and CVD risk factors, but the breakfast type that produces the greatest health benefits remains unclear. We compared the effects of consuming a high-fibre breakfast, a non-fibre breakfast, or no-breakfast control on body weight, CVD risk factors and appetite. A total of thirty-six overweight participants (eighteen men and eighteen women) (mean age 33.9 (sd 7.5) years, mean BMI 32.8 (sd 4.7) kg/m(2)) were randomly assigned to consume oat porridge (n = 12), frosted cornflakes (n = 12) or a water control (n = 12) breakfast daily for 4 weeks. Appetite ratings were collected on the first day and weekly thereafter. Before and after the intervention, body weight, composition, blood pressure and resting energy expenditure (REE) were measured and a fasting blood sample was collected. Across the 4 weeks, fullness was higher and hunger was lower in the oat porridge group compared with the control group (P < 0.05). Mean weight change over the intervention was significantly different in the control group (-1.18 (sd 1.16) kg) compared with both the cornflakes (-0.12 (sd 1.34) kg) and oat porridge (+0.26 (sd 0.91) kg) groups (P < 0.05). However, the control group also showed elevated total cholesterol concentrations relative to the cornflakes and oat porridge groups (P < 0.05). There were no differences between groups in changes in body composition, blood pressure, REE or other CVD risk factors. In conclusion, although skipping breakfast led to weight loss, it also resulted in increased total cholesterol concentrations compared with eating either oat porridge or frosted cornflakes for breakfast. PMID- 26101625 TI - A gene expression programme induced by bovine colostrum whey promotes growth and wound-healing processes in intestinal epithelial cells. AB - Bovine colostrum is well known for its beneficial properties on health and development. It contains a wide variety of bioactive ingredients that are known to promote a number of cellular processes. Therefore the use of colostrum whey as a feed additive to promote intestinal health has been proposed, yet little is known about mechanisms implicated in its beneficial properties on intestinal epithelial cells. In the present paper, casein were removed from bovine colostrum and the remaining liquid, rich in bioactive compounds, was evaluated for its capacity to modulate cellular processes in porcine intestinal epithelial cell line IPEC-J2 and human colon adenocarcinoma cell line Caco-2/15. First, we verified the effect of colostrum whey and cheese whey on processes involved in intestinal wound healing, including cell proliferation, attachment, morphology and migration. Our results showed that colostrum whey promoted proliferation and migration, and decreased specifically the attachment of Caco-2/15 cells on the culture dish. On the other hand, cheese whey induced proliferation and morphological changes in IPEC-J2 cells, but failed to induce migration. The gene expression profile of IPEC-J2 cells following colostrum whey treatment was evaluated by microarray analysis. Results revealed that the expression of a significant number of genes involved in cell migration, adhesion and proliferation was indeed affected in colostrum whey-treated cells. In conclusion, colostrum specific bioactive content could be beneficial for intestinal epithelial cell homoeostasis by controlling biological processes implicated in wound healing through a precise gene expression programme. PMID- 26101626 TI - How often do primary care veterinarians record the overweight status of dogs? AB - Obesity is a prevalent medical condition in dogs caused by the excess accumulation of fat, with negative effects on quality of life, longevity and the risk of developing associated pathologies. However, it is unclear how frequently first-opinion veterinarians record dogs as overweight (OW) or obese in medical records, and what factors determine when they do. Data sourced through the Small Animal Surveillance Network were used to determine the relative frequency of recording OW status (obesity or OW) in dogs presented to the UK first-opinion practices. Cases were identified using a search of clinical record-free text for relevant keywords. A case-control study was then conducted, comparing dogs where the OW status was recorded with a control group of obese dogs with no diagnosis recorded. Of 49 488 consultations, the OW status was recorded in 671 dogs (relative frequency 1.4 %). Using multiple logistic regression, the OW status of a dog was more likely to be recorded when the consultation was for osteoarthritis (OR 5.42; 95 % CI 2.09, 14.07; P < 0.001) or lameness (OR 2.02; 95 % CI 1.20, 3.42; P = 0.006). Furthermore, the OW status was more commonly recorded in dogs that were members of a practice health scheme (OR 5.35; 95 % CI 1.57, 18.17; P = 0.04) and less commonly recorded in microchipped dogs (OR 0.43; 95 % CI 0.41, 0.91; P = 0.02). These results suggest that OW and obesity are underdiagnosed in the first-opinion practice. However, a presentation for orthopaedic disease appears a key prompt for recording the OW status. Further studies are now warranted to determine the reasons for such marked underdiagnosis. PMID- 26101627 TI - Increasing volume of food by incorporating air reduces energy intake. AB - Major challenges with weight management using weight-loss diets include hunger and rapid consumption of food, both of which lead to poor owner compliance. The aim of the present study was to determine the effect of increasing volume, by incorporating air, into dry expanded food, on satiety in dogs. Three studies have been performed. The first study aimed to measure the effect of volume of food on meal duration in dogs fed at their maintenance energy requirement. The purpose of the second study was to determine the effect of volume of food on satiety. The aim of the third study was to compare the satiety effect of the test diet with a maintenance dry diet commonly used in adult dogs. Throughout the studies, faecal score remained optimal. As volume of diet increased, the duration of food intake significantly increased (P < 0.001) and energy intake significantly decreased (P = 0.012). The present study has demonstrated that incorporating air into food to increase the volume of diet induces a satiety effect, independent of macronutrient profile, possibly by slowing food intake. Consequently, incorporating air into food might be a useful strategy for weight management in companion animals. PMID- 26101628 TI - Effect of feeding frequency of a diet containing soya hulls on the food intake and behaviour of dogs. AB - Dietary fibre may promote satiety and reduce energy consumption per gram of food. Associated with feeding management, dietary fibre may contribute to reduce anxiety in dogs submitted to food restriction to lose weight. The objective of the present study was to evaluate the food intake and the behaviour of dogs fed diets without soya hulls (0SH) or with soya hulls (16SH) once (1*) or twice (2*) daily. Eight adult Beagle dogs, with 11.3 (se 1.6) kg body weight (BW), 4.1 (se 0.1) years of age and body condition score between 4 and 7, were distributed in 4 * 4 Latin square design (n 8/treatment, 5 d/period) in a 2 * 2 factorial arrangement (0SH v. 16SH; 1* v. 2*). Food allowance was 50 % in excess of the daily metabolisable energy (ME) requirements; food residues were weighed. The behavioural test consisted in continuously observations for 24 h, using the scanning sampling technique (observations every 10 min). General behaviours, such as sleeping, barking, standing and others were recorded. Food intake in g/kg BW(0.75) per d of 0SH and 16SH was not different (P > 0.05). However, dogs fed the 0SH diet presented higher (P > 0.05) energy intake (kJ/kg BW(0.75) per d; P < 0.05) compared with those fed the 16SH diet. Dogs fed 2* daily had higher intake, both in g and in kJ, compared with those fed 1 * , independently of diet. There was no interaction between diets and feeding frequency (P > 0.05). No behavioural differences were observed (P > 0.05). The diet containing 16SH, despite reducing ME intake, did not restrict food intake (in g). Dogs fed 1* per d had lower food intake, possibly due to gastric capacity limitation. PMID- 26101629 TI - Maternal high-fat diet consumption impairs exercise performance in offspring. AB - The aim of the present study was to scrutinise the influence of maternal high-fat diet (mHFD) consumption during gestation and lactation on exercise performance and energy metabolism in male mouse offspring. Female C3H/HeJ mice were fed either a semi-synthetic high-fat diet (HFD; 40 % energy from fat) or a low-fat diet (LFD; 10 % energy from fat) throughout gestation and lactation. After weaning, male offspring of both groups received the LFD. At the age of 7.5 weeks half of the maternal LFD (n 20) and the mHFD (n 21) groups were given access to a running wheel for 28 d as a voluntary exercise training opportunity. We show that mHFD consumption led to a significantly reduced exercise performance (P < 0.05) and training efficiency (P < 0.05) in male offspring. There were no effects of maternal diet on offspring body weight. Lipid and glucose metabolism was disturbed in mHFD offspring, with altered regulation of cluster of differentiation 36 (CD36) (P < 0.001), fatty acid synthase (P < 0.05) and GLUT1 (P < 0.05) gene expression in skeletal muscle. In conclusion, maternal consumption of a HFD is linked to decreased exercise performance and training efficiency in the offspring. We speculate that this may be due to insufficient muscle energy supply during prolonged exercise training. Further, this compromised exercise performance might increase the risk of obesity development in adult life. PMID- 26101630 TI - Fat digestibility is reduced in old cats with subnormal cobalamin concentrations. AB - Fat digestibility is decreased in old cats for unknown reasons. Subclinical gastrointestinal diseases and pancreatic dysfunction, both related to ageing, can affect food digestibility. The aim of the present study was to elucidate the prevalence of subnormal cobalamin concentration and pancreatic disease in old cats and study the relationship between both markers and fat digestibility. A total of sixty-four cats without evident signs of gastrointestinal disease were included and grouped according to age: (1) fifteen middle-aged (MA), aged 3-7 years; and (2) forty-nine old, aged 10-17 years. All cats were tested for serum cobalamin, specific feline pancreatic lipase (fPL) and feline trypsin-like immunoreactivity. Then, sixteen of the old cats were selected and grouped according to cobalamin and fPL concentrations: control (normal cobalamin and fPL); low vitamin B12 (cobalamin <290 ng/l; normal fPL); and high fPL (normal cobalamin; fPL >4 ug/ml). A food digestibility trial with a high-fat diet (21.6 %) was performed. In the old group, cobalamin was lower and fPL higher than in MA cats. Of the old cats (n 49), 14 % had subnormal cobalamin, 8 % had a severe increase in fPL, 2 % had both alterations and 14 % had a slight increase in fPL. By contrast, MA cats did not have cobalamin deficiency or an increase in fPL concentrations. Fat digestibility was lower in low vitamin B12 cats than control cats. Decreased fat digestibility is not present in all old cats but could be a characteristic of subclinical chronic gastrointestinal disease. Cobalamin concentration, as a marker of gastrointestinal disease, could be useful for the routine evaluation of old cats. PMID- 26101631 TI - Evaluation of eight commercial dog diets. AB - Estimation of the quality of commercial diets is a topic of interest for the majority of dog owners. Recently, in a French consumer association magazine, an evaluation of eight dog commercial dry diets (from super-premium, basic nutrition, private-label and economy brands) according to several nutritional criteria was published. The aims of the study were: (1) to evaluate the apparent digestibility of these diets; (2) to score these diets according to digestibility results; and (3) to compare these data with the scoring of the magazine. Six adult Beagle dogs were enrolled for the digestibility trials. Diets were scored according to energy, crude protein and crude fat (CF) apparent digestibility coefficients, digestible protein-to-energy ratios and ash content. Each of the five criteria was scored from 4 to 20 points. The ranges of crude protein, CF, crude fibre and ash content were 20.9-30.6 %, 6.8-19.7 %, 2.2-3.3 % and 4.6-9.7 % on a DM basis, respectively. The ranges of energy, crude protein and CF apparent digestibility coefficients were 72.6-87.7 %, 70.4-82.5 % and 76.1-95.4 %, respectively. The range of the protein-to-energy ratio was 10-14 digestible crude protein per MJ metabolisable energy. Little overlap in the scoring systems was found, but the private-label brand and economy brand diets presented the lowest scores in the two systems. These results showed that the evaluation of commercial diets should take into account multiple nutritional aspects. In particular, analytical and biological (digestibility) criteria should be considered as complementary in the evaluation of dry dog commercial diets. PMID- 26101632 TI - Less invasive left ventricular assist device implantation-a match changer! PMID- 26101633 TI - Effect of initial antihypertensive combination therapy on primary stroke prevention. PMID- 26101634 TI - Low bone mineral density is associated with increased arterial stiffness in participants of a health records based study. AB - AIMS: Many epidemiological studies have shown that low bone mineral density (BMD) and atherosclerosis appear to be related. However, their precise correlation is not completely understood after full adjustment the shared confounders of atherosclerosis and bone metabolism. The aim of this cross-sectional study was to investigate the relationship between BMD and subclinical atherosclerosis in a healthy Chinese population and the difference in gender. METHODS: The study population consisted of 2,487 subjects (1,467 men, 1,020 women) who participated in health check-up programs and were selected to be free of major diseases which might affect atherosclerosis and bone metabolism. Bone status was assessed by BMD in lumbar spine. The brachial-ankle PWV (baPWV) was assessed as a functional marker of atherosclerosis. The ankle-brachial index (ABI), carotid artery intima media thickness (CIMT), estimated glomerular filtration rate (eGRF) and microalbuminuria were evaluated as indexes of structural markers of atherosclerosis. RESULTS: After adjustment for risk factors, significant association was shown between baPWV and BMD in both genders (male: r=-0.084, P=0.035; female: r=-0.088, P=0.014). The correlation was stronger in females than in males, and in females, the correlation was stronger after menopause. Similarly, mean baPWV differed significantly according to the decreased BMD (normal BMD, Osteopenia, Osteoporosis). In contrast, no significant differences were observed for ABI, CIMT, eGFR or microalbuminuria with BMD. CONCLUSIONS: Independent of confounding factors, low BMD is associated with the functional marker of subclinical atherosclerosis (increased baPWV), but not with structural markers (ABI, CIMT, eGFR or microalbuminuria) among healthy females and males. PMID- 26101635 TI - Meta-analysis of the diagnostic yield and safety of electromagnetic navigation bronchoscopy for lung nodules. AB - OBJECTIVE: This meta-analysis is to evaluate the overall diagnostic yield and accuracy of electromagnetic navigation bronchoscopy (ENB)-based targeted biopsies in detecting peripheral lesions. METHODS: A systematic search in PubMed was performed using "electromagnetic navigation bronchoscopy" crossed with "peripheral lesions" and "lung nodules". Test performance characteristics with the use of forest plots, summary receiver operating characteristic curves (SROCs) and bivariate random effects were summarized using Meta-Disc software. Adverse events and complications were recorded if reported. RESULTS: A total of 17 studies (1,106 patients with peripheral lung lesions) were included in this analysis. The pooled sensitivity, specificity, positive likelihood ratios (PLRs), negative likelihood ratios (NLRs), and diagnostic odds ratios (DORs) of ENB was 82%, 100%, 19.36, 0.23, and 97.62, respectively. The area under the curve (AUC) for the SROC was 0.9786. No procedure-related complication was found. CONCLUSIONS: ENB is an effective and safe procedure in diagnosing peripheral lung lesions. PMID- 26101636 TI - Initial thrombolysis treatment compared with anticoagulation for acute intermediate-risk pulmonary embolism: a meta-analysis. AB - BACKGROUND: The use of thrombolysis in patients with acute, intermediate-risk pulmonary embolism (PE) remains controversial. This meta-analysis compared the efficacy and safety of thrombolysis and anticoagulation treatments for intermediate-risk PE patients. METHODS: Two investigators independently reviewed the literature and collected data from randomized controlled trials (RCTs) of thrombolysis for intermediate-risk PE in the PubMed, MEDLINE, EMBASE, the Cochrane Library, and Chinese Biomedical Literature Databases (CBM). RESULTS: A total of 1,631 intermediate-risk PE patients from seven studies were included. Significant differences were not found regarding the 30-day, all-cause mortality rates between the thrombolytic and anticoagulant groups [odds ratio (OR), 0.60; 95% confident interval (CI), 0.34-1.06; P=0.08]. The rate of clinical deterioration in the thrombolytic group was lower than that in the anticoagulant group (OR, 0.27; 95% CI, 0.18-0.41; P<0.01). Recurrent PE in the thrombolytic group was also significantly lower than that in the anticoagulant group (OR, 0.34; 95% CI, 0.15-0.77; P=0.01). Comparing the thrombolytic and anticoagulation groups, the incidence of minor bleeding was significantly higher in the thrombolytic group (OR, 5.33; 95% CI, 2.85-9.97; P<0.00001), but there were no difference in the incidences of major bleeding events (OR, 2.07; 95% CI, 0.60 7.16; P=0.25). CONCLUSIONS: Thrombolytic treatment for intermediate-risk PE patients, if not contraindicated, could reduce clinical deterioration and recurrence of PE, and trends towards a decrease in all-cause, 30-day mortality. Despite thrombolytic treatment having an increased total bleeding risk, there was no difference in the incidence of major bleeding events, compared with patients receiving anticoagulation treatment. PMID- 26101637 TI - Prognostic role of p53 and Ki-67 immunohistochemical expression in patients with surgically resected lung adenocarcinoma: a retrospective study. AB - OBJECTIVE: p53 mutations and the Ki-67 protein are frequently observed in various types of human cancer; the abnormal expression of p53 and Ki-67 in the tumor is associated with poor survival of lung cancer patients. We aimed to assess the prognostic role of immunohistochemical (IHC) expression of p53 and Ki-67 in lung adenocarcinoma tissue. METHODS: Tumor samples from 136 patients who had undergone surgical resection for lung adenocarcinoma were retrospectively evaluated for p53 and Ki-67 expression by immunohistochemistry. Associations of clinical and pathologic variables with p53 and Ki-67 were determined using the chi(2) test. After excluding two patients (follow-up loss), 134 cases were evaluated for associations between p53, Ki-67, clinical and pathologic variables, and survival by using the Cox proportional hazards regression model and Kaplan-Meier method. RESULTS: In the 136 patients, p53 was positive in 71.0% (93/131), and Ki-67 showed high in 49.2% (61/124). Unlike p53, Ki-67 was associated with male sex, smoking, and poor tumor differentiation (P=0.004, P=0.001 and P=0.006). Of these, poor tumor differentiation strongly was correlated with high level of Ki-67 expression (P=0.008). Neither p53 nor Ki-67 was associated with increased risk of death (P=0.318, P=0.053); however, age >=60 years and lymph node involvement were significant predictors of death (P=0.039 and P=0.042). The log-rank test revealed a significant association between Ki-67 and lower survival in all patients (chi(2)=5637; P=0.018); however, the risk was limited to stage III cases (chi(2)=5.939; P=0.015). Unlike p53, patients with high level of Ki-67 expression showed lower 3-year actuarial survival than those without (log-rank test, chi(2)=4.936; P=0.026). CONCLUSIONS: IHC expression of Ki-67 in lung adenocarcinoma tissue shows stronger association with poor tumor differentiation, and negatively affects patients' survival in advanced-stage lung cancer; however, the role of p53 on patient outcome needs further study. PMID- 26101638 TI - Thoracoscopic double sleeve lobectomy in 13 patients: a series report from multi centers. AB - BACKGROUND: This study aims to explore the feasibility and safety of video assisted thoracic surgery (VATS) double sleeve lobectomy in patients with non small lung cell cancer (NSCLC). METHODS: Between June 2012 and August 2014, 13 NSCLC patients underwent thoracoscopic double sleeve lobectomy and mediastinal lymphadenectomy at three institutions. A retrospective analysis of clinical characteristics, operative data, postoperative events and follow-up was performed. RESULTS: Thirteen NSCLC patients (median age, 60 years; range, 43-67 years) underwent thoracoscopic double sleeve lobectomy. There were no conversions to thoracotomy. Left upper lobectomy was most frequently performed (eleven patients). Median operative time was 263 minutes (range, 218-330 minutes), and median blood loss was 224 mL (range, 60-400 mL). The learning curve revealed reductions in both operative times and blood loss of ten cases from one center. Median data were duration of blocking pulmonary artery (PA) 72 minutes (range, 44 143 minutes), resected lymph nodes 24 (range, 10-46), stations of retrieved lymph nodes 6 (range, 5-9), thoracic drainage 1,042 mL (range, 500-1,700 mL), duration of thoracic drainage 5 days (range, 3-8 days), postoperative hospital stay 10 days (range, 7-20 days), and ICU stay 1 day (range, 1-2 days). One patient (1/13, 7.70%) suffered from pneumonia after surgery. There were no deaths at 30 days. Median duration of follow-up was 6 months (range, 1-26 months). And no local recurrences or distant metastasis were reported. CONCLUSIONS: Thoracoscopic double sleeve lobectomy is a technically challenging, but feasible procedure for NSCLC patients and it should be restricted to skilled VATS surgeons. PMID- 26101639 TI - Clinical characteristics of idiopathic pulmonary fibrosis patients with gender, age, and physiology staging at Okinawa Chubu Hospital. AB - BACKGROUND: Gender, age, and physiology (GAP) staging was recently advocated for idiopathic pulmonary fibrosis (IPF). However, clinical findings of GAP staging for IPF are limited. We aimed to investigate the clinical characteristics of IPF patients according to GAP staging in our hospital. METHODS: We retrospectively reviewed patient medical records and chest high-resolution computed tomography (HRCT) images from June 1, 2002, to December 31, 2012. RESULTS: We identified 54 IPF patients with [36 men; mean age: 71 years (range, 53-85 years)]. Mean fibrosis and ground glass opacity (GGO) scores were 1.9 (0-4) and 1.6 (1-3.3), respectively. Mean percent predicted forced vital capacity (% FVC), percent predicted diffusing capacity of the lung for carbon monoxide (% DLco) were 70.6 (6.4-114.3), 49.2 (15-105.9), respectively. Cox proportional hazards model showed that gender, percent predicted diffusing capacity of the lung for carbon monoxide (% DLco), and composite physiologic index (CPI) were strong predictors of mortality. Stage III patients had more pulmonary hypertension (50% vs. 23%, 0%) and progressive modified Medical Research Council (mMRC) changes at 1 year (1.3 vs. 0.6, 1.1; P=0.07) compared with other stages. CONCLUSIONS: In our cohort, GAP staging was useful for evaluating IPF severity. Stage III patients might had more pulmonary hypertension and progressive dyspnea. Multicenter analyses are warranted to confirm these findings. PMID- 26101640 TI - Expression of paired basic amino acid-cleaving enzyme 4 (PACE4) correlated with prognosis in non-small cell lung cancer (NSCLC) patients. AB - BACKGROUND: Paired basic amino acid-cleaving enzyme 4 (PACE4) was shown to enhance tumor cells proliferation and invasive. This study provides the first investigation of PACE4 expression in non-small cell lung cancer (NSCLC) and the correlation with clinicopathologic features, prognostic indicators of 172 cases. METHODS: Quantitative real-time PCR (RT-PCR) and immunofluorescence (IF) were applied to detect PACE4 expression in NSCLC and 16HBE cell lines, then 172 consecutive NSCLC and 15 normal lung tissues were studied through immunohistochemistry (IHC). The association between PACE4 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of PACE4 expression on survival. RESULTS: PACE4 expression in NSCLC were significantly higher than normal lung cell and tissues (P<0.05). PACE4 had cytoplasmic expression and was observed in 111 of the 172 (64.5%) NSCLC patients. Clinicopathologically, PACE4 expression was significantly associated with lymph node metastasis (N stage) (P=0.007), and clinical stage (P=0.024). Multivariable analysis confirmed that PACE4 expression increased the hazard of death after adjusting for other clinicopathological factors [hazards ratio (HR): 1.584; 95% confidence interval (CI): 1.167-2.151; P<0.001]. Overall survival (OS) was significantly prolonged in PACE4 negative group when compared with PACE4 positive group (5-year survival rates, 23.1% vs. 54.5%, log-rank test, chi(2)=17.717, P<0.001), as was disease-free survival (DFS) (5-year survival rates, 23.4% vs. 55.4%, log-rank test, chi(2)=20.486, P<0.001). CONCLUSIONS: Our results suggest that positive expression of PACE4 is an independent factor for NSCLC patients and it might serve as a potential prognostic biomarker for patients with NSCLC. PMID- 26101641 TI - One-stage hybrid procedure without sternotomy for treating thoracic aortic pathologies that involve distal aortic arch: a single-center preliminary study. AB - OBJECTIVE: This study aims to evaluate the initial results of a hybrid procedure without sternotomy for treating descending thoracic aortic disease that involves distal aortic arch. It also intends to report our initial experience in performing this procedure. METHODS: A total of 45 patients (35 males and 10 females) with descending thoracic aortic disease underwent a hybrid procedure, namely, thoracic endovascular aortic repair (TEVAR) combined with supra-arch branch vessel bypass, in our center from April 2009 to August 2014. Right axillary artery to left axillary artery bypass (n=20) or right axillary artery to left common carotid artery (LCCA) and left axillary artery bypass (n=25) were performed. The conditions of all patients were followed up from the 2(nd) month to the 65(th) month postoperative (mean, 26.0+/-17.1). Mortality within 30 days, complications such as endoleak after the hybrid procedure, and stenosis or blockage of the bypass graft during the follow-up period was assessed. RESULTS: All the patients underwent a one-stage procedure. One case of death and one case of cerebral infarction were reported within 30 days. One patient died of the sudden drop in blood pressure during the 2(nd) day of operation. Meanwhile, another patient suffered from cerebral infarction. Two patients underwent open surgery, and one of them had to undergo a second TEVAR during the follow-up period. Moreover, endoleak occurred in two patients and a newly formed intimal tear was observed in one patient. Overall, 93.2% of the patients survived without any complication related to the hybrid procedure. CONCLUSIONS: Initial results suggest that the one-stage hybrid procedure is a suitable therapeutic option for thoracic aortic pathologies that involve distal aortic arch. However, this procedure is not recommended for type-B aortic dissection, in which a tear is located in the greater curvature or near the left subclavian artery (LSA), because of the high possibility of endoleak occurrence. PMID- 26101642 TI - Screening for pectus excavatum among primary students and establishment of a pectus excavatum screening program in Dongguan, China. AB - OBJECTIVE: To carry out pectus excavatum (PEx) screening among primary school students in Dongguan, with an attempt to establish a PEx screening program and provide epidemiological evidences for developing guidelines on the diagnosis and treatment of PEx for young children. METHODS: A total of 479,402 primary school students who were already in school in 2012 or newly enrolled in 2013 from 422 primary schools in 32 towns in Dongguan, Guangdong Province were screened for PEx. Meanwhile, about 420 medical staff from the infirmaries of 422 primary schools were provided with a serial of training, with an attempt to establish a PEx screening program and network. RESULTS: Valid screening results were obtained from 477,627 pupils (99.62%) from 406 primary schools in 31 towns. These students aged 4-15 years (mean: 8.78 years), among whom there were 244,545 males (N1; mean age: 8.22 years) and 233,082 females (N2; mean age: 8.89 years). Totally 257 PEx patients were identified, yielding a prevalence of 0.583%, among whom there were 176 males (N3; mean age: 8.79 years) and 81 females (N4; mean age: 8.77 years). With the PEx patients as the PEx group and the healthy children as the control group, chi square test with gender as the dependent variable showed that the incidence of PEx was significantly different between male and female students (P=0.00) (N3:N4 =2.172:1). In addition, 410 medical staff from the school infirmaries were trained, and a PEx screening program and network was established. CONCLUSIONS: The screening for PEx was successfully performed among pupils who were already in school in 2012 or newly enrolled in 2013 from 422 primary schools in Dongguan, Guangdong Province. Statistical analysis showed that the incidence of PEx differed between male and female pupils. A stable effective PEx screening program was established, which will provide personal and technical supports for the early diagnosis and treatment of this condition. PMID- 26101643 TI - Clinical features and mutation status of EGFR, KRAS, BRAF, EML4-ALK and ROS1 between surgical resection samples and non surgical resection samples in lung cancer. AB - BACKGROUND: Target therapy is the first-line treatment in lung cancer. The testing of driver gene mutations is crucial for decision of treatment. Many lung cancer patients are in advanced grade, and lose the chance of operation. METHODS: The tissue used to perform mutation testing is only from biopsy. In order to analysis the difference between surgical resection samples (SRSs) and non surgical resection samples (NSRSs), 1,357 surgical tissues and 145 biopsy samples histopathologically diagnosed with lung cancer were collected to detect the mutation status of EGFR, KRAS, BRAF, EML4-ALK and ROS1 in this study. RESULTS: There were no significant differences of age, gender, and histological type between the two group patients we collected; however, the significant difference was present in grade. More early stage patients were in the surgical group, but more advanced stage lung cancer patients were in non surgical group. In the mutation analysis, we also found no significant differences in all driver genes we detected between the two groups. CONCLUSIONS: Both surgical resection samples and biopsy samples could be used to perform the testing the driver gene mutation. PMID- 26101645 TI - Kinetics of plasma microRNA-499 expression in acute myocardial infarction. AB - BACKGROUND: MicroRNA (miRNA) is reported to be present in human plasma and has been increasingly suggested as a biomarker for diseases. Our study aimed to investigate the kinetics of cardiac-specific microR-499 (miR-499) in acute myocardial infarction (AMI). METHODS: Circulating concentrations of cardiac enriched miR-499 were measured by quantitative PCR in 73 patients with acute coronary syndrome (ACS), including 53 with AMI and 20 with unstable angina (UA). Thirty healthy subjects were used as controls. Plasma samples in AMI group were obtained immediately after admission and at 12 h, 24 h, 3 d and 7 d after onset of symptoms. Plasma samples in UA and healthy control groups were collected immediately after admission. The severity and extent of coronary stenotic lesions were evaluated on the basis of coronary angiography using Gensini score. RESULTS: miR-499 expression levels were significantly higher in the 53 AMI patients than in the 20 UA patients and 30 healthy controls immediately after admission (P<0.01). A measurable increase in miR-499 levels was observed in AMI patients within 24 h of the last onset of chest pain and the levels returned to the baseline after 7 d. Plasma miR-499 levels in the patients with AMI were positively-correlated with cTnI (r=0.384, P<0.01) and CK-MB (r=0.402, P<0.01). In addition, miR-499 levels in AMI patients with two- and three-vessel coronary artery disease (CAD) were significantly higher than those in patients with single vessel CAD (P<0.05). Gensini scores were used to evaluate the severity of coronary stenosis. miR-499 were positively correlated with Gensini scores (r=0.52, P<0.01). miR-499 levels at admission were significantly higher than that those 24 h after percutaneous coronary intervention (PCI) in AMI patients (P<0.01) and were negatively correlated with LVEF (r=0.36, P=0.008). CONCLUSIONS: Cardiac-specific miRNA-499 levels were found to be linearly proportional to myocardial damage. MiRNA-499 might prove to be a new biomarker for AMI and a predictor of the risk of myocardial ischemia. PMID- 26101644 TI - Benefit of initial dual-therapy on stroke prevention in Chinese hypertensive patients: a real world cohort study. AB - AIMS: Studies have shown that combination anti-hypertensive therapy is superior to mono-therapy in blood pressure control and prevention of cardiovascular events. However, whether such advantage exists in the prevention of stroke in Chinese hypertensive patients remains unclear. This study aimed to compare the impact of initial combination versus mono-therapy on stroke events in a large cohort of Chinese hypertensive patients. METHODS AND RESULTS: Hypertensive patients with uncontrolled blood pressure and without a history of stroke were screened from the Shanghai Community-dwelling Hypertensive Population Follow-up Database. Based on the initial treatment, individuals were divided into an initial mono-therapy group and initial dual combination group. Patients were followed for 42 months. 32,682 and 4,926 patients were included in the initial mono- and dual-therapy group. The achieved target blood pressure control rates of mono vs. combination groups at 6, 12, 24, and 42 months of follow-up, were 59.47% vs. 60.05%, 78.23% vs. 77.06%, 85.51% vs. 84.02%, and 86.90% vs. 85.44%, respectively. Their corresponding incidence densities of stroke were 0.792 vs. 0.489, 1.49 vs. 1.15, 2.79 vs. 2.38, and 4.25 vs. 4.32 (cases per 100 person year), respectively. The 6-month incidence of stroke in dual-therapy group was significantly lower than mono-therapy group (adjusted HR 0.64; 95% CI: 0.30 0.93). However, no significant group differences in the incidence density were observed at 12, 24, and 42 months. CONCLUSIONS: Our study demonstrates that, for patients with uncontrolled hypertension, initial dual therapy is more effective in the prevention of stroke during the first 6 months of treatment, but not thereafter. Combination antihypertensive therapy may be a beneficial initial strategy for early stroke prevention. PMID- 26101646 TI - The use of an online pictorial Epworth Sleepiness Scale in the assessment of age and gender specific differences in excessive daytime sleepiness. AB - BACKGROUND: Excessive daytime sleepiness (EDS) is a non-specific but highly prevalent cardinal symptom of sleep disorders. We hypothesized that with modern media and an online pictorial Epworth Sleepiness Scale (ESS) age and gender specific differences of EDS could be identified on a large scale. This could be helpful in the screening of patients with sleep disorders. PATIENTS AND METHODS: In 8,098 subjects, age and gender were recorded in addition to an online pictorial ESS (range 0-24 points). The cut-off for EDS (ESS >10 points) was chosen in line with the traditional ESS. RESULTS: The prevalence of EDS was slightly higher in male subjects (45% vs. 43%, P=0.033). When age was considered, female subjects tended to be sleepier in their 3(rd) and 4(th) lifetime decade (P=0.01 and P=0.003, respectively), whilst male subjects scored significantly higher in their 7(th) decade (P<0.0001); there was a trend to more daytime symptoms with higher age (P for trend <0.001). CONCLUSIONS: The online pictorial ESS identifies gender differences in EDS and reveals increased levels of sleepiness associated with higher age. The use of modern media facilitates reaching out to the general population to raise awareness of conditions associated with EDS such as sleep apnoea. PMID- 26101647 TI - Post-treatment change in Mycobacterium tuberculosis antigen-stimulated tumor necrosis factor-alpha release in patients with active tuberculosis. AB - BACKGROUND: Monitoring tuberculosis (TB) treatment response remains challenging due to lack of reliable laboratory markers. In recent years, increased efforts have been exerted toward development of new biomarkers reflecting treatment response appropriately. While performance of interferon-gamma release assays (IGRAs) to monitor anti-TB treatment has been extensively evaluated, there is no data about post-treatment changes in Mycobacterium tuberculosis (MTB) antigen stimulated tumor necrosis factor-alpha (TNF-alpha) release in active TB patients. Herein, we explored whether the MTB antigen-stimulated TNF-alpha release would be useful for monitoring responses to anti-TB treatment. METHODS: We compared unstimulated (TNF-alphaNil), MTB antigen-stimulated (TNF-alphaAg), and MTB antigen-stimulated minus unstimulated TNF-alpha levels (TNF-alphaAg-Nil) in supernatants from QuantiFERON-TB Gold In-Tube tests before and after treatment in 16 active TB patients, 25 latent TB infection (LTBI) subjects, and 10 healthy controls (HC). RESULTS: TNF-alphaAg and TNF-alphaAg-Nil levels decreased significantly after treatment in patients with active TB. In addition, TNF alphaNil, TNF-alphaAg, and TNF-alphaAg-Nil levels were significantly higher in untreated active TB patients compared to LTBI subjects and HC. CONCLUSIONS: This finding cautiously suggests that MTB Ag-stimulated TNF-alpha response may be a potential adjunctive marker for monitoring treatment response in active TB patients. PMID- 26101648 TI - Inflammatory myofibroblastic tumour of the lung: a reactive lesion or a true neoplasm? AB - Inflammatory myofibroblastic tumour (IMT) of the lung represents an extremely rare type of inflammatory pseudo tumor that appears most commonly in children and young individuals. There has been an ongoing controversy whether an IMT is a reactive lesion or a true neoplasm making the further management extremely challenging. Purpose of the paper is through a literature review to highlight the existence of this rare tumour along with its key features and the management options available. PMID- 26101649 TI - Established vascular effects of continuous positive airway pressure therapy in patients with obstructive sleep apnoea-an update. AB - The aim of this review was to summarize the current data from randomised controlled trials (RCTs) on vascular effects of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA). There is good evidence from RCTs that CPAP lowers blood pressure (BP) to a clinically significant amount. The effect seems to be dependent on the hours of nightly CPAP usage. Data from RCTs have also proven a beneficial effect of CPAP on measures of vascular function such as endothelial function and arterial stiffness. However, there is still a lack of evidence from RCTs proving that CPAP reduces vascular events and mortality. PMID- 26101650 TI - Epidemiological aspects of obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is probably the most common respiratory disorder, with recent data from the United States and Europe suggesting that between 14% and 49% of middle-aged men have clinically significant OSA. The intimate relationship between OSA and obesity means that its prevalence will only increase as the global obesity epidemic evolves. At an individual level, OSA leads to a significant decrease in quality of life (QOL) and functional capacity, alongside a markedly increased risk of cardiovascular disease and death. Emerging data also suggest that the presence and severity of OSA and associated nocturnal hypoxemia are associated with an increased risk of diabetes and cancer. At a societal level, OSA not only leads to reduced economic productivity, but also constitutes a major treatable risk factor for hypertension, coronary artery disease (CAD) and stroke. This article addresses OSA from an epidemiological perspective, from prevalence studies to economic aspects to co-morbidity. PMID- 26101651 TI - Central sleep apnoea-a clinical review. AB - Central sleep apnoea (CSA) is characterised by recurrent apnoeas during sleep with no associated respiratory effort. It mostly results from withdrawal of the wakefulness drive in sleep leaving ventilation under metabolic control. A detailed physiological understanding of the control of breathing in wakefulness and sleep is essential to the understanding of CSA. It encompasses a diverse group of conditions with differing aetiologies and pathophysiology. Likewise treatment varies according to underlying aetiology. Some of the conditions such as idiopathic (primary) CSA (ICSA) are relatively rare and benign. On the other hand Cheyne-Stokes breathing (CSB) pattern is quite common in patients with heart failure and might be a prognostic indicator of poor outcome. Unfortunately modern medical management of heart failure does not seem to have significantly reduced the prevalence of CSA in this group. Since the adoption of positive airway pressure (PAP) as a common treatment modality of obstructive sleep apnoea (OSA), complex CSA has been increasingly observed either as treatment emergent or persistent CSA. Depending on the particular condition, various treatment strategies have been tried in the past two decades which have included hypnotic therapy, respiratory stimulants, judicious administration of carbon dioxide, oxygen therapy, PAP and bi-level ventilatory support with a backup rate. In the past decade adaptive servo ventilation (ASV) has been introduced with much promise. Various studies have shown its superiority over other treatment modalities. Ongoing long term studies will hopefully shed more light on its impact on cardiovascular morbidity and mortality. Other rare forms are still poorly understood and treatments remain suboptimal. PMID- 26101652 TI - Patients' preference of established and emerging treatment options for obstructive sleep apnoea. AB - BACKGROUND: Obstructive sleep apnoea (OSA) is the most common form of sleep disordered breathing. The standard treatment, continuous positive airway pressure (CPAP), has limited long-term compliance. Alternative treatment options are required and new methods, including hypoglossal nerve stimulation (HNS) and continuous transcutaneous electrical stimulation (CTES), are currently emerging. We report on patients' preference for different treatments of OSA. METHODS: We recorded patients' age, gender, body mass index (BMI), Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire with 10 questions (FOSQ10), severity of OSA, and current treatment. We showed pictures of existing [CPAP, mandibular advancement device (MAD)] and emerging treatments (HNS and CTES). We then asked (I) whether participants were interested in further information about HNS/CTES; (II) if they would be willing to try HNS/CTES; and (III) if they were to choose only one of the four listed treatments, which one would they prefer to use every night. RESULTS: One hundred sixty-two patients completed the survey {81 males, mean age 52 [12] years, BMI 34 [7] kg/m(2), ESS 10.2 (6.0) points, FOSQ10 28.5 (8.1) points}. The majority of the respondents (89.5%) had been diagnosed with OSA. A total of 91.3% of the respondents were interested in more information and were willing to try HNS/CTES. Most respondents preferred the potential use of CTES (56.7%), while 21.7% chose HNS, 17.8% CPAP, and 3.8% the MAD. There were no differences in the characteristics of the patients who preferred CTES compared to those who preferred other treatments, but a regression analysis revealed that a low ESS score was an independent predictor of patients choosing CTES (P<0.05). CONCLUSIONS: More than 9 out of 10 of the respondents were interested in trying emerging technologies to treat OSA, most preferring CTES. Less sleepy patients were more likely to choose less invasive treatments. These findings will likely impact on future research and development of therapies for sleep-disordered breathing. PMID- 26101654 TI - Artificial neural networks for small dataset analysis. AB - Artificial neural networks (ANNs) are usually considered as tools which can help to analyze cause-effect relationships in complex systems within a big-data framework. On the other hand, health sciences undergo complexity more than any other scientific discipline, and in this field large datasets are seldom available. In this situation, I show how a particular neural network tool, which is able to handle small datasets of experimental or observational data, can help in identifying the main causal factors leading to changes in some variable which summarizes the behaviour of a complex system, for instance the onset of a disease. A detailed description of the neural network tool is given and its application to a specific case study is shown. Recommendations for a correct use of this tool are also supplied. PMID- 26101653 TI - Respiratory management of the obese patient undergoing surgery. AB - As a reflection of the increasing global incidence of obesity, there has been a corresponding rise in the proportion of obese patients undergoing major surgery. This review reports the physiological effect of these changes in body composition on the respiratory system and discusses the clinical approach required to maximize safety and minimize the risk to the patient. The changes in respiratory system compliance and lung volumes, which can adversely affect pulmonary gas exchange, combined with upper airways obstruction and sleep-disordered breathing need to be considered carefully in the peri-operative period. Indeed, these challenges in the obese patient have led to a clear focus on the clinical management strategy and development of peri-operative pathways, including pre operative risk assessment, patient positioning at induction and under anesthesia, modified approach to intraoperative ventilation and the peri-operative use of non invasive ventilation (NIV) and continuous positive airways pressure. PMID- 26101655 TI - Beware the 'raised right hemidiaphragm' in a female patient with previous pneumothorax surgery: liver herniation through a massive endometrosis-related diaphragmatic fenestration. AB - A 44-year-old non-smoking woman presented with recurrent right spontaneous pneumothorax 9 years after a right-side surgical pleurodesis via a video-assisted thoracic surgery (VATS) approach for suspected primary pneumothorax in another center. Histological examination of tissue excised during the earlier operation confirmed catamenial pneumothorax, but no further treatment was given. During the 9 years since, she had had persistent right lower chest pain and chest X-ray (CXR) had shown a "persistently elevated right diaphragm", but these had been treated as iatrogenic neuropathic pain and phrenic nerve palsy respectively. A redo right surgical exploration was performed for the current recurrence. Intra operatively, the right half of the liver was found to have herniated into the chest via a massive fenestration (10 cm * 9 cm) in the right hemidiaphragm. The defect was repaired via a combined thoracotomy and laparotomy approach. This case serves as an advisory that in patients with persistent ipsilateral chest pain and a raised hemidiaphragm following surgery for catamenial pneumothorax, diaphragmatic fenestration and abdominal visceral herniation should be suspected amongst the differential diagnoses. PMID- 26101656 TI - Migratory eosinophilic alveolitis caused by radiation therapy. AB - Although radiation pneumonitis is usually confined to irradiated areas, some studies have reported that radiation-induced lymphocytic alveolitis can also spread to the non-irradiated lung. However, there have been few reports of radiation-induced eosinophilic alveolitis. We report the case of a 27-year-old female with radiation pneumonitis, occurring 4 months after radiation therapy for cancer of the left breast. Clinical and radiological relapse followed withdrawal of corticosteroids. Examination of bronchoalveolar lavage (BAL) in patchy airspace consolidations revealed increased eosinophil counts. Finally, clinical and radiological signs resolved rapidly after reintroduction of corticosteroids. Eosinophilic alveolitis may be promoted by radiation therapy. In the present case report, possible mechanisms for radiation-induced eosinophilic alveolitis are also reviewed. PMID- 26101657 TI - Single incision thoracoscopic lobectomy through a 2.5 cm skin incision. AB - Single incision thoracoscopic surgery (SITS) involves only one intercostal space with minimal skin incision, which means it can be the most minimally invasive technique up to date. We minimized the skin incision to a length of 2.5 cm to achieve the less chest wall trauma and the more cosmesis during SITS lobectomy for benign pulmonary disease. Four patients who had bronchiectasis [left lower lobe (LLL)], congenital lobar emphysema [left upper lobe (LUL)], aspergilloma [right upper lobe (RUL)], and hamartoma (RUL) were planned to undergo 2.5 cm SITS lobectomy. There were no conversion cases to multi-port video-assisted thoracic surgery (VATS) or thoracotomy. The mean operation time was 182+/-25 minutes. Chest drains were removed on postoperative day (POD) 2 in all patients. Three patients discharged on POD 3. One patient who discharged on POD 5 readmitted for delayed pleural effusion and treated with mini-tube insertion. There were no late complications or symptom relapses during the median follow-up of 13.5 months. A 2.5 cm SITS lobectomy can be alternative option for relatively young patients with benign lung disease. PMID- 26101658 TI - Malignant glomus tumor in pleural cavity. AB - Glomus tumors, an uncommon hypervascular tumor, arise from modified smooth muscle cells of the glomus body that plays a significant role in the regulation of skin circulation. The tumors are usually located in the extremities, typically in the subungual region of the fingers. Primary glomus tumors of the chest are extremely rare, and to our knowledge, there are no cases have been described in thoracic cavity to date. We here report a case of intrathoracic glomus tumor in a 31-year old man who presented with a persistent chest pain. Chest computed tomography scans demonstrated an irregularly shaped mass in the left thorax. Left thoracotomy was performed under the suspicious diagnosis of unexplained thorax tumor, and a tumor located in the left upper portion of thorax was founded. Complete resection of tumor along with the partial structure of chest wall was performed. Postoperative diagnosis was malignant glomus tumor. PMID- 26101659 TI - Fixation of sternal fracture using absorbable plating system, three years follow up. AB - Sternal fractures occur due to severe chest wall trauma in a small number of patients. They are often conservatively treated. The surgical intervention, although controversial, is indicated in case of deformity, severe pain, and ventilatory complications. We report the first case where absorbable plate has been used to fix a traumatic fracture in a 42-year-old female. After 3 years, the patient is still free of symptoms and CT scanning reveals intact sternal bone structure. PMID- 26101660 TI - Protocolized weaning from mechanical strategy in chronic obstructive pulmonary disease: respiratory therapists versus physician directed-who guides best? PMID- 26101661 TI - Author response to letter to the editor "Protocolized weaning from mechanical strategy in COPD: respiratory therapists versus physician directed-who guides best?". PMID- 26101662 TI - The AME Special Competition 2015: 4 rounds, 27 contestants, countless lessons learned about China. PMID- 26101663 TI - Expert consensus on image-guided radiofrequency ablation of pulmonary tumors-2015 edition. PMID- 26101664 TI - Health Care Consumption during Pregnancy in relation to Maternal Body Mass Index: A Swedish Population Based Observational Study. AB - OBJECTIVE: To assess whether antenatal health care consumption is associated with maternal body mass index (BMI). DESIGN: A register based observational study. METHODS: The Swedish Medical Birth Register, the Maternal Health Care Register, and the Inpatient Register were used to determine antenatal health care consumption according to BMI categories for primiparous women with singleton pregnancies, from 2006 to 2008, n = 71,638. Pairwise comparisons among BMI groups are obtained post hoc by Tukey HSD test. RESULT: Obese women were more often admitted for in-patient care (p < 0.001), had longer antenatal hospital stays (p < 0.001), and were more often sick-listed by an obstetrician (p < 0.001) during their pregnancy, compared to women with normal weight women. Preeclampsia was more than four times as common, hypertension five times as common, and gestational diabetes 11 times as common when comparing in-patient care, obese to normal weight women (p < 0.001 for all comparisons). Underweight mothers had longer stay in hospitals (p < 0.05) and hydronephrosis and hyperemesis gravidarum were more than twice as common (both p < 0.001). CONCLUSION: Obese and underweight mothers consumed significantly more health care resources and obese women were significantly more often sick-listed during their pregnancy when compared to pregnant women of normal weight. PMID- 26101665 TI - Comment on "Intervention Effects of a School-Based Health Promotion Programme on Obesity Related Behavioural Outcomes". PMID- 26101666 TI - Associations of Physical Activity and Sedentary Behaviors with Dietary Behaviors among US High School Students. AB - BACKGROUND: Physical activity (PA), sedentary behaviors, and dietary behaviors are each associated with overweight and obesity among youth. However, the associations of PA and sedentary behaviors with dietary behaviors are complex and not well understood. PURPOSE: To describe the associations of PA and sedentary behaviors with dietary behaviors among a representative sample of US high school students. METHODS: We analyzed data from the 2010 National Youth Physical Activity and Nutrition Study (NYPANS). Using logistic regression models which controlled for sex, race/ethnicity, grade, body weight status, and weight management goals, we compared dietary behaviors among students who did and did not meet national recommendations for PA and sedentary behaviors. RESULTS: Students who participated in recommended levels of daily PA (DPA) and muscle strengthening PA (MSPA) were more likely than those who did not to eat fruits and vegetables. Students who exceeded recommended limits for television (TV) and computer/video game (C/VG) screen time were less likely than those who did not to consume fruits and vegetables and were more likely to consume fast food and sugar sweetened beverages. CONCLUSIONS: Researchers may want to address PA, sedentary behaviors, and dietary behaviors jointly when developing health promotion and obesity prevention programs for youth. PMID- 26101667 TI - Expression and Characterization of the Novel Gene fr47 during Freezing in the Wood Frog, Rana sylvatica. AB - The wood frog, Rana sylvatica, has numerous adaptations that allow it to survive freezing of up to 65% of its total body water during the winter. Such adaptations have been found to include the expression of novel freeze responsive genes that are thought to be important for adaptation and survival. In this study, the tissue-specific stress responsive expression of one novel gene, fr47, was assessed in seven wood frog tissues. In response to freezing, the transcript expression of fr47 increased significantly in six tissues: heart, lung, liver, skeletal muscle, kidney, and testes. The expression of fr47 was also strongly upregulated by component stresses of freezing, namely, anoxia and dehydration. A dynamic change in fr47 expression was also observed during tadpole development, with expression low in embryonic stages (Gosner stages 14-20), increasing through intermediate (stages 26-43) and transformation phases (stages 44-45). These results indicated that fr47 potentially has a role to play in development and metamorphosis, in addition to freeze, anoxia, and dehydration tolerance. De novo analysis of FR47 protein structure revealed a likelihood of membrane associated function and possible GRB2 association. It is hypothesized that this interaction may influence inositol 1,4,5-trisphosphate production, known to increase during wood frog freezing. PMID- 26101668 TI - Association between Prenatal One-Hour Glucose Challenge Test Values and Delivery Mode in Nondiabetic, Pregnant Black Women. AB - OBJECTIVE: We examined the association between 1-hour glucose challenge test (GCT) values and risk of caesarean section. STUDY DESIGN: A prospective cohort study recruited 203 pregnant Black women to participate. At ~28 weeks of gestation, participants underwent a routine 1-hour 50 g GCT to screen for gestational diabetes mellitus. Logistic regression was used to examine the association between 1-hour GCT value and delivery mode. RESULTS: Of the 158 participants included, 53 (33.5%) delivered via C-section; the majority (n = 29; 54.7%) were nulliparous. Mean 1-hour GCT values were slightly, but not significantly, higher among women delivering via C-section; versus vaginally (107.8 +/- 20.7 versus 102.4 +/- 21.5 mg/dL, resp.; P = 0.13). After stratifying by parity and adjusting for maternal age, previous C-section, and prepregnancy body mass index, 1-hour GCT value was significantly associated with increased risk of C-section among parous women (OR per 1 mg/dL increase in GCT value = 1.05; 95% CI OR: 1.00, 1.05; P = 0.045). CONCLUSION: Even slightly elevated 1 hour 50 g GCT values may be associated with delivery mode among parous Black women. PMID- 26101669 TI - Comparison of Patient-Reported Outcome from Neck-Preserving, Short-Stem Arthroplasty and Resurfacing Arthroplasty in Younger Osteoarthritis Patients. AB - Hip resurfacing has been considered a good treatment option for younger, active osteoarthritis patients. However, there are several identified issues concerning risk for neck fractures and issues related to current metal-on-metal implant designs. Neck-preserving short-stem implants have been discussed as a potential alternative, but it is yet unclear which method is better suited for younger adults. We compared hip disability and osteoarthritis outcome scores (HOOS) from a young group of patients (n = 52, age 48.9 +/- 6.1 years) who had received hip resurfacing (HR) with a cohort of patients (n = 73, age 48.2 +/- 6.6 years) who had received neck-preserving, short-stem implant total hip arthroplasty (THA). Additionally, durations for both types of surgery were compared. HOOS improved significantly preoperatively to last followup (>1 year) in both groups (p < 0.0001, eta (2) = 0.69); there were no group effects or interactions. Surgery duration was significantly longer for resurfacing (104.4 min +/- 17.8) than MiniHip surgery (62.5 min +/- 14.8), U = 85.0, p < 0.0001, eta (2) = 0.56. The neck-preserving short-stem approach may be preferable to resurfacing due to the less challenging surgery, similar outcome, and controversy regarding resurfacing implant designs. PMID- 26101671 TI - Transient Left-Sided Paralysis following Robotic-Assisted Laparoscopic Uteropexy. AB - We describe a case report of a 47-year-old ASA 2 female patient who exhibits severe headache and hemineurology during awakening following robotic pelvic prolapse surgery. The symptoms resolved spontaneously during the first postoperative day. We could not find any explicit root cause. Robotic surgery associated adverse events are discussed. PMID- 26101670 TI - Inhibition of Hyperpolarization-Activated Cation Current in Medium-Sized DRG Neurons Contributed to the Antiallodynic Effect of Methylcobalamin in the Rat of a Chronic Compression of the DRG. AB - Recently several lines of evidence demonstrated that methylcobalamin (MeCbl) might have potential analgesic effect in experimental and clinical studies. However, it was reported that MeCbl had no effect on treating lumbar spinal stenosis induced pain. Thus, the effects of short-term and long-term administration of MeCbl were examined in the chronic compression of dorsal root ganglion (CCD) model. We found that mechanical allodynia was significantly inhibited by a continuous application of high dose and a single treatment of a super high dose of MeCbl. Little is known about mechanisms underlying the analgesia of MeCbl. We examined the effect of MeCbl on the spontaneous activity (SA), the excitability, and hyperpolarization-activated nonselective cation ion current in compressed medium-sized dorsal root ganglion (DRG) neurons using extracellular single fiber recording in vivo and whole-cell patch clamp in vitro. We found that MeCbl significantly inhibited the SA of A-type sensory neurons in a dose-dependent manner and inhibited the excitability of medium-sized DRG neurons. In addition, MeCbl also decreased I h current density in injured medium-sized DRG neurons. Our results proved that MeCbl might exert an analgesic effect through the inhibition I h current and then might inhibit the hyperexcitability of primary sensory neurons under neuropathic pain state. PMID- 26101672 TI - Pulmonary Hemorrhage Secondary to Disseminated Strongyloidiasis in a Patient with Systemic Lupus Erythematosus. AB - Introduction. Pulmonary hemorrhage secondary to disseminated strongyloidiasis is an unusual, well-recognized entity in immunocompromised patients with autoimmune disease, which is associated with the hyperinfection syndrome, sepsis, and a high mortality rate. Case Presentation. We present a case of a 44-year-old Mexican woman with systemic lupus erythematosus and acute bacterial meningitis who developed pulmonary hemorrhage with acute respiratory failure requiring mechanical ventilation, treated with broad spectrum systemic antibiotics and high dose methylprednisolone, who subsequently developed a characteristic purpuric skin eruption and septic shock and died two days later of refractory hypoxemia caused by massive pulmonary bleeding. The postmortem examination reports filariform larvae of S. stercolaris in lung, skin, and other organs. Conclusion. This case highlights the importance of considering disseminated strongyloidiasis in the differential diagnosis of diffuse alveolar hemorrhage in systemic lupus erythematosus, and screening for S. stercolaris infection before initiation of immunosuppressive therapy should be considered, especially in endemic areas. Disseminated strongyloidiasis has a high mortality rate, explained in part by absence of clinical suspicion. PMID- 26101673 TI - Phencyclidine Induced Oculogyric Crisis Responding Well to Conventional Treatment. AB - Background. Oculogyric crisis is a form of acute dystonic reaction characterized by involuntary upward deviation of eye ball. Its causes are broad with antipsychotics and antiemetics as the most common causes. Case Presentation. A 25 year-old man with the past medical history of marijuana use presented to ED with involuntary upward deviation of eye 1 day after using phencyclidine (PCP) for the first time. He did not have any other symptoms and was hemodynamically stable. All laboratory investigations were normal except urine drug screen which was positive for PCP. Patient was treated with IV diphenhydramine which improved his symptoms. Conclusion. Illicit drug abuse is a growing problem in our society with increasingly more patients presenting to ED with its complications. The differential diagnosis of acute dystonic reactions should be extended to include illicit drugs as the potential cause of reversible acute dystonias especially in high risk patients. PMID- 26101674 TI - Bilateral Adrenal Incidentalomas: A Rare Presentation of Lung Cancer. AB - Adrenal incidentalomas are found incidentally during a radiologic examination performed for indications other than an adrenal disease, and 15% of them are bilateral adrenal masses. This study describes a 51-year-old male smoker patient admitted with diabetes mellitus. An abdominal ultrasonography performed due to his anemia revealed bilateral adrenal masses. His chest X-ray showed abnormal 10 cm opacity at the right upper lung, and brain, thorax, and abdomen CT scans showed multiple lesions compatible with lung cancer metastases. The pathological examination of the transthoracic lung biopsy specimen was consistent with lung adenocarcinoma. Findings in this patient indicate that, in middle aged patients with bilateral adrenal mass and a history or finding of any malignancy, the first diagnosis which should be considered is adrenal metastasis, and confirming the diagnosis by adrenal biopsy may be useless. Furthermore, screening all smoking patients by chest X-ray or thoracic CT for lung cancer may not be accepted as a routine procedure, but in smokers admitted to a hospital due to signs and symptoms attributed to a pulmonary disease, at least a chest X-ray should be requested. PMID- 26101675 TI - Marked Direct Hyperbilirubinemia due to Ceftriaxone in an Adult with Sickle Cell Disease. AB - Drugs are a significant cause of liver injury. Drug-induced liver injury (DILI) can cause acute hepatitis, cholestasis, or a mixed pattern. Ceftriaxone is a commonly used antibiotic and has been associated with reversible biliary sludge, pseudolithiasis, and cholestasis. A 32-year-old male with sickle cell disease was admitted to the hospital for acute sickle cell crisis. On the second day of hospitalization, he developed cough and rhonchi with chest X-ray revealing right middle lobe infiltrates. Ceftriaxone and azithromycin were initiated. Subsequently, he developed conjugated hyperbilirubinemia and mild transaminitis. His total bilirubin trended upwards from 3.3 mg/dL on admission to 17 mg/dL. It was predominantly conjugated bilirubin, with preadmission bilirubin levels of 3-4 mg/dL. His transaminases were mildly elevated as well compared to previous levels. Extensive workup for bilirubin elevation was unremarkable. Ceftriaxone was switched to levofloxacin and the hyperbilirubinemia improved. On ambulatory follow-up, his bilirubin remained below 4 mg/dL. Ceftriaxone may be associated with marked direct hyperbilirubinemia particularly in sickle cell patients with chronic liver chemistry abnormalities. In the case of elevated bilirubin with concomitant ceftriaxone use, elimination of the offending agent should be considered. PMID- 26101676 TI - Posterior Reversible Encephalopathy Syndrome due to High Dose Corticosteroids for an MS Relapse. AB - Increased blood pressure is a known adverse effect associated with corticosteroids but little is published regarding the risk with the high doses used in multiple sclerosis (MS). A 53-year-old female with known relapsing remitting MS presented with a new brainstem relapse. Standard of care treatment for an acute MS relapse, 1250 mg of oral prednisone for 5 days, was initiated. She developed an occipital headache and dizziness and felt generally unwell. These symptoms persisted after treatment was complete. On presentation to medical attention, her blood pressure was 199/110 mmHg, although she had no history of hypertension. MRI changes were consistent with posterior reversible encephalopathy syndrome (PRES), demonstrating abnormal T2 signal in both thalami, the posterior occipital and posterior parietal white matter with mild sulcal effacement. As her pressure normalized with medication, her symptoms resolved and the MRI changes improved. No secondary cause of hypertension was found. This is the first reported case of PRES secondary to high dose corticosteroid use for an MS relapse without a history of hypertension and with no other secondary cause of hypertension identified. This rare complication should be considered in MS patients presenting with a headache or other neurological symptoms during treatment for a relapse. PMID- 26101677 TI - Primary T-Cell Non-Hodgkin Lymphoma of the Vagina. AB - The primary vaginal T-cell non-Hodgkin lymphoma is a rare form of lymphoma. Most of the previously published cases were about B-cell non-Hodgkin lymphomas. We present the case of a vaginal mass in an 82-year-old patient presenting vaginal bleeding. The results of the immunohistological studies of the mass revealed the presence of a cytotoxic T-cell non-Hodgkin lymphoma, which is the least common subtype. PMID- 26101678 TI - Primary Mediastinal Synovial Sarcoma Presenting as Superior Vena Cava Syndrome: A Rare Case Report and Review of the Literature. AB - Primary mediastinal sarcomas are aggressive tumors with a very rare incidence. This report describes the case of a 35-year-old male patient who presented with acute symptoms of dyspnoea, facial puffiness, voice-hoarseness, and engorged neck veins. With the clinical picture consistent with the superior vena cava (SVC) syndrome, the patient was investigated with computed tomography of the chest. This revealed a large soft tissue density mass lesion compressing the SVC along with other critical superior mediastinal structures. Histopathological evaluation of the mass revealed features consistent with a soft tissue sarcoma and positive staining was observed for vimentin and S-100. Cytogenetic analysis by fluorescent in situ hybridisation (FISH) demonstrated the t(X:18) translocation. Thus diagnosis was established as primary mediastinal synovial sarcoma. Patient was treated with three cycles of neoadjuvant chemotherapy, to which there was a partial response as per the RECIST criteria. Surgical excision of the mediastinal mass was performed, and further postoperative treatment with adjuvant chemoradiotherapy was provided. Patient currently is free of disease. This is to the best of our knowledge the first report in the world literature of a successfully treated case of "primary mediastinal sarcomas presenting as SVC syndrome." Patient is under regular surveillance at our clinic and remains free of recurrence one year after treatment completion. PMID- 26101679 TI - Combined Effect of a Locking Plate and Teriparatide for Incomplete Atypical Femoral Fracture: Two Case Reports of Curved Femurs. AB - In surgical treatment for atypical femoral fractures (AFFs), reconstruction nail fixation is recommended for both complete and incomplete fractures. Although it has been reported that AFF is affected by many factors, The ASBMR Task Force 2013 Revised Case Definition of AFFs states that a curved femur is often seen in Asian patients. It is sometimes difficult to insert a nail into a femur in incomplete AFF patients with severely curved femurs. We report two incomplete bisphosphonate related AFF patients with marked femoral curvatures treated by locking plates and teriparatide, showing early bone unions and favorable long-term outcomes. PMID- 26101680 TI - Simultaneous Bilateral Femoral Neck Stress Fracture in a Young Stone Mason. AB - Unilateral stress fractures of the femoral neck are very uncommon and bilateral involvement is even rarer. They commonly occur in athletes, military recruits, older persons, or individuals with underlying metabolic disorders and very seldom in normal individuals. We present a rare case of simultaneous bilateral fracture neck of femur in a 25-year-old man who came with complaints of pain in bilateral groin for 1 month. There was no history of trauma or history suggestive of excessive activity prior to the onset of pain, but there was history of lifting heavy weights daily. On evaluation with MRI scan bilateral fracture of the femur neck was diagnosed and patient was operated on bilaterally with internal fixation done using dynamic hip screw. Patient then regained his routine activity over a period of 6 months and on follow-up at 1 year no avascular necrosis changes were seen in the femur head. We presented this case because of its unusual presentation and the diagnostic challenge it poses. PMID- 26101681 TI - Short Stature in Chronic Kidney Disease Treated with Growth Hormone and an Aromatase Inhibitor. AB - We describe an alternative strategy for management of severe growth failure in a 14-year-old child who presented with advanced chronic kidney disease close to puberty. The patient was initially treated with growth hormone for a year until kidney transplantation, followed immediately by a year-long course of an aromatase inhibitor, anastrozole, to prevent epiphyseal fusion and prolong the period of linear growth. Outcome was excellent, with successful transplant and anticipated complete correction of height deficit. This strategy may be appropriate for children with chronic kidney disease and short stature who are in puberty. PMID- 26101682 TI - Postinjection Muscle Fibrosis from Lupron. AB - We describe the case of a 6.5-year-old girl with central precocious puberty (CPP), which signifies the onset of secondary sexual characteristics before the age of eight in females and the age of nine in males as a result of stimulation of the hypothalamic-pituitary-gonadal axis. Her case is likely related to her adoption, as children who are adopted internationally have much higher rates of CPP. She had left breast development at Tanner Stage 2, adult body odor, and mildly advanced bone age. In order to halt puberty and maximize adult height, she was prescribed a gonadotropin releasing hormone analog, the first line treatment for CPP. She was administered Lupron (leuprolide acetate) Depot-Ped (3 months) intramuscularly. After her second injection, she developed swelling and muscle pain at the injection site on her right thigh. She also reported an impaired ability to walk. She was diagnosed with muscle fibrosis. This is the first reported case of muscle fibrosis resulting from Lupron injection. PMID- 26101683 TI - Cotard Syndrome without Depressive Symptoms in a Schizophrenic Patient. AB - Introduction. Cotard syndrome is a rare condition characterized by nihilistic delusions concerning body or life that can be found in several neuropsychiatry conditions. It is typically associated with depressive symptoms. Method. We present a case of Cotard syndrome without depressive symptoms in the context of known paranoid schizophrenia. A literature review of Cotard syndrome in schizophrenia was performed. Results. Although there are few descriptions of this syndrome in schizophrenia, patients usually present depressive mood and psychomotor retardation, features not seen in our patient. Loss of the sense of the inner self, present in schizophrenia, could explain patient's symptomatology but neurobiological bases of this syndrome remain unclear. Conclusion. Despite not being considered in actual classifications, Cotard syndrome is still relevant and psychiatric evaluation is critical to diagnosing and treating this condition in psychiatric patients. PMID- 26101684 TI - A Case of Immunoglobulin G4-Related Disease with Extensive Multiorgan Involvements. AB - We report a case of IgG4-related disease (IgG4-RD) with multiple ten-organ involvement. This case showed many clinical findings, such as bilateral swelling of salivary and lacrimal glands, autoimmune pancreatitis, interstitial nephritis, retroperitoneal fibrosis, periaortitis, systemic swelling of lymph nodes, pulmonary lesions, splenomegaly, and jejunal lesions. He was suspected as having SLE or malignant lymphoma but diagnosed as having IgG4-RD by the elevated serum IgG4 level and histological findings from kidney and lymph node. We report a case of IgG4-RD with multiple ten-organ involvement that was successfully treated with prednisolone therapy. PMID- 26101685 TI - Primitive Neuroectodermal Tumor of the Pancreas: A Case Report and Review of the Literature. AB - Primitive neuroectodermal tumors (PNETs) are presented as rare malignant neoplasms. In unusual cases, those neoplasms may arise in solid organs containing neuroendocrine cells, such as the pancreas. Herein the case of a 28-year-old patient that underwent gastroduodenopancreatectomy after the diagnosis of a huge mass (PNET) located in both head and body of the pancreas is reported. This is the 19th case of pancreatic PNET reported in literature. PMID- 26101686 TI - Surgical Extirpation of Apical Left Ventricular Thrombus in Takotsubo Cardiomyopathy. AB - We report a patient with takotsubo cardiomyopathy who underwent surgical resection of apical left ventricular thrombus. A 59-year-old woman was transferred to our hospital in shock with hypothermia and diabetic ketoacidosis. The electrocardiogram showed ST segment elevation, while echocardiography revealed a reduced ejection fraction with apical and midventricular akinesis. Emergency coronary angiography showed normal coronary arteries, so takotsubo cardiomyopathy was diagnosed. Follow-up echocardiography revealed improvement of the ejection fraction. A mobile apical thrombus was also detected. Thrombectomy was performed via a left apical incision and postoperative recovery was uneventful. PMID- 26101687 TI - Adrenal Schwannomas: Rare Tumor of the Retroperitoneum. AB - Schwannoma is a benign neurogenic tumor originating from Schwann cells. These produce the myelin sheath that covers peripheral nerves that are often affected. This latter localization is extremely rare, and only a few case reports can be found in the medical literature. Studies have shown that approximately 0.5% to 5% of schwannomas are retroperitoneal, constituting 0.2% of adrenal incidental tumors. These usually present as incidental findings, nonsecreting adrenal masses in asymptomatic patients. Diagnosis of a schwannoma is based on detection of spindle cells with Antoni A and Antoni B regions in histological sections and positive staining for S-100 protein by immunohistochemical analysis. We report a case of an incidentally identified during an abdominal ultrasound examination with schwannoma localized in the left adrenal gland. PMID- 26101688 TI - Midline Prostatic Cyst Marsupialization Using Holmium Laser. AB - Many of the prostatic cysts are asymptomatic and only 5% are symptomatic (Hamper et al., 1990; Higashi et al., 1990). These symptoms include pelvic pain, hematospermia, infertility, voiding dysfunction, prostatitis-like syndrome, and painful ejaculation. Treatment of prostatic cysts includes TRUSG guided drainage, endoscopic transurethral resection, and in some cases even open surgery. In the literature, endoscopic interventions use marsupialization of the midline prostatic cyst with transurethral resection (TUR) or transurethral incision with endoscopic urethrotomy (Dik et al., 1996; Terris, 1995). Holmium: YAG laser was employed for the marsupialization of the cyst wall in midline prostatic cyst treatment for the first time in the present study. Symptoms, treatment, and follow-up are presented in this paper. PMID- 26101689 TI - Stent Placement for Acute Superior Mesenteric Artery Occlusion Associated with Type B Aortic Dissection. AB - A 50-year-old man had a mesenteric ischemia related to superior mesenteric artery (SMA) occlusion associated with a type B aortic dissection. We decided to perform stent placement for the SMA and could avoid mesenteric ischemia. We think the stent placement in the SMA might be an option for the treatment of mesenteric ischemia caused by aortic dissection. PMID- 26101690 TI - Mindfulness Training among Individuals with Parkinson's Disease: Neurobehavioral Effects. AB - Objective. To investigate possible neurobehavioral changes secondary to a mindfulness based intervention (MBI) training for individuals living with Parkinson's disease (PD). Background. In the context of complementary medicine, MBIs are increasingly being used for stress reduction and in patient populations coping with chronic illness. The use of alternative and complementary medicine may be higher in patients with chronic conditions such as PD. However, behavioral effects of mindfulness training in PD have not yet been reported in the literature and this points to an unmet need and warrants further examination. Methods. A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Questionnaires and the UPDRS I-IV were obtained at baseline and 8-week follow-up. Results. Significant changes after the MBI were found including a 5.5 point decrease on the UPDRS motor score, an increase of 0.79 points on Parkinson's disease questionnaire (PDQ-39) pain item, and a 3.15 point increase in the Five Facet Mindfulness Questionnaire observe facet. Conclusions. To the best of our knowledge, this is the first quantitative analysis of neurobehavioral effects of MBI in PD. PMID- 26101692 TI - Ultra High Performance Liquid Chromatography Method for the Determination of Two Recently FDA Approved TKIs in Human Plasma Using Diode Array Detection. AB - Generally, tyrosine kinase inhibitors have narrow therapeutic window and large interpatient variability compared to intrapatient variability. In order to support its therapeutic drug monitoring, two fast and accurate methods were developed for the determination of recently FDA approved anticancer tyrosine kinase inhibitors, afatinib and ibrutinib, in human plasma using ultra high performance liquid chromatography coupled to PDA detection. Diclofenac sodium was used as internal standard. The chromatographic separation was achieved on an Acquity UPLC BEH C18 analytical column using a mobile phase combining ammonium formate buffer and acetonitrile at a constant flow rate of 0.4 mL/min using gradient elution mode. A uSPE (solid phase extraction) procedure, using Oasis MCX uElution plates, was processed and it gave satisfying and reproducible results in terms of extraction yields. Additionally, the methods were successfully validated using the accuracy profiles approach (beta = 95% and acceptance limits = +/-15%) over the ranges 5-250 ng/mL for afatinib and from 5 to 400 ng/mL for ibrutinib in human plasma. PMID- 26101693 TI - Capillary Electrophoresis Single-Strand Conformational Polymorphisms as a Method to Differentiate Algal Species. AB - Capillary electrophoresis single-strand conformational polymorphism (CE-SSCP) was explored as a fast and inexpensive method to differentiate both prokaryotic (blue green) and eukaryotic (green and brown) algae. A selection of two blue-green algae (Nostoc muscorum and Anabaena inaequalis), five green algae (Chlorella vulgaris, Oedogonium foveolatum, Mougeotia sp., Scenedesmus quadricauda, and Ulothrix fimbriata), and one brown algae (Ectocarpus sp.) were examined and CE SSCP electropherogram "fingerprints" were compared to each other for two variable regions of either the 16S or 18S rDNA gene. The electropherogram patterns were remarkably stable and consistent for each particular species. The patterns were unique to each species, although some common features were observed between the different types of algae. CE-SSCP could be a useful method for monitoring changes in an algae species over time as potential shifts in species occurred. PMID- 26101694 TI - Applying (1)H NMR Spectroscopy to Detect Changes in the Urinary Metabolite Levels of Chinese Half-Pipe Snowboarders after Different Exercises. AB - Monitoring physical training is important for the health and performance of athletes, and real-time assessment of fatigue is crucial to improve training efficiency. The relationship between key biomarkers and exercise has been reported. The aim of this study was to determine the effects of different levels of training exercises on the urine metabolome. (1)H NMR-based metabolomics analysis was performed on urine samples from half-pipe snowboarders, and spectral profiles were subjected to PCA and PLS-DA. Our results show that metabolic profiles varied during different stages of exercises. Lactate, alanine, trimethylamine, malonate, taurine, and glycine levels decreased while TMAO and phenylalanine levels increased in the stage with higher amount and intensity of exercise. Although the amount of exercise was reduced in subsequent stage, no significant variations of metabolic profile were found. Metabolic changes induced by training level were analyzed with related metabolic pathway. Studying metabolome changes can provide a better understanding of the physiology of athletes and could aid in adjusting training. PMID- 26101691 TI - Factors Associated with Poststroke Fatigue: A Systematic Review. AB - Background. Poststroke fatigue (PSF) is a frequent, disabling symptom that lacks a consensual definition and a standardized evaluation method. The (multiple) causes of PSF have not been formally characterized. Objective. To identify factors associated with PSF. Method. A systematic review of articles referenced in MEDLINE. Only original studies having measured PSF and potentially associated factors were included. Data was extracted from articles using predefined data fields. Results. Although PSF tends to be more frequent in female patients and older patients, sociodemographic factors do not appear to have a major impact. There are strong associations between PSF and emotional disturbances (such as depression and anxiety). PSF may also be linked to attentional disturbances (mainly slowing in processing speed). The literature data have failed to demonstrate a clear impact of the type and severity of stroke. It has been suggested that PSF results from alterations in the frontothalamostriatal system and/or inflammatory processes. Pain, sleep disorders, and prestroke fatigue also appeared to be associated with PSF. Implications. A better understanding of PSF may improve stroke patient care and facilitate the development of effective treatments. PMID- 26101695 TI - Determination of Nicotine in Tobacco by Chemometric Optimization and Cation Selective Exhaustive Injection in Combination with Sweeping-Micellar Electrokinetic Chromatography. AB - Nicotine is a potent chemical that excites the central nervous system and refreshes people. It is also physically addictive and causes dependence. To reduce the harm of tobacco products for smokers, a law was introduced that requires tobacco product containers to be marked with the amount of nicotine as well as tar. In this paper, an online stacking capillary electrophoresis (CE) method with cation-selective exhaustive injection sweeping-micellar electrokinetic chromatography (CSEI-sweeping-MEKC) is proposed for the optimized analysis of nicotine in tobacco. A higher conductivity buffer (160 mM phosphate buffer (pH 3)) zone was injected into the capillary, allowing for the analytes to be electrokinetically injected at a voltage of 15 kV for 15 min. Using 50 mM sodium dodecyl sulfate and 25% methanol in the sweeping buffer, nicotine was detected with high sensitivity. Thus, optimized conditions adapted from a chemometric approach provided a 6000-fold increase in the nicotine detection sensitivity using the CSEI-sweeping-MEKC method in comparison to normal CZE. The limits of detection were 0.5 nM for nicotine. The stacking method in combination with direct injection which matrix components would not interfere with assay performance was successfully applied to the detection of nicotine in tobacco samples. PMID- 26101696 TI - Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect. AB - Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A "plumbing model" is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells. PMID- 26101698 TI - Heterogeneity of chemokine cell-surface receptor expression in triple-negative breast cancer. AB - INTRODUCTION: Tumor heterogeneity is a well-established concept in cancer research. In this paper, we examine an additional type of tumor cell heterogeneity - tumor cell-surface receptor heterogeneity. METHODS: We use flow cytometry to measure the frequency and numbers of cell-surface receptors on triple negative breast cancer cell lines. RESULTS: We find two distinct populations of human triple-negative breast cancer cells MDA-MB-231 when they are grown in culture, one with low surface levels of various chemokine receptors and a second with much higher levels. The population with high surface levels of these receptors is increased in the more metastatic MDA-MB-231-luc-d3h2ln cell line. CONCLUSION: We hypothesize that this high cell-surface receptor population is involved in metastasis. We find that the receptor high populations can be modulated by tumor conditioned media and IL6 treatment indicating that the tumor microenvironment is important for the maintenance and sizes of these populations. PMID- 26101697 TI - L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. AB - The L-type amino acid transporter (LAT) family are Na(+)-independent transporters, which deliver neutral amino acids into cells. The four LATs, LAT1 (SLC7A5), LAT2 (SLC7A8), LAT3 (SLC43A1) and LAT4 (SLC43A2), are responsible for the majority of cellular leucine uptake. They show increased expression in many cancers, and are critical for control of protein translation and cell growth through the mTORC1 pathway. The increased transporter expression observed in cancers is regulated by transcriptional pathways such as hormone receptors, c-myc and nutrient starvation responses. We review the expression and function of the LAT family in cancer, as well as the recent development of specific inhibitors targeting LAT1 or LAT3. These LAT family inhibitors may be useful adjuvant therapeutics in multiple cancers. PMID- 26101699 TI - Mogrol represents a novel leukemia therapeutic, via ERK and STAT3 inhibition. AB - Unlike solid tumors, the primary strategy for leukemia treatment is chemotherapy. However, leukemia chemotherapy is associated with adverse drug effects and drug resistance. Therefore, it is imperative to identify novel agents that effectively treat leukemia while minimizing adverse effects. The Raf/MEK/extracellular regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) pathways have been implicated in leukemia carcinogenesis, and provide novel molecular targets for therapeutic intervention in cancer. Mogrol, a biometabolite of mogrosides found in Siraitia grosvenorii, has exhibited anti cancer activities; however, the underlying mechanism of this effect remains unclear. To clarify its anti-cancer activity and mechanism of action, we treated K562 leukemia cells with mogrol. Mogrol suppressed leukemia cell growth via inhibition of the ERK1/2 and STAT3 pathways, in particular, through the suppression of p-ERK1/2 and p-STAT3. Inhibition of these pathways suppressed Bcl 2 expression, thereby inducing K562 cell apoptosis. Furthermore, mogrol enhanced p21 expression, resulting in G0/G1 cell cycle arrest. The findings provide new perspectives regarding the role of mogrol in leukemia treatment. PMID- 26101700 TI - [6]-Gingerol inhibits de novo fatty acid synthesis and carnitine palmitoyltransferase-1 activity which triggers apoptosis in HepG2. AB - The de novo fatty acid synthesis catalyzed by key lipogenic enzymes, including fatty acid synthase (FASN) has emerged as one of the novel targets of anti-cancer approaches. The present study explored the possible inhibitory efficacy of [6] gingerol on de novo fatty acid synthesis associated with mitochondrial-dependent apoptotic induction in HepG2 cells. We observed a dissipation of mitochondrial membrane potential accompanied by a reduction of fatty acid levels. [6]-gingerol administration manifested inhibition of FASN expression, indicating FASN is a major target of [6]-gingerol inducing apoptosis in HepG2 cells. Indeed, we found that increased ROS generation could likely be a mediator of the anti-cancer effect of [6]-gingerol. A reduction of fatty acid levels and induction of apoptosis were restored by inhibition of acetyl-CoA carboxylase (ACC) activity, suggesting an accumulation of malonyl-CoA level could be the major cause of apoptotic induction of [6]-gingerol in HepG2 cells. The present study also showed that depletion of fatty acid following [6]-gingerol treatment caused an inhibitory effect on carnitine palmitoyltransferase-1 activity (CPT-1), whereas C75 augmented CPT-1 activity, indicating that [6]-gingerol exhibits the therapeutic benefit on suppression of fatty acid beta-oxidation. PMID- 26101701 TI - Targeted inhibition of histone deacetylases and hedgehog signaling suppress tumor growth and homologous recombination in aerodigestive cancers. AB - Standard combined modality therapies for aerodigestive tract malignancies have suboptimal outcomes, and targeting cancer-specific molecular pathways in combination with radiation could improve the therapeutic ratio. Dysregulation of epigenetic modulators such as histone deacetylases (HDACs), and developmental morphogens such as the hedgehog (HH) pathway have been implicated in aerodigestive tumor progression and metastasis. We hypothesized that simultaneous targeting of HDACs and the HH-pathway mediator Smoothened (Smo) represents an opportunity to overcome therapeutic resistance in these cancers. We evaluated the effects of the HDAC inhibitor SAHA and Smo inhibitor GDC-0449 with radiation in multiple aerodigestive cancer cell lines. Isobologram analyses showed that SAHA and GDC-0449 synergistically suppressed cancer cell proliferation in vitro. SAHA and GDC-0449 cooperatively enhanced G0/G1 cell cycle arrest which was associated with up-regulation of p21(waf). GDC-0449 prevented SAHA-induced up-regulation of Gli-1 and Gli-2. Both Smo and Ptc-1 expression was cooperatively suppressed by SAHA and GDC-0449. The combination of SAHA and GDC-0449 induced radiation sensitization with 2 Gy as determined by colony formation assays and cytogenetic analyses, which correlated with higher residual gamma-H2AX and 53BP1 foci. In mouse tumor xenografts of the SqCC/Y1 cell line, SAHA and GDC-0449 delayed tumor growth longer and prolonged survival more than either agent alone. In summary, we have identified synergistic effect of HDAC and HH signaling for radiosensitization to improve therapeutic outcomes for aerodigestive malignancies. PMID- 26101702 TI - URI expression in cervical cancer cells is associated with higher invasion capacity and resistance to cisplatin. AB - Cervical cancer is a common and devastating female cancer worldwide. The etiology of cervical cancer has been largely attributed to human papillomavirus (HPV) infection and activation of the P13K/AKT/mTOR (mammalian target of rapamycin) pathway. However, the limited HPV-directed therapy, as well as therapeutic approach targeting P13K/AKT/mTOR pathway, has not yet been established or effective. A deeper understanding of cervical carcinogenesis and finding of novel candidate molecules for cervical cancer therapeutics is largely warranted. The unconventional prefoldin RPB5 interactor (URI or URI1), a known transcription factor involving the TOR signaling pathway, has recently been implicated a role in multiple tumorigenesis. We recently reported significant upregulation of URI in precancerous cervical intra-epithelial neoplasia (CIN) and invasive cervical cancer, suggesting its role in cervical carcinogenesis. However, the effect and underlying mechanism of URI in cervical cancer development have never been elucidated. Here, we aimed to investigate the in vitro effect of URI on cervical cancer using two cervical cancer cell lines CaSki and C33A, which are HPV positive and HPV-negative respectively. We have shown that forced over-expression of URI in C33A and CaSki cells markedly promoted cell growth, while down regulation of URI mediated by siRNA inhibited cell proliferation. We have found that URI over-expression enhanced resistance of cervical cancer cells to cisplatin. In contrast, knockdown of URI promoted apoptosis by influencing cell response to cisplatin, supporting URI as an oncogenic protein for cervical cancer cells. We have also shown that URI promoted the migration and invasive capacity of cervical cancer cells by up-regulation of Vimentin, a mesenchymal cell migration marker relating to the epithelial-mesenchymal transition (EMT) program. Our data support an important function of URI in the biological behavior of cervical cancer cells and provide novel mechanistic insights into the role of URI in cervical cancer progression and possibly, metastasis. PMID- 26101703 TI - Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma. AB - AIMS: High constitutive expression of Nrf2 has been found in many types of cancers, and this high level of Nrf2 also favors resistance to drugs and radiation. Here we investigate how isoliquiritigenin (ISL), a natural antioxidant, inhibits the Nrf2-dependent antioxidant pathway and enhances the radiosensitivity of HepG2 cells and HepG2 xenografts. RESULTS: Treatment of HepG2 cells with ISL for 6 h selectively enhanced transcription and expression of Keap1. Keap1 effectively induced ubiquitination and degradation of Nrf2, and inhibited translocation of Nrf2 to the nucleus. Consequently, expression of Nrf2 downstream genes was reduced, and the Nrf2-dependent antioxidant system was suppressed. Endogenous ROS was higher than before ISL treatment, causing redox imbalance and oxidative stress in HepG2 cells. Moreover, pretreatment with ISL for 6 h followed by X-ray irradiation significantly increased gamma-H2AX foci and cell apoptosis, and reduced clonogenic potential compared with cells irradiated with X-rays alone. In addition, HepG2 xenografts, ISL, and X-ray co-treatments induced greater apoptosis and tumor growth inhibition, when compared with X-ray treatments alone. Additionally, HepG2 xenografts, in which Nrf2 was expressed at very low levels due to ectopic expression of Keap1, showed that ISL-mediated radiosensitization was Keap1 dependent. INNOVATION AND CONCLUSIONS: ISL inhibited the Nrf2-antioxidant pathway by increasing the levels of Keap1 and ultimately inducing oxidative stress via disturbance of the redox status. The antioxidant ISL possessed pro-oxidative properties, and enhanced the radiosensitivity of liver cancer cells, both in vivo and in vitro. Taken together, these results demonstrated the effectiveness of using ISL to decrease radioresistance, suggesting that ISL could be developed as an adjuvant radiosensitization drug. Disturbance of redox status could be a potential target for radiosensitization. PMID- 26101704 TI - MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2. AB - Colorectal cancer remains the third most common cause of death from cancer worldwide. MicroRNA emerges as a good area of research for current cancer therapy. Here, we identified miR-135b to be a contributor to anti-apoptosis and chemoresistance in colorectal cancer. We observed high levels of miR-135b in colorectal cancer cell lines and clinical tissues, compared to colorectal epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-135b attenuated doxorubicin-induced apoptosis in colorectal cells. (Doxorubicin alone can trigger significant apoptosis). In elucidating the molecular mechanism by which miR-135b participate in the regulation of apoptosis and chemoresistance in colorectal cancer, we discovered that large tumor suppressor kinase 2 (LATS2) is a direct target of miR-135b. The role of miR-135b was confirmed in colorectal tumor xenograft models. The growth of established tumors was suppressed by an inhibition of miR-135b expression and enhanced apoptosis was further assessed by TUNEL assay. Taken together, our results reveal that miR-135b and LATS2 axis may be a novel therapeutic target for colorectal cancer. PMID- 26101705 TI - Netrin-1 promotes cell migration and invasion by down-regulation of BVES expression in human hepatocellular carcinoma. AB - The axon guidance cues netrin-1 has been reported to be associated with cancer progression in various types of human cancers. However, the underlying molecular mechanism of netrin-1-mediated metastasis remains obscure. In this study, we found that overexpression of netrin-1 promoted HCC cell migration and invasion as determined by transwell assay and 3D cell culture assay. However, netrin-1 knockdown inhibited these processes. Further investigation indicated that netrin 1 decreased the expression of Blood Vessel Epicardial Substance (BVES), which was down-regulated in HCC. Interestingly, LY294002, a special inhibitor to PI3K/AKT signaling which was determined as a downstream pathway of netrin-1, restored the reduction in BVES caused by netrin-1. In addition, BVES exhibited an opposite effect on HCC cell metastasis to that of netrin-1. Importantly, up-regulating BVES expression significantly attenuated netrin-1-enhanced migration and invasion, whereas silencing BVES expression rescued the metastatic phenotype in netrin-1 knockdown cells. Moreover, netrin-1 expression was negatively correlated with BVES in HCC tissues and cell lines with different metastatic potential. Taken together, these results reveal that netrin-1 promotes HCC cell metastasis by regulating BVES expression via AKT activation. PMID- 26101706 TI - HnRNP A1 tethers KSRP to an exon splicing silencer that inhibits an erythroid specific splicing event in PU.1-induced erythroleukemia. AB - Exon 16 inclusion is a critical splicing event that triggers the production of a functional protein 4.1R in mature normal erythroblasts, and is obviated in PU.1 induced erythroleukemia cells. Exon 16 contains an exonic splicing silencer (ESS16) that interacts with hnRNP A/B in heterologous cell context. We here show that ESS16 promotes the recruitment of a protein complex containing hnRNP A1 and a 79-kDa protein in nuclear extracts from either proliferative erythroleukemia cells or cells induced to terminal differentiation. By using 2D gel fractionation and mass spectrometry, we unambiguously identified KSRP as the 79-kDa component interacting with ESS16. Furthermore, we show that KSRP slightly decreases in erythroleukemia cells induced to terminal erythroid differentiation. Yet, KSRP inducible knockdown, through stable transfection of small hairpin KSRP RNA, did not alter exon 16 splicing, suggesting that KSRP alone does not modulate the splicing event. Interestingly, absence of hnRNP A1 prevented KSRP from binding to ESS16. Reciprocally, KSRP interaction with ESS16 was recovered when hnRNP A1 expression is restored in hnRNP A1-null cells. Collectively, this study establishes that hnRNPA1 is part of a KSRP-containing RNP complex, and emphasizes that, aside from its function in AU-rich element-mediated mRNA decay and its role in microRNA biogenesis, KSRP associates with hnRNP A1 to bind an ESS. These findings further support the role of members of the KH-domain protein family in organizing large RNA-protein complex formation, rather than primarily in modulating specific splicing events. PMID- 26101707 TI - Metformin inhibits gastric cancer via the inhibition of HIF1alpha/PKM2 signaling. AB - Recent evidence suggests that anti-diabetic drug metformin prevents cancer progression, but the mechanism by which metformin inhibits tumor growth remains elusive. In this study, we investigated the anticancer role of metformin in gastric cancer and explored the underlying mechanism. The expression of hypoxia inducible factor 1alpha (HIF1alpha) and pyruvate kinase M2 (PKM2) in different stages of gastric cancer tissues was detected by immunohistochemistry. Gastric cancer cell viability was evaluated by CCK-8 assay; apoptosis and cell cycle were analyzed by flow cytometry. The expression of PI3K, Akt, HIF1alpha, PARP, PKM2 and COX in gastric cancer cells was detected by immunofluorescence and Western blot analysis. We found that HIF1alpha and PKM2 protein expression levels were higher in advanced gastric cancer tissues than in gastritis tissues. Metformin reduced gastric cancer cell viability, invasion and migration. Metformin induced apoptosis and cell cycle arrest in part through inhibiting PARP expression. Metformin downregulated PI3K, Akt, HIF1alpha, PARP, PKM2 and COX expression. Moreover, overexpression of HIF1alpha increased gastric cancer cell viability, invasion and migration. In summary, metformin has profound antitumor effect for gastric cancer by inducing intrinsic apoptosis via the inhibition of HIF1alpha/PKM2 signaling pathway. PMID- 26101708 TI - miR-30c negatively regulates the migration and invasion by targeting the immediate early response protein 2 in SMMC-7721 and HepG2 cells. AB - miR-30c has been reported to act as a tumor suppressor and negatively regulate cancer metastasis by directly targeting metastasis associated genes; however, miR 30c has also been shown to promote the invasion of metastatic breast cancer cells, suggesting that miR-30c might be involved in cancer cell metastasis in different ways via targeting different genes. In this study, we demonstrated that over-expression and knockdown of immediate early response protein 2 (IER2) modulated the general capacity of the migration and invasion in hepatocellular carcinoma cell line SMMC-7721 and HepG2, whereas overexpression and knockdown of miR-30c decreased and promoted cell motility, respectively. Further studies revealed that miR-30c overexpression down-regulated the expression of IER2 protein but not its mRNA level, and miR-30c can directly target the 3' untranslated region (3'UTR) of IER2, and subsequently reducing its expression. Moreover, we also showed that suppression of cell motility by miR-30c was partially rescued by IER2 re-expression. Our results indicated that miR-30c may function as a negative regulator in cell motility, with IER2 as a direct and functional target in SMMC-7721 and HepG2 cells. PMID- 26101710 TI - Role of RHOT1 on migration and proliferation of pancreatic cancer. AB - Pancreatic cancer (PC) is one of the most malignant tumors. Rho GTPases can affect several types of human cancers, including PC. In this study, we investigated the role of Ras homolog family member T1 (RHOT1), a new member of Rho GTPases in PC. IHC results showed that RHOT1 was expressed significantly higher in PC tissues than paracancerous tissues (P<0.01) and SMAD family member 4 (SMAD4) was expressed lower in PC tissues (P<0.01). RHOT1 was widely expressed in PC cell lines analyzed by reverse transcription PCR (RT-PCR), real-time quantitative PCR (RT-qPCR) and western blotting (WB). SiRNA-RHOT1 significantly suppressed the proliferation and migration of SW1990 cells. Moreover, SMAD4 was identified as an effector of RHOT1. Our findings suggest that RHOT1 can regulate cell migration and proliferation by suppressing the expression of SMAD4 in PC, which may provide a novel sight to explore the mechanism and therapeutic strategy for PC. PMID- 26101709 TI - SP1-mediated microRNA-520d-5p suppresses tumor growth and metastasis in colorectal cancer by targeting CTHRC1. AB - Recent evidence suggests that miR-520 family has an important role in regulating tumorigenesis and development of various types of solid cancers. However, as one of the most common cancers in the world, there is little known about the underlying regulatory mechanisms of miR-520 in colorectal cancer (CRC). In the present study, we investigated the expression of microRNA-520d-5p (miR-520d-5p) in CRC specimens and then explored its potential role and mechanism in CRC progression. We found that miR-520d-5p was markedly down-regulated in CRC clinical specimens compared with adjacent normal tissues by real-time PCR. Dual luciferase assays confirmed that miR-520d-5p directly targeting CTHRC1 and SP1 transactivate miR-520d-5p by binding to its upstream promoter region. The biological functional experiments showed that ectopic re-expression of miR-520d 5p suppressed CRC cell proliferation, migration and invasion, whereas the inhibition of miR-520d-5p displayed an inverse effect in vitro and in vivo. Western blot shown that miR-520d-5p abrogated the epithelial-mesenchymal transition by inactivating the phosphorylation of Erk1/2. In conclusion, our findings indicate that miR-520d-5p is significantly down-expressed and involved in CRC progression and metastasis by targeting CTHRC1 and regulated by SP1, which provide new support for miR-520d-5p maybe as a novel anti-onco molecular target for the treatment of CRC in the future. PMID- 26101711 TI - Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis. AB - Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1(+) tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the "classical-like" (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients' outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1(+) cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1(-) cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1(+) cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID- 26101712 TI - S100A14, a mediator of epithelial-mesenchymal transition, regulates proliferation, migration and invasion of human cervical cancer cells. AB - S100A14 is an EF-hand calcium-binding protein that has been reported to exert its biological effects on different types of cells. However, the potential clinical significance and biological functions of S100A14 in cervical cancer has not yet been clarified. In this study, we firstly examined the correlation between S100A14 expression and clinical-pathological parameters in cervical cancers. Next, we observed the effect of S100A14 on cell cycle progression, cell proliferation, migration and invasion by employing lentiviral-mediated overexpression and knockdown of S100A14 in cervical cancer cells. Furthermore, we investigated the underlying mechanism of S100A14 affecting cell migration and invasion. Immunohistochemistry analysis demonstrated that S100A14 expression was associated with the International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.025) and lymph node (LN) metastasis (P = 0.001). Functional assays showed that S100A14 overexpression increased the proportion of G2/M phase, promoted cell proliferation, migration, and invasion, whereas S100A14 knockdown exhibited adverse effect on above properties. Mechanistic investigation demonstrated that S100A14 can act as a mediator of epithelial-mesenchymal transition (EMT). And overexpression of S100A14 increased expression of N cadherin and Vimentin while decreased expression of E-cadherin. The opposite results were observed in S100A14-silenced cells. Taken together, our data indicate that S100A14 has a crucial role in cervical cancer progression. This study significantly increases our understanding of S100A14 functional roles in cervical cancer, which may lead to the development of a novel therapeutic target for cervical cancer. PMID- 26101713 TI - Preclinical evaluation of PI3K inhibitor BYL719 as a single agent and its synergism in combination with cisplatin or MEK inhibitor in nasopharyngeal carcinoma (NPC). AB - Nasopharyngeal carcinoma (NPC) is endemic to Southeast Asia and over 40% of NPC tissues harbor PIK3CA amplifications. This study aims to study the preclinical activity of a novel PI3K inhibitor, BYL719, in 6 NPC cell lines: C666-1, CNE-2, HK1, HK1-EBV, HONE-1 and HONE-1-LMP1. Over 70% of growth inhibition was attained when NPC cell lines were exposed to increasing concentrations of BYL719, with IC50 values at the low micro-molar range. Two BYL719-sensitive cell lines that harbor PIK3CA mutations, CNE-2 and HONE-1, were selected for further analysis on the effect of BYL719 on cell cycle progression, apoptosis and PI3K signaling. BYL719 significantly reduced the phosphorylation of Akt, and the Akt-mTOR axis downstream effector S6 in these 2 cell lines, but a feedback activation of MAPK was observed at 72 hours post-treatment. BYL719 induced G0/G1 cell cycle arrest and apoptosis in both cell lines. In 3D cell culture models, the growth of NPC spheroids was significantly inhibited in a dose-depending manner. When BYL719 was combined with a MEK inhibitor (AZD6244) in a 3D cell culture system, strong synergism on NPC cell growth was observed with attenuation of MAPK activation. A synergistic inhibitory effect on growth was observed when BYL719 was combined with higher dose levels of cisplatin. These data suggest that BYL719 has preclinical activity in NPC cell lines especially in those which harbor PIK3CA mutation. Combination with a MEK inhibitor maybe a useful strategy that warrants further investigation. PMID- 26101714 TI - Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms. AB - Variable clinical responses, tumor heterogeneity, and drug resistance reduce long term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF(V600E) models showed acquired drug resistance, one BRAF(V600E) model had a complete and durable response, and a BRAF(V600V) model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next generation drug combinations. PMID- 26101715 TI - Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer. AB - The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. We previously demonstrated that KDM4C is significantly amplified and overexpressed in aggressive basal-like breast cancers and functions as a transforming oncogene. However, information regarding the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer remains largely incomplete. Here, we conducted a meta analysis of KDM4A, B, C and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We demonstrated that KDM4A and D are also significantly overexpressed in basal-like breast cancer, whereas KDM4B overexpression is more dominant in estrogen-receptor positive, luminal breast cancer. Next, we investigated the therapeutic potential of a novel histone demethylase inhibitor, NCDM-32B, in breast cancer. The treatment of basal breast cancer cell lines with NCDM-32B resulted in the decrease of cell viability and anchorage independent growth in soft agar. Furthermore, we found that NCDM-32B impaired several critical pathways that drive cellular proliferation and transformation in breast cancer. Our findings demonstrate genetic amplification and overexpression of the KDM4 demethylases in different subtypes of breast cancer. Furthermore, histone methylation is reversible and KDM4 demethylases are druggable targets. Thus, KDM4 inhibitors may serve as a novel therapeutic approach for a subset of aggressive breast cancer. PMID- 26101716 TI - Sprouty 1 predicts prognosis in human epithelial ovarian cancer. AB - Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase (RTK) signaling. We have previously reported inverse correlation of the Sprouty 1 (Spry1) protein expression with ovarian cancer cell proliferation, migration, invasion and survival. In the present study, the expression status of Spry1 protein and its clinical relevance in patients with epithelial ovarian cancer were explored. Matched tumor and normal tissue samples from 100 patients with epithelial ovarian cancer were immunohistochemically stained for Spry1. Expression of ERK, p-ERK, Ki67, FGF-2, VEGF and IL-6 and their correlation with Spry1 were also evaluated. In addition, correlation between Spry1 and clinicopathological characteristics and predictive significance of Spry1 for overall survival (OS) and disease-free survival (DFS) were analysed. Our data indicated that Spry1 was significantly downregulated in tumor tissues (p=0.004). Spry1 showed significant inverse correlation with p-ERK/ERK (p=0.045), Ki67 (p=0.010), disease stage (p=0.029), tumor grade (p=0.037), recurrence (p=0.001) and lymphovascular invasion (p=0.042). It was revealed that Spry1 low-expressing patients had significantly poorer OS (p=0.010) and DFS (p=0.012) than those with high expression of Spry1. Multivariate analysis showed that high Spry1 (p=0.030), low stage (p=0.048) and no residual tumor (p=0.007) were independent prognostic factors for a better OS, among which high Spry1 (p=0.035) and low stage (p=0.035) remained as independent predictors of DFS, too. We also found that the expression of Spry1 significantly correlates with the expression of Spry2 (p<0.001), but not that of Spry4. In conclusion, we report for the first time to our knowledge that Spry1 protein is downregulated in human epithelial ovarian cancer. Spry1 expression significantly impacts tumor behavior and shows predictive value as an independent prognostic factor for survival and recurrence. PMID- 26101717 TI - MYBL2 is an independent prognostic marker that has tumor-promoting functions in colorectal cancer. AB - The MYBL2 gene plays an important role in the genesis and progression of tumors; however, few studies to date have defined the role of this gene in colorectal cancer (CRC). The aim of this study was to determine the relationship between MYBL2 and the prognosis of patients with CRC and to determine the possible effect of MYBL2 on colorectal carcinogenesis. Solid CRC tissues (n=180) preserved with RNAlater were collected to examine the mRNA levels of MYBL2 by real-time quantitative PCR (RT-qPCR). Formalin-fixed, paraffin-embedded (FFPE) blocks of CRC tissues (n=97) and adjacent noncancerous tissues (ANCTs, n=104) were obtained to detect MYBL2 protein levels by immunohistochemistry (IHC). siRNA was used to downregulate MYBL2 expression in the SW480 cell line to detect changes in proliferation, cell cycle progression, apoptosis, migration and invasion. The protein levels of MYBL2 were significantly higher in CRC tissues compared with ANCTs (P<0.05). Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in CRC patients in whom MYBL2 was overexpressed (at both the mRNA and protein levels) compared with patients not overexpressing MYBL2. Cox multivariate analysis revealed MYBL2 overexpression as an independent prognostic factor for poor patient survival. In addition, siRNA downregulation of MYBL2 suppressed SW480 cell proliferation, delayed cell cycle progression and induced apoptosis; however, changes in cell migration were minor. Western blot analysis demonstrated an association between MYBL2 expression and that of MMP9, Vimentin, and E-cadherin. MYBL2 is overexpressed in CRC and may therefore play an important role in tumourigenesis. PMID- 26101718 TI - Programmed cell death protein 1 and programmed death-ligand 1 are expressed on the surface of some small-cell lung cancer lines. AB - INTRODUCTION: Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) play a major role in suppressing the immune system during the formation of the PD-1/PD-L1 pathway, which transmits an inhibitory signal to reduce T cell activity. PD-L1 is often expressed in various malignant tumors. In contrast, PD-1 is generally observed in activated lymphocytes and myeloid-derived dendritic cells. Of the malignant cells, only Jurkat cells under special conditions and angioimmunoblastic T-cell lymphoma tissue cells express PD-1 on their surface. METHODS: To clarify whether the PD-1/PD-L1 pathway participates in the immunotolerance of small-cell lung cancer (SCLC) cells, we examined the expressions of PD-1 and PD-L1 on the cell surface of SCLC cell lines using flow cytometry and reverse transcription polymerase chain reaction. RESULTS: Among the four SCLC cell lines examined, only SBC-3 expressed both PD-1 and PD-L1. CONCLUSIONS: We demonstrated that both PD-1 and PD-L1 molecules were co-expressed on the surface of SCLC cells. Although the biological implications of this remain unclear, we speculate that PD-1 and its ligand on the SCLC cells may participate in the growth inhibition of tumor cells as reported in cytotoxic T cells. PMID- 26101719 TI - Potential therapeutic target for malignant paragangliomas: ATP synthase on the surface of paraganglioma cells. AB - F1FoATP synthase (ATP synthase) is a ubiquitous enzyme complex in eukaryotes. In general it is localized to the mitochondrial inner membrane and serves as the last step in the mitochondrial oxidative phosphorylation of ADP to ATP, utilizing a proton gradient across the inner mitochondrial membrane built by the complexes of the electron transfer chain. However some cell types, including tumors, carry ATP synthase on the cell surface. It was suggested that cell surface ATP synthase helps tumor cells thriving on glycolysis to survive their high acid generation. Angiostatin, aurovertin, resveratrol, and antibodies against the alpha and beta subunits of ATP synthase were shown to bind and selectively inhibit cell surface ATP synthase, promoting tumor cell death. Here we show that ATP synthase beta (ATP5B) is present on the cell surface of mouse pheochromocytoma cells as well as tumor cells of human SDHB-derived paragangliomas (PGLs), while being virtually absent on chromaffin primary cells from bovine adrenal medulla by confocal microscopy. The cell surface location of ATP5B was verified in the tissue of an SDHB-derived PGL by immunoelectron microscopy. Treatment of mouse pheochromocytoma cells with resveratrol as well as ATP5B antibody led to statistically significant proliferation inhibition. Our data suggest that PGLs carry ATP synthase on their surface that promotes cell survival or proliferation. Thus, cell surface ATP synthase may present a novel therapeutic target in treating metastatic or inoperable PGLs. PMID- 26101720 TI - Nanoparticle-mediated down-regulation of TWIST increases radiosensitivity of nasopharyngeal carcinoma cells via ERK pathway. AB - Evidence suggests that over-expression of TWIST, an epithelial-mesenchymal transition inducer, might have a correlation with cancer progression and chemoresistance. However, its roles in radioresistance of cancer have rarely been reported. High TWIST expression was detected in nasopharyngeal carcinoma (NPC) and associated with poor prognosis. Thus, in the present study, we aimed to determine whether knockdown of TWIST can increase radiosensitivity of NPC cells. Chitosan-encapsulated TWIST-siRNA nanoparticles were constructed and used to silence TWIST expression in CNE2 cells. The cell viability and apoptosis as well as possible MAPKs pathways were assessed after irradiation treatment. The results showed that the nanoparticles successfully suppressed TWIST expression in CNE2 cells, and TWIST depletion significantly sensitized CNE2 cells to irradiation by inducing activation of ERK pathway but not JNK or p-38 pathways. The data suggested that TWIST depletion might be a promising approach sensitizing NPC cells to irradiation. Further investigations are needed to confirm the results. PMID- 26101721 TI - Intraocular Lens Fragmentation Using Femtosecond Laser: An In Vitro Study. AB - PURPOSE: To transect intraocular lenses (IOLs) using a femtosecond laser in cadaveric human eyes. To determine the optimal in vitro settings, to detect and characterize gasses or particles generated during this process. METHODS: A femtosecond laser was used to transect hydrophobic and hydrophilic acrylic lenses. The settings required to enable easy separation of the lens fragment were determined. The gasses and particles generated were analysed using gas chromatography mass spectrometer (GC-MS) and total organic carbon analyzer (TOC), respectively. RESULTS: In vitro the IOL fragments easily separated at the lowest commercially available energy setting of 1 MUJ, 8-MUm spot, and 2-MUm line separation. No particles were detected in the 0.5- to 900-MUm range. No significant gasses or other organic breakdown by products were detected at this setting. At much higher energy levels 12 MUJ (4 * 6 MUm spot and line separation) significant pyrolytic products were detected, which could be harmful to the eye. In cadaveric explanted IOL capsule complex the laser pulses could be applied through the capsule to the IOL and successfully fragment the IOL. CONCLUSION: IOL transection is feasible with femtosecond lasers. Further in vivo animal studies are required to confirm safety. TRANSLATIONAL RELEVANCE: In clinical practice there are a number of large intraocular lenses that can be difficult to explant. This in-vitro study examines the possibility of transecting the lasers quickly using femtosecond lasers. If in-vivo studies are successful, then this innovation could help ophthalmic surgeons in IOL explantation. PMID- 26101722 TI - Aniseikonia Tests: The Role of Viewing Mode, Response Bias, and Size-Color Illusions. AB - PURPOSE: To identify the factors responsible for the poor validity of the most common aniseikonia tests, which involve size comparisons of red-green stimuli presented haploscopically. METHODS: Aniseikonia was induced by afocal size lenses placed before one eye. Observers compared the sizes of semicircles presented haploscopically via color filters. The main factor under study was viewing mode (free viewing versus short presentations under central fixation). To eliminate response bias, a three-response format allowed observers to respond if the left, the right, or neither semicircle appeared larger than the other. To control decisional (criterion) bias, measurements were taken with the lens-magnified stimulus placed on the left and on the right. To control for size-color illusions, measurements were made with color filters in both arrangements before the eyes and under binocular vision (without color filters). RESULTS: Free viewing resulted in a systematic underestimation of lens-induced aniseikonia that was absent with short presentations. Significant size-color illusions and decisional biases were found that would be mistaken for aniseikonia unless appropriate action is taken. CONCLUSIONS: To improve their validity, aniseikonia tests should use short presentations and include control conditions to prevent contamination from decisional/response biases. If anaglyphs are used, presence of size-color illusions must be checked for. TRANSLATIONAL RELEVANCE: We identified optimal conditions for administration of aniseikonia tests and appropriate action for differential diagnosis of aniseikonia in the presence of response biases or size-color illusions. Our study has clinical implications for aniseikonia management. PMID- 26101723 TI - Paclitaxel-Releasing Thin Biodegradable Film for Prevention of Bleb Avascularity Without Compromising Filtration in Rabbits. AB - PURPOSE: A honeycomb-patterned film (HPF) prevents bleb scarring and mitomycin C (MMC)-related bleb avascularity in a rabbit model of filtration surgery. In this study, we examined whether a HPF-releasing paclitaxel (PTX) can prevent bleb avascularity without compromising filtration. METHODS: Filtration surgery was performed in one eye of rabbits. A 14-MUm thick HPF made from poly(L-lactide-co epsilon-caprolactone) was placed subconjunctivally over the filtration site with the honeycomb surface turned toward the subconjunctival Tenon tissue. The rabbits were divided into four groups (n = 5 each): 1, HPF with no drug; 2, HPF + PTX 50 MUg; 3, HPF + 5 MUg; 4, HPF + 0.5 MUg. Intraocular pressure (IOP) measurements and bleb evaluations using ultrasound biomicroscopy were performed periodically for 4 weeks followed by histological examination. A longer follow-up study (12 weeks) was performed for group 4 (experiment 2; n = 8). RESULTS: Among all groups at the 4-week follow up, two blebs failed in group 1. The postoperative IOP decrease was significantly greater in PTX-treated eyes than in group 1. The bleb avascular area persisted for 4 weeks in groups 2 and 3. However, no avascular area was observed in groups 1 and 4 at 4 weeks postoperatively. Histology showed minimal fibrosis at the filtration site in all the PTX groups. In experiment 2, some blebs became flatter starting at 10 weeks after surgery. CONCLUSIONS: PTX released from HPF promoted bleb survival and IOP decrease. The lowest dose of PTX (0.5 MUg) was effective at preventing bleb avascularity without compromising filtration. PMID- 26101724 TI - Topical Ocular Drug Delivery to the Back of the Eye by Mucus-Penetrating Particles. AB - PURPOSE: Enhanced drug exposure to the ocular surface typically relies on inclusion of viscosity-enabling agents, whereas delivery to the back of the eye generally focuses on invasive means, such as intraocular injections. Using our novel mucus-penetrating particle (MPP) technology, which rapidly and uniformly coats and penetrates mucosal barriers, we evaluated if such drug formulations could increase ocular drug exposure and improve topical drug delivery. METHODS: Pharmacokinetic (PK) profiling of topically administered loterprednol etabonate formulated as MPP (LE-MPP) was performed in rabbits and a larger species, the mini-pig. Pharmacodynamic evaluation was done in a rabbit model of VEGF-induced retinal vascular leakage. Cellular potency and PK profile were determined for a second compound, KAL821, a novel receptor tyrosine kinase inhibitor (RTKi). RESULTS: We demonstrated in animals that administration of LE-MPP increased exposure at the ocular surface and posterior compartments. Furthermore using a rabbit vascular leakage model, we demonstrated that biologically effective drug concentrations of LE were delivered to the back of the eye using the MPP technology. We also demonstrated that a novel RTKi formulated as MPPs provided drug levels to the back of the eye above its cellular inhibitory concentration. CONCLUSIONS: Topical dosing of MPPs of LE or KAL821 enhanced drug exposure at the front of the eye, and delivered therapeutically relevant drug concentrations to the back of the eye, in animals. TRANSLATIONAL RELEVANCE: These preclinical data support using MPP technology to engineer topical formulations to deliver therapeutic drug levels to the back of the eye and could provide major advancements in managing sight-threatening diseases. PMID- 26101725 TI - Chemoprevention Trial Feasibility Using Botanicals in Exceptionally High Risk Populations for Lung Cancer. AB - : While chemoprevention with botanicals shows promise in reducing cancer risk, recruitment and retention of participants for trials continues to be costly and presents unique challenges. Knowledge of interest, willingness of target populations and evaluation of design challenges are critical to improve accrual in these chemoprevention trials. OBJECTIVE: The study assessed interest and willingness of former smokers to participate in a chemoprevention trial using a botanical agent. METHODS: An introductory letter and survey instrument were mailed to 609 consecutive, former heavy smokers, with no cancer, from a database of 826 subjects at the Moffitt Cancer Center. RESULTS: 202 (40.4%) subjects returned completed surveys. 92-96% reported interest in receiving free lung exams and knowing their lung cancer risk. 88% were interested in participating in a trial evaluating a botanical agent for lung cancer prevention. Over 92% of subjects reported willingness to comply with study requirements; multiple blood draws and trips to the Center, spiral CTs and chest x-rays. Subjects were relatively less enthusiastic (73-79%) about bronchoscopy, taking multiple study agents and assignment to placebo arm. CONCLUSIONS: Our study strongly suggests feasibility, highlights potential challenges and the significant interest and willingness of this exceptionally high risk population to participate in chemoprevention trials. PMID- 26101726 TI - Evolving Techniques in Corneal Transplantation. AB - Corneal transplantation is one of the most common types of human transplant surgery. By removing a scarred or damaged host cornea and replacing it with a clear and healthy donor transplant, this procedure helps to restore vision in a variety of corneal diseases. The traditional technique for corneal transplantation, penetrating keratoplasty (PKP), involves transplantation of all corneal layers. Over the past decade though, there has been a trend away from PKP as surgeons have developed partial thickness transplant procedures, such as deep anterior lamellar keratoplasty and Descemet stripping automated endothelial keratoplasty. These partial thickness transplant procedures selectively replace diseased host corneal tissue, while conserving healthy and functioning tissue. This review describes current surgical techniques in the field of corneal transplantation, with special emphasis on indications for transplantation and postoperative outcomes. PMID- 26101727 TI - Alendronate associated focal segmental glomerulosclerosis: a case report and review of the literature. AB - Although kidney injury associated with intravenous bisphosphonate therapy is well documented, there are very few reported instances of oral bisphosphonate therapy leading to focal segmental glomerulosclerosis (FSGS) and kidney failure. We report the case of a 79-year-old woman who developed acute kidney injury due to collapsing FSGS while receiving therapy with weekly oral alendronate therapy for osteoporosis. Withdrawal of alendronate and treatment with corticosteroids resulted in partial recovery of kidney function for a period of 16 months until she developed progressive kidney failure needing long-term dialysis. This case report and the literature review highlight the fact that oral bisphosphonates may be associated with a risk of developing FSGS. PMID- 26101728 TI - Incidence and impact of interstitial lung disease and malignancy in patients with polymyositis, dermatomyositis, and clinically amyopathic dermatomyositis: a retrospective cohort study. AB - The aims of this study were to retrospectively review Japanese consecutive cases of polymyositis (PM), dermatomyositis (DM), and clinically amyopathic dermatomyositis (CADM), focusing on interstital lung disease (ILD) and malignancy, and to document any differences in the incidence, clinical features, and impact on prognosis among patients with PM, DM, and CADM. We retrospectively reviewed 62 consecutive patients diagnosed with PM, DM, and CADM according to Bohan and Peter's criteria (PM/DM) and Sontheimer's criteria and Gerami's criteria (CADM), focusing on ILD and malignancy. ILD occurrence rates were 48 % (11/23) in patients with PM, 46 % (11/24) in DM, and 100 % (15/15) in CADM. Malignancy occurred during diagnosis or the observation period in 14 patients; 86 % were without ILD, and 64 % were DM without ILD. Multivariate logistic regression analysis showed that the risk of newly diagnosed malignancy was significantly lower in patients with ILD [odds ratio, 0.0688; 95 % confidence interval (CI), 0.00127-0.372; p = 0.00190] and significantly higher in patients with DM (odds ratio, 5.21; 95 % CI, 1.17-23.1; p = 0.0299) than in other patients. Patients with malignancies had shorter survival than those without malignancies; no clinically meaningful difference in survival was observed among the different myositis types and for presence of ILD. In CADM-ILD, 80 % fatal cases died from refractory ILD <=90 days from the first visit; neither death nor recurrence occurred subsequently. In conclusion, a positive association between DM and malignancy and a negative association between ILD and malignancy were noted. In the present study, malignancy was a predictor of poor long-term prognosis, but ILD were not. ILD associated with CADM contributed greatly to poor short-term prognosis, but neither death nor recurrence occurred subsequently. PMID- 26101729 TI - FDG-PET findings of Ameloblastoma: a case report. AB - INTRODUCTION: Ameloblastoma is a benign odontogenic neoplasm of the jaw, rarely presenting as a malignant tumor. Although it is very important to discriminate ameloblastoma from ameloblastic carcinoma in order to decide the appropriate operative procedure, this is difficult using conventional CT and MRI. CASE DESCRIPTIONS: We report a case of maxillar ameloblastoma in a 78-year-old man where FDG-PET/CT was useful for making this discrimination. CT demonstrated a 31 * 43 * 46-mm mass in the left posterior maxillary sinus with destruction of its posterior and lateral wall and alveolar bone. MRI demonstrated a hypo- to isointense heterogeneous pattern on T1WI, heterogeneous hyperintensity with a prominent high-signal spot on T2WI, high signal intensity on DWI reflecting restricted diffusion, and strong heterogeneous enhancement. Because FDG-PET/CT showed mild FDG uptake (SUVmax 2.40) by the mass, ameloblastoma, rather than ameloblastic carcinoma, was considered to be the correct diagnosis. DISCUSSION AND EVALUATION: It appears that ameloblastic carcinoma shows intense FDG uptake, whereas ameloblastoma shows mild or moderate FDG uptake, and only rarely intense FDG uptake. Our experience suggests that FDG-PET/CT may be effective for discriminating ameloblastoma from ameloblastic carcinoma. Especially, in cases showing mild FDG uptake, benign ameloblastoma would seem the most likely diagnosis. CONCLUSIONS: FDG-PET/CT may be useful as an adjunctive modality for diagnosis, treatment planning and surveillance of ameloblastoma and ameloblastic carcinoma. PMID- 26101730 TI - The aspect of experience in ultra-triathlon races. AB - Previous experience seems to be an important predictor for endurance and ultra endurance performance. The present study investigated whether the number of previously completed races and/or the personal best times in shorter races is more predictive for performance in longer non-stop ultra-triathlons such as a Deca Iron ultra-triathlon. All female and male ultra-triathletes who had finished between 1985 and 2014 at least one Double Iron ultra-triathlon (i.e. 7.6 km swimming, 360 km cycling and 84.4 km running), one Triple Iron ultra-triathlon (i.e. 11.4 km swimming, 540 km cycling and 126.6 km running), one Quintuple Iron ultra-triathlon (i.e. 19 km swimming, 900 km cycling and 221 km running) and one Deca Iron ultra-triathlon (i.e. 38 km swimming, 1,800 km cycling and 422 km running) were identified and their best race times for each distance were recorded. Multiple regression analysis (stepwise, forward selection, p of F for inclusion <0.05, p of F for exclusion >0.1, listwise deletion) was used to determine all variables correlating to overall race time and performance in split disciplines for both Quintuple and Deca Iron ultra-triathlon. The number of finished shorter races (i.e. Double and Triple Iron ultra-triathlon) was not associated with the number of finished longer races (i.e. Quintuple and Deca Iron ultra-triathlon) whereas both split and overall race times correlated to split and overall race times of the longer races with the exception of the swimming split times in Double Iron ultra-triathlon showing no correlation with swimming split times in both Quintuple and Deca Iron ultra-triathlon. In summary, previous experience seemed of importance in performance for longer ultra-triathlon races (i.e. Quintuple and Deca Iron ultra-triathlon) where the personal best times of shorter races (i.e. Double and Triple Iron ultra-triathlon) were important, but not the number of previously finished races. For athletes and coaches, fast race times in shorter ultra-triathlon races (i.e. Double and Triple Iron ultra triathlon) are more important than a large of number finished races in order to achieve a fast race time in a longer ultra-triathlon (i.e. Quintuple and Deca Iron ultra-triathlon). PMID- 26101732 TI - Dietary supplemental vitamin B6 increases carnosine and anserine concentrations in the heart of rats. AB - This study was performed to examine the effect of dietary level of vitamin B6 on the concentrations of carnosine and anserine, antioxidants, in the heart of rats. Analysis using UPLC-MS/MS showed that the concentrations of these dipeptides in the 7 and 35 mg pyridoxine HCl/kg groups were significantly higher than those in the 1 mg pyridoxine HCl/kg group, implying the novel role of dietary vitamin B6 as a determinant of the dipeptides favorable for heart. PMID- 26101731 TI - Unmanipulated native fat exposed to high-energy diet, but not autologous grafted fat by itself, may lead to overexpression of Ki67 and PAI-1. AB - BACKGROUND: Although its unclear oncological risk, which led to more than 20 years of prohibition of its use, fat grafting to the breast is widely used nowadays even for aesthetic purposes. Thus, we proposed an experimental model in rats to analyze the inflammatory activity, cellular proliferation and levels of Plasminogen Activator Inhibitor (PAI-1) in grafted fat, and in native fat exposed to high-energy diet in order to study the oncological potential of fat tissue. METHODS: Samples of grafted fat of rats on regular-energy diet were compared with paired samples of native fat from the same rat on regular-energy diet and on high energy diet in a different time. Analysis involved microscopic comparisons using hematoxylin-eosin staining, immunohistochemistry with anti-CD68-labelled macrophages, and gene expression of Ki-67 and PAI-1. RESULTS: Hematoxylin-eosin staining analyses did not find any atypical cellular infiltration or unusual tissue types in the samples of grafted fat. The inflammatory status, assessed through immunohistochemical identification of CD68-labelled macrophages, was similar among samples of native fat and grafted fat of rat on regular-energy diet and of native fat of rats on high-energy diet. Real-time PCR revealed that high energy diet, but not fat grafting, leads to proliferative status on adipose tissue (overexpression of ki-67, p = 0.046) and raised its PAI-1 levels, p < 0.001. CONCLUSION: While the native adipose tissue overexpressed PAI-1 and KI67 when exposed to high-energy diet, the grafted fat by itself was unable to induce cellular proliferation, chronic inflammatory activity and/or elevation of PAI-1 levels. PMID- 26101733 TI - Production objectives and breeding practices of urban goat and sheep keepers in West Africa: regional analysis and implications for the development of supportive breeding programs. AB - To better understand the relative importance of the multi-purpose functions of small ruminants for their urban owners and related breeding practices including selection criteria, we undertook a comparative analysis across the West African cities of Kano (Nigeria), Bobo Dioulasso (Burkina Faso) and Sikasso (Mali). Semi structured questionnaires were used to collect the required information from 301 sheep farmers (100, 102 and 99 in Kano, Bobo Dioulasso and Sikasso) and 306 goat farmers (100, 99 and 107 in Kano, Bobo Dioulasso and Sikasso). Sheep and goats were kept for a variety of reasons including income generation, insurance (sale for cash to meet unexpected expenditures) and economic security (sale for cash to support foreseeable expenses), social/religious functions and prestige in ownership. The relative importance given by respondents to the different functions varied significantly (p < 0.001) across cities and between species within a city. However, irrespective of city, both species were primarily kept for their financial functions whereby sheep were perceived as having higher economic value. Although breeding practices were very similar in many respects (low practice of castration, culling and replacement strategies, uncontrolled mating, no record keeping and selection criteria), the emphasis put on each selection criteria varied across cities and between species. Irrespective of city, most of the goats were of the indigenous type while keeping crossbred animals and/or maintaining more than one genotype in the same flock was more commonly practiced by sheep keepers. This points to a higher motivation for strategic breeding among sheep than goat keepers and indicates that the former might be interested in joining carefully designed participatory flock improvement programs. PMID- 26101734 TI - Large pseudoangiomatous stromal hyperplasia complicated with gynecomastia and lobular differentiation in a male breast. AB - Pseudoangiomatous stromal hyperplasia (PASH) is a benign lesion often observed in parts of the mammary stroma in a variety of breast diseases. It is characterized by stromal myofibroblastic proliferation that possesses irregularly anastomosing slit-like pseudovascular spaces lined by a layer of spindle cells. PASH commonly occurs in premenopausal women; however, it has also been observed in men with gynecomastia. Although tumor-forming lesions are rare, we report on a case with a large PASH in a male breast complicated with gynecomastia. Imaging showed a tumor with a diameter of >10 cm in the left breast, and aspiration cytology revealed a benign lesion. Since the tumor was large and gradually increased in size, a simple mastectomy was performed. The tumorous lesion was diagnosed as PASH based on the pathological and immunohistological findings. It was complicated by gynecomastia with acinar and lobular formation, which resembled female mammary gland secretory activity that is observed during lactation. PMID- 26101735 TI - Fusobacterium nucleatum: a rare cause of pyogenic liver abscess. AB - While pyogenic liver abscesses are uncommon, they are associated with significant mortality and morbidity. Most pyogenic liver abscesses are polymicrobial and are caused by enteric bacteria and anaerobes. Rarely, mono-microbial infections may occur, typically in immunocompromised individuals. We report the unusual case of a 69 year-old immunocompetent female who developed a pyogenic liver abscess due to Fusobacterium nucleatum infection, likely from a dental source. Poor oropharyngeal hygiene seems to have a major role in infection from this organism and therefore F. nucleatum should be considered as a differential for causes of pyogenic liver abscess in such patients. Drainage of the abscess and antibiotic therapy are the mainstays of therapy. PMID- 26101736 TI - Diabetes knowledge and glycemic control among patients with type 2 diabetes in Bangladesh. AB - AIMS: To explore the association between knowledge on diabetes and glycemic control among patients with type 2 diabetes in Bangladesh. METHODS: A cross sectional study was conducted among 515 patients with type 2 diabetes attending a tertiary hospital in Dhaka, Bangladesh. Trained interviewers were used to collect data on socioeconomic status, time since the onset of diabetes, co-morbidities, anthropometric measurements, blood tests, knowledge and perceptions about the causes, management, and complications of diabetes through face to face interviewers based on a structured questionnaire. Diabetes knowledge was reported using a composite score. Chi square tests and correlation analysis were performed to measure the association between knowledge on diabetes and glycemic control. RESULTS: Overall, 45.6% participants had good, 37.7% moderate and 16.7% poor knowledge on diabetes. The mean composite score was 0.75 +/- 0.28 and the proportion of participants with a score of <=50% was 16.7%. Only 24.3% participants identified physical inactivity as a risk factor for diabetes. Knowledge on diabetes was significantly associated with education, gender, monthly income, duration of diabetes, body mass index, family history of diabetes, and marital status but not with glycated hemoglobin (HbA1c). Correlation matrix showed weak negative association between diabetes knowledge score and glycemic control (p < 0.001). CONCLUSION: Patients with type 2 diabetes in Bangladesh have limited knowledge on the causes, management and risk factors for diabetes, despite receiving professional health education and care in a tertiary diabetic hospital. Strategies to improve the quality of diabetes education and identifying other potential factors for glycemic control are important for ensuring optimum management of diabetes in Bangladesh. PMID- 26101737 TI - Changes in foods selected and consumed after implementation of the new National School Lunch Program meal patterns in southeast Texas. AB - OBJECTIVE: We compared elementary students' school lunches selected and consumed before (Spring, 2011) and after (Spring, 2013) implementation of the new National School Lunch Program meal patterns in the fall of 2012. METHOD: Students in eight elementary schools in one Southeast Texas school district were observed during lunch: foods selected/consumed were recorded. The percentage of students who selected each food group was compared between years, as were the differences in consumption and the percent of food consumed by year, for students who selected the food group. All analyses controlled for student gender and grade and school free/reduced price meal status. RESULTS: Observations were conducted for 472 (2011) and 573 (2013) students. Significantly more 2013 students selected fruit, 100% juice, total fruit + 100% juice, other vegetables, whole grains, protein foods and milk, but fewer selected starchy vegetables. For those students selecting them, significantly more total fruit + 100% juice and red orange vegetables, but significantly less other vegetables, legumes, and protein foods were consumed. There were no differences in waste of fruit, whole grains, or vegetables, with the exception of legumes. More legumes were wasted in 2013 than 2011. CONCLUSION: The findings that students had similar consumption rates for fruit, whole grains, and most vegetables in this study are encouraging. Regular monitoring of student food selection and consumption at school is needed to assess whether the new meal patterns improve intake at school. PMID- 26101738 TI - The cytotoxicity of BAMLET complexes is due to oleic acid and independent of the alpha-lactalbumin component. AB - Lipid-protein complexes comprised of oleic acid (OA) non-covalently coupled to human/bovine alpha-lactalbumin, named HAMLET/BAMLET, display cytotoxic properties against cancer cells. However, there is still a substantial debate about the role of the protein in these complexes. To shed light into this, we obtained three different BAMLET complexes using varying synthesis conditions. Our data suggest that to form active BAMLET particles, OA has to reach critical micelle concentration with an approximate diameter of 250 nm. Proteolysis experiments on BAMLET show that OA protects the protein and is probably located on the surface, consistent with a micelle-like structure. Native or unfolded alpha-lactalbumin without OA lacked any tumoricidal activity. In contrast, OA alone killed cancer cells with the same efficiency at equimolar concentrations as its formulation as BAMLET. Our data show unequivocally that the cytotoxicity of the BAMLET complex is exclusively due to OA and that OA alone, when formulated as a micelle, is as toxic as the BAMLET complex. The contradictory literature results on the cytotoxicity of BAMLET might be explained by our finding that it was imperative to sonicate the samples to obtain toxic OA. PMID- 26101739 TI - Interaction of the dual targeting peptide of Thr-tRNA synthetase with the chloroplastic receptor Toc34 in Arabidopsis thaliana. AB - Organellar proteins synthesized in the cytosol are usually selective for only one destination in a cell but some proteins are localized in more than one compartment, for example in both mitochondria and chloroplasts. The mechanism of dual targeting of proteins to mitochondria and chloroplasts is yet poorly understood. Previously, we observed that the dual targeting peptide of threonyl tRNA synthetase in Arabidopsis thaliana (AtThrRS-dTP) interacts with the mitochondrial receptor AtTom20 mainly through its N-terminal part. Here we report on the interaction of AtThrRS-dTP with the chloroplastic receptor AtToc34, presenting for the first time the mode of interactions of a dual targeting peptide with both Tom20 and Toc34. By NMR spectroscopy we investigated changes in (15)N HSQC spectra of AtThrRS-dTP as a function of AtToc34 concentration. Line broadening shows that the interaction with AtToc34 involves residues along the entire sequence, which is not the case for AtTom20. The N-terminal phichichiphiphi motif, which plays an important role in AtTom20 recognition, shows no specificity for AtToc34. These results are supported by import competition studies into both mitochondria and chloroplasts, in which the effect of peptides corresponding to different segments of AtThrRS-dTP on in vitro import of organelle specific proteins was examined. This demonstrates that the N terminal A2-Y29 segment of AtThrRS-dTP is essential for import into both organelles, while the C-terminal L30-P60 part is important for chloroplastic import efficiency. In conclusion, we have demonstrated that the recognition of the dual targeting peptide of AtThr-tRNA synthetase is different for the mitochondrial and chloroplastic receptors. PMID- 26101740 TI - p38alpha controls self-renewal and fate decision of neurosphere-forming cells in adult hippocampus. AB - Neural stem cells (NSC) from the adult hippocampus easily lose their activity in vitro. Efficient in vitro expansion of adult hippocampus-derived NSC is important for generation of tools for research and cell therapy. Here, we show that a single copy disruption or pharmacological inhibition of p38alpha enables successful long-term neurosphere culture of adult mouse hippocampal cells. Expanded neurospheres with high proliferative activity differentiated into the three neuronal lineages under differentiating conditions. Thus, inhibition of p38alpha can maintain adult hippocampal NSC activity in vitro. PMID- 26101742 TI - Corrigendum to "Combination therapy with interferon and JAK1-2 inhibitor is feasible. Proof of concept with rapid reduction in JAK2V617F-allele burden in Polycythemia Vera" [Leuk. Res. Rep. 3 (2) (2014) 73-75]. AB - [This corrects the article DOI: 10.1016/j.lrr.2014.05.003.]. PMID- 26101741 TI - Development of reverse genetics for Ibaraki virus to produce viable VP6-tagged IBAV. AB - Ibaraki virus (IBAV) is a member of the epizootic hemorrhagic disease virus (EHDV) serogroup, which belongs to the Orbivirus genus of the Reoviridae family. Although EHDV, including IBAV, represents an ongoing threat to livestock in the world, molecular mechanisms of EHDV replication and pathogenesis have been unclear. The reverse genetics (RG) system is one of the strong tools to understand molecular mechanisms of virus replication. Here, we developed a RG system for IBAV to identify the nonessential region of a minor structural protein, VP6, by generating VP6-truncated IBAV. Moreover, several tags were inserted into the truncated region to produce VP6-tagged IBAV. We demonstrated that all VP6-tagged IBAV could replicate in BHK cells in the absence of any helper VP6 protein. Further, tagged-VP6 proteins were first assembled into puncta in cells infected with VP6-tagged IBAV. Our data suggests that, in order to initiate primary replication, IBAV VP6 is likely to accumulate in some parts of infected cells to assemble efficiently into the primary replication complex (subcore). PMID- 26101743 TI - The cestode community in northern fur seals (Callorhinus ursinus) on St. Paul Island, Alaska. AB - The diversity and ecology of cestodes from the northern fur seals, Callorhinus ursinus (NFS), were examined using newly collected material from 756 humanely harvested subadult males between 2011 and 2014. NFSs were collected from five different haul-outs on St. Paul Island, Alaska. A total of 14,660 tapeworms were collected with a prevalence of 98.5% and intensity up to 107 cestodes per host (mean intensity 19.7 +/- 16.5 SD). Three species of tapeworms were found: Adenocephalus pacificus (Diphyllobothriidea) was the most prevalent (prevalence 97.4%), followed by Diplogonoporus tetrapterus (49.7%), and 5 immature specimens of Anophryocephalus cf. ochotensis (Tetrabothriidea) (0.5%). Most of the cestodes found in the NFS were immature (69.7%). However, only 0.9% of cestodes were in larval (plerocercoid) stages. The species composition, prevalence and intensity of cestodes from these NFSs were not statistically different between the five separate haul-outs. Significant increases in the intensity of NFS infections were observed during the study period. PMID- 26101744 TI - Fatal systemic toxoplasmosis in Valley quail (Callipepla californica). AB - An adult, captive raised male Valley quail (Callipepla californica) acquired by a southern Brazilian aviary suddenly showed severe apathy, dyspnea and diarrhea, and died 18 hours after the onset of illness. At necropsy, pale muscles and whitish areas in the heart, splenomegaly, hepatomegaly, and consolidated red lungs were observed. Histological findings were mainly mononuclear inflammation with necrosis of liver, heart, spleen, bone marrow and lung. There were large numbers of Toxoplasma gondii tachyzoitesorganisms in the liver, heart, spleen, bone marrow, lungs, trachea, kidneys, adrenal glands, testes, intestines, and pancreas. These organisms were seen free in the organs' stroma or within macrophages and stained positively with polyclonal antiserum to T. gondii. Genomic DNA was extracted from the tissues and PCR was used to target the B1 gene of T. gondii. The genotypic characterization by PCR-RFLP with 11 markers (SAG1, SAG2 and alt. SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, Apico and CS3) revealed the ToxoDB-PCR-RFLP #87 genotype, the same as previously identified in a backyard chicken (TgCkBr156) in Rio Grande do Sul, Brazil. PMID- 26101745 TI - Coexistence of fixation-off sensitivity and inverted fixation-off sensitivity in a female child with Panayiotopoulos syndrome: Video-electroencephalography documentation. AB - Fixation-off sensitivity (FOS) is a rare phenomenon elicited by elimination of central vision and fixation, which even in the presence of light induces occipital paroxysms or generalized paroxysmal discharges. It is most commonly encountered in patients with idiopathic childhood occipital epilepsies but may also be observed in cases of symptomatic focal and generalized epilepsies. We describe a female Emirati child with Panayiotopoulos syndrome who exhibited FOS in addition to the reverse phenomenon called "inverted fixation-off sensitivity," in which the electroencephalographic discharges were suppressed by the absence of central vision or fixation and activated by central vision or fixation. PMID- 26101746 TI - Failure of antiepileptic drugs in controlling seizures in epilepsy: What do we do next? AB - Medically intractable epilepsy is a clinical condition of concern that arises when a patient with epilepsy suffers seizures, despite a trial of two or more antiepileptic drugs (AEDs) suitable for the type of epilepsy that are prescribed at maximum tolerated doses, does not achieve control of seizures. This diagnosis could be related to cortical dysplasias. We report the case of a 5-year-old girl with a previous normal neurological development and no family history of epilepsy who presented with focal-type seizures at age 4. She started treatment by taking different AEDs for seizure control. She continued having frequent seizures that sometimes progressed to generalized seizures and status epilepticus. After a focal cortical resection performed in the area where interictal spikes were detected, the pathology confirmed a type IIb cortical dysplasia as the cause of the epilepsy. This article discusses cortical dysplasias as a cause of pharmacoresistant epilepsy and its treatment. PMID- 26101747 TI - The ictal bradycardia syndrome: A case report. AB - We report a case of a 56-year-old man affected by frontal lobe seizures who has developed bradycardia followed by asystole. The patient had a positive family history for epilepsy. In fact, the mother, brothers, and one sister had epilepsy. Furthermore, the patient's two brothers suddenly died of unspecified heart disease at the ages of 26 and 53, respectively. The patient also experienced syncope once or twice a year. Three similar epileptic seizures, without the recurrence of asystole, were registered after pacemaker implantation. PMID- 26101748 TI - Gene expression profiles of Bapx1 expressing FACS sorted cells from wildtype and Bapx1-EGFP null mouse embryos. AB - The data described in this article refers to Chatterjee et al. (2015) "In vivo genome-wide analysis of multiple tissues identifies gene regulatory networks, novel functions and downstream regulatory genes for Bapx1 and its co-regulation with Sox9 in the mammalian vertebral column" (GEO GSE35649) [1]. Transcriptional profiling combined with genome wide binding data is a powerful tool to elucidate the molecular mechanism behind vertebrate organogenesis. It also helps to uncover multiple roles of a single gene in different organs. In the above mentioned report we reveal the function of the homeobox gene Bapx1 during the embryogenesis of five distinct organs (vertebral column, spleen, gut, forelimb and hindlimb) at a relevant developmental stage (E12.5), microarray analysis of isolated wildtype and mutant cells in is compared in conjunction with ChIP-Seq analysis. We also analyzed the development of the vertebral column by comparing microarray and ChIP Seq data for Bapx1 with similarly generated data sets for Sox9 to generate a gene regulatory network controlling various facets of the organogenesis. PMID- 26101749 TI - Splicing variants of porcine synphilin-1. AB - Parkinson's disease (PD), idiopathic and familial, is characterized by degradation of dopaminergic neurons and the presence of Lewy bodies (LB) in the substantia nigra. LBs contain aggregated proteins of which alpha-synuclein is the major component. The protein synphilin-1 interacts and colocalizes with alpha synuclein in LBs. The aim of this study was to isolate and characterize porcine synphilin-1 and isoforms hereof with the future perspective to use the pig as a model for Parkinson's disease. The porcine SNCAIP cDNA was cloned by reverse transcriptase PCR. The spatial expression of SNCAIP mRNA was investigated by RNAseq. The presented work reports the molecular cloning and characterization of the porcine (Sus scrofa) synphilin-1 cDNA (SNCAIP) and three splice variants hereof. The porcine SNCAIP cDNA codes for a protein (synphilin-1) of 919 amino acids which shows a high similarity to human (90%) and to mouse (84%) synphilin 1. Three shorter transcript variants of the synphilin-1 gene were identified, all lacking one or more exons. SNCAIP transcripts were detected in most examined organs and tissues and the highest expression was found in brain tissues and lung. Conserved splicing variants and a novel splice form of synhilin-1 were found in this study. All synphilin-1 isoforms encoded by the identified transcript variants lack functional domains important for protein degradation. PMID- 26101750 TI - Hypocholesterolemic effects of Balangu (Lallemantia royleana) seeds in the rabbits fed on a cholesterol-containing diet. AB - OBJECTIVES: Lallemantia royleana (Benth. in Wall.) Benth. (Lamiaceae) is a medicinal plant used in Iranian traditional and folklore medicine in the treatment of various nervous, hepatic, and renal diseases. In the present study, whole seeds of the herb were prepared and evaluated for hypolipidemic activities using an animal model. MATERIALS AND METHODS: Animals were fed normal diets or diets supplemented with cholesterol (0.5%) for 12 weeks to evoke hypercholesterolemia. Moreover, hypercholesterolemic animals were treated with different doses of whole seeds of Balangu (0, 5, 10, and 20%) for 12 weeks. RESULTS: Results showed that the serum total cholesterol and triglyceride decreased in all groups treated with Balangu seeds p<0.05. Changes in the distribution of cholesterol in low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were found. LDL-C and HDL-C decreased significantly in all of the groups treated with whole seeds of the herb with respect to hypercholesterolemic group p<0.05. CONCLUSION: Our results showed that L. royleana seeds decreased the serum cholesterol and triglyceride levels in hypercholesterolemic animals but led to the increase of atherogenic index in all treated groups. PMID- 26101751 TI - The synergic effect of glycyrrhizic acid and low frequency electromagnetic field on angiogenesis in chick chorioallantoic membrane. AB - OBJECTIVE: Much attention is paid to angiogenesis due to its mutual role in health and disease. Therefore, the effect of various chemical and physical agents on inhibition of this process has been recently studied. This study was conducted to investigate the synergic effect of glycyrrhizic acid and electromagnetic field on angiogenesis. MATERIALS AND METHODS: In this experimental study, 44 Ross fertilized chicken eggs were randomly divided into four groups, one control and three experimental. Control group was kept with dimethyl sulfoxide on the eighth day, experimental group 1 treated with 200 gauss, 50 Hz electromagnetic field on the 10th day, experimental group 2 treated with 1 mg/ml glycyrrhizic acid on the eighth day, and experimental group 3 simultaneously treated with glycyrrhizic acid on the eighth day and electromagnetic field on the 10th day. On the 12th day, the images of chorioallantoic membrane samples were prepared using photostreomicroscope and the number and length of vessels were measured. RESULTS: The mean number of vessels in the experimental groups 1 and 3 (29.31+/-3.60 and 27.43+/-4.61, respectively) was not significantly different from that in the control group (29.11+/-4.76) (p>0.05). The length of vessels in the experimental groups 1 and 3 (52.35+/-3.25 mm and 54.94+/-4.70 mm, respectively) decreased significantly (p<0.05) compared with the control group (61.79+/-6.46 mm). In experimental group 2, both length and number of vessels (54.53+/-5.85 mm and 23.96+/-3.94) decreased significantly compared with the control group (p<0.05). CONCLUSION: Electromagnetic field and glycyrrhizic acid separately led to inhibition of angiogenesis. However, use of electromagnetic field accompanied with glycyrrhizic acid not only did not increase but also decreased the inhibitory effect. PMID- 26101752 TI - Avicenna's Canon of Medicine: a review of analgesics and anti-inflammatory substances. AB - Naturally occurring substances mentioned in medieval medical literatures currently have, and will continue to have, a crucial place in drug discovery. Avicenna was a Persian physician who is known as the most influential medical writers in the Middle ages. Avicenna's Canon of Medicine, the most famous books in the history of medicine, presents a clear and organized summary of all the medical knowledge of the time, including a long list of drugs. Several hundred substances and receipts from different sources are mentioned for treatment of different illnesses in this book. The aim of the present study was to provide a descriptive review of all anti-inflammatory and analgesic drugs presented in this comprehensive encyclopedia of medicine. Data for this review were provided by searches of different sections of this book. Long lists of anti-inflammatory and analgesic substances used in the treatment of various diseases are provided. The efficacy of some of these drugs, such as opium, willow oil, curcuma, and garlic, was investigated by modern medicine; pointed to their potent anti-inflammatory and analgesic properties. This review will help further research into the clinical benefits of new drugs for treatment of inflammatory diseases and pain. PMID- 26101753 TI - The effect of hydro-alcoholic celery (Apiumgraveolens) leaf extract on cardiovascular parameters and lipid profile in animal model of hypertension induced by fructose. AB - OBJECTIVES: Hypertension is one of the most common diseases of the modern era. This study evaluates the effect of hydro-alcoholic celery leaf extract onsystolic blood pressure (SBP), heart rate (HR) and lipid profile in animals' model of hypertension induced by fructose. MATERIALS AND METHODS: Sprague Dawley rats were divided into five groups: 1) control group (free access to tap drinking water), 2) group receiving 200mg/kg celery leaf extract, 3) group receiving fructose 10%, and 4,5) receiving fructose and 100mg/kg or 200mg/kg of extract (n=8). In all groups, before and during the test period, SBP and HR were measured by Power lab system. Lipid profiles were determined by auto analysis. Repeated measurement and one way ANOVA were used for data analysis. P<0.05 was considered statistically significant. RESULTS: The SBP in the fructose group significantly increased compared to control group (P<0.01). SBP, in groups receiving fructose+100mg/kg extract, fructose and receiving 200mg/kg extract, and receiving 200mg/kg of extract, compared to fructose group significantly decreased. Heart rate in any of these groups showed no significant difference. Cholesterol, triglyceride, LDL and VLDL in the fructose group significantly increased; however, these effects significantly decreased in the recipient extract groups. HDL levels in the fructose group showed no difference while in the groups receiving the extract they significantly increased. CONCLUSIONS: Celery leaf extract reduces SBP, cholesterol, triglyceride, LDL and VLDL in animal model of fructose-induced hypertension. In conclusion, celery leaf extract with its blood pressure and lipid lowering effects, can be considered as an antihypertensive agent in chronic treatment of elevated SBP. PMID- 26101754 TI - Antibacterial activity of Tribulus terrestris and its synergistic effect with Capsella bursa-pastoris and Glycyrrhiza glabra against oral pathogens: an in vitro study. AB - OBJECTIVE: In this study, antimicrobial activities of an ethanol extract of Tribulus terrestris aloneand in combination with Capsella bursa-pastoris and Glycyrrhiza glabra were examined in vitro against six pathogens namely Streptococcus mutans, Streptococcus sanguis, Actinomyces viscosus, Enterococcus faecalis Staphylococcus aureus, and Escherichia coli. MATERIALS AND METHODS: Antibacterial activities of the extracts were examined using disc and well diffusion methods and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of ethanol extracts were determined against these microorganisms using agar and broth dilution methods. Chlorhexidine was used as positive control. RESULTS: Tribulus terrestris extract exhibited good antibacterial activity against all bacteria. Antibacterial activity of mixed extract was evaluated and exhibited that mixed extract was more effective against all bacteria than any of the cases alone which indicates the synergistic effect between these three extracts (p?0.05). No strain showed resistance against these extracts. In agar dilution, Tribulus terrestris exhibited MIC values ranging from 35.0 to 20.0 mg/ml and mixed extract showed MIC values ranging from 12.5 to 5.0 mg/ml. The results of broth dilution method were consistent with the findings of the agar dilution method. CONCLUSION: This in-vitro study was a preliminary evaluation of antibacterial activity of the plants. It provided scientific evidence to support uses of T. terrestris and its mixture with C. bursa-pastoris and G. glabra for the treatment of oral infections. In-vivo studies are also required to better evaluate the effect of these extracts. PMID- 26101756 TI - Protective effect of Hibiscus sabdariffa against serum/glucose deprivation induced PC12 cells injury. AB - OBJECTIVES: Findings natural products with antioxidant and antiapoptotic properties has been one of the interesting challenges in the search for the treatment of neurodegenerative diseases including ischemic stroke. Serum/glucose deprivation (SGD) has been used as a model for the understanding of the molecular mechanisms of neuronal damage during ischemia in vitro and for the expansion of neuroprotective drugs against ischemia-induced brain injury. Recent studies showed that Hibiscus sabdariffa exert pharmacological actions such as potent antioxidant. Therefore, in this study we investigated the protective effect of extract of H. sabdariffa against SGD-induced PC12 cells injury. MATERIALS AND METHODS: Cells were pretreated with different concentrations of H. sabdariffa extract (HSE) for 2 hr, and then exposed to SGD condition for 6, 12 and 18 hr. RESULTS: SGD caused a major reduction in cell viability after 6, 12, and 18 hr as compared with control cells (p< 0.001). Pretreatment with HSE (30-500 ??g/mL) significantly increased cell viability following SGD insult for 6, 12 and 18 hr. A significant increase in cell apoptosis was seen in cells under SGD condition after 12hr as compared with control cells (p< 0.001). Pretreatment with HSE significantly decreased cell apoptosis subsequent SGD conditionafter12hr at concentration of 60, 125 and 250. CONCLUSION: These data showed that HSE had a protective property under SGD condition in PC12 cells, suggesting that H. sabdariffa has the potential to be used as a new therapeutic approach for neurodegenerative disorders. PMID- 26101755 TI - Antinociceptive effects, acute toxicity and chemical composition of Vitex agnus castus essential oil. AB - OBJECTIVE: Vitex agnus-castus (VAC) and its essential oil have been traditionally used to treat many conditions and symptoms such as premenstrual problems, mastalgia, inflammation, sexual dysfunction, and pain. In this study, the effects of essential oil extracted from Vitex agnus-castus (EOVAC) leaves were investigated in three behavioral models of nociception in adult male Wistar rats. MATERIALS AND METHODS: Chemical composition of EOVAC was analyzed using gas chromatography - mass spectrometry (GC-MS) and also its possible toxicity was determined in mice. Analgesic effect of EOVAC was determined using tail immersion test, formalin test, and acetic acid-induced visceral pain in rats. RESULTS: EOVAC (s.c.) and morphine (i.p.) significantly (p<0.05) reduced pain responses in both formalin and tail immersion tests. In the study of evolved mechanisms, pretreatment with naloxone or atropine significantly (p <0.05) reversed the essential oil-induced analgesia in both formalin and tail immersion tests. Moreover, EOVAC and Piroxicam produced significant (p<0.05) inhibition in the acetic acid-induced writhing response. EOVAC did not show any mortality even at high dose (5 g/kg, p.o.) of administration in toxicity test. Moreover, according to GC-MS results, major components of the EOVAC were alpha-pinene (14.83%), limonene (10.29%), beta-caryophyllene (6.9%), sabinene (5.27%), and beta farnesene (5.9%). CONCLUSIONS: These results suggest that endogenous opioidergic system as well as muscarinergic receptors of cholinergic system may be involve in the antinociceptive activity of Vitex agnus-castus essential oil in these models of pain in rats. PMID- 26101757 TI - Hepatoprotective activity of aerial parts of Otostegia persica against carbon tetrachloride-induced liver damage in rats. AB - OBJECTIVE: To evaluate the hepatoprotective properties of Otostegia persica (O. persica) ethanol extract on carbon tetrachloride-induced liver damage in rats. MATERIALS AND METHODS: Fifty adult male Wistar rats were randomly divided into five groups. Group I served as normal control and was given only olive oil intraperitoneally (i.p.). Group II, III, IV, and V were administered CCl4 mixed with olive oil 1:1 (1 ml/kg) i.p., twice a week for 8 weeks. Group II was maintained as CCl4-intoxicated control (hepatotoxic group). Group III, IV, and V received O. persica extract at a dose of 40, 80, and 120 mg/kg for 8 weeks every 48 h orally, respectively. Biochemical parameters including aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin (TB), albumin (ALB), total protein (TP), and lipid peroxidation marker (Malonaldialdehyde, (MDA) were determined in serum. After 8 weeks, animals were sacrificed, livers dissected out, and evaluated for histomorphological changes. RESULTS: The administration of CCl4 increased AST, ALT, ALP, TB, and MDA in serum but it decreased TP , and ALB compared with normal control. Treatment with O. persica extract at three doses resulted in decreased enzyme markers, bilirubin levels, and lipid peroxidation marker (MDA) and increased TP and ALB compared with CCl4 group. The results of pathological study also support the hepatoprotective effects which were observed at doses of 80 and 120 mg/kg. CONCLUSION: The results of the present study indicate that ethanol extract of O. persica may have hepatoprotective effect which is probably due to its antioxidant property. PMID- 26101758 TI - In Vitro effect of the ethanolic extract of Tephrosia Vogelii on Rhipicephalus Sanguineus in Abomey-Calavi. AB - OBJECTIVES: Ticks are vectors of several diseases, of which many are zoonosis transmissible to humans. The use of Tephrosia leafs' extract as a low cost acaricide is spreading among farmers in central Kenya. MATERIALS AND METHODS: The present study's aim is to inventory endogenous control methods against dogs' ticks among which Rhipicephalus sanguineus, in the Municipality of Abomey-Calavi. From September to October 2013, a survey was made on forty randomly selected breeders and ticks samples were collected on forty dogs. The web platform, www.epicollect.net, was used for the survey. In total, 77.5% (n=40) of examined dogs were infested with ticks. RESULTS: Three species of ticks were identified: Rhipicephalus sanguineus, Haemaphysalis leachi, and Amblyomma variegatum. They were found on 77.5%, 17.5%, and 15% of examined dogs, respectively. The numerical abundance of the three species was 87.06%, 11.9%, and 1.03%, respectively. The average number of ticks per animal was 16.83+/-5.04, 2.3+/-1.64, and 0.2+/-0.08 for Rhipicephalus sanguineus, Haemaphysalis leachi, and Amblyomma variegatum, respectively. Farmers used manual diptank (67.5%), plant ash (37.5%), petroleum (12.5%), motor oil (2.50 %), and sea water (7.5%) to fight against ticks. CONCLUSION: The phytochemical screening of the leafy stem's powder of Tephrosia vogelii revealed the presence of catechol tannins, saponins, sugars, leuco anthocyanins, polyterpenes, and sterols. A 100% larval mortality was observed at the concentration of 20% the ethanolic extract of the leafy stem of Tephrosia vogelii. The LC50 of this ethanolic extract against Rhipicephalus sanguineus larvae was equal to 2.6%. PMID- 26101759 TI - Anticonvulsant and neuroprotective effects of Rosa damascena hydro-alcoholic extract on rat hippocampus. AB - OBJECTIVE: Previously, analgesic, hypnotic, and anticonvulsant effects have been suggested for Rosa damascena (R. damascena). In the present study, possible anti seizure and neuro-protective effects of hydro-alcoholic extract of R. damascena has been investigated after inducing seizures in rats by pentylenetetrazole (PTZ). MATERIALS AND METHODS: The rats were divided to five groups: (1) CONTROL: received saline, (2) PTZ: 100 mg/kg, i.p., (3) PTZ- Extract 50 mg/kg (PTZ-Ext 50), (4) PTZ- Extract 100 mg/kg (PTZ-Ext 100), and (5) PTZ- Extract 200 mg/kg (PTZ-Ext 200) groups which were treated with 50, 100, and 200 mg/kg respectively of hydro-alcoholic extract of R. dam ascena for one week before PTZ injection. The animals were examined for electrocorticography (ECoG) recording and finally, the brains were removed for histological study. RESULTS: The hydro-alcoholic extract of R. dam ascena significantly prolonged the latency of seizure attacks and reduced the frequency and amplitude of epileptiform burst discharges induced by PTZ injection. Moreover, all three doses of the extract significantly inhibited production of dark neurons in different regions of the hippocampus in the mentioned animal model. CONCLUSION: The present study showed that the hydro alcoholic extract of R. dam ascena has anticonvulsant and neuroprotective effects. More investigations are needed to be done in order to better understand the responsible compound(s) as well as the possible mechanism(s). PMID- 26101760 TI - Validation of the Ottawa Ankle Rules in Indian Scenario. AB - BACKGROUND: Ankle injuries are one of the most common presentations in emergency department. Ottawa Ankle Rules (OARs) have been used to predict the requirement of radiographs. OBJECTIVES: This study aimed to validate the OARs protocol for predicting ankle and midfoot fractures in Indian population. PATIENTS AND METHODS: A prospective study was conducted in a teaching hospital in north India, during a period of nine months, including all patients who presented with complaints in the ankle region and evolution of less than 48 hours. The study excluded patients with multiple trauma and Glasgow coma scale of less than 15. All patients underwent clinical evaluation, followed by radiographs depending upon the location of the complaints. Radiographic study results were evaluated by orthopedic surgeons who had not seen the patient. RESULTS: We evaluated 140 patients (84 males and 60 females) with the mean age of 35.2 (range, 8 - 76 years). Of the 140 evaluable patients, 71 had positive criteria for radiological evaluation of which 43 presented with fracture, 69 had negative criteria for radiography with no fracture. The sensitivity of OARs to detect fractures was 100%. The implementation of the OARs appears to have the potential to reduce the number of radiographs for the assessment of these patients by about 51%. CONCLUSIONS: The implementations of OARs have the potential to reduce the number of X-ray graphics needed to assess these patients by about 51%. The results of this study demonstrate no false negatives and are in agreement with results from other similar studies. It encourages us to implement these criteria in our services urgently, with all the resulting socio-economic implications. PMID- 26101761 TI - Comparing Cognitive Failures and Metacognitive Beliefs in Mild Traumatic Brain Injured Patients and Normal Controls in Kashan. AB - BACKGROUND: Head trauma is associated with multiple destructive cognitive symptoms and cognitive failure. Cognitive failures include problems with memory, attention and operation. Cognitive failures are considered as a process associated with metacognition. OBJECTIVES: This study aimed to compare cognitive failures and metacognitive beliefs in mild Traumatic Brain Injured (TBI) patients and normal controls in Kashan. PATIENTS AND METHODS: The study was performed on 40 TBI patients referred to the Shahid Beheshti Hospital of Kashan city and 40 normal controls in Kashan. Traumatic brain injured patients and normal controls were selected by convenience sampling. Two groups filled out the demographic sheet, Cognitive Failures Questionnaire (CFQ) and Meta-Cognitions Questionnaire 30 (MCQ-30). The data were analyzed by the SPSS-19 software with multivariate analysis of variance. RESULTS: The results of this study showed that there were no significant differences between TBI and controls in total scores and subscales of CFQ and MCQ (F = 0.801, P = 0.61). CONCLUSIONS: Based on these findings, it seems that mild brain injuries don't make significant metacognitive problems and cognitive failures. PMID- 26101762 TI - Tangential View and Intraoperative Three-Dimensional Fluoroscopy for the Detection of Screw-Misplacements in Volar Plating of Distal Radius Fractures. AB - BACKGROUND: Volar locking plate fixation has become the gold standard in the treatment of unstable distal radius fractures. Juxta-articular screws should be placed as close as possible to the subchondral zone, in an optimized length to buttress the articular surface and address the contralateral cortical bone. On the other hand, intra-articular screw misplacements will promote osteoarthritis, while the penetration of the contralateral bone surface may result in tendon irritations and ruptures. The intraoperative control of fracture reduction and implant positioning is limited in the common postero-anterior and true lateral two-dimensional (2D)-fluoroscopic views. Therefore, additional 2D-fluoroscopic views in different projections and intraoperative three-dimensional (3D) fluoroscopy were recently reported. Nevertheless, their utility has issued controversies. OBJECTIVES: The following questions should be answered in this study; 1) Are the additional tangential view and the intraoperative 3D fluoroscopy useful in the clinical routine to detect persistent fracture dislocations and screw misplacements, to prevent revision surgery? 2) Which is the most dangerous plate hole for screw misplacement? PATIENTS AND METHODS: A total of 48 patients (36 females and 13 males) with 49 unstable distal radius fractures (22 x 23 A; 2 x 23 B, and 25 x 23 C) were treated with a 2.4 mm variable angle LCP Two-Column volar distal radius plate (Synthes GmbH, Oberdorf, Switzerland) during a 10-month period. After final fixation, according to the manufactures' technique guide and control of implant placement in the two common perpendicular 2D-fluoroscopic images (postero-anterior and true lateral), an additional tangential view and intraoperative 3D fluoroscopic scan were performed to control the anatomic fracture reduction and screw placements. Intraoperative revision rates due to screw misplacements (intra-articular or overlength) were evaluated. Additionally, the number of surgeons, time and radiation-exposure, for each step of the operating procedure, were recorded. RESULTS: In the standard 2D fluoroscopic views (postero-anterior and true lateral projection), 22 screw misplacements of 232 inserted screws were not detected. Based on the additional tangential view, 12 screws were exchanged, followed by further 10 screws after performing the 3D fluoroscopic scan. The most lateral screw position had the highest risk for screw misplacement (accounting for 45.5% of all exchanged screws). The mean number of images for the tangential view was 3 +/- 2.5 images. The mean surgical time was extended by 10.02 +/- 3.82 minutes for the 3D fluoroscopic scan. An additional radiation exposure of 4.4 +/- 4.5seconds, with a dose area product of 39.2 +/- 14.5 cGy/cm(2) were necessary for the tangential view and 54.4 +/- 20.9 seconds with a dose area product of 2.1 +/- 2.2 cGy/cm(2), for the 3D fluoroscopic scan. CONCLUSIONS: We recommend the additional 2D fluoroscopic tangential view for detection of screw misplacements caused by overlength, with penetration on the dorsal cortical surface of the distal radius, predominantly observed for the most lateral screw position. The use of intraoperative 3D fluoroscopy did not become accepted in our clinical routine, due to the technical demanding and time consuming procedure, with a limited image quality so far. PMID- 26101763 TI - Intraarticular Entrapment of Os Subfibulare Following a Severe Inversion Injury of the Ankle: A Case Report. AB - INTRODUCTION: Anterior Talofibular Ligament (ATFL) rupture is the most commonly injured anatomic structure in lateral ankle sprain. In some cases, ATFL avulsion fracture from the lateral malleolus may occur instead of purely ligamentous injuries. The ATFL avulsion fracture is detected as a small ossicle at the tip of lateral malleolus on direct radiographs, which is called os subfibulare in chronic cases. CASE PRESENTATION: Severe displacement of this ossicle to the tibiotalar joint space is an extremely rare injury. Herein, a case of intra articular entrapment of os subfibulare following a severe inversion injury of the ankle, which caused a diagnostic challenge was presented. CONCLUSIONS: To the best of our knowledge, this is the first case of entrapment of os subfibulare in the talotibial joint space. Fixation of the os subfibulare to lateral malleolus resulted in union and excellent functional results. PMID- 26101764 TI - Predictors for Readmission up to 1 Year Following Hip Fracture. AB - BACKGROUND: At Altnagelvin, a district general hospital in Northern Ireland, we have observed that a significant number of hip fracture admissions are later readmitted for treatment of other medical conditions. These readmissions place increasing stress on the already significant burden that orthopedic trauma poses on national health services. OBJECTIVES: The aim of this study was to review a series of consecutive patients managed at our unit at least 1 year prior to the onset of the study. Also, we aimed to identify predictors for raised admission rates following treatment for hip fracture. PATIENTS AND METHODS: We reviewed a prospective fracture database and online patient note system for patient details, past medical history, discharge destination and routine blood tests for any factors that may influence readmission rates up to 1 year. Data were analyzed using SPSS software. RESULTS: Over 2 years, 451 patients were reviewed and 23 were managed conservatively. There was a 1-year readmission rate of 21%. Most readmission diagnoses were medical including bronchopneumonia, falls, urosepsis, cardiac exacerbations and stroke. Prolonged length of stay and discharge to a residential, fold or nursing home were found to increase readmission rate. Readmission diagnoses closely reflected the perioperative diagnoses that prolonged length of stay. Increased odds radio and risk of readmission were also found with female gender, surgery with a cephalomedullary nail, hip hemiarthroplasty or total hip replacement, time to surgery < 36 hours, alcohol consumption, smoking status, Hb drop > 2 g/dL and also if a blood transfusion was received. CONCLUSIONS: Our results indicate that hip fracture treatment begins at acute fracture clerk in, with consideration of comorbid status and ultimate discharge planning remaining significant predictors for morbidity and subsequent readmission. PMID- 26101765 TI - Epidemiology of Urban Traffic Accident Victims Hospitalized More Than 24 Hours in a Level III Trauma Center, Kashan County, Iran, During 2012-2013. AB - BACKGROUND: Urban traffic accidents are an extensively significant problem in small and busy towns in Iran. This study tried to explore the epidemiological pattern of urban traffic accidents in Kashan and Aran-Bidgol cities, Iran. OBJECTIVES: This study aimed to assess various epidemiological factors affecting victims of trauma admitted to a main trauma center in Iran. PATIENTS AND METHODS: During a retrospective study, data including age, sex, injury type and pattern, outcome, hospital stay and treatment expenditures regarding urban Road Traffic Accidents (RTAs) for one year (March 2012-March 2013) were obtained from the registry of trauma research center, emergency medical services and deputy of health of Kashan University of Medical Sciences. One-way ANOVA and chi-square tests were used to analyze data using SPSS version 16.0. P value < 0.05 was considered significant. RESULTS: A total of 1723 victims (82.6% male, sex ratio of almost 5:1) were considered in this study. Mortality rate in trauma cases hospitalized more than 24 hours during our study was 0.8%. Young motorcyclist men with the rate of more than 103 per 10000 were the most vulnerable group. The most common injury was head injury (73.6%) followed by lower limb injury (33.2%). A significant association was found between mechanism of injury and head, lower limb, multiple injuries and high risk age group. CONCLUSIONS: Urban RTAs are one of the most important problems in Kashan and Aran-Bidgol cities, which impose a great economic burden on health system. Motorcyclists are the most vulnerable victims and multiple trauma and head injury are seen among them extensively. PMID- 26101766 TI - Role of Anesthesia Team in Prehospital Care: The Hidden Treasure in Critical Settings. PMID- 26101767 TI - Antiherpes Activity and Skin/Mucosa Distribution of Flavonoids from Achyrocline satureioides Extract Incorporated into Topical Nanoemulsions. AB - This study investigated the inhibitory effects of Achyrocline satureioides extract (ASE) incorporated into a topical nanoemulsion on Herpes Simplex Virus type 1 (HSV-1/KOS strain) replication, as well as the distribution of the main ASE flavonoids (quercetin, luteolin, and 3-O-methylquercetin) in porcine skin and mucosa. The ASE-loaded nanoemulsion showed more pronounced effects against HSV-1 replication when compared to the ASE or pure quercetin, as determined by the viral plaque number reduction assay. All flavonoids were detected in the skin epidermis (2.2 ug/cm(2)) and the mucosa upper layers (3.0 ug/cm(2)) from ASE loaded nanoemulsion until 8 h after topical application. A higher amount of flavonoids was detected when these tissues were impaired, especially in deeper mucosa layers (up to 7-fold). Flavonoids were detected in the receptor fluid only when the mucosa was injured. Such results were supported by confocal microscopy images. Overall, these findings suggest that the tested ASE-loaded nanoemulsion has potential to be used topically for herpes infections. PMID- 26101768 TI - The Use of Natural Polysaccharides as Biomaterials. PMID- 26101769 TI - Impact of Volatile Anesthetics on Oxidative Stress and Inflammation. AB - The safety of anesthesia, which is an important step for surgery, can be determined by its impact on oxidative stress and inflammation. The effects of volatile anesthetics such as isoflurane and sevoflurane on oxidative stress and inflammation are reviewed in various (1) cell lines, (2) rodents, and (3) human studies. Isoflurane and sevoflurane are reported to have antioxidant and anti inflammatory effects in all cells with exception of neuronal cell lines. In addition, various animal studies have indicated that isoflurane and sevoflurane were not only safe but also reduced oxidative stress and inflammation in rodent models. In human studies, oxidative stress, inflammation, and DNA damage were not affected by isoflurane and sevoflurane in patients undergoing minor incision surgeries. On the other hand, elevated oxidative stress, inflammation, and DNA damage have been observed in patients undergoing major surgeries such as abdominal and orthopedic surgeries, hysterectomy, cholecystectomy, and thoracotomy. Although impact of anesthetics on oxidative stress and inflammation is still not clear due to the variations of patients' health conditions, types of surgery and the quantities of anesthetics, isoflurane, and sevoflurane can be considered safe anesthetics with respect to their effect on oxidative stress and inflammation in subjects undergoing minor surgery. Continuous effort evaluating the safety of anesthesia in various aspects is required. PMID- 26101770 TI - Sevoflurane Induces DNA Damage Whereas Isoflurane Leads to Higher Antioxidative Status in Anesthetized Rats. AB - Taking into account that there are controversial antioxidative effects of inhalational anesthetics isoflurane and sevoflurane and absence of comparison of genotoxicity of both anesthetics in animal model, the aim of this study was to compare DNA damage and antioxidant status in Wistar rats exposed to a single time to isoflurane or sevoflurane. The alkaline single-cell gel electrophoresis assay (comet assay) was performed in order to evaluate DNA damage in whole blood cells of control animals (unexposed; n = 6) and those exposed to 2% isoflurane (n = 6) or 4% sevoflurane (n = 6) for 120 min. Plasma antioxidant status was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was no statistically significant difference between isoflurane and sevoflurane groups regarding hemodynamic and temperature variables (P > 0.05). Sevoflurane significantly increased DNA damage compared to unexposed animals (P = 0.02). In addition, Wistar rats anesthetized with isoflurane showed higher antioxidative status (MTT) than control group (P = 0.019). There were no significant differences in DNA damage or antioxidant status between isoflurane and sevoflurane groups (P > 0.05). In conclusion, our findings suggest that, in contrast to sevoflurane exposure, isoflurane increases systemic antioxidative status, protecting cells from DNA damage in rats. PMID- 26101771 TI - In Vitro Properties of Potential Probiotic Indigenous Lactic Acid Bacteria Originating from Traditional Pickles. AB - The suitable properties of potential probiotic lactic acid bacteria (LAB) strains (preselected among 153 strains on the basis of their potential technological properties) isolated from traditional Cubuk pickles were examined in vitro. For this purpose, these strains (21 Lactobacillus plantarum, 11 Pediococcus ethanolidurans, and 7 Lactobacillus brevis) were tested for the ability to survive at pH 2.5, resistance to bile salts, viability in the presence of pepsin pancreatin, ability to deconjugate bile salts, cholesterol assimilation, and surface hydrophobicity properties. Most of the properties tested could be assumed to be strain-dependent. However, L. plantarum and L. brevis species were found to possess desirable probiotic properties to a greater extent compared to P. ethanolidurans. In contrast to P. ethanolidurans strains, the tested L. plantarum and L. brevis strains exhibited bile salt tolerance, albeit to different extent. All tested strains showed less resistance to intestinal conditions than gastric juice environment. Based on the survival under gastrointestinal conditions, 22 of the 39 strains were selected for further characterization. The eight strains having the highest cholesterol assimilation and surface hydrophobicity ratios could be taken as promising probiotic candidates for further in vivo studies, because of the strongest variations found among the tested strains with regard to these properties. PMID- 26101772 TI - Evaluation of an Indirect-ELISA Test for Trypanosoma evansi Infection (Surra) in Buffaloes and Its Application to a Serological Survey in Thailand. AB - Surra, caused by Trypanosoma evansi, is a neglected disease due to frequent subclinical evolution, especially in bovines in Asia. However, acute and chronic signs are regularly observed, with significant sanitary and economic impacts. In this study, we evaluated and applied an indirect-ELISA test for the detection of anti-T. evansi immunoglobulin G in buffaloes using antibovine conjugate. Based on buffalo reference sera from the Philippines, a two-graph receiver operating characteristics analysis (TG-ROC) was conducted to define an optimal cut-off value; sensitivity and specificity were estimated at 92.5% and 94.2%, respectively. A cross-sectional serological survey was carried out in the major buffalo breeding areas of Thailand; 892 buffaloes from 8 provinces were sampled in North, Northeastern, and Southern Thailand. Seropositive buffaloes were found in all 8 provinces, on 20.3% of farms for an overall prevalence of 12.2% (95% CI 10.2-14.5%). Nearly one-third of the sampled population was exposed to infection. Broader sampling would be necessary but is not possible in the southern half-wild breeding systems. According to our results, buffaloes may constitute a large and robust reservoir for T. evansi, which is a permanent threat to other livestock such as cattle and horses as well as wild animals such as elephants in Southest Asia. PMID- 26101774 TI - Epigenetics of Meningiomas. AB - Meningiomas account for one-third of all adult central nervous system tumours and are divided into three WHO grades. In contrast to the relatively well characterized genetic alterations, our current understanding of epigenetic modifications involved in the meningioma-genesis and progression is rather incomplete. Contrary to genetic alterations, epigenetic changes do not alter the primary DNA sequence and their reversible nature serves as an excellent basis for prevention and development of novel personalised tumour therapies. Indeed, growing body of evidence suggests that disturbed epigenetic regulation plays a key role in the pathogenesis of meningiomas. Altered DNA methylation, microRNA expression, histone, and chromatin modifications are frequently noted in meningiomas bearing prognostic and therapeutic relevance. In this review we provide an overview on recently identified epigenetic alterations in meningiomas and discuss their role in tumour initiation, progression, and recurrence. PMID- 26101775 TI - Insufficient Discriminatory Power of Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometry Dendrograms to Determine the Clonality of Multi Drug-Resistant Acinetobacter baumannii Isolates from an Intensive Care Unit. AB - While pulsed-field gel electrophoresis (PFGE) is recognized as the gold standard method for clonality analysis, MALDI-TOF MS has recently been spotlighted as an alternative tool for species identification. Herein, we compared the dendrograms of multi-drug-resistant (MDR) Acinetobacter baumannii isolates by using MALDI-TOF MS with those by using PFGE. We used direct colony and protein extraction methods for MALDI-TOF MS dendrograms. The isolates with identical PFGE patterns were grouped into different branches in MALDI-TOF MS dendrograms. Among the isolates that were classified as very close isolates in MALDI-TOF MS dendrogram, PFGE band patterns visually showed complete differences. We numeralized similarity among isolates by measuring distance levels. The Spearman rank correlation coefficient values were 0.449 and 0.297 between MALDI-TOF MS dendrogram using direct colony and protein extraction method versus PFGE, respectively. This study is the first paper focusing solely on the dendrogram function of MALDI-TOF MS compared with PFGE. Although MALDI-TOF MS is a promising tool to identify species in a rapid manner, our results showed that MALDI-TOF MS dendrograms could not substitute PFGE for MDR Acinetobacter baumannii clonality analysis. PMID- 26101773 TI - Monoamine Oxidases as Potential Contributors to Oxidative Stress in Diabetes: Time for a Study in Patients Undergoing Heart Surgery. AB - Oxidative stress is a pathomechanism causally linked to the progression of chronic cardiovascular diseases and diabetes. Mitochondria have emerged as the most relevant source of reactive oxygen species, the major culprit being classically considered the respiratory chain at the inner mitochondrial membrane. In the past decade, several experimental studies unequivocally demonstrated the contribution of monoamine oxidases (MAOs) at the outer mitochondrial membrane to the maladaptative ventricular hypertrophy and endothelial dysfunction. This paper addresses the contribution of mitochondrial dysfunction to the pathogenesis of heart failure and diabetes together with the mounting evidence for an emerging role of MAO inhibition as putative cardioprotective strategy in both conditions. PMID- 26101776 TI - The Effect of Phospholipids (Surfactant) on Adhesion and Biomechanical Properties of Tendon: A Rat Achilles Tendon Repair Model. AB - Adhesion of the tendon is a major challenge for the orthopedic surgeon during tendon repair. Manipulation of biological environment is one of the concepts to prevent adhesion. Lots of biochemicals have been studied for this purpose. We aimed to determine the effect of phospholipids on adhesion and biomechanical properties of tendon in an animal tendon repair model. Seventy-two Wistar rats were divided into 4 groups. Achilles tendons of rats were cut and repaired. Phospholipids were applied at two different dosages. Tendon adhesion was determined histopathologically and biomechanical test was performed. At macroscopic evaluation of adhesion, there are statistically significant differences between multiple-dose phospholipid injection group and Control group and also hyaluronic acid group and Control group (p < 0.008). At microscopic evaluation of adhesion, there was no statistically significant difference (p > 0.008). Ultimate strength was highest at hyaluronic acid injection group and lowest at multiple-dose phospholipid injection group. Single-dose phospholipids (surfactant) application may have a beneficial effect on the tendon adhesion. Although multiple applications of phospholipids seem the most effective regime to reduce the tendon adhesion among groups, it deteriorated the biomechanical properties of tendon. PMID- 26101778 TI - Outcome of Elderly Patients with Meningioma after Image-Guided Stereotactic Radiotherapy: A Study of 100 Cases. AB - Introduction. Incidence of meningioma increases with age. Surgery has been the mainstay treatment. Elderly patients, however, are at risk of severe morbidity. Therefore, we conducted this study to analyze long-term outcomes of linac-based fractionated stereotactic radiotherapy (FSRT) for older adults (aged >=65 years) with meningioma and determine prognostic factors. Materials and Methods. Between October 1998 and March 2009, 100 patients (>=65, median age, 71 years) were treated with FSRT for meningioma. Two patients were lost to follow-up. Eight patients each had grade I and grade II meningiomas, and five patients had grade III meningiomas. The histology was unknown in 77 cases (grade 0). Results. The median follow-up was 37 months, and 3-year, 5-year, and 10-year progression-free survival (PFS) rates were 93.7%, 91.1%, and 82%. Patients with grade 0/I meningioma showed 3- and 5-year PFS rates of 98.4% and 95.6%. Patients with grade II or III meningiomas showed 3-year PFS rates of 36%. 93.8% of patients showed local tumor control. Multivariate analysis did not indicate any significant prognostic factors. Conclusion. FSRT may play an important role as a noninvasive and safe method in the clinical management of older patients with meningioma. PMID- 26101777 TI - The Sea Lamprey as an Etiological Model for Biliary Atresia. AB - Biliary atresia (BA) is a progressive, inflammatory, and fibrosclerosing cholangiopathy in infants that results in obstruction of both extrahepatic and intrahepatic bile ducts. It is the most common cause for pediatric liver transplantation. In contrast, the sea lamprey undergoes developmental BA with transient cholestasis and fibrosis during metamorphosis, but emerges as a fecund adult with steatohepatitis and fibrosis in the liver. In this paper, we present new histological evidence and compare the sea lamprey to existing animal models to highlight the advantages and possible limitations of using the sea lamprey to study the etiology and compensatory mechanisms of BA and other liver diseases. Understanding the signaling factors and genetic networks underlying lamprey BA can provide insights into BA etiology and possible targets to prevent biliary degeneration and to clear fibrosis. In addition, information from lamprey BA can be used to develop adjunct treatments for patients awaiting or receiving surgical treatments. Furthermore, the cholestatic adult lamprey has unique adaptive mechanisms that can be used to explore potential treatments for cholestasis and nonalcoholic steatohepatitis (NASH). PMID- 26101779 TI - From Grey Scale B-Mode to Elastosonography: Multimodal Ultrasound Imaging in Meningioma Surgery-Pictorial Essay and Literature Review. AB - The main goal in meningioma surgery is to achieve complete tumor removal, when possible, while improving or preserving patient neurological functions. Intraoperative imaging guidance is one fundamental tool for such achievement. In this regard, intra-operative ultrasound (ioUS) is a reliable solution to obtain real-time information during surgery and it has been applied in many different aspect of neurosurgery. In the last years, different ioUS modalities have been described: B-mode, Fusion Imaging with pre-operative acquired MRI, Doppler, contrast enhanced ultrasound (CEUS), and elastosonography. In this paper, we present our US based multimodal approach in meningioma surgery. We describe all the most relevant ioUS modalities and their intraoperative application to obtain precise and specific information regarding the lesion for a tailored approach in meningioma surgery. For each modality, we perform a review of the literature accompanied by a pictorial essay based on our routinely use of ioUS for meningioma resection. PMID- 26101780 TI - Correlates of Protection for M Protein-Based Vaccines against Group A Streptococcus. AB - Group A streptococcus (GAS) is known to cause a broad spectrum of illness, from pharyngitis and impetigo, to autoimmune sequelae such as rheumatic heart disease, and invasive diseases. It is a significant cause of infectious disease morbidity and mortality worldwide, but no efficacious vaccine is currently available. Progress in GAS vaccine development has been hindered by a number of obstacles, including a lack of standardization in immunoassays and the need to define human correlates of protection. In this review, we have examined the current immunoassays used in both GAS and other organisms, and explored the various challenges in their implementation in order to propose potential future directions to identify a correlate of protection and facilitate the development of M protein-based vaccines, which are currently the main GAS vaccine candidates. PMID- 26101782 TI - Benefits and Risks in Secondary Use of Digitized Clinical Data: Views of Community Members Living in a Predominantly Ethnic Minority Urban Neighborhood. AB - BACKGROUND: There is potential to increase the speed of scientific discovery and implement personalized health care by using digitized clinical data collected on the patient care experience. The use of these data in research raises concerns about the privacy and confidentiality of personal health information. This study explored community members' views on the secondary use of digitized clinical data to (1) recruit participants for clinical studies; (2) recruit family members of persons with an index condition for primary studies; and (3) conduct studies of information related to stored biospecimens. METHODS: A qualitative descriptive design was used to examine the bioethical issues outlined from the perspective of urban-dwelling community members. Focus groups were used for data collection, and emergent content analysis was employed to organize and interpret the data. RESULTS: Thirty community members attended one of four focus groups ranging in size from 4 to 11 participants. Five critical themes emerged from the focus-group material: (1) perceived motivators for research participation; (2) objective or "real-life" barriers to research participation; (3) a psychological component of uncertainty and mistrust; (4) preferred mechanisms for recruitment and participation; and (5) cultural characteristics that can impact understanding and willingness to engage in research. CONCLUSIONS: The overriding concern of community members regarding research participation and/or secondary clinical and nonclinical use of digitized information was that their involvement would be safe and the outcome would be meaningful to them and to others. According to participants, biospecimens acquired during routine clinical visits or for research are no longer possessions of the participant. Although the loss of privacy was a concern for participants, they preferred that researchers access their personal health information using a digitized clinical file rather than through a paper-based medical record. PMID- 26101783 TI - Acceptance-based behavioral treatment for weight control: a review and future directions. PMID- 26101781 TI - Harnessing the Microbiome to Enhance Cancer Immunotherapy. AB - The microbiota plays a key role in regulating the innate and adaptive immune system. Herein, we review the immunological aspects of the microbiota in tumor immunity in mice and man, with a focus on toll-like receptor (TLR) agonists, vaccines, checkpoint modulators, chemotherapy, and adoptive T cell transfer (ACT) therapies. We propose innovative treatments that may safely harness the microbiota to enhance T cell-based therapies in cancer patients. Finally, we highlight recent developments in tumor immunotherapy, particularly novel ways to modulate the microbiome and memory T cell responses to human malignancies. PMID- 26101784 TI - Toxic Effects of Ethyl Cinnamate on the Photosynthesis and Physiological Characteristics of Chlorella vulgaris Based on Chlorophyll Fluorescence and Flow Cytometry Analysis. AB - The toxic effects of ethyl cinnamate on the photosynthetic and physiological characteristics of Chlorella vulgaris were studied based on chlorophyll fluorescence and flow cytometry analysis. Parameters, including biomass, F(v)/F(m) (maximal photochemical efficiency of PSII), F(PSII) (actual photochemical efficiency of PSII in the light), FDA, and PI staining fluorescence, were measured. The results showed the following: (1) The inhibition on biomass increased as the exposure concentration increased. 1 mg/L ethyl cinnamate was sufficient to reduce the total biomass of C. vulgaris. The 48-h and 72-h EC50 values were 2.07 mg/L (1.94-2.20) and 1.89 mg/L (1.82-1.97). (2) After 24 h of exposure to 2-4 mg/L ethyl cinnamate, the photosynthesis of C. vulgaris almost ceased, manifesting in F(PSII) being close to zero. After 72 h of exposure to 4 mg/L ethyl cinnamate, the Fv /Fm of C. vulgaris dropped to zero. (3) Ethyl cinnamate also affected the cellular physiology of C. vulgaris, but these effects resulted in the inhibition of cell yield rather than cell death. Exposure to ethyl cinnamate resulted in decreased esterase activities in C. vulgaris, increased average cell size, and altered intensities of chlorophyll a fluorescence. Overall, esterase activity was the most sensitive variable. PMID- 26101785 TI - Analysis of Japanese Patients Treated with or without Long-Term Epirubicin Plus Ara-C Intravesical Instillation Therapy for Low-Grade Superficial Bladder Cancer. AB - The high incidence of tumor recurrence following transurethral resection (TUR) represents a major problem encountered in the management of bladder cancer. This study examined the efficacy of intravesical chemotherapy in superficial bladder cancer. We retrospectively analyzed 90 Japanese cases with low-grade superficial transitional cell carcinoma (stage T1, grades 1 and 2) who were rendered tumor free by TURBT (TUR of bladder tumor) and who thereafter were treated with or without intravesical chemotherapy. Among them, instillation was terminated in 2 patients due to adverse effects (severe but reversible chemical cystitis). Remaining 88 patients were divided into 2 groups according to therapy: the TURBT only group (n = 46), defined as patients treated with TURBT alone, and the Instillation group (n = 42), defined as patients treated with weekly intravesical instillation therapies using epirubicin plus Ara-C. Recurrence-free rate was significantly higher in the Instillation group than in the TURBT-only group (p = 0.02, HR = 0.457). The 5-year recurrence-free rate was 58.5% for the Instillation group and 38.6% for the TURBT-only group. Our instillation schedule represents the most intensive regimen among previously reported therapies and resulted in a 54.3% decrease in incidence of tumor recurrence. We believe that the results of this study could provide useful information on management of bladder cancer. PMID- 26101786 TI - Subacute Toxicity Profile of Lacidipine Nanoformulation in Wistar Rats. AB - The present study was aimed at investigating the safety of Lacidipine (LCDP) loaded nanostructured lipid carriers (NLCs) in Wistar rats. NLCs were formulated using ultrasound dispersion technique. Animals were orally treated once daily with NLCs containing 0.140 mg, 0.350 mg, and 0.875 mg of LCDP as low, medium, and high dose per kg body weight, respectively, during 28 days along with blank formulation and pure LCDP. Control rats were fed with water. Animals were observed throughout experiment period and their body weight was recorded once weekly. Overnight fasted rats were sacrificed on the 29th day. Study revealed no signs or symptoms of toxicity or morbidity. No significant changes in the body weight were observed between treated and control group. Significant increase in left testis weight and liver weight was observed in male and female rats, respectively. Haematological estimation revealed significant decrease in haemoglobin count in male rats while female rats showed significant increase in granulocyte count. All the serum clinical parameters were within the normal range and no gross histopathological changes were observed. No delayed effect was noted in satellite group. The results indicate that developed LCDP loaded NLCs are safe when administered orally in rats. PMID- 26101789 TI - Delivering the Goods for Genome Engineering and Editing. AB - A basic understanding of genome evolution and the life and impact of microorganisms, like viruses and bacteria, has been fundamental in the quest for efficient genetic therapies. The expanding tool box for genetic engineering now contains transposases, recombinases, and nucleases, all created from naturally occurring genome-modifying proteins. Whereas conventional gene therapies have sought to establish sustained expression of therapeutic genes, genomic tools are needed only in a short time window and should be delivered to cells ideally in a balanced "hit-and-run" fashion. Current state-of-the-art delivery strategies are based on intracellular production of protein from transfected plasmid DNA or in vitro-transcribed RNA, or from transduced viral templates. Here, we discuss advantages and challenges of intracellular production strategies and describe emerging approaches based on the direct delivery of protein either by transfer of recombinant protein or by lentiviral protein transduction. With focus on adapting viruses for protein delivery, we describe the concept of "all-in-one" lentiviral particles engineered to codeliver effector proteins and donor sequences for DNA transposition or homologous recombination. With optimized delivery methods-based on transferring DNA, RNA, or protein-it is no longer far-fetched that researchers in the field will indeed deliver the goods for somatic gene therapies. PMID- 26101788 TI - A single-molecule digital enzyme assay using alkaline phosphatase with a cumarin based fluorogenic substrate. AB - Digitalization of fluorogenic enzymatic assays through the use of femtoliter chamber array technology is an emerging approach to realizing highly quantitative bioassays with single-molecule sensitivity. However, only a few digital fluorogenic enzyme assays have been reported, and the variations of the digital enzyme assays are basically limited to fluorescein- and resorufin-based fluorogenic assays. This limitation hampers the realization of a multiplex digital enzyme assay such as a digital enzyme-linked immunosorbent assay (ELISA). In this study, after optimization of buffer conditions, we achieved a single molecule digital enzyme alkaline phosphatase (ALP) assay with a cumarin-based fluorogenic substrate, 4-methylunbelliferyl phosphate (4-MUP). When ALP molecules were encapsulated in a 44-femtoliter chamber array at a low ratio of less than 1 molecule per chamber, each chamber showed a discrete fluorescence signal in an all-or-none manner, allowing the digital counting of the number of active enzyme molecules. The fraction of fluorescent chambers linearly decreased with the enzyme concentration, obeying the Poisson distribution as expected. We also demonstrated a dual-color digital enzyme assay with a ALP/4-MUP and beta galactosidase (beta-gal)/resorufin-beta-d-galactopyranoside combination. The activities of single ALP and beta-gal molecules were clearly detected simultaneously. The method developed in this study will enable us to carry out a parallelized, multiplex digital ELISA. PMID- 26101787 TI - Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists. AB - Toll-like receptor (TLR) agonists activate both the innate and the adaptive immune systems. These TLR agonists have been exploited as potent vaccine adjuvants and antitumor agents. We describe the identification and characterization of a small molecule, N-methyl-4-nitro-2-(4-(4 (trifluoromethyl)phenyl)-1 H-imidazol-1-yl)aniline (CU-T12-9), that directly targets TLR1/2 to initiate downstream signaling. CU-T12-9 specifically induces TLR1/2 activation, which can be blocked by either the anti-hTLR1 or the anti hTLR2 antibody, but not the anti-hTLR6 antibody. Using a variety of different biophysical assays, we have demonstrated the binding mode of CU-T12-9. By binding to both TLR1 and TLR2, CU-T12-9 facilitates the TLR1/2 heterodimeric complex formation, which in turn activates the downstream signaling. Fluorescence anisotropy assays revealed competitive binding to the TLR1/2 complex between CU T12-9 and Pam3CSK4 with a half-maximal inhibitory concentration (IC50) of 54.4 nM. Finally, we showed that CU-T12-9 signals through nuclear factor kappaB (NF kappaB) and invokes an elevation of the downstream effectors tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and inducible nitric oxide synthase (iNOS). Thus, our studies not only provide compelling new insights into the regulation of TLR1/2 signaling transduction but also may facilitate future therapeutic developments. PMID- 26101790 TI - Successful Treatment of Dissociative Identity Disorder in an Adolescent with Quetiapine. PMID- 26101791 TI - Direct Observation of Charge Inversion in Divalent Nanofluidic Devices. AB - Solid-state nanofluidic devices have proven to be ideal systems for studying the physics of ionic transport at the nanometer length scale. When the geometrical confining size of fluids approaches the ionic Debye screening length, new transport phenomena occur, such as surface mediated transport and permselectivity. Prior work has explored these effects extensively in monovalent systems (e.g., predominantly KCl and NaCl). In this report, we present a new characterization method for the study of divalent ionic transport and have unambiguously observed divalent charge inversion at solid/fluid interfaces. This observation has important implications in applications ranging from biology to energy conversion. PMID- 26101792 TI - Dissolution of Wood Pulp in Aqueous NaOH/Urea Solution via Dilute Acid Pretreatment. AB - Wood pulps with certain amounts of lignin were successfully dissolved in aqueous NaOH/urea solution by subjecting them to the dilute acid pretreatment. After the acid hydrolysis, viscosity-average degree of polymerization (DPv) of the pulps decreased. The results revealed that both the DPv and lignin contents influenced the dissolved proportions of wood pulps. When they were not so high, the wood pulps could almost completely dissolve with dissolved proportions >90%. In particular, the acid-pretreated unbleached kraft pulp with DPv of about 500 and lignin content of 6.9% could dissolve in NaOH/urea solvent and achieve a maximum pulp concentration of 4 wt % in the obtained lignocellulose solution. Moreover, the acid-pretreated bleached thermomechanical pulp with a high lignin content of 14.2% also almost completely dissolved. The lignocellulose films prepared from these wood pulp/NaOH/urea solutions exhibited good transparency and bendability, thus maybe promising as new biobased materials. PMID- 26101793 TI - Imaging Bradykinin B1 Receptor with 68Ga-Labeled [des-Arg10]Kallidin Derivatives: Effect of the Linker on Biodistribution and Tumor Uptake. AB - Bradykinin B1 receptor (B1R) that is overexpressed in cancers but minimally expressed in normal healthy tissues represents an attractive biomarker for the development of cancer imaging agents. The goal of this study was to evaluate the effect of different linkers on the pharmacokinetics and tumor uptake of a B1R targeting radio-peptide sequence, 68Ga-DOTA-linker-Lys-Arg-Pro-Hyp-Gly-Cha-Ser Pro-Leu. Four peptides, SH01078, P03034, P04115, and P04168, with 6-aminohexanoic acid, 9-amino-4,7-dioxanonanoic acid, Gly-Gly, and 4-amino-(1 carboxymethyl)piperidine, respectively, as the linker were synthesized and evaluated. In vitro competition binding assays showed that the Ki values of SH01078, P03034, P04115, and P04168 were 27.8+/-4.9, 16.0+/-1.9, 11.4+/-2.5, and 3.6+/-0.2 nM, respectively. Imaging and biodistribution studies were performed in mice bearing both B1R-positive HEK293T::hB1R and B1R-negative HEK293T tumors. All tracers showed mainly renal excretion with excellent tumor visualization and minimal background activity except for kidneys and bladder. The average uptake of 68Ga-labeled SH01078, P03034, and P04115 in HEK293T::hB1R tumor was similar (1.96 2.17%ID/g) at 1 h postinjection. 68Ga-P04168 generated higher HEK293T::hB1R tumor uptake (4.15+/-1.13%ID/g) and lower background activity, leading to a >2-fold improvement in HEK293T::hB1R tumor-to-background (HEK293T tumor, blood, muscle, and liver) contrasts over those of 68Ga-labeled SH01078, P03034, and P04115. Our results indicate that the choice of linker affects binding affinity, pharmacokinetics, and tumor targeting. The use of the cationic 4-amino-(1 carboxymethyl)piperidine linker improved tumor visualization, and the resulting 68Ga-P04168 might be promising for clinical application for imaging B1R expressing tumors with positron emission tomography. PMID- 26101794 TI - Methoxyflurane: a review with emphasis on its role in dental practice. AB - Methoxyflurane was developed as an anaesthetic agent and introduced into clinical practice in 1960. It soon became evident that it possessed analgesic properties that other drugs did not. Due to toxicity concerns, it lost favour in general anaesthesia and had been largely abandoned by the late 1970s. The manufacturer withdrew it in 1999, and the Food and Drug Administration in the United States did not renew its licence in 2005. It has also been withdrawn by the European Union. However, it continues to be used in Australasia, primarily as an inhaled self-administered analgesic by emergency services immediately following trauma. It has become attractive for use in dental practice, likely due to its effectiveness as an analgesic and its additional sedative qualities. Its acceptance is controversial as its use in dentistry is largely elective. Despite its good safety record in analgesic doses, adverse reactions have been recorded. Practitioners should be well aware of risks associated with its use before considering administration, and carefully assess whether or not there are equally good alternative options that do not the carry the same risks. Methoxyflurane is reviewed below with an emphasis on its use in dental practice. PMID- 26101795 TI - A novel OFET-based biosensor for the selective and sensitive detection of lactate levels. AB - Biosensors based on organic field effect transistors (OFETs) are one of the more promising device applications in organic electronics. However, OFET-based biosensors are still in their early stages of development compared to other electrochemical biosensors. This study is the first to report on an extended-gate type organic field effect transistor (OFET) for lactate detection in aqueous media. Here, the extended-gate electrode of the OFET was modified with layers of a lactate oxidase and a horseradish peroxidase osmium-redox polymer on a flexible plastic film substrate for an enzymatic redox reaction of lactate. The device exhibited both high selectivity and sensitivity. The limit of detection (LOD) and the limit of quantification (LOQ) were estimated to be 66 nM and 220 nM, respectively, which are the sufficient detection limit for practical sensor applications. The obtained results confirm that extended-gate type OFET devices are applicable to enzyme-based biosensors for detecting lactate levels. PMID- 26101796 TI - Investigation of irradiated rats DNA in the presence of Cu(II) chelates of amino acids Schiff bases. AB - The new synthesized Cu(II) chelates of amino acids Schiff bases were studied as a potential radioprotectors. Male albino rats of Wistar strain were exposed to X ray whole-body irradiation at 4.8 Gy. This dose caused 30% mortality of the animals (LD30). The survival of animals exposed to radiation after preliminary administration of 10 mg/kg Cu(II)(Nicotinyl-L-Tyrosinate)2 or Cu(II)(Nicotinyl-L Tryptophanate)2 prior to irradiation was registered about 80 and 100% correspondingly. Using spectrophotometric melting and agarose gel electrophoresis methods, the differences between the DNA isolated from irradiated rats and rats pretreated with Cu(II) chelates were studied. The fragments of DNA with different breaks were revealed in DNA samples isolated from irradiated animals. While, the repair of the DNA structure was observed for animals pretreated with the Cu(II) chelates. The results suggested that pretreatment of the irradiated rats with Cu(II)(Nicotinyl-L-Tyrosinate)2 and Cu(II)(Nicotinyl-L-Tryptophanate)2 compounds improves the liver DNA characteristics. PMID- 26101798 TI - Effects of non-protein-type amino acids of fine particulate matter on E-cadherin and inflammatory responses in mice. AB - Exposure to particulate matter less than 2.5 MUm (PM2.5) in size is an urgent issue for the protection of human health. Chemicals with PM2.5 collected during a period of intensive haze episodes in Beijing (BJ), Xian (XA) and Hong Kong (HK) were characterised for organic carbon (OC), elemental carbon (EC), total carbon (TC) and free amino acids. BALB/c mice underwent aspiration exposure of 50 or 150 MUg of PM2.5/mouse (BJ, XA and HK) on days 1 and 7 and were euthanised on day 14. The effects of these exposures on E-cadherin and inflammatory responses in the mouse lungs were analysed. The PM2.5 chemicals consisted of significant amounts of OC: 36.6 +/- 17.2 MUg/m(3) for BJ, 38.8 +/- 3.8 MUg/m(3) for XA and 7.2 +/- 1.4 MUg/m(3) for HK. A total of 23 free amino compounds for the PM2.5 samples were analysed: 4075 +/- 1578 pmol/m(3) for BJ, 4718 +/- 2190 pmol/m(3) for XA and 1145 +/- 213 pmol/m(3) for HK. Exposure to PM2.5 resulted in the suppression of E cadherin levels in the lung tissues and increased IFN-gamma, IL-2, IL-4, IL-6 and IL-10 in the bronchoalveolar lavage fluid. The alterations in E-cadherin, IFN gamma, IL-6 and IL-10 were associated with OC, TC and some amino acids, particularly non-protein-type amino acids. These data emphasised the deleterious health effects of PM2.5. PMID- 26101797 TI - An integrated view of cisplatin-induced nephrotoxicity and ototoxicity. AB - Cisplatin is one of the most widely-used drugs to treat cancers. However, its nephrotoxic and ototoxic side-effects remain major clinical limitations. Recent studies have improved our understanding of the molecular mechanisms of cisplatin induced nephrotoxicity and ototoxicity. While cisplatin binding to DNA is the major cytotoxic mechanism in proliferating (cancer) cells, nephrotoxicity and ototoxicity appear to result from toxic levels of reactive oxygen species and protein dysregulation within various cellular compartments. In this review, we discuss molecular mechanisms of cisplatin-induced nephrotoxicity and ototoxicity. We also discuss potential clinical strategies to prevent nephrotoxicity and ototoxicity and their current limitations. PMID- 26101799 TI - Roscovitine treatment caused impairment of fertilizing ability in mice. AB - OBJECTIVE: To explore the adverse effect of roscovitine on reproductive system of male mice. MATERIALS AND METHODS: Male hSOD1(G93A) transgenetic mice received roscovitine 72 nmol/day (d) for 4 weeks (w), with normal control and dimethyl sulfoxide (DMSO)-treated animals served as controls (n=4). Male C57BL/6 mice were treated with roscovitine at either 72 nmol/d or 144 nmol/d for 4 w or 8 w, and normal control and DMSO treated mice served as controls. Fertility of male mice, sperm quality parameters, histological and related pathological changes of seminiferous tubules associated with roscovitine treatment were evaluated. RESULTS: In male hSOD1(G93A) transgenetic mice treated with 72 nmol/d roscovitine for 4 w and C57BL/6 male mice treated with 72 nmol/d roscovitine for 8w and 144 nmol/d roscovitine for 4 w and 8 w, sperm counts and sperm motility rates decreased and sperm abnormality rates increased, and damage of seminiferous tubules were detected. Roscovitine treatment induced inhibition of CDK5 activities and decrease of BrdU-positive tubuler cells. CONCLUSION: These results demonstrated that roscovitine treatment induced interference of male reproductive system and caused impairment of fertilizing ability. Reproductive system of ALS male mice was more susceptible to roscovitine induced impaired fertilizing ability. PMID- 26101800 TI - The IL-6/STAT3 pathway via miR-21 is involved in the neoplastic and metastatic properties of arsenite-transformed human keratinocytes. AB - Inflammation and microRNAs are involved in human skin cancer; however, their molecular mechanisms remain unclear. Further, a concern in skin cancer research is the identification of biomarkers for early diagnosis and accurate prognosis. To explore new biomarkers of chemical exposure in risk assessment of chemical carcinogenesis and arsenite-induced skin cancer, we investigated the roles of interleukin-6 (IL-6) regulation of microRNA-21 (miR-21), functioning via activation of signal transducers and activators of transcription 3 (STAT3), in neoplastic and metastatic properties of immortalized human keratinocytes (HaCaT cells) transformed by arsenite. In HaCaT cells, arsenite caused increases of IL-6 and miR-21 levels and activation of STAT3, which induced the epithelial mesenchymal transition (EMT). Blocking IL-6 with anti-IL-6 antibody inhibited the activation of STAT3 and increases of miR-21 levels. Knock-down of STAT3 by siRNA blocked the increases of miR-21. In arsenite-transformed HaCaT (HaCaT-30T) cells, down-regulation of STAT3 by siRNA blocked the process of EMT and decreased their neoplastic properties and migratory capacity, effects that were antagonized by over-expression of miR-21.Thus, the IL-6/STAT3 pathway via miR-21 is involved in EMT, neoplastic properties, and migratory capacity of arsenite-transformed HaCaT cells. The results may lead to development of biomarkers for early diagnosis and accurate prognosis of arsenite-induced skin cancer. PMID- 26101801 TI - The N,N'-dioxide/Ni(II)-catalyzed asymmetric inverse-electron-demand hetero-Diels Alder reaction of methyleneindolinones with hetero-substituted alkenes. AB - The highly efficient catalytic asymmetric inverse-electron-demand hetero-Diels Alder reaction of methyleneindolinones with hetero-substituted alkenes has been accomplished under mild reaction conditions. In the presence of chiral N,N' dioxide/Ni(II) complexes, a wide range of optically active dihydropyran-fused indoles were obtained in up to 99% yield, >95 : 5 dr and 99% ee. PMID- 26101802 TI - Formation of Hydroxyapatite Skeletal Materials from Hydrogel Matrices via Artificial Biomineralization. AB - Several kinds of hydrogels were prepared as mimics for the collagen/acidic protein hydrogel employed as the polymer matrix for mineralization in natural bone formation. The hydrogels prepared as mineralization matrices were employed for synthesizing artificial bones. The artificial bone made from a network of poly(vinyl alcohol) (PVA) and poly(acrylic acid) (PAA) prepared by heating (PVA/PAA-h-network) exhibited mechanical properties comparable with those of fish scales. To elucidate the formation mechanism of the artificial bone, we synthesized four further kinds of matrix. Artificial bones were obtained from both a PVA/PAA network prepared by repeated freezing and thawing (PVA/PAA-ft network) and a chitosan/PAA network, in which hydrogen bonding exists between the two constituent polymers, similar to that observed in a natural collagen/acidic protein network. The artificial bone made from the chitosan/PAA network was confirmed to be formed by the phase transformation of a cartilaginous precursor by a process similar to the transformation of cartilaginous tissue to natural bone. In addition, skeletal phase material, i.e., a homogeneous solid phase of hydroxyapatite/polymers, was formed in the cartilaginous phase, i.e., the hypercomplex gel. The skeletal phase grew thicker at the expense of the cartilaginous phase until it formed the entirety of the composite. Artificial bones were also obtained from a gelatin/PAA network and a poly[N-(2 hydroxyethyl)acrylamide]-co-(acrylic acid) network. These experimental results suggested that the coexistence of proton donor and proton acceptor functions in the hydrogel is a key factor for bone formation. The hydroxyapatite content of our artificial bones was almost conterminous with those of natural bones. PMID- 26101803 TI - Metal-polypyridyl catalysts for electro- and photochemical reduction of water to hydrogen. AB - Climate change, rising global energy demand, and energy security concerns motivate research into alternative, sustainable energy sources. In principle, solar energy can meet the world's energy needs, but the intermittent nature of solar illumination means that it is temporally and spatially separated from its consumption. Developing systems that promote solar-to-fuel conversion, such as via reduction of protons to hydrogen, could bridge this production-consumption gap, but this effort requires invention of catalysts that are cheap, robust, and efficient and that use earth-abundant elements. In this context, catalysts that utilize water as both an earth-abundant, environmentally benign substrate and a solvent for proton reduction are highly desirable. This Account summarizes our studies of molecular metal-polypyridyl catalysts for electrochemical and photochemical reduction of protons to hydrogen. Inspired by concept transfer from biological and materials catalysts, these scaffolds are remarkably resistant to decomposition in water, with fast and selective electrocatalytic and photocatalytic conversions that are sustainable for several days. Their modular nature offers a broad range of opportunities for tuning reactivity by molecular design, including altering ancillary ligand electronics, denticity, and/or incorporating redox-active elements. Our first-generation complex, [(PY4)Co(CH3CN)2](2+), catalyzes the reduction of protons from a strong organic acid to hydrogen in 50% water. Subsequent investigations with the pentapyridyl ligand PY5Me2 furnished molybdenum and cobalt complexes capable of catalyzing the reduction of water in fully aqueous electrolyte with 100% Faradaic efficiency. Of particular note, the complex [(PY5Me2)MoO](2+) possesses extremely high activity and durability in neutral water, with turnover frequencies at least 8500 mol of H2 per mole of catalyst per hour and turnover numbers over 600 000 mol of H2 per mole of catalyst over 3 days at an overpotential of 1.0 V, without apparent loss in activity. Replacing the oxo moiety with a disulfide affords [(PY5Me2)MoS2](2+), which bears a molecular MoS2 triangle that structurally and functionally mimics bulk molybdenum disulfide, improving the catalytic activity for water reduction. In water buffered to pH 3, catalysis by [(PY5Me2)MoS2](2+) onsets at 400 mV of overpotential, whereas [(PY5Me2)MoO](2+) requires an additional 300 mV of driving force to operate at the same current density. Metalation of the PY5Me2 ligand with an appropriate Co(ii) source also furnishes electrocatalysts that are active in water. Importantly, the onset of catalysis by the [(PY5Me2)Co(H2O)](2+) series is anodically shifted by introducing electron withdrawing functional groups on the ligand. With the [(bpy2PYMe)Co(CF3SO3)](1+) system, we showed that introducing a redox-active moiety can facilitate the electro- and photochemical reduction of protons from weak acids such as acetic acid or water. Using a high-throughput photochemical reactor, we examined the structure-reactivity relationship of a series of cobalt(ii) complexes. Taken together, these findings set the stage for the broader application of polypyridyl systems to catalysis under environmentally benign aqueous conditions. PMID- 26101805 TI - Nonparametric randomization-based covariate adjustment for stratified analysis of time-to-event or dichotomous outcomes. AB - Time-to-event or dichotomous outcomes in randomized clinical trials often have analyses using the Cox proportional hazards model or conditional logistic regression, respectively, to obtain covariate-adjusted log hazard (or odds) ratios. Nonparametric Randomization-Based Analysis of Covariance (NPANCOVA) can be applied to unadjusted log hazard (or odds) ratios estimated from a model containing treatment as the only explanatory variable. These adjusted estimates are stratified population-averaged treatment effects and only require a valid randomization to the two treatment groups and avoid key modeling assumptions (e.g., proportional hazards in the case of a Cox model) for the adjustment variables. The methodology has application in the regulatory environment where such assumptions cannot be verified a priori. Application of the methodology is illustrated through three examples on real data from two randomized trials. PMID- 26101804 TI - Selenite-Releasing Bone Mineral Nanoparticles Retard Bone Tumor Growth and Improve Healthy Tissue Functions In Vivo. AB - Selenite-doped bone mineral nanoparticles can retard the growth of osteosarcoma in a nude mice model, through sustained release of selenite ions. The selenite ions released from the nanoparticles through a degradation-mediated fashion inhibit tumor metastasis. Blood routine analysis indicates that selenite ions can also improve the functions of liver, kidney, and heart. PMID- 26101807 TI - The effect of metal ions on photocatalytic performance based on an isostructural framework. AB - A series of 2D layered isostructural coordination complexes {[M3(L)2(H2O)6].H2O}n (M = Mn (1), Mn0.7Co0.3 (2), Mn0.5Co0.5 (3), Mn0.3Co0.7 (4), and Co (5), respectively, H3L = 1-aminobenzene-3,4,5-tricarboxylic acid) have been synthesized under hydrothermal conditions, and applied to catalyze the reaction of degenerating organic dyes under visible light irradiation. The photocatalytic results indicate that complex 5 exhibits good photocatalytic properties in the presence of H2O2, while 1 can restrain the photodegradation of organic dyes. Remarkably, when Mn ions are gradually replaced by Co ions in the complexes, the photocatalytic activities of 1-5 turn from inhibition to promotion, which is a controllable regulation of photocatalytic properties via changing metal ions. Moreover, by using novel magnetic analysis methods and diffuse-reflectance UV/Vis spectra analysis methods, we explain the influence of central metal ions on the photocatalytic performance. PMID- 26101806 TI - ATF7 is stabilized during mitosis in a CDK1-dependent manner and contributes to cyclin D1 expression. AB - The transcription factor ATF7 undergoes multiple post-translational modifications, each of which has distinct effects upon ATF7 function. Here, we show that ATF7 phosphorylation on residue Thr112 exclusively occurs during mitosis, and that ATF7 is excluded from the condensed chromatin. Both processes are CDK1/cyclin B dependent. Using a transduced neutralizing monoclonal antibody directed against the Thr112 epitope in living cells, we could demonstrate that Thr112 phosphorylation protects endogenous ATF7 protein from degradation, while it has no effect on the displacement of ATF7 from the condensed chromatin. The crucial role of Thr112 phosphorylation in stabilizing ATF7 protein during mitosis was confirmed using phospho-mimetic and phospho-deficient mutants. Finally, silencing ATF7 by CRISPR/Cas9 technology leads to a decrease of cyclin D1 protein expression levels. We propose that mitotic stabilized ATF7 protein re-localizes onto chromatin at the end of telophase and contributes to induce the cyclin D1 gene expression. PMID- 26101809 TI - Respiratory Distress Following Cleft Palate Repair in Children With Robin Sequence. AB - Objective The aim of this study is to assess prevalence, severity, and duration of respiratory distress following palatoplasty in children with Robin sequence and to evaluate perioperative management. Design Retrospective chart review study. Data were collected for patients who were born between 2009 and 2012 and underwent palatoplasty in the Sophia Children's Hospital-Erasmus Medical Center. Results Of the 75 patients with cleft palate, 30 with Robin sequence and a control group of 45 cleft without Robin sequence underwent palatoplasty. Prior to closure, 26 of 30 patients with Robin sequence had been treated by prone positioning, and four needed additional treatment. The mean age at closure was 12.4 months for patients with Robin sequence and 10.9 months for patients without Robin sequence (P = .05). On the basis of the results of preoperative polysomnography with palatal plate, closure was postponed in two patients with Robin sequence. In the Robin sequence group, eight of the 30 patients developed postoperative respiratory distress within 48 hours and one patient, after 7 days; whereas none within the non-Robin sequence group developed respiratory distress. In all nine cases of Robin sequence the obstructive problems resolved within a few days, with four children requiring a temporary nasopharyngeal tube (NPT). There were no significant differences between preoperative polysomnography results of the nine patients with Robin sequence who developed postoperative respiratory distress compared with those patients with Robin sequence who did not. Conclusion Despite delayed closure compared with children without Robin sequence, 30% of the children with Robin sequence developed respiratory distress following palatoplasty, which resolved within a few days. This study emphasizes the need for close perioperative monitoring of patients with Robin sequence who undergo palatoplasty. PMID- 26101808 TI - Assessment of Parylene C Thin Films for Heart Valve Tissue Engineering. AB - BACKGROUND: Scaffolds are a key component of tissue-engineered heart valves (TEHVs). Several approaches had been adopted in the design of scaffolds using both natural and synthetic resources. We have investigated the suitability of parylene C (PC), a vapor deposited polymeric material, for the use as a scaffold in TEHV. AIMS: To evaluate the adsorption of extracellular matrix components onto plasma-activated PC and study the biocompatibility of PC by measuring cellular adhesion, viability, apoptosis, and phenotypic expression of valve endothelial and interstitial cells. Finally, the mechanical properties of PC were compared with those of native aortic valve cusp tissue. METHODS: PC slides were plasma activated and then coated with gelatin, type I collagen, or fibronectin. Porcine pulmonary valve endothelial and interstitial cells were then grown on plasma oxidized PC with different types of coatings and their adhesion was observed after 20 h of incubation. Cell viability was tested using the MTS assay, and apoptosis was estimated using TUNEL staining. The mechanical properties of PC and valve tissue were measured using a Bose Mechanical Tester. Finally, cell-seeded PC films were exposed to pulsatile pressure and aortic shear stress, respectively, to test their durability in a dynamic environment. RESULTS: Our findings show that collagen and fibronectin could bind to plasma oxidized PC. Both valve endothelial and interstitial cells adhered to protein-coated ECM. PC had a profile of mechanical stiffness and ultimate tensile strength that were comparable with or in excess of those seen in porcine aortic valve cusps. Cells were still attached to PC films after 3 days of exposure to up to 50 mmHg pulsatile pressure or aortic levels of shear stress. CONCLUSION: PC is a promising candidate for use as a scaffold in tissue engineering heart valves. Additional studies are required to determine both the durability and long-term performance of cell-seeded PC when in a similar hemodynamic environment to that of the aortic valve. PMID- 26101810 TI - Reporting of Randomized Controlled Trials in Cleft Lip and Palate: A 10-Year Review. AB - OBJECTIVES: Reviews of the quality of reporting of randomized controlled trials (RCTs) have recently been conducted in different surgical specialties. In this review of RCTs relating to cleft lip, cleft palate, and cleft lip and palate (CL/P), we investigate the quality of reporting against the Consolidated Standards of Reporting Trials (CONSORT) checklist. DESIGN: A systematic review of CL/P RCTs published from 2004 to 2013, with the included articles scored against the CONSORT checklist. PATIENTS, PARTICIPANTS: The literature search identified 174 articles. Studies were selected for participants with CL/P who were involved in an RCT with prospective data collection and reported in a full journal article. A total of 6352 participants were included from 65 CL/P RCTs during the study period. MAIN OUTCOME MEASURES: The methodological quality of RCTs was assessed using the CONSORT checklist and Jadad scale. RESULTS: The mean CONSORT score was 15.8, and the mean Jadad score was 3.3. There was a significant positive correlation between the CONSORT and Jadad score (P < .0001, rho = .47). The only significant correlation showed that with an increasing number of authors, both the CONSORT and the Jadad score increased. CONCLUSION: This analysis has shown that that there are deficiencies in the transparent reporting of factors such as randomization implementation, blinding, and participant flow. Interventions, outcomes, and the interpretation of results are well presented. We would recommend that RCTs are conceived and undertaken using the CONSORT checklist and reported in a clear and reproducible manner. PMID- 26101811 TI - Improving the Evaluation of Alveolar Bone Grafts With Cone Beam Computerized Tomography. AB - OBJECTIVE: Cone Beam computed tomography (CBCT) is used increasingly as a replacement for periapical x-rays when evaluating alveolar bone grafting. The manufacturer's standard settings for dental imaging may not, however, represent the optimal settings for evaluating postoperative alveolar bone grafts. We examined the influence of exposure parameters on CBCT image quality to optimize the quality of CBCT images while reducing the radiation dose to the minimum level necessary to obtain adequate images. METHODS: A defect was created in a cadaver head to simulate an alveolar cleft, and the area was filled with a synthetic material to simulate an alveolar bone graft. Serial CBCT scans were acquired, systematically varying tube voltage and tube current settings from 72 to 96kV and 3 to 12mA. Region of interest analysis was undertaken, and image quality was evaluated by comparing the ratios of native alveolar bone to soft tissue and the ratios of synthetic bone graft to soft tissue and by assessing image noise. RESULTS: Twenty-one CBCT data sets were obtained. Reducing tube voltage (kV) resulted in increased contrast ratio between bone and soft tissue and between synthetic bone graft and soft tissue, with maximal contrast at values of 76 kV/11 mA, 72 kV/12 mA, and 72 kV/11 mA. Of these, the setting with lowest image noise was 76 kV/11 mA. This setting also resulted in a radiation dose of less than half of the manufacturer's recommended settings for the same scan volume. CONCLUSIONS: There is potential to improve CBCT image quality significantly while dramatically reducing the radiation dose during postoperative examinations for alveolar bone grafting in patients with cleft lip and palate. PMID- 26101812 TI - Structure-activity relationships of bumetanide derivatives: correlation between diuretic activity in dogs and inhibition of the human NKCC2A transporter. AB - BACKGROUND AND PURPOSE: The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na+ , K+ and Cl- ions across cell membranes. There are two isoforms of this cation co-transporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered by screening ~5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure activity studies on effects of bumetanide derivatives on NKCC2 are not available. EXPERIMENTAL APPROACH: In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. KEY RESULTS: Bumetanide blocked hNKCC2A transport with an IC50 of 4 MUM. There was good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A (r2 = 0.817; P < 0.01). Replacement of the carboxylic group of bumetanide by a non-ionic residue, for example, an anilinomethyl group, decreased inhibition of hNKCC2A, indicating that an acidic group was required for transporter inhibition. Exchange of the phenoxy group of bumetanide for a 4-chloroanilino group or the sulfamoyl group by a methylsulfonyl group resulted in compounds with higher potency to inhibit hNKCC2A than bumetanide. CONCLUSIONS AND IMPLICATIONS: The X. laevis oocyte expression system used in these experiments allowed analysis of the structural requirements that determine relative potency of loop diuretics on human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics. PMID- 26101813 TI - Acyl acceptor recognition by Enterococcus faecium L,D-transpeptidase Ldtfm. AB - In Mycobacterium tuberculosis and ampicillin-resistant mutants of Enterococcus faecium, the classical target of beta-lactam antibiotics is bypassed by L,D transpeptidases that form unusual 3 -> 3 peptidoglycan cross-links. beta-lactams of the carbapenem class, such as ertapenem, are mimics of the acyl donor substrate and inactivate l,d-transpeptidases by acylation of their catalytic cysteine. We have blocked the acyl donor site of E. faecium L,D-transpeptidase Ldt(fm) by ertapenem and identified the acyl acceptor site based on analyses of chemical shift perturbations induced by binding of peptidoglycan fragments to the resulting acylenzyme. An nuclear magnetic resonance (NMR)-driven docking structure of the complex revealed key hydrogen interactions between the acyl acceptor and Ldt(fm) that were evaluated by site-directed mutagenesis and development of a cross-linking assay. Three residues are reported as critical for stabilisation of the acceptor in the Ldt(fm) active site and proper orientation of the nucleophilic nitrogen for the attack of the acylenzyme carbonyl. Identification of the catalytic pocket dedicated to the acceptor substrate opens new perspectives for the design of inhibitors with an original mode of action that could act alone or in synergy with beta-lactams. PMID- 26101814 TI - Pain Among High-Risk Patients on Methadone Maintenance Treatment. AB - The complexity of treating concurrent pain and opioid dependence among many methadone-maintained individuals presents a major challenge in many clinical settings. Furthermore, recent expert guidelines have called for increased research on the safety of methadone in the context of chronic pain. This study explores the prevalence and correlates of pain among a prospective cohort of people who use illicit drugs in Vancouver, British Columbia, Canada, who reported enrollment in methadone maintenance treatment (MMT) between 2011 and 2014. Among the 823 participants eligible for this analysis, 338 (40.9%) reported moderate pain and 91 (11.1%) reported extreme pain at the first study visit. In multivariable, generalized, linear mixed model analyses, higher pain severity was positively and independently associated with self-managing pain (adjusted odds ratio [AOR] 2.15, 95% confidence interval [CI] 1.77-2.60), patient perception of methadone dose being too low (AOR 1.82, 95% CI 1.41-2.34), older age (AOR 1.31, 95% CI 1.13-1.51), having a physical disability (AOR 4.59, 95% CI 3.73-5.64), having ever been diagnosed with a mental illness (AOR 1.44, 95% CI 1.13-1.84), white ethnicity (AOR 1.42, 95% CI 1.10-1.83), and marijuana use (AOR 1.25, 95% CI 1.02-1.52). These findings suggest several areas for clinical intervention, particularly related to patient education and alternative analgesic approaches for MMT patients experiencing pain. Perspective: To better understand the complexity of concurrent pain and opioid dependency among individuals on methadone maintenance treatment, this article describes the prevalence and correlates of higher pain severity among methadone-maintained people who use illicit drugs. Patients on methadone with comorbid pain may benefit from education and alternative analgesic approaches. PMID- 26101815 TI - Keeping kids sun safe: exploring parents' beliefs about their young child's sun protective behaviours. AB - OBJECTIVES: Melanoma of the skin is the third most commonly diagnosed cancer in Australia. Given the high incidence of sunburn in children and the level of sun protection provided by parents is often infrequent and/or insufficient, this research employed qualitative methodology to examine parents' beliefs about their young child's sun safe behaviour. METHODS: Parents (N = 21; n = 14 mothers, n = 7 fathers) of children aged 2-5 years participated in focus groups to identify commonly held beliefs about their decision to sun protect their child. Data were analysed using thematic content analysis. RESULTS: Parents generally had knowledge of the broad sun safe recommendations; however, the specific details of the recommendations were not always known. Parents reported adopting a range of sun-protective measures for their child, which depended on the time of year. A range of advantages (e.g. reducing the risk of skin cancer, developing good habits early and parental peace of mind), disadvantages (e.g. false sense of safety and preventing vitamin D absorption), barriers (e.g. child refusal) and facilitators (e.g. routine and accessibility) to performing sun safe practices were identified. Normative pressures and expectations also affected parents' motivation to be sun safe for their child. CONCLUSIONS: These identified beliefs can be used to inform interventions to improve sun safe behaviours in young children who reside in a region that has the highest skin cancer incidence in the world. PMID- 26101816 TI - Efficacy and long-term durability of intradermal recombinant hepatitis B virus vaccine among intramuscular vaccine nonresponders: A prospective study in healthcare personnel. AB - BACKGROUND: Data on efficacy, safety, and durability of intradermal vaccine administration in persons who have not responded appropriately to intramuscular administration of hepatitis B virus (HBV) vaccine are relatively scarce. METHODS: We designed a prospective case series in an urban tertiary care hospital in Israel. The medical records of 4007 healthcare personnel who had worked in the hospital between 1996 and 2006 were examined and those with an unsatisfactory level (<10 mIU/ml) of hepatitis B surface antibody (HBsAb) following two courses of a three-dose intramuscular HBV vaccine ("nonresponders") were identified. Nonresponders were vaccinated with three doses of 5 ug of intradermal recombinant hepatitis B surface antigen-based vaccine at weeks 0, 2, and 4. Level of HBsAb was determined 4 weeks after the last dose, and an additional dose was administered as needed. HBsAb level was again determined 24 weeks after the final vaccine dose to assess late immune reactivity and long-term durability of the vaccine. Vaccine safety was assessed at each vaccination and testing session. RESULTS: Twenty-seven subjects were included in the study, and 21 completed the study. The proportion of subjects with satisfactory HBsAb level at 4 weeks after the last administered dose was 70.3% (19/27). The proportion of subjects with sustained immune response at 24 weeks was 62.9% (17/27) according to intention-to treat analysis and 80.9% (17/21) according to per protocol analysis. There were no reports of adverse events in response to the administration of the vaccine. CONCLUSIONS: Intradermal administration of HBV vaccine offers an efficient, safe, and durable option for intramuscular vaccine nonresponders and represents a means to optimize utilization of the widespread HBs antigen-based vaccine formulation. PMID- 26101817 TI - Electrophoretic deposition to promote layer-by-layer assembly for in situ gene delivery application. AB - In this study, layer-by-layer (LbL) assembly of polyelectrolyte was facilitated using electric field assistance (EFA). To elucidate the EFA effects on polyelectrolyte multilayers (PEMs), the electric fields were solely administrated to either chitosan or DNA adsorption. Both DNA and chitosan adsorptions can be augmented under low electric field due to the electrophoretic deposition. However, the ensuing electrochemical reactions on electrode interfered with interactions between multilayers when the bias was larger than 0.5V, leading to retard deposition. Subsequent delivery experiments indicated that EFA during DNA deposition demonstrated superior DNA release. In contrast, no obvious improvements were observed for the groups using the EFA during chitosan deposition. Moreover, water contact angle experiments revealed different effects of electric fields on multilayer structure. Using EFA during DNA deposition led to a layered-form composition, whereas interpenetration of electrolytes was enhanced with the application of the electric field during chitosan deposition. For in vitro experiments, EFA during DNA deposition significantly enhanced in situ transfection performances of PEMs that the transgene expression levels were increased and the periods were extended, suggesting this method is potential to quantitatively and temporally improve substrate-mediated gene delivery. PMID- 26101818 TI - A multi-layered vascular scaffold with symmetrical structure by bi-directional gradient electrospinning. AB - Multi-layered scaffolds are advantageous in vascular tissue engineering, in consideration of better combination of biomechanics, biocompatibility and biodegradability than the scaffolds with single structure. In this study, a bi directional gradient electrospinning method was developed to fabricate poly(l lactide-co-caprolactone) (P(LLA-CL)), collagen and chitosan based tubular scaffold with multi-layered symmetrical structure. The multi-layered composite scaffold showed improved mechanical property and biocompatibility, in comparison to the blended scaffold using the same proportion of raw materials. Endothelialization on the multi-layered scaffold was accelerated owing to the bioactive surface made of pure natural materials. hSMCs growth showed the similar results because of its better biocompatibility. Additionally, fibers morphology change, pH value balance and long term mechanical support results showed that the gradient structure effectively improved biodegradability. PMID- 26101819 TI - Effect of cationic polyelectrolytes on the performance of paper diagnostics for blood typing. AB - We investigated the effect that two common types of cationic polyelectrolytes used in papermaking might have on the performance of paper diagnostics using blood typing as an example. The results were analyzed in terms of red blood cells (RBC) retention and antibody-antigen specificity. Two questions were addressed: (1) can poly(amido-amine) epichlorohydrin (PAE) typically used for paper wet strength affect the diagnostic performance? (2) can high molecular weight cationic polyacrylamide (CPAM) employed as retention aid enhance or affect the selectivity and sensitivity of paper diagnostics? A series of paper varying in type of fibers and drying process were constructed with PAE and tested for blood typing performance. Residual PAE has no significant effect on blood typing paper diagnostics under normal conditions. Positives are unaffected with PAE, while negatives lose slight sharpness as some RBCs are unselectively retained. CPAM, the most common retention aid, can also be used to retain cells and biomolecules on paper. Paper towel was treated with CPAM solutions varying in polymer concentration and charge density and tested for blood typing. We found that CPAM dried on paper can retain RBC. CPAM affects the negative tests by retaining non specifically individual RBC on fibers. RBC retention increases non-linearly with the CPAM charge density and concentration. As expected, wet CPAM retain RBCs at concentrations higher than 0.1wt%. As paper diagnostics are becoming a reality, more realistic papers than the Whatman filter paper will be engineered. This study provides guidance on how best use the required polymeric wet-strength and retention agents. PMID- 26101820 TI - Cyto/hemocompatible magnetic hybrid nanoparticles (Ag2S-Fe3O4) with luminescence in the near-infrared region as promising theranostic materials. AB - Small hybrid nanoparticles composed of highly biocompatible Ag2S quantum dots (QD) emitting in the near-infrared region and superparamagnetic iron oxide (SPION) are produced in a simple extraction method utilizing ligand exchange mechanism. Hybrid nanoparticles luminesce at the same wavelength as the parent QD, therefore an array of hybrid nanoparticles with emission between 840 and 912nm were easily produced. Such hybrid structures have (1) strong luminescence in the medical imaging window eliminating the autofluoresence of cells as effective optical probes, (2) strong magnetic response for magnetic targeting and (3) good cyto/hemocompatibility. An interesting size dependent cytotoxicity behavior was observed in HeLa and NIH/3T3 cell lines: smallest particles are internalized significantly more by both of the cell lines, yet showed almost no significant cytotoxicity in HeLa between 10 and 25MUg/mL Ag concentration but were most toxic in NIH/3T3 cells. Cell internalization and hence the cytotoxicity enhanced when cells were incubated with the hybrid nanoparticles under magnetic field, especially with the hybrid nanoparticles containing larger amounts of SPION in the hybrid composition. These results prove them as effective optical imaging agents and magnetic delivery vehicles. Combined with the known advantages of SPIONs as a contrast agent in MRI, these particles are a step forward for new theranostics for multimode imaging and magnetic targeting. PMID- 26101821 TI - Are We Digital or What? PMID- 26101823 TI - Trends in US Contact Lens Prescribing 2002 to 2014. AB - PURPOSE: To document contact lens prescribing patterns in the United States between 2002 and 2014. METHODS: A survey of contact lens prescribing trends was conducted each year between 2002 and 2014, inclusive. Randomly selected contact lens practitioners were asked to provide information relating to 10 consecutive contact lens fits between January and March each year. RESULTS: Over the 13-year survey period, 1650 survey forms were received from US practitioners representing details of 7702 contact lens fits. The mean (+/-SD) age of lens wearers was 33.6 (+/-15.2) years, of whom 65.2% were female. Rigid lens new fits decreased from 13.0% in 2002 to 9.4% in 2014. Across this period, silicone hydrogels have replaced mid water contact lens hydrogels as the soft lens material of choice. Toric lenses represented about 25 to 30% of all soft lens fits. Multifocal soft lenses are generally preferred to monovision. Daily disposable lens fits have recently increased, and in 2014, they represented 27.1% of all soft lens fits. Most lenses are prescribed on 1 to 2 weekly or monthly lens replacement regimen. Extended wear remains a minority lens wearing modality. The vast majority of those wearing reusable lenses use multipurpose lens care solutions. Lenses are mostly worn 7 d/wk. CONCLUSIONS: This survey has revealed prescribing trends and preferences in the United States over the past 13 years. PMID- 26101826 TI - Intramembrane protease PARL defines a negative regulator of PINK1- and PARK2/Parkin-dependent mitophagy. AB - Mutations in PINK1 and PARK2/Parkin are a main risk factor for familial Parkinson disease. While the physiological mechanism of their activation is unclear, these proteins have been shown in tissue culture cells to serve as a key trigger for autophagy of depolarized mitochondria. Here we show that ablation of the mitochondrial rhomboid protease PARL leads to retrograde translocation of an intermembrane space-bridging PINK1 import intermediate. Subsequently, it is rerouted to the outer membrane in order to recruit PARK2, which phenocopies mitophagy induction by uncoupling agents. Consistent with a role of this retrograde translocation mechanism in neurodegenerative disease, we show that pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. Altogether we suggest that PARL is an important intrinsic player in mitochondrial quality control, a system substantially impaired in Parkinson disease as indicated by reduced removal of damaged mitochondria in affected patients. PMID- 26101827 TI - Motor sequencing abnormalities are the trait marking neurological soft signs of schizophrenia. AB - We describe the profile of NSS across the one-year course of schizophrenia in 84 Nigerian first-episode patients. They were assessed at baseline and 3 monthly for 12 months using the Neurological Evaluation Scale and the Positive and Negative Syndrome Scale (PANSS), and treated with flupenthixol decanoate. The pattern of NSS total and sub-category scores obtained from repeated measurements were investigated for responders (>= 50% reduction of baseline PANSS scores) and non responders using the method of repeated measures analysis of variance. Trait-like features of NSS categories were quantified using intraclass correlation coefficients (ICCs). NSS were present in 96.4% of the patients at baseline (mean 21.5 +/- 11.1). The motor-sequencing sub-category was found unrelated to changes in schizophrenia psychopathology with treatment (positive, r=0.19, p=0.136., negative, r=0.12, p=0.350; disorganization, r=0.16, p=0.245; overall, r=0.20, p=0.112). Regardless of decrements in psychopathology, motor-sequencing scores remained relatively unchanged across the course of the disease (main effects: 'responders' F=2.44, p=0.930, 'poor responders' F=0.27, p=0.764, entire sample F=1.87, p=0.160). ICC was "substantial" at 0.8 (95% C.I=0.6-0.9). Only the motor sequencing NSS appear to be trait marker of schizophrenia in this sample. Other NSS seem to reflect symptomatic states of the disorder. PMID- 26101828 TI - Neuroprotective effect of combined therapy with hyperbaric oxygen and madopar on 6-hydroxydopamine-induced Parkinson's disease in rats. AB - Parkinson's disease (PD) is a common movement disorder in the elderly. In the present study, we examined whether the combination of hyperbaric oxygen (HBO) and madopar therapy provided a neuroprotective effect on dopaminergic neurons in the substantia nigra using a rat model of PD. Rotational assessments revealed that both HBO and combination therapy significantly attenuated apomorphine-induced turning in PD rats. Our results indicated that the combination therapy increased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities and reduced the malondialdehyde (MDA) content in the SN. Furthermore, the combination therapy resulted in significant protection against the loss of neurons, and specifically tyrosine hydroxylase (TH)-positive neurons, in the SN and also alleviated the production of glial fibrillary acidic protein (GFAP). The levels of Bcl-2 were increased and Bax were decreased following the HBO or combination therapy. In brief, the neuroprotective effect of combined therapy with HBO and madopar against 6-OHDA-induced PD rats may rely on its ability to reduce oxidative stress and protect against Bax/Bcl-2-mediated apoptosis. PMID- 26101829 TI - Progesterone alleviates acute brain injury via reducing apoptosis and oxidative stress in a rat experimental subarachnoid hemorrhage model. AB - This study aimed to investigate the therapeutic effect of progesterone on acute brain injury after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage was induced in male Sprague-Dawley rats (n=72) by endovascular perforation. Progesterone (8 mg/kg or 16 mg/kg) was administered to rats at 1, 6, and 12h after SAH. Mortality, neurologic deficits, cell apoptosis, expression of apoptotic markers, the level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were assayed at 24h after experimental SAH. Mortality, cell apoptosis and the expression of caspase-3 were decreased, and improved neurological function was observed in the progesterone-treated SAH rats. Further, exploration demonstrated that progesterone significantly reduced the ratio of Bax/Bcl-2 and attenuated the release of cytochrome c from mitochondria. Progesterone also induced anti-oxidative effects by elevating the activity of SOD and decreasing MDA content after SAH. Furthermore, dose-response relationships for progesterone treatment were observed, and high doses of progesterone enhanced the neuroprotective effects. Progesterone treatment could alleviate acute brain injury after SAH by inhibiting cell apoptosis and decreasing damage due to oxidative stress. The mechanism involved in the anti-apoptotic effect was related to the mitochondrial pathway. These results indicate that progesterone possesses the potential to be a novel therapeutic agent for the treatment of acute brain injury after SAH. PMID- 26101830 TI - Glycine transporter GlyT1, but not GlyT2, is expressed in rat dorsal root ganglion--Possible implications for neuropathic pain. AB - Glycinergic inhibitory neurotransmission plays a pivotal role in the development of neuropathic pain. The glycine concentration in the synaptic cleft is controlled by the glycine transporters GlyT1 and GlyT2. GlyT1 is expressed throughout the central nervous system, while GlyT2 is exclusively located in glycinergic neurons. Aim of the present study was to investigate whether GlyTs are also expressed in the peripheral sensory nervous system and whether their expression is modulated in experimental neuropathic pain. Neuropathic pain was induced in male Wistar rats by Chronic Constriction Injury (CCI) and verified by assessment of mechanical allodynia (von Frey method). Expression patterns of GlyTs and the glycine binding subunit NR1 of the N-methyl-d-aspartate (NMDA) receptor in the spinal cord and dorsal root ganglia (DRG) were analyzed by Western blot analysis, PCR and immunohistochemistry. While both GlyT1 and GlyT2 were detected in the spinal cord, only GlyT1, but not GlyT2, was detected in DRG. Immunofluorescence revealed a strictly neuronal localization of GlyT1 and a co localization of GlyT1 and NR1 in DRG. Compared to sham procedure, spinal cord and DRG expression of GlyT1 was not altered and NR1 was unchanged in DRG 12 days after CCI. GlyT1, but not GlyT2, is expressed in the peripheral sensory nervous system. The co-expression of GlyT1 and NMDA receptors in DRG suggests that GlyT1 regulates glycine concentration at the glycine binding site of the NMDA receptor. Differential regulation of GlyT1 expression in the spinal cord or DRG, however, does not seem to be associated with the development of neuropathic pain. PMID- 26101831 TI - Tight binding of NAP-22 with acidic membrane lipids. AB - Recovery of various signal transduction molecules in the detergent-resistant membrane microdomain (DRM) fraction suggests the importance of this region in cellular functions. Insolubility of the outer leaflet of DRM to the non-ionic detergent is ascribed to the tight association of cholesterol and sphingolipid. Since, poor localization of sphingolipid is observed in the inner leaflet, the physicochemical background of the insolubility of the inner leaflet is hence still an enigma. NAP-22 (also called BASP1 or CAP-23) is a neuron-enriched calmodulin-binding protein and one of the major proteins in the DRM of the neuronal cell membrane. A previous study showed the presence of several lipids in a NAP-22 fraction after the process of extraction and column chromatography. In this study, the effect of lipid extraction on NAP-22 was studied through native gel electrophoresis, ultracentrifugation, and electron microscopic observation. The mobility of NAP-22 in native-PAGE was shifted from low to high after delipidation. Delipidated NAP-22 bound phosphatidylserine (PS), phosphatidylinosotol, and ganglioside. Some part of the mixture of PS and NAP-22 was recovered in the insoluble fraction after Triton X-100 treatment and the addition of cholesterol enhanced the amount of NAP-22 in the insoluble fraction. PMID- 26101832 TI - Alterations in the functional connectivity of a verbal working memory-related brain network in patients with left temporal lobe epilepsy. AB - The aim of this study was to investigate the alterations in a verbal working memory (VWM)-related network in left temporal lobe epilepsy (lTLE) at rest. We evaluated 14 patients with lTLE and 14 control subjects by resting-state functional connectivity (RSFC). The region of interest was defined by the voxel with the highest Z-score during a VWM task according to functional magnetic resonance imaging in 16 healthy volunteers. Our study revealed that the network of RSFC was similar to the task-induced network in the healthy volunteers. Moreover, the patients with lTLE exhibited significantly decreased RSFC in the bilateral middle frontal gyrus, the inferior frontal gyrus and the inferior parietal lobule at rest compared to the control subjects. We found no significant correlation between the mean reaction time of the accurate responses in a 2-back task and the mean z-values within the regions that exhibited significant differences in RSFC at the individual level. The alterations in FCs of VWM related network in lTLE suggested that epileptiform discharges can damage the brain regions, both local focus and remote areas and that the alterations were not associated with VWM performance. PMID- 26101833 TI - Multifunctionalization of wool fabrics through nanoparticles: A chemical route towards smart textiles. AB - A new approach towards the design of smart nanotextiles with innovative properties is presented. Silica (SiO2), titania (TiO2), and silver (Ag) nanoparticles (NPs), were synthesized without the use of any toxic organic compound and then were used, alone and in combination, to functionalize wool fabrics. Electrostatic forces, influenced by a low pH of the solutions, allowed the interactions between wool fabrics and NPs, enabling a robust functionalization. This was verified by X-ray microfluorescence and visualized by scanning electron microscopy measurements. The antibacterial Ag NPs were embedded in a polymer, alginic acid, to reduce the possible side effect due to their direct contact with the skin. SiO2 NPs, instead, were used to change the hydrophilicity of wool while the functionalization with TiO2 NPs was chosen to provide self-cleaning properties. The antibacterial activity of the fabrics was studied against the bacteria Escherichia coli, while the hydrophilicity of wool was studied by contact angle measurements and the self-cleaning properties were tested by estimating the visible discoloring of a dye stain under sunlight irradiation. Interestingly the combination of three different types of NPs provided the best results. SiO2 and Ag made the wool superhydrophilic providing at the same time the best antibacterial properties, while fabrics with titania (alone or in combination) were hydrophobic and showed the best self-cleaning properties. PMID- 26101834 TI - Simple preparation of Pd-NP/polythiophene nanospheres for heterogeneous catalysis. AB - A very simple preparation was developed for catalytically active Pd-nanoparticles (Pd-NPs) decorating polythiophene conducting polymer nanospheres by the redox reaction between PdCl4(2-) ion and 2-thiophenemethanol (2-TPM) in an aqueous solution at room temperature. 2-TPM polymerized to form polythiophene nanospheres in the presence of PdCl4(2-) ions, reduced to Pd-NPs without the need for extra reducing agents or organic surface capping ligands for sub-20 nm Pd-NPs that uniformly cover polythiophene nanospheres whose dimensions range from 120 nm to 200 nm. The Pd-NP/polythiophene nanospheres were characterized by scanning transmission electron microscopy (STEM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), and inductively-coupled plasma atomic emission spectroscopy (ICP-AES). The Pd-NP/polythiophene nanospheres were found to be an excellent catalyst for Suzuki-Miyaura cross-coupling reaction for a wide range of substrates under mild aerobic reaction conditions. PMID- 26101835 TI - Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. AB - OBJECTIVE: To detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD). METHODS: We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population-based allele frequencies. RESULTS: Overall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered. INTERPRETATION: Targeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease-related mechanisms and potential therapies. PMID- 26101836 TI - High- and low-frequency transcutaneous electrical nerve stimulation does not reduce experimental pain in elderly individuals. AB - Despite its widespread clinical use, the efficacy of transcutaneous electrical nerve stimulation (TENS) remains poorly documented in elderly individuals. In this randomized, double-blind crossover study, we compared the efficacy of high frequency (HF), low-frequency (LF), and placebo (P) TENS in a group of 15 elderly adults (mean age: 67 +/- 5 years). The effect of HF-, LF-, and P-TENS was also evaluated in a group of 15 young individuals (26 +/- 5 years; same study design) to validate the effectiveness of the TENS protocols that were used in the elderly group. Each participant came to the laboratory on 3 separate occasions to receive, in random order, HF-, LF-, and P-TENS. Pain intensity and pain perception thresholds were assessed before, during, and after TENS, using an experimental heat pain paradigm. For the young group, there was a significant decrease in pain intensity during and after HF- and LF-TENS when compared with baseline, with both HF- and LF-TENS being superior to P-TENS. In the older group, HF- and LF-TENS did not reduce pain when compared with baseline and no difference was observed between the 2 active TENS sessions and P-TENS. High-frequency, LF-, and P-TENS all increased pain thresholds in young individuals, whereas in older individuals, only LF-TENS increased pain thresholds. Taken together, these results suggest that TENS is effective in young, but not in older, individuals. Future studies should be conducted to confirm these results in pain populations and to identify strategies that could enhance the effect of TENS in the elderly. PMID- 26101837 TI - The organisation of spinoparabrachial neurons in the mouse. AB - The anterolateral tract (ALT), which originates from neurons in lamina I and the deep dorsal horn, represents a major ascending output through which nociceptive information is transmitted to brain areas involved in pain perception. Although there is detailed quantitative information concerning the ALT in the rat, much less is known about this system in the mouse, which is increasingly being used for studies of spinal pain mechanisms because of the availability of genetically modified lines. The aim of this study was therefore to determine the extent to which information about the ALT in the rat can be extrapolated to the mouse. Our results suggest that as in the rat, most lamina I ALT projection neurons in the lumbar enlargement can be retrogradely labelled from the lateral parabrachial area, that the majority of these cells (~ 90%) express the neurokinin 1 receptor (NK1r), and that these are larger than other NK1r-expressing neurons in this lamina. This means that many lamina I spinoparabrachial cells can be identified in NK1r-immunostained sections from animals that have not received retrograde tracer injections. However, we also observed certain species differences, in particular we found that many spinoparabrachial cells in laminae III and IV lack the NK1r, meaning that they cannot be identified based solely on the expression of this receptor. We also provide evidence that the majority of spinoparabrachial cells are glutamatergic and that some express substance P. These findings will be important for studies designed to unravel the complex neuronal circuitry that underlies spinal pain processing. PMID- 26101838 TI - Acquired right diaphragmatic hernia following pediatric living donor orthotopic liver transplantation. AB - ADH following OLT is a rare entity. Herein, we report a case of Alagille syndrome who developed ADH secondary to OLT, and possible etiological causes are discussed in light of the literature. PMID- 26101839 TI - Using Molecular Dynamics Simulations as an Aid in the Prediction of Domain Swapping of Computationally Designed Protein Variants. AB - In standard implementations of computational protein design, a positive-design approach is used to predict sequences that will be stable on a given backbone structure. Possible competing states are typically not considered, primarily because appropriate structural models are not available. One potential competing state, the domain-swapped dimer, is especially compelling because it is often nearly identical with its monomeric counterpart, differing by just a few mutations in a hinge region. Molecular dynamics (MD) simulations provide a computational method to sample different conformational states of a structure. Here, we tested whether MD simulations could be used as a post-design screening tool to identify sequence mutations leading to domain-swapped dimers. We hypothesized that a successful computationally designed sequence would have backbone structure and dynamics characteristics similar to that of the input structure and that, in contrast, domain-swapped dimers would exhibit increased backbone flexibility and/or altered structure in the hinge-loop region to accommodate the large conformational change required for domain swapping. While attempting to engineer a homodimer from a 51-amino-acid fragment of the monomeric protein engrailed homeodomain (ENH), we had instead generated a domain-swapped dimer (ENH_DsD). MD simulations on these proteins showed increased B-factors derived from MD simulation in the hinge loop of the ENH_DsD domain-swapped dimer relative to monomeric ENH. Two point mutants of ENH_DsD designed to recover the monomeric fold were then tested with an MD simulation protocol. The MD simulations suggested that one of these mutants would adopt the target monomeric structure, which was subsequently confirmed by X-ray crystallography. PMID- 26101840 TI - Dividing and Conquering the Family of RNA Recognition Motifs: A Representative Case Based on hnRNP L. PMID- 26101841 TI - Over-Expression Analysis of All Eight Subunits of the Molecular Chaperone CCT in Mammalian Cells Reveals a Novel Function for CCTdelta. AB - Chaperonin containing tailless complex polypeptide 1 (CCT) forms a classical chaperonin barrel structure where two rings of subunits surround a central cavity. Each ring consists of eight distinct subunits, creating a complex binding interface that makes CCT unique among the chaperonins. In addition to acting as a multimeric chaperonin, there is increasing evidence indicating that the CCT subunits, when monomeric, possess additional functions. Here we assess the role of the CCT subunits individually, using a GFP (green fluorescent protein) tagging approach to express each of the subunits in their monomeric form in cultured mammalian cells. Over-expression of CCTdelta, but not the other seven CCT subunits, results in the appearance of numerous protrusions at the cell surface. Two point mutations, one in the apical domain and one in the ATP binding pocket of CCTdelta, that abolish protrusion formation have been identified, consistent with the apical domain containing a novel interaction site that is influenced by the ATPase activity in the equatorial domain. Structured illumination microscopy, together with sub-cellular fractionation, reveals that only the wild-type CCTdelta is associated with the plasma membrane, thus connecting spatial organization with surface protrusion formation. Expression of the equivalent subunit in yeast, GFP-Cct4, rescues growth of the temperature-sensitive strain cct4-1 at the non-permissive temperature, indicative of conserved subunit specific activities for CCTdelta. PMID- 26101843 TI - Which journal will take the best care of my paper? PMID- 26101842 TI - The Structure of Escherichia coli TcdA (Also Known As CsdL) Reveals a Novel Topology and Provides Insight into the tRNA Binding Surface Required for N(6) Threonylcarbamoyladenosine Dehydratase Activity. AB - Escherichia coli TcdA (also known as CsdL) was previously shown to catalyze the ATP-dependent dehydration/cyclization of hypermodified tRNA N(6) threonylcarbamoyladenosine into further cyclic N(6)-threonylcarbamoyladenosine. In this study, we report the X-ray crystal structures of E. coli TcdA with either AMP or ATP bound. The AMP/ATP-bound N-terminal sub-domain of TcdA resembles the ATP-binding Rossmann fold of E. coli ThiF and MoeB that are enzymes respectively taking part in the biosynthesis of thiamine and molybdopterin; however, the remaining C-terminal sub-domain of TcdA adopts a structure unrelated to any other known folds. In TcdA, the ATP-utilizing adenylation of tRNA N(6) threonylcarbamoyladenosine and a subsequent thioester formation via an active cysteine, similar to the mechanisms in ThiF and MoeB, could take place for the dehydratase function. Analysis of the structure with sequence alignment suggests the disordered Cys234 of TcdA as the most likely catalytic residue. The structure further indicates that the C-terminal sub-domain can provide a binding interface for the tRNA substrate. Binding study using the surface mutants of TcdA and tRNA reveals that the positively charged regions of mainly the C-terminal sub-domain are important for the tRNA recognition. PMID- 26101844 TI - Probing the roles of conserved residues in uridyltransferase domain of Escherichia coli K12 GlmU by site-directed mutagenesis. AB - N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is a bifunctional enzyme that catalyzes both acetyltransfer and uridyltransfer reactions in the prokaryotic UDP-GlcNAc biosynthesis pathway. Our previous study demonstrated that the uridyltransferase domain of GlmU (tGlmU) exhibited a flexible substrate specificity, which could be further applied in unnatural sugar nucleotides preparation. However, the structural basis of tolerating variant substrates is still not clear. Herein, we further investigated the roles of several highly conserved amino acid residues involved in substrate binding and recognition by structure- and sequence-guided site-directed mutagenesis. Out of total 16 mutants designed, tGlmU Q76E mutant which had a novel catalytic activity to convert CTP and GlcNAc-1P into unnatural sugar nucleotide CDP-GlcNAc was identified. Furthermore, tGlmU Y103F and N169R mutants were also investigated to have enhanced uridyltransferase activities compared with wide-type tGlmU. PMID- 26101846 TI - Drosophila sperm surface alpha-L-fucosidase interacts with the egg coats through its core fucose residues. AB - Sperm-oocyte interaction during fertilization is multiphasic, with multicomponent events, taking place between egg's glycoproteins and sperm surface receptors. Protein-carbohydrate complementarities in gamete recognition have observed in cases throughout the whole evolutionary scale. Sperm-associated alpha-L fucosidases have been identified in various organisms. Their wide distribution and known properties reflect the hypothesis that fucose and alpha-L-fucosidases have fundamental function(s) during gamete interactions. An alpha-L-fucosidase has been detected as transmembrane protein on the surface of spermatozoa of eleven species across the genus Drosophila. Immunofluorescence labeling showed that the protein is localized in the sperm plasma membrane over the acrosome and the tail, in Drosophila melanogaster. In the present study, efforts were made to analyze with solid phase assays the oligosaccharide recognition ability of fruit fly sperm alpha-L-fucosidase with defined carbohydrate chains that can functionally mimic egg glycoconjugates. Our results showed that alpha-L fucosidase bound to fucose residue and in particular it prefers N-glycans carrying core alpha1,6-linked fucose and core alpha1,3-linked fucose in N-glycans carrying only a terminal mannose residue. The ability of sperm alpha-L-fucosidase to bind to the micropylar chorion and to the vitelline envelope was examined in in vitro assays in presence of alpha-L-fucosidase, either alone or in combination with molecules containing fucose residues. No binding was detected when alpha-L fucosidase was pre-incubated with fucoidan, a polymer of alpha-L-fucose and the monosaccharide fucose. Furthermore, egg labeling with anti-horseradish peroxidase, that recognized only core alpha1,3-linked fucose, correlates with alpha-L-fucosidase micropylar binding. Collectively, these data support the hypothesis of the potential role of this glycosidase in sperm-egg interactions in Drosophila. PMID- 26101845 TI - Pain Sensitivity and Pain Catastrophizing Are Associated With Persistent Pain and Disability After Lumbar Spine Surgery. AB - OBJECTIVE: To examine whether pain sensitivity and pain catastrophizing are associated with persistent pain and disability after lumbar spine surgery. DESIGN: Prospective observational cohort study. SETTING: Academic medical center. PARTICIPANTS: Patients (N=68; mean age, 57.9+/-13.1y; 40 women [58.8%]) undergoing spine surgery for a degenerative condition from March 1, 2012 to April 30, 2013 were assessed 6 weeks, 3 months, and 6 months after surgery. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The main outcome measures were persistent back pain intensity, pain interference, and disability. Patients with persistent back pain intensity, pain interference, or disability were identified as those patients reporting Brief Pain Inventory scores >=4 and Oswestry Disability Index scores >=21 at all postoperative time points. RESULTS: From 6 weeks to 6 months after surgery, approximately 12.9%, 24.2%, and 46.8% of patients reported persistent back pain intensity, pain interference, or disability, respectively. Increased pain sensitivity at 6 weeks was associated with having persistent back pain intensity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.0-4.1) after surgery. Increased pain catastrophizing at 6 weeks was associated with having persistent back pain intensity (OR, 1.1; 95% CI, 1.0 1.2), pain interference (OR, 1.1; 95% CI, 1.0-1.2), and disability (OR, 1.3; 95% CI, 1.1-1.4). An interaction effect was not found between pain sensitivity and pain catastrophizing on persistent outcomes (P>.05). CONCLUSIONS: The findings suggest the importance of early postoperative screening for pain sensitivity and pain catastrophizing to identify patients at risk for poor postoperative pain intensity, pain interference, and/or disability outcomes. Future research should consider the benefit of targeted therapeutic strategies for patients with these postoperative prognostic factors. PMID- 26101847 TI - A Fas associated factor negatively regulates anti-bacterial immunity by promoting Relish degradation in Bombyx mori. AB - Negative regulation is required to keep NF-kappaB-dependent immune response under tight control. In previous study, we have identified a Fas associated factor (FAF) family member in Bombyx mori, BmFAF, and proposed it may act as a negative regulator in immune response. In this study, we found knock-down of BmFAF by RNAi led to a remarkable increase in transcriptional level of several antimicrobial peptide genes, including BmCecropinA1 and BmMoricin, and higher survival rate to Gram-negative bacterial infection. We also confirmed the regulatory role of BmFAF in suppressing NF-kappaB-dependent transcription by employing an inducible promoter in BmE cells. Consistent with these physiological phenotypes, BmFAF suppressed the activity of the essential transcription factor, Relish, in IMD signaling pathway by promoting its proteasomal degradation through direct interaction. In addition, by constructing various truncation mutants, we further demonstrated that UBA domain in BmFAF is required for the inhibitory role, and potential ubiquitination also occurs in this domain. Taken together, our results suggest that BmFAF is a negative regulator of IMD pathway by mediating degradation of Relish. PMID- 26101848 TI - Heazlewoodite, Ni3S2: A Potent Catalyst for Oxygen Reduction to Water under Benign Conditions. AB - Electrodeposited thin films and nanoparticles of Ni3S2 are highly active, poison- and corrosion-resistant catalysts for oxygen reduction to water at neutral pH. In pH 7 phosphate buffer, Ni3S2 displays catalytic onset at 0.8 V versus the reversible hydrogen electrode, a Tafel slope of 109 mV decade(-1), and high faradaic efficiency for four-electron reduction of O2 to water. Under these conditions, the activity and stability of Ni3S2 exceeds that of polycrystalline platinum and manganese, nickel, and cobalt oxides, illustrating the catalytic potential of pairing labile first-row transition metal active sites with a more covalent sulfide host lattice. PMID- 26101849 TI - Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways. AB - Rodent models implicate metabotropic glutamate receptors (mGluRs) and downstream signaling pathways in addictive behaviors through metaplasticity. One way mGluRs can influence synaptic plasticity is by regulating the local translation of AMPA receptor trafficking proteins via eukaryotic elongation factor 2 (eEF2). However, genetic variation in this pathway has not been examined with human alcohol use phenotypes. Among a sample of adults living in Detroit, Michigan (Detroit Neighborhood Health Study; n = 788; 83% African American), 206 genetic variants across the mGluR-eEF2-AMPAR pathway (including GRM1, GRM5, HOMER1, HOMER2, EEF2K, MTOR, EIF4E, EEF2, CAMK2A, ARC, GRIA1 and GRIA4) were found to predict number of drinking days per month (corrected P-value < 0.01) when considered as a set (set based linear regression conducted in PLINK). In addition, a CpG site located in the 3'-untranslated region on the north shore of EEF2 (cg12255298) was hypermethylated in those who drank more frequently (P < 0.05). Importantly, the association between several genetic variants within the mGluR-eEF2-AMPAR pathway and alcohol use behavior (i.e., consumption and alcohol-related problems) replicated in the Grady Trauma Project (GTP), an independent sample of adults living in Atlanta, Georgia (n = 1034; 95% African American), including individual variants in GRM1, GRM5, EEF2, MTOR, GRIA1, GRIA4 and HOMER2 (P < 0.05). Gene based analyses conducted in the GTP indicated that GRM1 (empirical P < 0.05) and EEF2 (empirical P < 0.01) withstood multiple test corrections and predicted increased alcohol consumption and related problems. In conclusion, insights from rodent studies enabled the identification of novel human alcohol candidate genes within the mGluR-eEF2-AMPAR pathway. PMID- 26101850 TI - Translational utility of rodent hippocampal auditory gating in schizophrenia research: a review and evaluation. AB - Impaired gating of the auditory evoked P50 potential is one of the most pharmacologically well-characterized features of schizophrenia. This deficit is most commonly modeled in rodents by implanted electrode recordings from the hippocampus of the rodent analog of the P50, the P20-N40. The validity and effectiveness of this tool, however, has not been systematically reviewed. Here, we summarize findings from studies that have examined the effects of pharmacologic modulation on gating of the rodent hippocampal P20-N40 and the human P50. We show that drug effects on the P20-N40 are highly predictive of human effects across similar dose ranges. Furthermore, mental status (for example, anesthetized vs alert) does not appear to diminish the predictive capacity of these recordings. We then discuss hypothesized neuropharmacologic mechanisms that may underlie gating effects for each drug studied. Overall, this review supports continued use of hippocampal P20-N40 gating as a translational tool for schizophrenia research. PMID- 26101851 TI - Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study. AB - Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10,422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development. PMID- 26101852 TI - Developmental changes in gamma-aminobutyric acid levels in attention deficit/hyperactivity disorder. AB - While the neurobiological basis and developmental course of attention deficit/hyperactivity disorder (ADHD) have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD. This study examined the changes in cerebral levels of GABA+, glutamate and glutamine in children and adults with ADHD using edited magnetic resonance spectroscopy. We studied 89 participants (16 children with ADHD, 19 control children, 16 adults with ADHD and 38 control adults) in a subcortical voxel (children and adults) and a frontal voxel (adults only). ADHD adults showed increased GABA+ levels relative to controls (P = 0.048), while ADHD children showed no difference in GABA+ in the subcortical voxel (P > 0.1), resulting in a significant age by disorder interaction (P = 0.026). Co-varying for age in an analysis of covariance model resulted in a nonsignificant age by disorder interaction (P = 0.06). Glutamine levels were increased in children with ADHD (P = 0.041), but there was no significant difference in adults (P > 0.1). Glutamate showed no difference between controls and ADHD patients but demonstrated a strong effect of age across both groups (P < 0.001). In conclusion, patients with ADHD show altered levels of GABA+ in a subcortical voxel which change with development. Further, we found increased glutamine levels in children with ADHD, but this difference normalized in adults. These observed imbalances in neurotransmitter levels are associated with ADHD symptomatology and lend new insight in the developmental trajectory and pathophysiology of ADHD. PMID- 26101854 TI - Age cutoff for Epstein-Barr virus-positive diffuse large B-cell lymphoma--is it necessary? AB - Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly (EBV+ DLBCL-e) is a molecularly distinct variant of DLBCL, characterized by a monoclonal B-cell proliferation that occurs in patients >50 years of age without a history or clinicopathologic evidence of immunodeficiency. However, patients with EBV+ DLBCL younger than 50-years-old also exist in Western countries. We evaluated the clinicopathologic, immunophenotypic and genetic features in Cacausian patients with EBV+ DLBCL who are <=50 years of age and compared this patient group to patients who are >50 years. In patients who are <=50 years, less frequent expression of BCL6 and a trend of more frequent expression of CD30 and pSTAT3 were found in patients with EBV+ DLBCL. In patients who are >50 years, common expression of CD30, p50, pSTAT3 and less frequent expression of BCL6 were observed. Older patients also more commonly had a poor performance status (ECOG>=2). Comparing EBV+ DLBCL patients in <=50 years versus >50 years, both groups had similar clinicopathologic, immunophenotypic and genetic features. Gene expression profiling, microRNA profiling and treatment outcome of the younger patients with EBV+ DLBCL was not distinctive from tumors in older patients. Based on our data, we suggest that the arbitrary age cutoff for EBV+ DLBCL is unnecessary and should be eliminated in the WHO lymphoma classification scheme. PMID- 26101855 TI - beta-catenin activation drives thymoma initiation and progression in mice. AB - Thymoma is the most commonly identified cancer in the anterior mediastinum. To date, the causal mechanism that drives thymoma progression is not clear. Here, we generated K5-a??N64Ctnnb1/ERT2 transgenic mice, which express an N-terminal deletion mutant of beta-catenin fused to a mutated ligand-binding domain of estrogen receptor (ERT2) under the control of the bovine cytokeratin 5 (K5) promoter. The transgenic mouse lines named Tg1 and Tg4 were characterized. Forced expression of a??N64Ctnnb1/ERT2 in the Tg1 and Tg4 mice developed small thymoma lesions in response to tamoxifen treatment. In the absence of tamoxifen, the Tg1 mice exhibited leaky activation of beta-catenin, which activated the TOP-Gal transgene and Wnt/beta-catenin-targeted genes. As the Tg1 mice aged in the absence of tamoxifen, manifest thymomas were found at 10-12 months. Interestingly, we detected loss of AIRE and increase of p63 in the thymomas of Tg1 mice, similar to that observed in human thymomas. Moreover, the beta5t protease subunit, which was reported as a differential marker for human type B3 thymoma, was expressed in the Tg1 thymomas. Thus, the Tg1 mice generated in this study accurately mimic the characteristics of human thymomas and may serve as a model for understanding thymoma pathogenesis. PMID- 26101856 TI - P73 tumor suppressor and its targets, p21 and PUMA, are required for madin-darby canine kidney cell morphogenesis by maintaining an appropriate level of epithelial to mesenchymal transition. AB - P73, a member of p53 tumor suppressor family, plays a crucial role in tumor suppression and neural development. Due to the usage of two promoters, p73 is expressed as two isoforms, TAp73 and a??Np73, with opposing functions. Here, we investigated the potential role of p73 in epithelial polarity and morphogenesis by using Madin-Darby canine kidney (MDCK) cells as a model system. We found that knockdown of TAp73 enhances, whereas knockdown of a??Np73 inhibits, MDCK cell proliferation and migration in two-dimensional (2-D) culture. We also found that knockdown of TAp73, but not a??Np73, disrupts cyst formation of MDCK cells in three-dimensional (3-D) culture. Interestingly, we found that p21 and PUMA, both of which are induced by TAp73 but repressed by a??Np73, are required for suppressing cell proliferation and migration in 2-D culture and for MDCK ce ll morphogenesis in 3-D culture. Finally, we showed knockdown of TAp73, p21 or PUMA induces epithelial to mesenchymal transition (EMT) with a decrease in E-cadherin and an increase in EMT transcription factors. Together, our data suggest that TAp73, p21 and PUMA play a critical role in modulating MDCK cell morphogenesis by maintaining an appropriate level of the EMT. PMID- 26101857 TI - Involvement of cellular metabolism in age-related LTP modifications in rat hippocampal slices. AB - Recent studies emphasized crucial role of astrocytic glycogen metabolism in regulation of synaptic transmission and plasticity in young animals. However, the interplay between age-related synaptic plasticity impairments and changes in energetic metabolism remains obscure. To address this issue, we investigated, in hippocampal slices of young (one month) and aged rats (20-22-months), the impact of glycogen degradation inhibition on LTP, mRNA expression for glycogen metabolism enzymes and morphology of dendritic spines. We show that, whereas in young hippocampi, inhibition of glycogen phosphorolysis disrupts the late phase of LTP in the Schaffer collateral-CA1 pathway, in aged rats, blockade of glycogen phosphorylase tends to enhance it. Gene expression for key energy metabolism enzymes, such as glycogen synthase and phosphorylase and glutamine synthetase showed marked differences between young and aged groups and changes in expression of these enzymes preceded plasticity phenomena. Interestingly, in the aged group, a prominent expression of these enzymes was found also in neurons. Concluding, we show that LTP in the considered pathway is differentially modulated by metabolic processes in young and aging animals, indicating a novel venue of studies aiming at preventing cognitive decline during aging. PMID- 26101859 TI - [Early Rehabilitation--A Step Child of Psychiatry]. PMID- 26101860 TI - [Psychiatric Intensive Care Units--Pro]. PMID- 26101858 TI - APOepsilon2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study. AB - Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. beta-amyloid neuritic plaques (Abeta-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOepsilon4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOepsilon2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOepsilon2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology. PMID- 26101861 TI - [Psychiatric Intensive Care Units--Contra]. PMID- 26101862 TI - [Cost-Effectiveness of the Treatment of Depression in Old Age]. AB - OBJECTIVE: To conduct a systematic literature review of cost-effectiveness studies evaluating the treatment of depression in old age. METHODS: Systematic literature search in electronic databases in March 2014. RESULTS: Nine studies were included in the review. They were conducted in the Netherlands, the United Kingdom and the United States. The studies investigated psychological interventions (N = 3), pharmacotherapy (N = 1), and integrated care models (N = 5). The results varied greatly. CONCLUSION: The variation of the results in the included studies does not permit generalized conclusions, especially not for the widespread and recommended pharmacotherapy. Cost-effectiveness of psychological interventions and integrated care programs differed depending on the details of the program designs. PMID- 26101863 TI - [Report of the Working Group of Physician Executives of Psychiatry and Psychotherapy Clinics in German General Hospitals]. PMID- 26101864 TI - [Report of the Federal Directors Conference]. PMID- 26101865 TI - Obituary: Giulio Jori, 1939-2014. PMID- 26101866 TI - Successful and Safe Long-Term Standard Antiviral Therapy in a Patient with "Explosive" Immune Response in Course of HCV-Related Liver Cirrhosis. AB - Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin's lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen. PMID- 26101867 TI - Hepatoma-Derived Growth Factor: Its Possible Involvement in the Progression of Hepatocellular Carcinoma. AB - The development of hepatocellular carcinoma (HCC) is an important complication of viral infection induced by hepatitis virus C, and our major research theme is to identify a new growth factor related to the progression of HCC. HDGF (hepatoma derived growth factor) is a novel growth factor that belongs to a new gene family. HDGF was initially purified from the conditioned medium of a hepatoma cell line. HDGF promotes cellular proliferation as a DNA binding nuclear factor and a secreted protein acting via a receptor-mediated pathway. HDGF is a unique multi-functional protein that can function as a growth factor, angiogenic factor and anti-apoptotic factor and it participates in the development and progression of various malignant diseases. The expression level of HDGF may be an independent prognostic factor for predicting the disease-free and overall survival in patients with various malignancies, including HCC. Furthermore, the overexpression of HDGF promotes the proliferation of HCC cells, while a reduction in the HDGF expression inhibits the proliferation of HCC cells. This article provides an overview of the characteristics of HDGF and describes the potential role of HDGF as a growth-promoting factor for HCC. PMID- 26101868 TI - Expression Profiling of Circulating MicroRNAs in Canine Myxomatous Mitral Valve Disease. AB - MicroRNAs (miRNAs) are small non-coding RNAs that have shown promise as noninvasive biomarkers in cardiac disease. This study was undertaken to investigate the miRNA expression profile in dogs with myxomatous mitral valve disease (MMVD). 277 miRNAs were quantified using RT-qPCR from six normal dogs (American College of Veterinary Internal Medicine Stage A), six dogs with MMVD mild to moderate cardiac enlargement (ACVIM Stage B1/B2) and six dogs with MMVD and congestive heart failure (ACVIM Stage C/D). Eleven miRNAs were differentially expressed (False Discovery Rate < 0.05). Dogs in Stage B1/B2 or C/D had four upregulated miRNAs, including three cfa-let-7/cfa-miR-98 family members, while seven others were downregulated, compared to Stage A. Expression of six of the 11 miRNAs also were significantly different between dogs in Stage C/D and those in Stage B1/B2. The expression changes were greater as disease severity increased. These miRNAs may be candidates for novel biomarkers and may provide insights into genetic regulatory pathways in canine MMVD. PMID- 26101869 TI - Novel Therapeutic GPCRs for Psychiatric Disorders. AB - G protein-coupled receptors (GPCRs) are the most common targets of the neuropharmacological drugs in the central nervous system (CNS). GPCRs are activated by manifold neurotransmitters, and their activation in turn evokes slow synaptic transmission. They are deeply involved in multiple neurological and psychiatric disorders such as Parkinson's disease and schizophrenia. In the brain, the striatum is strongly innervated by the ventral tegmental area (VTA) and plays a central role in manifestation of psychiatric disorders. Recently, anatomical and comprehensive transcriptome analysis of the non-odorant GPCR superfamily revealed that the orphan GPCRs GPR88, GPR6, and GPR52, as well as dopamine D1 and D2 receptors and the adenosine A2a receptor, are the most highly enriched in the rodent striatum. Genetically engineered animal models and molecular biological studies have suggested that these striatally enriched GPCRs have a potential to be therapeutic psychiatric receptors. This review summarizes the current understanding of the therapeutic GPCR candidates for psychiatric disorders. PMID- 26101871 TI - Current surgical management of macroglossia. AB - PURPOSE OF REVIEW: To discuss the current surgical management of macroglossia. RECENT FINDINGS: Traditional surgical management of severe macroglossia has been with anterior wedge or keyhole resection. Long-term follow-up has been limited, and only recently have assessments been done regarding functional and aesthetic outcomes. New methods including double stellate and combination approaches have shown promise, though with limited case size reports. Addressing macroglossia in three dimensions may be the most effective way of achieving positive positional, speech and aesthetic outcomes, but comparative studies are lacking. Other causes of macroglossia, such as vascular malformations, can be managed with less aggressive measures such as laser and radio-frequency ablation. SUMMARY: The aggressiveness of the management should match the severity of the symptoms. The anterior wedge resection and modified keyhole incisions are the most well studied operative strategies. Short and long-term outcome data are limited, and neither method is definitively superior. Less aggressive measures are options for less severe macroglossia. Surgical management of macroglossia should be tailored to each individual patient and in accordance to surgeon experience and expertise. PMID- 26101872 TI - Update in disease-specific quality-of-life studies in facial plastic surgery. AB - PURPOSE OF REVIEW: Improvements in the quality of life (QOL) of patients undergoing facial plastic and reconstructive surgery are readily apparent to any practitioner performing these procedures and interacting with these patients. However, proving these benefits objectively has become ever more important in the current practice environment and there has been a body of literature reported to address this need. RECENT FINDINGS: As techniques for facial reanimation, revision cleft surgery and other procedures are further developed and the tailored treatments of these ailments are honed, the body of literature for QOL improvements is growing. A better understanding of the nature of these disorders and the elements that are more impactful to patients has led to procedures that more specifically address these objectives and improve functional and psychological outcomes. SUMMARY: Interest in QOL data to support the interventions performed by facial plastic and reconstructive surgeons has and will continue to expand. The addition of QOL surveys to everyday practice, reporting of objective data in the literature and most importantly the focus of the practitioner on improving the patient's overall health and welfare are testaments to the tailoring of practice to not only address the functional and cosmetic goals but also the overall wellbeing. PMID- 26101870 TI - Circulating Cell-Free Tumour DNA in the Management of Cancer. AB - With the development of new sensitive molecular techniques, circulating cell-free tumour DNA containing mutations can be identified in the plasma of cancer patients. The applications of this technology may result in significant changes to the care and management of cancer patients. Whilst, currently, these "liquid biopsies" are used to supplement the histological diagnosis of cancer and metastatic disease, in the future these assays may replace the need for invasive procedures. Applications include the monitoring of tumour burden, the monitoring of minimal residual disease, monitoring of tumour heterogeneity, monitoring of molecular resistance and early diagnosis of tumours and metastatic disease. PMID- 26101873 TI - Dentoalveolar reconstruction: modern approaches. AB - PURPOSE OF REVIEW: A variety of bone grafting materials is available to facilitate the augmentation of defective alveolar ridges. This review evaluates current literature regarding bone grafting materials with emphasis on autologous and allogeneic bone block augmentation. RECENT FINDINGS: Autogenous bone is a reliable grafting material providing predictable long-term results with high implant survival/success rates and low morbidity rates. The resorption properties of the iliac crest are well known and are compared with calvarial grafts more prominent. Recent studies demonstrated surgical techniques to prevent graft resorption after iliac crest grafting. Allogeneic block graft and implant survival rates appear promising in short-term clinical studies. SUMMARY: At this stage, iliac crest remains the gold standard in large alveolar bone defects. Autogenous material is not a panacea; however, none of the available materials can currently surpass it. Rather, each material has its specific advantage for certain indications. Evident long-term studies of allogeneic bone grafting are lacking. Detected cells in allogeneic bone substitute material are positive for major histocompatibility complex classes I and II. Despite the promising clinical results achieved with allogeneic bone grafts, the current literature lacks sufficient data on antigenicity. PMID- 26101874 TI - Management of orbital tumours. AB - PURPOSE OF REVIEW: The management of orbital tumours has evolved significantly over the last two decades, as the body of knowledge about these tumours grows and new techniques are introduced that reduce surgical morbidity. The purpose of this review is to highlight and evaluate the most recent advancements in the management of these tumours. RECENT FINDINGS: Several recent retrospective series emphasize the broad range of pathologic processes that can arise within the orbit. In addition, there have been a number of recent studies describing advances in endonasal endoscopic techniques for resection of orbital tumours. SUMMARY: This articles summarizes the current opinion regarding the management of orbital tumours. Recent studies reviewing the range of diseases that affect the orbit and technical advances are summarized. PMID- 26101875 TI - Current trends in medical management of infantile hemangioma. AB - PURPOSE OF REVIEW: Infantile hemangiomas are the most common benign, soft-tissue tumors of infancy, affecting between 5 and 10% of newborns, and up to 30% of premature infants. Morbidity may include disfigurement and scarring, difficulty in feeding, ulceration, vision loss, airway compromise, congestive heart failure, and death. Advances in understanding the pathogenesis of infantile hemangiomas have given rise to a number of promising treatments. This article reviews the current options for medical management of infantile hemangiomas. RECENT FINDINGS: In the proliferative phase of infantile hemangiomas, vascular endothelial growth factor and basic fibroblast growth factor have shown increased expression, and vascular endothelial growth factor expression has been up-regulated by adrenergic stimulation. Moreover, the role of the renin-angiotensin system in the pathogenesis of infantile hemangiomas has been demonstrated. Numerous medical options have been under investigation. Since 2008, propanolol has become the first-line therapy, whereas other medical treatments are used less frequently or when propanolol is unsuccessful. SUMMARY: Propranolol has been recently adopted as the first-line medical treatment for complicated infantile hemangiomas. Although emerging treatment options and modalities have shown promising results, there need to be high-quality multicenter randomized trials to support these preliminary data. PMID- 26101876 TI - Botulinum toxin in the management of facial paralysis. AB - PURPOSE OF REVIEW: Complete flaccid facial paralysis, as well as the synkinetic and hyperkinetic sequelae of partial recovery, has significant impact on quality of life. Patients suffer from functional deficiencies, cosmetic deformity, discomfort and social consequences leading to emotional distress. Despite an extensive and sophisticated array of available interventions for facial reanimation, most patients have persistent issues that require consistent follow up. In long-term management, botulinum toxin (BT) injection remains a critical tool in the treatment of the facial paralysis patient, particularly in the case of synkinesis, hyperkinesis and imbalance. We review the recent scientific literature and highlight key principles and developments in the use of BT in the management of facial paralysis, including less common applications for acute facial paralysis, hyperlacrimation and pseudoptosis. RECENT FINDINGS: We reviewed the literature for the latest advances in the use of BT in facial paralysis, including applications and technique, as well as measurement tools and adjunct exercises. We also share our experience in treating our own patient population. SUMMARY: BT continues to be a well tolerated and effective tool in the long-term management of facial paralysis, specifically in treating synkinesis, imbalance and hyperkinesis, as well as hyperlacrimation and pseudoptosis. Consistent measurement tools and adjunct neuromuscular retraining are crucial in the successful deployment of BT. Controversy exists as to whether BT should be used to manage facial paralysis during the acute phase, and whether BT application to the nonparalyzed face can improve long-term recovery in the paralyzed side. PMID- 26101877 TI - Density and length in the neighborhood: Explaining cross-linguistic differences in learning to read in English and Dutch. AB - Two experiments examined underlying cognitive processes that may explain why it is harder to learn to read in English than in more transparent orthographies such as German and Dutch. Participants were English and Dutch readers from Grades 3 and 4. Experiment 1 probed the transition from serial to more parallel processing, as measured by the word length effect for words and pseudowords. English children took longer to make the transition to more parallel reading strategies for words than Dutch children. In contrast, Dutch children continued to use more serial reading strategies for pseudowords. Experiment 2 investigated children's sensitivity to the orthographic overlap between words, as measured by the size of orthographic neighborhood effects for words and pseudowords. Children reading Dutch showed greater sensitivity to the overlap between both words and pseudowords than English children. Cross-linguistic differences in the transition from serial to parallel reading strategies are discussed within the framework offered by the self-teaching hypothesis and the orthographic depth hypothesis. Finally, it is argued that differences between the two languages in the effect of orthographic neighborhood size are a result of cross-linguistic differences in orthographic density and not cross-linguistic differences in orthographic transparency. PMID- 26101878 TI - Young children's acceptance of within-species variation: Implications for essentialism and teaching evolution. AB - Neglecting within-species variation plays a crucial role in students' misconceptions about adaptation by natural selection. Prior research on the development of this propensity suggests that this neglect is due to a strong early-arising essentialist bias to treat species as invariant. Across two studies, we examined the strength of this bias by exploring 5- and 6-year-olds' and 7- and 8-year-olds' assumptions about variation in contexts similar to those used in a recent early educational intervention teaching adaptation. In Study 1, children heard about fictitious animals' physical and behavioral traits and their beneficial functions. They then judged whether all other species members would vary or be invariant on those traits. Across age groups, children showed a marginal essentialist tendency to reject variation. In Study 2, the same method was used, but all references to beneficial trait functions were removed. The 5- and 6-year-olds' responding did not differ from Study 1, but the 7- and 8-year olds' acceptance of variation increased to above chance rates. Parental religious and evolution beliefs correlated with younger children's responses but not with older children's responses. Together, the findings suggest that under certain facilitative contexts children display greater abilities to represent variation than assumptions of a robust and inflexible essentialist bias would predict. By 7 to 8 years of age, children displayed autonomy from their parents' beliefs and tended to expect variation. However, priming their teleological intuitions undermined their non-essentialist expectations. Theoretical and educational implications are discussed. PMID- 26101880 TI - Trophic Strategies of a Non-Native and a Native Amphibian Species in Shared Ponds. AB - One of the critical factors for understanding the establishment, success and potential impact on native species of an introduced species is a thorough knowledge of how these species manage trophic resources. Two main trophic strategies for resource acquisition have been described: competition and opportunism. In the present study our objective was to identify the main trophic strategies of the non-native amphibian Discoglossus pictus and its potential trophic impact on the native amphibian Bufo calamita. We determine whether D. pictus exploits similar trophic resources to those exploited by the native B. calamita (competition hypothesis) or alternative resources (opportunistic hypothesis). To this end, we analyzed the stable isotope values of nitrogen and carbon in larvae of both species, in natural ponds and in controlled laboratory conditions. The similarity of the delta15N and delta13C values in the two species coupled with isotopic signal variation according to pond conditions and niche partitioning when they co-occurred indicated dietary competition. Additionally, the non-native species was located at higher levels of trophic niches than the native species and B. calamita suffered an increase in its standard ellipse area when it shared ponds with D. pictus. These results suggest niche displacement of B. calamita to non-preferred resources and greater competitive capacity of D. pictus in field conditions. Moreover, D. pictus showed a broader niche than the native species in all conditions, indicating increased capacity to exploit the diversity of resources; this may indirectly favor its invasiveness. Despite the limitations of this study (derived from potential variability in pond isotopic signals), the results support previous experimental studies. All the studies indicate that D. pictus competes with B. calamita for trophic resources with potential negative effects on the fitness of the latter. PMID- 26101881 TI - Infected Nonhealing Wound in a Kidney Transplant Recipient: Successful Treatment With Topical Homologous Platelet-Rich Gel. AB - Impaired would healing is a known adverse effect of chronic immunosuppression. Solid-organ transplant recipients undergoing major abdominal surgery have an increased risk of wound-related complications compared with the general population. In this subset of patients, surgical site infections and wound dehiscence must be aggressively treated to avoid sepsis, graft loss, and death. Recently, topical application of platelet-rich plasma has been proposed as an alternative therapeutic option to enhance wound healing in difficult cases. Unfortunately, randomized controlled trials evaluating the efficacy of platelet rich plasma compared with standard or advanced wound management are lacking, and the literature mostly refers to anecdotal reports in patients with no evidence of wound infection. This report documents a kidney transplant recipient who experienced spontaneous bladder rupture because of gangrenous cystitis. After an exploratory laparotomy and bladder repair, the patient developed a deep surgical site infection by multidrug resistant Acinetobacter baumannii and extensive wound dehiscence. Advanced wound management and vacuum-assisted closure therapy were ineffective. Topical homologous platelet-rich gel was used resulting in significant wound healing, without infections or immunologic complications. PMID- 26101879 TI - CT Screening for Lung Cancer: Nonsolid Nodules in Baseline and Annual Repeat Rounds. AB - PURPOSE: To address the frequency of identifying nonsolid nodules, diagnosing lung cancer manifesting as such nodules, and the long-term outcome after treatment in a prospective cohort, the International Early Lung Cancer Action Program. MATERIALS AND METHODS: A total of 57,496 participants underwent baseline and subsequent annual repeat computed tomographic (CT) screenings according to an institutional review board, HIPAA-compliant protocol. Informed consent was obtained. The frequency of participants with nonsolid nodules, the course of the nodule at follow-up, and the resulting diagnoses of lung cancer, treatment, and outcome are given separately for baseline and annual repeat rounds of screening. The chi(2) statistic was used to compare percentages. RESULTS: A nonsolid nodule was identified in 2392 (4.2%) of 57,496 baseline screenings, and pathologic pursuit led to the diagnosis of 73 cases of adenocarcinoma. A new nonsolid nodule was identified in 485 (0.7%) of 64,677 annual repeat screenings, and 11 had a diagnosis of stage I adenocarcinoma; none were in nodules 15 mm or larger in diameter. Nonsolid nodules resolved or decreased more frequently in annual repeat than in baseline rounds (322 [66%] of 485 vs 628 [26%] of 2392, P < .0001). Treatment of the cases of lung cancer was with lobectomy in 55, bilobectomy in two, sublobar resection in 26, and radiation therapy in one. Median time to treatment was 19 months (interquartile range [IQR], 6-41 months). A solid component had developed in 22 cases prior to treatment (median transition time from nonsolid to part-solid, 25 months). The lung cancer-survival rate was 100% with median follow-up since diagnosis of 78 months (IQR, 45-122 months). CONCLUSION: Nonsolid nodules of any size can be safely followed with CT at 12 month intervals to assess transition to part-solid. Surgery was 100% curative in all cases, regardless of the time to treatment. PMID- 26101882 TI - Interaction Effects of Social Isolation and Peripheral Work Position on Risk of Disability Pension: A Prospective Study of Swedish Women and Men. AB - PURPOSE: The study examines various combinations of levels of social isolation in private life and peripheral work position as predictors of disability pension (DP). A second aim was to test the potential interaction effects (above additivity) of social isolation and peripheral work position on the future risk of DP, and to provide results for men and women by age. METHOD: The study was based on a sample of 45567 women and men from the Swedish population who had been interviewed between 1992 and 2007. Further information on DP and diagnoses was obtained from the Swedish Social Insurance Agency's database (1993-2011). The studied predictors were related to DP using Cox's proportional hazard regression. The analyses were stratified on sex and age (20-39 years, 40-64 years), with control for selected confounders. RESULTS: Increased risks of DP were found for most combinations of social isolation and peripheral work position in all strata. The hazard ratios (HRs) for joint exposure to high degree of social isolation and a peripheral work position were particularly strong among men aged 20-39 (HR 5.70; CI 95% 3.74-8.69) and women aged 20-39 (HR 4.07; CI 2.99-5.56). An interaction effect from combined exposure was found for women in both age groups as well as a tendency in the same direction among young men. However, after confounder control the effects did not reach significance. CONCLUSIONS: Individuals who were socially isolated and in a peripheral work position had an increased risk of future DP. The fact that an interaction effect was found among women indicates that a combination of social isolation and peripheral work position may reinforce adverse health effects. There was no evidence that a peripheral work position can be compensated by a high degree of social intergration in private life. PMID- 26101883 TI - Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy. AB - BACKGROUND AND OBJECTIVES: Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE). METHODS: Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes. RESULTS: Among seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-alpha therapy was needed in two. CONCLUSION: This case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals. PMID- 26101884 TI - Polychlorinated Biphenyls Induce Mitochondrial Dysfunction in SH-SY5Y Neuroblastoma Cells. AB - Chronic exposure to polychlorinated biphenyls (PCBs), ubiquitous environmental contaminants, can adversely affect the development and function of the nervous system. Here we evaluated the effect of PCB exposure on mitochondrial function using the PCB mixture Aroclor-1254 (A1254) in SH-SY5Y neuroblastoma cells. A 6 hour exposure to A1254 (5 MUg/ml) reduced cellular ATP production by 45%+/-7, and mitochondrial membrane potential, detected by TMRE, by 49%+/-7. Consistently, A1254 significantly decreased oxidative phosphorylation and aerobic glycolysis measured by extracellular flux analyzer. Furthermore, the activity of mitochondrial protein complexes I, II, and IV, but not V (ATPase), measured by BN PAGE technique, was significantly reduced after 6-hour exposure to A1254. The addition of pyruvic acid during exposure to A1254 significantly prevent A1254 induced cell injury, restoring resting mitochondrial membrane potential, ATP levels, oxidative phosphorylation and aerobic glycolysis. Furthermore, pyruvic acid significantly preserved the activity of mitochondrial complexes I, II and IV and increased basal activity of complex V. Collectively, the present results indicate that the neurotoxicity of A1254 depends on the impairment of oxidative phosphorylation, aerobic glycolysis, and mitochondrial complexes I, II, and IV activity and it was counteracted by pyruvic acid. PMID- 26101885 TI - Latitudinal Gradient in Otolith Shape among Local Populations of Atlantic Herring (Clupea harengus L.) in Norway. AB - Otolith shape analysis of Atlantic herring (Clupea harengus) in Norwegian waters shows significant differentiation among fjords and a latitudinal gradient along the coast where neighbouring populations are more similar to each other than to those sampled at larger distances. The otolith shape was obtained using quantitative shape analysis, the outlines were transformed with Wavelet and analysed with multivariate methods. The observed morphological differences are likely to reflect environmental differences but indicate low dispersal among the local herring populations. Otolith shape variation suggests also limited exchange between the local populations and their oceanic counterparts, which could be due to differences in spawning behaviour. Herring from the most northerly location (69 degrees N) in Balsfjord, which is genetically more similar to Pacific herring (Clupea pallasii), differed in otolith shape from all the other populations. Our results suggest that the semi-enclosed systems, where the local populations live and breed, are efficient barriers for dispersal. Otolith shape can thus serve as a marker to identify the origin of herring along the coast of Norway. PMID- 26101888 TI - Size and Structure of Clusters Formed by Shear Induced Coagulation: Modeling by Discrete Element Method. AB - The coagulation process has a dramatic impact on the properties of dispersions of colloidal particles including the change of optical, rheological, as well as texture properties. We model the behavior of a colloidal dispersion with moderate particle volume fraction, that is, 5 wt %, subjected to high shear rates employing the time-dependent Discrete Element Method (DEM) in three spatial dimensions. The Derjaguin-Landau-Verwey-Overbeek (DLVO) theory was used to model noncontact interparticle interactions, while contact mechanics was described by the Johnson-Kendall-Roberts (JKR) theory of adhesion. The obtained results demonstrate that the steady-state size of the produced clusters is a strong function of the applied shear rate, primary particle size, and the surface energy of the particles. Furthermore, it was found that the cluster size is determined by the maximum adhesion force between the primary particles and not the adhesion energy. This observation is in agreement with several simulation studies and is valid for the case when the particle-particle contact is elastic and no plastic deformation occurs. These results are of major importance, especially for the emulsion polymerization process, during which the fouling of reactors and piping causes significant financial losses. PMID- 26101886 TI - Use of Electronic Loggers to Measure Changes in the Rates of Hand Washing with Soap in Low-Income Urban Households in India. AB - We evaluated the utility of electronic loggers to measure the effects of a simple intervention designed to influence the rates of hand washing with soap within enclosed toilets and bathrooms in low-income urban households in Kerala, India. 58 households were given three items with embedded electronic loggers for a period of 2-5 days. Two logged soaps tracked hand and body washing in the bathroom. The third logged item was a water vessel used for flushing the toilet and for post-defecation anal cleansing; this served as a marker of toilet use. In addition, 28 households in a Soap by toilet arm were given an additional logged soap, to be kept by the toilet, and used for hand washing. Compared with the Soap in bathroom arm, the loggers in the Soap by toilet households recorded 73% greater daily use of soaps designated for hand washing (t(36)=2.92, p<0.01) and 172% greater use within 2 minutes of the use of the water vessel (t(36)=3.51, p = 0.001). We conclude that the loggers were capable of detecting changes in the rates of hand washing with soap and changes in hand washing with soap after use of the toilet. Further adoption of logger technologies would enable more insightful studies of hand washing within urban environments. PMID- 26101887 TI - Persistence of Pathogenic and Non-Pathogenic Escherichia coli Strains in Various Tropical Agricultural Soils of India. AB - The persistence of Shiga-like toxin producing E. coli (STEC) strains in the agricultural soil creates serious threat to human health through fresh vegetables growing on them. However, the survival of STEC strains in Indian tropical soils is not yet understood thoroughly. Additionally how the survival of STEC strain in soil diverges with non-pathogenic and genetically modified E. coli strains is also not yet assessed. Hence in the present study, the survival pattern of STEC strain (O157-TNAU) was compared with non-pathogenic (MTCC433) and genetically modified (DH5alpha) strains on different tropical agricultural soils and on a vegetable growing medium, cocopeat under controlled condition. The survival pattern clearly discriminated DH5alpha from MTCC433 and O157-TNAU, which had shorter life (40 days) than those compared (60 days). Similarly, among the soils assessed, the red laterite and tropical latosol supported longer survival of O157 TNAU and MTCC433 as compared to wetland and black cotton soils. In cocopeat, O157 recorded significantly longer survival than other two strains. The survival data were successfully analyzed using Double-Weibull model and the modeling parameters were correlated with soil physico-chemical and biological properties using principal component analysis (PCA). The PCA of all the three strains revealed that pH, microbial biomass carbon, dehydrogenase activity and available N and P contents of the soil decided the survival of E. coli strains in those soils and cocopeat. The present research work suggests that the survival of O157 differs in tropical Indian soils due to varied physico-chemical and biological properties and the survival is much shorter than those reported in temperate soils. As the survival pattern of non-pathogenic strain, MTCC433 is similar to O157-TNAU in tropical soils, the former can be used as safe model organism for open field studies. PMID- 26101889 TI - B(C6F5)3-Catalyzed Hydrodesulfurization Using Hydrosilanes--Metal-Free Reduction of Sulfides. AB - B(C6F5)3-catalyzed hydrodesulfurization of carbon-sulfur bonds was achieved using triethylsilane as the reducing agent. The corresponding products were obtained in good yields under mild reaction conditions. This protocol could be applied to the reduction of sulfides, including benzyl and alkyl sulfides and dithianes, with high chemoselectivities. PMID- 26101890 TI - Solid-State (63)Cu, (65)Cu, and (31)P NMR Spectroscopy of Photoluminescent Copper(I) Triazole Phosphine Complexes. AB - The results of a solid-state (63/65)Cu and (31)P NMR investigation of several copper(I) complexes with functionalized 3-(2'-pyridyl)-1,2,4-triazole and phosphine ligands that have shown potential in the preparation of photoluminescent devices are reported. For each complex studied, distinct NMR parameters, with moderate (63)Cu nuclear quadrupolar coupling constant (CQ) values ranging from -17.2 to -23.7 MHz, are attributed to subtle variations in the distorted four-coordinate environments about the copper nuclei. The spans of the copper chemical shift (CS) tensors, delta11-delta33, for the mono- and bisphosphine complexes are also similar, ranging from 1000 to 1150 ppm, but that for a complex with a strained bidentate phosphine ligand is only 650 ppm. The effects of residual dipolar and indirect spin-spin coupling arising from the (63/65)Cu- (31)P spin pairs, observed in the solid-state (31)P NMR spectra of these complexes, yield information about the orientations of the copper electric field gradient (EFG) tensors relative to the Cu-P bond. Variable-temperature (31)P NMR measurements for [Cu(bptzH)(dppe)]ClO4 (bptzH = 5-tert-butyl-3-(2' pyridyl)-1,2,4-triazole; dppe = 1,2-bis(diphenylphosphino)ethane), undertaken to investigate the cause of the broad unresolved spectra observed at room temperature, demonstrate that the broadening arises from partial self-decoupling of the (63/65)Cu nuclei, a consequence of rapid quadrupolar relaxation. Ab initio calculations of copper EFG and CS tensors were performed to probe relationships between NMR parameters and molecular structure. The analysis demonstrated that CQ((63/65)Cu) is negative for all complexes studied here and that the largest components of the EFG tensors are generally coincident with delta11. PMID- 26101891 TI - Light controllable surface coating for effective photothermal killing of bacteria. AB - Although the electronic properties of conducting films have been widely explored in optoelectronic fields, the optical absorption abilities of surface-coated films for photothermal conversion have been relatively less explored in the production of antibacterial coatings. Here, we present catechol-conjugated poly(vinylpyrrolidone) sulfobetaine (PVPS) and polyaniline (PANI) tightly linked by ionic interaction (PVPS:PANI) as a novel photothermal antibacterial agent for surface coating, which can absorb broadband near-infrared (NIR) light. Taking advantage of the NIR light absorption, this coating film can release eminent photothermal heat for the rapid killing of surface bacteria. The NIR light triggers a sharp rise in photothermal heat, providing the rapid and effective killing of 99.9% of the Gram-positive and -negative bacteria tested within 3 min of NIR light exposure when used at the concentration of 1 mg/mL. Although considerable progress has been made in the design of antibacterial coatings, the user control of NIR-irradiated rapid photothermal destruction of surface bacteria holds increasing attention beyond the traditional boundaries of typical antibacterial surfaces. PMID- 26101892 TI - pH-Sensitive Polymeric Nanoparticles with Gold(I) Compound Payloads Synergistically Induce Cancer Cell Death through Modulation of Autophagy. AB - Various nanomaterials have been demonstrated as autophagy inducers owing to their endocytosis cell uptake pathway and impairment of lysosomes. pH-dependent nanomaterials as drug delivery systems that are capable of dissociating in weakly acidic lysosomal environment (pH 4-5) and consequently releasing the payloads into the cytoplasm have been paid extensive attention, but their autophagy modulating effects are less reported so far. In this study, we report pH sensitive micelle-like nanoparticles (NPs) that self-assembled from poly(beta amino ester)s to induce cell autophagy. By encapsulation of gold(I) compounds (Au(I)) into hydrophobic domains of NPs, the resultant Au(I)-loaded NPs (Au(I)?NPs) shows synergistic cancer cell killing performance. The Au(I)?NPs enter cells through endocytosis pathway and accumulate into acidic lysosomes. Subsequently, the protonation of tertiary amines of poly(beta-amino ester)s triggers the dissociation of micelles, damages the lysosomes, and blocks formation of autolysosomes from fusion of lysosomes with autophagosomes. In addition, Au(I) preferentially inhibits thioredoxin reductase (TrxR) in MCF-7 human breast cancer cells that directly links to up-regulate reactive oxygen species (ROS) and consequently induce autophagy and apoptosis. The blockade of autophagy leads to excessive depletion of cellular organelles and essential proteins and ultimately results in cell death. Therefore, pH-sensitive polymeric nanoparticles with gold(I) compound payloads can synergistically induce cancer cell death through regulation of autophagy. Identification of the pH-sensitive nanomaterials for synergistically inducing cell death through regulation autophagy may open a new avenue for cancer therapy. PMID- 26101894 TI - Temperature Dependence of Low-Frequency Spectra in Molten Bis(trifluoromethylsulfonyl)amide Salts of Imidazolium Cations Studied by Femtosecond Raman-Induced Kerr Effect Spectroscopy. AB - In this study, the temperature dependence of the low-frequency spectra of liquid bis(trifluoromethylsulfonyl)amide salts of the monocations 1-methyl-3 propylimidazolium and 1-hexyl-3-methylimidazolium and the dications 1,6-bis(3 methylimidazolium-1-yl)hexane and 1,12-bis(3-methylimidazolium-1-yl)dodecane has been investigated by means of femtosecond optical heterodyne-detected Raman induced Kerr effect spectroscopy. The intensity in the low-frequency region below 20 cm(-1) in the spectra of the four ionic liquids increases with rising temperature. From a line-shape analysis of the broadened low-frequency spectra of the ionic liquids, it is clear that the lowest-frequency component, which peaks at approximately 5 cm(-1), contributes to the temperature dependence of the spectra. This implies that the activity of the intermolecular translational vibrational motion is increasing with rising temperature. It is also possible that decoupling in the crossover process between intermolecular vibrational motion and structural relaxation occurs as a result of a deterioration of the non Markovian feature or the loss of memory caused by the higher temperature. The peak of the highest-frequency component, which is due mainly to the imidazolium ring libration, shifts to lower frequency with increasing temperature. This is attributed to weaker interactions of the ionic liquids at higher temperatures. Temperature-dependent viscosities from 293 to 353 K of the four ionic liquids have also been characterized. PMID- 26101893 TI - Physical activity, and not fat mass is a primary predictor of circadian parameters in young men. AB - Circadian rhythms are ~24 h oscillations in physiology and behavior, and disruptions have been shown to have negative effects on health. Wrist skin temperature has been used by several groups as a valid method of assessing circadian rhythms in humans. We tested the hypothesis that circadian temperature amplitude (TempAmp) and stability (TempStab) would significantly differ among groups of healthy young men of varying adiposities, and that we could identify physiological and behavioral measures that were significantly associated with these temperature parameters. Wrist skin temperatures taken at 10 min intervals for 7 consecutive days were determined in 18 optimal (OGroup), 20 fair (FGroup) and 21 poor (PGroup) %Fat grouped young men and subsequently analyzed using available validated software. Body composition, cardiorespiratory fitness, actigraphy, daily nutritional and sleep data, and fasting lipid, insulin and glucose concentration measures were also determined. Significant changes in TempAmp and TempStab parameters in subjects with a single metabolic syndrome (MetS) risk factor compared to those with no MetS factors was observed. In addition, stepwise multivariate regression analyses showed that 50% of the variance in TempAmp was explained by actigraphy (mean steps taken per day; MSTPD), cardiorespiratory fitness, and late night eating per week (#LNE); and 57% in TempStab by MSTPD, time spent in moderate-to-vigorous activity per day, fat mass, and #LNE. Overwhelmingly, physical activity was the most important measure associated with the differences in circadian rhythm parameters. Further research is warranted to determine the effects of increasing the amount and timing of physical activity on the status of the circadian system in a variety of populations. PMID- 26101896 TI - Enhanced Fenton Catalytic Efficiency of gamma-Cu-Al2O3 by sigma-Cu2+-Ligand Complexes from Aromatic Pollutant Degradation. AB - Mesoporous Cu-doped gamma-Al2O3 (gamma-Cu-Al2O3) was prepared via an evaporation induced self-assembly process, in which Cu(+/2+) was co-incorporated into mesoporous gamma-Al2O3 by chemical bonding of Al-O-Cu. The catalyst was found to be highly effective and stable for the degradation and mineralization of aromatic pollutants, as demonstrated with bisphenol A, 2,4-dichlorophenoxyacetic acid, ibuprofen, diphenhydramine, and phenytoin in the presence of H2O2 under neutral pH conditions. In addition, the high utilization efficiency of H2O2 was maintained at approximately 90% prior to the disappearance of the initial aromatic pollutants. On the basis of all of the characterization results, the pollutant degradation processes predominantly occurred on the surface of the catalyst due to the formation of sigma-Cu-ligand complexes between the phenolic OH group and the surface Cu. In the reaction system, in addition to the unselective oxidation by (*)OH, H2O2 directly attacked the sigma-Cu(2+)-complexes aromatic ring with the phenolic OH group, which resulted in the formation of (*)OH and HO-adduct radicals that were oxidized to hydroxylation products by reduction of Cu(2+) in the sigma-Cu(2+)-complexes to Cu(+). The process prevented Cu(2+) from oxidizing H2O2 to form HO2(*)/O2(*-) or O2, and enhanced the Cu(+)/Cu(2+) cycle, the formation of (*)OH, and the utilization efficiency of H2O2. Therefore, an extraordinarily high degradation and mineralization of the aromatic pollutants was observed. PMID- 26101897 TI - Cell cycle and dystrophin dysregulation in GIST. PMID- 26101895 TI - Optimized Replicating Renilla Luciferase Reporter HIV-1 Utilizing Novel Internal Ribosome Entry Site Elements for Native Nef Expression and Function. AB - We previously developed replication-competent reporter HIV-1 (referred to herein as LucR.T2A reporter viruses), utilizing a "ribosome skipping" T2A peptide strategy to link Renilla luciferase (LucR) with Nef expression. The demonstrated utility for HIV-1 vaccine and transmission study applications included measurement of neutralizing antibody (NAb) activity in vaccine sera, improved cell-mediated virus inhibition assays, such as T cell-mediated virus inhibition and antibody-dependent cell-mediated cytotoxicity (ADCC) assays, and humanized mouse models. Herein, we extend our prior work and introduce reporter virus technology for applications that require fully functional Nef. We demonstrate that in CD4(+) T cells productively infected with LucR.T2A reporter viruses, T2A peptide-driven Nef expression and function, such as down-regulation of surface CD4 and MHC-I, were impaired. We overcame this limitation of LucR.T2A reporter viruses and achieved physiological Nef expression and function by engineering novel LucR reporter HIV-1 comprising 11 different internal ribosome entry site (IRES) elements chosen for size and relative activity. A range of Nef expression was observed in 293T cells transfected with the different LucR.IRES reporter virus constructs. Iteratively, we identified IRES reporter genomes that expressed Nef closest to physiological levels and produced virus with infectivity, titers, and replication kinetics similar to nonreporter viruses. Our results demonstrated that LucR reporter activity was stable over multiple replication cycles in peripheral blood mononuclear cells (PBMCs). Furthermore, we analyzed Nef functionality, i.e., down-modulation of MHC-I and CD4, following infection of T cell lines and PBMCs. Unlike LucR.T2A reporter virus, one of the redesigned LucR.IRES reporter viruses [containing the modified encephalomyocarditis virus (EMCV) 6ATR IRES element, "6ATRi"] demonstrated Nef expression and function similar to parental "nonreporter" virus. In a previously validated (nef independent) T cell-based NAb neutralization assay, LucR.6ATRi reporter virus performed indistinguishably from LucR.T2A reporter virus. In summary, reporter viruses comprising the "6ATRi" element promise to augment HIV-1 vaccine and transmission research approaches requiring a sensitive reporter readout combined with wild-type Nef function. PMID- 26101898 TI - Fully 3D-Printed Preconcentrator for Selective Extraction of Trace Elements in Seawater. AB - In this study, we used a stereolithographic 3D printing technique and polyacrylate polymers to manufacture a solid phase extraction preconcentrator for the selective extraction of trace elements and the removal of unwanted salt matrices, enabling accurate and rapid analyses of trace elements in seawater samples when combined with a quadrupole-based inductively coupled plasma mass spectrometer. To maximize the extraction efficiency, we evaluated the effect of filling the extraction channel with ordered cuboids to improve liquid mixing. Upon automation of the system and optimization of the method, the device allowed highly sensitive and interference-free determination of Mn, Ni, Zn, Cu, Cd, and Pb, with detection limits comparable with those of most conventional methods. The system's analytical reliability was further confirmed through analyses of reference materials and spike analyses of real seawater samples. This study suggests that 3D printing can be a powerful tool for building multilayer fluidic manipulation devices, simplifying the construction of complex experimental components, and facilitating the operation of sophisticated analytical procedures for most sample pretreatment applications. PMID- 26101899 TI - FGDF motif regulation of stress granule formation. AB - RNA stress granules (SGs) represent a cell-intrinsic antiviral defense mechanism. The assembly of SGs in response to viral infection is coordinated by the cellular protein G3BP, which is targeted by many viruses to block SG formation. We recently showed that proteins containing the short linear motif Phe-Gly-Asp-Phe (FGDF), bind G3BP in a hydrophobic groove on the surface of the nuclear transport factor-2-like domain. Binding in this manner blocks the ability of G3BP to form SGs and allows efficient replication of viruses carrying this motif. PMID- 26101900 TI - Analysis of organic and elemental carbon in heating and non-heating periods in four locations of Beijing. AB - The concentrations of elemental carbon (EC) and organic carbon (OC) in PM2.5 atmospheric aerosol were measured at four different sites in Beijing: Beijing Olympic Forest Park (OF), Jiufeng National Forest Park (JF), Beijing Forestry University campus lawn (G), and roads near the Beijing Forestry University (S). The winter heating period concentrations were 30-45% higher than the spring non heating period. Possible reasons for this could be the severe convective weather in spring due to the temperate monsoon, deposition of PM2.5 to plants in spring, stable atmospheric conditions in winter, and/or a greater number of sources of carbonaceous aerosols in winter. The proportion of total carbon (i.e. EC + OC) in PM2.5 in Beijing is high. The OC/EC value was 2.45 (OF) and 2.39 (JF) in winter and 1.6 (OF) and 1.43 (JF) in spring. These ratios and the high correlation of OC with EC in the winter samples indicate a strong primary source of OC. Eight carbon fractions from the four different sampling locations were analysed, and the OC1-4 values were found to vary considerably. In winter, the OC1 values from all four sites were higher than the spring values. Although there were differences at each site, the percentages of OC2, OC3, EC1-OP, and EC2 were the largest. Secondary organic carbon (SOC) formed during long-range transport from the emission sources to the monitoring sites, and the increase of OC2 and OC3 concentrations could be associated with SOC. PMID- 26101901 TI - AMBRA1: When autophagy meets cell proliferation. AB - A growing amount of evidence reported in the literature in recent years strongly supports the relevance of the interplay between autophagy and other pathways. In this context, the study of the link between autophagy and cell proliferation regulation has been among the most challenging. In our recent publications, we finely characterize a role for the pro-autophagic protein AMBRA1 in the regulation of cell proliferation. AMBRA1 modulates autophagy and interacts with PPP2/PP2A (protein phosphatase 2), thus also modulating MYC protein levels and the cell proliferation rate. Interestingly, this pathway of regulation is controlled by the master regulator of autophagy and cell growth, MTORC1. Notably, in our study we demonstrate the relevance of the AMBRA1-mediated regulation of MYC in tumorigenesis, also identifying AMBRA1 as a tumor suppressor gene. PMID- 26101902 TI - The role of strength and power during performance of high intensity military tasks under heavy load carriage. AB - OBJECTIVE: Previous research has investigated the physiological determinants of heavy load carriage while performing medium to long distance road marching, yet research examining the physiological underpinnings of high-intensity battlefield tasks is limited. This study sought to examine the role of strength and power during high-intensity combat tasks under heavy load carriage. METHODS: Eighteen recreationally trained men (mean+/-SD: age, 21+/-2 years; height, 172+/-6 cm; weight, 80+/-13 kg) participated in this study and performed an anaerobic combat course under 2 randomized experimental conditions; unloaded and loaded. Subjects performed 3 trials under each condition on separate days, with a 5-minute rest between each trial. In the unloaded trial, subjects wore a uniform with boots weighing approximately 3.2 kg. During the loaded trial, in addition to the uniform and boots, subjects wore Interceptor body armor (6.94 kg-9.10 kg) and a MOLLE rucksack weighing 30 kg. The course consisted of 3 consecutive tasks, which began from the prone position, led into a 30 m sprint, followed by a 27 m zigzag run, and ended with a 10 m casualty drag weighing approximately 79.4 kg. RESULTS: Pearson correlations showed significant (P<=.05) strong correlations between lower body strength (r=-0.63, -0.62), lower body power (r=-0.67, -0.67) and upper body strength (r=-0.60, -0.62) and overall performance times in the unloaded and loaded condition, respectively. CONCLUSION: Strength and power are strongly related to high-intensity military tasks with and without heavy load carriage. PMID- 26101903 TI - Musculoskeletal, biomechanical, and physiological gender differences in the US military. AB - The repeal of the Direct Ground Combat Assignment Rule has renewed focus on examining performance capabilities of female military personnel and their ability to occupy previously restricted military occupational specialties. Previous research has revealed female Soldiers suffer a greater proportion of musculoskeletal injuries compared to males, including a significantly higher proportion of lower extremity, knee, and overuse injuries. Potential differences may also exist in musculoskeletal, biomechanical, and physiological characteristics between male and female Soldiers requiring implementation of gender-specific training in order to mitigate injury risk and enhance performance. PURPOSE: To examine differences in musculoskeletal, biomechanical, and physiological characteristics in male and female Soldiers. METHODS: A total of 406 101st Airborne Division (Air Assault) Soldiers (348 male; 58 female) participated. Subjects underwent testing for flexibility, isokinetic and isometric strength (percent body weight), single-leg balance, lower body biomechanics during a stop jump and drop landing, body composition, anaerobic power/capacity, and aerobic capacity. Independent t tests assessed between-group comparisons. RESULTS: Women demonstrated significantly greater flexibility (P<.01 P<.001) and better balance (P<=.001) than men. Men demonstrated significantly greater strength (P<=.001), aerobic capacity (47.5+/-7.6 vs 40.3+/-5.4 ml/kg/min, P<.001), anaerobic power (13.3+/-2.1 vs 9.5+/-1.7 W/kg, P<.001), and anaerobic capacity (7.8+/-1.0 vs 6.1+/-0.8 W/kg, P<.001) and lower body fat (20.1+/-7.5 vs 26.7+/-5.7 (%BF), P<.001). Women demonstrated significantly greater hip flexion and knee valgus at initial contact during both the stop jump and drop landing tasks and greater knee flexion at initial contact during the drop landing task (P<.05-P<.001). CONCLUSIONS: Gender differences exist in biomechanical, musculoskeletal, and physiological characteristics. Sex-specific interventions may aid in improving such characteristics to optimize physical readiness and decrease the injury risk during gender-neutral training, and decreasing between sex variability in performance characteristics may result in enhanced overall unit readiness. Identification of sex-specific differences in injury patterns and characteristics should facilitate adjustments in training in order for both sexes to meet the gender-neutral occupational demands for physically demanding military occupational specialties. PMID- 26101904 TI - The effects of cross-training on fitness and injury in women. AB - BACKGROUND: As combat arms occupations become available to women, adequate muscular strength and aerobic endurance will be essential for the completion of physically demanding job-related tasks. Therefore, in addition to US Army Physical Readiness Training, Soldiers will often engage in their own personal physical fitness training programs. PURPOSE: To evaluate fitness and injury outcomes for women participating in personal cross-training programs compared to women performing one mode of training or having no personal fitness program. METHODS: Demographics, physical training activities, physical fitness, and injuries were obtained from surveys administered to female Soldiers in an infantry division. Women were categorized into the following 4 groups based on their personal physical fitness program: cross-training (CT), running only (R), weight training only (WT), and no personal fitness program (NPF). An ANOVA was used to compare physical training, health behaviors, and physical fitness across groups. A chi2 test was used to compare injury rates between fitness programs. Risk (%), risk ratios (RR) and 95% confidence intervals (95% CI) were used to determine injury risk. RESULTS: A total of 620 women completed the survey and indicated whether or not they had a personal fitness program (cross-training, n=260; running only, n=93; weight training only, n=86; no personal fitness program, n=181). Average age and body mass index was 26.2+/-5.8 years and 24.5+/ 3.3 kg/m2 respectively with no differences between the 4 fitness groups. The cross-training group had higher physical performance on the muscular endurance (push-ups and sit-ups) portion of the Army physical fitness test (APFT) when compared to the 3 other groups (CT 42 push-ups vs (R 38, WT 35, NPF 36)); (CT 68 sit-ups vs (R 63, WT 62, NPF 62)). For the aerobic endurance (2-mile run) portion of the APFT, the cross-training group had higher performance when compared to those with no personal fitness program (CT 17.4 minutes vs NPF 18.5 minutes). Overall, 53% of female Soldiers sustained an injury over a 12-month period. All injury rates and lower extremity injury rates among women with a cross-training personal fitness program were not different from the other personal fitness programs. Those performing cross-training were 2.6 and 2.1 times more likely to experience a running related injury when compared to those in the weight training and no personal fitness group, respectively. On the other hand, women performing cross-training were 65% less likely to experience a lifting/moving heavy objects related injury when compared to the weight training only group. CONCLUSIONS: Women who participated in a cross-training program for personal physical fitness training had higher muscular endurance compared to the other fitness groups and higher aerobic endurance when compared to the no personal fitness group. There were no differences for all injuries and lower body injuries between cross training and other fitness programs. Cross-training may be the best option for improving physical fitness when compared to just one mode of fitness training. PMID- 26101906 TI - Physical fitness and injury reporting among active duty and National Guard/Reserve women: associations with risk and lifestyle factors. AB - OBJECTIVE: As more women enter the military, it is important to understand how different risks and lifestyle factors influence physical fitness and injury among women in both active duty (AD) and National Guard/Reserve (NG/R). Women in military service are less fit and more likely to suffer musculoskeletal injuries during physical training than men. They also use more medical care during deployment than men. Using data from the Comprehensive Soldier and Family Fitness Global Assessment Tool 2.0 (GAT 2.0), self-reported health and lifestyle and behavioral risk factors were analyzed in nondeployed Army personnel, with the goals of examining (1) service-component differences across traditional risk and lifestyle factors, and (2) correlates of physical performance and physical activity-related injury. METHODS: Self-report GAT 2.0 data included health risk factors (overall perceived health, sleep, diet, tobacco and alcohol use), self reported health metrics (height, weight, Army Physical Fitness Test (APFT) scores), and history of physical activity-related injury. The GAT 2.0 was completed by 1,322 AD and 1,033 NG/R women, and APFT data were available for a subsample of 605 AD and 582 NG/R women. RESULTS: Initial analyses of GAT 2.0 data indicated that AD had higher rates of fair/poor perceived health, poor sleep, and unhealthy diet compared to NG/R women. However, AD women had a lower APFT fail rate (8%) than NG (27%) and R (28%). Active duty women were more likely to experience a physical injury in the past 6 months (38%) than NG (19%) and R (22%) women, and more likely to seek medical care than NG/R women. Across all service components, predictive factors for APFT failure included high body mass index (BMI), fair/poor health, and unhealthy diet. Predictive factors for physical injury included high BMI, fair/poor health, and binge drinking. CONCLUSION: Our analyses suggest that AD women Soldiers are more physically fit than NG/R women Soldiers, which is accompanied by a greater prevalence of physical activity related injuries. As women's roles expand into combat military occupation specialties, a thorough understanding of service component differences will be critical to inform training programs, mitigate physical injury, and enhance force health protection and readiness. PMID- 26101905 TI - Physical training, smoking, and injury during deployment: a comparison of men and women in the US Army. AB - PURPOSE: To investigate changes in physical training (PT), fitness, and injury during deployment and identify differences between men and women. METHODS: Data were collected on male and female US Army Soldiers through self-reported surveys completed before and after deployment to Afghanistan. Changes in physical training activities, physical fitness, injury incidence, BMI, and smoking status were analyzed. Descriptive statistics were used to compare before deployment and deployment results and differences between men and women. RESULTS: Surveys were completed by 727 men and 43 women. The percentage of Soldiers engaging in unit PT running of 5 miles or more per week decreased by almost half for men and women. The percentage of Soldiers doing personal PT running of 5 miles or more per week and engaged in resistance training 3 or more days per week more than doubled for men and women during deployment. Cardiorespiratory endurance for women improved by 50 seconds (P=.06) and for men declined by 29 seconds (P<.01), while muscular endurance increased by 0.6 repetitions (P<.01) during deployment. Injury rates for men decreased, on average, 36.2 to 19.0 injuries per 1,000 Soldiers per month (P=.01). Injury rates for women decreased on average from 42.6 to 14.0 injuries per 1,000 Soldiers per month (P=.02). During deployment, BMI did not change for men or women and smoking increased 19% for men (P<.01), but did not increase for women. CONCLUSION: Comparisons of physical training activities and health behavior among men and women before and during deployment suggests that increased resistance training could be recommended for women and smoking cessation for men. Given the potentially important role of personal PT in maintaining physical fitness in the deployment environment, future work should support provision of the necessary environment and equipment for Soldiers to perform personal PT effectively and safely on their own. Further, the physical training gaps between men and women should be addressed, with suggestions regarding where improvements can be made, especially for women interested in seeking combat positions with high physical demands. PMID- 26101907 TI - Women and exertional heat illness: identification of gender specific risk factors. AB - OBJECTIVE: With the expanding role of women into previously closed combat military occupational specialties, women will likely be exposed more to challenging and extreme conditions. Physical work or exercise in extreme environments could increase the risk for exertional heat illness (EHI) and exertional heat stroke (EHS), the most severe type of EHI. Although men have higher rates of EHS than women, women have slightly higher rates of other EHI. Women may respond differently to exertion in the heat than men, as they typically have higher percentage of body fat (BF%) and lower aerobic power. Further, published pilot-data using the Israeli heat tolerance test (HTT) indicate that women are more likely to be classified as heat intolerant than men. The objectives of the present study were to (1) compare male and female classification patterns of heat tolerance, and (2) identify EHI risk factors that might account for the relationship between heat tolerance classification and sex. METHODS: Fifty-five male and 20 female participants were recruited from military and university communities to participate in a standardized HTT. Subjects underwent measures to calculate anthropometric variables (BF%, body surface area, and waist circumference), a maximal oxygen uptake test to assess aerobic power (VO2max), and a standardized HTT, which consisted of treadmill walking at 5 km/h at a 2% grade for 120 minutes at 40 degrees C and 40% relative humidity. Heat intolerance was defined as attaining a maximum heart rate (HR) greater than 150 bpm or a core body temperature (Tc) more than 38.5 degrees C. Separate hierarchical regressions were conducted using categorical (heat tolerant/intolerant) and continuous (physiological strain index, maximum HR, Tc) HTT outcomes. Risk factors were identified with and without controlling for sex. RESULTS: Women were 3.7 (95% CI, 1.21-11.24) times more likely to be heat intolerant than men (chi2=6.85, P<.01). Compared to men, women had significantly higher BF% and lower body surface area, waist circumference, and VO2max. All heat intolerant participants had lower VO2max and higher BF% than those who were classified as heat tolerant. When VO2max and BF% were entered into regression equations to predict HTT outcomes, sex became nonsignificant; VO2max predicted maximum HR and physiological strain index after controlling for sex. CONCLUSION: The present study found that differences between men and women in heat tolerance classification are largely explained by VO2max. The higher rates of heat intolerance among women likely correlate with higher EHI risk, and underscore the need to understand the physiological and thermoregulatory differences between men and women. As lower aerobic power is a major risk factor for EHI, maximizing the aerobic power of women will be critical to force health protection and readiness as they integrate into combat military occupational specialties. PMID- 26101908 TI - Effects of basic combat training on iron status in male and female soldiers: a comparative study. AB - OBJECTIVE: Iron is an essential micronutrient known to affect physical and cognitive performance. Studies indicate a significant reduction in iron status in female Soldiers immediately following military training, although the comparative effects of military training on iron status between male and female Soldiers have not been examined. The objective of this study was to compare the longitudinal effects of US Army basic combat training (BCT) on iron status indicators in a group of male and female Soldiers. METHODS: A total of 154 male and female Soldiers (89 and 65, respectively) completed the study. Blood was collected at 4 time-points during BCT (weeks 0, 3, 6, 9) and dietary iron intake was assessed at weeks 0 and 9. Iron status indicators included hemoglobin, serum ferritin (SF), soluble transferrin receptor (sTfR), and transferrin saturation (TS). RESULTS: Iron status was greater in male Soldiers than female Soldiers, as hemoglobin and SF levels were higher (P<.05) and sTfR levels were lower (P<.05) in males as compared to females at each time-point. Despite a mean increase of greater than 25% in iron intake (mg/day) among both male (15+/-13 to 20.2+/-14.4) and female Soldiers (12.8+/-9.7 to 16+/-6.2) over the course of BCT, iron status declined in both groups. As compared to baseline, SF declined (P<.05) by 21% and 47%, sTfR increased (P<.05) by 17% and 30%, and TS declined (P<.05) by 23% and 54% in male and female Soldiers, respectively, over the course of BCT. CONCLUSIONS: These data indicate that although dietary iron intake improves, iron status declines in both male and female Soldiers during BCT, and the decline in female Soldiers is of a greater magnitude. Future studies should aim to determine the mechanism by which iron status declines during military training, with a focus on functional outcomes affecting Soldier health and performance. PMID- 26101909 TI - Female combat amputees have higher rates of posttraumatic stress disorder disability. AB - BACKGROUND: The civilian trauma literature suggests that the sexes differ in physical and mental health outcomes following traumatic injury. In order to determine if the reaction to combat injury is different between the sexes in a specific war wounded population, service members with amputations, we examined the disability profiles of male and female amputees. METHODS: All US combatants who sustained a major extremity amputation between October 2001 and July 2011 were examined for demographic and injury information from the Department of Defense Trauma Registry and for disability outcomes in the service specific Physical Evaluation Boards. The proportions of women versus men with various disabling conditions were compared using Fisher's Exact Test and the mean disability ratings for each condition were compared using student's t tests. FINDINGS: Among 1,107 amputees, 21 were female. There was no difference in the average age, military rank, or Injury Severity Score between the sexes. While the most common military occupation of male amputees was infantry service, the most common occupation for the female amputee was military police. The overall disability ratings between females and males were not different (82% for females, 75% for males). Female amputees had more frequent disability from posttraumatic stress disorder (PTSD, 8/21 [38%] vs 168/818 [17%]). Disability ratings from PTSD tended to also be higher in women. CONCLUSIONS: Outside of variable occupational descriptions, both male and female amputees were exposed to explosions resulting in their injuries. Consistent with many civilian trauma and veterans' population studies, female amputees have higher frequencies of disability from PTSD. These results support the need for additional effort and attention directed towards optimizing physical and mental fitness following deployment in order to reduce disability and promote return to duty. Because certain conditions, such as PTSD, may be more or less common in men versus women veterans, postdeployment fitness may need to be tailored in a gender specific way. PMID- 26101910 TI - Comparison of female and male casualty cohorts from conflicts in Iraq and Afghanistan. AB - Although there has been interest in the literature regarding the casualties within the recent US military conflicts in Iraq and Afghanistan, very little to date has looked specifically at a difference between the sexes. As the role of the female Soldier has changed over the years, so have the risk and the nature of the female casualty. Combat injuries in women are an important medical consideration that has yet to be studied. For the purposes of this study, the following questions pertained: Do female and male casualties from the US military in recent conflicts differ in age, service, rank, military operation, or other demographic characteristics? Do female and male casualties from the US military in recent conflicts differ in their injury characteristics such as Injury Severity Score (ISS), Abbreviated Injury Score (AIS), injury type (blunt versus penetrating), injury cause (mechanism of injury), and injury date? The Department of Defense Trauma Registry (DoDTR) was queried, returning results for 425 female and 14,982 male subjects who sustained musculoskeletal injuries from October 2003 (beginning of hostilities in Iraq) to December 2012. The female and male cohorts were compared and analyzed for significance in demographics (age, service, rank, and military operation) and injury characteristics (ISS, AIS, injury type, injury cause, and injury date). Female casualties differ from their male counterparts in that they are slightly younger (F=26.11, M=27.83 years; P<.001), proportionally more female casualties were in the Army (F=81.5%, M=72.2%; P<.001), and proportionally more women were injured during Operation Iraqi Freedom (F=75.6%, M=63.2%; P<.001). Female casualties showed on average lower ISS (F=7.49; M=9.68; P<.001) and lower AIS specific to the skeletal anatomic region (F=2.06; M=2.36; P<.001); however when broken down into battle versus nonbattle injury, the difference disappeared. Women were less likely to be injured in battle (F=33.1%; M=70.9%; P<.001) and less likely to be injured due to an explosive device (F=27.7%, M=55.2%; P<.001). Women comprised 2.75% of the DoDTR casualties during the studied time frame and were less likely to be involved in explosions or during battle. The ISS were significantly different when comparing battle and nonbattle injuries for both of the sexes. However, since men were more likely to be injured in battle, their total ISS mean was higher. PMID- 26101911 TI - Creating and sustaining a military women's Health Research Interest Group. AB - In 2008, four doctorate military nurse scientists representing the triservices (Army, Navy, and Air Force) identified a common interest in the health and care of all women in the armed forces. For 7 years, the team's shared vision to improve servicewomen's health inspired them to commit to a rigorous schedule of planning, developing, and implementing an innovative program that has the capability of advancing scientific knowledge and influencing health policy and practice through research. The ultimate goal of the Military Women's Health Research Interest Group (MWHRIG) is to support military clinicians and leaders in making evidence-based practice and policy decisions. They developed a 4-pronged approach to cultivate the science of military women's healthcare: evaluate the existing evidence, develop a research agenda that addresses gaps in knowledge, facilitate the collaboration of multidisciplinary research, and build the bench of future researchers. The MWHRIG has been a resource to key leaders; its value has been validated by multiservice and multidisciplinary consultations. However, the journey to goal attainment has only been achieved by the enduring commitment of these MWHRIG leaders and their passion to ensure the health and wellbeing of the many women who serve in the United States military. This article describes their journey of dedication. PMID- 26101912 TI - Complex d-TGA status post Rastelli repair presenting with palpitations: cardiac CTA imaging findings and discussion of long term outcomes. PMID- 26101913 TI - Spontaneously-forming spheroids as an in vitro cancer cell model for anticancer drug screening. AB - The limited translational value in clinic of analyses performed on 2-D cell cultures has prompted a shift toward the generation of 3-dimensional (3-D) multicellular systems. Here we present a spontaneously-forming in vitro cancer spheroid model, referred to as spheroids(MARY-X), that precisely reflects the pathophysiological features commonly found in tumor tissues and the lymphovascular embolus. In addition, we have developed a rapid, inexpensive means to evaluate response following drug treatment where spheroid dissolution indices from brightfield image analyses are used to construct dose-response curves resulting in relevant IC50 values. Using the spheroids(MARY-X) model, we demonstrate the unique ability of a new class of molecules, containing the caged Garcinia xanthone (CGX) motif, to induce spheroidal dissolution and apoptosis at IC50 values of 0.42 +/-0.02 MUM for gambogic acid and 0.66 +/-0.02 MUM for MAD28. On the other hand, treatment of spheroids(MARY-X) with various currently approved chemotherapeutics of solid and blood-borne cancer types failed to induce any response as indicated by high dissolution indices and subsequent poor IC50 values, such as 7.8 +/-3.1 MUM for paclitaxel. Our studies highlight the significance of the spheroids(MARY-X) model in drug screening and underscore the potential of the CGX motif as a promising anticancer pharmacophore. PMID- 26101914 TI - A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity. AB - Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate "on-target" toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (alphaFR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with alphaFR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based alphaFR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for alphaFR protein and exhibited reduced recognition of normal cells expressing low levels of alphaFR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and "on target off-tumor" toxicity that plague trials utilizing CARs containing mouse derived, high affinity scFvs. PMID- 26101915 TI - Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). AB - Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38's prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers. PMID- 26101917 TI - The Medicare Outpatient Imaging Efficiency Measure for Low Back Pain ("OP-8"). PMID- 26101916 TI - Serum dickkopf-1 is a novel serological biomarker for the diagnosis and prognosis of pancreatic cancer. AB - PURPOSE: To identify whether Dickkopf-1 (DKK1) could be a potential biomarker for early detection and prognosis in patients with pancreatic cancer (PC). METHODS: Serum was collected from 140 patients with pancreatic adenocarcinoma and 92 control patients without pancreatic adenocarcinoma. Serological levels of DKK1 were examined by enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity was compared with carbohydrate antigen 19-9 (CA19-9). A 2-year follow up was monitored to evaluate the correlation between DKK1 serum levels and overall survival. The expression of DKK1 in PC tumor tissues was also evaluated using immunohistochemistry staining. RESULTS: Serum levels of DKK1 and CA19-9 were elevated in PC patients in the early-stage cases. These levels increased with the advancement of clinical stage. There was significant difference in DKK1 serum levels between early and advanced PC stages. Receiver operating characteristic curve (ROCC) analysis showed that DKK1 was significantly better than CA19-9 in differentiating patients with PC from the controls (area under the curve (AUC) 0.919 versus 0.853, respectively), especially in distinguishing early stage cancer from chronic pancreatitis (CP). The expression of DKK1 in PC tissues correlated with its expression in serum samples. The overall survival rate was 24.4% in the group with higher DKK1 levels and was found to be significantly different from the group with lower DKK1 levels (33.3%). CONCLUSION: DKK1 may be a novel diagnostic/prognostic biomarker for PC. PMID- 26101918 TI - Recently Published Stroke Trials: What the Radiologist Needs to Know. PMID- 26101919 TI - Luminescence-based Imaging Approaches in the Field of Interventional Molecular Imaging. AB - Luminescence imaging-based guidance technologies are increasingly gaining interest within surgical and radiologic disciplines. Their promise to help visualize molecular features of disease in real time and with microscopic detail is considered desirable. Integrating luminescence imaging with three-dimensional radiologic- and/or nuclear medicine-based preinterventional imaging may overcome limitations such as the limited tissue penetration of luminescence signals. At the same time, the beneficial features of luminescence imaging may be used to complement the routinely used radiologic- and nuclear medicine-based modalities. To fully exploit this integrated concept, and to relate the largely experimental luminesce-based guidance approaches into perspective with routine imaging approaches, it is essential to understand the advantages and limitations of this relatively new modality. By providing an overview of the available luminescence technologies and the various clinically evaluated exogenous luminescent tracers (fluorescent, hybrid, and theranostic tracers), this review attempts to place luminescence-based interventional molecular imaging technologies into perspective to the available radiologic- and/or nuclear medicine-based imaging technologies. At the same time, the transition from anatomic to physiologic and even molecular interventional luminescence imaging is illustrated. PMID- 26101924 TI - Case 219: Pelvic Actinomycosis Mimicking Malignant Tumor. AB - A 53-year-old woman presented with a 3-month history of left inguinocrural and lumbar pain and anorexia with weight loss. No fever was reported. The patient had no prior pelvic surgery. Physical examination revealed a palpable nontender mass in the left groin area. There was no bloody or purulent discharge. Laboratory findings revealed inflammation with an increased C-reactive protein level (127 mg/L [1209 nmol/L]), leukocytosis (13 800/mm(3)), and microcytic anemia (hemoglobin level, 7.2 g/dL). Computed tomography (CT), fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT, and magnetic resonance (MR) imaging were performed. PMID- 26101920 TI - Endovascular Interventions for Acute and Chronic Lower Extremity Deep Venous Disease: State of the Art. AB - The societal and individual burden caused by acute and chronic lower extremity venous disease is considerable. In the past several decades, minimally invasive endovascular interventions have been developed to reduce thrombus burden in the setting of acute deep venous thrombosis to prevent both short- and long-term morbidity and to recanalize chronically occluded or stenosed postthrombotic or nonthrombotic veins in symptomatic patients. This state-of-the-art review provides an overview of the techniques and challenges, rationale, patient selection criteria, complications, postinterventional care, and outcomes data for endovascular intervention in the setting of acute and chronic lower extremity deep venous disease. Online supplemental material is available for this article. PMID- 26101925 TI - Age-related Association of Pancreatic Cysts, Pancreatic Adenocarcinoma, and All Cause Mortality. PMID- 26101926 TI - What Hath God Wrought. PMID- 26101927 TI - Prostatic Arterial Embolization versus Transurethral Resection of the Prostate for Benign Prostatic Hyperplasia. PMID- 26101928 TI - Screening Mammography Guidelines. PMID- 26101929 TI - Glioblastoma Multiforme: Exploratory Radiogenomic Analysis by Using Quantitative Image Features. PMID- 26101930 TI - Deborah M. Forrester, MD. PMID- 26101933 TI - Development of SHIVs with circulating, transmitted HIV-1 variants. AB - SHIV/macaque model is critical for pre-clinical HIV-1 research. The ability of this model to predict efficacious intervention(s) in humans depends on how faithfully the model recapitulates key features of HIV-1 transmission and pathogenesis. Here, we provide insights for rationally designing SHIVs with transmitted HIV-1 variants for vaccine and prevention research. PMID- 26101935 TI - Outcomes of endo-radiological approach to management of bile leakage after right lobe living donor liver transplantation. AB - BACKGROUND AND AIM: Bile leakage is a major complication after right lobe living donor liver transplantation (RLDLT). It can result in significant morbidities and, occasionally, mortalities. Endo-radiology is a non-surgical means that has been used to manage this complication. This study reviews the outcomes of the endo-radiological approach to the management of bile leakage after RLDLT with duct-to-duct anastomosis (DDA) at a high-volume center. METHOD: A retrospective study was conducted on all adult patients who received RLDLT at our center between January 2001 and December 2013. There were 496 RLDLTs performed during the study period. Only patients who had DDA as the only bile duct reconstruction method were included in the study. RESULTS: Twelve (3.7%) out of the 328 study subjects developed bile leakage after RLDLT. Six out of these 12 patients were successfully treated with the endo-radiological approach without the need for laparotomy. They had endoscopic retrograde cholangiography with stenting followed by percutaneous drainage of biloma. One of the 12 patients died from recurrence of hepatocellular carcinoma 37 months after transplantation. The remaining 11 patients are all alive. CONCLUSION: The endo-radiological approach should be the first-line management for bile leakage for selected patients with DDA as the bile duct reconstruction method. PMID- 26101936 TI - A Cu(II)-based strategy for catalytic enantioselective beta-borylation of alpha,beta-unsaturated acceptors. AB - Cu(I)-based chemistry has flourished over the last decade because of the reliable use of species such as soft acids. However, the unique nature of Cu(II) catalysts allows the well-documented Cu(I)-based chemistry to be extended. Prominent advantages of this approach include the ease of handling, the avoidance of strong base, and a wider substrate scope in enantioselective beta-borylation. PMID- 26101934 TI - Selective activation of D1 dopamine receptors impairs sensorimotor gating in Long Evans rats. AB - BACKGROUND AND PURPOSE: Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the prepulse inhibition (PPI) of the acoustic startle reflex. Notably, PPI deficits are associated with numerous neuropsychiatric conditions characterized by gating disturbances, including schizophrenia and Tourette syndrome. Ample evidence has shown that dopamine plays a key role in PPI regulation and, in particular, rodent studies indicate that this neurotransmitter modulates PPI through D1 and D2 dopamine receptors. In mice, the relative contributions of these two families of receptors are strain dependent. Conversely, the role of D1 receptors in the regulation of PPI across different rat strains remains unclear. EXPERIMENTAL APPROACH: We tested the effects of selective D1 and D2 receptor agonists and antagonists on the startle reflex and PPI of Sprague-Dawley, Wistar and Long-Evans rats. KEY RESULTS: In contrast with Sprague-Dawley and Wistar rats, the full D1 receptor agonist SKF82958 elicited significant PPI deficits in Long-Evans rats, an effect sensitive to the selective D1 antagonist SCH23390. CONCLUSIONS AND IMPLICATIONS: Our results suggest that, in Long-Evans rats, D1 receptor activation may be sufficient to significantly impair PPI. These data emphasize the role of D1 receptors in the pathophysiology of neuropsychiatric disorders featuring alterations in sensorimotor gating, and uphold the importance of the genetic background in shaping the role of dopamine receptors in the regulation of this key information-processing function. LINKED ARTICLES: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. PMID- 26101938 TI - Successful Liver Transplant Complicated by Severe Portopulmonary Hypertension After an Initial Aborted Attempt: Case Report and Review of Treatment Options. AB - Good right ventricular function and responsiveness to vasodilator therapy are the most important prerequisites for successful liver transplant in patients with portopulmonary hypertension. A patient with portopulmonary hypertension and good right ventricular function presented for deceased-donor liver transplant. Pulmonary arterial pressure was controlled with epoprostenol and sildenafil preoperatively. After anesthesia induction, pulmonary arterial pressure increased significantly and the procedure was aborted. Additional medical treatment included aggressive vasodilator therapy and the transplant was successfully performed 1 month later. During the procedure, elevations in pulmonary arterial pressure responded to a combination of inhaled nitric oxide, intravenous milrinone and nitroglycerin, and optimization of mechanical ventilation. PMID- 26101939 TI - Homohalocyclization: Electrophilic Bromine-Induced Cyclizations of Cyclopropanes. AB - An efficient method for the halocyclization of cyclopropanes has been developed. The cyclopropanes undergo a 1,3-addition reaction to form homohalocyclization products compared to conventional alkene halocyclizations. The reaction can be induced by various electrophilic halogenating agents including 1,3-dibromo-5,5 dimethylhydantoin and N-iodosuccinimide. In cyclopropane derivatives with a preexisting stereocenter, excellent induced diastereoselectivities can be observed. PMID- 26101940 TI - Organic Solvent-Free, One-Step Engineering of Graphene-Based Magnetic-Responsive Hybrids Using Design of Experiment-Driven Mechanochemistry. AB - In this study, we propose an organic solvent-free, one-step mechanochemistry approach to engineer water-dispersible graphene oxide/superparamagnetic iron oxide (GO/SPIOs) hybrids, for biomedical applications. Although mechanochemistry has been proposed in the graphene field for applications such as drug loading, exfoliation or polymer-composite formation, this is the first study to report mechanochemistry for preparation of GO/SPIOs hybrids. The statistical design of experiment (DoE) was employed to control the process parameters. DoE has been used to control formulation processes of other types of nanomaterials. The implementation of DoE for controlling the formulation processes of graphene-based nanomaterials is, however, novel. DoE approach could be of advantage as one can tailor GO-based hybrids of predicted yields and compositions. Hybrids were characterized by TEM, AFM FT-IR, Raman spectroscopy, and TGA. The dose-response magnetic resonance (MR) properties were confirmed by MR imaging of phantoms. The biocompatibility of the hybrids with A549 and J774 cell lines was confirmed by the modified LDH assay. PMID- 26101941 TI - Simple and Rapid Functionalization of Gold Nanorods with Oligonucleotides Using an mPEG-SH/Tween 20-Assisted Approach. AB - DNA conjugated gold nanorods (AuNRs) are widely applied for nanostructure assembly, gene therapy, biosensing, and drug delivery. However, it is still a great challenge to attach thiolated DNA on AuNRs, because the positively charged AuNRs readily aggregate in the presence of negatively charged DNA. This article reports an mPEG-SH/Tween 20-assisted method to load thiolated DNA on AuNRs in 1 h. Tween 20 and mPEG-SH are used to synergistically displace CTAB on the surface of AuNRs by repeated centrifugation and resuspension, and thiolated DNA are attached to AuNRs in the presence of 1 M NaCl, 100 mM MgCl2, or 100 mM citrate. AuNRs with different sizes and aspect ratios can be functionalized with DNA by this method. The number of DNA loaded on each AuNR can be easily controlled by the concentrations of mPEG-SH and Tween 20 or the ratio between DNA and AuNR. Functionalized AuNRs were used for nanoparticle assembly and cancer cell imaging to confirm that DNA anchored on the surface of AuNRs retains its hybridization and molecular recognition capability. The new method is easy, rapid, and robust for the preparation of DNA functionalized AuNRs for a variety of applications such as cancer therapy, drug delivery, self-assembly, and imaging. PMID- 26101943 TI - Regioselective Pd-Catalyzed Synthesis of 2,3,6-Trisubstituted Pyridines from Isoxazolinones. AB - Substituted pyridines are prevalent heterocycles of fundamental importance. Their efficient regioselective preparation is often still a challenge despite a large number of reported synthetic methodologies. In this letter we report an operationally simple approach that makes use of readily accessible isoxazolinones. The protocol involves a Pd(II)-catalyzed C-regioselective 1,4 addition to vinylketones, followed by a Pd(0)-catalyzed transformation, which is assumed to proceed via vinylnitrene-Pd intermediates. Both hydrogen and air are necessary for the pyridine formation step and could be employed at ratios above the upper explosive limit thus avoiding a safety issue. This new strategy allows an effective, scalable and practical access to various previously unknown 2,3,6 trisubstituted pyridines. PMID- 26101942 TI - Double Electron-Electron Spin Resonance Tracks Flavodoxin Folding. AB - Protein folding is one of the important challenges in biochemistry. Understanding the folding process requires mapping of protein structure as it folds. Here we test the potential of distance determination between paramagnetic spin-labels by a pulsed electron paramagnetic resonance method. We use double electron-electron spin resonance (DEER) to study the denaturant-dependent equilibrium folding of flavodoxin. This flavoprotein is spin-labeled with MTSL ((1-oxy-,2,2,5,5 tetramethyl-d-pyrroline-3-methyl)-methanethiosulfonate) at positions 69 and 131. We find that nativelike spin-label separation dominates the distance distributions up to 0.8 M guanidine hydrochloride. At 2.3 M denaturant, the distance distributions show an additional component, which we attribute to a folding intermediate. Upon further increase of denaturant concentration, the protein expands and evidence for a larger number of conformations than in the native state is found. We thus demonstrate that DEER is a versatile technique to expand the arsenal of methods for investigating how proteins fold. PMID- 26101944 TI - An observational study on disturbed peripheral circadian rhythms in hemodialysis patients. AB - The quality of life of hemodialysis (HD) patients is hampered by reduced nocturnal sleep quality and excessive daytime sleepiness. In addition to the sleep/wake cycle, levels of circadian biomarkers (e.g. melatonin) are disturbed in end-stage renal disease (ESRD). This suggests impaired circadian clock performance in HD patients, but the underlying mechanism is unknown. In this observational study, diurnal rhythms of sleep, serum melatonin and cortisol concentrations and clock gene mRNA expression are compared between HD patients (n = 9) and healthy control subjects (n = 9). In addition, the presence of circulating factors that might affect circadian rhythmicity is tested in vitro with cell culture experiments. Reduced sleep quality (median sleep onset latency [interquartile range] of 23.9 [17.3] min for patients versus 5.0 [10] minutes for controls, p < 0.01; mean (+/- SD) sleep efficiency 70.2 +/- 8.1% versus 82.9 +/- 10.9%, p = 0.02 and mean awake minutes after sleep onset 104.8 +/- 27.9 versus 54.6 +/- 41.6 minutes, p = 0.01) and increased daytime sleepiness (mean Epworth Sleepiness Score of 10.0 +/- 4.8 versus 3.9 +/- 2.0, p < 0.01) were confirmed in HD patients. Reduced nocturnal melatonin concentrations (1 AM: 98.1 [122.9] pmol/L versus 12.5 [44.2] pmol/L, p = 0.019; 5 AM: 114.0 [131.6] pmol/L versus 11.8 [86.8] pmol/L, p = 0.031) and affected circadian control of cortisol rhythm and circadian expression of the clock gene REV-ERBalpha were found. HD patient serum had a higher capacity to synchronize cells in vitro, suggesting an accumulated level of clock resetting compounds in HD patients. These compounds were not cleared by hemodialysis treatment or related to frequently used medications. In conclusion, the abovementioned results strongly suggest a disturbance in circadian timekeeping in peripheral tissues of HD patients. Accumulation of clock resetting compounds possibly contributes to this. Future studies are needed for a better mechanistic understanding of the interaction between renal failure and perturbation of the circadian clock. PMID- 26101945 TI - Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine. AB - Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process. PMID- 26101947 TI - Theta-gamma phase-phase coupling during working memory maintenance in the human hippocampus. AB - The theta-gamma neural coding theory suggests that multiple items are represented in working memory (WM) by a superposition of gamma cycles on theta oscillations. To enable a stable, non-interfering representation of multiple items, such a theta-gamma neural code may be reflected by phase-phase coupling, i.e., a precise locking of gamma subcycles to specific theta phases. Recent data have indicated that the hippocampus critically contributes to multi-item working memory. Therefore, we investigated phase-phase coupling patterns in the hippocampus based on intracranial EEG recordings in presurgical epilepsy patients performing a variant of the serial Sternberg WM task. In accordance with predictions of the theta-gamma coding theory, we observed increased phase-phase coupling between theta and beta/gamma activity during working memory maintenance compared to inter trial intervals. These phase-phase coupling patterns were apparent during maintenance of two and four items, but not during maintenance of a single item, where prominent lower coupling ratios occurred. Furthermore, we observed that load-dependent changes of coupling factors correlated with individual WM capacities. Our data demonstrate that multi-item WM is associated with changes in hippocampal phase-phase coupling between theta and beta/gamma activity. PMID- 26101946 TI - Inflammatory and Immune Activation in Intestinal Myofibroblasts Is Developmentally Regulated. AB - We previously demonstrated that intestinal myofibroblasts from immature tissue produce excessive IL-8 in response to Escherichia coli lipopolysaccharide (LPS) compared to cells from mature tissue. However, it is unknown whether other cytokines and TLR agonists contribute to this developmentally regulated response. The aim of this study was to further characterize differences in inflammatory signaling in human primary intestinal fibroblasts from fetal (FIF) and infant (IIF) tissue and examine their potential to activate the adaptive immune response in vitro. Cytokine profiles of LPS-stimulated FIF and IIF were assessed by cytokine profile array. IL-8, IL-6, and IL-10 production in response to TLR2, TLR2/6, TLR4, and TLR5 agonists was determined by quantitative ELISA. The potential of activated myofibroblasts to activate adaptive immunity was determined by measuring surface class II MHC expression using flow cytometry. LPS stimulated FIF produced a distinct proinflammatory cytokine profile consisting of MCP-1, GRO-alpha, IL-6, and IL-8 expression. FIF produced significant IL-8 and IL 6 in response to TLR4 agonist. IIF produced significant levels of IL-8 and IL-6 in the presence of TLR5 and TLR2 agonists. IFN-gamma-treated FIF expressed greater HLA-DR levels compared to unstimulated controls and IFN-gamma- and LPS treated IIF. Activated FIF produce a more diverse inflammatory cytokine profile and greater levels of IL-8 and IL-6 in response to TLR4 stimulation compared to IIF. FIF express class II MHC proteins associated with activation of the adaptive immune response. These data suggest that FIF may contribute to bacterial associated gut inflammation in the immature intestine. PMID- 26101948 TI - Nurse practitioners' work hours and overtime: How much, and under what working conditions? AB - PURPOSE: To explore the nature and prevalence of nurse practitioner (NP) overtime, work hours, and their relationship to practice within NP work conditions. DATA SOURCES: A secondary analysis of data extracted from the 2012 National Sample Survey of Nurse Practitioners. The focus in this study was on data from NPs in active practice in clinical settings. The final analytic sample consisted of 9010 NPs. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: NPs working in hospitals and long-term care settings tended to work more than 40 h/week (p < .001). When healthcare facilities used electronic health records (p < .001) or had recently adopted electronic health records (p = .002), NPs were found to work more hours per week than those who did not. Regarding the type of relationships with physicians, NPs who worked more than 40 h/week either had hierarchical relationships with them (p < 0.001), or relationships in which the physician examined and signed off on patients whom the NP had examined (p < .001). These analyses provide a preliminary description of the nature and prevalence of NP work hours/overtime and work conditions related to longer work hours. Further study is indicated to assess the potential impact of work hours/overtime on NP roles and patient outcomes. PMID- 26101949 TI - Ureteral obstruction in cancer patients: a qualitative study. PMID- 26101951 TI - Gradient-induced voltages on 12-lead ECGs during high duty-cycle MRI sequences and a method for their removal considering linear and concomitant gradient terms. AB - PURPOSE: To restore 12-lead electrocardiographic (ECG) signal fidelity inside MRI by removing magnetic field gradient-induced voltages during high gradient duty cycle sequences. THEORY AND METHODS: A theoretical equation was derived to provide first- and second-order electrical fields induced at individual ECG electrodes as a function of gradient fields. Experiments were performed at 3T on healthy volunteers using a customized acquisition system that captured the full amplitude and frequency response of ECGs, or a commercial recording system. The 19 equation coefficients were derived via linear regression of data from accelerated sequences and were used to compute induced voltages in real-time during full resolution sequences to remove ECG artifacts. Restored traces were evaluated relative to ones acquired without imaging. RESULTS: Measured induced voltages were 0.7 V peak-to-peak during balanced steady state free precession (bSSFP) with the heart at the isocenter. Applying the equation during gradient echo sequencing, three-dimensional fast spin echo, and multislice bSSFP imaging restored nonsaturated traces and second-order concomitant terms showed larger contributions in electrodes further from the magnet isocenter. Equation coefficients are evaluated with high repeatability (rho = 0.996) and are dependent on subject, sequence, and slice orientation. CONCLUSION: Close agreement between theoretical and measured gradient-induced voltages allowed for real-time removal. Prospective estimation of sequence periods in which large induced voltages occur may allow hardware removal of these signals. PMID- 26101952 TI - Administration of alpha-Galactosylceramide Improves Adenine-Induced Renal Injury. AB - Natural killer T (NKT) cells are a subset of lymphocytes that reacts to glycolipids presented by CD1d. Invariant NKT cells (iNKT) correspond to >90% of the total population of NKTs and reacts to alpha-galactosylceramide (alphaGalCer). alphaGalCer promotes a complex mixture of Th1 and Th2 cytokines, as interferon (IFN)-gamma and interleukin (IL)-4. NKT cells and IFN-gamma are known to participate in some models of renal diseases, but further studies are still necessary to elucidate their mechanisms. The aim of our study was to analyze the participation of iNKT cells in an experimental model of tubule interstitial nephritis. We used 8-wk-old C57BL/6j, Jalpha18KO and IFN-gammaKO mice. They were fed a 0.25% adenine diet for 10 d. Both adenine-fed wild-type (WT) and Jalpha18KO mice exhibited renal dysfunction, but adenine-fed Jalpha18KO mice presented higher expression of kidney injury molecule-1 (KIM-1), tumor necrosis factor (TNF)-alpha and type I collagen. To analyze the role of activated iNKT cells in our model, we administered alphaGalCer in WT mice during adenine ingestion. After alphaGalCer injection, we observed a significant reduction in serum creatinine, proinflammatory cytokines and renal fibrosis. However, this improvement in renal function was not observed in IFN-gammaKO mice after alphaGalCer treatment and adenine feeding, illustrating that this cytokine plays a role in our model. Our findings may suggest that IFN-gamma production is one of the factors contributing to improved renal function after alphaGalCer administration. PMID- 26101953 TI - Inhibition of IkappaB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock. AB - Nuclear factor-kappa B (NF-kappaB) activation is widely implicated in multiple organ failure (MOF); however, a direct inhibitor of IkappaB kinase (IKK), which plays a pivotal role in the activation of NF-kappaB, has not been investigated in shock. Thus, the aim of the present work was to investigate the effects of an IKK inhibitor on the MOF associated with hemorrhagic shock (HS). Therefore, rats were subjected to HS and were resuscitated with the shed blood. Rats were treated with the inhibitor of IKK or vehicle at resuscitation. Four hours later, blood and organs were assessed for organ injury and signaling events involved in the activation of NF-kappaB. Additionally, survival following serum deprivation was assessed in HK-2 cells treated with the inhibitor of IKK. HS resulted in renal dysfunction, lung, liver and muscular injury, and increases in serum inflammatory cytokines. Kidney and liver tissue from HS rats revealed increases in phosphorylation of IKKalphabeta and IkappaBalpha, nuclear translocation of NF kappaB and expression of inducible isoform of nitric oxide synthase (iNOS). IKK16 treatment upon resuscitation attenuated NF-kappaB activation and activated the Akt survival pathway, leading to a significant attenuation of all of the above parameters. Furthermore, IKK16 exhibited cytoprotective effects in human kidney cells. In conclusion, the inhibitor of IKK complex attenuated the MOF associated with HS. This effect may be due to the inhibition of the NF-kappaB pathway and activation of the survival kinase Akt. Thus, the inhibition of the IKK complex might be an effective strategy for the prevention of MOF associated with HS. PMID- 26101954 TI - Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia. AB - Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons. Suppression of Nav1.3 activity can attenuate neuropathic pain induced by peripheral nerve injury. Previous studies have shown that expression of Nav1.3 is upregulated in dorsal root ganglion (DRG) neurons of diabetic rats that exhibit neuropathic pain. Here, we hypothesized that viral-mediated knockdown of Nav1.3 in painful diabetic neuropathy would reduce neuropathic pain. We used a validated recombinant adeno-associated virus (AAV)-shRNA-Nav1.3 vector to knockdown expression of Nav1.3, via a clinically applicable intrathecal injection method. Three weeks following vector administration, we observed a significant rate of transduction in DRGs of diabetic rats that concomitantly reduced neuronal excitability of dorsal horn neurons and reduced behavioral evidence of tactile allodynia. Taken together, these findings offer a novel gene therapy approach for addressing chronic diabetic neuropathic pain. PMID- 26101956 TI - Polymorphisms in LPL, CETP, and HL protect HIV-infected patients from atherogenic dyslipidemia in an allele-dose-dependent manner. AB - HIV-infected patients treated with highly active antiretroviral therapy (HAART) may be predisposed to a lipid profile, associated with increased cardiovascular risk, derived from having high triglycerides (TG) and low high-density lipoprotein cholesterol (HDLc) levels. We propose that genetic variability leaves some HIV-infected patients more predisposed to this lipid profile than others. We performed a cross-sectional, observational study including 321 antiretroviral treated HIV-infected patients classified as normolipidemic (n=173) or presenting with high TG (>=1.7 mmol/liter) and low HDLc [<1.02 (men) or 1.28 mmol/liter (women)] (n=148) to investigate the impact of 13 polymorphisms of 9 genes affecting lipid metabolism (APOA5, APOC3, LPL, CETP, HL, MTP, APOE, LRP5, and VLDLR genes). The polymorphism rs328 in LPL was 40% significantly more frequent in normolipidemics (p=0.018), and in the same group, polymorphisms rs708272 in CETP and rs1800588 in HL were 10% significantly more frequent (p=0.037 for both polymorphisms). Patients who presented a combination of one to six alleles from these polymorphisms had 10% increased HDLc levels [1.13 (0.40) vs. 1.24 (0.23) mmol/liter, p=0.002] and a trend toward lower triglycerides [2.23 (2.34) vs. 1.89 (1.24) mmol/liter] and lower remnant-like particle cholesterol (RLPc) [16.41 (11.42) vs. 12.99 (11.69) mmol/liter]. This effect was dependent on the number of protective alleles and independent of the regimen administered. Polymorphisms in LPL, CETP, and HL protect HIV-infected patients from developing the dyslipidemia derived from high TG and low HDLc levels in a dose-dependent manner. PMID- 26101957 TI - Molecular Dynamics Study of the Gold/Ionic Liquids Interface. AB - The results of a systematic molecular dynamics study of the interfacial structure between the gold (100) surface and two room-temperature ionic liquids, namely, 1 butyl-3-methylimidazolium hexafluorophosphate ([BMIm][PF6]) and 1-butyl-3 methylimadazolium bis(trifluoromethylsulfonyl)imide ([BMIm][NTf2]), are herein reported. It is found that near an uncharged surface the IL structure differs from its bulk, having an enhanced density extended until the two first layers. Interfacial layering is clearly observed at the gold surface, with a higher effect for the [BMIm][NTf2] IL but a higher packing for [BMIm][PF6]. In both ILs the alkyl side chains are oriented parallel to the interface while the imidazolium rings tend to be parallel to the interface in about 60% of the cases. The presence of the interface has a higher impact on the orientation of the cations than on the chemical properties of the counterion. The surface potential drop across the interface is more pronounced toward a negative value for ([BMIm][PF6]) than for ([BMIm][NTf2]), due to relatively larger local density of the anions for ([BMIm][PF6]) near the gold surface. PMID- 26101955 TI - Aspirin's Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses. AB - Salicylic acid (SA) and its derivatives have been used for millennia to reduce pain, fever and inflammation. In addition, prophylactic use of acetylsalicylic acid, commonly known as aspirin, reduces the risk of heart attack, stroke and certain cancers. Because aspirin is rapidly de-acetylated by esterases in human plasma, much of aspirin's bioactivity can be attributed to its primary metabolite, SA. Here we demonstrate that human high mobility group box 1 (HMGB1) is a novel SA-binding protein. SA-binding sites on HMGB1 were identified in the HMG-box domains by nuclear magnetic resonance (NMR) spectroscopic studies and confirmed by mutational analysis. Extracellular HMGB1 is a damage-associated molecular pattern molecule (DAMP), with multiple redox states. SA suppresses both the chemoattractant activity of fully reduced HMGB1 and the increased expression of proinflammatory cytokine genes and cyclooxygenase 2 (COX-2) induced by disulfide HMGB1. Natural and synthetic SA derivatives with greater potency for inhibition of HMGB1 were identified, providing proof-of-concept that new molecules with high efficacy against sterile inflammation are attainable. An HMGB1 protein mutated in one of the SA-binding sites identified by NMR chemical shift perturbation studies retained chemoattractant activity, but lost binding of and inhibition by SA and its derivatives, thereby firmly establishing that SA binding to HMGB1 directly suppresses its proinflammatory activities. Identification of HMGB1 as a pharmacological target of SA/aspirin provides new insights into the mechanisms of action of one of the world's longest and most used natural and synthetic drugs. It may also provide an explanation for the protective effects of low-dose aspirin usage. PMID- 26101958 TI - Reductive Dehalogenation of Oligocyclic Phenolic Bromoaromatics by Dehalococcoides mccartyi Strain CBDB1. AB - Dehalococcoides mccartyi strains transform many halogenated compounds and are used for bioremediation. Such anaerobic transformations were intensively studied with chlorinated and simply structured compounds such as chlorinated benzenes, ethenes, and ethanes. However, many halogenated oligocyclic aromatic compounds occur in nature as either naturally produced materials or as part of commercial products such as pharmaceuticals, pesticides, or flame retardants. Here, we demonstrate that the D. mccartyi strain CBDB1 reductively debrominated two oligocyclic aromatic phenolic compounds, tetrabromobisphenol A (TBBPA) and bromophenol blue (BPB). The strain CBDB1 completely converted TBBPA to bisphenol A and BPB to phenol red with a stepwise removal of all bromide substituents. Debromination (but no cell growth) was detected in the cultures cultivated with TBBPA. In contrast, strain CBDB1 grew when interacting with BPB, demonstrating that this substrate was used as an electron acceptor for organobromine respiration. High doses of BPB delayed debromination and inhibited growth in the early cultivation phase. A higher toxicity of TBBPA compared with that of BPB might be due to the higher lipophilicity of TBBPA. Mass spectrometric analyses of whole-cell extracts demonstrated that two proteins encoded by the reductive dehalogenase homologous genes CbdbA1092 and CbdbA1503 were specifically induced by the used oligocyclic compounds, whereas others (e.g., CbdbA84 (CbrA)) were downregulated. PMID- 26101959 TI - Microwave-Assisted Multicomponent Synthesis of Dihydroquinoxalinones on Soluble Polymer Support. AB - A one-pot and two-step reaction of four components, including aldehydes, Fmoc protected alpha-amino acid, isocyanide, and soluble polymer-supported 4-fluoro-3 amino benzoate ester, was developed for an efficient synthesis of dihydroquinoxalinones under microwave irradiation. Fmoc deprotection followed by intramolecular cyclization of the diamide gave a facile access to novel bicyclic quinoxalin-2-ones. On the basis of this approach, a new route to synthesize this privileged scaffold from the diamide intermediate was designed and accomplished with high yields. Use of multicomponent reaction (MCR) has been shown to display a good functional group tolerance, while the product isolation and purification is straightforward by precipitation and washings. Current library discusses the synthesis and diversification of 21 compounds produced using this strategy. PMID- 26101960 TI - Poly-3-hydroxybutyrate (PHB) production from alkylphenols, mono and poly-aromatic hydrocarbons using Bacillus sp. CYR1: A new strategy for wealth from waste. AB - In the present study five different types of alkylphenols, each of the two different types of mono and poly-aromatic hydrocarbons were selected for degradation, and conversion into poly-3-hydroxybutyrate (PHB) using the Bacillus sp. CYR1. Strain CYR1 showed growth with various toxic organic compounds. Degradation pattern of all the organic compounds at 100 mg/l concentration with or without addition of tween-80 were analyzed using high pressure liquid chromatography (HPLC). Strain CYR1 showed good removal of compounds in the presence of tween-80 within 3 days, but it took 6 days without addition of tween 80. Strain CYR1 showed highest PHB production with phenol (51 +/- 5%), naphthalene (42 +/- 4%), 4-chlorophenol (32 +/- 3%) and 4-nonylphenol (29 +/- 3%). The functional groups, structure, and thermal properties of the produced PHB were analyzed. These results denoted that the strain Bacillus sp. CYR1 can be used for conversion of different toxic compounds persistent in wastewaters into useable biological polyesters. PMID- 26101961 TI - Strategies of preserving lipids in microorganism after fermentation. AB - Microbial oil is accumulated by microorganisms as stored energy during cultivation, and will be degraded to generate energy when they are not able to obtain external energy source. As the lipid is the desired production, the in situ degradation of oil by microorganisms after fermentation or during downstream processing has to be prevented. This study investigated the effect of pH, thermal, salinity, bead milling, ultrasonication, and microwave treatment on the viability of Trichosporon oleaginosus when it was used for lipid production. The cells in broth were completely inactivated with the treatment of pH 1 and 2 for 1h, temperature 80 degrees C for 10 min, ultrasonication for 8 min, and microwave for 6 min, respectively. It was observed that these treatments had no impact on final product (biodiesel) composition and were considered as safe and efficient methods to preserve lipid in cells. PMID- 26101962 TI - New yeast-based approaches in production of palmitoleic acid. AB - Palmitoleic acid is found in certain dairy products and has broad applications in medicine and cosmetics. We tried to find a suitable producer of this acid among traditional biotechnological yeast species (Kluyveromyces polysporus, Torulaspora delbrueckii, Saccharomyces cerevisiae) characterized by high biomass yield and Candida krusei, Yarrowia lipolytica and Trichosporon cutaneum accumulating large amounts of lipids. The main factor affecting the content of palmitoleic acid was found to be the C/N ratio in the culture medium, with ammonium sulfate as an optimum nitrogen source leading to highest biomass yield with concomitantly increased lipid accumulation, and an increased content of omega6-linoleic acid, the precursor of prostaglandins, leukotrienes, and thromboxanes. We found that C. krusei can be conveniently used for the purpose, albeit only under certain cultivation conditions, whereas S. cerevisiae can produce high and stable amounts of palmitoleic acid in a broad range of cultivation conditions ranging from conventional to nutrient limitations. PMID- 26101963 TI - Use of PCR-DGGE based molecular methods to assessment of microbial diversity during anaerobic treatment of antibiotic combinations. AB - As it is currently often not know how anaerobic bioreactors, e.g. for biogas production, react if the substrate is contaminated by toxic compounds like antibiotics. This study evaluated how anaerobic sequencing batch reactors were affected by amendments of different antibiotics and stepwise increasing concentrations. The compositions of microbial community were determined in the seed sludge using 16S rRNA gene clone libraries and PCR-DGGE analyses were used for the detection of microbial community changes upon antibiotics additions. According to PCR-DGGE results, the syntrophic interaction of acetogens and methanogens is critical to the performance of the reactors. Failure to maintain the stability of these microorganisms resulted in a decrease in the performance and stability of the anaerobic reactors. Assessment of DGGE data is also useful for suggesting the potential to control ultimate microbial community structure, especially derived from Gram-negative bacteria, through bioaugmentation to successful for antibiotic biodegradation. PMID- 26101964 TI - Performance of mesophilic biohydrogen-producing cultures at thermophilic conditions. AB - In this study, batch tests were conducted to investigate the performance of mesophilic anaerobic digester sludge (ADS) at thermophilic conditions and estimate kinetic parameters for co-substrate fermentation. Starch and cellulose were used as mono-substrate and in combination as co-substrates (1:1 mass ratio) to conduct a comparative assessment between mesophilic (37 degrees C) and thermophilic (60 degrees C) biohydrogen production. Unacclimatized mesophilic ADS responded well to the temperature change. The highest hydrogen yield of 1.13 mol H2/mol hexose was observed in starch-only batches at thermophilic conditions. The thermophilic cellulose-only yield (0.42 mol H2/mol hexose) was three times the mesophilic yield (0.13 mol H2/mol hexose). Interestingly, co-fermentation of starch-cellulose at mesophilic conditions enhanced the hydrogen yield by 26% with respect to estimated mono-substrate yields, while under thermophilic conditions no enhancement in the overall yield was observed. Interestingly, the estimated overall Monod kinetic parameters showed higher rates at mesophilic than thermophilic conditions. PMID- 26101965 TI - Nitrification recovery behavior by bio-accelerators in copper-inhibited activated sludge system. AB - Copper (Cu) is a toxic heavy metal which can cause inhibitory effects on nitrification process in biological wastewater treatment systems. However, few studies have done to dose accelerators into Cu-inhibited activated sludge system to promote bioactivity recovery of ammonia-oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB). In this study, four ingredients of bio-accelerators were developed and dosed in five parallel SBRs. The effluent NH4(+)-N, NO2(-)-N and NO3(-)-N concentrations, specific oxygen uptake rate (SOUR), and Cu distribution were investigated to assess the bioactivity recovery effects. Results showed that, among biotin, L-aspartic acid and cytokinin, L-aspartic acid was the most effective for the fast bioactivity recovery of nitrifying bacteria. The combination of these three substances was optimum and Cu-inhibited activated sludge system could be 100% recovered in 8 days. The bio-accelerators proposed in this study can be potentially applied in the emergency treatment in biological wastewater treatment systems. PMID- 26101966 TI - Cross-Linking Cellulosic Fibers with Photoreactive Polymers: Visualization with Confocal Raman and Fluorescence Microscopy. AB - The properties of paper sheets can be tuned by adjusting the surface or bulk chemistry using functional polymers that are applied during (online) or after (offline) papermaking processes. In particular, polymers are widely used to enhance the mechanical strength of the wet state of paper sheets. However, the mechanical strength depends not only on the chemical nature of the polymeric additives but also on the distribution of the polymer on and in the lignocellulosic paper. Here, we analyze the photochemical attachment and distribution of hydrophilic polydimethylacrylamide-co-methacrylate-benzophenone P(DMAA-co-MABP) copolymers with defined amounts of photoreactive benzophenone moieties in model paper sheets. Raman microscopy was used for the unambiguous identification of P(DMAA-co-MABP) and cellulose specific bands and thus the copolymer distribution within the cellulose matrix. Two-dimensional Raman spectral maps at the intersections of overlapping cellulose fibers document that the macromolecules only partially surround the cellulose fibers, favor to attach to the fiber surface, and connect the cellulose fibers at crossings. Moreover, the copolymer appears to accumulate preferentially in holes, vacancies, and dips on the cellulose fiber surface. Correlative brightfield, Raman, and confocal laser scanning microscopy finally reveal a reticular three-dimensional distribution of the polymer and show that the polymer is predominately deposited in regions of high capillarity (i.e., in proximity to fine cellulose fibrils). These data provide deeper insights into the effects of paper functionalization with a copolymer and aid in understanding how these agents ultimately influence the local and overall properties of paper. PMID- 26101967 TI - Pattern Recognition-Based Approach for Identifying Metabolites in Nuclear Magnetic Resonance-Based Metabolomics. AB - Identification and assignments of metabolites is an important step in metabolomics and is necessary for the discovery of new biomarkers. In nuclear magnetic resonance (NMR) spectroscopy-based studies, the conventional approach involves a database search, wherein chemical shifts are assigned to specific metabolites by use of a tolerance limit. This is inefficient because deviation in chemical shifts associated with pH or temperature variations, as well as missing peaks, impairs a robust comparison with the database. We propose here a novel method based on matching the pattern of peaks rather than absolute tolerance thresholds, using a combination of geometric hashing and similarity scoring techniques. Tests with 719 metabolites from the Human Metabolome Database (HMDB) show that 100% of the metabolites can be assigned correctly when accurate data are available. A high success rate is obtained even in the presence of large chemical shift deviations such as 0.5 ppm in (1)H and 3 ppm in (13)C and missing peaks (up to 50%), compared to nearly no assignments obtained under these conditions with existing methods that employ a direct database search approach. The method was evaluated on experimental data on a mixture of 16 metabolites at eight different combinations of pH and temperature conditions. The pattern recognition approach thus helps in identification and assignment of metabolites independent of the pH, temperature, and ionic strength used, thereby obviating the need for spectral calibration with internal or external standards. PMID- 26101968 TI - Synthesis and optimization of Ag-TiO2 composite nanofibers for photocatalytic treatment of impaired water sources. AB - In this work, Ag-TiO2 composite nanofibers were fabricated by electrospinning, where the composition and crystallinity were tuned by controlling the precursor composition and annealing conditions. Characterization revealed that bulk embedded Ag nanoparticles inhibited anatase-to-rutile phase transformation and a decrease in band gap from 3.2 down to 2.8 eV with increase in the Ag content. The photocatalytic activity of 0.5 at.% Ag-TiO2 nanofibers toward phenol degradation was the greatest, outperforming both unmodified TiO2 nanofibers and commercially available TiO2 Aeroxide((r)) P25 by a factor of ~3. The high reactivity of the low content Ag-TiO2 nanofibers can be attributed to the addition of electron traps, which provide efficient carrier separation and, therefore, decreased recombination. However, further increase in Ag content led to lower photoreactivity, most likely due to the growth of the Ag nanoparticles, which suggests an optimal size of 2 to 3 nm for the Ag nanoparticles at 0.5 at.% provided the greatest photoreactivity. Ag-TiO2 nanofibers show great promise as innovative and highly performing nanomaterials for future nanotechnology-based treatment systems, particularly when the photoreactivity demonstrate herein is used in synergy with the established antimicrobial activity of nano-Ag. PMID- 26101969 TI - Enhanced azo dye removal in a continuously operated up-flow anaerobic filter packed with henna plant biomass. AB - Effects of henna plant biomass (stem) packed in an up-flow anaerobic bio-filter (UAF) on an azo dye (AO7) removal were investigated. AO7 removal, sulfanilic acid (SA) formation, and pseudo first-order kinetic constants for these reactions (kAO7 and kSA) were higher in the henna-added UAF (R2) than in the control UAF without henna (R1). The maximum kAO7 in R1 and R2 were 0.0345 and 0.2024 cm(-1), respectively, on day 18; the corresponding molar ratios of SA formation to AO7 removal were 0.582 and 0.990. Adsorption and endogenous bio-reduction were the main AO7 removal pathways in R1, while in R2 bio-reduction was the dominant. Organics in henna could be released and fermented to volatile fatty acids, acting as effective electron donors for AO7 reduction, which was accelerated by soluble and/or fixed lawsone. Afterwards, the removal process weakened over time, indicating the demand of electron donation and lawsone-releasing during the long term operation of UAF. PMID- 26101970 TI - Complexation of cationic-neutral block polyelectrolyte with insulin and in vitro release studies. AB - Insulin (INS) was incorporated into complexes with the block polyelectrolyte quaternized poly[3,5-bis(dimethylaminomethylene)hydroxystyrene]-b-poly(ethylene oxide) (QNPHOSEO), which is a cationic-neutral block polyelectrolyte. Light scattering techniques are used in order to examine the size, the size distribution and the zeta-potential of the nanocarriers in aqueous and biological media, which are found to depend on the ratio of the components and the physicochemical parameters during and after complex preparation. Circular dichroism and infrared spectroscopy, employed to investigate the structure of the complexed INS, show no alteration of protein structure after complexation. In vitro release profiles of the entrapped protein are found to depend on the ratio of the components and the solution conditions used during preparation of the complexes. PMID- 26101971 TI - Catalytic Enantioselective Peroxidation of alpha,beta-Unsaturated Aldehydes for the Asymmetric Synthesis of Biologically Important Chiral Endoperoxides. AB - We have developed an unprecedented highly enantioselective catalytic peroxidation of enals. Critical to this development is the discovery that varying the structure of the hydroperoxide has a significant impact on the enantioselectivity of the organocatalytic asymmetric peroxidation. This novel transformation enabled the development of an enantioselective route toward the core structure shared by all members of the stolonoxide family of anticancer natural products, a connected trans-3,6-disubstituted-1,2-dioxane and trans-2,5-disubstituted-tetrahydrofuran ring system. Our route also features an unprecedented cyclization cascade of a chiral bis(epoxy)hydroperoxide. The new methodology and synthetic strategy established in this work should be applicable to the enantioselective synthesis of a broad range of chiral 1,2-dioxolanes and 1,2-dioxanes, thereby facilitating biological and medicinal chemistry studies of peroxy natural products. PMID- 26101972 TI - Impact of Postoperative Antibiotic Prophylaxis Duration on Surgical Site Infections in Autologous Breast Reconstruction. AB - BACKGROUND: Although some surgeons prescribe prolonged postoperative antibiotics after autologous breast reconstruction, evidence is lacking to support this practice. We used the Tracking Operations and Outcomes for Plastic Surgeons database to evaluate the association between postoperative antibiotic duration and the rate of surgical site infection (SSI) in autologous breast reconstruction. STUDY DESIGN: The intervention of interest for this study was postoperative duration of antibiotic prophylaxis: either discontinued 24 hours after surgery or continued beyond 24 hours. The primary outcome variable of interest for this study was the presence of SSI within 30 days of autologous breast reconstruction. Cohort characteristics and 30-day outcomes were compared using chi2 and Fischer exact tests for categorical variables and Student t tests for continuous variables. Multivariate logistic regression was used to control for confounders. RESULTS: A total of 1036 patients met inclusion criteria for our study. Six hundred fifty-nine patients (63.6%) received antibiotics for 24 hours postoperatively, and 377 patients (36.4%) received antibiotics for greater than 24 hours. The rate of SSI did not differ significantly between patients given antibiotics for only 24 hours and those continued on antibiotics beyond the 24 hour postoperative time period (5.01% vs 2.92%, P = 0.109). Furthermore, antibiotic duration was not predictive of SSI in multivariate regression modeling. CONCLUSIONS: We did not find a statistically significant difference in the rate of SSI in patients who received 24 hours of postoperative antibiotics compared to those that received antibiotics for greater than 24 hours. These findings held for both purely autologous reconstruction as well as latissimus dorsi reconstruction in conjunction with an implant. Thus, our study does not support continuation of postoperative antibiotics beyond 24 hours after autologous breast reconstruction. PMID- 26101973 TI - Effects of Cleft Width and Veau Type on Incidence of Palatal Fistula and Velopharyngeal Insufficiency After Cleft Palate Repair. AB - BACKGROUND: Postoperative fistulae and velopharyngeal insufficiency (VPI) are 2 important complications after cleft palate repair. The effects of preoperative cleft width on outcomes after cleft palate repair have been rarely studied. METHODS: A retrospective review of all patients undergoing primary cleft palatoplasty by a single surgeon between 2004 and 2011 was performed. Primary outcomes were palatal fistula and VPI, defined as the need for corrective surgery after failing conservative speech-language therapy. Logistic regression analysis was performed to identify factors associated with the primary outcomes. RESULTS: One hundred seventy-seven patients (84 men and 93 women) were identified. Median age at repair was 10 months with median follow-up of 3.80 years. Preoperative cleft width was 10 mm or less for 72 (41%) patients, 11 to 14 mm for 54 (30%) patients, and 15 mm or greater for 51 (29%) patients. Palatal fistula was observed in 8 (4.5%) patients, but required surgical repair in only 2 (1.1%). Fistula was overall associated with Veau IV classification (odds ratio, 8.13; P < 0.01) but not with cleft width. Velopharyngeal insufficiency needing surgical intervention occurred in 9 patients (7.38% of patients older than 4 years) and was associated with increasing cleft width (odds ratio, 1.29; P = 0.011). Outcomes were similar for patients undergoing surgery in the earlier and later halves of the study. CONCLUSIONS: This retrospective review is one of the first from the United States to explore the associations between measured cleft width and outcomes after palatoplasty. Overall rates of palatal fistula and VPI were low, corroborating previous studies showing good outcomes with the 2-flap palatoplasty. After adjusting for multiple variables including Veau type, cleft width was associated with higher VPI rates but not with fistula formation. Cleft width is a unique preoperative factor that should be considered and studied as a potential predictor of outcomes. PMID- 26101974 TI - Tanshinone IIA Inhibits Proliferation and Induces Apoptosis Through the Downregulation of Survivin in Keloid Fibroblasts. AB - Keloids are considered benign dermal fibroproliferative tumors. Keloid fibroblasts (KFs) persistently proliferate and fail to undergo apoptosis, and no treatment is completely effective against these lesions. Tanshinone IIA induces apoptosis and inhibits the proliferation of various tumor cell types. In this study, we investigated the effect of tanshinone IIA on the regulation of proliferation, cell cycle, and apoptosis in KFs, and investigated potential mechanisms involved in the effects. First, KFs and normal skin fibroblasts (NSFs) were treated with various concentrations of tanshinone IIA. Cell counting kit-8 (CCK-8) was used to assess the proliferative activity of KFs and NSFs, and flow cytometry was used to investigate the cell cycle and apoptosis in KFs. We found that the proliferation of all tanshinone IIA-treated KFs was significantly decreased after treatment for 72 hours (P < 0.001). Also, NSFs treated with tanshinone IIA did not exhibit noticeable effects compared with KFs. In addition, the percentages of G0/G1 cells in all tanshinone IIA-treated KFs were significantly increased after treatment for 72 hours (P < 0.001). And the percentages of cells undergoing early apoptosis in all tanshinone IIA-treated KFs were significantly increased after treatment for 120 hours (P < 0.001). Furthermore, the apoptosis antibody array kit and Western blot analysis revealed that tanshinone IIA decreased survivin expression in KFs (P < 0.001). In conclusion, tanshinone IIA downregulates survivin and deactivates KFs, thus suggesting that tanshinone IIA could serve as a potential clinical keloid treatment. PMID- 26101975 TI - Alleviation of Neuropathic Scar Pain Using Autologous Fat Grafting. PMID- 26101976 TI - Management of a Common Breast Augmentation Complication: Treatment of the Double Bubble Deformity With Fat Grafting. AB - The double-bubble deformity is one of the most common problems in breast augmentation, with or without mastopexy. Classically, open techniques have been used to treat this deformity, including elevation and reconstruction of the inframammary crease or parenchymal scoring. In this study, the author reports experience with a simple, closed technique of serial fat grafting procedures to treat the double-bubble deformity. Twenty-eight patients with double-bubble deformities were retrospectively evaluated. Fifteen patients had undergone primary augmentation, whereas 13 patients had undergone augmentation mastopexy. Eight patients presented with bilateral double-bubble deformity. Up to 3 sessions of fat grafting were performed on each patient, with a mean of 2.1 sessions required for patients in the series. An average of 27 cm3 of fat was injected with each treatment per breast. Fat was injected with a 1.5-mm blunt cannula into the subdermal and superficial breast tissue layers beneath the old inframammary fold. There were no oil cysts, infections, or donor site problems noted in the series. Twelve patients with limited breast tissue underwent magnetic resonance imaging examination at the conclusion of the fat grafting sessions, and no implant injury or disruption was noted. All patients were pleased with the results of treatment, and no revisional surgery was required. This study suggests that fat grafting is an effective treatment of the breast double-bubble deformity. The procedure allows the correction of a challenging deformity with a simple, closed technique which is safe and cost-effective. PMID- 26101977 TI - Anatomy of the Anterior Deep Temporal Nerve: Implications for Neurotization in Blinking Restoration in Facial Paralysis. AB - Facial paralysis can lead to dysfunctions in eyelid closure, which is called lagophthalmos. A number of surgical procedures, both dynamic and static, have been described to restore the innervation of the orbicularis oculi muscle that closes the eyelids. This cadaver-based anatomical study aimed to evaluate the anatomy of the anterior, middle, and posterior deep temporal nerves; nerves to the temporalis muscle; and their availability for direct muscle neurotization of the orbicularis oculi. A total of 10 hemisectioned head specimens from 5 adult cadavers (2 men and 3 women) were used in this study. The adequacy of the length of the anterior deep temporal nerve was assessed for direct neorotization of the orbicularis oculi muscle. The mean distances between the originating point of the deep temporal nerves from the mandibular nerve in the infratemporal fossa and their terminal entry points into the muscle were 46.4 (42-51 mm), 42.2 (38-46 mm), and 33.4 mm (26-40 mm) for the anterior, middle and posterior branches of the nerves, respectively. We conclude that the anterior deep temporal nerve is a versatile nerve that can be used for direct muscle neurotization, nerve transfer, and babysitter procedures in selective blinking restoration. Before proceeding with any further clinical use, an anatomical study should be performed with fresh specimens from cadavers. PMID- 26101978 TI - The Use of Glabrous Skins Grafts in the Treatment of Pediatric Palmar Hand Burns. AB - BACKGROUND: An often overlooked, yet useful, technique in the treatment of palmar hand burns is the use of glabrous skin grafting, particularly in dark-skinned individuals. Pediatric palmar burns are a particularly unique subset of burns. The typical split-thickness or full-thickness skin grafts leave a notably different skin texture and pigmentation. It is also known that the psychological aspects of a pediatric burn can be quite burdensome for a child as he or she progresses through childhood and adolescence. For a dark-skinned patient the placement a standard full-thickness skin graft in a nonpigmented palm provides for a constant reminder of a traumatic event. We report a case series of pediatric patients who were managed with glabrous skin grafting from the plantar aspect of the foot. METHODS: A retrospective review of palmar skin burns requiring grafting at a single pediatric burn center experience over a 2 and a half year time period was performed. Seventeen patients were identified. Our treatment algorithm for deep partial thickness burns first relies on a combination of operative and nonoperative measures to expedite the demarcation of the burn injury. If the burn is full thickness in nature or if a lack of progression of healing is identified within the first 14 days of injury, then skin grafting is recommended. Our technique for performing the graft is described. RESULTS: The average age at time of surgery was 2.05 years (6 months to 6.8 years). Fourteen of the 17 patients had darker skin types (Fitzpatrick Type III-VI) and identified themselves as either Hispanic or African American. The average size of the area requiring skin graft after debridement was 0.94% total body surface area (0.5%-2.0%). Of the patients that were not lost to follow up, 1 patient required additional grafting after developing a finger contracture for splint noncompliance. Aesthetically, the wounds went on to heal with an excellent pigment match and an inconspicuous donor site. CONCLUSIONS: In the management of deep-partial or full-thickness palmar skin burns in the pediatric population that require grafting, the use of plantar glabrous skin grafts offers a reliable option for coverage. The aesthetic and functional results are improved over standard techniques. PMID- 26101979 TI - Autologous Fat Grafting After Breast Reconstruction in Postmastectomy Patients: Complications, Biopsy Rates, and Locoregional Cancer Recurrence Rates. AB - BACKGROUND: Autologous fat grafting is widely used for refinements in postmastectomy breast reconstruction. However, there are few studies evaluating outcomes in this patient population. The purpose of this study was to assess outcomes of autologous fat grafting after breast reconstruction in postmastectomy patients. METHODS: We retrospectively reviewed the records of consecutive postmastectomy patients who underwent autologous fat grafting after breast reconstruction at a university center over a 5-year period. Patients with at least 6 months of follow-up were included. Medical records were reviewed for demographics, operative details, complications, incidence of palpable masses, and/or suspicious breast imaging findings requiring biopsy, and locoregional cancer recurrence. Descriptive statistics were generated. RESULTS: Between January 2008 and July 2013, 108 women and a total of 167 breast reconstructions underwent autologous fat grafting for revision of postmastectomy breast reconstruction. Their ages ranged from 22 to 71 years (mean, 48 years). Fat grafts were harvested, processed, and injected using the Coleman technique. The mean number of fat grafting procedures was 1.3 (range, 1-4) per breast. Follow-up ranged from 6 to 57 months (mean, 20.2 months). Fifty-three (31.7%) breasts underwent imaging after autologous fat grafting. Suspicious imaging findings requiring biopsy were discovered in 4 (2.4%) breasts, and clinically palpable lesions combined with suspicious imaging findings requiring biopsy were present in another 4 (2.4%) breasts. All 8 biopsies showed fat necrosis, scar, or oil cysts without evidence of malignancy. One (0.6%) local complication (a wound infection at the recipient site requiring oral antibiotics) after autologous fat grafting was reported. During the limited follow-up period, there were no locoregional cancer recurrences. CONCLUSIONS: Autologous fat grafting in conjunction with breast reconstruction resulted in a biopsy rate of 4.8%, and no cases of locoregional cancer recurrence were observed. Based on these preliminary findings, autologous fat grafting appears to be a relatively safe procedure for refinement of the reconstructed breast in postmastectomy patients. PMID- 26101980 TI - The Protective Effects of Botulinum Toxin A Against Flap Necrosis After Perforator Twisting and Its Underlying Molecular Mechanism in a Rat Model. AB - PURPOSE: The purpose of this study was to examine our hypotheses that botulinum toxin A (BoTA) protect necrosis of perforator flap from perforator twisting. METHODS: Twenty-four rats were randomly divided into 2 groups. Twelve International Units of BoTA versus 1.2 mL normal saline was injected subdermally 3 days before flap elevation. In each group, bilateral before deep inferior epigastric perforator (DIEP) flaps, 5 * 3 cm in size, were created. The right and left (180 and 360 degrees of perforator twisting) DIEP flaps were separated. At 1 and 3 days postoperatively, skin above the perforator of the DIEP flaps was harvested to examine the degrees of gene expressions. Final survival percentage of flap and histology were assessed at postoperative day 5. RESULTS: The survival percentage of flap was significantly higher in the BoTA group than in the control group at both DIEP flaps after 180 and 360 degrees of perforator twisting at postoperative day 5 (95.23 +/- 2.85% vs 91.00 +/- 3.77%; P = 0.021 and 91.59 +/- 2.87% vs 30.03 +/- 6.91%; P < 0.001, respectively).Higher fibroblast density, enhanced epithelial necrosis, and inflammation were noted in the control group than in the BoTA group. In 180 degrees of perforator twisting group, BoTA may augment angiogenesis possibly via nuclear factor-kappaB-induced destabilization and the nuclear factor-kappaB/hypoxia-inducible factor 1-alpha/vascular endothelial growth factor pathway, whereas in the 360 degrees of perforator twisting group, the mechanistic target of rapamycin/hypoxia-inducible factor 1 alpha/vascular endothelial growth factor pathway may participate in BoTA-induced effective angiogenesis. CONCLUSIONS: We demonstrated that pretreatment with BoTA protects perforator flap caused by perforator at the pathological and molecular level using an experimental rat model. PMID- 26101981 TI - Correction of Medial Blowout Fractures According to the Fracture Types. AB - BACKGROUND: Regarding the issue of blowout fracture, a variety of approaches and surgical techniques have been reported to improve postoperative results. However, there are no extant guidelines for the selection of these various methods. The current authors classified the medial blowout fracture into 3 different types and adapted to suitable surgical techniques. METHODS: Between October 2010 and March 2013, 89 patients who had medial blowout fracture were included in this study. We classified the study patients into 3 different categories: greenstick, simple, and complex. The greenstick type used the transnasal endoscopic approach and was reduced with packing after applying a silastic sheet. The simple type used an onlay covering technique. The complex type was treated using the transcaruncular approach and inlay implanting technique. After surgery, the continuity of orbital wall was checked by computed tomography. Patients were then examined for the following conditions: diplopia, eyeball movement, and enophthalmos. RESULTS: The greenstick category consisted of 12 cases, most cases were satisfied. One case relapsed after removal of the packing. In the simple category, a total of 9 cases were treated by onlay covering technique. In all 68 cases of the complex type, we could obtain suitable anatomical reconstruction with inlay implanting technique. Only 2 cases complained of transient diplopia and moderate enophthalmos. CONCLUSIONS: Appropriate clinical classification, depending on the type of fracture and selection of optimal treatment methods, could obtain the satisfactory result and improve the treatment outcomes in the correction of medial orbital wall fracture. PMID- 26101982 TI - Fascicular Phrenic Nerve Neurotization for Restoring Physiological Motion in a Congenital Diaphragmatic Hernia Reconstruction With a Reverse Innervated Latissimus Dorsi Muscle Flap. AB - Congenital diaphragmatic hernia is a severe developmental anomaly characterized by the malformation of the diaphragm. An innervated reversed latissimus dorsi flap reconstruction for recurrent congenital diaphragmatic hernia has been described as an alternative to prosthetic patch repair to achieve pleuroperitoneal separation. However, there is very little supporting scientific data; therefore, there is no real basic understanding of the condition of the phrenic nerve in the absence of diaphragmatic muscle or even the neurotization options for restoring neodiaphragmatic muscle motion. We have reviewed the literature regarding phrenic nerve anatomy and neurotization options, and to our knowledge, this is the first time that the application of a fascicular repair is being described where the continuity of one remaining fascicle of the diaphragm has been preserved close to the phrenic nerve distal division. The procedure was undertaken in a 3 year-old boy, with the diagnosis of congenital large posteromedial diaphragmatic hernia and dependence of mechanical ventilation in consequence of severe bronchopulmonary dysplasia.The phrenic nerve divides itself into several terminal branches, usually three, at the diaphragm level, or just above it. This allows the selective coaptation of separate fascicular branches. In the case described, videofluoroscopy evaluation showed no evidence of paradoxical neodiaphragmatic motion, with synchronous contraction movements and intact pleura-peritoneal separation. The child is now asymptomatic and shows improvement of his previous restrictive pulmonary disease.We believe that fascicular repair can achieve some reinnervation of the flap without jeopardizing the potential of diaphragmatic function by contraction of reminiscent native diaphragm. PMID- 26101983 TI - Optimizing Efficiency in Deep Inferior Epigastric Perforator Flap Breast Reconstruction. AB - BACKGROUND: The process of harvesting and performing microsurgical anastomosis in a deep inferior epigastric perforator (DIEP) flap for breast reconstruction can be a lengthy procedure, which could affect outcomes and patient safety. We hypothesize that the implementation of a high volume center, preoperative planning, and the adaptation of key intraoperative components will optimize the efficiency of perforator flap surgery for breast reconstruction. METHODS: A retrospective review of 68 consecutive patients who underwent 104 DIEP flaps for immediate or delayed breast reconstruction was performed. Standardized preoperative planning, including computed tomography/magnetic resonance imaging angiogram, operating room setup, and operative technique, was followed. The times of flap harvest, internal mammary vessel harvest, microsurgical anastomosis, flap inset, wound closure, and total length of procedure were reviewed as well as patient outcomes. RESULTS: The average length of surgery for a unilateral DIEP was 3 hours and 21 minutes and for a bilateral DIEP was 5 hours and 46 minutes. In bilateral DIEP flaps, a significantly longer operative time was noted in immediate (363 +/- 14 minutes) compared to delayed (296 +/- 17 minutes) (P < 0.05) reconstruction and between procedures performed by 1 surgeon (400 +/- 29 minutes) versus 2 surgeons (326 +/- 11 minutes) (P < 0.05). Interestingly, no significant difference in operative time was seen in DIEP flaps performed on patients with a body mass index (BMI) less than 30 (193 +/- 7.6, 352 +/- 17 minutes) versus a BMI greater than 30 (213 +/- 11, 333 +/- 14 minutes) in both unilateral and bilateral procedures, respectively. CONCLUSIONS: Efficiency is optimized by preoperative planning with computed tomography/magnetic resonance imaging angiogram, a dedicated operating room team, including 2 microsurgeons and a systematic approach for surgery. The BMI may not significantly affect the duration of surgery. PMID- 26101984 TI - The Evolving Role of Members of the American Board of Plastic Surgery in Burn Surgery. AB - INTRODUCTION: Outcomes for patients with burn injuries are optimized by multidisciplinary care in a specialized burn center. Plastic surgeons traditionally have played a significant role in the care of burn patients; however, this may be evolving. We aim to examine the role and employment satisfaction of plastic surgeons in burn surgery. METHODS: Members of the American Society of Plastic Surgery with available contact information and US senior plastic surgery residents were asked to complete a survey examining practice profiles and employment satisfaction. Responses were analyzed between groups stating that their practice did and did not involve burn surgery. RESULTS: Of the 573 attending respondents, 135 (23.6%) indicated that part of their practice included burn surgery. Nineteen (41.9%) residents indicated they desired their practice to include burn surgery. About 41.9% of respondents with less than 3 years of experience, 25% with between 3 and 10 years of experience, and 21.7% with greater than 10 years of experience practiced burn surgery. Twenty-one (15.3%) respondents were completely satisfied with their practice, 62 (45.3%) were mostly satisfied, and 36 (26.3%) were satisfied. Fourteen (10.2%) respondents were mostly dissatisfied and 4 (2.9%) were completely dissatisfied (P = 0.0315). CONCLUSIONS: Despite residents' interest and junior plastic surgeons' involvement in burn surgery, the role of burn surgery in responding plastic surgeons' practices diminished over time. Those practicing burn surgery are less likely to be satisfied and more likely to be dissatisfied with their practice. Plastic surgeons should therefore examine their role in burn surgery to optimize their desired involvement and satisfaction within the field. PMID- 26101985 TI - Inhibition of the Notch Pathway Promotes Flap Survival by Inducing Functional Angiogenesis. PMID- 26101986 TI - Understanding and Optimizing the Patient Experience in Breast Reconstruction. AB - BACKGROUND: Optimizing the patient experience is a central pillar in healthcare quality. Although this may be recognized as important in breast reconstruction, surgeons are often unaware of how well they and members of their team achieve this goal. The objective of our study was to evaluate patient satisfaction with the experience of care in a multicenter, prospective cohort of patients undergoing breast reconstruction. Specifically, we sought to determine which aspects of the care experience might be most amenable to quality improvement. METHODS: As part of the Mastectomy Reconstruction Outcomes Consortium Study, 2093 patients were recruited from 11 centers in North America. Of these, 1534 (73.3%) completed the BREAST-Q Satisfaction with Care scales (satisfaction with information, surgeon, medical team, and office staff) at 3 months after reconstruction and were included in the analysis. RESULTS: Patients scored lowest on 'Satisfaction with Information' (mean = 72.8) compared to all other Satisfaction with Care scales (mean, 89.5-95.5). Patients with immediate reconstruction were less satisfied with their plastic surgeon compared to those with delayed reconstruction. The racial category, "Other" (Asians, Pacific Islanders, Hawaiians, American Indians), was the least satisfied group across all Satisfaction with Care scales. CONCLUSIONS: Patients undergoing breast reconstruction perceive significant gaps in their knowledge and understanding of expected outcomes. Immediate reconstruction patients and minority racial groups may require additional resources and attention. As a means to improve quality of care, these findings highlight an important unmet need and suggest that improving patient education may be central to providing patient-centered care. PMID- 26101988 TI - The Effect of Web-Based Education on Patient Satisfaction, Consultation Time and Conversion to Surgery. AB - INTRODUCTION: To evaluate the effect of web-based education on (1) patient satisfaction, (2) consultation times, and (3) conversion to surgery. METHODS: A retrospective review of 767 new patient consultations seen by 4 university-based plastic surgeons was conducted between May 2012 and August 2013 to determine the effect a web-based education program has on patient satisfaction and consultation time. A standard 5-point Likert scale survey completed at the end of the consultation was used to assess satisfaction with their experience. Consult times were obtained from the electronic medical record. All analyses were done with Statistical Analysis Software version 9.2 (SAS Inc., Cary, NC). A P value less than 0.05 was considered statistically significant. RESULTS: Those who viewed the program before their consultation were more satisfied with their consultation compared to those who did not (satisfaction scores, mean +/- SD: 1.13 +/- 0.44 vs 1.36 +/- 0.74; P = 0.02) and more likely to rate their experience as excellent (92% vs 75%; P = 0.02). Contrary to the claims of Emmi Solutions, patients who viewed the educational program before consultation trended toward longer visits compared to those who did not (mean time +/- SD: 54 +/- 26 vs 50 +/- 35 minutes; P = 0.10). More patients who completed the program went on to undergo a procedure (44% vs 37%; P = 0.16), but this difference was not statistically significant. DISCUSSION: Viewing web-based educational programs significantly improved plastic surgery patients' satisfaction with their consultation, but patients who viewed the program also trended toward longer consultation times. Although there was an increase in converting to surgical procedures, this did not reach statistical significance. PMID- 26101989 TI - What Effect Does Self-Citation Have on Bibliometric Measures in Academic Plastic Surgery? AB - BACKGROUND: Research productivity plays a significant role in academic promotions. Currently, various bibliometric measures utilizing citation counts are used to judge an author's work. With increasing numbers of journals, numbers of open access publications, ease of online submission, and expedited indexing of accepted manuscripts, it is plausible that an author could influence his/her own bibliometric measures through self-citation. The purpose of this study was to determine the impact of self-citation in academic plastic surgery. METHODS: A cohort of full-time academic plastic surgeons was identified from 9 U.S. plastic surgery training programs. For all included faculty, academic rank was retrieved from department/division websites, and bibliometric measures were assessed using a subscription bibliographic citation database (Scopus, Reed Elsevier, London, UK). Bibliometric measures included the Hirsch index (h-index, the number of publications h which are cited >= h times), total number of publications, and total number of citations. The h-index and total number of citations were collected with and without self-citations. Percent changes in the h-index and total citations were calculated after removal of self-citations and compared across academic ranks and levels of research productivity (total publications, h index, and total citations). RESULTS: The study cohort consisted of 169 full-time academic plastic surgeons. The h-index and total citations experienced decreases of 2.8 +/- 5.0% (P < 0.0001) and 4.5 +/- 4.6% (P < 0.0001), respectively, after correction for self-citation. More than half of the cohort (n = 113, 67%) did not experience a change in the h-index after removal of self-citations. These decreases did not vary across academic rank. Surgeons who self-cited at rates greater than 5% were 9.8 times more likely (95% confidence interval, 4.5-21.9; P < 0.001) to have their h-index change as a result of self-citation (after adjusting for academic rank). There were weak correlations between percent decreases in the h-index and total citations and various biblimoteric measures (total publications, h-index, total citations; r < 0.32). CONCLUSIONS: Self citation has a minor impact on common bibliometric measures in academic plastic surgery. The influence of self-citation is consistent across academic ranks and increasing levels of bibliometric measures, suggesting that authors are not manipulating the system with increasing experience. PMID- 26101990 TI - Accuracy of High-Resolution Ultrasonography in the Detection of Extensor Tendon Lacerations. AB - BACKGROUND: Lacerations to the extensor mechanism are usually diagnosed clinically. Ultrasound (US) has been a growing diagnostic tool for tendon injuries since the 1990s. To date, there has been no publication establishing the accuracy and reliability of US in the evaluation of extensor mechanism lacerations in the hand. The purpose of this study is to determine the accuracy of US to detect extensor tendon injuries in the hand. METHODS: Sixteen fingers and 4 thumbs in 4 fresh-frozen and thawed cadaveric hands were used. Sixty-eight 0.5-cm transverse skin lacerations were created. Twenty-seven extensor tendons were sharply transected. The remaining skin lacerations were used as sham dissection controls. One US technologist and one fellowship-trained musculoskeletal radiologist performed real-time dynamic US studies in and out of water bath. A second fellowship trained musculoskeletal radiologist subsequently reviewed the static US images. Dynamic and static US interpretation accuracy was assessed using dissection as "truth." RESULTS: All 27 extensor tendon lacerations and controls were identified correctly with dynamic imaging as either injury models that had a transected extensor tendon or sham controls with intact extensor tendons (sensitivity = 100%, specificity = 100%, positive predictive value = 1.0; all significantly greater than chance). Static imaging had a sensitivity of 85%, specificity of 89%, and accuracy of 88% (all significantly greater than chance). The results of the dynamic real time versus static US imaging were clearly different but did not reach statistical significance. CONCLUSIONS: Diagnostic US is a very accurate noninvasive study that can identify extensor mechanism injuries. Clinically suspected cases of acute extensor tendon injury scanned by high-frequency US can aid and/or confirm the diagnosis, with dynamic imaging providing added value compared to static. Ultrasonography, to aid in the diagnosis of extensor mechanism lacerations, can be successfully used in a reliable and accurate manner. PMID- 26101991 TI - An Algorithm for Forefoot Reconstruction With the Innervated Free Medial Plantar Flap. AB - BACKGROUND: Because of shearing forces, the forefoot is more prone to trophic ulcers than the heel. Reconstruction of trophic ulcers and other forefoot defects is a vexing challenge. We favor the innervated free medial plantar flap to replace like-with-like and confer protective sensation. We investigate the feasibility of this flap with the largest series to date and the first to describe ipsilateral flap transfer. METHODS: Between 2009 and 2013, 7 patients with forefoot defects were treated with innervated free medial plantar flaps. The average age of 4 men and 3 women was 35.1 years (range, 8-50 years). Indications were secondary reconstruction after trauma and coverage of oncologic defects. The mean defect was 5 * 7 cm (range, 4-6 cm * 6-10 cm). Four patients were treated with contralateral flaps and 3 with ipsilateral flaps using interposition vein graft. RESULTS: The mean flap size was 8.1 +/- 1.6 cm * 5.9 +/- 1.2 cm. There was no perioperative complication, venous congestion, or arterial insufficiency. Patients were followed clinically for 38.5 months (range, 6 months to 10 years). One patient died from complications of metastatic disease 7 months after plantar flap reconstruction. Two patients underwent sensory testing and gait analysis. The appearance was satisfactory, ambulation returned to normal, and there was protective sensation in every case. In 2 cases, hyperkeratotic tissue was excised in revision procedures. CONCLUSIONS: The innervated free medial plantar flap is an attractive and feasible option for coverage of medium-to-large defects of the plantar forefoot in the hands of a skilled microsurgeon. It has a place in our algorithmic approach to forefoot reconstruction. PMID- 26101992 TI - Redefining the Vascular Classifications of the Lateral Supramalleolar Flap. AB - BACKGROUND: The blood supply of the lateral supramalleolar flap (LSMF) generally comes from the perforating branch of the peroneal artery. However, the cutaneous branch may also receive blood from the anterior tibial artery. The main objective of the present study was to clarify the vascular anatomy of the LSMF. METHODS: Anatomical dissections were performed on 28 perfused fresh cadaver legs. The cutaneous branches of LSMF were identified, and the anatomic relationship between the cutaneous branches and the peroneal and anterior tibial arteries was analyzed. RESULTS: The vascular supply for LSMF was divided into 2 main types. A collateral inferolateral branch from the anterior tibial artery anastomosed with the perforating branch of the peroneal artery around the inferior tibiofibular angle, and the main cutaneous branch of the flap arose from this arterial anastomosis in 20 of 28 limbs (71.4%). The collateral inferolateral branch was absent or very small in the other 8 of 28 dissections (28.6%), and the cutaneous branches solely arose from the perforating branch of the peroneal artery. The anastomosis of the descending branch of the peroneal artery and anterior lateral malleolar artery was always (100%) found around the tibiotalar joint. CONCLUSIONS: In addition to the perforating branch of the peroneal artery, the LSMF may also receive blood from the anterior tibial artery through the collateral inferolateral branch. New modified proximally based flaps could be designed, and caution is warranted for these variations when a distally based flap is performed. PMID- 26101993 TI - Is Propranolol Safe and Effective for Outpatient Use for Infantile Hemangioma? A Prospective Study of 679 Cases From One Center in China. AB - BACKGROUND: The protocol for the treatment of infantile hemangioma with propranolol varies among different clinical centers. METHODS: Six hundred seventy nine patients who were 1 to 12 months old were recruited in this prospective study to receive propranolol treatment. The response to the propranolol therapy was classified as 4 levels. The results were primarily evaluated using color Doppler ultrasound examinations before and after propranolol treatment. RESULTS: The response was excellent in 176 (25.9%), good in 492 (72.5%), stable in 5 (0.7%), and poor in 6 (0.9%) of the patients. The mean age at the initiation of the therapy was 3.3 months (range, 1 to 10.9 months) and the mean duration of the therapy was 7.1 months (range, 3-17 months). The mean duration of the follow-up time after the discontinuation of the therapy was 5.3 months (range, 3-17 months). Regrowth of the hemangioma was observed in 92 cases (13.5%). Seventy nine (11.6%) of the parents complained of their child's minor discomfort during the therapy. CONCLUSIONS: Propranolol (2 mg/kg per day) may significantly reduce the size of a hemangioma. As an outpatient therapy, propranolol was found to be safe for Chinese children and to have minor side effects. PMID- 26101994 TI - Three-Dimensional Approach to Zygoma Reduction: Review of 221 Patients Over 7 Years. AB - BACKGROUND: Zygoma reduction is commonly performed in Asian patients because a broad face is considered stubborn in appearance and unattractive. Consequently, a number of different techniques have been developed for zygoma reduction, the majority of which involve simple manipulations. However, no consensus has been reached on the optimal method. In the present report, we introduce a new method involving ostectomy and fixation that uses a 3-dimensional approach to zygoma reduction. METHODS: From 2007 to 2013, 221 Korean patients (39 men, 182 women) underwent zygoma reduction using this technique. The bone was accessed via an intraoral and preauricular incision and removed in the body area using a small L shaped osteotome through bone cutting in the arch area. The zygoma was moved anteriorly, medially, and caudally, and then fixed with a miniplate and screws. RESULTS: All patients were followed up for over 6 months and asked whether they were satisfied with the results. Four patients (1.8%) required further reduction and underwent a reoperation, but all were eventually satisfied. Two patients (0.9%) experienced overcorrection with a sunken area around the zygoma, which was corrected with autologous fat grafting after 6 months. Two patients complained of sensory changes around the upper lip, which resolved within 6 months. Two patients experienced dizziness, temporomandibular joint pain, infection, and/or cheek drooping. CONCLUSIONS: This new surgical technique causes less frequent and less pronounced cheek drooping and requires less bone stepping, resulting in greater patient satisfaction. PMID- 26101995 TI - Quantifying difference in gene expression profile between bovine blastocysts derived by in vitro fertilization and somatic cell nuclear transfer. AB - Epigenetic reprogramming intensely occurs in somatic-cell nuclear transfer (SCNT) embryos, which highlights the importance of proper expressions of reprogramming related genes in SCNT embryos. We here assessed gene expression profiles (GEPs) difference between bovine blastocyst groups derived by in-vitro fertilization (IVF) or SCNT; in SCNT, cumulus cells and ear skin fibroblasts were used for cSCNT and fSCNT blastocysts, respectively. We obtained GEPs of 15 reprogramming related genes in single blastocysts using multiplex PCR and found a broad range of variations in their GEPs. Weighted root-mean-square deviation (wRMSD) analysis, which calculates the deviation of SCNT blastocysts' GEPs from IVF blastocysts' mean GEP, found a significant difference between IVF and fSCNT and between cSCNT and fSCNT blastocysts (p < 0.001) but not between IVF and cSCNT. Since the fibroblasts' GEP was more distant from the IVF blastocysts' than the cumulus cells', it might partly explain the less similarity of fSCNT blastocysts' GEPs to the IVF's mean GEP. Our wRMSD method succeeds in expressing in figures how different two comparable embryo groups of different derivations are in GEP, which would be useful to select a better embryo derivation protocol among the candidates prior to field applications. PMID- 26101997 TI - Physicians' and Nurses' Perceptions of and Attitudes Toward Incident Reporting in Palestinian Hospitals. AB - OBJECTIVES: Underreporting of incidents that happen in health care services undermines the ability of the systems to improve patient safety. This study assessed the attitudes of physicians and nurses toward incident reporting and the factors influencing reporting in Palestinian hospitals. It also examined clinicians' views about the preferred features of incident reporting system. METHODS: Cross-sectional self-administered survey of 475 participants, 152 physicians and 323 nurses, from 11 public hospitals in the West Bank; response rate, 81.3%. RESULTS: There was a low level of event reporting among participants in the past year (40.3%). Adjusted for sex and age, physicians were 2.1 times more likely to report incidents than nurses (95% confidence interval, 1.32-3.417; P = 0.002). Perceived main barriers for reporting were grouped under lack of proper structure for reporting, prevalence of blame, and punitive environment. The clinicians indicated fear of administrative sanctions, social and legal liability, and of their competence being questioned (P > 0.05). Getting help for patients, learning from mistakes, and ethical obligation were equally indicated motivators for reporting (P > 0.05). Meanwhile, clinicians prefer formal reporting (77.8%) of all type of errors (65.5%), disclosure of reporters (52.7%), using reports to improve patient safety (80.3%), and willingness to report to immediate supervisors (57.6%). CONCLUSION: Clinicians acknowledge the importance of reporting incidents; however, prevalence of punitive culture and inadequate reporting systems are key barriers. Improving feedback about reported errors, simplifying procedures, providing clear guidelines on what and who should report, and avoiding blame are essential to enhance reporting. Moreover, health care organizations should consider the opinions of the clinicians in developing reporting systems. PMID- 26101996 TI - Dynamic remodeling of the extra cellular matrix during zebrafish fin regeneration. AB - Extracellular matrix plays a dynamic role during the process of wound healing, embryogenesis and tissue regeneration. Caudal fin regeneration in zebrafish is an excellent model to study tissue and skeletal regeneration. We have analyzed the expression pattern of some of the well characterized ECM proteins during the process of caudal fin regeneration in zebrafish. Our results show that a transitional matrix analogous to the one formed during newt skeletal and heart muscle regeneration is synthesized during fin regeneration. Here we demonstrate that a provisional matrix rich in hyaluronic acid, tenascin C, and fibronectin is synthesized following amputation. Additionally, we observed that the link protein Hapln1a dependent ECM, consisting of Hapln1a, hyaluronan and proteoglycan aggrecan, is upregulated during fin regeneration. Laminin, the protein characteristic of differentiated tissues, showed only modest change in the expression pattern. Our findings on zebrafish fin regeneration implicates that changes in the extracellular milieu represent an evolutionarily conserved mechanism that proceeds during tissue regeneration, yet with distinct players depending on the type of tissue that is involved. PMID- 26101998 TI - Provider and Patient Perceptions of an External Medication History Function. AB - OBJECTIVES: To determine the awareness and use of an external medication history (EMH) function within an electronic health record and its impact on patient perception of medication adherence. METHODS: Two self-administered surveys were given: one to providers and one to patients. Participants included providers from an academic medical center and patients from 2 general internal medicine clinics. RESULTS: Of 154 completed provider surveys, 61% were aware the EMH existed. More of the respondents aware of the EMH were primary care and medicine subspecialty providers (79.1%) when compared with surgical providers (20.9%, P < 0.0001). The most common reasons chosen for looking at the EMH included checking for medication adherence (44%), questions about a specific medication (40%), and checking controlled substance prescription history (37%). Of those aware of the EMH, 65% found medications on the EMH that they were not aware their patient was getting filled. Of the 94 patient surveys, 34% felt the EMH feature might change their medication taking behavior, and 48% responded that it already had. Patients with a history of depression and/or anxiety were less likely to report the intent to change their medication taking behavior, OR, 0.34 [95% CI, 0.13-0.87]. CONCLUSION: An external medication history function can provide further insight about a patient's medication profile and prescription filling. Knowledge attained from the EMH may improve patient safety by helping to uncover nonadherence, dosing discrepancies, and medications prescribed by other providers. Additionally, patient knowledge of this feature might improve medication adherence. Although further studies are needed to obtain objective data, the external medication history function may have significant impact on both providers and patients, and its benefit should be widely publicized. PMID- 26101999 TI - The Relationships Among Perceived Patients' Safety Culture, Intention to Report Errors, and Leader Coaching Behavior of Nurses in Korea: A Pilot Study. AB - OBJECTIVES: This study was undertaken to explore the correlations among nurses' perceptions of patient safety culture, their intention to report errors, and leader coaching behaviors. METHODS: The participants (N = 289) were nurses from 5 Korean hospitals with approximately 300 to 500 beds each. Sociodemographic variables, patient safety culture, intention to report errors, and coaching behavior were measured using self-report instruments. Data were analyzed using descriptive statistics, Pearson correlation coefficient, the t test, and the Mann Whitney U test. RESULTS: Nurses' perceptions of patient safety culture and their intention to report errors showed significant differences between groups of nurses who rated their leaders as high-performing or low-performing coaches. Perceived coaching behavior showed a significant, positive correlation with patient safety culture and intention to report errors, i.e., as nurses' perceptions of coaching behaviors increased, so did their ratings of patient safety culture and error reporting. CONCLUSIONS: There is a need in health care settings for coaching by nurse managers to provide quality nursing care and thus improve patient safety. Programs that are systematically developed and implemented to enhance the coaching behaviors of nurse managers are crucial to the improvement of patient safety and nursing care. Moreover, a systematic analysis of the causes of malpractice, as opposed to a focus on the punitive consequences of errors, could increase error reporting and therefore promote a culture in which a higher level of patient safety can thrive. PMID- 26102000 TI - Enhanced Morbidity and Mortality Meeting and Patient Safety Education for Specialty Trainees. AB - INTRODUCTION: Mortality and morbidity (M&M) meetings present a forum to discuss and review in-hospital deaths and complications to improve patient care. However, it remains an untapped resource to improve the exposure of the trainees to the principles of patient safety METHODS: We modified the departmental M&M meetings to enhance the delivery of patient safety education. The meeting started with a 5 minute overview of general patient safety principles, followed by a trainee-led discussion of a recent patient safety incident where opinions were sought about key learning points and ways to prevent the incident from happening in future. The discussion concluded with a patient safety presentation summarizing the salient points that were mapped to the WHO Patient Safety Curriculum. The suggestions from the meeting were noted, and the changes were instituted in the department over the next month and were reported back in the next meeting. RESULTS: From January to August 2012, seven enhanced M&M meetings were organized and attended by orthopaedic specialty trainees in a postgraduate Deanery. We explored the early impact of these monthly discussions by using the Junior Doctors' Patient Safety Attitudes and Climate Questionnaire as an assessment tool. The questionnaire reports an early impact on patient safety knowledge, awareness, and attitudes to patient safety; however, more work is needed to improve the workplace safety climate. CONCLUSIONS: We recommend immediate introduction of the enhanced M&M meetings focusing on patient safety in the other disciplines and postgraduate deaneries. PMID- 26102001 TI - A Patient Safety Rounds Pilot Program at Clinics Affiliated With a Large Research and Education Institution. AB - OBJECTIVE: In 2012, a 6-month Patient Safety Rounds pilot program was conducted to examine the provider perspective of patient safety and to educate personnel about national patient safety goals at clinics associated with a large research and education institution. METHODS: The Patient Safety Rounds (PSR) team, consisting of 3 to 4 rotating members from executive leadership, physician and nursing groups, and administrative staff, identified contacts within clinical departments and made arrangements for monthly visits. Patient safety issues were preselected by committee for presentation and discussion at a premeeting held with supervisors and administrators during the first few minutes of PSR. After the premeeting, the PSR team split up and met individually with care providers, between patient visits, to review the monthly safety topic and any patient safety concerns that they wanted to discuss during the visit. RESULTS: Approximately 37 patient safety issues were identified, recorded, and classified during these PSR team visits. If the issues could not be immediately addressed, they were either addressed shortly thereafter or referred to appropriate personnel for resolution. CONCLUSIONS: This PSR pilot program was viewed as a success by participants because it identified provider perspective concerns, which led to the identification and resolution of numerous patient safety issues. This interesting pilot program, however, was discontinued owing to the departure of key leadership and the reorganization and reprioritization of resources. PMID- 26102002 TI - Dosing Cefepime for Renal Function Does Not Completely Prevent Neurotoxicity in a Patient With Kidney Transplant. AB - Dosing cefepime for renal function does not completely prevent neurotoxicity in a kidney transplant patient. Cefepime neurotoxicity has been reported primarily among patients with renal insufficiency who received standard doses of the antibiotic. We report a case of nonconvulsive status epilepticus from dose adjusted cefepime in a kidney transplant patient. The timing of symptoms along with clinical and electroencephalographic improvement after discontinuation of cefepime was critical to the diagnosis. Whether we should adjust the dose of cefepime differently in a patient with transplanted kidney to prevent neurotoxicity is unknown. PMID- 26102003 TI - Activation of the antigen presentation function of mononuclear phagocyte populations associated with the basilar membrane of the cochlea after acoustic overstimulation. AB - The immune response is an important component of the cochlear response to stress. As an important player in the cochlear immune system, the basilar membrane immune cells reside on the surface of the scala tympani side of the basilar membrane. At present, the immune cell properties in this region and their responses to stress are not well understood. Here, we investigated the functional role of these immune cells in the immune response to acoustic overstimulation. This study reveals that tissue macrophages are present in the entire length of the basilar membrane under steady-state conditions. Notably, these cells in the apical and the basal sections of the basilar membrane display distinct morphologies and immune protein expression patterns. Following acoustic trauma, monocytes infiltrate into the region of the basilar membrane, and the infiltrated cells transform into macrophages. While monocyte infiltration and transformation occur in both the apical and the basal sections of the basilar membrane, only the basal monocytes and macrophages display a marked increase in the expression of major histocompatibility complex (MHC) II and class II transactivator (CIITA), a MHC II production cofactor, suggesting the site-dependent activation of antigen presenting function. Consistent with the increased expression of the antigen presenting proteins, CD4(+) T cells, the antigen-presenting partner, infiltrate into the region of the basilar membrane where antigen-presenting proteins are upregulated. Further pathological analyses revealed that the basal section of the cochlea displays a greater level of sensory cell damage, which is spatially correlated with the region of antigen-presenting activity. Together, these results suggest that the antigen-presenting function of the mononuclear phagocyte population is activated in response to acoustic trauma, which could bridge the innate immune response to adaptive immunity. PMID- 26102005 TI - Docosahexaenoic acid attenuates hyperglycemia-enhanced hemorrhagic transformation after transient focal cerebral ischemia in rats. AB - Hemorrhagic transformation (HT) is a feared complication of cerebral ischemic infarction, especially following the use of thrombolytic therapy. In this study, we examined whether docosahexaenoic acid (DHA; 22:6n-3), an omega-3 essential fatty acid family member, can protect the brain from injury and whether DHA can decrease the risk of HT enhanced by hyperglycemia after focal ischemic injury. Male Sprague-Dawley rats were injected with 50% dextrose (6ml/kg intraperitoneally) to induce hyperglycemia 10min before 1.5h of filament middle cerebral artery occlusion (MCAO) was performed. Treatment with DHA (10mg/kg) 5min before reperfusion reduced HT and further improved the 7-day neurological outcome. It also reduced infarct volume, which is consistent with the restricted DWI and T2WI hyperintensive area. Reduced Evans Blue extravasation and increased expression of collagen IV indicated the improved integrity of the blood-brain barrier (BBB) in DHA-treated rats. Moreover, DHA reduced the expression of the intercellular adhesion molecule-1 (ICAM-1) in the ischemic injured brain. Therefore, we conclude that DHA attenuated hyperglycemia-enhanced HT and improved neurological function by preserving the integrity of BBB and reducing inflammation. PMID- 26102004 TI - Mouse models of fear-related disorders: Cell-type-specific manipulations in amygdala. AB - Fear conditioning is a model system used to study threat responses, fear memory and their dysregulation in a variety of organisms. Newly developed tools such as optogenetics, Cre recombinase and DREADD technologies have allowed researchers to manipulate anatomically or molecularly defined cell subtypes with a high degree of temporal control and determine the effect of this manipulation on behavior. These targeted molecular techniques have opened up a new appreciation for the critical contributions different subpopulations of cells make to fear behavior and potentially to treatment of fear and anxiety disorders. Here we review progress to date across a variety of techniques to understand fear-related behavior through the manipulation of different cell subtypes within the amygdala. PMID- 26102006 TI - Constitutive and functional expression of YB-1 in microglial cells. AB - Y-box-binding protein (YB-1) is a member of the cold-shock protein family and participates in a wide variety of DNA/RNA-dependent cellular processes including DNA repair, transcription, mRNA splicing, packaging, and translation. At the cellular level, YB-1 is involved in cell proliferation and differentiation, stress responses, and malignant cell transformation. A general role for YB-1 during inflammation has also been well described; however, there are minimal data concerning YB-1 expression in microglia, which are the immune cells of the brain. Therefore, we studied the expression of YB-1 in a clinically relevant global ischemia model for neurological injury following cardiac arrest. This model is characterized by massive neurodegeneration of the hippocampal CA1 region and the subsequent long-lasting activation of microglia. In addition, we studied YB-1 expression in BV-2 cells, which are an accepted microglia culture model. BV-2 cells were stressed by oxygen/glucose deprivation (OGD), OGD-relevant mediators, lipopolysaccharide (LPS), and phagocytosis-inducing cell debris and nanoparticles. Using quantitative polymerase chain reaction (PCR), we show constitutive expression of YB-1 transcripts in unstressed BV-2 cells. The functional upregulation of the YB-1 protein was demonstrated in microglia in vivo and in BV-2 cells in vitro. All stressors except for LPS were potent enhancers of the level of YB-1 protein, which appears to be regulated primarily by proteasomal degradation and, to a lesser extent, by the activation (phosphorylation) of the translation initiation factor eIF4E. The proteasome of BV-2 cells is impaired by OGD, which results in decreased protein degradation and therefore increased levels of YB-1 protein. LPS induces proteasome activity, which enables the level of YB-1 protein to remain at control levels despite enhanced protein ubiquitination. The proteasome inhibitor MG-132 was able to increase YB-1 protein levels in control and LPS-treated cultures. YB-1 upregulation was not accompanied by its translocation from the cytoplasm to the nucleus. YB-1 induction appeared to be related to microglial proliferation because it was partially co-regulated with Ki67. In addition, YB-1 protein levels correlated with microglia phagocytic activity because its upregulation could also be induced by inert NPs. PMID- 26102007 TI - Safranal as a novel anti-tubulin binding agent with potential use in cancer therapy: An in vitro study. AB - Safranal, a component of saffron, indicates anti-tumor activities; however, the precise mechanism of this effect has remained elusive. In this study we investigated tubulin assembly and structure in the presence of safranal to open the new horizons about the potential of safranal as an anti-tumor agent via microtubule disfunction. Anti-microtubule activity of safranal was evaluated by turbidimetric method and transmission electron microscopy (TEM). Safranal (0.1 70MUM) was incubated with tubulin (5MUM) and tubulin structural changes was surveyed using fluorometry. Tubulin binding site with safranal was estimated by molecular docking. Microtubule polymerization decreased significantly in the presence of safranal, regardless of its concentration and the IC50 value was obtained 72.19MUM. Safranal was situated between alpha and beta tubulin closer to alpha-tubulin and hydrogen bond with Gly 142 and hydrophobic interactions played critical roles for safranal molecule stabilization in binding site. It seems that decline of tubulin assembly could result from tubulin structural changes through safranal bindings between alpha and beta tubulin with DeltaG(0) of -5.63kcal/mol. Safranal can be taken into account as an anticancer agent; however, in vivo experiments are required to confirm this conclusion. PMID- 26102008 TI - Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver. AB - Oxyresveratrol is a polyphenolic phytoalexin produced by plants as an antioxidant. This study investigated the hepatoprotective effects of oxyresveratrol as well as its underlying mechanism of action. Here, we evaluated the protective effects of oxyresveratrol against tert-butyl hydroperoxide (tBHP) induced severe oxidative stress in HepG2 cells as well as acute liver injury caused by carbon tetrachloride (CCl4) in mice. tBHP-induced reactive oxygen species production and cell death in hepatocytes were blocked by oxyresveratrol, as indicated by MTT, TUNEL, and FACS analyses. Moreover, pretreatment with oxyresveratrol increased nuclear translocation and transactivation of NF-E2 related factor 2 (Nrf2), as assessed by antioxidant response element reporter gene expression and immunofluorescence staining, and transactivated expression of both hemeoxygenase-1 and glutamate-cysteine ligase catalytic subunit. More importantly, oxyresveratrol induced phosphorylation of Nrf2 mediated through activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Further, ERK inhibitors such as PD98059 and U0126 blocked phosphorylation of Nrf2 as well as the protective effect of oxyresveratrol in mitochondria. In mice, oral administration of oxyresveratrol significantly prevented hepatocyte degeneration, inflammatory cell infiltration, as well as elevation of plasma markers such as ALT and AST induced by CCl4 injection. In conclusion, this study confirmed that oxyresveratrol protected hepatocytes against oxidative stress and mitochondrial dysfunction, which might be associated with activation of Nrf2. PMID- 26102010 TI - Effect of tetrahydrocurcumin on the profiles of drug-metabolizing enzymes induced by a high fat and high fructose diet in mice. AB - Cytochrome P450 (CYP), a superfamily of hepatic monooxygenase enzymes, catalyzes biotransformation of endogenous compounds and xenobiotics. Modification of CYPs associated with metabolic diseases and continuous consumption of diet with excessive energy levels. Tetrahydrocurcumin (THC) exhibited beneficial effects in metabolic syndromes such as diabetic mellitus and dyslipidemia. The present study aimed to investigate the effects of THC and vitamin E (vitE) on the expression profiles of CYPs in the livers of mice fed with the high fat and high fructose diet. In addition to ad libitum access to commercial regular diet, the high fat and high fructose diet (HFD) group of adult male ICR mice was administered a HFD, which consisted of intragastric administration of hydrogenated soybean oil (1mL/day) and the addition of 20% fructose to the drinking water for 8weeks. During the induction period, subgroups of mice (n=5) were daily intragastrically administered with THC (100 or 200mg/kg/day) or vitE (100mg/kg/day). The expressions of CYP mRNA and protein were quantified using real-time PCR and the levels of these proteins were quantified using immunoblotting. Continuous consuming of high fat and high fructose for 8weeks significantly increased the expressions of Cyp1a1, Cyp1a2, Cyp1b1, Cyp2c29, and Cyp3a11 while THC ultimately normalized these CYPs profiles. In the control mice, most of the investigated CYPs was unchanged by THC, with the exception that the Cyp1a1, Cyp2b9, and Cyp3a11 proteins were elevated. These findings provided additional important information on the effects of THC on diet induced-metabolic dysfunctions. However, drug interactions due to the use of THC as an alternative supplement are of concern, particularly in the combinations that include a drug that is a substrate of Cyp1a1, Cyp2b9, and Cyp3a11. PMID- 26102009 TI - Protective effect of cavidine on acetic acid-induced murine colitis via regulating antioxidant, cytokine profile and NF-kappaB signal transduction pathways. AB - Ulcerative colitis is an inflammatory disorder characterized by neutrophils infiltration, oxidative stress, upregulation of pro-inflammatory mediators and cytokines. Cavidine possesses anti-inflammatory activity and has been used to treat various inflammatory diseases but its effect on ulcerative colitis has not been previously explored. The present study aims to evaluate the effect of cavidine on acetic acid-induced ulcerative colitis in mice. Colitis mice induced by intra-rectal acetic acid (5%, v/v) administration received cavidine (1, 5 and 10mg/kg, i.g) or sulfasalazine (500mg/kg, i.g) for seven consecutive days. After euthanized by cervical dislocation, colonic segments of mice were excised for clinical, macroscopic, biochemical and histopathological examinations. Results suggested treatment with cavidine significantly decreased mortality rate, body weight loss, disease activity index (DAI), wet colon weight, macroscopic and histological score when compared with that of acetic acid-induced controls. In addition, administration of cavidine effectively modulated expressions of MPO, GSH, SOD and MDA. Furthermore cavidine inhibited the level of TNF-alpha and IL-6 in the serum and colon tissue in response to the regulation of p65 NF-kappaB protein expression. All these results indicated cavidine exerts marked protective effect in experimental colitis, possibly by regulating the expression of oxygen metabolites, NF-kappaB and subsequent pro-inflammatory cytokines production. PMID- 26102011 TI - Influence of polar and nonpolar carotenoids on structural and adhesive properties of model membranes. AB - Carotenoids, which are known primarily for their photoprotective and antioxidant properties, may also strongly influence the physical properties of membranes. The localization and orientation of these pigments in the lipid bilayer depends on their structure and is determined by their interactions with lipid molecules. This affects both phase behavior and the mechanical properties of membranes. Differential scanning calorimetry (DSC) and atomic force microscopy (AFM) allowed us to gain a direct insight into the differences between the interaction of the non-polar beta-carotene and polar zeaxanthin embedded into DPPC liposomes. DSC results showed that zeaxanthin, having polar ionone rings, interacts more strongly with the membrane lipids than beta-carotene. The decrease in molar heat capacity by a factor of 2 with a simultaneous broadening of the main phase transition (gel-to-liquid crystalline phase transition) as compared to the two other systems studied suggests some increased length of the coupled interactions between the polar xanthophyll and lipids. Long-distance interactions lead to the formation of larger clusters which may exhibit higher flexibility than small clusters when only short-distance interactions occur. AFM experiments show that adhesive forces are 2 and 10 times higher for DPPC membranes enriched in beta carotene and zeaxanthin, respectively, than those observed for an untreated system. Temperature dependent measurements of adhesion revealed that subphases can be formed in the gel lamellar state of DPPC bilayers. The presence of the non polar carotenoid enhanced the effect and even a bifurcation of the substates was detected within a temperature range of 30.0-32.5 degrees C prior to pretransition. It is the first time when the presence of subphases has been demonstrated. This knowledge can be helpful in better understanding the functioning of carotenoids in biological membranes. AFM seem to be a very unique and sensitive method for detecting such fine changes in the lipid bilayers. PMID- 26102012 TI - Tetrahydrocurcumin exerts protective effect on vincristine induced neuropathy: Behavioral, biochemical, neurophysiological and histological evidence. AB - Hyperalgesia, allodynia, delayed motor nerve conduction velocity, oxidative stress and axonal damage are signs and symptoms of chemotherapy induced peripheral neuropathy (CIPN). Present treatment/preventive strategies of CIPN are futile and the neuropathy may even lead to discontinuation of chemotherapy. In this study, we evaluated the protective effect of tetrahydrocurcumin (THC) 40 and 80mg/kg in experimental vincristine induced neuropathy in rats. Hyperalgesia was assessed by hot plate (thermal), Randall-Selitto (mechanical) test, allodynia was assessed by cold plate (thermal) test, functional loss was measured by sciatic function index, nociception was evaluated by formalin test. Neurophysiological recordings were carried out to assess motor nerve conduction velocity. Total calcium levels, oxidative stress and TNF-alpha was measured in sciatic nerve tissue homogenate to assess neuropathy. Histopathological changes was observed on sciatic nerve to assess the protective effect of THC against the vincristine. Pregabalin was used as a standard in this study. Rats administered with THC at 80mg/kg significantly attenuated the vincristine induced neuropathic pain manifestations which may be due to its multiple actions including anti nociceptive, anti-inflammatory, neuroprotective, calcium inhibitory and antioxidant effect. This study delineates that THC can be a promising candidate for the prevention of CIPN by chemotherapeutic agents. PMID- 26102013 TI - Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: Role of myeloperoxidase and arylamine free radicals. AB - In this study, the cellular effects resulting from the metabolism of aminoglutethimide by myeloperoxidase were investigated. Human promyelocytic leukemia (HL-60) cells were treated with aminoglutethimide (AG), an arylamine drug that has a risk of adverse drug reactions, including drug-induced agranulocytosis. HL-60 cells contain abundant amounts of myeloperoxidase (MPO), a hemoprotein, which catalyzes one-electron oxidation of arylamines using H2O2 as a cofactor. Previous studies have shown that arylamine metabolism by MPO results in protein radical formation. The purpose of this study was to determine if pathways associated with a toxic response could be determined from conditions that produced protein radicals. Conditions for AG-induced protein radical formation (with minimal cytotoxicity) were optimized, and these conditions were used to carry out proteomic studies. We identified 43 proteins that were changed significantly upon AG treatment among which 18 were up-regulated and 25 were down regulated. The quantitative proteomic data showed that AG peroxidative metabolism led to the down-regulation of critical anti-apoptotic proteins responsible for inhibiting the release of pro-apoptotic factors from the mitochondria as well as cytoskeletal proteins such as nuclear lamina. This overall pro-apoptotic response was confirmed with flow cytometry which demonstrated apoptosis to be the main mode of cell death, and this was attenuated by MPO inhibition. This response correlated with the intensity of AG-induced protein radical formation in HL-60 cells, which may play a role in cell death signaling mechanisms. PMID- 26102014 TI - The Real-World Treatment of Hemorrhages Associated With Dabigatran and Rivaroxaban: A Multicenter Evaluation. AB - PURPOSE: Adoption of the target-specific oral anticoagulants (TSOACs) has been slow; accordingly, lack of guidance for emergent reversal confounded by the need for "direct" reversal agents has contributed significantly to warfarin entrenchment in the medical community. The purpose of this analysis is to provide real-world experiences regarding the management of the hemorrhaging patient secondary to dabigatran and rivaroxaban. METHODS: Retrospective review of patients admitted with a hemorrhage secondary to dabigatran or rivaroxaban were evaluated. Descriptive statistics were utilized for analysis. RESULTS: Four hundred forty-four patients were screened for inclusion into the study; notably, 419 (94%) of the patients were excluded because the bleed was secondary to warfarin therapy. Of those included in this analysis (n = 25), gastrointestinal bleeding accounted for 21 events (84%), followed by intracranial (n = 2; 8%) and epistaxis (n = 2; 8%). Two patients (8%) expired during admission and 6 patients (24%) expired within 6 months after discharge from the hospital. Three (12%) minor bleeds, 7 (28%) major bleeds, and 15 (60%) life-threatening bleeds were identified. Minor bleeds required careful monitoring, supportive care, and cessation of anticoagulation therapy, whereas increasing severity required multiple interventions with prothrombin complex concentrate, recombinant activated factor 7, fresh frozen plasma, packed red blood cells, cryoprecipitate, and platelets. CONCLUSION: The approach to the management of bleeding events borne from TSOACs has proven to be very heterogeneous. In the midst of this observation period, these facilities developed protocols, which created a stratification of bleeds and a more regimented approach to managing them. Although bleeding is less with new agents, the creation of pathways/algorithms for the management of TSOACs and education regarding clinical decision-making may be beneficial for the expeditious and appropriate management when these events arise. PMID- 26102015 TI - Heparin Versus Bivalirudin in Contemporary Percutaneous Coronary Intervention: A Welcome Back to an Old Friend Unfractionated Heparin. AB - The results of randomized trials and observational studies make a strong argument for the use of bivalirudin rather than heparin plus systematic glycoprotein (GP) IIb/IIIa inhibitors for the great majority of patients undergoing percutaneous coronary interventions (PCI). However, there is no doubt that the benefit observed with bivalirudin was achieved because of the major bleeding complications with heparin plus GP IIb/IIIa inhibitors. Therefore, if we diminish bleeding complications by eliminating the systematic utilization of GP IIb/IIIa inhibitors, there would be a lesser benefit with the use of bivalirudin. When this latter drug was compared with unfractionated heparin alone there was no benefit in ischemic complications but a decrease in major bleeding complications with bivalirudin. However, a very recent meta-analysis shed more insights on the utilization of bivalirudin versus heparin regimens during PCI. Findings from this meta-analysis suggest that routine use of bivalirudin offers little advantage over heparin among PCI patients. In a detailed analysis of some randomized trials and observational studies with bivalirudin in non-ST-segment elevation acute coronary syndrome patients done by myself and published almost 4 years ago in this journal, I rendered some reflections on the future widespread use of bivalirudin. "In the setting of PCI and in the absence of GP IIb/IIIa inhibitors, bivalirudin did not offer any beneficial effect in the incidence of the composite end points when compared with heparin. For now, in real world practice, one would probably choose a well-known cheaper drug that has already passed the test of time, heparin. There may be reinforcement in the sole utilization of heparin confining GP IIb/IIIa inhibitors and other intravenous antithrombotics to bailout therapy for periprocedural PCI complications in acute coronary syndrome patients." Therefore, is it the beginning of a new era with bivalirudin or is it a welcome back to an old friend, heparin? Indeed, after more than two decades, it is always good to welcome back an old friend, unfractionated heparin. PMID- 26102016 TI - Chest Pain Centers: A Comparison of Accreditation Programs in Germany and the United States. AB - OBJECTIVE: The implementation of chest pain centers (CPC)/units (CPU) has been shown to improve emergency care in patients with suspected cardiac ischemia. METHODS: In an effort to provide a systematic and specific standard of care for patients with acute chest pain, the Society of Cardiovascular Patient Care (SCPC) as well as the German Cardiac Society (GCS) introduced criteria for the accreditation of specialized units. RESULTS: To date, 825 CPCs in the United States and 194 CPUs in Germany have been successfully certified by the SCPC or GCS, respectively. Even though there are differences in the accreditation processes, the goals are quite similar, focusing on enhanced operational efficiencies in the care of the acute coronary syndrome patients, reduced time delays, improved diagnostic and therapeutic strategies using adapted standard operating procedures, and increased medical as well as community awareness by the implementation of nationwide standardized concepts. In addition to national efforts, both societies have launched international initiatives, accrediting CPCs/CPU in the Middle East and China (SCPC) and Switzerland (GCS). CONCLUSION: Enhanced collaboration among international bodies interested in promoting high quality care might extend the opportunity for accreditation of facilities that treat cardiovascular patients, with national programs designed to meet local needs and local healthcare system requirements. PMID- 26102018 TI - Obstructive Sleep Apnea and Atrial Fibrillation: Pathophysiology and Implications for Treatment. AB - Obstructive sleep apnea (OSA) is increasingly recognized as an important risk factor for arrhythmogenesis. Epidemiological and clinical studies have suggested a strong association between OSA and atrial fibrillation (AF). With the increasing global epidemic of obesity, the incidence of OSA is also expected to rise. Various mechanisms mediated through adverse electrical and structural changes have been proposed to explain the increased risk of AF in patients with OSA. Multiple studies have also observed a greater risk of AF recurrence after cardioversion and catheter ablation (CA) in the patients with untreated OSA. The epidemiological and pathophysiological associations between OSA and AF have significant implications on the treatment outcomes of rhythm-control strategies for AF. Adequate screening and optimal management of OSA are of key importance to help improve the clinical outcomes following cardioversion and CA. In this review, we sought to describe the role of various mechanisms by which OSA mediates the pathogenesis of AF and contributes to adverse outcomes following CA. PMID- 26102017 TI - Agreement Between Cardiovascular Disease Risk Scores in Resource-Limited Settings: Evidence from 5 Peruvian Sites. AB - It is unclear how well currently available risk scores predict cardiovascular disease (CVD) risk in low-income and middle-income countries. We aim to compare the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort risk equations (ACC/AHA model) with 6 other CVD risk tools to assess the concordance of predicted CVD risk in a random sample from 5 geographically diverse Peruvian populations. We used data from 2 Peruvian, age and sex-matched, population-based studies across 5 geographical sites. The ACC/AHA model were compared with 6 other CVD risk prediction tools: laboratory Framingham risk score for CVD, non-laboratory Framingham risk score for CVD, Reynolds risk score, systematic coronary risk evaluation, World Health Organization risk charts, and the Lancet chronic diseases risk charts. Main outcome was in agreement with predicted CVD risk using Lin's concordance correlation coefficient. Two thousand one hundred and eighty-three subjects, mean age 54.3 (SD +/- 5.6) years, were included in the analysis. Overall, we found poor agreement between different scores when compared with ACC/AHA model. When each of the risk scores was used with cut-offs specified in guidelines, ACC/AHA model depicted the highest proportion of people at high CVD risk predicted at 10 years, with a prevalence of 29.0% (95% confidence interval, 26.9-31.0%), whereas prevalence with World Health Organization risk charts was 0.6% (95% confidence interval, 0.2-8.6%). In conclusion, poor concordance between current CVD risk scores demonstrates the uncertainty of choosing any of them for public health and clinical interventions in Latin American populations. There is a need to improve the evidence base of risk scores for CVD in low-income and middle-income countries. PMID- 26102019 TI - Bohr effect of hemoglobins: Accounting for differences in magnitude. AB - The basis of the difference in the Bohr effect of various hemoglobins has remained enigmatic for decades. Fourteen amino acid residues, identical in pairs and located at specific 'Bohr group positions' in human hemoglobin, are implicated in the Bohr effect. All 14 are present in mouse, 11 in dog, eight in pigeon and 13 in guinea pig hemoglobin. The Bohr data for human and mouse hemoglobin are identical: the 14 Bohr groups appear at identical positions in both molecules. The dog data are different from the human because three Bohr group positions are occupied by non-ionizable groups in dog hemoglobin; the pigeon data are vastly different from the human because six Bohr group positions are occupied by non-ionizable groups in pigeon hemoglobin. The guinea pig data are quite complex. Quantitative analyses showed that only the pigeon data could be fitted with the Wyman equation for the Bohr effect. We demonstrate that, apart from guinea pig hemoglobin, the difference between the Bohr effect of each of the other hemoglobins and of pigeon hemoglobin can be accounted for quantitatively on the basis of the occupation of some of their Bohr group positions by non ionizable groups in pigeon hemoglobin. We attribute the anomalous guinea pig result to a new salt-bridge formed in its R2 quaternary structure between the terminal NH3(+) group of one beta-chain and the COO(-) terminal group of the partner beta-chain in the same molecule. The pKas of this NH3(+) group are 6.33 in the R2 and 4.59 in the T state. PMID- 26102020 TI - Motor automaticity in Parkinson's disease. AB - Bradykinesia is the most important feature contributing to motor difficulties in Parkinson's disease (PD). However, the pathophysiology underlying bradykinesia is not fully understood. One important aspect is that PD patients have difficulty in performing learned motor skills automatically, but this problem has been generally overlooked. Here we review motor automaticity associated motor deficits in PD, such as reduced arm swing, decreased stride length, freezing of gait, micrographia and reduced facial expression. Recent neuroimaging studies have revealed some neural mechanisms underlying impaired motor automaticity in PD, including less efficient neural coding of movement, failure to shift automated motor skills to the sensorimotor striatum, instability of the automatic mode within the striatum, and use of attentional control and/or compensatory efforts to execute movements usually performed automatically in healthy people. PD patients lose previously acquired automatic skills due to their impaired sensorimotor striatum, and have difficulty in acquiring new automatic skills or restoring lost motor skills. More investigations on the pathophysiology of motor automaticity, the effect of L-dopa or surgical treatments on automaticity, and the potential role of using measures of automaticity in early diagnosis of PD would be valuable. PMID- 26102021 TI - Rapid antidepressant actions of scopolamine: Role of medial prefrontal cortex and M1-subtype muscarinic acetylcholine receptors. AB - Clinical studies demonstrate that scopolamine, a non-selective muscarinic acetylcholine receptor (mAchR) antagonist, produces rapid therapeutic effects in depressed patients, and preclinical studies report that the actions of scopolamine require glutamate receptor activation and the mechanistic target of rapamycin complex 1 (mTORC1). The present study extends these findings to determine the role of the medial prefrontal cortex (mPFC) and specific muscarinic acetylcholine receptor (M-AchR) subtypes in the actions of scopolamine. The administration of scopolamine increases the activity marker Fos in the mPFC, including the infralimbic (IL) and prelimbic (PrL) subregions. Microinfusions of scopolamine into either the IL or the PrL produced significant antidepressant responses in the forced swim test, and neuronal silencing of IL or PrL blocked the antidepressant effects of systemic scopolamine. The results also demonstrate that the systemic administration of a selective M1-AChR antagonist, VU0255035, produced an antidepressant response and stimulated mTORC1 signaling in the PFC, similar to the actions of scopolamine. Finally, we used a chronic unpredictable stress model as a more rigorous test of rapid antidepressant actions and found that a single dose of scopolamine or VU0255035 blocked the anhedonic response caused by CUS, an effect that requires the chronic administration of typical antidepressants. Taken together, these findings indicate that mPFC is a critical mediator of the behavioral actions of scopolamine and identify the M1-AChR as a therapeutic target for the development of novel and selective rapid-acting antidepressants. PMID- 26102022 TI - Low levels of astroglial markers in Parkinson's disease: relationship to alpha synuclein accumulation. AB - Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinson's disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral alpha-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to alpha-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen>substantia nigra>caudate>frontal cortex) and PSP (substantia nigra>caudate>putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with alpha-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with alpha-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive alpha-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful. PMID- 26102024 TI - Inhibition of autophagy induces IL-1beta release from ARPE-19 cells via ROS mediated NLRP3 inflammasome activation under high glucose stress. AB - Autophagy plays an important role in the development of diabetic retinopathy (DR). Retinal pigment epithelial (RPE) cells are the main cells involved in DR, a process in which hyperglycemia plays a crucial role. This study was conducted to investigate the protective effect of autophagy against high glucose-induced inflammatory response in ARPE-19 cells and its underlying mechanism. In the present study we subjected ARPE-19 cells to high glucose stress and showed that ARPE-19 cells respond to high glucose with an increase in autophagy. 3 methyladenine (3-MA) inhibited occurrence of autophagy and it leaded to the accumulation of damaged-mitochondria-producing-ROS, and the activation of NLRP3 inflammasome, and subsequently, caused IL-1beta secretion. PMID- 26102025 TI - CCR7 is involved in BCR-ABL/STAP-2-mediated cell growth in hematopoietic Ba/F3 cells. AB - Chronic myeloid leukemia is a clonal disease characterized by the presence of the Philadelphia chromosome and its oncogenic product, BCR-ABL, which activates multiple pathways involved in cell survival, growth promotion, and disease progression. We previously reported that in murine hematopoietic Ba/F3 cells, signal transducing adaptor protein-2 (STAP-2) binds to BCR-ABL and up-regulates BCR-ABL phosphorylation, leading to enhanced activation of its downstream signaling molecules. The binding of STAP-2 to BCR-ABL also influenced the expression levels of chemokine receptors, such as CXCR4 and CCR7. For the induction of CCR7 expression, signals mediated by the MAPK/ERK pathway were critical in Ba/F3 cells expressing BCR-ABL and STAP-2. In addition, STAP-2 cooperated with BCR-ABL to induce the production of CCR7 ligands, CCL19 and CCL21. Our results demonstrate a contribution of CCR7 to STAP-2-dependent enhancement of BCR-ABL-mediated cell growth in Ba/F3 cells. PMID- 26102023 TI - Oxidative stress and lipid peroxidation are upstream of amyloid pathology. AB - Oxidative stress is a common feature of the aging process and of many neurodegenerative disorders, including Alzheimer's disease. Understanding the direct causative relationship between oxidative stress and amyloid pathology, and determining the underlying molecular mechanisms is crucial for the development of more effective therapeutics for the disease. By employing microdialysis technique, we report local increase in the amyloid-beta42 levels and elevated amyloid-beta42/40 ratio in the interstitial fluid within 6h of direct infusion of oxidizing agents into the hippocampus of living and awake wild type mice. The increase in the amyloid-beta42/40 ratio correlated with the pathogenic conformational change of the amyloid precursor protein-cleaving enzyme, presenilin1/gamma-secretase. Furthermore, we found that the product of lipid peroxidation 4-hydroxynonenal, binds to both nicastrin and BACE, differentially affecting gamma- and beta-secretase activity, respectively. The present study demonstrates a direct cause-and-effect correlation between oxidative stress and altered amyloid-beta production, and provides a molecular mechanism by which naturally occurring product of lipid peroxidation may trigger generation of toxic amyloid-beta42 species. PMID- 26102026 TI - A phosphomimetic mutant TDP-43 (S409/410E) induces Drosha instability and cytotoxicity in Neuro 2A cells. AB - Two DNA/RNA binding proteins, TDP-43 and FUS/TLSU, are involved in RNA processing, and their aberrant mutations induce inherited amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions. Wild type TDP-43 and FUS (wtTDP-43 and wtFUS) are mainly localized in the nucleus and biochemically interact with the microRNA processing enzyme Drosha. In this study, we investigated Drosha stability in Neuro 2A cells by gain and loss of function studies of wtTDP-43 and wtFUS and cycloheximide mediated protein degradation assay. We also generated three different phosphomimetic mutants of TDP-43 (S379E, S403/404E and S409/410E) by using a site-directed mutagenesis method and examined Drosha stability to elucidate a correlation between the phosphorylated TDP-43 mutants and Drosha stability. Overexpression of wtTDP-43 and/or wtFUS increased Drosha stability in Neuro 2A cells and double knockdown of wtTDP-43 and wtFUS reduced its stability. However, knockdown of wtTDP-43 or wtFUS did not affect Drosha stability in Neuro 2A cells. Interestingly, a phosphomimetic mutant TDP-43 (S409/410E) significantly reduced Drosha stability via prevention of protein-protein interactions between wtFUS and Drosha, and induced cytotoxicity in Neuro 2A cells. Our findings suggest that TDP-43 and FUS controls Drosha stability in Neuro 2A cells and that a phosphomimetic mutant TDP 43 (S409/410E) which is associated with Drosha instability can induce neuronal toxicity. PMID- 26102027 TI - Tumor-suppressive effects of natural-type interferon-beta through CXCL10 in melanoma. AB - INTRODUCTION: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-beta (IFN-beta) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up regulated by IFN-beta treatment of lymphatic endothelial cells. MATERIALS AND METHODS: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-beta, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-beta treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-beta and CXCL10 in melanoma cells. RESULTS: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up regulated by IFN-beta in lymphatic endothelial cells. IFN-beta treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-beta. CXCL10 reduced melanoma cell proliferation in IFN-beta-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-beta. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-beta and down-regulated in melanoma cells with medium to low sensitivity. CONCLUSIONS: Our data suggest that IFN-beta suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-beta may be associated with resistance to IFN beta. PMID- 26102028 TI - Phosphoproteomic analysis of kinase-deficient mice reveals multiple TAK1 targets in osteoclast differentiation. AB - TAK1 (encoded by Map3k7) is a mitogen-activated protein kinase kinase kinase (MAP3K), which activates the transcription factors AP-1 and NF-kappaB in response to receptor activator of NF-kappaB ligand (RANKL) stimulation, thus constituting a key regulator of osteoclast differentiation. Here we report the functional relevance of the kinase activity of TAK1 in the late stage of osteoclast differentiation in vivo using Ctsk-Cre mice and TAK1 mutant mice in which the TAK1 kinase domain was flanked by loxP. The Map3k7(flox/kd)Ctsk(Cre/+) mice displayed a severe osteopetrotic phenotype due to a marked decrease in osteoclast number. RANKL-induced activation of MAPK and NF-kappaB was impaired in the late stage of osteoclast differentiation. The absence of suppressive effect of an administered NF-kappaB inhibitor on the late stage of osteoclastogenesis led us to investigate unknown TAK1 targets in osteoclast differentiation. We performed a phosphoproteomic analysis of RANKL-stimulated osteoclast precursor cells from Map3k7(flox/kd)Ctsk(Cre/+) mice, revealing multiple targets regulated by TAK1 during osteoclastogenesis. Thus, TAK1 functions as a critical regulator of the phosophorylation status of various cellular proteins that govern osteoclastogenesis. PMID- 26102029 TI - Essential role of kruppel-like factor 5 during tumor necrosis factor alpha induced phenotypic conversion of vascular smooth muscle cells. AB - Tumor necrosis factor alpha (TNFalpha) plays an essential role in the regulation of vascular smooth muscle cell (VSMC) phenotype. In the present study, we provide evidence that kruppel-like factor 5 (KLF5) plays an essential role in TNFalpha induced phenotypic conversion of VSMCs. Ectopic expression of KLF5 completely blocked phenotypic conversion of VSMCs from synthetic to contractile type. In addition, stimulation of VSMCs with TNFalpha facilitated expression of KLF5, whereas expression of smooth muscle marker genes such as SM22alpha and smooth muscle actin (SMA) was significantly down-regulated. TNFalpha significantly enhanced the promoter activity of KLF5 as well as mRNA level, which is significantly suppressed by the inhibition of the MAPK pathway. Silencing of KLF5 suppressed TNFalpha-induced phenotypic conversion of VSMCs, whereas overexpression of KLF5 stimulated phenotypic conversion of VSMCs and facilitated the loss of angiotensin II (AngII)-dependent contraction. Finally, overexpression of KLF5 significantly attenuated the promoter activity of SM22alpha and SMA. Therefore, we suggest that TNFalpha-dependent induction of KLF5 may play an essential role in phenotypic modulation of VSMCs. PMID- 26102030 TI - ANKRD1 modulates inflammatory responses in C2C12 myoblasts through feedback inhibition of NF-kappaB signaling activity. AB - Transcription factors of the nuclear factor-kappa B (NF-kappaB) family play a pivotal role in inflammation, immunity and cell survival responses. Recent studies revealed that NF-kappaB also regulates the processes of muscle atrophy. NF-kappaB activity is regulated by various factors, including ankyrin repeat domain 2 (AnkrD2), which belongs to the muscle ankyrin repeat protein family. Another member of this family, AnkrD1 is also a transcriptional effector. The expression levels of AnkrD1 are highly upregulated in denervated skeletal muscle, suggesting an involvement of AnkrD1 in NF-kappaB mediated cellular responses to paralysis. However, the molecular mechanism underlying the interactive role of AnkrD1 in NF-kappaB mediated cellular responses is not well understood. In the current study, we examined the effect of AnkrD1 on NF-kappaB activity and determined the interactions between AnkrD1 expression and NF-kappaB signaling induced by TNFalpha in differentiating C2C12 myoblasts. TNFalpha upregulated AnkrD1 mRNA and protein levels. AnkrD1-siRNA significantly increased TNFalpha induced transcriptional activation of NF-kappaB, whereas overexpression of AnkrD1 inhibited TNFalpha-induced NF-kappaB activity. Co-immunoprecipitation studies demonstrated that AnkrD1 was able to bind p50 subunit of NF-kappaB and vice versa. Finally, CHIP assays revealed that AnkrD1 bound chromatin at a NF-kappaB binding site in the AnrkD2 promoter and required NF-kappaB to do so. These results provide evidence of signaling integration between AnkrD1 and NF-kappaB pathways, and suggest a novel anti-inflammatory role of AnkrD1 through feedback inhibition of NF-kappaB transcriptional activity by which AnkrD1 modulates the balance between physiological and pathological inflammatory responses in skeletal muscle. PMID- 26102031 TI - Decoy receptor 3 suppresses FasL-induced apoptosis via ERK1/2 activation in pancreatic cancer cells. AB - Resistance to Fas Ligand (FasL) mediated apoptosis plays an important role in tumorigenesis. Decoy receptor 3 (DcR3) is reported to interact with FasL and is overexpressed in some malignant tumors. We sought to investigate the role of DcR3 in resistance to FasL in pancreatic cancer. We compared expression of apoptosis related genes between FasL-resistant SW1990 and FasL-sensitive Patu8988 pancreatic cell lines by microarray analysis. We explored the impact of siRNA knockdown of, or exogenous supplementation with, DcR3 on FasL-induced cell growth inhibition in pancreatic cancer cell lines and expression of proteins involved in apoptotic signaling. We assessed the level of DcR3 protein and ERK1/2 phosphorylation in tumor and non-tumor tissue samples of 66 patients with pancreatic carcinoma. RNAi knockdown of DcR3 expression in SW1990 cells reduced resistance to FasL-induced apoptosis, and supplementation of Patu8988 with rDcR3 had the opposite effect. RNAi knockdown of DcR3 in SW1990 cells elevated expression of caspase 3, 8 and 9, and reduced ERK1/2 phosphorylation (P < 0.05), but did not alter phosphorylated-Akt expression. 47 tumor tissue specimens, but only 15 matched non-tumor specimens stained for DcR3 (chi(2) = 31.1447, P < 0.001). The proliferation index of DcR3 positive specimens (14.26 +/- 2.67%) was significantly higher than that of DcR3 negative specimens (43.58 +/- 7.88%, P < 0.01). DcR3 expression positively correlated with p-ERK1/2 expression in pancreatic cancer tissues (r = 0.607, P < 0.001). DcR3 enhances ERK1/2 phosphorylation and opposes FasL signaling in pancreatic cancer cells. PMID- 26102032 TI - Ablation of Lgr4 enhances energy adaptation in skeletal muscle via activation of Ampk/Sirt1/Pgc1alpha pathway. AB - Leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is a newfound obese-associated gene. Previous study reveals that heterozygous mutation of Lgr4 correlates with decreased body weight in human. In our recent study, we demonstrate that Lgr4 ablation promotes browning of white adipose tissue and improves whole-body metabolic status. However little is known about its role in other metabolic tissues. Herein, we show that Lgr4 homozygous mutant (Lgr4(m/m)) mice show increased respiratory exchange ratio (RER, closer to 1.0) than wild type mice at 12:00 AM (food-intake time for mice) while decreased RER (closer to 0.75) at 12:00 PM (fasting for mice), indicating a glucose-prone versus fatty acid-prone metabolic pattern, respectively. Furthermore, Lgr4 ablation increases lipid oxidation-related gene expression while suppresses glucose transporter type 4 (Glut4) levels in skeletal muscle under fasting condition. These data suggest that Lgr4 ablation enhances the flexibility of skeletal muscle to switch energy provider from glucose to fatty acid in response to glucose depletion. We further reveal the activation of Ampk/Sirt1/Pgc1alpha pathway during this adaptive fuel shift due to Lgr4 ablation. This study suggests that Lgr4 might serve as an adaptive regulator between glucose and lipid metabolism in skeletal muscle and reveals a potentially new regulator for a well-established adaptive network. PMID- 26102033 TI - Glucocorticoid-mediated co-regulation of RCAN1-1, E4BP4 and BIM in human leukemia cells susceptible to apoptosis. AB - Glucocorticoids (GCs) are known to induce apoptosis of leukemia cells via gene regulatory changes affecting key pro-and anti-apoptotic genes. Three genes previously implicated in GC-evoked apoptosis in the CEM human T-cell leukemia model, RCAN1, E4BP4 and BIM, were studied in a panel of human lymphoid and myeloid leukemia cell lines. Of the two RCAN1 transcripts, the synthetic GC Dexamethasone (Dex) selectively upregulates RCAN1-1, but not RCAN1-4, in GC susceptible Sup-B15, RS4;11, Kasumi-1 cells but not in GC-resistant Sup T1 and Loucy cells. E4BP4 and BIM regulation correlated with that of RCAN1-1. A putative GRE and four EBPREs were identified within 1500bp upstream from the transcription start site of RCAN1-1. GC-refractory CEM C1-15 cells sensitized to GC-evoked apoptosis by ectopic E4BP4 expression, CEM C1-15mE#3, showed restored RCAN1-1 upregulation, suggesting that RCAN1-1 is a downstream target of E4BP4. A model for coordinated regulation of RCAN1-1, E4BP4 and BIM, and their role in GC-evoked apoptosis is proposed. PMID- 26102034 TI - Lafora disease proteins laforin and malin negatively regulate the HIPK2-p53 cell death pathway. AB - Lafora disease (LD) is an autosomal recessive, progressive, and fatal form of a neurodegenerative disorder characterized by the presence of Lafora polyglucosan bodies. LD is caused by defects in either the laforin protein phosphatase or the malin E3 ubiquitin ligase. Laforin and malin were shown play key roles in proteolytic processes, unfolded stress response, and glycogen metabolism. Therefore, the LD proteins laforin and malin are thought to function as pro survival factors and their loss thus could result in neurodegeneration. To understand the molecular pathway leading to the cell death in LD, in the present study, we investigated the possible role of LD proteins in the p53-mediated cell death pathway. We show that loss of laforin or malin results in the increased level and activity of p53, both in cellular and animal models of LD, and that this is primarily due to the increased levels of Hipk2, a proapoptotic activator of p53. Overexpression of laforin or malin confers protection against Hipk2 mediated cell death by targeting the Hipk2 to the cytoplasmic compartment. Taken together, our study strengthens the notion that laforin and malin are pro survival factors, and that the activation of Hipk2-p53 cell death pathway might underlie neurodegeneration in LD. PMID- 26102035 TI - 1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling. AB - The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. PMID- 26102036 TI - MTERF4 regulates the mitochondrial dysfunction induced by MPP(+) in SH-SY5Y cells. AB - Mitochondrial transcription termination factor 4, MTERF4, a member of the MTERF family, has been implicated in the regulation of mitochondrial translation by targeting NSUN4 to the large mitochondrial ribosome. Here, we found a novel role for MTERF4 in regulating mitochondrial dysfunction induced by MPP(+). We observed that knockdown of MTERF4 in SH-SY5Y cells resulted in increased mitochondrial DNA transcription levels and decreased mitochondrial DNA translation levels. In addition, after treatment with 2 mM MPP(+) for 24 h, the expression levels of MTERF4 were decreased compared to wide-type SH-SY5Y cells. Moreover, after exposure to 2 mM MPP(+) for 24 h, knockdown of MTERF4 in SH-SY5Y cells worsened the mitochondrial dysfunction induced by MPP(+), including increased reactive oxygen species, accumulated cleaved PARP-1, decreased mitochondrial membrane potential and depressed mitochondrial complexes. Furthermore, overexpression of MTERF4 in SH-SY5Y cells partially alleviated the mitochondrial dysfunction induced by MPP(+). Based on these findings, we suggest that the main function of MTERF4 is regulating mtDNA expression, and it is the crucial factor in the mechanism of mitochondrial dysfunction in SH-SY5Y cells induced by MPP(+). MTERF4 probably is the triggering of the pathogenesis of Parkinson's disease induced by environmental toxin. PMID- 26102037 TI - Identification of the chlE gene encoding oxygen-independent Mg-protoporphyrin IX monomethyl ester cyclase in cyanobacteria. AB - The fifth ring (E-ring) of chlorophyll (Chl) a is produced by Mg-protoporphyrin IX monomethyl ester (MPE) cyclase. There are two evolutionarily unrelated MPE cyclases: oxygen-independent (BchE) and oxygen-dependent (ChlA/AcsF) MPE cyclases. Although ChlA is the sole MPE cyclase in Synechocystis PCC 6803, it is yet unclear whether BchE exists in cyanobacteria. A BLAST search suggests that only few cyanobacteria possess bchE. Here, we report that two bchE candidate genes from Cyanothece strains PCC 7425 and PCC 7822 restore the photosynthetic growth and bacteriochlorophyll production in a bchE-lacking mutant of Rhodobacter capsulatus. We termed these cyanobacterial bchE orthologs "chlE." PMID- 26102038 TI - The DJ-1 superfamily member Hsp31 repairs proteins from glycation by methylglyoxal and glyoxal. AB - Hsp31 belongs to the PfpI/Hsp31/DJ-1 superfamily, and has been reported to display chaperone, peptidase and glutathione-independent glyoxalase activities. Here, we show that Hsp31 repairs glyoxal- and methylglyoxal-glycated amino acids and proteins and releases repaired proteins and lactate or glycolate, respectively. Hsp31 deglycates cysteine, arginine and lysine by acting on early glycation intermediates (hemithioacetals and aminocarbinols) and prevents the formation of Schiff bases and advanced glycation endproducts. Hsp31 repairs glycated serum albumin, glyceraldehyde-3-phosphate dehydrogenase, fructose biphosphate aldolase and aspartate aminotransferase. Moreover, we show that bacterial extracts from the hchA mutant display increased glycation levels and that the apparent glyoxalase activity of Hsp31 reflects its deglycase activity. Our results suggest that other Hsp31 members, previously characterized as glutathione-independent glyoxalases, likely function as protein deglycases. PMID- 26102039 TI - Ubiquitin E3 ligase UHRF1 regulates p53 ubiquitination and p53-dependent cell apoptosis in clear cell Renal Cell Carcinoma. AB - Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) is a multi-domain ubiquitin E3 ligase that plays critical roles in regulation of DNA methylation and histone ubiquitination. In this study, we found UHRF1 is frequently overexpressed in human clear cell Renal Cell Carcinoma (ccRCC) tissues both at mRNA and protein levels. We showed that UHRF1 directly interacts with p53 both in vivo and in vitro. A new domain (PD) in UHRF1 was required for interaction with p53. We found that UHRF1 down-regulates p53 transactivation activity which was depends on the ubiquitin E3 ligase function. UHRF1 can promote non-degradative ubiquitination of p53, suppress p53 pathway activation and p53-dependent apoptosis in ccRCC cells. Together, our study suggests that UHRF1, which overexpressed ccRCC, may act as a p53 regulator, suppress p53 pathway activation and help ccRCC cells to escape from p53-dependent apoptosis. PMID- 26102040 TI - Strategies to maintain operating room functionality following the complete loss of the recovery room due to an internal disaster. AB - The post-anesthesia care unit (PACU) is a major contributor to the operating room (OR) process flow and efficiency. A sudden failure of hospital facility infrastructure due to a burst pipe resulted in the complete loss of a 66-bed combined preoperative and PACU facility of a major academic medical center. The OR suites were undamaged. The clinical and administrative challenges of caring for surgical patients without the usual preoperative and postoperative care areas are discussed. Our strategy for maintaining OR functions and management of patient flow, OR personnel, case prioritization, and equipment needs are detailed from the time of initial crisis until restoration of these clinical care areas. Utilization of the hospital disaster Incident Command Structure and the activation and decision support provided by the hospital Emergency Operations Center (EOC) for the week immediately following the crisis, helped maintain OR functionality. PMID- 26102041 TI - Comparison of START triage categories to emergency department triage levels to determine need for urgent care and to predict hospitalization. AB - OBJECTIVE: To compare Emergency Severity Index (ESI) triage levels and Simple Triage and Rapid Treatment (START) triage colors for urgent care and hospitalization. DESIGN: Cross sectional. SETTING: Inner city emergency department (ED). PARTICIPANTS: Patients years transported by Emergency Medical Services (EMS) participating in the state triage tag exercise, October 9-15, 2011. INTERVENTIONS: EMS assigned each patient a START triage tag. ED staff recorded tag number and color. Demographics, vital signs, 22 emergent interventions, and disposition were obtained via chart review. Institutional review board approval was obtained. MAIN OUTCOME MEASURES: Presence of more than two abnormal vital sign on arrival and need for more than one emergent intervention in ED were considered indicators of acuity and severity. START triage colors were recategorized as urgent (Red, Yellow) and less acute (Green, White), and ESI was recategorized as urgent (1, 2, 3) and less acute (4, 5). RESULTS: Both ED and EMS staff were blinded to the study, and 95% confidence intervals were presented for statistical significance. Of 233 participants, START triage colors were Black=0, Red=12 percent, Yellow=26 percent, Green=53 percent, and White=9 percent. ESI triage levels were level 1=1 percent, level 2=34 percent, level 3=51 percent, level 4=14 percent, and level 5=1 percent. ESI (1, 2, 3) identified 88 percent (75-95 percent) of 49 patients with abnormal vital signs; START (Red, Yellow) only identified 51 percent (35-64 percent). Twenty-one patients needed emergent intervention. ESI (1, 2, 3) identified 95 percent (76-99 percent) of these patients; START (Red, Yellow) identified 33 percent (17-55 percent). ESI (1, 2, 3) identified 98 percent of the 96(92-100 percent) admitted patients; only 48 percent (38-58 percent) were tagged START (Red, Yellow). CONCLUSION: ESI better identified patients with abnormal vital signs, those who needed emergent interventions, and those admitted than START. PMID- 26102042 TI - Emergency preparedness of families of children with developmental disabilities: what public health and safety emergency planners need to know. AB - OBJECTIVE: To assess the emergency preparedness knowledge, behaviors, and training needs of families of children with developmental disabilities (DD). DESIGN: An online survey. PARTICIPANTS: A sample of 314 self-selecting US parents/guardians of children with DD, aged birth-21 years. MAIN OUTCOME MEASURES: 1) Preparedness self-assessment; 2) self-report regarding the extent to which families followed 11 specific preparedness action steps derived from publicly available preparedness guides; and 3) parent training and support needs. RESULTS: Although most participants assessed themselves to be somewhat to moderately well prepared, even those who reported being "very well prepared" had taken fewer than half of 11 recommended action steps. Most participants expressed a need for preparedness support; virtually all the respondents felt that training was either important or very important. CONCLUSIONS: Children with disabilities are known to be particularly vulnerable to negative disaster impacts. Overall, parents in this study appeared under-prepared to meet family disaster needs, although they recognized its importance. The results suggest opportunities and methods for public health and safety planning, education and outreach to parents of children with DD who would benefit from targeted training such as information and skill building to develop effective family preparedness plans and connections to local emergency management and responders. PMID- 26102043 TI - The contribution of on-call, volunteer first responders to mass-casualty terrorist attacks in Israel. AB - OBJECTIVE: To describe the contributions of on-call, volunteer first responders to mass-casualty terrorist attacks in Israel during the Second Intifada. DESIGN: Descriptive study evaluating data obtained from postevent debriefings after 15 terrorist attacks in Israel between 2001 and 2004. RESULTS: An average of 7.9 deaths (median 7.0, interquartile range [IQR] 2.5-12.5) and 53.8 injuries (median 50.0, IQR 34.0-62.0) occurred in each of these attacks. The average number of volunteers responding to each event was 50.3 (median 43.0, IQR 27.5-55.5). The volunteers were involved in extricating victims from imminent danger, and performing emergent tasks such as bag-valve ventilation, tourniquet application, and intravenous line insertion. They were also integral to the rapid evacuation of casualties from the scene. CONCLUSION: On-call, volunteer first responders are an integral part of Israel's emergency medical response to mass-casualty terrorist attacks. This system may be used as a model for the development of similar services worldwide. PMID- 26102044 TI - Local health department workers, public policy, and willingness to respond during emergencies. AB - OBJECTIVES: To determine whether an association exists between a state's authority to declare a public health emergency and local public health workers' response willingness. DESIGN: The 2009-2010 Johns Hopkins~Public Health Infrastructure Response Survey Tool included questions about demographics and attitudes/beliefs regarding local public health workers' response willingness during public health emergencies. Survey data were merged with data about presence/absence of a law granting states the authority to declare a public health emergency. Logistic regression analyses were performed with the presence/absence of the law and were adjusted for individuals' demographic and locale characteristics. SETTING: Data were collected from eight clusters of local health department workers in nine states. PARTICIPANTS: Two thousand nine hundred ninety-three local health department workers. MAIN OUTCOME MEASURE: Willingness to respond to four different public health emergency scenarios. RESULTS: For naturally occurring and human-caused disasters, in unadjusted analyses, there was no statistically significant difference in willingness to respond between individuals living in states with a law that allowed for a governmental declaration of public health emergency and those living in states without such a law. Adjusted analyses yielded similar results. CONCLUSIONS: While laws giving the state the authority to declare a public health emergency are not associated with response willingness, findings may reflect the fact that states rarely declare public health emergencies, giving local public health workers few opportunities to become familiar with the implementation of these laws. In light of this, local health departments should consider altering their own internal policies to promote response willingness among their employees. PMID- 26102045 TI - Development of a disaster preparedness curriculum for medical students: a pilot study of incorporating local events into training opportunities. AB - OBJECTIVE: Contemporary disasters, like the outbreak of Ebola in West Africa, have piqued the interest of medical students in disaster preparedness. The topic is also a requirement of undergraduate medical education.(1) Yet current literature suggests that disaster preparedness education is lacking. Our objective was to pilot a curriculum to augment medical students' disaster preparedness education by marshalling local resources to provide practical hands on experiences. DESIGN: This pilot curriculum consisted of lectures; simulations; asynchronous learning materials; a large-scale, regional disaster exercise; and preparation for and participation in a real-time mass gathering. Outcomes were measured by student performance on written tests and evaluations of each activity. SETTING: Academic Health Center with associated medical school. PARTICIPANTS: Fifty-two medical students participated in at least one of the six activities during this voluntary pilot program. Premedical students and residents (n=57) participated in some activities. RESULTS: Forty-one medical students took either the pretest or the post-test over the curriculum. Only eight students took both. A paired t test comparing pretest to post-test scores using imputed missing data (t=-11.72, df=40, p<=0.001) was consistent with an analysis using only complete data (t=-2.35, df=7, p=0.05), implying that student scores improved significantly over time. Evaluations indicated a student preference for hands-on over didactic or independent learning activities. CONCLUSIONS: This pilot curriculum was designed to capitalize on practical hands-on training opportunities for our medical students, including participation in a disaster exercise and a mass-gathering event. These opportunities provided effective and engaging disaster preparedness education. PMID- 26102046 TI - Effects of sternal intraosseous and intravenous administration of Hextend on time of administration and hemodynamics in a swine model of hemorrhagic shock. AB - OBJECTIVE: Disasters may cause traumatic injuries leading to hemorrhage. Hemorrhage is the leading cause of death for military and civilian trauma casualties. The US Army's Tactical Combat Casualty Care guidelines recommend administering a 500 mL Hextend bolus via the intravenous (IV) or intraosseous (IO) routes for patients in hypovolemic shock. The purposes of this study were to compare administration time of Hextend and the effects on hemodynamics when Hextend is administered by the sternal IO (SIO) and IV routes in a swine model of hemorrhagic shock. DESIGN: This was a prospective, experimental study with random assignment. SETTING: The study was implemented at an animal vivarium. SUBJECTS: Yorkshire-cross (N=21) swine were used. INTERVENTION: Each swine was hemorrhaged 30 percent of their total blood volume to simulate a class II hemorrhage; 500 mL of Hextend was administered by the SIO and IV routes after hemorrhage. The control group did not receive any resuscitative fluids. MAIN OUTCOME MEASUREMENTS: The predetermined variables of the study were time of administration and hemodynamics over 8 minutes. Hemodynamic data were collected every 2 minutes until administration was complete. RESULTS: There were no significant differences in the time to administer Hextend between the SIO (616+/ 166 seconds) and the IV groups (534+/-151 seconds) (p=0.37). There were no significant differences between the SIO and IV groups relative to hemodynamics (p>0.05), but both were significantly different than the control group (p<0.05). CONCLUSION: The SIO route is an effective method of administering Hextend. PMID- 26102047 TI - Simple infrared thermometry in fever detection: consideration in mass fever screening. AB - OBJECTIVE: The need to rapidly screen patients during outbreaks has prompted Cutaneous Infrared Thermometry (CIT) use. Little is known of CIT performance in this context. What are the performance characteristics of simple CIT in detecting fever? DESIGN: Prospective cohort, sequential convenience sample. PARTICIPANTS: All patients presenting to the study Emergency Department for care. INTERVENTION: CIT and oral temperature measurements. MAIN OUTCOMES: Fever defined as oral temperature>=38 degrees C. CIT is measured simultaneously with oral temperatures. Comparisons of temperatures are expressed as means and 95% confidence intervals. Means are compared using Student's t test. Limits of agreement are measured using Bland-Altman. Receiver operating characteristics are determined. RESULTS: There are 548 cases comprising 224 males, 324 females, with mean age 26 years. The mean temperature difference is 12.95 degrees C, (13.18-9.08 degrees C) p<=0.0001. Bland-Altman demonstrates bias at 8.680 (-9.084 to -8.275) p<=0.0001 with upper and lower level bias values of 18.124 (18.819-17.435) and 0.768 (0.076-1.459), respectively. Based on Receiver Operator Characteristics analysis, detection of hyperpyrexia at a CIT of 35.3 degrees C provided sensitivity of 0.236 (0.143 0.359), specificity 0.977 (0.959-0.989), positive predictive value 0.589 (0.325 0.810), negative predictive value 0.904 (0.891-0.919), and accuracy of 0.888 (0.861-0.913). CONCLUSIONS: The use of a readily available CIT measurement device predicted hyperpyrexia about 59 percent of the time and the absence of hyperpyrexia about 90 percent of the time. This is consistent with previous reports of more complex infrared measurement devices. Although commonly used in mass fever screening, the current performance characteristics of CIT are limited and may add little to detection of target diseases in a mass screening context. PMID- 26102049 TI - [New horizont in the fight against bacterial resistance]. PMID- 26102048 TI - Use of an automated drug distribution cabinet system in a disaster response mobile emergency department. AB - OBJECTIVE: This article describes the innovative use of an automated drug distribution cabinet system for medication supply in a disaster response mobile Emergency Department vehicle. Prior to the use of the automated drug distribution cabinet system described in this article, the mobile hospitals were stocked as needed with drugs in individual boxes and draws. Experience with multiple deployments found this method to be very cumbersome and labor intensive, both in preparation, operational use, and demobilization. SETTING: For a recent deployment to provide emergency medical care at the 2014 Super Bowl football event, the automated drug distribution cabinet system in the Institution's main campus Emergency Department was duplicated and incorporated into the mobile Emergency Department. RESULTS: This method of drug stocking and dispensing was found to be far more efficient than gathering and placing drugs in onboard draws and racks. CONCLUSIONS: Automated drug distribution cabinet systems can be used to significantly improve patient care and overall efficiency in mobile hospital deployments. PMID- 26102050 TI - [Quality of life in patients with prostate cancer: validation of an instrument for clinical practice]. AB - OBJECTIVES: Currently there are instruments to evaluate the different features of the impact on quality of life in those patients with prostate cancer undergoing any type of treatment, but most of them have 50 or more questions and they are difficult to apply in clinical practice. An English validation of a shortened version of the EPIC (Expanded Prostate Cancer Composite), the most used instrument to measure the quality of life in patients with prostate cancer, has been published recently. This version called EPIC-CP (Expanded Prostate Cancer Composite-Clinical Practice) consists of 16 questions arranged in a page, for easy and rapid clinical application. The objective of this work is to validate a Spanish version of the EPIC-CP. METHOD: An inversa-directa Spanish translation of the original version was performed. The EPIC-CP and EQ5D questionnaires were applied to 46 patients eligible to be subjected to different treatments - open prostatectomy (OP), Robotic Prostatectomy (RP), brachytherapy (Br) or conformational radiotherapy (CR) - and 82 patients already treated (9 OP, 13 RP, 7 Br, 4 CR). For reliability evaluation, the Cronbach's alpha was used to test the internal consistency for each domain of the EPIC-CP. Treated and untreated patients' scores were compared with the Wilcoxon range sum test to assess the sensitivity to change. RESULTS: Cronbach's alpha was elevated in all the EPIC-CP domains (near or greater than 0.7), indicating a high internal consistency. There was no significant difference in age and educational level between treated and untreated patients. We found significant differences between treated and untreated patients in the total EPIC CP score, in the domains of urinary incontinence, bowel function, sexual function and hormonal function. CONCLUSION: The Spanish version of the EPIC-CP is reliable and valid, so it is a useful tool to measure the quality of life in patients with prostate cancer, as well as the impact of different treatments. PMID- 26102051 TI - [Expression of P504S and matrix metalloproteinase-2 in circulating prostate cells disseminated as a result of transrectal ultrasound guided biopsy as determined by immunocytochemistry: Clinical implications]. AB - OBJECTIVES: Surgical manipulation of cancer has been shown to increase blood borne cancer cell dissemination and increase the risk of metastasis. We present the effect of prostate biopsy on prostate cell dissemination and the phenotypic characteristics of these cells. METHODS: 50 men undergoing initial prostate biopsy for suspicion of prostate cancer were studied. Blood samples were taken immediately before, and 1 and 24 hours after biopsy for circulating prostate cells (CPC) determination and phenotypic characterization. CPCs were detected and counted using standard immunocytochemistry using anti-PSA and then characterized using anti-P504S and anti-matrix metalloproteinase-2 (MMP-2). RESULTS: 14 (28%) men had cancer detected on biopsy. 13/14 had P504S (+) and MMP-2 (+) cells detected prior to biopsy. One hour after biopsy there was a mixture of P504S (+) and P504S (-) cells detected, as well as MMP-2 (+) and MMP-2 (-) cells detected. 24 hours after biopsy the same 13/14 men remained positive, although the number of CPCs increased 1 hour after biopsy and then the numbers decreased to pre biopsy levels after 24 hours. In cancer negative men, P504S (-) and MMP-2 (-) cells were detected, some of these cells persisted 24 hours after biopsy. CONCLUSIONS: Prostate biopsy causes dissemination of prostate cells into the circulation, both malignant and benign; the majority of them are cleared within 24 hours. There was no conversion of negative to positive result in men with cancer, this suggests that the inherent capacity of malignant CPCs to disseminate is more important than the effect of dissemination caused by prostate biopsy. PMID- 26102052 TI - [Analysis of budgetary impact of moderate and high risk non muscle-invasive bladder cancer by means of neoadjuvant hyperthermia chemotherapy compared to the standard adjuvant treatment with BCG]. AB - OBJECTIVES: To study the relationship between cost-effectiveness and budgetary impact the application of a neoadjuvant chemo-hyperthermia treatment on 15 patients with NMI multi-recurrent bladder cancer and/or whose risk of recurrence and progression is medium-high, compared with the standard neoadjuvant BCG treatment, has had on the Hospital Comarcal de Monforte de Lemos (Lugo). METHODS: A model was designed from an SNS perspective with a temporary horizon of three years to compare the costs of applying neoadjuvant chemo-hyperthermia on the patients of the clinical test (8 instillations weekly of 80 mg Mitomycin C recirculating at 43 C for an hour prior to carrying out a transurethral resection of the bladder tumor) with the costs of treating 15 patients with the same risk profile with the standard adjuvant treatment of BCG (control group). The effective available costs corresponding to drugs, disposables and those relative to TURBT, cold biopsy and tumor relapse were included. The costs of diagnostic tests and follow-up were discarded from the model because they did not vary between groups. RESULTS: The model built with effective and published cost data establishes a favourable difference in favour of the neoadjuvant treatment with chemo hyperthermia in terms of 3 year costs with a minimum global savings of 10,300? and 687? per patient, together with an improvement in the effectiveness of the treatment. These values could reach a minimum savings of 25,960? and 1,731? per patient, if a change in protocol is made after the neoadjuvant treatment, which uses the cold biopsy to check the results. Of the 15 patients pre-treated with chemo-hyperthermia, 11 high-risk and 4 medium-risk, 9 have responded completely (absence of residual tumor) and 6 partially (shrinking of the tumor). The number of expected relapses has been reduced from 8 to 2 and progression from 3 to 0. CONCLUSIONS: The neoadjuvant treatment with chemo hyperthermia constitutes a cost-effective therapeutic strategy. PMID- 26102053 TI - Magnetic resonance spectroscopic imaging 3T and prostate cancer: correlation with transperineal ultrasound guided prostate biopsy. AB - OBJECTIVES: The aim of our study was to correlate the results obtained by 3T Magnetic Resonance Spectroscopic Imaging (MRSI3T) with those obtained by histological examination of samples of the trans-perineal ultrasound-guided prostate biopsy (TPUS-B). METHODS: 34 patients were enrolled in the study. All patients had a clinical suspicion of cancer due to increased PSA and/or positive digital rectal examination. Patients were subjected to an MRSI 3T examination and subsequently to TPUS-B. RESULTS: Of the 22 (22/34) patients who presented abnormalities MRSI at 3T, 9 had a histological diagnosis of Prostate adenocarcinoma. Of the remaining 13 patients, 6 were found to be histologically positive for Benign Prostatic Hypertrophy and 7 Chronic Interstitial Inflammation or High Grade Prostatic Intraepithelial Neoplasia. 12 (12/34) patients found to have no peripheral alterations in their prostate on 3T MRSI, none were positive for ADK or inflammation on histology. The sensitivity, specificity, positive predictive value and negative predictive value were 100%, 48%, 40% and 100% respectively. DISCUSSION: In this study, we correlated the values obtained from 3T MRSI with the results of histologically examined prostate biopsies. Our work shows that 72.8% of the voxels in which there was a change in ratio of Cit/(Cho + Cr), corresponded to areas of prostate tissue disease. Of these, 73.2% were positive for ADK and 26.8% for CII or HG PIN. In literature, it is noted that PCa can be distinguished from areas of benign tissue, in the peripheral zone, on the basis of the values of the ratio Cit/(Cho + Cr) (17), although some benign conditions, such as prostatitis or PINHG, can alter these values (18-19). CONCLUSIONS: In conclusion, the use of MRSI 3T before performing prostate biopsies may represent a valid aid for the urologist in the diagnosis of PCa, allowing them to avoid unnecessary prostate biopsies that may be negative. Furthermore, it would also be possible to reduce the total number of biopsies, thus decreasing patient exposure to the unnecessary risks associated with biopsy. PMID- 26102054 TI - [Vesicovaginal Reflux and Urocolpos]. AB - OBJECTIVE: Vesico-vaginal reflux (VVR) is defined as the reflux of urine into the vaginal vault during voiding, occasionally seen in pre- adolescent girls. The typical history consists in post voiding leaks in the daytime, that correspond to the progressive urine discharge from the vagina, after it has been filled up during micturition. We intend to show two cases presenting with significant urocolpos. METHODS: Description of two clinical cases observed in the pediatric urology office. RESULTS: Clinical case 1.- A 10-year-old girl presented with the complaint of diurnal incontinence (in the immediate post-voiding minutes). The early voiding phase in the cystourethrogram (VCUG) demonstrated progressive gross distension of the vagina (urocolpos) due to retrograde filling as the bladder emptied. The girl was managed with behavioural modifications, and was dry afterwards. Clinical case 2.- A 9-year-old girl presented with history of incomplete voiding. In infancy, she had right-sided vesicoureteral reflux (VUR) and was endoscopically treated at the age of 2. VCUG showed VVR, and no VUR. She was then successfully treated with behavioural modifications. Clinical case 3.- A 10-year-old girl complained of diurnal urinary incontinence, described as post voiding leaks. Again, a VCUG showed VVR and a small urocolpos. After re-education of voiding habits, leaks disappeared, but recurred 6 months afterwards, when she acknowledged no adherence to the therapy. DISCUSSION: Between 12 to 15% of girls referred to Urological clinics because of urine incontinence present VVR. In the absence of a clear anatomical obstruction, reflux happens as the urine flow encounters a natural obstacle in the labia majora usually in girls that close their legs as they void. Instructions on proper voiding form a key element in the management of VVR, and if not enough, the behavioural modification consists on a reverse position during voiding. PMID- 26102055 TI - [Penile necrosis as clinical presentation of systemic Calciphylaxis: Report of two cases and bibliographic review]. AB - OBJECTIVE: Calciphylaxis is a potentially lethal syndrome reported mainly in patients with ESRD on hemodialysis. Etiopathogenesis remains unclear and there is much controversy regarding optimal diagnostic and therapeutic approach. Penile necrosis as a disease presentation is extremely rare. We report two clinical cases treated in our center and perform an evidence review. METHODS: Clinical data was obtained from both patients and an evidence review was performed on PubMed under the criteria "penile necrosis" and "Calciphylaxis". RESULTS: Both patients underwent partial penectomy due to severe penile necrosis. After surgery both patients received treatment with sodium thiosulfate (STS) 20mg in every hemodialysis session. Both patients showed stabilization of necrotic lesions. DISCUSSION: The same way that biopsying the ischemic lesions produced by Calciphylaxis is discussed and even misadvised, the role of aggressive surgery as first line therapy might be uncertain specially with the raising of new specific drugs such as sodium thiosulfate (STS) that have shown efficacy stopping disease progression. PMID- 26102056 TI - In vivo exposure of marine mussels to carbamazepine and 10-hydroxy-10,11-dihydro carbamazepine: Bioconcentration and metabolization. AB - Aquatic organisms are exposed to pharmaceuticals present in natural waters, but few data are available on the accumulation of these substances in such organisms. The present study evaluated the in vivo bioconcentration of two anticonvulsants- carbamazepine (CBZ) and 10-hydroxy-10,11-dihydro-carbamazepine (10 OH)--in marine mussels (Mytilus galloprovincialis) exposed to nominal 10 MUg L(-1) concentrations for one week. The bioconcentration factors (BCFs) were 3.9 and 4.5 L kg(-1) dry weight (dw) for CBZ and 10 OH, respectively. CBZ accumulation reached an average tissue concentration of 29.3 +/- 4.8 ng g(-1) dw, and 10 OH accumulated up to 40.9 +/- 4.6 ng g(-1) dw in tissues within one week, showing first-order kinetics. BCF obtained with linear QSAR models correctly estimated the CBZ bioconcentration and overestimated the 10 OH bioconcentration to some extent. The detection of two metabolites (carbamazepine-10,11-epoxide and acridine) among the five sought suggested an active metabolism for CBZ. In contrast, none of the 10 OH metabolites were detected in mussels exposed to 10 OH. CBZ showed higher accumulation in the digestive gland, where some relevant metabolites were detected, than in other studied tissues. The implication of those findings on field biomonitoring is discussed. PMID- 26102058 TI - Date palm and the activated sludge co-composting actinobacteria sanitization potential. AB - The objective of this study was to find a connection between the development of the compost actinobacteria and the potential involvement of antagonistic thermophilic actinomycetes in compost sanitization as high temperature additional role. An abundance of actinobacteria and coliforms during the activated sludge and date palm co-composting is determined. Hundred actinomycete isolates were isolated from the sample collected at different composting times. To evaluate the antagonistic effects of the different recovered actinomycete isolates, several wastewater-linked microorganisms known as human and plant potential pathogens were used. The results showed that 12 isolates have an in vitro inhibitory effect on at least 9 of the indicator microorganisms while only 4 active strains inhibit all these pathogens. The antimicrobial activities of sterilized composting time extracts are also investigated. PMID- 26102057 TI - Predicting characteristics of rainfall driven estrogen runoff and transport from swine AFO spray fields. AB - Animal feeding operations (AFOs) have been implicated as potentially major sources of estrogenic contaminants into the aquatic environment due to the relatively minimal treatment of waste and potential mobilization and transport of waste components from spray fields. In this study a Bayesian network (BN) model was developed to inform management decisions and better predict the transport and fate of natural steroidal estrogens from these sites. The developed BN model integrates processes of surface runoff and sediment loss with the modified universal soil loss equation (MUSLE) and the soil conservation service curve number (SCS-CN) runoff model. What-if scenario simulations of lagoon slurry wastes to the spray fields were conducted for the most abundant natural estrogen estrone (E1) observed in the system. It was found that E1 attenuated significantly after 2 months following waste slurry application in both spring and summer seasons, with the overall attenuation rate predicted to be higher in the summer compared to the spring. Using simulations of rainfall events in conjunction with waste slurry application rates, it was predicted that the magnitude of E1 runoff loss is significantly higher in the spring as compared to the summer months, primarily due to spray field crop management plans. Our what if scenario analyses suggest that planting Bermuda grass in the spray fields is likely to reduce runoff losses of natural estrogens near the water bodies and ecosystems, as compared to planting of soybeans. PMID- 26102059 TI - New kid on the block: ONC201 in NHL. PMID- 26102060 TI - Minireview: The Complexities of IGF/Insulin Signaling in Aging: Why Flies and Worms Are Not Humans. AB - A remarkable plasticity in life span has been uncovered in recent years, offering hope that the basic mechanisms of aging and interventions that delay aging may be identified in the coming decades. Life span extension has been achieved by genetic manipulation in multiple organisms including Sarcomyces cervisae, Caenorhabditis elegans, and Drosophila melanogaster, resulting in more than a doubling of life span in some cases. Typically, a reduction in function has been the most effective approach to extending life span, and a reduction in the insulin/IGF-1 signaling pathway appears to provide the most robust increase in life span. This highly conserved pathway integrates growth/survival signals with nutrient status. In mammals, it comprises part of the neuroendocrine axis, a critical regulator of growth and development. Reduced functionality of the neuroendocrine axis itself promotes life span extension in mammals; however, reduced activity of the IGF-1 signaling pathway specifically leads to less robust increases in life span. This review examines the differences in the insulin/IGF-1 axis between invertebrate and mammalian systems and discusses implications of these differences in terms of life span modulation. PMID- 26102062 TI - miR-135a Targets and Regulates Prolactin Receptor Gene in Goat Mammary Epithelial Cells. AB - Mammary gland development and lactation are typical traits controlled by multiple genes, hormones, and regulatory factors. Prolactin receptor (PRLR), a specific receptor of prolactin, has been reported to have important physiological functions in regulating mammogenesis and lactogenesis. However, the post transcriptional regulation mechanisms of PRLR expression have not yet been shown in detail. In this study, the expression of miR-135a and PRLR at different development stages of Laoshan dairy goat mammary gland tissues was investigated. After overexpression and silencing expression of miR-135a in cultured primary mammary epithelial cells, the regulatory relationship between miR-135a and PRLR was examined through dual-luciferase reporter assay, and the expression of PRLR at both mRNA and protein levels was examined by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Collectively, our results suggested that PRLR is a direct target gene of miR-135a, miR-135a is a novel regulator of PRLR, and it might play an essential role in the regulation of animal mammary gland development and lactation. PMID- 26102063 TI - Minimally invasive approach to lumbosacral decompression in a cadaveric canine model. AB - AIMS: To determine efficacy of a minimally invasive (MI) surgical approach using a human MI lumbar retractor for canine lumbosacral dorsal laminectomy and partial discectomy and to compare this technique to the standard open surgical (OS) approach. METHODS: Lumbosacral dorsal laminectomy and partial discectomy was performed on 16 large-breed canine cadavers using either a standard OS (n=8) or MI (n=8) approach. Skin and fascial incision length, procedure time, and intraoperative complications were recorded. Postoperatively specimens were evaluated for laminectomy and discectomy dimensions, and visible damage to the cauda equina and exiting nerve roots. RESULTS: Median length of skin and fascial incisions in the OS group were longer than in the MI group (p<0.001). Median laminectomy length was similar between both approaches (p=0.234) but width was greater for the MI than OS approach (p=0.002). Both approaches achieved similar partial discectomy width (p=0.279). Overall surgical time was longer for MI approaches compared to OS, with a median of 18.5 (min 15.5, max 21.8) minutes for MI compared to 14.6 (min 13.1, max 16.9) minutes for OS (p=0.001). CONCLUSIONS: The MI approach reduced incision lengths while retaining comparable laminectomy and discectomy dimensions. For this in vitro model the MI approach required more time to complete, but this difference may not be relevant in clinical cases. CLINICAL RELEVANCE: Dogs undergoing lumbosacral dorsal laminectomy are commonly large-breed dogs. The traditional open approach requires a large skin incision and soft tissue dissection, especially in overweight animals. A MI approach accomplishing the same surgical result while minimising soft tissue trauma could reduce post-operative pain and recovery time, and may lower wound-related complications. Clinical studies are needed to confirm postoperative benefit and assess operating times in vivo. PMID- 26102061 TI - Extrusion of mitochondrial contents from lipopolysaccharide-stimulated cells: Involvement of autophagy. AB - Sepsis/endotoxemia is elicited by the circulatory distribution of pathogens/endotoxins into whole bodies, and causes profound effects on human health by causing inflammation in multiple organs. Mitochondrial damage is one of the characteristics of the cellular degeneration observed during sepsis/endotoxemia. Elimination of damaged mitochondria through the autophagy lysosome system has been reported in the liver, indicating that autophagy should play an important role in liver homeostasis during sepsis/endotoxemia. An increased appearance of mitochondrial DNA and proteins in the plasma is another feature of sepsis/endotoxemia, suggesting that damaged mitochondria are not only eliminated within the cells, but also extruded through currently unknown mechanisms. Here we provide evidence for the secretion of mitochondrial proteins and DNA from lipopolysaccharide (LPS)-stimulated rat hepatocytes as well as mouse embryonic fibroblasts (MEFs). The secretion of mitochondrial contents is accompanied by the secretion of proteins that reside in the lumenal space of autolysosomes (LC3-II and CTSD/cathepsin D), but not by a lysosomal membrane protein (LAMP1). The pharmacological inhibition of autophagy by 3MA blocks the secretion of mitochondrial constituents from LPS-stimulated hepatocytes. LPS also stimulates the secretion of mitochondrial as well as autolysosomal lumenal proteins from wild-type (Atg5(+/+)) MEFs, but not from atg5(-/-) MEFs. Furthermore, we show that direct exposure of purified mitochondria activates polymorphonuclear leukocytes (PMNs), as evident by the induction of IL1B/interlekin-1beta, a pro-inflammatory cytokine. Taken together, the data suggest the active extrusion of mitochondrial contents, which provoke an inflammatory response of immune cells, through the exocytosis of autolysosomes by cells stimulated with LPS. PMID- 26102064 TI - Liposome-based Formulation for Intracellular Delivery of Functional Proteins. AB - The intracellular delivery of biologically active protein represents an important emerging strategy for both fundamental and therapeutic applications. Here, we optimized in vitro delivery of two functional proteins, the beta-galactosidase (beta-gal) enzyme and the anti-cytokeratin8 (K8) antibody, using liposome-based formulation. The guanidinium-cholesterol cationic lipid bis (guanidinium)-tren cholesterol (BGTC) (bis (guanidinium)-tren-cholesterol) combined to the colipid dioleoyl phosphatidylethanolamine (DOPE) (dioleoyl phosphatidylethanolamine) was shown to efficiently deliver the beta-gal intracellularly without compromising its activity. The lipid/protein molar ratio, protein amount, and culture medium were demonstrated to be key parameters affecting delivery efficiency. The protein itself is an essential factor requiring selection of the appropriate cationic lipid as illustrated by low K8 binding activity of the anti-K8 antibody using guanidinium-based liposome. Optimization of various lipids led to the identification of the aminoglycoside lipid dioleyl succinyl paromomycin (DOSP) associated with the imidazole-based helper lipid MM27 as a potent delivery system for K8 antibody, achieving delivery in 67% of HeLa cells. Cryo-transmission electron microscopy showed that the structure of supramolecular assemblies BGTC:DOPE/beta-gal and DOSP:MM27/K8 were different depending on liposome types and lipid/protein molar ratio. Finally, we observed that K8 treatment with DOSP:MM27/K8 rescues the cyclic adenosine monophosphate (cAMP)-dependent chloride efflux in F508del-CFTR expressing cells, providing a new tool for the study of channelopathies. PMID- 26102065 TI - The thioredoxin system and not the Michaelis-Menten equation should be fitted to substrate saturation datasets from the thioredoxin insulin assay. AB - INTRODUCTION: The thioredoxin system, consisting of thioredoxin reductase, thioredoxin and NADPH, is present in most living organisms and reduces a large array of target protein disulfides. OBJECTIVE: The insulin reduction assay is commonly used to characterise thioredoxin activity in vitro, but it is not clear whether substrate saturation datasets from this assay should be fitted and modeled with the Michaelis-Menten equation (thioredoxin enzyme model), or fitted to the thioredoxin system with insulin reduction described by mass-action kinetics (redox couple model). METHODS: We utilized computational modeling and in vitro assays to determine which of these approaches yield consistent and accurate kinetic parameter sets for insulin reduction. RESULTS: Using computational modeling, we found that fitting to the redox couple model, rather than to the thioredoxin enzyme model, resulted in consistent parameter sets over a range of thioredoxin reductase concentrations. Furthermore, we established that substrate saturation in this assay was due to the progressive redistribution of the thioredoxin moiety into its oxidised form. We then confirmed these results in vitro using the yeast thioredoxin system. DISCUSSION: This study shows how consistent parameter sets for thioredoxin activity can be obtained regardless of the thioredoxin reductase concentration used in the insulin reduction assay, and validates computational systems biology modeling studies that have described the thioredoxin system with the redox couple modeling approach. PMID- 26102066 TI - Triel Bonds, pi-Hole-pi-Electrons Interactions in Complexes of Boron and Aluminium Trihalides and Trihydrides with Acetylene and Ethylene. AB - MP2/aug-cc-pVTZ calculations were performed on complexes of aluminium and boron trihydrides and trihalides with acetylene and ethylene. These complexes are linked through triel bonds where the triel center (B or Al) is characterized by the Lewis acid properties through its pi-hole region while pi-electrons of C2H2 or C2H4 molecule play the role of the Lewis base. Some of these interactions possess characteristics of covalent bonds, i.e., the Al-pi-electrons links as well as the interaction in the BH3-C2H2 complex. The triel-pi-electrons interactions are classified sometimes as the 3c-2e bonds. In the case of boron trihydrides, these interactions are often the preliminary stages of the hydroboration reaction. The Quantum Theory of "Atoms in Molecules" as well as the Natural Bond Orbitals approach are applied here to characterize the pi-hole-pi electrons interactions. PMID- 26102067 TI - Comparative Label-Free Mass Spectrometric Analysis of Mildly versus Severely Affected mdx Mouse Skeletal Muscles Identifies Annexin, Lamin, and Vimentin as Universal Dystrophic Markers. AB - The primary deficiency in the membrane cytoskeletal protein dystrophin results in complex changes in dystrophic muscles. In order to compare the degree of secondary alterations in differently affected subtypes of skeletal muscles, we have conducted a global analysis of proteome-wide changes in various dystrophin deficient muscles. In contrast to the highly degenerative mdx diaphragm muscle, which showed considerable alterations in 35 distinct proteins, the spectrum of mildly to moderately dystrophic skeletal muscles, including interosseus, flexor digitorum brevis, soleus, and extensor digitorum longus muscle, exhibited a smaller number of changed proteins. Compensatory mechanisms and/or cellular variances may be responsible for differing secondary changes in individual mdx muscles. Label-free mass spectrometry established altered expression levels for diaphragm proteins associated with contraction, energy metabolism, the cytoskeleton, the extracellular matrix and the cellular stress response. Comparative immunoblotting verified the differences in the degree of secondary changes in dystrophin-deficient muscles and showed that the up-regulation of molecular chaperones, the compensatory increase in proteins of the intermediate filaments, the fibrosis-related increase in collagen levels and the pathophysiological decrease in calcium binding proteins is more pronounced in mdx diaphragm as compared to the less severely affected mdx leg muscles. Annexin, lamin, and vimentin were identified as universal dystrophic markers. PMID- 26102068 TI - Characterization and Pharmacokinetic Study of Aprepitant Solid Dispersions with Soluplus(r). AB - Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions. The solid dispersions were characterized by dissolution, FTIR, XRPD, DSC, SEM and pharmacokinetic studies in rats. The dissolution rate of the aprepitant was significantly increased by solid dispersions, and XRD, DSC, and SEM analysis indicated that the aprepitant existed in an amorphous form within the solid dispersions. The result of dissolution study showed that the dissolution rate of SDs was nearly five-fold faster than aprepitant. FTIR spectrometry suggested the presence of intermolecular hydrogen bonds between the aprepitant and polymer. Pharmacokinetic studies in rats indicated that the degree drug absorption was comparable with that of Emend(r). Aprepitant exists in an amorphous state in solid dispersions and the solid dispersions can markedly improve the dissolution and oral bioavailability of the aprepitant. The AUC0-t of the SDs was 2.4-fold that of the aprepitant. In addition, the method and its associated techniques are very easy to carry out. PMID- 26102069 TI - Individual Constituents from Essential Oils Inhibit Biofilm Mass Production by Multi-Drug Resistant Staphylococcus aureus. AB - Biofilm formation by Staphylococcus aureus represents a problem in both the medical field and the food industry, because the biofilm structure provides protection to embedded cells and it strongly attaches to surfaces. This circumstance is leading to many research programs seeking new alternatives to control biofilm formation by this pathogen. In this study we show that a potent inhibition of biofilm mass production can be achieved in community-associated methicillin-resistant S. aureus (CA-MRSA) and methicillin-sensitive strains using plant compounds, such as individual constituents (ICs) of essential oils (carvacrol, citral, and (+)-limonene). The Crystal Violet staining technique was used to evaluate biofilm mass formation during 40 h of incubation. Carvacrol is the most effective IC, abrogating biofilm formation in all strains tested, while CA-MRSA was the most sensitive phenotype to any of the ICs tested. Inhibition of planktonic cells by ICs during initial growth stages could partially explain the inhibition of biofilm formation. Overall, our results show the potential of EOs to prevent biofilm formation, especially in strains that exhibit resistance to other antimicrobials. As these compounds are food additives generally recognized as safe, their anti-biofilm properties may lead to important new applications, such as sanitizers, in the food industry or in clinical settings. PMID- 26102070 TI - Covalently Cross-Linked Arabinoxylans Films for Debaryomyces hansenii Entrapment. AB - In the present study, wheat water extractable arabinoxylans (WEAX) were isolated and characterized, and their capability to form covalently cross-linked films in presence of Debaryomyces hansenii was evaluated. WEAX presented an arabinose to xylose ratio of 0.60, a ferulic acid and diferulic acid content of 2.1 and 0.04 ug?mg(-1) WEAX, respectively and a Fourier Transform Infra-Red (FT-IR) spectrum typical of WEAX. The intrinsic viscosity and viscosimetric molecular weight values for WEAX were 3.6 dL?g(-1) and 440 kDa, respectively. The gelation of WEAX (1% w/v) with and without D. hansenii (1 * 10(7) CFU?cm(-2)) was rheologically investigated by small amplitude oscillatory shear. The entrapment of D. hansenii decreased gel elasticity from 1.4 to 0.3 Pa, probably by affecting the physical interactions between WEAX chains. Covalently cross-linked WEAX films containing D. hansenii were prepared by casting. Scanning electron microscopy images show that WEAX films containing D. hansenii were porous and consisted of granular-like and fibre microstructures. Average tensile strength, elongation at break and Young's modulus values dropped when D. hansenii was present in the film. Covalently cross-lined WEAX containing D. hansenii could be a suitable as a functional entrapping film. PMID- 26102071 TI - Xanthones from the Leaves of Garcinia cowa Induce Cell Cycle Arrest, Apoptosis, and Autophagy in Cancer Cells. AB - Two new xanthones, cowaxanthones G (1) and H (2), and 23 known analogues were isolated from an acetone extract of the leaves of Garcinia cowa. The isolated compounds were evaluated for cytotoxicity against three cancer cell lines and immortalized HL7702 normal liver cells, whereby compounds 1, 5, 8, and 15-17 exhibited significant cytotoxicity. Cell cycle analysis using flow cytometry showed that 5 induced cell cycle arrest at the S phase in a dose-dependent manner, 1 and 16 at the G2/M phase, and 17 at the G1 phase, while 16 and 17 induced apoptosis. Moreover, autophagy analysis by GFP-LC3 puncta formation and western blotting suggested that 17 induced autophagy. Taken together, our results suggest that these xanthones possess anticancer activities targeting cell cycle, apoptosis, and autophagy signaling pathways. PMID- 26102073 TI - From Here to Eternity--The Theory and Practice of a Really Long Experiment. AB - In February 1988, Richard Lenski set up 12 replicate populations of a single genotype of Escherichia coli in a simple nutrient medium. He has been following their evolution ever since. Here, Lenski answers provocative questions from Jeremy Fox about his iconic "Long-Term Evolution Experiment" (LTEE). The LTEE is a remarkable case study of the interplay of determinism and chance in evolution and in the conduct of science. PMID- 26102072 TI - Introduction of Non-Native Pollinators Can Lead to Trans-Continental Movement of Bee-Associated Fungi. AB - Bees are essential pollinators for many flowering plants, including agriculturally important crops such as apple. As geographic ranges of bees or their host plants change as a result of human activities, we need to identify pathogens that could be transmitted among newly sympatric species to evaluate and anticipate their effects on bee communities. We used PCR screening and DNA sequencing to evaluate exposure to potentially disease-causing microorganisms in a pollinator of apple, the horned mason bee (Osmia cornifrons). We did not detect microsporidia, Wolbachia, or trypanosomes, which are common pathogens of bees, in any of the hundreds of mason bees screened. We did detect both pathogenic and apathogenic (saprophytic) fungal species in the genus Ascosphaera (chalkbrood), an unidentified species of Aspergillus fungus, and a strain of bacteria in the genus Paenibacillus that is probably apathogenic. We detected pathogenic fungal strains in asymptomatic adult bees that therefore may be carriers of disease. We demonstrate that fungi from the genus Ascosphaera have been transported to North America along with the bee from its native range in Japan, and that O. cornifrons is exposed to fungi previously only identified from nests of other related bee species. Further study will be required to quantify pathogenicity and health effects of these different microbial species on O. cornifrons and on closely related native North American mason bees that may now be exposed to novel pathogens. A global perspective is required for pathogen research as geographic ranges of insects and microorganisms shift due to intentional or accidental introductions. PMID- 26102074 TI - Hepatitis E Virus of Subtype 3a in a Pig Farm, South-Eastern France. AB - Hepatitis E virus (HEV) has emerged during the past decade as a causative agent of autochthonous hepatitis and is a clinical concern in Western developed countries. It has been increasingly recognized that pigs are a major reservoir of HEV of genotypes 3 and 4 worldwide and pig-derived food items represent a potential source of infections by these viruses in humans. Hepatitis E virus RNA testing was performed here on faeces from rectal swabs sampled in 2012 from 50 3 month-old farm pigs from the same farm located in south-eastern France than in a previous work conducted in 2007. Pig HEV sequences corresponding to genomic fragments of ORF2 and ORF1 genes were obtained after RT-PCR amplification with in house protocols. Hepatitis E virus genotype was determined by phylogenetic analysis. Prevalence was similar to that determined 5 years earlier (68% versus 62%). Two robust phylogenetic clusters of HEV subtypes 3a and 3f were identified, and these sequences obtained in 2012 largely differ compared with those obtained in 2007. Notably, HEV sequences obtained in 2012 from a majority (62%) of the infected pigs belonged to subtype 3a, which was not previously described in France, including not being found in any of humans, pigs or wild boars. Further studies are needed to assess the circulation of HEV-3a in pigs and humans in this country. In addition, along with previous findings, this study supports the need for increased information to the public on the risk of HEV infection through contacts with pigs or consumption of pig-derived products in France. PMID- 26102075 TI - Large-scale production of pharmaceutical proteins in plant cell culture-the Protalix experience. AB - Protalix Biotherapeutics develops recombinant human proteins and produces them in plant cell culture. Taliglucerase alfa has been the first biotherapeutic expressed in plant cells to be approved by regulatory authorities around the world. Other therapeutic proteins are being developed and are currently at various stages of the pipeline. This review summarizes the major milestones reached by Protalix Biotherapeutics to enable the development of these biotherapeutics, including platform establishment, cell line selection, manufacturing process and good manufacturing practice principles to consider for the process. Examples of the various products currently being developed are also presented. PMID- 26102077 TI - Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF kappaB- and MAPK-ERK1/2-mediated COX-2 expression. AB - BACKGROUND AND PURPOSE: This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti HCV activity. EXPERIMENTAL APPROACH: HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-kappaB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with other HCV inhibitors was also determined to assess its use as an anti-HCV supplement. KEY RESULTS: BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-alpha, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-kappaB and ERK1/2 of the MAPK signalling pathway. CONCLUSIONS AND IMPLICATIONS: BA inhibits HCV replication by suppressing the NF kappaB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV infected patients. PMID- 26102076 TI - Oxidative and proteolysis-related parameters of skeletal muscle from hamsters with experimental pulmonary emphysema: a comparison between papain and elastase induction. AB - The objective of this study was to investigate whether emphysema induced by elastase or papain triggers the same effects on skeletal muscle, related to oxidative stress and proteolysis, in hamsters. For this purpose, we evaluated pulmonary lesions, body weight, muscle loss, oxidative stress (thiobarbituric acid-reactive substances, total and oxidized glutathiones, chemiluminescence stimulated by tert-butyl hydroperoxide and carbonyl proteins), chymotrypsin-like and calpain-like proteolytic activities and muscle fibre cross-sectional area in the gastrocnemius muscles of emphysemic hamsters. Two groups of animals received different intratracheal inductions of experimental emphysema: by 40 mg/ml papain (EP) or 5.2 IU/100 g animal (EE) elastase (n = 10 animals/group). The control group received intratracheal instillation of 300 MUl sterile NaCl 0.9%. Compared with the control group, the EP group had reduced muscle weight (18.34%) and the EE group had increased muscle weight (8.37%). Additionally, tert-butyl hydroperoxide-initiated chemiluminescence, carbonylated proteins and chymotrypsin like proteolytic activity were all elevated in the EP group compared to the CS group, while total glutathione was decreased compared to the EE group. The EE group showed more fibres with increased cross-sectional areas and increased calpain-like activity. Together, these data show that elastase and papain, when used to induce experimental models of emphysema, lead to different speeds and types of adaptation. These findings provide more information on choosing a suitable experimental model for studying skeletal muscle adaptations in emphysema. PMID- 26102078 TI - Dabigatran-induced esophagitis: The prevalence and endoscopic characteristics. AB - BACKGROUND AND AIM: There have been some descriptions of dabigatran-induced esophagitis in the literature. The aim of this study was to examine the prevalence and endoscopic characteristics of the disease. METHODS: We reviewed the endoscopic database and medical records of 91 patients with dabigatran internal use who underwent upper gastrointestinal endoscopy. The frequency of dabigatran-induced esophagitis and its endoscopic findings were retrospectively analyzed. In addition, the clinical characteristics were compared between patients with dabigatran-induced esophagitis and those without the disease. RESULTS: Dabigatran-induced esophagitis was found in 19 of 91 (20.9%) patients. Of the 19 patients with the esophagitis, 18 (94.7%) showed longitudinally sloughing epithelial casts in the mid and/or lower esophagus, which may be characteristic endoscopic findings of this disease. Symptomatic patients were more frequent in patients with dabigatran-induced esophagitis (68.4%) than those without (37.5%, P = 0.02). Other factors including age, gender, coexistence of hiatal hernia, gastroesophageal reflux disease, or concomitant other medications did not differ between the two groups. CONCLUSIONS: Dabigatran causes the esophageal mucosal injury in approximately 20% of patients. Longitudinally sloughing casts in the distal esophagus are characteristic of dabigatran-induced esophagitis. PMID- 26102079 TI - Prevalence, Awareness, Treatment and Influence of Socioeconomic Variables on Control of High Blood Pressure: Results of the ELSA-Brasil Study. AB - High blood pressure (HBP) is the leading risk factor for years of life lost in Brazil. Factors associated with HBP awareness, treatment and control need to be understood better. Our aim is to estimate prevalence, awareness, and types of anti-hypertensive treatment and to investigate the association of HBP control with social position. Data of 15,103 (54% female) civil servants in six Brazilian state capitals collected at the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) baseline (2008-2010) were used to estimate prevalence and cross sectional association of HBP control with education, per capita family income and self-reported race, using multiple logistic regression. Blood pressure was measured by the oscillometric method. 35.8% were classified as presenting HBP; 76.8% of these used anti-hypertensive medication. Women were more aware than men (84.8% v. 75.8%) and more often using medication (83.1% v. 70.7%). Adjusted HBP prevalence was, in ascending order, Whites (30.3%), Browns (38.2%) and Blacks (49.3%). The therapeutic schemes most used were angiotensin-converting enzyme inhibitors, in isolation (12.4%) or combined with diuretics (13.3%). Among those in drug treatment, controlled blood pressure was more likely in the (postgraduate) higher education group than among participants with less than secondary school education (PR = 1.21; 95% CI: 1.14-1.28), and among Asian (PR = 1.21; 95% CI: 1.12-1.32) and 'Whites (PR = 1.19; 95% CI: 1.12-1.26) compared to Blacks. Socioeconomic and racial inequality-as measured by different indicators are strongly associated with HBP control, beyond the expected influence of health services access. PMID- 26102080 TI - Immunization with Heat Shock Protein A and gamma-Glutamyl Transpeptidase Induces Reduction on the Helicobacter pylori Colonization in Mice. AB - The human gastric pathogen Helicobacter pylori (H. pylori) is a successful colonizer of the stomach. H. pylori infection strongly correlates with the development and progression of chronic gastritis, peptic ulcer disease, and gastric malignances. Vaccination is a promising strategy for preventing H. pylori infection. In this study, we evaluated the candidate antigens heat shock protein A (HspA) and H. pylori gamma-glutamyl transpeptidase (GGT) for their effectiveness in development of subunit vaccines against H. pylori infection. rHspA, rGGT, and rHspA-GGT, a fusion protein based on HspA and GGT, were constructed and separately expressed in Escherichia coli and purified. Mice were then immunized intranasally with these proteins, with or without adjuvant. Immunized mice exhibited reduced bacterial colonization in stomach. The highest reduction in bacterial colonization was seen in mice immunized with the fusion protein rHspA-GGT when paired with the mucosal adjuvant LTB. Protection against H. pylori colonization was mediated by a strong systemic and localized humoral immune response, as well as a balanced Th1/Th2 cytokine response. In addition, immunofluorescence microscopy confirmed that rHspA-GGT specific rabbit antibodies were able to directly bind H. pylori in vitro. These results suggest antibodies are essential to the protective immunity associated with rHspA-GGT immunization. In summary, our results suggest HspA and GGT are promising vaccine candidates for protection against H. pylori infection. PMID- 26102081 TI - Time-resolved spectroscopy of the singlet excited state of betanin in aqueous and alcoholic solutions. AB - The photophysical properties of betanin in aqueous and alcoholic solutions were determined at room temperature using ultrafast UV-vis-NIR transient absorption spectroscopy (lambdaexc = 535 nm). Its S1 -> Sn (n > 1) absorption bands appear with maxima at about lambda ~ 450 and 1220 nm. The short betanin S1 state lifetime (6.4 ps in water) is mainly determined by the efficient S1 -> S0 radiationless relaxation, probably requiring a strong change in geometry, since the S1 lifetime grows to 27 ps in the more viscous ethylene glycol. The fluorescence quantum yield is very low (Phif ~ 0.0007 in water), therefore this deactivation path is of minor importance. Other processes, such as S1 -> T1 intersystem crossing or photoproduct formation, are virtually absent, since full S0 <- S1 ground state recovery is observed within tens of picoseconds after photoexcitation. The observed fast light-to-heat conversion in the absence of triplet excited state formation supports the idea that betanin is a photoprotector in vivo. PMID- 26102082 TI - Heterogeneous Coupling between Interdependent Lattices Promotes the Cooperation in the Prisoner's Dilemma Game. AB - In the research realm of game theory, interdependent networks have extended the content of spatial reciprocity, which needs the suitable coupling between networks. However, thus far, the vast majority of existing works just assume that the coupling strength between networks is symmetric. This hypothesis, to some extent, seems inconsistent with the ubiquitous observation of heterogeneity. Here, we study how the heterogeneous coupling strength, which characterizes the interdependency of utility between corresponding players of both networks, affects the evolution of cooperation in the prisoner's dilemma game with two types of coupling schemes (symmetric and asymmetric ones). Compared with the traditional case, we show that heterogeneous coupling greatly promotes the collective cooperation. The symmetric scheme seems much better than the asymmetric case. Moreover, the role of varying amplitude of coupling strength is also studied on these two interdependent ways. Current findings are helpful for us to understand the evolution of cooperation within many real-world systems, in particular for the interconnected and interrelated systems. PMID- 26102084 TI - Optimal Cutoff Age for Predicting Mortality Associated with Differentiated Thyroid Cancer. AB - Patient's age at the time of diagnosis is an important prognostic factor for differentiated thyroid cancer (DTC) as reflected in various staging and risk stratification systems. However, discrepancies exist among the different staging systems on an optimal cut-off age for predicting the clinical outcome of patients with DTC. To determine the age at diagnosis most predictive of clinical outcomes of DTC, a population-based cohort study was performed composed of 35,323 patients with DTC between 1988 and 2010 using the Surveillance, Epidemiology, and End Results (SEER) database. The Youden index J was used to determine the most predictive age-at-diagnosis for thyroid-cancer-specific death. The multivariate Cox proportional hazards model was used to determine the hazard ratios (HRs) for each age group. With a median follow-up of 5.4 years (range, 0-22.9 years), DTC associated mortality was 1.5% (n = 533) and the rate of death from overall cause was 7.0% (n = 2482). The optimal cutoff age at diagnosis for thyroid-cancer specific death was 57. Multivariate analysis found that the age-at-diagnosis is the most prognostic factor for thyroid-cancer-specific death (HR 10.02, 95% CI 8.18-12.28). Age at diagnosis is the most important prognostic factor for DTC patients. Based on our analysis, age at diagnosis of 57 might be the optimal predictor of thyroid-cancer-specific death. This finding might be used as consideration in revision of the risk stratification system for treatment of DTC patients. PMID- 26102085 TI - Prevalence of Pulmonary Hypertension in the General Population: The Rotterdam Study. AB - BACKGROUND: Pulmonary hypertension is characterized by increased pulmonary artery pressure and carries an increased mortality. Population-based studies into pulmonary hypertension are scarce and little is known about its prevalence in the general population. We aimed to describe the distribution of echocardiographically-assessed pulmonary artery systolic pressure (ePASP) in the general population, to estimate the prevalence of pulmonary hypertension, and to identify associated factors. METHODS: Participants (n = 3381, mean age 76.4 years, 59% women) from the Rotterdam Study, a population-based cohort, underwent echocardiography. Echocardiographic pulmonary hypertension was defined as ePASP>40 mmHg. RESULTS: Mean ePASP was 26.3 mmHg (SD 7.0). Prevalence of echocardiographic pulmonary hypertension was 2.6% (95%CI: 2.0; 3.2). Prevalence was higher in older participants compared to younger ones (8.3% in those over 85 years versus 0.8% in those between 65 and 70), and in those with underlying disorders versus those without (5.9% in subjects with COPD versus 2.3%; 9.2% in those with left ventricular systolic dysfunction versus 2.3%; 23.1% in stages 3 or 4 left ventricular diastolic dysfunction versus 1.9% in normal or stage 1). Factors independently associated with higher ePASP were older age, higher BMI, left ventricular diastolic dysfunction, COPD and systemic hypertension. CONCLUSION: In this large population-based study, we show that pulmonary hypertension as measured by echocardiography has a low prevalence in the overall general population in the Netherlands, but estimates may be higher in specific subgroups, especially in those with underlying diseases. Increased pulmonary arterial pressure is likely to gain importance in the near future due to population aging and the accompanying prevalences of underlying disorders. PMID- 26102087 TI - Tuning of exchange coupling by the Mn-O distance and phenoxido bridging angle: an experimental and theoretical study of the family of Mn(iii) dimers with salen type ligands. AB - Three new Mn(III) complexes [Mn2L2(ClO4)2] (1), [Mn2L2(NCS)2] (2) and [Mn2L2N(CN)2]ClO4.CH3CN (3) have been synthesized from the Schiff base ligand H2L (where H2L = N,N'-bis(2-hydroxypropiophenone)-1,2- ethanediamine) and various anionic coligands e.g. perchlorate, thiocyanate and dicyanamide. X-ray crystal structure analysis reveals that 1 and 2 are dinuclear complexes, joined together by Mn?O (phenoxido) interactions. Whereas 3 consists of an alternating phenoxido and MU1,5 dicyanamido bridge, resulting in a 1D chain. In 1 and 2 ferromagnetic coupling exists between the Mn(III) centres within the dimer but 3 possesses antiferromagnetic interaction. This difference in magnetic exchange interactions has been rationalized on the basis of structural parameters like longer bridging Mn-O distance and Mn-O-Mn angle in these complexes with the help of DFT calculations. PMID- 26102086 TI - Elongation Factor 1A-1 Is a Mediator of Hepatocyte Lipotoxicity Partly through Its Canonical Function in Protein Synthesis. AB - Elongation factor 1A-1 (eEF1A-1) has non-canonical functions in regulation of the actin cytoskeleton and apoptosis. It was previously identified through a promoter trap screen as a mediator of fatty acid-induced cell death (lipotoxicity), and was found to participate in this process downstream of ER stress. Since ER stress is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), we investigated the mechanism of action of eEF1A-1 in hepatocyte lipotoxicity. HepG2 cells were exposed to excess fatty acids, followed by assessments of ER stress, subcellular localization of eEF1A-1, and cell death. A specific inhibitor of eEF1A-1 elongation activity, didemnin B, was used to determine whether its function in protein synthesis is involved in lipotoxicity. Within 6 h, eEF1A-1 protein was modestly induced by high palmitate, and partially re-localized from its predominant location at the ER to polymerized actin at the cell periphery. This early induction and subcellular redistribution of eEF1A-1 coincided with the onset of ER stress, and was later followed by cell death. Didemnin B did not prevent the initiation of ER stress by high palmitate, as indicated by eIF2alpha phosphorylation. However, consistent with sustained inhibition of eEF1A-1 dependent elongation activity, didemnin B prevented the recovery of protein synthesis and increase in GRP78 protein that are normally associated with later phases of the response to ongoing ER stress. This resulted in decreased palmitate induced cell death. Our data implicate eEF1A-1, and its function in protein synthesis, in hepatocyte lipotoxicity. PMID- 26102088 TI - Forensic electrochemistry: indirect electrochemical sensing of the components of the new psychoactive substance "Synthacaine". AB - "Synthacaine" is a New Psychoactive Substance which is, due to its inherent psychoactive properties, reported to imitate the effects of cocaine and is therefore consequently branded as "legal cocaine". The only analytical approach reported to date for the sensing of "Synthacaine" is mass spectrometry. In this paper, we explore and evaluate a range of potential analytical techniques for its quantification and potential use in the field screening "Synthacaine" using Raman spectroscopy, presumptive (colour) testing, High Performance Liquid Chromatography (HPLC) and electrochemistry. HPLC analysis of street samples reveals that "Synthacaine" comprises a mixture of methiopropamine (MPA) and 2 aminoindane (2-AI). Raman spectroscopy and presumptive (colour) tests, the Marquis, Mandelin, Simon's and Robadope test, are evaluated towards a potential in-the-field screening approach but are found to not be able to discriminate between the two when they are both present in the same sample, as is the case in the real street samples. We report for the first time a novel indirect electrochemical protocol for the sensing of MPA and 2-AI which is independently validated in street samples with HPLC. This novel electrochemical approach based upon one-shot disposable cost effective screen-printed graphite macroelectrodes holds potential for in-the-field screening for "Synthacaine". PMID- 26102089 TI - Divergent Functionalization of Indoles with Acryloyl Silanes via Rhodium Catalyzed C-H Activation. AB - A protocol enabled by rhodium-catalyzed C-H functionalization of indoles with acryloyl silanes was developed, providing a convenient and highly effective method for the synthesis of functionalized acylsilane derivatives. By tuning the reaction condition, this C-H-activation-initiated reaction proceeds divergently with acryloyl silianes to selectively afford alkylation or alkenylation products via hydroarylation or oxidative cross-coupling, respectively. The mild reaction conditions employed in both cases enable the tolerance of a wide scope of functionalities as well as high reaction efficiency. Furthermore, polycyclic indole derivatives were easily accessed from 2-alkenylation products through a visible-light-induced reaction cascade. PMID- 26102090 TI - Successful Living-Related Renal Allograft in a Recipient With Factor V Leiden Deficiency: A Case Report. AB - Thrombophilia due to activated protein C resistance (Leiden mutation) is the most common inherited thrombophilic disorder with 5% incidence in whites. Renal transplant of these patients entails a risk of vascular thrombosis soon after the transplant; and acute rejection episodes and graft loss within the first year. We present a case of a successful living-related renal transplant in man with a recent history of repeat episodes of vascular access thrombosis attributed to inherited thrombophilia (heterozygosity for factor V mutation Q506 and homozygosity for mutation T677 for methylene-tetrahydrofolate reductase). Transplant recipient was administered anticoagulation therapy with low molecular weight heparin pre- and postoperatively. No thrombotic or hemorrhagic events occurred posttransplant. A high suspicion of thrombophilic disorders in patients with end-stage renal disease with vascular access thrombotic events should be screened further to prevent failure of a subsequent renal transplant. Inherited thrombophilic disorders may not exclude living-related kidney transplant provided that anticoagulation therapy is admin-istered perioperatively. PMID- 26102091 TI - Potential of centrifugal seeding method in improving cells distribution and proliferation on demineralized cancellous bone scaffolds for tissue-engineered meniscus. AB - Tissue-engineered meniscus offers a possible solution to the regeneration and replacement problem of meniscectomy. However, the nonuniform distribution and declined proliferation of seeded cells on scaffolds hinder the application of tissue-engineered meniscus as a new generation of meniscus graft. This study systematically investigated the performances of different seeding techniques by using the demineralized cancellous bone (DCB) as the scaffold. Static seeding, injection seeding, centrifugal seeding, and vacuum seeding methods were used to seed the meniscal fibrochondrocytes (MFCs) and mesenchymal stem cells (MSCs) to scaffolds. Cell-binding efficiency, survival rate, distribution ability, and long term proliferation effects on scaffolds were quantitatively evaluated. Cell adhesion was compared via cell-binding kinetics. Cell viability and morphology were assessed by using fluorescence staining. Combined with the reconstructed three-dimensional image, the distribution of seeded cells was investigated. The Cell Counting Kit-8 assay and DNA assay were employed to assess cell proliferation. Cell-binding kinetics and cell survival of the MFCs were improved via centrifugal seeding compared to injection or vacuum seeding methods. Seeded MFCs by centrifugation showed a more homogeneous distribution throughout the scaffold than cells seeded by other methods. Moreover, the penetration depth in the scaffold of seeded MFCs by centrifugation was 300-500 MUm, much higher than the value of 100-300 MUm by the surface static and injection seeding. The long term proliferation of the MFCs in the centrifugal group was also significantly higher than that in the other groups. The results of the MSCs were similar to those of the MFCs. The centrifugal seeding method could significantly improve MFCs or MSCs distribution and proliferation on the DCB scaffolds, thus providing a simple, cost-effective, and effective cell-seeding protocol for tissue engineered meniscus. PMID- 26102092 TI - Liposome-Templated Hydrogel Nanoparticles as Vehicles for Enzyme-Based Therapies. AB - Several diseases are related to the lack or to the defective activity of a particular enzyme; therefore, these proteins potentially represent a very interesting class of therapeutics. However, their application is hampered by their rapid degradation and immunogenic side effects. Most attempts to increase the bioavailability of therapeutic enzymes are based on formulations in which the protein is entrapped within a scaffold structure but needs to be released to exert its activity. In this work, an alternative method will be described, designed to keep the enzyme in its active form inside a nanoparticle (NP) without the need to release it, thus maintaining the protective action of the nanoscaffold during the entire period of administration. In this approach, liposomes were used as nanotemplates for the synthesis of polyacrylamide hydrogel NPs under nondenaturing conditions, optimizing the polymer properties to obtain a mesh size small enough to limit the enzyme release while allowing the free diffusion of its substrates and products. The enzyme Cu, Zn-superoxide dismutase was chosen as a test case for this study, but our results indicate that the approach is generalizable to other enzymes. Biocompatible, size-tunable nanoparticles have been obtained, with a good encapsulation efficiency (37%), in which the enzyme maintains its activity. This system represents a promising tool for enzyme-based therapy, which would protect the protein from antibodies and degradation while allowing it to exert its catalytic activity. PMID- 26102093 TI - A preliminary study on the relationships between diurnal melatonin secretion profile and sleep variables in patients emergently admitted to the coronary care unit. AB - To clarify the significance of melatonin secretion under intensive care conditions, we investigated melatonin secretion profiles and sleep parameters of 23 patients just after admission to the coronary care unit (CCU) and 19 age matched controls. Sleep parameters were evaluated by actigraphy, and melatonin secretion was assessed by measuring the urinary 6-sulphatoxy melatonin (6-SMT). 6 SMT secretion was lower and nocturnal sleep parameters were less satisfactory in the subjects than those in the controls, and there were positive correlations between these variables, particularly in the subject patients. The lowered melatonin secretion might be involved in the mechanism of insomnia in CCU patients. PMID- 26102094 TI - Solanum tuberosum L. cv Jayoung Epidermis Extract Inhibits Mite Antigen-Induced Atopic Dermatitis in NC/Nga Mice by Regulating the Th1/Th2 Balance and Expression of Filaggrin. AB - Solanum tuberosum L. cv Jayoung (JY) is a potato with dark purple flesh and contains substantial amounts of polyphenols. In this study, we evaluated the therapeutic effects of S. tuberosum L. cv JY in a mouse model of Dermatophagoides farinae body (Dfb)-induced atopic dermatitis (AD). The ethanol extract of the peel of JY (EPJ) ameliorated Dfb-induced dermatitis severity, serum levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine. Histological analysis of the skin also revealed that EPJ treatment significantly decreased mast cell infiltration. The suppression of dermatitis by EPJ treatment was accompanied by a decrease in the skin levels of type 2 helper T-cell cytokines such as interleukin (IL)-4, IL-5, and IL-13. The induction of thymic stromal lymphopoietin, which leads to a systemic Th2 response, was also decreased in the skin by EPJ. Nuclear translocation of nuclear factor-kappaB p65 was decreased by EPJ in Dfb-induced NC/Nga mice. The protein expression of filaggrin in the AD-like skin lesions was restored by EPJ treatment. These results suggested that EPJ may be a potential therapeutic tool for the treatment of AD. PMID- 26102095 TI - Photonic Crystals with a Reversibly Inducible and Erasable Defect State Using External Stimuli. AB - The controlled introduction of artificial extrinsic defects is critical to achieve the functions of photonic crystals. Smart defects capable of responding to external stimuli lead to more advanced applications. Here we report a microgel colloidal crystal with a defect state which could be induced and erased reversibly by external stimuli. The crystal was assembled from PNIPAM microgel and P(NIPAM-AAc) microgel of the same size. The resulting doped crystal does not exhibit a defect state in its stop band because of the similar optical properties of the dopant and the host. By increasing the pH value, however, the dopant P(NIPAM-AAc) spheres swell to a larger size and turn into real defects in the crystal, resulting in the appearance of defect state. Adjusting the pH value back restores the size of the dopant spheres, and thus erases the defect state. Temperature, a second external stimulus, could also be used to induce and erase defect states of the crystal. PMID- 26102096 TI - Fifteen years of external quality assessment in leukemia/lymphoma immunophenotyping in The Netherlands and Belgium: A way forward. AB - In 1985, external quality assurance was initiated in the Netherlands to reduce the between-laboratory variability of leukemia/lymphoma immunophenotyping and to improve diagnostic conclusions. This program consisted of regular distributions of test samples followed by biannual plenary participant meetings in which results were presented and discussed. A scoring system was developed in which the quality of results was rated by systematically reviewing the pre-analytical, analytical, and post-analytical assay stages using three scores, i.e., correct (A), minor fault (B), and major fault (C). Here, we report on 90 consecutive samples distributed to 40-61 participating laboratories between 1998 and 2012. Most samples contained >20% aberrant cells, mainly selected from mature lymphoid malignancies (B or T cell) and acute leukemias (myeloid or lymphoblastic). In 2002, minimally required monoclonal antibody (mAb) panels were introduced, whilst methodological guidelines for all three assay stages were implemented. Retrospectively, we divided the study into subsequent periods of 4 ("initial"), 4 ("learning"), and 7 years ("consolidation") to detect "learning effects." Uni- and multivariate models showed that analytical performance declined since 2002, but that post-analytical performance improved during the entire period. These results emphasized the need to improve technical aspects of the assay, and reflected improved interpretational skills of the participants. A strong effect of participant affiliation in all three assay stages was observed: laboratories in academic and large peripheral hospitals performed significantly better than those in small hospitals. (c) 2015 International Clinical Cytometry Society. PMID- 26102098 TI - [Emerging and re-emerging infectious diseases and their determinants]. PMID- 26102097 TI - Time-efficient, high-resolution, whole brain three-dimensional macromolecular proton fraction mapping. AB - PURPOSE: Macromolecular proton fraction (MPF) mapping is a quantitative MRI method that reconstructs parametric maps of a relative amount of macromolecular protons causing the magnetization transfer (MT) effect and provides a biomarker of myelination in neural tissues. This study aimed to develop a high-resolution whole brain MPF mapping technique using a minimal number of source images for scan time reduction. METHODS: The described technique was based on replacement of an actually acquired reference image without MT saturation by a synthetic one reconstructed from R1 and proton density maps, thus requiring only three source images. This approach enabled whole brain three-dimensional MPF mapping with isotropic 1.25 * 1.25 * 1.25 mm(3) voxel size and a scan time of 20 min. The synthetic reference method was validated against standard MPF mapping with acquired reference images based on data from eight healthy subjects. RESULTS: Mean MPF values in segmented white and gray matter appeared in close agreement with no significant bias and small within-subject coefficients of variation (<2%). High-resolution MPF maps demonstrated sharp white-gray matter contrast and clear visualization of anatomical details, including gray matter structures with high iron content. CONCLUSIONS: The proposed synthetic reference method improves resolution of MPF mapping and combines accurate MPF measurements with unique neuroanatomical contrast features. PMID- 26102099 TI - [Editorial policy on the ethics of human research]. PMID- 26102100 TI - [5'cap -independent translation of dengue virus genomic RNA]. AB - OBJETIVES: To analyze the involvement of methyl guanosine triphosphate cap (5?cap) and the start site of the genomic RNA of Dengue virus serotype 2 (DENV-2) American genotype in translation, using a cell-free system prepared from human placenta. MATERIALS AND METHODS: The recombinant plasmid pTZ18R-D2 was prepared containing DNA encoding the 5?UTR and the first 201 nucleotides of the viral capsid. This plasmid was used to transcribe the corresponding RNA (RNA-D2) without the 5? cap. The RNA-D2 was translated in a system consisting of the postmitochondrial fraction (S-30) from human placenta and the incorporation of [14C] aminoacids in the presence of RNA-D2 and in its absence (control) was evaluated. Seven antisense oligonucleotides (OAs1-7) directed against sequences of the SLA, SLB and CHP structures of RNA-D2 were designed and the effect thereof on RNA-D2 translation was analyzed. RESULTS: The RNA-D2 produced a significant increase (p<0.001) in the incorporation of [14C] amino acids, with 75% stimulation of translational activity compared to the control. Analysis of the translation products showed peak incorporation corresponding to peptides with apparent molecular weight close to the expected (7.746 kDa).The OAs5, complementary to a sequence of SLB structure of RNA-D2, completely inhibited translation. CONCLUSIONS: The RNA-D2 was translated specifically and efficiently under conditions similar to human intracellular conditions, by an alternative 5? cap-independent mechanism, which would involve the SLB structure. This mechanism might be seen as an aim in the development of antisense therapies to inhibit virus replication. PMID- 26102101 TI - [Educational intervention for the control of dengue in family environments in a community in Colombia]. AB - OBJECTIVES: To evaluate the effectiveness of an educational intervention to induce changes in behavior to eliminate breeding places for the dengue vector in families from a community in the Municipality of Sincelejo, Colombia. MATERIALS AND METHODS: An educational intervention type was performed before and after, with a group of 54 families selected by convenience sampling. An educational program designed with the results of a knowledge test, a semi-structured interview, observation guide and the main concepts of the Communication for Behavioural Impact (COMBI) toolkit was applied. The impact was measured by proportion changes and the McNemar test. RESULTS: Post-intervention changes were made in the levels of inadequate knowledge about dengue and behavior of the vector from 14.8% to 3.7% (p=0.109), in their inadequate beliefs from 20.4% to 5.6% (p=0.008) and in adequate practices from 24 to 87% (p=0.001). At the end of the process with each of the participant groups, 64.8% were classified in the action stage. There was a reduction of the number of intradomiciliary Aedes breeding places from 92.6% to 35.2% (p=0.001). CONCLUSIONS: The intervention lead participants to adhere to the behavior changes that were promoted. It was useful to subdivide the population into those who apply preventive measures and those who only have the intention of making them, because this enables the health personnel to adopt actions according to the characteristics of each group. PMID- 26102102 TI - [Extended-spectrum beta-lactamase (esbl)-producing enterobacteriaceae in fecal samples at the National Institute of Child Health, Peru]. AB - OBJECTIVES: To describe the frequency of extended-spectrum beta-lactamase (ESBL) producing enterobacteriaceae in fecal samples at the National Institute of Child Health, Lima, Peru. MATERIALS AND METHODS: Stool samples received between July 2012 and March 2013 with colonies suspected to be ESBL-producing enterobacteriaceae that developed in Karmali agar were analyzed. Conventional methods were performed for biochemical identification and the confirmation of the ESBL phenotype. Genotypic analysis to detect the beta-lactamase gene CTX-M family was performed by PCR. RESULTS: Of the 235 fecal samples analyzed, 64.2% of ESBL producing enterobacteria was isolated being 86.1% Escherichia coli, 7.9% Klebsiella pneumoniae, 2.6% Salmonella sp, 2.0% Enterobacter cloacae, and 1.3% Proteus mirabilis. 89.1% of the ESBL-producing enterobacteria presented the CTX-M gene. We found high resistance to nalidixic acid 84.8%, 74.2% ciprofloxacin and trimethoprim-sulfamethoxazole 81.5%.The resistance to amikacin was 1.3% and all isolates were susceptible to imipenem and meropenem. CONCLUSIONS: A high frequency of ESBL-producing enterobacteria was found in fecal samples of outpatients seen in the outpatient and emergency departments of the National Institute of Child Health of Peru. PMID- 26102103 TI - [Infectivity of promastigotes in stationary phase of Leishmania (viannia) braziliensis and leishmania (viannia) peruviana, In cell line dh82]. AB - OBJECTIVES: To determine the infectivity of promastigotes of Leishmania (V.) peruviana and Leishmania (V.) braziliensis in monocyte-macrophage cell line DH82 of Canis familiaris. MATERIALS AND METHODS: Was conducted a experimental study during the months of january to december 2013. Were used strains of Leishmania were used (V.) braziliensis MHOM/PE/84/LC53 and Leishmania (V.) peruviana MHOM/PE/84/LC26. The cell line was infected with stationary phase promastigotes and infectivity was determined as the product of percent infected macrophages average amastigotes per macrophage observed in epifluorescence microscope. RESULTS: 13% of metacyclic forms to Leishmania (V.) braziliensis corresponded to 17.5 days post inoculation and Leishmania (V.) peruviana a percentage of 9.5% on the day 14.5. No significant difference was found between infectivity of stationary phase promastigotes of both species. CONCLUSIONS: It is recommended assess the infectivity of metacyclic promastigotes peruviana strains of Leishmania (V.) and Leishmania (V.) braziliensis cell lines in order to determine the most appropriate model in vitro infection, allowing leishmanicidas make the drug more effective susceptibility studies for disease control. PMID- 26102104 TI - [Demand for training and availability of health science professionals in Peru]. AB - OBJECTIVES: To describe the availability and demand of professional training programs for eight health science professions in Peru. Study the profiles of the physicians, nurses and midwives that these programs train and their competencies to work at the primary health care level. MATERIALS AND METHODS: Cross-sectional study using data on the volume of applicants, students and graduates of these eight professional training programs during the period 2007 - 2011. In addition, the curricula of professional training programs for physicians, nurses and midwives from public and private universities were analyzed, along with competency profiles developed by Professional Colleges and the Ministry of Health. RESULTS: Admission rates in public and private universities vary by program: 4% and 28% respectively for medical schools, and 18% and 90% for nursing. Graduation rates were estimated at approximately 43% and 53% of students entering medicine and nursing training programs respectively. Contrasting the profiles of recently graduated professionals in medicine, nursing and midwifery, with the skills required by the Ministry of Health for professionals working in primary care the first level of care, indicate that these recently graduated professionals are not necessarily or specifically trained to work in primary care. CONCLUSIONS: Demand for professional training in health sciences exists and its supply is met predominantly by private universities. Competency profiles developed by the MOH for the basic professional health team in primary care shows a clear disconnect regarding the current supply of trained professionals. PMID- 26102105 TI - [Therapeutic adherence in users of a cardiovascular health program in primary care in Chile]. AB - OBJECTIVES: To analyze therapeutic adherence in users of a cardiovascular health program in primary care in the community of San Pedro de la Paz in the region of Bio Bio, Chile. MATERIALS AND METHODS: Cross-sectional and correlational study with a sample of 257 people aged 18-60 years. A questionnaire that included the Miller's health behavior scale to measure adherence, and review of medical records was performed. Descriptive univariate and bivariate analyses supported in SPSS were performed. RESULTS: Of the total participants, 157 (61.1%) were women. The health behavior scale reflected non-adherence of participants, as only 4 (1.5%) indicated that they always followed the instructions provided by the health team. The subscale monitoring stress management had the highest average, indicating that in this aspect there was greater adherence of the participants. Associations between therapeutic adherence and doing paid work (p=0.025) and with participation in social activities (p=0.005) were found. CONCLUSIONS: Therapeutic adherence in users of the cardiovascular health program was low. It is important to develop strategies that favor therapeutic adherence from the perspective of equity and social determinants of health. PMID- 26102106 TI - [Differences in the indicators of quality of life for older adults with hypertension living in urban and rural areas of Minas Gerais, Brazil]. AB - OBJECTIVES: To compare socioeconomic, illnesses, and quality of life variables for older adults with arterial hypertension who are residents of urban and rural areas of Minas Gerais, Brazil. MATERIALS AND METHODS: Cross-sectional study comprised of 1,302 older adults from the urban area and 463 from the rural area who reported suffering from arterial hypertension. Descriptive analysis was performed, as well as the chi square test, t-test, and multiple and logistic regression. RESULTS: In urban areas, females were more prevalent (66.5%; p<0.001) and older adults aged 75 and over (34.3%; p<0.001) were the most prevalent age group. In rural areas there was a higher prevalence of individuals living with a partner (65%; p<0.001), living alone (16.2%; p=0.021) and a lower prevalence of diseases such as arthritis/osteoarthritis (p<0.001), osteoporosis (p<0.001), asthma/bronchitis (p=0.028), stroke (p<0.001), heart problems (p<0.001), poor circulation (varices) (p<0.001), constipation (p<0.001 ), cataracts (p<0.001), benign tumors (p=0.002) and vision problems (p<0.001). Older adults in urban areas had lower averages in the physical (p<0.001), psychological (p<0.001) and social (p<0.001) domains, aspects of autonomy (p<0.001), activities in the past, present and future (p<0.001), social participation (p<0.001) and intimacy (p<0.001).Older adults living in rural areas showed lower scores on aspects of the functioning of the senses (p<0.001) and death and dying (p<0.001). CONCLUSIONS: It is necessary for health professionals to promote the monitoring of the elderly, taking into account the conditions of the location where they live. PMID- 26102107 TI - [Information about the medicines and adherence to high activity antiretroviral treatment in patients with HIV/AIDS in a hospital of Lima, Peru]. AB - OBJECTIVES: Determine the association between the information received on high activity antiretroviral treatment (HAART) and the adherence to this treatment in patients with HIV / AIDS of a hospital of Lima, Peru. MATERIALS AND METHODS: Cross-sectional analytical study. Through interviews were applied the questionnaire SIMS (Satisfaction with Information about Medicines Scale) to measure satisfaction with information received about medications and SMAQ (Simplified Medication Adherence Questionnaire) to determine adherence to HAART. By reviewing medical records sociodemographic and clinical data were collected. RESULTS: 364 patients were interviewed. Satisfaction with the information received about drugs was not associated with adherence to HAART (p = 0.611). Factors associated with the satisfaction with information were: female (ORa = 0.52; 95% CI 0.30 to 0.90); level of higher education (ORa = 0.45; 95% CI 0.27 to 0.75) and age (ORa = 1.05; 95% CI 1.02 to 1.08). There were more satisfaction with the information received on the action and drug use compared with information about potential adverse events (48.9% vs. 43.1%; p = 0.0291). CONCLUSIONS: Satisfaction with information received about drugs was not associated with adherence to HAART. This satisfaction increases with age and is lower in females and in the degree of higher education. There are desires for further information on the potential adverse reactions to HAART. PMID- 26102108 TI - [Evaluation of food and nutrition security in families in the district of los morochucos in Ayacucho, Peru]. AB - OBJECTIVES: To evaluate food and nutrition security in families of Los Morochucos district in Ayacucho, Peru. MATERIALS AND METHODS: A study based on interpretation of available information from official sources and surveys carried out to gather information not recorded in these sources. Sampling was stratified and two-staged comprising 128 families with at least one child under 12 years. The variables were the level of food security, family perception of their situation of availability of and access to food, exclusive breastfeeding, feeding during episodes of diarrhea, frequency of food consumption, consumption of safe water, hand washing, proper toilets, stable food supply, nutrition and health status, chronic malnutrition, anemia and parasitic infections in children aged 6 months to three years. RESULTS: 39.1% of families had food security, 37.5% were food insecure without hunger, 18.8% had food insecurity with hunger, and 4.7% had food insecurity with severe hunger. They had acceptable calorie intake, but did not have a balanced diet. There was no chlorinated water. During the episodes of diarrhea, 72% of mothers fed the child with mate (tea) or broth. A great quantity of their crops were lost in 2011. Of children 6 months to three years, 34.5% presented chronic malnutrition, 42.4% had anemia and 61.6% had parasites. CONCLUSIONS: Food and nutrition insecurity in this district of Ayacucho is considerable and there should be prioritization of the implementation of investment projects with the aim of contributing to the development of the community. PMID- 26102109 TI - [Protective effect of Helianthus annuus (sunflower) on myocardial infarction in New Zealand rabbit]. AB - OBJECTIVES: Determine the protective effect of oil Helianthus annuus (Sunflower) on myocardial infarction induced by epinephrine in New Zealand rabbits. MATERIALS AND METHODS: The rabbits were randomized into five groups (8 per group): blank, negative control, experimental 1 (10 mg / kg), experimental 2 (20 mg / kg) and three experimental (40 mg/ kg). Experimental groups 1, 2 and 3 received Helianthus annuus oil for two weeks. Epinephrine (2 mg/Kg) to the negative, Experimental Control 1, 2 and 3 groups was given over two consecutive days with an interval of 24 h after pretreatment with oil. Twenty four hours after the last administration, the rabbits were anesthetized and sacrificed. Serum troponin I and polymorphonuclear evaluated by .mu.m.sup.2. RESULTS: Significant difference between the negative control group and the experimental groups 1, 2 and 3 was found in the serum variables troponin I and polymorphonuclear by .mu.m.sup.2. CONCLUSIONS: Helianthus annuus oil at doses of 20 mg/kg has protective effect on myocardial infarction induced by epinephrine in New Zealand rabbits. PMID- 26102111 TI - [Routes of public transport and the situation of tuberculosis in Lima, Peru]. AB - In order to determine the association between the number of formal urban public transport routes and the situation of tuberculosis (TB) in each district of Lima, a correlational analysis and linear regression model between the two variables was performed. Also determined were the number of public transport routes most likely to transmit TB, the areas of greatest activity of these routes and a mapping of these routes. There is a positive correlation between the number of formal routes through each district of Lima and the situation of tuberculosis; a percentage of the TB situation could be explained by the number of public transport routes. Of the 404 formal routes that run through Lima, 147 (36.4%) are routes of greater probability of transmission of TB. Public transport should be considered in the ongoing fight against TB. PMID- 26102110 TI - [Outbreak of norovirus Group II in a military training center, Peru 2013]. AB - We report an outbreak of norovirus(NoV) which occurred at a military training center in Peru. Thirteenstool samples that were taken from initial cases turned out positive for NoV GII by RT-PCR. A case-control study was performedto determine factorsassociated with infection.164 probable cases (45.2%clinical attack rate) were identified. The only factor associatedwith infection was "having shared room with a case" (ORa = 1.7; 95% CI 1.1 to 2.7).Epidemiological findings suggestthat the virus was spread person to person. Future investigations of outbreaks of diarrhea in Peru should consider the NoV as an etiologicagent. PMID- 26102112 TI - [One year prognosis after suffering the onset of cerebrovascular disease in patients from a public hospital in Lima, Peru]. AB - In Latin America, there is almost nonexistense information about the prognosis of patients with stroke. We tried to find one- year vital and functional prognosis from patients with "first-ever stroke". We did a prospective cohort study, recruiting patients in the medicine service of a public hospital, and follow them up to one year after their first-ever stroke. We collected baseline data, such as previous medical history and information about their stroke. We found mortality proportions, differences among subgroups, and compared their actual and initial functionality. We included 101 patients, 20.8% of whom died during the follow-up, with higher mortality in people over 65 years old and those severely disabled after the stroke. The functionality did not improve after one year. One out of five patients with a first-ever stroke dies a year after it, with higher mortality in elders and in people with severe disability. We conclude it is mandatory to develop a follow-up and support program to prevent unfavorable outcomes in patients who suffer stroke. PMID- 26102113 TI - [Letters to the editor published in Peruvian biomedical journals indexed in SciELO-Peru 2006-2013]. AB - This bibliometric study describes the characteristics of letters to the editor published between 2006-2013 in biomedical journals indexed in SciELO-Peru.253 letters (10.3% of total publications) were collected. Most letters (139) were in the Peruvian Journal of Experimental Medicine and Public Health, with marked increase throughout those years. 25% of letters submitted included medical student participation. 14% of authors presented with international affiliations and 27% with endogenous affiliation - common in university journals (Anales de la Facultad de Medicina, Revista Medica Herediana).The usual criteria justifying the publication of letters were: opinion of medical fact or public domain (35.6%) and discussion of results, methodological flaws or interpretation (22.9%). In biomedical journals indexed in SciELO Peru the letters to the editor comprise a percentage of publications that has increased in recent years, with low publication of letters of findings or primary data, compared with opinion or criticism. PMID- 26102114 TI - [Effect of intravenous infusion of KCl on the electrocardiogram and serum potassium in dogs with normal renal function]. AB - Variations in serum potassium (K+) and electrocardiographic changes at different infusion speeds of intravenous K+ were studied in dogs. Solutions of 20, 40, 60 and 80 mEq of K+ were infused in one hour to dogs with normal renal function and normal serum K+. Nine dogs were studied: three without prior hydration and six with previous hydration. Infusing 20 mEq/hour of K+ produced an increase in heart rate without changes in the electrocardiogram. With 40 mEq/hour there were changes in the "t" and "p" waves, and with 60 and 80 mEq/hour, alterations consistent with cardiac ischemia and ventricular tachycardia. Dogs without hydration had more obvious and fatal electrocardiographic changes. Doses of 20 mEq/hour of K + caused no morbidity or mortality in the animals studied. Higher doses showed various complications which depended on the hydration status of the animal, its urinary flow and potassium level. PMID- 26102115 TI - [Balancing risks and benefits of mammography screening for breast cancer: would you support its recommendation in Peruvian women?]. AB - The aim of this study is to assess the balance between benefits and risks of population-based mammography screening programs in Peruvian women. We followed the criteria proposed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group. A generic search strategy for published studies was performed using Medline and other sources of national data (gray literature). The evidence of benefits, risks, costs and preferences of the population was used in order to state a recommendation in favour, or against, screening. We found five systematic reviews (SR) that evaluated the balance between benefit and risks, two economic evaluations based on Peruvian data, and one study that reported the preferences of Peruvian women. The quality of evidence of the SR was moderate in favour of screening in women aged 50-69 years. The balance of risks and benefits showed a higher probability of overdiagnosis compared with the reduction in mortality. The most cost-effective strategy was the triennial mammography. Perceived barriers could seriously compromise the participation of women. In conclusion, the recommendation of mammography screening for Peruvian women is weak, even more if we take into account other health necessities of the population. However, if implemented, triennial mammography in women aged 50-69 years could be the more suitable screening strategy. PMID- 26102116 TI - [Estimators of internal consistency in health research: the use of the alpha coefficient]. AB - Academic production has increased in the area of health, increasingly demanding high quality in publications of great impact. One of the ways to consider quality is through methods that increase the consistency of data analysis, such as reliability which, depending on the type of data, can be evaluated by different coefficients, especially the alpha coefficient. Based on this, the present review systematically gathers scientific articles produced in the last five years, which in a methodological manner gave the alpha coefficient psychometric use as an estimator of internal consistency and reliability in the processes of construction, adaptation and validation of instruments. The identification of the studies was conducted systematically in the databases BioMed Central Journals, Web of Science, Wiley Online Library, Medline, SciELO, Scopus, Journals@Ovid, BMJ and Springer, using inclusion and exclusion criteria. Data analyses were performed by means of triangulation, content analysis and descriptive analysis. It was found that most studies were conducted in Iran (f=3), Spain (f=2) and Brazil (f=2). These studies aimed to test the psychometric properties of instruments, with eight studies using the alpha coefficient to assess reliability and nine for assessing internal consistency. All studies were classified as methodological research when their objectives were analyzed. In addition, four studies were also classified as correlational and one as descriptive correlational. It can be concluded that though the alpha coefficient is widely used as one of the main parameters for assessing internal consistency of questionnaires in health sciences, its use as an estimator of trust of the methodology used and internal consistency has some critiques that should be considered. PMID- 26102117 TI - [Emerging antibiotic resistance: a global threat and critical healthcare problem]. AB - After the development and mass commercialization of antibiotics, pathogenic and environmental bacteria have developed resistance to antibiotics since the last century, so that the infection caused by antibiotic-resistant organisms (AROs) could be considered an emerging infection. As a result, its control should be prioritized as a threat to all nations, regardless of territory and economic situation. Increased surveillance in the United States, Europe and East Asia has illustrated the rapid spread leading to an increasing burden of infections caused by AROs. However, the information available in countries of continued development in Latin America is limited. This review describes recent information on AROs surveillance studies in Latin America as well as common sources of AROs and possible strategies for their control. PMID- 26102118 TI - [Dengue in Peru: a quarter century after its reemergence]. AB - A health problem each time more frequent and dispersed in tropical and subtropical areas of the world, including Peru where it entered in 1990, is dengue. It is produced by the dengue virus with four serotypes and transmitted by Aedes aegypti, a vector that coexists with humans and whose presence is favored by deficient sanitary, social and economic conditions. Manifestations of severe forms of the disease such as shock and bleeding, are related to the frequent co circulation of the four serotypes and the emergence of new genotypes such as American/Asian serotype 2. The new classification of the disease by WHO as dengue with or without warning signs and severe dengue, is contributing to more timely diagnosis and treatment, enabling reductions in mortality. Of note is the need to highlight the surveillance of acute febrile illness and Aedes indices that contribute to a timely diagnosis and guide vector control measures through sanitary education and environmental management with community and intersectoral participation, in a creative manner according to ecological niches. An alternative for complementary prevention would be vaccination using tetravalent vaccines whose safety and efficacy must be guaranteed before its use in the population under the framework of comprehensive strategies. PMID- 26102120 TI - [New transmission scenarios of the Argentine hemorrhagic fever since the introduction of the live attenuated junin virus vaccine (Candid #1): an experience in migrant workers]. AB - The Argentine hemorrhagic fever (AHF) is a severe acute viral disease caused by the Junin virus of the Arenaviridae family. The AHF endemic area coincides geographically with the largest grain export agro-industrial complex of the country [Argentina]. Since the implementation of vaccination with the Candid #1 vaccine, a significant reduction in incidence was achieved and risk patterns were modified. A previous study allowed characterizing these changes and identifying three transmission scenarios: classic, emergent-reemergent, and traveler. The latter scenario includes seasonal migrant workers who move each year, mainly from the province of Santiago del Estero, the endemic area to work in the detasseling of maize. With the objective of protecting this group of workers, a prevention campaign was initiated which included: capacity building of health personnel in the province, health education, and immunization with the vaccine Candid #1. 3,021 workers were vaccinated. Prior to vaccination, serum samples were taken from a group of 104 volunteers. Tests for neutralizing antibodies specific to the Junin virus were performed and 6 (5.76%) tested positive. The unexpected finding of a high percentage of workers with antibodies suggests the need to evaluate several hypotheses: a) that the result is the product of non-probabilistic sampling; b) that it could be people who fell ill in previous travels, c) or who were vaccinated in previous travels; or d) consider this region as an emerging scenario. PMID- 26102119 TI - [Relevant public health enteropathogens]. AB - Diarrhea remains the third leading cause of death in children under five years, despite recent advances in the management and prevention of this disease. It is caused by multiple pathogens, however, the prevalence of each varies by age group, geographical area and the scenario where cases (community vs hospital) are recorded. The most relevant pathogens in public health are those associated with the highest burden of disease, severity, complications and mortality. In our country, norovirus, Campylobacter and diarrheagenic E. coli are the most prevalent pathogens at the community level in children. In this paper we review the local epidemiology and potential areas of development in five selected pathogens: rotavirus, norovirus, Shiga toxin-producing E. coli (STEC), Shigella and Salmonella. Of these, rotavirus is the most important in the pediatric population and the main agent responsible for child mortality from diarrhea. The introduction of rotavirus vaccination in Peru will have a significant impact on disease burden and mortality from diarrhea. However, surveillance studies are needed to determine the impact of vaccination and changes in the epidemiology of diarrhea in Peru following the introduction of new vaccines, as well as antibiotic resistance surveillance of clinical relevant bacteria. PMID- 26102121 TI - [Lessons learned in the control of Aedes aegypti to address dengue and the emergency of chikungunya in Iquitos, Peru]. AB - Dengue has affected Iquitos since 1990 causing outbreaks of major impact on public health and for this reason great efforts have been made for its temporal control. Currently, with the expansion of the chikungunya virus in the Americas and the threat of the emergence of the virus in Iquitos, we reflect on lessons learned by way of the activities undertaken in the area of vector control; epidemiological surveillance, diagnosis and clinical management during periods of outbreaks of dengue, in a way that will allow us to better face the threat of an outbreak of chikungunya virus in the largest city in the Peruvian Amazon. PMID- 26102122 TI - [Coinfection of dengue and leptospirosis in a girl from the peruvian amazon]. AB - We report the case of a 10 year old girl, born and raised in the city of Iquitos in Peru who presented with headache, fever, chills, musculoskeletal pain, mild epigastric pain, epistaxis and hematemesis. On physical examination, the patient was afebrile and in good general condition. Serological tests confirmed infection of dengue and leptospirosis. The patient received intravenous hydration with sodium chloride 0.9% and penicillin G sodium, achieving a favorable clinical course such that she was discharged a few days after admission to the hospital. Although these diseases are common in the Peruvian Amazon, the simultaneous presence of both in the pediatric population is little documented; therefore, a good clinical history and laboratory tests are important for diagnosis and treatment. PMID- 26102123 TI - [Paracoccidiomicosis in the central nervous system: a case report]. AB - Paracoccidioidomycosis is a fungal disease which can compromise the central nervous system (CNS).We present a case of an immunocompetent 45 year old man from Satipo, Peru who developed paracoccidioidomycosis in the CNS without any apparent point of entry or infection. The patient was diagnosed by imaging with a cerebellar granuloma, followed by a craniotomy where tissue and secretion of the granuloma abscess was obtained. Histological and microbiological diagnoses were performed on the tissue and secretion, respectively. Yeasts were observed in the histological section and growth of the fungus in the culture. The patient initially received antifungals, then acquired an intrahospital infection, received colistin and subsequently died. The case report emphasizes the importance of early and correct diagnosis for good outcomes of paracoccidioidomycosis cases. PMID- 26102125 TI - [Vertical transmission of dengue virus in Aedes aegypti, Peru]. PMID- 26102124 TI - [Disseminated cutaneous sporotrichosis with joint involvement in a woman with type 2 diabetes]. AB - Disseminated sporotrichosis is a rare presentation of this mycosis. Although it has been described in immunocompetent individuals, there is often T cell-mediated immune compromise. We report the case of a woman with uncontrolled Type 2 diabetes who developed disseminated cutaneous sporotrichosis. The course of the disease presented several complications including hepatitis secondary to itraconazole and knee arthritis with culture positive for Sporothrix schenckii during treatment with saturated solution of potassium iodide. The case discussion includes aspects of the pathogenesis of disseminated sporotrichosis and management of the infection and its complications. PMID- 26102126 TI - [Scientific crowdfunding: alternative financing for young researchers in Peru]. PMID- 26102127 TI - [About the redistributive impact of the SERUMS program (Rural and Urban Margin Health Care Service) on the availability of physicians in Peru]. PMID- 26102128 TI - [Is there unjust equity? For the elimination of the mandatory SERUMS program (Rural and Urban Margin Health Care Service)]. PMID- 26102129 TI - [Measurement and magnitude of bullying in Peru]. PMID- 26102130 TI - [The cutoff point of hemoglobin to define maternal anemia in altitude should not be corrected]. PMID- 26102131 TI - [Replica: el punto de corte de la hemoglobina para definir anemia materna en la altura no debe ser corregido]. PMID- 26102132 TI - [Use of information resources available on the Internet: limitations and recommendations]. PMID- 26102133 TI - [Comments to the article: arterial blood gases in clinically healthy adults at 3,350 meters above sea level]. PMID- 26102134 TI - [Replica: gasometria arterial en adultos clinicamente sanos a 3350 metros de altitud]. PMID- 26102135 TI - [Time to wait for surgery in a hospital in Chiclayo, Peru]. PMID- 26102136 TI - 2015 Award Winners of the Aerospace Medical Association. PMID- 26102137 TI - Human Performance and the Year of the Aerospace Medicine Professional. PMID- 26102138 TI - Simulator Study of Helmet-Mounted Symbology System Concepts in Degraded Visual Environments. AB - BACKGROUND: A sudden loss of external visual cues during critical phases of flight results in spatial disorientation. This is due to undetected horizontal and vertical drift when there is little tolerance for error and correction delay as the helicopter is close to the ground. Three helmet-mounted symbology system concepts were investigated in the simulator as potential solutions for the legacy Griffon helicopters. METHOD: Thirteen Royal Canadian Air Force (RCAF) Griffon pilots were exposed to the Helmet Display Tracking System for Degraded Visual Environments (HDTS), the BrownOut Symbology System (BOSS), and the current RCAF AVS7 symbology system. For each symbology system, the pilot performed a two-stage departure and a single-stage approach. The presentation order of the symbology systems was randomized. Objective performance metrics included aircraft speed, altitude, attitude, and distance from the landing point. Subjective measurements included situation awareness, mental effort, perceived performance, perceptual cue rating, and NASA Task Load Index. Repeated measures analysis of variance and subsequent planned comparison for all the objective and subjective measurements were performed between the AVS7, HDTS, and BOSS. RESULTS: Our results demonstrated that HDTS and BOSS showed general improvement over AVS7 in two-stage departure. However, only HDTS performed significantly better in heading error than AVS7. During the single-stage approach, BOSS performed worse than AVS7 in heading root mean square error, and only HDTS performed significantly better in distance to landing point and approach heading than the others. DISCUSSION: Both the HDTS and BOSS possess their own limitations; however, HDTS is the pilots' preferred flight display. PMID- 26102139 TI - Upper Body Aerobic Exercise as a Possible Predictor of Lower Body Performance. AB - BACKGROUND: Aerobic exercise capacity provides information regarding cardiorespiratory health and physical capacity. However, in many populations the ability to measure whole-body or leg aerobic exercise capacity is limited due to physical disability or lack of appropriate equipment. Clinically there is a need to evaluate aerobic capacity in individuals who cannot use their legs for locomotion. In astronauts the habitable space for exercise testing in the next generation of space exploration systems may be restricted and may not support the traditional lower body testing. Therefore, the purpose was to determine if upper body physical performance could estimate lower body aerobic capacity. METHODS: Maximal O2uptake (Vo(2max)), gas exchange threshold (GET), and the highest sustainable rate of aerobic metabolism [arm cranking critical power ((A)CP) and lower body critical speed ((L)CS)] were determined in 55 conditioned men and women during arm-cranking and treadmill running. RESULTS: Vo(2max) and GET (48.6 +/- 7.6 and 29.0 +/- 4.8 ml . kg-1 . min-1, respectively) were significantly lower during arm-cranking exercise compared to running (27.1 +/- 7.6 and 13.5 +/- 2.6 ml . kg-1 . min-1, respectively). The Vo2at ACP was significantly lower than the Vo2at the (L)CS (18.4 +/- 5.01 vs. 39.5 +/- 8.1 ml . kg-1 . min-1, respectively). There was a significant correlation between arm-cranking and lower body Vo2max, GET, and the Vo2at (L)CS and ACP. Backward stepwise regression analyses revealed that arm-cranking physical fitness could explain 67%, 40%, and 49% of the variance in lower body Vo(2max), GET, and (L)CS, respectively. DISCUSSION: Results suggest arm-cranking exercise can be used to obtain an approximation of lower body aerobic capacity. PMID- 26102140 TI - Statistical Evaluation of Causal Factors Associated with Astronaut Shoulder Injury in Space Suits. AB - INTRODUCTION: Shoulder injuries due to working inside the space suit are some of the most serious and debilitating injuries astronauts encounter. Space suit injuries occur primarily in the Neutral Buoyancy Laboratory (NBL) underwater training facility due to accumulated musculoskeletal stress. We quantitatively explored the underlying causal mechanisms of injury. METHODS: Logistic regression was used to identify relevant space suit components, training environment variables, and anthropometric dimensions related to an increased propensity for space-suited injury. Two groups of subjects were analyzed: those whose reported shoulder incident is attributable to the NBL or working in the space suit, and those whose shoulder incidence began in active duty, meaning working in the suit could be a contributing factor. RESULTS: For both groups, percent of training performed in the space suit planar hard upper torso (HUT) was the most important predictor variable for injury. Frequency of training and recovery between training were also significant metrics. The most relevant anthropometric dimensions were bideltoid breadth, expanded chest depth, and shoulder circumference. Finally, record of previous injury was found to be a relevant predictor for subsequent injury. The first statistical model correctly identifies 39% of injured subjects, while the second model correctly identifies 68% of injured subjects. DISCUSSION: A review of the literature suggests this is the first work to quantitatively evaluate the hypothesized causal mechanisms of all space-suited shoulder injuries. Although limited in predictive capability, each of the identified variables can be monitored and modified operationally to reduce future impacts on an astronaut's health. PMID- 26102141 TI - Hypoxia, Hypobaria, and Exercise Duration Affect Acute Mountain Sickness. AB - INTRODUCTION: This study simultaneously quantified the effects of normobaric hypoxia (NH), hypobaric hypoxia (HH), exercise duration, and exposure time on acute mountain sickness severity (AMS-C). METHODS: Thirty-six subjects (27.7 +/- 7.8 yr) participated in a partial repeated measures study, completing two of six conditions: normobaric normoxia (NN: 300 m/984 ft equivalent), NH or HH (Po2 = 91 mmHg; 4400 m/14,436 ft equivalent), combined with moderate intensity cycling for 10 or 60 min. Subjects completed the Environmental Symptoms Questionnaire and oxygen saturation (Spo2) was measured before, 1.5 h, 4 h, and 6.5 h into an 8-h exposure, and 1.5 h post-exposure. We fit multiple linear regression models with cluster adjusted standard errors on the exposure times using NH, HH, and long exercise as indicator variables, and AMS-C as the outcome variable. The Spo2and pre-exposure AMS-C score were used as covariates. RESULTS: NH and HH led to substantial and progressively increasing AMS-C, but NN did not. The effect of HH on AMS-C was significantly different from NH, with AMS-C in HH being 1.6 times higher than in NH. HH led to significantly increasing AMS-C, regardless of the exercise duration, while NH only did so in combination with longer exercise. DISCUSSION: Increases in AMS-C were each independently related to NH, HH, and long duration exercise, with HH affecting AMS-C more severely. This suggests that hypobaria may affect AMS development above the level induced by hypoxia alone. This further suggests that NH and HH may not be interchangeable for studying AMS and that exercise duration may impact physiological responses. PMID- 26102142 TI - Ground and Helicopter Emergency Medical Services Time Tradeoffs Assessed with Geographic Information. AB - INTRODUCTION: We describe how geographic information systems (GIS) can be used to assess and compare estimated transport time for helicopter and ground emergency medical services. Recent research shows that while the odds of a trauma patient's survival increase with helicopter emergency medical services (HEMS), they may not increase to the extent necessary to make HEMS cost effective. This study offers an analytic tool to objectively quantify the patient travel time advantage that HEMS offers compared to ground emergency medical services (GEMS). METHODS: Using helicopter dispatch data from the Maryland State Police from 2000-2011, we computed transport time estimates for HEMS and GEMS, compare these results to a reference transport time of 60 min, and use geospatial interpolation to extrapolate the total response times for each mode across the study region. RESULTS: Mapping the region's trauma incidents and modeling response times, our findings indicate the GIS framework for calculating transportation time tradeoffs is useful in identifying which areas can be better served by HEMS or GEMS. DISCUSSION: The use of GIS and the analytical methodology described in this study present a method to compare transportation by air and ground in the prehospital setting that accounts for how mode, distance, and road infrastructure impact total transport time. Whether used to generate regional maps in advance or applied real-time, the presented framework provides a tool to identify earlier incident locations that favor HEMS over GEMS transport modes. PMID- 26102143 TI - Challenges of Estimating Fracture Risk with DXA: Changing Concepts About Bone Strength and Bone Density. AB - INTRODUCTION: Bone loss due to weightlessness is a significant concern for astronauts' mission safety and health upon return to Earth. This problem is monitored with bone densitometry (DXA), the clinical tool used to assess skeletal strength. DXA has served clinicians well in assessing fracture risk and has been particularly useful in diagnosing osteoporosis in the elderly postmenopausal population for which it was originally developed. Over the past 1-2 decades, however, paradoxical and contradictory findings have emerged when this technology was widely employed in caring for diverse populations unlike those for which it was developed. Although DXA was originally considered the surrogate marker for bone strength, it is now considered one part of a constellation of factors described collectively as bone quality-that makes bone strong and resists fracturing, independent of bone density. These characteristics are beyond the capability of routine DXA to identify, and as a result, DXA can be a poor prognosticator of bone health in many clinical scenarios. New clinical tools are emerging to make measurement of bone strength more accurate. This article reviews the historical timeline of bone density measurement (dual X-ray absorptiometry), expands upon the clinical observations that modified the relationship of DXA and bone strength, discusses some of the new clinical tools to predict fracture risk, and highlights the challenges DXA poses in the assessment of fracture risk in astronauts. PMID- 26102144 TI - Historical Review of Lower Body Negative Pressure Research in Space Medicine. AB - Cephalad redistribution of intravascular and extravascular fluid occurs as a result of weightlessness during spaceflight. This provokes cardiovascular, cardiopulmonary, and autonomic nervous system responses. The resulting altered functional state can result in orthostatic hypotension and intolerance upon landing and return to a gravity environment. In-flight lower body negative pressure (LBNP) transiently restores normal body fluid distribution. Early in the U.S. space program, LBNP was devised as a way to test for orthostatic intolerance. With the development of the Skylab Program and longer duration spaceflight, it was realized that it could provide a method of monitoring orthostatic intolerance in flight and predicting the post-landing orthostatic response. LBNP was also investigated not only as an in-flight cardiovascular orthostatic stress test, but also as a countermeasure to cardiovascular deconditioning on Soviet space stations, Skylab, and the Shuttle. It is still being used by the Russian program on the International Space Station as an end-of flight countermeasure. PMID- 26102145 TI - A Methodology to Determine the Psychomotor Performance of Helicopter Pilots During Flight Maneuvers. AB - INTRODUCTION: Helicopter flying is a complex psychomotor task requiring continuous control inputs to maintain stable flight and conduct maneuvers. Flight safety is impaired when this psychomotor performance is compromised. A comprehensive understanding of the psychomotor performance of helicopter pilots, under various operational and physiological conditions, remains to be developed. The purpose of this study was to develop a flight simulator-based technique for capturing psychomotor performance data of helicopter pilots. METHODS: Three helicopter pilots conducted six low-level flight sequences in a helicopter simulator. Accelerometers applied to each flight control recorded the frequency and magnitude of movements. RESULTS: The mean (+/- SEM) number of control inputs per flight was 2450 (+/- 136). The mean (+/- SEM) number of control inputs per second was 1.96 (+/- 0.15). The mean (+/- SEM) force applied was 0.44 G (+/- 0.05 G). No significant differences were found between pilots in terms of flight completion times or number of movements per second. The number of control inputs made by the hands was significantly greater than the number of foot movements. The left hand control input forces were significantly greater than all other input forces. DISCUSSION: This study shows that the use of accelerometers in flight simulators is an effective technique for capturing accurate, reliable data on the psychomotor performance of helicopter pilots. This technique can be applied in future studies to a wider range of operational and physiological conditions and mission types in order to develop a greater awareness and understanding of the psychomotor performance demands on helicopter pilots. PMID- 26102146 TI - Spatial Pattern of Eye Fixations and Evidence of Ultradian Rhythms in Aircraft Pilots. AB - INTRODUCTION: Eye fixations can be distributed in three ways: randomly, in clusters, and regularly. However, there is always a continuum among these types, because these spatial patterns are the result of a process evolving over time. The focus of the present work was to study the changes over time observed in the Nearest Neighbor Index (NNI), an index derived from the spatial distribution of eye fixations that has been reported to be sensitive to variations in mental workload. Of particular interest are periodic changes in the ultradian timescale (an ultradian rhythm is a recurrent period or cycle repeated throughout a 24-h circadian day). METHODS: Data from a previously reported experiment were further analyzed using temporal spectral analysis, which is one of the most commonly used techniques for studying measurements collected at regularly spaced intervals of time. RESULTS: An ultradian rhythm with a periodicity between 2 and 15 min was found, which is compatible with results obtained by analyzing reaction times in prolonged vigilance tasks. DISCUSSION: The identification of a periodicity in the allocation of mental resources should be considered in the design of automation support that is dynamically matched to mental workload. PMID- 26102147 TI - Dental Barotrauma in French Military Divers: Results of the POP Study. AB - OBJECTIVE: The aim of the POP (odontological problems among divers) study was to assess dental barotrauma among French military divers exposed to an underwater environment. METHODS: A questionnaire on dental barotrauma was completed by the divers who presented at the SMHEP (Centre for Hyperbaric Medicine and Diving Expertise) for their quadrennial medical exam from March 2011 to July 2014. RESULTS: There were 1317 questionnaires completed, representing 60.6% of all French military divers. A total of 5.3% of divers had a dental barotrauma (70/1317), mainly fracture and/or loss of dental restoration. Dental barotrauma disrupted diving in 34.3% of cases. A total of 76.4% of divers were informed by a military physician of the importance of maintaining good oral health and 88.5% of divers consult their dentist at least once a year. Of the participants, 82.5% made their dentist aware they are divers, but only 4.9% of the dental practitioners advised their patient not to dive after some types of dental treatments and 12.8% indicated that, as divers, they need adapted dental treatments. CONCLUSIONS: Dental barotrauma was experienced by 1 in 19 military divers. Nevertheless, a contradiction exists between the frequency of dental barotraumas and the rigorous medical and dental follow-up of military divers. We note that there is inadequate dental management of divers when dental issues are identified. To avoid this unsatisfactory situation, "diving dentistry" should be taught to military and civilian dentists and physicians to make them aware of the potential dental complications and preventive measures associated with operating in a subaquatic environment. PMID- 26102148 TI - AsMA Medical Guidelines for Air Travel: Fitness to Fly and Medical Clearances. AB - INTRODUCTION: Medical Guidelines for Airline Travel provide information that enables healthcare providers to properly advise patients who plan to travel by air. Not everyone is fit to travel by air and physicians should advise their patients accordingly. They should review the passenger's medical condition, giving special consideration to the dosage and timing of any medications, contagiousness, and the need for special assistance during travel. In general, an individual with an unstable medical condition should not fly; cabin altitude, duration of exposure, and altitude of the destination airport are all considerations when recommending a passenger for flight. PMID- 26102149 TI - AsMA Medical Guidelines for Air Travel: Airline Special Services. AB - INTRODUCTION: Medical Guidelines for Airline Travel provide information that enables healthcare providers to properly advise patients who plan to travel by air. Treating physicians should advise patients in need of special services to contact the airline well before travel to find out if the required services will be available. Ensuring the required services are available throughout a journey can be challenging, especially when different airlines and aircraft types are involved. For example, airlines carry a limited supply of oxygen for use in the event of an unexpected in-flight emergency; however, this supply is not intended for use by passengers needing supplemental oxygen. Arrangements must be made in advance with the airline. Therefore, early contact with the airline is helpful. PMID- 26102150 TI - Storing and Processing Complex Data Sets with HDF5. PMID- 26102151 TI - You're the Flight Surgeon. PMID- 26102152 TI - You're the Flight Surgeon. PMID- 26102153 TI - This Month in Aerospace Medicine History. PMID- 26102154 TI - Correction to Biodegradable Nanoneedles for Localized Delivery of Nanoparticles in Vivo: Exploring the Biointerface. PMID- 26102155 TI - Water Mediated Interactions and the Protein Folding Phase Diagram in the Temperature-Pressure Plane. AB - The temperature-pressure behavior of two proteins, ubiquitin and lambda repressor, is explored using a realistically coarse-grained physicochemical model, the associative memory, water mediated, structure and energy model (AWSEM). The phase diagram across the temperature-pressure plane is obtained by perturbing the water mediated interactions in the Hamiltonian systematically. The phase diagrams calculated with direct simulations along with an extended bridge sampling estimator show the main features found experimentally, including both cold- and pressure-denaturation. The denatured ensembles in different parts of the phase diagram are characterized and found to be structurally distinct. The protein energy landscape is found to be funneled throughout the phase diagram, but modest changes in the entropy and free energy of the water are found to drive both cold and pressure induced denaturation. PMID- 26102156 TI - Nocturnal hypoxemia severity and renin-angiotensin system activity in obstructive sleep apnea. AB - RATIONALE: Obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with chronic kidney disease and up-regulation of the renin-angiotensin system (RAS), which is deleterious to renal function. The extent to which the magnitude of RAS activation is influenced by the severity of nocturnal hypoxemia and comorbid obesity has not been determined. OBJECTIVES: To determine the association between the severity of nocturnal hypoxemia and RAS activity and whether this is independent of obesity in patients with OSA. METHODS: Effective renal plasma flow (ERPF) response to angiotensin II (AngII) challenge, a marker of renal RAS activity, was measured by paraaminohippurate clearance technique in 31 OSA subjects (respiratory disturbance index, 51 +/- 25 h(-1)), stratified according to nocturnal hypoxemia status (mean nocturnal SaO2, >=90% [moderate hypoxemia] or <90% [severe hypoxemia]) and 13 obese control subjects. MEASUREMENTS AND MAIN RESULTS: Compared with control subjects, OSA subjects demonstrated decreased renovascular sensitivity (ERPF, -153 +/- 79 vs. -283 +/- 31 ml/min; P = 0.004) (filtration fraction, 5.4 +/- 3.8 vs. 7.1 +/- 2.6%; P = 0.0025) in response to 60 minutes of AngII challenge (mean +/- SD; all P values OSA vs. control). The fall in ERPF in response to AngII was less in patients with severe hypoxemia compared with those with moderate hypoxemia (P = 0.001) and obese control subjects after 30 minutes (P < 0.001) and 60 minutes (P < 0.001) of AngII challenge, reflecting more augmented renal RAS activity. Severity of hypoxemia was not associated with the blood pressure or the systemic circulating RAS component response to AngII. CONCLUSIONS: The severity of nocturnal hypoxemia influences the magnitude of renal, but not the systemic, RAS activation independently of obesity in patients with OSA. PMID- 26102157 TI - Ion-Mediated Gelation of Aqueous Suspensions of Cellulose Nanocrystals. AB - Nanofibrillar hydrogels are an important class of biomaterials with applications as catalytic scaffolds, artificial extracellular matrixes, coatings, and drug delivery materials. In the present work, we report the results of a comprehensive study of nanofibrillar hydrogels formed by cellulose nanocrystals (CNCs) in the presence of cations with various charge numbers and ionic radii. We examined sol gel transitions in aqueous CNC suspensions and the rheological and structural properties of the CNC hydrogels. At a particular CNC concentration, with increasing charge and cation size, the dynamic shear moduli and mesh size in the hydrogel increased. These effects were ascribed to a stronger propensity of CNCs for side-by-side association. The resulting hydrogels had an isotropic nanofibrillar structure. A combination of complementary techniques offered insight into structure-property relationships of CNC hydrogels, which are important for their potential applications. PMID- 26102158 TI - Chemical Functionalization of Germanium with Dextran Brushes for Immobilization of Proteins Revealed by Attenuated Total Reflection Fourier Transform Infrared Difference Spectroscopy. AB - Protein immobilization studied by attenuated total reflection Fourier transform infrared (ATR-FT-IR) difference spectroscopy is an emerging field enabling the study of proteins at atomic detail. Gold or glass surfaces are frequently used for protein immobilization. Here, we present an alternative method for protein immobilization on germanium. Because of its high refractive index and broad spectral window germanium is the best material for ATR-FT-IR spectroscopy of thin layers. So far, this technique was mainly used for protein monolayers, which lead to a limited signal-to-noise ratio. Further, undesired protein-protein interactions can occur in a dense layer. Here, the germanium surface was functionalized with thiols and stepwise a dextran brush was generated. Each step was monitored by ATR-FT-IR spectroscopy. We compared a 70 kDa dextran with a 500 kDa dextran regarding the binding properties. All surfaces were characterized by atomic force microscopy, revealing thicknesses between 40 and 110 nm. To analyze the capability of our system we utilized N-Ras on mono-NTA (nitrilotriacetic acid) functionalized dextran, and the amount of immobilized Ras corresponded to several monolayers. The protein stability and loading capacity was further improved by means of tris-NTA for immobilization. Small-molecule-induced changes were revealed with an over 3 times higher signal-to-noise ratio compared to monolayers. This improvement may allow the observation of very small and so far hidden changes in proteins upon stimulus. Furthermore, we immobilized green fluorescent protein (GFP) and mCherry simultaneously enabling an analysis of the surface by fluorescence microscopy. The absence of a Forster resonance energy transfer (FRET) signal demonstrated a large protein-protein distance, indicating an even distribution of the protein within the dextran. PMID- 26102159 TI - Defining Product Intake Fraction to Quantify and Compare Exposure to Consumer Products. AB - There is a growing consciousness that exposure studies need to better cover near field exposure associated with products use. To consistently and quantitatively compare human exposure to chemicals in consumer products, we introduce the concept of product intake fraction, as the fraction of a chemical within a product that is eventually taken in by the human population. This metric enables consistent comparison of exposures during consumer product use for different product-chemical combinations, exposure duration, exposure routes and pathways and for other life cycle stages. We present example applications of the product intake fraction concept, for two chemicals in two personal care products and two chemicals encapsulated in two articles, showing how intakes of these chemicals can primarily occur during product use. We demonstrate the utility of the product intake fraction and its application modalities within life cycle assessment and risk assessment contexts. The product intake fraction helps to provide a clear interface between the life cycle inventory and impact assessment phases, to identify best suited sentinel products and to calculate overall exposure to chemicals in consumer products, or back-calculate maximum allowable concentrations of substances inside products. PMID- 26102160 TI - Visualizing Specific Cross-Protomer Interactions in the Homo-Oligomeric Membrane Protein Proteorhodopsin by Dynamic-Nuclear-Polarization-Enhanced Solid-State NMR. AB - Membrane proteins often form oligomeric complexes within the lipid bilayer, but factors controlling their assembly are hard to predict and experimentally difficult to determine. An understanding of protein-protein interactions within the lipid bilayer is however required in order to elucidate the role of oligomerization for their functional mechanism and stabilization. Here, we demonstrate for the pentameric, heptahelical membrane protein green proteorhodopsin that solid-state NMR could identify specific interactions at the protomer interfaces, if the sensitivity is enhanced by dynamic nuclear polarization. For this purpose, differently labeled protomers have been assembled into the full pentamer complex embedded within the lipid bilayer. We show for this proof of concept that one specific salt bridge determines the formation of pentamers or hexamers. Data are supported by laser-induced liquid bead ion desorption mass spectrometry and by blue native polyacrylamide gel electrophoresis analysis. The presented approach is universally applicable and opens the door toward analyzing membrane protein interactions within homo oligomers directly in the membrane. PMID- 26102161 TI - Selection and refinement: the malaria parasite's infection and exploitation of host hepatocytes. AB - Plasmodium parasites belong to the Apicomplexan phylum, which consists mostly of obligate intracellular pathogens that vary dramatically in host cell tropism. Plasmodium sporozoites are highly hepatophilic. The specific molecular mechanisms, which facilitate sporozoite selection and successful infection of hepatocytes, remain poorly defined. Here, we discuss the parasite and host factors which are critical to hepatocyte infection. We derive a model where sporozoites initially select host cells that constitute a permissive environment and then further refine the chosen hepatocyte during liver stage development, ensuring life cycle progression. While many unknowns of pre-erythrocytic infection remain, advancing models and technologies that enable analysis of human malaria parasites and of single infected cells will catalyze a comprehensive understanding of the interaction between the malaria parasite and its hepatocyte host. PMID- 26102162 TI - Inhibition of porcine reproductive and respiratory syndrome virus by Cecropin D in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) continues to cause substantial economic losses to the pig industry worldwide. Although vaccines are commercially available for the control of PRRSV infection, no vaccination regimen has been proved sustained success in terms of generating a protective immune response. Therefore, the development of novel antivirals is urgently needed. Antimicrobial peptides display broad-spectrum antimicrobial activities against bacteria, fungi, and viruses and play an important role in host innate immune response. Here, we tested whether Cecropin D (CD) could inhibit PRRSV infection and replication in vitro. The inhibitory effect of CD occurred during viral attachment and the early period of viral entry into Marc-145 cells. CD also attenuated virus-induced apoptosis during the late phase of PRRSV infection and suppressed virus release in Marc-145 cells, which might contribute to the inhibition of PRRSV infection. Similar inhibitory effects on PRRSV infection were also found with CD treatment in porcine alveolar macrophages, the major target cell type of PRRSV infection in pigs in vivo. These findings suggest that CD has the potential to develop a new therapeutic agent against PRRSV infection. PMID- 26102163 TI - Changing Prognosis. PMID- 26102164 TI - Cardiopulmonary Exercise Testing in Children and Adolescents With Dystrophinopathies: A Pilot Study. AB - PURPOSE: To determine exercise response during cardiopulmonary exercise testing in children and adolescents with dystrophinopathies. METHODS: Exercise response on the cardiopulmonary exercise test (CPET) was compared with a standard care test protocol. RESULTS: Nine boys (aged 10.8 +/- 4.7 years) with Becker muscular dystrophy (n = 6) and Duchenne muscular dystrophy (n = 3) were included. The feasibility of the CPET was similar to a standard care test protocol, and no serious adverse events occurred. In 67% of the subjects with normal or only mildly impaired functional capacity, the CPET could be used to detect moderate to severe cardiopulmonary exercise limitations. CONCLUSIONS: The CPET seems to be a promising outcome measure for cardiopulmonary exercise limitations in youth with mild functional limitations. Further research with larger samples is warranted to confirm current findings and investigate the additional value of the CPET to longitudinal follow-up of cardiomyopathy and the development of safe exercise programs for youth with dystrophinopathies. PMID- 26102165 TI - Commentary on "Cardiopulmonary Exercise Testing in Children and Adolescents With Dystrophinopathies: A Pilot Study". PMID- 26102166 TI - Two Seating Systems' Effects on an Adolescent With Cerebral Palsy and Severe Scoliosis. AB - BACKGROUND AND PURPOSE: To compare physiological functioning, communication switch activation, and response accuracy in a 19-year-old young man with quadriplegic cerebral palsy and neurological scoliosis using 2 seating systems within the school setting. METHODS: Prospective single-subject alternating treatment design with 2 conditions: baseline phase with standard planar inserts (A1), custom-molded back with original seat (B), and return to baseline (A2). Measures included oxygen saturation (SaO2), heart rate (HR), respiration rate (RR), body temperature (BT), processing time to activate switches, and response accuracy. RESULTS: SaO2 levels increased from "distressed" to "normal"; variability decreased. HR, RR, and BT fluctuations decreased with the custom molded back. Processing time decreased with increased variability, affected by subject's motivation; accuracy improved slightly. Reported social approachability and student-initiated communication increased. CONCLUSIONS: SaO2 increased and HR, RR, and BT fluctuations decreased with a custom-molded back. Graphing data may help determine seating effect with complex clients. PMID- 26102167 TI - Commentary on "Two Seating Systems' Effect on an Adolescent With Cerebral Palsy and Severe Scoliosis". PMID- 26102168 TI - Supporting Play Exploration and Early Development Intervention From NICU to Home: A Feasibility Study. AB - PURPOSE: To determine the feasibility of completing a clinical trial of Supporting Play Exploration and Early Development Intervention (SPEEDI) that blends early and intense intervention with family support during the transition from the neonatal intensive care unit (NICU) to home and the community. METHODS: Ten infants born preterm were randomly assigned to intervention or usual care groups. Data on intervention frequency and parent feedback were used to determine the feasibility of SPEEDI. Effect sizes were calculated for motor and problem solving outcome measures at the end of the intervention, 3 months adjusted age. RESULTS: Infants received on average 96.4% and 100.3% of anticipated NICU and home intervention. Only 28% of infants were receiving early intervention services during the SPEEDI period. Effect sizes were large and in the anticipated direction. CONCLUSIONS: SPEEDI is a feasible intervention and appropriate for future clinical trials. VIDEO ABSTRACT: For more insights from the authors, see Supplemental Digital Content 1, available at http://links.lww.com/PPT/A83. PMID- 26102169 TI - Commentary on "Supporting Play Exploration and Early Developmental Intervention from NICU to Home: A Feasibility Study". PMID- 26102170 TI - Clinical Feasibility of 2-Dimensional Video Analysis of Active Cervical Motion in Congenital Muscular Torticollis. AB - PURPOSE: The purpose of this study was to evaluate the clinical feasibility of using a 2-dimensional (2D) video analysis (VA) system compared with visual estimation (VE) for measurement of active cervical rotation and lateral flexion in infants with congenital muscular torticollis. METHODS: Twelve infants participated in this study. Active cervical motion in rotation and lateral flexion was measured by VE and 2D VA. RESULTS: Significant differences between VE and VA were found for left lateral flexion, right lateral flexion, and right rotation. Average total time for VA was 23.96 minutes. CONCLUSIONS: This study suggests that the use of VA may improve the measurement of active cervical motion to improve clinical assessment of infants with congenital muscular torticollis. However, VA time is excessive and, therefore, not clinically feasible. Further studies are indicated to explore other software for this application. PMID- 26102171 TI - Commentary on "Clinical Feasibility of 2-Dimensional Video Analysis of Active Cervical Motion in Congenital Muscular Torticollis". PMID- 26102172 TI - P-Selectin (CD62P) Expression in Liver Tissue of Biliary Atresia: A New Perspective in Etiopathogenesis. AB - OBJECTIVES: The etiology of biliary atresia (BA) is still elusive. Inflammation plays a key role in bile duct and liver injury. The recruitment and accumulation of inflammatory cells is largely dependent on adhesion molecules. We aimed to investigate P-selectin (CD62P) expression in liver tissue in patients with BA compared with other neonatal cholestatic disorders. METHODS: The study included 63 infants with neonatal cholestasis in 2 groups: BA group (n = 32) and non-BA group (n = 31) with non-BA cholestatic disorders as controls. Demographic, clinical, laboratory, ultrasonographic, and histopathological parameters were collected. P-selectin immunostaining was performed. Immunostaining in bile duct epithelium, cellular infiltrate, and vascular endothelial cells were scored as positive or negative. RESULTS: The frequency of P-selectin-positive endothelium, platelets, and bile duct epithelium was significantly higher in the BA group (72%, 72%, and 63%, respectively) than in the non-BA group (32%, 16%, and 13%, respectively) with P of 0.002, <0.0001, and <0.0001, respectively. Few mononuclear cellular infiltrates in portal tract expressed P-selectin and were comparable in both groups (P = 0.932). Of interest, the platelet count was significantly higher in the BA group (532 +/- 172) than in the non-BA group (406 +/- 158), and 68.8% of the BA group had thrombocytosis versus 25% in the controls (P = 0.001 for both). CONCLUSIONS: The significant expression of P-selectin in endothelium, platelets, and bile duct epithelium in patients with BA suggests a potential role for this adhesion molecule in the pathogenesis of this devastating neonatal hepatic disorder. It further suggests that platelets in BA are activated and may have a role in the inflammatory process in BA. PMID- 26102173 TI - Feasibility of Pump Speed Modulation for Restoring Vascular Pulsatility with Rotary Blood Pumps. AB - Continuous flow (CF) left ventricular assist devices (LVAD) diminish vascular pressure pulsatility, which may be associated with clinically reported adverse events including gastrointestinal bleeding, aortic valve insufficiency, and hemorrhagic stroke. Three candidate CF LVAD pump speed modulation algorithms designed to augment aortic pulsatility were evaluated in mock flow loop and ischemic heart failure (IHF) bovine models by quantifying hemodynamic performance as a function of mean pump speed, modulation amplitude, and timing. Asynchronous and synchronous copulsation (high revolutions per minute [RPM] during systole, low RPM during diastole) and counterpulsation (low RPM during systole, high RPM during diastole) algorithms were tested for defined modulation amplitudes (+/ 300, +/-500, +/-800, and +/-1,100 RPM) and frequencies (18.75, 37.5, and 60 cycles/minute) at low (2,900 RPM) and high (3,200 RPM) mean LVAD speeds. In the mock flow loop model, asynchronous, synchronous copulsation, and synchronous counterpulsation algorithms each increased pulse pressure (DeltaP = 931%, 210%, and 98% and reduced left ventricular external work (LVEW = 20%, 22%, 16%). Similar improvements in vascular pulsatility (1,142%) and LVEW (40%) were observed in the IHF bovine model. Asynchronous modulation produces the largest vascular pulsatility with the advantage of not requiring sensor(s) for timing pump speed modulation, facilitating potential clinical implementation. PMID- 26102174 TI - Examining Noncardiac Surgical Procedures in Patients on Extracorporeal Membrane Oxygenation. AB - As extracorporeal membrane oxygenation (ECMO) is increasingly used for patients with cardiac and/or pulmonary failure, the need for noncardiac surgical procedures (NCSPs) in these patients will continue to increase. This study examined the NCSP required in patients supported with ECMO and determined which variables affect outcomes. The National Inpatient Sample Database was examined for patients supported with ECMO from 2007 to 2010. There were 563 patients requiring ECMO during the study period. Of these, 269 (47.8%) required 380 NCSPs. There were 149 (39.2%) general surgical procedures, with abdominal exploration/bowel resection (18.2%) being most common. Vascular (29.5%) and thoracic procedures (23.4%) were also common. Patients requiring NCSP had longer median length of stay (15.5 vs. 9.2 days, p = 0.001), more wound infections (7.4% vs. 3.7%, p = 0.02), and more bleeding complications (27.9% vs. 17.3%, p = 0.01). The incidences of other complications and inpatient mortality (54.3% vs. 58.2%, p = 0.54) were similar. On logistic regression, the requirement of NCSPs was not associated with mortality (odds ratio [OR]: 0.91, 95% confidence interval [CI]: 0.68-1.23, p = 0.17). However, requirement of blood transfusion was associated with mortality (OR: 1.70, 95% CI: 1.06-2.74, p = 0.03). Although NCSPs in patients supported with ECMO does not increase mortality, it results in increased morbidity and longer hospital stay. PMID- 26102175 TI - Ultraviolet Radiation Affects Thoratec HeartMate II Driveline Mechanical Properties: A Pilot Experiment. AB - Longevity and quality of life for left ventricular assist device (LVAD) patients are plagued by driveline exit site infections. Ultraviolet (UV) radiation, a current treatment in wound healing clinics, could potentially treat LVAD exit site infections. However, the effect of UV radiation on the tensile properties of HeartMate II (HMII) driveline material is unknown. The sleeve of a single HMII driveline was distributed into six exposure groups (n = 10/group). The six groups were further divided into two treatment cohorts designed to replicate wound treatment schedules of postimplant LVAD patients. Strip biaxial tensile tests were performed on both unexposed and exposed samples to analyze changes in material elasticity (Young's modulus), point of deformation (yield strength), and breaking point. Our data suggest that UV exposure changes the elasticity of the HMII driveline. However, the material endured aberrantly large forces and the properties remained within the safety threshold of device performance. This study warrants further examination of the effect of UV light on driveline material, to determine safety, reliability, and efficacy of UV treatment on exit site infections. PMID- 26102176 TI - Safety of Prothombin Complex Concentrate to Control Excess Bleeding During Continuous Flow LVAD Insertion. AB - In cardiovascular surgery, hemostatic complexities require the provision of blood products to control bleeding as well as the use of a number of hemostatic agents, some of which cause significant morbidity. Among these agents is prothrombin complex concentrates (PCC), however there is no clear consensus on PCC use in cardiovascular surgery. To investigate the safety of PCC in patients undergoing left ventricular assist device (LVAD) placement, we reviewed our single institution experience to examine the incidence of thromboembolic events and a variety of hospital markers including morbidity and mortality. A retrospective review was conducted of patients who underwent LVAD placement between January 2010 and October 2012. Patients who received intraoperative PCC constituted the PCC group (n = 41) and those who did not constituted the non-PCC group (n = 27). The overall incidence of thromboembolic events at 3 months postoperative was 12 (29.3%) in the PCC group compared with six (22.2%) in the non-PCC group, respectively (p > 0.05). Morbidity did not differ between groups and one patient in the PCC group died. The intraoperative use of PCC in LVAD insertion does not appear to be associated with a significant increase in thromboembolic events; however, larger randomized trials are needed to confirm these findings. PMID- 26102177 TI - Sensorless Suction Recognition in the Self-Regulating Cleveland Clinic Continuous Flow Total Artificial Heart. AB - The Cleveland Clinic continuous-flow total artificial heart passively regulates itself in regard to the relative performance of systemic and pulmonary pumps. The system incorporates real-time monitoring to detect any indication of incipient left or right suction as input for automatic controller response. To recognize suction, the external controller compares the waveforms of modulating speed input and power feedback. Deviations in periodic waveforms indicate sudden changes to flow impedance, which are characteristic of suction events as the pump speed is modulating. Incipient suction is indicated within 3 seconds of being detected in the power wave form, allowing timely controller response before mean flow is affected. This article describes the results obtained from subjecting the system to severe hemodynamic manipulation during an acute study in a calf. PMID- 26102179 TI - Comparative pharmacokinetics of arctigenin in normal and type 2 diabetic rats after oral and intravenous administration. AB - Arctigenin is the main active ingredient of Fructus Arctii for the treatment of type 2 diabetes. In this study, the pharmacokinetics of arctigenin in normal and type 2 diabetic rats following oral and intravenous administration was investigated. As compared to normal rats, Cmax and AUC(0-10h) values of oral arctigenin in diabetic rats increased by 356.8% and 223.4%, respectively. In contrast, after intravenous injection, the Cmax and AUC(0-10h) values of arctigenin showed no significant difference between diabetic and normal rats. In order to explore how the bioavailability of oral arctigenin increased under diabetic condition, the absorption behavior of arctigenin was evaluated by in situ single-pass intestinal perfusion (SPIP). The results indicated that arctigenin was a substrate of P-glycoprotein (P-gp). The absorption difference of arctigenin in the normal and diabetic rats could be eliminated by the pretreatment of classic P-gp inhibitor verapamil, suggesting that P-gp might be the key factor causing the absorption enhancement of arctigenin in diabetic rats. Further studies revealed that the uptake of rhodamine 123 (Rho123) in diabetic rats was significantly higher, indicating that diabetes mellitus might impair P gp function. Consistently, a lower mRNA level of P-gp in the intestine of diabetic rats was found. In conclusion, the absorption of arctigenin after oral administration was promoted in diabetic rats, which might be partially attribute to the decreased expression and impaired function of P-gp in intestines. PMID- 26102178 TI - A Nitric Oxide-Releasing Self-Assembled Peptide Amphiphile Nanomatrix for Improving the Biocompatibility of Microporous Hollow Fibers. AB - Oxygenators are critical components of extracorporeal circuits used frequently in cardiopulmonary bypass and intensive care, but platelet activation and induction of a complex inflammatory response are usually observed with their use. To improve the biocompatibility of oxygenators, we developed a nitric oxide (NO) releasing, self-assembled peptide amphiphile nanomatrix. The nanomatrix formed a homogenous coating over the microporous hollow fibers as demonstrated by scanning electron microscopy. We quantitated platelet adhesion to the artificial fibers by measuring absorbance/area of platelets (Abs/A; nm/m2) using acid phosphatase assay. There was a 17-fold decrease in platelet adhesion to the nanomatrix (Abs/A = 0.125) compared with collagen controls (Abs/A = 2.07; p < 0.05) and a 22-fold decrease compared with uncoated fibers (Abs/A = 2.75; p < 0.05). Importantly, the nanomatrix coating did not impede oxygen transfer in water through coated fiber modules (p > 0.05) in a benchtop test circuit at different flow rates as estimated by change in partial pressure of oxygen in relation to water velocity through fibers. These findings demonstrate the feasibility of coating microporous hollow fibers with a NO-releasing self-assembled amphiphile nanomatrix that may improve the biocompatibility of the hollow fibers without affecting their gas exchange capacity. PMID- 26102180 TI - Fungal plasma membrane H+-ATPase inhibitory activity of o-hydroxybenzylated flavanones and chalcones from Uvaria chamae P. Beauv. AB - In our ongoing efforts of finding natural fungicides to fight food and feed spoilage during production and storage, the antifungal potential of Ghanaian Uvaria chamae P. Beauv. was investigated, with emphasis on plant metabolites targeting the fungal plasma membrane (PM) H(+)-ATPase. Ethyl acetate extract of U. chamae was subjected to high-resolution fungal PM H(+)-ATPase inhibition screening followed by structural elucidation by high-performance liquid chromatography-high-resolution mass spectrometry-solid-phase extraction-nuclear magnetic resonance spectroscopy (HPLC-HRMS-SPE-NMR). This led to identification of a series of uncommon o-hydroxybenzylated flavanones and chalcones, i.e., chamanetin (8), isochamanetin (9), isouvaretin (10), uvaretin (11), dichamanetin (12), and diuvaretin (15). Preparative-scale isolation of the active metabolites allowed determination of IC50 values for inhibition of the PM H(+)-ATPase, and growth inhibition of Saccharomyces cerevisiae and Candida albicans. These revealed a strong correlation between o-hydroxybenzyl substituents and PM H(+) ATPase activity, with dichamanetin being the most potent compound, but showing moderate activity in the fungal growth inhibition assays. PMID- 26102181 TI - Incidence and Predictors of Lower Limb Split-Skin Graft Failure and Primary Closure Dehiscence in Day-Case Surgical Patients. AB - BACKGROUND: After general surgery, the lower limb experiences some of the highest complication rates. However, little is known about contributing factors to surgical site failure in the lower limb dermatological surgery population. OBJECTIVE: To determine the incidence of lower limb surgical site failure and to explore the predictors that contribute to surgical site failure. METHODS: A prospective observational study design was used to collect data from 73 participants, from July 2010, to March 2012. Incidence was determined as a percentage of surgical site failure from the total population. Predictors were determined by the use of a binary logistic regression model. RESULTS: The surgical site failure rate was 53.4%. Split-skin grafting had a higher failure rate than primary closures, 66% versus 26.1%. Predictors of lower limb surgical site failure were identified as increasing age (p = .04) and the presence of postoperative hematoma (p = .01), with all patients who developed surgical site infection experiencing surgical site failure (p = .01). CONCLUSION: Findings from this study confirmed that the lower limb is at high risk of surgical site failure. Two predictors of surgical site failure from this cohort were determined. However, to understand this phenomenon and make recommendations to assist and reduce surgical site complications, further research in this field is required. PMID- 26102182 TI - Repair of Lower Face Defects. PMID- 26102183 TI - In Vivo Reflectance Confocal Microscopy Combined With the "Spaghetti" Technique: A New Procedure for Defining Surgical Margins of Genital Paget Disease. PMID- 26102184 TI - Relay of cyclin-dependent kinases in the regulation of axonal growth. AB - One of the most perplexing problems in neuronal morphogenesis is how local polarity signals echo genetic instructions to establish structural and functional asymmetry of neuronal compartments, i.e., axons, dendrites, and synapses. However studying these phenomena is complicated because both genes and the local environment influence the phenotype of developing neurons. Cell cycle-associated nuclear transcription regulators involved in axon extension, for example Cdk12 and Cdk13, thus provide ideal models for connecting spatially separated events at specific developmental time points. PMID- 26102185 TI - Sex and the money--How gender stereotypes modulate economic decision-making: An ERP study. AB - In the present event-related potential study, we investigated whether and how participants playing the ultimatum game as responders modulate their decisions according to the proposers' stereotypical identity. The proposers' identity was manipulated using occupational role nouns stereotypically marked with gender (e.g., Teacher; Engineer), paired with either feminine or masculine proper names (e.g., Anna; David). Greater FRN amplitudes reflected the early processing of the conflict between the strategic rule (i.e., earning as much money as possible) and ready-to-go responses (i.e., refusing unequal offers and discriminating proposers according to their stereotype). Responders were found to rely on a dual-process system (i.e., automatic and heuristic-based system 1 vs. cognitively costly and deliberative system 2), the P300 amplitude reflecting the switch from a decision making system to another. Greater P300 amplitudes were found in response to both fair and unfair offers and male-stereotyped proposers' offers reflecting an automatic decision making based on heuristics, while lower P300 amplitudes were found in response to 3? offers and the female-stereotyped proposers' offers reflecting a more deliberative reasoning. Overall, the results indicate that participants were more motivated to engage in a costly deliberative reasoning associated with an increase in acceptation rate when playing with female stereotyped proposers, who may have induced more positive and emphatic feelings in the participants than did male-stereotyped proposers. Then, we assume that people with an occupation stereotypically marked with female gender and engaged in an economic negotiation may benefit from their occupation at least in the case their counterparts lose their money if the negotiation fails. PMID- 26102186 TI - Roaring lions and chirruping lemurs: How the brain encodes sound objects in space. AB - The dual-stream model of auditory processing postulates separate processing streams for sound meaning and for sound location. The present review draws on evidence from human behavioral and activation studies as well as from lesion studies to argue for a position-linked representation of sound objects that is distinct both from the position-independent representation within the ventral/What stream and from the explicit sound localization processing within the dorsal/Where stream. PMID- 26102187 TI - Single trial beta oscillations index time estimation. AB - Recent work shows that putamen-originating beta power oscillations serve as a carrier for temporal information during tapping tasks, with higher beta power associated with longer temporal reproductions. However, given the nature of tapping tasks, it is difficult to determine whether beta power dynamics observed in these tasks are linked to the generation or execution of motor programs or to the internal representation of time. To assess whether recent findings in animals generalize to human studies we reanalyzed existing EEG data of participants who estimated a 2.5s time interval with self-paced onset and offset keypresses. The results showed that the trial-to-trial beta power measured after the onset predicts the produced duration, such that higher beta power indexes longer produced durations. Moreover, although beta power measured before the first key press also influenced the estimated interval, it did so independently from post first-keypress beta power. These results suggest that initial motor inhibition plays an important role in interval production, and that this inhibition can be interpreted as a biased starting point of the decision processes involved in time estimation. PMID- 26102188 TI - The contribution of neurodegenerative diseases to the modelling of semantic memory: A new proposal and a review of the literature. AB - This paper provides a focused review of the literature on semantic impairment in semantic dementia (SD) and Alzheimer's disease (AD). An attempt is made to interpret the most relevant phenomena in the light of a new model of semantic memory. This model comprises a language-based component (disrupted in SD and AD), which supports our ability to establish reliable token vs. type relationships in the service of propositional thinking, and a philogenetically older sensorimotor component, which is needed to categorize our environment in a more implicit way. Extant neuropsychological models of semantic memory are also reviewed and compared with the new model in terms of their ability to explain the observed phenomena and to deal with the problem of establishing token vs. type relationships starting from inconsistent cross modal input representations and arbitrary category boundaries. PMID- 26102189 TI - Longitudinal cognitive decline in the AIBL cohort: The role of APOE epsilon4 status. AB - The epsilon4 polymorphism of the APOE gene confers a substantially increased risk of developing Alzheimer's disease. However, the influence of the epsilon4 allele on age-related cognitive functioning is more contentious. Previously, we demonstrated relatively little evidence for a role of the epsilon4 allele on baseline cognitive performance in older adults in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing (Foster et al., 2013). We here investigated whether the APOE epsilon4 allele influenced cognitive status over time when the AIBL cohort was studied longitudinally over a 3-year period. The AIBL neuropsychological test battery was administered at baseline, after 18 months and again after 36 months. Participants comprised 764 Healthy Controls and 131 Mild Cognitively Impaired individuals enrolled in the AIBL Study of Ageing. We compared individuals within each group with and without an epsilon4 allele. Healthy Controls with an epsilon4 allele manifested a modest acceleration in cognitive decline over 36 months on measures of verbal episodic memory. By contrast, Mild Cognitively Impaired individuals with an epsilon4 allele showed increased cognitive decline across a range of cognitive tasks, putatively reflecting early cognitive signs of Alzheimer's disease. Given the long prodromal period that has been noted in late onset Alzheimer's disease, we suggest that these findings are consistent with a prodromal account rather than a phenotypic account of epsilon4-related cognitive ageing. PMID- 26102191 TI - The role of tactile afference in shaping motor behaviour and implications for prosthetic innovation. AB - The present review focusses on how tactile somatosensory afference is encoded and processed, and how this information is interpreted and acted upon in terms of motor control. We relate the fundamental workings of the sensorimotor system to the rehabilitation of amputees using modern prosthetic interventions. Our sense of touch is central to our everyday lives, from allowing us to manipulate objects accurately to giving us a sense of self-embodiment. There are a variety of specialised cutaneous mechanoreceptive afferents, which differ in terms of type and density according to the skin site. In humans, there is a dense innervation of our hands, which is reflected in their vast over-representation in somatosensory and motor cortical areas. We review the accumulated evidence from animal and human studies about the precise interplay between the somatosensory and motor systems, which is highly integrated in many brain areas and often not separable. The glabrous hand skin provides exquisite, discriminative detail about touch, which is useful for refining movements. When these signals are disrupted, such as through injury or amputation, the consequences are considerable. The development of sensory feedback in prosthetics offers a promising avenue for the full integration of a missing body part. Real-time touch feedback from motor intentions aids in grip control and the ability to distinguish different surfaces, even introducing the possibility of pleasure in artificial touch. Thus, our knowledge from fundamental research into sensorimotor interactions should be used to develop more realistic and integrative prostheses. PMID- 26102190 TI - The effect of age on cognitive performance of frontal patients. AB - Age is known to affect prefrontal brain structure and executive functioning in healthy older adults, patients with neurodegenerative conditions and TBI. Yet, no studies appear to have systematically investigated the effect of age on cognitive performance in patients with focal lesions. We investigated the effect of age on the cognitive performance of a large sample of tumour and stroke patients with focal unilateral, frontal (n=68), or non-frontal lesions (n=45) and healthy controls (n=52). We retrospectively reviewed their cross sectional cognitive and imaging data. In our frontal patients, age significantly predicted the magnitude of their impairment on two executive tests (Raven's Advanced Progressive Matrices, RAPM and the Stroop test) but not on nominal (Graded Naming Test, GNT) or perceptual (Incomplete Letters) task. In our non-frontal patients, age did not predict the magnitude of their impairment on the RAPM and GNT. Furthermore, the exacerbated executive impairment observed in our frontal patients manifested itself from middle age. We found that only age consistently predicted the exacerbated executive impairment. Lesions to specific frontal areas, or an increase in global brain atrophy or white matter abnormalities were not associated with this impairment. Our results are in line with the notion that the frontal cortex plays a critical role in aging to counteract cognitive and neuronal decline. We suggest that the combined effect of aging and frontal lesions impairs the frontal cortical systems by causing its computational power to fall below the threshold needed to complete executive tasks successfully. PMID- 26102192 TI - Electrophysiological assessment of the time course of bilingual visual word recognition: Early access to language membership. AB - Previous research examining the time course of lexical access during word recognition suggests that phonological processing precedes access to semantic information, which in turn precedes access to syntactic information. Bilingual word recognition likely requires an additional level: knowledge of which language a specific word belongs to. Using the recording of event-related potentials, we investigated the time course of access to language membership information relative to semantic (Experiment 1) and syntactic (Experiment 2) encoding during visual word recognition. In Experiment 1, Spanish-English bilinguals viewed a series of printed words while making dual-choice go/nogo and left/right hand decisions based on semantic (whether the word referred to an animal or an object) and language membership information (whether the word was in English or in Spanish). Experiment 2 used a similar paradigm but with syntactic information (whether the word was a noun or a verb) as one of the response contingencies. The onset and peak latency of the N200, a component related to response inhibition, indicated that language information is accessed earlier than semantic information. Similarly, language information was also accessed earlier than syntactic information (but only based on peak latency). We discuss these findings with respect to models of bilingual word recognition and language comprehension in general. PMID- 26102193 TI - Electron confinement at the LaAlO3/SrTiO3 interface. AB - Physical and structural phenomena originating from polar discontinuities have generated enormous activity. In the last ten years, the oxide interface between polar LaAlO(3) and non-polar SrTiO(3), both band insulators, has attracted particular interest, as it hosts an electron liquid with remarkable properties: it superconducts, has a sizeable spin-orbit interaction and its properties are tunable by an electric field. The profile of the carrier density at the interface and the exact band structure are properties strongly linked and still objects of debate. Here we review the experimental findings on the origin and the extension of the electron liquid and discuss the theoretical models developed to describe the charge profile and the band structure. We also introduce a model to account for the effect of interface disorder which could modify the charge distribution. PMID- 26102194 TI - Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRalpha signaling in THP-1 macrophage-derived foam cells. AB - Curcumin, a traditional Chinese derivative from the rhizomes of Curcuma longa, is beneficial to health by modulating lipid metabolism and suppressing atherogenesis. A key part of atherosclerosis is the failure of macrophages to restore their cellular cholesterol homeostasis and the formation of foam cells. In this study, results showed that curcumin dramatically increased the expression of ATP-binding cassette transporter 1 (ABCA1), promoted cholesterol efflux from THP-1 macrophage-derived foam cells, and reduced cellular cholesterol levels. Curcumin activated AMP-activated protein kinase (AMPK) and SIRT1, and then activated LXRalpha in THP-1 macrophage-derived foam cells. Inhibiting AMPK/SIRT1 activity by its specific inhibitor or by small interfering RNA could inhibit LXRalpha activation and abolish curcumin-induced ABCA1 expression and cholesterol efflux. Thus, curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through activating AMPK-SIRT1-LXRalpha signaling in THP-1 macrophage derived foam cells. This study describes a possible mechanism for understanding the antiatherogenic effects of curcumin on attenuating the progression of atherosclerosis. PMID- 26102196 TI - Medical day hospital care for older people versus alternative forms of care. AB - BACKGROUND: The proportion of the world's population aged over 60 years is increasing. Therefore, there is a need to examine different methods of healthcare provision for this population. Medical day hospitals provide multidisciplinary health services to older people in one location. OBJECTIVES: To examine the effectiveness of medical day hospitals for older people in preventing death, disability, institutionalisation and improving subjective health status. SEARCH METHODS: Our search included the Cochrane Effective Practice and Organisation of Care (EPOC) Group Register of Studies, CENTRAL (2013, Issue 7), MEDLINE via Ovid (1950-2013 ), EMBASE via Ovid (1947-2013) and CINAHL via EbscoHost (1980-2013). We also conducted cited reference searches, searched conference proceedings and trial registries, hand searched select journals, and contacted relevant authors and researchers to inquire about additional data. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing medical day hospitals with alternative care for older people (mean/median > 60 years of age). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and risk of bias and extracted data from included trials. We used standard methodological procedures expected by the Cochrane Collaboration. Trials were sub-categorised as comprehensive care, domiciliary care or no comprehensive care. MAIN RESULTS: Sixteen trials (3689 participants) compared day hospitals with comprehensive care (five trials), domiciliary care (seven trials) or no comprehensive care (four trials). Overall there was low quality evidence from these trials for the following results.For the outcome of death, there was no strong evidence for or against day hospitals compared to other treatments overall (odds ratio (OR) 1.05; 95% CI 0.85 to 1.28; P = 0.66), or to comprehensive care (OR 1.26; 95% CI 0.87 to 1.82; P = 0.22), domiciliary care (OR 0.97; 95% CI 0.61 to 1.55; P = 0.89), or no comprehensive care (OR 0.88; 95% CI 0.63 to 1.22; P = 0.43).For the outcome of death or deterioration in activities of daily living (ADL), there was no strong evidence for day hospital attendance compared to other treatments (OR 1.07; 95% CI 0.76 to 1.49; P = 0.70), or to comprehensive care (OR 1.18; 95% CI 0.63 to 2.18; P = 0.61), domiciliary care (OR 1.41; 95% CI 0.82 to 2.42; P = 0.21) or no comprehensive care (OR 0.76; 95% CI 0.56 to 1.05; P = 0.09).For the outcome of death or poor outcome (institutional care, dependency, deterioration in physical function), there was no strong evidence for day hospitals compared to other treatments (OR 0.92; 95% CI 0.74 to 1.15; P = 0.49), or compared to comprehensive care (OR 1.05; 95% CI 0.79 to 1.40; P = 0.74) or domiciliary care (OR 1.08; 95% CI 0.67 to 1.74; P = 0.75). However, compared with no comprehensive care there was a difference in favour of day hospitals (OR 0.72; 95% CI 0.53 to 0.99; P = 0.04).For the outcome of death or institutional care, there was no strong evidence for day hospitals compared to other treatments overall (OR 0.85; 95% CI 0.63 to 1.14; P = 0.28), or to comprehensive care (OR 1.00; 95% CI 0.69 to 1.44; P = 0.99), domiciliary care (OR 1.05; 95% CI 0.57 to1.92; P = 0. 88) or no comprehensive care (OR 0.63; 95% CI 0.40 to 1.00; P = 0.05).For the outcome of deterioration in ADL, there was no strong evidence that day hospital attendance had a different effect than other treatments overall (OR 1.11; 95% CI 0.68 to 1.80; P = 0.67) or compared with comprehensive care (OR 1.21; 0.58 to 2.52; P = 0.61), or domiciliary care (OR 1.59; 95% CI 0.87 to 2.90; P = 0.13). However, day hospital patients showed a reduced odds of deterioration compared with those receiving no comprehensive care (OR 0.61; 95% CI 0.38 to 0.97; P = 0.04) and significant subgroup differences (P = 0.04).For the outcome of requiring institutional care, there was no strong evidence for day hospitals compared to other treatments (OR 0.84; 95% CI 0.58 to 1.21; P = 0.35), or to comprehensive care (OR 0.91; 95% CI 0.70 to 1.19; P = 0.49), domiciliary care (OR 1.49; 95% CI 0.53 to 4.25; P = 0.45), or no comprehensive care (OR 0.58; 95% CI 0.28 to 1.20; P = 0.14). AUTHORS' CONCLUSIONS: There is low quality evidence that medical day hospitals appear effective compared to no comprehensive care for the combined outcome of death or poor outcome, and for deterioration in ADL. There is no clear evidence for other outcomes, or an advantage over other medical care provision. PMID- 26102195 TI - The translational regulator Cup controls NMJ presynaptic terminal morphology. AB - During oogenesis and early embryonic development in Drosophila, translation of proteins from maternally deposited mRNAs is tightly controlled. We and others have previously shown that translational regulatory proteins that function during oogenesis also have essential roles in the nervous system. Here we examine the role of Cup in neuromuscular system development. Maternal Cup controls translation of localized mRNAs encoding the Oskar and Nanos proteins and binds to the general translation initiation factor eIF4E. In this paper, we show that zygotic Cup protein is localized to presynaptic terminals at larval neuromuscular junctions (NMJs). cup mutant NMJs have strong phenotypes characterized by the presence of small clustered boutons called satellite boutons. They also exhibit an increase in the frequency of spontaneous glutamate release events (mEPSPs). Reduction of eIF4E expression synergizes with partial loss of Cup expression to produce satellite bouton phenotypes. The presence of satellite boutons is often associated with increases in retrograde bone morphogenetic protein (BMP) signaling, and we show that synaptic BMP signaling is elevated in cup mutants. cup genetically interacts with two genes, EndoA and Dap160, that encode proteins involved in endocytosis that are also neuronal modulators of the BMP pathway. Endophilin protein, encoded by the EndoA gene, is downregulated in a cup mutant. Our results are consistent with a model in which Cup and eIF4E work together to ensure efficient localization and translation of endocytosis proteins in motor neurons and control the strength of the retrograde BMP signal. PMID- 26102197 TI - Predictors for Mild and Severe Hypoglycemia in Insulin-Treated Japanese Diabetic Patients. AB - The objective of this study was to explore predictors, including social factors, lifestyle factors, and factors relevant to glycemic control and treatment, for mild and severe hypoglycemia in insulin-treated Japanese diabetic patients. This study included 123 insulin-treated diabetic patients who were referred to the diabetes clinic between January and July 2013 at Shiga University of Medical Science Hospital. After a survey examining the various factors, patients were followed for 6 months. During the follow-up period, blood glucose was self monitored. Mild hypoglycemia was defined as blood glucose level 50-69 mg/dl, and severe hypoglycemia was defined as blood glucose level <=49 mg/dl. Multinomial logistic regression was used to estimate the adjusted odds ratio (OR) and 95% confidence interval (CI) of each factor for mild and severe hypoglycemia. During the 6-month follow-up period, 41 (33.3%) patients experienced mild hypoglycemia, and 20 (16.3%) experienced severe hypoglycemia. In multivariable-adjusted analyses, assistance from family members at the time of the insulin injection [presence/absence, OR (95% CI): 0.39 (0.16-0.97)] and drinking [current drinker/non- and ex-drinker, OR (95% CI): 4.89 (1.68-14.25)] affected mild hypoglycemia. Assistance from family members at the time of insulin injection [presence/absence, OR (95% CI): 0.19 (0.05-0.75)] and intensive insulin therapy [yes/no, OR (95% CI): 3.61 (1.06-12.26)] affected severe hypoglycemia. In conclusion, our findings suggest that not only a factor relevant to glycemic control and treatment (intensive insulin therapy) but also a social factor (assistance from family members) and a lifestyle factor (current drinking) were predictors for mild or severe hypoglycemia in Japanese insulin-treated diabetic patients. PMID- 26102198 TI - Cinnamon and Its Metabolite Sodium Benzoate Attenuate the Activation of p21rac and Protect Memory and Learning in an Animal Model of Alzheimer's Disease. AB - This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in attenuating oxidative stress and protecting memory and learning in an animal model of Alzheimer's disease (AD). NaB, but not sodium formate, was found to inhibit LPS induced production of reactive oxygen species (ROS) in mouse microglial cells. Similarly, NaB also inhibited fibrillar amyloid beta (Abeta)- and 1-methyl-4 phenylpyridinium(+)-induced microglial production of ROS. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on ROS production by mevalonate, and geranylgeranyl pyrophosphate, but not cholesterol, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the antioxidant effect of NaB. Furthermore, we demonstrate that an inhibitor of p21rac geranylgeranyl protein transferase suppressed the production of ROS and that NaB suppressed the activation of p21rac in microglia. As expected, marked activation of p21rac was observed in the hippocampus of subjects with AD and 5XFAD transgenic (Tg) mouse model of AD. However, oral feeding of cinnamon (Cinnamonum verum) powder and NaB suppressed the activation of p21rac and attenuated oxidative stress in the hippocampus of Tg mice as evident by decreased dihydroethidium (DHE) and nitrotyrosine staining, reduced homocysteine level and increased level of reduced glutathione. This was accompanied by suppression of neuronal apoptosis, inhibition of glial activation, and reduction of Abeta burden in the hippocampus and protection of memory and learning in transgenic mice. Therefore, cinnamon powder may be a promising natural supplement in halting or delaying the progression of AD. PMID- 26102200 TI - Temperature and Concentration Stratification Effects in Mixed Convection Flow of an Oldroyd-B Fluid with Thermal Radiation and Chemical Reaction. AB - This research addresses the mixed convection flow of an Oldroyd-B fluid in a doubly stratified surface. Both temperature and concentration stratification effects are considered. Thermal radiation and chemical reaction effects are accounted. The governing nonlinear boundary layer equations are converted to coupled nonlinear ordinary differential equations using appropriate transformations. Resulting nonlinear systems are solved for the convergent series solutions. Graphs are plotted to examine the impacts of physical parameters on the non-dimensional temperature and concentration distributions. The local Nusselt number and the local Sherwood number are computed and analyzed numerically. PMID- 26102199 TI - Metabolic Consequences of Chronic Alcohol Abuse in Non-Smokers: A Pilot Study. AB - An alcohol use disorder (AUD) is associated with an increased susceptibility to respiratory infection and injury and, upon hospitalization, higher mortality rates. Studies in model systems show effects of alcohol on mitochondrial function, lipid metabolism and antioxidant systems. The present study applied high-resolution metabolomics to test for these changes in bronchoalveolar lavage fluid (BALF) of subjects with an AUD. Smokers were excluded to avoid confounding effects and compliance was verified by cotinine measurements. Statistically significant metabolic features, differentially expressed by control and AUD subjects, were identified by statistical and bioinformatic methods. The results show that fatty acid and acylcarnitine concentrations were increased in AUD subjects, consistent with perturbed mitochondrial and lipid metabolism. Decreased concentrations of methyl-donor compounds suggest altered one-carbon metabolism and oxidative stress. An accumulation of peptides suggests proteolytic activity, which could reflect altered epithelial barrier function. Two metabolites of possible microbial origin suggest subclinical bacterial infection. Furthermore, increased diacetylspermine suggests additional metabolic perturbations, which could contribute to dysregulated alveolar macrophage function and vulnerability to infection. Together, the results show an extended metabolic consequence of AUD in the bronchoalveolar space. PMID- 26102201 TI - Adaptive Role of Inversion Polymorphism of Drosophila subobscura in Lead Stressed Environment. AB - Local adaptation to environmental stress at different levels of genetic polymorphism in various plants and animals has been documented through evolution of heavy metal tolerance. We used samples of Drosophila subobscura populations from two differently polluted environments to analyze the change of chromosomal inversion polymorphism as genetic marker during laboratory exposure to lead. Exposure to environmental contamination can affect the genetic content within a particular inversion and produce targets for selection in populations from different environments. The aims were to discover whether the inversion polymorphism is shaped by the local natural environments, and if lead as a selection pressure would cause adaptive divergence of two populations during the multigenerational laboratory experiment. The results showed that populations retain signatures from past contamination events, and that heavy metal pollution can cause adaptive changes in population. Differences in inversion polymorphism between the two populations increased over generations under lead contamination in the laboratory. The inversion polymorphism of population originating from the more polluted natural environment was more stable during the experiment, both under conditions with and without lead. Therefore, results showed that inversion polymorphism as a genetic marker reflects a strong signature of adaptation to the local environment, and that historical demographic events and selection are important for both prediction of evolutionary potential and long-term viability of natural populations. PMID- 26102203 TI - Ionic liquid- and surfactant-controlled crystallization of WO3 films. AB - WO3 films were obtained via evaporation-induced self-assembly (EISA) using ionic surfactants such as long-chain ionic liquids 1-hexadecyl-3-methyl imidazolium chloride and bromide (C16mimCl and C16mimBr, respectively) and cetyltrimethylammonium chloride and bromide (CTAC and CTAB, respectively) as additives. Owing to the presence of the ionic surfactants, WO3 films crystallize in a preferred orientation along the a-axis on different substrates, as evidenced by X-ray diffraction. WO3 films with this orientation show improved electrochromic properties when compared to films with a lower degree of crystallographic orientation, prepared in an analogue fashion. PMID- 26102202 TI - What Shapes the Phylogenetic Structure of Anuran Communities in a Seasonal Environment? The Influence of Determinism at Regional Scale to Stochasticity or Antagonistic Forces at Local Scale. AB - Ecological communities are structured by both deterministic and stochastic processes. We investigated phylogenetic patterns at regional and local scales to understand the influences of seasonal processes in shaping the structure of anuran communities in the southern Pantanal wetland, Brazil. We assessed the phylogenetic structure at different scales, using the Net Relatedness Index (NRI), the Nearest Taxon Index (NTI), and phylobetadiversity indexes, as well as a permutation test, to evaluate the effect of seasonality. The anuran community was represented by a non-random set of species with a high degree of phylogenetic relatedness at the regional scale. However, at the local scale the phylogenetic structure of the community was weakly related with the seasonality of the system, indicating that oriented stochastic processes (e.g. colonization, extinction and ecological drift) and/or antagonist forces drive the structure of such communities in the southern Pantanal. PMID- 26102205 TI - Another day, another tennis coaching intervention, but does this one do what coaches purport? AB - A proficient serve is critical to successful tennis performance, and consequently coaches and players devote considerable time refining this stroke. In so doing, a wide variety of interventions are used or trialled, generally with very little empirical support. This study examined the efficacy of a commonly used service intervention, where players focus on exaggerating their finish (arabesque) position to promote specific changes in lower limb and trunk kinematics. The kinematics of eight high-performance junior players hitting flat serves were compared to the acute changes in kinematics elicited by the arabesque follow through position on serves using a 10-camera VICON MX motion analysis system. The significantly greater front (landing leg) hip flexion (p < 0.05) and forward trunk flexion (p < 0.05) confirmed the more exaggerated arabesque landing position following the arabesque instruction. The arabesque instruction resulted in increased frontal plane trunk range of motion and peak angular velocity in the forward swing, and increased leg drive during the drive phase. Practically, the results support the use of the arabesque instruction, effectively promoting the desired acute changes in trunk kinematics (i.e. increased frontal plane trunk rotation angular velocity) and leg drive (i.e. increased back knee extension angular velocity and front/back vertical hip velocity). PMID- 26102204 TI - Exploring Metrics to Express Energy Expenditure of Physical Activity in Youth. AB - BACKGROUND: Several approaches have been used to express energy expenditure in youth, but no consensus exists as to which best normalizes data for the wide range of ages and body sizes across a range of physical activities. This study examined several common metrics for expressing energy expenditure to determine whether one metric can be used for all healthy children. Such a metric could improve our ability to further advance the Compendium of Physical Activities for Youth. METHODS: A secondary analysis of oxygen uptake (VO2) data obtained from five sites was completed, that included 947 children ages 5 to 18 years, who engaged in 14 different activities. Resting metabolic rate (RMR) was computed based on Schofield Equations [Hum Nutr Clin Nut. 39(Suppl 1), 1985]. Absolute oxygen uptake (ml.min-1), oxygen uptake per kilogram body mass (VO2 in ml.kg 1.min-1), net oxygen uptake (VO2 - resting metabolic rate), allometric scaled oxygen uptake (VO2 in ml.kg-0.75.min-1) and YOUTH-MET (VO2.[resting VO2] -1) were calculated. These metrics were regressed with age, sex, height, and body mass. RESULTS: Net and allometric-scaled VO2, and YOUTH-MET were least associated with age, sex and physical characteristics. For moderate-to-vigorous intensity activities, allometric scaling was least related to age and sex. For sedentary and low-intensity activities, YOUTH-MET was least related to age and sex. CONCLUSIONS: No energy expenditure metric completely eliminated the influence of age, physical characteristics, and sex. The Adult MET consistently overestimated EE. YOUTH-MET was better for expressing energy expenditure for sedentary and light activities, whereas allometric scaling was better for moderate and vigorous intensity activities. From a practical perspective, The YOUTH-MET may be the more feasible metric for improving of the Compendium of Physical Activities for Youth. PMID- 26102206 TI - Integration of Metabolic and Quorum Sensing Signals Governing the Decision to Cooperate in a Bacterial Social Trait. AB - Many unicellular organisms live in multicellular communities that rely on cooperation between cells. However, cooperative traits are vulnerable to exploitation by non-cooperators (cheaters). We expand our understanding of the molecular mechanisms that allow multicellular systems to remain robust in the face of cheating by dissecting the dynamic regulation of cooperative rhamnolipids required for swarming in Pseudomonas aeruginosa. We combine mathematical modeling and experiments to quantitatively characterize the integration of metabolic and population density signals (quorum sensing) governing expression of the rhamnolipid synthesis operon rhlAB. The combined computational/experimental analysis reveals that when nutrients are abundant, rhlAB promoter activity increases gradually in a density dependent way. When growth slows down due to nutrient limitation, rhlAB promoter activity can stop abruptly, decrease gradually or even increase depending on whether the growth-limiting nutrient is the carbon source, nitrogen source or iron. Starvation by specific nutrients drives growth on intracellular nutrient pools as well as the qualitative rhlAB promoter response, which itself is modulated by quorum sensing. Our quantitative analysis suggests a supply-driven activation that integrates metabolic prudence with quorum sensing in a non-digital manner and allows P. aeruginosa cells to invest in cooperation only when the population size is large enough (quorum sensing) and individual cells have enough metabolic resources to do so (metabolic prudence). Thus, the quantitative description of rhlAB regulatory dynamics brings a greater understating to the regulation required to make swarming cooperation stable. PMID- 26102207 TI - Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms With Acute Rejection in Liver Transplant Recipients. AB - OBJECTIVES: Polymorphisms of the endothelial nitric oxide synthase gene have been associated with altered endothelial nitric oxide synthase activity. The purpose of this study was to investigate the relation between endothelial nitric oxide synthase -786T/C and 894G/T polymorphism and their haplotypes on the occurrence of acute rejection episodes in liver transplant recipients. MATERIALS AND METHODS: We conducted a case control study in which 100 liver transplant recipients and 100 healthy controls were recruited from Shiraz Transplant Center. The patients used triple therapy including tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression maintenance. DNA was extracted from peripheral blood and endothelial nitric oxide synthase polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: Patients included 60 men and 40 women (mean age, 32.35 +/- 10.2 y). There was a significant association of endothelial nitric oxide synthase 894G/T and acute rejection episode. The GT* gen-otype and acute rejection episodes had a significant association (odds ratio, 2.42; 95% confidence interval, 0.97-6.15; P = .03). The GG and GT* genotype and T* allele frequency were significantly different between patients and control subjects (P = .001). Haplotype TT* was higher in recipients than control subjects (odds ratio, 2.17; 95% confidence interval, 1.12-4.25; P = .01). Haplotype TG was higher in the control group (odds ratio, 0.62; 95% confidence interval, 0.40-0.96; P = .02). CONCLUSIONS: Our results suggest a relation between different endothelial nitric oxide synthase geno-types and risk of acute rejection episodes. However, further study is necessary to determine genetic susceptibility for transplant patients. PMID- 26102208 TI - Long-term safety and outcome of percutaneous transhepatic venous balloon angioplasty for Budd-Chiari syndrome. AB - BACKGROUND AND AIMS: The restenosis following percutaneous transluminal balloon angioplasty (PTBA) is high for Budd-Chiari syndrome (BCS) patients with hepatic venous obstruction (HVO). We aim to evaluate the safety and long-term outcome of PTBA with a large balloon catheter in a large series of patients with HVO. METHODS: Between January 2005 and December 2013, 93 consecutive BCS patients with HVO were referred for PTBA and subsequently underwent color Doppler ultrasonography or angiography follow-up. Data were retrospectively collected, and follow-up observations were performed at 1-, 2-, 2- to 5-, and 5- to 8-years postoperatively. RESULTS: Percutaneous transluminal balloon angioplasty was technically successful in all patients. Ninety-one patients (97.85%) were treated with PTBA and two with PTBA and stent. Major procedure-related complications occurred in six of the 93 patients (6.45%). The cumulative 1-, 2-, 2- to 5-, and 5- to 8-year primary patency rates were 97.5%, 92.9%, 90%, and 86.5%, respectively. Cumulative 1-, 2-, 2- to 5-, and 5- to 8-year secondary patency rates were 100%, 100%, 98.6%, and 97.3%, respectively. Mean and median primary patency rates were 51.50 +/- 3.01 months and 55.0 +/- 3.63 months, respectively. Cumulative 1-, 2-, 2- to 5-, and 5- to 8-year survival rates were 98.75%, 98.6%, 100%, and 100%, respectively. Mean and median survival times were 53.10 +/- 3.04 months and 55.0 +/- 3.64 months, respectively. CONCLUSION: Percutaneous transluminal balloon angioplasty with a large balloon is a safe and effective treatment that could provide excellent rates of long-term patency and survival for the majority of Chinese patients with BCS and HVO. PMID- 26102210 TI - The pancreatic beta-cell in deadly encounter with apolipoprotein CIII. PMID- 26102209 TI - Genetic deficit of KCa 3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation. AB - BACKGROUND AND PURPOSE: The intermediate conductance calcium/calmodulin-regulated K+ channel KCa 3.1 produces hyperpolarizing K+ currents that counteract depolarizing currents carried by transient receptor potential (TRP) channels, and provide the electrochemical driving force for Cl- and fluid movements. We investigated whether a deficiency in KCa 3.1 (KCa 3.1-/- ) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels. EXPERIMENTAL APPROACH: An opener of TRPV4 channels, GSK1016790A, was infused in wild-type (wt) and KCa 3.1-/- mice; haemodynamic parameters, histology and pulmonary vascular reactivity were measured; and patch clamp was performed on pulmonary arterial endothelial cells (PAEC). KEY RESULTS: In wt mice, GSK1016790A decreased right ventricular and systemic pressure leading to a fatal circulatory collapse that was accompanied by increased protein permeability, lung haemorrhage and fluid extravasation. In contrast, KCa 3.1-/- mice exhibited a significantly smaller drop in pressure to GSK1016790A infusion, no haemorrhage and fluid water extravasation, and the mice survived. Moreover, the GSK1016790A-induced relaxation of pulmonary arteries of KCa 3.1-/- mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and KCa 3.1-/ mice, which co-activated KCa 3.1 and disrupted membrane resistance in wt PAEC, but not in KCa 3.1-/- PAEC. CONCLUSIONS AND IMPLICATIONS: Our findings show that a genetic deficiency of KCa 3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium permeable TRPV4 channels. Therefore, inhibition of KCa 3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse. PMID- 26102211 TI - PM2.5 source apportionment with organic markers in the Southeastern Aerosol Research and Characterization (SEARCH) study. AB - Positive matrix factorization (PMF) and effective variance (EV) solutions to the chemical mass balance (CMB) were applied to PM(2.5) (particulate matter with an aerodynamic diameter <2.5 MUm) mass and chemically speciated measurements for samples taken from 2008 to 2010 at the Atlanta, Georgia, and Birmingham, Alabama, sites. Commonly measured PM(2.5) mass, elemental, ionic, and thermal carbon fraction concentrations were supplemented with detailed nonpolar organic speciation by thermal desorption-gas chromatography/mass spectrometry (TD-GC/MS). Source contribution estimates were calculated for motor vehicle exhaust, biomass burning, cooking, coal-fired power plants, road dust, vegetative detritus, and secondary sulfates and nitrates for Atlanta. Similar sources were found for Birmingham, with the addition of an industrial source and the separation of biomass burning into open burning and residential wood combustion. EV-CMB results based on conventional species were qualitatively similar to those estimated by PMF-CMB. Secondary ammonium sulfate was the largest contributor, accounting for 27-38% of PM(2.5), followed by biomass burning (21-24%) and motor vehicle exhaust (9-24%) at both sites, with 4-6% of PM(2.5) attributed to coal-fired power plants by EV-CMB. Including organic compounds in the EV-CMB reduced the motor vehicle exhaust and biomass burning contributions at both sites, with a 13-23% deficit for PM(2.5) mass. The PMF-CMB solution showed mixing of sources within the derived factors, both with and without the addition of speciated organics, as is often the case with complex source mixtures such as those at these urban-scale sites. The nonpolar TD-GC/MS compounds can be obtained from existing filter samples and are a useful complement to the elements, ions, and carbon fractions. However, they should be supplemented with other methods, such as TD-GC/MS on derivitized samples, to obtain a wider range of polar compounds such as sterols, sugars, and organic acids. The PMF and EV solutions to the CMB equations are complementary to, rather than replacements for, each other, as comparisons of their results reveal uncertainties that are not otherwise evident. IMPLICATIONS: Organic markers can be measured on currently acquired PM(2.5) filter samples by thermal methods. These markers can complement element, ion, and carbon fraction measurements from long-term speciation networks. Applying the positive matrix factorization and effective variance solutions for the chemical mass balance equations provides useful information on the accuracy of the source contribution estimates. Nonpolar compounds need to be complemented with polar compounds to better apportion cooking and secondary organic aerosol contributors. PMID- 26102212 TI - Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study. AB - BACKGROUND: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients' refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. MATERIALS AND METHODS: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. RESULTS AND CONCLUSION: MTD was defined as 10.2 mg/m(2), with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m(2) under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy. PMID- 26102215 TI - Detection accuracy of root fractures in cone-beam computed tomography images: a systematic review and meta-analysis. AB - The aim of this review was to evaluate whether CBCT is reliable for the detection of root fractures in teeth without root fillings, and whether the voxel size has an impact on diagnostic accuracy. The studies published in PubMed, Web of Science, ScienceDirect, Cochrane Library, Embase, Scopus, CNKI and Wanfang up to May 2014 were the data source. Studies on nonroot filled teeth with the i-CAT (n = 8) and 3D Accuitomo CBCT (n = 5) units were eventually selected. In the studies on i-CAT, the pooled sensitivity was 0.83 and the pooled specificity was 0.91; in the 3D Accuitomo studies, the pooled sensitivity was 0.95 and pooled specificity was 0.96. The i-CAT group comprised 5 voxel size subgroups and the 3D Accuitomo group contained 2 subgroups. For the i-CAT group, there was a significant difference amongst the five subgroups (0.125, 0.2, 0.25, 0.3 and 0.4 mm; P = 0.000). Pairwise comparison revealed that 0.125 mm voxel subgroup was significantly different from those of 0.2, 0.25 and 0.3 mm voxel subgroups, but not from the 0.4 mm voxel subgroup. There were no significant differences amongst any other two subgroups (by alpha' = 0.005). No significant difference was found between 0.08 mm and 0.125 mm voxel subgroups (P = 0.320) for the 3D Accuitomo group. The present review confirms the detection accuracy of root fractures in CBCT images, but does not support the concept that voxel size may play a role in improving the detection accuracy of root fractures in nonroot filled teeth. PMID- 26102213 TI - Hepatic Steatosis as a Marker of Metabolic Dysfunction. AB - Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal. PMID- 26102216 TI - The effect of in vitro gastrointestinal digestion on the anti-inflammatory activity of Vitis vinifera L. leaves. AB - Botanicals are widely consumed all over the world for health purposes, with increased usage in the general population, in many different types of products, including foods and plant food supplements. Several reports support for the beneficial effects of botanicals against gastrointestinal inflammation. However, no studies regarding the anti-inflammatory activity in the gastrointestinal tract of red vine leaves have been reported so far. The present work investigates the biological activity of Vitis vinifera L. water extract (VVWE) from dried leaves in two in vitro models of gastric and intestinal inflammation. The extract was characterized by a validated HPLC-DAD method, and tested on human epithelial gastric (AGS) and intestinal (Caco-2) cells with the aim to investigate the inhibitory effect on IL-8 secretion and promoter activity, before and after in vitro gastric or gastrointestinal digestion. Our results show that the water extract from red vine leaves inhibits TNFalpha-induced IL-8 secretion and expression in human gastric epithelial cells; the effect should be maintained, although to a lesser extent, after gastric digestion. In contrast, the effect after intestinal digestion is dramatically decreased since degradation of the active components in the gut does not allow the extract to efficiently counteract TNFalpha or IL-1beta induced IL-8 expression and the NF-kappaB pathway. The main molecular target of VVWE at the gastric level includes TNFalpha-induced activation of NF-kappaB and occurs at concentrations easily reachable after PFS consumption based on red vine leaf water extract as the ingredient. Our findings suggest that PFS containing water extracts from Vitis vinifera L. leaves could be useful to inhibit/attenuate gastric inflammation inhibiting IL-8 secretion and expression through impairment of the NF-kappaB pathway. PMID- 26102217 TI - Oxidative photodegradation of herbicide fenuron in aqueous solution by natural iron oxide alpha-Fe2O3, influence of polycarboxylic acids. AB - The photodegradation of the herbicide fenuron (1,1-dimethyl-3-phenylurea) by using a natural iron oxide (NIO), alpha-Fe2O3, in aqueous solution at acidic pH has been undertaken. The NIO was characterized by the Raman spectroscopy method. The degradation pathways and the formation of degradation products were studied. A high-pressure mercury lamp and sunlight were employed as light source. Fenuron photodegradation using NIO with oxalic acid followed the pseudo-first-order kinetics, the optimal experimental conditions were [oxalic acid]0 = 10(-3) M and [NIO] = 0.1 g L(-1) at pH 3. A UVA/NIO/oxalic acid system led to a low fenuron half-life (60 min). The results were even better when solar light is used (30 min). The variables studied were the doses of iron oxide, of carboxylic acids, the solution pH and the effect of sunlight irradiation. The effects of four carboxylic acids, oxalic, citric, tartaric and malic acids, on the fenuron photodegradation with NIO have been investigated, oxalic acid was the most effective carboxylic acid used at pH 3. A similar trend was observed for the removal of total organic carbon (TOC), 75% of TOC was removed. The analytical study showed many aromatic intermediates, short-chain carboxylic acids and inorganic ion. PMID- 26102218 TI - Efficient charge separation based on type-II g-C3N4/TiO2-B nanowire/tube heterostructure photocatalysts. AB - Separation of photo-generated charges has played a crucial role in controlling the actual performance of a photocatalytic system. Here we have successfully fabricated g-C3N4/TiO2-B nanowire/tube heterostructures through facile urea degradation reactions. Owing to the effective separation of photo-generated charges associated with the type-II band alignment and intimate interfacial contacts between g-C3N4 and TiO2-B nanowires/tubes, such heterostructures demonstrate an improved photocatalytic activity over individual moieties. Synthetic conditions such as hydrothermal temperatures for the preparation of TiO2-B and the weight ratio of TiO2-B to urea were systematically investigated. A high crystallinity of TiO2-B as well as the proper growth of g-C3N4 on its surface are critical factors for a better performance. Our simple synthetic method and the prolonged lifetime of photo-generated charges signify the importance of type-II heterostructures in the photocatalytic applications. PMID- 26102219 TI - Assembly of a basket-like {Sr ? P6Mo18O73} cage from 0D dimmer to 2D network and its photo-/electro-catalytic properties. AB - A series of basket-like heteropoly blues, formulated as (H4bth)[{Cu(H2O)}2{Sr ? P6MoV2MoVI16O73}].4H2O (1), {H2bih}3[{FeII(H2O)2}{Sr ? P6MoV2MoVI16O73}].2H2O (2), (H2bih)3[{CoII(H2O)2}{Sr ? P6MoV2MoVI16O73}].2H2O (3), (H2bih)3[{NiII(H2O)2}{Sr ? P6MoV2MoVI16O73}].2H2O (4), (H2bih)2(H2bip)[{Zn (H2O)0.5}{Sr ? P6MoV2MoVI16O73}].5.5H2O (5), (bth = 1,6-bis(triazole)hexane; bih = 1,6-bis(imidazol)hexane; bip = 1,5-bis(imidazol)pentane) have been synthesized hydrothermally and fully characterized. The structural analysis shows that all the compounds contain two electron reduced polyanions [Sr ? P6MoV2MoVI16O73]8- (abbreviated as {P6Mo18O73}), which consists of a tetra vacant gamma-Dawson type{P2Mo14} unit and a "handle"-shaped {P4Mo4} segment encapsulating a Sr2+ cation in the central cavity. Compound 1 is a 6-connected two-dimensional (2D) layer, which represents the first 2D assembly of basket-type polyoxometalates. Compounds 2-4 are isostructural one-dimensional zigzag chains linked by an M(H2O)2 linker (M = iron for 2, cobalt for 3, and nickel for 4). Compound 5 is a dimeric cluster supported by a binuclear {Zn2(H2O)} unit. The optical band gaps of 1-5 reveal their semiconductive natures. The compounds if used as photocatalysts exhibit a universal high efficiency degradation ability for dyes such as methylene blue, Rhodamine B, and Azon phloxine. The lifetime and reaction mechanism of the catalysts were investigated with a series of experiments. The compounds also show good bifunctional electrocatalytic behavior for the oxidation of ascorbic acid (AA) and reduction of nitrite ions. PMID- 26102214 TI - Mechanistic Effects of Calcitriol in Cancer Biology. AB - Besides its classical biological effects on calcium and phosphorus homeostasis, calcitriol, the active vitamin D metabolite, has a broad variety of actions including anticancer effects that are mediated either transcriptionally and/or via non-genomic pathways. In the context of cancer, calcitriol regulates the cell cycle, induces apoptosis, promotes cell differentiation and acts as anti inflammatory factor within the tumor microenvironment. In this review, we address the different mechanisms of action involved in the antineoplastic effects of calcitriol. PMID- 26102220 TI - Accelerated food source location in aging Drosophila. AB - Adequate energy stores are essential for survival, and sophisticated neuroendocrine mechanisms evolved to stimulate foraging in response to nutrient deprivation. Food search behavior is usually investigated in young animals, and it is not known how aging alters this behavior. To address this question in Drosophila melanogaster, we compared the ability to locate food by olfaction in young and old flies using a food-filled trap. As aging is associated with a decline in motor functions, learning, and memory, we expected that aged flies would take longer to enter the food trap than their young counterparts. Surprisingly, old flies located food with significantly shorter latency than young ones. Robust food search behavior was associated with significantly lower fat reserves and lower starvation resistance in old flies. Food-finding latency (FFL) was shortened in young wild-type flies that were starved until their fat was depleted but also in heterozygous chico mutants with reduced insulin receptor activity and higher fat deposits. Conversely, food trap entry was delayed in old flies with increased insulin signaling. Our results suggest that the difference in FFL between young and old flies is linked to age-dependent differences in metabolic status and may be mediated by reduced insulin signaling. PMID- 26102222 TI - Development of 2-Deoxy-2-[(18)F]fluororibose for Positron Emission Tomography Imaging Liver Function in Vivo. AB - Life-threatening acute liver failure can be triggered by a variety of factors, including common drugs such as acetaminophen. Positron emission tomography (PET) is rarely used to monitor liver function, in part because of a lack of specific imaging agents for liver function. Here we report a new PET probe, 2-deoxy-2 [(18)F]fluororibose ([(18)F]-2-DFR), for use in imaging liver function. [(18)F]-2 DFR was synthesized and validated as a competitive substrate for the ribose salvage pathway. [(18)F]-2-DFR was prepared through an efficient late stage radiofluorination. The desired selectivity of fluorination was achieved using an unorthodox protecting group on the precursor, which could withstand harsh SN2 reaction conditions with no side reactions. [(18)F]-2-DFR accumulated preferentially in the liver and was metabolized by the same enzymes as ribose. [(18)F]-2-DFR could distinguish between healthy liver and liver damaged by acetaminophen. [(18)F]-2-DFR is expected to be a useful PET probe for imaging and quantifying liver functions in vivo, with likely significant clinical utility. PMID- 26102223 TI - Male prevalent enhancement of leftward asymmetric development of the cerebellar cortex in ferrets (Mustela putorius). AB - The present study was conducted in MRI-based volumetry to characterize the sexual dimorphism of the cerebellum in young adult ferrets. High spatial resolution 3D anatomical MRI at 7-tesla were acquired ex vivo from fixed cerebella of 90-day old male and female ferrets. The 3D morphology and topology of cerebellar structures were reproduced well by volume-rendered images obtained from MRI. Volume of the whole cerebellum was significantly larger in males than in females. The cerebellar cortex was further divided into five transverse domains: the anterior zone (AZ; lobules I-V), central zone anterior (lobule VI), central zone posterior (CZp; lobule VII), posterior zone (PZ; lobules VIII-IXa) and nodular zone (NZ; lobules IXb -X). Significantly greater volumes in males than in females were detected bilaterally in the AZ, CZp, and NZ, and leftward in PZ. Notably, the significant volume asymmetry was detected leftward in the CZp of males. By asymmetry quotient analysis, the counterclockwise torque asymmetry of the cerebellum was revealed, and it was more striking in males than in females. The present results suggest that sexual dimorphism of the ferret cerebellum is characterized by enhancing the leftward laterality in the CZp in males, forming the distinctive counterclockwise torque asymmetry. PMID- 26102221 TI - Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. AB - Asthma is prevalent in Western countries, and recent explanations have evoked the actions of the gut microbiota. Here we show that feeding mice a high-fibre diet yields a distinctive gut microbiota, which increases the levels of the short chain fatty acid, acetate. High-fibre or acetate-feeding led to marked suppression of allergic airways disease (AAD, a model for human asthma), by enhancing T-regulatory cell numbers and function. Acetate increases acetylation at the Foxp3 promoter, likely through HDAC9 inhibition. Epigenetic effects of fibre/acetate in adult mice led us to examine the influence of maternal intake of fibre/acetate. High-fibre/acetate feeding of pregnant mice imparts on their adult offspring an inability to develop robust AAD. High fibre/acetate suppresses expression of certain genes in the mouse fetal lung linked to both human asthma and mouse AAD. Thus, diet acting on the gut microbiota profoundly influences airway responses, and may represent an approach to prevent asthma, including during pregnancy. PMID- 26102224 TI - Distributed Patterns of Reactivation Predict Vividness of Recollection. AB - According to the principle of reactivation, memory retrieval evokes patterns of brain activity that resemble those instantiated when an event was first experienced. Intuitively, one would expect neural reactivation to contribute to recollection (i.e., the vivid impression of reliving past events), but evidence of a direct relationship between the subjective quality of recollection and multiregional reactivation of item-specific neural patterns is lacking. The current study assessed this relationship using fMRI to measure brain activity as participants viewed and mentally replayed a set of short videos. We used multivoxel pattern analysis to train a classifier to identify individual videos based on brain activity evoked during perception and tested how accurately the classifier could distinguish among videos during mental replay. Classification accuracy correlated positively with memory vividness, indicating that the specificity of multivariate brain patterns observed during memory retrieval was related to the subjective quality of a memory. In addition, we identified a set of brain regions whose univariate activity during retrieval predicted both memory vividness and the strength of the classifier's prediction irrespective of the particular video that was retrieved. Our results establish distributed patterns of neural reactivation as a valid and objective marker of the quality of recollection. PMID- 26102225 TI - Preparatory Activity in Posterior Temporal Cortex Causally Contributes to Object Detection in Scenes. AB - Theories of visual selective attention propose that top-down preparatory attention signals mediate the selection of task-relevant information in cluttered scenes. Neuroimaging and electrophysiology studies have provided correlative evidence for this hypothesis, finding increased activity in target-selective neural populations in visual cortex in the period between a search cue and target onset. In this study, we used online TMS to test whether preparatory neural activity in visual cortex is causally involved in naturalistic object detection. In two experiments, participants detected the presence of object categories (cars, people) in a diverse set of photographs of real-world scenes. TMS was applied over a region in posterior temporal cortex identified by fMRI as carrying category-specific preparatory activity patterns. Results showed that TMS applied over posterior temporal cortex before scene onset (-200 and -100 msec) impaired the detection of object categories in subsequently presented scenes, relative to vertex and early visual cortex stimulation. This effect was specific to category level detection and was related to the type of attentional template participants adopted, with the strongest effects observed in participants adopting category level templates. These results provide evidence for a causal role of preparatory attention in mediating the detection of objects in cluttered daily-life environments. PMID- 26102226 TI - Autobiographical Planning and the Brain: Activation and Its Modulation by Qualitative Features. AB - To engage in purposeful behavior, it is important to make plans, which organize subsequent actions. Most studies of planning involve "look-ahead" puzzle tasks that are unrelated to personal goals. We developed a task to assess autobiographical planning, which involves the formulation of personal plans in response to real-world goals, and examined autobiographical planning in 63 adults during fMRI scanning. Autobiographical planning was found to engage the default network, including medial-temporal lobe and midline structures, and executive control regions in lateral pFC and parietal cortex and caudate. To examine how specific qualitative features of autobiographical plans modulate neural activity, we performed parametric modulation analyses. Ratings of plan detail, novelty, temporal distance, ease of plan formulation, difficulty in goal completion, and confidence in goal accomplishment were used as covariates in six hierarchical linear regression models. This modeling procedure removed shared variance among the ratings, allowing us to determine the independent relationship between ratings of interest and trial-wise BOLD signal. We found that specific autobiographical planning, describing a detailed, achievable, and actionable planning process for attaining a clearly envisioned future, recruited both default and frontoparietal brain regions. In contrast, abstract autobiographical planning, plans that were constructed from more generalized semantic or affective representations of a less tangible and distant future, involved interactions among default, sensory perceptual, and limbic brain structures. Specific qualities of autobiographical plans are important predictors of default and frontoparietal control network engagement during plan formation and reflect the contribution of mnemonic and executive control processes to autobiographical planning. PMID- 26102228 TI - Language Membership Identification Precedes Semantic Access: Suppression during Bilingual Word Recognition. AB - Previous research suggests that bilingual comprehenders access lexical representations of words in both languages nonselectively. However, it is unclear whether global language suppression plays a role in guiding attention to target language representations during ongoing lexico-semantic processing. To help clarify this issue, this study examined the relative timing of language membership and meaning activation during visual word recognition. Spanish-English bilinguals performed simultaneous semantic and language membership classification tasks on single words during EEG recording. Go/no-go ERP latencies provided evidence that language membership information was accessed before semantic information. Furthermore, N400 frequency effects indicated that the depth of processing of words in the nontarget language was reduced compared to the target language. These results suggest that the bilingual brain can rapidly identify the language to which a word belongs and subsequently use this information to selectively modulate the degree of processing in each language accordingly. PMID- 26102227 TI - Dopamine and Consolidation of Episodic Memory: Timing is Everything. AB - Memory consolidation underpins adaptive behavior and dopaminergic networks may be critical for prolonged, selective information storage. To understand the time course of the dopaminergic contribution to memory consolidation in humans, here we investigate the effect of dopaminergic medication on recall and recognition in the short and longer term in Parkinson disease (PD). Fifteen people with PD were each tested on or off dopaminergic medication during learning/early consolidation (Day 1) and/or late consolidation (Day 2). Fifteen age-matched healthy participants were tested only once. On Day 1 participants learned new information, and early episodic memory was tested after 30 min. Then on Day 2, recall and recognition were retested after a 24-hr delay. Participants on medication on Day 1 recalled less information at 30 min and 24 hr. In contrast, patients on medication on Day 2 (8-24 hr after learning) recalled more information at 24 hr than those off medication. Although recognition sensitivity was unaffected by medication, response bias was dependent on dopaminergic state: Medication during learning induced a more liberal bias 24 hr later, whereas patients off medication during learning were more conservative responders 24 hr later. We use computational modeling to propose possible mechanisms for this change in response bias. In summary, dopaminergic medication in PD patients during learning impairs early consolidation of episodic memory and makes delayed responses more liberal, but enhances late memory consolidation presumably through a dopamine-dependent consolidation pathway that may be active during sleep. PMID- 26102229 TI - Inferences of Others' Competence Reduces Anticipation of Pain When under Threat. AB - On a daily basis, we place our lives in the hands of strangers. From dentists to pilots, we make inferences about their competence to perform their jobs and consequently to keep us from harm. Here we explore whether the perceived competence of others can alter one's anticipation of pain. In two studies, participants (Receivers) believed their chances of experiencing an aversive stimulus were directly dependent on the performance of another person (Players). We predicted that perceiving the Players as highly competent would reduce Receivers' anxiety when anticipating the possibility of an electric shock. Results confirmed that high competence ratings consistently corresponded with lower reported anxiety, and complementary fMRI data showed that increased competence perception was further expressed as decreased activity in the bilateral posterior insula, a region localized to actual pain stimulation. These studies suggest that inferences of competence act as predictors of protection and reduce the expectation of negative outcomes. PMID- 26102230 TI - Evidence of Change of Intention in Picking Situations. AB - Intending to perform an action and then immediately executing it is a mundane process. The cognitive and neural mechanisms involved in this process of "proximal" intention formation and execution, in the face of multiple options to choose from, are not clear, however. Especially, it is not clear how intentions are formed when the choice makes no difference. Here we used behavioral and electrophysiological measures to investigate the temporal dynamics of proximal intention formation and "change of intention" in a free picking scenario, in which the alternatives are on a par for the participant. Participants pressed a right or left button following either an instructive visible arrow cue or a visible neutral "free-choice" cue, both preceded by a masked arrow prime. The goal of the prime was to induce a bias toward pressing the left or right button. Presumably, when the choice is arbitrary, such bias should determine the decision. EEG lateralized readiness potentials and EMG measurements revealed that the prime indeed induced an intention to move in one direction. However, we discovered a signature of "change of intention" in both the Instructed and Free choice decisions. These results suggest that, even in arbitrary choices, biases present in the neural system for choosing one or another option may be overruled and point to a curious "picking deliberation" phenomenon. We discuss a possible neural scenario that could explain this phenomenon. PMID- 26102231 TI - Congruent and Incongruent Corticospinal Activations at the Level of Multiple Effectors. AB - Motor resonance is defined as the subliminal activation of the motor system while observing actions performed by others. However, resonating with another person's actions is not always an appropriate response: In real life, people do not just imitate but rather respond in a suitable fashion. A growing body of neurophysiologic studies has demonstrated that motor resonance can be overridden by complementary motor responses (such as preparing a precision grip on a small object when seeing an open hand in sign of request). In this study, we investigated the relationship between congruent and incongruent corticospinal activations at the level of multiple effectors. The modulation of motor evoked potentials evoked by single-pulse TMS over the motor cortex was assessed in upper and lower limb muscles of participants observing a soccer player performing a penalty kick straight in their direction. Study results revealed a double dissociation: Seeing the soccer player kicking the ball triggered a motor resonance in the observer's lower limb, whereas the upper limb response afforded by the object was overridden. On the other hand, seeing the ball approaching the observers elicited a complementary motor activation in upper limbs while motor resonance in lower limbs disappeared. Control conditions showing lateral kicks, mimicked kicks, and a ball in penalty area were also included to test the motor coding of object affordances. Results point to a modulation of motor responses in different limbs over the course of action and in function of their relevance in different contexts. We contend that ecologically valid paradigms are now needed to shed light on the motor system functioning in complex forms of interaction. PMID- 26102232 TI - Highly sensitive detection of carbon dioxide by a pyrimido[1,2-a]benzimidazole derivative: combining experimental and theoretical studies. AB - In the present paper, a "light-up" chemsensor with a high specificity for carbon dioxide detection using a pyrimido[1,2-a]benzimidazole derivative (P1H) in liquid media has been developed. The results show that P1H reacts with carbon dioxide activated by a basic ion to form a carboxylic acid compound (P1-COOH). These results also provide a possible method for carboxylation reactions of P1H using carbon dioxide based on a vinyl carbanion. The complete reaction mechanism cycle was also described using DFT calculations. PMID- 26102233 TI - Studies of 1-Amino-2,2-difluorocyclopropane-1-carboxylic Acid: Mechanism of Decomposition and Inhibition of 1-Aminocyclopropane-1-carboxylic Acid Deaminase. AB - 1-Amino-2,2-difluorocyclopropane-1-carboxylic acid (DFACC) is of interest in the study of 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase due to the increased reactivity of its cyclopropyl functionality. It is shown that DFACC is unstable under near-physiological conditions where it primarily decomposes via specific-base catalysis to 3-fluoro-2-oxobut-3-enoic acid with a rate constant of 0.18 +/- 0.01 min(-1). Upon incubation with ACC deaminase, DFACC is found to be a slow-dissociating inhibitor of ACC deaminase with submicromolar affinity. PMID- 26102234 TI - Expression of the immunoglobulin superfamily cell membrane adhesion molecule Cd146 in acute leukemia. AB - BACKGROUND: The expression of the immunoglobulin superfamily cell membrane adhesion molecule CD146 has been reported on several normal and pathological cell types in human. The aim of this study was to investigate CD146 expression in acute leukemia using a multiparametric cytofluorimetric approach. METHODS: Cytofluorimetric and cytogenetic studies were performed on peripheral blood and bone marrow samples from 162 patients with acute myeloid leukemia (AML, n = 121) and acute lymphoblastic leukemia (ALL, n = 41). ALL patients were subdivided in B ALL (n = 38) and T-ALL (n = 3). Adult (n = 18) and pediatric (n = 20) B-ALL were considered as a whole group. RESULTS: Four out of 121 (3.3%) AML cases, 14/38 (36.8%) B-ALL, and 2/3 (66.6%) T-ALL expressed CD146 on 12-98% of blasts (p < 0.001). CD146 expression was not observed in 10 healthy controls. Among B-ALL CD146-positive cases, 78.6% were associated with a "common"/BII-ALL and 21.4% with a pre-B/BIII-ALL immunophenotype while pro-B/BI-ALL and mature-B/BIV-ALL cases were CD146-negative. Statistical analysis showed CD146 expression strongly associated with Ph+ positivity in B-ALL with the highest percentage of CD146 positive blasts in all Ph-positive B-ALL cases (84 +/- 22% Ph-positive B-ALL SD vs. 40 +/- 24% SD in Ph-negative B-ALL; p < 0,001). CONCLUSION: In our series, CD146 was expressed in all cases of Ph-positive B-ALL and in the vast majority of T-ALL, whereas it was rarely expressed by AML blasts. We suggest that CD146 may be considered as an additional marker for acute lymphoblastic leukemia diagnosis and monitoring of minimal residual disease in those cases which are CD146 positive at diagnosis. (c) 2015 International Clinical Cytometry Society. PMID- 26102235 TI - Labeling Cell Surface GPIs and GPI-Anchored Proteins through Metabolic Engineering with Artificial Inositol Derivatives. AB - Glycosylphosphatidylinositol (GPI) anchoring of proteins to the cell surface is important for various biological processes, but GPI-anchored proteins are difficult to study. An effective strategy was developed for the metabolic engineering of cell-surface GPIs and GPI-anchored proteins by using inositol derivatives carrying an azido group. The azide-labeled GPIs and GPI-anchored proteins were then tagged with biotin on live cells through a click reaction, which allows further elaboration with streptavidin-conjugated dyes or other molecules. The strategy can be used to label GPI-anchored proteins with various tags for biological studies. PMID- 26102236 TI - A chronotype comparison of South African and Dutch marathon runners: The role of scheduled race start times and effects on performance. AB - Recently, a high prevalence of morning-types was reported among trained South African endurance athletes. Proposed explanations for this observation were that either the chronotype of these athletes is better suited to coping with the early morning start times of endurance events in South Africa; or habitual early waking for training or endurance events may have conditioned the athletes to adapt and become morning-types. The South African endurance athletes also had earlier chronotypes compared to a control population of less active individuals, suggesting that individuals who are more physically active may have earlier chronotypes. However, since both the South African athlete and control groups showed an overrepresentation of morning-types compared to European and American populations, the South African climate may in part have explained this bias towards morningness. Given the latitude and climate differences between South Africa and the Netherlands, and that South African marathons typically start at about 06:30 while those in the Netherlands start later (+/-11:00), comparison of South African and Dutch marathon runners and active controls would allow for simultaneous assessment of the effects of marathon start time, degree of physical activity and climate on chronotype. Therefore, the primary aims of this study were: (i) to assess the effect of marathon start time on chronotype in marathon runners and (ii) to determine the extent to which either degree of physical activity or climate might explain the bias towards morningness observed in South African athletes and controls. A secondary aim was to determine whether any relationships exist between chronotype, PERIOD3 (PER3) variable number tandem repeat (VNTR) polymorphism genotype, habitual training habits and marathon performance. Trained male marathon runners from South Africa (n = 95) and the Netherlands (n = 90), and active but non-competitive male controls from South Africa (n = 97) and the Netherlands (n = 98) completed a questionnaire capturing demographics, training and race history, as well as the Horne-Ostberg morningness eveningness personality questionnaire. All participants donated buccal cell samples from which genomic DNA was extracted and polymerase chain reaction analysis was used to genotype them for the PER3 VNTR polymorphism, which has previously been associated with chronotype. The main finding was that South African runners were significantly more morning-orientated than Dutch runners suggesting that participation in an endurance sport with an earlier start time may influence chronotype. Secondly, both the South African and Dutch runners were significantly more morning-orientated than their respective control groups, indicating that individuals who train for and participate in recreational endurance sport races have an earlier chronotype than physically active but non competitive males. Thirdly, mean chronotype scores were similar between the South African and Dutch control groups, suggesting that climate does not seem to affect chronotype in these groups. Fourthly, the PER3 VNTR polymorphism distribution was similar between the four groups and was not associated with chronotype, suggesting that the difference in chronotype between the four groups in this study is not explained by the PER3 VNTR genotype. Lastly, in the South African runners group, a higher preference for mornings was associated with a better personal best half-marathon and current marathon performance. PMID- 26102237 TI - Self-Assembly of Recombinant Hagfish Thread Keratins Amenable to a Strain-Induced alpha-Helix to beta-Sheet Transition. AB - Hagfish slime threads are assembled from protein-based bundles of intermediate filaments (IFs) that undergo a strain-induced alpha-helical coiled-coil to beta sheet transition. Draw processing of native fibers enables the creation of mechanically tuned materials, and under optimized conditions this process results in mechanical properties similar to spider dragline silk. In this study, we develop the foundation for the engineering of biomimetic recombinant hagfish thread keratin (TK)-based materials. The two protein constituents from the hagfish Eptatretus stoutii thread, named EsTKalpha and EsTKgamma, were expressed in Escherichia coli and purified. Individual (rec)EsTKs and mixtures thereof were subjected to stepwise dialysis to evaluate their protein solubility, folding, and self-assembly propensities. Conditions were identified that resulted in the self assembly of coiled-coil rich IF-like filaments, as determined by circular dichroism (CD) and transmission electron microscopy (TEM). Rheology experiments indicated that the concentrated filaments assembled into gel-like networks exhibiting a rheological response reminiscent to that of IFs. Notably, the self assembled filaments underwent an alpha-helical coiled-coil to beta-sheet transition when subjected to oscillatory shear, thus mimicking the critical characteristic responsible for mechanical strengthening of native hagfish threads. We propose that our data establish the foundation to create robust and tunable recombinant TK-based materials whose mechanical properties are controlled by a strain-induced alpha-helical coiled-coil to beta-sheet transition. PMID- 26102238 TI - Chromatin and development: a special issue. PMID- 26102240 TI - To Be Free and Normal: Addiction, Governance, and the Therapeutics of Buprenorphine. AB - Methadone maintenance has dominated opiate addiction treatment in the United States for decades. Since 2002, opiate addiction has also been treated in general medical settings with a substance called buprenorphine. Based on interviews and participant observation conducted in northern California, this article analyzes how discourses of freedom and normalcy in patient and provider narratives reflect and affect experiences with this treatment modality. I discuss how buprenorphine treatment, in contrast to methadone maintenance, offers patients and providers a greater sense of autonomy and flexibility in how they receive and deliver treatment. It presents them with new obligations, responsibilities, and choices around care and conduct. It simultaneously perpetuates and shapes a desire to be "free" and "normal." I argue that the therapeutics of buprenorphine govern patients and providers through this desire for freedom and normalcy. Buprenorphine is thus a technology of governmentality that extends neoliberal discourses and values and produces self-governing subjects. PMID- 26102241 TI - Molecular Orientation and Structural Transformations in Phthalic Anhydride Thin Films on MgO(100)/Ag(100). AB - Structural control of organic thin films on dielectric substrates is the key to tailoring the physical properties of hybrid materials, for example, for application in solar energy conversion, molecular electronics, or catalysis. In this work, we investigate the molecular orientation of phthalic anhydride (PAA) films on atomically well-defined MgO(100) on Ag(100) using temperature-programmed infrared reflection absorption spectroscopy (TP-IRAS) in combination with density functional theory (DFT). A robust procedure is presented to determine the orientation of the PAA molecules, which relies on the intensity ratios of vibrational bands only. We show that even at deposition temperatures of 110 K, the PAA multilayer grows with a specific molecular orientation; that is, the PAA molecular plane is preferentially aligned parallel with the MgO surface. No change of molecular orientation occurs up to a temperature of 145 K. Between 145 and 160 K, the film restructures adopting a nearly flat-lying molecular orientation. Between 170 and 205 K, the film undergoes a second structural transition to a crystalline phase. This transition is associated with a pronounced molecular reorientation. The molecules adopt a tilted orientation and, simultaneously, rotate around their C2 axes. The reorientation behavior suggests that the molecular orientation in the crystalline phase is controlled by the interaction with the MgO(100) substrate. At higher temperature, no further restructuring is observed until the PAA multilayer desorbs at temperatures above 230 K. PMID- 26102239 TI - Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases. AB - Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis- and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2 fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 * 10(-4)). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions. PMID- 26102243 TI - Correction to "Palladium-Catalyzed Alkoxycarbonylation of Conjugated Enyne Oxiranes: A Diastereoselective Method for the Synthesis of 7-Hydroxy-2,3,5 trienoates". PMID- 26102242 TI - Listener Perception of Monopitch, Naturalness, and Intelligibility for Speakers With Parkinson's Disease. AB - PURPOSE: Given the potential significance of speech naturalness to functional and social rehabilitation outcomes, the objective of this study was to examine the effect of listener perceptions of monopitch on speech naturalness and intelligibility in individuals with Parkinson's disease (PD). METHOD: Two short utterances were extracted from monologue samples of 16 speakers with PD and 5 age matched adults without PD. Sixteen listeners evaluated these stimuli for monopitch, speech naturalness and intelligibility using the visual sort and rate method. RESULTS: Naive listeners can reliably judge monopitch, speech naturalness, and intelligibility with minimal familiarization. While monopitch and speech intelligibility were only moderately correlated, monopitch and speech naturalness were highly correlated. CONCLUSIONS: A great deal of attention is currently being paid to improvement of vocal loudness and thus speech intelligibility in PD. Our findings suggest that prosodic characteristics such as monopitch should be explored as adjuncts to this treatment of dysarthria in PD. Development of such prosodic treatments may enhance speech naturalness and thus improve quality of life. PMID- 26102244 TI - Halogen Bonding and Chalcogen Bonding in 4,7-Dibromo-5,6-dinitro-2,1,3 benzothiadiazole. AB - An organic solid, 4,7-dibromo-5,6-dinitro-2,1,3-benzothiadiazole, has been designed to serve as an illustrative example to quantitatively evaluate the relative merits of halogen and chalcogen bonding in terms of charge density features. The compound displays two polymorphic modifications, one crystallizing in a non-centrosymmetric space group (Z' = 1) and the other in a centrosymmetric space group with two molecules in the asymmetric unit (Z' = 2). Topological analysis based on QTAIM clearly brings out the dominance of the chalcogen bond over the halogen bond along with an indication that halogen bonds are more directional compared to chalcogen bonds. The cohesive energies calculated with the absence of both strong and weak hydrogen bonds as well as stacking interaction are indicative of the stabilities associated with the polymorphic forms. PMID- 26102245 TI - Cell-Cell Communication in Yeast Using Auxin Biosynthesis and Auxin Responsive CRISPR Transcription Factors. AB - An engineering framework for synthetic multicellular systems requires a programmable means of cell-cell communication. Such a communication system would enable complex behaviors, such as pattern formation, division of labor in synthetic microbial communities, and improved modularity in synthetic circuits. However, it remains challenging to build synthetic cellular communication systems in eukaryotes due to a lack of molecular modules that are orthogonal to the host machinery, easy to reconfigure, and scalable. Here, we present a novel cell-to cell communication system in Saccharomyces cerevisiae (yeast) based on CRISPR transcription factors and the plant hormone auxin that exhibits several of these features. Specifically, we engineered a sender strain of yeast that converts indole-3-acetamide (IAM) into auxin via the enzyme iaaH from Agrobacterium tumefaciens. To sense auxin and regulate transcription in a receiver strain, we engineered a reconfigurable library of auxin-degradable CRISPR transcription factors (ADCTFs). Auxin-induced degradation is achieved through fusion of an auxin-sensitive degron (from IAA corepressors) to the CRISPR TF and coexpression with an auxin F-box protein. Mirroring the tunability of auxin perception in plants, our family of ADCTFs exhibits a broad range of auxin sensitivities. We characterized the kinetics and steady-state behavior of the sender and receiver independently as well as in cocultures where both cell types were exposed to IAM. In the presence of IAM, auxin is produced by the sender cell and triggers deactivation of reporter expression in the receiver cell. The result is an orthogonal, rewireable, tunable, and, arguably, scalable cell-cell communication system for yeast and other eukaryotic cells. PMID- 26102246 TI - Why Do Some Water Utilities Recycle More than Others? A Qualitative Comparative Analysis in New South Wales, Australia. AB - Although the recycling of municipal wastewater can play an important role in water supply security and ecosystem protection, the percentage of wastewater recycled is generally low and strikingly variable. Previous research has employed detailed case studies to examine the factors that contribute to recycling success but usually lacks a comparative perspective across cases. In this study, 25 water utilities in New South Wales, Australia, were compared using fuzzy-set Qualitative Comparative Analysis (fsQCA). This research method applies binary logic and set theory to identify the minimal combinations of conditions that are necessary and/or sufficient for an outcome to occur within the set of cases analyzed. The influence of six factors (rainfall, population density, coastal or inland location, proximity to users; cost recovery and revenue for water supply services) was examined for two outcomes, agricultural use and "heavy" (i.e., commercial/municipal/industrial) use. Each outcome was explained by two different pathways, illustrating that different combinations of conditions are associated with the same outcome. Generally, while economic factors are crucial for heavy use, factors relating to water stress and geographical proximity matter most for agricultural reuse. These results suggest that policies to promote wastewater reuse may be most effective if they target uses that are most feasible for utilities and correspond to the local context. This work also makes a methodological contribution through illustrating the potential utility of fsQCA for understanding the complex drivers of performance in water recycling. PMID- 26102247 TI - Macroscopically Aligned Graphite Films Prepared from Iodine-Doped Stretchable Polyacetylene Films Using Morphology-Retaining Carbonization. AB - We prepared graphite films using typical Shirakawa-type and stretchable polyacetylene (PA) films as precursors through a morphology-retaining carbonization. A macroscopically aligned PA film was prepared from the drawable PA film using a mechanical-stretching procedure. The degree of orientation of the aligned PA film was evaluated by measuring polarized infrared absorption spectra and an azimuthal-angle profile of a Laue X-ray diffraction (XRD) pattern. The carbonization was performed from the iodine-doped PA films as precursors at 800 degrees C. The carbon films were subsequently graphitized at 1400-3000 degrees C, yielding graphite films with almost the same surface morphology as that of the original PA films and that of the carbon films as precursors. The typical PA film graphitized at 2600 degrees C exhibited tensile strengths of up to 224 MPa, moduli of up to 10 GPa, and an average electrical conductivity of 2.5 * 10(2) S/cm. In contrast, the graphite film prepared from the stretched PA film presented a Laue XRD pattern in which graphitic crystal structures are aligned parallel to the direction of stretching of the PA film. The anisotropic graphite film showed an enhanced conductivity of up to 1.5 * 10(3) S/cm along the stretching direction. We demonstrated that an iodine-doped PA film is a highly efficient carbon source for producing graphite films with good mechanical and electrical properties. The total yield of a graphite film is as high as 61-74% at up to 3000 degrees C, which is considerably higher than that of polyacrylonitrile-based carbon fiber and polyimide-based graphite film. PMID- 26102248 TI - The C4280A (rs5705) gene polymorphism of the renin (REN) gene is associated with risk of developing coronary artery disease, but not with restenosis after coronary stenting. AB - The aim of the present study was to evaluate the role of AGT and REN gene polymorphisms as susceptibility markers for coronary artery disease (CAD) and/or restenosis after coronary stent placement in a group of Mexican patients. Five polymorphisms of the AGT (rs699, rs4762, rs5051, rs5049, rs5046) and two of the REN (rs5707, rs5705) genes were analyzed by 5' exonuclease TaqMan genotyping assays in 240 patients with CAD who underwent coronary artery stenting (76 with restenosis and 164 without restenosis). A group of 610 individuals without clinical and familial antecedents of cardiovascular diseases were included as controls. The results showed that the distribution of AGT and REN polymorphisms were similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under co-dominant, dominant, heterozygous and additive models, the REN A4280C (rs5705) polymorphism was associated with increased risk of CAD (OR=1.76, PCo dom=0.006, OR=1.81, PDom=0.001, OR=1.75, PHet=0.003 and OR=1.59, PAdd=0.003, respectively). All models were adjusted for age, gender, diabetes, dyslipidemia, hypertension and smoking habit. The TC haplotype of the REN gene was associated with increased risk of CAD (OR=1.53, P=0.014). The data suggest that the REN C4280A (rs5705) polymorphism plays an important role in the risk of developing CAD with the highest risk for C allele, but do not support its role as a risk factor for developing restenosis after coronary stenting. PMID- 26102249 TI - Quantum dot-based multispectral fluorescent imaging to quantitatively study co expressions of Ki67 and HER2 in breast cancer. AB - Both Ki67 and HER2 are key prognostic molecules for invasive breast cancer (BC), but the individual relative impacts on prognosis of these molecules are not known. This study was aimed at establishing a quantum dot (QD)-based double-color in-situ quantitative imaging technique to study the co-expressions of Ki67 and HER2, and delineate the individual impacts of these molecules on prognosis. The QD-based fluorescent immunostaining technique could simultaneously image the co expressions of Ki67 and HER2 in BC specimens, with the former stained as clear red fluorescence in cancer cell nucleus, and the latter as bright green fluorescence on cancer cell membrane. Both Ki67 and HER2 expressions were significantly correlated with 8-year disease free survival (8-DFS) (P<0.05). However, the two molecules had different weights in terms of negative impacts on clinical prognosis. The median 8-DFS was statistically significantly shorter in High-Ki67 High-HER2 subgroup than Low-Ki67 High-HER2 subgroup (11.7 vs. 60.1months, P<0.05), shorter in High-Ki67 Low-HER2 subgroup than Low-Ki67 Low HER2 subgroup (16.4 vs. 96.0months, P<0.01), shorter in High-Ki67 High-HER2 subgroup than Low-Ki67 Low-HER2 subgroup (11.7 vs. 96.0months, P<0.01), but there were no statistically significant differences in median 8-DFS between High-Ki67 Low-HER2 subgroup and High-Ki67 High-HER2 subgroup (11.7 vs. 16.4months, P=0.586). The hazard ratio (HR) of Ki67 negative impact on 8-DFS was about 3 fold of that of HER2 (HR 4.493 vs. 1.481). This study demonstrated that QD-based fluorescent imaging technique could help the quantitative study on the co expressions of Ki67 and HER2 in BC, and Ki67 has a greater negative impact on BC prognosis than HER2. PMID- 26102250 TI - Beyond the Team: Understanding Interprofessional Work in Two North American ICUs. AB - OBJECTIVE: To examine the ways in which healthcare professionals work together in the ICU setting, through a consideration of the contextual, organizational, processual, and relational factors that impact their interprofessional collaboration. DESIGN: Data from over 350 hours of ethnographic observation and 35 semistructured interviews with clinicians in two ICUs were collected by two medical anthropologists over a period of 6 months. SETTING: Medical surgical ICUs in two urban research hospitals in Canada and the United States. MAIN RESULTS: Although the concept of teamwork is often central to interventions to improve patient safety in the ICU, our observations suggest that this concept does not fully describe how interprofessional work actually occurs in this setting. With the exception of crisis situations, most interprofessional interactions in the two ICUs we studied could be better described as forms of interprofessional work other than teamwork, which include collaboration, coordination, and networking. CONCLUSIONS: A singular notion of team is too reductive to account for the ways in which work happens in the ICU and therefore cannot be taken for granted in quality improvement initiatives or among healthcare professionals in this setting. Adapting interventions to the complex nature of interprofessional work and each ICUs unique local context is an important and necessary step to ensure the delivery of safe and effective patient care. PMID- 26102253 TI - Time-course of recovery of peak oxygen uptake after exercise-induced muscle damage. AB - VO2 peak has been shown to be reduced 48 h following exercise-induced muscle damage (EIMD), but it is unclear how long this reduction may persist. In this study eight endurance trained participants (21.5 +/- 1.1 years old) performed a maximal exercise tests over 10-days followings EIMD. Cardiorespiratory variables were collected via open-circuit spirometry and soreness, maximal strength (MVC), motor-unit recruitment, and contractile properties were assessed prior to each test. MVC was reduced for up to 4-days (p <= 0.05) and soreness was evident for 10-days in the quadriceps (p < 0.05). VO2peak was reduced 7.4% 2-days post EIMD (55.5 +/- 6.0 vs. 51.3 +/- 5.8; p = 0.006) and remained reduced in 6 of 8 participants at 10-days post (p = 0.005). No relationship was found between changes in MVC, soreness, motor-unit recruitment, and contractile properties and changes in VO2peak (p > 0.05). EIMD resulted in small, but prolonged reductions in VO2peak. Our findings suggest mechanisms aside from force loss and soreness are primarily responsible for the reductions in VO2peak after EIMD. PMID- 26102251 TI - County-Level Effects of Prehospital Regionalization of Critically Ill Patients: A Simulation Study. AB - OBJECTIVE: Regionalization may improve critical care delivery, yet stakeholders cite concerns about its feasibility. We sought to determine the operational effects of prehospital regionalization of nontrauma, nonarrest critical illness. SETTING: King County, Washington. DESIGN: Discrete event simulation study. PATIENTS: All 2006 hospital discharge data, linked to all adult, eligible patients transported by county emergency medical services agencies. INTERVENTIONS: We simulated active triage of high-risk patients to designated referral centers using a validated prehospital risk score; we studied three regionalization scenarios: 1) up triage, 2) up and down triage, and 3) up and down triage after reducing ICU beds by 25%. We determined the effect on patient routing, ICU occupancy at referral and nonreferral hospitals, and emergency medical services transport times. MEASUREMENTS AND MAIN RESULTS: A total of 119,117 patients were hospitalized at 11 nonreferral centers and 76,817 patients were hospitalized at three referral centers. Among 20,835 emergency medical services patients, 7,817 patients (43%) were eligible for up triage and 10,242 patients (57%) were eligible for down triage. At baseline, mean daily ICU bed occupancy was 61% referral and 47% at nonreferral hospitals. Up triage increased referral ICU occupancy to 68%, up and down triage to 64%, and up and down triage with bed reduction to 74%. Mean daily nonreferral ICU occupancy did not exceed 60%. Total emergency medical services transport time increased by less than 3% with up and down triage. CONCLUSIONS: Regionalization based on prehospital triage of the critically ill can allocate high-risk patients to referral hospitals without adversely affecting ICU occupancy or prehospital travel time. PMID- 26102252 TI - A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome. AB - OBJECTIVES: There are no current pharmacological therapies for the prevention or treatment of acute respiratory distress syndrome. Early dysregulated inflammation likely plays a role in acute respiratory distress syndrome development and possibly acute respiratory distress syndrome outcomes. p38 mitogen-activated protein kinase is central to the regulation of multiple inflammatory mediators implicated in acute organ dysfunction and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. In preclinical models, p38 inhibitors reduce lung injury following pancreatitis and burn injury. DESIGN: We conducted a phase IIa, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and tolerability of dilmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in patients at risk for developing acute respiratory distress syndrome admitted with an Injury Severity Score more than 16, excluding head trauma. Enrolled patients received 4- or 24-hour IV dilmapimod infusions at different doses or placebo, daily for 3 days, in four separate cohorts. SETTING: Multicenter randomized clinical trial of large, academic trauma centers. MEASUREMENTS AND MAIN RESULTS: Seventy-seven patients were enrolled. Although adverse events were common in this critically ill population, dilmapimod was well tolerated, with no clinically relevant safety findings. Pharmacokinetic models indicated that the higher dose of 10 mg given as continuous infusion over 24 hours had the most favorable plasma concentration profile. Likewise, measures of soluble inflammatory markers including interleukin 6, C-reactive peptide, interleukin-8, and soluble tumor necrosis factor receptor 1 were most different between this dosing arm and placebo. Although the study was not specifically designed with acute respiratory distress syndrome as an outcome, the number of patients who developed acute respiratory distress syndrome was small (2/77). CONCLUSIONS: The novel p38 mitogen-activated protein kinase inhibitor dilmapimod appears well tolerated and may merit further evaluation for prevention of acute respiratory distress syndrome and other organ injury in larger clinical trials. Furthermore, results of this early-phase trial may aid in design of future studies aimed at prevention of acute respiratory distress syndrome and other organ injury. PMID- 26102254 TI - Phenotypic responses to social defeat are associated with differences in cued and contextual fear discrimination. AB - Conflict among individuals is one of the most common forms of stressors experienced across a variety of species, including humans. Social defeat models in mice produce two phenotypic behavioral responses characterized by prolonged social avoidance (susceptibility) or continued social interaction (resistance). The resistant phenotype has been proposed as a model of resilience to chronic stress-induced depression in humans. Previously, we have found that mice that are resistant to social defeat stress display significant impairments in extinction learning and retention, suggesting that continued social interaction following the experience of social defeat may be associated with maladaptive fear responses. Here, we examined how individual differences in response to social defeat may be related to differences in cued and context fear discrimination. Following defeat, resistant mice showed increased fear to a neutral cued stimulus (CS-) compared to control and susceptible mice, but were still able to significantly discriminate between the CS+ and CS-. Likewise, both phenotypes were generally able to discriminate between the training context and neutral context at all retention intervals tested (1, 5, 14 days). However, susceptible mice displayed significantly better discrimination compared to resistant and non defeated control mice when assessing the discrimination ratio. Thus, at a time when most animals begin exhibiting generalization to contextual cues, susceptible mice retain the ability to discriminate between fearful and neutral contexts. These data suggest that the differences observed in context and cued discrimination between susceptible and resistant mice may be related to differences in their coping strategies in response to social defeat. In particular, resistance or resilience to social defeat as traditionally characterized may be associated with altered inhibitory learning. Understanding why individual differences arise in response to stress, including social confrontation is important in understanding the development and treatment of stress related pathologies such as PTSD. PMID- 26102255 TI - Attentional Focus Effects in Standing Long Jump Performance: Influence of a Broad and Narrow Internal Focus. AB - The content of instructions that strength coaches give can have a significant impact on how an athlete or client performs. Research on motor learning has shown an advantage of instructions focusing on the effects of movements (external focus) over those focusing on the movements themselves (internal focus) in the performance of motor skills. Internally focused cues are abundant in coaching, therefore the purpose of this study was to test whether some internally focused cues might be more helpful than others. Participants (68) were randomly assigned to either an external focus (EX), broad internal focus (B-IN), narrow internal focus (N-IN), or a control group (CON), and performed 5 standing long jumps. All groups were instructed that the goal was to jump as far as possible. In addition, the EX group was told to "jump as far past the start line as possible." The B-IN group was told to "use your legs." The N-IN group was told to "extend your knees as rapidly as possible," and the CON group received no additional instruction. An analysis of covariance showed that the EX group (198.09 +/- 31.89 cm) jumped significantly farther than both the B-IN group (173.74 +/- 35.36 cm), p = 0.010 and the N-IN group (178.53 +/- 31.17 cm), p = 0.049, with no group different from the CON group. The results suggest that a broad internal focus is no more effective than a narrow internal focus, and that an external focus leads to the greatest jump distance. Strength and conditioning professionals should carefully word their instructions to induce an external focus of attention whenever possible. PMID- 26102256 TI - Usage of Running Drills in an Interval Training Program: Implications Related to Biomechanical Parameters of Running. AB - The purpose of this study was to investigate the effects of running drills during an interval training program on biomechanical parameters of running. Thirty recreational runners, divided into 2 groups (control group and experimental group [EG]), were submitted to a 15-week interval training, but only EG performed running drills in the training. The test sessions were accomplished before and after intervention. Spatiotemporal and kinetic variables were analyzed at 2 speeds: maximum (Smax) and comfortable (Scomf). For moment effect, significant increases were observed for Scomf (8.9%) and Smax (10.7%) after training. Variables related to mechanical load were also higher after training for both speeds (LR1: 16.4% and Imp75: 7.8% at Scomf; LR1: 21.4% and Imp75: 8.1% at Smax). For training approach effect, higher value of Imp75 was observed in EG (10.1% at Scomf and 11.9% at Smax, without performance improvements). Also, EG presented higher values of Fy2 (6.7% at Scomf and 6.1% at Smax) and FT (13.3% at Scomf), variables related to the center of mass oscillation. As a conclusion, including running drills in a 15-week interval running training seems not to be an efficient procedure to improve parameters related to mechanical load and performance. PMID- 26102257 TI - Effects of Eight Months of Whole-Body Vibration Training on the Muscle Mass and Functional Capacity of Elderly Women. AB - Few intervention studies have used whole-body vibration (WBV) training in the elderly, and there is inconclusive evidence about its health benefits. We examined the effect of 8 months of WBV training on muscle mass and functional capacity in elderly women. A total of 37 women (aged 82.4 +/- 5.7 years) voluntarily participated in this study. Subjects were randomly assigned to a vibration group (n = 19) or a control group (n = 18). The vibration group trained on a vertical vibration platform twice a week. The control group was requested not to change their habitual lifestyle. The quadriceps femoris muscle cross sectional area was determined by magnetic resonance imaging. All participants were evaluated by a battery of tests (Senior Fitness Test) to determine their functional capacity, as well as handgrip strength and balance/gait. General linear repeated-measure analysis of variance (group by time) was performed to examine the effect of the intervention on the outcomes variables. After 8 months, nonstatistically significant differences in the quadriceps CSA (pre-training: 8,516.16 +/- 1,271.78 mm2 and post-training: 8,671.63 +/- 1,389.03 mm2) (p > 0.05) were found in the WBV group (Cohen's d: -0.12), whereas the CON group significantly decreased muscle mass (pre-training: 9,756.18 +/- 1,420.07 mm2 and post-training: 9,326.82 +/- 1,577.53 mm2), with moderate effect size evident (Cohen's d: 0.29). In both groups, no changes were observed in the functional capacity, handgrip strength and balance/gait. The WBV training could prevent the loss of quadriceps CSA in elderly women. PMID- 26102258 TI - Effects of Six Weeks of Medicine Ball Training on Throwing Velocity, Throwing Precision, and Isokinetic Strength of Shoulder Rotators in Female Handball Players. AB - The aim of this study was to investigate the effects of 6 weeks of medicine ball training (MBT) on throwing velocity, throwing precision, and isokinetic strength of shoulder rotators in competitive female handball players. Twenty-eight players (mean +/- SD; age: 20.8 +/- 3.3 years, height: 170.5 +/- 5.6 cm, body mass: 65.2 +/- 8.0 kg) were randomly assigned to an MBT group (TG; n = 15) and a control group (CG; n = 13). TG performed a supervised MBT program, 3 times a week for a total of 6 weeks, focusing on handball-specific movement patterns. Both groups, TG and CG, also conducted a supervised shoulder injury prevention program with elastic tubes, as part of the warm-up, finishing with regular handball throws. Results showed a significant group * time interaction in throwing velocity (p < 0.001) with the TG posttest results being significantly higher compared with CG (d = 2.1), and also a significant main time effect (p < 0.001), with an increase in throwing velocity of 14% (d = 3.0) and 3.7% (d = 0.3) for both TG and CG, respectively. Throwing precision did not significantly differ between groups and time points. Isokinetic strength measures revealed a significant group * time interaction (p <= 0.05) with the TG posttest results being significantly higher compared with CG (d = 0.9) and also a significant main time effect (p < 0.01) with an increase of 15% (d = 0.9) in concentric shoulder internal rotation at 180 degrees .s-1 in the dominant arm in TG, whereas no significant changes occurred in CG. The present results indicate that 6 weeks of MBT elicit significant improvements in functional performance (i.e., throwing velocity) in female handball players, whereas throwing precision remained unaffected. Medicine ball training exercises seem to be a useful and inexpensive strength training strategy in enhancing functional performance by closely mimicking sport-specific movement activities. PMID- 26102259 TI - Effect of Practical Precooling on Neuromuscular Function and 5-km Time-Trial Performance in Hot, Humid Conditions Among Well-Trained Male Runners. AB - This study investigated whether torso and thigh precooling during a warm-up effects neuromuscular function and 5-km time-trial performance in hot, humid conditions. Eight well-trained male runners completed 3 randomized time-trials in 32.2 +/- 0.8 degrees C and 48.6 +/- 6.7% relative humidity. A 30-minute warm-up was completed with no cooling (Control), precooling by an ice vest (Vest), or ice packs covering the thighs (Packs). Before the warm-up and after the time-trial, supramaximal femoral nerve stimulation was delivered during and following maximal isometric contractions. Core and skin temperature, heart rate, and perceptual ratings were recorded before and during the warm-up and time-trial. Overall performance time was improved in Packs compared with Control (1,407 +/- 80 seconds vs. 1,492 +/- 88 seconds; p <= 0.05) but not in Vest (1,444 +/- 71 seconds; p > 0.05). In Packs, a higher exercise intensity (p <= 0.05) and less cumulative time (p < 0.01) were evident during the last kilometer compared with Control. Maximum voluntary force, voluntary activation, muscle contractility, and membrane excitability were not different after exercise or between conditions. Ten minutes after the warm-up, skin temperature was lower in Vest and Packs compared with Control (p < 0.01). Thermal strain and body heat content change was lower in Vest and Packs, respectively (p <= 0.05). Findings indicate that torso and thigh precooling during a warm-up reduces thermoregulatory strain. However, thigh opposed to torso precooling provides greater performance improvements. Neuromuscular function did not aid performance, indicating that transient changes in afferent feedback and muscle recruitment may enhance endurance trial performance. PMID- 26102260 TI - Effects of Kettlebell Training on Aerobic Capacity. AB - This study examined the effects of a kettlebell training program on aerobic capacity. Seventeen female National Collegiate Athletic Association Division I collegiate soccer players (age: 19.7 +/- 1.0 years, height: 166.1 +/- 6.4 cm, weight: 64.2 +/- 8.2 kg) completed a graded exercise test to determine maximal oxygen consumption (VO2max). Participants were assigned to a kettlebell intervention group (KB) (n = 9) or a circuit weight-training (CWT) control group (n = 8). Participants in the KB group completed a kettlebell snatch test to determine individual snatch repetitions. Both groups trained 3 days a week for 4 weeks in addition to their off-season strength and conditioning program. The KB group performed the 15:15 MVO2 protocol (20 minutes of kettlebell snatching with 15 seconds of work and rest intervals). The CWT group performed multiple free weight and dynamic body-weight exercises as part of a continuous circuit program for 20 minutes. The 15:15 MVO2 protocol significantly increased VO2max in the KB group. The average increase was 2.3 ml.kg-1.min-1, or approximately a 6% gain. There was no significant change in VO2max in the CWT control group. Thus, the 4 week 15:15 MVO2 kettlebell protocol, using high-intensity kettlebell snatches, significantly improved aerobic capacity in female intercollegiate soccer players and could be used as an alternative mode to maintain or improve cardiovascular conditioning. PMID- 26102261 TI - Reliability and Usefulness of the 30-15 Intermittent Fitness Test in Rugby League. AB - This study examined the reliability and usefulness of the 30-15 Intermittent Fitness Test (30-15(IFT)) within rugby league. Fifty-five young rugby league players participated in the study. These included representative players from Under 16s (n = 19; 15.6 +/- 0.3 years; 78.1 +/- 10.9 kg), Under 18s (n = 21; 17.4 +/- 0.5 years; 86.9 +/- 11.2 kg), and Under 20s (n = 15; 19.4 +/- 0.5 years; 95.9 +/- 8.7 kg) squads within a professional rugby league club. Players performed the 30-15(IFT) twice within 9 days of each other. Maximal intermittent running velocity (V(IFT)) and heart rate at exhaustion (HR(peak)) were collected for both tests. Intraclass correlation coefficients (ICCs) for the "Combined" and Under 20s were very large (r > 0.7), whereas the ICCs for Under 16s and Under 18s were almost perfect (r > 0.9). Coefficients of variation were 1.9% (95% confidence interval, 1.6-2.4) for the combined test-retest of the 30-15(IFT) and 0.6% (0.5 1.0) for HR(peak). As the typical error of measurement (TE) (0.36 km.h-1) was greater than the smallest worthwhile change (SWC) (0.21 km.h-1) value, the usefulness of the V(IFT) was rated as "marginal." The TE for HR(peak) was similar to the SWC, rating the usefulness of this variable as "OK." Despite the usefulness of the 30-15(IFT) being deemed Marginal, a change as small as 0.5 km.h 1 (1 stage) in V(IFT) could be considered substantial or "real." As a consequence, the 30-15(IFT) presents as both a reliable and useful field test in the assessment of intermittent fitness for rugby league players. PMID- 26102262 TI - Reliability of 1RM Split-Squat Performance and the Efficacy of Assessing Both Bilateral Squat and Split-Squat 1RM in a Single Session for Non-Resistance Trained Recreationally Active Men. AB - The purpose of this study was to determine the reliability of 1 repetition maximum (1RM) split squat (SS) and establish the efficacy of collecting 1RM-SS and 1RM bilateral squat (BLS) data in the same session, for a non-resistance trained recreationally active population. Fourteen males performed a submaximal familiarization session and 5 testing sessions. After familiarization, the 1RM-SS was tested in the following 3 sessions. In session 4, subjects were tested in both 1RM-SS and 1RM-BLS, with half performing SS then BLS and the remainder BLS then SS. In session 5, the testing order was reversed. Reliability statistics calculated included the following: changes in mean across sessions, coefficient of variation calculated from the typical error (TE) scores (%CV(TE)), and test retest reliability (intraclass correlation coefficient [ICC]) of 1RM-SS. Statistically significant differences between the mean 1RM-SS in sessions 1 and 2 (2.14 kg, p = 0.001), and sessions 1 and 3 (2.86 kg, p < 0.003) were found, indicating the requirement for an additional familiarization session before 1RM SS data collection. The %CV(TE) was 2.53% and the ICC was 0.97 for the 1RM-SS protocol. Performing SS before BLS tended to increase the mean 1RM-BLS (+2.1%), although the difference was not significant (p = 0.055). A reliable measure of 1RM-SS can be determined after 1 submaximal and 1 maximal familiarization session in non-resistance-trained recreationally active men. Analysis of the current data suggests that it is appropriate to perform both 1RM-SS and 1RM-BLS tests within the same testing session if 1RM-SS is performed before 1RM-BLS. However, further testing is warranted to firmly establish the effects of 1RM-SS on subsequent 1RM BLS. PMID- 26102263 TI - A combined experimental and theoretical study of the structural, electronic and vibrational properties of bulk and few-layer Td-WTe2. AB - The recent discovery of non-saturating giant positive magnetoresistance has aroused much interest in Td-WTe(2). We have investigated structural, electronic and vibrational properties of bulk and few-layer Td-WTe(2) experimentally and theoretically. Spin-orbit coupling is found to govern the semi-metallic character of Td-WTe(2) and its structural link with the metallic 1 T form provides an understanding of its structural stability. There is a metal-to-insulator switch over in the electrical conductivity and a change in the sign of the Seebeck coefficient around 373 K. Lattice vibrations of Td-WTe(2) have been analyzed using first-principles calculations. Out of the 33 possible zone-center Raman active modes, five distinct Raman bands are observed around 112, 118, 134, 165 and 212 cm(-1) in bulk Td-WTe(2). Based on symmetry analysis and calculated Raman tensors, we assign the intense bands at 165 cm(-1) and 212 cm(-1) to the A'(1)and A''(1) modes, respectively. Most of the Raman bands stiffen with decreasing thickness, and the ratio of the integrated intensities of the A''(1) to A'(1) bands decreases in the few-layer sample, while all the bands soften in both the bulk and few-layer samples with increasing temperature. PMID- 26102264 TI - Ultrasound evaluation of an atypical traumatic rupture of the tunica albuginea. PMID- 26102265 TI - Assessing the association of hyperglycaemia with mortality in patients with hip fractures. PMID- 26102266 TI - Response to Li and colleagues on hyperglycemia in hip fracture patients. PMID- 26102267 TI - Characterization of bottom hydrodynamic conditions on the central western Portuguese continental shelf based on benthic foraminifera and sedimentary parameters. AB - Dead benthic foraminiferal assemblages from the central western Portuguese continental shelf have been studied to identify the prevalent oceanographic processes in the study area. Sediment samples collected at 46 stations along transepts perpendicular to the coastal line, between the latitudes of 38-40 degrees N and 17-190 m water depth, in April/May 2008, were analysed for selected physicochemical parameters (temperature, redox potential), grain size, organic matter content, and benthic foraminifera. Statistical analysis identified two main groups of stations, the Inshore/Offshore groups, which are not only defined by their geographical positions, but easily distinguishable by different hydrodynamic conditions. The Offshore Group is mainly represented by deeper stations characterized by a higher percentage of fines and TOM, negative values of redox potential and by the higher foraminiferal density and species diversity than the Inshore one. Foraminiferal assemblages of the Offshore Group are dominated/represented by species (such as Cassidulina laevigata/Cassidulina carinata, Bolivina spathulata, Bolivina ordinaria, Globocassidulina minuta, Bulimina elongata/Bulimina gibba and Bulimina marginata) common in areas with significant concentrations of organic matter. The benthic foraminiferal assemblages of the Inshore Group are instead characterized by epifaunal species such as Lobatula lobatula, Cibicides ungerianus, Planorbulina mediterranensis, Gavelinopsis praegeri and Quinqueloculina seminula. Both the sedimentary and foraminiferal results suggest that this group of stations is subjected to stronger bottom hydrodynamic conditions, caused by waves and swell activity and coastal currents, than the Offshore Group. Bray-Curtis similarity comparison between the stations of both groups reveals that the Offshore Group has a higher internal similarity than the Inshore Group. These differences seem to stem from topographic forcing, from the presence of rocky outcrops, from canyons and capes, from the distribution of rivers and from the magnitude of their discharges, which determine specific hydrodynamic features and differences in the sedimentary deposits and biological productivity. The influence of the Tagus river (supply of fresh water, detritus and organic matter from continental sources), the presence of canyons and capes, which leave the most important imprint on the study area, are marked by changes in the foraminiferal assemblages both in the Inshore and Offshore groups. PMID- 26102269 TI - Evaluating Parameters Affecting Fluoroscopy Time During Percutaneous Nephrolithotomy: Focus on the Predictive Role of Guy's, S.T.O.N.E., and CROES Scoring Systems. AB - OBJECTIVE: To identify parameters predicting prolonged fluoroscopy time (FT) during percutaneous nephrolithotomy (PCNL) and to evaluate the predictive ability of Guy's stone score, S.T.O.N.E. nephrolithometry, and CROES nomogram. PATIENTS AND METHODS: We evaluated 153 consecutive patients who underwent a PCNL by a single experienced surgeon. Several preoperative, intraoperative, and postoperative parameters, including the three scoring systems, were assessed for their ability to predict FT. RESULTS: FT was significantly associated with stone burden, stone location, number of stones, number of punctures, and number of tracts. It was also significantly associated with all scoring systems. Fluoroscopy use was significantly higher in patients who were effectively treated in these with longer hospitalization, probably reflecting case complexity. No association was found with postoperative complications. CONCLUSIONS: FT during PCNL can be affected by several parameters. Identifying the ones that can affect FT can lead to fluoroscopy and radiation exposure decrease. Guy's stone score, S.T.O.N.E. nephrolithometry, and CROES nomogram can all predict complexed cases and the need for increased FT. PMID- 26102268 TI - Disfluency characteristics of Kannada-English bilingual adults who stutter. AB - The primary purpose of the present study was to investigate whether stuttering frequency differs between two languages in Kannada-English bilingual adults who stutter. The second purpose was to compare the relationship between grammatical class (content-function word dichotomy) and stuttering frequency in two languages. In addition, we also examined whether types of disfluencies vary between content and function words in two languages. Twenty-five bilingual adults who stutter that were proficient in both languages (mean age=22.5 years, SD=3.0) participated in the present study. Spontaneous speech samples were recorded in both Kannada and English and stuttering frequencies were calculated in both languages and for each type of grammatical category. Further, different types of disfluencies were noted for each type of grammatical category in both the languages. Results revealed significantly greater stuttering in L2 (English) compared to L1 (Kannada). In both the languages, significantly higher content words were stuttered compared to function words. When the comparison was done between two languages, significantly higher content words were stuttered in L1 compared to L2, whereas significantly higher function words were stuttered in L2 compared to L1. The types of disfluencies did not vary between content and function words and between two languages. Present results suggest that frequency and other aspects of stuttering may depend on the proficiency of the language. PMID- 26102270 TI - Steroids in teleost fishes: A functional point of view. AB - Steroid hormones are involved in the regulation of a variety of processes like embryonic development, sex differentiation, metabolism, immune responses, circadian rhythms, stress response, and reproduction in vertebrates. Teleost fishes and humans show a remarkable conservation in many developmental and physiological aspects, including the endocrine system in general and the steroid hormone related processes in particular. This review provides an overview of the current knowledge about steroid hormone biosynthesis and the steroid hormone receptors in teleost fishes and compares the findings to the human system. The impact of the duplicated genome in teleost fishes on steroid hormone biosynthesis and perception is addressed. Additionally, important processes in fish physiology regulated by steroid hormones, which are most dissimilar to humans, are described. We also give a short overview on the influence of anthropogenic endocrine disrupting compounds on steroid hormone signaling and the resulting adverse physiological effects for teleost fishes. By this approach, we show that the steroidogenesis, hormone receptors, and function of the steroid hormones are reasonably well understood when summarizing the available data of all teleost species analyzed to date. However, on the level of a single species or a certain fish-specific aspect of physiology, further research is needed. PMID- 26102271 TI - Local glucocorticoid production in the thymus. AB - Besides generating immunocompetent T lymphocytes, the thymus is an established site of de novo extra-adrenal glucocorticoid (GC) production. Among the compartments of the thymus, both stromal thymic epithelial cells (TECs) and thymocytes secrete biologically active GCs. Locally produced GCs secreted by the various thymic cellular compartments have been suggested to have different impact on thymic homeostasis. TEC-derived GCs may regulate thymocyte differentiation whereas thymocyte-derived GCs might regulate age-dependent involution. However the full biological significance of thymic-derived GCs is still not fully understood. In this review, we summarize and describe recent advances in the understanding of local GC production in the thymus and immunoregulatory steroid production by peripheral T cells and highlight the possible role of local GCs for thymus function. PMID- 26102272 TI - Regional cerebral blood flow single photon emission computed tomography for detection of Frontotemporal dementia in people with suspected dementia. AB - BACKGROUND: In the UK, dementia affects 5% of the population aged over 65 years and 25% of those over 85 years. Frontotemporal dementia (FTD) represents one subtype and is thought to account for up to 16% of all degenerative dementias. Although the core of the diagnostic process in dementia rests firmly on clinical and cognitive assessments, a wide range of investigations are available to aid diagnosis.Regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) is an established clinical tool that uses an intravenously injected radiolabelled tracer to map blood flow in the brain. In FTD the characteristic pattern seen is hypoperfusion of the frontal and anterior temporal lobes. This pattern of blood flow is different to patterns seen in other subtypes of dementia and so can be used to differentiate FTD.It has been proposed that a diagnosis of FTD, (particularly early stage), should be made not only on the basis of clinical criteria but using a combination of other diagnostic findings, including rCBF SPECT. However, more extensive testing comes at a financial cost, and with a potential risk to patient safety and comfort. OBJECTIVES: To determine the diagnostic accuracy of rCBF SPECT for diagnosing FTD in populations with suspected dementia in secondary/tertiary healthcare settings and in the differential diagnosis of FTD from other dementia subtypes. SEARCH METHODS: Our search strategy used two concepts: (a) the index test and (b) the condition of interest. We searched citation databases, including MEDLINE (Ovid SP), EMBASE (Ovid SP), BIOSIS (Ovid SP), Web of Science Core Collection (ISI Web of Science), PsycINFO (Ovid SP), CINAHL (EBSCOhost) and LILACS (Bireme), using structured search strategies appropriate for each database. In addition we searched specialised sources of diagnostic test accuracy studies and reviews including: MEDION (Universities of Maastricht and Leuven), DARE (Database of Abstracts of Reviews of Effects) and HTA (Health Technology Assessment) database.We requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies and used the related articles feature in PubMed to search for additional studies. We tracked key studies in citation databases such as Science Citation Index and Scopus to ascertain any further relevant studies. We identified 'grey' literature, mainly in the form of conference abstracts, through the Web of Science Core Collection, including Conference Proceedings Citation Index and Embase. The most recent search for this review was run on the 1 June 2013.Following title and abstract screening of the search results, full-text papers were obtained for each potentially eligible study. These papers were then independently evaluated for inclusion or exclusion. SELECTION CRITERIA: We included both case-control and cohort (delayed verification of diagnosis) studies. Where studies used a case-control design we included all participants who had a clinical diagnosis of FTD or other dementia subtype using standard clinical diagnostic criteria. For cohort studies, we included studies where all participants with suspected dementia were administered rCBF SPECT at baseline. We excluded studies of participants from selected populations (e.g. post-stroke) and studies of participants with a secondary cause of cognitive impairment. DATA COLLECTION AND ANALYSIS: Two review authors extracted information on study characteristics and data for the assessment of methodological quality and the investigation of heterogeneity. We assessed the methodological quality of each study using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. We produced a narrative summary describing numbers of studies that were found to have high/low/unclear risk of bias as well as concerns regarding applicability. To produce 2 x 2 tables, we dichotomised the rCBF SPECT results (scan positive or negative for FTD) and cross-tabulated them against the results for the reference standard. These tables were then used to calculate the sensitivity and specificity of the index test. Meta-analysis was not performed due to the considerable between-study variation in clinical and methodological characteristics. MAIN RESULTS: Eleven studies (1117 participants) met our inclusion criteria. These consisted of six case-control studies, two retrospective cohort studies and three prospective cohort studies. Three studies used single-headed camera SPECT while the remaining eight used multiple-headed camera SPECT. Study design and methods varied widely. Overall, participant selection was not well described and the studies were judged as having either high or unclear risk of bias. Often the threshold used to define a positive SPECT result was not predefined and the results were reported with knowledge of the reference standard. Concerns regarding applicability of the studies to the review question were generally low across all three domains (participant selection, index test and reference standard).Sensitivities and specificities for differentiating FTD from non-FTD ranged from 0.73 to 1.00 and from 0.80 to 1.00, respectively, for the three multiple-headed camera studies. Sensitivities were lower for the two single-headed camera studies; one reported a sensitivity and specificity of 0.40 (95% confidence interval (CI) 0.05 to 0.85) and 0.95 (95% CI 0.90 to 0.98), respectively, and the other a sensitivity and specificity of 0.36 (95% CI 0.24 to 0.50) and 0.92 (95% CI 0.88 to 0.95), respectively.Eight of the 11 studies which used SPECT to differentiate FTD from Alzheimer's disease used multiple-headed camera SPECT. Of these studies, five used a case-control design and reported sensitivities of between 0.52 and 1.00, and specificities of between 0.41 and 0.86. The remaining three studies used a cohort design and reported sensitivities of between 0.73 and 1.00, and specificities of between 0.94 and 1.00. The three studies that used single-headed camera SPECT reported sensitivities of between 0.40 and 0.80, and specificities of between 0.61 and 0.97. AUTHORS' CONCLUSIONS: At present, we would not recommend the routine use of rCBF SPECT in clinical practice because there is insufficient evidence from the available literature to support this.Further research into the use of rCBF SPECT for differentiating FTD from other dementias is required. In particular, protocols should be standardised, study populations should be well described, the threshold for 'abnormal' scans predefined and clear details given on how scans are analysed. More prospective cohort studies that verify the presence or absence of FTD during a period of follow up should be undertaken. PMID- 26102273 TI - Transcriptome-wide measurement of ribosomal occupancy by ribosome profiling. AB - Gene expression profiling provides a tool to analyze the internal states of cells or organisms, and their responses to perturbations. While global measurements of mRNA levels have thus been widely used for many years, it is only through the recent development of the ribosome profiling technique that an analogous examination of global mRNA translation programs has become possible. Ribosome profiling reveals which RNAs are being translated to what extent and where the translated open reading frames are located. In addition, different modes of translation regulation can be distinguished and characterized. Here, we present an optimized, step-by-step protocol for ribosome profiling. Although established in Caenorhabditis elegans, our protocol and optimization approaches should be equally usable for other model organisms or cell culture with little adaptation. Next to providing a protocol, we compare two different methods for isolation of single ribosomes and two different library preparations, and describe strategies to optimize the RNase digest and to reduce ribosomal RNA contamination in the libraries. Moreover, we discuss bioinformatic strategies to evaluate the quality of the data and explain how the data can be analyzed for different applications. In sum, this article seeks to facilitate the understanding, execution, and optimization of ribosome profiling experiments. PMID- 26102274 TI - Cholinergic chemosensory cells of the thymic medulla express the bitter receptor Tas2r131. AB - The thymus is the site of T cell maturation which includes positive selection in the cortex and negative selection in the medulla. Acetylcholine is locally produced in the thymus and cholinergic signaling influences the T cell development. We recently described a distinct subset of medullary epithelial cells in the murine thymus which express the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT) and components of the canonical taste transduction cascade, i.e. transient receptor potential melastatin-like subtype 5 channel (TRPM5), phospholipase Cbeta(2), and Galpha-gustducin. Such a chemical phenotype is characteristic for chemosensory cells of mucosal surfaces which utilize bitter receptors for detection of potentially hazardous compounds and cholinergic signaling to initiate avoidance reflexes. We here demonstrate mRNA expression of bitter receptors Tas2r105, Tas2r108, and Tas2r131 in the murine thymus. Using a Tas2r131-tauGFP reporter mouse we localized the expression of this receptor to cholinergic cells expressing the downstream elements of the taste transduction pathway. These cells are distinct from the medullary thymic epithelial cells which promiscuously express tissue-restricted self-antigens during the process of negative selection, since double-labeling immunofluorescence showed no colocalization of autoimmune regulator (AIRE), the key mediator of negative selection, and TRPM5. These data demonstrate the presence of bitter taste-sensing signaling in cholinergic epithelial cells in the thymic medulla and opens a discussion as to what is the physiological role of this pathway. PMID- 26102275 TI - The Biogeography of Putative Microbial Antibiotic Production. AB - Understanding patterns in the distribution and abundance of functional traits across a landscape is of fundamental importance to ecology. Mapping these distributions is particularly challenging for species-rich groups with sparse trait measurement coverage, such as flowering plants, insects, and microorganisms. Here, we use likelihood-based character reconstruction to infer and analyze the spatial distribution of unmeasured traits. We apply this framework to a microbial dataset comprised of 11,732 ketosynthase alpha gene sequences extracted from 144 soil samples from three continents to document the spatial distribution of putative microbial polyketide antibiotic production. Antibiotic production is a key competitive strategy for soil microbial survival and performance. Additionally, novel antibiotic discovery is highly relevant to human health, making natural antibiotic production by soil microorganisms a major target for bioprospecting. Our comparison of trait-based biogeographical patterns to patterns based on taxonomy and phylogeny is relevant to our basic understanding of microbial biogeography as well as the pressing need for new antibiotics. PMID- 26102276 TI - Effect of APOE and CD33 on Cognitive Decline. AB - OBJECTIVE: An Alzheimer's disease (AD) diagnosis is preceded by a long period of cognitive decline. We previously demonstrated increased risk of decline among individuals possessing one or more APOE epsilon4 alleles together with a family history of AD. The objective of this study is to investigate the possibility that such an increased risk might be due to AD risk genes with small effects in combination with APOE. METHODS: Participants in the Health and Retirement Study (HRS) over the age of 65, who contributed DNA, and had two or more evaluations with an abbreviated version of the modified Telephone Interview for Cognitive Status (TICS-m) were eligible for the study (n = 7451). A genetic risk score (g score) was derived using AD risk genes' meta-analyses data, assigning risk according to the number of risk alleles and summed over all the risk genes. Trajectories of cognitive function were modeled in four groups of Caucasian participants with and without one or more APOE epsilon4 alleles and either a high or low g-score: APOE epsilon4-/low g-score; APOE epsilon4-/high g-score; APOE epsilon4+/low g-score; and APOE epsilon4+/high g-score. Post hoc analyses evaluated interactions between individual genes and APOE. RESULTS: Individuals in the APOE epsilon4+/high g-score group exhibited the greatest cognitive decline over time (p<.0001). This risk appeared to be greater than the sum of the effects of either high g-score or APOE epsilon4 alone. When gene interactions were individually tested with APOE, a statistically significant interaction with CD33 was discovered (p = 0.04) although the interaction was no longer significant when adjusted for multiple comparisons. CONCLUSIONS: Individuals with multiple AD risk genes in addition to having one or more APOE epsilon4 alleles are at greater risk of cognitive decline than individuals with either APOE epsilon4 or a high genetic risk score. Among those with one or more APOE epsilon4 alleles, having one or more copies of the CD33 C (risk) allele may further increase the risk of cognitive decline. PMID- 26102279 TI - Identification of Two Homozygous Sequence Variants in the COL7A1 Gene Underlying Dystrophic Epidermolysis Bullosa by Whole-Exome Analysis in a Consanguineous Family. AB - Dystrophic epidermolysis bullosa (DEB) is an inherited skin disorder with variable severity and heterogeneous genetic involvement. Diagnostic approaches for this condition include clinical evaluations and electron microscopy of patients' skin biopsies, followed by Sanger sequencing (SS) of a large gene (118 exons) that encodes the alpha chain of type VII collagen (COL7A1) located on Chromosome 3p21.1. However, the use of SS may hinder diagnostic efficiency and lead to delays because it is costly and time-consuming. We evaluated a 5 generation consanguineous family with 3 affected individuals presenting the severe generalised DEB phenotype. Human whole-exome sequencing (WES) revealed 2 homozygous sequence variants: the previously reported variant p.Arg578* in exon 13 and a novel variant p.Arg2063Gln in exon 74 of the COL7A1 gene. Validation by SS, performed on all family members, confirmed the cosegregation of the 2 variants with the disease phenotype. To the best of our knowledge, 2 homozygous COL7A1 variants have never been simultaneously reported in DEB patients; however, the upstream protein truncation variant is more likely to be disease-causing than the novel missense variant. WES can be used as an efficient molecular diagnostic tool for evaluating autosomal recessive forms of DEB. PMID- 26102277 TI - Identification of Ganglioside GM3 Molecular Species in Human Serum Associated with Risk Factors of Metabolic Syndrome. AB - Serum GM3 molecular species were quantified in 125 Japanese residents using tandem mass spectrometry multiple reaction monitoring. Individuals were categorized by the presence or absence of metabolic disease risk factors including visceral fat accumulation, hyperglycemia and dyslipidemia. A total of 23 GM3 molecular species were measured, of these, eight were found to be significantly elevated in individuals with visceral fat accumulation and metabolic disease, defined as the presence of hyperglycemia and dyslipidemia. All of the GM3 molecular species were composed of the sphingoid base sphingosine (d18:1 (Delta4)) and, interestingly, six of the eight elevated GM3 molecular species contained a hydroxylated ceramide moiety. The hydroxylated GM3 species were, in order of decreasing abundance, d18:1-h24:0 ~ d18:1-h24:1 > d18:1-h22:0 " d18:1-h20:0 > d18:1-h21:0 > d18:1-h18:1. Univariate and multiple linear regression analyses were conducted using a number of clinical health variables associated with obesity, type 2 diabetes, metabolic disease, atherosclerosis and hypertension. GM3(d18:1-h24:1) was identified as the best candidate for metabolic screening, proving to be significantly correlated with intima-media thickness, used for the detection of atherosclerotic disease in humans, and a number of metabolic disease risk factors including autotaxin, LDL-c and homeostatic model assessment insulin resistance (HOMA-IR). PMID- 26102280 TI - Clinical chemistry measurements with commercially available test slides on a smartphone platform: Colorimetric determination of glucose and urea. AB - BACKGKROUND: Rapidly increasing healthcare costs in economically advantaged countries are currently unsustainable, while in many developing nations, even 50 year-old technologies are too expensive to implement. New and unconventional technologies are being explored as solutions to this problem. In this study, we examined the use of a smartphone as the detection platform for 2 well-developed, relatively inexpensive, commercially available clinical chemistry assays as a model for rapid and inexpensive clinical diagnostic testing. METHODS: An Apple iPhone 4 camera phone equipped with a color analysis application (ColorAssist) was combined with Vitros(r) glucose and urea colorimetric assays. Color images of assay slides at various concentrations of glucose or urea were collected with the iPhone 4 and quantitated in three different spectral ranges (red/green/blue or RGB) using the ColorAssist app. When the diffuse reflectance data was converted into absorbance, it was possible to quantitate glucose or blood urea nitrogen (BUN) over their clinically important concentration ranges (30-515mg/dl for glucose or 2-190mg/dl for BUN), with good linearity (R(2)=0.9994 or 0.9996, respectively [n=5]). RESULTS: Data collected using the iPhone 4 and canine serum samples were in agreement with results from the instrumental "gold standard" (Beckman Coulter AU480 Chemistry System) (R(2)=0.9966 and slope=1.0001 for glucose; R(2)=0.9958 and slope=0.9454 for BUN). Glucose determinations of serum samples made using this smartphone method were as accurate as or more accurate than a commercial colorimetric dry slide analyzer (Heska(r) Element DC Chemistry Analyzer, Loveland, CO) and 2 glucometers: ReliOn(r) Ultima (Abbott Diabetes Care Inc) and Presto(r) (AgaMatrix Inc.H). BUN determinations made using the smartphone approach were comparable in accuracy to the Heska instrument. CONCLUSION: This demonstration shows that smartphones have the potential to be used as simple, effective colorimetric detectors for quantitative diagnostic tests, and may be applicable for both point-of-care applications in the developed world and field deployment in developing nations. PMID- 26102281 TI - Platelet aggregation in citrated whole blood of the first trimester of pregnancy. AB - BACKGROUND: It was recently suggested that platelet reactivity is reduced in early pregnancy. This study was performed to determine whether the citrated whole blood from 33 pregnant women in their first trimester showed spontaneous platelet aggregation and whether it differed in extent from that of 11 non-pregnant women. METHODS: The platelet count and number of platelet aggregates (PA) were serially determined in the same citrated whole blood specimens at 15, 30, 45, 60, 75, and 90min after blood sampling using a hematology analyzer. RESULTS: The number of PA increased significantly at 30min and thereafter in both groups, but was consistently lower for pregnant than non-pregnant women over the 90-min observation period. The platelet count decreased significantly in a time dependent manner in both groups, but was significantly lower at 30 and 90min for non-pregnant than pregnant women. The number of PA showed a significant positive correlation with net decrease in platelet count for both pregnant and non pregnant women. PA counts were also significantly positively correlated with the mean platelet volume. CONCLUSION: Platelet reactivity monitored by the increase in number of PA and the fall in platelet count was reduced in early pregnancy compared with non-pregnant healthy controls. PMID- 26102282 TI - Effects of Nucleotides Supplementation of Infant Formulas on Plasma and Erythrocyte Fatty Acid Composition: A Meta-Analysis. AB - OBJECTIVE: Nucleotides (NTs) have been added to infant formulas for several years due to their health benefits. However, studies have reported inconsistent findings regarding the association between NTs and fatty acid (FA) composition. A meta-analysis was performed to assess the effects of NTs supplementation of infant formula on erythrocyte and plasma FA composition. METHODS: Randomized controlled trials that evaluated the association between NTs supplementation and FA composition and were published before October 2014 were included. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed using Q and I2 tests. RESULTS: Eight studies (364 infants) were included in the meta-analysis. NTs supplementation did not affect the concentrations of total saturated FAs (SMD= 0.05; 95% CI= -0.23-0.32; P = 0.75) or total monounsaturated FAs (SMD= -0.01; 95% CI= -0.28-0.27; P = 0.95) in erythrocyte membranes. Erythrocyte total n-3 (SMD= 0.15; 95% CI= -0.11-0.41; P = 0.27) and n-6 PUFA (SMD= -0.16; 95% CI= -0.42-0.10, P = 0.22) concentrations did not increase with NTs supplementation. The concentrations of erythrocyte n-3 PUFA (18:3, 20:5, 22:5, and 22:6) and n-6 PUFA (18:2, 20:3, 20:4, and 22:4) were not affected by NTs supplementation. NTs significantly increased plasma concentrations of 18:2 n-6 (SMD= 0.90; 95% CI= 0.47-1.33; P < 0.0001), 20:3 n-6 (SMD= 0.56; 95% CI= 0.14-0.97; P = 0.009), and 20:4 n-6 PUFA (SMD= 0.92; 95% CI= 0.50-1.35; P < 0.0001), and significantly decreased the concentration of plasma 18:3 n-3 PUFA (SMD= -0.60; 95% CI -1.12 to -0.09; P = 0.02). No effect was obtained on plasma 20:2 n-6 PUFA concentrations (SMD= 0.06; 95 % CI, -1.03 to 0.2; P = 0.93). CONCLUSIONS: Our meta-analysis revealed that NTs supplementation significantly increased plasma 18:2 n-6, 20:3 n-6, and 20:4 n-6 PUFA concentrations in infants, but did not affect erythrocyte FA composition. PMID- 26102283 TI - Dendritic cell chimerism in oral mucosa of transplanted patients affected by graft-versus-host disease. AB - OBJECTIVE: Graft-versus-host disease (GVHD) is one of the main complications after haematopoietic stem cell transplantation. Clinical features of GVHD include either an acute (aGVHD) or a chronic (cGVHD) condition that affects locations such as the oral mucosa. While the involvement of the host's dendritic cells (DCs) has been demonstrated in aGVHD, the origin (donor/host) and mechanisms underlying oral cGVHD have not been completely elucidated. In this study, we intend to determine the origin of DCs present in mucosal tissue biopsies from the oral cavity of transplanted patients affected by cGVHD. METHODS: We purified DCs, from oral biopsies of three patients with cGVHD, through immunobeads and subsequently performed DNA extraction. The origin of the obtained DCs was determined by PCR amplification of 13 informative short tandem repeat (STR) alleles. We also characterised the DCs phenotype and the inflammatory infiltrate from biopsies of two patients by immunohistochemistry. RESULTS: Clinical and histological features of the biopsies were concordant with oral cGVHD. We identified CD11c-, CD207- and CD1a-positive cells in the epithelium and beneath the basal layer. Purification of DCs from the mucosa of patients affected by post transplantation cGVHD was >95%. PCR-STR data analysis of DCs DNA showed that 100% of analysed cells were of donor origin in all of the evaluated patients. CONCLUSION: Our results demonstrate that resident DCs isolated from the oral tissue of allotransplanted patients affected by cGVHD are originated from the donor. Further research will clarify the role of DCs in the development and/or severity of oral cGVHD. PMID- 26102284 TI - Expression of Genes for Drug Transporters in the Human Female Genital Tract and Modulatory Effect of Antiretroviral Drugs. AB - Anti-retroviral (ARV) -based microbicides are one of the strategies pursued to prevent HIV-1 transmission. Delivery of ARV drugs to subepithelial CD4+ T cells at concentrations for protection is likely determined by drug transporters expressed in the cervicovaginal epithelium. To define the role of drug transporters in mucosal disposition of topically applied ARV-based microbicides, these must be tested in epithelial cell line-based biopharmaceutical assays factoring the effect of relevant drug transporters. We have characterised gene expression of influx and efflux drug transporters in a panel of cervicovaginal cell lines and compared this to expression in cervicovaginal tissue. We also investigated the effect of dapivirine, darunavir and tenofovir, currently at advanced stages of microbicides development, on expression of drug transporters in cell lines. Expression of efflux ABC transporters in cervical tissue was best represented in HeLa, Ect1/E6E7 and End1/E6E7 cell lines. Expression of influx OCT and ENT transporters in ectocervix matched expression in Hela while expression of influx SLCO transporters in vagina was best reflected in VK2/E6E7 cell line. Stimulation with darunavir and dapivirine upregulated MRP transporters, including MRP5 involved in transport of tenofovir. Dapivirine also significantly downregulated tenofovir substrate MRP4 in cervical cell lines. Treatment with darunavir and dapivirine showed no significant effect on expression of BCRP, MRP2 and P-glycoprotein implicated in efflux of different ARV drugs. Darunavir strongly induced expression in most cell lines of CNT3 involved in cell uptake of nucleotide/nucleoside analogue reverse transcriptase inhibitors and SLCO drug transporters involved in cell uptake of protease inhibitors. This study provides insight into the suitability of cervicovaginal cell lines for assessment of ARV drugs in transport kinetics studies. The modulatory effect of darunavir and dapivirine on expression of drug transporters involved in transport of tenofovir points to the possibility of combining these drugs to improve retention of individual drugs at target tissues. PMID- 26102285 TI - Integrative Transcriptome Profiling of Cognitive Aging and Its Preservation through Ser/Thr Protein Phosphatase Regulation. AB - Environmental enrichment has been reported to delay or restore age-related cognitive deficits, however, a mechanism to account for the cause and progression of normal cognitive decline and its preservation by environmental enrichment is lacking. Using genome-wide SAGE-Seq, we provide a global assessment of differentially expressed genes altered with age and environmental enrichment in the hippocampus. Qualitative and quantitative proteomics in naive young and aged mice was used to further identify phosphorylated proteins differentially expressed with age. We found that increased expression of endogenous protein phosphatase-1 inhibitors in aged mice may be characteristic of long-term environmental enrichment and improved cognitive status. As such, hippocampus dependent performances in spatial, recognition, and associative memories, which are sensitive to aging, were preserved by environmental enrichment and accompanied by decreased protein phosphatase activity. Age-associated phosphorylated proteins were also found to correspond to the functional categories of age-associated genes identified through transcriptome analysis. Together, this study provides a comprehensive map of the transcriptome and proteome in the aging brain, and elucidates endogenous protein phosphatase-1 inhibition as a potential means through which environmental enrichment may ameliorate age-related cognitive deficits. PMID- 26102286 TI - The Link between Microbial Diversity and Nitrogen Cycling in Marine Sediments Is Modulated by Macrofaunal Bioturbation. AB - OBJECTIVES: The marine benthic nitrogen cycle is affected by both the presence and activity of macrofauna and the diversity of N-cycling microbes. However, integrated research simultaneously investigating macrofauna, microbes and N cycling is lacking. We investigated spatio-temporal patterns in microbial community composition and diversity, macrofaunal abundance and their sediment reworking activity, and N-cycling in seven subtidal stations in the Southern North Sea. SPATIO-TEMPORAL PATTERNS OF THE MICROBIAL COMMUNITIES: Our results indicated that bacteria (total and beta-AOB) showed more spatio-temporal variation than archaea (total and AOA) as sedimentation of organic matter and the subsequent changes in the environment had a stronger impact on their community composition and diversity indices in our study area. However, spatio-temporal patterns of total bacterial and beta-AOB communities were different and related to the availability of ammonium for the autotrophic beta-AOB. Highest bacterial richness and diversity were observed in June at the timing of the phytoplankton bloom deposition, while richness of beta-AOB as well as AOA peaked in September. Total archaeal community showed no temporal variation in diversity indices. MACROFAUNA, MICROBES AND THE BENTHIC N-CYCLE: Distance based linear models revealed that, independent from the effect of grain size and the quality and quantity of sediment organic matter, nitrification and N-mineralization were affected by respectively the diversity of metabolically active beta-AOB and AOA, and the total bacteria, near the sediment-water interface. Separate models demonstrated a significant and independent effect of macrofaunal activities on community composition and richness of total bacteria, and diversity indices of metabolically active AOA. Diversity of beta-AOB was significantly affected by macrofaunal abundance. Our results support the link between microbial biodiversity and ecosystem functioning in marine sediments, and provided broad correlative support for the hypothesis that this relationship is modulated by macrofaunal activity. We hypothesized that the latter effect can be explained by their bioturbating and bio-irrigating activities, increasing the spatial complexity of the biogeochemical environment. PMID- 26102287 TI - Inference of Network Dynamics and Metabolic Interactions in the Gut Microbiome. AB - We present a novel methodology to construct a Boolean dynamic model from time series metagenomic information and integrate this modeling with genome-scale metabolic network reconstructions to identify metabolic underpinnings for microbial interactions. We apply this in the context of a critical health issue: clindamycin antibiotic treatment and opportunistic Clostridium difficile infection. Our model recapitulates known dynamics of clindamycin antibiotic treatment and C. difficile infection and predicts therapeutic probiotic interventions to suppress C. difficile infection. Genome-scale metabolic network reconstructions reveal metabolic differences between community members and are used to explore the role of metabolism in the observed microbial interactions. In vitro experimental data validate a key result of our computational model, that B. intestinihominis can in fact slow C. difficile growth. PMID- 26102288 TI - Heterotrophic-autotrophic sequential system for reductive nitrate and perchlorate removal. AB - Nitrate and perchlorate were identified as significant water contaminants all over the world. This study aims at evaluating the performances of the heterotrophic-autotrophic sequential denitrification process for reductive nitrate and perchlorate removal from drinking water. The reduced nitrate concentration in the heterotrophic reactor increased with increasing methanol concentrations and the remaining nitrate/nitrite was further removed in the following autotrophic denitrifying process. The performances of the sequential process were studied under varying nitrate loads of [Formula: see text] at a fixed hydraulic retention time of 2 h. The C/N ratio in the heterotrophic reactor varied between 1.24 and 2.77 throughout the study. Nitrate and perchlorate reduced completely with maximum initial concentrations of [Formula: see text] and 1000 ug/L, respectively. The maximum denitrification rate for the heterotrophic reactor was [Formula: see text] when the bioreactor was fed with [Formula: see text] and 277 mg/L methanol. For the autotrophic reactor, the highest denitrification rate was [Formula: see text] in the first period when the heterotrophic reactor performance was low. Perchlorate reduction was initiated in the heterotrophic reactor, but completed in the following autotrophic process. Effluent sulphate concentration was below the drinking water standard level of 250 mg/L and pH was in the neutral level. PMID- 26102290 TI - Significance of weak interactions in imidazolium picrate ionic liquids: spectroscopic and theoretical studies for molecular level understanding. AB - The effects of interionic hydrogen bonding and pi-pi stacking interactions on the physical properties of a new series of picrate anion based ionic liquids (ILs) have been investigated experimentally and theoretically. The existence of aromatic (C2-HO) and aliphatic (C7-HO-N22 and C6-HO-N20) hydrogen bonding and pi pi stacking interactions in these ILs has been observed using various spectroscopic techniques. The aromatic and aliphatic C-HO hydrogen bonding interactions are found to have a crucial role in binding the imidazolium cation and picrate anion together. However, the pi-pi stacking interactions between two successive layers are found to play a decisive role in tight packing in ILs leading to differences in physical properties. The drastic difference in the melting points of the methyl and propyl derivatives (mmimPic and pmimPic respectively) have been found to be primarily due to the difference in the strength and varieties of pi-pi stacking interactions. While in mmimPic, several different types of pi-pi stacking interactions between the aromatic rings (such as picrate-picrate, picrate-imidazole and imidazolium-imidazolium cation rings) are observed, only one type of pi-pi stacking interaction (picrate-picrate rings) is found to exist in the pmimPic IL. NMR spectroscopic studies reveal that the interaction of these ILs with solvent molecules is different and depends on the dielectric constant of the solvent. While an ion solvation model explains the solvation in high dielectric solvents, an ion-pair solvation model is found to be more appropriate for low dielectric constant solvents. The enhanced stability of these investigated picrate ILs compared with that of inorganic picrate salts under high doses of gamma radiation clearly indicates the importance of weak interionic interactions in ILs, and also opens up the possibility of the application of picrate ILs as prospective diluents in nuclear separation for advanced fuel cycling process. PMID- 26102289 TI - CD4 T cell differentiation in type 1 diabetes. AB - Susceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention. PMID- 26102292 TI - Multicolor fluorescent graphene quantum dots colorimetrically responsive to all pH and a wide temperature range. AB - Smart functional nanomaterials colorimetrically responsive to all-pH and a wide temperature range are urgently needed due to their widespread applications in biotechnology, drug delivery, diagnosis and optical sensing. Although graphene quantum dots possess remarkable advantages in biological applications, they are only stable in neutral or weak acidic solutions, and strong acidic or alkaline conditions invariably suppress or diminish the fluorescence intensity. Herein, we report a new type of water-soluble, multicolor fluorescent graphene quantum dot which is responsive to all-pH from 1 to 14 with the naked eye. The synthesis was accomplished by electrolysis of the graphite rod, followed by refluxing in a concentrated nitric and sulfuric acid mixed solution. We demonstrate the novel red fluorescence of quinone structures transformed from the lactone structures under strong alkaline conditions. The fluorescence of the resulting graphene quantum dots was also found to be responsive to the temperature changes, demonstrating their great potential as a dual probe of pH and temperature in complicated environments such as biological media. PMID- 26102291 TI - Environmental (Saprozoic) Pathogens of Engineered Water Systems: Understanding Their Ecology for Risk Assessment and Management. AB - Major waterborne (enteric) pathogens are relatively well understood and treatment controls are effective when well managed. However, water-based, saprozoic pathogens that grow within engineered water systems (primarily within biofilms/sediments) cannot be controlled by water treatment alone prior to entry into water distribution and other engineered water systems. Growth within biofilms or as in the case of Legionella pneumophila, primarily within free living protozoa feeding on biofilms, results from competitive advantage. Meaning, to understand how to manage water-based pathogen diseases (a sub-set of saprozoses) we need to understand the microbial ecology of biofilms; with key factors including biofilm bacterial diversity that influence amoebae hosts and members antagonistic to water-based pathogens, along with impacts from biofilm substratum, water temperature, flow conditions and disinfectant residual-all control variables. Major saprozoic pathogens covering viruses, bacteria, fungi and free-living protozoa are listed, yet today most of the recognized health burden from drinking waters is driven by legionellae, non-tuberculous mycobacteria (NTM) and, to a lesser extent, Pseudomonas aeruginosa. In developing best management practices for engineered water systems based on hazard analysis critical control point (HACCP) or water safety plan (WSP) approaches, multi factor control strategies, based on quantitative microbial risk assessments need to be developed, to reduce disease from largely opportunistic, water-based pathogens. PMID- 26102293 TI - Monocyte-macrophage differentiation of acute myeloid leukemia cell lines by small molecules identified through interrogation of the Connectivity Map database. AB - The transcription factor C/EBPalpha is required for granulocytic differentiation of normal myeloid progenitors and is frequently inactivated in acute myeloid leukemia (AML) cells. Ectopic expression of C/EBPalpha in AML cells suppresses proliferation and induces differentiation suggesting that restoring C/EBPalpha expression/activity in AML cells could be therapeutically useful. Unfortunately, current approaches of gene or protein delivery in leukemic cells are unsatisfactory. However, "drug repurposing" is becoming a very attractive strategy to identify potential new uses for existing drugs. In this study, we assessed the biological effects of candidate C/EBPalpha-mimetics identified by interrogation of the Connectivity Map database. We found that amantadine, an antiviral and anti-Parkinson agent, induced a monocyte-macrophage-like differentiation of HL60, U937, Kasumi-1 myeloid leukemia cell lines, as indicated by morphology and differentiation antigen expression, when used in combination with suboptimal concentration of all trans retinoic acid (ATRA) or Vit D3. The effect of amantadine depends, in part, on increased activity of the vitamin D receptor (VDR), since it induced VDR expression and amantadine-dependent monocyte macrophage differentiation of HL60 cells was blocked by expression of dominant negative VDR. These results reveal a new function for amantadine and support the concept that screening of the Connectivity Map database can identify small molecules that mimic the effect of transcription factors required for myelo monocytic differentiation. PMID- 26102295 TI - Simple synthesis of Prussian blue analogues in room temperature ionic liquid solution and their catalytic application in epoxidation of styrene. AB - In this article, a new application of the room temperature ionic liquid, tetramethylammonium tetrafluoroborate, is described. This ionic liquid is used as a stabilizing agent and the reaction medium for the synthesis of CoFe Prussian blue analogue nanoparticles using N,N-dimethyl formamide as a complexing agent. The as-synthesized Prussian blue analogues were characterized by various techniques and were used to catalyze the reaction of epoxidation of styrene. The catalytic activity of Prussian blue analogues prepared in ionic liquid was superior to that of Prussian blue analogues prepared in aqueous solution. PMID- 26102294 TI - Role of stress-activated OCT4A in the cell fate decisions of embryonal carcinoma cells treated with etoposide. AB - Tumor cellular senescence induced by genotoxic treatments has recently been found to be paradoxically linked to the induction of "stemness." This observation is critical as it directly impinges upon the response of tumors to current chemo radio-therapy treatment regimens. Previously, we showed that following etoposide (ETO) treatment embryonal carcinoma PA-1 cells undergo a p53-dependent upregulation of OCT4A and p21Cip1 (governing self-renewal and regulating cell cycle inhibition and senescence, respectively). Here we report further detail on the relationship between these and other critical cell-fate regulators. PA-1 cells treated with ETO display highly heterogeneous increases in OCT4A and p21Cip1 indicative of dis-adaptation catastrophe. Silencing OCT4A suppresses p21Cip1, changes cell cycle regulation and subsequently suppresses terminal senescence; p21Cip1-silencing did not affect OCT4A expression or cellular phenotype. SOX2 and NANOG expression did not change following ETO treatment suggesting a dissociation of OCT4A from its pluripotency function. Instead, ETO induced OCT4A was concomitant with activation of AMPK, a key component of metabolic stress and autophagy regulation. p16ink4a, the inducer of terminal senescence, underwent autophagic sequestration in the cytoplasm of ETO-treated cells, allowing alternative cell fates. Accordingly, failure of autophagy was accompanied by an accumulation of p16ink4a, nuclear disintegration, and loss of cell recovery. Together, these findings imply that OCT4A induction following DNA damage in PA-1 cells, performs a cell stress, rather than self-renewal, function by moderating the expression of p21Cip1, which alongside AMPK helps to then regulate autophagy. Moreover, this data indicates that exhaustion of autophagy, through persistent DNA damage, is the cause of terminal cellular senescence. PMID- 26102297 TI - Membrane Active Small Molecules Show Selective Broad Spectrum Antibacterial Activity with No Detectable Resistance and Eradicate Biofilms. AB - Treating bacterial biofilms with conventional antibiotics is limited due to ineffectiveness of the drugs and higher propensity to develop bacterial resistance. Development of new classes of antibacterial therapeutics with alternative mechanisms of action has become imperative. Herein, we report the design, synthesis, and biological evaluations of novel membrane-active small molecules featuring two positive charges, four nonpeptidic amide groups, and variable hydrophobic/hydrophilic (amphiphilic) character. The biocides synthesized via a facile methodology not only displayed good antibacterial activity against wild-type bacteria but also showed high activity against various drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE), and beta-lactam resistant Klebsiella pneumoniae. Further, these biocides not only inhibited the formation of biofilms but also disrupted the established S. aureus and E. coli biofilms. The membrane-active biocides hindered the propensity to develop bacterial resistance. Moreover, the biocides showed negligible toxicity against mammalian cells and thus bear potential to be used as therapeutic agents. PMID- 26102299 TI - Synthesis of N-Imidoyl and N-Oxoimidoyl Sulfoximines from 1-Alkynes, N-Sulfonyl Azides, and Sulfoximines. AB - N-Imidoylation of sulfoximines is developed from a Cu-catalyzed three-component reaction from 1-alkynes, N-sulfonyl azides, and sulfoximines in THF at room temperature under air. In addition, N-oxoimidoylation of sulfoximines is accessed from a Cu-catalyzed three-component reaction from 1-alkynes, N-sulfonyl azides, and sulfoximines in THF at room temperature followed by a Cu-catalyzed oxidative reaction at 50 degrees C under air, producing N-oxoimidoyl sulfoximines. PMID- 26102296 TI - Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota. AB - Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative anti-diabetic effects. Here, we show that a water extract of Ganoderma lucidum mycelium (WEGL) reduces body weight, inflammation and insulin resistance in mice fed a high-fat diet (HFD). Our data indicate that WEGL not only reverses HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels but also maintains intestinal barrier integrity and reduces metabolic endotoxemia. The anti-obesity and microbiota-modulating effects are transmissible via horizontal faeces transfer from WEGL-treated mice to HFD-fed mice. We further show that high molecular weight polysaccharides (>300 kDa) isolated from the WEGL extract produce similar anti-obesity and microbiota-modulating effects. Our results indicate that G. lucidum and its high molecular weight polysaccharides may be used as prebiotic agents to prevent gut dysbiosis and obesity-related metabolic disorders in obese individuals. PMID- 26102298 TI - Automated Telephone Self-Management Support for Diabetes in a Low-Income Health Plan: A Health Care Utilization and Cost Analysis. AB - The objective was to determine whether automated telephone self-management support (ATSM) for low-income, linguistically diverse health plan members with diabetes affects health care utilization or cost. A government-sponsored managed care plan for low-income patients implemented a demonstration project between 2009 and 2011 that involved a 6-month ATSM intervention for 362 English-, Spanish , or Cantonese-speaking members with diabetes from 4 publicly funded clinics. Participants were randomized to immediate intervention or a wait-list. Medical and pharmacy claims used in this analysis were obtained from the managed care plan. Medical claims included hospitalizations, ambulance use, emergency department visits, and outpatient visits. In the 6-month period following enrollment, intervention participants generated half as many emergency department visits and hospitalizations (rate ratio 0.52, 95% CI 0.26, 1.04) compared to wait listed participants, but these differences did not reach statistical significance (P=0.06). With adjustment for prior year cost, intervention participants also had a nonsignificant reduction of $26.78 in total health care costs compared to wait listed individuals (P=0.93). The observed trends suggest that ATSM could yield potential health service benefits for health plans that provide coverage for chronic disease patients in safety net settings. ATSM should be further scaled up to determine whether it is associated with a greater reduction in health care utilization and costs. PMID- 26102300 TI - Effect of Viscous Agents on Corneal Density in Dry Eye Disease. AB - PURPOSE: To investigate the effect of the viscous agents, hydroxypropyl methylcellulose (HPMC), carbomer, povidone, and a combination of HPMC and povidone on corneal density in patients with dry eye disease. METHODS: In total, 98 eyes of 49 patients suffering from dry eye and 65 eyes of 33 healthy age matched individuals were included in this prospective, randomized study. Corneal morphology was documented with Scheimpflug photography and corneal density was analyzed in 5 anatomical layers (epithelium, bowman membrane, stroma, descemet's membrane, and endothelium). Corneal density was evaluated for the active ingredients HPMC, carbomer, povidone, and a combination of HPMC and povidone as the viscous agents contained in the artificial tear formulations used by the dry eye patients. Data were compared to the age-matched healthy control group without medication. RESULTS: Corneal density in dry eye patients was reduced in all 5 anatomical layers compared to controls. Corneal density was highest and very close to control in patients treated with HPMC containing ocular lubricants. Patients treated with lubricants, including carbomer as the viscous agent displayed a significant reduction of corneal density in layers 1 and 2 compared to control. CONCLUSION: HPMC containing ocular lubricants can help to maintain physiological corneal density and may be beneficial in the treatment of dry eye disease. PMID- 26102301 TI - Integration of the nuclear receptor REV-ERBalpha linked with circadian oscillators in the expressions of Alas1, Ppargc1a, and Il6 genes in rat granulosa cells. AB - The nuclear receptor REV-ERBalpha links circadian rhythms and numerous physiological processes, but its physiological role in ovaries remains largely unknown. The aim of this study was to determine the potential role of REV ERBalpha in the regulation of the transcription of its putative target genes in granulosa cells (GCs) prepared from Per2-destablized luciferase (dLuc) reporter gene transgenic rats. Alas1, Ppargc1a, and Il6 were chosen as representatives for genes analysis. A real-time monitoring system of Per2 promoter activity was performed to detect Per2-dLuc circadian oscillations. Two agonists (GSK4112, heme) and an antagonist (SR8278) of REV-ERBalpha as well as Rev-erbalpha siRNA knockdown were used to identify its target genes. Clear Per2-dLuc circadian oscillations were generated in matured GCs after synchronization with GSK4112 or SR8278. GSK4112 treatment lengthened and SR8278 treatment shortened the period of circadian oscillations in matured GCs stimulated with or without luteinizing hormone (LH). GSK4112 showed an inhibitory effect on the amplitude of circadian oscillations and caused an arrhythmic expression of canonical clock genes. SR8278 also had a subtle effect on their daily expression profiles, but the treatment resulted only in the arrhythmic expression of Rev-erbalpha. These findings indicate the functional biological activity of REV-ERBalpha in response to its ligands. Its natural ligand heme further elongated the period of circadian oscillations and alleviated their amplitudes in GCs cultured with LH. Heme treatment also repressed the expressions of clock genes, Alas1, Il6, and Ppargc1a. Rev-erbalpha knockdown up-regulated these transcript levels. Collectively, these data extend the recent finding to rat GCs and demonstrate that REV-ERBalpha represses the expressions of Alas1, Ppargc1a, and Il6, providing novel insights into the physiological significance of REV-ERBalpha in ovarian circadian oscillators. PMID- 26102302 TI - Cubane: 50 years later. PMID- 26102303 TI - Detection of Significant Aprotic Solvent Effects on the Conformational Distribution of Methyl 4-Nitrophenyl Sulfoxide: From Gas-Phase Rotational to Liquid-Crystal NMR Spectroscopy. AB - The conformational equilibrium of methyl 4-nitrophenyl sulfoxide (MNPSO) was experimentally investigated in the gas phase by using microwave spectroscopy and in isotropic and nematic liquid-crystal solutions, in which the solvents are nonaqueous and aprotic, by using NMR spectroscopy; moreover, it was theoretically studied in vacuo and in solution at different levels of theory. The overall set of results indicates a significant dependence of the solute conformational distribution on the solvent dielectric permittivity constant: when dissolved in low-polarity media, the most stable conformation of MNPSO proved to be strongly twisted with respect to that in more polar solvents, in which the conformational distribution maximum essentially coincides with that obtained in the gas phase. We discuss a possible explanation of this behavior, which rests on electrostatic solute-solvent interactions and is supported by calculations of the solute electric dipole moment as a function of the torsional angle. This function shows that the least polar conformation of MNPSO is located at a twist angle close to that of the conformational distribution maximum found in less-polar solvents. This fact, associated with a relatively flat torsional potential, can justify the stabilization of the twisted conformation by the less-polar solvents. PMID- 26102304 TI - Hydrogen bond-aromaticity cooperativity in self-assembling 4-pyridone chains. AB - Self-assembling building blocks like the 4-pyridone can exhibit extraordinary H bond-aromaticity coupling effects. Computed dissected nucleus independent chemical shifts (NICS(1)zz), natural bond orbital (NBO) charges, and energy decomposition analyses (EDA) for a series of hydrogen (H-) bonded 4-pyridone chains (4-py)n (n = 2 to 8) reveal that H-bonding interactions can polarize the 4 pyridone exocyclic C=O bonds and increase 4n+2 pi-electron delocalization in the six-membered ring. The resulting H-bonded 4-pyridone units display enhanced pi aromatic character (both magnetically and energetically) and their corresponding N-H...O=C interactions are strengthened. These pi-electron polarization effects do not depend on the relative orientations (co-planar or perpendicular) of the neighboring 4-pyridone units, but increase with the number of H-bonded units. PMID- 26102305 TI - Electrocardiographic QRS Fragmentation as a Marker for Myocardial Fibrosis in Hypertrophic Cardiomyopathy. AB - INTRODUCTION: Myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM) usually shows a patchy distribution, which may not be detected by pathological Q waves on 12-lead ECGs. Fragmented QRS complexes (fQRS) reflect intraventricular conduction delay and can be a marker of myocardial fibrosis. We assessed whether fQRS show better correlation with myocardial fibrosis than pathological Q waves in HCM. METHODS AND RESULTS: This cross-sectional study included 108 patients with HCM who underwent 12-lead ECG and cardiac magnetic resonance imaging with late gadolinium enhancement (LGE-CMR). The number of leads with pathological Q waves was not correlated with the extent of LGE measured at any different standard deviations (SDs) (2, 4, 6, 8, and 10 SD), whereas the number of leads with fQRS showed the best correlation with LGE at 6 SD (r = 0.32, P = 0.0008). Further, the number of leads with fQRS was an independent predictor for the extent of LGE at 6 SD. fQRS showed higher accuracy for detecting myocardial fibrosis defined by LGE at 6 SD than pathological Q waves; the overall sensitivity, specificity, and accuracy of fQRS were 40%, 80%, and 64%, respectively, whereas those of pathological Q waves were 7%, 97%, and 60%, respectively. fQRS in lateral leads showed the highest accuracy (75%), followed by inferior leads (59%) and anterior leads (57%), for detecting LGE at 6 SD in the corresponding left ventricular segment. CONCLUSIONS: These findings suggest that fQRS may have a substantially higher sensitivity and diagnostic accuracy compared with pathological Q waves for detecting myocardial fibrosis in HCM. PMID- 26102306 TI - Ultrasound of the Groin: Techniques, Pathology, and Pitfalls. AB - OBJECTIVE: In a patient with symptoms referable to the groin, there can be a number of causes to consider and at times the cause of the symptoms is multifactorial. Although ultrasound can be effective in the evaluation of the groin, the depth and complexity of the anatomy can be problematic. A protocol driven approach for ultrasound evaluation of the groin will help to ensure an accurate and comprehensive evaluation. This article summarizes the ultrasound technique and protocol for evaluation of the groin to include evaluation of the hip joint, anterior hip musculature, the iliopsoas bursa, the inguinal lymph nodes, the pubic symphyseal region, and the inguinal region for hernias. Common pathologic conditions and pitfalls related to ultrasound evaluation of the groin will be reviewed. CONCLUSION: There are many potential pathologic conditions in a patient with groin symptoms. Because symptoms may be multifactorial and history may be ambiguous or misleading, a protocol-driven evaluation with ultrasound is recommended. The hip joint is evaluated for effusion, synovitis, and labral abnormalities. The muscles and tendons, including the common aponeurosis at the pubic symphysis, are evaluated for tendinosis and tears. Dynamic evaluation should be considered to assess for snapping hip syndrome. Iliopsoas bursal distention and lymph node enlargement are other considerations. Last, inguinal region hernias must be evaluated during the Valsalva maneuver and documented in two orthogonal planes to avoid several important diagnostic pitfalls. PMID- 26102307 TI - Sarcopenia: Current Concepts and Imaging Implications. AB - OBJECTIVE: The purpose of this article is to review the nomenclature, clinical impact, and diagnostic techniques characterizing sarcopenia. CONCLUSION: Sarcopenia-defined as significant loss of muscle-is associated with cachexia and frailty. Specific diagnostic criteria for sarcopenia continue to evolve, but imaging can play a role in the detection and quantification of muscle depletion. Emerging evidence indicates that sarcopenia is a relevant predictor of quality and quantity of life, particularly in patients who are elderly, have cancer, or undergo surgery. PMID- 26102308 TI - Vascular Imaging With Ferumoxytol as a Contrast Agent. AB - OBJECTIVE: Ferumoxytol is increasingly reported as an alternative to gadolinium based contrast agents for MR angiography (MRA), particularly for patients with renal failure. This article summarizes more than 3 years of clinical experience with ferumoxytol-enhanced MRA for a range of indications and anatomic regions. CONCLUSION: Ferumoxytol-enhanced MRA has many advantages including that it is safe for patients with renal failure and provides a lengthy plateau of vascular signal as a blood pool agent that allows longer navigated MRA sequences. PMID- 26102309 TI - Acute Middle East Respiratory Syndrome Coronavirus: Temporal Lung Changes Observed on the Chest Radiographs of 55 Patients. AB - OBJECTIVE: The objective of our study was to describe lung changes on serial chest radiographs from patients infected with the acute Middle East respiratory syndrome corona-virus (MERS-CoV) and to compare the chest radiographic findings and final outcomes with those of health care workers (HCWs) infected with the same virus. Chest radiographic scores and comorbidities were also examined as indicators of a fatal outcome to determine their potential prognostic value. MATERIALS AND METHODS: Chest radiographs of 33 patients and 22 HCWs infected with MERS-CoV were examined for radiologic features indicative of disease and for evidence of radiographic deterioration and progression. Chest radiographic scores were estimated after dividing each lung into three zones. The scores (1 [mild] to 4 [severe]) for all six zones per chest radiographic examination were summed to provide a cumulative chest radiographic score (range, 0-24). Serial radiographs were also examined to assess for radiographic deterioration and progression from type 1 (mild) to type 4 (severe) disease. Multivariate logistic regression analysis, Kaplan-Meier survival curve analysis, and the Mann-Whitney U test were used to compare data of deceased patients with those of individuals who recovered to identify prognostic radiographic features. RESULTS: Ground-glass opacity was the most common abnormality (66%) followed by consolidation (18%). Overall mortality was 35% (19/55). Mortality was higher in the patient group (55%, 18/33) than in the HCW group (5%, 1/22). The mean chest radiographic score for deceased patients was significantly higher than that for those who recovered (13 +/- 2.6 [SD] vs 5.8 +/- 5.6, respectively; p = 0.001); in addition, higher rates of pneumothorax (deceased patients vs patients who recovered, 47% vs 0%; p = 0.001), pleural effusion (63% vs 14%; p = 0.001), and type 4 radiographic progression (63% vs 6%; p = 0.001) were seen in the deceased patients compared with those who recovered. Univariate and logistic regression analyses identified the chest radiographic score as an independent predictor of mortality (odds ratio [OR], 1.38; 95% CI, 1.07-1.77; p = 0.01). The number of comorbidities in the patient group (n = 33) was significantly higher than that in the HCW group (n = 22) (mean number of comorbidities, 1.90 +/- 1.27 vs 0.17 +/- 0.65, respectively; p = 0.001). The Kaplan-Meier analysis revealed a median survival time of 15 days (95% CI, 4-26 days). CONCLUSION: Ground-glass opacity in a peripheral location was the most common abnormality noted on chest radiographs. A higher chest radiographic score coupled with a high number of medical comorbidities was associated with a poor prognosis and higher mortality in those infected with MERS-CoV. Younger HCWs with few or no comorbidities had a higher survival rate. PMID- 26102310 TI - Multidrug resistance-associated protein 4 expression in ammonia-treated cultured rat astrocytes and cerebral cortex of cirrhotic patients with hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a neuropsychiatric syndrome frequently accompanying liver cirrhosis and reflects the clinical manifestation of a low grade cerebral edema associated with cerebral oxidative/nitrosative stress. The multidrug resistance-associated protein (Mrp) 4 is an export pump which transports metabolites that were recently suggested to play a major role in the pathogenesis of HE such as neurosteroids and cyclic nucleotides. We therefore studied Mrp4 expression changes in ammonia-exposed cultured astrocytes and postmortem human brain samples of cirrhotic patients with HE. NH4 Cl increased Mrp4 mRNA and protein levels in astrocytes in a dose- and time-dependent manner up to threefold after 72 h of exposure and concurrently inhibited N-glycosylation of Mrp4 protein. Upregulation of Mrp4 mRNA and protein as well as impaired N glycosylation of Mrp4 protein by ammonia were sensitive towards the glutamine synthetase inhibitor l-methionine-S-sulfoximine and were not induced by CH3 NH3 Cl (5 mmol/L). Upregulation of Mrp4 mRNA required ammonia-induced activation of nitric oxide synthases or NADPH oxidase and p38MAPK -dependent activation of PPARalpha. Inhibition of Mrp4 by ceefourin 1 synergistically enhanced both, inhibition of astrocyte proliferation as well as transcription of the oxidative stress surrogate marker heme oxygenase 1 by forskolin (10 umol/L, 72 h) or NH4 Cl (5 mmol/L, 72 h) in cultured rat astrocytes. Increased Mrp4 mRNA and protein levels were also found in postmortem brain samples from patients with liver cirrhosis with HE but not in those without HE. The data show that Mrp4 is upregulated in HE, which may be relevant for the handling of neurosteroids and cyclic nucleotides in response to ammonia. GLIA 2015;63:2092-2105. PMID- 26102311 TI - Hydrate Shell Growth Measured Using NMR. AB - Benchtop nuclear magnetic resonance (NMR) pulsed field gradient (PFG) and relaxation measurements were used to monitor the clathrate hydrate shell growth occurring in water droplets dispersed in a continuous cyclopentane phase. These techniques allowed the growth of hydrate inside the opaque exterior shell to be monitored and, hence, information about the evolution of the shell's morphology to be deduced. NMR relaxation measurements were primarily used to monitor the hydrate shell growth kinetics, while PFG NMR diffusion experiments were used to determine the nominal droplet size distribution (DSD) of the unconverted water inside the shell core. A comparison of mean droplet sizes obtained directly via PFG NMR and independently deduced from relaxation measurements showed that the assumption of the shell model-a perfect spherical core of unconverted water-for these hydrate droplet systems is correct, but only after approximately 24 h of shell growth. Initially, hydrate growth is faster and heat-transfer-limited, leading to porous shells with surface areas larger than that of spheres with equivalent volumes. Subsequently, the hydrate growth rate becomes mass-transfer limited, and the shells become thicker, spherical, and less porous. PMID- 26102312 TI - Annuloselectivity in Reactions of Diacyl Dichlorides and Imines: Combined Experimental and Theoretical Studies. AB - The annuloselectivity defined as the annulation selectivity between [2 + 2] and cascade annulations of diacyl dichlorides and imines in the presence of organic bases to afford bis-beta-lactams and 2,3-dihydro-1,3-oxazin-4-ones has been studied extensively with a combination of experiments and density functional theory (DFT) calculations. The present results indicate that it is the preference of diacyl dichlorides in the formation of cyclic alpha-oxoketenes in the presence of organic bases that controls the annuloselectivity. The cascade annulations of hexanedioyl and heptanedioyl dichlorides undergo the chloride-assisted cyclization of the corresponding omega-chlorocarbonylalkylketenes as the rate determining step in the presence of triethylamine, rather than the generation of bisketenes followed by dimerization, affording five- and six-membered cyclic alpha-oxoketenes followed by the [4 + 2] annulations with imines to furnish 2,3 dihydro-1,3-oxazin-4-ones. This is an energetically competitive pathway to the normal Staudinger cycloaddition. Further decreasing (pentanedioyl dichloride) or increasing the linker length (octanedioyl and nonanedioyl dichlorides) results in the enhanced energetic barriers for the cyclization, which is less competitive to the direct Staudinger cycloaddition to afford bis-trans-beta-lactams as the sole products. The current results provide an insight into the annuloselective control in the reactions of diacyl dichlorides and imines. PMID- 26102313 TI - Pre-hospital non-invasive ventilation for acute respiratory failure: a systematic review and cost-effectiveness evaluation. AB - BACKGROUND: Non-invasive ventilation (NIV), in the form of continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP), is used in hospital to treat patients with acute respiratory failure. Pre hospital NIV may be more effective than in-hospital NIV but requires additional ambulance service resources. OBJECTIVES: We aimed to determine the clinical effectiveness and cost-effectiveness of pre-hospital NIV compared with usual care for adults presenting to the emergency services with acute respiratory failure and to identify priorities for future research. DATA SOURCES: Fourteen electronic databases and research registers (including MEDLINE In-Process & Other Non Indexed Citations, MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to August 2013, supplemented by hand-searching reference lists and contacting experts in the field. REVIEW METHODS: We included all randomised or quasi-randomised controlled trials of pre hospital NIV in patients with acute respiratory failure. Methodological quality was assessed according to established criteria. An aggregate data network meta analysis (NMA) of mortality and intubation was used to jointly estimate intervention effects relative to usual care. A NMA, using individual patient level data (IPD) and aggregate data where IPD were not available, was carried out to assess whether or not covariates were treatment effect modifiers. A de novo economic model was developed to explore the costs and health outcomes when pre hospital NIV (specifically CPAP provided by paramedics) and standard care (in hospital NIV) were applied to a hypothetical cohort of patients with acute respiratory failure. RESULTS: The literature searches identified 2284 citations. Of the 10 studies that met the inclusion criteria, eight were randomised controlled trials and two were quasi-randomised trials (six CPAP; four BiPAP; sample sizes 23-207 participants). IPD were available from seven trials (650 patients). The aggregate data NMA suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639), and reduced both mortality [odds ratio (OR) 0.41, 95% credible interval (CrI) 0.20 to 0.77] and intubation rate (OR 0.32, 95% CrI 0.17 to 0.62) compared with standard care. The effect of BiPAP on mortality (OR 1.94, 95% CrI 0.65 to 6.14) and intubation rate (OR 0.40, 95% CrI 0.14 to 1.16) compared with standard care was uncertain. The combined IPD and aggregate data NMA suggested that sex was a statistically significant treatment effect modifier for mortality. The economic analysis showed that pre-hospital CPAP was more effective and more expensive than standard care, with an incremental cost effectiveness ratio of L20,514 per quality-adjusted life-year (QALY) and a 49.5% probability of being cost-effective at the L20,000-per-QALY threshold. Variation in the incidence of eligible patients had a marked impact on cost-effectiveness and the expected value of sample information for a future randomised trial. LIMITATIONS: The meta-analysis lacked power to detect potentially important differences in outcome (particularly for BiPAP), the intervention was not always compared with the best alternative care (in-hospital NIV) in the primary studies and findings may not be generalisable. CONCLUSIONS: Pre-hospital CPAP can reduce mortality and intubation rates, but cost-effectiveness is uncertain and the value of further randomised evaluation depends on the incidence of suitable patients. A feasibility study is required to determine if a large pragmatic trial of clinical effectiveness and cost-effectiveness is appropriate. STUDY REGISTRATION: The study is registered as PROSPERO CRD42012002933. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26102314 TI - Stress-related changes to immune cells in the skin prior to wounding may impair subsequent healing. AB - Higher psychological stress is associated with slower dermal wound healing, but the immunological mechanisms behind this effect are only partially understood. This paper aims to investigate whether immune cells present in the skin prior to wounding can affect subsequent healing in high-stress and low-stress participants. Two studies are presented in which skin biopsies were analysed using immunohistochemistry for numbers of macrophages and Langerhans cells, and immune cell activation (Study 2 only). Immune cells were related to perceived stress levels and subsequent healing. Study 1 included 19 healthy older adults and showed that higher stress was associated with significantly fewer macrophages in the skin. Study 2 included 22 younger adults and showed that higher stress was associated with significantly lower activation of immune cells in the skin. Furthermore, lower activation of immune cells (as measured by human leukocyte antigen (HLA expression)) and fewer Langerhans cells were associated with slower healing. Together these studies show the first preliminary evidence that the number and activation of immune cells in the skin prior to wounding are affected by stress and can impact healing. Larger studies are needed to confirm these effects. PMID- 26102315 TI - Uranyl Ion Complexes with 1,1'-Biphenyl-2,2',6,6'-tetracarboxylic Acid: Structural and Spectroscopic Studies of One- to Three-Dimensional Assemblies. AB - 1,1'-Biphenyl-2,2',6,6'-tetracarboxylic acid (H4L) was reacted with uranyl nitrate, either alone or in the presence of additional metal cations (Ni(2+), Cu(2+), Dy(3+)) under (solvo)-hydrothermal conditions, giving six complexes which were characterized by their crystal structure and, in all but one case, their emission spectrum in the solid state. [Ni(bipy)3][UO2(H2L)(H2O)]2(NO3)2.3H2O (1) crystallizes as a one-dimensional (1D), ribbon-like coordination polymer, while the homometallic complex [(UO2)2(L)(H2O)3].H2O.CH3CN (2) and the heterometallic complexes [UO2Cu(L)(H2O)2].H2O (3), [UO2Cu(L)(H2O)].H2O (4), and [(UO2)5Cu4(HL)6(bipy)4].2H2O (5) display two-dimensional (2D) arrangements. Lastly, the uranyl-lanthanide heterometallic complex [(UO2)8Dy(HL)6(H2O)8](I).8H2O (6) crystallizes as a three-dimensional (3D) framework. Although these assemblies adopt different topologies, the {4(2).6} linear motif found in 1 is discernible in the structures of 2, 5, and 6, in which the higher dimensionality arises from further bridging of these subunits by uranyl (2), copper (5), or both uranyl and dysprosium (6) cations. The tetracarboxylic/ate ligands have their two aromatic rings nearly perpendicular to one another. No two of them adopt the same coordination mode in this series (except in the similar complexes 3 and 4), but chelation involving one carboxylate group from each ring is nearly ubiquitous, and the ensuing position of the cation favors the formation of planar architectures. The emission spectra of complexes 2-5 measured in the solid state show the usual uranyl vibronic fine structure, although with significant differences in the emission intensity, while complete quenching of the luminescence is observed in 1. PMID- 26102316 TI - Islet Volume and Indexes of beta-Cell Function in Humans. AB - Islet volume and endocrine pancreas architecture (islet size distribution) may be independent determinants of beta-cell function. Furthermore, the accuracy of homeostatic model assessment (HOMA) indexes in predicting beta-cell mass has never been assessed. Here we investigated the relationships between islet volume, islet density, and islet size distribution, estimated after pancreatic tissue digestion, with established indexes of beta-cell function in humans. We included in this study 42 patients who were candidates for islet autotransplantation and had well-characterized glucose metabolism. Indexes of insulin secretion were calculated and compared with the islet volume, as a surrogate of beta-cell mass, obtained after digestion of pancreas. Islet counting analysis showed considerable interindividual variation in islet density and size. Islet volume, but not density nor size, was the only independent determinant of beta-cell function assessed by insulin HOMA beta-cell. Islet volume was significantly reduced in the patients with overt hyperglycemia, but not in patients with impaired fasting glucose. Insulin HOMA beta-cell predicted islet volume better than other measures of fasting insulin secretion. In conclusion, the present study documented a close direct relationship between indexes of beta-cell function and islet volume in humans. The insulin HOMA beta-cell provides a more reliable estimate of pancreatic islet volume than fasting glucose before islet isolation. PMID- 26102317 TI - Aqueous Lithium-Iodine Solar Flow Battery for the Simultaneous Conversion and Storage of Solar Energy. AB - Integrating both photoelectric-conversion and energy-storage functions into one device allows for the more efficient solar energy usage. Here we demonstrate the concept of an aqueous lithium-iodine (Li-I) solar flow battery (SFB) by incorporation of a built-in dye-sensitized TiO2 photoelectrode in a Li-I redox flow battery via linkage of an I3(-)/I(-) based catholyte, for the simultaneous conversion and storage of solar energy. During the photoassisted charging process, I(-) ions are photoelectrochemically oxidized to I3(-), harvesting solar energy and storing it as chemical energy. The Li-I SFB can be charged at a voltage of 2.90 V under 1 sun AM 1.5 illumination, which is lower than its discharging voltage of 3.30 V. The charging voltage reduction translates to energy savings of close to 20% compared to conventional Li-I batteries. This concept also serves as a guiding design that can be extended to other metal-redox flow battery systems. PMID- 26102318 TI - The Gray Mouse Lemur: A Model for Studies of Primate Metabolic Rate Depression. Preface. PMID- 26102319 TI - Understanding Large Database Studies. AB - There are several problems unique to large data sets. Large amounts of biased data are still biased and clinical significance is not always the same as statistical significance. Large number of predictors of outcome can confound conclusions, but there are several ways to manage wide ranging data sets including matching, regression, propensity scores, and randomization. PMID- 26102320 TI - Primary Care Physicians' Knowledge and Attitudes Regarding Prescription Opioid Abuse and Diversion. AB - OBJECTIVES: Physicians are a key stakeholder in the epidemic of prescription opioid abuse. Therefore, we assessed their knowledge of opioid abuse and diversion, as well as their support for clinical and regulatory interventions to reduce opioid-related morbidity and mortality. MATERIALS AND METHODS: We conducted a nationally representative postal mail survey of 1000 practicing internists, family physicians, and general practitioners in the United States between February and May 2014. RESULTS: The adjusted response rate was 58%, and all physicians (100%) believed that prescription drug abuse was a problem in their communities. However, only two-thirds (66%) correctly reported that the most common route of abuse was swallowing pills whole, and nearly one-half (46%) erroneously reported that abuse-deterrent formulations were less addictive than their counterparts. In addition, a notable minority of physicians (25%) reported being "not at all" or "only slightly concerned" about the potential for opioid diversion from the licit to the illicit market when this practice is common at all levels of the pharmaceutical supply chain. Most physicians supported clinical and regulatory interventions to reduce prescription opioid abuse, including the use of patient contracts (98%), urine drug testing (90%), requiring prescribers to check a centralized database before prescribing opioids (88%), and instituting greater restrictions on the marketing and promotion of opioids (77% to 82%). Despite this, only one-third of physicians (33%) believed that interventions to reduce prescription opioid abuse had a moderate or large effect on preventing patients' clinically appropriate access to pain treatment. DISCUSSION: Although physicians are unaware of some facets of prescription opioid-related morbidity, most support a variety of clinical and regulatory interventions to improve the risk-benefit balance of these therapies. PMID- 26102321 TI - ORS Interview with Otu Inyang. PMID- 26102322 TI - Excreta Sampling as an Alternative to In Vivo Measurements at the Hanford Site. AB - The capabilities of indirect radiobioassay by urine and fecal sample analysis were compared with the direct radiobioassay methods of whole body counting and lung counting for the most common radionuclides and inhalation exposure scenarios encountered by Hanford workers. Radionuclides addressed by in vivo measurement included 137Cs, 60Co, 154Eu, and 241Am as an indicator for plutonium mixtures. The same radionuclides were addressed using gamma energy analysis of urine samples, augmented by radiochemistry and alpha spectrometry methods for plutonium in urine and fecal samples. It was concluded that in vivo whole body counting and lung counting capability should be maintained at the Hanford Site for the foreseeable future, however, urine and fecal sample analysis could provide adequate, though degraded, monitoring capability for workers as a short-term alternative, should in vivo capability be lost due to planned or unplanned circumstances. PMID- 26102323 TI - A New Storage Facility for Institutional Radioactive Wastes at IPEN. AB - IPEN, the Nuclear and Energy Research Institute in Sao Paulo, Brazil, has been managing the radioactive wastes generated in its own activities of research and radioisotope production as well as those received from many radioisotope users in the country since its start up in 1958. Final disposal options are presently unavailable for the wastes that cannot be managed by release after decay. Treated and untreated wastes including disused sealed radioactive sources and solid and liquid wastes containing radionuclides of the uranium and thorium series or fission and activation products are among the categories that are under safe and secure storage. This paper discusses the aspects considered in the design and describes the startup of a new storage facility for these wastes. PMID- 26102324 TI - Operational Check Source Recalibration. AB - A formal protocol whereby a segregated source is used for later quality control trending and recalibration of operational sources is described. The method is of potential use for any quality radioactive assay program where multiple sources may be in use such that long term loss in activity is possible and not readily detected and corrected using common statistical assessment criteria. The method relies upon a rigorous initial characterization effort that can later be credited to minimize error propagation during recalibration to monitor the overall uncertainty budget. A simple example attachment for use in written procedures is also provided. PMID- 26102325 TI - Web Implementation of Quality Assurance (QA) for X-ray Units in Balkanic Medical Institutions. AB - Diagnostic radiology is the major contributor to the total dose of the population from all artificial sources. In order to reduce radiation exposure and optimize diagnostic x-ray image quality, it is necessary to increase the quality and efficiency of quality assurance (QA) and audit programs. This work presents a web application providing completely new QA solutions for x-ray modalities and facilities. The software gives complete online information (using European standards) with which the corresponding institutions and individuals can evaluate and control a facility's Radiation Safety and QA program. The software enables storage of all data in one place and sharing the same information (data), regardless of whether the measured data is used by an individual user or by an authorized institution. The software overcomes the distance and time separation of institutions and individuals who take part in QA. Upgrading the software will enable assessment of the medical exposure level to ionizing radiation. PMID- 26102326 TI - Comparison of U.S. Environmental Protection Agency's CAP88 PC Versions 3.0 and 4.0. AB - The Savannah River National Laboratory (SRNL) with the assistance of Georgia Regents University, completed a comparison of the U.S. Environmental Protection Agency's (U.S. EPA) environmental dosimetry code CAP88 PC V3.0 with the recently developed V4.0. CAP88 is a set of computer programs and databases used for estimation of dose and risk from radionuclide emissions to air. At the U.S. Department of Energy's Savannah River Site, CAP88 is used by SRNL for determining compliance with U.S. EPA's National Emission Standards for Hazardous Air Pollutants (40 CFR 61, Subpart H) regulations. Using standardized input parameters, individual runs were conducted for each radionuclide within its corresponding database. Some radioactive decay constants, human usage parameters, and dose coefficients changed between the two versions, directly causing a proportional change in the total effective dose. A detailed summary for select radionuclides of concern at the Savannah River Site (60Co, 137Cs, 3H, 129I, 239Pu, and 90Sr) is provided. In general, the total effective doses will decrease for alpha/beta emitters because of reduced inhalation and ingestion rates in V4.0. However, for gamma emitters, such as 60Co and 137Cs, the total effective doses will increase because of changes U.S. EPA made in the external ground shine calculations. PMID- 26102327 TI - Operational Testing of a Combined Hardware-Software Strategy for Triage of Radiologically-Contaminated Persons. AB - After a radiological dispersal device (RDD) event, it is possible for radionuclides to enter the human body through inhalation, ingestion, and skin and wound absorption. The dominant pathway will be through inhalation. From a health physics perspective, it is important to know the magnitude of the intake to perform dosimetric assessments. From a medical perspective, removal of radionuclides leading to dose (hence risk) aversion is of high importance. The efficacy of medical decorporation strategies is extremely dependent upon the time of treatment delivery after intake. The "golden hour," or more realistically 3-4 h, is imperative when attempting to increase removal of radionuclides from extracellular fluids prior to cellular incorporation. To assist medical first response personnel in making timely decisions regarding appropriate treatment delivery modes, a software tool has been developed which compiles existing radionuclide decorporation therapy data and allows a user to perform simple triage leading to potential appropriate decorporation treatment strategies. Three triage algorithms were included: (1) multi-parameter model (MPM), (2) clinical decision guidance (CDG) model, and (3) annual limit on intake (ALI) model. A radiation triage mask (RTM) has simultaneously been developed to provide a simple and rapid hardware solution for first responders to triage internally exposed personnel in the field. The hardware/software strategy was field tested with a military medical unit and was found by end-users to be relatively simple to learn and use. PMID- 26102328 TI - Degeneracy in carbon nanotubes under transverse magnetic delta-fields. AB - The aim of this article was to study the degeneracy of the energy spectrum in a nanotube under a transverse magnetic field. The massless Dirac-Weyl equation has been used to describe the low energy states of this system. The particular case of a singular magnetic field approximated by Dirac delta distributions is considered. It is shown that, under general symmetry conditions, there is a double degeneracy corresponding to periodic solutions with null axial momentum k(z)=0. Also, there may be a kind of sporadic degeneracy for non-vanishing values of k(z), which are explicitly computed in the present example. The proof of these properties is obtained by means of the supersymmetric structure of the Dirac-Weyl Hamiltonian. PMID- 26102329 TI - Site-selective in situ growth of fluorescent polymer-antibody conjugates with enhanced antigen detection by signal amplification. AB - This paper reports a new and general in situ methodology to grow fluorescent polymer conjugates from the interchain disulfide bridging sites of a monoclonal antibody. Atom transfer radical polymerization (ATRP) initiators were attached to a monoclonal antibody at its interchain disulfide bridging sites by disulfide re bridging to yield a macroinitiator. Subsequent in situ ATRP of PEG-like monomers with dye-functionalized monomers from the macroinitiator formed antibody-polymer dye conjugates with site-selectivity and tunable dye-to-antibody ratios. Notably, these conjugates can amplify antigen detection signal by reducing label-density dependent fluorescence quenching and by increasing dye-to-antibody ratios. The method developed may be applicable to a variety of antibodies, dyes and drugs to create a number of antibody-polymer-dye/drug conjugates for advanced diagnosis and therapy of diseases. PMID- 26102330 TI - Biosorbent encapsulation in calcium alginate: Effects of process variables on Cr(VI) removal from solutions. AB - Selected biosorbents, brewers draff and grape waste, have been encapsulated in calcium alginate beads and used for the removal of Cr(VI) from aqueous solutions. The effects of encapsulation variables, including the type of waste, the percentage of waste in the beads and the curing time of the beads in CaCl2, on the diameters of the beads and Cr(VI) sorption kinetics have been evaluated. In total, 21 different types of beads were produced. The diameters of the beads increased with increasing amounts of encapsulated biomaterial. Beads that contained grape waste were larger than those containing brewers draff. The most efficient beads for Cr(VI) removal were beads that contained 4% (w/w) of grape waste. No significant differences in the kinetics of Cr(VI) sorption were found with respect to the curing time variable in the case of grape waste calcium alginate beads. Statistical analysis confirmed that the type and percentage of waste are the critical parameters influencing the diameters of the beads and Cr(VI) removal. It was proven that the sorption efficiencies of the beads containing draff and grape waste encapsulated under the optimum conditions were much higher than the efficiencies obtained when using both wastes in their native states. PMID- 26102331 TI - Inhibition of amyloid fibrillation and cytotoxicity of lysozyme fibrillation products by polyphenols. AB - An increasing number of studies conducted under in vitro and in vivo conditions, have concluded that polyphenols, compounds frequently occurring in many herbs with antioxidant properties, prevent and reverse amyloid fibril formation. However, the mechanisms by which these natural products modulate the protein aggregation process are poorly understood. Herein, a range of techniques including thioflavin T (ThT) and ANS fluorescence assays, electron microscopy and circular dichroism have been employed to determine the efficacy of rosmarinic acid (RA) and resveratrol (Res) on the inhibition/reversion of fibrillogenesis and hindering cytotoxicity induced by protofibrils and amyloid fibrils of hen egg white lysozyme (HEWL). Results demonstrated that both polyphenols effectively inhibit fibrillogenesis and destabilize preformed fibrils of HEWL in a concentration-dependent manner. Cytotoxicity protection on PC12 cells was also observed using the MTT assay, ROS production assay, and phase-contrast microscopy. It is suggested that the mechanism underlying the inhibitory effects of RA and Res is to prevent hydrophobic interactions between HEWL amyloidogenic prefibrillar species, although additional studies is needed to elucidate the detailed mechanisms involved. A combination of antioxidative and anti amyloidogenic properties of these molecules may provide them with the described neuroprotective capacities. PMID- 26102332 TI - The Value of Open Conversion Simulations During Robot-Assisted Radical Prostatectomy: Implications for Robotic Training Curricula. AB - INTRODUCTION: There is a lack of protocols, formal guidance, and procedural training regarding open conversions from robot-assisted radical prostatectomy (RARP) to open radical prostatectomy (ORP). An open conversion places complex demands on the healthcare team and has recently been shown to be associated with adverse perioperative outcomes. AIMS: To perform a root cause analysis of open conversion simulations from RARP to ORP to identify errors that may contribute to adverse events. METHODS: From May 2013 to December 2013, with a team of two surgeons, an anesthesiologist, and three nurses, we simulated 20 emergencies during RARP that require open conversion. A human simulation model was intubated and prepared in the Trendelenburg position; a robot da Vinci SI was locked to it. All simulations were timed, transcribed, and filmed to identify errors and areas for improvement. An institutional conversion protocol was developed at the end of the conversion training. RESULTS: The average conversion time was 130.9 (interquartile range [IQR] 90-201) seconds. Frequencies of the observed errors were as follows: lack of task sequence (70%), errors in robot movements (50%), loss of sterility (50%), space conflict (40%), communication errors (25%), lack of leadership (25%), and accidental fall of surgical devices (25%). Four main strategies were implemented to reduce errors: improving leadership, clearly defining roles, improving knowledge base, and surgical room reorganization. By the last simulation, conversions were performed without errors and using 55.2% less time compared with initial simulations. CONCLUSIONS: In this preliminary study, repeated simulations, increased leadership, improved role delineation, and surgical room reorganization enabled faster and less flawed conversions. Further studies are needed to identify if such protocols may translate to actual safety improvement during open conversions. PMID- 26102333 TI - Poly-gamma-glutamic acid microneedles with a supporting structure design as a potential tool for transdermal delivery of insulin. AB - Incomplete insertion is a common problem associated with polymer microneedles (MNs) that results in a limited drug delivery efficiency and wastage of valuable medication. This paper presents a fully insertable MN system that is composed of poly-gamma-glutamic acid (gamma-PGA) MNs and polyvinyl alcohol (PVA)/polyvinyl pyrrolidone (PVP) supporting structures. The PVA/PVP supporting structures were designed to provide an extended length for counteracting skin deformation during insertion and mechanical strength for fully inserting the MNs into the skin. When inserted into the skin, both the supporting structures and MNs can be dissolved in the skin within 4min, thus quickly releasing the entire drug load from the MNs. To evaluate the feasibility and reproducibility of using the proposed system for treating diabetes, we administered insulin-loaded MNs to diabetic rats once daily for 2days. The results indicated that the hypoglycemic effect in the rats receiving insulin-loaded MNs was comparable to that observed in rats receiving subcutaneous insulin injections. The relative pharmacological availability and relative bioavailability of the insulin were in the range of 90-97%, indicating that the released insulin retained its pharmacological activity. We observed no significant differences in the plasma insulin concentration profiles between the first and second administrations, confirming the stability and accuracy of using the proposed MN system for insulin delivery. These results indicated that the gamma-PGA MNs containing the supporting structure design enable complete and efficient delivery of encapsulated bioactive molecules and have great potential for the relatively rapid and convenient transdermal delivery of protein drugs. STATEMENT OF SIGNIFICANCE: Incomplete insertion of microneedles largely limits drug delivery efficiency and wastage of valuable medication. To address this problem, we developed a fully insertable poly-glutamic acid microneedles with a supporting structure design to ensure complete and efficient delivery of encapsulated drugs. The supporting structures were designed to provide an extended length for counteracting skin compressive deformation during puncture and mechanical strength for fully inserting the microneedles into the skin. When inserted into the skin, both the supporting structures and microneedles can be dissolved in the skin within 4min, thus quickly releasing the entire drug load. This study demonstrated that the proposed microneedle system featuring this unique design allows more convenient and efficient self-administration of drugs into the skin. PMID- 26102334 TI - beta-Type titanium alloys for spinal fixation surgery with high Young's modulus variability and good mechanical properties. AB - Along with a high strength, ductility, and work hardening rate, a variable Young's modulus is crucial for materials used as implant rods in spinal fixation surgery. The potential in this context of Ti-(9,8,7)Cr-0.2O (mass%) alloys is reported herein. The microstructural and mechanical properties of the alloys were systematically examined as a function of their chromium content, and the ion release of the optimized alloy was investigated to assess its suitability as an implant material. In terms of the deformation-induced omega-phase transformation required for a variable Young's modulus, the balance between beta-phase stability and athermal omega-phase content is most favorable in the Ti-9Cr-0.2O alloy. In addition, this composition affords a high tensile strength (>1000MPa), elongation at break (~20%), and work hardening rate to solution-treated (ST) samples. These excellent properties are attributed to the combined effects of deformation induced omega-phase transformation, deformation twinning, and dislocation gliding. Furthermore, the ST Ti-9Cr-0.2O alloy proves resistant to metal ion release in simulated body fluid. This combination of a good biocompatibility, variable Young's modulus and a high strength, ductility, and work hardening rate is ideal for spinal fixation applications. STATEMENT OF SIGNIFICANCE: Extensive efforts have been devoted over the past decades to developing beta-type titanium alloys with low Young's moduli for biomedical applications. In spinal fixation surgery however, along with excellent mechanical properties, the spinal-support materials should possess high Young's modulus for showing small springback during surgery to facilitate manipulation but low Young's modulus close to bone once implanted to avoid stress shielding. None of currently used metallic biomaterials can satisfy these abovementioned requirements. In the present study, we have developed a novel alloy, Ti-9Cr-0.2O. Remarkably variable Young's modulus and excellent mechanical properties can be achieved in this alloy via phase transformations and complex deformation mechanisms, which makes the Ti-9Cr-0.2O preferred material for spinal fixation surgery. PMID- 26102335 TI - Negative Poisson's ratios in tendons: An unexpected mechanical response. AB - Tendons are visco-elastic structures that connect bones to muscles and perform the basic function of force transfer to and from the skeleton. They are essential for positioning as well as energy storing when involved in more abrupt movements such as jumping. Unfortunately, they are also prone to damage, and when injuries occur, they may have dilapidating consequences. For instance, there is consensus that injuries of tendons such as Achilles tendinopathies, which are common in athletes, are difficult to treat. Here we show, through in vivo and ex vivo tests, that healthy tendons are highly anisotropic and behave in a very unconventional manner when stretched, and exhibit a negative Poisson's ratio (auxeticity) in some planes when stretched up to 2% along their length, i.e. within their normal range of motion. Furthermore, since the Poisson's ratio is highly dependent on the material's microstructure, which may be lost if tendons are damaged or diseased, this property may provide a suitable diagnostic tool to assess tendon health. STATEMENT OF SIGNIFICANCE: We report that human tendons including the Achilles tendons exhibits the very unusual mechanical property of a negative Poisson's ratio (auxetic) meaning that they get fatter rather than thinner when stretched. This report is backed by in vivo and ex vivo experiments we performed which clearly confirm auxeticity in this living material for strains which correspond to those experienced during most normal everyday activities. We also show that this property is not limited to the human Achilles tendon, as it was also found in tendons taken from sheep and pigs. This new information about tendons can form the scientific basis for a test for tendon health as well as enable the design of better tendon prosthesis which could replace damaged tendons. PMID- 26102336 TI - Protein adsorption steers blood contact activation on engineered cobalt chromium alloy oxide layers. AB - Biomaterials upon implantation are immediately covered by blood proteins which direct the subsequent blood activation. These early events determine the following cascade of biological reactions and consequently the long-term success of implants. The ability to modulate surface properties of biomaterials is therefore of considerable clinical significance. Goal of this study was an in depth understanding of the biological response to cobalt chromium stent alloys with engineered surface oxide layers, which showed altered body reactions in vivo. We analyzed in vitro the biological events following initial blood contact on engineered cobalt chromium surfaces featuring said oxide layers. Surface specific blood reactions were confirmed by scanning electron microscopy and the adsorbed protein layers were characterized by mass spectrometry. This powerful proteomics tool allowed the identification and quantification of over hundred surface-adhering proteins. Proteins associated with the coagulation cascade, platelet adhesion and neutrophil function correlated with the various blood surface activations observed. Furthermore, results of pre-coated surfaces with defined fibrinogen-albumin mixtures suggest that neutrophil adhesion was controlled by fibrinogen orientation and conformation rather than quantity. This study highlights the importance of controlling the biological response in the complex protein-implant surface interactions and the potential of the surface modifications to improve the clinical performance of medical implants. STATEMENT OF SIGNIFICANCE: The blood contact activation of CoCr alloys is determined by their surface oxide layer properties. Modifications of the oxide layer affected the total amount of adsorbed proteins and the composition of the adsorbed protein layer. Additionally fibrinogen coatings mediated the surface-dependent neutrophil adhesion in a concentration-independent manner, indicating the influence of conformation and/or orientation of the adsorbed protein. Despite the complexity of protein-implant interactions, this study highlights the importance of understanding and controlling mechanisms of protein adhesion in order to improve and steer the performance of medical implants. It shows that modification of the surface oxide layer is a very attractive strategy to directly functionalize metallic implant surfaces and optimize their blood interaction for the desired orthopedic or cardiovascular applications. PMID- 26102337 TI - Therapeutic efficacy of doxorubicin delivery by a CO2 generating liposomal platform in breast carcinoma. AB - Drug delivery using thermosensitive liposomes (TSL) has significant potential for tumor drug targeting and can be combined with local hyperthermia to trigger drug release. Although TSL-mediated drug delivery can be effective by itself, we developed doxorubicin (DOX)-containing CO2 bubble-generating TSL (TSL-C) that were found to enhance the antitumor effects of DOX owing to the synergism between burst release of drug and hyperthermia-induced CO2 generation. An ultrasound imaging system was used to monitor hyperthermia-induced CO2 generation in TSL-C and the results revealed that hyperthermia-induced CO2 generation in TSL-C led to increased DOX release compared to that observed for non-CO2-generating TSL. Moreover, TSL-C significantly inhibited the tumor growth in MDA-MB-231 tumor bearing mice compared to TSL (p<0.004). Taken together, we demonstrated that the TSL-C platform increased the therapeutic efficacy of cancer chemotherapy and showed the applicability of this approach to increase drug release within the tumor microenvironment. As a novel and highly effective drug delivery platform, TSL-C has great potential for use in a broad range of applications for the treatment of various human diseases. STATEMENT OF SIGNIFICANCE: We have developed a novel method for drug release from liposomes by gas (CO2) generation in tumor microenvironment. In addition, we demonstrate therapeutic efficacy in breast carcinoma. CO2-generated liposomal doxorubicin is a novel and highly attractive delivery system for anticancer drug with the potential for broad applications in human disease. PMID- 26102338 TI - Peritoneal adhesion prevention by a biodegradable hyaluronic acid-based hydrogel formed in situ through a cascade enzyme reaction initiated by contact with body fluid on tissue surfaces. AB - Postsurgical peritoneal adhesion is a serious surgical complication. In situ hydrogel formation on the surface of tissues, which will develop adhesions, is a recent feasible approach to prevent peritoneal adhesion. Here, we report on tissue surface formation of a hyaluronic acid-based hydrogel by administration of a pre-hydrogel aqueous solution. The hydrogelation was initiated by contact with body fluid containing glucose on tissue surfaces. During the hydrogelation, a hyaluronic acid derivative possessing phenolic hydroxyl moieties (HA-Ph) was cross-linked by a cascade reaction of glucose oxidase (GOx) and horseradish peroxidase (HRP). About 5s of hydrogelation was accomplished using a solution containing 1.5% (w/v) HA-Ph, 5U/mL HRP, and 2.5U/mL GOx in 1mg/mL glucose that is equivalent to the normal blood glucose concentration. The hydrogel was degradable by hyaluronidase and much softer than rat peritoneal sidewalls. We confirmed the efficiency of the hydrogel to prevent post-operative peritoneal adhesions by applying the solution containing HA-Ph, GOx, and HRP to animals with bowel abrasion-abdominal sidewall defects. A significant reduction in the development of peritoneal adhesions was found compared with animals applied with phosphate buffered saline or saline containing HA-Ph alone. STATEMENT OF SIGNIFICANCE: Postsurgical peritoneal adhesion is a serious surgical complication. In this paper, we report a novel system for preventing it through an on-tissue surface formation of a biodegradable and biocompatible hyaluronic acid-based hydrogel by administration of a pre-hydrogel aqueous solution. The in situ hydrogelation is mediated by a cascade enzyme reaction of glucose oxidase (GOx) and horseradish peroxidase (HRP) initiated by contacting with body fluid containing glucose. The efficiency of the system was confirmed by applying the system to animals with bowel abrasion-abdominal sidewall defects. PMID- 26102339 TI - Soluble expression and enzymatic activity evaluation of protease from reticuloendotheliosis virus. AB - The protease (PR) encoded by most retroviruses is deeply involved in the lifecycle and infection process of retroviruses by possessing the specificity necessary to correctly cleave the viral polyproteins and host cell proteins. However, as an important representative of avian retroviruses, the enzymatic properties of PR from reticuloendotheliosis virus (REV) have not been clearly documented. The recombinant PR, its mutant fused with a His-tag, and its substrate p18-p30 fused with a GST-tag were expressed in the Escherichia coli system as soluble enzymes. The soluble PR and p18-p30 were purified using Ni-NTA His Bind Resin and Glutathione Sepharose 4B, respectively. The enzymatic activity of PR was analyzed using the substrate of p18-p30. The expressed prokaryotic protease has enzyme activity that is dependent on such conditions as temperature, pH, and ions, and its activity can be inhibited by caspase inhibitor and the divalent metal ions Ca(2+) and Ni(2+). In addition, the key role of the residue Thr (amino acids 28) for the enzymatic activity of PR was identified. Furthermore, the caspase inhibitor Z-VAD-FMK was confirmed to inhibit the PR enzymatic activity of REV. For the first time, the PR of REV was expressed in the soluble form, and the optimal enzymatic reaction system in vitro was developed and preliminarily used. This study provides essential tools and information for further understanding the infection mechanism of REV and for the development of antiviral drugs treating retroviruses. PMID- 26102340 TI - Cloning, heterologous expression, and enzymatic characterization of a novel glucoamylase GlucaM from Corallococcus sp. strain EGB. AB - The gene encoding a novel glucoamylase (GlucaM) from the Corallococcus sp. strain EGB was cloned and heterologous expressed in Escherichia coli BL21(DE3), and the enzymatic characterization of recombinant GlucaM (rGlucaM) was determined in the study. The glucaM had an open reading frame of 1938 bp encoding GlucaM of 645 amino acids with no signal peptide. GlucaM belongs to glycosyl hydrolase family 15 and shares the highest identity 96% with the GH15 glucoamylase of Corallococcus coralloides DSM 2259. The rGlucaM with His-tag was purified by the Ni2+-NTA resin, with a specific activity from 3.4 U/mg up to 180 U/mg, and the molecular weight of rGlucaM was approximately 73 kDa on SDS-PAGE. The Km and Vmax of rGlucaM for soluble starch were 1.2 mg/mL and 46 U/mg, respectively. rGlucaM was optimally active at pH 7.0 and 50 degrees C and had highly tolerance to high concentrations of salts, detergents, and various organic solvents. rGlucaM hydrolyzed soluble starch to glucose, and hydrolytic activities were also detected with amylopectin, amylase, glycogen, starch (potato), alpha cyclodextrin, starch (corn and potato). The analysis of hydrolysis products shown that rGlucaM with alpha-(1-4),(1-6)-D-glucan glucohydrolase toward substrates. These characteristics indicated that the GlucaM was a new member of glucoamylase family and a potential candidate for industrial application. PMID- 26102341 TI - Measles Virus Infection Among Vaccinated and Unvaccinated Children in Nigeria. AB - This study investigated measles infection in vaccinated and unvaccinated children presenting with fever and maculopapular rash during measles outbreaks in the southern and western states of Nigeria. Measles, an acute viral illness caused by a virus in the family Paramyxoviridae, is a vaccine-preventable disease. Measles outbreak is common in Nigeria, despite the national immunization program. Children presenting with symptoms of measles infection in general hospitals and health centers in the states of southern and western Nigeria were recruited for this study. Vaccination history, clinical details, and 5 mL of blood were obtained from the children. Their sera samples were screened for specific immunoglobulin M antibodies to measles virus. Of 234 children tested (124 [53.2%] female), 133 (56.8%) had previously been vaccinated against measles virus, while 93 (39.7%) had not been vaccinated. Vaccination information for eight children could not be retrieved. One hundred and forty-three (62.4%) had measles IgM antibodies. Of these, 79 (55.3%) had been vaccinated for measles, while 65 (44.7%) had not. Despite the ongoing vaccination program in Nigeria, a high number of children are still being infected with measles, despite their vaccination status. Therefore, there is need to identify the reason for the low level of vaccine protection. PMID- 26102343 TI - Water balance during parturition and early puerperium: A prospective open trial. AB - OBJECTIVES: To investigate how water balance is regulated during labor and 27h postpartum. DESIGN AND METHODS: A prospective open trial with 49 women giving birth vaginally. Ringer-acetate was infused intravenously and combined with epidural analgesia in seven women (fluid group). Intravenous infusions of oxytocin in 5% glucose were given to 12 women (oxytocin group). Thirty women delivered their babies without infusion (nofluid group). Blood and urine samples were collected at arrival, at early stage 1, at early stage 2, and at aftercare, and 9, 15, and 27h postpartum. Plasma osmolality, sodium, cystatin C, vasopressin, oxytocin, urine flow, urine osmolality, and urine sodium were measued. RESULTS: The oxytocin group had significantly lower plasma osmolality than the nofluid group before parturition, and they had lower plasma sodium concentration at early stage 1 and 2. Plasma vasopressin concentration was low and did not differ between groups or before and after parturition. Water diuresis developed postpartum in all groups. The cystatin C concentration decreased significantly after parturition in the oxytocin and nofluid groups. CONCLUSIONS: The vasopressin levels were suppressed during parturition irrespective of the P osmolality and the nongravid regulation of water balance had not returned within 27h postpartum. PMID- 26102342 TI - Genetic Influence on Slope Variability in a Childhood Reflexive Attention Task. AB - Individuals are not perfectly consistent, and interindividual variability is a common feature in all varieties of human behavior. Some individuals respond more variably than others, however, and this difference may be important to understanding how the brain works. In this paper, we explore genetic contributions to response time (RT) slope variability on a reflexive attention task. We are interested in such variability because we believe it is an important part of the overall picture of attention that, if understood, has the potential to improve intervention for those with attentional deficits. Genetic association studies are valuable in discovering biological pathways of variability and several studies have found such associations with a sustained attention task. Here, we expand our knowledge to include a reflexive attention task. We ask whether specific candidate genes are associated with interindividual variability on a childhood reflexive attention task in 9-16 year olds. The genetic makers considered are on 11 genes: APOE, BDNF, CHRNA4, COMT, DRD4, HTR4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25. We find significant associations with variability with markers on nine and we discuss the results in terms of neurotransmitters associated with each gene and the characteristics of the associated measures from the reflexive attention task. PMID- 26102344 TI - Polymorphisms in FTO and TCF7L2 genes of Euro-Brazilian women with gestational diabetes. AB - OBJECTIVE: To investigate the association between fat mass and obesity-associated (FTO) gene polymorphisms rs8050136C>A and rs9939609T>A, and transcription factor 7-like 2 (TCF7L2) gene polymorphisms rs12255372G>T and rs7903146C>T, in a sample group of pregnant Euro-Brazilian women with or without gestational diabetes mellitus (GDM). METHODS: Subjects were classified as either healthy pregnant control (n=200) or GDM (n=200) according to the 2010 criteria of the American Diabetes Association. The polymorphisms were genotyped using fluorescent probes (TaqMan(r)). RESULTS: All groups were in the Hardy-Weinberg equilibrium. The genotype and allele frequencies of the examined polymorphisms did not exhibit significant difference (P>0.05) between the groups. In the healthy and GDM pregnant women groups, the A-allele frequencies (95% CI) of FTO polymorphisms rs8050136 and rs9939609 were 39% (34-44%); 38% (33-43%) and 40% (35-45%); 41% (36 46%), respectively; and the T-allele frequencies of TCF7L2 polymorphisms rs12255372 and rs7903146 were 30% (26-35%), 32% (27-37%) and 29% (25-34%), 36% (31-41%), respectively. CONCLUSION: The examined polymorphisms were not associated with GDM in the Euro-Brazilian population studied. PMID- 26102345 TI - Understanding the effect of touchdown distance and ankle joint kinematics on sprint acceleration performance through computer simulation. AB - This study determined the effects of simulated technique manipulations on early acceleration performance. A planar seven-segment angle-driven model was developed and quantitatively evaluated based on the agreement of its output to empirical data from an international-level male sprinter (100 m personal best = 10.28 s). The model was then applied to independently assess the effects of manipulating touchdown distance (horizontal distance between the foot and centre of mass) and range of ankle joint dorsiflexion during early stance on horizontal external power production during stance. The model matched the empirical data with a mean difference of 5.2%. When the foot was placed progressively further forward at touchdown, horizontal power production continually reduced. When the foot was placed further back, power production initially increased (a peak increase of 0.7% occurred at 0.02 m further back) but decreased as the foot continued to touchdown further back. When the range of dorsiflexion during early stance was reduced, exponential increases in performance were observed. Increasing negative touchdown distance directs the ground reaction force more horizontally; however, a limit to the associated performance benefit exists. Reducing dorsiflexion, which required achievable increases in the peak ankle plantar flexor moment, appears potentially beneficial for improving early acceleration performance. PMID- 26102346 TI - Semiparametric estimation in the proportional hazard model accounting for a misclassified cause of failure. AB - Misclassified causes of failures are a common phenomenon in competing risks survival data such as cancer mortality. We propose new estimating equations for a semiparametric proportional hazards (PH) model with misattributed causes of failures. Unlike other methods, the estimator does not require any parametric assumptions on baseline cause-specific hazard rates. It is shown that the estimators for regression coefficients are consistent and asymptotically normal. Simulation results support the theoretical analysis in finite samples. The methods are applied to analyze prostate cancer survival. PMID- 26102348 TI - Chemokine levels in serum of children with atopic dermatitis with regard to severity and sensitization status. AB - BACKGROUND: Many infants with atopic dermatitis (AD) are sensitized against food or airborne allergens. The severity of AD, using the SCORAD, seems to correlate with elevated serum levels of TARC/CCL17. Other chemokines, such as CCL20 or CCL25, have been described in the context of allergic inflammation. The aim of this study was to analyze whether chemokine serum levels differ within a cohort of infants suffering from varying severities of AD with or without allergic sensitization. METHODS: Chemokine serum levels (CCL8, CCL17, CCL20, CCL25) as well as food and airborne allergen-specific IgE were analyzed in infants with AD. RESULTS: About 60.9% (78/128) infants with AD (median age 8.8 months, 49 (38%) girls and 79 (62%) boys) showed a positive screening test to common food allergens and 26.6% to common airborne allergens. There was a strong correlation between serum levels of CCL17 and SCORAD in food-sensitized infants (r(s) = 0.646, p = <1e-04) and airborne-sensitized infants (r(s) = 0.587, p = 0.00065) in contrast to non-sensitized ones. Moreover, food-sensitized infants showed significantly higher levels of CCL25 compared to non-food-sensitized ones (p = 0.007). CONCLUSION: The strong correlation between TARC/CCL17 and SCORAD in infants with specific sensitizations may be accounted for by the impaired skin barrier. As TARC/CCL17 has been found mainly in the (inflamed) skin but not in the gut, the detection of significantly higher levels of CCL25, ligand of CCR9, localized primarily in the gastrointestinal tract, suggests its impact on food allergen-induced inflammation processes in food-sensitized infants. PMID- 26102347 TI - Loss of IKKbeta but Not NF-kappaB p65 Skews Differentiation towards Myeloid over Erythroid Commitment and Increases Myeloid Progenitor Self-Renewal and Functional Long-Term Hematopoietic Stem Cells. AB - NF-kappaB is an important regulator of both differentiation and function of lineage-committed hematopoietic cells. Targeted deletion of IkappaB kinase (IKK) beta results in altered cytokine signaling and marked neutrophilia. To investigate the role of IKKbeta in regulation of hematopoiesis, we employed Mx1 Cre mediated IKKbeta conditional knockout mice. As previously reported, deletion of IKKbeta in hematopoietic cells results in neutrophilia, and we now also noted decreased monocytes and modest anemia. Granulocyte-macrophage progenitors (GMPs) accumulated markedly in bone marrow of IKKbeta deleted mice whereas the proportion and number of megakaryocyte-erythrocyte progenitors (MEP) decreased. Accordingly, we found a significantly reduced frequency of proerythroblasts and basophilic and polychromatic erythroblasts, and IKKbeta-deficient bone marrow cells yielded a significantly decreased number of BFU-E compared to wild type. These changes are associated with elevated expression of C/EBPalpha, Gfi1, and PU.1 and diminished Gata1, Klf1, and SCL/Tal1 in IKKbeta deficient Lineage-Sca1+c Kit+ (LSK) cells. In contrast, no effect on erythropoiesis or expression of lineage-related transcription factors was found in marrow lacking NF-kappaB p65. Bone marrow from IKKbeta knockout mice has elevated numbers of phenotypic long and short term hematopoietic stem cells (HSC). A similar increase was observed when IKKbeta was deleted after marrow transplantation into a wild type host, indicating cell autonomous expansion. Myeloid progenitors from IKKbeta- but not p65-deleted mice demonstrate increased serial replating in colony-forming assays, indicating increased cell autonomous self-renewal capacity. In addition, in a competitive repopulation assay deletion of IKKbeta resulted in a stable advantage of bone marrow derived from IKKbeta knockout mice. In summary, loss of IKKbeta resulted in significant effects on hematopoiesis not seen upon NF-kappaB p65 deletion. These include increased myeloid and reduced erythroid transcription factors, skewing differentiation towards myeloid over erythroid differentiation, increased progenitor self-renewal, and increased number of functional long term HSCs. These data inform ongoing efforts to develop IKK inhibitors for clinical use. PMID- 26102349 TI - Phosphorylation of the BNIP3 C-Terminus Inhibits Mitochondrial Damage and Cell Death without Blocking Autophagy. AB - BNIP3 is a dual function protein, able to activate autophagy and induce cell death. Upon expression of BNIP3, which is upregulated by hypoxia, the protein induces mitochondrial dysfunction, often leading to cell death. However, some highly respiring cells and cancer cells tolerate BNIP3 expression, suggesting that a yet unknown mechanism exists to restrain the lethal effects of BNIP3 on mitochondria. Here we present evidence that BNIP3 undergoes several phosphorylation events at its C-terminus, adjacent to the transmembrane domain. Phosphorylation at these residues inhibits BNIP3-induced mitochondrial damage, preventing a loss of mitochondrial mass and mitochondrial membrane potential, as well as preventing an increase in reactive oxygen species. This decrease in mitochondrial damage, as well as the reduction of cell death upon C-terminal BNIP3 phosphorylation, can be explained by a diminished interaction between BNIP3 and OPA1, a key regulator of mitochondrial fusion and mitochondrial inner membrane structure. Importantly, phosphorylation of these C-terminal BNIP3 residues blocks cell death without preventing autophagy, providing evidence that the two functional roles of BNIP3 can be regulated independently. These findings establish phosphorylation as a switch to determine the pro-survival and pro-death effects of the protein. Our findings also suggest a novel target for the regulation of these activities in transformed cells where BNIP3 is often highly expressed. PMID- 26102350 TI - Traumatic Spinal Cord Injury Emergency Service Triage Patterns and the Associated Emergency Department Outcomes. AB - Paralysis is an indication for trauma patients to be preferentially triaged by emergency services to designated level I or II trauma centers (TC). We sought to describe triage practices for patients with acute traumatic spinal cord injury (TSCI) and its associated emergency department (ED) outcomes. Adults ages >= 18 years with a diagnosis of acute TSCI (International Classification of Diseases-9: 806 and 952) in the 2006-2011 United States Nationwide Emergency Department Sample were included in these analyses. Outcomes assessed include triage to non trauma centers (NTC), which is referred to as "under-triage," and ED mortality. Of 117,444 adults with TSCI, 33.4% were under-triaged to NTC. Under-triage was more prevalent with increasing age. Among patients under-triaged to NTC, 37.4% had new injury severity score (NISS) >15, representing severe injuries or polytrauma. Among patients with NISS >15, the odds of ED mortality in NTC were four-fold greater compared to level I trauma centers (TC-I) (adjusted odds ratio [AOR] = 4.06; 95% confidence interval = 1.87-8.79; p < 0.001). In conclusion, under-triage of adults with acute TSCI occurred in at least one-third of the cases. Patients triaged to NTC rather than TC-I experienced higher likelihood of death in the ED even after controlling for personal and injury characteristics. Further research is necessary to elucidate detailed clinical and logistical factors that may be associated with under-triage of acute TSCI, to facilitate interventions aimed at improving patient experience and outcomes. PMID- 26102351 TI - A Cross-Sectional Study of the Psychological Needs of Adults Living with Cystic Fibrosis. AB - BACKGROUND: Depression and anxiety are prevalent in people with cystic fibrosis (CF), yet psychological services are rarely accessible in CF clinics. This cross sectional single center study reports on a psychological needs assessment of people with CF. METHODS: We asked adults attending a CF clinic, without integrated psychological services, to complete a psychological needs assessment survey that included items on: a) past access to psychological services (via a CF referral service), b) concerns relevant to discuss with a psychologist, and c) their likelihood of accessing psychological services if available at the CF clinic, and standardized measures of depression (CES-D) and anxiety (GAD-7). RESULTS: We enrolled 49 participants and 45 (91.8%) completed the survey. Forty percent reported elevated symptoms of depression and 13% had elevated anxiety. A majority of individuals (72.2% and 83.3%, respectively) indicated they would be likely to use psychological services, if available at the clinic. Concerns considered most relevant to discuss with a psychologist were: 1) worries (51.1%), 2) mood (44.4%), 3) life stress (46.6%), 4) adjustment to CF (42.2%), 5) life transitions (42.2%) and 6) quality of life (42.2%). CONCLUSIONS: This study highlights the rationale for screening adults with CF for depression and anxiety, and to facilitate provision of psychological services and preventative mental health interventions as an integral component of multi-disciplinary CF care. PMID- 26102352 TI - Design of a mediated enzymatic fuel cell to generate power from renewable fuel sources. AB - The present work reported a compartment-less enzymatic fuel cell (EFC) based on newly synthesized Poly(pyrrole-2-carboxylic acid-co-3-thiophene acetic acid) film containing glucose oxidase and laccase effectively wired by p-benzoquinone incorporated into the copolymer structure. The resulting system generated a power density of 18.8 uW/cm(2) with 30 mM of glucose addition at +0.94 V at room temperature. Improvements to maximize the power output were ensured with step-by step optimization of electrode fabrication design and operational parameters for operating the system with renewable fuel sources. We demonstrated that the improved fuel cell could easily harvest glucose produced during photosynthesis to produce electrical energy in a simple, renewable and sustainable way by generating a power density of 10 nW/cm(2) in the plant leaf within 2 min. An EFC for the first time was successfully operated in municipal wastewater which contained glycolytic substances to generate electrical energy with a power output of 3.3 uW/cm(2). PMID- 26102353 TI - Leadless Pacemakers: Putting Them In and Taking Them Out. PMID- 26102355 TI - Effects of genotype on rates of substitution during experimental evolution. AB - Rates of molecular evolution may vary widely between populations, yet the causes of this variation are still incompletely understood. Genetic differences between populations may make an important contribution to variation in rates of evolution, owing to differences in fitness, population size, mutation rates, or in the distribution of fitness effects (DFEs) of available beneficial mutations. By whole genome sequencing of Escherichia coli populations experimentally evolved in the presence of a quinolone antibiotic, we found that rates of substitution varied by genotype, with evidence for a contribution from a genotype's starting fitness. Subsequent targeted sequencing showed that genotypes with high average substitution rates were more likely to undergo the simultaneous fixation of several mutations, consistent with theoretical models of multiple mutation dynamics. Moreover, patterns of substitution were indicative of epistatic relationships between known resistance mutations. PMID- 26102354 TI - Pharmacological Investigation of Fluoro-Gold Entry into Spinal Neurons. AB - The fluorescent tracer Fluoro-Gold has been widely used to label neurons retrogradely. Here we show that Fluoro-Gold can also enter neurons through AMPA receptor endocytosis. We found that a 30 minute application of Fluoro-Gold to the isolated spinal cord labeled neurons under control conditions and in the presence of glutamatergic agonists including NMDA and AMPA. The labeling was abolished or greatly reduced by glutamatergic antagonists and the endocytic inhibitors Dynasore and dynamin inhibitory peptide. Whole cell recordings from spinal neurons exposed to extracellular AMPA revealed large inward currents that spontaneously decayed in the presence of the agonist but were maintained when a dynamin inhibitory peptide was included in the electrode. These findings suggest that Fluoro-Gold enters spinal neurons through AMPA-mediated receptor internalization. Drugs used to induce locomotor-like activity in the spinal cord also increased and decreased Fluoro-Gold labeling in a drug and lamina specific manner, indicating that AMPAR endocytosis is altered in the presence of the locomotor cocktail. Our findings suggest that endocytosis of Fluoro-Gold could potentially complicate the interpretation of experiments in which the tracer is used to label neurons retrogradely. Moreover, they also demonstrate that many drugs, including the locomotor cocktail, can modulate the number and/or the composition of AMPA receptors on spinal neurons and thereby affect network excitability. PMID- 26102356 TI - Computational Study of Computed Tomography Contrast Gradients in Models of Stenosed Coronary Arteries. AB - Recent computed tomography coronary angiography (CCTA) studies have noted higher transluminal contrast agent gradients in arteries with stenotic lesions, but the physical mechanism responsible for these gradients is not clear. We use computational fluid dynamics (CFD) modeling coupled with contrast agent dispersion to investigate the mechanism for these gradients. Simulations of blood flow and contrast agent dispersion in models of coronary artery are carried out for both steady and pulsatile flows, and axisymmetric stenoses of severities varying from 0% (unobstructed) to 80% are considered. Simulations show the presence of measurable gradients with magnitudes that increase monotonically with stenotic severity when other parameters are held fixed. The computational results enable us to examine and validate the hypothesis that transluminal contrast gradients (TCG) are generated due to the advection of the contrast bolus with time-varying contrast concentration that appears at the coronary ostium. Since the advection of the bolus is determined by the flow velocity in the artery, the magnitude of the gradient, therefore, encodes the coronary flow velocity. The correlation between the flow rate estimated from TCG and the actual flow rate in the computational model of a physiologically realistic coronary artery is 96% with a R2 value of 0.98. The mathematical formulae connecting TCG to flow velocity derived here represent a novel and potentially powerful approach for noninvasive estimation of coronary flow velocity from CT angiography. PMID- 26102357 TI - In situ crystallization for fabrication of a core-satellite structured BiOBr-CdS heterostructure with excellent visible-light-responsive photoreactivity. AB - We demonstrate the fabrication of a core-satellite structured BiOBr-CdS photocatalyst with highly efficient photocatalytic reactivity via a facile in situ crystallization approach at room temperature. The transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HR-TEM) results reveal that the BiOBr flakes are surrounded by CdS particles. The coverage of the satellites on the surface of the BiOBr nanosheets could be controlled by changing the content of the CdS, which contributes to the enhanced level of photocatalytic performance. The UV-vis diffuse reflection spectra demonstrate that the visible light absorption of the BiOBr-CdS photocatalyst is also enhanced by the CdS loaded. The excellent structural and spectral properties endow the BiOBr-CdS heterojunctions with improved photocatalytic performance pertaining to bisphenol A (BPA) degradation and photocurrent generation. Under visible light irradiation, the optimum photocatalytic activity of BiOBr-CdS at a molar ratio of 1 : 5 (CdS/BiOBr) is almost 2.8 times and 24.6 times as high as that of pure BiOBr and CdS. The remarkably enhanced photoreactivity should be attributed to the match in the energy levels and close core-satellite structural coupling between the CdS and BiOBr, which greatly facilitates the separation and transfer of photoinduced electron-hole pairs, as confirmed by photoluminescence (PL) and electrochemical impedance spectra (EIS). The present work sheds new light on the construction of highly efficient core-satellite heterojunctional photocatalysts for practical applications. PMID- 26102359 TI - Direct injection of cell-free Kir1.1 protein into Xenopus oocytes replicates single-channel currents derived from Kir1.1 mRNA. AB - The development of integral membrane protein cell-free synthesis permits in-vitro labeling of accessible cysteines for real-time FRET and LRET measurements. The functional integrity of these synthetic ion channel proteins has been verified at the whole oocyte level by direct injection into, and recording from, Xenopus oocytes. However, the microscopic single-channel properties of cell-free translated protein have not been systematically examined. In the present study, we compare patch-clamp currents originating from cell-free protein with currents derived from mRNA injection, using the same (single-Cys) inward rectifier DNA template (C189-Kir1.1b). Results indicate that cell-free Kir protein, incorporated into liposomes and injected into oocytes, is trafficked to the plasma membrane where it inserts in an outside-out orientation and exhibits single-channel characteristics identical to that derived from a corresponding mRNA. PMID- 26102358 TI - Endocytosis of Nanomedicines: The Case of Glycopeptide Engineered PLGA Nanoparticles. AB - The success of nanomedicine as a new strategy for drug delivery and targeting prompted the interest in developing approaches toward basic and clinical neuroscience. Despite enormous advances on brain research, central nervous system (CNS) disorders remain the world's leading cause of disability, in part due to the inability of the majority of drugs to reach the brain parenchyma. Many attempts to use nanomedicines as CNS drug delivery systems (DDS) were made; among the various non-invasive approaches, nanoparticulate carriers and, particularly, polymeric nanoparticles (NPs) seem to be the most interesting strategies. In particular, the ability of poly-lactide-co-glycolide NPs (PLGA-NPs) specifically engineered with a glycopeptide (g7), conferring to NPs' ability to cross the blood brain barrier (BBB) in rodents at a concentration of up to 10% of the injected dose, was demonstrated in previous studies using different routes of administrations. Most of the evidence on NP uptake mechanisms reported in the literature about intracellular pathways and processes of cell entry is based on in vitro studies. Therefore, beside the particular attention devoted to increasing the knowledge of the rate of in vivo BBB crossing of nanocarriers, the subsequent exocytosis in the brain compartments, their fate and trafficking in the brain surely represent major topics in this field. PMID- 26102361 TI - The effect of carbon-polyaniline hybrid coating on high-temperature electrochemical performance of perovskite-type oxide LaFeO3 for MH-Ni batteries. AB - An efficient carbon-polyaniline (PANI)-coated method was applied for perovskite type oxide LaFeO3 to enhance its high-temperature electrochemical performance. Transmission electron microscopy (TEM) results reveal that LaFeO3 particles are evenly coated with carbon and PANI hybrid layers after carbon-PANI treatment. The carbon layers prevent the nanosized LaFeO3 particles from aggregation and allow the electrolyte to penetrate in every direction inside the particles. The PANI layers also enhance the electrocatalytic activity, facilitating hydrogen protons transferring from the electrolyte to the electrode interface. The cooperation of carbon and PANI hybrid layers results in a significant enhancement of the electrochemical performance at high temperatures. At an elevated temperature (60 degrees C), the maximum discharge capacity of the LaFeO3 electrodes remarkably increases from 231 mA h g(-1) to 402 mA h g(-1) and the high rate dischargeability at a discharge current density of 1500 mA g(-1) (HRD1500) increases from 22.7% to 44.3%. Moreover, the hybrid layers mitigate the corrosion of LaFeO3 electrodes by reducing the loss of active materials in the alkaline electrolyte, leading to increase in the capacity retention rate from 67.1% to 77.6% after 100 cycles (S100). PMID- 26102362 TI - When mismatch repair met translesion synthesis. PMID- 26102360 TI - Effects of a Balanced Translocation between Chromosomes 1 and 11 Disrupting the DISC1 Locus on White Matter Integrity. AB - OBJECTIVE: Individuals carrying rare, but biologically informative genetic variants provide a unique opportunity to model major mental illness and inform understanding of disease mechanisms. The rarity of such variations means that their study involves small group numbers, however they are amongst the strongest known genetic risk factors for major mental illness and are likely to have large neural effects. DISC1 (Disrupted in Schizophrenia 1) is a gene containing one such risk variant, identified in a single Scottish family through its disruption by a balanced translocation of chromosomes 1 and 11; t(1;11) (q42.1;q14.3). METHOD: Within the original pedigree, we examined the effects of the t(1;11) translocation on white matter integrity, measured by fractional anisotropy (FA). This included family members with (n = 7) and without (n = 13) the translocation, along with a clinical control sample of patients with psychosis (n = 34), and a group of healthy controls (n = 33). RESULTS: We report decreased white matter integrity in five clusters in the genu of the corpus callosum, the right inferior fronto-occipital fasciculus, acoustic radiation and fornix. Analysis of the mixed psychosis group also demonstrated decreased white matter integrity in the above regions. FA values within the corpus callosum correlated significantly with positive psychotic symptom severity. CONCLUSIONS: We demonstrate that the t(1;11) translocation is associated with reduced white matter integrity in frontal commissural and association fibre tracts. These findings overlap with those shown in affected patients with psychosis and in DISC1 animal models and highlight the value of rare but biologically informative mutations in modeling psychosis. PMID- 26102363 TI - Developing Models to Predict Persistent High-Cost Cases in Florida Medicaid. AB - This paper examined individual characteristics associated with being a high-cost case in multiple years for Medicaid-covered health care services. In addition, the accuracy of models that predict future persistent high-cost cases was examined. Florida Medicaid claims from 2005 to 2010 were used to examine characteristics, diagnoses, and services associated with individual costs being in the top 1% of recipients. Regression models were estimated with diagnoses and service use in a base year used to predict future high-cost cases. Several different perspectives were used that focus on predicting current year high-cost cases based on prior persistence, predicting future persistence of high costs, and a combination of using past persistence to predict future persistence. Average annual costs for persistent high-cost cases were more than $140,000. Overall, models were predictive of future high-cost cases. The receipt of intermediate case facility (mental retardation) services was the strongest predictor of future high-cost cases. Inpatient, outpatient, pharmacy, and nursing home services, along with diagnoses, all provided important information for predicting high-cost cases. Diagnosis-based models in conjunction with prior costs can predict future high-cost cases with a high degree of accuracy. However, given that many high-cost cases reside in intermediate care facilities, it is not clear that such individuals would benefit from intensive case management. Service use patterns in prior years, diagnoses, and prior costs should all be used to identify individuals who may benefit from intensive case management. PMID- 26102364 TI - Regional climate impacts of a possible future grand solar minimum. AB - Any reduction in global mean near-surface temperature due to a future decline in solar activity is likely to be a small fraction of projected anthropogenic warming. However, variability in ultraviolet solar irradiance is linked to modulation of the Arctic and North Atlantic Oscillations, suggesting the potential for larger regional surface climate effects. Here, we explore possible impacts through two experiments designed to bracket uncertainty in ultraviolet irradiance in a scenario in which future solar activity decreases to Maunder Minimum-like conditions by 2050. Both experiments show regional structure in the wintertime response, resembling the North Atlantic Oscillation, with enhanced relative cooling over northern Eurasia and the eastern United States. For a high end decline in solar ultraviolet irradiance, the impact on winter northern European surface temperatures over the late twenty-first century could be a significant fraction of the difference in climate change between plausible AR5 scenarios of greenhouse gas concentrations. PMID- 26102365 TI - The effect of TiO2 nanoflowers as a compact layer for CdS quantum-dot sensitized solar cells with improved performance. AB - Currently, TiO2 on a fluorine-doped tin oxide substrate is the most commonly used type of photoelectrode in high-efficiency quantum dot-sensitized solar cells (QDSSCs). The power conversion efficiency (PCE) of TiO2 photoelectrodes is limited because of higher charge recombination and lower QD loading on the TiO2 film. This article describes the effect of a TiO2 compact layer on a TiO2 film to enhance the performance of QDSSCs. TiO2 nanoparticles were coated on an FTO substrate by the doctor-blade method and then the TiO2 compact layer was successfully fabricated on the surface of the nanoparticles by a simple hydrothermal method. QDSSCs were made using these films as photoelectrodes with NiS counter electrodes. Under one sun illumination (AM 1.5 G, 100 mW cm(-2)), the QDSSCs showed PCEs of 2.19 and 2.93% for TCL1 and TCL2 based photoelectrodes, which are higher than the 1.33% value obtained with bare TiO2. The compact-layer coated film electrodes provide a lower charge-transfer resistance and higher light harvesting. The compact layer on the TiO2 film is a more efficient photocatalyst than pure TiO2 film and physically separates the injected electrons in the TiO2 from the positively charged CdS QD/electrolyte. PMID- 26102368 TI - Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2-Substituted 2,3 Dihydro-4-quinolones by a Protecting-Group-Free Approach. AB - Chiral 2-substituted 2,3-dihydro-4-quinolones were synthesized based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields with high enantioselectivities. PMID- 26102366 TI - MicroRNA-137 Contributes to Dampened Tumorigenesis in Human Gastric Cancer by Targeting AKT2. AB - MiRNAs play important roles in tumorigenesis. This study focused on exploring the effects and regulation mechanism of miRNA-137 on the biological behaviors of gastric cancer. Total RNA was extracted from tissues of 100 patients with gastric cancer and from four gastric cancer cell lines. Expression of miR-137 was detected by real-time PCR from 100 patients. The effects of miR-137 overexpression on gastric cancer cells' proliferation, apoptosis, migration and invasion ability were investigated in vitro and in vivo. The target gene of miR 137 was predicted by Targetscan on line software, screened by dual luciferase reporter gene assay and demonstrated by western blot. As a result, the expression of miR-137 was significant reduced in gastric cancer cell line HGC-27, HGC-803, SGC-7901 and MKN-45 as well as in gastric cancer tissues compared with GES-1 cell or matched adjacent non-neoplastic tissues (p<0.001). The re-introduction of miR 137 into gastric cancer cells was able to inhibit cell proliferation, migration and invasion. The in vivo experiments demonstrated that the miR-137 overexpression can reduce the gastric cancer cell proliferation and metastasis. Bioinformatic and western blot analysis indicated that the miR-137 acted as tumor suppressor roles on gastric cancer cells through targeting AKT2 and further affecting the Bad and GSK-3beta. In conclusion, the miR-137 which is frequently down-regulated in gastric cancer is potentially involved in gastric cancer tumorigenesis and metastasis by regulating AKT2 related signal pathways. PMID- 26102367 TI - Translational Upregulation of an Individual p21Cip1 Transcript Variant by GCN2 Regulates Cell Proliferation and Survival under Nutrient Stress. AB - Multiple transcripts encode for the cell cycle inhibitor p21(Cip1). These transcripts produce identical proteins but differ in their 5' untranslated regions (UTRs). Although several stresses that induce p21 have been characterized, the mechanisms regulating the individual transcript variants and their functional significance are unknown. Here we demonstrate through (35)S labeling, luciferase reporter assays, and polysome transcript profiling that activation of the Integrated Stress Response (ISR) kinase GCN2 selectively upregulates the translation of a p21 transcript variant containing 5' upstream open reading frames (uORFs) through phosphorylation of the eukaryotic translation initiation factor eIF2alpha. Mutational analysis reveals that the uORFs suppress translation under basal conditions, but promote translation under stress. Functionally, ablation of p21 ameliorates G1/S arrest and reduces cell survival in response to GCN2 activation. These findings uncover a novel mechanism of p21 post-transcriptional regulation, offer functional significance for the existence of multiple p21 transcripts, and support a key role for GCN2 in regulating the cell cycle under stress. PMID- 26102369 TI - Click Chemistry in Lead Optimization of Boronic Acids as beta-Lactamase Inhibitors. AB - Boronic acid transition-state inhibitors (BATSIs) represent one of the most promising classes of beta-lactamase inhibitors. Here we describe a new class of BATSIs, namely, 1-amido-2-triazolylethaneboronic acids, which were synthesized by combining the asymmetric homologation of boronates with copper-catalyzed azide alkyne cycloaddition for the stereoselective insertion of the amido group and the regioselective formation of the 1,4-disubstituted triazole, respectively. This synthetic pathway, which avoids intermediate purifications, proved to be flexible and efficient, affording in good yields a panel of 14 BATSIs bearing three different R1 amide side chains (acetamido, benzylamido, and 2-thienylacetamido) and several R substituents on the triazole. This small library was tested against two clinically relevant class C beta-lactamases from Enterobacter spp. and Pseudomonas aeruginosa. The K(i) value of the best compound (13a) was as low as 4 nM with significant reduction of bacterial resistance to the combination of cefotaxime/13a. PMID- 26102371 TI - Hydrolysis-Sensitive Dithiolethione Prodrug Micelles. AB - Prodrug micelles carrying 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), a compound possessing chemopreventive properties, are prepared from amphiphilic block copolymers linking ADT-OH via an ester bond using glycine (PAM-PGlyADT) and isoleucine linkers (PAM-PIleADT). The release of ADT-OH from the PAM-PIleADT micelles is much slower than the PAM-PGlyADT micelles. The PAM-PGlyADT micelles show comparable toxicity with ADT-OH in different cancer cell lines, whereas the PAM-PIleADT micelles are not toxic up to 400 uM. This ADT-ester prodrug micelle approach enables to modulate the release rate of ADT-OH and thus might find application in cancer therapy and prevention. PMID- 26102370 TI - Formation and Fragmentation of Protonated Molecules after Ionization of Amino Acid and Lactic Acid Clusters by Collision with Ions in the Gas Phase. AB - Collisions between O(3+) ions and neutral clusters of amino acids (alanine, valine and glycine) as well as lactic acid are performed in the gas phase, in order to investigate the effect of ionizing radiation on these biologically relevant molecular systems. All monomers and dimers are found to be predominantly protonated, and ab initio quantum-chemical calculations on model systems indicate that for amino acids, this is due to proton transfer within the clusters after ionization. For lactic acid, which has a lower proton affinity than amino acids, a significant non-negligible amount of the radical cation monomer is observed. New fragment-ion channels observed from clusters, as opposed to isolated molecules, are assigned to the statistical dissociation of protonated molecules formed upon ionization of the clusters. These new dissociation channels exhibit strong delayed fragmentation on the microsecond time scale, especially after multiple ionization. PMID- 26102372 TI - Ugi-derived dehydroalanines as a pivotal template in the diversity oriented synthesis of aza-polyheterocycles. AB - Various readily available, Ugi-derived dehydroalanines were used as pivotal templates to easily and efficiently assemble diverse pharmacologically important polyheterocyclic systems through cascade palladium-catalyzed C-C bond formation processes. Allyl, homoallyl and propargylamine led to the formation of benzopyrrolizidinones, benzoindolizidinones and pyrazinoisoquinolines, respectively, while benzylamines and o-bromobenzylamines were used as precursors of tetracyclic-fused systems and pyrazionoisoquinolindiones. PMID- 26102373 TI - A revision of existing Karolinska Sleepiness Scale responses to light: A melanopic perspective. AB - A new photometric measure of light intensity that takes into account the relatively large contribution of the ipRGCs to the non-image forming (NIF) system was recently proposed. We set out to revise publications reporting on alertness scores as measured by the Karolinska Sleepiness Scale (KSS) under different light conditions in order to assess the extendibility of the equivalent-melanopic function to NIF responses in humans. The KSS response (-Delta KSS) to the different light conditions used on previous studies, preferably including a comparison to a dim light condition, was assessed. Based on the light descriptions of the different studies, the equivalent melanopic lux (m illuminance) was calculated. The -Delta KSS was plotted against photopic illuminance and m-illuminance, and fitted to a sigmoidal function already shown to described KSS responses to different light intensities. The root mean-squared error and r(2) were used as criteria to explain the best-describing light unit measurement. Studies that compared only the influence of light under otherwise same conditions and in which participants were not totally sleep deprived were included. Our results show that the effects of light on KSS are better explained by a melanopic unit measurement than by photopic lux. The present analysis allowed for the construction of a melanopic alertness response curve. This curve needs to be validated with appropriate designs. Nonetheless, it may serve as starting point for the development of hypothesis of predictions on the relative changes in KSS under a given condition due to changes in light properties. PMID- 26102374 TI - Automated Activation and Pace-Mapping to Guide Ablation Within the Outflow Tract. PMID- 26102375 TI - Risk Prediction for Adverse Pregnancy Outcomes in a Medicaid Population. AB - BACKGROUND: Despite prior efforts to develop pregnancy risk prediction models, there remains a lack of evidence to guide implementation in clinical practice. The current aim was to develop and validate a risk tool grounded in social determinants theory for use among at-risk Medicaid patients. METHODS: This was a retrospective cohort study of 409 women across 17 Cincinnati health centers between September 2013 and April 2014. The primary outcomes included preterm birth, low birth weight, intrauterine fetal demise, and neonatal death. After random allocation into derivation and validation samples, a multivariable model was developed, and a risk scoring system was assessed and validated using area under the receiver operating characteristic curve (AUROC) values. RESULTS: The derived multivariable model (n=263) included: prior preterm birth, interpregnancy interval, late prenatal care, comorbid conditions, history of childhood abuse, substance use, tobacco use, body mass index, race, twin gestation, and short cervical length. Using a weighted risk score, each additional point was associated with an odds ratio of 1.57 for adverse outcomes, p<0.001, AUROC=0.79. In the validation sample (n=146), each additional point conferred an odds ratio of 1.20, p=0.03, AUROC=0.63. Using a cutoff of 20% probability for the outcome, sensitivity was 29%, with specificity 82%. Positive and negative predictive values were 22% and 85%, respectively. CONCLUSIONS: Risk scoring based on social determinants can discriminate pregnancy risk within a Medicaid population; however, performance is modest and consistent with prior prediction models. Future research is needed to evaluate whether implementation of risk scoring in Medicaid prenatal care programs improves clinical outcomes. PMID- 26102377 TI - Use of MDCT to Differentiate Autoimmune Pancreatitis From Ductal Adenocarcinoma and Interstitial Pancreatitis. AB - OBJECTIVE: The purposes of this study were to identify the most common imaging features of autoimmune pancreatitis and to evaluate the utility of MDCT for differentiating autoimmune pancreatitis from two more frequently encountered differential diagnoses--pancreatic ductal adenocarcinoma and acute interstitial pancreatitis. MATERIALS AND METHODS: Dual-phase contrast-enhanced MDCT images of 91 patients (39 with autoimmune pancreatitis, 25 with pancreatic ductal adenocarcinoma, 27 with acute interstitial pancreatitis) were evaluated by two radiologists in consensus for distribution of pancreatic abnormality, sausage shape, low-attenuation halo, pancreatic duct dilatation, peripancreatic stranding, lymphadenopathy, biliary abnormality, vascular involvement, and renal lesions. Chi-square tests, multiple logistic regression analysis, and ROC analysis were performed. RESULTS: The most common imaging features of autoimmune pancreatitis were sausage shape (25/39 [64%]) and low-attenuation halo (23/39 [59%]). Pancreatic duct dilatation (20/25 [80%]) and biliary dilatation (11/25 [44%]) were most frequent in pancreatic ductal adenocarcinoma. Peripancreatic stranding (22/27 [81%]) was most frequent in acute interstitial pancreatitis. Sausage shape, low-attenuation halo, and absence of a pancreatic duct or biliary dilatation differentiated autoimmune pancreatitis from pancreatic ductal adenocarcinoma with an accuracy of 0.88. Sausage shape and absence of peripancreatic stranding differentiated autoimmune pancreatitis from acute interstitial pancreatitis with an accuracy of 0.82. There was no significant difference in the frequency of vascular involvement or of lymphadenopathy among these diagnoses. CONCLUSION: Typical cases of autoimmune pancreatitis can be accurately differentiated from pancreatic ductal adenocarcinoma and acute interstitial pancreatitis on the basis of characteristic MDCT features. However, autoimmune pancreatitis should be considered in the presence of atypical features. PMID- 26102378 TI - Diagnosing Borderline Hepatic Nodules in Hepatocarcinogenesis: Imaging Performance. AB - OBJECTIVE: The purposes of this article are to describe the pathologic and radiologic features of small nodular lesions and to offer insight into the multistep process of hepatocarcinogenesis by describing the progression of imaging changes that link dysplastic nodules and early hepatocellular carcinoma, (HCC) to small HCC that has progressed. CONCLUSION: Nodules larger than 1 cm found during ultrasound surveillance of a cirrhotic liver should be investigated further with diagnostic imaging. Contrast-enhanced CT and dynamic MRI are the primary diagnostic studies for the diagnosis of HCC; contrast-enhanced ultrasound can be used as an alternative test. If a nodule has the typical hallmark of hypervascularity in the hepatic arterial phase with washout in the portal venous or delayed phase, a definitive diagnosis of HCC can be made. Nodules found during ultrasound surveillance that are smaller than 1 cm can be followed with ultrasound examinations at intervals of 3-6 months. PMID- 26102379 TI - Imaging of Large Airways Disorders. AB - OBJECTIVE: Recent technical advances, including the routine use of CT thin sections and techniques such as 2D minimum-intensity-projection and 3D volume images, have increased our ability to detect large airways diseases. Furthermore, dedicated CT protocols allow the evaluation of dynamic airway dysfunction. CONCLUSION: With diseases of the large airways more commonly seen in daily practice, it is important that radiologists be familiar with the appearances, differential diagnosis, and clinical implications of these entities. PMID- 26102380 TI - Location of Prostate Cancers Determined by Multiparametric and MRI-Guided Biopsy in Patients With Elevated Prostate-Specific Antigen Level and at Least One Negative Transrectal Ultrasound-Guided Biopsy. AB - OBJECTIVE: The purpose of this article is to identify histopathologically proven prostate cancer locations using MRI followed by MRI-guided biopsy in patients with elevated prostate-specific antigen (PSA) levels and at least one negative transrectal ultrasound (TRUS)-guided biopsy session. Our hypothesis is that in this patient group most cancers are located in the anterior portion of the prostate. This may have implications for the biopsy strategy regarding the location of sampling. MATERIALS AND METHODS: This retrospective study consisted of 872 consecutive men who had undergone MRI-guided prostate biopsy. Inclusion criteria were PSA level greater than or equal to 4 ng/mL, one or more negative TRUS-guided biopsy session, the presence of suspicious lesions on previous multiparametric MRI, and prostate cancer histopathologically proven by MRI-guided biopsy. Thereafter, the location of intermediate- or high-risk cancers and cancers with a maximum cancer core length of 6 mm or longer were determined. The proportion of cancer locations was compared using a chi-square test. One-way ANOVA analyses were performed to compare patient characteristics. RESULTS: Results were presented on both a patient and lesion basis because a single patient can have multiple lesions. In total, 176 of 872 patients met the inclusion criteria. Prostate cancer was detected in 202 of 277 (73%) suspicious lesions. In total, 76% of patients had cancer of the transition zone and anterior fibromuscular stroma. Peripheral zone cancers were found in 30% of the patients, and 6% had cancers in both zones. In 70% of cases (141/202; 95%, CI, 63-76%), lesions were located anteriorly; this included 75% (132/176; 95%, CI, 69-81%) of patients. Intermediate- or high-risk prostate cancer was found in 93% (128/138; 95%, CI, 88-96%) of patients. Of these patients, 73% (94/128; 95%, CI, 66-81%) had anterior involvement. Cancers with a maximum cancer core length of 6 mm or more were more likely to be located in the anterior part of the prostate than were cancers with a core length of less than 6 mm (66% vs 6%). Most cancers 58% (102/176; 95% CI, 51-65%) were found in the mid prostate. Anterior involvement of prostate cancer detected by MRI-guided biopsy was statistically significantly (p = 0.04) higher in patients with two or more negative TRUS-guided biopsy sessions (79%) than in those with one negative TRUS-guided biopsy session (55%). CONCLUSION: Anterior involvement was high (76%) in patients with an elevated PSA level and one or more negative TRUS-guided biopsy session, and the majority of these cancers (93%) were intermediate or high risk. PMID- 26102381 TI - A Phase I Dosing Study of Ferumoxytol for MR Lymphography at 3 T in Patients With Prostate Cancer. AB - OBJECTIVE: The objective of our study was to determine the optimal dose of ferumoxytol for performing MR lymphography (MRL) at 3 T in patients with prostate cancer. SUBJECTS AND METHODS: This phase I trial enrolled patients undergoing radical prostatectomy (RP) with bilateral pelvic lymph node dissection (PLND). Three groups of five patients each (total of 15 patients) received IV ferumoxytol before RP with bilateral PLND at each of the following doses of iron: 4, 6, and 7.5 mg Fe/kg. Patients underwent abdominopelvic MRI at 3 T before and 24 hours after ferumoxytol injection using T2- and T2*-weighted sequences. Normalized signal intensity (SI) and normalized SD changes from baseline to 24 hours after injection within visible lymph nodes were calculated for each dose level. Linear mixed effects models were used to estimate the effects of dose on the percentage SI change and log-transformed SD change within visible lymph nodes to determine the optimal dose of ferumoxytol for achieving uniform low SI in normal nodes. RESULTS: One patient who was excluded from the study group had a mild allergic reaction requiring treatment after approximately 2.5 mg Fe/kg ferumoxytol injection whereupon the injection was interrupted. The 15 study group patients tolerated ferumoxytol at all dose levels. The mean percentage SI change in 13 patients with no evidence of lymph metastasis was -36.4%, -45.4%, and -65.1% for 4, 6, and 7.5 mg Fe/kg doses, respectively (p = 0.041). CONCLUSION: A dose level of 7.5 mg Fe/kg ferumoxytol was safe and effective in deenhancing benign lymph nodes. This dose therefore can be the starting point for future phase II studies regarding the efficacy of ferumoxytol for MRL. PMID- 26102382 TI - Feasibility Study of 3-T DWI of the Prostate: Readout-Segmented Versus Single Shot Echo-Planar Imaging. AB - OBJECTIVE: The purpose of this prospective study was to assess the clinical utility of generalized autocalibrating partial parallel acquisition (GRAPPA) accelerated readout-segmented echo-planar imaging (rs-EPI) DWI and compare it with standard single-shot EPI ( ss-EPI) DWI in visualization of the prostate during 3-T MRI. SUBJECTS AND METHODS: One hundred sixteen consecutively registered patients (mean age, 63.5 years; range 24-93 years) underwent 3-T MRI that included rs-EPI DWI and standard ss-EPI DWI with identical FOVs, slices, acceleration factors, b values, and image postprocessing procedure. The datasets were independently evaluated by two blinded radiologists. Images were evaluated for sharpness, anatomic distortion, imaging contrast, lesion conspicuity, detailed anatomic visualization, and overall image quality on a 5-point Likert scale (1, nondiagnostic; 5, excellent). RESULTS: The kappa values were 0.73 for image sharpness, 0.71 for anatomic distortion, 0.54 for imaging contrast, 0.56 for lesion conspicuity, 0.61 for detailed anatomic visualization, and 0.63 for overall image quality (all p < 0.05), indicating moderate to substantial agreement between the two observers. The mean Likert scores for standard ss-EPI and rs-EPI were as follows: image sharpness, 2.9 and 4.6; distortion level, 2.8 and 4.4; contrast, 3.1 and 3.8; lesion conspicuity, 3.0 and 4.0; structure, 3.1 and 4.2; and overall image quality, 3.1 and 4.2. The rs-EPI DWI sequence was associated with significantly better image quality and fewer susceptibility artifacts than was ss-EPI (all p < 0.05). The rs-EPI sequence was considered better overall in 90% of cases. CONCLUSION: The technique of rs-EPI DWI combined with GRAPPA enables robust prostate imaging with high image quality and may provide great benefit in routine clinical practice. PMID- 26102383 TI - Rates of Breakthrough Reactions in Inpatients at High Risk Receiving Premedication Before Contrast-Enhanced CT. AB - OBJECTIVE: The purpose of this study was to determine the rate of allergiclike breakthrough reactions among inpatients at high risk receiving premedication before undergoing CT with IV iodinated low-osmolality contrast material (LOCM). MATERIALS AND METHODS: Inpatients (n = 1051) completing a 13-hour corticosteroid and diphenhydramine premedication regimen before LOCM-enhanced CT from January 1, 2010, through December 31, 2013, were included in the study. Breakthrough reaction rates were compared with the ordinary allergiclike reaction rate in the general population (0.6% [545/84,928]) by use of chi-square tests. Multivariate logistic regression was performed. Number needed to treat (NNT) was calculated for patients premedicated for a previous contrast reaction. RESULTS: Sixty percent (626/1051) of premedicated patients had had a previous reaction to iodinated contrast material, and 40% (425/1051) were premedicated for other reasons. The overall breakthrough reaction rates were 1.2% (13/1051) (p < 0.0001 vs the general population), 2.1% (13/626) for those with a previous iodinated contrast reaction (p < 0.0001), and 0% (0/425) for those premedicated for other reasons (p = 0.18). There were no severe breakthrough reactions. Younger age (p = 0.046; odds ratio, 1.03 per year; 95% CI, 1.001-1.07) and multiple indications for premedication (p < 0.0001; odds ratio, 2.7 per indication; 95% CI, 1.5-4.8) significantly increased the likelihood of a breakthrough reaction. The estimated NNTs were 69 (95% CI, 39-304) to prevent a reaction of any severity and 569 (95% CI, 389-1083) to prevent a severe reaction. CONCLUSION: Patients premedicated for a previous reaction to iodinated contrast material have a breakthrough reaction rate 3-4 times the ordinary reaction rate in the general population. Patients receiving premedication for other reasons have a breakthrough reaction rate near 0%. Many patients must receive premedication to prevent one reaction. PMID- 26102384 TI - Effect of Model-Based Iterative Reconstruction on CT Number Measurements Within Small (10-29 mm) Low-Attenuation Renal Masses. AB - OBJECTIVE: The purpose of this study was to assess the effect of model-based iterative reconstruction (MBIR) on CT number measurements within small (10-29 mm) low-attenuation renal masses. MATERIALS AND METHODS: One hundred 10- to 29-mm exophytic or endophytic low-attenuation renal lesions imaged with CT (unenhanced and nephrographic [100 seconds] phases, 120 kVp, variable mA, 2.5-mm slice thickness) were identified in 100 patients. The raw CT source data were prospectively reconstructed twice: once using Veo MBIR and once using a blend of 30% adaptive statistical iterative reconstruction (ASiR) and filtered back projection (FBP). Lesions were chosen to form four equal-sized (n = 25) groups stratified by lesion size (10-19 or 20-29 mm) and growth pattern (endophytic or exophytic). Attenuation (in HU) was measured using identical ROIs and compared with two-tailed t tests. The effects of patient diameter and lesion anatomy on attenuation discrepancies of 5 HU or more were assessed using binary logistic regression. RESULTS: Mean MBIR attenuation was not significantly different than mean 30% ASiR/FBP attenuation in the overall study population (unenhanced phase, 17 +/- 13 vs 17 +/- 13 HU, p = 0.74; nephrographic phase, 31 +/- 27 vs 30 +/- 26 HU, p = 0.89) or in any subgroup (p = 0.63-0.95). Only lesion size predicted discrepancies of 5 HU or more (p = 0.008; odds ratio, 1.20 [95% CI, 1.05-1.34] per 1 mm decrease) (p = 0.19-0.98 for the other variables). Seven lesions had enhancement of 20 HU or more with only one reconstruction method (MBIR = 4; 30% ASiR = 3). CONCLUSION: Veo MBIR has no significant or consistent effect on attenuation measurements within small (10-29 mm) low-attenuation renal masses and is therefore unlikely to change clinically accepted attenuation thresholds for renal mass characterization. PMID- 26102385 TI - Radiology Department Preparedness for the Management of Severe Acute Iodinated Contrast Reactions: Do We Need to Change Our Approach? AB - OBJECTIVE: The purpose of this study was to identify opportunities for reducing epinephrine administration errors after a sentinel event entailing an overdose of i.v. epinephrine occurred in a radiology department. MATERIALS AND METHODS: A root cause analysis was performed that included review and analysis of current system protocols, a medication audit, and access to treatment algorithms. A proctored three-question multiple-choice test was administered to radiology attending physicians, fellows, residents, and nurses to gauge baseline knowledge of epinephrine use. Chi-square analysis was performed. RESULTS: Twelve of 13 radiology department central pharmacy automation system locations lacked epinephrine ampules. As a result, personnel had to access i.v. epinephrine stocked on hospital code carts designed for use during cardiac arrest. This led to errors related to appropriate dosing. Test participants included 46 attending physicians, 23 fellows, 28 residents, and 25 nurses (n = 122). Almost all (99%) correctly identified epinephrine as the medication to administer in this situation. Approximately one half (52%) correctly identified the dose of intramuscular epinephrine, but only 29% knew the dose and rate of administration of i.v. epinephrine (p < 0.001). Attending physicians were more likely to administer i.v. epinephrine correctly than were the other groups (p < 0.0001). CONCLUSION: Stocking and routine auditing of medication availability are essential. The use of epinephrine intended for cardiac arrest stocked on code carts should be avoided during contrast reactions. It would be optimal if first line responders to contrast reactions included attending physicians, but this may not always be the case at academic institutions. PMID- 26102386 TI - Creating a Patient-Centered Radiology Practice Through the Establishment of a Diagnostic Radiology Consultation Clinic. AB - OBJECTIVE: The purposes of this study were to assess the feasibility of and to create a referral mechanism for a diagnostic radiology consultation clinic. SUBJECTS AND METHODS: A pilot program was instituted with patients from a single primary care clinic over a 3-week period. Patients with findings of common problems at routine imaging, such as atherosclerosis, emphysema, and hepatic steatosis, were eligible to participate. As the patients arrived for their routine primary care visits, office staff informed them of the opportunity to formally meet with a radiologist to review their most recent imaging findings. The office staff of the primary care clinic then contacted the radiologist covering the diagnostic radiology consultation clinic to schedule a consultation. A survey was administered before and after the session. RESULTS: Twenty-two patients participated (88% participation rate). Participants rated the consultation as very helpful (mean, 4.8 on 1-5 scale), and all participants would take the opportunity to review studies with the radiologist again. Significantly more patients preferred the involvement of the radiologist in communicating the results of an imaging examination after the consultation compared with before the consultation (p = 0.001). After the consultation session, patients had significantly improved understanding of a radiologist's role (p = 0.004), and all participants were able to correctly identify the radiologist as a physician who interprets medical images. CONCLUSION: A referral mechanism for a diagnostic radiology consultation clinic can be effectively integrated into the everyday workflow of both the referring physician and the radiologist. The consultations are useful to patients and help to increase their awareness of the role of the radiologist. PMID- 26102387 TI - Size-Specific Dose Estimates for Evaluation of Individual Patient Dose in CT Protocol for Renal Colic. AB - OBJECTIVE: The purpose of this study is to retrospectively evaluate size-specific dose estimates of a renal-colic CT protocol and to assess the quality and diagnostic value of obtained images. MATERIALS AND METHODS: The study population included 82 consecutive adult patients with acute renal colic undergoing CT with a reduced radiation dose (noise index, 59.1). The control group included 82 consecutive patients who underwent clinically indicated CT examination of the abdomen and pelvis with a routine-dose CT protocol (noise index, 22.0). The size specific dose estimate was calculated with volume CT dose index and patient effective diameter. Subjective image quality analysis was based on visibility of the ureter. Ureters were tracked from the renal pelvis to the vesicoureteral junction. Objective image quality was based on the signal-to-noise ratio (SNR) and the contrast-to-noise ratio (CNR). RESULTS: The size-specific dose estimates in the renal-colic group were 2.7 times lower than those in the control group. A linear relationship between patient size and size-specific dose estimate was noted. In the smallest patient, the conversion factor for the size-specific dose estimate calculation was 1.65. Overall image quality was better for the control patients, but there was no statistically significant difference in ureter visibility. The SNR was higher for the control group, whereas no difference in CNR was found. CONCLUSION: Small patients need the biggest correction for body size and require special attention in radiation dose estimation. We suggest the modification of scanning parameters on the basis of size-specific dose estimate to decrease patient dose in large patients. PMID- 26102388 TI - Imaging Diagnosis of Solitary Tumors of the Phalanges and Metacarpals of the Hand. AB - OBJECTIVE: Tumors and tumorlike lesions of the tubular bones of the hand, often incidentally discovered lesions, present a unique but challenging differential diagnosis. CONCLUSION: Imaging, including both radiography and cross-sectional imaging, can allow the radiologist to generate a clinically useful differential diagnosis based on the distinguishing features of these entities. Recognition of these lesions is important because clinical management and treatment by orthopedic oncologists vary depending on the diagnosis. PMID- 26102389 TI - Quantification of Fatty Degeneration Within the Supraspinatus Muscle by Using a 2 Point Dixon Method on 3-T MRI. AB - OBJECTIVE: The objective of this study was to quantify fatty degeneration of the supraspinatus muscle by using a 2-point Dixon technique on 3-T MRI and to evaluate the correlation of muscular atrophy and fat fraction values among different severities of rotator cuff tears across differing ages and sexes. SUBJECTS AND METHODS: Patients with shoulder pain (n = 359) were evaluated by shoulder MRI on a 3-T unit, including a 2-point Dixon sequence for quantification of muscle atrophy and fatty degeneration within the supraspinatus muscle. Two board-certified musculoskeletal radiologists evaluated the degree of rotator cuff tears in three groups: full-thickness tear (n = 63), partial tear (n = 54), and no tear (n = 242). In quantitative analysis, we measured signal intensity values of in-phase images (SIn) and fat images (SFat) within the supraspinatus muscle, and the fat fraction was calculated as SFat/SIn. The Thomazeau occupation ratio was used as a quantitative index of muscular atrophy. Fat fraction and muscle atrophy were evaluated among these groups. RESULTS: Fat fraction values were changed with the degree of rotator cuff tears and were (mean +/- SD) 0.258 +/- 0.123 among patients with full-thickness tears, 0.166 +/- 0.067 among patients with partial tears, and 0.128 +/- 0.061 among patients with no tears, with statistically significant differences (p < 0.001). The values were higher in female than in male patients in all groups. The Pearson correlation coefficient was 0.348 between age and fat fraction value, and 0.664 between muscular atrophy rate and fat fraction value. CONCLUSION: An increase in supraspinatus fatty degeneration was statistically significantly correlated with severity of supraspinatus tears and moderately correlated with muscular atrophy. Fatty degeneration tends to progress more rapidly than muscular atrophy in female patients, with statistically significant sex differences. PMID- 26102390 TI - Is Biopsying the Paravertebral Soft Tissue as Effective as Biopsying the Disk or Vertebral Endplate? 10-Year Retrospective Review of CT-Guided Biopsy of Diskitis Osteomyelitis. AB - OBJECTIVE: The purpose of this study was to determine whether there is a difference in biopsying bone (endplate), disk, or paravertebral soft tissue to culture the pathogenic organism causing diskitis-osteomyelitis. MATERIALS AND METHODS: A retrospective review was conducted of 111 spinal biopsies performed between 2002 and 2011. Pathologic examination was used as the reference standard for detecting diskitis-osteomyelitis. Microbiologic yield, sensitivity, and specificity were calculated. The yields for different groups were compared by use of Fisher exact test. The analysis was repeated with biopsy samples from patients not being treated with antibiotics at the time of biopsy. RESULTS: A total of 122 biopsy specimens were obtained from 111 spinal biopsy procedures on 102 patients. Overall, 27 (22%) biopsies were performed on the endplate-disk, 61 (50%) on the disk only, and 34 (28%) on paravertebral soft tissue only. The microbiologic yield was 36% for all biopsies, 19% for endplate-disk biopsies, 39% for disk-only biopsies, and 44% for soft-tissue biopsies. The sensitivity and specificity of the microbiologic results for all specimens were 57% and 89%; endplate-disk, 38% and 86%; disk only, 57% and 89%; and paravertebral soft tissue, 68% and 92%. There was no statistically significant difference between the yields of the endplate-disk, disk-only, and paravertebral soft-tissue biopsies. CONCLUSION: Paravertebral soft-tissue changes, when present, may be considered a viable target for biopsy in cases of diskitis-osteomyelitis, even in the absence of a paravertebral abscess. PMID- 26102391 TI - Assessment of Femoral Antetorsion With MRI: Comparison of Oblique Measurements to Standard Transverse Measurements. AB - OBJECTIVE: Abnormal femoral antetorsion is associated with the development of femoroacetabular impingement (FAI). Anatomically correct antetorsion measurements are performed on transverse MR images over the proximal and distal femur, but some authors use alternative measurements on oblique images parallel to the femoral neck axis. We set out to assess the relationship between these two measurement methods and to obtain reference values for oblique measurements in patients with FAI and healthy control subjects. We also evaluated whether the oblique measurements could be used to predict the standard transverse measurements. SUBJECTS AND METHODS: MRI data of 126 individuals, 63 asymptomatic volunteers and 63 patients with FAI (age 20-50 years), were included in this prospective study. Two readers independently assessed antetorsion with oblique measurements and standard transverse measurements. Differences between subgroups were compared with the unpaired t test. Trigonometric calculations were used to predict standard antetorsion measurements on the basis of oblique measurements. Interobserver agreement and Bland-Altman plots were calculated. RESULTS: Reference values for assessing femoral antetorsion with the oblique method were established, with mean (+/- SD) values of 9.4 degrees +/- 7.9 degrees (reader 1) and 9.8 degrees +/- 8.4 degrees (reader 2) for patients and 9.2 degrees +/- 8.4 degrees (reader 1) and 9.6 degrees +/- 9.1 degrees (reader 2) for asymptomatic volunteers. The oblique method generated smaller antetorsion values than the standard transverse method (p < 0.001), with an average difference of 3.5 degrees +/- 3.2 degrees for reader 1 and 3.6 degrees +/- 3.5 degrees for reader 2. Differences between predicted antetorsion values based on oblique measurements and standard measurements were minimal: 0.1 degrees +/- 2.9 degrees (p = 0.62) for reader 1 and 0.3 degrees +/- 3.3 degrees (p = 0.29) for reader 2. Interobserver agreement was high for all antetorsion measurements (intra-class correlation coefficient, 0.945-0.977). CONCLUSION: Oblique measurements of femoral antetorsion were smaller than standard transverse measurements, but they can be used to accurately predict standard measurements. PMID- 26102392 TI - Digital Tomosynthesis to Evaluate Fracture Healing: Prospective Comparison With Radiography and CT. AB - OBJECTIVE: Radiography, currently the standard for postoperative fracture imaging, is limited by overlapping bone and hardware. Tomosynthesis has the benefit of level-by-level imaging without the disadvantages of metal artifacts, increased radiation, and higher costs of CT, the current problem-solving tool. The purpose of this study was to compare tomosynthesis with radiography for evaluating fracture healing. SUBJECTS AND METHODS: In a prospective study, patients within 1 year of wrist hardware fixation underwent radiography, tomosynthesis, and CT, and the images were interpreted by three readers. The diagnostic accuracy of radiology and tomosynthesis was assessed with ROC curves, and interreader agreement was assessed with Cohen kappa. Fracture scores were correlated with Disabilities of the Arm, Shoulder, and Hand (DASH) and pain scores. RESULTS: The study participants were 49 patients with 51 fractures. The most common fracture sites were distal radius (43%), scaphoid (18%), and metacarpals (18%). Rates of cortex obscuration by hardware were 2% for CT, 8% for tomosynthesis, and 15% for radiography (p < 0.01 between one modality and another). Detection of cortical fracture lines was significantly better with tomosynthesis than with radiography (AUC, 0.84 vs 0.76, p = 0.01). Inter-reader agreement was moderate for both radiography and tomosynthesis (kappa = 0.44 vs 0.55, p = 0.051). There was no significant correlation between fracture scores and DASH scores. There was significant correlation between reported pain levels and both tomosynthesis (r = 0.28, p = 0.03) and CT (r = 0.29, p = 0.04) fracture scores. CONCLUSION: Tomosynthesis provides diagnostic information superior to that of ra diography in postoperative evaluation of wrist fractures with lower cost and radiation than CT and should be considered in fracture follow-up imaging of other bones. PMID- 26102393 TI - Knee MRI: Vascular Pathology. AB - OBJECTIVE: Patients who undergo knee MRI for presumed musculoskeletal disease can have unexpected vascular findings or pathology in the imaged field. Some vascular processes are limb threatening and affect treatment planning and patient outcome. CONCLUSION: Unexpected vascular findings on knee MRI can range from incidental to symptomatic and can include such processes as variant anatomy, aneurysm, traumatic injury, and neoplasm. The assessment for vascular pathology should be a key component of every radiologist's search pattern when evaluating knee MRI. PMID- 26102395 TI - Extraosseous Findings on Bone Scintigraphy Using Fusion SPECT/CT and Correlative Imaging. AB - OBJECTIVE: Extraosseous radioactivity outside of the expected biodistribution is often encountered on (99m)Tc-methylene diphosphate (MDP) bone scintigraphy, and proper interpretation requires an understanding of the mechanisms underlying this uptake and knowledge of the possible causes, depending on the site or structure involved. CONCLUSION: We present examples of extraosseous radiotracer uptake seen on (99m)Tc-MDP bone scans in which either SPECT with integrated CT or correlative imaging improved the study's interpretation. PMID- 26102396 TI - Pediatric Body MR Angiography: Principles, Techniques, and Current Status in Body Imaging. AB - OBJECTIVE: The purpose of this article is to describe the principles and various techniques of MR angiography (MRA) that can be applied to pediatric body imaging and the current noncardiac, nonneurologic applications of MRA of children. CONCLUSION: The choice between CT angiography and MRA for body imaging should depend on the clinical query, ROI, and vessel size. MRA is useful for assessment of stenosis of the main renal artery, portal hypertension, tumor vascularity, vascular malformations, generalized vasculopathy in vasculitis and syndromes, and thoracic outlet syndrome. PMID- 26102394 TI - Transcranial MRI-Guided Focused Ultrasound: A Review of the Technologic and Neurologic Applications. AB - OBJECTIVE: This article reviews the physical principles of MRI-guided focused ultra-sound and discusses current and potential applications of this exciting technology. CONCLUSION: MRI-guided focused ultrasound is a new minimally invasive method of targeted tissue thermal ablation that may be of use to treat central neuropathic pain, essential tremor, Parkinson tremor, and brain tumors. The system has also been used to temporarily disrupt the blood-brain barrier to allow targeted drug delivery to brain tumors. PMID- 26102397 TI - Imaging Findings of Fetal-Neonatal Ovarian Cysts Complicated With Ovarian Torsion and Autoamputation. AB - OBJECTIVE: Large nonresolving neonatal ovarian cysts may be a risk factor for complications such as torsion, mass effect, rupture, intracystic hemorrhage, and autoamputation. Torsed cysts and autoamputated cysts can cause a diagnostic dilemma. The objective of our study was to correlate the imaging findings of intrauterine ovarian torsion and autoamputated ovaries with their pathologic findings. MATERIALS AND METHODS: We retrospectively analyzed the pre- and postnatal medical records, sonographic findings, operation notes, and pathologic reports of 15 patients with ovarian torsion. All patients had complex cysts noted on postnatal sonographic examination. A complex heterogeneous ovarian cyst was defined by the presence of a fluid-debris level indicating hemorrhage within the cyst, a retracting clot, septations with or without internal echoes, calcification, and a solid component. RESULTS: On ultrasound examination, four cysts had solid components, and 11 were heterogeneous and had a fluid-debris level. Calcifications were seen in two patients. The mean patient age at the time of surgery was 3.9 months. Exploratory laparotomy was performed on all patients. Torsed ovaries were identified in five patients. Ten patients had ovaries that were floating free in the peritoneal cavity at the time of surgery. Histopathologic evaluation revealed that 11 of the cysts consisted of extensive hemorrhagic, necrotic autolytic tissue with dystrophic calcification. None of the cysts contained any ovarian tissue. CONCLUSION: A complex heterogeneous ovarian cyst with a fluid-debris level indicating hemorrhage is a significant sonographic hallmark for the diagnosis of ovarian torsion. A calcified abdominal mass, with or without wandering, can be an autoamputated ovary. PMID- 26102398 TI - The Timing and Presentation of Major Hemorrhage After 18,947 Image-Guided Percutaneous Biopsies. AB - OBJECTIVE: The objective of our study was to characterize the temporal and clinical manifestation of major bleeding events after biopsy to guide clinicians in the institution of appropriate surveillance. MATERIALS AND METHODS: We performed a retrospective review of percutaneous image-guided biopsies performed between September 1, 2005, and May 31, 2012, including 18,947 biopsy events. According to routine protocol, follow-up telephone calls were made to patients 24 hours after biopsy, and chart review was performed 3 months after biopsy. Bleeding complications were defined using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) established by the National Cancer Institute. In patients with a grade 3 or greater bleeding complication, a retrospective chart review was performed to characterize the details of the complication including the timing of the complication and the primary clinical presentation of the event. RESULTS: Grade 3 hemorrhage was associated with 64 of 18,947 (0.3%) procedures, and there were three deaths associated with the biopsy event (0.02% or ~ 2/10,000). Hemorrhage was most commonly associated with biopsy of a native kidney (17/1407, 1.2%). Twenty patients (31%) presented with a bleeding complication within 1 hour of biopsy. Twenty-seven patients (42%) presented within 2 hours of biopsy. Fifty-two patients (81%) presented within 24 hours, and the remaining 12 patients (19%) presented more than 24 hours after biopsy. Pain was the most common presentation of patients with bleeding complications, occurring in 39 (61%) patients. CONCLUSION: The incidence of major bleeding after percutaneous biopsies is very low, but delayed complications occur more frequently than anticipated. Pain is the most common clinical presentation of major bleeding complications. PMID- 26102399 TI - Feasibility of Intraprocedural Transluminal Hepatic and Femoral Artery Blood Pressure Measurements as an Alternative Embolization Safety Endpoint When Antireflux Devices Are Used During Lobar Chemoembolization. AB - OBJECTIVE: The purpose of this study was to describe the technique for evaluating hepatic arterial blood pressure changes during lobar chemoembolization using antireflux devices. Intraprocedural femoral and hepatic arterial blood pressures were measured and chemoembolization terminated when significant reduction in the difference occurred. Liver toxicity was evaluated. Eleven patients underwent 24 lobar chemoembolization procedures. Early termination of delivery occurred in 11 of 24 (46%) procedures in which the mean relative reduction in systemic-hepatic arterial pressure differential was 48%. The mean liver toxicity score was 1.2. This compares to delivery of the entire dose in 13 of 24 (54%) procedures in which the mean relative reduction in systemic-hepatic arterial pressure differential was 12% with a mean liver toxicity score of 1.2. CONCLUSION: When antireflux devices are used, intraprocedural assessment of hepatic artery blood pressure changes may be a useful embolization safety endpoint. PMID- 26102400 TI - Diagnostic Value of Ultrasound in Female Patients With Nipple Discharge. AB - OBJECTIVE: The purpose of this study was to assess the contribution of ultrasound to the evaluation of patients with pathologic nipple discharge. MATERIALS AND METHODS: A retrospective review was conducted of the records of females who presented with nipple discharge between January 1, 2009, and December 31, 2011. Pathologic nipple discharge was defined as discharge with one or more of the following features: unilateral, clear or bloody, and spontaneous. Patients underwent bilateral mammography followed by ultrasound directed at the subareolar portion of the affected breast. Radiologic findings and pathologic results were reviewed. RESULTS: Over a 3-year period, 327 females (mean age, 48 years; range, 13-88 years) presented with nipple discharge. Among these patients, 273 (83%) underwent surgical excision or clinical or radiographic follow-up at least 2 years after presentation and composed the study population. Among the 273 patients, 262 (96%) underwent mammography and 246 (90%) underwent sonography. Among 252 patients who had at least one pathologic feature of nipple discharge and underwent surgical excision or at least 2 years of follow-up, a total of 20 (8%) cases of ductal carcinoma in situ (DCIS) or invasive adenocarcinoma were diagnosed. DCIS or invasive adenocarcinoma was diagnosed in eight patients with normal sonographic findings. For the detection of DCIS and invasive adenocarcinoma, the sensitivity and specificity of ultrasound were 56% (10/18) and 75% (170/228); the sensitivity and specificity of mammography were 15% (3/20) and 98% (237/242). CONCLUSION: For females presenting with pathologic nipple discharge, ultrasound is a useful diagnostic tool and may be worth including in the routine evaluation. PMID- 26102401 TI - Incidental Internal Mammary Lymph Nodes Visualized on Screening Breast MRI. AB - OBJECTIVE: The frequency of visualization and size of internal mammary lymph nodes in women undergoing high-risk screening breast MRI is unknown. When these nodes are discovered on staging MRI of newly diagnosed breast cancer patients, management could present a treatment dilemma because normal size criteria do not exist. The aim of this study was to establish the average size and frequency of internal mammary lymph nodes observed in asymptomatic high-risk women undergoing screening breast MRI. MATERIALS AND METHODS: We conducted a retrospective review of 108 women at high risk for breast cancer who underwent screening breast MRI between January 2010 and January 2014. Patients with new or previous diagnosis of breast cancer, prior nonbreast malignancy affecting the thorax or mediastinum, or previous radiation to the thorax were excluded. The presence, diameter, laterality, intercostal space, relationship to the internal mammary vessels, age, morphology, and clinical history of internal mammary lymph nodes were recorded. RESULTS: Internal mammary lymph nodes were visualized in 50 of 108 high-risk patients, with an average size of 4.5 mm (range [+/- SD], 2-9 +/- 1.59 mm). In the 50 women who had internal mammary lymph nodes visible on MRI, an average of 1.4 nodes (range, 1-3 nodes) were present. Internal mammary lymph nodes were more frequently visualized on the left (p < 0.001), at the second and third intercostal spaces (p = 0.007), and medial to the internal mammary vessels (p < 0.001). CONCLUSION: In this small cohort, 1-3 presumed normal internal mammary lymph nodes measuring 2-9 mm (mean diameter 4.5 mm) were detected in about half of asymptomatic high-risk women presenting for screening MRI of the breasts. PMID- 26102402 TI - Patients' Perceptions of Radiation Exposure Associated With Mammography. AB - OBJECTIVE: Radiation associated with breast imaging is a sensitive issue, particularly for women who undergo mammography as a screening measure to detect breast cancer. Misinformation and misunderstanding regarding the risks associated with ionizing radiation have created heightened public concern and fear, which may result in avoidance of diagnostic procedures. The objectives of this study were to ascertain patients' knowledge and opinion of ionizing radiation as a whole and specifically in mammography, as well as to determine common misunderstandings and points of view that may affect women's decisions about whether to have a mammogram. MATERIALS AND METHODS: Over a 9-month period, a total of 1725 patients presenting for a mammogram completed a 25-point questionnaire focused on the following: general knowledge of radiation dose in common imaging modalities, the amount of radiation associated with a mammogram relative to five radiation benchmarks, and patients' opinions of the involvement of radiation in their health care. RESULTS: Although 65% of the women receiving a mammogram responded that they had been informed of the risks and benefits of the examination, 60% overestimated the radiation in a mammogram. CONCLUSION: Efforts should be made to accurately inform women of the risks and benefits of mammography, specifically highlighting the low dose of mammographic ionizing radiation and providing objective facts to ensure that they are making an informed decision regarding screening. PMID- 26102403 TI - Subcategorization of Suspicious Breast Lesions (BI-RADS Category 4) According to MRI Criteria: Role of Dynamic Contrast-Enhanced and Diffusion-Weighted Imaging. AB - OBJECTIVE: The purposes of this study were to investigate whether dynamic contrast-enhanced MRI is adequate for subcategorization of suspicious lesions (BI RADS category 4) and to evaluate whether use of DWI improves diagnostic performance. MATERIALS AND METHODS: The study group was composed of 103 suspicious lesions found in 83 subjects. Patient ages and lesion sizes were compiled, and two radiologists reanalyzed the images; subcategorized the findings as BI-RADS 4A, 4B, or 4C; and calculated apparent diffusion coefficient (ADC) values. The stratified variables were tested by univariate analysis and inserted in two multivariate predictive models, which were used to generate ROC curves and compare AUCs. Positive predictive values (PPVs) for each subcategory and ADC level were calculated, and interobserver agreement was tested. RESULTS: Forty four (42.7%) suspicious findings proved malignant. Except for age (p = 0.08), all stratified predictor variables were significant in univariate analyses (p < 0.01). Logistic regression models did not differ substantially after comparison of the ROC curves (p = 0.09), but the one including ADC values was slightly better: AUC of 0.89 (95% CI, 0.82-0.95) against AUC of 0.85 (95% CI, 0.78-0.93). PPV increased progressively in each BI-RADS 4 subcategory (4A, 0.15; 4B, 0.37; 4C, 0.84). ADC values of 1.10 * 10(-3) mm(2)/s or less had the second highest PPV (0.77). Interobserver agreement was substantial at a kappa value of 0.80 (95% CI, 0.70-0.90; p < 0.01). CONCLUSION: Risk stratification of suspicious lesions (BI RADS category 4) can be satisfactorily performed with DCE-MRI and slightly improved when DWI is introduced. PMID- 26102404 TI - Corrections. PMID- 26102405 TI - Why Does Patient Dose Increase With Tube Energy in CT When It Does the Opposite in Radiography? PMID- 26102406 TI - Prevalence of Imaging Features on CT Thought to Be Associated With Femoroacetabular Impingement: A Retrospective Analysis of 473 Asymptomatic Adult Hip Joints. AB - OBJECTIVE: The objective of our study was to investigate the prevalence of imaging features on CT thought to be associated with femoroacetabular impingement (FAI) and the associations among them. MATERIALS AND METHODS: Of 430 consecutive adult patients (age range, 18-40 years) who underwent hip CT at our institution for hip symptoms or trauma surveillance, the asymptomatic hips were selected for the study, which resulted in the inclusion of 473 hip joints in the study group. Images were obtained using an MDCT scanner and were reformatted using a bone algorithm. The CT images were retrospectively evaluated by two radiologists for features indicative of FAI such as the alpha angle, femoral head-neck offset, acetabular version angle, and center-edge angle. The intraclass correlation coefficient was used to evaluate intra- and interobserver variabilities. Associations among these parameters were evaluated by calculating the odds ratio between each of the parameters separately. RESULTS: Of the 473 asymptomatic hip joints we studied, 190 (40%) joints showed at least one of the following features on CT: alpha angle greater than 55 degrees , head-neck offset less than 8 mm, acetabular version angle less than 15 degrees , or center-edge angle greater than 40 degrees . At least one feature was found in the hips of male patients (43.2%), which is more frequently than in the hips of female patients (35.4%). There was a high degree of coexistence (odds ratio > 2) among these CT findings. CONCLUSION: Imaging features on CT that are known to be associated with FAI are common in asymptomatic adult hip joints, especially in men, with a high degree of coexistence among the findings. PMID- 26102407 TI - Impact of ROI Positioning and Lesion Morphology on Apparent Diffusion Coefficient Analysis for the Differentiation Between Benign and Malignant Nonfatty Soft Tissue Lesions. AB - OBJECTIVE: The objective of our study was to assess the impact of two methods of apparent diffusion coefficient (ADC) selection on the diagnostic performance of DWI in the characterization of nonfatty soft-tissue masses. SUBJECTS AND METHODS: Sixty-five histologically confirmed soft-tissue tumors imaged from November 2009 through October 2012 were evaluated. The minimal ADC (ADCmin) and average ADC (ADCavg) values for each tumor were obtained using two ROI-positioning methods: manual and semiautomatic. Two readers correlated the findings to lesion histology and morphology on conventional MRI sequences. RESULTS: The ADCmin values obtained using the manual method presented a better sensitivity with a similar specificity when compared with the ADCmin values obtained using the semiautomatic method (manual vs semiautomatic: 75-83% and 59-63% vs 58-67% and 63% and 63%, respectively). The interobserver agreement for the ADCmin values was similar between the ADC selection methods (intraclass correlation coefficient = 0.81 and 0.87 for manual and semiautomatic methods, respectively). In the subgroup of solid lesions, the ADCavg values obtained using the manual method offered a better sensitivity for benign-malignant differentiation (60-81% vs 60% and 60% for ADCavg and ADCmin, respectively). CONCLUSION: The ADCmin values obtained with manual ROI positioning offered the best diagnostic performance for tumor characterization. The semiautomatic method yielded similar specificity values. For solid masses, the ADCavg values were better correlated with tumor histology than the ADCmin values. PMID- 26102408 TI - Antitumoral Effect of Mural Cells Assessed With High-Resolution MRI and Fluorescence Microscopy. AB - OBJECTIVE: The purpose of this study was to detect labeled mural cells in vivo and study their therapeutic effect on tumor growth and on functional changes in the vascular network by use of MRI and fibered confocal fluorescence microscopy (FCFM). MATERIALS AND METHODS: Twenty-eight mice were allocated to the following three groups 7 days after injection of TC1 tumor cells (C157 black 6): control, no injection (n = 7); sham, injection of phosphate-buffered saline solution (n = 10); and treated, injection of human mural cells (n = 11). Tumor growth was measured with calipers. Labeled mural cells were tracked with high-resolution MRI and FCFM. Microvessel density was assessed with MRI and FCFM, and the findings were compared with the histologic results. RESULTS: Tumor growth was significantly slowed in the treated group starting on day 10 (p = 0.001). Round signal-intensity voids were observed in the center of six of seven tumors treated with magnetically labeled mural cells. Positive staining for iron was observed in histologic sections of two of five of these tumors. Microvessel density measured with FCFM was greater in the treated mice (p = 0.03). Flow cytometry revealed viable human mural cells only in treated tumors. CONCLUSION: In this study, imaging techniques such as high-resolution MRI and FCFM showed the therapeutic effect of mural cell injection on tumor growth and microvessel function. PMID- 26102409 TI - Juvenile Osteochondritis Dissecans: Correlation Between Histopathology and MRI. AB - OBJECTIVE: The objective of our study was to correlate specimens of juvenile osteochondritis dissecans (OCD) lesions of the knee to MRI examinations to elucidate the histopathologic basis of characteristic imaging features. MATERIALS AND METHODS: Five children (three boys and two girls; age range, 12-13 years old) who underwent transarticular biopsy of juvenile OCD lesions of the knee were retrospectively included in this study. Two radiologists reviewed the MRI examinations and a pathologist reviewed the histopathologic specimens and recorded characteristic features. Digital specimen photographs were calibrated to the size of the respective MR image with the use of a reference scale. Photographs were rendered semitransparent and over-laid onto the MR image with the location chosen on the basis of the site of the prior biopsy. RESULTS: A total of seven biopsy specimens were included. On MRI, all lesions showed cystlike foci in the subchondral bone, bone marrow edema pattern on proton density-or T2-weighted images, and relatively thick unossified epiphyseal cartilage. In four patients, a laminar signal intensity pattern was seen, and two patients had multiple breaks in the subchondral bone plate. Fibrovascular tissue was found at histopathology in all patients. Cleft spaces near the cartilage-bone interface and were seen in all patients while chondrocyte cloning was present in most cases. Focal bone necrosis and inflammation were infrequent MRI findings. Precise correlation of the MRI appearance to the histopathologic overlays consistently was found. CONCLUSION: A direct correlation exists between the histopathologic findings and the MRI features in patients with juvenile OCD. Additional studies are needed to correlate these MRI features with juvenile OCD healing success rates. PMID- 26102410 TI - Upright Biplanar Slot Scanning in Pediatric Orthopedics: Applications, Advantages, and Artifacts. AB - OBJECTIVE: Digital slot scanning is a relatively new technology that has been used for imaging of pediatric orthopedic conditions such as scoliosis and leg length discrepancies. This article will review the clinical applications, advantages, and unique artifacts of this new technology. CONCLUSION: Upright biplanar slot scanners acquire high-resolution radiographs simultaneously in two orthogonal planes with reduced radiation dose. Other advantages include a more physiologic weightbearing imaging position, improved Cobb angle measurements, and 3D modeling. PMID- 26102411 TI - Preliminary Results of Percutaneous Radiologic Gastrostomy in a Pediatric Population: A Modified Chiba-Needle Puncture Technique With Single Gastropexy. AB - OBJECTIVE: The purpose of this study was to evaluate the technical feasibility, safety, and clinical effectiveness of percutaneous radiologic gastrostomy using a modified Chiba-needle puncture technique with single gastropexy in pediatric patients. MATERIALS AND METHODS: From July 2006 to December 2013, percutaneous radiologic gastrostomy was performed in 12 children (median age, 21 months; range, 6-46 months). Their stomachs were punctured using a 21-gauge Chiba needle. A single Cope gastrointestinal suture anchor was used for gastropexy, and a tube was inserted through the same tract as the anchor using a 12- or 14-French Dawson Mueller pigtail drainage catheter. We then evaluated the technical success of the procedure, the number of puncture attempts using a 21-gauge Chiba needle, the procedure time, complications, and treatment of complications. RESULTS: Percutaneous radiologic gastrostomy was technically successful in all patients. Only a single puncture attempt was required in 10 patients (83%); two attempts were needed in two patients (17%). The average procedure time was 10 minutes 25 seconds (range, 5 minutes 5 seconds to 25 minutes 24 seconds). Pneumoperitoneum requiring tube exchange occurred in two of the 12 patients (17%). Two patients experienced pain immediately after the procedure. Three patients who had esophagogastric reflux after percutaneous radiologic gastrostomy underwent conversion percutaneous radiologic gastrojejunostomy. CONCLUSION: Percutaneous radiologic gastrostomy using a modified Chiba-needle technique with single gastropexy in pediatric patients is technically feasible and safe. PMID- 26102412 TI - MEDICOLEGAL-Malpractice and Ethical Issues in Radiology. Does Employment of Physician Assistants Increase the Likelihood of Malpractice Litigation? PMID- 26102413 TI - Complications Associated With Inflammatory Colitis. PMID- 26102414 TI - Iterative Reconstruction Techniques in Abdominopelvic CT: Technical Concepts and Clinical Implementation. AB - OBJECTIVE: This article discusses the clinical challenge of low-radiation-dose examinations, the commonly used approaches for dose optimization, and their effect on image quality. We emphasize practical aspects of the different iterative reconstruction techniques, along with their benefits, pitfalls, and clinical implementation. CONCLUSION: The widespread use of CT has raised concerns about potential radiation risks, motivating diverse strategies to reduce the radiation dose associated with CT. CT manufacturers have developed alternative reconstruction algorithms intended to improve image quality on dose-optimized CT studies, mainly through noise and artifact reduction. Iterative reconstruction techniques take unique approaches to noise reduction and provide distinct strength levels or settings. PMID- 26102415 TI - I Am Confused About the Cancer Risks Associated With CT: How Can We Summarize What Is Currently Known? PMID- 26102416 TI - Acute Pancreatitis: Revised Atlanta Classification and the Role of Cross Sectional Imaging. AB - OBJECTIVE: The 2012 revision of the Atlanta Classification emphasizes accurate characterization of collections that complicate acute pancreatitis: acute peripancreatic fluid collections, pseudocysts, acute necrotic collections, and walled-off necroses. As a result, the role of imaging in the management of acute pancreatitis has substantially increased. CONCLUSION: This article reviews the imaging findings associated with acute pancreatitis and its complications on cross-sectional imaging and discusses the role of imaging in light of this revision. PMID- 26102417 TI - Facial Fracture in the Setting of Whole-Body CT for Trauma: Incidence and Clinical Predictors. AB - OBJECTIVE: The objective of our study was to identify the incidence and clinical predictors of facial fracture in the setting of whole-body MDCT for trauma. MATERIALS AND METHODS: The clinical data from the electronic medical records, including the final radiology reports, of 486 consecutive patients who underwent MDCT for trauma (head, cervical spine, chest, abdomen, and pelvis examinations) with dedicated maxillofacial reconstructions from October 1, 2011, to July 31, 2013, were studied. The clinical variables were compared between cohorts of patients with and those without facial fracture. The two-sample t test was used to compare continuous variables, and the Fisher exact test was used to compare categoric variables. RESULTS: Two hundred sixteen (44.4%) patients had at least one fracture on the dedicated maxillofacial CT examinations, 215 of whom had facial physical examination findings (sensitivity = 99.5%). Of the 28 patients without documented physical examination findings, 27 did not have a facial fracture (negative predictive value = 96.4%). Statistically significant differences were found between positive and negative cases of facial fracture in patients with a Glasgow coma scale (GCS) score of 8 or less (p < 0.0001), an injury severity score of 16 or greater (p < 0.0001), acute alcohol intoxication according to blood alcohol concentration (BAC) (p = 0.0387), intubation at presentation (p < 0.0001), positive physical examination findings (p < 0.0001), and loss of consciousness (p = 0.0364). Falls from a height greater than standing height and open-vehicle collisions had the highest fracture rates (80.0% and 58.3%, respectively). CONCLUSION: A negative finding at facial physical examination reliably excluded fracture. Clinical variables positively associated with facial fracture included the following: GCS score of 8 or less, ISS of 16 or greater, alcohol intoxication according to BAC, intubation at presentation, loss of consciousness, and the presence of abnormal facial findings at physical examination. PMID- 26102418 TI - MRI of Rectal Cancer: An Overview and Update on Recent Advances. AB - OBJECTIVE: MRI is the modality of choice for rectal cancer staging. The high soft tissue contrast of MRI accurately assesses the extramural tumor spread and relation to mesorectal fascia and the sphincter complex. This article reviews the role of MRI in the staging and treatment of rectal cancer. The relevant anatomy, MRI techniques, preoperative staging, post-chemoradiation therapy (CRT) imaging, and tumor recurrence are discussed with special attention to recent advances in knowledge. CONCLUSION: MRI is the modality of choice for staging rectal cancer to assist surgeons in obtaining negative surgical margins. MRI facilitates the accurate assessment of mesorectal fascia and the sphincter complex for surgical planning. Multiparametric MRI may also help in the prediction and estimation of response to treatment and in the detection of recurrent disease. PMID- 26102419 TI - Contrast-Enhanced Ultrasound of Focal Liver Lesions. AB - OBJECTIVE: The purpose of this article is to discuss the use of contrast-enhanced ultra-sound (CEUS) in focal liver lesions. CONCLUSION: Focal liver lesions are usually detected incidentally during abdominal ultrasound. The injection of microbubble ultrasound contrast agents improves the characterization of focal liver lesions that are indeterminate on conventional ultrasound. The use of CEUS is recommended in official guidelines and suggested as a second diagnostic step after ultrasound detection of indeterminate focal liver lesions to immediately establish the diagnosis, especially for benign liver lesions, such as hemangiomas, avoiding further and more expensive examinations. PMID- 26102420 TI - Absolute Versus Relative Myocardial Blood Flow by Dynamic CT Myocardial Perfusion Imaging in Patients With Anatomic Coronary Artery Disease. AB - OBJECTIVE: The purpose of this study was to evaluate differences in the diagnostic accuracy of absolute and relative territorial myocardial blood flow (MBF) derived from stress dynamic CT myocardial perfusion imaging (MPI) for the detection of significant coronary artery stenosis. MATERIALS AND METHODS: Dynamic CT MPI and coronary CT angiography (CTA) datasets from a multicenter registry of 137 patients (mean age, 60.9 +/- 8.4 years; 88 men) with suspected or known coronary artery disease were retrospectively analyzed. For each coronary territory, absolute MBF and the MBF relative to remote myocardium (MBF ratio) were calculated. Coronary CTA datasets were visually assessed for significant stenosis (>= 50% luminal narrowing) in consensus by two observers. RESULTS: Significant stenosis was detected in 137 of 411 (33.3%) vessels. Mean absolute MBF and MBF ratio were statistically significantly lower in territories supplied by arteries with stenosis (80.7 +/- 33.7 vs 140.0 +/- 38.4 mL/100 mL/min and 0.52 vs 0.89, respectively; both p < 0.0001). ROC analysis showed better discrimination by MBF ratio than by absolute MBF (AUC, 0.925 vs 0.882; p = 0.0022) and increased sensitivity (90.7% vs 82.4%; p < 0.04) and specificity (93.1% vs 80.5%; p < 0.03) for MBF ratio and absolute MBF cutoff values of 0.71 or less and 103 mL/100 mL/min or less, respectively. CONCLUSION: In stress dynamic CT MPI, relative MBF provides superior diagnostic accuracy compared with absolute territorial MBF values for coronary CTA-detected significant coronary artery stenosis. PMID- 26102421 TI - Diagnosis of Extracapsular Extension of Prostate Cancer on Prostate MRI: Impact of Second-Opinion Readings by Subspecialized Genitourinary Oncologic Radiologists. AB - OBJECTIVE: The purpose of this article is to investigate the added value of second-opinion evaluation of prostate MRI by subspecialized genitourinary oncologic radiologists for the assessment of extracapsular extension (ECE) of prostate cancer. MATERIALS AND METHODS: We performed a retrospective evaluation of initial and second-opinion radiology reports of 76 patients who underwent MRI of the prostate before prostatectomy for histologically proven prostate cancer. Initial outside reports and second-opinion reports were unpaired and reviewed in random order by a urologist who was blinded to patients' clinical details and histopathologic data. Histopathologic analysis of the prostatectomy specimen served as the reference standard. RESULTS: Among cases with diagnostic-quality images available (71/76; 93%), disagreement between the initial report and the second-opinion report was observed in 30% of cases (21/71; kappa = 0.35); in 18 of these 21 cases (86%), histopathologic analysis proved that the second-opinion report was correct. The second-opinion interpretations had statistically significantly higher sensitivity (66% vs 24%; p < 0.0001) than did the initial reports, whereas there was no statistically significant difference in specificity (87% vs 93%; p = 0.317). On ROC curve analysis, the second-opinion reports yielded a statistically significantly higher AUC for the detection of ECE (0.80 vs 0.65; p = 0.004). CONCLUSION: The reinterpretation of prostate MRI examinations by subspecialized genitourinary oncologic radiologists improved the detection of ECE of prostate cancer. PMID- 26102422 TI - Predictive Value of Chemical-Shift MRI in Distinguishing Clear Cell Renal Cell Carcinoma From Non-Clear Cell Renal Cell Carcinoma and Minimal-Fat Angiomyolipoma. AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of chemical-shift MRI in the differentiation of clear cell renal cell carcinoma (RCC) from minimal-fat angiomyolipoma (AML) and non-clear cell RCC. MATERIALS AND METHODS: In this retrospective study, 97 patients with solid renal tumors without macroscopic fat and with a pathologic diagnosis of clear cell RCC (n = 40), non clear cell RCC (n = 31), or minimal-fat AML (n = 26) who had undergone renal chemical-shift MRI were included. Size, location, morphology, and signal intensity (SI) of the tumors and the contralateral normal kidneys on T2-weighted and in-phase and opposed-phase images were recorded by readers blinded to the pathology. Percentage tumor-to-renal parenchymal SI drop (percentage SI drop) was calculated and correlated to tumor histology. The statistical analysis was done using Kruskal-Wallis, one-way ANOVA, chi-square, and Fisher exact tests. RESULTS: The percentage SI drop was significantly higher in clear cell RCC compared with non-clear cell RCC and minimal-fat AML (p < 0.001). Percentage SI drop of greater than 20% had 57.5% sensitivity, 96.5% specificity, and 92% positive predictive value (PPV); and percentage SI drop greater than 29% had 40% sensitivity and 100% specificity for diagnosis of clear cell RCC within the cohort of clear cell RCC, minimal-fat AML, and non-clear cell RCC. A significant proportion of minimal-fat AML (46.2%) displayed homogeneous low T2-weighted SI as opposed to clear cell RCC (5%) and non-clear cell RCC (29%) (p < 0.001). CONCLUSION: The percentage SI drop on chemical-shift MRI had high specificity and moderate sensitivity in predicting clear cell RCC over non-clear cell RCC and minimal-fat AML. A percentage SI drop greater than 20% in a renal mass without macroscopically visible fat has high PPV for clear cell RCC over minimal-fat AML and non-clear cell RCC. Among morphologic features, homogeneous low T2 SI favors minimal-fat AML over RCC. PMID- 26102423 TI - Characteristics of Detected and Missed Prostate Cancer Foci on 3-T Multiparametric MRI Using an Endorectal Coil Correlated With Whole-Mount Thin Section Histopathology. AB - OBJECTIVE: The objective of this study was to determine the characteristics of prostate cancer foci missed on 3-T multiparametric MRI performed with an endorectal coil. MATERIALS AND METHODS: The MRI examinations of 122 patients who underwent 3-T multiparametric MRI of the prostate with an endorectal coil were compared with whole-mount histopathology obtained after radical prostatectomy. The mean age of the patients was 60.6 years (SD, 7.6 years), and the mean prostate-specific antigen value was 7.2 ng/mL (SD, 5.9 ng/mL). The clinical, multiparametric MRI (i.e., T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging), and histopathologic features were obtained. After an independent review, two blinded genitourinary radiologists matched each case with a genitourinary pathologist. A structured reporting system was used to classify the multiparametric MRI features of each MRI-detected lesion. A chi square analysis was performed for categoric variables, and the t test was performed for continuous variables. RESULTS: On whole-mount histopathology, 285 prostate cancer foci were detected in 122 patients. Of the 285 cancer foci detected at histopathology, 153 (53.3%) were missed on MRI and 132 (46.7%) were detected on MRI. Of the missed lesions, 75.2% were low-grade prostate cancer. Multiparametric MRI had a significantly higher sensitivity for prostate cancer foci 1 cm or larger than for subcentimeter foci (81.1% vs 18.9%, respectively; p < 0.001), for lesions with a Gleason score of 7 or greater than for lesions with a Gleason score of 6 (72.7% vs 27.3%; p < 0.01), and for index lesions than for satellite lesions (80.3% vs 20.8%; p < 0.01). The 3-T multiparametric MRI examinations showed a higher detection rate for lesions in the midgland or base of the gland compared with lesions in the apex (52.3% vs 22.0%, respectively; p < 0.01). CONCLUSION: Compared with the prostate cancer lesions that were detected on multiparametric MRI, the prostate cancer lesions that were missed were significantly smaller, were more likely to be low-grade lesions (i.e., Gleason score of 6), were more commonly satellite lesions, and were more likely to be located in the prostatic apex. PMID- 26102424 TI - Automated Technique to Measure Noise in Clinical CT Examinations. AB - OBJECTIVE: The purpose of this study was to develop and validate an automated method to measure noise in clinical CT examinations. MATERIALS AND METHODS: An automated algorithm was developed to measure noise in CT images. To assess its validity, the global noise level was compared with image noise measured using an image subtraction technique in an anthropomorphic phantom. The global noise level was further compared with image noise values from clinical patient CT images obtained by an observer study. Finally, the clinical utility of the global noise level was shown by assessing variability of image noise across scanner models for abdominopelvic CT examinations performed in 2358 patients. RESULTS: The global noise level agreed well with the phantom-based and clinical image-based noise measurements, with an average difference of 3.4% and 4.7% from each of these measures, respectively. No significant difference was detected between the global noise level and the validation dataset in either case. It further indicated differences across scanners, with the median global noise level varying significantly between different scanner models (15-35%). CONCLUSION: The global noise level provides an accurate, robust, and automated method to measure CT noise in clinical examinations for quality assurance programs. The significant difference in noise across scanner models indicates the unexploited potential to efficiently assess and subsequently improve protocol consistency. Combined with other automated characterization of imaging performance (e.g., dose monitoring), the global noise level may offer a promising platform for the standardization and optimization of CT protocols. PMID- 26102425 TI - Flexible Lamination Encapsulation. AB - A novel flexible encapsulation method (Flex Lami-capsulation) is reported, which can be applied in the roll-to-roll process for mass production of organic electronic devices. Flex Lami-capsulation is very simple, fast, and getter-free, and is as effective as glass encapsulation. Use of this method is feasible in large-area flexible displays and does not have the drawbacks of conventional encapsulation methods. PMID- 26102426 TI - Construction of a Near-Infrared-Activatable Enzyme Platform To Remotely Trigger Intracellular Signal Transduction Using an Upconversion Nanoparticle. AB - Photoactivatable (caged) bioeffectors provide a way to remotely trigger or disable biochemical pathways in living organisms at a desired time and location with a pulse of light (uncaging), but the phototoxicity of ultraviolet (UV) often limits its application. In this study, we have demonstrated the near-infrared (NIR) photoactivatable enzyme platform using protein kinase A (PKA), an important enzyme in cell biology. We successfully photoactivated PKA using NIR to phosphorylate its substrate, and this induced a downstream cellular response in living cells with high spatiotemporal resolution. In addition, this system allows NIR to selectively activate the caged enzyme immobilized on the nanoparticle surface without activating other caged proteins in the cytosol. This NIR responsive enzyme-nanoparticle system provides an innovative approach to remote control proteins and enzymes, which can be used by researchers who need to avoid direct UV irradiation or use UV as a secondary channel to turn on a bioeffector. PMID- 26102427 TI - Synthesis and Optical Properties of Imidazole- and Benzimidazole-Based Fused pi Conjugated Compounds: Influence of Substituent, Counteranion, and pi-Conjugated System. AB - Fused pi-conjugated imidazolium chlorides having hydrogen (1-Cl), octyloxy (2 Cl), N,N-dibutylamino (3-Cl), trifluoromethyl (4-Cl), and cyano (5-Cl) groups substituted on the benzene ring at the 2-position of imidazole were prepared. Counteranion exchanges from chloride to bis(trifluoromethanesulfonyl)imidate (2 TFSI) and tetrafluoroborate (2-BF4) were performed. The optical properties of these compounds (absorption and emission wavelengths, fluorescence quantum yield, and solvatochromism) were influenced by both the substituent and anion character, which was investigated by theoretical calculations using the density functional theory (DFT) and symmetry-adapted cluster-configuration interaction (SAC-CI) methods. Fused pi-conjugated benzimidazolium chlorides having N,N-dibutylamino (6 Cl) and cyano (7-Cl) groups were also prepared to observe the different solvatochromic shifts. PMID- 26102428 TI - Large Area Fabrication of Periodic TiO2 Nanopillars Using Microsphere Photolithography on a Photopatternable Sol-Gel Film. AB - The authors demonstrate a unique low cost process to print 2D, submicron size, and high refractive index nanopillars using a direct colloidal-photolithography process. A well collimated i-line source emitting at 365 nm wavelength illuminates a mono layer of silica microspheres of 1 MUm diameter deposited on a photosensitive TiO2-based sol-gel layer. No etching process is needed since this layer is directly UV photo patternable like a negative photoresist. Furthermore, this thin layer offers interesting optical properties (high refractive index and optical transparency) and good mechanical and chemical stability and thus can be directly used as a functional microstructure (for PV or sensor applications, for example). The paper describes the modeling of the electric field distribution below the spheres during the illumination process, the photochemistry of the TiO2 sol-gel layer process, and preliminary results of TiO2 nanopillars of around 200 nm in diameter fabricated on a three-inch substrate. PMID- 26102429 TI - Psychological predictors of opportunistic snacking in the absence of hunger. AB - Increased frequency of eating in the absence of homeostatic need, notably through snacking, is an important contributor to overconsumption and may be facilitated by increased availability of palatable food in the obesogenic environment. Opportunistic initiation of snacking is likely to be subject to individual differences, although these are infrequently studied in laboratory-based research paradigms. This study examined psychological factors associated with opportunistic initiation of snacking, and predictors of intake in the absence of homeostatic need. Fifty adults (mean age 34.5years, mean BMI 23.9kg/m(2), 56% female) participated in a snack taste test in which they ate a chocolate snack to satiation, after which they were offered an unanticipated opportunity to initiate a second eating episode. Trait and behavioural measures of self control, sensitivity to reward, dietary restraint and disinhibited eating were taken. Results showed that, contrary to expectations, those who initiated snacking were better at inhibitory control compared with those who did not initiate. However, amongst participants who initiated snacking, intake (kcal) was predicted by higher food reward sensitivity, impulsivity and BMI. These findings suggest that snacking initiation in the absence of hunger is an important contributor to overconsumption. Consideration of the individual differences promoting initiation of eating may aid in reducing elevated eating frequency in at-risk individuals. PMID- 26102430 TI - Molybdenum Trihydride Complexes: Computational Determinations of Hydrogen Positions and Rearrangement Mechanisms. AB - In crystal structures of the molybdenum complexes [(1,2,4-C5H2(t)Bu3)Mo(PMe3)2H3] (Cp(t)Bu3) and [(C5H(i)Pr4)Mo(PMe3)2H3] (Cp(i)Pr4), the Mo-bound hydrogen positions were resolved for Cp(t)Bu3, but not for Cp(i)Pr4. NMR experiments revealed the existence of an unknown mechanism for hydrogen atom exchange in these molecules, which can be "frozen out" for Cp(t)Bu3 but not for Cp(i)Pr4. Density functional theory calculations of the most stable conformations for both complexes in the gas phase and in a continuum solvent model indicate that the H's of the Cp(i)Pr4 complex are unresloved because of their disorder, which does not occur for Cp(t)Bu3. A corresponding examination of alternative rearrangement pathways shows that the rearrangements of the H's could occur by two mechanisms: parallel to the cyclopentadienyl (Cp) ring in a single step and perpendicular to the Cp ring in two steps. The parallel pathway is preferred for both molecules, but it has a lower energy barrier for Cp(i)Pr4 than for Cp(t)Bu3. PMID- 26102431 TI - Monitoring of mycophenolate mofetil metabolites in children with nephrotic syndrome and the proposed novel target values of pharmacokinetic parameters. AB - The aim of the study was to estimate target values of mycophenolate mofetil (MMF) pharmacokinetic parameters in children with proteinuric glomerulopathies by calculating the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA], free MPA [fMPA] and MPA glucuronide [MPAG]) and assessing their relation to proteinuria recurrence. One hundred and sixty-eight blood samples were collected from children, aged 3-18 years, diagnosed with nephrotic syndrome or lupus nephritis. MMF metabolites concentrations were examined before drug administration (Ctrough) and up to 12h afterward employing high-performance liquid chromatography. Dose-normalized MPA Ctrough and area under the concentration-time curve from 0 to 12h (AUC12) were within 0.29-6.47 MUg/mL/600 mg/m(2) and 9.97-105.52 MUg h/mL/600 mg/m(2), respectively. MPA Ctrough was twofold lower (p=0.024) in children with proteinuria recurrence. MPA, fMPA and MPAG concentrations correlated positively to respective AUC12. It may be suggested MMF metabolites monitoring in children with proteinuric glomerulopathies is justified by MPA Ctrough<2 MUg/mL in patients at risk of the proteinuria recurrence. Such a recurrence is most probably caused by not sufficient MPA concentration during proteinuric glomerulopathies treatment. MPA Ctrough>3 MUg/mL may be considered as an efficient one to avoid proteinuria recurrence. Finally, MPA target AUC12 should exceed 60 MUg h/mL to ensure the safe and effective treatment in children with nephrotic syndrome, however, the upper limit is still to be established. PMID- 26102432 TI - Quantitative Intramolecular Singlet Fission in Bipentacenes. AB - Singlet fission (SF) has the potential to significantly enhance the photocurrent in single-junction solar cells and thus raise the power conversion efficiency from the Shockley-Queisser limit of 33% to 44%. Until now, quantitative SF yield at room temperature has been observed only in crystalline solids or aggregates of oligoacenes. Here, we employ transient absorption spectroscopy, ultrafast photoluminescence spectroscopy, and triplet photosensitization to demonstrate intramolecular singlet fission (iSF) with triplet yields approaching 200% per absorbed photon in a series of bipentacenes. Crucially, in dilute solution of these systems, SF does not depend on intermolecular interactions. Instead, SF is an intrinsic property of the molecules, with both the fission rate and resulting triplet lifetime determined by the degree of electronic coupling between covalently linked pentacene molecules. We found that the triplet pair lifetime can be as short as 0.5 ns but can be extended up to 270 ns. PMID- 26102433 TI - IDENTIFICATION OF FLUID ON OPTICAL COHERENCE TOMOGRAPHY BY TREATING OPHTHALMOLOGISTS VERSUS A READING CENTER IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENTS TRIALS. AB - PURPOSE: To examine treatment decisions by ophthalmologists versus reading center fluid identification from optical coherence tomography in Comparison of Age Related Macular Degeneration Treatments Trials (CATT). METHODS: Fluid in 6,210 optical coherence tomography scans (598 patients) in "as needed treatment" arm of CATT Year 1 was compared with ophthalmologist's treatment: positive fluid agreement (PFA, fluid+, treatment+) and positive fluid discrepancy (PFD, fluid+, treatment-), negative fluid agreement (fluid-, treatment-) and negative fluid discrepancy (fluid-, treatment+). For PFDs, fluid location and visual acuity were characterized. RESULTS: Treatment and reading center fluid determination agreed in 72.1% (53.0% PFA, 19.1% negative fluid agreement) and disagreed in 27.9% (25.7% PFD, 2.2% negative fluid discrepancy) of visits, with no discrepancies for 20.9% of patients. Compared with PFA, PFD occurred more commonly with lower total foveal thickness (mean +/- SD: 265 +/- 103 PFD, 366 +/- 151 MUm PFA), presence of intraretinal fluid only, smaller fluid areas (PFA areas greater than twice those of PFD, P < 0.001), and greater decrease in retinal and lesion thickness. Mean acuities before, at, and after PFD were 65.8, 66.9, and 66.3 letters. CONCLUSION: Treatment decisions by ophthalmologists matched reading center fluid determination in the majority of visits. More pronounced response to treatment and smaller foci of fluid likely contributed to PFD. Positive fluid discrepancy did not have substantial impact on subsequent visual acuity. PMID- 26102434 TI - SWITCHING TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION FROM BEVACIZUMAB TO RANIBIZUMAB: Who is Likely to Benefit From the Switch? AB - PURPOSE: To evaluate the safety and efficacy of switching from bevacizumab to ranibizumab in patients with neovascular age-related macular degeneration. METHODS: Retrospective study of patients with neovascular age-related macular degeneration initially treated with bevacizumab and switched to ranibizumab. Visual acuity and central retinal thickness (CRT) were retrieved at four time points: before the last three bevacizumab injections, at the switch, after the first three ranibizumab injections, and at the end of follow-up. RESULTS: One hundred and fourteen eyes of 110 patients were included. Switching from bevacizumab to ranibizumab did not achieve a significant change in visual acuity, and a significant reduction in CRT was achieved after the first three injections but was not maintained by the end of follow-up. Eyes that lost >=0.1 logMAR before the switch were more likely to improve in visual acuity (P = 0.013), and eyes with >=10% increase in CRT before the switch were more likely to improve anatomically (P = 0.0003). In 47.3% of the eyes, the CRT was reduced by >=10% after the first 3 ranibizumab injections, and the reduction was maintained with additional injections. CONCLUSION: Switching to ranibizumab should be considered in patients with visual acuity decrease or CRT increase, despite monthly bevacizumab injections. The response should be evaluated after the first three injections to guide future treatment. PMID- 26102435 TI - CHOROIDAL NEOVASCULARIZATION IN CAUCASIAN PATIENTS WITH LONGSTANDING CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To report the frequency of choroidal neovascularization (CNV) in Caucasian patients with chronic central serous chorioretinopathy (CSC). METHODS: Retrospective consecutive series of 272 eyes (136 patients) who were diagnosed as having chronic CSC based on clinical and multimodal fundus imaging findings and documented disease activity for at least 6 months. The CNVs were mainly determined by indocyanine-green angiography. RESULTS: Patients were evaluated and followed for a maximum of 6 years, with an average follow-up of 14 +/- 12 months. Distinct CNV was identified in 41 eyes (34 patients). Based on fluorescein angiography, 37 eyes showed occult with no classic CNV, 3 eyes showed predominantly classic and 1 eye had a disciform CNV. Furthermore, indocyanine green angiography revealed polypoidal choroidal vasculopathy lesions, in 27 of the 37 eyes, classified as occult CNV on fluorescein angiography. In total, 17.6% of our patients with chronic CSC were found to have CNV that upon indocyanine green angiography were recognized as being polypoidal choroidal vasculopathy. CONCLUSION: In our series of Caucasian patients, we found a significant correlation between chronic CSC and CNV, in which the majority of patients with CNV were found to have polypoidal choroidal vasculopathy. Our findings suggest that indocyanine-green angiography is an indispensable tool in the investigation of chronic CSC. PMID- 26102436 TI - IMPROVED SPECIFICITY OF POLYPOIDAL CHOROIDAL VASCULOPATHY DIAGNOSIS USING A MODIFIED EVEREST CRITERIA. AB - PURPOSE: To evaluate the performance of polypoidal choroidal vasculopathy (PCV) diagnosis using fundus camera-based indocyanine green angiography, comparing a single sign of "subretinal focal hyperfluorescence" on indocyanine green angiography with a modification of the EVEREST criteria. METHODS: Color fundus photograph, flash fundus camera-based fluorescein angiography, and indocyanine green angiography of 241 eyes of 230 consecutive patients with exudative maculopathy due to PCV or typical age-related macular degeneration were graded independently by 2 retinal specialists using a modified EVEREST criteria, which requires the presence of subretinal focal hyperfluorescence plus any 1 of 5 additional criteria. Discordant cases were adjudicated by a senior retinal specialist to arrive at the final diagnosis. Sensitivity, specificity, and area under the receiver operating curve of subretinal focal hyperfluorescence versus the EVEREST criteria and combinations of individual EVEREST criteria were compared. RESULTS: Among the 241 eyes with exudative maculopathy, 131 eyes had PCV and 110 eyes had typical age-related macular degeneration. Using a single sign of subretinal focal hyperfluorescence alone for the diagnosis of PCV, sensitivity was 85.3% and specificity was 80.9%, with an area under the receiver operating curve of 83.1%. When applying the EVEREST definition, sensitivity was reduced to 78.4% but specificity improved to 87.1% with a similar area under the receiver operating curve of 82.8%. The frequency of individual criteria was highly variable, with stereo nodular appearance (73.7%) and orange nodule (55.0%) being the most common and branching vascular network, massive hemorrhage, and hypofluorescent halo in the presence of subretinal focal hyperfluorescence being less common (21.5%-28.1%). CONCLUSION: The EVEREST criteria have a higher specificity for the diagnosis of PCV than subretinal focal hyperfluorescence alone and may be applied to flash fundus camera-based indocyanine green angiography in a clinical setting. Stereo nodular appearance is the most important additional criterion. PMID- 26102437 TI - DEXAMETHASONE IMPLANT FOR MACULAR EDEMA SECONDARY TO CENTRAL RETINAL VEIN OCCLUSION IN PATIENTS YOUNGER THAN 50 YEARS. AB - PURPOSE: To evaluate the effects of dexamethasone implant for macular edema secondary to central retinal vein occlusion in patients younger than 50 years. METHODS: Patients with no previous treatment, macular edema with central foveal thickness >250 MUm and best-corrected visual acuity between 1.30 LogMAR and 0.30 LogMAR were prospectively recruited for a 12-month follow-up study. After baseline dexamethasone implant, re-treatment was performed starting from the fourth month if a best-corrected visual acuity deterioration with central foveal thickness >250 MUm occurred after an initial improvement. The primary outcome was the change in the best-corrected visual acuity. Secondary outcomes included the proportion of eyes gaining at least 3 Early Treatment Diabetic Retinopathy Study lines, the change in the central foveal thickness, and the number of treatments. RESULTS: Mean best-corrected visual acuity changed significantly from 0.60 +/- 0.38 LogMAR at baseline to 0.43 +/- 0.48 at the 12-month examination (P = 0.03). Eight of 16 eyes (50%) gained 3 Early Treatment Diabetic Retinopathy Study lines. Mean central foveal thickness improved significantly from 705 +/- 202 MUm at baseline to 408 +/- 196 MUm at 12-month visit (P < 0.001). The patients received a mean of 1.8 +/- 0.9 implants with 8/16 eyes and 3/16 receiving 1 and 2 implants, respectively. CONCLUSION: This present investigation indicates that dexamethasone implant can provide a 3-line improvement in half of the patients younger than 50 years and affected by macular edema secondary to central retinal vein occlusion. PMID- 26102439 TI - EFFECT OF INTERNAL LIMITING MEMBRANE PEELING ON LONG-TERM VISUAL OUTCOMES FOR DIABETIC MACULAR EDEMA. AB - PURPOSE: To evaluate the effect of internal limiting membrane (ILM) peeling on the long-term visual outcomes in eyes with diffuse, nontractional diabetic macular edema. METHODS: One hundred and sixteen eyes of 58 patients with the same degree of diabetic macular edema in both eyes underwent pars plana vitrectomy with the creation of a posterior vitreous detachment in both eyes. Internal limiting membrane peeling was performed in one randomly selected eye (ILM-off group), and ILM peeling was not performed (ILM-on group) in the fellow eye. The postoperative follow-up period ranged from 12 months to 161 months (average, 80.4 months). RESULTS: In the ILM-off group, the mean best-corrected visual acuity in logMAR units (Snellen equivalent) increased from 0.55 +/- 0.31 (20/71) before surgery to 0.35 +/- 0.35 (20/45) at 1 year (P < 0.0001) and 0.46 +/- 0.43 (20/59) at the final visit (P = 0.058). In the ILM-on group, the mean best-corrected visual acuity increased from 0.55 +/- 0.41 (20/71) before surgery to 0.43 +/- 0.38 (20/54) at 1 year (P = 0.010) and 0.44 +/- 0.45 (20/56) at the final visit (P = 0.043). The differences in the best-corrected visual acuity between the two groups were not significant at any time point. CONCLUSION: Pars plana vitrectomy with or without ILM peeling improves the long-term visual acuity of nontractional diabetic macular edema. Internal limiting membrane peeling does not affect the postoperative best-corrected visual acuity significantly. PMID- 26102438 TI - DEXAMETHASONE IMPLANT FOR MACULAR EDEMA SECONDARY TO ISCHEMIC RETINAL VEIN OCCLUSIONS. AB - PURPOSE: To evaluate the effects of dexamethasone implant for the treatment of macular edema secondary to ischemic retinal vein occlusions (IRVO). METHODS: Consecutive patients affected by macular edema related to IRVO were prospectively recruited. After a comprehensive ophthalmological examination, including visual acuity, fluorescein angiography, and optical coherence tomography, each patient received a first implant. Further re-treatments were performed on the basis of macular edema detection from the fourth month on. The primary outcome measure was the change in Early Treatment Diabetic Retinopathy Study letter score at the 12 month examination. Secondary outcome measures included changes in central foveal thickness and number of implants over the follow-up. RESULTS: Fifteen patients with central IRVO and 14 patients with branch IRVO were recruited. The median ETDRS letter score at baseline was 10 (Snellen Equivalent 20/640) in the central IRVO subgroup, improving to 37 (Snellen Equivalent 20/2002+) at the 12-month examination. The median ETDRS letter score in the branch retinal vein occlusion subgroup changed from 48 (Snellen equivalent 20/1253+) at baseline to 62 (Snellen equivalent 20/632+) at the 12-month examination. The baseline median central foveal thickness was 749 MUm in central IRVO, and 459 MUm in branch IRVO, improving to 363 MUm and 323 MUm, respectively, at the 12-month examination. Mean number of implants was 2.8 in the central IRVO and 2 in the branch IRVO. CONCLUSION: Dexamethasone implant can reduce macular edema in eyes affected by IRVO, leading to a slight improvement in visual acuity. PMID- 26102440 TI - INTRAVITREAL DEXAMETHASONE IMPLANT IN PATIENTS WITH RANIBIZUMAB PERSISTENT DIABETIC MACULAR EDEMA. AB - PURPOSE: To study the efficacy of intravitreal injection (IVI) of dexamethasone implant as second-line treatment in patients with resistant chronic diabetic macular edema nonresponsive to 6 monthly consecutive IVI of ranibizumab. METHODS: A retrospective study was conducted over 9 months. Best-corrected visual acuity and central macular thickness were noted. Patients with best-corrected visual acuity <=20/40 using Snellen chart, central macular thickness >=300 MUm, and poor response to 6 monthly consecutive IVI of ranibizumab were included. Patients received IVI of dexamethasone implant and were examined at 1, 3, 6, and 9 months. RESULTS: Thirteen eyes of 12 patients were included (6 men and 6 women; mean age, 64 +/- 7.8 years). Best-corrected visual acuity increased by a mean of 5.58 letters at Month 1 (P = 0.017), 4.61 at Month 3 (P = 0.05), 4.61 at Month 6 (P = 0.042), and 5.77 at Month 9 (P = 0.017). Central macular thickness decreased from 594 MUm to 402 MUm at Month 1 (P = 0.0002), 428 MUm at Month 3 (P = 0.002), 459 MUm at Month 6 (P = 0.02), and 489 MUm at Month 9 (P = 0.03). Mean number of dexamethasone IVI was 1.07. Two patients (15.3%) developed elevated intraocular pressure, and 1 patient was operated for cataract at 6 months (9% of phakic patients). CONCLUSION: Intravitreal injection of dexamethasone implant seems as an effective second-line treatment in diabetic macular edema persistent after 6 monthly consecutive intravitreal ranibizumab injections in real life. PMID- 26102441 TI - SURGICAL OUTCOME OF SIMULTANEOUS INTRAOCULAR LENS RESCUE AND SUTURELESS INTRASCLERAL TUNNEL FIXATION OF DISLOCATED INTRAOCULAR LENSES. AB - PURPOSE: To report short-term surgical outcomes of single-stage simultaneous rescue and sutureless intrascleral fixation of dislocated intraocular lens (IOLs). METHODS: Sixteen eyes of 16 patients who underwent simultaneous rescue and intrascleral fixation of dislocated 3-piece IOLs were retrospectively evaluated. Partial thickness limbal-based scleral flaps (2.0 * 2.0 mm) were created, and a 22-gauge round needle was used to create a sclerotomy at 1.5 mm from the limbus under the previously created scleral flap, and a 23-gauge trans pars plana vitrectomy was performed. Bimanual maneuvers using two 23-gauge end grasping forceps under chandelier illumination and a wide-angle viewing system enabled 1 step rescue of IOLs from the posterior vitreous cavity with 1 hand and simultaneous haptic externalization through sclerotomy with the other hand. An externalized haptic was placed into the 3-mm intrascleral tunnel created using a bent 26-gauge needle. Fibrin glue was used to fixate haptics and close the scleral flaps. RESULTS: Intraocular lenses were successfully rescued and sclera fixated through intrascleral tunnels in all 16 eyes (mean age, 56.56 +/- 19.89 years). The mean preoperative logarithm of the minimum angle of resolution best corrected visual acuity was 0.92 +/- 0.68, and this significantly improved at 6 months to 0.289 +/- 0.36 (P = 0.003). During the follow-up period (10.1 +/- 3.21 months), no significant change of endothelial cell count or central foveal thickness was noted postoperatively (P = 0.203 and P = 0.979, respectively). There were no significant postoperative complications such as IOL dislocation, IOL decentration, retinal detachment, endophthalmitis, or postoperative hypotony. CONCLUSION: Simultaneous rescue and sutureless intrascleral haptic fixation of dislocated 3-piece IOLs using bimanual maneuvers is an effective, safe, and minimally invasive surgical method to rescue and fixate the dislocated IOL without further explant. PMID- 26102442 TI - Tobacco Cessation May Improve Lung Cancer Patient Survival. AB - INTRODUCTION: This study characterizes tobacco cessation patterns and the association of cessation with survival among lung cancer patients at Roswell Park Cancer Institute: an NCI Designated Comprehensive Cancer Center. METHODS: Lung cancer patients presenting at this institution were screened with a standardized tobacco assessment, and those who had used tobacco within the past 30 days were automatically referred to a telephone-based cessation service. Demographic, clinical information, and self-reported tobacco use at last contact were obtained via electronic medical records and the Roswell Park Cancer Institute tumor registry for all lung cancer patients referred to the service between October 2010 and October 2012. Descriptive statistics and Cox proportional hazards models were used to assess whether tobacco cessation and other factors were associated with lung cancer survival through May 2014. RESULTS: Calls were attempted to 313 of 388 lung cancer patients referred to the cessation service. Eighty percent of patients (250 of 313) were successfully contacted and participated in at least one telephone-based cessation call; 40.8% (102 of 250) of persons contacted reported having quit at the last contact. After controlling for age, pack year history, sex, Eastern Cooperative Oncology Group performance status, time between diagnosis and last contact, tumor histology, and clinical stage, a statistically significant increase in survival was associated with quitting compared with continued tobacco use at last contact (HR = 1.79; 95% confidence interval: 1.14 2.82) with a median 9 month improvement in overall survival. CONCLUSIONS: Tobacco cessation among lung cancer patients after diagnosis may increase overall survival. PMID- 26102444 TI - Preventing Deaths Due to Exercise-Associated Hyponatremia: The 2015 Consensus Guidelines. PMID- 26102443 TI - Implementation of Amplicon Parallel Sequencing Leads to Improvement of Diagnosis and Therapy of Lung Cancer Patients. AB - INTRODUCTION: The Network Genomic Medicine Lung Cancer was set up to rapidly translate scientific advances into early clinical trials of targeted therapies in lung cancer performing molecular analyses of more than 3500 patients annually. Because sequential analysis of the relevant driver mutations on fixated samples is challenging in terms of workload, tissue availability, and cost, we established multiplex parallel sequencing in routine diagnostics. The aim was to analyze all therapeutically relevant mutations in lung cancer samples in a high throughput fashion while significantly reducing turnaround time and amount of input DNA compared with conventional dideoxy sequencing of single polymerase chain reaction amplicons. METHODS: In this study, we demonstrate the feasibility of a 102 amplicon multiplex polymerase chain reaction followed by sequencing on an Illumina sequencer on formalin-fixed paraffin-embedded tissue in routine diagnostics. Analysis of a validation cohort of 180 samples showed this approach to require significantly less input material and to be more reliable, robust, and cost-effective than conventional dideoxy sequencing. Subsequently, 2657 lung cancer patients were analyzed. RESULTS: We observed that comprehensive biomarker testing provided novel information in addition to histological diagnosis and clinical staging. In 2657 consecutively analyzed lung cancer samples, we identified driver mutations at the expected prevalence. Furthermore we found potentially targetable DDR2 mutations at a frequency of 3% in both adenocarcinomas and squamous cell carcinomas. CONCLUSION: Overall, our data demonstrate the utility of systematic sequencing analysis in a clinical routine setting and highlight the dramatic impact of such an approach on the availability of therapeutic strategies for the targeted treatment of individual cancer patients. PMID- 26102445 TI - Statement of the Third International Exercise-Associated Hyponatremia Consensus Development Conference, Carlsbad, California, 2015. PMID- 26102446 TI - Estimating HIV-1 Transmission Routes for Patients With Unknown Risk Histories by Viral Sequence Phylogenetic Analyses. AB - OBJECTIVE: To estimate routes of transmission among HIV-infected persons with unknown-risk histories in China. DESIGN/METHOD: All newly reported cases of HIV infection between year 1985 and 2009 were obtained from the National Databank of Chinese Center for Disease Control and Prevention (China CDC). A large number of unknown-risk HIV-positive samples were found. To estimate the transmission routes, HIV gag sequences were amplified by reverse transcription polymerase chain reaction and phylogenetically analyzed. The cases with unknown-risk history were compared with those with known-risk histories from the same local region and time period. A statistical model was developed to predict the transmission routes and was validated on known-risk samples, before testing 324 unknown-risk samples collected from 1996 to 2006. RESULTS: Newly reported cases of HIV infection in China increased steadily between 1985 and 2009, from just a handful of cases to 30,340 in 2009. Injecting drug use (IDU) was the dominant route of transmission among reported cases in the early years and decreased from 83.4% in 1985-2001 to 28.2% in 2009. Conversely, sexual transmission increased from 6.9% in 1985-2001 to 60.9% in 2009. Among the 324 unknown-risk HIV sequences collected from 1996 to 2006, our model identified 100 samples most likely transmitted by blood, 114 by IDU, and 110 by sexual transmission. Our validation samples showed that our model has 90.8%, 94.8%, and 69.6% sensitivity and 87.3%, 87.5%, and 85.5% specificity, for blood, IDU, and sexual transmission, respectively. CONCLUSIONS: We developed a model to estimate transmission route of unknown-risk HIV-positive samples and found that these unknown-risk patients could be transmitted by blood, IDU, or sex. PMID- 26102447 TI - Cost-Effectiveness of Collaborative Care for Depression in HIV Clinics. AB - OBJECTIVE: To examine the cost-effectiveness of the HIV Translating Initiatives for Depression Into Effective Solutions (HITIDES) intervention. DESIGN: Randomized controlled effectiveness and implementation trial comparing depression collaborative care with enhanced usual care. SETTING: Three Veterans Health Administration HIV clinics in the Southern United States. SUBJECTS: Two hundred forty-nine HIV-infected patients completed the baseline interview; 123 were randomized to the intervention and 126 to usual care. INTERVENTION: HITIDES consisted of an offsite HIV depression care team that delivered up to 12 months of collaborative care. The intervention used a stepped-care model for depression treatment, and specific recommendations were based on the Texas Medication Algorithm Project and the VA/Department of Defense Depression Treatment Guidelines. MAIN OUTCOME MEASURES: Quality-adjusted life years (QALYs) were calculated using the 12-Item Short Form Health Survey, the Quality of Well Being Scale, and by converting depression-free days to QALYs. The base case analysis used outpatient, pharmacy, patient, and intervention costs. Cost-effectiveness was calculated using incremental cost-effectiveness ratios (ICERs) and net health benefit. ICER distributions were generated using nonparametric bootstrap with replacement sampling. RESULTS: The HITIDES intervention was more effective and cost saving compared with usual care in 78% of bootstrapped samples. The intervention net health benefit was positive and therefore deemed cost-effective using an ICER threshold of $50,000/QALY. CONCLUSIONS: In HIV clinic settings, this intervention was more effective and cost saving compared with usual care. Implementation of offsite depression collaborative care programs in specialty care settings may be a strategy that not only improves outcomes for patients but also maximizes the efficient use of limited health care resources. PMID- 26102448 TI - A Data-Driven Simulation of HIV Spread Among Young Men Who Have Sex With Men: Role of Age and Race Mixing and STIs. AB - OBJECTIVE: Young men who have sex with men (YMSM) in the United States have a high HIV incidence with substantial racial disparities that are poorly understood. We use a data-driven simulation model to understand the impact of network-level mechanisms and sexually transmitted infections on the spread of HIV among YMSM. METHODS: We designed and parameterized a stochastic agent-based network simulation model using results of a longitudinal cohort study of YMSM in Chicago. Within this model, YMSM formed and dissolved partnerships over time, and partnership types were stratified by length of partnership, sex, and age of the partner. In each partnership, HIV, gonorrhea, and chlamydia could be transmitted. Counterfactual scenarios were run to examine drivers of HIV. RESULTS: Over a 15 year simulation, the HIV epidemic among YMSM continued to rise, with Latino/white YMSM facing a steeper increase in the HIV burden compared with black YMSM. YMSM in partnerships with older MSM, in particular black YMSM with older black MSM, were at highest risk for HIV, and 1 infection prevented with an older partner would prevent 0.8 additional infections among YMSM. Additionally, racial disparities in HIV were driven by differences in the HIV prevalence of YMSM partners. Finally, of all HIV infections among YMSM, 14.6% were attributable to NG and CT infections. CONCLUSION: Network-level mechanisms and sexually transmitted infections play a significant role in the spread of HIV and in racial disparities among YMSM. HIV prevention efforts should target YMSM across race, and interventions focusing on YMSM partnerships with older MSM might be highly effective. PMID- 26102449 TI - Spontaneous HIV Controllers Exhibit Preserved Immune Parameters in Peripheral Blood and Gastrointestinal Mucosa. AB - BACKGROUND: HIV infection induces several gradual alterations on the peripheral and mucosal immune systems, with different magnitudes between infected individuals. In this regard, spontaneous HIV controllers exhibit either low or undetectable viral loads in the absence of treatment along with decreased immune alterations compared to HIV progressors. Yet, it is unknown how similar immune peripheral and mucosal parameters are when comparing HIV controllers to uninfected individuals. METHODS: We evaluated a cohort of 11 HIV controllers who were compared to 20 seronegative donors. Peripheral blood (PB) and gut associated lymphoid tissue (GALT) samples were obtained to analyze the following: 1) the frequency and phenotype of immune cells by flow cytometry; 2) the expression of apoptotic molecules by immunohistochemistry; 3) the expression of transcriptional factors associated with T cell profiles by real time PCR; and 4) the serum level of microbial translocation by an enzymatic reaction. RESULTS: We found that HIV controllers have a conserved frequency of most immune cell populations in PB and GALT, but a reduced percentage of CD4 T cells. The immune activation levels were similar in both groups of individuals, as well as the expression of cleaved caspase-3, transcriptional factors, and the level of microbial translocation. Interestingly, the frequency of CD8 T cells expressing HLA-DR but not CD38, previously associated with high effector functions, were preserved in HIV controllers. CONCLUSIONS: Our results suggest that despite the infection, HIV controllers have preserved immune parameters, which can be associated with the spontaneous control of viral replication. PMID- 26102451 TI - Electronic structure of a new layered bismuth oxyselenide superconductor: LaO0.5F0.5BiSe2. AB - LaO(0.5)F(0.5)BiSe(2) is a new layered superconductor discovered recently, which shows the superconducting transition temperature of 3.5 K. With angle-resolved photoemission spectroscopy, we study the electronic structure of LaO(0.5)F(0.5)BiSe(2) comprehensively. Two electron-like bands are located around the X point of the Brillouin zone, and the outer pockets connect with each other and form large Fermi surface around Gamma and M. These bands show negligible k(z) dispersion, indicating their two-dimensional nature. Based on the Luttinger theorem, the carrier concentration is about 0.53 e(-) per unit cell, close to its nominal value. Moreover, the photoemission data and the band structure calculations agree very well, and the renormalization factor is nearly 1.0, indicating the electron correlations in this material are rather weak. Our results suggest that LaO(0.5)F(0.5)BiSe(2) is a conventional BCS superconductor without strong electron correlations. PMID- 26102450 TI - Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men. AB - BACKGROUND: Gait speed predicts functional decline, disability, and death and is considered a biomarker of biological aging. Changes in gait speed in persons aging with HIV may provide an important method of gauging health and longevity in an under assessed population. The objective of this study was to evaluate and quantify the rate of gait speed decline in HIV-infected (HIV+) men compared with HIV-uninfected (HIV-) men. METHODS: The study was nested in the Multicenter AIDS Cohort Study. The primary outcome was usual gait speed in meters per second measured between 2007 and 2013. Differences in the rate of gait speed decline and the incidence of clinically slow gait (<1.0 m/s) were assessed using multivariate linear regression models and Cox proportional hazards models, respectively. RESULTS: A total of 2025 men (973 HIV+ and 1052 HIV-) aged 40 years and older contributed 21,187 person-visits (9955 HIV+ and 11,232 HIV-) to the analysis. Average gait speeds at the age 50 years were 1.24 and 1.19 m/s in HIV- and HIV+ men, respectively (P < 0.001). In fully adjusted models, gait speed decline averaged 0.009 m/s per year after age 50 years (P < 0.001); this decline was 0.025 m/s per year greater in HIV+ men (P < 0.001). Moreover, HIV+ men had a 57% greater risk of developing clinically slow gait (adjusted hazard ratio = 1.57, 95% confidence interval: 1.27 to 1.91). CONCLUSIONS: These findings indicate a faster rate of functional decline in HIV-infected men, suggesting greater risks of disability and death with advancing age. PMID- 26102452 TI - [Unsafe abortions in countries that restrict legal abortions. Epidemiologic, clinical, and prognostic aspects at the University Hospital Center Yalgado Ouedraogo of Ouagadougou]. AB - OBJECTIVE: to describe the epidemiologic, clinical, and prognostic aspects of the management of the complications of women who had unsafe (illegal) abortions. MATERIAL AND METHODS: this prospective, descriptive cross-sectional study took place the Yalgado Ouedraogo University Hospital Center (UHC-YO) in Ouagadougou during the 12-month period from June 2012 to May 2013. The study included all women admitted to the obstetrics-gynecology department during the study period and diagnosed after clinical examination with complications of an unsafe abortion. Data were collected with standardized case report forms. The analysis was conducted with Epi Info 3.5.1 software and Student's, Fisher's, and Pearson's Chi-square tests to compare the data. The threshold for statistical significance was set at 5%. RESULTS: during the study period, 111 women were admitted for complications of unsafe abortions, for a rate of 1 per 47 deliveries. The women's mean age was 23.6 years and ranged from 15 to 45 years. More than half the women (n=62, 55%) were pregnant for the first time. Hemorrhage was the primary reason for admission: 78 women, or 75%. Only 18 women (16%) admitted to having had an illegal intentional abortions. Complications included endometritis in 10 women (11%), anemia in 6 (5%), and hepatonephritis, also in 6 (5%). Six women died, for a mortality rate of 24%. CONCLUSION: the epidemiologic profile of women with complications from unsafe abortions is that of a young women pregnant for the first time, who has no income-producing activity. Morbidity is dominated by infectious or hemorrhagic complications and mortality is high. Strengthening activities for prevention, health and sex education, and dissemination of knowledge of and access to contraceptive methods will help to reduce these abortions and their consequences. PMID- 26102454 TI - Simultaneous iterative reconstruction technique software for spectral-spatial EPR imaging. AB - Continuous wave electron paramagnetic resonance imaging (EPRI) experiments often suffer from low signal to noise ratio. The increase in spectrometer time required to acquire data of sufficient quality to allow further analysis can be counteracted in part by more processing effort during the image reconstruction step. We suggest a simultaneous iterative reconstruction algorithm (SIRT) for reconstruction of continuous wave EPRI experimental data as an alternative to the widely applied filtered back projection algorithm (FBP). We show experimental and numerical test data of 2d spatial images and spectral-spatial images. We find that for low signal to noise ratio and spectral-spatial images that are limited by the maximum magnetic field gradient strength SIRT is more suitable than FBP. PMID- 26102453 TI - Molecular neurobiology of Drosophila taste. AB - Drosophila is a powerful model in which to study the molecular and cellular basis of taste coding. Flies sense tastants via populations of taste neurons that are activated by compounds of distinct categories. The past few years have borne witness to studies that define the properties of taste neurons, identifying functionally distinct classes of sweet and bitter taste neurons that express unique subsets of gustatory receptor (Gr) genes, as well as water, salt, and pheromone sensing neurons that express members of the pickpocket (ppk) or ionotropic receptor (Ir) families. There has also been significant progress in terms of understanding how tastant information is processed and conveyed to higher brain centers, and modulated by prior dietary experience or starvation. PMID- 26102455 TI - Radiation Exposure During Percutaneous Ablation of Small Renal Masses: A Multi Institutional Multimodality Analysis. AB - OBJECTIVE: To understand the effective radiation dose during percutaneous cryoablation (CA) and radiofrequency ablation (RFA) and characterize variables that may affect the individual dose. MATERIALS AND METHODS: The effective radiation dose was determined by conversion of the dose-length product from CT scans performed during percutaneous CA or RFA for patients with solitary renal masses (<4 cm) at four academic centers. Radiation dose per case was compared between patients and institutions using multivariate and univariate analysis. Lifetime attributable risk of cancer was calculated for each institution and utilized to determine the number needed to harm for a range of ages at the time of exposure. RESULTS: One hundred twenty-three patients met the inclusion criteria with a mean age of 71 years. Sixty-nine percent of patients were male, mean body-mass index (BMI) was 29.4, and mean tumor size was 2.2 cm. The mean effective radiation dose per ablation was 40 mSv (range 3.7-147). On multivariate analysis, only BMI and institution were associated with the radiation dose. No significant difference in radiation exposure was seen for RFA or CA procedures. CONCLUSIONS: Radiation exposure during percutaneous ablation is similar to a multiphase CT scan. However, there is wide variability in individual treatment exposure, varying from 3.7 to 147 mSv, depending primarily on institution and BMI. Standardization of protocols is required to achieve as low as reasonably achievable levels of radiation. PMID- 26102456 TI - Can the Luminex xTAG gastrointestinal pathogen panel really save money? PMID- 26102457 TI - Are high drug prices for hematologic malignancies justified? A critical analysis. AB - In the past 15 years, treatment outcomes for hematologic malignancies have improved substantially. However, drug prices have also increased drastically. This commentary examines the value of the treatment of hematologic malignancies at current prices in the United States through a reanalysis of a systematic review evaluating 29 studies of 9 treatments for 4 hematologic malignancies. Incremental cost-effectiveness ratios (ICERs) were calculated on the basis of drug prices in the United States in 2014. Sixty-three percent of the studies (15 of 24) had ICERs higher than $50,000 per quality-adjusted life-year (QALY), the benchmark widely used by health economists to define cost-effectiveness. In studies evaluating the current standard-of-care treatments for chronic myeloid leukemia, the ICERs for tyrosine kinase inhibitors versus hydroxyurea or interferon ranged from $210,000 to $426,000/QALY. The lower ICER values were mostly obtained from 11 studies evaluating rituximab, which was approved by the Food and Drug Administration in 1997 (ICER range, $37,000-$69,000/QALY). In conclusion, the costs of the majority of new treatments for hematologic cancers are too high to be deemed cost-effective in the United States. PMID- 26102458 TI - Transcriptome-wide identification, molecular evolution and expression analysis of Toll-like receptor family in a Tibet fish, Gymnocypris przewalskii. AB - Toll-like receptors (TLR) are key components of innate immunity that play significant roles in immune defense against pathogens invasion. Recent frequent outbreaks of the "white spot disease" caused by parasitic infection in farmed Tibetan fishes had resulted in great economic losses. However, to our knowledge, the roles of TLRs in mediating immune response to parasitic infection in Tibetan fishes remain to be determined. Here, we performed data-mining on a widely-farmed Tibetan fish (Gymnocypris przewalskii or Gp) transcriptome to determine the genetic variation and expression pattern of TLRs. We totally obtained 14 GpTLRs and identified 5 with a complete coding sequence. Phylogenetic analysis verified their identities and supported the classification of TLRs into six families as in other vertebrates. The TLR family motifs, such as leucine rich repeat (LRR) and Toll/interleukin (IL)-1 receptor (TIR) domain, are conserved in GpTLR1-5. Selective pressure test demonstrated that all known GpTLRs are under purifying selection, except GpTLR4 underwent positive selection. Further, site model analysis suggested that 11 positively selected sites are found in LRR domain of GpTLR4. Three positively selected sites are located on outside surface of TLR4 3D structure, indicating that function of GpTLR4 may be affected. Tissue specific expression analysis showed all GpTLRs are present in gill, head-kidney and spleen but the relative abundance varied among tissues. In response to parasite Ichthyophthirius multifiliis infection, 5 GpTLR (GpTLR1, -2, -4, -9 and -20) expressions were induced. Intriguingly, GpTLR4 was significantly up-regulated in gills, while GpTLR19 and GpTLR21 unexpectedly showed no any change. In summary, these results revealed the first genomic resources of TLR family and several parasitic infection responsive TLRs in Tibetan fish. These findings provide key information for future studies aiming to understand the molecular mechanisms underlying the immune response to pathogen invasion in Tibetan fishes. PMID- 26102459 TI - Identification and functional characterization of the TAB2 gene from Litopenaeus vannamei. AB - In Drosophila, TAB2, an important intermediate in the IMD signaling pathway, plays critical roles in the innate immune response in response to bacterial and viral infection. However, the role of TAB-related proteins in the immune response of shrimp has not yet been established. Here, we reported the identification of a TAB2-like gene in Litopenaeus vannamei designated as LvTAB2. The full-length cDNA of LvTAB2 was 2160 bp with an open reading frame of 1827 bp, which encoded a putative protein of 608 amino acids including a ubiquitin binding domain (CUE) at the N-terminal and a Zinc Finger domain (ZnF) at the C-terminus. Real-time RT-PCR analysis showed that LvTAB2 was expressed in all tested tissues and the expression levels of LvTAB2 in gills and hemocytes were positively induced in response to LPS, Vibrio parahemolyticus and White Spot Syndrome Virus (WSSV) challenges. Dual luciferase reporter assays demonstrated that LvTAB2 was able to induce the expression of antimicrobial peptide (AMP) genes, including Drosophila Attacin A and shrimp Penaeidins. Interestingly, over-expression of LvTAB2 could up-regulate the promoter activities of L. vannamei Vago1, Vago3 and Vago4 genes in S2 cells. To our knowledge, it was the first report that TAB2 participated in innate immune signaling to regulate the expression of Vago genes in invertebrates. Moreover, RNAi-mediated knockdown of LvTAB2 enhanced sensitivity of L. vannamei to Vibrio parahaemolyticus infection and caused elevated virus loads after WSSV infection. We suggested that the LvTAB2 may play important roles in the shrimp innate immunity. PMID- 26102460 TI - Molecular cloning and comparative responses of Toll-like receptor 22 following ligands stimulation and parasitic infection in yellowtail (Seriola lalandi). AB - TLR22 is exclusively present in teleosts and amphibians and is expected to play the distinctive role in innate immunity. In this study, we cloned the full-length cDNA sequence of yellowtail (Seriola lalandi) TLR22 (SlTLR22). The complete cDNA sequence of SlTLR22 was 4208 bp and encodes a polypeptide of 961 amino acids. Analysis of the deduced amino acid sequence indicated that SlTLR22 has typical structural features of proteins belonging to the TLR family. These included 17 LRR domains (residues 91-633) and one C-terminal LRR domain (LRR-CT, residues 693 744) in the extracellular region, and a TIR domain (residues 800-943) in the cytoplasmic region. Comparison with homologous proteins showed that the deduced SlTLR22 has the highest sequence identity to turbot TLR22 (76%). Quantitative real-time PCR (qPCR) analysis demonstrated the constitutive expression of SlTLR22 mRNA in all examined tissues with higher levels in the head kidney, intestine, skin and spleen. Further, SlTLR22 expression was significantly up-regulated following TLR ligands injection with lipopolysaccharide (LPS), CpG ODN2006 and polyinosinic: polycytidylic acid (poly I:C) in spleen and liver. Amyloodinium ocellatum infection also induced a high expression of SlTLR22 in spleen, intestine, muscle, skin and gill, with maximum increases ranging from 1000 to 100 fold upon different ligands and organs. Finally, histological examination in gill tissue confirmed infection by the parasite and histopathological lesion was observed also in spleen and skin. These findings suggest a possible role of SlTLR22 in the immune responses to the infections of a broad range of pathogens that include DNA and RNA viruses and parasites. PMID- 26102461 TI - Is it possible to make a diagnosis of raw, heated, and baked egg allergy in children using cutoffs? A systematic review. AB - The diagnosis of IgE-mediated egg allergy lies both on a compatible clinical history and on the results of skin prick tests (SPTs) and IgEs levels. Both tests have good sensitivity but low specificity. For this reason, oral food challenge (OFC) is the ultimate gold standard for the diagnosis. The aim of this study was to systematically review the literature in order to identify, analyze, and synthesize the predictive value of SPT and specific IgEs both to egg white and to main egg allergens and to review the cutoffs suggested in the literature. A total of 37 articles were included in this systematic review. Studies were grouped according to the degree of cooking of the egg used for OFC, age, and type of allergen used to perform the allergy workup. In children <2 years, raw egg allergy seems very likely when SPTs with egg white extract are >=4 mm or specific IgEs are >=1.7 kUA /l. In children >=2 years, OFC could be avoided when SPTs with egg white extract are >=10 mm or prick by prick with egg white is >=14 mm or specific IgE is >=7.3 kUA /l. Likewise, heated egg allergy can be diagnosed if SPTs with egg white extract are >5 and >11 mm in children <2 and >=2 years, respectively. Further and better-designed studies are needed to determine the remaining diagnostic cutoff of specific IgE and SPT for heated and baked egg allergy. PMID- 26102462 TI - A review on the basketball jump shot. AB - The ability to shoot an effective jump shot in the sport of basketball is critical to a player's success. In an attempt to better understand the aspects related to expert performance, researchers have investigated successful free throws and jump shots of various basketball players and identified movement variables that contribute to their success. The purpose of this study was to complete a systematic review of the scientific literature on the basketball free throw and jump shot for the purpose of revealing the critical components of shooting that coaches, teachers, and players should focus on when teaching, learning, practising, and performing a jump shot. The results of this review are presented in three sections: (a) variables that affect ball trajectory, (b) phases of the jump shot, and PMID- 26102463 TI - Ovarian cancer in obese women: risk and optimal medical and surgical treatment options. PMID- 26102464 TI - Could urine testing be the future of cervical cancer screening? PMID- 26102465 TI - Secondary fracture prevention via a Fracture Liaison Service. PMID- 26102466 TI - VolitionRx begins first ovarian cancer detection study. PMID- 26102467 TI - Advanced abdominal ectopic pregnancy: lessons from three cases from Zimbabwe and a literature appraisal of diagnostic and management challenges. AB - We report three cases illustrating difficulties in diagnosis and challenges with management of the placenta in a low-resource country where ultrasound scanning, methotrexate, interventional radiology or blood products are often not accessible for the majority of patients. Even in situations where an ultrasound scan is available prenatally as in our three cases, the diagnosis is often missed. All the cases presented with vague abdominal symptoms, which are common in pregnancy anyway. Only one case was correctly diagnosed before surgery by ultrasound scan. For the two cases in the second trimester as expected the fetuses did not survive. The one advanced pregnancy had a good perinatal outcome. Maternal morbidity and mortality usually results from perioperative hemorrhage from the placental attachment site. The most important aspect of management is the management of the placenta. In the two cases with second trimester pregnancies, it was possible to remove the placentas, even though blood loss was significant, hemostasis was achieved at surgery. All three mothers recovered well and survived. PMID- 26102468 TI - Lapatinib: an oral dual tyrosine kinase inhibitor for HER-2-positive breast cancer. AB - Breast cancer is the most common form of cancer and the second leading cause of cancer deaths among women in the USA. A quarter of all newly diagnosed cases are characterized by overexpression of HER-2 which is associated with poor prognosis. In March 2007, lapatinib, an oral dual-tyrosine kinase inhibitor was approved in combination with capecitabine for metastatic HER-2-positive breast cancer that has progressed on prior trastuzumab therapy, and in combination with letrozole for postmenopausal women with HER-2 and hormone receptor-positive advanced breast cancer. In the future, lapatinib may play an important role in dual HER-2 blockade with trastuzumab and other targeted agents for women with HER-2 overexpressing breast cancer. PMID- 26102469 TI - Should all women be screened for thyroid dysfunction in pregnancy? AB - The subject of universal thyroid screening in pregnancy generates impassioned debate. Thyroid dysfunction is common, has significant adverse implications for fetal and maternal well-being, is readily detectable and can be effectively and inexpensively treated. Furthermore, the currently recommended case-finding strategy does not identify a substantially proportion of women with thyroid dysfunction thus favoring universal screening. On the other hand subclinical thyroid dysfunction forms the bulk of gestational thyroid disorders and the paucity of high-level evidence to support correction of these asymptomatic biochemical abnormalities weighs against universal screening. This review critically appraises the literature, examines the pros and cons of universal thyroid screening in pregnancy, highlighting the now strong case for implementing universal screening and explores strategies for its implementation. PMID- 26102470 TI - The outcomes of complementary and alternative medicine use among pregnant and birthing women: current trends and future directions. AB - Complementary and alternative medicine is used by a substantial number of pregnant women and maternity care providers are often faced with the task of ensuring women are using safe and effective treatments while respecting a woman's right to autonomous decision-making. In the era of evidence-based medicine maternity health professionals are expected to draw upon the best available evidence when making clinical decisions and providing health advice. This review will outline the current trends in research evidence associated with the outcomes of complementary and alternative medicine use amongst pregnant and birthing women as well as highlight some potential directions for future development in this important yet largely unknown topic in contemporary maternity care. PMID- 26102471 TI - Factors to consider in breast reconstruction. AB - Women considering breast ablative therapy are confronted with a variety of decisions that include the type of mastectomy (partial, total, skin sparing, nipple areolar sparing), the type of reconstruction (prosthetic, autologous, oncoplastic) and the need for adjuvant therapy (chemotherapy, radiation). The parameters for each are multifactorial and require significant thought and counseling. Therapeutic options are essentially individualized and dependent upon a variety of factors such as tumor size and location, lymph node involvement, comorbidities, expectations and body characteristics. The role of reconstructive surgery is now well appreciated and an integral component of the multidisciplinary care of the patient and is influenced by the opinions and recommendations of surgical, medical and radiation oncologists. This manuscript will review the role of reconstructive surgery and the many factors to consider. PMID- 26102472 TI - New insights into endocrine therapy for young women with breast cancer. AB - Managing estrogen receptor-positive breast cancer in young women (<40 years) requires a multidisciplinary/personalized approach, covering both clinical and psychosocial aspects. Five years of tamoxifen has been the standard adjuvant endocrine therapy for many years. Recent data from the adjuvant randomized trials TEXT-SOFT show that the aromatase inhibitor exemestane plus ovarian suppression significantly reduces recurrences as compared with tamoxifen plus ovarian suppression. The ATLAS and aTToM trials represent the first evidence of a beneficial effect of extended endocrine therapy with tamoxifen in premenopausal women. Outside of a clinical trial, no data support neoadjuvant endocrine therapy in young women. In the metastatic setting, tamoxifen or aromatase inhibitors, both with ovarian suppression/ablation, should be the preferred choice, unless rapid tumor shrinkage is needed. No data are available with fulvestrant in young patients. PMID- 26102473 TI - The next steps in improving the outcomes of advanced ovarian cancer. AB - Worldwide ovarian cancer affects over 200,000 women per year. Overall survival rates are poor due to two predominate reasons. First, the majority of patients present with advanced disease creating significant difficulty with effecting disease eradication. Second, acquisition of chemotherapy resistance results in untreatable progressive disease. Advances in treatment of advanced ovarian cancer involve a spectrum of interventions including improvements in frontline debulking surgery and combination chemotherapy. Anti-angiogenic factors have been shown to have activity in frontline and recurrent disease while novel chemotherapeutic agents and targeted treatments are in development particularly for disease that is resistant to platinum-based chemotherapy. These developments aim to improve the progression-free and overall survival of women with advanced ovarian cancer. PMID- 26102474 TI - Past, present and future ultrasonographic techniques for analyzing ovarian masses. AB - Ultrasonography is today the method of choice for distinguishing between benign and malignant adnexal pathologies. Using pattern recognition several types of tumors can be recognized according to their characteristic appearance on gray scale imaging. Color Doppler imaging should be used only to perform a semiquantitative color score or evaluate the flow location. International Ovarian Tumor Analysis group had standardized definitions characterizing adnexal masses and suggested the use of 'simple rules' in premenopausal women. Recently, the use of 3D vascular indices has been proposed but its potential use in clinical practice is debated. Also computerized aided diagnosis algorithms showed encouraging results to be confirmed in the future. PMID- 26102475 TI - Reducing women's cardiovascular disease risk profile. AB - Heart disease is the leading cause of death in women. Unique risk factors have been recognized, including pre-eclampsia, eclampsia and autoimmune diseases. Diabetes and hypertension (HTN) also play a unique role in women. Women with diabetes have a higher risk for coronary heart disease and microvascular disease compared with males. Additionally, older women have a high prevalence of uncontrolled HTN and women tend to have more treatment resistant HTN, increasing risk for cardiovascular events and mortality. The outcomes of cardiovascular disease have shown an increase in the number of heart attacks in younger women, though there is decreasing mortality. Treatment with coronary artery bypass graft surgery and percutaneous intervention has also shown to have poorer outcomes in women. PMID- 26102476 TI - Psychiatric symptoms and disorders associated with reproductive cyclicity in women: advances in screening tools. AB - Female-specific psychiatric illness including premenstrual dysphoria, perinatal depression, and psychopathology related to the perimenopausal period are often underdiagnosed and treated. These conditions can negatively affect the quality of life for women and their families. The development of screening tools has helped guide our understanding of these conditions. There is a wide disparity in the methods, definitions, and tools used in studies relevant to female-specific psychiatric illness. As a result, there is no consensus on one tool that is most appropriate for use in a research or clinical setting. In reviewing this topic, we hope to highlight the evolution of various tools as they have built on preexisting instruments and to identify the psychometric properties and clinical applicability of available tools. It would be valuable for researchers to reach a consensus on a core set of screening instruments specific to female psychopathology to gain consistency within and between clinical settings. PMID- 26102478 TI - Multivariate product-shot-noise Cox point process models. AB - We introduce a new multivariate product-shot-noise Cox process which is useful for modeling multi-species spatial point patterns with clustering intra-specific interactions and neutral, negative, or positive inter-specific interactions. The auto- and cross-pair correlation functions of the process can be obtained in closed analytical forms and approximate simulation of the process is straightforward. We use the proposed process to model interactions within and among five tree species in the Barro Colorado Island plot. PMID- 26102477 TI - Effect of groundwater quality on sustainability of groundwater resource: A case study in the North China Plain. AB - The North China Plain (NCP) is one of the most severe water shortage areas in China. Due to the scarcity of surface water in the NCP, groundwater system is seriously over-exploited and use of nitrogen fertilizers is greatly increasing year by year to improve soil fertility and crop production, causing a variety of environmental issues in the processes of abstracting groundwater. Considering that previous research was limited on approaches to assess sustainability of groundwater through flow modeling and water level decline, this study focuses on addressing the implications of groundwater contaminant for water resource sustainability in the central part of NCP. Based on the previously developed groundwater flow model, a reaction modular code for the reactive transport in three-dimensional aquifers (RT3D) is developed for simulating the reactive process of nitrogen species transport in groundwater system. The management optimization model coupled with the nitrogen reactive transport model under consideration of water quality constraints is then conducted to quantify and improve the sustainability of groundwater utilization in the study area. Thus, the optimal pumping well locations and pumping rates that lead to the maximum total yield or the minimum total management costs subjecting to a series of groundwater level constraints are obtained from the optimization models. Compared with the optimization model without water quality constraints, this study could provide a more useful tool for developing cost-effective strategies for sustainable management of groundwater resource in the NCP, and greatly improve groundwater management level and water quality. PMID- 26102479 TI - Gametic selection, developmental trajectories, and extrinsic heterogeneity in Haldane's rule. AB - Deciphering the genetic and developmental causes of the disproportionate rarity, inviability, and sterility of hybrid males, Haldane's rule, is important for understanding the evolution of reproductive isolation between species. Moreover, extrinsic and prezygotic factors can contribute to the magnitude of intrinsic isolation experienced between species with partial reproductive compatibility. Here, we use the nematodes Caenorhabditis briggsae and C. nigoni to quantify the sensitivity of hybrid male viability to extrinsic temperature and developmental timing, and test for a role of mito-nuclear incompatibility as a genetic cause. We demonstrate that hybrid male inviability manifests almost entirely as embryonic, not larval, arrest and is maximal at the lowest rearing temperatures, indicating an intrinsic-by-extrinsic interaction to hybrid inviability. Crosses using mitochondrial substitution strains that have reciprocally introgressed mitochondrial and nuclear genomes show that mito-nuclear incompatibility is not a dominant contributor to postzygotic isolation and does not drive Haldane's rule in this system. Crosses also reveal that competitive superiority of X-bearing sperm provides a novel means by which postmating prezygotic factors exacerbate the rarity of hybrid males. These findings highlight the important roles of gametic, developmental, and extrinsic factors in modulating the manifestation of Haldane's rule. PMID- 26102481 TI - Analyses of interactions among pair-rule genes and the gap gene Kruppel in Bombyx segmentation. AB - In the short-germ insect Tribolium, a pair-rule gene circuit consisting of the Tribolium homologs of even-skipped, runt, and odd-skipped (Tc-eve, Tc-run and Tc odd, respectively) has been implicated in segment formation. To examine the application of the model to other taxa, I studied the expression and function of pair-rule genes in Bombyx mori, together with a Bombyx homolog of Kruppel (Bm Kr), a known gap gene. Knockdown embryos of Bombyx homologs of eve, run and odd (Bm-eve, Bm-run and Bm-odd) exhibited asegmental phenotypes similar to those of Tribolium knockdowns. However, pair-rule gene interactions were similar to those of both Tribolium and Drosophila, which, different from Tribolium, shows a hierarchical segmentation mode. Additionally, the Bm-odd expression pattern shares characteristics with those of Drosophila pair-rule genes that receive upstream regulatory input. On the other hand, Bm-Kr knockdowns exhibited a large posterior segment deletion as observed in short-germ insects. However, a detailed analysis of these embryos indicated that Bm-Kr modulates expression of pair-rule genes like in Drosophila, although the mechanisms appear to be different. This suggested hierarchical interactions between Bm-Kr and pair-rule genes. Based on these results, I concluded that the pair-rule gene circuit model that describes Tribolium development is not applicable to Bombyx. PMID- 26102480 TI - A critical role for the chromatin remodeller CHD7 in anterior mesoderm during cardiovascular development. AB - CHARGE syndrome is caused by spontaneous loss-of-function mutations to the ATP dependant chromatin remodeller chromodomain-helicase-DNA-binding protein 7 (CHD7). It is characterised by a distinct pattern of congenital anomalies, including cardiovascular malformations. Disruption to the neural crest lineage has previously been emphasised in the aetiology of this developmental disorder. We present evidence for an additional requirement for CHD7 activity in the Mesp1 expressing anterior mesoderm during heart development. Conditional ablation of Chd7 in this lineage results in major structural cardiovascular defects akin to those seen in CHARGE patients, as well as a striking loss of cardiac innervation and embryonic lethality. Genome-wide transcriptional analysis identified aberrant expression of key components of the Class 3 Semaphorin and Slit-Robo signalling pathways in Chd7(fl/fl);Mesp1-Cre mutant hearts. CHD7 localises at the Sema3c promoter in vivo, with alteration of the local chromatin structure seen following Chd7 ablation, suggestive of direct transcriptional regulation. Furthermore, we uncover a novel role for CHD7 activity upstream of critical calcium handling genes, and demonstrate an associated functional defect in the ability of cardiomyocytes to undergo excitation-contraction coupling. This work therefore reveals the importance of CHD7 in the cardiogenic mesoderm for multiple processes during cardiovascular development. PMID- 26102482 TI - Time course for tail regression during metamorphosis of the ascidian Ciona intestinalis. AB - In most ascidians, the tadpole-like swimming larvae dramatically change their body-plans during metamorphosis and develop into sessile adults. The mechanisms of ascidian metamorphosis have been researched and debated for many years. Until now information on the detailed time course of the initiation and completion of each metamorphic event has not been described. One dramatic and important event in ascidian metamorphosis is tail regression, in which ascidian larvae lose their tails to adjust themselves to sessile life. In the present study, we measured the time associated with tail regression in the ascidian Ciona intestinalis. Larvae are thought to acquire competency for each metamorphic event in certain developmental periods. We show that the timing with which the competence for tail regression is acquired is determined by the time since hatching, and this timing is not affected by the timing of post-hatching events such as adhesion. Because larvae need to adhere to substrates with their papillae to induce tail regression, we measured the duration for which larvae need to remain adhered in order to initiate tail regression and the time needed for the tail to regress. Larvae acquire the ability to adhere to substrates before they acquire tail regression competence. We found that when larvae adhered before they acquired tail regression competence, they were able to remember the experience of adhesion until they acquired the ability to undergo tail regression. The time course of the events associated with tail regression provides a valuable reference, upon which the cellular and molecular mechanisms of ascidian metamorphosis can be elucidated. PMID- 26102483 TI - Relationships between job organisational factors, biomechanical and psychosocial exposures. AB - The relationships between work organisational, biomechanical and psychosocial factors were studied using cross-sectional data from a pooled dataset of 1834 participants. The work organisational factors included: job rotation, overtime work, having second jobs and work pace. Task and job level biomechanical variables were obtained through sub-task data collected in the field or analysed in the laboratory. Psychosocial variables were collected based on responses to 10 questions. The results showed that job rotations had significant effects on all biomechanical and most psychosocial measures. Those with job rotations generally had higher job biomechanical stressors, and lower job satisfaction. Overtime work was associated with higher job biomechanical stressors, and possibly self reported physical exhaustion. Those having second jobs reported getting along with co-workers well. Work pace had significant influences on all biomechanical stressors, but its impact on job biomechanical stressors and psychosocial effects are complicated. PRACTITIONER SUMMARY: The findings are based on a large number of subjects collected by three research teams in diverse US workplaces. Job rotation practices used in many workplaces may not be effective in reducing job biomechanical stressors for work-related musculoskeletal disorders. Overtime work is also associated with higher biomechanical stressors. PMID- 26102484 TI - White emission magnetic nanoparticles as chemosensors for sensitive colorimetric and ratiometric detection, and degradation of ClO- and SCN- in aqueous solutions based on a logic gate approach. AB - Fluorescent chemosensors for detecting single anions have been largely synthesized. However, the simultaneous detection and degradation of multiple anions remain a major challenge. Herein we report the synthesis of a white emission nanoprobe on the basis of a Coumarin-Rhodamine CR1-Eu complex coordinated to dipicolinic acid (dpa)-PEG-Fe3O4 nanoparticles for the selective detection of ClO(-) and SCN(-) ions on controlling by a logic gate. The obtained nanoprobe exhibits three individual primary colors (blue, green, and red) as well as white emission at different excitation energies. Interestingly, this nanoprobe shows a marked rose red to violet emission color change in response to ClO(-), a reversible violet to rose red emission color change in response to SCN(-), and high ClO(-) and SCN(-) selectivity and sensitivity with a detection limit of 0.037 and 0.250 nM, respectively. Furthermore, the SCN(-) and ClO(-) can degrade simultaneously through the redox reaction between ClO(-) and SCN(-). PMID- 26102485 TI - Earth-like aqueous debris-flow activity on Mars at high orbital obliquity in the last million years. AB - Liquid water is currently extremely rare on Mars, but was more abundant during periods of high obliquity in the last few millions of years. This is testified by the widespread occurrence of mid-latitude gullies: small catchment-fan systems. However, there are no direct estimates of the amount and frequency of liquid water generation during these periods. Here we determine debris-flow size, frequency and associated water volumes in Istok crater, and show that debris flows occurred at Earth-like frequencies during high-obliquity periods in the last million years on Mars. Results further imply that local accumulations of snow/ice within gullies were much more voluminous than currently predicted; melting must have yielded centimetres of liquid water in catchments; and recent aqueous activity in some mid-latitude craters was much more frequent than previously anticipated. PMID- 26102486 TI - Predicting Complete Ground Reaction Forces and Moments During Gait With Insole Plantar Pressure Information Using a Wavelet Neural Network. AB - In general, three-dimensional ground reaction forces (GRFs) and ground reaction moments (GRMs) that occur during human gait are measured using a force plate, which are expensive and have spatial limitations. Therefore, we proposed a prediction model for GRFs and GRMs, which only uses plantar pressure information measured from insole pressure sensors with a wavelet neural network (WNN) and principal component analysis-mutual information (PCA-MI). For this, the prediction model estimated GRFs and GRMs with three different gait speeds (slow, normal, and fast groups) and healthy/pathological gait patterns (healthy and adolescent idiopathic scoliosis (AIS) groups). Model performance was validated using correlation coefficients (r) and the normalized root mean square error (NRMSE%) and was compared to the prediction accuracy of the previous methods using the same dataset. As a result, the performance of the GRF and GRM prediction model proposed in this study (slow group: r = 0.840-0.989 and NRMSE% = 10.693-15.894%; normal group: r = 0.847-0.988 and NRMSE% = 10.920-19.216%; fast group: r = 0.823-0.953 and NRMSE% = 12.009-20.182%; healthy group: r = 0.836 0.976 and NRMSE% = 12.920-18.088%; and AIS group: r = 0.917-0.993 and NRMSE% = 7.914-15.671%) was better than that of the prediction models suggested in previous studies for every group and component (p < 0.05 or 0.01). The results indicated that the proposed model has improved performance compared to previous prediction models. PMID- 26102487 TI - Simultaneous Voltammetric/Amperometric Determination of Sulfide and Nitrite in Water at BDD Electrode. AB - This work reported new voltammetric/amperometric-based protocols using a commercial boron-doped diamond (BDD) electrode for simple and fast simultaneous detection of sulfide and nitrite from water. Square-wave voltammetry operated under the optimized working conditions of 0.01 V step potential, 0.5 V modulation amplitude and 10 Hz frequency allowed achieving the best electroanalytical parameters for the simultaneous detection of nitrite and sulfide. For practical in-field detection applications, the multiple-pulsed amperometry technique was operated under optimized conditions, i.e., -0.5 V/SCE for a duration of 0.3 s as conditioning step, +0.85 V/SCE for a duration of 3 s that assure the sulfide oxidation and +1.25 V/SCE for a duration of 0.3 s, where the nitrite oxidation occurred, which allowed the simultaneously detection of sulfide and nitrite without interference between them. Good accuracy was found for this protocol in comparison with standardized methods for each anion. Also, no interference effect was found for the cation and anion species, which are common in the water matrix. PMID- 26102489 TI - On-Board Event-Based State Estimation for Trajectory Approaching and Tracking of a Vehicle. AB - For the problem of pose estimation of an autonomous vehicle using networked external sensors, the processing capacity and battery consumption of these sensors, as well as the communication channel load should be optimized. Here, we report an event-based state estimator (EBSE) consisting of an unscented Kalman filter that uses a triggering mechanism based on the estimation error covariance matrix to request measurements from the external sensors. This EBSE generates the events of the estimator module on-board the vehicle and, thus, allows the sensors to remain in stand-by mode until an event is generated. The proposed algorithm requests a measurement every time the estimation distance root mean squared error (DRMS) value, obtained from the estimator's covariance matrix, exceeds a threshold value. This triggering threshold can be adapted to the vehicle's working conditions rendering the estimator even more efficient. An example of the use of the proposed EBSE is given, where the autonomous vehicle must approach and follow a reference trajectory. By making the threshold a function of the distance to the reference location, the estimator can halve the use of the sensors with a negligible deterioration in the performance of the approaching maneuver. PMID- 26102488 TI - DNA-Based Nanobiosensors as an Emerging Platform for Detection of Disease. AB - Detection of disease at an early stage is one of the biggest challenges in medicine. Different disciplines of science are working together in this regard. The goal of nanodiagnostics is to provide more accurate tools for earlier diagnosis, to reduce cost and to simplify healthcare delivery of effective and personalized medicine, especially with regard to chronic diseases (e.g., diabetes and cardiovascular diseases) that have high healthcare costs. Up-to-date results suggest that DNA-based nanobiosensors could be used effectively to provide simple, fast, cost-effective, sensitive and specific detection of some genetic, cancer, and infectious diseases. In addition, they could potentially be used as a platform to detect immunodeficiency, and neurological and other diseases. This review examines different types of DNA-based nanobiosensors, the basic principles upon which they are based and their advantages and potential in diagnosis of acute and chronic diseases. We discuss recent trends and applications of new strategies for DNA-based nanobiosensors, and emphasize the challenges in translating basic research to the clinical laboratory. PMID- 26102490 TI - Citizen Sensors for SHM: Towards a Crowdsourcing Platform. AB - This paper presents an innovative structural health monitoring (SHM) platform in terms of how it integrates smartphone sensors, the web, and crowdsourcing. The ubiquity of smartphones has provided an opportunity to create low-cost sensor networks for SHM. Crowdsourcing has given rise to citizen initiatives becoming a vast source of inexpensive, valuable but heterogeneous data. Previously, the authors have investigated the reliability of smartphone accelerometers for vibration-based SHM. This paper takes a step further to integrate mobile sensing and web-based computing for a prospective crowdsourcing-based SHM platform. An iOS application was developed to enable citizens to measure structural vibration and upload the data to a server with smartphones. A web-based platform was developed to collect and process the data automatically and store the processed data, such as modal properties of the structure, for long-term SHM purposes. Finally, the integrated mobile and web-based platforms were tested to collect the low-amplitude ambient vibration data of a bridge structure. Possible sources of uncertainties related to citizens were investigated, including the phone location, coupling conditions, and sampling duration. The field test results showed that the vibration data acquired by smartphones operated by citizens without expertise are useful for identifying structural modal properties with high accuracy. This platform can be further developed into an automated, smart, sustainable, cost-free system for long-term monitoring of structural integrity of spatially distributed urban infrastructure. Citizen Sensors for SHM will be a novel participatory sensing platform in the way that it offers hybrid solutions to transitional crowdsourcing parameters. PMID- 26102491 TI - Fingerprint Liveness Detection in the Presence of Capable Intruders. AB - Fingerprint liveness detection methods have been developed as an attempt to overcome the vulnerability of fingerprint biometric systems to spoofing attacks. Traditional approaches have been quite optimistic about the behavior of the intruder assuming the use of a previously known material. This assumption has led to the use of supervised techniques to estimate the performance of the methods, using both live and spoof samples to train the predictive models and evaluate each type of fake samples individually. Additionally, the background was often included in the sample representation, completely distorting the decision process. Therefore, we propose that an automatic segmentation step should be performed to isolate the fingerprint from the background and truly decide on the liveness of the fingerprint and not on the characteristics of the background. Also, we argue that one cannot aim to model the fake samples completely since the material used by the intruder is unknown beforehand. We approach the design by modeling the distribution of the live samples and predicting as fake the samples very unlikely according to that model. Our experiments compare the performance of the supervised approaches with the semi-supervised ones that rely solely on the live samples. The results obtained differ from the ones obtained by the more standard approaches which reinforces our conviction that the results in the literature are misleadingly estimating the true vulnerability of the biometric system. PMID- 26102492 TI - Loop Closing Detection in RGB-D SLAM Combining Appearance and Geometric Constraints. AB - A kind of multi feature points matching algorithm fusing local geometric constraints is proposed for the purpose of quickly loop closing detection in RGB D Simultaneous Localization and Mapping (SLAM). The visual feature is encoded with BRAND (binary robust appearance and normals descriptor), which efficiently combines appearance and geometric shape information from RGB-D images. Furthermore, the feature descriptors are stored using the Locality-Sensitive Hashing (LSH) technique and hierarchical clustering trees are used to search for these binary features. Finally, the algorithm for matching of multi feature points using local geometric constraints is provided, which can effectively reject the possible false closure hypotheses. We demonstrate the efficiency of our algorithms by real-time RGB-D SLAM with loop closing detection in indoor image sequences taken with a handheld Kinect camera and comparative experiments using other algorithms in RTAB-Map dealing with a benchmark dataset. PMID- 26102493 TI - Radar Sensing for Intelligent Vehicles in Urban Environments. AB - Radar overcomes the shortcomings of laser, stereovision, and sonar because it can operate successfully in dusty, foggy, blizzard-blinding, and poorly lit scenarios. This paper presents a novel method for ground and obstacle segmentation based on radar sensing. The algorithm operates directly in the sensor frame, without the need for a separate synchronised navigation source, calibration parameters describing the location of the radar in the vehicle frame, or the geometric restrictions made in the previous main method in the field. Experimental results are presented in various urban scenarios to validate this approach, showing its potential applicability for advanced driving assistance systems and autonomous vehicle operations. PMID- 26102494 TI - Gaze-Assisted User Intention Prediction for Initial Delay Reduction in Web Video Access. AB - Despite the remarkable improvement of hardware and network technology, the inevitable delay from a user's command action to a system response is still one of the most crucial influence factors in user experiences (UXs). Especially for a web video service, an initial delay from click action to video start has significant influences on the quality of experience (QoE). The initial delay of a system can be minimized by preparing execution based on predicted user's intention prior to actual command action. The introduction of the sequential and concurrent flow of resources in human cognition and behavior can significantly improve the accuracy and preparation time for intention prediction. This paper introduces a threaded interaction model and applies it to user intention prediction for initial delay reduction in web video access. The proposed technique consists of a candidate selection module, a decision module and a preparation module that prefetches and preloads the web video data before a user's click action. The candidate selection module selects candidates in the web page using proximity calculation around a cursor. Meanwhile, the decision module computes the possibility of actual click action based on the cursor-gaze relationship. The preparation activates the prefetching for the selected candidates when the click possibility exceeds a certain limit in the decision module. Experimental results show a 92% hit-ratio, 0.5-s initial delay on average and 1.5-s worst initial delay, which is much less than a user's tolerable limit in web video access, demonstrating significant improvement of accuracy and advance time in intention prediction by introducing the proposed threaded interaction model. PMID- 26102495 TI - Performance Analysis of Several GPS/Galileo Precise Point Positioning Models. AB - This paper examines the performance of several precise point positioning (PPP) models, which combine dual-frequency GPS/Galileo observations in the un differenced and between-satellite single-difference (BSSD) modes. These include the traditional un-differenced model, the decoupled clock model, the semi decoupled clock model, and the between-satellite single-difference model. We take advantage of the IGS-MGEX network products to correct for the satellite differential code biases and the orbital and satellite clock errors. Natural Resources Canada's GPSPace PPP software is modified to handle the various GPS/Galileo PPP models. A total of six data sets of GPS and Galileo observations at six IGS stations are processed to examine the performance of the various PPP models. It is shown that the traditional un-differenced GPS/Galileo PPP model, the GPS decoupled clock model, and the semi-decoupled clock GPS/Galileo PPP model improve the convergence time by about 25% in comparison with the un-differenced GPS-only model. In addition, the semi-decoupled GPS/Galileo PPP model improves the solution precision by about 25% compared to the traditional un-differenced GPS/Galileo PPP model. Moreover, the BSSD GPS/Galileo PPP model improves the solution convergence time by about 50%, in comparison with the un-differenced GPS PPP model, regardless of the type of BSSD combination used. As well, the BSSD model improves the precision of the estimated parameters by about 50% and 25% when the loose and the tight combinations are used, respectively, in comparison with the un-differenced GPS-only model. Comparable results are obtained through the tight combination when either a GPS or a Galileo satellite is selected as a reference. PMID- 26102496 TI - A 3-Axis Miniature Magnetic Sensor Based on a Planar Fluxgate Magnetometer with an Orthogonal Fluxguide. AB - A new class of tri-axial miniature magnetometer consisting of a planar fluxgate structure with an orthogonal ferromagnetic fluxguide centrally situated over the magnetic cores is presented. The magnetic sensor possesses a cruciform ferromagnetic core placed diagonally upon the square excitation coil under which two pairs of pick-up coils for in-plane field detection are allocated. Effective principles and analysis of the magnetometer for 3-D field vectors are described and verified by numerically electromagnetic simulation for the excitation and magnetization of the ferromagnetic cores. The sensor is operated by applying the second-harmonic detection technique that can verify V-B relationship and device responsivity. Experimental characterization of the miniature fluxgate device demonstrates satisfactory spatial magnetic field detection results in terms of responsivity and noise spectrum. As a result, at an excitation frequency of 50 kHz, a maximum in-plane responsivity of 122.4 V/T appears and a maximum out-of plane responsivity of 11.6 V/T is obtained as well. The minimum field noise spectra are found to be 0.11 nT/?Hz and 6.29 nT/?Hz, respectively, in X- and Z axis at 1 Hz under the same excitation frequency. Compared with the previous tri axis fluxgate devices, this planar magnetic sensor with an orthogonal fluxguide provides beneficial enhancement in both sensory functionality and manufacturing simplicity. More importantly, this novel device concept is considered highly suitable for the extension to a silicon sensor made by the current CMOS-MEMS technologies, thus emphasizing its emerging applications of field detection in portable industrial electronics. PMID- 26102497 TI - Decompressive Craniectomy Increases Brain Lesion Volume and Exacerbates Functional Impairment in Closed Head Injury in Mice. AB - Decompressive craniectomy has been widely used in patients with head trauma. The randomized clinical trial on an early decompression (DECRA) demonstrated that craniectomy did not improve the neurological outcome, in contrast to previous animal experiments. The goal of our study was to analyze the effect of decompressive craniectomy in a murine model of head injury. Male mice were assigned into the following groups: sham, decompressive craniectomy, closed head injury (CHI), and CHI followed by craniectomy. At 24 h post-trauma, animals underwent the Neurological Severity Score test (NSS) and Beam Balance Score test (BBS). At the same time point, magnetic resonance imaging was performed, and volume of edema and contusion was assessed, followed by histopathological analysis. According to NSS, animals undergoing both trauma and craniectomy presented the most severe neurological impairment. Also, balancing time was reduced in this group compared with sham animals. Both edema and contusion volume were increased in the trauma and craniectomy group compared with sham animals. Histopathological analysis showed that all animals that underwent trauma presented substantial neuronal loss. In animals treated with craniectomy after trauma, a massive increase of edema with hemorrhagic transformation of contusion was documented. Decompressive craniectomy applied after closed head injury in mice leads to additional structural and functional impairment. The surgical decompression via craniectomy promotes brain edema formation and contusional blossoming in our model. This additive effect of combined mechanical and surgical trauma may explain the results of the DECRA trial and should be explored further in experiments. PMID- 26102498 TI - Structural insights into N-terminal to C-terminal interactions and implications for thermostability of a (beta/alpha)8-triosephosphate isomerase barrel enzyme. AB - Although several factors have been suggested to contribute to thermostability, the stabilization strategies used by proteins are still enigmatic. Studies on a recombinant xylanase from Bacilllus sp. NG-27 (RBSX), which has the ubiquitous (beta/alpha)8 -triosephosphate isomerase barrel fold, showed that just a single mutation, V1L, although not located in any secondary structural element, markedly enhanced the stability from 70 degrees C to 75 degrees C without loss of catalytic activity. Conversely, the V1A mutation at the same position decreased the stability of the enzyme from 70 degrees C to 68 degrees C. To gain structural insights into how a single extreme N-terminus mutation can markedly influence the thermostability of the enzyme, we determined the crystal structure of RBSX and the two mutants. On the basis of computational analysis of their crystal structures, including residue interaction networks, we established a link between N-terminal to C-terminal contacts and RBSX thermostability. Our study reveals that augmenting N-terminal to C-terminal noncovalent interactions is associated with enhancement of the stability of the enzyme. In addition, we discuss several lines of evidence supporting a connection between N-terminal to C terminal noncovalent interactions and protein stability in different proteins. We propose that the strategy of mutations at the termini could be exploited with a view to modulate stability without compromising enzymatic activity, or in general, protein function in diverse folds where N and C termini are in close proximity. DATABASE: The coordinates of RBSX, V1A and V1L have been deposited in the PDB database under the accession numbers 4QCE, 4QCF, and 4QDM, respectively. PMID- 26102499 TI - GABA and glutamate: the Yin and Yang of fragile X. PMID- 26102500 TI - Epitope Mapping of Antibodies Suggests the Novel Membrane Topology of B-Cell Receptor Associated Protein 31 on the Cell Surface of Embryonic Stem Cells: The Novel Membrane Topology of BAP31. AB - When located in the endoplasmic reticulum (ER) membrane, B-cell receptor associated protein 31 (BAP31) is involved in the export of secreted proteins from the ER to the plasma membrane. In a previous study, we generated two monoclonal antibodies (mAbs), 297-D4 and 144-A8, that bound to surface molecules on human embryonic stem cells (hESCs), but not to surface molecules on mouse embryonic stem cells (mESCs). Subsequent studies revealed that the mAbs recognized BAP31 on the surface of hESCs. To investigate the membrane topology of BAP31 on the cell surface, we first examined the epitope specificity of 297-D4 and 144-A8, as well as a polyclonal anti-BAP31 antibody (alpha-BAP31). We generated a series of GST fused BAP31 mutant proteins in which BAP31 was serially deleted at the C- terminus. GST-fused BAP31 mutant proteins were then screened to identify the epitopes targeted by the antibodies. Both 297-D4 and 144-A8 recognized C-terminal residues 208-217, while alpha-BAP31 recognized C-terminal residues 165-246, of BAP31 on hESCs, suggesting that the C-terminal domain of BAP31 is exposed on the cell surface. The polyclonal antibody alpha-BAP31 bound to mESCs, which confirmed that the C-terminal domain of BAP31 is also exposed on the surface of these cells. Our results show for the first time the novel membrane topology of cell surface-expressed BAP31 as the extracellular exposure of the BAP31 C-terminal domain was not predicted from previous studies. PMID- 26102501 TI - Feedback on Trait or Action Impacts on Caudate and Paracingulum Activity. AB - There is a general conception that positive associations to one's trait, e.g. 'I'm clever', are beneficial for cognitive performance. Scientific evidence shows that this is a simplification. In this functional magnetic resonance imaging (fMRI) study we used written trial-based trait feedback 'you are clever', or task feedback 'your choice was correct', on each correct response of a rule-switching task, to investigate how the character of positive self-associations influences performance outcome. Twenty participants took part in this crossover design study. We found that trait feedback was less beneficial for motivation and performance improvement, and resulting in enhanced neural activation on more difficult bivalent rule trials. This indicates that the task was treated as more complex in this condition. For example, 'you are clever' feedback led to enhanced activation in anterior caudate nucleus, an area known to process uncertainty. We further observed that activation in anterior paracingulate cortex was sensitive to whether self-reflection was imposed by external feedback or generated from internal processes, where the latter activation correlated positively with performance when following after task feedback. Our results illustrate how feedback can evoke self-reflections that either help or hinder motivation and performance, most likely by impacting on processes of uncertainty. The results support social psychological models stipulating that trait focus take resources away from task focus. PMID- 26102502 TI - A Genetic Algorithm for the Bi-Level Topological Design of Local Area Networks. AB - Local access networks (LAN) are commonly used as communication infrastructures which meet the demand of a set of users in the local environment. Usually these networks consist of several LAN segments connected by bridges. The topological LAN design bi-level problem consists on assigning users to clusters and the union of clusters by bridges in order to obtain a minimum response time network with minimum connection cost. Therefore, the decision of optimally assigning users to clusters will be made by the leader and the follower will make the decision of connecting all the clusters while forming a spanning tree. In this paper, we propose a genetic algorithm for solving the bi-level topological design of a Local Access Network. Our solution method considers the Stackelberg equilibrium to solve the bi-level problem. The Stackelberg-Genetic algorithm procedure deals with the fact that the follower's problem cannot be optimally solved in a straightforward manner. The computational results obtained from two different sets of instances show that the performance of the developed algorithm is efficient and that it is more suitable for solving the bi-level problem than a previous Nash-Genetic approach. PMID- 26102503 TI - Twilight, a Novel Circadian-Regulated Gene, Integrates Phototropism with Nutrient and Redox Homeostasis during Fungal Development. AB - Phototropic regulation of circadian clock is important for environmental adaptation, organismal growth and differentiation. Light plays a critical role in fungal development and virulence. However, it is unclear what governs the intracellular metabolic response to such dark-light rhythms in fungi. Here, we describe a novel circadian-regulated Twilight (TWL) function essential for phototropic induction of asexual development and pathogenesis in the rice-blast fungus Magnaporthe oryzae. The TWL transcript oscillates during circadian cycles and peaks at subjective twilight. GFP-Twl remains acetylated and cytosolic in the dark, whereas light-induced phosphorylation (by the carbon sensor Snf1 kinase) drives it into the nucleus. The mRNA level of the transcription/repair factor TFB5, was significantly down regulated in the twl? mutant. Overexpression of TFB5 significantly suppressed the conidiation defects in the twl? mutant. Furthermore, Tfb5-GFP translocates to the nucleus during the phototropic response and under redox stress, while it failed to do so in the twl? mutant. Thus, we provide mechanistic insight into Twl-based regulation of nutrient and redox homeostasis in response to light during pathogen adaptation to the host milieu in the rice blast pathosystem. PMID- 26102505 TI - Phenols from green tea as a dual functional coating to prepare devices for energy storage and molecular separation. AB - Polyphenols from green tea were used to electrolessly deposit gold on silk cocoons (SCs) and nanoporous aluminum oxide (AAO) templates. The gold coated cocoons were used as electrodes in supercapacitors and showed a capacitance as high as 254 F g(-1) and a specific power of 2287 W kg(-1). A metal coated AAO template was used for molecular separation. PMID- 26102504 TI - KIT Mutation and Loss of 14q May Be Sufficient for the Development of Clinically Symptomatic Very Low-Risk GIST. AB - The aim of this study was to determine the minimal set of genetic alterations required for the development of a very low risk clinically symptomatic gastro intestinal stromal tumour within the stomach wall. We studied the genome of a very low-risk gastric gastro-intestinal stromal tumour by whole-genome sequencing, comparative genomic hybridisation and methylation profiling. The studied tumour harboured two typical genomic lesions: loss of the long arm of chromosome 14 and an activating mutation in exon 11 of KIT. Besides these genetic lesions, only two point mutations that may affect tumour progression were identified: A frame-shift deletion in RNF146 and a missense mutation in a zinc finger of ZNF407. Whilst the frameshift deletion in RNF146 seemed to be restricted to this particular tumour, a similar yet germline mutation in ZNF407 was found in a panel of 52 gastro-intestinal stromal tumours from different anatomical sites and different categories. Germline polymorphisms in the mitotic checkpoint proteins Aurora kinase A and BUB1 kinase B may have furthered tumour growth. The epigenetic profile of the tumour matches that of other KIT-mutant tumours. We have identified mutations in three genes and loss of the long arm of chromosome 14 as the so far minimal set of genetic abnormalities sufficient for the development of a very low risk clinically symptomatic gastric stromal tumour. PMID- 26102507 TI - Raft-partitioning of calcium channels regulates their function. PMID- 26102506 TI - Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. AB - We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3 b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development. PMID- 26102508 TI - Enhanced saturation magnetization in buckypaper-films of thin walled carbon nanostructures filled with Fe3C, FeCo, FeNi, CoNi, Co and Ni crystals: the key role of Cl. AB - We report an advanced chemical vapour deposition approach which allows the direct in situ synthesis of cm-length ultrathin buckypapers comprising carbon nanostructures filled with Fe3C, FeCo, FeNi, CoNi, Co and Ni by sublimation and pyrolysis of single or combined metallocenes with very low quantities of dichlorobenzene. As a result, extremely high saturation magnetizations of 117 emu g(-1), 90 emu g(-1) and 80 emu g(-1) are obtained for the specific cases of Fe3C, FeCo and FeNi, respectively, while variable saturation magnetizations of 70 emu g(-1), 58 emu g(-1) and 6.7 emu g(-1) are obtained for Co, CoNi and Ni respectively. PMID- 26102510 TI - Copper-/Silver-Mediated Arylation of C(sp(2))-H Bonds with 2-Thiophenecarboxylic Acids. AB - A copper/silver-mediated arylation of (hetero)aryl C-H bonds with 2 thiophenecarboxylic acids has been achieved. The protocol features a broad substrate scope and high functional group tolerance. Preliminary mechanistic studies indicate that a cascade protodecarboxylation/dehydrogenative coupling process is likely involved. PMID- 26102511 TI - Activity-Based Probe for N-Acylethanolamine Acid Amidase. AB - N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid signaling molecules that includes oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Among the reported NAAA inhibitors, alpha-amino-beta-lactone (3-aminooxetan-2-one) derivatives have been shown to prevent FAE hydrolysis in innate-immune and neural cells and to reduce reactions to inflammatory stimuli. Recently, we disclosed two potent and selective NAAA inhibitors, the compounds ARN077 (5-phenylpentyl-N-[(2S,3R)-2 methyl-4-oxo-oxetan-3-yl]carbamate) and ARN726 (4-cyclohexylbutyl-N-[(S)-2 oxoazetidin-3-yl]carbamate). The former is active in vivo by topical administration in rodent models of hyperalgesia and allodynia, while the latter exerts systemic anti-inflammatory effects in mouse models of lung inflammation. In the present study, we designed and validated a derivative of ARN726 as the first activity-based protein profiling (ABPP) probe for the in vivo detection of NAAA. The newly synthesized molecule 1 is an effective in vitro and in vivo click chemistry activity based probe (ABP), which is able to capture the catalytically active form of NAAA in Human Embryonic Kidney 293 (HEK293) cells overexpressing human NAAA as well as in rat lung tissue. Competitive ABPP with 1 confirmed that ARN726 and ARN077 inhibit NAAA in vitro and in vivo. Compound 1 is a useful new tool to identify activated NAAA both in vitro and in vivo and to investigate the physiological and pathological roles of this enzyme. PMID- 26102512 TI - The Impact of the Risk Evaluation Mitigation Strategy for Erythropoiesis Stimulating Agents on Their Use and the Incidence of Stroke in Medicare Subjects with Chemotherapy-Induced Anemia with Lung and/or Breast Cancers. AB - Erythropoiesis-stimulating agents (ESAs), found to be effective in reducing anemia in chemotherapy-treated cancer patients, also are associated with an increased risk of cardiovascular events, including stroke. In an attempt to mitigate the risk, the Food and Drug Administration implemented a Risk Evaluation Mitigation Strategy (REMS) in February 2010. The purpose of this study is to evaluate change over time in the incidence of stroke among these patients before and after implementation of REMS. A retrospective data analysis using the Medicare 5% Sample Dataset, 2008-2011, was performed. Patients had to be 65 years of age or older at the start of at least 1 year of continuous enrollment and to have lung and/or breast cancers along with chemotherapy-induced anemia (CIA) in both pre-REMS and post-REMS periods (1Q2008 through 4Q2009 and 1Q2010 through 4Q2011, respectively). Logistic regression was used to evaluate differences in proportions of patients who received ESAs and experienced a stroke pre and post REMS. The pre-REMS cohort included 1252 eligible patients prescribed ESAs; the post-REMS cohort included 949 patients. No statistically significant change in stroke incidence was observed post REMS among patients with CIA who received ESAs. There was a 29.5% decrease in ESA use in patients with lung cancer and a 27.8% decrease in patients with breast cancer. Both were statistically significant. Results adjusted for baseline characteristics and comorbid conditions were similar. There was a statistically significant decrease in ESA use in patients with breast and/or lung cancers post REMS; no statistically significant reduction in the incidence of stroke was observed regardless of cancer type. PMID- 26102509 TI - Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. AB - Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germline ETV6 p. L349P mutation in a kindred affected by thrombocytopenia and ALL. A second ETV6 p. N385fs mutation was identified in an unrelated kindred characterized by thrombocytopenia, ALL and secondary myelodysplasia/acute myeloid leukemia. Leukemic cells from the proband in the second kindred showed deletion of wild type ETV6 with retention of the ETV6 p. N385fs. Enforced expression of the ETV6 mutants revealed normal transcript and protein levels, but impaired nuclear localization. Accordingly, these mutants exhibited significantly reduced ability to regulate the transcription of ETV6 target genes. Our findings highlight a novel role for ETV6 in leukemia predisposition. PMID- 26102513 TI - Prevalence and Clinicopathological Characteristics of HER2 and BRAF Mutation in Chinese Patients with Lung Adenocarcinoma. AB - AIMS: To determine the prevalence and clinicopathological characteristics of BRAF V600E mutation and HER2 exon 20 insertions in Chinese lung adenocarcinoma (ADC) patients. METHODS: Given the fact that the driver mutations are mutually exclusive in lung ADCs, 204 EGFR/KRAS wild-type cases were enrolled in this study. Direct Sanger sequencing was performed to examine BRAF V600E and HER2 exon 20 mutations. The association of BRAF and HER2 mutations with clinicopathological characteristics was statistically analyzed. RESULTS: Among the 204 lung ADCs tested, 11 cases (5.4%) carried HER2 exon 20 insertions and 4 cases (2.0%) had BRAF V600E mutation. HER2 mutation status was identified to be associated with a non-smoking history (p<0.05). HER2 mutation occurs in 9.4% of never smokers (10/106), 8.7% of female (8/92) and 2.7% of male (3/112) in this selected cohort. All four BRAF mutated patients were women and three of them were never-smokers. No HER2 mutant patients harbor BRAF mutation. CONCLUSIONS: HER2 and BRAF mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer and the availability of targeted therapy, Chinese lung ADC patients without EGFR and KRAS mutations are recommended for HER2 and BRAF mutations detection, especially for those never smokers. PMID- 26102514 TI - Attention-Deficit Hyperactivity Disorder and Long-QT Syndrome: Risky Business. PMID- 26102515 TI - Analysis of genetic and aflatoxin diversity among Aspergillus flavus isolates collected from sorghum seeds. AB - Thirty-four Aspergillus flavus isolates were recovered from sorghum seeds sampled across five states in India. Our study included (1) species confirmation through PCR assay, (2) quantification of total aflatoxin concentrations by the indirect competitive-ELISA (ic-ELISA) method, and (3) analysis of molecular diversity among the A. flavus isolates using beta-tubulin, ITS, and ISSR markers. Among the isolates studied, 28 were found to be positive for the production of aflatoxins. ITS and beta-tubulin phylogenetic analysis segregated the A. flavus sample population into two major groups or clades with little to no subdivision based on geography. In contrast, ISSR analysis also separated the A. flavus isolates into two main clusters, showing a distance of 0.0-0.5, with one cluster exhibiting a high level of diversity though no geographic or chemotype subdivision could be observed. The majority of sampled A. flavus isolates were highly toxigenic, and also highly diversified in terms of toxin-producing potential in-vitro. Genetic diversity among the sorghum isolates of A. flavus further warrants the development of appropriate farming management practices as well as improved aflatoxin detection measures in India. PMID- 26102517 TI - Preparation of a gamma-Fe2 O3 /Ag nanowire coaxial nanocable for high-performance lithium-ion batteries. AB - In this study, we report the design and synthesis of a silver nanowire-gamma-Fe2 O3 coaxial nanocable architecture (Ag NWs@gamma-Fe2 O3 nanocable) through mild oxidation of [Fe(CO)5 ] on the surface of silver nanowires followed by a calcination process. After optimization of the structural design, the Ag NWs@gamma-Fe2 O3 nanocable could deliver superior lithium storage performance in terms of high reversible capacity, good rate performance, and excellent stability, such as a high reversible capacity of about 890 mA h g(-1) after 60 cycles at a current rate of 0.1 C (1.0 C=1005 mA g(-1) ). The reversible capacity remains as high as about 550 mA h g(-1) even at a high current rate of 2.0 C. This dramatic performance is mainly attributed to the smart coaxial design, which can not only alleviate the large volume change and prevent the aggregation of gamma-Fe2 O3 nanoparticles, but also enables good conductivity and thus enhances fast charge transfer. The unique structural features of the Ag NWs@gamma-Fe2 O3 nanocable represent a promising anode material in lithium-ion battery applications. PMID- 26102516 TI - The Epidemiology of Transfusion-related Acute Lung Injury Varies According to the Applied Definition of Lung Injury Onset Time. AB - RATIONALE: Research that applies an unreliable definition for transfusion-related acute lung injury (TRALI) may draw false conclusions about its risk factors and biology. The effectiveness of preventive strategies may decrease as a consequence. However, the reliability of the consensus TRALI definition is unknown. OBJECTIVES: To prospectively study the effect of applying two plausible definitions of acute respiratory distress syndrome onset time on TRALI epidemiology. METHODS: We studied 316 adults admitted to the intensive care unit and transfused red blood cells within 24 hours of blunt trauma. We identified patients with acute respiratory distress syndrome, and defined acute respiratory distress syndrome onset time two ways: (1) the time at which the first radiographic or oxygenation criterion was met, and (2) the time both criteria were met. We categorized two corresponding groups of TRALI cases transfused in the 6 hours before acute respiratory distress syndrome onset. We used Cohen's kappa to measure agreement between the TRALI cases and implicated blood components identified by the two acute respiratory distress syndrome onset time definitions. In a nested case-control study, we examined potential risk factors for each group of TRALI cases, including demographics, injury severity, and characteristics of blood components transfused in the 6 hours before acute respiratory distress syndrome onset. MEASUREMENTS AND MAIN RESULTS: Forty-two of 113 patients with acute respiratory distress syndrome were TRALI cases per the first acute respiratory distress syndrome onset time definition and 63 per the second definition. There was slight agreement between the two groups of TRALI cases (kappa = 0.16; 95% confidence interval, -0.01 to 0.33) and between the implicated blood components (kappa = 0.15, 95% confidence interval, 0.11-0.20). Age, Injury Severity Score, high plasma-volume components, and transfused plasma volume were risk factors for TRALI when applying the second acute respiratory distress syndrome onset time definition but not when applying the first definition. CONCLUSIONS: The epidemiology of TRALI varies when applying two plausible definitions of acute respiratory distress syndrome onset time to severely injured trauma patients. A TRALI definition that standardizes acute respiratory distress syndrome onset time might improve reliability and align efforts to understand epidemiology, biology, and prevention. PMID- 26102518 TI - Artificial Light at Night (ALAN) and breast cancer incidence worldwide: A revisit of earlier findings with analysis of current trends. AB - In a study published in Cancer Causes & Control in 2010, Kloog with co-authors tested, apparently for the first time, the association between population-level ambient exposure to artificial light at night (ALAN) and incidence of several cancers in women from 164 countries worldwide. The study was based on 1996-2002 data and concluded that breast cancer (BC) incidence was significantly and positively associated with ALAN, while no such association was revealed for other cancer types. An open question, however, remains whether the trends revealed by Kloog and co-authors were time specific or also hold true for more recent data. Using information obtained from the GLOBOCAN, US-DMSP and World Bank's 2002 and 2012 databases, we reanalyzed the strength of association between BC incidence rates in 180 countries worldwide and ALAN, controlling for several country-level predictors, including birth rates, percent of urban population, per capita GDP and electricity consumption. We also compared BC age-standardized rates (ASRs) with multi-annual ALAN measurements, considering potentially different latency periods. Compared with the results of Kloog et al.'s analysis of the year-2002 BC data, the association between BC and ALAN appears to have weakened overall, becoming statistically insignificant in the year 2012 after being controlled for potential confounders (t < 0.3; p > 0.5). However, when the entire sample of countries was disaggregated into geographic clusters of similarly developed countries, a positive BC-ALAN association re-emerged as statistically significant (t > 2.2; p < 0.01), helping to explain, along with other factors covered by the analysis, about 65-85% of BC ASR variability worldwide, depending on the model type. Although the present analysis reconfirms a positive BC-ALAN association, this association appeared to diverge regionally in recent years, with countries in Western Europe showing the highest levels of such association, while countries in Southeast Asia and Gulf States exhibiting relatively low BC rates against the backdrop of relatively high ALAN levels. This regional stratification may be due to additional protective mechanisms, diminishing BC risks and potentially attributed to the local diet and lifestyles. PMID- 26102519 TI - Extraction of intercalated O2 from aligned carbon nanotubes: the breaking of intertube paths and exponential changes in resistance. AB - In carbon nanotube films, the alignment of carbon nanotubes creates Lennard-Jones potentials at intertube junctions and trapped O2 appears to oscillate at elevated temperatures. Electrical measurements reveal a low hopping barrier along the transverse direction and an underlying mechanism that involves intercalated molecules acting as charge carriers between tubes. Ab initio calculations support dynamic intercalation and charge transfer through O2 bouncing between tubes. PMID- 26102520 TI - Probing the Mucoadhesive Interactions Between Porcine Gastric Mucin and Some Water-Soluble Polymers. AB - This study investigates the structural features of porcine gastric mucin (PGM) in aqueous dispersions and its interactions with water-soluble polymers (poly(acrylic acid) (PAA), poly(methacrylic acid) (PMAA), poly(ethylene oxide), and poly(ethylene glycol)) using isothermal titration calorimetry, turbidimetric titration, dynamic light scattering, and transmission electron microscopy. It is established that PAA (450 kDa) and PMAA (100 kDa) exhibit strong specific interactions with PGM causing further aggregation of its particles, while PAA (2 kDa), poly(ethylene oxide) (1 000 kDa), and poly(ethylene glycol) (10 kDa) do not show any detectable effects on mucin. Sonication of mucin dispersions prior to their mixing with PAA (450 kDa) and PMAA (100 kDa) leads to more pronounced intensity of interactions. PMID- 26102522 TI - Nanofilament Dynamics in Resistance Memory: Model and Validation. AB - Filamentary resistive random-access memory (ReRAM) employs a single nanoscale event to trigger a macroscopic state change. While fundamentally it involves a gradual electrochemical evolution in a nanoscale filament that culminates in an abrupt change in filament's resistance, understanding over many length and time scales from the filament level to the device level is needed to inform the device behavior. Here, we demonstrate the nanoscale elements have corresponding elements in an empirical equivalent circuit. Specifically, the filament contains a variable resistor and capacitor that switch at a critical voltage. This simple model explains several observations widely reported on disparate filamentary ReRAMs. In particular, its collective system dynamics incorporating the power-law time-relaxation of the variable capacitance can accurately account for the responses of variously sized single-filament HfOx ReRAMs to DC/quasi-static and pulse electrical stimulation, exhibiting Avrami-like switching kinetics and a pulse-rate dependence in on/off voltages. PMID- 26102521 TI - Influence of Retirement on Adherence to Statins in the Insurance Medicine All Sweden Total Population Data Base. AB - BACKGROUND: Retirement has been suggested to reduce medication adherence, but no evidence is available for statins. We investigated changes in adherence to statins among Swedish adults after retirement. METHODS: A prospective cohort study was carried out on all individuals living in Sweden on 31 December 2004, alive in 2010, having purchased statins in the second half of 2005, and retired in 2008 (n=11 718). We used prescription dispensing data in 2006-2010 to determine nonadherence (defined as <80% of days covered by filled prescriptions) before and after old-age or disability retirement. Using multiple repeat measurements of filled statin prescriptions, we calculated the annual prevalence rates of nonadherence for those who continued therapy. Discontinuation was defined as no statin dispensations during a calendar year. RESULTS: After adjustment for age at retirement, the prevalence ratio (PR) of nonadherence after retirement in comparison with those before retirement was 1.23 [95% confidence interval (CI) 1.17-1.29] for the men and 1.19 (95% CI 1.13-1.26) for the women. A post-retirement increase in nonadherence was consistently observed across the strata of age at retirement, marital status, education, income, type of retirement, and participants with and without cardiovascular disease, the largest increases being observed for statin use in secondary prevention (men: PR 1.38, 95% CI 1.26-1.54; women: PR 1.43, 1.18-1.72). For primary prevention, the corresponding prevalence ratios were 1.18 (95% CI 1.13-1.25) and 1.18 (95% CI 1.11-1.24), respectively. INTERPRETATION: Retirement appears to be associated with increased nonadherence to statin therapy among Swedish men and women. PMID- 26102523 TI - Organocatalytic, Enantioselective Synthesis of 1- and 3-Substituted Isochromans via Intramolecular Oxa-Michael Reaction of Alkoxyboronate: Synthesis of (+) Sonepiprazole. AB - The enantioselective oxa-Michael reaction of alkoxyboronate strategy was demonstrated to provide a new and practical route to enantioriched 1- and 3 substituted isochromans using a chiral bifunctional organocatalyst. Furthermore, this methodology was extended to the enantioselective synthesis of (+) sonepiprazole, a dopamine receptor antagonist. PMID- 26102524 TI - Solid State Flexible Asymmetric Supercapacitor Based on Carbon Fiber Supported Hierarchical Co(OH)xCO3 and Ni(OH)2. AB - Conducting flexible carbon fiber (CF) cloth was used as a substrate for the hydrothermal growth of nickel hydroxide (Ni(OH)2) and cobalt hydroxy carbonate [Co(OH)xCO3] with unique hierarchical flowery architecture and then was used as a flexible supercapacitor electrode. In a three-electrode configuration in 6 M KOH aqueous electrolyte, the CF-Ni(OH)2 and CF-Co(OH)xCO3 electrode showed the maximum specific capacitance of 789 F/g and 550 F/g, respectively, at 2A/g current accompanied by outstanding cycle stability by retaining 99.9% and 99.5% specific capacitance over 1500 consecutive charge-discharge cycles at 5 A/g. However, the low cell voltage (0.4 V) restricted the respective specific energy to 4.38 and 3.05 Wh/kg at a specific power of 100 W/kg. To overcome the issue, two solid state flexible asymmetric supercapacitors were fabricated using the CF Ni(OH)2 and CF-Co(OH)xCO3 as the anode and sonochemically deposited CNT over carbon fiber as the cathode material in PVA-KOH gel electrolyte. The as fabricated flexible supercapacitors CF-Ni(OH)2//CF-CNT and CF-Co(OH)xCO3//CF-CNT were able to deliver high specific energy of 41.1 and 33.48 Wh/kg, respectively, at high specific power of 1.4 kW/kg accompanied by excellent cycle stability (retaining 98% and 97.6% specific capacitance, respectively, over 3000 charge discharge cycle at 5 A/g). PMID- 26102525 TI - A genetic toolkit for tagging intronic MiMIC containing genes. AB - Previously, we described a large collection of Minos-Mediated Integration Cassettes (MiMICs) that contain two phiC31 recombinase target sites and allow the generation of a new exon that encodes a protein tag when the MiMIC is inserted in a codon intron (Nagarkar-Jaiswal et al., 2015). These modified genes permit numerous applications including assessment of protein expression pattern, identification of protein interaction partners by immunoprecipitation followed by mass spec, and reversible removal of the tagged protein in any tissue. At present, these conversions remain time and labor-intensive as they require embryos to be injected with plasmid DNA containing the exon tag. In this study, we describe a simple and reliable genetic strategy to tag genes/proteins that contain MiMIC insertions using an integrated exon encoding GFP flanked by FRT sequences. We document the efficiency and tag 60 mostly uncharacterized genes. PMID- 26102526 TI - Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants. AB - Electroencephalogram (EEG) approaches may provide important information about developmental changes in brain-state dynamics during general anesthesia. We used multi-electrode EEG, analyzed with multitaper spectral methods and video recording of body movement to characterize the spatio-temporal dynamics of brain activity in 36 infants 0-6 months old when awake, and during maintenance of and emergence from sevoflurane general anesthesia. During maintenance: (1) slow-delta oscillations were present in all ages; (2) theta and alpha oscillations emerged around 4 months; (3) unlike adults, all infants lacked frontal alpha predominance and coherence. Alpha power was greatest during maintenance, compared to awake and emergence in infants at 4-6 months. During emergence, theta and alpha power decreased with decreasing sevoflurane concentration in infants at 4-6 months. These EEG dynamic differences are likely due to developmental factors including regional differences in synaptogenesis, glucose metabolism, and myelination across the cortex. We demonstrate the need to apply age-adjusted analytic approaches to develop neurophysiologic-based strategies for pediatric anesthetic state monitoring. PMID- 26102527 TI - A panel of induced pluripotent stem cells from chimpanzees: a resource for comparative functional genomics. AB - Comparative genomics studies in primates are restricted due to our limited access to samples. In order to gain better insight into the genetic processes that underlie variation in complex phenotypes in primates, we must have access to faithful model systems for a wide range of cell types. To facilitate this, we generated a panel of 7 fully characterized chimpanzee induced pluripotent stem cell (iPSC) lines derived from healthy donors. To demonstrate the utility of comparative iPSC panels, we collected RNA-sequencing and DNA methylation data from the chimpanzee iPSCs and the corresponding fibroblast lines, as well as from 7 human iPSCs and their source lines, which encompass multiple populations and cell types. We observe much less within-species variation in iPSCs than in somatic cells, indicating the reprogramming process erases many inter-individual differences. The low within-species regulatory variation in iPSCs allowed us to identify many novel inter-species regulatory differences of small magnitude. PMID- 26102529 TI - Unsymmetrical Chelation of N-Thioether-Functionalized Bis(diphenylphosphino)amine Type Ligands and Substituent Effects on the Nuclearity of Iron(II) Complexes: Structures, Magnetism, and Bonding. AB - Starting from the short-bite ligands N-thioether-functionalized bis(diphenylphosphino)amine-type (Ph2P)2N(CH2)3SMe (1) and (Ph2P)2N(p-C6H4)SMe (2), the Fe(II) complexes [FeCl2(1)]n (3), [FeCl2(2)]2 (4), [Fe(OAc)(1)2]PF6 (5), and [Fe(OAc)(2)2]PF6 (6) were synthesized and characterized by Fourier transform IR, mass spectrometry, elemental analysis, and also by X-ray diffraction for 3, 4, and 6. Complex 3 is a coordination polymer in which 1 acts as a P,P pseudochelate and a (P,P),S-bridge, whereas 4 has a chlorido-bridged dinuclear structure in which 2 acts only as a P,P-pseudochelate. Since these complexes were obtained under strictly similar synthetic and crystallization conditions, these unexpected differences were ascribed to the different spacer between the nitrogen atom and the -SMe group. In both compounds, one Fe-P bond was found to be unusually long, and a theoretical analysis was performed to unravel the electronic or steric reasons for this difference. Density functional theory calculations were performed for a set of complexes of general formula [FeCl2(SR2){R21PN(R2)P'R23}] (R = H, Me; R1, R2, and R3 = H, Me, Ph), to understand the reasons for the significant deviation of the iron coordination sphere away from tetrahedral as well as from trigonal bipyramidal and the varying degree of unsymmetry of the two Fe-P bonds involving pseudochelating PN(R)P ligands. Electronic factors nicely explain the observed structures, and steric reasons were further ruled out by the structural analysis in the solid-state of the bis-chelated complex 6, which displays usual and equivalent Fe-P bond lengths. Magnetic susceptibility studies were performed to examine how the structural differences between 3 and 4 would affect the interactions between the iron centers, and it was concluded that 3 behaves as an isolated high-spin Fe(II) mononuclear complex, while significant intra- and intermolecular ferromagnetic interactions were evidenced for 4 at low temperatures. Complexes 3 and 4 were also tested in catalytic ethylene oligomerization but did not exhibit any significant activity under the studied conditions. PMID- 26102528 TI - Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing. AB - How tissue shape emerges from the collective mechanical properties and behavior of individual cells is not understood. We combine experiment and theory to study this problem in the developing wing epithelium of Drosophila. At pupal stages, the wing-hinge contraction contributes to anisotropic tissue flows that reshape the wing blade. Here, we quantitatively account for this wing-blade shape change on the basis of cell divisions, cell rearrangements and cell shape changes. We show that cells both generate and respond to epithelial stresses during this process, and that the nature of this interplay specifies the pattern of junctional network remodeling that changes wing shape. We show that patterned constraints exerted on the tissue by the extracellular matrix are key to force the tissue into the right shape. We present a continuum mechanical model that quantitatively describes the relationship between epithelial stresses and cell dynamics, and how their interplay reshapes the wing. PMID- 26102531 TI - Lower Ribavirin Plasma Concentrations in HCV/HIV-Coinfected Patients Than in HCV Monoinfected Patients Despite Similar Dosage. AB - BACKGROUND: Hepatitis C virus (HCV)/HIV-coinfected patients respond worse to dual therapy with ribavirin (RBV)/peginterferon compared with HCV-monoinfected patients. Several trials found that lower RBV plasma concentrations are associated with impaired virological response rates. The aim of this study was to determine RBV plasma concentrations in a cohort of HCV-monoinfected and HCV/HIV coinfected patients. Our hypothesis is that HCV/HIV-coinfected patients have lower RBV plasma concentrations, which may in part explain their inferior response to dual therapy. METHODS: A retrospective cohort study was performed in chronic HCV-monoinfected and HCV/HIV-coinfected patients who received peginterferon and weight-based RBV. Plasma RBV concentrations were determined at weeks 4 and 12 by a validated high-performance liquid chromatography assay. RBV concentrations were compared between monoinfected and coinfected patients. We calculated the proportion of patients with a subtherapeutic RBV plasma concentration defined as <2.0 mg/L. RESULTS: A total of 61 HCV-infected patients were included, of whom 21 (34%) were coinfected with HIV. Although there was no difference in the weight-based dose of RBV between monoinfected and coinfected patients, RBV exposure was significantly lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients: the mean +/- SD RBV plasma concentrations were 1.82 +/- 0.63 mg/L versus 2.25 +/- 0.80 mg/L (P = 0.04) at week 4 and 2.14 +/- 0.65 mg/L versus 2.62 +/- 0.81 mg/L (P = 0.05) at week 12, respectively. The percentage of patients with subtherapeutic plasma concentrations of RBV in coinfected patients versus monoinfected patients was 62% versus 46% (P = 0.240) at week 4 and 50% versus 16% (P = 0.01) at week 12 of treatment, respectively. CONCLUSIONS: HIV/HCV-coinfected patients yield significantly lower plasma concentrations of RBV than HCV-monoinfected patients. This puts them at an increased risk of not achieving sustained virological response. PMID- 26102532 TI - In grateful appreciation of Dr. Margery Gass for her dedication and service to NAMS on her retirement. PMID- 26102530 TI - Conformational Stability and Pathogenic Misfolding of the Integral Membrane Protein PMP22. AB - Despite broad biochemical relevance, our understanding of the physiochemical reactions that limit the assembly and cellular trafficking of integral membrane proteins remains superficial. In this work, we report the first experimental assessment of the relationship between the conformational stability of a eukaryotic membrane protein and the degree to which it is retained by cellular quality control in the secretory pathway. We quantitatively assessed both the conformational equilibrium and cellular trafficking of 12 variants of the alpha helical membrane protein peripheral myelin protein 22 (PMP22), the intracellular misfolding of which is known to cause peripheral neuropathies associated with Charcot-Marie-Tooth disease (CMT). We show that the extent to which these mutations influence the energetics of Zn(II)-mediated PMP22 folding is proportional to the observed reduction in cellular trafficking efficiency. Strikingly, quantitative analyses also reveal that the reduction of motor nerve conduction velocities in affected patients is proportional to the extent of the mutagenic destabilization. This finding provides compelling evidence that the effects of these mutations on the energetics of PMP22 folding lie at the heart of the molecular basis of CMT. These findings highlight conformational stability as a key factor governing membrane protein biogenesis and suggest novel therapeutic strategies for CMT. PMID- 26102533 TI - Not all SERMs are created equal: chapter 2. PMID- 26102534 TI - Systems integration of innate and adaptive immunity. AB - The pathogens causing AIDS, malaria, and tuberculosis have proven too complex to be overcome by classical approaches to vaccination. The complexities of human immunology and pathogen-induced modulation of the immune system mandate new approaches to vaccine discovery and design. A new field, systems vaccinology, weds holistic analysis of innate and adaptive immunity within a quantitative framework to enable rational design of new vaccines that elicit tailored protective immune responses. A key step in the approach is to discover relationships between the earliest innate inflammatory responses to vaccination and the subsequent vaccine-induced adaptive immune responses and efficacy. Analysis of these responses in clinical studies is complicated by the inaccessibility of relevant tissue compartments (such as the lymph node), necessitating reliance upon peripheral blood responses as surrogates. Blood transcriptomes, although indirect to vaccine mechanisms, have proven very informative in systems vaccinology studies. The approach is most powerful when innate and adaptive immune responses are integrated with vaccine efficacy, which is possible for malaria with the advent of a robust human challenge model. This is more difficult for AIDS and tuberculosis, given that human challenge models are lacking and efficacy observed in clinical trials has been low or highly variable. This challenge can be met by appropriate clinical trial design for partially efficacious vaccines and by analysis of natural infection cohorts. Ultimately, systems vaccinology is an iterative approach in which mechanistic hypotheses-derived from analysis of clinical studies-are evaluated in model systems, and then used to guide the development of new vaccine strategies. In this review, we will illustrate the above facets of the systems vaccinology approach with case studies. PMID- 26102535 TI - Low tetanus, diphtheria and acellular pertussis (Tdap) vaccination coverage among HIV infected individuals in Austria. AB - Current management guidelines of HIV infected adults include recommendation to immunization against common vaccine preventable diseases. This effort is hindered by the scarce knowledge regarding the immunization status of this especially vulnerable patient group. This study analyzed the serostatus for pertussis, diphtheria and tetanus of more than 700 HIV infected individuals residing in Austria. These individuals were representative for the Austrian HIV cohort regarding sex, age, transmission risk and HIV progression markers. Overall, 73.6% were on suppressive HAART, mean CD4 cell count was 603c/MUl. Seropositivity was 84% for diphtheria, 51% for tetanus and 1% for pertussis. Migrants had a lower chance of tetanus seropositivity (OR 0.30 (CI 0.21 to 0.43)). Increase in CDC classification were associated with increased diphtheria seropositivity (OR 1.42 (CI 1.02 to 1.98)) and a CD4 nadir<200c/MUl was associated with increased pertussis seropositivity (OR 12.2, 95% CI 1.2 to 121). Importantly due to the well preserved immune status of nearly all participants vaccination would be feasible in the majority of the seronegative patients. In patients with a CD4 count>200c/MUl, 95% lacked seroprotection to at least one of the antigens included in the triple vaccine Tdap and could be vaccinated. Thus, a proactive approach would largely reduce the number of patients at risk for these vaccine preventable diseases. PMID- 26102536 TI - Quantitative proteomics unravels that the post-transcriptional regulator Crc modulates the generation of vesicles and secreted virulence determinants of Pseudomonas aeruginosa. AB - Recent research indicates that the post-transcriptional regulator Crc modulates susceptibility to antibiotics and virulence in Pseudomonas aeruginosa. Several P. aeruginosa virulence factors are secreted or engulfed in vesicles. To decipher the Crc modulation of P. aeruginosa virulence, we constructed a crc deficient mutant and measure the proteome associated extracellular vesicles and the vesicle free secretome using iTRAQ. Fifty vesicle-associated proteins were more abundant and 14 less abundant in the crc-defective strain, whereas 37 were more abundant and 17 less abundant in the vesicle-free secretome. Among them, virulence determinants, such as ToxA, protease IV, azurin, chitin-binding protein, PlcB and Hcp1, were less abundant in the crc-defective mutant. Transcriptomic analysis revealed that some of the observed changes were post-transcriptional and, thus, could be attributed to a direct Crc regulatory role; whereas, for other differentially secreted proteins, the regulatory role was likely indirect. We also observed that the crc mutant presented an impaired vesicle-associated secretion of quorum sensing signal molecules and less cytotoxicity than its wild type strain. Our results offer new insights into the mechanisms by which Crc regulates P. aeruginosa virulence, through the modulation of vesicle formation and secretion of both virulence determinants and quorum sensing signals. This article is part of a Special Issue entitled: HUPO 2014. PMID- 26102537 TI - Finite temperature orbital and spin magnetism of small Fe linear chains. AB - The finite temperature spin and orbital magnetism of N<= 10 Fe(N) linear chains is theoretically studied in the framework of a spin fluctuation theory based on a realistic d-band model Hamiltonian, which includes the spin-orbit coupling interaction in a non-perturbative way. Spin and orbital magnetic moments are calculated as a function of the temperature by using an exchange Monte Carlo method that takes into account in a full way the short-range magnetic order. The finite temperature anisotropy effects on the spin and orbital cluster moment values are analysed by considering magnetization directions perpendicular to and along the chain axis. The temperature dependence of the orbital cluster moment follows a general trend similar to that of the spin one and shows clear anisotropy effects at low and intermediate temperatures, before total thermal disorder appears. Interesting anisotropy effects driven by thermal spin fluctuations are also observed for the spin results in most of the systems. PMID- 26102538 TI - Surgical Management of Giant Scalp Neurofibroma After Ultra-Selective Embolization of Nutrient Artery. AB - OBJECTIVES: Neurofibroma, a common benign tumor in soft tissue, continues to grow, so it often appears to be giant. Surgical management of giant neurofibroma is a challenge due to the risk of excessive bleeding. Embolization of tumor's nutrient artery may reduce the blood loss in operation. This study introduces the surgical management of giant scalp neurofibroma with preoperative ultra-selective embolization of nutrient artery. METHODS: From January 2006 to December 2013, 9 patients with giant scalp neurofibroma were enrolled into the study. Digital subtraction angiography (DSA) showed tumor's nutrient artery. Ultra-catheter was inserted into the nutrient artery and its branches as close as possible to the tumor. Then ultra-selective embolization was performed with gelatin sponge particles. Surgical removal of tumor was performed in 3 days after embolization. The wound was repaired by skin graft. RESULTS: All of the 9 patients underwent successful DSA and ultra-selective embolization. Among them, occipital artery was embolized in 3 patients (left side in 1 patient and right side in 2 patients). Both occipital artery and superficial temporal artery were embolized in 6 patients (left side in 2 patients, right side in 3 patients, and both side in 1 patient). No complications, such as ectopic embolism, occurred in the patients. All of the tumors were resected completely without blood transfusion. The skin graft survived very well on the wounds. CONCLUSIONS: Preoperative ultra-selective embolization of nutrient artery is a feasible, safe, and effective method to reduce the blood loss in operation and facilitate the surgical management of giant scalp neurofibroma. PMID- 26102539 TI - Orthoptic Sequelae Following Conservative Management of Pure Blowout Orbital Fractures: Anecdotal or Clinically Relevant? AB - The aim of this study was to prospectively assess the prevalence of orthoptic anomalies following conservative management of pure blowout orbital fractures and to evaluate their clinical relevance. Clinical and radiologic data of patients with unilateral conservatively managed pure blowout orbital fractures with a minimum follow-up of 6 months were reviewed. Eligible patients were contacted and invited to undergo an extended ophthalmologic examination as follows: distance and near visual acuities, Hertel exophthalmometry, corneal light reflex (Hirschberg test), ductions and versions in the 6 cardinal fields of gaze, eye deviation with prisms and alternate cover test in all of the 9-gaze directions with Maddox rod, degrees of incyclo/excyclotorsion with right and left eye fixation, horizontal and vertical deviation with Hess-Weiss coordimetry, degree of horizontal/vertical and incyclo/excyclotorsion deviation with Harms wall deviometry, and vertical deviation with Bielschowsky head-tilt test. Of the 69 patients contacted, 49 declined to participate given that they were asymptomatic. Twenty patients agreed to undergo the examination. One patient complained of minimal double vision limited to the extreme downgaze. Four patients had asymptomatic ocular motility disturbances limited to the extreme gaze. Seven patients had asymptomatic horizontal heterophoria. These disturbances did not interfere with daily or professional activities in any of the patients. The current study demonstrated that conservative management of pure orbital blowout fractures can result in orthoptic anomalies. These sequelae were restricted to a very limited portion of the binocular field of the vision and were not found to be clinically relevant. PMID- 26102540 TI - New Screw Design for Securing Buried Distractors Usefulness and Ease of Removal. AB - There are 2 types of distraction devices for mandibular distraction: buried and external. The advantage of buried devices is the stability, but the difficulty in removing the screws is the greatest disadvantage. To resolve this problem, an osteosynthesis screw (Farina Screw) has been designed, which greatly facilitates its removal when buried distractors are used. PMID- 26102541 TI - The Risk of Blepharoptosis in Contact Lens Wearers. AB - The aim of this systematic review was to summarize and evaluate the risk of blepharoptosis in contact lens wearers. In a PubMed search, 393 papers were found using the terms "lens and ptosis." The abstracts were read and 16 full text articles were reviewed. Among them, 5 articles were analyzed. Five studies were subgrouped and a meta-analysis of these data suggested there is an increased risk of blepharoptosis in hard contact lens wearers over nonwearers (n = 7426, OR, 17.38, 95% CI = 3.71-81.29, P < 0.00001). One study was subgrouped and these data suggested there is also an increased risk of blepharoptosis in soft contact lens wearers over nonwearers (n = 90, OR, 8.12, 95% CI = 2.68-24.87, P < 0.0002). Patients wearing rigid contact lenses should be advised of the risk of ptosis, and a history of contact lens use should be sought in all patients who have acquired ptosis as the previous authors have recommended. PMID- 26102542 TI - Late Scalp Metastasis in Papillary Thyroid Carcinoma. PMID- 26102543 TI - Frontal Sinolith. AB - Sinolith in the paranasal sinus is still a rare entity. A sinolith in the frontal sinus is extremely rare, and only 2 patients have been reported in the English literature. Herein, the authors present an additional patient of frontal sinolith in a 78-year-old woman. The patient was preoperatively diagnosed with fungus ball of the frontal sinus, based on radio-opaque densities on computed tomography. Endoscopic surgery was performed and surgical biopsy was interpreted as sinolith. Clinical manifestations of frontal sinolith, including imaging study findings, are discussed with a review of the literature pertaining to this condition. Despite its rarity, frontal sinolith should be considered in the differential diagnosis of radio-densities in the frontal sinus. PMID- 26102544 TI - Effectiveness and Safety of Selective Neck Dissection in Lymph Node-Positive Squamous Cell Carcinoma of the Head and Neck. AB - The aim of this study was to investigate the effectiveness and safety of selective neck dissection in patients with lymph node-positive head and neck squamous cell carcinoma to determine regional control and survival rates. Eighty patients with lymph node-positive head and neck squamous cell carcinoma who underwent selective dissection were included in the study. Regional control, survival rates, and factors affecting survival were analyzed. Regional control was 90%, disease-specific survival was 93.4%, and the overall survival rate was 87.25%. T stage, N stage, age, and extracapsular spread were included in hazard regression models. None of the factors were statistically significant. Selective neck dissection is an effective and oncologically safe treatment option in selected cases. T stage, N stage, and extracapsular spread had no significant impact on disease-specific survival. PMID- 26102545 TI - Aging as the Impact Factor on Septoplasty Success. AB - OBJECTIVE: The aim of the study was to discuss the impact of aging on septoplasty success. STUDY DESIGN AND SETTING: This prospective case control study was conducted at the Umraniye Education and Research Hospital. METHODS: Our study group consists of 23 patients older than 60-year-old who have septal deviation and have previously been postponed for this surgery due to various reasons. Twenty-six patients under 40-year-old are randomly chosen as the control group who were running to septoplasty. Postoperative Glasgow Benefit Inventory Index, preoperative and postoperative NOSE score, and nasal mucociliary clearance time (MCCt) were noted for both the groups. All collected data were compared between the groups. RESULTS: In both the groups, postoperative NOSE scores decreased significantly compared to preoperative values (P < 0.01). This decrease was not significantly different between the groups. In both the groups, a significant decrease was noted in nasal MCCt with surgery (P = 0.004). However, this difference between two groups was not statistically significant. In addition, the Glasgow Benefit Inventory (GBI) index of control group was notably higher than the study group and this was statistically significant (P = 0.027). Also, the decrease of NOSE scores was conversely related to high GBI indexes and this is statistically significant (P = 0.005). CONCLUSION: For many surgical procedures, aging is considered as one of the important prognostic factors on success. To date no study in the literature discussed this relationship between aging and the success of septoplasty. At this point, our results showed that septoplasty is a successfully performed procedure in all ages. But, satisfaction of patients is statistically decreasing with aging. PMID- 26102546 TI - Giant Solitary Fibrous Tumor of Orbit. AB - Solitary fibrous tumors (SFTs) have been reported in various locations in the body. Solitary fibrous tumors are extremely rare tumors, especially when located in the orbit. Diagnosis of SFT cannot be made based on histopathology only because it exhibits a variable microscopic appearance, and necessitates immunohistochemistry to confirm the diagnosis. A 51-year-old man was admitted to our clinic for the evaluation of a mass bulging in his left eye. Clinical examination revealed a painless mass extruding out of the orbital cavity with dimensions of 8 * 7 cm. Exenteration of the left eye including the upper and lower eyelid and reconstruction of the orbital cavity using a temporoparietal fascia flap and a temporal muscle flap was performed. SFT of orbital region is known as a slow growing and painless tumor. Based on previous studies, increased mitotic rate of the tumor gives the impression that the tumor has a malignant nature. Until now a small number or orbital SFTs were reported and none of them presented with a giant mass protruding out of the orbital cavity. We present a unique case of orbital SFT filling the whole orbital cavity and protruding outward as a giant mass. This case has been reported to expand our knowledge in this debated entity. PMID- 26102547 TI - [Factors associated with preterm birth in an urban African environment: A case control study at the University Teaching Hospital of Ouagadougou and Saint Camille Medical Center]. AB - OBJECTIVE: To study the risk factors associated with preterm delivery in two busy obstetrics centers in Ouagadougou. MATERIAL AND METHODS: This prospective case control study included 115 women with preterm deliveries and 230 control patients, or two controls per case, recruited from January through June 2011. The study took place in the maternity and neonatology departments of the University Hospital Center Yalgado-Ouedraogo (UHC-YO) and the Saint-Camille medical center, in the same city. Stillbirths were excluded from the study. Case infants were born at gestational ages ranging from 28 to 37 weeks. RESULTS: During the study period, the preterm delivery rate was 6.1%. Multivariate analysis with logistic regression enabled us to identify the factors associated with preterm delivery. These factors were: advanced maternal age (>30 years) (OR = 0.4 [0.2-0.8]), history of intentional abortions (OR = 3.3 [1.43-7.6], high stress (OR = 4.03 [2.14-3.39]), too few prenatal care visits (OR = 4.92 [3.03-8]), fever during pregnancy (OR = 1.59 [1.01-2.5]), premature rupture of membranes (OR = 3.72 [1.11 4.34]), urinary infections (OR = 2.55 [1.55-4.19]), and threatened preterm delivery (OR = 3.3 [1.43-7.6]). CONCLUSION: Preterm delivery is very frequent at both these Ouagadougou health care facilities. Many factors are associated with preterm birth, including social and demographic as well as clinical characteristics. The effort to reduce the rate of preterm births, which are associated with neonatal morbidity, must be strengthened by refocusing on prenatal consultations. PMID- 26102548 TI - Computerized measurement of melanocytic tumor depth in skin histopathological images. AB - Measuring the tumor depth of invasion in skin tissue is of great importance for decision making in treatment of melanoma. Traditionally, measuring the tumor depth is based on the examination of histopathological slides by pathologist under the microscope which is time consuming and prone to intra and inter observer variability. In this paper, we propose a method for computer assisted measurement of tumor depth. At first, cornified layer is segmented based on entropy of the ridges detected in the image. Then, segmentation of cells nuclei is done using color features and active contour model. Melanocytes are distinguished from lymphocytes by applying convergence index filter and Fourier feature extraction. Experimental results indicate that the method performs well in automated measurement of tumor invasion depth. PMID- 26102549 TI - The standardized Lycium chinense fruit extract protects against Alzheimer's disease in 3xTg-AD mice. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. This disease is a progressive and irreversible brain disorder accompanied with severe learning and memory impairment. This study investigated whether treatment with standardized Lycii Fructus Extract (LFE) would improve the cognitive function and the pathological features of AD in 3xTg-AD mice. ETHNOPHARMACOLOGICAL RELEVANCE: Lycii Fructus is a fruit of Lycium chinense Miller and widely distributed in East Asia and has been used traditionally for anti-aging purposes. MATERIALS AND METHODS: The cognitive function of 3xTg-AD mice was assessed using the Morris water maze test. The levels of the amyloid beta deposits and NeuN in the hippocampus were evaluated with immunohistochemistry. Brain neurotrophic derived factor (BDNF) and tyrosine kinase B (TrkB) expressions were examined by western blot analysis. RESULTS: LFE treatment significantly ameliorated learning and memory deficits in AD mice, as shown by increased time spent in the target zone during probe tests. In addition, LFE significantly decreased Abeta deposits, increased NeuN-positive cells, and upregulated the expression of BDNF and TrkB in the 3xTg AD mice. CONCLUSIONS: The present study suggests that LFE treatment can be a useful strategy for treating memory impairment induced by several neurodegenerative diseases. PMID- 26102550 TI - Antibacterial mode of action of the hydroethanolic extract of Leonotis nepetifolia (L.) R. Br. involves bacterial membrane perturbations. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leonotis nepetifolia (L) R. Br., Lamiaceae, a pantropical shrub, popularly known in Brazil as "cordao-de-frade", "rubim", is reportedly used in Brazilian ethnomedicine as well as in different countries in the treatments of ailments such as infections, inflammations, wounds, stomach disorders, among others. AIM OF THE STUDY: To evaluate its potential cytotoxicity and antibacterial mode of action of the hydroethanolic extract of L. nepetifolia (HELn) leaves, including phytochemical analysis. MATERIALS AND METHODS: The cytotoxicity of HELn was investigated by Alamar blue assay, using CHO-K1 cells. Antibacterial activity of HELn was tested by broth microdilution methods against a panel of bacteria of clinical interest. The mode of action of L. nepetifolia was studied by targeting bacterial membranes. Phytochemical analysis was performed by determining total secondary metabolites with spectrophotometric assays and HPLC. RESULTS: HELn is not cytotoxic in the in vitro evaluation (IC50>200 MUg/mL). It demonstrated a good spectrum of antibacterial activity with major activity against Shigella flexneri, Enterococcus faecalis, Staphylococcus aureus and Bacillus subtilis with MIC=6.25 ug/mL, Helicobacter pylori with MIC of 25 ug/mL and Streptococcus pyogenes with MIC of 50 ug/mL. Its mode of action is associated, at least partly, with changes in the permeability of bacterial membranes, as evidenced by the increased entry of hydrophobic antibiotics in Shigella flexneri and intense efflux of K(+) and nucleotide leakage in E. faecalis and Shigella flexneri. In addition, the presence of phenols, flavonoids and carotenoids, described in the literature to possess antibacterial effects, were detected in the composition of HELn, with high phenol content (11.55%), especially the flavonoids (6.47%). CONCLUSION: The results indicate that HELn has low cytotoxicity and potent antibacterial activity. It is bacteriostatic in nature, possibly acting at the level of bacterial membranes, especially on the cytoplasmic membrane and outer membrane, thus supporting its popular use in infectious processes. In addition, the presence of phenols, flavonoids, carotenoids, fatty acids and steroids, described in the literature as possessing antimicrobial activity, were detected in the composition of HELn. PMID- 26102551 TI - Traditional preparation of Phaleria nisidai, a Palauan tea, reduces exposure to toxic daphnane-type diterpene esters while maintaining immunomodulatory activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Phaleria nisidai Kaneh. (Thymelaeaceae) are brewed into a tea commonly used as a tonic, strengthening beverage and immune enhancer in Palau, Micronesia. Recently, the leaves of P. nisidai have been shown to contain toxic daphnane diterpene esters which may pose a public health threat to Palauans. AIMS OF THE STUDY: This project documents the use frequency, preparation and side effects of P. nisidai. The content of daphnane diterpene esters in aqueous and methanol extracts and infusions prepared by healers in Palau is compared to assess the risk of daphnane ingestion associated with traditional consumption. Quantitative results are correlated with an in vitro assessment of the immunomodulating activity of the extracts. MATERIALS AND METHODS: Research participants, comprising traditional healers and laypeople, were interviewed concerning use patterns and side effects of P. nisidai. Several traditional healers prepared and provided boiled tea samples for chemical analysis. Leaves were collected and methanolic and aqueous extractions were prepared in the laboratory. Peripheral blood mononuclear cells (PBMCs) were cultured with various concentrations of methanol and aqueous leaf extracts and their output of IFNgamma was measured using ELISA. Cell proliferation was also assessed using the MTT assay. The concentration of selected daphnane diterpene esters in healer-prepared infusions, lab methanol and lab aqueous extracts was quantified using ultraperformance liquid chromatography-mass spectrometry-triple quadrupole detection (UPLC-MS-TQD). RESULTS: Through structured interviews it was determined that P. nisidai tea was used frequently, with many participants drinking it daily. The reported side effects were mild, and with the exception of diarrhea (n=2), no side effect was mentioned more than once. Methanol extracts contained 4.0MUg simplexin, 17.6MUg acetoxyhuratoxin and 2.3MUg huratoxin per g dry leaf material. In traditional water infusions provided by healers and in standardized lab-prepared aqueous extracts all three compounds were below the limit of detection (16.3ng/mL) using our UPLC-MS-TQD method. Methanol and aqueous extracts increased the release of IFNgamma by PBMCs (p<0.05); however, methanol extracts were significantly more active than aqueous extracts (p<0.05). Methanol and aqueous extracts significantly increased proliferation of PBMCs, causing at least 60% more cell proliferation than negative control (p<0.05). CONCLUSIONS: The presence of daphnane diterpene esters in a frequently consumed traditional beverage was initially viewed as a public health concern, though interview data reveal that Palauans do not observe toxicity or side effects associated with their use of P. nisidai tea. Concurrently, daphnanes are present in methanolic extracts but not detected in aqueous preparations indicating that the traditional method of preparation avoids the extraction of these potentially toxic compounds, while still maintaining immunostimulant activity. PMID- 26102552 TI - Pilot study that evaluated the clinical effectiveness and safety of a phytopharmaceutical elaborated with an extract of Ageratina pichinchensis in patients with minor recurrent aphthous stomatitis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The plant species Ageratina pichinchensis (Schauer) R.M.King & H.Rob. (Asteraceae) in a wild plant native to Mexico that is utilized in traditional medicine for the treatment of skin problems and for mouth ulcers. AIM OF THE STUDY: The objective of the present study was to evaluate the clinical effectiveness and therapeutic safety of a phytopharmaceutical elaborated with a unpigmented hexane-ethyl acetate extract of A. pichinchensis at a concentration of 5% in patients with a clinical condition of Minor Recurrent aphthous stomatitis (MiRAS). MATERIALS AND METHODS: We conducted a double-blind, randomized, and controlled pilot study in which the experimental treatment was a phytopharmaceutical elaborated with a unpigmented hexane-ethyl acetate extract of A. pichinchensis at a 5% concentration and, as control treatment, we utilized Triamcinolone at 0.1%. Study participants were patients with a diagnosis of MiRAS, elderly males and females, with a disease evolution of no. >3 days. Lesion size was measured by means of a tracing sheet and pain, by the Visual analog scale (VAS). Output variables comprised clinical effectiveness, treatment adherence, therapeutic failure, and therapeutic success. RESULTS AND DISCUSSION: Fifty six patients participated in the study and we distributed these into two study groups (28 in each group). The results obtained did not show statistically significant differences between the experimental and the control treatments. Among patients treated with the A. pichinchensis extract, the time required for achieving the absence of pain was 4.0 days, while that of the control treatment was 4.1 days. In patients treated with A. pichinchensis, the time necessary for healing was 4.5 days and for the Triamcinolone 0.1%-treated group, this was 4.7 days. Greater clinical effectiveness was evidenced on days 2, 3, and 4 of treatment. During the first 7 follow-up days, there was clinical effectiveness in 92.8% of experimental-group and in 89.2% of control-group patients. At the end of the study, 100% therapeutic effectiveness was able to be scored. PMID- 26102553 TI - This divided land: An examination of regional inequalities in exposure to brownfield land and the association with morbidity and mortality in England. AB - This paper is the first empirical examination of the association between brownfield land and spatial inequalities in health. Linear mixed modelling of ward-level data suggests that there is higher exposure and susceptibility to brownfield land in the Northern compared to the Southern regions (with the exception of London); that brownfield exposure has an association with regional inequalities in mortality and morbidity within regions (particularly in the North West); that brownfield has an association with inequalities between regions (particularly between the North West and the South East); but that brownfield land only makes a small independent contribution to the North-South health divide in England. However, brownfield land could be a potentially important and previously overlooked independent environmental determinant of spatial inequalities in health in England. PMID- 26102554 TI - Fate of Alicyclobacillus spp. in enrichment broth and in juice concentrates. AB - In this study, the fate of Alicyclobacillus acidoterrestris spores in different types of juice concentrates stored under different conditions was investigated. In addition, the impact of dilution procedures during the enrichment step for the detection of Alicyclobacillus in lemon juice concentrates was studied. Pear, red grape, mango, tangerine, carrot and lemon juice concentrates (50-69.4 degrees Brix, pH1.7-4.3) were inoculated with A. acidoterrestris spores (10(3) spore/mL) and stored at 4 degrees C and 20 degrees C, after which the spores were counted at 0, 2, 5, 9, 17, 21, 28, 36, 43, and 50 days. No significant differences in the number of Alicyclobacillus spores were observed at storage temperatures of 4 degrees C and 20 degrees C (p>0.05). The results also indicated that the number of spores of A. acidoterrestris remained stable in all types of juice concentrates during the storage period, except in lemon juice concentrate. In lemon juice concentrate, a decline in A. acidoterrestris spore populations of 0.3 0.8 log CFU/mL was observed within 5-10 days of storage. The decline in A. acidoterrestris spore populations was more pronounced in cloudy lemon juice concentrate, which contained higher concentrations of flavonoids (mainly eriocitrin and hesperidin) than clarified lemon juice concentrate. It was also found that dilution of lemon juice concentrate samples in the proportion of 1:19 allowed the germination of A. acidoterrestris spores and the growth of populations of up to 10(7) CFU/mL. In contrast, the proportion (1:9) recommended in internationally recognized methods led to a reduction in the population of this microorganism that would yield false negative results. Data presented in this study demonstrated that Alicyclobacillus spores remain stable in most juice concentrates during storage, but that natural antimicrobial compounds present in some of them may decrease spore counts and inhibit their recovery by detection procedures. PMID- 26102555 TI - Towards spatially smart abatement of human pharmaceuticals in surface waters: Defining impact of sewage treatment plants on susceptible functions. AB - For human pharmaceuticals, sewage treatment plants (STPs) are a major point of entry to surface waters. The receiving waters provide vital functions. Modeling the impact of STPs on susceptible functions of the surface water system allows for a spatially smart implementation of abatement options at, or in the service area of, STPs. This study was performed on a nation-wide scale for the Netherlands. Point source emissions included were 345 Dutch STPs and nine rivers from neighboring countries. The Dutch surface waters were represented by 2511 surface water units. Modeling was performed for two extreme discharge conditions. Monitoring data of 7 locations along the rivers Rhine and Meuse fall mostly within the range of modeled concentrations. Half of the abstracted volumes of raw water for drinking water production, and a quarter of the Natura 2000 areas (European Union nature protection areas) hosted by the surface waters, are influenced by STPs at low discharge. The vast majority of the total impact of all Dutch STPs during both discharge conditions can be attributed to only 19% of the STPs with regard to the drinking water function, and to 39% of the STPs with regard to the Natura 2000 function. Attributing water treatment technologies to STPs as one of the possible measures to improve water quality and protect susceptible functions can be done in a spatially smart and cost-effective way, using consumption-based detailed hydrological and water quality modeling. PMID- 26102556 TI - Thulium Laser Endoscopic En Bloc Enucleation of Nonmuscle-Invasive Bladder Cancer. AB - OBJECTIVES: To evaluate if thulium laser enucleation of bladder tumor (ThuLEBT) offers any advantage over monopolar resection of nonmuscle-invasive bladder cancer (NMIBC) without increasing complications. PATIENTS AND METHODS: From February 2012 to September 2013, 58 patients (41 males and 17 females) newly diagnosed with having a single papillary bladder tumor more than 1 cm in diameter were selected for this prospective study on ThuLEBT. A similar historical cohort of 61 patients who underwent traditional monopolar resection (TURB-T) of NMIBC (Group B) was used to compare the two procedures. RESULTS: Mean tumor diameter in the ThuLEBT group was 2.5 cm (range 0.5-4.5). Mean operative time was 25 minutes (range 12-30). Re-resection and cold cup biopsy of the tumor base (in 90 days) were negative for bladder cancer (BC) persistence or recurrence in all patients with NMIBC treated with ThuLEBT. In Group B, seven patients were found with disease persistence. In eight cases of TURB-T patients, no detrusor muscle was identified, while it was always easily identified in the ThuLEBT group. No patient in Group A experienced obturator nerve reflection intraoperatively and no bladder perforation was evidenced in dome-located neoplasm; when involved, ureteral meatus was sharply excised without subsequent postoperative evidence of distortion. No significant intraoperative or postoperative bleeding occurred in all but one patient in the two groups. CONCLUSIONS: ThuLEBT may represent a potential alternative to TURB-T, which nowadays is considered the standard for diagnosis and treatment of NMBIC. In our study, ThuLEBT allowed accurate reporting of neoplastic depth invasion, suggesting the possibility to avoid a second-look resection at 90 days. All the different intravesical sites of the BC may be enucleated with the thulium laser, which offers advantages over the monopolar energy, especially when the tumor is located in the lateral bladder wall, at the bladder dome, or in the perimeatal zone. PMID- 26102557 TI - Transcriptome of the Antarctic brooding gastropod mollusc Margarella antarctica. AB - 454 RNA-Seq transcriptome data were generated from foot tissue of the Antarctic brooding gastropod mollusc Margarella antarctica. A total of 6195 contigs were assembled de novo, providing a useful resource for researchers with an interest in Antarctic marine species, phylogenetics and mollusc biology, especially shell production. PMID- 26102558 TI - Occurrence of Natural Hybrids Among Sympatric Karyomorphs in Hoplerythrinus unitaeniatus (Characiformes, Erythrinidae). AB - In this study, 43 specimens of Hoplerythrinus unitaeniatus from the Sao Francisco River basin were chromosomally analyzed by conventional Giemsa staining, C banding, silver nitrate impregnation, and fluorescence in situ hybridization (FISH) with probes of 5S and 18S rDNA. The diploid numbers found were 50 and 52 chromosomes, showing the existence of two well-defined biological entities in sympatry. Specimens with 51 chromosomes, which showed three distinct karyotypic forms, were also found and are characterized as natural hybrids due to the correspondence with the chromosomes of the specimens with 50 and 52 chromosomes. By FISH using 5S and 18S rDNA probes, it was possible to detect specific chromosomal markers for the specimens with 50 and 52 chromosomes, as well as the occurrence of common sites in both. The specimens with 51 chromosomes showed intermediate patterns for these markers, reinforcing the hypothesis that these are actual natural hybrids. A review and new classification for the karyomorphs of H. unitaeniatus have also been proposed. PMID- 26102559 TI - Reliability of an experimental method to analyse the impact point on a golf ball during putting. AB - This study aimed to examine the reliability of an experimental method identifying the location of the impact point on a golf ball during putting. Forty trials were completed using a mechanical putting robot set to reproduce a putt of 3.2 m, with four different putter-ball combinations. After locating the centre of the dimple pattern (centroid) the following variables were tested; distance of the impact point from the centroid, angle of the impact point from the centroid and distance of the impact point from the centroid derived from the X, Y coordinates. Good to excellent reliability was demonstrated in all impact variables reflected in very strong relative (ICC = 0.98-1.00) and absolute reliability (SEM% = 0.9-4.3%). The highest SEM% observed was 7% for the angle of the impact point from the centroid. In conclusion, the experimental method was shown to be reliable at locating the centroid location of a golf ball, therefore allowing for the identification of the point of impact with the putter head and is suitable for use in subsequent studies. PMID- 26102562 TI - Using the transit of Venus to probe the upper planetary atmosphere. AB - During a planetary transit, atoms with high atomic number absorb short-wavelength radiation in the upper atmosphere, and the planet should appear larger during a primary transit observed in high-energy bands than in the optical band. Here we measure the radius of Venus with subpixel accuracy during the transit in 2012 observed in the optical, ultraviolet and soft X-rays with Hinode and Solar Dynamics Observatory missions. We find that, while Venus's optical radius is about 80 km larger than the solid body radius (the top of clouds and haze), the radius increases further by >70 km in the extreme ultraviolet and soft X-rays. This measures the altitude of the densest ion layers of Venus's ionosphere (CO2 and CO), useful for planning missions in situ, and a benchmark case for detecting transits of exoplanets in high-energy bands with future missions, such as the ESA Athena. PMID- 26102560 TI - Gender modulates the development of theta event related oscillations in adolescents and young adults. AB - The developmental trajectories of theta band (4-7 Hz) event-related oscillations (EROs), a key neurophysiological constituent of the P3 response, were assessed in 2170 adolescents and young adults ages 12 to 25. The theta EROs occurring in the P3 response, important indicators of neurocognitive function, were elicited during the evaluation of task-relevant target stimuli in visual and auditory oddball tasks. These tasks call upon attentional and working memory resources. Large differences in developmental rates between males and females were found; scalp location and task modality (visual or auditory) differences within males and females were small compared to gender differences. Trajectories of interregional and intermodal correlations between ERO power values exhibited increases with age in both genders, but showed a divergence in development between auditory and visual systems during ages 16 to 21. These results are consistent with previous electrophysiological and imaging studies and provide additional temporal detail about the development of neurophysiological indices of cognitive activity. Since measures of the P3 response has been found to be a useful endophenotypes for the study of a number of clinical and behavioral disorders, studies of its development in adolescents and young adults may illuminate neurophysiological factors contributing to the onset of these conditions. PMID- 26102561 TI - Sex and strain influence attribution of incentive salience to reward cues in mice. AB - The propensity to attribute incentive salience to reward cues, measured by Pavlovian sign-tracking, is strongly associated with addiction-related traits including cocaine self-administration, impulsivity, novelty reactivity, and novelty preference. Despite its critical role in addiction, the genetic underpinnings of incentive salience attribution and its relationship to drug addiction are unknown. Mouse genetics can be a powerful means to discover genetic mechanisms underlying this relationship. However, feasibility of genetic dissection of sign-tracking in mice is unknown as only a single study limited to male C57BL/6J mice has rigorously examined this behavior, and limited sign tracking was observed. Highly diverse mouse populations such as the Collaborative Cross (CC) and Diversity Outbred population (DO) possess a greater range of behavioral and genetic variation than conventional laboratory strains. In the present study, we evaluated sign-tracking and the related phenotype goal-tracking in mice of both sexes from five inbred CC and DO founder strains. Male CAST/EiJ mice exhibited robust sign-tracking; male NOD, male C57BL/6J, and female A/J mice also exhibited significant sign-tracking. Male and female mice from all strains exhibited significant goal-tracking, and significant strain and sex differences were observed. Sign-tracking in males was genetically correlated with exploration of a novel environment, and heritability of sign-tracking and goal-tracking ranged from .32 to .41. These data highlight the importance of considering genetic diversity when evaluating the occurrence of specific behavioral traits in the laboratory mouse and demonstrate that the CC and DO mouse populations can be used to discover mechanisms underlying genetic relationships among sign-tracking and addiction-related behaviors. PMID- 26102563 TI - CARD15 gene overexpression reduces effect of etanercept, infliximab, and adalimumab on cytokine secretion from PMA activated U937 cells. AB - Crohn's disease (CD), a subcategory of inflammatory bowel disease, is an immune related disorder characterized by inflammation of the gastrointestinal mucosa, which can take place in any region along the alimentary tract. The most important gene involved in the etiology of CD is NOD2/CARD15 located on chromosome 16. It has been shown that CARD15 is overexpressed in monocytes of CD patients. The common treatment for the disease is anti-TNF-alpha drugs, the most hopeful of which are probably infliximab and etanercept. Infliximab rapidly reduces signs and symptoms of active Crohn's disease. In contrast, etanercept shows no such effect. In the present study, we evaluated the effects of the CARD15 gene overexpression in monocytic cell line U937 in the production of anti-inflammatory cytokine, IL-10, and proinflammatory cytokine, Il-1 beta, produced after incubation with infliximab, adalimumab, and etanercept separately. Our results show that infliximab and adalimumab significantly decreased IL-10 and IL-1beta secretion levels. However, etanercept inhibition of secretion was less compared with infliximab or adalimumab. In all three cases, suppression of cytokine production is reduced by CARD15 overexpression. PMID- 26102564 TI - Ursolic acid enhances pentobarbital-induced sleeping behaviors via GABAergic neurotransmission in mice. AB - Prunella vulgaris is widely used as a herbal medicine for cancers, inflammatory diseases, and other infections. Although it has long been used, few studies have examined its effects on central nervous system function. Here, we first observed that ethanolic extracts of P. vulgaris (EEPV) prolonged pentobarbital-induced sleep duration in mice. It is known that EEPV consists of many active components including triterpenoid (ursolic acid and oleanolic acid), which have many biological activities. Therefore, we evaluated which EEPV components induced sleep extension in pentobarbital-mediated sleeping model in mice. Surprisingly, despite their structural similarity and other common functions such as anti inflammation, anti-cancer, and tissue protection, only ursolic acid enhanced sleep duration in pentobarbital-treated mice. These results were attenuated by bicuculline treatment, which is a GABAA receptor antagonist. The present results suggest that ursolic acid from P. vulgaris enhances sleep duration through GABAA receptor activation and could be a therapeutic candidate for insomnia treatment. PMID- 26102565 TI - Aegeline from Aegle marmelos stimulates glucose transport via Akt and Rac1 signaling, and contributes to a cytoskeletal rearrangement through PI3K/Rac1. AB - Aegeline is an alkaloidal-amide, isolated from the leaves of Aegle marmelos and have shown antihyperglycemic as well as antidyslipidemic activities in the validated animal models of type 2 diabetes mellitus. Here we delineate, aegeline enhanced GLUT4 translocation mediated 2-deoxy-glucose uptake in both time and concentration-dependent manner. 2-deoxy-glucose uptake was completely stymied by the transport inhibitors (wortmannin and genistein) in C2C12 myotubes. Pharmacological inhibition of Akt (also known as protein kinase B) and Ras related C3 botulinum toxin substrate 1 (Rac1) suggest that both Akt and Rac1 operate aegeline-stimulated glucose transport via distinct parallel pathways. Moreover, aegeline activates p21 protein-activated kinase 1 (PAK1) and cofilin (an actin polymerization regulator). Rac1 inhibitor (Rac1 inhib II) and PAK1 inhibitor (IPA-3) completely blocked aegeline-induced phosphorylation of cofilin and p21 protein-activated kinase 1 (PAK1). In summary, these findings suggest that aegeline stimulates the glucose transport through Akt and Rac1 dependent distinct parallel pathways and have cytoskeletal roles via stimulation of the PI3 kinase-Rac1-PAK1-cofilin pathway in the skeletal muscle cells. Therefore, multiple targets of aegeline in the improvement of insulin sensitivity of the skeletal muscle cells may be suggested. PMID- 26102566 TI - Effects of beta(3)-adrenoceptor activation on expression of pancreatic adrenoceptors and angiotensin II receptors in ApoE(-/-) mice. AB - Hyperlipidemia can be harmful to the pancreas and beta3-adrenoceptor agonist can improve lipid metabolism disorder. We aimed to study the effects of beta3 adrenoceptor activation on glucose, insulin and the expression of pancreatic adrenoceptors and angiotensin II receptors. Ten C57BL/6J mice at the age of 10 weeks served as normal control, and forty age-matched apolipoprotein E knockout (ApoE(-/-)) mice were randomly divided into hyperlipidaemia model group, low-dose and high-dose beta3-adrenoceptor agonist group and beta3-adrenoceptor antagonist group. After 26 weeks of high-fat diet, treatments were given for 12 weeks. Serum glucose and insulin levels in 48 weeks old mice were measured using an automatic biochemical detector. Quantitative rt-PCR and Western blot were used to analyze the mRNA and protein expression of alpha1A-, alpha2A-, beta2-, beta3 adrenoceptors and angiotensin II type 1 and type 2 receptors in pancreas. We found that beta3-adrenoceptor agonist could decrease serum glucose and insulin levels in aged ApoE(-/-) mice (P<0.01) and down-regulate the expression of alpha1A-adrenoceptor and angiotensin II type 1 receptor which were significantly increased in model mice (P<0.05, P<0.01). Compared with the model mice, alpha2A-, beta2-, beta3-adrenoceptor and angiotensin II type 2 receptor expression were up regulated in beta3-adrenoceptor agonist treat mice (P<0.05, P<0.01). These results suggest that chronic beta3-adrenoceptor activation regulated the expression of adrenoceptors and angiontensin II receptors towards contrary direction, which indicates that there are interactions between beta3-adrenoceptor and subtypes of adrenoceptor and angiotensin II receptor, and these interactions may play a protective role in pancreas and improve glucose metabolism disorders. PMID- 26102567 TI - Assessing complex cognitive functioning requires multiple tasks. PMID- 26102568 TI - Targets but not flankers are suppressed in crowding as revealed by EEG frequency tagging. AB - Perception of a visual target can strongly deteriorate in the presence of flanking elements (crowding). For example, adding lines next to a vernier makes vernier offset discrimination difficult. Crowding is often considered a bottleneck of low-level vision, determined by the unavoidable limitations of the early visual system. In accordance with this proposal, neural processing of the flankers should be impaired in crowding as much as that of the target. To test this prediction, we used steady-state visually evoked potentials (ssVEPs) to separate target responses from flanker responses. We presented a vernier target either alone or flanked by lines, which had the same color as the vernier or a different color. Crowding by same-color flankers was stronger than by different color flankers. Mirroring the behavioral results, ssVEP amplitudes corresponding to the target were higher for different-color flankers than for same-color flankers. Flanker related ssVEPs, however, did not depend on crowding strength. It seems that target, but not flanker processing, is susceptible to crowding. In line with previous results, we suggest that crowding is not caused by low-level interferences but is linked to target-flanker grouping instead. PMID- 26102569 TI - What drives selection on flowering time? An experimental manipulation of the inherent correlation between genotype and environment. AB - The optimal timing of the seasonal switch from somatic growth to reproduction can depend on an individual's condition at reproduction, the quality of the environment in which it will reproduce, or both. In annual plants, vegetative size (a function of age at flowering) affects resources available for seed production, whereas exposure to mutualists, antagonists, and abiotic stresses in the environment (functions of Julian date of flowering) influences success in converting resources into offspring. The inherent tight correlation between age, size, and environment obscures their independent fitness contributions. We isolated the fitness effects of these factors by experimentally manipulating the correlation between age at flowering and date of flowering in Brassica rapa. We staggered the planting dates of families with differing ages at flowering to produce experimental populations in which age at flowering and date of flowering were positively, negatively, or uncorrelated. In all populations, plants with an early date of flowering produced more seed than those flowering late, regardless of age or size at flowering onset. The temporal environment was thus the principal driver of selection on flowering time, but its importance relative to that of age and size varied with the presence/absence of herbivores and seed predators. PMID- 26102570 TI - Bayesian model-averaged benchmark dose analysis via reparameterized quantal response models. AB - An important objective in biomedical and environmental risk assessment is estimation of minimum exposure levels that induce a pre-specified adverse response in a target population. The exposure points in such settings are typically referred to as benchmark doses (BMDs). Parametric Bayesian estimation for finding BMDs has grown in popularity, and a large variety of candidate dose response models is available for applying these methods. Each model can possess potentially different parametric interpretation(s), however. We present reparameterized dose-response models that allow for explicit use of prior information on the target parameter of interest, the BMD. We also enhance our Bayesian estimation technique for BMD analysis by applying Bayesian model averaging to produce point estimates and (lower) credible bounds, overcoming associated questions of model adequacy when multimodel uncertainty is present. An example from carcinogenicity testing illustrates the calculations. PMID- 26102571 TI - Influence of Age on Cerebral Housekeeping Gene Expression for Normalization of Quantitative Polymerase Chain Reaction after Acute Brain Injury in Mice. AB - To prevent methodological errors of quantitative PCR (qPCR) normalization with reference genes is obligatory. Although known to influence gene expression, impact of age on housekeeping gene expression has not been determined after acute brain lesions such as traumatic brain injury (TBI). Therefore, expression of eight common control genes was investigated at 15 min, 24 h, and 72 h after experimental TBI in 2- and 21-month-old C57Bl6 mice. Expression of beta2 microglobulin (B2M), beta-actin (ActB), and porphobilinogen deaminase (PBGD) increased after TBI in both ages. beta2M demonstrated age-dependent differences and highest inter- and intragroup variations. Expression of cyclophilin A, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), hypoxanthine ribosyltransferase (HPRT), S100B, and 18SrRNA remained stable. Cyclophilin A and HPRT demonstrated strongest inter- and intragroup stability. The data indicate that the expression of most but not all control genes is stable during aging. The correct choice of housekeeping genes is of key importance to ensure adequate normalization of qPCR data. With respect to insult and age, normalization strategies should consider cyclophilin A as a single normalizer. Normalization with two reference genes is recommended with cyclophilin A and HPRT in young mice and in mixed age studies and with cyclophilin A and GAPDH in old mice. In addition, the present study suggests not to use beta2-microglobulin, beta-actin or PBGD as single control genes because of strong regulation after CCI in 2- and 21-month-old mice. PMID- 26102572 TI - Determination of biodistribution of ultrasmall, near-infrared emitting gold nanoparticles by photoacoustic and fluorescence imaging. AB - This study compares fluorescence and photoacoustic (PA) imaging of ex vivo tumors and organs from tumor-bearing mice injected intravenously with ultrasmall (<3 nm ) tiopronin-capped Au nanoparticles and compares the data with inductively coupled plasma mass spectrometry (ICP-MS). Good agreement is seen in particle distributions and concentrations at the organ level. The spatial resolution from the imaging techniques allows for localization of the particles within organ structures. Although the particles do not have a plasmon peak, their absorbance in the near-infrared (NIR) is sufficient for PA excitation. PA imaging shows an increase of signal as particle concentrations increase, with changes in spectrum if particles aggregate. Fluorescence imaging using the particles' native NIR emission shows agreement in general intensity in each organ, though quenching of emission can be seen at very high concentrations. Both of these imaging techniques are noninvasive and labor-saving alternatives to organ digestion and ICP-MS and may provide insight into cellular distribution of particles. The simple construct avoids the use of toxic semiconductor materials or dyes, relying upon the gold itself for both the fluorescence and PA signal. This provides a useful alternative to more complex approaches to multimodal imaging and one that is readily translatable to the clinic. PMID- 26102573 TI - Wide-field imaging of retinal vasculature using optical coherence tomography based microangiography provided by motion tracking. AB - Optical coherence tomography (OCT)-based optical microangiography (OMAG) is a high-resolution, noninvasive imaging technique capable of providing three dimensional in vivo blood flow visualization within microcirculatory tissue beds in the eye. Although the technique has demonstrated early clinical utility by imaging diseased eyes, its limited field of view (FOV) and the sensitivity to eye motion remain the two biggest challenges for the widespread clinical use of the technology. Here, we report the results of retinal OMAG imaging obtained from a Zeiss Cirrus 5000 spectral domain OCT system with motion tracking capability achieved by a line scan ophthalmoscope (LSO). The tracking LSO is able to guide the OCT scanning, which minimizes the effect of eye motion in the final results. We show that the tracking can effectively correct the motion artifacts and remove the discontinuities and distortions of vascular appearance due to microsaccade, leading to almost motion-free OMAG angiograms with good repeatability and reliability. Due to the robustness of the tracking LSO, we also show the montage scan protocol to provide unprecedented wide field retinal OMAG angiograms. We experimentally demonstrate a 12 x 16 mm2 retinal OMAG angiogram acquired from a volunteer, which is the widest FOV retinal vasculature imaging up to now in the community. PMID- 26102574 TI - Physcomitrella patens auxin conjugate synthetase (GH3) double knockout mutants are more resistant to Pythium infection than wild type. AB - Auxin homeostasis is involved in many different plant developmental and stress responses. The auxin amino acid conjugate synthetases belonging to the GH3 family play major roles in the regulation of free indole-3-acetic acid (IAA) levels and the moss Physcomitrella patens has two GH3 genes in its genome. A role for IAA in several angiosperm--pathogen interactions was reported, however, in a moss- oomycete pathosystem it had not been published so far. Using GH3 double knockout lines we have investigated the role of auxin homeostasis during the infection of P. patens with the two oomycete species, Pythium debaryanum and Pythium irregulare. We show that infection with P. debaryanum caused stronger disease symptoms than with P. irregulare. Also, P. patens lines harboring fusion constructs of an auxin-inducible promoter from soybean (GmGH3) with a reporter (beta-glucuronidase) showed higher promoter induction after P. debaryanum infection than after P. irregulare, indicating a differential induction of the auxin response. Free IAA was induced upon P. debaryanum infection in wild type by 1.6-fold and in two GH3 double knockout (GH3-doKO) mutants by 4- to 5-fold. All GH3-doKO lines showed a reduced disease symptom progression compared to wild type. Since P. debaryanum can be inhibited in growth on medium containing IAA, these data might indicate that endogenous high auxin levels in P. patens GH3-doKO mutants lead to higher resistance against the oomycete. PMID- 26102575 TI - Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis. AB - The posaconazole extended release tablet formulation was developed to improve bioavailability relative to the oral suspension. Therapeutic drug monitoring has been used to optimise posaconazole dosing to achieve a target trough level >=0.7 MUg ml(-1). We retrospectively evaluated 28 patients with haematological malignancies who received posaconazole tablets for antifungal prophylaxis. Posaconazole serum trough levels were obtained 5 days after initiation of therapy. Mean trough level was 1.19 +/- 0.63 MUg ml(-1), and 71% achieved a trough level >=0.7 MUg ml(-1). Diarrhoea was associated with lower mean trough levels (0.65 +/- 0.08 MUg ml(-1) vs. 1.31 +/- 0.13 MUg ml(-1)), P = 0.002. Mean trough levels were lower in patients >=90 kg (0.74 +/- 0.09 MUg ml(-1)) vs. <90 kg (1.32 +/- 0.14 MUg ml(-1)), P = 0.002 and in patients with body mass index (BMI) >=30 (0.89 +/- 0.13 MUg ml(-1)) vs. BMI <30 (1.29 +/- 0.14 MUg ml(-1)), P = 0.05. Posaconazole delayed release tablets attain appropriate trough levels in most patients, but patients with a higher weight and those experiencing diarrhoea are more likely to have lower levels. PMID- 26102576 TI - Ordered mesoporous polymers in situ coated on a stainless steel wire for a highly sensitive solid phase microextraction fibre. AB - Development of facile and effective methods for fabrication of high-performance solid phase microextraction (SPME) fibres remains a great challenge. Herein, a new class of ordered mesoporous polymers (OMPs) in situ coated on a stainless steel wire were successfully developed and utilized as a highly sensitive and stable SPME fibre for the first time. Because of the highly ordered mesoporous structure of its OMP coating, the pi-pi interactions and the dispersion forces, the OMP-coated SPME fibre exhibited much better extraction properties as compared to the commercial PDMS fibre. The findings could provide a new benchmark for preparing well-defined porous materials for the SPME application. PMID- 26102577 TI - Not so fast: dietary restriction improves chemotherapy-related toxicity. PMID- 26102579 TI - Correction: Hollingworth, R.; Grand, R.J. Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses. Viruses 2015, 7, 2542-2591. PMID- 26102578 TI - Coordinated DNA Replication by the Bacteriophage T4 Replisome. AB - The T4 bacteriophage encodes eight proteins, which are sufficient to carry out coordinated leading and lagging strand DNA synthesis. These purified proteins have been used to reconstitute DNA synthesis in vitro and are a well characterized model system. Recent work on the T4 replisome has yielded more detailed insight into the dynamics and coordination of proteins at the replication fork. Since the leading and lagging strands are synthesized in opposite directions, coordination of DNA synthesis as well as priming and unwinding is accomplished by several protein complexes. These protein complexes serve to link catalytic activities and physically tether proteins to the replication fork. Essential to both leading and lagging strand synthesis is the formation of a holoenzyme complex composed of the polymerase and a processivity clamp. The two holoenzymes form a dimer allowing the lagging strand polymerase to be retained within the replisome after completion of each Okazaki fragment. The helicase and primase also form a complex known as the primosome, which unwinds the duplex DNA while also synthesizing primers on the lagging strand. Future studies will likely focus on defining the orientations and architecture of protein complexes at the replication fork. PMID- 26102580 TI - Exosomes and Their Role in the Life Cycle and Pathogenesis of RNA Viruses. AB - Exosomes are membrane-enclosed vesicles actively released into the extracellular space, whose content reflect the physiological/pathological state of the cells they originate from. These vesicles participate in cell-to-cell communication and transfer of biologically active proteins, lipids, and RNAs. Their role in viral infections is just beginning to be appreciated. RNA viruses are an important class of pathogens and affect millions of people worldwide. Recent studies on Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), human T-cell lymphotropic virus (HTLV), and Dengue Virus (DENV) have demonstrated that exosomes released from infected cells harbor and deliver many regulatory factors including viral RNA and proteins, viral and cellular miRNA, and other host functional genetic elements to neighboring cells, helping to establish productive infections and modulating cellular responses. Exosomes can either spread or limit an infection depending on the type of pathogen and target cells, and can be exploited as candidates for development of antiviral or vaccine treatments. This review summarizes recent progress made in understanding the role of exosomes in RNA virus infections with an emphasis on their potential contribution to pathogenesis. PMID- 26102581 TI - RNA Viruses and RNAi: Quasispecies Implications for Viral Escape. AB - Due to high mutation rates, populations of RNA viruses exist as a collection of closely related mutants known as a quasispecies. A consequence of error-prone replication is the potential for rapid adaptation of RNA viruses when a selective pressure is applied, including host immune systems and antiviral drugs. RNA interference (RNAi) acts to inhibit protein synthesis by targeting specific mRNAs for degradation and this process has been developed to target RNA viruses, exhibiting their potential as a therapeutic against infections. However, viruses containing mutations conferring resistance to RNAi were isolated in nearly all cases, underlining the problems of rapid viral evolution. Thus, while promising, the use of RNAi in treating or preventing viral diseases remains fraught with the typical complications that result from high specificity of the target, as seen in other antiviral regimens. PMID- 26102583 TI - Guanosine-based hydrogen-bonded 2D scaffolds: metal-free formation of G-quartet and G-ribbon architectures at the solid/liquid interface. AB - We report on the synthesis and self-assembly of three novel lipophilic guanosine derivatives exposing a ferrocene moiety in the C(5') position of the sugar unit. Their self-association in solution, and at the solid/liquid interface, can be tuned by varying the size and nature of the C(8)-substituent, leading to the generation of either G-ribbons, lamellar G-dimer based arrays or the G4 cation free architectures. PMID- 26102582 TI - Characterization of Equine Infectious Anemia Virus Integration in the Horse Genome. AB - Human immunodeficiency virus (HIV)-1 has a unique integration profile in the human genome relative to murine and avian retroviruses. Equine infectious anemia virus (EIAV) is another well-studied lentivirus that can also be used as a promising retro-transfection vector, but its integration into its native host has not been characterized. In this study, we mapped 477 integration sites of the EIAV strain EIAVFDDV13 in fetal equine dermal (FED) cells during in vitro infection. Published integration sites of EIAV and HIV-1 in the human genome were also analyzed as references. Our results demonstrated that EIAVFDDV13 tended to integrate into genes and AT-rich regions, and it avoided integrating into transcription start sites (TSS), which is consistent with EIAV and HIV-1 integration in the human genome. Notably, the integration of EIAVFDDV13 favored long interspersed elements (LINEs) and DNA transposons in the horse genome, whereas the integration of HIV-1 favored short interspersed elements (SINEs) in the human genome. The chromosomal environment near LINEs or DNA transposons potentially influences viral transcription and may be related to the unique EIAV latency states in equids. The data on EIAV integration in its natural host will facilitate studies on lentiviral infection and lentivirus-based therapeutic vectors. PMID- 26102584 TI - Effects of Sand Dune Stabilization on the Spatial Pattern of Artemisia ordosica Population in Mu Us Desert, Northwest China. AB - Vegetation patterns are strongly influenced by sand mobility in desert ecosystems. However, little is known about the spatial patterns of Artemisia ordosica, a dominant shrub in the Mu Us desert of Northwest China, in relation to sand fixation. The aim of this study was to investigate and contrast the effects of sand dune stabilization on the population and spatial distribution of this desert shrub. Spatial autocorrelation, semi-variance analysis, and point-pattern analysis were used jointly in this study to investigate the spatial patterns of A. ordosica populations on dunes in Yanchi County of Ningxia, China. The results showed that the spatial autocorrelation and spatial heterogeneity declined gradually, and the distance between the clustered individuals shortened following sand dune fixation. Seedlings were more aggregated than adults in all stage of dune stabilization, and both were more aggregated on shifting sand dunes separately. Spatial associations of the seedlings with the adults were mostly positive at distances of 0-5 m in shifting sand dunes, and the spatial association changed from positive to neutral in semi-fixed sand dunes. The seedlings were spaced in an almost random pattern around the adults, and their distances from the adults did not seem to affect their locations in semi-fixed sand dunes. Furthermore, spatial associations of the seedlings with the adults were negative in the fixed sand dune. These findings demonstrate that sand stabilization is an important factor affecting the spatial patterns of A. ordosica populations in the Mu Us desert. These findings suggest that, strong association between individuals may be the mechanism to explain the spatial pattern formation at preliminary stage of dune fixation. Sand dune stabilization can change the spatial pattern of shrub population by weakening the spatial association between native shrub individuals, which may affect the development direction of desert shrubs. PMID- 26102585 TI - Land Use History Shifts In Situ Fungal and Bacterial Successions following Wheat Straw Input into the Soil. AB - Soil microbial communities undergo rapid shifts following modifications in environmental conditions. Although microbial diversity changes may alter soil functioning, the in situ temporal dynamics of microbial diversity is poorly documented. Here, we investigated the response of fungal and bacterial diversity to wheat straw input in a 12-months field experiment and explored whether this response depended on the soil management history (grassland vs. cropland). Seasonal climatic fluctuations had no effect on the diversity of soil communities. Contrastingly fungi and bacteria responded strongly to wheat regardless of the soil history. After straw incorporation, diversity decreased due to the temporary dominance of a subset of copiotrophic populations. While fungi responded as quickly as bacteria, the resilience of fungal diversity lasted much longer, indicating that the relative involvement of each community might change as decomposition progressed. Soil history did not affect the response patterns, but determined the identity of some of the populations stimulated. Most strikingly, the bacteria Burkholderia, Lysobacter and fungi Rhizopus, Fusarium were selectively stimulated. Given the ecological importance of these microbial groups as decomposers and/or plant pathogens, such regulation of the composition of microbial successions by soil history may have important consequences in terms of soil carbon turnover and crop health. PMID- 26102586 TI - The interactome of soybean GmWRKY53 using yeast 2-hybrid library screening to saturation. AB - Soybean GmWRKY53 functions in both biotic and abiotic stress signaling. Using GmWRKY53 as a bait yeast 2-hybrid library screening to saturation isolated multiple independent fragments for many interacting proteins, enabling delineation of minimal interacting domains and computation of a confidence score. Multiple independent clones coding for the LATE ELONGATED HYPOCOTYL clock protein GmLCL2 (MYB114) were isolated and the binding site for GmWRKY53 was mapped to 90 amino acids separate from the MYB domain. This suggests a direct input from the clock on GmWRKY53 activity. The GmWRKY53-interacting proteins also included 3 water stress-inducible AP2/ERF transcription factors. One of these (Glyma03g26310) is one of the most strongly water stress induced genes in soybean roots, suggesting that GmWRKY53/ERF complexes regulate water stress responses. PMID- 26102587 TI - Sex-Related Responses of Populus cathayana Shoots and Roots to AM Fungi and Drought Stress. AB - We investigated the impact of drought and arbuscular mycorrhizal (AM) fungi on the morphological structure and physiological function of shoots and roots of male and female seedlings of the dioecious plant Populus cathayana Rehder. Pot grown seedlings were subjected to well watered or water-limiting conditions (drought) and were grown in soil that was either inoculated or not inoculated with the AM fungus Rhizophagus intraradices. No significant differences were found in the infection rates between the two sexes. Drought decreased root and shoot growth, biomass and root morphological characteristics, whereas superoxide radical (O2-) and hydrogen peroxide content, peroxidase (POD) activity, malondialdehyde (MDA) concentration and proline content were significantly enhanced in both sexes. Male plants that formed an AM fungal symbiosis showed a significant increase in shoot and root morphological growth, increased proline content of leaves and roots, and increased POD activity in roots under both watering regimes; however, MDA concentration in the roots decreased. By contrast, AM fungi either had no effect or a slight negative effect on the shoot and root growth of female plants, with lower root biomass, total biomass and root/shoot ration under drought. In females, MDA concentration increased in leaves and roots under both watering regimes, and the proline content and POD activity of roots increased under drought conditions; however, POD activity significantly decreased under well-watered conditions. These findings suggest that AM fungi enhanced the tolerance of male plants to drought by improving shoot and root growth, biomass and the antioxidant system. Further investigation is needed to unravel the complex effects of AM fungi on the growth and antioxidant system of female plants. PMID- 26102588 TI - Rice stripe1-2 and stripe1-3 Mutants Encoding the Small Subunit of Ribonucleotide Reductase Are Temperature Sensitive and Are Required for Chlorophyll Biosynthesis. AB - We induced mutants, stripe1-2 (st1-2) and stripe1-3 (st1-3), from rice (Oryza sativa L.) Indica 9311 using Ethyl methanesulfonate (EMS). Both st1-2 and st1-3 mutants encoded the small subunit of ribonucleotide reductase 1 (RNRS1), differed in the location of the mutated base, and displayed white-stripe from the L2 stage through maturity. The mutants were sensitive to temperature, and their chlorophyll content increased with the increase in temperature; however, they did not revert to normal green leaf phenotype under field conditions. The mutant st1 2 showed loosely arranged thylakoid lamellar structure as compared with wild-type (WT) plants. Contrastingly, st1-3 displayed normal thylakoid lamellar structure, good agronomic traits, and higher yield than st1-2 but lower yield than WT. Three dimensional structure prediction for RNRS1 indicated that the mutation in Val-171 residue in st1-2 influenced the connection of RNRS1 to iron, causing abnormal development of chloroplasts. Real-time PCR analysis showed that the expression levels associated with chlorophyll biosynthetic pathway and photosynthesis were affected in st1-2 and st1-3 at different temperatures and different developmental stages. PMID- 26102589 TI - The Synthesis of a New Class of Highly Fluorescent Chromones via an Inverse Demand Hetero-Diels-Alder Reaction. AB - A new class of fluorophores has been developed utilizing an inverse-demand hetero Diels-Alder reaction with silyl enol ethers and substituted 3-formylchromones. These compounds yield blue to green fluorescence with quantum yields up to 73%. They also exhibit good potential for use as fluorescent probes in biological systems, as they are cell membrane permeable with low cytotoxicity. PMID- 26102590 TI - Hydration of the sulfate dianion in cold nanodroplets: SO4(2-)(H2O)12 and SO4(2 )(H2O)13. AB - The structures, energetics and infrared spectra of SO4(2-)(H2O)12 and SO4(2 )(H2O)13 have been investigated by a combination of classical polarizable molecular dynamics and static quantum chemical calculations. Snapshots extracted from MD trajectories were used as inputs for local DFT optimization. Energies of the most stable structures were further refined at the ab initio level. A number of new low energy structures have thus been identified. The most stable structures of SO4(2-)(H2O)12 have the sulfate on the surface of the water cluster, while it may be slightly more burried in SO4(2-)(H2O)13, however still with an incomplete first hydration shell. Differences in the infrared spectra arise in part from mixing of sulfate stretching and water librational modes in the 900-1100 cm(-1) region, leading to some sensitivity of the IR spectrum to the structure. Second shell water molecules however do not generate signatures that are specific enough to relate spectra to structures straightforwardly, at least in this frequency range. Thus the emergence of a new band at 970 cm(-1) in the SO4(2-)(H2O)13 spectrum cannot be taken as a clue as to the number of water molecules which is necessary for a cluster to close the first hydration shell of sulfate. This number is at least 14 and possibly larger. However the density of low energy isomers is large enough that individual structures may loose meaning at all but the lowest temperatures. PMID- 26102591 TI - Axonal autophagosomes use the ride-on service for retrograde transport toward the soma. AB - Degradation of autophagic vacuoles (AVs) via lysosomes is an important homeostatic process in cells. Neurons are highly polarized cells with long axons, thus facing special challenges to transport AVs generated at distal processes toward the soma where mature acidic lysosomes are relatively enriched. We recently revealed a new motor-adaptor sharing mechanism driving autophagosome transport to the soma. Late endosome (LE)-loaded dynein-SNAPIN motor-adaptor complexes mediate the retrograde transport of autophagosomes upon their fusion with LEs in distal axons. This motor-adaptor sharing mechanism enables neurons to maintain effective autophagic clearance in the soma, thus reducing autophagic stress in axons. Therefore, our study reveals a new cellular mechanism underlying the removal of distal AVs engulfing aggregated misfolded proteins and dysfunctional organelles associated with several major neurodegenerative diseases. PMID- 26102592 TI - Evolution and Initial Experience of a Statewide Care Transitions Quality Improvement Collaborative: Preventing Avoidable Readmissions Together. AB - Increasing scrutiny of hospital readmission rates has spurred a wide variety of quality improvement initiatives. The Preventing Avoidable Readmissions Together (PART) initiative is a statewide quality improvement learning collaborative organized by stakeholder organizations in South Carolina. This descriptive report focused on initial interventions with hospitals. Eligible participants included all acute care hospitals plus home health organizations, nursing facilities, hospices, and other health care organizations. Measures were degree of statewide participation, curricular engagement, adoption of evidence-based improvement strategies, and readmission rate changes. Fifty-nine of 64 (92%) acute care hospitals and 9 of 10 (90%) hospital systems participated in collaborative events. Curricular engagement included: webinars and coaching calls (49/59, 83%), statewide in-person meetings (35/59, 59%), regional in-person meetings (44/59, 75%), and individualized consultations (46/59, 78%). Among 34 (58%) participating hospitals completing a survey at the completion of Year 1, respondents indicated complete implementation of multidisciplinary rounding (58%), post-discharge telephone calls (58%), and teach-back (32%), and implementation in process of high-quality transition records (52%), improved discharge summaries (45%), and timely follow-up appointments (39%). A higher proportion of hospitals had significant decreases (>=10% relative change) in all-cause readmission rates for acute myocardial infarction (55.6% vs. 30.4%, P=0.01), heart failure (54.2% vs. 31.7%, P=0.09), and chronic obstructive pulmonary disease (41.7% vs. 33.3%, P=0.83) between 2011-2013 compared to earlier (2009-2011) trends. Focus on reducing readmissions is driving numerous, sometimes competing, quality improvement initiatives. PART successfully engaged the majority of acute care facilities in one state to harmonize and accelerate adoption of evidence-based care transitions strategies. PMID- 26102593 TI - Size- and shape-dependent peroxidase-like catalytic activity of MnFe2O4 Nanoparticles and their applications in highly efficient colorimetric detection of target cancer cells. AB - The catalytic activity of nanocrystal catalysts depends strongly on their chemical composition, size, and shape. Herein, we report four different sizes and shapes of MnFe2O4 nanoparticles (NPs) prepared by a hydrothermal procedure. In addition, the size- and shape-dependent peroxidase-like activity of these NPs was first explored using 3,3',5,5'-tetramethyl-benzidine and H2O2 as peroxidase substrates. The results showed that the peroxidase-like activities of the MnFe2O4 NPs were size- and shape-dependent and followed the order of 4 nm (spherical) > 18 nm (plate-like) > 27 nm (near-cubic) > 16 nm (spherical); this order was closely related to their surface-to-volume ratio and atom arrangements. Such an investigation is of great significance for peroxidase nanomimetics with enhanced activity and utilization. Furthermore, folic acid (FA)-conjugated MnFe2O4 NPs allow the detection of folate receptor-rich cancer cells. Such investigation can be widely utilized for the identification of important target molecules. PMID- 26102595 TI - Thin Layer Chromatography-Autography-High Resolution Mass Spectrometry Analysis: Accelerating the Identification of Acetylcholinesterase Inhibitors. AB - INTRODUCTION: The prevailing treatment for Alzheimer's disease is the use of acetylcholinesterase (AChE) inhibitors. Natural extracts are the principal source of AChE's inhibitors. However, their chemical complexity demands for simple, selective and rapid assays. OBJECTIVE: To develop a strategy for identification of AChE inhibitors present in mixtures employing high resolution mass spectrometry (HRMS) and thin layer chromatography (TLC)-biological staining. METHODOLOGY: The strategy uses an autographic assay based on the alpha-naphthyl acetate - fast blue B system for the detection of AChE activity. The immobilisation of AChE in agar allowed the extraction of the compounds for analysis by HRMS. Three TLC experiments employing different solvent systems were used in parallel and the mass spectra of the compounds extracted from the inhibition halos, were compared. The analysis was performed under MatLab environment. RESULTS: The strategy was used to detect the presence of physostigmine in an extract of Brassica rapa L. spiked with the inhibitor. Similarly, caffeine was straightforwardly spotted as responsible for the inhibitory properties of an extract of Ilex paraguariensis Saint-Hilaire. Comparison of the HRMS profiles lead to the facile identification of the [M+H](+) and [M+Na](+) of the compounds responsible for the inhibition. CONCLUSION: The proposed methodology, coupling TLC-AChE autography-HRMS, illustrates the feasibility of assigning molecular formulas of active compounds present in complex mixtures directly from autography. The new AChE agar-immobilised assay presented a more homogenous colour and a better definition than direct spraying methods, reducing the cost of the assay and improving its sensitivity. PMID- 26102594 TI - Regulation of the Apelinergic System and Its Potential in Cardiovascular Disease: Peptides and Small Molecules as Tools for Discovery. AB - Apelin peptides and the apelin receptor represent a relatively new therapeutic axis for the potential treatment of cardiovascular disease. Several reports suggest apelin receptor activation with apelin peptides results in cardioprotection as noted through positive ionotropy, angiogenesis, reduction of mean arterial blood pressure, and apoptosis. Considering the potential therapeutic benefit attainable through modulation of the apelinergic system, research is expanding to develop novel therapies that limit the inherent rapid degradation of endogenous apelin peptides and produce metabolically stable small molecule agonists and antagonists to more rigorously interrogate the apelin receptor system. This review details the structure-activity relationships for chemically modified apelin peptides and recent disclosures of small molecule agonists and antagonists and summarizes the peer reviewed and patented literature. Development of metabolically stable ligands of apelin receptor and their effects in various models over the coming years will hopefully lead to establishment of this receptor as a validated target for cardiovascular indications. PMID- 26102596 TI - Back in Black. AB - In this issue of Developmental Cell, Iyengar and colleagues (2015) employ live imaging of melanocyte regeneration in adult zebrafish to define a bias in progenitor cell fates that enables both rapid pigment cell renewal and maintenance of regenerative capacity. PMID- 26102597 TI - Nuclear beta-Catenin under Control. AB - During Wnt stimulation, beta-catenin accumulates in the nucleus, where it regulates gene transcription. In this issue of Developmental Cell, Lu et al. (2015) report a mechanism that specifically targets this nuclear pool for degradation, using lysine demethylation as ubiquitination signal. PMID- 26102598 TI - Bending or Building: Multifaceted Functions of Amphipathic Helices in Basket Nucleoporins. AB - Recently reporting in Developmental Cell, Meszaros et al. (2015) and Vollmer et al. (2015) extend the inventory of membrane-binding and -bending nuclear pore proteins to peripheral nucleoporins localized at the nuclear basket. PMID- 26102599 TI - Translating Membrane Tension into Cytoskeletal Action by FBP17. AB - A recent article by Tsujita et al. (2015) in Nature Cell Biology provides insight into how cells sense and translate plasma membrane tension toward polarized actin polymerization and migration. They identify FBP17 as a multifunctional adaptor that senses membrane curvature and delivers feedback to actin dynamics and directed cell migration. PMID- 26102600 TI - Enantioselective Amine-Catalyzed [4 + 2] Annulations of Allene Ketones and 2,3 Dioxopyrrolidine Derivatives: Synthesis of 4H-Pyran Derivatives. AB - An efficient cinchona alkaloid-derived amine catalyzed asymmetric [4 + 2] cycloaddition is successfully developed. 4H-Pyran fused pyrrolin-2-one products are readily obtained in moderate to high yields with good enantioselectivites by employing allene ketones and 2,3-dioxopyrrolidine derivatives as substrates. PMID- 26102601 TI - New Clasp Assembly for Distal Extension Removable Partial Dentures: The Reverse RPA Clasp. AB - Several clasp types are used in distal extension removable partial dentures. In some cases the terminal abutments have only distal retentive undercuts that can be occupied by bar clasps; however, bar clasps may be contraindicated with no suitable alternative. This article presents a reasonable solution by introducing a new clasp design as a modification to the well-known RPA clasp. The design includes a mesial rest, proximal plate, and buccal retentive arm arising from the rest and extending to reach the distal retentive undercut. PMID- 26102602 TI - ThPt2: A New Representative of Close Packed Tetragonal Structures. AB - ThPt2 crystallizes with unique type of structure (space group I4/mmm, a = 4.1565(1) A, c = 14.3663(7) A, Pearson symbol tI12), which belongs to the group of the close packed tetragonal structures. An analysis of the chemical bonding by the electron localizability approach reveals the formation of two-dimensional layered platinum anionic substructures interlinked by strongly polar bonds to Th. Measurements of magnetic susceptibility, electrical resistivity, and specific heat show ThPt2 to be diamagnetic with metallic type of electrical conductivity in good agreement with the calculated electronic structure (N(EF) = 0.9 states eV(-1) f.u.(-1)). PMID- 26102603 TI - On-Chip Generation, Routing, and Detection of Resonance Fluorescence. AB - Quantum optical circuits can be used to generate, manipulate, and exploit nonclassical states of light to push semiconductor based photonic information technologies to the quantum limit. Here, we report the on-chip generation of quantum light from individual, resonantly excited self-assembled InGaAs quantum dots, efficient routing over length scales >=1 mm via GaAs ridge waveguides, and in situ detection using evanescently coupled integrated NbN superconducting single photon detectors fabricated on the same chip. By temporally filtering the time-resolved luminescence signal stemming from single quantum dots we use the quantum optical circuit to perform time-resolved excitation spectroscopy on single dots and demonstrate resonance fluorescence with a line-width of 10 +/- 1 MUeV; key elements needed for the use of single photons in prototypical quantum photonic circuits. PMID- 26102604 TI - Nanostar Clustering Improves the Sensitivity of Plasmonic Assays. AB - Star-shaped Au nanoparticles (Au nanostars, AuNS) have been developed to improve the plasmonic sensitivity, but their application has largely been limited to single-particle probes. We herein describe a AuNS clustering assay based on nanoscale self-assembly of multiple AuNS and which further increases detection sensitivity. We show that each cluster contains multiple nanogaps to concentrate electric fields, thereby amplifying the signal via plasmon coupling. Numerical simulation indicated that AuNS clusters assume up to 460-fold higher field density than Au nanosphere clusters of similar mass. The results were validated in model assays of protein biomarker detection. The AuNS clustering assay showed higher sensitivity than Au nanosphere. Minimizing the size of affinity ligand was found important to tightly confine electric fields and improve the sensitivity. The resulting assay is simple and fast and can be readily applied to point-of care molecular detection schemes. PMID- 26102605 TI - Scanning and transmission electron microscopy and X-ray analysisof leaf salt glands of Limoniastrum guyonianum Boiss. under NaCl salinity. AB - Leaf salt glands of Limoniastrum guyonianum were examined by scanning and transmission electron microscopes and energy dispersive X-ray analysis (EDAX) system, after growing for three months on sandy soil with or without 300 mM NaCl. Results showed that salt glands were irregularly scattered on both leaf sides and sunk under the epidermal level. Salt excretion occurred in both conditions and is mainly composed of calcium and magnesium in control plants, and essentially sodium and chloride in plants subjected to salt treatment. A salt gland is comprised of collecting, accumulating, and central compartments, and is made up of total thirty-two cells. The collecting cells were characterized by large central vacuoles. Accumulating cells contain numerous, large, and unshaped vacuoles and rudimentary chloroplasts. The central compartment was comprised of four basal cells and each one is surmounted by an apical cell. The basal cells are granulated, containing large nucleus, numerous mitochondria, endoplasmic reticulum, ribosomes, polyribosomes, and small vacuoles or vesicles. Equally, the apical cells are rich in organelles. Application of 300 mM NaCl to the culture medium increased vacuoles number and size, and organelles density especially the mitochondria which suggests energy requirement for ions transport. The reduction in size and number of vacuoles toward the interior of salt glands of treated plants and the fusion of the smallest ones with the plasma membrane substantiate the implication of such vacuoles in salt excretion process. The current study which is the first report on L. guyonianum salt gland has provided an in-depth understanding on structure-function relationship in the multicellular salt glands. PMID- 26102606 TI - "Superchiral" Spectroscopy: Detection of Protein Higher Order Hierarchical Structure with Chiral Plasmonic Nanostructures. AB - Optical spectroscopic methods do not routinely provide information on higher order hierarchical structure (tertiary/quaternary) of biological macromolecules and assemblies. This necessitates the use of time-consuming and material intensive techniques, such as protein crystallography, NMR, and electron microscopy. Here we demonstrate a spectroscopic phenomenon, superchiral polarimetry, which can rapidly characterize ligand-induced changes in protein higher order (tertiary/quaternary) structure at the picogram level, which is undetectable using conventional CD spectroscopy. This is achieved by utilizing the enhanced sensitivity of superchiral evanescent fields to mesoscale chiral structure. PMID- 26102607 TI - Flexible nanoscale thread of MnSn(OH)6 crystallite with liquid-like behavior and its application in nanocomposites. AB - We reported a solvent-free nanofluid based on MnSn(OH)6 crystallite with thread like morphology through sulfuric-acid-terminated organosilanes as corona and polyether amine as canopy. The resultant is characterized by various analytical techniques and shows excellent solubility, good dispersity, improved processability and fluidity at room temperature in the absence of any solvents, which offer great potential in applications such as plasticizers with effects of toughening and reinforcement in nanocomposites. In addition, as a kind of plasticizer, it can also improve the Tg of its nanocomposites. These advantages of the flexible nanoscale thread of MnSn(OH)6 crystallite make it can be easily applied on the fabrication of high performance of nanocomposites. PMID- 26102609 TI - Sarcoidosis, complete heart block, and warm autoimmune hemolytic anemia in a young woman. AB - Sarcoidosis is a multisystem granulomatous disease that affects 10-40 people per 100,000 in the United States and Europe, with an increased prevalence among blacks compared with whites. The clinical presentation of sarcoidosis is variable. Sarcoidosis frequently involves the lungs and can have numerous extrapulmonary manifestations including skin, joint, cardiac, and eye lesions. We present a rare case of sarcoidosis with concurrent third-degree heart block and warm autoimmune hemolytic anemia and discuss possible mechanisms behind this presentation. PMID- 26102608 TI - Distant skin metastases as primary presentation of gastric cancer. AB - Distant gastric metastasis to the skin is uncommonly a presenting symptom, although nonspecific paraneoplastic syndromes with dermatologic manifestation including diffuse seborrheic keratoses (Leser-Trelat sign), tripe palms, and acanthosis nigricans have been described in the literature. We report here the case of a 49-year-old woman with gastric adenocarcinoma who presented with cutaneous metastasis as an initial symptom. In our case, metastatic skin lesions responded significantly to EOX chemotherapy (epirubicin+oxaliplatin+capecitabine) despite progression of systemic disease. In similar presentations, a high index of clinical suspicion and skin biopsy are important. PMID- 26102610 TI - Association Between Organ Procurement Organization Social Network Centrality and Kidney Discard and Transplant Outcomes. AB - BACKGROUND: Given growth in kidney transplant waitlists and discard rates, donor kidney acceptance is an important problem. We used network analysis to examine whether organ procurement organization (OPO) network centrality affects discard and outcomes. METHODS: We identified 106,160 deceased donor kidneys recovered for transplant from 2000 to 2010 in Scientific Registry of Transplant Recipients. We constructed the transplant network by year with each OPO representing a node and each kidney-sharing relationship between OPOs representing a directed tie between nodes. Primary exposures were the number of different OPOs to which an OPO has given a kidney or from which an OPO has received a kidney in year preceding procurement year. Primary outcomes were discard, cold-ischemia time, delayed graft function, and 1-year graft loss. We used multivariable regression, restricting analysis to the 50% of OPOs with highest discard and stratifying remaining OPOs by kidney volume. Models controlled for kidney donor risk index, waitlist time, and kidney pumping. RESULTS: An increase in one additional OPO to which a kidney was given by a procuring OPO in a year was associated with 1.4% lower likelihood of discard for a given kidney (odds ratio, 0.986; 95% confidence interval, 0.974-0.998) among OPOs procuring high kidney volume, but 2% higher likelihood of discard (odds ratio, 1.021; 95% confidence interval, 1.006-1.037) among OPOs procuring low kidney volume, with mixed associations with recipient outcomes. CONCLUSIONS: Our study highlights the value of network analysis in revealing how broader kidney sharing is associated with levels of organ acceptance. We conclude interventions to promote broader inter-OPO sharing could be developed to reduce discard for a subset of OPOs. PMID- 26102611 TI - Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft. AB - BACKGROUND: Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia. METHODS: Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags. RESULTS: The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA 1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis. CONCLUSIONS: Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment. PMID- 26102612 TI - Cancer-Specific and All-Cause Mortality in Kidney Transplant Recipients With and Without Previous Cancer. AB - BACKGROUND: For dialysis patients with a cancer history, a period of surveillance is generally recommended before listing for transplantation. However, the outcomes of patients with cancer recurrence and/or a second primary cancer after transplantation are unknown. AIM: To determine the prognosis of kidney transplant recipients who developed cancer after transplantation and whether this varied with cancer types (first cancer, recurrence, second primary cancer). METHODS: Using data from the Australian and New Zealand Dialysis and Transplant Registry, we compared the cancer-specific and all-cause mortality among recipients with different cancer types using adjusted Cox proportional hazard models. RESULTS: Of the 21,415 recipients transplanted between 1965 and 2012, 3% (651 of 21,415) had a previous cancer history. A total of 2840 (13%) recipients developed cancer after the first transplant, of whom 2760 (97.2%) developed a first cancer, 23 (0.8%) experienced cancer recurrence, and 57 (2%) developed a second primary cancer. There were no significant differences in the risks of cancer-specific and all-cause mortality between recipients who developed their first cancer after transplant, those with cancer recurrence (adjusted hazard ratios [aHRs], 0.79; 95% confidence interval [95% CI], 0.38-1.67; P = 0.54 and aHRs, 0.86; 95% CI, 0.45-1.66; P = 0.66, respectively) and recipients who developed a second primary cancer after transplantation (aHRs, 1.01; 95%CI, 0.63-1.62; P = 0.95 and aHRs, 1.16; 95% CI, 0.79-1.69; P = 0.45, respectively). CONCLUSION: Among patients with a previous history of malignancy, recurrent and second primary cancers are infrequent after renal transplantation. A history of previous malignancy does not have an additive effect on the cancer-specific and overall survival of kidney transplant recipients who develop cancer. PMID- 26102613 TI - Adipose- and Bone Marrow-Derived Mesenchymal Stem Cells Prolong Graft Survival in Vascularized Composite Allotransplantation. AB - BACKGROUND: Strategies aiming at minimization or elimination of systemic immunosuppression are key immediate goals for clinical expansion of vascularized composite allotransplantation (VCA). We compared the in vitro and in vivo immunomodulatory efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) and bone marrow (BM)-derived MSCs in a rat VCA model. METHODS: Both cell types were tested in vitro for suppressor function using mixed lymphocyte reactivity assays. AD-MSCs or BM-MSCs were administered intravenously (1 * 10 or 5 * 10 cells/animal) to Lewis rat recipients of mismatched Brown Norway hindlimb transplants. Short course tacrolimus (FK-506) monotherapy was withdrawn at postoperative day 21. In vivo regulatory T-cell induction, peripheral blood chimerism, and microchimerism in lymphatic organs were analyzed. RESULTS: AD-MSCs and BM-MSCs exhibited strong dose-dependent suppressor function in vitro, which was significantly more pronounced for AD cells. In vivo, all animals revealed peripheral multi-lineage chimerism at four weeks (P < 0.01) independent of cell type and dosage. Regulatory T-cell levels were increased with both cell types, the most in AD-MSC groups. These immunomodulatory effects were only transient. MSC treatment resulted in long-term (>120 day) allograft survival in 47% of the animals, which correlated with durable microchimerism in BM and spleen. CONCLUSIONS: AD-MSCs and BM-MSCs exert immunomodulatory effects that prolong survival of immunogenic skin-bearing VCA grafts with short course (21 day) tacrolimus induction therapy. The in vivo findings in terms of allograft survival did not reflect superior immunomodulatory characteristics of AD-MSCs found in vitro. PMID- 26102614 TI - Diffuse Myocardial Fibrosis in Children After Heart Transplantations: A Magnetic Resonance T1 Mapping Study. AB - BACKGROUND: It is unclear whether the myocardium undergoes accelerated fibrotic remodeling in children after heart transplantation (HTx). METHODS: In this prospective study, cardiac magnetic resonance (CMR) studies in 17 patients 1.3 years (median, range 0.03-12.6 years) after HTx (mean age, 9.8 +/- 6.2 years; 8 girls) were compared to CMR studies in 9 healthy controls (mean age, 12.4 +/- 2.4 years; 4 girls). T1 measurements were performed at a midventricular short axis slice before (ie, native T1 times) and after the application of 0.2 mmol/kg gadopentetate dimeglumine in the interventricular septum, left ventricular (LV) free wall and encompassing the entire LV myocardium. The tissue-blood partition coefficient (TBPC), reflecting the degree of diffuse myocardial fibrosis, was calculated as a function of the ratio of T1 change of myocardium compared to blood. Native T1 times and TBPC were correlated with echocardiographic parameters of diastolic function. RESULTS: Native T1 times were significantly higher in HTx patients compared to controls in all regions assessed (LV free wall 973 +/- 42 vs 923 +/- 12 ms; P < 0.005; interventricular septum 1003 +/- 31 vs 974 +/- 21 ms, P < 0.05; entire LV myocardium 987 +/- 33 vs 951 +/- 16 ms; P < 0.005) and correlated with LV E/e' as an echocardiographic marker of diastolic dysfunction (r = 0.54, P < 0.05). The TBPC was elevated in the LV free wall (0.45 +/- 0.06 vs 0.40 +/- 0.03, P < 0.005) and the entire LV myocardium (0.47 +/- 0.06 vs 0.43 +/- 0.03, P < 0.05). CONCLUSIONS: Evidence of diffuse myocardial fibrosis and is already present in children after HTx. It appears to be associated with diastolic dysfunction. PMID- 26102616 TI - Influence of Current and Previous Smoking on Cancer and Mortality After Kidney Transplantation. AB - BACKGROUND: Evidence is limited regarding the effect of stopping smoking before kidney transplantation. METHODS: Collaborative Transplant Study data from 46 548 recipients of first kidney transplants (1995-2012) were analyzed to 10 years after transplantation. RESULTS: Compared with patients who had never smoked (n = 31,462), patients who stopped smoking before transplantation (n = 10,291) only had a modestly increased risk of all-cause graft failure (hazard ratio [HR], 1.1; 95% confidence interval [95% CI], 1.0-1.1; P < 0.001) or death (HR,1.1; 95% CI, 1.0-1.2; P < 0.001) and a similar risk of death-censored graft failure (HR,1.0, 95% CI, 1.0-1.1; P = 0.19), but a 40% increase in death from malignancy (HR, 1.4; 95% CI, 1.2-1.7; P < 0.001). The risk of events was generally markedly higher in patients who continued to smoke (n = 4795) versus those who had stopped. For tumors of the lip, oral cavity and pharynx, digestive organs, respiratory tract, female genitalia and urinary tract, HR values increased significantly from never smoked to former smokers to current smokers. The risk of respiratory tumors or cervical cancer was approximately halved when smoking was stopped versus continued. CONCLUSIONS: This large series provides clear evidence that patients who stop smoking before transplantation experience substantial benefits, including a substantial reduction in certain types of malignancy. PMID- 26102615 TI - The Evolving Roles of Memory Immune Cells in Transplantation. AB - Memory cells are the products of immune responses but also exert significant impact on subsequent immunity and immune tolerance, thus placing them in a unique position in transplant research. Memory cells are heterogeneous, including not only memory T cells but also memory B cells and innate memory cells. Memory cells are a critical component of protective immunity against invading pathogens, especially in immunosuppressed patients, but they also mediate graft loss and tolerance resistance. Recent studies suggest that some memory cells unexpectedly act as regulatory cells, promoting rather than hindering transplant survival. This functional diversity makes therapeutic targeting of memory cells a challenging task in transplantation. In this article, we highlight recent advances in our understanding of memory cells, focusing on diversity of memory cells and mechanisms involved in their induction and functions. We also provide a broad overview on the challenges and opportunities in targeting memory cells in the induction of transplant tolerance. PMID- 26102617 TI - Single Versus Double Ureteral Stent Placement After Laser Endoureterotomy for the Management of Benign Ureteral Strictures: A Randomized Clinical Trial. AB - BACKGROUND AND PURPOSE: Endoureterotomy is a viable option for treating patients with benign ureteral stricture. We compared the efficacy and safety of double versus single ureteral stent placement after laser endoureterotomy. PATIENTS AND METHODS: This study included 55 patients with benign ureteral strictures; all patients underwent retrograde laser endoureterotomy. Patients were randomized either to single or double ureteral stents. Single stents were placed in 27 ureters while double stents were placed in 28 ureters. The stent diameter used was 7 F, and stents were indwelling for 8 weeks. Imaging was performed 1 month after stent removal and repeated regularly every 3 months. Clinical characteristics, operative results, and functional outcomes were compared for strictures managed in both groups. Success was evaluated both subjectively and objectively. RESULTS: Fifty-five patients with a mean age of 46 (16-75) years had benign ureteral strictures; the mean stricture length was 1.92 (1-3) cm. The mean follow-up was 25.7 (9-42) months. The overall success rate was 67.3% (37 patients) with no radiologic evidence of obstruction, 6 (10.9%) patients showed symptomatic improvement while 12 (21.8%) patients underwent surgical reconstruction. Success was significantly higher for ureteral strictures (>1.5 cm) managed with double stent placement (82.4%), compared with single stent placement (38.9%) with a P value of 0.009. CONCLUSIONS: Double stent placement of the ureter after laser endoureterotomy achieved a higher success rate compared with single stent placement in cases of benign ureteral strictures. Although ureteral strictures (<=1.5 cm) achieved better outcome after laser endoureterotomy, strictures (>1.5 cm) favored better with double stent versus single stent placement. PMID- 26102618 TI - Lanthanide Label Array Method for Identification and Adulteration of Honey and Cacao. AB - A generic, cost-effective, and simple method has been developed to fingerprint liquids to differentiate food brands and ingredients. The method is based on a label array using nonspecific long lifetime unstable luminescent lanthanide labels. The interaction between the liquid sample and the label is typically detrimental to the luminescence of the unstable chelate leading to a sample dependent luminescence-intensity array. The label-array method is a unique approach as the array of unstable chelates is extremely inexpensive to produce and possesses high sensitivity due to spectral as well as unstable structural properties of the lanthanide label. The global method has been applied to distinguish commercial honey and cacao brands to demonstrate its feasibility as honey and cacao are among the most adulterated food products. PMID- 26102619 TI - Microvascular Decompression for Hemifacial Spasm Associated with Bilateral Vertebral Artery Compression. AB - BACKGROUND: Microvascular decompression (MVD) has been established as an effective treatment for hemifacial spasm (HFS). However, replacement of bilateral vertebral arteries (VAs) from the root exit zone (REZ) is difficult and requires special techniques. Reports of HFS cases associated with bilateral VA compression are quite rare. This study investigated the characteristics of these arteries and methods for safe and definite decompression. METHODS: Among 131 patients who underwent MVD for HFS, 33 patients (25.2%) had associated VA compression; 4 patients (3.1%) had bilateral VA compression. Sufficient dissection of the arachnoid membrane allowed good visualization around the REZ, and the dolichoectatic VAs were successfully transposed and fixed to the nearby dura mater in 3 cases. RESULTS: The offending arteries were bilateral VAs plus the posterior inferior cerebellar artery in 2 cases, bilateral VAs plus the anterior inferior cerebellar artery-posterior inferior cerebellar artery in 1 case, and bilateral VAs in 1 case. The contralateral VA of the symptomatic side was more ectatic, dolichoectatic, and tougher than the ipsilateral VA in 3 patients and was difficult to remove. In 3 patients treated with the transposition method, complete resolution of spasm was experienced immediately after surgery. Minimal residual spasm occurred in 1 patient treated with the interposition method. Transient facial palsy developed in 1 case, and moderate hearing loss developed in another case. CONCLUSIONS: HFS caused by bilateral VA compression is rare; however, replacement of VAs from the REZ is not easy because such VAs are invariably dolichoectatic and tough. Treatment of such cases requires special techniques. PMID- 26102620 TI - Ethmoidal Arteries and Vascularized Anterior Skull Base Lesions. PMID- 26102621 TI - Putting quality at the heart of HIV programs. PMID- 26102622 TI - The leadership of communities in HIV service delivery. AB - HIV treatment and prevention strategies are life-long endeavours, requiring not only comprehensive, high-quality, consistent and equitable medical services but also appropriate political and cultural milieus to be effective. Communities directly affected by HIV offer a unique expertise and understanding in developing services to meet the needs of people seeking out and utilizing HIV treatment, prevention and support services. Through their organizations and networks, and through partnerships with health systems, these communities provide leadership, services and advocacy to ensure the delivery of high-quality, comprehensive services to meet the needs of diverse populations affected by HIV. This article describes integrated approaches to service delivery in which affected communities play a key role in the development and implementation of HIV programmes. Further scale-up of these approaches to care can improve overall quality, reduce stigma and discrimination, increase demand for services and improve retention in care. PMID- 26102623 TI - Monitoring quality at scale: implementing quality assurance in a diverse, multicountry HIV program. AB - The centrality of quality as a strategy to achieve impact within the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) has been widely recognized. However, monitoring program quality remains a challenge for many HIV programs, particularly those in resource-limited settings, where human resource constraints and weaker health systems can pose formidable barriers to data collection and interpretation. We describe the practicalities of monitoring quality at scale within a very large multicountry PEPFAR-funded program, based largely at health facilities. The key elements include the following: supporting national programs and strategies; developing a conceptual framework and programmatic model to define quality and guide the provision of high-quality services; attending to program context, as well as program outcomes; leveraging existing and routinely collected data whenever possible; developing additional indicators for judicious use in targeted, in-depth assessments; providing hands-on support for data collection and use at the facility, sub-national, and national levels; utilizing web-based databases for data entry, analysis, and dissemination; and multidisciplinary support from a large team of clinical and strategic information advisors. PMID- 26102624 TI - The role of quality improvement in achieving effective large-scale prevention of mother-to-child transmission of HIV in South Africa. AB - INTRODUCTION: After a late start and poor initial performance, the South African Prevention of Mother-To-Child Transmission (PMTCT) programme achieved rapid progress in achieving effective national-scale implementation of a complex intervention across a large number of different geographic and socioeconomic contexts. This study shows how quality-improvement methods played a significant part in PMTCT improvements. METHODS: The South African rollout of the PMTCT programme underwent significant evolution, from a largely ineffective, context insensitive, top-down cascaded training approach to a sophisticated bottom-up health systems' intervention that used modern adaptive designs. Several demonstration projects used quality-improvement methods to improve the performance of the PMTCT programme. These results prompted a national redesign of key elements of the PMTCT programme which were rapidly scaled up across the country using a unified, simplified data-driven approach. RESULTS: The scale up of the quality-improvement approach contributed to a dramatic fall in the nationally reported transmission rate for mother to child transmission of HIV. By 2012, measured infection rate of HIV-exposed infants at around 6 weeks after birth was 2.6%, close to the reported transmission rates under clinical trial conditions. CONCLUSION: Quality-improvement methods can be used to improve reliability of complex treatment programmes delivered at primary-care level. Rapid scale up and effective population coverage can be accomplished through a sequence of demonstration, testing and rapid spread of locally tested implementation strategies supported by real-time feedback of a simplified indicator dataset and multilevel leadership support. PMID- 26102625 TI - A standards-based approach to quality improvement for HIV services at Zambia Defence Force facilities: results and lessons learned. AB - INTRODUCTION: The Zambia Defence Force adopted the Standards-Based Management and Recognition approach to improve the quality of the HIV-related services at its health facilities. This quality improvement intervention relies on comprehensive, detailed assessment tools to communicate and verify adherence to national standards of care, and to test and implement changes to improve performance. METHODS: A quasi-experimental evaluation of the intervention was conducted at eight Zambia Defence Force primary health facilities (four facilities implemented the intervention and four did not). Data from three previous analyses are combined to assess the effect of Standards-Based Management and Recognition on three domains: facility readiness to provide services; observed provider performance during antiretroviral therapy (ART) and antenatal care consultations; and provider perceptions of the work environment. RESULTS: Facility readiness scores for ART improved on four of the eight standards at intervention sites, and one standard at comparison sites. Facility readiness scores for prevention of mother-to-child transmission (PMTCT) of HIV increased by 15 percentage points at intervention sites and 7 percentage points at comparison sites. Provider performance improved significantly at intervention sites for both ART services (from 58 to 84%; P < 0.01) and PMTCT services (from 58 to 73%; P = 0.003); there was no significant change at comparison sites. Providers' perceptions of the work environment generally improved at intervention sites and declined at comparison sites; differences in trends between study groups were significant for eight items. CONCLUSIONS: A standards-based approach to quality improvement proved effective in supporting healthcare managers and providers to deliver ART and PMTCT services in accordance with evidence-based standards in a health system suffering from staff shortages. PMID- 26102626 TI - Using adapted quality-improvement approaches to strengthen community-based health systems and improve care in high HIV-burden sub-Saharan African countries. AB - INTRODUCTION: Achieving long-term retention in HIV care is an important challenge for HIV management and achieving elimination of mother-to-child transmission. Sustainable, affordable strategies are required to achieve this, including strengthening of community-based interventions. Deployment of community-based health workers (CHWs) can improve health outcomes but there is a need to identify systems to support and maintain high-quality performance. Quality-improvement strategies have been successfully implemented to improve quality and coverage of healthcare in facilities and could provide a framework to support community-based interventions. METHODS: Four community-based quality-improvement projects from South Africa, Malawi and Mozambique are described. Community-based improvement teams linked to the facility-based health system participated in learning networks (modified Breakthrough Series), and used quality-improvement methods to improve process performance. Teams were guided by trained quality mentors who used local data to help nurses and CHWs identify gaps in service provision and test solutions. Learning network participants gathered at intervals to share progress and identify successful strategies for improvement. RESULTS: CHWs demonstrated understanding of quality-improvement concepts, tools and methods, and implemented quality-improvement projects successfully. Challenges of using quality-improvement approaches in community settings included adapting processes, particularly data reporting, to the education level and first language of community members. CONCLUSION: Quality-improvement techniques can be implemented by CHWs to improve outcomes in community settings but these approaches require adaptation and additional mentoring support to be successful. More research is required to establish the effectiveness of this approach on processes and outcomes of care. PMID- 26102627 TI - Going beyond the vertical: leveraging a national HIV quality improvement programme to address other health priorities in Haiti. AB - Although the central role of quality to achieve targeted population health goals is widely recognized, how to spread the capacity to measure and improve quality across programmes has not been widely studied. We describe the successful leveraging of expertise and framework of a national HIV quality improvement programme to spread capacity and improve quality across a network of clinics in HIV and other targeted areas of healthcare delivery in rural Haiti.The work was led by Zamni LaSante, a Haitian nongovernment organization and its sister organization, Partners In Health working in partnership with the Haitian Ministry of Health in the Plateau Central and Lower Artibonite regions in 12 public sector facilities.Data included routinely collected organizational assessments of facility quality improvement capacity, national HIV performance measures and Zamni LaSante programme records.We found that facility quality improvement capacity increased with spread from HIV to other areas of inpatient and outpatient care, including tuberculosis (TB), maternal health and inpatient services in all 12 supported healthcare facilities. A significant increase in the quality of HIV care was also seen in most areas, including CD4 monitoring, TB screening, HIV treatment (all P < 0.01) and nutritional assessment and prevention of mother-to-child transmission (both P < .05), with an increase in average facility performance from 39 to 72% (P < .01).In conclusion, using a diagonal approach to leverage a national vertical programme for wider benefit resulted in accelerated change in professional culture and increased capacity to spread quality improvement activities across facilities and areas of healthcare delivery. This led to improvement within and beyond HIV care and contributed to the goal of quality of care for all. PMID- 26102628 TI - Creating a national culture of quality: the Tanzania experience. AB - Although quality improvement has been a priority for Tanzania's health sector since the 1970s, few effective quality improvement initiatives were implemented, due to limited expertise, political commitment and resources. More recently, as the HIV epidemic gained momentum within the country, an influx of funding and of international organizations with quality improvement expertise accelerated the implementation of quality improvement projects, as well as efforts to institutionalize quality improvement at the national level. The support of US President's Emergency Plan for AIDS Relief (PEPFAR) and other donors, and the increasing numbers of HIV-implementing partners focused on quality management, and quality improvement strategies catalysed the development of HIV-specific quality improvement initiatives first, and then of national quality improvement frameworks. The diversity of quality improvement approaches championed by various donors and partners also presented important challenges to harmonization and institutionalization of quality improvement programmes. PMID- 26102629 TI - A quality improvement approach to capacity building in low- and middle-income countries. AB - OBJECTIVES: To describe the HEALTHQUAL framework consisting of the following three components: performance measurement, quality improvement and the quality management program, representing an adaptive approach to building capacity in national quality management programs in low and middle-income countries. DESIGN: We present a case study from Namibia illustrating how this approach is adapted to country context. METHODS: HEALTHQUAL partners with Ministries of Health to build knowledge and expertise in modern improvement methods, including data collection, analysis and reporting, process analysis and the use of data to implement quality improvement projects that aim to improve systems and processes of care. Clinical performance measures are selected in each country by the Ministry of Health on the basis of national guidelines. Patient records are sampled using a standardized statistical table to achieve a minimum confidence interval of 90%, with a spread of +/-8% in participating facilities. Data are routinely reviewed to identify gaps in patient care, and aggregated to produce facility mean scores that are trended over time. A formal organizational assessment is conducted at facility and national levels to review the implementation progress. RESULTS: Aggregate mean rates of performance for 10 of 11 indicators of HIV care improved for adult HIV-positive patients between 2008 and 2013. CONCLUSIONS: Quality improvement is an approach to capacity building and health systems strengthening that offers adaptive methodology. Synergistic implementation of elements of a national quality program can lead to improvements in care, in parallel with systematic capacity development for measurement, improvement and quality management throughout the healthcare delivery system. PMID- 26102630 TI - Improving care for patients on antiretroviral therapy through a gap analysis framework. AB - OBJECTIVE: To improve quality of care through decreasing existing gaps in the areas of coverage, retention, and wellness of patients receiving HIV care and treatment. DESIGN: The antiretroviral therapy (ART) Framework utilizes improvement methods and the Chronic Care Model to address the coverage, retention, and wellness gaps in HIV care and treatment. This is a time-series study. SETTING: The ART Framework was applied in five health centers in Buikwe District, Uganda. PARTICIPANTS: Quality improvement teams, consisting of healthcare workers and expert patients, were established in each of the five healthcare facilities. INTERVENTION: The intervention period was October 2010 to September 2012. It consisted of quality improvement teams analyzing their facility and systems of care from the perspective of the Chronic Care Model to identify areas of improvement. They implemented the ART Framework, collected data and assessed outcomes, focused on self-management support for patients, to improve coverage, retention, and wellness gaps in HIV care and treatment. MAIN OUTCOME MEASURE(S): Coverage was defined as every patient who needs ART in the catchment area, receives it. Retention was defined as every patient who receives ART stays on ART, and wellness defined as having a positive clinical, immunological, and/or virological response to treatment without intolerable or unmanageable side-effects. RESULTS: Results from Buikwe show the gaps in coverage, retention, and wellness greatly decreased a gap in coverage of 44-19%, gap in retention of 49-24%, and gap in wellness of 53-14% during a 2-year intervention period. CONCLUSION: The ART Framework is an innovative and practical tool for HIV program managers to improve HIV care and treatment. PMID- 26102632 TI - Novel enzymatic synthesis of spacer-linked P(k) trisaccharide targeting for neutralization of Shiga toxin. AB - A novel alkyl spacer-conjugated derivative of P(k) trisaccharide (P(k)), one of the active receptors of Shiga toxins (Stxs; Stx1 and Stx2) produced by pathogenic Escherichia coli (STEC), was designed and synthesized by a combination of cellulase-mediated condensation from Trichoderma reesei and alpha1,4 galactosyltransferase (LgtC) from Neisseria gonorrhoeae. The specific activity of N. gonorrhoeae LgtC was 66U/mg, which was 13-fold higher than that from N. meningitidis expressed in E. coli. 5-trifluoroacetamidopentyl-beta-P(k) (TFAP P(k)) was synthesized (yield of 86%, based on the amount of TFAP-lactose added) and its binding to Stx1a-B and Stx2a-B was evaluated. The dissociation constants (KDs) of Stx1a-B and Stx2a-B to the spacer-linked P(k), immobilized on a CM5 sensor chip, were 6.8*10(-6) M (kon=4.1*10(1)M(-1)S(-1), koff=2.8*10(-4)S(-1)) and 2.2*10(-5)M (kon=3.9*10(2)M(-1)S(-1), koff=8.6*10(-3)S(-1)), respectively. This result suggests that the monovalent P(k)-derivative, conjugated to a pentylamino group, represents a promising Stx-neutralizing agent. This cellulase mediated condensation using cellulase and glycosyltransferase is a valuable tool for the synthesis of spacer-linked oligosaccharide. PMID- 26102631 TI - Characterization of recombinantly expressed dihydroxy-acid dehydratase from Sulfobus solfataricus-A key enzyme for the conversion of carbohydrates into chemicals. AB - Dihydroxyacid dehydratases (DHADs) are excellent biocatalysts for the defunctionalization of biomass. Here, we report on the recombinant production of DHAD from Sulfolobus solfataricus (SsDHAD) in E. coli and its characterization with special focus on activity toward non-natural substrates, thermo-stability, thermo-inactivation kinetics and activation capabilities and its application within multi-step cascades for chemicals production. Using a simple heat treatment of cell lysate as major purification step we achieved a specific activity of 4.4 units per gram cell mass toward the substrate d-gluconate. The optimal temperature and pH value for this reaction are 77 degrees C and pH 6.2. The inhibitory concentration (IC50, 50% residual activity) of different alcohols was determined to be 15% (v/v) for ethanol, 4.5% (v/v) for butanol and 4% (v/v) for isobutanol. Besides d-gluconate and the natural substrate 2,3 dihydroxyisovalerate (DHIV) SsDHAD is able to convert the C3-sugar-acid d glycerate to pyruvate, a reaction, which does not occur in natural metabolic pathways, with a specific activity of 10.7+/-0.4mU/mg. The specific activity of the enzyme can be increased 3-fold by incubation with 2-mercaptoethanol. The activation has no impact on temperature dependence, but modulates the thermo inactivation tolerance at 50 degrees C. The total turnover numbers for all of the three reactions was found to be 35.5*10(3)+/-1.0*10(3) for the conversion of d gluconate to 2-keto-3-deoxygluconate (KDG), 28.2*10(3)+/-0.8*10(3) for DHIV to 2 ketovalerate (KIV) and 943+/-0.28*10(2) for d-glycerate to pyruvate. With activated SsDHAD these values could be further increased 5- and 4-fold for the d gluconate and d-glycerate conversion, respectively. PMID- 26102634 TI - Development of an aptamer-affinity chromatography for efficient single step purification of Concanavalin A from Canavalia ensiformis. AB - Herein, an aptamer-based affinity chromatography method for rapid and single step purification of Concanavalin A is developed and validated. We have used a 41ntssDNA aptamer of Con A (Con A aptabody) as an affinity reagent in the developed aptamer-affinity chromatography. Stationary phase of the method consists of surface functionalized agarose beads carrying covalently immobilized Con A-aptabody. Affinity purification of Con A from jack bean (Canavalia ensiformis) seed using developed aptamer-affinity columns has resulted in >=66% recovery with 90% purity and 336-fold purification of Con A. The developed aptamer-affinity chromatography has shown efficient scalability and consistent purification when analysed over 13mm, 20mm and 25mm diameter columns having a bed height of 60mm each. Also, the developed aptamer-agarose columns were found to be reusable with recovery decrease of 12.9% in seven sequential cycles of purification. Therefore, the developed aptamer-affinity chromatography provides a novel, efficient and single-step methodology for isolation and purification of Con A. PMID- 26102633 TI - The Eukaryotic-Like Ser/Thr Kinase PrkC Regulates the Essential WalRK Two Component System in Bacillus subtilis. AB - Most bacteria contain both eukaryotic-like Ser/Thr kinases (eSTKs) and eukaryotic like Ser/Thr phosphatases (eSTPs). Their role in bacterial physiology is not currently well understood in large part because the conditions where the eSTKs are active are generally not known. However, all sequenced Gram-positive bacteria have a highly conserved eSTK with extracellular PASTA repeats that bind cell wall derived muropeptides. Here, we report that in the Gram-positive bacterium Bacillus subtilis, the PASTA-containing eSTK PrkC and its cognate eSTP PrpC converge with the essential WalRK two-component system to regulate WalR regulon genes involved in cell wall metabolism. By continuously monitoring gene expression throughout growth, we consistently find a large PrkC-dependent effect on expression of several different WalR regulon genes in early stationary phase, including both those that are activated by WalR (yocH) as well as those that are repressed (iseA, pdaC). We demonstrate that PrkC phosphorylates WalR in vitro and in vivo on a single Thr residue located in the receiver domain. Although the phosphorylated region of the receiver domain is highly conserved among several B. subtilis response regulators, PrkC displays specificity for WalR in vitro. Consistently, strains expressing a nonphosphorylatable WalR point mutant strongly reduce both PrkC dependent activation and repression of yocH, iseA, and pdaC. This suggests a model where the eSTK PrkC regulates the essential WalRK two component signaling system by direct phosphorylation of WalR Thr101, resulting in the regulation of WalR regulon genes involved in cell wall metabolism in stationary phase. As both the eSTK PrkC and the essential WalRK two-component system are highly conserved in Gram-positive bacteria, these results may be applicable to further understanding the role of eSTKs in Gram-positive physiology and cell wall metabolism. PMID- 26102635 TI - Optimisation and validation of ultra-high performance liquid chromatographic tandem mass spectrometry method for qualitative and quantitative analysis of potato steroidal alkaloids. AB - An ultra-high performance liquid chromatographic-tandem mass spectrometry (UHPLC MS/MS) method for quantification of potato steroidal alkaloids, namely alpha solanine, alpha-chaconine, solanidine and demissidine was developed and validated. Three different column chemistries, i.e. ethylene bridged hybrid (BEH) C18, hydrophilic lipophilic interaction and amide columns, were assessed. The BEH C18 column showed best separation and sensitivity for the alkaloids. Validation data (inter-day and intra-day combined) for accuracy and recovery ranged from 94.3 to 107.7% and 97.0 to 103.5%, respectively. The accuracy data were within the acceptable range of 15% as outlined in the United States Food and Drug Administration (USFDA) guidelines. The recovery data were consistent and reproducible with a coefficient of variation (CV) ranging from 6.2 to 9.7%. In addition, precision of the method also met the criteria of the USFDA with CV values lower than 15% even at lower limit of quantification (LLOQ), while the permissible variation is considered acceptable below 20%. The limit of detection and LLOQ of the four alkaloids were in the range of 0.001-0.004MUg/mL whereas the linearities of the standard curves were between 0.980 and 0.995. PMID- 26102637 TI - Reverse Case Study: A New Perspective on an Existing Teaching Strategy. PMID- 26102636 TI - [Prolonged seizures in children in sub-Saharan Africa Clinical aspects and management]. AB - BACKGROUND: There is a paucity of epidemiologic studies of prolonged seizures (persisting for more than 5 minutes) in the Democratic Republic of Congo (DRC) and in Rwanda. OBJECTIVE: We sought to analyze the clinical presentation, causes, pharmacologic management, and shortterm course of these seizures. METHODS: We enrolled 436 children, aged five months to ten years, who presented with prolonged seizures at the pediatric emergency departments of nine hospitals. Findings: Overall, 57.8% of the children were younger than three years; 7% had pre-existing psychomotor delay. Although 21% had had previous seizures, only 13% were receiving antiepileptic therapy. On presentation, 63.5% of the patients had fever and 26% were in status epilepticus. The seizures were focal in 21% of the cases. Malaria was the most common cause, involving 63% of the cases. The recurrence rate was 38%, and the mortality rate 4%. CONCLUSION: Prolonged seizures in DRC and Rwanda are frequently associated with fever, most commonly caused by malaria. The immediate use of long-acting antiepileptic drug could improve their outcomes. PMID- 26102638 TI - Toward a Shared Definition of Scholarly Writing Styles: A Call to Action for Readers, Writers, and Reviewers. PMID- 26102639 TI - Using Standardized Patients in Nursing Education: Effects on Students' Psychomotor Skill Development. AB - The present study used a quasi-experimental design to examine the effects of using standardized patients for the psychomotor skills development of nursing students. The performance of the experimental group in blood pressure measurement was significantly higher than that of the control group; however, there was no significant difference between the groups with regard to their administration of subcutaneous injections. The results indicated that standardized patients can be integrated into nursing education for developing psychomotor skills of students. PMID- 26102989 TI - Application of bacteriophages to reduce biofilms formed by hydrogen sulfide producing bacteria on surfaces in a rendering plant. AB - Hydrogen sulfide producing bacteria (SPB) in raw animal by-products are likely to grow and form biofilms in the rendering processing environments, resulting in the release of harmful hydrogen sulfide (H2S) gas. The objective of this study was to reduce SPB biofilms formed on different surfaces typically found in rendering plants by applying a bacteriophage cocktail. Using a 96-well microplate method, we determined that 3 SPB strains of Citrobacter freundii and Hafnia alvei are strong biofilm formers. Application of 9 bacteriophages (10(7) PFU/mL) from families of Siphoviridae and Myoviridae resulted in a 33%-70% reduction of biofilm formation by each SPB strain. On stainless steel and plastic templates, phage treatment (10(8) PFU/mL) reduced the attached cells of a mixed SPB culture (no biofilm) by 2.3 and 2.7 log CFU/cm(2) within 6 h at 30 degrees C, respectively, as compared with 2 and 1.5 log CFU/cm(2) reductions of SPB biofilms within 6 h at 30 degrees C. Phage treatment was also applied to indigenous SPB biofilms formed on the environmental surface, stainless steel, high-density polyethylene plastic, and rubber templates in a rendering plant. With phage treatment (10(9) PFU/mL), SPB biofilms were reduced by 0.7-1.4, 0.3-0.6, and 0.2 0.6 log CFU/cm(2) in spring, summer, and fall trials, respectively. Our study demonstrated that bacteriophages could effectively reduce the selected SPB strains either attached to or in formed biofilms on various surfaces and could to some extent reduce the indigenous SPB biofilms on the surfaces in the rendering environment. PMID- 26102988 TI - Is the ferret a suitable species for studying perinatal brain injury? AB - Complications of prematurity often disrupt normal brain development and/or cause direct damage to the developing brain, resulting in poor neurodevelopmental outcomes. Physiologically relevant animal models of perinatal brain injury can advance our understanding of these influences and thereby provide opportunities to develop therapies and improve long-term outcomes. While there are advantages to currently available small animal models, there are also significant drawbacks that have limited translation of research findings to humans. Large animal models such as newborn pig, sheep and nonhuman primates have complex brain development more similar to humans, but these animals are expensive, and developmental testing of sheep and piglets is limited. Ferrets (Mustela putorius furo) are born lissencephalic and undergo postnatal cortical folding to form complex gyrencephalic brains. This review examines whether ferrets might provide a novel intermediate animal model of neonatal brain disease that has the benefit of a gyrified, altricial brain in a small animal. It summarizes attributes of ferret brain growth and development that make it an appealing animal in which to model perinatal brain injury. We postulate that because of their innate characteristics, ferrets have great potential in neonatal neurodevelopmental studies. PMID- 26102990 TI - Global Gene-Expression Analysis to Identify Differentially Expressed Genes Critical for the Heat Stress Response in Brassica rapa. AB - Genome-wide dissection of the heat stress response (HSR) is necessary to overcome problems in crop production caused by global warming. To identify HSR genes, we profiled gene expression in two Chinese cabbage inbred lines with different thermotolerances, Chiifu and Kenshin. Many genes exhibited >2-fold changes in expression upon exposure to 0.5- 4 h at 45 degrees C (high temperature, HT): 5.2% (2,142 genes) in Chiifu and 3.7% (1,535 genes) in Kenshin. The most enriched GO (Gene Ontology) items included 'response to heat', 'response to reactive oxygen species (ROS)', 'response to temperature stimulus', 'response to abiotic stimulus', and 'MAPKKK cascade'. In both lines, the genes most highly induced by HT encoded small heat shock proteins (Hsps) and heat shock factor (Hsf)-like proteins such as HsfB2A (Bra029292), whereas high-molecular weight Hsps were constitutively expressed. Other upstream HSR components were also up-regulated: ROS-scavenging genes like glutathione peroxidase 2 (BrGPX2, Bra022853), protein kinases, and phosphatases. Among heat stress (HS) marker genes in Arabidopsis, only exportin 1A (XPO1A) (Bra008580, Bra006382) can be applied to B. rapa for basal thermotolerance (BT) and short-term acquired thermotolerance (SAT) gene. CYP707A3 (Bra025083, Bra021965), which is involved in the dehydration response in Arabidopsis, was associated with membrane leakage in both lines following HS. Although many transcription factors (TF) genes, including DREB2A (Bra005852), were involved in HS tolerance in both lines, Bra024224 (MYB41) and Bra021735 (a bZIP/AIR1 [Anthocyanin-Impaired-Response-1]) were specific to Kenshin. Several candidate TFs involved in thermotolerance were confirmed as HSR genes by real time PCR, and these assignments were further supported by promoter analysis. Although some of our findings are similar to those obtained using other plant species, clear differences in Brassica rapa reveal a distinct HSR in this species. Our data could also provide a springboard for developing molecular markers of HS and for engineering HS tolerant B. rapa. PMID- 26102991 TI - WTC-01, a novel synthetic oxime-flavone compound, destabilizes microtubules in human nasopharyngeal carcinoma cells in vitro and in vivo. AB - BACKGROUND AND PURPOSE: Dynamic polymerization of microtubules is essential for cancer cell growth and metastasis, and microtubule-disrupting agents have become the most successful anti-cancer agents in clinical use. Besides their antioxidant properties, flavonoids also exhibit strong microtubule-disrupting activity and inhibit tumour growth. We have designed, synthesized and tested a series of oxime/amide-containing flavone derivatives. Here we report the evaluation of one compound, WTC-01 for its anti-proliferative effects in human cancer cells. EXPERIMENTAL APPROACH: We used a range of cancer cell lines including two human nasopharyngeal carcinoma (NPC) cell lines, measuring proliferation, cell cycle and apoptosis, along with caspase levels and mitochondrial membrane potentials. Assays of tubulin polymerisation in vitro and computer modelling of the colchicine binding site in tubulin were also used. In mice, pharmacokinetics and growth of NPC-derived tumours were studied. KEY RESULTS: WTC-01 was most potent against proliferation of NPC cells (IC50 = 0.45 MUM), inducing accumulation of cells in G2 /M and increasing apoptosis, time- and concentration-dependently. The colchicine competition-binding experiments and computer modelling results suggested that WTC-01 causes microtubule disruption via binding to the colchicine binding site of tubulin resulting in mitochondrial membrane damage and cell apoptosis via activation of caspase-9/-3 without noticeable activation of the caspase-8. Notably, our in vivo studies demonstrated that at doses of 25 and 50 mg.kg(-1) , WTC-01 exhibited good pharmacokinetic properties and completely inhibited the growth of NPC-TW01 cells in a xenograft nude mouse model. CONCLUSIONS AND IMPLICATIONS: WTC-01, a new synthetic oxime-containing flavone, exhibited potent anti-tumour activity against NPC cells and merits further investigation. PMID- 26102993 TI - Some Thoughts About Thinking. AB - In this first-person case history, the writer Alberto Manguel chronicles the experience of losing his ability to write and speak during a stroke. He was reassured somewhat by his continued ability to read and to quote mentally from literature that he had memorized. Within hours after the stroke, he regained the ability to write. He remained unable to speak for a month. In this essay he ponders eloquently the relationship between thought and language, and describes how it felt not to be able to bridge the gap between thought and speech during his period of aphasia. PMID- 26102992 TI - Enhanced therapeutic neovascularization by CD31-expressing cells and embryonic stem cell-derived endothelial cells engineered with chitosan hydrogel containing VEGF-releasing microtubes. AB - Various stem cells and their progeny have been used therapeutically for vascular regeneration. One of the major hurdles for cell-based therapy is low cell retention in vivo, and to improve cell survival several biomaterials have been used to encapsulate cells before transplantation. Vascular regeneration involves new blood vessel formation which consists of two processes, vasculogenesis and angiogenesis. While embryonic stem cell (ESC)-derived endothelial cells (ESC-ECs) have clearer vasculogenic potency, adult cells exert their effects mainly through paracrine angiogenic activities. While these two cells have seemingly complementary advantages, there have not been any studies to date combining these two cell types for vascular regeneration. We have developed a novel chitosan based hydrogel construct that encapsulates both CD31-expressing BM-mononuclear cells (BM-CD31(+) cells) and ESC-ECs, and is loaded with VEGF-releasing microtubes. This cell construct showed high cell survival and minimal cytotoxicity in vitro. When implanted into a mouse model of hindlimb ischemia, it induced robust cell retention, neovascularization through vasculogenesis and angiogenesis, and efficiently induced recovery of blood flow in ischemic hindlimbs. This chitosan-based hydrogel encapsulating mixed adult and embryonic cell derivatives and containing VEGF can serve as a novel platform for treating various cardiovascular diseases. PMID- 26102994 TI - Using the Theories of Joseph Babinski to Manage Functional Vision Loss. AB - OBJECTIVE: To report our use of persuasion to treat patients with functional vision loss and to place them in the context of both Joseph Babinski's theories on hysteria and the current literature on management of functional vision loss. BACKGROUND: Conversion disorders, such as functional vision loss, can develop in response to a traumatic event. Recent functional imaging studies have found that, rather than being malingerers, patients with conversion disorders show changes within neuromodulatory pathways, suggesting organic dysfunction rather than a purely psychological disorder. METHODS: We conducted a retrospective analysis of 8 consecutive patients (7 female, 1 male; mean age 16 years) who had presented to a university-based neuro-ophthalmology clinic with vision loss from a conversion disorder. The patients had been given a lengthy visual task to perform at home, with the suggestion that their vision would improve by the time they completed the task. RESULTS: All 8 patients had evidence of a dissociation between real and perceived visual acuity and fields. All the patients performed the assigned visual task at home, and all either reported improvement or showed improved visual function at follow-up. CONCLUSIONS: A century after Joseph Babinski proposed using persuasion in managing patients with vision loss from a conversion disorder, we report that his method remains a viable and pathophysiologically sound option. Future case-controlled studies that include functional magnetic resonance imaging, other neurophysiologic imaging, and neuroradiographic evaluation may strengthen the correlation between persuasion therapy and recovery of normal vision. PMID- 26102995 TI - A Longitudinal Investigation of Sleep Quality in Adolescents and Young Adults After Mild Traumatic Brain Injury. AB - OBJECTIVE AND BACKGROUND: We examined sleep-related problems in adolescents and young adults after a mild traumatic brain injury (MTBI) or orthopedic injury. We extended the analysis of data from a study of early emotional and neuropsychological sequelae in these populations (McCauley et al. 2014. J Neurotrauma. 31:914). METHODS: We gave the Pittsburgh Sleep Quality Index to 77 participants with MTBI, 71 with orthopedic injury, and 43 non-injured controls. The age range was 12 to 30 years. We tested sleep quality within 96 hours of injury and at 1- and 3-month follow-up. Participants also completed measures of pain and fatigue, drug and alcohol use, and post-traumatic stress symptoms. RESULTS: Older participants (mean age=25 years) in the MTBI group exhibited a sharp increase in sleep-related symptoms between the baseline assessment and 1 month, and still had difficulties at 3 months. Younger participants with MTBI (mean age=15 years) and older participants with an orthopedic injury had modest increases in sleep difficulties between baseline and 1 month. The participants with MTBI also had more clinically significant sleep difficulties at all 3 assessments. At 3 months, Pittsburgh Sleep Quality Index scores in younger participants with MTBI and all participants with orthopedic injury did not differ significantly from the non-injured controls'. The controls had no significant change in their sleep symptoms during the 3 months. CONCLUSIONS: Sleep difficulties in young adults may persist for <=3 months after MTBI and exceed those after orthopedic injury. Clinicians should seek and treat sleep-related problems after MTBI. PMID- 26102997 TI - On the Relationship Between Semantic Knowledge and Prejudice About Social Groups in Patients with Dementia. AB - OBJECTIVE AND BACKGROUND: Patterns of brain-damaged individuals' deficits in categorizing living versus non-living things indicate separation of semantic knowledge categories in the brain. Recent work in patients with dementia suggested that semantic knowledge about social groups differs from knowledge about living and non-living things. In this study we analyzed patients' social appraisal by testing whether their degree of impairment in social-group knowledge predicted their social-group evaluative reactions (prejudice). We hypothesized that impaired knowledge about social groups would correlate with either heightened or reduced prejudice. METHODS: In Rumiati et al, Cogn Neurosci (2014) http://dx.doi.org/10.1080/17588928.2013.876981, we had given a sorting task to 21 patients with frontotemporal dementia or dementia of the Alzheimer type and 23 healthy controls, to test their knowledge of social groups and living and non living things. In this study we asked the same participants to evaluate social groups. We used controls' evaluations to rank 20 social groups from extremely negative to extremely positive. We used patients' severity of deficit in sorting social groups to predict the patients' evaluations of the groups, controlling for their levels of deficit in sorting living and non-living items. We also compared the evaluations by patients+/-deficits in social-group sorting to controls' evaluations. RESULTS: The patients with impaired social-group knowledge evaluated the less-admired groups more positively than did controls, and the more-admired groups less positively. CONCLUSIONS: Impaired social-group knowledge, not a general semantic loss, predicts reduced evaluative bias. Our findings are consistent with neuroimaging evidence for a relationship between semantic and evaluative social-group processes. PMID- 26102996 TI - Differential Cognitive and Affective Theory of Mind Abilities at Mild and Moderate Stages of Behavioral Variant Frontotemporal Dementia. AB - OBJECTIVE: To study the affective and cognitive components of theory of mind (ToM) performance in patients with behavioral variant frontotemporal dementia (bvFTD), focusing on differential impairment at mild and moderate disease stages. BACKGROUND: ToM, a central capacity for appropriate social behavior, is critically impaired in patients with bvFTD, even early in the disease. No previous study has explored how the cognitive and affective components of ToM may relate differentially to disease severity. METHODS: We assessed 40 patients with an established diagnosis of bvFTD and 18 healthy controls, using a complete neuropsychological battery that featured executive function and ToM tasks. We used patients' Clinical Dementia Rating scores to classify them as having either mild or moderate bvFTD. RESULTS: Both groups of patients showed deficits in the affective and cognitive components of ToM relative to the controls. The patients with mild bvFTD outperformed the group with moderate bvFTD in cognitive ToM capacities; however, affective ToM was equally impaired in both bvFTD groups. The cognitive, but not the affective, component of ToM correlated with performance on the executive function tests. CONCLUSIONS: Our results suggest that affective ToM is markedly diminished even during the initial stages of bvFTD; as the disease progresses, deficits in cognitive ToM become more prominent. These findings may relate to the pattern of cortical atrophy described for bvFTD. We also found significant correlations between the cognitive component of ToM and executive functions. PMID- 26102998 TI - Self-Regulation of Driving Behavior in People with Parkinson Disease. AB - OBJECTIVE: To determine the extent and nature of driving self-regulation in drivers with Parkinson disease (PD) and factors associated with self-regulatory practices. BACKGROUND: Although people with PD have consistently been shown to have driving impairments, few studies have examined self-regulatory driving practices and their relationship to driving performance. METHODS: We used a self report driving questionnaire to examine driving self-regulation in 37 drivers with PD and 37 healthy age-matched controls. We also analyzed factors associated with self-regulatory practices, primarily demographic, disease-related, psychological, and simulated driving performance variables. RESULTS: The drivers with PD reported significantly higher rates of self-perceived decline in their driving ability (P=0.008) and driving significantly shorter distances per week (P=0.004) than controls. Unfamiliar situations (P=0.009), in-car distractions (P<0.001), low visibility conditions (P=0.004), and long journeys (P=0.003) were particularly challenging for the drivers with PD, and their pattern of driving avoidance mirrored these difficulties. The use of self-regulatory strategies among drivers with PD was associated with female sex (rho=0.42, P=0.009) and perceived decline in driving ability (rho=-0.55, P<0.001), but not with age or objective measures of disease severity, cognition, or simulated driving performance. CONCLUSIONS: Drivers with PD reported driving less overall and restricting their driving to avoid particularly difficult circumstances. Further research is warranted on effective use of self-regulation strategies to improve driving performance in people with PD. PMID- 26103000 TI - A novel satellite DNA sequence in the Peromyscus genome (PMSat): Evolution via copy number fluctuation. AB - Satellite DNAs (satDNA) are tandemly arrayed repeated sequences largely present in eukaryotic genomes, which play important roles in genome evolution and function, and therefore, their analysis is vital. Here, we describe the isolation of a novel satellite DNA family (PMSat) from the rodent Peromyscus eremicus (Cricetidae, Rodentia), which is located in pericentromeric regions and exhibits a typical satellite DNA genome organization. Orthologous PMSat sequences were isolated and characterized from three species belonging to Cricetidae: Cricetus cricetus, Phodopus sungorus and Microtus arvalis. In these species, PMSat is highly conserved, with the absence of fixed species-specific mutations. Strikingly, different numbers of copies of this sequence were found among the species, suggesting evolution by copy number fluctuation. Repeat units of PMSat were also found in the Peromyscus maniculatus bairdii BioProject, but our results suggest that these repeat units are from genome regions outside the pericentromere. The remarkably high evolutionary sequence conservation along with the preservation of a few numbers of copies of this sequence in the analyzed genomes may suggest functional significance but a different sequence nature/organization. Our data highlight that repeats are difficult to analyze due to the limited tools available to dissect genomes and the fact that assemblies do not cover regions of constitutive heterochromatin. PMID- 26102999 TI - Temporal Variant Frontotemporal Dementia is Associated with Globular Glial Tauopathy. AB - Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disorder associated with atrophy of the frontal and temporal lobes. Most patients with focal temporal lobe atrophy present with either the semantic dementia subtype of FTD or the behavioral variant subtype. For patients with temporal variant FTD, the most common cause found on post-mortem examination has been a TDP-43 (transactive response DNA-binding protein 43 kDa) proteinopathy, but tauopathies have also been described, including Pick's disease and mutations in the microtubule-associated protein tau (MAPT) gene. We report the clinical and imaging features of 2 patients with temporal variant FTD associated with a rare frontotemporal lobar degeneration pathology known as globular glial tauopathy. The pathologic diagnosis of globular glial tauopathy should be considered in patients with temporal variant FTD, particularly those who have atypical semantic dementia or an atypical parkinsonian syndrome in association with the right temporal variant. PMID- 26103001 TI - Detecting reticulate relationships among diploid Leucanthemum Mill. (Compositae, Anthemideae) taxa using multilocus species tree reconstruction methods and AFLP fingerprinting. AB - We examined the evolutionary history of the diploid representatives of the genus Leucanthemum Mill. (Compositae, Anthemideae), which constitutes an extensive polyploid complex comprising around 41 species with ploidy levels ranging from 2x to 22x. The inference of phylogenetic relationships even on the diploid level is complicated in this genus due to the overlay of hybridisation and incomplete lineage sorting processes leading to incongruence among gene trees based on nuclear and plastid sequence information. Species tree and network reconstructions were based on gene trees from nine low-copy nuclear markers and the concatenated sequence information for five intergenic spacer regions of the chloroplast genome, either sequenced by Roche 454 pyrosequencing techniques or traditional Sanger sequencing techniques. Additional phylogenetic information came from multi-locus AFLP-fingerprinting of representative individuals of all diploid taxa under study and the subsequent analysis of AFLP patterns with Bayesian clustering and network reconstruction methods. To distinguish between hybridisation and incomplete lineage sorting, we developed and utilized a new 'hybrid index' calculation for individual taxa of the data set, which was compared to a simulated null-distribution assuming the occurrence of incomplete lineage sorting alone for pinpointing taxa with a significant hybrid signal. As a result, two species groups with contrasting patterns of gene flow and/or hybrid speciation signals could be identified in the diploids of Leucanthemum: (a) an early-diverging stock of allopatrically distributed diploid species with a lack of evidence for recent hybridisation events among its members and (b) a more recently radiated taxon assemblage with morphologically less clearly circumscribed taxa and a pronounced signal of gene flow among lineages and several candidate taxa, for which a homoploid hybrid origin may be considered. PMID- 26103002 TI - Personalized Computational Modeling of Mitral Valve Prolapse: Virtual Leaflet Resection. AB - Posterior leaflet prolapse following chordal elongation or rupture is one of the primary valvular diseases in patients with degenerative mitral valves (MVs). Quadrangular resection followed by ring annuloplasty is a reliable and reproducible surgical repair technique for treatment of posterior leaflet prolapse. Virtual MV repair simulation of leaflet resection in association with patient-specific 3D echocardiographic data can provide quantitative biomechanical and physiologic characteristics of pre- and post-resection MV function. We have developed a solid personalized computational simulation protocol to perform virtual MV repair using standard clinical guidelines of posterior leaflet resection with annuloplasty ring implantation. A virtual MV model was created using 3D echocardiographic data of a patient with posterior chordal rupture and severe mitral regurgitation. A quadrangle-shaped leaflet portion in the prolapsed posterior leaflet was removed, and virtual plication and suturing were performed. An annuloplasty ring of proper size was reconstructed and virtual ring annuloplasty was performed by superimposing the ring and the mitral annulus. Following the quadrangular resection and ring annuloplasty simulations, patient specific annular motion and physiologic transvalvular pressure gradient were implemented and dynamic finite element simulation of MV function was performed. The pre-resection MV demonstrated a substantial lack of leaflet coaptation which directly correlated with the severe mitral regurgitation. Excessive stress concentration was found along the free marginal edge of the posterior leaflet involving the chordal rupture. Following the virtual resection and ring annuloplasty, the severity of the posterior leaflet prolapse markedly decreased. Excessive stress concentration disappeared over both anterior and posterior leaflets, and complete leaflet coaptation was effectively restored. This novel personalized virtual MV repair strategy has great potential to help with preoperative selection of the patient-specific optimal MV repair techniques, allow innovative surgical planning to expect improved efficacy of MV repair with more predictable outcomes, and ultimately provide more effective medical care for the patient. PMID- 26103003 TI - MicroRNA-34a targets FMNL2 and E2F5 and suppresses the progression of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common malignancies. Increasing evidences indicate that dysregulation of miRNAs is a frequent event in CRC and contributes to the pathogenesis of CRC. In this study, we found that over expression of miR-34a inhibited cell proliferation and invasion, induced a cell cycle arrest and triggered apoptosis, while knockdown of miR-34a showed the opposite effects. Moreover, ectopic miR-34a suppressed tumor growth and metastasis of CRC cells in vivo. FMNL2 and E2F5 were identified as direct targets of miR-34a. Reintroduction of FMNL2 or E2F5 without 3'UTR region reversed the inhibitory effects of miR-34a on cell proliferation and invasion. MiR-34a was down-regulated in CRC cells and inversely correlated with FMNL2 and E2F5 expressions. Our study suggests that miR-34a is an important tumor suppressor of CRC progression by targeting FMNL2 and E2F5, thus providing new insight into the molecular mechanisms underlying CRC progression and establishing a strong potential for the application of miR-34a as a novel therapeutic marker against CRC. PMID- 26103004 TI - A 1.8-kb insertion in the 3'-UTR of RXFP2 is associated with polledness in sheep. AB - Sheep breeds show a broad spectrum of different horn phenotypes. In most modern production breeds, sheep are polled (absence of horns), whereas horns occur mainly in indigenous breeds. Previous studies mapped the responsible locus to the region of the RXFP2 gene on ovine chromosome 10. A 4-kb region of the 3'-end of RXFP2 was amplified in horned and polled animals from seven Swiss sheep breeds. Sequence analysis identified a 1833-bp genomic insertion located in the 3'-UTR region of RXFP2 present in polled animals only. An efficient PCR-based genotyping method to determine the polled genotype of individual sheep is presented. Comparative sequence analyses revealed evidence that the polled-associated insertion adds a potential antisense RNA sequence of EEF1A1 to the 3'-end of RXFP2 transcripts. PMID- 26103005 TI - Impact of Physical Chemical Characteristics of Abutment Implant Surfaces on Bacteria Adhesion. AB - Surface attachment is the first step in biofilm formation, and the ability of bacteria to adhere to surfaces and develop a biofilm is directly influenced by electrostatic interactions between the bacteria and the chemical composition of material surfaces. Here, we investigated the influence of physical and chemical characteristics of titanium (Ti) and zirconia (ZrO2) as implant abutment surfaces on the bacterial adhesion phase and compared the results to bovine enamel (BE) simulating a human tooth. To achieve this goal, we used 2 common pathogens of the oral cavity, Streptococcus mutans UA140 and Porphyromonas gingivalis 33277. To investigate the influence of material surfaces on bacterial adhesion, we studied the surface free energy as well as the topography by atomic force microscopy, and the chemical elements composition by scanning electron microscopy equipped with an energy dispersive X-ray spectroscope. Our results indicated a hydrophobic characteristic for all of the materials; however, the presence of polar and nonpolar components could aid in understanding why greater numbers of bacteria had adhered to BE compared to the other surfaces. Our confocal microscopy data support the proposition that electrostatic interactions, indeed, affected the initial adhesion phase. Within the limitations of a laboratory study, the results revealed bacterial adhered on BE and no bacteria could be observed by confocal images on Ti and ZrO2 implant abutment surfaces. PMID- 26103006 TI - Association of GSTO2 (N142D), GSTT1, and GSTM1 Polymorphisms With Graft-Versus Host Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients. AB - OBJECTIVES: Graft-versus-host disease is a major problem after bone marrow transplant. GSTM1, GSTT1, and GSTO2 are important genes that interfere with xenobiotic and drug metabolism. Polymorphisms of these genes may influence the metabolism of immunosuppressive drugs given for inhibition of graft-versus-host disease and may influence their susceptibility to diseases, which bone marrow transplant could alleviate. MATERIALS AND METHODS: We examined the polymorphisms of 2 groups: The first group was composed of 88 patients who had undergone a bone marrow transplant and 100 otherwise healthy persons; the second group was composed of 54 patients without graft-versus-host disease and 34 patients with graft-versus-host disease. We used polymerase chain reaction-restriction fragment length polymorphism method for genotyping GSTO2 and also for multiplexing polymerase chain reactions for GSTT1 and GSTM1 genotypes. RESULTS: No significant association existed between the genotypes GSTO2 (DD: P = .458, OR 0.422), GSTM1 (P = .349, OR 1.52), or GSTT1 (P = .887, OR 1.086), and the incidence of GVHD. Moreover, we saw no association between these polymorphisms and the problems that lead to bone marrow transplant (GSTO2: DD, P = .181, OR 0.465; GSTM1: P = .699, OR 0.892; GSTT1: P = .656, OR 0.845). We showed that men have more bone marrow transplants than do women (P = .019, OR 2.034). CONCLUSIONS: Our results show that these poly-morphisms may have no effect on the metabolism of drugs used to treat graft-versus-host disease and also, may play no significant role in creating the problems that lead to bone marrow transplant. PMID- 26103007 TI - Nogo to IFN by Ras. PMID- 26103008 TI - Constraints on adaptation of Escherichia coli to mixed-resource environments increase over time. AB - Can a population evolved in two resources reach the same fitness in both as specialist populations evolved in each of the individual resources? This question is central to theories of ecological specialization, the maintenance of genetic variation, and sympatric speciation, yet relatively few experiments have examined costs of generalism over long-term adaptation. We tested whether selection in environments containing two resources limits a population's ability to adapt to the individual resources by comparing the fitness of replicate Escherichia coli populations evolved for 6000 generations in the presence of glucose or lactose alone (specialists), or in varying presentations of glucose and lactose together (generalists). We found that all populations had significant fitness increases in both resources, though the magnitude and rate of these increases differed. For the first 4000 generations, most generalist populations increased in fitness as quickly in the individual resources as the corresponding specialist populations. From 5000 generations, however, a widespread cost of adaptation affected all generalists, indicating a growing constraint on their abilities to adapt to two resources simultaneously. Our results indicate that costs of generalism are prevalent, but may influence evolutionary trajectories only after a period of cost-free adaptation. PMID- 26103009 TI - Concentration-dependent structure and structural transition from chirality to nonchirality at the liquid-solid interface by coassembly. AB - Understanding the formation and structural transition of the two-dimensional chirality of self-assembly is a subject which still gains significant interest in surface or interface chirality studies. Here, we present the solvent-induced chiral structural transition of a 2-hydroxy-7-pentadecyloxy-9-fluorenone (HPF) molecules' self-assembled adlayer through coassembly with achiral aliphatic solvents under different concentrations. Polymorphic chiral patterns are obtained at low concentrations of aliphatic solvents with different chain lengths. The HPF molecules form coassembled structures with these solvents through van der Waals interactions. At the same time, at high concentrations, HPF molecules uniformly form a nonchiral multimer structure without coadsorbed aliphatic solvent molecules. What is interesting is that these structures under different concentrations will finally change into a zigzag structure, which is the thermodynamically most stable configuration. Especially when using n-hexadecane as the solvent, the adlayer shows perfect steric matching due to the close chain length of HPF and n-hexadecane, which can maximize the molecule-solvent interactions. Thus, HPF molecules in n-hexadecane exhibit the most diversiform configuration. The distinct concentration-dependence has proven that the solvent molecules can act as a coadsorbed component through van der Waals interactions rather than simply a dispersant and further result in the probability and stability of chiral self-assembled monolayers by subtle tuning of the solvent molecule and solvent-substrate interactions. This result provides a simple and alternative strategy to construct the 2D chiral assembled monolayer. PMID- 26103012 TI - The Church Supper: James Baare Turnbull. PMID- 26103022 TI - Broadly Neutralizing Antibodies and the Development of Vaccines. PMID- 26103023 TI - The 2015 US Dietary Guidelines: Lifting the Ban on Total Dietary Fat. PMID- 26103024 TI - A PIECE OF MY MIND. I'm Sorry. PMID- 26103025 TI - Underutilization of Implantable Cardioverter-Defibrillators in Older Patients. PMID- 26103026 TI - Medical Marijuana: Is the Cart Before the Horse? PMID- 26103027 TI - Implantable Cardioverter-Defibrillator Use Among Medicare Patients With Low Ejection Fraction After Acute Myocardial Infarction. AB - IMPORTANCE: Implantable cardioverter-defibrillators (ICDs) are not recommended within 40 days of myocardial infarction (MI); thus, ICD implantation might not be considered during the post-MI care transition. OBJECTIVE: To examine ICD implantation rates and associated mortality among older MI patients with low ejection fraction (EF). DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study of Medicare beneficiaries with an EF of 35% or less after MI, treated at 441 US hospitals between 2007 and 2010, excluding patients with prior ICD implantation. Follow-up data were available through December 2010. EXPOSURES: ICD implantation within 1 year of MI vs no ICD implantation within 1 year of MI. MAIN OUTCOMES AND MEASURES: Patient characteristics associated with receiving an ICD within 1 year after discharge and 2-year mortality associated with ICD implantation. RESULTS: Among 10,318 MI patients with EF of 35%or lower, the cumulative 1-year ICD implantation rate was 8.1% (95%CI, 7.6%-8.7%). Patients with ICD implantation were more likely to have prior coronary artery bypass graft procedures, higher peak troponin levels, in-hospital cardiogenic shock, and cardiology follow-up within 2 weeks after discharge relative to patients who did not receive an ICD within 1 year. Implantation of ICD was associated with lower 2 year mortality (15.3 events per 100 patient-years [128 deaths in 838 patient years] vs 26.4 events per 100 patient-years [3033 deaths in 11 479 patient years]; adjusted HR, 0.64; 95%CI, 0.53-0.78). [table: see text] CONCLUSIONS AND RELEVANCE: In this large registry study of older patients who experienced MI from 2007-2010, fewer than 1 in 10 eligible patients with low EF received an ICD within 1 year after MI, although ICD implantation was associated with lower risk adjusted mortality at 2 years. Additional research is needed to determine evidence-based approaches to increase ICD implantation among eligible patients. PMID- 26103028 TI - Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants. AB - IMPORTANCE: There is currently no consensus for the screening and treatment of patent ductus arteriosus (PDA) in extremely preterm infants. Less pharmacological closure and more supportive management have been observed without evidence to support these changes. OBJECTIVE: To evaluate the association between early screening echocardiography for PDA and in-hospital mortality. DESIGN, SETTING, AND PARTICIPANTS: Comparison of screened and not screened preterm infants enrolled in the EPIPAGE 2 national prospective population-based cohort study that included all preterm infants born at less than 29 weeks of gestation and hospitalized in 68 neonatal intensive care units in France from April through December 2011. Two main analyses were performed to adjust for potential selection bias, one using propensity score matching and one using neonatal unit preference for early screening echocardiography as an instrumental variable. EXPOSURES: Early screening echocardiography before day 3 of life. MAIN OUTCOMES AND MEASURES: The primary outcome was death between day 3 and discharge. The secondary outcomes were major neonatal morbidities (pulmonary hemorrhage, severe bronchopulmonary dysplasia, severe cerebral lesions, and necrotizing enterocolitis). RESULTS: Among the 1513 preterm infants with data available to determine exposure, 847 were screened for PDA and 666 were not; 605 infants from each group could be paired. Exposed infants were treated for PDA more frequently during their hospitalization than nonexposed infants (55.1% vs 43.1%; odds ratio [OR], 1.62 [95% CI, 1.31 to 2.00]; absolute risk reduction [ARR] in events per 100 infants, -12.0 [95% CI, -17.3 to -6.7). Exposed infants had a lower hospital death rate (14.2% vs 18.5% ; OR, 0.73 [95% CI, 0.54 to 0.98]; ARR, 4.3 [95% CI, 0.3 to 8.3]) and a lower rate of pulmonary hemorrhage (5.6% vs 8.9%; OR, 0.60 [95% CI, 0.38 to 0.95]; ARR, 3.3 [95% CI, 0.4 to 6.3]). No differences in rates of necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions were observed. In the overall cohort, instrumental variable analysis yielded an adjusted OR for in-hospital mortality of 0.62 [95% CI, 0.37 to 1.04]. CONCLUSIONS AND RELEVANCE: In this national population-based cohort of extremely preterm infants, screening echocardiography before day 3 of life was associated with lower in-hospital mortality and likelihood of pulmonary hemorrhage but not with differences in necrotizing enterocolitis, severe bronchopulmonary dysplasia, or severe cerebral lesions. However, results of the instrumental variable analysis leave some ambiguity in the interpretation, and longer-term evaluation is needed to provide clarity. PMID- 26103029 TI - Use of Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction and Risk of Malignant Melanoma. AB - IMPORTANCE: The target for the oral erectile dysfunction drugs, phosphodiesterase type 5 (PDE5) inhibitors, is part of a pathway implicated in the development of malignant melanoma. An increased risk of melanoma in sildenafil users was recently reported. OBJECTIVE: To examine the association between use of PDE5 inhibitors and melanoma risk, including data on specific PDE5 inhibitors, number of prescriptions, and melanoma stage. DESIGN, SETTING, AND PARTICIPANTS: Nationwide, population-based, nested case-control study in the Swedish Prescribed Drug Register, the Swedish Melanoma Register, and other health care registers and demographic databases in Sweden, including 4065 melanoma cases diagnosed from 2006 through 2012 and 5 randomly selected controls per case with matching year of birth. EXPOSURES: Number of filled prescriptions for the PDE5 inhibitors sildenafil and vardenafil or tadalafil. MAIN OUTCOMES AND MEASURES: Risk of melanoma; overall and by stage and risk of basal cell carcinoma in multivariable logistic regression analyses. RESULTS: Of 4065 melanoma cases, 435 men (11%) had filled prescriptions for PDE5 inhibitors, as did 1713 men of 20,325 controls (8%). In multivariable analysis, there was an increased risk of melanoma in men taking PDE5 inhibitors (OR, 1.21 [95% CI, 1.08-1.36]). The most pronounced increase in risk was observed in men who had filled a single prescription (OR, 1.32 [95% CI, 1.10-1.59]; exposure rate, 4% for cases vs 3% for controls), but was not significant among men with multiple filled prescriptions (for 2-5 prescriptions: OR, 1.14 [95% CI, 0.95-1.37], 4% for cases and 3% for controls; for >=6 prescriptions: OR, 1.17 [95% CI, 0.95-1.44], 3% for cases vs 2% for controls). PDE5 inhibitors were significantly associated with melanoma stage 0 (OR, 1.49 [95% CI, 1.22-1.83], 13% for cases vs 8% for controls) and stage I (OR, 1.21 [95% CI, 1.02-1.43], 12% for cases vs 10% for controls), but not stage II through IV (OR, 0.83 [95% CI, 0.63-1.09], 6% for cases vs 7% for controls). The risk estimates were similar for sildenafil and vardenafil or tadalafil. PDE5 inhibitor use was also associated with an increased risk of basal cell carcinoma (OR, 1.19 [95% CI, 1.14-1.25], 9% for cases vs 8% for controls). Men taking PDE5 inhibitors had a higher educational level and annual income, factors that were also significantly associated with melanoma risk. CONCLUSIONS AND RELEVANCE: In a Swedish cohort of men, the use of PDE5 inhibitors was associated with a modest but statistically significant increased risk of malignant melanoma. However, the pattern of association (eg, the lack of association with multiple filled prescriptions) raises questions about whether this association is causal. PMID- 26103030 TI - Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. OBJECTIVE: To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. DATA SOURCES: Twenty-eight databases from inception to April 2015. STUDY SELECTION: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random effects meta-analysis. MAIN OUTCOMES AND MEASURES: Patient-relevant/disease specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. RESULTS: A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10 point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. CONCLUSIONS AND RELEVANCE: There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short term AEs. PMID- 26103032 TI - Metformin as Initial Oral Therapy in Type 2 Diabetes. PMID- 26103031 TI - Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. AB - IMPORTANCE: As of March 2015, 23 states and the District of Columbia had medical marijuana laws in place. Physicians should know both the scientific rationale and the practical implications for medical marijuana laws. OBJECTIVE: To review the pharmacology, indications, and laws related to medical marijuana use. EVIDENCE REVIEW: The medical literature on medical marijuana was reviewed from 1948 to March 2015 via MEDLINE with an emphasis on 28 randomized clinical trials of cannabinoids as pharmacotherapy for indications other than those for which there are 2 US Food and Drug Administration-approved cannabinoids (dronabinol and nabilone), which include nausea and vomiting associated with chemotherapy and appetite stimulation in wasting illnesses. FINDINGS: Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications. CONCLUSIONS AND RELEVANCE: Medical marijuana is used to treat a host of indications, a few of which have evidence to support treatment with marijuana and many that do not. Physicians should educate patients about medical marijuana to ensure that it is used appropriately and that patients will benefit from its use. PMID- 26103033 TI - Perioperative beta-Blocker Therapy. PMID- 26103034 TI - Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. PMID- 26103035 TI - Housing for Homeless Adults With Mental Illness. PMID- 26103036 TI - Housing for Homeless Adults With Mental Illness--Reply. PMID- 26103037 TI - Flaws in Patient Safety Measures. PMID- 26103038 TI - Flaws in Patient Safety Measures--Reply. PMID- 26103039 TI - Dosing Recommendations for New Oral Anticoagulants. PMID- 26103041 TI - Wording and Data Errors in the Text and Table. PMID- 26103040 TI - Dosing Recommendations for New Oral Anticoagulants--Reply. PMID- 26103043 TI - Correspondence: Ben Franklin's Views. PMID- 26103044 TI - JAMA PATIENT PAGE. Medical Marijuana. PMID- 26103045 TI - Atomic force microscope caliper for critical dimension measurements of micro and nanostructures through sidewall scanning. AB - A novel atomic force microscope (AFM) dual-probe caliper for critical dimension (CD) metrology has been developed. The caliper is equipped with two facing tilted optical fiber probes (OFPs) wherein each can be used independently to scan either sidewall of micro and nanostructures. The OFP tip with length up to 500 MUm (aspect ratio 10:1, apex diameter ?10 nm) has unique features of scanning deep trenches and imaging sidewalls of relatively high steps with exclusive profiling possibilities. The caliper arms-OFPs can be accurately aligned with a well calibrated opening distance. The line width, line edge roughness, line width roughness, groove width and CD angles can be measured through serial scan of adjacent or opposite sidewalls with each probe. Capabilities of the presented AFM caliper have been validated through experimental CD measurement results of comb microstructures and AFM calibration grating TGZ3. PMID- 26103046 TI - Peculiar rotation of electron vortex beams. AB - Standard electron optics predicts Larmor image rotation in the magnetic lens field of a TEM. Introducing the possibility to produce electron vortex beams with quantized orbital angular momentum brought up the question of their rotational dynamics in the presence of a magnetic field. Recently, it has been shown that electron vortex beams can be prepared as free electron Landau states showing peculiar rotational dynamics, including no and cyclotron (double-Larmor) rotation. Additionally very fast Gouy rotation of electron vortex beams has been observed. In this work a model is developed which reveals that the rotational dynamics of electron vortices are a combination of slow Larmor and fast Gouy rotations and that the Landau states naturally occur in the transition region in between the two regimes. This more general picture is confirmed by experimental data showing an extended set of peculiar rotations, including no, cyclotron, Larmor and rapid Gouy rotations all present in one single convergent electron vortex beam. PMID- 26103047 TI - Thon rings from amorphous ice and implications of beam-induced Brownian motion in single particle electron cryo-microscopy. AB - We have recorded dose-fractionated electron cryo-microscope images of thin films of pure flash-frozen amorphous ice and pre-irradiated amorphous carbon on a Falcon II direct electron detector using 300 keV electrons. We observe Thon rings [1] in both the power spectrum of the summed frames and the sum of power spectra from the individual frames. The Thon rings from amorphous carbon images are always more visible in the power spectrum of the summed frames whereas those of amorphous ice are more visible in the sum of power spectra from the individual frames. This difference indicates that while pre-irradiated carbon behaves like a solid during the exposure, amorphous ice behaves like a fluid with the individual water molecules undergoing beam-induced motion. Using the measured variation in the power spectra amplitude with number of electrons per image we deduce that water molecules are randomly displaced by a mean squared distance of ~1.1 A(2) for every incident 300 keV e(-)/A(2). The induced motion leads to an optimal exposure with 300 keV electrons of 4.0 e(-)/A(2) per image with which to observe Thon rings centred around the strong 3.7 A scattering peak from amorphous ice. The beam-induced movement of the water molecules generates pseudo-Brownian motion of embedded macromolecules. The resulting blurring of single particle images contributes an additional term, on top of that from radiation damage, to the minimum achievable B-factor for macromolecular structure determination. PMID- 26103048 TI - The Evaluation and Quantitation of Dihydrogen Metabolism Using Deuterium Isotope in Rats. AB - PURPOSE: Despite the significant interest in molecular hydrogen as an antioxidant in the last eight years, its quantitative metabolic parameters in vivo are still lacking, as is an appropriate method for determination of hydrogen effectivity in the mammalian organism under various conditions. BASIC PROCEDURES: Intraperitoneally-applied deuterium gas was used as a metabolic tracer and deuterium enrichment was determined in the body water pool. Also, in vitro experiments were performed using bovine heart submitochondrial particles to evaluate superoxide formation in Complex I of the respiratory chain. MAIN FINDINGS: A significant oxidation of about 10% of the applied dose was found under physiological conditions in rats, proving its antioxidant properties. Hypoxia or endotoxin application did not exert any effect, whilst pure oxygen inhalation reduced deuterium oxidation. During in vitro experiments, a significant reduction of superoxide formation by Complex I of the respiratory chain was found under the influence of hydrogen. The possible molecular mechanisms of the beneficial effects of hydrogen are discussed, with an emphasis on the role of iron sulphur clusters in reactive oxygen species generation and on iron species-dihydrogen interaction. PRINCIPAL CONCLUSIONS: According to our findings, hydrogen may be an efficient, non-toxic, highly bioavailable and low cost antioxidant supplement for patients with pathological conditions involving ROS-induced oxidative stress. PMID- 26103049 TI - Rare zoonotic infection with Microsporum persicolor with literature review. AB - We report a case of dermatophytosis caused by Microsporum persicolor in a 38-year old male from Poland. Direct microscopic examination revealed high amounts of fungal hyphae from the right elbow material. The mould recovered in multiple cultures was identified as Microsporum persicolor by molecular identification based on partial of beta-tubulin gene (BT2), internal transcribed spacer, partial small ribosomal subunit (SSU) and large ribosomal subunit, partial translation elongation factor (TEF1) and RNA polymerase second largest subunit (RPB1) loci sequence data. The patient was treated with terbinafine. Clinical and mycological cure was achieved with this regimen and the patient was subsequently followed for 1 year without relapse. Microsporum persicolor is a very rare causative agent of dermatophytosis worldwide. The source of infection for the patient remained unclear and zoonotic transmission could not be confirmed. PMID- 26103050 TI - Intra-Genomic Heterogeneity in 16S rRNA Genes in Strictly Anaerobic Clinical Isolates from Periodontal Abscesses. AB - BACKGROUND: Members of the genera Prevotella, Veillonella and Fusobacterium are the predominant culturable obligate anaerobic bacteria isolated from periodontal abscesses. When determining the cumulative number of clinical anaerobic isolates from periodontal abscesses, ambiguous or overlapping signals were frequently encountered in 16S rRNA gene sequencing chromatograms, resulting in ambiguous identifications. With the exception of the genus Veillonella, the high intra chromosomal heterogeneity of rrs genes has not been reported. METHODS: The 16S rRNA genes of 138 clinical, strictly anaerobic isolates and one reference strain were directly sequenced, and the chromatograms were carefully examined. Gene cloning was performed for 22 typical isolates with doublet sequencing signals for the 16S rRNA genes, and four copies of the rrs-ITS genes of 9 Prevotella intermedia isolates were separately amplified by PCR, sequenced and compared. Five conserved housekeeping genes, hsp60, recA, dnaJ, gyrB1 and rpoB from 89 clinical isolates of Prevotella were also amplified by PCR and sequenced for identification and phylogenetic analysis along with 18 Prevotella reference strains. RESULTS: Heterogeneity of 16S rRNA genes was apparent in clinical, strictly anaerobic oral bacteria, particularly in the genera Prevotella and Veillonella. One hundred out of 138 anaerobic strains (72%) had intragenomic nucleotide polymorphisms (SNPs) in multiple locations, and 13 strains (9.4%) had intragenomic insertions or deletions in the 16S rRNA gene. In the genera Prevotella and Veillonella, 75% (67/89) and 100% (19/19) of the strains had SNPs in the 16S rRNA gene, respectively. Gene cloning and separate amplifications of four copies of the rrs-ITS genes confirmed that 2 to 4 heterogeneous 16S rRNA copies existed. CONCLUSION: Sequence alignment of five housekeeping genes revealed that intra-species nucleotide similarities were very high in the genera Prevotella, ranging from 94.3-100%. However, the inter-species similarities were relatively low, ranging from 68.7-97.9%. The housekeeping genes rpoB and gyrB1 were demonstrated to be alternative classification markers to the species level based on intra- and inter-species comparisons, whereas based on phylogenetic tree rpoB proved to be reliable phylogenetic marker for the genus Prevotella. PMID- 26103051 TI - Hemodynamics in the Circle of Willis with Internal Carotid Artery Stenosis under Cervical Rotatory Manipulation: A Finite Element Analysis. AB - BACKGROUND: The circle of Willis (CoW) plays an important role in cerebral collateral circulation. The hemodynamics changes in the CoW have usually been associated with the internal carotid artery (ICA) stenosis, but whether rotatory manipulation will affect it remains unknown. MATERIAL AND METHODS: In this study we attempted to analyze the influence of rotatory manipulation on the hemodynamics in the CoW in models with or without ICA stenosis by means of finite element analysis. For this purpose, the CoW was reasonably simplified and a fluid solid coupling 3D finite element model was created by using MIMICS10.0 and ANSYS14.5. The healthy (without stenosis) and the diseased (ratios of stenosis include 15%, 30%, 45%, 60%, 70%, 80%, and 90%) situations were simulated. A remote displacement of 60 degrees was applied at a distal ICA (the right ICA was chosen here) to imitate the rotatory manipulation. Blood flow was then monitored at the anterior communicating artery (ACoA) and posterior communicating arteries (PCoA). RESULTS: Before the conduction of rotatory manipulation, blood flow changed significantly only when the stenosis ratio was increased to more than 70%, and the situation did not have significant difference after the application of remote displacement except the model with stenosis ration of 90%. CONCLUSIONS: The result suggests that the rotatory manipulation does not have an obvious influence on the blood flow in the CoW when the stenosis of ICA is less than 90%, and this kind of manipulation is suggested to be a safe technique in most of the clinical applications. PMID- 26103052 TI - Asymmetric Synthesis of Deoxypropionate Derivatives via Catalytic Hydrogenolysis of Enantioenriched Z-Ketene Heterodimers. AB - A diastereoselective approach to deoxypropionate derivatives through Pd/C catalyzed hydrogenolysis of enantioenriched ketene heterodimers is described. Catalytic hydrogenolysis of the Z-isomer of ketene heterodimers facilitates access to anti-deoxypropionate derivatives (10 examples with dr 7:1 to >20:1). Transfer of chirality from the Z-ketene heterodimer to an acid product was good to excellent in most cases (78-99% ee for 12 examples). PMID- 26103053 TI - Molecular Features of Triple Negative Breast Cancer: Microarray Evidence and Further Integrated Analysis. AB - PURPOSE: Breast cancer is a heterogeneous disease usually including four molecular subtypes such as luminal A, luminal B, HER2-enriched, and triple negative breast cancer (TNBC). TNBC is more aggressive than other breast cancer subtypes. Despite major advances in ER-positive or HER2-amplified breast cancer, there is no targeted agent currently available for TNBC, so it is urgent to identify new potential therapeutic targets for TNBC. METHODS: We first used microarray analysis to compare gene expression profiling between TNBC and non TNBC. Furthermore an integrated analysis was conducted based on our own and published data, leading to more robust, reproducible and accurate predictions. Additionally, we performed qRT-PCR in breast cancer cell lines to verify the findings in integrated analysis. RESULTS: After searching Gene Expression Omnibus database (GEO), two microarray studies were obtained according to the inclusion criteria. The integrated analysis was conducted, including 30 samples of TNBC and 77 samples of non-TNBC. 556 genes were found to be consistently differentially expressed (344 up-regulated genes and 212 down-regulated genes in TNBC). Functional annotation for these differentially expressed genes (DEGs) showed that the most significantly enriched Gene Ontology (GO) term for molecular functions was protein binding (GO: 0005515, P = 6.09E-21), while that for biological processes was signal transduction (GO: 0007165, P = 9.46E-08), and that for cellular component was cytoplasm (GO: 0005737, P = 2.09E-21). The most significant pathway was Pathways in cancer (P = 6.54E-05) based on Kyoto Encyclopedia of Genes and Genomes (KEGG). DUSP1 (Degree = 21), MYEOV2 (Degree = 15) and UQCRQ (Degree = 14) were identified as the significant hub proteins in the protein-protein interaction (PPI) network. Five genes were selected to perform qRT-PCR in seven breast cancer cell lines, and qRT-PCR results showed that the expression pattern of selected genes in TNBC lines and non-TNBC lines was nearly consistent with that in the integrated analysis. CONCLUSION: This study may help to understand the pathogenesis of different breast cancer subtypes, contributing to the successful identification of therapeutic targets for TNBC. PMID- 26103054 TI - Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling. AB - Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T3) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS) that damage mitochondria. However, the mechanism for maintenance of mitochondrial activity and quality control by this hormone is not known. Here, we used both in vitro and in vivo hepatic cell models to demonstrate that induction of mitophagy by T3 is coupled to oxidative phosphorylation and ROS production. We show that T3 induction of ROS activates CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, beta) mediated phosphorylation of PRKAA1/AMPK (5' AMP-activated protein kinase), which in turn phosphorylates ULK1 (unc-51 like autophagy activating kinase 1) leading to its mitochondrial recruitment and initiation of mitophagy. Furthermore, loss of ULK1 in T3-treated cells impairs both mitophagy as well as OXPHOS without affecting T3 induced general autophagy/lipophagy. These findings demonstrate a novel ROS-AMPK-ULK1 mechanism that couples T3-induced mitochondrial turnover with activity, wherein mitophagy is necessary not only for removing damaged mitochondria but also for sustaining efficient OXPHOS. PMID- 26103055 TI - Widespread Distribution and Expression of Gamma A (UMB), an Uncultured, Diazotrophic, gamma-Proteobacterial nifH Phylotype. AB - Marine dinitrogen (N2) fixation studies have focused nearly exclusively on cyanobacterial diazotrophs; however gamma-proteobacteria are an abundant component of the marine community and have been largely overlooked until recently. Here we present a phylogenetic analysis of all nifH gamma proteobacterial sequences available in public databases and qPCR data of a gamma proteobacterial phylotype, Gamma A (UMB), obtained during several research cruises. Our analysis revealed a complex diversity of diazotrophic gamma proteobacteria. One phylotype in particular, Gamma A, was described in several traditional and quantitative PCR studies. Though several gamma-proteobacterial nifH sequences have been described as laboratory contaminants, Gamma A is part of a large cluster of sequences isolated from marine environments and distantly related to the clade of contaminants. Using a TaqMan probe and primer set, Gamma A nifH DNA abundance and expression were analyzed in nearly 1000 samples collected during 15 cruises to the Atlantic and Pacific Oceans. The data showed that Gamma A is an active, cosmopolitan diazotroph found throughout oxygenated, oligotrophic waters reaching maximum abundances of 8 x 104 nifH DNA copies l-1 and 5 x 105 nifH transcript copies l-1. Gamma A nifH transcript abundances were on average 3 fold higher than nifH DNA abundances. The widespread distribution and activity of Gamma A indicate that it has potential to be a globally important N2 fixing organism. PMID- 26103057 TI - Caval agenesis in the pediatric liver donor. AB - The following is the first report of a pediatric organ donor with caval agenesis and the subsequent use of this liver for transplantation. Caval embryology and potential implications of utilizing a donor liver with caval agenesis are reviewed. PMID- 26103056 TI - Electrocatalysis by subcellular liver fractions bound to carbon nanostructures for stereoselective green drug metabolite synthesis. AB - A novel, reusable, cofactor-free, and mediator-free human liver microsomal bioreactor constructed on carbon nanostructure electrodes for stereoselective green syntheses of drug metabolites and specialty chemicals is reported here for the first time. Drug metabolites are useful for examining pharmaceutical and pharmacological properties of new drugs under development. PMID- 26103058 TI - Tuning the properties of copper-based catalysts based on molecular in situ studies of model systems. AB - Studying catalytic processes at the molecular level is extremely challenging, due to the structural and chemical complexity of the materials used as catalysts and the presence of reactants and products in the reactor's environment. The most common materials used on catalysts are transition metals and their oxides. The importance of multifunctional active sites at metal/oxide interfaces has been long recognized, but a molecular picture of them based on experimental observations is only recently emerging. The initial approach to interrogate the surface chemistry of catalysts at the molecular level consisted of studying metal single crystals as models for reactive metal centers, moving later to single crystal or well-defined thin film oxides. The natural next iteration consisted in the deposition of metal nanoparticles on well-defined oxide substrates. Metal nanoparticles contain undercoordinated sites, which are more reactive. It is also possible to create architectures where oxide nanoparticles are deposited on top of metal single crystals, denominated inverse catalysts, leading in this case to a high concentration of reactive cationic sites in direct contact with the underlying fully coordinated metal atoms. Using a second oxide as a support (host), a multifunctional configuration can be built in which both metal and oxide nanoparticles are located in close proximity. Our recent studies on copper based catalysts are presented here as an example of the application of these complementary model systems, starting from the creation of undercoordinated sites on Cu(111) and Cu2O(111) surfaces, continuing with the formation of mixed-metal copper oxides, the synthesis of ceria nanoparticles on Cu(111) and the codeposition of Cu and ceria nanoparticles on TiO2(110). Catalysts have traditionally been characterized before or after reactions and analyzed based on static representations of surface structures. It is shown here how dynamic changes on a catalyst's chemical state and morphology can be followed during a reaction by a combination of in situ microscopy and spectroscopy. In addition to determining the active phase of a catalyst by in situ methods, the presence of weakly adsorbed surface species or intermediates generated only in the presence of reactants can be detected, allowing in turn the comparison of experimental results with first principle modeling of specific reaction mechanisms. Three reactions are used to exemplify the approach: CO oxidation (CO + 1/2O2 -> CO2), water gas shift reaction (WGSR) (CO + H2O -> CO2 + H2), and methanol synthesis (CO2 + 3H2 -> CH3OH + H2O). During CO oxidation, the full conversion of Cu(0) to Cu(2+) deactivates an initially outstanding catalyst. This can be remedied by the formation of a TiCuOx mixed-oxide that protects the presence of active partially oxidized Cu(+) cations. It is also shown that for the WGSR a switch occurs in the reaction mechanism, going from a redox process on Cu(111) to a more efficient associative pathway at the interface of ceria nanoparticles deposited on Cu(111). Similarly, the activation of CO2 at the ceria/Cu(111) interface allows its facile hydrogenation to methanol. Our combined studies emphasize the need of searching for optimal metal/oxide interfaces, where multifunctional sites can lead to new efficient catalytic reaction pathways. PMID- 26103059 TI - Quantum phase transitions in interfacing two gapped systems of ordinary fermions driven by external strain and atomic adsorption. AB - We study how the electronic structure of a single bilayer Bi on a single quintuple layer Bi2Se3 (Bi2Te3) changes with interface polarization, strain and H adsorption using first-principles calculations. We find that for strained systems the Dirac cone state does not show in the band gap. Coupled with strain and H adsorption, the six spin-polarized Dirac cones in the band gap are created by the interfacing two gapped films. The internal electrical field can result in variations in the work function relative to Bi and Bi2Se3 surfaces. Our findings confirm that the interface polarization, strain and atomic adsorption are the effective means to manipulate electronic structures and topological states on non metallic surfaces, which could be helpful for realizing atomically thin spintronic devices. PMID- 26103060 TI - Macrocyclic Cu(ii)-organophosphonate building block with room temperature magnetic ordering. AB - Engineering a copper coordination sphere with organoimine ligands and tuning the organophosphonate protonation states produced [{Cu(2,2'-bpy)}2(HO3P(CH2)8PO3H2)4] (1) and [{Cu(terpy)}2(2,7-FDA-H2)2].(2,7-FDA-H4)(2H2O) (2) (2,7-FDA-H4 = 2,7 fluorenonediphosphonic acid) macrocyclic copper-organophosphonate building blocks. 1 exhibits high temperature magnetic ordering, while 2 is paramagnetic. The structures were characterized by single crystal X-ray diffraction. PMID- 26103061 TI - Biological Efficacy and Toxicity of Diamidines in Myotonic Dystrophy Type 1 Models. AB - Myotonic dystrophy type 1 (DM1) is a disease characterized by errors in alternative splicing, or "mis-splicing". The causative agent of mis-splicing in DM1 is an inherited CTG repeat expansion located in the 3' untranslated region of the DM protein kinase gene. When transcribed, CUG repeat expansion RNA sequesters muscleblind-like (MBNL) proteins, which constitute an important family of alternative splicing regulators. Sequestration of MBNL proteins results in the mis-splicing of its regulated transcripts. Previous work has demonstrated that pentamidine, a diamidine which is currently FDA-approved as an antiparasitic agent, was able to partially reverse mis-splicing in multiple DM1 models, albeit at toxic concentrations. In this study, we characterized a series of pentamidine analogues to determine their ability to reverse mis-splicing and their toxicity in vivo. Experiments in cell and mouse models demonstrated that compound 13, also known as furamidine, effectively reversed mis-splicing with equal efficacy and reduced toxicity compared to pentamidine. PMID- 26103063 TI - Population Health Considerations for Pediatric Asthma: Findings from the 2011 2012 California Health Interview Survey. AB - Childhood asthma is a prevalent and costly chronic condition. Optimal management enables secondary and tertiary prevention. The goal was to identify population health considerations for pediatric asthma in California to inform the development of quality improvement interventions. California Health Interview Survey 2011-2012 is a random-digit dial telephone survey conducted in 5 languages. It includes 44,000 households from all 58 counties in California. This study assessed factors related to symptom control and health care use in children ages 2-11 years with asthma. An estimated 492,385 (9.6%) of children in California currently have asthma. Urban and rural residents face comparable asthma disease burdens. School-age male children as well as Asian and African American children are disproportionately affected. Asthma causes significant morbidity, with poorer health status, high utilization of emergency care, and the need for daily medication use. Only 38% of children with asthma have a recent asthma management plan. Half of all children with asthma did not receive influenza immunization in the past year, although this reflects the overall low rate of influenza vaccination. Parents of children with asthma frequently utilize the Internet for health information and communication with their child's health care provider. Children with asthma in California face several population-level challenges, including poor health status, low influenza vaccination rates, high use of emergency care, and suboptimal use of health literacy tools. Focusing on improved care coordination and preventive care for high-risk groups is especially urgent given the expansion of public health insurance and impending shortages in the primary care workforce. (Population Health Management 2016;19:145-151). PMID- 26103064 TI - Correction to "Polarizable Density Embedding: A New QM/QM/MM-based Computational Strategy". PMID- 26103062 TI - The dynamics of Rho GTPase signaling and implications for targeting cancer and the tumor microenvironment. AB - Numerous large scale genomics studies have demonstrated that cancer is a molecularly heterogeneous disease, characterized by acquired changes in the structure and DNA sequence of tumor genomes. More recently, the role of the equally complex tumor microenvironment in driving the aggressiveness of this disease is increasingly being realized. Tumor cells are surrounded by activated stroma, creating a dynamic environment that promotes cancer development, metastasis and chemoresistance. The Rho family of small GTPases plays an essential role in the regulation of cell shape, cytokinesis, cell adhesion, and cell motility. Importantly, these processes need to be considered in the context of a complex 3-dimensional (3D) environment, with reciprocal feedback and cross talk taking place between the tumor cells and host environment. Here we discuss the role of molecular networks involving Rho GTPases in cancer, and the therapeutic implications of inhibiting Rho signaling in both cancer cells and the emerging concept of targeting the surrounding stroma. PMID- 26103065 TI - Gas Sorption, Second-Order Nonlinear Optics, and Luminescence Properties of a Multifunctional srs-Type Metal-Organic Framework Built by Tris(4 carboxylphenylduryl)amine. AB - A chiral 8-fold interpenetrating srs-type metal-organic framework FIR-28 (FIR denotes Fujian Institute of Research) exhibits a surface area of 1029 m(2)/g and high C3H8/CH4 separation capacity in excess of 154 and displays strong powder second-harmonic-generation efficiency, with more than half over potassium dihydrogen phosphate powder. Moreover, the luminescence properties of FIR-28 are dependent on the solvent guests. PMID- 26103066 TI - Rapid Separation of Three Proanthocyanidin Dimers from Iris lactea Pall. var. Chinensis (Fisch.) Koidz by High-Speed Counter-Current Chromatography With Continuous Sample Load and Double-Pump Balancing Mode. AB - INTRODUCTION: The dried seeds of Iris lactea have been used in traditional Chinese medicine. Previous studies have been focused on irisquinones while other chemical components are rarely reported. OBJECTIVE: To establish an efficient high-speed counter-current chromatography (HSCCC) separation method with continuous sample load (CSL) and double-pump balancing (DPB) mode to isolate proanthocyanidins from I. lactea. METHODS: Firstly, an ethyl acetate extract of I. lactea was pre-fractionated by silica column chromatography for the enrichment of proanthocyanidins. Secondly, the enriched proanthocyanidins sample (EPS) was further fractionated by HSCCC with a two-phase solvent system ethyl acetate:n butanol:water (9:1:10, v/v/v) using DPB mode. The flow rate of the two phases was 2.2 mL/min, the revolution speed was 900 rpm, the separation temperature was 30 degrees C and the detection wavelength was 280 nm. Finally, the structures of the three isolated proanthocyanidins were elucidated by spectroscopic methods and compared with published data. RESULTS: Under the optimized conditions, 600 mg of the EPS with six continuous injections (100 mg/time) was fractionated, yielding 57 mg of prodelphinidin B3, 198 mg of procyanidin B3, and 162 mg of procyanidin B1, at purities of 97.2%, 98.1% and 97.3%, respectively. CONCLUSIONS: The HSCCC separation method with CSL and DPB proved to be rapid, convenient and economical, constituting an efficient strategy for the isolation of proanthocyanidins. PMID- 26103067 TI - Extension of conjugation: probing anion binding strength and reporter mechanisms in (phenyl)cyclopentadienyl and indenyl receptors. AB - Two families of novel organo-iron functionalized boranes have been developed for anion binding/detection. Synthetically simple phenylferrocene systems, while stable to air and moisture, possess similar binding affinities to FcBMes2 and no workable discrimination between F(-) and CN(-). In addition, reduced electronic communication between receptor and reporter sites brought about by a lack of conformational rigidity means that photochemical and electrochemical responses to anion binding are intrinsically weak. Receptors based on a more rigid indenyl framework are available in two steps from organic precursors (in ca. 50% yield), and feature intrinsically higher binding constants for F(-) and especially CN(-), consistent with the lower LUMO energies implied by extended conjugation. One such system, (4-dimesitylboryl-indenyl)cyclopentadienyl-iron(ii), can be shown to bind cyanide in protic media with an accompanying green to red/pink colour change. Extremely high selectivity over fluoride and hydroxide and a detection limit of ca. 10 ppm represent a highly desirable combination among borane derived cyanide receptors. PMID- 26103085 TI - A review on the salt bridge ASP177-ARG163 (O-N) of wild-type rabbit prion protein. PMID- 26103086 TI - Correction to Molecular Basis for Fe(III)-Independent Curcumin Potentiation of Cystic Fibrosis Transmembrane Conductance Regulator Activity. PMID- 26103087 TI - Experimental and Theoretical Investigations on the Nanoscale Kinetic Friction in Ambient Environmental Conditions. AB - The liquid lubrication, thermolubricity and dynamic lubricity due to mechanical oscillations are investigated with an atomic force microscope in ambient environmental conditions with different relative humidity (RH) levels. Experimental results demonstrate that high humidity at low-temperature regime enhances the liquid lubricity while at high-temperature regime it hinders the effect of the thermolubricity due to the formation of liquid bridges. Friction response to the dynamic lubricity in both high- and low-temperature regimes keeps the same trends, namely the friction force decreases with increasing the amplitude of the applied vibration on the tip regardless of the RH levels. An interesting finding is that for the dynamic lubricity at high temperature, high humidity condition leads to the friction forces higher than that at low-humidity condition while at low temperature the opposite trend is observed. An extended two-dimensional dynamic model accounting for the RH is proposed to interpret the frictional mechanism in ambient conditions. PMID- 26103088 TI - Efficacy of non-surgical periodontal therapy with adjunct Nd:YAG laser therapy in the treatment of periodontal inflammation among patients with and without type 2 diabetes mellitus: A short-term pilot study. AB - BACKGROUND AND AIM: Effect of non-surgical periodontal therapy (NSPT) with and without adjunctneodymium-doped:yttrium, aluminum and garnet (Nd:YAG) lasertherapy in the treatment of periodontal inflammation in patients with type 2 diabetes mellitus (T2DM) remains uninvestigated. The aim of the present short-term pilot study was to assess efficacy of NSPT with adjunct Nd:YAG laser therapy in the treatment of periodontal inflammation in patients with and without T2DM. METHODS: Twenty-two patients with T2DM (Group-1) and 22 controls (Group-2) were included. Teeth on test- and control-sites underwent NSPT with and without Nd:YAG laser therapy, respectively. Periodontal parameters (plaque index [PI], bleeding on probing [BOP] and probing pocket depth?4mm [PPD]) were measured at baseline and after 1 and 3months. Hemoglobin A1c (HbA1c) levels were measured at baseline and after 3months. RESULTS: In Group-1, PI, BOP and PPD?4mm were higher at the control-sites (6.4% [P<0.05], 5.5% [P<0.05] and 3.5% [P<0.05], respectively) than test-sites (1.5%, 2.1% and 1.1%, respectively) at 1-month follow-up. In Group-2, PI, BOP and PPD?4mm were higher at the control-sites (4.2% [P<0.05], 2.2% [P<0.05] and 2.2% [P<0.05], respectively) than test-sites (1.2%, 1.3% and 1.1%, respectively). At 3-months follow-up, there was no difference in PI, BOP and PPD?4mm among test- and control-sites in both groups. At 3-month follow-up, mean HbA1c levels were comparable among patients in groups 1 and 2 (5+/-0.2% and 4.6+/ 0.1%, respectively). CONCLUSION: These short-term pilot results support our hypothesis that NSPT+Nd:YAG laser therapy is more effective in reducing periodontal inflammation in patients with and without T2DM than when NSPT is used alone. Further long-term randomized controlled clinical trials are needed in this regard. PMID- 26103089 TI - An electron dynamics mechanism of charge separation in the initial-stage dynamics of photoinduced water splitting in X-Mn-water (X=OH, OCaH) and electron-proton acceptors. AB - An electron dynamics mechanism of charge separation in the initial stage of excited-state reactions of the class of X?Mn?OH2 ???A${ ?to }$X?Mn?OH???HA (X=OH or OCaH; A=N-methylformamidine, guanidine, imidazole, or ammonia cluster) is reported. The dynamic effect of calcium doping is also revealed. This study provides a novel factor to be considered in designing efficient systems for photoinduced water splitting. PMID- 26103091 TI - Editorial Comment for George et al. PMID- 26103090 TI - Pleiotropy as the Mechanism for Evolving Novelty: Same Signal, Different Result. AB - In contrast to the probabilistic way of thinking about pleiotropy as the random expression of a single gene that generates two or more distinct phenotypic traits, it is actually a deterministic consequence of the evolution of complex physiology from the unicellular state. Pleiotropic novelties emerge through recombinations and permutations of cell-cell signaling exercised during reproduction based on both past and present physical and physiologic conditions, in service to the future needs of the organism for its continued survival. Functional homologies ranging from the lung to the kidney, skin, brain, thyroid and pituitary exemplify the evolutionary mechanistic strategy of pleiotropy. The power of this perspective is exemplified by the resolution of evolutionary gradualism and punctuated equilibrium in much the same way that Niels Bohr resolved the paradoxical duality of light as Complementarity. PMID- 26103092 TI - Skeletal muscle-resident MSCs and bone formation. AB - Recent research has highlighted the importance of bone and muscle interactions during development and regeneration. There still remains, however, a large gap in the current understanding of the cells and mechanisms involved in this interplay. In particular, how muscle-derived cells, specifically mesenchymal stromal cells (MSCs), can impact bone regeneration or lead to pathologic ectopic bone formation is unclear. Here, a review is given of the evidence supporting the contribution of muscle-derived MSC to bone regeneration and suggesting a critical role for the inflammatory milieu. This article is part of a Special Issue entitled "Muscle Bone Interactions". PMID- 26103093 TI - Osteoblast-specific overexpression of amphiregulin leads to transient increase in femoral cancellous bone mass in mice. AB - The epidermal growth factor receptor ligand amphiregulin (AREG) has been implicated in bone physiology and in bone anabolism mediated by intermittent parathyroid hormone treatment. However, the functions of AREG in bone have been only incipiently evaluated in vivo. Here, we generated transgenic mice overexpressing AREG specifically in osteoblasts (Col1-Areg). pQCT analysis of the femoral metaphysis revealed increased trabecular bone mass at 4, 8, and 10weeks of age in Col1-Areg mice compared to control littermates. However, the high bone mass phenotype was transient and disappeared in older animals. Micro-CT analysis of the secondary spongiosa confirmed increased trabecular bone volume and trabecular number in the distal femur of 4-week-old AREG-tg mice compared to control littermates. Furthermore, MU-CT analysis of the primary spongiosa revealed unaltered production of new bone trabeculae in distal femora of Col1 Areg mice. Histomorphometric analysis revealed a reduced number of osteoclasts in 4-week-old Col1-Areg mice, but not at later time points. Cancellous bone formation rate remained unchanged in Col1-Areg mice at all time points. In addition, bone mass and bone turnover in lumbar vertebral bodies were similar in Col1-Areg and control mice at all ages examined. Proliferation and differentiation of osteoblasts isolated from neonatal calvariae did not differ between Col1-Areg and control mice. Taken together, these data suggest that AREG overexpression in osteoblasts induces a transient high bone mass phenotype in the trabecular compartment of the appendicular skeleton by a growth-related, non-cell autonomous mechanism, leading to a positive bone balance with unchanged bone formation and lowered bone resorption. PMID- 26103094 TI - CTRP3 acts as a negative regulator of osteoclastogenesis through AMPK-c-Fos NFATc1 signaling in vitro and RANKL-induced calvarial bone destruction in vivo. AB - Adipokines derived from adipocytes are important factors that act as circulating regulators of bone metabolism. C1q/tumor necrosis factor (TNF)-related Protein-3 (CTRP3) is a novel adipokine with multiple effects such as lowering glucose levels, inhibiting gluconeogenesis in the liver, and increasing angiogenesis and anti-inflammation. However, the effects and the mechanisms of CTRP3 on bone metabolism, which is regulated by osteoblasts and osteoclasts, have not been investigated. Here, we found that CTRP3 inhibited osteoclast differentiation induced by osteoclastogenic factors in bone marrow cell-osteoblast co-cultures, but did not affect the ratio of receptor activator of nuclear factor kappaB (NF kappaB) ligand (RANKL) to osteoprotegerin (OPG) induced by osteoclastogenic factors in osteoblasts. We also found that CTRP3 inhibited osteoclast differentiation from mouse bone marrow macrophages (BMMs) induced by RANKL in a dose-dependent manner without cytotoxicity. Functionally, CTRP3 inhibited the F actin formation and bone resorbing activity of mature osteoclasts. Pretreatment with CTRP3 significantly inhibited RANKL-induced expression of c-Fos and nuclear factor of activated T-cells (NFATc1), essential transcription factors for osteoclast development. Surprisingly, the activation of AMP-activated protein kinase (AMPK) was considerably increased by pretreatment with CTRP3 for 1h. The CTRP3-stimulated AMPK activation was also maintained during RANKL-induced osteoclastogenesis. CTRP3 did not affect RANKL-induced p38, ERK, JNK, Akt, IkappaB, CREB, and calcium signaling (Btk and PLCgamma2). These results suggest that CTRP3 plays an important role as a negative regulator of RANKL-mediated osteoclast differentiation by acting as an inhibitor of NFATc1 activation through the AMPK signaling pathway. Furthermore, CTRP3 treatment reduced RANKL-induced osteoclast formation and bone destruction in mouse calvarial bone in vivo based on micro-CT and histologic analysis. In conclusion, these findings strongly suggest that CTRP3 deserves new evaluation as a potential treatment target in various bone diseases associated with excessive osteoclast differentiation and bone destruction. PMID- 26103095 TI - Defining success with HIV pre-exposure prophylaxis: a prevention-effective adherence paradigm. PMID- 26103096 TI - Multiple chronic conditions and labor force outcomes: A population study of U.S. adults. AB - BACKGROUND: Although 1-in-5 adults have multiple (>= 2) chronic conditions, limited attention has been given to the association between multiple chronic conditions and employment. METHODS: Cross-sectional data (2011 National Health Interview Survey) and multivariate regression analyses were used to examine the association among multiple chronic conditions, employment, and labor force outcomes for U.S. adults aged 18-64 years, controlling for covariates. RESULTS: Among U.S. adults aged 18-64 years (unweighted, n = 25,458), having multiple chronic conditions reduced employment probability by 11-29%. Some individual chronic conditions decreased employment probability. Among employed adults (unweighted, n = 16,096), having multiple chronic conditions increased the average number of work days missed due to injury/illness in the past year by 3-9 days. CONCLUSIONS: Multiple chronic conditions are a barrier to employment and increase the number of work days missed, placing affected individuals at a financial disadvantage. Researchers interested in examining consequences of multiple chronic conditions should give consideration to labor force outcomes. PMID- 26103098 TI - The evolution of soybean mosaic virus: An updated analysis by obtaining 18 new genomic sequences of Chinese strains/isolates. AB - Soybean mosaic virus (SMV) is widely recognized as a highly damaging pathogen of soybean, and various strains/isolates have been reported to date. However, the pathogenic differences and phylogenetic relationships of these SMV strains/isolates have not been extensively studied. In the present work, by first obtaining 18 new genomic sequences of Chinese SMV strains/isolates and further compiling these with available data, we have explored the evolution of SMV from multiple aspects. First, as in other potyviruses, recombination has occurred frequently during SMV evolution, and a total of 32 independent events were detected. Second, using a maximum-likelihood method and removing recombinant fragments, a phylogeny covering 83 SMV sequences sampled from all over the world was reconstructed and the results showed four separate SMV clades, with clade I and II recovered for the first time. Third, the population structure analysis of SMV revealed significant genetic differentiations between China and two other countries (Korea and U.S.A.). Fourth, certain SMV-encoded genes, such as P1, HC Pro and P3, exhibited higher non-synonymous substitution rate (dN) than synonymous substitution rate (dS), indicating that positive selection has influenced these genes. Finally, four Chinese SMV strains/isolates were selected for inoculation of both USA and Chinese differential soybean cultivars, and their pathogenic phenotypes were significantly different from that of the American strains. Overall, these findings have further broadened our understanding on SMV evolution, which would assist researchers to better deal with this harmful virus. PMID- 26103099 TI - Functional characterization and proteomic analysis of the nucleocapsid protein of porcine deltacoronavirus. AB - Porcine deltacoronavirus (PDCoV) is a newly discovered enterotropic swine coronavirus that causes enteritis and diarrhea in piglets. Like other coronaviruses, PDCoV commonly contains 4 major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Among these, the N protein is known to be the most abundant and multifunctional viral component. Therefore, as the first step toward understanding the biology of PDCoV, the present study investigated functional characteristics and expression dynamics of host proteins in a stable porcine cell line constitutively expressing the PDCoV N protein. Similar to N proteins of other coronaviruses, the PDCoV N protein was found to interact with itself to form non-covalently linked oligomers and was mainly localized to the nucleolus. We then assessed alterations in production levels of proteins in the N-expressing PK (PK-PDCoV-N) cells at different time points by means of proteomic analysis. According to the results of high resolution two-dimensional gel electrophoresis, a total of 43 protein spots were initially found to be differentially expressed in PK-PDCoV-N cells in comparison with control PK cells. Of these spots, 10 protein spots showed a statistically significant alteration, including 8 up-regulated and 2 down-regulated protein spots and were picked for subsequent protein identification by peptide mass fingerprinting following matrix-assisted laser desorption/ionization time-of flight mass spectrometry. The affected cellular proteins that we identified in this study were classified into the functional groups involved in various cellular processes such as cell division, metabolism, the stress response, protein biosynthesis and transport, cytoskeleton networks and cell communication. Notably, two members of the heat shock protein 70 family were found to be up regulated in PK-PDCoV-N cells. These proteomic data will provide insights into the specific cellular response to the N protein during PDCoV infection. PMID- 26103100 TI - Confirmation of Y haplogroup tree topologies with newly suggested Y-SNPs for the C2, O2b and O3a subhaplogroups. AB - Y chromosome single nucleotide polymorphisms (Y-SNPs) are useful markers for reconstructing male lineages through hierarchically arranged allelic sets known as haplogroups, and are thereby widely used in the fields such as human evolution, anthropology and forensic genetics. The Y haplogroup tree was recently revised with newly suggested Y-SNP markers for designation of several subgroups of haplogroups C2, O2b and O3a, which are predominant in Koreans. Therefore, herein we analyzed these newly suggested Y-SNPs in 545 unrelated Korean males who belong to the haplogroups C2, O2b or O3a, and investigated the reconstructed topology of the Y haplogroup tree. We were able to confirm that markers L1373, Z1338/JST002613-27, Z1300, CTS2657, Z8440 and F845 define the C2 subhaplogroups, C2b, C2e, C2e1, C2e1a, C2e1b and C2e2, respectively, and that markers F3356, L682, F11, F238/F449 and F444 define the O subhaplogroups O2b1, O2b1b, O3a1c1, O3a1c2 and O3a2c1c, respectively. Among six C2 subhaplogroups (C2b, C2e, C2e1*, C2e1a, C2e1b and C2e2), the C2e haplogroup and its subhaplogroups were found to be predominant, and among the four O2b subhaplogroups (O2b*, O2b1*, O2b1a and O2b1b), O2b1b was most frequently observed. Among the O3a subhaplogroups, O3a2c1 was predominant and it was further divided into the subhaplogroups O3a2c1a and O3a2c1c with a newly suggested marker. However, the JST002613-27 marker, which had been known to define the haplogroup C2f, was found to be an ancestral marker of the C2e haplogroup, as is the Z1338 marker. Also, the M312 marker for the O2b1 haplogroup designation was replaced by F3356, because all of the O2b1 haplotypes showed a nucleotide change at F3356, but not at M312. In addition, the F238 marker was always observed to be phylogenetically equivalent to F449, while both of the markers were assigned to the O3a1c2 haplogroup. The confirmed phylogenetic tree of this study with the newly suggested Y-SNPs could be valuable for anthropological and forensic investigations of East Asians including Koreans. PMID- 26103097 TI - New insights into the expression and functions of the Kaposi's sarcoma-associated herpesvirus long noncoding PAN RNA. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) is a clinically relevant pathogen associated with several human diseases that primarily affect immunocompromised individuals. KSHV encodes a noncoding polyadenylated nuclear (PAN) RNA that is essential for viral propagation and viral gene expression. PAN RNA is the most abundant viral transcript produced during lytic replication. The accumulation of PAN RNA depends on high levels of transcription driven by the Rta protein, a KSHV transcription factor necessary and sufficient for latent-to-lytic phase transition. In addition, KSHV uses several posttranscriptional mechanisms to stabilize PAN RNA. A cis-acting element, called the ENE, prevents PAN RNA decay by forming a triple helix with its poly(A) tail. The viral ORF57 and the cellular PABPC1 proteins further contribute to PAN RNA stability during lytic phase. PAN RNA functions are only beginning to be uncovered, but PAN RNA has been proposed to control gene expression by several different mechanisms. PAN RNA associates with the KSHV genome and may regulate gene expression by recruiting chromatin-modifying factors. Moreover, PAN RNA binds the viral latency-associated nuclear antigen (LANA) protein and decreases its repressive activity by sequestering it from the viral genome. Surprisingly, PAN RNA was found to associate with translating ribosomes, so this noncoding RNA may be additionally used to produce viral peptides. In this review, I highlight the mechanisms of PAN RNA accumulation and describe recent insights into potential functions of PAN RNA. PMID- 26103101 TI - Degree of bother from pelvic floor dysfunction in women one year after first delivery. AB - OBJECTIVE: To investigate rates and range of pelvic floor dysfunction complaints, including anterior and posterior compartments and sexual function, in an unselected population of primiparous women one year from delivery, and examine the degree of bother they cause. STUDY DESIGN: Cross sectional study. Primiparous women who delivered their first child in our delivery wards 10-14 months previously, were approached by phone and asked to complete the Pelvic Floor Symptom Bother Questionnaire (PFBQ) and provide general demographic information. Details regarding participants' labor and delivery were extracted from electronic medical records. PFBQ score was correlated to demographic and labor and delivery parameters. RESULTS: 198 women completed the questionnaire. Response rate was 94%. Scores ranged from 0 to 44.4 (out of a possible 100). At least one symptom of PFD was reported by 64% of respondents. Various degrees of urinary incontinence were reported by 9.1-12.1% of women. Some degree of fecal or flatus incontinence was reported by 10.1% of women; 11.1% reported some degree of obstructed defecation. Severe degree of bother from one or more PFD symptoms was reported by 40.1-90.9%. Some level of dyspareunia was reported by 37.3%. A "dose response" trend between mode of delivery and rate of dyspareunia was observed. CONCLUSIONS: Two-thirds of primiparous women one year after delivery suffer PFD symptoms that cause some degree of bother. When asked, women are willing to discuss pelvic floor function; caregivers should initiate discussion and refer women promptly to interventions where necessary. PMID- 26103102 TI - [Cancer screening in the elderly?]. PMID- 26103103 TI - [Study of vitamin D supplementation in people over 65 years in primary care]. AB - BACKGROUND: Most of the elderly have vitamin D deficiency, which is defined as a serum level below 30 ng/mL. OBJECTIVES: To identify the characteristics of patients over 65 receiving vitamin D supplements by their primary care physician. A descriptive and transverse study was performed on patients over 65 years old admitted to Care Following at the La Croix Rouge in Nantes from September 2012 to February 2013. The criteria for vitamin D supplementation, the type (vitamin D2 or D3, continuous prescription or not, route of administration) and starting date of vitamin D supplementation were identified. Serum 25-hydroxyvitamin D (25OHD) was measured at admission. RESULTS: Of 163 patients included, 44% received vitamin D supplements (n=71). The patient aged over 80 benefited more often from vitamin D supplementation (p=0.019), so did women (p=0.034), patients with fractures (p=0.05), patients with osteoporosis treatments (p<0.001) and those treated with long-term corticosteroids (p<0.001). Dark skinned patients received vitamin D supplementation less often than the others (p=0.046). The dosage of the vitamin D was normal for 28% of patients (n=46). CONCLUSIONS: The prescription of vitamin D supplements to the elderly is still too scarce and should be encouraged, especially in non-bone indications. PMID- 26103104 TI - [Cancer screening practices in elderly with dementia]. AB - Current demographic trends and medical practices raise the question of cancer screening in the elderly, especially those with dementia. Furthermore, studies have suggested that patient with Alzheimer disease showed a reduced risk of cancer. However, this link may be biased by the absence of cancer screening. That's why we conducted a survey to poll general practitioners' (GP) opinion on screening cancer in the elderly. In this study, 304 general practitioners were asked, from May to March 2014, about their cancer screening practices and on the elements influencing it. Eighty-two physicians responded. The rate of response was 29.4%. Forty-nine (60%) GP said practicing cancer screening in the elderly, 60 (64%) thought that screening does not lead to treatment, 51 (62%) GP were not favorable to cancer screening in patients with dementia, 63 (77%) GP thought that there is a lack of recommendations to guide cancer screening in the elderly. Finally, this study shows that cancer screening is less performed in patients with dementia. Further, promote exchange between general practitioners and specialists, by strengthening Cancer and Geriatrics networks, could probably increase cancer screening in the elderly, with or without dementia. PMID- 26103105 TI - [Management and new current French recommendations for tetanus care]. AB - Tetanus is an acute severe disease induced by an exotoxin, often lethal. All cases occur in untreated or inadequately vaccinated patients and mainly in elderly patients who accumulate many risk factors. The current management of wounds faced difficulties in the assessment of immunization status and wound risks status. Indeed, all injuries can potentially lead to tetanus. Minor risks and chronic wounds are mainly found as tetanus cause. Vaccination remains the key element in reducing the morbidity and mortality associated with tetanus. It is estimated that the vaccine's coverage is fairly good, but decreases with age. To improve tetanus prevention, new vaccine recommendations have been established which recommend vaccine's injections at fixed age, but their impact seems to be limited especially in the elderly. The immunochromatographic tests have demonstrated cost-effectiveness in the Emergency department settings. They are currently not available outside hospital while general practionners also face a significant risk. Effectiveness of these tests should be studied in outpatients population including cost-effectiveness. PMID- 26103106 TI - [Interventions based on mindfulness for the elderly chronic pain: review of the literature]. AB - The chronic pain-bio-psycho-social phenomenon would index a transition between a pain alarm and a pain disease, with reshaping of the inhibitive brain areas and a takeover of psychological factors on the modulatory systems. The current treatment of elders' chronic pain suffers from many limits, and this article addresses this issue by discussing a new and innovative non-pharmacological intervention (mindfulness therapy) to reduce consequences of chronic pain in daily-life. Mindfulness therapy mainly targets two transdiagnostic mental processes - avoidance and self-centered ruminations - which leads to emotional dysregulation in chronic pain patients. Although many studies documented the beneficial effect of mindfulness therapy on psychological symptoms in adults, there is still a lack of studies testing the effect of mindfulness therapy on emotional regulation and psychological symptoms in elderly population with chronic pain. It is therefore necessary to investigate therapeutic efficacy with this population. In conclusion, we formulate several lines of research to test the hypothesis that the effect of the mindfulness therapy on targeted processes would improve elders' ability to cope with chronic pain and would reduce disturbances associated with chronic pain. PMID- 26103107 TI - [Late-onset lupus in the elderly after 65 years: retrospective study of 18 cases]. AB - OBJECTIVE: The aim of our study was to investigate characteristics of late-onset lupus after 65 years compared to younger ones. METHOD: Patients with lupus revealed after 65 years were investigated in four French hospitals between 1985 and 2013. Patients with 4 ACR criteria or more were included. Clinical and biological characteristics, prognosis, treatment, comorbidities were described retrospectively and compared to the cohort of 1000 lupus patients of Cervera et al. RESULTS: Eighteen patients were included (14 women and 4 men). The most frequent features were arthritis (13/18), skin involvement (9/18). Hemolytic anemia and thrombosis were more frequently found in elderly lupus (p<0.05). During evolution, only cutaneous involvement were less frequent than in young subjects (p <0.05). Corticosteroids were often used (16/18), but iatrogenic complications were frequent (10/16). CONCLUSION: Diagnosis is difficult because of non-specific clinical features. Treatment needed a rigourous follow-up because of iatrogenic complications. PMID- 26103108 TI - [Measuring the impact of an "age-friendly city" approach on a territory by setting up cross-cutting indicators]. AB - The "Age-friendly cities" program has been developing in France since 2010. So far the existing protocols had not allowed cities to assess actions taken in favor of elderly people comprehensively. The work done with the Francophone network of age-friendly cities (RFVAA) has led to the definition of an indicator consisting of 12 points; the relative importance of each target was weighted using a decision-making tool. This work has demonstrated the major role of governance in the implementation of cross-cutting policies for the benefit of older people. PMID- 26103109 TI - [Night of the Alzheimer's patient: the nightmare of the caregiver via the caregivers'guides]. AB - Care for Alzheimers' patients is quite a burden on the caregivers. Guides have been devoted to improve their knowledge about the disease and to help to provide the best care for the patient. A recent study on the reluctance of caregivers'spouses to seek external help, shows that none of 31 spouses had read a caregiver's guide. The aim of this study was to assess if caregiver's guides would help caregivers to deal with sleep/wake disorders. Amongst the 46 French guides, published between 1988 and 2013, thirty three raised the subject of the night sleep with more or less details. In these guides sleep disturbances are considered either as a symptom to be monitored or a natural aging process to be supported. We made a survey of the content of the caregiver's guides, of their goals and why they have been designed to. Then we analyze how the night sleep issue is dealt with in the guides, and eventually we consider the place to be granted to the patient in the management of his/her sleep disturbances. PMID- 26103110 TI - [Brain tumors, cognitive and mental disorders in adults]. AB - Cognitive and mental disorders are observed in 15-20% of brain tumors, and can be the first symptoms. The severity of cognitive deficits varies from attention and raisoning disorders to major syndromes such as delirium, amnesic syndrome or dementia. Mental disorders range from apathy, irritability to major depressive or psychotic symptoms. Cognitive and mental disorders are related to many factors including the localization and nature of the tumor, peritumoral and remote changes, and personal suceptibility. The diagnosis of brain tumor is presently made by brain imagery, but the difficulty remains to determine when imagery is to be used in cognitive or mental disorders. PMID- 26103111 TI - [Hearing loss and Alzheimer's disease]. AB - Recent studies suggest that subjects with hearing loss are more likely to develop Alzheimer's disease. Hearing loss can be consecutive to presbycusis and/or to central auditory dysfunction. Standard audiometric measures (pure tone and speech intelligibility) allow the diagnosis of presbycusis. However, to demonstrate central auditory dysfunction, specific audiometric tests are needed such as noisy and/or dichotic tests. Actually, no consensus exists to investigate hearing loss in people with Alzheimer's disease though hearing loss may be an early manifestation of Alzheimer's disease. Until now, investigations and clinical procedure related to the diagnosis of Alzheimer's disease ignored the hearing ability of the patient. However, the major part of care management and investigations implies the patient's communication ability with the caregivers. Hearing loss may be one of the most unrecognized deficit in subjects with Alzheimer's disease. Auditory rehabilitation could benefit to the patient in order to lessen cognitive decline, but this must be investigated during longitudinal studies in order to clearly demonstrate their efficiency. PMID- 26103112 TI - [Anxiety disorders in older adults]. AB - Prevalence of anxiety disorders is high in the elderly (between 3.2 and 14.2% of the subjects) with, by order of frequency, phobic disorders and generalized anxiety disorder rank ahead of panic disorders, obsessive-compulsive disorder or post-traumatic stress disorder. Anxiety disorders very often start in adulthood and become chronic thereafter. It should be pointed out that each anxiety disorder has clinical characteristics that are modified with aging. Among the psychiatric comorbidity, depressive disorders and addictions, mainly to alcohol, especially stand out. Very few studies on anxiety disorders were specifically performed in the elderly. Drug treatments are mainly based on antidepressants (selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors) and there is little consensus over the duration of the treatment. On the other hand, non-pharmacological treatments are proposed, such as supportive psychotherapy and cognitive-behavioural therapies, with specific programs to improve anxiety disorders in the elderly. PMID- 26103113 TI - [Do the structure and functioning of the elderly's social network influence functional health: a preliminary study]. AB - We examined structural and functional characteristics of social networks related to health and well-being among community-dwelling older adults. A survey was performed in Brussels, using an original name-generating network inventory, to explore the structure and types of social ties (e.g. children, friends, neighbors) which forms the elderly's network. Different kinds of support (instrumental, emotional, social) were assessed due to the multiple contents of social exchanges between the elderly and their network's members. Our results highlighted some important social network resources. Especially, social participation, contacts with friends of the same age and reciprocity of social relationships are likely to promote functional health and well-being in later life. We discuss our findings in relation to major social network's typologies referring to older adults. PMID- 26103114 TI - [The SQK: a semantic knowledge questionnaire to specify the severity of semantic deterioration in Alzheimer's disease patients]. AB - Lexico-semantic difficulties are common in Alzheimer's disease (AD). The bottom up process theory is today well accepted: superordinate attributes tend to decline slower than subordinate ones. However, a specific issue in semantic memory investigation in AD is to determine the severity of the semantic impairment. Given that the regularity of the semantic disorder in early AD is uncertain, we argue that the constitution of experimental AD groups must consider the semantic deterioration stage. We thus propose a specific semantic knowledge questionnaire (SKQ), based on Laiacona et al.'s work (1993). SKQ was proposed to 49 AD patients and 33 healthy old people. Three experimental AD groups were created, based on the global cognitive deterioration. In a second study, we explore the possibility for early AD to display different semantic deterioration profile. Our results show a significant group effect, a significant type of question effect (superordinate vs subordinate) and a significant interaction effect. Moreover, a significant correlation between the total errors at the SKQ and the MMSE score is observed. Finally, we observe that early AD patients can show different semantic alteration, with mild or very mild semantic deterioration without any differences in the global cognitive alteration. The SKQ seems adapted to highlight the semantic deterioration and the bottom-up process in AD: superordinate information are better preserved than subordinate information. It can also distinguish different semantic deterioration in early AD. Our result clearly show that research on semantic deterioration in early stage of AD must take into account the severity of the semantic alteration. PMID- 26103115 TI - Interactions between multisensory inputs with voluntary spatial attention: an fMRI study. AB - Cross-modal attention and multisensory integration are very essential for us to perceive the world. The most intuitive feelings about the environment around us are based on what we see and what we hear. Therefore, it is important to understand the interactions between visual inputs and auditory inputs. Previous studies have shown that multisensory integration can be modulated by attention. However, how top-down attention is controlled or allocated across the sensory modalities remains unclear. In this study, we measured the cortical areas activated by the cue-target spatial attention paradigm in both visual and auditory fields using functional MRI. The reaction times of the behavioral results indicated that interactions between the two types of stimuli exist. The imaging results indicated that interactions between multisensory inputs can lead to enhancement or depression of the cortical response with top-down spatial attention. Moreover, the activation of the middle temporal gyrus and insula in tasks with irrelevant stimuli appears to indicate that multisensory integration proceeds automatically. PMID- 26103116 TI - The process of change in hemodynamics after revascularization in the ischemic brain. AB - In patients with a high-degree of internal carotid artery stenosis, cerebral hemodynamics and metabolism are compromised during ischemia. Revascularization improves cortical hemodynamics and oxygen metabolism during functional activity, but the process by which it occurs is still controversial. Therefore, using functional near-infrared spectroscopy (fNIRS), we investigated the process by which cerebral hemodynamics improve after revascularization surgery. Eight patients with severe carotid artery stenosis were examined using fNIRS during a motor task before and after surgery. We evaluated postoperative changes in total hemoglobin and deoxyhemoglobin (HbR), at 2 weeks after surgery, and again at 3 months after surgery. Parameters measured were the TTP (time to peak) value, defined as the time taken to reach 70% of the maximum total hemoglobin concentration, and the increase in HbR during the motor task. TTP was higher in four patients preoperatively, but this was no longer evident in two of the patients at 2 weeks after surgery. An increase in HbR during the task was observed in six patients before surgery, and was maintained at 2 weeks after surgery. However, in three of these patients, this increase was no longer evident 3 months later. These changes observed using fNIRS suggest that the increase in cerebral blood flow after revascularization surgery is followed by improvement in parenchymal vasodilation and neuronal oxygen metabolism. PMID- 26103117 TI - Effects of cathodal transcranial direct current stimulation to primary somatosensory cortex on short-latency afferent inhibition. AB - The aim of this study was to investigate the effects of cathodal transcranial direct current stimulation (tDCS) applied over the primary somatosensory cortex (S1) on short-interval afferent inhibition (SAI). Thirteen healthy individuals participated in this study. Cathodal tDCS was applied for 15 min at 1 mA over the left S1. Motor-evoked potentials (MEPs) were measured from the right first dorsal interosseous muscle in response to transcranial magnetic stimulation (TMS) of the left motor cortex before tDCS (pre), immediately after tDCS (immediately), and 15 min after tDCS (post-15 min). SAI was evaluated by measuring MEPs in response to TMS pulses applied 40 ms after peripheral electrical stimulation of the index finger. For each measurement period (pre, immediately, and post-15 min), MEP amplitude was significantly smaller when TMS followed index finger stimulation (SAI condition) than when TMS was delivered alone (single TMS) (P<0.01), indicating expression of SAI. The MEP ratio (MEP of SAI/MEP of single TMS) at post-15 min was significantly larger than that of pre (P<0.05), indicating suppression of SAI. However, no significant difference was observed between pre and immediately, and immediately and post-15 min. These results suggest that cathodal tDCS applied over the S1 causes a decrease in S1 excitability following peripheral electrical stimulation and cathodal tDCS applied over the S1 decreased the inhibitory effects of SAI. PMID- 26103118 TI - Increased serum levels of brain-derived neurotrophic factor in autism spectrum disorder. AB - The aim of this study was to investigate the potential role of brain-derived neurotrophic factor (BDNF) in children with autism spectrum disorders (ASD) by measuring serum circulating levels of BDNF as well as calcium and comparing them with age-matched and sex-matched normal controls. The study included 75 drug naive ASD children and 75 age-sex-matched healthy children. The concentration of serum BDNF was determined using the enzyme-linked immunosorbent assay method at baseline. Clinical information was collected. The severity of ASD was assessed at admission using the Childhood Autism Rating Scale total score. The results indicated that the mean serum BDNF levels were significantly (P<0.0001) higher in children with ASD compared with the control cases (17.59+/-5.55 vs. 11.21+/-2.79 ng/ml; t=8.902). On the basis of the receiver operating characteristic curve, the optimal cutoff value of serum BDNF levels as an indicator for auxiliary diagnosis of autism was projected to be 12.65 ng/ml, which yielded a sensitivity of 80.8% and a specificity of 70.2%; the area under the curve was 0.840 [95% confidence interval (CI), 0.777-0.904]. In univariate logistic regression analysis, with an unadjusted odds ratio of 9.42 (95% CI, 4.33-25.95; P<0.0001), BDNF of 12.65 ng/ml or more had an association with a diagnosis of ASD. After adjusting for possible covariates, BDNF of 12.65 ng/ml or more is still an independent indicator of ASD, with an adjusted odds ratio of 7.33 (95% CI, 2.98-16.55; P<0.0001). Serum BDNF levels may be associated independently with the severity of ASD, and higher BDNF levels could be considered an independent diagnostic marker of ASD. PMID- 26103119 TI - Eye surface temperature detects stress response in budgerigars (Melopsittacus undulatus). AB - Previous studies have suggested that stressors not only increase body core temperature but also body surface temperature in many animals. However, it remains unclear whether surface temperature could be used as an alternative to directly measure body core temperature, particularly in birds. We investigated whether surface temperature is perceived as a stress response in budgerigars. Budgerigars have been used as popular animal models to investigate various neural mechanisms such as visual perception, vocal learning, and imitation. Developing a new technique to understand the basic physiological mechanism would help neuroscience researchers. First, we found that cloacal temperature correlated with eye surface temperature. Second, eye surface temperature increased after handling stress. Our findings suggest that eye surface temperature is closely related to cloacal temperature and that the stress response can be measured by eye surface temperature in budgerigars. PMID- 26103120 TI - Emotional effect on cognitive control in implicit memory tasks in patients with schizophrenia. AB - The aim of this study was to reveal a potential effect of emotion on cognitive control in the implicit memory task with emotionally neutral and unpleasant words in healthy controls and patients with schizophrenia using a 3.0 T functional MRI (fMRI). A total of 15 patients with schizophrenia and 15 healthy controls underwent the fMRI. fMRI data were obtained while the participants performed the implicit memory tasks with emotionally neutral and unpleasant words. During the implicit memory retrieval with emotionally neutral words, the predominant activation areas observed in patients in contrast to healthy controls included the precuneus, superior parietal gyrus, and dorsolateral prefrontal cortex (dlPFC). In the implicit memory retrieval with unpleasant words, patients with schizophrenia showed dominant activities in the superior and middle temporal gyri, fusiform gyrus, supramarginal gyrus, postcentral gyrus, occipital gyrus, lingual gyrus, parahippocampal gyrus, amygdala, and insula as well as precuneus, superior parietal gyrus, and dlPFC. Blood-oxygen-level-dependent signal changes in the dlPFC were correlated positively with the scores of the negative symptoms under the PANSS during implicit memory retrieval with unpleasant words in patients with schizophrenia. These findings would be useful to understand the neural mechanisms related to general impairment of cognitive and emotional functions commonly observed in schizophrenia. PMID- 26103121 TI - Elevated neuronal alpha-synuclein promotes microglia activation after spinal cord ischemic/reperfused injury. AB - The present study aimed to investigate the mechanism of injured neurons caused by ischemia/reperfusion in the induction of microglia activation. Spinal neurons were prepared and exposed to ischemic/reperfused conditions. The alpha-synuclein protein levels in these cells were analyzed by western blot, immunofluorescence, or enzyme-linked immunosorbent assay. Ischemia/reperfusion exposure led to elevated alpha-synuclein protein expression and release. Furthermore, when cocultured with injured neurons or supernatants from injured neurons, nitric oxide generation, H2O2 production, and tumor necrosis factor-alpha expression were promoted in microglia. Nevertheless, this effect was impeded by pretreatment of the alpha-synuclein antibody in the supernatants from injured neurons. Moreover, toll-like receptor 2 (TLR2) rather than TLR3 or TLR4 mediated microglia activation by alpha-synuclein. This process involved p38 MAPK and NF-kappaB activation, the inhibition of which resulted in reduced NADPH oxidase 2 (Nox2) in microglia. In conclusion, ischemia/reperfusion-injured neurons could express and release increased levels of alpha-synuclein and cause microglia activation through TLR2 both in vitro and in vivo. PMID- 26103123 TI - Effective risk stratification in patients with moderate cardiovascular risk using albuminuria and atherosclerotic plaques in the carotid arteries. AB - OBJECTIVES: The aim of this study was to investigate whether subclinical vascular damage improved traditional risk prediction, reclassifying individuals with regard to primary prevention. METHODS: Two thousand and fifty-nine healthy individuals aged 41, 51, 61, and 71 years were divided into age, Systematic COronary Risk Evaluation (SCORE), and Framingham risk score (FRS) groups. Subclinical vascular damage was defined as carotid-femoral pulse wave velocity at least 12 m/s, and carotid atherosclerotic plaques or urine albumin/creatinine ratio (UACR) at least 90th percentile of 0.73/1.06 mg/mmol in men/women. The composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was recorded (n = 229). RESULTS: Both elevated UACR (P = 0.002) and atherosclerotic plaques (P < 0.0001) identified a subgroup of moderate SCORE risk patients and high intermediate FRS risk patients with high risk (P = 0.04 and P = 0.001, respectively), whereas elevated carotid-femoral pulse wave velocity did not. Elevated UACR or presence of atherosclerotic plaques reclassified patients from moderate to high SCORE risk [net reclassification improvement of 6.4%; P = 0.025), or from high intermediate to high FRS risk (net reclassification improvement 8.8%; P = 0.002). Assuming primary prevention could reduce the relative cardiovascular risk by 24-27%, on the basis of actual levels of blood pressure and cholesterol, one composite endpoint could be avoided by giving primary prevention to 19 or 24 reclassified patients found by screening 52 or 104 patients with high-intermediate FRS or moderate SCORE risk, respectively. CONCLUSION: Elevated UACR and presence of atherosclerotic plaques could in a potentially cost-effective manner identify patients with moderate SCORE risk or high-intermediate FRS with actual high cardiovascular risk who will benefit from primary prevention. PMID- 26103122 TI - The Yeast GSK-3 Homologue Mck1 Is a Key Controller of Quiescence Entry and Chronological Lifespan. AB - Upon starvation for glucose or any other core nutrient, yeast cells exit from the mitotic cell cycle and acquire a set of G0-specific characteristics to ensure long-term survival. It is not well understood whether or how cell cycle progression is coordinated with the acquisition of different G0-related features during the transition to stationary phase (SP). Here, we identify the yeast GSK-3 homologue Mck1 as a key regulator of G0 entry and reveal that Mck1 acts in parallel to Rim15 to activate starvation-induced gene expression, the acquisition of stress resistance, the accumulation of storage carbohydrates, the ability of early SP cells to exit from quiescence, and their chronological lifespan. FACS and microscopy imaging analyses indicate that Mck1 promotes mother-daughter cell separation and together with Rim15, modulates cell size. This indicates that the two kinases coordinate the transition-phase cell cycle, cell size and the acquisition of different G0-specific features. Epistasis experiments place MCK1, like RIM15, downstream of RAS2 in antagonising cell growth and activating stress resistance and glycogen accumulation. Remarkably, in the ras2? cells, deletion of MCK1 and RIM15 together, compared to removal of either of them alone, compromises respiratory growth and enhances heat tolerance and glycogen accumulation. Our data indicate that the nutrient sensor Ras2 may prevent the acquisition of G0 specific features via at least two pathways. One involves the negative regulation of the effectors of G0 entry such as Mck1 and Rim15, while the other likely to involve its functions in promoting respiratory growth, a phenotype also contributed by Mck1 and Rim15. PMID- 26103124 TI - Aerobic exercise training increases nitrergic innervation function and decreases sympathetic innervation function in mesenteric artery from rats fed a high-fat diet. AB - INTRODUCTION: We investigated whether high-fat diet (HFD)-induced obesity was associated with modifications in mesenteric innervation function, the mechanisms involved, and the possible effects of aerobic exercise training on these changes. MATERIALS AND METHODS: Male Wistar rats were divided into three groups: rats fed a standard diet (control group); rats fed a HFD (35% fat) for 8 weeks; and HFD rats submitted to aerobic exercise training (8 weeks, 5 times per week for 50 min). Segments of isolated mesenteric arteries were exposed to electric field stimulation (EFS) with or without phentolamine, suramin, or Nomega nitro-L arginine methyl ester. Noradrenaline, ATP, and nitric oxide release, and total and phosphorylated neuronal nitric oxide synthase (nNOS, P-nNOS) expression were also measured. RESULTS: EFS contraction was greater in sedentary HFD than in control rats. Phentolamine reduced EFS contractions more markedly in HFD rats. Suramin decreased EFS contractions only in control rats. Phentolamine + suramin practically abolished EFS-induced contraction in control rats, whereas it did not modify it in the HFD rats. Noradrenaline release was greater and ATP was lower in HFD rats. Nomega nitro-L-arginine methyl ester increased contractions to EFS only in segments from control rats. Nitric oxide release and nNOS and P-nNOS expressions were lower in arterial segments from HFD rats than from control rats. None of these changes in sedentary HFD rats was present in the trained HFD rats. CONCLUSIONS: Enhanced sympathetic and diminished nitrergic components contributed to increased vasoconstrictor responses to EFS in sedentary HFD rats. All these changes were avoided by aerobic exercise training, suggesting that aerobic exercise could reduce peripheral vascular resistance in obesity. PMID- 26103125 TI - Circulating tissue inhibitor of matrix metalloproteinase-1 is associated with aldosterone-induced diastolic dysfunction. AB - OBJECTIVE: To test if collagen markers are associated with aldosterone-induced diastolic dysfunction. BACKGROUND: Although primary aldosteronism is associated with more prominent cardiac remodeling and diastolic dysfunction, the reversibility of diastolic function is unclear. In addition, there is no known biomarker associated with aldosterone-induced diastolic dysfunction. METHODS: We enrolled 27 patients with aldosterone-producing adenoma (APA) preparing for adrenalectomy, and 27 patients with essential hypertension prospectively from October 2006 to March 2010 at a tertiary referral center. Plasma matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were measured, and echocardiography including tissue Doppler images was performed in both groups and 1 year after receiving adrenalectomy in the APA group. RESULTS: The baseline plasma TIMP-1 level (88.4 +/- 38.7 vs. 63.6 +/- 32.5 ng/ml; P = 0.014), left ventricular mass index (LVMI), and E/E' ratio (11.5 +/- 2.9 vs. 9.0 +/- 2.1; P < 0.001) were significantly higher in the APA group. The baseline plasma TIMP-1 level significantly correlated with the E/E' ratio, LVMI, interventricular septum, and left atrial diameter. The plasma MMP-2 level did not correlate with the left ventricular structure parameters, except for interventricular septum thickness. After adrenalectomy, LVMI and E/E' ratio improved significantly. The postadrenalectomy plasma TIMP-1 levels, but not MMP-2 levels, also decreased. The change of plasma TIMP-1 levels was negatively associated with the postadrenalectomy E/E' ratio after adjustment for age, sex, BMI, and mean blood pressure (beta-coefficient = - 3.6, P = 0.004). CONCLUSION: Excess of aldosterone induces cardiac diastolic dysfunction, which is reversible by adrenalectomy. TIMP-1 is associated with the aldosterone-induced diastolic dysfunction. PMID- 26103126 TI - Plasma copeptin levels and ambulatory blood pressure characteristics in healthy adults. AB - OBJECTIVE: We investigated whether copeptin - a well characterized vasopressin related stress hormone - is associated with circadian ambulatory blood pressure (BP) variability and/or mean BP levels in young adults. METHOD AND RESULTS: We studied a population-based sample of healthy adults aged 25-41 years. Individuals with diabetes, treated hypertension, and cardiovascular disease were excluded. Ambulatory 24-h BP monitoring was performed using validated devices. To evaluate the relationships of copeptin with mean ambulatory BP levels and BP variability during daytime and night-time, multivariable adjusted regression models were constructed. BP variability was defined as SD of all intraindividual BP values. Of the 2012 individuals included in this study, 53% were women and the median age was 37 years. Median plasma copeptin levels were 3.9 (interquartile range 2.7, 5.8) in men and 2.3 pmol/l (interquartile range 1.6, 3.6) in women (P < 0.0001). In multivariable linear regression models, log-transformed copeptin was significantly associated with systolic and diastolic night-time BP levels among men [beta = 1.9, 95% confidence interval (CI) 0.6, 3.1, P = 0.003; and beta = 1.4, 95% CI 0.6, 2.3, P = 0.001, respectively], but not among women. In addition, copeptin was strongly associated with an increased systolic and diastolic daytime (beta = 0.5, 95% CI 0.2, 0.7, P = 0.001; beta = 0.5, 95% CI 0.3, 0.8, P < 0.0001, respectively) and night-time BP variability (beta = 0.6, 95% CI 0.3, 0.9, P = 0.0002; beta = 0.4, 95% CI 0.2, 0.7, P = 0.002, respectively). CONCLUSION: In this large population-based study of young and healthy adults, plasma levels of copeptin were significantly associated with an increased BP variability in both sexes and an elevated night-time BP among men. PMID- 26103127 TI - Association of visceral and total body fat with hypertension and prehypertension in a middle-aged Chinese population. AB - OBJECTIVE: This article investigates the relative effects of percentage body fat (PBF) and visceral fat index (VFI) on the prevalence of hypertension and prehypertension, and evaluates if excess visceral deposition of body fat increased the risk of hypertension or prehypertension. METHODS: A general population-based sample of men (n = 5297) and women (n = 6232), aged 35-64 years, was studied. Based on blood pressure (BP) levels, normotensive, prehypertensive, and hypertensive study participants were identified. Multivariate linear regression models with SBP or DBP as a dependent variable and multivariate ordinal logistic regression models with BP categories as a dependent variable were performed. RESULTS: In the normotensive, prehypertensive, and hypertensive participants, the mean (standard deviation) PBF was 27.83 (6.85), 28.91 (6.65), and 30.2 (6.73), respectively, whereas VFI was 6.97 (3.78), 8.89 (4.35), and 10.75 (5.05), respectively. After adjusting for age, smoking, alcohol consumption, education, regions (north or south), areas (urban or rural), diabetes, and family history, PBF and VFI (in separate models) showed a strong positive association with hypertension or prehypertension (P < 0.0001). However, when both PBF and VFI were adjusted for in the same multivariate model, VFI but not PBF remained positively associated with hypertension and prehypertension for both genders (P < 0.0001). A similar positive association was reported with the VFI/PBF ratio (P < 0.0001). CONCLUSION: As excess visceral body fat is strongly associated with higher risk of hypertension and prehypertension, measurements of VFI or VFI/PBF ratio, in addition to PBF, will provide a better understanding of adiposity-related risks for hypertension and prehypertension. PMID- 26103128 TI - Two candidate genes for two quantitative trait loci epistatically attenuate hypertension in a novel pathway. AB - OBJECTIVES: Multiple quantitative trait loci (QTLs) for blood pressure (BP) have been detected in rat models of human polygenic hypertension. They influence BP physiologically via epistatic modules. Little is known about the causal genes and virtually nothing is known on modularized mechanisms governing their regulatory connections. METHODS AND RESULTS: Two genes responsible for two individual BP QTLs on rat Chromosome 18 have been identified that belong to the same epistatic module. Treacher Collins-Franceschetti syndrome 1 (Tcof1) gene is the only function candidate for C18QTL3. Haloacid dehalogenase like hydrolase domain containing 2 (Hdhd2), although a gene of previously unknown function, is C18QTL4, and encodes a newly identified phosphatase. The current work has provided the premier evidence that Hdhd2/C18QTL4 and Tcof1/C18QTL3 may be involved in polygenic hypertension. Hdhd2/C18QTL4 can regulate the function of Tcof1/C18QTL3 via de-phosphorylation, and, for the first time, furbishes a molecular mechanism in support of a genetically epistatic hierarchy between two BP QTLs, and thus authenticates the epistasis-common pathway paradigm. CONCLUSION: The pathway initiated by Hdhd2/C18QTL4 upstream of Tcof1/C18QTL3 reveals novel mechanistic insights into BP modulations. Their discovery might yield innovative therapeutic targets and diagnostic tools predicated on a novel BP cause and mechanism that is determined by a regulatory hierarchy. Optimizing the de-phosphorylation capability and its downstream target could be antihypertensive. The conceptual paradigm of an order and regulatory hierarchy may help unravel genetic and molecular relationships among certain human BP QTLs. PMID- 26103129 TI - n-3 fatty acids reduce plasma 20-hydroxyeicosatetraenoic acid and blood pressure in patients with chronic kidney disease. AB - BACKGROUND: Metabolism of arachidonic acid by cytochrome P450 omega-hydroxylase leads to the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) that regulates vascular function, sodium homeostasis and blood pressure (BP). Supplementation with n-3 fatty acids is known to alter arachidonic acid metabolism and reduce the formation of the lipid peroxidation products F2 isoprostanes, but the effect of n-3 fatty acids on 20-HETE has not been studied. METHOD: We previously reported a significant effect of n-3 fatty acids but not coenzyme Q10 (CoQ) to reduce BP in a double-blind, placebo-controlled intervention, wherein patients with chronic kidney disease (CKD) were randomized to n-3 fatty acids (4 g), CoQ (200 mg), both supplements or control (4 g olive oil), daily for 8 weeks. This study examined the effect of n-3 fatty acids on plasma and urinary 20-HETE in the same study, as well as plasma and urinary F2 isoprostanes, and relate these to changes in BP. RESULTS: Seventy-four patients completed the 8-week intervention. n-3 fatty acids but not CoQ significantly reduced plasma 20-HETE (P = 0.001) and F2-isoprostanes (P < 0.001). In regression models adjusted for BP at baseline, postintervention plasma 20-HETE was a significant predictor of the fall in SBP (P < 0.0001) and DBP (P < 0.0001) after n-3 fatty acids. CONCLUSION: This is the first report that n-3 fatty acid supplementation reduces plasma 20-HETE in humans and that this associates with reduced BP. These results provide a plausible mechanism for the reduction in BP observed in patients with CKD following n-3 fatty acid supplementation. PMID- 26103130 TI - Family history of hypertension and serum triglycerides predict future insulin sensitivity: a 17-year follow-up study of young men. AB - OBJECTIVE: Low insulin sensitivity is closely related to both cardiovascular diseases and diabetes development. Still, correlates of insulin sensitivity have mainly been examined in cross-sectional studies. As far as we are aware, the longitudinal stability of insulin sensitivity in young men is largely unknown. We aimed for the first time to examine both the stability (tracking) and longitudinal predictors of future insulin sensitivity in healthy young men with and without a family history of diabetes or hypertension. METHODS: We performed a 17-year follow-up study of a cohort of 100 healthy young men. Cardiovascular risk markers, including insulin sensitivity measured by the gold standard method- hyperinsulinaemic isoglycaemic glucose clamp--were examined both at baseline and at follow-up. RESULTS: Baseline insulin sensitivity showed no significant correlation with insulin sensitivity at follow-up, whereas all other measured cardiovascular risk markers had significant correlation (tracking coefficients 0.4-0.7). In multiple regression analyses, family history of hypertension and baseline triglycerides remained the negative predictors of future insulin sensitivity. This was driven by the strong correlations in men with family history of diabetes. CONCLUSION: Our data suggest that clamp-derived insulin sensitivity is not a stable feature in young men, and that family history of hypertension and baseline triglycerides were associated with future insulin sensitivity, especially in men with a family history of diabetes, and irrespective of blood pressure status 17 years earlier. These findings provide further insight into the development of insulin sensitivity and related diseases. PMID- 26103131 TI - Accuracy of home versus ambulatory blood pressure monitoring in the diagnosis of white-coat and masked hypertension. AB - BACKGROUND: We investigated accuracy of home blood pressure (BP) monitoring in the diagnosis of white-coat and masked hypertension in comparison with ambulatory BP monitoring. METHODS: Our study participants were enrolled in the China Ambulatory and Home BP Registry, and underwent clinic, home, and 24-h ambulatory BP measurements. We defined white-coat hypertension as an elevated clinic SBP/DBP (>=140/90 mmHg) and a normal 24-h ambulatory (<130/80 mmHg) or home SBP/DBP (<135/85 mmHg), and masked hypertension as a normal clinic SBP/DBP (<140/90 mmHg) and an elevated 24-h ambulatory (>=130/80 mmHg) or home SBP/DBP (>=135/85 mmHg). RESULTS: In untreated patients (n = 573), the prevalence of white-coat hypertension (13.1 vs. 19.9%), masked hypertension (17.8 vs. 13.1%), and sustained hypertension (46.4 vs. 39.6%) significantly (P <= 0.02) differed between 24-h ambulatory and home BP monitoring. In treated patients (n = 1201), only the prevalence of masked hypertension differed significantly (18.7 vs. 14.5%; P = 0.005). Regardless of the treatment status, home compared with 24-h ambulatory BP had low sensitivity (range 47-74%), but high specificity (86-94%), and accordingly low positive (41-87%), but high negative predictive values (80 94%), and had moderate diagnostic agreement (82-85%) and Kappa statistic (0.41 0.66). In untreated and treated patients, age advancing was associated with a higher prevalence of white-coat hypertension and a lower prevalence of masked hypertension defined by 24-h ambulatory (P <= 0.03) but not home BP (P >= 0.10). CONCLUSION: Home BP monitoring has high specificity, but low sensitivity in the diagnosis of white-coat and masked hypertension, and may therefore behave as a complementary to, but not a replacement of, ambulatory BP monitoring. PMID- 26103133 TI - Factors influencing blood pressure levels. PMID- 26103132 TI - New developments in the pathogenesis of obesity-induced hypertension. AB - Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of alpha-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity. PMID- 26103134 TI - Environmental factors that shape biofilm formation. AB - Cells respond to the environment and alter gene expression. Recent studies have revealed the social aspects of bacterial life, such as biofilm formation. Biofilm formation is largely affected by the environment, and the mechanisms by which the gene expression of individual cells affects biofilm development have attracted interest. Environmental factors determine the cell's decision to form or leave a biofilm. In addition, the biofilm structure largely depends on the environment, implying that biofilms are shaped to adapt to local conditions. Second messengers such as cAMP and c-di-GMP are key factors that link environmental factors with gene regulation. Cell-to-cell communication is also an important factor in shaping the biofilm. In this short review, we will introduce the basics of biofilm formation and further discuss environmental factors that shape biofilm formation. Finally, the state-of-the-art tools that allow us investigate biofilms under various conditions are discussed. PMID- 26103135 TI - Coaggregation between Rhodococcus and Acinetobacter strains isolated from the food industry. AB - In this study, coaggregation interactions between Rhodococcus and Acinetobacter strains isolated from food-processing surfaces were characterized. Rhodococcus sp. strain MF3727 formed intrageneric coaggregates with Rhodococcus sp. strain MF3803 and intergeneric coaggregates with 2 strains of Acinetobacter calcoaceticus (MF3293, MF3627). Stronger coaggregation between A. calcoaceticus MF3727 and Rhodococcus sp. MF3293 was observed after growth in batch culture at 30 degrees C than at 20 degrees C, after growth in tryptic soy broth than in liquid R2A medium, and between cells in exponential and early stationary phases than cells in late stationary phase. The coaggregation ability of Rhodococcus sp. MF3727 was maintained even after heat and Proteinase K treatment, suggesting its ability to coaggregate was protein independent whereas the coaggregation determinants of the other strains involved proteinaceous cell-surface-associated polymers. Coaggregation was stable at pH 5-9. The mechanisms of coaggregation among Acinetobacter and Rhodococcus strains bare similarity to those displayed by coaggregating bacteria of oral and freshwater origin, with respect to binding between proteinaceous and nonproteinaceous determinants and the effect of environmental factors on coaggregation. Coaggregation may contribute to biofilm formation on industrial food surfaces, protecting bacteria against cleaning and disinfection. PMID- 26103137 TI - Effects of chronic cocaine treatment during adolescence in Lewis and Fischer-344 rats: Novel location recognition impairment and changes in synaptic plasticity in adulthood. AB - The use of Lewis (LEW) together with Fischer-344 (F344) rats has been proposed as an addiction model because of the addiction behavior differences of these two strains. We have previously suggested that these differences could be related to learning and memory processes and that they depend on the genetic background of these two strains of rats. Adolescence is a period of active synaptic remodeling, plasticity and particular vulnerability to the effects of environmental insults such as drugs of abuse. We have evaluated spatial memory using novel location recognition in LEW and F344 adult rats undergoing a chronic treatment with cocaine during adolescence or adulthood. In order to study whether synaptic plasticity mechanisms were involved in the possible changes in learning after chronic cocaine treatment, we carried out electrophysiological experiments in hippocampal slices from treated animals. Our results showed that, in LEW cocaine treated rats, hippocampal memory was only significantly impaired when the drug was administered during adolescence whereas adult administration did not produce any detrimental effect in spatial memory measured in this protocol. Moreover, F344 rats showed clear difficulties carrying out the protocol even in standard conditions, confirming the spatial memory problems observed in previous reports and demonstrating the genetic differences in spatial learning and memory. Our experiments show that the effects in behavioral experiments are related to synaptic plasticity mechanisms. Long-term depression induced by the glutamate agonist NMDA (LTD-NMDA) is partially abolished in cocaine-treated animals in hippocampal slices from LEW rats. Hippocampal LTD-NMDA is partially inhibited in F344 animals regardless of whether saline or cocaine administration, suggesting the lack of plasticity of this strain that could be related to the inability of these animals to carry out the novel object location protocol. PMID- 26103136 TI - PKCepsilon phosphorylates alpha4beta2 nicotinic ACh receptors and promotes recovery from desensitization. AB - BACKGROUND AND PURPOSE: Nicotinic (ACh) receptor recovery from desensitization is modulated by PKC, but the PKC isozymes and the phosphorylation sites involved have not been identified. We investigated whether PKCepsilon phosphorylation of alpha4beta2 nAChRs regulates receptor recovery from desensitization. EXPERIMENTAL APPROACH: Receptor recovery from desensitization was investigated by electrophysiological characterization of human alpha4beta2 nAChRs. Phosphorylation of the alpha4 nAChR subunit was assessed by immunoblotting of mouse synaptosomes. Hypothermia induced by sazetidine-A and nicotine was measured in Prkce(-/-) and wild-type mice. KEY RESULTS: Inhibiting PKCepsilon impaired the magnitude of alpha4beta2 nAChR recovery from desensitization. We identified five putative PKCepsilon phosphorylation sites in the large intracellular loop of the alpha4 subunit, and mutating four sites to alanines also impaired recovery from desensitization. alpha4 nAChR subunit phosphorylation was reduced in synaptosomes from Prkce(-/-) mice. Sazetidine-A-induced hypothermia, which is mediated by alpha4beta2 nAChR desensitization, was more severe and prolonged in Prkce(-/-) than in wild-type mice. CONCLUSIONS AND IMPLICATIONS: PKCepsilon phosphorylates the alpha4 nAChR subunit and regulates recovery from receptor desensitization. This study illustrates the importance of phosphorylation in regulating alpha4beta2 receptor function, and suggests that reducing phosphorylation prolongs receptor desensitization and decreases the number of receptors available for activation. PMID- 26103138 TI - Kisspeptin-13 enhances memory and mitigates memory impairment induced by Abeta1 42 in mice novel object and object location recognition tasks. AB - Kisspeptin (KP), the endogenous ligand of GPR54, is a recently discovered neuropeptide shown to be involved in regulating reproductive system, anxiety related behavior, locomotion, food intake, and suppression of metastasis across a range of cancers. KP is transcribed within the hippocampus, and GPR54 has been found in the amygdala and hippocampus, suggesting that KP might be involved in mediating learning and memory. However, the role of KP in cognition was largely unclear. Here, we investigated the role of KP-13, one of the endogenous active isoforms, in memory processes, and determined whether KP-13 could mitigate memory impairment induced by Abeta1-42 in mice, using novel object recognition (NOR) and object location recognition (OLR) tasks. Intracerebroventricular (i.c.v.) infusion of KP-13 (2MUg) immediately after training not only facilitated memory formation, but also prolonged memory retention in both tasks. The memory improving effects of KP-13 could be blocked by the GPR54 receptor antagonist, kisspeptin-234 (234), and GnRH receptors antagonist, Cetrorelix, suggesting pharmacological specificity. Then the memory-enhancing effects were also presented after infusion of KP-13 into the hippocampus. Moreover, we found that i.c.v. injection of KP-13 was able to reverse the memory impairment induced by Abeta1-42, which was inhibited by 234. To sum up, the results of our work indicate that KP-13 could facilitate memory formation and prolong memory retention through activation of the GPR54 and GnRH receptors, and suppress memory impairing effect of Abeta1-42 through activation of the GPR54, suggesting that KP 13 may be a potential drug for enhancing memory and treating Alzheimer's disease. PMID- 26103140 TI - Mechanical ventilation strategies for the surgical patient. AB - PURPOSE OF REVIEW: To summarize clinical evidence for intraoperative ventilation settings, which could protect against postoperative pulmonary complications (PPCs) in surgical patients with uninjured lungs. RECENT FINDINGS: There is convincing evidence for protection against PPCs by low tidal volumes: benefit was found in several randomized controlled trials, and was recently confirmed in meta analyses. Evidence for protection against PPCs by high levels of positive end expiratory pressure (PEEP) is less definite. Although benefit was found in several randomized controlled trials, most of them compared a bundle of low tidal volume and high level of PEEP with conventional ventilation; one recent large randomized controlled trial that compared high with low levels of PEEP showed that ventilation with high level of PEEP did not protect against PPCs but caused intraoperative complications instead. A recent individual patient data meta analysis of trials comparing bundles of low tidal volume and high levels of PEEP to conventional intraoperative ventilation suggested that protection against PPCs comes from tidal volume reductions, and not from increasing levels of PEEP. SUMMARY: The understanding on the protective roles of tidal volume and PEEP settings against PPCs has rapidly expanded. During intraoperative ventilation, low tidal volumes are protective, the protective role of high levels of PEEP is uncertain. PMID- 26103139 TI - SWAP-70 contributes to spontaneous transformation of mouse embryo fibroblasts. AB - Mouse embryo fibroblasts (MEFs) grow slowly after cultivation from animals, however, after an extended period of cultivation, their growth accelerates. We found that SWAP-70 deficient MEFs failed to increase growth rates. They maintain normal growth rates and proliferation cycles for at least 5 years. Complementing SWAP-70 deficiency in one of these MEF clones, MEF1F2, by expressing human SWAP 70 resulted in fast growth of the cells after further cultivation for a long period. The resulting cells show a transformation phenotype, since they grow on top of each other and do not show contact inhibition. This phenotype was reverted when sanguinarine, a putative SWAP-70 inhibitor, was added. Two SWAP-70 expressing clones were examined in detail. Even after cell density became very high their cdc2 and NFkappaB were still activated suggesting that they do not stop growing. One of the clones formed colonies in soft agar and formed tumors in nude mice. Lately, one more clone became transformed being able to make colonies in soft agar. We maintain 4 human SWAP-70 expressing MEF1F2 cell lines. Three out of 4 clones exhibited transforming phenotypes. The mouse SWAP-70 gene also promoted transformation of MEFs. Taken together our data suggest that SWAP-70 is not a typical oncogene, but is required for spontaneous transformation of MEFs. PMID- 26103141 TI - Are all fluids bad for the kidney? AB - PURPOSE OF REVIEW: To describe the harmful effects of intravenous fluids on kidney structure and function and summarize recent comparisons between different fluids and their effect on kidney outcome. RECENT FINDINGS: Administration of intravenous fluids may contribute to the development and sustention of acute kidney injury. In excess, fluids cause kidney interstitial edema and venous congestion, which prevents renal blood flow and glomerular filtration rate. In contrast to balanced crystalloids, chloride-rich solutions impair renal blood flow via autoregulatory mechanisms. Synthetic colloids, such as hydroxyethyl starches, gelatins, and dextrans are potentially nephrotoxic because they can cause osmotic nephrosis, which, in susceptible patients, might precede permanent kidney damage. Albumin solutions appear well tolerated to use in septic patients, although their renal efficacy over balanced crystalloids is not established. In contrast, administration of albumin solutions to patients with decompensated liver failure effectively prevents and ameliorates hepatorenal syndrome. SUMMARY: Being nephrotoxic, synthetic colloids should be avoided in patients with reduced renal reserve, such as in critically ill patients and in patients with preexisting renal dysfunction. Suggested adverse effects with chloride-rich solutions need confirmation from ongoing trials. Albumin solutions are well tolerated in patients with sepsis and/or liver failure and improve outcomes in the latter. PMID- 26103142 TI - The perioperative immune response. AB - PURPOSE OF REVIEW: A host of immune modulators are now available in clinical practice. The perioperative period is characterized by profound alterations in host immunity, which can result in poor outcomes, which include infection, cancer recurrence and organ failure. Manipulation of the perioperative immune response has the potential to improve outcomes. A complete understanding of the mechanisms and clinical consequences of altered immune function in this setting is therefore imperative. RECENT FINDINGS: Recent in-vivo data have emerged which further our understanding of the interaction between tissue damage, immune modulation and clinical outcomes by utilizing novel laboratory techniques capable of monitoring single-cell immune signatures. Traditional gene expression assays have continued to demonstrate their utility and have been instrumental in defining the host response to perioperative allogeneic blood transfusion. These mechanistic studies are complemented by large clinical studies describing associations between anaesthetic modalities and immune-related outcomes. SUMMARY: Laboratory techniques are now available that can monitor the perioperative immune response and could be further developed to introduce personalized care pathways. Consideration must also be given to anaesthesia techniques and perioperative treatments that, although not immediately harmful, may be associated with poor outcomes temporally distant from the treatment, secondary to induced immunosuppression. PMID- 26103143 TI - Fluids and coagulation. AB - PURPOSE OF REVIEW: Infusion therapy is essential in intravascular hypovolaemia and extravascular fluid deficits. Crystalloidal fluids and colloidal volume replacement affect blood coagulation when infused intravenously. The question remains if this side-effect of infusion therapy is clinically relevant in patients with and without bleeding manifestations, and if fluid-induced coagulopathy is a risk factor for anaemia, blood transfusion, and mortality, and a driver for resource use and costs. RECENT FINDINGS: Pathomechanisms of dilutional coagulopathy and evidence for its clinical relevance in perioperative and critically ill patients are reviewed. Furthermore, the article discusses medicolegal aspects. SUMMARY: The dose-dependent risk of dilutional coagulopathy differs between colloids (dextran > hetastarch > pentastarch > tetrastarch, gelatins > albumin). Risk awareness includes monitoring for early signs of side effects. With rotational thromboelastometry/thrombelastography, the deterioration not only in clot strength but also in clot formation and in platelet interaction can be assessed. Fibrinogen concentrate administration may be considered in severe bleeding as well as relevant dilutional coagulopathy. Targeted doses of gelatins and tetrastarches seem to have no proven adverse effect on anaemia and allogeneic blood transfusions. Further studies are needed. PMID- 26103144 TI - What is the ideal crystalloid? AB - PURPOSE OF REVIEW: We discuss the importance of the composition of intravenous crystalloid solutions. On the basis of current physiologic principles, evidence from basic science and clinical experiments, recent observational studies, and clinical trials, we conclude that the 'ideal crystalloid' depends on clinical context. We make recommendations on solutions that may be used during critical illness, major surgery, and certain clinical situations. RECENT FINDINGS: The routine use of solutions with a supraphysiologic chloride content and a low strong ion difference (SID), such as isotonic saline solution, may be associated with adverse outcomes, especially among critically ill patients. On the contrary, solutions with a physiologic chloride content and a 'balanced' electrolyte composition (SID closer to plasma) may improve the likelihood of survival. The distribution of different types of crystalloids across traditional 'body compartments' is a function of osmolality of the fluid infused relative to plasma, integrity of the glycocalyx, and the hemodynamic/'volume' state of the patient. During critical illness, the routine administration of colloids may offer no clinical benefits compared with the use of crystalloids. SUMMARY: Crystalloids, like other types of intravenous fluids, are drugs with important effects on clinical outcomes that may be mediated by osmolality, chloride content, and SID. PMID- 26103145 TI - Using cardiac output monitoring to guide perioperative haemodynamic therapy. AB - PURPOSE OF REVIEW: The aim of this study was to review recent advances and evidence for the use of cardiac output monitors to guide perioperative haemodynamic therapy. RECENT FINDINGS: There are multiple different cardiac output monitoring devices available for clinical use which are coupled with many different intervention protocols to manipulate perioperative haemodynamics. There is little evidence to demonstrate superiority of any one device. Previous small studies and meta-analyses have suggested that perioperative haemodynamic therapy guided by cardiac output monitoring improves outcomes after major surgery. Despite relatively low-quality evidence several national bodies have recommended 'perioperative goal-directed therapy' (GDT) as a standard of care.Recent larger trials of GDT have mostly failed to prove a benefit of GDT and one explanation for this is the increased quality of usual care that may be occurring because of initiatives such as enhanced recovery after surgery and the WHO Safer Surgery programmes. SUMMARY: Perioperative GDT remains an exciting intervention to reduce significant morbidity following major surgery; however, it is not yet a proven standard of care. Further large pragmatic trials are required to demonstrate its effectiveness particularly in the era of enhanced recovery after surgery programmes. PMID- 26103146 TI - Which intravenous fluid for the surgical patient? AB - PURPOSE OF REVIEW: This review appraises recent evidence and provides clinical guidance on optimal perioperative fluid therapy. RECENT FINDINGS: Choice of perioperative intravenous fluid continues to be the source of much debate. Not all crystalloids are equivalent, and there is growing evidence that balanced solutions are superior to 0.9% saline in many situations. Recent evidence from the critical care population has highlighted risks associated with synthetic colloids; this and the absence of demonstrable benefit in the surgical population make it difficult to recommend their use in the perioperative period. Giving the correct amount of fluid may be as important as the choice of the fluid used. There is increasing evidence that excessive positive fluid balance is harmful to patients but there have been no randomized trials comparing maintenance fluid strategy. A knowledge of the physiology and accurate estimation of fluid balance is important for water and electrolyte homeostasis until the patient is able to resume adequate enteral nutrition. SUMMARY: Balanced crystalloids are the fluid of choice for perioperative resuscitation and optimization in patients not requiring blood products. Avoidance of a grossly positive sodium and water balance during the maintenance phase is likely to be important, but has not been assessed in randomized trials. PMID- 26103148 TI - Fluid therapy and the hypovolemic microcirculation. AB - PURPOSE OF REVIEW: In shock states, optimizing intravascular volume is crucial to promote an adequate oxygen delivery to the tissues. Our current practice in fluid management pivots on the Frank-Starling law of the heart, and the effects of fluids are measured according to the induced changes on stroke volume. The purpose of this review is to evaluate the boundaries of current macrohemodynamic approach to fluid administration, and to introduce the microcirculatory integration as a fundamental part of tissue perfusion monitoring. RECENT FINDINGS: Macrocirculatory changes induced by volume expansion are not always coupled to proportional changes in microcirculatory perfusion. Loss of hemodynamic coherence limits the value of guiding fluid therapy according to macrohemodynamics, and highlights the importance of evaluating the ultimate target of volume administration, the microcirculation. SUMMARY: Current approach to intravascular volume optimization is made from a macrohemodynamic perspective. However, several situations wherein macrocirculatory and microcirculatory coherence is lost have been described. Future clinical trials should explore the usefulness of integrating the microcirculatory evaluation in fluid optimization. PMID- 26103147 TI - How to avoid fluid overload. AB - PURPOSE OF REVIEW: This review highlights the recent evidence describing the outcomes associated with fluid overload in critically ill patients and provides an overview of fluid management strategies aimed at preventing fluid overload during the resuscitation of patients with shock. RECENT FINDINGS: Fluid overload is a common complication of fluid resuscitation and is associated with increased hospital costs, morbidity and mortality. SUMMARY: Fluid management goals differ during the resuscitation, optimization, stabilization and evacuation phases of fluid resuscitation. To prevent fluid overload, strategies that reduce excessive fluid infusions and emphasize the removal of accumulated fluids should be implemented. PMID- 26103149 TI - Albumin in critically ill patients: the ideal colloid? AB - PURPOSE OF REVIEW: The use of albumin-containing solutions in critically ill patients has been recently revisited, following evidence on harmful effects of synthetic colloids, and novel randomized controlled trials (RCTs) in sepsis. Here, we review the most recent findings on albumin administration in acutely ill and septic patients. RECENT FINDINGS: The revision of Starling's theory on microvascular fluid dynamics has highlighted the role of albumin in preserving intravascular compartment volume. In cirrhosis, albumin may be important in maintaining immune system reactivity and cardiac contractility. Preliminary analyses indicate albumin as beneficial in patients with burn, while being associated with increased risk of acute kidney injury after cardiac surgery. The first RCT (ALBIOS trial) testing the efficacy of albumin replacement in severe sepsis did not show a survival benefit associated with albumin, although observing at post-hoc analysis a benefit in septic shock. All the eight meta analyses performed on albumin in sepsis reveal an absence of harm, and likely a benefit lower than expected, whereas suggesting an advantage, to be verified, in septic shock. SUMMARY: Further studies are needed to clarify physiology and clinical impact of albumin in critically ill patients, considering specific phenotypes and secondary outcomes other than survival, yet clinically relevant. PMID- 26103150 TI - Microcirculatory disorders during septic shock. AB - PURPOSE OF REVIEW: Despite the progress made over the past 20 years in the treatment of septic shock, mortality remains high. Microcirculatory disorders raise considerable interest aiming to improve the understanding of the physiopathology of septic shock and its management. RECENT FINDINGS: Numerous experimental and clinical studies have gradually focused on the analysis of microcirculatory blood flow and identified alterations in small vessels. These microcirculatory abnormalities appear early, are heterogeneous, and are directly linked to organ failure, as well as the patient's prognosis. These anomalies vary from one patient to the other, and their evolution during resuscitation cannot be predicted by the isolated analysis of global hemodynamic parameters such as blood pressure or heart rate. SUMMARY: Microcirculatory disorders appear at a central place of the physiopathology and are highly associated with the patient prognosis; it therefore seems important to develop and integrate parameters reflecting tissue perfusion in the management of septic shock. PMID- 26103152 TI - Risk of cancer of unknown primary after hospitalization for autoimmune diseases. AB - Cancer of unknown primary (CUP) is a heterogeneous syndrome diagnosed at metastatic sites. The etiology is unknown but immune dysfunction may be a contributing factor. Patients with autoimmune diseases were identified from the Swedish Hospital Discharge Register and linked to the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for subsequent CUP and compared with subjects without autoimmune diseases. A total of 789,681 patients were hospitalized for any of 32 autoimmune diseases during years 1964-2012; 2,658 developed subsequent CUP, giving an overall SIR of 1.27. A total of 16 autoimmune diseases were associated with an increased risk for CUP; polymyositis/dermatomyositis showed the highest SIR of 3.51, followed by primary biliary cirrhosis (1.81) and Addison's disease (1.77). CUP risk is known to be reduced in long-time users of pain-relieving nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin. For patients with ankylosing spondylitis and with some other autoimmune diseases, with assumed chronic medication by NSAIDSs, CUP risks decreased in long-term follow-up. The overall risk of CUP was increased among patients diagnosed with autoimmune diseases, which call for clinical attention and suggest a possible role of immune dysfunction in CUP. The associations with many autoimmune diseases were weak which may imply that autoimmunity may not synergize with CUP-related immune dysfunction. However, long-term NSAID medication probably helped to curtail risks in some autoimmune diseases and CUP risks were generally higher in autoimmune diseases for which NSAIDs are not used and for these CUP appears to be a serious side effect. PMID- 26103151 TI - Accelerated Growth Rate and Increased Drought Stress Resilience of the Model Grass Brachypodium distachyon Colonized by Bacillus subtilis B26. AB - Plant growth-promoting bacteria (PGB) induce positive effects in plants, for instance, increased growth and reduced abiotic stresses susceptibility. The mechanisms by which these bacteria impact the host plant are numerous, diverse and often specific. Here, we studied the agronomical, molecular and biochemical effects of the endophytic PGB Bacillus subtilis B26 on the full life cycle of Brachypodium distachyon Bd21, an established model species for functional genomics in cereal crops and temperate grasses. Inoculation of Brachypodium with B. subtilis strain B26 increased root and shoot weights, accelerated growth rate and seed yield as compared to control plants. B. subtilis strain B26 efficiently colonized the plant and was recovered from roots, stems and blades as well as seeds of Brachypodium, indicating that the bacterium is able to migrate, spread systemically inside the plant, establish itself in the aerial plant tissues and organs, and is vertically transmitted to seeds. The presence of B. subtilis strain B26 in the seed led to systemic colonization of the next generation of Brachypodium plants. Inoculated Brachypodium seedlings and mature plants exposed to acute and chronic drought stress minimized the phenotypic effect of drought compared to plants not harbouring the bacterium. Protection from the inhibitory effects of drought by the bacterium was linked to upregulation of the drought response genes, DREB2B-like, DHN3-like and LEA-14-A-like and modulation of the DNA methylation genes, MET1B-like, CMT3-like and DRM2-like, that regulate the process. Additionally, total soluble sugars and starch contents increased in stressed inoculated plants, a biochemical indication of drought tolerance. In conclusion, we show a single inoculation of Brachypodium with a PGB affected the whole growth cycle of the plant, accelerating its growth rates, shortening its vegetative period, and alleviating drought stress effects. These effects are relevant to grasses and cereal crops. PMID- 26103153 TI - Relative Contribution of Trabecular and Cortical Bone to Primary Implant Stability: An In Vitro Model Study. AB - The specific aim of this study was to examine the relative contributions to the implant insertion torque value (ITV) by cortical and trabecular components of an in vitro bone model. Simulated bone blocks of polyurethane were used with 2 densities of foam (0.08 g/cm(3) to mimic trabecular bone and 0.64 g/cm(3) to mimic cortical bone). We have developed a new platform technology to collect data that enables quantitative evaluation of ITV at different implant locations. Seven groups were used to model varying thicknesses of cortical bone over a lower quality trabecular bone that have clinical significance: a solid 0.08 g/cm(3) block; 1 mm, 2 mm, and 3 mm thick 0.64 g/cm(3) sheets with no underlayer; and 1 mm, 2 mm, and 3 mm thick 0.64 g/cm(3) sheets laminated on top of a 4 cm thick 0.08 g/cm(3) block. The ITVs were recorded as a function of insertion displacement distance. Relative contributions of ITV ranged from 3% to 18% from trabecular bone, and 62% to 74% from cortical bone depending on the thickness of the cortical layer. Inserting an implant into 2-mm and 3-mm cortical layers laminated atop trabecular blocks had a synergistic effect on ITVs. Finally, an implant with a reverse bevel design near the abutment showed final average torque values that were 14% to 34% less than their maximum torque values. This work provides basic quantitative information for clinicians to understand the influence of composite layers of bone in relation to mechanical torque resistances during implant insertion in order to obtain desired primary implant stability. PMID- 26103154 TI - Modeling Measles Transmission in the North American Amish and Options for Outbreak Response. AB - Measles outbreaks in the United States continue to occur in subpopulations with sufficient numbers of undervaccinated individuals, with a 2014 outbreak in Amish communities in Ohio pushing the annual cases to the highest national number reported in the last 20 years. We adapted an individual-based model developed to explore potential poliovirus transmission in the North American Amish to characterize a 1988 measles outbreak in the Pennsylvania Amish and the 2014 outbreak in the Ohio Amish. We explored the impact of the 2014 outbreak response compared to no or partial response. Measles can spread very rapidly in an underimmunized subpopulation like the North American Amish, with the potential for national spread within a year or so in the absence of outbreak response. Vaccination efforts significantly reduced the transmission of measles and the expected number of cases. Until global eradication, measles importations will continue to pose a threat to clusters of underimmunized individuals in the United States. Aggressive outbreak response efforts in Ohio probably prevented widespread transmission of measles within the entire North American Amish. PMID- 26103155 TI - The Cooperative Landscape of Multinational Clinical Trials. AB - The scale and nature of cooperative efforts spanning geopolitical borders in clinical research have not been elucidated to date. In a cross-sectional study of 110,428 interventional trials registered in Clinicaltrials.gov, we characterized the evolution, trial demographics, and network properties of multinational clinical research. We reveal that the relative growth of international collaboratives has remained stagnant in the last two decades, although clinical trials have evolved to become much larger in scale. Multinational clinical trials are also characterized by higher patient enrollments, industry funding, and specific clinical disciplines including oncology and infectious disease. Network analyses demonstrate temporal shifts in collaboration patterns between countries and world regions, with developing nations now collaborating more within themselves, although Europe remains the dominant contributor to multinational clinical trials worldwide. Performances in network centrality measures also highlight the differential contribution of nations in the global research network. A city-level clinical trial network analysis further demonstrates how collaborative ties decline with physical distance. This study clarifies evolving themes and highlights potential growth mechanisms and barriers in multinational clinical trials, which may be useful in evaluating the role of national and local policies in organizing transborder efforts in clinical endeavors. PMID- 26103156 TI - CuBr catalyzed aerobic oxidative coupling of 2-aminopyridines with cinnamaldehydes: direct access to 3-formyl-2-phenyl-imidazo[1,2-a]pyridines. AB - Copper bromide catalyzed aerobic oxidative coupling of 2-aminopyridines with cinnamaldehydes directly led to the formation of 3-formyl-2-phenyl-imidazo[1,2 a]pyridines. The quantum chemical calculations were performed to trace the reaction mechanism and get insights into the possible reaction pathway. 2 Aminopyridines on coupling with cinnamaldehyde generate (E)-3-phenyl-3-(pyridin-2 ylamino)acrylaldehyde IV as a key intermediate, which undergoes C-N bond formation reaction to produce 3-formyl-2-phenyl-imidazo[1,2-a]pyridines. PMID- 26103157 TI - The crabs that live where hot and cold collide. AB - The distribution of Kiwa tyleri with the large male individual in the high temperature flow (right hand side - fluid flow indicated by shimmering water) and the mixed sex assemblage (left). Note the heavy coat of epibiotic bacteria (grey colouring) on the individual in the hottest section of the vent, as expected from being closest to the sulphide needed to sustain the epibiotic bacteria that this species harvests for its food. Image courtesy of Dr. L. Marsh (Credit: NERC ChEsSo Consortium). In Focus: Marsh, L., Copley, J.T., Tyler, P.A. & Thatje, S. (2015) In hot and cold water: differential life-history traits are key to success in contrasting thermal deep-sea environments. Journal of Animal Ecology, 84, 898 913. Southern Ocean hydrothermal vents juxtapose two extremes - intense food-poor cold and scalding food-rich oases. At these vents, Marsh et al. (2015) found a community of Kiwa (Yeti) crabs that separated themselves along this gradient with the largest males sitting in hot, food-rich waters, while smaller males and females co-occur in an intermediate zone of warmth. However, as their eggs start to develop, females embark away from the vent to the food-poor yet stable cold of the Southern Ocean. This species has found an intriguing way to balance foraging risk and population persistence at the interface of hot and cold. PMID- 26103158 TI - Peroxisomal fission controls yeast life span. PMID- 26103159 TI - The Impact of Subclinical Disease and Mechanism of Detection on the Rise in Thyroid Cancer Incidence: A Population-Based Study in Olmsted County, Minnesota During 1935 Through 2012. AB - BACKGROUND: An ongoing epidemic of thyroid carcinoma (TC) has affected Americans since 1975. Understanding the contribution of subclinical disease and the mechanism of such disease detection may help to alter the course of this epidemic. METHODS: We used Rochester Epidemiology Project resources to examine the incidence of TC cases, disease specific mortality, and method of diagnosis during 1935 through 2012. During 2000-2012, we also extracted the mechanism of detection of clinically occult tumors. RESULTS: The age-adjusted incidence (AAI) for TC increased from 7.1 [95% confidence interval (CI) 5.5-8.8] per 100,000 person-years (p-y) during 1990-1999 to 13.7 [CI 11.8-15.6] per 100,000 p-y during 2000-2012, with no change in disease-specific mortality since 1935. The incidence trend analysis stratified by the mechanism of detection revealed the AAI of clinically recognized TC was 5.5 per 100,000 p-y [CI 3.4-7.5] in 1960-1969, a rate similar to the incidence seen during 2000-2012. However, AAI of clinically occult TC increased from 0.2 per 100,000 p-y [CI 0.0-0.6] in 1935-1949 to 1.9 per 100,000 p-y [CI 1.2-2.9] in 1990-1999 and to 7.4 per 100,000 p-y [CI 6.0-8.8] in 2000-2012. During 2000-2012, the most frequent reasons for recognition of "occult" tumors were (1) incidental discovery during diagnostic neck imaging in 40 (19%), (2) pathology review of specimens from thyroid surgery for benign conditions in 29 (14%), and (3) investigations of patients with symptoms or palpable nodules that were clearly not associated with coexistent but occult TC but triggered the use of diagnostic neck imaging in 37 (27%). CONCLUSIONS: In this population-based study conducted in Olmsted County, Minnesota, the rapid increased incidence of TC during 2000-2012 can be completely attributed to the increased diagnosis of occult TCs, which are mainly found through the use of diagnostic neck imaging. The incidence of clinical TC and disease-specific TC mortality remains stable since 1970, implying that the observed increased incidence is due to the increased detection of subclinical lesions. PMID- 26103160 TI - Differentiation of Human-Induced Pluripotent Stem Cells Into Insulin-Producing Clusters by MicroRNA-7. AB - OBJECTIVES: Diabetes results from inadequate insulin production from pancreatic beta-cells. Islet cell replacement is an effective approach for diabetes treatment; however, it is not sufficient for all diabetic patients. Thus, finding a new source with effective maturation of beta-cells is the major goal of many studies. MicroRNAs are a class of small noncoding ribonucleic acid that regulate gene expression through posttranscriptional mechanisms. MicroRNA-7 has high expression level during pancreatic islet development in humans, thereby playing a critical role in pancreatic beta-cell function. We study aimed to develop a protocol to differentiate human-induced pluripotent stem cells efficiently into isletlike cell clusters in vitro by using microRNA-7. MATERIALS AND METHODS: Human-induced pluripotent stem cell colonies were transfected with hsa-microRNA-7 by using siPORT NeoFX transfection agent. Total ribonucleic acid was extracted 24 and 48 hours after transfection. The expression of transcription factors which were important during pancreases development was also performed. On the third day, the potency of the clusters was assessed in response to high glucose levels. Diphenylthiocarbazone was used to identify the existence of the beta-cells. The presence of insulin and Neurogenin-3 proteins was investigated by immunocytochemistry. RESULTS: Morphologic changes were observed on the first day after chemical transfection, and cell clusters were formed on the third day. The expression of pancreatic specific transcription factors was increased on the first day and significantly increased on the second day. The isletlike cell clusters were positive for insulin and Neurogenin-3 proteins in immunocytochemistry. The clusters were stained with Diphenylthiocarbazone and secreted insulin in a glucose challenge test. CONCLUSIONS: MicroRNA-7 transcription factor network is important in pancreatic endocrine differentiation. Chemical transfection with microRNA-7 can differentiate human induced pluripotent stem cells into functional isletlike cell clusters in a short time. PMID- 26103161 TI - The Antitumor Activity of the Novel Compound Jesridonin on Human Esophageal Carcinoma Cells. AB - Jesridonin, a small molecule obtained through the structural modification of Oridonin, has extensive antitumor activity. In this study, we evaluated both its in vitro activity in the cancer cell line EC109 and its in vivo effect on tumor xenografts in nude mice. Apoptosis induced by Jesridonin was determined using an MTT assay, Annexin-V FITC assay and Hoechest 33258 staining. Apoptosis via mitochondrial and death receptor pathways were confirmed by detecting the regulation of MDM2, p53, and Bcl-2 family members and by activation of caspase-3/ 8/-9. In addition, vena caudalis injection of Jesridonin showed significant inhibition of tumor growth in the xenograft model, and Jesridonin-induced cell apoptosis in tumor tissues was determined using TUNEL. Biochemical serum analysis of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), total protein (TP) and albumin (ALB) indicated no obvious effects on liver function. Histopathological examination of the liver, kidney, lung, heart and spleen revealed no signs of JD-induced toxicity. Taken together, these results demonstrated that Jesridonin exhibits antitumor activity in human esophageal carcinomas EC109 cells both in vitro and in vivo and demonstrated no adverse effects on major organs in nude mice. These studies provide support for new drug development. PMID- 26103162 TI - Location Isn't Everything: Timing of Spawning Aggregations Optimizes Larval Replenishment. AB - Many species of reef fishes form large spawning aggregations that are highly predictable in space and time. Prior research has suggested that aggregating fish derive fitness benefits not just from mating at high density but, also, from oceanographic features of the spatial locations where aggregations occur. Using a probabilistic biophysical model of larval dispersal coupled to a fine resolution hydrodynamic model of the Florida Straits, we develop a stochastic landscape of larval fitness. Tracking virtual larvae from release to settlement and incorporating changes in larval behavior through ontogeny, we found that larval success was sensitive to the timing of spawning. Indeed, propagules released during the observed spawning period had higher larval success rates than those released outside the observed spawning period. In contrast, larval success rates were relatively insensitive to the spatial position of the release site. In addition, minimum (rather than mean) larval survival was maximized during the observed spawning period, indicating a reproductive strategy that minimizes the probability of recruitment failure. Given this landscape of larval fitness, we take an inverse optimization approach to define a biological objective function that reflects a tradeoff between the mean and variance of larval success in a temporally variable environment. Using this objective function, we suggest that the length of the spawning period can provide insight into the tradeoff between reproductive risk and reward. PMID- 26103163 TI - Multi-Dimensional Measurement of Antibody-Mediated Heterosubtypic Immunity to Influenza. AB - The human immune response to influenza vaccination depends in part on preexisting cross-reactive (heterosubtypic) immunity from previous infection by, and/or vaccination with, influenza strains that share antigenic determinants with the vaccine strains. However, current methods for assessing heterosubtypic antibody responses against influenza, including the hemagglutination-inhibition (HAI) assay and ELISA, are time and labor intensive, and require moderate amounts of serum and reagents. To address these issues we have developed a fluorescent multiplex assay, mPlex-Flu, that rapidly and simultaneously measures strain specific IgG, IgA, and IgM antibodies against influenza hemagglutinin (HA) from multiple viral strains. We cloned, expressed and purified HA proteins from 12 influenza strains, and coupled them to multiplex beads. Assay validation showed that minimal sample volumes (<5 MUl of serum) were needed, and the assay had a linear response over a four Log10 range. The assay detected nanogram levels of anti-influenza specific antibodies, had high accuracy and reproducibility, with an average percentage coefficient of variation (%CV) of 9.06 for intra-assay and 12.94 for inter-assay variability. Pre- and post-intramuscular trivalent influenza vaccination levels of virus specific Ig were consistent with HAI titer and ELISA measurements. A significant advantage of the mPLEX-Flu assay over the HAI assay is the ability to perform antigenic cartography, determining the antigenic distances between influenza HA's, without mathematical correction for HAI data issues. For validation we performed antigenic cartography on 14 different post-influenza infection ferret sera assayed against 12 different influenza HA's. Results were in good agreement with a phylogenetic tree generated from hierarchical clustering of the genomic HA sequences. This is the first report of the use of a multiplex method for antigenic cartography using ferret sera. Overall, the mPlex-Flu assay provides a powerful tool to rapidly assess the influenza antibody repertoire in large populations and to study heterosubtypic immunity induced by influenza vaccination. PMID- 26103165 TI - Application of off-line image processing for optimization in chest computed radiography using a low cost system. AB - The objective of this study was to improve the visibility of anatomical details by applying off-line postimage processing in chest computed radiography (CR). Four spatial domain-based external image processing techniques were developed by using MATLAB software version 7.0.0.19920 (R14) and image processing tools. The developed techniques were implemented to sample images and their visual appearances confirmed by two consultant radiologists to be clinically adequate. The techniques were then applied to 200 chest clinical images and randomized with other 100 images previously processed online. These 300 images were presented to three experienced radiologists for image quality assessment using standard quality criteria. The mean and ranges of the average scores for three radiologists were characterized for each of the developed technique and imaging system. The Mann-Whitney U-test was used to test the difference of details visibility between the images processed using each of the developed techniques and the corresponding images processed using default algorithms. The results show that the visibility of anatomical features improved significantly (0.005 <= p <= 0.02) with combinations of intensity values adjustment and/or spatial linear filtering techniques for images acquired using 60 <= kVp <= 70. However, there was no improvement for images acquired using 102 <= kVp <= 107 (0.127 <= p <= 0.48). In conclusion, the use of external image processing for optimization can be effective in chest CR, but should be implemented in consultations with the radiologists. PMID- 26103164 TI - Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements. AB - INTRODUCTION: The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. METHODS: Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. RESULTS: Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. DISCUSSION: Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non contractile content of tissue in children with DMD. PMID- 26103166 TI - Investigation on the performance of dedicated radiotherapy positioning devices for MR scanning for prostate planning. AB - The purpose of this study was to investigate performance of the couch and coil mounts designed for MR-simulation prostate scanning using data from ten volunteers. Volunteers were scanned using the standard MR scanning protocol with the MR coil directly strapped on the external body and the volunteer lying on the original scanner table. They also were scanned using a MR-simulation table top and pelvic coil mounts. MR images from both setups were compared in terms of body contour variation and image quality effects within particular organs of interest. Six-field conformal plans were generated on the two images with assigned bulk density for dose calculation. With the MR-simulation devices, the anterior skin deformation was reduced by up to 1.7 cm. The hard tabletop minimizes the posterior body deformation which can be up to 2.3 cm on the standard table, depending on the weight of volunteer. The image signal-to-noise ratio reduced by 14% and 25% on large field of view (FOV) and small FOV images, respectively, after using the coil mount; the prostate volume contoured on two images showed difference of 1.05 +/- 0.66 cm3. The external body deformation caused a mean dose reduction of 0.6 +/- 0.3 Gy, while the coverage reduced by 22% +/- 13% and 27% +/ 6% in V98 and V100, respectively. A dedicated MR simulation setup for prostate radiotherapy is essential to ensure the agreement between planning anatomy and treatment anatomy. The image signal was reduced after applying the coil mount, but no significant effect was found on prostate contouring. PMID- 26103167 TI - Baseline correction of a correlation model for improving the prediction accuracy of infrared marker-based dynamic tumor tracking. AB - We previously found that the baseline drift of external and internal respiratory motion reduced the prediction accuracy of infrared (IR) marker-based dynamic tumor tracking irradiation (IR Tracking) using the Vero4DRT system. Here, we proposed a baseline correction method, applied immediately before beam delivery, to improve the prediction accuracy of IR Tracking. To perform IR Tracking, a four dimensional (4D) model was constructed at the beginning of treatment to correlate the internal and external respiratory signals, and the model was expressed using a quadratic function involving the IR marker position (x) and its velocity (v), namely function F(x,v). First, the first 4D model, F1st(x,v), was adjusted by the baseline drift of IR markers (BDIR) along the x-axis, as function F'(x,v). Next, BDdetect, that defined as the difference between the target positions indicated by the implanted fiducial markers (Pdetect) and the predicted target positions with F'(x,v) (Ppredict) was determined using orthogonal kV X-ray images at the peaks of the Pdetect of the end-inhale and end-exhale phases for 10 s just before irradiation. F'(x,v) was corrected with BDdetect to compensate for the residual error. The final corrected 4D model was expressed as Fcor(x,v) = F1st{(x-BDIR),v} BDdetect. We retrospectively applied this function to 53 paired log files of the 4D model for 12 lung cancer patients who underwent IR Tracking. The 95th percentile of the absolute differences between Pdetect and Ppredict (|Ep|) was compared between F1st(x,v) and Fcor(x,v). The median 95th percentile of |Ep| (units: mm) was 1.0, 1.7, and 3.5 for F1st(x,v), and 0.6, 1.1, and 2.1 for Fcor(x,v) in the left-right, anterior-posterior, and superior-inferior directions, respectively. Over all treatment sessions, the 95th percentile of |Ep| peaked at 3.2 mm using Fcor(x,v) compared with 8.4 mm using F1st(x,v). Our proposed method improved the prediction accuracy of IR Tracking by correcting the baseline drift immediately before irradiation. PMID- 26103168 TI - Technical evaluation of different respiratory monitoring systems used for 4D CT acquisition under free breathing. AB - Respiratory monitoring systems are required to supply CT scanners with information on the patient's breathing during the acquisition of a respiration correlated computer tomography (RCCT), also referred to as 4D CT. The information a respiratory monitoring system has to provide to the CT scanner depends on the specific scanner. The purpose of this study is to compare two different respiratory monitoring systems (Anzai Respiratory Gating System; C-RAD Sentinel) with respect to their applicability in combination with an Aquilion Large Bore CT scanner from Toshiba. The scanner used in our clinic does not make use of the full time dependent breathing signal, but only single trigger pulses indicating the beginning of a new breathing cycle. Hence the attached respiratory monitoring system is expected to deliver accurate online trigger pulse for each breathing cycle. The accuracy of the trigger pulses sent to the CT scanner has to be ensured by the selected respiratory monitoring system. Since a trigger pulse (output signal) of a respiratory monitoring system is a function of the measured breathing signal (input signal), the typical clinical range of the input signal is estimated for both examined respiratory monitoring systems. Both systems are analyzed based on the following parameters: time resolution, signal amplitude, noise, signal-to-noise ratio (SNR), signal linearity, trigger compatibility, and clinical examples. The Anzai system shows a better SNR (>= 28 dB) than the Sentinel system (>= 14.6 dB). In terms of compatibility with the cycle-based image sorting algorithm of the Toshiba CT scanner, the Anzai system benefits from the possibility to generate cycle-based triggers, whereas the Sentinel system is only able to generate amplitude-based triggers. In clinical practice, the combination of a Toshiba CT scanner and the Anzai system will provide better results due to the compatibility of the image sorting and trigger release methods. PMID- 26103169 TI - Evaluation of 4D CT acquisition methods designed to reduce artifacts. AB - Four-dimensional computed tomography (4D CT) is used to account for respiratory motion in radiation treatment planning, but artifacts resulting from the acquisition and postprocessing limit its accuracy. We investigated the efficacy of three experimental 4D CT acquisition methods to reduce artifacts in a prospective institutional review board approved study. Eighteen thoracic patients scheduled to undergo radiation therapy received standard clinical 4D CT scans followed by each of the alternative 4D CT acquisitions: 1) data oversampling, 2) beam gating with breathing irregularities, and 3) rescanning the clinical acquisition acquired during irregular breathing. Relative values of a validated correlation-based artifact metric (CM) determined the best acquisition method per patient. Each 4D CT was processed by an extended phase sorting approach that optimizes the quantitative artifact metric (CM sorting). The clinical acquisitions were also postprocessed by phase sorting for artifact comparison of our current clinical implementation with the experimental methods. The oversampling acquisition achieved the lowest artifact presence among all acquisitions, achieving a 27% reduction from the current clinical 4D CT implementation (95% confidence interval = 34-20). The rescan method presented a significantly higher artifact presence from the clinical acquisition (37%; p < 0.002), the gating acquisition (26%; p < 0.005), and the oversampling acquisition (31%; p < 0.001), while the data lacked evidence of a significant difference between the clinical, gating, and oversampling methods. The oversampling acquisition reduced artifact presence from the current clinical 4D CT implementation to the largest degree and provided the simplest and most reproducible implementation. The rescan acquisition increased artifact presence significantly, compared to all acquisitions, and suffered from combination of data from independent scans over which large internal anatomic shifts occurred. PMID- 26103171 TI - Moving gantry method for electron beam dose profile measurement at extended source-to-surface distances. AB - A novel method has been put forward for very large electron beam profile measurement. With this method, absorbed dose profiles can be measured at any depth in a solid phantom for total skin electron therapy. Electron beam dose profiles were collected with two different methods. Profile measurements were performed at 0.2 and 1.2 cm depths with a parallel plate and a thimble chamber, respectively. 108cm * 108 cm and 45 cm * 45 cm projected size electron beams were scanned by vertically moving phantom and detector at 300 cm source-to-surface distance with 90 degrees and 270 degrees gantry angles. The profiles collected this way were used as reference. Afterwards, the phantom was fixed on the central axis and the gantry was rotated with certain angular steps. After applying correction for the different source-to-detector distances and incidence of angle, the profiles measured in the two different setups were compared. Correction formalism has been developed. The agreement between the cross profiles taken at the depth of maximum dose with the 'classical' scanning and with the new moving gantry method was better than 0.5 % in the measuring range from zero to 71.9 cm. Inverse square and attenuation corrections had to be applied. The profiles measured with the parallel plate chamber agree better than 1%, except for the penumbra region, where the maximum difference is 1.5%. With the moving gantry method, very large electron field profiles can be measured at any depth in a solid phantom with high accuracy and reproducibility and with much less time per step. No special instrumentation is needed. The method can be used for commissioning of very large electron beams for computer-assisted treatment planning, for designing beam modifiers to improve dose uniformity, and for verification of computed dose profiles. PMID- 26103170 TI - Accelerated tomotherapy delivery with TomoEdge technique. AB - TomoEDGE is an advanced delivery form of tomotherapy which uses a dynamic secondary collimator. This plan comparison study describes the new features, their clinical applicability, and their effect on plan quality and treatment speed. For the first 45 patients worldwide that were scheduled for a treatment with TomoEdge, at least two plans were created: one with the previous "standard"mode with static jaws and 2.5 cm field width (Reg 2.5) and one with TomoEdge technique and 5 cm field width (Edge 5). If, after analysis in terms of beam on time, integral dose, dose conformity, and organ at risk sparing the treating physician decided that the Edge 5 plan was not suitable for clinical treatment, a plan with TomoEdge and 2.5 cm field width was created (Edge 2.5) and used for the treatment. Among the 45 cases, 30 were suitable for Edge 5 treatment, including treatments of the head and neck, rectal cancer, anal cancer, malignancies of the chest, breast cancer, and palliative treatments. In these cases, the use of a 5 cm field width reduced beam on time by more than 30% without compromising plan quality. The 5 cm beam could not be clinically applied to treatments of the pelvic lymph nodes for prostate cancer and to head and neck irradiations with extensive involvement of the skull, as dose to critical organs at risk such as bladder (average dose 28 Gy vs. 29 Gy, Reg 2.5 vs. Edge 5), small bowel (29% vs. 31%, Reg 2.5 vs. Edge 5) and brain (average dose partial brain 19 Gy vs. 21 Gy, Reg 2.5 vs. Edge 5) increased to a clinically relevant, yet not statistically significant, amount. TomoEdge is an advantageous extension of the tomotherapy technique that can speed up treatments and thus increase patient comfort and safety in the majority of clinical settings. PMID- 26103172 TI - CT image quality over time: comparison of image quality for six different CT scanners over a six-year period. AB - UNSCEAR concluded that increased use of CT scanning caused dramatic changes in population dose. Therefore, international radiation protection authorities demand: 1) periodical quality assurance tests with respect to image quality and radiation dose, and 2) optimization of all examination protocols with respect to image quality and radiation dose. This study aimed to evaluate and analyze multiple image quality parameters and variability measured throughout time for six different CT scanners from four different vendors, in order to evaluate the current methodology for QA controls of CT systems. The results from this study indicate that there is minor drifting in the image noise and uniformity and in the spatial resolution over time for CT scanners, independent of vendors. The HU for different object densities vary between different CT scanner models from different vendors, and over time for one specific CT scanner. Future tests of interphantom and intraphantom variations, along with inclusion of more CT scanners, are necessary to establish robust baselines and recommendations of methodology for QA controls of CT systems, independent of model and vendor. PMID- 26103173 TI - Comparison between an in-house 1D profile correction method and a 2D correction provided in Varian's PDPC Package for improving the accuracy of portal dosimetry images. AB - While commissioning Varian's Portal Dose Image Prediction (PDIP) algorithm for portal dosimetry, an asymmetric radial response in the portal imager due to backscatter from the support arm was observed. This asymmetric response led to differences on the order of 2%-3% for simple square fields (< 20 * 20 cm2) when comparing the measured to predicted portal fluences. A separate problem was that discrepancies of up to 10% were seen in measured to predicted portal fluences at increasing off-axis distance (> 10 cm). We have modified suggested methods from the literature to provide a 1D correction for the off-axis response problem which adjusts the diagonal profile used in the portal imager calibration. This inherently cannot fix the 2D problem since the PDIP algorithm assumes a radially symmetric response and will lead to some uncertainty in portal dosimetry results. Varian has recently released generic "2D correction" files with their Portal Dosimetry Pre-configuration (PDPC) package, but no independent testing has been published. We present the comparison between QA results using the Varian correction method to results using our 1D profile correction method using the gamma passing rates with a 3%, 3 mm criterion. The average, minimum, and maximum gamma pass rates for nine fixed-field IMRT fields at gantry 0 degrees using our profile correction method were 98.1%, 93.7%, and 99.8%, respectively, while the results using the PDPC correction method were 98.4%, 93.1%, and 99.8%. For four RapidArc fields, the average, minimum, and maximum gamma pass rates using our correction method were 99.6%, 99.4%, and 99.9%, respectively, while the results using the PDPC correction method were 99.8%, 99.5%, and 99.9%. The average gamma pass rates for both correction methods are quite similar, but both show improvement over the uncorrected results. PMID- 26103174 TI - Intrafractional prostate motion during external beam radiotherapy monitored by a real-time target localization system. AB - This paper investigates the clinical significance of real-time monitoring of intrafractional prostate motion during external beam radiotherapy using a commercial 4D localization system. Intrafractional prostate motion was tracked during 8,660 treatment fractions for 236 patients. The following statistics were analyzed: 1) the percentage of fractions in which the prostate shifted 2-7 mm for a certain duration; 2) the proportion of the entire tracking time during which the prostate shifted 2-7mm; and 3) the proportion of each minute in which the shift exceeded 2-7 mm. The ten patients exhibiting maximum intrafractional-motion patterns were analyzed separately. Our results showed that the percentage of fractions in which the prostate shifted by > 2, 3, 5, and 7 mm off the baseline in any direction for > 30 s was 56.8%, 27.2%, 4.6%, and 0.7% for intact prostate and 68.7%, 35.6%, 10.1%, and 1.8% for postprostatectomy patients, respectively. For the ten patients, these percentages were 91.3%, 72.4%, 36.3%, and 6%, respectively. The percentage of tracking time during which the prostate shifted > 2, 3, 5, and 7 mm was 27.8%, 10.7%, 1.6%, and 0.3%, respectively, and it was 56.2%, 33.7%, 11.2%, and 2.1%, respectively, for the ten patients. The percentage of tracking time for a > 3 mm posterior motion was four to five times higher than that in other directions. For treatments completed in 5 min (VMAT) and 10 min (IMRT), the proportion for the prostate to shift by > 3mm was 4% and 12%, respectively. Although intrafractional prostate motion was generally small, caution should be taken for patients who exhibit frequent large intrafractional motion. For those patients, adjustment of patient positioning may be necessary or a larger treatment margin may be used. After the initial alignment, the likelihood of prostate motion increases with time. Therefore, it is favorable to use advanced techniques (e.g., VMAT) that require less delivery time in order to reduce the treatment uncertainty resulting from intrafractional prostate motion. PMID- 26103175 TI - Comparing the dosimetric characteristics of the electron beam from dedicated intraoperative and conventional radiotherapy accelerators. AB - The specific design of the mobile dedicated intraoperative radiotherapy (IORT) accelerators and different electron beam collimation system can change the dosimetric characteristics of electron beam with respect to the conventional accelerators. The aim of this study is to measure and compare the dosimetric characteristics of electron beam produced by intraoperative and conventional radiotherapy accelerators. To this end, percentage depth dose along clinical axis (PDD), transverse dose profile (TDP), and output factor of LIAC IORT and Varian 2100C/D conventional radiotherapy accelerators were measured and compared. TDPs were recorded at depth of maximum dose. The results of this work showed that depths of maximum dose, R90, R50, and RP for LIAC beam are lower than those of Varian beam. Furthermore, for all energies, surface doses related to the LIAC beam are substantially higher than those of Varian beam. The symmetry and flatness of LIAC beam profiles are more desirable compared to the Varian ones. Contrary to Varian accelerator, output factor of LIAC beam substantially increases with a decrease in the size of the applicator. Dosimetric characteristics of beveled IORT applicators along clinical axis were different from those of the flat ones. From these results, it can be concluded that dosimetric characteristics of intraoperative electron beam are substantially different from those of conventional clinical electron beam. The dosimetric characteristics of the LIAC electron beam make it a useful tool for intraoperative radiotherapy purposes. PMID- 26103176 TI - Compliance with AAPM Practice Guideline 1.a: CT Protocol Management and Review - from the perspective of a university hospital. AB - The purpose of this paper is to describe our experience with the AAPM Medical Physics Practice Guideline 1.a: "CT Protocol Management and Review Practice Guideline". Specifically, we will share how our institution's quality management system addresses the suggestions within the AAPM practice report. We feel this paper is needed as it was beyond the scope of the AAPM practice guideline to provide specific details on fulfilling individual guidelines. Our hope is that other institutions will be able to emulate some of our practices and that this article would encourage other types of centers (e.g., community hospitals) to share their methodology for approaching CT protocol optimization and quality control. Our institution had a functioning CT protocol optimization process, albeit informal, since we began using CT. Recently, we made our protocol development and validation process compliant with a number of the ISO 9001:2008 clauses and this required us to formalize the roles of the members of our CT protocol optimization team. We rely heavily on PACS-based IT solutions for acquiring radiologist feedback on the performance of our CT protocols and the performance of our CT scanners in terms of dose (scanner output) and the function of the automatic tube current modulation. Specific details on our quality management system covering both quality control and ongoing optimization have been provided. The roles of each CT protocol team member have been defined, and the critical role that IT solutions provides for the management of files and the monitoring of CT protocols has been reviewed. In addition, the invaluable role management provides by being a champion for the project has been explained; lack of a project champion will mitigate the efforts of a CT protocol optimization team. Meeting the guidelines set forth in the AAPM practice guideline was not inherently difficult, but did, in our case, require the cooperation of radiologists, technologists, physicists, IT, administrative staff, and hospital management. Some of the IT solutions presented in this paper are novel and currently unique to our institution. PMID- 26103177 TI - Commissioning and quality assurance of Dynamic WaveArc irradiation. AB - A novel three-dimensional unicursal irradiation technique "Dynamic WaveArc" (DWA), which employs simultaneous and continuous gantry and O-ring rotation during dose delivery, has been implemented in Vero4DRT. The purposes of this study were to develop a commissioning and quality assurance procedure for DWA irradiation, and to assess the accuracy of the mechanical motion and dosimetric control of Vero4DRT. To determine the mechanical accuracy and the dose accuracy with DWA irradiation, 21 verification test patterns with various gantry and ring rotational directions and speeds were generated. These patterns were irradiated while recording the irradiation log data. The differences in gantry position, ring position, and accumulated MU (EG, ER, and EMU, respectively) between the planned and actual values in the log at each time point were evaluated. Furthermore, the doses delivered were measured using an ionization chamber and spherical phantom. The constancy of radiation output during DWA irradiation was examined by comparison with static beam irradiation. The mean absolute error (MAE) of EG and ER were within 0.1 degrees and the maximum error was within 0.2 degrees . The MAE of EMU was within 0.7 MU, and maximum error was 2.7 MU. Errors of accumulated MU were observed only around control points, changing gantry, and ring velocity. The gantry rotational range, in which EMU was greater than or equal to 2.0 MU, was not greater than 3.2%. It was confirmed that the extent of the large differences in accumulated MU was negligibly small during the entire irradiation range. The variation of relative output value for DWA irradiation was within 0.2%, and this was equivalent to conventional arc irradiation with a rotating gantry. In conclusion, a verification procedure for DWA irradiation was designed and implemented. The results demonstrated that Vero4DRT has adequate mechanical accuracy and beam output constancy during gantry and ring rotation. PMID- 26103178 TI - An evaluation of the stability of image-quality parameters of Varian on-board imaging (OBI) and EPID imaging systems. AB - Quality assurance (QA) of the image quality for image-guided localization systems is crucial to ensure accurate visualization and localization of regions of interest within the patient. In this study, the temporal stability of selected image parameters was assessed and evaluated for kV CBCT mode, planar radiographic kV, and MV modes. The motivation of the study was to better characterize the temporal variability in specific image-quality parameters. The CATPHAN, QckV-1, and QC-3 phantoms were used to evaluate the image-quality parameters of the imaging systems on a Varian Novalis Tx linear accelerator. The planar radiographic images were analyzed in PIPSpro with high-contrast spatial resolution (f30, f40,f50 lp/mm) being recorded. For OBI kV CBCT, high-quality head full-fan acquisition and pelvis half-fan acquisition modes were evaluated for uniformity, noise, spatial resolution, HU constancy, and geometric distortion. Dose and X-ray energy for the OBI were recorded using the Unfors RaySafe Xi system with the R/F High Detector for kV planar radiographic and the CT detector for kV CBCT. Dose for the MV EPID was recorded using a PTW975 Semiflex ion chamber, PTW UNIDOS electrometer, and CNMC Plastic Water. For each image-quality parameter, values were normalized to the mean, and the normalized standard deviations were recorded to evaluate the parameter's temporal variability. For planar radiographic modes, the normalized standard deviations of the spatial resolution (f30, f40, & f50) were 0.015, 0.008, 0.004 lp/mm and 0.006, 0.009, 0.018 lp/mm for the kV and MV, respectively. The normalized standard deviation of dose for kV and MV were 0.010 mGy and 0.005mGy, respectively. The standard deviations for full- and half-fan kV CBCT modes were averaged together. The following normalized standard deviations for each kV CBCT parameter were: 0.075 HU (uniformity), 0.071 HU (noise), 0.006mm (AP-geometric distortion), 0.005 mm (LAT-geometric distortion), 0.058mm (slice thickness), 0.124 (f50), 0.031 (HU constancy - Lung), 0.063 (HU constancy- Water), 0.020 (HU constancy - Bone), 0.006 mGy (Dose - Center), 0.004 mGy (Dose -Periphery). Using control chart analysis, institutional QA tolerances were reported as warning and action thresholds based on 1sigma and 2sigma thresholds. A study was performed to characterize the stability of image-quality parameters recommended by AAPM Task Group-142 for the Varian OBI and EPID imaging systems. Both imaging systems show consistent imaging and dosimetric properties over the evaluated time frame. PMID- 26103179 TI - Estimation of patient setup uncertainty using BrainLAB Exatrac X-Ray 6D system in image-guided radiotherapy. AB - The purpose of this study was to evaluate setup uncertainties for brain sites with ExacTrac X-Ray 6D system and to provide optimal margin guidelines. Fifteen patients with brain tumor were included in this study. Two X-ray images with ExacTrac X-Ray 6D system were used to verify patient position and tumor target localization before each treatment. The 6D fusion software first generates various sets of DRRs with position variations in both three translational and three rotational directions (six degrees of freedom) for the CT images. Setup variations (translation and rotation) after correction were recorded and corrected before treatment. The 3D deviations are expressed as mean +/- standard deviation. The random error (Sigma(sigmai)), systematic error (MUi), and group systematic error (M(MUi)) for the different X-ray were calculated using the definitions of van Herk.(1) Mean setup errors were calculated from X-ray images acquired after all fractions. There is moderate patient-to-patient variation in the vertical direction and small variations in systematic errors and magnitudes of random errors are smaller. The global systematic errors were measured to be less than 2.0 mm in each direction. Random component of all patients are smaller ranging from 0.1-0.3 mm small. The safety margin (SM) to the lateral, is 0.5 mm and 2.6 mm for van Herk(1) and Stroom et al.,(2) respectively, craniocaudal axis is 1.5 mm and 3.4 mm, respectively, and with respect to the antero-posterior axis, 2.3 mm and 3.9 mm. Daily X-ray imaging is essential to compare and assess the accuracy of treatment delivery to different anatomical locations. PMID- 26103180 TI - Interfraction positional variation in pancreatic tumors using daily breath-hold cone-beam computed tomography with visual feedback. AB - We assessed interfraction positional variation in pancreatic tumors using daily breath-hold cone-beam computed tomography at end-exhalation (EE) with visual feedback (BH-CBCT). Eleven consecutive patients with pancreatic cancer who underwent BH intensity-modulated radiation therapy with visual feedback were enrolled. All participating patients stopped oral intake, with the exception of drugs and water, for > 3 hr before treatment planning and daily treatment. Each patient was fixed in the supine position on an individualized vacuum pillow. An isotropic margin of 5 mm was added to the clinical target volume to create the planning target volume (PTV). The prescription dose was 42 to 51 Gy in 15 fractions. After correcting initial setup errors based on bony anatomy, the first BH-CBCT scans were performed before beam delivery in every fraction. BH-CBCT acquisition was obtained in three or four times breath holds by interrupting the acquisition two or three times, depending on the patient's BH ability. The image acquisition time for a 360 degrees gantry rotation was approximately 90 s, including the interruption time due to BH. The initial setup errors were corrected based on bony structure, and the residual errors in the target position were then recorded. The magnitude of the interfraction variation in target position was assessed for 165 fractions. The systematic and random errors were 1.2 and 1.8 mm, 1.1 and 1.8 mm, and 1.7 and 2.9 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. Absolute interfraction variations of > 5 mm were observed in 18 fractions (11.0%) from seven patients because of EE-BH failure. In conclusion, target matching is required to correct interfraction variation even with visual feedback, especially to ensure safe delivery of escalated doses to patients with pancreatic cancer. PMID- 26103181 TI - Evaluation and mitigation of potential errors in radiochromic film dosimetry due to film curvature at scanning. AB - This work considers a previously overlooked uncertainty present in film dosimetry which results from moderate curvature of films during the scanning process. Small film samples are particularly susceptible to film curling which may be undetected or deemed insignificant. In this study, we consider test cases with controlled induced curvature of film and with film raised horizontally above the scanner plate. We also evaluate the difference in scans of a film irradiated with a typical brachytherapy dose distribution with the film naturally curved and with the film held flat on the scanner. Typical naturally occurring curvature of film at scanning, giving rise to a maximum height 1 to 2 mm above the scan plane, may introduce dose errors of 1% to 4%, and considerably reduce gamma evaluation passing rates when comparing film-measured doses with treatment planning system calculated dose distributions, a common application of film dosimetry in radiotherapy. The use of a triple-channel dosimetry algorithm appeared to mitigate the error due to film curvature compared to conventional single-channel film dosimetry. The change in pixel value and calibrated reported dose with film curling or height above the scanner plate may be due to variations in illumination characteristics, optical disturbances, or a Callier-type effect. There is a clear requirement for physically flat films at scanning to avoid the introduction of a substantial error source in film dosimetry. Particularly for small film samples, a compression glass plate above the film is recommended to ensure flat-film scanning. This effect has been overlooked to date in the literature. PMID- 26103182 TI - Erratum: Coronary calcium quantification using contrast-enhanced dual-energy computed tomography scans. PMID- 26103183 TI - An image-based method to synchronize cone-beam CT and optical surface tracking. AB - The integration of in-room X-ray imaging and optical surface tracking has gained increasing importance in the field of image guided radiotherapy (IGRT). An essential step for this integration consists of temporally synchronizing the acquisition of X-ray projections and surface data. We present an image-based method for the synchronization of cone-beam computed tomography (CBCT) and optical surface systems, which does not require the use of additional hardware. The method is based on optically tracking the motion of a component of the CBCT/gantry unit, which rotates during the acquisition of the CBCT scan. A calibration procedure was implemented to relate the position of the rotating component identified by the optical system with the time elapsed since the beginning of the CBCT scan, thus obtaining the temporal correspondence between the acquisition of X-ray projections and surface data. The accuracy of the proposed synchronization method was evaluated on a motorized moving phantom, performing eight simultaneous acquisitions with an Elekta Synergy CBCT machine and the AlignRT optical device. The median time difference between the sinusoidal peaks of phantom motion signals extracted from the synchronized CBCT and AlignRT systems ranged between -3.1 and 12.9 msec, with a maximum interquartile range of 14.4 msec. The method was also applied to clinical data acquired from seven lung cancer patients, demonstrating the potential of the proposed approach in estimating the individual and daily variations in respiratory parameters and motion correlation of internal and external structures. The presented synchronization method can be particularly useful for tumor tracking applications in extracranial radiation treatments, especially in the field of patient-specific breathing models, based on the correlation between internal tumor motion and external surface surrogates. PMID- 26103184 TI - Commissioning and quality assurance for the treatment delivery components of the AccuBoost system. AB - The objective for this work was to develop a commissioning methodology for the treatment delivery components of the AccuBoost system, as well as to establish a routine quality assurance program and appropriate guidance for clinical use based on the commissioning results. Various tests were developed: 1) assessment of the accuracy of the displayed separation value; 2) validation of the dwell positions within each applicator; 3) assessment of the accuracy and precision of the applicator localization system; 4) assessment of the combined dose profile of two opposed applicators to confirm that they are coaxial; 5) measurement of the absolute dose delivered with each applicator to confirm acceptable agreement with dose based on Monte Carlo modeling; 6) measurements of the skin-to-center dose ratio using optically stimulated luminescence dosimeters; and 7) assessment of the mammopad cushion's effect on the center dose. We found that the difference between the measured and the actual paddle separation is < 0.1 cm for the separation range of 3 cm to 7.5 cm. Radiochromic film measurements demonstrated that the number of dwell positions inside the applicators agree with the values from the vendor, for each applicator type and size. The shift needed for a good applicator-grid alignment was within 0.2 cm. The dry-run test using film demonstrated that the shift of the dosimetric center is within 0.15 cm. Dose measurements in water converted to polystyrene agreed within 5.0% with the Monte Carlo data in polystyrene for the same applicator type, size, and depth. A solid water-to-water (phantom) factor was obtained for each applicator, and all future annual quality assurance tests will be performed in solid water using an average value of 1.07 for the solid water-to-water factor. The skin-to-center dose ratio measurements support the Monte Carlo-based values within 5.0% agreement. For the treatment separation range of 4 cm to 8cm, the change in center dose would be < 1.0% for all applicators when using a compressed pad of 0.2 cm to 0.3 cm. The tests performed ensured that all treatment components of the AccuBoost system are functional and that a treatment plan can be delivered with acceptable accuracy. Based on the commissioning results, a quality assurance manual and guidance documents for clinical use were developed. PMID- 26103185 TI - Retracted: Reducing motion artifacts in 4D MR images using principal component analysis (PCA) combined with linear polynomial fitting model. AB - We have previously developed a retrospective 4D-MRI technique using body area as the respiratory surrogate, but generally, the reconstructed 4D MR images suffer from severe or mild artifacts mainly caused by irregular motion during image acquisition. Those image artifacts may potentially affect the accuracy of tumor target delineation or the shape representation of surrounding nontarget tissues and organs. So the purpose of this study is to propose an approach employing principal component analysis (PCA), combined with a linear polynomial fitting model, to remodel the displacement vector fields (DVFs) obtained from deformable image registration (DIR), with the main goal of reducing the motion artifacts in 4D MR images. Seven patients with hepatocellular carcinoma (2/7) or liver metastases (5/7) in the liver, as well as a patient with non-small cell lung cancer (NSCLC), were enrolled in an IRB-approved prospective study. Both CT and MR simulations were performed for each patient for treatment planning. Multiple slice, multiple-phase, cine-MRI images were acquired in the axial plane for 4D MRI reconstruction. Single-slice 2D cine-MR images were acquired across the center of the tumor in axial, coronal, and sagittal planes. For a 4D MR image dataset, the DVFs in three orthogonal direction (inferior-superior (SI), anterior posterior (AP), and medial-lateral (ML)) relative to a specific reference phase were calculated using an in-house DIR algorithm. The DVFs were preprocessed in three temporal and spatial dimensions using a polynomial fitting model, with the goal of correcting the potential registration errors introduced by three dimensional DIR. Then PCA was used to decompose each fitted DVF into a linear combination of three principal motion bases whose spanned subspaces combined with their projections had been validated to be sufficient to represent the regular respiratory motion. By wrapping the reference MR image using the remodeled DVFs, 'synthetic' MR images with reduced motion artifacts were generated at selected phase. Tumor motion trajectories derived from cine-MRI, 4D CT, original 4D MRI, and 'synthetic' 4D MRI were analyzed in the SI, AP, and ML directions, respectively. Their correlation coefficient (CC) and difference (D) in motion amplitude were calculated for comparison. Of all the patients, the means and standard deviations (SDs) of CC comparing 'synthetic' 4D MRI and cine-MRI were 0.98 +/- 0.01, 0.98 +/- 0.01, and 0.99 +/- 0.01 in SI, AP, and ML directions, respectively. The mean +/- SD Ds were 0.59 +/- 0.09 mm, 0.29+/- 0.10 mm, and 0.15 +/- 0.05 mm in SI, AP and ML directions, respectively. The means and SDs of CC comparing 'synthetic' 4D MRI and 4D CT were 0.96 +/- 0.01, 0.95+/- 0.01, and 0.95 +/- 0.01 in SI, AP, and ML directions, respectively. The mean +/- SD Ds were 0.76 +/- 0.20 mm, 0.33 +/- 0.14 mm, and 0.19+/- 0.07 mm in SI, AP, and ML directions, respectively. The means and SDs of CC comparing 'synthetic' 4D MRI and original 4D MRI were 0.98 +/- 0.01, 0.98+/- 0.01, and 0.97+/- 0.01 in SI, AP, and ML directions, respectively. The mean +/- SD Ds were 0.58 +/- 0.10 mm, 0.30 +/- 0.09mm, and 0.17 +/- 0.04 mm in SI, AP, and ML directions, respectively. In this study we have proposed an approach employing PCA combined with a linear polynomial fitting model to capture the regular respiratory motion from a 4D MR image dataset. And its potential usefulness in reducing motion artifacts and improving image quality has been demonstrated by the preliminary results in oncological patients. PMID- 26103186 TI - Commissioning a 50-100 kV X-ray unit for skin cancer treatment. AB - This study provides the authors' experience along with dosimetric data from the commissioning of two Sensus SRT-100 50-100 kV X-ray units. Data collected during the commissioning process included: a) HVL, b) output (dose rate), c) applicator cone factors, and d) percentage depth dose. A Farmer-type chamber (PTW-N23333), and a thin-window parallel plate ion chamber (PTW-N23342) were used for dose rate measurements and dose profiles were measured with EBT3 GafChromic film. The average HVL values for 50, 70, and 100 kV of the two treatment units were found to be 0.52, 1.15, and 2.20 mm Al, respectively. The HVL's were 5%-9% lower when measured with the Farmer chamber, as compared to measurements with the parallel plate chamber, for energies of 70 and 100 kV. Dose rates were also measured to be 3%-4% lower with the Farmer chamber. The dose rate variation between the two units was found to be 2%-9% for 50, 70, and 100 kV. The dose uniformity over a circle of 2 cm diameter was within 4% in four cardinal directions; however, the dose profiles for the 5 cm applicator were nonuniform, especially in the cathode anode direction. Measurements indicated as much as 15% lower dose for the 50 kV beam at field edge on the anode side, when normalized to the center. The crossline profile was relatively more symmetric, with a maximum deviation of 10% at the field edge. All ion chamber readings agreed with film measurements within 3%. The nonuniform profile produced by these units may introduce uncertainty in dose rate measurements, especially for larger applicators. Since there is no intrinsic tool (crosshair or field light) for alignment with the beam axis, the user should take care when positioning the chamber for output measurements. The data obtained with a Farmer-type chamber should be used cautiously and as a reference only for the SRT-100 X-ray treatment unit. PMID- 26103187 TI - Quantifying isocenter measurements to establish clinically meaningful thresholds. AB - A dataset range of isocenter congruency verification tests have been examined from a statistical perspective for the purpose of establishing tolerance levels that are meaningful, based on the fundamental limitation of linear accelerator isocentricity and the demands of a high-precision stereotactic radiosurgery program. Using a laser-defined isocenter, a total of 149 individual isocenter congruency tests were examined with recorded values for ideal spatial corrections to the isocenter test tool. These spatial corrections were determined from radiation exposures recorded on an electronic portal imaging device (EPID) at various gantry, collimator, and treatment couch combinations. The limitations of establishing an ideal isocenter were quantified from each variable which contributed to uncertainty in isocenter definition. Individual contributors to uncertainty, specifically, daily positioning setup errors, gantry sag, multileaf collimator (MLC) offset, and couch walkout, were isolated from isocenter congruency measurements to determine a clinically meaningful isocenter measurement. Variations in positioning of the test tool constituted, on average, 0.38 mm magnitude of correction. Gantry sag and MLC offset contributed 0.4 and 0.16 mm, respectively. Couch walkout had an average degrading effect to isocenter of 0.72 mm. Considering the magnitude of uncertainty contributed by each uncertainty variable and the nature of their combination, an appropriate schedule action and immediate action level were determined for use in analyzing daily isocenter congruency test results in a stereotactic radiosurgery (SRS) program. The recommendations of this study for this linear accelerator include a schedule action level of 1.25 mm and an immediate action level of 1.50mm, requiring prompt correction response from clinical medical physicists before SRS or stereotactic body radiosurgery (SBRT) is administered. These absolute values were derived from considering relative data from a specific linear accelerator and, therefore, represent a means by which a numerical quantity can be used as a test threshold with relative specificity to a particular linear accelerator. PMID- 26103188 TI - MLC positional accuracy evaluation through the Picket Fence test on EBT2 films and a 3D volumetric phantom. AB - The accuracy of MLC positions during radiotherapy is important as even small positional deviations can translate into considerable dose delivery errors. This becomes crucial when radiosensitive organs are located near the treated volume and especially during IMRT, where dose gradients are steep. A test commonly conducted to measure the positional accuracy of the MLCs is the Picket Fence test. In this study two alterations of the Picket Fence test were performed and evaluated, the first one using radiochromic EBT2 films and the second one the Delta4PT diode array phantom and its software. Our results showed that EBT2 films provide a relatively fast, qualitative visual inspection of the significant leaf dispositions. When slight inaccuracies need to be revealed or precise numerical results for each leaf position are needed, Delta4PT provides the desired accuracy of 1 mm. In treatment modalities where a higher accuracy is required in the delivered dose distribution, such as in IMRT, precise numerical values of the measurements for the MLC positional inspection are required. PMID- 26103189 TI - Dosimetric validation and clinical implementation of two 3D dose verification systems for quality assurance in volumetric-modulated arc therapy techniques. AB - A pretreatment quality assurance program for volumetric techniques should include redundant calculations and measurement-based verifications. The patient-specific quality assurance process must be based in clinically relevant metrics. The aim of this study was to show the commission, clinical implementation, and comparison of two systems that allow performing a 3D redundant dose calculation. In addition, one of them is capable of reconstructing the dose on patient anatomy from measurements taken with a 2D ion chamber array. Both systems were compared in terms of reference calibration data (absolute dose, output factors, percentage depth-dose curves, and profiles). Results were in good agreement for absolute dose values (discrepancies were below 0.5%) and output factors (mean differences were below 1%). Maximum mean discrepancies were located between 10 and 20 cm of depth for PDDs (-2.7%) and in the penumbra region for profiles (mean DTA of 1.5 mm). Validation of the systems was performed by comparing point-dose measurements with values obtained by the two systems for static, dynamic fields from AAPM TG 119 report, and 12 real VMAT plans for different anatomical sites (differences better than 1.2%). Comparisons between measurements taken with a 2D ion chamber array and results obtained by both systems for real VMAT plans were also performed (mean global gamma passing rates better than 87.0% and 97.9% for the 2%/2 mm and 3%/3 mm criteria). Clinical implementation of the systems was evaluated by comparing dose-volume parameters for all TG-119 tests and real VMAT plans with TPS values (mean differences were below 1%). In addition, comparisons between dose distributions calculated by TPS and those extracted by the two systems for real VMAT plans were also performed (mean global gamma passing rates better than 86.0% and 93.0% for the 2%/2 mm and 3%/ 3 mm criteria). The clinical use of both systems was successfully evaluated. PMID- 26103190 TI - Initial clinical experience with a radiation oncology dedicated open 1.0T MR simulation. AB - The purpose of this study was to describe our experience with 1.0T MR-SIM including characterization, quality assurance (QA) program, and features necessary for treatment planning. Staffing, safety, and patient screening procedures were developed. Utilization of an external laser positioning system (ELPS) and MR-compatible couchtop were illustrated. Spatial and volumetric analyses were conducted between CT-SIM and MR-SIM using a stereotactic QA phantom with known landmarks and volumes. Magnetic field inhomogeneity was determined using phase difference analysis. System-related, in-plane distortion was evaluated and temporal changes were assessed. 3D distortion was characterized for regions of interest (ROIs) 5-20 cm away from isocenter. American College of Radiology (ACR) recommended tests and impact of ELPS on image quality were analyzed. Combined ultrashort echotime Dixon (UTE/Dixon) sequence was evaluated. Amplitude-triggered 4D MRI was implemented using a motion phantom (2-10 phases, ~ 2 cm excursion, 3-5 s periods) and a liver cancer patient. Duty cycle, acquisition time, and excursion were evaluated between maximum intensity projection (MIP) datasets. Less than 2% difference from expected was obtained between CT-SIM and MR-SIM volumes, with a mean distance of < 0.2 mm between landmarks. Magnetic field inhomogeneity was < 2 ppm. 2D distortion was < 2 mm over 28.6-33.6 mm of isocenter. Within 5 cm radius of isocenter, mean 3D geometric distortion was 0.59 +/- 0.32 mm (maximum = 1.65 mm) and increased 10-15 cm from isocenter (mean = 1.57 +/- 1.06 mm, maximum = 6.26 mm). ELPS interference was within the operating frequency of the scanner and was characterized by line patterns and a reduction in signal-to-noise ratio (4.6-12.6% for TE = 50-150 ms). Image quality checks were within ACR recommendations. UTE/Dixon sequences yielded detectability between bone and air. For 4D MRI, faster breathing periods had higher duty cycles than slow (50.4% (3 s) and 39.4% (5 s), p < 0.001) and ~fourfold acquisition time increase was measured for ten-phase versus two-phase. Superior-inferior object extent was underestimated 8% (6 mm) for two-phase as compared to ten-phase MIPs, although < 2% difference was obtained for >= 4 phases. 4D MRI for a patient demonstrated acceptable image quality in ~ 7 min. MR SIM was integrated into our workflow and QA procedures were developed. Clinical applicability was demonstrated for 4D MRI and UTE imaging to support MR-SIM for single modality treatment planning. PMID- 26103192 TI - Evaluation of image lag in a flat-panel, detector-equipped cardiovascular X-ray machine using a newly developed dynamic phantom. AB - We developed a dynamic phantom for use in routine checks. This phantom can be used to physically evaluate image lag that occurs in dynamic images. It has a unique measurement method. ROIs on the target are chosen, and, with the position of ROIs fixed on the image, changes in pixel value are detected physically when the target passes through the ROIs over time and perceived as image lag. Thus, it was possible to physically detect different intensities of image lag lasting less than one second while maintaining the same intensity trends. The checking technique we propose with the dynamic phantom that we developed could be effective for routine checking of fluoroscopy X-ray machines, and could become an established method. PMID- 26103191 TI - Quantitative comparison of automatic and manual IMRT optimization for prostate cancer: the benefits of DVH prediction. AB - A recent publication indicated that the patient anatomical feature (PAF) model was capable of predicting optimal objectives based on past experience. In this study, the benefits of IMRT optimization using PAF-predicted objectives as guidance for prostate were evaluated. Three different optimization methods were compared.1) Expert Plan: Ten prostate cases (16 plans) were planned by an expert planner using conventional trial-and-error approach started with institutional modified OAR and PTV constraints. Optimization was stopped at 150 iterations and that plan was saved as Expert Plan. 2) Clinical Plan: The planner would keep working on the Expert Plan till he was satisfied with the dosimetric quality and the final plan was referred to as Clinical Plan. 3) PAF Plan: A third sets of plans for the same ten patients were generated fully automatically using predicted DVHs as guidance. The optimization was based on PAF-based predicted objectives, and was continued to 150 iterations without human interaction. DMAX and D98% for PTV, DMAX for femoral heads, DMAX, D10cc, D25%/D17%, and D40% for bladder/rectum were compared. Clinical Plans are further optimized with more iterations and adjustments, but in general provided limited dosimetric benefits over Expert Plans. PTV D98% agreed within 2.31% among Expert, Clinical, and PAF plans. Between Clinical and PAF Plans, differences for DMAX of PTV, bladder, and rectum were within 2.65%, 2.46%, and 2.20%, respectively. Bladder D10cc was higher for PAF but < 1.54% in general. Bladder D25% and D40% were lower for PAF, by up to 7.71% and 6.81%, respectively. Rectum D10cc, D17%, and D40% were 2.11%, 2.72%, and 0.27% lower for PAF, respectively. DMAX for femoral heads were comparable (< 35 Gy on average). Compared to Clinical Plan (Primary + Boost), the average optimization time for PAF plan was reduced by 5.2 min on average, with a maximum reduction of 7.1min. Total numbers of MUs per plan for PAF Plans were lower than Clinical Plans, indicating better delivery efficiency. The PAF-guided planning process is capable of generating clinical-quality prostate IMRT plans with no human intervention. Compared to manual optimization, this automatic optimization increases planning and delivery efficiency, while maintainingplan quality. PMID- 26103193 TI - Clinical experience using a video-guided spirometry system for deep inhalation breath-hold radiotherapy of left-sided breast cancer. AB - The purpose was to report clinical experience of a video-guided spirometry system in applying deep inhalation breath-hold (DIBH) radiotherapy for left-sided breast cancer, and to study the systematic and random uncertainties, intra- and interfraction motion and impact on cardiac dose associated with DIBH. The data from 28 left-sided breast cancer patients treated with spirometer-guided DIBH radiation were studied. Dosimetric comparisons between free-breathing (FB) and DIBH plans were performed. The distance between the heart and chest wall measured on the digitally reconstructed radiographs (DRR) and MV portal images, dDRR(DIBH) and dport(DIBH), respectively, was compared as a measure of DIBH setup uncertainty. The difference (Deltad) between dDRR(DIBH) and dport(DIBH) was defined as the systematic uncertainty. The standard deviation of Deltad for each patient was defined as the random uncertainty. MV cine images during radiation were acquired. Affine registrations of the cine images acquired during one fraction and multiple fractions were performed to study the intra- and interfraction motion of the chest wall. The median chest wall motion was used as the metric for intra- and interfraction analysis. Breast motions in superior inferior (SI) direction and "AP" (defined on the DRR or MV portal image as the direction perpendicular to the SI direction) are reported. Systematic and random uncertainties of 3.8 mm and 2mm, respectively, were found for this spirometer guided DIBH treatment. MV cine analysis showed that intrafraction chest wall motions during DIBH were 0.3mm in "AP" and 0.6 mm in SI. The interfraction chest wall motions were 3.6 mm in "AP" and 3.4 mm in SI. Utilization of DIBH with this spirometry system led to a statistically significant reduction of cardiac dose relative to FB treatment. The DIBH using video-guided spirometry provided reproducible cardiac sparing with minimal intra- and interfraction chest wall motion, and thus is a valuable adjunct to modern breast treatment techniques. PMID- 26103194 TI - Evaluation of a single-scan protocol for radiochromic film dosimetry. AB - The purpose of this study was to evaluate a single-scan protocol using Gafchromic EBT3 film (EBT3) by comparing it with the commonly used 24-hr measurement protocol for radiochromic film dosimetry. Radiochromic film is generally scanned 24 hr after film exposure (24-hr protocol). The single-scan protocol enables measurement results within a short time using only the verification film, one calibration film, and unirradiated film. The single-scan protocol was scanned 30 min after film irradiation. The EBT3 calibration curves were obtained with the multichannel film dosimetry method. The dose verifications for each protocol were performed with the step pattern, pyramid pattern, and clinical treatment plans for intensity-modulated radiation therapy (IMRT). The absolute dose distributions for each protocol were compared with those calculated by the treatment planning system (TPS) using gamma evaluation at 3% and 3 mm. The dose distribution for the single-scan protocol was within 2% of the 24-hr protocol dose distribution. For the step pattern, the absolute dose discrepancies between the TPS for the single scan and 24-hr protocols were 2.0 +/- 1.8 cGy and 1.4 +/- 1.2 cGy at the dose plateau, respectively. The pass rates were 96.0% for the single-scan protocol and 95.9% for the 24-hr protocol. Similarly, the dose discrepancies for the pyramid pattern were 3.6 +/- 3.5cGy and 2.9 +/- 3.3 cGy, respectively, while the pass rates for the pyramid pattern were 95.3% and 96.4%, respectively. The average pass rates for the four IMRT plans were 96.7% +/- 1.8% for the single-scan protocol and 97.3% +/- 1.4% for the 24-hr protocol. Thus, the single-scan protocol measurement is useful for dose verification of IMRT, based on its accuracy and efficiency. PMID- 26103195 TI - Optimization of a general-purpose, actively scanned proton beamline for ocular treatments: Geant4 simulations. AB - The Italian National Center for Hadrontherapy (CNAO, Centro Nazionale di Adroterapia Oncologica), a synchrotron-based hospital facility, started the treatment of patients within selected clinical trials in late 2011 and 2012 with actively scanned proton and carbon ion beams, respectively. The activation of a new clinical protocol for the irradiation of uveal melanoma using the existing general-purpose proton beamline is foreseen for late 2014. Beam characteristics and patient treatment setup need to be tuned to meet the specific requirements for such a type of treatment technique. The aim of this study is to optimize the CNAO transport beamline by adding passive components and minimizing air gap to achieve the optimal conditions for ocular tumor irradiation. The CNAO setup with the active and passive components along the transport beamline, as well as a human eye-modeled detector also including a realistic target volume, were simulated using the Monte Carlo Geant4 toolkit. The strong reduction of the air gap between the nozzle and patient skin, as well as the insertion of a range shifter plus a patient-specific brass collimator at a short distance from the eye, were found to be effective tools to be implemented. In perspective, this simulation toolkit could also be used as a benchmark for future developments and testing purposes on commercial treatment planning systems. PMID- 26103196 TI - Percent depth-dose distribution discrepancies from very small volume ion chambers. AB - As very small ion chambers become commercially available, medical physicists may be inclined to use them during the linear accelerator commissioning process to better characterize the beam in steep dose gradient areas. For this work, a total of eight different ion chambers (volumes from 0.007 cc to 0.6 cc) and four different scanning systems were used to scan PDDs at both +300V and -300V biases. We observed a reproducible, significant difference (overresponse with depth) in PDDs acquired when using very small ion chambers, with specific bias/water tank combinations - up to 5% at a depth of 25 cm in water. This difference was not observed when the PDDs were sampled using the ion chamber in static positions in conjunction with an external electrometer. This suggests noise/signal interference produced by the controller box and cable system assemblies, which can become relatively significant for the very small current signals collected by very small ion chambers, especially at depth as the signal level is even further reduced. Based on the results observed here, the use of very small active volume chambers under specific scanning conditions may lead to collection of erroneous data, introducing systematic errors into the treatment planning system. In case the use of such a chamber is required, we recommend determining whether such erroneous effect exists by comparing the scans with those obtained with a larger chamber. PMID- 26103197 TI - Efficacy and workload analysis of a fixed vertical couch position technique and a fixed-action-level protocol in whole-breast radiotherapy. AB - Quantification of the setup errors is vital to define appropriate setup margins preventing geographical misses. The no-action-level (NAL) correction protocol reduces the systematic setup errors and, hence, the setup margins. The manual entry of the setup corrections in the record-and-verify software, however, increases the susceptibility of the NAL protocol to human errors. Moreover, the impact of the skin mobility on the anteroposterior patient setup reproducibility in whole-breast radiotherapy (WBRT) is unknown. In this study, we therefore investigated the potential of fixed vertical couch position-based patient setup in WBRT. The possibility to introduce a threshold for correction of the systematic setup errors was also explored. We measured the anteroposterior, mediolateral, and superior-inferior setup errors during fractions 1-12 and weekly thereafter with tangential angled single modality paired imaging. These setup data were used to simulate the residual setup errors of the NAL protocol, the fixed vertical couch position protocol, and the fixed-action-level protocol with different correction thresholds. Population statistics of the setup errors of 20 breast cancer patients and 20 breast cancer patients with additional regional lymph node (LN) irradiation were calculated to determine the setup margins of each off-line correction protocol. Our data showed the potential of the fixed vertical couch position protocol to restrict the systematic and random anteroposterior residual setup errors to 1.8 mm and 2.2 mm, respectively. Compared to the NAL protocol, a correction threshold of 2.5mm reduced the frequency of mediolateral and superior-inferior setup corrections with 40% and 63%, respectively. The implementation of the correction threshold did not deteriorate the accuracy of the off-line setup correction compared to the NAL protocol. The combination of the fixed vertical couch position protocol, for correction of the anteroposterior setup error, and the fixed-action-level protocol with 2.5 mm correction threshold, for correction of the mediolateral and the superior-inferior setup errors, was proved to provide adequate and comparable patient setup accuracy in WBRT and WBRT with additional LN irradiation. PMID- 26103198 TI - TBI lung dose comparisons using bilateral and anteroposterior delivery techniques and tissue density corrections. AB - This study compares lung dose distributions for two common techniques of total body photon irradiation (TBI) at extended source-to-surface distance calculated with, and without, tissue density correction (TDC). Lung dose correction factors as a function of lateral thorax separation are approximated for bilateral opposed TBI (supine), similar to those published for anteroposterior-posteroanterior (AP PA) techniques in AAPM Report 17 (i.e., Task Group 29). 3D treatment plans were created retrospectively for 24 patients treated with bilateral TBI, and for whom CT data had been acquired from the head to the lower leg. These plans included bilateral opposed and AP-PA techniques- each with and without - TDC, using source to-axis distance of 377 cm and largest possible field size. On average, bilateral TBI requires 40% more monitor units than AP-PA TBI due to increased separation (26% more for 23 MV). Calculation of midline thorax dose without TDC leads to dose underestimation of 17% on average (standard deviation, 4%) for bilateral 6 MV TBI, and 11% on average (standard deviation, 3%) for 23 MV. Lung dose correction factors (CF) are calculated as the ratio of midlung dose (with TDC) to midline thorax dose (without TDC). Bilateral CF generally increases with patient separation, though with high variability due to individual uniqueness of anatomy. Bilateral CF are 5% (standard deviation, 4%) higher than the same corrections calculated for AP-PA TBI in the 6 MV case, and 4% higher (standard deviation, 2%) for 23 MV. The maximum lung dose is much higher with bilateral TBI (up to 40% higher than prescribed, depending on patient anatomy) due to the absence of arm tissue blocking the anterior chest. Dose calculations for bilateral TBI without TDC are incorrect by up to 24% in the thorax for 6 MV and up to 16% for 23 MV. Bilateral lung CF may be calculated as 1.05 times the values published in Table 6 of AAPM Report 17, though a larger patient pool is necessary to better quantify this trend. Bolus or customized shielding will reduce lung maximum dose in the anterior thorax. PMID- 26103199 TI - Measurement-guided volumetric dose reconstruction for helical tomotherapy. AB - It was previously demonstrated that dose delivered by a conventional linear accelerator using IMRT or VMAT can be reconstructed - on patient or phantom datasets - using helical diode array measurements and a technique called planned dose perturbation (PDP). This allows meaningful and intuitive analysis of the agreement between the planned and delivered dose, including direct comparison of the dose-volume histograms. While conceptually similar to modulated arc techniques, helical tomotherapy introduces significant challenges to the PDP formalism, arising primarily from TomoTherapy delivery dynamics. The temporal characteristics of the delivery are of the same order or shorter than the dosimeter's update interval (50 ms). Additionally, the prevalence of often small and complex segments, particularly with the 1 cm Y jaw setting, lead to challenges related to detector spacing. Here, we present and test a novel method of tomotherapy-PDP (TPDP) designed to meet these challenges. One of the novel techniques introduced for TPDP is organization of the subbeams into larger subunits called sectors, which assures more robust synchronization of the measurement and delivery dynamics. Another important change is the optional application of a correction based on ion chamber (IC) measurements in the phantom. The TPDP method was validated by direct comparisons to the IC and an independent, biplanar diode array dosimeter previously evaluated for tomotherapy delivery quality assurance. Nineteen plans with varying complexity were analyzed for the 2.5 cm tomotherapy jaw setting and 18 for the 1 cm opening. The dose differences between the TPDP and IC were 1.0% +/- 1.1% and 1.1% +/- 1.1%, for 2.5 and 1.0 cm jaw plans, respectively. Gamma analysis agreement rates between TPDP and the independent array were: 99.1%+/- 1.8% (using 3% global normalization/3 mm criteria) and 93.4% +/- 7.1% (using 2% global/2 mm) for the 2.5 cm jaw plans; for 1 cm plans, they were 95.2% +/- 6.7% (3% G/3) and 83.8% +/- 12% (2% G/2). We conclude that TPDP is capable of volumetric dose reconstruction with acceptable accuracy. However, the challenges of fast tomotherapy delivery dynamics make TPDP less precise than the IMRT/VMAT PDP version, particularly for the 1 cm jaw setting. PMID- 26103200 TI - Effect of ROI filtering in 3D cone-beam rotational angiography on organ dose and effective dose in cerebral investigations. AB - The assessment of intracranial aneurysms is increasingly performed using three dimensional cone-beam rotational angiography (3D CBRA). To reduce the dose to the patient during 3D CBRA procedures, filtered region-of-interest imaging (FROI) is presented in literature to be an effective technique as the dose in regions of low interest is reduced, while high image quality is preserved in the ROI. The purpose of this study was to quantify the benefit of FROI imaging during a typical 3D CBRA procedure in a patient's head region. A cone-beam rotational angiography unit (Infinix) was modeled in GMctdospp, an EGSnrc-based Monte Carlo software, which calculates patient dose distributions in rotational computed tomography. Kodak Lanex, a gadolinium compound, was chosen to be the ROI filter material. The adult female ICRP reference phantom was integrated in GMctdospp to calculate organ and effective doses in simulations of FROI-CBRA examinations. During the Monte Carlo simulations, different parameters as the ROI filter thickness, the ROI opening size, the tube voltage, and the isocenter position were varied. The results showed that the reduction in dose clearly depends on these parameters. Comparing the reduction in organ dose in standard 3D CBRA and FROI-CBRA, a maximum reduction of about 60%-80% could be achieved with a small sized ROI filter and about 40%-70% of the dose could be saved using a ROI filter with a large opening. Further we could show that dose reduction strongly depends on filter thickness, the location of the organ in the radiated area, and the position of the isocenter. As a consequence, dose reduction partially differs from theoretically calculated values by a factor up to 1.6. The effective dose could be reduced to a minimum of about 40%. Due to the fact that standard 3D CBRA is only used for the assessment of aneurysms at present and, thus, most of the patient dose originates from the aneurysm treatment (with 2D techniques) itself, the dose reduction effect of ROI filtering in 3D CBRA tends to be much smaller, if the patient dose of a whole aneurysm treatment procedure is considered. PMID- 26103201 TI - SPARSE: Seed Point Auto-Generation for Random Walks Segmentation Enhancement in medical inhomogeneous targets delineation of morphological MR and CT images. AB - In medical image processing, robust segmentation of inhomogeneous targets is a challenging problem. Because of the complexity and diversity in medical images, the commonly used semiautomatic segmentation algorithms usually fail in the segmentation of inhomogeneous objects. In this study, we propose a novel algorithm imbedded with a seed point autogeneration for random walks segmentation enhancement, namely SPARSE, for better segmentation of inhomogeneous objects. With a few user-labeled points, SPARSE is able to generate extended seed points by estimating the probability of each voxel with respect to the labels. The random walks algorithm is then applied upon the extended seed points to achieve improved segmentation result. SPARSE is implemented under the compute unified device architecture (CUDA) programming environment on graphic processing unit (GPU) hardware platform. Quantitative evaluations are performed using clinical homogeneous and inhomogeneous cases. It is found that the SPARSE can greatly decrease the sensitiveness to initial seed points in terms of location and quantity, as well as the freedom of selecting parameters in edge weighting function. The evaluation results of SPARSE also demonstrate substantial improvements in accuracy and robustness to inhomogeneous target segmentation over the original random walks algorithm. PMID- 26103202 TI - Planning for mARC treatments with the Eclipse treatment planning system. AB - While modulated arc (mARC) capabilities have been available on Siemens linear accelerators for almost two years now, there was, until recently, only one treatment planning system capable of planning these treatments. The Eclipse treatment planning system now offers a module that can plan for mARC treatments. The purpose of this work was to test the module to determine whether it is capable of creating clinically acceptable plans. A total of 23 plans were created for various clinical sites and all plans delivered without anomaly. The average 3%/3 mm gamma pass rate for the plans was 98.0%, with a standard deviation of 1.7%. For a total of 14 plans, an equivalent static gantry IMRT plan was also created to compare delivery time. In all but two cases, the mARC plans delivered significantly faster than the static gantry plan. We have confirmed the successful creation of mARC plans that are deliverable with high fidelity on an ARTISTE linear accelerator, thus demonstrating the successful implementation of the Eclipse mARC module. PMID- 26103203 TI - The meaning of the MS Degree in Medical Physics, Part 4. PMID- 26103204 TI - Dimensionality Controlled Octahedral Symmetry-Mismatch and Functionalities in Epitaxial LaCoO3/SrTiO3 Heterostructures. AB - Epitaxial strain provides a powerful approach to manipulate physical properties of materials through rigid compression or extension of their chemical bonds via lattice-mismatch. Although symmetry-mismatch can lead to new physics by stabilizing novel interfacial structures, challenges in obtaining atomic-level structural information as well as lack of a suitable approach to separate it from the parasitical lattice-mismatch have limited the development of this field. Here, we present unambiguous experimental evidence that the symmetry-mismatch can be strongly controlled by dimensionality and significantly impact the collective electronic and magnetic functionalities in ultrathin perovskite LaCoO3/SrTiO3 heterojunctions. State-of-art diffraction and microscopy reveal that symmetry breaking dramatically modifies the interfacial structure of CoO6 octahedral building-blocks, resulting in expanded octahedron volume, reduced covalent screening, and stronger electron correlations. Such phenomena fundamentally alter the electronic and magnetic behaviors of LaCoO3 thin-films. We conclude that for epitaxial systems, correlation strength can be tuned by changing orbital hybridization, thus affecting the Coulomb repulsion, U, instead of by changing the band structure as the common paradigm in bulks. These results clarify the origin of magnetic ordering for epitaxial LaCoO3 and provide a route to manipulate electron correlation and magnetic functionality by orbital engineering at oxide heterojunctions. PMID- 26103205 TI - The synthesis and evaluation of near-infrared probes with barbituric acid acceptors for in vivo detection of amyloid plaques. AB - A new array of near-infrared probes containing barbituric acid acceptors has been developed as Abeta imaging agents. These probes displayed long-emission wavelengths and large Stokes shifts, as well as high affinities for Abeta aggregates. In vivo and ex vivo studies demonstrated that BBTOM-3 could intensely label Abeta plaques in the brains of transgenic mice. PMID- 26103206 TI - Exploring PtSO4 and PdSO4 phases: an evolutionary algorithm based investigation. AB - Metal sulfate formation is one of the major challenges to the emission aftertreatment catalysts. Unlike the incredibly sulfation prone nature of Pd to form PdSO4, no experimental evidence exists for PtSO4 formation. Given the mystery of nonexistence of PtSO4, we explore PtSO4 using a combined approach of an evolutionary algorithm based search technique and quantum mechanical computations. Experimentally known PdSO4 is considered for the comparison and validation of our results. We predict many possible low-energy phases of PtSO4 and PdSO4 at 0 K, which are further investigated in a wide range of temperature pressure conditions. An entirely new low-energy (tetragonal P42/m) structure of PtSO4 and PdSO4 is predicted, which appears to be the most stable phase of PtSO4 and a competing phase of the experimentally known monoclinic C2/c phase of PdSO4. Phase stability at a finite temperature is further examined and verified by Gibbs free energy calculations of sulfates towards their possible decomposition products. Finally, temperature-pressure phase diagrams are computationally established for both PtSO4 and PdSO4. PMID- 26103207 TI - Good-enough linguistic representations and online cognitive equilibrium in language processing. AB - We review previous research showing that representations formed during language processing are sometimes just "good enough" for the task at hand and propose the "online cognitive equilibrium" hypothesis as the driving force behind the formation of good-enough representations in language processing. Based on this view, we assume that the language comprehension system by default prefers to achieve as early as possible and remain as long as possible in a state of cognitive equilibrium where linguistic representations are successfully incorporated with existing knowledge structures (i.e., schemata) so that a meaningful and coherent overall representation is formed, and uncertainty is resolved or at least minimized. We also argue that the online equilibrium hypothesis is consistent with current theories of language processing, which maintain that linguistic representations are formed through a complex interplay between simple heuristics and deep syntactic algorithms and also theories that hold that linguistic representations are often incomplete and lacking in detail. We also propose a model of language processing that makes use of both heuristic and algorithmic processing, is sensitive to online cognitive equilibrium, and, we argue, is capable of explaining the formation of underspecified representations. We review previous findings providing evidence for underspecification in relation to this hypothesis and the associated language processing model and argue that most of these findings are compatible with them. PMID- 26103208 TI - Exploiting the Complementarity between Dereplication and Computer-Assisted Structure Elucidation for the Chemical Profiling of Natural Cosmetic Ingredients: Tephrosia purpurea as a Case Study. AB - The aqueous-ethanolic extract of Tephrosia purpurea seeds is currently exploited in the cosmetic industry as a natural ingredient of skin lotions. The aim of this study was to chemically characterize this ingredient by combining centrifugal partition extraction (CPE) as a fractionation tool with two complementary identification approaches involving dereplication and computer-assisted structure elucidation. Following two rapid fractionations of the crude extract (2 g), seven major compounds namely, caffeic acid, quercetin-3-O-rutinoside, ethyl galactoside, ciceritol, stachyose, saccharose, and citric acid, were unambiguously identified within the CPE-generated simplified mixtures by a recently developed (13)C NMR-based dereplication method. The structures of four additional compounds, patuletin-3-O-rutinoside, kaempferol-3-O-rutinoside, guaiacylglycerol 8-vanillic acid ether, and 2-methyl-2-glucopyranosyloxypropanoic acid, were automatically elucidated by using the Logic for Structure Determination program based on the interpretation of 2D NMR (HSQC, HMBC, and COSY) connectivity data. As more than 80% of the crude extract mass was characterized without need for tedious and labor-intensive multistep purification procedures, the identification tools involved in this work constitute a promising strategy for an efficient and time-saving chemical profiling of natural extracts. PMID- 26103209 TI - Diagnostic accuracy of the Aspergillus-specific bronchoalveolar lavage lateral flow assay in haematological malignancy patients. AB - We evaluated the performance of the Aspergillus-specific lateral-flow device (LFD) test for diagnosing invasive pulmonary aspergillosis (IPA) in patients with underlying haematological malignancies. Participating centres were the two Austrian University Hospitals of Graz and Innsbruck. LFD performance was evaluated with 95 bronchoalveolar lavage fluid (BALF) samples from 72 patients collected prospectively in Graz, and with 24 BALF bio bank samples from 23 patients (21 samples with probable IPA) in Innsbruck. Invasive fungal infections were classified according to the revised European Organization of Research and Treatment of Cancer/Mycoses Study Group criteria. Overall, 27 patients (30 samples) had probable IPA, 32 (43 samples) possible and 36 (46 samples) did not fulfil IPA criteria. The vast majority of patients - in particular those with probable IPA - received mould-active treatment before bronchoscopy. Sensitivity, specificity, positive predictive value and negative-predictive-value for probable IPA diagnosis using the BALF-LFD test were 71%, 76%, 35% and 94% for the Graz cohort. Sensitivity of the BALF-LFD test for probable IPA was 57% in Innsbruck bio bank samples. Our results indicate that the BALF-LFD-test provides fast results with moderate sensitivities in patients with underlying haematological malignancies. Similar to other diagnostic tests and biomarkers sensitivity of the test may be influenced by ongoing systemic mould-active treatment. PMID- 26103211 TI - Spectroscopic and Structural Elucidation of Uranium Dioxophenoxazine Complexes. AB - Uranium derivatives of a redox-active, dioxophenoxazine ligand, (DOPO(q))2UO2, (DOPO(sq))UI2(THF)2, (DOPO(cat))UI(THF)2, and Cp*U(DOPO(cat))(THF)2 (DOPO = 2,4,6,8-tetra-tert-butyl-1-oxo-1H-phenoxazin-9-olate), have been synthesized from U(VI) and U(III) starting materials. Full characterization of these species show uranium complexes bearing ligands in three different oxidation states. The electronic structures of these complexes have been explored using (1)H NMR and electronic absorption spectroscopies, and where possible, X-ray crystallography and SQUID magnetometry. PMID- 26103210 TI - Australian deceased donor kidney allocation protocols: Transplant waiting and graft quality for children and adolescents. AB - DD kidney allocation protocols may influence timing of transplantation and graft quality for pediatric recipients. This study aimed to evaluate the effects of these protocols, including pediatric priority, on waiting time on dialysis, transplant type, donor age, and HLA matching according to state of transplant in Australia. De-identified information on patients <15 yr of age who commenced RRT in NSW, Qld, and Victoria from 2002 to 2011 was retrieved from the ANZDATA. Transplant type, donor age, and HLA mismatching were compared between states, with competing risk regression used to examine the time to transplant. There were significant differences in waiting time to DD transplantation between the three states. Children in NSW and Qld waited a median of 14 and 11 months vs. 21 months in Victoria. The ratio of LD to DD transplants was lower in NSW and Qld. Differences correlated with DD pediatric priority in NSW and Qld. DDs in NSW were older than in the other states. HLA matching did not differ. DD kidney allocation protocols with pediatric priority in Australian states were associated with shorter waiting times and increased DD proportion. PMID- 26103422 TI - Hippocampal Cortactin Levels are Reduced Following Spatial Working Memory Formation, an Effect Blocked by Chronic Calpain Inhibition. AB - The mechanism by which the hippocampus facilitates declarative memory formation appears to involve, among other things, restructuring of the actin cytoskeleton within neuronal dendrites. One protein involved in this process is cortactin, which is an important link between extracellular signaling and cytoskeletal reorganization. In this paper, we demonstrate that total hippocampal cortactin, as well as Y421-phosphorylated cortactin are transiently reduced following spatial working memory formation in the radial arm maze (RAM). Because cortactin is a substrate of the cysteine protease calpain, we also assessed the effect of chronic calpain inhibition on RAM performance and cortactin expression. Calpain inhibition impaired spatial working memory and blocked the reduction in hippocampal cortactin levels following RAM training. These findings add to a growing body of research implicating cortactin and calpain in hippocampus dependent memory formation. PMID- 26103419 TI - Evolutionary trends and functional anatomy of the human expanded autophagy network. AB - All eukaryotic cells utilize autophagy for protein and organelle turnover, thus assuring subcellular quality control, homeostasis, and survival. In order to address recent advances in identification of human autophagy associated genes, and to describe autophagy on a system-wide level, we established an autophagy centered gene interaction network by merging various primary data sets and by retrieving respective interaction data. The resulting network ('AXAN') was analyzed with respect to subnetworks, e.g. the prime gene subnetwork (including the core machinery, signaling pathways and autophagy receptors) and the transcription subnetwork. To describe aspects of evolution within this network, we assessed the presence of protein orthologs across 99 eukaryotic model organisms. We visualized evolutionary trends for prime gene categories and evolutionary tracks for selected AXAN genes. This analysis confirms the eukaryotic origin of autophagy core genes while it points to a diverse evolutionary history of autophagy receptors. Next, we used module identification to describe the functional anatomy of the network at the level of pathway modules. In addition to obvious pathways (e.g., lysosomal degradation, insulin signaling) our data unveil the existence of context-related modules such as Rho GTPase signaling. Last, we used a tripartite, image-based RNAi - screen to test candidate genes predicted to play a role in regulation of autophagy. We verified the Rho GTPase, CDC42, as a novel regulator of autophagy-related signaling. This study emphasizes the applicability of system-wide approaches to gain novel insights into a complex biological process and to describe the human autophagy pathway at a hitherto unprecedented level of detail. PMID- 26103423 TI - The effect of cross-border mobility on alcohol and drug use among Mexican American residents living at the U.S.-Mexico border. AB - INTRODUCTION: Little epidemiological evidence exists on alcohol or other substance use and related problems along the U.S.-Mexico border, although the border has been the focus of recent media attention related to the escalating drug/violence "epidemic". The purpose of this study was to analyze the association of variables related to crossing the border (cross-border mobility) with three substance use outcomes reported for the last year: 1) heavy drinking (5+ drinks per day for men or 4+ for women), 2) alcohol use disorder (AUD), and 3) co-occurring heavy drinking and drug use (any use of illicit and/or non medically prescribed drugs). METHODS: Household surveys were conducted, using area probability sampling of 1565 Mexican-American residents, aged 18-65, living at the Texas-Mexico border in the metropolitan areas of Laredo and McAllen/Brownsville. RESULTS: Among those 18-29, more frequent crossing of the border was significantly predictive of AUD (OR = 1.61, p < 0.01) and co-occurring heavy drinking and drug use (OR = 1.70, p < 0.01). Staying more than one full day was predictive of AUD (OR = 3.07, p < 0.001) and crossing to obtain over-the counter or prescription drugs ("drug tourism") or for nightlife/drinking were predictive of heavy drinking (ORs = 4.14, p < 0.001; 3.92, p < 0.01, respectively), AUD (ORs = 7.56, p < 0.001; 7.68, p < 0.01, respectively) and co occurring heavy drinking and drug use (ORs = 8.53, p < 0.01; 4.96, p < 0.01, respectively). Among those 30-65, staying more than a full day and crossing for pharmaceutical reasons were predictive of heavy drinking (OR = 2.54, p < 0.001; 2.61, p < 0.05, respectively) and co-occurring heavy drinking and drug use (OR = 3.31, p < 0.001; 4.86, p < 0.01, respectively), while none of the mobility variables were predictive of AUD in this age group. CONCLUSIONS: Cross-border mobility may play an important role in substance use and problems, especially among those 18-29. Findings also highlight the importance of "drug tourism" in substance use across the age spectrum. PMID- 26103424 TI - Stressful life events, ethnic identity, historical trauma, and participation in cultural activities: Associations with smoking behaviors among American Indian adolescents in California. AB - INTRODUCTION: American Indian (AI) adolescents have the highest prevalence of commercial tobacco use of any ethnic group in the United States. This study examines ethnic identity (EI), participation in cultural activities, and stressful life events (SLEs) as correlates of smoking and examines historical trauma (HT) as a mediator of these associations. METHODS: California AI youth (N = 969, ages 13-19, recruited from 49 tribal youth organizations and cultural activities in urban and reservation areas in California) completed a tobacco survey. Structural equation modeling was used to test a model examining HT as a potential mediator of the associations of EI, participation in cultural activities, and SLEs with cigarette smoking. RESULTS: Model fit was adequate. EI, participation in cultural activities, and SLEs predicted HT. HT mediated the associations of participation in cultural activities and SLEs with past-month smoking. Stronger EI predicted greater past-month smoking and this effect was mediated by greater HT. The direct effects from HT to both smoking outcomes were positive and the direct effect from EI to past-month smoking was negative. CONCLUSIONS: HT is a risk factor for cigarette smoking both directly and in mediating the links of EI, cultural activities, and SLEs. More efforts are needed to help AI youth to process these thoughts and empower themselves to contribute to their own lives and those of their families and communities without resorting to unhealthy addictive behaviors such as commercial tobacco use. PMID- 26103425 TI - The interactive effect of paternal problem drinking and maternal problem drinking on adolescent internalizing problems. AB - INTRODUCTION: This study examined the effects of both paternal problem drinking and maternal problem drinking on adolescent internalizing problems (depression and anxiety symptomatology). METHODS: Surveys were administered to 566 10th and 11th grade students from the Mid-Atlantic region of the U.S. in the spring of 2007 and again in the spring of 2008. RESULTS: Although significant main effects were not observed, significant interactions were found between paternal problem drinking and maternal problem drinking for internalizing problems, especially for boys. In general, these interactions indicated that when paternal problem drinking was high, depression symptomatology and anxiety symptomatology were lower if maternal problem drinking was low. CONCLUSIONS: Findings from this study highlight the need to consider both paternal and maternal problem drinking when examining the effects that parental problem drinking may have on adolescent adjustment. PMID- 26103426 TI - Health anxiety and the non-medical use of prescription drugs in young adults: A cross-sectional study. AB - INTRODUCTION: Studies have demonstrated a relation between health anxiety (hypochondriasis) and substance use, but this minimal body of literature has focused on alcohol or illicit drugs. The use of medications without a physician's prescription (i.e., non-medical use of prescription drugs, NMUPD) is increasingly prevalent among young adults. Health anxiety, a tendency to worry excessively about health, is a factor that could contribute to NMUPD, but this has not been examined. The purpose of the current study was to examine the relations among health anxiety, NMUPD, and other psychological variables related to substance use. METHODS: In the present study, young adult college students (N = 758), ages 18-25, completed an anonymous online survey assessing demographics, health anxiety, NMUPD, and other psychological characteristics, including depression and general anxiety. RESULTS: Participants who reported NMUPD had higher scores in health anxiety, as well as more frequent healthcare appointments, and were more likely to report having a chronic health condition. Given that multiple factors influence a decision to engage in NMUPD, a multivariable logistic regression analysis was performed. Results suggested that hopelessness, sensation-seeking, and health anxiety were risk factors for NMUPD, and that health anxiety predicted NMUPD over and above these other variables. CONCLUSIONS: Medical professionals and mental health service providers should be aware of the increased risk of NMUPD for patients with health anxiety. Future research on NMUPD should more closely examine the role of health anxiety. PMID- 26103427 TI - Carbon dioxide generated from carbonates and acids for sampling blood-feeding arthropods. AB - Carbon dioxide (CO2) is utilized to attract mosquitoes and other blood-feeding arthropods to traps around the world. Commercial forms of CO2 (e.g., dry ice and compressed gas) are often unavailable or extremely expensive in developing nations, where vector surveillance is essential to make life-saving decisions. We developed and tested inexpensive and reproducible methods of CO2 production from the combination of acids and carbonates, ranging from very basic (crushed seashells and vinegar) to relatively elaborate (a device that controls the timing of the acid-carbonate reaction and extends the reaction over several hours). When utilized with mosquito traps in Florida, USA and black fly traps in Region des Cascades, Burkina Faso, these carbonate-acid CO2 sources attracted significantly greater numbers of both vector groups, than did unbaited traps. CO2 was generated for more than four hours at levels sufficient to attract vectors over the entire period. The utility of this simple methodology in developing nations should be further evaluated. PMID- 26103428 TI - A roadmap to success in photopharmacology. AB - Light is a fascinating phenomenon that ties together physics, chemistry, and biology. It is unmatched in its ability to confer information with temporal and spatial precision and has been used to map objects on the scale of tens of nanometers (10(-8) m) to light years (10(16) m). This information, gathered through super-resolution microscopes or space-based telescopes, is ultimately funneled through the human visual system, which is a miracle in itself. It allows us to see the Andromeda galaxy at night, an object that is 2.5 million light years away and very dim, and ski the next day in bright sunlight at an intensity that is 12 orders of magnitude higher. Human vision is only one of many photoreceptive systems that have evolved on earth and are found in all kingdoms of life. These systems rely on molecular photoswitches, such as retinal or tetrapyrrols, which undergo transient bond isomerizations or bond formations upon irradiation. The set of chromophores that have been employed in Nature for this purpose is surprisingly small. Nevertheless, they control a wide variety of biological functions, which have recently been significantly increased through the rapid development of optogenetics. Optogenetics originated as an effort to control neural function with genetically encoded photoreceptors that use abundant chromophores, in particular retinal. It now covers a variety of cellular functions other than excitability and has revolutionized the control of biological pathways in neuroscience and beyond. Chemistry has provided a large repertoire of synthetic photoswitches with highly tunable properties. Like their natural counterparts, these chromophores can be attached to proteins to effectively put them under optical control. This approach has enabled a new type of synthetic photobiology that has gone under various names to distinguish it from optogenetics. We now call it photopharmacology. Here we trace our involvement in this field, starting with the first light-sensitive potassium channel (SPARK) and concluding with our most recent work on photoswitchable fatty acids. Instead of simply providing a historical account of our efforts, we discuss the design criteria that guided our choice of molecules and receptors. As such, we hope to provide a roadmap to success in photopharmacology and make a case as to why synthetic photoswitches, properly designed and made available through well-planned and efficient syntheses, should have a bright future in biology and medicine. PMID- 26103429 TI - Quantitative Correlation of in Vivo Properties with in Vitro Assay Results: The in Vitro Binding of a Biotin-DNA Analogue Modifier with Streptavidin Predicts the in Vivo Avidin-Induced Clearability of the Analogue-Modified Antibody. AB - Quantitative prediction of in vivo behavior using an in vitro assay would dramatically accelerate pharmaceutical development. However, studies quantitatively correlating in vivo properties with in vitro assay results are rare because of the difficulty in quantitatively understanding the in vivo behavior of an agent. We now demonstrate such a correlation as a case study based on our quantitative understanding of the in vivo chemistry. In an ongoing pretargeting project, we designed a trifunctional antibody (Ab) that concomitantly carried a biotin and a DNA analogue (hereafter termed MORF). The biotin and the MORF were fused into one structure prior to conjugation to the Ab for the concomitant attachment. Because it was known that avidin-bound Ab molecules leave the circulation rapidly, this design would theoretically allow complete clearance by avidin. The clearability of the trifunctional Ab was determined by calculating the blood MORF concentration ratio of avidin-treated Ab to non-avidin-treated Ab using mice injected with these compounds. In theory, any compromised clearability should be due to the presence of impurities. In vitro, we measured the biotinylated percentage of the Ab-reacting (MORF-biotin)?-NH2 modifier, by addition of streptavidin to the radiolabeled (MORF-biotin)?-NH2 samples and subsequent high-performance liquid chromatography (HPLC) analysis. On the basis of our previous quantitative understanding, we predicted that the clearability of the Ab would be equal to the biotinylation percentage measured via HPLC. We validated this prediction within a 3% difference. In addition to the high avidin-induced clearability of the trifunctional Ab (up to ~95%) achieved by the design, we were able to predict the required quality of the (MORF-biotin)? NH2 modifier for any given in vivo clearability. This approach may greatly reduce the steps and time currently required in pharmaceutical development in the process of synthesis, chemical analysis, in vitro cell study, and in vivo validation. PMID- 26103430 TI - An eosin Y-based "turn-on" fluorescent sensor for detection of perfluorooctane sulfonate. AB - In this paper, a novel sensing method with a higher sensitivity of perfluorooctane sulfonate (PFOS) than perfluorooctanoic acid (PFOA) has been proposed detection of PFOS in aqueous solution replying on the "off-on" switch of eosin Y/polyethyleneimine (PEI)/PFOS fluorescence system due to the higher affinity of PEI to PFOS than eosin Y. In pH 7.0 Britton-Robinson buffer solution, eosin Y reacts with protonated PEI to form complex by electrostatic attraction, which leads to a strong fluorescence quenching of the eosin Y. When PFOS presents, the fluorescence of eosin Y is recover due to the electrostatic and hydrophobic interactions between PFOS and PEI. The recovered fluorescence intensity is proportional to the concentration of PFOS in the ranging from 0 to 2.0*10(-6) mol/L with the limit of detection (LOD, 3sigma) being 1.5*10(-8) mol/L without preconcentration. In this study, the optimum reaction conditions and the interferences of foreign substances were investigated. In addition, the effects of PFOA, the analog of PFOS, on the fluorescence recovery of the system were also studied. The presented approach has been successfully used to detect PFOS in real samples with RSD ?2.9%. PMID- 26103431 TI - Theoretical study of intermolecular interactions in CB4H8-HOX (X=F, Cl, Br, I) complexes. AB - The molecular aggregation based on intermolecular interactions between CB4H8 and HOX (X=F, Cl, Br and I) with particular emphasis on their bonding characteristics have been investigated using second order Moller-Plesset perturbation (MP2) method with aug-cc-pVDZ basis set. Different kinds of interactions including hydrogen bond (HB; H?O, XH; H?X), dihydrogen bond (DiHB; H?H) and non-classical B B?H interactions were found between CB4H8 and HOX molecules. The structures of complexes have been analyzed using AIM and natural bond orbital methodologies. Good correlations have been found between the interaction energies (SE), the second-order perturbation energies E((2)), and the charge transfer qCT in the studied systems. PMID- 26103432 TI - A simple method for determination of carmine in food samples based on cloud point extraction and spectrophotometric detection. AB - In this paper, a simple and cost effective method was developed for extraction and pre-concentration of carmine in food samples by using cloud point extraction (CPE) prior to its spectrophotometric determination. Carmine was extracted from aqueous solution using Triton X-100 as extracting solvent. The effects of main parameters such as solution pH, surfactant and salt concentrations, incubation time and temperature were investigated and optimized. Calibration graph was linear in the range of 0.04-5.0 MUg mL(-1) of carmine in the initial solution with regression coefficient of 0.9995. The limit of detection (LOD) and limit of quantification were 0.012 and 0.04 MUg mL(-1), respectively. Relative standard deviation (RSD) at low concentration level (0.05 MUg mL(-1)) of carmine was 4.8% (n=7). Recovery values in different concentration levels were in the range of 93.7-105.8%. The obtained results demonstrate the proposed method can be applied satisfactory to determine the carmine in food samples. PMID- 26103433 TI - Examining palliative care program use and place of death in rural and urban contexts: a Canadian population-based study using linked data. AB - INTRODUCTION: Palliative care has been both more available and more heavily researched in urban than in rural areas. This research studies factors associated with palliative care program (PCP) enrollment and place of death across the urban/rural continuum. Importantly, rather than simply comparing urban and rural areas, this article examines how the effects of demographic, geographic, and socioeconomic factors differ across service delivery settings within the Canadian province of Nova Scotia. METHODS: This study linked PCP patient enrollment files from three districts to Nova Scotia vital statistics death certificate data. Postal codes of the decedents were mapped to 2006 Canadian dissemination area census data. The study examined 23 860 adult residents of three district health authorities, who died from 2003 to 2009 with a terminal illness, organ failure, or frailty and who were not nursing home residents. Demographic, geographic, and socioeconomic predictors of PCP enrollment and place of death were investigated using logistic regression across the entire study area, and stratified by district of residence. Univariate and multivariate (adjusted) odds ratios (OR) and their 95% confidence intervals (CI) are reported. RESULTS: Overall, 40.3% of the study subjects were enrolled in a PCP, and 73.4% died in hospital. Odds of PCP enrollment were highest for females (OR: 1.30; 95%CI: 1.22, 1.39), persons aged 50-64 years (OR: 1.50; 95%CI: 1.35, 1.67), and persons with a terminal disease such as cancer. While in overall multivariate analysis residents of census metropolitan areas and agglomerations had higher odds of enrollment (OR: 1.51; 95%CI: 1.29, 1.77), and those at greater distance from a PCP had lower odds (OR: 0.33; 95%CI: 0.27, 0.40), stratified analysis revealed a more nuanced picture. Within each district, travel time to PCP remained a significant predictor of enrollment but the magnitude of its effect differed markedly. There was no consistent relationship with urban/rural residence, social deprivation, or economic deprivation. Enrollment in a PCP was associated with lower adjusted odds of dying in hospital (OR: 0.78; 95%CI: 0.72, 0.84), and those living at greater distance from a PCP had higher odds of hospitalization (OR: 1.52; 95%CI: 1.28, 1.81), but there was no consistent relationship for urban/rural residence or across districts. CONCLUSIONS: Geographic patterns of PCP enrollment and place of death differed by district, as did the impact of economic and social deprivation. Analysis and reporting of population-based indicators of access should be grounded in an understanding of the characteristics of geographic areas and local context of health services. Although more research is needed, these findings show promise that disparities in access between urban and rural settings are not unavoidable, and positive aspects of rural and remote communities may be leveraged to improve care at end of life. PMID- 26103434 TI - G17V RHOA: Genetic evidence of GTP-unbound RHOA playing a role in tumorigenesis in T cells. AB - RHOA is a member of RHO family small GTPases. Over the past 2 decades, numerous biochemical and cell biological studies on RHOA have demonstrated signalings such as activation of RHO-associated coiled-coil forming kinases through guanine nucleotide exchange and GTP hydrolysis, cellular responses such as actin fiber formation and myocin activation, biological consequences such as cell motility and cytokineses, etc. There have also been a plenty of active discussion on the roles of RHOA in tumorigenesis, primarily based on gain- and loss-of-function experiments. However, cell-type-specific functions of RHOA have only recently been delineated by conditional gene targeting strategies. Furthermore, very little information had been available on human cancer genetics until we and others recently reported frequent somatic RHOA mutations in a distinct subtype of T-cell-type malignant lymphoma called angioimmunoblastic T-cell lymphoma (AITL), and other T-cell lymphoma with AITL-like features. The RHOA mutations were very specific to these types of lymphoma among hematologic malignancies, and a single hotspot, glycine at the 17th position, was affected by the replacement with valine (G17V). Remarkably, G17V RHOA did not bind GTP, and moreover, it inhibited the GTP binding to wild-type RHOA. How G17V RHOA contributes to T-cell lymphomagenesis needs to be clarified. PMID- 26103436 TI - Mantle cell lymphoma: 2015 update on diagnosis, risk-stratification, and clinical management. AB - DISEASE OVERVIEW: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma characterized by involvement of the lymph nodes, spleen, blood and bone marrow with a short remission duration to standard therapies and a median overall survival (OS) of 4-5 years. DIAGNOSIS: Diagnosis is based on lymph node, bone marrow, or tissue morphology of centrocytic lymphocytes, small cell type, or blastoid variant cells. A chromosomal translocation t (11:14) is the molecular hallmark of MCL, resulting in the overexpression of cyclin D1. Cyclin D1 is detected by immunohistochemistry in 98% of cases. The absence of SOX-11 or a low Ki-67 may correlate with a more indolent form of MCL. The differential diagnosis of MCL includes small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma. RISK STRATIFICATION: The MCL International Prognostic Index (MIPI) is the prognostic model most often used and incorporates ECOG performance status, age, leukocyte count, and lactic dehydrogenase. A modification of the MIPI also adds the Ki-67 proliferative index if available. The median OS for the low-risk group was not reached (5-year OS of 60%). The median OS for the intermediate risk group was 51 months and 29 months for the high risk group. RISK ADAPTED THERAPY: For selected indolent, low MIPI MCL patients, initial observation may be appropriate therapy. For younger patients with intermediate or high risk MIPI MCL, aggressive therapy with a cytotoxic regimen +/- autologous stem cell transplantation should be considered. For older MCL patients with intermediate or high risk MIPI, combination chemotherapy with R-CHOP, R Bendamustine, or a clinical trial should be considered. In addition, rituximab maintenance therapy may prolong the progression-free survival. At the time of relapse, agents directed at activated pathways in MCL cells such as bortezomib (NFkB inhibitor), lenalidamide (anti-angiogenesis) and Ibruitinib (Bruton's Tyrosine Kinase [BTK] inhibitor) have demonstrated excellent clinical activity in MCL patients. Autologous or allogeneic stem cell transplantation can also be considered in young patients. Clinical trials with novel agents are always a consideration for MCL patients. PMID- 26103437 TI - The development of a conceptual model and self-reported measure of occupational health and safety vulnerability. AB - Injuries at work have a substantial economic and societal burden. Often groups of labour market participants, such as young workers, recent immigrants or temporary workers are labelled as being "vulnerable" to work injury. However, defining groups in this way does little to enable a better understanding of the broader factors that place workers at increased risk of injury. In this paper we describe the development of a new measure of occupational health and safety (OH&S) vulnerability. The purpose of this measure was to allow the identification of workers at increased risk of injury, and to enable the monitoring and surveillance of OH&S vulnerability in the labour market. The development included a systematic literature search, and conducting focus groups with a variety of stakeholder groups, to generate a pool of potential items, followed by a series of steps to reduce these items to a more manageable pool. The final measure is 29 item instrument that captures information on four related, but distinct dimensions, thought to be associated with increased risk of injury. These dimensions are: hazard exposure; occupational health and safety policies and procedures; OH&S awareness; and empowerment to participate in injury prevention. In a large sample of employees in Ontario and British Columbia the final measure displayed minimal missing responses, reasonably good distributions across response categories, and strong factorial validity. This new measure of OH&S vulnerability can identify workers who are at risk of injury and provide information on the dimensions of work that may increase this risk. This measurement could be undertaken at one point in time to compare vulnerability across groups, or be undertaken at multiple time points to examine changes in dimensions of OH&S vulnerability, for example, in response to a primary prevention intervention. PMID- 26103438 TI - Development and evaluation of a finite element model of the THOR for occupant protection of spaceflight crewmembers. AB - New vehicles are currently being developed to transport humans to space. During the landing phases, crewmembers may be exposed to spinal and frontal loading. To reduce the risk of injuries during these common impact scenarios, the National Aeronautics and Space Administration (NASA) is developing new safety standards for spaceflight. The Test Device for Human Occupant Restraint (THOR) advanced multi-directional anthropomorphic test device (ATD), with the National Highway Traffic Safety Administration modification kit, has been chosen to evaluate occupant spacecraft safety because of its improved biofidelity. NASA tested the THOR ATD at Wright-Patterson Air Force Base (WPAFB) in various impact configurations, including frontal and spinal loading. A computational finite element model (FEM) of the THOR to match these latest modifications was developed in LS-DYNA software. The main goal of this study was to calibrate and validate the THOR FEM for use in future spacecraft safety studies. An optimization-based method was developed to calibrate the material models of the lumbar joints and pelvic flesh. Compression test data were used to calibrate the quasi-static material properties of the pelvic flesh, while whole body THOR ATD kinematic and kinetic responses under spinal and frontal loading conditions were used for dynamic calibration. The performance of the calibrated THOR FEM was evaluated by simulating separate THOR ATD tests with different crash pulses along both spinal and frontal directions. The model response was compared with test data by calculating its correlation score using the CORrelation and Analysis rating system. The biofidelity of the THOR FEM was then evaluated against tests recorded on human volunteers under 3 different frontal and spinal impact pulses. The calibrated THOR FEM responded with high similarity to the THOR ATD in all validation tests. The THOR FEM showed good biofidelity relative to human volunteer data under spinal loading, but limited biofidelity under frontal loading. This may suggest a need for further improvements in both the THOR ATD and FEM. Overall, results presented in this study provide confidence in the THOR FEM for use in predicting THOR ATD responses for conditions, such as those observed in spacecraft landing, and for use in evaluating THOR ATD biofidelity. PMID- 26103440 TI - Layer-specific residual deformations and uniaxial and biaxial mechanical properties of thoracic porcine aorta. AB - In this paper we hypothesize that the layer-separated residual stresses and mechanical properties of layer-separated thoracic aorta arteries may be dependent on arterial location of the vessel. To demonstrate any possible position differences, we measured the axial pre-stretch and opening angle and performed uniaxial and biaxial tests under physiological loads to study the mechanical behavior of both intact and layer-separated porcine aortic samples taken from thoracic region. In addition, we also provided constitutive parameters for each layer that can be used by biomedical engineers for investigating better therapies and developing artery-specific devices. We found that the opening angle for whole artery and adventitia layer are smaller and intima greater for proximal segments than for the distal thoracic ones. For the axial pre-stretch, our results showed significant increased values of the stretch ratios with location. We found that lower thoracic samples are stiffer than upper ones with the most important differences corresponding to those between the proximal and distal behaviors in the circumferential direction. The anisotropy represented by the different circumferential and longitudinal response is more remarkable in lower thoracic aorta. Finally, adventitia and intima samples present a tendency to be stiffer and more isotropic than the corresponding media samples in both directions for upper thoracic aorta and to be more anisotropic for lower thoracic aorta. PMID- 26103441 TI - Image Guidance in Ventricular Cerebrospinal Fluid Shunt Catheter Placement: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Ventricular shunt placement for treating hydrocephalus is one of the most common neurosurgical procedures. The rate of shunt failure, however, has not appreciably changed with time. OBJECTIVE: To investigate whether intraoperative image guidance using ultrasound or stereotaxy contributes to accurate shunt catheter placement and survival. METHODS: We performed a systematic literature review using PubMed and MEDLINE databases for studies that use ultrasound and frameless stereotaxy for ventricular catheter placement for hydrocephalus. All articles assessed the accuracy of catheter tip placement and/or overall shunt survival, and the rate of accurate shunt catheter placement, the overall failure rate, and the average time to shunt failure were extracted for analysis. RESULTS: Although each modality (ultrasound/stereotaxy) did not increase catheter placement accuracy, a combined random-effects meta-analysis of 738 catheters (136 guided by ultrasound, 168 guided by frameless stereotaxy, and 434 freehand) demonstrated a weak benefit of image guidance (risk ratio: 1.19, 95% confidence interval: 1.02-1.39, P = .02), but this result was limited by considerable heterogeneity among studies (I2 = 86%, P < .001 by Cochrane's Q test). A meta analysis could not be performed for shunt survival due to heterogeneity in data reporting. CONCLUSION: Although image guidance offers a promising solution to lower the risk of inaccurate catheter placement, which could lead to lower premature failure of ventricular shunts, our review demonstrated that there is not yet a clear benefit of these technologies. Current literature is limited to case series and cohort studies, and significant between-study heterogeneity in methodology and reporting currently limits a higher order analysis. PMID- 26103439 TI - Mathematical models of the steps involved in the systemic delivery of a chemotherapeutic to a solid tumor: From circulation to survival. AB - The efficacy of an intravenously administered chemotherapeutic for treatment of a solid tumor is dependent on a sequence of steps, including circulation, extravasation by the enhanced permeability and retention effect, transport in the tumor microenvironment, the mechanism of cellular uptake and trafficking, and the mechanism of drug action. These steps are coupled since the time dependent concentration in circulation determines the concentration and distribution in the tumor microenvironment, and hence the amount taken up by individual cells within the tumor. Models have been developed for each of the steps in the delivery process although their predictive power remains limited. Advances in our understanding of the steps in the delivery process will result in refined models with improvements in predictive power and ultimately allow the development of integrated models that link systemic administration of a drug to the probability of survival. Integrated models that predict outcomes based on patient specific data could be used to select the optimum therapeutic regimens. Here we present an overview of current models for the steps in the delivery process and highlight knowledge gaps that are key to developing integrated models. PMID- 26103442 TI - Use of Omnipaque Intraoperative Dye in the Surgical Treatment of Pan-Spinal Epidural Abscesses: Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Spinal epidural abscesses are difficult to diagnose and could have high morbidity and mortality if left untreated. If patients present with acute neurological deficits and evidence of a multilevel ventral spine abscess on neuroimaging, blood cultures should be taken and the abscess emergently evacuated in patients able to tolerate surgical interventions. CLINICAL PRESENTATION: A 57-year-old man presented with lower back pain, which progressed to include urinary retention and evidence of lumbar discitis/osteomyelitis on magnetic resonance imaging. The patient was started on antibiotic therapy. After the patient developed new cervical pain, interval magnetic resonance imaging showed extension of the abscess to involve the cervical, thoracic, and lumbar spine with intraventricular extension. The decision was made to perform a C4 corpectomy and insert a flexible ventriculoperitoneal catheter to serially flush out the abscess. Omnipaque dye was then used to ensure that the entire abscess was evacuated and no septations existed in the anterior epidural space. CONCLUSION: The patient's neurological deficits completely resolved, and he is intact a year after the operation. In selected patients with pan-spinal epidural abscesses associated with acute neurological deficits, a combination of an open approach and a catheter-based procedure in addition to an intraoperative monitoring option to ensure complete evacuation of the abscess and absence of septations in the anterior epidural space is a low-morbidity option in the armamentarium of the surgeon. PMID- 26103443 TI - Endotracheal Tube Electrodes to Assess Vocal Cord Motor Function During Surgery in the Cerebellopontine Angle. AB - BACKGROUND: The 10th cranial nerve (CN X) is at risk during surgery in the lower cerebellopontine angle (CPA). OBJECTIVE: To evaluate endotracheal surface electrodes for assessment of CN X motor function during CPA surgery. METHODS: Twenty patients were enrolled. Electrophysiological recordings were analyzed and retrospectively correlated with clinical, imaging, and intraoperative data. RESULTS: Recordings from endotracheal surface electrodes were reliable and eligible for analyses in 17 patients; in 3 patients, no surface electrode compound motor action potentials (CMAPs) could be obtained. Those patients with sufficient recordings underwent surgery in the CPA for tumors in 14 patients and for nontumor pathologies in 3 patients. In 12 patients, bipolar stimulation of motor rootlets in the CPA resulted in simultaneous CMAPs recorded from both surface electrodes and needle electrodes placed in the soft palate. Coactivation was particularly seen in patients with an intricate relationship between lower cranial nerves and tumor formations (n = 9/10). Amplitudes and latencies of vocal cord CMAPs showed high interindividual but low intraindividual variability. Parameters were not well correlated with the type of surgery (tumor vs nontumor surgery) and lower CN anatomy (displaced vs undisplaced). In 2 patients, vocal cord CMAPs were lost during tumor surgery, which was associated with postoperative dysphagia and hoarseness in 1 patient. CONCLUSION: Endotracheal surface electrodes allow identification of vocal cord motor rootlets in the CPA. Worsening of CMAP parameters might indicate functional impairment. These aspects support the use of endotracheal surface electrodes in selected patients in whom the vagus nerve might be at risk during CPA surgery. PMID- 26103444 TI - Usefulness of a Virtual Reality Percutaneous Trigeminal Rhizotomy Simulator in Neurosurgical Training. AB - BACKGROUND: Simulation-based training may be incorporated into neurosurgery in the future. OBJECTIVE: To assess the usefulness of a novel haptics-based virtual reality percutaneous trigeminal rhizotomy simulator. METHODS: A real-time augmented reality simulator for percutaneous trigeminal rhizotomy was developed using the ImmersiveTouch platform. Ninety-two neurosurgery residents tested the simulator at American Association of Neurological Surgeons Top Gun 2014. Postgraduate year (PGY), number of fluoroscopy shots, the distance from the ideal entry point, and the distance from the ideal target were recorded by the system during each simulation session. Final performance score was calculated considering the number of fluoroscopy shots and distances from entry and target points (a lower score is better). The impact of PGY level on residents' performance was analyzed. RESULTS: Seventy-one residents provided their PGY-level and simulator performance data; 38% were senior residents and 62% were junior residents. The mean distance from the entry point (9.4 mm vs 12.6 mm, P = .01), the distance from the target (12.0 mm vs 15.2 mm, P = .16), and final score (31.1 vs 37.7, P = .02) were lower in senior than in junior residents. The mean number of fluoroscopy shots (9.8 vs 10.0, P = .88) was similar in these 2 groups. Linear regression analysis showed that increasing PGY level is significantly associated with a decreased distance from the ideal entry point (P = .001), a shorter distance from target (P = .05), a better final score (P = .007), but not number of fluoroscopy shots (P = .52). CONCLUSION: Because technical performance of percutaneous rhizotomy increases with training, we proposed that the skills in performing the procedure in our virtual reality model would also increase with PGY level, if our simulator models the actual procedure. Our results confirm this hypothesis and demonstrate construct validity. PMID- 26103445 TI - A Perforating Artery Compressing the Nerve Rootlet and Causing Glossopharyngeal Neuralgia. AB - BACKGROUND: A surgical procedure for glossopharyngeal neuralgia (GPN) was selected from microvascular decompression, glossopharyngeal and upper vagal rhizotomy, or a combination of these procedures based on the presence of arteries compressing the glossopharyngeal and vagal rootlets. The offending artery is usually a main trunk or branch of the cerebellar arteries. A perforating artery is a known but uncommon variation of the offending artery that causes GPN. The appropriate procedure for such cases is unknown. OBJECTIVE: To analyze the clinical significance of the perforating artery in GPN, we describe 2 patients with a perforating artery compressing the rootlet, and its mobilization relieved neuralgia. We examined the validity of decompressing a perforating artery as an alternative to rhizotomy in such cases. METHODS: We independently reviewed 12 GPN patients treated with microvascular decompression. The patients' pain severity, medication doses, preoperative imaging studies, intraoperative findings, and outcomes were examined. RESULTS: Eleven patients had neurovascular compression of the glossopharyngeal nerve. In 2 of the patients, a perforating artery compressed the rootlet, thereby generating an indentation and creating a discoloration of the rootlet. Mobilizing the perforating artery with no additional rhizotomy provided complete pain relief with no significant complications and allowed the discontinuation of medications. CONCLUSION: Even a small perforating artery can cause GPN when it compresses the rootlet. In such cases, mobilization of the perforating artery with no additional rhizotomy is an effective surgical option. PMID- 26103447 TI - Baicalin protects sertoli cells from heat stress-induced apoptosis via activation of the Fas/FasL pathway and Hsp72 expression. AB - Certain Chinese herbal medicines have antipyretic effects in both animal and human clinical practice. However, no report indicates their antipyretic effects on heat-stressed cells. The present study aimed to identify the protective effects of baicalin on the apoptosis of primary cultured bovine sertoli cells (SCs) subjected to heat stress (HS). The results demonstrated that HS induced apoptosis in the SCs exposed to 43 degrees C for 1h as Fas/FasL was activated and caspase-3 was cleaved, the cells apoptotic rate was decreased. Moreover, the mRNA and protein levels of Hsp72 increased, whereas the cells apoptotic rate and expression of Fas, FasL, caspases 8 and 3 decreased in the SCs pretreated with various concentrations (0.1, 1, 10, 20MUg/mL) of baicalin prior to HS. In conclusion, baicalin ameliorates heat stress-induced cell apoptosis via the modulation of the cell survival rate through Fas/FasL pathway activation and the upregulation of Hsp72 expression in bovine SCs. PMID- 26103448 TI - Resveratrol derivative-rich melinjo (Gnetum gnemon L.) seed extract improves obesity and survival of C57BL/6 mice fed a high-fat diet. AB - Melinjo (Gnetum gnemon L.) seed extracts (MSEs) are rich in resveratrol dimers (gnemonoside A, C, D, gnetin C), trans-resveratrol, and other resveratrol derivatives. trans-Resveratrol is a widely studied caloric restriction mimetic. In mice fed a high-fat diet (HFD), trans-resveratrol protects against obesity, type 2 diabetes, and premature death. Here, treatment of HFD-fed mice with 2.0% MSE significantly reduced body weight gain (p < 0.001), blood insulin (p < 0.01), and HOMA-IR (p < 0.05) after 8 weeks compared with untreated HFD-fed mice. Additionally, 0.2% MSE treatment of HFD-fed mice significantly improved physiological activity (p < 0.05) at 18 months of age and reduced risk of death due to HFD by 25% (hazard ratio = 0.75, p = 0.036). These data show that MSE can improve several aspects of metabolic syndrome and survival in mice and may have health benefits as a dietary supplement. PMID- 26103446 TI - Screening for Anal Cancer in Women. AB - OBJECTIVE: The incidence of anal cancer is higher in women than men in the general population and has been increasing for several decades. Similar to cervical cancer, most anal cancers are associated with human papillomavirus (HPV), and it is believed that anal cancers are preceded by anal high-grade squamous intraepithelial lesions (HSIL). Our goals were to summarize the literature on anal cancer, HSIL, and HPV infection in women and to provide screening recommendations in women. METHODS: A group of experts convened by the American Society for Colposcopy and Cervical Pathology and the International Anal Neoplasia Society reviewed the literature on anal HPV infection, anal SIL, and anal cancer in women. RESULTS: Anal HPV infection is common in women but is relatively transient in most. The risk of anal HSIL and cancer varies considerably by risk group, with human immunodeficiency virus-infected women and those with a history of lower genital tract neoplasia at highest risk compared with the general population. CONCLUSIONS: While there are no data yet to demonstrate that identification and treatment of anal HSIL leads to reduced risk of anal cancer, women in groups at the highest risk should be queried for anal cancer symptoms and required to have digital anorectal examinations to detect anal cancers. Human immunodeficiency virus-infected women and women with lower genital tract neoplasia may be considered for screening with anal cytology with triage to treatment if HSIL is diagnosed. Healthy women with no known risk factors or anal cancer symptoms do not need to be routinely screened for anal cancer or anal HSIL. PMID- 26103449 TI - Virulence and antimicrobial susceptibility of clinical and environmental strains of Aeromonas spp. from northeastern Brazil. AB - The aims of the present study were to isolate and identify clinical and environmental strains of Aeromonas spp. by means of biochemical tests and the automated method VITEK 2 and to investigate the presence of the virulence genes cytotoxic enterotoxin (act), hemolysin (asa-1), and type III secretion system (ascV), and also the in vitro antimicrobial susceptibility of the strains. From the clinical isolates, 19 Aeromonas hydrophila, 3 Aeromonas veronii bv. sobria, and 1 Aeromonas caviae were identified, while from the environmental strains, 11 A. hydrophila, 22 A. veronii bv. sobria, 1 A. veronii bv. veronii, and 1 A. caviae were recovered. The gene act was detected in 69.5% of clinical isolates, asa-1 in 8.6%, and ascV in 34.7%. In the environmental strains, the detection rates were 51.4%, 45.7%, and 54.2% for the genes act, asa-1, and ascV, respectively. Resistance to amoxicillin-clavulanate and piperacillin-tazobactam was observed in 15 and 3 clinical strains, respectively, and resistance to ceftazidime, meropenem, imipenem, ciprofloxacin, and trimethoprim sulfamethoxazole was observed in 1 strain for each drug. Resistance to amoxicillin-clavulanate and piperacillin-tazobactam was detected in 17 and 1 environmental strain, respectively. Higher resistance percentages were observed in clinical strains, but environmental strains also showed this phenomenon and presented a higher detection rate of virulence genes. Thus, it is important to monitor the antimicrobial susceptibility and pathogenic potential of the environmental isolates. PMID- 26103451 TI - 16S rDNA analysis of archaea indicates dominance of Methanobacterium and high abundance of Methanomassiliicoccaceae in rumen of Nili-Ravi buffalo. AB - The molecular diversity of rumen methanogens was investigated using 16S rDNA gene library prepared from the rumen contents of Nili-Ravi buffaloes. Microbial genomic DNA was isolated from four adult male fistulated buffaloes and PCR conditions were set up using specific primers. Amplified product was cloned into a suitable vector, and the inserts of positive clones were sequenced. A total of 142 clones were examined, and the analysis revealed 46 species level (0.01 distance) operational taxonomic units (OTUs). Twenty six OTUs comprising 89 clones (63% of the total clones) were taxonomically assigned to Methanobacterium genus and the majority of them had highest percent identity with Methanobacterium flexile among cultured methanogens. Five OTUs comprising 27 clones (19% of total clones) were taxonomically assigned to Methanomicrobium genus and these clones showed highest sequence identity with Methanomicrobium mobile. Only two OTUs comprising 6 clones (4% of total clones) were assigned to Methanobrevibacter genus. A total of 17 clones belonging to 10 species level OTUs showed highest percent identity (ranging from 85 to 95%) with Methanomassilicoccus luminyensis and were taxonomically classified as Methanomassiliicocaceae. Out of the 142 rDNA clones, 112 clones, which constitute 79% of the total clones representing 42 OTUs, had less than 98.5% sequence identity with any of the cultured strains of methanogens and represent novel species of methanogens. This study has revealed the largest assortment of hydrogenotrophic methanogen phylotypes ever identified from the rumen of Nili-Ravi buffaloes. The study indicates that Methanobacterium is the most dominant methanogen in the rumen of Nili-Ravi buffalo. This is also the first report on the presence of methanogens phylogenetically close to M. luminyensis, an H2 dependent methylotrophic methanogen, in the rumen of buffaloes at such a high level of abundance. PMID- 26103450 TI - Activation of EP4 receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function. AB - BACKGROUND AND PURPOSE: Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE2 , via activation of E-prostanoid (EP)4 receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP4 receptor activation in murine models of acute pulmonary inflammation. EXPERIMENTAL APPROACH: Pulmonary inflammation in male BALB/c mice was induced by LPS (20 MUg per mouse intranasally) or oleic acid (0.15 MUL.g-1 , i.v. ). In vitro, endothelial barrier function was determined by measuring electrical impedance. KEY RESULTS: PGE2 activation of EP4 receptors reduced neutrophil infiltration, pulmonary vascular leakage and TNF-alpha concentration in bronchoalveolar lavage fluid from LPS-induced pulmonary inflammation. Similarly, pulmonary vascular hyperpermeability induced by oleic acid was counteracted by EP4 receptor activation. In lung function assays, the EP4 agonist ONO AE1-329 restored the increased resistance and reduced compliance upon methacholine challenge in mice treated with LPS or oleic acid. In agreement with these findings, EP4 receptor activation increased the in vitro vascular barrier function of human and mouse pulmonary microvascular endothelial cells and diminished the barrier disruption induced by LPS. The EP2 agonist ONO AE1-259 likewise reversed LPS-induced lung dysfunction without enhancing vascular barrier function. CONCLUSION AND IMPLICATIONS: Our results show that activation of the EP4 receptor strengthens the microvascular barrier function and thereby ameliorates the pathology of acute lung inflammation, including neutrophil infiltration, vascular oedema formation and airway dysfunction. This suggests a potential benefit for EP4 agonists in acute pulmonary inflammation. PMID- 26103452 TI - Study of the combined effect of electro-activated solutions and heat treatment on the destruction of spores of Clostridium sporogenes and Geobacillus stearothermophilus in model solution and vegetable puree. AB - The combined effect of heat treatment and electro-activated solution (EAS) on the heat resistance of spores of Clostridium sporogenes and Geobacillus stearothermophilus was assessed under various heating and exposure time combinations. The acid and neutral EAS showed the highest inhibitory activity, indicating that these solutions may be considered as strong sporicidal disinfectants. These EAS were able to cause a reduction of >=6 log of spores of C. sporogenes at 60 degrees C in only 1 min of exposition. For G. stearothermophilus spores, a reduction of 4.5 log was observed at 60 degrees C in 1 min, while in 5 min, >=7 log CFU/ml reduction was observed. Inoculated puree of pea and corn were used as a food matrix for the determination of the heat resistance of these spores during the treatments in glass capillaries. The inactivation kinetics of the spores was studied in an oil bath. Combined treatment by EAS and temperature demonstrated a significant decrease in the heat resistance of C. sporogenes. The D100 degrees C in pea puree with NaCl solution was 66.86 min while with acid and neutral EAS it was reduced down to 3.97 and 2.19 min, respectively. The spore of G. stearothermophilus displayed higher heat resistance as confirmed by other similar studies. Its D130 degrees C in pea puree showed a decrease from 1.45 min in NaCl solution down to 1.30 and 0.93 min for acid and neutral EAS, respectively. The differences between the spores of these species are attributable to their different sensitivities with respect to pH, Redox potential and oxygen. PMID- 26103454 TI - Quality of life in patients with hypopituitarism. AB - PURPOSE OF REVIEW: Quality of life (QoL) is impaired in patients with adults with growth hormone deficiency (AGHD) of any cause, especially if additional hypopituitarism is present, and improves after replacement therapy with recombinant human growth hormone (rhGH). This review includes relevant publications since 2013. RECENT FINDINGS: Recent findings confirm that most patients with AGHD who improve their QoL after rhGH therapy experience persistent effects for years, if replacement therapy is maintained. Sometimes, however, QoL may not normalize completely, especially if it is caused by a craniopharyngioma (because of concomitant neuropsychological comorbidities that affect autonomy and cognitive function), or functional pituitary tumours, i.e., in Cushing's disease, in which chronic brain exposure to hypercortisolism is associated with more depression, anxiety, loss of memory and emotional distress. Another group in which QoL and energy rarely normalize despite improving after rhGH is hypopituitarism because of traumatic brain injury. Worse QoL is seen in patients who also suffer insomnia, depression, negative illness perceptions and are treated in a rural (compared with an urban) healthcare environment. Better QoL after rhGH is seen in AGHD patients who are not depressed, after successful surgery, living in Europe (rather than the USA), with poorer baseline QoL scores, less obesity and no impaired vision. SUMMARY: Further improvement of QoL may be possible with individualized psychosocial interventions. PMID- 26103457 TI - Accumulation of metabolic cardiovascular risk factors in Black and White young adults over 20 years. PMID- 26103458 TI - Simultaneous Application of Bone Morphogenetic Protein-2 and Platelet-Rich Fibrin for the Treatment of Bisphosphonate-Related Osteonecrosis of Jaw. PMID- 26103456 TI - Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins. AB - Insulin and its receptor are critical for the regulation of metabolic functions, but the mechanisms underlying insulin receptor (IR) trafficking to the plasma membrane are not well understood. Here, we show that Bardet Biedl Syndrome (BBS) proteins are necessary for IR localization to the cell surface. We demonstrate that the IR interacts physically with BBS proteins, and reducing the expression of BBS proteins perturbs IR expression in the cell surface. We show the consequence of disrupting BBS proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes. These findings demonstrate the importance of BBS proteins in underlying IR cell surface expression. Our data identify defects in trafficking and localization of the IR as a novel mechanism accounting for the insulin resistance commonly associated with human BBS. This is supported by the reduced surface expression of the IR in fibroblasts derived from patients bearing the M390R mutation in the BBS1 gene. PMID- 26103453 TI - Persistent changes in peripheral and spinal nociceptive processing after early tissue injury. AB - It has become clear that tissue damage during a critical period of early life can result in long-term changes in pain sensitivity, but the underlying mechanisms remain to be fully elucidated. Here we review the clinical and preclinical evidence for persistent alterations in nociceptive processing following neonatal tissue injury, which collectively point to the existence of both a widespread hypoalgesia at baseline as well as an exacerbated degree of hyperalgesia following a subsequent insult to the same somatotopic region. We also highlight recent work investigating the effects of early trauma on the organization and function of ascending pain pathways at a cellular and molecular level. These effects of neonatal injury include altered ion channel expression in both primary afferent and spinal cord neurons, shifts in the balance between synaptic excitation and inhibition within the superficial dorsal horn (SDH) network, and a 'priming' of microglial responses in the adult SDH. A better understanding of how early tissue damage influences the maturation of nociceptive circuits could yield new insight into strategies to minimize the long-term consequences of essential, but invasive, medical procedures on the developing somatosensory system. PMID- 26103459 TI - Oxidative stress-induced methemoglobinemia is the silent killer during snakebite: a novel and strategic neutralization by melatonin. AB - Oxidative stress-induced methemoglobinemia remained an untouched area in venom pharmacology till date. This study for the first time explored the potential of animal venoms to oxidize hemoglobin to methemoglobin. In in vitro whole-blood assay, methemoglobin forming ability of venoms varied as Naja naja > Ophiophagus hannah > Echis carinatus > Daboia russellii > Apis mellifera > Mesobuthus tamulus > Hippasa partita. Being highly potential, N. naja venom was further studied to observe methemoglobin formation in RBCs and in combinations with PMNs and PBMCs, where maximum effect was observed in RBCs + PMNs combination. Naja naja venom/externally added methemoglobin-induced methemoglobin formation was in parallel with ROS generation in whole blood/RBCs/RBCs + PMNs/RBCs + PBMCs. In in vivo studies, the lethal dose (1 mg/kg body weight, i.p.) of N. naja venom readily induced methemoglobin formation, ROS generation, expression of inflammatory markers, and hypoxia-inducible factor-3alpha. Although the mice administered with three effective doses of antivenom recorded zero mortality; the methemoglobin and ROS levels remained high. However, one effective dose of antivenom when administered along with melatonin (1:50; venom/melatonin, w/w), not only offered 100% survival of experimental mice, but also significantly reduced methemoglobin level, and oxidative stress markers including hypoxia inducible factor-3alpha. This study provides strong drive that, complementing melatonin would not only reduce the antivenom load, but for sure greatly increase the success rate of antivenom therapy and drastically minimize the global incidence of snakebite deaths. However, further detailed investigations are needed before translating the combined therapy towards the bed side. PMID- 26103460 TI - Numerical Modeling of Mechanical Behavior for Buried Steel Pipelines Crossing Subsidence Strata. AB - This paper addresses the mechanical behavior of buried steel pipeline crossing subsidence strata. The investigation is based on numerical simulation of the nonlinear response of the pipeline-soil system through finite element method, considering large strain and displacement, inelastic material behavior of buried pipeline and the surrounding soil, as well as contact and friction on the pipeline-soil interface. Effects of key parameters on the mechanical behavior of buried pipeline were investigated, such as strata subsidence, diameter-thickness ratio, buried depth, internal pressure, friction coefficient and soil properties. The results show that the maximum strain appears on the outer transition subsidence section of the pipeline, and its cross section is concave shaped. With the increasing of strata subsidence and diameter-thickness ratio, the out of roundness, longitudinal strain and equivalent plastic strain increase gradually. With the buried depth increasing, the deflection, out of roundness and strain of the pipeline decrease. Internal pressure and friction coefficient have little effect on the deflection of buried pipeline. Out of roundness is reduced and the strain is increased gradually with the increasing of internal pressure. The physical properties of soil have a great influence on the mechanical properties of buried pipeline. The results from the present study can be used for the development of optimization design and preventive maintenance for buried steel pipelines. PMID- 26103461 TI - Highly enantioselective synthesis of non-natural aliphatic alpha-amino acids via asymmetric hydrogenation. AB - By employing a rhodium-Duanphos complex as the catalyst, beta-alkyl (Z)-N acetyldehydroamino esters were smoothly hydrogenated in a highly efficient and enantioselective way. Excellent enantioselectivities together with excellent yields were achieved for a series of substrates. An efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drugs Alogliptin and Linagliptin in the DPP-4 inhibitor class was also developed. PMID- 26103462 TI - Structure and aggregation properties of a Schiff-base zinc(II) complex derived from cis-1,2-diaminocyclohexane. AB - This contribution explores the effect of the bridging diamine upon the aggregation properties of a Zn(II) Schiff-base complex, , both in the solid state and in solution. The X-ray structure of , resulting from the harvest of good quality crystals using chloroform and diethyl ether as solvents, shows the presence of a densely packed dimer in the solid state which pentacoordinates two Zn atoms involved in a MU-phenoxo bridge. Detailed studies in solution, through (1)H NMR, DOSY NMR, and optical spectroscopic investigations, indicate the typical aggregation/deaggregation behaviour on switching from non-coordinating to coordinating solvents, in relation to the Lewis acidic character of such Zn(II) complexes. Thus, while in DMSO-d6 both (1)H NMR and DOSY studies suggest the existence of monomeric species, in chloroform solution experimental data support the existence of aggregates. However, unlike our previous studies, (1)H NMR data in chloroform solution indicate the existence of an asymmetric dimer, as observed in the X-ray crystal structure. This further evidences a very rigid backbone of the dimeric aggregate and can be related to the defined stereochemistry of the chelate cis-1,2-diaminocyclohexane bridge. PMID- 26103463 TI - Two serine residues in Pseudomonas syringae effector HopZ1a are required for acetyltransferase activity and association with the host co-factor. AB - Gram-negative bacteria inject type III secreted effectors (T3SEs) into host cells to manipulate the immune response. The YopJ family effector HopZ1a produced by the plant pathogen Pseudomonas syringae possesses acetyltransferase activity and acetylates plant proteins to facilitate infection. Using mass spectrometry, we identified a threonine residue, T346, as the main autoacetylation site of HopZ1a. Two neighboring serine residues, S349 and S351, are required for the acetyltransferase activity of HopZ1a in vitro and are indispensable for the virulence function of HopZ1a in Arabidopsis thaliana. Using proton nuclear magnetic resonance (NMR), we observed a conformational change of HopZ1a in the presence of inositol hexakisphosphate (IP6), which acts as a eukaryotic co-factor and significantly enhances the acetyltransferase activity of several YopJ family effectors. S349 and S351 are required for IP6-binding-mediated conformational change of HopZ1a. S349 and S351 are located in a conserved region in the C terminal domain of YopJ family effectors. Mutations of the corresponding serine(s) in two other effectors, HopZ3 of P. syringae and PopP2 of Ralstonia solanacerum, also abolished their acetyltransferase activity. These results suggest that, in addition to the highly conserved catalytic residues, YopJ family effectors also require conserved serine(s) in the C-terminal domain for their enzymatic activity. PMID- 26103465 TI - Recommendations for the Improved Effectiveness and Reporting of Telemedicine Programs in Developing Countries: Results of a Systematic Literature Review. AB - BACKGROUND: A lack of decisive evidence on the impact of telemedicine on financial and clinical outcomes has not prohibited significant investment in developing countries. Understanding characteristics that facilitate effective telemedicine programs is required to allow telemedicine to be used to its full potential. This systematic review aimed to identify organizational, technological, and financial features of successful telemedicine programs providing direct clinical care in developing countries. MATERIALS AND METHODS: Databases were searched, and the results were reviewed systematically according to predefined inclusion/exclusion criteria. Information on location(s), measure of success, and organizational, technological, and financial characteristics were extracted. This review was impeded by inadequate program reporting, and so a concise checklist was developed to aid improved reporting, enabling future reviews to identify key characteristics of effective programs. RESULTS: This systematic review identified 46 articles reporting 36 programs that fulfilled the inclusion/exclusion criteria. Programs were distributed globally, including regional, national, and international programs. Technological modalities included synchronous technology, real-time teleconsultations, and asynchronous technology. Program integration with existing systems and twinning of international institutions were identified as factors enabling program success. Other factors included simple and easy-to-use technology, ability to reduce the burden on healthcare professionals, and technology able to maintain functionality in challenging environmental circumstances. Reports describing effectiveness and costs were limited. CONCLUSIONS: This systematic review identified key factors associated with telemedicine program success. However, inconsistencies in reporting represent an obstacle to establishment of successful programs in developing countries by limiting the application of previous experiences. Adhering to the guidelines suggested here may allow more quantitative assessments of effectiveness and impact for future programs. PMID- 26103464 TI - Np9, a cellular protein of retroviral ancestry restricted to human, chimpanzee and gorilla, binds and regulates ubiquitin ligase MDM2. AB - Humans and primates are long-lived animals with long reproductive phases. One factor that appears to contribute to longevity and fertility in humans, as well as to cancer-free survival, is the transcription factor and tumor suppressor p53, controlled by its main negative regulator MDM2. However, p53 and MDM2 homologs are found throughout the metazoan kingdom from Trichoplacidae to Hominidae. Therefore the question arises, if p53/MDM2 contributes to the shaping of primate features, then through which mechanisms. Previous findings have indicated that the appearances of novel p53-regulated genes and wild-type p53 variants during primate evolution are important in this context. Here, we report on another mechanism of potential relevance. Human endogenous retrovirus K subgroup HML-2 (HERV-K(HML-2)) type 1 proviral sequences were formed in the genomes of the predecessors of contemporary Hominoidea and can be identified in the genomes of Nomascus leucogenys (gibbon) up to Homo sapiens. We previously reported on an alternative splicing event in HERV-K(HML-2) type 1 proviruses that can give rise to nuclear protein of 9 kDa (Np9). We document here the evolution of Np9-coding capacity in human, chimpanzee and gorilla, and show that the C-terminal half of Np9 binds directly to MDM2, through a domain of MDM2 that is known to be contacted by various cellular proteins in response to stress. Np9 can inhibit the MDM2 ubiquitin ligase activity toward p53 in the cell nucleus, and can support the transactivation of genes by p53. Our findings point to the possibility that endogenous retrovirus protein Np9 contributes to the regulation of the p53-MDM2 pathway specifically in humans, chimpanzees and gorillas. PMID- 26103466 TI - Age and Sex of Mice Markedly Affect Survival Times Associated with Hyperoxic Acute Lung Injury. AB - Mortality associated with acute lung injury (ALI) remains substantial, with recent estimates of 35-45% similar to those obtained decades ago. Although evidence for sex-related differences in ALI mortality remains equivocal, death rates differ markedly for age, with more than 3-fold increased mortality in older versus younger patients. Strains of mice also show large differences in ALI mortality. To tease out genetic factors affecting mortality, we established a mouse model of differential hyperoxic ALI (HALI) survival. Separate genetic analyses of backcross and F2 populations generated from sensitive C57BL/6J (B) and resistant 129X1/SvJ (X1) progenitor strains identified two quantitative trait loci (QTLs; Shali1 and Shali2) with strong, equal but opposite, within-strain effects on survival. Congenic lines confirmed these opposing QTL effects, but also retained the low penetrance seen in the 6-12 week X1 control strain. Sorting mice into distinct age groups revealed that 'age at exposure' inversely correlated with survival time and explained reduced penetrance of the resistance trait. While B mice were already sensitive by 6 weeks old, X1 mice maintained significant resistance up to 3-4 weeks longer. Reanalysis of F2 data gave analogous age-related findings, and also supported sex-specific linkage for Shali1 and Shali2. Importantly, we have demonstrated in congenic mice that these age effects on survival correspond with B alleles for Shali1 (6-week old mice more sensitive) and Shali2 (10-week old mice more resistant) placed on the X1 background. Further studies revealed significant sex-specific survival differences in subcongenics for both QTLs. Accounting for age and sex markedly improved penetrance of both QTLs, thereby reducing trait variability, refining Shali1 to <8.5Mb, and supporting several sub-QTLs within the Shali2 interval. Together, these congenics will allow age- and sex-specific studies to interrogate myriad subphenotypes affected during ALI development and progression and identify intermediary injury biomarkers that can predict outcome. PMID- 26103467 TI - A systematic review of the sleep, sleepiness, and performance implications of limited wake shift work schedules. AB - OBJECTIVES: The aim of this review was to identify which limited wake shift work schedules (LWSW) best promote sleep, alertness, and performance. LWSW are fixed work/rest cycles where the time-at-work does is <=8 hours and there is >1 rest period per day, on average, for >=2 consecutive days. These schedules are commonly used in safety-critical industries such as transport and maritime industries. METHODS: Literature was sourced using PubMed, Embase, PsycInfo, Scopus, and Google Scholar databases. We identified 20 independent studies (plus a further 2 overlapping studies), including 5 laboratory and 17 field-based studies focused on maritime watch keepers, ship bridge officers, and long-haul train drivers. The measurement of outcome measures was varied, incorporating subjective and objective measures of sleep: sleep diaries (N=5), actigraphy (N=4), and polysomnography, (N=3); sleepiness: Karolinska Sleepiness Scale (N=5), visual analog scale (VAS) alertness (N=2) and author-derived measures (N=2); and performance: Psychomotor Vigilance Test (PVT) (N=5), Reaction Time or Vigilance tasks (N=4), Vector and Letter Cancellation Test (N=1), and subjective performance (N=2). RESULTS: Of the three primary rosters examined (6 hours-on/6 hours-off, 8 hours-on/8 hours-off and 4 hours-on/8 hours-off), the 4 hours-on/8 hours-off roster was associated with better sleep and lower levels of sleepiness. Individuals working 4 hours-on/8 hours-off rosters averaged 1 hour more sleep per night than those working 6 hours-on/6 hours-off and 1.3 hours more sleep than those working 8 hours-on/8 hours-off (P<0.01). More broadly, findings indicate that LWSW schedules were associated with better sleep and lower sleepines in the case of (i) shorter time-at-work, (ii) more frequent rest breaks, (iii) shifts that start and end at the same clock time every 24 hours, and (iv) work shifts commencing in the daytime (as opposed to night). The findings for performance remain incomplete due to the small number of studies containing a performance measure and the heterogeneity of performance measures within those that did. CONCLUSION: The literature supports the utility of LWSW in industries where individuals sleep at or near the workplace as they facilitate at least some sleep during the biological night and minimize deficits associated with time-on-shift with shorter shifts. Overall, the 4 hour-on/8 hour-off roster best promoted sleep and minimized sleepiness compared to other LWSW schedules. Nevertheless, and considering the safety-critical nature of industries which employ LWSW, the limited literature needs to be greatly expanded with specific focus on the consequences for performance and comparison to mainstream rosters. PMID- 26103468 TI - Clinical Relevance of Apheretic Graft Composition in Patients With Acute Myeloblastic Leukemia Who Received a Busulfan-Fludarabine-Antithymocyte Globulin Conditioning Regimen for Allogeneic Transplant. AB - OBJECTIVES: Sparse data are available about the effects of apheretic graft composition on the clinical transplant outcome in allotransplanted patients who have hematologic malignant disease. Major obstacles in recent studies have included heterogeneity of patient populations and differences in the conditioning regimens used. MATERIALS AND METHODS: This prospective study included 50 patients who had acute myeloblastic leukemia and received busulfan-fludarabine antithymocyte globulin-based conditioning for peripheral allogeneic stem cell transplant. The concentration of CD34+ cells, T-cell subsets, B cells, and natural killer cells in the graft were analyzed by flow cytometry in the donors who were matched for human leukocyte antigen. RESULTS: In univariate analysis, infusion with a higher dose of natural killer cells (> 1.55 * 106/kg) was associated with improved survival (P = .007 for disease-free survival; P = .024 for overall survival) in patients with acute myeloblastic leukemia. Cox regression models revealed that increased concentration of natural killer cells and CD34+ cells positively affected the clinical outcome of allotransplanted patients (P = .005 for both cell types). According to univariate analysis, these findings were dependent on minimal residual disease and acute graft-versus-host disease. Graft-versus-host disease (acute and chronic forms) was not affected by graft composition. CONCLUSIONS: Our results suggest that increased concentration of natural killer cells and CD34+ cells in the apheretic product may predict better survival. In contrast, busulfan-fludarabine-antithymocyte globulin-based conditioning eliminates the disadvantages that resulted from the high content of T-cell subsets and B cells, and the course of the transplant and clinical parameters were not affected by the amount of T and B cells. PMID- 26103470 TI - Evaluation of an electron Monte Carlo dose calculation algorithm for treatment planning. AB - The purpose of this study is to evaluate the accuracy of the electron Monte Carlo (eMC) dose calculation algorithm included in a commercial treatment planning system and compare its performance against an electron pencil beam algorithm. Several tests were performed to explore the system's behavior in simple geometries and in configurations encountered in clinical practice. The first series of tests were executed in a homogeneous water phantom, where experimental measurements and eMC-calculated dose distributions were compared for various combinations of energy and applicator. More specifically, we compared beam profiles and depth-dose curves at different source-to-surface distances (SSDs) and gantry angles, by using dose difference and distance to agreement. Also, we compared output factors, we studied the effects of algorithm input parameters, which are the random number generator seed, as well as the calculation grid size, and we performed a calculation time evaluation. Three different inhomogeneous solid phantoms were built, using high- and low-density materials inserts, to clinically simulate relevant heterogeneity conditions: a small air cylinder within a homogeneous phantom, a lung phantom, and a chest wall phantom. We also used an anthropomorphic phantom to perform comparison of eMC calculations to measurements. Finally, we proceeded with an evaluation of the eMC algorithm on a clinical case of nose cancer. In all mentioned cases, measurements, carried out by means of XV-2 films, radiographic films or EBT2 Gafchromic films. were used to compare eMC calculations with dose distributions obtained from an electron pencil beam algorithm. eMC calculations in the water phantom were accurate. Discrepancies for depth-dose curves and beam profiles were under 2.5% and 2 mm. Dose calculations with eMC for the small air cylinder and the lung phantom agreed within 2% and 4%, respectively. eMC calculations for the chest wall phantom and the anthropomorphic phantom also showed a positive agreement with the measurements. The retrospective dosimetric comparison of a clinical case, which presented scatter perturbations by air cavities, showed a difference in dose of up to 20% between pencil beam and eMC algorithms. When comparing to the pencil beam algorithm, eMC calculations are definitely more accurate at predicting large dose perturbations due to inhomogeneities. PMID- 26103469 TI - LPS Down-Regulates Specificity Protein 1 Activity by Activating NF-kappaB Pathway in Endotoxemic Mice. AB - BACKGROUND: Specificity protein (Sp) 1 mediates the transcription of a large number of constitutive genes encoding physiological mediators. NF-kappaB mediates the expression of hundreds of inducible genes encoding pathological mediators. Crosstalk between Sp1 and NF-kappaB pathways could be pathophysiologically significant, but has not been studied. This study examined the crosstalk between the two pathways and defined the role of NF-kappaB signaling in LPS-induced down regulation of Sp1 activity. METHODS AND MAIN FINDINGS: Challenge of wild type mice with samonelia enteritidis LPS (10 mg/kg, i.p.) down-regulated Sp1 binding activity in lungs in a time-dependent manner, which was concomitantly associated with an increased NF-kappaB activity. LPS down-regulates Sp1 activity by inducing an LPS inducible Sp1-degrading enzyme (LISPDE) activity, which selectively degrades Sp1 protein, resulting in Sp1 down-regulation. Blockade of NF-kappaB activation in mice deficient in NF-kappaB p50 gene (NF-kappaB-KO) suppressed LISPDE activity, prevented Sp1 protein degradation, and reversed the down regulation of Sp1 DNA binding activity and eNOS expression (an indicator of Sp1 transactivation activity). Inhibition of LISPDE activity using a selective LISPDE inhibitor mimicked the effects of NF-kappaB blockade. Pretreatment of LPS challenged WT mice with a selective LISPDE inhibitor increased nuclear Sp1 protein content, restored Sp1 DNA binding activity and reversed eNOS protein down regulation in lungs. Enhancing tissue level of Sp1 activity by inhibiting NF kappaB-mediated Sp1 down-regulation increased tissue level of IL-10 and decreased tissue level of TNF- alphain the lungs. CONCLUSIONS: NF-kappaB signaling mediates LPS-induced down-regulation of Sp1 activity. Activation of NF-kappaB pathway suppresses Sp1 activity and Sp1-mediated anti-inflammatory signals. Conversely, Sp1 signaling counter-regulates NF-kappaB-mediated inflammatory response. Crosstalk between NF-kappaB and Sp1 pathways regulates the balance between pro- and anti-inflammatory cytokines. PMID- 26103471 TI - Technical evaluation of TomoTherapy automatic roll correction. AB - The TomoTherapy Hi.Art System allows the application of rotational corrections as a part of the pretreatment image guidance process. This study outlines a custom method to perform an end-to-end evaluation of the TomoTherapy Hi.Art roll correction feature. A roll-sensitive plan was designed and delivered to a cylindrical solid water phantom to test the accuracy of roll corrections, as well as the ability of the automatic registration feature to detect induced roll. Cylindrical target structures containing coaxial inner avoidance structures were placed adjacent to the plane bisecting the phantom and 7 cm laterally off central axis. The phantom was positioned at isocenter with the target-plane parallel to the couch surface. Varying degrees of phantom roll were induced and dose to the targets and inner avoidance structures was measured using Kodak EDR2 films placed in the target-plane. Normalized point doses were compared with baseline (no roll) data to determine the sensitivity of the test and the effectiveness of the roll correction feature. Gamma analysis comparing baseline, roll-corrected, and uncorrected films was performed using film analysis software. MVCT images were acquired prior to plan delivery. Measured roll was compared with induced roll to evaluate the automatic registration feature's ability to detect rotational misalignment. Rotations beyond 0.3 degrees result in statistically significant deviation from baseline point measurements. Gamma pass rates begin to drop below 90% at approximately 0.5 degrees induced rotation at 3%/3 mm and between 0.2 degrees and 0.3 degrees for 2%/2 mm. With roll correction applied, point dose measurements for all rotations are indistinguishable from baseline, and gamma pass rates exceed 96% when using 3% and 3 mm as evaluation criteria. Measured roll via the automatic registration algorithm agrees with induced rotation to within the test sensitivity for nearly all imaging settings. The TomoTherapy automatic registration system accurately detects induced rotations, and the method presented here for evaluation of the roll correction feature is easily implemented by any clinic with a TomoTherapy Hi.Art unit. This method is sensitive to well within half a degree and demonstrates that the TomoTherapy Hi.Art roll correction feature accurately corrects for induced rotational misalignments to within this level of uncertainty. PMID- 26103472 TI - Increased dose near the skin due to electromagnetic surface beacon transponder. AB - The purpose of this study was to evaluate the increased dose near the skin from an electromagnetic surface beacon transponder, which is used for localization and tracking organ motion. The bolus effect due to the copper coil surface beacon was evaluated with radiographic film measurements and Monte Carlo simulations. Various beam incidence angles were evaluated for both 6 MV and 18 MV experimentally. We performed simulations using a general-purpose Monte Carlo code MCNPX (Monte Carlo N-Particle) to supplement the experimental data. We modeled the surface beacon geometry using the actual mass of the glass vial and copper coil placed in its L-shaped polyethylene terephthalate tubing casing. Film dosimetry measured factors of 2.2 and 3.0 enhancement in the surface dose for normally incident 6 MV and 18 MV beams, respectively. Although surface dose further increased with incidence angle, the relative contribution from the bolus effect was reduced at the oblique incidence. The enhancement factors were 1.5 and 1.8 for 6 MV and 18 MV, respectively, at an incidence angle of 60 degrees . Monte Carlo simulation confirmed the experimental results and indicated that the epidermal skin dose can reach approximately 50% of the dose at dmax at normal incidence. The overall effect could be acceptable considering the skin dose enhancement is confined to a small area (~ 1 cm2), and can be further reduced by using an opposite beam technique. Further clinical studies are justified in order to study the dosimetric benefit versus possible cosmetic effects of the surface beacon. One such clinical situation would be intact breast radiation therapy, especially large-breasted women. PMID- 26103473 TI - Potential of 3D printing technologies for fabrication of electron bolus and proton compensators. AB - In electron and proton radiotherapy, applications of patient-specific electron bolus or proton compensators during radiation treatments are often necessary to accommodate patient body surface irregularities, tissue inhomogeneity, and variations in PTV depths to achieve desired dose distributions. Emerging 3D printing technologies provide alternative fabrication methods for these bolus and compensators. This study investigated the potential of utilizing 3D printing technologies for the fabrication of the electron bolus and proton compensators. Two printing technologies, fused deposition modeling (FDM) and selective laser sintering (SLS), and two printing materials, PLA and polyamide, were investigated. Samples were printed and characterized with CT scan and under electron and proton beams. In addition, a software package was developed to convert electron bolus and proton compensator designs to printable Standard Tessellation Language file format. A phantom scalp electron bolus was printed with FDM technology with PLA material. The HU of the printed electron bolus was 106.5 +/- 15.2. A prostate patient proton compensator was printed with SLS technology and polyamide material with -70.1 +/- 8.1 HU. The profiles of the electron bolus and proton compensator were compared with the original designs. The average over all the CT slices of the largest Euclidean distance between the design and the fabricated bolus on each CT slice was found to be 0.84 +/- 0.45 mm and for the compensator to be 0.40 +/- 0.42 mm. It is recommended that the properties of specific 3D printed objects are understood before being applied to radiotherapy treatments. PMID- 26103474 TI - Assessment of Eclipse electron Monte Carlo output prediction for various topologies. AB - Monte Carlo simulation is deemed to be the leading algorithm for accurate dose calculation with electron beams. Patient anatomy (contours and tissue densities) as well as irradiation geometry is accounted for. The accuracy of the Monitor Unit (MU) determination is one essential aspect of a treatment planning system. Patient-specific quality assurance of a Monte Carlo plan usually involves verification of the MUs with an independent simpler calculation approach, in which flat geometry is to be assumed. The magnitude of the discrepancies between flat and varied surfaces for a few scenarios has been investigated in this study. The ability to predict MUs for various surface topologies by the commercial electron Monte Carlo implementation from Varian Eclipse system (Eclipse eMC) has been evaluated and compared to the Generalized Gaussian Pencil Beam (GGPB) algorithm. Ten phantoms with different topologies were constructed of water equivalent material. Measurements with a parallel plate ionization chamber were performed using these phantoms to gauge their relative impact on outputs for 6, 9, 12, 16, and 20MeV electron beams from a Varian TrueBeam with cone sizes ranging from 6 * 6 cm2 to 25 * 25 cm2. The corresponding Monte Carlo simulations of the measured geometries were carried out using the CT scans of these phantoms. The results indicated that the Eclipse eMC algorithm can predict these output changes within 3% for most scenarios. However, at the lowest energy, the discrepancy was the greatest, up to 6%. In comparison, the Eclipse GGPB algorithm had much worse agreement, with discrepancies up to 17% at the lowest energies. PMID- 26103475 TI - Site-specific tolerance tables and indexing device to improve patient setup reproducibility. AB - While the implementation of tools such as image-guidance and immobilization devices have helped to prevent geometric misses in radiation therapy, many treatments remain prone to error if these items are not available, not utilized for every fraction, or are misused. The purpose of this project is to design a set of site-specific treatment tolerance tables to be applied to the treatment couch for use in a record and verify (R&V) system that will insure accurate patient setup with minimal workflow interruption. This project also called for the construction of a simple indexing device to help insure reproducible patient setup for patients that could not be indexed with existing equipment. The tolerance tables were created by retrospective analysis on a total of 66 patients and 1,308 treatments, separating them into five categories based on disease site: lung, head and neck (H&N), breast, pelvis, and abdomen. Couch parameter tolerance tables were designed to encompass 95% of treatments, and were generated by calculating the standard deviation of couch vertical, longitudinal, and lateral values using the first day of treatment as a baseline. We also investigated an alternative method for generating the couch tolerances by updating the baseline values when patient position was verified with image guidance. This was done in order to adapt the tolerances to any gradual changes in patient setup that would not correspond with a mistreatment. The tolerance tables and customizable indexing device were then implemented for a trial period in order to determine the feasibility of the system. During this trial period we collected data from 1,054 fractions from 65 patients. We then analyzed the number of treatments that would have been out of tolerance, as well as whether or not the tolerances or setup techniques should be adjusted. When the couch baseline values were updated with every imaging fraction, the average rate of tolerance violations was 10% for the lung, H&N, abdomen, and pelvis treatments. Using the indexing device, tolerances for patients with pelvic disease decreased (e.g., from 5.3 cm to 4.3 cm longitudinally). Unfortunately, the results from breast patients were highly variable due to the complexity of the setup technique, making the couch an inadequate surrogate for measuring setup accuracy. In summary, we have developed a method to turn the treatment couch parameters within the R&V system into a useful alert tool, which can be implemented at other institutions, in order to identify potential errors in patient setup. PMID- 26103476 TI - Helical 4D CT pitch management for the Brilliance CT Big Bore in clinical practice. AB - In external beam radiotherapy treatment planning for patients with thoracic malignancies, respiratory-correlated CT (4D CT) is used to obtain high quality studies in the presence of respiratory motion. When helical 4D CT scans are acquired with a Brilliance CT Big Bore, the pitch must meet two conditions. It must be low enough to avoid motion artifacts, and high enough to cover the entire scan length within 120 s to prevent overheating of the X-ray tube. We developed a nomogram that can be used to obtain a suitable pitch satisfying both requirements. We also assessed the effects on the image quality of a pitch that exceeds the maximum pitch, and of a field of view (FOV) reduction. It was shown that, for AVG and MIP reconstructions, the manufacturer's maximum pitch equation yields an underestimation due to its FOV term. PMID- 26103477 TI - In vivo endorectal dosimetry of prostate tomotherapy using dual MOSkin detectors. AB - Verification of dose to the anterior rectal wall in helical tomotherapy to the prostate is important due to the close proximity of the rectal wall to the treatment field. The steep dose gradient makes these measurements challenging. A phantom-based study was completed, aimed at developing a system for measurement of anterior rectal wall doses during hypofractionated prostate stereotactic body radiotherapy (SBRT) utilizing tomotherapy delivery. An array of four dual MOSkinTM dosimeters, spaced 1 cm apart, was placed on a replica Rectafix(r) immobilization spacer device. This Perspex probe is a more rigid alternative to rectal balloons, to improve geometric reproducibility. The doses at each point were measured in real time and compared to doses calculated by the treatment planning system (TPS). Additionally, distance-to-agreement (DTA) measurements were acquired to assist in the comparison of measured and predicted doses. All dual MOSkin detectors measured dose to within +/- 5% of the TPS at the anterior rectal wall. Whilst several points were outside of experimental error, the largest deviation from the TPS predicted dose represented a DTA of only 1.3 mm, within the acceptable DTA tolerance of 3 mm. Larger deviations of up to -11.9% were observed for the posterior and side walls; however, if acceptable DTA measurements are accounted for, then an agreement of 75% was observed. Although larger differences were observed at the other rectal wall locations, the overall effect of dose at these points was not as significant, given the lower doses. Despite the very high-dose gradient region, real-time measurements of the anterior rectal wall doses were within acceptable limits of TPS-predicted doses. The differences between measured and planned data were due to difficulties in precisely locating each detector on the TPS dose grid, which presented large variations in dose between CT voxels in regions of steep dose gradients. The dual MOSkin system would, therefore, be a useful device for detecting errors in real time, such as patient shifts or incorrect setup, during tomotherapy of the prostate. PMID- 26103478 TI - Simulation of a medical linear accelerator for teaching purposes. AB - Simulation software for medical linear accelerators that can be used in a teaching environment was developed. The components of linear accelerators were modeled to first order accuracy using analytical expressions taken from the literature. The expressions used constants that were empirically set such that realistic response could be expected. These expressions were programmed in a MATLAB environment with a graphical user interface in order to produce an environment similar to that of linear accelerator service mode. The program was evaluated in a systematic fashion, where parameters affecting the clinical properties of medical linear accelerator beams were adjusted independently, and the effects on beam energy and dose rate recorded. These results confirmed that beam tuning adjustments could be simulated in a simple environment. Further, adjustment of service parameters over a large range was possible, and this allows the demonstration of linear accelerator physics in an environment accessible to both medical physicists and linear accelerator service engineers. In conclusion, a software tool, named SIMAC, was developed to improve the teaching of linear accelerator physics in a simulated environment. SIMAC performed in a similar manner to medical linear accelerators. The authors hope that this tool will be valuable as a teaching tool for medical physicists and linear accelerator service engineers. PMID- 26103479 TI - Modeling a superficial radiotherapy X-ray source for relative dose calculations. AB - The purpose of this study was to empirically characterize and validate a kilovoltage (kV) X-ray beam source model of a superficial X-ray unit for relative dose calculations in water and assess the accuracy of the British Journal of Radiology Supplement 25 (BJR 25) percentage depth dose (PDD) data. We measured central axis PDDs and dose profiles using an Xstrahl 150 X-ray system. We also compared the measured and calculated PDDs to those in the BJR 25. The Xstrahl source was modeled as an effective point source with varying spatial fluence and spectra. In-air ionization chamber measurements were made along the x- and y-axes of the X-ray beam to derive the spatial fluence and half-value layer (HVL) measurements were made to derive the spatially varying spectra. This beam characterization and resulting source model was used as input for our in-house dose calculation software (kVDoseCalc) to compute radiation dose at points of interest (POIs). The PDDs and dose profiles were measured using 2, 5, and 15 cm cone sizes at 80, 120, 140, and 150 kVp energies in a scanning water phantom using IBA Farmer-type ionization chambers of volumes 0.65 and 0.13 cc, respectively. The percent difference in the computed PDDs compared with our measurements range from -4.8% to 4.8%, with an overall mean percent difference and standard deviation of 1.5% and 0.7%, respectively. The percent difference between our PDD measurements and those from BJR 25 range from -14.0% to 15.7%, with an overall mean percent difference and standard deviation of 4.9% and 2.1%, respectively - showing that the measurements are in much better agreement with kVDoseCalc than BJR 25. The range in percent difference between kVDoseCalc and measurement for profiles was -5.9% to 5.9%, with an overall mean percent difference and standard deviation of 1.4% and 1.4%, respectively. The results demonstrate that our empirically based X-ray source modeling approach for superficial X-ray therapy can be used to accurately compute relative dose in a homogeneous water-equivalent medium. They also show limitations in the accuracy of theBJR 25 PDD data. PMID- 26103480 TI - An accurate algorithm to match imperfectly matched images for lung tumor detection without markers. AB - In order to locate lung tumors on kV projection images without internal markers, digitally reconstructed radiographs (DRRs) are created and compared with projection images. However, lung tumors always move due to respiration and their locations change on projection images while they are static on DRRs. In addition, global image intensity discrepancies exist between DRRs and projections due to their different image orientations, scattering, and noises. This adversely affects comparison accuracy. A simple but efficient comparison algorithm is reported to match imperfectly matched projection images and DRRs. The kV projection images were matched with different DRRs in two steps. Preprocessing was performed in advance to generate two sets of DRRs. The tumors were removed from the planning 3D CT for a single phase of planning 4D CT images using planning contours of tumors. DRRs of background and DRRs of tumors were generated separately for every projection angle. The first step was to match projection images with DRRs of background signals. This method divided global images into a matrix of small tiles and similarities were evaluated by calculating normalized cross-correlation (NCC) between corresponding tiles on projections and DRRs. The tile configuration (tile locations) was automatically optimized to keep the tumor within a single projection tile that had a bad matching with the corresponding DRR tile. A pixel-based linear transformation was determined by linear interpolations of tile transformation results obtained during tile matching. The background DRRs were transformed to the projection image level and subtracted from it. The resulting subtracted image now contained only the tumor. The second step was to register DRRs of tumors to the subtracted image to locate the tumor. This method was successfully applied to kV fluoro images (about 1000 images) acquired on a Vero (BrainLAB) for dynamic tumor tracking on phantom studies. Radiation opaque markers were implanted and used as ground truth for tumor positions. Although other organs and bony structures introduced strong signals superimposed on tumors at some angles, this method accurately located tumors on every projection over 12 gantry angles. The maximum error was less than 2.2 mm, while the total average error was less than 0.9mm. This algorithm was capable of detecting tumors without markers, despite strong background signals. PMID- 26103481 TI - Comparison between two different algorithms used for pretreatment QA via aSi portal images. AB - Several algorithms exist to perform quality assurance for volumetric-modulated arc therapy (VMAT) treatments based on electronic portal imaging devices (EPID). These algorithms are used to compare doses (convert into water, GLAaS) and fluences (in amorphous silicon (aSi), Varian portal dosimetry). The aim of this study is to compare the two methods using clinical data. In this study, Varian portal dosimetry (VPD) and Epiqa solutions were compared. We used a same set of patient images data treated with 6 MV and 20 MV photon energies and different locations. The response of the portal imaging device was also investigated with different field sizes, monitor units, dose rates, sag effect, and linac daily output. All images were acquired on an electronic portal imaging device (EPID) positioned at source detector distance (SDD) of 100 cm. A virtual water phantom was used for Epiqa to calculate the dose matrices at the maximum depth doses dmax. The 2D gamma evaluation index (GAI) was performed to quantitatively compare the results given by the two solutions. The response of the EPID gave a good agreement with Epiqa (deviation less than 1%) for MU greater than 20 for both 6 MV and 20 MV photon energies. For VPD, the upward sloping trend showed a good agreement for MU higher than 50. Dose rate evaluations for both methods gave a deviation of, respectively, 0.4 and 0.5 % for 6 MV and 20 MV. The gamma criteria of 3 mm for distance to agreement and 3 % for dose difference was, as mean +/- 1SD, 99.81% +/- 1.48% and 99.42% +/- 0.97% for VPD and Epiqa, respectively, for 6 MV photon energy. The mean values of the gamma criteria for the collected data using 20 MV photon energy were, respectively, 98.33% +/- 2.41% and 98.12% +/- 1.99% for VPD and Epiqa. The output constancy deviation correction (a 10 * 10cm2 reference field plan to obtain absorbed dose despite the linac monitor daily variations) showed a mean deviation of, respectively, 0.07% +/- 0.57% and 0.16% +/- 1.38% for 6 MV and 20 MV photon energies. For sag effect, a slight improvement was noticed for realignment of the integrated image and was 0.25%+/- 0.69% for 6 MV and 0.40% +/- 0.57% for 20 MV. The clinical data were used for pretreatment QA with the two systems, both VPD and Epiqa software, showed acceptable and similar results for low and high energies. Furthermore, Epiqa shows better linearity response for low MU. PMID- 26103483 TI - A special report of current state of the medical physicist workforce - results of the 2012 ASTRO Comprehensive Workforce Study. AB - The medical physics profession is undergoing significant changes. Starting in 2014, candidates registering for certification exams by the American Board of Radiology must have completed a CAMPEP-accredited residency. This requirement, along with tightened state regulations, uncertainty in future reimbursement, and a stronger emphasis on board certification, have raised questions concerning the state of the medical physics workforce and its ability to adapt to changing requirements. In 2012, ASTRO conducted a workforce study of the comprehensive field of radiation oncology. This article reviews the findings of the medical physics section of the study, including age and gender distribution, educational background, workload, and primary work setting. We also report on job satisfaction, the perceived supply and demand of medical physicists, and the medical physicists' main concerns pertaining to patient safety and quality assurance. PMID- 26103482 TI - Flattening filter-free accelerators: a report from the AAPM Therapy Emerging Technology Assessment Work Group. AB - This report describes the current state of flattening filter-free (FFF) radiotherapy beams implemented on conventional linear accelerators, and is aimed primarily at practicing medical physicists. The Therapy Emerging Technology Assessment Work Group of the American Association of Physicists in Medicine (AAPM) formed a writing group to assess FFF technology. The published literature on FFF technology was reviewed, along with technical specifications provided by vendors. Based on this information, supplemented by the clinical experience of the group members, consensus guidelines and recommendations for implementation of FFF technology were developed. Areas in need of further investigation were identified. Removing the flattening filter increases beam intensity, especially near the central axis. Increased intensity reduces treatment time, especially for high-dose stereotactic radiotherapy/radiosurgery (SRT/SRS). Furthermore, removing the flattening filter reduces out-of-field dose and improves beam modeling accuracy. FFF beams are advantageous for small field (e.g., SRS) treatments and are appropriate for intensity-modulated radiotherapy (IMRT). For conventional 3D radiotherapy of large targets, FFF beams may be disadvantageous compared to flattened beams because of the heterogeneity of FFF beam across the target (unless modulation is employed). For any application, the nonflat beam characteristics and substantially higher dose rates require consideration during the commissioning and quality assurance processes relative to flattened beams, and the appropriate clinical use of the technology needs to be identified. Consideration also needs to be given to these unique characteristics when undertaking facility planning. Several areas still warrant further research and development. Recommendations pertinent to FFF technology, including acceptance testing, commissioning, quality assurance, radiation safety, and facility planning, are presented. Examples of clinical applications are provided. Several of the areas in which future research and development are needed are also indicated. PMID- 26103484 TI - Breaking bad IMRT QA practice. AB - Agreement between planned and delivered dose distributions for patient-specific quality assurance in routine clinical practice is predominantly assessed utilizing the gamma index method. Several reports, however, fundamentally question current IMRT QA practice due to poor sensitivity and specificity of the standard gamma index implementation. An alternative is to employ dose volume histogram (DVH)-based metrics. An analysis based on the AAPM TG 53 and ESTRO booklet No.7 recommendations for QA of treatment planning systems reveals deficiencies in the current "state of the art" IMRT QA, no matter which metric is selected. The set of IMRT benchmark plans were planned, delivered, and analyzed by following guidance of the AAPM TG 119 report. The recommended point dose and planar dose measurements were obtained using a PinPoint ionization chamber, EDR2 radiographic film, and a 2D ionization chamber array. Gamma index criteria {3% (global), 3 mm} and {3% (local), 3 mm} were used to assess the agreement between calculated and delivered planar dose distributions. Next, the AAPM TG 53 and ESTRO booklet No.7 recommendations were followed by dividing dose distributions into four distinct regions: the high-dose (HD) or umbra region, the high-gradient (HG) or penumbra region, the medium-dose (MD) region, and the low-dose (LD) region. A different gamma passing criteria was defined for each region, i.e., a "divide and conquer" (D&C) gamma method was utilized. The D&C gamma analysis was subsequently tested on 50 datasets of previously treated patients. Measured point dose and planar dose distributions compared favorably with TG 119 benchmark data. For all complex tests, the percentage of points passing the conventional {3% (global), 3 mm} gamma criteria was 97.2% +/- 3.2% and 95.7% +/- 1.2% for film and 2D ionization chamber array, respectively. By dividing 2D ionization chamber array dose measurements into regions and applying 3mm isodose point distance and variable local point dose difference criteria of 7%, 15%, 25%, and 40% for HD, HG, MD, and LD regions, respectively, a 93.4% +/- 2.3% gamma passing rate was obtained. Identical criteria applied using the D&C gamma technique on 50 clinical treatment plans resulted in a 97.9% +/- 2.3% gamma passing score. Based on the TG 119 standard, meeting or exceeding the benchmark results would indicate an exemplary IMRT QA program. In contrast to TG 119 analysis, a different scrutiny on the same set of data, which follows the AAPM TG 53 and ESTRO booklet No.7 guidelines, reveals a much poorer agreement between calculated and measured dose distributions with large local point dose differences within different dose regions. This observation may challenge the conventional wisdom that an IMRT QA program is producing acceptable results. PMID- 26103485 TI - Use of 3D printers to create a patient-specific 3D bolus for external beam therapy. AB - The purpose of this paper is to demonstrate that an inexpensive 3D printer can be used to manufacture patient-specific bolus for external beam therapy, and to show we can accurately model this printed bolus in our treatment planning system for accurate treatment delivery. Percent depth-dose measurements and tissue maximum ratios were used to determine the characteristics of the printing materials, acrylonitrile butadiene styrene and polylactic acid, as bolus material with physical density of 1.04 and 1.2 g/cm3, and electron density of 3.38 * 1023 electrons/cm3 and 3.80 * 1023 electrons/ cm3, respectively. Dose plane comparisons using Gafchromic EBT2 film and the RANDO phantom were used to verify accurate treatment planning. We accurately modeled a printing material in Eclipse treatment planning system, assigning it a Hounsfield unit of 260. We were also able to verify accurate treatment planning using gamma analysis for dose plane comparisons. With gamma criteria of 5% dose difference and 2 mm DTA, we were able to have 86.5% points passing, and with gamma criteria of 5% dose difference and 3 mm DTA, we were able to have 95% points passing. We were able to create a patient specific bolus using an inexpensive 3D printer and model it in our treatment planning system for accurate treatment delivery. PMID- 26103486 TI - Evaluation of patient DVH-based QA metrics for prostate VMAT: correlation between accuracy of estimated 3D patient dose and magnitude of MLC misalignment. AB - The purpose of this study was to evaluate the accuracy of commercially available software, using patient DVH-based QA metrics, by investigating the correlation between estimated 3D patient dose and magnitude of MLC misalignments. We tested 3DVH software with an ArcCHECK. Two different calculating modes of ArcCHECK Planned Dose Perturbation (ACPDP) were used: "Normal Sensitivity" and "High Sensitivity". Ten prostate cancer patients treated with hypofractionated VMAT (67.6 Gy/26 Fr) in our hospital were studied. For the baseline plan, we induced MLC errors (-0.75, -0.5, -0.25, 0.25, 0.5, and 0.75 mm for each single bank). We calculated the dose differences between the ACPDP dose with error and TPS dose with error using gamma passing rates and using DVH-based QA metrics. The correlations between dose estimation error and MLC position error varied with each structure and metric. A comparison using 1%/1 mm gamma index showed that the larger was the MLC error-induced, the worse were the gamma passing rates. Slopes of linear fit to dose estimation error versus MLC position error for mean dose and D95 to the PTV were 1.76 and 1.40% mm-1, respectively, for "Normal Sensitivity", and -0.53 and -0.88% mm-1, respectively, for "High Sensitivity", showing better accuracy for "High Sensitivity" than "Normal Sensitivity". On the other hand, the slopes for mean dose to the rectum and bladder, V35 to the rectum and bladder and V55 to the rectum and bladder, were -1.00, -0.55, -2.56, -1.25, 3.53, and -1.85%mm-1, respectively, for "Normal Sensitivity", and -2.89, -2.39, 4.54, -3.12, -6.24, and -4.11% mm-1, respectively, for "High Sensitivity", showing significant better accuracy for "Normal Sensitivity" than "High Sensitivity". Our results showed that 3DVH had some residual error for both sensitivities. Furthermore, we found that "Normal Sensitivity" might have better accuracy for the DVH metric for the PTV and that "High Sensitivity" might have better accuracy for DVH metrics for the rectum and bladder. We must be willing to tolerate this residual error in clinical care. PMID- 26103487 TI - Potential systematic uncertainties in IGRT when FBCT reference images are used for pancreatic tumors. AB - The purpose of this study was to quantify the systematic uncertainties resulting from using free breathing computed tomography (FBCT) as a reference image for image-guided radiation therapy (IGRT) for patients with pancreatic tumors, and to quantify the associated dosimetric impact that resulted from using FBCT as reference for IGRT. Fifteen patients with implanted fiducial markers were selected for this study. For each patient, a FBCT and an average intensity projection computed tomography (AIP) created from four-dimensional computed tomography (4D CT) were acquired at the simulation. The treatment plan was created based on the FBCT. Seventy-five weekly kilovoltage (kV) cone-beam computed tomography (CBCT) images (five for each patient) were selected for this study. Bony alignment without rotation correction was performed 1) between the FBCT and CBCT, 2) between the AIP and CBCT, and 3) between the AIP and FBCT. The contours of the fiducials from the FBCT and AIP were transferred to the corresponding CBCT and were compared. Among the 75 CBCTs, 20 that had > 3 mm differences in centers of mass (COMs) in any directions between the FBCT and AIP were chosen for further dosimetric analysis. These COM discrepancies were converted into isocenter shifts in the corresponding planning FBCT, and dose was recalculated and compared to the initial FBCT plans. For the 75 CBCTs studied, the mean absolute differences in the COMs of the fiducial markers between the FBCT and CBCTs were 3.3 mm +/- 2.5 mm, 3.5 mm +/- 2.4 mm, and 5.8 mm +/- 4.4 mm in the right-left (RL), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. Between the AIP and CBCTs, the mean absolute differences were 3.2 mm +/- 2.2mm, 3.3 mm +/- 2.3 mm, and 6.3 mm +/- 5.4 mm. The absolute mean discrepancies in these COMs shifts between FBCT/CBCT and AIP/CBCT were 1.1 mm +/- 0.8 mm, 1.3 mm +/- 0.9 mm, and 3.3 mm +/- 2.6 mm in RL, AP, and SI, respectively. This represented a potential systematic error. For the 20 CBCTs that had COM discrepancies > 3 mm in any direction, the average reduction in planning target volume (PTV) coverage (PTV volume receiving 100% of prescription dose) was 5.3% +/- 3.1% (range: 0.7%-12.8%). Using FBCT as a reference for IGRT may introduce potential interfractional systematic COM shifts if the FBCT is acquired at a different breathing phase than the average breathing phase. The potential systematic error could be significant in the SI direction and varied among patients for the other directions. AIP is a better choice of reference image set for IGRT in order to correct interfractional variations due to respiratory motion and nonrespiratory organ displacement. PMID- 26103488 TI - Is there a preferred IMRT technique for left-breast irradiation? AB - Not all clinics have breath-hold radiotherapy available for left-breast irradiation. However intensity-modulated radiotherapy (IMRT) has also been advocated as a means of lowering heart doses. There is currently no large-scale, long-term follow-up data after breast IMRT and, since dose distributions may differ from classic tangent-based radiotherapy, caution is needed to avoid unexpected worsening of the late toxicity profile. We compared four IMRT techniques for free-breathing left-breast irradiation. Consistent with the aforementioned concerns, our goal in planning was to prioritize organ at risk (OAR) sparing in a way that mimicked tangent-based radiotherapy. Ten simultaneous integrated boost treatment plans (PTVelective = 15 * 2.67 Gy; PTVboost = 15 * 3.35 Gy) were created using 1) hybrid-IMRT (H-IMRT), 2) full IMRT (F-IMRT), and 3) volumetric-modulated arc therapy with two partial arcs (2ARC) and 4) six partial arcs (6ARC). Reduction in OAR mean and low dose was prioritized. End points included OAR sparing (e.g., heart, left anterior descending artery [LAD+3 mm], lungs, and contralateral breast) and PTV coverage/dose homogeneity. Under these conditions we found the following: 1) H-IMRT provided the best mean and low dose OAR sparing, PTVelective coverage (mean V95% = 98%), PTVboost coverage (V95% = 98%), and PTV homogeneity. However, it delivered most intermediate-high dose to the heart, LAD+3 mm and ipsilateral lung; 2) 6ARC had the best intermediate-high dose sparing, followed by F-IMRT, but this was at the expense of more dose in the contralateral lung and breast and worse PTV coverage (PTVelective mean V95% = 96%/97% and PTVboost mean V95% = 91%/96% for 6ARC/F-IMRT). When trying to spare mean and low dose to OARs, the preferred IMRT technique for left-breast irradiation without breath-hold was H-IMRT. This is currently the standard solution in our institution for left-breast radiotherapy under free-breathing and breath-hold conditions. PMID- 26103489 TI - Dosimetric characterization of the M-15 high-dose-rate Iridium-192 brachytherapy source using the AAPM and ESTRO formalism. AB - The Source Production & Equipment Co. (SPEC) model M-15 is a new Iridium-192 brachytherapy source model intended for use as a temporary high-dose-rate (HDR) brachytherapy source for the Nucletron microSelectron Classic afterloading system. The purpose of this study is to characterize this HDR source for clinical application by obtaining a complete set of Monte Carlo calculated dosimetric parameters for the M-15, as recommended by AAPM and ESTRO, for isotopes with average energies greater than 50 keV. This was accomplished by using the MCNP6 Monte Carlo code to simulate the resulting source dosimetry at various points within a pseudoinfinite water phantom. These dosimetric values next were converted into the AAPM and ESTRO dosimetry parameters and the respective statistical uncertainty in each parameter also calculated and presented. The M-15 source was modeled in an MCNP6 Monte Carlo environment using the physical source specifications provided by the manufacturer. Iridium-192 photons were uniformly generated inside the iridium core of the model M-15 with photon and secondary electron transport replicated using photoatomic cross-sectional tables supplied with MCNP6. Simulations were performed for both water and air/vacuum computer models with a total of 4 * 109 sources photon history for each simulation and the in-air photon spectrum filtered to remove low-energy photons belowdelta = 10 keV. Dosimetric data, including D.(r,theta), gL(r), F(r,theta), phian(r), and phi-an, and their statistical uncertainty were calculated from the output of an MCNP model consisting of an M-15 source placed at the center of a spherical water phantom of 100 cm diameter. The air kerma strength in free space, SK, and dose rate constant, Lambda, also was computed from a MCNP model with M-15 Iridium-192 source, was centered at the origin of an evacuated phantom in which a critical volume containing air at STP was added 100 cm from the source center. The reference dose rate, D.(r0,theta0) = D. (1cm,pi/2), is found to be 4.038 +/- 0.064 cGy mCi-1 h-1. The air kerma strength, SK, is reported to be 3.632 +/- 0.086 cGy cm2 mCi-1 g-1, and the dose rate constant, Lambda, is calculated to be 1.112 +/- 0.029 cGy h-1 U-1. The normalized dose rate, radial dose function, and anisotropy function with their uncertainties were computed and are represented in both tabular and graphical format in the report. A dosimetric study was performed of the new M-15 Iridium-192 HDR brachytherapy source using the MCNP6 radiation transport code. Dosimetric parameters, including the dose-rate constant, radial dose function, and anisotropy function, were calculated in accordance with the updated AAPM and ESTRO dosimetric parameters for brachytherapy sources of average energy greater than 50 keV. These data therefore may be applied toward the development of a treatment planning program and for clinical use of the source. PMID- 26103490 TI - Anatomy-based, patient-specific VMAT QA using EPID or MLC log files. AB - In this project, we investigated the use of an electronic portal imaging device (EPID), together with the treatment planning system (TPS) and MLC log files, to determine the delivered doses to the patient and evaluate the agreement between the treatment plan and the delivered dose distribution. The QA analysis results are presented for 15 VMAT patients using the EPID measurements, the ScandiDos Delta4 dosimeter, and the beam fluence calculated from the multileaf collimator (MLC) log file. EPID fluence images were acquired in continuous acquisition mode for each of the patients and they were processed through an in-house MATLAB program to create an opening density matrix (ODM), which was used as the input fluence for the dose calculation in the TPS (Pinnacle3). The EPID used in this study was the aSi1000 Varian on a Novalis TX linac equipped with high-definition MLC. The actual MLC positions and gantry angles were retrieved from the MLC log files and the data were used to calculate the delivered dose distributions in Pinnacle. The resulting dose distributions were then compared against the corresponding planned dose distributions using the 3D gamma index with 3 mm/3% passing criteria. The ScandiDos Delta4 phantom was also used to measure a 2D dose distribution for all the 15 patients and a 2D gamma was calculated for each patient using the Delta4 software. The average 3D gamma using the EPID images was 96.1% +/- 2.2%. The average 3D gamma using the log files was 98.7% +/- 0.5%. The average 2D gamma from the Delta4 was 98.1% +/- 2.1%. Our results indicate that the use of the EPID, combined with MLC log files and a TPS, is a viable method for QA of VMAT plans. PMID- 26103491 TI - AAPM Medical Physics Practice Guideline 3.a: Levels of supervision for medical physicists in clinical training. AB - The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education and professional practice of medical physics. The AAPM has more than 8,000 members and is the principal organization of medical physicists in the United States.The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner.Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized.The following terms are used in the AAPM practice guidelines:Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline.Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. PMID- 26103493 TI - Development of a novel remote-controlled and self-contained audiovisual-aided interactive system for immobilizing claustrophobic patients. AB - In radiotherapy, only a few immobilization systems, such as open-face mask and head mold with a bite plate, are available for claustrophobic patients with a certain degree of discomfort. The purpose of this study was to develop a remote controlled and self-contained audiovisual (AV)-aided interactive system with the iPad mini with Retina display for intrafractional motion management in brain/H&N (head and neck) radiotherapy for claustrophobic patients. The self-contained, AV aided interactive system utilized two tablet computers: one for AV-aided interactive guidance for the subject and the other for remote control by an operator. The tablet for audiovisual guidance traced the motion of a colored marker using the built-in front-facing camera, and the remote control tablet at the control room used infrastructure Wi-Fi networks for real-time communication with the other tablet. In the evaluation, a programmed QUASAR motion phantom was used to test the temporal and positional accuracy and resolution. Position data were also obtained from ten healthy volunteers with and without guidance to evaluate the reduction of intrafractional head motion in simulations of a claustrophobic brain or H&N case. In the phantom study, the temporal and positional resolution was 24 Hz and 0.2 mm. In the volunteer study, the average superior-inferior and right-left displacement was reduced from 1.9 mm to 0.3 mm and from 2.2 mm to 0.2 mm with AV-aided interactive guidance, respectively. The superior-inferior and right-left positional drift was reduced from 0.5 mm/min to 0.1 mm/min and from 0.4 mm/min to 0.04 mm/min with audiovisual-aided interactive guidance. This study demonstrated a reduction in intrafractional head motion using a remote-controlled and self-contained AV-aided interactive system of iPad minis with Retina display, easily obtainable and cost-effective tablet computers. This approach can potentially streamline clinical flow for claustrophobic patients without a head mask and also allows patients to practice self-motion management before radiation treatment delivery. PMID- 26103492 TI - Use of a novel two-dimensional ionization chamber array for pencil beam scanning proton therapy beam quality assurance. AB - The need to accurately and efficiently verify both output and dose profiles creates significant challenges in quality assurance of pencil beam scanning (PBS) proton delivery. A system for PBS QA has been developed that combines a new two dimensional ionization chamber array in a waterproof housing that is scanned in a water phantom. The MatriXX PT has the same detector array arrangement as the standard MatriXX(Evolution) but utilizes a smaller 2 mm plate spacing instead of 5mm. Because the bias voltage of the MatriXX PT and Evolution cannot be changed, PPC40 and FC65-G ionization chambers were used to assess recombination effects. The PPC40 is a parallel plate chamber with an electrode spacing of 2mm, while the FC65-G is a Farmer chamber FC65-G with an electrode spacing of 2.8 mm. Three bias voltages (500, 200, and 100 V) were used for both detectors to determine which radiation type (continuous, pulse or pulse-scanned beam) could closely estimate Pion from the ratios of charges collected. In comparison with the MatriXX(Evolution), a significant improvement in measurement of absolute dose with the MatriXX PT was observed. While dose uncertainty of the MatriXX(Evolution) can be up to 4%, it is < 1% for the MatriXX PT. Therefore the MatriXX(Evolution) should not be used for QA of PBS for conditions in which ion recombination is not negligible. Farmer chambers should be used with caution for measuring the absolute dose of PBS beams, as the uncertainty of Pion can be > 1%; chambers with an electrode spacing of 2 mm or smaller are recommended. PMID- 26103494 TI - Effect of radiation dose reduction on image quality in adult head CT with noise suppressing reconstruction system with a 256 slice MDCT. AB - The purpose of our study was to investigate the effect of iterative reconstruction (IR) as a dose reduction system on the image quality (IQ) of the adult head computed tomography (CT) at various low-dose levels, and to identify ways of setting the amount of dose reduction. We performed two noncontrast low dose (LD) adult head CT protocols modified by lowering the tube current with IR which were decided in the light of a group of phantom studies. Two groups of patients, each 100 underwent noncontrast head CT with LD-I and LD-II, respectively. These groups were compared with 100 consecutive standard dose (STD) adult head CT protocol in terms of quantitative and qualitative IQ. The signal-to noise ratio (SNR) of the white matter (WM) and gray matter (GM) and contrast-to noise ratio (CNR) values in the LD groups were higher than the STD group. The differences were statistically significant. When the STD and the LD groups were compared qualitatively, no significant differences were found in overall quality. By selecting the appropriate level of IR 34%, radiation dose reduction in adult head CT can be achieved without compromising IQ. PMID- 26103495 TI - Tangent field technique of TomoDirect improves dose distribution for whole-breast irradiation. AB - TomoDirect (TD) is an intensity-modulated radiotherapy system that uses a fixed gantry angle instead of rotational beam delivery. Here, we investigated the effect of the multiple beam technique of TomoDirect on dose distribution compared with commonly-used tangential beams. We included 45 consecutive patients with right breast cancer who underwent postoperative radiotherapy in our institute in the present study. Clinical target volume (CTV) was the whole right breast. The planning target volume (PTV) was created by expanding the CTV by a 0.5 cm margin. Paired TD plans were generated for each patient; a two-beam plan using paired tangential beams and a six-beam plan with four additional beams with modified gantry angles of +/- 5 degrees from the original tangential beam set. A prescribed dose of 50 Gy was defined for 50% isodoses of the PTV. The six-beam plan delivered significantly more homogeneous doses to the PTV than the two-beam plan; and the mean dose to the PTV in the six-beam plan more closely reflected the prescribed dose. V20Gy and mean dose to the right lung and mean dose to the whole body were also significantly decreased in the six-beam plan. However, duration of radiation exposure was 1 min longer in the six-beam plan than in the two-beam plan. The dose distribution to the target and organs at risk were improved with the six-beam plan relative to the two-beam plan without increasing the whole-body radiation dose. The six-beam plan using TD is a simple technique that can be routinely applied to whole-breast irradiation in clinical practice. PMID- 26103497 TI - Portal dosimetry in wedged beams. AB - Portal dosimetry using electronic portal imaging devices (EPIDs) is often applied to verify high-energy photon beam treatments. Due to the change in photon energy spectrum, the resulting dose values are, however, not very accurate in the case of wedged beams if the pixel-to-dose conversion for the situation without wedge is used. A possible solution would be to consider a wedged beam as another photon beam quality requiring separate beam modeling of the dose calculation algorithm. The aim of this study was to investigate a more practical solution: to make aSi EPID-based dosimetry models also applicable for wedged beams without an extra commissioning effort of the parameters of the model. For this purpose two energy dependent wedge multiplication factors have been introduced to be applied for portal images taken with and without a patient/phantom in the beam. These wedge multiplication factors were derived from EPID and ionization chamber measurements at the EPID level for wedged and nonwedged beams, both with and without a polystyrene slab phantom in the beam. This method was verified for an EPID dosimetry model used for wedged beams at three photon beam energies (6, 10, and 18 MV) by comparing dose values reconstructed in a phantom with data provided by a treatment planning system (TPS), as a function of field size, depth, and off axis distance. Generally good agreement, within 2%, was observed for depths between dose maximum and 15 cm. Applying the new model to EPID dose measurements performed during ten breast cancer patient treatments with wedged 6 MV photon beams showed that the average isocenter underdosage of 5.3% was reduced to 0.4%. Gamma-evaluation (global 3%/3 mm) of these in vivo data showed an increase in percentage of points with gamma <= 1 from 60.2% to 87.4%, while gammamean reduced from 1.01 to 0.55. It can be concluded that, for wedged beams, the multiplication of EPID pixel values with an energy-dependent correction factor provides good agreement between dose values determined by an EPID and a TPS, indicating the usefulness of such a practical solution. PMID- 26103496 TI - Evaluation of the scatter doses in the direction of the buccal mucosa from dental metals. AB - The presence of dental metals creates radiation dose perturbation due to scattered radiation during radiation therapy for the head and neck region. The purpose of our study was to compare the scatter doses resulting from various dental metals in the direction of the buccal mucosa among a single-field technique, three-dimensional conformal radiation therapy (3D CRT), and intensity modulated radiation therapy (IMRT) during radiation therapy for the head and neck region. We used nine metal cubes with 10 mm sides, which were placed inside a water phantom. The scatter doses from the cubes in the direction of the buccal mucosa were measured using radiochromic films. The films were placed perpendicularly to the surface of the cubes. The phantom was irradiated with a 4 MV photon energy by a linear accelerator for all techniques. In the single-field technique, the scatter doses from dental metals showed 3.7%-19.3% dose increases, and gold showed the largest dose increase. In 3D CRT, the scatter doses from dental metals showed 1.4%-6.9% dose increases, which were within the measurement uncertainty (except for gold). In IMRT, the scatter doses from dental metals showed only 1.4%-4.3% dose increases, which were all within the measurement uncertainty. During radiation therapy for the head and neck region, the scatter doses from the tested dental metals in the direction of the buccal mucosa in 3D CRT or IMRT were lower than those using the single-field technique. However, there were no differences between the scatter doses resulting from particular dental metals in the direction of the buccal mucosa in 3D CRT and those in IMRT, except for gold. PMID- 26103498 TI - AutoLock: a semiautomated system for radiotherapy treatment plan quality control. AB - A semiautomated system for radiotherapy treatment plan quality control (QC), named AutoLock, is presented. AutoLock is designed to augment treatment plan QC by automatically checking aspects of treatment plans that are well suited to computational evaluation, whilst summarizing more subjective aspects in the form of a checklist. The treatment plan must pass all automated checks and all checklist items must be acknowledged by the planner as correct before the plan is finalized. Thus AutoLock uniquely integrates automated treatment plan QC, an electronic checklist, and plan finalization. In addition to reducing the potential for the propagation of errors, the integration of AutoLock into the plan finalization workflow has improved efficiency at our center. Detailed audit data are presented, demonstrating that the treatment plan QC rejection rate fell by around a third following the clinical introduction of AutoLock. PMID- 26103499 TI - Radiographic film dosimetry of proton beams for depth-dose constancy check and beam profile measurement. AB - Radiographic film dosimetry suffers from its energy dependence in proton dosimetry. This study sought to develop a method of measuring proton beams by the film and to evaluate film response to proton beams for the constancy check of depth dose (DD). It also evaluated the film for profile measurements. To achieve this goal, from DDs measured by film and ion chamber (IC), calibration factors (ratios of dose measured by IC to film responses) as a function of depth in a phantom were obtained. These factors imply variable slopes (with proton energy and depth) of linear characteristic curves that relate film response to dose. We derived a calibration method that enables utilization of the factors for acquisition of dose from film density measured at later dates by adapting to a potentially altered processor condition. To test this model, the characteristic curve was obtained by using EDR2 film and in-phantom film dosimetry in parallel with a 149.65 MeV proton beam, using the method. An additional validation of the model was performed by concurrent film and IC measurement perpendicular to the beam at various depths. Beam profile measurements by the film were also evaluated at the center of beam modulation. In order to interpret and ascertain the film dosimetry, Monte Carlos simulation of the beam was performed, calculating the proton fluence spectrum along depths and off-axis distances. By multiplying respective stopping powers to the spectrum, doses to film and water were calculated. The ratio of film dose to water dose was evaluated. Results are as follows. The characteristic curve proved the assumed linearity. The measured DD approached that of IC, but near the end of the spread-out Bragg peak (SOBP), a spurious peak was observed due to the mismatch of distal edge between the calibration and measurement films. The width of SOBP and the proximal edge were both reproducible within a maximum of 5mm; the distal edge was reproducible within 1 mm. At 5 cm depth, the dose was reproducible within 10%. These large discrepancies were identified to have been contributed by film processor uncertainty across a layer of film and the misalignment of film edge to the frontal phantom surface. The deviations could drop from 5 to 2 mm in SOBP and from 10% to 4.5% at 5 cm depth in a well-controlled processor condition(i.e., warm up). In addition to the validation of the calibration method done by the DD measurements, the concurrent film and IC measurement independently validated the model by showing the constancy of depth-dependent calibration factors. For profile measurement, the film showed good agreement with ion chamber measurement. In agreement with the experimental findings, computationally obtained ratio of film dose to water dose assisted understanding of the trend of the film response by revealing relatively large and small variances of the response for DD and beam profile measurements, respectively. Conclusions are as follows. For proton beams, radiographic film proved to offer accurate beam profile measurements. The adaptive calibration method proposed in this study was validated. Using the method, film dosimetry could offer reasonably accurate DD constancy checks, when provided with a well-controlled processor condition. Although the processor warming up can promote a uniform processing across a single layer of the film, the processing remains as a challenge. PMID- 26103500 TI - Volumetric-modulated arc therapy planning using multicriteria optimization for localized prostate cancer. AB - The purpose of this work is to evaluate the volumetric-modulated arc therapy (VMAT) multicriteria optimization (MCO) algorithm clinically available in the RayStation treatment planning system (TPS) and its ability to reduce treatment planning time while providing high dosimetric plan quality. Nine patients with localized prostate cancer who were previously treated with 78 Gy in 39 fractions using VMAT plans and rayArc system based on the direct machine parameter optimization (DMPO) algorithm were selected and replanned using the VMAT-MCO system. First, the dosimetric quality of the plans was evaluated using multiple conformity metrics that account for target coverage and sparing of healthy tissue, used in our departmental clinical protocols. The conformity and homogeneity index, number of monitor units, and treatment planning time for both modalities were assessed. Next, the effects of the technical plan parameters, such as constraint leaf motion CLM (cm/ degrees ) and maximum arc delivery time T (s), on the accuracy of delivered dose were evaluated using quality assurance passing rates (QAs) measured using the Delta4 phantom from ScandiDos. For the dosimetric plan's quality analysis, the results show that the VMAT-MCO system provides plans comparable to the rayArc system with no statistical difference for V95% (p < 0.01), D1% (p < 0.01), CI (p < 0.01), and HI (p < 0.01) of the PTV, bladder (p < 0.01), and rectum (p < 0.01) constraints, except for the femoral heads and healthy tissues, for which a dose reduction was observed using MCO compared with rayArc (p < 0.01). The technical parameter study showed that a combination of CLM equal to 0.5 cm/degree and a maximum delivery time of 72 s allowed the accurate delivery of the VMAT-MCO plan on the Elekta Versa HD linear accelerator. Planning evaluation and dosimetric measurements showed that VMAT-MCO can be used clinically with the advantage of enhanced planning process efficiency by reducing the treatment planning time without impairing dosimetric quality. PMID- 26103501 TI - Evaluation of Dosimetry Check software for IMRT patient-specific quality assurance. AB - The purpose of this study is to evaluate the use of the Dosimetry Check system for patient-specific IMRT QA. Typical QA methods measure the dose in an array dosimeter surrounded by homogenous medium for which the treatment plan has been recomputed. With the Dosimetry Check system, fluence measurements acquired on a portal dosimeter is applied to the patient's CT scans. Instead of making dose comparisons in a plane, Dosimetry Check system produces isodose lines and dose volume histograms based on the planning CT images. By exporting the dose distribution from the treatment planning system into the Dosimetry Check system, one is able to make a direct comparison between the calculated dose and the planned dose. The versatility of the software is evaluated with respect to the two IMRT techniques - step and shoot and volumetric arc therapy. The system analyzed measurements made using EPID, PTW seven29, and IBA MatriXX, and an intercomparison study was performed. Plans from patients previously treated at our institution with treated anatomical site on brain, head & neck, liver, lung, and prostate were analyzed using Dosimetry Check system for any anatomical site dependence. We have recommendations and possible precautions that may be necessary to ensure proper QA with the Dosimetry Check system. PMID- 26103502 TI - Medical Physics Practice Guideline 4.a: Development, implementation, use and maintenance of safety checklists. AB - The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education and professional practice of medical physics. The AAPM has more than 8,000 members and is the principal organization of medical physicists in the United States.The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner.Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized.The following terms are used in the AAPM practice guidelines:Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline.Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. PMID- 26103503 TI - First experiences in using a dose control system on a TomoTherapy Hi.Art II. AB - The purpose of this study was to investigate the impact of a dose control system (DCS) servo installed on two fully commissioned TomoTherapy Hi.Art II treatment units. This servo is designed to actively adjust machine parameters to control the output variation of a tomotherapy unit to within +/- 0.5% of the nominal dose rate. Machine output, dose rate, and patient-specific quality assurance data were retrospectively analyzed for periods prior to and following the installation of the servo system. Quality assurance tests indicate a reduction in the rotational variation of the output during a procedure, where the peak-to-peak amplitude of the variation was +/- 1.30 prior to DCS and equal to +/- 0.4 with DCS. Comparing two tomotherapy unit static outputs over four years the percentage error was 1.05% +/- 0.7% and -0.4% +/- 0.66% and, once DCS was installed, was reduced to 0.22% +/- 0.29% and -0.08% +/- 0.16%. The results of the quality assurance tests indicate that the dose control system reduced the output variation of each machine for both static and rotational delivery, leading to an improvement in the overall performance of the machine and providing greater certainty in treatment delivery. PMID- 26103504 TI - A Web application for the management of clinical workflow in image-guided and adaptive proton therapy for prostate cancer treatments. AB - Image-guided radiotherapy (IGRT), based on radiopaque markers placed in the prostate gland, was used for proton therapy of prostate patients. Orthogonal X rays and the IBA Digital Image Positioning System (DIPS) were used for setup correction prior to treatment and were repeated after treatment delivery. Following a rationale for margin estimates similar to that of van Herk,(1) the daily post-treatment DIPS data were analyzed to determine if an adaptive radiotherapy plan was necessary. A Web application using ASP.NET MVC5, Entity Framework, and an SQL database was designed to automate this process. The designed features included state-of-the-art Web technologies, a domain model closely matching the workflow, a database-supporting concurrency and data mining, access to the DIPS database, secured user access and roles management, and graphing and analysis tools. The Model-View-Controller (MVC) paradigm allowed clean domain logic, unit testing, and extensibility. Client-side technologies, such as jQuery, jQuery Plug-ins, and Ajax, were adopted to achieve a rich user environment and fast response. Data models included patients, staff, treatment fields and records, correction vectors, DIPS images, and association logics. Data entry, analysis, workflow logics, and notifications were implemented. The system effectively modeled the clinical workflow and IGRT process. PMID- 26103507 TI - Retraction Notice: Reducing motion artifacts in 4D MR images using principal component analysis (PCA) combined with linear polynomial fitting model. PMID- 26103506 TI - Proton-beam therapy: are physicists ignoring clinical realities? PMID- 26103508 TI - A Life of Service: Lawrence Williams (Larry) Berkley. PMID- 26103510 TI - Bis(sigma-B-H) complexes of copper(i): precursors to a heterogeneous amine-borane dehydrogenation catalyst. AB - A series of bis(sigma-B-H) complexes of copper(i) have been prepared by displacement of arene solvent from a beta-diketiminate copper(i) complex by four coordinate boranes, H3B-L (L = NMe3, lutidine). In the presence of the same copper arene complex, the secondary amine-borane H3B-NMe2H undergoes dehydrogenation. We provide evidence for formation of a heterogengous catalyst from decomposition of the solution species. PMID- 26103511 TI - Negative Capacitance in Organic/Ferroelectric Capacitor to Implement Steep Switching MOS Devices. AB - Because of the "Boltzmann tyranny" (i.e., the nonscalability of thermal voltage), a certain minimum gate voltage in metal-oxide-semiconductor (MOS) devices is required for a 10-fold increase in drain-to-source current. The subthreshold slope (SS) in MOS devices is, at best, 60 mV/decade at 300 K. Negative capacitance in organic/ferroelectric materials is proposed in order to address this physical limitation in MOS technology. Here, we experimentally demonstrate the steep switching behavior of a MOS device-that is, SS ~ 18 mV/decade (much less than 60 mV/decade) at 300 K-by taking advantage of negative capacitance in a MOS gate stack. This negative capacitance, originating from the dynamics of the stored energy in a phase transition of a ferroelectric material, can achieve the step-up conversion of internal voltage (i.e., internal voltage amplification in a MOS device). With the aid of a series-connected negative capacitor as an assistive device, the surface potential in the MOS device becomes higher than the applied gate voltage, so that a SS of 18 mV/decade at 300 K is reliably observed. PMID- 26103512 TI - Integration of DNA bio-gates and duplex-specific nuclease signal amplification: towards electrochemiluminescence detection of survivin mRNA. AB - Using the DNA bio-gate and duplex-specific nuclease assisted target recycling, a facile electrochemiluminescence assay was developed for the sensitive detection of survivin mRNA. PMID- 26103513 TI - Behavior of Early Warnings near the Critical Temperature in the Two-Dimensional Ising Model. AB - Among the properties that are common to complex systems, the presence of critical thresholds in the dynamics of the system is one of the most important. Recently, there has been interest in the universalities that occur in the behavior of systems near critical points. These universal properties make it possible to estimate how far a system is from a critical threshold. Several early-warning signals have been reported in time series representing systems near catastrophic shifts. The proper understanding of these early-warnings may allow the prediction and perhaps control of these dramatic shifts in a wide variety of systems. In this paper we analyze this universal behavior for a system that is a paradigm of phase transitions, the Ising model. We study the behavior of the early-warning signals and the way the temporal correlations of the system increase when the system is near the critical point. PMID- 26103514 TI - Learning Environment, Preparedness and Satisfaction in Osteopathy in Europe: The PreSS Study. AB - OBJECTIVE: 1) to assess the preparedness to practice and satisfaction in learning environment amongst new graduates from European osteopathic institutions; 2) to compare the results of preparedness to practice and satisfaction in learning environment between and within countries where osteopathy is regulated and where regulation is still to be achieved; 3) to identify possible correlations between learning environment and preparedness to practice. METHOD: Osteopathic education providers of full-time education located in Europe were enrolled, and their final year students were contacted to complete a survey. Measures used were: Dundee Ready Educational Environment Measure (DREEM), the Association of American Medical Colleges (AAMC) and a demographic questionnaire. Scores were compared across institutions using one-way ANOVA and generalised linear model. RESULTS: Nine European osteopathic education institutions participated in the study (4 located in Italy, 2 in the UK, 1 in France, 1 in Belgium and 1 in the Netherlands) and 243 (77%) of their final-year students completed the survey. The DREEM total score mean was 121.4 (SEM: 1.66) whilst the AAMC was 17.58 (SEM:0.35). A generalised linear model found a significant association between not-regulated countries and total score as well as subscales DREEM scores (p<0.001). Learning environment and preparedness to practice were significantly positively correlated (r=0.76; p<0.01). DISCUSSION: A perceived higher level of preparedness and satisfaction was found amongst students from osteopathic institutions located in countries without regulation compared to those located in countries where osteopathy is regulated; however, all institutions obtained a 'more positive than negative' result. Moreover, in general, cohorts with fewer than 20 students scored significantly higher compared to larger student cohorts. Finally, an overall positive correlation between students' preparedness and satisfaction were found across all institutions recruited. PMID- 26103515 TI - Uranium-mediated oxidative addition and reductive elimination. AB - Oxidative addition, and its reverse reaction reductive elimination, constitute two key reactions that underpin organometallic chemistry and catalysis. Although these reactions have been known for decades in main group and transition metal systems, they are exceptionally rare or unknown for the f-block. However, in recent years much progress has been made. In this Perspective article, advances in uranium-mediated oxidative addition/reductive elimination, since the point that this research area was initiated in the early-1980s, are summarised. We principally divide the Perspective into two parts of oxidative addition and reductive elimination, along with a separate section concerning reactions where there is no change of uranium oxidation state in reactant and product but the reaction has the formal appearance of a 'concerted' reductive elimination/oxidative addition from the perspective of the net result. This body of work highlights that whilst uranium is capable of performing reactions that to some extent conform to traditional reactivity types, novel reactivity that has no counterpart anywhere else can be performed, thus adding to the rich palate of redox chemistry that uranium can mediate. PMID- 26103516 TI - Treatment of Solitary Painful Osseous Metastases with Radiotherapy, Cryoablation or Combined Therapy: Propensity Matching Analysis in 175 Patients. AB - PURPOSE: aim of this study was to identify outcomes in pain relief and quality of life in patients with a solitary painful osseous metastasis treated by radiotherapy, cryoablation or the combination using a propensity score matching study design. MATERIALS AND METHODS: 175 patients with painful bone metastases were included in the study. Twenty-five of them underwent a radiation course (20 Gy in five daily fractions) 15 days after the cryoablation. These subjects were retrospectively matched by propensity analysis with a group of subjects treated by radiotherapy (125 subjects) and with a group treated byCryoablation (25 subjects). The pain relief in terms of complete response, rate of subjects requiring analgesics after treatments and the changes in self-rated quality of life were measured. Informed consent was obtained from the subject and the study was approved by the local Ethical Committee. RESULTS: An higher proportion of subjects treated by cryoablation (32%) or cryoablation followed by RT (72%;) experienced a complete response compared with patients treated by radiotherapy alone (11.2%). After Bonferroni correction strategy, the addition of radiotherapy to cryoablation significantly improved the rate of complete response compared with cryoablation alone (p = 0.011) and this paralleled with an improved self rated quality of life. Seventeen subjects (13.6%) of patients in the radiotherapy group, 9 (36%) in the cryoablation group, and 19 (76)% in the cryoablation- radiotherapy group did not require narcotic medications. CONCLUSIONS: The addition of radiotherapy to cryoablation favorably impacts on perceived pain, with a favorable toxicity profile. However, our data should be interpreted with caution and could serve as a framework around which to design future trials. PMID- 26103517 TI - Koumine, Humantenine, and Yohimbane Alkaloids from Gelsemium elegans. AB - Nine new alkaloids of the koumine (1-4), humantenine (5-7), and yohimbane (8, 9) types as well as 12 known analogues were isolated from the leaves and vine stems of Gelsemium elegans. Compound 1 is the first N-4-demethyl alkaloid of the koumine type, compound 7 is the first nor-humantenine alkaloid, and compounds 8 and 9 are the first N-1-oxide and the first seco-E-ring alkaloids, respectively, of the yohimbane type. Compounds 1 and 7 exhibited moderate cytotoxicity against five human tumor cell lines with IC50 values in the range 4.6-9.3 MUM. PMID- 26103519 TI - Mycobacterium tuberculosis class II apurinic/apyrimidinic-endonuclease/3'-5' exonuclease III exhibits DNA regulated modes of interaction with the sliding DNA beta-clamp. AB - The class-II AP-endonuclease (XthA) acts on abasic sites of damaged DNA in bacterial base excision repair. We identified that the sliding DNA beta-clamp forms in vivo and in vitro complexes with XthA in Mycobacterium tuberculosis. A novel 239 QLRFPKK245 motif in the DNA-binding domain of XthA was found to be important for the interactions. Likewise, the peptide binding-groove (PBG) and the C-terminal of beta-clamp located on different domains interact with XthA. The beta-clamp-XthA complex can be disrupted by clamp binding peptides and also by a specific bacterial clamp inhibitor that binds at the PBG. We also identified that beta-clamp stimulates the activities of XthA primarily by increasing its affinity for the substrate and its processivity. Additionally, loading of the beta-clamp onto DNA is required for activity stimulation. A reduction in XthA activity stimulation was observed in the presence of beta-clamp binding peptides supporting that direct interactions between the proteins are necessary to cause stimulation. Finally, we found that in the absence of DNA, the PBG located on the second domain of the beta-clamp is important for interactions with XthA, while the C-terminal domain predominantly mediates functional interactions in the substrate's presence. PMID- 26103520 TI - Mycophenolate mofetil for treatment of steroid-refractory acute graft-versus-host disease after pediatric hematopoietic stem cell transplantation. AB - A standard treatment is yet to be established for steroid-refractory acute aGVHD following HSCT. The effects of MMF have not been well studied in children with aGVHD. We evaluated the effectiveness of oral MMF in 14 children with steroid refractory aGVHD (grade II in one patient, grade III to IV in 13 patients). The median initial dose of MMF was 40 mg/kg/day (range, 30-74) and was increased by 1.5-2 times if manifestations of GVHD did not improve. Within four wk of treatment, seven patients (50%) achieved CR, and four (29%) had a PR. Within eight wk, 11 patients (79%) achieved CR without using additional agents. Overall, 12 patients are alive and in remission with a median follow-up of 35 months (range, 14-86). The median maximum dose of MMF was 60 mg/kg/day (range, 34-107). No fatal toxicity was observed, including MMF-related infections. MMF appears to be highly effective for steroid-refractory aGVHD when used at a higher dose than has been described previously. Larger studies and pharmacokinetic analysis are required to evaluate its efficacy and toxicity and find the optimal dose of MMF in children. PMID- 26103521 TI - Ferromagnetic Coupling in "Double-Bridged" Dihydrogenpyrophosphate Complexes of Cobalt(II) and Nickel(II). AB - Three isostructural compounds of the formula {[M(bipy)(H2O)(H2P2O7)]2.2H2O} [bipy = 2,2'-bipyridine; M = Ni (1), Co (2), Mn (3)] have been isolated from aqueous solutions containing the corresponding metal(II) chloride hydrate with a bipy and sodium pyrophosphate solution in a 1:1:2 molar ratio, and their structures were determined by single-crystal X-ray diffraction. The structures of 1-3 consist of neutral aqua(2,2'-bipyridine)metal(II) dinuclear units bridged by two dihydrogenpyrophosphate groups adopting a bidentate/monodentate mode. Each metal ion in 1-3 is six-coordinate in a distorted octahedral geometry, with the reduced value of the angle subtended by the chelating bipy at the metal ion [79.6(1) degrees (1), 77.32(7) degrees (2), and 72.9(1) degrees (3)] being the main source of this distortion. The values of the intramolecular metal-metal separation are 5.271(1) A (1), 5.3065(8) A (2), and 5.371(1) A (3). Magnetic susceptibility measurements on polycrystalline samples of 1-3 in the temperature range 1.9-300 K shows weak intramolecular ferromagnetic [J = +1.86(2) cm(-1) (1) and +0.25(1) cm(-1) (2)] and antiferromagnetic [J = -0.48(1) cm(-1) (3)] coupling, with the spin Hamiltonian being defined as H = -JSM1.SM1a. This rarely observed coordination mode for dihydrogenpyrophosphate leads to ferromagnetic coupling in complexes of nickel(II) or cobalt(II). PMID- 26103522 TI - Total Synthesis of Proposed Structure of Yuremamine and All Diastereomers Using [3+2]-Cycloaddition of Platinum-Containing Azomethine Ylide. AB - Total synthesis of the proposed structure of yuremamine has been achieved for the first time based on the intermolecular [3+2]-cycloaddition reaction of the platinum-containing azomethine ylide. All the possible diastereomers of yuremamine were also synthesized via the common intermediate. Through these syntheses, it was confirmed that the proposed structure of yuremamine and the diastereomers differ from the natural product. PMID- 26103524 TI - Hydrogen-Bonding Toughened Hydrogels and Emerging CO2-Responsive Shape Memory Effect. AB - A double hydrogen bonding (DHB) hydrogel is constructed by copolymerization of 2 vinyl-4,6-diamino-1,3,5-triazine (hydrophobic hydrogen bonding monomer) and N,N dimethylacrylamide (hydrophilic hydrogen bonding monomer) with polyethylene glycol diacrylates. The DHB hydrogels demonstrate tunable robust mechanical properties by varying the ratio of hydrogen bonding monomer or crosslinker. Importantly, because of synergistic energy dissipating mechanism of strong diaminotriazine (DAT) hydrogen bonding and weak amide hydrogen bonding, the DHB hydrogels exhibit high toughness (up to 2.32 kJ m(-2)), meanwhile maintaining 0.7 MPa tensile strength, 130% elongation at break, and 8.3 MPa compressive strength. Moreover, rehydration can help to recover the mechanical properties of the cyclic loaded-unloaded gels. Attractively, the DHB hydrogels are responsive to CO2 in water, and demonstrate unprecedented CO2-triggered shape memory behavior owing to the reversible destruction and reconstruction of DAT hydrogen bonding upon passing and degassing CO2 without introducing external acid. The CO2 triggering mechanism may point out a new approach to fabricate shape memory hydrogels. PMID- 26103523 TI - Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. AB - Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from in-vivo ischemia reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEB mediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fasting-induced autophagy in myocardial ischemia reperfusion injury. PMID- 26103526 TI - Development of a sensitive and rapid method for rifampicin impurity analysis using supercritical fluid chromatography. AB - A novel simple, fast and efficient supercritical fluid chromatography (SFC) method was developed and compared with RPLC method for the separation and determination of impurities in rifampicin. The separation was performed using a packed diol column and a mobile phase B (modifier) consisting of methanol with 0.1% ammonium formate (w/v) and 2% water (v/v). Overall satisfactory resolutions and peak shapes for rifampicin quinone (RQ), rifampicin (RF), rifamycin SV (RSV), rifampicin N-oxide (RNO) and 3-formylrifamycinSV (3-FR) were obtained by optimization of the chromatography system. With gradient elution of mobile phase, all of the impurities and the active were separated within 4 min. Taking full advantage of features of SFC (such as particular selectivity, non-sloping baseline in gradient elution, and without injection solvent effects), the method was successfully used for determination of impurities in rifampicin, with more impurity peaks detected, better resolution achieved and much less analysis time needed compared with conventional reversed-phase liquid chromatography (RPLC) methods. PMID- 26103527 TI - Dewar Lesion Formation in Single- and Double-Stranded DNA is Quenched by Neighboring Bases. AB - UV-induced Dewar lesion formation is investigated in single- and double-stranded oligonucleotides with ultrafast vibrational spectroscopy. The quantum yield for the conversion of the (6-4) lesion to the Dewar isomer in DNA strands is reduced by a factor of 4 in comparison to model dinucleotides. Time resolved spectroscopy reveals a fast process in the excited state with spectral characteristics of bases which are adjacent to the excited (6-4) lesion. These kinetic components have large amplitudes and indicate that an additional quenching channel acts in the stranded DNA systems and reduces the Dewar formation yield. Presumably relaxation evolves via a charge transfer to the neighboring guanine and the paired cytosine participates in a double-stranded oligomer. Changes in the decay of the relaxed excited electronic state of the (6-4) chromophore point to modifications in the excited state energy landscape which may lead to an additional reduction of the Dewar formation yield. PMID- 26103525 TI - PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein. AB - The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Borjeson-Forssman-Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis. PMID- 26103529 TI - Prepregnancy body mass index in a first uncomplicated pregnancy and outcomes of a second pregnancy. AB - OBJECTIVE: This study examined the effect of body mass index (BMI) before a first uncomplicated pregnancy on maternal and fetal outcomes in a subsequent pregnancy, including preterm births, preeclampsia, cesarean delivery, small for gestational age, large for gestational age, and neonatal deaths. STUDY DESIGN: We conducted a population-based cohort study (n = 121,092) using the Missouri maternally linked birth registry (1989 through 2005). Multivariable binary logistic regression models were fit to estimate odds ratios and 95% confidence intervals for the parameters of interest after controlling for sociodemographic and pregnancy related confounders in the second pregnancy. RESULTS: Compared to women with a normal BMI in their first pregnancy, those who were underweight prepregnancy had increased odds for preterm birth by 20% and small for gestational age by 40% in their second pregnancy, while those with prepregnancy obesity had increased odds for large for gestational age, preeclampsia, cesarean delivery, and neonatal deaths in their second pregnancy by 54%, 156%, 85%, and 37%, respectively. CONCLUSION: Women starting a first pregnancy with suboptimal BMI may be at risk of adverse maternal and fetal outcomes in a subsequent pregnancy, even if their first pregnancy was uncomplicated or if they reached a normal weight by their second pregnancy. The long-term consequences of suboptimal BMI carry considerable public health implications. PMID- 26103528 TI - Pharmacokinetics of cefazolin prophylaxis in obese gravidae at time of cesarean delivery. AB - OBJECTIVE: The objective of the study was to compare the pharmacokinetics of 2 g and 3 g doses of cefazolin when used for perioperative prophylaxis in obese gravidae undergoing cesarean delivery. STUDY DESIGN: We performed a double blinded, randomized controlled trial from August 2013 to April 2014. Twenty-six obese women were randomized to receive either 2 or 3 g intravenous cefazolin within 30 minutes of a skin incision. Serial maternal plasma samples were obtained at specific time points up to 8 hours after drug administration. Umbilical cord blood was obtained after placental delivery. Maternal adipose samples were obtained prior to fascial entry, after closure of the hysterotomy, and subsequent to fascial closure. Pharmacokinetic parameters were determined via noncompartmental analysis. RESULTS: The median area under the plasma concentration vs time curve was significantly greater in the 3 g group than in the 2 g group (27204 MUg/mL per minute vs 14058 MUg/mL per minute; P = .001). Maternal plasma concentrations had an impact by body mass index. For every 1 kg/m(2) increase in body mass index at the time of the cesarean delivery, there was an associated 13.77 MUg/mL lower plasma concentration of cefazolin across all time points (P = .01). By the completion of cesarean delivery, cefazolin concentrations in maternal adipose were consistently above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria with both the 2 g and 3 g doses. The median umbilical cord blood concentrations were significantly higher in the 3 g vs the 2 g group (34.5 MUg/mL and 21.4 MUg/mL; P = .003). CONCLUSION: Cefazolin concentrations in maternal adipose both at time of hysterotomy closure and fascial closure were above the minimal inhibitory concentration for both Gram-positive and Gram-negative bacteria when either 2 g or 3 g cefazolin was administered as perioperative surgical prophylaxis. Maternal cefazolin concentrations in plasma and maternal adipose tissue are related to both dose and body mass index. PMID- 26103531 TI - Efficient Delivery of Structurally Diverse Protein Cargo into Mammalian Cells by a Bacterial Toxin. AB - Platforms enabling targeted delivery of proteins into cells are needed to fully realize the potential of protein-based therapeutics with intracellular sites-of action. Bacterial toxins are attractive systems to consider as templates for designing protein transduction systems as they naturally bind and enter specific cells with high efficiency. Here we investigated the capacity of diphtheria toxin to function as an intracellular protein delivery vector. We report that diphtheria toxin delivers an impressive array of passenger proteins spanning a range of sizes, structures, and stabilities into cells in a manner that indicates that they are "invisible" to the translocation machinery. Further, we show that alpha-amylase delivered into cells by a detoxified diphtheria toxin chimera digests intracellular glycogen in live cells, providing evidence that delivered cargo is folded, active, and abundant. The efficiency and versatility of diphtheria toxin over existing systems open numerous possibilities for intracellular delivery of bioactive proteins. PMID- 26103530 TI - Histone deacetylases inhibitors effects on Cryptococcus neoformans major virulence phenotypes. AB - Cryptococcus neoformans undergoes phenotypical changes during host infection in order to promote persistence and survival. Studies have demonstrated that such adaptations require alterations in gene transcription networks by distinct mechanisms. Drugs such as the histone deacetylases inhibitors (HDACi) Sodium Butyrate (NaBut) and Trichostatin A (TSA) can alter the chromatin conformation and have been used to modulate epigenetic states in the treatment of diseases such as cancer. In this work, we have studied the effect of NaBut and TSA on the expression of C. neoformans major virulence phenotypes and on the survival rate of an animal model infected with drugs-treated yeasts. Both drugs affected fungal growth at 37 degrees C more intensely than at 30 degrees C; nonetheless, drugs did not affect cell viability at the concentrations we studied. HDACi also provoked the reduction of the fungal capsule expansion. Phospholipases enzyme activity decreased; mating process and melanin synthesis were also affected by both inhibitors. NaBut led to an increase in the population of cells in G2/M. Treated yeast cells, which were washed in order to remove the drugs from the culture medium prior to the inoculation in the Galleria mellonela infection model, did not cause significant difference at the host survival curve when compared to non-treated cells. Overall, NaBut effects on the impairment of C. neoformans main virulence factors were more intense and stable than the TSA effects. PMID- 26103532 TI - Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice. AB - Maternal immune activation (MIA) results in the development of autism in the offspring via hyperactivation of IL-6 signaling. Furthermore, experimental studies showed that the MIA-associated activation of interleukin-1beta (IL-1beta) concurrently with IL-6 increases the rate and the severity of hippocampal kindling in mice, thus, offering an explanation for autism-epilepsy comorbidity. We examined whether epileptic phenotype triggered by prenatal exposure to IL-6 and IL-1beta combination is restricted to kindling or whether it is reproducible in another model of epilepsy, whereby spontaneous seizures develop following kainic acid (KA)-induced status epilepticus. We also examined whether in mice prenatally exposed to IL-6 and IL-6+IL-1beta, the presence of spontaneous seizures would exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57BL/6J mice received daily injections of IL-6, IL-1beta, or IL-6+IL 1beta combination. At postnatal day 40, male offspring were examined for the presence of social behavioral deficit, and status epilepticus was induced by intrahippocampal KA injection. After 6weeks of monitoring for spontaneous seizures, sociability was tested again. Both IL-6 and IL-6+IL-1beta offspring presented with social behavioral deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6+IL-1beta exacerbated, the severity of KA-induced epilepsy. Increased severity of epilepsy in the IL-6+IL-1beta mice correlated with the improvement of autism-like behavior. We conclude that complex and not necessarily agonistic relationships exist between epileptic and autism-like phenotypes in an animal model of MIA coupled with KA-induced epilepsy and that the nature of these relationships depends on components of MIA involved. PMID- 26103533 TI - Experiences with Patient Refusal of Off-Label Prescribing of Psychotropic Medications to Children and Adolescents in Japan. AB - OBJECTIVE: In child and adolescent psychiatry, the off-label prescribing of psychotropic medications is common. The purpose of this study was to examine the experiences of Japanese child and adolescent psychiatrists with off-label prescribing to children and/or adolescents (hereafter referred to as "children") and to identify the factors associated with these experiences. METHODS: A prospective questionnaire was sent to 1628 psychiatrists belonging to the Japanese Society for Child and Adolescent Psychiatry. Stepwise logistic regression analyses were used to determine whether demographic characteristics or categories of psychotropic medications were able to independently predict patient refusals of off-label prescribing. RESULTS: The final sample included 447 psychiatrists, and 93% of the respondents (416/447) had experiences with off label prescribing to children. In addition, 39.7% of the respondents (165/416) experienced patient refusal of off-label prescribing when they informed the children and/or parents of the prescribing. The most commonly prescribed off label psychotropic medications were antipsychotics (82.0%). Patient refusal was significantly more frequent when the respondents informed parents (p=0.02) and children (p<0.01) about off-label prescribing than when they did not. A stepwise logistic regression analysis revealed that informing parents (odds ratio [OR], 2.73; 95% confidence interval [CI], 1.09-6.82) or children (OR, 1.70; 95% CI, 1.12-2.58) about off-label prescribing and antidepressant use (OR, 2.98; 95% CI, 1.25-7.10) increased the odds of patient refusal of off-label prescribing; however, prescribers' years in practice decreased the odds (OR, 0.98; 95% CI, 0.96-1). CONCLUSIONS: Off-label prescribing of psychotropic medications is common among child and adolescent psychiatrists in Japan. Furthermore, the psychiatrists' experiences with patient refusal of off-label prescribing were significantly associated with informing the parents/patients about off-label prescribing, particularly with regard to use of antidepressants. Further studies are required to support the development of decision making among clinicians. PMID- 26103534 TI - Supramolecular modeling of mono-copper enzyme active sites with calix[6]arene based funnel complexes. AB - Supramolecular bioinorganic chemistry is a natural evolution in biomimetic metallic systems since it constitutes a further degree of complexity in modeling. The traditional approach consisting of mimicking the first coordination sphere of metal sites proved to be very efficient, because valuable data are extracted from these examples to gain insight in natural systems mechanisms. But it does not reproduce several specific aspects of enzymes that can be mimicked by the implementation of a cavity embedding the labile active site and thus controlling the properties of the metal ion by noncovalent interactions. This Account reports on a strategy aimed at reproducing some supramolecular aspects encountered in the natural systems. The cavity complexes described herein display a coordination site constructed on a macrocycle. Thanks to a careful design of the cavity-based ligands, complexes orienting their labile site specifically toward the inside of the macrocycle were obtained. The supramolecular systems are based on the flexible calix[6]arene core that surrounds the metal ion labile site, thereby constraining exogenous molecules to pass through the conic funnel to reach the metal center. Such an architecture confers to the metal ion very unusual properties and behaviors, which in many aspects are biologically relevant. Three generations of calix[6]-based ligands are presented and discussed in the context of modeling the monocopper sites encountered in some enzymes. A wide range of phenomena are highlighted such as the impact that the size and shape of the access channel to the metal center have on the selectivity and rate of the binding process, the possible remote control of the electronics through small modifications operated on the cavity edges, induced-fit behavior associated with host-guest association (shoe-tree effect) that affects the redox properties of the metal ion and the electron exchange pathway, consequences of forbidden associative ligand exchange allowing a redox switch to drive an "antithermodynamic" ligand exchange, drastic effects of the full control of the second coordination sphere, and dioxygen activation in a confined chamber conducted to a selective and unusual four-electron redox process. All these findings bring new clues for better understanding the control exerted by the proteic environment on a metal center, allow the identification of new reaction pathways, and lead to new proposals for enzymatic catalytic cycle (such as the formation of an alkylhydroperoxide intermediate for mononuclear Cu-hydroxylases). The supramolecular systems may also be exploited for designing highly selective and sensitive probes for molecules of particular function and shape or to design new selective catalysts. PMID- 26103535 TI - Molecular characterisation of Bacillus thuringiensis strain MEB4 highly toxic to the Mediterranean flour moth Ephestia kuehniella Zeller (Lepidoptera: Pyralidae). AB - BACKGROUND: Cry2 proteins play an essential role in current Bacillus thuringiensis (Bt) applications and in the prevention of insect resistance to Cry1A toxins. This paper reports on the screening and characterisation of novel Bt strains harbouring effective cry2A-type genes and higher insecticidal activity to Ephestia kuehniella. RESULTS: A total of 29 native Bt strains were screened to search for the potent strain against E. kuehniella. The plasmid pattern of the selected strains showed interesting variability. PCR-RFLP analysis of two amplified regions showed high sequence identity within the selected cry2A-type genes. SDS-PAGE and western blot analysis revealed the presence of Cry2Aa toxin only in the MEB4 and BLB240 strains. The activation of Cry2Aa protoxins by larval midgut juice, trypsin or chymotrypsin enzymes revealed significant differences in terms of proteolysis profiles. Interestingly, a 49 kDa band was detected in the proteolysis pattern of BLB240, suggesting the presence of a chymotrypsin cleavage site that might have affected its insecticidal activity. Further, bioassays demonstrated that MEB4 (103.08 +/- 36 ug g(-1)) was more active than BLB240 (153.77 +/- 45.65 ug g(-1)) against E. kuehniella. CONCLUSION: Based on its potent insecticidal activity, the MEB4 strain could be considered to be an effective alternative agent for the control of E. kuehniella. PMID- 26103536 TI - Comparison of two approaches of INR-follow-up and determinants of INR-stability. AB - INTRODUCTION: Patients with atrial fibrillation (AF) and treated with coumarins need a close follow-up of the international normalized ratio (INR)-values. This can be done by the general practitioner (GP) or by a haematologist in an outpatient hospital clinic. OBJECTIVE: To compare both ways of follow-up and to investigate determinants of stable INR-patterns. METHODS: Cross-sectional single centre study in patients with AF treated at the UZ Brussel, a university hospital in Brussels. Of the 113 patients included in the study, 71 had their INR followed up by their GP and 42 similar patients were followed-up by a haematologist. Data of these 113 patients were further analysed to identify possible determinants for stable INR-values. RESULTS: The time in therapeutic range (TTR) did not significantly differ between both groups. However, patients in the GP-group had significantly more INR-values under 2.0 compared to patients from the haematologist-group (P = 0.044), whereas patients in the haematologist-group had significantly more INR-values above 3.0 compared to patients from the GP-group (P = 0.038). Reimbursement costs of both ways of follow-up were comparable, but the out-of-pocket costs for the patient were lower in the GP-group. The time since AF diagnosis was the only significant determinant predicting a higher TTR. CONCLUSION: Both approaches of follow-up seem to lead to the same TTR, yielding no reason to advocate one approach above the other. However, the patient costs were lower when followed-up by the GP. PMID- 26103537 TI - Prevalence and risk factors of low bone mineral density in patients with multiple sclerosis. AB - OBJECTIVES: To determine the prevalence and risk factors of low bone mineral density (BMD) in patients with multiple sclerosis (MS). METHODS: Patients with MS who had undergone a BMD evaluation via dual-energy X-ray absorptiometry (DXA) between January 2010 and December 2013 were included in the study. Descriptive data, BMD values, and risk factors for osteoporosis along with the details regarding MS, such as age at onset, duration of disease, clinical type of MS, expanded disability status scale (EDSS) scores, and lifetime steroid intake were obtained from the medical record database and telephone interview. RESULTS: The study group comprised 67 patients with a mean age of 41.1 +/- 10.2 years. Of the patients, 20.9% revealed low BMD for chronological age. Vitamin D insufficiency (25(OH)D < 20 ng/ml) rate was 86.6%. Comorbidity and EDSS scores of patients with low BMD were significantly higher than those of the remaining patients (P = 0.000 and P = 0.015, respectively). Neck BMD was inversely correlated with comorbidity score, disease duration, relapse number, and lifetime steroid intake (r = - 0.270, r = - 0.263, r = - 0.359, and r = - 0.314, respectively). CONCLUSION: The current study revealed that low BMD and vitamin D insufficiency were common in patients with MS. Longer disease duration, higher comorbidity score, and severe disability level led to lower BMD values. In conclusion, it is of paramount importance for clinicians to pay more attention on bone health in MS and to tailor preventative measures meticulously. PMID- 26103538 TI - Inflammatory markers and cardiometabolic diseases. AB - OBJECTIVES: A growing body of evidence emerges that obesity, metabolic syndrome, type 2 diabetes and cardiovascular disease are intimately related to chronic inflammation. METHODS: A narrative review summarizing the most recent data of the literature describing the pathological implications of inflammation in obese patients with cardiometabolic disorders. RESULTS: Besides high-sensitive C reactive protein, various circulating or in situ inflammatory markers have been identified, presumably reflecting the presence of inflammation in various key organs (visceral adipose tissue, skeletal muscle, pancreatic islets, liver, intestine, arterial wall). Available data support the concept that targeting inflammation, not only reduces systemic inflammatory markers, but also improves insulin sensitivity and ameliorates glucose control in insulin-resistant patients, thus potentially reducing the risk of cardiovascular complications. CONCLUSION: These observations confirm the role of inflammation in cardiometabolic diseases and support the development of pharmacological strategies that aim at reducing inflammation, especially in patients with type 2 diabetes. PMID- 26103539 TI - Hoarseness revealing Ortner's syndrome. AB - Hoarseness is a common phenomenon that can be caused by uncommon pathology. One seldom cause is Ortner's syndrome, a rare cardiovocal disease that can lead to hoarseness due to left recurrent laryngeal nerve palsy induced by mechanical compression of the nerve by cardiovascular structures. This case report describes a case of a 41-year-old woman with sudden onset of hoarseness. The patient had known pulmonary hypertension and Eisenmenger's syndrome. PMID- 26103540 TI - Thrombolytic therapy regimens for prosthetic valve thrombosis. PMID- 26103541 TI - Primary role of thrombolysis in the prosthetic valve thrombosis. PMID- 26103542 TI - Compound heterozygosity for hemoglobins S and D. PMID- 26103543 TI - Do Tumor Necrosis Factor (TNF) Inhibitors Improve the Glycemic Control in Patients with Rheumatoid Arthritis and Concomitant Diabetes Mellitus? AB - Inflammation and insulin resistance are closely linked to each other. Inflammatory rheumatic diseases including rheumatoid arthritis (RA) are associated with increased insulin resistance and reduced insulin sensitivity by virtue of proinflammatory cytokines, mainly tumor necrosis factor alpha (TNF alpha). TNF inhibitors have been shown to improve the insulin sensitivity and reduce the risk of incident diabetes in patients with RA. We hypothesize that TNF inhibitors may improve the glycemic control in patients with concomitant RA and diabetes mellitus. PMID- 26103544 TI - Magnetic fields suppress Pseudomonas aeruginosa biofilms and enhance ciprofloxacin activity. AB - Due to the refractory nature of pathogenic microbial biofilms, innovative biofilm eradication strategies are constantly being sought. Thus, this study addresses a novel approach to eradicate Pseudomonas aeruginosa biofilms. Magnetic nanoparticles (MNP), ciprofloxacin (Cipro), and magnetic fields were systematically evaluated in vitro for their relative anti-biofilm contributions. Twenty-four-hour biofilms exposed to aerosolized MNPs, Cipro, or a combination of both, were assessed in the presence or absence of magnetic fields (Static one sided, Static switched, Oscillating, Static + oscillating) using changes in bacterial metabolism, biofilm biomass, and biofilm imaging. The biofilms exposed to magnetic fields alone exhibited significant metabolic and biomass reductions (p < 0.05). When biofilms were treated with a MNP/Cipro combination, the most significant metabolic and biomass reductions were observed when exposed to static switched magnetic fields (p < 0.05). The exposure of P. aeruginosa biofilms to a static switched magnetic field alone, or co-administration with MNP/Cipro/MNP + Cipro appears to be a promising approach to eradicate biofilms of this bacterium. PMID- 26103545 TI - Immune outcomes in the liver: Is CD8 T cell fate determined by the environment? AB - The liver is known for its tolerogenic properties. This unique characteristic is associated with persistent infection of the liver by the hepatitis B and C viruses. Improper activation of cellular adaptive immune responses within the liver and immune exhaustion over time both contribute to ineffective cytotoxic T cell responses to liver-expressed antigens in animal models, and likely play a role in incomplete clearance of chronic hepatitis virus infections in humans. However, under some conditions, functional immune responses can be elicited against hepatic antigens, resulting in control of hepatotropic infections. In order to develop improved therapeutics in immune-mediated chronic liver diseases, including viral hepatitis, it is essential to understand how intrahepatic immunity is regulated. This review focuses on CD8 T cell immunity directed towards foreign antigens expressed in the liver, and explores how the liver environment dictates the outcome of intrahepatic CD8 T cell responses. Potential strategies to rescue unresponsive CD8 T cells in the liver are also discussed. PMID- 26103546 TI - Population data of 17 Y-STR haplotypes in Jining Han population from Shandong province, East China. PMID- 26103547 TI - Hsp47 mediates Cx43-dependent skeletal growth and patterning in the regenerating fin. AB - Skeletal morphogenesis describes how bones achieve their correct shape and size and appropriately position joints. We use the regenerating caudal fin of zebrafish to study this process. Our examination of the fin length mutant short fin (sof (b123)) has revealed that the gap junction protein Cx43 is involved in skeletal morphogenesis by promoting cell proliferation and inhibiting joint formation, thereby coordinating skeletal growth and patterning. Here we demonstrate that serpinh1b is molecularly and functionally downstream of cx43. The gene serpinh1b codes for a protein called Hsp47, a molecular chaperone responsible for proper folding of procollagen molecules. Knockdown of Hsp47 in regenerating fins recapitulates the sof (b123) phenotypes of reduced fin length, reduced segment length and reduced level of cell proliferation. Furthermore, Hsp47 knockdown affects the organization and localization of the collagen-based actinotrichia. Together, our findings reveal that serpinh1b acts in a cx43 dependent manner to regulate cell proliferation and joint formation. We conclude that disruption of the collagen-based extracellular matrix influences signaling events required for cell proliferation, as well as the patterning of skeletal precursor cells that influences segment length. Therefore, we suggest that Hsp47 function is necessary for skeletal growth and patterning during fin regeneration. PMID- 26103548 TI - The vascular niche in adult neurogenesis. AB - Blood vessels (BVs) not only serve as conduits for oxygen and nutrients but may also fulfill perfusion-independent functions. A growing body of data suggests that blood vessels are an integral component of stem cell niches, including stem cell niches in the adult brain. This review summarizes in vivo studies supporting the contention that blood vessels may indeed control function of neuronal stem cells (NSCs) residing in the two major neurogenic niches of the adult brain, namely the sub-ventricular zone and the hippocampus. The review discusses different modes of BV-NSC communication and possible mechanisms by which BV may modulate NSC behavior and responses to external stimuli. PMID- 26103549 TI - The Drosophila blood-brain barrier as interface between neurons and hemolymph. AB - The blood-brain barrier is an evolutionary ancient structure that provides direct support and protection of the nervous system. In all systems, it establishes a tight diffusion barrier that hinders uncontrolled paracellular diffusion into the nervous system. In invertebrates, the blood-brain barrier separates the nervous system from the hemolymph. Thus, the barrier-forming cells need to actively import ions and nutrients into the nervous system. In addition, metabolic or environmental signals from the external world have to be transmitted across the barrier into the nervous system. The first blood-brain barrier that formed during evolution was most likely based on glial cells. Invertebrates as well as primitive vertebrates still have a purely glial-based blood-brain barrier. Here we review the development and function of the barrier forming glial cells at the example of Drosophila. PMID- 26103552 TI - Middle East respiratory syndrome coronavirus in healthcare settings. AB - PURPOSE OF REVIEW: Attracting global attention, Middle East respiratory syndrome coronavirus (MERS-CoV) continues to cause sporadic cases and a potential risk of healthcare-associated infections. In this review, we highlight what is known about the risk of transmission within healthcare facilities and discuss interventions to halt its transmission within healthcare. RECENT FINDINGS: MERS CoV causes a wide range of infections from asymptomatic infections, mild or moderately symptomatic cases, to fatal disease. Two years after the initial reported case, MERS-CoV has caused limited disease outside the Arabian Peninsula with several cases in Europe, Asia, and the United States. Epidemiologically, these infections are linked to exposures from the region and their diagnosis outside is related to travel. Several reported clusters of disease report multiple transmissions of MERS-CoV within healthcare settings that have been attributed to poor compliance with the basic infection control measures. Factors contributing to the spread and control of MERS-CoV within healthcare settings have not been elucidated so far. Data suggest the overcrowding, late recognition of MERS-CoV cases, and inadequate infection control practices contribute significantly to the transmission. SUMMARY: Understanding factors contributing to the spread and the dynamic of MERS-CoV transmission within healthcare settings would further enhance the control of the disease in and outside the healthcare setting. PMID- 26103554 TI - Identification and functional characterisation of a novel KCNJ2 mutation, Val302del, causing Andersen-Tawil syndrome. AB - Loss-of-function mutations of the KCNJ2 gene encoding for the inward rectifier potassium channel subunit Kir2.1 cause Andersen-Tawil Syndrome (ATS), a rare genetic disorder characterised by periodic paralysis, ventricular arrhythmias, and dysmorphic features. Clinical manifestations of the disease appear to vary greatly with the nature of mutation, therefore, functional characterisation of ATS-causing mutations is of clinical importance. In this study, we describe the identification and functional analysis of a novel KCNJ2 mutation, Val302del, identified in a patient with ATS. Heterologously expressed wild type (WT) and Val302del mutant alleles showed similar subcellular distribution of the Kir2.1 protein with high intensity labelling from the membrane region, demonstrating normal membrane trafficking of the Val302del Kir2.1 variant. Cells transfected with the WT allele displayed a robust current with strong inward rectification, while no current above background was detected in cells expressing the Val302del Kir2.1 subunit. Co-transfection of CHO cells with the WT and the Val302del Kir2.1 revealed a dose-dependent inhibitory effect of the Val302del Kir2.1 mutant subunit on WT Kir2.1 currents. These observations indicate that the WT and the Val302del mutant subunits co-assemble in the cell membrane and that the mutation affects potassium conductivity and (or) gating of the WT/Val302del heteromeric Kir2.1 channels. PMID- 26103555 TI - Achieving Systemic and Scalable Private Sector Engagement in Tuberculosis Care and Prevention in Asia. PMID- 26103556 TI - Roles of leptin and ghrelin in adipogenesis and lipid metabolism of rainbow trout adipocytes in vitro. AB - Leptin and ghrelin are important regulators of energy homeostasis in mammals, whereas their physiological roles in fish have not been fully elucidated. In the present study, the effects of leptin and ghrelin on adipogenesis, lipolysis and on expression of lipid metabolism-related genes were examined in rainbow trout adipocytes in vitro. Leptin expression and release increased from preadipocytes to mature adipocytes in culture, but did not affect the process of adipogenesis. While ghrelin and its receptor were identified in cultured differentiated adipocytes, ghrelin did not influence either preadipocyte proliferation or differentiation, indicating that it may have other adipose-related roles. Leptin and ghrelin increased lipolysis in mature freshly isolated adipocytes, but mRNA expression of lipolysis markers was not significantly modified. Leptin significantly suppressed the fatty acid transporter-1 expression, suggesting a decrease in fatty acid uptake and storage, but did not affect expression of any of the lipogenesis or beta-oxidation genes studied. Ghrelin significantly increased the mRNA levels of lipoprotein lipase, fatty acid synthase and peroxisome proliferator-activated receptor-beta, and thus appears to stimulate synthesis of triglycerides as well as their mobilization. Overall, the study indicates that ghrelin, but not leptin seems to be an enhancer of lipid turn-over in adipose tissue of rainbow trout, and this regulation may at least partly be mediated through autocrine/paracrine mechanisms. The mode of action of both hormones needs to be further explored to better understand their roles in regulating adiposity in fish. PMID- 26103557 TI - Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity. AB - Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie-rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo-adiponectinemia have been linked to the pathophysiology of the obesity-related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders. PMID- 26103558 TI - En Bloc Resection of a Giant Cell Tumor in the Sacrum via a Posterior-Only Approach Without Nerve Root Sacrifice: Technical Case Report. AB - BACKGROUND AND IMPORTANCE: Giant cell tumors (GCTs) are rare primary bone neoplasms. The best long-term prognosis is achieved via complete tumor excision, but this feat is challenging in the spine due to proximity of blood vessels and nervous tissue. When occurring in the sacrum, GCTs have been removed in an en bloc fashion via combined anterior/posterior approaches, oftentimes with nerve root sacrifice. The purpose of this article is to present a case of a single staged, posterior-only approach for en bloc resection of a sacral GCT without nerve root sacrifice. CLINICAL PRESENTATION: A 45-year-old female presented with intractable lower back and leg pain, saddle anesthesia, and lower extremity weakness. She underwent imaging studies, which revealed a lesion involving the S1 and S2 vertebral bodies. Computed tomography guided biopsy revealed the lesion to be a GCT. The patient underwent a posterior-only approach without nerve root sacrifice to achieve an en bloc resection, followed by lumbopelvic reconstruction. CONCLUSION: Sacrectomy via a single-staged posterior approach with nerve root preservation is a challenging yet feasible procedure for the treatment of giant cell tumors in carefully selected patients. PMID- 26103559 TI - Clinical and Radiographic Evaluation of Immediate Loaded Dental Implants With Local Application of Melatonin: A Preliminary Randomized Controlled Clinical Trial. AB - Immediate loading of dental implants in situations where low bone density exist, such as the posterior maxillary region, became possible recently after the introduction of biomimetic agents. This 1-year preliminary clinical trial was carried out to clinically and radiographically evaluate immediate-loaded 1-piece implants with local application of melatonin in the osteotomy site as a biomimetic material. 14 patients with missing maxillary premolars were randomized to receive 14 implants of 1-piece type that were subjected to immediate loading after 2 weeks of initial placement. Group I included 7 implants with acid-etched surface while group II included 7 implants with acid-etched surface combined with local application of melatonin gel at the osteotomy site. Patients were recalled for follow up at 1, 3, 6, and 12 months after loading. All implants were considered successful after 12 months of follow-up. Significant difference (P < 0.05) was found between both groups at 1 month of implant loading when considering the implant stability. At 1 and 3 months there were significant differences in the marginal bone level between the 2 groups. These results suggest that the local application of melatonin at the osteotomy site is associated with good stability and minimal bone resorption. However, more studies for longer follow-up periods are required to confirm the effect of melatonin hormone on osseointegration of dental implants. PMID- 26103560 TI - Inflammasome activity is essential for one kidney/deoxycorticosterone acetate/salt-induced hypertension in mice. AB - BACKGROUND AND PURPOSE: Inflammasomes are multimeric complexes that facilitate caspase-1-mediated processing of the pro-inflammatory cytokines IL-1beta and IL 18. Clinical hypertension is associated with renal inflammation and elevated circulating levels of IL-1beta and IL-18. Therefore, we investigated whether hypertension in mice is associated with increased expression and/or activation of the inflammasome in the kidney, and if inhibition of inflammasome activity reduces BP, markers of renal inflammation and fibrosis. EXPERIMENTAL APPROACH: Wild-type and inflammasome-deficient ASC(-/-) mice were uninephrectomized and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt). Control mice were uninephrectomized but received a placebo pellet and water. BP was measured by tail cuff; renal expression of inflammasome subunits and inflammatory markers was measured by real-time PCR and immunoblotting; macrophage and collagen accumulation was assessed by immunohistochemistry. KEY RESULTS: 1K/DOCA/salt induced hypertension in mice was associated with increased renal mRNA expression of inflammasome subunits NLRP3, ASC and pro-caspase-1, and the cytokine, pro-IL 1beta, as well as protein levels of active caspase-1 and mature IL-1beta. Following treatment with 1K/DOCA/salt, ASC(-/-) mice displayed blunted pressor responses and were also protected from increases in renal expression of IL-6, IL 17A, CCL2, ICAM-1 and VCAM-1, and accumulation of macrophages and collagen. Finally, treatment with a novel inflammasome inhibitor, MCC950, reversed hypertension in 1K/DOCA/salt-treated mice. CONCLUSIONS AND IMPLICATIONS: Renal inflammation, fibrosis and elevated BP induced by 1K/DOCA/salt treatment are dependent on inflammasome activity, highlighting the inflammasome/IL-1beta pathway as a potential therapeutic target in hypertension. PMID- 26103561 TI - The C-terminal alpha-helix of YsxC is essential for its binding to 50S ribosome and rRNAs. AB - YsxC is an essential P-loop GTPase that interacts with the 50S subunit of the ribosome. The putative implication in ribosome binding of two basic clusters of YsxC, a conserved positively charged patch including R31, R116, H117 and K146 lying adjacent to the nucleotide-binding site, and the C-terminal alpha helix, was investigated. C-terminal truncation variants of YsxC were unable to bind to both ribosome and rRNAs, whereas mutations in the other cluster did not affect YsxC binding. Our results indicate that the basic C-terminal region of YsxC is required for its binding to the 50S ribosomal subunit. PMID- 26103563 TI - Reviewing the relevance of fluorescence in biological systems. AB - Fluorescence is emitted by diverse living organisms. The analysis and interpretation of these signals may give information about their physiological state, ways of communication among species and the presence of specific chemicals. In this manuscript we review the state of the art in the research on the fluorescence emitted by plant leaves, fruits, flowers, avians, butterflies, beetles, dragonflies, millipedes, cockroaches, bees, spiders, scorpions and sea organisms and discuss its relevance in nature. PMID- 26103562 TI - Towards combinatorial mixing devices without any pumps by open-capillary channels: fundamentals and applications. AB - In chemistry, biology, medical sciences and pharmaceutical industries, many reactions have to be checked by transporting and mixing expensive liquids. For such purposes, microfluidics systems consisting of closed channels with external pumps have been useful. However, the usage has been limited because of high fabrication cost and need for a fixed setup. Here, we show that open-capillary channels, which can be fabricated outside a clean room on durable substrates and are washable and reusable, are considerably promising for micro-devices that function without pumps, as a result of detailed studies on the imbibition of open micro-channels. We find that the statics and dynamics of the imbibition follow simple scaling laws in a wide and practical range; although a precursor film obeying a universal dynamics appears in the vertical imbibition, it disappears in the horizontal mode to make the design of complex micro-channel geometry feasible. We fabricate micro open-channel devices without any pumps to express the green fluorescent protein (GFP) by transporting highly viscous solutions and to accomplish simultaneous chemical reactions for the Bromothymol blue (BTB) solution. We envision that open-capillary devices will become a simple and low cost option to achieve microfluidic devices that are usable in small clinics and field studies. PMID- 26103564 TI - Inclusion of human immunodeficiency virus Type 2 (HIV-2) in a multiplex transcription-mediated amplification assay does not affect detection of HIV-1 and hepatitis B and C virus genotypes: a multicenter performance evaluation study. AB - BACKGROUND: The Ultrio Elite assay (Hologic/Grifols) runs on the Panther blood screening system and is comparable to the Ultrio Plus assay apart from the addition of oligonucleotides for human immunodeficiency virus Type 2 (HIV-2) detection. In this multicenter evaluation study the analytical sensitivity and genotype detection efficiency of the two assay versions were compared. STUDY DESIGN AND METHODS: The analytical sensitivity and genotype detection efficiency were analyzed by replicate (18-303) testing of 27 hepatitis B virus (HBV), hepatitis C virus (HCV), HIV-1, and HIV-2 standard dilution panels calibrated in international units (IUs) and copies/mL. A wider range of subgenotypes was tested at 25 copies/mL. Specificity was evaluated in 30,756 donor samples. RESULTS: The 95% lower limits of detection (LODs) in Ultrio Elite assay on WHO standards were 4.6, 7.3, 23.5, and 23.3 IU/mL for HBV, HCV, HIV-1, and HIV-2, respectively, and ranged from 13 to 44, 7 to 23, 6 to 15, and 9 copies/mL on genotype panels of the respective viruses. Comparable LODs had been previously found on the same panels with the Ultrio Plus assay. The specificity was 99.95% on initial test and 100% in the repeat test algorithm. CONCLUSION: The change in the oligonucleotide design of the Ultrio Elite assay to enable HIV-2 detection has not affected the analytical sensitivity for the other viruses regardless of the genotype. Genotype reference panels are instrumental to compare the sensitivity of nucleic acid test assay versions and could serve as an alternative to seroconversion panels. PMID- 26103565 TI - An Evaluation of the Feasibility and Safety of a Home-Based Telemental Health Treatment for Posttraumatic Stress in the U.S. Military. AB - BACKGROUND: Although home-based telemental health options have the potential to greatly expand the range of services available to U.S. military service members, there remains a need to demonstrate that home-based care is technically feasible, safe, and effective and meets the military health system's standards of care before widespread implementation can be achieved. The purpose of this preliminary study was to evaluate the feasibility and safety of providing U.S. military service members with a behavioral health treatment delivered directly to the home using videoconferencing. MATERIALS AND METHODS: Ten previously deployed soldiers volunteered to complete eight sessions of a novel behavioral activation treatment for posttraumatic stress disorder. The primary clinical outcomes assessed included symptoms of posttraumatic stress and depression. Patient safety data and attitudes about seeking mental health services, treatment satisfaction, treatment adherence, and treatment compliance were also assessed. RESULTS: Clinically significant reductions in posttraumatic stress symptom severity and depression symptoms were observed. Soldiers indicated high levels of satisfaction with the treatment, and there were no adverse events requiring activation of emergency safety procedures. Technical problems associated with the network were observed but successfully mitigated. CONCLUSIONS: The results provide initial support for the feasibility and safety of telemental health treatments delivered by videoconferencing to the homes of soldiers. The optimal technical infrastructure needs to be determined to support expansion of synchronous videoconferencing capabilities to the home. The findings provide preliminary evidence of the feasibility, safety, and high user satisfaction with home-based telemental health in the military setting. PMID- 26103566 TI - Fresh WNT into the regulation of mitosis. AB - Canonical Wnt signaling triggering beta-catenin-dependent gene expression contributes to cell cycle progression, in particular at the G1/S transition. Recently, however, it became clear that the cell cycle can also feed back on Wnt signaling at the G2/M transition. This is illustrated by the fact that mitosis specific cyclin-dependent kinases can phosphorylate the Wnt co-receptor LRP6 to prime the pathway for incoming Wnt signals when cells enter mitosis. In addition, there is accumulating evidence that various Wnt pathway components might exert additional, Wnt-independent functions that are important for proper regulation of mitosis. The importance of Wnt pathways during mitosis was most recently enforced by the discovery of Wnt signaling contributing to the stabilization of proteins other than beta-catenin, specifically at G2/M and during mitosis. This Wnt mediated stabilization of proteins, now referred to as Wnt/STOP, might on one hand contribute to maintaining a critical cell size required for cell division and, on the other hand, for the faithful execution of mitosis itself. In fact, most recently we have shown that Wnt/STOP is required for ensuring proper microtubule dynamics within mitotic spindles, which is pivotal for accurate chromosome segregation and for the maintenance of euploidy. PMID- 26103567 TI - Analysis of Alpha-2 Macroglobulin from the Long-Lived and Cancer-Resistant Naked Mole-Rat and Human Plasma. AB - BACKGROUND: The naked mole-rat (NMR) is a long-lived and cancer resistant species. Identification of potential anti-cancer and age related mechanisms is of great interest and makes this species eminent to investigate anti-cancer strategies and understand aging mechanisms. Since it is known that the NMR expresses higher liver mRNA-levels of alpha 2-macroglobulin than mice, nothing is known about its structure, functionality or expression level in the NMR compared to the human A2M. RESULTS: Here we show a comprehensive analysis of NMR- and human plasma-A2M, showing a different prediction in glycosylation of NMR-A2M, which results in a higher molecular weight compared to human A2M. Additionally, we found a higher concentration of A2M (8.3+/-0.44 mg/mL vs. and 4.4+/-0.20 mg/mL) and a lower total plasma protein content (38.7+/-1.79 mg/mL vs. 61.7+/ 3.20 mg/mL) in NMR compared to human. NMR-A2M can be transformed by methylamine and trypsin resulting in a conformational change similar to human A2M. NMR-A2M is detectable by a polyclonal antibody against human A2M. Determination of tryptic and anti-tryptic activity of NMR and human plasma revealed a higher anti-tryptic activity of the NMR plasma. On the other hand, less proteolytic activity was found in NMR plasma compared to human plasma. CONCLUSION: We found transformed NMR-A2M binding to its specific receptor LRP1. We could demonstrate lower protein expression of LRP1 in the NMR liver tissue compared to human but higher expression of A2M. This was accompanied by a higher EpCAM protein expression as central adhesion molecule in cancer progression. NMR-plasma was capable to increase the adhesion in human fibroblast in vitro most probably by increasing CD29 protein expression. This is the first report, demonstrating similarities as well as distinct differences between A2M in NMR and human plasma. This might be directly linked to the intriguing phenotype of the NMR and suggests that A2M might probably play an important role in anti-cancer and the anti-aging mechanisms in the NMR. PMID- 26103568 TI - Association Study of IL-12B Polymorphisms Susceptibility with Ankylosing Spondylitis in Mainland Han Population. AB - OBJECTIVE: This study aims to determine whether the genetic polymorphisms of IL 12B gene is a susceptibility factor to Ankylosing spondylitis (AS) in mainland Han Chinese population. METHOD: Eight single-nucleotide polymorphisms (SNPs) (rs10045431, rs11167764, rs3212227, rs6556412, rs6556416, rs6871626, rs6887695 and rs7709212) in the IL-12B gene were genotyped by iMLDR Assay technology in 400 patients [96% (384/400) HLA-B27(+)] and 395 geographically and ethnically matched healthy controls in mainland Han Chinese population. The correlation between IL 12B genetic polymorphisms and AS activity index (BASDAI, BASFI) were tested. RESULTS: The significant difference was found in genotype distribution between AS and healthy controls (chi2 = 6.942, P-value = 0.031) of the SNP rs6871626. Furthermore, significant evidence was also detected under the recessive model for minor allele A. The AA genotype carrier had 1.830 fold risk compared with C allele carrier (with CC and AC genotypes) [OR (95% CI) = 1.830 (1.131-2.961), P value = 0.014]. Nevertheless, the difference was no longer significant after Bonferroni correction. Subset analysis on cases with HLA-B27(+) did find the same results. Three genotypic groups (AA, CC and CA) in rs6871626 site was highly associated with the BASDAI and BASFI (P-value = 0.012 and P-value = 0.023, respectively), after adjustment for effect of age, sex, and disease duration, the P-value was 0.031 and 0.041, respectively. The AA genotype of rs6871626 was also significantly correlated with an increased BASDAI and BASFI compared to the AC and CC genotypes in AS patients. CONCLUSION: Our findings suggest that rs6871626 may be associated AS susceptibility and with disease activity (BASDAI, BASFI) in mainland Han Chinese population. PMID- 26103571 TI - Comment on: 'Trends in the lifetime risk of developing cancer in Great Britain: comparison of risk for those born from 1930 to 1960'--cancer predictions need more context. PMID- 26103570 TI - Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. AB - BACKGROUND: The natural history of prostate cancer is highly variable and difficult to predict accurately. Better markers are needed to guide management and avoid unnecessary treatment. In this study, we validate the prognostic value of a cell cycle progression score (CCP score) independently and in a prespecified linear combination with standard clinical variables, that is, a clinical-cell cycle-risk (CCR) score. METHODS: Paraffin sections from 761 men with clinically localized prostate cancer diagnosed by needle biopsy and managed conservatively in the United Kingdom, mostly between 2000 and 2003. The primary end point was prostate cancer death. Clinical variables consisted of centrally reviewed Gleason score, baseline PSA level, age, clinical stage, and extent of disease; these were combined into a single predefined risk assessment (CAPRA) score. Full data were available for 585 men who formed a fully independent validation cohort. RESULTS: In univariate analysis, the CCP score hazard ratio was 2.08 (95% CI (1.76, 2.46), P<10(-13)) for one unit change of the score. In multivariate analysis including CAPRA, the CCP score hazard ratio was 1.76 (95% CI (1.44, 2.14), P<10(-6)). The predefined CCR score was highly predictive, hazard ratio 2.17 (95% CI (1.83, 2.57), chi(2)=89.0, P<10(-20)) and captured virtually all available prognostic information. CONCLUSIONS: The CCP score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment. PMID- 26103572 TI - Reproductive and hormonal factors and mortality among women with colorectal cancer in the NIH-AARP Diet and Health Study. AB - BACKGROUND: Although use of menopausal hormone therapy (MHT) and some reproductive factors have been associated with colorectal cancer (CRC) risk, relations between these factors and survival after CRC diagnosis are unclear. METHODS: Among 2053 post-menopausal women diagnosed with incident CRC in the NIH AARP Diet and Health Study, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards regression to test associations between oral contraceptive (OC) use, menarche age, age at first birth, parity, menopausal age, and MHT use with all-cause and CRC-specific mortality. RESULTS: There were 759 deaths (332 CRC-related deaths) over a median follow-up of 7.7 years. We observed no statistically significant associations between OC use, menarche age, age at first birth, parity, menopausal age, and mortality. Compared with never MHT use, former use was not associated with mortality, but we found an inverse association among baseline current users, for both all-cause (HR=0.79, 95% CI 0.66-0.94) and CRC mortality (0.76, 0.59-0.99). CONCLUSION: Future studies should further focus on the mechanisms by which exogenous oestrogen exposure might affect tumour progression and CRC survival. PMID- 26103569 TI - MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M SKIP project. AB - BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype. PMID- 26103573 TI - Personal history of rosacea and risk of incident cancer among women in the US. AB - BACKGROUND: Rosacea is an inflammatory skin disease. We examined the association between personal history of rosacea and risk of incident cancers. METHODS: A total of 75 088 whites were included from the Nurses' Health Study II (1991 2011). Information on clinician-diagnosed rosacea and diagnosis year was collected in 2005. All cancers other than basal cell carcinoma (BCC) were confirmed. RESULTS: During 1 447 205 person-years, we identified 5194 cases with internal malignancies and 5788 with skin cancers. We did not observe significant associations between personal history of rosacea and internal malignancies, except for thyroid cancer (hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.07-2.36). Among skin cancers, personal history of rosacea was associated with an elevated risk of BCC (HR=1.50, 95% CI=1.35-1.67). CONCLUSIONS: We suggest possible associations between personal history of rosacea and an increased risk of thyroid cancer and BCC. Further studies are warranted to replicate our findings and to explore the underlying mechanisms. PMID- 26103575 TI - [Time to work for the increase of newly graduated physicians' salaries]. PMID- 26103574 TI - Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN negative prostate cancer. AB - BACKGROUND: Survivin and monoamine oxidase A (MAOA) levels are elevated in prostate cancer (PCa) compared to normal prostate glands. However, the relationship between survivin and MAOA in PCa is unclear. METHODS: We examined MAOA expression in the prostate lobes of a conditional PTEN-deficient mouse model mirroring human PCa, with or without survivin knockout. We also silenced one gene at a time and examined the expression of the other. We further evaluated the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCa cells. RESULTS: Survivin and MAOA levels are both increased in clinical PCa tissues and significantly associated with patients' survival. Survivin depletion delayed MAOA increase during PCa progression, and silencing MAOA decreased survivin expression. The combination of MAOA inhibitors and the survivin suppressants (YM155 and SC144) showed significant synergy on the inhibition of PCa cell growth, migration and invasion with concomitant decrease in survivin and MMP-9 levels. CONCLUSIONS: There is a positive feedback loop between survivin and MAOA expression in PCa. Considering that survivin suppressants and MAOA inhibitors are currently available in clinical trials and clinical use, their synergistic effects in PCa support a rapid translation of this combination to clinical practice. PMID- 26103576 TI - [Whooping cough--time to reconsider the vaccination program]. PMID- 26103577 TI - [Life-threatening bed capacity shortage requiring urgent action. The minister of healthcare should appoint a crisis commission]. PMID- 26103578 TI - [Work is in progress for higher wages]. PMID- 26103579 TI - Attitudes of Medical Students From Different Countries About Organ Donation. AB - OBJECTIVES: Although there have been some case studies that measure the medical students' knowledge and attitude about organ donation, there is no such global survey in the literature. MATERIALS AND METHODS: An online questionnaire was prepared to measure the knowledge and attitudes about organ donation. RESULTS: A total of 1541 medical students from 104 different countries responded to the questionnaire. The participants who have received education before were more successful, had a higher self-donation rate, and showed a more-positive attitude toward organ donation than did those who did not receive an education, or a higher self-donation rate, or a more-positive attitude toward organ donation. Opposition against promotion of the organ donation by medical doctors was more widespread among men, preclinical students, African participants, and participants who did not support organ donation. The two most important decisions about increasing the level of organ donation involved in achieving support of the media and the education of the health care workers. CONCLUSIONS: Educational programs would improve the knowledge and attitudes of medical students about organ donation and transplantation. PMID- 26103581 TI - A chiral phosphoric acid catalyst for asymmetric construction of 1,3-dioxanes. AB - A novel method of enantioselective 1,3-dioxane construction via a hemiacetalization/intramolecular oxy-Michael addition cascade by a chiral phosphoric acid catalyst was developed. The product was successfully transformed into an optically active 1,3-polyol motif, indicating that the proposed reaction can provide useful chiral building blocks for the de novo synthesis of polyketides. PMID- 26103580 TI - Long-Term Exposure to Ambient Air Pollution and Metabolic Syndrome in Adults. AB - Air pollutants (AP) play a role in subclinical inflammation, and are associated with cardiovascular morbidity and mortality. Metabolic syndrome (MetS) is inflammatory and precedes cardiovascular morbidity and type 2 diabetes. Thus, a positive association between AP and MetS may be hypothesized. We explored this association, (taking into account, pathway-specific MetS definitions), and its potential modifiers in Swiss adults. We studied 3769 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, reporting at least four-hour fasting time before venepuncture. AP exposures were 10-year mean residential PM10 (particulate matter <10MUm in diameter) and NO2 (nitrogen dioxide). Outcomes included MetS defined by World Health Organization (MetS-W), International Diabetes Federation (MetS-I) and Adult Treatment Panel-III (MetS-A) using four- and eight-hour fasting time limits. We also explored associations with individual components of MetS. We applied mixed logistic regression models to explore these associations. The prevalence of MetS-W, MetS-I and MetS-A were 10%, 22% and 18% respectively. Odds of MetS-W, MetS-I and MetS-A increased by 72% (51-102%), 31% (11-54%) and 18% (4-34%) per 10MUg/m3 increase in 10-year mean PM10. We observed weaker associations with NO2. Associations were stronger among physically-active, ever-smokers and non-diabetic participants especially with PM10 (p<0.05). Associations remained robust across various sensitivity analyses including ten imputations of missing observations and exclusion of diabetes cases. The observed associations between AP exposure and MetS were sensitive to MetS definitions. Regarding the MetS components, we observed strongest associations with impaired fasting glycemia, and positive but weaker associations with hypertension and waist-circumference-based obesity. Cardio-metabolic effects of AP may be majorly driven by impairment of glucose homeostasis, and to a less strong extent, visceral adiposity. Well-designed prospective studies are needed to confirm these findings. PMID- 26103583 TI - Cyclodextrin and phosphorus(III): a versatile combination for coordination chemistry and catalysis. AB - With the advent of efficient methods for functionalising cyclodextrins, the synthesis of a variety of cyclodextrin-based P(iii) ligands has been made possible. Capable of acting both as first and second coordination sphere ligands towards various transition metals, these compounds have found many applications in homogeneous catalysis. This perspective article describes the different approaches that have been used to covalently associate the ubiquitous P(iii) donor atom with a cyclodextrin cavity. In addition, special emphasis is placed on the influence the cyclodextrin receptor has on the coordination and catalytic properties of these cavity-shaped ligands. PMID- 26103582 TI - Discovery of Dark pH-Dependent H(+) Migration in a [NiFe]-Hydrogenase and Its Mechanistic Relevance: Mobilizing the Hydrido Ligand of the Ni-C Intermediate. AB - Despite extensive studies on [NiFe]-hydrogenases, the mechanism by which these enzymes produce and activate H2 so efficiently remains unclear. A well-known EPR active state produced under H2 and known as Ni-C is assigned as a Ni(III)-Fe(II) species with a hydrido ligand in the bridging position between the two metals. It has long been known that low-temperature photolysis of Ni-C yields distinctive EPR-active states, collectively termed Ni-L, that are attributed to migration of the bridging-H species as a proton; however, Ni-L has mainly been regarded as an artifact with no mechanistic relevance. It is now demonstrated, based on EPR and infrared spectroscopic studies, that the Ni-C to Ni-L interconversion in Hydrogenase-1 (Hyd-1) from Escherichia coli is a pH-dependent process that proceeds readily in the dark-proton migration from Ni-C being favored as the pH is increased. The persistence of Ni-L in Hyd-1 must relate to unassigned differences in proton affinities of metal and adjacent amino acid sites, although the unusually high reduction potentials of the adjacent Fe-S centers in this O2 tolerant hydrogenase might also be a contributory factor, impeding elementary electron transfer off the [NiFe] site after proton departure. The results provide compelling evidence that Ni-L is a true, albeit elusive, catalytic intermediate of [NiFe]-hydrogenases. PMID- 26103584 TI - Validation of a New Counter for Direct Observation of Physical Activity in Parks. AB - PURPOSE: This study aims to examine the reliability of a 12-button counter to simultaneously assess physical activity (PA) by age and gender subgroups in park settings. METHODS: A total of 1,160 pairs of observations were conducted in 481 target areas of 19 neighborhood parks in the great Los Angeles, California, area between June 2013 and March 2014. Interrater reliability was assessed by Pearson's correlation, intraclass correlation (ICC), and agreement probability in metabolic equivalents (METs). Cosine similarity was used to check the resemblance of distributions among age and gender categories. Pictures taken in a total of 112 target areas at the beginning of the observations were used as a second reliability check. RESULTS: Interrater reliability was high for the total METs and METs in all age and gender categories (between 0.82 and 0.97), except for male seniors (correlations and ICC between 0.64 and 0.77, agreement probability 0.85 to 0.86). Reliability was higher for total METs than for METs spent in moderate-to-vigorous PA. Correlation and ICC between observers' measurement and picture-based counts are also high (between 0.79 and 0.94). CONCLUSION: Trained observers can reliably use the 12-button counter to accurately assess PA distribution and disparities by age and gender. PMID- 26103585 TI - FliL associates with the stator to support torque generation of the sodium-driven polar flagellar motor of Vibrio. AB - Flagellar motors generate torque to rotate flagellar filaments and drive bacterial cells. Each motor is composed of a rotor and many stators. The stator is a force-generating complex that converts ion flux into torque. Previous reports have suggested that the membrane protein FliL is located near the stator and is involved in torque generation. We investigated the role of FliL in the sodium-driven polar flagellar motor of Vibrio alginolyticus. Our results revealed that FliL is a cytoplasmic membrane protein and is located at the base of flagellum. The deletion of fliL did not affect the cell morphology or flagellation but resulted in a significant decrease of swimming speed, especially at a higher load thus suggesting that FliL is important for torque generation at high load conditions. Furthermore, the polar localization of the stator was decreased in a DeltafliL mutant, but the sodium-dependent assembly of the stator complex was still retained. The polar localization of FliL was lost in the absence of the stator complex, indicating that FliL interacts directly or indirectly with the stator. Our results suggest that FliL is localized along with the stator in order to support the motor functioning for swimming at high load conditions by maintaining the stator assembly. PMID- 26103586 TI - Successful use of reduced-intensity conditioning and matched-unrelated hematopoietic stem cell transplant in a child with Diamond-Blackfan anemia and cirrhosis. AB - For patients with DBA who are transfusion dependent, HSCT is the only cure. Chronic transfusions can lead to cirrhosis secondary to iron overload, making them poor candidates for myeloablative HSCT. RIC regimens are associated with lower morbidity and mortality compared to myeloablative regimens, but use of RIC in DBA has been limited. Here we present a 14-yr-old girl with DBA and multiple comorbidities including liver cirrhosis, who underwent MUD HSCT utilizing a RIC regimen that is novel to this condition. She tolerated the regimen well, and at 21 months, she remains transfusion independent with chimerisms at 99%. PMID- 26103587 TI - Blood Plasma TGF- beta1 Concentration in Sporadic Dilatative Pathology of Ascending Aorta: More Questions than Answers. AB - Transforming growth factor beta1 (TGF- beta1) is a cytokine that participates in a broad range of cellular regulatory processes and is associated with various diseases including aortic aneurysm. Increased TGF- beta1 levels are associated with Marfan syndrome (MFS) caused by FBN1 mutations and subsequent defects in signaling system. We studied TGF- beta1 levels in 62 patients with sporadic, non syndromic, dilatative pathology of ascending aorta (DPAA) and in reference group subjects (n = 212). An initial screening of 212 reference individuals identified TGF- beta1 gender discrepancies and age-dependent cytokine increase in women. Patients with DPAA had increased levels of TGF- beta1 in comparison to reference group subjects (median 7.7 ng/ml, range 2.1-25.3, and median 6.2 ng/ml, range 1.0 33.1, respectively). There is a significant association between TGF-beta1 concentration and DPAA (OR 1.084, CI 1.027-1.144, p = 0.004) but the mechanisms of cause and effect have not been established yet. Slightly increased TGF-beta1 concentrations in patients with sporadic DPAA in comparison to the reference subjects show a potential use of TGF-beta1 as a biomarker for the disease. However, cytokine dependence on age, gender, and other unknown factors among individuals with no cardiovascular complains reduces its specificity for DPAA. We would also like to raise awareness regarding the choice of methods when measuring TGF-beta1 levels with an emphasis on preanalytical phase and the choice of sample. PMID- 26103588 TI - Correction: Improved Lower Bounds of DNA Tags Based on a Modified Genetic Algorithm. PMID- 26103590 TI - Mechanism of the Aerobic Homocoupling of Phenylboronic Acid on Au20-: A DFT Study. AB - The mechanism of the gold nanocluster-catalyzed aerobic homocoupling of arylboronic acids has been elucidated by means of DFT calculations with Au20(-) as a model cluster for the Au:[poly(N-vinylpyrrolidin-2-one)] catalyst. We found that oxygen affects the adsorption of phenylboronic acid and, by lowering the energy barrier, a water molecule enhances dissociation of the C-B bond, which is probably the rate-determining step. The key role of oxygen is in activating the surface of the gold cluster by generating Lewis acidic sites for adsorption and activation of the phenylboronic acid, leading to the formation of biphenyl through a superoxo-like species. Moreover, the oxygen adsorbed on the Au nanocluster can act as an oxidant for phenylboronic acid, giving phenol as a byproduct. As shown by NBO analysis, the basic aqueous reaction medium facilitates the reductive elimination process by weakening the Au-C bond, thereby enhancing the formation of biphenyl. The coupling of phenyl and reductive elimination of biphenyl occur at the top or facet site with low-energy-barrier through spillover of phenyl group on Au NC. The present findings are useful for the interpretation or design of other coupling reactions with Au NC. PMID- 26103589 TI - Complete Chloroplast Genome of Tanaecium tetragonolobum: The First Bignoniaceae Plastome. AB - Bignoniaceae is a Pantropical plant family that is especially abundant in the Neotropics. Members of the Bignoniaceae are diverse in many ecosystems and represent key components of the Tropical flora. Despite the ecological importance of the Bignoniaceae and all the efforts to reconstruct the phylogeny of this group, whole chloroplast genome information has not yet been reported for any members of the family. Here, we report the complete chloroplast genome sequence of Tanaecium tetragonolobum (Jacq.) L.G. Lohmann, which was reconstructed using de novo and referenced-based assembly of single-end reads generated by shotgun sequencing of total genomic DNA in an Illumina platform. The gene order and organization of the chloroplast genome of T. tetragonolobum exhibits the general structure of flowering plants, and is similar to other Lamiales chloroplast genomes. The chloroplast genome of T. tetragonolobum is a circular molecule of 153,776 base pairs (bp) with a quadripartite structure containing two single copy regions, a large single copy region (LSC, 84,612 bp) and a small single copy region (SSC, 17,586 bp) separated by inverted repeat regions (IRs, 25,789 bp). In addition, the chloroplast genome of T. tetragonolobum has 38.3% GC content and includes 121 genes, of which 86 are protein-coding, 31 are transfer RNA, and four are ribosomal RNA. The chloroplast genome of T. tetragonolobum presents a total of 47 tandem repeats and 347 simple sequence repeats (SSRs) with mononucleotides being the most common and di-, tri-, tetra-, and hexanucleotides occurring with less frequency. The results obtained here were compared to other chloroplast genomes of Lamiales available to date, providing new insight into the evolution of chloroplast genomes within Lamiales. Overall, the evolutionary rates of genes in Lamiales are lineage-, locus-, and region-specific, indicating that the evolutionary pattern of nucleotide substitution in chloroplast genomes of flowering plants is complex. The discovery of tandem repeats within T. tetragonolobum and the presence of divergent regions between chloroplast genomes of Lamiales provides the basis for the development of markers at various taxonomic levels. The newly developed markers have the potential to greatly improve the resolution of molecular phylogenies. PMID- 26103591 TI - Therapeutic Community Treatment of an Inmate Population with Substance Use Disorders: Post-Release Trends in Re-Arrest, Re-Incarceration, and Drug Misuse Relapse. AB - This systematic literature review maps the evidence for the effectiveness of the therapeutic community interventions (TCI) in reducing re-arrest, re-incarceration or drug misuse following release from prison, including the extent to which these effects are retained over time. The databases searched for the review included PsychINFO, Medline and Scopus and reference lists from relevant articles published between 2007 and 2014. Only quantitative studies that examined the effectiveness of TCI for a prisoner population with drug dependence at the time of initial incarceration were considered. Fourteen studies were identified for inclusion in the review. Three-quarters of the studies reported TCI were effective in reducing rates of re-incarceration. About 70% of studies that examined follow-up rates of drug misuse relapse found TCI effective in reducing rates of drug misuse amongst participants. TCI participation reduced re-arrests events in 55% of the studies. Results suggest TCI effective in the short-term rather than longer term for reducing rates of re-incarceration among participants, and to a slightly lesser extent, drug misuse relapse. PMID- 26103592 TI - Social Support, Stigma and Disclosure: Examining the Relationship with HIV Medication Adherence among Ryan White Program Clients in the Mid-South USA. AB - Social support from friends and family is positively related to better health outcomes among adults living with HIV. An extension of these networks such as religious communities may be an untapped source of social support for promoting HIV medical adherence. This paper explores the association of HIV medication adherence to satisfaction with support from family, friends and church members, as well as HIV-related stigma, and HIV disclosure. In partnership with the Shelby County Health Department, the Memphis Ryan White Part A Program, and the University of Memphis School of Public Health, a total of 286 interviewer administered surveys were conducted with Ryan White clients. Seventy-six percent (n = 216) of participants reported being prescribed antiretroviral medication (ARVs). Nearly all participants (n = 202, 94%) prescribed ARVs reported disclosing their HIV status to someone. Almost 20% (n = 40) of those prescribed ARVs reported not being satisfied with support received from his/her church. Interestingly, participants reported rarely experiencing stigma as a result of their HIV status. The extent to which satisfaction with support from personal networks and institutional settings like the church affect medication adherence is yet to be understood. The complexity of HIV disclosure and HIV stigma in relation to these supports warrants further investigation to understand how best to improve HIV health outcomes. PMID- 26103593 TI - Determinants of suicidal ideation in gynecological cancer patients. AB - OBJECTIVE: Gynecological cancer survivors are at increased risk of psychological problems including suicide risk. Suicidal ideation, which was thought to be precursor to suicide attempts, has not been well studied. This study aimed to investigate the prevalence, and determinants of suicidal ideation for women with gynecological cancer, and then to assess the effect of coping style and social support on suicidal ideation. METHODS: Patients with cervical, ovarian and endometrial cancers seen at Hunan Provincial Tumor Hospital from September 2012 to June 2013 were consecutively recruited and were asked to complete the Zung Self-Rating Depression Scale, Suicidal Ideation of Self-rating Scale, Medical Coping Modes Questionnaire and Social Support Rating Scale. Path analysis was used to examine the relationship among coping style, social support, depression symptoms and suicidal ideation. RESULTS: A total of 579 (579/623, 93.0%) gynecological cancer patients were enrolled in this study and completed all investigations between September 2012 and June 2013. Among them, 105 (18.1%) patients reported suicidal ideation, with the highest rate in patients with ovarian cancer (30.16%). Suicidal ideation was associated with depression symptoms, care providers, chemotherapy history and acceptance-resignation. Path analysis showed that the acceptance-resignation affected suicidal ideation directly as well as mediated by social support and depression symptoms, while confrontation and avoidance affected suicidal ideation entirely through social support and depression symptoms. CONCLUSIONS: Suicidal ideation is high among patients with gynecological cancer, especially among ovarian cancer patients. Coping strategies such as confrontation and avoidance, and social support may be helpful for preventing suicidal ideation among them. PMID- 26103594 TI - Confirmatory factor analyses of DSM-5 posttraumatic stress disorder symptoms in psychiatric samples differing in Criterion A status. AB - We examined the symptom structure of posttraumatic stress disorder (PTSD), as defined by American Psychiatric Association (2013. Diagnostic and statistical manual of mental disorders (DSM-5) (5th ed.). Washington, DC: Author). DSM-5 introduced notable changes to PTSD criteria, and the structural impact of these changes is unclear. We conducted confirmatory factor analyses comparing seven commonly investigated or recently proposed PTSD models in a large sample of interviewed psychiatric outpatients reporting a Criterion A trauma (n = 310) or a sub-threshold (non-Criterion A) stressful life event (n = 284). A novel six factor dysphoria model and recently proposed seven-factor hybrid model outperformed other models and fit the data equally well in both groups. Our results suggest equal fit for both models, although the six-factor model is more parsimonious. These results have implications for research regarding the mechanisms underlying and the treatments targeting PTSD. PMID- 26103595 TI - Application of 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole in analysis: Fluorescent dyes and unexpected reaction with tertiary amines. AB - 4-Chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) is widely applied as a fluorescent tagging reagent in biochemistry, as a derivatization agent in analytical chemistry, and as a component for design of fluorescent nanoparticles. Four new 7-nitrobenzo-2-oxa-1,3-diazole (NBD)-tagged polyamines containing two to four amine moieties were synthesized and used as an effective tool for staining of siliceous frustules of the diatom algae and spicules of the siliceous sponges, including fossilized samples. An unexpected reaction between NBD-Cl and tertiary amine groups was found, giving rise to NBD-tagged amines with elimination of an alkyl group. The reaction proceeds through the Meisenheimer complex and quaternary salt, which transform to the product by Hofmann reaction (alkene elimination) or nucleophilic substitution (halogenated compound formation). In the case of polyamines, NBD-Cl causes chain scissoring, giving a set of NBD tagged amines. The found NBD-Cl reaction with tertiary amines must be taken into account when using NBD-Cl and similar activated aromatic systems for amine derivatization in analytical and biochemistry applications. The reaction with polyamines opens the way to libraries of NBD-tagged compounds. PMID- 26103597 TI - CFA-7: an interpenetrated metal-organic framework of the MFU-4 family. AB - The novel interpenetrated metal-organic framework CFA-7 (Coordination Framework Augsburg University-7), [Zn5Cl4(tqpt)3], has been synthesized containing the organic linker {H2-tqpt = 6,6,14,14-tetramethyl-6,14-dihydroquinoxalino[2,3 b]phenazinebistriazole}. Reaction of H2-tqpt and anhydrous ZnCl2 in N,N dimethylformamide (DMF) yields CFA-7 as pseudo-cubic crystals. CFA-7 serves as precursor for the synthesis of isostructural frameworks with redox-active metal centers, which is demonstrated by postsynthetic metal exchange of Zn(2+) by different M(2+) (M = Co, Ni, Cu) ions. The novel framework is robust upon solvent removal and has been structurally characterized by single-crystal X-ray diffraction, TGA and IR spectroscopy, as well as gas sorption (Ar, CO2 and H2). PMID- 26103596 TI - Relative distribution of virulence-associated factors among Australian bovine Staphylococcus aureus isolates: Potential relevance to development of an effective bovine mastitis vaccine. PMID- 26103598 TI - Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D-first study. AB - Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/MUL for NK cells and 347/MUL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP. PMID- 26103599 TI - A case of "order insensitivity"? Natural and artificial language processing in a man with primary progressive aphasia. AB - Processing of linear word order (linear configuration) is important for virtually all languages and essential to languages such as English which have little functional morphology. Damage to systems underpinning configurational processing may specifically affect word-order reliant sentence structures. We explore order processing in WR, a man with primary progressive aphasia (PPA). In a previous report, we showed how WR showed impaired processing of actives, which rely strongly on word order, but not passives where functional morphology signals thematic roles. Using the artificial grammar learning (AGL) paradigm, we examined WR's ability to process order in non-verbal, visual sequences and compared his profile to that of healthy controls, and aphasic participants with and without severe syntactic disorder. Results suggested that WR, like some other patients with severe syntactic impairment, was unable to detect linear configurational structure. The data are consistent with the notion that disruption of possibly domain-general linearization systems differentially affects processing of active and passive sentence structures. Further research is needed to test this account, and we suggest hypotheses for future studies. PMID- 26103601 TI - Syntax, action verbs, action semantics, and object semantics in Parkinson's disease: Dissociability, progression, and executive influences. AB - Several studies have recently shown that basal ganglia (BG) deterioration leads to distinctive impairments in the domains of syntax, action verbs, and action semantics. In particular, such disruptions have been repeatedly observed in Parkinson's disease (PD) patients. However, it remains unclear whether these deficits are language-specific and whether they are equally dissociable from other reported disturbances -viz., processing of object semantics. To address these issues, we administered linguistic, semantic, and executive function (EFs) tasks to two groups of non-demented PD patients, with and without mild cognitive impairment (PD-MCI and PD-nMCI, respectively). We compared these two groups with each other and with matched samples of healthy controls. Our results showed that PD patients exhibited linguistic and semantic deficits even in the absence of MCI. However, not all domains were equally related to EFs and MCI across samples. Whereas EFs predicted disturbances of syntax and object semantics in both PD-nMCI and PD-MCI, they had no impact on action-verb and action-semantic impairments in either group. Critically, patients showed disruptions of action-verb production and action semantics in the absence of MCI and without any executive influence, suggesting a sui generis deficit present since early stages of the disease. These findings indicate that varied language domains are differentially related to the BG, contradicting popular approaches to neurolinguistics. PMID- 26103602 TI - Effects of Adjuvant Systems on the cardiovascular and respiratory functions in telemetered conscious dogs and anaesthetised rats. AB - Adjuvants Systems (AS) containing immunostimulant combinations are used in human vaccines. Safety pharmacology studies evaluated the cardiorespiratory effects of AS in conscious telemetered dogs and in anaesthetised rats. Sixteen telemetered beagle dogs (4/group) received intramuscular injections of saline at Day 0, and one clinical dose of AS01, AS03, AS04 or AS15 at Day 7 (7* the equivalent human dose on a bodyweight basis). Bodyweights were measured through Day 14 and cardiorespiratory parameters and body temperature through 72 h post-treatment. Anaesthetised rats (4/group) received one intravenous injection of AS01, AS03 or AS15 at 1 mL/kg bodyweight (140* the equivalent human dosages), or saline. Cardiorespiratory parameters were measured for 120 min post-dose. In dogs, food consumption and mean bodyweight decreased with AS03, and mean body temperature slightly increased with AS01, AS03 and AS15, but were not considered to be adverse. Cardiovascular effects (a slight, reversible increase in mean heart rate and shortened mean RR/PR/QT-intervals) were observed with AS15. No relevant clinical effects or effects on QRS-complex/QTc-interval durations, arterial pressure or respiratory parameters were observed. In rats, there were no consistent treatment-related effects. Collectively, this suggests that AS01, AS03, AS04 and AS15 are not associated with potentially deleterious effects on ventricular repolarisation, atrio/intra-ventricular conductivities or respiratory functions. PMID- 26103600 TI - Classification and clinicoradiologic features of primary progressive aphasia (PPA) and apraxia of speech. AB - The consensus criteria for the diagnosis and classification of primary progressive aphasia (PPA) have served as an important tool in studying this group of disorders. However, a large proportion of patients remain unclassifiable whilst others simultaneously meet criteria for multiple subtypes. We prospectively evaluated a large cohort of patients with degenerative aphasia and/or apraxia of speech using multidisciplinary clinical assessments and multimodal imaging. Blinded diagnoses were made using operational definitions with important differences compared to the consensus criteria. Of the 130 included patients, 40 were diagnosed with progressive apraxia of speech (PAOS), 12 with progressive agrammatic aphasia, 9 with semantic dementia, 52 with logopenic progressive aphasia, and 4 with progressive fluent aphasia, while 13 were unclassified. The PAOS and progressive fluent aphasia groups were least impaired. Performance on repetition and sentence comprehension was especially poor in the logopenic group. The semantic and progressive fluent aphasia groups had prominent anomia, but only semantic subjects had loss of word meaning and object knowledge. Distinct patterns of grey matter loss and white matter changes were found in all groups compared to controls. PAOS subjects had bilateral frontal grey matter loss, including the premotor and supplementary motor areas, and bilateral frontal white matter involvement. The agrammatic group had more widespread, predominantly left sided grey matter loss and white matter abnormalities. Semantic subjects had bitemporal grey matter loss and white matter changes, including the uncinate and inferior occipitofrontal fasciculi, whereas progressive fluent subjects only had left sided temporal involvement. Logopenic subjects had diffuse and bilateral grey matter loss and diffusion tensor abnormalities, maximal in the posterior temporal region. A diagnosis of logopenic aphasia was strongly associated with being amyloid positive (46/52 positive). Our findings support consideration of an alternative way of identifying and categorizing subtypes of degenerative speech and language disorders. PMID- 26103603 TI - Subject transfer BCI based on Composite Local Temporal Correlation Common Spatial Pattern. AB - In this paper, a subject transfer framework is proposed for the classification of Electroencephalogram (EEG) signals in brain-computer interfaces (BCIs). This study introduces a modification of Common Spatial Pattern (CSP) for subject transfer BCIs, where similar characteristics are considered to transfer knowledge from other subjects' data. With this aim, we proposed a new approach based on Composite Local Temporal Correlation CSP, namely Composite LTCCSP with selected subjects, which considers the similarity between subjects using Frobenius distance. The performance of the proposed method is compared with different methods like traditional CSP, Composite CSP, LTCCSP and Composite LTCCSP. Experimental results have shown that our proposed method has increased the performance compared to all these different methods. Furthermore, our results suggest that it is worth emphasizing the data of subjects with similar characteristics in a subject transfer diagram. The suggested framework, as demonstrated by experimental results, can obtain a positive knowledge transfer for enhancing the performance of BCIs. PMID- 26103604 TI - Relationships of Childhood Adverse Experiences With Mental Health and Quality of Life at Treatment Start for Adult Refugees Traumatized by Pre-Flight Experiences of War and Human Rights Violations. AB - Adverse and potentially traumatic experiences (PTEs) in childhood were examined among 54 adult refugee patients with pre-flight PTEs of war and human rights violations (HRVs) and related to mental health and quality of life at treatment start. Extent of childhood PTEs was more strongly related to mental health and quality of life than the extent of war and HRV experiences. Childhood PTEs were significantly related to arousal and avoidance symptoms of posttraumatic stress disorder (PTSD) and to quality of life, whereas pre-flight war and HRV experiences were significantly related to reexperiencing symptoms of PTSD only. Within childhood adversities, experiences of family violence and external violence, but not of loss and illness, were significantly related to increased mental health symptoms and reduced quality of life. These results point to the importance of taking childhood adverse experiences into account in research and treatment planning for adult refugees with war and HRVs trauma. PMID- 26103606 TI - Ghrelin and atherosclerosis. AB - PURPOSE OF REVIEW: The increasing prevalence of metabolic syndrome and the consequent cardiovascular diseases has stimulated an active search for novel risk factors. The hormones regulating energy balance are of special interest as potential risk factor indicators of cardiovascular diseases. Ghrelin provides an attractive target for studies of atherosclerosis being a gastric peptide hormone having multiple functions including orexigenic and growth hormone-releasing effects and is also involved in the regulation of cardiovascular and immunomodulatory system. RECENT FINDINGS: The aim of the present article is to review recent studies on the role of ghrelin in the atherosclerosis. Ghrelin seems to influence known risk factors of atherosclerosis, endothelial dysfunction, inflammation and oxidation. These themes will be covered by the present article and a summary of clinical studies of ghrelin in atherosclerosis will be given. SUMMARY: Ghrelin plays a beneficial role in multiple processes of atherogenesis and vascular function. However, ghrelin's effects are not as strong as those of traditional known risk factors. PMID- 26103605 TI - What an anticardiovascular diet should be in 2015. AB - PURPOSE OF REVIEW: Given scientific and public debate about optimal diet to prevent cardiovascular disease, and interest in diet and other chronic diseases, we propose that following a few simple dietary principles would reduce chronic disease incidence. RECENT FINDINGS: Nutrition research has been criticized for focusing on individual nutrients and foods, treated like drug therapy. With a few important exceptions, clinical trials of supplemental nutrients have not shown benefit. Although highly specific nutrition information is elusive, diet patterns have provided consistent answers, important for public health. Observational cohort studies have found that some dietary patterns are reported with high reliability over long periods and predict future cardiovascular and other inflammatory-related diseases. Two randomized clinical trials confirmed this finding. There are many common features of Mediterranean and prudent diets, particularly the plant-centered aspect, coupled with variety of foods eaten. A dietary pattern characterized by high fruit, vegetable, legume, whole grain, nut, berry, seed, and fish intakes, and possibly by intakes of dairy, coffee, tea, chocolate, and alcohol (not in excess), but low meat and detrimentally processed foods is associated with reduced incidence of cardiovascular disease and rates of noncardiovascular, noncancer chronic inflammatory-related mortality. SUMMARY: A plant-centered diet may be broadly recommended. PMID- 26103607 TI - Proprotein convertases in atherogenesis. AB - PURPOSE OF REVIEW: The proprotein convertases subtilisin/kexin (PCSKs) are endoproteases identified as activators of precursors from hormones and peptides. On the basis of the variety of substrates and regulation in disease, they have been recognized as mediators in atherogenesis. The discovery of PCSK9, which regulates low-density lipoprotein receptor cell membrane availability, has led to a resurgence of interest in these enzymes and their function in cardiovascular diseases. RECENT FINDINGS: Recent data demonstrate that PCSKs are expressed in human atheroma and are regulated in animal models of atherosclerosis. In animal models, inhibition of PCSKs, such as PCSK3, affects cell proliferation and migration as well as inflammation, reducing atherosclerosis. In addition, targeting PCSK9 lowers cholesterol levels and has now been demonstrated to lessen vascular lesion formation in mice. Experimentally investigated novel anti-PCSK9 strategies include genome editing and vaccination. Furthermore, studies show that PCSKs contribute to the initiation and progression of cardiometabolic risk factors, such as insulin resistance and obesity. SUMMARY: PCSKs affect cardiovascular diseases on multiple levels, including atherosclerotic lesion formation as well as their contribution to cardiometabolic risk factors. PCSK9 is a key regulator of plasma cholesterol levels, thereby potentially affecting atherosclerosis and has rapidly emerged as a pharmacological target. PMID- 26103608 TI - Should we assess cardiovascular risk in young adults born preterm? AB - PURPOSE OF REVIEW: Eleven percent of infants are born preterm worldwide. Preterm infants continue their development and growth in a substantially different environment than in uterus. The prenatal and postnatal period have long-lasting effects on a child's health. Previous studies have shown that adults born preterm with very low birth weight show enhancement of cardiometabolic risk factors such as elevated blood pressure and impaired glucose regulation compared with their peers born at term. RECENT FINDINGS: Recent studies have more often included individuals born less preterm, as over 70% of premature infants are born late preterm (in 34-36 gestational weeks). Adults born preterm have elevated levels of cardiometabolic-risk factors concerning several aspects such as body size and composition, energy metabolism, blood pressure, vascular structure, glucose and lipid metabolism, lifestyle, and some emerging cardiometabolic-risk factors. SUMMARY: Most of the cardiometabolic-risk factors related to preterm birth are modifiable. Favorable early-life circumstances of premature infants, such as optimal nutrition and growth, might reduce the risk of later cardiometabolic disorders. In addition, adults born preterm might particularly benefit from screening of risk factors and promotion of a healthy lifestyle. PMID- 26103609 TI - Rapid emergence of atherosclerosis in Asia: a systematic review of coronary atherosclerotic heart disease epidemiology and implications for prevention and control strategies. AB - PURPOSE OF REVIEW: There is a global epidemic of coronary heart disease (CHD) caused by atherosclerosis. We discussed its emergence, underlying reasons, and implications for prevention and control strategies in Asia. RECENT FINDINGS: Most countries in Asia are experiencing the challenges from CHD, with the mortality rate varying from 103 to 366 per 100 000 adult populations, reported by recently published studies. Raised population cholesterol levels played a pivotal role. Men, older adults, and those with dyslipidemia, hypertension, and diabetes were high-risk individuals. During the past decade, there was a marked rising trend of atherosclerosis-related burden particularly in Eastern Asia where an alarming increase of 117.2 and 115.3% of total deaths and disability adjusted life-years, respectively, were observed. The rise of CHD could be attributed to unhealthy lifestyles, clinical-risk factors, psychosocial factors, and public health transitions. Ageing, urbanization, and increase in prosperity may serve as underlying key drivers. SUMMARY: The burden of CHD is substantial, whereas contributors are multifactorial. This grand challenge should be a top priority for injecting healthcare resources. The formulation of public health measures will need to adopt an integrated and life-course approach, based on the need and risks of different population subgroups in Asia. PMID- 26103610 TI - Dysbetalipoproteinemia: an extreme disorder of remnant metabolism. AB - PURPOSE OF REVIEW: Lipoprotein metabolism and the role of apolipoprotein E in the pathogenesis of dysbetalipoproteinemia. RECENT FINDINGS: Remnant lipoproteins, modulated by lifestyle and genetic factors, are atherogenic. Dysbetalipoproteinemia could be viewed as a monogenic disorder of remnant metabolism. SUMMARY: Elevated plasma triglyceride and cholesterol concentrations (mixed hyperlipidemias) are commonly encountered and dysbetaliproteinemia should be considered in this setting. Dysbetalipoproteinemia (remnant clearance disease, Fredrickson type III hyperlipidemia) is an uncommon dyslipoproteinemia related to mutations in apolipoprotein E that disrupt the clearance of remnants of triglyceride-rich lipoproteins; it may be overlooked because xanthomata of the skin and/or tendons occur in a minority of patients. The diagnosis ideally requires the demonstration of remnant lipoprotein accumulation and a genetic cause. Genotyping for apolipoprotein E2 may not prove the diagnosis as it may be associated with low plasma lipid values. The recent association of remnant lipoproteins with atherosclerosis along with many factors that modulate remnant lipoprotein metabolism underscores the importance of recognising dysbetalipoproteinemia as an extreme state of remnant lipoprotein accumulation. Although there may be some differences between remnants in the general population and dysbetalipoproteinemia, it is clear that remnants promote atherosclerosis. Current treatment strategies are adequate but new strategies could also be of benefit in dysbetalipoproteinemia. PMID- 26103611 TI - Importance of early recognition of heterozygous familial hypercholesterolaemia. AB - PURPOSE OF REVIEW: To outline recent updates in the diagnosis and management of heterozygous familial hypercholesterolaemia. RECENT FINDINGS: Recent guidelines have suggested that familial hypercholesterolaemia is vastly underdiagnosed in most countries worldwide. Improvements in next-generation sequencing have led to the detection of novel mutations and the cheaper cost of this technology makes the early identification of asymptomatic individuals a feasible option. With more widespread use of high doses of more potent statins in affected adults, cardiovascular mortality has decreased in adults with hypercholesterolaemia. SUMMARY: Barriers to cascade testing of relatives of index cases remain worldwide despite improvements in gene technology and the marked recent decrease in costs of genetic testing. Recent guidelines recommending screening of young children, for example, 8-10 years with measurement of LDL cholesterol concentrations will increase the diagnosis of familial hypercholesterolaemia among children but long term safety data of the use of statins in this young age group are not available. To date, the benefit of statin-induced decreases in LDL cholesterol concentration in children is based on effects of treatment on proxy measures of cardiovascular disease and not a reduction in cardiovascular events. PMID- 26103612 TI - Bariatric surgery, lipoprotein metabolism and cardiovascular risk. AB - PURPOSE OF REVIEW: To summarize recent epidemiological, preclinical and clinical studies on the effects of Roux-en-Y-gastric bypass (RYGBP) surgery on cardiovascular risk factors and the underlying mechanisms. RECENT FINDINGS: Although RYGBP has mechanical effects on the gastrointestinal tract, the reduced gastric pouch and intestinal calorie absorption cannot fully explain the metabolic improvements. SUMMARY: Obesity predisposes to cardiovascular risk factors such as dyslipidemia, type 2 diabetes, nonalcoholic fatty liver disease and hypertension. In contrast to the limited success of pharmacological and lifestyle interventions, RYGBP induces sustained weight loss, metabolic improvements and decreases morbidity/mortality. In line, RYGBP reduces cardiovascular risk factors. Although the mechanisms are not entirely understood, RYGBP induces complex changes in the gut affecting other organs through endocrine and metabolic signals from the intestine to all key metabolic organs, which can link RYGBP and decreased cardiovascular risk. Here, we discuss the roles of changes in lipid absorption and metabolism, bile acid metabolism, gut hormones and the microbiote as potential mechanisms in the decreased cardiovascular risk and metabolic improvement after RYGBP. PMID- 26103613 TI - Unintended positive and negative effects of drugs on lipoproteins. AB - PURPOSE OF REVIEW: Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism. RECENT FINDING: Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects. SUMMARY: Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear. PMID- 26103614 TI - How HDL protects LDL against atherogenic modification: paraoxonase 1 and other dramatis personae. AB - PURPOSE OF REVIEW: To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL. RECENT FINDINGS: Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties. SUMMARY: The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates. PMID- 26103615 TI - Finite-time boundedness and stabilization of uncertain switched neural networks with time-varying delay. AB - This paper deals with the finite-time boundedness and stabilization problem for a class of switched neural networks with time-varying delay and parametric uncertainties. Based on Lyapunov-like function method and average dwell time technique, some sufficient conditions are derived to guarantee the finite-time boundedness of considered uncertain switched neural networks. Furthermore, the state feedback controller is designed to solve the finite-time stabilization problem. Moreover, the proposed sufficient conditions can be simplified into the form of linear matrix equalities for conveniently using Matlab LMI toolbox. Finally, two numerical examples are given to show the effectiveness of the main results. PMID- 26103616 TI - Supporting malaria elimination with 21st century antimalarial agent drug discovery. AB - The burden of malaria has been considerably reduced over recent years. However, to achieve disease elimination, drug discovery for the next generation needs to focus on blocking disease transmission and on targeting the liver-stage forms of the parasite. Properties of the 'ideal' new antimalarial drug and the key scientific and technological advances that have led to recent progress in antimalarial drug discovery are reviewed. Using these advances, Novartis has built a robust pipeline of next-generation antimalarials. The preclinical and clinical development of two candidate drugs: KAE609 and KAF156, provide a framework for the path to breakthrough treatments that could be taking us a step closer to the vision of malaria elimination. PMID- 26103617 TI - Therapeutic approaches of magnetic nanoparticles for the central nervous system. AB - The diseases of the central nervous system (CNS) represent one of the fastest growing areas of concern requiring urgent medical attention. Treatment of CNS ailments is hindered owing to different physiological barriers including the blood-brain barrier (BBB), which limits the accessibility of potential drugs. With the assistance of a nanotechnology-based drug delivery strategy, the problems could be overcome. Recently, magnetic nanoparticles (MNPs) have proven immensely useful as drug carriers for site-specific delivery and as contrast agents owing to their magnetic susceptibility and biocompatibility. By utilizing MNPs, diagnosis and treatment of CNS diseases have progressed by overcoming the hurdles of the BBB. In this review, the therapeutic aspect and the future prospects related to the theranostic approach of MNPs are discussed. PMID- 26103618 TI - Ocular Trauma From Dog Bites: Characterization, Associations, and Treatment Patterns at a Regional Level I Trauma Center Over 11 Years. AB - PURPOSE: Canine bites frequently result in periocular injury. The authors aimed to further characterize the dog breeds, types of injuries inflicted, and treatment outcomes. METHODS: A retrospective chart review was performed on all dog bites recorded in the University of Washington trauma registry from 2003 to 2013. Cases involving ocular injury were further investigated to identify ocular tissues affected, treatment patterns, and outcomes. RESULTS: A total of 342 dog bite victims were identified, of whom 91 sustained ocular trauma (27%). The mean age of patients with ocular injuries was significantly lower than those without (14.1 +/- 1.9 vs. 30.0 +/- 1.3 years, p < 0.001). Children bitten by dogs were 4.2 times more likely to sustain ocular injuries than adults (45.2% vs. 10.8%). The most common breed of dog inflicting ocular injury was the pit bull (25%). Forty percent of patients with ocular trauma sustained canalicular lacerations and epiphora was noted in only 3 patients (8%) after repair. Three percent had orbital fractures and 2% sustained ruptured globes. Infections were rare, affecting only 2% of patients. CONCLUSIONS: To our knowledge, this study is the largest to date to report the incidence and characteristics of ocular injuries sustained from dog bites. These injuries were disproportionately more common in children and have a high incidence of canalicular laceration. Though rare, globe injuries and orbital fractures were seen in this population. Importantly, this study establishes that pit bulls are the most frequent breed associated with ocular injuries from dog bites. PMID- 26103619 TI - Altered distribution of ICa impairs Ca release at the t-tubules of ventricular myocytes from failing hearts. AB - In mammalian cardiac ventricular myocytes, Ca influx and release occur predominantly at t-tubules, ensuring synchronous Ca release throughout the cell. Heart failure is associated with disrupted t-tubule structure, but its effect on t-tubule function is less clear. We therefore investigated Ca influx and release at the t-tubules of ventricular myocytes isolated from rat hearts ~18weeks after coronary artery ligation (CAL) or corresponding Sham operation. L-type Ca current (ICa) was recorded using the whole-cell voltage-clamp technique in intact and detubulated myocytes; Ca release at t-tubules was monitored using confocal microscopy with voltage- and Ca-sensitive fluorophores. CAL was associated with cardiac and cellular hypertrophy, decreased ejection fraction, disruption of t tubule structure and a smaller, slower Ca transient, but no change in ryanodine receptor distribution, L-type Ca channel expression, or ICa density. In Sham myocytes, ICa was located predominantly at the t-tubules, while in CAL myocytes, it was uniformly distributed between the t-tubule and surface membranes. Inhibition of protein kinase A with H-89 caused a greater decrease of t-tubular ICa in CAL than in Sham myocytes; in the presence of H-89, t-tubular ICa density was smaller in CAL than in Sham myocytes. The smaller t-tubular ICa in CAL myocytes was accompanied by increased latency and heterogeneity of SR Ca release at t-tubules, which could be mimicked by decreasing ICa using nifedipine. These data show that CAL decreases t-tubular ICa via a PKA-independent mechanism, thereby impairing Ca release at t-tubules and contributing to the altered excitation-contraction coupling observed in heart failure. PMID- 26103620 TI - Transmission of Multidrug-Resistant and Drug-Susceptible Tuberculosis within Households: A Prospective Cohort Study. AB - BACKGROUND: The "fitness" of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug susceptible index patients. METHODS AND FINDINGS: This 3-y (2010-2013) prospective cohort household follow-up study in South Lima and Callao, Peru, measured the incidence of tuberculosis disease among 1,055 household contacts of 213 MDRTB index cases and 2,362 household contacts of 487 drug-susceptible index cases. A total of 35/1,055 (3.3%) household contacts of 213 MDRTB index cases developed tuberculosis disease, while 114/2,362 (4.8%) household contacts of 487 drug-susceptible index patients developed tuberculosis disease. The total follow up time for drug-susceptible tuberculosis contacts was 2,620 person-years, while the total follow-up time for MDRTB contacts was 1,425 person-years. Using multivariate Cox regression to adjust for confounding variables including contact HIV status, contact age, socio-economic status, and index case sputum smear grade, the hazard ratio for tuberculosis disease among MDRTB household contacts was found to be half that for drug-susceptible contacts (hazard ratio 0.56, 95% CI 0.34-0.90, p = 0.017). The inference of transmission in this study was limited by the lack of genotyping data for household contacts. Capturing incident disease only among household contacts may also limit the extrapolation of these findings to the community setting. CONCLUSIONS: The low relative fitness of MDRTB estimated by this study improves the chances of controlling drug-resistant tuberculosis. However, fitter multidrug-resistant strains that emerge over time may make this increasingly difficult. PMID- 26103621 TI - Kinetics of protein-ligand unbinding via smoothed potential molecular dynamics simulations. AB - Drug discovery is expensive and high-risk. Its main reasons of failure are lack of efficacy and toxicity of a drug candidate. Binding affinity for the biological target has been usually considered one of the most relevant figures of merit to judge a drug candidate along with bioavailability, selectivity and metabolic properties, which could depend on off-target interactions. Nevertheless, affinity does not always satisfactorily correlate with in vivo drug efficacy. It is indeed becoming increasingly evident that the time a drug spends in contact with its target (aka residence time) can be a more reliable figure of merit. Experimental kinetic measurements are operatively limited by the cost and the time needed to synthesize compounds to be tested, to express and purify the target, and to setup the assays. We present here a simple and efficient molecular-dynamics-based computational approach to prioritize compounds according to their residence time. We devised a multiple-replica scaled molecular dynamics protocol with suitably defined harmonic restraints to accelerate the unbinding events while preserving the native fold. Ligands are ranked according to the mean observed scaled unbinding time. The approach, trivially parallel and easily implementable, was validated against experimental information available on biological systems of pharmacological relevance. PMID- 26103622 TI - Cross section measurements of deuteron induced nuclear reactions on natural titanium up to 34 MeV. AB - Experimental cross sections for deuteron induced nuclear reactions on natural titanium were measured, using the stacked-foil technique and gamma spectrometry, up to 34 MeV with beams provided by the ARRONAX cyclotron. The experimental cross section values were monitored using the (nat)Ti(d,x)(48)V reaction, recommended by the IAEA. The excitation functions for (nat)Ti(d,x)(44m,46,47,48)Sc are presented and compared with the existing ones and with the TALYS 1.6 code calculations using default models. Our experimental values are in good agreement with data found in the literature. TALYS 1.6 is not able to give a good estimation of the production cross sections investigated in this work. These production cross sections of scandium isotopes fit with the new Coordinated Research Project (CRP) launched by the International Atomic Energy Agency (IAEA) to expand the database of monitor reactions. PMID- 26103623 TI - Uranium beam characterization at CIRCE for background and contamination determinations. AB - The Accelerator Mass Spectrometry (AMS) is the most sensitive technique, compared either to the Inductively Coupled Plasma (ICP-MS) or Thermal Ionization (TI-MS) mass spectrometer, for the actinide (e.g. (236)U, (x)Pu isotopes) measurements. They are present in environmental samples at the ultra trace level since atmospheric tests of Nuclear Weapons (NWs) performed in the past, deliberate dumping of nuclear waste, nuclear fuel reprocessing, on a large scale, and operation of Nuclear Power Plants (NPPs), on a small scale, have led to the release of a wide range of radioactive nuclides in the environment. At the Center for Isotopic Research on Cultural and Environmental heritage (CIRCE) in Caserta, Italy, an upgraded actinide AMS system, based on a 3-MV pelletron tandem accelerator, has been developed and routinely operated. At CIRCE a charge state distribution as a function of terminal voltage, the beam emittance, measured in the 20 degrees actinides dedicated beam line, as well as the energy and position validation of the U ions were performed in order to determine the best measurement conditions. A (236)U/(238)U isotopic ratio background level of about 5*10(-12) or 3*10(-13), depending on the Time of Flight-Energy (TOF-E) configurations, as well as the spatial distribution of the (235)U, (238)U interferences ions and a (236)U contamination mass of about 0.5 fg have been determined. PMID- 26103624 TI - Advanced Microcirculatory Parameters of Lower Extremity Free Flaps during Dangling and Their Influencing Factors. AB - BACKGROUND: Dangling of the leg to habituate a free flap to the lower extremity is common practice. However, little is known about the microcirculatory changes in free flaps and the influence of comorbidities. METHODS: Tissue oxygen saturation (StO2) and hemoglobin content (tissue hemoglobin index [THI]) of 39 lower extremity free flaps was measured during dangling on postoperative days (PODs) 6 to 9. We assessed the maximal desaturation during dangling and re elevation and the maximal increase in THI as well as the time required to reach a stable plateau during dangling, among others. RESULTS: All parameters showed significant changes during dangling (desaturation during dangling: 0.23 +/- 10.7 vs. - 4.66 +/- 12.6%, p = 0.001 for POD 6 vs. 7; further desaturation after re elevation: - 11.1 +/- 7.4 versus - 14.5 +/- 7.8%, p = 0.001 for POD 6 vs. 9; THI increase during dangling: from 3.4 +/- 1.6 to 4.2 +/- 1.8 AU, p = 0.008, time to THI plateau: 1.7 +/- 1.2 vs. 2.5 +/- 1.7 minutes, p = 0.004 for POD 6 vs. 7). Age, gender, and smoking did not influence the mentioned parameters. Nondiabetic patients showed a significant increase of baseline StO2, whereas diabetic patients did not (p = 0.009 vs. 0.11). For THI, both diabetic and hypertensive patients showed a lower increase in THI on the first day of dangling (p = 0.056; p = 0.009) and significantly lower baseline values on the last day (0.046 for both). CONCLUSION: Duration of dependency seems to have the greatest impact on microcirculation during dangling, although comorbidities may interfere with the adaptive processes. An earlier start of dangling could safely be applied in most patients. Special care needs to be taken in diabetic and hypertensive patients. PMID- 26103625 TI - Establishment of Magnetic Microparticles-Assisted Time-Resolved Fluoroimmunoassay for Determinating Biomarker Models in Human Serum. AB - In order to early screen and detect suspected biomarkers from pathogens and the human body itself, tracers or reaction strategies that can act as signal enhancers have been proposed forth at purpose. In this paper, we discussed the applicability of magnetic microparticles-assisted time-resolved fluoroimmunoassay (MMPs-TRFIA) for sensitive determination of potential analytes. Hepatitis B e antigen, antibody to hepatitis B surface antigen and free triiodothyronine were used as biomarker models to explore the reliability of the method. By coupling with bioprobes, MMPs were used as immunoassay carriers to capture target molecules. Under optimal condition, assay performance, including accuracy, precision and specificity, was outstanding and demonstrated satisfactory. To further evaluate the performance of the MMPs-TRFIA in patients, a total of 728 serum samples from hospital were analyzed for three biomarkers in parallel with the proposed method and chemiluminescence immunoassay kit commercially available. Fairly good agreements are obtained between the two methods via data analysis. Not only that but the reliability of MMPs-TRFIA has also been illustrated by three different reaction models. It is confirmed that the novel method modified with MMPs has been established and showed great potential applications in both biological detection and clinical diagnosis, including big molecule protein and low molecular weight haptens. PMID- 26103627 TI - On the role of the extracellular space on the holistic behavior of the brain. AB - Multiple players are involved in the brain integrative action besides the classical neuronal and astrocyte networks. In the past, the concept of complex cellular networks has been introduced to indicate that all the cell types in the brain can play roles in its integrative action. Intercellular communication in the complex cellular networks depends not only on well-delimited communication channels (wiring transmission) but also on diffusion of signals in physically poorly delimited extracellular space pathways (volume transmission). Thus, the extracellular space and the extracellular matrix are the main players in the intercellular communication modes in the brain. Hence, the extracellular matrix is an 'intelligent glue' that fills the brain and, together with the extracellular space, contributes to the building-up of the complex cellular networks. In addition, the extracellular matrix is part of what has been defined as the global molecular network enmeshing the entire central nervous system, and plays important roles in synaptic contact homeostasis and plasticity. From these premises, a concept is introduced that the global molecular network, by enmeshing the central nervous system, contributes to the brain holistic behavior. Furthermore, it is suggested that plastic 'brain compartments' can be detected in the central nervous system based on the astrocyte three-dimensional tiling of the brain volume and on the existence of local differences in cell types and extracellular space fluid and extracellular matrix composition. The relevance of the present view for neuropsychiatry is discussed. A glossary box with terms and definitions is provided. PMID- 26103626 TI - CXCL8 and CCL20 Enhance Osteoclastogenesis via Modulation of Cytokine Production by Human Primary Osteoblasts. AB - Generalized osteoporosis is common in patients with inflammatory diseases, possibly because of circulating inflammatory factors that affect osteoblast and osteoclast formation and activity. Serum levels of the inflammatory factors CXCL8 and CCL20 are elevated in rheumatoid arthritis, but whether these factors affect bone metabolism is unknown. We hypothesized that CXCL8 and CCL20 decrease osteoblast proliferation and differentiation, and enhance osteoblast-mediated osteoclast formation and activity. Human primary osteoblasts were cultured with or without CXCL8 (2-200 pg/ml) or CCL20 (5-500 pg/ml) for 14 days. Osteoblast proliferation and gene expression of matrix proteins and cytokines were analyzed. Osteoclast precursors were cultured with CXCL8 (200 pg/ml) and CCL20 (500 pg/ml), or with conditioned medium (CM) from CXCL8 and CCL20-treated osteoblasts with or without IL-6 inhibitor. After 3 weeks osteoclast formation and activity were determined. CXCL8 (200 pg/ml) and CCL20 (500 pg/ml) enhanced mRNA expression of KI67 (2.5-2.7-fold), ALP (1.6-1.7-fold), and IL-6 protein production (1.3-1.6 fold) by osteoblasts. CXCL8-CM enhanced the number of osteoclasts with 3-5 nuclei (1.7-fold), and with >5 nuclei (3-fold). CCL20-CM enhanced the number of osteoclasts with 3-5 nuclei (1.3-fold), and with >5 nuclei (2.8-fold). IL-6 inhibition reduced the stimulatory effect of CXCL8-CM and CCL20-CM on formation of osteoclasts. In conclusion, CXCL8 and CCL20 did not decrease osteoblast proliferation or gene expression of matrix proteins. CXCL8 and CCL20 did not directly affect osteoclastogenesis. However, CXCL8 and CCL20 enhanced osteoblast mediated osteoclastogenesis, partly via IL-6 production, suggesting that CXCL8 and CCL20 may contribute to osteoporosis in rheumatoid arthritis by affecting bone cell communication. PMID- 26103628 TI - Immunomodulatory activity of methanolic leaf extract of Moringa oleifera in Wistar albino rats. AB - BACKGROUND: Globally, Moringa oleifera is used by different communities to treat various ailments including modulation of the immune system though with limited scientific evidence. The aim was to study the immunomodulatory activity of M. oleifera methanolic leaf extract in Wistar albino rats. METHODS: An experimental laboratory-based study was done following standard methods and procedures. Nine experimental groups (I, II, III, IV, V, VI, VII, VIII, IX) each comprising of six animals were used. Group I received normal saline. Groups II to IX received 200 mg/kg bwt cyclophosphamide at the beginning of the study. Group III received 50 mg/kg bwt of an immunostimulatory drug levamisole. Groups IV to IX were dosed daily for 14 days with extract at doses of 250, 500, and 1000 mg/kg bwt, respectively, using an intragastric tube. Complete blood count (CBC), delayed type hypersensitivity reaction (DTH), neutrophil adhesion test, and hemagglutination antibody titer were determined using standard methods and procedures. Statistical analysis was performed using GraphPad prism 5.0a Software. RESULTS: There was an increment in WBC, lymphocyte, and neutrophil counts at a dose of 1000 mg/kg bwt similar to the levamisole-positive control group. The neutrophil adhesion was statistically significant (p<=0.05) for treatment groups that received 1000 mg/kg bwt (29.94%) and 500 mg/kg bwt at 17.28%. The mean percentage increment in footpad thickness was highest (26.9%) after 8 h of injection of antigen in the footpad of rats dosed 500 mg/kg bwt and this later reduced to 25.6% after 24 h. There was a dose-dependent increment in the mean hemagglutination antibody titer to sheep red blood cells (SRBC) from 10.73+/-0.57 HA units/MUL for the 250 mg/kg bwt to 26.22+/-1.70 HA units/MUL for the 1000 mg/kg bwt. CONCLUSIONS: Methanolic leaf extract of M. oleifera caused a significant immunostimulatory effect on both the cell-mediated and humoral immune systems in the Wistar albino rats. PMID- 26103629 TI - The impact of Tween 20 on repeatability of amyloid beta and tau measurements in cerebrospinal fluid. PMID- 26103630 TI - Analytical assessment of the novel homocysteine liquid enzymatic assay on Beckman Coulter AU5800. PMID- 26103631 TI - Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer. AB - Testicular germ cell cancer manifests mainly in young adults as a seminoma or non seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men. PMID- 26103632 TI - Metal bridges to probe membrane ion channel structure and function. AB - Ion channels are integral membrane proteins that undergo important conformational changes as they open and close to control transmembrane flux of different ions. The molecular underpinnings of these dynamic conformational rearrangements are difficult to ascertain using current structural methods. Several functional approaches have been used to understand two- and three-dimensional dynamic structures of ion channels, based on the reactivity of the cysteine side-chain. Two-dimensional structural rearrangements, such as changes in the accessibility of different parts of the channel protein to the bulk solution on either side of the membrane, are used to define movements within the permeation pathway, such as those that open and close ion channel gates. Three-dimensional rearrangements - in which two different parts of the channel protein change their proximity during conformational changes - are probed by cross-linking or bridging together two cysteine side-chains. Particularly useful in this regard are so-called metal bridges formed when two or more cysteine side-chains form a high-affinity binding site for metal ions such as Cd2+ or Zn2+. This review describes the use of these different techniques for the study of ion channel dynamic structure and function, including a comprehensive review of the different kinds of conformational rearrangements that have been studied in different channel types via the identification of intra-molecular metal bridges. Factors that influence the affinities and conformational sensitivities of these metal bridges, as well as the kinds of structural inferences that can be drawn from these studies, are also discussed. PMID- 26103634 TI - Transformer Incipient Fault Prediction Using Combined Artificial Neural Network and Various Particle Swarm Optimisation Techniques. AB - It is important to predict the incipient fault in transformer oil accurately so that the maintenance of transformer oil can be performed correctly, reducing the cost of maintenance and minimise the error. Dissolved gas analysis (DGA) has been widely used to predict the incipient fault in power transformers. However, sometimes the existing DGA methods yield inaccurate prediction of the incipient fault in transformer oil because each method is only suitable for certain conditions. Many previous works have reported on the use of intelligence methods to predict the transformer faults. However, it is believed that the accuracy of the previously proposed methods can still be improved. Since artificial neural network (ANN) and particle swarm optimisation (PSO) techniques have never been used in the previously reported work, this work proposes a combination of ANN and various PSO techniques to predict the transformer incipient fault. The advantages of PSO are simplicity and easy implementation. The effectiveness of various PSO techniques in combination with ANN is validated by comparison with the results from the actual fault diagnosis, an existing diagnosis method and ANN alone. Comparison of the results from the proposed methods with the previously reported work was also performed to show the improvement of the proposed methods. It was found that the proposed ANN-Evolutionary PSO method yields the highest percentage of correct identification for transformer fault type than the existing diagnosis method and previously reported works. PMID- 26103633 TI - SYTO-13, a Viability Marker as a New Tool to Monitor In Vitro Pharmacodynamic Parameters of Anti-Pneumocystis Drugs. AB - While Pneumocystis pneumonia (PcP) still impacts the AIDS patients, it has a growing importance in immunosuppressed HIV-negative patients. To determine the anti-Pneumocystis therapeutic efficacy of new compounds, animal and in vitro models have been developed. Indeed, well-designed mouse or rat experimental models of pneumocystosis can be used to describe the in vivo anti-Pneumocystis activity of new drugs. In vitro models, which enable the screening of a large panel of new molecules, have been developed using axenic cultures or co-culture with feeder cells; but no universally accepted standard method is currently available to evaluate anti-Pneumocystis molecules in vitro. Thus, we chose to explore the use of the SYTO-13 dye, as a new indicator of Pneumocystis viability. In the present work, we established the experimental conditions to define the in vitro pharmacodynamic parameters (EC50, Emax) of marketed compounds (trimethoprim/sulfamethoxazole, pentamidine, atovaquone) in order to specifically measure the intrinsic activity of these anti-P. carinii molecules using the SYTO 13 dye for the first time. Co-labelling the fungal organisms with anti-P. carinii specific antibodies enabled the measurement of viability of Pneumocystis organisms while excluding host debris from the analysis. Moreover, contrary to microscopic observation, large numbers of fungal cells can be analyzed by flow cytometry, thus increasing statistical significance and avoiding misreading during fastidious quantitation of stained organisms. In conclusion, the SYTO-13 dye allowed us to show a reproducible dose/effect relationship for the tested anti-Pneumocystis drugs. PMID- 26103635 TI - Simulation of Runoff Hydrograph on Soil Surfaces with Different Microtopography Using a Travel Time Method at the Plot Scale. AB - In this study, a simple travel time-based runoff model was proposed to simulate a runoff hydrograph on soil surfaces with different microtopographies. Three main parameters, i.e., rainfall intensity (I), mean flow velocity (vm) and ponding time of depression (tp), were inputted into this model. The soil surface was divided into numerous grid cells, and the flow length of each grid cell (li) was then calculated from a digital elevation model (DEM). The flow velocity in each grid cell (vi) was derived from the upstream flow accumulation area using vm. The total flow travel time through each grid cell to the surface outlet was the sum of the sum of flow travel times along the flow path (i.e., the sum of li/vi) and tp. The runoff rate at the slope outlet for each respective travel time was estimated by finding the sum of the rain rate from all contributing cells for all time intervals. The results show positive agreement between the measured and predicted runoff hydrographs. PMID- 26103637 TI - The Effects of Kinesiotape Applied to the Lateral Aspect of the Ankle: Relevance to Ankle Sprains--A Systematic Review. AB - OBJECTIVE: To identify, evaluate and synthesise evidence on the effect of kinesiotape applied to the lateral aspect of the ankle, through a systematic review of quantitative studies. DATA SOURCES: A search for quantitative studies was undertaken using key terms of "kinesiotape" and "ankle" in seven electronic databases, using the maximum date ranges. Databases included: the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Medline, Physiotherapy Evidence Database, Scopus, SPORTDiscus and Web of Science. STUDY SELECTION: Database hits were evaluated against explicit inclusion criteria. From 107 database hits, 8 quantitative studies were included. DATA EXTRACTION: Two independent reviewers appraised the methodological rigour of the studies using the McMaster Critical Review Form for Quantitative Studies. Data were extracted on participant characteristics, kinesiotape parameters, comparison interventions, outcome measures and findings. DATA SYNTHESES: Most studies (n=7) had good to very good methodological rigour. Meta-analysis was not possible due to heterogeneity in participants, interventions and outcome measures. No adverse events were reported. Kinesiotape may produce different effects in healthy and injured ankles. In healthy ankles, kinesiotape may increase postural control, whereas in injured ankles it may improve proprioception, plantarflexor endurance and the performance of activities. These trends were identified from a small body of evidence including 276 participants. CONCLUSIONS: It is recommended that kinesiotape may be used in clinical practice to prevent lateral ankle injuries (through its effects on postural control) and manage lateral ankle injuries due to its positive effects on proprioception, muscle endurance and activity performance. It appears that kinesiotape may not provide sufficient mechanical support to improve postural control in unstable ankles. Adverse events associated with kinseiotape are unlikely. PMID- 26103636 TI - Alpha-2-Macroglobulin Is Acutely Sensitive to Freezing and Lyophilization: Implications for Structural and Functional Studies. AB - Alpha-2-macroglobulin is an abundant secreted protein that is of particular interest because of its diverse ligand binding profile and multifunctional nature, which includes roles as a protease inhibitor and as a molecular chaperone. The activities of alpha-2-macroglobulin are typically dependent on whether its conformation is native or transformed (i.e. adopts a more compact conformation after interactions with proteases or small nucleophiles), and are also influenced by dissociation of the native alpha-2-macroglobulin tetramer into stable dimers. Alpha-2-macroglobulin is predominately present as the native tetramer in vivo; once purified from human blood plasma, however, alpha-2 macroglobulin can undergo a number of conformational changes during storage, including transformation, aggregation or dissociation. We demonstrate that, particularly in the presence of sodium chloride or amine containing compounds, freezing and/or lyophilization of alpha-2-macroglobulin induces conformational changes with functional consequences. These conformational changes in alpha-2 macroglobulin are not always detected by standard native polyacrylamide gel electrophoresis, but can be measured using bisANS fluorescence assays. Increased surface hydrophobicity of alpha-2-macroglobulin, as assessed by bisANS fluorescence measurements, is accompanied by (i) reduced trypsin binding activity, (ii) increased chaperone activity, and (iii) increased binding to the surfaces of SH-SY5Y neurons, in part, via lipoprotein receptors. We show that sucrose (but not glycine) effectively protects native alpha-2-macroglobulin from denaturation during freezing and/or lyophilization, thereby providing a reproducible method for the handling and long-term storage of this protein. PMID- 26103639 TI - Dose-Dependent Effects of L-Arginine on PROP Bitterness Intensity and Latency and Characteristics of the Chemical Interaction between PROP and L-Arginine. AB - Genetic variation in the ability to taste the bitterness of 6-n-propylthiouracil (PROP) is a complex trait that has been used to predict food preferences and eating habits. PROP tasting is primarily controlled by polymorphisms in the TAS2R38 gene. However, a variety of factors are known to modify the phenotype. Principle among them is the salivary protein Ps-1 belonging to the basic proline rich protein family (bPRP). Recently, we showed that oral supplementation with Ps 1 as well as its related free amino acids (L-Arg and L-Lys) enhances PROP bitterness perception, especially for PROP non-tasters who have low salivary levels of Ps-1. Here, we show that salivary L-Arg levels are higher in PROP super tasters compared to medium tasters and non-tasters, and that oral supplementation with free L-Arg enhances PROP bitterness intensity as well as reduces bitterness latency in a dose-dependent manner, particularly in individuals with low salivary levels of both free L-Arg and Ps-1 protein. Supplementation with L-Arg also enhanced the bitterness of caffeine. We also used 1H-NMR spectroscopy and quantum mechanical calculations carried out by Density Functional Theory (DFT) to characterize the chemical interaction between free L-Arg and the PROP molecule. Results showed that the -NH2 terminal group of the L-ArgH+ side chain interacts with the carbonyl or thiocarbonyl groups of PROP by forming two hydrogen bonds with the resulting charged adduct. The formation of this PROP*ArgH+ hydrogen bonded adduct could enhance bitterness intensity by increasing the solubility of PROP in saliva and its availability to receptor sites. Our data suggest that L Arg could act as a 'carrier' of various bitter molecules in saliva. PMID- 26103641 TI - Authors' response. PMID- 26103642 TI - To: The economic effect of extracorporeal membrane oxygenation to support adults with severe respiratory failure in Brazil: a hypothetical analysis. PMID- 26103640 TI - IGFBP-5 Promotes Fibrosis Independently of Its Translocation to the Nucleus and Its Interaction with Nucleolin and IGF. AB - BACKGROUND: Insulin-like growth factor binding protein (IGFBP)-5 levels are increased in systemic sclerosis (SSc) skin and lung. We previously reported that IGFBP-5 is a pro-fibrotic factor that induces extracellular matrix (ECM) production and deposition. Since IGFBP-5 contains a nuclear localization signal (NLS) that facilitates its nuclear translocation, we sought to examine the role of nuclear translocation on the fibrotic activity of IGFBP-5 and identify IGFBP-5 binding partners relevant for its nuclear compartmentalization. METHODS: We generated functional wild type IGFBP-5 and IGFBP-5 with a mutated NLS or a mutated IGF binding site. Abrogation of nuclear translocation in the NLS mutant was confirmed using immunofluorescence and immunoblotting of nuclear and cytoplasmic cellular extracts. Abrogation of IGF binding was confirmed using western ligand blot. The fibrotic activity of wild type and mutant IGFBP-5 was examined in vitro in primary human fibroblasts and ex vivo in human skin. We identified IGFBP-5 binding partners using immunoprecipitation and mass spectrometry. We examined the effect of nucleolin on IGFBP-5 localization and function via sequence-specific silencing in primary human fibroblasts. RESULTS: Our results show that IGFBP-5-induced ECM production in vitro in primary human fibroblasts is independent of its nuclear translocation. The NLS-mutant also induced fibrosis ex vivo in human skin, thus confirming and extending the in vitro findings. Similar findings were obtained with the IGF-binding mutant. Nucleolin, a nucleolar protein that can serve as a nuclear receptor, was identified as an IGFBP-5 binding partner. Silencing nucleolin reduced IGFBP-5 translocation to the nucleus but did not block the ability of IGFBP-5 to induce ECM production and a fibrotic phenotype. CONCLUSIONS: IGFBP-5 transport to the nucleus requires an intact NLS and nucleolin. However, nuclear translocation is not necessary for IGFBP-5 fibrotic activity; neither is IGF binding. Our data provide further insights into the role of cellular compartmentalization in IGFBP 5-induced fibrosis. PMID- 26103644 TI - Presumption of Herbicide Exposure and Presumption of Disability During Service for Reservists Presumed Exposed to Herbicide. Interim final rule. AB - The Department of Veterans Affairs (VA) is amending its regulation governing individuals presumed to have been exposed to certain herbicides. Specifically, VA is expanding the regulation to include an additional group consisting of individuals who performed service in the Air Force or Air Force Reserve under circumstances in which they had regular and repeated contact with C-123 aircraft known to have been used to spray an herbicide agent ("Agent Orange'') during the Vietnam era. In addition, the regulation will establish a presumption that members of this group who later develop an Agent Orange presumptive condition were disabled during the relevant period of service, thus establishing that this service constituted "active, naval, military or air service.'' The effect of this action is to presume herbicide exposure for these individuals and to allow individuals who were exposed to herbicides during reserve service to establish veteran status for VA purposes and eligibility for some VA benefits. The need for this action results from a recent decision by the Secretary of Veterans Affairs to acknowledge that individuals who had regular and repeated exposure to C-123 aircraft that the United States Air Force used to spray the herbicides in Vietnam during Operation Ranch Hand were exposed to Agent Orange. PMID- 26103643 TI - Theoretical and practical aspects in total uncemented hip arthroplasty by using short femoral stem prosthesis. AB - Hip arthrosis, primary or secondary, is an osteoarthritic degenerative process that affects the hip joint. Primary hip arthrosis has an unknown etiology, and secondary hip arthrosis has well defined causes; of these causes, some are known to lead to arthrosis of the hip in the young age patient. The surgical treatment aims either to preserve the patient's hip joint, or to replace the joint. The most commonly used procedure at this time is the total hip arthroplasty. The femoral component may have a short or a long stem. The short femoral stem prosthesis is usually impacted by using a unique technique and unique instruments, according to the manufacturer's specifications. There are several models of short stem femoral prosthesis, but no matter which one is chosen, the surgical indication, the surgical technique and a well-conducted recovery program are important. The choosing of each arthroplastic implant must be made with care, taking into consideration the patient's benefit, his expectations, and also the surgeon's experience. PMID- 26103646 TI - [View on the problem of Klatskin tumor]. AB - Klatskin tumor arises from the common hepatic duct and its bifurcation the bile ducts and is the most common primary malignancy of the biliary tree. the location of the tumor and its close relationship with vascular structures at the hepatic hilum have resulted in a low resectability and high morbidity and mortality. Improvement of instrumental diagnostics and operative techniques allows to perform extended resection and complex interventions on the liver, bile ducts and vascular structures at the hepatic hilum. The role of chemoratiotherapy and photodynamic therapy is not fully understood. thus, questions of treatment and prognosis of the disease are remain relevant and require further study. PMID- 26103647 TI - [Internal drainage of pancreatic pseudocysts]. PMID- 26103648 TI - [Optimization of postoperative period in patients after colon resection]. PMID- 26103649 TI - [The role of medical service for combat losses replenishment in personnel during the Great Patriotic War (to the anniversary of the Great Victory)]. PMID- 26103650 TI - [To the 90th anniversary from the birthday]. PMID- 26103651 TI - [Research progress on objective diagnosis of Meniere's disease]. PMID- 26103652 TI - [The appilication of artificial intelligence in diagnosis of vertigo]. PMID- 26103653 TI - [Study on evaluating quality of life of allergy rhinitis patients and risk factors]. AB - OBJECTIVE: To investigate the level of life quality and the influence factors and to furnish basis for improving life quality and treatment compliance of patients with allerge rhinitis. METHOD: Adopt the rhino conjunctivitis quality of life questionnaire (RQLQ), visual analogue scales (VAS), curing to obey the sex grade point questionnaire. quality of life and patient's compliance on cross-sectional study. One hundred and twenty the examples enter the inquisitional sufferer to press whether accepted to is divided into the A1 set and B1 sets with the medicine leading and whether accepted to use the medicine the direct is divided into the A2 set and B2 sets, the A set accepts use the medicine leading and use the medicine direct. Multiple databases were established based on questionnaire. SPSS 17.0 software was used in statistical analysis. RESULT: Coefficient correlation of patient's compliance, cognition level, questionnaire with quality of life has statistical significance, and is positive correlation. CONCLUSION: Treatment compliance of patients, duration and level of education have great impact on the quality of life for patients AR. Enhance patient compliance with treatment can improve the quality of life of patients with AR. PMID- 26103654 TI - [Value of patient education in the treatment of allergic rhinitis]. AB - OBJECTIVE: To evaluate the effect of patient education on patients with allergic rhinitis (AR). METHOD: From January 2009 to December 2013, 100 cases of allergic rhinitis were treated. The patients were randomly divided into experimental group or control group by Stochastic tables law,50 patients in control group accepted only drug treatment, 50 patients in experimental group accepted both drug treatment and patient education. The difference in compliance with treatment, treatment effect, incidence of adverse drug reactions and complications, average costs and times of treatment between two groups were evaluated by the rhinoconjunctivitis quality of life questionnaire (RQLQ) score. The independent sample t-test and chi2 test were used for statistical analysis. RESULT: The patients of experimental group showed more positive attitude to treatment compared to the patients of control group (P < 0.01). The average scores of each classification and overall symptoms after treatment in experimental group were lower than those in control group (P < 0.05). The incidence of adverse drug reactions (nose-bleed, dry nose,nasal mucosa ulcer)and complications in patients with AR (asthma, chronic cough, secretory otitis media) in experimental group was lower than that in control group, with statistically differences (P < 0.05). The average times of treatment and costs of diagnosis and treatment(calculation of budesonide nasal spray)in experimental group were significantly lower than those in control group (P < 0.01). The total score for RQLQ and the scores of seven dimensions in experimental group were lower than those in control group (P < 0.05). CONCLUSIONS: Patient education can help the patients with AR to cooperate actively with treatment, to reduce the incidence of adverse drug reactions and AR complications, and to save medical costs and improve the quality of life. PMID- 26103655 TI - [Progress in diagnosis and treatment of children allergic rhinitis]. AB - Children allergic rhinitis, referred to as children allergic rhinitis (AR), is a kind of non-infectious inflammation of the nasal mucosa mediated by IgE with the main symtoms of paroxysmal sneezing, rhinorrhoea, nasal itching and nasal obstruction when the susceptible individuals contact the allergen. It is a high reaction disease of the respiratory mucosa common with childhood, which has serious implications to the Children's quality of life, study, rest and growth. The global sampling survey reveals that the morbidity is about 14%, of which 10% in our country and there is an upward trend year by year. At present, drug therapy is still one of the most important methods for children AR. Definite diagnosis, standardized drug therapy and the development of new specific immune therapy make children AR in a good control . This review updates the diagnosis and treatment for children AR, referring to the newest guide by WHO about allergic rhinitis and its impact on asthma (ARIA). PMID- 26103656 TI - [Analysis of allergens spectrum in children with allergic rhinitis in Zhengzhou district]. AB - OBJECTIVE: To analyze the main allergens in children with allergic rhinitis and provide scientific basis for prevention and treatment in Zhengzhou district. METHOD: Twenty standardization allergens were used to perform skin prick test in 412 children with AR, and the results were statistically analyzed. RESULT: Three hundred and twenty-nine of 412 cases (79.85%) showed positive reaction. The positive rate of dermatophagoides farina (87.54%) was the highest in inhaled allergens, followed by dermatophagoides pteronyssinus (86.32%), cat hair (62.31%), fungus I (47.72%) and dog hair (43.16%). The positive rate of shrimp (13.68%) was the highest in ingestive allergens, then egg (5.17%), carp (4.56%), meat I (3. 04%) and milk (3.04%). CONCLUSION: Dust mites, cat hair, fungus,dog hair were the most common allergens in children in Zhengzhou district. Improving living environment of children with AR and avoiding contacting with allergens were pretty important. PMID- 26103657 TI - [Distribution characteristics and influencing factors of children with allergic rhinitis in a domestic dust mites allergens content distribution characteristics and influencing factors]. AB - OBJECTIVE: To observe the household environment dust mites allergens content distribution characteristics and influence factors of children with allergic rhinitis to dust mites in Wuhu. METHOD: Collect the surface dust in bedroom and living room floor, mattresses, pillows, sofa of 102 children with allergic rhinitis families. Dust mite allergen components 1 (Der f1) and house dust mites allergens 1 components (Der p1) of the dust samples were determined by enzyme linked immunosorbent assay (ELISA). RESULT: One hundred and twenty samples were collected . In a domestic dust mites samples, with a median of M (Min and Max) said dust mite allergen levels, Der f1 and Der p1 content was 2.66 (0.03, 26.63), 3.48 (0, 03, 33.68), respectively. Der f1 was significantly less than Der p1, and the difference was statistically significant (P < 0.05). According to the classification of urban and township, there were 68 cases and 34 cases. Der f1 content in the samples was 2.91 (0.31, 26.63), 2.40 (0.08, 16.02), respectively. Der p1 content was 4.28 (0.03, 20.77), 3.88 (0.14, 33.68), respectively. The dust mites content of urban was significantly more than that of villages and towns, the difference was statistically significant (P < 0.05). Samples were also classified by gender. The dust mites allergens content in either boy's or girl's family were similar, there was no statistically significant difference (P > 0.05). CONCLUSION: The household dust mites of children allergic rhinitisin Wuhu area is given priority to with Der p1, and urban dust mites are significantly more than village's and town's. Enhancing health education, controlling dust mites allergens contamination inside the bedroom, especially urban areas, are positive differences for the prevention and treatment of allergic diseases such as allergic rhinitis in children. PMID- 26103658 TI - [The cultivation and migration in vitro of olfactory ensheathing cells from human olfactory mucosa]. AB - OBJECTIVE: To investigate the bionomics of the olfactory ensheathing cells (OECs) of human olfactory mucosa. METHOD: To separate and cultivate the OECs of human and rat olfactory mucosa. To observe the cell growth, cell grouping and cell migration in vitro of the two types of OECs. RESULT: Successfully separated and cultivated the OECs of human and rat olfactory mucosa. OECs of the human and rat olfactory mucosa had the similar cell growth, cell grouping and cell migration ability in vitro. CONCLUSION: OECs of the human and rat olfactory mucosa have the similar bionomics in vitro, as a result, OECs of the human olfactory mucosa could be a reliable source of cell transplant for nerve injury. PMID- 26103659 TI - [The clinical curative effect of the low temperature plasma ablation adenoidectomy and tympanic membrane indwelling catheter in parallel or not used on childhood patients with secretory otitis media]. AB - OBJECTIVE: To observe the clinical effect of endoscope-guided low temperature plasma ablateing adenoidectomy with tympanic membrane incision drainage and tympanic membrane indwelling catheter to treat secretory otitis media of children. METHOD: Fifty-two cases (98 ears) of secretory otitis media in children with adenoid hypertrophy were treated. Respectively endoscope-guided tympanic membrane incision drainage parallel low temperature plasma ablateing adenoidectomy and endoscope-guided tympanic membrane indwelling catheter parallel low temperature plasma ablateing adenoidectomy. RESULT: In group A, 30 cases of 58 ears, cure 36 ears, improving 14 ears, invalid 8 ears, the effective rate was 86.2%. In group B, 22 cases of 40 ears, cured 32 ears, improvement in 6 ears, invalid 2 ears, the effective rate was 95.0%. According to statistical analysis of curative effect, there was no significant difference by effective rate between two groups. CONCLUSION: For the patients with secretory otitis media caused by adenoidal hypertrophy, the endoscope-guided tympanic membrane incision drainage parallel low temperature plasma ablateing adenoidectomy can be regarded as a kind of method to reduce the risk of tympanic membrane perforation. PMID- 26103660 TI - [Clinical analysis of simple orbital blowout fracture]. AB - OBJECTIVE: To discuss the clinical features and treatment methods for simple orbital blowout fracture. METHOD: Retrospective analysis of the CT images of 16 orbital blowout fracture case, and identification of the sites, degree, patterns and features of fractures. Among the 16 cases, 2 cases adopted conservative treatment; 11 cases gained a reduction of orbital fracture through endoscopic transnasal surgery; the other 3 patients choosed endoscopic transnasal surgery and Caldwell-Luc operations. RESULT: Among 16 diplopia cases, 13 cases were completely cured, and 3 patients' vision were significantly improved. Among 11 enophthalmos cases, 10 patients were cured, and the effect of the other one was not satisfied. Among the 15 eye movement disorder cases, 13 patients' eye movement gained a full recovery, and the other 2 cases were nearly normal. All patients' vision were improved in different extents, and no one got a complication. CONCLUSION: Computerized Tomography is helpful to the diagnosis of simple orbital blowout fracture. Caldwell-Luc operation with transnasal endoscope is an effective method for the treatment of orbital fractures. PMID- 26103661 TI - [Detection and grading of endolymphatic hydrops in Meniere's disease using 3D FLAIR MRI]. AB - OBJECTIVE: To evaluate the extent of endolymphatic hydrops as shown by three dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D FLAIR MRI) performed 24 hours after bilateral intratympanic gadolinium administration and discuss the positive rate of endolymphatic hydrops in vestibule and cochlea. METHOD: Twenty-four hours after bilateral intra-tympanic 8 times diluted gadolinium administration, three-dimensional fluid-attenuated inversion recovery MRI, using a three-Tesla unit, was performed in 48 patients, and then assessed the extent of endolymphatic hydrops in the MRI images. RESULT: Forty-eight patients showed different levels of enhancement of perilymth in the inner ear. In these patients, obvious signs of endolymphatic hydrops were visualized in vestibule,including 8 slight hydrops, 17 mild hydrops and 23 severe hydrops with a diagnostic rate of 83.3%. There were almost no complications in all 48 patients after bilateral intra-tympanic injection except short vertigo in some of them. CONCLUSION: 3D FLAIR MRI resonance imaging has a high positive diagnostic rate in assessing endolymphatic hydrops of Meniere's disease and provides direct imaging evidence for diagnosing Meniere's disease. PMID- 26103662 TI - [A new classification of extensions of the sphenoid sinus of Chinese adult by CT]. AB - OBJECTIVE: To examine various pneumatized extensions of the sphenoid sinus of Chinese people. METHOD: The sphenoid sinus and its surrounding structures were examined from 100 computed tomography images of the sinus. The type of the sphenoid sinus was classified according to the various extensions of the sinus. RESULT: The type of the sphenoid sinus was classified into the following 6 basic types based on the direction of pneumatization: sphenoid body, lateral, clival, lesser wing, anterior, and combined. CONCLUSION: The variations in the extensions of pneumatization of the sphenoid sinus may facilitate entry into areas bordering the sphenoid sinus. PMID- 26103663 TI - [The function of tubomanometry in forcasting the progonosis of acute otitis media with effusion]. AB - OBJECTIVE: To evaluate the function of tubomanometry (TMM) in forcasting the progonosis of acute otitis media with effusion (OME). METHOD: We used the technique of TMM to quantify the degree of eustachian tube (ET) dysfunction in 65 patients with OME. The opening of the ET and the transportation of gas into the middle ear were registered by a pressure sensor in the occluded outer ear after applying the stimulus of a controlled gas bolus into the nasopharynx during swallowing. Three excess pressure values were tested subsequently (30, 40, and 50 mbar). If tube opening was registered, the time of opening in relation to pressure applied was measured. The TMM calculated the opening latency index or index R. An R value of < 1 indicated early opening of the tube at the start of application of the stimulus, which was considered optimal. A value > 1 indicated late opening of the tube occurring after the initial stimulus and was interpreted as suboptimal. Inability to calculate the index R value indicated that the tube was unable to actively open at all. The TMM results, were weighted as follows: no R with 0 points, R > 1 with 1 point and R < 1 with 2 points for the measurements at 30, 40, and 50 mbar, respectively. The points of these three tests were added so the ET score (ETS) ranges from 0 (worst value) to 6 (best value). According to the medical history, the patients were divided into two groups, chronic OME group (defined as positive control group), 30 cases with 38 ears; and acute OME group, 35 cases with 46 ears. The healthy ears of all patients were defined as normal control group, 46 cases with 46 ears. The same regular treatments, including classic medical treatments and intratympanic dexamethasone injections, were used to acute OME group in the following 1-2 months. On the basis of therapeutic effect, acute OME group was subdivided into valid group (26 cases with 33 ears) and invalid group (9 cases with 13 ears). RESULT: The ETS of normal control group was 5.11 +/- 1.32 while it was 1.08 +/- 1.32 in positive control group. It was found marked differences between the two groups (P < 0.01). The ETS of both valid and invalid subgroup of actue OME group were significantly lower than normal control group (P < 0.01), but in valid subgroup it was significantly higher than positive control group (P < 0.01), and no marked difference was found between the invalid subgroup and positive control group. After treatments, a significant improvement of the ETS was found in both valid and invalid subgroup (P < 0.05) there was no marked difference between valid subgroup and normal control group. But in invalid subgroup it was still significantly lower than normal cohtrol group (P < 0. 01). CONCLUSION: TMM could forecast the prognosis of acute OME. Patients with acute OME suffered from ET dysfunction of varied degrees. Those with high ETS could be cured by classic medical treatments and intratympanic dexamethasone injections. But those with poor ETS could not be cured in short period, tube insertion should be considered. If ETS could not be improved by ventilation tube placement, more active treatment, for example, balloon Eustachian tuboplasty (BET), should be used to prevent transforming into chronic OME. PMID- 26103664 TI - [The clinical research of aviatic nasal diseases with medical evaluation prevention and control intervention]. AB - OBJECTIVE: Exploring the clinical features of aviatic nasal diseases to provide references for medical evaluation, prevention and control measures in aircrew. METHOD: To analysis and summary 605 cases with 503 pilots of nasal diseases in aircrew during 1966 to 2013. RESULT: (1) There were 605 cases of aviatic nasal diseases, including 550 cases of general diseases and 55 cases of specific diseases. The general nasal diseases included 140 cases of anatomical abnormalities in nasal cavity type, 290 cases of inflammation in nasal cavity, 73 cases of allergy type, 47 cases of cyst and tumor type, and the specific nasal diseases were 55 cases of sinus barotrauma (SB). (2) The, constituent ratio of SB, which was happened in frontal sinus and /or maxillary sinus, was 95.55%. (3) The constituent ratio of cyst and tumor type in nasal cavity was easier causing to SB than anatomical abnormalities, inflammation, allergy disease in nasal cavity (P < 0.05). (4) The grounded constituent ratio of secondary SB was higher than anatomical abnormalities, inflammation, allergy, cyst and tumor disease in nasal cavity (P < 0.05). (5) The ways of hypobaric chamber tests were different for the kinds of aircrew. The qualified adjustment function of sinuses for barometric pressure was an essential condition for aircrew to continue flying. (6) The key point for the treatment of aviatic nasal diseases was to remove pathological change in nasal cavity and sinus and restore sinus ostium patency. The key point for the medical evaluation was to restore normal sinus pressure balance function. CONCLUSION: The key point of medical evaluation about aviatic nasal diseases is to assess the sinus pressure balance function in hypobaric chamber tests. Normative treatment and medical evaluation can effectively avoid flight accidents and improve the attendance rate for aircrew. PMID- 26103665 TI - [Expression and significance of C/EBPalpha and CK10 in nasal inverted papilloma]. AB - OBJECTIVE: The expression of C/EBPalpha, CK10 in nasal inverted papilloma (NIP) were detected in the study. Further discussed their significance in genesia, development and recurrence of NIP. METHOD: Three groups including nasal cavity mucosae (NM 10 cases), nasal polyp (NP 20 cases) and NIP (30 cases) were selected in the study. Expretion of C/EBPalpha, CK10 were detected by immunohistochemisty PV-6000 method. RESULT: (1) The different expression of C/EBPalpha and CK10 in the group of NM, NP and NIP was statistically significant (P < 0.05). (2) The different expression of C/EBPalpha, CK10 in the group of benign NIP and NIP with atypical hyperplasia was statistically significant (P < 0.05). (3) The different expression of C/EBPalpha and CK10 in the group of NIP with recurrence and NIP with no recurrence was statistically significant, P < 0.05, respectively. (4) Our result indicate that the relationship of C/EBPalpha and CK10 (r = 0.578, P < 0.01) was direct correlation. The difference was statistically significant. CONCLUSION: In conclusion, the present results describe C/EBPalpha, CK10 expression in NIP and their possible implication in the regulation of tumor growth and differentiation. C/EBPalpha and CK10 production may prove useful in terms of a prognostic marker for the recurrence in nasal inverted papilloma. PMID- 26103666 TI - [The study of auditory performance of prelingual deaf cochlear implant recipients using Chinese version of categories of auditory performance]. AB - OBJECTIVE: Applying Chinese version of categories of auditory performance (CAP) to assess cochlear implant (CI) recipients of prelingual deaf and test the reliability of Chinese version of CAP. METHOD: Fifty CI recipients of prelingual deaf were interviewed by a parent and a speech therapist using Chinese version of CAP. Kappa coefficient analysis was applied to test the reliability of Chinese version of CAP. RESULT: Thirty-five of 50 cases (70%) were found completely coincident, 12 cases (24%) were one category different, 3 cases (6%) were 2 categories different. Kappa coefficient was 0.624. CONCLUSION: Chinese version of CAP was found reliable and useful to evaluate auditory performance of prelingual deaf pediatric after cochlear implantation. PMID- 26103667 TI - [Olfactory function in patients with Alzheimer' disease]. AB - OBJECTIVE: To analyze the relationship between olfactory bulb (OB) volume, depth of olfactory sulcus (OS) and olfactory function in patients with Alzheimer' disease (AD). METHOD: Fifty patients with AD patients and 50 healthy subjects were examined by olfactory function T&T testing, OB volume and depth of OS assessed with Magnetic resonance imaging (MRI). RESULT: T&T olfactory testing revealed that AD patients had higher scores than control group (1.50 +/- 0.17, 2.80 +/- 0.31, P < 0.05). Bilateral and average OB volumes were smaller in AD group [(29.78 +/- 5.17) mm3, (30.14 +/- 4.87)mm3, (30.05 +/- 5.08) mm3] than in control group [(36.65 +/- 4.08)mm3, (36.56 +/- 4.12)mm3, (36.46 +/- 4.11)mm3] (P < 0.01). OS depth study revealed no statistical difference between AD patients and control groups (P > 0.05). Olfactory discriminate threshold was negatively correlated with average olfactory bulb volumes (r = -0. 711, P < 0.05), and was not correlated with depth of OS (r = -0.127, P > 0.05) in AD patients. CONCLUSION: The OB volume were lower in AD patients as compare to controls, the depth of OS has no significant changes in AD patients; The OB volume is correlated with olfactory function, the depth of OS is no correlated with olfactory function. Cognitive impairment degree in AD patients is accordance with the lower degree olfactory function. The olfactory loss may be the earlier period and objective diagnosis indicator for AD patients. PMID- 26103668 TI - [Comparative study of nasal packs and postoperative negative-pressure septal drainage in patients undergoing nasal septal surgery]. AB - OBJECTIVE: To study whether negative-pressure septal drainage could be an alternative to packs after septoplasty. METHOD: This was a randomized controlled trial. The study involved 60 patients who underwent septoplasty. Patients were randomly divided into two groups, one with anterior nasal packs and the other with negative-pressure septal drainage. Patients were asked to record pain levels using a visual analogue scale (VAS). Postoperative symptoms and complications were compared during 24 h and 48 h postoperative period including pain, drying sensation of mouth, sleep difficulty, conjunctival congestion, haemorrhage. VAS scores and incidence were evaluated during 1 week and 6 weeks postoperative period including pain, bleeding, haematoma, septal perforation, synechiae and septal perforation. RESULT: Patients of negative-pressure septal drainage suffered from less pain than patients of nasal packs during the first 24 h and 48 h postoperative period. The results for pain, drying sensation of mouth, sleep difficulty, conjunctival congestion, haemorrhage were different between groups (P < 0.05), especially the amount of bleeding during 48 h postoperatively in patients undergoing negative pressure drainage [(0.52 +/- 0.63)ml] was significantly less than the group who received anterior nasal packs [(21.03 +/- 5.88) ml] (P < 0.01). On the other hand, haematoma, synechiae and perforation were not statistically different between groups during 1 week and 6 weeks follow up period (P > 0.05). CONCLUSION: Using negative-pressure drainage instead of nasal packs after septoplasty seems a more reasonable option. The negative pressure drainage technique may be the preferred option to provide higher patient satisfaction and has the same level of postoperative complica.tion to nasal packs as for septoplasty surgery. PMID- 26103669 TI - [Different intranasal corticosteroids effects on nasal airway remodeling of allergic rhinitis murine and matrix metalloproteinase-9]. AB - OBJECTIVE: To discuss the effect of different doses intranasal corticosteroids on remodeling of allergic rhinitis (AR) mice nasal mucosa and expression level of matrix metalloproteinase-9 (MMP-9). METHOD: Thirty BALB/c female mice were divided into five groups randomly and received OVA or normal saline (NS) with intraperitoneal injection or nasal challenge, respectively. The treatment groups received additional different doses of budesonide (0.6 MUg/20 g, 3.0 MUg/20 g and 15.0 MUg/20 g) daily for 16 weeks. We assessed the nasal symptoms at 4 and 16 weeks. Collected the mice nasal tissue, and then stained with hematoxylin-eosin, Masson's Trichrome, and periodic acid-schiff respectively to evaluate airway remodeling at 16 weeks. MMP-9 was measured with enzyme-linked immunosorbent assay (ELISA). Result: Times of rubbing, sneezes and infiltrate of eosinophil increased more in B group than in A group, and subepithelial fibrosis, collagen deposition, goblet cell hyperplasia, and submucosal gland hypertrophy were only observed in B group at 16 weeks. The nasal symptoms and eosinophil infiltration were inhibited by treatment with budesonide from a dose of 0.6 MUg onwards, while the prevention of structure changes was only observed with 3.0 MUg onwards. In addition, intranasal budesonide reduced MMP-9 in the nasal of AR mice. CONCLUSION: The study suggests that higher dose intranasal corticosteroids might inhibit the airway remodeling of nasal mucosa by reducing MMP-9. PMID- 26103670 TI - [The changes of microRNA in nasal mucosa after the specific immunotherapy for allergic rhinitis in mice]. AB - OBJECTIVE: To explore the changes of microRNAs in nasal mucosa after the specific immunotherapy (SIT) for allergic rhinitis (AR) in mice. METHOD: Female BALB/c mice, 6-8 weeks of age, were randomly divided into control group, model group and treatment group. AR model were established by intraperitoneal injection and intranasal challenge of ovalbumin and SIT was performed by inguinal subcutaneous injections. AR symptom scores were documented. The eosinophils (EOS) in the nasal mucosa were measured. Ovalbumin-specific IgE (OVA-sIgE) in the serum and expression of interferon-gamma and interleukin-4 in the nasal lavage were measured by enzyme-linked immunosorbent assay meanwhile the ratio of interferon gamma and interleukin-4 was calculated. The microRNAs in the nasal mucosa were preliminary screened by microRNA gene microarray. Comparing with model group, the Fold changes of microRNA of the treatment group were >= 2.0 and the P < 0.05. MicroRNA target genes were predicted with GeneSpring 12.5 software. We took the intersection between genes in the signal pathway which associated with immune response,inflammation and target genes. The MEV-4-6-0 and Cytoscape_v2. 8. 2. software was applied to perform the cluster analysis and target gene regulatory networks maps. RESULT: The model of AR in mice and its SIT were successful. Comparing with the model group, the Fold changes of 15 microRNAs, of which 9 microRNAs were up-regulated and 6 microRNAs were down-regulated, were >= 2.0 in treatment group (P < 0.05). Cluste analysis showed clearly that microRNAs in the treatment group and model group respectively aggregated in two branches. The 15 microRNAs had 5302 target genes, of which, 451 genes were related more with SIT by the intersection. One microRNA can regulate many target genes, and one gene can also be affected by many microRNAs. Their synergistic effects may be involved in the mechanism of SIT. CONCLUSION: The expressions of microRNAs are changed in nasal mucosa after SIT for AR in mice and we can speculate that microRNAs are involved in the process of SIT for AR. Bioinformatics methods can diminish the scope of target genes of microRNAs, which will help us studying the effect of changed microRNA on its relative target genes after SIT, and make us better understanding the mechanism of the disease and its SIT. PMID- 26103672 TI - [Diagnosis and treatment of 17 cases of nasal foreign body by button battery]. PMID- 26103673 TI - [The electric coagulation under nasal endoscopic treatment for refractory nasal bleeding in 168 cases]. PMID- 26103671 TI - [The relization of EABR test out of cochlea and the effects of different location of electrode on EABR wave]. AB - OBJECTIVE: To investigate the feasibility of the round window stimulation electrical evoked auditory brainstem response (EABR) test, and optimize the parameters of recording and stimulation electrodes positions. METHOD: Ten healthy Hartley guinea pigs (20 ears) were used for the EABR test. The positive stimulation electrodes were placed into the round window niche, the animals were divided into three group according to the negative electrodes position, group A: the electric field was parallel with the projection of cochlear modiolus on the tympanic membrane, group B: the electric field was perpendicular to modiolus projection toward to the mastoid, group C: the electric field was perpendicular to modiolus projection toward to the zygomatic process. A series of optimized recording and stimulation parameters were uesed to reduce the electrical artifact. RESULT: All the 20 ears were normal in the ABR testing, and EABR waves were stable and well-differentiated in the EABR tests out of cochlea. But EABR waves of group A were more stable and differentiated than those of group B and C. In group A, the threshold of EABR was (0.54 +/- 0.11) mA, and latency of wave III was (1.71 +/- 0.05) ms when the stimulus intensity was 0.8 mA. In group B, the threshold of EABR was (0.62 +/- 0.12) mA, and latency of wave III was (1.77 +/- 0.03) ms. In group C, the threshold of EABR was (0.70 +/- 0.14) mA, and latency of wave III was (1.86 +/- 0.04)ms. The threshold of EABR and latency of wave III were significantly different among the three groups by statistic analysis. CONCLUSION: EABR waves were stable and well-differentiated in the EABR tests out of cochlea. The EABR waves were recorded more stably and differentiated when the stimulating electrode and recording electrode were paralleled with the projection of modiolus on the tympanic membrane. PMID- 26103674 TI - [Myoepithelioma of nasal cavity: a case report]. AB - Myoepithelioma is an uncommon benign tumor that most likely occurs in the salivary gland. Extra-salivary myoepithelioma are sporadic and rare, especially the quantities occur in the sinonasal cavity are fewer in related literature reported. In this paper, we present a rare case of benign myoepithelioma that occurred in the nasal cavity, and the related process of pathogenesis, diagnosis, treatment and prognosis are discussed. PMID- 26103675 TI - [Nasal malignant granular cell tumor: a case report]. AB - We reported a case of nasal malignant granular cell tumor. The patient was a 51 years old man who went to the hospital because of "right nasal intermittent bleeding for half a year". The pathological examination after resection showed malignant granular cell tumor. No recurrence was noted during a year after resection. The etiology and pathogenesis, clinical features, pathological features and treatments of malignant granular cell tumor were reviewed. PMID- 26103676 TI - [Olfactory neuroblastoma with initial manifestations of hyponatremia: a case report]. AB - Clinical records of a patient with olfactory neuroblastoma presented with hyponatremia as initial symptoms were analyzed and the literatures were reviewed. At initial onset, the patient presented with hyponatremia. After pathological examination, the diagnosis was olfactory neuroblastoma. The blood sodium has been normal after operation and radiotherapy. The incidence rate of olfactory neuroblastoma is low, and it is easily misdiagnosed. Its diagnosis relies on pathological examination. We should pay more attention to the unspecific symptoms of patients with hyponatremia, which can help to improve early diagnosis and the prognosis. PMID- 26103677 TI - [Nasal primitive neuroectodermal tumor: a case report]. AB - Primitive neuroectodermal tumor (PNET) is a small round cell malignancies, normally confined to the chest wall and soft tissues of children and young adults, and reports of this tumor existing in nasal cavity are scarce. We herein present a case of nasal PNET. A 35-year-old male patient presented with a chief complaint of stuffy nose was diagnosed with a primary nasal pPNET by the clinical, microscopic, immunohistochemical features. Since these tumors are highly aggressive and patient prognosis is typically very poor, early diagnosis, immediate surgical resection and re-resection if possible, early radiotherapy and chemotherapy and close follow-up are required. We also review literatures on pPNET. PMID- 26103678 TI - [Why should rhinologic doctor pay attention to the lower respiratory tract of chronic rhinosinusitis patients?]. AB - The purpose of this review is to explain the relationship between chronic rhinosinusitis (CRS) and lower respiratory tract inflammation, especially asthma and introduce the new advances in the treatment of CRS patient with asthma. We also introduce our treatment strategy for these patients, including surgery technique and perioperative management. PMID- 26103679 TI - Genetic Variation of Salmo trutta L. Populations from the Catchment Areas of the Rega, Parseta and Wieprza Rivers Evaluated by RAPD and SSR Markers. AB - By using simple sequence repeats (SSR) and random amplification of polymorphic DNA (RAPD) markers, the genetic variability of three Salmo trutta L. populations from three rivers, the Wieprza, the Rega and the Parseta, was determined. The investigated populations showed a high level of genetic variability. Microsatellites showed that observed heterozygosity (Ho) was higher than the expected heterozygosity (He), with most heterozygotes found in the population from the Parseta river and the fewest in the Wieprza population. The F(IS) coefficient in all investigated populations of the sea trout indicate a high excess of heterozygotes. The highest genetic differentiation was observed between the sea trout from the Rega river and those from the Wieprza (0.366). The obtained results based on microsatellite and RAPD analysis showed that the investigated populations formed two groups. The first group consisted of the sea trout populations from the Wieprza and the Parseta rives, while the second group was formed solely by the Rega river population. PMID- 26103680 TI - Frequency of Cytoplasmic Droplets Depends on the Breed and Age of Insemination Boars. AB - In this study an attempt was made to analyse morphological changes in sperm with particular attention to sperm with a cytoplasmic droplet, taking into account the age and breed of the boar. The material for the study consisted of ejaculates of insemination boars of five breeds. Morphological examination of sperm was carried out in 30 randomly selected boars--6 individuals from each breed. The morphology of 500 spermatozoa was evaluated in each slide. The percentage of sperm with normal morphology in the semen of the boars varied between breeds and was dependent in varying degrees on the age of the boar. The primary defects in sperm occurred more frequently in Duroc and Pietrain boars than in other breeds and were more dependent on the age of the boar. The high percentage of primary defects in the sperm of young Duroc boars was determined by the frequency of sperm cells with a proximal cytoplasmic droplet on the midpiece. A particularly high percentage of sperm cells with secondary defects was noted in the initial stage of the reproductive life of the boars. The high number of sperm cells with secondary defects noted in the semen of the Duroc and Pietrain boars and the changes occurring with age in the frequency of secondary morphological defects were mainly determined by the frequency of sperm cells with a distal protoplasmic droplet in the middle piece and to a lesser degree by that of sperm cells with a pseudodroplet. PMID- 26103681 TI - Genetic identification of a rare record of Ommastrephes Bartramii (Cephalopoda: Ommastrephidae) from the Eastern Adriatic Sea. AB - The neon flying squid Ommastrephes bartramii Lesueur, 1821 belongs to the Ommastrephidae, Cephalopoda family. The family Ommastrephidae (Mollusca: Cephalopoda) includes many commercially important species, dispersed around the world. The Ommastrephidae family is conventionally divided into three subfamilies (Illicinae, Todarodinae, and Ommastrephinae). We report a specimen of neon flying squid caught in the winter 2013 at Luka Sipanska, Island of Sipan, Croatia and identified at the genetic level using the standard mitochondrial COI barcode region. This record represents the first genetic identification of a neon flying squid from the Adriatic Sea. PMID- 26103682 TI - Preliminary Results Concerning the Influence of Human Kisspeptin on LH Secretion in Prussian Carp (Carassius gibelio) Females at the Stage of Ovarian Recrudescence and Spawning Season. AB - The aim of the experiments was to evaluate the influence of human kisspeptin on LH secretion of Prussian carp (Carassius gibelio) females during ovarian recrudescence and spawning season. For the experiments, human kisspeptin KISS1 (0.1 mg kg(-1) of body weight--b.w.), GnRH analogue (Des Gly(10), D-Ala(6)) GnRH A (20 ug kg(-1) b.w.) and dopamine antagonist (pimozide) (5 mg kg(-1) b.w.) were used alone or in combinations. At 3, 6, 12, 24 hours after injection(s) blood samples were collected from all fish. LH levels were measured in plasma with the use of the ELISA method. KISS1 did not show any significant effects on spontaneous LH secretion in both tested seasons. At 12 hours sampling time (both stages of gonad maturity) a combination of tested compounds (GnRH-A+KISS1) significantly increased LH release in comparison with the control. In the stage of gonad recrudescence KISS1 significantly increased LH secretion evoked by pimozide at 24 hours. A combination of three components: KISS1, GnRH-A, and pimozide significantly decreased LH secretion in comparison to LH secretion evoked by GnRH-A and pimozide during stage of gonad recrudescence. These results suggest that kisspeptin is involved in seasonal control of reproduction in Prussian carp. The possible interaction of kisspeptin and the dopaminergic system is also discussed. PMID- 26103683 TI - Inbreeding and Offspring Sex Ratio in the Pygmy Hippopotamus (Cheoropsis liberiensis) Population Kept in Zoological Gardens. AB - The aim of this study was to estimate the inbreeding level and its impact on offspring sex ratio in the pygmy hippopotamus population kept in zoological gardens. Records of pygmy hippopotamus born between 1873-2013 were extracted from the international studbook. Totally, 1357 individuals originating from 148 breeding units were included (individuals with unknown sex were omitted). The offspring sex ratio is defined as the number of sons to the total number of progeny of each dam and sire. Spearman's rank correlation was employed to examine the relationships between the inbreeding level and offspring sex ratio. Inbreeding coefficients and individual increase in inbreeding coefficients (included as a linear co-variable) were examined as well as the geographic region and birth period using general linear models. The average inbreeding coefficient was 5.39%. The following sex proportion was observed for the inbred population: 57% and 43% for females and males, respectively. A significant relationship between inbreeding level of parents and their offspring sex ratio were estimated for European zoological gardens, whereas in others geographic regions the dependencies were insignificant. PMID- 26103684 TI - Examination of Growth Hormone (GH) Gene Polymorphism and its Association with Body Weight and Selected Body Dimensions in Ducks. AB - The main objective of the study was to assess the polymorphism in intron 2 of the GH gene and its association with some morphological traits (body weight--BW, length of trunk with neck--LTN, length of trunk--LT, chest girth--CG, length of breast bone--LBB, length of shank--LS). Polymorphism in intron 2 of the GH gene was evaluated for four duck populations (Pekin ducks AF51, Muscovy ducks from a CK and CRAMMLCFF mother and Mulard ducks). Genetic polymorphism was determined with the PCR-RFLP method using the BsmFI restriction enzyme. In the studied duck sample two alleles (GH(C) and GH(T)) and three genotypes (GH/TT, GH/CT, GH/CC) were found at locus GH/BsmFI. In both groups of Muscovies and in Mulards the dominant allele was GH(T). On the contrary in Pekin ducks AF51, the frequency of both alleles was found to be similar. The most frequent genotype in the examined ducks was GH/TT. In Pekin ducks AF51 three genotypes were observed, while in Mulard ducks and in male Muscovy ducks from a mother marked as CK, two genotypes (GH/TT and GH/CT) were identified. Muscovy duck females from a CK mother and all males and females of Muscovy duck from a CRAMMLCFF mother were monomorphic with only the GH/TTgenotype detected. The results showed that males of Pekin duck AF51 with the GH/TT genotype were characterized by higher (P < 0.01) BW value than those with the GH/CC and GH/CTgenotype. In females of Pekin ducks AF51, this same trend was observed; individuals with GH/TT genotype were superior (P < 0.05 and P < 0.01) to birds with two other detected genotypes in respect to BW, CG, LBB and LS. In the case of Mulards, ducks with the GH/TT genotype were distinguished by higher values of all evaluated traits compared to ducks with GH/CT and GH/CC genotypes, however most of the recorded differences were not significant. The only trait markedly impacted (P < 0.05) by the polymorphism of the GH gene intron 2 was the LS value in males. PMID- 26103685 TI - No ALAD Polymorphism in Bank Vole Populations from Unpolluted and Lead-Zinc Polluted Areas in Poland. AB - Although a variety of biomarkers has been developed to assess the adverse effect of lead on human and animal populations, studies show that the most important factor conditioning the response may be the genetic make-up of an individual. ALAD (delta aminolevulinic acid dehydratase) gene polymorphism found in human populations results in the existence of two alleles: ALAD1 and ALAD2. The difference between them is the result of one nucleotide change (G177C, rs1800435) which implicates different enzyme affinity for lead ions. As a result, carriers of these alleles respond differently to lead exposure in terms of tissue lead content, as well as neurobehavioral response. The aim of our study was to determine if such a phenomenon is present in wild animal populations. Two hypotheses were tested: (i) does the same ALAD polymorphism occur in lead exposed rodent species and is the frequency of different alleles similar to that of humans, (ii) if polymorphism exists, is the tissue lead content higher in individuals having ALAD2 alleles. We used bank voles (Myodes glareolus) inhabiting different lead contaminated sites for this purpose. The results obtained show no polymorphism in the bank vole populations that were studied. Contrary to the results obtained for humans, our study shows that all animals were found to have the C nucleotide. In human populations this nucleotide determines the ALAD2 allele and is much less frequent. PMID- 26103686 TI - Polymorphism of the CTNNB1 and FOXL2 Genes is not Associated with Canine XX Testicular/Ovotesticular Disorder of Sex Development. AB - 78,XX testicular or ovotesticular disorder of sex development (DSD) is the most common sex anomaly in dogs, but its molecular background remains unknown. It was hypothesized that the causative mutation may reside in canine chromosome 23 (CFA23), where two genes playing a pivotal role in ovarian development (CTNNB1 and FOXL2) are located. The aim of our study was to search for polymorphism in both candidate genes in 15 DSD dogs (78,XX and a lack of the SRYgene) and 29 normal females. Altogether, 7 novel polymorphic variants were identified: 5 SNPs in CTNNB1 and 2 indels in the FOXL2 gene. The distribution of the identified variants was similar in the DSD and control dogs. Therefore, we concluded that the conducted research did not prove an association between these polymorphisms and canine testicular or ovotesticular XX DSD. PMID- 26103687 TI - Changes in Quail Blastodermal Cell Status as a Result of Selection. AB - Genetic selection over many years has significantly improved the growth rate of broilers and increased the number of eggs laid by egg laying chicken breeds. Selection has improved desired parameters, but has caused some negative effects as well. Adverse effects of selection may negatively affect embryonic development. The number of live and apoptotic blastodermal cells (BCs) at the X stage of embryogenesis may be a good indicator of changes in selected individuals. In this paper, a comparison of the number of live and apoptotic BCs was made for three lines of quail: Pharaoh (F33), meat-type line, selected for body weight; egg laying line (S33), selected for egg number; and laying line (S22), additionally selected (for 17 generations) for high yolk cholesterol content. Apoptotic BCs were separated by the magnetic activated cell sorting (MACS) method. The percentage of live and apoptotic BCs was different (P <= 0.01) for F33 (35.8% and 64.2%, respectively) and S33 (60.0% and 36.4%). The number of apoptotic BCs for F33 embryos (45,098) was higher (P <= 0.01) compared to the number of apoptotic BCs for S33 embryos (26,667). The selection for high yolk cholesterol content caused an increase (P <= 0.01) in the total number of BCs from 78,403 (S33) to 140,139 (S22). The percentage of apoptotic BCs was lower (P <= 0.01) in the S22 line (17.1%) compared to the S33 line (36.4%). The results showed that it is possible to evaluate the effects of selection in the early stage of embryonic development. PMID- 26103688 TI - Species Relationships in the Genus Bryodaemon (Coleoptera: Curculionidae). AB - Establishing reliable taxonomy and phylogeny of similar, evolutionarily young species is among the greatest challenges in biology. Clearly the best approach is to use a combination of informative traits, including molecular markers and morphometric measurements. The objective of this study was to verify the taxonomy and phylogeny of four morphologically similar Carpathian species of Bryodaemon Podlussany, 1998 (Coleoptera: Curculionidae). Species relationships were studied using three molecular markers: two nuclear (ITS-2 and EF1-alpha) and one mitochondrial (COI, barcoding marker). We also took morphometric measurements of 35 taxonomically derived characteristics of body parts and genital apparatus. The potential presence of apomorphic features also was determined. We then compared our results with data concerning the ecology and geography of previously studied species. Our analyses confirmed the monophyly ofthis group and established a phylogeny for the genus. We propose that B. hanakii is the earliest derived species, based on morphometric measurements, apomorphies and the EF-lalpha phylogeny. The pattern ofnucleotide variation in this marker also indicates that B. rozneri and B. boroveci are the youngest species. This hypothesis is consistent with geographical ranges and ecological preferences of Carpathian Bryodaemon species. We also considered an alternative hypothesis based on the COI gene tree which indicated that B. rozneri was the oldest species. However, this arrangement is inconsistent with our morphological data. PMID- 26103689 TI - Molecular Identification of Paramecium bursaria Syngens and Studies on Geographic Distribution using Mitochondrial Cytochrome C Oxidase Subunit I (COI). AB - Paramecium bursaria is composed of five syngens that are morphologically indistinguishable but sexually isolated. The aim of the present study was to confirm by molecular methods (analyses of mitochondrial COI) the identification of P. bursaria syngens originating from different geographical locations. Phylograms constructed using both the neighbor-joining and maximum-likelihood methods based on a comparison of 34 sequences of P. bursaria strains and P. multimicronucleatum, P. caudatum and P.calkinsi strains used as outgroups revealed five clusters which correspond to results obtained previously by mating reaction. Our analysis shows the existence of 24 haplotypes for the COI gene sequence in the studied strains. The interspecies haplotype diversity was Hd = 0.967. We confirmed genetic differentiation between strains of P. bursaria and the occurrence of a correlation between geographical distribution and the correspondent syngen. PMID- 26103690 TI - Preventing and Controlling Cervical Cancer in Africa: A Call for Action. PMID- 26103691 TI - Community Factors Influencing Birth Spacing among Married Women in Uganda and Zimbabwe. AB - Short birth spacing continues to be a problem in Uganda and Zimbabwe, resulting in negative infant, child, and maternal health outcomes. This study investigates community-level influences on birth spacing outcomes among women aged 15-49 in Uganda and Zimbabwe, using Demographic and Health Surveys conducted in 2011 (Uganda) and 2010-2011 (Zimbabwe). Women living in communities with higher mean maternal age, mean age at marriage, and mean parity were significantly more likely to have longer birth spacing. Women living in communities with higher levels of contraceptive use and low levels of unmet contraceptive need were more likely to have short birth spacing. The significance of community-level demographic and fertility norms, gender norms, economic prosperity, and family planning behaviors demonstrate the broad influence of community variables on birth spacing outcomes. This analysis highlights the importance of moving beyond individual and household-level interventions in order to harness the power of contextual influences on birth spacing. PMID- 26103692 TI - Skilled Birth Attendance in Nigeria: A Function of Frequency and Content of Antenatal Care. AB - The utilization rate of maternal services remains low in sub-Saharan Africa and may be contributing to the region's high maternal mortality rate. This study examines the influence of antenatal care (ANC) on skilled birth attendance (SBA) in Nigeria. The data used were collected from a nationally representative sample of women (aged 15-49) in 2011. The sample is restricted to women who were within two years postpartum (weighted n = 9879). Multivariate logistic regression was used to assess the association between ANC (number of visits attended and services received during last pregnancy) and SBA. Despite 70% of the women receiving any ANC, only 49% had SBA during their last childbirth. The number of ANC services received, rather than the number of ANC visits attended, was positively associated with having SBA during last childbirth after controlling for relevant covariates (p < 0.05). The focus, therefore, should be on increasing the number of services received during ANC. PMID- 26103693 TI - Social Networks and Decision Making for Clandestine Unsafe Abortions: Evidence from Kenya. AB - Little is known about the role of social networks in promoting clandestine abortions. This study investigated the role social networks play in decision making for and facilitation of clandestine abortions. It was a mixed method study in which 320 women treated for complications of unsafe abortions were interviewed in a cross sectional survey to determine their consultation with social networks and how this ended up in clandestine abortions. Information obtained was supplemented with information from focus group discussions, case studies and key informant interviews. It was found that 95% of women consulted their social networks as part of decision making before aborting clandestinely and unsafely. The man responsible for pregnancy, friend of same sex and woman's mother were the most consulted at 64%, 32% and 23% respectively. 92% of advice was for the woman to abort. The man responsible for pregnancy and the woman's mother were the most influential advisors (p < 0.05). Intermediaries linked the woman to clandestine and unsafe abortion and included agents and previous clients of clandestine abortion providers and the woman's friends and relatives. Decision making and seeking for clandestine abortion were therefore found to be shared responsibilities. It is recommended that programs for reducing unsafe abortions be designed with this fact in mind. PMID- 26103694 TI - Factors Influencing Prevention and Control of Malaria among Pregnant Women Resident in Urban Slums, Southern Ghana. AB - Throughout Africa and particularly in Ghana, there are concerns about malaria infection during pregnancy. This study aimed to investigate factors that influence malaria prevention and control practices among pregnant women residing in Chorkor and Korle-Gonno in Accra, Ghana. One hundred and twenty pregnant women between ages 18-49 were randomly recruited during antenatal sessions at a maternity facility in Accra, as participants for the study. An interviewer administered questionnaire was used to collect data, which were analysed using SPSS version16.0. It was found that in Chorkor and Korle-Gonno, 57.4% and 42.6% participants respectively reported having been infected with malaria during their current pregnancy. There was no significant relationship between religious beliefs of participants and their malaria prevention and control practices (X2 = 0.28, P = .53). However, there was a significant relationship between malaria prevention and control practices of participants and their income earning (X2 = 53.94, P = .00) and employment (X2 = 61.76, P = .00) statuses. With the exception of ethnicity (X2 = 35.62, P =.22), other socio-cultural conditions had a significant relationship with malaria prevention and control practices of the participants. The findings suggest the need to consider and integrate factors, such as poverty and poor living conditions in malaria prevention and control strategies. PMID- 26103695 TI - Human Resource Challenges to Integrating HIV Pre-Exposure Prophylaxis (PrEP) into the Public Health System in Kenya: A Qualitative Study. AB - Extensive planning will be necessary to integrate HIV pre-exposure prophylaxis (PrEP) into public health systems. In Bondo and Kisumu, Kenya, we conducted interviews with 16 district and provincial public health stakeholders and held consultations with 18 provincial and 23 national public health stakeholders on topics related to PrEP rollout. We coded interview transcripts and created memos summarizing responses. We documented consultation discussions through note taking. Human resource challenges identified included increased workload and insufficient personnel, the need for task shifting/sharing, training needs, infrastructural requirements, discrimination and stigma by staff towards at-risk clients, and providers' personal priorities about offering PrEP. These challenges paralleled current challenges related to integration of antiretroviral therapy (ART) and could be partially addressed prior to PrEP rollout. The recommendations for training staff are likewise grounded in lessons from ART and have practical application for program planners developing training curricula for PrEP delivery. PMID- 26103696 TI - "Over my Dead Body": Knowledge and Attitude of Children towards HIV and AIDS in the Cape Coast Metropolis of Ghana. AB - In Ghana, it was estimated in 2013 that some 34,557 children were living with HIV and AIDS. Researches on children's perception of risk, knowledge and support services for infected persons have been rarely undertaken. This paper is based on responses obtained from 120 in-school children aged 9-13 years drawn from three schools in the Cape Coast Metropolis of Ghana. The respondents provided qualitative data through essays and quantitative data through questionnaires. All the respondents have had some knowledge on HIV and AIDS and knew of where to access HIV and AIDS information. More than seventy per cent of them were not willing to purchase fresh vegetables from AIDS vendors nor were willing to allow AIDS infected female teachers to continue teaching them. It was recommended that children should be targeted with behavioural change communication messages especially by teachers to enable them live harmoniously with people infected and affected with AIDS. PMID- 26103697 TI - Accessing Sexual and Reproductive Health Information and Services: A Mixed Methods Study of Young Women's Needs and Experiences in Soweto, South Africa. AB - Young women and girls in South Africa are at high risk of unintended pregnancy and HIV. Previous studies have reported barriers to contraceptive and other sexual and reproductive health (SRH) services among young women in this context. We aimed to assess young women's SRH knowledge and experiences and to determine how they get SRH information and services in Soweto, South Africa using quantitative and qualitative methods. Young women, aged 18-24, recruited from primary health clinics and a shopping mall, reported that they have access to SRH information and know where to obtain services. However there are challenges to accessing and utilizing information and services including providers' unsupportive attitudes, uneven power dynamics in relationships and communication issues with parents and community members. There is a need to assist young women in understanding the significance of SRH information. They need access to age appropriate, youth-friendly services in order to have healthy sexual experiences. PMID- 26103698 TI - Prevalence and Correlates of Sexual abuse among Female Out-of- School Adolescents in Iwaya Community, Lagos State, Nigeria. AB - This study set out to document the prevalence and predictors of sexual intercourse with persons below the age of consent (statutory rape) and outright sex without consent (rape) among out-of-school adolescents in an urban slum in Lagos, Nigeria. Data gathered from a survey of 480 participants were employed. About 14% and 35% of the participants had been victims of rape and statutory rape respectively. Experience of rape was found to be a function of age and basic deprivation (Cox and Snell's R2 of 0.060 and a Nagelkerke's R2 of 0.108). Another model (with a Cox and Snell's R2 of 0.286 and a Nagelkerke's R2 of 0.394) shows that predictors of the experience of statutory rape include age, basic deprivation, living arrangement and previous attendance of school. In view of the overarching influence of basic deprivation on the experience of sexual abuse, an intervention programme that addresses the material conditions of adolescent girls in Nigeria is recommended. PMID- 26103699 TI - Prevalence and Factors Associated with Intimate Partner Violence among Married Women in an Urban Community in Lagos State, Nigeria. AB - Violence against women is a major public health problem globally. A cross sectional descriptive study was conducted in Ikosi Isheri LCDA of Lagos State among 400 married women. A multistage sampling method was used to select the respondents. The lifetime prevalence for physical violence, sexual violence and psychological violence were 50.5%, 33.8% and 85.0% respectively. Predictive factors for physical IPV include lower educational status of the women (AOR 3.22 95% CI: 1.54-6.77) and partner's daily alcohol intake (AOR: 1.84 95% CI: 1.05 3.23). The predictors of sexual violence include unemployment status of the partners (OR 5.89:1.39-24.84) and daily/weekly alcohol use (AOR 1.87 95% CI: 1.05 3.33). Predictors of psychological violence include respondents witness of parental violence (AOR 2.80 95% CI: 1.04-7.5) and daily alcohol use by partners (AOR 2.71 95% CI: 1.19-6.18). Preventive interventions such as increasing the educational status of women and reducing the intake of alcohol by men may help break the cycle of abuse. PMID- 26103700 TI - Adolescent Sexuality and Life Skills Education in Nigeria: To What Extent have Out-of-School Adolescents Been Reached? AB - The introduction of school-based adolescent sexuality and life skills education in Nigeria's formal education sector raises the misgiving that out-of-school youths who constitute more than half of the youth population might be neglected. This study investigated the extent to which out-of-school adolescents have been reached with sexuality education in Nigeria. The study took place in the six geopolitical zones and the Federal Capital Territory Abuja, and involved out-of school adolescents, Non-Governmental Organizations, and community leaders. The qualitative research approaches were employed. Most of the youths had been exposed to sexuality education through seminars, trainings and workshops organized by different organizations. However, states in the south were better served than those in the north. Sexually Transmitted Infections including HIV/AIDS prevention accounted for more than 40% of the content of sexuality and life skills education received by out-of-school adolescents. The programmes have impacted positively on adolescents' disposition and relationship with the opposite sex, knowledge and skill building. PMID- 26103701 TI - Obstetric Fistula "Disease" and Ensuing Care: Patients' Views in West-Africa. AB - We explored obstetric fistula patients' real-life experience of care in modern Health System. Our aim was to analyze how these women's views impacted their care uptake and coping. We conducted 67 in-depth interviews with 35 fistula patients or former patients in 5 fistula repair centers within referral hospitals in Mali and Niger. Perceptions of obstetric fistula influenced the care experience and vice versa. Obstetric fistula was viewed as a severe chronic disease due to length of care process, limitation of surgery and persisting physical and moral suffering. We highlight the opportunity to build on patients' views on obstetric fistula trauma and care in order to implement an effective holistic care process. PMID- 26103702 TI - Perceived Health System Causes of Obstetric Fistula from Accounts of Affected Women in Rural Tanzania: A Qualitative Study. AB - Obstetric fistula is still a major problem in low income countries. While its main cause is untreated obstructed labour, misconceptions about it still persist. This study aimed at exploring and describing perceived health system causes of obstetric fistula from women affected by it in rural Tanzania. This exploratory qualitative study included twenty-eight women affected by obstetric fistula. Semi structured interviews and focus group discussions were held and thematic analysis used to analyse perceived health system causes of obstetric fistula from women's account. Perceived health system causes of obstetric fistula fundamentally reflected the poor quality of obstetric care women received at health care facilities relating to staff unaccountability, late referral, and torture by nurses. The women's perception emphasizes the importance of improving the quality of obstetric care provided by health care providers in health care facilities. PMID- 26103703 TI - Epidemiology of Cervical Squamous Intraepithelial Lesions in HIV Infected Women in Kenya: a cross-Sectional Study. AB - Cervical cancer is the second most common cancer among women worldwide. Infection with the human immunodeficiency virus (HIV) and its related immunosuppression are associated with an increased risk of prevalent, incident, and persistent squamous intraepithelial lesions (SILs) of the cervix. The objective of the study was to describe the prevalence and predictors of high-risk HPV and cervical cancer to support the need for strengthening cervical cancer screening programs for HIV infected women in Kenya. A cross sectional study was conducted in a hospital in Central Kenya, Kiambu district. The study population constituted of HIV positive women attending the ART treatment clinic. A total of 715 HIV positive women initiated on Antiretroviral Therapy (ART) were enrolled in this study. About 359 (52.1%) were less than 40 years of age and 644 (90.3%) of the patients were widowed. About 642 (92.6%) of the HIV infected women were in follow-up period of >= 1 year. The outcome/prognosis of the patients undergoing ICC was 3 cured, 5 good and 4 poor respectively. In a multivariable ordinal logistic regression analysis showed that for a one-unit decrease of CD4, we expect 1.23 log odds of increasing the severity of cervical cancer (B = 1.23, P < 0.0 15), given that all of the other variables in the model are held constant. In conclusion screening of all HIV infected women, who are under HIV care and treatment, enrolling patients on HAART with higher CD4 counts is recommended to see the net effect of HAART response. PMID- 26103704 TI - Cervical Cancer and Human Papilloma Virus Knowledge and Acceptance of Vaccination among Medical Students in Southwest Nigeria. AB - Human papillomavirus (HPV) is the commonest viral sexually transmitted infection in the world and the leading cause of cervical cancer. Medical students as future healthcare providers will play a role in influencing patients' decision to receive HPV vaccination. This study was aimed at determining the knowledge of cervical cancer and HPV as well as the acceptance of HPV vaccination among medical students of the University of Lagos. A descriptive cross-sectional study was carried out among 280 medical students sampled using stratified sampling technique. Self-administered questionnaires were used to collect relevant data. Most respondents were aware of cervical cancer (95.4%), HPV (85.4%) and HPV vaccination (69.3%) and the most common source of information was school teaching. Good knowledge of cervical cancer, HPV and HPV vaccination was demonstrated by 51.8%, 67.1% and 21.1% respectively; only 39.6% fully accepted HPV vaccination. Inadequate information and high costs were the obstacles identified to receiving vaccine and recommending it to others. Older age and higher levels of study were significantly associated with good knowledge of HPV. Good knowledge of HPV and HPV vaccination respectively were significantly associated with full acceptance of vaccination. There is need for more education on cervical cancer, HPV infection and HPV vaccination for the medical students via school teaching and other media, and inclusion of the HPV vaccine in the National Program on Immunization to improve access. PMID- 26103705 TI - Preface. PMID- 26103706 TI - Diagnosis of Fetal Anomaly and the Increased Maternal Psychological Toll Associated with Pregnancy Termination. AB - Approximately 4% of U.S. abortions occur in desired pregnancies, with many resulting from fetal anomalies. The majority of terminations occur in the second trimester; however in recent years first-trimester ultrasound measurement for nuchal translucency, calculation of risk based on maternal age, and biochemistry at 11-14 weeks gestation, have resulted in earlier prenatal diagnoses for chromosomal abnormalities. First trimester ultrasound can also now lead to diagnoses of major structural abnormalities including anecephaly, ventral wall defects, and limb abnormalities. The American College of Medical Genetics released recommendations underscoring the crucial importance of ethical counseling and substantive communication with parents facing a prenatal diagnosis of fetal anomaly. Unfortunately, the inability of health care providers to understand and empathize with the ardent desire of some parents to refuse termination is likely to be a large factor in the common practice of professionals attempting to steer expectant parents toward termination. Perinatal hospice is family-centered, comprehensive, and integrative in nature. The care provided by perinatal hospice units is delivered by an interdisciplinary team of obstetricians, pediatricians, nurses, social workers and chaplains in 130 locations throughout the U.S. Support is offered from diagnosis until death and beyond with time for "bonding, loving, and losing." "Hospice care is an interactive, and at times intense, form of care. Rather than simply 'letting nature take its course,' this approach empowers the family to take control of some of the consequences of their unfortunate situation." A primary focus of perinatal hospice is on fear reduction. Parents facing the death of an infant often fear isolation and abandonment in addition to worrying about their child experiencing pain. Parents are assured that they will be cared for and supported throughout this entire chapter of their lives, as their babies are kept comfortable and free of pain until death. The approach is realistic without shattering hope that the diagnosis was wrong or that a miracle will take place as there is recognition that hope keeps parents going. There is also recognition that building memories is essential to the grieving process and frequent use of ultrasound is designed to provide visualization experience. Perinatal hospice teams assist in the development of birth plans, address the type and location of the delivery as well as aftercare of the mother and infant. PMID- 26103707 TI - Sociological Environmental Causes are Insufficient to Explain Autism Changepoints of Incidence. AB - The Environmental Protection Agency (EPA) recently published a study analyzing time trends in the cumulative incidence of autistic disorder (AD) in the U.S., Denmark, and worldwide. A birth year changepoint (CP) around 1988 was identified. It has been argued that the epidemic rise in autism over the past three decades is partly due to a combination of sociologic factors along with the potential contribution of thimerosal containing vaccines. Our work conducted an expanded analysis of AD changepoints in CA and U.S., and determined whether changepoints in time trends of AD rates temporally coincide with changepoints for the proposed causative sociologic and environmental factors. Birth year changepoints were identified for 1980.9 [95% CI, 1978.6-1983.1], 1988.4 [95% CI, 1987.8-1989.0] and 1995.6 [95% CI, 1994.6-1996.6] for CA and U.S. data, confirming and expanding the EPA results. AD birth year changepoints significantly precede the changepoints calculated for indicators of increased social awareness of AD. Furthermore, the 1981 and 1996 AD birth year changepoints don't coincide with any predicted changepoints based on altered thimerosal content in vaccines nor on revised editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). PMID- 26103708 TI - Epidemiologic and Molecular Relationship Between Vaccine Manufacture and Autism Spectrum Disorder Prevalence. AB - OBJECTIVES: To assess the public health consequences of fetal cell line manufactured vaccines that contain residual human fetal DNA fragments utilizing laboratory and ecological approaches including statistics, molecular biology and genomics. METHOD: MMR coverage and autism disorder or autism spectrum disorder prevalence data for Norway, Sweden and the UK were obtained from public and government websites as well as peer reviewed published articles. Biologically, the size and quantity of the contaminating fetal DNA in Meruvax II and Havrix as well as the propensity of various cell lines for cellular and nuclear uptake of primitive human DNA fragments were measured and quantified using gel electrophoresis, fluorescence microscopy and fluorometry. Lastly, genomic analysis identified the specific sites where fetal DNA fragment integration into a child's genome is most likely to occur. RESULTS: The average MMR coverage for the three countries fell below 90% after Dr. Wakefield's infamous 1998 publication but started to recover slowly after 2001 until reaching over 90% coverage again by 2004. During the same time period, the average autism spectrum disorder prevalence in the United Kingdom, Norway and Sweden dropped substantially after birth year 1998 and gradually increased again after birth year 2000. Average single stranded DNA and double stranded DNA in Meruvax II were 142.05 ng/vial and 35.00 ng/vial, respectively, and 276.00 ng/vial and 35.74 ng/vial in Havrix respectively. The size of the fetal DNA fragments in Meruvax II was approximately 215 base pairs. There was spontaneous cellular and nuclear DNA uptake in HFF1 and NCCIT cells. Genes that have been linked to autism (autism associated genes; AAGs) have a more concentrated susceptibility for insults to genomic stability in comparison to the group of all genes contained within the human genome. Of the X chromosome AAGs, 15 of 19 have double strand break motifs less than 100 kilobases away from the center of a meiotic recombination hotspot located within an exon. CONCLUSION: Vaccines manufactured in human fetal cell lines contain unacceptably high levels of fetal DNA fragment contaminants. The human genome naturally contains regions that are susceptible to double strand break formation and DNA insertional mutagenesis. The "Wakefield Scare" created a natural experiment that may demonstrate a causal relationship between fetal cell line manufactured vaccines and ASD prevalence. PMID- 26103709 TI - The Epidemiology of Abortion And Its Prevention in Chile. AB - Mortality by abortion has continuously decreased over the past fifty years in Chile. In fact, maternal death as a result of an induced abortion has become an exceptionally rare phenomenon in epidemiological terms (a risk of 1 in 4 million pregnant women of fertile age or 0.4 per 100,000 life births for abortion of any type, excluding ectopic pregnancy). After abortion became illegal in 1989, deaths related to abortion continued to decrease from 10.8 to 0.39 per 100,000 live births. This scientific fact challenges the common notion that less permissive abortion laws lead to greater mortality associated with abortion. PMID- 26103710 TI - AAPLOG Practice Bulletin No. 1: Perinatal Hospice--Care with Compassion for Families with an Adverse Prenatal Diagnosis. PMID- 26103711 TI - Parental Notification/Consent for Treatment of the Adolescent. AB - A continuing debate exists in both law and medicine regarding an adolescent's capacity to make rational, independent decisions. This is particularly true concerning an adolescent's capacity to make an informed decision with regard to abortion. Neuroscience research responds to the question by noting that the area of the brain involved in critical thinking and decision-making does not reach full maturity until the early to mid-twenties. Consequently, teens are more likely to act impulsively, rather than with rational and goal-oriented thought. Relying upon outdated information, medical organizations have generally maintained that most teens are fully competent to understand the risks and consequences of, and give informed consent to, medical procedures including abortion without parental knowledge, involvement, or consent. The American College of Pediatricians examines the data and challenges this position, emphasizing the important contribution of parents in advising their adolescent children about such life-changing decisions. PMID- 26103712 TI - Our reach matters: Expanding occupational therapy knowledge sharing and creation using the Internet. PMID- 26103713 TI - Metacognition in persons with substance abuse: Findings and implications for occupational therapists. AB - BACKGROUND: Addiction is a massive public health problem in which a person's occupational life is compromised and metacognition is impaired. Occupational therapists may play a critical role in addiction rehabilitation, but more information about patterns of metacognitive deficit co-occurring with addictive behaviour is needed to develop interventions that specifically target these impairments. PURPOSE: This study examined whether persons with addiction(s) demonstrated specific patterns of metacognitive deficit on four subscales of metacognition measuring self-reflectivity, understanding others' thoughts, decentration, and mastery. METHOD: Using a mixed-methods design, qualitative data were obtained via the Indiana Psychiatric Illness Interview, which was then rated using a quantitative scale, the Metacognition Assessment Scale-Abbreviated. FINDINGS: Persons with addiction(s) demonstrated significant impairments in metacognitive mastery but not other areas of metacognition. IMPLICATIONS: Occupational therapy interventions for addiction should focus on improving metacognitive mastery. Future efficacy studies of interventions to improve mastery and overall outcomes are warranted. PMID- 26103714 TI - A call for sustainable practice in occupational therapy. AB - BACKGROUND: The ability of the earth to sustain health among humans and in the natural world is under threat from overpopulation, environmental degradation, and climate change. These global threats are anticipated to harm health and human occupation in many direct and indirect ways. Strategies are needed to mitigate the effects of these threats and to build individual and community capacities to foster resilience. PURPOSE: This paper links issues of sustainability with occupational therapy philosophy and discusses how employing a sustainability lens with professional reasoning can help practitioners integrate sustainability into their practice. KEY ISSUES: Human occupation is inseparable from the environments in which people live. Human occupation has caused the current environmental crisis, and targeted human action is required to safeguard future health and well being. IMPLICATIONS: Occupational therapists have an ethical obligation to use professional reasoning strategies that, taken collectively, can help to build a sustainable and resilient future. PMID- 26103715 TI - [Reappropriation of residential space of families with a person with a spinal cord injury]. AB - BACKGROUND: To date, we do not know how home adaptations transform the residential experience of people with disabilities and their families. PURPOSE: This study aimed to describe the residential reappropriation process of people with spinal cord injury and their families. METHOD: Interviews with 31 people with spinal cord injuries and 31 family members focused on the adaptations, satisfaction with the adaptations, territorial behaviour at home, and family functioning. FINDINGS: Adaptations aimed to sustain the disabled person's autonomy and mobility. Participants were satisfied with the physical adaptations, particularly in regard to convenience and feeling safe. Territorial behaviour supported the need for control and freedom. A more successful reappropriation process was associated with more effective family functioning. IMPLICATIONS: Territorial behaviours and effective family functioning should be considered by occupational therapists working with families. PMID- 26103716 TI - Assessment practices of Canadian occupational therapists working with adults with mental disorders. AB - BACKGROUND: Little is known about assessment practices of occupational therapists working with adults with mental disorders. PURPOSE: This study investigates the assessment practices of occupational therapists working with clients experiencing symptoms of schizophrenia or major depressive disorder. METHOD: We conducted a national survey of assessment practices using case vignettes of hypothetical clients. FINDINGS: From 343 vignettes completed by 286 respondents, 68.4% included the use of one or more standardized measures during treatment. Measures were rarely repeated. Results showed that the Canadian Occupational Performance Measure was the most frequently used, suggesting a focus on assessing global functioning, while the Assessment of Motor and Process Skills was listed as the most desired assessment tool. Implementing nonstandardized assessments was common. IMPLICATIONS: Despite wide variations in occupational therapists' assessment practices, the use of standardized assessments is prevalent. The low rate of repeated measures (0% to 25.9%) suggests a need to better monitor changes and treatment outcomes. PMID- 26103717 TI - Empowering people to change occupational behaviours to address critical global issues. AB - BACKGROUND: The greatest threat to human well-being in this century is climate change and related global issues. PURPOSE: We examined the effectiveness of the Modified Instrumentalism in Occupational Therapy model as a framework for facilitating occupational behaviour change to address climate change and related issues. METHOD: Eleven individuals participated in this mixed-methods single subject-design study. Data were gathered using the Modified Assessment and Intervention Instrument for Instrumentalism in Occupational Therapy and Daily Occupational Inventories. Quantitative data were analyzed using two- and three standard deviation band methods. Qualitative data were analyzed using heuristic phenomenological procedures. FINDINGS: Occupational performance changed for five participants. Participants' feelings shifted from frustration and helplessness to empowerment and a desire for action. They felt empowered to find occupation-based solutions to the global issues. IMPLICATIONS: Occupation-based interventions that increase personal awareness of the connection between occupational performance and global issues could empower people to be agents for action to ameliorate the issues. PMID- 26103718 TI - [The Integration and Regulation of Hormone-Sensitive Lipase in Reproductive System]. AB - Hormone-sensitive lipase (HSL) has long been considered as a classical rate limiting enzyme during lipolysis since it was first described in 1960s. HSL is regulated mainly by catecholamine, including adrenalin. Studies in recent years indicated that the substrates for HSL are not only triglycerides, but also diacylglycerol with the catalytic activity is ten times that of triglycerides, glycerol esters and cholesterol esters, which overthrow the opinion that HSL is specific to triglyceride. The scientists have generated HSL gene knockout mice and confirmed HSL is widely located in the reproductive system, which indicates that HSL may play an important role in the regulation of physiological and pathophysiological process in the reproductive system. Here, we will focus on the features of the HSL gene, mRNA and its protein, and summarize the HSL functions in the reproductive system. PMID- 26103719 TI - [The Progress of Research About Pancreatic Lipase]. AB - During the digestive procedure, pancreatic lipase is known as the main enzyme in vivo for digestion and absorption of dietary fat, consisting of pancreatic triglyceride lipase, pancreatic lipase related proteins 1 and 2, bile salt - stimulated Lipase and phospholipase A2. The changes of the development pattern of pancreatic lipase have confirmed associations with metabolic diseases such as obesity, not only because age is connected with the development of pancreatic lipase, but also pancreatic lipase itself is regulated by the dietary structure and endocrine hormone. PMID- 26103720 TI - [The Development of Gene Knockout Technologies in Large and Medium Animal Models]. AB - Technique of homologous recombination based gene targeting developed in the late 1980s and won the Nobel Prize in Physiology or Medicine in 2007. However, this technique could only performed in mice which embryonic stem (ES) cells could keep in the potential of multifunction in vitro. Therefore gene knockout technology was difficult to be applied in other species of animals for a long time. Since 2008, with the development of the new technologies, such as the new ES cell gene targeting, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clusters of regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9), building gene knockout in large and medium animals models which are similar to human in disease research becomes possible. This review describes some new gene knockout technologies in large and medium animal models for recent years. PMID- 26103721 TI - [MicroRNAs Regulation of Cancer Stem Cells]. AB - Cancer stem cells(CSCs) have been reported in many human tumors and are associated with tumor initiation and progression. CSCs share many biological properties with normal somatic stem cells, such as self-renewal, the propagation of differentiated progeny. However, they also have differences in their chemoresistance and tumorigenic and metastatic activity. CSCs have potential clinical importance, but the regulation at the molecular level is not well understood. MicroRNAs(miRNAs) are a class of endogenous non-coding RNAs, and play important role in the regulation of several cellular processes. Varieties of evidence show that, miRNAs can regulates the CSCs at a molecular level and are associated with tumor initiation and progression. Better understanding of the regulation of CSCs gene expression by miRNAs could be used to identify the biomarkers and therapeutic targets. In the present review, we summarize the major development on the regulation of CSCs by miRNAs. PMID- 26103722 TI - [Endothelium Aging and Oxidative Stress]. AB - In the endothelium, ROS mainly derive from mitochondria, endothelial nitric oxide synthases and NADPH oxidases 4. Excessive ROS are a major cause of oxidative stress, the primary stimulus of vascular dysfunction and oxidative stress-related diseases. However, cellular evolution has made possible the development of adaptive antioxidant systems that scavenge excessive ROS, such as Nrf2/Keapl-ARE, PPAR-y, SIRT and FOXO, etc. Among them, the Nrf2/Keapl-ARE signaling pathway is perhaps the most prominent. What is more, there are the "crosstalk" among these antioxidant stress-related signaling pathways aim to alleviate oxidative stress injurys and promote cells survival. The understanding of the relationship between endothelial aging and oxidative stress may serve as a therapeutic clues in the treatment of oxidative stress-related diseases. PMID- 26103723 TI - [Immune tolerance induced by Foxp3' Treg and organ transplantotion]. PMID- 26103725 TI - [Function of miRNA passenger strand]. PMID- 26103724 TI - [The new approaches of aptamer-based therapeutics to combating human immunodeficiency virus]. PMID- 26103726 TI - [Investigation for the memory of enzyme]. PMID- 26103728 TI - [Apelin/APJ system--the important targets for the regulation of energy metabolism]. PMID- 26103727 TI - [Research progress of complement-C1q/tumor necrosis factor-related protein]. PMID- 26103729 TI - [Progress in signal pathways of ABCA1 mediated cholesterol efflux and anti inflammatory]. PMID- 26103730 TI - [Progress in the sleep of female]. PMID- 26103731 TI - [The role of histone deacetylases in the regulation of energy metabolism]. PMID- 26103732 TI - [Progress in roles and mechanism of FHFs in arrhythmia]. PMID- 26103734 TI - [The effect and advance of Kupffer cells in the mechanism of ischemia reperfusion injury after liver transplantion]. PMID- 26103733 TI - [The doubt, progress and challenges of female germline stem cells in mammalian research]. PMID- 26103735 TI - [The physiological and pathophysiological function of TRPC6 in lung]. PMID- 26103736 TI - Regional versus general anesthesia for spine surgery. A comprehensive review. AB - The use of regional anesthesia techniques for intra-operative anesthesia remains very controversial for patients scheduled to undergo spinal interventions. Spine surgery is still mostly performed under general anesthesia. This has to be explained by the patient's position required during surgery, the extent and duration of some procedures, the preference of the surgeon and/or anesthesiologist and a trend which becomes more and more prominent to abandon central nerve blocks in general. The presence of foreign material in the neighborhood of the surgical field may be a reason for surgeons to refuse such techniques. Nevertheless, during the last decade the available literature has increased progressively in support of regional anesthesia for these interventions. The present overview will focus on the feasibility of different regional techniques to be used intra-operatively. These techniques may also be of interest or even intended for prolonged postoperative analgesia and benefit even after a single bolus injection, continuous or intermittent administration. Although all techniques described offered favorable success rates, future research is mandatory to determine their superiority over general intra-operative anesthesia and conventional pain therapy. PMID- 26103737 TI - Cerebral tissue oxygen saturation during arthroscopic shoulder surgery in the beach chair and lateral decubitus position. AB - Arthroscopic shoulder surgery is a common procedure and can be performed with the patient in the lateral decubitus position (LDP) or beach chair position (BCP). Although the BCP is associated with better visualization and less bleeding, it has also been associated with hemodynamic changes and consequently cerebral hypoperfusion. Devastating events reported after surgery in the BCP were attributed to a combination of the upright position and hypotension. Besides position and blood pressure, ventilator management and type of anesthesia should be taken into account. Near infrared spectroscopy might be able to provide an early warning sign of cerebral hypoperfusion during shoulder surgery in the BCP. It was therefore recommended to continuously monitor cerebral oxygenation in patients undergoing shoulder surgery in the BCP, to potentially prevent devastating outcomes. However, more clinical research on the safe lower limits of cerebral tissue oxygen saturation is needed for this recommendation to gain broad acceptance. PMID- 26103738 TI - Skin Temperature during Cold Pressor Test in Fibromyalgia: an Evaluation of the Autonomic Nervous System? AB - INTRODUCTION: Fibromyalgia (FM) is a common chronic pain disorder characterized by whole-body pain and multiple symptoms. This study investigated potential dysfunctions of the Autonomic Nervous System (ANS) in FM patients through the measurement of the autonomic response during a cold-water test. METHODS: 23 female patients with FM and 15 healthy female controls were recruited. First, FM patients filled out the following questionnaires: PainDETECT, American College of Rheumatology (ACR) criteria of FM, and Profile of Mood States (POMS). Healthy controls only filled out the POMS. Subsequently, all participants immersed their forearm into 1 degrees C cold-water as long as they could tolerate for a maximum of 120 seconds. A thermographic camera recorded skin temperature and its recuperation process. RESULTS: The two groups differed significantly regarding central body temperature, forearm thermography, and peripheral (forearm)-central (ear) temperature ratio. FM patients showed less tolerance to cold water than control participants. Although total temperature decrease, cool-down rate, recuperation between 0 and 20 minutes after withdrawal showed significant intergroup differences, thermal recovery followed similar patterns in both groups. DISCUSSION: Peculiar ANS baseline characteristics are seen in FM patients. Although those patients have reduced ability to sustain low temperatures, therefore limiting extrapolation of inter-group analysis, their thermal-adaptive responses were found different as compared to controls. PMID- 26103739 TI - Postsurgical compartment syndrome of the forearm diagnosed in a child receiving a continuous infra-clavicular peripheral nerve block. AB - Opinions diverge as to whether or not regional anaesthesia delays the diagnosis of evolving acute compartment syndrome. Withholding regional anaesthesia from patients with painful orthopaedic injuries may be ethically unacceptable, however. In this report, we describe a case of acute compartment syndrome in a 4 year old child who underwent resection of a forearm osteochondroma. Analgesia was satisfactory during the first post-operative night, but the child later complained of pain despite an effective infra-clavicular block. Motor function and sensibility were disturbed and the fingers were swollen. The forearm cast was removed as it was suspected to be causing external compression. Pain disappeared while motor function and sensation recovered. The child was discharged without any complications. Despite an effective peripheral nerve block and the young age of the patient, the diagnosis of acute compartment syndrome could be made thanks to a well-defined post-operative analgesia protocol, a high level of suspicion and careful clinical assessment when break-through pain occurred. PMID- 26103740 TI - Anaesthetic consideration of a child with concomitant craniovertebral junction anomaly and arrested hydrocephalus. AB - Congenital malformations of various sorts account for a large percentage of childhood hydrocephalus but associated Craniovertebral junction (CVJ) anomaly has not been reported earlier. Though the anaesthetic concerns for isolated arrested hydrocephalus and CVJ anomaly has been reported but the concomitant occurrence of both and its anaesthetic implications is not mentioned in literature. Here we present the anaesthetic management of a child with arrested hydrocephalus along with CVJ anomaly leading to compression of cervicomedullary junction and myelopathy scheduled for decompression and fixation of craniovertebral junction. PMID- 26103741 TI - Infant Formula: The Addition of Minimum and Maximum Levels of Selenium to Infant Formula and Related Labeling Requirements. Final rule. AB - The Food and Drug Administration (FDA or we) is amending the regulations on nutrient specifications and labeling for infant formula to add the mineral selenium to the list of required nutrients and to establish minimum and maximum levels of selenium in infant formula. PMID- 26103742 TI - National Vaccine Injury Compensation Program: Addition of Intussusception as Injury for Rotavirus Vaccines to the Vaccine Injury Table. Final rule. AB - On July 24, 2013, the Secretary of Health and Human Services (the Secretary) published in the Federal Register a Notice of Proposed Rulemaking (NPRM) proposing changes to the regulations governing the National Vaccine Injury Compensation Program (VICP). Specifically, the Secretary proposed revisions to the Vaccine Injury Table (Table). The basis for this change is consistent with the Secretary's findings that intussusceptions can reasonably be determined in some circumstances to be caused by rotavirus vaccines. The Secretary is now making this amendment to the Table and to the Qualifications and Aids to Interpretation (QAI), described below under Background Information, as proposed in the NPRM. These regulations will apply only to petitions for compensation under the VICP filed after this final rule becomes effective. PMID- 26103743 TI - Experiences and Attitudes of Primary Care Providers Under the First Year of ACA Coverage Expansion: Findings from the Kaiser Family Foundation/Commonwealth Fund 2015 National Survey of Primary Care Providers. AB - A new survey from The Kaiser Family Foundation and The Commonwealth Fund asked primary care providers--physicians, nurse practitioners, and physician assistants -about their views of and experiences with the Affordable Care Act (ACA) and other changes in health care delivery and payment, as well as their thoughts on the future of primary care. In this first brief based on the survey, many providers reported seeing an increased number of patients since the coverage expansions went into effect, but not an accompanying compromise in quality of care. A large majority of primary care providers are satisfied with their medical practice, but a substantial percentage of physicians expressed pessimism about the future of primary care. Similar to the population overall, providers' views of the ACA are divided along party lines. A second brief will report on providers' reactions to other changes occurring in primary care delivery and payment. PMID- 26103744 TI - An Introduction to Chemical Knowledge in the Early Modern World. PMID- 26103745 TI - Transmuting Sericon: Alchemy as "Practical Exegesis" in Early Modern England. AB - An influential strand of English alchemy was the pursuit of the "vegetable stone," a medicinal elixir popularized by George Ripley (d. ca. 1490), made from a metallic substance, "sericon." Yet the identity of sericon was not fixed, undergoing radical reinterpretation between the fifteenth and seventeenth centuries as Ripley's lead-based practice was eclipsed by new methods, notably the antimonial approach of George Starkey (1628-65). Tracing "sericonian" alchemy over 250 years, I show how alchemists fed their practical findings back into textual accounts, creating a "feedback loop" in which the authority of past adepts was maintained by exegetical manipulations--a process that I term "practical exegesis." PMID- 26103746 TI - Aubeta Quecksilber und Schwefel Rein: Johann Mathesius (1504-65) and Sulfur Mercurius in the Silver Mines of Joachimstal. AB - The Sarepta, oder Bergpostill (1562) by Johann Mathesius is a book of sermons on mining and mineral subjects in which the composition and generation of metals in ore veins are discussed in terms of the sulfur-mercurius theory. Gur was an embodiment of mercurius or of sulfur and mercurius. Sulfur was evident in the sulfurous odor of the mines, in the supposed effects of subterranean heat, and in the deposition of mineral sulfur during the roasting of the ores. The toxic smoke given off during smelting was considered to be an additional manifestation of mercurius. Mathesius's sermons offer a glimpse of the ways miners' understanding of ores overlapped with alchemists' theories. PMID- 26103747 TI - Eloquence in the Marketplace: Erudition and Pragmatic Humanism in the Restoration of Chymia. AB - This chapter focuses upon the relation between textual and social practices that influenced the formation of a communal approach to acquiring chemical knowledge in the early seventeenth century. It also describes the utilitarian purpose of a humanist-inspired program of chemical learning that blended practices of textual/linguistic expertise and artisanal know-how. Humanism, made pragmatic, sought to define the principles for "making things well." In the design of Andreas Libavius (ca. 1555-1616), interpretive intuitions resulting from practiced reading of ancient and medieval texts combined with a knowledge of workshop language to build consensus about chymia's tools, procedures, and materials and to define its principia artificialia. PMID- 26103748 TI - Robert Boyle, Transmutation, and the History of Chemistry before Lavoisier: A Response to Kuhn. AB - In an influential article of 1952, Thomas Kuhn argued that Robert Boyle had little or no influence on the subsequent development of chemistry. This essay challenges Kuhn's view on two fronts. First, it shows that Johann Joachim Becher developed his hierarchical matter theory under the influence of Boyle and then transmitted it to the founder of the phlogiston theory, G. E. Stahl. Second, this essay argues that transmutational matter theories were not necessarily opposed to the existence of stable chemical species, pace Kuhn. Boyle's corpuscular theory descended largely from the tradition of "chymical atomism," which often advocated both chrysopoeia and the reality of robust chemical substances. PMID- 26103749 TI - The Chymistry of "The Learned Dr Plot" (1640-96). AB - In the seventeenth century, there were developing norms of openness in the presentation of scientific knowledge that were at odds with traditions of secrecy among chymists, particularly practitioners of chrysopoeia, or the transmutation of metals. This chapter analyzes how Dr. Robert Plot, the first professor of chymistry at Oxford, negotiated these boundaries within an institutional context. I first delineate his chymical and experimental practice, which incorporated procedures from medieval alchemical sources, particularly the Lullian corpus, as well as more novel practices from seventeenth-century chymistry. Then, I analyze how personal and institutional ambitions and economic considerations shaped to what extent Plot negotiated the boundaries between secrecy and the public dissemination of chymical knowledge. PMID- 26103750 TI - The End of Alchemy? The Repudiation and Persistence of Chrysopoeia at the Academie Royale des Sciences in the Eighteenth Century. AB - The general abandonment of serious endeavor toward metallic transmutation represents a major development in the history of chemistry, yet its exact causes and timing remain unclear. This essay examines the fate of chrysopoeia at the eighteenth-century Academie Royale des Sciences. It reveals a long-standing tension between Academie chemists, who pursued transmutation, and administrators, who tried to suppress it. This tension provides background for Etienne-Francois Geoffroy's 1722 paper describing fraudulent practices around transmutation. Although transmutation seems to disappear after Geoffroy's paper, manuscripts reveal that most of the institution's chemists continued to pursue it privately until at least the 1760s, long after widely accepted dates for the "demise of alchemy" in learned circles. PMID- 26103751 TI - Etienne-Francois Geoffroy (1672-1731), a Chemist on the Frontiers. AB - Etienne-Francois Geoffroy is certainly the most representative chemist of the Paris Academie Royale des Sciences in the early eighteenth century. Interested in Newtonian ideas, he did not reject Cartesian mechanism. He is the inventor of the "Table des rapports entre les substances chimiques," which remained in use throughout the eighteenth century, but he drew from the alchemical tradition. He readily theorized about the composition of metals or the laws of chemical affinities, but he practiced a chemistry that was rooted in laboratory work and the search for substances useful to craftsmen. PMID- 26103752 TI - Communications of Chemical Knowledge: Georg Ernst Stahl and the Chemists at the French Academy of Sciences in the First Half of the Eighteenth Century. AB - Histories of eighteenth-century chemistry often assert that the works of the German chemist Georg Ernst Stahl (1659-1734), especially his ideas about phlogiston, were largely unknown to French chemists until the 1740s. A careful analysis of Stahl's writings and the publications of the Royal Academy of Sciences in Paris shows that academy chemists were well informed about, and even integrated, Stahl's chemical theories, experiments, and methods beginning in the 1710s, and that Stahl kept abreast of the work by his colleagues at the Paris Academy. It also reveals the frequency and significance of the communication between French and German chemical communities in the first half of the eighteenth century. PMID- 26103753 TI - Measuring Fire: Herman Boerhaave and the Introduction of Thermometry into Chemistry. AB - This essay examines Herman Boerhaave's work with the instrument maker, Daniel Gabriel Fahrenheit, on integrating the thermometer into the practice of eighteenth-century chemistry. Boerhaave utilized the thermometer to generate empirical evidence for the existence and actions of his instrument, "fire," by incorporating the instrument into pedagogical demonstrations, chemical research on heat, and, finally, the performing of operations. I examine how the use of the thermometer altered the chemists' traditional approach to heat, based on skilled sense perception and experiential judgment, and suggest that the threat to traditional practice posed by the instrument explains some of the resistance to it among some chemists in the mid-eighteenth century. PMID- 26103754 TI - How to See a Diagram: A Visual Anthropology of Chemical Affinity. AB - In 1766, Thomas Cochrane entered the Edinburgh classroom of Joseph Black (1728 99) to learn chemistry for the first time. Cochrane was studying medicine, and, like so many of Black's students, he dutifully recorded several diagrams in his notebooks. These visualizations were not complex. They were, in fact, simple. One of them, reproduced in this essay, was a single "X" a chiasm. Black used it to illustrate ratios of chemical attraction. This diagram is particularly important for the history of chemistry because it is often held to be the first chemical formula, and, as such, historians have endeavored to explain why it was unique and how Black invented it. In this essay, I wish to turn the foregoing premise on its head by arguing that Black's chiasm was neither visually unique nor invented by him. I do this by approaching a number of his diagrams via a visual anthropology that allows me to examine how students learned to attach meaning to patterns that were already familiar to them. In the end, we will see that Black's diagrams were successful because their visual simplicity and familiarity made them ideally suited to represent the chemical theories that he so skillfully attached to them. PMID- 26103755 TI - Between the Workshop and the Laboratory: Lavoisier's Network of Instrument Makers. AB - Throughout his career, Lavoisier paid particular attention to the apparatuses he intended to use in his experimental pursuits. Lavoisier engaged many instrument makers in Paris, the French provinces, and abroad, and he made several efforts, more or less successful, to design a new environment for chemical experimentation. In addition to working with famous instrument makers such as Fortin, Megnie, and Ramsden, Lavoisier had his instruments made by more than seventy other different makers. In this essay, I outline their contributions and make a preliminary attempt to establish their role in the design of Lavoisier's instruments and in the changes that occurred in chemical experimentation. PMID- 26103756 TI - An Empire's Extract: Chemical Manipulations of Cinchona Bark in the Eighteenth Century Spanish Atlantic World. AB - In 1790, the Spanish Crown sent a "botanist-chemist" to South America to implement production of a chemical extract made from cinchona bark, a botanical medicament from the Andes used throughout the Atlantic World to treat malarial fevers. Even though the botanist-chemist's efforts to produce the extract failed, this episode offers important insight into the role of chemistry in the early modern Atlantic World. Well before the Spanish Crown tried to make it a tool of empire, chemistry provided a vital set of techniques that circulated among a variety of healers, who used such techniques to make botanical medicaments useful and intelligible in new ways. PMID- 26103757 TI - Elements in the Melting Pot: Merging Chemistry, Assaying, and Natural History, Ca. 1730-60. AB - This essay examines how the modern concept of the chemical element emerged during the eighteenth century. It traces this concept to a group of assayers, mineralogists, and chemists active at the Swedish Bureau of Mines (Bergskollegium). Driven by a deep ontological pragmatism, these "mining chemists" came to regard all inquiries into the component parts of metals as useless speculation. Instead, metals were treated as immutable species that made mineralogical taxonomy possible. Their work was a form of Enlightenment boundary work, which associated chrysopoeia and the pursuit of the components of metals with superstition and disreputable activities such as astrology. PMID- 26103758 TI - Pierre-Joseph Macquer: Chemistry in the French Enlightenment. AB - Despite recent studies of chemistry courses and of academic research at the beginning of the eighteenth century, the perception of chemistry in the French Enlightenment has often been overshadowed by Lavoisier's works. This article proposes three specific case studies selected from Pierre Joseph Macquer's (1718 84) rich career to show the continuous evolution of chemistry throughout the century: medicinal chemistry through the application of the Comte de La Garaye's metallic salt solutions, the emergence of industrial chemistry through a few of Macquer's evaluations at the Bureau du Commerce, and finally communal academic research through the experiments on diamonds using Tschirnhaus's lens. These examples attempt to illustrate the innovative, creative, dynamic, multicultural, and multifaceted chemistry of the Enlightenment. PMID- 26103759 TI - Chemical Expertise: Chemistry in the Royal Prussian Porcelain Manufactory. AB - Eighteenth-century chemists defined chemistry as both a "science and an art." By "chemical art" they meant not merely experimentation but also parts of certain arts and crafts. This raises the question of how to identify the "chemical parts" of the arts and crafts in eighteenth-century Europe. In this essay I tackle this question with respect to porcelain manufacture. My essay begins with a brief discussion of historiographical problems related to this question. It then analyzes practices involved in porcelain manufacture that can be reasonably identified as chemical practices or a chemical art. My analysis yields evidence for the argument that chemical experts and expertise fulfilled distinct technical functions in porcelain manufacture and, by extension, in eighteenth-century "big industry," along with its system of division of labor. PMID- 26103760 TI - Pharmacy and Chemistry in the Eighteenth Century: What Lessons for the History of Science? AB - This essay questions the continuity of chemistry across the eighteenth century based on an analysis of its relationship to pharmacy in France. Comparing a text by Nicolas Lemery (1675) with one by Antoine Baume (1773), the article argues for a key transformation in chemistry across this period. The elimination of the practical side of pharmacy (indications and dosages) from chemistry texts is symptomatic of a reorientation of chemistry toward more theoretical or philosophical concerns. The essay considers several possible explanations for this change in orientation, including developments within pharmacy, but in the end privileges an approach in terms of the changing publics for chemistry in eighteenth-century France. PMID- 26103761 TI - Concluding Remarks: A View of the Past through the Lens of the Present. AB - Reflecting on the upsurge of interest among historians of chemistry in the material, artisanal, and commercial aspects of early modern chemistry, this essay argues that they are attracting attention because of a number of similarities between the style of chemistry cultivated in this period and the new cultures of chemistry being developed today. The close interactions between knowing and making, academic knowledge and practical applications, the social value and prestige attached to chemistry, the public engagement in chemical culture, the concern with recycling, and even a specific relational ontology instantiated in the term "rapport" are characteristic features of the current technoscientific culture. However, these analogies between early modern chemistry and the technoscientific paradigm may turn into obstacles if they end up in hasty rapprochements and whiggish interpretations of the past. In keeping with the attempts displayed in many articles in this volume to identify and understand the meaning of the actors' categories, this essay emphasizes the contrast between the visions of the past and the future developed by eighteenth-century chemists and the concept of time that prevails nowadays. The concept of "regime of historicity" provides a useful conceptual tool to take a view of chemistry as embedded in a culture and integral part of the horizon of expectation of an epoch. On the basis of this contrast between the regimes of historicity, the essay recommends the pluralism of concepts of time (polychronism) as an antidote to anachronisms. PMID- 26103762 TI - [Horizon 00]. PMID- 26103763 TI - [Risk communication in travel medicine]. AB - Recommendations for malaria prevention for travelers planning a trip in medium to low risk countries differ between countries, despite the fact that people are exposed to the same risk in the travelled country. Decision aids have been developed and tested in a population of travelers planning a trip in such countries n order to present travelers the various prevention options and involve them in the decision. The use of the decision aid showed that he majority of people choose not to take chemoprophylaxis and that they could motivate their choice with valid reasons. The development of decision aids based on recognized quality criteria is foreseen; these will allow to improving the relevance of the recommendations and enable travelers to choose a prevention option that will be the closest to their values and preferences while following to the principles of medical ethics. PMID- 26103764 TI - [Reemergence of Chikungunya virus]. AB - Arboviral diseases transmitted by mosquitoes such as Dengue, Chikungunya and West Nile are global health issues of growing magnitude. Their dissemination in new areas is triggered by increased mobility of persons, animal reservoirs and vectors. This article describes virological, epidemiological and clinical aspects of Chikungunya, which causes sporadic cases or epidemics, sometimes massive, such as the one spreading in the Americas since December 2013. Chikungunya should be suspected in all travellers presenting with fever, arthralgia and sometimes a rash returning from an endemic area. In the absence of vaccine, individual protection relies on the prevention of mosquito bites. PMID- 26103765 TI - [Acute schistosomiasis: lessons learned from a cohort of 42 exposed travelers]. AB - Acute schistosomiasis is a regularly encountered disease in travelers. Because of the temporal delay, its unspecific presentation and the spontaneous resolution, acute schistosomiasis can easily remain unrecognized by physicians who are not familiar with tropical pathologies. In December 2011, a female traveler was admitted to the hospital with undetermined fever after having returned from Madagascar where she bathed in fresh water. Acute schistosomiasis was diagnosed and infection was suspected among other travelers of her group. Seroconversion was confirmed among 78% of participants. This article intends to clarify the preventive and diagnostic strategies based on the lessons learned from this cluster of 42 travelers exposed to schistosomiasis. PMID- 26103766 TI - [The tropical traveling child: risks and prevention]. AB - Children increasingly travel to the tropics. Compared with adults, the risks of severe malaria, dehydration due to diarrhea, and the number of infectious episodes, are higher. Paradoxically, children receive less pre-travel advice than adults, and some parents are opposed to vaccinations. The consultation must target essential prevention topics. We present the age-related schedules for immunizations against yellow and typhoid fevers, hepatitis A and B, tick-borne and Japanese encephalitis, and rabies. We discuss the preventive measures for malaria, accidents, altitude, and prescriptions for antimalarial drugs, rehydration solutions and standby antibiotics according to weight. PMID- 26103767 TI - [Elderly travellers: review and advices]. AB - Thanks to improved health and transport means, an increasing number of elderly people travel. This population shows characteristics that necessitate adaptations of the pre-travel consultation. Travel-associated diseases are related to the presence of pre-existing underlying conditions. Indeed, a healthy elderly traveller does not have more risk to get sick during travel than a younger traveller. However, the frequency and severity of complications of some travel related diseases are increased. The aim of the pre-travel consultation in elderly will not be restrained to the usual prevention advices and immunization, but will also evaluate the risks of decompensation of pre-existing comorbidities, adapt if necessary ongoing medications to the conditions of travel, and plan access to care in case of acute decompensation. PMID- 26103768 TI - [Malaria and HIV: which interactions?]. AB - People living with HIV (PLHIV) frequently travel, including to the tropics, with a variable risk of infection by one of the species of Plasmodium, the hemoprotozoan parasite responsible for malaria. The HIV-malaria co-infection increases the risk of severe malaria, in proportion to the degree of immunosuppression. Protective measures against mosquito bites and antimalarial drug prophylaxis are recommended for PLHIV travelling to malaria highly endemic areas. PLHIV, as compared to the general population, are less likely to attend a pre-travel consultation prior to departure. Among returning travelers with malaria, early diagnosis and artemisinin-based treatments are the main determinants of successful treatment outcome. PMID- 26103769 TI - [Diverticulitis: operate or not?]. PMID- 26103771 TI - [The mortal danger of the averages and scores]. PMID- 26103770 TI - [Nausea and cough (in children): questions about drug treatments]. PMID- 26103772 TI - [2015: Has the time come to find the paths of Asilomar?]. PMID- 26103774 TI - [Xylella fastidiosa: the new plant pest that threatens the Old Continent]. PMID- 26103773 TI - [Smoking and health: harmful effects well beyond the classic associations?]. PMID- 26103775 TI - [Drug pricing: down 4 to 5%]. PMID- 26103776 TI - [PID: the slogans of political parties]. PMID- 26103777 TI - [New in the production of human GMOs]. PMID- 26103778 TI - Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis. AB - OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and >=15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status. PMID- 26103779 TI - Perinatal outcome of singleton versus twin late preterm infants: do twins mature faster than singletons? AB - OBJECTIVE: To determine whether as a result of an assumed advanced maturation late preterm twin infants have a more favorable perinatal outcome than singleton late preterm infants. METHODS: Over a 36-month period (from September 2011 to September 2014), 277 late preterm infants (153 from singleton and 124 from twin pregnancies) were hospitalised in NICU, University Hospital Center "Sisters of Mercy" Zagreb, Croatia, and were retrospectively studied by review of maternal and neonatal charts for gestational age, sex, birth weight, mode of delivery, 5 min Apgar score and for several outcome variables expected for preterm infants, until the day of discharge. RESULTS: There was statistically no significant difference in the incidence of any of the observed and compared outcomes, except in the incidence of phototherapy which was higher in singletons group (49.01 versus 13.7%, p < 0.0001). The mean birth weight, as expected, was smaller in the twin group. CONCLUSIONS: We found no evidence to support the traditional belief that twin late preterm infants have accelerated maturation and better neonatal outcome compared with singleton late preterm infants. Our findings suggest that late preterm twins have a prognosis similar to that of singleton late preterm infants born at the same gestational age. PMID- 26103780 TI - Fetal midgut volvulus: report of eight cases. AB - OBJECTIVE: To evaluate whether prenatal diagnosis of intestinal midgut volvulus (a rare condition due to the small bowel loops twisting) can improve the prognosis of the newborns. METHODS: In our Prenatal Diagnosis Center, eight cases of intestinal volvulus observed between 2007 and 2014 were retrospectively considered. Ultrasonographic signs can be direct and specific (whirlpool sign, coffee bean sign) or indirect and non-specific (abdominal mass, dilated bowel loops, pseudocysts, ascites, polyhydramnios). RESULTS: Prenatal diagnosis was performed at 20-34 weeks of gestation. All newborns were exposed to an emergency surgery: the major complication was due to cystic fibrosis. CONCLUSIONS: An early suspicion of intestinal volvulus allows the clinician to refer the patient to a tertiary center so to confirm the diagnosis and perform an appropriate follow-up in order to identify the proper time of delivery. The prognosis of the babies with prenatal intestinal volvulus depends on the length of the segment involved, on the level of intestinal obstruction, on the presence of meconium peritonitis and on the gestational age at birth. Our experience, according with the literature, suggests that ascites and absence of abdominal peristalsis are ultrasonographic signs that, in the third trimester of pregnancy, correctly lead to an immediate delivery intervention. PMID- 26103781 TI - A comparison of manual versus automated saturation of peripheral oxygenation in the neonatal intensive care unit. AB - BACKGROUND: It is vital to maintain the saturation of peripheral oxygenation (SpO2) in a targeted range in extremely premature infants to improve survival without significant morbidities. OBJECTIVES: To compare manual versus automated monitor documentations of daily upper and lower values of SpO2 in premature infants. METHODS: In a prospective observational study, the highest and lowest daily SpO2 manually recorded values from electronic medical records were compared with automatically recorded values from bedside cardiorespiratory monitors. RESULTS: Eighteen infants were monitored for 605 patient days, with a mean birth weight of 859 +/- 183 g, and gestational age of 26.0 +/- 1.3 wks. Within the lowest SpO2 values, manually recorded values were consistently higher than the simultaneous automatically recorded monitor values. The highest SpO2 point differences in documentation was seen in patients with SpO2 range <= 70% (16 +/- 13 points), followed by 71-80% (10 +/- 7 points) and 81-90% (7 +/- 4 points); p < 0.01. CONCLUSIONS: The difference between manually and automatically recorded SpO2 is large in lower SpO2 ranges and small in higher SpO2 ranges. Automated oxygen administering systems should be considered to reduce potential errors. PMID- 26103782 TI - Effects of neonatal sepsis on thrombocyte tests. AB - OBJECTIVE: Hemostatic disorders are common complications in sepsis, and coagulation abnormalities occur in almost all the septic patients. Thrombocytes have a key role in the pathogenesis of coagulation abnormalities in sepsis. This study aimed to investigate thrombocyte function disorders as a likely cause of hemorrhagic diathesis in patients with neonatal sepsis. MATERIAL AND METHODS: The study included 70 septic newborns (sepsis group) and 59 healthy newborns (control group). Blood samples were collected from the patients within the first 24 h of hospitalization. Thrombocyte aggregation and secretion tests were performed by optical aggregometry and lumi-aggregometry, respectively. Collagen (2 MUg/mL), epinephrine (5 MUM), standard (5 MUM) and high (10 MUM) doses of adenosine diphosphate (ADP), standard (1 unit) and high (4 units) doses of thrombin, ristocetin (1.25 mg/mL) and arachidonic acid (0.5 mM) were used as the agonists. RESULTS: The mean age of the septic newborns was significantly higher than that of the controls (6.78 +/- 14.47 days versus 1.25 +/- 1.17, p < 0.001). There was no difference between the groups regarding gender- and birth-related characteristics. No difference was observed between the groups regarding platelet count (293.37 +/- 144.48 * 10(9)/L in the sepsis group and 254.22 +/- 65.26 * 10(9)/L in the control group, p = 0.195). Platelet secretion induced by collagen, epinephrine, standard and high (10 MUM) doses of ADP, or arachidonic acid and platelet aggregation induced by collagen, high-dose ADP, arachidonic acid, ristocetin or thrombin (1 unit) were significantly higher in the sepsis group than in the control group. CONCLUSION: Based on the results, we concluded that large-scale studies with recurrent tests performed in different periods of sepsis are needed. PMID- 26103783 TI - Cord clamping time in spontaneously breathing preterm neonates in the first minutes after birth: impact on cerebral oxygenation - a prospective observational study. AB - OBJECTIVE: To analyse impact of delayed cord clamping (DCC60sec) on cerebral regional tissue oxygenation (crSO2) and fractional tissue oxygen extraction (cFTOE) in spontaneously breathing preterm neonates during the first 15 min after birth. METHODS: Two-centre observational study, crSO2 and cFTOE was monitored in neonates with DCC60sec or early cord clamping (ECC < 30 s). RESULTS: Seventy-six infants (birth weight and gestational age 1736 +/- 508 g and 31.8 +/- 2.5 weeks) were included. DCC was associated with lower initial crSO2 and higher cFTOE and lower initial Apgar-score and heart rate. CONCLUSION: Attending practitioners should be aware that DCC might impact initial immediate transition in spontaneously breathing preterm neonates. PMID- 26103784 TI - VapB type 8 plasmids in Rhodococcus equi isolated from the small intestine of pigs and comparison of selective culture media. AB - The virulence-plasmid profile of Rhodococcus equi strains isolated from Suidae and humans is similar. Recent evidence suggests that the consumption of pork products contaminated with faeces might be a potential source of R. equi infections in humans, mainly to patients with rhodococcosis without history of contact with pigs or pig farms. This study investigated the virulence-associated genes (vapA and vapB) and plasmid profiles of R. equi among the 150 samples of small intestinal content obtained from slaughtered pigs. In addition, all samples were subjected to microbiological culture in conventional sheep blood agar and CAZ-NB, TCP and TVP selective media. A total of 40 (26.7%) of the samples recovered R. equi, with two samples recovering isolates harbouring the VapB type 8 plasmid. Among the 150 pigs sampled herein, CAZ-NB was considered the best selective medium for the isolation of R. equi from faeces. Our results provide evidence that the contamination of slaughtered pig carcasses with pathogenic R. equi might occur through faeces, representing a public health concern. Furthermore, this study is the first description of R. equi strains carrying the VapB plasmid in the gut of pigs. SIGNIFICANCE AND IMPACT OF THE STUDY: Intermediately virulent (VapB) is a common plasmid-type harboured by R. equi isolated from pigs and humans with AIDS. Curiously, humans with rhodococcosis usually have no history of contact with pigs or pig farms. Virulence-plasmid profile of 40 R. equi isolated among 150 small intestine content samples from pigs revelled two carrying isolates with the VapB type-8 plasmids. Moreover, comparison of three selective culture media shows that CAZ-NB was the best. Our results provide evidence that contamination of slaughtered pig carcasses with pathogenic R. equi might occur through faeces, representing a public health concern. Furthermore, R. equi carrying VapB type-8 plasmids types are described for the first time in the gut of the pig. PMID- 26103785 TI - Registration of randomized clinical trials--a challenge. AB - BACKGROUND: Registration of interventional studies is necessary according to the Declaration of Helsinki but implementation has been a challenge for many journals. Acta Anaesthesiologica Scandinavica (Acta) requires registration for studies conducted after January 1(st) 2010. We aimed to assess the proportion of correctly registered randomized controlled trials (RCTs) published in Acta from 2009 to 2014. METHODS: We manually searched all Acta issues from 2009 to 2014 for RCTs. Information about timing of data collection and registration in trial registries was extracted. We classified RCTs as correctly registered when it could be verified that patient enrolment was started after registration in a trial registry. RESULTS: We identified 200 RCTs. Dates for patient enrolment were not specified in 51 (25.5%). The proportion of correctly registered trials increased significantly from 17.1% (19/111) for trials starting enrolment before 2010 to 63.2% after 2010 (24/38, P < 0.01). Most clinical trials were registered at clinicaltrials.gov. CONCLUSION: Many published randomized controlled trials from Acta Anaesthesiologica Scandinavica were not adequately registered but the requirement of trial registration has resulted in a significant increase in the proportion of correctly registered trials. PMID- 26103786 TI - Deconstructing the power resistance relationship for squats: A joint-level analysis. AB - Generating high leg power outputs is important for executing rapid movements. Squats are commonly used to increase leg strength and power. Therefore, it is useful to understand factors affecting power output in squatting. We aimed to deconstruct the mechanisms behind why power is maximized at certain resistances in squatting. Ten male rowers (age = 20 +/- 2.2 years; height = 1.82 +/- 0.03 m; mass = 86 +/- 11 kg) performed maximal power squats with resistances ranging from body weight to 80% of their one repetition maximum (1RM). Three-dimensional kinematics was combined with ground reaction force (GRF) data in an inverse dynamics analysis to calculate leg joint moments and powers. System center of mass (COM) velocity and power were computed from GRF data. COM power was maximized across a range of resistances from 40% to 60% 1RM. This range was identified because a trade-off in hip and knee joint powers existed across this range, with maximal knee joint power occurring at 40% 1RM and maximal hip joint power at 60% 1RM. A non-linear system force-velocity relationship was observed that dictated large reductions in COM power below 20% 1RM and above 60% 1RM. These reductions were due to constraints on the control of the movement. PMID- 26103787 TI - Pyrolysis Reactions of 3-Oxetanone. AB - The pyrolysis products of gas-phase 3-oxetanone were identified via matrix isolation Fourier transform infrared spectroscopy and photoionization mass spectrometry. Pyrolysis was conducted in a hyperthermal nozzle at temperatures from 100 to 1200 degrees C with the dissociation onset observed at ~600 degrees C. The ring strain in the cyclic structure of 3-oxetanone causes the molecule to decompose at relatively low temperatures. Previously, only one dissociation channel, producing formaldehyde and ketene, was considered as significant in photolysis. This study presents the first experimental measurements of the thermal decomposition of 3-oxetanone demonstrating an additional dissociation channel that forms ethylene oxide and carbon monoxide. Major products include formaldehyde, ketene, carbon monoxide, ethylene oxide, ethylene, and methyl radical. The first four products stem from initial decomposition of 3-oxetanone, while the additional products, ethylene and methyl radical, are believed to be due to further reactions involving ethylene oxide. PMID- 26103788 TI - Successful treatment with ustekinumab of psoriasis vulgaris in a patient undergoing hemodialysis. AB - Psoriasis is a common chronic inflammatory skin disease but psoriasis patients with renal impairment undergoing dialysis are not frequently seen. Furthermore, the published work contains little information on the treatment with biologic drugs of patients with end-stage renal disease. We describe a 57-year-old man with refractory plaque-type psoriasis and end-stage renal disease due to polycystic kidney disease undergoing hemodialysis. He had tried topical medications and ultraviolet therapy for many years and was then treated with ustekinumab (an interleukin-12 and interleukin-23 blocker), which resulted in good clinical response along with stable renal function. After a few years of therapy, no side-effects have been observed. Our experience with this patient expands the spectrum of ustekinumab to include psoriasis patients with renal failure undergoing hemodialysis. PMID- 26103789 TI - First-line Bismuth-containing Five-day Concomitant Quintuple Therapy for Helicobacter Pylori Eradication. AB - BACKGROUND: Widespread use of antibiotics has resulted in increased rates of antibiotic resistance and decreased rates of Helicobacter pylori (H. pylori) eradication, leading to a search for newer therapeutic options. This study aimed to examine the efficacy, tolerability, and patient compliance of a first-line bismuth-containing 5-day concomitant quintuple therapy. MATERIALS AND METHODS: This prospective study included 144 eradication treatment naive H. pylori positive patients with dyspeptic complaints. Patients received the following concomitant quintuple therapy for 5 days: bismuth subcitrate 300 mg q.i.d, omeprazole 20 mg b.i.d, clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg t.i.d. Eradication was assessed with H. pylori stool antigen test or urea-breath test 6 weeks after the completion of therapy. RESULTS: Treatment compliance rate in this study was 97.2%. Intention to treat and per protocol eradication rates were 134/144 (93.1%, 95% CI, 88.9-97.2) and 134/140 (95.7%, 95% CI, 92.2-98.6), respectively. Side effect was reported by 8.5% of the patients that attended follow-up visits, including epigastric pain (2.8%), nausea/vomiting (2.1%), diarrhea (1.4%), taste disturbance (1.4%), and fatigue (0.7%). CONCLUSIONS: Bismuth-containing, short course, quintuple concomitant therapy appears to be an effective and safe therapeutic option for the first-line H. pylori eradication, particularly in populations with high resistance. PMID- 26103790 TI - Self-perceived health versus actual cardiovascular disease risks. AB - AIM: Self-perceived poor health is related to cardiovascular disease (CVD) risk perception, cardiovascular event, hospital readmission, and death from CVD. This study evaluated the associations between self-perceived health and actual CVD risk in South Koreans as well as the influence of sociodemographic and cardiovascular risk factors on self-perceived poor health. METHODS: This is a secondary data analysis of the 2010 Korea National Health and Nutrition Examination Survey. The sample was 4535 South Koreans aged 30-74 years without CVD. Self-perceived health status was compared with actual cardiovascular risk separately by sex using chi(2) -tests. Logistic regressions were used to identify potential sociodemographic and cardiovascular risk factors of self-perceived poor health. RESULTS: Self-perceived poor health was related to higher CVD risk but there were substantial gaps between them. Among cardiovascular risk factors, dyslipidemia, obesity, smoking, and a family history of CVD did not affect self perceived health. CONCLUSION: Gaps between perceived health and actual CVD risk should be closed to optimize cardiovascular health of South Koreans. Koreans need to increase risk perception to a level commensurate with their actual risk. Healthcare providers should try to provide individuals at increased CVD risk with better information more frequently, especially those who have favorable perceptions of their health but smoke or have elevated cholesterol levels and bodyweight. PMID- 26103791 TI - Developing logistic regression models using purchase attributes and demographics to predict the probability of purchases of regular and specialty eggs. AB - Consumers' interest in specialty eggs appears to be growing in Europe and North America. The objective of this research was to develop logistic regression models that utilise purchaser attributes and demographics to predict the probability of a consumer purchasing a specific type of table egg including regular (white and brown), non-caged (free-run, free-range and organic) or nutrient-enhanced eggs. These purchase prediction models, together with the purchasers' attributes, can be used to assess market opportunities of different egg types specifically in British Columbia (BC). An online survey was used to gather data for the models. A total of 702 completed questionnaires were submitted by BC residents. Selected independent variables included in the logistic regression to develop models for different egg types to predict the probability of a consumer purchasing a specific type of table egg. The variables used in the model accounted for 54% and 49% of variances in the purchase of regular and non-caged eggs, respectively. Research results indicate that consumers of different egg types exhibit a set of unique and statistically significant characteristics and/or demographics. For example, consumers of regular eggs were less educated, older, price sensitive, major chain store buyers, and store flyer users, and had lower awareness about different types of eggs and less concern regarding animal welfare issues. However, most of the non-caged egg consumers were less concerned about price, had higher awareness about different types of table eggs, purchased their eggs from local/organic grocery stores, farm gates or farmers markets, and they were more concerned about care and feeding of hens compared to consumers of other eggs types. PMID- 26103792 TI - Multifocal small bowel obstruction in an infant. AB - This is a case report of an acute small bowel obstruction in a 17-month-old girl with no significant past medical history. Computerized tomography (CT) of the abdomen demonstrated complete obstruction at the proximal jejunum as well as perplexing dilation and air-fluid levels within the distal jejunum beyond the initial obstruction. Imaging demonstrated no evidence of malrotation, volvulus, or intussusception, but a clear diagnosis was not evident. Exploratory laparotomy was performed and multiple foreign bodies that appeared to be rubber balls were found within the small bowel. This case study identifies important clinical and radiologic considerations when assessing infants for small bowel obstruction. PMID- 26103793 TI - Postoperative outcome and survival in relation to small intestinal involvement of total colonic aganglionosis. AB - BACKGROUND: The prognosis and treatment of total colonic aganglionosis (TCA) vary according to the presence and extent of small bowel involvement. METHODS: Medical records of TCA patients treated in Helsinki University Children's Hospital during 1984-2013 (n=21) were reviewed. RESULTS: The aganglionosis extended up to cecum or distal ileum (n=12), mid small bowel (n=4), or duodenojejunal flexure (n=5). Patients underwent resection of distal aganglionic bowel with ileoanal (IAA) or jejunoanal anastomosis (JAA) with (n=9) or without J-pouch (n=5), Lester-Martin pull-through (n=1), or were left with an end-jejunostomy (n=6). Further procedures included autologous intestinal reconstruction (n=3) and ITx/listing for ITx (n=2). Compared to distal ileum aganglionosis, patients with more proximal disease required parenteral nutrition (PN) more often (100% vs. 25%) and weaned off PN less frequently (p=0.001). At last follow-up 6.5 (interquartile range 2.5-14.5) years postoperatively, all patients with distal ileum aganglionosis were off PN and alive compared to 78% on PN (p<0.001) and 67% alive (p=0.063) of those with more proximal disease. All had normal plasma bilirubin and patients with preserved intestinal continuity (n=13) were continent. CONCLUSIONS: Outcomes following restorative proctocolectomy for aganglionosis extending up to mid small bowel are promising, whereas long-term outlook in proximal small intestinal disease is dismal without ITx. PMID- 26103795 TI - Editorial: Practising with our hearts and minds: nurses and intimate partner violence. PMID- 26103794 TI - Diabetes telemonitoring reduces the risk of hypoglycaemia during Ramadan: a pilot randomized controlled study. AB - AIM: This pilot study evaluated the short-term benefits of a telemonitoring supplemented focused diabetic education compared with education alone in participants with Type 2 diabetes who were fasting during Ramadan. METHODS: In this pilot mixed-method study, we identified 37 participants and randomly allocated them to either a telemonitoring group (n = 18) or a group receiving Ramadan-focused pre-education only (usual care; n = 19). The telemonitoring group received goal-setting and personalized feedback. RESULTS: The telemonitoring group was less likely to experience hypoglycaemia than the usual care group (odds ratio: 0.1273; 95% confidence interval: 0.0267-0.6059). No significant differences were noted in glycaemic control at the end of study. Participants viewed telemedicine as a more convenient alternative although technological barriers remain a concern. CONCLUSIONS: The results of this study reinforce the need for monitoring as well as educational initiatives for Muslims with diabetes who fast during Ramadan. Telemonitoring offers an attractive option requiring further research. (Clinical Trial Registry No. NCT02189135). PMID- 26103796 TI - PRE-EMPT (PRE-eclampsia-Eclampsia Monitoring, Prevention and Treatment): A low and middle income country initiative to reduce the global burden of maternal, fetal and infant death and disease related to pre-eclampsia. PMID- 26103797 TI - Review: Potential druggable targets for the treatment of early onset preeclampsia. AB - Placental delivery is the only known cure for early onset preeclampsia, a major cause of maternal and neonatal morbidity and mortality worldwide. Prolonging pregnancy beyond 25weeks without undue maternal risk favors fetal survival, improves neonatal outcome and saves money. In vitro experiments using human placental tissue and in vivo studies employing "preeclamptic" animal models reveal the presence of likely druggable targets, especially within the maladapted intracellular nucleotide transduction pathways of preeclampsia. This review focuses on some novel pharmacological treatment options targeting early onset severe preeclampsia. Human and animal derived experimental data support the possible roles of nitric oxide donors (glyceryltrinitrate), aspirin, dietary supplements (calcium, l-Arginine, anti-oxidant vitamins), phosphodiesterase-5 inhibitors, statins, carbon monoxide and most recently, hydrogen sulfide. Extension of pregnancy or improvement of the disorder using means applicable in under resourced areas of the world would have a major positive impact on women's health globally. We therefore advocate the immediate launch of clinical trials testing simple innovative therapies in large obstetric units of developing countries such as South Africa or Brazil where preeclampsia is endemic and a regular killer of both mothers and offspring. PMID- 26103798 TI - Urine protein concentration estimation for biomarker discovery. AB - Recent advances have been made in the study of urinary proteomics as a diagnostic tool for renal disease and pre-eclampsia which requires accurate measurement of urinary protein. We compared different protein assays (Bicinchoninic acid (BCA), Lowry and Bradford) against the 'gold standard' amino-acid assay in urine from 43 women (8 non-pregnant, 34 pregnant, including 8 with pre-eclampsia). BCA assay was superior to both Lowry and Bradford assays (Bland Altman bias: 0.08) compared to amino-acid assay, which performed particularly poorly at higher protein concentrations. These data highlight the need to use amino-acid or BCA assays for unprocessed urine protein estimation. PMID- 26103799 TI - First trimester screening of serum soluble fms-like tyrosine kinase-1 and placental growth factor predicting hypertensive disorders of pregnancy. AB - OBJECTIVE: To assess the accuracy of first trimester soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) in predicting pregnancy hypertension and pre-eclampsia; and compare with the accuracy of routinely collected maternal and clinical risk factors. STUDY DESIGN: In this population based cohort study, serum sFlt-1 and PlGF levels were measured in first trimester in 2,681 women with singleton pregnancies in New South Wales, Australia. MAIN OUTCOME MEASURES: Prediction of pregnancy hypertension and pre-eclampsia. RESULTS: There were 213 (7.9%) women with pregnancy hypertension, including 68 (2.5%) with pre-eclampsia. The area under the curve (AUC) for both sFlt-1 and PlGF was not different from chance, but combined was 0.55 (P=0.005). Parity and previous diagnosed hypertension had better predictive accuracy than serum biomarkers (AUC=0.64, P<0.001) and the predictive accuracy for all maternal and clinical information was fair (AUC=0.70, P<0.001 for pregnancy hypertension and AUC=0.74, P<0.001 for pre-eclampsia). Adding sFlt-1 and PlGF to maternal risk factors did not improve the ability of the models to predict pregnancy hypertension or pre-eclampsia. CONCLUSIONS: Maternal first trimester serum concentrations of sFlt-1 and PlGF do not predict hypertensive disorders in pregnancy any better than routinely collected clinical and maternal risk factor information. Screening for sFlt-1 and PlGF levels in early pregnancy would not identify those pregnancies at-risk. PMID- 26103800 TI - Evaluation of the value of the first and third trimester maternal mean platelet volume (MPV) for prediction of pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia is one of the most serious complications of pregnancy and one of the major causes of maternal mortality. Thus its prediction is a matter for serious concern. OBJECTIVE: The purpose of the present study is to determine the value of mean platelet volume (MPV) measurement in the first and third trimesters of pregnancy for the prediction of pre-eclampsia. METHOD: A prospective nested case-control study was performed on pregnant women who were at 9-12weeks of pregnancy. In the first trimester and again in 26-28weeks, MPV was calculated. All eligible women were then monitored to delivery and the MPV of women who were pre-eclamptic was compared with the MPV of normotensive women. RESULTS: Pre-eclamptic women were compared with 269 normotensive women. MPV at the first trimester of pre-eclamptic women was significantly higher than normotensive women (10.2+/-1.06fl VS 9.68+/-1.09fl, P=0.008). Also, MPV at the third trimester of pregnancy of pre-eclamptic women was more than normotensives (10.16+/-1.23fl VS 9.62+/-1.12fl, P=0.009). Area under the curve in receiver operating characteristics (ROC) curve was calculated as 0.64 for the predictive value of MPV at the first and third trimesters of pregnancy, which showed a low value of this test for predicting of pre-eclampsia. CONCLUSION: MPV at the first and third trimesters of pregnancy are higher in women who eventually would be pre eclamptic, but has low predictive value and is not a good predictor of pre eclampsia. PMID- 26103801 TI - The brain study: Cognition, quality of life and social functioning following preeclampsia; An observational study. AB - OBJECTIVES: Previously preeclamptic women may express cognitive difficulties, which have largely been unappreciated or attributed to stresses of a complicated pregnancy. This study aimed to explore the scope of perceived neurocognitive and psychosocial problems as well as quality of life following preeclampsia. STUDY DESIGN: Observational study. Through website promotion and e-mail, registrants of the USA-based Preeclampsia Foundation who experienced preeclampsia in the past 20years were invited to complete a web-based survey. Participants were requested to ask an acquaintance that had a normotensive pregnancy to also complete the survey (controls). MAIN OUTCOME MEASURES: The Cognitive Failures Questionnaire (CFQ), abbreviated WHO Quality Of Life questionnaire (WHOQOL-BREF), Social Functioning Questionnaire (SFQ) and Breslau Short Screening Scale for DSM-IV Posttraumatic Stress Disorder were used in the survey. Analysis was performed using Mann-Whitney U tests and linear regression. RESULTS: 966 cases and 342 controls completed the survey (median age 34, median time since first pregnancy 4 vs. 5years). Cases scored significantly worse on CFQ (median 35 vs. 27), WHOQOL BREF domains physical health (15 vs. 17), psychological (13 vs. 15), social relationships (13 vs. 15) and environment (15 vs. 16), and SFQ (8 vs. 7). All p<0.001. Multivariable analysis showed an independent significant effect of eclampsia on CFQ and of migraine on all questionnaires and the effect of preeclampsia was still present after adjustment for confounders. Posttraumatic stress symptoms accounted for part of the relationships. CONCLUSIONS: Previously preeclamptic women appear to perceive more cognitive and social problems, and report poorer quality of life compared to a group of women with normotensive pregnancies. Research relating to the origin and management of these issues is needed. PMID- 26103802 TI - Expectant management in pregnant women with early and severe preeclampsia and concomitant risk factors. AB - AIM: The aim of this study was to demonstrate that women with severe early-onset preeclampsia and concomitant risk factors benefit from expectant management. METHODS: This retrospective study was conducted between January 2009 and December 2010. Stable women with severe preeclampsia between 23+6 and 33+6weeks of gestation were admitted to the IOCU for conservative management. They were classified into two groups: those with concomitant risk factors, i.e. associated medical conditions, HELLP syndrome, severe oligohydramnios, fetal growth restriction and multiple pregnancies (group A) and those without (group B). P values lesser than 0.05 were considered statistically significant. RESULTS: No significant differences were found in maternal and perinatal outcomes between groups. Neither were differences observed in pregnancy prolongation (mean: 8.42days (SD+/-7.462) in group A and 10.5days (SD+/-8.235) in group B (p=0.391)). At the start of expectant management, 31.8% of fetuses had an abnormal middle cerebral artery Doppler; prior to delivery, this percentage was 77.4%. CONCLUSION: Pregnant women with severe early-onset preeclampsia and associated risk factors benefited from expectant management. During expectant management using a continuous magnesium sulfate regimen, the majority of fetuses showed cerebral vasodilatation. The exact clinical value of this finding should be clarified in further studies. PMID- 26103803 TI - High blood pressure six weeks postpartum after hypertensive pregnancy disorders at term is associated with chronic hypertension. AB - OBJECTIVES: Hypertension in pregnancy is associated with cardiovascular disease (CVD) later in life. Blood pressure monitoring in women who experienced hypertension in pregnancy after puerperium has been suggested to be important for early detection and prevention of CVD. The aim of this study is to evaluate if hypertension six weeks postpartum is associated with chronic hypertension in women with a history of term hypertensive pregnancy disorders. STUDY DESIGN: Women with a history of term gestational hypertension or preeclampsia were included in a follow up study of the HYPITAT trial. Blood pressures were measured six weeks and 2.5years postpartum according to the study protocol. MAIN OUTCOME MEASURES: Hypertension was defined as a diastolic blood pressure ?90mmHg and/or a systolic blood pressure ?140mmHg or use of antihypertensive medication. Differences in categorical variables between groups were analyzed by Chi-Square tests. Blood pressure was analyzed using unpaired t-tests and Wilcox ranked tests. RESULTS: Among 187 women who had term hypertensive pregnancy disorders, 75 (40%) had hypertension at six weeks postpartum. Of these 46 (61%) had hypertension 2.5years postpartum. In contrast, of 112 women without hypertension at six weeks postpartum, 36 (32%) had hypertension 2.5years (OR 3.3, 95% CI 1.8 6.2). CONCLUSION: Among 61% of women who had hypertensive pregnancy disorders at term, high blood pressure at six weeks postpartum indicated chronic hypertension. This warrants the importance of identification of hypertension 6weeks postpartum for women's future health. PMID- 26103804 TI - Clinical risk factors for gestational hypertensive disorders in pregnant women at high risk for developing preeclampsia. AB - OBJECTIVES: To evaluate clinical risk factors for the development of gestational hypertensive disorders in a group of pregnant women at high risk for developing preeclampsia. Secondly we evaluated the incidence and recurrence rate of preeclampsia and pregnancy-induced hypertension. STUDY DESIGN: A prospective analysis of data obtained from a cohort study was performed. Pregnant women were included who had at least one of the following risk factors for preeclampsia: previous history of preeclampsia, previous history of HELLP syndrome, chronic hypertension, diabetes mellitus, multiple pregnancy, obesity, or autoimmune disease. Univariate and multivariate logistic regression analyses were used to evaluate the role of clinical characteristics and risk factors in the development of hypertensive disorders. MAIN OUTCOME MEASURES: Development of gestational hypertensive disorders. RESULTS: Thirty-five percent (36/103) developed a hypertensive disorder. The univariate analysis identified preeclampsia in a previous pregnancy (OR 2.94, 95% CI: 1.25-6.91, p=0.013) as a significant risk factor. Multivariate logistic regression revealed that a previous history of preeclampsia was the only significant independent risk factor for gestational hypertensive disorders (OR 2.89, 95% CI: 1.17-7.08, p=0.021). Women with a previous history of PE had the highest incidence rate of 51.4% for hypertensive disorders compared to the incidence rates of other risk factors (20.8%-38.5%). CONCLUSION: A previous history of preeclampsia proves to be a strong independent clinical risk factor for gestational hypertensive disorders in high-risk pregnant women, even in our relatively small cohort study. PMID- 26103805 TI - Hypertensive disorders of pregnancy and risk of screening positive for Posttraumatic Stress Disorder: A cross-sectional study. AB - OBJECTIVES: Hypertensive Disorders of Pregnancy (HDP) encompass a spectrum of disorders that affect 6-8% of US pregnancies. We aim to determine the impact of self-reported history of HDP as a risk factor for screening positive for Posttraumatic Stress Disorder (PTSD), which results from exposure to a traumatic event, and to evaluate whether the risk of PTSD differed by severity of HDP. STUDY DESIGN: We conducted an online survey on the Preeclampsia Foundation website that is accessed worldwide by women who have experienced HDP, as well as their friends and family. 1448 women in total responded to the survey, including 1076 women who reported a history of HDP in at least one prior pregnancy and 372 women who reported no history of HDP during any prior pregnancy. MAIN OUTCOME MEASURES: We measured PTSD outcome with the Breslau Short Screening Scale for DSM IV PTSD. We used logistic regression to model the relationship between PTSD and HDP. RESULTS: Women who reported a history of HDP were more than four times as likely to screen positive for PTSD than women who reported having a normotensive pregnancy history (ORadj=4.46, 95% CI: 3.20-6.20). In addition, there was a marked trend toward increasing risk of screening positive for PTSD as the severity of HDP increased from gestational hypertension to eclampsia (p<0.001). CONCLUSIONS: Women with a history of HDP may be at increased risk of PTSD, with severe cases most likely to suffer from symptoms. Clinicians should consider implementing routine screenings during post-partum visits in this vulnerable population. PMID- 26103806 TI - Non-invasive assessment of maternal hemodynamics in early pregnancy. AB - OBJECTIVES: Non-invasive assessment of maternal hemodynamics in early pregnancy may be promising in evaluating maternal hemodynamic (mal)adaptation to pregnancy. We explored usage of applanation tonometry and Doppler ultrasound for assessment of cardiac output (CO), systemic vascular resistance (SVR) and arterial stiffness in early pregnancy. METHODS: Pregnant healthy nulliparous women were studied during first trimester. Radial artery pressure waveform (augmentation index(AIx)), carotid-femoral pulse wave velocity (PWV) and cardiac output (CO) were measured by applanation tonometry (SphygmoCor), electrocardiogram and Doppler ultrasound (USCOM) and related to maternal demographic characteristics and literature concerning advanced pregnancy and non-pregnant subjects. RESULTS: 116 women were studied during gestational age range of 7(+2)-14weeks. Systolic and diastolic central blood pressure were correlated with systolic and diastolic brachial blood pressure respectively. Both measures of arterial stiffness (heart rate corrected AIx(AIx@75) and PWV) were correlated. AIx@75, PWV and SVR were correlated with central mean arterial pressure. CO was negatively correlated with AIx and associated with BMI. PWV was associated with age and BMI, whereas SVR was associated with age. CONCLUSIONS: Applanation tonometry and Doppler Ultrasound for assessment of maternal hemodynamics in early pregnancy revealed similar associations between different hemodynamic parameters and maternal characteristics as have previously been reported in advanced pregnancy and non pregnant subjects. The SphygmoCor and the USCOM appear to be reliable methods for the assessment of maternal hemodynamics in early pregnancy. Obtaining a comprehensive hemodynamic profile using these modalities may offer insight in maternal (mal)adaptation to pregnancy. Future work needs to be done relating such measures to pregnancy outcome. PMID- 26103807 TI - Biophysical interaction between blood pressure and uterine artery Doppler for the occurrence of early-onset preeclampsia: A prospective cohort study. AB - OBJECTIVES: We evaluated the biological interaction between blood pressure (BP) and uterine artery Doppler (UAD) in the second trimester for early-onset preeclampsia (EO-PE) risk. STUDY DESIGN: A prospective cohort study. MAIN OUTCOME MEASURES: In 2410 pregnant women, mean pulsatility index (mPI) and mean notch depth index (mNDI) were examined by UAD at 16-23weeks' gestation. We defined EO PE as PE with onset at <34weeks, abnormal UAD as coexistence of mPI?90th percentile and mNDI?90th percentile, and high BP as systolic BP/diastolic BP?120/80mmHg. Abnormal UAD and high BP were combined as a series of dummy variables, and were entered into a logistic regression model. The relative excess risk due to biological interaction (RERI) was calculated using the following equation: RERI=odds ratio (OR) in women with both high BP and abnormal UAD - OR in women with high BP alone - OR in women with abnormal UAD alone +1. RERI?10 was considered as strong. RESULTS: EO-PE and late-onset PE (LO-PE) occurred in 1.1% and 1.2%, respectively. Adjusted odds ratio (95% CI) in women with abnormal UAD alone, high BP alone, and both high BP and abnormal UAD for predicting EO-PE was 4.3 (0.37-49), 12 (2.6-55) and 85 (17-422), respectively; and that for predicting LO-PE was 6.3 (1.5-27), 6.1 (2.1-17) and 15 (3.6-61), respectively. The RERI for EO-PE and LO-PE was 70 and 3.3, respectively. CONCLUSION: High BP and abnormal UAD may have a strong biological interaction for the occurrence of EO-PE. PMID- 26103808 TI - Porcine retinal cell line VIDO R1 and Chlamydia suis to modelize ocular chlamydiosis. AB - Human ocular Chlamydia trachomatis infections can lead to trachoma, the major cause of infectious blindness worldwide. Trachoma control strategies are very helpful but logistically challenging, and a trachoma vaccine is needed but not available. Pigs are a valuable large animal model for various immunological questions and could facilitate the study of human ocular chlamydial infections. In addition, a recent study identified the zoonotic potential of Chlamydia suis, the natural pathogen of pigs. In terms of the One Health Initiative, understanding the host-pathogen-interactions and finding a vaccine for porcine chlamydia infections would also benefit human health. Thus, we infected the porcine retinal cell line VIDO R1 with C. suis and analyzed the chlamydial life cycle and the innate immune response of the infected cells. Our results indicate that C. suis completes its life cycle in VIDO R1 cells within 48 h, comparable to C. trachomatis in humans. C. suis infection of VIDO R1 cells led to increased levels of various innate immune mediators like pathogen recognition receptors, cytokines and chemokines including IL6, TNFalpha, and MMP9, also most relevant in human C. trachomatis infections. These results illustrate the first steps in the host-pathogen-interactions of ocular C. suis infections in pigs and show their similarity to C. trachomatis infections in humans, justifying further testing of pigs as an animal model for human trachoma. PMID- 26103810 TI - [A case of combined central and peripheral demyelination]. AB - A 22-year-old man had had difficulty running fast since about he was 10 years old. In June 2011, he was referred to us because of worsened unsteady gait. A neurological examination revealed mild ataxic speech, weakness of the four limbs, with spasticity, and pes cavus. Magnetic resonance T2-weighted images showed multiple high-intensity lesions in the bilateral periventricular white matter, brainstem, and thoracic spinal cord. Peripheral nerve conduction studies revealed marked motor conduction velocities were markedly reduced and sensory nerve velocities were not evoked in the upper and lower limbs. A sural nerve biopsy showed highly active demyelinating lesions. The patient was treated with high dose steroid therapy (intravenous methylprednisolone, 1,000 mg/day * 3 days) followed by self-injection of interferon beta. With these treatments, his symptoms gradually improved. In this case, we could not detect the causative factors, and all autoantibodies tested, except for the anti-neurofascin antibody, were negative. The anti-neurofascin antibody might induce demyelination in the central and peripheral nervous systems. However, in the literature, the evidence of an association between this antibody and these clinical characteristics is not conclusive. We need more studies on the pathogenesis of combined central and peripheral demyelination to establish more effective therapies. PMID- 26103809 TI - Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities. AB - Podocyte injuries are associated with progression of diabetic nephropathy (DN). Apelin, an adipocyte-derived peptide, has been reported to be a promoting factor for DN. In this study, we aim to determine whether apelin promotes progression of DN by inducing podocyte dysfunction. kk-Ay mice were used as models for DN. Apelin and its antagonist, F13A were intraperitoneally administered for 4 weeks, respectively. Renal function and foot process proteins were analysed to evaluate the effects of apelin on kk-Ay mice and podocytes. Apelin increased albuminuria and decreased podocyte foot process proteins expression in kk-Ay mice, which is consistent with the results that apelin receptor (APLNR) levels increased in glomeruli of patients or mice with DN. In cultured podocytes, high glucose increased APLNR expression and apelin administration was associated with increased permeability and decreased foot process proteins levels. All these dysfunctions were associated with decreased 26S proteasome activities and increased polyubiquitinated proteins in both kk-Ay mice and cultured podocytes, as demonstrated by 26S proteasome activation with cyclic adenosine monophosphate (cAMP) or oleuropein. These effects seemed to be related to endoplasmic reticulum (ER) stress, as apelin increased C/EBP homologous protein (CHOP) and peiFalpha levels while cAMP or oleuropein reduced it in high glucose and apelin treated podocytes. These results suggest that apelin induces podocyte dysfunction in DN through ER stress which was induced by decreased proteasome activities in podocytes. PMID- 26103811 TI - [A case of bilateral auricular chondritis with anti-glutamate receptor (GluRepsilon2) antibody-positive non-herpetic acute limbic encephalitis]. AB - A 62-year-old man experienced pain and swelling in both of his auricles. One and a half months later, he was referred to us because of a memory disturbance. A neurological examination revealed disorientation and recent memory impairment. Diffusion-weighted and fluid-attenuated inversion recovery magnetic resonance images showed high intensity and swelling lesions in the bilateral medial temporal regions. In cerebrospinal fluid, mononuclear cell counts and total protein concentration were increased, but a herpes polymerase chain reaction was negative. Thus, he was suspected to have non-herpetic acute limbic encephalitis (NHALE). In addition, relapsing polychondritis (RP) was suspected because of the bilateral auricular chondritis and type-II collagen antibody positivity in the serum. He was treated with high-dose steroid therapy (two cycles of intravenous methylprednisolone, 500 mg per day for 3 days), which was followed by oral steroid therapy. With these treatments, his symptoms, including the painful auricular swelling and memory disturbance, gradually improved. This case exhibited anti-glutamate receptor (GluRepsilon2) antibody positivity in both serum and cerebrospinal fluid, but anti-N-methyl-D-aspartate glutamate receptor antibody (NR1 + NR2) by cell-based assay negative in cerebrospinal fluid. Although a vascular mechanism of NHALE that is associated with RP has been suggested in the literature, this autoantibody might have induced NHALE as the mechanism of neuronal damage to target neuron in our case. More studies on the pathogenesis of NHALE that is associated with RP are needed. PMID- 26103812 TI - [Two cases of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)]. AB - We, herein, report two independent cases with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) inherited in an autosomal dominant fashion. Their common clinical features are slowly progressive proximal dominant muscular atrophy, fasciculations and mild to moderate distal sensory disturbance with areflexia. Nerve conduction study revealed an absence of sensory nerve action potentials, in contrast to almost normal compound muscle action potentials. Gene analysis in both patients elucidated heterozygous mutation (c.854C>T, p.Pro285Leu) in the TFG, which is an identical mutation, already described by Ishiura et al. Okinawa and Shiga are two foci of HMSN-P in Japan. Eventually, one patient is from Okinawa and the other is from a mountain village in Shiga prefecture. When we see a patient who has symptoms suggestive of motor neuron disease with sensory neuropathy, HMSN-P should be considered as a differential diagnosis despite the patient's actual resident place. PMID- 26103813 TI - [A long-term follow up of right ophthalmoplegia and severe right middle cerebral artery stenosis with right herpes zoster ophthalmics: a case report]. AB - Here we report a case of a 68-year-old man with severe stenosis of the right middle cerebral artery (MCA) following herpes zoster ophthalmicus. He presented with right-sided ptosis and ophthalmoplegia 2 months after herpes zoster ophthalmicus. Cerebrospinal fluid (CSF) analysis revealed monocytosis, increased protein levels, and positivity for herpes zoster virus immunoglobulin M (IgM). Brain magnetic resonance imaging (MRI) revealed a small asymptomatic infarct in the right basal ganglia and severe stenosis of the right MCA (M1 segment). One month later, he presented with muscle weakness of the fingers of the left hand. Repeat CSF analysis revealed similar abnormalities to the previous analysis, and MRI showed a new small infarct in the right-sided motor area corresponding to the left fingers. He was treated with acyclovir (750 mg/day), prednisolone (1 mg/kg/day), and aspirin (100 mg/day). O2-gas positron emission tomography (PET) revealed decreased cerebral blood flow (CBF) after acetazolamide injection and normal cerebral vascular reactivity (CVR). He was on continuous treatment with prednisolone and aspirin for 1 year. The muscle weakness of the fingers of the left hand and right-sided ophthalmoplegia improved, and magnetic resonance angiography revealed considerable decrease in the stenosis of the right middle cerebral artery. CBF before and after acetazolamide injection and CVR on O2-gas PET also normalized. These results suggested that long-term treatment may prevent subsequent infarcts following herpes zoster ophthalmics. PMID- 26103814 TI - [Effect of sodium pyruvate on exercise intolerance and muscle weakness due to mitochondrial myopathy: a case report]. AB - We report the case of a 19-year-old woman who had been suffering from general fatigue and exercise intolerance since 15 years old. At 18 years old, she experienced muscle weakness and myalgia of the calves. Six months later, she was admitted to our hospital. She showed muscle weakness of the neck and proximal limbs, and myalgia of the calves was prominent. Serum levels of creatine kinase (CK) and lactic acid were elevated, as was the level of lactic acid in cerebrospinal fluid. T2-weighted and short-inversion-time inversion recovery (STIR) imaging of the lower limbs showed hyperintensity on bilateral gastrocnemius muscles, and the region revealed Gd enhancement. Based on histopathological findings from muscle and identification of a m.3271T>C point mutation, mitochondrial myopathy was diagnosed. Rest and administration of vitamins B1 and B2, coenzyme Q10, and L-carnitine improved serum CK levels; however, exercise intolerance, myalgia, and lactic acidemia remained. Sodium pyruvate was then administered, and lactic acid levels, exercise intolerance, and findings on magnetic resonance imaging improved. Sodium pyruvate could prove effective in addressing both elevated serum lactic acid levels and exercise intolerance in mitochondrial disease. PMID- 26103815 TI - [A case of multiple sclerosis who relapsed early after fingolimod therapy introduced]. AB - The patient was a 46-year-old woman having a history of multiple sclerosis (MS) for 14 years. She had been treated with interferon beta-1b since 2001, but discontinued because of psychiatric problems in 2006. Thereafter relapses were observed 1-2 times a year, and EDSS became 2.5 to 6.5. In April 2012, relapse of MS was noticed and the patient received introduction of fingolimod (FTY) after methylprednisolone (mPSL) pulse therapy. Twenty days later, dysarthria and lower limb weakness were appeared. Brain MRI showed more than 20 several millimeter Gd enhanced lesions in periventricular white matter, juxta-cortical white matter, and cerebellum. Careful determination and observation are required upon the FTY administration into the MS with high frequency of relapse. PMID- 26103816 TI - [A case of recurrent aseptic meningitis induced by ergot agents]. AB - We describe the case of a 29-year-old woman with recurrent aseptic meningitis that was caused by ergot agents. She miscarried at age 27, and the uterus constrictor methylergometrine was prescribed. Three days later, she developed aseptic meningitis and was hospitalized. Two years later, she again developed aseptic meningitis the day after she took ergotamine tartrate. In both events, her symptoms improved rapidly when the medication was stopped. The drug-induced lymphocyte stimulation test for methylergometrine yielded a value of 180%. Drug induced meningitis is a rare form of recurrent aseptic meningitis. Many studies have reported cases of meningitis caused by non-steroidal anti-inflammatory drugs, but many other drugs can induce aseptic meningitis. To the best of our knowledge, this is the first case of aseptic meningitis induced by ergot agents. PMID- 26103817 TI - [A case of Creutzfeldt-Jakob disease with a double mutation (V180I/M232R) in the PRNP gene]. AB - Creutzfeldt-Jakob disease (CJD) presents with rapidly progressive dementia associated with several symptoms including pyramidal, extrapyramidal, and cerebellar signs. In Japan, patients with PRNP gene mutations comprise 18.3% of CJD cases. In the present study, we report a 74-year-old man with a double mutation in the PRNP gene. He showed dysarthria, gait disturbance, and cognitive impairment. High signal intensity was observed in the bilateral cortex on brain MRI in diffusion-weighted images. There were high total Tau protein and 14-3-3 protein levels in the cerebrospinal fluid. We diagnosed him as having CJD clinically, and analyzed the PRNP gene, which revealed a V180I mutation and a M232R one, i.e., a compound heterozygous status. In our patient, the disease has very slowly progressive (total disease course, 37 months). The V180I and M232R mutations are specific mutations to Japanese CJD patients. For patients with a double PRNP gene mutation, only V180I and M232R have been known. Patients with a double mutation (V180I /M232R) in the PRNP gene might show an atypical disease course with a slow progression. PMID- 26103818 TI - [A case of Behcet disease developing recurrent ischemic stroke with fever and scrotal ulcers]. AB - A 30-year-old man, who was diagnosed with Behcet disease at 10 years of age, was hospitalized because of transient right hemiparesis after presenting with high fever and scrotal ulcers. Brain MRI revealed ischemic lesions in the area supplied by the anterior cerebral arteries. Analysis of cerebrospinal fluid (CSF) showed pleocytosis and a high interleukin-6 (IL-6) concentration (668 pg/ml). The patient was diagnosed with acute ischemic stroke associated with exacerbation of Behcet disease. After initiation of corticosteroid therapy, his clinical symptoms improved, and the CSF IL-6 concentration decreased. One year later, the patient developed high fever and scrotal ulcers after the onset of transient left upper limb plegia. Brain MRI showed an acute ischemic lesion in the right putamen, and CSF analysis showed an elevated IL-6 concentration (287 pg/ml). Brain CT angiography revealed stenosis of the left anterior cerebral artery and occlusion of the right anterior cerebral artery, which had been well visualized one year previously. Involvement of the intracranial cerebral arteries in Behcet disease is extremely rare. To the best of our knowledge, this is the first case report of a patient with recurrent symptomatic ischemic stroke associated with high fever and scrotal ulcers, which suggests exacerbation of Behcet disease. PMID- 26103819 TI - [A case of 16q linked autosomal dominant cerebellar ataxia (16q-ADCA) presenting dystonia]. PMID- 26103820 TI - [A case of 77-year-old male with spinocerebellar ataxia type 31 with left dominant dystonia]. PMID- 26103821 TI - [Encephalopathy in HIV patients on antiretroviral therapy]. PMID- 26103826 TI - [Editor' Note]. PMID- 26103822 TI - [Response regarding "HIV encephalopathy due to drug resistance despite 2-year suppression of HIV viremia by cART"]. PMID- 26103827 TI - NHS needs a workforce plan, not border control. PMID- 26103829 TI - Majority vote against covert filming. PMID- 26103828 TI - Outgoing RCN general secretary urges nurses to speak up and unite. PMID- 26103830 TI - RCN president calls for staffing guidance U-turn. PMID- 26103831 TI - Stress is a leading cause of nurses' sickness absence. PMID- 26103832 TI - Protest over end of NICE's project on safe staffing. PMID- 26103833 TI - Senior nurse exodus threatens to disrupt plans for seven-day NHS. PMID- 26103834 TI - Charity highlights unsafe inhaler use. PMID- 26103836 TI - Mental health wards offered L 5m for more social activities. PMID- 26103837 TI - Colleagues celebrate Windrush legacy. PMID- 26103838 TI - 'The NHS is paying millions to rent overseas nurses temporarily'. PMID- 26103839 TI - How safer clinical practice could prevent needless asthma deaths. PMID- 26103845 TI - Violence at work. PMID- 26103846 TI - A nurse who never gives up. PMID- 26103847 TI - Fit for the future. PMID- 26103857 TI - The Academy of Fabulous NHS Stuff. PMID- 26103848 TI - Why women ignore first signs of cancer. PMID- 26103859 TI - NUH Staff. PMID- 26103861 TI - We need more registered nursing staff on the wards. PMID- 26103862 TI - Post-registration training must be part of the education debate. PMID- 26103863 TI - A greater degree of pride is needed to build a better NHS. PMID- 26103864 TI - I vow to keep making 'noise' about the importance of safe staffing levels. PMID- 26103865 TI - Immigration change for nurses not the same as 'deportation'. PMID- 26103867 TI - Correction. PMID- 26103870 TI - Diagnosis of dementia. AB - There are two stages to making a diagnosis of dementia: establishing the presence of a dementia syndrome and determining the likely cause. Dementia should be distinguished from mild cognitive impairment, in which any cognitive and functional changes are less marked. Diagnosis of dementia is essentially clinical but investigations are helpful in excluding other disorders and in determining the underlying cause of the condition. International diagnostic criteria exist for the most common causes of dementia and these are useful for clinical and research purposes. At and following diagnosis, patients and their families require information, support and guidance about the future. PMID- 26103871 TI - Use of interviews in nursing research. AB - Conducting interviews is one of the most common ways of collecting data in healthcare research. In particular, interviews are associated with qualitative research, where researchers seek to understand participants' experiences through their own words and perspectives. This article will help healthcare researchers prepare to carry out interviews as part of their research. It will also emphasise important skills to consider during the interview process. Consideration will also be given to remedying interviews that do not go according to plan, as well as identifying appropriate debriefing processes post-interview. With this knowledge, healthcare researchers are more likely to conduct effective interviews that will yield better quality data and protect the participant. PMID- 26103872 TI - Managing fatigue in adults with multiple sclerosis. AB - Fatigue is one of the most common symptoms experienced by people with multiple sclerosis (MS) and has a significant effect on all aspects of daily living and on quality of life. It is important for healthcare professionals working with patients with MS to identify fatigue where present and to be able to offer clinically effective treatment options. This article explores assessment and measurement of fatigue, evidence-based pharmacological and non-pharmacological treatments for managing fatigue and the role of MS specialist nurses and therapists. PMID- 26103873 TI - Writing for publication. PMID- 26103874 TI - Your chance to shine. PMID- 26103875 TI - Volunteering in a disaster zone. PMID- 26103877 TI - Ward off unwanted advances. PMID- 26103878 TI - Covering letter is your big chance to stand out. PMID- 26103879 TI - Novel protein C gene mutation in a compound heterozygote resulting in catastrophic thrombosis in early adulthood: diagnosis and long-term treatment with subcutaneous protein C concentrate. PMID- 26103880 TI - miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one carbon metabolism via SHMT-2 and MECP-2, respectively. AB - The aim of this study was to determine the mechanism underlying the association between one-carbon metabolism and DNA methylation during chronic degenerative joint disorder, osteoarthritis (OA). Articular chondrocytes were isolated from human OA cartilage and normal cartilage biopsied, and the degree of cartilage degradation was determined by safranin O staining. We found that the expression levels of SHMT-2 and MECP-2 were increased in OA chondrocytes, and 3'UTR reporter assays showed that SHMT-2 and MECP-2 are the direct targets of miR-370 and miR 373, respectively, in human articular chondrocytes. Our experiments showed that miR-370 and miR-373 levels were significantly lower in OA chondrocytes compared to normal chondrocytes. Overexpression of miR-370 or miR-373, or knockdown of SHMT-2 or MECP-2 reduced both MMP-13 expression and apoptotic cell death in cultured OA chondrocytes. In vivo, we found that introduction of miR-370 or miR 373 into the cartilage of mice that had undergone destabilization of the medial meniscus (DMM) surgery significantly reduced the cartilage destruction in this model, whereas introduction of SHMT-2 or MECP-2 increased the severity of cartilage destruction. Together, these results show that miR-370 and miR-373 contribute to the pathogenesis of OA and act as negative regulators of SHMT-2 and MECP-2, respectively. PMID- 26103881 TI - Membrane Protein Folding & Lipid Interactions: Theory & Experiment. PMID- 26103882 TI - Editorial Comment from Dr Li to Varicocele is associated with varicose veins: A population-based case-control study. PMID- 26103883 TI - Editorial: Chemical Ecology. PMID- 26103886 TI - Intermolecular carbon-carbon, nitrogen-nitrogen and oxygen-oxygen non-covalent bonding in dipolar molecules. AB - Clear evidence for the existence of intermolecular carbon-carbon (C...C), nitrogen-nitrogen (N...N) and oxygen-oxygen (O...O) interactions between atoms in similar chemical environments in homogeneous dimers of organic dipolar molecules has been obtained from molecular orbital (MO), natural bond orbital (NBO) and atoms-in-molecule (AIM) electron density analyses at the M06L/6-311++G(d,p) level of density functional theory (DFT). These X...X type interactions are mainly the result of local polarization effects, causing segregation of electron-rich and electron-deficient regions in the X atoms, leading to complementary electrostatic interactions. NBO analysis provides evidence of charge transfer between the two X atoms. Even in symmetrical molecules such as acetylene, induced dipoles in the dimer create C...C bonding interactions. The strength of this type of interaction increases with increase in the dipole moment of the molecule. Energy decomposition analysis (EDA) shows that the electrostatic component of the interaction energy (Eint) is very high, up to 95.86%. The C...C interactions between similar carbon atoms are located for several crystal structures obtained from the literature. In addition, MO, AIM and electrostatic potential analyses support interactions between similar oxygen (O...O) and nitrogen (N...N) atoms in a variety of molecular dimers. Good prediction of Eint is achieved in terms of the total gain in electron density at non-covalently interacting intermolecular bonds (?rho) and the monomer dipole moment (MU). A rigorously tested QSAR equation has been derived to predict Eint for all dimer systems: Eint (kcal mol( 1)) = -138.395?rho(au) - 0.551MU (Debye). This equation suggests that the polarization-induced bonding interaction between atoms in a similar chemical environment could well be a general chemical phenomenon. The results have been further validated by different density functional methods and also by G3MP2 method. PMID- 26103887 TI - The History of Pyrosequencing((r)). AB - One late afternoon in the beginning of January 1986, bicycling from the lab over the hill to the small village of Fulbourn, the idea for an alternative DNA sequencing technique came to my mind. The basic concept was to follow the activity of DNA polymerase during nucleotide incorporation into a DNA strand by analyzing the pyrophosphate released during the process. Today, the technique is used in multidisciplinary fields in academic, clinical, and industrial settings all over the word. This technique can be used for both single-base sequencing and whole-genome sequencing, depending on the format used.In this chapter, I give my personal account of the development of Pyrosequencing((r))-beginning on a winter day in 1986, when I first envisioned the method-until today, nearly 30 years later. PMID- 26103885 TI - Controlled synthesis of series NixCo3-xO4 products: Morphological evolution towards quasi-single-crystal structure for high-performance and stable lithium ion batteries. AB - Transition metal oxides are very promising alternative anode materials for high performance lithium-ion batteries (LIBs). However, their conversion reactions and concomitant volume expansion cause the pulverization, leading to poor cycling stability, which limit their applications. Here, we present the quasi-single crystal Ni(x)Co(3-x)O4 hexagonal microtube (QNHM) composed of continuously twinned single crystal submicron-cubes as anode materials for LIBs with high energy density and long cycle life. At the current density of 0.8 A g(-1), it can deliver a high discharge capacities of 1470 mAh g(-1) over 100 cycles (105% of the 2nd cycle) and 590 mAh g(-1) even after 1000 cycles. To better understand what underlying factors lead our QNHMs to achieve excellent electrochemical performance, a series of Ni(x)Co(3-x)O4 products with systematic shape evolution from spherical to polyhedral, and cubic particles as well as circular microtubes consisted of spheres and square microtubes composed of polyhedra have been synthesized. The excellent electrochemical performance of QNHMs is attributed to the unique stable quasi-single-crystal structure, which can both provide efficient electrical transport pathway and suppress the electrode pulverization. It is important to note that such quasi-single-crystal structure would be helpful to explore other high-energy lithium storage materials based on alloying or conversion reactions. PMID- 26103884 TI - Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease. AB - Down syndrome (DS) is the most common genetic cause of intellectual disability and is primarily caused by the triplication of chromosome 21. The overexpression of amyloid precursor protein gene may be sufficient to drive Alzheimer's disease (AD) neuropathology that is observed in virtually all individuals with DS by the age of 40 years. There is relatively little information about inflammation in the DS brain and how the genetics of DS may alter inflammatory responses and modify the course of AD pathogenesis in this disorder. Using the macrophage classification system of M1, M2a, M2b, and M2c inflammatory phenotypes, we have shown that the early stages of AD are associated with a bias toward an M1 or M2a phenotype. In later stages of AD, markers of M1, M2a and M2c are elevated. We now report the inflammatory phenotype in a DS autopsy series to compare this with the progression in sporadic AD. Tissue from young DS cases (under 40 years of age, pre-AD) show a bias toward M1 and M2b states with little M2a or M2c observed. Older DS cases (over 40 with AD pathology) show a distinct bias toward an M2b phenotype. Importantly, this is distinct from sporadic AD where the M2b phenotype has been rarely, if ever observed in postmortem studies. Stimulated by immune complex activation of microglial cells and toll-like receptor activation, the M2b phenotype represents a unique neuroinflammatory state in diseased brain and may have significant implications for therapeutic intervention for persons with DS. PMID- 26103888 TI - PyroMark(r) Instruments, Chemistry, and Software for Pyrosequencing(r) Analysis. AB - Since the early 2000s, Pyrosequencing((r)) technology has been adapted for various instrument platforms to enable users to examine the role of epigenetic DNA methylation in gene expression regulation, genetic markers for specific phenotypes in livestock, drug resistance development in pathogens, and polymorphisms in forensic samples of mitochondrial DNA.The instruments, software, and chemistry have been modified to facilitate different sample throughputs and sample amounts. Just recently, major changes have been implemented to enable increased read length and more precise Pyrosequencing results. These improvements were made possible through a number of changes to various system components. In addition, assay development has been streamlined through the availability of optimized PCR and Pyrosequencing reagents, automated assay design tools, and a number of predesigned Pyrosequencing assays.In future, instruments with smaller footprints and the ability to automate crucial steps of the Pyrosequencing protocol will be available and will provide even more convenient and standardized Pyrosequencing analysis with flexible throughput. PMID- 26103889 TI - Software-Based Pyrogram(r) Evaluation. AB - Pyrosequencing((r)) is a widely used technology to detect gene mutations in a molecular research or diagnostics laboratory. Compared to Sanger sequencing, it is inherently more quantitative with a superior limit of detection, although it has a shorter read length and has difficulty with homopolymeric sequences.Results of Pyrosequencing experiments are typically presented as traces with sequential peaks, called Pyrograms((r)). For the majority of clinical diagnostic cases, Pyrograms are straightforward to read. However, there are occasionally complex results that are uninterpretable or difficult to interpret. In this chapter, we demonstrate a computer software, named Pyromaker that has been developed to help with the analysis of Pyrograms. Pyromaker is a freely and publically available software program to assist in the recognition of patterns of mutations, interpretation of difficult or ambiguous testing results and design of an optimal strategy to detect potential mutations by generating simulated Pyrograms. In addition to help diagnostic activities, Pyromaker can also be used as a virtual and user-friendly educational tool to teach newcomers the fundamental mechanism of Pyrosequencing, and correct interpretation of actual Pyrosequencing data. PMID- 26103890 TI - Quantitative Validation and Quality Control of Pyrosequencing(r) Assays. AB - Pyrosequencing((r)) offers the opportunity to quantify the amount of nucleotides incorporated during the sequencing reaction. This enables the precise and sensitive quantification of DNA methylation, allele-specific expression, or mutation load. However, only a few studies addressed the question how precise and sensitive Pyrosequencing really is. Many publications claiming precise measurement (with two decimal places) fail to demonstrate performance figures like precision or reproducibility. And most publications reporting the detection (and quantification) of very weak signals by Pyrosequencing do omit to report the technical sensitivity of the assay used (i.e., limit of blank, limit of detection, limit of quantification).Therefore, this chapter aims at providing (1) an introduction to important basic concepts defining quantitative analytical assays, (2) an outline of a minimal set of validation measurements every study employing Pyrosequencing should include, especially if values close to the analytical threshold are reported. PMID- 26103891 TI - Extended KRAS and NRAS Mutation Profiling by Pyrosequencing(r). AB - With the advent of targeted therapies-drugs that specifically target molecules of tumor-driving signalling pathways-and the availability of biomarkers that predict the response of an individual patient on such a targeted therapy, the analysis of the status of the biomarker became an integral part of the therapy. For metastatic colorectal cancer, anti-EGFR-targeted antibodies (Cetuximab/Erbitux((r)), Panitumumab/Vectibix((r))) fall into this category of drugs as it was shown in several clinical studies that oncogenic mutations in exons 2-4 of the RAS genes KRAS or NRAS result in therapeutic resistance of the metastatic colorectal cancers against the action of both targeted drugs. Therefore, mutations in the RAS genes exclude patients from this kind of targeted therapy (negative biomarker). Thus the molecular-pathological testing of the mutational status of KRAS and NRAS has become an important cornerstone in planning oncological strategies in the treatment of metastatic colorectal cancer. As the profile of mutations in the RAS genes is characterized by hotspot mutations in only a small number of codons (12, 13 in exon 2-59, 61 in exon 3 117, 146 in exon 4). Pyrosequencing((r)) is an ideal and robust tool in the molecular-pathological detection. A detailed protocol for this detection procedure employing Pyrosequencing(r) is given here. PMID- 26103892 TI - Universal BRAF State Detection by the Pyrosequencing(r)-Based U-BRAF(V600) Assay. AB - Malignant melanoma is a highly aggressive type of malignancy with considerable metastatic potential and frequent resistance to cytotoxic agents. BRAF mutant protein was recently recognized as therapeutic target in metastatic melanoma.We present the newly developed U-BRAF(V600) approach (Patent No. 12153477.0-1404)-a universal Pyrosequencing((r))-based assay for mutation detection within the activation segment in exon 15 of human BRAF. We identified five different BRAF mutations in a single assay analyzing 75 different formalin-fixed paraffin embedded samples of cutaneous melanoma metastases from 29 patients. All mutant variants were quantitatively detectable by the newly developed U-BRAF(V600) assay. These results were confirmed by ultra-deep sequencing. In contrast to all other BRAF state detection methods, the U-BRAF(V600) assay is capable of automated quantitative identification of at least 36 previously published BRAF mutations. Under the precaution of a minimum of 5 % mutated cells in a background of wild-type cells, the U-BRAF(V600) assay design completely excludes false negative wild-type results. The corresponding algorithm for classification of BRAF-mutated variants is provided in this chapter together with a detailed step by-step protocol for the Pyrosequencing reaction.The single-reaction format and automation of data analysis make our approach suitable for the assessment of large clinical cohorts. Therefore, we suggest U-BRAF(V600) assay as a powerful sequencing-based diagnostic tool to automatically identify BRAF status. PMID- 26103893 TI - Pyrosequencing(r)-Based Identification of Low-Frequency Mutations Enriched Through Enhanced-ice-COLD-PCR. AB - A number of molecular diagnostic assays have been developed in the last years for mutation detection. Although these methods have become increasingly sensitive, most of them are incompatible with a sequencing-based readout and require prior knowledge of the mutation present in the sample. Consequently, coamplification at low denaturation (COLD)-PCR-based methods have been developed and combine a high analytical sensitivity due to mutation enrichment in the sample with the identification of known or unknown mutations by downstream sequencing experiments. Among these methods, the recently developed Enhanced-ice-COLD-PCR appeared as the most powerful method as it outperformed the other COLD-PCR-based methods in terms of the mutation enrichment and due to the simplicity of the experimental setup of the assay. Indeed, E-ice-COLD-PCR is very versatile as it can be used on all types of PCR platforms and is applicable to different types of samples including fresh frozen, FFPE, and plasma samples. The technique relies on the incorporation of an LNA containing blocker probe in the PCR reaction followed by selective heteroduplex denaturation enabling amplification of the mutant allele while amplification of the wild-type allele is prevented. Combined with Pyrosequencing((r)), which is a very quantitative high-resolution sequencing technology, E-ice-COLD-PCR can detect and identify mutations with a limit of detection down to 0.01 %. PMID- 26103894 TI - Analysis of Mutational Hotspots in Routinely Processed Bone Marrow Trephines by Pyrosequencing(r). AB - Formalin-fixed, paraffin-embedded (FFPE) bone marrow trephines are widely used in pathology, because they best preserve the morphological details of the bone marrow. However, DNA isolated from FFPE material is fragmented, limiting the size of amplification products, which is a challenge for all sequencing applications.Pyrosequencing((r)) is a quantitative and sensitive method for the detection of single-nucleotide variations (SNVs) in DNA samples. Pyrosequencing can easily be performed in a 96-well-plate format with a cost-effective medium sized throughput.This chapter provides a general outline of SNV detection in FFPE bone marrow trephines, including a detailed protocol of the Pyrosequencing procedure and guidelines for the design of new assays and evaluation of Pyrograms. The strengths of this approach are discussed using myeloproliferative neoplasms as an example. PMID- 26103895 TI - Analysis of Copy Number Variation by Pyrosequencing(r) Using Paralogous Sequences. AB - The determination of gene copy numbers of highly similar genes is difficult with conventional PCR-based methods. However, by amplification of similar genes in the same PCR reaction followed by Pyrosequencing((r)), one may distinguish the genes based on a single-nucleotide difference. The ratio between the peak heights of gene-specific nucleotides obtained in the Pyrosequencing reaction may thereby be used to calculate the relative copy numbers of target genes. This method is easy and cost effective compared to other methods, and allows for the determination of copy numbers of genes that were previously difficult to achieve. PMID- 26103896 TI - Prenatal Diagnosis of Chromosomal Aneuploidies by Quantitative Pyrosequencing(r). AB - One of the major reasons for pregnant women to ask for prenatal diagnosis is to detect fetal chromosomal aneuploidies. Analysis of allele ratios of SNPs has been used for prenatal detection of fetal aneuploidies using MALDI-TOF mass spectrometry (MS). However, quantitative SNP genotyping by MALDI-TOF MS is challenging. To obtain a better quantification of allelic ratios, a Pyrosequencing((r)) protocol for SNP genotyping has been developed to perform prenatal diagnosis of aneuploidies.To avoid the laborious process and risk of cross-contamination brought in by DNA extraction procedures, a PCR assay, which can amplify DNA directly from cells in amniotic fluid, has been developed. Pre amplification steps such as cell enrichment and heating are required to obtain sufficient amounts of amplification products.In this chapter, SNPs on chromosome 21 are used to detect trisomy 21 as an example of aneuploidy by quantifying the allele ratio using Pyrosequencing. Primer selection for PCRs and Pyrosequencing reactions, optimization of nucleotide dispensation orders, establishment of cutoff values for trisomy 21, and interpretation of data are all factors essential for a successful diagnosis and are discussed in detail herein. PMID- 26103897 TI - HLA-B and HLA-C Supratyping by Pyrosequencing(r). AB - Usually, HLA typing has been performed either by serology-based typing incubating a panel of known anti-HLA antibodies with viable lymphocytes of unknown HLA type or by molecular typing including medium-resolution HLA typing by Sequence Specific Oligonucleotide Probes (SSOP) or high-resolution HLA typing by Sequence Based Typing (SBT). Traditionally, HLA antigens have been defined using serological techniques, but these methods have several disadvantages, such as low resolution, the requirement for viable cells, and cell surface expression of HLA molecules. HLA type screening methods are categorized as low, medium, and high resolution, and only sequencing-based typing methods provide the highest resolution and are considered the gold standard for HLA typing.Among the HLA SBT based-methods, the Pyrosequencing((r)) technique is an extremely versatile and accurate real-time sequencing technique with some advantages compared to classic Sanger method.Here, we describe a quick and inexpensive method that allows through the use of Pyrosequencing subtyping of HLA class I molecules, into HLA Bw6, -Bw4 I80, or -Bw4 T80 and HLA-C1, or -C2 groups. In particular, this analysis is focused on the amino acids around residue 80. This method demonstrated good sensitivity, specificity, and reproducibility. Using a quantitative allele acquisition mode, the method provides accurate sequence information required for the definition of heterozygous and/or homozygous samples. PMID- 26103898 TI - Allele Quantification Pyrosequencing(r) at Designated SNP Sites to Detect Allelic Expression Imbalance and Loss-of-Heterozygosity. AB - Pyrosequencing((r)) is able to quantitate the level of a nucleotide at a designated germ-line or somatic variant, including single nucleotide polymorphisms (SNPs). SNPs within a gene of interest may be used to distinguish between the two genetic alleles and study their behavior in heterozygous individuals. With regard to cancer etiology and development, identification of alleles and the detection of allelic imbalances, such as transcriptional loss from one allele or loss-of-heterozygosity (due to deletion of one allele), within a tumor are particularly useful. Lynch syndrome, the most common form of hereditary bowel and uterine cancer, is caused by heterozygous germ-line mutations within the DNA mismatch repair genes and tumors develop following inactivation of the remaining functional allele within somatic tissues, usually by acquired loss-of-heterozygosity. MLH1 is the most frequently mutated gene in Lynch syndrome; however, some cases whose tumors display immunohistochemical loss of the MLH1 protein have no apparent mutation within the coding region of MLH1. Allelic loss of expression or reduced function of MLH1 can also result in the propensity to develop Lynch syndrome associated cancers. In this chapter we describe allele quantification Pyrosequencing assays designed at a common benign SNP within the MLH1 coding region for application to either DNA or mRNA (cDNA) templates, which enabled us to detect pathological allelic imbalances in such cases with suspected Lynch syndrome. Our allele quantification Pyrosequencing assays at the MLH1 c.655A > G (rs1799977) exonic SNP were applied to clinical specimens and detected both constitutional allelic expression loss and tumor loss of-heterozygosity in some cases, facilitating the identification of the mechanistic cause underlying their cancer development. We provide detailed protocols for implementing these Pyrosequencing assays and illustrative examples of their application in patients. PMID- 26103899 TI - Quantitative DNA Methylation Analysis by Pyrosequencing(r). AB - DNA methylation is an epigenetic mark playing an important role in development and disease. Aberrant DNA methylation was identified as an alternative mechanism for gene inactivation complementing deletions and mutations in cancer initiation and progression. However, to accurately compare differences in DNA methylation among various tissue types, adequate quantitative approaches are required. Pyrosequencing((r)), as a sequencing-by-synthesis method, allows such quantification with single CpG resolution and the ability for threshold determination. This book chapter provides a detailed protocol for DNA methylation analysis by Pyrosequencing, including information on assay design and practical procedure. Additionally, emphasis is placed on the discussion of strengths and weaknesses of the methodology. PMID- 26103900 TI - Quantitative Methylation Analysis of the PCDHB Gene Cluster. AB - Long Range Epigenetic Silencing (LRES) is a repressed chromatin state of large chromosomal regions caused by DNA hypermethylation and histone modifications and is commonly observed in cancer. At 5q31 a LRES region of 800 kb includes three multi-gene clusters (PCDHA@, PCDHB@, and PCDHG@, respectively). Multiple experimental evidences have led to consider the PCDHB cluster as a DNA methylation marker of aggressiveness in neuroblastoma, second most common solid tumor in childhood. Because of its potential involvement not only in neuroblastoma but also in other malignancies, an easy and fast assay to screen the DNA methylation content of the PCDHB cluster might be useful for the precise stratification of the patients into risk groups and hence for choosing the most appropriate therapeutic protocol. Accordingly, we have developed a simple and cost-effective Pyrosequencing((r)) assay to evaluate the methylation level of 17 genes in the protocadherin B cluster (PCDHB@). The rationale behind this Pyrosequencing assay can in principle be applied to analyze the DNA methylation level of any gene cluster with high homologies for screening purposes. PMID- 26103901 TI - Assessment of Changes in Global DNA Methylation Levels by Pyrosequencing(r) of Repetitive Elements. AB - Transposable elements (TE) comprise half of the human genome. LINE-1 and ALU are the most common TE, and they have been used to assess changes in the DNA methylation of repetitive elements in response to intrinsic and extrinsic cellular events. Pyrosequencing((r)) is a real-time sequencing technology that enables quantitative assessment of TE methylation at single-base resolution. In Pyrosequencing, a region of interest is first amplified from bisulfite-converted DNA by polymerase chain reaction (PCR), before PCR amplicons are rendered single stranded and annealed with the Pyrosequencing primer prior to sequencing. In this chapter, we provide an overview of the analysis of repetitive element DNA methylation by bisulfite Pyrosequencing, and we describe a protocol that can be used for such purposes. PMID- 26103902 TI - Global Analysis of DNA 5-Methylcytosine Using the Luminometric Methylation Assay, LUMA. AB - The study of epigenetic alterations of the genome is becoming increasingly important in order to understand how environment and genetic background interact to build and regulate the functional genome. There are several types of epigenetic modifications to both DNA and histone proteins in eukaryotic cells; chiefly studied among these are changes to cytosine, where methylation of the 5 carbon position is the most prominent. Although this has many consequences for gene regulation and cell differentiation, other modifications have recently emerged as biologically relevant. Since global DNA methylation states may be used as a general measure of the methylome, cost-effective, rapid, and specific analytical tools are wanted.This protocol described here focuses on the Luminometric Methylation Assay (LUMA), a method which analyzes global DNA 5 methylcytosine (5mC) through the use of restriction enzymes and detection with Pyrosequencing((r)). Up to 96 samples can be simultaneously analyzed. In contrast to the majority of other methods focused on 5mC analysis, with appropriate enzymes, LUMA does not appear to detect 5-hydroxymethylcytosine (5hmC) and is therefore more specific than most 5mC techniques. PMID- 26103903 TI - Limiting Dilution Bisulfite Pyrosequencing(r): A Method for Methylation Analysis of Individual DNA Molecules in a Single or a Few Cells. AB - Bisulfite-based methods for DNA methylation analysis of small amounts of DNA from a limited number of cells are technologically challenging. Degradation of genomic DNA by bisulfite treatment, contamination with foreign DNA, and biases in the amplification of individual DNA molecules can generate results, which are not representative of the starting sample. Limiting dilution (LD) bisulfite Pyrosequencing((r)) (BSP) is a relatively simple technique to circumvent these problems. The bisulfite-treated DNA of a single or a few cells is diluted to an extent, that only a single DNA target molecule is present in the reaction. Then each individual DNA molecule in the starting sample is separately amplified and analyzed by Pyrosequencing. This allows the detection of rare alleles that are easily masked when pools of DNA target molecules are analyzed. Amplicons containing a heterozygous single nucleotide polymorphism (SNP) allow one to delineate the parental origin of the recovered molecules in addition to their methylation status. The number of cells (DNA target molecules) in the starting sample determines the dilution level and the number of reactions that have to be performed. LD-BSP allows methylation analysis of small cell pools (i.e., 5-10 microdissected cells) and even individual cells. The primers and PCR conditions described here have been successfully employed to analyze the methylation status of up to eight target genes in individual 2-16 cell embryos, germinal vesicle (GV) oocytes, and haploid sperms. PMID- 26103904 TI - Detection of Loss of Imprinting by Pyrosequencing(r). AB - Genomic imprinting is an epigenetically regulated process determining allele specific expression in a parent-of-origin dependent manner. Altered expression of imprinted genes characterizes numerous congenital diseases including Beckwith Wiedemann, Silver-Russell, Angelman, and Prader-Willi syndromes as well as acquired disorders such as cancer. The detection of imprinting alterations has important translational implications in clinics and the application of the Pyrosequencing((r)) technology offers the possibility to identify accurately also subtle modifications in allele-specific expression and in DNA methylation levels.Here, we describe two methods to investigate genomic imprinting defects (loss of imprinting, LOI) using Pyrosequencing: (1) Allele-specific expression analysis based on single nucleotide polymorphism (SNP), and (2) quantification of DNA methylation.The protocol for the quantification of the allele-specific expression is carried out by analyzing an informative SNP located within the transcribed portion of an imprinted gene. The method includes the cDNA amplification of the region containing the SNP and the Pyrosequencing-based analysis for the quantitative allelic discrimination comparing the ratio of the two alleles.The second protocol allows the accurate quantification of the DNA methylation levels at the Imprinting Control Regions (ICRs). Imprinted genes are clustered in chromosomal regions and their expression is mainly regulated by DNA methylation at CpG sites located within the ICRs. After bisulfite modification of the genomic DNA, the region of interest is amplified by PCR and analyzed by Pyrosequencing. The methylation value at each CpG site is calculated by the CpG software, which determines the ratio of the incorporation of "C" and "T" and converts the value in methylation percentage. PMID- 26103905 TI - Analysis of DNA Methylation Patterns in Single Blastocysts by Pyrosequencing(r). AB - Extensive epigenetic reprogramming occurs during mammalian gametogenesis and preimplantation development. DNA methylation patterns that are laid down during these stages are essential for subsequent normal foetal development. The requirement for more precise assessment of the epigenetic programming of in vitro derived human preimplantation embryo has become of paramount importance following the identification of epigenetic diseases that are associated with assisted reproduction and/or infertility. Such techniques are also useful and applicable to experimental reproductive biology. In order to expand our knowledge of epigenetic marks, including DNA methylation, during mammalian reproduction and early development, it is necessary to test new and sufficiently sensitive protocols. There are, however, unique challenges to obtain DNA methylation data from the small cell numbers that are present in the preimplantation embryo. In this protocol, we describe the successful application of Pyrosequencing((r)) to yield quantitative DNA methylation data over several CpG sites at differentially methylated regions (DMRs) at imprinted loci in single blastocysts, in this case, human blastocysts. Future developments of the protocol will allow DNA methylation analysis of a more extensive panel of genes for each embryo and at the same time, since the protocol allows for the extraction of mRNA from the embryo, the comparison between DNA methylation and gene expression. PMID- 26103906 TI - Allele-Specific DNA Methylation Detection by Pyrosequencing(r). AB - DNA methylation is an epigenetic modification that plays important roles in healthy as well as diseased cells, by influencing the transcription of genes. In spite the fact that human somatic cells are diploid, most of the currently available methods for the study of DNA methylation do not provide information on the methylation status of individual alleles of genes. This information may be of importance in many situations. In particular, in cancer both alleles of tumour suppressor genes generally need to be inactivated for a phenotypic effect to be observed. Here, we present a simple and cost-effective protocol for allele specific DNA methylation detection based on Pyrosequencing((r)) of methylation specific PCR (MSP) products including a single nucleotide polymorphism (SNP) within the amplicon. PMID- 26103907 TI - SNP-Based Quantification of Allele-Specific DNA Methylation Patterns by Pyrosequencing(r). AB - The analysis of allele-specific DNA methylation patterns has recently attracted much interest as loci of allele-specific DNA methylation overlap with known risk loci for complex diseases and the analysis might contribute to the fine-mapping and interpretation of non-coding genetic variants associated with complex diseases and improve the understanding between genotype and phenotype. In the presented protocol, we present a method for the analysis of DNA methylation patterns on both alleles separately using heterozygous Single Nucleotide Polymorphisms (SNPs) as anchor for allele-specific PCR amplification followed by analysis of the allele-specific DNA methylation patterns by Pyrosequencing((r)). Pyrosequencing is an easy-to-handle, quantitative real-time sequencing method that is frequently used for genotyping as well as for the analysis of DNA methylation patterns. The protocol consists of three major steps: (1) identification of individuals heterozygous for a SNP in a region of interest using Pyrosequencing; (2) analysis of the DNA methylation patterns surrounding the SNP on bisulfite-treated DNA to identify regions of potential allele-specific DNA methylation; and (3) the analysis of the DNA methylation patterns associated with each of the two alleles, which are individually amplified using allele specific PCR. The enrichment of the targeted allele is re-enforced by modification of the allele-specific primers at the allele-discriminating base with Locked Nucleic Acids (LNA). For the proof-of-principle of the developed approach, we provide assay details for three imprinted genes (IGF2, IGF2R, and PEG3) within this chapter. The mean of the DNA methylation patterns derived from the individual alleles corresponds well to the overall DNA methylation patterns and the developed approach proved more reliable compared to other protocols for allele-specific DNA methylation analysis. PMID- 26103908 TI - DNA Methylation Analysis of ChIP Products at Single Nucleotide Resolution by Pyrosequencing(r). AB - Interaction and co-occurrence of protein and DNA-based epigenetic modifications have become a topic of interest for many fundamental and biomedical questions. We describe within this chapter a protocol that combines two techniques in order to determine the methylation status of the DNA specifically associated with a protein of interest. First, DNA that directly interacts with the selected protein (such as a specific histone modification, a transcription factor, or any other DNA-associated protein) is purified by standard chromatin immunoprecipitation (ChIP). Second, the level of DNA methylation of this immunoprecipitated DNA is measured by bisulfite conversion and Pyrosequencing, a quantitative sequencing-by synthesis method. This procedure allows determining the methylation status of genomic DNA associated to a specific protein at single nucleotide resolution. PMID- 26103909 TI - Multiplex Pyrosequencing(r): Simultaneous Genotyping Based on SNPs from Distant Genomic Regions. AB - Pyrosequencing((r)) is a technique that allows the quick sequencing of short stretches of DNA, and results can be inspected in real time as they are generated. As such, it is a highly useful tool for the typing of organisms, based on single-nucleotide polymorphisms (SNPs). However, if a single polymorphism is not sufficient for typing and several distant genomic regions need to be examined, multiple Pyrosequencing reactions have to be performed for each organism. This strongly increases both workload and reagent costs. Alternatively, multiplex Pyrosequencing can be performed, in which the multiple sequencing reactions for all analyzed genomic regions are performed in a single reaction. However, when using this method, special care has to be taken while designing the assay and analyzing the results.Here we present a detailed protocol using our newly developed software mPSQed for assay design and MultiPSQ for data analysis. PMID- 26103910 TI - Detection of Drug-Resistant Mycobacterium tuberculosis. AB - Tuberculosis (TB) remains a global health problem. The increasing prevalence of drug-resistant Mycobacterium tuberculosis, the causative agent of TB, demands new measures to combat the situation. Rapid and accurate diagnosis of the pathogen and its drug susceptibility pattern is essential for timely initiation of optimal treatment, and, ultimately, control of the disease. We have developed a molecular method for detection of first- and second-line drug resistance in M. tuberculosis by Pyrosequencing((r)). The method consists of seven Pyrosequencing assays for the detection of mutations in the genes or promoter regions, which are most commonly responsible for resistance to the drugs rifampicin, isoniazid, ethambutol, amikacin, kanamycin, capreomycin, and fluoroquinolones. The method was validated on clinical isolates and it was shown that the sensitivity and specificity of the method were comparable to those of Sanger sequencing. In the protocol in this chapter we describe the steps necessary for setting up and performing Pyrosequencing for M. tuberculosis. The first part of the protocol describes the assay development and the second part of the protocol describes utilization of the method. PMID- 26103911 TI - Application of Pyrosequencing(r) in Food Biodefense. AB - The perpetration of a bioterrorism attack poses a significant risk for public health with potential socioeconomic consequences. It is imperative that we possess reliable assays for the rapid and accurate identification of biothreat agents to make rapid risk-informed decisions on emergency response. The development of advanced methodologies for the detection of biothreat agents has been evolving rapidly since the release of the anthrax spores in the mail in 2001, and recent advances in detection and identification techniques could prove to be an essential component in the defense against biological attacks. Sequence based approaches such as Pyrosequencing((r)), which has the capability to determine short DNA stretches in real time using biotinylated PCR amplicons, have potential biodefense applications. Using markers from the virulence plasmids and chromosomal regions, my laboratory has demonstrated the power of this technology in the rapid, specific, and sensitive detection of B. anthracis spores and Yersinia pestis in food. These are the first applications for the detection of the two organisms in food. Furthermore, my lab has developed a rapid assay to characterize the antimicrobial resistance (AMR) gene profiles for Y. pestis using Pyrosequencing. Pyrosequencing is completed in about 60 min (following PCR amplification) and yields accurate and reliable results with an added layer of confidence, thus enabling rapid risk-informed decisions to be made. A typical run yields 40-84 bp reads with 94-100 % identity to the expected sequence. It also provides a rapid method for determining the AMR profile as compared to the conventional plate method which takes several days. The method described is proposed as a novel detection system for potential application in food biodefense. PMID- 26103912 TI - Forensic Analysis of Mitochondrial and Autosomal Markers Using Pyrosequencing(r). AB - Forensic casework analyses often face challenges, such as limited genetic material with or without fragmentation and damage. To compensate for low amounts and degradation, shorter amplicons are often applied in the analysis. Also, a change of markers might be necessary using mitochondrial instead of autosomal markers. In addition, forensic research often involves analysis of large number of samples for marker evaluation and population-database compilation. Therefore, a flexible, robust but also rapid method for the detection of variation is highly useful. Pyrosequencing((r)) is a rapid, reliable, easy-to-use method for sequence analysis. The method is well suited for rapid forensic analysis of a few targets or analysis of a single target in many samples. It allows sequencing of very short amplicons, which facilitates analysis of degraded DNA. Here we present the use of Pyrosequencing, a robust method for sensitive forensic analysis of mitochondrial DNA, autosomal STRs, and Y-chromosome STRs and SNPs. PMID- 26103913 TI - Tissue-Specific DNA Methylation Patterns in Forensic Samples Detected by Pyrosequencing(r). AB - In certain circumstances the outcome of a trial may hinge on the ability of a forensic laboratory to determine the identity of biological stains present at crime scenes. An example of such a situation would be the detection of blood, saliva, vaginal fluid, or other body fluid in a specific location whereby its presence would reinforce the victim's or suspect's version of the events that happened during the commission of a crime. However, current serological methods used for identifying body fluids may lack the sensitivity and specificity to identify these fluids, particularly for trace levels. New procedures using proteomic methods and RNA-based gene expression show promise in addressing this issue; however, concerns about stability and relative levels of gene expression remain. An alternative approach is to utilize patterns of epigenetic DNA methylation. DNA methylation is an epigenetic mechanism that regulates the specificity of genes being expressed or silenced in cells. Regions in the human genome referred to as tissue-specific differentially methylated regions account for unique patterns of DNA methylation that are specific for each cell type. This chapter addresses the application of bisulfite-modified PCR combined with Pyrosequencing((r)) to detect tissue-specific DNA methylation patterns and perform trace serological analysis. The quantitative nature and precision available with Pyrosequencing presents major advantages in these studies as it permits detection of and contrast between cells with differential levels of methylation. The procedure can be applied to a variety of biological fluids which may be present at crime scenes. PMID- 26103914 TI - BMP protein-mediated crosstalk between inflammatory cells and human pluripotent stem cell-derived cardiomyocytes. AB - Following cardiac injury, the ischaemic heart tissue is characterized by the invasion of pro-inflammatory (M1) and pro-healing (M2) macrophages. Any engineered cardiac tissue will inevitably interact with the inflammatory environment found at the site of myocardial infarction at the time of implantation. However, the interactions between the inflammatory and the cardiac repair cells remain poorly understood. Here we recapitulated in vitro some of the important cellular events found at the site of myocardial injury, such as macrophage recruitment and their effect on cardiac differentiation and maturation, by taking into account the involvement of paracrine-mediated signalling. By using a 3D inverted invasion assay, we found that cardiomyocyte (CM) conditioned medium can trigger the recruitment of pro-inflammatory (M1) macrophages, through a mechanism that involves, in part, CM-derived BMP4. Pro inflammatory (M1) macrophages were also found to affect CM proliferation and differentiation potential, in part due to BMP molecules secreted by macrophages. These effects involved the activation of the canonical outside-in signalling pathways, such as SMAD1,5,8, which are known to be activated during myocardial injury in vivo. In the present study we propose a new role for CM- and macrophage derived BMP proteins during the recruitment of macrophage subtypes and the maturation of repair cells, representing an important step towards creating a functional cardiac patch with superior therapeutic properties. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26103915 TI - Safe transcranial electric stimulation motor evoked potential monitoring during posterior spinal fusion in two patients with cochlear implants. AB - Transcranial electric stimulation (TES) motor evoked potentials (MEPs) have become a regular part of intraoperative neurophysiologic monitoring (IONM) for posterior spinal fusion (PSF) surgery. Almost all of the relative contraindications to TES have come and gone. One exception is in the case of patients with a cochlear implant (CI). Herein we illustrate two cases of pediatric patients with CIs who underwent PSF using TES MEPs as part of IONM. In both instances the patients displayed no untoward effects from TES, and post operatively both CIs were intact and functioning as they were prior to surgery. PMID- 26103916 TI - Ethical problems in health research with indigenous or originary peoples in Peru. AB - The varied, abrupt and amazing geography of the land of Peru is home of one of the major concentrations of indigenous peoples in the world. The asymmetry of power, however, in their relationship with the rest of society and the State is still very evident in their social exclusion, their gap in social and economic development, barriers in their access to health services as well as their marginalization and exploitation as subjects of health research. In this paper, we analyse two cases of research on indigenous populations in Peru, discuss them from the point of view of bioethics and reflect on important issues for researchers, research participants and the society, such as the need to respect different cultures, the need that the research being done is relevant to the needs of the population in which it is conducted and the necessity to empower indigenous communities in participatory research, to strengthen the institutions and to protect human rights, namely through ethics committees for research and the free, informed and meaningful informed consent. This approach should foster quality research, while at the same time fully respecting human rights and bioethics. We cannot forget that advancements in genetics, throughout the world, are very much in debt to indigenous populations. PMID- 26103917 TI - Covalent docking using autodock: Two-point attractor and flexible side chain methods. AB - We describe two methods of automated covalent docking using Autodock4: the two point attractor method and the flexible side chain method. Both methods were applied to a training set of 20 diverse protein-ligand covalent complexes, evaluating their reliability in predicting the crystallographic pose of the ligands. The flexible side chain method performed best, recovering the pose in 75% of cases, with failures for the largest inhibitors tested. Both methods are freely available at the AutoDock website (http://autodock.scripps.edu). PMID- 26103918 TI - Optimum predictors of therapeutic outcome in HCV patients in Pakistan. AB - Hepatitis C virus (HCV) constitutes a major public health issue in Pakistan. Interferon alpha and ribavirin is used widely in routine practice in HCV infected patients in Pakistan.Treatment prediction is an important tool in therapy management. The present study aims to evaluate trends of predictive variables of treatment outcome in patients with different genotypes. The analysis comprised of 921 patients infected with different HCV genotypes. All the patients received IFN alpha-2b combined with ribavirin for 24 weeks. Overall, 60.2% patients achieved Sustained virologic response (SVR). In females sustained virologic response (SVR) was higher in age group <40 years (77.2%) than >=40-50 years (60%) but in male SVR was almost equal in both age groups. We also found higher SVR with low pretreatment viral load (72.4%, P < 0.0001). Sustained Virologic Response in genotype 3a was 63.1%, 3b was 55%, 1a was 36.3% and 1b was 35% 3a +3b was 55.0% and 1a+3a was 42.9%. According to multivariable logistic regression analysis age < 40 years (2.0; 95%CI, 1.49-2.84; P = 0.0001), low pretreatment RNA level<800,000 IU/ml (4.0; 95%CI, 2.64-6.17; P = 0.0001), early virologic response at week 12 (12.3; 95%CI, 8.18-18.58; P < 0.0001) and non-fatty liver (2.5; 95%CI, 3.6-6.2; P = 0.005) showed significance for SVR. Nucleotide substitution in 5'UTR before treatment failed to show any characteristic pattern that has correlation with sustained response. Subtype 3a showed 95% presence among patients with age <40 years while older patients showed 79.9%. PMID- 26103919 TI - Effects of Home Visitation on Maternal Competencies, Family Environment, and Child Development: a Randomized Controlled Trial. AB - Based on the US Nurse-Family Partnership (NFP) program, the German home visiting program "Pro Kind" offered support for socially and financially disadvantaged first-time mothers from pregnancy until the children's second birthday. A multi centered, longitudinal randomized controlled trial (RCT) was conducted to assess its effectiveness on mothers and children. A total of 755 women with multiple risk factors were recruited, 394 received regular home visits (treatment group), while 361 only had access to standard community services (control group). Program influences on family environment (e.g., quality of home, social support), maternal competencies (e.g., maternal self-efficacy, empathy, parenting style), and child development (e.g., cognitive and motor development) were assessed from mothers' program intake in pregnancy to children's second birthday based on self reports in regular interviews and developmental tests. Generalized estimating equations (GEE) models showed small, but significant positive treatment effects on parental self-efficacy, and marginally significant effects on social support, and knowledge on child rearing. Maternal stress, self-efficacy, and feelings of attachment in the TG tend to show a more positive development over time. Subgroup effects were found for high-risk mothers in the TG, who reported more social support over time and, generally, had children with higher developmental scores compared to their CG counterparts. Post hoc analyses of implementation variables revealed the quality of the helping relationship as a significant indicator of treatment effects. Results are discussed in terms of implementation and public policy differences between NFP and Pro Kind. PMID- 26103920 TI - Changing Latino Adolescents' Substance Use Norms and Behaviors: the Effects of Synchronized Youth and Parent Drug Use Prevention Interventions. AB - While parent and youth substance use prevention interventions have shown beneficial effects on preadolescents, many programs have typically targeted US born European American and African American families while overlooking the unique factors that characterize recent immigrant Latino families. This article presents the results on youth substance use when adding a culturally grounded parenting component, Familias Preparando la Nueva Generacion (FPNG), to the existing and already proven efficacious classroom-based drug abuse prevention intervention, keepin'it REAL (kiR). Data come from youth (N = 267) participating in the randomized control trial of the interventions who were surveyed at baseline (beginning at 7th grade) and 18 months later (end of 8th grade). Using multivariate linear regression path analyses, results indicate when FPNG and kiR are combined, youth had significantly lowered alcohol and cigarettes use at the end of 8th grade, mediated through anti-drug norms, when compared with youth who only participated in kiR without parental participation in FPNG. These findings indicate that adolescent normative beliefs and related behaviors can be changed through synchronized culturally grounded parent and youth interventions and together can play an important role in reducing adolescent substance use. PMID- 26103921 TI - Pilot Test of an Adapted, Evidence-Based HIV Sexual Risk Reduction Intervention for Homeless Women. AB - Women experiencing homelessness are at heightened risk for HIV, yet risk reduction interventions specifically designed for this population are lacking. This study reports on a pilot efficacy trial of a brief evidence-based intervention, Sister To Sister (STS), that we specifically adapted for homeless women in the temporary/emergency settings where they typically seek services. Seventy-nine women, recruited from three service sites in Los Angeles County, were assigned to the 40-min adapted STS intervention or an information-only control group. At 30-day follow-up, intervention participants reported significantly greater condom use, intentions to use condoms, and sexual impulse control (as well as marginally higher positive condom beliefs and condom self efficacy) compared to control participants. Results provide preliminary evidence that HIV risk reduction can be achieved for homeless women through a brief skill based intervention. A randomized controlled trial employing a longer follow-up period to monitor outcomes will be necessary to determine efficacy of the adapted intervention. PMID- 26103922 TI - BAFF-driven autoimmunity requires CD19 expression. AB - B cell activating factor of the tumor necrosis factor family (BAFF or BLyS) is a critical factor for B cell survival and maturation. BAFF-transgenic (BAFF-Tg) mice develop autoimmunity that resembles systemic lupus erythematosus (SLE) in a T cell-independent but MyD88-dependent manner, implicating toll-like receptor (TLR) signaling. The specific B cell subtypes that make pro-inflammatory autoantibodies in BAFF-Tg mice are TLR-activated innate B cells known as marginal zone (MZ) and B1 B cells. These cells infiltrate the salivary glands and kidneys of diseased BAFF-Tg mice. However, loss of B1a or MZ B cells does not protect BAFF-Tg mice against disease, suggesting that B1b B cells might be the important pathogenic B cell subset. To test this hypothesis, we have generated BAFF-Tg mice that retained follicular B cells, but are deficient in B1a, B1b and MZ B cells, by crossing BAFF-Tg mice to CD19-deficient mice (BTg-CD19(-/-)). The BTg-CD19(-/ ) mice did not produce autoantibodies and were protected from splenomegaly, kidney pathology and all signs of autoimmunity. This work suggests that B1b B cells, rather than MZ or B1a B cells, are sufficient and possibly required for the development of autoimmunity. Loss of the majority of innate-like B cells was able to protect BAFF-Tg mice from developing disease, so we can now conclude that autoimmunity induced by excessive BAFF production requires B1b B cells and CD19 signaling. PMID- 26103923 TI - Exosomes released by keratinocytes modulate melanocyte pigmentation. AB - Cells secrete extracellular vesicles (EVs), exosomes and microvesicles, which transfer proteins, lipids and RNAs to regulate recipient cell functions. Skin pigmentation relies on a tight dialogue between keratinocytes and melanocytes in the epidermis. Here we report that exosomes secreted by keratinocytes enhance melanin synthesis by increasing both the expression and activity of melanosomal proteins. Furthermore, we show that the function of keratinocyte-derived exosomes is phototype-dependent and is modulated by ultraviolet B. In sum, this study uncovers an important physiological function for exosomes in human pigmentation and opens new avenues in our understanding of how pigmentation is regulated by intercellular communication in both healthy and diseased states. PMID- 26103924 TI - Epidemiology of Lyme disease in low-incidence states. AB - Lyme disease is the most common vector-borne disease in the U.S. Surveillance data from four states with a low-incidence of Lyme disease was evaluated. Most cases occurred after travel to high-incidence Lyme disease areas. Cases without travel-related exposure in low-incidence states differed epidemiologically; misdiagnosis may be common in these areas. PMID- 26103925 TI - Identification of non-host semiochemicals for the brown dog tick, Rhipicephalus sanguineus sensu lato (Acari: Ixodidae), from tick-resistant beagles, Canis lupus familiaris. AB - Studies have shown that the brown dog tick, Rhipicephalus sanguineus sensu lato, when fed on the beagle breed of dog, Canis lupus familiaris, development negatively affected in comparison with tick development after feeding on the English cocker spaniel breed. Thus leading to the suggestion that beagle dogs are be tick-resistant dogs. Behavioural studies have demonstrated that more ticks are attracted by extracts from cocker spaniels than from beagles and that the odour of beagles is a repellent. To test the hypothesis that resistant hosts produce repellent compounds, we undertook comparative chemical analysis on beagle odour and cocker spaniel extracts using coupled high-resolution gas chromatography-mass spectrometry (GC-MS) and also used Petri-dish and olfactometer behavioural assays to assess the response of ticks to identified non-host compounds. The beagle odour extracts contained almost three times as many chemical compounds as cocker spaniel samples. Several non-host compounds were identified, i.e. 2-hexanone, benzaldehyde, nonane, decane and undecane. In Petri-dish assays, 2-hexanone was repellent at 30 min at concentrations of 0.200 and 0.050 mg cm(-2), whilst at 10 min, the 0.100 mg cm(-2) concentration was repellent. Benzaldehyde repelled ticks at 30 min (0.200 mg cm(-2)) and at 5 min (0.050 mg cm(-2)). Undecane was repellent for R. sanguineus s.l. ticks for the first 5 min at the highest concentration tested. Nonane and decane did not show any significant repellency at any concentration or time evaluated. When 2-hexanone and benzaldehyde were combined, an increase in the repellency rate was observed, with activity comparable or better than N,N-diethyl-3-methylbenzamide (DEET). In olfactometer bioassays, a 1:1 mixture of 2-hexanone:benzaldehyde and DEET were repellent for R. sanguineus s.l. adults at the concentration of 0.200 mg cm(-2). This study identified non-host semiochemicals that mediate avoidance of the beagle dog breed by R. sanguineus s.l. This finding may enable development of new approaches to control this tick. PMID- 26103926 TI - Common maxillofacial terminology: Do our patients understand who we are? PMID- 26103927 TI - Relevance of Whitnall's tubercle and auditory meatus in diagnosing exclusions during skull-photo superimposition. AB - Video vision mixer based skull-photo superimposition is a popular method for identifying skulls retrieved from unidentified human remains. A report on the reliability of the superimposition method suggested increased failure rates of 17.3 to 32% to exclude and 15 to 20% to include skulls while using related and unrelated face photographs. Such raise in failures prompted an analysis of the methods employed for the research. The protocols adopted for assessing the reliability are seen to vary from those suggested by the practitioners in the field. The former include overlaying the skull- and face-images on the basis of morphology by relying on anthropometric landmarks on the front plane of the face images and evaluating the goodness of match depending on mix-mode images; the latter consist of orienting the skull considering landmarks on both the eye and ear planes of the face- and skull-images and evaluating the match utilizing images seen in wipe-mode in addition to those in mix-mode. Superimposition of a skull with face-images of five living individuals in two sets of experiments, one following the procedure described for the research on reliability and the other applying the methods suggested by the practitioners has shown that overlaying the images on the basis of morphology depending on the landmarks on the front plane alone and assessing the match in mix-mode fails to exclude the skull. However, orienting the skull relying on the relationship between the anatomical landmarks on the skull- and face-images such as Whitnall's tubercle and exocanthus in the front (eye) plane and the porion and tragus in the rear (ear) plane as well as assessing the match using wipe-mode images enables excluding that skull while superimposing with the same set of face-images. PMID- 26103928 TI - Practical relevance of prescribing superimposition for determining a frontal sinus pattern match. AB - A research that tested the methods suitable for comparing ante- and post-mortem radiographic patterns of frontal sinuses concluded that superimposition should be followed as a stringent method for establishing individual identification. We verified the practical relevance of prescribing superimposition by superimposing ante- and post-mortem frontal sinus patterns recorded in case situations as well as simulated ante- and post-mortem of frontal sinus patterns recorded using archived skulls. For superimposition, the wipe facility available in the vision mixer was employed in addition to the mix mode. Ante- and post-mortem radiographic patterns that were available in two earlier cases were not superimposable. Related simulated ante- and post-mortem radiographic patterns of frontal sinuses are superimposable only when the skull that is initially oriented for recording the ante-mortem radiograph is retained in the same posture for recording the post-mortem radiograph also. Once the skull has been removed from the X-ray table, after recording the simulated ante-mortem radiograph, and repositioned for the simulated post-mortem radiograph, even when the intervening time is 1min, the sinus patterns in these radiographs are not superimposable. Superimposition cannot be used as a conditional requirement for side-by-side comparison of radiographic patterns of frontal sinuses. PMID- 26103930 TI - Amphiphilic graphene oxide stabilisation of hexagonal BN and MoS2 sheets. AB - A simple and scalable method has been developed for directly forming water dispersible van der Waals solids involving mixing aqueous solution of graphene oxide (GO) with hexagonal boron nitride (BN) or molybdenum disulphide (MoS2) in N methylpyrrolidone. The GO acts as an amphiphile in stabilising the colloidal solutions of the heterolaminar material in water. PMID- 26103929 TI - Efficacy of treatment of edge stenosis of endografts inserted for superficial femoral artery stenotic disease. AB - OBJECTIVE: The role of endografts in the treatment of extensive superficial femoral artery (SFA) occlusive disease is enlarging. Results are limited by the occurrence of edge stenosis. The aim of the study was to retrospectively evaluate the efficacy of treatment of edge stenosis of endografts inserted for SFA occlusive disease. METHODS: All patients, treated between November 2001 and December 2011, with a self-expandable polytetrafluoroethylene-endograft were gathered in a prospective database in three hospitals. The incidence of primary edge stenosis and the incidence of re-edge stenosis after treatment were retrospectively noted and a comparison was made between the results of percutaneous transluminal angioplasty (PTA) and extension of the endograft. RESULTS: A total of 88 patients presented with 115 edge stenoses, of which the majority presented within 1 year after insertion of the endograft (mean time to edge stenosis 10.7 +/- 8.2 months). Seventy-three stenoses (63%) manifested at the proximal and 42 at the distal edge (37%). The 1-year incidence of restenosis and/or occlusion was 45% after PTA and 43% after endograft extension, with 1-year patency rates of 81% and 92%, respectively. The incidence of restenosis/occlusion after treatment with PTA was 12% higher at two years compared to extension of the endograft (55% vs. 43%, respectively). CONCLUSION: Edge stenosis may well be treated with either PTA or extension of the endograft. The incidence of restenosis and/or occlusion after both PTA and extension is high, but patency rates are acceptable. Aggressive surveillance is needed during the first year after insertion. PMID- 26103931 TI - An iterative procedure for extracting skill maps from data. AB - The methodologies for the construction of a knowledge structure mainly refer to the query to experts, the skill maps, and the data-driven approaches. This last method is of growing interest in recent literature. In this paper, an iterative procedure for building a skill map from a set of data is introduced. This procedure is based on the minimization of the distance between the knowledge structure delineated by a given skill map and the data. The accuracy of the proposed method is tested through a number of simulation studies where the amount of noise in the data is manipulated as well as the kind of structure to be reconstructed. Results show that the procedure is accurate and that its performance tends to be sufficiently stable even with high error rates. The procedure is compared to two already-existing methodologies to derive knowledge structures from a set of data. The use of the corrected Akaike Information Criterion (AICc) as a stopping criterion of the iterative reconstruction procedure is tested against the app criterion introduced by Schrepp. Moreover, two empirical applications on clinical data are reported, and their results show the applicability of the procedure. PMID- 26103932 TI - Major hepatectomies for perihilar cholangiocarcinoma: Predictors for clinically relevant postoperative complications using the International Study Group of Liver Surgery definitions. AB - BACKGROUND/AIM: Major hepatectomies are widely used in curative-intent surgery for perihilar cholangiocarcinoma, but morbidity rates are high. The aim of the study is to explore potential predictors for clinically relevant complications after major hepatectomies for perihilar cholangiocarcinoma. METHODS: Seventy patients were included. Univariate and multivariate analyses were performed for risk factors of morbidities using the International Study Group of Liver Surgery definitions. RESULTS: Severe morbidity rate was 36.5%. Clinically relevant posthepatectomy liver failure, bile leak, and hemorrhage rates were 24%, 22%, and 8.5%, respectively. A neutrophil-to-lymphocyte ratio > 3.3 is an independent prognostic factor for severe complications (hazard ratio = 1.258; 95% confidence interval 1.008-1.570; p = 0.042) while the number of blood units > 3 is an independent prognostic factor for clinically relevant liver failure (hazard ratio = 1.254; 95% confidence interval 1.082-1.452; p = 0.003). Biliary drainage and portal vein resection were not statistically correlated with any postoperative complication (p >= 0.101). Significantly higher bilirubinemia levels were observed in patients with postoperative hemorrhage (p = 0.023). CONCLUSION: Clinically relevant morbidity rates after major hepatectomies for perihilar cholangiocarcinoma are high. Liver failure represents the main complication and is correlated with the number of transfused blood units. A patient with increased bilirubinemia appears to have a high risk for postoperative hemorrhage. Biliary drainage and portal vein resection does not appear to have a detrimental effect on morbidities. Neutrophil-to-lymphocyte ratio is a novel independent predictor for severe morbidity after major hepatectomies for perihilar cholangiocarcinoma and may contribute to better and informed decision-making. PMID- 26103933 TI - Simultaneous resection of pulmonary tumor following cardiovascular surgery. AB - BACKGROUND: A pulmonary tumor is occasionally detected on a chest computed tomography (CT) scan before cardiovascular surgery. PURPOSE: In this study, we examined clinical courses of patients who had undergone the simultaneous resection of a pulmonary tumor following cardiovascular surgery. METHODS: From 2008 to 2013, 18 patients (13 men and 5 women) with a median age of 69.8 years underwent the wedge pulmonary resection for a lung tumor through a median thoracotomy following cardiovascular surgery in our hospital. Cardiovascular surgeries consisted of off-pump coronary artery bypass grafting (CABG) in six patients, aortic valve replacement and/or mitral valve plasty in 10 patients, total arch replacement in 10 patients and descending aorta replacement in 10 patients. RESULTS: No complications associated with pulmonary resections were observed. Pathological examination revealed that 15 patients (83.3%) were diagnosed with lung cancers including 13 adenocarcinomas and two squamous cell carcinomas, with the clinical stages of 1A in 13 patients, 2A in one patient and 2B in one patient. Among them, five patients received the radical pulmonary resection subsequently, whereas 10 patients were unable to receive it due to their poor cardiopulmonary function. Kaplan-Meier analysis of patients with lung cancer revealed that the 5-year survival rate and progression-free survival (PFS) rate after 3 years from the surgery were 46.2% and 73.8%, respectively. CONCLUSION: The simultaneous resection of pulmonary tumor following cardiovascular surgery is safely performed, and is useful for the pathological diagnosis of the tumor. Further studies are warranted, however, this procedure may contribute to controlling the progression of lung cancer in patients with cardiovascular disease with comorbidities. PMID- 26103934 TI - Co-occurrence of tannin and tannin-less vacuoles in sensitive plants. AB - Vacuoles of different types frequently coexist in the same plant cell, but the duality of the tannin/tannin-less vacuoles observed in Mimosa pudica L. is rare. In this plant, which is characterized by highly motile leaves, the development and original features of the double vacuolar compartment were detailed in primary pulvini from the young to the mature leaf stage. In young pulvini, the differentiation of tannin vacuoles first occurred in the epidermis and progressively spread toward the inner cortex. In motor cells of nonmotile pulvini, tannin deposits first lined the membranes of small vacuole profiles and then formed opaque clusters that joined together to form a large tannin vacuole (TV), the proportion of which in the cell was approximately 45%. At this stage, transparent vacuole profiles were rare and small, but as the parenchyma cells enlarged, these profiles coalesced to form a transparent vacuole with a convexity toward the larger-sized tannin vacuole. When leaf motility began to occur, the two vacuole types reached the same relative proportion (approximately 30%). Finally, in mature cells displaying maximum motility, the large transparent colloidal vacuole (CV) showed a relative proportion increasing to approximately 50%. At this stage, the proportion of the tannin vacuole, occurring in the vicinity of the nucleus, decreased to approximately 10%. The presence of the condensed type of tannins (proanthocyanidins) was proven by detecting their fluorescence under UV light and by specific chemical staining. This dual vacuolar profile was also observed in nonmotile parts of M. pudica (e.g., the petiole and the stem). Additional observations of leaflet pulvini showing more or less rapid movements showed that this double vacuolar structure was present in certain plants (Mimosa spegazzinii and Desmodium gyrans), but absent in others (Albizzia julibrissin, Biophytum sensitivum, and Cassia fasciculata). Taken together, these observations strongly suggest that a direct correlation cannot be found between the presence of a tannin vacuole and the osmoregulated motility of pulvini. PMID- 26103935 TI - Determination of methylisothiazolinone and methylchloroisothiazolinone in cosmetic products by ultra high performance liquid chromatography with tandem mass spectrometry. AB - Isothiazolinone biocides are broad-spectrum preservatives that are widely used in cosmetics, household, and industrial products. An increase in the number of cases of allergic contact dermatitis to isothiazolinone preservatives, namely, methylisothiazolinone and methylchloroisothiazolinone, have been recently noticed. The Food and Drug Administration relies on analytical methods to quantify levels of use of cosmetic ingredients and support enforcement action against products that are not in compliance with the law. In this study, an efficient ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for the determination of methylisothiazolinone and methylchloroisothiazolinone in selected cosmetic products. The lower limit of quantitation was determined to be 0.1 MUg/g for both preservatives. A survey of 24 cosmetic products was conducted and found concentrations of methylisothiazolinone and methylchloroisothiazolinone ranging from not quantified, or below the lower limit of quantitation, to 89.64 MUg/g and not quantified to 10.31 MUg/g, respectively. PMID- 26103936 TI - [Hip arthroplasty in the presence of proximal femoral deformity]. AB - INTRODUCTION: Proximal femoral deformities may result in pain in the ipsilateral hip joint and profound functional disability, ultimately requiring arthroplasty. PROCEDURE: Primary hip replacement procedures in the presence of markedly altered anatomy of the proximal femur present a technical challenge for the orthopedic surgeon. The deformity and its underlying condition, whether congenital or acquired, may complicate canal preparation and affect the choices of implant, exposure and postoperative physiotherapy protocol. Furthermore, a two- or multi stage treatment may be required, e.g. for implant removal, for femoral osteotomy or to rule out infection. DISCUSSION: Treatment strategies must be individually tailored, respecting patient needs, the etiology, the anatomic site and the geometry of the deformity encountered, bone quality, soft tissue deficits, the presence of retained implants in the proximal femur, infection status and comorbidities. PMID- 26103937 TI - [Patellofemoral instability in trisomy 21: MPFL-Reconstruction as a single procedure]. AB - BACKGROUND: Patellar instability is a common orthopaedic condition which is often seen in younger individuals. Biomechanical studies have shown that the medial patellofemoral ligament (MPFL) is the most important soft tissue that restrains lateral subluxation of the patella in the beginning of flexion of the knee joint. METHODS: MPFL reconstruction is an effective procedure to treat recurrent patellar dislocation. Double-bundle and single-bundle procedures have been described. If double-bundle reconstruction is not possible, there are good postoperative outcomes with single-bundle procedure as well. DISCUSSION: This is the first report of MPFL reconstruction as a single procedure to treat patellar instability in patients with down syndrome. PMID- 26103938 TI - When should we change our clinical practice based on the results of a clinical study? Study endpoints. PMID- 26103939 TI - Effects of electrolyte, catalyst, and membrane composition and operating conditions on the performance of solar-driven electrochemical reduction of carbon dioxide. AB - Solar-driven electrochemical cells can be used to convert carbon dioxide, water, and sunlight into transportation fuels or into precursors to such fuels. The voltage efficiency of such devices depends on the (i) physical properties of its components (catalysts, electrolyte, and membrane); (ii) operating conditions (carbon dioxide flowrate and pressure, current density); and (iii) physical dimensions of the cell. The sources of energy loss in a carbon dioxide reduction (CO2R) cell are the anode and cathode overpotentials, the difference in pH between the anode and cathode, the difference in the partial pressure of carbon dioxide between the bulk electrolyte and the cathode, the ohmic loss across the electrolyte and the diffusional resistances across the boundary layers near the electrodes. In this study, we analyze the effects of these losses and propose optimal device configurations for the efficient operation of a CO2R electrochemical cell operating at a current density of 10 mA cm(-2). Cell operation at near-neutral bulk pH offers not only lower polarization losses but also better selectivity to CO2R versus hydrogen evolution. Addition of supporting electrolyte to increase its conductivity has a negative impact on cell performance because it reduces the electric field and the solubility of CO2. Addition of a pH buffer reduces the polarization losses but may affect catalyst selectivity. The carbon dioxide flowrate and partial pressure can have severe effects on the cell efficiency if the carbon dioxide supply rate falls below the consumption rate. The overall potential losses can be reduced by use of an anion, rather than a cation, exchange membrane. We also show that the maximum polarization losses occur for the electrochemical synthesis of CO and that such losses are lower for the synthesis of products requiring a larger number of electrons per molecule, assuming a fixed current density. We also find that the reported electrocatalytic activity of copper below -1 V vs. RHE is strongly influenced by excessive polarization of the cathode and, hence, does not represent its true activity at bulk conditions. This article provides useful guidelines for minimizing polarization losses in solar-driven CO2R electrochemical cells and a method for predicting polarization losses and obtaining kinetic overpotentials from measured partial current densities. PMID- 26103940 TI - Zebrafish as a model for studying the developmental neurotoxicity of propofol. AB - Anesthetics can cause widespread apoptotic neurodegeneration and adverse effects on synaptogenesis during early postnatal life. Synaptogenesis correlates with several proteins, including myelin basic protein (MBP). However, little is known about the adverse effects of exposure to propofol on MBP, particularly during embryonic development. Our goal was to use zebrafish to explore the effect of propofol on embryonic development, apoptosis and MBP expression. Zebrafish embryos were exposed to propofol at defined doses and stages from 6 to 48 h postfertilization by immersion. The survival rate, hatchability, aberration rate, cell apoptosis and gene expression were analyzed at defined stages. Analysis revealed that doses of 1, 2 and 3 ug ml(-1) propofol were reasonable anesthetic concentrations for zebrafish embryos. These doses of propofol caused a significant decrease in hatchability and an increase in aberration rate. Moreover, 6 days postfertilization (dpf) larvae are anesthetized by immersion into water containing 1, 2 or 3 ug ml(-1) of propofol. The number of apoptotic cells in the head of propofol-treated 36 h postfertilization embryos were significantly increased, and the expression of caspases-3, -8 and -9 were upregulated. Apoptosis was also induced in the brain of 3 dpf larvae exposed to propofol. However, propofol caused a decrease in mbp gene and protein (dose dependent) expression levels in the central nervous system of 3 dpf zebrafish. These data show that embryonic exposure to propofol is neurotoxic, causing increased apoptosis and decreased MBP expression. We believe zebrafish can be used as a novel model to explore the mechanisms of propofol neurotoxicity. PMID- 26103941 TI - Influence of Family and Childhood Memories in the Development and Manifestation of Paranoid Ideation. AB - : Several studies point out to the influence of social experiences on perceptions of the environment and others in cognitive functioning and different aspects of psychopathology. The current study aimed at studying the influence of the psychosocial risk factors in a mixed sample of participants from the general population and affected by paranoid schizophrenia. The extent to which the existence of negative life events and events that are threatening to the inner models of the self (i.e., history of maltreatment, physical, social or psychological abuse) or the memories of these traumatic events occurring during childhood are related to the existence of paranoid beliefs in adulthood was explored. Results suggested that memories of parental behaviours characterized by antipathy from both parental figures, submissiveness and bullying victimization were important predictors of paranoid ideation in adult life. This further emphasizes the need for understanding the family and social dynamics of people presenting paranoid ideations to the development of therapeutic interventions that can effectively reduce the invalidation caused by severe psychopathology, as is the case of schizophrenia. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Memories of family dynamics characterized by behaviours of antipathy from both parental figures, submissiveness and bullying victimization are important predictors of paranoid ideation in adult life. The study highlights the importance of exploring subjective recalls of feelings and behaviours associated with early rearing experiences, peer relationships and themes related to social rank theory in the roots of internal models of relationship with the self and others in the general sample, patients diagnosed with schizophrenia and their first-degree relatives. Our findings indicate that schizophrenic patients in active phase differ regarding memories of threat and submission and are more likely to remember childhood experiences perceived as threatening during an active phase than when in remission. It is possible that by changing these internal models and social interaction styles, patients may be able to get involved in more cooperating and affiliative interactions, disconfirming these early beliefs about others being rejecting, critical or hostile towards the self, and more effectively reducing the invalidation caused by positive and negative symptomatology of schizophrenia on social functioning. PMID- 26103942 TI - Grb2 monomer-dimer equilibrium determines normal versus oncogenic function. AB - The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression. PMID- 26103943 TI - From Paul Broca's great limbic lobe to the limbic system. AB - Paul Broca's concept of the "great limbic lobe" has had a huge impact on neuroscience. In this commentary, which accompanies the first English translation of the original paper, we comment on Broca's contribution and its influence on the understanding of the brain bases of emotion. PMID- 26103944 TI - Iron(II) supramolecular helicates condense plasmid DNA and inhibit vital DNA related enzymatic activities. AB - The dinuclear iron(II) supramolecular helicates [Fe2 L3 ]Cl4 (L=C25 H20 N4 ) bind to DNA through noncovalent (i.e., hydrogen-bonding, electrostatic) interactions and exhibit antimicrobial and anticancer effects. In this study, we show that the helicates condense plasmid DNA with a much higher potency than conventional DNA condensing agents. Notably, molecules of DNA in the presence of the M enantiomer of [Fe2 L3 ]Cl4 do not form intermolecular aggregates typically formed by other condensing agents, such as spermidine or spermine. The helicates inhibit the activity of several DNA-processing enzymes, such as RNA polymerase, DNA topoisomerase I, deoxyribonuclease I, and site-specific restriction endonucleases. However, the results also indicate that the DNA condensation induced by the helicates does not play a crucial role in these inhibition reactions. The mechanisms for the inhibitory effects of [Fe2 L3 ]Cl4 helicates on DNA-related enzymatic activities have been proposed. PMID- 26103945 TI - Toward a genome-wide approach for detecting hybrids: informative SNPs to detect introgression between domestic cats and European wildcats (Felis silvestris). AB - Endemic gene pools have been severely endangered by human-mediated hybridization, which is posing new challenges in the conservation of several vertebrate species. The endangered European wildcat is an example of this problem, as several natural populations are suffering introgression of genes from the domestic cat. The implementation of molecular methods for detecting hybridization is crucial for supporting appropriate conservation programs on the wildcat. In this study, genetic variation at 158 single-nucleotide polymorphisms (SNPs) was analyzed in 139 domestic cats, 130 putative European wildcats and 5 captive-bred hybrids (N=274). These SNPs were variable both in wild (HE=0.107) and domestic cats (HE=0.340). Although we did not find any SNP that was private in any population, 22 SNPs were monomorphic in wildcats and pairwise FCT values revealed marked differences between domestic and wildcats, with the most divergent 35 loci providing an average FCT>0.74. The power of all the loci to accurately identify admixture events and discriminate the different hybrid categories was evaluated. Results from simulated and real genotypes show that the 158 SNPs provide successful estimates of admixture, with 100% hybrid individuals (two to three generations in the past) being correctly identified in STRUCTURE and over 92% using the NEWHYBRIDS' algorithm. None of the unclassified cats were wrongly allocated to another hybrid class. Thirty-five SNPs, showing the highest FCT values, provided the most parsimonious panel for robust inferences of parental and first generations of admixed ancestries. This approach may be used to further reconstruct the evolution of wildcat populations and, hopefully, to develop sound conservation guidelines for its legal protection in Europe. PMID- 26103946 TI - Abiotic stress does not magnify the deleterious effects of spontaneous mutations. AB - Although the effects of deleterious alleles often are predicted to be greater in stressful environments, there is no theoretical basis for this prediction and the empirical evidence is mixed. Here we characterized the effects of three types of abiotic stress (thermal, oxidative and hyperosmotic) on two sets of nematode (Caenorhabditis elegans) mutation accumulation (MA) lines that differ by threefold in fitness. We compared the survival and egg-to-adult viability between environments (benign and stressful) and between fitness categories (high-fitness MA, low-fitness MA). If the environment and mutation load have synergistic effects on trait means, then the difference between the high and low-fitness MA lines should be larger in stressful environments. Although the stress treatments consistently decreased survival and/or viability, we did not detect significant interactions between fitness categories and environment types. In contrast, we did find consistent evidence for synergistic effects on (micro)environmental variation. The lack of signal in trait means likely reflects the very low starting fitness of some low-fitness MA lines, the potential for cross-stress responses and the context dependence of mutational effects. In addition, the large increases in the environmental variance in the stressful environments may have masked small changes in trait means. These results do not provide evidence for synergism between mutation and stress. PMID- 26103947 TI - Genetic and phenotypic influences on copulatory plug survival in mice. AB - Across a diversity of animals, male seminal fluid coagulates upon ejaculation to form a hardened structure known as a copulatory plug. Previous studies suggest that copulatory plugs evolved as a mechanism for males to impede remating by females, but detailed investigations into the time course over which plugs survive in the female's reproductive tract are lacking. Here, we cross males from eight inbred strains to females from two inbred strains of house mice (Mus musculus domesticus). Plug survival was significantly affected by male genotype. Against intuition, plug survival time was negatively correlated with plug size: long-lasting plugs were small and relatively more susceptible to proteolysis. Plug size was associated with divergence in major protein composition of seminal vesicle fluid, suggesting that changes in gene expression may play an important role in plug dynamics. In contrast, we found no correlation to genetic variation in the protein-coding regions of five genes thought to be important in copulatory plug formation (Tgm4, Svs1, Svs2, Svs4 and Svs5). Our study demonstrates a complex relationship between copulatory plug characteristics and survival. We discuss several models to explain unexpected variation in plug phenotypes. PMID- 26103948 TI - Using multiple markers to elucidate the ancient, historical and modern relationships among North American Arctic dog breeds. AB - Throughout most of the Americas, post-colonial dogs largely erased the genetic signatures of pre-historical dogs. However, the North American Arctic harbors dogs that are potentially descended from pre-historical ancestors, as well as those affected by post-colonial translocations and admixtures. In particular, Inuit dogs from Canada and Greenland are thought to descend from dogs associated with Thule peoples, who relied on them for transportation ca. 1000 years ago. Whether Thule dogs reflected an earlier colonization by Paleoeskimo dogs ca. 4500 years ago is unknown. During the Alaskan Gold Rush, additional sled dogs, possibly of post-colonial derivation, the Alaskan Husky, Malamute and Siberian Husky, were used in the Arctic. The genealogical relationships among and origins of these breeds are unknown. Here we use autosomal, paternal and maternal DNA markers to (1) test the hypothesis that Inuit dogs have retained their indigenous ancestry, (2) characterize their relationship to one another and to other Arctic breeds, and (3) estimate the age of North American indigenous matrilines and patrilines. On the basis of the agreement of all three markers we determined that Inuit dogs have maintained their indigenous nature, and that they likely derive from Thule dogs. In addition, we provide support for previous research that the Inuit dogs from Canada and Greenland dog should not be distinguished as two breeds. The Alaskan Husky displayed evidence of European introgression, in contrast to the Malamute and Siberian Husky, which appear to have maintained most of their ancient Siberian ancestry. PMID- 26103949 TI - The fruits of a functional approach for psychological science. AB - The current paper introduces relational frame theory (RFT) as a functional contextual approach to complex human behaviour and examines how this theory has contributed to our understanding of several key phenomena in psychological science. I will first briefly outline the philosophical foundation of RFT and then examine its conceptual basis and core concepts. Thereafter, I provide an overview of the empirical findings and applications that RFT has stimulated in a number of key domains such as language development, linguistic generativity, rule following, analogical reasoning, intelligence, theory of mind, psychopathology and implicit cognition. PMID- 26103950 TI - High incidence of primary melanomas in an MC1R RHC homozygote/CDKN2A mutant genotype patient. AB - Melanoma incidence in Australia remains the highest in the world; hence understanding its causation is paramount for future therapeutic developments. Multiple primary melanomas are also common occurrences among the Australian population with identified risk factors such as personal and family history of melanoma, fair skin type, dysplastic naevus syndrome and history of significant ultraviolet exposure. The roles of both environmental and genetic factors have been elucidated in melanoma development, but the synergy of interactions between the two remains complex given the heterogeneous nature of the disease. We present a rare case of a 57-year-old female with 20 cutaneous melanomas and review the role of genetic and environmental factors in development of her multiple primary melanomas. PMID- 26103951 TI - Melanoma survival is superior in females across all tumour stages but is influenced by age. AB - Among patients with invasive melanoma, females are known to have higher survival than males globally. However, this survival advantage has not been explored in thin melanomas, the most common form of the disease. In addition, it is unclear if this advantage is true across all age groups. We aimed to compare melanoma survival between males and females by clinical stage and within age groups. Melanomas from 1995 to 2008 were extracted from the Queensland Cancer Registry and the Surveillance, Epidemiology, and End Results (SEER) Program, and melanoma specific deaths were ascertained up to 2011. Flexible parametric survival models compared survival between groups. The Queensland cohort of 28,979 patients experienced 1712 melanoma deaths and the SEER cohort of 57,402 patients included 6929 melanoma deaths. Survival rates were in favour of females across nearly all tumour stages, including thin invasive tumours in both cohorts after adjusting for demographic and clinical factors [odds ratio (OR) death female:male for stage I melanoma = 0.64 in Queensland; and OR = 0.79 in the US, both P < 0.001]. The sex influence on survival interacted with age categories. In particular, the survival advantage was inconsistent in females with stage I melanoma aged under 60. Females with melanoma have a survival advantage over males including in stage I melanomas. However, this advantage is dependent on age at diagnosis, suggesting an underlying biological mechanism influenced by age that exists from the very early stages of the disease. PMID- 26103952 TI - Adjuvant regimens with trastuzumab administered for small HER2-positive breast cancer in routine clinical practice. AB - PURPOSE: Trastuzumab has proven to improve the prognosis of HER2-positive breast cancer, but the information available about its administration for small tumors is still limited. Therefore, we assessed the use of adjuvant regimens with trastuzumab for the treatment of small HER2-positive breast cancer in routine clinical practice. METHODS: This observational study was conducted in patients with HER2-positive breast adenocarcinoma <=1.5 cm who received trastuzumab-based adjuvant treatment in clinical practice. Clinical/histopathological data were retrieved from patients' medical charts. RESULTS: A total of 101 evaluable patients were enrolled (median age [range], 56.7 [49.0-64.8] years; ECOG 0, 98.0 %; ductal carcinoma, 88.1 %; lymph nodes N0, 79.2 %). Only five (5.0 %) patients received neoadjuvant treatment, while all patients underwent tumor surgery. Adjuvant trastuzumab was administered at a mean (+/-SD) dose of 5.9 +/- 1.5 mg/kg/cycle, and mostly in a three-weekly schedule (89 [89.0 %] patients). The most frequent adjuvant therapy used with trastuzumab was chemotherapy (87 [86.1 %] patients), followed by radiotherapy (63 [62.4 %] patients) and hormone therapy (52 [51.5 %] patients). Chemotherapy regimens mainly included doxorubicin, cyclophosphamide and paclitaxel/docetaxel (n = 30), docetaxel and cyclophosphamide (n = 15), docetaxel and carboplatin (n = 13). Hormone therapy mainly included letrozole (n = 17) and tamoxifen (n = 17). Nine (8.9 %) patients reported trastuzumab-related adverse events; only one allergic reaction reached grade 3 toxicity. CONCLUSION: This study shows that trastuzumab-based adjuvant treatment of small HER2-positive breast cancer is mostly based on chemotherapy mainly paclitaxel/docetaxel. Adjuvant administration of trastuzumab for small HER2-positive breast cancer seems to be similar to that used for larger tumors. PMID- 26103953 TI - miR-448 negatively regulates ovarian cancer cell growth and metastasis by targeting CXCL12. AB - OBJECTIVES: The purpose of the study is to investigate the roles of miR-448 in ovarian cancer. METHODS: miR-448 and CXCL12 mRNA expression were examined using qRT-PCR. CXCL12 promoter activity was detected by luciferase activity system. Cell proliferation was assayed by MTT or colony formation. Migration and invasion was assayed by transwell chamber. RESULTS: miR-448 expression was usually under expressed in ovarian cancer tissues and cell lines compared with their normal ones. Ectopic expression of miR-448 inhibited cell proliferation, migration and invasion in ovarian cancer cells. Moreover, bioinformatic prediction suggested that CXCL12 was a target gene of miR-448. We also demonstrated that restored expression of CXCL12 dampened miR-448-mediated suppression of tumor progression, which suggests the important role of miR-448 in tumor progression. CONCLUSION: Our data indicate that miR-448 functions as a tumor suppressor in ovarian cancer, which exerts its activity by suppressing the expression of CXCL12. PMID- 26103955 TI - Sleep apnoea headache in obstructive sleep apnoea syndrome patients presenting with morning headache: comparison of the ICHD-2 and ICHD-3 beta criteria. AB - BACKGROUND: Morning headache is associated with obstructive sleep apnoea syndrome (OSAS); however, OSAS patients present with various characteristics of morning headache, and they often do not fulfil the International Classification of Headache Disorders (ICHD)-2 criteria for "sleep apnoea headache". The aims of this study were to assess the new ICHD-3 beta criteria for sleep apnoea headache in OSAS patients and to evaluate the differences with the ICHD-2. METHODS: We conducted a cross-sectional survey regarding morning and sleep apnoea headaches that included 235 OSAS outpatients receiving continuous positive airway pressure (CPAP) treatment. The presence of morning headache was evaluated by reviewing the medical records before administration of CPAP treatment. RESULTS: Of all of the OSAS patients, 48 (20.4%) reported morning headaches. Of the 48 patients with morning headaches, 29 (60.4%) and 39 (81.3%) fulfilled the ICHD-2 and ICHD-3 beta criteria for sleep apnoea headache, respectively. The increased frequency of individuals who qualified for diagnosis was likely attributable to the extension of headache duration from 30 min to 4 h. The severity of OSAS was not associated with the presence of sleep apnoea headache. CONCLUSIONS: The utilisation of ICHD 3 beta criteria is clinically useful for diagnosing sleep apnoea headache in patients with OSAS. Applying the ICHD-3 beta criteria was of clinical significance when considering the marked response of these headaches to CPAP therapy. The cause of sleep apnoea headache remains to be elucidated. PMID- 26103956 TI - P-Type Photochromism of New Helical Naphthopyrans: Synthesis and Photochemical, Photophysical and Theoretical Study. AB - Two novel helical naphthopyrans have been synthesised. The helical scaffold has the interesting effect of increasing the thermal stability of the transoid-trans (TT) open isomer formed upon UV irradiation of the closed form (CF), which transforms these naphthopyrans from thermal to photochemical photochromes. The photochromic performance is excellent in both polar and apolar solvents and the conversion percentage from the CF to the TT form can be as high as 92.8 %. We propose a new method to determine the quantum yields of the photochemical processes that lead to transoid-cis (TC) and TT isomers, and their molar absorption coefficients. The thermal stability of the TT and TC isomers has been studied in different solvents. The quantum yields of fluorescence before and after irradiation, along with the decay lifetimes, have also been measured. TD DFT calculations have been performed to determine the relative thermodynamic stability of the species involved in the photochromic mechanism and to rationalise their spectral properties. PMID- 26103957 TI - Serum Leptin Levels and Well-Differentiated Thyroid Cancer: A True Association: Reply. PMID- 26103958 TI - [Prevalence of pica in iron deficiency anemia in Marrakech (Morocco)]. AB - INTRODUCTION: Pica is an eating disorder, defined by long-term ingestion of non nutritive substances. PURPOSE: To determine the frequency of pica in patients with iron deficiency anemia and to describe the population with both iron deficiency anemia and pica. PATIENTS AND METHODS: This retrospective study examined records from the department of hematology at the Mohammed VI University Hospital Center in Marrakech of all adult patients seen from January 1, 2005, through December 31, 2010 who met both criteria. Results: During the 6-year study period, 320 patients with iron deficiency anemia were seen: 256 women and 64 men (sex-ratio F/M: 4). The prevalence of pica among the patients with iron deficiency anemia was 17.5% (56/320). All the patients with pica were women, for a prevalence of 21.8% (56/256); their average age was 23 years; 40 were white (71.4%) and 16 black (28.6%). The clinical signs were primarily pallor (100%) and asthenia (100%). The mean level of hemoglobin was 7.6 g/dL and of ferritin, 6.4 mg/L. Geophagia was the most common form of pica (75%). Iron supplementation induced regression of pica in 64.3% of patients. CONCLUSION: Our study shows a high prevalence of pica in patients with iron deficiency anemia. PMID- 26103959 TI - Crenosoma vulpis in wild and domestic carnivores from Italy: a morphological and molecular study. AB - Crenosoma vulpis is a metastrongyloid nematode primarily associated with respiratory tract infections of red foxes in North America and Europe. Sporadic cases have also been reported in domestic dogs. The present study aimed to provide morphological, molecular, and epidemiological data on the geographical distribution of this nematode throughout Italy. From 2012 to 2014, 12 of the 138 foxes examined, three dogs and one badger scored positive for C. vulpis. Forty adults were isolated from foxes and the badger, whereas first-stage larvae were detected in the three dogs. All specimens were morphologically identified as C. vulpis, and 28 nematodes were also molecularly characterized by sequencing mitochondrial (12S ribosomal DNA (rDNA)) and nuclear (18S rDNA) ribosomal genes. Four haplotypes were identified based on the 12S rDNA target gene, with the most representative (78.5%) designated as haplotype I. No genetic variability was detected for the 18S rDNA gene. The molecular identification was consistent with the distinct separation of species-specific clades inferred by the phylogenetic analyses of both mitochondrial and ribosomal genes. Data herein reported indicates that C. vulpis has a wide distribution in foxes from southern Italy, and it also occurs in dogs from southern and northern regions of the country. Practitioners should consider the occurrence of this nematode in the differential diagnosis of canine respiratory disease, particularly in dogs living close to rural areas where foxes are present. PMID- 26103960 TI - Plasma endotoxin core antibody concentration and linear growth are unrelated in rural Malawian children aged 2-5 years. AB - BACKGROUND: Environmental enteropathy is subclinical inflammation of the upper gastrointestinal tract associated with reduced linear growth in developing countries. Usually investigators have used biopsy or a dual sugar absorption test to assess environmental enteropathy. Such tests are time and resource intensive, restricting their utility as screening methods. Serum endotoxin core antibody (EndoCab) concentration is a potential indicator of intestinal inflammation and integrity, and thus may be useful to predict environmental enteropathy. We analyzed the association of serum EndoCab levels versus linear growth and lactulose-mannitol assay results in 2-5 year old rural Malawian children. METHODS: This was an observational study of 388 rural, asymptomatic Malawian children who had anthropometric measurements taken at least every 3 months since birth. In June and July 2011, dual sugar permeability tests were performed and serum samples were drawn for EndoCab assays. Pearson correlation, Student's t test and multivariable linear regression were used to compare ln EndoCab concentrations with height-for-age z scores (HAZ) at time of sampling and 3 months later. Identical analysis was also performed for ln EndoCab versus measurements from dual sugar permeability testing performed in conjunction with serum sampling. In a subgroup of children with anthropometric data in the months prior to serum sampling, Pearson correlation was used to estimate the relationship between ln EndoCab and recent linear growth. RESULTS: Ln EndoCab concentrations were not correlated with HAZ at time of measurement (B = -0.078, P = 0.14) nor change in HAZ over the subsequent 3 months HAZ (B = -0.018, P = 0.27). EndoCab concentration was not associated with %lactulose excretion (B < 0.001, P = 0.98) nor the lactulose:mannitol ratio (B = 0.021, P = 0.62). Subgroup analysis also did not reveal any significant association between EndoCab and recent growth. CONCLUSION: EndoCab titers were not correlated with measurements of growth or intestinal permeability in rural pre-school aged Malawian children. PMID- 26103961 TI - "That pulled the rug out from under my feet!" - adverse experiences and altered emotion processing in patients with functional neurological symptoms compared to healthy comparison subjects. AB - BACKGROUND: Medically unexplained movement or sensibility disorders, recently defined in DSM-5 as functional neurological symptoms (FNS), are still insufficiently understood. Stress and trauma have been addressed as relevant factors in FNS genesis. Altered emotion processing has been discussed. The present study screened different types and times of adverse experiences in childhood and adulthood in patients with FNS as well as in healthy individuals. The relationship between stress profile, aspects of emotion processing and symptom severity was examined, with the hypothesis that particularly emotional childhood adversities would have an impact on dysfunctional emotion processing as a mediator of FNS. METHODS: Adverse childhood experiences (ACE), recent negative life events (LE), alexithymia, and emotion regulation style were assessed in 45 inpatients diagnosed with dissociative disorder expressing FNS, and in 45 healthy comparison subjects (HC). RESULTS: Patients reported more severe FNS, more (particularly emotional) ACE, and more LE than HC. FNS severity varied with emotional ACE and negative LE, and LE partially mediated the relation between ACE and FNS. Alexithymia and suppressive emotion regulation style were stronger in patients than HC, and alexithymia varied with FNS severity. Structural equation modeling verified partial mediation of the relationship between emotional ACE and FNS by alexithymia. CONCLUSIONS: Early, emotional and accumulating stress show a substantial impact on FNS-associated emotion processing, influencing FNS. Understanding this complex interplay of stress, emotion processing and the severity of FNS is relevant not only for theoretical models, but, as a consequence also inform diagnostic and therapeutic adjustments. PMID- 26103962 TI - Metabolic interactions between hyperhomocysteinemia and endothelin-1 among Tunisian patients with acute coronary diseases. AB - BACKGROUND: Acute coronary syndromes (ACS) are complex and polygenic diseases which are a real problem of public health. These syndromes require multidisciplinary studies to understand the pathogenesis mechanisms and metabolic interactions between different risk factors.This study aimed to explore the variation of two coronary risk parameters not mentioned by Framingham cohorts, hyperhomocysteinemia and endothelin-1 (ET-1) in Tunisian coronary and the study of the variation of these parameters based on various cardiac risk factors and metabolic relationship between them.To 157 coronary and 142 healthy subjects, the concentration of homocysteine was quantified by fluorescence polarization immunoassay; the concentration of ET-1 was measured by an analytical technique, the High Performance Liquid Chromatography (HPLC) coupled with mass spectrometry. RESULTS: Our study showed that homocysteine and ET-1 were significantly higher in patients compared to healthy subjects (24.40 +/- 12.5 MUmol/L vs 7.44 +/- 2.5 MUmol/L p <0.00001) for homocysteine and (15.2 +/- 5.3 nmol/L vs 7.1 +/- 2.7 nmol/L, p <0.00001) for ET-1. On the other hand, homocysteine varies according to tobacco and diabetes while ET-1 depends on the sex, hypertension, smoking, obesity and dyslipidemia and a statistically negative correlation was shown between homocysteine and ET-1 in coronary patients (r = -0.66 p <0.00001). CONCLUSION: The study of the variation of these two parameters in coronary patients and metabolic exploration of the relationship between homocysteine and ET-1 according to various risk factors and the interactions between themselves facilitates the decision of therapeutic treatment. PMID- 26103964 TI - Differential hepatotoxicity of dietary and DNL-derived palmitate in the methionine-choline-deficient model of steatohepatitis. AB - BACKGROUND: Saturated fatty acids are toxic to liver cells and are believed to play a central role in the pathogenesis of non-alcoholic steatohepatitis. In experimental steatohepatitis induced by feeding mice a methionine-choline deficient (MCD) diet, the degree of liver damage is related to dietary sugar content, which drives de novo lipogenesis and promotes the hepatic accumulation of saturated fatty acids. The objective of this study was to determine whether dietary palmitate exerts the same toxicity as carbohydrate-derived palmitate in the MCD model of fatty liver disease. METHODS: We fed mice custom MCS and MCD formulas containing 4 different carbohydrate-fat combinations: starch-oleate, starch-palmitate, sucrose-oleate and sucrose-palmitate. After 3 wk, we compared their metabolic and disease outcomes. RESULTS: Mice fed the custom MCD formulas developed varying degrees of hepatic steatosis and steatohepatitis, in the order starch-oleate < starch-palmitate < sucrose-oleate < sucrose-palmitate. Liver injury correlated positively with the degree of hepatic lipid accumulation. Liver injury also correlated positively with the amount of palmitate in the liver, but the relationship was weak. Importantly, mice fed MCD starch-palmitate accumulated as much hepatic palmitate as mice fed MCD sucrose-oleate, yet their degree of liver injury was much lower. By contrast, mice fed MCD sucrose-palmitate developed severe liver injury, worse than that predicted by an additive influence of the two nutrients. CONCLUSION: In the MCD model of steatohepatitis, carbohydrate-derived palmitate in the liver is more hepatotoxic than dietary palmitate. Dietary palmitate becomes toxic when combined with dietary sugar in the MCD model, presumably by enhancing hepatic de novo lipogenesis. PMID- 26103963 TI - Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation. AB - BACKGROUND: Cone and cone-rod dystrophies are clinically and genetically heterogeneous inherited retinal disorders with predominant cone impairment. They should be distinguished from the more common group of rod-cone dystrophies (retinitis pigmentosa) due to their more severe visual prognosis with early central vision loss. The purpose of our study was to document mutation spectrum of a large French cohort of cone and cone-rod dystrophies. METHODS: We applied Next-Generation Sequencing targeting a panel of 123 genes implicated in retinal diseases to 96 patients. A systematic filtering approach was used to identify likely disease causing variants, subsequently confirmed by Sanger sequencing and co-segregation analysis when possible. RESULTS: Overall, the likely causative mutations were detected in 62.1 % of cases, revealing 33 known and 35 novel mutations. This rate was higher for autosomal dominant (100 %) than autosomal recessive cases (53.8 %). Mutations in ABCA4 and GUCY2D were responsible for 19.2 % and 29.4 % of resolved cases with recessive and dominant inheritance, respectively. Furthermore, unexpected genotype-phenotype correlations were identified, confirming the complexity of inherited retinal disorders with phenotypic overlap between cone-rod dystrophies and other retinal diseases. CONCLUSIONS: In summary, this time-efficient approach allowed mutation detection in the most important cohort of cone-rod dystrophies investigated so far covering the largest number of genes. Association of known gene defects with novel phenotypes and mode of inheritance were established. PMID- 26103965 TI - Effect of BMP7 on podocyte transdifferentiation and Smad7 expression induced by hyperglycemia. AB - OBJECTIVE: To investigate the effect of BMP7 on the transdifferentiation and Smad7 expression of podocytes induced by high glucose in vitro and to explore its possible protective mechanisms. METHODS: Mouse podocytes were cultured and divided into normal glucose group (NG), high glucose group (HG), mannitol group, NG+BMP7 group, and HG+BMP7 group. Real-time PCR and Western blot were applied respectively to detect the mRNA and protein expression levels of synaptopodin, desmin, and Smad7. RESULTS: The cells significantly up-regulated the mRNA and protein expression of desmin and reduced the expression of both synaptopodin and Smad7 after 48 hours (vs. NG, p < 0.01). BMP7 dramatically suppressed the mRNA and protein expression of desmin and protected the expression of synaptopodin and Smad7 after incubation with high glucose for 48 hours (vs. HG, p < 0.01). CONCLUSIONS: BMP7 can inhibit the epithelial-to-mesenchymal cell transformation (EMT) of podocytes induced by high glucose; Smad7 may mediate the blunting effects of BMP7 on high glucose in podocytes. PMID- 26103966 TI - Characteristics of oseltamivir-resistant influenza A (H1N1) pdm09 virus during the 2013-2014 influenza season in Mainland China. AB - BACKGROUND: In this study, we analyzed the characteristics of oseltamivir resistant influenza A (H1N1) pdm09 virus isolated from patients in mainland China during the influenza season from September 2013 through March 2014, and provide guidance on which antiviral to be used for clinical treatment. METHODS: The all viruses collected from September 1, 2013 through March 31, 2014 were obtained from the Chinese National Influenza Surveillance Network. A fluorescence-based assay was used to detect virus sensitivity to neuraminidase inhibitors (NAIs). The hemagglutinin (HA) and neuraminidase (NA) gene of the oseltamivir-resistant viruses were sequenced. RESULTS: A total of 24 (2.14 %) influenza A (H1N1) pdm09 viruses that were resistant to oseltamivir were identified. These 24 viruses were isolated from 23 patients and no epidemiological link among them could be identified. Except for one virus with the H275H/Y mixture substitution, all the other 23 viruses had H275Y substitution in the NA protein. Sequence analysis revealed that the amino acid substitutions in the HA protein of influenza A (H1N1) pdm09 viruses with H275Y substitution isolated from mainland China were similar to the viruses from clustered cases reported in the United States, and the amino acid substitutions in the NA protein were similar to the viruses reported in Sapporo, Japan in 2013-2014. All of the oseltamivir-resistant viruses in mainland China and Japan possessed additional substitutions N386K, V241I and N369K in the NA protein, while most (>89 %) resistant-viruses from the United States during the same period possess V241I and N369K and did not have the N386K substitution. The N386K substitution was also exist in most sensitive viruses during the same period in mainland China. The amino acid substitutions in both HA and NA protein differed from the clustered cases from Australia reported in 2011 with additional substitutions. The drug-resistant influenza A(H1N1) pdm09 viruses were from patients without any known NAIs medication history prior to sampling. CONCLUSIONS: During the influenza season from September 2013 through March 2014 in Mainland China, oseltamivir-resistant influenza A(H1N1)pdm09 viruses were much more frequently detected than ever since the appearance of the virus in 2009. PMID- 26103967 TI - Modified Release Biodegradable Polymeric Microspheres of Stavudine: Cell Viability, Cellular Uptake, Hemolysis Studies and In Vivo Pharmacokinetics. AB - Family of retroviruses which replicates through the use of the reverse transcriptase enzyme or the enzyme needed to convert RNA to DNA for replication bears Human Immunodeficiency Virus (HIV). It causes irreversible destruction of the immune system leading to the occurrence of opportunistic infections and malignancies. The eradication of HIV is highly unlikely as the cells of the mononuclear phagocyte system (MPS) besides CD4 T lymphocytes are the specific hosts for HIV which need to be targeted even after extended blood plasma profile of antiviral drug to maintain viral suppression and reduced disease progression. Aiming the current goal, biodegradable polymeric microspheres of PLGA 50: 50 (RESOMER((r)) 505H) were developed and evaluated. These polymeric particles encapsulating Stavudine (d4T) exhibited nearly 100% cell viability during cytotoxicity studies in comparison to pure d4T. The histological studies have revealed the in vivo biocompatibility while hemolysis studies certified the liability of formulation to be used parenteraly exhibiting no significant hemolytic toxixicty. The in vivo pharmacokinetics has shown the extended drug release from microsphere matrix upto a month. The calculated AUCtotal for d4T loaded polymeric microspheres was found to be 3341.656 MUM h/ml; which was nearly 54 times than the total AUC of free d4T injected subcutaneously to the control group of animals; exhibiting the stable d4T concentration in blood avoiding fluctuation of the same indicating decreased probabilities of development of resistance against the treatment. Combination of targeted and subcutaneous administration of d4T will not only provide the stable and extended release of drug but also eradicate the hidden HIV hosted by macrophages. The concomitant regimen will potentially enhance the therapeutic efficacy with patient compliance; renewing new hopes for complete cure and improved quality of life in the AIDS patient. PMID- 26103968 TI - Asymptomatic transmission and the resurgence of Bordetella pertussis. AB - BACKGROUND: The recent increase in whooping cough incidence (primarily caused by Bordetella pertussis) presents a challenge to both public health practitioners and scientists trying to understand the mechanisms behind its resurgence. Three main hypotheses have been proposed to explain the resurgence: 1) waning of protective immunity from vaccination or natural infection over time, 2) evolution of B. pertussis to escape protective immunity, and 3) low vaccine coverage. Recent studies have suggested a fourth mechanism: asymptomatic transmission from individuals vaccinated with the currently used acellular B. pertussis vaccines. METHODS: Using wavelet analyses of B. pertussis incidence in the United States (US) and United Kingdom (UK) and a phylodynamic analysis of 36 clinical B. pertussis isolates from the US, we find evidence in support of asymptomatic transmission of B. pertussis. Next, we examine the clinical, public health, and epidemiological consequences of asymptomatic B. pertussis transmission using a mathematical model. RESULTS: We find that: 1) the timing of changes in age specific attack rates observed in the US and UK are consistent with asymptomatic transmission; 2) the phylodynamic analysis of the US sequences indicates more genetic diversity in the overall bacterial population than would be suggested by the observed number of infections, a pattern expected with asymptomatic transmission; 3) asymptomatic infections can bias assessments of vaccine efficacy based on observations of B. pertussis-free weeks; 4) asymptomatic transmission can account for the observed increase in B. pertussis incidence; and 5) vaccinating individuals in close contact with infants too young to receive the vaccine ("cocooning" unvaccinated children) may be ineffective. CONCLUSIONS: Although a clear role for the previously suggested mechanisms still exists, asymptomatic transmission is the most parsimonious explanation for many of the observations surrounding the resurgence of B. pertussis in the US and UK. These results have important implications for B. pertussis vaccination policy and present a complicated scenario for achieving herd immunity and B. pertussis eradication. PMID- 26103970 TI - Detection of Shiga Toxin-Producing Escherichia coli from Nonhuman Sources and Strain Typing. AB - Shiga toxin-producing Escherichia coli (STEC) strains are commonly found in the intestine of ruminant species of wild and domestic animals. Excretion of STEC with animal feces results in a broad contamination of food and the environment. Humans get infected with STEC through ingestion of contaminated food, by contact with the environment, and from STEC-excreting animals and humans. STEC strains can behave as human pathogens, and some of them, called enterohemorrhagic E. coli (EHEC), may cause hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS). Because of the diversity of STEC types, detection strategies for STEC and EHEC are based on the identification of Shiga toxins or the underlying genes. Cultural enrichment of STEC from test samples is needed for identification, and different protocols were developed for this purpose. Multiplex real-time PCR protocols (ISO/CEN TS13136 and USDA/FSIS MLG5B.01) have been developed to specifically identify EHEC by targeting the LEE (locus of enterocyte effacement)-encoded eae gene and genes for EHEC-associated O groups. The employment of more genetic markers (nle and CRISPR) is a future challenge for better identification of EHEC from any kinds of samples. The isolation of STEC or EHEC from a sample is required for confirmation, and different cultivation protocols and media for this purpose have been developed. Most STEC strains present in food, animals, and the environment are eae negative, but some of these strains can cause HC and HUS in humans as well. Phenotypic assays and molecular tools for typing EHEC and STEC strains are used to detect and characterize human pathogenic strains among members of the STEC group. PMID- 26103969 TI - NKX2.1-Related Disorders: a novel mutation with mild clinical presentation. AB - BACKGROUND: A highly variable phenotype characterized by thyroid, respiratory and neurological defects has been reported in an already established group of disorders namely NKX2.1-related disorders. We describe here the case of an infant with a novel mutation of the NKX2.1 gene characterized by mild clinical presentation. Aim of the study was to elucidate the genotype-phenotype correlation in our patient. METHODS: We performed genetic analysis of the NKX2.1 gene in an infant with no neonatal respiratory distress and near-normal results at neonatal screening test for congenital hypothyroidism, choreoathetosis, ataxia and delayed independent walking. RESULTS: A novel mutation of the NKX2.1 gene has been identified, that is responsible for a mild framework of congenital hypothyroidism and neurological symptoms. CONCLUSIONS: The frequency of congenital hypothyroidism cases associated with NKX2.1 mutations is expected to be higher in a subgroup of patients, selected according to the neurological presentation. In these patients the analysis of NKX2.1 mutational status is recommended. PMID- 26103971 TI - Mycobacterial Lipidomics. AB - Lipidomics is a distinct subspecialty of metabolomics concerned with hydrophobic molecules that organize into membranes. Most of the lipid classes present in Mycobacterium tuberculosis are found only in Actinobacteria and show extreme structural diversity. This article highlights the conceptual basis and the practical challenges associated with the mass spectrometry-based lipidomic study of M. tuberculosis to solve basic questions about the virulence of this lipid laden organism. PMID- 26103972 TI - The Physiology and Genetics of Oxidative Stress in Mycobacteria. AB - During infection, Mycobacterium tuberculosis is exposed to a diverse array of microenvironments in the human host, each with its own unique set of redox conditions. Imbalances in the redox environment of the bacillus or the host environment serve as stimuli, which could regulate virulence. The ability of M. tuberculosis to evade the host immune response and cause disease is largely owing to the capacity of the mycobacterium to sense changes in its environment, such as host-generated gases, carbon sources, and pathological conditions, and alter its metabolism and redox balance accordingly for survival. In this article we discuss the redox sensors that are, to date, known to be present in M. tuberculosis, such as the Dos dormancy regulon, WhiB family, anti-sigma factors, and MosR, in addition to the strategies present in the bacillus to neutralize free radicals, such as superoxide dismutases, catalase-peroxidase, thioredoxins, and methionine sulfoxide reductases, among others. M. tuberculosis is peculiar in that it appears to have a hierarchy of redox buffers, namely, mycothiol and ergothioneine. We discuss the current knowledge of their biosynthesis, function, and regulation. Ergothioneine is still an enigma, although it appears to have distinct and overlapping functions with mycothiol, which enable it to protect against a wide range of toxic metabolites and free radicals generated by the host. Developing approaches to quantify the intracellular redox status of the mycobacterium will enable us to determine how the redox balance is altered in response to signals and environments that mimic those encountered in the host. PMID- 26103973 TI - Taxonomy Meets Public Health: The Case of Shiga Toxin-Producing Escherichia coli. AB - To help assess the clinical and public health risks associated with different Shiga toxin-producing Escherichia coli (STEC) strains, an empirical classification scheme was used to classify STEC into five "seropathotypes" (seropathotype A [high risk] to seropathotypes D and E [minimal risk]). This definition is of considerable value in cases of human infection but is also problematic because not all STEC infections are fully characterized and coupled to reliable clinical information. Outbreaks with emerging hybrid strains continuously challenge our understanding of virulence potential and may result in incorrect classification of specific pathotypes; an example is the hybrid strain that caused the 2011 outbreak in Germany, STEC/EAggEC O104:H4, which may deserve an alternative seropathotype designation. The integration of mobile virulence factors in the stepwise and parallel evolution of pathogenic lineages of STEC collides with the requirements of a good taxonomy, which separates elements of each group into subgroups that are mutually exclusive, unambiguous, and, together, include all possibilities. The concept of (sero)-pathotypes is therefore challenged, and the need to identify factors of STEC that absolutely predict the potential to cause human disease is obvious. Because the definition of hemolytic-uremic syndrome (HUS) is distinct, a basic and primary definition of HUS-associated E. coli (HUSEC) for first-line public health action is proposed: stx2 in a background of an eae- or aggR-positive E. coli followed by a second line subtyping of stx genes that refines the definition of HUSEC to include only stx2a and stx2d. All other STEC strains are considered "low-risk" STEC. PMID- 26103974 TI - Enterohemorrhagic Escherichia coli Adhesins. AB - Adhesins are a group of proteins in enterohemorrhagic Escherichia coli (EHEC) that are involved in the attachment or colonization of this pathogen to abiotic (plastic or steel) and biological surfaces, such as those found in bovine and human intestines. This review provides the most up-to-date information on these essential adhesion factors, summarizing important historical discoveries and analyzing the current and future state of this research. In doing so, the proteins intimin and Tir are discussed in depth, especially regarding their role in the development of attaching and effacing lesions and in EHEC virulence. Further, a series of fimbrial proteins (Lpf1, Lpf2, curli, ECP, F9, ELF, Sfp, HCP, and type 1 fimbria) are also described, emphasizing their various contributions to adherence and colonization of different surfaces and their potential use as genetic markers in detection and classification of different EHEC serotypes. This review also discusses the role of several autotransporter proteins (EhaA-D, EspP, Saa and Sab, and Cah), as well as other proteins associated with adherence, such as flagella, EibG, Iha, and OmpA. While these proteins have all been studied to varying degrees, all of the adhesins summarized in this article have been linked to different stages of the EHEC life cycle, making them good targets for the development of more effective diagnostics and therapeutics. PMID- 26103975 TI - Molecular Basis of Drug Resistance in Mycobacterium tuberculosis. AB - In this chapter we review the molecular mechanisms of drug resistance to the major first- and second-line antibiotics used to treat tuberculosis. PMID- 26103976 TI - Genetics of Mycobacterial Trehalose Metabolism. AB - Trehalose [alpha-D-glucopyranosyl-(1->1)-alpha-D-glucopyranoside] is a highly abundant disaccharide in mycobacteria that fulfills many biological roles and has a plethora of possible metabolic fates. Trehalose is synthesized in mycobacteria de novo either from glycolytic intermediates or from alpha-glucans via two alternative routes, the OtsA-OtsB and the TreY-TreZ pathways, respectively. Intracellular trehalose can serve as an endogenous remobilizable carbon storage compound and as a biocompatible stress protectant. Furthermore, trehalose functions as the sugar core of many glycolipids with important structural or immunomodulatory functions such as the cord factor trehalose dimycolate, sulfolipids, and polyacyltrehalose. Moreover, trehalose plays a central role in the formation of the mycolic acid cell wall layer because it serves as a carrier molecule that shuttles mycolic acids in the form of the glycolipid trehalose monomycolate between the cytoplasm and the periplasm. In this process, a specific importer recycles the free trehalose that is extracellularly released as a by product during mycolate processing via the antigen 85 complex, which might represent a specific adaptation to the intracellular lifestyle of Mycobacterium tuberculosis with limited carbohydrate availability. Finally, trehalose is converted to glycogen-like branched alpha-glucans by a four-step metabolic pathway involving the essential maltosyltransferase GlgE, which may be further processed to derivatives with intracellular or extracellular destinations such as polymethylated lipopolysaccharides or capsular alpha-glucans, respectively. In this article we summarize the current knowledge of the genetic basis of trehalose biosynthesis and metabolism in mycobacteria, the biological functions of trehalose-based molecules, and their roles in virulence of the human pathogen M. tuberculosis. PMID- 26103978 TI - Metabolomics of Central Carbon Metabolism in Mycobacterium tuberculosis. AB - Metabolism is a biochemical activity of all cells, thought to fuel the physiologic needs of a given cell in a quantitative, rather than qualitatively specific, manner. Mycobacterium tuberculosis is a chronic facultative intracellular pathogen that resides in humans as its only known host and reservoir. Within humans, M. tuberculosis resides chiefly in the macrophage phagosome, the cell type and compartment most committed to its eradication. M. tuberculosis thus occupies the majority of its decades-long life cycle in a state of slowed or arrested replication. At the same time, M. tuberculosis remains poised to reenter the cell cycle to ensure its propagation as a species. M. tuberculosis has thus evolved its metabolic network to both maintain and propagate its survival as a species within a single host. Knowledge of the specific ways in which its metabolic network serves these distinct though interdependent functions, however, remains highly incomplete. In this article we review existing knowledge of M. tuberculosis's central carbon metabolism as reported by studies of its basic genetic and biochemical composition, regulation, and organization, with the hope that such knowledge will inform our understanding of M. tuberculosis's ability to traverse the stringent and heterogeneous niches encountered in the host. PMID- 26103977 TI - Metallobiology of Tuberculosis. AB - Transition metals are essential constituents of all living organisms, playing crucial structural and catalytic parts in many enzymes and transcription factors. However, transition metals can also be toxic when present in excess. Their uptake and efflux rates must therefore be carefully controlled by biological systems. In this chapter, we summarize the current knowledge about uptake and efflux systems in Mycobacterium tuberculosis for mainly three of these metals, namely iron, zinc, and copper. We also propose questions for future research in the field of metallobiology of host-pathogen interactions in tuberculosis. PMID- 26103979 TI - Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). AB - Tumour necrosis factor (TNF)-blocker tapering has been proposed for patients with rheumatoid arthritis (RA) in remission. OBJECTIVE: The trial aims to compare the effect of progressive spacing of TNF-blocker injections (S-arm) to their maintenance (M-arm) for established patients with RA in remission. METHODS: The study was an 18-month equivalence trial which included patients receiving etanercept or adalimumab at stable dose for >=1 year, patients in remission on 28 joint Disease Activity Score (DAS28) for >=6 months and patients with stable joint damage. Patients were randomised into two arms: maintenance or injections spacing by 50% every 3 months up to complete stop. Spacing was reversed to the previous interval in case of relapse, and eventually reattempted after remission was reachieved. The primary outcome was the standardised difference of DAS28 slopes, based on a linear mixed-effects model (equivalence interval set at +/ 30%). RESULTS: 64 and 73 patients were included in the S-arm and M-arm, respectively, which was less than planned. In the S-arm, TNF blockers were stopped for 39.1%, only tapered for 35.9% and maintained full dose for 20.3%. The equivalence was not demonstrated with a standardised difference of 19% (95% CI 5% to 46%). Relapse was more common in the S-arm (76.6% vs 46.5%, p=0.0004). However, there was no difference in structural damage progression. CONCLUSIONS: Tapering was not equivalent to maintenance strategy, resulting in more relapses without impacting structural damage progression. Further studies are needed to identify patients who could benefit from such a strategy associated with substantial cost savings. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00780793; EudraCT identifier: 2007-004483-41. PMID- 26103980 TI - Smoking cessation strategies may increase quit rates among adults of low socioeconomic status. PMID- 26103982 TI - Network biology approach to epithelial-mesenchymal transition in cancer metastasis: three stage theory. AB - Epithelial-mesenchymal transition (EMT) plays a critical role in promoting cancer metastasis. In this study, cancer EMT is considered as an overall structural change in the gene regulatory network (GRN), and its essential features are elucidated by the network biology approach. We first defined the state space of GRN as a set of all possible activation patterns of GRN, and then introduced the quasi-potential field into this space to show the relative stability distribution of each state. The quasi-potential was determined empirically by collecting gene expression profiles from public databases. Changes of GRN states during the EMT process were traced in the state space, by using time-course data of gene expression profiles of a cell line inducing EMT from the database. It was found that cancer EMT occurred in three sequential stable stages, each of which formed a potential basin along the EMT trajectory. As confirmation, structural changes of GRN were estimated by applying the ARACNe algorithm to the same time-course data, and then applying master regulator analysis to extract the main regulations. Each group of master regulators was found to be alternatively active in the subsequent three stages to cause overall structural changes of GRN during cancer EMT. PMID- 26103981 TI - Why the communicable/non-communicable disease dichotomy is problematic for public health control strategies: implications of multimorbidity for health systems in an era of health transition. AB - In today's globalized world, rapid urbanization, mechanization of the rural economy, and the activities of trans-national food, drink and tobacco corporations are associated with behavioral changes that increase the risk of chronic non-communicable diseases (NCDs). These changes include less healthy diet, lower physical activity, tobacco smoking and increased alcohol consumption. As a result, population health profiles are rapidly changing. For example, the global burden of type 2 diabetes mellitus is expected to double by 2030, with 80% of adult cases occurring in low and middle-income countries (LMIC). Many LMIC are undergoing rapid changes associated with developing high rates of NCD while concomitantly battling high levels of certain communicable diseases, including HIV, TB and malaria. This has population health, health systems and economic implications for these countries. This critical review synthesizes evidence on the overlap and interactions between established communicable and emerging NCD epidemics in LMIC. The review focuses on HIV, TB and malaria and explores the disease-specific interactions with prevalent NCDs in LMIC including diabetes, cardiovascular disease, chronic obstructive pulmonary disease, chronic renal disease, epilepsy and neurocognitive diseases. We highlight the complexity, bi directionality and heterogeneity of these interactions and discuss the implications for health systems. PMID- 26103983 TI - BMA demands that health services be excluded from trade treaty. PMID- 26103984 TI - Natriuretic Peptides and Cardiometabolic Health. AB - Natriuretic peptides are cardiac-derived hormones with a range of protective functions, including natriuresis, diuresis, vasodilation, lusitropy, lipolysis, weight loss, and improved insulin sensitivity. Their actions are mediated through membrane-bound guanylyl cyclases that lead to production of the intracellular second-messenger cyclic guanosine monophosphate. A growing body of evidence demonstrates that genetic and acquired deficiencies of the natriuretic peptide system can promote hypertension, cardiac hypertrophy, obesity, diabetes mellitus, the metabolic syndrome, and heart failure. Clinically, natriuretic peptides are robust diagnostic and prognostic markers, and augmenting natriuretic peptides is a target for therapeutic strategies in cardiometabolic disease. This review will summarize current understanding and highlight novel aspects of natriuretic peptide biology. PMID- 26103985 TI - Specificity of arrestin subtypes in regulating airway smooth muscle G protein coupled receptor signaling and function. AB - Arrestins have been shown to regulate numerous G protein-coupled receptors (GPCRs) in studies employing receptor/arrestin overexpression in artificial cell systems. Which arrestin isoforms regulate which GPCRs in primary cell types is poorly understood. We sought to determine the effect of beta-arrestin-1 or beta arrestin-2 inhibition or gene ablation on signaling and function of multiple GPCRs endogenously expressed in airway smooth muscle (ASM). In vitro [second messenger (calcium, cAMP generation)], ex vivo (ASM tension generation in suspended airway), and in vivo (invasive airway resistance) analyses were performed on human ASM cells and murine airways/whole animal subject to beta arrestin-1 or -2 knockdown or knockout (KO). In both human and murine model systems, knockdown or KO of beta-arrestin-2 relative to control missense small interfering RNA or wild-type mice selectively increased (40-60%) beta2 adrenoceptor signaling and function. beta-arrestin-1 knockdown or KO had no effect on signaling and function of beta2-adrenoceptor or numerous procontractile GPCRs, but selectively inhibited M3 muscarinic acetylcholine receptor signaling (~50%) and function (~25% ex vivo, >50% in vivo) without affecting EC50 values. Arrestin subtypes differentially regulate ASM GPCRs and beta-arrestin-1 inhibition represents a novel approach to managing bronchospasm in obstructive lung diseases. PMID- 26103986 TI - Involvement of 14-3-3 in tubulin instability and impaired axon development is mediated by Tau. AB - 14-3-3 proteins act as adapters that exert their function by interacting with their various protein partners. 14-3-3 proteins have been implicated in a variety of human diseases including neurodegenerative diseases. 14-3-3 proteins have recently been reported to be abundant in the neurofibrillary tangles (NFTs) observed inside the neurons of brains affected by Alzheimer's disease (AD). These NFTs are mainly constituted of phosphorylated Tau protein, a microtubule associated protein known to bind 14-3-3. Despite this indication of 14-3-3 protein involvement in the AD pathogenesis, the role of 14-3-3 in the Tauopathy remains to be clarified. In the present study, we shed light on the role of 14-3 3 proteins in the molecular pathways leading to Tauopathies. Overexpression of the 14-3-3sigma isoform resulted in a disruption of the tubulin cytoskeleton and prevented neuritic outgrowth in neurons. NMR studies validated the phosphorylated residues pSer214 and pSer324 in Tau as the 2 primary sites for 14-3-3 binding, with the crystal structure of 14-3-3sigma in complex with Tau-pSer214 and Tau pSer324 revealing the molecular details of the interaction. These data suggest a rationale for a possible pharmacologic intervention of the Tau/14-3-3 interaction. PMID- 26103987 TI - Circadian timing in central and peripheral tissues in a migratory songbird: dependence on annual life-history states. AB - Predictable seasonal change in photoperiod triggers a sequential change in the daily activity-rest pattern, adaptive for migration in several bird species. The night-migratory black-headed bunting (Emberiza melanocephala) is day active under short photoperiods (8 h light:16 h dark, short day sensitive). Under long photoperiods (16 h light:8 h dark), the buntings are initially day active (long day premigratory) but subsequently become intensely night active (long day migratory) and after few weeks again return to a day active pattern (long day refractory). However, it is unclear how the daily expression of circadian genes changes during photoperiod-induced seasonal life-history states (LHSs). We measured period 2 (Per2), cryptochrome 1 (Cry1), brain and muscle arnt-like protein 1 (Bmal1), and circadian locomotor output cycles kaput (Clock) mRNA expressions in various neural and peripheral tissues of buntings in different LHSs and discovered differences of ~2 to 6 h in the phase and 2- to 4-fold in amplitude of circadian oscillations of Per2, Cry1, and Bmal1 between photoperiod induced LHSs. Phase relationship in mRNA oscillations was altered between oscillator components in the circadian pacemaker system (retina, pineal, hypothalamus) as well as in the peripheral (liver, muscle) tissues. These results show for the first time altered waveforms of clock gene expressions in all tissues in parallel with behavioral shifts and suggest the involvement of circadian system in photoperiod induction of seasonal LHSs in a migratory species. PMID- 26103988 TI - Development of thermal energy storage materials for biomedical applications. AB - The phase change materials (PCMs) have been utilized widely for solar thermal energy storage (TES) devices. The quality of these materials to remain at a particular temperature during solid-liquid, liquid-solid phase transition can also be utilized for many biomedical applications as well and has been explored in recent past already. This study reports some novel PCMs developed by them, along with some existing PCMs, to be used for such biomedical applications. Interestingly, it was observed that the heating/cooling properties of these PCMs enhance the quality of a variety of biomedical applications with many advantages (non-electric, no risk of electric shock, easy to handle, easy to recharge thermally, long life, cheap and easily available, reusable) over existing applications. Results of the present study are quite interesting and exciting, opening a plethora of opportunities for more work on the subject, which require overlapping expertise of material scientists, biochemists and medical experts for broader social benefits. PMID- 26103989 TI - Convection-enhanced delivery for glioblastoma: targeted delivery of antitumor therapeutics. AB - Glioblastoma is the most common primary brain tumor in adults and carries a dismal prognosis despite advancements in treatment. Diffuse tumor infiltration precludes curative surgical resection and necessitates advancements in drug delivery mechanisms. Convection-enhanced delivery (CED) enables continuous local drug delivery for a diverse population of antitumor agents. Importantly, CED circumvents therapeutic challenges posed by the blood-brain barrier by facilitating concentrated local therapeutic drug delivery with limited systemic effects. Here, we present a concise review of properties essential for safe and efficient convection-enhanced drug delivery, as well as a focused review of clinical studies evaluating CED in the treatment of glioblastoma. PMID- 26103990 TI - Genetic diversity of Trichomonas vaginalis clinical isolates from Henan province in central China. AB - Trichomonas vaginalis is a flagellated protozoan parasite that infects the human urogenital tract, causing the most common non-viral, sexually transmitted disease worldwide. In this study, genetic variants of T. vaginalis were identified in Henan Province, China. Fragments of the small subunit of nuclear ribosomal RNA (18S rRNA) were amplified from 32 T. vaginalis isolates obtained from seven regions of Henan Province. Overall, 18 haplotypes were determined from the 18S rRNA sequences. Each sampled population and the total population displayed high haplotype diversity (Hd), accompanied by very low nucleotide diversity (Pi). In these molecular genetic variants, 91.58% genetic variation was derived from intra regions. Phylogenetic analysis revealed no correlation between phylogeny and geographic distribution. Demographic analysis supported population expansion of T. vaginalis isolates from central China. Our findings showing moderate-to-high genetic variations in the 32 isolates of T. vaginalis provide useful knowledge for monitoring changes in parasite populations for the development of future control strategies. PMID- 26103991 TI - Ethylene Response Factors: A Key Regulatory Hub in Hormone and Stress Signaling. AB - Ethylene is essential for many developmental processes and a key mediator of biotic and abiotic stress responses in plants. The ethylene signaling and response pathway includes Ethylene Response Factors (ERFs), which belong to the transcription factor family APETALA2/ERF. It is well known that ERFs regulate molecular response to pathogen attack by binding to sequences containing AGCCGCC motifs (the GCC box), a cis-acting element. However, recent studies suggest that several ERFs also bind to dehydration-responsive elements and act as a key regulatory hub in plant responses to abiotic stresses. Here, we review some of the recent advances in our understanding of the ethylene signaling and response pathway, with emphasis on ERFs and their role in hormone cross talk and redox signaling under abiotic stresses. We conclude that ERFs act as a key regulatory hub, integrating ethylene, abscisic acid, jasmonate, and redox signaling in the plant response to a number of abiotic stresses. PMID- 26103992 TI - MicroRNA396-Targeted SHORT VEGETATIVE PHASE Is Required to Repress Flowering and Is Related to the Development of Abnormal Flower Symptoms by the Phyllody Symptoms1 Effector. AB - Leafy flowers are the major symptoms of peanut witches' broom (PnWB) phytoplasma infection in Catharanthus roseus. The orthologs of the phyllody symptoms1 (PHYL1) effector of PnWB from other species of phytoplasma can trigger the proteasomal degradation of several MADS box transcription factors, resulting in leafy flower formation. In contrast, the flowering negative regulator gene SHORT VEGETATIVE PHASE (SVP) was up-regulated in PnWB-infected C. roseus plants, but most microRNA (miRNA) genes had repressed expression. Coincidentally, transgenic Arabidopsis (Arabidopsis thaliana) plants expressing the PHYL1 gene of PnWB (PHYL1 plants), which show leafy flower phenotypes, up-regulate SVP of Arabidopsis (AtSVP) but repress a putative regulatory miRNA of AtSVP, miR396. However, the mechanism by which PHYL1 regulates AtSVP and miR396 is unknown, and the evidence of miR396 mediated AtSVP degradation is lacking. Here, we show that miR396 triggers AtSVP messenger RNA (mRNA) decay using genetic approaches, a reporter assay, and high throughput degradome profiles. Genetic evidence indicates that PHYL1 plants and atmir396a-1 mutants have higher AtSVP accumulation, whereas the transgenic plants overexpressing MIR396 display lower AtSVP expression. The reporter assay indicated that target-site mutation results in decreasing the miR396-mediated repression efficiency. Moreover, degradome profiles revealed that miR396 triggers AtSVP mRNA decay rather than miRNA-mediated cleavage, implying that AtSVP caused miR396-mediated translation inhibition. We hypothesize that PHYL1 directly or indirectly interferes with miR396-mediated AtSVP mRNA decay and synergizes with other effects (e.g. MADS box transcription factor degradation), resulting in abnormal flower formation. We anticipate our findings to be a starting point for studying the posttranscriptional regulation of PHYL1 effectors in symptom development. PMID- 26103994 TI - Incremental value of pulmonary artery diameter indexed for BSA in pulmonary hypertension. PMID- 26103993 TI - Molecular Evidence for Functional Divergence and Decay of a Transcription Factor Derived from Whole-Genome Duplication in Arabidopsis thaliana. AB - Functional divergence between duplicate transcription factors (TFs) has been linked to critical events in the evolution of land plants and can result from changes in patterns of expression, binding site divergence, and/or interactions with other proteins. Although plant TFs tend to be retained post polyploidization, many are lost within tens to hundreds of million years. Thus, it can be hypothesized that some TFs in plant genomes are in the process of becoming pseudogenes. Here, we use a pair of salt tolerance-conferring transcription factors, DWARF AND DELAYED FLOWERING1 (DDF1) and DDF2, that duplicated through paleopolyploidy 50 to 65 million years ago, as examples to illustrate potential mechanisms leading to duplicate retention and loss. We found that the expression patterns of Arabidopsis thaliana (At)DDF1 and AtDDF2 have diverged in a highly asymmetric manner, and AtDDF2 has lost most inferred ancestral stress responses. Consistent with promoter disablement, the AtDDF2 promoter has fewer predicted cis-elements and a methylated repetitive element. Through comparisons of AtDDF1, AtDDF2, and their Arabidopsis lyrata orthologs, we identified significant differences in binding affinities and binding site preference. In particular, an AtDDF2-specific substitution within the DNA-binding domain significantly reduces binding affinity. Cross-species analyses indicate that both AtDDF1 and AtDDF2 are under selective constraint, but among A. thaliana accessions, AtDDF2 has a higher level of nonsynonymous nucleotide diversity compared with AtDDF1. This may be the result of selection in different environments or may point toward the possibility of ongoing functional decay despite retention for millions of years after gene duplication. PMID- 26103995 TI - Palliative care for patients with advanced fibrotic lung disease: a randomised controlled phase II and feasibility trial of a community case conference intervention. AB - BACKGROUND: Those affected by advanced fibrotic interstitial lung diseases (ILDs) have considerable unmet symptom and psychological needs. Case conferencing has been proposed to address these issues, but requires evaluation. AIM: To obtain preliminary information on the impact of a case conference intervention delivered in the home (Hospital2Home) on palliative care concerns of patients and their carers, and to evaluate feasibility and acceptability. METHODS: Hospital2Home was trialled at a specialist centre using a Phase II fast-track randomised controlled trial with qualitative interviews. The primary outcome for effect was mean change from baseline of Palliative Care Outcome Scale (POS) (a measure of symptoms and concerns) at 4 weeks. Secondary outcomes included symptom control, quality of life, consent and recruitment rates and percentage of patients in the fast-track group receiving case conferences within 14 days. RESULTS: 53 patients were recruited (26 fast-track, 27 controls). Mean (SD) POS scores at 4 weeks were -5.7 (7.5) fast-track vs -0.4 (8.0) control, (mean change difference between the two arms was -5.3 (95% CI -9.8 to -0.7) independent t test p=0.02); effect size (95% CI) -0.7 (-1.2 to -0.1). The secondary outcomes of quality of life, anxiety and depression were superior in the fast-track arm, and none were worse. Qualitative findings corroborate these data. Recruitment was successful and 53/67 (79%) of eligible patients consented. 6/25 (24%) had case conferences within 14 days. CONCLUSIONS: Community case conferences improve palliative symptoms and quality of life after 4 weeks. Hospital2Home for the most part is both feasible and acceptable. It now requires further testing in multicentre trials. TRIAL REGISTRATION NUMBER: NCT01450644. PMID- 26103997 TI - Persistence of asthma following allergen avoidance is associated with proTh2 myeloid dendritic cell activation. AB - BACKGROUND: The natural history of asthma includes in some patients periods of disease remission, but the underlying mechanisms are unknown. OBJECTIVES: We explored whether type 1 myeloid dendritic cell (mDC) dysfunction could be involved in the persistence of asthma, studying the controlled setting of occupational asthma after allergen avoidance. METHODS: We recruited 32 patients with occupational asthma to flour or latex ascertained by specific inhalation challenge and who were no longer exposed to the causal allergen. Leukapheresis was performed in each patient to isolate and characterise blood type 1 mDCs, and their functionality was studied in coculture with allogeneic CD4(+) T cells from controls. RESULTS: At follow-up, 11/32 patients (34%) were characterised by the absence of symptoms and non-specific bronchial hyper-responsiveness to histamine and were considered to be cured. When compared with cured patients, mDCs from patients with persistent disease increased the production of interleukin (IL) 5 and IL-13 by CD4(+) T cells, and upregulated programmed death ligand 2 (PD-L2) upon allergen pulsing. In addition, IL-5 and IL-13 responses could be reversed by exogenous IL-12, as well as by PD-L2 blockade. CONCLUSIONS: This study indicates that pro-Th2 features of mDCs correlate with disease activity in asthma after cessation of exposure to the causal allergen. The findings also highlight that the Th2 programming by dendritic cells is flexible and partly mediated by PD-L2. PMID- 26103996 TI - Asthma in Latin America. AB - Consistent with the diversity of Latin America, there is profound variability in asthma burden among and within countries in this region. Regional variation in asthma prevalence is likely multifactorial and due to genetics, perinatal exposures, diet, obesity, tobacco use, indoor and outdoor pollutants, psychosocial stress and microbial or parasitic infections. Similarly, non-uniform progress in asthma management leads to regional variability in disease morbidity. Future studies of distinct asthma phenotypes should follow-up well-characterised Latin American subgroups and examine risk factors that are unique or common in Latin America (eg, stress and violence, parasitic infections and use of biomass fuels for cooking). Because most Latin American countries share the same barriers to asthma management, concerted and multifaceted public health and research efforts are needed, including approaches to curtail tobacco use, campaigns to improve asthma treatment, broadening access to care and clinical trials of non pharmacological interventions (eg, replacing biomass fuels with gas or electric stoves). PMID- 26103998 TI - Characterization of Interstrand DNA-DNA Cross-Links Derived from Abasic Sites Using Bacteriophage phi29 DNA Polymerase. AB - Interstrand cross-links in cellular DNA are highly deleterious lesions that block transcription and replication. We recently characterized two new structural types of interstrand cross-links derived from the reaction of abasic (Ap) sites with either guanine or adenine residues in duplex DNA. Interestingly, these Ap-derived cross-links are forged by chemically reversible processes, in which the two strands of the duplex are joined by hemiaminal, imine, or aminoglycoside linkages. Therefore, understanding the stability of Ap-derived cross-links may be critical in defining the potential biological consequences of these lesions. Here we employed bacteriophage phi29 DNA polymerase, which can couple DNA synthesis and strand displacement, as a model system to examine whether dA-Ap cross-links can withstand DNA-processing enzymes. We first demonstrated that a chemically stable interstrand cross-link generated by hydride reduction of the dG-Ap cross link completely blocked primer extension by phi29 DNA polymerase at the last unmodified nucleobase preceding cross-link. We then showed that the nominally reversible dA-Ap cross-link behaved, for all practical purposes, like an irreversible, covalent DNA-DNA cross-link. The dA-Ap cross-link completely blocked progress of the phi29 DNA polymerase at the last unmodified base before the cross-link. This suggests that Ap-derived cross-links have the power to block various DNA-processing enzymes in the cell. In addition, our results reveal phi29 DNA polymerase as a tool for detecting the presence and mapping the location of interstrand cross-links (and possibly other lesions) embedded within regions of duplex DNA. PMID- 26103999 TI - Voltage-Gated Transport of Nanoparticles across Free-Standing All-Carbon-Nanotube Based Hollow-Fiber Membranes. AB - Understanding the mechanism underlying controllable transmembrane transport observed in biological membranes benefits the development of next-generation separation membranes for a variety of important applications. In this work, on the basis of common structural features of cell membranes, a very simple biomimetic membrane system exhibiting gated transmembrane performance has been constructed using all-carbon-nanotube (CNT)-based hollow-fiber membranes. The conductive CNT membranes with hydrophobic pore channels can be positively or negatively charged and are consequently capable of regulating the transport of nanoparticles across their pore channels by their "opening" or "closing". The switch between penetration and rejection of nanoparticles through/by CNT membranes is of high efficiency and especially allows dynamic control. The underlying mechanism is that CNT pore channels with different polarities can prompt or prevent the formation of their noncovalent interactions with charged nanoparticles, resulting in their rejection or penetration by/through the CNT membranes. The theory about noncovalent interactions and charged pore channels may provide new insight into understanding the complicated ionically and bimolecularly gated transport across cell membranes and can contribute to many other important applications beyond the water purification and resource recovery demonstrated in this study. PMID- 26104000 TI - Association Between Acute Medical Exacerbations and Consuming or Producing Web Based Health Information: Analysis From Pew Survey Data. AB - BACKGROUND: The Internet is an increasingly important resource for individuals who seek information from both health professionals and peers. While the demographic and health characteristics of persons who use health information technology has been well described, less is known about the relationship between these health characteristics and level of engagement with health information technology. Even less is known about whether persons who produce Web-based health information differ in health status from persons who consume such content. OBJECTIVE: We explored the health characteristics of persons who engage with the Internet for the purposes of consuming or producing Web-based health information, and specifically, whether healthier versus sicker persons engage with health information technology in different ways. METHODS: We analyzed data from the 2012 Pew Health survey, a landline and cell phone survey of 3104 adults in the United States. Using multiple logistic regression with sampling weights, we examined the association between sociodemographic and health characteristics and the consumption or production of Web-based health information. Sociodemographic variables included age, sex, race, and education. Health characteristics included self-reported health status, presence of chronic condition(s), and having an acute medical exacerbation. Acute medical exacerbations were defined as an emergency department visit, hospitalization, or other serious medical emergency in the last 12 months. RESULTS: The majority of the sample reported good or excellent health (79.7%), although 50.3% reported having at least one chronic condition. About a fifth (20.2%) of the sample experienced an acute medical exacerbation in the past year. Education was the sociodemographic characteristic most strongly associated with consuming Web-based health information. The strongest health-related predictors of consuming Web-based health information were an acute medical exacerbation (OR 2.39, P<.001) and having a chronic condition (OR 1.54, P=.007). Having an acute medical exacerbation was the only predictor of producing Web-based health information (OR 1.97, P=.003). All participants, regardless of health status, were most interested in Web-based health information regarding diseases or medical problems. However, persons with acute medical exacerbations were more likely to seek Web-based health information regarding medical tests, procedures, and drugs compared to persons without acute medical exacerbations. CONCLUSIONS: Producers of Web-based health information differ from consumers of this information in important health characteristics that could skew the content of peer-generated Web-based health information and overrepresent the experiences of persons with acute medical exacerbations. Providers may have a role to play in directing patients towards high-quality, easy-to-understand online information, especially information regarding treatments and procedures. PMID- 26104001 TI - [Nosocomial outbreaks and resistant microorganisms]. AB - OBJECTIVE: To determine the number and duration of nosocomial outbreaks caused by highly resistant microorganisms (HRMO) posing a potential threat to public health, in order to undertake a risk assessment. DESIGN: Descriptive study. METHOD: Data on nosocomial outbreaks were collected from April 2012 to June 2014. The following characteristics were recorded at the start and end of each outbreak: type of microorganism, reason for reporting, phase of outbreak, number of patients colonised and infected, and infection prevention measures implemented. RESULTS: 47 medical institutions reported 87 outbreaks (mean: 3 outbreaks per month). 20 outbreaks were reported in 2012 (2.2/month), 39 in 2013 (3.3/month), and 28 in the first six months of 2014 (4.7/month). Outbreaks of vancomycin-resistant enterococci (n = 26), methicillin-resistant Staphylococcus aureus (MRSA; n = 23) and resistant or highly resistant Enterobacteriaceae (n = 17) were reported most frequently. 65 outbreaks (75%) were controlled within two months of reporting. CONCLUSION: Transparent reporting of HRMO outbreaks is important for correct public perceptions of the safety of hospitals and nursing homes in the Netherlands. Reports to the Hospital-acquired Infection and Antimicrobial Resistance Monitoring Group show that HRMO outbreaks are an almost daily occurrence in Dutch hospitals. However, most outbreaks are quickly controlled without posing a threat to public health. PMID- 26104003 TI - [Thyroid autoantibodies]. AB - Here we describe the role of laboratory assessment of autoantibodies against the thyroid antigens thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR) and thyroglobulin (TG) in the diagnosis of disorders of the thyroid. The practical use of these tests is illustrated by two case studies. This is followed by an in-depth discussion of the most recent literature, including national and international guidelines for thyroid disorders. The applicability of TPO antibodies in subclinical hypothyroidism, THSR antibodies in pregnant women with a history of Graves' hyperthyroidism, and TG antibodies in the follow-up of differentiated thyroid carcinoma, are highlighted. PMID- 26104005 TI - [Abdominal splenosis]. AB - Splenosis is a common benign finding that occurs after splenic trauma or after splenectomy. It is auto-transplantation of splenic tissue and can be seen intra abdominally, intra-thoracically and even subcutaneously. Splenosis is usually found incidentally at laparoscopy, laparotomy or on radiological examination and is mostly asymptomatic. Treatment is only required if a patient complains of abdominal pain, obstruction or bleeding. On radiological examination splenosis can mimic a metastatic malignant disease. For this reason it is important to recognise splenosis and know the patient's medical history concerning splenic trauma or splenectomy, thus avoiding diagnostic laparoscopy or ultrasound guided biopsy. This paper presents two patients with splenosis. Additionally, we describe how to diagnose this entity by scintigraphy with (99m) Technetium labelled heat-denatured erythrocytes. PMID- 26104006 TI - [A sore throat: tumour, tuberculosis or both?]. AB - The incidence of tuberculosis in the Netherlands has dropped dramatically over the past 50 years. With declining experience of tuberculosis, misdiagnosis can easily happen. Laryngeal tuberculosis often presents as a tumorous mass that may initially be mistaken for cancer. As laryngeal tuberculosis is usually highly infectious, this poses a risk to the patient as well as his/her contacts including healthcare providers. We describe three patients with (suspected) laryngeal tuberculosis and discuss potential pitfalls. Pivotal for a correct diagnosis are thorough history-taking, physical examination and relatively simple radiological and laboratory tests. Risk groups have been identified for tuberculosis and this can provide a clue. Differentiation between tuberculosis and cancer can be difficult, and the two diseases may concur. Even in low incidence settings for tuberculosis, knowledge of the disease remains necessary as it is curable and further spread can be prevented with simple measures. PMID- 26104007 TI - [A child with a S-shaped skin condition on his abdomen]. AB - A 14-year-old boy with a pruritic erythematous plaque on his abdomen along the lines of Blaschko, visited the dermatology outpatient clinic. Histopathology of a skin biopsy confirmed the clinical diagnosis linear cutaneous lupus erythematosus. We treated the patient with potent topical corticosteroids. PMID- 26104008 TI - FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation. AB - The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells. PMID- 26104010 TI - Denisovan Ancestry in East Eurasian and Native American Populations. AB - Although initial studies suggested that Denisovan ancestry was found only in modern human populations from island Southeast Asia and Oceania, more recent studies have suggested that Denisovan ancestry may be more widespread. However, the geographic extent of Denisovan ancestry has not been determined, and moreover the relationship between the Denisovan ancestry in Oceania and that elsewhere has not been studied. Here we analyze genome-wide single nucleotide polymorphism data from 2,493 individuals from 221 worldwide populations, and show that there is a widespread signal of a very low level of Denisovan ancestry across Eastern Eurasian and Native American (EE/NA) populations. We also verify a higher level of Denisovan ancestry in Oceania than that in EE/NA; the Denisovan ancestry in Oceania is correlated with the amount of New Guinea ancestry, but not the amount of Australian ancestry, indicating that recent gene flow from New Guinea likely accounts for signals of Denisovan ancestry across Oceania. However, Denisovan ancestry in EE/NA populations is equally correlated with their New Guinea or their Australian ancestry, suggesting a common source for the Denisovan ancestry in EE/NA and Oceanian populations. Our results suggest that Denisovan ancestry in EE/NA is derived either from common ancestry with, or gene flow from, the common ancestor of New Guineans and Australians, indicating a more complex history involving East Eurasians and Oceanians than previously suspected. PMID- 26104011 TI - Duplication and Adaptive Evolution of a Key Centromeric Protein in Mimulus, a Genus with Female Meiotic Drive. AB - The fundamental asymmetry of female meiosis creates an arena for genetic elements to compete for inclusion in the egg, promoting the selfish evolution of centromere variants that maximize their transmission to the future egg. Such "female meiotic drive" has been hypothesized to explain the paradoxically complex and rapidly evolving nature of centromeric DNA and proteins. Although theoretically widespread, few cases of active drive have been observed, thereby limiting the opportunities to directly assess the impact of centromeric drive on molecular variation at centromeres and binding proteins. Here, we characterize the molecular evolutionary patterns of CENH3, the centromere-defining histone variant, in Mimulus monkeyflowers, a genus with one of the few known cases of active centromere-associated female meiotic drive. First, we identify a novel duplication of CENH3 in diploid Mimulus, including in lineages with actively driving centromeres. Second, we demonstrate long-term adaptive evolution at several sites in the N-terminus of CENH3, a region with some meiosis-specific functions that putatively interacts with centromeric DNA. Finally, we infer that the paralogs evolve under different selective regimes; some sites in the N terminus evolve under positive selection in the pro-orthologs or only one paralog (CENH3_B) and the paralogs exhibit significantly different patterns of polymorphism within populations. Our finding of long-term, adaptive evolution at CENH3 in the context of centromere-associated meiotic drive supports an antagonistic, coevolutionary battle for evolutionary dominance between centromeric DNA and binding proteins. PMID- 26104009 TI - Convergent Evolution of Head Crests in Two Domesticated Columbids Is Associated with Different Missense Mutations in EphB2. AB - Head crests are important display structures in wild bird species and are also common in domesticated lineages. Many breeds of domestic rock pigeon (Columba livia) have crests of reversed occipital feathers, and this recessive trait is associated with a nonsynonymous coding mutation in the intracellular kinase domain of EphB2 (Ephrin receptor B2). The domestic ringneck dove (Streptopelia risoria) also has a recessive crested morph with reversed occipital feathers, and interspecific crosses between crested doves and pigeons produce crested offspring, suggesting a similar genetic basis for this trait in both species. We therefore investigated EphB2 as a candidate for the head crest phenotype of ringneck doves and identified a nonsynonymous coding mutation in the intracellular kinase domain that is significantly associated with the crested morph. This mutation is over 100 amino acid positions away from the crest mutation found in rock pigeons, yet both mutations are predicted to negatively affect the function of ATP-binding pocket. Furthermore, bacterial toxicity assays suggest that "crest" mutations in both species severely impact kinase activity. We conclude that head crests are associated with different mutations in the same functional domain of the same gene in two different columbid species, thereby representing striking evolutionary convergence in morphology and molecules. PMID- 26104012 TI - Assessment of subclinical left ventricular dysfunction in patients with psoriasis by speckle tracking echocardiography: A Speckle Tracking Study. AB - BACKGROUND: Psoriasis is a systemic inflammatory disease and is reportedly associated with adverse cardiovascular risks. Left ventricular (LV) function has not been studied comprehensively in psoriasis. OBJECTIVES: This study was conducted to study LV mechanics in patients with psoriasis by speckle tracking echocardiography. METHODS: The study population consisted of 40 patients with psoriasis and 35 age- and sex-matched control subjects. Two-dimensional echocardiography images were obtained from LV apical four-chamber (4C), long axis (LAX), and two-chamber (2C) views. Peak longitudinal strain and strain rate were obtained from 4C, LAX, and 2C views. Global strain and strain rate were calculated by averaging data for the three apical views. RESULTS: Patients with psoriasis had significantly lower mean +/- standard deviation (SD) 4C (17.1 +/- 1.7 vs. 19.2 +/- 2.3; P < 0.01), LAX (16.6 +/- 1.5 vs. 19.5 +/- 2.3; P < 0.01), and 2C (16.5 +/- 1.5 vs. 19.4 +/- 2.2; P < 0.01) peak longitudinal strain values compared with the control group. Moreover, mean +/- SD LV global strain (16.6 +/- 1.5 vs. 19.9 +/- 2.1; P < 0.01) and strain rate (1.39 +/- 0.30 vs. 1.51 +/- 0.20; P < 0.01) values were found to be significantly lower in the psoriasis group. In a multiple regression model, global strain was independently associated with high sensitivity C-reactive protein (beta = 0.29, P = 0.04), duration of disease (beta = 0.35, P < 0.01), ejection fraction (EF) (beta = 0.38, P =0.01), and the ratio of early diastolic mitral inflow velocity to early diastolic annular velocity (E/E' ratio) (beta = 0.34, P =0.02). Also, in a multiple regression model, global strain rate was independently associated with duration of disease (beta = 0.36, P < 0.01), EF (beta = 0.32, P = 0.01), and E/E' ratio (beta = 0.35, P < 0.01). CONCLUSIONS: Using 2-D strain imaging, we have demonstrated that patients with psoriasis have lower LV functions. PMID- 26104014 TI - Effect-site concentration of remifentanil for attenuating QTc interval prolongation following intubation in hypertensive female patients. AB - BACKGROUND: Haemodynamic changes after sympathetic stimuli like tracheal intubation are more pronounced in hypertensive patients than in normotensive patients. Heart rate (HR)-corrected QT (QTc) interval changes related to intubation may also be more prominent in hypertensive patients. We hypothesised that there would be a difference in the effect-site concentration (Ce) of remifentanil to attenuate QTc interval prolongation in normotensive and hypertensive patients following intubation. METHODS: Twenty-two normotensive and 22 hypertensive female patients (>= 50 year) were enrolled and anaesthesised with remifentanil and propofol using a target-controlled infusion. All hypertensive patients received oral antihypertensive medications for > 6 months and took the medications in the morning of the surgery. The effective concentration of remifentanil Ce in 50% (EC50 ) and 95% of the population (EC95 ) required to maintain QTc interval prolongation < 15 ms following intubation was calculated using the isotonic regression and a bootstrapping approach following the Dixon's up-and-down method. RESULTS: Median duration of hypertension was 6 years. Isotonic regression revealed that the EC50 (83% confidence interval) of remifentanil Ce for reducing QTc interval prolongation following intubation was 3.8 (3.5-4.1) ng/ml in normotensive and 6.1 (5.8-6.2) ng/ml in hypertensive female patients. The EC95 (95% confidence interval) of remifentanil Ce was 4.4 (4.3-4.5) ng/ml in normotensive and 6.5 (6.4-6.5) ng/ml in hypertensive female patients. CONCLUSION: The Ce of remifentanil required to attenuate QTc interval prolongation following intubation was significantly higher in hypertensive patients than it was in normotensive patients. Thus, more caution should be taken related to QTc interval prolongation when intubating hypertensive patients. PMID- 26104013 TI - Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome. AB - BACKGROUND: A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h. AIM: To determine the efficacy of a low FODMAP diet in childhood IBS and whether gut microbial composition and/or metabolic capacity are associated with its efficacy. METHODS: In a double-blind, crossover trial, children with Rome III IBS completed a 1-week baseline period. They then were randomised to a low FODMAP diet or typical American childhood diet (TACD), followed by a 5-day washout period before crossing over to the other diet. GI symptoms were assessed with abdominal pain frequency being the primary outcome. Baseline gut microbial composition (16S rRNA sequencing) and metabolic capacity (PICRUSt) were determined. Metagenomic biomarker discovery (LEfSe) compared Responders (>=50% decrease in abdominal pain frequency on low FODMAP diet only) vs. Nonresponders (no improvement during either intervention). RESULTS: Thirty three children completed the study. Less abdominal pain occurred during the low FODMAP diet vs. TACD [1.1 +/- 0.2 (SEM) episodes/day vs. 1.7 +/- 0.4, P < 0.05]. Compared to baseline (1.4 +/- 0.2), children had fewer daily abdominal pain episodes during the low FODMAP diet (P < 0.01) but more episodes during the TACD (P < 0.01). Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity (e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii) and three Kyoto Encyclopedia of Genes and Genomes orthologues, of which two relate to carbohydrate metabolism. CONCLUSIONS: In childhood IBS, a low FODMAP diet decreases abdominal pain frequency. Gut microbiome biomarkers may be associated with low FODMAP diet efficacy. ClinicalTrials.gov identifier: NCT01339117. PMID- 26104015 TI - Emotional intelligence in sport and exercise: A systematic review. AB - This review targets emotional intelligence (EI) in sport and physical activity. We systematically review the available literature and offer a sound theoretical integration of differing EI perspectives (the tripartite model of EI) before considering applied practice in the form of EI training. Our review identified 36 studies assessing EI in an athletic or physical activity context. EI has most often been conceptualized as a trait. In the context of sport performance, we found that EI relates to emotions, physiological stress responses, successful psychological skill usage, and more successful athletic performance. In the context of physical activity, we found that trait EI relates to physical activity levels and positive attitudes toward physical activity. There was a shortage of research into the EI of coaches, officials, and spectators, non-adult samples, and longitudinal and experimental methods. The tripartite model proposes that EI operates on three levels - knowledge, ability, and trait - and predicts an interplay between the different levels of EI. We present this framework as a promising alternative to trait and ability EI conceptualizations that can guide applied research and professional practice. Further research into EI training, measurement validation and cultural diversity is recommended. PMID- 26104016 TI - Low-oxygen tensions found in Salmonella-infected gut tissue boost Salmonella replication in macrophages by impairing antimicrobial activity and augmenting Salmonella virulence. AB - In Salmonella infection, the Salmonella pathogenicity island-2 (SPI-2)-encoded type three secretion system (T3SS2) is of key importance for systemic disease and survival in host cells. For instance, in the streptomycin-pretreated mouse model SPI-2-dependent Salmonella replication in lamina propria CD11c(-)CXCR1(-) monocytic phagocytes/macrophages (MPhi) is required for the development of colitis. In addition, containment of intracellular Salmonella in the gut critically depends on the antimicrobial effects of the phagocyte NADPH oxidase (PHOX), and possibly type 2 nitric oxide synthase (NOS2). For both antimicrobial enzyme complexes, oxygen is an essential substrate. However, the amount of available oxygen upon enteroinvasive Salmonella infection in the gut tissue and its impact on Salmonella-MPhi interactions was unknown. Therefore, we measured the gut tissue oxygen levels in a model of Salmonella enterocolitis using luminescence two-dimensional in vivo oxygen imaging. We found that gut tissue oxygen levels dropped from ~78 Torr (~11% O2) to values of ~16 Torr (~2% O2) during infection. Because in vivo virulence of Salmonella depends on the Salmonella survival in MPhi, Salmonella-MPhi interaction was analysed under such low oxygen values. These experiments revealed an increased intracellular replication and survival of wild-type and t3ss2 non-expressing Salmonella. These findings were paralleled by blunted nitric oxide and reactive oxygen species (ROS) production and reduced Salmonella ROS perception. In addition, hypoxia enhanced SPI-2 transcription and translocation of SPI-2-encoded virulence protein. Neither pharmacological blockade of PHOX and NOS2 nor impairment of T3SS2 virulence function alone mimicked the effect of hypoxia on Salmonella replication under normoxic conditions. However, if t3ss2 non-expressing Salmonella were used, hypoxia did not further enhance Salmonella recovery in a PHOX and NOS2-deficient situation. Hence, these data suggest that hypoxia-induced impairment of antimicrobial activity and Salmonella virulence cooperate to allow for enhanced Salmonella replication in MPhi. PMID- 26104017 TI - Case of respiratory discomfort due to myositis after administration of nivolumab. PMID- 26104018 TI - The Enhanced liver fibrosis score is associated with clinical outcomes and disease progression in patients with chronic liver disease. AB - BACKGROUND AND AIMS: Current tools for risk stratification of chronic liver disease subjects are limited. We aimed to determine whether the serum-based ELF (Enhanced Liver Fibrosis) test predicted liver-related clinical outcomes, or progression to advanced liver disease, and to compare the performance of ELF to liver biopsy and non-invasive algorithms. METHODS: Three hundred patients with ELF scores assayed at the time of liver biopsy were followed up (median 6.1 years) for liver-related clinical outcomes (n = 16) and clear evidence of progression to advanced fibrosis (n = 18), by review of medical records and clinical data. RESULTS: Fourteen of 73 (19.2%) patients with ELF score indicative of advanced fibrosis (>=9.8, the manufacturer's cut-off) had a liver-related clinical outcome, compared to only two of 227 (<1%) patients with ELF score <9.8. In contrast, the simple scores APRI and FIB-4 would only have predicted subsequent decompensation in six and four patients respectively. A unit increase in ELF score was associated with a 2.53-fold increased risk of a liver-related event (adjusted for age and stage of fibrosis). In patients without advanced fibrosis on biopsy at recruitment, 55% (10/18) with an ELF score >=9.8 showed clear evidence of progression to advanced fibrosis (after an average 6 years), whereas only 3.5% of those with an ELF score <9.8 (8/207) progressed (average 14 years). In these subjects, a unit increase in ELF score was associated with a 4.34-fold increased risk of progression. CONCLUSIONS: The ELF score is a valuable tool for risk stratification of patients with chronic liver disease. PMID- 26104019 TI - Acute myeloid leukaemia in pregnancy. PMID- 26104020 TI - Sparing Native Upper Lobes in Living-Donor Lobar Lung Transplantation: Five Cases From a Single Center. AB - Living-donor lobar lung transplantation (LDLLT) is indicated for rapidly deteriorating patients, and the total volume of two lower lobe grafts must be sufficient for the recipient. To rescue patients with small lobar grafts, we performed five LDLLTs sparing native upper lobes. This strategy was used when upper lobes or segments were preoperatively less impaired. There were no hospital deaths. Extracorporeal circulation time and operative time were similar to those of conventional LDLLTs. The length of intensive care unit stay was also similar. Late complications attributed to the spared lungs were airway infection in one recipient and pneumothorax in two but they were successfully managed. All recipients were discharged without supplemental oxygen. The spared lung volumes measured by volumetry did not change after LDLLT. Lung perfusion scintigraphy performed at 1 year showed remaining perfusion in the spared lungs, although much less than in the grafts. These results suggested that the spared lobes kept adequate space in the thoracic cavity and kept functioning to a limited extent. The new lobar-sparing strategy appears feasible and effective in LDLLT using small grafts for selected patients when the upper lobes or segments are less impaired. PMID- 26104021 TI - Efficacy and safety of antihyperglycaemic drug regimens added to metformin and sulphonylurea therapy in Type 2 diabetes: a network meta-analysis. AB - AIM: To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy. METHODS: We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (>= 1500 mg metformin or maximum tolerated dose; >= 50% of maximum sulphonylurea dose for >= 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed. RESULTS: A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92 7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. CONCLUSIONS: When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents. PMID- 26104022 TI - Tailored versus Triple plus Bismuth or Concomitant Therapy as Initial Helicobacter pylori Treatment: A Randomized Trial. AB - BACKGROUND: With markedly increased antibiotic resistance and unsatisfactory efficacies of common empiric eradication regimens in the mainland of China, tailored therapy may be the best choice to achieve good efficacy. This study compared the eradication rates, safety, and compliance of tailored therapy to those of triple therapy plus bismuth and concomitant therapy in the naive patients with Helicobacter pylori infection. MATERIALS AND METHODS: Between September 2013 and April 2014, 1050 patients with H. pylori infection at three tertiary hospitals were randomly assigned to 10-day treatment with tailored, triple plus bismuth, or concomitant regimens. In tailored therapy, medications were adjusted according to clarithromycin sensitivity and cytochrome P450 isoenzyme 2C19 genotype. The antimicrobial susceptibility testing (E test) was performed. Eradication status was assessed 4-12 weeks after treatment. RESULTS: The eradication rate was significantly higher in tailored group than in triple plus bismuth and concomitant groups in both intention-to-treat (88.7 vs 77.4 vs 78.3%, p < .001) and per-protocol (93.3 vs 87.0 vs 87.4%, p = .021) analyses in a setting with high antibiotic resistance (clarithromycin 48.8%, metronidazole 65.7%, and dual resistance 35.3%). Significantly, fewer adverse effects occurred in tailored group than in concomitant group (22.0 vs 31.7%, p = .018). The eradication rates of dual clarithromycin and metronidazole resistance, isolated clarithromycin resistance, isolated metronidazole resistance, and dual susceptible were 78.7, 82.4, 94.8, and 94.4% in triple therapy plus bismuth and 75.9, 87.2, 92.9, and 95.2% in concomitant therapy, respectively. CONCLUSIONS: First-line tailored therapy achieves significantly higher eradication rates and fewer side effects, compared to triple therapy plus bismuth and concomitant therapy in a setting with high rates of clarithromycin and metronidazole resistance. PMID- 26104023 TI - Improved antioxidant status by omega-3 fatty acid supplementation in breast cancer patients undergoing chemotherapy: a case series. AB - INTRODUCTION: Breast cancer is the second leading cause of cancer death in women worldwide and the third most common cancer in India. Various studies have reported that chemotherapy reduces the antioxidant status in patients with cancer. A diet rich in omega-3 fatty acids has been shown to offer protection against breast cancer through various mechanisms. However, there are no reports suggesting a relationship between consumption of omega-3 fatty acids during chemotherapy and antioxidant status in patients with breast cancer. Thus, the objective of this study was to evaluate whether fish oil supplementation could improve the antioxidant status of five women with breast cancer undergoing chemotherapy. CASE PRESENTATION: We report on the cases of five Indian women with breast cancer, in the age group of 34 to 60 years, who had poorly differentiated breast carcinoma and underwent modified radical mastectomy. Postsurgery, the patients were given fish oil capsules containing eicosapentaenoic acid (180 mg) and docosahexaenoic acid (120 mg)/capsule during their chemotherapy. Informed consent was obtained from each participant and they were followed-up to the completion of six chemotherapy cycles at 21-day intervals. CONCLUSIONS: The supplementation of fish oil significantly (p < 0.01) increased superoxide dismutases, glutathione reductase and catalase activity in red blood cells as well as the total plasma antioxidant status in the patients. This approach of using omega-3 fatty acids as an adjuvant treatment for breast cancer may help oncologists to manage the side effects of ongoing chemotherapy by improving the antioxidant status in patients. PMID- 26104024 TI - Predictors of hepatitis A vaccine coverage among university students in Korea. AB - AIM: To investigate the status of hepatitis A vaccination, knowledge, and health beliefs among university students in Korea and identify factors influencing their hepatitis A vaccination rate. METHODS: A self-reporting survey was conducted with 367 university students in Korea via descriptive survey. Data were collected on demographics, status of hepatitis A vaccination, knowledge, and health beliefs. RESULTS: The hepatitis A vaccination rate was 23.4%. The hepatitis A vaccination rate was significantly higher in those who had a general awareness about the hepatitis A (odds ratio [OR] = 3.56, P = 0.003), those with some overseas travel experience (OR = 2.64, P = 0.025), those perceiving the benefits of hepatitis A vaccination (OR = 1.66, P = 0.023), and those perceiving barriers (inversed) to hepatitis A vaccination (OR = 1.95, P = 0.011). CONCLUSION: To promote hepatitis A vaccination among university students, information and education should be provided to improve their health beliefs. In addition, this demographic should be a major target population for hepatitis A vaccination. This study's results suggest that the development of national promotional campaigns and hepatitis A vaccination programs based on predictors of the vaccination rate are needed. PMID- 26104025 TI - Does the type of abortion provider influence contraceptive uptake after abortion? An analysis of longitudinal data from 64 health facilities in Ghana. AB - BACKGROUND: Understanding what factors influence the receipt of postabortion contraception can help improve comprehensive abortion care services. The abortion visit is an ideal time to reach women at the highest risk of unintended pregnancy with the most effective contraceptive methods. The objectives of this study were to estimate the relationship between the type of abortion provider (consultant physician, house officer, or midwife) and two separate outcomes: (1) the likelihood of adopting postabortion contraception; (2) postabortion contraceptors' likelihood of receiving a long-acting and permanent versus a short acting contraceptive method. METHODS: We used retrospective cohort data collected from 64 health facilities in three regions of Ghana. The dataset includes information on all abortion procedures conducted between 1 January 2008 and 31 December 2010 at each health facility. We used fixed effect Poisson regression to model the associations of interest. RESULTS: More than half (65 %) of the 29,056 abortion clients received some form of contraception. When midwives performed the abortion, women were more likely to receive postabortion contraception compared to house officers (RR: 1.18; 95 % CI: 1.13, 1.24) or physicians (RR: 1.21; 95 % CI: 1.18, 1.25), after controlling for facility-level variation and client-level factors. Compared to women seen by house officers, abortion clients seen by midwives and physicians were more likely to receive a long-acting and permanent rather than a short-acting contraceptive method (RR: 1.46; 95 % CI: 1.23, 1.73; RR: 1.58; 95 % CI: 1.37, 1.83, respectively). Younger women were less likely to receive contraception than older women irrespective of provider type and indication for the abortion (induced or PAC). CONCLUSIONS: When comparing consultant physicians, house officers, and midwives, the type of abortion provider is associated with whether women receive postabortion contraception and with whether abortion clients receive a long-acting and permanent or a short acting method. New strategies are needed to ensure that women seen by physicians and house officers can access postabortion contraception and to ensure that women seen by house officers have access to long-acting and permanent contraceptive methods. PMID- 26104026 TI - Editorial Comment to High neutrophil-to-lymphocyte ratio predicts poor clinical outcome in patients with castration-resistant prostate cancer treated with docetaxel chemotherapy. PMID- 26104028 TI - Identification and Purification of the CPD Photolyase in Vibrio parahaemolyticus RIMD2210633. AB - Photoreactivation is an error-free mechanism of DNA repair, utilized by prokaryotes and most eukaryotes and is catalyzed by specific enzymes called DNA photolyases. Photoreactivation has been reported in Vibrio parahaemolyticus WP28; however, information on photolyases in V. parahaemolyticus (V.p) strains has not been reported. This study examined the photoreactivation in V.p RIMD2210633. The photolyase responsible for repairing cyclobutane pyrimidine dimer (CPD) in DNA was identified, and the corresponding gene was determined as VPA1471. The protein was overexpressed in Escherichia coli and was purified for functional assessment in vitro. The mRNA level and protein expression level of this gene increased after ultraviolet A (UVA) illumination following ultraviolet C (UVC) irradiation. In vitro experiments confirmed that the protein encoded by VPA1471 could reduce the quantity of CPD in DNA. We designated the corresponding gene and protein of VPA1471 phr and Phr, respectively, although the function of two other photolyase/cryptochrome family members, VPA0203 and VPA0204, remains unclear. UV (ultraviolet) irradiation experiments suggest that these two genes possess some photorepairing ability. Therefore, we hypothesize that VPA0203 and VPA0204 encode (6-4) photolyase in V. parahaemolyticus RIMD2210633. PMID- 26104027 TI - Partial eNOS deficiency causes spontaneous thrombotic cerebral infarction, amyloid angiopathy and cognitive impairment. AB - BACKGROUND: Cerebral infarction due to thrombosis leads to the most common type of stroke and a likely cause of age-related cognitive decline and dementia. Endothelial nitric oxide synthase (eNOS) generates NO, which plays a crucial role in maintaining vascular function and exerting an antithrombotic action. Reduced eNOS expression and eNOS polymorphisms have been associated with stroke and Alzheimer's disease (AD), the most common type of dementia associated with neurovascular dysfunction. However, direct proof of such association is lacking. Since there are no reports of complete eNOS deficiency in humans, we used heterozygous eNOS(+/-) mice to mimic partial deficiency of eNOS, and determine its impact on cerebrovascular pathology and perfusion of cerebral vessels. RESULTS: Combining cerebral angiography with immunohistochemistry, we found thrombotic cerebral infarctions in eNOS(+/-) mice as early as 3-6 months of age but not in eNOS(+/+) mice at any age. Remarkably, vascular occlusions in eNOS(+/ ) mice were found almost exclusively in three areas: temporoparietal and retrosplenial granular cortexes, and hippocampus this distribution precisely matching the hypoperfused areas identified in preclinical AD patients. Moreover, progressive cerebral amyloid angiopaphy (CAA), blood brain barrier (BBB) breakdown, and cognitive impairment were also detected in aged eNOS(+/-) mice. CONCLUSIONS: These data provide for the first time the evidence that partial eNOS deficiency results in spontaneous thrombotic cerebral infarctions that increase with age, leading to progressive CAA and cognitive impairments. We thus conclude that eNOS(+/-) mouse may represent an ideal model of ischemic stroke to address early and progressive damage in spontaneously-evolving chronic cerebral ischemia and thus, study vascular mechanisms contributing to vascular dementia and AD. PMID- 26104029 TI - Predictors and Proarrhythmic Consequences of Inappropriate Implantable Cardioverter-Defibrillator Therapy. AB - BACKGROUND: Despite the benefits of implantable cardioverter-defibrillator (ICD) therapy, inappropriate shocks can lead to multiple adverse effects. The aim of this study was to clarify the predictors of inappropriate ICD shocks and their proarrhythmic consequences. METHODS AND RESULTS: We retrospectively studied 316 consecutive patients who underwent ICD implantation from December 2000 to December 2011. Of them, 70 (22%) experienced inappropriate ICD shocks without proarrhythmia requiring some intervention; 2 patients (0.6%) had proarrhythmic inappropriate ICD therapy by antitachycardia pacing (ATP), thereby calculated to be 0.18% of patients per year. However, they did not have syncope from this inappropriate ATP. Multivariate analysis identified younger age (<=56 years: hazard ratio [HR] 1.68, 95% confidence interval [CI] 1.02-2.77, P=0.043), paroxysmal atrial fibrillation (HR 3.00, 95% CI 1.64-5.31, P=0.0002), stroke (HR 2.23, 95% CI 1.11-4.47, P=0.024), and no diuretic use (HR 1.72, 95% CI 1.03-2.93, P=0.039) as independent predictors of the occurrence of inappropriate ICD shocks. CONCLUSIONS: Young age, paroxysmal atrial fibrillation, stroke, and no use of diuretics were independently associated with inappropriate ICD shocks. Proarrhythmic inappropriate ICD therapy was observed with an annual incidence of 0.18% by ATP. PMID- 26104030 TI - New Modified CHA2DS2-VA Scoring System for Japanese Patients With Non-Valvular Atrial Fibrillation. PMID- 26104032 TI - Pitavastatin therapy in polymedicated patients is associated with a low risk of drug-drug interactions: analysis of real-world and phase 3 clinical trial data. AB - OBJECTIVES: Medications that interact with the pathways responsible for statin metabolism may increase the risk of statin-associated myalgia. Pharmacokinetic studies show that pitavastatin is carried into the liver by a range of transporters and is minimally metabolized by cytochrome P450 in healthy volunteers, indicating a reduced potential for drug-drug interactions (DDIs). This post hoc analysis investigates the incidence of adverse events in patients receiving pitavastatin with concomitant medication in two large data sets. METHODS: The largest pitavastatin patient data sets are the LIVALO Effectiveness and Safety (LIVES) postmarketing surveillance study in Japan (n = 19,925) and the European phase 3 clinical trial program (n = 2,396). Adverse events were classified according to the Medical Dictionary for Regulatory Activities (Med DRA) and whether they occurred in patients taking medications that interact with hepatocyte organic anion-transporting polypeptide or cytochrome P450 (CYP) isoenzyme pathways. RESULTS: Concomitant administration of pitavastatin with other medications was not associated with clinically significant increases in the incidence of adverse drug reactions (ADRs), even when given with medications that interact with CYP2C9, responsible for the minimal CYP metabolism of pitavastatin. There was a significant interaction with biguanides in LIVES, but this was associated with a reduced risk of muscle ADRs. CONCLUSION: In clinical trials, pitavastatin is associated with a low incidence of adverse events related to DDIs, consistent with data from healthy volunteers. Prescribing a metabolically stable statin, such as pitavastatin, may improve patient adherence to medication, thus facilitating the attainment of lipid targets and reducing cardiovascular risk. PMID- 26104031 TI - A novel dynamic exercise initiative for older people to improve health and well being: study protocol for a randomised controlled trial. AB - BACKGROUND: Exercise is an important and effective approach to preventing falls in older people, but adherence to exercise participation remains a persistent problem. A unique purpose-built exercise park was designed to provide a fun but physically challenging environment to support exercise in a community setting. This project is a randomised controlled trial designed to evaluate the effectiveness of an exercise intervention using an exercise park specifically designed for older people in reducing the risk of falls. METHODS/DESIGN: This study will be a parallel randomised control trial with pre and post intervention design. One hundred and twenty people aged between 60 and 90 years old will be recruited from Melbourne suburbs and will be randomly allocated to either an exercise park intervention group (EPIG) or a control group (CG). The CG will receive social activities and an educational booklet on falls prevention. The BOOMER balance test will be used as the primary outcome measure. Secondary outcome measures will include hand grip strength, two minute walk test, lower limb strength test, spatio-temporal walking parameters, health related quality of life, feasibility, adherence, safety, and a number of other psychosocial measures. Outcome assessment will be conducted at baseline and at 18 and 26 weeks after intervention commencement. Participants will inform their falls and physical activity history for a 12-month period via monthly calendars. Mixed linear modelling incorporating intervention and control groups at the baseline and two follow up time points (18 weeks and 26 weeks after intervention commencement) will be used to assess outcomes. DISCUSSION: This planned trial will be the first to provide evidence if the exercise park can improve functional and physiological health, psychological and well-being. In addition, this study will provide empirical evidence for effectiveness and explore the barriers to participation and the acceptability of the senior exercise park in the Australian older community. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry-Registry No. ACTRN12614000700639 registered on Jul 3rd 2014. PMID- 26104033 TI - Population pharmacokinetics and safety of eptifibatide in healthy Chinese volunteers and simulations on the dose regimens approved for a Western population. AB - OBJECTIVE: This study was designed to evaluate the pharmacokinetics (PK) and safety of eptifibatide in healthy Chinese volunteers and provide information for the further study in the Chinese population. METHODS: 30 healthy volunteers (15 male) were enrolled in the study and divided into three dose groups (45 ug x kg 1, 90 ug x kg-1, and 180 ug x kg-1). Plasma and urine samples were drawn after one single-bolus administration and measured by LC-MS/MS. The plasma and urine data were analyzed simultaneously by the population approach using the NONMEM software and evaluated by the visual predicted check (VPC) and bootstraping. The PK profiles of dose regimens approved for a Western population in the Chinese population were simulated. RESULTS: A two-compartment model adequately described the PK profiles of eptifibatide. The clearance (CL) and the distribution volume (V1) of the central compartment were 0.128 L x h-1 x kg-1 and 0.175 L x kg-1, respectively. The clearance (Q) and V2of the peripheral compartment were 0.0988 L x h-1 x kg-1 and 0.147 L x kg-1, respectively. The elimination fraction from plasma to urine (F0) was 17.2%. No covariates were found to have a significant effect. Inter-individual variabilites were all within 33.9%. The VPC plots and bootstrap results indicated good precision and prediction of the model. The simulations of the approved regimens in the Chinese population showed much lower steady-state concentrations than the target concentration obtained from the Western clinical trials. No severe safety events were found in this study. CONCLUSIONS: The PK model of eptifibatide was established and could provide PK information for further studies in the Chinese population. PMID- 26104034 TI - Effect of CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1 C3435T on the pharmacokinetics of nifedipine in healthy Chinese volunteers. AB - OBJECTIVE: Nifedipine is a calcium channel blocker that is widely used in the treatment of cardiovascular disease. However, significant individual variances in the disposition of nifedipine have been reported, and genetic factors are considered to play an important role. The aim of the present study was to investigate the effect of CYP3A4*1G, CYP3A5*3, ABCB1-C3435T, and POR*28 genetic polymorphisms on nifedipine pharmacokinetics in healthy Chinese volunteers. METHODS: 45 healthy Chinese volunteers enrolled in this study received a single oral dose of 90 mg nifedipine after providing written informed consent. Volunteers were genotyped for CYP3A4*1G, CYP3A5*3, POR*28, and ABCB1-C3435T. The blood concentrations of nifedipine were determined by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method. RESULTS AND DISCUSSION: There were significant differences of AUC00-infinity and AUC0-48h in the different CYP3A5*3 genotype groups (p = 0.043 and p = 0.048, respectively). The CYP3A5*3 GG group and POR*28 CT/TT group were found to have lower AUC00 infinity and Cmax compared with the POR*28 CC group (p = 0.046 and p = 0.002, respectively). In addition, the POR*28 CT/TT group was found to have longer t1/2 but lower Cmax than the CYP3A4*1G GG group (p = 0.032 and p = 0.002, respectively) as well as the CYP3A4*1G GG and the CYP3A5*3 GG group (p = 0.038 and p = 0.036, respectively) compared with the POR*28 CC group. No significant associations were found between CYP3A4*1G/ABCB1-C3435T polymorphism and pharmacokinetics of nifedipine. CONCLUSION: Both CYP3A5*3 and POR*28 polymorphisms are found to be associated with the difference in disposition of nifedipine; POR*28 is considered to have an impact on CYP3A4 activity. PMID- 26104035 TI - Evidence supporting the need for considering the effects of smoking on drug disposition and effectiveness in medication practices: a systematic narrative review. AB - This study was conducted to provide a narrative overview of interactions between smoking and drug effectiveness/ pharmacokinetics. Database searches were performed to identify review articles published prior to March 10, 2013. Eligible articles reporting altered pharmacokinetic profiles, drug response, or adverse drug effects due to drug-smoking interactions were selected. Information on mechanism of action and clinical effects from the selected articles (n = 83) were summarized by therapeutic drug class. For cardiovascular drugs, smoking effects were variable. Smoking reduced aspirin response but increased clopidogrel response by increasing active metabolites. Warfarin, which has a narrow therapeutic range, required dosage adjustment in smokers due to its rapid clearance. Smoking is a risk factor for respiratory disease, leading to a lower response to corticosteroid and requiring increased doses or additional drugs. Higher doses of theophylline and some antipsychotics, which are mainly metabolized by CYP1A2, are required to reach an optimal plasma concentration in smokers. Smoking is also a risk factor for cancer, especially for lung cancer. Erlotinib or gefitinib are epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for lung cancer and showed lower anticancer effects in smokers. This summary of the interactions between smoking and drug pharmacological properties will aid healthcare professionals in providing patients with appropriate drug therapies, and emphasizes the need for considering smoking status as a patient factor in the clinical setting. PMID- 26104036 TI - Impact of pharmacist interventions on rational prophylactic antibiotic use and cost saving in elective cesarean section. AB - OBJECTIVES: To assess the impact of pharmacist interventions on rational use of prophylactic antibiotics and cost saving in elective cesarean section and the economic outcomes of implementing pharmacist interventions. METHODS: A pre-to post intervention design was applied to the practices of prophylactic antibiotic use in the department of gynecology and obstetrics in a Chinese tertiary hospital. Patients admitted during a 3-month period from June to August 2012 and during that from October to December 2012 undergoing elective cesarean section were assigned to the pre-intervention and the post-intervention group, respectively. Pharmacist interventions were performed in the post-intervention group, including obstetrician education, realtime monitoring of clinical records and making recommendations to obstetricians on prophylactic antibiotic prescription based on the criteria set at the beginning of the study. Data from the two groups were then compared to evaluate the outcomes of pharmacist interventions. Cost-outcome analysis was performed to determine the economic effect of implementing pharmacist interventions in preoperative antibiotic prophylaxis. RESULTS: Pharmacist interventions led to significant reductions in antibiotic usage cost/patient-day (p < 0.001), mean antibiotic cost (p < 0.001), mean total drug cost (p < 0.001), mean total hospitalization cost (p < 0.001), the duration of prophylaxis antibiotics (p < 0.001) and a significant increase by 19.29% in the percentage of cases adhering to all of the four criteria (p < 0.001). The ratio of the saving in antibiotic use to the cost of pharmacist time was 27.23 : 1 and the net cost benefit was $65,255.84. CONCLUSION: This study provides evidence that pharmacist interventions promoted rational use of prophylactic antibiotics and substantial cost saving in elective cesarean section. PMID- 26104037 TI - Physicians' and pharmacists' acceptance of online, real-time "drug combinations to avoid" messages. AB - Drug-induced prolongation of the electrocardiogram QT interval, a risk factor for ventricular arrhythmia and death, has been observed for some small drugs with masses < 1 kDa. Over the last two decades, patient exposure to large molecule monoclonal antibody drugs with masses > 40 kDa has increased dramatically; hence, the aim of this study was to systematically review the scientific literature for evidence of QT prolongation induced by these drugs. METHODS: The PubMed and Embase databases were searched for cases indicative of drug-induced QT prolongation for 28 pre-identified monoclonal antibody drugs authorized in Europe. Cases were identified by applying a standardized search string and a subsequent text search and manual review. In parallel, the public European Medicines Agency (EMA) database was searched for reported frequencies of adverse events indicative of QT prolongation. RESULTS: A valid case of drug-induced QT prolongation, caused indirectly by hypocalcaemia, could be identified for only 1 out of 28 monoclonal antibody drugs (denosumab) from the PubMed and Embase search. The EMA database showed no hits for denosumab. Considering that hypocalcaemia-mediated QT prolongation is an already-identified and labelled risk for denosumab, the current study did not identify any additional evidence of QT prolongation caused by monoclonal antibody drugs. PMID- 26104038 TI - Regulation of cytokinesis and its clinical significance. AB - Dysregulation of the cell cycle leads to polyploid cells, which are classified into mononuclear or binuclear polyploid cells depending on the number of nuclei. Polyploidy is common in plants and in animals. Physiologically, polyploidy and binucleation are differentiation markers and also features of the aging process. In fact, although they provide multiple copies of genes required for survival, a negative correlation between growth capacity and polyploidy has been reported, and thus, suppression or reversal of this phenomenon may be a growth advantage. On the other hand, unscheduled polyploidization may cause genomic instability that might lead to neoplastic aneuploidy. The aim of this review is to analyze the mechanisms that lead to polyploidy, and particularly binucleation, and highlight the potential of ploidy as a marker of illness severity or the success of the adaptive response for an injury, with special emphasis in the liver under physiological and pathological conditions. Hepatocyte binucleation occurs in late fetal development and postnatal maturation, especially after weaning via phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt). It also increases upon aging of the liver as well as in liver cirrhosis and cancer. Liver binucleation mainly indicates the severity of the damage. Furthermore, the eventual increase in hepatocyte binucleation points out compensatory proliferation associated with liver injury. Ploidy conveyor would also permit hepatocyte adaptation to xenobiotic or nutritional injury. In contrast, polyploidy is a feature of many human cancers, and it may predispose to genomic instability and generation of aneuploidization that play a major role in carcinogenesis. Finally, a better understanding of the polyploidization process is needed in order to approach clinical research but also, to get deeper knowledge of cell cycle control. The fascinating regulation of cell cycle in liver and the generation and reversal of ploidies will provide more clues for the mystery of liver regeneration. PMID- 26104040 TI - Introduction: Calculations on Large Systems. PMID- 26104039 TI - Pharmacokinetics, tissue distribution and excretion study of a furostanol glycoside-based standardized fenugreek seed extract in rats. AB - The furostanol glycoside isolated from the seed of fenugreek (SFSE-G) has an array of pharmacological activities. To date, no validated high-performance liquid chromatography (HPLC) method has been reported for quantification of SFSE G in biological samples. Hence, the aim of the present study was to study the pharmacokinetics, tissue distribution and excretion profiles of SFSE-G after oral administration in rats. A rapid, sensitive, selective, robust and reproducible HPLC method has been developed for determination of SFSE-G in the rat biological samples. The chromatographic separation was accomplished on a reversed-phase C18 column using formic acid and acetonitrile (80:20) as mobile phase at a flow rate of 1.0 mL/min and 274 nm as a detection wavelength. The assay was linear for SFSE G with the correlation coefficients (R(2)) >0.996. The analytes were stable during samples storage and handling, and no matrix effects were observed. After oral dosing of SFSE-G at a dose of 200 mg/kg, the elimination half-life was app. 40.10 h. It showed relatively slowly distribution and eliminated in urine and feces after 24 h, and could be detected until 108 h post-dosing. Following oral single dose (200 mg/kg), SFSE-G was detected in lung and brain which indicated that it could cross the blood-brain barrier. It is a major route of elimination is excretion through urine and feces. In conclusion, oral administration of SFSE G showed slow distribution to tissues, such as lung and brain, but showed fast renal elimination. PMID- 26104041 TI - Effects of reallocating time in different activity intensities on health and fitness: a cross sectional study. AB - BACKGROUND: The effects of replacing time in specific activity categories for other categories (e.g. replacing sedentary time with light activity) on health and fitness are not well known. This study used isotemporal substitution to investigate the effects of substituting activity categories in an equal time exchange fashion on health and fitness in young people. METHODS: Participants were drawn from schools in Camden, London (n = 353, mean age 9.3 +/- 2.3 years). Time sedentary, in light and in moderate-to-vigorous activity (MVPA) was measured via accelerometry. The effects of substituting time in activity categories (sedentary, light and MVPA) with equivalent time in another category on health and fitness were examined using isotemporal substitution. RESULTS: In single and partition models, MVPA was favourably associated with body fat %, horizontal jump distance and flexibility. Time sedentary and in light activity were not associated with health and fitness outcomes in these models. In substitution models, replacing one hour of sedentary time with MVPA was favourably associated with body fat % (B = -4.187; 95% confidence interval (CI), -7.233, -1.142), horizontal jump distance (B = 16.093; 95% CI, 7.476, 24.710) and flexibility (B = 4.783; 95% CI, 1.910, 7.656). Replacing time in light activity with MVPA induced similar benefits but there were null effects for replacing sedentary with light intensity. CONCLUSION: Substituting time sedentary and in light activity with MVPA was associated with favourable health and fitness. Time in sedentary behaviour may only be detrimental to health and fitness when it replaces time in MVPA in young people. PMID- 26104042 TI - Interfacial Polymerization of Dopamine in a Pickering Emulsion: Synthesis of Cross-Linkable Colloidosomes and Enzyme Immobilization at Oil/Water Interfaces. AB - Colloidosomes are promising carriers for immobilizing enzyme for catalytic purposes in aqueous/organic media. However, they often suffer from one or more problems regarding catalytic performance, stability, and recyclability. Here, we report a novel approach for the synthesis of cross-linkable colloidosomes by the selective polymerization of dopamine at oil/water interfaces in a Pickering emulsion. An efficient enzyme immobilization method was further developed by covalently bonding enzymes to the polydopamine (PDA) layer along with the formation of such colloidosomes with lipase as a model enzyme. In this enzyme system, the PDA layer served as a cross-linking layer and enzyme support for simultaneously enhancing the colloidosomes' stability and improving surface availability of the enzymes for catalytic reaction. It was found that the specific activity of lipases immobilized on the colloidosome shells was 8 and 1.4 times higher than that of free lipase and encapsulated lipase positioned in the aqueous cores of colloidosomes, respectively. Moreover, the immobilized lipases demonstrated excellent operational stability and recyclability, retaining 86.6% of enzyme activity after 15 cycles. It is therefore reasonable to expect that this novel approach for enzyme immobilization has great potential to serve as an important technique for the construction of biocatalytic systems. PMID- 26104043 TI - DHA protects against experimental colitis in IL-10-deficient mice associated with the modulation of intestinal epithelial barrier function. AB - A defect in the intestinal barrier is one of the characteristics of Crohn's disease (CD). The tight junction (TJ) changes and death of epithelial cells caused by intestinal inflammation play an important role in the development of CD. DHA, a long-chain PUFA, has been shown to be helpful in treating inflammatory bowel disease in experimental models by inhibiting the NF-kappaB pathway. The present study aimed at investigating the specific effect of DHA on the intestinal barrier function in IL-10-deficient mice. IL-10-deficient mice (IL-10(-/-)) at 16 weeks of age with established colitis were treated with DHA (i.g. 35.5 mg/kg per d) for 2 weeks. The severity of their colitis, levels of pro-inflammatory cytokines, epithelial gene expression, the distributions of TJ proteins (occludin and zona occludens (ZO)-1), and epithelial apoptosis in the proximal colon were measured at the end of the experiment. DHA treatment attenuated the established colitis and was associated with reduced infiltration of inflammatory cells in the colonic mucosa, lower mean histological scores and decreased levels of pro inflammatory cytokines (IL-17, TNF-alpha and interferon-gamma). Moreover, enhanced barrier function was observed in the DHA-treated mice that resulted from attenuated colonic permeability, rescued expression and corrected distributions of occludin and ZO-1. The results of the present study indicate that DHA therapy may ameliorate experimental colitis in IL-10(-/-) mice by improving the intestinal epithelial barrier function. PMID- 26104045 TI - Selective decontamination and antibiotic resistance in ICUs. AB - Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) have been associated with reduced mortality and lower ICU acquired bacteremia and ventilator-associated pneumonia rates in areas with low levels of antibiotic resistance. However, the effect of selective decontamination (SDD/SOD) in areas where multidrug-resistant Gram-negative bacteria are endemic is less clear. It will be important to determine whether SDD/SOD improves patient outcome in such settings and how these measures affect the epidemiology of multidrug-resistant Gram-negative bacteria. Here we review the current evidence on the effects of SDD/SOD on antibiotic resistance development in individual ICU patients as well as the effect on ICU ecology, the latter including both ICU level antibiotic resistance and antibiotic resistance development during long term use of SDD/SOD. PMID- 26104044 TI - Patient Portals and Patient Engagement: A State of the Science Review. AB - BACKGROUND: Patient portals (ie, electronic personal health records tethered to institutional electronic health records) are recognized as a promising mechanism to support greater patient engagement, yet questions remain about how health care leaders, policy makers, and designers can encourage adoption of patient portals and what factors might contribute to sustained utilization. OBJECTIVE: The purposes of this state of the science review are to (1) present the definition, background, and how current literature addresses the encouragement and support of patient engagement through the patient portal, and (2) provide a summary of future directions for patient portal research and development to meaningfully impact patient engagement. METHODS: We reviewed literature from 2006 through 2014 in PubMed, Ovid Medline, and PsycInfo using the search terms "patient portal" OR "personal health record" OR "electronic personal health record". Final inclusion criterion dictated that studies report on the patient experience and/or ways that patients may be supported to make competent health care decisions and act on those decisions using patient portal functionality. RESULTS: We found 120 studies that met the inclusion criteria. Based on the research questions, explicit and implicit aims of the studies, and related measures addressed, the studies were grouped into five major topics (patient adoption, provider endorsement, health literacy, usability, and utility). We discuss the findings and conclusions of studies that address the five topical areas. CONCLUSIONS: Current research has demonstrated that patients' interest and ability to use patient portals is strongly influenced by personal factors such age, ethnicity, education level, health literacy, health status, and role as a caregiver. Health care delivery factors, mainly provider endorsement and patient portal usability also contribute to patient's ability to engage through and with the patient portal. Future directions of research should focus on identifying specific populations and contextual considerations that would benefit most from a greater degree of patient engagement through a patient portal. Ultimately, adoption by patients and endorsement by providers will come when existing patient portal features align with patients' and providers' information needs and functionality. PMID- 26104046 TI - Is one motor cortex enough for two hands? AB - We report on a patient with mirror movements sustained by a mono-hemispheric fast control of bilateral hand muscles and normal hand function. Transcranial magnetic stimulation of the right motor cortex evoked contractions of muscles in both hands while no responses were observed from the left hemisphere. Somatosensory evoked potentials, functional magnetic resonance, and diffusion tractography showed evidence of sensorimotor dissociation and asymmetry of corticospinal projections, suggestive of reorganization after early unilateral left brain lesion. This is the first evidence that, in certain rare conditions, good hand function is possible with ipsilateral corticospinal reorganization, supporting the role of unexplored mechanisms of motor recovery. PMID- 26104047 TI - Efficacy and safety of anti-TNF therapy in elderly patients with inflammatory bowel disease. AB - BACKGROUND: The general increased life expectancy is reflected in the age of patients with inflammatory bowel disease (IBD). The knowledge about efficacy and safety of anti-tumour necrosis factor (TNF) therapy in elderly is scarce and conflicting. AIM: To assess the efficacy and safety of anti-TNF therapy in elderly patients taking into account eventual comorbidity. METHODS: Observational and retrospective single-centred study where 66 IBD patients initiating anti-TNF treatment at age >=65 years (cases: >=65 anti-TNF) were compared with 112 IBD patients initiating anti-TNF <65 years (controls <65 anti-TNF) and 61 anti-TNF naive IBD patients treated with immunosuppressants (IMS) and/or corticosteroids (CS) >=65 years (controls >=65 IMS/CS). Controls were matched to cases for IBD type, follow-up, disease duration and anti-TNF type. Comorbidity was assessed by using the Charlson Comorbidity Index (CCI). Both efficacy and safety of treatment were adjusted for comorbidity. RESULTS: The short-term clinical response to anti TNF at 10 weeks was significantly lower in cases: >=65 anti-TNF (68% vs. 89%; P < 0.001), whereas at >=6 months, differences were not significant (79.5% vs. 82.8%; P = 0.639). The risk for any severe adverse events was higher in cases: >=65 anti TNF than in controls <65 anti-TNF (RR = 4.7; P < 0.001) or controls >=65 IMS/CS (RR = 3.09; P = 0.0008). Age older than 65 and CCI > 0 were independent risk factors for malignancy and mortality regardless of the medication. CONCLUSION: Elderly patients treated with anti-TNF have a lower rate of short-term clinical response and a higher rate of severe adverse events than the younger patients under the same treatment. PMID- 26104048 TI - Early warning score predicts acute mortality in stroke patients. AB - OBJECTIVES: Clinical deterioration and death among patients with acute stroke are often preceded by detrimental changes in physiological parameters. Systematic and effective tools to identify patients at risk of deterioration early enough to intervene are therefore needed. The aim of the study was to investigate whether the aggregate weighted track and trigger system early warning score (EWS) can be used as a simple observational tool to identify patients at risk and predict mortality in a population of patients with acute stroke. MATERIALS AND METHODS: Patients admitted with acute stroke at the Copenhagen University Hospital, Nordsjaellands Hospital, Denmark, from May to September 2012 were enrolled in a retrospective cohort study (n = 274). Vital signs were measured immediately after admission and consistently during the hospitalization period. Based on the vital signs, a single composite EWS was calculated. Death within 30 days was used as outcome. Area under the receiver operating characteristics curve (AUROC) and a Kaplan-Meier curve were computed to examine the prognostic validity of EWS. RESULTS: A total of 24 patients (8.8%) died within 30 days. The prognostic performance was high for both the EWS at admission (AUROC 0.856; 95% CI 0.760 0.951; P-value < 0.001) and the maximal EWS measured (AUROC 0.949; 95% CI 0.919 0.980; P-value < 0.001). Mortality rates were lowest for admission EWS 0-1 (2%) and highest for admission EWS >= 5 (63%). CONCLUSIONS: Early warning score is a simple and valid tool for identifying patients at risk of dying after acute stroke. Readily available physiological parameters are converted to a single score, which can guide both nurses and physicians in clinical decision making and resource allocation. PMID- 26104049 TI - Changes in Warfarin Sensitivity During Decompensated Heart Failure and Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Heart failure (HF) has been associated with an elevated international normalized ratio (INR) in patients on warfarin. OBJECTIVES: Compare warfarin sensitivity during hospital admission for HF exacerbation and chronic obstructive pulmonary disease (COPD) exacerbation with admissions unrelated to HF or COPD (controls) as well as during disease stability. METHODS: We conducted a case controlled observational study. Patients admitted to a tertiary teaching hospital for HF exacerbation (n = 37), COPD exacerbation (n = 26), and admissions unrelated to HF or COPD (controls, n = 60) were included. Warfarin sensitivity (INR per daily mg dose of warfarin) at admission was compared to periods of disease stability and also compared between the 3 groups. RESULTS: The increase in warfarin sensitivity at admission was 94% for HF patients (P < 0.0001), 59% for COPD (P = 0.003) patients, and 24% for controls (P = 0.002). HF patients with New York Heart Association (NYHA) class 3 and 4 and NYHA class 1 and 2 experienced changes in warfarin sensitivity of 125% (P = 0.006) and 50% (P = 0.13) at admission. HF patients had higher warfarin sensitivity at admission (mean = 1.62 [SD = 1.27]) compared to the control group (0.91 [0.52], P < 0.0001) and COPD group (1.03 [0.79], P = 0.04). and required greater intervention with vitamin K than controls (14% vs 0%, P = 0.007). CONCLUSION: HF and COPD patients were more sensitive to warfarin during disease exacerbation, with HF exacerbation having the largest impact, resulting in clinically significant management implications. PMID- 26104050 TI - Implementation of a Meningitis Care Bundle in the Emergency Room Reduces Mortality Associated With Acute Bacterial Meningitis. AB - BACKGROUND: Prompt administration of antibiotics, adjunctive steroid therapy, and optimization of antibiotic delivery to cerebrospinal fluid (CSF) are factors associated with improved outcome of patients hospitalized for acute bacterial meningitis (ABM). However, the impact of a bundle of these procedures has not been reported. OBJECTIVE: To assess mortality and neurological sequelae at hospital discharge in a cohort of patients with ABM managed according to a predefined bundle. METHODS: Prospective study of all the patients hospitalized for ABM in two provinces of Northern Italy, over two consecutive periods (2005 2009, 2010-2013). The bundle included: i) supportive care if needed; ii) immediate administration of dexamethasone and 3rd generation cephalosporin; and iii) addition of levofloxacin if turbid CSF. Patients managed according to the bundle were compared with a historical group of patients cared for ABM before the bundle was implemented. RESULTS: Overall, 85 patients with ABM were managed according to the bundle and were compared with 92 historical controls. In hospital mortality rates for bundle and control group were 4.7% and 14.1% (p=0.04). Among survivors, 13.5% and 18.9% (p=0.4) of bundle and control-group patients presented neurological sequelae. The only variable associated with mortality at multivariate analysis was ICU admission (HR 3.65). After adjusting for ICU admission, patients managed according with the ABM bundle had significantly lower mortality rate compared to historical controls. CONCLUSIONS: Use of a bundled protocol and antibiotics with excellent CSF penetration for the initial management of ABM in emergency department is feasible and associated with significant reduction in mortality. PMID- 26104051 TI - Is Fluconazole or an Echinocandin the Agent of Choice for Candidemia. AB - OBJECTIVE: Candidemia is among the most common nosocomial bloodstream infections and is associated with high mortality, increased length of hospital stay, and significant economic burden. The introduction of the echinocandins in the 2000s has expanded the armamentarium against Candida spp and provides therapeutic options that are effective, safe, and tolerable. Although the Infectious Diseases Society of America favors echinocandins as treatment for candidemia in selected settings (at least as initial therapy), there remain divergent opinions about whether an echinocandin or fluconazole is the preferred agent for candidemia, and clinical practice guidelines are in flux. In this review, the currently available laboratory and clinical data are summarized and critically evaluated. DATA SOURCES: A MEDLINE search of the English language literature was performed using the search terms echinocandin, fluconazole, and candidemia. References of review articles and guidelines were also screened for inclusion. STUDY SELECTION AND DATA EXTRACTION: Studies whose primary goal was to compare echinocandins with fluconazole were evaluated as well as studies that differentiated pharmacological and pharmacokinetic properties between agents. DATA SYNTHESIS: It is clear that echinocandins and fluconazole each have roles in the management of candidemia. Specific recommendations are provided that will hopefully optimize outcomes in candidemia while incorporating stewardship concepts of cost-effectiveness and limiting the emergence of resistance. CONCLUSIONS: Despite the advantages brought by the echinocandins and fluconazole, outcomes among patients with candidemia remain suboptimal. Improved treatment of candidemia may ultimately be achieved by optimizing the use of antifungal agents rather than the development of new drugs. PMID- 26104052 TI - Dosing of Target-Specific Oral Anticoagulants in Special Populations. AB - OBJECTIVE: To review current literature for target-specific oral anticoagulants (TSOACs) and provide critical analysis for dosing recommendations in special population groups. DATA SOURCES: A literature search was conducted in Medline (1996 to April week 2 2015) and Embase (1980 to 2015 week 16) using key terms dabigatran, rivaroxaban, apixaban, edoxaban, kidney diseases, liver diseases, elderly, obesity, and special populations. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials in English assessing efficacy and safety of TSOACs in healthy adults and special populations were selected for analysis. DATA SYNTHESIS: Phase 3 trials for TSOACs predominately excluded patients with severe renal impairment or active liver disease. There were no exclusion criteria based on age, body weight or body mass index. Additional conclusions were made in special populations, including those with renal or liver impairment and obese and elderly patients, based on secondary analyses, pharmacokinetic, and pharmacodynamic studies. CONCLUSIONS: Pharmacokinetic and pharmacodynamic changes associated special populations may alter clinical decision with regard to drug selection and dosing. It is valuable to understand the rationale for labeled dosing recommendations in nonvalvular atrial fibrillation and venous thromboembolism treatment and prevention, particularly in patients that fall into special population groups. Furthermore, the use of TSOACs is likely to increase as clinicians gain experience with these agents and additional TSOACs and indications are approved. PMID- 26104053 TI - Levetiracetam Use With Continuous Renal Replacement Therapy. PMID- 26104054 TI - Evaluating Vitamin D Repletion Regimens and Effects in Veteran Patients. AB - BACKGROUND: There are wide variations in recommended dosing for vitamin D repletion. The identification of specific dosing thresholds to optimize repletion of 25-hydroxyvitamin D3 (also known as 25(OH)D) may help narrow the wide spectrum of vitamin D dosing. OBJECTIVE: The primary objective of this study was to evaluate vitamin D treatment regimens and their dose response effect on vitamin D serum levels. Secondary outcomes include evaluation of the frequency of monitoring vitamin D serum levels and prescription adherence. METHODS: This was a multicenter, retrospective data extraction analysis conducted in patients who initiated monotherapy of ergocalciferol and cholecalciferol between January 1, 2005 and December 31, 2010. Following vitamin D therapy initiation, changes in laboratory values, frequency of laboratory monitoring, and prescription adherence were assessed. Ergocalciferol and cholecalciferol groups were separately organized into quartiles to identify dosing ranges that had the most impact on changes in 25(OH)D laboratory values. RESULTS: There were 2272 and 4140 monotherapy patients in the ergocalciferol and cholecalciferol groups, respectively. Cholecalciferol mean doses between 600 and 1100 IU had similar changes in 25(OH)D ranging from 8 to 9.1 ng/mL. Cholecalciferol mean doses of 2700 IU had 12.7 ng/mL 25(OH)D increase (P < 0.05). Ergocalciferol at mean doses of 11 000 IU had a 19.9 ng/mL increase of 25(OH)D (P < 0.05). At baseline 25(OH)D levels less than 15 ng/mL, 90% of subjects reached a therapeutic 25(OH)D level with a cumulative 300 000 IU cholecalciferol dose. Adherence, calculated by medication possession ratio, was greater with cholecalciferol than ergocalciferol (87% compared with 68%). CONCLUSIONS: Lower vitamin D dose ranges had a comparable effect on 25(OH)D change. Higher doses can produce higher levels, but the relationship is not linear. PMID- 26104055 TI - Nutritional intake and anthropometric changes of professional road cyclists during a 4-day competition. AB - Appropriate nutrition through adequate dietary intake of total calories, macronutrients, and micronutrients is an essential component of optimizing the performance of all elite athletes. The aim of this study was to describe the food intake, body composition, and biochemical profile of professional cyclists during the Tour of Andalusia, a four-stage race covering a total distance of 647.6 km. Nutritional data were collected by trained investigators who weighed all of the food and fluid ingested by the cyclists. The nutritional intake of the cyclists was as follows: CHO, 12.8 +/- 1.7 g/kg of body weight (BW; 62.3%); fat, 2.1 +/- 0.2 g/kg BW (23.2%); proteins, 3.0 +/- 0.3 g/kg BW (14.5%); total kcal was 5644.3 +/- 593.1. Intake of all micronutrients, except for folate and potassium [which were 93.7% and 91.3% of Recommended Dietary Allowances (RDA)] exceeded the RDA/I. Percentage of body fat and fat weight significantly decreased (P < 0.05) while weight of muscle mass remained unchanged after the Tour. Concentrations of urea, aspartate aminotransferase, alanine aminotransferase, creatine kinase, myoglobin, and high-density lipoproteins significantly increased (P < 0.05) after the Tour. To our knowledge, this is the first study to describe both nutritional intake and the body and biochemical composition of a sample of professional road cyclists during a top-class cycling race. PMID- 26104056 TI - Synthetic and Natural Monoamine Oxidase Inhibitors as Potential Lead Compounds for Effective Therapeutics. AB - Monoamine oxidases A and B (MAO-A and B) play a critical role in the metabolism of intracellular neurotransmitters of the central nervous system. For decades, MAO inhibitors have proven their clinical efficacy as potential drug targets for several neurological and neurodegenerative diseases. Use of first generation non selective MAO inhibitors as neuropsychiatric drugs elicited several side effects like hypertensive crisis and cheese reaction. Therefore their use is now limited due to non-selectivity towards MAO isoforms and inhibition of metabolizing enzymes like cytochrome P450. Development of selective and specific MAO inhibitors like moclobemide, toloxatone improves their efficacy as disease modifying effects in monotherapy as well as adjunctive therapy. Recently a lot of research has been done to elucidate the pharmacological potential of medicinal plants and their isolated bioactive constituents having MAO inhibitory activity. Herbs containing MAO inhibitors are extensively used for the development of potent synthetic drugs and as safe and effective alternatives to the available synthetic drugs in the treatment of neurodegenerative diseases such as depression, Parkinson and Alzheimer's. In several diseases like Parkinson natural MAO inhibitors prevented the neuron denaturalization by their dual action via enhancing neurotransmission of dopamine as well as lowering the generation of free radicals and toxins. Currently development of selective MAO inhibitors is still under study to achieve more effective therapies by using Computer Aided Drug Designing, Ligand-based models and structure-activity hypothesis. These approaches also facilitate understanding the interaction of newly designed molecule with MAO enzymes and the rationalization of probable mechanisms of action. PMID- 26104057 TI - Subfascial lipoma in the temporal muscle that extended to under the zygomatic arch. PMID- 26104058 TI - Tricyclic antidepressants for the treatment of tenesmus associated with rectal prolapse. AB - AIM: Tenesmus in rectal prolapse leads to a vicious circle of straining with deterioration of prolapse. The primary phenomenon triggering this may be rectal hypersensitivity. We aimed to assess whether treatment with tricyclic antidepressants (TCAs) may break the vicious circle and improve tenesmus. METHOD: A retrospective review was carried out of patients with rectal prolapse and severe tenesmus who were poor surgical candidates or had refused surgery. They were treated at our tertiary centre with low dose tricyclic antidepressants. RESULTS: Twenty-three (18 female) patients were included, with mean age 75.3 (+/ SD 14.6) years. The mean duration of symptoms was 10.8 (+/- 8.6) months. Full thickness rectal prolapse was diagnosed in 16 (70%) patients while seven (30%) had mucosal or incomplete prolapse. Ten (43%), eight (35%) and five (22%) patients were treated with nortriptyline (25 mg daily), amitriptyline (10 mg daily) and desipramine (25 mg daily). After a mean follow-up of 9.05 (+/- 8.2) months, 14 (61%) patients reported significant improvement in symptoms, five (22%) had a partial response, three (13%) were lost to follow-up and one (4%) failed to respond. The response rates for nortriptyline, desipramine and amitriptyline were 90%, 100% and 62.5%. CONCLUSION: To the best of our knowledge this is the first report to address the symptomatic, conservative treatment of tenesmus in patients with rectal prolapse. TCAs may be an acceptable option for poor surgical candidates or patients refusing surgery. PMID- 26104059 TI - HCV-associated B-cell non-Hodgkin lymphomas and new direct antiviral agents. AB - BACKGROUND & AIMS: Hepatitis C virus-related B-cell proliferation is a model of virus-driven autoimmune/neoplastic disorder leading to mixed cryoglobulinaemia and/or B-cell non-Hodgkin lymphoma. These lymphomas are often marginal zone lymphomas or diffuse large B-cell lymphomas. Peginterferon/Ribavirin therapy has proved its crucial role in the cure of these non-Hodgkin lymphomas, but data are lacking concerning new direct anti-viral agents. METHODS: We report five cases of Hepatitis C virus-associated B-cell non-Hodgkin lymphoma treated with direct anti viral agents: two marginal zone lymphomas received direct anti-viral agents alone (one with a leukaemic phase only, one with splenic and deep lymph nodes localizations); one renal marginal zone lymphoma with renal insufficiency received direct anti-viral agents and four rituximab infusions simultaneously; two diffuse large B-cell lymphomas were treated with direct ant-viral agents following chemotherapy. RESULTS: Sustained virological response was obtained in all patients, and complete remission of NHL was noted 6 months after cessation of any treatment except for one patient with a persistent small leukaemic phase. CONCLUSION: Direct anti-viral agents might be proposed as a first-line treatment in marginal zone lymphomas in the case of no life-threatening complications with the precaution of a long-term follow-up. In the setting of diffuse large B-cell lymphomas, well-tolerated direct anti-viral agents could potentially be introduced very early not only to prevent relapse of these lymphomas but also to limit the liver toxicity of chemotherapy and rituximab by preventing outbreaks of viral load. New observations and trials should support these assumptions. PMID- 26104060 TI - Diabetes management in psychiatric inpatients: time to change? PMID- 26104061 TI - Enteropathy-associated T-cell lymphoma in the US: higher incidence and poorer survival among Asians. PMID- 26104063 TI - Insights on leadership from early career nurse academics: findings from a mixed methods study. AB - AIM: To explore the perceptions of early career nursing academics on leadership in academia. BACKGROUND: There is growing emphasis on leadership capacity building across all domains of nursing. However, there is limited evidence on leadership capacity in early career academics. This study tested an intervention to develop leadership capacity amongst early career nursing academics in two Australian universities. METHODS: A sequential mixed methods design, using online surveys and semi-structured interviews, was used to collect data. RESULTS: Twenty three early career nursing academics participated. Most had experience of formal leadership roles and were aware of its importance to them as they developed their academic careers. Participants were able to discuss their own views of themselves as leaders; their perceptions of their own needs for leadership development, and ways in which they could seek to develop further as leaders. CONCLUSION: There is a need to provide initial and ongoing opportunities for leadership development amongst nurse academics. These opportunities should be contextualised and recognise factors such as gender, and the effects of structural oppression. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse academics are involved in the preparation of the next generation of clinical leaders and it is imperative that they are able to articulate a clear view of leadership. PMID- 26104062 TI - Treatment with tetrahydrobiopterin overcomes brain death-associated injury in a murine model of pancreas transplantation. AB - Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co-factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham operated controls, donor BD resulted in intragraft inflammation reflected by induced IL-1beta, IL-6, VCAM-1, and P-selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4 treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non-BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD-associated injury after transplantation. PMID- 26104064 TI - Health-related quality of life in patients with idiopathic normal pressure hydrocephalus. AB - BACKGROUND AND PURPOSE: Factors affecting health-related quality of life (HRQoL) were explored in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Using the 15D instrument HRQoL was evaluated in 132 patients diagnosed with iNPH by clinical and neuroradiological examinations. The severity of iNPH symptoms was measured with the iNPH grading scale (iNPHGS), depressive symptoms with the Beck Depression Inventory (BDI-21) and cognitive impairment with the Mini-Mental State Examination. RESULTS: The mean (SD) 15D score (on a 0-1 scale) of patients with iNPH was significantly lower than that of an age- and gender matched sample of the general population [0.718 (0.103) vs. 0.870 (0.106); P < 0.001]. The mean 15D score was lower in iNPH patients with moderate or severe depressive symptoms than in patients without depressive symptoms (P = 0.003). According to stepwise multiple linear regression analysis, a higher total iNPHGS score (b = -0.62, P < 0.001) and a higher BDI-21 total score (beta = -0.201, P = 0.025) predicted a lower 15D score; in combination, these explained 51% of the variance in the 15D score (R(2) = 0.506, P < 0.001). CONCLUSIONS: Idiopathic normal pressure hydrocephalus impairs patients' HRQoL on multiple dimensions, similarly to other chronic diseases. Potentially treatable depressive symptoms contribute greatly to the HRQoL impairment of iNPH patients, but only if they are moderate or severe. The 15D portrayed HRQoL dimensions affected by iNPH in a similar way to broader assessment batteries and thus is a potentially useful tool for treatment evaluation and cost-utility analysis. PMID- 26104065 TI - Erectile Dysfunction is Associated with Subsequent Cardiovascular and Respiratory Mortality in Cohort of 1,436 Chinese Elderly Men. AB - INTRODUCTION: Erectile dysfunction (ED) is commonly shown to be associated with subsequent cardiovascular mortality, but not respiratory mortality, despite respiratory disease being highly prevalent among ED patients. AIM: We aim to examine associations of ED with all-cause and cause-specific (i.e., cardiovascular and respiratory) mortality in a prospective cohort of 1,436 Chinese men, followed up from 2001 for a median of 11.5 years. METHODS: ED measurement was based on a single question of four categories at the 4-year follow up. MAIN OUTCOME MEASURES: Outcome measures include all-cause and cause specific mortality (i.e., cardiovascular and respiratory mortality, classified according to the International Classification of Disease-version 10 [ICD-10]). Multivariable regression models estimated associations between ED and all-cause and cause-specific mortality, adjusting for the presence of chronic conditions, and socio-demographics and lifestyle factors. For each category of disease specific mortality, subjects with the corresponding diseases and death cases from other causes were excluded. Cancer mortality was included for comparison. RESULTS: Participants who were completely impotent had significantly increased risk of all-cause (HR = 1.63, 95% CI = 1.20-2.23), cardiovascular (HR = 3.94, 95% CI = 1.77-8.76) and respiratory mortality (HR = 3.16, 95% CI = 1.46-6.81) compared with non-impotent participants, adjusting for chronic conditions, and socio-demographics and lifestyle factors. CONCLUSION: ED is significantly associated with subsequent all-cause mortality, possibly via its association with cardiovascular and respiratory mortality. Primary care practitioners should pay attention to ED patients' cardiovascular and respiratory risk profiles, which may benefit their prognosis. PMID- 26104066 TI - Comparative analysis of pulmonary and extrapulmonary tuberculosis of 411 cases. AB - BACKGROUND: Tuberculosis is a disease that can involve every organ system. While pulmonary tuberculosis is the most common presentation, extrapulmonary tuberculosis (EPT) is also an important clinical problem. The current study aimed to outline and compare the demographic and clinical features of pulmonary and extrapulmonary tuberculosis cases in adults. METHODS: Medical records of 411 patients (190 women, 221 men) treated between January 2010 and July 2014 in provincial tuberculosis control dispensary was retrospectively reviewed. Demographic and clinical characteristics were compared for pulmonary and extrapulmonary tuberculosis cases. RESULTS: Of these 411 cases, 208 (50.6%) had pulmonary tuberculosis (PTB) and 203 were diagnosed with extrapulmonary tuberculosis (EPTB) (49.4%). The average ages for PTB and EPTB groups were 33.00 27.00 and 31.00-29.75, respectively (p = 0.513). Men were more frequently affected by PTB (59.6%), while EPTB was more commonly detected in women (52.2%) (p = 0.016). Main diagnostic modalities for PTB were sputum/smear analyses (72.7%), clinical-radiological data (21.7%) and biopsy (6.1%); while biopsy (71.5%), sputum/fluid analysis (18.8%) and clinical-radiological data (4.9%) were used for confirming EPTB (p < 0.0019). The most common sites of EPTB involvement were lymph nodes (39.4%), followed by pleura (23.6%), peritoneum (9.9%) and bone (7.4%). CONCLUSIONS: Extrapulmonary involvement of tuberculosis is common and females are more likely to be affected. Increased clinical awareness is important since atypical presentations of the disease may constitute diagnostic and therapeutic challenges. PMID- 26104067 TI - Ortner's syndrome presenting as thoracic aortic aneurysm mimicking thoracic malignancy: a case report. AB - INTRODUCTION: Ortner's syndrome is defined as left recurrent laryngeal nerve palsy caused by a cardiovascular pathology. Here we report the case of a 68-year old man who presented to our hospital with hoarseness, whose initial chest imaging mimicked a thoracic neoplastic process with left pleural effusion. The final diagnosis was Ortner's syndrome due to the silent rupture of a thoracoabdominal aortic aneurysm. Diagnostic thoracentesis, before computed tomography, in resource-poor settings, may have resulted in an adverse outcome in our case. CASE PRESENTATION: A 68-year-old Sri Lankan man was referred to us by an otolaryngologist for further evaluation of a suspected thoracic malignancy. His presenting symptom was hoarseness of three months duration. He had essential hypertension for the last four years and had a history of 25 pack-years of cigarettes smoking. His chest X-ray showed a left-sided mediastinal mass with mild to moderate pleural effusion. An ultrasound appeared to show an encysted pleural fluid collection. However, we proceeded with computed tomography before diagnostic thoracentesis. The diagnosis of Ortner's syndrome was made after the computed tomography due to the silent rupture of his thoracoabdominal aortic aneurysm. CONCLUSIONS: Hoarseness due to left recurrent laryngeal nerve palsy can be the presenting symptom of cardiovascular pathologies, Ortner's syndrome. Silent rupture of thoracic aortic aneurysms can mimic that of thoracic malignancy, which is reported in literature. We illustrate the importance of a high degree of suspicion of cardiovascular pathology in order to avoid an adverse outcome following diagnostic thoracentesis. PMID- 26104068 TI - The Early Childhood Obesity Prevention Program (ECHO): an ecologically-based intervention delivered by home visitors for newborns and their mothers. AB - BACKGROUND: Obesity is a major problem in the United States, particularly among socio-economically disadvantaged Latino and Black children. Effective interventions that can be disseminated to large numbers of at-risk children and their families are needed. The goals of the Early Childhood Obesity Prevention Program (ECHO) are to examine the 12-month efficacy of a primary obesity prevention program targeting the first year of life that is delivered by home visitors and that engages mothers as agents of change to modify their own behavior and their infant's behavior through education and skill-building around nutrition, physical activity, and wellness, and then "echoes" her training with linkages to neighborhood programs and resources. METHODS/DESIGN: Six family centers located in low-income neighborhoods in Hartford, CT were randomized into control and intervention neighborhoods. Fifty-seven mothers were recruited either prenatally or shortly after delivery into the Nurturing Families Network home visitation program; 27 lived in a control neighborhood and received the standard home visitation program and 30 lived in an intervention neighborhood and received both the standard home visitation program and the ECHO intervention. The intervention increases maternal skills in goal-setting, stimulus control and problem-solving, engages family members to support changes, links mothers to neighborhood resources and is embedded in the standard home visitation program. ECHO targets include breastfeeding, solids, juice and sugar-sweetened beverages, routines for sleep and responding to infant cues, television/screen time, and maternal diet and physical activity. We hypothesize that infants in ECHO will have been breastfed longer and exclusively, will have delayed introduction of solids and juice, have longer sleep duration, decreased television/screen time and a lower weight for length z-score at 12 months, and their mothers will have greater fruit and vegetable consumption and higher levels of physical activity. DISCUSSION: ECHO will provide important information about whether an enhanced behavior change curriculum integrated into an existing home visitation program, focused on the mother as the agent of change and linked to neighborhood resources is effective in changing energy balance behaviors in the infant and in the mother. If effective, the intervention could be widely disseminated to prevent obesity in young children. TRIAL REGISTRATION: ClinicalTrials.gov NCT02052518 January 30, 2014. PMID- 26104069 TI - Surgical stress and postoperative complications related to regional and radical mastectomy in dogs. AB - BACKGROUND: Surgery is the treatment of choice for regional control of mammary neoplasms in female dogs. Various surgical techniques may be used, as long as mammary gland anatomy, lymphatic drainage, and known prognostic factors are respected. The purpose of this study was to compare surgical stress-including duration of surgery, nociception and hematological changes-and postoperative complications in dogs undergoing regional and unilateral radical mastectomy. Eighteen dogs were selected for each technique. Postoperative pain (nociception), hematological changes, and postoperative complications were compared between the two groups. RESULTS: The group treated with radical mastectomy had a longer surgical duration, showed more intense physiological changes, achieved higher scores on nociception scales, and experienced more postoperative complications. CONCLUSION: Compared to regional mastectomy, radical mastectomy was associated with longer surgical duration, greater nociceptive stimulus, greater surgical stress, and higher incidence of postoperative complications in dogs. Although evaluation of long-term results was not a goal of this study, it is suggested that postoperative recovery and patient quality of life should be considered when choosing a surgical approach for treating mammary tumors in dogs. PMID- 26104070 TI - Correlation between Morphologic Changes and Autism Spectrum Tendency in Obsessive Compulsive Disorder. AB - OBJECTIVES: Obsessive-compulsive disorder (OCD) is one of the most debilitating psychiatric disorders, with some speculating that a reason for difficulty in its treatment might be its coexistence with autism spectrum. We investigated the tendency for autistic spectrum disorders (ASD) in patients with OCD from a neuroimaging point of view using voxel-based morphometry. METHODS: We acquired T1 weighted images from 20 patients with OCD and 30 healthy controls and investigated the difference in regional volume between the groups as well as the correlation between Autism-Spectrum Quotient (AQ) scores and regional cerebral volumes of patients with OCD. RESULTS: Volumes in the bilateral middle frontal gyri were significantly decreased in patients with OCD compared to controls. Correlational analysis showed significant positive correlations between AQ scores and regional gray matter (GM) volumes in the left dorsolateral prefrontal cortex (DLPFC) and left amygdala. Furthermore, GM volumes of these regions were positively correlated with each other. CONCLUSIONS: The positive correlation of ASD traits in patients with OCD with regional GM volumes in the left DLPFC and amygdala could reflect the heterogeneity of patient symptoms. Our results suggest that differences in GM volume might allow classification of patients with OCD for appropriate therapy based on their particular traits. PMID- 26104071 TI - Radiofrequency-shielding Effect of a Titanium Mesh Implanted for Cranioplasty. AB - PURPOSE: After cranioplasty with a titanium mesh, radiofrequency (RF)-shielding images appear during magnetic resonance (MR) imaging. To clarify their influence, we evaluated the effect of mesh position, phase-encoding direction, and type of coil employed. MATERIALS AND METHODS: On a 1.5-tesla MR imager, we placed a titanium mesh board (100 * 100 * 0.8 mm) on the surface of a cubic phantom to mimic a human brain and used a quadrature coil and an 8-channel neurovascular coil to measure nonuniformity, signal decay ratio, and the B1 map. RESULTS: Nonuniformity was 6.7 times higher at the quadrature head coil and 1.6 times higher at the neurovascular coil when the mesh was on the phantom's right side or anterior to it than when it was on its superior end or absent. The profile of the signal decay ratio increased by 1.9% mm(-1) from 0 to 40 mm from the mesh side to the base value at the quadrature head coil when the mesh was on the phantom's right side and 0.9% mm(-1) from 0 to 80 mm at the neurovascular coil when the mesh was on the phantom's right side or anterior to it. The quadrature head coil showed greater incline of the profile when the mesh was on the right in coronal and axial views and no notable change in the profile in coronal and sagittal views when the mesh was on the superior end. In the B1 map, the flip angle was lower when the mesh was nearer. CONCLUSION: The response to the RF-shielding effect from a titanium mesh depends on the location of the mesh and the RF coil used but not on the phase-encoding direction. PMID- 26104072 TI - Assessment of MR Imaging as a Tool to Differentiate between the Major Histological Types of Uterine Sarcomas. AB - OBJECTIVES: We retrospectively compared and quantified magnetic resonance (MR) images to distinguish major histological types of uterine sarcomas and malignant and benign tumors. METHODS: MR images were obtained from patients who underwent preoperative examinations. We compared 25 pathologically confirmed uterine sarcomas (8 leiomyosarcomas, 11 carcinosarcomas, 6 endometrial stromal sarcomas) with 25 uterine leiomyomas. MR findings included tumor size, location, contour, signal intensity (SI), and contrast enhancement. Analysis focused on the contrast ratio (CR) of SI in T2-weighted images for the areas of lowest, highest, and main SI of each tumor as well as the contrast-enhanced ratio (CER) for the main solid part of each tumor in contrast-enhanced T1-weighted images. We evaluated diffusion-weighted (DW) images and apparent diffusion coefficient (ADC) values in 18 tumors (4 sarcomas, 14 leiomyomas). RESULTS: Uterine sarcomas and leiomyomas differed significantly in tumor location, contour, hemorrhaging, necrotic and cystic components, CR for the area of lowest SI (P < 0.05), CR for the area of main SI (P < 0.01), and CER (P < 0.05). Leiomyosarcomas were larger than carcinosarcomas or endometrial stromal sarcomas, and the CR for the area of lowest SI of leiomyosarcomas (P < 0.05) was significantly lower. The CER for endometrial stromal sarcomas (P < 0.05) showed the most homogeneous enhancement. Hemorrhagic or necrotic and cystic components were found more often in larger tumors, although there was no significant difference in their occurrence between sarcoma types. All uterine sarcomas showed high intensity on DW images. The ADC values were lower of uterine sarcomas than leiomyomas, although the difference was not statistically significant. CONCLUSION: Quantitative assessment using the CR or CER was useful for distinguishing benign and malignant uterine tumors as well as major histological types of uterine sarcomas. PMID- 26104073 TI - Ventricular Temperatures in Idiopathic Normal Pressure Hydrocephalus (iNPH) Measured with DWI-based MR Thermometry. AB - PURPOSE: The brain produces intense heat as a result of cerebral metabolism and cerebral blood flow, and the generated heat is removed mainly through circulation of the intracranial blood vessels and cerebrospinal fluid (CSF). Because magnetic resonance (MR) images are constructed from analysis of the spin of various molecules, the diffusion coefficient can be used as a parameter that reflects the temperature of water molecules. We used diffusion-weighted imaging (DWI)-based MR imaging to measure the temperature of the CSF around the lateral ventricles in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Our study included 33 cases of iNPH (Group N, mean age, 75.1 years) and 40 age-matched controls (Group C, mean age, 74.5 years). We calculated CSF temperature in the ventricular domain using the conversion formula to evaluate the feasibility of iNPH study. RESULTS: The mean temperatures were significantly higher in Group N (37.6 degrees C +/- 0.4 degrees C) than Group C (36.7 degrees C +/- 0.5 degrees C; P < 0.01). The cut-off value of 37.2 degrees C (more than the mean + 2 standard deviations [SD] of the values in Group C) showed sensitivity of 72.4% and specificity of 77.5% for distinguishing the 2 groups. We confirmed improved CSF temperature in the lateral ventricles in all patients examined both before and after shunting. CONCLUSIONS: Elevated ventricular temperatures in patients with iNPH (Group N) may represent a disturbance in heat balance. Our results showed that thermometry using DWI-based MR imaging can help in the noninvasive and consistent evaluation of CSF temperature and may thus provide a useful supplementary brain biomarker for iNPH. PMID- 26104075 TI - Diffusion-weighted MR Imaging of Deep Vein Thrombosis. PMID- 26104074 TI - Clinical Significance of Discrepancy between Arterial Spin Labeling Images and Contrast-enhanced Images in the Diagnosis of Brain Tumors. AB - PURPOSE: In the imaging of intra-axial brain tumors, we sometimes found areas of high signal intensity around the enhanced tumor lesions on arterial spin labeling (ASL) magnetic resonance (MR) imaging. We undertook this study to investigate the relationship between high signal intensity on ASL imaging outside the area of contrast enhancement (CE) and histological diagnosis of intra-axial brain tumors. METHODS: We examined images from 28 consecutive patients with intra-axial brain tumors who underwent ASL and CE MR imaging-three with low grade glioma (LGG), 13 with high grade glioma (HGG), six with metastasis, and six with primary central nervous system lymphoma (PCNSL)-and divided imaging findings into an "ASL dominant" group when hyperintensity on ASL was found outside the CE area and a "CE dominant" group when hyperintensity on ASL was not found outside the area of enhancement. We then analyzed the relationship between imaging findings and the histological diagnosis of the tumors. RESULTS: Four cases were excluded because of poor quality of ASL images, 7 cases were classified as ASL dominant, and 17 cases were classified as CE dominant. The histological diagnoses of ASL dominant cases were LGG in 3 cases, HGG in 3 cases, and PCNSL in one case. Those of CE dominant cases were HGG in 10 cases, metastasis in 5 cases, and PCNSL in 2 cases. All cases with brain metastasis were classified as CE dominant. CONCLUSION: The high signal intensity outside the area of contrast enhancement is probably caused by increased perfusion or vascular proliferation, which indicates the presence of glioma or PCNSL and not metastasis. This finding indicates a new utility for ASL images in the diagnosis of brain tumors as a supplement to the conventional measurement of perfusion obtained from ASL images. PMID- 26104076 TI - Comparison of Brain Tumor Contrast-enhancement on T1-CUBE and 3D-SPGR Images. AB - PURPOSE: T1-Cube (GE HealthCare) is a relatively new 3-dimensional (3D) fast spin echo (FSE)-based magnetic resonance (MR) imaging sequence that uses a variable flip angle to acquire gap-free volume scans. We compared the gadolinium enhancement characteristics of a heterogeneous population of brain tumors imaged by T1-Cube and then 3D fast spoiled gradient recall acquisition in steady state (3D FSPGR) 3-tesla MR imaging to identify the superior modality for specific diagnostic purposes. METHODS: We examined 61 lesions from 32 patients using the 2 sequences after administration of gadopentetic acid (Gd-DTPA; 0.1 mmol/kg). Two neuroradiologists independently measured each lesion twice using a region-of interest (ROI) method. We measured the contrast-to-noise ratio (CNR), the difference in signal intensity (SI) between the tumor and normal white matter relative to the standard deviation (SD) of the SI within the lesion, for both post-contrast 3D FSPGR and post-contrast T1-Cube images of the same tumor and compared modality-specific CNRs for all tumors and in subgroups defined by tumor size, enhancement ratio, and histopathology. RESULTS: The mean CNR was significantly higher on T1-Cube images than 3D FSPGR images for the total tumor population (1.85 +/- 0.97 versus 1.12 +/- 1.05, P < 0.01) and the histologic types, i.e., metastasis (P < 0.01) and lymphoma (P < 0.05). The difference in CNR was even larger for smaller tumors in the metastatic group (4.95 to 23.5 mm(2)) (P < 0.01). In contrast, mean CNRs did not differ between modalities for high grade glioma and meningioma. CONCLUSIONS: Gadolinium enhancement of brain tumors was generally higher when imaged by T1-Cube than 3D FSPGR, and T1-Cube with Gd enhancement may be superior to 3D FSPGR for detecting smaller metastatic tumors. PMID- 26104077 TI - Fusion of Delayed-enhancement MR Imaging and Contrast-enhanced MR Angiography to Visualize Radiofrequency Ablation Scar on the Pulmonary Vein. AB - Delayed-enhancement magnetic resonance imaging (DE-MRI) is reported to detect the radiofrequency (RF) ablation scar of pulmonary vein isolation. However, the precise localization of RF scar is difficult to recognize due to the poor anatomical information of the 3-dimensionally reconstructed DE-MRI. We report 2 cases in which fusion of DE-MRI and contrast-enhanced MR angiography facilitated the identification of RF scar, and we detail our fusion method. PMID- 26104078 TI - Optimization of Scan Parameters to Reduce Acquisition Time for Diffusion Kurtosis Imaging at 1.5T. AB - PURPOSE: To shorten acquisition of diffusion kurtosis imaging (DKI) in 1.5-tesla magnetic resonance (MR) imaging, we investigated the effects of the number of b values, diffusion direction, and number of signal averages (NSA) on the accuracy of DKI metrics. METHODS: We obtained 2 image datasets with 30 gradient directions, 6 b-values up to 2500 s/mm(2), and 2 signal averages from 5 healthy volunteers and generated DKI metrics, i.e., mean, axial, and radial kurtosis (MK, K?, and K?) maps, from various combinations of the datasets. These maps were estimated by using the intraclass correlation coefficient (ICC) with those from the full datasets. RESULTS: The MK and K? maps generated from the datasets including only the b-value of 2500 s/mm(2) showed excellent agreement (ICC, 0.96 to 0.99). Under the same acquisition time and diffusion directions, agreement was better of MK, K?, and K? maps obtained with 3 b-values (0, 1000, and 2500 s/mm(2)) and 4 signal averages than maps obtained with any other combination of numbers of b-value and varied NSA. Good agreement (ICC > 0.6) required at least 20 diffusion directions in all the metrics. CONCLUSION: MK and K? maps with ICC greater than 0.95 can be obtained at 1.5T within 10 min (b-value = 0, 1000, and 2500 s/mm(2); 20 diffusion directions; 4 signal averages; slice thickness, 6 mm with no interslice gap; number of slices, 12). PMID- 26104079 TI - Added Value of a Gadoxetic Acid-enhanced Hepatocyte-phase Image to the LI-RADS System for Diagnosing Hepatocellular Carcinoma. AB - PURPOSE: We investigated the added value of the hypointensity on hepatocyte-phase (HP) imaging of gadoxetic acid-enhanced MRI (EOB-MRI) in the 2014 version of the Liver Imaging Reporting and Data System (LI-RADS) for distinguishing hepatocellular carcinoma (HCC) from benign hepatic lesions in patients with chronic liver disease. METHODS: We retrospectively evaluated targeted lesions (111 HCCs, 28 benign hepatic lesions) of 139 patients (101 men, 38 women; aged 18 to 89 years, mean age, 68 +/- 11 years) with chronic liver disease. EOB-MRI and dynamic contrast-enhanced computed tomography (CECT) were performed within 3 months. Two abdominal radiologists independently reviewed 3 imaging datasets: (1) EOB-MRI without an HP image using the LI-RADS system (MR imaging without HP); (2) EOB-MRI with an HP image using a modified version of the LI-RADS system in which hypointensity on the HP image was used as an additional major criterion of malignancy (MR imaging with HP); and (3) dynamic contrast-enhanced computed tomography (CECT) images using the LI-RADS system. We evaluated intra- and inter reader agreement with kappa statistics along with 95% confidence intervals and compared diagnostic sensitivity and specificity of the 3 imaging datasets with McNemar's test. RESULTS: The sensitivities of MR imaging were statistically higher with HP (Reader 1, 95% [107/111]; Reader 2, 95% [106/111]) than without HP (Reader 1, 84% [93/111], P = 0.002; Reader 2, 86% [96/111], P = 0.002). Specificity was comparably high between MR imaging with HP (Reader 1, 96% [27/28]; Reader 2, 96% [27/28]) and dynamic CECT (Reader 1, 100% [28/28], P = 0.317; Reader 2, 100% [28/28], P = 0.317) and MR imaging without HP (Reader 1, 96% [27/28], P = 1.00; Reader 2, 100% [28/28], P = 0.317). CONCLUSION: The use of an HP image from EOB-MRI as an additional major criterion improved the sensitivity of LI-RADS to distinguish HCCs from benign hepatic lesions while retaining high specificity. PMID- 26104080 TI - Removing Ambiguity Caused by T2 Shine-through using Weighted Diffusion Subtraction (WDS). AB - We propose a novel image processing technique that combines images routinely acquired with low and high b values to create a single image that contains clinically useful information without the ambiguity of T2 shine-through. The contrast of resulting images is similar to that of a T2 image, but the signals of pixels with low apparent diffusion coefficient (ADC) values are inverted. The proposed technique takes the threshold ADC value as the one adjustable parameter. PMID- 26104081 TI - Squamous Cell Carcinoma of the Head and Neck: Comparison of Diffusion-weighted MRI at b-values of 1,000 and 2,000 s/mm(2) to Predict Response to Induction Chemotherapy. AB - PURPOSE: Recent publications have reported contradictory results of pretreatment diffusion-weighted magnetic resonance imaging (DWI) for the prediction of chemoradiotherapeutic response in primary squamous cell carcinomas of the head and neck (HNSCC). Therefore, we evaluated the diagnostic performance of DWI obtained with both standard (b = 0 and 1,000 s/mm2) and high (b = 0 and 2,000 s/mm2) b-values for predicting response to induction chemotherapy in HNSCCs. METHODS: For 25 patients with primary HNSCC who underwent DWI with both standard and high b-values prior to treatment, we calculated corresponding apparent diffusion coefficient (ADC) maps. Regions of interest containing the tumor were drawn on every section of ADC maps and summated to make volume-based data of the entire tumor. Histogram parameters (mean ADC, kurtosis, and skewness) were correlated with treatment response using unpaired Student t test. Univariate and multivariate analysis of the ADC parameters, patient age, sex, whole tumor volume, and T stage were also performed to predict tumor response to induction chemotherapy. RESULTS: Response to induction chemotherapy was good in 13 of the 25 patients and poor in 12. The mean ADC values of good responders at standard b value (ADC1000), 1.23 +/- 0.34 (* 10-3 mm2/s), and high b-value (ADC2000), 0.62 +/- 0.14 (* 10-3 mm2/s), were lower than those of poor responders (ADC1000, 1.32 +/- 0.28 [* 10-3 mm2/s]; ADC2000, 0.76 +/- 0.15 [* 10-3 mm2/s]), but significant difference was achieved only at the ADC2000 map (P = 0.02). In addition, mean tumor volume prior to treatment of good responders was smaller than that of poor responders. However, at multiple logistic regression analysis, only the mean ADC2000 value remained as a significant predictor of response to induction chemotherapy. CONCLUSION: DWI with high b-values (b = 0 and 2,000 s/mm2) as an assessment of ADC values may help predict tumor response to neoadjuvant chemotherapy for primary HNSCCs. PMID- 26104082 TI - Intraindividual Crossover Comparison of Gadoxetic Acid Dose for Liver MRI in Normal Volunteers. AB - PURPOSE: We performed a quantitative intraindividual comparison of the performance of 0.025- and 0.05-mmol/kg doses for gadoxetic acid-enhanced liver magnetic resonance (MR) imaging. MATERIALS AND METHODS: Eleven healthy volunteers underwent liver MR imaging twice, once with a 0.025- and once with a 0.05-mmol/kg dose of gadoxetic acid. MR spectroscopy and 3-dimensional gradient-echo T1 weighted images (3D-GRE) were obtained before and 3, 10, and 20 min after injection of the contrast medium to measure T1 and T2 values and signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) performance. During the dynamic phase, highly time-resolved 3D-GRE was used to estimate the relative CNR (CNRrel) of the hepatic artery and portal vein (PV) to the liver. We used paired t-tests to compare the results of different doses. RESULTS: During the hepatobiliary phase, we observed shorter T1 values and higher SNRs of the liver (P < 0.001) and higher liver-to-PV and liver-to-muscle CNRs (P < 0.002) using 0.05 mmol/kg compared to 0.025 mmol/kg. Increasing the dose to 0.05 mmol/kg yielded a greater T1-shortening effect at 10 min delay even compared with 0.025 mmol/kg at 20 min (P < 0.001). During the dynamic phase, the peak CNRrel for the hepatic artery and portal vein were higher using 0.05 mmol/kg (P = 0.007 to 0.035). CONCLUSION: Use of gadoxetic acid at a dose of 0.05 mmol/kg leads to significantly higher SNR and CNR performance than with 0.025 mmol/kg. Quantitatively, a 10-min delay may be feasible for hepatobiliary-phase imaging when using 0.05 mmol/kg of gadoxetic acid. PMID- 26104083 TI - What We Have Learned about Human Primary Visual Cortex from High Resolution Functional Magnetic Resonance Imaging. AB - This article reviews our exploration of structures and functions of the human visual cortex using high resolution (submillimeter) functional magnetic resonance imaging (fMRI). It discusses factors that restrict the spatial resolution of blood oxygenation-level dependent (BOLD) fMRI-the point-spread function of the BOLD signal, limited by both imaging techniques to be used and neurovascular units to be studied, and the signal-to-noise ratio. I offer personal thoughts regarding optimal solutions for dealing with these issues, summarize techniques we have developed over the years for using high resolution fMRI to visualize functional architectures and explore physiological properties in the primary visual cortex of humans, including choices of imaging hardware and pulse sequences, experimental procedures, and stimulation paradigms, and finally offer my personal opinions regarding the future of high resolution fMRI. PMID- 26104085 TI - Two cases of in-frame deletion mutation in juxtamembrane domain of the FLT3. PMID- 26104086 TI - David Roger Oldroyd (20 January 1936--7 November 2014) An Appreciation. PMID- 26104084 TI - Genetics of anaplastic large cell lymphoma. AB - Anaplastic large cell lymphoma (ALCL) comprises a group of T-cell non-Hodgkin lymphomas unified by common morphologic and immunophenotypic characteristics, but with a spectrum of clinical presentations and behaviors. Early identification of anaplastic lymphoma kinase (ALK) gene rearrangements in some ALCLs led to recognition of ALK as an important diagnostic and prognostic biomarker, and a key driver of ALCL pathobiology. Rearrangements and other genetic abnormalities of ALK subsequently were identified in diverse other human malignancies. Recent clinical, pathologic, and genetic data have begun to shed light on ALK-negative ALCLs, revealing significant heterogeneity within this more ill-defined entity. PMID- 26104087 TI - Poinsinet's Edition of the Naturalis historia (1771-1782) and the Revival of Pliny in the Sciences of the Enlightenment. AB - This paper analyses the revival of Pliny's Naturalis historia within the scientific culture of the late eighteenth and early nineteenth centuries, focusing on a French effort to produce an edition with annotations by scientists and scholars. Between the Renaissance and the early eighteenth century, the Naturalis historia had declined in scientific importance. Increasingly, it was relegated to the humanities, as we demonstrate with a review of editions. For a variety of reasons, however, scientific interest in the Naturalis historia grew in the second half of the eighteenth century. Epitomizing this interest was a plan for a scientifically annotated, Latin-French edition of the Naturalis historia. Initially coordinated by the French governmental minister Malesherbes in the 1750s, the edition was imperfectly realized by Poinsinet a few decades later. It was intended to rival two of the period's other distinguished multi volume books of knowledge, Diderot and D'Alembert's Encyclopedie and Buffon's Histoire naturelle, to which we compare it. Besides narrating the scientific revival of the Historia naturalis during this period, we examine its causes and the factors contributing to its end in the first half of the nineteenth century. PMID- 26104088 TI - Ruling Engines, Diffraction Gratings and Wavelength Measurements before the Rowland Era. AB - Diffraction gratings have contributed enormously to modern science. Although some historians have written about them, there is much more to be brought to light. This paper discusses their development and use in the period up to about 1880 before Rowland began to produce them. Rittenhouse described the action of a diffraction grating in 1786, but no explanation was possible until the wave theory of light was developed. Fraunhofer discovered the dark lines in the solar spectrum in 1814, and then investigated diffraction, producing the first ruled gratings, making detailed measurements and calculating the wavelengths of prominent spectral lines. After Bunsen and Kirchhoff showed the association between spectral lines and chemical elements there was an upsurge of interest in measuring wavelengths. The gratings used in this work almost all came from one source, a relatively unknown instrument maker called Nobert, who made them by an extremely laborious process using a machine he had built himself. The most significant wavelength measurements were made by Angstrom, but Mascart, Van der Willigen, Stefan, Ditscheiner and Cornu also did important work. Nobert gratings were investigated by Quincke, copied photographically by Rayleigh, and were known and discussed in the USA. Nobert's work helped to advance spectroscopy much more than has been acknowledged. PMID- 26104089 TI - [The delayed emergence of the printing chronograph in French observatories (late 19th - early 20th centuries]. AB - Western observatories became scientific factories from the mid-19th century. Astrometry symbolized the transition to an industrious economy of scientific practices. The printing chronograph, which reduced the personal equations of the observers, was, first in the United States, then in England, the symbolic instrument of this transformation. In France, the initiatives of the astronomer Liais were prototypical. In the practices of the Hendaye Observatory, and thanks to the abbe Verschaffel, the printing chronograph made its definitive entry in French observatories at the beginning of the 20th century. Excessive centralization of French astronomy, the authoritarianism of Urbain Le Verrier, the director of the Paris Observatory, and the poor market for scientific instruments explain why the printing chronograph took root, belatedly, in France. PMID- 26104090 TI - Galileo's Discorsi as a Tool for the Analytical Art. AB - A heretofore overlooked response to Galileo's 1638 Discorsi is described by examining two extant copies of the text (one which has received little attention in the historiography, the other apparently unknown) which are heavily annotated. It is first demonstrated that these copies contain annotations made by Seth Ward and Sir Christopher Wren. This article then examines one feature of Ward's and Wren's responses to the Discorsi, namely their decision to re-write several of Galileo's geometrical demonstrations into the language of symbolic algebra. It is argued that this type of active reading of period mathematical texts may have been part of the regular scholarly and pedagogical practices of early modern British mathematicians like Ward and Wren. A set of Appendices contains a transcription and translation of the analytical solutions found in these annotated copies. PMID- 26104101 TI - A Scalable Method toward Superhydrophilic and Underwater Superoleophobic PVDF Membranes for Effective Oil/Water Emulsion Separation. AB - A superhydrophilic and underwater superoleophobic PVDF membrane (PVDFAH) has been prepared by surface-coating of a hydrogel onto the membrane surface, and its superior performance for oil/water emulsion separation has been demonstrated. The coated hydrogel was constructed by an interfacial polymerization based on the thiol-epoxy reaction of pentaerythritol tetrakis (3-mercaptopropionate) (PETMP) with diethylene glycol diglycidyl ether (PEGDGE) and simultaneously tethered on an alkaline-treated commercial PVDF membrane surface via the thio-ene reaction. The PVDFAH membranes can be fabricated in a few minutes under mild conditions and show superhydrophilic and underwater superoleophobic properties for a series of organic solvents. Energy dispersive X-ray (EDX) analysis shows that the hydrogel coating was efficient throughout the pore lumen. The membrane shows superior oil/water emulsion separation performance, including high water permeation, quantitative oil rejection, and robust antifouling performance in a series oil/water emulsions, including that prepared from crude oil. In addition, a 24 h Soxhlet-extraction experiment with ethanol/water solution (50:50, v/v) was conducted to test the tethered hydrogel stability. We see that the membrane maintained the water contact angle below 5 degrees , indicating the covalent tethering stability. This technique shows great promise for scalable fabrication of membrane materials for handling practical oil emulsion purification. PMID- 26104103 TI - Formation of hexagonal-molybdenum trioxide (h-MoO3) nanostructures and their pseudocapacitive behavior. AB - The crystallographic structure and morphology of redox active transition metal oxides have a pronounced effect on their electrochemical properties. In this work, h-MoO3 nanostructures with three distinct morphologies, i.e., pyramidal nanorod, prismatic nanorod and hexagonal nanoplate, were synthesized by a facile solvothermal method. The morphologies of h-MoO3 nanostructures were tailored by a controlled amount of hexamethylenetetramine. An enhanced specific capacitance about 230 F g(-1) at an applied current density of 0.25 A g(-1) was achieved in h MoO3 pyramidal nanorods. Electrochemical studies confirmed that the h-MoO3 pyramidal nanorods exhibit superior charge-storage ability. This improved performance can be ascribed to the coexistence of its well exposed crystallographic planes with abundant active sites, i.e., hexagonal window (HW), trigonal cavity (TC) and four-coordinated square window (SW). The mechanism of charge-storage is likely facilitated by the vehicle mechanism of proton transportation due to the availability of the vehicles, i.e., NH4(+) and H2O. The promising, distinct and unexploited features of h-MoO3 nanostructures reveal a strong candidate for pseudocapacitive electrode materials. PMID- 26104102 TI - Mapping pathological changes in brain structure by combining T1- and T2-weighted MR imaging data. AB - INTRODUCTION: A workflow based on the ratio between standardized T1-weighted (T1 w) and T2-weighted (T2-w) MR images has been proposed as a new tool to study brain structure. This approach was previously used to map structural properties in the healthy brain. Here, we evaluate whether the T1-w/T2-w approach can support the assessment of structural impairments in the diseased brain. We use schizophrenia data to demonstrate the potential clinical utility of the technique. METHODS: We analyzed T1-w and T2-w images of 36 schizophrenic patients and 35 age-matched controls. These were collected for the Function Biomedical Informatics Research Network (fBIRN) collaborative project, which had an IRB approval and followed the HIPAA guidelines. We computed T1-w/T2-w images for each individual and compared intensities in schizophrenic and control groups on a voxel-wise basis, as well as in regions of interest (ROIs). RESULTS: Our results revealed that the T1-w/T2-w image permits to discriminate brain regions showing group-level differences between patients and controls with greater accuracy than conventional T1-w and T2-w images. Both the ROIs and the voxel-wise analysis showed globally reduced gray and white matter values in patients compared to controls. Significantly reduced values were found in regions such as insula, primary auditory cortex, hippocampus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus. CONCLUSION: Our findings were consistent with previous meta-analyses in schizophrenia corroborating the hypothesis of a potential "disconnection" syndrome in conjunction with structural alterations in local gray matter regions. Overall, our study suggested that the T1-w/T2-w technique permits to reliably map structural differences between the brains of patients and healthy individuals. PMID- 26104104 TI - farFRET: Extending the Range in Single-Molecule FRET Experiments beyond 10 nm. AB - Single-molecule Forster resonance energy transfer (smFRET) has become a powerful nanoscopic tool in studies of biomolecular structures and nanoscale objects; however, conventional smFRET measurements are generally blind to distances above 10 nm thus impeding the study of long-distance phenomena. Here, we report the development of farFRET, a technique that extends the range in smFRET measurements beyond the 10 nm line by enhanced energy transfer using multiple acceptors. We demonstrate that farFRET can be readily employed to quantify FRET efficiencies and conformational dynamics using double-stranded DNA molecules, RecA-filament formation on single-stranded DNA and Holliday junction dynamics. farFRET allows quantitative measurements of large biomolecular complexes and nanostructures thus bridging the remaining gap to superresolution microscopy. PMID- 26104105 TI - Application of Partial Least Square (PLS) Analysis on Fluorescence Data of 8 Anilinonaphthalene-1-Sulfonic Acid, a Polarity Dye, for Monitoring Water Adulteration in Ethanol Fuel. AB - Fluorescence characteristic of 8-anilinonaphthalene-1-sulfonic acid (ANS) in ethanol-water mixture in combination with partial least square (PLS) analysis was used to propose a simple and sensitive analytical procedure for monitoring the adulteration of ethanol by water. The proposed analytical procedure was found to be capable of detecting even small adulteration level of ethanol by water. The robustness of the procedure is evident from the statistical parameters such as square of correlation coefficient (R(2)), root mean square of calibration (RMSEC) and root mean square of prediction (RMSEP) that were found to be well with in the acceptable limits. PMID- 26104106 TI - A systematic review of studies investigating the care of stroke survivors in long term care facilities. AB - PURPOSE: The burden of stroke is immense, with approximately 30 million stroke survivors globally. Approximately one-quarter of residents in long-term care (LTC) facilities are stroke survivors. This review aims to integrate the existing knowledge from the literature and elucidate themes around the care of stroke survivors in LTC facilities. METHOD: A systematic search was performed in PubMed, Ovid MEDLINE, the Cochrane Library and CINAHL. Articles that met the eligibility criteria were selected. Synthesis of results according to similar themes was performed. RESULTS: A total of 1920 articles were screened for eligibility, of which 22 met the eligibility criteria. Of the 22 articles selected, five and 17 articles comprised interventional and observational studies, respectively. Three themes were identified: rehabilitation, stroke specific care and secondary stroke drug prevention. These were found to be lacking within LTC facilities. There is also a dearth of interventional studies in stroke survivors from LTC facilities. CONCLUSIONS: The care of stroke survivors in LTC facilities is lacking in rehabilitation, stroke specific care and secondary stroke prevention. This needs to be addressed through conducting further research to build a strong body of evidence to influence change in the care of this vulnerable group of patients. Implications for Rehabilitation Care of stroke survivors in long-term care facilities Stroke survivors make up almost a quarter of residents in long-term care facilities. They suffer from functional impairments and many other disabilities as a result of more severe stroke, precluding them from living in their own homes. Rehabilitation, stroke-specific care and secondary stroke prevention for stroke survivors are lacking in long-term care facilities despite strong evidence showing benefits for these interventions in stroke survivors living in the community. Interventions to address the unmet need in stroke survivors living in long-term care facilities are vital for optimal care of this vulnerable group of patients. PMID- 26104107 TI - Psychosocial factors associated with physical activity in ambulatory and manual wheelchair users with spinal cord injury: a mixed-methods study. AB - PURPOSE: To identify psychosocial factors which explain lower levels of leisure time physical activity (LTPA) in persons with spinal cord injury (SCI) who are ambulatory relative to those who use manual wheelchairs. METHOD: For the quantitative study component, 347 adults with SCI (78% male; M age = 47.7) completed baseline measures of LTPA attitudes, subjective norms, perceived behavioural control and intentions. Six months later, LTPA was assessed. The qualitative component involved semi-structured interviews with six ambulant adults with SCI (five male, M age = 52.8) addressing LTPA experiences with an emphasis on barriers and facilitators. RESULTS: Ambulatory individuals had poorer attitudes towards LTPA than chair users (p = 0.004). Their attitudes had significant indirect effects on LTPA, through intentions. Perceived behavioural control was a significant negative predictor of LTPA. Qualitative analysis revealed three themes: an underestimated disability, low wheelchair skill self efficacy and experiencing chronic pain. CONCLUSIONS: Poorer attitudes towards LTPA may partially explain why ambulatory individuals are less active. The qualitative and quantitative data suggest ambulators are an often-overlooked subgroup in need of targeted resources to enhance their attitudes, wheelchair skill self-efficacy and awareness of LTPA opportunities. Implications for Rehabilitation Rehabilitation practitioners must be sensitive to the unique needs of spinal cord injured individuals who are ambulatory, and tailor physical activity promotional strategies to suit the needs of this distinct group. Lack of wheelchair skills is a participation barrier for ambulators; ambulators should be introduced to activities that do not require wheelchair use, such as swimming, hand-cycling and adapted forms of circuit training. Strategies that encourage wheelchair skill development in non-wheelchair using ambulators, may increase physical activity opportunities for this segment of the spinal injured population. PMID- 26104108 TI - mTOR is expressed in polymyositis but not in sporadic inclusion body myositis. PMID- 26104110 TI - Upper Airway Obstruction in Children. AB - Children with upper airway obstruction are both unique and variable in their presentation and management, often posing a challenge to the pediatrician. Several anatomical and physiologic peculiarities make a child vulnerable to develop an obstruction of upper airways. The characteristic finding in upper airway obstruction is stridor-inspiratory, biphasic or expiratory. The etiologies vary widely throughout the age groups and according to the mode of presentation. The approach starts with suspicion, mandates careful clinical evaluation of the degree of obstruction and many a times emergency measures precede any investigation or even precise diagnosis. Maintaining an open and stable airway is of the utmost importance, often requiring a team approach of emergency physician, pediatrician, otorhinolaryngologist and pediatric pulmonologist. The commonest condition presenting with upper airway obstruction in pediatric population is viral croup. Croup is a clinical diagnosis in a febrile child, with barking cough and stridor preceded by upper respiratory infection. It is treated with systemic or inhaled steroids and nebulized epinephrine. Epiglottitis and bacterial tracheitis are acute bacterial infections of upper airways, presenting as true airway emergencies. Though the mainstay of therapy is IV antibiotics, the prime concern is maintenance of airway, which frequently requires endotracheal intubation. Rigid bronchoscopy is the procedure of choice for airway foreign bodies, a common cause of upper airway obstruction in children below 3 y of age. Airway malacias are the commonest cause of chronic stridor and are mostly managed conservatively. PMID- 26104109 TI - Changing risk awareness and personal protection measures for low to high pathogenic avian influenza in live-poultry markets in Taiwan, 2007 to 2012. AB - BACKGROUND: Outbreaks of low and high pathogenic avian influenza (LPAI, HPAI) H5N2 in chickens have occurred in Taiwan since 2003 and 2012, respectively. Fully understanding the different awareness, attitudes and protective behaviors adopted by workers in live-poultry markets (LPMWs) and local community residents (CRs) to face the challenges of LPAI and HPAI is very important to minimize viral adaptations to human populations. METHODS: A structural questionnaire containing information on respondents' occupation, personal risk awareness, attitudes toward different policies, and preventative measures was administered. The two-stage survey (before and after HPAI H5N2 outbreaks) was conducted from 2007 to 2012, including: (1) 430 LPMWs and 418 CRs at LPMs from different geographical areas of Taiwan after the government announced outbreaks of LPAI H5N2 during 2007-2009, and (2) 73 LPMWs and 152 CRs at two LPMs in central Taiwan after the HPAI H5N2 outbreaks in 2012. The chi-squared test and logistic regression were applied for univariate and multivariate analyses, respectively. RESULTS: Before HPAI-H5N2 outbreaks, higher educated respondents demonstrated greater risk awareness and concerns regarding AI. However, LPM-workers protected themselves less from AI viruses (AIVs) and had lower acceptance of human or avian influenza vaccines. Most importantly, the participants who opposed (versus agreed with) the policy on banning live-poultry slaughtering at LPMs reported lower awareness of government prevention and control policies [Odds Ratio (OR): 0.76, 95 % Confidence Interval (CI): 0.56-1.01] or practiced preventive measures (OR: 0.42, 95 % CI: 0.25-0.70). After HPAI-H5N2 outbreaks, the risk awareness about AI in central Taiwan significantly increased [LPAI to HPAI LPMWs: 34.6 to 65.6 %, p < 0.05; CRs: 44.0 to 76.5 %, p < 0.05] and LPMWs' belief in the effectiveness of vaccination to prevent human or avian influenza virus infection strikingly decreased (92.3 to 68.5 %, p < 0.05). CONCLUSIONS: Risk awareness depends on high or low pathogenicity of AIVs, working in LPMs, levels of education, age, and proximity to the sites of severe AI outbreaks. Regardless of novel LPAI or HPAI virus reassortants that pose public health risks, prompt and clear risk communication focusing on both correct information about AIVs and the most appropriate preventive measures are important for effective prevention of human infection. PMID- 26104111 TI - Targeted Next Generation Sequencing Identifies a Novel Deletion in LAMA2 Gene in a Merosin Deficient Congenital Muscular Dystrophy Patient. PMID- 26104112 TI - Validity, reliability, and usability of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test for autism spectrum disorders. AB - AIM: This study aimed to explore the test-retest reliability of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test for autism spectrum disorders (PEDI-CAT [ASD]), the concurrent validity of this test with the Vineland Adaptive Behavior Scales (VABS-II), and parents' perceptions of usability. METHOD: A convenience sample of participants (n=39) was recruited nationally through disability organizations. Parents of young people aged 10 to 18 years (mean age 14y 10mo, SD 2y 8mo; 34 males, five females) who reported a diagnosis of autism were eligible to participate. Parents completed the VABS-II questionnaire once and the PEDI-CAT (ASD) twice (n=29) no more than 3 weeks apart (mean 12d) using computer-simulated administration. Parents also answered questions about the usability of these instruments. We examined score reliability using intraclass correlation coefficients (ICCs) and we explored the relationship between instruments using Spearman's rank correlation coefficients. Parent responses were grouped by common content; content categories were triangulated by an additional reviewer. RESULTS: Intraclass correlation coefficients indicate excellent reliability for all PEDI-CAT (ASD) domain scores (ICC >= 0.86). PEDI CAT (ASD) and VABS-II domain scores correlated as expected or stronger than expected (0.57-0.81). Parents reported that the computer-based PEDI-CAT (ASD) was easy to use and included fewer irrelevant questions than the VABS-II instrument. INTERPRETATION: These findings suggest that the PEDI-CAT (ASD) is a reliable assessment that parents can easily use. The PEDI-CAT (ASD) operationalizes the International Classification of Function, Disability and Health for Children and Youth constructs of 'activity' and 'participation', and this preliminary research suggests that the instrument's constructs are related to those of VABS-II. PMID- 26104113 TI - Surface plasmon & visible light for polymer functionalization of mesopores and manipulation of ionic permselectivity. AB - The near-field of surface plasmons is locally confined to nanometer dimensions. Here, we use surface plasmons to initiate polymer-functionalization of mesoporous silica films allowing subsequent ionic permselectivity gating based on polymer charge. We expect this functionalization approach to open a new dimension of functional miniaturization e.g. in nanofluidics. PMID- 26104114 TI - Effectiveness, Mediators, and Effect Predictors of Internet Interventions for Chronic Cancer-Related Fatigue: The Design and an Analysis Plan of a 3-Armed Randomized Controlled Trial. AB - BACKGROUND: Internet interventions offer advantages that especially cancer survivors who suffer from fatigue could benefit from. Given the growing number of such patients, Internet interventions could supplement and strengthen currently available health care. OBJECTIVE: This paper describes the design and analysis plan that will be used to study 2 Internet interventions aimed at reducing severe fatigue in cancer survivors: a mobile ambulant activity feedback therapy supported through a weekly email by a physiotherapist and a weekly Web- and mindfulness-based cognitive therapy supported online by a psychologist. The data resulting from this trial will be used to (1) investigate the effectiveness, (2) investigate potential mediators of these interventions, and (3) explore participant characteristics that can predict the effect of these interventions. METHODS: A 3-armed randomized controlled trial is proposed that compares both Internet interventions with an active control condition that solely consists of receiving psycho-educational emails. The intervention period is 9 weeks for all 3 conditions. Six months after baseline, participants in the control condition can choose to follow 1 of the 2 experimental Internet interventions. Outcomes are measured in terms of fatigue severity, mental health, and self-perceived work ability. All are Web-assessed at baseline, 2 weeks after the intervention period, and at 6 and 12 months after baseline. Fatigue severity, mindfulness, physical activity, expectations and credibility of the intervention, therapeutic working alliance, sleep quality, and sense of control over fatigue are assessed 3 times during the intervention period for identifying mediators of the interventions. Recruitment is performed nationally throughout the Netherlands through patient organizations and their websites, newspapers, and by informing various types of health professionals. All participants register at an open-access website. We aim at including 330 cancer survivors who have finished curative-intent cancer treatment at least 3 months previously, and have been suffering from severe fatigue ever since. All cancer types are included. A detailed analysis plan is described to address the research questions, which allows for individual variation, and fully exploits the longitudinal design. RESULTS: Recruitment started in April 2013 and will proceed until April 2015. CONCLUSIONS: This paper describes a systematic trial design for studying 2 different interventions for chronic cancer-related fatigue in order to gain insight into the effectiveness and mediators of the interventions. This design will also be used to identify predictors for the interventions' effect on fatigue. By publishing our hypotheses and analysis plan before completion of data collection, this paper is a first step in reporting on this trial comprehensively. TRIAL REGISTRATION: The Netherlands National Trial Register (NTR3483). (Archived by WebCite at http://www.webcitation.org/6NWZqon3o). PMID- 26104115 TI - Geometric-attributes-based segmentation of cortical bone slides using optimized neural networks. AB - In cortical bone, solid (lamellar and interstitial) matrix occupies space left over by porous microfeatures such as Haversian canals, lacunae, and canaliculi containing clusters. In this work, pulse-coupled neural networks (PCNN) were used to automatically distinguish the microfeatures present in histology slides of cortical bone. The networks' parameters were optimized using particle swarm optimization (PSO). When forming the fitness functions for the PSO, we considered the microfeatures' geometric attributes-namely, their size (based on measures of elliptical perimeter or area), shape (based on measures of compactness or the ratio of minor axis length to major axis length), and a two-way combination of these two geometric attributes. This hybrid PCNN-PSO method was further enhanced for pulse evaluation by combination with yet another method, adaptive threshold (AT), where the PCNN algorithm is repeated until the best threshold is found corresponding to the maximum variance between two segmented regions. Together, this framework of using PCNN-PSO-AT constitutes, we believe, a novel framework in biomedical imaging. Using this framework and extracting microfeatures from only one training image, we successfully extracted microfeatures from other test images. The high fidelity of all resultant segments was established using quantitative metrics such as precision, specificity, and Dice indices. PMID- 26104116 TI - Comparison of treatment effects of teriparatide and the bisphosphonate risedronate in an aged, osteopenic, ovariectomized rat model under various clinical conditions. AB - Teriparatide and bisphosphonates are osteoporosis medications that increase bone mineral density (BMD) and prevent fracture, but each has a different mechanism of action. Teriparatide promotes bone formation, while bisphosphonates suppress bone resorption. In the clinical setting, however, drug selection is not always tailored to the particular clinical condition of the patient or mechanism of action of the drug. We compared the effects of teriparatide and the bisphosphonate risedronate on bone metabolism using two ovariectomized rat models to elucidate the optimal use of these two drugs in the clinical setting. We first performed dose-finding experiments to determine the equivalent effective doses of each drug (5.6 and 3.0 ug/kg for teriparatide and risedronate, respectively). We then compared the effects of these doses on bone metabolism after subcutaneous administration three times weekly for 4 months starting either the day after ovariectomy (preventive study) or 12 months after ovariectomy (therapeutic study). The increase in proximal tibial BMD under the physical conditions that increased bone turnover at 1 to 2 months after ovariectomy was greater in the risedronate group than in the teriparatide group. In contrast, the increases in lumbar vertebral BMD and bone strength under the physical conditions that significantly decreased BMD and bone strength at 12 months after ovariectomy were greater in the teriparatide group than in the risedronate group. The present study provides important information on the selection of antiosteoporotic drugs, including teriparatide and risedronate, in treatment protocols tailored to the clinical conditions of patients and drug mechanisms. PMID- 26104119 TI - What's new in the quantification of causal effects from longitudinal cohort studies: a brief introduction to marginal structural models for intensivists. PMID- 26104120 TI - Erratum to: Impact of follow-up consultations for ICU survivors on post-ICU syndrome: a systematic review and meta-analysis. PMID- 26104117 TI - Saliva from nymph and adult females of Haemaphysalis longicornis: a proteomic study. AB - BACKGROUND: Haemaphysalis longicornis is a major vector of Theileria spp., Anaplasma phagocytophilum, Babesia spp. and Coxiella burnetti in East Asian countries. All life stages of ixodid ticks have a destructive pool-feeding style in which they create a pool-feeding site by lacerating host tissue and secreting a variety of biologically active compounds that allows the tick to evade host responses, enabling the uptake of a blood meal. The identification and functional characterization of tick saliva proteins can be useful to elucidate the molecular mechanisms involved in tick development and to conceive new anti-tick control methods. METHODS: H. longicornis tick saliva was collected from fully engorged nymphs and fully engorged adults induced by dopamine or pilocarpine, respectively. Saliva was digested with trypsin for LC-MS/MS sequencing and peptides were searched against tick and rabbit sequences. RESULTS: A total of 275 proteins were identified, of which 135 were tick and 100 were rabbit proteins. Of the tick proteins, 30 proteins were identified exclusively in fully engorged nymph saliva, 74 in fully engorged adult females, and 31 were detected in both stages. The identified tick proteins include heme/iron metabolism-related proteins, oxidation/detoxification proteins, enzymes, proteinase inhibitors, tick specific protein families, and cytoskeletal proteins. Proteins involved in signal transduction, transport and metabolism of carbohydrate, energy, nucleotide, amino acids and lipids were also detected. Of the rabbit proteins, 13 were present in nymph saliva, 48 in adult saliva, and 30 were present in both. The host proteins include immunoglobulins, complement system proteins, antimicrobial proteins, serum albumin, peroxiredoxin, serotransferrin, apolipoprotein, hemopexin, proteinase inhibitors, and hemoglobin/red blood cells-related products. CONCLUSIONS: This study allows the identification of H. longicornis saliva proteins. In spontaneously detached tick saliva various proteins were identified, although results obtained with saliva of fully engorged ticks need to be carefully interpreted. However, it is interesting to note that proteins identified in this study were also described in other tick saliva proteomes using partially engorged tick saliva, including hemelipoprotein, proteases, protease inhibitors, proteins related to structural functions, transporter activity, metabolic processes, and others. In conclusion, these data can provide a deeper understanding to the biology of H. longicornis. PMID- 26104118 TI - Molecular targets and pathways involved in liver metastasis of colorectal cancer. AB - We here summarize the current view of molecular mechanisms involved in the dissemination process of colorectal cancer cells to the liver as deduced from preclinical models. We focus on molecular aspects of the current understanding of the biology of liver metastases formation and survival, both being crucial for identification and validation of possible therapeutic targets and review the latest findings elucidating some features of the liver as a metastatic niche. In more detail, we outline the role of proteases and of major pathways such asc-MET signaling and its modulation by factors such as MACC1 and TIMP1, as well as Notch and TGFbeta signaling. The relevance of these signalling pathways during tumor stroma interactions in this context will be addressed. In addition, the functional role and validation of targets such as PRL3, Trop-2, L1CAM, S100A4, S100P, CD133, LIPC, and APOBEC3G are summarized. PMID- 26104121 TI - Response to Girbes et al.: Investigating associations between ICU level and quality of care in the Netherlands: reporting only SMRs is not the whole story. PMID- 26104122 TI - ESGAR 2015 Book of Abstracts. PMID- 26104123 TI - Multidetector CT imaging of complications after laparoscopic nephron-sparing surgery. AB - PURPOSE: Laparoscopic nephron-sparing surgery (L-NSS) is increasingly performed to treat localised renal lesions. However, the associated morbidity is non negligible, with a rate of major complications approaching 10 %. METHODS AND RESULTS: This paper provides an overview of indications, surgical techniques and results of L-NSS; explains the incidence, risk factors and manifestations of postoperative complications; discusses the preferred multidetector computed tomography (CT) acquisition techniques; illustrates the appearance of normal postoperative images following L-NSS; and reviews, with example images, the most common and unusual iatrogenic complications. These include haematuria, haemorrhage, vascular injuries, infections and urinary leaks. Most emphasis is placed on CT, which provides rapid, reliable triage and follow-up of iatrogenic complications after L-NSS, identifying occurrences that require transarterial embolisation or repeated surgery. CONCLUSIONS: Multidetector CT allows precise assessment of the surgical resection site; detection of pneumoperitoneum and subcutaneous emphysema; quantification of retroperitoneal blood; and identification of active bleeding, pseudoaneurysms, arterio-venous fistulas, abscess collections and extravasated urine. TEACHING POINTS: * Laparoscopic nephron-sparing surgery (NSS) is increasingly performed to treat renal lesions. * Radiologists are increasingly requested to investigate suspected post-surgical NSS complications. * Post-NSS complications include haemorrhage, haematuria, vascular injuries, infections and urinary leaks. * Multidetector CT allows choice between conservative treatment, transarterial embolisation or surgery. PMID- 26104124 TI - Why is Pain Still Under-Treated in the Emergency Department? Two New Hypotheses. AB - Across the world, pain is under-treated in emergency departments (EDs). We canvass the literature testifying to this problem, the reasons why this problem is so important, and then some of the main hypotheses that have been advanced in explanation of the problem. We then argue for the plausibility of two new hypotheses: pain's under-treatment in the ED is due partly to (1) an epistemic preference for signs over symptoms on the part of some practitioners, and (2) some ED practices that themselves worsen pain by increasing patients' anxiety and fear. Our argument includes the following logic. Some ED practitioners depart from formal guidance in basing their acute pain assessments on observable features rather than on patient reports of pain. This is potentially due to an epistemic preference for signs over symptoms which aims to circumvent intentional and/or unintentional misrepresentation on the part of patients. However, conducting pain assessments in line with this epistemic preference contributes to the under-treatment of pain in at least three respects, which we detail. Moreover, it may do little to help the practitioner circumvent any intentional misrepresentation on the part of the patient, as we explain. Second, we examine at least four ED practices that may be contributing to the under-treatment of pain by increasing patient anxiety and fear, which can worsen pain. These practices include failing to provide orienting information and partially objectifying patients so as to problem-solve along lines pre-established by modern medical science. We conclude by touching on some potential solutions for ED practice. PMID- 26104125 TI - Cesarean section and the risk of emergency peripartum hysterectomy in high-income countries: a systematic review. AB - INTRODUCTION: Our objective was to determine the incidence and mortality rates associated with emergency peripartum hysterectomy, factors that lead to uncontrolled hemorrhage and emergency peripartum hysterectomy, and to determine the relationship between cesarean section and risk of emergency peripartum hysterectomy. MATERIALS AND METHODS: Studies published between January 1, 2000 and December 31, 2012 were identified using PubMed, OVID and Web of Science databases. Studies were included if they reported incidence rates for emergency peripartum hysterectomy, factors that lead to hemorrhage and emergency peripartum hysterectomy, or the association of emergency peripartum hysterectomy with cesarean section in high-income countries. RESULTS: Four hundred and fifty-one studies were identified, and 52 were included. The incidence of emergency peripartum hysterectomy ranged from 0.20 to 5.09 per 1000 deliveries with a median incidence rate of 0.61 per 1000 deliveries. These rates have increased over time. Rates varied by region/country, specifically with the United States reporting higher rates than North American, Asian, Oceania, and European countries. The most common factor leading to emergency peripartum hysterectomy was placental abnormalities. Both cesarean section and prior cesarean section were strong risk factors for emergency peripartum hysterectomy with higher risks conferred for each additional cesarean section. The mean percentage of maternal deaths for EPH survivors was 3.0 %. CONCLUSION: Given the association of cesarean section with emergency peripartum hysterectomy, the increased risk of emergency peripartum hysterectomy should be factored into the decision of whether to proceed with cesarean delivery, particularly for women who desire more children. PMID- 26104126 TI - Surgery, endometriosis-related infertility and negative impact on ovarian reserve: "which came first, the hen or the egg?" An unresolved dilemma. PMID- 26104127 TI - Relationship between preeclampsia, gestational hypertension, and vitamin D receptor (VDR) gene polymorphisms. PMID- 26104128 TI - Response to: relationship between preeclampsia, gestational hypertension, and vitamin D receptor (VDR) gene polymorphisms. PMID- 26104129 TI - Charge density waves in individual nanoribbons of orthorhombic-TaS3. AB - Orthorhombic-TaS3 is a quasi-1D material that undergoes a Peierls' transition to become a charge density wave conductor at low temperatures. Electrical transport measurements of individual single-crystalline TaS3 nanoribbons prepared by a novel bottom-up method from elemental precursors indicate a depression of the Peierls' ordering temperature to 205 K, broadening of the electric-field-induced depinning of the charge density wave below the Peierls' transition temperature, and a greatly increased threshold voltage for nucleation of charge density wave dislocations posited to be a result of surface confinement and finite size effects. Single-nanoribbon measurements of broad-band noise indicate discrete phase slip events near the depinning threshold. Three distinct regimes are identified with the normalized noise spectrum showing a distinctive maxima near the threshold voltage for depinning of the charge density wave, corresponding to sampling of different metastable states that balance ordered and sliding charge density waves. PMID- 26104130 TI - Triple decker sandwiches and related compounds of the first row transition metals with cyclopentadienyl and hexafluorobenzene rings: remarkable effects of fluorine substitution. AB - The complete series of Cp2M2(MU-C6F6) (M = Ti, V, Cr, Mn, Fe, Co, Ni) structures have been examined theoretically for comparison with their unsubstituted Cp2M2(MU C6H6) analogues. The singlet triple decker sandwich titanium complex Cp2Ti2(eta(6),eta(6)-C6F6) with a closed shell electronic structure and a non planar C6F6 ring is preferred energetically by a wide margin (>20 kcal mol(-1)) over other isomers and spin states. This is in contrast to the hydrogen analogue for which related triplet spin state structures are clearly preferred. A similar low-energy triple-decker sandwich Cp2V2(eta(6),eta(6)-C6F6) structure is found for vanadium but with a quintet spin state. The later transition metals from Cr to Ni energetically prefer the so-called "rice-ball" cis-Cp2M2(MU-C6F6) structures with varying hapticities of metal-ring bonding, a range of formal orders of metal-metal bonding, and varying spin states depending on the metal atom. Thus the lowest energy Cp2Cr2(MU-C6F6) structures are triplet and quintet structures with pentahapto-trihapto eta(5),eta(3)-MU-C6F6 rings and formal Cr=Cr double bonds. This contrasts with the structure of Cp2Cr2(MU-C6H6) having a bis(tetrahapto) eta(4),eta(4)-C6H6 ring and a formal Cr-Cr quadruple bond. The lowest energy Cp2Mn2(MU-C6F6) structures are trans and cis quintet spin state structures. This contrasts with Cp2Mn2(MU-C6H6) for which a closed-shell singlet triple decker sandwich structure is preferred. The lowest energy Cp2Fe2(MU-C6F6) structure is a triplet cis structure with a tetrahapto-dihapto eta(4),eta(2)-MU C6F6 ring and a formal Fe-Fe single bond. The lowest energy Cp2Co2(MU-C6F6) structures are singlet spin state structures with formal M-M single bonds and either bridging bis(trihapto) eta(3),eta(3)-C6F6 or tetrahapto-dihapto eta(4),eta(2)-C6F6 rings. For Cp2Ni2(MU-C6F6) low energy singlet cis and trans structures are both found. The singlet cis-Cp2Ni2(MU-C6F6) structure has a Ni-Ni single bond of length ~2.5 A and a bridging bis(dihapto) eta(2),eta(2)-C6F6 ligand with an uncomplexed C=C double bond. The singlet trans-Cp2Ni2(MU-C6F6) structure has a bis(trihapto) eta(3),eta(3)-C6F6 ligand. PMID- 26104131 TI - Cardiovascular disease among people with drug use disorders. AB - OBJECTIVES: To present the prevalence and incidence of cardiovascular disease (CVD) in a national cohort of patients seeking treatment for drug use disorders (DUD). METHODS: This is a longitudinal record linkage study of consecutive DUD treatment admissions between 2000 and 2006 from Denmark. RESULTS: Of 17,642 patients seeking treatment for DUD, 828 individuals (4.53%) had a history of CVD at treatment entry. Among the remaining patients, 16,820 were traced and 1535 new incident cases of CVD were observed during a mean follow-up time of 7.5 years. The incidence of CVD was associated with intravenous drug use [subhazard ratio (SHR) = 1.41, p < 0.001], not responding to injection question (SHR = 1.23, p = 0.005), older age (SHR = 1.04 per year, p = 0.000), use of prescription methadone (SHR = 1.32, p < 0.001), use of benzodiazepines (SHR = 1.21, p = 0.005), and being referred to methadone treatment (SHR = 1.15, p = 0.022). The use of amphetamines was negatively associated with the risk of CVD within this cohort (SHR = 0.75, p = 0.001). CONCLUSIONS: Patients injecting drugs using prescribed methadone were at elevated risk for cardiovascular disease and should be monitored for CVD. Opioid medications should be evaluated in terms of their cardiovascular sequelae. PMID- 26104132 TI - Positive HBcAb is associated with higher risk of early recurrence and poorer survival after curative resection of HBV-related HCC. AB - BACKGROUND & AIMS: Previous studies predicted the prognosis of hepatocellular carcinoma (HCC) mainly based on tumour-related factors, whereas the impacts of hepatitis B virus (HBV)-related factors are usually ignored. The objective of this exploratory study was to investigate the prognostic role of hepatitis B core antibody (HBcAb) on post-operative survival and recurrence of HCC. METHODS: A retrospective analysis of 3388 HBsAg positive (HBV-related) HCC patients treated by curative resection was performed. Multivariate analysis of independent prognostic factors was performed by Cox proportional hazards regression model. RESULTS: HBcAb positivity was an independent prognostic factor for recurrence free survival (RFS) of HBV-related patients (P < 0.001, HR: 1.723, 95% CI: 1.278 2.324), and the 1-, 3-, 5-year RFS rates for HBcAb-negative patients were significantly better than those of HBcAb-positive patients (92.5%, 72.1% and 65.9% vs 77.9%, 58.6% and 46.9%, P < 0.001). HBcAb-positive HCC was much bigger (P = 0.006), more often involved with vascular invasion (P = 0.001), elevated AFP (P = 0.001) and ALT (P = 0.046) levels, but less often involved with capsule formation (P = 0.034). Besides vascular invasion, tumour size, interferon-alpha treatment, AFP and GGT level, HBcAb positivity was an independent prognostic factor for early intrahepatic recurrence of HBV-related patients (P = 0.025, HR: 1.766, 95% CI: 1.073-2.907) and the majority of HBcAb-positive recurrence were early recurrence while most of HBcAb-negative recurrence were late recurrence (P = 0.004). CONCLUSION: Positive HBcAb may represent a more invasive phenotype of HBV-related HCC, and is associated with a higher risk of early intrahepatic recurrence and poorer RFS of HBV-related patients after curative resection. PMID- 26104133 TI - Effects of aortic irregularities on blood flow. AB - Anatomic aortic anomalies are seen in many medical conditions and are known to cause disturbances in blood flow. Turner syndrome (TS) is a genetic disorder occurring only in females where cardiovascular anomalies, particularly of the aorta, are frequently encountered. In this study, numerical simulations are applied to investigate the flow characteristics in four TS patient- related aortic arches (a normal geometry, dilatation, coarctation and elongation of the transverse aorta). The Quemada viscosity model was applied to account for the non Newtonian behavior of blood. The blood is treated as a mixture consisting of water and red blood cells (RBC) where the RBCs are modeled as a convected scalar. The results show clear geometry effects where the flow structures and RBC distribution are significantly different between the aortas. Transitional flow is observed as a jet is formed due to a constriction in the descending aorta for the coarctation case. RBC dilution is found to vary between the aortas, influencing the WSS. Moreover, the local variations in RBC volume fraction may induce large viscosity variations, stressing the importance of accounting for the non Newtonian effects. PMID- 26104134 TI - Light and electron microscopic studies of the intestinal epithelium in Notoplana humilis (Platyhelminthes, Polycladida): the contribution of mesodermal/gastrodermal neoblasts to intestinal regeneration. AB - Some free-living flatworms in the phylum Platyhelminthes possess strong regenerative capability that depends on putative pluripotent stem cells known as neoblasts. These neoblasts are defined based on several criteria, including their proliferative capacity and the presence of cellular components known as chromatoid bodies. Polyclads, which are marine flatworms, have the potential to be a good model system for stem cell research, yet little information is available regarding neoblasts and regeneration. In this study, transmission electron microscopy and immunostaining analyses, using antibodies against phospho histone H3 and BrdU, were used to identify two populations of neoblasts in the polyclad Notoplana humilis: mesodermal neoblasts (located in the mesenchymal space) and gastrodermal neoblasts (located within the intestine, where granular club cells and phagocytic cells are also located). Light and electron microscopic analyses also suggested that phagocytic cells and mesodermal/gastrodermal neoblasts, but not granular club cells, migrated into blastemas and remodeled the intestine during regeneration. Therefore, we suggest that, in polyclads, intestinal regeneration is accomplished by mechanisms underlying both morphallaxis (remodeling of pre-existing tissues) and epimorphosis (de novo tissue formation derived from mesodermal/gastrodermal neoblasts). Based on the assumption that gastrodermal neoblasts, which are derived from mesodermal neoblasts, are intestinal stem cells, we propose a model to study intestinal regeneration. PMID- 26104135 TI - SrGAP3 knockout mice display enlarged lateral ventricles and specific cilia disturbances of ependymal cells in the third ventricle. AB - In several mouse models of mental retardation, ventricular enlargements have been observed. Mutation in the SrGAP3 gene residing on chromosome 3p25 has previously been associated with intellectual disability in humans. In addition, SrGAP3 is related to Rho-GAPs signaling pathways, which play essential roles in the development and plasticity of the nervous system. About 10 % of postnatal homozygous SrGAP3-deficient mice die due to hydrocephalus, whereas the remaining mice survive into adulthood but display enlarged ventricles. We analyze the ventricular enlargement of these mice by performing a post-mortem MRI approach. We found a more than 15-fold enlargement of the lateral ventricles of homozygous SrGAP3-deficient mice. Moreover, we demonstrate that this phenotype was not accompanied by a stenosis of the aqueduct. Instead, SrGAP3 knockout mice displayed reduced densities of cilia of ependymal cells in These third ventricle compared to age-matched controls. This results indicate that the ventricular enlargement may be due to ciliopathy. PMID- 26104136 TI - Testicular Embolism After Endovascular Aneurysm Repair: A Rare Complication of Endovascular Repair of Abdominal Aortic Aneurysms. PMID- 26104137 TI - Anagen effluvium due to thallium poisoning derived from the intake of Chinese herbal medicine and rodenticide containing thallium salts. PMID- 26104138 TI - Developing a theoretical maintenance model for disordered eating in Type 1 diabetes. AB - BACKGROUND: According to the literature, eating disorders are an increasing problem for more than a quarter of people with Type 1 diabetes and they are associated with accentuated diabetic complications. The clinical outcomes in this group when given standard eating disorder treatments are disappointing. The Medical Research Council guidelines for developing complex interventions suggest that the first step is to develop a theoretical model. AIM: To review existing literature to build a theoretical maintenance model for disordered eating in people with Type 1 diabetes. METHOD: The literature in diabetes relating to models of eating disorder (Fairburn's transdiagnostic model and the dual pathway model) and food addiction was examined and assimilated. RESULTS: The elements common to all eating disorder models include weight/shape concern and problems with mood regulation. The predisposing traits of perfectionism, low self-esteem and low body esteem and the interpersonal difficulties from the transdiagnostic model are also relevant to diabetes. The differences include the use of insulin mismanagement to compensate for breaking eating rules and the consequential wide variations in plasma glucose that may predispose to 'food addiction'. Eating disorder symptoms elicit emotionally driven reactions and behaviours from others close to the individual affected and these are accentuated in the context of diabetes. CONCLUSION: The next stage is to test the assumptions within the maintenance model with experimental medicine studies to facilitate the development of new technologies aimed at increasing inhibitory processes and moderating environmental triggers. PMID- 26104139 TI - Effect of diet/atorvastatin on atherosclerotic lesions associated to nonalcoholic fatty liver disease in chickens. AB - Comparative histological examination of both liver and the supra-aortic arteries have not previously examined the consequences of atherosclerosis and nonalcoholic fatty liver disease (NAFLD), and their response to diet and atorvastatin therapy. This study evaluates the effects of diet alone or in combination with atorvastatin therapy on the progression/regression of atherosclerosis and its correlation with NAFLD. This research was performed on a cohort of chickens on standard (SD) or hyperlipidemic diets (HD), either with or without atorvastatin therapy. The development of atherosclerotic lesions was assessed by histology, immunohistochemistry and quantitative image analysis and correlated with liver histology. The lowest levels of atherosclerotic lesions were found in animals on the HD for 3 months, followed by 3 months of SD in combination with oral atorvastatin. There was a strong association between the histologic findings of atherosclerosis and those of NAFLD. These studies show that standard diet and atorvastatin therapy can positively affect both arterial and hepatic lesions, influencing the regression of the changes. These results support the hypothesis that NAFLD and atherosclerosis may be actually two aspects of a shared disease and suggest the possibility of regression of both disorders with dietary and pharmacologic manipulations. PMID- 26104140 TI - Enantiomer-specific analysis of multi-component mixtures by correlated electron imaging-ion mass spectrometry. AB - Simultaneous, enantiomer-specific identification of chiral molecules in multi component mixtures is extremely challenging. Many established techniques for single-component analysis fail to provide selectivity in multi-component mixtures and lack sensitivity for dilute samples. Here we show how enantiomers may be differentiated by mass-selected photoelectron circular dichroism using an electron-ion coincidence imaging spectrometer. As proof of concept, vapours containing ~1% of two chiral monoterpene molecules, limonene and camphor, are irradiated by a circularly polarized femtosecond laser, resulting in multiphoton near-threshold ionization with little molecular fragmentation. Large chiral asymmetries (2-4%) are observed in the mass-tagged photoelectron angular distributions. These asymmetries switch sign according to the handedness (R- or S ) of the enantiomer in the mixture and scale with enantiomeric excess of a component. The results demonstrate that mass spectrometric identification of mixtures of chiral molecules and quantitative determination of enantiomeric excess can be achieved in a table-top instrument. PMID- 26104142 TI - Xiakemycin A, a novel pyranonaphthoquinone antibiotic, produced by the Streptomyces sp. CC8-201 from the soil of a karst cave. PMID- 26104141 TI - Development of a multiplex PCR system and its application in detection of blaSHV, blaTEM, blaCTX-M-1, blaCTX-M-9 and blaOXA-1 group genes in clinical Klebsiella pneumoniae and Escherichia coli strains. AB - Resistance to beta-lactam antibiotics through beta-lactamase production by Enterobacteriaceae continues to burden the health-care sector worldwide. Traditional methods for detection of beta-lactamases are time-consuming and labor intensive and newer methods with varying capabilities continue to be developed. The objective of this study was to develop a multiplex PCR (M-PCR) system for the detection of blaSHV, blaTEM, blaCTX-M-1, blaCTX-M-9 and blaOXA-1 group genes and to apply it in clinical Klebsiella pneumoniae and Escherichia coli strains. To do this, we used group-specific PCR primers in singleplex reactions followed by optimization into multiplex reactions. Specificity and sensitivity of the M-PCR were then evaluated using 58 reference strains before its application to detect bla group genes in 203 clinical Enterobacteriaceae strains. PCR amplicons were sequenced to determine the beta-lactamase subtypes. The M-PCR system exhibited 100% specificity and sensitivity. In all, 83.7% of K. pneumoniae and 89.8% of E. coli clinical strains harbored bla group genes with 46.9%, 40.1%, 15.0%, 21.1% and 6.1% of K. pneumoniae having blaSHV, blaTEM, blaCTX-M-1, blaCTX-M-9 and blaOXA-1 group genes, respectively, whereas 12.2%, 77.6%, 22.4%, 36.7% and 8.2% of E. coli had blaSHV, blaTEM, blaCTX-M-1, blaCTX-M-9 and blaOXA-1 group genes, respectively. BlaSHV-1, blaSHV-11, blaSHV-27, blaSHV-33, blaSHV-144, blaTEM-1, blaTEM-135, blaOXA-1, blaCTX-M-3, blaCTX-M-9, blaCTX-M-14, blaCTX-M-15, blaCTX-M 27, blaCTX-M-55, blaCTX-M-65 and blaCTX-M-104 were detected. In conclusion, the M PCR system was efficient and versatile with an advantage of simultaneously detecting all the targeted bla group genes. Hence, it is a potential candidate for developing M-PCR kits for the screening of these genes for clinical or epidemiological purposes. PMID- 26104143 TI - Abnormal ABO typing. PMID- 26104144 TI - Prediction of structural features and application to outer membrane protein identification. AB - Protein three-dimensional (3D) structures provide insightful information in many fields of biology. One-dimensional properties derived from 3D structures such as secondary structure, residue solvent accessibility, residue depth and backbone torsion angles are helpful to protein function prediction, fold recognition and ab initio folding. Here, we predict various structural features with the assistance of neural network learning. Based on an independent test dataset, protein secondary structure prediction generates an overall Q3 accuracy of ~80%. Meanwhile, the prediction of relative solvent accessibility obtains the highest mean absolute error of 0.164, and prediction of residue depth achieves the lowest mean absolute error of 0.062. We further improve the outer membrane protein identification by including the predicted structural features in a scoring function using a simple profile-to-profile alignment. The results demonstrate that the accuracy of outer membrane protein identification can be improved by ~3% at a 1% false positive level when structural features are incorporated. Finally, our methods are available as two convenient and easy-to-use programs. One is PSSM 2-Features for predicting secondary structure, relative solvent accessibility, residue depth and backbone torsion angles, the other is PPA-OMP for identifying outer membrane proteins from proteomes. PMID- 26104145 TI - Polymorphisms in a desaturase 2 ortholog associate with cuticular hydrocarbon and male mating success variation in a natural population of Drosophila serrata. AB - Elucidating the nature of genetic variation underlying both sexually selected traits and the fitness components of sexual selection is essential to understanding the broader consequences of sexual selection as an evolutionary process. To date, there have been relatively few attempts to connect the genetic variance in sexually selected traits with segregating DNA sequence polymorphisms. We set out to address this in a well-characterized sexual selection system--the cuticular hydrocarbons (CHCs) of Drosophila serrata--using an indirect association study design that allowed simultaneous estimation of the genetic variance in CHCs, sexual fitness and single nucleotide polymorphism (SNP) effects in an outbred population. We cloned and sequenced an ortholog of the D. melanogaster desaturase 2 gene, previously shown to affect CHC biosynthesis in D. melanogaster, and associated 36 SNPs with minor allele frequencies > 0.02 with variance in CHCs and sexual fitness. Three SNPs had significant multivariate associations with CHC phenotype (q-value < 0.05). At these loci, minor alleles had multivariate effects on CHCs that were weakly associated with the multivariate direction of sexual selection operating on these traits. Two of these SNPs had pleiotropic associations with male mating success, suggesting these variants may underlie responses to sexual selection due to this locus. There were 15 significant male mating success associations (q-value < 0.1), and interestingly, we detected a nonrandom pattern in the relationship between allele frequency and direction of effect on male mating success. The minor-frequency allele usually reduced male mating success, suggesting a positive association between male mating success and total fitness at this locus. PMID- 26104146 TI - Temporal tweezing of light through the trapping and manipulation of temporal cavity solitons. AB - Optical tweezers use laser light to trap and move microscopic particles in space. Here we demonstrate a similar control over ultrashort light pulses, but in time. Our experiment involves temporal cavity solitons that are stored in a passive loop of optical fibre pumped by a continuous wave 'holding' laser beam. The cavity solitons are trapped into specific time slots through a phase modulation of the holding beam, and moved around in time by manipulating the phase profile. We report both continuous and discrete manipulations of the temporal positions of picosecond light pulses, with the ability to simultaneously and independently control several pulses within a train. We also study the transient drifting dynamics and show complete agreement with theoretical predictions. Our study demonstrates how the unique particle-like characteristics of cavity solitons can be leveraged to achieve unprecedented control over light. These results could have significant ramifications for optical information processing. PMID- 26104148 TI - Open synovectomy of the ankle joint in young haemophiliacs: mid-term to long- term results of a single-centre series of 32 procedures. AB - INTRODUCTION: In haemophiliacs, recurrent hemarthrosis and chronic synovitis lead to chronic arthropathy. Synovectomy is indicated when medical treatment fails. Few studies report the results of open synovectomy of the ankle in haemophiliacs with a small number of procedures and also a limited follow-up. AIM: The aim of this paper is to report the long-term results of open surgical synovectomy of the tibio-talar joint. METHODS: Thirty-two open synovectomies were performed in 21 young haemophiliacs in the same haemophilia center using an antero-lateral and postero-medial approaches. The median follow-up was 15.4 years. Clinical (Petrini scores) and radiological evaluations (Pettersson scores) were made preoperatively and at each multidisciplinary follow-up visit. Wilcoxon and Spearman's tests were used for the statistical analysis. RESULTS: Preoperative median Petrini score was 6 (range 3-12), and improved at 2 and 5 years follow-up (P = 0.0003 and P = 0.0001 respectively). At 10 and 15 years follow-ups, median score remained below preoperative score (median 3.5, range 0-11). Ten ankles had a follow-up of more than 20 years. Preoperative median Petterson score presented a slight but continuous worsening in the first 2 and 5 years of follow-ups (P = 0.02, P = 0.003), but not correlation between clinical and radiological results was observed. CONCLUSION: Our long-term results support that clinical scores are improved even if radiological scores progress. Open synovectomy retards the progression of the arthropathy, but not stops it. Bleeding and pain are controlled and even if recurrence of bleedings is frequent, it is less severe, less painful and requiring less factors replacement. PMID- 26104147 TI - Experience with central venous access devices (CVADs) in the Canadian hemophilia primary prophylaxis study (CHPS). AB - INTRODUCTION: Haemophilia A treatment with factor VIII concentrates requires frequent venipunctures; a central venous access device (CVAD) may be required to facilitate reliable venous access, especially in young children. While CVADs provide reliable venous access, complications such as infection and thrombosis may occur. AIM: The aim of this study was to assess CVAD use in the Canadian Hemophilia Primary Prophylaxis Study (CHPS), a single-arm, multi-centre prospective study whereby factor use is tailored to individual prophylactic need. METHODS: Participants received a tailored, escalating dose, prophylaxis regimen of increasing frequency of FVIII infusions: step-1: 50 IU kg(-1) once weekly; step-2: 30 IU kg(-1) twice weekly; and step-3: 25 IU kg(-1) on alternate days, according to their level of bleeding. CVAD insertion was at the discretion of the local health care team. Details regarding CVAD use during this protocol were analysed. RESULTS: Fifty six boys were enrolled, 21 required 25 CVADs due to difficult venous access. CVADs were inserted at a median age of 1.3 years (range: 0.6-2.1) and were removed at a median age of 8.7 years (range 6.3-11.8). Six participants experienced non-life threatening CVAD-complications, the most frequent being device malfunction requiring CVAD replacement (n = 4). Two boys were shown to have CVAD-associated thrombosis detected on routine imaging; one required removal due to infusion difficulties and the other was asymptomatic and did not require device removal. No CVAD-related infections were documented. CONCLUSION: Our study shows that the CHPS tailored prophylaxis regimen is associated with a decreased requirement for CVADs and with few device-related complications. PMID- 26104149 TI - Commentary on: Sex Offenders Seeking Treatment for Sexual Dysfunction--Ethics, Medicine, and the Law. PMID- 26104150 TI - Islet heparan sulfate but not heparan sulfate proteoglycan core protein is lost during islet isolation and undergoes recovery post-islet transplantation. AB - Islet beta cells in situ express intracellular heparan sulfate (HS), a property previously shown in vitro to be important for their survival. We report that HS levels inside islet beta cells correlate with the novel intracellular localization of the HSPG core proteins for collagen type XVIII (Col18), a conventional extracellular matrix component. Syndecan-1 (Sdc1) and CD44 core proteins were similarly localized inside beta cells. During isolation, mouse islets selectively lose HS to 11-27% of normal levels but retain their HSPG core proteins. Intra-islet HS failed to recover substantially during culture for 4 days and was not reconstituted in vitro using HS mimetics. In contrast, significant recovery of intra-islet HS to ~40-50% of normal levels occurred by 5 10 days after isotransplantation. Loss of islet HS during the isolation procedure is independent of heparanase (a HS-degrading endoglycosidase) and due, in part, to oxidative damage. Treatment with antioxidants reduced islet cell death by ~60% and increased the HS content of isolated islets by ~twofold compared to untreated islets, preserving intra-islet HS to ~60% of the normal HS content of islets in situ. These findings suggest that the preservation of islet HS during the islet isolation process may optimize islet survival posttransplant. PMID- 26104152 TI - Determinants of dietary behavior and physical activity among Canadian Inuit: a systematic review. AB - BACKGROUND: Increased dependence on Western diets and low physical activity have largely contributed to weight gain and associated chronic diseases in the Canadian Inuit population. The purpose of this study was to systematically review factors influencing dietary and physical activity behaviors to guide health promotion interventions and provide recommendations for future studies. METHOD: We conducted a systematic literature review to identify relevant articles. Searches were conducted between May 2014 and July 2014, and inclusive of articles published up until July 2014. Articles were searched using four databases: PubMed, PsycINFO, SocINDEX, and Psychology and Behavioral Sciences Collection. Eligible studies focused on diet and/or physical activity or determinants of diet and/or physical activity in Canadian Inuit population, and were published in English. RESULTS: A total of 45 articles were included in the analysis. A detailed appraisal of the articles suggested that many Inuit have disconnected from the traditional ways of life, including harvesting and processing of traditional food species and the associated physical activity. In the last two decades there has been a significant shift from consumption of healthy traditional foods to energy-dense store-bought foods particularly among younger Inuit (<50 years of age). Additionally, low socioeconomic status (SES) and high transportation cost affect food accessibility and contribute to poor dietary choices in the population. However, a few articles that described the mediating role of psychosocial factors reported that higher SES, increased healthful food knowledge, and self-efficacy towards healthy dietary behavior, were associated with greater intentions to make healthier food choices and participate in physical activity. CONCLUSION: It is evident that the rapid social, cultural, and environmental changes in the Arctic have altered dietary and physical activity behaviors of Canadian Inuit. However, our understanding is limited on how these behaviours might be influenced in the face of these changes. Prospective studies are needed to advance our knowledge of cognitive and environmental determinants of Inuit energy balance-related behaviours. These studies can inform the development of health promotion interventions in the population. PMID- 26104153 TI - Initial combination anti-viral therapy with lamivudine and adefovir dipivoxil decreases short-term fatality rate of hepatitis-B-virus-related acute-on-chronic liver failure. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is a common serious hepatitis B virus (HBV)-related disease and has a poor prognosis. Until recently, initial combination antiviral treatment in ACLF patients was rarely reported. This study evaluated the effect of initial combination treatment with lamivudine and adefovir dipivoxil on the prognosis of HBV-related ACLF. METHODS: In this retrospective study, 131 eligible ACLF patients, including 61 treated with 100 mg lamivudine and 10 mg adefovir dipivoxil daily and 70 not treated with any nucleoside analogs (NAs), were selected and assigned into the NA and non-NA groups. All the patients received standard medicinal therapy. At weeks 0-4 and 12, serum markers for hepatic and renal functions were measured in all patients and accumulated fatality rates were calculated. Statistical analyses, including Student's t test, chi(2) test and unconditional logistic regression analysis, were performed using SPSS version 17.0 software. RESULTS: Clinical data indicated that improvement of hepatic function was better in the NA than in the non-NA group. The accumulated fatality rate in the NA group was lower than in the non-NA group at weeks 2-4 and 12, and these differences were significant. Univariate analysis showed that age, prothrombin activity, model of end-stage liver disease (MELD) score, and treatment without NAs were risk factors for short-term survival of ACLF. Further research by unconditional logistic regression analysis identified that older age, high MELD score and treatment without NAs were independent risk factors for short-term survival of ACLF. CONCLUSIONS: Initial combination antiviral treatment is effective in decreasing short-term fatality of HBV-related ACLF. PMID- 26104154 TI - The complete mitochondrial genome of the medicinal fungus Ganoderma applanatum (Polyporales, Basidiomycota). AB - We have determined the complete nucleotide sequence of the mitochondrial genome of the medicinal fungus Ganoderma applanatum (Pers.) Pat. using the next generation sequencing technology. The circular molecule is 119,803 bp long with a GC content of 26.66%. Gene prediction revealed genes encoding 15 conserved proteins, 25 tRNAs, the large and small ribosomal RNAs, all genes are located on the same strand except trnW-CCA. Compared with previously sequenced genomes of G. lucidum, G. meredithiae and G. sinense, the order of the protein and rRNA genes is highly conserved; however, the types of tRNA genes are slightly different. The mitochondrial genome of G. applanatum will contribute to the understanding of the phylogeny and evolution of Ganoderma and Ganodermataceae, the group containing many species with high medicinal values. PMID- 26104151 TI - Characteristics of natural antibody-secreting cells. AB - Natural IgM plays a critical role in protection from pathogens and the prevention of autoimmunity. While its importance has been shown in many different settings, its origins are incompletely understood. This review focuses on the properties of the natural IgM antibody-secreting cells (ASCs), which arise mainly from the B-1 cell lineage. B-1 cells are generated in multiple waves during development, mostly in the fetal and early postfetal periods. The developmental time points can affect their repertoire: prenatal B-1 cells express a mainly germ line encoded repertoire, while postnatally developing B-1 cells can express Ig with a greater degree of variation. Spleen and bone marrow, but not the body cavities, are primary sites of natural IgM secretion. Within these tissues heterogeneous populations of IgM ASCs can be found. While some ASCs express classical markers of B-1 lymphocytes, others express those of terminally differentiated plasma cells. A better understanding of the properties of these different natural IgM ASCs could aid their future therapeutic exploitation. PMID- 26104155 TI - Hints for panmixia in Scomberomorus commerson in Indian waters revealed by mitochondrial ATPase 6 and 8 genes. AB - Scomberomorus commerson is an economically important migratory fish distributed worldwide. The genetic stock structure of S. commerson distributed along the Indian waters was identified using mitochondrial ATPase 6 and 8 genes. A total of 842 bp sequence of ATPase 6/8 genes obtained in this study revealed 23 haplotypes with mean low nucleotide diversity and high haplotype diversity. Co-efficient of genetic differentiation (FST) values obtained for pair wise populations were low and non-significant with an overall value of -0.02074. The high haplotype and low nucleotide diversity values together with mismatch distribution analysis suggested a history of genetic bottleneck events or founder effect, with subsequent population expansion in S. commerson. The findings of the present study indicated the panmixia nature of the species which can be managed as a unit stock in Indian waters. PMID- 26104156 TI - Two complete chloroplast genome sequences of Cannabis sativa varieties. AB - In this study, we determined the complete chloroplast (cp) genomes from two varieties of Cannabis sativa. The genome sizes were 153,848 bp (the Korean non drug variety, Cheungsam) and 153,854 bp (the African variety, Yoruba Nigeria). The genome structures were identical with 131 individual genes [86 protein-coding genes (PCGs), eight rRNA, and 37 tRNA genes]. Further, except for the presence of an intron in the rps3 genes of two C. sativa varieties, the cp genomes of C. sativa had conservative features similar to that of all known species in the order Rosales. To verify the position of C. sativa within the order Rosales, we conducted phylogenetic analysis by using concatenated sequences of all PCGs from 17 complete cp genomes. The resulting tree strongly supported monophyly of Rosales. Further, the family Cannabaceae, represented by C. sativa, showed close relationship with the family Moraceae. The phylogenetic relationship outlined in our study is well congruent with those previously shown for the order Rosales. PMID- 26104157 TI - The complete mitochondrial genome of bearded pig, Sus barbatus, and comparative mitochondrial genomics of Cetartiodactyla. AB - In this study, the complete mitochondrial genome sequence of bearded pig, Sus barbatus, with the total length of 16,480 bp, is determined for the first time. This mitogenome harbors 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and one control region (D-loop). The overall base composition is A (34.80%), C (26.07%), G (13.12%), and T (26.01%), so the slight A-T bias (60.81%) was detected. Most of the genes are distributed on the H strand, except for the ND6 subunit gene and eight tRNA genes. To obtain the phylogenetic relationship of the Cetartiodactyla, 11 mitochondrial genomes were used for phylogenetic analysis. The mitochondrial genome of S. barbatus presented here will contribute to a better understanding of the population genetics. PMID- 26104159 TI - Multiplexed pyrosequencing of nine sea anemone (Cnidaria: Anthozoa: Hexacorallia: Actiniaria) mitochondrial genomes. AB - Six complete and three partial actiniarian mitochondrial genomes were amplified in two semi-circles using long-range PCR and pyrosequenced in a single run on a 454 GS Junior, doubling the number of complete mitogenomes available within the order. Typical metazoan mtDNA features included circularity, 13 protein-coding genes, 2 ribosomal RNA genes, and length ranging from 17,498 to 19,727 bp. Several typical anthozoan mitochondrial genome features were also observed including the presence of only two transfer RNA genes, elevated A + T richness ranging from 54.9 to 62.4%, large intergenic regions, and group 1 introns interrupting NADH dehydrogenase subunit 5 and cytochrome c oxidase subunit I, the latter of which possesses a homing endonuclease gene. Within the sea anemone Alicia sansibarensis, we report the first mitochondrial gene order rearrangement within the Actiniaria, as well as putative novel non-canonical protein-coding genes. Phylogenetic analyses of all 13 protein-coding and 2 ribosomal genes largely corroborated current hypotheses of sea anemone interrelatedness, with a few lower-level differences. PMID- 26104158 TI - Complete mitochondrial genome of the Loligo duvaucelii. AB - In this study, we determined the complete mitochondrial genome of the little squid (Loligo duvaucelii). The genome is 17,413 bp in length, containing 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 3 main non coding regions. The overall base composition of L. duvaucelii is 40.01% A, 32.33% T, 19.14% C and 8.52% G, with a high A + T bias of 72.34%. All of the three control regions (CR) contain termination-associated sequences and conserved sequence blocks. Here, we describe a phylogenetic analysis of 10 species of Cephalopoda based on the complete mitochondrial genome, the result showed that the Loliolus uyii is most closely related to L. duvaucelii. This mitogenome sequence data would play an important role in the investigation of phylogenetic relationship, taxonomic resolution and phylogeography of the Cephalopoda. PMID- 26104161 TI - Introduction: Atomism and Organic Chemistry in Context: Essays in Honour of Alan J. Rocke. PMID- 26104160 TI - Small RNAs in metastatic and non-metastatic oral squamous cell carcinoma. AB - BACKGROUND: Small non-coding regulatory RNAs control cellular functions at the transcriptional and post-transcriptional levels. Oral squamous cell carcinoma is among the leading cancers in the world and the presence of cervical lymph node metastases is currently its strongest prognostic factor. In this work we aimed at finding small RNAs expressed in oral squamous cell carcinoma that could be associated with the presence of lymph node metastasis. METHODS: Small RNA libraries from metastatic and non-metastatic oral squamous cell carcinomas were sequenced for the identification and quantification of known small RNAs. Selected markers were validated in plasma samples. Additionally, we used in silico analysis to investigate possible new molecules, not previously described, involved in the metastatic process. RESULTS: Global expression patterns were not associated with cervical metastases. MiR-21, miR-203 and miR-205 were highly expressed throughout samples, in agreement with their role in epithelial cell biology, but disagreeing with studies correlating these molecules with cancer invasion. Eighteen microRNAs, but no other small RNA class, varied consistently between metastatic and non-metastatic samples. Nine of these microRNAs had been previously detected in human plasma, eight of which presented consistent results between tissue and plasma samples. MiR-31 and miR-130b, known to inhibit several steps in the metastatic process, were over-expressed in non-metastatic samples and the expression of miR-130b was confirmed in plasma of patients showing no metastasis. MiR-181 and miR-296 were detected in metastatic tumors and the expression of miR-296 was confirmed in plasma of patients presenting metastasis. A novel microRNA-like molecule was also associated with non-metastatic samples, potentially targeting cell-signaling mechanisms. CONCLUSIONS: We corroborate literature data on the role of small RNAs in cancer metastasis and suggest the detection of microRNAs as a tool that may assist in the evaluation of oral squamous cell carcinoma metastatic potential. PMID- 26104162 TI - Atomic Theory and Multiple Combining Proportions: The Search for Whole Number Ratios. AB - John Dalton's atomic theory, with its postulate of compound formation through atom-to-atom combination, brought a new perspective to weight relationships in chemical reactions. A presumed one-to-one combination of atoms A and B to form a simple compound AB allowed Dalton to construct his first table of relative atomic weights from literature analyses of appropriate binary compounds. For such simple binary compounds, the atomic theory had little advantages over affinity theory as an explanation of fixed proportions by weight. For ternary compounds of the form AB2, however, atomic theory made quantitative predictions that were not deducible from affinity theory. Atomic theory required that the weight of B in the compound AB2 be exactly twice that in the compound AB. Dalton, Thomas Thomson and William Hyde Wollaston all published within a few years of each other experimental data that claimed to give the predicted results with the required accuracy. There are nonetheless several experimental barriers to obtaining the desired integral multiple proportions. In this paper I will discuss replication experiments which demonstrate that only Wollaston's results are experimentally reliable. It is likely that such replicability explains why Wollaston's experiments were so influential. PMID- 26104163 TI - Chemical Research and Instruction in Zurich, 1833-1872. AB - The development of universities and technical schools in nineteenth century Switzerland is commonly assumed to be similar to the development of comparable schools in Germany. To a large extent this is correct, but there are subtle differences in the founding and organization of Swiss institutions that are reflective of the Swiss national and local cantonal contexts. In the case of Zurich, the specific local political and financial conditions underlying the formation of the University of Zurich, the Zurich Cantonal School and the Swiss Federal Polytechnic resulted in a complex set of dual appointments and shared facilities that were absent at comparable chemical laboratories at German universities. This essay outlines the origins of these complex relationships under Carl Lowig (1833-1853) and Georg Stadeler (1853-1870) and follows in more detail the complex career path of Johannes Wislicenus in Zurich from his appointment as Privatdozent in 1860 to his appointment as Director of the Polytechnic in 1871. Wislicenus' career path illustrates the institutional context of chemistry in Zurich and shows how this context, including the roles of cantonal and federal support, and the physical constraints created by shared laboratory facilities, shaped chemical research and instruction in Zurich. PMID- 26104164 TI - Chemical Identity Crisis: Glass and Glassblowing in the Identification of Organic Compounds. AB - This essay explains why and how nineteenth-century chemists sought to stabilize the melting and boiling points of organic substances as reliable characteristics of identity and purity and how, by the end of the century, they established these values as 'Constants of Nature'. Melting and boiling points as characteristic values emerge from this study as products of laboratory standardization, developed by chemists in their struggle to classify, understand and control organic nature. A major argument here concerns the role played by the introduction of organic synthesis in driving these changes. Synthetic organic chemistry vastly increased the number of known organic substances, precipitating the chemical identity crisis of my title. Successful natural product synthesis, moreover, depended on chemists' ability to demonstrate the absolute identity of synthetic product and natural target--something late nineteenth-century chemists eventually achieved by making reliable, replicable melting and boiling point measurements. In the period before the establishment of national standards laboratories, chemists and scientific glassblowers worked together to standardize melting and boiling points as physical constants, such collaborations highlighting the essential importance of chemical glassware and glassblowing skill in the development of nineteenth-century organic chemistry. PMID- 26104165 TI - William Barlow and the Determination of Atomic Arrangement in Crystals. AB - William Barlow (1845-1934) was an important if unconventional scientist, known for having developed the 'closest-packing' atomic models of crystal structure. He resumed an early nineteenth-century tradition of utilizing crystallographical and chemical data to determine atomic arrangements in crystals. This essay recounts Barlow's career and scientific activity in three parts: (a) His place in the tradition of determining atomic arrangement in context of this earlier tradition and of contemporaneous developments of crystallography and chemistry, (b) his unconventional career, and (c) the 'success' of his program to determine atomic arrangements in crystals and its influence on the work of William Lawrence Bragg. PMID- 26104166 TI - Dilemmas of 19th-century Liberalism among German Academic Chemists: Shaping a National Science Policy from Hofmann to Fischer, 1865-1919. AB - This paper's primary goal is to compare the personalities, values, and influence of August Wilhelm Hofmann and Emil Fischer as exemplars and acknowledged leaders of successive generations of the German chemical profession and as scientists sharing a 19th-century liberal, internationalist outlook from the German wars of unification in the 1860s to Fischer's death in 1919 in the aftermath of German defeat in World War I. The paper will consider the influence of Hofmann and Fischer on the shaping of national scientific institutions in Germany, from founding of the German Chemical Society in 1867 to the first institutes of the Kaiser Wilhelm Society founded in 1911, their academic leadership in other areas including the shaping of a successful academic-industrial symbiosis in organic chemistry, and finally their response to war as a force disruptive of scientific internationalism. All of these developments posed serious dilemmas, exacerbated by emerging strains of nationalism and anti-Semitism in German society. Whereas Hofmann's lifework came to a relatively successful end in 1892, Fischer was not so fortunate, as the war brought him heavy responsibilities and terrible personal losses, but with no German victory and no peace of reconciliation--a bleak end for Fischer and the 19th-century liberal ideals that had inspired him. PMID- 26104167 TI - Benzene and Beyond: Pursuing the Core of Aromaticity. AB - Kekule first suggested a hexagonal structure for benzene in 1865. For over a half century after, chemists struggled to reconcile proposed structures for benzene and other aromatic compounds with their resistance to chemical transformation and tendency to maintain the type during reaction. The combined structural and reactivity features of these compounds were eventually covered by the term 'aromaticity'. Kekule, Bamberger and Thiele had each proposed a criterion for aromaticity; all were either empirically contradicted or incapable of evaluation. In the 1930s, two rival quantum mechanical methods succeeded in establishing a physical basis for aromaticity. Using valence bond theory, Pauling attributed benzene's stability to its being a resonance hybrid of several Lewis structures. Calculating resonance energies was challenging but manipulating Lewis structures was not; that procedure provided qualitative insights into aromatic structure and reactivity. Resonance theory appealed especially to organic chemists and eclipsed Huckel's contemporaneous molecular orbital approach, which remained relatively inaccessible. In the 1950s, however, simple rules derived from Huckel's mathematics, combined with proton NMR data, provided seemingly universal criteria for aromaticity. In the event, post-1950 discoveries of non-organic, three dimensional compounds such as ferrocene and the fullerenes that exhibit aromatic properties led chemists to doubt the utility and universality of 'aromaticity' as a concept. A recent consensus maintains that aromaticity is a multi-variable phenomenon that cannot be reduced to a strict definition, a property it shares with other core chemical concepts such as 'acidity' and 'reactivity'. PMID- 26104168 TI - Today, Will T.H. Huxley Dig the Garden or Paper the Parlour? PMID- 26104175 TI - Quantitative Assessment of Mitral Apparatus Geometry Using Dual-Source Computed Tomography in Mitral Regurgitation. AB - To quantitatively assess the geometric changes in mitral valve apparatus in mitral regurgitation (MR) by dualsource computed tomography (DSCT) and to analyze its impact on MR.The study subjects consisted of 20 controls, 20 patients with mild MR, and 30 patients with moderate to severe MR, all of whom underwent DSCT. The geometric parameters of the mitral valve were measured by CT and compared among the 3 groups. The correlations between DSCT measurements and MR severity were also analyzed.As regurgitation worsened, our results showed progressive enlargements of the mitral annular area, anteroposterior diameter, and mitral valve tenting area at the central level. Moreover, a higher mitral valve sphericity index and longer distance between the heads of the papillary muscles reflected a more outward displacement of the papillary muscles. The mitral annular area and tenting area at the central level had strong correlations with regurgitation severity.DSCT is available to quantitatively assess mitral valve morphology and provide additional information regarding its geometry. The mitral annular area and tenting area at the central level were the strongest determinants of MR severity. PMID- 26104176 TI - Association Between Genetic Variation in the SCN10A Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy. AB - Arrhythmias are associated with reduced quality of life and poor prognosis in patients with hypertrophic cardiomyopathy (HCM). Recent genome-wide association studies revealed that a nonsynonymous single nucleotide polymorphism, rs6795970, in the SCN10A gene was associated with the PR interval. We examined whether the PR prolonging allele (A allele) in the SCN10A gene may be associated with cardiac conduction abnormalities in HCM patients.We genotyped the polymorphism in 149 HCM patients. Conduction abnormalities were defined as first-degree heart block, bundle-branch block, and bifascicular heart block. Patients were divided into two groups: group A consisted of 122 patients (82%) without a conduction abnormality; and group B consisted of 27 patients (18%) with one or more cardiac conduction abnormalities. The frequency distribution of the SCN10A genotypes (G/G, G/A, and A/A) among the patients with HCM was 71%, 26%, and 3%, respectively. A cardiac conduction abnormality was documented in 9% with G/G and 40% with G/A or A/A. There was a significant difference in the genotype distribution between the two groups (P = 0.0002). In the dominant A allele model, there was a significant difference in genotypes between the two groups (P < 0.0001). In addition, the A allele remained significant after adjusting for other covariates in a multivariate model (odds ratio = 6.30 [95% confidence interval: 2.24 to 19.09], P = 0.0005).The rs6795970 in the SCN10A gene, which is reported to carry a high risk of heart block, might be associated with cardiac conduction abnormalities in HCM patients. PMID- 26104177 TI - Reversible Cardiomyopathy After Epirubicin Administration. AB - Anthracycline-containing chemotherapy can cause irreversible and progressive left ventricular dysfunction. Epirubicin, which is widely used for breast cancer chemotherapy, is an anthracycline that has less cardiac toxicity than doxorubicin. The present report describes the case of a 70-year-old woman with breast cancer who developed severe congestive heart failure and severe cardiac dysfunction at 6 weeks from epirubicin final administration. Left ventricular function gradually improved after intensive treatment for heart failure and recovered completely within 2 months. To the best of our knowledge, this is the first report to describe epirubicin-induced subacute reversible cardiotoxicity. PMID- 26104178 TI - Analysis of Gene Expression During the Development of Congestive Heart Failure After Myocardial Infarction in Rat Models. AB - Our study aimed to investigate the gene expression at different myocardial infarction (MI) phases and to understand the development mechanisms of congestive heart failure (CHF) after MI. Dataset GSE1957 including 24 samples of rat left ventricles at 1-day post MI or sham operation and 7-day post MI or sham operation was downloaded from Gene Expression Ominibus. The data were normalized with an affyPLM package and differentially expressed genes (DEGs) were identified with a Linear Models for Microarray Data package. Heat maps of the DEGs were constructed using Cluster 3.0. GO (Gene Ontology) enrichment analysis of the DEGs was performed in Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed by Biomolecular Interaction Network Database and visualized by Cytoscape, and a subnetwork was analyzed using plugin ClusterONE in Cytoscape. A total of 5 DEGs at 1-day post MI, 5 DEGs at 7-day post-MI, and 7 DEGs between the MI and sham groups at 1-day and 7-day post-MI were identified. For the GO category analysis, DEGs at 1-day post-MI were enriched in response to cytokine stimulus. DEGs at 7-day post-MI were enriched in response to inorganic substance and chemical homeostasis. DEGs between 1-day and 7-day post-MI including CDK2 and CDC20 were significantly enriched in mitosis. CDK2, ANXA1, CDC20, and AQP2 were included in the PPI network, and CDK2 was the only DEG included in the subnetwork. In conclusion, the induction of DEGs at 7-day post-MI might participate in the response to a hormone and endogenous stimulus to regulate the development of CHF after MI. PMID- 26104179 TI - Impact of Admission Anemia on Coronary Microcirculation and Clinical Outcomes in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. AB - Microvascular dysfunction after primary percutaneous coronary intervention (PCI) augments myocardial damage and prognosis in acute myocardial infarction. However, the relationship between baseline anemia and coronary microcirculation in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. We performed primary PCI in 337 consecutive patients with STEMI. Anemia was defined as a hemoglobin level < 13 g/dL in men and < 12 g/dL in women. Admission anemia was present in 17.5% of the patients enrolled. Data on epicardial coronary flow, STsegment resolution (STR) on electrocardiography, myocardial injury, and the incidence of adverse cardiac events defined as cardiac death or hospitalization for congestive heart failure were analyzed. The median follow-up period was 54.8 months. Despite comparable epicardial coronary flow, the rate of STR >= 50% was lower in anemic patients compared with non-anemic patients (55.9% versus 71.2%, P = 0.02). On multivariate logistic regression analysis, baseline anemia was an independent negative predictor of STR >= 50% (odds ratio, 0.53; 95% confidence interval: 0.31-0.92, P = 0.03). Moreover, anemic patients had higher maximum creatine kinase levels normalized for body surface area (2,215 +/- 1,318 IU/L/m(2) versus 1,797 +/- 1,199 IU/L/m(2), P = 0.047). Anemia remained an independent significant predictor of adverse events on multivariate Cox proportional hazard analysis (hazard ratio, 2.34; 95% confidence interval: 1.01 5.64, P = 0.048). In conclusion, admission anemia was related to microcirculatory dysfunction and poor prognosis in patients with STEMI. The decreased oxygen delivery might exacerbate microvascular function. PMID- 26104180 TI - Impact of Either GLP-1 Agonists or DPP-4 Inhibitors on Pathophysiology of Heart Failure. AB - Since diabetes mellitus (DM) is the most common cause of heart failure (HF), it is critically important to clarify whether incretin hormones including glucagon like peptide-1 (GLP-1), which play an important role in blood glucose control, mediate cardioprotection. There are many lines of basic research evidence indicating that GLP-1 improves the pathophysiology of HF: In murine and canine HF models, either GLP-1 analogues or DPP-IV inhibitors improved cardiac functions. The first question that arises is how either GLP-1 analogues or DPP-IV inhibitors mediate cardioprotection. Cardiovascular diseases are tightly linked to impaired glucose tolerance (IGT): IGT is not only one of the causes of cardiovascular events but also the result of HF. Indeed, the treatment of IGT improved HF, showing that one of the mechanisms attributable to DPP-IV inhibitors is related to the improvement of IGT. Intriguingly, either DPP-IV inhibitors or GLP-1 analogues mediate cardioprotection even without IGT, suggesting two possible explanations: One is that GLP-1 analogues directly activate the prosurvival kinases, such as Akt and Erk1/2, and another is that DPP-IV inhibition increases cardioprotective peptides such as BNP and SDF-1alpha. The next question is whether cardioprotection is translated to clinical medicine. Small scale clinical trials proved their cardioprotective effects; however, several large scale clinical trials have not proved the beneficial effects of DPP-IV inhibitors. Taken together, GLP-1 analogues or DPP-IV inhibitors can mediate cardioprotection, however, what needs to be clarified is who mainly receives their benefits among the patients with cardiovascular diseases and/or DM. PMID- 26104181 TI - Holy Grail Deformity of Distal Disc Hubless Atrial Septal Occluders in Pediatric Hearts. AB - A special deformity associated with the use of left atrial disc hubless atrial septal occluders has been described in 3 children. This chalice-shaped deformity that occurred during the use of Occlutech and Lifetech septal occluders was given the name "Holy Grail Configuration". Despite being easily reversible, reduction of the metal load on the left atrium has been suggested to have some negative effects. PMID- 26104182 TI - Interfacial electron-shuttling processes across KolliphorEL monolayer grafted electrodes. AB - Covalently grafted KolliphorEL (a poly(ethylene glycol)-based transporter molecule for hydrophobic water-insoluble drugs; MW, ca. 2486; diameter, ca. 3 nm) at the surface of a glassy-carbon electrode strongly affects the rate of electron transfer for aqueous redox systems such as Fe(CN)6(3-/4-). XPS data confirm monolayer grafting after electrochemical anodization in pure KolliphorEL. On the basis of voltammetry and impedance measurements, the charge transfer process for the Fe(CN)6(3-/4-) probe molecule is completely blocked after KolliphorEL grafting and in the absence of a "guest". However, in the presence of low concentrations of suitable ferrocene derivatives as guests, mediated electron transfer across the monolayer via a shuttle mechanism is observed. The resulting amplification of the ferrocene electroanalytical signal is investigated systematically and compared for five ferrocene derivatives. The low-concentration electron shuttle efficiency decreases in the following sequence: (dimethylaminomethyl)ferrocene > n-butyl ferrocene > ferrocene dimethanol > ferroceneacetonitrile > ferroceneacetic acid. PMID- 26104183 TI - Quenching of the upconversion luminescence of NaYF4:Yb3+,Er3+ and NaYF4:Yb3+,Tm3+ nanophosphors by water: the role of the sensitizer Yb3+ in non-radiative relaxation. AB - We have studied the mechanisms of water-based quenching of the upconversion photoluminescence of upconverting nanophosphors (UCNPs) via luminescence decay measurements for a better understanding of the non-radiative deactivation pathways responsible for the relatively low upconversion luminescence efficiency in aqueous solutions. This included both upconversion luminescence measurements and the direct excitation of emissive energy states of Er(3+) and Yb(3+) dopants in NaYF4:Yb(3+),Er(3+) UCNPs by measuring the decays at 550 and 655 nm upon 380 nm excitation and at 980 nm upon 930 nm excitation, respectively. The luminescence intensities and decays were measured from both bare and silanized NaYF4:Yb(3+),Er(3+) and NaYF4:Yb(3+),Tm(3+) UCNPs in H2O and D2O. The measurements revealed up to 99.9% quenching of the upconversion photoluminescence intensity of both Er(3+) and Tm(3+) doped bare nanophosphors by water. Instead of the multiphonon relaxation of excited energy levels of the activators, the main mechanism of quenching was found to be the multiphonon deactivation of the Yb(3+) sensitizer ion caused by OH-vibrations on the surface of the nanophosphor. Due to the nonlinear nature of upconversion, the quenching of Yb(3+) has a higher order effect on the upconversion emission intensity with the efficient Yb-Yb energy migration in the ~35 nm nanocrystals making the whole nanophosphor volume susceptible to surface quenching effects. The study underlines the need of efficient surface passivation for the use of UCNPs as labels in bioanalytical applications performed in aqueous solutions. PMID- 26104185 TI - Fructose induces prothrombotic phenotype in human endothelial cells : A new role for "added sugar" in cardio-metabolic risk. AB - Intake of large amounts of added sweeteners has been associated with the pathogenesis of cardiometabolic risk. Several studies have shown that fructose increases the cardiovascular risk by modulating endothelial dysfunction and promoting atherosclerosis. Recently, a potential role for fructose in cardiovascular thrombosis has been suggested but with controversial results. Tissue factor (TF) plays a pivotal role in the pathophysiology of cardiovascular thrombosis by triggering the formation of intracoronary thrombi following endothelial injury. This study investigates the effects of fructose, in a concentration range usually observed in the plasma of patients with increased cardiovascular risk, on TF in human umbilical endothelial cells (HUVECs). Cells were stimulated with increasing concentrations of fructose (0.25, 1 and 2.5 mM) and then processed to evaluate TF-mRNA levels by real-time PCR as well as TF expression/activity by FACS analysis and procoagulant activity. Finally, a potential molecular pathway involved in modulating this phenomenon was investigated. We demonstrate that fructose induces transcription of mRNA for TF. In addition, we show that this monosaccharide promotes surface expression of TF that is functionally active. Fructose effects on TF appear modulated by the oxygen free radicals through activation of the transcription factor NF-kappaB since superoxide dismutase and NF-kappaB inhibitors suppressed TF expression. Data of the present study, although in vitro, indicate that fructose, besides promoting atherosclerosis, induces a prothrombotic phenotype in HUVECs, thus indicating one the mechanism(s) by which this sweetener might increase cardiometabolic risk. PMID- 26104186 TI - Lycium intricatum Boiss.: An unexploited and rich source of unsaturated fatty acids, 4-desmethylsterols and other valuable phytochemicals. AB - BACKGROUND: Lycium intricatum Boiss., a Solanaceous shrubbery is used in Tunisia as a windbreak and medicinal plant. However, it is considered as underexploited specie despite its high potential to serve as source with economic and nutritional value. To date only limited information about its phytochemistry, especially of its oil has been published. This work provides data on fatty acids, phytosterols and vitamin D composition of L. intricatum seed oil. It opens up new possibilities of developing L. intricatum as a new crop that contains phytochemicals with high added value little influenced by selection or commercial breeding. FINDINGS: The composition of fatty acids, phytosterols and vitamin D in L. intricatum seed oil was assessed by GC-FID. The main fatty acids of L. intricatum seed oil were linoleic acid (49.47%), palmitoleic acid (27.96%) and erucic acid (13.62%). Palimtic acid was present at low percentage (0.63%). The content of unsaturated fatty acids was high as 94.04%. The sterolic fraction was composed of stigmasterol (18.56 mg/100 g), beta-sitosterol (13.04 mg/100 g). L. intricatum oil is an oily matrix that contains hydrocarbons, mainly squalene (63.36 mg/100 g), and two triterpenic alcohol erythrodiol (80.36 mg/100 g) and uvaol (24.06 mg/100 g). provitamin D was present in high quantity (8.12 mg/100 g). CONCLUSIONS: From these results it has been shown that L. intricatum seeds have great potential as a source of fatty acids and phytosterols for natural health products. PMID- 26104187 TI - Coagulopathy and spontaneous hemorrhage in a patient with nephrotic syndrome. AB - Patients with nephrotic syndrome, particularly those with membranous nephropathy tend to be in a hypercoagulable state and often present with thromboembolic phenomena. The association of nephrotic syndrome with a bleeding diathesis however is much less common and the etiologies less well recognized. We report a patient who presented with coagulopathy and recurrent spontaneous hemorrhage in association with nephrotic syndrome. The case highlights key diagnostic and therapeutic challenges and strategies: 1) work up to establish a unifying etiology for both nephrotic syndrome and the bleeding disorder; 2) decision making to obtain a tissue biopsy, select the site of biopsy and understand the relative yields for each site; 3) recognizing the risk and managing peri procedural bleeding; and 5) developing a treatment strategy with the lowest risk of possible complications. Our patient underwent a kidney biopsy without any complications and a definitive diagnosis of AL amyloidosis was reached. He was treated with anti-plasma cell chemotherapy followed by autologous stem cell transplant with resultant complete hematologic response, improved coagulation parameters, and no further bleeding. PMID- 26104188 TI - Lumbo-sacral epidural anaesthesia as a complement to dissociative anaesthesia during scrotal herniorrhaphy of livestock pigs in the field. AB - BACKGROUND: In Sweden, scrotal or inguinal herniorrhaphy of livestock pigs in the field has traditionally been an important part of the surgical skills training of veterinary students. Few substances meet the legal requirements for field anaesthesia of production animals in the European Union but a protocol based on azaperone-detomidine-butorphanol-ketamine does. Unfortunately the anaesthesia is characterised by unpredictable duration and depth and of abrupt awakenings which is not acceptable from an animal welfare perspective and impedes surgical training. Lumbo-sacral epidural analgesia is proven to provide sufficient analgesia to allow abdominal surgery, but there are few reports on the field use of this loco-regional technique. The study aim was to evaluate whether lumbo sacral anaesthesia can be safely and successfully used in the field by a veterinary student and whether the combination of dissociative and lumbo-sacral epidural anaesthesia improves analgesia and anaesthesia to guarantee animal welfare during herniorrhaphy in livestock pigs, enabling surgical skills training. RESULTS: Pigs in the control-group (placebo) responded significantly stronger to surgery, with five out of 11 requiring additional doses of detomidine and ketamine. There were no significant differences between groups in respiratory rate, heart rate, blood pressure, SpO2 or blood gases. SpO2 levels <94 % were recorded in several pigs in both groups. No post-injection complications were reported at follow-up. CONCLUSIONS: The results from this study showed that lumbo sacral epidural anaesthesia with lidocaine could successfully be administered during dissociative anaesthesia of livestock pigs by a veterinary student and without reported post-injection complications. It improved analgesia and anaesthesia during herniorrhaphy of sufficient duration to enable surgical skills training. The risks and consequences of hypoxaemia and hypoventilation should be considered. PMID- 26104190 TI - Burr-like, laser-made 3D microscaffolds for tissue spheroid encagement. AB - The modeling, fabrication, cell loading, and mechanical and in vitro biological testing of biomimetic, interlockable, laser-made, concentric 3D scaffolds are presented. The scaffolds are made by multiphoton polymerization of an organic inorganic zirconium silicate. Their mechanical properties are theoretically modeled using finite elements analysis and experimentally measured using a Microsquisher((r)). They are subsequently loaded with preosteoblastic cells, which remain live after 24 and 72 h. The interlockable scaffolds have maintained their ability to fuse with tissue spheroids. This work represents a novel technological platform, enabling the rapid, laser-based, in situ 3D tissue biofabrication. PMID- 26104189 TI - Using an electronic activity monitor system as an intervention modality: A systematic review. AB - BACKGROUND: Obesity is a growing global health concern that may lead to cardiovascular disease, type II diabetes, and cancer. Several systematic reviews have shown that technology is successful in combating obesity through increased physical activity, but there is no known review on interventions that use an electronic activity monitor system (EAMS). EAMSs are defined as a wearable device that objectively measures lifestyle physical activity and can provide feedback, beyond the display of basic activity count information, via the monitor display or through a partnering application to elicit continual self-monitoring of activity behavior. These devices improve upon standard pedometers because they have the ability to provide visual feedback on activity progression, verbal encouragement, and social comparison. This systematic review aimed to synthesize the efficacy and feasibility results of EAMSs within published physical activity interventions. METHODS: Electronic databases and journal references were searched for relevant articles. Data sources included CINAHL, Cochrane CENTRAL, Medline Ovid, PsycINFO, and clinicaltrials.gov. Out of the 1,574 retrieved, 11 articles met the inclusion criteria. These articles were reviewed for quality and content based on a risk of bias tool and intervention components. RESULTS: Most articles were determined to be of medium quality while two were of low quality, and one of high quality. Significant pre-post improvements in the EAMS group were found in five of nine studies for physical activity and in four of five studies for weight. One found a significant increase in physical activity and two studies found significant weight loss in the intervention group compared with the comparator group. The EAMS interventions appear to be feasible with most studies reporting continual wear of the device during waking hours and a higher retention rate of participants in the EAMS groups. CONCLUSION: These studies provide preliminary evidence suggesting that EAMS can increase physical activity and decrease weight significantly, but their efficacy compared to other interventions has not yet been demonstrated. More high-quality randomized controlled trials are needed to evaluate the overall effect of EAMS, examine which EAMS features are most effective, and determine which populations are most receptive to an EAMS. PMID- 26104191 TI - Plasma treatment for next-generation nanobiointerfaces. AB - Energy deficiency, global poverty, chronic hunger, chronic diseases, and environment conservation are among the major problems threatening the whole mankind. Nanostructure-based technologies could be a possible solution. Such techniques are now used for the production of many vitally important products including cultured and fermented food, antibiotics, various medicines, and biofuels. On the other hand, the nanostructure-based technologies still demonstrate low efficiency and controllability, and thus still are not capable to decisively address the global problems. Furthermore, future technologies should ensure lowest possible environmental impact by implementing green production principles. One of the most promising approaches to address these challenges are the sophisticatedly engineered biointerfaces. Here, the authors briefly evaluate the potential of the plasma-based techniques for the fabrication of complex biointerfaces. The authors consider mainly the atmospheric and inductively coupled plasma environments and show several examples of the artificial plasma created biointerfaces, which can be used for the biotechnological and medical processes, as well as for the drug delivery devices, fluidised bed bioreactors, catalytic reactors, and others. A special attention is paid to the plasma-based treatment and processing of the biointerfaces formed by arrays of carbon nanotubes and graphene flakes. PMID- 26104192 TI - Vector-Mediated In Vivo Antibody Expression. AB - This article focuses on a novel vaccine strategy known as vector-mediated antibody gene transfer, with a particular focus on human immunodeficiency virus (HIV). This strategy provides a solution to the problem of current vaccines that fail to generate neutralizing antibodies to prevent HIV-1 infection and AIDS. Antibody gene transfer allows for predetermination of antibody affinity and specificity prior to "immunization" and avoids the need for an active humoral immune response against the HIV envelope protein. This approach uses recombinant adeno-associated viral (rAAV) vectors, which have been shown to transduce muscle with high efficiency and direct the long-term expression of a variety of transgenes, to deliver the gene encoding a broadly neutralizing antibody into the muscle. Following rAAV vector gene delivery, the broadly neutralizing antibodies are endogenously synthesized in myofibers and passively distributed to the circulatory system. This is an improvement over classical passive immunization strategies that administer antibody proteins to the host to provide protection from infection. Vector-mediated gene transfer studies in mice and monkeys with anti-HIV and simian immunodeficiency virus (SIV)-neutralizing antibodies demonstrated long-lasting neutralizing activity in serum with complete protection against intravenous challenge with virulent HIV and SIV. These results indicate that existing potent anti-HIV antibodies can be rapidly moved into the clinic. However, this methodology need not be confined to HIV. The general strategy of vector-mediated antibody gene transfer can be applied to other difficult vaccine targets such as hepatitis C virus, malaria, respiratory syncytial virus, and tuberculosis. PMID- 26104193 TI - Conjugation in Gram-Positive Bacteria. AB - Conjugative transfer is the most important means of spreading antibiotic resistance and virulence factors among bacteria. The key vehicles of this horizontal gene transfer are a group of mobile genetic elements, termed conjugative plasmids. Conjugative plasmids contain as minimum instrumentation an origin of transfer (oriT), DNA-processing factors (a relaxase and accessory proteins), as well as proteins that constitute the trans-envelope transport channel, the so-called mating pair formation (Mpf) proteins. All these protein factors are encoded by one or more transfer (tra) operons that together form the DNA transport machinery, the Gram-positive type IV secretion system. However, multicellular Gram-positive bacteria belonging to the streptomycetes appear to have evolved another mechanism for conjugative plasmid spread reminiscent of the machinery involved in bacterial cell division and sporulation, which transports double-stranded DNA from donor to recipient cells. Here, we focus on the protein key players involved in the plasmid spread through the two different modes and present a new secondary structure homology-based classification system for type IV secretion protein families. Moreover, we discuss the relevance of conjugative plasmid transfer in the environment and summarize novel techniques to visualize and quantify conjugative transfer in situ. PMID- 26104194 TI - Animal Reservoirs of Shiga Toxin-Producing Escherichia coli. AB - Shiga toxin-producing Escherichia coli (STEC) strains have been detected in a wide diversity of mammals, birds, fish, and several insects. Carriage by most animals is asymptomatic, thus allowing for dissemination of the bacterium in the environment without detection. Replication of the organism may occur in the gastrointestinal tract of some animals, notably ruminants. Carriage may also be passive or transient, without significant amplification of bacterial numbers while in the animal host. Animals may be classified as reservoir species, spillover hosts, or dead-end hosts. This classification is based on the animal's ability to (i) transmit STEC to other animal species and (ii) maintain STEC infection in the absence of continuous exposure. Animal reservoirs are able to maintain STEC infections in the absence of continuous STEC exposure and transmit infection to other species. Spillover hosts, although capable of transmitting STEC to other animals, are unable to maintain infection in the absence of repeated exposure. The large diversity of reservoir and spillover host species and the survival of the organism in environmental niches result in complex pathways of transmission that are difficult to interrupt. PMID- 26104195 TI - Animal Models of Enterohemorrhagic Escherichia coli Infection. AB - The first major outbreaks caused by enterohemorrhagic Escherichia coli (EHEC) raised public and medical awareness of the risks associated with acquiring this potentially deadly infection. The widespread presence of these organisms in the environment, the severity of the clinical sequelae, and the lack of treatment options and effective preventive measures demand that we obtain a better understanding of how this group of organisms cause disease. Animal models allow study of the processes and factors that contribute to disease and, as such, form a valuable tool in the repertoire of infectious disease researchers. Yet despite more than 30 years of research, it seems that no single model host reproduces the full spectrum of clinical disease induced by EHEC in humans. In the first part of this review, a synopsis of what is known about EHEC infections is garnered from human outbreaks and biopsy specimens. The main features and limitations of EHEC infection models that are based on the three most commonly used species (pigs, rabbits, and mice) are described within a historical context. Recent advances are highlighted, and a brief overview of models based on other species is given. Finally, the impact of the host on moderating EHEC infection is considered in light of growing evidence for the need to consider the biology and virulence strategies of EHEC in the context of its niche within the intestine. PMID- 26104196 TI - Plasmid Replication Control by Antisense RNAs. AB - Plasmids are selfish genetic elements that normally constitute a burden for the bacterial host cell. This burden is expected to favor plasmid loss. Therefore, plasmids have evolved mechanisms to control their replication and ensure their stable maintenance. Replication control can be either mediated by iterons or by antisense RNAs. Antisense RNAs work through a negative control circuit. They are constitutively synthesized and metabolically unstable. They act both as a measuring device and a regulator, and regulation occurs by inhibition. Increased plasmid copy numbers lead to increasing antisense-RNA concentrations, which, in turn, result in the inhibition of a function essential for replication. On the other hand, decreased plasmid copy numbers entail decreasing concentrations of the inhibiting antisense RNA, thereby increasing the replication frequency. Inhibition is achieved by a variety of mechanisms, which are discussed in detail. The most trivial case is the inhibition of translation of an essential replication initiator protein (Rep) by blockage of the rep-ribosome binding site. Alternatively, ribosome binding to a leader peptide mRNA whose translation is required for efficient Rep translation can be prevented by antisense-RNA binding. In 2004, translational attenuation was discovered. Antisense-RNA-mediated transcriptional attenuation is another mechanism that has, so far, only been detected in plasmids of Gram-positive bacteria. ColE1, a plasmid that does not need a plasmid-encoded replication initiator protein, uses the inhibition of primer formation. In other cases, antisense RNAs inhibit the formation of an activator pseudoknot that is required for efficient Rep translation. PMID- 26104197 TI - Shiga Toxin-Producing Escherichia coli (STEC) in Fresh Produce--A Food Safety Dilemma. AB - Produce contains high levels of mixed microflora, including coliforms and Escherichia coli, but occasionally pathogens may also be present. Enterotoxigenic E. coli and Shigatoxin-producing E. coli (STEC) have been isolated from various produce types, especially spinach. The presence of STEC in produce is easily detected by PCR for the Shiga toxin (Stx) gene, stx, but this is insufficient for risk analysis. STEC comprises hundreds of serotypes that include known pathogenic serotypes and strains that do not appear to cause severe illness. Moreover, Stx without a binding factor like intimin (encoded by eae) is deemed to be insufficient to cause severe disease. Hence, risk analyses require testing for other virulence or serotype-specific genes. Multiplex PCR enables simultaneous testing of many targets, but, in a mixed flora sample, not all targets detected may be coming from the same cell. The need to isolate and confirm STEC in produce is critical, but it is time- and labor-intensive due to the complexity of the group. Studies showed that only a handful of STEC strains in produce have eae, and most belonged to recognized pathogenic serotypes so are of definite health risks. Several eae-negative strains belonged to serotypes O113:H21 and O91:H21 that historically have caused severe illness and may also be of concern. Most of the other STEC strains in produce, however, are only partially serotyped or are unremarkable serotypes carrying putative virulence factors, whose role in pathogenesis is uncertain, thus making it difficult to assess the health risks of these STEC strains. PMID- 26104198 TI - Genetics of Mycobacterial Arabinogalactan and Lipoarabinomannan Assembly. AB - The cell wall of Mycobacterium tuberculosis is unique in that it differs significantly from those of both Gram-negative and Gram-positive bacteria. The thick, carbohydrate- and lipid-rich cell wall with distinct lipoglycans enables mycobacteria to survive under hostile conditions such as shortage of nutrients and antimicrobial exposure. The key features of this highly complex cell wall are the mycolyl-arabinogalactan-peptidoglycan (mAGP)-based and phosphatidyl-myo inositol-based macromolecular structures, with the latter possessing potent immunomodulatory properties. These structures are crucial for the growth, viability, and virulence of M. tuberculosis and therefore are often the targets of effective chemotherapeutic agents against tuberculosis. Over the past decade, sophisticated genomic and molecular tools have advanced our understanding of the primary structure and biosynthesis of these macromolecules. The availability of the full genome sequences of various mycobacterial species, including M. tuberculosis, Mycobacterium marinum, and Mycobacterium bovis BCG, have greatly facilitated the identification of large numbers of drug targets and antigens specific to tuberculosis. Techniques to manipulate mycobacteria have also improved extensively; the conditional expression-specialized transduction essentiality test (CESTET) is currently used to determine the essentiality of individual genes. Finally, various biosynthetic assays using either purified proteins or synthetic cell wall acceptors have been developed to study enzyme function. This article focuses on the recent advances in determining the structural details and biosynthesis of arabinogalactan, lipoarabinomannan, and related glycoconjugates. PMID- 26104199 TI - Physiology and Sporulation in Clostridium. AB - Clostridia are Gram-positive, anaerobic, endospore-forming bacteria, incapable of dissimilatory sulfate reduction. Comprising approximately 180 species, the genus Clostridium is one of the largest bacterial genera. Physiology is mostly devoted to acid production. Numerous pathways are known, such as the homoacetate fermentation by acetogens, the propionate fermentation by Clostridium propionicum, and the butyrate/butanol fermentation by C. acetobutylicum, a well known solvent producer. Clostridia degrade sugars, alcohols, amino acids, purines, pyrimidines, and polymers such as starch and cellulose. Energy conservation can be performed by substrate-level phosphorylation as well as by the generation of ion gradients. Endospore formation resembles the mechanism elucidated in Bacillus. Morphology, contents, and properties of spores are very similar to bacilli endospores. Sporulating clostridia usually form swollen mother cells and accumulate the storage substance granulose. However, clostridial sporulation differs by not employing the so-called phosphorelay. Initiation starts by direct phosphorylation of the master regulator Spo0A. The cascade of sporulation-specific sigma factors is again identical to what is known from Bacillus. The onset of sporulation is coupled in some species to either solvent (acetone, butanol) or toxin (e.g., C. perfringens enterotoxin) formation. The germination of spores is often induced by various amino acids, often in combination with phosphate and sodium ions. In medical applications, C. butyricum spores are used as a C. difficile prophylaxis and as treatment against diarrhea. Recombinant spores are currently under investigation and testing as antitumor agents, because they germinate only in hypoxic tissues (i.e., tumor tissue), allowing precise targeting and direct killing of tumor cells. PMID- 26104200 TI - Functions of Antibodies. AB - Antibodies can impact pathogens in the presence or in the absence of effector cells or effector molecules such as complement, and experiments can often sort out with precision the mechanisms by which an antibody inhibits a pathogen in vitro. In addition, in vivo models, particularly those engineered to knock in or knock out effector cells or effector molecules, are excellent tools for understanding antibody functions. However, it is highly likely that multiple antibody functions occur simultaneously or sequentially in the presence of an infecting organism in vivo. The most critical incentive for measuring antibody functions is to provide a basis for vaccine development and for the development of therapeutic antibodies. In this respect, some functions, such as virus neutralization, serve to inhibit the acquisition of a pathogen or limit its pathogenesis. However, antibodies can also enhance replication or contribute to pathogenesis. This review emphasizes those antibody functions that are potentially beneficial to the host. In addition, this review will focus on the effects of antibodies on organisms themselves, rather than on the toxins the organisms may produce. PMID- 26104201 TI - The Molecular Genetics of Fluoroquinolone Resistance in Mycobacterium tuberculosis. AB - The fluoroquinolones (FQs) are synthetic antibiotics effectively used for curing patients with multidrug-resistant tuberculosis (TB). When a multidrug-resistant strain develops resistance to the FQs, as in extensively drug-resistant strains, obtaining a cure is much more difficult, and molecular methods can help by rapidly identifying resistance-causing mutations. The only mutations proven to confer FQ resistance in M. tuberculosis occur in the FQ target, the DNA gyrase, at critical amino acids from both the gyrase A and B subunits that form the FQ binding pocket. GyrA substitutions are much more common and generally confer higher levels of resistance than those in GyrB. Molecular techniques to detect resistance mutations have suboptimal sensitivity because gyrase mutations are not detected in a variable percentage of phenotypically resistant strains. The inability to find gyrase mutations may be explained by heteroresistance: bacilli with a resistance-conferring mutation are present only in a minority of the bacterial population (>1%) and are therefore detected by the proportion method, but not in a sufficient percentage to be reliably detected by molecular techniques. Alternative FQ resistance mechanisms in other bacteria--efflux pumps, pentapeptide proteins, or enzymes that inactivate the FQs--have not yet been demonstrated in FQ-resistant M. tuberculosis but may contribute to intrinsic levels of resistance to the FQs or induced tolerance leading to more frequent gyrase mutations. Moxifloxacin is currently the best anti-TB FQ and is being tested for use with other new drugs in shorter first-line regimens to cure drug susceptible TB. PMID- 26104202 TI - Genetics of Capsular Polysaccharides and Cell Envelope (Glyco)lipids. AB - This article summarizes what is currently known of the structures, physiological roles, involvement in pathogenicity, and biogenesis of a variety of noncovalently bound cell envelope lipids and glycoconjugates of Mycobacterium tuberculosis and other Mycobacterium species. Topics addressed in this article include phospholipids; phosphatidylinositol mannosides; triglycerides; isoprenoids and related compounds (polyprenyl phosphate, menaquinones, carotenoids, noncarotenoid cyclic isoprenoids); acyltrehaloses (lipooligosaccharides, trehalose mono- and di mycolates, sulfolipids, di- and poly-acyltrehaloses); mannosyl-beta-1 phosphomycoketides; glycopeptidolipids; phthiocerol dimycocerosates, para hydroxybenzoic acids, and phenolic glycolipids; mycobactins; mycolactones; and capsular polysaccharides. PMID- 26104203 TI - EHEC Genomics: Past, Present, and Future. AB - This article examines the role of genomics in the understanding and identification of O157:H7 enterohemorrhagic Escherichia coli (EHEC). We highlight the development of novel molecular typing systems that are based on the genomic sequence that has been generated for this pathotype. The genomic comparisons of EHEC to other E. coli strains highlight the close relatedness of the O157 and O55 isolates and also identify other non-O157 clades of isolates that appear to have a different genomic history. Analysis within the EHEC isolates must be completed on a fine scale using whole-genome sequence-based approaches to assess both the conserved and lateral acquired gene content. The plethora of genomic data for EHEC isolates has provided the ability to examine this pathotype in detail, which has provided opportunities for novel surveillance, detection, and diagnostics. PMID- 26104204 TI - Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities. AB - Isoniazid (INH) is the cornerstone of tuberculosis (TB) chemotherapy, used for both treatment and prophylaxis of TB. The antimycobacterial activity of INH was discovered in 1952, and almost as soon as its activity was published, the first INH-resistant Mycobacterium tuberculosis strains were reported. INH and its structural analog and second-line anti-TB drug ethionamide (ETH) are pro-drugs. INH is activated by the catalase-peroxidase KatG, while ETH is activated by the monooxygenase EthA. The resulting active species reacts with NAD+ to form an INH NAD or ETH-NAD adduct, which inhibits the enoyl ACP reductase InhA, leading to mycolic acid biosynthesis inhibition and mycobacterial cell death. The major mechanism of INH resistance is mutation in katG, encoding the activator of INH. One specific KatG variant, S315T, is found in 94% of INH-resistant clinical isolates. The second mechanism of INH resistance is a mutation in the promoter region of inhA (c-15t), which results in inhA overexpression and leads to titration of the drug. Mutations in the inhA open reading frame and promoter region are also the major mechanism of resistance to ETH, found more often in ETH resistant clinical isolates than mutations in the activator of ETH. Other mechanisms of resistance to INH and ETH include expression changes of the drugs' activators, redox alteration, drug inactivation, and efflux pump activation. In this article, we describe each known mechanism of resistance to INH and ETH and its importance in M. tuberculosis clinical isolates. PMID- 26104205 TI - Mechanisms of Pyrazinamide Action and Resistance. AB - Pyrazinamide (PZA) is a unique antituberculosis (anti-TB) drug that plays a key role in shortening TB therapy. PZA kills nonreplicating persisters that other TB drugs fail to kill, which makes it an essential drug for inclusion in any drug combinations for treating drug-susceptible and drug-resistant TB such as multidrug-resistant TB. PZA acts differently from common antibiotics by inhibiting multiple targets such as energy production, trans-translation, and perhaps pantothenate/coenzyme A required for persister survival. Resistance to PZA is mostly caused by mutations in the pncA gene encoding pyrazinamidase, which is involved in conversion of the prodrug PZA to the active form pyrazinoic acid. Mutations in the drug target ribosomal protein S1 (RpsA) are also found in some PZA-resistant strains. The recent finding that panD mutations are found in some PZA-resistant strains without pncA or rpsA mutations may suggest a third PZA resistance gene and a potential new target of PZA. Current phenotype-based PZA susceptibility testing is not reliable due to false resistance; sequencing of the pncA gene represents a more rapid, cost-effective, and reliable molecular test for PZA susceptibility testing and should be used for guiding improved treatment of multidrug-resistant and extensively multidrug-resistant TB. Finally, the story of PZA has important implications for not only TB therapy but also chemotherapy in general. PZA serves as a model prototype persister drug and hopefully a "tipping point" that inspires new efforts at developing a new type of antibiotic or drug that targets nonreplicating persisters for improved treatment of not only TB but also other persistent bacterial infections. PMID- 26104206 TI - The Inflammatory Response during Enterohemorrhagic Escherichia coli Infection. AB - The inflammatory response is an integral part of host defense against enterohemorrhagic Escherichia coli (EHEC) infection and also contributes to disease pathology. In this article we explore the factors leading to inflammation during EHEC infection and the mechanisms EHEC and other attaching and effacing (A/E) pathogens have evolved to suppress inflammatory signaling. EHEC stimulates an inflammatory response in the intestine through host recognition of bacterial components such as flagellin and lipopolysaccharide. In addition, the activity of Shiga toxin and some type III secretion system effectors leads to increased tissue inflammation. Various infection models of EHEC and other A/E pathogens have revealed many of the immune factors that mediate this response. In particular, the outcome of infection is greatly influenced by the ability of an infected epithelial cell to mount an effective host inflammatory response. The inflammatory response of infected enterocytes is counterbalanced by the activity of type III secretion system effectors such as NleE and NleC that modify and inhibit components of the signaling pathways that lead to proinflammatory cytokine production. Overall, A/E pathogens have taught us that innate mucosal immune responses in the gastrointestinal tract during infection with A/E pathogens are highly complex and ultimate clearance of the pathogen depends on multiple factors, including inflammatory mediators, bacterial burden, and the function and integrity of resident intestinal epithelial cells. PMID- 26104207 TI - Prevention of Respiratory Syncytial Virus Infection: From Vaccine to Antibody. AB - Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children. Initial efforts to develop a vaccine to prevent RSV lower respiratory tract disease in children were halted because of serious adverse events that occurred when children were infected with RSV following vaccination, including vaccine-related deaths. Subsequently, a major focus for researchers was to understand what led to these adverse events. Investment in a vaccine for RSV continues, and new strategies are under development. Success to prevent RSV disease was met by the development of immunoprophylaxis, first with intravenous immunoglobulin and then with recombinant monoclonal antibody. The story of immunoprophylaxis for RSV includes the first-in-class use of antibody technology for infectious disease, and palivizumab currently remains the only way to prevent serious lower respiratory tract disease due to RSV infection. PMID- 26104208 TI - Genetic Strategies for Identifying New Drug Targets. AB - Genetic strategies have yet to come into their own as tools for antibiotic development. While holding a lot of initial promise, they have only recently started to bear fruit in the quest for new drug targets. An ever-increasing body of knowledge is showing that genetics can lead to significant improvements in the success and efficiency of drug discovery. Techniques such as high-frequency transposon mutagenesis and expression modulation have matured and have been applied successfully not only to the identification and characterization of new targets, but also to their validation as tractable weaknesses of bacteria. Past experience shows that choosing targets must not rely on gene essentiality alone, but rather needs to incorporate knowledge of the system as a whole. The ability to manipulate genes and their expression is key to ensuring that we understand the entire set of processes that are affected by drug treatment. Focusing on exacerbating these perturbations, together with the identification of new targets to which resistance has not yet occurred--both enabled by genetic approaches--may point us toward the successful development of new combination therapies engineered based on underlying biology. PMID- 26104209 TI - The Locus of Enterocyte Effacement and Associated Virulence Factors of Enterohemorrhagic Escherichia coli. AB - A subset of Shiga toxin-producing Escherichia coli strains, termed enterohemorrhagic E. coli (EHEC), is defined in part by the ability to produce attaching and effacing (A/E) lesions on intestinal epithelia. Such lesions are characterized by intimate bacterial attachment to the apical surface of enterocytes, cytoskeletal rearrangements beneath adherent bacteria, and destruction of proximal microvilli. A/E lesion formation requires the locus of enterocyte effacement (LEE), which encodes a Type III secretion system that injects bacterial proteins into host cells. The translocated proteins, termed effectors, subvert a plethora of cellular pathways to the benefit of the pathogen, for example, by recruiting cytoskeletal proteins, disrupting epithelial barrier integrity, and interfering with the induction of inflammation, phagocytosis, and apoptosis. The LEE and selected effectors play pivotal roles in intestinal persistence and virulence of EHEC, and it is becoming clear that effectors may act in redundant, synergistic, and antagonistic ways during infection. Vaccines that target the function of the Type III secretion system limit colonization of reservoir hosts by EHEC and may thus aid control of zoonotic infections. Here we review the features and functions of the LEE-encoded Type III secretion system and associated effectors of E. coli O157:H7 and other Shiga toxin-producing E. coli strains. PMID- 26104210 TI - Shiga Toxin/Verocytotoxin-Producing Escherichia coli Infections: Practical Clinical Perspectives. AB - Escherichia coli strains that produce Shiga toxins/verotoxins are rare, but important, causes of human disease. They are responsible for a spectrum of illnesses that range from the asymptomatic to the life-threatening hemolytic uremic syndrome; diseases caused by E. coli belonging to serotype O157:H7 are exceptionally severe. Each illness has a fairly predictable trajectory, and good clinical practice at one phase can be inappropriate at other phases. Early recognition, rapid and definitive microbiology, and strategic selection of tests increase the likelihood of good outcomes. The best management of these infections consists of avoiding antibiotics, antimotility agents, and narcotics and implementing aggressive intravenous volume expansion, especially in the early phases of illness. PMID- 26104211 TI - Enterohemorrhagic Escherichia coli Virulence Gene Regulation. AB - Coordinated expression of enterohemorrhagic Escherichia coli virulence genes enables the bacterium to cause hemorrhagic colitis and the complication known as hemolytic-uremic syndrome. Horizontally acquired genes and those common to E. coli contribute to the disease process, and increased virulence gene expression is correlated with more severe disease in humans. Researchers have gained considerable knowledge about how the type III secretion system, secreted effectors, adhesin molecules, and the Shiga toxins are regulated by environmental signals and multiple genetic pathways. Also emergent from the data is an understanding of how enterohemorrhagic E. coli regulates response to acid stress, the role of flagellar motility, and how passage through the human host and bovine intestinal tract causes disease and supports carriage in the cattle reservoir, respectively. Particularly exciting areas of discovery include data suggesting how expression of the myriad effectors is coordinately regulated with their cognate type III secretion system and how virulence is correlated with bacterial metabolism and gut physiology. PMID- 26104212 TI - The Interplay between Different Stability Systems Contributes to Faithful Segregation: Streptococcus pyogenes pSM19035 as a Model. AB - The Streptococcus pyogenes pSM19035 low-copy-number theta-replicating plasmid encodes five segregation (seg) loci that contribute to plasmid maintenance. These loci map outside of the minimal replicon. The segA locus comprises beta2 recombinase and two six sites, and segC includes segA and also the gamma topoisomerase and two ssiA sites. Recombinase beta2 plays a role both in maximizing random segregation by resolving plasmid dimers (segA) and in catalyzing inversion between two inversely oriented six sites. segA, in concert with segC, facilitates replication fork pausing at ssiA sites and overcomes the accumulation of "toxic" replication intermediates. The segB1 locus encodes omega, epsilon, and zeta genes. The short-lived epsilon2 antitoxin and the long-lived zeta toxin form an inactive zetaepsilon2zeta complex. Free zeta toxin halts cell proliferation upon decay of the epsilon2 antitoxin and enhances survival. If epsilon2 expression is not recovered, by loss of the plasmid, the toxin raises lethality. The segB2 locus comprises delta and omega genes and six parS sites. Proteins delta2 and omega2, by forming complexes with parS and chromosomal DNA, pair the plasmid copies at the nucleoid, leading to the formation of a dynamic delta2 gradient that separates the plasmids to ensure roughly equal distribution to daughter cells at cell division. The segD locus, which comprises omega2 (or omega2 plus omega22) and parS sites, coordinates expression of genes that control copy number, better-than-random segregation, faithful partition, and antibiotic resistance. The interplay of the seg loci and with the rep locus facilitates almost absolute plasmid stability. PMID- 26104213 TI - Genetics of Peptidoglycan Biosynthesis. AB - The complex cell envelope is a hallmark of mycobacteria and is anchored by the peptidoglycan layer, which is similar to that of Escherichia coli and a number of other bacteria but with modifications to the monomeric units and other structural complexities that are likely related to a role for the peptidoglycan in stabilizing the mycolyl-arabinogalactan-peptidoglycan complex (MAPc). In this article, we will review the genetics of several aspects of peptidoglycan biosynthesis in mycobacteria, including the production of monomeric precursors in the cytoplasm, assembly of the monomers into the mature wall, cell wall turnover, and cell division. Finally, we will touch upon the resistance of mycobacteria to beta-lactam antibiotics, an important class of drugs that, until recently, have not been extensively exploited as potential antimycobacterial agents. We will also note areas of research where there are still unanswered questions. PMID- 26104214 TI - The Molecular Genetics of Mycolic Acid Biosynthesis. AB - Mycolic acids are major and specific long-chain fatty acids that represent essential components of the Mycobacterium tuberculosis cell envelope. They play a crucial role in the cell wall architecture and impermeability, hence the natural resistance of mycobacteria to most antibiotics, and represent key factors in mycobacterial virulence. Biosynthesis of mycolic acid precursors requires two types of fatty acid synthases (FASs), the eukaryotic-like multifunctional enzyme FAS I and the acyl carrier protein (ACP)-dependent FAS II systems, which consists of a series of discrete mono-functional proteins, each catalyzing one reaction in the pathway. Unlike FAS II synthases of other bacteria, the mycobacterial FAS II is incapable of de novo fatty acid synthesis from acetyl-coenzyme A, but instead elongates medium-chain-length fatty acids previously synthesized by FAS I, leading to meromycolic acids. In addition, mycolic acid subspecies with defined biological properties can be distinguished according to the chemical modifications decorating the meromycolate. Nearly all the genetic components involved in both elongation and functionalization of the meromycolic acid have been identified and are generally clustered in distinct transcriptional units. A large body of information has been generated on the enzymology of the mycolic acid biosynthetic pathway and on their genetic and biochemical/structural characterization as targets of several antitubercular drugs. This chapter is a comprehensive overview of mycolic acid structure, function, and biosynthesis. Special emphasis is given to recent work addressing the regulation of mycolic acid biosynthesis, adding new insights to our understanding of how pathogenic mycobacteria adapt their cell wall composition in response to environmental changes. PMID- 26104216 TI - Predictors of blood pressure response: Obesity is associated with a less pronounced treatment response after renal denervation. AB - OBJECTIVES: The purpose of this study was to identify predictors of BP response. BACKGROUND: Catheter-based renal denervation (RDN) causes significant blood pressure (BP) reductions in a large number of patients with resistant hypertension. METHODS: One hundred one consecutive patients with resistant hypertension who underwent RDN with the SymplicityTM catheter were included in this retrospective study. Primary endpoint was the change in office systolic BP after 6 months. Uni- and multivariate logistic regression analyses were performed to detect baseline predictors of a significant BP response 6 months after RDN (age, gender, office and ambulatory BP, renal function, body mass index [BMI], diabetes mellitus, antihypertensive medication, number of ablations). RESULTS: The procedure was technically uneventful in all patients. Mean BP at baseline was 166.6/90.2 +/- 22.5/16.4 mmHg and decreased by -14.7 (P < 0.0001)/-5.3 (P < 0.001) +/- 22.8/14.1 mm Hg at 6-month follow-up. Similarly, paired analysis of 24 hr-ambulatory BP measurement (n = 71) showed a significant reduction of mean systolic BP by 6.8 +/- 14.4 mm Hg (P < 0.0002). Upon univariate analyses, a higher baseline office systolic BP (P < 0.0001) and lower BMI (P = 0.014) were identified as significant predictors of the magnitude of BP response after 6 months. Importantly, on multivariate analysis, baseline office systolic BP (standardized beta = -0.46; r = -0.47; P < 0.0001) and BMI (standardized beta = 0.21; r = 0.95; P = 0.019) remained significant. CONCLUSION: Blood pressure reductions after RDN were more pronounced in patients with higher baseline blood pressure and lower BMI. These findings may have implications regarding patient selection for renal denervation. (c) 2015 Wiley Periodicals, Inc. PMID- 26104217 TI - A near-infrared multifunctional fluorescent probe with an inherent tumor targeting property for bioimaging. AB - A mitochondria-targeting probe, by conjugating a quaternary ammonium cation with glucosamine modified pH-activated cyanine, was designed and synthesized. This probe has excellent selectivity and sensitivity toward pH, stability, cellular membrane permeability and low cytotoxicity. Owing to the acidic feature of tumors and the more negative mitochondrial membrane potential of tumor cells than that of normal cells, this probe can selectively accumulate in tumor cells and light up its fluorescence. It has been successfully applied for in vivo tumor imaging with a high signal-to-noise ratio. Moreover, this multifunctional switchable sensor was also employed for the fluorescent imaging of the fluctuation of intracellular pH in HeLa cells. PMID- 26104215 TI - Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features. AB - BACKGROUND: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. METHODS: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. RESULTS: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. CONCLUSION: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup. PMID- 26104218 TI - Species sensitivity analysis of heavy metals to freshwater organisms. AB - Acute toxicity data of six heavy metals [Cu, Hg, Cd, Cr(VI), Pb, Zn] to aquatic organisms were collected and screened. Species sensitivity distributions (SSD) curves of vertebrate and invertebrate were constructed by log-logistic model separately. The comprehensive comparisons of the sensitivities of different trophic species to six typical heavy metals were performed. The results indicated invertebrate taxa to each heavy metal exhibited higher sensitivity than vertebrates. However, with respect to the same taxa species, Cu had the most adverse effect on vertebrate, followed by Hg, Cd, Zn and Cr. When datasets from all species were included, Cu and Hg were still more toxic than the others. In particular, the toxicities of Pb to vertebrate and fish were complicated as the SSD curves of Pb intersected with those of other heavy metals, while the SSD curves of Pb constructed by total species no longer crossed with others. The hazardous concentrations for 5 % of the species (HC5) affected were derived to determine the concentration protecting 95 % of species. The HC5 values of the six heavy metals were in the descending order: Zn > Pb > Cr > Cd > Hg > Cu, indicating toxicities in opposite order. Moreover, potential affected fractions were calculated to assess the ecological risks of different heavy metals at certain concentrations of the selected heavy metals. Evaluations of sensitivities of the species at various trophic levels and toxicity analysis of heavy metals are necessary prior to derivation of water quality criteria and the further environmental protection. PMID- 26104219 TI - Association between new indices in the locomotive syndrome risk test and decline in mobility: third survey of the ROAD study. AB - BACKGROUND: We aimed to clarify the association between new indices in a locomotive syndrome risk test and decline in mobility. METHODS: In the third survey of the Research on Osteoarthritis/osteoporosis Against Disability (ROAD) study, data on the indices were obtained from 1575 subjects (513 men, 1062 women) of the 1721 participants in mountainous and coastal areas. As outcome measures for decline in mobility, we used the five-times-sit-to-stand test (FTSST) and walking speed with cutoff values of 12 s and 0.8 m/s, respectively. RESULTS: We first estimated the prevalence of the indices in locomotive syndrome risk test stage 1, including two-step test score <1.3, difficulty with one-leg standing from a 40-cm-high seat in the stand-up test, and 25-question GLFS score >=7, which were found to be 57.4, 40.6, and 22.6 %, respectively. Next, we investigated the prevalence of the indices in locomotive syndrome risk test stage 2, including two-step test score <1.1, difficulty with standing from a 20-cm-high seat using both legs in the stand-up test, and 25-question GLFS score >=16, which were found to be 21.1, 7.9, and 10.6 %, respectively. Logistic regression analysis using slow FTSST time or slow walking speed as the objective factor, and presence or absence of indices as the independent factor, after adjusting for confounders, showed all three indices in both stages 1 and 2 were significantly and independently associated with immobility. Finally, we clarified the risk of immobility according to an increasing number of indices in both stages 1 and 2 and found that the odds ratio for both slow FTSST time and slow walking speed increased exponentially. CONCLUSION: We found that the three indices independently predicted immobility and that accumulation of indices increased the risk of immobility exponentially. PMID- 26104221 TI - Asthma exacerbations and lung function in patients with severe or difficult-to treat asthma. PMID- 26104220 TI - Development of a support tool for the clinical diagnosis of symptomatic lumbar intra- and/or extra-foraminal stenosis. AB - BACKGROUND: Not all lumbar intra- and/or extra-foraminal stenosis (LIEFS) on MRI is symptomatic. Therefore, the establishment of clinical diagnostic tools that can identify patients with symptomatic LIEFS is crucial in the clinical setting. The aim of this study was to develop a support tool for clinical diagnosis of LIEFS. METHODS: Patients with L5 radiculopathy alone were prospectively enrolled. Fifty-one patients with lumbar spinal canal stenosis only at the L4-5 level and 49 patients with LIEFS only at the L5-S1 level were extracted from this cohort. We compared the two groups with regard to 12 variables--three subjective and three objective items from the Japanese Orthopaedic Association (JOA) score; Kemp's sign; results of the lumbar flexion test, Bonnet test, and Freiberg test; pain on sitting; and pain when recumbent--to determine which factors were associated with a high index of clinical suspicion of LIEFS. RESULTS: The significant predictors of a final diagnosis of LIEFS were identified as follows: pain when recumbent, Freiberg and Bonnet test results, and pain on sitting. To develop a diagnostic tool, a scoring system (0-20 points) was formulated on the basis of the contribution ratios of these risk factors. To determine the contribution ratio, an integer score was assigned to the identified risk factors as follows: pain when recumbent = 9 points, Freiberg = 5 points, Bonnet = 3 points, and pain on sitting = 3 points. The Hosmer-Lemeshow statistic for this scoring system was p = 0.063, and confirmed that it was a good model. Receiver operating characteristic (ROC) curve analysis demonstrated a cut-off value of 5 points, an area under the ROC curve of 0.87435, sensitivity of 75.5 %, and specificity of 82.3 %. CONCLUSIONS: We believe that the use of this tool in the clinical setting will improve the accuracy of diagnosing symptomatic LIEFS, which will lead to improved quality of patient care. PMID- 26104222 TI - The Painful Legacy of Childhood Violence: Migraine Headaches Among Adult Survivors of Adverse Childhood Experiences. AB - BACKGROUND: Childhood adversities have been associated with adult migraine in the general population. However, most research has focused on only a few types of maltreatment and has not always controlled for factors correlated with early adversities and migraine. OBJECTIVES: The aim of this study was to investigate the relationship between early adversities and migraine, while controlling for a range of potential explanatory factors. METHODS: We analyzed data from the 2012 Canadian Community Health Survey - Mental Health. Using a representative sample of 10,358 men and 12,638 women, we undertook gender-specific logistic regression analyses to determine the association between number and type of self-reported childhood adversities (physical abuse, sexual abuse, and witnessing parental domestic violence) and migraine, while controlling for sociodemographics, comorbid adversities, health behaviors, depression, and anxiety. RESULTS: In total, 6.5% of men and 14.2% of women reported migraines. All three adversities were significantly associated with migraine for both genders, even after controlling for a range of variables. The fully adjusted odds of migraine associated with physical abuse, parental domestic violence, and sexual abuse were 1.61 (95% confidence interval [CI] = 1.42-1.83), 1.64 (95% CI = 1.39-1.93), and 1.32 (95% CI = 1.11-1.57), respectively, for women, and 1.50 (95% CI = 1.25 1.80), 1.52 (95% CI = 1.16-1.98), and 1.70 (95% CI = 1.22-2.36) for men. Greater number of adversities was also associated with increasing odds of migraine. Men reporting all three adversities had over three times (odds ratio = 3.26; 95% CI = 2.09-5.07) and women over two times (OR = 2.85; 95% CI = 2.25-3.60) the odds of migraine compared with those without childhood adversities. CONCLUSIONS: Number and type of early adversities are associated with migraine among Canadian men and women. PMID- 26104223 TI - Effectiveness of Three Types of Interventions in Patients with Fibromyalgia in a Region of Southern Catalonia. AB - Several pharmacological and nonpharmacological treatments can be used to alleviate the symptoms of fibromyalgia, although none of them are completely effective at present. In this study, we analyzed the effectiveness of different therapies in three groups of people diagnosed with fibromyalgia. The sample for this randomized controlled trial was made up of 66 people diagnosed with fibromyalgia in southern Catalonia. In turn, this sample was divided into three groups of 22 participants each, who were treated with: i) cervical infiltration with botulinum toxin, ii) group problem-solving therapy, or iii) both therapies. The variables recorded were quality of life, suicidal thoughts, perception of pain, quality of sleep, and satisfaction. Female patients composed 96.9% (n = 64) of the study sample. Satisfaction with the infiltration was 5.1 +/- 2.7 points, while in group problem-solving therapy it was 6.6 +/- 3.2. Self-perceived health in the infiltration group (p = .016) and the therapy group (p = .001) improved after the intervention took place. The risk of suicide decreased in the both treatments/groups (p = .049). Pain was reduced by 31.8% with infiltration, 13.6% with therapy, and 22.7% with both treatments. Anxiety/depression decreased by 45% with therapy, 36.3% with infiltration, and 36.3% with both treatments. The results also showed that the use of both treatments significantly reduces suicidal thoughts (p = .049). In conclusion, this study showed the complexity of reducing chronic pain and increasing the quality of life of people with fibromyalgia. PMID- 26104224 TI - IgG4-related disease in the sinonasal cavity accompanied by intranasal structure loss. AB - IgG4-related disease was recently proposed under the classification of systemic chronic inflammatory disease. In the field of otolaryngology, organ-specific diagnostic criteria have been established for the occurrence of this condition in the salivary glands, but not in the sinonasal cavity. Here we report a case involving a 70-year-old man with IgG4-related disease in the sinonasal cavity. The patient, with the chief complaint of nasal bleeding, first visited a physician. However, the patient experienced recurrent bleeding with intranasal structure loss and was subsequently referred to our hospital. His IgG4 level was elevated, and histopathological examination of a tissue sample obtained from the edematous sphenoid sinus showed increased IgG4-positive plasma cells and storiform fibrosclerosis. A definitive diagnosis of IgG4-related rhinosinusitis was made on the basis of comprehensive criteria for IgG4-related disease. The disease showed a progressively destructive course that was clearly different from that of chronic sinusitis and represented a very rare case of IgG4-related rhinosinusitis. IgG4-related disease originating in the sinonasal cavity is rare, and, to the best of our knowledge, this is the first primary case of IgG4-related disease that originated in one side of the sinonasal cavity and showed progressive destruction. PMID- 26104226 TI - Editorial. PMID- 26104225 TI - Hypertrophic olivary degeneration resulting from posterior fossa masses and their treatments. AB - PURPOSE: Characterize hypertrophic olivary degeneration (HOD) that develops from posterior fossa masses and their treatments. METHODS: Retrospectively reviewed MR images and clinical data of 10 patients with posterior fossa masses and HOD. RESULTS: Eight patients had cerebellar lesions, and two patients had pontine lesions. Lesions consisted of tumors, demyelination, and nonspecific necrosis. MRI showed T2 hyperintense signal in the inferior olive a median 86 days after the diagnosis of a posterior fossa lesion. HOD presented prior to surgery (n=2), after surgery (n=3), after surgery/radiation therapy (n=4), or without treatment (n=1). CONCLUSIONS: HOD may develop from posterior fossa masses and surgical and/or radiation therapy. PMID- 26104227 TI - Pre-eclampsia: Definitions, paternal contributions and a four stage model. AB - It is 40 years since I started researching pre-eclampsia. Much has changed but some old problems persist. These include the debate of how to define a syndrome, the inheritance and genetics of pre-eclampsia, why primiparae are so susceptible and is primipaternity important? If it is, in a multiparous pregnancy (after changing partners), the old hypothesis that pre-eclampsia is the outcome of failed maternal immunoregulation to accommodate nature's transplant - the fetus - must be confronted. These points are briefly reviewed and a four stage model of pre-eclampsia derived. PMID- 26104228 TI - Biomarkers of oxidative stress in pre-eclampsia. AB - Pre-eclampsia is associated with oxidative stress, confirmed by measurement of biomarkers and relevant antioxidant enzymes in the placenta and maternal circulation. Studies in vitro have described the pathways by which placental ischaemia can lead to oxidative stress as well as endoplasmic reticulum stress, which is coupled to synthesis of reactive oxygen species. However, clinical trials of antioxidants vitamins C and E, with an associated increase of plasma vitamins C and E concentrations have shown no benefit in prevention of the disorder, which may infer lack of a mechanistic role. Before oxidative stress is dismissed as an irrelevant accompaniment to pre-eclampsia further studies of proven biomarkers of oxidative stress are required to determine whether vitamins C and E supplementation leads to evidence of reversal of oxidative processes and tissue damage. If not, alternative antioxidant strategies may be worthy of consideration. PMID- 26104229 TI - Circulating predictive biomarkers in preeclampsia. AB - The aim of the paper was to review promising prediction biomarkers for preeclampsia. The methods included review of abstracts on PubMed, using "preeclampsia", "biomarker", "prediction" as key words, followed by review of primary papers investigating blood based biomarkers. Angiogenic factors, such as PlGf and sFlt1, and PP13 seem presently to have the best predictive test values for preeclampsia, but sensitivity and specificity is still too low to prove useful in a population screening setting. Biomarker testing should still be part of research protocols. Biomarkers could provide useful in selecting high-risk women for prophylactic trials as well as identifying pregnancies that could profit from closer follow-up. PMID- 26104230 TI - Inflammation and preeclampsia. AB - No individual can claim credit for all the advances made during his lifetime. However, certain individuals have a far greater influence than others. Prof. Christopher Redman has had a huge role to play in increasing the understanding of the aetiology, pathology, progression and management of preeclampsia. The work he did personally, led in others and stimulated in colleagues, both friend and foe, has helped to progress preeclampsia from a disease that came from nowhere to one that is more understood and safely managed. In this paper, it is the work in immunology that will be concentrated on in a chronological way but this will be linked to other relevant research and clinical practice. The understanding that preeclampsia is a two-stage disease starting in the placenta and progressing systemically has led to greater understanding as well as more questions. The universal role of immunology first as an acceptor within the placental bed then as a disease driver in the systemic circulation emphasises the good and the bad in physiological systems. Prof. Redman has been present in all these areas of discovery and enlightenment as will be described. PMID- 26104231 TI - Endothelial progenitor cells: Their potential role in pregnancy and preeclampsia. AB - The normal maternal cardiovascular adaptation to pregnancy involves a complex physiologic response to the growing conceptus, including alterations in maternal vascular endothelial cells that contribute to a profound fall in total systemic vascular resistance. There is a large body of evidence that adverse changes in the vascular endothelium underlie the multisystemic maternal manifestations of the hypertensive pregnancy disorder preeclampsia. Our knowledge is incomplete regarding the mechanisms of adaptive endothelial changes of normal pregnancy, and why these changes are attenuated or fail in women who develop preeclampsia. Endothelial progenitor cells (EPCs) are a heterogeneous population of cells that exist in both the fetus and adult. These cells can be mobilized into the circulation by growth factors and can then support the health of the vascular endothelium by several mechanisms. This review highlights some of the current understanding of EPCs, their potential role in pregnancy, and emerging evidence for EPC dysfunction in preeclampsia. We speculate that interference with nitric oxide (NO)-driven mobilization or activity of EPCs in the maternal circulation partially contributes to the widespread endothelial dysfunction underlying the clinical manifestations of preeclampsia. Potential roles of EPCs in the placenta and fetus are also considered. PMID- 26104232 TI - The functions of microparticles in preeclampsia. AB - Circulating blood cells, trophoblast cells and endothelial cells release microparticles (MP) into the maternal blood by membrane shedding. This process occurs upon activation or apoptosis of these cells. Evidence is accumulating that MP play a role in the development of thrombotic diseases. In recent years, the importance of changes in circulating MP numbers and in composition in preeclampsia has been recognized and research is now directed to discover the functional consequences of these changes. In this review we will discuss the structure and function of MP, with special emphasis on the changes in MP numbers, composition and function in pregnancy and preeclampsia. PMID- 26104233 TI - Endovascular trophoblast and preeclampsia: A reassessment. AB - Since the earliest report on impaired spiral artery remodelling in preeclamptic human pregnancies, numerous studies have been devoted to possible mechanisms of impaired trophoblast invasion. A better knowledge of early uteroplacental blood flow has provided a physiological context for the processes of spiral artery invasion and associated remodelling, revealing a closely timed relationship between increasing flow and early steps in vascular remodelling. Concerning the impaired trophoblast invasion in preeclampsia, it has also to be considered that impaired invasion not only concerns invasion depth per se, but also the extension of this deep invasion from the central towards the more lateral spiral arteries of the placental bed. Since also in preeclampsia the very central spiral arteries may be normally invaded, the existence of such spatial gradient provides a further dimension to the problem. A practical consequence is that frequently used rodent models, which show invasion of two or three spiral arteries only, may be less useful for studying this particular aspect of the disease. Amongst non-human primates, baboons and rhesus monkeys are 'shallow invaders', and only in some of the great apes deep trophoblast invasion and associated spiral artery remodelling occurs. A better knowledge of the evolutionary history of deep invasion and its possible selective benefit might ultimately improve our understanding of failed deep invasion and impaired spiral artery remodelling in preeclampsia. PMID- 26104234 TI - Trophoblast differentiation, fetal growth restriction and preeclampsia. AB - The number of hypotheses trying to decipher the etiologies of preeclampsia and fetal growth restriction (FGR) is still increasing. However, for preeclampsia the actual knowledge we have is that the placenta is a prerequisite for the development of the syndrome. The recent years have seen a shift in understanding of the causes of preeclampsia from mostly focusing on the extravillous trophoblast towards the dysregulation of villous trophoblast development and maintenance. It seems as if a failure of the villous syncytiotrophoblast differentiation results in abnormal release of non-apoptotic fragments into maternal blood. In preeclampsia such necrotic or aponecrotic fragments can be found in maternal blood systemically and seem to be causative in the development of the inflammatory response of the mother. In cases with fetal growth restriction (FGR) extravillous trophoblast fails to adequately transform uterine spiral arteries. However, in FGR cases abnormal development of villous cytotrophoblast may have an impact on fetal nutrition without the induction of an inflammatory response of the mother. It is still unclear why the villous trophoblast fails to achieve an adequate turnover both in preeclampsia and in FGR. However, the detection of new biomarkers for preeclampsia such as placental protein 13 (PP13) has helped in clarifying the issue of when the syndrome starts to develop. PP13 levels in maternal serum are significantly altered already at six to seven weeks of gestation in women subsequently developing preeclampsia. Thus, there needs to be a very early alteration of villous development in such placentas. Herein the changes in villous trophoblast in preeclampsia and FGR are compared and differences between both scenarios are presented. PMID- 26104235 TI - Placental oxidative stress, selenium and preeclampsia. AB - There is considerable evidence that placental oxidative stress plays a significant role in the etiology of preeclampsia. Prophylactic use of exogenous anti-oxidants such as vitamins E and C have proven to be ineffective and potentially dangerous. The current study addresses the role of endogenous anti oxidant systems in preeclampsia. In particular, data on the selenodependent enzymes glutathione peroxidase and thioredoxin reductase will be presented and the role of selenium in preeclampsia will be considered. The aim of these studies was to determine the levels of endogenous antioxidants, selenium, and biological oxidation in normal and preeclamptic placental tissues. Furthermore, animal studies were conducted to assess the impact of selenium depletion on anti-oxidant expression and activity, oxidative stress and symptoms of preeclampsia. Selenium depletion generated placental oxidative stress and produced a preeclamptic like syndrome in pregnant rats suggesting a link between placental oxidative stress, endogenous antioxidant disequilibria and the pathogenesis of preeclampsia that may be linked to insufficient dietary selenium. The selenium of status of preeclamptic mothers was also considered and lower levels of selenium were observed when compared to normal controls. Selenium supplementation improves endogenous anti-oxidant expression in trophoblast cells and might provide an effective method of protecting the placenta from oxidative stress during preeclampsia. Clinical studies are now underway to investigate the benefits of low dose selenium supplementation on the development and progression of preeclampsia. PMID- 26104236 TI - Studies using routine data versus specific data collection: What can we learn about the epidemiology of eclampsia and the impact of changes in management of gestational hypertensive disorders? AB - Evidence-based changes in practice, services and policy may impact on the spectrum of pregnancy hypertensive disorders at many levels. Demonstration of clinical benefit relies on assessment of changes in disease incidence or complications. Two main alternative observational methodologies may be used to investigate changes in disease incidence; the first using routinely collected data and the second with specially designed prospective data collection. Routinely collected data have been shown to have limitations; the introduction of specific prospective data collection systems, such as the UK Obstetric Surveillance System, allow for an increased robustness and range of disease incidence and outcome studies, and thus enhance our ability to investigate the impact of changes in practice. The comparison of recent national studies using these systems shows that the incidence of eclampsia has declined in the UK, but that the incidence of eclampsia is higher in the Netherlands and Scandinavia. The decrease in the UK is clearly due to a fall in the number of women with diagnosed pre-eclampsia who go on to have an eclamptic fit; figures from the Netherlands and Scandinavia suggest that eclamptic fits in the group with prior diagnosed pre eclampsia are less effectively prevented and this may be the reason for the observed higher incidence of eclampsia. This information may help to further inform management and preventive strategies, and illustrates the additional benefits of international comparisons of severe maternal morbidities. PMID- 26104237 TI - Action on Pre-eclampsia: Crisis and recovery. AB - This is a review of the antenatal guidelines developed under the auspices of the charity Action on Preeclampsia since 2001. They are evidence-based and cover the screening and diagnosis of preeclampsia. They include a risk assessment early in pregnancy, referral for specialist input, a two tier schedule of assessment based on risk, signs and symptoms, referral for step-up care and confirmation of diagnosis, including blood tests. They describe methods for improving reliability of proteinuria testing, and reducing errors in the measurement of blood pressure. Management flowcharts are provided. PMID- 26104238 TI - Purification of vandaterosides from Vanda teres (Orchidaceae) by stepwise gradient centrifugal partition chromatography. AB - Vandaterosides are polar glucosyloxybenzyl eucomate derivatives found in Vanda teres (Orchidaceae), which display biological activities that slow the skin ageing process. In order to obtain larger quantities to allow us to go further in the bioassays, the hydroalcoholic extract of aerial parts (leaves and stems) of V. teres were fractionated by centrifugal partition chromatography, combining isocratic, gradient, and dual elution modes. The first fractionation was performed on the extract maintained in the stationary phase as water saturated in butanol, while increasing the polarity of the mobile phase by changing the proportions of ethyl acetate/1-butanol/water, in order to obtain two enriched fractions. Vandateroside I was then purified by isocratic mode with ethyl acetate/ethanol/water (46:14:40), while vandateroside II was obtained by combining isocratic elution with ethyl acetate/isopropanol/water (30:20:50) followed by a multiple dual mode with ethyl acetate/ethanol/water (46:14:40). In this manner, hundreds of milligrams of vandateroside I and II were recovered from 10 g of V. teres extract. PMID- 26104239 TI - Relationship between postoperative bulla neogenesis at the staple line and the resected lung volume in primary spontaneous pneumothorax. AB - PURPOSE: In patients with primary spontaneous pneumothorax (PSP), bullae are generally resected using autosutures under video-assisted thoracoscopic surgery (VATS). However, postoperative bulla neogenesis (POBN) along the staple line is not rare and is a factor promoting PSP recurrence. POBN is attributed to tension along the staple line, and we surmise that the resected lung volume affects this tension. Therefore, in this study, we retrospectively examined the relationship between POBN and the resected lung volume in patients who underwent surgical treatment of PSP. METHODS: Between February 2011 and May 2015, 70 lung resection sites in 56 PSP patients who underwent primary VATS at our hospital were evaluated. POBN was diagnosed on high-resolution computed tomography 1 year postoperatively in principle. RESULTS: POBN was detected at 26 of 70 (37.1 %) sites. On univariate analysis, lung weight >=1.5 g, lung length >=4.0 cm, resected site: apical, age <25 years old and non-smoking habit were identified as significant, and the POBN rates for cases with lung weight >=1.5 g or lung length >=4.0 cm were 47.9 % (P = 0.004) and 44.1 % (P < 0.001), respectively. On multivariate analysis, lung weight >=1.5 g was only significant factor for POBN (P = 0.043). CONCLUSION: A resected lung weight >=1.5 g was only significant risk factor of POBN in patients with PSP. PMID- 26104240 TI - Moral Philosophy, Moral Expertise, and the Argument from Disagreement. AB - Several recent articles have weighed in on the question of whether moral philosophers can be counted as moral experts. One argument denying this has been rejected by both sides of the debate. According to this argument, the extent of disagreement in modern moral philosophy prevents moral philosophers from being classified as moral experts. Call this the Argument From Disagreement (AD). In this article, I defend a version of AD. Insofar as practical issues in moral philosophy are characterized by disagreement between moral philosophers who are more or less equally well credentialed on the issue, non-philosophers have no good reasons to defer to their views. PMID- 26104241 TI - Structure-function correlations in tyrosinases. AB - Tyrosinases are metalloenzymes belonging to the type-3 copper protein family which contain two copper ions in the active site. They are found in various prokaryotes as well as in plants, fungi, arthropods, and mammals and are responsible for pigmentation, wound healing, radiation protection, and primary immune response. Tyrosinases perform two sequential enzymatic reactions: hydroxylation of monophenols and oxidation of diphenols to form quinones which polymerize spontaneously to melanin. Two other members of this family are catechol oxidases, which are prevalent mainly in plants and perform only the second oxidation step, and hemocyanins, which lack enzymatic activity and are oxygen carriers. In the last decade, several structures of plant and bacterial tyrosinases were determined, some with substrates or inhibitors, highlighting features and residues which are important for copper uptake and catalysis. This review summarizes the updated information on structure-function correlations in tyrosinases along with comparison to other type-3 copper proteins. PMID- 26104242 TI - Bilateral Cavernous Carotid Aneurysms: The Growth Potential of a Contralateral Aneurysm after Therapeutic Unilateral Internal Carotid Artery Occlusion. AB - BACKGROUND: Although the introduction of flow-diverter stents has been recognized as a major revolution in the treatment of cavernous carotid aneurysms (CCAs), therapeutic internal carotid artery occlusion (TICAO) remains a reliable procedure for alleviating symptoms caused by CCAs. However, TICAO has the potential risk of the enlargement of coexisting aneurysms that are frequently detected in CCA patients. The purpose of this study is to assess the occurrence of the enlargement of aneurysms coexisting with CCAs after TICAO. METHODS: We reviewed medical charts of CCA patients who were managed using unilateral TICAO. Coexisting aneurysms were identified using angiograms obtained before TICAO, and imaging data in long follow-up periods were retrospectively examined to determine the extent of the enlargement after TICAO. RESULTS: Of 12 patients with CCAs, 10 had 12 coexisting aneurysms; 5 of the coexisting aneurysms (41.7%) showed enlargement during a mean follow-up period of 8.1 years, and all enlarged aneurysms were smaller of the bilateral CCAs; the larger CCA had been managed by TICAO. Five of 6 (83.3%) patients with bilateral CCAs showed enlargement of the contralateral aneurysm after TICAO. Two contralateral CCAs showed marked enlargement after TICAO and were subsequently treated with stent-assisted coil embolization. CONCLUSIONS: Contralateral, smaller aneurysms frequently enlarge after unilateral TICAO in patients with bilateral CCAs. The findings emphasize the importance of long-term observation after TICAO and appropriate interventions against enlarging contralateral aneurysms. PMID- 26104244 TI - A Eulogy and Tribute to Andrea Luigi Tranquilli. PMID- 26104243 TI - Adherence to Mediterranean diet and 10-year incidence (2002-2012) of diabetes: correlations with inflammatory and oxidative stress biomarkers in the ATTICA cohort study. AB - BACKGROUND: The purpose of this work was to investigate the links between oxidative stress, inflammation and coagulation and their effect on Mediterranean diet-diabetes relationship. METHODS: In 2001-2002, a random sample of 1514 men (18-87 years old) and 1528 women (18-89 years old) was selected to participate in the ATTICA study, where Athens is the major metropolis. A validated questionnaire was used to assess lifestyle and dietary factors. Adherence to Mediterranean diet was recorded using MedDietScore. Among others, oxidative stress and inflammatory biomarkers were recorded. During 2011-2012, the 10-year follow-up was performed. Diabetes incidence was defined according to the American Diabetes Association criteria. RESULTS: A total of 191 incident cases of diabetes were documented, yielding an incidence of 12.9% (13.4% in men and 12.4% in women). Medium and high adherence was found to decrease diabetes risk by 49% (95% CI: 0.30, 0.88) and 62% (95% CI: 0.16, 0.88), respectively, compared with low adherence. A logarithmic trend between Mediterranean diet and diabetes incidence was also revealed (p for trend = 0.042). Individuals with abnormal waist circumference (>94 for men, >80 for women) were benefited the most. Wholegrain cereals, fruits and legumes had the greatest predictive ability. The anti-diabetic effect of Mediterranean diet correlated with measurements of tumour necrosis factor-alpha, homocysteine and total antioxidant capacity. CONCLUSIONS: The reported results support the role of Mediterranean diet as a promising dietary tool for the primary prevention of diabetes, by attenuating inflammation and fostering total antioxidant capacity. This dietary pattern may have therapeutic potential for many cardiometabolic disorders associated with inflammation and/or oxidative stress. PMID- 26104245 TI - The relationship between Activin A and anti-angiogenic factors in the development of pre-eclampsia. AB - Anti-angiogenic factors such as sFlt/sEng contribute to the pathology seen in preeclampsia. Activin A, which is released by the placenta following exposure to oxidative stress and elevated in preeclampsia, may interact with sFlt/sEng during the disease process. Using placental explant cultures, we determined that transcription of sFLT1, ENG and INHBA was upregulated following exposure to oxidative stress or IL-6. Explants treated with Activin A did not increase transcription of sFLT1, ENG. Conversely, treatment of placental explants with sFlt/sEng did not increase transcription of INHBA. These data may suggest that Activin A and sFlt/sEng contribute to preeclampsia via separate pathways. PMID- 26104246 TI - Trophoblast calcyclin is elevated in placental tissue from patients with early pre-eclampsia. AB - The aetiology of pre-eclampsia is thought to originate from aberrant spiral artery remodelling and invasion evoking cellular oxidative stress. Previously, we discovered differentially expressed proteins in trophoblast cells of pre eclamptic pregnancies. One of these proteins is calcyclin (S100A6); a Ca(2+) binding protein associated with cellular stress response. By immunohistochemistry on formalin-fixed paraffin-embedded placental tissue, calcyclin expression was compared between women with early pre-eclampsia (n=72) and non-hypertensive control patients (n=66) (chi(2), p=0.006) blindly by two observers. Significantly more intense staining was seen in trophoblast cells of pre-eclamptic pregnancies compared to control placentas suggesting that trophoblast calcyclin is elevated in early pregnancy. PMID- 26104247 TI - Reduced circulating miR-196b levels is associated with preeclampsia. AB - MicroRNAs (miRs) are small noncoding RNAs, highly stable in plasma, that regulate gene expression by base-pairing to the 3'-untranslated region of target mRNAs. We compared the expression of 3 circulating miRs (miR-125b, miR-146a, and miR-196b), which is related to the control of cell proliferation, differentiation, and apoptosis in preeclamptic (n=19) and healthy pregnant women (n=14). We found that women with preeclampsia (PE) presented lower expression of miR-196b (-2.9-fold change). The other miRs were at similar levels. This study is the first to demonstrate this difference, and highlights new opportunities for investigation into the role of miRs in PE. PMID- 26104248 TI - Haplotype analysis of TGF-beta1 gene in a preeclamptic population of northern Mexico. AB - OBJECTIVE: To determine the frequencies of -800G/A (rs1800468), -509C/T (rs1800469) and 869T/C (rs1800470) polymorphisms and their haplotypes in the TGF beta1 gene and their association with preeclampsia in a population of northern Mexico. DESIGN AND METHODS: This case-control study involved 175 preeclamptic and 253 normoevolutive pregnant women. The polymorphisms were genotyped by real time PCR. RESULTS: The allele and genotype frequencies of polymorphisms showed no significant differences between cases and controls; the -800AA genotype had a very low frequency in cases (1%) and controls (0.4%). The TT genotype of the 869T/C polymorphism is a protective factor of severe preeclampsia (OR 0.56, 95% CI 0.32-0.98). The -509C/T and 869T/C polymorphisms were in linkage disequilibrium (D'=.537, p=.009). The most common haplotypes in case and control groups were -800G/-509C/869C, 34.95% and 37.24%, respectively. We found no increased risk of preeclampsia by haplotype. CONCLUSIONS: Our results suggest that -800G/A, -509C/T and 869T/C polymorphisms of TGF-beta1 gene or their haplotypes are not associated with preeclampsia and that only the TT genotype of 869T/C polymorphism is a protective factor of severe preeclampsia in a population of northern Mexico. PMID- 26104249 TI - Hydralazine vs labetalol for the treatment of severe hypertensive disorders of pregnancy. A randomized, controlled trial. AB - Hydralazine and labetalol for intravenous use are equally effective in the management of hypertensive crisis in pregnant patients (24weeks or more) with severe hypertensive disorders of pregnancy, showing a similar frequency of adverse effects in both groups. PMID- 26104250 TI - Association of NT-proBNP with plasma renin activity and plasma aldosterone concentration in women with singleton pregnancy. AB - OBJECTIVE: To determine the association of the N-terminal fragment of precursor protein brain-type natriuretic peptide (NT-proBNP) levels with plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in singleton pregnancies. DESIGN: Serum NT-proBNP levels, PRA and PAC were determined in 215 blood specimens from 139 women with singleton pregnancies, including 34 and 105 women who did and did not develop hypertensive disorders in pregnancy, respectively. Twenty-five blood specimens were obtained from 25 women who later developed hypertension (systolic BP?140mmHg and/or diastolic BP?90mmHg), but were normotensive at the time of blood sampling. RESULTS: The serum NT-proBNP levels [pg/ml, median (range), 32 (5-142)] did not change in normotensive women, but increased significantly to 97 (23-436) after the development of hypertension (D/H). The PRA [ng/ml/h, median (range), 7.1 (1-20)] did not change in normotensive women, but decreased significantly to 1.9 (1-16) after D/H. PAC (pg/ml) increased significantly from 397 (94-1750) to 667 (123-2010) between the 2nd and 3rd trimesters in normotensive women. However, as PAC of hypertensive women did not change significantly before and after D/H, PAC [293 (116-1720)] after D/H was significantly lower than that [667 (123-2010)] of the 3rd trimester in the normotensive women. The serum levels of NT-proBNP were significantly and negatively correlated with both PRA and PAC. CONCLUSIONS: The renin-angiotensin aldosterone system is suppressed in pregnant women with cardiac conditions associated with higher NT-proBNP levels. PMID- 26104251 TI - Maternal serum CA-125 level is elevated in severe preeclampsia. AB - AIM: The aim of this study was to determine the relationship between serum concentrations of cancer antigen-125 (CA-125) and pre-eclampsia severity. METHODS: We evaluated 91 females with a singleton pregnancy. Serum CA-125 levels were measured in subjects with severe pre-eclampsia (n=34) and those with mild pre-eclampsia (n=24). Females with healthy pregnancies (n=31) served as the control group. The three study groups were statistically similar in terms of maternal age, gestational age, and body mass index. RESULTS: The CA-125 level was significantly higher in the severe pre-eclampsia group than that in the mild pre eclampsia and control groups (p<0.05). No significant difference in CA-125 levels between the mild pre-eclampsia and control groups was observed. CA-125 level was positively correlated with proteinuria (r=0.489, p=0.000), systolic blood pressure (r=0.503, p=0.018), and diastolic blood pressure (r=0.532, p=0.000). In contrast, CA-125 was negatively correlated with birth weight (r=0.266, p=0.012) and gestational age at birth (r=0.250, p=0.018). CONCLUSIONS: CA-125 level increased in severe pre-eclampsia, which reflected abnormal trophoblastic invasion and chronic inflammation. Elevated levels of CA-125 in pre-eclamptic patients may be a marker of the disease severity. PMID- 26104252 TI - The risk of preeclampsia beyond the first pregnancy among women with type 1 diabetes parity and preeclampsia in type 1 diabetes. AB - AIM: To estimate the incidence of preeclampsia (PE) among nulliparous and multiparous patients with type 1 diabetes and to study predictors of PE. METHODS: We prospectively collected data on all pregnancies of patients with pregestational type 1 diabetes, followed at our Prenatal Medicine Unit between 1993 and 2008. Medical records were prospectively reviewed by two obstetricians for maternal demographics, pregnancy data, maternal and fetal outcomes. Data were analyzed according to the development of PE and parity. RESULTS: We identified and collected data on 291 eligible pregnancies (195 among nulliparae and 96 among multiparae). The incidence of PE was 9.2% (95% CI: 5.6-14.2) among nulliparae and 9.4% (95% CI: 4.4-17.0) among multiparae. Patients who developed PE had higher HbA1c during pregnancy compared to patients who did not (p=0.026 among nulliparae and p=0.032 among multiparae). Chronic hypertension [OR 17.12 (3.22, 91.00)], microalbuminuria at the beginning of the pregnancy [OR 3.77 (1.22, 11.61)], weight gain during pregnancy [OR 1.13 (1.04, 1.23)] and HbA1c in the first trimester [2.81 (1.12, 7.05)], but not parity, were significant predictors of PE. CONCLUSIONS: Among patients with type 1 diabetes the incidence of PE was similar among nulliparae and multiparae, unlikely in the general population where PE is a disease of the first pregnancy. An increased risk of PE should be assumed for both nulliparous and multiparous women with pregestational diabetes. PMID- 26104253 TI - Blood pressure in pregnancy and magnesium sensitive genes. AB - OBJECTIVES: High blood pressure during the last part of pregnancy is a risk indicator of pre-eclampsia and eclampsia which augment infant and maternal morbidity and mortality. Magnesium deficiency has been related to the risk of hypertension. A study was performed to assess the relation between pregnancy induced hypertension, excretion of urinary magnesium and expression of magnesium sensitive genes (MgSG). METHODS: A cohort of healthy, nulliparous women with singleton pregnancies was recruited. Blood pressure was recorded throughout pregnancy. Urinary magnesium excretion and expression of MgSGs in leukocytes were determined. RESULTS: The expression of the gene TRPM6 was higher among pregnant women compared to non-pregnant controls at week 12. All other genes had lower expressions in pregnant women. At week 37 the expressions of all genes were lower than at week 12. The expressions of SLC41A1, SLC41A3, and TRPM7 were related to the systolic and diastolic blood pressures. Furthermore, the expression of TRPM6 was related to the urinary excretion of magnesium and the change in diastolic blood pressure weeks 12-37 was inversely related to the change in magnesium excretion. CONCLUSIONS: Systolic and diastolic blood pressure and the excretion of magnesium during pregnancy were related to the expression of different MgSGs. The results suggest that magnesium is involved in the regulation of blood pressure during pregnancy. PMID- 26104254 TI - Effect of age, parity, and race on the incidence of pregnancy associated hypertension and eclampsia in the United States. AB - PURPOSE: To describe the incidence of pregnancy associated hypertension and eclampsia from adolescence through the fifth decade of life, including the effect of parity and race, in the United States. METHODS: Data were evaluated from the National Center for Health Statistics (vital statistics section). The data were stratified by maternal age group, parity (G1, first pregnancy; G2+, second or higher pregnancy), and racial group. RESULTS: The incidence of pregnancy associated hypertension (PAH) decreased with increased age in late adolescence in the G2+ group but not the G1 group (total and all racial groups). The incidence of PAH was significantly greater for non-Hispanic black or non-Hispanic white than Hispanic groups for all age groups (P?.02) except age ?15years (G2+ group) and 45-54years (both G1 and G2+ groups). The incidence of eclampsia decreased with increased age in late adolescence in the G2+ group (total and all racial groups) and the G1 group (total and non-Hispanic black groups). The incidence of eclampsia was significantly greater for non-Hispanic black than non-Hispanic white and for non-Hispanic white than Hispanic groups for all age groups except age ?15years in the G2+ group. The incidence of PAH and eclampsia increased substantially in both G1 and G2+ groups in the fifth decade of life (total and all racial groups). CONCLUSIONS: The incidence of PAH (G2+ group) and eclampsia (G1 and G2+ groups) decreased with increased age during adolescence and increased in the fifth decade (G1 and G2+ groups). PMID- 26104255 TI - Obstetric implications of fetal inherited thrombophilia in thrombophilic women. AB - OBJECTIVES: The relationship between fetal thrombophilic polymorphism and adverse pregnancy outcomes is still unclear. The aim of this study is to evaluate if fetal thrombophilia may affect obstetric and perinatal outcomes in thrombophilic women. STUDY DESIGN: From 2007 to 2011 all patients with a known inherited thrombophilic mutation consecutively admitted to our labor ward at ?25weeks of gestation with a singleton viable pregnancy were considered eligible for the purpose of the study. At the age of 1year, the infants were tested for inherited thrombophilic mutations. Patients were then divided into two groups according to the presence or absence of any neonatal mutation. MAIN OUTCOME MEASURES: The following outcome variables were then compared between the two groups: gestational age at delivery, birth weight, incidence of hypertensive disorders of pregnancy and SGA neonates. RESULTS: Overall, 67 pregnancies of 49 women were studied. Among them, the G20210A Prothrombin (32/67 or 47.7%) mutation and the Factor V Leiden mutation (31/67 or 46.3%) were the commonest findings, with a single patient presenting both. A thrombophilic mutation was found in 38 mother infant pairs. The risk of all maternal and perinatal events including the incidence of hypertensive disorders disorders (5/29 or 17.2% vs 6/38 or 15.7% p=1.00) and of SGA neonates (3/29 or 10.3% vs 7/38 or 18.4%, p=0.49) was comparable between the two groups irrespective of the associated fetal thrombophilia. CONCLUSIONS: Our data suggest that women with inherited thrombophilia carrying a thrombophilic fetus are not at increased risk of adverse pregnancy outcomes. PMID- 26104256 TI - Association of COMT G675A and MTHFR C677T polymorphisms with hypertensive disorders of pregnancy in Mexican mestizo population. AB - OBJECTIVE: To investigate the relationship between COMT G675A and MTHFR C677T polymorphisms and hypertension disorders of pregnancy (HDP) in a Mexican mestizo population. DESIGN AND METHODS: This case-control study involved 194 HDP and 194 normoevolutive pregnant women. The polymorphisms were genotyped by real time PCR. RESULTS: Our results showed that the COMT AA genotype increases the risk to HDP (OR: 2.67; 95% CI 1.33-5.35), preeclampsia (OR: 2.69; 95% CI 1.00-7.22) and gestational hypertension (OR: 3.87; 95% CI 1.25-12.0). Furthermore, the double mutant genotype (COMTAA/MTHFRTT) potency the risk to HDP more than two times (OR: 5.21; 95% CI 1.12-24.3, p=0.019). CONCLUSION: Our work provides evidence that COMT 675AA genotype is a risk factor for HDP and that this risk is increased by the presence of MTHFR 677TT genotype in a Mexican mestizo population. PMID- 26104257 TI - Endothelial nitric oxide synthase (eNOS) gene Glu298Asp polymorphism and expression in North Indian preeclamptic women. AB - BACKGROUND: Pathophysiological processes in preeclampsia (PE) are influenced by genetic factors, nitric oxide synthases seem to play important roles, although their expression in and their role is still unclear. To better characterize the host genetic factors determining the susceptibility to PE, we evaluated the influence of polymorphisms (Glu298Asp) in the endothelial nitric oxide synthase (eNOS) gene on the risk of developing PE by checking the expression level. METHODS: We conducted a hospital-based case-control study including 300 women with preeclampsia and 200 healthy pregnant women. Their blood samples were analyzed for levels of nitric oxide, eNOS gene polymorphism and expression. eNOS mRNA levels were determined using RT-PCR and expressed as arbitrary units after correction with control beta-Actin gene mRNA levels. RESULTS: The mRNA expression of eNOS gene was found to be significantly lower in blood (P<0.05) from women with PE compared to that from normal pregnancies. The total nitric oxide levels (P<0.001) were decreased in study Group as compared to healthy pregnant patients. The intergenotypic variation of nitric oxide levels in preeclamptic women was found to be significant (P<0.001). CONCLUSIONS: These results indicate the relationship between reduced nitric oxide levels and eNOS gene polymorphism leading to its altered expression in preeclamptic women. PMID- 26104258 TI - Altered metabolic profile in early and late onset preeclampsia: An FTIR spectroscopic study. AB - OBJECTIVE: Metabolic anomalies, if any, between early and late onset preeclampsia [PE] were explored using Fourier transform infrared [FTIR] spectroscopy. SETTING: Department of Gynecology and Obstetrics, SSKM Hospital, IPGMER, Kolkata and Midnapur Medical College Hospital, Midnapur, India. SAMPLE: 80 pregnant women attending routine antenatal care units; (i) early onset PE [gestational age; GA<34weeks] (ii) late onset PE [GA>34weeks] (iii) early onset control [GA 24 34weeks] and (iv) late onset control [GA>34weeks]. METHODS: Serum FTIR spectra were obtained in the wave-number range of 600-4000cm(-1) at 4cm(-1) resolution. (1)H NMR and estimation of atherosclerotic index (AI) were performed to validate the FTIR findings. MAIN OUTCOME MEASURE(S): Clinical characteristics and metabolic profile. RESULTS: 13 spectral peaks corresponding to the carbohydrate, protein and lipid region were significantly altered in early onset PE [P<0.001; at 95% confidence interval]. Discriminant analysis identified five highly significant wave-numbers (1078, 1088, 1122, 1169 and 1171cm(-1)) having ?80% overall accuracy. Hierarchical cluster analysis of the obtained spectra at these 5 wave-numbers provided excellent segregation of early and late onset PE with respect to their controls. Principal component analysis revealed that these 5 wave-numbers significantly separated the two sub-groups of PE (97.95% of the total variance). (1)H NMR results showed that serum levels of glutamate, choline, alanine and lactate were significantly higher while ariginine and citrate were significantly decreased in early onset PE as compared to late onset cases. CONCLUSION: Our study reveals differences in metabolomic profiles of early and late onset preeclamptic cases. PMID- 26104259 TI - Expectant management of severe preeclampsia with severe fetal growth restriction in the second trimester. AB - OBJECTIVE: We investigated whether women with severe fetal growth restriction (FGR <5th percentile) associated with severe preeclampsia (PE) occurring in the second trimester are candidates for expectant management. STUDY DESIGN: This is a retrospective study involving 33 women who developed severe PE or superimposed PE in the second trimester and were expectantly managed at a tertiary center. They were divided into groups with and without severe FGR on admission (severe FGR (+) group: 17 women; severe FGR (-) group: 16 women) for comparison of the duration of pregnancy prolongation, major maternal complications, and perinatal outcomes. The data are presented as medians (range) or frequencies (percentage). RESULTS: The duration of pregnancy prolongation was 10days in both groups. Major maternal complications occurred in 5 of 17 women (29.4%) in the severe FGR (+) and 5 of 16 (31.3%) in the severe FGR (-) group, showing very similar incidence rates in the 2 groups. The perinatal survival rates were favorable at 82.4% (14/17) in the severe FGR (+) and 100% (16/16) in the severe FGR (-) group. CONCLUSION: Regarding expectant management of severe preeclampsia occurring in the second trimester, there was no difference in the duration of pregnancy prolongation between the groups with and without severe FGR on admission. Because favorable perinatal outcomes can be expected without compromising maternal safety by prolonging pregnancy as expectant management for severe FGR, it was suggested that women with severe FGR are suitable candidates for expectant management. PMID- 26104260 TI - Spot urine protein-creatinine ratio and 24-h urine protein excretion: Diagnostic accuracy in women with pre-eclampsia. AB - OBJECTIVE: To compare the efficacy of spot urinary protein/creatinine ratio with 24h urinary protein excretion in women with pre-eclampsia. METHODS: A total of 85 women with hypertensive disorders during pregnancy were prospectively studied. Urine protein/creatinine ratio in spot urine sample was compared with 24h urinary protein. Sensitivity and specificity for urinary spot P/C (protein/creatinine) ratio was assessed, and receiver operating curve was used to determine the value against the gold standard of >300mg proteinuria in 24h urinary sample. RESULTS: Of 85 women, complete data were available for 81 women. There was a strong correlation between spot urinary P/C ratio and 24h urine protein excretion (r=0.81, P value <0.000). The optimal spot P/C ratio cut-off point was 0.14 for 300mg/24h of protein excretion (preeclampsia) with a sensitivity of 82% and specificity of 79%. CONCLUSION: We found a strong correlation between spot urinary P/C and 24h urinary protein. Spot urinary protein/creatinine ratio is a good predictor of proteinuria for pre-eclampsia. PMID- 26104261 TI - Pre-eclampsia and gestational hypertension are less common in HIV infected women. AB - OBJECTIVE: To determine whether pre-eclampsia and gestational hypertension are less common in HIV infected women. METHODS: This prospective cohort study was performed in the Western Cape province of South Africa. HIV negative and positive pregnant women without chronic renal or chronic hypertensive disease were continuously recruited. During the study period HIV positive patients received either mono- or triple (HAART) antiretroviral therapy for prevention of vertical transmission or maternal care. Only routine clinical management was performed. The development of hypertensive disease during pregnancy was recorded. RESULTS: 1093 HIV positive and 1173 HIV negative cases were identified during pregnancy and evaluated again after delivery. Significantly fewer cases of pre-eclampsia n=35 (3.2%) were recorded in the HIV positive group than in the HIV negative group, n=57 (4.9%) (p=0.045; OR 0.65 95% CI 0.42-0.99). There were also significantly fewer cases of gestational hypertension recorded in the HIV positive group compared to the HIV negative group (p=0.026; OR 0.53 95% CI 0.30 0.94). Multiple logistic regression analysis confirmed the reductive effect of HIV on pre-eclampsia and gestational hypertension. CONCLUSION: Pre-eclampsia and gestational hypertension are less common in HIV infected women being managed with mono- or triple anti-retroviral therapy. PMID- 26104263 TI - Neocortical neuronal morphology in the newborn giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana). AB - Although neocortical neuronal morphology has been documented in the adult giraffe (Giraffa camelopardalis tippelskirchi) and African elephant (Loxodonta africana), no research has explored the cortical architecture in newborns of these species. To this end, the current study examined the morphology of neurons from several cortical areas in the newborn giraffe and elephant. After cortical neurons were stained with a modified Golgi technique (N = 153), dendritic branching and spine distributions were analyzed by using computer-assisted morphometry. The results showed that newborn elephant neurons were considerably larger in terms of all dendritic and spine measures than newborn giraffe neurons. Qualitatively, neurons in the newborns appeared morphologically comparable to those in their adult counterparts. Neurons in the newborn elephant differed considerably from those observed in other placental mammals, including the giraffe, particularly with regard to the morphology of spiny projection neurons. Projection neurons were observed in both species, with a much larger variety in the elephant (e.g., flattened pyramidal, nonpyramidal multipolar, and inverted pyramidal neurons). Although local circuit neurons (i.e., interneurons, neurogliaform, Cajal-Retzius neurons) resembled those observed in other eutherian mammals, these were usually spiny, which contrasts with their adult, aspiny equivalents. Newborn projection neurons were smaller than the adult equivalents in both species, but newborn interneurons were approximately the same size as their adult counterparts. Cortical neuromorphology in the newborn giraffe is thus generally consistent with what has been observed in other cetartiodactyls, whereas newborn and adult elephant morphology appears to deviate substantially from what is commonly observed in other placental mammals. PMID- 26104262 TI - Mothers', fathers' and children's perceptions of parents' expectations about children's family obligations in nine countries. AB - Children's family obligations involve assistance and respect that children are expected to provide to immediate and extended family members and reflect beliefs related to family life that may differ across cultural groups. Mothers, fathers and children (N = 1432 families) in 13 cultural groups in 9 countries (China, Colombia, Italy, Jordan, Kenya, Philippines, Sweden, Thailand and United States) reported on their expectations regarding children's family obligations and parenting attitudes and behaviours. Within families, mothers and fathers had more concordant expectations regarding children's family obligations than did parents and children. Parenting behaviours that were warmer, less neglectful and more controlling as well as parenting attitudes that were more authoritarian were related to higher expectations regarding children's family obligations between families within cultures as well as between cultures. These international findings advance understanding of children's family obligations by contextualising them both within families and across a number of diverse cultural groups in 9 countries. PMID- 26104264 TI - Antinociceptive roles of galanin receptor 1 in nucleus accumbens of rats in a model of neuropathic pain. AB - It has been reported that galanin and its receptors might be involved in the modulation and transmission of nociception in the central nervous system. Our previous research has also demonstrated that galanin induces antinociception in the nucleus accumbens (NAc) of intact rats. However, the interaction between galanin and its receptors in the NAc and the underlying mechanism of suppressing pain transmission remain unclear. The present study seeks to determine the antinociception induced by galanin receptor (GalR)-1 stimulation in the NAc of rats with neuropathic pain. The left sciatic nerve of rats was ligated to mimic a neuropathic pain model. Western blots showed that the expression of GalR1 was significantly upregulated in the NAc of rats with neuropathic pain. Intra-NAc injection of GalR1 agonist M617 induced a dose-dependent increase in hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulations in rats with neuropathic pain. Also, the effect of M617 was attenuated by M35, a GalR1/2 antagonist; at the same time, M35 reduced the galanin-induced antinociception, suggesting that GalR1 mediates antinociception induced by galanin in the NAc of rats with neuropathic pain. Furthermore, we found that M617-induced antinociception in rats with neuropathic pain was stronger than the antinociception in intact rats. We also found that injections of M617 and galanin each induced significant increases in HWL, but the galanin-induced antinociception was stronger than that of M617. All these results suggest that GalR1 plays an important role in antinociception and that other GalRs also are involved in pain modulation induced by galanin in the NAc of rats with neuropathic pain. PMID- 26104265 TI - The possible preventive effect of caffeic acid phenethyl ester (CAPE) against myringosclerosis. PMID- 26104266 TI - Highly trans-selective arylation of Achmatowicz rearrangement products by reductive gamma-deoxygenation and Heck-Matsuda reaction: asymmetric total synthesis of (-)-musellarins A-C and their analogues. AB - Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6 dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji-Trost-type reactions, was finally enabled by an unprecedented, highly regioselective gamma-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck-Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads. PMID- 26104268 TI - Synthetic chemistry with nitrous oxide. AB - This review article summarizes efforts to use nitrous oxide (N2O, 'laughing gas') as a reagent in synthetic chemistry. The focus will be on reactions which are carried out in homogeneous solution under (relatively) mild conditions. First, the utilization of N2O as an oxidant is discussed. Due to the low intrinsic reactivity of N2O, selective oxidation reactions of highly reactive compounds are possible. Furthermore, it is shown that transition metal complexes can be used to catalyze oxidation reactions, in some cases with high turnover numbers. In the final part of this overview, the utilization of N2O as a building block for more complex molecules is discussed. It is shown that N2O can be used as an N-atom donor for the synthesis of interesting organic molecules such as triazenes and azo dyes. PMID- 26104267 TI - Morphological analyses and a novel de novo DLX3 mutation associated with tricho dento-osseous syndrome in a Chinese family. AB - Tricho-dento-osseous (TDO) syndrome, an autosomal-dominant disorder, affects the morphological appearance of the tooth enamel, hair, and bone. Previous studies have confirmed that mutations in the DLX3 gene are responsible for TDO. In this study, we describe a Chinese patient with the typical traits of TDO - kinky hair, enamel hypoplasia, skull and jaw bones thickening, and sclerosis. Unfortunately, as a result of excessive attrition, we were unable to assess taurodontism. Examination of the tooth ground section showed a thin layer of enamel with no rods on the patient's tooth and abnormalities in Tomes' granular layer and the dentinal tubules. Scanning electron microscopy and energy-dispersive X-ray spectroscopy of the tooth enamel showed significant differences between the patient and the control individuals. A hair sample from the patient observed under a laser-scanning microscope showed longitudinal grooves in the hair shaft. Dual-energy X-ray absorptiometry measurement showed that the bone mineral density values of the patient's bones was much higher than normal. Finally, genetic analysis revealed a novel de novo missense mutation c.533A>G (p.Q178R) in the conserved homeodomain of the DLX3 gene. This DLX3 mutation is the sixth causative mutation for TDO to be identified so far. PMID- 26104269 TI - Orbit and spin resolved magnetic properties of size selected [ConRh]+ and [ConAu]+ nanoalloy clusters. AB - Bi-metallic nanoalloys of mixed 3d-4d or 3d-5d elements are promising candidates for technological applications. The large magnetic moment of the 3d materials in combination with a high spin-orbit coupling of the 4d or 5d materials give rise to a material with a large magnetic moment and a strong magnetic anisotropy, making them ideally suitable in for example magnetic storage devices. Especially for clusters, which already have a higher magnetic moment compared to the bulk, these alloys can profit from the cooperative role of alloying and size reduction in order to obtain magnetically stable materials with a large magnetic moment. Here, the influence of doping of small cobalt clusters on the spin and orbital magnetic moment has been studied for the cations [Co(8-14)Au](+) and [Co(10 14)Rh](+). Compared to the undoped pure cobalt [Co(N)](+) clusters we find a significant increase in the spin moment for specific Co(N-1)Au(+) clusters and a very strong increase in the orbital moment for some Co(N-1)Rh(+) clusters, with more than doubling for Co12Rh(+). This result shows that substitutional doping of a 3d metal with even just one atom of a 4d or 5d metal can lead to dramatic changes in both spin and orbital moment, opening up the route to novel applications. PMID- 26104270 TI - The Nordic diet and cognition--The DR's EXTRA Study. AB - The rapid increase in the prevalence of dementia associated with ageing populations has stimulated interest in identifying modifiable lifestyle factors that could prevent cognitive impairment. One such potential preventive lifestyle factor is the Nordic diet that has been shown to reduce the risk of CVD; however, its effect on cognition has not been studied. The aim of the present study was to estimate the cross-sectional and longitudinal associations of the baseline Nordic diet with cognitive function at baseline and after a 4-year follow-up in a population-based random sample (n 1140 women and men, age 57-78 years) as secondary analyses of the Finnish Dose-Responses to Exercise Training study. The Nordic diet score was created based on reported dietary components in 4-d food records. Cognition was assessed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery and the Mini-mental State Examination (MMSE). The baseline Nordic diet score had been positively associated with Verbal Fluency (beta 0.08 (95% CI 0.00, 0.16), P = 0.039) and Word List Learning (beta 0.06 (95% CI 0.01, 0.10), P = 0.022) at 4 years but not with the Consortium to Establish a Registry for Alzheimer's Disease total score (CERAD-TS) or MMSE at 4 years, after adjustment for baseline cognitive scores, demographic factors and health-related factors. After excluding individuals with impaired cognition at baseline, the baseline Nordic diet score had also been positively associated with the CERAD-TS (beta 0.10 (95% CI 0.00, 0.20), P = 0.042) and MMSE (beta 0.03 (95% CI 0.00, 0.06), P = 0.039) at 4 years. These associations disappeared after further adjustment for energy intake. In conclusion, the Nordic diet might have a positive association with cognition in individuals with normal cognition. PMID- 26104271 TI - Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases. AB - BACKGROUND & AIMS: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA induced DILI. METHODS: Twenty-two males (70 +/- 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 +/- 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. RESULTS: From 1993 to 2013, 22 patients were retrieved. Latency was 163 +/- 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 +/- 13 * ULN, ALP 0.7 +/- 0.7 * ULN and total serum bilirubin 14 +/- 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CONCLUSIONS: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient. PMID- 26104272 TI - Comparison of Intracranial Aneurysms Treated by 2-D Versus 3-D Coils: A Matched Pairs Analysis. AB - OBJECTIVE: Knowledge on the influence of 2D and 3D coils to occlude intracranial aneurysms is poor. Therefore, aim of our analysis was to evaluate whether the use of 3-D versus 2-D coils alone may improve the efficacy of endovascular aneurysm treatment. PATIENTS AND METHODS: We performed a matched pair analysis comparing aneurysms treated by 3-D coils as initial "framing" coils to aneurysms treated exclusively by 2-D coils. Number of coils, implanted coil length/volume, and associated packing density were calculated. Aneurysmal occlusion was assessed and monitored 6 months (DSA; magnetic resonance angiography (MRA)) and 18 months (MRA) after embolization. Periprocedural complications and retreatment rate of each group were analyzed. RESULTS: Our retrospective analysis revealed 50 pairs. Concerning the 3-D group, number of coils (353 in total, median 7; p = 0.002), implanted coil length (55.69 +/- 48.4 cm), implanted coil length per volume (5.92 mm/mm3), and packing density (30 %; p = 0.017) was higher than in the 2-D group (259 in total, median 5 coils; 38.52 +/- 43.13 cm; 4.54 mm/mm3; 23 %). Occlusion was not significantly different immediately after treatment but at 6 and 18 months follow-up in favor of 3-D coils. Retreatment was performed in 2 cases of the 3-D group and in 3 cases of the 2-D group and therefore in a similar range (p = 0.564). CONCLUSION: Initial use of 3-D coils revealed a higher packing density and a higher long-term occlusion. Therefore, we recommend initial use of 3-D coils. PMID- 26104274 TI - Some Considerations on the Kernohan-Woltman Notch Phenomenon. PMID- 26104273 TI - Tract-Specific Diffusion Tensor Imaging in Cervical Spondylotic Myelopathy Before and After Decompressive Spinal Surgery: Preliminary Results. AB - PURPOSE: Diffusion tensor imaging (DTI) metrics of the cervical spinal cord in patients with cervical spondylotic myelopathy (CSM) were compared to those measured in healthy volunteers, using tract-specific region of interests (ROIs) across all cervical intervertebral disc levels. METHODS: Magnetic resonance (MR) imaging of the cervical spinal cord was performed in four patients with CSM and in five healthy volunteers on a 3-T MR scanner. Region-specific fractional anisotropy (FA) and mean diffusivity (MD) were calculated on axial imaging with ROI placement in the anterior, lateral, and posterior regions of the spinal cord. FA and MD were also calculated on sagittal acquisitions. Nonparametric statistical tests were used to compare controls and patients before and after surgery. RESULTS: FA values were significantly lower (p = 0.050) and MD values were significantly higher (p = 0.014) in CSM patients measured at level of maximal compression before surgery than in healthy controls in lateral and posterior ROIs, respectively. In posterior ROIs, MD values were significantly higher in patients before surgery compared to controls at all levels except C7 T1. CONCLUSION: Patients with CSM may demonstrate region-specific changes in DTI metrics when compared to healthy controls. Changes in DTI metrics may also occur at levels remote from site of compression. PMID- 26104275 TI - Adult feeding moths (Sphingidae) differ from non-adult feeding ones (Saturniidae) in activity-timing overlap and temporal niche width. AB - According to classic ecology, resource partitioning by segregation along at least one of the three main niche axes (time, food, and space) must take place for the coexistence of species with similar ecological requirements. We used nocturnal light traps to investigate the assemblage structuration of two moth families: Sphingidae (23 species) and Saturniidae (13 species). Because competition for food among adults potentially occurs only among sphingids, only for this family did we expect less overlap of diel activity patterns than expected by chance and also a greater temporal niche width compared to saturniids. Moreover, we expected a greater number of sphingid species pairs to differ in activity timing compared to saturniid pairs. We also hypothesized that in the case of a lack of temporal structuration, sphingids would be morphologically structured in relation to proboscis length. Contrary to what we expected, both families overlapped their activity patterns more than expected by chance alone and sphingid moths were not morphologically structured. Nevertheless, there were 173 significant pairwise differences in temporal activity between sphingids, contrasting with no interspecific differences between saturniids. Sphingid species also showed a wider temporal niche width than saturniids, as expected. Predation risk and abiotic factors may have caused the overall similarities in activity patterns for both families. The temporal niche seemed not to be determinant for the assemblage structuration of moths as a whole for either of the studied families, but segregation along the temporal niche axis of some potentially competing species pairs can be a relevant factor for the coexistence of nectar-feeding species. PMID- 26104276 TI - Seasonal associations of climatic drivers and malaria in the highlands of Ethiopia. AB - BACKGROUND: The impacts of interannual climate fluctuations on vector-borne diseases, especially malaria, have received considerable attention in the scientific literature. These effects can be significant in semi-arid and high elevation areas such as the highlands of East Africa because cooler temperature and seasonally dry conditions limit malaria transmission. Many previous studies have examined short-term lagged effects of climate on malaria (weeks to months), but fewer have explored the possibility of longer-term seasonal effects. METHODS: This study assessed the interannual variability of malaria occurrence from 2001 to 2009 in the Amhara region of Ethiopia. We tested for associations of climate variables summarized during the dry (January-April), early transition (May-June), and wet (July-September) seasons with malaria incidence in the early peak (May July) and late peak (September-December) epidemic seasons using generalized linear models. Climate variables included land surface temperature (LST), rainfall, actual evapotranspiration (ET), and the enhanced vegetation index (EVI). RESULTS: We found that both early and late peak malaria incidence had the strongest associations with meteorological conditions in the preceding dry and early transition seasons. Temperature had the strongest influence in the wetter western districts, whereas moisture variables had the strongest influence in the drier eastern districts. We also found a significant correlation between malaria incidence in the early and the subsquent late peak malaria seasons, and the addition of early peak malaria incidence as a predictor substantially improved models of late peak season malaria in both of the study sub-regions. CONCLUSIONS: These findings suggest that climatic effects on malaria prior to the main rainy season can carry over through the rainy season and affect the probability of malaria epidemics during the late malaria peak. The results also emphasize the value of combining environmental monitoring with epidemiological surveillance to develop forecasts of malaria outbreaks, as well as the need for spatially stratified approaches that reflect the differential effects of climatic variations in the different sub-regions. PMID- 26104277 TI - Morphometric study of the greater palatine canal: cone-beam computed tomography. AB - PURPOSE: To analyze greater palatine canal (GPC) dimensions using cone-beam computed tomography (CBCT) images, and to evaluate the position of the greater palatine foramen (GPF) with respect to various landmarks selected in relation to dental status. METHODS: This study included 150 CBCTs. Axial slices were used to determine the position and dimensions of the GPF. Sagittal slices were used to assess GPC length. Reference lines were established to evaluate the GPC diameter in sagittal and coronal slices. RESULTS: From the 77 GPF analyzed, 76 were located on level 2. Average posterior GPF distance was 6.59 +/- 3.27 mm on right side and 7.35 +/- 3.40 mm on left side. Several measurements to determine the position and dimensions of the GPF presented significant values (p <= 0.05). GPC length was 12.31 +/- 1.96 mm on right side and 12.52 +/- 2.15 mm on left side, statistically significant differences were detected between genders only on right canal (p <= 0.004). Sagittal and coronal reference lines presented significantly higher values for men except for the S3 (p < 0.062) and C1 (p < 0.067) in the left GPC. CONCLUSIONS: CBCT is a useful tool for evaluating GPC morphometrically in the three anatomical slices. The sagittal nasal plane and posterior nasal plane are two intraoral anatomical landmarks for the location of the GPF. Their scant variability allows accurate identification of GPFs in both dentate as well as edentulous patients. PMID- 26104278 TI - Response to Rosival: Pathophysiology of diabetic ketoacidosis. PMID- 26104279 TI - Perifollicular elastolysis associated with pseudofolliculitis of Behcet's disease. PMID- 26104280 TI - How to use... lumbar puncture in children. AB - Lumbar puncture (LP) is a useful diagnostic tool in a wide spectrum of paediatric clinical situations. A common indication is to rule out a serious intracranial infection in a febrile child. Success rate can be optimised by proper positioning, appropriate technique and enhanced operator's skill in performing the procedure. The purpose of this review is to explore the indications and contraindications for performing paediatric LP, to describe the anatomical and physiological knowledge required to maximise success rates and to describe complications and their management. We will also provide advice on requesting various cerebrospinal fluid studies, interpretation of results and clinical situations in which LP may be indicated. PMID- 26104282 TI - Help us find and honour the stars of South Asian healthcare. PMID- 26104281 TI - Multiple synchronous sites of origin of vestibular schwannomas in neurofibromatosis Type 2. AB - BACKGROUND: Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve. METHODS: High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve. RESULTS: Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN. DISCUSSION: This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease. PMID- 26104283 TI - Space, time and aliens: charting the dynamic structure of Galapagos pollination networks. AB - Oceanic archipelagos are threatened by the introduction of alien species which can severely disrupt the structure, function and stability of native communities. Here we investigated the pollination interactions in the two most disturbed Galapagos Islands, comparing the three main habitats and the two seasons, and assessing the impacts of alien plant invasions on network structure. We found that the pollination network structure was rather consistent between the two islands, but differed across habitats and seasons. Overall, the arid zone had the largest networks and highest species generalization levels whereas either the transition between habitats or the humid habitat showed lower values. Our data suggest that alien plants integrate easily into the communities, but with low impact on overall network structure, except for an increase in network selectiveness. The humid zone showed the highest nestedness and the lowest modularity, which might be explained by the low species diversity and the higher incidence of alien plants in this habitat. Both pollinators and plants were also more generalized in the hot season, when networks showed to be more nested. Alien species (both plants and pollinators) represented a high fraction (~56 %) of the total number of interactions in the networks. It is thus likely that, in spite of the overall weak effect we found of alien plant invasion on pollination network structure, these introduced species influence the reproductive success of native ones, and by doing so, they affect the functioning of the community. This certainly deserves further investigation. PMID- 26104284 TI - Incidence of human adenoviruses and Hepatitis A virus in the final effluent of selected wastewater treatment plants in Eastern Cape Province, South Africa. AB - BACKGROUND: Municipal effluent constitutes a large reservoir of human enteric viruses and bacteria. Contemporary monitoring practices rely on indicator bacteria, and do not test for viruses. Different viruses, including Norwalk-like viruses, Hepatitis A virus (HAV), adenoviruses, and rotaviruses, are important agents of illnesses in humans. The burden of disease caused by adenoviruses manifests as pneumonia, bronchiolitis, otitis media, conjunctivitis, and tonsillitis, whereas HAV infection can manifest as acute inflammatory diseases of the liver, fever, anorexia, malaise, nausea, and abdominal discomfort, followed by jaundice and dark urine. The public health implications of these viruses depend upon the physiological status of the wastewater microbial community. METHODS: The occurrence of human adenovirus (HAdV) and HAV was determined in the final effluents of five wastewater treatment plants (WWTPs) in the Eastern Cape, South Africa, over 12 months (September 2012-August 2013). The viruses were detected with real-time PCR, and conventional PCR was used for serotyping. RESULTS: Adenovirus was detected in effluent samples from all five WWTPs and in 64 % of the total samples, whereas HAV was not detected in any effluent sample. At WWPT-A, samples were collected from the final effluent tank (adenoviral concentrations ranged from 1.05 * 10(1) to 1.10 * 10(4) genome/L, with a 41.7 % detection rate) and the discharge point (adenoviral concentrations ranged between 1.2 * 10(1) and 2.8 * 10(4) genome/L, with a 54.5 % detection rate). At WWPT-B, HAdV was detected in 91.7 % of samples, with viral concentrations of 7.92 * 10(1) 2.37 * 10(5) genome/L. The HAdV concentrations at WWPT-C were 5.32 * 10(1)-2.20 * 10(5) genome/L, and the detection rate was 75 %. The adenoviral concentrations at WWPT-D were 1.23 * 10(3)-1.05 * 10(4) genome/L, and the detection rate was 66.7 %. At WWPT-E, the viral concentrations were 1.08 * 10(1)-5.16 * 10(4) genome/L, and the detection rate was 54.5 %. Characterization of the adenoviruses revealed HAdV serotypes 2 (1.4 %) and 41 (7.1 %), in species C and F, respectively. CONCLUSIONS: This study is the first to report the prevalence of HAdV in the final effluents of WWTPs in the Eastern Cape, South Africa. The adenoviral detection rates indicate the potential contamination of the environment, with adverse effects on public health. PMID- 26104285 TI - The effects of perturbed cerebral blood flow and cerebrovascular reactivity on structural MRI and behavioral readouts in mild traumatic brain injury. AB - This study investigated the effects of perturbed cerebral blood flow (CBF) and cerebrovascular reactivity (CR) on relaxation time constant (T2), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and behavioral scores at 1 and 3 hours, 2, 7, and 14 days after traumatic brain injury (TBI) in rats. Open skull TBI was induced over the left primary forelimb somatosensory cortex (N=8 and 3 sham). We found the abnormal areas of CBF and CR on days 0 and 2 were larger than those of the T2, ADC, and FA abnormalities. In the impact core, CBF was reduced on day 0, increased to 2.5 times of normal on day 2, and returned toward normal by day 14, whereas in the tissue surrounding the impact, hypoperfusion was observed on days 0 and 2. CR in the impact core was negative, most severe on day 2 but gradually returned toward normal. T2, ADC, and FA abnormalities in the impact core were detected on day 0, peaked on day 2, and pseudonormalized by day 14. Lesion volumes peaked on day 2 and were temporally correlated with forelimb asymmetry and foot-fault scores. This study quantified the effects of perturbed CBF and CR on structural magnetic resonance imaging and behavioral readouts. PMID- 26104286 TI - CDK5 knockdown prevents hippocampal degeneration and cognitive dysfunction produced by cerebral ischemia. AB - Acute ischemic stroke is a cerebrovascular accident and it is the most common cause of physical disabilities around the globe. Patients may present with repeated ictuses, experiencing mental consequences, such as depression and cognitive disorders. Cyclin-dependent kinase 5 (CDK5) is a kinase that is involved in neurotransmission and plasticity, but its dysregulation contributes to cognitive disorders and dementia. Gene therapy targeting CDK5 was administered to the right hippocampus of ischemic rats during transient cerebral middle artery occlusion. Physiologic parameters (blood pressure, pH, pO2, and pCO2) were measured. The CDK5 downregulation resulted in neurologic and motor improvement during the first week after ischemia. Cyclin-dependent kinase 5 RNA interference (RNAi) prevented dysfunctions in learning, memory, and reversal learning at 1 month after ischemia. These observations were supported by the prevention of neuronal loss, the reduction of microtubule-associated protein 2 (MAP2) immunoreactivity, and a decrease in astroglial and microglia hyperreactivities and tauopathy. Additionally, CDK5 silencing led to an increase in the expression of brain-derived neurotrophic factor (BDNF), its Tropomyosin Receptor kinase B (TRKB) receptor, and activation of cyclic AMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK), which are important targets in neuronal plasticity. Together, our findings suggest that gene therapy based on CDK5 silencing prevents cerebral ischemia-induced neurodegeneration and motor and cognitive deficits. PMID- 26104287 TI - Metabolic changes in early poststatus epilepticus measured by MR spectroscopy in rats. AB - There is little experimental in vivo data on how differences in seizure duration in experimental status epilepticus influence metabolic injury. This is of interest given that in humans, status duration is a factor that influences the probability of subsequent development of epilepsy. This question is studied using 7-T magnetic resonance (MR) spectroscopy, T2 relaxometry in the incremented kainate rodent model of temporal lobe epilepsy, using two durations of status epilepticus, 1.5 and 3 hours. Histologic evaluation was performed in a subset of animals. Three days after status, single-voxel (8 mm(3)) point resolved spectroscopy (PRESS) MR spectroscopic measurements were acquired at 7 T to assess the cerebral metabolites measured as a ratio to total creatine (tCr). The status injury resulted in decreased N-acetylaspartate NAA/tCr, increased myo inositol/tCr and glutamine/tCr, increased T2, and significant declines in NeuN stained neuronal counts in both status groups. Regressions were identified in the status groups that provide evidence for neuronal injury and astrocytic reaction after status in both the short and long status duration groups. The long status group displays changes in glutathione/tCr that are not identified in the short status group, this difference possibly representing a maturation of injury and antioxidant response that occurs in synchrony with glutamatergic injury and glial activation. PMID- 26104288 TI - Effects of anesthesia on BOLD signal and neuronal activity in the somatosensory cortex. AB - Most functional magnetic resonance imaging (fMRI) animal studies rely on anesthesia, which can induce a variety of drug-dependent physiological changes, including depression of neuronal activity and cerebral metabolism as well as direct effects on the vasculature. The goal of this study was to characterize the effects of anesthesia on the BOLD signal and neuronal activity. Simultaneous fMRI and electrophysiology were used to measure changes in single units (SU), multi unit activity (MUA), local field potentials (LFP), and the blood oxygenation level-dependent (BOLD) response in the somatosensory cortex during whisker stimulation of rabbits before, during and after anesthesia with fentanyl or isoflurane. Our results indicate that anesthesia modulates the BOLD signal as well as both baseline and stimulus-evoked neuronal activity, and, most significantly, that the relationship between the BOLD and electrophysiological signals depends on the type of anesthetic. Specifically, the behavior of LFP observed under isoflurane did not parallel the behavior of BOLD, SU, or MUA. These findings suggest that the relationship between these signals may not be straightforward. BOLD may scale more closely with the best measure of the excitatory subcomponents of the underlying neuronal activity, which may vary according to experimental conditions that alter the excitatory/inhibitory balance in the cortex. PMID- 26104289 TI - De novo expression of dopamine D2 receptors on microglia after stroke. AB - Dopamine is the predominant catecholamine in the brain and functions as a neurotransmitter. Dopamine is also a potent immune modulator. In this study, we have characterized the expression of dopamine receptors on murine microglia. We found that cultured primary microglia express dopamine D1, D2, D3, D4, and D5 receptors. We specifically focused on the D2 receptor (D2R), a major target of antipsychotic drugs. Whereas D2Rs were strongly expressed on striatal neurons in vivo, we did not detect any D2R expression on resident microglia in the healthy brains of wild-type mice or transgenic mice expressing the green fluorescent protein (GFP) under the control of the Drd2 promoter. However, cerebral ischemia induced the expression of D2R on Iba1-immunoreactive inflammatory cells in the infarct core and penumbra. Notably, D2R expression was confined to CD45(hi) cells, and GFP BM chimeras revealed that D2R was expressed on activated resident microglia as well as on peripherally derived macrophages in the ischemic brain. Importantly, the D2/3R agonist, pramipexole, enhanced the secretion of nitrite by cultured microglia in response to proinflammatory stimuli. Thus, dopamine may serve as a modulator of microglia function during neuroinflammation. PMID- 26104290 TI - Selective astrocytic endothelin-1 overexpression contributes to dementia associated with ischemic stroke by exaggerating astrocyte-derived amyloid secretion. AB - Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-alpha, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production. PMID- 26104291 TI - The functional and structural changes in the basilar artery due to overpressure blast injury. AB - Overpressure blast-wave induced brain injury (OBI) leads to progressive pathophysiologic changes resulting in a reduction in brain blood flow, blood brain barrier breakdown, edema, and cerebral ischemia. The aim of this study was to evaluate cerebral vascular function after single and repeated OBI. Male Sprague-Dawley rats were divided into three groups: Control (Naive), single OBI (30 psi peak pressure, 1 to 2 msec duration), and repeated (days 1, 4, and 7) OBI (r-OBI). Rats were killed 24 hours after injury and the basilar artery was isolated, cannulated, and pressurized (90 cm H2O). Vascular responses to potassium chloride (KCl) (30 to 100 mmol/L), endothelin-1 (10(-12) to 10(-7) mol/L), acetylcholine (ACh) (10(-10) to 10(-4) mol/L) and diethylamine-NONO-ate (DEA-NONO-ate) (10(-10) to 10(-4) mol/L) were evaluated. The OBI resulted in an increase in the contractile responses to endothelin and a decrease in the relaxant responses to ACh in both single and r-OBI groups. However, impaired DEA NONO-ate-induced vasodilation and increased wall thickness to lumen ratio were observed only in the r-OBI group. The endothelin-1 type A (ET(A)) receptor and endothelial nitric oxide synthase (eNOS) immunoreactivity were significantly enhanced by OBI. These findings indicate that both single and r-OBI impairs cerebral vascular endothelium-dependent dilation, potentially a consequence of endothelial dysfunction and/or vascular remodelling in basilar arteries after OBI. PMID- 26104292 TI - Cerebral hypoperfusion: a new pathophysiologic concept in multiple sclerosis? AB - The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS. PMID- 26104293 TI - Protocols for uncontrolled donation after circulatory death: a systematic review of international guidelines, practices and transplant outcomes. AB - INTRODUCTION: A chronic shortage of organs remains the main factor limiting organ transplantation. Many countries have explored the option of uncontrolled donation after circulatory death (uDCD) in order to expand the donor pool. Little is known regarding the variability of practices and outcomes between existing protocols. This systematic review addresses this knowledge gap informing policy makers, researchers, and clinicians for future protocol implementation. METHODS: We searched MEDLINE, EMBASE, and Google Scholar electronic databases from 2005 to March 2015 as well as the reference lists of selected studies, abstracts, unpublished reports, personal libraries, professional organization reports, and government agency statements on uDCD. We contacted leading authors and organizations to request their protocols and guidelines. Two reviewers extracted main variables. In studies reporting transplant outcomes, we added type, quantity, quality of organs procured, and complications reported. Internal validity and the quality of the studies reporting outcomes were assessed, as were the methodological rigour and transparency in which a guideline was developed. The review was included in the international prospective register of systematic reviews (Prospero, CRD42014015258). RESULTS: Six guidelines and 18 outcome studies were analysed. The six guidelines are based on limited evidence and major differences exist between them at each step of the uDCD process. The outcome studies report good results for kidney, liver, and lung transplantation with high discard rates for livers. CONCLUSIONS: Despite procedural, medical, economic, legal, and ethical challenges, the uDCD strategy is a viable option for increasing the organ donation pool. Variations in practice and heterogeneity of outcomes preclude a meta-analysis and prevented the linking of outcomes to specific uDCD protocols. Further standardization of protocols and outcomes is required, as is further research into the role of extracorporeal resuscitation and other novel therapies for treatment of some refractory cardiac arrest. It is essential to ensure the maintenance of trust in uDCD programs by health professionals and the public. PMID- 26104294 TI - Differentially expressed and activated proteins associated with non small cell lung cancer tissues. AB - BACKGROUND: Lung cancer is a leading cause of mortality. The most common cancer subtype, non small cell lung cancer (NSCLC), accounts for 85-90% all cases and is mainly caused by environmental and genetic factors. Mechanisms involved in lung carcinogenesis include deregulation of several kinases and molecular pathways affecting cell proliferation, apoptosis and differentiation. Despite advances in lung cancer detection, diagnosis and staging, survival rate still remains poor and novel biomarkers for both diagnosis and therapy need to be identified. In the present study, we have explored the potential of novel specific biomarkers in the diagnosis of NSCLC, and the over-expression/activation of several kinases involved in disease development and progression. METHOD: Lung tumor tissue specimens and adjacent cancer-free tissues from 8 NSCLC patients undergoing surgery were collected. The differential activation status of ERK1/2, AKT and IKBalpha/NF-kappabeta was analyzed. Subsequently, protein expression profile of NSCLC vs normal surrounding tissue was compared by a proteomic approach using LC MS MS. Subsequently, MS/MS outputs were analyzed by the Protein Discoverer platform for label-free quantitation analysis. Finally, results were confirmed by western blotting analysis. RESULTS: This study confirms the involvement of ERK1/2, AKT, IKBalpha and NF-kappabeta proteins in NSCLC demonstrating a significant over-activation of all tested proteins. Furthermore, we found significant differential expression of 20 proteins (Rsc >= 1.50 or <= -1.50) of which 7 are under-expressed and 13 over-expressed in NSCLC lung tissues. Finally, we validated, by western blotting, the two most under-expressed NSCLC tissue proteins, carbonic anhydrase I and II isoforms. CONCLUSION: Our data further support the possibility of developing both diagnostic tests and innovative targeted therapy in NSCLC. In addition to selective inhibitors of ERK1/2, AKT, IKBalpha and NF-kappabeta, as therapeutic options, our data, for the first time, indicates carbonic anhydrase I and II as attractive targets for development of diagnostic tools enabling selection of patients for a more specific therapy in NSCLC. PMID- 26104295 TI - Splenic lymphocyte subtypes in immune thrombocytopenia: increased presence of a subtype of B-regulatory cells. PMID- 26104297 TI - Atypical cytological features of a solid pseudopapillary neoplasm of the pancreas metastatic to the liver. PMID- 26104296 TI - The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts. AB - BACKGROUND: Clinical therapy for metastatic colorectal cancer (CRC) remains limited, especially when the tumor harbors a KRAS mutation. This study aimed to identify prognostic biomarkers in CRC that are accessible for therapeutic inhibition. METHODS: Conditioned media from human CRC epithelial cells and myofibroblasts were screened by cytokine arrays for tumorigenic factors. The protein and mRNA expressions of these factors were determined by immunohistochemistry and gene microarrays in human CRC tissues. Prognostic biomarkers were determined by correlation of mRNA expression to overall survival in stage IV CRC patients. Inhibition of CXCL1 was performed with specific neutralizing antibody and lentiviral shRNAs. Malignant growth was assessed by soft agar growth assays and xenograft tumor growth in immunocompromised mice. RESULTS: CXCL1 was highly secreted by KRAS mutant human CRC cells and myofibroblasts in a complementary adaptive response to serum deprivation. Elevated CXCL1 level promoted anchorage-independent growth of murine fibroblasts and human CRC cells. Inhibition of CXCL1 by neutralizing antibody and specific shRNAs decreased CRC tumor growth. Highly elevated CXCL1 expression significantly correlated with decreased overall survival in stage IV CRC patients (hazard ratio 0.28; 95% CI 0.11-0.72). CONCLUSIONS: High CXCL1 expression is a poor prognostic biomarker in metastatic CRC. CXCL1 inhibition suppressed tumorigenic growth of KRAS mutant CRC cells. PMID- 26104298 TI - Digital microfluidic immunocytochemistry in single cells. AB - We report a new technique called Digital microfluidic Immunocytochemistry in Single Cells (DISC). DISC automates protocols for cell culture, stimulation and immunocytochemistry, enabling the interrogation of protein phosphorylation on pulsing with stimulus for as little as 3 s. DISC was used to probe the phosphorylation states of platelet-derived growth factor receptor (PDGFR) and the downstream signalling protein, Akt, to evaluate concentration- and time-dependent effects of stimulation. The high time resolution of the technique allowed for surprising new observations-for example, a 10 s pulse stimulus of a low concentration of PDGF is sufficient to cause >30% of adherent fibroblasts to commit to Akt activation. With the ability to quantitatively probe signalling events with high time resolution at the single-cell level, we propose that DISC may be an important new technique for a wide range of applications, especially for screening signalling responses of a heterogeneous cell population. PMID- 26104300 TI - Ivor Owen Grattan-Guinness (1941-2014). PMID- 26104301 TI - Time, Weather and Empires: The Campos Rodrigues Observatory in Lourenco Marques, Mozambique (1905-1930). AB - In 1905 the Campos Rodrigues Observatory (CRO) was founded in Lourenco Marques (nowadays Maputo), the capital of Mozambique, by then part of the Portuguese overseas empire. In this paper the inception and early history of the CRO are analysed in the broader context of the interwoven history of the Portuguese and British empires in Africa, and specifically with respect to the scientific relations between Mozambique and South Africa. The equipment, personnel, practices and networks involved in the inception and early development of the CRO are brought into focus in order to illustrate the problems and strategies that shaped the establishment and functioning of this observatory, which was conceived essentially as a symbol of imperial stamina and colonial prowess. It is suggested that by providing a focal point for the development of scientific relations between Mozambique and South Africa, the CRO served both Portuguese ambitions for recognition as an imperial power and the emergence of South African nationalism. PMID- 26104302 TI - [A Fragment Of De speculis comburentibus of Regiomontanus Copied by Toscanelli and Inserted in the Books of Leonardo (Codex Atlanticus, 611rb / 915ra)]. AB - This article studies a fragment on the conic sections that appear in the Codex Atlanticus, fols. 611rb/915ra. Arguments are put forward to assemble these two folios. Their comparison with the Latin texts available before 1500 shows that they derive from the De speculis comburentibus of Alhacen and the De speculis comburentibus of Regiomontanus, joined together in his autograph manuscript (Vienna, Oster. Nationalbibliothek, Cod. 5258). Having identified the sources, and discussed their mathematics, the issue of their transmission is targeted. It is shown that these notes were written by Paolo dal Pozzo Toscanelli, through whom they reached the notebooks of Leonardo da Vinci. PMID- 26104303 TI - Editing Newton in Geneva and Rome: The Annotated Edition of the Principia by Calandrini, Le Seur and Jacquier. AB - This contribution examines the circumstances of composition of the annotated edition of Newton's Principia that was printed in Geneva in 1739-1742, which ran to several editions and was still in print in Britain in the mid-nineteenth century. This edition was the work of the Genevan Professor of Mathematics, Jean Louis Calandrini, and of two Minim friars based in Rome, Thomas Le Seur and Francois Jacquier. The study of the context in which this edition was conceived sheds light on the early reception of Newtonianism in Geneva and Rome. By taking into consideration the careers of Calandrini, Le Seur and Jacquier, as authors, lecturers and leading characters of Genevan and Roman cultural life, I will show that their involvement in the enterprise of annotating Newton's Principia answered specific needs of Genevan and Roman culture. The publication and reception of the Genevan annotated edition has also a broader European dimension. Both Calandrini and Jacquier were in touch with the French republique des lettres, most notably with Clairaut and Du Chatelet, and with the Bernoulli family in Basel. Therefore, this study is also relevant for the understanding of the dissemination of Newton's ideas in Europe. PMID- 26104304 TI - Vital Instability: Life and Free Will in Physics and Physiology, 1860-1880. AB - During the period 1860-1880, a number of physicists and mathematicians, including Maxwell, Stewart, Cournot and Boussinesq, used theories formulated in terms of physics to argue that the mind, the soul or a vital principle could have an impact on the body. This paper shows that what was primarily at stake for these authors was a concern about the irreducibility of life and the mind to physics, and that their theories can be regarded primarily as reactions to the law of conservation of energy, which was used among others by Helmholtz and Du Bois Reymond as an argument against the possibility of vital and mental causes in physiology. In light of this development, Maxwell, Stewart, Cournot and Boussinesq showed that it was still possible to argue for the irreducibility of life and the mind to physics, through an appeal to instability or indeterminism in physics: if the body is an unstable or physically indeterministic system, an immaterial principle can act through triggering or directing motions in the body, without violating the laws of physics. PMID- 26104305 TI - The Correspondence of Michael Faraday. PMID- 26104310 TI - Low density lipoprotein cholesterol control status among Canadians at risk for cardiovascular disease: findings from the Canadian Primary Care Sentinel Surveillance Network Database. AB - BACKGROUND: To determine the prevalence of uncontrolled LDL-C in patients with high cardiovascular disease (CVD) risks across Canada and to examine its related factors. METHODS: Non-pregnant adults >20 years-old, who had a lipid test completed between January 1, 2009 and December 31, 2011 and were included in the Canadian Primary Care Surveillance Network (CPCSSN) database were studied. The Framingham-Risk-Score was calculated to determine the risk levels. A serum LDL-C level of >2.0 mmol/L was considered as being poorly controlled. Patients with a previous record of a cerebrovascular accident, peripheral artery disease, or an ischemic heart disease were regarded as those under secondary prevention. Logistic regression modeling was performed to examine the factors associated with the LDL-C control. RESULTS: A total of 6,405 high-risk patients were included in the study and, of this population, 68% had a suboptimal LDL-C, which was significantly associated with the female gender (OR: 3.26; 95% CI: 2.63-4.05, p < 0.0001) and no medication therapy (OR: 6.31, 95% CI: 5.21-7.65, p < 0.0001). Those with comorbidities of diabetes, hypertension, obesity, and smokers had a better LDL-C control. Rural residents (OR: 0.64, 95% CI: 0.52-0.78, p < 0.0001), and those under secondary prevention (OR: 0.42; 95 % CI: 0.35-0.51, p < 0.0001), were also more likely to have a better LDL-C control. CONCLUSION: A high proportion of high-cardiac risk patients in Canadian primary care settings have suboptimal LDL-C control. A lack of medication therapy appears to be the major contributing factor to this situation. PMID- 26104311 TI - Microbial respiration with chlorine oxyanions: diversity and physiological and biochemical properties of chlorate- and perchlorate-reducing microorganisms. AB - Chlorine oxyanions are valuable electron acceptors for microorganisms. Recent findings have shed light on the natural formation of chlorine oxyanions in the environment. These suggest a permanent introduction of respective compounds on Earth, long before their anthropogenic manufacture. Microorganisms that are able to grow by the reduction of chlorate and perchlorate are affiliated with phylogenetically diverse lineages, spanning from the Proteobacteria to the Firmicutes and archaeal microorganisms. Microbial reduction of chlorine oxyanions can be found in diverse environments and different environmental conditions (temperature, salinities, pH). It commonly involves the enzymes perchlorate reductase (Pcr) or chlorate reductase (Clr) and chlorite dismutase (Cld). Horizontal gene transfer seems to play an important role for the acquisition of functional genes. Novel and efficient Clds were isolated from microorganisms incapable of growing on chlorine oxyanions. Archaea seem to use a periplasmic Nar type reductase (pNar) for perchlorate reduction and lack a functional Cld. Chlorite is possibly eliminated by alternative (abiotic) reactions. This was already demonstrated for Archaeoglobus fulgidus, which uses reduced sulfur compounds to detoxify chlorite. A broad biochemical diversity of the trait, its environmental dispersal, and the occurrence of relevant enzymes in diverse lineages may indicate early adaptations of life toward chlorine oxyanions on Earth. PMID- 26104312 TI - Vorapaxar, a Protease-Activated Receptor-1 Antagonist, a Double-Edged Sword! AB - Acute coronary syndrome (ACS) constitutes a group of pathophysiological entities resulting from reduced blood flow in the coronary arteries leading to decreased or improper functioning or death of heart muscle. Such patients are usually prescribed combination antiplatelet drug therapy, containing acetylsalicylic acid (aspirin) and an adenosine diphosphate receptor inhibitor to prevent recurrence of ischemic events. The combination prophylactic therapy to certain extend has been successful in preventing secondary complications including ischemic/thrombotic events in these patients. However, research is still on for newer advances in anti-thrombotic therapy that can further prevent secondary complications of Acute Coronary Syndrome. Vorapaxar is a newer drug recommended along with aspirin or clopidogril for prevention of recurrence of cardiac events. Vorapaxar, a thrombin receptor antagonist acts by reversible inhibition of the protease-activated receptor-1 (PAR-1). PAR-1 is expressed on platelets, and it inhibits platelet aggregation, both thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced. Various trials world -wide have documented its efficacy as an anti-platelet agent for preventing recurrent cardiovascular ischemic events but at the expense of increased bleeding complications including intracranial haemorrhage (ICH), when compared to standard therapy alone. For the same reason, vorapaxar is contraindicated in patients with prior stroke, transient ischemic attack and ICH. U.S. Food and Drug Administration (FDA) approved vorapaxar in May 2014 as an antiplatelet agent along with standard anti platelet therapy for the reduction of recurring thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Vorapaxar is developed and marketed by Merck Sharp Dohme and is available by the brand name 'Zontivity' as 2.5 mg oral tablet equivalent to 2.08 mg of vorapaxar sulfate. There are two patents protecting this drug. PMID- 26104313 TI - The beneficial effect of alpha-blockers for ureteral stent-related discomfort: systematic review and network meta-analysis for alfuzosin versus tamsulosin versus placebo. AB - BACKGROUND: This study was carried out a network meta-analysis of evidence from randomized controlled trials (RCTs) to evaluate stent-related discomfort in patients with alfuzosin or tamsulosin versus placebo. METHODS: Relevant RCTs were identified from electronic databases. The proceedings of appropriate meetings were also searched. Seven articles on the basis of RCTs were included in our meta analysis. Using pairwise and network meta-analyses, comparisons were made by qualitative and quantitative syntheses. Evaluation was performed with the Ureteric Stent Symptoms Questionnaire to assess the urinary symptom score (USS) and body pain score (BPS). RESULTS: One of the seven RCTs was at moderate risk of bias for all quality criteria; two studies had a high risk of bias. In the network meta-analysis, both alfuzosin (mean difference [MD];-4.85, 95 % confidence interval [CI];-8.53--1.33) and tamsulosin (MD;-8.84, 95 % CI;-13.08- 4.31) showed lower scores compared with placebo; however, the difference in USS for alfuzosin versus tamsulosin was not significant (MD; 3.99, 95 % CI;-1.23 9.04). Alfuzosin (MD;-5.71, 95 % CI;-11.32--0.52) and tamsulosin (MD;-7.77, 95 % CI;-13.68--2.14) showed lower scores for BPS compared with placebo; however, the MD between alfuzosin and tamsulosin was not significant (MD; 2.12, 95 % CI;-4.62 8.72). In the rank-probability test, tamsulosin ranked highest for USS and BPS, and alfuzosin was second. CONCLUSION: The alpha-blockers significantly decreased USS and BPS in comparison with placebo. Tamsulosin might be more effective than alfuzosin. PMID- 26104314 TI - Involvement of cAMP-guanine nucleotide exchange factor II in hippocampal long term depression and behavioral flexibility. AB - BACKGROUND: Guanine nucleotide exchange factors (GEFs) activate small GTPases that are involved in several cellular functions. cAMP-guanine nucleotide exchange factor II (cAMP-GEF II) acts as a target for cAMP independently of protein kinase A (PKA) and functions as a GEF for Rap1 and Rap2. Although cAMP-GEF II is expressed abundantly in several brain areas including the cortex, striatum, and hippocampus, its specific function and possible role in hippocampal synaptic plasticity and cognitive processes remain elusive. Here, we investigated how cAMP GEF II affects synaptic function and animal behavior using cAMP-GEF II knockout mice. RESULTS: We found that deletion of cAMP-GEF II induced moderate decrease in long-term potentiation, although this decrease was not statistically significant. On the other hand, it produced a significant and clear impairment in NMDA receptor-dependent long-term depression at the Schaffer collateral-CA1 synapses of hippocampus, while microscopic morphology, basal synaptic transmission, and depotentiation were normal. Behavioral testing using the Morris water maze and automated IntelliCage system showed that cAMP-GEF II deficient mice had moderately reduced behavioral flexibility in spatial learning and memory. CONCLUSIONS: We concluded that cAMP-GEF II plays a key role in hippocampal functions including behavioral flexibility in reversal learning and in mechanisms underlying induction of long-term depression. PMID- 26104316 TI - Challenges in definitive fracture management of blast injuries. AB - The United States military remains engaged in the longest armed conflict in this nation's history. The majority of casualties in the global war on terror come from blast-related injuries. Multiple centers have published their experience and outcomes with these complex patients. Findings from the study of injured military personnel have implications for mass casualty events resulting from industrial accidents or terrorism in the civilian sector. This article will review the pathophysiology of blast-related injury. The authors will summarize treatment considerations, priorities, and techniques that have proven successful. Finally, the authors will discuss the incidence and management of common complications after blast-related injuries. PMID- 26104317 TI - Esculentoside A suppresses Abeta(1-42)-induced neuroinflammation by down regulating MAPKs pathways in vivo. AB - INTRODUCTION: Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous studies have demonstrated that EsA exerts strong anti-inflammatory effects in peripheral immune inflammation. This study is to determine whether EsA is effective in inflammation-related neurodegenerative diseases, such as Alzheimer's disease (AD). METHODS: Male C57BL/6(B6) mice were divided into three groups of six mice as follows: (1) control group; (2) AD model group (Abeta(1-42)-induced AD mice with saline); (3) EsA group (Abeta(1-42) induced AD mice with EsA, 5 mg/kg/day, i.p. for 15 days). Behavioural testing was performed after 15 days of EsA treatment. Real time PCR and Western blot were used to assess the level of inflammation factors and mitogen-activated protein kinases (MAPKs). Immunostaining was used to determine the level of activated microglia and astrocyte. RESULTS: The results showed that EsA attenuated memory deficits in Abeta(1-42)-induced AD mice. Esculentoside A decreased the pro-inflammatory factors and microglia and astrocyte activation in the hippocampi of Abeta(1-42)-induced AD mice. Moreover, Abeta(1-42) activated phosphorylation of ERK, JNK and p38 MAPKs in the hippocampi of mice in the AD model group, while EsA significantly decreased the phosphorylation levels. CONCLUSION: These findings indicate that EsA provides protective effects against neuroinflammation triggered by beta-amyloid. PMID- 26104315 TI - Mesenchymal stem cell therapy for doxorubicin cardiomyopathy: hopes and fears. AB - Chemotherapy has made an essential contribution to cancer treatment in recent decades despite its adverse effects. As cancer survivors have increased, concern about ex-patient lifespan has become more important too. Doxorubicin is an effective anti-neoplastic drug that produces a cardiotoxic effect. Cancer survivors who received doxorubicin became more vulnerable to cardiac disease than the normal population did. Many efforts have been made to prevent cardiac toxicity in patients with cancer. However, current therapies cannot guarantee permanent cardiac protection. One of their main limitations is that they do not promote myocardium regeneration. In this review, we summarize and discuss the promising use of mesenchymal stem cells for cardio-protection or cardio regeneration therapies and consider their regenerative potential without leaving aside their controversial effects on tumor progression. PMID- 26104318 TI - Clitorodynia: A Descriptive Study of Clitoral Pain. AB - INTRODUCTION: Clitorodynia is classified as a type of localized vulvodynia. Our knowledge of this problem is limited to case studies and one published report. AIMS: The objective of the present study was to describe quantitatively the clinical characteristics of clitoral pain, to assess interference with sexual function, and to investigate whether clitoral pain is a unitary category. METHODS: One hundred twenty-six women with clitoral pain completed an online questionnaire that assessed demographic information, descriptive pain characteristics, intensity and impact on daily activities, sexual function, and gynecological and medical histories. MAIN OUTCOME MEASURES: The main outcome measures used for the study are the following: clitoral pain characteristics (e.g., intensity, duration, quality, distress, etc.), short-form McGill pain questionnaire-2, and the female sexual function index. RESULTS: Clitoral pain is characterized by frequent and intense pain episodes that can either be provoked or unprovoked, and causes significant impairment in both daily and sexual function. The pain can be localized to the clitoris only or can occur with other genital pain. Comorbidity with other chronic pain disorders is common. A cluster analysis suggested two distinct patterns of clitoral pain, one localized and one generalized. CONCLUSION: Our findings indicate that women with clitoral pain suffer from significant, distressing, and often long-term pain, which interferes with sexual and daily activities. Two subtypes of clitoral pain may exist, each with distinct pain characteristics and subjective experiences. PMID- 26104319 TI - Systematic review: effect of whole-body computed tomography on mortality in trauma patients. AB - BACKGROUND: The initial diagnostic evaluation and management of trauma patients is mainly based on Advanced Trauma Life Support (ATLS) guidelines worldwide. Based on ATLS principles, conventional diagnostics such as conventional radiography (CR) and focused abdominal sonography in trauma (FAST) should precede selective use of CT. Whole-body CT (WBCT) is highly accurate and allows detection of life threatening injuries with good sensitivity and specificity. WBCT is faster than conventional diagnostics and saves more time in management of trauma patients. This study aims to review studies investigating the effect of WBCT on mortality in trauma patients. METHODS: Literatures were found by searching keywords in Medline, PubMed and Cochrane library. The relevant articles were selected by two independent reviewers based on title, abstract and introduction sections. Full-texts of selected articles were reviewed and those investigating effect of WBCT on mortality in trauma patients were included. RESULTS: Searching the keywords in Medline and PubMed resulted in 178 and 167 articles, respectively. Nine studies met the inclusion criteria and were reviewed. These included 8 retrospective and 1 prospective cohort studies. Mortality was measured as mortality rate or standardised mortality ratio (SMR) in the included studies. CONCLUSIONS: Unlike previous systematic reviews, this review indicates that use of WBCT in blunt trauma patients is associated with reduced overall mortality rate and that WBCT can potentially improve the probability of survival in haemodynamically stable and unstable blunt trauma patients. High quality RCTs are required to describe a causal relationship between WBCT and mortality in trauma patients. PMID- 26104321 TI - Ultralow noise miniature external cavity semiconductor laser. AB - Advanced applications in optical metrology demand improved lasers with high spectral purity, in form factors that are small and insensitive to environmental perturbations. While laboratory-scale lasers with extraordinarily high stability and low noise have been reported, all-integrated chip-scale devices with sub-100 Hz linewidth have not been previously demonstrated. Lasers integrated with optical microresonators as external cavities have the potential for substantial reduction of noise. However, stability and spectral purity improvements of these lasers have only been validated with rack-mounted support equipment, assembled with fibre lasers to marginally improve their noise performance. In this work we report on a realization of a heterogeneously integrated, chip-scale semiconductor laser featuring 30-Hz integral linewidth as well as sub-Hz instantaneous linewidth. PMID- 26104320 TI - Molecular determinants of acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is a condition that leads to a rapid deterioration of renal function associated with impairment to maintain electrolyte and acid balance, and, if left untreated, ultimately irreversible kidney damage and renal necrosis. There are a number of causes that can trigger AKI, ranging from underlying conditions as well as trauma and surgery. Specifically, the global rise in surgical procedures led to a substantial increase of AKI incidence rates, which in turn impacts on mortality rates, quality of life and economic costs to the healthcare system. However, no effective therapy for AKI exists. Current approaches, such as pharmacological intervention, help in alleviating symptoms in slowing down the progression, but do not prevent or reverse AKI-induced organ damage. METHODS: An in-depth understanding of the molecular machinery involved in and modulated by AKI induction and progression is necessary to specifically pharmacologically target key molecules. A major hurdle to devise a successful strategy is the multifactorial and complex nature of the disorder itself, whereby the activation of a number of seemingly independent molecular pathways in the kidney leads to apoptotic and necrotic events. RESULTS: The renin-angiotensin-aldosterone-system (RAAS) axis appears to be a common element, leading to downstream events such as triggers of immune responses via the NF?B pathway. Other pathways intricately linked with AKI-induction and progression are the tumor necrosis factor alpha (TNF?) and transforming growth factor beta (TGF?) signaling cascades, as well as a number of other modulators. Surprisingly, it has been shown that the involvement of the glutamatergic axis, believed to be mainly a component of the neurological system, is also a major contributor. CONCLUSIONS: Here we address the current understanding of the molecular pathways evoked in AKI, their interplay, and the potential to pharmacologically intervene in the effective prevention and/or progression of AKI. PMID- 26104322 TI - Green and scalable production of colloidal perovskite nanocrystals and transparent sols by a controlled self-collection process. AB - Colloidal perovskite oxide nanocrystals have attracted a great deal of interest owing to the ability to tune physical properties by virtue of the nanoscale, and generate thin film structures under mild chemical conditions, relying on self assembly or heterogeneous mixing. This is particularly true for ferroelectric/dielectric perovskite oxide materials, for which device applications cover piezoelectrics, MEMs, memory, gate dielectrics and energy storage. The synthesis of complex oxide nanocrystals, however, continues to present issues pertaining to quality, yield, % crystallinity, purity and may also suffer from tedious separation and purification processes, which are disadvantageous to scaling production. We report a simple, green and scalable "self-collection" growth method that produces uniform and aggregate-free colloidal perovskite oxide nanocrystals including BaTiO3 (BT), Ba(x)Sr(1-x)TiO3 (BST) and quaternary oxide BaSrTiHfO3 (BSTH) in high crystallinity and high purity. The synthesis approach is solution processed, based on the sol-gel transformation of metal alkoxides in alcohol solvents with controlled or stoichiometric amounts of water and in the stark absence of surfactants and stabilizers, providing pure colloidal nanocrystals in a remarkably low temperature range (15 degrees C-55 degrees C). Under a static condition, the nanoscale hydrolysis of the metal alkoxides accomplishes a complete transformation to fully crystallized single domain perovskite nanocrystals with a passivated surface layer of hydroxyl/alkyl groups, such that the as-synthesized nanocrystals can exist in the form of super-stable and transparent sol, or self accumulate to form a highly crystalline solid gel monolith of nearly 100% yield for easy separation/purification. The process produces high purity ligand-free nanocrystals excellent dispersibility in polar solvents, with no impurity remaining in the mother solution other than trace alcohol byproducts (such as isopropanol). The afforded stable and transparent suspension/solution can be treated as inks, suitable for printing or spin/spray coating, demonstrating great capabilities of this process for fabrication of high performance dielectric thin films. The simple "self-collection" strategy can be described as green and scalable due to the simplified procedure from synthesis to separation/purification, minimum waste generation, and near room temperature crystallization of nanocrystal products with tunable sizes in extremely high yield and high purity. PMID- 26104323 TI - Erratum to: Diagnostic Performance of (68)Ga-DOTATATE PET/CT, (18)F-FDG PET/CT and (131)I-MIBG Scintigraphy in Mapping Metastatic Pheochromocytoma and Paraganglioma. AB - [This corrects the article DOI: 10.1007/s13139-015-0331-7.]. PMID- 26104324 TI - Effects of exercise on soleus in severe burn and muscle disuse atrophy. AB - BACKGROUND: Muscle loss is a sequela of severe burn and critical illness with bed rest contributing significantly to atrophy. We hypothesize that exercise will mitigate muscle loss after burn with bed rest. MATERIALS AND METHODS: Male rats were assigned to sham ambulatory (S/A), burn ambulatory (B/A), sham hindlimb unloading (S/H), or burn hindlimb unloading (B/H). Rats received a 40% scald burn or sham and were ambulatory or placed in hindlimb unloading, a model of bed rest. Half from each group performed twice daily resistance climbing. Hindlimb isometric forces were measured on day 14. RESULTS: Soleus mass and muscle function were not affected by burn alone. Mass was significantly lower in hindlimb unloading (79 versus 139 mg, P < 0.001) and no exercise (103 versus 115 mg, P < 0.01). Exercise significantly increased soleus mass in B/H (86 versus 77 mg, P < 0.01). Hindlimb unloading significantly decreased muscle force in the twitch (12 versus 31 g, P < 0.001), tetanic (55 versus 148 g, P < 0.001), and specific tetanic measurements (12 versus 22 N/cm(2), P < 0.001). Effects of exercise on force depended on other factors. In B/H, exercise significantly increased twitch (14 versus 8 g, P < 0.05) and specific tetanic force (14 versus 7 N/cm(2), P < 0.01). Fatigue index was lower in ambulatory (55%) and exercise (52%) versus hindlimb (69%, P = 0.03) and no exercise (73%, P = 0.002). CONCLUSIONS: Hindlimb unloading is a significant factor in muscle atrophy. Exercise increased the soleus muscle mass, twitch, and specific force in this model. However, the fatigue index decreased with exercise in all groups. This suggests exercise contributes to functional muscle change in this model of disuse and critical illness. PMID- 26104326 TI - Surgery for the treatment of obesity in children and adolescents. AB - BACKGROUND: Child and adolescent overweight and obesity have increased globally, and are associated with significant short and long term health consequences. OBJECTIVES: To assess the effects of surgical interventions for treating obesity in childhood and adolescence. SEARCH METHODS: We searched the Cochrane Library, MEDLINE, PubMed, EMBASE as well as LILACS, ICTRP Search Portal and ClinicalTrials.gov (all from database inception to March 2015). References of identified studies and systematic reviews were checked. No language restrictions were applied. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of surgical interventions for treating obesity in children and adolescents (age < 18 years) with a minimum of six months follow-up. Interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity were excluded. Pregnant females were also excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data. Where necessary authors were contacted for additional information. MAIN RESULTS: We included one RCT (a total of 50 participants, 25 in both the intervention and comparator group). The intervention focused on laparoscopic adjustable gastric banding surgery, which was compared to a control group receiving a multi component lifestyle programme. The participating population consisted of Australian adolescents (a higher proportion of girls than boys) aged 14 to 18 years, with a mean age of 16.5 and 16.6 years in the gastric banding and lifestyle group, respectively which was conducted in a private hospital, receiving funding from the gastric banding manufacturer. The study authors were unable to blind participants, personnel and outcome assessors which may have resulted in a high risk of performance and detection bias. Attrition bias was noted as well. The study authors reported a mean reduction in weight of 34.6 kg (95% confidence interval (CI) 30.2 to 39.0) at two years, representing a change in body mass index (BMI) of 12.7 (95% CI 11.3 to 14.2) for the surgery intervention; and a mean reduction in weight of 3.0 kg (95% CI 2.1 to 8.1) representing a change in BMI of 1.3 (95% CI 0.4 to 2.9) for the lifestyle intervention. The differences between groups were statistically significant for all weight measures at 24 months (P < 0.001). The overall quality of the evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was low. Adverse events were reported in 12/25 (48%) participants in the intervention group compared to 11/25 (44%) in the control group (low quality evidence). A total of 28% of the adolescents undergoing gastric banding required revisional surgery. No data were reported for all-cause mortality, behaviour change, participants views of the intervention and socioeconomic effects. At two years, the gastric banding group performed better than the lifestyle group in two of eight health-related quality of life concepts (very low quality evidence) as measured by the Child Health Questionnaire (physical functioning score (94 versus 78, community norm 95) and change in health score (4.4 versus 3.6, community norm 3.5)). AUTHORS' CONCLUSIONS: Laparoscopic gastric banding led to greater body weight loss compared to a multi component lifestyle program in one small study with 50 patients. These results do not provide enough data to assess efficacy across populations from different countries, socioeconomic and ethnic backgrounds, who may respond differently. This systematic review highlights the lack of RCTs in this field. Future studies should assess the impact of the surgical procedure and post operative care to minimise adverse events, including the need for post operative adjustments and revisional surgery. Long-term follow up is also critical to comprehensively assess the impact of surgery as participants enter adulthood. PMID- 26104327 TI - Unravelling viral camouflage: approaches to the study and characterization of conformational epitopes. AB - Antibodies are broadly used in clinical and basic research. Many of monoclonal antibodies are successfully adopted for therapeutic and diagnostic targeting of viral pathogens. Efficacy of antiviral neutralizing or protective antibodies depends on their ability to recognize epitopes interfering with viral infection. However, viruses are able to incessantly change their antigenic determinants to escape surveillance of humoral immune system and therefore the successful antiviral therapies require continuous development. Characterization of interactions of antibodies with prevalently conformational viral epitopes is important for understanding antibody mode of action and can help to identify conserved regions that may be exploited in designing new vaccines and virus neutralizing antibodies. In this article, we are reviewing techniques in use for characterization of conformational epitopes of monoclonal antibodies with focus on viruses. PMID- 26104325 TI - Kv7 channels in the nucleus accumbens are altered by chronic drinking and are targets for reducing alcohol consumption. AB - Alcohol use disorders (AUDs) are a major public health issue and produce enormous societal and economic burdens. Current Food and Drug Administration (FDA) approved pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in a subset of individuals. It is therefore essential to find improved medications for the management of AUDs. Emerging evidence suggests that anticonvulsants are a promising class of drugs for treating individuals with AUDs. In these studies, we used integrative functional genomics to demonstrate that genes that encode Kv7 channels (i.e. Kcnq2/3) are related to alcohol (ethanol) consumption, preference and acceptance in rodents. We then tested the ability of the FDA-approved anticonvulsant retigabine, a Kv7 channel opener, to reduce voluntary ethanol consumption of Wistar rats in a two-bottle choice intermittent alcohol access paradigm. Systemic administration and microinjections of retigabine into the nucleus accumbens significantly reduced alcohol drinking, and retigabine was more effective at reducing intake in high- versus low-drinking populations of Wistar rats. Prolonged voluntary drinking increased the sensitivity to the proconvulsant effects of pharmacological blockade of Kv7 channels and altered surface trafficking and SUMOylation patterns of Kv7.2 channels in the nucleus accumbens. These data implicate Kcnq2/3 in the regulation of ethanol drinking and demonstrate that long-term drinking produces neuroadaptations in Kv7 channels. In addition, these results have identified retigabine as a potential pharmacotherapy for treating AUDs and Kv7 channels as a novel therapeutic target for reducing heavy drinking. PMID- 26104328 TI - Efficiency of live attenuated and inactivated rabies viruses in prophylactic and post exposure vaccination against the street virus strain. AB - Rabies remains an enigmatic and widely discussed global infectious disease and causes an increasing number of deaths. The currently used highly effective prophylactic and post exposure (p.e.) vaccination depends solely upon inexpensive, effective and safe vaccines to counteract the spread of the disease. In this study, the potential of an attenuated Chinese rabies vaccine (SRV9) strain in prophylactic and p.e. vaccination against the street strain of rabies virus (RV) was evaluated in mice. Prophylactic vaccination consisting of one intramuscular (i.m.) dose of SRV9 protected 100% of mice from intracerebral (i.c.) challenge with a lethal dose of the street virus. The latter was detected in the brain of mice at day 6 post challenge by RT-PCR. Post exposure vaccination was performed at days 1, 2, 3, 4, 5 and 6 post infection (p.i.) with either SRV9 or inactivated rabies vaccine. The survival rates after i.m. inoculation of SRV9 at the indicated days were 70%, 50%, 30%, 20%, 10%, and 0%, respectively; the corresponding survival rates for the inactivated rabies vaccine were 30%, 20%, 10%, 0%, 0%, and 0%, respectively. However, 100%, 90%, 70%, 50%, 20%, 10%, and 10% of mice survived after i.c. inoculation of SRV9 at the indicated days. The increased permeability of the blood-brain barrier and the infiltration of CD19+ B cells into the central nervous system after i.c. inoculation of SRV9 are regarded as prerequisites for the clearance of the street virus. The obtained data suggest that SRV9 is a promising candidate for prophylactic and p.e. vaccination against rabies infection and that it exhibits a potential for the control of rabies in China. PMID- 26104329 TI - Association of tomato leaf curl New Delhi virus DNA-B with bhendi yellow vein mosaic virus in okra showing yellow vein mosaic disease symptoms. AB - Okra samples showing yellow vein mosaic, vein twisting and bushy appearance were collected from different locations of India during the surveys conducted between years 2005-2009. The dot blot and PCR detection revealed that 75.14% of the samples were associated with monopartite begomovirus and remaining samples with bipartite virus. Whitefly transmission was established for three samples representing widely separated geographical locations which are negative to betasatellites and associated with DNA-B. Genome components of these three representative isolates were cloned and sequenced. The analysis of DNA-A-like sequence revealed that three begomovirus isolates shared more than 93% nucleotide sequence identity with bhendi yellow vein mosaic virus from India (BYVMV), a monopartite begomovirus species that was reported previously as causative agent of bhendi yellow mosaic disease in association of bhendi yellow vein mosaic betasatellite. Further, the DNA-B-like sequences associated with the three virus isolates shared no more than 90% sequence identity with tomato leaf curl New Delhi virus (ToLCNDV). Analyses of putative iteron-binding sequence required for trans-replication suggests that begomovirus sequences shared compatible rep binding iterons with DNA-B of ToLCNDV. Our data suggest that the monopartite begomovirus associated with okra yellow vein disease has captured DNA-B of ToLCNDV to infect okra. Widespread distribution of the complex shows the increasing trend of the capturing of DNA-B of ToLCNDV by monopartite begomoviruses in the Indian subcontinent. The recombination analysis showed that the DNA-A might have been derived from the inter-specific recombination of begomoviruses, while DNA-B was derived from the ToLCNDV infecting different hosts. PMID- 26104330 TI - Sequence and phylogenetic analyses of five low pathogenic avian influenza H5N2 viruses isolated in China. AB - Five H5N2 avian influenza viruses (AIVs) were isolated in Xianghai National Nature Reserve, Jilin Province, China in October 2011. They were all identified as low pathogenic AIVs (LPAIVs) based on their deduced amino acid sequences at the cleavage site of HA protein. Phylogenetic analysis revealed that all gene segments clustered in the Eurasian lineage and that the nucleotide homology of the five isolates was greater for HA and NA genes than for the genes for internal proteins PB2, PB1, PA, M, NP and NS. PMID- 26104331 TI - Induction of interferon lambda in influenza a virus infected cells treated with shRNAs against M1 transcript. AB - RNA interference (RNAi) represents a form of post-transcriptional gene silencing mediated by small interfering RNAs (siRNA) and provides a powerful tool to specifically inhibit viral infection. To investigate therapeutic capacity of siRNAs targeting M gene, six vectors with U1-short hairpin RNA (shRNA) expression system were prepared and tested in infected cells and animals. In infected cells, three of six shRNAs targeting M1 gene significantly (P <0,01) reduced the virus titer to 66%, 45% or 21%, respectively. Replication of IAV and levels of M1 RNAs were significantly reduced in the cells transfected with shRNAs, which decreased the virus titer. IFN-alpha/beta altered in shRNAs-treated cells. The level of IFN lambda (type III interferon) mRNA was significantly increased in the infected cells treated with shM22, shM349, shM522, and (type I interferon) as well as IP 10 (type II interferon) mRNAs were not significantly their mixtures. The increased level of IFN-lambda mRNA corresponded to significantly increased level of RIG-1 mRNA. shRNAs inhibited influenza virus infection in a gene-specific manner in co-operation with IFN-lambda. Some constructs targeting the M1 transcript prolonged the survival of infected mice. PMID- 26104332 TI - Pathotyping of recent Indian field isolates of Marek's disease virus serotype 1. AB - A study was undertaken to assess the virulence of Marek's disease virus (MDV) serotype 1 field isolates obtained from poultry flocks of southern part of India. Five representative MDV serotype 1 strains were isolated from eighty-six blood samples collected from fifteen farms. Three out of five isolates which were free from avian leukosis virus (ALV) and reticuloendotheliosis virus (REV) were adapted in chicken embryo fibroblast (CEF) culture and designated as Ind/TN/11/01, Ind/KA/12/02 and Ind/TN/12/03. Pathotyping assay was conducted in two trials. In the first trial, non-vaccinated chickens were challenged (trial I), while in second trial, two types of vaccinated chickens along with non vaccinated controls were challenged (trial II). Birds inoculated with field isolate Ind/TN/12/03 had very low body (75.34 +/- 3.04 g 15 days post infection (dpi)) and bursa Fabricii weight (1.64 +/- 0.06 at 15 dpi) when compared to those inoculated with the other two isolates (Ind/TN/11/01 and Ind/KA/12/02) and uninoculated controls (body weight 111.33 +/- 1.30 g and bursa Fabricii weight 4.33 +/- 0.11 15 dpi). Incidence of early mortality syndrome (53%) and lymphoma (86%) induced by Ind/TN/12/03 was comparable with very virulent strains published elsewhere. In protection test, the percentage of Marek's disease (MD) incidence induced by Ind/TN/12/03 was 57.5% and 25% in monovalent and bivalent vaccine inoculated birds respectively compared to uninoculated control (100%). Based on the above findings in pathotyping experimental trials with a supportive evidence of histopathological observations, isolate Ind/TN/12/03 was considered as very virulent MDV and other two isolates were considered as virulent MDVs. PMID- 26104333 TI - Virus-neutralizing antibody response of mice to consecutive infection with human and avian influenza A viruses. AB - In this work we simulated in a mouse model a naturally occurring situation of humans, who overcame an infection with epidemic strains of influenza A, and were subsequently exposed to avian influenza A viruses (IAV). The antibody response to avian IAV in mice previously infected with human IAV was analyzed. We used two avian IAV (A/Duck/Czechoslovakia/1956 (H4N6) and the attenuated virus rA/Viet Nam/1203-2004 (H5N1)) as well as two human IAV isolates (virus A/Mississippi/1/1985 (H3N2) of medium virulence and A/Puerto Rico/8/1934 (H1N1) of high virulence). Two repeated doses of IAV of H4 or of H5 virus elicited virus specific neutralizing antibodies in mice. Exposure of animals previously infected with human IAV (of H3 or H1 subtype) to IAV of H4 subtype led to the production of antibodies neutralizing H4 virus in a level comparable with the level of antibodies against the human IAV used for primary infection. In contrast, no measurable levels of virus-neutralizing (VN) antibodies specific to H5 virus were detected in mice infected with H5 virus following a previous infection with human IAV. In both cases the secondary infection with avian IAV led to a significant increase of the titer of VN antibodies specific to the corresponding human virus used for primary infection. Moreover, cross-reactive HA2-specific antibodies were also induced by sequential infection. By virtue of these results we suggest that the differences in the ability of avian IAV to induce specific antibodies inhibiting virus replication after previous infection of mice with human viruses can have an impact on the interspecies transmission and spread of avian IAV in the human population. PMID- 26104334 TI - Molecular characterization of cucumber mosaic virus isolates infecting tomato in Hamedan and Tehran provinces of Iran. AB - Here we identified four isolates, MS, 3H, 50A, and 2K of cucumber mosaic virus (CMV) infecting tomato, on the basis of their non-coding intergenic region and a part of the coat protein (CP) sequence in the CMV genomic RNA3. The sequences from the four isolates were compared with other previously characterized isolates of CMV isolated from different plant species across the globe. Sequence comparisons revealed that the two CMV isolates from Hamedan province (MS and 3H) had the highest sequence identity with CMV-G10 (98%), which was previously reported as a severe Hellenic tomato isolate of CMV, while the CMV isolates from Tehran province, including CMV-2K (isolated from Karaj region) and CMV-50A (isolated from Varamin region), had the highest sequence identity with that of CMV-ALF (99%). Phylogenetic analysis of the nucleotide sequences showed that CMV MS and CMV-3H belong to group IB, while CMV-2K and CMV-50A belong to group IA. This is the first report on the molecular characterization of novel isolates of CMV infecting tomato plants in Iran. PMID- 26104335 TI - Prion protein prevents heavy metals overloading of cells and thus protects them against their toxicity. AB - Physiological function of a prion protein (PrP) is not known yet. Regarding the relation of PrP to heavy metals it is known that PrP is able to bind divalent ions of copper, zinc, manganese and nickel through its octarepeat region. It has been hypothesized but not yet confirmed that PrP could play a role in copper metabolism. In this study, cells expressing human full-length PrP (HuPrP1) and PrP-knockout (PrP0/0/1) cells were incubated with various concentrations of copper, zinc, manganese and nickel for 4 days and then were assayed for intracellular content of these metals and cell viability. The results showed that HuPrP1 cells accumulated less heavy metals than PrP0/0/1 cells when concentrations of heavy metals exceeded physiological level. In conclusion, HuPrP1 cells are more resistant to chronic overload with copper, manganese, zinc or nickel than PrP0/0/1 cells. The resistance to metals overload is caused solely by the presence of PrP, since HuPrP1 and PrP0/0/1 cells differ only in the expression of PrP. These results indicate that one of the functions of PrP can be the modulation of trace heavy metal concentrations in cells and protection of cells against heavy metals overload and subsequent oxidative stress. PMID- 26104336 TI - Detection of sweet potato virus C, sweet potato virus 2 and sweet potato feathery mottle virus in Portugal. AB - Field sweet potato plants showing virus-like symptoms, as stunting, leaf distortion, mosaic and chlorosis, were collected in southwest Portugal and tested for the presence of four potyviruses, sweet potato virus C (SPVC), sweet potato virus 2 (SPV2), sweet potato feathery mottle virus (SPFMV), sweet potato virus G (SPVG), and the crinivirus sweet potato chlorotic stunt virus (SPCSV). DsRNA fractions were extracted from symptomatic leaves and used as templates in single and multiplex RT-PCR assays using previously described specific primers for each analyzed virus. The amplified reaction products for SPVC, SPV2 and SPFMV were of expected size, and direct sequencing of PCR products revealed that they correspond to the coat protein gene (CP) and showed 98%, 99% and 99% identity, respectively, to those viruses. Comparison of the CP genomic and amino acid sequences of the Portuguese viral isolates recovered here with those of ten other sequences of isolates obtained in different countries retrieved from the GenBank showed very few differences. The application of the RT-PCR assays revealed for the first time the presence of SPVC and SPFMV in the sweet potato crop in Portugal, the absence of SPVG and SPCSV in tested plants, as well as the occurrence of triple virus infections under field conditions. PMID- 26104337 TI - Preparation of vesicular stomatitis virus pseudotype with Chikungunya virus envelope protein. AB - Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes Chikungunya fever (CHIKF) in millions of people mainly in developing countries. CHIKF is characterized by high fever, fatigue, headache, nausea, vomiting, rash, myalgia and severe arthralgia. To date, there is no specific treatment and no licensed vaccine against CHIKV infection. In this study, we developed a safe, efficient and easy neutralization assay of CHIKV based on vesicular stomatitis virus (VSV) pseudotype with CHIKV envelope protein and the green fluorescent protein (GFP) or luciferase as reporter gene, which could be used under a reduced safety level. The VSV pseudotype can be applied to the epidemic survey by measuring the expression of GFP or luciferase activity in infected cells. This system can also be used to study the mechanisms of virus entry. PMID- 26104338 TI - Comparative analysis of sialidase protein in velogenic and lentogenic strains of Newcastle disease virus. AB - The sialidase protein is a major part of hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV), which is an important multifunctional envelope protein. This protein plays key roles in virus attachment to cells and virus-cell fusion. In this study, we compared the sialidase protein of Iranian virulent velogenic field strains with that of avirulent lentogenic strains. Six of seventeen variations in amino acid 395, 523, 550 432, 479 and 540 were observed near the catalytic and glycosylation sites in the sialidase protein. The obtained results showed fundamental differences in various biological parameters such as post-translational modification, antigenic index and electrostatic potential of tertiary structure of the sialidase protein. We suggest these six amino acids might play an effective role in the pathogenesis of NDV. PMID- 26104339 TI - Serum total antioxidant capacity status of HTLV-1 infected patients. AB - Many aspects of the pathogenesis of Human T-cell lymphotropic virus type 1 (HTLV 1) still need further elucidations. Previous studies have indicated that oxidative stress occurs during infection with the other retrovirus, human immunodeficiency virus 1 (HIV-1). Similar results have been observed in some other chronic viral infections including hepatitis B (HBV) and hepatitis C (HCV). In order to reveal possible oxidative stress in HTLV-1-infected patients, we evaluated serum total antioxidant capacity (TAC) as an indicator of oxidative stress in these patients. Forty-four HTLV-1-seropositive individuals were included in this study, consisting of 12 symptomatic and 32 asymptomatic (carrier) cases. Controls consisted of 36 apparently healthy, HTLV-1-, HIV- and hepatitis-seronegative individuals. All symptomatic patients had HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Serum TAC levels in patients and healthy individuals were measured using a quantitative TAC assay. The antioxidant capacity in HTLV-1-seropositive cases was significantly reduced compared to control group (P = 0.001). In addition, TAC was lower in patients with more than 5 years history of HAM/TSP compared to those with <=5 years duration of the myelopathy (P = 0.03). Our results show a depletion of TAC during HTLV-1 infection, which intensifies along with the disease progress. This finding indicates a role of the oxidative stress in pathogenesis of HTLV-1. These results may prompt further research to evaluate any possible therapeutic effect of antioxidant dietary supplements for HTLV-1 infected individuals. PMID- 26104340 TI - Characterization of tomato aspermy virus isolated from chrysanthemum and elucidation of its complete nucleotide sequence. PMID- 26104341 TI - The Short Questionnaire to Assess Health-Enhancing (SQUASH) Physical Activity in Adolescents: A Validation Using Doubly Labeled Water. AB - BACKGROUND: Accurate assessment of physical activity energy expenditure (PAEE) among adolescents is important for surveillance, evaluating interventions, and understanding the relation between energy balance and normal physiological and behavioral growth and development. The purpose of this study was to examine the validity of the Short Questionnaire to Assess Health-Enhancing Physical Activity (SQUASH)13 for measuring PAEE among adolescents. METHODS: The participants were seventeen adolescents (9 females; Mean age = 17.53; SD = 0.62). Energy expenditure was measured during a 9-day period with doubly labeled water (DLW). The SQUASH was self-administered on the morning of the 10th day and assessed commuting activities, leisure time activities, household activities, and activities at work and school over the previous 9 days. RESULTS: A Bland-Altman plot indicated that the SQUASH underestimated PAEE compared with DLW by a mean difference of 126 kcal.d-1 (95% limits of agreement: -1,207 to 1,459 kcal.d-1), representative of a 10% underestimation. The Spearman rank order correlation coefficient showed there was a significant association between the SQUASH and DLW (r = .50, P = .04), for estimating PAEE. CONCLUSION: When using a sample of highly active adolescents, the SQUASH is a valid self-report tool for measuring PAEE at the group and individual rank order level. PMID- 26104343 TI - Evasion of Innate and Adaptive Immunity by Mycobacterium tuberculosis. AB - Through thousands of years of reciprocal coevolution, Mycobacterium tuberculosis has become one of humanity's most successful pathogens, acquiring the ability to establish latent or progressive infection and persist even in the presence of a fully functioning immune system. The ability of M. tuberculosis to avoid immune mediated clearance is likely to reflect a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity. These include the manipulation of their phagosomal environment within host macrophages, the selective avoidance or engagement of pattern recognition receptors, modulation of host cytokine production, and the manipulation of antigen presentation to prevent or alter the quality of T-cell responses. In this article we review an extensive array of published studies that have begun to unravel the sophisticated program of specific mechanisms that enable M. tuberculosis and other pathogenic mycobacteria to persist and replicate in the face of considerable immunological pressure from their hosts. Unraveling the mechanisms by which M. tuberculosis evades or modulates host immune function is likely to be of major importance for the development of more effective new vaccines and targeted immunotherapy against tuberculosis. PMID- 26104342 TI - Structure and function of the mammalian middle ear. I: Large middle ears in small desert mammals. AB - Many species of small desert mammals are known to have expanded auditory bullae. The ears of gerbils and heteromyids have been well described, but much less is known about the middle ear anatomy of other desert mammals. In this study, the middle ears of three gerbils (Meriones, Desmodillus and Gerbillurus), two jerboas (Jaculus) and two sengis (elephant-shrews: Macroscelides and Elephantulus) were examined and compared, using micro-computed tomography and light microscopy. Middle ear cavity expansion has occurred in members of all three groups, apparently in association with an essentially 'freely mobile' ossicular morphology and the development of bony tubes for the middle ear arteries. Cavity expansion can occur in different ways, resulting in different subcavity patterns even between different species of gerbils. Having enlarged middle ear cavities aids low-frequency audition, and several adaptive advantages of low-frequency hearing to small desert mammals have been proposed. However, while Macroscelides was found here to have middle ear cavities so large that together they exceed brain volume, the bullae of Elephantulus are considerably smaller. Why middle ear cavities are enlarged in some desert species but not others remains unclear, but it may relate to microhabitat. PMID- 26104344 TI - Resolution of Multimeric Forms of Circular Plasmids and Chromosomes. AB - One of the disadvantages of circular plasmids and chromosomes is their high sensitivity to rearrangements caused by homologous recombination. Odd numbers of crossing-over occurring during or after replication of a circular replicon result in the formation of a dimeric molecule in which the two copies of the replicon are fused. If they are not converted back to monomers, the dimers of replicons may fail to correctly segregate at the time of cell division. Resolution of multimeric forms of circular plasmids and chromosomes is mediated by site specific recombination, and the enzymes that catalyze this type of reaction fall into two families of proteins: the serine and tyrosine recombinase families. Here we give an overview of the variety of site-specific resolution systems found on circular plasmids and chromosomes. PMID- 26104345 TI - Spore Surface Display. AB - A variety of bioactive peptides and proteins have been successfully displayed on the surface of recombinant spores of Bacillus subtilis and other sporeformers. In most cases, spore display has been achieved by stably anchoring the foreign molecules to endogenous surface proteins or parts of them. Recombinant spores have been proposed for a large number of potential applications ranging from oral vaccine vehicles to bioremediation tools, and including biocatalysts, probiotics for animal or human use, as well as the generation and screening of mutagenesis libraries. In addition, a nonrecombinant approach has been recently developed to adsorb antigens and enzymes on the spore surface. This nonrecombinant approach appears particularly well suited for applications involving the delivery of active molecules to human or animal mucosal surfaces. Both the recombinant and nonrecombinant spore display systems have a number of advantages over cell- or phage-based systems. The stability, safety of spores of several bacterial species, and amenability to laboratory manipulations, together with the lack of some constraints limiting the use of other systems, make the spore a highly efficient platform to display heterologous proteins. PMID- 26104346 TI - New Therapeutic Developments against Shiga Toxin-Producing Escherichia coli. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) is an etiologic agent of bloody diarrhea. A serious sequela of disease, the hemolytic uremic syndrome (HUS) may arise in up to 25% of patients. The development of HUS after STEC infection is linked to the presence of Stx. STEC strains may produce one or more Stxs, and the Stxs come in two major immunological groups, Stx1 and Stx2. A multitude of possible therapeutics designed to inhibit the actions of the Stxs have been developed over the past 30 years. Such therapeutics are important because antibiotic treatment of STEC infections is contraindicated due to an increased potential for development of HUS. The reason for the increased risk of HUS after antibiotic treatment is likely because certain antibiotics induce expression of the Stxs, which are generally associated with lysogenic bacteriophages. There are a few potential therapeutics that either try to kill STEC without inducing Stx expression or target gene expression within STEC. However, the vast majority of the treatments under development are designed to limit Stx receptor generation or to prevent toxin binding, trafficking, processing, or activity within the cell. The potential therapies described in this review include some that have only been tested in vitro and several that demonstrate efficacy in animals. The therapeutics that are currently the furthest along in development (completed phase I and II trials) are monoclonal antibodies directed against Stx1 and Stx2. PMID- 26104347 TI - DNA Assembly Tools and Strategies for the Generation of Plasmids. AB - Since the discovery of restriction enzymes and the generation of the first recombinant DNA molecule over 40 years ago, molecular biology has evolved into a multidisciplinary field that has democratized the conversion of a digitized DNA sequence stored in a computer into its biological counterpart, usually as a plasmid, stored in a living cell. In this article, we summarize the most relevant tools that allow the swift assembly of DNA sequences into useful plasmids for biotechnological purposes. We cover the main components and stages in a typical DNA assembly workflow, namely in silico design, de novo gene synthesis, and in vitro and in vivo sequence assembly methodologies. PMID- 26104348 TI - Conditional Activation of Toxin-Antitoxin Systems: Postsegregational Killing and Beyond. AB - Toxin-antitoxin (TA) systems are small genetic modules formed by a stable toxin and an unstable antitoxin that are widely present in plasmids and in chromosomes of Bacteria and Archaea. Toxins can interfere with cell growth or viability, targeting a variety of key processes. Antitoxin inhibits expression of the toxin, interacts with it, and neutralizes its effect. In a plasmid context, toxins are kept silent by the continuous synthesis of the unstable antitoxins; in plasmid free cells (segregants), toxins can be activated owing to the faster decay of the antitoxin, and this results in the elimination of these cells from the population (postsegregational killing [PSK]) and in an increase of plasmid-containing cells in a growing culture. Chromosomal TA systems can also be activated in particular circumstances, and the interference with cell growth and viability that ensues contributes in different ways to the physiology of the cell. In this article, we review the conditional activation of TAs in selected plasmidic and chromosomal TA pairs and the implications of this activation. On the whole, the analysis underscores TA interactions involved in PSK and points to the effective contribution of TA systems to the physiology of the cell. PMID- 26104349 TI - Veterinary Public Health Approach to Managing Pathogenic Verocytotoxigenic Escherichia coli in the Agri-Food Chain. AB - Verocytoxigenic Escherichia coli (VTEC) comprises many diverse serogroups, but seven serogroups, O157, O26, O103, O145, O111, O21, and O45, have been most commonly linked to severe human infections, though illness has also been reported from a range of other VTEC serogroups. This poses challenges in assessing the risk to humans from the diverse range of VTEC strains that may be recovered from animals, the environment, or food. For routine assessment of risk posed by VTEC recovered from the agri-food chain, the concept of seropathotype can be used to rank the human risk potential from a particular VTEC serogroup on the basis of both serotype (top seven serogroups) and the presence of particular virulence genes (vt in combination with eae, or aaiC plus aggR). But for other VTEC serogroups or virulence gene combinations, it is not currently possible to fully assess the risk posed. VTEC is shed in animal feces and can persist in the farm environment for extended periods ranging from several weeks to many months, posing an ongoing reservoir of contamination for grazing animals, water courses, and fresh produce and for people using farmland for recreational purposes. Appropriate handling and treatment of stored animal waste (slurries and manures) will reduce risk from VTEC in the farm environment. Foods of animal origin such as milk and dairy products and meat may be contaminated with VTEC during production and processing, and the pathogen may survive or grow during processing operations, highlighting the need for well-designed and validated Hazard Analysis Critical Control Point management systems. This article focuses on a veterinary public health approach to managing VTEC, highlighting the various routes in the agri-food chain for transmission of human pathogenic VTEC and general approaches to managing the risk. PMID- 26104350 TI - Nucleotide Metabolism and DNA Replication. AB - The development and application of a highly versatile suite of tools for mycobacterial genetics, coupled with widespread use of "omics" approaches to elucidate the structure, function, and regulation of mycobacterial proteins, has led to spectacular advances in our understanding of the metabolism and physiology of mycobacteria. In this article, we provide an update on nucleotide metabolism and DNA replication in mycobacteria, highlighting key findings from the past 10 to 15 years. In the first section, we focus on nucleotide metabolism, ranging from the biosynthesis, salvage, and interconversion of purine and pyrimidine ribonucleotides to the formation of deoxyribonucleotides. The second part of the article is devoted to DNA replication, with a focus on replication initiation and elongation, as well as DNA unwinding. We provide an overview of replication fidelity and mutation rates in mycobacteria and summarize evidence suggesting that DNA replication occurs during states of low metabolic activity, and conclude by suggesting directions for future research to address key outstanding questions. Although this article focuses primarily on observations from Mycobacterium tuberculosis, it is interspersed, where appropriate, with insights from, and comparisons with, other mycobacterial species as well as better characterized bacterial models such as Escherichia coli. Finally, a common theme underlying almost all studies of mycobacterial metabolism is the potential to identify and validate functions or pathways that can be exploited for tuberculosis drug discovery. In this context, we have specifically highlighted those processes in mycobacterial DNA replication that might satisfy this critical requirement. PMID- 26104351 TI - Double-Strand DNA Break Repair in Mycobacteria. AB - Discontinuity of both strands of the chromosome is a lethal event in all living organisms because it compromises chromosome replication. As such, a diversity of DNA repair systems has evolved to repair double-strand DNA breaks (DSBs). In part, this diversity of DSB repair systems has evolved to repair breaks that arise in diverse physiologic circumstances or sequence contexts, including cellular states of nonreplication or breaks that arise between repeats. Mycobacteria elaborate a set of three genetically distinct DNA repair pathways: homologous recombination, nonhomologous end joining, and single-strand annealing. As such, mycobacterial DSB repair diverges substantially from the standard model of prokaryotic DSB repair and represents an attractive new model system. In addition, the presence in mycobacteria of a DSB repair system that can repair DSBs in nonreplicating cells (nonhomologous end joining) or when DSBs arise between repeats (single-strand annealing) has clear potential relevance to Mycobacterium tuberculosis pathogenesis, although the exact role of these systems in M. tuberculosis pathogenesis is still being elucidated. In this article we will review the genetics of mycobacterial DSB repair systems, focusing on recent insights. PMID- 26104352 TI - The Interplay between the Microbiota and Enterohemorrhagic Escherichia coli. AB - The gastrointestinal tract of mammals is home to a plethora of microbial species that comprise the microbiota. The role of the microbiota in human health is at the forefront of science in recent years, because it is now appreciated that this intricate microbe-host association shapes the host's immune response and physiology. Many diseases are associated with changes in the microbiota, called dysbiosis. Dysbiosis is associated with obesity, metabolic syndromes, inflammatory bowel-disease, inflammatory bowel syndrome, cancer, diabetes, allergies, and autism. The microbiota is largely regarded as a barrier to enteric infections, such as with enterohemorrhagic Escherichia coli (EHEC). However, the interactions between pathogens and the microbiota are largely unknown, as is how these interactions influence the outcome of enteric disease. The microbial composition of the gastrointestinal tract shapes the landscape in which EHEC survives within the host. This organism competes for nutrients derived from the host diet, liberates additional resources from dietary and host sources, and produces signaling molecules sensed by EHEC to direct gene expression. To successfully colonize the recto-anal junction of a ruminant, the EHEC reservoir, or the colon of a human, an accidental host, EHEC must alter its physiology to survive within the host digestive tract. In this article, we explore the classes of molecules produced or modified by the microbiota that appear to be instrumental in governing virulence gene expression of EHEC. We also explore how interaction with different microbiotas influences EHEC infectivity and host interaction. PMID- 26104353 TI - High-Throughput DNA Sequencing Analysis of Antibody Repertoires. AB - New high-throughput DNA sequencing (HTS) technologies developed in the past decade have begun to be applied to the study of the complex gene rearrangements that encode human antibodies. This article first reviews the genetic features of Ig loci and the HTS technologies that have been applied to human repertoire studies, then discusses key choices for experimental design and data analysis in these experiments and the insights gained in immunological and infectious disease studies with the use of these approaches. PMID- 26104354 TI - Efficient Methods To Isolate Human Monoclonal Antibodies from Memory B Cells and Plasma Cells. AB - In this article, we highlight the advantages of isolating human monoclonal antibodies from the human memory B cells and plasma cell repertoires by using high-throughput cellular screens. Memory B cells are immortalized with high efficiency using Epstein-Barr virus (EBV) in the presence of a toll-like receptor (TLR) agonist, while plasma cells are maintained in single-cell cultures by using interleukin 6 (IL-6) or stromal cells. In both cases, multiple parallel assays, including functional assays, can be used to identify rare cells that produce antibodies with unique properties. Using these methods, we have isolated potent and broadly neutralizing antibodies against a variety of viruses, in particular, a pan-influenza-A-neutralizing antibody and an antibody that neutralizes four different paramyxoviruses. Given the high throughput and the possibility of directly screening for function (rather than just binding), these methods are instrumental to implement a target-agnostic approach to identify the most effective antibodies and, consequently, the most promising targets for vaccine design. This approach is exemplified by the identification of unusually potent cytomegalovirus-neutralizing antibodies that led to the identification of the target, a pentameric complex that we are developing as a candidate vaccine. PMID- 26104355 TI - Spore Resistance Properties. AB - Spores of various Bacillus and Clostridium species are among the most resistant life forms known. Since the spores of some species are causative agents of much food spoilage, food poisoning, and human disease, and the spores of Bacillus anthracis are a major bioweapon, there is much interest in the mechanisms of spore resistance and how these spores can be killed. This article will discuss the factors involved in spore resistance to agents such as wet and dry heat, desiccation, UV and gamma-radiation, enzymes that hydrolyze bacterial cell walls, and a variety of toxic chemicals, including genotoxic agents, oxidizing agents, aldehydes, acid, and alkali. These resistance factors include the outer layers of the spore, such as the thick proteinaceous coat that detoxifies reactive chemicals; the relatively impermeable inner spore membrane that restricts access of toxic chemicals to the spore core containing the spore's DNA and most enzymes; the low water content and high level of dipicolinic acid in the spore core that protect core macromolecules from the effects of heat and desiccation; the saturation of spore DNA with a novel group of proteins that protect the DNA against heat, genotoxic chemicals, and radiation; and the repair of radiation damage to DNA when spores germinate and return to life. Despite their extreme resistance, spores can be killed, including by damage to DNA, crucial spore proteins, the spore's inner membrane, and one or more components of the spore germination apparatus. PMID- 26104356 TI - The Influence of Biofilms in the Biology of Plasmids. AB - The field of plasmid biology has historically focused on bacteria growing in liquid culture. Surface-attached communities of bacterial biofilms have recently been understood to be the normal environment of bacteria in the natural world. Thus, studies examining plasmid replication, maintenance, and transfer in biofilms are essential for a true understanding of bacterial plasmid biology. This article reviews the current knowledge of the interplay between bacterial biofilms and plasmids, focusing on the role of plasmids in biofilm development and the role of biofilms in plasmid maintenance, copy-number control, and transfer. The studies examined herein highlight the importance of biofilms as an important ecological niche in which bacterial plasmids play an essential role. PMID- 26104357 TI - A Unique DNA Recombination Mechanism of the Mating/Cell-type Switching of Fission Yeasts: a Review. AB - Cells of the highly diverged Schizosaccharomyces (S.) pombe and S. japonicus fission yeasts exist in one of two sex/mating types, called P (for plus) or M (for minus), specified by which allele, M or P, resides at mat1. The fission yeasts have evolved an elegant mechanism for switching P or M information at mat1 by a programmed DNA recombination event with a copy of one of the two silent mating-type genes residing nearby in the genome. The switching process is highly cell-cycle and generation dependent such that only one of four grandchildren of a cell switches mating type. Extensive studies of fission yeast established the natural DNA strand chirality at the mat1 locus as the primary basis of asymmetric cell division. The asymmetry results from a unique site- and strand-specific epigenetic "imprint" at mat1 installed in one of the two chromatids during DNA replication. The imprint is inherited by one daughter cell, maintained for one cell cycle, and is then used for initiating recombination during mat1 replication in the following cell cycle. This mechanism of cell-type switching is considered to be unique to these two organisms, but determining the operation of such a mechanism in other organisms has not been possible for technical reasons. This review summarizes recent exciting developments in the understanding of mating type switching in fission yeasts and extends these observations to suggest how such a DNA strand-based epigenetic mechanism of cellular differentiation could also operate in diploid organisms. PMID- 26104358 TI - Plasmid-Mediated Antibiotic Resistance and Virulence in Gram-Negatives: the Klebsiella pneumoniae Paradigm. AB - Plasmids harbor genes coding for specific functions including virulence factors and antibiotic resistance that permit bacteria to survive the hostile environment found in the host and resist treatment. Together with other genetic elements such as integrons and transposons, and using a variety of mechanisms, plasmids participate in the dissemination of these traits, resulting in the virtual elimination of barriers among different kinds of bacteria. In this article we review the current information about the physiology of plasmids and their role in virulence and antibiotic resistance from the Gram-negative opportunistic pathogen Klebsiella pneumoniae. This bacterium has acquired multidrug resistance and is the causative agent of serious community- and hospital-acquired infections. It is also included in the recently defined ESKAPE group of bacteria that cause most U.S. hospital infections. PMID- 26104359 TI - Enterohemorrhagic Escherichia coli Pathogenesis and the Host Response. AB - Enterohemorrhagic Escherichia coli (EHEC) is a highly pathogenic bacterial strain capable of causing watery or bloody diarrhea, the latter termed hemorrhagic colitis, and hemolytic-uremic syndrome (HUS). HUS is defined as the simultaneous development of non-immune hemolytic anemia, thrombocytopenia, and acute renal failure. The mechanism by which EHEC bacteria colonize and cause severe colitis, followed by renal failure with activated blood cells, as well as neurological symptoms, involves the interaction of bacterial virulence factors and specific pathogen-associated molecular patterns with host cells as well as the host response. The innate immune host response comprises the release of antimicrobial peptides as well as cytokines and chemokines in addition to activation and/or injury to leukocytes, platelets, and erythrocytes and activation of the complement system. Some of the bacterial interactions with the host may be protective in nature, but, when excessive, contribute to extensive tissue injury, inflammation, and thrombosis, effects that may worsen the clinical outcome of EHEC infection. This article describes aspects of the host response occurring during EHEC infection and their effects on specific organs. PMID- 26104360 TI - The Spectrum of Drug Susceptibility in Mycobacteria. AB - A major factor complicating efforts to control the tuberculosis epidemic is the long duration of treatment required to successfully clear the infection. One reason that long courses of treatment are required may be the fact that mycobacterial cells arise during the course of infection that are less susceptible to antibiotics. Here we describe the paradigms of phenotypic drug tolerance and resistance as they apply to mycobacteria. We then discuss the mechanisms by which phenotypically drug-tolerant and -resistant cells arise both at a population level and in specialized subpopulations of cells that may be especially important in allowing the bacterium to survive in the face of treatment. These include general mechanisms that have been shown to alter the susceptibility of mycobacteria to antibiotics including growth arrest, efflux pump induction, and biofilm formation. In addition, we discuss emerging data from single-cell studies of mycobacteria that have identified unique ways in which specialized subpopulations of cells arise that vary in their frequency, in their susceptibility to drug, and in their stability over time. PMID- 26104361 TI - Human Metapneumovirus. AB - Human metapneumovirus (HMPV), a paramyxovirus identified in 2001, is a leading cause of respiratory tract infections in both children and adults. Seroprevalence studies demonstrate that the primary infection occurs before the age of 5 years, and humans are reinfected throughout life. The four subgroups of HMPV occur with year-to-year variability, and infection with one subgroup confers some serologic cross-protection. Experimental vaccines elicit a humoral response in both animal and human models and have been used to identify antigenic determinants. The main target of protective antibodies is the fusion (F) protein, although many of the remaining eight proteins are immunogenic. Monoclonal antibodies (mAbs) targeting the F protein are both protective and therapeutic in animal models. Most recently, the identification of broadly neutralizing antibodies against HMPV and respiratory syncytial virus demonstrates that common epitopes are present between the two viruses. Broadly neutralizing mAbs have significant clinical implications for prophylaxis and treatment of high-risk hosts as well as vaccine development. PMID- 26104362 TI - Risk Factors for Shiga Toxin-Producing Escherichia coli-Associated Human Diseases. AB - We have reviewed the risk factors for the occurrence of Shiga toxin-producing Escherichia coli (STEC)-associated human diseases. The analysis of STEC surveillance data and trends shows differences in frequency and severity of the illnesses across countries, whereas the economic and social costs for the affected families, the community, and the health system are better estimated in developed countries. The occurrence of STEC infections is determined by the interaction of the pathogen, the reservoirs, and the biological, cultural, and behavioral aspects of the host. The main risk factors identified in earlier case control and population-based studies were dietary behaviors and beef consumption. However, in recent years, other risky exposures have also emerged, like the consumption of raw vegetables and sprouts, working or camping in rural areas, visiting farms, and person-to-person transmission. Epidemiological changes have also been determined by the intensification of cattle production, the increase in centralized food production and distribution, and the growth in the volume of international trade of foods. The main lessons learned from recent large outbreaks are knowledge of virulence determinants of new pathogenic strains, recognition of new vehicles of infection, development of new methodologies for detecting STEC in foods and humans, improvement in food regulations and hygiene guidelines, new therapeutic approaches in the treatment of infected patients, establishment of continuous educational programs for food consumers, and enhanced cooperation and teamwork of regional and international networks. PMID- 26104363 TI - Tn7. AB - The bacterial transposon Tn7 is distinguished by the levels of control it displays over transposition and its capacity to utilize different kinds of target sites. Transposition is carried out using five transposon-encoded proteins, TnsA, TnsB, TnsC, TnsD, and TnsE, which facilitate transfer of the element while minimizing the chances of inactivating host genes by using two pathways of transposition. One of these pathways utilizes TnsD, which targets transposition into a single site found in bacteria (attTn7), and a second utilizes TnsE, which preferentially directs transposition into plasmids capable of moving between bacteria. Control of transposition involves a heteromeric transposase that consists of two proteins, TnsA and TnsB, and a regulator protein TnsC. Tn7 also has the ability to inhibit transposition into a region already occupied by the element in a process called target immunity. Considerable information is available about the functional interactions of the Tn7 proteins and many of the protein-DNA complexes involved in transposition. Tn7-like elements that encode homologs of all five of the proteins found in Tn7 are common in diverse bacteria, but a newly appreciated larger family of elements appears to use the same core TnsA, TnsB, and TnsC proteins with other putative target site selector proteins allowing different targeting pathways. PMID- 26104364 TI - "Preharvest" Food Safety for Escherichia coli O157 and Other Pathogenic Shiga Toxin-Producing Strains. AB - Preharvest food safety refers to the concept of reducing the rates of contamination of unprocessed foods with food-borne disease pathogens in order to reduce human exposure and disease. This article addresses the search for effective preharvest food safety practices for application to live cattle to reduce both contamination of foods of bovine origin and environmental contamination resulting from cattle. Although this research has resulted in several practices that significantly decrease contamination by Escherichia coli O157, the effects are limited in magnitude and unlikely to affect the incidence of human disease without much wider application and considerably higher efficacy than is presently apparent. Infection of cattle with E. coli O157 is transient and seasonally variable, likely resulting from a complex web of exposures. It is likely that better identification of the true maintenance reservoir of this agent and related Shiga toxin-producing E. coli is required to develop more effective control measures for these important food- and waterborne disease agents. PMID- 26104365 TI - Evolution in the Bacillaceae. AB - The family Bacillaceae constitutes a phenotypically diverse and globally ubiquitous assemblage of bacteria. Investigation into how evolution has shaped, and continues to shape, this family has relied on several widely ranging approaches from classical taxonomy, ecological field studies, and evolution in soil microcosms to genomic-scale phylogenetics, laboratory, and directed evolution experiments. One unifying characteristic of the Bacillaceae, the endospore, poses unique challenges to answering questions regarding both the calculation of evolutionary rates and claims of extreme longevity in ancient environmental samples. PMID- 26104366 TI - Shiga Toxin (Verotoxin)-Producing Escherichia coli in Japan. AB - A series of outbreaks of infection with Shiga toxin (verocytotoxin)-producing Escherichia coli or enterohemorrhagic E. coli (EHEC) O157:H7 occurred in Japan in 1996, the largest outbreak occurring in primary schools in Sakai City, Osaka Prefecture, where more than 7,500 cases were reported. Although the reason for the sudden increase in the number of reports of EHEC isolates in 1996 is not known, the number of reports has grown to more than 3,000 cases per year since 1996, from an average of 105 reports each year during the previous 5-year period (1991-1995). Despite control measures instituted since 1996, including designating Shiga toxin-producing E. coli infection as a notifiable disease, and nationwide surveillance effectively monitoring the disease, the number of reports remains high, around 3,800 cases per year. Serogroup O157 predominates over other EHEC serogroups, but isolation frequency of non-O157 EHEC has gone up slightly over the past few years. Non-O157 EHEC has recently caused outbreaks where consumption of a raw beef dish was the source of the infection, and some fatal cases occurred. Laboratory surveillance comprised prefectural and municipal public health institutes, and the National Institute of Infectious Diseases has contributed to finding not only multiprefectural outbreaks but recognizing sporadic cases that could have been missed as an outbreak without the aid of molecular subtyping of EHEC isolates. This short overview presents recent information on the surveillance of EHEC infections in Japan. PMID- 26104368 TI - Mycobacterial Biofilms. AB - Bacteria have a natural propensity to grow as sessile, matrix-encapsulated, multicellular communities called biofilms. Formation of biofilms proceeds through genetically programmed, distinct developmental stages signaled by intricate networks of communication among the constituent population and their environment. Growing in the complex and heterogeneous microenvironments of biofilms, the resident bacteria acquire unique phenotypes that are generally not associated with their planktonic counterparts. Most notable among these is an extraordinary level of tolerance to a variety of environmental stresses, including antibiotics. Although mycobacteria have long been observed to spontaneously form complex multicellular structures in vitro, it has only recently become apparent that these structures are not only formed through dedicated genetic pathways but are also tolerant to antibiotics. In this article, we review the recent advances in the understanding of mycobacterial biofilms in vitro. We further consider the possible linkage between biofilm-like lifestyles and characteristic persistence of mycobacterial infections against host-defense mechanisms as well as antibiotics. PMID- 26104369 TI - Historical Events That Spawned the Field of Plasmid Biology. AB - This chapter revisits the historical development and outcome of studies focused on the transmissible, extrachromosomal genetic elements called plasmids. Early work on plasmids involved structural and genetic mapping of these molecules, followed by the development of an understanding of how plasmids replicate and segregate during cell division. The intriguing property of plasmid transmission between bacteria and between bacteria and higher cells has received considerable attention. The utilitarian aspects of plasmids are described, including examples of various plasmid vector systems. This chapter also discusses the functional attributes of plasmids needed for their persistence and survival in nature and in man-made environments. The term plasmid biology was first conceived at the Fallen Leaf Lake Conference on Promiscuous Plasmids, 1990, Lake Tahoe, California. The International Society for Plasmid Biology was established in 2004 (www.ISPB.org). PMID- 26104367 TI - The Pup-Proteasome System of Mycobacteria. AB - Proteasomes are ATP-dependent, barrel-shaped proteases found in all three domains of life. In eukaryotes, proteins are typically targeted for degradation by posttranslational modification with the small protein ubiquitin. In 2008, the first bacterial protein modifier, Pup (prokaryotic ubiquitin-like protein), was identified in Mycobacterium tuberculosis. Functionally analogous to ubiquitin, conjugation with Pup serves as a signal for degradation by the mycobacterial proteasome. Proteolysis-dependent and -independent functions of the M. tuberculosis proteasome are essential for virulence of this successful pathogen. In this article we describe the discovery of the proteasome as a key player in tuberculosis pathogenesis and the biology and biochemistry of the Pup-proteasome system. PMID- 26104370 TI - Retroviral DNA Transposition: Themes and Variations. AB - Retroviruses and LTR retrotransposons are transposable elements that encapsidate the RNAs that are intermediates in the transposition of DNA copies of their genomes (proviruses), from one cell (or one locus) to another. Mechanistic similarities in DNA transposase enzymes and retroviral/retrotransposon integrases underscore the close evolutionary relationship among these elements. The retroviruses are very ancient infectious agents, presumed to have evolved from Ty3/Gypsy LTR retrotransposons (1), and DNA copies of their sequences can be found embedded in the genomes of most, if not all, members of the tree of life. All retroviruses share a specific gene arrangement and similar replication strategies. However, given their ancestries and occupation of diverse evolutionary niches, it should not be surprising that unique sequences have been acquired in some retroviral genomes and that the details of the mechanism by which their transposition is accomplished can vary. While every step in the retrovirus lifecycle is, in some sense, relevant to transposition, this Chapter focuses mainly on the early phase of retroviral replication, during which viral DNA is synthesized and integrated into its host genome. Some of the initial studies that set the stage for current understanding are highlighted, as well as more recent findings obtained through use of an ever-expanding technological toolbox including genomics, proteomics, and siRNA screening. Persistence in the area of structural biology has provided new insight into conserved mechanisms as well as variations in detail among retroviruses, which can also be instructive. PMID- 26104371 TI - The Plasmid Mobilome of the Model Plant-Symbiont Sinorhizobium meliloti: Coming up with New Questions and Answers. AB - Rhizobia are Gram-negative Alpha- and Betaproteobacteria living in the underground which have the ability to associate with legumes for the establishment of nitrogen-fixing symbioses. Sinorhizobium meliloti in particular the symbiont of Medicago, Melilotus, and Trigonella spp.-has for the past decades served as a model organism for investigating, at the molecular level, the biology, biochemistry, and genetics of a free-living and symbiotic soil bacterium of agricultural relevance. To date, the genomes of seven different S. meliloti strains have been fully sequenced and annotated, and several other draft genomic sequences are also available. The vast amount of plasmid DNA that S. meliloti frequently bears (up to 45% of its total genome), the conjugative ability of some of those plasmids, and the extent of the plasmid diversity has provided researchers with an extraordinary system to investigate functional and structural plasmid molecular biology within the evolutionary context surrounding a plant associated model bacterium. Current evidence indicates that the plasmid mobilome in S. meliloti is composed of replicons varying greatly in size and having diverse conjugative systems and properties along with different evolutionary stabilities and biological roles. While plasmids carrying symbiotic functions (pSyms) are known to have high structural stability (approaching that of chromosomes), the remaining plasmid mobilome (referred to as the non-pSym, functionally cryptic, or accessory compartment) has been shown to possess remarkable diversity and to be highly active in conjugation. In light of the modern genomic and current biochemical data on the plasmids of S. meliloti, the current article revises their main structural components, their transfer and regulatory mechanisms, and their potential as vehicles in shaping the evolution of the rhizobial genome. PMID- 26104372 TI - Plasmids as Tools for Containment. AB - Active containment systems are a major tool for reducing the uncertainty associated with the introduction of monocultures, genetically engineered or not, into target habitats for a large number of biotechnological applications (e.g., bioremediation, bioleaching, biopesticides, biofuels, biotransformations, live vaccines, etc.). While biological containment reduces the survival of the introduced organism outside the target habitat and/or upon completion of the projected task, gene containment strategies reduce the lateral spread of the key genetic determinants to indigenous microorganisms. In fundamental research, suicide circuits become relevant tools to address the role of gene transfer, mainly plasmid transfer, in evolution and how this transfer contributes to genome plasticity and to the rapid adaptation of microbial communities to environmental changes. Many lethal functions and regulatory circuits have been used and combined to design efficient containment systems. As many new genomes are being sequenced, novel lethal genes and regulatory elements are available, e.g., new toxin-antitoxin modules, and they could be used to increase further the current containment efficiencies and to expand containment to other organisms. Although the current containment systems can increase the predictability of genetically modified organisms in the environment, containment will never be absolute, due to the existence of mutations that lead to the appearance of surviving subpopulations. In this sense, orthogonal systems (xenobiology) appear to be the solution for setting a functional genetic firewall that will allow absolute containment of recombinant organisms. PMID- 26104373 TI - Committing the Oldest Sins in the Newest Kind of Ways-Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head. AB - The globular head of the trimeric influenza hemagglutinin (HA) contains the receptor-binding domain (RBD) and is the target of potently neutralizing human monoclonal antibodies (mAbs) with high in vivo activity. In general, these mAbs are induced easily by vaccination, but only infrequently display cross neutralizing activity against antigenic drift variants or even against HA molecules from viruses of heterologous subtypes. Recently, the atomic resolution structures of several such antibodies in complex with HA have been determined by X-ray crystallography. Not surprisingly, cross-reactive globular head antibodies target, at least partially, the conserved RBD. The cross-reactive potential of such mAbs is limited by contacts of hypervariable HA residues outside the conserved RBD. The RBD of H2 HA seems especially immunogenic. Increasing the immunogenicity of the RBD of other HA subtypes may be a step toward a universal influenza vaccine. The germ line-encoded Phe54 residue of the CDR-H2 of the VH1 69 germ line sequence appears to be ideally suited not only to reach into a conserved, hydrophobic pocket on the HA stem, but also to reach into the conserved, hydrophobic pocket that is the RBD. We have cloned antibodies from different individuals that are encoded by the VH1-69 germ line gene segment that contact the universally conserved Trp153 on the bottom of the RBD. These antibodies serve as further evidence of antibody genetic sequence convergence across individuals. PMID- 26104375 TI - Mobilizable Rolling-Circle Replicating Plasmids from Gram-Positive Bacteria: A Low-Cost Conjugative Transfer. AB - Conjugation is a key mechanism for horizontal gene transfer in bacteria. Some plasmids are not self-transmissible but can be mobilized by functions encoded in trans provided by other auxiliary conjugative elements. Although the transfer efficiency of mobilizable plasmids is usually lower than that of conjugative elements, mobilizable plasmids are more frequently found in nature. In this sense, replication and mobilization can be considered important mechanisms influencing plasmid promiscuity. Here we review the currently available information on two families of small mobilizable plasmids from Gram-positive bacteria that replicate via the rolling-circle mechanism. One of these families, represented by the streptococcal plasmid pMV158, is an interesting model since it contains a specific mobilization module (MOBV) that is widely distributed among mobilizable plasmids. We discuss a mechanism in which the promiscuity of the pMV158 replicon is based on the presence of two origins of lagging strand synthesis. The current strategies to assess plasmid transfer efficiency as well as to inhibit conjugative plasmid transfer are presented. Some applications of these plasmids as biotechnological tools are also reviewed. PMID- 26104376 TI - Sporulation in Bacteria: Beyond the Standard Model. AB - Endospore formation follows a complex, highly regulated developmental pathway that occurs in a broad range of Firmicutes. Although Bacillus subtilis has served as a powerful model system to study the morphological, biochemical, and genetic determinants of sporulation, fundamental aspects of the program remain mysterious for other genera. For example, it is entirely unknown how most lineages within the Firmicutes regulate entry into sporulation. Additionally, little is known about how the sporulation pathway has evolved novel spore forms and reproductive schemes. Here, we describe endospore and internal offspring development in diverse Firmicutes and outline progress in characterizing these programs. Moreover, comparative genomics studies are identifying highly conserved sporulation genes, and predictions of sporulation potential in new isolates and uncultured bacteria can be made from these data. One surprising outcome of these comparative studies is that core regulatory and some structural aspects of the program appear to be universally conserved. This suggests that a robust and sophisticated developmental framework was already in place in the last common ancestor of all extant Firmicutes that produce internal offspring or endospores. The study of sporulation in model systems beyond B. subtilis will continue to provide key information on the flexibility of the program and provide insights into how changes in this developmental course may confer advantages to cells in diverse environments. PMID- 26104374 TI - Transposable Phage Mu. AB - Transposable phage Mu has played a major role in elucidating the mechanism of movement of mobile DNA elements. The high efficiency of Mu transposition has facilitated a detailed biochemical dissection of the reaction mechanism, as well as of protein and DNA elements that regulate transpososome assembly and function. The deduced phosphotransfer mechanism involves in-line orientation of metal ion activated hydroxyl groups for nucleophilic attack on reactive diester bonds, a mechanism that appears to be used by all transposable elements examined to date. A crystal structure of the Mu transpososome is available. Mu differs from all other transposable elements in encoding unique adaptations that promote its viral lifestyle. These adaptations include multiple DNA (enhancer, SGS) and protein (MuB, HU, IHF) elements that enable efficient Mu end synapsis, efficient target capture, low target specificity, immunity to transposition near or into itself, and efficient mechanisms for recruiting host repair and replication machineries to resolve transposition intermediates. MuB has multiple functions, including target capture and immunity. The SGS element promotes gyrase-mediated Mu end synapsis, and the enhancer, aided by HU and IHF, participates in directing a unique topological architecture of the Mu synapse. The function of these DNA and protein elements is important during both lysogenic and lytic phases. Enhancer properties have been exploited in the design of mini-Mu vectors for genetic engineering. Mu ends assembled into active transpososomes have been delivered directly into bacterial, yeast, and human genomes, where they integrate efficiently, and may prove useful for gene therapy. PMID- 26104377 TI - Effects of transcutaneous electrical nerve stimulation on rats with the third lumbar vertebrae transverse process syndrome. AB - OBJECTIVE: To investigate the analgesic and anti-inflammatory effects of transcutaneous electrical nerve stimulation (TENS) at local or distant acupuncture points in a rat model of the third lumbar vertebrae transverse process syndrome. METHODS: Forty Sprague-Dawley rats were randomly divided into control, model, model plus local acupuncture point stimulation at BL23 (model+LAS) and model plus distant acupuncture point stimulation at ST36 (model+DAS) groups. All rats except controls underwent surgical third lumbar vertebrae transverse process syndrome modelling on day 2. Thereafter, rats in the model+LAS and model+DAS groups were treated daily with TENS for a total of six treatments (2/100 Hz, 30 min/day) from day 16 to day 29. Thermal pain thresholds were measured once a week during treatment and were continued until day 57, when local muscle tissue was sampled for RT-PCR and histopathological examination after haematoxylin and eosin staining. mRNA expression of interleukin-1 beta (IL 1beta), tumour necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) was determined. RESULTS: Thermal pain thresholds of all model rats decreased relative to the control group. Both LAS and DAS significantly increased the thermal pain threshold at all but one point during the treatment period. Histopathological assessment revealed that the local muscle tissues around the third lumbar vertebrae transverse process recovered to some degree in both the model+LAS and model+DAS groups; however, LAS appeared to have a greater effect. mRNA expression of IL-1beta, TNF-alpha and iNOS in the local muscle tissues was increased after modelling and attenuated in both model+LAS and model+DAS groups. The beneficial effect was greater after LAS than after DAS. CONCLUSIONS: TENS at both local (BL23) and distant (ST36) acupuncture points had a pain-relieving effect in rats with the third lumbar vertebrae transverse process syndrome, and LAS appeared to have greater anti-inflammatory and analgesic effects than DAS. TRIAL REGISTRATION NUMBER: 09073. PMID- 26104378 TI - Clinical outcomes and predictors of fetal and maternal consequences of pregnancy in lupus nephritis patients. AB - OBJECTIVE: To define the outcomes and risk predictors of fetal and maternal consequences of pregnancy in lupus nephritis (LN) patients. METHODS: Maternal and fetal outcomes of pregnancy in 52 systemic lupus erythematosus (SLE) patients were observed. Patients were allocated into two groups according to the presence or absence of LN. RESULTS: LN patients were subject to a higher risk of fetal complications, including fetal loss (7/24, 29.2 %, P = 0.001), lower birth weight (2548.2 +/- 540.8 vs. 2949.1 +/- 592.6 g, P = 0.028) and a higher frequency of small for gestational age births (33.3 vs. 10.7 %, P = 0.002). Higher rates of lupus flares (83.3 vs. 21.4 %, P = 0.001) and increased LAI-P scores (0.65 +/- 0.36 vs. 0.21 +/- 0.27, P = 0.001) during pregnancy were observed in LN patients. Multivariate analysis showed that increased SLE activity (P = 0.02, OR 4.2, 95 % CI 1.2-14.5), renal damage (P = 0.001, OR 8.4, 95 % CI 2.2-31.8), hypocomplementemia (P = 0.05, OR 3.23, 95 % CI 1.0-10.7), hypoalbuminemia (P = 0.011, OR 5.62, 95 % CI 1.4-23.0) and hypertension (P = 0.021, OR 6.0, 95 % CI 1.5-24.2) during pregnancy were predictors of adverse fetal outcomes. CONCLUSIONS: Pregnancy in LN patients should be monitored before and during pregnancy because of poor fetal and maternal outcomes. Increased LAI-P scores, renal damage, hypocomplementemia, hypoalbuminemia and hypertension are predictors of adverse fetal outcomes for SLE patients. PMID- 26104379 TI - Risk stratification model, including preoperative serum C-reactive protein and estimated glomerular filtration rate levels, in patients with upper urinary tract urothelial carcinoma undergoing radical nephroureterectomy. AB - PURPOSE: To investigate the prognostic indicators, including clinicopathological and preoperative hematological factors, in patients undergoing radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC), and to develop a prognostic factor-based risk stratification model. METHODS: The clinicopathological data and preoperative parameters were collected from 345 UTUC patients treated with RNU without neoadjuvant therapy, retrospectively. The prognostic values of preoperative hematological parameters and clinicopathological factors were evaluated. Then, a risk stratification model was developed to predict poor survival after RNU using the regression coefficients of multivariate analysis. RESULTS: In multivariate analysis, high serum C-reactive protein (CRP) levels (>=0.5 mg/dl), low estimated glomerular filtration rate (eGFR) levels (<50 ml/min/1.73 m(2)), Eastern Cooperative Oncology Group Performance status >=1, number of tumor foci >1, tumor grade (G3), positive LN, and positive surgical margin were independent factors predicting poor cancer specific survival (CSS). Patients were stratified into three groups, and the risk stratification model revealed significant differences in CSS between the three subgroups. The 5-year CSS in patients at low, intermediate, and high risk was 92.7, 75.4, and 31.5 %, respectively. CONCLUSION: This study indicates that preoperative hematological markers, such as low eGFR and high CRP levels predict a poor survival in patients with UTUC. Our risk stratification model may provide physicians with useful prognostic information for identifying patients who may be candidates for multimodal treatment. PMID- 26104380 TI - The role of DCs in the immunopathogenesis of chronic HBV infection and the methods of inducing DCs maturation. AB - Chronic hepatitis B virus (HBV) infection is the result of an inadequate immune response towards the virus. Dendritic cells (DCs), as the most efficient professional antigen-presenting cells (APCs), possess the strongest antigen presenting the effect in the body and can stimulate the initial T cell activation and proliferation. DCs of patients with chronic HBV infection are impaired, resulting in more tolerogenic rather than immunogenic responses, which may contribute to viral persistence. Recently, numerous methods have been developed to induce DCs maturation. To date, recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) combined with interleukin-4 (rhIL-4) has been a classic culture combination to DCs. The recently classified type III interferon group interferon-lambda (IFN-lambda) displays antiviral, antitumor, and immunoregulatory activity. In our laboratory, we demonstrate that IFN-lambda1 combined with rhGM-CSF and rhIL-4 can significantly increase the expression of DC surface molecules and the secretion of interleukin-12 (IL-12) and interferon gamma (IFN-gamma) in patients with chronic hepatitis B infection. In this review, we emphasize on the role of DCs in the immunopathogenesis of chronic HBV infection. Importantly, we systematic review that the latest update in the current status of knowledge on the methods of inducing DCs maturation in anti-HBV immunity. What's more, we conclude that IFN-lambda1 combined with GM-CSF and IL-4 can induce DCs maturation, which could become a possibility to be applied to the autologus dendritic cell vaccine to treat chronic hepatitis B. PMID- 26104381 TI - Understanding the Association Between School Climate and Future Orientation. AB - Promoting students' future orientation is inherently a goal of the educational system. Recently, it has received more explicit attention given the increased focus on career readiness. This study aimed to examine the association between school climate and adolescents' report of future orientation using data from youth (N = 27,698; 49.4 % female) across 58 high schools. Three-level hierarchical linear models indicated that perceptions of available emotional and service supports, rules and consequences, and parent engagement were positively related to adolescents' future orientation. Additionally, the school-level average future orientation was significantly related to individuals' future orientation, indicating a potential influence of contextual effects on this construct. Taken together, these findings suggest that interventions targeting school climate may hold promise for promoting future orientation. PMID- 26104382 TI - Fontan Completion for Younger than 3 Years of Age: Outcome in Patients with Functional Single Ventricle. AB - Most single ventricle patients undergo Fontan procedure earlier in current era. However, optimal timing of Fontan completion after an intermediate staging surgery is controversial. We present children who had Fontan surgeries younger than 3 years of age comparing the data with older patients. Between 2000 and 2013, 45 patients with functional single ventricle underwent extracardiac total cavopulmonary connection (TCPC) using GORE-TEX((r)) conduit at a single institution. Children were divided into group A (age < 36 months; n = 15) and group B (age >= 36 months; n = 30), and retrospectively reviewed. Median follow up was 2.9 [interquartile range (IQR) 2-4.4] years. There were two hospital deaths and one late death (all in group B, p = 0.286). One TCPC was taken down in group A. The median intensive care unit and hospital stay were 90 (IQR 46-140) h and 21 (IQR 16-33) days for group A versus 65 (IQR 45-115) h and 29 (IQR 20.8 38.5) days for group B, respectively (p = 0.322 and p = 0.057). Ventricular ejection fraction and GORE-TEX((r)) conduit size were similar in both groups. The time of chest drain stay was significantly lower in group A (median 12 days, IQR 7-22) than in group B (22 days, IQR 16-32.5) (p = 0.014). Extracardiac TCPC can be performed earlier with good intermediate results. Earlier Fontan procedure might be advantageous for reducing chest drains stay. PMID- 26104384 TI - Steps to combat climate change would also improve human health, commission says. PMID- 26104383 TI - Nox2 is a mediator of ischemia reperfusion injury. AB - Delayed graft function (DGF) results from ischemia-reperfusion injury (IRI) and the generation of reactive oxygen species. We hypothesized that NADPH oxidase 2 (Nox2) plays an important role in pathways leading to DGF. We tested this hypothesis in vitro, in an animal model of IRI using wild type and Nox2(-/-) mice, and in patients with DGF. Under hypoxic conditions, primary tubular epithelial cells from Nox2(-/-) mice had reduced expression of MMP2, vimentin, and HSP27. BUN and creatinine levels were significantly increased in both Nox2(-/ ) and WT mice at 4 weeks and 6 months after IRI, suggesting the development of acute and chronic kidney injury. At 4 weeks, kidney fibrosis (alpha-SMA, picrosirius) and oxidative stress (dihydroethidine, HNE) were significantly reduced in Nox2(-/-) mice, confirming the oxidative and pro-fibrotic effects of Nox2. The molecular signature of IRI using genomic analyses demonstrated a significant decline in hypoxia reponse, oxidative stress, fibrosis, and inflammation in Nox2(-/-) mice. Immunohistochemical analyses of pre-implanatation kidney allograft biopsies from patients with subsequent DGF showed significantly greater Nox2 levels and vascular injury compared with patients without DGF. These studies demonstrate that Nox2 is a modulator of IRI and its absence is associated with reduced inflammation, OS, and fibrosis. PMID- 26104385 TI - Hyperoxia-induced methylation decreases RUNX3 in a newborn rat model of bronchopulmonary dysplasia. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) in premature infants is a predominantly secondary occurrence to intrauterine inflammation/infection and postpartum mechanical ventilation; in recent years, an association with epigenetics has also been found. DNA methylation, catalyzed by DNA methyl transferases (DNMTs), and tri-methylation of lysine 27 on histone H3 (H3K27me3), mediated by the methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), are some of the most commonly found modifications in epigenetics. Runt-related transcription factor 3 (RUNX3) is associated with pulmonary epithelial and vascular development and regulates expression at the post-transcriptional level by DNA methylation through DNMT1 or DNMT3b. However, the involvements of these epigenetic factors in the occurrence of BPD are, as yet, unclear. METHODS: Newborn rats were randomly assigned to a model, hyperoxia (85 % O2) or control, normoxia group (21 % O2). Lung tissues and alveolar type 2 (AT2) epithelial cells were collected between 1-14 days. The expression of DNMTs, and EZH2 was detected by immunohistochemistry, Western blot and real-time PCR. The percentage of DNA methylation and H3K27me3 levels in the RUNX3 promoter region was measured by bisulfite sequencing PCR and chromatin immunoprecipitation assay. RUNX3 protein and mRNA expression in AT2 cells was also measured after inhibition using the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, the H3K27me3 inhibitor, JMJD3, and the EZH2 inhibitor, DZNep. RESULTS: Compared with the control group, RUNX3 protein was downregulated and DNMT3b and EZH2 were highly expressed in lung tissues and AT2 cells of the model group (P < 0.05), while high DNA methylation and H3K27me3 modifications were present in the RUNX3 promoter region, in lung tissues of the model group (P < 0.05). Following hyperoxia in the model group, JMJD3 and DZNep significantly reversed the hyperoxia-induced down-regulation of RUNX3 expression in AT2 cells (P < 0.05), more so than 5-Aza-2'-deoxycytidine (P < 0.05). CONCLUSIONS: 1) DNA methylation and H3K27 trimethylation are present in the BPD model; 2) RUNX3 down-regulation is attributed to both DNMT3b-catalyzed DNA methylation and EZH2-catalyzed histone methylation. PMID- 26104386 TI - Lipid stability, antioxidant potential and fatty acid composition of broilers breast meat as influenced by quercetin in combination with alpha-tocopherol enriched diets. AB - BACKGROUND: Dietary supplementation of antioxidants is a vital route to affect the oxidative stability and fatty acid profile of broiler meat. The supplementation of feed with antioxidants decreases degradation of lipids in muscles thereby enhances meat stability. METHODS: The present study was carried out to investigate the influence of dietary quercetin in combination with alpha tocopherol on growth performance, antioxidant potential, lipid stability and fatty acid composition in breast meat of birds. Accordingly, one day old 300 Hubbard strain male broiler birds were given three levels of quercetin @100, 200 and 300 mg/kg feed in combination with alpha-tocopherol @150, 225 and 300 mg/kg feed. The resultant meat was subjected to antioxidant assay, lipid stability, quantification of antioxidants followed by fatty acid profile of broiler breast meat. RESULTS: The results explicated that feed treatments imparted momentous effect on gain in weight, and feed conversion efficiency however, intake of feed in birds affected non-momentously. The highest weight gain recorded in T9 as 2374.67 & 2388 g/bird followed by T8 & T6 2350 & 2353.33 and 2293.33 & 2307 g/bird, respectively whilst the lowest in T0 as 1992.67 & 1999 g/bird during the experimental year 2013 and 2014. The results regarding antioxidant potential revealed that among treatments, T9 exhibited highest values for total phenolic contents (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) & ferric reducing antioxidant power assay (FRAP) i.e. 158.70 +/- 0.84 mg GAE/100 g, 82.40 +/- 0.93% and 682 +/- 2.11 MUmol/Fe(+2/)g, respectively as compared to T0 104.27 +/- 1.64 mg GAE/100 g, 54.71 +/- 0.64% and 542.67 +/- 1.74 MUmol/Fe(+2) /g of meat, correspondingly. The TBARS assay indicated that malondialdehydes production in meat increased during storage however, antioxidants deposition varied significantly among treatments. Fatty acid compositional analysis revealed that addition of quercetin with alpha-tocopherol in the bird's diet decreased the fatty acid generation particularly saturated fatty acids. CONCLUSION: Conclusively, dietary supplementation of quercetin along with alpha-tocopherol improves growth performance, antioxidant capacity, stability of lipids and fatty acid composition in breast meat of birds. PMID- 26104387 TI - Braces versus Invisalign(r): gingival parameters and patients' satisfaction during treatment: a cross-sectional study. AB - BACKGROUND: Fixed orthodontic appliances (FOA) temporarily interfere with periodontal health of patients, as the appliance complicates oral hygiene. The use of aligners in orthodontic therapy increased strongly during the last decade. In the literature, the reports about effects of aligner treatment on oral hygiene and gingival conditions are scarce. This cross-sectional study evaluated oral hygiene and patient's satisfaction during orthodontic treatment of patients with FOA or Invisalign(r). METHODS: 100 patients (FOA = 50, Invisalign(r) = 50) were included who underwent orthodontic treatment for more than 6 months. Clinical examinations were performed to evaluate patients' periodontal condition and were compared with clinical data at the beginning of the orthodontic treatment. Oral hygiene, patients' satisfaction and dietary habits were documented by a detailed questionnaire. For statistical analysis, the Mann-Whitney U-Test and Fisher's Exact Test were used; as multiple testing was applied, a Bonferroni correction was performed. RESULTS: At the time of clinical examinations, patients with FOA were in orthodontic therapy for 12.9 +/- 7.2 months, whereas patients with Invisalign(r) were in orthodontic therapy for 12.6 +/- 7.4 months. Significantly better gingival health conditions were recorded in Invisalign(r) patients (GI: 0.54 +/- 0.50 for FOA versus 0.35 +/- 0.34 for Invisalign(r); SBI: 15.2 +/- 7.6 for FOA versus 7.6 +/- 4.1 for Invisalign(r)), whereas the amount of dental plaque was also less but not significantly different (API: 37.7 % +/- 21.9 for FOA versus 27.8 % +/- 24.6 for Invisalign(r)). The evaluation of the questionnaire showed greater patients' satisfaction in patients treated with Invisalign(r) than with FOA. CONCLUSION: Patients treated with Invisalign(r) have a better periodontal health and greater satisfaction during orthodontic treatment than patients treated with FOA. PMID- 26104388 TI - Developing a set of quality indicators for breast cancer care in China. AB - OBJECTIVE: Large gaps exist between clinical practice and recommended care of breast cancer. Evidence demonstrates that assessment of breast cancer care can help bridge these gaps. However, no valid indicators are currently available for measurement of breast cancer care in China. This study aimed to develop a set of quality indicators to measure and improve the quality of breast cancer care. DESIGN: A modified Delphi process was implemented, and each of the six selection criteria (scientific evidence, utility, interpretability, validity, preventability and data availability) for potential indicators was evaluated on a 5-point scale. PARTICIPANTS: A 16-member expert panel was assembled, including 10 medical oncologists, 5 surgical oncologists and 1 radiation oncologist. MAIN OUTCOME MEASURE: Quality indicators with mean ratings >=4, coefficient of variation equal to or <25% and selectivity >=81.25% in each of the six selection criteria were retained for the face-to-face round. RESULTS: Twenty-six indicators were retained from the rating round and five indicators were retrieved in the face-to-face round. A total of 31 indicators constituted the final set of quality indicators, and the number of indicators pertaining to structure, process, communication and cooperation, management of symptoms or treatment toxicity and outcome was 1, 24, 2, 2 and 2, respectively. CONCLUSIONS: Quality indicators for breast cancer care can be systematically developed and will be utilized as a quality measurement tool for breast cancer care. PMID- 26104389 TI - Protective effects of n-3 polyunsaturated fatty acids levels in patients with acute myocardial infarction - A new target to prevent reperfusion injury. PMID- 26104390 TI - Hollow tubular porous covalent organic framework (COF) nanostructures. AB - Hollow and tubular TpPa-COF structures have been synthesized by template-assisted replication of nanometer sized ZnO-nanorods. The hollow structures composed of microporous TpPa shells have high periodicity, moderate porosity, chemical stability and capsule shaped morphology as revealed by X-ray diffraction, porosity measurements, and SEM and TEM analyses. PMID- 26104391 TI - Novel function of PIWIL1 in neuronal polarization and migration via regulation of microtubule-associated proteins. AB - BACKGROUND: Young neurons in the developing brain establish a polarized morphology for proper migration. The PIWI family of piRNA processing proteins are considered to be restrictively expressed in germline tissues and several types of cancer cells. They play important roles in spermatogenesis, stem cell maintenance, piRNA biogenesis, and transposon silencing. Interestingly a recent study showed that de novo mutations of PIWI family members are strongly associated with autism. RESULTS: Here, we report that PIWI-like 1 (PIWIL1), a PIWI family member known to be essential for the transition of round spermatid into elongated spermatid, plays a role in the polarization and radial migration of newborn neurons in the developing cerebral cortex. Knocking down PIWIL1 in newborn cortical neurons by in utero electroporation of specific siRNAs resulted in retardation of the transition of neurons from the multipolar stage to the bipolar stage followed by a defect in their radial migration to the proper destination. Domain analysis showed that both the RNA binding PAZ domain and the RNA processing PIWI domain in PIWIL1 were indispensable for its function in neuronal migration. Furthermore, we found that PIWIL1 unexpectedly regulates the expression of microtubule-associated proteins in cortical neurons. CONCLUSIONS: PIWIL1 regulates neuronal polarization and radial migration partly via modulating the expression of microtubule-associated proteins (MAPs). Our finding of PIWIL1's function in neuronal development implies conserved functions of molecules participating in morphogenesis of brain and germline tissue and provides a mechanism as to how mutations of PIWI may be associated with autism. PMID- 26104392 TI - Road traffic noise is associated with increased cardiovascular morbidity and mortality and all-cause mortality in London. AB - AIMS: Road traffic noise has been associated with hypertension but evidence for the long-term effects on hospital admissions and mortality is limited. We examined the effects of long-term exposure to road traffic noise on hospital admissions and mortality in the general population. METHODS AND RESULTS: The study population consisted of 8.6 million inhabitants of London, one of Europe's largest cities. We assessed small-area-level associations of day- (7:00-22:59) and nighttime (23:00-06:59) road traffic noise with cardiovascular hospital admissions and all-cause and cardiovascular mortality in all adults (>=25 years) and elderly (>=75 years) through Poisson regression models. We adjusted models for age, sex, area-level socioeconomic deprivation, ethnicity, smoking, air pollution, and neighbourhood spatial structure. Median daytime exposure to road traffic noise was 55.6 dB. Daytime road traffic noise increased the risk of hospital admission for stroke with relative risk (RR) 1.05 [95% confidence interval (CI): 1.02-1.09] in adults, and 1.09 (95% CI: 1.04-1.14) in the elderly in areas >60 vs. <55 dB. Nighttime noise was associated with stroke admissions only among the elderly. Daytime noise was significantly associated with all-cause mortality in adults [RR 1.04 (95% CI: 1.00-1.07) in areas >60 vs. <55 dB]. Positive but non-significant associations were seen with mortality for cardiovascular and ischaemic heart disease, and stroke. Results were similar for the elderly. CONCLUSIONS: Long-term exposure to road traffic noise was associated with small increased risks of all-cause mortality and cardiovascular mortality and morbidity in the general population, particularly for stroke in the elderly. PMID- 26104393 TI - Factors affecting larval tick feeding success: host, density and time. AB - BACKGROUND: Ectoparasites rely on blood-feeding to sustain activity, support development and produce offspring. Blood-feeding is also a route for transmission of diverse vector-borne pathogens. The likelihood of successfully feeding is thus an important aspect of ectoparasite population dynamics and pathogen transmission. Factors that affect blood-feeding include ectoparasite density, host defenses, and ages of the host and ectoparasite. How these factors interact to affect feeding success is not well understood. METHODS: We monitored blood feeding success of larval Rocky Mountain wood ticks (RMWTs; Dermacentor andersoni) on deer mice (Peromyscus maniculatus) in several experiments to determine how tick density, host defense, and ages of mice and ticks interact to influence feeding success. In the first experiment, tick-naive deer mice were infested with one of several densities of RMWT larvae, while a second cohort of mice were infested with 50 larvae each. Two weeks after ticks dropped off, mice in the first cohort were re-exposed to 50 larvae each and mice in the second cohort were re-exposed to varying densities of larvae. In the second experiment mice of different ages (45-374 days old) were exposed to 50 larvae each. Two weeks later mice were re-exposed to 50 larvae each. We combined data from these and several similar experiments to test the generality of the patterns we observed. Lastly, we tested whether tick feeding success was consistent on individual mice that were challenged on four occasions. RESULTS: Mice acquired resistance such that feeding success declined dramatically from the first to the second infestation. Feeding success also declined with tick density and tick age. Mice, however, became more permissive with age. The sizes of these effects were similar and additive. Surprisingly, over successive infestations the relative resistance among mice changed among hosts within a cohort. CONCLUSIONS: We predict that larval blood-feeding success, and thus development to the nymph stage, will change due to variation in tick age and density, as well as the age and history of the host. Incorporating these biotic factors into modeling of tick population dynamics may improve predictions of tick-borne pathogen transmission. PMID- 26104394 TI - African Indigenous Cattle: Unique Genetic Resources in a Rapidly Changing World. AB - At least 150 indigenous African cattle breeds have been named, but the majority of African cattle populations remain largely uncharacterized. As cattle breeds and populations in Africa adapted to various local environmental conditions, they acquired unique features. We know now that the history of African cattle was particularly complex and while several of its episodes remain debated, there is no doubt that African cattle population evolved dramatically over time. Today, we find a mosaic of genetically diverse population from the purest Bos taurus to the nearly pure Bos indicus. African cattle are now found all across the continent, with the exception of the Sahara and the river Congo basin. They are found on the rift valley highlands as well as below sea level in the Afar depression. These unique livestock genetic resources are in danger to disappear rapidly following uncontrolled crossbreeding and breed replacements with exotic breeds. Breeding improvement programs of African indigenous livestock remain too few while paradoxically the demand of livestock products is continually increasing. Many African indigenous breeds are endangered now, and their unique adaptive traits may be lost forever. This paper reviews the unique known characteristics of indigenous African cattle populations while describing the opportunities, the necessity and urgency to understand and utilize these resources to respond to the needs of the people of the continent and to the benefit of African farmers. PMID- 26104395 TI - Estimation of Genetic Parameters for Pork Belly Components in Yorkshire Pigs. AB - This study was conducted to estimate the genetic parameters for pork belly traits and muscles in Yorkshire pigs. Each pork belly was cut into nine parts perpendicular to the thoracic vertebrae (6th to 14th). Traits of belly muscles including the deep pectoral, latissimus dorsi, cutaneous trunci, rectus abdominis, external and internal abdominal oblique from 382 purebred pigs were recorded and analyzed using SAS Package (9.1) and Derivative-free restricted maximum likelihood methods. Heritability estimates for belly traits ranged from 0.27 to 0.49, while they were 0.12 to 0.66 for belly muscles. Moderate to high heritability estimates were noted in belly weight (0.33), belly length (0.28), and belly width (0.49). In belly muscles, the latissimus dorsi and deep pectoral, which are located only in the 6th to 9th vertebrae sections, were found to have heritability estimates ranging from 0.21 to 0.29 and 0.23 to 0.35, respectively. Strong heritability estimates were observed in the 7th to 13th sections of cutaneous trunci muscle ranging from 0.42 to 0.66. Genetic correlations of latissimus dorsi m. with belly length were positive (0.50), while cutaneous trunci m. with belly weight also revealed a positive relationship that ranged from 0.35 to 0.47. The estimated genetic parameters indicate that belly weight can be improved by genetic selection. Differences in the levels of heritability occurred among various parameters of Yorkshire pork belly, which should be considered when performing selection to improve pork belly quality. Moreover, these results can provide valuable information that can be used as the basis for further investigations to improve pork belly. PMID- 26104396 TI - Multiple Linkage Disequilibrium Mapping Methods to Validate Additive Quantitative Trait Loci in Korean Native Cattle (Hanwoo). AB - The efficiency of genome-wide association analysis (GWAS) depends on power of detection for quantitative trait loci (QTL) and precision for QTL mapping. In this study, three different strategies for GWAS were applied to detect QTL for carcass quality traits in the Korean cattle, Hanwoo; a linkage disequilibrium single locus regression method (LDRM), a combined linkage and linkage disequilibrium analysis (LDLA) and a BayesCpi approach. The phenotypes of 486 steers were collected for weaning weight (WWT), yearling weight (YWT), carcass weight (CWT), backfat thickness (BFT), longissimus dorsi muscle area, and marbling score (Marb). Also the genotype data for the steers and their sires were scored with the Illumina bovine 50K single nucleotide polymorphism (SNP) chips. For the two former GWAS methods, threshold values were set at false discovery rate <0.01 on a chromosome-wide level, while a cut-off threshold value was set in the latter model, such that the top five windows, each of which comprised 10 adjacent SNPs, were chosen with significant variation for the phenotype. Four major additive QTL from these three methods had high concordance found in 64.1 to 64.9Mb for Bos taurus autosome (BTA) 7 for WWT, 24.3 to 25.4Mb for BTA14 for CWT, 0.5 to 1.5Mb for BTA6 for BFT and 26.3 to 33.4Mb for BTA29 for BFT. Several candidate genes (i.e. glutamate receptor, ionotropic, ampa 1 [GRIA1], family with sequence similarity 110, member B [FAM110B], and thymocyte selection-associated high mobility group box [TOX]) may be identified close to these QTL. Our result suggests that the use of different linkage disequilibrium mapping approaches can provide more reliable chromosome regions to further pinpoint DNA makers or causative genes in these regions. PMID- 26104397 TI - Whole Genome Association Study to Detect Single Nucleotide Polymorphisms for Behavior in Sapsaree Dog (Canis familiaris). AB - The purpose of this study was to characterize genetic architecture of behavior patterns in Sapsaree dogs. The breed population (n = 8,256) has been constructed since 1990 over 12 generations and managed at the Sapsaree Breeding Research Institute, Gyeongsan, Korea. Seven behavioral traits were investigated for 882 individuals. The traits were classified as a quantitative or a categorical group, and heritabilities (h(2)) and variance components were estimated under the Animal model using ASREML 2.0 software program. In general, the h(2) estimates of the traits ranged between 0.00 and 0.16. Strong genetic (r G ) and phenotypic (r P ) correlations were observed between nerve stability, affability and adaptability, i.e. 0.9 to 0.94 and 0.46 to 0.68, respectively. To detect significant single nucleotide polymorphism (SNP) for the behavioral traits, a total of 134 and 60 samples were genotyped using the Illumina 22K CanineSNP20 and 170K CanineHD bead chips, respectively. Two datasets comprising 60 (Sap60) and 183 (Sap183) samples were analyzed, respectively, of which the latter was based on the SNPs that were embedded on both the 22K and 170K chips. To perform genome-wide association analysis, each SNP was considered with the residuals of each phenotype that were adjusted for sex and year of birth as fixed effects. A least squares based single marker regression analysis was followed by a stepwise regression procedure for the significant SNPs (p<0.01), to determine a best set of SNPs for each trait. A total of 41 SNPs were detected with the Sap183 samples for the behavior traits. The significant SNPs need to be verified using other samples, so as to be utilized to improve behavior traits via marker-assisted selection in the Sapsaree population. PMID- 26104398 TI - Influence of Temperature and Humidity on Pregnancy Rate of Murrah Buffaloes under Subtropical Climate. AB - Heat stress has adverse effects on fertility of dairy animals. Decline in fertility is linearly associated with an increase in combination of both temperature and humidity. The purpose of this study was to investigate the relationship between temperature humidity index (THI) and the pregnancy rate of Murrah buffaloes in a subtropical climate. The effects of genetic and non-genetic factors viz., sire, parity, period of calving and age group at first calving were found non-significant on pregnancy rate. The effect of THI was found significant (p<0.001) on pregnancy rate of Murrah buffaloes calved for first time and overall pregnancy rate. The threshold THI affecting the pregnancy rate was identified as THI 75. The months from October to March showed THI<75 and considered as non heat stress zone (NHSZ), while months from April to September were determined as heat stress zone (HSZ) with THI>=75. The lowest overall pregnancy rate (0.25) was obtained in July with THI 80.9, while the highest overall pregnancy rate (0.59) was found in November with THI 66.1. May and June were identified as critical heat stress zone (CHSZ) within the HSZ with maximum decline (-7%) in pregnancy rate with per unit increase in THI. The highest overall pregnancy rate was estimated as 0.45 in NHSZ with THI value 56.7 to 73.2. The pregnancy rate was found to have declined to 0.28 in HSZ with THI 73.5 to 83.7. However, the lowest pregnancy rate was estimated as 0.27 in CHSZ with THI value 80.3 to 81.6. PMID- 26104399 TI - Effects of Supplementation of Eucalyptus (E. Camaldulensis) Leaf Meal on Feed Intake and Rumen Fermentation Efficiency in Swamp Buffaloes. AB - Four rumen fistulated swamp buffaloes were randomly assigned according to a 4*4 Latin square design to investigate the effects of Eucalyptus (E. Camaldulensis) leaf meal (ELM) supplementation as a rumen enhancer on feed intake and rumen fermentation characteristics. The dietary treatments were as follows: T1 = 0 g ELM/hd/d; T2 = 40 g ELM/hd/d; T3 = 80 g ELM/hd/d; T4 = 120 g ELM/hd/d, respectively. Experimental animals were kept in individual pens and concentrate was offered at 0.3% BW while rice straw was fed ad libitum. The results revealed that voluntary feed intake and digestion coefficients of nutrients were similar among treatments. Ruminal pH, temperature and blood urea nitrogen concentrations were not affected by ELM supplementation; however, ELM supplementation resulted in lower concentration of ruminal ammonia nitrogen. Total volatile fatty acids, propionate concentration increased with the increasing level of EML (p<0.05) while the proportion of acetate was decreased (p<0.05). Methane production was linearly decreased (p<0.05) with the increasing level of ELM supplementation. Protozoa count and proteolytic bacteria population were reduced (p<0.05) while fungal zoospores and total viable bacteria, amylolytic, cellulolytic bacteria were unchanged. In addition, nitrogen utilization and microbial protein synthesis tended to increase by the dietary treatments. Based on the present findings, it is suggested that ELM could modify the rumen fermentation and is potentially used as a rumen enhancer in methane mitigation and rumen fermentation efficiency. PMID- 26104400 TI - Effects of Dietary Lycopene Supplementation on Plasma Lipid Profile, Lipid Peroxidation and Antioxidant Defense System in Feedlot Bamei Lamb. AB - Lycopene, a red non-provitamin A carotenoid, mainly presenting in tomato and tomato byproducts, has the highest antioxidant activity among carotenoids because of its high number of conjugated double bonds. The objective of this study was to investigate the effect of lycopene supplementation in the diet on plasma lipid profile, lipid peroxidation and antioxidant defense system in feedlot lamb. Twenty-eight Bamei male lambs (90 days old) were divided into four groups and fed a basal diet (LP0, 40:60 roughage: concentrate) or the basal diet supplemented with 50, 100, and 200 mg/kg lycopene. After 120 days of feeding, all lambs were slaughtered and sampled. Dietary lycopene supplementation significantly reduced the levels of plasma total cholesterol (p<0.05, linearly), total triglycerides (TG, p<0.05) and low-density lipoprotein cholesterol (LDL-C, p<0.05), as well as atherogenic index (p<0.001), whereas no change was observed in high-density lipoprotein cholesterol (p>0.05). The levels of TG (p<0.001) and LDL-C (p<0.001) were decreased with the feeding time extension, and both showed a linear trend (p<0.01). Malondialdehyde level in plasma and liver decreased linearly with the increase of lycopene inclusion levels (p<0.01). Dietary lycopene intake linearly increased the plasma antioxidant vitamin E level (p<0.001), total antioxidant capacity (T-AOC, p<0.05), and activities of catalase (CAT, p<0.01), glutathione peroxidase (GSH-Px, p<0.05) and superoxide dismutase (SOD, p<0.05). The plasma T AOC and activities of GSH-Px and SOD decreased with the extension of the feeding time. In liver, dietary lycopene inclusion showed similar antioxidant effects with respect to activities of CAT (p<0.05, linearly) and SOD (p<0.001, linearly). Therefore, it was concluded that lycopene supplementation improved the antioxidant status of the lamb and optimized the plasma lipid profile, the dosage of 200 mg lycopene/kg feed might be desirable for growing lambs to prevent environment stress and maintain normal physiological metabolism. PMID- 26104401 TI - Nighttime Cooling Is an Effective Method for Improving Milk Production in Lactating Goats Exposed to Hot and Humid Environment. AB - Heat production in ruminants follows a diurnal pattern over the course of a day peaking 3 hours following afternoon feeding and then gradually declining to its lowest point prior to morning feeding. In order to clarify the cooling period most effective in reducing decreases in feed intake and milk production, experiments were carried out based on the diurnal rhythm of heat production and heat dissipation. In experiment 1, the effects of hot environment on milk production were investigated. The animals were kept first in a thermoneutral environment (20.0 degrees C, 80.0%) for 12 days, they were then transitioned to a hot environment (32 degrees C, 80.0%) for 13 days before being returned to second thermoneutral environment for a further 12 days. In experiment 2, the effectiveness of daytime cooling or nighttime cooling for improving milk production in hot environment was compared. While ten lactating Japanese Saanen goats (aged 2 years, weighing 41.0 kg) during early lactation were used in experiment 1, ten lactating goats (aged 2 years, weighing 47.5 kg) during mid lactation were used in experiment 2. The animals were fed 300 g of concentrated feed and excessive amounts of crushed alfalfa hay cubes twice daily. Water was given ad libitum. The animals were milked twice daily. When exposed to a hot environment, milk yield and composition decreased significantly (p<0.05). Milk yield in the hot environment did not change with daytime cooling, but tended to increase with nighttime cooling. Compared to the daytime cooling, milk components percentages in the nighttime cooling were not significantly different but the milk components yields in the nighttime cooling were significantly higher (p<0.05). The results indicate that nighttime cooling is more effective than daytime cooling in the reduction of milk production declines in lactating goats exposed to a hot environment. PMID- 26104402 TI - Lipid Sources with Different Fatty Acid Profile Alters the Fatty Acid Profile and Quality of Beef from Confined Nellore Steers. AB - The present study was conducted to determine the effects of lipid sources with different fatty acids profile on meat fatty acids profile and beef quality traits of Nellore. A total of 45 Nellore animals with an average initial body weight of 419+/-11 kg (at 15+/-2 mo) were distributed in a completely randomized design consisting of 5 treatments and 9 replicates. The roughage feed was maize silage (600 g/kg on a dry matter [DM] basis) plus concentrate (400 g/kg on a DM basis). The dietary treatments were as follows: without fat (WF), palm oil (PO), linseed oil (LO), protected fat (PF), and soybean grains (SG). No effects of lipid sources were observed (p>0.05) on beef color, pH, water-holding capacity, and sarcomere length. Beef from cattle fed PO had greater shear-force values (p<0.05) compared to beef from cattle fed WF. Deposition of main unsaturated fatty acids (oleic, linoleic, and linolenic) was greater in treatments WF, SG, and LO, respectively, while the values of conjugated linoleic acid (CLA) were greater when animals were fed LO. The inclusion of LO in the diet enhances the concentration of CLA in longissimus muscle and subcutaneous fat besides improving the atherogenicity index and elongase activity. As such, LO can be used with the aim to improve the quality of beef from confined Nellore cattle. Conversely, the use of PO is not recommended since it may increase the concentration of undesirable unsaturated fatty acids in muscle and subcutaneous fat, shear-force and the atherogenicity index. PMID- 26104403 TI - Effects of Palm Kernel Expellers on Growth Performance, Nutrient Digestibility, and Blood Profiles of Weaned Pigs. AB - This experiment was conducted to investigate the effects of palm kernel expellers on growth performance, nutrient digestibility, and blood profiles of weaned pigs. A total of 88 weaned pigs (6.94+/-0.76 kg body weight [BW]; 28 d old) were randomly allotted to 2 dietary treatments (4 pigs/pen; 11 replicates/treatment) in a randomized complete block design (sex as a block). The dietary treatments were a typical nursery diet based on corn and soybean meal (CON) and CON added with 20% of palm kernel expellers (PKE). Pigs were fed for 6 wk using a 3-phase feeding program with declining diet complexity and with phases of 1, 2, and 3 wk, respectively. Blood was collected from randomly selected 2 pigs in each pen before weaning and on d 7 after weaning. Pigs were fed respective dietary treatments containing 0.2% chromic oxide from d 29 to 35 after weaning. Fecal samples were collected from randomly selected 2 pigs in each pen daily for the last 3 days after the 4-d adjustment period. Measurements were growth performances, digestibility of dry matter, nitrogen and energy, white and red blood cell counts, packed cell volume, and incidence of diarrhea. The PKE increased average daily gain (ADG) (246 vs 215 g/d; p = 0.06) and average daily feed intake (ADFI) (470 vs 343 g/d; p<0.05) and decreased gain-to-feed ratio (G:F) (0.522 vs 0.628 g/g; p<0.05) during phase 2 compared with CON, but did not affect growth performance during phase 1 and 3. During overall experimental period, PKE increased ADG (383 vs 362 g/d; p = 0.05) and ADFI (549 vs 496 g/d; p<0.05) compared with CON, but did not affect G:F. However, no differences were found on digestibility of dry matter, nitrogen, and energy between CON and PKE. The PKE reduced frequency of diarrhea (15% vs 25%; p = 0.08) for the first 2 wk after weaning compared with CON. Similarly, PKE decreased white blood cells (8.19 vs 9.56*10(3)/MUL; p = 0.07), red blood cells (2.92 vs 3.25*10(6)/MUL; p = 0.09), and packed cell volume (11.1% vs 12.6%; p = 0.06) on d 7 after weaning compared with CON. In conclusion, addition of 20% palm kernel expellers to nursery diet based on corn and soybean meal had no negative effects on growth performance, nutrient digestibility, and blood profiles of weaned pigs. PMID- 26104404 TI - Prediction of Eggshell Ultrastructure via Some Non-destructive and Destructive Measurements in Fayoumi Breed. AB - Possibilities of predicting eggshell ultrastructure from direct non-destructive and destructive measurements were examined using 120 Fayoumi eggs collected from the flock at 45 weeks of age. The non-destructive measurements included weight, length and width of the egg. The destructive measurements were breaking strength and shell thickness. The eggshell ultrastructure traits involved the total thickness of eggshell layer, thickness of palisade layer, cone layer and total score. Prediction of total thickness of eggshell layer based on non-destructive measurements individually or simultaneously was not possible (R(2) = 0.01 to 0.16). The destructive measurements were far more accurate than the non destructive in predicting total thickness of eggshell layer. Prediction based on breaking strength alone was more accurate (R(2) = 0.85) than that based on shell thickness alone (R(2) = 0.72). Adding shell thickness to breaking strength (the best predictor) increased the accuracy of prediction by 5%. The results obtained indicated that both non-destructive and destructive measurements were not useful in predicting the cone layer (R(2) not exceeded 18%). The maximum accuracy of prediction of total score (R(2) = 0.48) was obtained from prediction based on breaking strength alone. Combining shell thicknesses and breaking strength into one equation was no help in improving the accuracy of prediction. PMID- 26104405 TI - The Effect of Bacillus-based Feed Additive on Growth Performance, Nutrient Digestibility, Fecal Gas Emission, and Pen Cleanup Characteristics of Growing finishing Pigs. AB - Bacillus-based feed additive was evaluated for its efficacy on growth performance, nutrient digestibility, fecal gas emission, and the consumption of time and amount of water for cleaning the pen of growing finishing pigs. A total of 120 growing pigs (23.59+/-1.41 kg) were used in a 16-wk feeding trial. Pigs were randomly distributed into 1 of 2 treatments on the basis of body weight and sex. There were 12 replicate pens per treatment, with 5 pigs (3 barrows and 2 gilts) per pen. Dietary treatments were CON which was basal diet, and T1 which was CON+62.5 ppm microbial feed additive that provided 1.47*10(8) cfu of Bacillus organisms per gram of supplement. During the weeks 0 to 6, average daily gain (ADG) in T1 treatment was higher (p<0.05) than CON, but no improvement in average daily feed intake (ADFI) and feed efficiency (G:F) was noted. During 6 to 16 weeks, no difference (p>0.05) was noted in growth performance. However, ADG was improved (p<0.05) and overall ADFI tended (p = 0.06) to improve in T1 compared with CON. At week 6, the co-efficient of apparent total tract digestibility (CATTD) of dry matter (DM) nitrogen (N) was increased (p<0.05) in T1 compared with CON. Fecal NH3 emission was decreased (p<0.05) in T1 compared with CON, at the end of 6th and 15th weeks. The time and water consumed for washing the pens were decreased (p<0.05) in T1 compared with CON. In conclusion, supplementation with Bacillus-based feed additive could improve the overall growth performances, increase the CATTD of DM and decrease the fecal NH3 content and the time and water consumed in washing the pens for growing-finishing pigs. PMID- 26104406 TI - Effect of gamma-Aminobutyric Acid-producing Lactobacillus Strain on Laying Performance, Egg Quality and Serum Enzyme Activity in Hy-Line Brown Hens under Heat Stress. AB - Heat-stress remains a costly issue for animal production, especially for poultry as they lack sweat glands, and alleviating heat-stress is necessary for ensuring animal production in hot environment. A high gamma-aminobutyric acid (GABA) producer Lactobacillus strain was used to investigate the effect of dietary GABA producer on laying performance and egg quality in heat-stressed Hy-line brown hens. Hy-Line brown hens (n = 1,164) at 280 days of age were randomly divided into 4 groups based on the amount of freeze-dried GABA-producer added to the basal diet as follows: i) 0 mg/kg, ii) 25 mg/kg, iii) 50 mg/kg, and iv) 100 mg/kg. All hens were subjected to heat-stress treatment through maintaining the temperature and the relative humidity at 28.83+/-3.85 degrees C and 37% to 53.9%, respectively. During the experiment, laying rate, egg weight and feed intake of hens were recorded daily. At the 30th and 60th day after the start of the experiment, biochemical parameters, enzyme activity and immune activity in serum were measured. Egg production, average egg weight, average daily feed intake, feed conversion ratio and percentage of speckled egg, soft shell egg and misshaped egg were significantly improved (p<0.05) by the increasing supplementation of the dietary GABA-producer. Shape index, eggshell thickness, strength and weight were increased linearly with increasing GABA-producer supplementation. The level of calcium, phosphorus, glucose, total protein and albumin in serum of the hens fed GABA-producing strain supplemented diet was significantly higher (p<0.05) than that of the hens fed the basal diet, whereas cholesterol level was decreased. Compared with the basal diet, GABA-producer strain supplementation increased serum level of glutathione peroxidase (p = 0.009) and superoxide dismutase. In conclusion, GABA-producer played an important role in alleviating heat-stress, the isolated GABA-producer strain might be a potential natural and safe probiotic to use to improve laying performance and egg quality in heat-stressed hens. PMID- 26104407 TI - Effects of Supplemental Beta-mannanase on Digestible Energy and Metabolizable Energy Contents of Copra Expellers and Palm Kernel Expellers Fed to Pigs. AB - The purpose of this study was to determine the effect of beta-mannanase supplementation on digestible energy (DE) and metabolizable energy (ME) contents of copra expellers (CE) and palm kernel expellers (PKE) fed to pigs. Six barrows with an initial body weight of 38.0 kg (standard deviation = 1.5) were randomly allotted to a 6*6 Latin square design with 6 dietary treatments and 6 periods. Six experimental diets were prepared in a 3*2 factorial treatment arrangement with 3 diets of a corn-soybean meal-based diet, a CE 30% diet, and a PKE 30% diet and with 2 concentrations of supplemental beta-mannanase at 0 or 2,400 U/kg. All diets had the same proportion of corn:soybean meal ratio at 2.88:1. The marker-to marker procedure was used for fecal and urine collection with 4-d adaptation and 5-d collection periods. No interactive effects were observed between diet and beta-mannanase on energy digestibility and DE and ME contents of experimental diets. However, diets containing CE or PKE had less (p<0.05) DE and ME contents compared with the corn-soybean meal-based diet. The DE and ME contents in CE and PKE were not affected by supplemental beta-mannanase. Taken together, we failed to find the effect of beta-mannanase supplementation on energy utilization in CE and PKE fed to pigs. PMID- 26104408 TI - Effect of Different Tumbling Marination Methods and Time on the Water Status and Protein Properties of Prepared Pork Chops. AB - The combined effect of tumbling marination methods (vacuum continuous tumbling marination, CT; vacuum intermittent tumbling marination, IT) and effective tumbling time (4, 6, 8, and 10 h) on the water status and protein properties of prepared pork chops was investigated. Results showed that regardless of tumbling time, CT method significantly decreased the muscle fiber diameter (MD) and significantly increased the total moisture content, product yield, salt soluble proteins (SSP) solubility, immobilized water component (p<0.05) compared with IT method. With the effective tumbling time increased from 4 h to 10 h, the fat content and the MD were significantly decreased (p<0.05), whereas the SSP solubility of prepared pork chops increased firstly and then decreased. Besides, an interactive effect between CT method and effective tumbling time was also observed for the chemical composition and proportion of immobilized water (p<0.05). These results demonstrated that CT method of 8 h was the most beneficial for improving the muscle structure and water distribution status, increasing the water-binding capacity and accelerating the marinade efficiency of pork chops; and thus, it should be chosen as the most optimal treatment method for the processing production of prepared pork chops. PMID- 26104409 TI - Relationships between Descriptive Sensory Attributes and Physicochemical Analysis of Broiler and Taiwan Native Chicken Breast Meat. AB - Unique organoleptic characteristics such as rich flavors and chewy texture contribute to the higher popularity of native chicken in many Asian areas, while the commercial broilers are well-accepted due to their fast-growing and higher yields of meat. Sensory attributes of foods are often used to evaluate food eating quality and serve as references during the selection of foods. In this study, a three-phase descriptive sensory study was conducted to evaluate the sensory attributes of commercial broiler (BR) and Taiwan native chicken (TNC) breast meat, and investigate correlations between these sensory attributes and instrumental measurements. The results showed that for the first bite (phase 1), TNC meat had significantly higher moisture release, hardness, springiness, and cohesiveness than BR meat. After chewing for 10 to 12 bites (phase 2), TNC meat presented significantly higher chewdown hardness and meat particle size, whereas BR meat had significantly higher cohesiveness of mass. After swallowing (phase 3), TNC meat had higher chewiness and oily mouthcoat and lower residual loose particles than BR meat. TNC meat also provided more intense chicken flavors. This study clearly demonstrates that descriptive sensory analysis provides more detailed and more objectively information about the sensory attributes of meats from various chicken breeds. Additionally, sensory textural attributes vary between BR and TNC meat, and are highly correlated to the shear force value and collagen content which influence meat eating qualities greatly. The poultry industry and scientists should be able to recognize the sensory characteristics of different chicken meats more clearly. Accordingly, based on the meat's unique sensory and physicochemical characteristics, future work might address how meat from various breeds could best satisfy consumer needs using various cooking methods. PMID- 26104410 TI - Effects of Mixing on the Aggressive Behavior of Commercially Housed Pigs. AB - In this study, we investigated the effects of mixing on the aggressive behavior of commercially housed pigs. The behavioral patterns of 36 groups of pigs (a total of 360 animals) were observed over 3 consecutive days directly after weaning (25+/-1.2 days of age), and 25 and 50 days later with the aid of video technology. Fight latency and total duration and frequency of fighting were significantly different among the age groups. The aggressive behaviors decreased in 75-day old pigs if compared to 25- and 50-day old animals. Moreover, dominance index (DI) was higher in 25-day old and lower in 75-day old pigs. A comparison of dominant (DI>0) and submissive (DI<0) pigs showed significant differences (p<0.05) for major aggressive behaviors in all age groups. Dominant pigs were involved in more aggressive interactions, had longer fights, and initiated more fights than submissive pigs. Post-mixing aggressive behavior was altered by previous experience of mixing. Aggressive behavior and DI are suitable methods for analyzing the effects of mixing on commercially housed growing pigs. PMID- 26104411 TI - Modelling Pasture-based Automatic Milking System Herds: The Impact of Large Herd on Milk Yield and Economics. AB - The aim of this modelling study was to investigate the effect of large herd size (and land areas) on walking distances and milking interval (MI), and their impact on milk yield and economic penalties when 50% of the total diets were provided from home grown feed either as pasture or grazeable complementary forage rotation (CFR) in an automatic milking system (AMS). Twelve scenarios consisting of 3 AMS herds (400, 600, 800 cows), 2 levels of pasture utilisation (current AMS utilisation of 15.0 t dry matter [DM]/ha, termed as 'moderate'; optimum pasture utilisation of 19.7 t DM/ha, termed as 'high') and 2 rates of incorporation of grazeable complementary forage system (CFS: 0, 30%; CFS = 65% farm is CFR and 35% of farm is pasture) were investigated. Walking distances, energy loss due to walking, MI, reduction in milk yield and income loss were calculated for each treatment based on information available in the literature. With moderate pasture utilisation and 0% CFR, increasing the herd size from 400 to 800 cows resulted in an increase in total walking distances between the parlour and the paddock from 3.5 to 6.3 km. Consequently, MI increased from 15.2 to 16.4 h with increased herd size from 400 to 800 cows. High pasture utilisation (allowing for an increased stocking density) reduced the total walking distances up to 1 km, thus reduced the MI by up to 0.5 h compared to the moderate pasture, 800 cow herd combination. The high pasture utilisation combined with 30% of the farm in CFR in the farm reduced the total walking distances by up to 1.7 km and MI by up to 0.8 h compared to the moderate pasture and 800 cow herd combination. For moderate pasture utilisation, increasing the herd size from 400 to 800 cows resulted in more dramatic milk yield penalty as yield increasing from c.f. 2.6 and 5.1 kg/cow/d respectively, which incurred a loss of up to $AU 1.9/cow/d. Milk yield losses of 0.61 kg and 0.25 kg for every km increase in total walking distance (voluntary return trip from parlour to paddock) and every one hour increase in MI, respectively. The high pasture utilisation combined with 30% of the farm in CFR in the farm increased milk yield by up to 1.5 kg/cow/d, thereby reducing loss by up to $0.5/cow/d (c.f. the moderate pasture and 800 cow herd scenario). Thus, it was concluded that the successful integration of grazeable CFS with pasture has the potential to improve financial performance compared to the pasture only, large herd, AMS. PMID- 26104412 TI - Struvite Crystallization of Anaerobic Digestive Fluid of Swine Manure Containing Highly Concentrated Nitrogen. AB - In this study, the optimal operation factors for struvite crystallization for removing and recovering nitrogen and phosphorus from anaerobic digestive fluid of swine manure containing highly concentrated nitrogen was determined. Every experiment for the struvite crystallization reaction was conducted by placing 1,000 mL of digestion fluid in a 2,000 mL Erlenmeyer flask at various temperatures, pH, and mixing speed. Except for special circumstances, the digestion fluid was centrifuged (10,000 rpm, 10 min) and then the supernatant was used for the experiment at room temperature and 100 rpm. The optimal mole ratio of PO4 (3-):Mg(2+) was 1:1.5, and the pH effect ranging from 9 to 11 was similar, when mixed for 1 hour. Under this condition, the removal efficiency of NH4 (+)-N and PO4 (3-)-P was 40% and 88.6%, respectively. X-shaped crystal was observed by light and scanning electron microscopy. In addition, struvite crystal structure was confirmed through X-ray diffraction analysis. PMID- 26104413 TI - Determinants of use of care provided by complementary and alternative health care practitioners to pregnant women in primary midwifery care: a prospective cohort study. AB - BACKGROUND: Pregnant women visit complementary/alternative health care practitioners in addition to regular maternal health care practitioners. A wide variation has been reported with regard to rates and determinants of use of complementary/alternative medicine (CAM), which may be due to heterogeneous populations. The aim of this study was to examine the prevalence and determinants of use of CAM practitioners by a homogeneous population of low-risk pregnant women in the Netherlands. METHODS: Data from the population-based DELIVER study was used, concerning 1500 clients from twenty midwifery practices across the Netherlands in 2009 and 2010. CAM use was measured based on patient reports. Potential determinants were derived from Andersen's behavioural model of health care utilization. RESULTS: The prevalence of CAM practitioner use by low-risk pregnant women was 9.4 %. Women were more likely to use CAM if they had supplementary health care insurance (OR 3.11; CI 1.41-6.85), rated their health as 'bad/fair' (OR 2.63; CI 1.65-4.21), reported a chronic illness or handicap (OR 1.93; CI 1.14-3.27), smoked during pregnancy (OR 1.88; CI 1.06-3.33), or used alcohol during pregnancy (OR 2.30; CI 1.46-3.63). CONCLUSIONS: CAM is relatively frequently used by low-risk pregnant women. Determinants revealed in this study diverge from other studies using heterogeneous populations. Maternal health care practitioners must be aware of CAM use by low-risk pregnant women and incorporate this knowledge into daily practice by actively discussing this subject with pregnant women. PMID- 26104414 TI - Different tenogenic differentiation capacities of different mesenchymal stem cells in the presence of BMP-12. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are regarded as a promising cell-based therapeutic tool for tendon repair. This study aimed to compare the different tenogenic differentiation capacities of the three types of MSCs in the presence of bone morphogenic protein 12 (BMP-12). METHODS: MSCs were isolated from rat bone marrow (BM), inguinal adipose tissue (AD), and synovium (SM) from the knee joint. MSCs were characterized by morphology, proliferation, trilineage differentiation, and surface marker analysis. Tenogenic differentiation potential was initially assessed using real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay in vitro. Histological assessments were also performed after subcutaneous implantation of BMP-12 recombinant adenovirus infected MSCs in nude mice in vivo. RESULTS: The three types of MSCs exhibited similar fibroblast-like morphology and surface markers but different differentiation potentials toward adipogenic, osteogenic, and chondrogenic lineage fates. Bone marrow-derived MSCs (BM-MSCs) showed the most superior in vitro tenogenic differentiation capacity, followed by synovial membrane-derived MSCs (SM-MSCs) and then adipose-derived MSCs (AD-MSCs). After implantation, all three types of MSC masses infected with BMP-12 recombinant adenovirus emerged in the form of fiber-like matrix, especially in 6-week specimens, compared with the control MSCs in vivo. BM-MSCs and SM-MSCs revealed more intense staining for collagen type I (Col I) compared with AD-MSCs. Differences were not observed between BM-MSCs and SM-MSCs. However, SM-MSCs demonstrated higher proliferation capacity than BM-MSCs. CONCLUSION: BM-MSCs exhibited the most superior tenogenic differentiation capacity, followed by SM-MSCs. By contrast, AD-MSCs demonstrated the inferior capacity among the three types of MSCs in the presence of BMP-12 both in vivo and in vitro. PMID- 26104415 TI - Spinal cord stimulation modulates supraspinal centers of the descending antinociceptive system in rats with unilateral spinal nerve injury. AB - BACKGROUND: The descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5 hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine beta-hydroxylase (DbetaH)] in the spinal dorsal horn. RESULTS: Intrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an alpha2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to contralateral immunoreactivity ratio of DbetaH increased in the LC of SNL rats and reached the level seen in naive rats, even though the number of pCREB positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DbetaH in the spinal dorsal horn. CONCLUSIONS: The serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord. PMID- 26104417 TI - The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP. PMID- 26104416 TI - Human-induced pluripotent stem cells generated from intervertebral disc cells improve neurologic functions in spinal cord injury. AB - INTRODUCTION: Induced pluripotent stem cells (iPSCs) have emerged as a promising cell source for immune-compatible cell therapy. Although a variety of somatic cells have been tried for iPSC generation, it is still of great interest to test new cell types, especially those which are hardly obtainable in a normal situation. METHODS: In this study, we generated iPSCs by using the cells originated from intervertebral disc which were removed during a spinal operation after spinal cord injury. We investigated the pluripotency of disc cell-derived iPSCs (diPSCs) and neural differentiation capability as well as therapeutic effect in spinal cord injury. RESULTS: The diPSCs displayed similar characteristics to human embryonic stem cells and were efficiently differentiated into neural precursor cells (NPCs) with the capability of differentiation into mature neurons in vitro. When the diPSC-derived NPCs were transplanted into mice 9 days after spinal cord injury, we detected a significant amelioration of hindlimb dysfunction during follow-up recovery periods. Histological analysis at 5 weeks after transplantation identified undifferentiated human NPCs (Nestin(+)) as well as early (Tuj1(+)) and mature (MAP2(+)) neurons derived from the transplanted NPCs. Furthermore, NPC transplantation demonstrated a preventive effect on spinal cord degeneration resulting from the secondary injury. CONCLUSION: This study revealed that intervertebral discs removed during surgery for spinal stabilization after spinal cord injury, previously considered a "waste" tissue, may provide a unique opportunity to study iPSCs derived from difficult-to-access somatic cells and a useful therapeutic resource for autologous cell replacement therapy in spinal cord injury. PMID- 26104418 TI - Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. AB - OBJECTIVE: This guideline summarizes the quality of the evidence to date and provides a reasonable approach to the diagnosis, evaluation and treatment of the hypertensive disorders of pregnancy (HDP). EVIDENCE: The literature reviewed included the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) HDP guidelines from 2008 and their reference lists, and an update from 2006. Medline, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Registry of Controlled Trials (CCRCT) and Database of Abstracts and Reviews of Effects (DARE) were searched for literature published between January 2006 and March 2012. Articles were restricted to those published in French or English. Recommendations were evaluated using the criteria of the Canadian Task Force on Preventive Health Care and GRADE. PMID- 26104419 TI - Magnesium in pregnancy blood pressure and pre-eclampsia - A review. AB - Magnesium is an important cation present in more than 300 enzymes in the body. This review evaluates the information on magnesium and pregnancy. In normal pregnancies Mg responsive genes are upregulated, suggesting Mg deficiency. Blood pressure increase is related to the urinary excretion of Mg. In pregnancies complicated by preeclampsia the Mg homeostasis is different from normal pregnancies. Supplementation with Mg has shown beneficial effects on high blood pressure and infant conditions in some studies. Although several studies show important relationships between Mg homeostasis and pregnancy, particularly those with pre-eclampsia, further studies are needed to assess the relationship and formulate requirements for intervention programmes. PMID- 26104420 TI - The l-arginine/nitric oxide pathway is impaired in overweight/obese pregnant women. AB - OBJECTIVE: To evaluate the l-arginine/NO system and its role in insulin signaling and endothelial function during the pregnancy of women of different BMI categories. STUDY DESIGN: Twelve women with BMI?25 were compared with 10 normal weight women in a fasting condition after the infusion of l-arginine (20g in 3h) and after the evaluation of the flow-mediated vasodilation (FMD) of the brachial artery between the 9th-12th and 24th-27th weeks. Blood samples for insulin and nitrite/nitrate (NOx) were collected at baseline and after 1, 2 and 3h after initiating the infusion. RESULTS: In both trimesters, the baseline NOx levels were similar among groups. In the 1st trimester of the lean women, there was a NOx increase in response to l-Arg (AUC: 1328; 3, 3173), which had increased by the 2nd trimester (AUC: 3884; 1905, 7686); in overweight/obese women, no responses to l-Arg were found in the 1st or 2nd trimesters. In the 1st trimester, the insulin levels were significantly reduced in both groups after l-Arg infusion. Although the insulin levels in all BMI categories were higher in the 2nd trimester, such levels during weeks 24-27 were suppressed only in normal weight women after l-Arg infusion. The FMD was higher during both trimesters in the lean controls and was impaired in the overweight/obese subjects. CONCLUSIONS: NO availability is impaired in overweight/obese women during pregnancy, which affects endothelial functioning and interferes with insulin regulation. These mechanisms could be involved in the development of hypertensive disorders and glucose intolerance in this population. PMID- 26104421 TI - How accurate are placental growth factor, urate, lactate dehydrogenase and proteinuria in diagnosing preeclampsia and its severity? AB - OBJECTIVE: The objective was to assess the diagnostic accuracy of serum and urinary placental growth factor (sPlGF and uPlGF, respectively), urate, lactate dehydrogenase (LDH), and proteinuria for diagnosing and differentiating between women with preeclampsia and women with a normal healthy pregnancy, gestational hypertension, and gestational proteinuria. STUDY DESIGN: Urine and blood samples were taken from pregnant women diagnosed with late-onset severe preeclampsia (30 patients), mild preeclampsia (30 patients), gestational hypertension without meeting the criteria for preeclampsia (30 patients), gestational proteinuria without meeting the criteria for preeclampsia (30 patients), and healthy pregnant control women (30 patients). A receiver operating characteristic (ROC) curves analysis was performed to evaluate the diagnostic accuracy and to select the optimal cutoff points for different markers. RESULTS: sPlGF is the best test for differentiating women with severe preeclampsia from women in all of the other groups (p=0.001). However, there was no significant difference between sPlGF and proteinuria in the 24-h urine collection (p=0.329) in this differentiation. uPlGF can be used to differentiate women with severe preeclampsia from women in all of the other groups. However, proteinuria in the 24-h urine collection is better than uPlGF for this differentiation (p=0.013). CONCLUSION: sPlGF and uPlGF can be used to diagnose women with severe preeclampsia and should be considered at least as important as proteinuria in the diagnosis of preeclampsia. A large study that considers the cost-effectiveness of adding these markers to the diagnosis of preeclampsia should be conducted before our recommendation is applied. PMID- 26104422 TI - A study on the role of HLA-G 14bp and ACE IN/DEL polymorphisms in pre-eclamptic South Indian women. AB - Pre-eclampsia (PE) is a pregnancy specific syndrome characterized by hypertension and proteinuria. Defective placentation during early stages of pregnancy in combination with maternal and environmental factors could lead to systemic inflammation, endothelial dysfunction and the manifestation of the clinical symptoms. HLA-G is considered essential for feto-maternal immune tolerance and successful placentation in pregnancy. ACE promotes decidualization, trophoblast proliferation and plays an important role in blood pressure homeostasis. The HLA G 14bp and ACE IN/DEL polymorphisms have been reported to be associated with the development of pre-eclampsia (PE). The present study aimed at investigating the role of HLA-G and ACE gene polymorphisms in the aetiopathogenesis of PE. A total of 412 (206 PE patients and 206 normal pregnant women) blood samples were collected from Govt. maternity hospital, Hyderabad, India. Genotyping was carried out for both the genes using PCR followed by PAGE for HLA-G and AGE for ACE gene polymorphisms. DD(ACE) genotype was observed to be elevated (52.9% vs. 31.1%) in the patient group and ID(ACE) (29.6% vs. 54.8%) in the control group (p<0.05). However, HLA-G polymorphism did not differ between patients and controls (p>0.05). Further, combined genotype analysis revealed ID(HLA-G) DD(ACE) to be predisposing genotypes and ID(HLA-G) ID(ACE) to be protective toward preeclampsia in south Indian Women. The ACE genotype (DD(ACE)) is associated with high levels of angiotensin and seems to predispose the individual to PE. However, women carrying the intermediate levels of ACE and HLA-G associated combined genotype (ID(HLA-G) ID(HLA-G)) appear to be protective against developing PE. PMID- 26104423 TI - Is there any relationship between ABO/Rh blood group and patients with pre eclampsia? AB - OBJECTIVES: The purpose of the present study was to evaluate the association between pre-eclampsia and blood groups in a group of pregnant women hospitalized in a University Hospital in Porto Alegre, Brazil - Hospital Sao Lucas (HSL)/PUCRS. STUDY DESIGN: Our sample consisted of 10,040 pregnant women admitted to the maternity department of HSL between 2005 and 2010. The patients were reviewed retrospectively for inclusion. Medical records of 414 women were diagnosed as preeclampsia/eclampsia and 9611 women were identified to the control group. The patients were divided into two groups: the group with preeclampsia/eclampsia and the control group, and their blood groups were considered. Data were analyzed using SPSS for Windows version 17.0. Categorical data were summarized by counts and percentages, with the statistical significance evaluated by the Chi-square test. The null hypothesis was rejected when p<0.05. MAIN OUTCOME MEASURES: Maternal parameters were compared between control group and pre-eclampsia, respectively, Systolic Blood Pressure (117+/-19.98 vs. 165+/ 19.99); Diastolic Blood Pressure (73+/-14.23 vs. 106+/-14.24) and maternal weight at booking (73+/-33 vs. 83+/-33). For all data: mean+SD; p<0.05. In relation to blood groups, firstly they were stratified by Rh and ABO phenotypes, separately. After that the groups were put together. RESULTS: No differences in blood group distribution were observed between controls and pre-eclampsia for any analysis. (p>0.05). CONCLUSIONS: When we adopted stricter criteria for pre-eclampsia and a large sample from the same region we noted that the results did not show any association between blood groups and the development of pre-eclampsia. PMID- 26104424 TI - Plasma antithrombin levels correlate with albumin and total protein in gestational hypertension and preeclampsia. AB - OBJECTIVE: To analyze the antithrombin-III (AT-III) activity in the plasma in relation to the serum albumin and total protein in preeclampsia and gestational hypertension. STUDY DESIGN: The medical records of 139 patients who were diagnosed with gestational hypertension (n=33) and preeclampsia (n=106) were reviewed, and the relationships between the activity of AT-III and serum albumin or total protein were evaluated. MAIN OUTCOME MEASURES: The plasma AT-III activity in gestational hypertension and preeclampsia was correlated with the serum albumin and TP levels. RESULTS: There were significant correlations between AT-III activity and albumin in gestational hypertension (r=0.504, p=0.003) and preeclampsia (r=0.343, p=0.003). There were also significant correlations between AT-III activity and TP in gestational hypertension (r=0.619, p=0.001) and preeclampsia (r=0.366, p=0.001). Regression coefficients between AT-III and albumin and between AT-III and TP in gestational hypertension (23.7 and 14.0, respectively) were significantly steeper than those in preeclampsia (14.6 and 9.6, respectively). CONCLUSIONS: The plasma AT-III activity in gestational hypertension and preeclampsia was correlated with the serum albumin and TP levels. This suggests that AT-III activity is more likely to decrease in gestational hypertension than in preeclampsia. PMID- 26104425 TI - Preeclampsia and cardiovascular disease share genetic risk factors on chromosome 2q22. AB - OBJECTIVE: Four putative single nucleotide polymorphism (SNP) risk variants at the preeclampsia susceptibility locus on chromosome 2q22; rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preeclampsia risk variants in an independent Australian population-based cohort. METHODS: The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1246 mothers and 1404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software. RESULTS: Nominal associations (P<0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P=0.005) and decreased blood glucose levels in adolescents (P=0.022). The LRP1B SNP was associated with increased maternal height (P=0.026) and decreased maternal weight (P=0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P=0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preeclamptic pregnancy (P=0.003) and having a mother with prior preeclamptic pregnancy (P=0.033). CONCLUSIONS: Our collective findings support the hypothesis that genetic mechanisms for preeclampsia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P<0.001). PMID- 26104427 TI - The strength in comparison: Franz von Leydig (May 21, 1821 - April 13, 1908). PMID- 26104428 TI - Role of Carboplatin in the Treatment of Triple Negative Early- Stage Breast Cancer. AB - Triple negative breast cancer (TNBC) is more prevalent in younger patients and those carrying BRCA mutations. Although the incidence of breast cancer in general has dropped during the last years, TNBC has shown a relative increase. It is recognized as a breast cancer subtype with a high risk of tumor relapse and mortality. However, patients who achieve pathological complete response (pCR) with the use of neoadjuvant treatments have better prognosis and may attain cure. The lack of effective targeted therapies makes the use of conventional chemotherapy the only alternative available to fight this disease. Since many TNBCs share at least some phenotypic characteristics with germline BRCA-mutated tumors (BRCAness) cross-linking agents, such platinum salts, are particularly useful. Recently, two randomized phase 2 clinical trials support this presumption. However, improvement in pCR rates does not come free of toxicity. Given the potential change in practice associated with the generalized use of carboplatin in the neoadjuvant setting for TNBC patients, the aim of this review is to discuss the benefits as well as the potential drawbacks linked with the use of this strategy. PMID- 26104429 TI - Lithological and hydrochemical controls on distribution and speciation of uranium in groundwaters of hard-rock granitic aquifers of Madurai District, Tamil Nadu (India). AB - Uranium is a radioactive element normally present in hexavalent form as U(VI) in solution and elevated levels in drinking water cause health hazards. Representative groundwater samples were collected from different litho-units in this region and were analyzed for total U and major and minor ions. Results indicate that the highest U concentration (113 ug l(-1)) was found in granitic terrains of this region and about 10 % of the samples exceed the permissible limit for drinking water. Among different species of U in aqueous media, carbonate complexes [UO2(CO3)(2)(2-)] are found to be dominant. Groundwater with higher U has higher pCO2 values, indicating weathering by bicarbonate ions resulting in preferential mobilization of U in groundwater. The major minerals uraninite and coffinite were found to be supersaturated and are likely to control the distribution of U in the study area. Nature of U in groundwater, the effects of lithology on hydrochemistry and factors controlling its distribution in hard rock aquifers of Madurai district are highlighted in this paper. PMID- 26104431 TI - Subtyping schizophrenia: A comparison of positive/negative and system-specific approaches. AB - BACKGROUND: Schizophrenia is a heterogeneous disorder. Over the years, different approaches have been proposed to approach this heterogeneity by categorizing symptom patterns. The study aimed to compare positive/negative and system specific approaches to subtyping. METHODS: We used the Positive and Negative Syndrome Scale (PANSS) and Bern Psychopathology Scale (BPS), which consists of subscales for three domains (language, affect and motor behavior) that are hypothesized to be related to specific brain circuits, to assess cross-sectional psychopathological characteristics in a sample of 100 inpatients with schizophrenia spectrum disorders. We then categorized participants into positive/negative and system-specific subgroups to allow comparisons of the two approaches. RESULTS: The analyses revealed correlations between the PANSS positive subscore and the BPS affective subscore (r=.446, p<.001) and between the PANSS negative subscore and the BPS motor behavior subscore (r=.227, p=.023). As regards the positive and negative subtype, more participants were classified as positive in the language-dominant subtype (30.3%) and affect-dominant subtype (30.3%), whereas more were classified as negative in the motor behavior-dominant subtype (44.4%). However, most patients met the criteria for the mixed subtype. CONCLUSIONS: The results suggest that the positive/negative and system-specific approaches can be regarded as complementary. Future studies should examine both approaches in a longitudinal assessment of psychopathological symptoms and link them with qualitative-phenomenological approaches. PMID- 26104430 TI - Stenting in Intracranial Stenosis: Current Controversies and Future Directions. AB - Angioplasty and stenting for intracranial atherosclerotic stenosis (ICAS) are a last resort for patients with high-grade intracranial stenosis with multiple ischemic events unresponsive to medical therapy. Medical management, consisting of aggressive risk factor control and dual antiplatelet therapy, is superior to angioplasty and stenting for the prevention of future stroke. Future studies of angioplasty and stenting in this population are important, as the stroke risk on medical therapy is 12 % at 1 year and post-procedure stroke rates are similar to rates with medical treatment. There are many issues that will need to be resolved for stenting to offer any benefit, however. Procedural risks of hemorrhagic and ischemic stroke are unacceptably high. High-risk subgroups, potentially based on hemodynamic factors, will need to be identified for future interventional trials. Nevertheless, it is still reasonable to consider angioplasty and stenting for selected patients with multiple recurrent events despite aggressive medical management, but benefits are unclear at this time. PMID- 26104432 TI - Is reflective functioning associated with clinical symptoms and long-term course in patients with personality disorders? AB - OBJECTIVE: Mentalization is the capacity to understand behavior as the expression of various mental states and is assumed to be important in a range of psychopathologies, especially personality disorders (PDs). The first aim of the present study was to investigate the relationship between mentalization capacity, operationalized as reflective functioning (RF), and clinical manifestations before entering study treatment. The second aim was to investigate the relationship between baseline RF and long-term clinical outcome both independent of treatment (predictor analyses) and dependent on treatment (moderator analyses). METHODS: Seventy-nine patients from a randomized clinical trial (Ulleval Personality Project) who had borderline and/or avoidant PD were randomly assigned to either a step-down treatment program, comprising short-term day hospital treatment followed by outpatient combined group and individual psychotherapy, or to outpatient individual psychotherapy. Patients were evaluated on variables including symptomatic distress, psychosocial functioning, personality functioning, and self-esteem at baseline, 8 and 18months, and 3 and 6years. RESULTS: RF was significantly associated with a wide range of variables at baseline. In longitudinal analyses RF was not found to be a predictor of long term clinical outcome. However, when considering treatment type, there were significant moderator effects of RF. Patients with low RF had better outcomes in outpatient individual therapy compared to the step-down program. In contrast, patients in the medium RF group achieved better results in the step-down program. CONCLUSION: These findings indicate that RF is associated with core aspects of personality pathology and capture clinically relevant phenomena in adult patients with PDs. Moreover, patients with different capacities for mentalization may need different kinds of therapeutic approaches. PMID- 26104433 TI - Diversity-generating Retroelements in Phage and Bacterial Genomes. AB - Diversity-generating retroelements (DGRs) are DNA diversification machines found in diverse bacterial and bacteriophage genomes that accelerate the evolution of ligand-receptor interactions. Diversification results from a unidirectional transfer of sequence information from an invariant template repeat (TR) to a variable repeat (VR) located in a protein-encoding gene. Information transfer is coupled to site-specific mutagenesis in a process called mutagenic homing, which occurs through an RNA intermediate and is catalyzed by a unique, DGR-encoded reverse transcriptase that converts adenine residues in the TR into random nucleotides in the VR. In the prototype DGR found in the Bordetella bacteriophage BPP-1, the variable protein Mtd is responsible for phage receptor recognition. VR diversification enables progeny phage to switch tropism, accelerating their adaptation to changes in sequence or availability of host cell-surface molecules for infection. Since their discovery, hundreds of DGRs have been identified, and their functions are just beginning to be understood. VR-encoded residues of many DGR-diversified proteins are displayed in the context of a C-type lectin fold, although other scaffolds, including the immunoglobulin fold, may also be used. DGR homing is postulated to occur through a specialized target DNA-primed reverse transcription mechanism that allows repeated rounds of diversification and selection, and the ability to engineer DGRs to target heterologous genes suggests applications for bioengineering. This chapter provides a comprehensive review of our current understanding of this newly discovered family of beneficial retroelements. PMID- 26104435 TI - Public Health Microbiology of Shiga Toxin-Producing Escherichia coli. AB - Shiga toxin-producing Escherichia coli (STEC) strains are the only pathogenic group of E. coli that has a definite zoonotic origin, with ruminants and, in particular, cattle being recognized as the major reservoir. Most human STEC infections are food borne, but the routes of transmission include direct contact with animals and a variety of environment-related exposures. Therefore, STEC public health microbiology spans the fields of medical, veterinary, food, water, and environmental microbiology, requiring a "One Health" perspective and laboratory scientists with the ability to work effectively across disciplines. Public health microbiology laboratories play a central role in the surveillance of STEC infections, as well as in the preparedness for responding to outbreaks and in providing scientific evidence for the implementation of prevention and control measures. This article reviews (i) how the integration of surveillance of STEC infections and monitoring of these pathogens in animal reservoirs and potential food vehicles may contribute to their control; (ii) the role of reference laboratories, in both the public health and veterinary and food sectors; and (iii) the public health perspectives, including those related to regulatory issues in both the European Union and the United States. PMID- 26104436 TI - Plasmid-Encoded Iron Uptake Systems. AB - Plasmids confer genetic information that benefits the bacterial cells containing them. In pathogenic bacteria, plasmids often harbor virulence determinants that enhance the pathogenicity of the bacterium. The ability to acquire iron in environments where it is limited, for instance the eukaryotic host, is a critical factor for bacterial growth. To acquire iron, bacteria have evolved specific iron uptake mechanisms. These systems are often chromosomally encoded, while those that are plasmid-encoded are rare. Two main plasmid types, ColV and pJM1, have been shown to harbor determinants that increase virulence by providing the cell with essential iron for growth. It is clear that these two plasmid groups evolved independently from each other since they do not share similarities either in the plasmid backbones or in the iron uptake systems they harbor. The siderophores aerobactin and salmochelin that are found on ColV plasmids fall in the hydroxamate and catechol group, respectively, whereas both functional groups are present in the anguibactin siderophore, the only iron uptake system found on pJM1 type plasmids. Besides siderophore-mediated iron uptake, ColV plasmids carry additional genes involved in iron metabolism. These systems include ABC transporters, hemolysins, and a hemoglobin protease. ColV- and pJM1-like plasmids have been shown to confer virulence to their bacterial host, and this trait can be completely ascribed to their encoded iron uptake systems. PMID- 26104437 TI - Biology of Three ICE Families: SXT/R391, ICEBs1, and ICESt1/ICESt3. AB - Integrative and Conjugative Elements (ICEs) are bacterial mobile genetic elements that play a key role in bacterial genomes dynamics and evolution. ICEs are widely distributed among virtually all bacterial genera. Recent extensive studies have unraveled their high diversity and complexity. The present review depicts the general conserved features of ICEs and describes more precisely three major families of ICEs that have been extensively studied in the past decade for their biology, their evolution and their impact on genomes dynamics. First, the large SXT/R391 family of ICEs disseminates antibiotic resistance genes and drives the exchange of mobilizable genomic islands (MGIs) between many enteric pathogens such as Vibrio cholerae. Second, ICEBs1 of Bacillus subtilis is the most well understood ICE of Gram-positive bacteria, notably regarding the regulation of its dissemination and its initially unforeseen extrachromosomal replication, which could be a common feature of ICEs of both Gram-positive and Gram-negative bacteria. Finally, ICESt1 and ICESt3 of Streptococcus thermophilus are the prototypes of a large family of ICEs widely distributed among various streptococci. These ICEs carry an original regulation module that associates regulators related to those of both SXT/R391 and ICEBs1. Study of ICESt1 and ICESt3 uncovered the cis-mobilization of related genomic islands (CIMEs) by a mechanism called accretion-mobilization, which likely represents a paradigm for the evolution of many ICEs and genomic islands. These three major families of ICEs give a glimpse about ICEs dynamics and their high impact on bacterial adaptation. PMID- 26104438 TI - Plasmid Diversity and Adaptation Analyzed by Massive Sequencing of Escherichia coli Plasmids. AB - Whole-genome sequencing is revolutionizing the analysis of bacterial genomes. It leads to a massive increase in the amount of available data to be analyzed. Bacterial genomes are usually composed of one main chromosome and a number of accessory chromosomes, called plasmids. A recently developed methodology called PLACNET (for plasmid constellation networks) allows the reconstruction of the plasmids of a given genome. Thus, it opens an avenue for plasmidome analysis on a global scale. This work reviews our knowledge of the genetic determinants for plasmid propagation (conjugation and related functions), their diversity, and their prevalence in the variety of plasmids found by whole-genome sequencing. It focuses on the results obtained from a collection of 255 Escherichia coli plasmids reconstructed by PLACNET. The plasmids found in E. coli represent a nonaleatory subset of the plasmids found in proteobacteria. Potential reasons for the prevalence of some specific plasmid groups will be discussed and, more importantly, additional questions will be posed. PMID- 26104434 TI - Host Factors in Retroviral Integration and the Selection of Integration Target Sites. AB - In order to replicate, a retrovirus must integrate a DNA copy of the viral RNA genome into a chromosome of the host cell. The study of retroviral integration has advanced considerably in the past few years. Here we focus on host factor interactions and the linked area of integration targeting. Genome-wide screens for cellular factors affecting HIV replication have identified a series of host cell proteins that may mediate subcellular trafficking for preintegration complexes, nuclear import, and integration target site selection. The cell transcriptional co-activator protein LEDGF/p75 has been identified as a tethering factor important for HIV integration, and recently, BET proteins (Brd2, 4, and 4) have been identified as tethering factors for the gammaretroviruses. A new class of HIV inhibitors has been developed targeting the HIV-1 IN-LEDGF binding site, though surprisingly these inhibitors appear to block assembly late during replication and do not act at the integration step. Going forward, genome-wide studies of HIV-host interactions offer many new starting points to investigate HIV replication and identify potential new inhibitor targets. PMID- 26104439 TI - Antibodies: Computer-Aided Prediction of Structure and Design of Function. AB - With the advent of high-throughput sequencing, and the increased availability of experimental structures of antibodies and antibody-antigen complexes, comes the improvement of computational approaches to predict the structure and design the function of antibodies and antibody-antigen complexes. While antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions, they also offer exciting opportunities: the central importance of antibodies for human health results in a wealth of structural and sequence information that-as a knowledge base-can drive the modeling algorithms by limiting the conformational and sequence search space to likely regions of success. Further, efficient experimental platforms exist to test predicted antibody structure or designed antibody function, thereby leading to an iterative feedback loop between computation and experiment. We briefly review the history of computer-aided prediction of structure and design of function in the antibody field before we focus on recent methodological developments and the most exciting application examples. PMID- 26104440 TI - Radiolabeled Antibodies for Therapy of Infectious Diseases. AB - Novel approaches to the treatment of infectious diseases are urgently needed. This need has resulted in renewing the interest in antibodies for therapy of infectious diseases. Radioimmunotherapy (RIT) is a cancer treatment modality that utilizes radiolabeled monoclonal antibodies. During the last decade we have translated RIT into the field of experimental fungal, bacterial, and HIV infections. In addition, successful proof of principle experiments with radiolabeled pan-antibodies that bind to antigens shared by major pathogenic fungi have been performed in vitro. The armamentarium of pan-antibodies would result in reducing our dependence on microorganism-specific antibodies and thus would speed up the development of RIT for infections. We believe that the time is ripe for deploying RIT in the clinic to combat infectious diseases. PMID- 26104441 TI - Retroviral Integrase Structure and DNA Recombination Mechanism. AB - Due to the importance of human immunodeficiency virus type 1 (HIV-1) integrase as a drug target, the biochemistry and structural aspects of retroviral DNA integration have been the focus of intensive research during the past three decades. The retroviral integrase enzyme acts on the linear double-stranded viral DNA product of reverse transcription. Integrase cleaves specific phosphodiester bonds near the viral DNA ends during the 3' processing reaction. The enzyme then uses the resulting viral DNA 3'-OH groups during strand transfer to cut chromosomal target DNA, which simultaneously joins both viral DNA ends to target DNA 5'-phosphates. Both reactions proceed via direct transesterification of scissile phosphodiester bonds by attacking nucleophiles: a water molecule for 3' processing, and the viral DNA 3'-OH for strand transfer. X-ray crystal structures of prototype foamy virus integrase-DNA complexes revealed the architectures of the key nucleoprotein complexes that form sequentially during the integration process and explained the roles of active site metal ions in catalysis. X-ray crystallography furthermore elucidated the mechanism of action of HIV-1 integrase strand transfer inhibitors, which are currently used to treat AIDS patients, and provided valuable insights into the mechanisms of viral drug resistance. PMID- 26104442 TI - Plasmid Partition Mechanisms. AB - The stable maintenance of low-copy-number plasmids in bacteria is actively driven by partition mechanisms that are responsible for the positioning of plasmids inside the cell. Partition systems are ubiquitous in the microbial world and are encoded by many bacterial chromosomes as well as plasmids. These systems, although different in sequence and mechanism, typically consist of two proteins and a DNA partition site, or prokaryotic centromere, on the plasmid or chromosome. One protein binds site-specifically to the centromere to form a partition complex, and the other protein uses the energy of nucleotide binding and hydrolysis to transport the plasmid, via interactions with this partition complex inside the cell. For plasmids, this minimal cassette is sufficient to direct proper segregation in bacterial cells. There has been significant progress in the last several years in our understanding of partition mechanisms. Two general areas that have developed are (i) the structural biology of partition proteins and their interactions with DNA and (ii) the action and dynamics of the partition ATPases that drive the process. In addition, systems that use tubulin like GTPases to partition plasmids have recently been identified. In this chapter, we concentrate on these recent developments and the molecular details of plasmid partition mechanisms. PMID- 26104443 TI - Clinical Studies of Escherichia coli O157:H7 Conjugate Vaccines in Adults and Young Children. AB - Pediatric immunization has been the most effective measure to prevent and reduce the burden of infectious diseases in children. The recent inclusion of pneumococcal and meningococcal polysaccharide conjugates in infant immunization further reinforces their importance. Currently there is no human vaccine against enterohemorrhagic Escherichia coli (EHEC) infections. This review focuses on the human EHEC vaccine that has been studied clinically, in particular, the polysaccharide conjugate against E. coli O157. The surface polysaccharide antigen, O-specific polysaccharide, was linked to rEPA, recombinant exotoxin A of Pseudomonas aeruginosa. In adults and children 2 to 5 years old, O157-rEPA conjugates, shown to be safe, induced high levels of antilipopolysaccharide immunoglobulin G with bactericidal activities against E. coli O157, a functional bioassay that mimics the killing of inoculum in vivo. A similar construct using the B subunit of Shiga toxin (Stx) 1 as the carrier protein elicited both bactericidal and toxin-neutralizing antibodies in mice. So far there is no clinical study of Stx-based human vaccine. Passive immunization of Stx-specific antibodies with humanized, chimeric, or human monoclonal antibodies, produced in transgenic mice, showed promising data in animal models and offered high prospects. Demonstrations of their safety and effectiveness in treating hemolytic uremic syndrome or patients with EHEC infections are under way, and results are much anticipated. For future development, other virulence factors such as the nontoxic Stx B subunit or intimin should be included, either as carrier protein in conjugates or as independent components. The additional antigens from O157 may provide broader coverage to non-O157 Stx-producing E. coli and facilitate both preventive and therapeutic treatment. PMID- 26104444 TI - Dengue Antibody-Dependent Enhancement: Knowns and Unknowns. AB - Dengue provides the most abundant example in human medicine and the greatest human illness burden caused by the phenomenon of intrinsic antibody-dependent infection enhancement (iADE). In this immunopathological phenomenon infection of monocytes or macrophages using infectious immune complexes suppresses innate antiviral systems, permitting logarithmic intracellular growth of dengue virus. The four dengue viruses evolved from a common ancestor yet retain similar ecology and pathogenicity, but although infection with one virus provides short-term cross-protection against infection with a different type, millions of secondary dengue infections occur worldwide each year. When individuals are infected in the virtual absence of cross-protective dengue antibodies, the dengue vascular permeability syndrome (DVPS) may ensue. This occurs in around 2 to 4% of second heterotypic dengue infections. A complete understanding of the biologic mechanism of iADE, dengue biology, and the mechanism of host responses to dengue infection should lead to a comprehensive and complete understanding of the pathogenesis of DVPS. A crucial emphasis must be placed on understanding ADE. Clinical and epidemiological observations of DVPS define the research questions and provide research parameters. This article will review knowledge related to dengue ADE and point to areas where there has been little research progress. These observations relate to the two stages of dengue illnesses: afferent phenomena are those that promote the success of the microorganism to infect and survive; efferent phenomena are those mounted by the host to inhibit infection and replication and to eliminate the infectious agent and infected tissues. Data will be discussed as "knowns" and "unknowns." PMID- 26104446 TI - Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite Plasmodium falciparum. AB - The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. These parasites invade and replicate within the circulating red blood cells of infected individuals leading to numerous disease manifestations, including severe anemia, altered circulation, and tissue inflammation. Malaria parasites are also known for their ability to maintain a chronic infection through antigenic variation, the ability to systematically alter the antigens displayed on the surface of infected cells and thereby avoid clearance by the host's antibody response. The genome of P. falciparum includes several large, multicopy gene families that encode highly variable forms of the surface proteins that are the targets of host immunity. Alterations in expression of genes within these families are responsible for antigenic variation. This process requires the continuous generation of new antigenic variants within these gene families, and studies have shown that new variants arise through extensive recombination and gene conversion events between family members. Malaria parasites possess an unusual complement of DNA repair pathways, thus the study of recombination between variant antigen encoding genes provides a unique view into the evolution of mobile DNA in an organism distantly related to the more closely studied model eukaryotes. PMID- 26104445 TI - vls Antigenic Variation Systems of Lyme Disease Borrelia: Eluding Host Immunity through both Random, Segmental Gene Conversion and Framework Heterogeneity. AB - Spirochetes that cause Lyme borreliosis (also called Lyme disease) possess the vls locus, encoding an elaborate antigenic variation system. This locus contains the expression site vlsE as well as a contiguous array of vls silent cassettes, which contain variations of the central cassette region of vlsE. The locus is present on one of the many linear plasmids in the organism, e.g. plasmid lp28-1 in the strain Borrelia burgdorferi B31. Changes in the sequence of vlsE occur continuously during mammalian infection and consist of random, segmental, unidirectional recombination events between the silent cassettes and the cassette region of vlsE. These gene conversion events do not occur during in vitro culture or the tick portion of the infection cycle of B. burgdorferi or the other related Borrelia species that cause Lyme disease. The mechanism of recombination is largely unknown, but requires the RuvAB Holliday junction branch migrase. Other features of the vls locus also appear to be required, including cis locations of vlsE and the silent cassettes and high G+C content and GC skew. The vls system is required for long-term survival of Lyme Borrelia in infected mammals and represents an important mechanism of immune evasion. In addition to sequence variation, immune selection also results in significant heterogeneity in the sequence of the surface lipoprotein VlsE. Despite antigenic variation, VlsE generates a robust antibody response, and both full-length VlsE and the C6 peptide (corresponding to invariant region 6) are widely used in immunodiagnostic tests for Lyme disease. PMID- 26104447 TI - Plasmid-Mediated Tolerance Toward Environmental Pollutants. AB - The survival capacity of microorganisms in a contaminated environment is limited by the concentration and/or toxicity of the pollutant. Through evolutionary processes, some bacteria have developed or acquired mechanisms to cope with the deleterious effects of toxic compounds, a phenomenon known as tolerance. Common mechanisms of tolerance include the extrusion of contaminants to the outer media and, when concentrations of pollutants are low, the degradation of the toxic compound. For both of these approaches, plasmids that encode genes for the degradation of contaminants such as toluene, naphthalene, phenol, nitrobenzene, and triazine or are involved in tolerance toward organic solvents and heavy metals, play an important role in the evolution and dissemination of these catabolic pathways and efflux pumps. Environmental plasmids are often conjugative and can transfer their genes between different strains; furthermore, many catabolic or efflux pump genes are often associated with transposable elements, making them one of the major players in bacterial evolution. In this review, we will briefly describe catabolic and tolerance plasmids and advances in the knowledge and biotechnological applications of these plasmids. PMID- 26104448 TI - Programmed Genome Rearrangements in Tetrahymena. AB - Ciliates are champions in programmed genome rearrangements. They carry out extensive restructuring during differentiation to drastically alter the complexity, relative copy number, and arrangement of sequences in the somatic genome. This chapter focuses on the model ciliate Tetrahymena, perhaps the simplest and best-understood ciliate studied. It summarizes past studies on various genome rearrangement processes and describes in detail the remarkable progress made in the past decade on the understanding of DNA deletion and other processes. The process occurs at thousands of specific sites to remove defined DNA segments that comprise roughly one-third of the genome including all transposons. Interestingly, this DNA rearranging process is a special form of RNA interference. It involves the production of double-stranded RNA and small RNA that guides the formation of heterochromatin. A domesticated piggyBac transposase is believed to cut off the marked chromatin, and the retained sequences are joined together through nonhomologous end-joining processes. Many of the proteins and DNA players involved have been analyzed and are described. This link provides possible explanations for the evolution, mechanism, and functional roles of the process. The article also discusses the interactions between parental and progeny somatic nuclei that affect the selection of sequences for deletion, and how the specific deletion boundaries are determined after heterochromatin marking. PMID- 26104450 TI - Programmed Rearrangement in Ciliates: Paramecium. AB - Programmed genome rearrangements in the ciliate Paramecium provide a nice illustration of the impact of transposons on genome evolution and plasticity. During the sexual cycle, development of the somatic macronucleus involves elimination of ~30% of the germline genome, including repeated DNA (e.g., transposons) and ~45,000 single-copy internal eliminated sequences (IES). IES excision is a precise cut-and-close process, in which double-stranded DNA cleavage at IES ends depends on PiggyMac, a domesticated piggyBac transposase. Genome-wide analysis has revealed that at least a fraction of IESs originate from Tc/mariner transposons unrelated to piggyBac. Moreover, genomic sequences with no transposon origin, such as gene promoters, can be excised reproducibly as IESs, indicating that genome rearrangements contribute to the control of gene expression. How the system has evolved to allow elimination of DNA sequences with no recognizable conserved motif has been the subject of extensive research during the past two decades. Increasing evidence has accumulated for the participation of noncoding RNAs in epigenetic control of elimination for a subset of IESs, and in trans-generational inheritance of alternative rearrangement patterns. This chapter summarizes our current knowledge of the structure of the germline and somatic genomes for the model species Paramecium tetraurelia, and describes the DNA cleavage and repair factors that constitute the IES excision machinery. We present an overview of the role of specialized RNA interference machineries and their associated noncoding RNAs in the control of DNA elimination. Finally, we discuss how RNA-dependent modification and/or remodeling of chromatin may guide PiggyMac to its cognate cleavage sites. PMID- 26104451 TI - The Serine Recombinases. AB - In site-specific recombination, two short DNA sequences ('sites') are each cut at specific points in both strands, and the cut ends are rejoined to new partners. The enzymes that mediate recognition of the sites and the subsequent cutting and rejoining steps are called recombinases. Most recombinases fall into one of two families according to similarities of their protein sequences and mechanisms; these families are known as the tyrosine recombinases and the serine recombinases, the names referring to the conserved amino acid residue that attacks the DNA phosphodiester and becomes covalently linked to a DNA strand end during catalysis. This chapter gives an overview of our current understanding of the serine recombinases, their types, biological roles, structures, catalytic mechanisms, mechanisms of regulation, and applications. PMID- 26104449 TI - Programmed Genome Rearrangements in the Ciliate Oxytricha. AB - The ciliate Oxytricha is a microbial eukaryote with two genomes, one of which experiences extensive genome remodeling during development. Each round of conjugation initiates a cascade of events that construct a transcriptionally active somatic genome from a scrambled germline genome, with considerable help from both long and small noncoding RNAs. This process of genome remodeling entails massive DNA deletion and reshuffling of remaining DNA segments to form functional genes from their interrupted and scrambled germline precursors. The use of Oxytricha as a model system provides an opportunity to study an exaggerated form of programmed genome rearrangement. Furthermore, studying the mechanisms that maintain nuclear dimorphism and mediate genome rearrangement has demonstrated a surprising plasticity and diversity of noncoding RNA pathways, with new roles that go beyond conventional gene silencing. Another aspect of ciliate genetics is their unorthodox patterns of RNA-mediated, epigenetic inheritance that rival Mendelian inheritance. This review takes the reader through the key experiments in a model eukaryote that led to fundamental discoveries in RNA biology and pushes the biological limits of DNA processing. PMID- 26104452 TI - Using Plasmids as DNA Vaccines for Infectious Diseases. AB - DNA plasmids can be used to induce a protective (or therapeutic) immune response by delivering genes encoding vaccine antigens. That naked DNA (without the refinement of coat proteins or host evasion systems) can cross from outside the cell into the nucleus and be expressed is particularly remarkable given the sophistication of the immune system in preventing infection by pathogens. As a result of the ease, low cost, and speed of custom gene synthesis, DNA vaccines dangle a tantalizing prospect of the next wave of vaccine technology, promising individual designer vaccines for cancer or mass vaccines with a rapid response time to emerging pandemics. There is considerable enthusiasm for the use of DNA vaccination as an approach, but this enthusiasm should be tempered by the successive failures in clinical trials to induce a potent immune response. The technology is evolving with the development of improved delivery systems that increase expression levels, particularly electroporation and the incorporation of genetically encoded adjuvants. This review will introduce some key concepts in the use of DNA plasmids as vaccines, including how the DNA enters the cell and is expressed, how it induces an immune response, and a summary of clinical trials with DNA vaccines. The review also explores the advances being made in vector design, delivery, formulation, and adjuvants to try to realize the promise of this technology for new vaccines. If the immunogenicity and expression barriers can be cracked, then DNA vaccines may offer a step change in mass vaccination. PMID- 26104453 TI - Plasmid-Mediated Antimicrobial Resistance in Staphylococci and Other Firmicutes. AB - In staphylococci and other Firmicutes, resistance to numerous classes of antimicrobial agents, which are commonly used in human and veterinary medicine, is mediated by genes that are associated with mobile genetic elements. The gene products of some of these antimicrobial resistance genes confer resistance to only specific members of a certain class of antimicrobial agents, whereas others confer resistance to the entire class or even to members of different classes of antimicrobial agents. The resistance mechanisms specified by the resistance genes fall into any of three major categories: active efflux, enzymatic inactivation, and modification/replacement/protection of the target sites of the antimicrobial agents. Among the mobile genetic elements that carry such resistance genes, plasmids play an important role as carriers of primarily plasmid-borne resistance genes, but also as vectors for nonconjugative and conjugative transposons that harbor resistance genes. Plasmids can be exchanged by horizontal gene transfer between members of the same species but also between bacteria belonging to different species and genera. Plasmids are highly flexible elements, and various mechanisms exist by which plasmids can recombine, form cointegrates, or become integrated in part or in toto into the chromosomal DNA or into other plasmids. As such, plasmids play a key role in the dissemination of antimicrobial resistance genes within the gene pool to which staphylococci and other Firmicutes have access. This chapter is intended to provide an overview of the current knowledge of plasmid-mediated antimicrobial resistance in staphylococci and other Firmicutes. PMID- 26104454 TI - Hairpin Telomere Resolvases. AB - Covalently closed hairpin ends, also known as hairpin telomeres, provide an unusual solution to the end replication problem. The hairpin telomeres are generated from replication intermediates by a process known as telomere resolution. This is a DNA breakage and reunion reaction promoted by hairpin telomere resolvases (also referred to as protelomerases) found in a limited number of phage and bacteria. The reaction promoted by these enzymes is a chemically isoenergetic two-step transesterification without a requirement for divalent metal ions or high-energy cofactors and uses an active site and mechanism similar to that for type IB topoisomerases and tyrosine recombinases. The small number of unrelated telomere resolvases characterized to date all contain a central, catalytic core domain with the active site, but in addition carry variable C- and N-terminal domains with different functions. Similarities and differences in the structure and function of the telomere resolvases are discussed. Of particular interest are the properties of the Borrelia telomere resolvases, which have been studied most extensively at the biochemical level and appear to play a role in shaping the unusual segmented genomes in these organisms and, perhaps, to play a role in recombinational events. PMID- 26104455 TI - Peri- and Postharvest Factors in the Control of Shiga Toxin-Producing Escherichia coli in Beef. AB - Certain Shiga toxin-producing Escherichia coli (STEC) strains are important causes of food-borne disease, with hemorrhagic colitis and, in some cases, hemolytic-uremic syndrome as the clinical manifestations of illness. Six serogroups and one serotype of STEC (O26, O45, O103, O111, O121, O145, and O157:H7) are responsible for the vast majority of cases in the United States. Based on recent data for all food commodities combined, 55.3% and 50.0% of the outbreaks of STEC O157 and non-O157 in the United States, respectively, are attributable to beef as a food source. Consequently, the U.S. Department of Agriculture, Food Safety and Inspection Service declared these organisms as adulterants in raw, nonintact beef. In North America, cattle are a major reservoir of STEC strains, with organisms shed in the feces and contaminated hides of the animals being the main vehicle for spread to carcasses at slaughter. A number of peri- and postharvest interventions targeting STEC have been developed, and significant progress has been made in improving the microbiological quality of beef in the past 20 years as a result. However, continued improvements are needed, and accurate assessment of these interventions, especially for non-O157 STEC, would greatly benefit from improvements in detection methods for these organisms. PMID- 26104456 TI - Vaccination of Cattle against Escherichia coli O157:H7. AB - Human infection with Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) is relatively rare, but the consequences can be serious, especially in the very young and the elderly. Efforts to control the flow of STEC O157 during beef processing have meaningfully reduced the incidence of human STEC O157 infection, particularly prior to 2005. Unfortunately, despite early progress, the incidence of STEC O157 infection has not changed meaningfully or statistically in recent years, suggesting that additional actions, for example, targeting the cattle reservoir, are necessary to further reduce STEC O157 illness. Ideally, preharvest interventions against STEC O157 should reduce the likelihood that cattle carry the organism, have practical application within the beef production system, and add sufficient value to the cattle to offset the cost of the intervention. A number of STEC O157 antigens are being investigated as potential vaccine targets. Some vaccine products have demonstrated efficacy to reduce the prevalence of cattle carrying STEC O157 by making the gut unfavorable to colonization. However, in conditions of natural exposure, efficacy afforded by vaccination depends on how the products are used to control environmental transmission within groups of cattle and throughout the production system. Although cattle vaccines against STEC O157 have gained either full or preliminary regulatory approval in Canada and the United States, widespread use by cattle feeders is unlikely until there is an economic signal to indicate that cattle vaccinated against STEC O157 are valued over other cattle. PMID- 26104457 TI - Plasmid Biopharmaceuticals. AB - Plasmids are currently an indispensable molecular tool in life science research and a central asset for the modern biotechnology industry, supporting its mission to produce pharmaceutical proteins, antibodies, vaccines, industrial enzymes, and molecular diagnostics, to name a few key products. Furthermore, plasmids have gradually stepped up in the past 20 years as useful biopharmaceuticals in the context of gene therapy and DNA vaccination interventions. This review provides a concise coverage of the scientific progress that has been made since the emergence of what are called today plasmid biopharmaceuticals. The most relevant topics are discussed to provide researchers with an updated overview of the field. A brief outline of the initial breakthroughs and innovations is followed by a discussion of the motivation behind the medical uses of plasmids in the context of therapeutic and prophylactic interventions. The molecular characteristics and rationale underlying the design of plasmid vectors as gene transfer agents are described and a description of the most important methods used to deliver plasmid biopharmaceuticals in vivo (gene gun, electroporation, cationic lipids and polymers, and micro- and nanoparticles) is provided. The major safety issues (integration and autoimmunity) surrounding the use of plasmid biopharmaceuticals is discussed next. Aspects related to the large-scale manufacturing are also covered, and reference is made to the plasmid products that have received marketing authorization as of today. PMID- 26104459 TI - Virulence Plasmids of Spore-Forming Bacteria. AB - Plasmid-encoded virulence factors are important in the pathogenesis of diseases caused by spore-forming bacteria. Unlike many other bacteria, the most common virulence factors encoded by plasmids in Clostridium and Bacillus species are protein toxins. Clostridium perfringens causes several histotoxic and enterotoxin diseases in both humans and animals and produces a broad range of toxins, including many pore-forming toxins such as C. perfringens enterotoxin, epsilon toxin, beta-toxin, and NetB. Genetic studies have led to the determination of the role of these toxins in disease pathogenesis. The genes for these toxins are generally carried on large conjugative plasmids that have common core replication, maintenance, and conjugation regions. There is considerable functional information available about the unique tcp conjugation locus carried by these plasmids, but less is known about plasmid maintenance. The latter is intriguing because many C. perfringens isolates stably maintain up to four different, but closely related, toxin plasmids. Toxin genes may also be plasmid encoded in the neurotoxic clostridia. The tetanus toxin gene is located on a plasmid in Clostridium tetani, but the botulinum toxin genes may be chromosomal, plasmid-determined, or located on bacteriophages in Clostridium botulinum. In Bacillus anthracis it is well established that virulence is plasmid determined, with anthrax toxin genes located on pXO1 and capsule genes on a separate plasmid, pXO2. Orthologs of these plasmids are also found in other members of the Bacillus cereus group such as B. cereus and Bacillus thuringiensis. In B. thuringiensis these plasmids may carry genes encoding one or more insecticidal toxins. PMID- 26104458 TI - V(D)J Recombination: Mechanism, Errors, and Fidelity. AB - V(D)J recombination, the mechanism responsible for generating antigen receptor diversity, has the potential to generate aberrant DNA rearrangements in developing lymphocytes. Indeed, the recombinase has been implicated in several different kinds of errors leading to oncogenic transformation. Here we review the basic aspects of V(D)J recombination, mechanisms underlying aberrant DNA rearrangements, and the types of aberrant events uncovered in recent genomewide analyses of lymphoid neoplasms. PMID- 26104460 TI - Escherichia coli O104:H4 Pathogenesis: an Enteroaggregative E. coli/Shiga Toxin Producing E. coli Explosive Cocktail of High Virulence. AB - A major outbreak caused by Escherichia coli of serotype O104:H4 spread throughout Europe in 2011. This large outbreak was caused by an unusual strain that is most similar to enteroaggregative E. coli (EAEC) of serotype O104:H4. A significant difference, however, is the presence of a prophage encoding the Shiga toxin, which is characteristic of enterohemorrhagic E. coli (EHEC) strains. This combination of genomic features, associating characteristics from both EAEC and EHEC, represents a new pathotype. The 2011 E. coli O104:H4 outbreak of hemorrhagic diarrhea in Germany is an example of the explosive cocktail of high virulence and resistance that can emerge in this species. A total of 46 deaths, 782 cases of hemolytic-uremic syndrome, and 3,128 cases of acute gastroenteritis were attributed to this new clone of EAEC/EHEC. In addition, recent identification in France of similar O104:H4 clones exhibiting the same virulence factors suggests that the EHEC O104:H4 pathogen has become endemically established in Europe after the end of the outbreak. EAEC strains of serotype O104:H4 contain a large set of virulence-associated genes regulated by the AggR transcription factor. They include, among other factors, the pAA plasmid genes encoding the aggregative adherence fimbriae, which anchor the bacterium to the intestinal mucosa (stacked-brick adherence pattern on epithelial cells). Furthermore, sequencing studies showed that horizontal genetic exchange allowed for the emergence of the highly virulent Shiga toxin-producing EAEC O104:H4 strain that caused the German outbreak. This article discusses the role these virulence factors could have in EAEC/EHEC O104:H4 pathogenesis. PMID- 26104461 TI - Plasmids from Euryarchaeota. AB - Many plasmids have been described in Euryarchaeota, one of the three major archaeal phyla, most of them in salt-loving haloarchaea and hyperthermophilic Thermococcales. These plasmids resemble bacterial plasmids in terms of size (from small plasmids encoding only one gene up to large megaplasmids) and replication mechanisms (rolling circle or theta). Some of them are related to viral genomes and form a more or less continuous sequence space including many integrated elements. Plasmids from Euryarchaeota have been useful for designing efficient genetic tools for these microorganisms. In addition, they have also been used to probe the topological state of plasmids in species with or without DNA gyrase and/or reverse gyrase. Plasmids from Euryarchaeota encode both DNA replication proteins recruited from their hosts and novel families of DNA replication proteins. Euryarchaeota form an interesting playground to test evolutionary hypotheses on the origin and evolution of viruses and plasmids, since a robust phylogeny is available for this phylum. Preliminary studies have shown that for different plasmid families, plasmids share a common gene pool and coevolve with their hosts. They are involved in gene transfer, mostly between plasmids and viruses present in closely related species, but rarely between cells from distantly related archaeal lineages. With few exceptions (e.g., plasmids carrying gas vesicle genes), most archaeal plasmids seem to be cryptic. Interestingly, plasmids and viral genomes have been detected in extracellular membrane vesicles produced by Thermococcales, suggesting that these vesicles could be involved in the transfer of viruses and plasmids between cells. PMID- 26104462 TI - Iteron Plasmids. AB - Iteron-containing plasmids are model systems for studying the metabolism of extrachromosomal genetic elements in bacterial cells. Here we describe the current knowledge and understanding of the structure of iteron-containing replicons, the structure of the iteron plasmid encoded replication initiation proteins, and the molecular mechanisms for iteron plasmid DNA replication initiation. We also discuss the current understanding of control mechanisms affecting the plasmid copy number and how host chaperone proteins and proteases can affect plasmid maintenance in bacterial cells. PMID- 26104463 TI - Xer Site-Specific Recombination: Promoting Vertical and Horizontal Transmission of Genetic Information. AB - Two related tyrosine recombinases, XerC and XerD, are encoded in the genome of most bacteria where they serve to resolve dimers of circular chromosomes by the addition of a crossover at a specific site, dif. From a structural and biochemical point of view they belong to the Cre resolvase family of tyrosine recombinases. Correspondingly, they are exploited for the resolution of multimers of numerous plasmids. In addition, they are exploited by mobile DNA elements to integrate into the genome of their host. Exploitation of Xer is likely to be advantageous to mobile elements because the conservation of the Xer recombinases and of the sequence of their chromosomal target should permit a quite easy extension of their host range. However, it requires means to overcome the cellular mechanisms that normally restrict recombination to dif sites harbored by a chromosome dimer and, in the case of integrative mobile elements, to convert dedicated tyrosine resolvases into integrases. PMID- 26104464 TI - The spectrum of epilepsy caused by POLG mutations. AB - Mutations in POLG are increasingly recognized as a cause of refractory occipital lobe epilepsy (OLE) and status epilepticus (SE). Our aim was to describe the epilepsy syndrome in seven patients with POLG mutations. We retrospectively reviewed the medical records of seven patients with POLG mutations and epilepsy. Mutation analysis was performed by direct sequencing of the coding exons of the POLG gene. Disease onset was at a median age of 18 years (range 12-26). Epilepsy was the presenting problem in six patients. All had focal seizures, with motor (n = 6) and visual (n = 6) phenomena. Six patients had secondarily generalized seizures and two patients had myoclonic seizures. Six patients had one or more episodes of refractory SE, including focal (n = 5), subtle (n = 4), myoclonic (n = 2) and convulsive (n = 3) SE. During or after SE, brain MRI showed lesions affecting the occipital lobe in all patients, probably due to continuous epileptic activity. Five of the six patients with SE died during treatment of SE, one due to valproate-induced hepatotoxicity. Associated clinical symptoms were ataxia (n = 6), polyneuropathy (n = 6), progressive external ophthalmoplegia (PEO) (n = 3) and migraine (n = 3). Epilepsy may be the first and dominant neurological problem caused by POLG mutations. The epilepsy may be severe and the condition of the patient may end in fatal SE. Refractory OLE and SE in a patient with polyneuropathy, ataxia, PEO or migraine warrant screening for POLG mutations. In this clinical setting, valproate should not be given in view of the risk of fatal hepatotoxicity. PMID- 26104465 TI - Suspected cancer (part 2--adults): reference tables from updated NICE guidance. PMID- 26104466 TI - Importance of lipid accumulation product index as a marker of CVD risk in PCOS women. AB - BACKGROUND: The polycystic ovary syndrome (PCOS) is considered the most common endocrine disease during the woman's reproductive life, with prevalence ranging from 5 to 10% of women of reproductive age. There is a paucity of studies regarding the use of the lipid accumulation product (LAP) as a risk marker for the development of cardiovascular disease (CVD). METHODS: A cross-sectional study was conducted on 78 women aged 18 to 42 years seen at University Hospital of Maranhao, with a diagnosis of polycystic ovary syndrome according to the Rotterdam criteria. The following variables of interest were recorded on a protocol form: sociodemographic and behavioral data, body mass index, waist circumference, fasting glucose, total cholesterol, triglycerides, low density lipoprotein cholesterol, high-density lipoprotein cholesterol, and systolic and diastolic blood pressure. RESULTS: Logistic regression showed that, except for HDL, all cardiovascular risk markers presented a higher chance of being altered when the lipid accumulation product was above the cut off value of 37.9 cm.mmol/L. CONCLUSION: The lipid accumulation product seems to be sufficient to indicate a risk of cardiovascular diseases in women with polycystic ovary syndrome. PMID- 26104467 TI - Histone modifications predispose genome regions to breakage and translocation. AB - Chromosome translocations are well-established hallmarks of cancer cells and often occur at nonrandom sites in the genome. The molecular features that define recurrent chromosome breakpoints are largely unknown. Using a combination of bioinformatics, biochemical analysis, and cell-based assays, we identify here specific histone modifications as facilitators of chromosome breakage and translocations. We show enrichment of several histone modifications over clinically relevant translocation-prone genome regions. Experimental modulation of histone marks sensitizes genome regions to breakage by endonuclease challenge or irradiation and promotes formation of chromosome translocations of endogenous gene loci. Our results demonstrate that histone modifications predispose genome regions to chromosome breakage and translocations. PMID- 26104468 TI - Adjuvant chemo-radiotherapy in the "sandwich" method for high risk endometrial cancer--a review of literature. AB - BACKGROUND: Endometrial cancer is a common female malignancy. Patients with high risk endometrial cancer have relatively high incidence of metastasis and recurrence. Despite complete resection, patients with stage III or IV are at high risk of local or distant recurrence. Systemic adjuvant treatment includes chemotherapy and radiotherapy. But the optimal scheduling is not known. Recently proposed sequential chemo-radiotherapy as sandwich therapy for high risk endometrial cancer have yielded encouraging results. This article is to review the adjuvant chemo-radiotherapy in the "sandwich" method for high risk endometrial cancer to help clinicians identify the most effective adjuvant treatment for patients with high risks of it. METHODS: We used MEDLINE, EMBASE, Cochrane Library and CBM databases to search the literature. RESULTS: A systematic review was made. And most data showed "sandwich" therapy is feasible, efficacious, well-tolerated and resulted in excellent long-term progression free and overall survival in the setting of advanced endometrial cancer. CONCLUSION: Randomized trials are necessary to compare chemo-radio therapy given in the "sandwich" fashion to other means of sequencing these treatment modalities. It is also necessary to define which population is best suited for "sandwich" adjuvant therapy. PMID- 26104469 TI - The recursive combination filter approach of pre-processing for the estimation of standard deviation of RR series. AB - Variation in the interval between the R-R peaks of the electrocardiogram represents the modulation of the cardiac oscillations by the autonomic nervous system. This variation is contaminated by anomalous signals called ectopic beats, artefacts or noise which mask the true behaviour of heart rate variability. In this paper, we have proposed a combination filter of recursive impulse rejection filter and recursive 20% filter, with recursive application and preference of replacement over removal of abnormal beats to improve the pre-processing of the inter-beat intervals. We have tested this novel recursive combinational method with median method replacement to estimate the standard deviation of normal to normal (SDNN) beat intervals of congestive heart failure (CHF) and normal sinus rhythm subjects. This work discusses the improvement in pre-processing over single use of impulse rejection filter and removal of abnormal beats for heart rate variability for the estimation of SDNN and Poncare plot descriptors (SD1, SD2, and SD1/SD2) in detail. We have found the 22 ms value of SDNN and 36 ms value of SD2 descriptor of Poincare plot as clinical indicators in discriminating the normal cases from CHF cases. The pre-processing is also useful in calculation of Lyapunov exponent which is a nonlinear index as Lyapunov exponents calculated after proposed pre-processing modified in a way that it start following the notion of less complex behaviour of diseased states. PMID- 26104470 TI - Length of stay and long-term mortality following ST elevation myocardial infarction. AB - BACKGROUND: Over the last few decades, there has been a significant reduction in hospital length of stay (LOS) among patients undergoing percutaneous intervention (PCI) for ST elevation myocardial infarction (STEMI). Although studies have looked at predictors of long hospital stay after STEMI, the impact of LOS on long term outcomes after PCI remains unknown. We aimed to evaluate the association between LOS at the time of index hospitalization for PCI and long-term mortality among patients presenting with STEMI. METHODS: We examined all patients undergoing PCI for STEMI at the Cleveland Clinic Catheterization Laboratory between 2002 and 2011. Long-term all-cause mortality was assessed using the Social Security Death Index and electronic medical record review. LOS was extracted from the discharge summary of the index hospitalization. RESULTS: A total of 1,963 patients were included in the study. Of these 1,963 patients undergoing PCI for STEMI, 126 (6.4%) died during the index hospitalization. Among survivors of this hospitalization, we observed a significant increase in long term mortality with an increase in LOS during index hospitalization (P < 0.001). Adjustment for demographic and clinical characteristics yielded statistically significant increased mortality among patients with LOS of 6-10 days [HR (95% CI): 2.2 (1.3-3.5)] and LOS > 10 days [HR (95% CI): 2.6 (1.6-4.3)], in comparison with patients with LOS of 1-2 days. CONCLUSIONS: Long hospital stay after PCI among patients with STEMI was associated with an increased long-term mortality. A long hospital stay may be used as a marker to identify patients at higher risk for long-term mortality. PMID- 26104472 TI - Changes in verbal learning of patients with schizophrenia: Results from a randomized, double-blind, placebo-controlled trial of amantadine adjunctive to antipsychotics. PMID- 26104474 TI - Investigation of the dynamics of the viral immediate-early protein 1 in different conformations and oligomerization states. AB - The viral immediate-early protein 1 (IE1) is crucial for efficient replication of cytomegalovirus (CMV). A recent crystal structure of the IE1 protein from rhesus CMV revealed that the protein exhibits a novel fold and crystallizes in two slightly different dimeric arrangements. Molecular dynamics simulations and energetic analyses performed in this study show that both dimers are stable and allowed us to identify a common set of five residues that appear particularly important for dimer formation. These residues are distributed over the entire dimer interface and do not form a typical hot spot for protein interactions. In addition, the dimer interface of IE1 proved to include a high portion of hydrophilic interactions pointing toward the transient nature of dimer formation. Characterization of monomeric and dimeric IE1 revealed three sequentially discontinuous dynamic domains that exhibit correlated motion within the domain and are simultaneously anti-correlated to the adjacent domains. The hinge motions observed between the dynamic domains increase the shape complementarity to the coiled-coil region of tripartite motif proteins, suggesting that the detected dynamics of IE1 might be physiologically important by enabling a better interaction with its cellular target molecules. PMID- 26104473 TI - Abnormal N-acetylglucosaminyltransferase expression in prefrontal cortex in schizophrenia. AB - Changes in the extent of the posttranslational modification glycosylation have been previously reported in several brain regions in schizophrenia. Quality control within the endoplasmic reticulum and Golgi, branching of glycans, intracellular trafficking and targeting, protein-protein interactions, and endocytosis are processes regulated by both N-linked and O-linked glycosylation. Previous studies in schizophrenia have found altered glycan biosynthesis and abnormal glycan levels in cerebrospinal fluid (CSF) and plasma, as well as altered expression in frontal cortex of glycosyltransferase transcripts encoding proteins associated with both N- and O-linked glycosylation. The N acetylglucosaminyltransferases (GlcNAcTs) are glycosylating enzymes that play a key role in adding N-acetylglucosamine (GlcNAc) to substrates to facilitate their proper trafficking, intracellular targeting, and cellular function. Given previous results indicating abnormal glycosylation in schizophrenia, we hypothesized that these GlcNAcTs may be abnormally expressed in this illness. We measured protein expression of nine distinct GlcNAcTs by Western blot analysis in postmortem samples of dorsolateral prefrontal cortex (DLPFC) from twelve pairs of elderly patients with schizophrenia and comparison subjects. We found decreased protein expression of UDP-GlcNAc:BetaGal Beta-1,3 GlcNAcT 8 (B3GNT8) and mannosyl (alpha-1,3-)-glycoprotein beta-1,4 GlcNAcT (MGAT4A) expression in schizophrenia. These data provide further evidence that glycosylation is dysregulated in schizophrenia, and suggest a potential mechanism associated with alterations in protein function, trafficking, and intracellular targeting in this illness. PMID- 26104471 TI - Individual-patient meta-analysis of three randomized trials comparing endovascular versus open repair for ruptured abdominal aortic aneurysm. AB - BACKGROUND: The benefits of endovascular repair of ruptured abdominal aortic aneurysm remain controversial, without any strong evidence about advantages in specific subgroups. METHODS: An individual-patient data meta-analysis of three recent randomized trials of endovascular versus open repair of abdominal aortic aneurysm was conducted according to a prespecified analysis plan, reporting on results to 90 days after the index event. RESULTS: The trials included a total of 836 patients. The mortality rate across the three trials was 31.3 per cent for patients randomized to endovascular repair/strategy and 34.0 per cent for those randomized to open repair at 30 days (pooled odds ratio 0.88, 95 per cent c.i. 0.66 to 1.18), and 34.3 and 38.0 per cent respectively at 90 days (pooled odds ratio 0.85, 0.64 to 1.13). There was no evidence of significant heterogeneity in the odds ratios between trials. Mean(s.d.) aneurysm diameter was 8.2(1.9) cm and the overall in-hospital mortality rate was 34.8 per cent. There was no significant effect modification with age or Hardman index, but there was indication of an early benefit from an endovascular strategy for women. Discharge from the primary hospital was faster after endovascular repair (hazard ratio 1.24, 95 per cent c.i. 1.04 to 1.47). For open repair, 30-day mortality diminished with increasing aneurysm neck length (adjusted odds ratio 0.69 (95 per cent c.i. 0.53 to 0.89) per 15 mm), but aortic diameter was not associated with mortality for either type of repair. CONCLUSION: Survival to 90 days following an endovascular or open repair strategy is similar for all patients and for the restricted population anatomically suitable for endovascular repair. Women may benefit more from an endovascular strategy than men and patients are, on average, discharged sooner after endovascular repair. PMID- 26104475 TI - A Muscular Etiology for Medial Implant Malposition Following Subpectoral Augmentation. AB - BACKGROUND: Implant malposition is becoming an increasingly recognized complication following subpectoral breast augmentation. Although several causes of medial malposition have been previously demonstrated, medial implant malposition secondary to unintended pectoralis muscle slips has not been previously described. OBJECTIVE: The goal of this study is to describe a form of medial implant malposition caused by pectoralis major and minor musculature vectors on the implant. METHODS: The primary investigator performed a retrospective review of all patients who underwent revisional breast surgery for the diagnosis of symmastia or medial implant malposition following subpectoral augmentation. Those patients with muscular-type etiology for medial implant malposition were identified. RESULTS: Five patients with pectoralis muscle slips causing medial implant malposition were identified. The pectoralis muscle slips were successfully diagnosed on preoperative exam and corrected with specific surgical procedures aimed at balancing surrounding forces and thus correcting malposition. CONCLUSIONS: Pectoralis muscle slips contributing to medial malposition can be found in some patients after subpectoral breast augmentation. The etiology of this deformity is unknown, but theorized to be caused by anatomic predisposition, with slips inadvertently formed during subpectoral pocket formation arising from the pectoralis minor and/or incompletely released or accessory pectoralis major muscles. PMID- 26104476 TI - Shared Decision-Making in Cosmetic Medicine and Aesthetic Surgery. AB - Shared decision-making (SDM) invokes the bidirectional communication between physicians and patients required to involve the patient's preference in the eventual treatment choice. This paper will explain what SDM is, why it is important, and how it is performed in clinical practice. It is an essential part of evidence-based medicine, as it helps determine whether the available evidence on the possible benefits and harms of treatment options match the patient's characteristics and preferences. Cosmetic medicine and aesthetic surgery seem to be obvious fields of medicine in which SDM should be applied to achieve high quality care. PMID- 26104477 TI - Transaxillary endoscopic breast augmentation with shaped gel implants. AB - BACKGROUND: At its inception, transaxillary breast augmentation was a blind technique associated with complications and unpredictable outcomes. The transaxillary approach now involves electrocautery dissection with direct endoscopic visualization and yields excellent aesthetic outcomes with a concealed scar. Shaped implant devices can be combined with transaxillary augmentation for natural-appearing results that can be individualized to the patient. OBJECTIVES: The authors sought to improve the results of transaxillary endoscopic breast augmentation by placing shaped gel implants in patients with an indistinct or absent inframammary fold (IMF), who wished to avoid a breast scar. METHODS: One hundred sixteen Asian women underwent transaxillary endoscopic breast augmentation with electrocautery dissection and were evaluated in a prospective study. A partial retropectoral plane pocket was created in 4 sequential dissection steps with direct endoscopic visualization and careful control of bleeding. Shaped cohesive gel implants were placed to produce smooth, natural appearing breast mounds and well-defined IMFs. RESULTS: Patients were monitored for 6 to 24 months after surgery (mean, 10 months; median, 12 months). There were no instances of pneumothorax, instrument-related skin burns, or severe implant deformation due to rotation or displacement of the implants postoperatively. Three of 116 patients (2.6%) experienced Baker 3 unilateral capsular contracture. One patient developed a unilateral hematoma at 3 weeks after surgery. CONCLUSIONS: Endoscopic breast surgery is associated with shortened recovery times, a reduced need for drainage, and excellent outcomes, including a well defined and symmetric IMF. This approach, combined with shaped gel implants, can yield natural-appearing results of transaxillary breast augmentation. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26104478 TI - Molecular characterisation of the tick Rhipicephalus microplus in Malaysia: new insights into the cryptic diversity and distinct genetic assemblages throughout the world. AB - BACKGROUND: The morphotaxonomy of Rhipicephalus microplus complex has been challenged in the last few years and prompted many biologists to adopt a DNA based method for distinguishing the members of this group. In the present study, we used a mitochondrial DNA analysis to characterise the genetic assemblages, population structure and dispersal pattern of R. microplus from Southeast Asia, the region where the species originated. METHODS: A phylogeographic analysis inferred from the 16S rRNA and cytochrome oxidase subunit I (COI) genes was performed with five populations of R. microplus collected from cattle in Malaysia. Malaysian R. microplus sequences were compared with existing COI and 16S rRNA haplotypes reported globally in NCBI GenBank. RESULTS: A total of seven and 12 unique haplotypes were recovered by the 16S rRNA and COI genes, respectively. The concatenated sequences of both 16S rRNA and COI revealed 18 haplotypes. Haplotype network and phylogenetic analyses based on COI+16S rRNA sequences revealed four genetically divergent groups among Malaysian R. microplus. The significantly low genetic differentiation and high gene flow among Malaysian R. microplus populations supports the occurrence of genetic admixture. In a broader context, the 16S rRNA phylogenetic tree assigned all isolates of Malaysian R. microplus into the previously described African/the Americas assemblage. However, the COI phylogenetic tree provides higher resolution of R. microplus with the identification of three main assemblages: clade A sensu Burger et al. (2014) comprises ticks from Southeast Asia, the Americas and China; clade B sensu Burger et al. (2014) is restricted to ticks that originated from China; and clade C sensu Low et al. (2015) is a new genetic assemblage discovered in this study comprising ticks from India and Malaysia. CONCLUSIONS: We conclude that the R. microplus complex consisting of at least five taxa: R. australis, R. annulatus, R. microplus clade A sensu Burger et al. (2014), R. microplus clade B sensu Burger et al. (2014) and the new taxon, R. microplus clade C sensu Low et al. (2015). The use of COI as the standard genetic marker in discerning the genetic assemblages of R. microplus from a broad range of biogeographical regions is proposed. PMID- 26104479 TI - Review of clinical and pathological features of 93 cases of well-differentiated thyroid carcinoma in pediatric age at the Lisbon Centre of the Portuguese Institute of Oncology between 1964 and 2006. AB - INTRODUCTION: Thyroid carcinoma is the most common endocrine malignancy. In childhood, thyroid carcinoma usually behaves aggressively and relapses frequently. Nevertheless, it has a favorable prognosis. Our aim is to present our experience with pediatric well-differentiated thyroid carcinoma (WDTC) treated at the Portuguese Institute of Oncology in Lisbon (L-PIO), between 1964 and 2006. METHODS: Review of clinical files of WDTC in<=18-year-old patients selected from the databases of the Endocrinology Service of L-PIO and the South Portugal Regional Cancer Registry (SPCR). RESULTS: 93 cases of WDTC were found. Of these, 70 (75.3%) were girls. The median age was 15 years old (range 5-18) with a median follow-up time of 15.1 years (range 0.2-47.8). The most common histological diagnosis was papillary carcinoma of the classical variant (n=60, 64.5%). Initial staging showed locoregional dissemination in 27 (29.0%) patients and distant metastasis in 16 (17.2%) patients. Median age was lower in patients with distant disease than in patients with locoregional disease or with disease confined to the thyroid (P=0.007). After the initial treatment, 44 (47.3%) patients were in remission and 46 (49.5%) had persistent disease (lost follow-up in 3). Of the disease-free patients after initial treatment, 11 (25.0%) relapsed later. At the last observation, most patients (n=63, 67.7%) showed no evidence of disease. CONCLUSION: Our study demonstrates that children with distant metastatic disease are younger than children with a less aggressive disease. However, in both groups the response to treatment is favorable and the prognosis is usually excellent. PMID- 26104480 TI - Tinnitus reported by children aged 7 and 12 years. AB - OBJECTIVES: To assess prevalence and risk factors of tinnitus reported by 7- and 12-year-old children from primary schools in Warsaw. A secondary objective was to test the relationship between hearing loss and tinnitus prevalence. METHODS: Observational cross-sectional study of 15,199 students aged 7 and 12 years (66.9% of the students of those ages) from all 173 public primary schools in Warsaw in the school year 2012/13. Audiometric hearing threshold levels were determined for the right and left ear of each student at frequencies of 0.5, 1, 2, 4, and 8kHz. Normal hearing was defined as air threshold values of 20dB HL or less for all tested frequencies. Unilateral and bilateral hearing loss cases were included into the analysis. Tinnitus experience was assessed with an audiological questionnaire administered verbally to the children. RESULTS: Overall 6.0% of the 7- and 12-year-old students reported tinnitus lasting for 5min or more. The prevalence of tinnitus was significantly related to the hearing loss and age. Children with the unilateral high-frequency hearing loss reported tinnitus significantly less often compared to other children from the unilateral loss group. Children with bilateral moderate hearing loss reported tinnitus significantly more often than other children from the bilateral hearing loss group. Frequency of tinnitus reported by children was equal between the sexes and also between the children with unilateral and bilateral hearing loss. CONCLUSION: Results obtained in this study with a large sample suggest that hearing loss and young age can be considered potential risk factors for tinnitus in school-age children. A consensus on how to define tinnitus is needed in order to enable direct comparison between data from different studies. PMID- 26104481 TI - Extraosseous chondroma of anterior neck in pediatric patient. AB - Extraosseous chondroma (EC) is uncommon soft tissue tumor composed of hyaline cartilage without connection to bone or periosteum. The frequent sites of EC are the hands and feet and rarely reported in the pediatric population and anterior neck lesion. We present an extremely rare case of anterior neck mass in a 5-year old male who underwent total resection, with the final diagnosis of EC. The review of the literature showed that all cases of EC in anterior neck lesion have been found in young age and preoperative diagnosis was difficult. PMID- 26104482 TI - Dynamic imaging of a single gold nanoparticle in liquid irradiated by off resonance femtosecond laser. AB - Plasmonic nanoparticles can lead to extreme confinement of the light in the near field. This unique ability of plasmonic nanoparticles can be used to generate nanobubbles in liquid. In this work, we demonstrate with single-particle monitoring that 100 nm gold nanoparticles (AuNPs) irradiated by off-resonance femtosecond (fs) laser in the tissue therapeutic optical window (lambda = 800 nm), can act as a durable nanolenses in liquid and provoke nanocavitation while remaining intact. We have employed combined ultrafast shadowgraphic imaging, in situ dark field imaging and dynamic tracking of AuNP Brownian motion to ensure the study of individual AuNPs/nanolenses under multiple fs laser pulses. We demonstrate that 100 nm AuNPs can generate multiple, highly confined (radius down to 550 nm) and transient (life time < 50 ns) nanobubbles. The latter is of significant importance for future development of in vivo AuNP-assisted laser nanosurgery and theranostic applications, where AuNP fragmentation should be avoided to prevent side effects, such as cytotoxicity and immune system's response. The experimental results have been correlated with theoretical modeling to provide an insight to the AuNP-safe cavitation mechanism as well as to investigate the deformation mechanism of the AuNPs at high laser fluences. PMID- 26104483 TI - HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese patients: a multicentre retrospective case control clinical study. PMID- 26104485 TI - Effects of priming self-construals on self-evaluations: Cultural game player perspective. AB - This study examined the validity of situational view on culture-specific behaviours focusing on self-evaluation. Two experiments with American students as samples were conducted to examine whether priming their self-construals would affect individuals' self-evaluation. In Experiment 1, the participants' self evaluation was compared across different conditions of primed self-contruals. In Experiment 2, the participants were split into 2 groups based on their initial default self-consturals and, the self-evaluations were compared across the 2 groups after priming self-contruals. The results demonstrated that although the participants' self-evaluation was initially in accord with their default self construal, it changed into accord with the primed self-construals. The findings supported the proposed cultural game player view. Implications on situational view of self-evaluation are also discussed. PMID- 26104484 TI - Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. AB - TLR2 promotes NLRP3 inflammasome activation via an early MyD88-IRAK1-dependent pathway that provides a priming signal (signal 1) necessary for activation of the inflammasome by a second potassium-depleting signal (signal 2). Here we show that TLR3 binding to dsRNA promotes post-translational inflammasome activation through intermediate and late TRIF/RIPK1/FADD-dependent pathways. Both pathways require the scaffolding but not the catalytic function of caspase-8 or RIPK1. Only the late pathway requires kinase competent RIPK3 and MLKL function. Mechanistically, FADD/caspase-8 scaffolding function provides a post-translational signal 1 in the intermediate pathway, whereas in the late pathway it helps the oligomerization of RIPK3, which together with MLKL provides both signal 1 and 2 for inflammasome assembly. Cytoplasmic dsRNA activates NLRP3 independent of TRIF, RIPK1, RIPK3 or mitochondrial DRP1, but requires FADD/caspase-8 in wildtype macrophages to remove RIPK3 inhibition. Our study provides a comprehensive analysis of pathways that lead to NLRP3 inflammasome activation in response to dsRNA. PMID- 26104487 TI - Synthesis and reactivity of TADDOL-based chiral Fe(II) PNP pincer complexes solution equilibria between kappa(2)P,N- and kappa(3)P,N,P-bound PNP pincer ligands. AB - Treatment of anhydrous FeX2 (X = Cl, Br) with 1 equiv. of the asymmetric chiral PNP pincer ligands PNP-R,TAD (R = iPr, tBu) with an R,R-TADDOL (TAD) moiety afforded complexes of the general formula [Fe(PNP)X2]. In the solid state these complexes adopt a tetrahedral geometry with the PNP ligand coordinated in kappa(2)P,N-fashion, as shown by X-ray crystallography and Mossbauer spectroscopy. Magnetization studies led to a magnetic moment very close to 4.9MUB reflecting the expected four unpaired d-electrons (quintet ground state). In solution there are equilibria between [Fe(kappa(3)P,N,P-PNP-R,TAD)X2] and [Fe(kappa(2)P,N-PNP-R,TAD)X2] complexes, i.e., the PNP-R,TAD ligand is hemilabile. At -50 degrees C these equilibria are slow and signals of the non coordinated P-TAD arm of the kappa(2)P,N-PNP-R,TAD ligand can be detected by (31)P{(1)H} NMR spectroscopy. Addition of BH3 to a solution of [Fe(PNP iPr,TAD)Cl2] leads to selective boronation of the pendant P-TAD arm shifting the equilibrium towards the four-coordinate complex [Fe(kappa(2)P,N-PNP iPr,TAD(BH3))Cl2]. DFT calculations corroborate the existence of equilibria between four- and five-coordinated complexes. Addition of CO to [Fe(PNP iPr,TAD)X2] in solution yields the diamagnetic octahedral complexes trans [Fe(kappa(3)P,N,P-PNP-iPr,TAD)(CO)X2], which react further with Ag(+) salts in the presence of CO to give the cationic complexes trans-[Fe(kappa(3)P,N,P-PNP iPr,TAD)(CO)2X](+). CO addition most likely takes place at the five coordinate complex [Fe(kappa(3)P,N,P-PNP-iPr,TAD)X2]. The mechanism for the CO addition was also investigated by DFT and the most favorable path obtained corresponds to the rearrangement of the pincer ligand first from a kappa(2)P,N- to a kappa(3)P,N,P coordination mode followed by CO coordination to [Fe(kappa(3)P,N,P-PNP iPr,TAD)X2]. Complexes bearing tBu substituents do not react with CO. Moreover, in the solid state none of the tetrahedral complexes are able to bind CO. PMID- 26104486 TI - The role of evolutionarily conserved germ-line DH sequence in B-1 cell development and natural antibody production. AB - Because of N addition and variation in the site of VDJ joining, the third complementarity-determining region of the heavy chain (CDR-H3) is the most diverse component of the initial immunoglobulin antigen-binding site repertoire. A large component of the peritoneal cavity B-1 cell component is the product of fetal and perinatal B cell production. The CDR-H3 repertoire is thus depleted of N addition, which increases dependency on germ-line sequence. Cross-species comparisons have shown that DH gene sequence demonstrates conservation of amino acid preferences by reading frame. Preference for reading frame 1, which is enriched for tyrosine and glycine, is created both by rearrangement patterns and by pre-BCR and BCR selection. In previous studies, we have assessed the role of conserved DH sequence by examining peritoneal cavity B-1 cell numbers and antibody production in BALB/c mice with altered DH loci. Here, we review our finding that changes in the constraints normally imposed by germ-line-encoded amino acids within the CDR-H3 repertoire profoundly affect B-1 cell development, especially B-1a cells, and thus natural antibody immunity. Our studies suggest that both natural and somatic selection operate to create a restricted B-1 cell CDR-H3 repertoire. PMID- 26104488 TI - Vascular precursor epilepsy - Old wine in new skins? PMID- 26104489 TI - Tuberous Sclerosis Complex: State-of-the-Art Review with a Focus on Pulmonary Involvement. AB - Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disease with high phenotypic variability. The incidence is approximately one in 5000 10,000 births. TSC is characterized by widespread hamartomas and benign or rarely malignant neoplasms affecting various organs, most commonly the brain, skin, retinas, kidneys, heart, and lungs. The wide range of organs affected reflects the roles of TSC1 and TSC2 genes in the regulation of cell proliferation and differentiation. Clinical diagnostic criteria are important because genetic testing does not identify the mutation in up to 25% of patients. Imaging is pivotal, as it allows a presumptive diagnosis of TSC and definition of the extent of the disease. Common manifestations of TSC include cortical tubers, subependymal nodules, white matter abnormalities, retinal abnormalities, cardiac rhabdomyoma, lymphangioleiomyomatosis (LAM), renal angiomyolipoma, and skin lesions. Pulmonary involvement consists of LAM and, less commonly, multifocal micronodular pneumocyte hyperplasia (MMPH), which causes cystic and nodular diseases, respectively. Recent reports indicate that pulmonary LAM is found by computed tomography in up to 35% of the female patients with TSC. MMPH is rare and may be associated with LAM or, less frequently, occurs as an isolated pulmonary manifestation in women with TSC. Dyspnea and pneumothorax are common clinical presentations of LAM, whereas MMPH is usually asymptomatic. The aim of this review is to describe the main clinical, imaging, and pathological aspects of TSC, with a focus on pulmonary involvement. PMID- 26104491 TI - A Giant Cell Tumor Arising from the Anterior Costal Arc in a Young Man. PMID- 26104490 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia of the Lung (DIPNECH): Current Best Evidence. AB - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is recognized as a preneoplastic condition by the World Health Organization. We reviewed our experience with 30 patients and performed a systematic review of the English literature to collect best evidence on the clinical features and disease course in 169 additional patients. Some patients presented with one or more carcinoid tumors associated with multiple small pulmonary nodules on imaging studies and showed DIPNECH as a somewhat unexpected pathologic finding. Others presented with multiple small pulmonary nodules that raised suspicion of metastatic disease on imaging. A third subset was presented with previously unexplained respiratory symptoms. In most patients, DIPNECH was associated with a good prognosis, with chronological progression into a subsequent carcinoid tumor noted in only one patient and death attributed directly to DIPNECH in only two patients. There is no best evidence to support the use of octreotide, steroids, or bronchodilators in DIPNECH patients. PMID- 26104492 TI - sFlt-1 and IP-10 in women with early-onset preeclampsia. AB - Intense inflammatory response and an anti-angiogenic state have been implicated in the pathogenesis of preeclampsia. Here, we investigated this hypothesis evaluating the serum concentrations of CXCL10/IP-10, sFlt-1, and PlGF in women with early-onset preeclampsia. CXCL10/IP-10 was measured by Cytometric Bead Array. sFlt-1 and PlGF were measured by automated electrochemiluminescence immunoassay. The median serum concentration of CXCL10/IP-10 was 109.5pg/mL in preeclamptic women, as compared with 52.28pg/mL in the controls (P=0.0028). The mean serum level of sFlt-1 was 13,636pg/mL in preeclamptic women, as compared with 2020pg/mL in the controls (P<0.0001). PlGF levels were significantly lower in women with preeclampsia. PMID- 26104493 TI - Clinical symptoms and laboratory parameters do not predict adverse maternal and fetal outcomes in HELLP. AB - AIM: To determine the ability of clinical symptoms and laboratory parameters to predict adverse outcomes in HELLP syndrome. METHODS: A retrospective chart analysis of pregnant women diagnosed with HELLP during a 5year (2005-2009) period at a tertiary care perinatal center. The diagnosis of HELLP was based on Sibai's criteria and categorized based on the Mississippi classification. Clinical symptoms and the presence of maternal and fetal adverse events were noted from the records. Receiver operator characteristics, likelihood ratios and adjusted odds ratios were used to determine the predictive ability of clinical symptoms and laboratory parameters. RESULTS: The medical records of 74 pregnant women with HELLP were analyzed. Any adverse (maternal and/or fetal) event was present in 40 (54.1%, 95% CI: 42.4%, 65.7%) pregnancies with HELLP syndrome in this population. One in four pregnancies with HELLP resulted in an adverse maternal event and 35% of pregnancies with HELLP in an adverse fetal event. There were no maternal deaths in this series and the perinatal mortality rate was 149 per 1000 births. Clinical symptoms or laboratory parameters were not predictive of adverse events. CONCLUSIONS: Further research is needed to identify factors that can predict adverse perinatal outcomes in HELLP. PMID- 26104494 TI - Plasma calprotectin as inflammation marker in pregnancies complicated by diabetes mellitus and superimposed preeclampsia. AB - OBJECTIVE: We hypothesized that pregnancies complicated by diabetes mellitus with or without preeclampsia show an elevated systemic inflammatory response evaluated by the inflammation markers calprotectin and high-sensitivity C-reactive protein (hsCRP). STUDY DESIGN: Third trimester EDTA plasma and serum from 138 women with diabetes mellitus (type 1, n=53; type 2, n=11; gestational diabetes mellitus (GDM), n=63; diabetes mellitus with preeclampsia, n=11) were analyzed for calprotectin and hsCRP and compared to previously published results from 37 healthy and 27 preeclamptic pregnancies. RESULTS: Median plasma calprotectin concentration was intermediate in women with GDM as compared to healthy and preeclamptic pregnancies (729 vs 552 and 1081MUg/L, P=.006 and P=.001, respectively). In diabetic pregnancies with preeclampsia, median plasma calprotectin concentration was elevated as compared to controls, but not different from women with preeclampsia alone (969 vs 552 and 1081MUg/L, P=.01 and P=.1, respectively). hsCRP was only elevated in type 2 diabetic pregnancies as compared to healthy pregnancies (6.6 vs 3.8mg/L, P=.02). CONCLUSION: Elevated plasma calprotectin concentrations in GDM may reflect an accentuated inflammatory process, possibly contributing to the augmented preeclampsia risk. Increased plasma calprotectin in diabetic pregnancies with preeclampsia may originate from the excess systemic inflammatory response associated with preeclampsia. PMID- 26104495 TI - S100B brain expression and plasma concentrations in a preeclampsia rat model. AB - OBJECTIVE: To assess brain damage using the neuroinflammation marker S100B in a preeclampsia rat model. METHODS: Non-pregnant and pregnant rats were infused with saline or low-dose-endotoxin on day 14 of pregnancy. S100B expression in the brain (immunohistochemistry) and S100B plasma concentrations (ELISA) were studied. RESULTS: No differences in S100B expression in brain tissue were observed between the four groups. Pregnant endotoxin treated animals did not show increased levels of plasma S100B levels as compared with control pregnant rats, while significantly higher plasma S100B levels were found in non-pregnant endotoxin versus pregnant endotoxin infused rats. CONCLUSION: Pregnancy nor experimental preeclampsia, alter S100B in rat brain, or in plasma. Increased plasma S100B in non-pregnant endotoxin-treated rats may indicate brain injury in these rats, whereas pregnancy might be protective. PMID- 26104496 TI - Homocysteine and folate plasma concentrations in mother and baby at delivery after pre-eclamptic or normotensive pregnancy: Influence of parity. AB - Pre-eclampsia affects between 2% and 7% of all pregnant women, contributing to perinatal and maternal morbidity. There are conflicting data on plasma homocysteine and folate in pre-eclampsia, and little about fetal concentrations. OBJECTIVES: Firstly, to compare the concentrations of homocysteine and folate in maternal and paired fetal (umbilical venous) plasma samples from normotensive or pre-eclamptic pregnancies at delivery; secondly, to identify any effect of parity on these concentrations. STUDY DESIGN: Hospital based cross-sectional study consisting of 24 normotensive and 16 pre-eclamptic pregnant White European women from whom maternal and fetal plasma samples were collected at delivery. MAIN OUTCOME MEASURES: Maternal and fetal plasma homocysteine and folate concentrations between normotensive and pre-eclamptic pregnancies with varying parity. RESULTS: There were no significant differences in either maternal or fetal plasma homocysteine or folate concentrations between normotensive and pre eclamptic pregnancies, or between homocysteine and folate. In both the normotensive and pre-eclamptic women, plasma folate concentration was higher in paired fetal compared to maternal plasma (P<0.001 and P=0.047, respectively). With regards to homocysteine, only the normotensive samples had higher fetal concentrations (P=0.002). Both maternal and fetal plasma folate concentrations were lower in parous women (P=0.001 and P=0.017, respectively), the lowest concentrations being in pre-eclamptic parous women (P=0.004), but homocysteine concentrations were similar (P>0.4 for both). CONCLUSIONS: The low plasma folate in parous women is an interesting finding and, when intake is also low, may contribute to adverse pregnancy outcomes, particularly in relation to pre eclampsia. PMID- 26104497 TI - Influence of the couple on hypertensive disorders during pregnancy: A retrospective cohort study. AB - OBJECTIVE: Our study investigates a possible couple predisposition for pregnancy related hypertensive disorders (PRHDs). MATERIALS AND METHODS: We selected 350 women with PRHDs and a random control cohort without PRHDs. We analyzed their clinical files and asked them and their partners about clinical information and family history for some common pathologies. Statistical bivariate and multivariate analysis was performed by R, considering significant p<0.05. RESULTS: Familial history reveals in cases more maternal grandparents hypertension and thrombophilia, and paternal, personal and familial, thrombophilia history than in controls. By multivariate analysis, the occurrence of PRHDs is influenced by stress, maternal BMI, maternal chronic hypertension, pre-pregnancy diabetes mellitus, nulliparity, maternal grandmother and grandfather hypertension; and academic degrees is a protective factor. Selecting only multipara, PRHDs correlate with advanced maternal age, higher maternal BMI, chronic hypertension, longer interpregnancy interval, stress, previous pregnancies affected by PRHDs, and paternal, personal and familial, thrombophilia history. Moreover the multivariate logistic regression models considering parents familial and personal history results are accurate to predict PRHDs with an AUC of 79% in the general population and 82% among multiparous women. CONCLUSIONS: The couple should be evaluated together for PRHDs risk, both parents familial history should be considered in PRHDs screening programs, and further studies are required, in a society continuously changing its characteristics and habits. PMID- 26104498 TI - The HELLP syndrome (hemolysis, elevated liver enzymes and low platelets): Clinical characteristics and maternal-fetal outcome in 172 patients. AB - OBJECTIVES: To analyze the frequency of the different clinical presentations of the disease in women with HELLP syndrome and the most important factors that can predict a different maternal and fetal outcome. STUDY DESIGN: This is a cross sectional, consecutive, case-series study, the subjects being all patients with HELLP syndrome admitted to our Hospital within the last decade (1999-2009). RESULTS: The rate of maternal complications was 43.0% and perinatal mortality 14.1%. The severity of the syndrome, measured by The Mississippi Classification, influenced the rate of maternal complications but not fetal mortality: the rate of maternal complications among women in class 1 HELLP syndrome was 67.6%, compared to 49.3% in class 2 and 24.0% in class 3 HELLP syndrome, p<0.0001. In a 21.8% of women, the onset of the disease was after delivery. We highlight the fact that those cases with an early puerperium onset of the disease were those with a higher number of maternal complications (odds ratio: 2.38; CI: 1.05-5.44). CONCLUSIONS: These results suggest the possibility of an increased complication rate when the onset of the syndrome appears after delivery and the necessity of having a high grade of suspicion in every case to diagnose the disease, even when the gestation and delivery were normal. PMID- 26104499 TI - Apoptosis and proliferation in first trimester trophoblast of further complicated and uncomplicated pregnancies related to maternal serum screening markers. AB - INTRODUCTION: Differences in proliferation and apoptosis in term trophoblast as well as maternal serum markers (MSM) for Down's syndrome in early pregnancy are related to adverse pregnancy outcomes. We investigated proliferation and apoptosis in first trimester chorionic villous sampling (CVS) as well as MSM and related these to pregnancy outcome. MATERIALS AND METHODS: We selected 51 samples of first trimester chorionic villi of pregnancies later complicated by hypertensive disorders (HD) (n=36) and intra-uterine growth restriction (IUGR) (n=15) with matched controls. Immunohistochemistry (cleaved caspase-3 for apoptosis and MIB-1 for proliferation) was performed. Apoptosis- (AI) and proliferation-index (PI) were determined and proliferation-apoptosis index (PA) was calculated by PI/AI. First trimester serum screening (n=39), samples taken at the time of CVS (n=108) or regular second trimester serum screening samples (n=99) were examined. RESULTS: The IUGR group compared to the hypertensive disorders group shows an increase of AI (p<0.05) and decrease in PA (p<0.03). Correlation is seen between PAPP-A and PI, AFP and AI and hCG and PA (all p<0.05). CONCLUSION: Proliferation and apoptosis differ already in first trimester placentas of pregnancies complicated by hypertensive disorders or IUGR. Serum screening markers show correlation with proliferation and apoptosis and a subsequent adverse pregnancy outcome. PMID- 26104500 TI - Comparative analysis of recommendations in local Dutch guidelines on 'Hypertension and pregnancy'. AB - OBJECTIVE: Hypertensive disorders in pregnancy remain the most prevalent cause of maternal and fetal morbidity and mortality. We hypothesise that incompleteness of local protocols 'Hypertension during pregnancy' might be associated with adverse obstetric outcome. Therefore, we analyzed the contents of the local Dutch protocols. STUDY DESIGN: We analyzed local Dutch protocols on 'Hypertension during pregnancy' using qualitative methods to score the completeness using the national guideline as standard. Indicators were designed using key recommendation from the national Dutch guideline 'Hypertension during pregnancy' (n=83 indicators), 22 of these indicators were classified as crucial indicators. Deficiencies in the local Dutch protocols, differences between the protocols and differences between the protocols of academically affiliated hospitals, teaching non-academic hospitals and non-teaching hospitals were analyzed using ANOVA test. RESULTS: The median total score of the local protocols is 32.5 (max 83, range from 2 to 55). Thirteen indicators were described in less than 10% of the local protocols. We found more indicators lacking in the non-teaching hospitals protocols compared to academically affiliated hospitals and teaching non academically hospitals protocols. (Six of the crucial indicators were described in less than 50% of the local protocols.) CONCLUSIONS: The data from this review imply incompleteness of the local Dutch protocols. Improvement of the protocols can result in improvement of implementation and subsequent improvement of quality care for pregnant women with hypertension finally resulting in better outcome of mother and child. PMID- 26104501 TI - Antihypertensive drug prescription pattern before and during pregnancy in France. AB - OBJECTIVE: This study provides firsthand information on antihypertensive prescriptions before and during pregnancy in France. METHODS: The study, on 23,898 women, was carried out using data from the French Health Insurance System. RESULTS: Before and during pregnancy, 1.1% and 5.1% of women received prescriptions for antihypertensive drugs: beta blockers and diuretics before, and nifedipine, nicardipine, labetalol and methyldopa during pregnancy. Sixty-six pregnant women were exposed to angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. CONCLUSION: Pregnant women still receive prescriptions for harmful drugs. In order to prevent such exposures, it should be recommended to avoid these prescriptions in women of child-bearing age who plan to be pregnant. PMID- 26104502 TI - Simultaneous determination of praziquantel, pyrantel embonate, febantel and its active metabolites, oxfendazole and fenbendazole, in dog plasma by liquid chromatography/mass spectrometry. AB - A liquid chromatography-electrospray-mass spectrometry method (LC/MS) has been developed and validated for determination of praziquantel (PZQ), pyrantel (PYR), febantel (FBT), and the active metabolites fenbendazole (FEN) and oxfendazole (OXF), in dog plasma, using mebendazole as internal standard (IS). The method consists of solid-phase extractions on Strata-X polymeric cartridges. Chromatographic separation was carried out on a Phenomenex Gemini C6 -Phenyl column using binary gradient elution containing methanol and 50 mm ammonium formate (pH 3). The method was linear (r(2) >= 0.990) over concentration ranges of 3-250 ng/mL for PYR andFEB, 5-250 ng/mL for OXF and FEN, and 24-1000 ng/mL for PZQ. The mean precisions were 1.3-10.6% (within-run) and 2.5-9.1% (between-run), and mean accuracies were 90.7-109.4% (within-run) and 91.6-108.2% (between-run). The relative standard deviations (RSD) were <9.1%. The mean recoveries of five targeted compounds from dog plasma ranged from 77 to 94%.The new LC/MS method described herein was fully validated and successfully applied to the bioequivalence studies of different anthelmintic formulations such as tablets containing PZQ, PYR embonate and FBT in dogs after oral administration. PMID- 26104503 TI - The impact of an exercise intervention on C - reactive protein during pregnancy: a randomized controlled trial. AB - BACKGROUND: C-reactive protein (CRP) during pregnancy has been associated with adverse maternal outcomes such as preeclampsia and gestational diabetes mellitus. Randomized trials suggest that exercise programs may be associated with reductions in CRP in non-pregnant populations; however, such studies have not been conducted among pregnant women. The purpose of this study was to evaluate the impact of an individually-tailored motivationally-matched exercise intervention on CRP in pregnant women. METHODS: The Behaviors Affecting Baby and You study was a randomized controlled trial of prenatal physical activity to prevent the development of gestational diabetes mellitus in women at increased risk. Women were randomized to either a 12-week exercise intervention (n = 84) or a comparison health and wellness intervention (n = 87). High sensitivity CRP (mg/dL) was measured using a commercial immunoassay kit. Physical activity was measured using the Pregnancy Physical Activity Questionnaire. Mixed model analyses were used to evaluate the impact of the intervention on change in CRP using an intent-to-treat approach. RESULTS: CRP decreased (-0.09 mg/dL, 95 % CI: 0.25, 0.07) from pre- to post-intervention in the exercise arm (p = 0.14) and increased (0.08 mg/dL, 95 % CI: -0.07, 0.24) (p = 0.64) in the health and wellness arm; however the between group difference was not statistically significant (p = 0.14). Findings did not differ according to ethnic group or pre pregnancy body mass index. In a secondary analysis based on self-reported physical activity, women who decreased their time spent in sports/exercise experienced a mean increase in CRP (0.09 mg/dL, 95 % CI: -0.14, 0.33), whereas women who maintained or increased their sports/ exercise experienced a mean decrease in CRP (-0.08 mg/dL, 95 % CI: -0.23, 0.08) (p = 0.046). CONCLUSIONS: Findings from this randomized trial in an ethnically and socio-economically diverse population of pregnant women were consistent with a positive impact of the exercise intervention on CRP levels, but not of statistical significance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00728377 . Registered 2 August 2008. PMID- 26104504 TI - Imaging phase separation in model lipid membranes through the use of BODIPY based molecular rotors. AB - In order to fully understand the dynamics of processes within biological lipid membranes, it is necessary to possess an intimate knowledge of the physical state and ordering of lipids within the membrane. Here we report the use of three molecular rotors based on meso-substituted boron-dipyrrin (BODIPY) in combination with fluorescence lifetime spectroscopy to investigate the viscosity and phase behaviour of model lipid bilayers. In phase-separated giant unilamellar vesicles, we visualise both liquid-ordered (Lo) and liquid-disordered (Ld) phases using fluorescence lifetime imaging microscopy (FLIM), determining their associated viscosity values, and investigate the effect of composition on the viscosity of these phases. Additionally, we use molecular dynamics simulations to investigate the orientation of the BODIPY probes within the bilayer, as well as using molecular dynamics simulations and fluorescence correlation spectroscopy (FCS) to compare diffusion coefficients with those predicted from the fluorescence lifetimes of the probes. PMID- 26104505 TI - Appropriateness of oral drugs for long-term treatment of lower urinary tract symptoms in older persons: results of a systematic literature review and international consensus validation process (LUTS-FORTA 2014). AB - AIM: we aimed to systematically review drugs to treat lower urinary tract symptoms (LUTS) regularly used in older persons to classify appropriate and inappropriate drugs based on efficacy, safety and tolerability by using the Fit fOR The Aged (FORTA) classification. METHODS: to evaluate the efficacy, safety and tolerability of drugs used for treatment of LUTS in older persons, a systematic review was performed. Papers on clinical trials and summaries of individual product characteristics were analysed regarding efficacy and safety in older persons (>=65 years). The most frequently used drugs were selected based on current prescription data. An interdisciplinary international expert panel assessed the drugs in a Delphi process. RESULTS: for the 16 drugs included here, a total of 896 citations were identified; of those, only 25 reported clinical trials with explicit data on, or solely performed in older people, underlining the lack of evidence in older people for drug treatment of LUTS. No drug was rated at the FORTA-A-level (indispensable). Only three were assigned to FORTA B (beneficial): dutasteride, fesoterodine and finasteride. The majority was rated FORTA C (questionable): darifenacin, mirabegron, extended release oxybutynin, silodosin, solifenacin, tadalafil, tamsulosin, tolterodine and trospium. FORTA D (avoid) was assigned to alfuzosin, doxazosin, immediate release oxybutynin, propiverine and terazosin. CONCLUSIONS: dutasteride, fesoterodine and finasteride were classified as beneficial in older persons or frail elderly people (FORTA B). For most drugs, in particular those from the group of alpha-blockers and antimuscarinics, use in this group seems questionable (FORTA C) or should be avoided (FORTA D). PMID- 26104507 TI - A proposal: the need for thrombotic thrombocytopenic purpura Specialist Centres- providing better outcomes. AB - Thrombotic thrombocytopenic purpura (TTP) is heralded by its demanding presentation and impending mortality. The complex and life-threatening characteristics of TTP justify the need for early referral and responsive management in centres with comprehensive multi-disciplinary resources. In an era where compromise of patient safety or experience is unsatisfactory, the provision of specialist-led, organized care for this patient group remains overdue. Patients and clinical teams continue to lack the knowledge, support and resources required to achieve consistently high levels of clinical care. This forms the rationale for development of TTP Specialist Centres. In this article we focus on what we believe to be the recognized and potential merits of a specialist service provision, highlighting individual components of a high level of integrated expertise. The challenges in managing the condition from acute diagnosis to long term care are described alongside defining key standards that represent excellence in patient care. The emphasis will be on understanding how the evolution of TTP Specialist Centres diverges from an ad hoc approach to managing this vulnerable patient group and offers promise in the translation to improved patient outcomes. PMID- 26104506 TI - Antibiotic prescribing and associated diarrhoea: a prospective cohort study of care home residents. AB - BACKGROUND: the risk factors for and frequency of antibiotic prescription and antibiotic-associated diarrhoea (AAD) among care home residents are unknown. AIM: to prospectively study frequency and risks for antibiotic prescribing and AAD for care home residents. DESIGN AND SETTING: a 12-month prospective cohort study in care homes across South Wales. METHOD: antibiotic prescriptions and the development of AAD were recorded on case report forms. We defined AAD as three or more loose stools in a 24-h period occurring within 8 weeks of exposure to an antibiotic. RESULTS: we recruited 279 residents from 10 care homes. The incidence of antibiotic prescriptions was 2.16 prescriptions per resident year (95% CI: 1.90-2.46). Antibiotics were less likely to be prescribed to residents from dual registered homes (OR compared with nursing homes: 0.38, 95% CI: 0.18-0.79). For those who were prescribed antibiotics, the incidence of AAD was 0.57 episodes per resident year (95% CI: 0.41-0.81 episodes). AAD was more likely in residents who were prescribed co-amoxiclav (hazards ratio, HR = 2.08, 95% confidence interval, CI: 1.18-3.66) or routinely used incontinence pads (HR = 2.54, 95% CI: 1.26-5.13) and less likely in residents from residential homes (HR compared with nursing homes: 0.14, 95% CI: 0.06-0.32). CONCLUSION: residents of care homes, particularly of nursing homes, are frequently prescribed antibiotics and often experience diarrhoea following such prescriptions. Co-amoxiclav is associated with greater risk of AAD. PMID- 26104508 TI - Antiplatelet Therapy During PCI for Patients with Stable Angina and Atrial Fibrillation. AB - The pharmacological treatment options for anticoagulation in patients with atrial fibrillation (Afib) have increased with the introduction of novel oral anticoagulants, compared with earlier times, when vitamin K antagonist was the drug of choice. As they age, many Afib patients require percutaneous coronary intervention (PCI), necessitating antiplatelet medication in addition to anticoagulation therapy. Choosing the appropriate combination and duration of anticoagulation and antiplatelet therapies may be challenging in stable coronary artery disease (CAD) and even more complicated during and after coronary intervention with the introduction of additional antithrombotic drugs. In this article, we review the scientific basis for the recent guidelines for anticoagulation and antithrombotic therapy in patients with Afib and stable CAD before, during, and after elective PCI. PMID- 26104509 TI - Natural Killer Cells: Key Players in Endometriosis. AB - Endometriosis affects more than 10% of women, causing significant pain and morbidity. It is also a significant cause of infertility. The aetiology of the disease remains an enigma, and the mechanisms responsible for the associated infertility are unclear. A role for immune cells in endometriosis has been postulated, with attention directed towards natural killer (NK) cells and macrophages. NK cells kill tumours and infected cells but also have roles in tissue remodelling in several organs including the uterus and are key to successful pregnancy. Here, we explore evidence (from peer-reviewed published articles) of phenotypic and functional abnormalities in NK cell subpopulations of women with endometriosis. It is clear that peripheral blood NK cells and peritoneal NK cells have reduced cytotoxic function in women with endometriosis. Uterine NK cells have a vital role in infertility, but very little research has been carried out in this area. We propose that abnormal u NK cell activity may contribute to the pathogenesis of endometriosis and its associated infertility and that future research should focus on this complex area. PMID- 26104510 TI - Clinical experience of strain imaging using DENSE for detecting infarcted cardiac segments. AB - BACKGROUND: We hypothesised that myocardial deformation determined with magnetic resonance imaging (MRI) will detect myocardial scar. METHODS: Displacement Encoding with Stimulated Echoes (DENSE) was used to calculate left ventricular strain in 125 patients (29 women and 96 men) with suspected coronary artery disease. The patients also underwent cine imaging and late gadolinium enhancement. 57 patients had a scar area >1% in at least one segment, 23 were considered free from coronary artery disease (control group) and 45 had pathological findings but no scar (mixed group). Peak strain was calculated in eight combinations: radial and circumferential strain in transmural, subendocardial and epicardial layers derived from short axis acquisition, and transmural longitudinal and radial strain derived from long axis acquisitions. In addition, the difference between strain in affected segments and reference segments, "differential strain", from the control group was analysed. RESULTS: In receiver-operator-characteristic analysis for the detection of 50% transmurality, circumferential strain performed best with area-under-curve (AUC) of 0.94. Using a cut-off value of -17%, sensitivity was 95% at a specificity of 80%. AUC did not further improve with differential strain. There were significant differences between the control group and global strain circumferential direction (-17% versus -12%) and in the longitudinal direction (-13% versus -10%). Interobserver and scan-rescan reproducibility was high with an intraclass correlation coefficient (ICC) >0.93. CONCLUSIONS: DENSE-derived circumferential strain may be used for the detection of myocardial segments with >50 % scar area. The repeatability of strain is satisfactory. DENSE-derived global strain agrees with other global measures of left ventricular ejection fraction. PMID- 26104512 TI - Estimation of Genetic Associations between Production and Meat Quality Traits in Duroc Pigs. AB - Data collected from 690 purebred Duroc pigs from 2009 to 2012 were used to estimate the heritability, and genetic and phenotypic correlations between production and meat quality traits. Variance components were obtained through the restricted maximum likelihood procedure using Wombat and SAS version 9.0. Animals were raised under the same management in five different breeding farms. The average daily gain, loin muscle area (LMA), backfat thickness (BF), and lean percent (LP) were measured as production traits. Meat quality traits included pH, cooking loss, lightness (L*), redness (a*), yellowness (b*), marbling score (MS), moisture content (MC), water holding capacity (WHC), and shear force. The results showed that the heritability estimates for meat quality traits varied largely from 0.19 to 0.79. Production traits were moderate to highly heritable from 0.41 to 0.73. Genotypically, the BF was positively correlated (p<0.05) with MC (0.786), WHC (0.904), and pH (0.328) but negatively correlated with shear force ( 0.533). The results of genetic correlations indicated that selection for less BF could decrease pH, moisture content, and WHC and increase the shear force of meat. Additionally, a significant positive correlation was recorded between average daily gain and WHC, which indicates pork from faster-growing animals has higher WHC. Furthermore, selection for larger LMA and LP could increase MS and lightness color of meat. The meat quality and production traits could be improved simultaneously if desired. Hence, to avoid further deterioration of pork characteristics, appropriate selection of traits should be considered. PMID- 26104511 TI - Epigenetics could explain some Moroccan population colorectal cancers peculiarities: microsatellite instability pathway exploration. AB - BACKGROUND: Colorectal Cancers (CRC) are one of the most common malignancies in the world. Their incidence in Morocco, between 2005 and 2007, was 5.6 for 100000 inhabitants, which is very low compared to what found in developed countries. In addition, CRCs show a high frequency of rectal localizations, and occurs in a younger population in Morocco compared to what found in developed countries. The purpose of this study is to confirm these CRC peculiarities in Morocco and try to explain them by exploring the microsatellite instability molecular pathway. METHODS: This is a prospective observational study conducted since January 2010, including 385 patients admitted in Hassan II University Hospital of Fez. We collected clinical, radiological and pathological data. We investigated the expression of mismatch repair (MMR) proteins in 214 patients and BRAF gene mutations in 159 patients. RESULTS: Mean age was 55.08 +/- 15.16 years. 36.5% of patients were less than 50 years old and 49.3% of tumors were localized in the rectum. Loss of MMR protein expression was observed in 11.2% of cases. It was independently associated with individual or family history of cancer belonging to Hereditary Non-Polyposis Colorectal Cancer (HNPCC) spectrum (p = 0.01) and proximal localization (p = 0.02). No BRAF mutation was detected in all cases. CONCLUSIONS: These results confirm the high occurrence of CRCs to young patients and the high frequency of rectal localizations in Moroccan population. They mostly show an absence of BRAF mutation, supposing a rarity of MLH1 promoter hypermethylation pathway, which may even partially explain the CRC peculiarities in our context. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5868184711716884. PMID- 26104513 TI - Y-Single Nucleotide Polymorphisms Diversity in Chinese Indigenous Horse. AB - In contrast to high genetic diversity of mitochondrial DNA (mtDNA), equine Y chromosome shows extremely low variability, implying limited patrilines in the domesticated horse. In this study, we applied direct sequencing and restriction fragment length polymorphism (RFLP) methods to investigate the polymorphisms of 33 Y chromosome specific loci in 304 Chinese indigenous horses from 13 breeds. Consequently, two Y-single nucleotide polymorphisms (SNPs) (Y-45701/997 and Y 50869) and one Y-indel (Y-45288) were identified. Of those, the Y-50869 (T>A) revealed the highest variation frequency (24.67%), whereas it was only 3.29% and 1.97% in Y-45288 (T/-) and Y-45701/997 (G>T) locus, respectively. These three mutations accounted for 27.96% of the total samples and identified five Y-SNP haplotypes, demonstrating genetic diversity of Y chromosome in Chinese horses. In addition, all the five Y-SNP haplotypes were shared by different breeds. Among 13 horse breeds analyzed, Balikun horse displayed the highest nucleotide diversity (pi = 5.6*10(-4)) and haplotype diversity (h = 0.527), while Ningqiang horse showed the lowest nucleotide diversity (pi = 0.00000) and haplotype diversity (h = 0.000). The results also revealed that Chinese horses had a different polymorphic pattern of Y chromosome from European and American horses. In conclusion, Chinese horses revealed genetic diversity of Y chromosome, however more efforts should be made to better understand the domestication and paternal origin of Chinese indigenous horses. PMID- 26104514 TI - Gene Expression Patterns Associated with Peroxisome Proliferator-activated Receptor (PPAR) Signaling in the Longissimus dorsi of Hanwoo (Korean Cattle). AB - Adipose tissue deposited within muscle fibers, known as intramuscular fat (IMF or marbling), is a major determinant of meat quality and thereby affects its economic value. The biological mechanisms that determine IMF content are therefore of interest. In this study, 48 genes involved in the bovine peroxisome proliferator-activated receptor signaling pathway, which is involved in lipid metabolism, were investigated to identify candidate genes associated with IMF in the longissimus dorsi of Hanwoo (Korean cattle). Ten genes, retinoid X receptor alpha, peroxisome proliferator-activated receptor gamma (PPARG), phospholipid transfer protein, stearoyl-CoA desaturase, nuclear receptor subfamily 1 group H member 3, fatty acid binding protein 3 (FABP3), carnitine palmitoyltransferase II, acyl-Coenzyme A dehydrogenase long chain (ACADL), acyl-Coenzyme A oxidase 2 branched chain, and fatty acid binding protein 4, showed significant effects with regard to IMF and were differentially expressed between the low- and high-marbled groups (p<0.05). Analysis of the gene co-expression network based on Pearson's correlation coefficients identified 10 up-regulated genes in the high-marbled group that formed a major cluster. Among these genes, the PPARG-FABP4 gene pair exhibited the strongest correlation in the network. Glycerol kinase was found to play a role in mediating activation of the differentially expressed genes. We categorized the 10 significantly differentially expressed genes into the corresponding downstream pathways and investigated the direct interactive relationships among these genes. We suggest that fatty acid oxidation is the major downstream pathway affecting IMF content. The PPARG/RXRA complex triggers activation of target genes involved in fatty acid oxidation resulting in increased triglyceride formation by ATP production. Our findings highlight candidate genes associated with the IMF content of the loin muscle of Korean cattle and provide insight into the biological mechanisms that determine adipose deposition within muscle. PMID- 26104515 TI - Single Nucleotide Polymorphism in the Coding Region of Bovine Chemerin Gene and Their Associations with Carcass Traits in Japanese Black Cattle. AB - Chemerin, highly expressed in adipose and liver tissues, regulates glucose and lipid metabolism and immunity in these tissues in ruminants and mice. Our previous reports showed that chemerin is involved in adipogenesis and lipid metabolism in adipose tissue as an adipokine. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) in the coding region of the chemerin gene and to analyze their effects on carcass traits and intramuscular fatty acid compositions in Japanese Black cattle. The SNPs in the bovine chemerin gene were detected in 232 Japanese Black steers (n = 161) and heifers (n = 71) using DNA sequencing. The results revealed five novel silent mutations: NM_001046020: c.12A>G (4aa), c.165GT (92aa), c.321 A>G (107aa), and c.396C>T (132aa). There was no association between 4 of the SNPs (c.12A>G [4aa], c.165GG [107aa], and c.396C>T) and carcass traits or intramuscular fatty acid compositions. Regarding the remaining SNP, c.276C>T, we found that cattle with genotype CC had a higher beef marbling score than that of cattle with genotype CT, whereas cattle with genotype CT had a higher body condition score (p<0.10). Further, cattle with genotype CC had significantly higher C18:0 content in their intramuscular fat tissue than that of cattle with genotype CT (p<0.05). On the other hand, cattle with genotype CT had significantly higher C14:0 and C16:0 content in their intramuscular fat tissue (p<0.05). Moreover, the number of individuals carrying the minor allele of c.276C>T SNP is small. It is suggested that the c.276C>T SNP of the chemerin gene has potential in cattle breeding using modern methods, such as marker assisted selection. So, further functional and physiological research elucidating the impact of the chemerin gene on bovine lipid metabolism including fatty acid synthesis will help in understanding these results. PMID- 26104516 TI - Genetic Variability of Show Jumping Attributes in Young Horses Commencing Competing. AB - The aim of the study was to select traits that may constitute a prospective criterion for breeding value prediction of young horses. The results of 1,232 starts of 894 four-, five-, six-, and seven-year-old horses, obtained during jumping championships for young horses which had not been evaluated in, alternative to championships, training centres were analyed. Nine traits were chosen of those recorded: ranking in the championship, elimination (y/n), conformation, rating of style on day one, two, and three, and penalty points on day one, two, and three of a championship. (Co)variance components were estimated via the Gibbs sampling procedure and adequate (co)variance component ratios were calculated. Statistical classifications were trait dependent but all fitted random additive genetic and permanent environment effects. It was found that such characteristics as penalty points and jumping style are potential indicators of jumping ability, and the genetic variability of the traits was within the range of 14% to 27%. Given the low genetic correlations between the conformation and other results achieved on the parkour, the relevance of assessment of conformation in four-years-old horses has been questioned. PMID- 26104517 TI - Pelleting in Associated with Sodium Monensin Increases the Conjugated Linoleic Acids Concentration in the Milk of Dairy Cows Fed Canola Seeds. AB - To evaluate the effects of the pelleting and the addition of sodium monensin on production, the chemical and lipid composition of milk and butter physical characteristics, 4 Holstein dairy cows (135 days of lactation) with an average milk production of 14.7 kg/d, were supplemented with a concentrate containing ground canola seeds. The cows were assigned to a 4*4 Latin square design with a 2*2 factorial arrangement of treatments: i) ground maize, soybean meal, mineral and vitamin supplements, and ground canola seeds (CG); ii) CG concentrate with 31.5 mg of monensin added per kg of dry matter (DM); iii) CG pelleted concentrate; iv) CG concentrate with monensin addition pelleted. There was no difference in milk production and composition. The addition of monensin increased milk concentration of polyunsaturated fatty acids (PUFA), the PUFA/saturated fatty acids (SFA) ratio, and omega 6. The pelleting increased the concentration of monounsaturated fatty acids, the PUFA/SFA ratio, and the omega 6/omega 3 ratio, but decreased the concentration of SFA. The association between pelleting and the addition of monensin increased the concentration of conjugated linoleic acids by 46.9%. The physical characteristics of butter were not affected by the evaluated diets. We concluded that the concentrate with 31.5 mg of monensin added per kg DM basis combined with the pelleting improves the lipid composition of milk from Holstein cows that are on pasture and supplemented with ground canola seeds, without changing the production, milk composition, and spreadability of butter. PMID- 26104518 TI - Influence of Restricted Grazing Time Systems on Productive Performance and Fatty Acid Composition of Longissimus dorsi in Growing Lambs. AB - Fifty 3-month-old male Tan lambs (similar in body weight) were divided into 5 groups to investigate the effects of different restricted pasture grazing times and indoor supplementation on the productive performances and fatty acid composition of the intramuscular fat in growing lambs. The lambs grazed for different periods of time (12 h/d, 8 h/d, 4 h/d, 2 h/d, and 0 h) and received various amounts of supplementary feedings during the 120-day trial. Pasture dry matter intake (DMI), total DMI, average daily gains and the live body weights of the lambs were measured during the experiment. The animals were slaughtered at the end of the study, their carcass traits were measured, and their longissimus dorsi muscles were sampled to analyze the intramuscular fat (IMF) content and fatty acid profiles. The results indicated that the different durations of grazing and supplementary feedings affected the animal performances and the composition of fatty acids. Grazing for 8 h/d or 2 h/d with the corresponding supplementary concentrate resulted in lambs with higher body weights, carcass weights and IMF contents. Lambs with longer grazing times and less concentrate accumulated more healthy fatty acids such as conjugated linoleic acid and n-3 polyunsaturated fatty acid and had higher n-3/n-6 ratios. Overall, a grazing allowance of 8 h/d and the corresponding concentrate was recommended to maintain a high quantity and quality of lamb meat. PMID- 26104519 TI - Influence of Sunflower Whole Seeds or Oil on Ruminal Fermentation, Milk Production, Composition, and Fatty Acid Profile in Lactating Goats. AB - This study aimed to investigate the effect of sunflower seeds, either as whole or as oil, on rumen fermentation, milk production, milk composition and fatty acids profile in dairy goats. Fifteen lactating Damascus goats were divided randomly into three groups (n = 5) fed a basal diet of concentrate feed mixture and fresh Trifolium alexandrinum at 50:50 on dry matter basis (Control) in addition to 50 g/head/d sunflower seeds whole (SS) or 20 mL/head/d sunflower seeds oil (SO) in a complete randomized design. Milk was sampled every two weeks during 90 days of experimental period for chemical analysis and rumen was sampled at 30, 60, and 90 days of the experiment for ruminal pH, volatile fatty acids (tVFA), and ammonia-N determination. Addition of SO decreased (p = 0.017) ruminal pH, whereas SO and SS increased tVFA (p<0.001) and acetate (p = 0.034) concentrations. Serum glucose increased (p = 0.013) in SO and SS goats vs Control. The SO and SS treated goats had improved milk yield (p = 0.007) and milk fat content (p = 0.002). Moreover, SO increased milk lactose content (p = 0.048) and feed efficiency (p = 0.046) compared to Control. Both of SS and SO increased (p<0.05) milk unsaturated fatty acids content specially conjugated linolenic acid (CLA) vs Control. Addition of SS and SO increased (p = 0. 021) C18:3N3 fatty acid compared to Control diet. Data suggested that addition of either SS or SO to lactating goats ration had beneficial effects on milk yield and milk composition with enhancing milk content of healthy fatty acids (CLA and omega 3), without detrimental effects on animal performance. PMID- 26104520 TI - Natural Lactic Acid Bacteria Population and Silage Fermentation of Whole-crop Wheat. AB - Winter wheat is a suitable crop to be ensiled for animal feed and China has the largest planting area of this crop in the world. During the ensiling process, lactic acid bacteria (LAB) play the most important role in the fermentation. We investigated the natural population of LAB in whole-crop wheat (WCW) and examined the quality of whole-crop wheat silage (WCWS) with and without LAB inoculants. Two Lactobacillus plantarum subsp. plantarum strains, Zhengzhou University 1 (ZZU 1) selected from corn and forage and grass 1 (FG 1) from a commercial inoculant, were used as additives. The silages inoculated with LAB strains (ZZU 1 and FG 1) were better preserved than the control, with lower pH values (3.5 and 3.6, respectively) (p<0.05) and higher contents of lactic acid (37.5 and 34.0 g/kg of fresh matter (FM), respectively) (p<0.05) than the control. Sixty LAB strains were isolated from fresh material and WCWS without any LAB inoculation. These LAB strains were divided into the following four genera and six species based on their phenotypic, biochemical and phylogenetic characteristics: Leuconostoc pseudomesenteroides, Leuconostoc citreum, Weissella cibaria, Lactococcus lactis subsp. lactis, Lactobacillus buchneri, and Lactobacillus plantarum subsp. plantarum. However, the prevalent LAB, which was predominantly heterofermentative (66.7%), consisted of Leuconostoc pseudomesenteroides, Leuconostoc citreum, Weissella cibaria, and Lactobacillus buchneri. This study revealed that most of isolated LAB strains from control WCWS were heterofermentative and could not grow well at low pH condition; the selective inoculants of Lactobacillus strains, especially ZZU 1, could improve WCWS quality significantly. PMID- 26104521 TI - The Technical and Financial Effects of Parenteral Supplementation with Selenium and Vitamin E during Late Pregnancy and the Early Lactation Period on the Productivity of Dairy Cattle. AB - This study aimed to determine the effects of parenteral selenium (Se) and vitamin E supplementation on economic impact, milk yield, and some reproductive parameters in high-yield dairy cows in the dry period and in those at the beginning of lactation. At the beginning of the dry period, cows (n = 323) were randomly divided into three groups as follows: Treatment 1 (T1), Treatment 2 (T2), and Control (C). Cows in group T1 received this preparation 21 days before calving and on calving day, and cows in group T2 received it only on calving day. The cows in the control group did not receive this preparation. Supplementation with Se increased Se serum levels of cows treated at calving day (p<0.05). Differences in milk yield at all weeks and the electrical conductivity values at the 8th and 12th weeks were significant (p<0.05). Supplementation with Se and Vitamin E decreased the incidence of metritis, the number of services per conception and the service period, but had no effects on the incidence of retained fetal membrane. A partial budgeting analysis indicated that Se supplementation was economically profitable; cows in group T1 averaged 240.6$ per cow, those in group T2 averaged 224.6$ per cow. Supplementation with Se and Vitamin E has been found to increase serum Se levels, milk yield, and has positive effects on udder health by decreasing milk conductivity values and incidence of sub-clinical mastitis. PMID- 26104522 TI - Effect of Age on Energy Requirement for Maintenance and Growth of Dorper and Hu Crossbred F1 Ewes Weighing 20 to 50 kg. AB - This research aimed to define the energy requirement of Dorper and Hu Hybrid F1 ewes 20 to 50 kg of body weight, furthermore to study energy requirement changes with age and evaluate the effect of age on energy requirement parameters. In comparative slaughter trial, thirty animals were divided into three dry matter intake treatments (ad libitum, n = 18; low restricted, n = 6; high restricted, n = 6), and were all slaughtered as baseline, intermediate, and final slaughter groups, to calculate body chemical components and energy retained. In digestibility trial, twelve ewes were housed in individual metabolic cages and randomly assigned to three feeding treatments in accordance with the design of a comparative slaughter trial, to evaluate dietary energetic values at different feed intake levels. The combined data indicated that, with increasing age, the net energy requirement for maintenance (NEm) decreased from 260.62+/-13.21 to 250.61+/-11.79 kJ/kg(0.75) of shrunk body weight (SBW)/d, and metabolizable energy requirement for maintenance (MEm) decreased from 401.99+/-20.31 to 371.23+/-17.47 kJ/kg(0.75) of SBW/d. Partial efficiency of ME utilization for maintenance (km, 0.65 vs 0.68) and growth (kg, 0.42 vs 0.41) did not differ (p>0.05) due to age; At the similar condition of average daily gain, net energy requirements for growth (NEg) and metabolizable energy requirements for growth (MEg) for ewes during late fattening period were 23% and 25% greater than corresponding values of ewes during early fattening period. In conclusion, the effect of age upon energy requirement parameters in the present study were similar in tendency with previous recommendations, values of energy requirement for growth (NEg and MEg) for Dorper and Hu crossbred female lambs ranged between the NRC (2007) recommendation for early and later maturating growing sheep. PMID- 26104523 TI - Effects of Palm Kernel Expellers on Productive Performance, Nutrient Digestibility, and White Blood Cells of Lactating Sows. AB - This experiment was conducted to investigate the effects of palm kernel expellers on productive performance, nutrient digestibility, and changes in white blood cells (WBC) of lactating sows. A total of 14 sows (200+/-12 kg of average body weight [BW]; 2.5 of average parity) were used and moved from gestation room to farrowing room on d 109 of gestation. Sows were randomly assigned to 2 dietary treatments in a completely randomized design. The treatments were a diet based on corn and soybean meal (CON) and CON added with 20% of palm kernel expellers (PKE). Sows were fed the treatments for 28 days (weaning) after farrowing. Blood was collected from each sow and 4 randomly selected piglets from each sow before farrowing or on d 3, 7, or 14 of lactation. Sows were fed respective treatments containing 0.2% chromic oxide from d 15 to 21 of lactation. Fecal samples were collected daily for the last 3 days after the 4-d adjustment period. Measurements were performances and WBC changes of sows and litter, nutrient digestibility of sows, and daily diarrhea of litter. Sows fed PKE had greater average daily feed intake (7.38 vs 7.10 kg/d; p<0.05) and lost less BW (-6.85 vs -8.54 kg; p<0.05) and backfat depth (-0.42 vs -0.71 mm; p<0.05) than those fed CON. However, there were no differences on digestibility of dry matter, nitrogen, and energy and weaning to estrus interval of sows fed either CON or PKE. Piglets from sows fed PKE gained more BW (203 vs 181 g/d; p = 0.08) and had less frequency of diarrhea (6.80 vs 8.56%; p = 0.07) than those from sows fed CON. On the other hand, no difference was found on preweaning mortality of piglets from sows fed either CON or PKE. Sows fed PKE had lower number of WBC (9.57 vs 11.82 *10(3)/MUL; p = 0.09) before farrowing than those fed CON, but no difference on d 3 and 7. Similarly, piglets from sows fed PKE had also lower number of WBC (7.86 vs 9.80 *10(3)/MUL; p<0.05) on d 14 of lactation than those from sows fed CON, but no difference on d 3 and 7. In conclusion, addition of 20% palm kernel expellers to lactation diet based on corn and soybean meal had no negative effects on productive performance, nutrient digestibility, and WBC changes of lactating sows. PMID- 26104524 TI - Estimating Apparent Nutrient Digestibility of Diets Containing Leucaena leucocephala or Moringa oleifera Leaf Meals for Growing Rabbits by Two Methods. AB - This study aimed to evaluate the nutrient digestibility of growing rabbits fed diets with different levels of either Leucaena leucocephala (LLM) or Moringa oleifera (MOLM) leaf meals and also to compare total collection and TiO2 marker methods for estimating digestibility. A total of 30 California growing rabbits (1.81+/-0.19 kg live weight on average) were randomly distributed into five experimental groups of six rabbits each and were housed in individual cages. The groups were control, 30% LLM, 40% LLM, 30% MOLM, and 40% MOLM. All groups received pelleted diets for two weeks; diets also contained 4 g/kg titanium dioxide as dietary marker. Daily feed intake was recorded during the whole experimental period and total feces were collected daily and weighed individually during four days. The results showed that there were no difference (p>0.05) in feed, dry matter (DM), organic matter (OM), crude protein (CP), digestible energy, and crude fiber (CF) intake between the control group and the other experimental groups. The apparent digestibility values of DM, OM, CP, CF, acid detergent fiber, and gross energy were the highest for control group (p = 0.001), meanwhile MOLM diets had generally higher nutrient digestibility coefficients than LLM diets. Increasing the inclusion level of leaf meal in the diet from 30% to 40% improved the digestibility of CF from 45.02% to 51.69% for LLM and from 48.11% to 55.89% for MOLM. Similar results for apparent nutrient digestibility coefficients were obtained when either total collection or indigestible marker method was used. In conclusion, the digestibility of MOLM containing diets were better than LLM diets, furthermore TiO2 as an external marker could be used as a simple, practical and reliable method to estimate nutrients digestibility in rabbit diets. PMID- 26104525 TI - Optimizing Production of Two Potential Probiotic Lactobacilli Strains Isolated from Piglet Feces as Feed Additives for Weaned Piglets. AB - Two probiotic strains, Lactobacillus johnsonii x-1d-2 and Lactobacillus mucosae x 4w-1, originally isolated from piglet feces, have been demonstrated to possess antimicrobial activities, antibiotic resistances and interleukin-6 induction ability in RAW 267.4 macrophages in our previous study. These characteristics make L. johnsonii x-1d-2 and L. mucosae x-4w-1 good candidates for application in feed probiotics. In this study, soybeal meal, molasses and sodium acetate were selected to optimize the growth medium for cultivation of L. johnsonii x-1d-2 and L. mucosae x-4w-1. These two strains were then freeze-dried and mixed into the basal diet to feed the weaned piglets. The effects of L. johnsonii x-1d-2 and L. mucosae x-4w-1 on the growth performance and fecal microflora of weaned piglets were investigated. The results showed that the bacterial numbers of L. johnsonii x-1d-2 and L. mucosae x-4w-1 reached a maximum of 8.90 and 9.30 log CFU/mL, respectively, when growing in optimal medium consisting of 5.5% (wt/vol) soybean meal, 1.0% (wt/vol) molasses and 1.0% (wt/vol) sodium acetate. The medium cost was 96% lower than the commercial de Man, Rogosa and Sharpe medium. In a further feeding study, the weaned piglets fed basal diet supplemented with freeze-dried probiotic cultures exhibited higher (p<0.05) body weight gain, feed intake, and gain/feed ratio than weaned piglets fed basal diet. Probiotic feeding also increased the numbers of lactobacilli and decreased the numbers of E. coli in the feces of weaned piglets. This study demonstrates that L. johnsonii x-1d-2 and L. mucosae x-4w-1 have high potential to be used as feed additives in the pig industry. PMID- 26104526 TI - Isolation, Culture and Identification of Porcine Skeletal Muscle Satellite Cells. AB - The objective of this study was to establish the optimum protocol for the isolation and culture of porcine muscle satellite cells. Mononuclear muscle satellite cells are a kind of adult stem cell, which is located between the basal lamina and sarcolemma of muscle fibers and is the primary source of myogenic precursor cells in postnatal muscle. Muscle satellite cells are a useful model to investigate the mechanisms of muscle growth and development. Although the isolation and culture protocols of muscle satellite cells in some species (e.g. mouse) have been established successfully, the culture system for porcine muscle satellite cells is very limited. In this study, we optimized the isolation procedure of porcine muscle satellite cells and elaborated the isolation and culture process in detail. Furthermore, we characterized the porcine muscle satellite cells using the immunofluorecence. Our study provides a reference for the isolation of porcine muscle satellite cells and will be useful for studying the molecular mechanisms in these cells. PMID- 26104527 TI - Effect of Various Phyto-extracts on Physico-chemical, Colour, and Oxidative Stability of Pork Frankfurters. AB - Lipid oxidation, colour stability and physico-chemical quality of pork frankfurters with the incorporation of 0.30% sea buckthorn (SBT), 0.10% grape seed (GSE), 0.03% green tea (GTE), 0.12% fenugreek seed (FSE) and 0.10% Acacia catechu (ACE) were studied during 20 days of refrigerated aerobic storage. The SBT and ACE were identified as being the most effective antioxidants to retard lipid oxidation with the potency decreasing in the following order: SBT>ACE>GSE>GTE>FSE based on thiobarbituric acid reacting substances, peroxide value and free fatty acids. In all samples pH and aw decreased during storage period. The L* value of treated as well as control samples decreased over time while SBT and ACE exhibited an increased redness producing higher a* values than other treatments. However, GTE was more effective in increasing b* values than other treatments at the end of storage. The results suggest that functional plant derived extracts can be valuable to the modification of frankfurter formulations for improved oxidative stability as well as quality characteristics. PMID- 26104528 TI - Effects of Dietary Restriction on the Expression of Lipid Metabolism and Growth Hormone Signaling Genes in the Longissimus dorsi Muscle of Korean Cattle Steers. AB - This study determined the effects of dietary restriction on growth and the expression of lipid metabolism and growth hormone signaling genes in the longissimus dorsi muscle (LM) of Korean cattle. Thirty-one Korean cattle steers (average age 10.5 months) were allocated to normal (N; n = 16) or dietary restriction (DR; n = 15) groups. The feeding trial consisted of two stages: for the 8-month growing period, the DR group was fed 80% of the food intake of the normal diet, and for the 6-month growth-finishing period, the DR group was fed a DR total mixed ration with 78.4% of the crude protein and 64% of the net energy for gain of the normal diet. The LM was biopsied 5 months (period 1 [P1] at 15.5 months of age) and 14 months (period 2 [P2] at 24.5 months of age) after the start of feeding. The mRNA levels were determined using real-time polymerase chain reaction. Body weight, daily feed intake, average daily gain, and feed efficiency were lower in the DR group compared with the normal group at both P1 and P2. At P1, the lipogenic fatty acid synthase (FASN) mRNA levels were lower (p<0.05) in the DR group compared with the normal group. The DR group tended (p = 0.06) to have higher of levels of growth hormone receptor (GHR) mRNA than the normal group. At P2, the DR group tended to have lower (p = 0.06) androgen receptor (AR) mRNA levels than the normal group. In conclusion, our results demonstrate that dietary restriction partially decreases the transcription of lipogenic FASN and growth hormone signaling AR genes, but increases transcription of the GHR gene. These changes in gene transcription might affect body fat accumulation and the growth of the animals. PMID- 26104529 TI - Consumption of Oxidized Soybean Oil Increased Intestinal Oxidative Stress and Affected Intestinal Immune Variables in Yellow-feathered Broilers. AB - This study investigated the effect of oxidized soybean oil in the diet of young chickens on growth performance and intestinal oxidative stress, and indices of intestinal immune function. Corn-soybean-based diets containing 2% mixtures of fresh and oxidized soybean oil provided 6 levels (0.15, 1.01, 3.14, 4.95, 7.05, and 8.97 meqO2/kg) of peroxide value (POV) in the diets. Each dietary treatment, fed for 22 d, had 6 replicates, each containing 30 birds (n = 1,080). Increasing POV levels reduced average daily feed intake (ADFI) of the broilers during d 1 to 10, body weight and average daily gain at d 22 but did not affect overall ADFI. Concentrations of malondialdehyde (MDA) increased in plasma and jejunum as POV increased but total antioxidative capacity (T-AOC) declined in plasma and jejunum. Catalase (CAT) activity declined in plasma and jejunum as did plasma glutathione S-transferase (GST). Effects were apparent at POV exceeding 3.14 meqO2/kg for early ADFI and MDA in jejunum, and POV exceeding 1.01 meqO2/kg for CAT in plasma and jejunum, GST in plasma and T-AOC in jejunum. Relative jejunal abundance of nuclear factor kappa B (NF-kappaB) P50 and NF-kappaB P65 increased as dietary POV increased. Increasing POV levels reduced the jejunal concentrations of secretory immunoglobulin A and cluster of differentiation (CD) 4 and CD8 molecules with differences from controls apparent at dietary POV of 3.14 to 4.95 meqO2/kg. These findings indicated that growth performance, feed intake, and the local immune system of the small intestine were compromised by oxidative stress when young broilers were fed moderately oxidized soybean oil. PMID- 26104530 TI - Effects of L-tryptophan, Fructan, and Casein on Reducing Ammonia, Hydrogen Sulfide, and Skatole in Fermented Swine Manure. AB - The effects of daily dietary Bacillus subtilis (Bs), and adding L-tryptophan, fructan, or casein to fecal fermentation broths were investigated as means to reduce the production of noxious gas during manure fermentation caused by ammonia, hydrogen sulfide (H2S), and 3-methylindole (skatole). Eighty swine (50.0+/-0.5 kg) were equally apportioned to an experimental group given Bs in daily feed, or a control group without Bs. After 6 weeks, fresh manure was collected from both groups for fermentation studies using a 3*3 orthogonal array, in which tryptophan, casein, and fructan were added at various concentrations. After fermentation, the ammonia, H2S, L-tryptophan, skatole, and microflora were measured. In both groups, L-tryptophan was the principle additive increasing skatole production, with significant correlation (r = 0.9992). L-tryptophan had no effect on the production of ammonia, H2S, or skatole in animals fed Bs. In both groups, fructan was the principle additive that reduced H2S production (r = 0.9981). Fructan and Bs significantly interacted in H2S production (p = 0.014). Casein was the principle additive affecting the concentration of ammonia, only in the control group. Casein and Bs significantly interacted in ammonia production (p = 0.039). The predominant bacteria were Bacillus spp. CWBI B1434 (26%) in the control group, and Streptococcus alactolyticus AF201899 (36%) in the experimental group. In summary, daily dietary Bs reduced ammonia production during fecal fermentation. Lessening L-tryptophan and increasing fructan in the fermentation broth reduced skatole and H2S. PMID- 26104531 TI - Lamb Production Costs: Analyses of Composition and Elasticities Analysis of Lamb Production Costs. AB - Since lamb is a commodity, producers cannot control the price of the product they sell. Therefore, managing production costs is a necessity. We explored the study of elasticities as a tool for basing decision-making in sheep production, and aimed at investigating the composition and elasticities of lamb production costs, and their influence on the performance of the activity. A representative sheep production farm, designed in a panel meeting, was the base for calculation of lamb production cost. We then performed studies of: i) costs composition, and ii) cost elasticities for prices of inputs and for zootechnical indicators. Variable costs represented 64.15% of total cost, while 21.66% were represented by operational fixed costs, and 14.19% by the income of the factors. As for elasticities to input prices, the opportunity cost of land was the item to which production cost was more sensitive: a 1% increase in its price would cause a 0.2666% increase in lamb cost. Meanwhile, the impact of increasing any technical indicator was significantly higher than the impact of rising input prices. A 1% increase in weight at slaughter, for example, would reduce total cost in 0.91%. The greatest obstacle to economic viability of sheep production under the observed conditions is low technical efficiency. Increased production costs are more related to deficient zootechnical indexes than to high expenses. PMID- 26104532 TI - Pulsed-field gel electrophoresis and multi locus sequence typing for characterizing genotype variability of Yersinia ruckeri isolated from farmed fish in France. AB - Yersinia ruckeri is a pathogen that has an impact on aquaculture worldwide. The disease caused by this bacterial species, yersiniosis or redmouth disease, generates substantial economic losses due to the associated mortality and veterinary costs. For predicting outbreaks and improving control strategies, it is important to characterize the population structure of the bacteria. The phenotypic and genetic homogeneities described previously indicate a clonal population structure as observed in other fish bacteria. In this study, the pulsed-field gel electrophoresis (PFGE) and multi locus sequence typing (MLST) methods were used to describe a population of isolates from outbreaks on French fish farms. For the PFGE analysis, two enzymes (NotI and AscI) were used separately and together. Results from combining the enzymes showed the great homogeneity of the outbreak population with a similarity > 80.0% but a high variability within the cluster (cut-off value = 80.0%) with a total of 43 pulsotypes described and an index of diversity = 0.93. The dominant pulsotypes described with NotI (PtN4 and PtN7) have already been described in other European countries (Finland, Germany, Denmark, Spain and Italy). The MLST approach showed two dominant sequence types (ST31 and ST36), an epidemic structure of the French Y. ruckeri population and a preferentially clonal evolution for rainbow trout isolates. Our results point to multiple types of selection pressure on the Y. ruckeri population attributable to geographical origin, ecological niche specialization and movements of farmed fish. PMID- 26104533 TI - When all else fails: extracorporeal life support in therapy-refractory cardiogenic shock. AB - OBJECTIVES: No guidelines for mechanical circulatory support in patients with therapy-refractory cardiogenic shock and multiorgan failure including ongoing cardiopulmonary resuscitation (CPR) exist. To achieve immediate cardiopulmonary stabilization, we established an interdisciplinary concept with on-site percutaneous extracorporeal life support (ECLS) implantation. METHODS: From February 2012 to November 2014, 96 patients were deemed eligible for ECLS implantation. Establishing ECLS was successful in 87 patients (mean age 54 +/- 13 years, 16% female, initial flow 4.4 +/- 0.9 l/min). Aetiologies included acute coronary syndromes (n = 52, 60%), cardiomyopathies (n = 25, 29%) and other pathologies. Fifty-nine patients (68%) had been resuscitated, and in 27 (31%), implantation was performed during CPR; 11 patients (13%) were awake at implantation and 20 (23%) underwent implantation in the referring hospital. RESULTS: Metabolic parameters differed in non-survivors versus survivors before ECLS implantation (pH 7.15 +/- 0.23 vs. 7.27 +/- 0.18, P = 0.007; lactate levels 10.90 +/- 6.00 mmol/l vs. 8.79 +/- 5.78 mmol/l, P = 0.091) and 6 h postimplantation (pH 7.27 +/- 0.11 vs. 7.37 +/- 0.11, P < 0.001; lactate levels 10.19 +/- 5.52 mmol/l vs. 5.52 +/- 4.17 mmol/l, P < 0.001). Altogether 44 patients could be weaned, and 9 were bridged to assist device implantation and 1 to heart transplantation. The mean time of support was 6 days, and the 30-day survival rate was 47% (n = 41). CONCLUSIONS: ECLS serves as a bridge-to-decision and bridge-to-treatment device. Our interdisciplinary ECLS programme achieved acceptable survival of critically ill patients despite a substantial percentage of patients having been resuscitated and no absolute exclusion criteria. Further studies defining inclusion- and exclusion criteria might additionally improve outcome. PMID- 26104534 TI - Interactions between pupae of the pine processionary moth (Thaumetopoea pityocampa) and parasitoids in a Pinus forest. AB - Parasitoids are significant enemies of many economically important insects and there is some evidence to suggest that their actions have a role in terminating the outbreaks of forest Lepidoptera populations. In this study, we examined the impact of parasitoids on the pupae of the pine processionary moth, and highlighted the presence of several parasitoid species for this developmental stage. A higher rate of parasitism was found when the pupal density in the soil was reduced, but the rate of parasitism was not influenced by pupal morphological traits or by the presence or absence of a cocoon around a pupa. Of the external factors examined, a delay in the time of descent of larvae from the trees had a positive effect on the level of parasitism. Observational data indicated that dipteran and hymenopteran were the most abundant parasitoids to emerge from moth pupae. Our study highlights the complexity of the parasitoid-host dynamics, and stresses the importance of carefully determining environmental effects on host parasitoid relations. PMID- 26104536 TI - Feeding strategy design for recombinant human growth hormone production by Bacillus subtilis. AB - Defined and semi-defined medium-based feeding strategies were developed to enhance recombinant human growth hormone (rhGH) production by Bacillus subtilis BGSC-1A178 (scoC (-)) strain carrying pMK4::pre(subC)::hGH. Defined medium-based feeding strategies were designed by exponential feeding of glucose and (NH4)2HPO4 at two pre-determined specific growth rates, u 0 = 0.10 and 0.17 h(-1). Semi defined medium-based feeding strategies were designed by exponential feeding of substrate solution consisting of glucose, (NH4)2HPO4, peptone, and trace salt solution (PTM1) at three pre-determined specific growth rates, u 0 = 0.10, 0.17, and 0.25 h(-1). At all the strategies applied, transition cultivation time from batch to fed-batch operation was t T = 4 h. The highest rhGH concentration was obtained as C rhGH = 0.5 g L(-1) with semi-defined medium-based feeding strategy designed with u 0 = 0.25 h(-1) using feed substrate stock solution containing 200 g L(-1) glucose, 117 g L(-1) (NH4)2HPO4, 100 g L(-1) peptone, and 5 mL L(-1) PTM1 at t = 22 h when the cell concentration reached to C X = 8.29 g L(-1). The overall product and cell yields on glucose were obtained as [Formula: see text] = 7.21 mg g(-1) and [Formula: see text] = 0.12 g g(-1), respectively. The results indicate the requirement of designing continuous feed stream in fed-batch production to enhance rhGH production by r-B. subtilis. PMID- 26104535 TI - Protease inhibitors-based therapy induces acquired spherocytic-like anaemia and ineffective erythropoiesis in chronic hepatitis C virus patients. AB - BACKGROUND & AIMS: The addition of protease inhibitors, boceprevir (BOC) or telaprevir (TRV), to peg-interferon and ribavirin (PR) increases the incidence of anaemia in patients with chronic hepatitis C virus (HCV) infection. Although genetic variants in inosine triphosphatase (ITPA) gene have been linked to the haemolytic anaemia induced by PR, the mechanism sustaining severe anaemia during triple therapy is still unknown. This study aims to elucidate the molecular mechanisms underlying anaemia in chronic HCV patients with combined therapy. METHODS: We studied 59 patients with chronic HCV genotype-1: 29 treated with TRV/PR and 30 with BOC/PR. We evaluated biochemical and haematological parameters, red cell index at baseline, 4, 12, 16 and 24 weeks of treatment; in a subgroup, we performed functional studies: osmotic fragility, red cell membrane protein separation, mass spectrometry analysis, quantification of erythroid microparticles release. IL28B and ITPA polymorphisms were also evaluated. RESULTS: We found early acute normochromic normocytic haemolytic anaemia (4-8 weeks) followed by a late macrocytic hypo-regenerative anaemia with inappropriate low reticulocyte count (12-24 weeks). Studies on red cells revealed: (i) presence of spherocytes; (ii) increased osmotic fragility; (iii) abnormalities in red cell membrane protein composition; (iv) reduced membrane-cytoskeleton stability; (v) increased release of erythroid microparticles. ITPA polymorphisms impacted only the early phase of anaemia. CONCLUSIONS: The bimodal pattern of anaemia in chronic HCV patients on triple therapy might be because of acquired spherocytic like anaemia in the early phase, followed by hyporegenerative anaemia, most likely related to the combined effects of PR and TRV or BOC on erythropoiesis. PMID- 26104537 TI - Enhancing enzyme stability and metabolic functional ability of beta-galactosidase through functionalized polymer nanofiber immobilization. AB - A functionalized polystyrene nanofiber (PSNF) immobilized beta-galactosidase assembly (PSNF-Gal) was synthesized as a nanobiocatalyst aiming to enhance the biocatalyst stability and functional ability. The PSNF fabricated by electrospinning was functionalized through a chemical oxidation method for enzyme binding. The bioengineering performance of the enzyme carriers was further evaluated for bioconversion of lactose to galacto-oligosaccharides (GOS). The modified PSNF-Gal demonstrated distinguished performances to preserve the same activity as the free beta-galactosidase at the optimum pH of 7.0, and to enhance the enzyme stability of PSNF-Gal in an alkaline condition up to pH 10. The PSNF assembly demonstrated improved thermal stability from 37 to 60 degrees C. The nanobiocatalyst was able to retain 30 % of its initial activity after ninth operation cycles comparing to four cycles with the unmodified counterpart. In contrast with free beta-galactosidase, the modified PSNF-Gal enhanced the GOS yield from 14 to 28 %. These findings show the chemically modified PSNF-based nanobiocatalyst may be pertinent for various enzyme-catalysed bioprocessing applications. PMID- 26104538 TI - Flow-injection chemiluminescence method for the determination of moxifloxacin in pharmaceutical tablets and human urine using silver nanoparticles sensitized calcein-KMnO4 system. AB - Silver nanoparticles have been synthesized and were utilized for the enhanced luminometric estimation of moxifloxacin antibiotic. During the experimental procedure, it was clearly found that the addition of silver nanoparticles intensifies the weak chemiluminescence signal intensity of calcein-KMnO4 system by several folds. It was also obvious that the intensity enhancement was linearly proportional to the moxifloxacin concentration and this phenomenon was further utilized for the quantitative determination of target analyte. Effects of the different chemical variables during the experiment were studied to achieve best chemiluminescence signal. Under the optimized experimental parameters, the linear calibration graph was established over the moxifloxacin concentration range of 6.0 * 10(-8) M to 2.5 * 10(-6) M with coefficient of correlation (r (2)) value 0.9998. The lower detection limit was found to be 5.6 * 10(-9) M. The percentage relative standard deviation calculated from five replicate chemiluminescence measurements was found to be 2.63 %. The developed chemiluminescence technique was successfully applied to the determination of moxifloxacin in tablet formulation and spiked human urine sample. PMID- 26104539 TI - Polymicrobial biofilms by diabetic foot clinical isolates. AB - Diabetes mellitus is a major chronic disease that continues to increase significantly. One of the most important and costly complications of diabetes is foot ulceration that may be colonized by pathogenic and antimicrobial resistant bacteria, which may express several virulence factors that could impair treatment success. These bacterial communities can be organized in polymicrobial biofilms, which may be responsible for diabetic foot ulcer (DFU) chronicity. We evaluated the influence of polymicrobial communities in the ability of DFU isolates to produce biofilm, using a microtiter plate assay and a multiplex fluorescent in situ hybridization, at three time points (24, 48, 72 h), after evaluating biofilm formation by 95 DFU isolates belonging to several bacterial genera (Staphylococcus, Corynebacterium, Enterococcus, Pseudomonas and Acinetobacter). All isolates were biofilm-positive at 24 h, and the amount of biofilm produced increased with incubation time. Pseudomonas presented the higher biofilm production, followed by Corynebacterium, Acinetobacter, Staphylococcus and Enterococcus. Significant differences were found in biofilm formation between the three time points. Polymicrobial communities produced higher biofilm values than individual species. Pseudomonas + Enterococcus, Acinetobacter + Staphylococcus and Corynebacterium + Staphylococcus produced higher biofilm than the ones formed by E. faecalis + Staphylococcus and E. faecalis + Corynebacterium. Synergy between bacteria present in dual or multispecies biofilms has been described, and this work represents the first report on time course of biofilm formation by polymicrobial communities from DFUs including several species. The biological behavior of different bacterial species in polymicrobial biofilms has important clinical implications for the successful treatment of these infections. PMID- 26104540 TI - Short-term stability of Borrelia garinii in cerebrospinal fluid. AB - The aim of our study was to find out the optimal conditions for short-term storage of cerebrospinal fluid (CSF) samples for direct diagnosis of Lyme disease. A mixture of Borrelia-negative CSFs spiked with a defined amount of cultured Borrelia garinii was used. Borrelia stability was investigated over 7 days at four different temperatures [room temperature (RT), +4, -20 and -70 degrees C]. Quantitative changes in CSF Borrelia were measured by quantitative PCR (qPCR), and morphological changes in the spirochetes were observed by transmission electron microscopy (TEM). These qPCR results were statistically evaluated. We found +4 degrees C to be an optimal temperature for short-term storage of CSF samples intended for TEM observation. There was no significant difference between the temperatures tested in the average quantity of Borrelia measured by qPCR. On the contrary, electron optical diagnosis of frozen samples and samples stored at RT showed destructive morphological changes and decreased spirochete counts. Our results show that optimal conditions for the pre analytical phase of investigation of one type of material can differ depending on the diagnostic method employed. PMID- 26104541 TI - [Specialized clinical facilities for the treatment of highly contagious, life threatening infectious diseases : a comparison between Germany and 15 European nations]. AB - BACKGROUND: Patients suffering from highly contagious, life-threatening infections should be treated in specialized clinical facilities that follow the highest infection control standards. Consensus statements defining technical equipment and operational procedures have been published in recent years, but the level of adherence to these has not been evaluated. METHODS: Data summarized here comparing German and European isolation facilities are the partial results of a cross-sectional analysis conducted by the "European Network for Highly Infectious Diseases" that included 48 clinical care facilities in 16 European nations. Data collection was conducted using questionnaires and on-site visits, focussing on aspects of infrastructure, technical equipment, and the availability of trained personnel. RESULTS: Although all centres enrolled were listed as "isolation units", all aspects evaluated differed broadly. Eighteen facilities fulfilled the definition of a 'High Level Isolation Unit', as 6/8 enrolled German facilities did. In contrast, 24 facilities could not operate independently from their co located hospital. DISCUSSION: Within and between nations contributing data disparities regarding the fulfilment of guidelines published were seen. German isolation facilities mostly fulfilled all criteria evaluated and performed on a high technical level. However, data presented do not reflect the current situation in Germany due to the time that has elapsed since the study was conducted. Hence, longitudinal data collection and harmonisation of terminology at least on national level needs to be implemented. PMID- 26104542 TI - Local control in Ewing sarcoma of the chest wall: results of the EURO-EWING 99 trial. AB - BACKGROUND: Primary Ewing sarcoma (ES) can sometimes present as a chest-wall tumor. Multidisciplinary management, including chemotherapy and local treatment consisting of surgery, radiotherapy (RT), or both, has improved the survival of patients with localized ES; however, the best approach to achieving local control remains controversial. METHODS: We retrospectively analyzed data from 198 patients with non-metastatic ES of the chest wall, who were registered in the database of the German Society of Pediatric Hematology and Oncology between July 1998 and April 2009. The majority of patients (n = 130) presented with rib tumors; 7 patients received RT only, 85 patients underwent surgery alone, and 106 patients were treated with a combination of surgery and RT. RESULTS: Overall survival in all patients was 78 and 71 % at 3 and 5 years, respectively. Event free survival at 5 years (5-year EFS) was 57 % in the RT group, 73 % in the surgery group and 63 % in the surgery + RT group. In patients with complete resections, 5-year EFS did not improve with the addition of RT compared with surgery alone. There was no difference in the 5-year EFS in patients with partial (63 %) or total (64 %) resection of the affected ribs, and median follow-up was 4.71 years (range 0.40-13.48). CONCLUSIONS: Complete tumor resection is the best way to achieve local control of ES of the chest wall; additional RT is only useful in patients with incomplete resection. The main limitation of this study was its retrospective nature, and the benefit of total resection of the affected ribs could not be proved. PMID- 26104543 TI - Surgical Resection of Remnant Gastric Cancer Following Distal Gastrectomy: A Retrospective Clinicopathological Study. AB - BACKGROUND: Remnant gastric cancer (RGC) is one of the less prevalent gastric cancers. The purpose of this study was to explore the clinicopathological characteristics and results of the operation of RGC following distal gastrectomy. In particular, we examined factors related to prognosis. METHODS: Between January 1970 and December 2012, 122 patients with RGC following distal gastrectomy underwent further surgery and were analyzed retrospectively. RESULTS: Initial gastric diseases included benign (49 patients, 40.2 %) and malignant diseases (73 patients, 59.8 %). Reconstructions by initial surgery included Billroth I (80 patients, 65.6 %) and Billroth II (42 patients, 34.4 %). Tumors were located at anastomotic (44 patients, 36.1 %) and nonanastomotic sites (78 patients, 63.9 %). There were 59 patients (48.4 %) classified with pathological (p) stage I, 19 as p stage II (15.6 %), 22 as p stage III (18.0 %), and 22 (18.0 %) as p stage IV. A total of 100 patients (82.0 %) underwent curative resection, and 22 underwent noncurative resection. The number of cases of postoperative morbidity, 90-day mortality, and adjuvant chemotherapy were 23 (18.9 %), 3 (2.5 %), and 20 (16.4 %), respectively. Univariate and multivariate analyses were performed to identify the prognostic factors of RGC. Multivariate analysis revealed historical periods, pathological venous invasion, curative resection, and postoperative morbidity to be independent prognostic factors. CONCLUSIONS: The prognosis of patients with RGC can be improved by aggressively performing curative resection without causing complications. PMID- 26104544 TI - Sperm DNA quality evaluated by comet assay and sperm chromatin structure assay in stallions after unilateral orchiectomy. AB - Unilateral orchiectomy (UO) may interfere with thermoregulation of the remaining testis caused by inflammation surrounding the incision site, thus altering normal spermatogenesis and consequently sperm quality. Two measures of sperm DNA quality (neutral comet assay and the sperm chromatin structure assay [SCSA]) were compared before UO (0 days) and at 14, 30, and 60 days after UO to determine whether sperm DNA changed after a mild testis stress (i.e., UO). The percent DNA in the comet tail was higher at 14 and 60 days compared to 0 days (P < 0.05) after UO. All other comet tail measures (i.e., length, moment, migration) were higher at all time periods after UO compared to 0 days (P < 0.05). Two SCSA measures (mean-alphat, mode-alphat) increased at 14 days after UO (P < 0.05), whereas two measures (SD-alphat and COMP-alphat) did not change. This study identified a decrease in sperm DNA quality using both the neutral comet assay and the SCSA, which was not identified using traditional measures of sperm quality. PMID- 26104545 TI - The significance of extracellular mucin in breast fine needle aspiration specimens. AB - OBJECTIVE: To determine if all breast fine needle aspiration (FNA) specimens with abundant extracellular mucin require excisional biopsy. METHODS: Fifty cases of breast FNA containing extracellular mucin, reported with a recommendation for biopsy and with histological follow-up were reviewed. Cellular features were noted, and the cases reclassified ignoring the presence of mucin and then correlated with histological outcome. RESULTS: Subsequent histology showed benign changes in 20% (10/50), two cases (4%) of atypical ductal hyperplasia (ADH) and 76% (38/50) to be malignant lesions, including three cases of ductal carcinoma in situ (DCIS). When the FNA cases were reviewed disregarding the presence of mucin, 11 cases were reclassified as benign and one case that contained mucin-like material but no epithelial cells reviewed as non-diagnostic. All cases of invasive mixed and mucinous carcinoma (MC) would have been reported with a recommendation for histological examination. In addition, the three cases each of fibroadenoma (FA) and a benign mucocoele-like lesion (MLL) were correctly identified as benign. However, two cases each of DCIS and ADH would have been reported benign with no recommendation for further histology. CONCLUSIONS: Breast FNA specimens with mucinous material may arise from sampling of a range of benign and malignant processes; however, a biopsy should be recommended, even in cases of low cellularity, owing to sampling problems and the frequent co-occurrence of significant lesions. FNA is highly accurate at predicting carcinoma with mucinous differentiation although it is not possible to reliably predict if the lesion represents pure MC or a mixed carcinoma. PMID- 26104546 TI - What doesn't kill you might make you stronger: functional basis for variation in body armour. AB - 1. Predation has been proposed to be a selective agent in the evolution of morphological antipredator strategies in prey. Among vertebrates, one of the morphological traits that evolved multiple times is body armour, including carapaces, thickened keratinized scales and plates of dermal bone. 2. It has been generally assumed that body armour provides protection against a predatory attack; yet, few explicit tests of the hypothesis exist. Cordylidae, a relatively small family of southern African lizards, show considerable variation in the degree of body armour. Hence, this family provides an opportunity to test the hypothesis that body armour serves as protection against predators. 3. Experiments were conducted to test whether the bite forces of four species of mammalian predators were high enough to penetrate the skins of Karusasaurus polyzonus, Namazonurus peersi, Cordylus cordylus and Cordylus macropholis, as well as those of Ouroborus cataphractus individuals originating from three localities that differed in their predator diversity. Furthermore, histological techniques were used to test whether variation in skin toughness was associated with concomitant changes in the degree of epidermal (i.e. beta-keratin) and dermal (i.e. osteoderm) armour. 4. The skin toughness values for four out of five cordylid lizards tested in this study were well below the bite forces of the mammalian predators. In contrast, the thick osteoderms in the dermis of O. cataphractus can withstand bites from several mongoose species. However, the significant variation in body armour that is present between the three populations of O. cataphractus does not seem to be related to predator diversity. 5. It is concluded that body armour can serve as protection against predation in O. cataphractus, but that alternative selection pressures, such as thermoregulation or predation by snakes, presumably underlie variation in defensive morphology in the other cordylid lizards. PMID- 26104547 TI - A Positive Allosteric Modulator of the Adenosine A1 Receptor Selectively Inhibits Primary Afferent Synaptic Transmission in a Neuropathic Pain Model. AB - In the spinal cord and periphery, adenosine inhibits neuronal activity through activation of the adenosine A1 receptor (A1R), resulting in antinociception and highlighting the potential of therapeutically targeting the receptor in the treatment of neuropathic pain. This study investigated the changes in adenosine tone and A1R signaling, together with the actions of a novel A1R positive allosteric modulator (PAM), VCP171 [(2-amino-4-(3 (trifluoromethyl)phenyl)thiophen-3-yl)(phenyl)methanone], on excitatory and inhibitory neurotransmission at spinal cord superficial dorsal horn synapses in a rat partial nerve-injury model of neuropathic pain. In the absence of A1R agonists, superfusion of the A1R antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 1 MUM), produced a significantly greater increase in electrically evoked alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated synaptic current (eEPSC) amplitude in both lamina I and II neurons from nerve injured animals than in controls, suggesting that endogenous adenosine tone is increased in the dorsal horn. Inhibitory GABAergic and glycinergic synaptic currents were also significantly increased by DPCPX in controls but there was no difference after nerve injury. The A1R agonist, N6-cyclopentyladenosine, produced greater inhibition of eEPSC amplitude in lamina II but not lamina I of the spinal cord dorsal horn in nerve-injured versus control animals, suggesting a functional increase in A1R sensitivity in lamina II neurons after nerve injury. The A1R PAM, VCP171, produced a greater inhibition of eEPSC amplitude of nerve-injury versus control animals in both lamina I and lamina II neurons. Enhanced adenosine tone and A1R sensitivity at excitatory synapses in the dorsal horn after nerve injury suggest that new generation PAMs of the A1R can be effective treatments for neuropathic pain. PMID- 26104548 TI - cAMP-Dependent Protein Kinase A (PKA)-Mediated c-Myc Degradation Is Dependent on the Relative Proportion of PKA-I and PKA-II Isozymes. AB - The transcription factor c-Myc regulates numerous target genes that are important for multiple cellular processes such as cell growth and differentiation. It is commonly deregulated in leukemia. Acute promyelocytic leukemia (APL) is characterized by a blockade of granulocytic differentiation at the promyelocyte stage. Despite the great success of all-trans retinoic acid (ATRA)-based therapy, which results in a clinical remission by inducing promyelocyte maturation, a significant number of patients relapse due to the development of ATRA resistance. A significant role has been ascribed to the cAMP/cAMP-dependent protein kinase A (PKA) signaling pathway in retinoid treatment since PKA activation is able to restore differentiation in some ATRA-resistant cells and eradicate leukemia initiating cells in vivo. In this study, using NB4 APL cell variants resistant to ATRA-induced differentiation, we reveal distinct functional roles of the two PKA isozymes, PKA type I (PKA-I) and PKA-type II (PKA-II), on the steady-state level of c-Myc protein, providing a likely mechanism by which cAMP-elevating agents can restore differentiation in ATRA maturation-resistant APL cells. Therefore, both the inhibition of c-Myc activity and the PKA-I/PKA-II ratio should be taken into account if cAMP-based therapy is considered in the clinical management of APL. PMID- 26104549 TI - The CRISPR-Cas Immune System and Genetic Transfers: Reaching an Equilibrium. AB - Horizontal gene transfer drives the evolution of bacterial genomes, including the adaptation to changing environmental conditions. Exogenous DNA can enter a bacterial cell through transformation (free DNA or plasmids) or through the transfer of mobile genetic elements by conjugation (plasmids) and transduction (bacteriophages). Favorable genes can be acquired, but undesirable traits can also be inadvertently acquired through these processes. Bacteria have systems, such as clustered regularly interspaced short palindromic repeat CRISPR associated genes (CRISPR-Cas), that can cleave foreign nucleic acid molecules. In this review, we discuss recent advances in understanding CRISPR-Cas system activity against mobile genetic element transfer through transformation and conjugation. We also highlight how CRISPR-Cas systems influence bacterial evolution and how CRISPR-Cas components affect plasmid replication. PMID- 26104550 TI - Phage and Yeast Display. AB - Despite the availability of antimicrobial drugs, the continued development of microbial resistance--established through escape mutations and the emergence of resistant strains--limits their clinical utility. The discovery of novel, therapeutic, monoclonal antibodies (mAbs) offers viable clinical alternatives in the treatment and prophylaxis of infectious diseases. Human mAb-based therapies are typically nontoxic in patients and demonstrate high specificity for the intended microbial target. This specificity prevents negative impacts on the patient microbiome and avoids driving the resistance of nontarget species. The in vitro selection of human antibody fragment libraries displayed on phage or yeast surfaces represents a group of well-established technologies capable of generating human mAbs. The advantage of these forms of microbial display is the large repertoire of human antibody fragments present during a single selection campaign. Furthermore, the in vitro selection environments of microbial surface display allow for the rapid isolation of antibodies--and their encoding genes- against infectious pathogens and their toxins that are impractical within in vivo systems, such as murine hybridomas. This article focuses on the technologies of phage display and yeast display, as these strategies relate to the discovery of human mAbs for the treatment and vaccine development of infectious diseases. PMID- 26104551 TI - Animal Models for the Pathogenesis, Treatment, and Prevention of Infection by Bacillus anthracis. AB - This article reviews the characteristics of the major animal models utilized for studies on Bacillus anthracis and highlights their contributions to understanding the pathogenesis and host responses to anthrax and its treatment and prevention. Advantages and drawbacks associated with each model, to include the major models (murine, guinea pig, rabbit, nonhuman primate, and rat), and other less frequently utilized models, are discussed. Although the three principal forms of anthrax are addressed, the main focus of this review is on models for inhalational anthrax. The selection of an animal model for study is often not straightforward and is dependent on the specific aims of the research or test. No single animal species provides complete equivalence to humans; however, each species, when used appropriately, can contribute to a more complete understanding of anthrax and its etiologic agent. PMID- 26104552 TI - Antibodies Targeting the Envelope of HIV-1. AB - Antibodies (Abs) are a critical component of the human immune response against viral infections. In HIV-infected patients, a robust Ab response against the virus develops within months of infection; however, due to numerous strategies, the virus usually escapes the biological effects of the various Abs. Here we provide an overview of the different viral evasion mechanisms, including glycosylation, high mutation rate, and conformational masking by the envelope glycoproteins of the virus. In response to virus infection and to its evolution within a host, "conventional Abs" are generated, and these can also be induced by immunization; generally, these Abs are limited in their neutralization breadth and potency. In contrast, "exceptional Abs" require extended exposure to virus to generate the required hypermutation in the immunoglobulin variable regions, and they occur only in rare HIV-infected individuals, but they display impressive breadth and potency. In this review, we describe the major regions of the HIV envelope spike that are targeted by conventional and exceptional Abs. These include the first, second, and third variable loops (V1, V2, and V3) located at the apex of the envelope trimer, the CD4 binding site, and the membrane-proximal external region of the gp41 ectodomain. Lastly, we discuss the challenging task of HIV immunogen design and approaches for choosing which immunogens might be used to elicit protective Abs. PMID- 26104553 TI - Transposons Tn10 and Tn5. AB - The study of the bacterial transposons Tn10 and Tn5 has provided a wealth of information regarding steps in nonreplicative DNA transposition, transpososome dynamics and structure, as well as mechanisms employed to regulate transposition. The focus of ongoing research on these transposons is mainly on host regulation and the use of the Tn10 antisense system as a platform to develop riboregulators for applications in synthetic biology. Over the past decade two new regulators of both Tn10 and Tn5 transposition have been identified, namely H-NS and Hfq proteins. These are both global regulators of gene expression in enteric bacteria with functions linked to stress-response pathways and virulence and potentially could link the Tn10 and Tn5 systems (and thus the transfer of antibiotic resistance genes) to environmental cues. Work summarized here is consistent with the H-NS protein working directly on transposition complexes to upregulate both Tn10 and Tn5 transposition. In contrast, evidence is discussed that is consistent with Hfq working at the level of transposase expression to downregulate both systems. With regard to Tn10 and synthetic biology, some recent work that incorporates the Tn10 antisense RNA into both transcriptional and translational riboswitches is summarized. PMID- 26104554 TI - Mobile Bacterial Group II Introns at the Crux of Eukaryotic Evolution. AB - This review focuses on recent developments in our understanding of group II intron function, the relationships of these introns to retrotransposons and spliceosomes, and how their common features have informed thinking about bacterial group II introns as key elements in eukaryotic evolution. Reverse transcriptase-mediated and host factor-aided intron retrohoming pathways are considered along with retrotransposition mechanisms to novel sites in bacteria, where group II introns are thought to have originated. DNA target recognition and movement by target-primed reverse transcription infer an evolutionary relationship among group II introns, non-LTR retrotransposons, such as LINE elements, and telomerase. Additionally, group II introns are almost certainly the progenitors of spliceosomal introns. Their profound similarities include splicing chemistry extending to RNA catalysis, reaction stereochemistry, and the position of two divalent metals that perform catalysis at the RNA active site. There are also sequence and structural similarities between group II introns and the spliceosome's small nuclear RNAs (snRNAs) and between a highly conserved core spliceosomal protein Prp8 and a group II intron-like reverse transcriptase. It has been proposed that group II introns entered eukaryotes during bacterial endosymbiosis or bacterial-archaeal fusion, proliferated within the nuclear genome, necessitating evolution of the nuclear envelope, and fragmented giving rise to spliceosomal introns. Thus, these bacterial self-splicing mobile elements have fundamentally impacted the composition of extant eukaryotic genomes, including the human genome, most of which is derived from close relatives of mobile group II introns. PMID- 26104556 TI - Mechanisms of Theta Plasmid Replication. AB - Plasmids are autonomously replicating pieces of DNA. This article discusses theta plasmid replication, which is a class of circular plasmid replication that includes ColE1-like origins of replication popular with expression vectors. All modalities of theta plasmid replication initiate synthesis with the leading strand at a predetermined site and complete replication through recruitment of the host's replisome, which extends the leading strand continuously while synthesizing the lagging strand discontinuously. There are clear differences between different modalities of theta plasmid replication in mechanisms of DNA duplex melting and in priming of leading- and lagging-strand synthesis. In some replicons duplex melting depends on transcription, while other replicons rely on plasmid-encoded trans-acting proteins (Reps); primers for leading-strand synthesis can be generated through processing of a transcript or in other replicons by the action of host- or plasmid-encoded primases. None of these processes require DNA breaks. The frequency of replication initiation is tightly regulated to facilitate establishment in permissive hosts and to achieve a steady state. The last section of the article reviews how plasmid copy number is sensed and how this feedback modulates the frequency of replication. PMID- 26104557 TI - Plasmid Rolling-Circle Replication. AB - Plasmids are DNA entities that undergo controlled replication independent of the chromosomal DNA, a crucial step that guarantees the prevalence of the plasmid in its host. DNA replication has to cope with the incapacity of the DNA polymerases to start de novo DNA synthesis, and different replication mechanisms offer diverse solutions to this problem. Rolling-circle replication (RCR) is a mechanism adopted by certain plasmids, among other genetic elements, that represents one of the simplest initiation strategies, that is, the nicking by a replication initiator protein on one parental strand to generate the primer for leading-strand initiation and a single priming site for lagging-strand synthesis. All RCR plasmid genomes consist of a number of basic elements: leading strand initiation and control, lagging strand origin, phenotypic determinants, and mobilization, generally in that order of frequency. RCR has been mainly characterized in Gram-positive bacterial plasmids, although it has also been described in Gram-negative bacterial or archaeal plasmids. Here we aim to provide an overview of the RCR plasmids' lifestyle, with emphasis on their characteristic traits, promiscuity, stability, utility as vectors, etc. While RCR is one of the best-characterized plasmid replication mechanisms, there are still many questions left unanswered, which will be pointed out along the way in this review. PMID- 26104558 TI - Site-specific DNA Inversion by Serine Recombinases. AB - Reversible site-specific DNA inversion reactions are widely distributed in bacteria and their viruses. They control a range of biological reactions that most often involve alterations of molecules on the surface of cells or phage. These programmed DNA rearrangements usually occur at a low frequency, thereby preadapting a small subset of the population to a change in environmental conditions, or in the case of phages, an expanded host range. A dedicated recombinase, sometimes with the aid of additional regulatory or DNA architectural proteins, catalyzes the inversion of DNA. RecA or other components of the general recombination-repair machinery are not involved. This chapter discusses site specific DNA inversion reactions mediated by the serine recombinase family of enzymes and focuses on the extensively studied serine DNA invertases that are stringently controlled by the Fis-bound enhancer regulatory system. The first section summarizes biological features and general properties of inversion reactions by the Fis/enhancer-dependent serine invertases and the recently described serine DNA invertases in Bacteroides. Mechanistic studies of reactions catalyzed by the Hin and Gin invertases are then explored in more depth, particularly with regards to recent advances in our understanding of the function of the Fis/enhancer regulatory system. These include the steps leading to the formation of the active recombination complex (invertasome) containing the recombinase tetramer and Fis/enhancer element and the process of DNA strand exchange by rotation of synapsed subunit pairs within the invertasome. The role of DNA topological forces that function in concert with the Fis/enhancer controlling element in specifying the overwhelming bias for DNA inversion over deletion and intermolecular recombination is also discussed. PMID- 26104559 TI - Mammalian Endogenous Retroviruses. AB - Over 40% of mammalian genomes comprise the products of reverse transcription. Among such retrotransposed sequences are those characterized by the presence of long terminal repeats (LTRs), including the endogenous retroviruses (ERVs), which are inherited genetic elements closely resembling the proviruses formed following exogenous retrovirus infection. Sequences derived from ERVs make up at least 8 to 10% of the human and mouse genomes and range from ancient sequences that predate mammalian divergence to elements that are currently still active. In this chapter we describe the discovery, classification and origins of ERVs in mammals and consider cellular mechanisms that have evolved to control their expression. We also discuss the negative effects of ERVs as agents of genetic disease and cancer and review examples of ERV protein domestication to serve host functions, as in placental development. Finally, we address growing evidence that the gene regulatory potential of ERV LTRs has been exploited multiple times during evolution to regulate genes and gene networks. Thus, although recently endogenized retroviral elements are often pathogenic, those that survive the forces of negative selection become neutral components of the host genome or can be harnessed to serve beneficial roles. PMID- 26104561 TI - Replication and Maintenance of Linear Phage-Plasmid N15. AB - The lambdoid phage N15 of Escherichia coli is very unusual among temperate phages in that its prophage is not integrated into the chromosome but is a linear plasmid molecule with covalently closed ends (telomeres). Upon infection, the phage DNA circularizes via cohesive ends, and then a special phage enzyme of the tyrosine recombinase family, protelomerase, cuts at another site and joins the ends, forming hairpin telomeres of the linear plasmid prophage. Replication of the N15 prophage is initiated at an internally located ori site and proceeds bidirectionally, resulting in the formation of duplicated telomeres. The N15 protelomerase cuts them, generating two linear plasmid molecules with hairpin telomeres. Stable inheritance of the plasmid prophage is ensured by a partitioning operon similar to the F factor sop operon. Unlike the F centromere, the N15 centromere consists of four inverted repeats dispersed in the genome. The multiplicity and dispersion of centromeres are required for efficient partitioning of a linear plasmid. The centromeres are located in the N15 genome regions involved in phage replication and control of lytic development, and binding of partition proteins at these sites regulates these processes. The family of N15-like linear phage-plasmids includes lambdoid phages phiKO2 and pY54, as well as Myoviridae phages PhiHAP-1, VHML, VP882, Vp58.5, and vB_VpaM_MAR of marine gamma-proteobacteria. The genomes of these phages contain similar protelomerase genes, lysogeny control modules, and replication genes, suggesting that these phages may belong to a group diverged from a common ancestor. PMID- 26104560 TI - Plasmid Detection, Characterization, and Ecology. AB - Plasmids are important vehicles for rapid adaptation of bacterial populations to changing environmental conditions. It is thought that to reduce the cost of plasmid carriage, only a fraction of a local population carries plasmids or is permissive to plasmid uptake. Plasmids provide various accessory traits which might be beneficial under particular conditions. The genetic variation generated by plasmid carriage within populations ensures the robustness toward environmental changes. Plasmid-mediated gene transfer plays an important role not only in the mobilization and dissemination of antibiotic resistance genes but also in the spread of degradative pathways and pathogenicity determinants of pathogens. Here we summarize the state-of-the-art methods to study the occurrence, abundance, and diversity of plasmids in environmental bacteria. Increasingly, cultivation-independent total-community DNA-based methods are being used to characterize and quantify the diversity and abundance of plasmids in relation to various biotic and abiotic factors. An improved understanding of the ecology of plasmids and their hosts is crucial in the development of intervention strategies for antibiotic-resistance-gene spread. We discuss the potentials and limitations of methods used to determine the host range of plasmids, as the ecology of plasmids is tightly linked to their hosts. The recent advances in sequencing technologies provide an enormous potential for plasmid classification, diversity, and evolution studies, but numerous challenges still exist. PMID- 26104555 TI - Related Mechanisms of Antibody Somatic Hypermutation and Class Switch Recombination. AB - The primary antibody repertoire is generated by mechanisms involving the assembly of the exons that encode the antigen-binding variable regions of immunoglobulin heavy (IgH) and light (IgL) chains during the early development of B lymphocytes. After antigen-dependent activation, mature B lymphocytes can further alter their IgH and IgL variable region exons by the process of somatic hypermutation (SHM), which allows the selection of B cells in which SHMs resulted in the production of antibodies with increased antigen affinity. In addition, during antigen-dependent activation, B cells can also change the constant region of their IgH chain through a DNA double-strand-break (DSB) dependent process referred to as IgH class switch recombination (CSR), which generates B cell progeny that produce antibodies with different IgH constant region effector functions that are best suited for a elimination of a particular pathogen or in a particular setting. Both the mutations that underlie SHM and the DSBs that underlie CSR are initiated in target genes by activation-induced cytidine deaminase (AID). This review describes in depth the processes of SHM and CSR with a focus on mechanisms that direct AID cytidine deamination in activated B cells and mechanisms that promote the differential outcomes of such cytidine deamination. PMID- 26104562 TI - Mobile DNA in the Pathogenic Neisseria. AB - The genus Neisseria contains two pathogenic species of prominant public health concern: Neisseria gonorrhoeae and Neisseria meningitidis. These pathogens display a notable ability to undergo frequent programmed recombination events. The recombination-mediated pathways of transformation and pilin antigenic variation in the Neisseria are well-studied systems that are critical for pathogenesis. Here we will detail the conserved and unique aspects of transformation and antigenic variation in the Neisseria. Transformation will be followed from initial DNA binding through recombination into the genome with consideration to the factors necessary at each step. Additional focus is paid to the unique type IV secretion system that mediates donation of transforming DNA in the pathogenic Neisseria. The pilin antigenic variation system uses programmed recombinations to alter a major surface determinant, which allows immune avoidance and promotes infection. We discuss the trans- and cis- acting factors which facilitate pilin antigenic variation and present the current understanding of the mechanisms involved in the process. PMID- 26104563 TI - Cre Recombinase. AB - The use of Cre recombinase to carry out conditional mutagenesis of transgenes and insert DNA cassettes into eukaryotic chromosomes is widespread. In addition to the numerous in vivo and in vitro applications that have been reported since Cre was first shown to function in yeast and mammalian cells nearly 30 years ago, the Cre-loxP system has also played an important role in understanding the mechanism of recombination by the tyrosine recombinase family of site-specific recombinases. The simplicity of this system, requiring only a single recombinase enzyme and short recombination sequences for robust activity in a variety of contexts, has been an important factor in both cases. This review discusses advances in the Cre recombinase field that have occurred over the past 12 years since the publication of Mobile DNA II. The focus is on those recent contributions that have provided new mechanistic insights into the reaction. Also discussed are modifications of Cre and/or the loxP sequence that have led to improvements in genome engineering applications. PMID- 26104564 TI - Use of Human Hybridoma Technology To Isolate Human Monoclonal Antibodies. AB - The human hybridoma technique offers an important approach for isolation of human monoclonal antibodies. A diversity of approaches can be used with varying success. Recent technical advances in expanding the starting number of human antigen-specific B cells, improving fusion efficiency, and isolating new myeloma partners and new cell cloning methods have enabled the development of protocols that make the isolation of human monoclonal antibodies from blood samples feasible. Undoubtedly, additional innovations that could improve efficiency are possible. PMID- 26104565 TI - Mining Environmental Plasmids for Synthetic Biology Parts and Devices. AB - The scientific and technical ambition of contemporary synthetic biology is the engineering of biological objects with a degree of predictability comparable to those made through electric and industrial manufacturing. To this end, biological parts with given specifications are sequence-edited, standardized, and combined into devices, which are assembled into complete systems. This goal, however, faces the customary context dependency of biological ingredients and their amenability to mutation. Biological orthogonality (i.e., the ability to run a function in a fashion minimally influenced by the host) is thus a desirable trait in any deeply engineered construct. Promiscuous conjugative plasmids found in environmental bacteria have evolved precisely to autonomously deploy their encoded activities in a variety of hosts, and thus they become excellent sources of basic building blocks for genetic and metabolic circuits. In this article we review a number of such reusable functions that originated in environmental plasmids and keep their properties and functional parameters in a variety of hosts. The properties encoded in the corresponding sequences include inter alia origins of replication, DNA transfer machineries, toxin-antitoxin systems, antibiotic selection markers, site-specific recombinases, effector-dependent transcriptional regulators (with their cognate promoters), and metabolic genes and operons. Several of these sequences have been standardized as BioBricks and/or as components of the SEVA (Standard European Vector Architecture) collection. Such formatting facilitates their physical composability, which is aimed at designing and deploying complex genetic constructs with new-to-nature properties. PMID- 26104566 TI - BMA annual meeting: Public health is threatened by "wholesale reductions" in staff and "dumbing down". PMID- 26104567 TI - Glucocerebrosidase deficiency and mitochondrial impairment in experimental Parkinson disease. AB - Gaucher disease is an autosomal recessive disease, caused by a lack or functional deficiency of the lysosomal enzyme, glucocerebrosidase (GCase). Recently, mutations in the glucocerebrosidase gene (GBA) have been associated with Parkinson's disease (PD) and GBA mutations are now considered the most important genetic vulnerability factor for PD. In this study, we have investigated (i) in vivo whether inhibition of the enzyme glucosylceramide synthase by miglustat may protect C57Bl/6 mice against subchronic 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) intoxication and (ii) in vitro whether a decrease of GCase activity may render dopaminergic neurons susceptible to MPP(+) (1-methyl-4 phenylpyridinium) or alpha-synuclein (alpha-Syn) toxicity and amenable to miglustat treatment. We could demonstrate that reduction of glucocerebroside by inhibition of glucosylceramide synthase partially protects mice against MPTP induced toxicity. Conversely, we could show that inhibition of GCase activity with conduritol-B-epoxide (CBE) enhances both alpha-Syn and MPP(+) induced toxicity in vitro. However, only CBE-induced enhancement of MPP(+) toxicity could be reversed by miglustat. Moreover, we were unable to reveal any alterations of complex I activity or cell respiration upon treatment with either CBE or miglustat. Our findings suggest that the reduction of GCase activity rather than an accumulation of glucocerebroside increases aSyn toxicity. PMID- 26104568 TI - A prediction model of falls for patients with neurological disorder in acute care hospital. AB - For the prevention of falls, individual fall risk assessment is the necessary first step. Thus, we attempted to identify independent risk factors for falls and develop a prediction model using a scoring system for patients with neurological disorders in acute hospital settings. This study was a secondary analysis of a previous study performed to compare the reliability and validity of three well known fall assessment tools in patients with neurological disorders. We considered comorbid diseases and potential medications in addition to variables included in the three tools. Multiple logistic regression analysis was used to develop a prediction model for falls. Predictive scores were calculated using the proportional odds ratio (OR) of each predictor. The discriminative power of this model was evaluated by receiver-operating characteristic (ROC) area under the curve (AUC) analysis. A total of 32 falls were noted among 1018 patients. History of falls (OR, 4.01; 95% CI, 1.61-9.98; p=.003), cerebrovascular disease (CVD) (OR, 2.61; 95% CI, 1.11-6.14; p=.028), severe impaired gait (OR, 7.28; 95% CI, 2.45-21.65; p<.001), and overestimate of one's own gait ability (OR, 9.14; 95% CI, 3.89-21.45; p<.001) were identified as meaningful predictors for falling after adjusting for age, diabetes, confusion or disorientation, up-and-go test, altered elimination, and antipsychotics by univariate analysis. The discriminative power of fall risk score calculated by the prediction model was 0.904 of AUC (p<.001). Our results suggest that in addition to fall history and the presence of CVD, neurological assessment for gait and insight into gait ability are imperative to predict falls in patients with neurological disorders. PMID- 26104569 TI - Iowa-type hereditary cerebral amyloid angiopathy in a Polish family. PMID- 26104570 TI - Multiple cerebral infarctions in a young patient with heroin-induced hypereosinophilic syndrome. AB - Hypereosinophilic syndrome represents a rare cause for cerebral infarctions and inflammatory neurological disorders. Various possible pathogenic mechanisms for cerebral infarctions have already been discussed. Complex mechanisms including a local hypercoagulability by eosinophilic granules as well as a direct damage to endothelial cells, leading to alterations of the microcirculation seem to be involved. The changing pattern of heroin use to inhalation/sniffing leading to an increasing abuse may cause a rise in the prevalence of Heroin induced eosinophilia, as it has been reported in a case of eosinophilic pneumonia associated with heroin inhalation. To our knowledge, the present case report displays the first description of stroke in the setting of heroin induced hypereosinophilia. Thus, besides usual vasoconstriction, HES should be considered in drug-induced cerebral infarctions. PMID- 26104571 TI - Association of aortic root calcification severity with the extent of coronary artery calcification assessed by calcium-scoring dual-source computed tomography. AB - PURPOSE: To investigate the association between aortic root calcification (ARC) and coronary artery calcification (CAC) assessed by coronary artery calcium scoring dual-source computed tomography (DSCT). MATERIALS AND METHODS: We retrospectively analyzed 143 consecutive patients who underwent coronary artery calcium-scoring during coronary DSCT angiography. 57 patients had findings of ARC on calcium-scoring scans. ARC volume (ARCV) and Agatston coronary artery calcium score (CACS) were calculated. Chi-square test was used to assess differences of categorical variables between patients with and without ARC. Statistical significances between both groups were assessed with the independent-Sample t test. RESULTS: Compared with patients without ARC (n=86), patients with ARC (n=57) showed a significantly higher presence of CAC (87.7% vs. 24.4%; P<0.001), and a higher mean CACS (700.6 +/- 941.2 vs. 256.4 +/- 724.3; P=0.009) in patients with CAC. Patients with a calculated ARCV > 40 mm(3) (n=32) showed significantly higher rates of severe CAC (56.3% vs. 24.0%; P=0.014) compared with patients with an ARCV< 40 mm(3) (n=25). Compared with patients without CAC (n=42), patients with CAC (n=101) showed a significantly higher presence of ARC (83.3% vs. 50.5%; P<0.001) and a higher mean ARCV (95.4 +/- 116.2mm(3) vs. 29.7 +/- 33.0 mm(3); P=0.003). Severe CAC (n=24) correlated with an increased mean ARCV (122.3 +/- 148.8mm(3)) compared to patients with minimal to moderate CAC (n=33, mean ARCV: 61.9 +/- 64.8mm(3); P<0.05). CONCLUSIONS: The extent of ARC is directly associated with the presence and degree of CAC on calcium-scoring scans during coronary DSCT angiography. PMID- 26104572 TI - Imaging of limb salvage surgery and pelvic reconstruction following resection of malignant bone tumours. AB - Advances in reconstructive orthopaedic techniques now allow for limb salvage and prosthetic reconstruction procedures to be performed on patients who would otherwise be required to undergo debilitating limb amputations for malignant bone tumours. The resulting post-operative imaging of such cases can be daunting for the radiologist to interpret, particularly in the presence of distorted anatomy and unfamiliar hardware. This article reviews the indications for limb salvage surgery, prosthetic reconstruction devices involved, expected post-operative imaging findings, as well as the potential hardware related complications that may be encountered in the management of such cases. PMID- 26104573 TI - Myelodysplastic syndromes in South America: a multinational study of 1080 patients. AB - There are previously reported data describing differences between Asian and European patients with Myelodysplastic Syndromes (MDS), few direct comparisons based on cancer registration characteristics or using cohorts to validate scoring systems. This is the first study from South-America, which attempts to describe demographic, clinical features, and outcome of MDS patients. We retrospectively analyzed 1,080 patients with de novo MDS from Argentina (635), Brazil (345), and Chile (100). Chilean patients were younger (P = 0.001) with female preponderance (P = 0.071). Brazilian series showed a higher predominance of RARS subtype regarding FAB and WHO classifications (P < 0.001). Hemoglobin levels were significantly lower in Brazilian and Chilean series (P < 0.001), and Chilean series also showed a lower platelet count (P = 0.028), with no differences concerning the neutrophil count, % BM blast, and the distribution of cytogenetic risk groups (P > 0.05). Chilean series depicted a lower overall survival (OS; 35 months vs. 56 months-Argentine; 55 months-Brazil, P = 0.030), which was consistent with a higher predominance of the high-risk group according both to the IPSS and IPSS-R (P = 0.046 and P < 0.001). The IPSS-R system and its variables showed a good reproducibility to predict clinical outcome for the whole South-American population. Epidemiological and clinical characteristics, distribution among prognostic subgroups, the OS, and the access to disease modifying therapies were more similar between Argentinean and Brazilian compared with Chilean MDS series. This will need further analysis in a larger group of patients. Descriptive and comparative studies are necessary to establish epidemiological features useful for public health attitudes to generate suitable therapeutic schemes. PMID- 26104574 TI - In Vitro infection of human dura-mater fibroblasts with Staphylococcus aureus: colonization and reactive production of IL-1beta. AB - OBJECTIVE: Post-operative meningitis, caused mainly by Staphylococcus aureus and Gram-negative rods, is a life-threatening complication after neurosurgery, and its pathogenesis is far from clear. The purpose of this work was to study the experimental infection of human dura-mater fibroblasts and whole human dura by S. aureus. METHODS: In vitro cultures of human dura-mater fibroblasts and organotypic cultures of small pieces of human dura mater were inoculated with a human-derived S. aureus strain. The pattern of bacterial infection as well as cytokines secretion by the infected fibroblasts was studied. RESULTS: Our results suggest that colonisation of human dura-mater fibroblasts in culture and whole dura-mater tissue by S. aureus includes bacterial growth on the cell surface, fibroblast intracellular invasion by bacteria and a significant synthesis of interleukin 1beta (IL-1beta) by the infected cells. CONCLUSION: This is the first report of human dura-mater fibroblast infection by S. aureus. Hopefully, these results can lead to a better understanding of the pathogenesis of meningitis caused by this bacterial species and to a more rational therapeutic approach. PMID- 26104576 TI - Rate and pattern of interproximal dental attrition. AB - Although occlusal and interproximal attrition occur because of diverse etiology and present dissimilar features, both progress with age. The objectives of this study were to reveal the rate and pattern of development of interproximal attrition facets (PAF) with age and to compare those with occlusal attrition (OA) changes. Five-hundred and ninety-four teeth were collected from 198 skulls (of adults, 20-71 yr of age). Three mandibular teeth [first premolar (P1), second premolar (P2), and first molar (M1)] were examined for PAF size and OA rate. Interproximal attrition and OA followed similar patterns of development until subjects reached 40-45 yr of age, after which they took different paths: PAF did not increase in size and were not as large as in younger groups, regardless of facet location, whereas OA continued to progress. The PAF changes with age differed between premolars and molars, unlike OA, which presented a similar rate for all teeth studied. Although OA scores presented significantly moderate correlations with age, PAF area size demonstrated low correlations with age. Low, but significant, correlations were found between the rate of OA and that of PAF. However, PAF and OA exhibited different patterns of development with age. Premolars and molars presented dissimilar development of PAF, which is probably caused by a unique attrition pattern in the molar teeth, different morphology, and force vectors. PMID- 26104575 TI - Paratransgenesis: a promising new strategy for mosquito vector control. AB - The three main mosquito genera, Anopheles, Aedes and Culex, transmit respectively malaria, dengue and lymphatic filariasis. Current mosquito control strategies have proved unsuccessful, and there still is a substantial number of morbidity and mortality from these diseases. Genetic control methods have now arisen as promising alternative strategies, based on two approaches: the replacement of a vector population by disease-refractory mosquitoes and the release of mosquitoes carrying a lethal gene to suppress target populations. However, substantial hurdles and limitations need to be overcome if these methods are to be used successfully, the most significant being that a transgenic mosquito strain is required for every target species, making genetically modified mosquito strategies inviable when there are multiple vector mosquitoes in the same area. Genetically modified bacteria capable of colonizing a wide range of mosquito species may be a solution to this problem and another option for the control of these diseases. In the paratransgenic approach, symbiotic bacteria are genetically modified and reintroduced in mosquitoes, where they express effector molecules. For this approach to be used in practice, however, requires a better understanding of mosquito microbiota and that symbiotic bacteria and effector molecules be identified. Paratransgenesis could prove very useful in mosquito species that are inherently difficult to transform or in sibling species complexes. In this approach, a genetic modified bacteria can act by: (a) causing pathogenic effects in the host; (b) interfering with the host's reproduction; (c) reducing the vector's competence; and (d) interfering with oogenesis and embryogenesis. It is a much more flexible and adaptable approach than the use of genetically modified mosquitoes because effector molecules and symbiotic bacteria can be replaced if they do not achieve the desired result. Paratransgenesis may therefore become an important integrated pest management tool for mosquito control. PMID- 26104577 TI - Waldenstrom macroglobulinemia with extramedullary involvement at initial diagnosis portends a poorer prognosis. AB - BACKGROUND: The prognostic importance of extramedullary involvement in patients with Waldenstrom macroglobulinemia (WM) at diagnosis and treatment options for these patients has not been well evaluated. In this study, we investigated the clinical manifestations, biological features, and effect of first-line therapy on the outcome of WM patients diagnosed with extramedullary involvement (EMWM) vs those with only bone marrow involvement (BMWM). METHODS: We analyzed the clinical data of 312 WM patients diagnosed with EMWM (n = 106) and BMWM (n = 206) at The University of Texas MD Anderson Cancer Center from 1994 to 2014. EMWM was confirmed by biopsy, positron emission tomography-computed tomography, or magnetic resonance imaging, and clinical laboratory analyses. RESULTS: Characteristics associated with EMWM were male sex (P = 0.027), age younger than 65 years (P = 0.048), presence of B symptoms (P < 0.001), high serum beta-2 macroglobulin (P < 0.001) level, low serum albumin level (P = 0.036), and cytogenetic abnormalities (P = 0.010). Kaplan-Meier survival analysis results showed that EMWM patients had a significantly shorter median overall survival (P < 0.001) and progression-free survival (PFS) (P < 0.001) than did BMWM patients. Chemotherapy combined with targeted therapy improved PFS for BMWM patients (P = 0.004) but not for EMWM patients. Additionally, initial treatment with rituximab significantly improved the PFS of BMWM patients (P = 0.012) but had no effect on EMWM patients. However, EMWM patients treated with nucleoside analogs attained a better PFS than those who did not (P = 0.021). CONCLUSIONS: We show that extramedullary involvement at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy with nucleoside analogs improved PFS for patients with EMWM. The study provides unique clinical and treatment observations in subtypes of WM patients. PMID- 26104578 TI - Myricetin induces apoptosis by inhibiting P21 activated kinase 1 (PAK1) signaling cascade in hepatocellular carcinoma. AB - Hepatocellular carcinoma is one of the most common malignancies worldwide and evidence suggests that Ras signaling regulates various hallmarks of cancer via regulating several effector pathways such as ERK and PI3K. The aim of the present study is to understand the efficacy of a flavonoid myricetin for the first time in inhibiting the downstream target p21 activated kinase 1 (PAK1) of Ras signaling pathway in hepatocellular carcinoma. The analysis of gene expression revealed that myricetin inhibits PAK1 by abrogating the Ras-mediated signaling by decelerating Wnt signaling, the downstream of Erk/Akt, thereby inducing intrinsic caspase-mediated mitochondrial apoptosis by downregulating the expression of anti apoptotic Bcl-2 and survivin and upregulating pro-apoptotic Bax. The results also provide striking evidence that the myricetin inhibits the development of HCC by inhibiting PAK1 via coordinate abrogation of MAPK/ERK and PI3K/AKT and their downstream signaling Wnt/beta-catenin pathway, thus being a promising candidate for cancer prevention and therapy. PMID- 26104579 TI - Urinary monocyte chemoattractant protein-1 and vitamin D-binding protein as biomarkers for early detection of diabetic nephropathy in type 2 diabetes mellitus. AB - Diabetic nephropathy is a serious complication of both type 1 and type 2 diabetes and, unless arrested, leads to end-stage renal disease. Therefore, early prediction and detection of DN would greatly benefit the disease management and delay its progression. The aim of this study is to evaluate the levels of urinary monocyte chemoattractant protein-1 (uMCP-1) and urinary vitamin D-binding protein (uVDBP) in type 2 diabetic patients with different degrees of diabetic nephropathy (DN) and to assess the value of uMCP-1 and uVDBP in the early detection of DN. Seventy-five type 2 diabetic patients with normoalbuminuria (n = 25), microalbuminuria (n = 25), macroalbuminuria (n = 25), and 25 healthy controls were included in this study. Urinary MCP-1 and VDBP levels were evaluated by enzyme-linked immunosorbent assay. A significant elevation in the uMCP-1 and uVDBP levels was found in macroalbuminuric (p < 0.001) and microalbuminuric (p < 0.01) diabetic patients compared to that in normoalbuminuric diabetic patients and control subjects (p < 0.001). Correlation study revealed that both uMCP-1 and uVDBP were significantly positively correlated to urinary albumin/creatinine ratio (r = 0.968, p < 0.001 and r = 0.973, p < 0.001, respectively), serum urea (r = 0.461, p = 0.001 and r = 0.456, p = 0.002, respectively), and serum creatinine (r = 0.475, p = 0.001 and r = 0.448, p = 0.004, respectively) and significantly inversely correlated to glomerular filtration rate (r = -0.983, p < 0.001 and r = -0.988, p < 0.001, respectively). Receiver operating characteristic (ROC) curve analysis of uMCP-1 and uVDBP levels for early diagnosis and detection of DN revealed that the cut off value of uMCP-1 was 110 pg/mg with 92% sensitivity and 100% specificity; whereas, the cut-off value of uVDBP was 550 ng/mg with 96% sensitivity and 84% specificity. The findings of the present study suggest that uMCP-1 and uVDBP may be considered as novel potential diagnostic biomarkers for the early detection of diabetic nephropathy. PMID- 26104580 TI - Prevalence of undiagnosed dysglycemia in an emergency department observation unit. AB - BACKGROUND: The proposed 2015 US Preventive Services Task Force guidelines recommend diabetes screening for individuals >=45 years or demonstrating other risk factors for dysglycemia. Still, many patients with dysglycemia remain undiagnosed, and opportunities for early intervention are lost. METHODS: To test novel approaches for diagnosis using the haemoglobin A1c (HbA1c ) test, we screened adult patients who were admitted to an observation unit from the emergency department with no known history of pre-diabetes or diabetes. RESULTS: Of 256 subjects, 9% were newly diagnosed with diabetes and 52% were newly diagnosed with pre-diabetes. Of those aged 18-29 years, 33% were newly diagnosed with dysglycemia, while 55% of those aged 30-44 years and 70% of those aged >=45 years were newly diagnosed with dysglycemia. CONCLUSIONS: Our results suggest that regardless of age, a large proportion of patients in the emergency department observation unit have undiagnosed dysglycemia, an important finding given the large number of observation admissions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26104581 TI - Characterization of potassium binding with human telomeres. AB - Human telomeres are G-rich tandem repeats that assume G-quadruplex structures at the ends of chromosomes. Stabilization of telomeric G-quadruplex represents a significant drug target for inhibiting the telomerase activity that is required in about 85% of cancers. Metal ions have been revealed as important stabilizers to DNA G-quadruplexes, but their binding process with human telomeric G quadruplex remains unclear. In this report, we show that K+ traverses into the G tetrads centre of two G-tetrad layers through the half-capped top pathway constructed by the two edge-wise loop bases. The binding is mediated by the electrostatic interactions between K+ and the nearby bases of G-tetrads. However, direct traverse of K+ into the interior of G-quadruplex is negatively regulated by the steric hindrance of water molecules. Once K+ enters the G-quadruplex, stabilization of the in-plane or sandwiched conformation of the telomeric G quadruplex-K+ complex is maintained by surrounding water molecules. These findings provide insights into the atomic interactions between K+ and telomere G tetrads for targeted drug design. PMID- 26104582 TI - Effects of Ixeris dentata water extract and caffeic acid on allergic inflammation in vivo and in vitro. AB - BACKGROUND: Ixeris dentata Nakai has been used for the treatment of mithridatism, calculous, indigestion, pneumonia, hepatitis, and tumors in Korea, China, and Japan. However, the effect of a water extract of Ixeris dentata (ID) and its molecular mechanism on allergic inflammation has not been elucidated. In this study, we attempted to evaluate the effects of ID and its major compound caffeic acid on allergic inflammation in vivo and in vitro. METHODS: ID was applied to 2, 4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis (AD)-like skin lesion mice and immune cell infiltration, cytokine production, and the activation of mitogen-activated protein kinases (MAPKs) were investigated. Moreover, the effect of ID on compound 48/80-induced anaphylactic shock was investigated in a mouse model. The human keratinocyte cell line (HaCaT cells) and human mast cells (HMC 1) were treated with ID or caffeic acid to investigate the effects on the production of chemokines and proinflammatory cytokines and on the activation of MAPKs. RESULTS: ID inhibited the serum levels of IgE and interleukin (IL)-1beta in DNFB-induced AD-like skin lesion mouse models and suppressed anaphylactic shock in the mouse models. ID and caffeic acid inhibited the production of chemokines and adhesion molecules in HaCaT cells. In addition, ID reduced the release of tumor necrosis factor-alpha and IL-8 via the inhibition of MAPKs phosphorylation in HMC-1 cells. CONCLUSIONS: These results suggest that ID is a potential therapeutic agent for allergic inflammatory diseases, including dermatitis. PMID- 26104584 TI - Recombinant Hepatitis E virus like particles can function as RNA nanocarriers. AB - BACKGROUND: Assembled virus-like particles (VLPs) without genetic material, with structure similar to infectious virions, have been successfully used as vaccines. We earlier described in vitro assembly, characterisation and tissue specific receptor dependent Clathrin mediated entry of empty HEV VLPs, produced from Escherichia coli expressed HEV capsid protein (pORF2). Similar VLP's have been described as a potential candidate vaccine (Hecolin) against HEV. FINDINGS: We have attempted to use such recombinant assembled Hepatitis E virus (HEV) VLPs as a carrier for heterologous RNA with protein coding sequence fused in-frame with HEV 5' region (containing cap and encapsidation signal) and investigated, if the relevant protein could be expressed and elicit an immune response in vivo. In vitro transcribed red fluorescent protein (RFP)/Hepatitis B virus surface antigen (HBsAg) RNA, fused to 5'-HEV sequence with cap and encapsidation signal (1-249 nt), was packaged into the recombinant HEV-VLPs and incubated with five different cell lines (Huh7, A549, Vero, HeLa and SiHa). The pORF2-VLPs could specifically transfer exogenous coding RNA into Huh7 and A549 cells. In vivo, Balb/c mice were immunized (intramuscular injections) with 100 ug pORF2-VLP encapsidated with 5' methyl-G-HEV (1-249 nt)-HBsAg RNA, blood samples were collected and screened by ELISA for anti-pORF2 and anti-HBsAg antibodies. Humoral immune response could be elicited in Balb/c mice against both HEV capsid protein and cargo RNA encoded HBsAg protein. CONCLUSIONS: These findings suggest that other than being a possible vaccine, HEV pORF2-VLPs can be used as a promising non-replicative tissue specific gene delivery system. PMID- 26104583 TI - Comprehensive identification and analysis of human accelerated regulatory DNA. AB - It has long been hypothesized that changes in gene regulation have played an important role in human evolution, but regulatory DNA has been much more difficult to study compared with protein-coding regions. Recent large-scale studies have created genome-scale catalogs of DNase I hypersensitive sites (DHSs), which demark potentially functional regulatory DNA. To better define regulatory DNA that has been subject to human-specific adaptive evolution, we performed comprehensive evolutionary and population genetics analyses on over 18 million DHSs discovered in 130 cell types. We identified 524 DHSs that are conserved in nonhuman primates but accelerated in the human lineage (haDHS), and estimate that 70% of substitutions in haDHSs are attributable to positive selection. Through extensive computational and experimental analyses, we demonstrate that haDHSs are often active in brain or neuronal cell types; play an important role in regulating the expression of developmentally important genes, including many transcription factors such as SOX6, POU3F2, and HOX genes; and identify striking examples of adaptive regulatory evolution that may have contributed to human-specific phenotypes. More generally, our results reveal new insights into conserved and adaptive regulatory DNA in humans and refine the set of genomic substrates that distinguish humans from their closest living primate relatives. PMID- 26104586 TI - Successful treatment with dapsone for skin lesions of amyopathic dermatomyositis. PMID- 26104585 TI - Predictors of vocational activity over the first year in inner-city early intervention in psychosis services. AB - AIM: Work and educational activities are an important part of recovery for young people with psychosis, and improving vocational outcomes is a key target for early intervention services (EIS). This study evaluated predictors of vocational activity for first-episode psychosis (FEP) patients during the first year of EIS care. It was hypothesized that longer duration of untreated psychosis (DUP) and minority ethnic status would predict poorer vocational outcomes, whereas a history of good vocational functioning would predict better vocational functioning during follow up. METHODS: FEP patients aged 14-35 years, who presented to seven EIS in London, UK, between 2003 and 2010, were followed for 1 year. Sociodemographic, clinical and vocational information (qualifications obtained and paid employment) were collected using the MiData audit tool at entry to EIS and 1 year later. RESULTS: Approximately one-third of patients (n = 345/1013) were studying or employed at some point during the first year of EIS care. Baseline vocational activity was the strongest predictor of vocational functioning during 1 year of follow up. Moreover, employment prior to entry into EIS strongly predicted change in vocational activity during 1 year of follow up. Individuals with DUP <6 months or of Asian or black African origin were more likely to be studying than their white British counterparts. CONCLUSION: This study confirms that a significant proportion of FEP patients are able to engage in meaningful vocational activities even within the first year of EIS care. However, services need to focus more resources on getting patients with poor educational or employment histories into training programmes to improve their vocational outcomes. PMID- 26104587 TI - Disease mapping for informing targeted health interventions: childhood pneumonia in Bohol, Philippines. AB - BACKGROUND: Acute lower respiratory tract infections (ALRI) are the leading cause of childhood mortality worldwide. Currently, most developing countries assign resources at a district level, and yet District Medical Officers have few tools for directing targeted interventions to high mortality or morbidity areas. Mapping of ALRI at the local level can guide more efficient allocation of resources, coordination of efforts and targeted interventions, which are particularly relevant for health management in resource-scarce settings. METHODS: An efficacy study of 11-valent pneumococcal vaccine was conducted in six municipalities in the Bohol Province of central Philippines from July 2000 to December 2004. Geocoded under-five pneumonia cases (using WHO classifications) were mapped to create spatial patterns of pneumonia at the local health unit (barangay) level. RESULTS: There were 2951 children with WHO-defined clinical pneumonia, of whom 1074 were severe or very severely ill, 278 were radiographic, and 219 were hypoxaemic. While most children with pneumonia were from urban barangays, there was a disproportionately higher distribution of severe/very severe pneumonia in rural barangays and the most severe hypoxaemic children were concentrated in the northern barangays most distant from the regional hospital. CONCLUSIONS: Mapping of ALRI at the local administrative health level can be performed relatively simply. If these principles are applied to routinely collected IMCI classification of disease at the district level in developing countries, such efforts can form the basis for directing public health and healthcare delivery efforts in a targeted manner. PMID- 26104588 TI - Medicare 40 years on: a privilege for the profession and a right for its patients. PMID- 26104589 TI - Contact lens management of keratoconus. AB - Contact lenses are the primary form of visual correction for patients with keratoconus. Contemporary advances in contact lens designs and materials have significantly expanded the available fitting options for patients with corneal ectasia. Furthermore, imaging technology, such as corneal topography and anterior segment optical coherence tomography, can be applied to both gain insight into corneal microstructural changes and to guide contact lens fitting. This paper provides a comprehensive review of the range of contact lens modalities, including soft lenses, hybrid designs, rigid lenses, piggyback configurations, corneo-scleral, mini-scleral and scleral lenses that are currently available for the optical management of keratoconus. The review also discusses the importance of monitoring for disease progression in patients with keratoconus, in particular children, who tend to undergo more rapid progressive changes, so as to facilitate appropriate modification to contact lens fitting and/or potential referral for corneal collagen cross-linking treatment, as appropriate. PMID- 26104590 TI - Therapeutic treatment of keratoconus: a survey of local optometric practice criteria. AB - BACKGROUND: Defining the threshold for therapeutic and surgical intervention in patients with keratoconus presents a considerable challenge given the lack of clear, evidence-based data. Little is known about the patterns of practice and referral criteria of optometrists within Australia. METHODS: All members of the NSW branch of Optometrist Association Australia were invited to complete an online survey in January 2013. This survey was designed to elicit practice information regarding the evaluation and therapeutic treatment of patients with keratoconus in the optometric setting. RESULTS: Responses were received from 71 optometrists, of whom 65.2 per cent had 15 years or greater experience as an optometrist. Many (35.4 per cent) responded that they prescribed soft contact lenses daily. This percentage dropped to 9.2 per cent for rigid gas-permeable lenses (RGP), although 47.7 per cent said they would prescribe RGP lenses at least once per month. The main barriers to prescribing were experience with fitting RGP lenses, time and low market demand. In terms of patient referral to an ophthalmologist, the results were variable, with 34.4 per cent stating that they would refer on progression of corneal signs, 23.4 per cent suggesting no set time and 7.8 per cent would refer on initial diagnosis. Many optometrists (62.9 per cent) would refer a patient for possible surgery, when visual acuity dropped to between 6/9 and 6/12. The size or location of the practice was not associated with the number of newly diagnosed cases of keratoconus. Optometrists with greater experience were more likely to prescribe RGP lenses and co-manage patients with ophthalmologists. Ownership of a corneal topographic unit suggested an increased likelihood of prescribing RGP lenses but did not appear to alter referral patterns. CONCLUSION: Optometrists have an integral role in the diagnosis and management of patients with keratoconus. Our survey provides a basic snapshot of current, local practice. Additionally, ophthalmology should continue to work with optometry to develop guidelines for referral and co management to optimise future outcomes for our patients. PMID- 26104591 TI - Effects of rigid contact lenses on optical coherence tomographic parameters in eyes with keratoconus. AB - BACKGROUND: The aim was to evaluate the effect of irregular astigmatism on the retinal nerve fibre layer (RNFL), macular thickness and ganglion cell analysis obtained by spectral domain optical coherence tomography (OCT) in eyes with keratoconus. METHODS: Fifty-two eyes of 31 patients (20 females) with keratoconus that required correction of irregular astigmatism with rigid gas-permeable (RGP) contact lenses were included to this study. The average, superior, nasal, inferior, temporal and 12 clock hour sector's RNFL, ganglion cell and macular thickness analyses before and 30 minutes after RGP contact lens (Rose K2 -Menicon Z material, David Thomas Contact Lenses Ltd, Northampton, United Kingdom) wear were performed to all patients with Cirrus HD spectral domain optical coherence tomography. RESULTS: The average thickness of the retinal nerve fibre layer, the thickness at the nasal quadrants and 1-2-3-4 o'clock hour sectors and mean signal strength were increased significantly by RGP contact lens wearing independent of the stage of keratoconus. Central sub-field thickness increased after correction with RGP contact lens (p = 0.037). After wearing RGP contact lenses, changes on ganglion cell analysis were not significant (all p values >= 0.111). CONCLUSIONS: OCT is a widely used device for retinal nerve fibre layer and macular thickness evaluation in patients with glaucoma and macular diseases. The study demonstrates that OCT parameters such as retinal nerve fibre layer, central sub-field thickness and mean signal strength are affected by irregular astigmatism. Correction of irregular astigmatism with RGP contact lenses should be recommended before analysing keratoconic eyes to obtain optimum results on OCT measurements. PMID- 26104592 TI - Rate of change and predictive factors for increasing minus contact lens powers in young myopes. AB - BACKGROUND: Understanding the factors associated with myopic progression is critical to properly recruit subjects into clinical trials for control of myopia. The purpose of this study is to describe the rate of change in soft contact lens (SCL) power and the associated predictive factors in a young clinical population from the Contact Lens Assessment in Youth study. METHODS: Data from a retrospective chart review of myopic SCL wearers aged eight to 22 years were analysed for rate of progression of myopia and associated characteristics using multivariate methods. RESULTS: Myopic subjects (n = 912) with at least six months of follow-up were observed (4,341 visits, mean follow-up 25 months, 37 per cent hydrogel and 63 per cent silicone hydrogel SCLs). During observation, 36 per cent of subjects experienced a change in soft contact lens power of -0.50 D or more. Significant predictors of future increase in minus lens power were: ages eight to 13 years, shorter time to the first increase in minus power and hydrogel soft contact lens material. The mean annualised increase in minus decreased with age ( 0.31D per year for eight to 13 year olds to -0.10 D per year for 20 to 22 year olds, p < 0.0001). Increases in minus were less common among users of silicone hydrogel materials than hydrogel daily disposable lenses after controlling for age (p = 0.039). CONCLUSION: In this retrospective chart review of young soft contact lens wearers, the mean annualised rate of increase in minus soft contact lens power decreased with age, longer time to first increase in power and was greater with hydrogel soft contact lenses. The rates observed were similar to progression rates in prospective myopia clinical trials that employed cylcoplegic autorefraction. PMID- 26104593 TI - Shape discrimination thresholds among subjects with emmetropia and corrected myopia. AB - BACKGROUND: Myopia is highly prevalent in some Asian countries yet the ability of subjects with myopia to discriminate shapes using radial frequency (RF) patterns circular patterns that are defined by sinusoidal modulation of the radius in polar coordinates-is not well documented. In this psychophysical study, we explore the relative ability of subjects with corrected myopia to discriminate shapes using radial frequency patterns. Specifically, the aims were to find if there are any differences in modulation detection thresholds among subjects with emmetropia and corrected myopia and to establish thresholds as a function of myopic refractive error. METHODS: Shape discrimination thresholds were measured for subjects with emmetropia (n = 20) and corrected myopia (n = 20) using circular D4 (fourth derivative of Gaussian) radial frequency patterns. A total of five radial frequency patterns (RF1 to RF16) with peak spatial frequencies of 2, 4, 6 and 8 (SF2 to SF8) cycles per degree were studied. The radial frequency suffix determines the number of deformation cycles present around the circumference, while the peak spatial frequency is related to the thickness of the circular contour. RESULTS: Overall, shape discrimination thresholds were not significantly different (p > 0.05) between subjects with emmetropia and corrected myopia. Similarly, there was no significant correlation (p > 0.05) in thresholds with the magnitude of corrected myopia. Shape discrimination performance was best for RF8 patterns, with thresholds ranging from nine to 12 seconds of arc for SF2 to SF6 patterns and from 20 to 22 seconds of arc for SF8 patterns. Thresholds were significantly higher (p < 0.05) for SF8 patterns compared to the other spatial frequency patterns (SF2 to SF6) for all radial frequency patterns. The average thresholds increased by about 1 to 1.5 log units from RF1 to RF4 and RF8. CONCLUSION: Across all patterns studied here, shape discrimination thresholds remain at hyperacuity levels and are not degraded in subjects with corrected myopia compared to emmetropia. PMID- 26104594 TI - Correlation of choroidal thickness with serum cortisol level. AB - BACKGROUND: The aim was to investigate the correlation of serum cortisol level with choroidal thickness. METHODS: Sixty-six healthy volunteers had no visual complaints or history of ocular disease. Subfoveal choroidal thickness at the foveal centre was measured with spectral domain optical coherence tomography (SD OCT). Morning serum cortisol levels were obtained at 8:00 am immediately following the SD-OCT measurement. Measurements of only the right eyes were included in the study. Age, gender, axial length and spherical equivalent were noted. Correlation of choroidal thickness with age, gender, axial length, spherical equivalent and serum cortisol level were investigated with linear and multiple regression analysis. RESULTS: Sixty-six eyes of 66 patients were evaluated. Mean age was 43.4 +/- 3.6 years (range: 40 to 53 years), mean spherical equivalent was -0.15 D (range: -1.25 to +1.50 D), mean axial length was 23.2 mm (range; 22.0 to 23.7 mm), mean choroidal thickness was 317.9 +/- 45.1 MUm (range: 206 to 394 MUm). Age and spherical equivalent were not significantly correlated with choroidal thickness. Axial length had a strong negative correlation with choroidal thickness (R(2): 0.488, p = 0.000). There was no significant correlation between serum cortisol level and choroidal thickness (R(2): 0.034, p = 0.139). CONCLUSION: Our results did not reveal any correlation between serum cortisol level and choroidal thickness. We believe that more prospective studies are needed to determine the relationship of cortisol and other hormones with choroidal thickness. PMID- 26104595 TI - Non-rhegmatogenous retinal detachment associated with hair-like object in vitreous: a case report. PMID- 26104596 TI - Case of extremely high refractive error misdiagnosed as normal by PlusoptiX S09 photoscreener. PMID- 26104599 TI - A genetic coding variant rs72474224 in GJB2 is associated with clinical features of psoriasis vulgaris in a Chinese Han population. AB - Our recent targeted sequencing study identified a missense single-nucleotide polymorphism rs72474224 (c.324C>T) in GJB2. To investigate the correlation between rs72474224 (c.324C>T) and subphenotypes of psoriasis, genotype data for rs72474224 (c.324C>T, p.Val37Ile) was analyzed in 9946 cases and 9906 controls. The additive model provided the best fit for rs72474224 (P = 7.34 * 10(-9)). The genotypic and allelic frequency distributions were associated with plaque psoriasis in case-only (Pgenotype = 2.67 * 10(-3), Pallele = 6.22 * 10(-4)) and subphenotype-control (Pgenotype = 1.58 * 10(-11), Pallele = 8.16 * 10(-12)) analyses. No other significant difference was found in case-only analyses. Rs72474224 in GJB2 is preferentially associated with plaque psoriasis in Chinese population and might contribute to the complexity of psoriasis clinical features. PMID- 26104600 TI - Safety and efficacy of canagliflozin in Japanese patients with type 2 diabetes mellitus: post hoc subgroup analyses according to body mass index in a 52-week open-label study. AB - BACKGROUND: The safety and efficacy of sodium glucose co-transporter 2 inhibitors in non-obese compared with obese patients with type 2 diabetes mellitus is unknown. METHODS: We conducted post hoc analyses of the results of a 52-week open label study of Japanese type 2 diabetes mellitus patients treated with 100 or 200 mg canagliflozin. Patients were divided into four subgroups according to their baseline body mass index (BMI): group I, BMI < 22 kg/m(2); group II, BMI >= 22 to < 25 kg/m(2); group III, BMI >= 25 to < 30 kg/m(2) and group IV, BMI >= 30 kg/m(2). RESULTS: The overall safety was similar among the four BMI subgroups, although there were slight differences in terms of the incidences of hypoglycemia, asymptomatic hypoglycemia, female genital infections and proportions of patients with total ketone body levels exceeding 1000 MUmol/l at any time for both canagliflozin doses. Hemoglobin A1c, fasting plasma glucose and body weight decreased significantly from baseline to week 52 at both canagliflozin doses. The changes in hemoglobin A1c, and fasting plasma glucose were not significantly different among the four BMI subgroups for either dose. CONCLUSION: Canagliflozin was tolerated in patients irrespective of their BMI at the start of treatment, although some caution may be needed. PMID- 26104601 TI - Continuous fast focusing in a trapezoidal void channel based on bidirectional isotachophoresis in a wide pH range. AB - This study concentrates on development of instrumentation for focusing and separation of analytes in continuous flow. It is based on bidirectional ITP working in wide pH range with separation space of closed void channel of trapezoidal shape and continuous supply of sample. The novel instrumentation is working with electrolyte system formulated previously and on the contrary to devices currently available, it allows preparative separation and concentration of cationic, anionic, and amphoteric analytes simultaneously and in wide pH range. The formation of sharp edges at zone boundaries as well as low conductivity zones are avoided in suggested system and thus, local overheating is eliminated allowing for high current densities at initial stages of focusing. This results in high focusing speed and reduction of analysis time, which is particularly advantageous for separations performed in continuous flow systems. The closed void channel is designed to avoid basic obstacles related to liquid leakage, bubbles formation, contacts with electrodes, channel height and complicated assembling. The performance of designed instrumentation and focusing dynamics were tested by using colored low molecular mass pH indicators for local pH determination, focusing pattern, and completion. In addition, feasibility and separation efficiency were demonstrated by focusing of cytochrome C and myoglobin. The collection of fractions at instrument output allows for subsequent analysis and identification of sample components that are concentrated and conveniently in form of solution for further processing. Since the instrumentation operates with commercially available simple defined buffers and compounds without need of carrier ampholytes background, it is economically favorable. PMID- 26104602 TI - A Preliminary Investigation on the Antimicrobial Activity of Listerine(r), Its Components, and of Mixtures Thereof. AB - Listerine(r) is one of the most popular mouthwashes worldwide and claims to combat harmful bacteria. In the past century, its recipe was changed from an essential oil mouthwash to a five-component mixture (thymol, menthol, eucalyptol, and methyl salicylate dissolved in 27% ethanol). The aim of this study was to get preliminary information about the antimicrobial activities of individual Listerine(r) components and their mixtures. We tested the bacterial strains Streptococcus mutans, Enterococcus faecalis, and Eikenella corrodens and the yeast Candida albicans. The established minimum inhibitory concentration (MIC) assay and the minimum bactericidal/fungicidal concentration (MBC/MFC) assay were applied. None of the combinations of two phenols at the concentrations contained within Listerine(r) were associated with either an additive or synergistic effect. Thymol had lower MIC and MBC/MFC values than the other Listerine(r) components and Listerine(r) against E. corrodens and C. albicans. The mixtures consisting of eucalyptol, methyl salicylate, and thymol were the most effective against S. mutans and E. faecalis and more effective than Listerine(r). Our results demonstrate that the phenols and their concentrations as contained within Listerine(r) could be further optimized in terms of selecting those which increase their general effectiveness, at concentrations that do not induce harm. PMID- 26104603 TI - State Legislation Related to Increasing Physical Activity: 2006-2012. AB - BACKGROUND: Strategies to improve physical activity prevalence often include policy and environmental changes. State-level policies can be influential in supporting access and opportunities for physical activity in schools and communities. The purpose of this study was to explore the prevalence of state legislation related to physical activity and identify the correlates of enactment of this legislation. METHODS: An online legislative database was used to collect bills from 50 states in the U.S. from 2006 to 2012 for 1010 topics related to physical activity. Bills were coded for content and compiled into a database with state-level variables (eg, obesity prevalence). With enactment status as the outcome, bivariate and multivariate analyses were conducted. RESULTS: Of the 1,542 bills related to physical activity introduced, 30% (N = 460) were enacted. Bills on public transportation and trails were more likely to be enacted than those without these topics. Primary sponsorship by the Republican Party, bipartisan sponsorship, and mention of specific funding amounts were also correlates of enactment. CONCLUSION: Policy surveillance of bills and correlates of enactment are important for understanding patterns in legislative support for physical activity. This information can be used to prioritize advocacy efforts and identify ways for research to better inform policy. PMID- 26104604 TI - Different levels of IL-1alpha, IL-6, TNF-alpha, NF-kappaB and PPAR-gamma in monocyte cultures exposed by plasma preeclampsia and normotensive pregnancy. AB - OBJECTIVE: To determine different levels of proinflammatory cytokines IL-1alpha, IL-6, TNF-alpha, nuclear NF-kappaB p50 and PPAR-gamma in monocyte cultures exposed to normotensive pregnancy plasma compared with those exposed to preeclamptic plasma. Study design The study involved primigravidae with preeclampsia (12) and normotensive pregnancy (12) in which their blood plasma was given to monocyte cultures from isolated PBMC of healthy and non-pregnant women. They were divided into 2 groups, the first group was incubated for 24h and the second one was incubated for 48h (step 1). The levels of IL-1alpha, IL-6, TNF alpha, and nuclear NF-kappaB p50 as well as PPAR-gamma of both groups were subsequently measured and compared (step 2). Data were analyzed to determine the differences and interaction between both treatment groups using one-way ANOVA. RESULTS: There was a significantly different level (p-value <0.05) of IL-1alpha in monocyte cultures incubated for 24h compared with those incubated for 48h, as shown in step 1 of the study. Meanwhile, step 2 of the study found significantly different levels of IL-1alpha, IL-6, TNF-alpha, and NF-kappaB p50 in monocyte cultures exposed to preeclamptic plasma compared with those exposed to normotensive pregnancy, in which the latter showed higher levels. Both groups also showed decreased levels of PPARgamma, in which monocyte culture exposed to severe preeclamptic plasma (p value <0.05). CONCLUSION: Preeclamptic plasma significantly increased levels of proinflammatory cytokines IL-1a, IL-6, and TNF a in monocyte cultures. This condition was consistent with the increasing of NF kappaB p50 and decreasing of PPARgamma. PMID- 26104605 TI - Prediction of recurrence of hypertensive disorders of pregnancy in the term period, a retrospective cohort study. AB - OBJECTIVES: To assess the recurrence risk of term hypertensive disease of pregnancy and to determine which potential risk factors are predictive of recurrence. STUDY DESIGN: We performed a retrospective cohort study in two secondary and one tertiary care hospitals in the Netherlands. We identified women with a hypertensive disorder in the index pregnancy and delivery after 37weeks of gestation between January 2000 and December 2002. Data were extracted from medical files and women were approached for additional information on subsequent pregnancies. Adverse outcome was defined as recurrence of a hypertensive disorder in the next subsequent pregnancy. MAIN OUTCOME MEASURES: The absolute risk of recurrence and a prediction model containing demographic and clinical factors predictive of recurrence. RESULTS: We identified 638 women for potential inclusion, of whom 503 could be contacted. Of these women, 312 (62%) had a subsequent pregnancy. Hypertensive disorders recurred in 120 (38%, 95% CI 33-44) women, of whom 15 (5%, 95% CI 3-7) delivered preterm. Women undergoing recurrence were more at risk to develop chronic hypertension after pregnancy (35% versus 16%, OR 2.8, 95% CI 1.5-5.3). Body mass index, non-White European origin, chronic hypertension, maximum diastolic blood pressure, no use of anticonvulsive medication and interpregnancy interval were predictors for recurrence. CONCLUSIONS: Women with hypertensive disorders and term delivery have a substantial chance of recurrence, but a small risk of preterm delivery. A number of predictors for recurrence could be identified and women with a recurrence more often developed chronic hypertension. PMID- 26104606 TI - Circulating endothelial progenitor cells and placental abruption in women with preeclampsia. AB - OBJECTIVE: Abnormalities in circulating angiogenic factors and endothelial progenitor cells (EPCs) have been reported in patients with preeclampsia and placental abruption. The objective of this study was to determine whether the number of EPCs is altered in patients with placental abruption. DESIGN: A case control study. SETTING: Hiroshima University Hospital in Japan. SAMPLE: Pregnant Japanese women with preeclampsia (n=27) and those without any complications (n=15). METHOD: The EPC (CD45(low)CD34(+)CD133(+) cells) counts were examined using flow cytometry in peripheral blood collected from 27 women with preeclampsia and 15 normal pregnant women. Among the 27 women with preeclampsia, five subsequently developed placental abruption. All subjects were divided into three groups: normal pregnancy (NP, n=15), preeclampsia without placenta abruption (PE, n=22) and preeclampsia with placental abruption (PA, n=5). MAIN OUTCOME MEASURES: The EPC counts were measured in pregnant women with preeclampsia who subsequently developed placental abruption. RESULTS: The EPC count in the PE group significantly decreased in comparison to that observed in the NP group (620cells/ml versus 1918 cells/ml, P<0.01). In the PA group, the EPC count was found to markedly decrease in comparison to that observed in the PE group (221cells/ml, P<0.05). CONCLUSIONS: The number of EPCs was found to significantly decrease in preeclamptic women who subsequently developed placental abruption. PMID- 26104607 TI - Maternal hypertensive diseases negatively affect offspring motor development. AB - OBJECTIVE: Hypertension in pregnancy and preeclampsia have been linked to poor outcomes in cognitive, mental and psychomotor development; however, few longitudinal studies have researched their effect on offspring motor development, particularly in late childhood and adolescence. The purpose of this study was to determine if maternal hypertensive diseases during pregnancy are a risk factor for compromised motor development at 10, 14, and 17years. STUDY DESIGN: Longitudinal cohort study using data from the Western Australian Pregnancy Cohort Study (Raine). MAIN OUTCOME MEASURE: Offspring (n=2868) were classified by their maternal blood pressure profiles during pregnancy: normotension (n=2133), hypertension (n=626) and preeclampsia (n=109). Offspring motor development, at 10, 14, and 17years was measured by the Neuromuscular Developmental Index (NDI) of the McCarron Assessment of Motor Development (MAND). METHODS: Linear mixed models were used to compare outcomes between pregnancy groups. RESULTS: Offspring from pregnancies complicated by preeclampsia had poorer motor outcomes at all ages than offspring from either normotensive mothers (p?0.001) or those with hypertension (p=0.002). CONCLUSION: Hypertensive diseases during pregnancy, in particular preeclampsia, have long term and possibly permanent consequences for motor development of offspring. PMID- 26104608 TI - 2-Methoxyestradiol deficiency is strongly related to hypertension in early onset severe pre-eclampsia. AB - OBJECTIVE: 2-Methoxyestradiol (2ME) deficiency leading to placental insufficiency has been related to pre-eclampsia (PE). Here we investigate whether 2ME is related to clinical profiles and vasoactive factors in early onset severe PE patients. METHODS: 28 severe PE patients and 20 uncomplicated normal pregnant women, with gestational weeks between 24 and 32weeks, were recruited. All cases and controls had singleton pregnancies and were matched for maternal age, parity, body mass index, and gestational weeks. Plasma levels of 2ME, estradiol (E2), soluble Fms-like tyrosine kinase-1 (sFLT-1), endothelin-1 (ET-1), nitric oxide (NO) were determined. RESULTS: PE patients had significant lower 2ME [906(422 1768) vs. 2032(1400-2910)pg/mL, P=0.002], higher sFLT-1 [5.55(3.24-11.22) vs. 3.13(2.17-5.36)ng/mL, P=0.015] and higher NO [122.40(72.92-168.23) vs. 45.83(25.52-61.46)MUmol/L, P=0.0008] levels in their plasma than the controls. In the PE group, plasma 2ME level correlated negatively with systolic pressure (r= 0.48, P=0.012), diastolic pressure (r=-0.52, P=0.007) and mean arterial pressure (r=-0.54, P=0.005) even after controlling for maternal age; 2ME level did not correlate with proteinuria, plasma levels of E2, sFLT-1, ET-1 or NO. In the control group, plasma 2ME level did not correlate with any of the above clinical profiles or laboratory measurements. CONCLUSIONS: 2ME levels were markedly lower in early onset severe PE and they correlated inversely with blood pressure only in women with PE. Although we cannot tell whether lower 2ME level is the causation or the result of PE, our study provides clinical evidences that 2ME deficiency is strongly related to hypertension in early onset severe PE patients. PMID- 26104609 TI - A comparison of Doppler waveform parameters versus flow-mediated vascular dilation of the brachial artery in pregnant women. AB - OBJECTIVE: Flow mediated dilation of the brachial artery is impaired with endothelial dysfunction. We previously identified that brachial artery waveforms were changed in preeclamptic women. We therefore sought to compare Doppler waveform analysis with flow mediated vascular dilation (FMVD) measurements in pregnant women. STUDY DESIGN: A cross sectional study of 71 pregnant women at >20weeks gestation comparing FMVD measurements with Doppler waveform parameters was performed. Research was conducted at three hospitals and two geographic settings; (1) Yale-New Haven Hospital in New Haven, CT, (2) Mount Hope Maternity and (3) Port of Spain General Hospital in Trinidad. Brachial artery Doppler waveform measurements were done at baseline and 90s post cuff-release. From the Doppler waveforms we assessed percent change in Peak Systolic Velocity (% DeltaPSV), systolic acceleration, acceleration time and pulsatility index and compared them with the percent change in FMVD. Statistical analysis using Student's t tests and correlation coefficient was done as necessary. RESULTS: Correlation analysis between the % change in the Doppler waveform parameters and the % change in mean FMVD identified only the waveform parameter of % DeltaPSV as significantly correlated (p=0.040). CONCLUSION: FMVD remains the gold standard for assessment of endothelial dysfunction. A correlation was observed between the Doppler measured % DeltaPSV and FMVD, which may allow it to be used to assess endothelial dysfunction changes under different conditions was identified. PMID- 26104610 TI - A trio of risk factors for the onset of preeclampsia in the second and early third trimesters. AB - OBJECTIVE: We evaluated the biological interaction among mean blood pressure (MBP), uterine artery Doppler (UAD), and the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio for preeclampsia (PE) risk. STUDY DESIGN: A prospective cohort study. MAIN OUTCOME MEASURES: In 1239 pregnant women, MBP and UAD were measured at 16-23weeks of gestation, and plasma levels of the sFlt-1/PlGF ratio at 19-25weeks and 26-31weeks. A Cox proportional hazard model was used. Women with a low sFlt-1/PlGF ratio and either low BP or normal UAD were set as controls. The relative excess risk due to biological interaction (RERI) was calculated using the following equation: RERI=hazard ratio (HR) in women with high sFlt-1/PlGF and both high BP and abnormal UAD (group 3) - HR in women with both high BP and abnormal UAD alone (group 1) - HR in women with high sFlt-1/PlGF alone (group 2)+1. RERI?10 was considered to be strong. RESULTS: At 19-25weeks, the HR and 95% confidence intervals (CI) in group 1, group 2, and group 3 were 7.4 (3.1-17.4), 15.3 (4.5-52.2), and 107.0 (41.0-279), respectively, and the RERI for PE was 85.3. At 26-31weeks, the HR and 95% CI in each group were 8.3 (2.9-23.2), 7.5 (0.97-57.8), and 69.0 (18.5-256), respectively; the RERI for PE was 54.2. CONCLUSIONS: We found a trio of risk factors for the onset of PE in the second and early third trimesters: high BP, abnormal UAD, and high sFlt 1/PlGF ratio. PMID- 26104611 TI - Exercise in pregnancy - UK women's views and experiences: results of an online survey. AB - Both NICE and RCOG recommend 30min of moderate physical activity, at least four times per week, for women with uncomplicated pregnancies, in all trimesters. The primary aims of this study were to establish the views of UK women regarding how much exercise they should undertake at each stage of pregnancy and whether they accumulated the recommended amount of physical activity through exercise during their current or most recent pregnancy. METHODS: An online survey was developed and advertised to women who had been or were pregnant via social media and websites related to pregnancy or parenting. Exercise was defined within the survey as including jogging, cycling, exercise classes and brisk but not gentle walking. RESULTS: 1001 women participated. 22.9% were currently pregnant, and 64.8% had been pregnant in the last three years. 38.5% of participants reported that women should exercise four or more times per week in the first trimester, and 23% in the third trimester. 21.3% reported exercising four or more times per week in their first trimester, and 11.4% in the third trimester. 46.9% reduced their exercise upon becoming pregnant, while 6.7% increased exercise and 12% stopped completely. Tiredness (62.7%), aches and pains (44.8%), morning sickness (41.4%) and worry about miscarriage (27.4%) were the most common reasons to avoid exercise. CONCLUSIONS: UK women may be unaware of the recommended levels of physical activity in pregnancy and may fail to meet recommendations through exercise. Despite no evidence of risk, women are concerned that exercise contributes to miscarriage. PMID- 26104612 TI - What women really think about gestational weight management: A thematic analysis of posts made in online parenting forums. AB - Traditional research methods may not assess true beliefs and views of sensitive topics such as obesity because the research situation tends to promote particular responses based on the perceived expectations of the researcher and pressure to be 'politically correct'. The publication of the NICE guidance on weight management in pregnancy in 2010, and the subsequent press coverage of it, provided a stimulus for discussion of gestational weight management on UK-based online parenting forums. A systematic search identified 21 UK parenting forums on which 400 posts referring to guidance on weight management in pregnancy were made by 202 women in the two-week period following the publication of the guidance. These posts were analysed thematically resulting in the identification of three main themes: (i) Perceived control/responsibility (ii) Risk perception (iii) Confused messages. Women differed in their perceptions of the level of control that people had over being overweight with some women reporting feeling guilty and experiencing significant obesity stigma. Information about the risks of overweight and obesity in pregnancy were difficult messages for women to hear, and for health professionals to deliver and they used a range of strategies to downplay their personal risk. Women reported being confused by the messages that they received. Health messages need to be delivered sensitively to women, and health professionals need support and training to do this. Risk information should always be accompanied with advice and support to help women to manage their weight in pregnancy. PMID- 26104613 TI - Choose to change maternity weight management pilot. AB - Obesity during pregnancy is associated with increased risk of adverse health outcomes during pregnancy. There is limited research available regarding effective interventions during pregnancy for obese women and this is combined with local inadequate service provision to support obese mothers in Greater Manchester (GM). Choose to Change (CTC) aims to develop, deliver and evaluate a community based weight management programme to limit excessive gestational weight gain. Participants (n=73) referred from January to December 2013 by Community Midwifery Teams (>18years) with a BMI >30 attended a healthy lifestyle intervention (1:1 or group) covering nutrition, physical activity and behaviour change over 12weeks. Baseline measures were weight, Body Mass Index (BMI), Blood Pressure, physical activity, dietary habits and psychological questionnaires measuring anxiety, self-esteem and dis-ordered eating. 28 clients were assigned to intervention (group (n=15), 1:1 (n=13). Mean age 29 (SD=5.78), mean BMI at referral was 38.96 (SD=4.87). Descriptive statistics suggest an average weight gain for clients (excluding drop outs n=12) is 0.94kg (SD=6.65). For those who have completed the programme (n=8) average weight gain was 1.03kg (SD=7.71). Results vary according to intervention type 1:1, 0.04kg (SD=8.82kg), group, 1.52kg (SD=3.17kg). Drop-out rate from referral to assessment was 62%, from assessment to intervention 32% and during intervention 26%. Overall the results of the present pilot study indicate that the CTC healthy lifestyle intervention can limit excessive gestational weight gain. CTC is looking at future directions for development including changing the assessment procedure to improve DORs, further analysis of various mediating factors including BMI and intervention type and exploration of post-measurements to show further improved health outcomes as the programme is rolled out across GM. PMID- 26104614 TI - Weight management during and after pregnancy: A multi-disciplinary approach. AB - The Specialist Weight Management Service (SWMS) Maternity Pathway was launched in January 2012 as a result of growing public health issues surrounding obesity and the production of NICE Guidelines for weight management before, during and after pregnancy (PH27). Our unique NHS service is aimed at pregnant women with a BMI>35 and supports them with introducing healthy lifestyle changes during pregnancy and safely minimising weight gain in this period. We also actively encourage service users to re-engage with the integrated SWMS pathway for up to 18months post partum. The majority of referrals are received directly from midwives, and women can also self-refer. Pregnant women who come to our service are seen in multi disciplinary clinics by a Dietitian, Physiotherapist and Health-Improvement Midwife. The service-users can also access Occupational Therapists, Medical Consultants and Health Trainers if required. Our staff use a patient-centred behavior change approach, often adopting motivational interviewing techniques to help engage patients with implementing positive lifestyle changes. The pathway also helps expectant mothers and their wider families access other services including smoking cessation, breastfeeding networks and healthy-start services to name a few. Plans are in place to launch an outreach service to the more deprived areas of the Borough, where drop-in sessions will be held at accessible locations to improve engagement of pregnant women in these areas. We believe that this multi-disciplinary approach to weight management is unique, and early statistics indicate that the support we offer pregnant women during the ante and post natal period are a success in terms of key outcome measures. PMID- 26104615 TI - Differential gene expression in obese pregnancy. AB - Maternal obesity is a major risk factor for maternal and perinatal complications, and is associated with increased risk of premature cardiovascular death in the offspring. We aimed to identify differentially expressed genes in obese and lean pregnancies. Pregnant women were recruited antenatally and whole-blood samples taken at gestational week 28. Women were classified as lean (BMI<25, n=5), overweight (BMI 25-30, n=11) or obese (BMI>30, n=4). Subcutaneous adipose tissue was obtained from a separate cohort of women undergoing elective Caesarean section (n=3 lean, n=6 overweight, n=9 obese). Total RNA was isolated and gene expression profiled by Illumina microarray technology. Differential gene expression was identified by Ingenuity Pathway Analysis and validated by TaqMan qRT-PCR. In whole blood, differential expression (p<0.05) of six genes (ANGPTL, COX7A2, EIF3A, PTS, CISD1 and GLRX) was identified between lean and non-lean pregnant women by microarray. When gene expression was studied in subcutaneous tissues, we observed a trend towards lower expression of the cytochrome c oxidase subunit 7A2 gene (COX7A2) in overweight vs lean (p=0.057) and obese vs lean (p=0.06) women, whereas expression was similar between overweight and obese women (p=0.55). Other genes were not differentially expressed across groups. Maternal obesity is associated with differential expression of multiple genes in whole blood. In subcutaneous tissue at term, there was a trend towards reduced COX7A2 expression in obese women. COX7A2 is a mitochondrial protein, with key roles in steroidogenesis and oxidative stress regulation and could provide a link between inflammation and obesity-related pregnancy complications. PMID- 26104616 TI - 'Healthy Eating and Lifestyle in Pregnancy (HELP)' trial: Process evaluation framework. AB - INTRODUCTION: We developed and tested in a cluster RCT a theory-driven group based intervention for obese pregnant women. It was designed to support women to moderate weight gain during pregnancy and reduce BMI one year after birth, in addition to targeting secondary health and wellbeing outcomes. In line with MRC guidance on developing and evaluating complex interventions in health, we conducted a process evaluation alongside the trial. This paper describes the development of the process evaluation framework. METHOD: This cluster RCT recruited 598 pregnant women. Women in the intervention group were invited to attend a weekly weight-management group. Following a review of relevant literature, we developed a process evaluation framework which outlined key process indicators that we wanted to address and how we would measure these. Central to the process evaluation was to understand the mechanism of effect of the intervention. We utilised a logic-modelling approach to describe the intervention which helped us focus on what potential mediators of intervention effect to measure, and how. RESULTS: The resulting process evaluation framework was designed to address 9 core elements; context, reach, exposure, recruitment, fidelity, recruitment, retention, contamination and theory-testing. These were assessed using a variety of qualitative and quantitative approaches. The logic model explained the processes by which intervention components bring about change in target outcomes through various mediators and theoretical pathways including self-efficacy, social support, self-regulation and motivation. CONCLUSION: Process evaluation is a key element in assessing the effect of any RCT. We developed a process evaluation framework and logic model, and the results of analyses using these will offer insights into why the intervention is or is not effective. PMID- 26104617 TI - Weight management in Pregnancy: Participants' experiences of 'Healthy Eating and Lifestyle in Pregnancy (HELP)', a maternity care intervention for obese pregnant women. AB - BACKGROUND: Around 1 in 5 pregnant women in the UK are obese. Obesity is linked to poor health and pregnancy complications. We developed and tested in a cluster RCT a group-based intervention for obese pregnant women, facilitated by midwives and slimming world consultants. It was designed to support obese women during pregnancy to moderate weight gain and reduce BMI one year after birth, in addition to targeting secondary health and wellbeing outcomes. This paper aims to explore participants' experiences of engaging in the 'HELP' trial in particular their views of the intervention and ongoing weight challenges. METHODS: Thirty participants took part in semi-structured telephone interviews as part of the process evaluation. The data were analysed using thematic analysis. RESULTS: Participants' accounts offered insights into the intervention group environment, the importance of social support and the value of each facilitator's involvement. Reasons for compliance were highlighted, with interesting discussion on aspects that encouraged and supported women to make behaviour changes during their pregnancy, barriers to engaging with the intervention and longer term behaviour change. Participants, especially those who had previously accessed maternity care, emphasised the benefits of this service being available where they obtained knowledge, skills and support in relation to weight and pregnancy. CONCLUSIONS: Engaging in the intervention can help women to adopt healthier habits leading to avoidance of excess weight gain during pregnancy, better outcomes for mother, baby and the wider family. Consideration of other factors may be required for impact on long term outcomes. PMID- 26104618 TI - The feasibility and acceptability of regular weighing of pregnant women by community midwives to prevent excessive weight gain: RCT. AB - Pregnancy is a critical period for the development of later obesity. Regular weighing of pregnant women is not currently recommended in the UK. This study aimed to demonstrate the feasibility of regular weighing by community midwives (CMWs) as a potential intervention to prevent excessive gestational weight gain. Low risk healthy/overweight pregnant women cared for by eight CMWs were randomised to usual care or usual care plus the intervention at 10-14 weeks of pregnancy. The intervention involved CMWs weighing and charting weight gain on an IOM weight gain chart, setting a weight target and giving brief feedback at antenatal appointments. The focus of the study was on process evaluation outcomes. Data on other outcomes were also collected including gestational weight gain. We interviewed women and CMWs about their views of the intervention. CMWs referred 123 women, 95 agreed to participate and 76 were randomised. Over 90% of women were weighed at 38 weeks of pregnancy demonstrating high follow up. There was no evidence the intervention caused anxiety. Most women commented they had found the intervention useful in encouraging them to think about their weight and believed it should be part of routine antenatal care. CMW's felt the intervention could be implemented within antenatal care without adding substantially to consultation length. To conclude, pregnant women were keen to participate in the study and the intervention was acceptable to pregnant women and CMWs. An effectiveness trial is now planned. PMID- 26104619 TI - Implementation of pregnancy weight management and obesity guidelines: A meta synthesis of healthcare professionals' barriers and facilitators using the Theoretical Domains Framework. PMID- 26104620 TI - Systematic review of randomised controlled trials on exercise interventions for weight management during pregnancy and up to one year postpartum among normal weight, overweight and obese women. AB - OBJECTIVE: To review the effectiveness of exercise interventions in managing weight among pregnant and postpartum women. METHODS: Ten databases were searched for randomised controlled studies, published between January 1990 and September 2013 that compared an exercise-based weight management intervention with routine care or another type of intervention. There were no restrictions to the type, frequency, duration, intensity or mode of exercise intervention. Interventions not specifically designed to target or affect weight were excluded. Study quality was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomised trials and the Consolidated Standards of Reporting Trials statement. RESULTS: The combined searches yielded 354 articles. Reasons for study exclusion included but were not limited to; non-randomisation, retrospective study design, duplicates, qualitative/baseline studies, not specifically designed to influence weight, combined intervention and study protocols. Five papers were included in this review (three trials with pregnant women and two trials with postpartum women). Two of the three pregnancy-related studies found that exercise interventions significantly reduced gestational weight gain. In addition, postpartum women in the intervention groups lost significantly more body weight than those in the control groups. CONCLUSIONS: There is a paucity of information on the efficacy of exercise-only interventions for the prevention of excessive gestational weight gain and retention. However, there is some limited evidence to suggest that exercise can be used for these groups to alleviate some of the issues associated with maternal obesity. PMID- 26104621 TI - Association between physical activity in obese pregnant women and offspring health. AB - BACKGROUND: Obesity in pregnancy is associated with macrosomia, neontatal fat mass and increased obesity and diabetes in the offspring. Physical activity during pregnancy may mediate the relationship between maternal insulin action and infant body composition. Interventions to increase physical activity might therefore improve metabolic outcomes for pregnant women and reduce the risk of obesity and diabetes in their offspring. The UK Pregnancy Better Eating and Activity Trial (UPBEAT) is a complex intervention, designed to improve pregnancy outcome through dietary change and increased physical activity. The analysis presented here includes data from 183 women recruited to the pilot phase of UPBEAT. METHODS: Physical activity was assessed by accelerometer at recruitment, at 27-28weeks' gestation and at 35-36weeks' gestation. The relationship between sedentary behaviour and moderate and vigorous physical activity (MVPA) and infant body composition at birth was examined using Spearman partial correlations. RESULTS: Maternal sedentary time at recruitment was inversely associated with neonatal abdominal circumference (-0.333, p=0.016), but at 35-36weeks' gestation was positively associated with neonatal abdominal circumference (0.435, p=0.023). Sedentary time was not associated with these outcomes at 27-28weeks' gestation. MVPA at 35-36weeks' gestation was inversely associated with neonatal abdominal circumference (-0.466, p=0.014). No associations between physical activity and birthweight were apparent. CONCLUSIONS: Our findings suggest that physical activity during pregnancy is associated with infant body composition and that maternal physical activity is an appropriate target for intervention to improve infant outcomes. UPBEAT is funded by NIHR-UK (RP-0407-10452). PMID- 26104622 TI - Timing of pregnancy in obese women after bariatric surgery. AB - AIMS: There is an increased risk of preterm and small-for-gestational-age births associated with bariatric surgery, especially if maternal early pregnancy body mass index (BMI) is <30.0kg/m(2). However, the relationship between timing of pregnancy post-bariatric surgery and effects on pregnancy outcome are unknown. The aim of this study was to investigate the timing of pregnancy post-bariatric surgery and compare early pregnancy BMI between women who became pregnant before or after the recommended 12month postoperative window. METHODS/RESULTS: Women who underwent either sleeve gastrectomy or gastric bypass and subsequently became pregnant were offered antenatal care in a multidisciplinary high-risk clinic. There were 50 such pregnancies in women who attended our high-risk clinic (n=26 <12months and n=24 >12months postoperatively, mean estimated times to conception 31.9+/-12.6weeks and 102.8+/-37.7weeks respectively). There was no significant difference in early pregnancy BMI between groups (33.2+/-6.8kg/m(2) and 32.5+2.1kg/m(2) respectively, p=0.78). There were 6 miscarriages in each group, however more women in the <12month (n=8) than in the >12months group (n=2) were lost-to-follow-up (likelihood ratio 4.2, p=0.04). CONCLUSIONS: Women who became pregnant <12months post-bariatric surgery were, for unknown reasons, less likely to attend follow-up in a specialist antenatal clinic than those who became pregnant >12months postoperatively. Further research is required to explore the relationship between timing of pregnancy post-bariatric surgery and pregnancy outcome and to identify predictors more clinically useful than early pregnancy BMI, in this high-risk pregnancy group. PMID- 26104623 TI - Maternal vitamin D status in Type 1 diabetic pregnancy: Impact on neonatal vitamin D status and association with maternal glycaemic control. AB - OBJECTIVE: 1. To examine relationships between 25-hydroxy vitamin D (25OHD) in women with type 1 diabetes (T1DM) during pregnancy, post-delivery and in cord blood. 2. To investigate interactions between maternal body mass index (BMI) and foetal vitamin D status. 3. To examine relationships between maternal 25OHD and glycosylated haemoglobin (HbA1c). METHODOLOGY: An observational study of 52 pregnant controls without diabetes and 65 pregnant women with T1DM in a university teaching hospital. 25OHD was measured by liquid chromatography tandem mass spectrometry. RESULTS: Vitamin D deficiency (25OHD <25nmol/L) was apparent in control and T1DM women in all 3 trimesters. All cord blood 25OHD were <50nmol/L. Maternal 25OHD correlated positively with cord 25OHD at all 3 trimesters in the T1DM group (p=0.02; p<0.001; p<0.001). Cord 25OHD was significantly lower for T1D women classified as obese vs. normal weight at booking [normal weight BMI <25kg/m(2) vs. obese BMI>30kg/m(2) (nmol/L+/-SD); 19.93+/-11.15 vs. 13.73+/-4.74, p=0.026]. In the T1DM group, HbA1c at booking was significantly negatively correlated with maternal 25OHD at all 3 trimesters (p=0.004; p=0.001; p=0.05). CONCLUSION: In T1DM pregnancy, low vitamin D levels persist throughout gestation and post-delivery. Cord blood vitamin D levels correlate with those of the mother, and are significantly lower in obese vs normal weight women. Maternal vitamin D levels exhibit a significant negative relationship with HbA1c, supporting a potential role for this vitamin in maintaining glycaemic control. PMID- 26104624 TI - Anthropometric and nutritional associations of food cravings in pregnancy. AB - Dietary cravings alter food intake however the nutritional and anthropometric consequences are unknown. This study aimed to assess the prevalence and types of foods craved during pregnancy and secondly to compare the anthropometric, clinical characteristics and nutritional intakes of women with and without food cravings. METHODS: Healthy pregnant women were participants in the Belfast cohort of Hyperglycaemic and Adverse Pregnancy Outcome study (HAPO), a prospective observational study examining maternal glycaemia and pregnancy outcome. Diet was assessed using a validated semi-quantitative food frequency questionnaire at 29weeks gestation which included subjective questions on food cravings. Mean daily nutrient intakes were analysed using Q Builder nutritional software (Tinuviel Software, UK) and SPSS Version 20. RESULTS: Data were available for 1639 women, mean age 30 (SD 5.5) years; mean BMI at booking (<16weeks gestation) 25.6kg/m(2) (range 16.5-50.8) of which 39% (n=635) experienced food cravings. Women who craved foods had a higher mean daily energy intake (9721kJ+3016) (p=0.002) and gained more weight (9.55kg+5.4) (p=0.049) throughout pregnancy than those who did not experience food cravings (9256kJ+2786 and 8.95kg+5.4 respectively). Women who were overweight (30%) or obese (16%) at booking, did not differ in their likelihood of reporting cravings to those who were under- or normal weight at booking. CONCLUSION: Cravings occur commonly in pregnancy and those women who craved foods had a higher mean energy intake and gained more weight throughout pregnancy than those who did not crave foods. This study was supported by a grant from Sugar Nutrition UK. PMID- 26104625 TI - Pre-pregnancy obesity and mental disorders during pregnancy and postpartum: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the prevalence and risk of antenatal and postnatal mental disorders among obese and overweight women. METHOD: Six databases (including MEDLINE, EMBASE, PsycINFO) were searched from inception to January 2013, in addition to citation tracking, hand-searches and expert recommendations. Studies were eligible if antenatal or postnatal mental disorders were assessed with diagnostic or screening tools among women who were obese or overweight at the start of pregnancy. Of the 4627 screened articles, 62 met the inclusion criteria for the review. RESULTS: Unadjusted odds ratios were pooled using random-effects meta-analysis for studies examining antenatal depression (n=29), postnatal depression (n=16), antenatal anxiety (n=10) and postnatal anxiety (n=3). Obese and overweight women had significantly higher odds of elevated depression symptoms than normal weight women, both during pregnancy and postpartum . Obese women also had higher odds of antenatal anxiety. The few studies identified for eating disorders (n=2) or serious mental illness (n=2) also suggested increased risk among obese pregnant women. CONCLUSIONS: Healthcare providers should be aware that women who are obese when they become pregnant are more likely to experience elevated antenatal and postpartum depression symptoms than normal weight women, with intermediate risks for overweight women. Further high quality studies are needed for other mental disorders, and to investigate the impact of co-morbid obesity and mental disorders on pregnancy outcomes. This review was carried out as part of a PhD studentship funded by the Medical Research Council and Tommy's Charity. PMID- 26104626 TI - Evaluation of 'Just4Mums' - A community based healthy eating and physical activity course for obese pregnant women. AB - Current NICE guidelines state that women in England need to be supported regarding eating healthily and being physically active during pregnancy. In response to these guidelines, the Just4Mums service was developed - a free six week community-based course for obese (BMI?30) pregnant women. The service encouraged a healthy weight gain in pregnancy through the provision of information on healthy eating and opportunities to be physically active. The aim of this evaluation was to provide preliminary evidence on efficacy. METHODS: Participants' were assessed at the beginning and end of the course, in terms of healthy eating and physical activity (PA) behaviour, mental well-being, and mediating variables (i.e. intentions, self-efficacy and attitudes towards healthy eating and PA). RESULTS: Thirty-four out of 60 women (57%) women completed the course. There were few differences between those women who completed and did not complete the course. After attending the service, the intention-to-treat analysis showed an improvement in healthy eating (higher intake of fruit and vegetables, lower intake of fast food), no change in PA, reduction in sedentary behaviour and an improvement in mental well-being. Participants also increased their attitude, intention and self-efficacy towards engaging in PA and intention to eat fruit and vegetables. CONCLUSIONS: These findings suggest that women who completed the Just4Mums service improved their health behaviours. More research is needed to identify why so many women dropped out of the service. PMID- 26104627 TI - 3-Epi-25 hydroxyvitamin D in pregnancy. AB - OBJECTIVE: The physiological importance of the C3 epimers of vitamin D (3-epi 25OHD2/3) is uncertain and there have been limited studies determining the levels of these epimers in human populations. The aims of the current study were (1) to determine 3-epi-25OHD2/3 levels throughout non-diabetic and T1DM pregnancy, (2) to examine the relationships between 25OHD and 3-epi-25OHD, (3) to assess the impact of maternal BMI on 3-epi-25OHD and examine associations with markers of glycaemic control. METHODOLOGY: An observational study of 52 pregnant controls without diabetes and 65 pregnant women with T1DM in a university teaching hospital. 25OHD and 3-epi-25OHD were measured by liquid chromatography tandem mass spectrometry. RESULTS: 3-Epi-25OHD was found in 90.2% of control (median 0.9nmol/L; range 0.1-5.9nmol/L), and in 94.5% of T1DM, women (median 1.4nmol/L; range 0.1-10.5nmol/L). In both control and T1DM groups, maternal and cord 3-epi 25OHD correlated significantly with 25OHD. Seasonal variation in maternal 3-epi 25OHD levels was evident in both groups; Summer levels were significantly higher than all other seasons in the control group (p<0.001) and significantly higher than Spring (p=0.003) and Winter (p<0.001) in the T1DM group. In T1DM women HbA1c was significantly negatively correlated with 3-epi-25OHD at trimesters 1 and 2 (p=0.049; p=0.001) and with cord 3-epi-25OHD (p=0.012). Maternal BMI >30kg/m(2) had a significant negative impact on 3-epi-25OHD. CONCLUSION: Maternal 3-epi 25OHD exhibits seasonal variation and, in common with cord 3-epi-25OHD, correlates with 25OHD throughout both non-diabetic and T1D pregnancy. In T1DM women 3-epi-25OHD is associated with a key marker of glycaemic control. PMID- 26104628 TI - Variation in outcomes in trials reporting effects of diet and lifestyle based intervention on pregnancy outcomes: a systematic review. AB - Obesity is a growing threat to women of childbearing age. Increased maternal weight or excessive weight gain in pregnancy is associated with adverse pregnancy outcomes. Interventions based on diet and physical activity minimise gestational weight gain with varied effect on a number of clinical outcomes. There is no consensus amongst the trialists on the core outcomes that need to be reported to inform the clinical care of pregnant women. The aim of this systematic review is to evaluate variation in the type and quality of outcomes reported in systematic reviews and randomised controlled trials on diet and lifestyle interventions on maternal and fetal outcomes. We will assess the correlation between the type of outcome, the quality of the studies and journal impact factor. We searched the major databases from the inception to October 2013 without language restrictions. We used current recommendations for quality of outcome reporting using a 6-point scale. The quality assessment of systematic reviews and RCTs was performed using the AMSTAR and Jadad scoring systems. Additionally we obtained journals' impact factor in the year of publication. We calculated Spearman rank coefficient to assess the correlation between the type of outcome, and study quality. An overview of outcome reporting will show the current attitude of the researchers towards outcomes of importance when conducting trials on diet and lifestyle management in pregnancy. If our abstract is accepted, we will provide the details of the results. PMID- 26104629 TI - Pregnancy and beyond - the role of BMI in predicting body satisfaction, eating behaviour and infant feeding across two countries. AB - INTRODUCTION: Weight change during pregnancy and maternal body mass index (BMI) are associated with negative body image and restrained eating. However, there are cross-cultural differences in how these changes are experienced and how this might in turn affect maternal eating or infant feeding. The present study aimed to: (1) examine if self-esteem, eating behaviours and body satisfaction measured during pregnancy changed following birth and varied according to country (Israel vs. UK); and (2) explore any relationship between these measurements and infant feeding/eating behavior. METHODS: Participants were asked to complete the following questionnaires: Rosenberg Self-Esteem Questionnaire, Body Image Scale, Dutch Eating Behaviour Questionnaire, Baby Eating Behaviour Questionnaire and the Infant Feeding Questionnaire. Multilevel linear modelling was used to account for differences over time and to assess the independent impact of BMI on questionnaire scores. RESULTS: 73 women and infants participated in the study 16(9) weeks following birth. Levels of self-esteem and eating behaviours did not significantly change. UK women showed significantly higher desire to be slim following birth compared to Israeli women. Mothers' perceptions of infant's eating did not vary according to BMI nor country, however heavier mothers reported a significantly higher tendency to feed their infant according to a schedule. CONCLUSION: BMI was the strongest and most stable predictor of maternal well being and eating behaviour. The lack of change post-pregnancy suggests that self esteem, body image and affect are relatively stable but that it is important to follow the mothers beyond the early stages of the postnatal period. PMID- 26104630 TI - Who are we missing? Examining non-participants in "Fit for Delivery", a randomized, controlled trial of a lifestyle intervention in pregnancy. AB - BACKGROUND: Fit for Delivery (FFD) is a randomized, controlled trial of a lifestyle intervention designed to limit weight gain and increase physical activity in pregnancy. A questionnaire for non-participants was included in the design of the study. METHODS: Nulliparous women residing in southern Norway were invited to participate in FFD if they had a singleton pregnancy at ?20weeks gestation, age ?18years and body mass index (BMI) of ?19kg/m(2). Women who declined participation were asked to complete an anonymous questionnaire with 7 questions. They were asked reason for non-participation (8 choices), age, height, pre-pregnancy weight, smoking status, educational level and frequency of physical activity. Study participants (n=606) completed a more comprehensive questionnaire before randomization. Responses were compared using independent-samples t-test and chi-square test for continuous and categorical data, respectively. RESULTS: Non-participants who completed the non-response questionnaire (n=60) most often cited satisfaction with their own nutrition and fitness plan (50%) and being too busy to exercise several days a week (43%). Compared with participants, non participants were younger (mean difference 1.48 years, CI 0.51-2.65 (p=0.013)), more often smokers (12.5% vs. 4%, p=0.014), and fewer had ?4years of higher education (9.4% vs. 35.6%, p<0.001). There were no significant differences between groups in weight, height, BMI or physical activity level. CONCLUSION: There is a statistically significant difference in age, smoking and educational status between FFD participants and non-participants. BMI and activity level do not differ between groups. These finding may help us in developing future interventions and trials. PMID- 26104631 TI - Altered maternal hypothalamic-pituitary-adrenal axis activity in obese pregnancy is associated with macrosomia and prolonged pregnancy. AB - BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is important for fetal growth and timing of parturition. Maternal obesity is associated with macrosomia (birthweight ?4000g) and prolonged pregnancy (?41weeks). We aimed to characterise HPA axis hormones in obese pregnancy and to test associations with these pregnancy outcomes. METHOD: Fasting cortisol was measured by radioimmunoassay in venous blood at 16, 28 and 36 weeks of gestation in 286 obese (BMI 44.05+/ 3.98kg/m(2)) and 137 lean (BMI 22.71+/-1.66kg/m(2)) pregnant women. In subsets (n=20 obese, 20 lean) we measured corticosteroid binding globulin (CBG) and CRH by radioimmunoassay; progesterone, estradiol (E2), estriol (E3) and sex-hormone binding-globulin (SHBG) by ELISA; and albumin by bromocresol green binding. Free cortisol levels were calculated using Coolen's equation. RESULTS: Cortisol, CBG, calculated free cortisol, CRH, E2, E3, progesterone and SHBG levels rose similarly during pregnancy in obese and lean, but were significantly lower in obese (p<0.05). In obese, lower free cortisol at 16 weeks was associated with higher birthweight (r=-0.46, p<0.05). Cortisol was not associated with labour onset. CRH was significantly lower at 36 weeks in women who delivered at ?41weeks and in women with macrosomic babies (p<0.05); and correlated negatively with gestation at delivery in obese (r=-0.557, p<0.05). CONCLUSION: Our findings suggest that decreased HPA axis activity in obese pregnancy may be a mechanism underlying macrosomia and prolonged pregnancy. PMID- 26104632 TI - Pregnancy after diabetes obesity surgery (PADOS): Qualitative study of pre pregnancy care. AB - Half of all bariatric surgical procedures are in women of childbearing age. Surgery may improve fertility yet exacerbate nutritional deficiencies, that may be disadvantageous to the fetus. A frequently encountered subgroup of obese women have type 2 diabetes. The health risks, to both mother and child, of diabetes in pregnancy are well described including 4.7* risk of stillbirth and 2* risk of congenital abnormality. What is not clear is whether bariatric surgery mitigates or complicates the health consequences of women with obesity and diabetes in pregnancy. In addition the influence of the type of surgery, the optimal interval between surgery and conception and evidence based preconception recommendations are unknown. This study complements wider research aiming to inform optimal management of this patient population. Obese diabetic women require clear guidance regarding pregnancy planning after surgery. This study will develop an understanding of the barriers and facilitators (psychological, behavioural, attitudinal and nutritional) to achieving effective pre-pregnancy health and care in women with type 2 diabetes who have undergone metabolic surgery. Currently women's perception of fertility issues and risks after bariatric surgery is unknown and thus a qualitative interpretive paradigm was chosen. Interviews with the target population will explore decision-making processes; experience regarding metabolic surgery and perceived pregnancy risk. Interviews with a broad range of health professionals involved in bariatric care will include rationale for selected surgical procedure and post surgery referral processes e.g. contraceptive care. This will advance understanding of how to provide targeted support and monitoring. PMID- 26104633 TI - Differences in health related pregnancy characteristics between White British and Pakistani women: The influence of the woman's, her partner's and their parents' place of birth. AB - BACKGROUND: Migration to high income countries can offer socioeconomic advantages such as improved education, employment opportunities, housing and health care. However, environmental improvements do not necessarily translate into improved health outcomes. It is possible that the unhealthy lifestyles associated with acculturation, characterised by less physical activity and high calorie diets, counteract any potential health advantage. Adoption of such lifestyles may be particularly harmful to South Asians who for a given BMI, have greater adiposity and an increased risk of diabetes and cardiovascular disease. METHODS: We compared BMI, fasting and postload glucose and fasting insulin between 5038 Pakistani and 4412 White British women recruited to the Born in Bradford study and examined whether differences varied depending on the woman's, her partner's and their parents' place of birth. RESULTS: BMI was lower among Pakistani compared to White British women (mean difference -1.12 95%CI -1.43, -0.81) but the difference was markedly greater where the partner was UK born irrespective of the woman's place of birth. Pakistani women had higher fasting and postload glucose (mean difference 0.20 95%CI 0.17, 0.24; 0.37 95%CI 0.28, 0.45) and higher fasting insulin than White British women (mean difference 25.71 95%CI 22.73, 28.69). This difference was greatest when women and their partners were South Asian born. CONCLUSIONS: Our results suggest some changes in health related pregnancy characteristics in response to migration to the UK. PMID- 26104635 TI - Welcome Message from the Chairman of Indonesia ISSHP. PMID- 26104634 TI - Pregnancy after diabetes obesity surgery (PADOS): Incidence and outcomes. AB - Half of all bariatric surgical procedures are in women of childbearing age but it remains unclear whether surgery is suitable for women who subsequently conceive: specifically the relative risks and benefits of potential nutrient deficiencies versus weight reduction. We will present data collected from Clinical Practice Research Databases on the maternal and fetal outcomes of pregnancies complicated either by obesity or previous bariatric surgery (BS). Two groups, matched to obese controls for BMI pre-BS and post-BS (at the time of ante-natal booking) will be compared. In this way, the effect of BS on pregnancy outcomes may be examined, independent of its effect on weight. A sub-group of women with antecedent Type 2 diabetes (T2DM) will allow for investigation of the additional impact and persistence of this co-morbidity. This builds upon pilot data collected from a retrospective cohort of women (18-45years) undergoing laparoscopic roux-en-Y (RYGB) surgery over a 24-month period (n=218). After exclusions and loss to follow up, data from 111 patients were analysed; 81 (73%) had conceived prior to RYGB, 20 (18%) became pregnant post RYGB and a further 22 patients (20%) were trying to conceive at the time of data collection. Three women had T2DM which resolved post BS. A suggestion of greater miscarriage risk prior to surgery in this sub-group will be confirmed as more women are recruited. Pregnancy is a frequent desire/occurrence after BS. This database study will advance understanding of the maternal and fetal outcomes of such pregnancies and inform antenatal care. PMID- 26104636 TI - Early and late-onset pre-eclampsia. AB - There is discrepancy in the literature on the definitions of severe and early onset pre-eclampsia. We aimed to determine those definitions for clinical purposes and to introduce them in the classification of the hypertensive disorders of pregnancy forpublication purposes. We circulated a questionnaire to the International Committee of the International Society for the Study of Hypertension in Pregnancy focusing on the thresholds for defining severe preeclampsia and the gestation at which to define early-onset preeclampsia, and on the definition and inclusion of the HELLPsyndrome or other clinical features in severe preeclampsia. The questions were closed, but all answers had space for more open detailed comments.There was a general agreement to define preeclampsia as severe if blood pressure was ?160mmHg systolic or 110mmHg diastolic. There was scarce agreement on the amount of proteinuria to define severity. The HELLP syndrome was considered a feature to include in the severe classification. Most investigators considered early-onset preeclampsia as that occurring before 34 weeks. A definition of pre-eclampsia is paramount for driving good clinical practice. Classifications on the other hand are useful to enable international comparisons of clinical data and outcomes. We used the results of this survey to update our previous classification for the purposes of providing clinical research definitions of severe and early onset pre- eclampsia that will hopefully be accepted in the international literature. PMID- 26104637 TI - Diagnostic and predictive accuracy of placental growth factor in suspected pre eclampsia. AB - The diagnosis of preeclampsia can be difficult with considerable uncertainty when the presenting features are borderline. Moreover underlying medical conditions may obscure or simulate the onset of pre-eclampsia. There is a clinical need to be able to diagnose, more accurately, those forms of the disease that are likely to progress to an adverse fetal or maternal outcome. Maternal circulating placental growth factor (PIGF) concentrations are decreased in these women, in correlation with disease severity and gestational age of onset. In this study its diagnostic performance was evaluated with an accurate, point of care test. The PELICAN study was a prospective observational cohort study, in seven maternity units in the British Isles. 625 women presenting between 20+0 and 40+6 weeks gestation with suspected preeclampsia were recruited, excluding those already diagnosed with preeclampsia. PIGF was measured (Alere Triage(r) PIGF test) in the enrolment sample after all participants had delivered so that clinical decisions were not affected by its results. ISSHP definitions of hypertensive disease were assigned, blinded to PIGF values. Analysis was conducted to assess diagnostic accuracy of the enrolment PIGF level for placental dysfunction requiring delivery within 14days. In women who presented before 35 week's gestation the PIGF test predicted placental dysfunction, that required deliverywithin the next 14days, with the following characteristics: sensitivity 0.95 (0.86-0.98); specificity 0.56 [0.49-0.63); NPV 0.97 (0.92-0.99); PPV0.42 (0.35-0.51). CONCLUSION: PIGF is a strong predictor of time-to-delivery and may be an independent and complementary tool to assist in diagnosis and risk stratification of pregnancies complicated by placental dysfunction. These valuable attributes are to be tested in prospecting randomised double-blind controlled trial. PMID- 26104638 TI - Pre-eclampsia: A complex and variable disease. AB - We would like to know the cause of pre-eclampsia. We would also like to be able to diagnose and treat it quickly and effectively, to be able to predict it accurately with one simple test and prevent it with safe and simple medication. But we cannot, nor on present evidence, will we ever be able to do so. Why is this? There are several reasons, which I will attempt to summarise: the heart of the problem is the complexity and variability of the disorder, which is so daunting that every specific statement about preeclampsia seems to have exceptions - it is truly a disease of exceptions. The cause of pre-eclampsia appears to be the placenta - in that the disorder can occur without a fetus as in hydatidiform mole, without a uterus as in abdominal pregnancy and is resolved by delivery (of the placenta). On the other hand some of the worst presentations are of women who are normal until delivery and then get a major crisis, eclampsia or the HELLP syndrome, immediately afterwards, when the placenta has gone. The placental problem is poor uteroplacental circulation secondary to inadequate remodelling of the spiral arteries that occurs between weeks 8 and week 18 (poor placentation). The maternal symptoms and signs arise from maternal endothelial dysfunction and an associated vascular inflammation. But the placental pathology can occur without features of pre-eclampsia and endothelial dysfunction can arise in mothers without placental disease (maternal pre-eclampsia). This apparent confusion can be resolved in part by recognising that pre-eclampsia is not a disease but a syndrome - encompassed by its defining features of new hypertension and proteinuria that remit after delivery. A syndrome is simply an empirical definition of a clinical presentation that demands action. It tells you nothing about pathogenesis. One syndrome usually encompasses several conditions and this is likely to be true of pre-eclampsia. The key here is to acknowledge that there are many routes to pre-eclampsia; that the final disorder arises from different mixes of environmental and genetic factors, with different contributions from the mother and the placenta. In terms of disease, the unique feature of the latter is that two individuals are involved, mother and baby, each with their different genetic make-ups. This can explain the heterogeneity of pre-eclampsia: for example the difference between early-onset disease with its high preponderance of fetuses that are growth restricted and prominent placental pathology in contrast to the late onset disease, which may be associated with large for gestational age fetuses and routinely reveals little placental pathology. Finally, many very mild features of pre-eclampsia arise towards term in normal healthy women. It is possible that all women are destined to get the disorder. Timing is the key feature, such that late gestation is a race against time: will spontaneous delivery occur before pre-eclampsia or vice versa? PMID- 26104639 TI - Pre-eclampsia - A disease of an individual couple. AB - Preeclampsia still ranks as one of obstetrics major problems. Clinicians typically encounter preeclampsia as maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal-paternal relationship is appreciated, and as such also the specific 'genetic conflict' that is characteristic of haemochorial placentation. From that perspective preeclampsia can also been seen as a disease of an individual couple with primarily maternal and fetal manifestations. Factors that are unique to a specific couple would include the length and type of sexual relationship, the maternal (decidual natural killer cells) acceptation of the invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming growth factor-b and probably other cytokines. The magnitude of the maternal response would be determined by factors including a maternal set of genes determining her characteristic inflammatory responsiveness, age, quality of her endothelium, obesity/insulin resistance and probably a whole series of susceptibility genes amongst which the thrombophilias received a lot of attention in recent years. The maternal and fetal genomes perform different roles during development. Inheritable paternal, rather than maternal, imprinting of the genome is necessary for normal trophoblast development. Preeclampsia may relate to a 'hefty' genetic conflict, or a mother unable to cope with a 'physiologic' genetic conflict. The paternal contribution to preeclampsia, in addition to the actual act of fertilization is demonstrated by. PMID- 26104640 TI - The role of maternal & fetal doppler in pre-eclampsia. AB - Pre-eclampsia is associated with significant maternal and fetal morbidity and mortality worldwide. Pregnancy complicated by preeclampsia and/or by fetal growth restriction are reported to have inadequate maternal vascular responses to placentation. This defective vascular response was due to the failure of second wave of endovascular trophoblast migration leading to both a reduced amount and depth of trophoblast invasion of myometrium followed by the development of placental hypoxia and ischemia that can be measured biophysically by means of Doppler Ultrasound. The role of Doppler in the screening and management of preeclampsia would be reviewed in here focusing on uterine artery, umbilicalartery (UA), middle cerebral artery (MCA) and ductus venosus (DV) waveforms. The commonly used flow velocity waveform (FVW) spectrum is used namely resistance index (RI), systolic/diastolic ratio (S/D) or pulsatility index (Pl). The presence or persistence of an early diastolic notch of uterine artery over 24 weeks of pregnancy is predictive of subsequent preeclampsia and or IUGR later on. Umbilical artery Pl falls with gestational age, although mean Pl is relatively stable after 30 weeks gestation. While elevated indices are predictive of adverse outcome, absent or reversed end-diastolic velocities (AREDV) are of particular significance for growth restriction. Mean MCA Pl increases to approximately 28weeks gestation and then falls to term. Progressive hypoxemia results in a reduction in MCA Pl and therefore values 5th centile are regarded as abnormal. The ratio of UA/MCA Pl has been widely used as an index of cerebral redistribution. The 9 51h centile for pulsatility index for vein (PIV) of ductus venosus FVW falls from 0.9 at 20 weeks to 0.7 at term, with values above this being regarded as abnormal. The absence or reversal of atrial systolic forward flow of DV FVW are of particular clinical significance. By using Doppler in the early detection of preeclampsia and its fetal complication namely growth restriction we can arrange the management decisions and monitoring strategy for preeclampsia. PMID- 26104641 TI - Genetic and preeclampsia. AB - Preeclampsia is usually called as a disease of theories where the real etipatology still unclear. Preeclampsia is a medical complication of pregnancy which is characterized by hypertension and proteinuria after 20week pregnancy. It is kown that preeclampsia has a clear genetic component. Polymorphism of the KIR genes might be associated with the genetic predisposition of preeclampsia. It is found that the KIR3DL2 (Killer cell immunoglobuline-like receptor 3 domains, long cytoplasmic tail, 2 (KIR3DL2) gene expression was obviously decreased in preeclampsia and assumed that decreased KIR3DL2 gene expression weakened the protection of trophoblasts from being attacked by maternal immunological cell and made in adequate trophoblast invasion in early pregnancy. It causes insufficient utero-placental blood flow and the defective piacentation. PMID- 26104642 TI - Molecular mechanisms and therapeutic implications of the carbon monoxide/hmox1 and the hydrogen sulfide/CSE pathways in the prevention of pre-eclampsia and fetal growth restriction. AB - The exact aetiology of preeclampsia is unknown, but there is a good association with an imbalance in angiogenic growth factors and abnormal placentation (Ahmad and Ahmed, 2004). The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt-1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. The identification of a protective role for HO-1 in pregnancy, offers HO/CO pathway as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, suggesting statins have the potential to ameliorate preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies. Hydrogen sulphide (H2S), a gaseous messenger produced mainly by cystathionineY-lyase (CSE), is pro-angiogenic vasodilator (Yang et al., 2008; Papapetropoulos et al., 2009). We hypothesized that a reduction in CSE activity may alter the angiogenic balance in pregnancy and induce abnormal placentation and maternal hypertension. Plasma levels of H2S were significantly decreased in preeclamptic women (p<-0.01), which was associated with reduced CSE message and protein expression in human placenta as determined by real - time PCR and immunohistochemistry. Inhibition of CSE activity by DL-propargylglycine (PAG) in first trimester (8-12weeks gestation) human placental explants had reduced placenta growth factor (PIGF) production as assessed by ELISA and inhibited trophoblast invasion in vitro. Endothelial CSE knockdown by siRNA transfection increased the endogenous release of soluble fms-Like tyrosine kinase-1 (sFlt-1) and soluble endoglin, (sEng) from human umbilical vein endothelial cells while adenoviral-mediated CSE overexpression inhibited their release. Administration of PAG to pregnant mice induced hypertension, liver damage, and promoted abnormal labyrinth vascularisation in the placenta and decreased fetal growth. Finally, a slow releasing, H2S-generating compound, GYY4137, inhibited circulating sFlt-1 and sEng levels and restored fetal growth that was compromised by PAG-treatment demonstrating that the effect of CSE inhibitor was due to inhibition of H2S production. These results imply that endogenous H2S is required for healthy placental vasculature and a decrease in of CSE/ H2S activity may contribute to the pathogenesis of preeclampsia. ACKNOWLEDGEMENTS: This work was supported by grants from the Medical Research Council (G0601295 and G0700288) and Aston University StrategicFunds. PMID- 26104643 TI - Maternal and fetal factors and placentation: implications for pre-eclampsia. AB - The etiology of preeclampsia is still mysterious and a source of a variety of hypotheses. Accordingly, there is a number of theories present today describing different pathways how this disorder may develop. The most cited hypothesis on the etiology of preeclampsia is based on an inadequate remodeling of uterine spiral arteries in the placental bed due to superficial trophoblast invasion followed by placental hypoxia. Since maternal blood into the placenta is only established after week 12 of gestation, an effect of a failure in arterial remodeling can only affect the placenta starting with the second trimester of pregnancy. Recent studies on early predictive biomarkers for preeclampsia (such as PP13, fetal hemoglobin and PIGF) have indicated that there are changes of the villous trophoblast already weeks before the onset of maternal blood flow into the placenta, i.e. during mid first trimester. Moreover, a number of studies has shown that in cases with impaired trophoblast invasion resulting in inadequate remodeling of uterine spiral arteries placental hypoxia does not occur. In all these studies where mostly indirect assessments of placental oxygen have been performed, a higher oxygen partial pressure within the placenta has been measured. This is in clear contrast to the old hypothesis where placental hypoxia is essential for the etiology of preeclampsia. New biomarkers from the maternal and/or fetal compartment for the early prediction of preeclampsia may help in identifying the real etiology of preeclampsia. We need to use this momentum to decipher the real causes of this syndrome. PMID- 26104644 TI - Oxygenation of the placenta and its role in pre-eclampsia. AB - Proper oxygenation of the placenta and hence the embryo/fetus is essential for a successful pregnancy. During the first trimester of pregnancy the partial pressure of oxygen in the placenta and the embryo is very low and does not exceed 20mmHg. At the end of the first trimester maternal blood flow towards the placenta is established leading to a sudden increase in placental oxygenation to about 50-60mmHg. This level of oxygenation is keptuntil delivery. One of the numerous hypotheses to describe the etiology of preeclampsia, which is still the most cited hypothesis today, is based on a failure of extravillous trophoblast to invade the uterine spiral arteries in the placental bed. This in turn is believed to result in placental hypoxia and subsequently to damage of the villous trophoblast. Following this hypothesis, there is a series of events following these hypoxic conditions of the placenta. There is a large number of articles published that have investigated the effect of different oxygen concentrations on the phenotype of trophoblasts in vitro and have used this data to corroborate the hypothesis above. Unfortunately, one important aspect has not been addressed until recently: What is the placental oxygen concentration in placental pathologies such as preeclampsia in vivo? All studies that have tried to elucidate the placental oxygen concentration have done this indirectly, since direct measurements of placental oxygen in the third trimester of pregnancy have been defined as unethical. Not a single of such studies has revealed that oxygenation of the placenta in pregnancy pathologies is decreased. At the same time a number of studies have shown that in intra-uterine growth restriction (IUGR) placental oxygenation is increased rather than decreased. This has been shown to be true in the presence and absence of preeclampsia. This data clearly disprove the above hypothesis and should open our minds to decipherthe realcauses of preeclampsia. PMID- 26104645 TI - The role of oxidative stress in the pathogenesis of pre-eclampsia. AB - Exclusively occurred during pregnancy, preeclampsia causing complex multisystem disorders that lead to maternal and fetal mortality and morbidity. The major burden in discovering pathogenesis of preeclampsia is still widely noticed. Oxidative stress believed to be one of the major causalin its pathophysiology. Its role on reducing blood perfusion thorugh ischemia results on abnormal placentation. Dysfunction assumed to be caused by oxidative damage and antioxidant defence imbalance as it becoming a central feature in the pathophysiology of preeclampsia. This pathway is widely studied and acknowledged recent years. PMID- 26104646 TI - Prediction, medical illness and the risk of pre-eclampsia. AB - Preeclampsia, the leading cause of maternal and perinatal morbidity and mortality, has been recently considered not only a pregnancy disease but also a risk factor for developing diseases later in life. Preeclampsia is becoming a disease of interest to internists and not just obstetricians. Women who have had preeclampsia seem to be at higher risk of premature death, mortality from ischemic heart disease, cardiovascular diseases including ischemic heart disease and hypertension, fatal and non-fatal stroke, venous thromboembolism.renal failure, type 2 diabetes mellitus, hypothyroidism, and cognitive defects, although they appear surprisingly protected from cancer. Furthermore, having had preeclampsia isa problem not only for the mother's future health, but it also affects the offspring's adult health. Children born from preeclamptic pregnancies are more prone to hypertension, insulin resistance and diabetes mellitus, neurological problems, stroke, and mental disorders along their life.Whether preeclampsia is a risk factor for disease later in life or it creates long-term organ damage is an intriguing question. Understanding the etiological background may provide guidance for the prevention and follow-up of women who experience preeclampsia. PMID- 26104647 TI - The characteristic of Indonesia's pre-eclampsia: From obstetric intensive care with ventilator until epidemiologic and its molecular biology profile of pulmonary edema in severe pre-eclampsia. AB - Pulmonary edema is among the least frequently diagnosed criteria for severe pre eclampsia. A higher incidence of pulmonary edema was noted in older patients, multigravidas, and patients with underlying chronic hypertension that developed prior to delivery. The development of pulmonary edema was also associated with the administration of excess colloid or crystaloid infusion. Two hundreds and thirty millions people occupying Indonesia as tropical and coastal country gave rise the problem of highly maternal mortality rate of 225/100,000 deliveries where pre-eclampsia and eclampsia as most possible cause. Over 5years from the year 2005 through 2009 our 160 eclampsia study observed about significantly correlation between typical estafet referred case and maternal mortality (Odds ratio 19.1 and P=0.065). Specifically those referred eclampsia cases arriving lately to our tertiary hospital, complication of pulmonary edema also apparently became determinant factor to uphold the increased maternal mortality (Odds ratio 6.1 and P=0.083) We found at our teaching hospital Dr. Soetomo Surabaya as referral center along the year 2012, 477 pre-eclampsia-eclampsia cases which complicated by 27 cases of pulmonary from which we apply obstetric intensive care unit for tightly monitoring treatment. The majority use of ventilator were applied on 22 cases (81.4%), that most approximately 16 cases (72%) need 48h under ventilator use and the remaining 6 cases was not untill 5days of extubation. The etiology of pulmonary edema in preeclamptic patients involves multi-factors; abnormal COP-PWCP gradient, increased pulmonary capillary permeability, and left ventricular failure were identified causes. It has been well known that the pathogenesis of pulmonary edema in severe pre-eclampsia eclampsia initiated by capillary alveolar leakage that leading increased capillary permeability and extravascular fluid oncotic as well as decreased plasma oncotic pressure. In severe pre-eclampsia appear that another circumstance directing its worst state of inhibited angiogenesis related pulmonary edema. The study confirmed that the decreased serum albumin of ?3g% and its content of amino acid essentiale acitvate endoplasmic reticulum stress response in which indicated by increasingly produced GRP (Glucose Related-Protein) 78. It may affect the decreased VEGFR and may also be inhibiting angiogenesis and hypoxia as well. At such moment apparently pulmonary edema patient get worsening clinical sign. PMID- 26104648 TI - Management of preeclampsia. AB - Most patients with a pregnancy-induced hypertensive disorder have no clinical symptoms. So it can only be reliably detected by repetitive searches (screening) for the early signs and symptoms in the 2nd half of pregnancy. Adequate and proper prenatal care is the most important part of management of preeclampsia. Maternal antenatal monitoring includes identifying women at increased risk, early detection of preeclampsia by recognizing clinical signs and symptoms, and to observe progression of the condition to the severe state. As the etiology of preeclampsia remains in question, the only effective treatment is to deliver the infant and placenta; ancillary therapy is predominantly symptomatic and not directed at underlying causes. Once the diagnosis of preeclampsia is made, subsequent therapy will depend on the results of initial maternal and fetal evaluation. The primary objective of management of preeclampsia must always be safety of the mother. Although delivery is always appropriate for the mother, it may not be optimal for the fetus that is extremely premature. The decision between delivery and expectant management depends on fetal gestational age, maternal and fetal status at time of initial evaluation, presence of labor or rupture of fetal membranes, and level of available neonatal and maternal services. It is important to emphasize that hypertension is merely one manifestation of this disease, albeit directly related to one of the most serious consequences for the mother, i.e cerebral involvement, which may manifest itself as convulsions, focal neurological events such as cortical blindness, and even cerebral hemorrhage. The benefits of acute pharmacologic control of severe hypertension prior to delivery are generally accepted. The more contentious issues are the role of pharmacologic therapy in allowing prolongation of pregnancy and the ability of such therapy to modify the course of the underlying systemic disorder and affect fetal and maternal outcome. Ali hypertensive drugs affect both the mother and the fetus; some may produce side effects in the mother and others may produce adverse effects on the fetus or the newborn. The indirect effects of antihypertensive drugs on the fetus may be by impairing uteroplacental perfusion or directly by influencing the fetal cardiovascular circulation. In general, women with mild disease developing at 37weeks' gestation or longer have a pregnancy outcome similar to that found in normotensive pregnancy. Thus, those patients should undergo induction of labor for delivery. Induction of labor and/or delivery is also recommended for those at or beyond 34 weeks' gestation in the presence of severe preeclampsia, labor or rupture of membranes, or non reassuring tests of fetal well-being because the mother is at slightly increased risk for development of placental abruption and progression to eclampsia. In women who remain undelivered, close maternal and fetal evaluation is essential. The type of test and frequency of evaluation will depend on fetal gestational age as well as severity of maternal condition, and presence or absence of IUGR. These tests should be repeated promptly in case of worsening maternal condition (progression to severe disease) or fetal condition (reduced fetal movement or suspected IUGR). Expectant management of severe preeclampsia:The clinical course of severe preeclampsia may be characterized by progressive deterioration in both maternal and fetal conditions. Because these pregnancies have been associated with increased rates of maternal morbidity and mortality and with significant risks for the fetus, there is universal agreement that such patients be delivered if the disease develops after 34weeks' gestational, 243. Delivery is also clearly indicated when there is imminent eclampsia (persistent severe symptoms), multiorgan dysfunction, severe IUGR, suspected placental abruption, or non reassuring fetal testing before 34 weeks' gestation. There is disagreement however, about treatment of patients with severe preeclampsia before 34 weeks' gestation where maternal condition is stable and fetal condition is reassuring. The Cochrane review on interventionist versus expectant care states that it is not possible to draw firm conclusions, as there are only two small trials (133 women) that have compared a policy of early elective delivery, with a policy of delayed delivery, and the confidence intervals for all outcomes are wide. However, the evidence is promising that short-term morbidity for the baby may be reduced by a policy of expectant care. Sibai and Barton recently reviewed the literature on maternal and perinatal of expected management of severe preeclampsia remote from term and reviewed the major studies in the literature. Based on this review, they concluded that the results of these studies suggest that expectant treatment in a select group of women with severe preeclampsia between 24 0/7 and 32 6/7weeks of gestation in a suitable hospital is safe and improves neonatal outcome. Most studies on expectant management report 7-10days of prolongation. For gestational age of 24 0/7weeks, expectant treatment was associated with high maternal morbidity with limited perinatal benefit. PMID- 26104649 TI - The six stages of pre-eclampsia. AB - For many years pre eclampsia has been considered to be a two-stage disease. The first stage comprises poor placentation. The second stage is the clinical expression of the disease namely new hypertension and new proteinuria. The first stage is preclinical and symptomless, which evolves between weeks 8 and 18 of pregnancy, when the uteroplacental circulation is established by spiral artery remodelling. Its consequence is dysfunctional perfusion of the intervillous space of the placenta with oxidative and haemodynamic stress. The damaged placenta releases excessive pro-inflammatory and antiangiogenic factors into the maternal circulation. With increasing knowledge, this model has become inadequate. First the antecedents of poor placentation have become clearer and are immunological in origin, reflecting the mother's ability to accommodate to the genetic foreignness of her unborn child. They begin, as discussed already in this meeting, with preconceptual tolerisation of the mother to the semen of the prospective father of her child. A lack of tolerisation, arising from a short interval between first coitus and conception increases the likelihood of poor placentation and pre eclampsia (Stage 1). This is presumed to affect the health and growth of the embryo immediately after implantation but there is little evidence of this at the moment (Stage 2). Placentation begins after week 8 when the uteroplacental circulation, which previously has been closed by trophoblast plugs in the spiral arteries, begins to open. Defective placentation may arise from premature opening, and perfusion of the intervillous space by oxygenised arterial blood before the placenta is equipped to cope with the stress. Placentation extends over about 10 weeks and, when it is defective, constitutes stage 3 of pre eclampsia. Stages 4-6 all occur in the second half of pregnancy. Stage 4 is associated with excessive or deficient placental derived factors in the mother's blood, secondary to placental damage, before the appearance of clinical signs. When the diagnosis of pre-eclampsia can be made stage 5 has begun. Stage 6 affects less than half of women with pre-eclampsia. It is the superimposition of a second and later spiral artery lesion called acute atherosis, which has some resemblance to atherosclerosis, which is suffered by middle and old-aged, non pregnant adults. Its importance is that it further reduces uteroplacental perfusion and predisposes to spiral artery thrombosis, which underlies the occurrence of placental infarcts. The evidence for and the mechanisms of these multiple stages will be briefly presented. PMID- 26104650 TI - The role of angiogenic factors in pre-eclampsia. AB - Preeclampsia is best described as a Pregnancy specific syndrome that can affect virtually every organ system. Preeclampsia, a systemic syndrome of pregnancy clinically characterized by new onset of proteinuria and hypertension, is associated with significant morbidity and mortality to both mothers and fetuses. Preeclampsia originates in the placenta, starting within adequate cytotrophoblast invasion and ending with widespread maternal endothelial dysfunction. Production of placental anti-angiogenic factors, specifically soluble fms-related tyrosine kinase 1 and soluble endoglin, have been shown to be upregulated in preeclampsia. These placental anti-angio-genic factors are released into the maternal circulation; their actions disrupt the maternal endothelium and result in hypertension, proteinuria, and the other systemic manifestations of preeclampsia. The molecular basis for placental dysregulation of these pathogenic factors remains unknown, remains unknown. Hypoxia is likely an important regulator. Other factors such as alterations in the renin-angiotensin-aldosterone axis, immune maladaption, excessive shedding of trophoblast debris, oxidative stress, and genetic factors likely contribute to the pathogenesis of the abnormal placentation. The only successful treatment for preeclampsia is delivery. No definitive preventive strategies have been identified. PMID- 26104651 TI - The role of albumin and endoplasmic reticulum in pathogenesis Preeclampsia. Changes of GRP78 and placental VEGF in preeclampsia. AB - Preeclampsia remains the highest causes of maternal mortality in Indonesia. This disease is known as "the disease of theories" since the etiology of this disease still obscure, but it is clearly accepted that this disease is correlated with placenta. The incidence of this disease increased in dr. Soetomo General Hospital during economic crisis in Indonesia, as nutritional problem occurred, but correlation between nutrition to preeclampsia still unclear. This study was conducted to find out the influence of hypoalbuminemia caused by alteration of amino acids and changes of GRP78 and placental VEGF in preeclampsia. METHOD: It was cross-sectional study among 10 patients with preeclampsia albumin ? gram/dL and 9 patients with preeclampsia albumin >3g/dL. Placenta collected was homogenized and blood was separated from the cells. Placental lysat, serum and plasma were stored -87 degrees C until laboratory analysis for GRP78 and VEGF. Data were analyzed using student t test, Manova. Pearson correlation, simple and multiple regressions. RESULT: There were alterations of amino acid's profile among albumin ?3g/dL compare with albumin >3g/dL. GRP78 concentration on albumin ?3g/dL group was higher, but were not significant. Weak negative correlation between albumins to GRP78 was found. Negative correlation were found in the groups of albumin ?3g/dL - GRP?425MUg/dL, but significant result only on albumin ?3g/dL - GRP?425MUg/dL. Positive correlation were found in the group of albumin >3g/dL - GRP>425MUg/dL. Response of Endoplasmic Reticulum Stress appeared different depends on levels of albumin (stressor) and GRP78 (stress response protein). Placental VEGF were significantly lower in albumin ?3g/dL (p<0.05). Correlation between GRP78 on placental VEGF was negative with coefficient correlation was 3.8%. Placental VEGF profoundly decreased as correlation between albumin and GRP78 stronger. CONCLUSION: Alteration of amino acids profile influenced Albumin concentration. Hypoalbuminemia was a stressor that induced reticulum endoplasmic response by increasing GRP78, decreasing placental VEGF. Responses of Endoplasmic Reticulum Stress depend on levels of stressor (albumin) and stress response protein (GRP78). PMID- 26104652 TI - Characterization of sulfur deposition over the period of industrialization in Japan using sulfur isotope ratio in Japanese cedar tree rings taken from stumps. AB - We characterized the sulfur deposition history over the period of industrialization in Japan based on the sulfur isotope ratio (delta(34)S) in tree rings of Japanese cedar (Cryptomeria japonica D. Don) stumps. We analyzed and compared delta(34)S values in the rings from two types of disk samples from 170 year-old stumps that had been cut 5 years earlier (older forest stand) and from 40-year-old living trees (younger forest stand) in order to confirm the validity of using stump disks for delta(34)S analysis. No differences in delta(34)S values by age were found between the sample types, indicating that stump disks can be used for delta(34)S analysis. The delta(34)S profile in tree rings was significantly correlated with anthropogenic SO2 emissions in Japan (r = -0.76, p < 0.05) and, thus, tree rings serve as a record of anthropogenic sulfur emissions. In addition, the values did not change largely from pre industrialization to the 1940s (+4.2 to +6.10/00). The values before the 1940s are expected to reflect the background sulfur conditions in Japan and, thus, disks containing rings formed before the 1940s contain information about the natural environmental sulfur, which is useful for biogeochemical studies. PMID- 26104653 TI - The cuticular plate: a riddle, wrapped in a mystery, inside a hair cell. AB - The mechanosensitive hair cells of the inner ear are crucial to hearing and vestibular function. Each hair cell detects the mechanical stimuli associated with sound or head movement with a hair bundle at the apical surface of the cell, consisting of a precise array of actin-based stereocilia. Each stereocilium inserts as a rootlet into a dense filamentous actin mesh known as the cuticular plate. Disruption of the parallel actin bundles forming the stereocilia results in hearing impairments and balance defects. The cuticular plate is thought to be involved in holding the stereocilia in place. However, the precise role of the cuticular plate in hair bundle development, maintenance, and hearing remains unknown. Ultrastructural studies have revealed a complex cytoskeletal architecture, but a lack of knowledge of proteins that inhabit the cuticular plate and a dearth of mutations that perturb relevant proteins have hindered our understanding of the functions of the cuticular plate. Here, we discuss what is known about the structure and development of this unique and poorly-understood actin-rich organelle. PMID- 26104654 TI - Phase 1 pharmacokinetic study of the oral pan-AKT inhibitor MK-2206 in Japanese patients with advanced solid tumors. AB - PURPOSE: MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors. METHODS: Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1. RESULTS: Twenty-four patients were treated at 45 mg (n = 3) or 60 mg (n = 9) QOD or at 135 mg (n = 3) or 200 mg (n = 9) QW. One patient experienced a DLT at 60 mg QOD, and three patients experienced DLTs at 200 mg QW. No DLTs were observed at 45 mg QOD or at 135 mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4 months. CONCLUSIONS: MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation. PMID- 26104655 TI - Sonographic appearances of the epididymis in boys with acute testicular torsion but preserved testicular blood flow on color Doppler. AB - BACKGROUND: Little attention has been given to the sonographic appearances of the epididymis in testicular torsion. OBJECTIVE: To describe the position and morphology of the epididymis in childhood acute testicular torsion when testicular flow is present on color Doppler sonography. MATERIALS AND METHODS: We studied the sonographic findings in boys with clinically and surgically proven acute testicular torsion who were examined sonographically from May 2013 to May 2014 and who had preserved intratesticular flow on color Doppler sonography. We retrospectively evaluated the sonograms with emphasis on the epididymal findings. RESULTS: In all nine boys with confirmed torsion but with preserved intratesticular flow on color Doppler sonography, the epididymal head had an unexpected configuration and size, and no close relationship with the upper pole of the testis. In five of these children the spermatic cord appeared twisted on the affected side. In the remaining four boys the spermatic cord appeared straight. CONCLUSION: The position and morphology of the head of the epididymis were abnormal in all boys with acute testicular torsion but with preserved testicular flow. PMID- 26104656 TI - Scylla serrata reovirus p35 protein expressed in Escherichia coli cells alters membrane permeability. AB - To promote viral entry, replication, release, and spread to neighboring cells, many cytolytic animal viruses encode proteins responsible for modification of host cell membrane permeability and for formation of ion channels in host cell membranes. Scylla serrata reovirus (SsRV) is a major pathogen that can severely damage mud crab (S. serrata) aquaculture. Protein p35, which is encoded by segment 10 of SsRV, contains two transmembrane domains. In this study, we found that SsRV p35 can induce membrane permeability changes when expressed in Escherichia coli. SsRV p35 expressed in bacterial cells existed as monomers under reducing conditions but formed homodimers and homotrimers under non-reducing conditions. These findings demonstrate that p35 may act as a viroporin; further studies are needed to elucidate the detailed structure-function relationships of this protein. PMID- 26104657 TI - Preventing malaria transmission by indoor residual spraying in Malawi: grappling with the challenge of uncertain sustainability. AB - BACKGROUND: In the past decade, there has been rapid scale-up of insecticide based malaria vector control in the context of integrated vector management (IVM) according to World Health Organization recommendations. Endemic countries have deployed indoor residual spraying (IRS) and long-lasting insecticidal nets as hallmark vector control interventions. This paper discusses the successes and continued challenges and the way forward for the IRS programme in Malawi. CASE DESCRIPTION: The National Malaria Control Programme in Malawi, with its efforts to implement an integrated approach to malaria vector control, was the 'case' for this study. Information sources included all available data and accessible archived documentary records on IRS in Malawi. A methodical assessment of published and unpublished documents was conducted via a literature search of online electronic databases. DISCUSSION: Malawi has implemented IRS as the main malaria transmission-reducing intervention. However, pyrethroid and carbamate resistance in malaria vectors has been detected extensively across the country and has adversely affected the IRS programme. Additionally, IRS activities have been characterized by substantial inherent logistical and technical challenges culminating into missed targets. As a consequence, programmatic IRS operations have been scaled down from seven districts in 2010 to only one district in 2014. The future of the IRS programme in Malawi is uncertain due to limited funding, high cost of alternative insecticides and technical resource challenges being experienced in the country. CONCLUSIONS: The availability of a long-lasting formulation of the organophosphate pirimiphos-methyl makes the re-introduction of IRS a possibility and may be a useful approach for the management of pyrethroid resistance. Implementing the IVM strategy, advocating for sustainable domestic funding, including developing an insecticide resistance monitoring and management plan and vector surveillance guidelines will be pivotal in steering entomologic monitoring and future vector control activities in Malawi. PMID- 26104659 TI - Clonal architecture of del(5q) myelodysplastic syndromes: aberrant CD5 or CD7 expression within the myeloid progenitor compartment defines a subset with high clonal burden. PMID- 26104658 TI - What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. PMID- 26104660 TI - Effects of p38alpha/beta inhibition on acute lymphoblastic leukemia proliferation and survival in vivo. AB - P38alpha/beta has been described as a tumor-suppressor controlling cell cycle checkpoints and senescence in epithelial malignancies. However, p38alpha/beta also regulates other cellular processes. Here, we describe a role of p38alpha/beta as a regulator of acute lymphoblastic leukemia (ALL) proliferation and survival in experimental ALL models. We also report first evidence that p38alpha/beta phosphorylation is associated with the occurrence of relapses in TEL-AML1-positive leukemia. First, in vitro experiments show that p38alpha/beta signaling is induced in a cyclical manner upon initiation of proliferation and remains activated during log-phase of cell growth. Next, we provide evidence that growth-permissive signals in the bone marrow activate p38alpha/beta in a novel avian ALL model, in which therapeutic targeting can be tested. We further demonstrate that p38alpha/beta inhibition by small molecules can suppress leukemic expansion and prolong survival of mice bearing ALL cell lines and primary cells. Knockdown of p38alpha strongly delays leukemogenesis in mice xenografted with cell lines. Finally, we show that in xenografted TEL-AML1 patients, ex vivo p38alpha/beta phosphorylation is associated with an inferior long-term relapse-free survival. We propose p38alpha/beta as a mediator of proliferation and survival in ALL and show first preclinical evidence for p38alpha/beta inhibition as an adjunct approach to conventional therapies. PMID- 26104661 TI - Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer. AB - To develop gene-modified T-cell-based antileukemia adoptive immunotherapy, concomitant administration of CD4(+) and CD8(+) T cells that have been gene modified using identical HLA class I-restricted leukemia antigen-specific T-cell receptor (TCR) gene transfer has not yet been fully investigated. Here, using CD4(+) and CD8(+) T cells that had been gene modified with a retroviral vector expressing HLA-A*24:02-restricted and Wilms' tumor 1 (WT1)-specific TCR alpha/beta genes and siRNAs for endogenous TCRs (WT1-siTCR/CD4(+) T cells and WT1 siTCR/CD8(+) T cells), we examined the utility of this strategy. WT1-siTCR/CD4(+) T cells sufficiently recognized leukemia cells in an HLA class I-restricted manner and provided target-specific Th1 help for WT1-siTCR/CD8(+) T cells. By using a xenografted mouse model, we found that WT1-siTCR/CD4(+) T cells migrated to leukemia sites and subsequently attracted WT1-siTCR/CD8(+) T cells via chemotaxis. Therapy-oriented experiments revealed effective enhancement of leukemia suppression mediated by concomitant administration of WT1-siTCR/CD4(+) T cells and WT1-siTCR/CD8(+) T cells. Importantly, this augmented efficacy in the presence of WT1-siTCR/CD4(+) T cells was correlated with longer survival and enhanced formation of memory T cells by WT1-siTCR/CD8(+) T cells. Collectively, our experimental findings strongly suggest that this strategy would be clinically advantageous for the treatment of human leukemia. PMID- 26104662 TI - Loss of HIF-1alpha accelerates murine FLT-3(ITD)-induced myeloproliferative neoplasia. AB - Hypoxia-induced signaling is important for normal and malignant hematopoiesis. The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) has a crucial role in quiescence and self-renewal of hematopoietic stem cells (HSCs), as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. We have investigated the effect of HIF-1alpha loss on the phenotype and biology of FLT-3(ITD)-induced myeloproliferative neoplasm (MPN). Using transgenic mouse models, we show that deletion of HIF-1alpha leads to an enhanced MPN phenotype reflected by an increased number of white blood cells, more severe splenomegaly and decreased survival. The proliferative effect of HIF 1alpha loss is cell intrinsic as shown by transplantation into recipient mice. HSC loss and organ-specific changes in the number and percentage of long-term HSCs were the most pronounced effects on a cellular level after HIF-1alpha deletion. Furthermore, we found a metabolic hyperactivation of malignant cells in the spleen upon loss of HIF-1alpha. Some of our findings are in contrary to what has been previously described for the role of HIF-1alpha in other myeloid hematologic malignancies and question the potential of HIF-1alpha as a therapeutic target. PMID- 26104665 TI - [The role of induced pluripotent stem cells in modeling of neurological diseases]. AB - The longitudinal follow-up of the development and course of central nervous system related diseases on a molecular level was unsolved for decades. Direct examination of the pathological state on organ or tissue levels was feasible in the late stage of the disease. Modeling diseases has an important role in studying the pathophysiological mechanism underlying central nervous system disorders but animals used as model organism due to species specific nervous system differences can lead to less valid conclusions in translational research. The model of induced pluripotent stem cells may help to solve partially these types of problems. In recent years this model had a strong effect on understanding the pathogenesis of neurodegenerative and neurodevelopmental disorders. Although induced pluripotent stem cells have a low impact on clinical research studies, they have a prominent role in the field of cell physiology and molecular biology research. PMID- 26104664 TI - Rapamycin impairs endothelial cell function in human internal thoracic arteries. AB - BACKGROUND: Definitive fate of the coronary endothelium after implantation of a drug-eluting stent remains unclear, but evidence has accumulated that treatment with rapamycin-eluting stents impairs endothelial function in human coronary arteries. The aim of our study was to demonstrate this phenomenon on functional, morphological and biochemical level in human internal thoracic arteries (ITA) serving as coronary artery model. METHODS: After exposure to rapamycin for 20 h, functional activity of ITA rings was investigated using the organ bath technique. Morphological analysis was performed by scanning electron microscopy and evaluated by two independent observers in blinded fashion. For measurement of endothelial nitric oxide synthase (eNOS) release, mammalian target of rapamycin (mTOR) and protein kinase B (PKB) (Akt) activation, Western blotting on human mammary epithelial cells-1 and on ITA homogenates was performed. RESULTS: Comparison of the acetylcholine-induced relaxation revealed a significant concentration-dependent decrease to 66 +/- 7 % and 36 +/- 7 % (mean +/- SEM) after 20-h incubation with 1 and 10 MUM rapamycin. Electron microscopic evaluation of the endothelial layer showed no differences between controls and samples exposed to 10 MUM rapamycin. Western blots after 20-h incubation with rapamycin (10 nM-1 MUM) revealed a significant and concentration-dependent reduction of p (Ser 1177)-eNOS (down to 38 +/- 8 %) in human mammary epithelial cells (Hmec)-1. Furthermore, 1 MUM rapamycin significantly reduced activation of p (Ser2481)-mTOR (58 +/- 11 %), p (Ser2481)-mTOR (23 +/- 4 %) and p (Ser473)-Akt (38 +/- 6 %) in ITA homogenates leaving Akt protein levels unchanged. CONCLUSIONS: The present data suggests that 20-h exposure of ITA rings to rapamycin reduces endothelium-mediated relaxation through down-regulation of Akt phosphorylation via the mTOR signalling axis within the ITA tissue without injuring the endothelial cell layer. PMID- 26104666 TI - [Next generation sequencing and its applications in non-invasive prenatal testing of aneuploidies]. AB - The development of the new generation sequencing techniques brought a new era in the field of DNA sequencing, that also revolutionized the prenatal screening for aneuploidy. In order to provide a more complete view, the authors describe some first generation methods as well as the theoretical and technical background of the next generation methods. In the second part of this review, the authors focuse on non-invasive prenatal testing, which is a fetal cell-free DNA based method requiring advanced sequencing procedures. After discussing the theoretical and technical background, the authors review current application and utility of non-invasive prenatal testing. They conclude that non-invasive prenatal testing is the most effective screening test in high risk pregnancies and its efficiency can be justified in studies involving low risk pregnancies as well. PMID- 26104663 TI - A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease. AB - Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14-15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs. PMID- 26104667 TI - [Cerebral hyperperfusion syndrome and blood pressure control]. AB - INTRODUCTION: Cerebral hyperperfusion syndrome is a rare, hardly known condition, which can result in serious complications either after surgical or endovascular revascularization. Recognition of the typical triad (headache, seizure, focal neurological deficit) and the prompt radiological diagnosis (sonography, computed tomography) are crucial to achieve a favourable outcome. AIM: The aim of the authors was to select the endangered group and set up an effective therapeutic protocol based their own experience in combination with relevant literature data. METHOD: From the beginning of 2010 up to now three cases with these symptoms pursuant to the criteria of cerebral hyperperfusion syndrome have been recognized by the authors. RESULTS: Each of the three patients were treated by similar principles on intensive care unit, but the applied therapy resulted in complete remission in one patient only. CONCLUSIONS: At present there is no efficient diagnostic way to screen the endangered group, hence the only opportunity for prevention is the appropriate perioperative blood pressure control. If symptoms have developed already, urgent treatment is required. PMID- 26104668 TI - [Relationship between Machiavellianism and emotional and behavioral difficulties in adolescence]. AB - INTRODUCTION: Machiavellianism is a personality trait that is characterized by intense interpersonal manipulation in order to achieve personal material goals. Previous studies revealed a relationship between Machiavellianism and diverse forms of psychological difficulties in adults. AIM: Studies also revealed such relationships in adolescents as well, but studies investigating the relationship between Machiavellianism and psychological difficulties in adolescents are still absent in Hungary. METHOD: In this study 502 secondary school students (356 girls) filled out questionnaires that measured Machiavellianism and psychological and behavioral difficulties. RESULTS: Machiavellianism was associated with higher total problem score. This resulted mainly from higher scores on scales measuring emotional and behavioral problems. Moreover, hyperactivity and lack of prosocial behavior were also associated with Machiavellianism. At the same time, Machiavellian adolescents did not differ in self-reported loneliness from their peers. CONCLUSIONS: The author discusses the results in the light of previous research and from the perspective of emotion and behavior regulation. Practical aspects of the results are also discussed in the context of prevention. PMID- 26104669 TI - [Not everything is coeliac disease what it seems]. AB - The prevalence of inflammatory bowel disease is ten times more common in patients with celiac disease; however, studies investigating the reverse relation have contradictory findings. Many gene polymorphisms are known to be present in both diseases; furthermore, similarities observed in their pathophysiological mechanism, their family concomitance, results of the serologic analysis and their macroscopic and microscopic symptoms in the gastro-intestinal system suggest a relevant association between the two diseases. The author presents the history of four patients, of whom two had both Crohn's and coeliac diseases. In the two other patients with inflammatory bowel disease the possible diagnosis of coeliac disease was suspected, but after additional examinations coeliac disease was excluded in one patient and seemed to be unlikely in the other patient. The author concludes that the differential diagnosis of the two diseases is not easy and if one of them is diagnosed, the possible presence of the other one should be taken into consideration. PMID- 26104670 TI - [The impact factor and those who dislike it]. AB - Since its introduction in 1976, the impact factor is permanently a subject of both criticism and glorification. This paper gives an overview on what actually the reservations and objections attack. A closer look often reveals that the criticisms are not against the specific substantial features of the impact factor. They may formulate much more general doubts or, on the other hand, superficial technical details, easily remediable flaws or inconsistensies resulting erroneous use. PMID- 26104671 TI - [Caesarean section performed by Semmelweis in Pest in 1857]. PMID- 26104672 TI - Membranes with artificial free-volume for biofuel production. AB - Free-volume of polymers governs transport of penetrants through polymeric films. Control over free-volume is thus important for the development of better membranes for a wide variety of applications such as gas separations, pharmaceutical purifications and energy storage. To date, methodologies used to create materials with different amounts of free-volume are based primarily on chemical synthesis of new polymers. Here we report a simple methodology for generating free-volume based on the self-assembly of polyethylene-b polydimethylsiloxane-b-polyethylene triblock copolymers. We have used this method to fabricate a series of membranes with identical compositions but with different amounts of free-volume. We use the term artificial free-volume to refer to the additional free-volume created by self-assembly. The effect of artificial free volume on selective transport through the membranes was tested using butanol/water and ethanol/water mixtures due to their importance in biofuel production. We found that the introduction of artificial free-volume improves both alcohol permeability and selectivity. PMID- 26104673 TI - Microbial community development on the surface of Hans and Werenskiold Glaciers (Svalbard, Arctic): a comparison. AB - Surface ice and cryoconite holes of two types of polythermal Svalbard Glaciers (Hans Glacier--grounded tidewater glacier and Werenskiold Glacier-land-based valley glacier) were investigated in terms of chemical composition, microbial abundance and diversity. Gathered data served to describe supraglacial habitats and to compare microbe-environment interactions on those different type glaciers. Hans Glacier samples displayed elevated nutrient levels (DOC, nitrogen and seston) compared to Werenskiold Glacier. Adjacent tundra formations, bird nesting sites and marine aerosol were candidates for allochtonic enrichment sources. Microbial numbers were comparable on both glaciers, with surface ice containing cells in the range of 10(4) mL(-1) and cryoconite sediment 10(8) g(-1) dry weight. Denaturating gradient gel electrophoresis band-based clustering revealed differences between glaciers in terms of dominant bacterial taxa structure. Microbial community on Werenskiold Glacier benefited from the snow-released substances. On Hans Glacier, this effect was not as pronounced, affecting mainly the photoautotrophs. Over-fertilization of Hans Glacier surface was proposed as the major factor, desensitizing the microbial community to the snow melt event. Nitrogen emerged as a limiting factor in surface ice habitats, especially to Eukaryotic algae. PMID- 26104675 TI - Causes and hemodynamic findings in chronic severe pulmonary regurgitation. AB - Severe pulmonary regurgitation (PR) most commonly occurs as a sequelae of treatment of pulmonic stenosis or Tetralogy of Fallot with fewer cases of primary pulmonic valvular regurgitation. The amount of PR is influenced by valvular integrity, right ventricular (RV) size, and RV diastolic pressures. In chronic severe PR, the RV remodels to accommodate the regurgitant flow and RV stroke volume increases to maintain effective forward blood flow. Hemodynamic changes include a widened pulmonary artery (PA) pulse pressure and low PA diastolic pressures. As the amount of regurgitation increases, RV end diastolic pressure becomes elevated and systemic cardiac output is reduced, especially with exercise. "Ventricularization" of the PA pressure tracing, in which the contour of the PA pressure is similar to the contour of the RV pressure, is a specific but not sensitive finding in severe PR. (c) 2015 Wiley Periodicals, Inc. PMID- 26104674 TI - Membrane-bound amylopullulanase is essential for starch metabolism of Sulfolobus acidocaldarius DSM639. AB - Sulfolobus acidocaldarius DSM639 produced an acid-resistant membrane-bound amylopullulanase (Apu) during growth on starch as a sole carbon and energy source. The physiological role of Apu in starch metabolism was investigated by the growth and starch degradation pattern of apu disruption mutant as well as biochemical properties of recombinant Apu. The Deltaapu mutant lost the ability to grow in minimal medium in the presence of starch, and the amylolytic activity observed in the membrane fraction of the wild-type strain was not detected in the Deltaapu mutant when the cells were grown in YT medium. The purified membrane bound Apu initially hydrolyzed starch, amylopectin, and pullulan into various sizes of maltooligosaccharides, and then produced glucose, maltose, and maltotriose in the end, indicating Apu is a typical endo-acting glycoside hydrolase family 57 (GH57) amylopullulanase. The maltose and maltotriose observed in the culture medium during the exponential and stationary phase growth indicates that Apu is the essential enzyme to initially hydrolyze the starch into small maltooligosaccharides to be transported into the cell. PMID- 26104677 TI - Suspected cancer (part 1--children and young adults): visual overview of updated NICE guidance. PMID- 26104676 TI - Age-related increases in amyloid beta and membrane attack complex: evidence of inflammasome activation in the rodent eye. AB - BACKGROUND: The membrane attack complex (MAC) is a key player in the pathogenesis of age-related macular degeneration (AMD) and is a putative activator of the NLRP3 inflammasome. Amyloid beta (Abeta), a component of drusen deposits, has also been implicated in inflammasome activation by our work and those of others. However, the interactions of MAC and Abeta are still poorly understood, especially their roles in aging and retinal degenerative pathologies. Since inflammasome activation may represent a key cellular pathway underlying age related chronic inflammation in the eye, the purpose of this study is to identify the effects associated with MAC and inflammasome activation in the retinal pigment epithelium (RPE)/choroid and to evaluate the therapeutic merits of MAC suppression. METHODS: Adult Long-Evans rats were divided into treatment and control groups. Treatment groups received oral aurin tricarboxylic acid complex (ATAC), a MAC inhibitor, in drinking-water, and control groups received drinking water alone (No ATAC). Groups were sacrificed at 7.5 or 11.5 months, after approximately 40 days of ATAC treatment. To study age-related changes of Abeta and MAC in RPE/choroid, naive animals were sacrificed at 2.5, 7.5, and 11.5 months. Eye tissues underwent immunohistochemistry and western blot analysis for MAC, Abeta, NF-kappaB activation, as well as cleaved caspase-1 and IL-18. Vitreal samples were collected and assessed by multiplex assays for secreted levels of IL 18 and IL-1beta. Statistical analyses were performed, and significance level was set at p <= 0.05. RESULTS: In vivo studies demonstrated an age-dependent increase in MAC, Abeta, and NF-kappaB activation in the RPE/choroid. Systemic ATAC resulted in a prominent reduction in MAC formation and a concomitant reduction in inflammasome activation measured by cleaved caspase-1 and secreted levels of IL 18 and IL-1beta, but not in NF-kappaB activation. In vitro studies demonstrated Abeta-induced MAC formation on RPE cells. CONCLUSIONS: Age-dependent increases in Abeta and MAC are present in the rodent outer retina. Our results suggest that suppressing MAC formation and subsequent inflammasome activation in the RPE/choroid may reduce chronic low-grade inflammation associated with IL-18 and IL-1beta in the outer retina. PMID- 26104678 TI - Reactivity of rat bone marrow-derived macrophages to neurotransmitter stimulation in the context of collagen II-induced arthritis. AB - INTRODUCTION: Numerous observations indicate that rheumatoid arthritis (RA) has a bone marrow component. In parallel, local synovial changes depend on neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze whether collagen II-induced arthritis (CIA) has an impact on number, adhesion, apoptosis, and proliferation of the macrophage subset of bone marrow cells and how alterations in neurotransmitter microenvironment affect these properties. METHODS: Bone marrow-derived macrophages (BMMs) were isolated from Dark Agouti rats at different stages of CIA, and number, adhesion, caspase 3/7 activity, and proliferation were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA), and vasoactive intestinal peptide (VIP). RESULTS: Opposed to enhanced CD11b(+) (cluster of differentiation 11b-positive) and EMR1(+) (epidermal growth factor-like module-containing mucin-like hormone receptor-like 1-positive) cells, characterizing the macrophage subset, in native bone marrow of rats with acute inflammatory arthritis, we found decreased numbers of CIA macrophages after enrichment and culture in comparison with healthy (control) animals. Adhesion studies revealed significantly reduced attachment to plastic in acute arthritis and collagen type I and fibronectin in chronic arthritis. Additionally, we found a strong reduction in proliferation of BMMs at CIA onset and in the chronic phase of CIA. Apoptosis remained unaffected. Neurotransmitter stimulation profoundly affected proliferation, adhesion, and apoptosis of BMMs from CIA and control rats, depending on disease time point. Cultured BMMs from CIA and control animals expressed neurotransmitter receptors for ACh, VIP and NA, but the expression profile seemed not to be affected by CIA. CONCLUSIONS: Induction of CIA distinctly inhibits proliferation of BMMs in low- and non inflammatory phases and reduces attachment to plastic at the acute inflammatory arthritis stage and adhesion to collagen I and fibronectin at the chronic stage. Influence of neurotransmitter stimulation on adhesion, apoptosis, and proliferation is altered by CIA depending on disease stage. We suggest an altered reactivity of BMMs to neurotransmitter stimulation caused by CIA and maybe also by aging. PMID- 26104679 TI - Impetigo herpetiformis with IL36RN mutations in a Chinese patient: A founder haplotype of c.115+6T>C in East Asia. PMID- 26104680 TI - Corticosteroid-induced psychiatric disturbances: It is time for pharmacists to take notice. AB - Corticosteroids are widely used to relieve signs and symptoms arising from many diseases, including common inflammatory and autoimmune disorders affecting a number of organ systems. However, corticosteroids also induce significant adverse effects; in particular, a range of severe psychiatric adverse effects may occur including delirium, depression, mania, psychosis and cognitive/memory impairment. These adverse effects occur in up to 60% of patients taking corticosteroids and recent studies show an increased rate of psychopathologies in this population. Long-term adverse effects on mood and behavior are severely debilitating, thereby influencing the quality of life, employment and health status of individuals taking corticosteroids. Strategies used to manage corticosteroid-induced psychiatric disturbances through psychotropic drugs vary significantly. This commentary summarizes existing literature on mechanisms underlying corticosteroid induced psychiatric adverse effects and evidence associated with using psychotropic drugs to manage these effects. Despite its importance, there is an absolute dearth in the literature examining pharmacists' understanding and perceptions of psychiatric adverse effects of corticosteroids. Educational programs need to be implemented so that pharmacists can counsel patients about how to recognize corticosteroid-induced psychiatric disturbances. Physicians do not consistently alert patients to watch for behavioral changes, and patients may feel that mood changes they experience fall within the category of 'normal behavior,' and thus are less likely to report them. Given that patients taking corticosteroids usually have complex medical histories, discussions of adverse effects with pharmacists are vital to improve health outcomes in this population. PMID- 26104681 TI - England's Healthy Living Pharmacy (HLP) initiative: Facilitating the engagement of pharmacy support staff in public health. AB - BACKGROUND: The concept of the Healthy Living Pharmacy (HLP) in England was first piloted in Portsmouth in 2010. HLPs proactively promote health and wellbeing, offering brief advice, services or signposting on a range of health issues such as smoking, physical activity, sexual health, healthy eating and alcohol consumption. OBJECTIVES: To explore the views and attitudes of pharmacy support staff on the Healthy Living Pharmacy (HLP) initiative. METHODS: Qualitative semi structured, face-to-face interviews were conducted with pharmacy support staff recruited from community pharmacies involved in the HLP initiative in the Northumberland region of England. A topic guide was developed which underwent face validity testing and piloting with one participant. Interviews were audio recorded, transcribed verbatim and analyzed using framework technique. RESULTS: A total of 21 pharmacy support staff from 12 HLPs participated in the study. Results suggest that involving pharmacy support staff at very early stages of the HLP planning process drives their motivation for service delivery. Level of engagement with HLP services was often related to support staff roles within pharmacy. Integration of public health roles with routine pharmacy activities was perceived to be more suited to pharmacy counter based roles than dispensing roles. Further training needs were identified around how to proactively deliver public health advice, mainly in service areas perceived 'difficult' by the participants, such as weight management. A total of 19 facilitators/barriers were identified from the data including training, access to information, client feedback, availability of space and facilities within pharmacies, time and competing priorities. CONCLUSIONS: Pharmacy support staff engagement with the HLP initiative can be promoted by involving them from the outset of the service introduction process. Support staff might benefit from targeted training around certain public health areas within the HLP initiative. Facilitators/barriers identified in this study will inform development and further roll out of HLP initiative in wider areas. PMID- 26104682 TI - YY1 regulates melanoma tumorigenesis through a miR-9 ~ RYBP axis. AB - BACKGROUND: The Yin Yang 1 (YY1) transcription factor has been identified to target a plethora of potential target genes, which are important for cell proliferation and differentiation. Although the role that YY1 plays in different human types of cancer has been reported, its biological and mechanistic significance in melanoma has not been well defined. METHODS: Quantitative RT-PCR analysis was used to determine whether aberrant YY1 and miR-9 expression occurred in melanoma, compared with benign nevi and normal tissue controls. Furthermore, the transcriptional regulation of YY1 on miR-9 expression was assessed by using quantitative ChIP-PCR assay. Subsequently, the effects of YY1 and miR-9 on proliferation, cell cycle, migration and invasion of melanoma cells were detected using CCK-8, flow cytometric analysis, wound healing and transwell invasion assays, respectively. Finally, the post-transcriptional regulation of miR-9 on RYBP was analyzed using luciferase reporter and immunoblot analysis. RESULTS: Elevated YY1 levels were observed in patients with melanoma, compared with benign nevi and normal tissue controls, and the increased YY1 was associated with melanoma metastasis state and tumor stage. Furthermore, YY1 negatively regulated miR-9 transcription. Silencing of YY1 inhibited proliferation, cell cycle progression, migration and invasion in melanoma cells, while ectopic of miR-9 did the same. Additionally, RYBP was shown to be a direct target of miR-9 through binding to its 3' UTR, thus forming a YY1 ~ miR-9 ~ RYBP axis. CONCLUSIONS: These results identify a novel YY1 ~ miR-9 ~ RYBP axis involved in melanoma tumorigenesis and reinforce the idea that regulatory circuitries involving miRNAs and TFs are prevalent mechanisms. PMID- 26104683 TI - Police referrals at the psychiatric emergency service in Taiwan. AB - INTRODUCTION: The police are the frontline workers in crisis situations involving patients with severe mental illness and act as a primary referral source for psychiatric emergency services (PES) in the community. The aims of this study were to investigate the distribution and characteristics of police referral among psychiatric patients in Taiwan. METHODS: The study cohort consisted of patients who visited the PES of Taipei City Psychiatric Center from January 2009 to December 2010. The associations between the factors of demographics, clinical characteristics, and psychiatric service utilization and police referral were evaluated. RESULTS: Among the 7656 psychiatric emergency visits, 3029 (39.6%) were referred by the police. These patients referred by police were more likely to be male and aged between 30 to 49 years. Clinical factors related to police referrals including a higher triage assessment level, chief problems included violence, disturbance, substance use, less anxiety, and a diagnosis of unspecified psychosis. The triage assessment level and chief problems assessed by nurses were major predictors. These patients tended to be referred from the catchment area and during the nighttime shift, were discharged during the daytime shift, and stayed longer in the PES. Disposition arrangements such as discharge against medical advice and involuntary admission were also associated with police referrals. DISCUSSION: Patients referred by the police to the PES were those with more severe psychiatric problems and illnesses assessed by psychiatric nurses and psychiatrists. They tended to have more complex service utilization at the PES. PMID- 26104684 TI - Resonant tunnelling in a quantum oxide superlattice. AB - Resonant tunnelling is a quantum mechanical process that has long been attracting both scientific and technological attention owing to its intriguing underlying physics and unique applications for high-speed electronics. The materials system exhibiting resonant tunnelling, however, has been largely limited to the conventional semiconductors, partially due to their excellent crystalline quality. Here we show that a deliberately designed transition metal oxide superlattice exhibits a resonant tunnelling behaviour with a clear negative differential resistance. The tunnelling occurred through an atomically thin, lanthanum delta-doped SrTiO3 layer, and the negative differential resistance was realized on top of the bipolar resistance switching typically observed for perovskite oxide junctions. This combined process resulted in an extremely large resistance ratio (~10(5)) between the high and low-resistance states. The unprecedentedly large control found in atomically thin delta-doped oxide superlattices can open a door to novel oxide-based high-frequency logic devices. PMID- 26104685 TI - Influence of day of surgery on mortality following elective colorectal resections. AB - BACKGROUND: The aim of this study was to investigate whether the increased mortality previously identified for surgery performed on Fridays was apparent following major elective colorectal resections and how this might be affected by case mix. METHODS: Patients undergoing elective colorectal resections in England from 2001 to 2011 were identified using Hospital Episode Statistics. Propensity scores were used to match patients having operations on a Friday in a 1 : 1 ratio with those undergoing surgery on other weekdays. Multivariable analyses were used to investigate overall deaths within 1 year of operation. RESULTS: A total of 204,669 records were extracted for patients undergoing major elective colorectal resections. Patients who had surgery on Fridays were more deprived (4780 (17.1 per cent) of 27,920 versus 28,317 (16.0 per cent) of 176,749; P < 0.001), a greater proportion had had an emergency admission in the 3 previous months (7870 (28.2 per cent) of 27,920 versus 48,623 (27.5 per cent) of 176,749; P = 0.019), underwent minimal access surgery (4565 (16.4 per cent) of 27,920 versus 23,783 (13.5 per cent) of 176,749; P < 0.001) and had surgery for benign diagnoses (6502 (23.3 per cent) of 27,920 versus 38,725 (21.9 per cent) of 176,749; P < 0.001) than those who had surgery on Mondays to Thursdays. In a matched analysis the odds ratio for 30-day mortality after colorectal resections performed on Fridays compared with other weekdays was 1.25 (95 per cent c.i. 1.13 to 1.37); odds ratios for 90-day and 1-year mortality were 1.16 (1.07 to 1.25) and 1.10 (1.04 to 1.16) respectively. CONCLUSION: Patients selected for colorectal resections on Fridays had a higher mortality rate than patients operated on from Monday to Thursday and had different characteristics, suggesting that increased mortality may reflect patient factors rather than hospital variables alone. PMID- 26104686 TI - In Vitro Evaluation of the Effect of 7-Methyl Substitution on Glucuronidation of Daphnetin: Metabolic Stability, Isoform Selectivity, and Bioactivity Analysis. AB - The C-8 phenol group is essential to exert the bioactivities of daphnetin, but it is readily conjugated with glucuronic acid prior to excretion. In this study, daphnetin-7-methylether (7M-DNP) was used to investigate the effect of 7-methyl substitution on daphnetin glucuronidation in human/rat liver (HLM/RLM) and intestine (HIM/RIM) microsomes, and recombinant UDP-glucuronosyltransferases (UGTs). Compared with daphnetin, the Vmax /Km values of 7M-DNP via 8-O glucuronidation were 2.1-fold lower in HLM, 1.7-fold lower in HIM, and 2.4-fold lower in RLM, suggesting an improvement in metabolic stability. Different from daphnetin 8-O-glucuronidation exclusively catalyzed by UGT1A6 and UGT1A9, UGT1A1, -1A3, -1A7, -1A8, and -1A9 showed glucuronidation activity toward 7M-DNP. Kinetics studies, chemical inhibition, and the relative activity factor approach were used to demonstrate that UGT1A9 was mainly responsible for the reaction in HLM, whereas UGT1A1 was a primary contributor in HIM. The Vmax /Km values of 7M DNP glucuronidation in HLM and HIM were 0.61-0.74-fold lower than those of rat, suggesting the differences between the two species. The bioactivity analysis demonstrated that 7M-DNP had an anti-inflammatory activity comparable to that of daphnetin. These findings indicated that the outcomes of 7-methyl substitution on daphnetin might be positive, but this should be confirmed in future in vivo studies. PMID- 26104687 TI - Continuous poly(2-oxazoline) triblock copolymer synthesis in a microfluidic reactor cascade. AB - Cationic ring-opening polymerizations of 2-oxazolines were investigated in continuous microflow reactors. Fast homopolymerizations of 2-ethyl-2-oxazoline (EtOx) and 2-n-propyl-2-oxazoline (nPropOx) were carried out up to 180 degrees C, yielding well-controlled polymers. Also well-defined diblock and triblock copolymers were produced in a microfluidic reactor cascade, demonstrating the high value of microflow synthesis for the built-up of advanced poly(2-oxazoline) based polymers. PMID- 26104688 TI - Reproducible and label-free biosensor for the selective extraction and rapid detection of proteins in biological fluids. AB - Erythropoietin (EPO), a glycoprotein hormone of ~ 34 kDa, is an important hematopoietic growth factor, mainly produced in the kidney and controls the number of red blood cells circulating in the blood stream. Sensitive and rapid recombinant human EPO (rHuEPO) detection tools that improve on the current laborious EPO detection techniques are in high demand for both clinical and sports industry. A sensitive aptamer-functionalized biosensor (aptasensor) has been developed by controlled growth of gold nanostructures (AuNS) over a gold substrate (pAu/AuNS). The aptasensor selectively binds to rHuEPO and, therefore, was used to extract and detect the drug from horse plasma by surface enhanced Raman spectroscopy (SERS). Due to the nanogap separation between the nanostructures, the high population and distribution of hot spots on the pAu/AuNS substrate surface, strong signal enhancement was acquired. By using wide area illumination (WAI) setting for the Raman detection, a low RSD of 4.92% over 150 SERS measurements was achieved. The significant reproducibility of the new biosensor addresses the serious problem of SERS signal inconsistency that hampers the use of the technique in the field. The WAI setting is compatible with handheld Raman devices. Therefore, the new aptasensor can be used for the selective extraction of rHuEPO from biological fluids and subsequently screened with handheld Raman spectrometer for SERS based in-field protein detection. PMID- 26104690 TI - The Ty1 LTR-Retrotransposon of Budding Yeast, Saccharomyces cerevisiae. AB - Long-terminal repeat (LTR)-retrotransposons generate a copy of their DNA (cDNA) by reverse transcription of their RNA genome in cytoplasmic nucleocapsids. They are widespread in the eukaryotic kingdom and are the evolutionary progenitors of retroviruses. The Ty1 element of the budding yeast Saccharomyces cerevisiae was the first LTR-retrotransposon demonstrated to mobilize through an RNA intermediate, and not surprisingly, is the best studied. The depth of our knowledge of Ty1 biology stems not only from the predominance of active Ty1 elements in the S. cerevisiae genome but also the ease and breadth of genomic, biochemical, and cell biology approaches available to study cellular processes in yeast. This review describes the basic structure of Ty1 and its gene products, the replication cycle, the rapidly expanding compendium of host cofactors known to influence retrotransposition, and the nature of Ty1's elaborate symbiosis with its host. Our goal is to illuminate the value of Ty1 as a paradigm to explore the biology of LTR-retrotransposons in multicellular organisms, where the low frequency of retrotransposition events presents a formidable barrier to investigations of retrotransposon biology. PMID- 26104689 TI - Antinociceptive and anti-inflammatory activities of the ethanolic extract of Annona vepretorum Mart. (Annonaceae) in rodents. AB - BACKGROUND: Annona vepretorum Mart. (Annonaceae) is a native tree from Caatinga (Brazilian Northeastern savanna biome), popularly known as "araticum" and "pinha da Caatinga". In this study, we investigated the effects of the crude ethanolic extract (Av-EtOH) in models of pain and inflammation in rodents. METHODS: The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing, formalin, hot plate and tail flick tests, while paw edema induced by carrageenan or histamine, and leukocyte migration to the peritoneal cavity were used for anti-inflammatory profile. Histological analyses also were carried out. RESULTS: Av-EtOH (25, 50 and 100 mg/kg, p.o) significantly reduced the number of writhing (P < 0.01) and decreased (P < 0.01) the paw licking time in both phases of the formalin test. In the hot plate and tail flick tests, this extract increased the reaction time, consequently reduced painful behavior. The effects in the formalin and hot plate tests were antagonized by naloxone. Av-EtOH inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan and histamine. In the peritonitis test, acute pre treatment with Av-EtOH inhibited leukocyte migration. Histological analysis showed less inflammation in the groups treated with the extract when the inflammation was induced by carrageenan or histamine. CONCLUSION: Thus, Av-EtOH has significant antinociceptive and anti-inflammatory properties, which are related probably with the activation of opioid receptors and inhibition of release of mediators of the inflammatory process. This specie is a potential target for drug discovery. PMID- 26104691 TI - Mariner and the ITm Superfamily of Transposons. AB - The IS630-Tc1-mariner (ITm) family of transposons is one of the most widespread in nature. The phylogenetic distribution of its members shows that they do not persist for long in a given lineage, but rely on frequent horizontal transfer to new hosts. Although they are primarily selfish genomic-parasites, ITm transposons contribute to the evolution of their hosts because they generate variation and contribute protein domains and regulatory regions. Here we review the molecular mechanism of ITm transposition and its regulation. We focus mostly on the mariner elements, which are understood in the greatest detail owing to in vitro reconstitution and structural analysis. Nevertheless, the most important characteristics are probably shared across the grouping. Members of the ITm family are mobilized by a cut-and-paste mechanism and integrate at 5'-TA dinucleotide target sites. The elements encode a single transposase protein with an N-terminal DNA-binding domain and a C-terminal catalytic domain. The phosphoryl-transferase reactions during the DNA-strand breaking and joining reactions are performed by the two metal-ion mechanism. The metal ions are coordinated by three or four acidic amino acid residues located within an RNase H like structural fold. Although all of the strand breaking and joining events at a given transposon end are performed by a single molecule of transposase, the reaction is coordinated by close communication between transpososome components. During transpososome assembly, transposase dimers compete for free transposon ends. This helps to protect the host by dampening an otherwise exponential increase in the rate of transposition as the copy number increases. PMID- 26104692 TI - Biofilm Development. AB - During the past decade we have gained much knowledge about the molecular mechanisms that are involved in initiation and termination of biofilm formation. In many bacteria, these processes appear to occur in response to specific environmental cues and result in, respectively, induction or termination of biofilm matrix production via the second messenger molecule c-di-GMP. In between initiation and termination of biofilm formation we have defined specific biofilm stages, but the currently available evidence suggests that these transitions are mainly governed by adaptive responses, and not by specific genetic programs. It appears that biofilm formation can occur through multiple pathways and that the spatial structure of the biofilms is species dependent as well as dependent on environmental conditions. Bacterial subpopulations, e.g., motile and nonmotile subpopulations, can develop and interact during biofilm formation, and these interactions can affect the structure of the biofilm. The available evidence suggests that biofilm formation is programmed in the sense that regulated synthesis of extracellular matrix components is involved. Furthermore, our current knowledge suggests that biofilm formation mainly is governed by adaptive responses of individual bacteria, although group-level activities are also involved. PMID- 26104693 TI - Tyrosine Recombinase Retrotransposons and Transposons. AB - Retrotransposons carrying tyrosine recombinases (YR) are widespread in eukaryotes. The first described tyrosine recombinase mobile element, DIRS1, is a retroelement from the slime mold Dictyostelium discoideum. The YR elements are bordered by terminal repeats related to their replication via free circular dsDNA intermediates. Site-specific recombination is believed to integrate the circle without creating duplications of the target sites. Recently a large number of YR retrotransposons have been described, including elements from fungi (mucorales and basidiomycetes), plants (green algae) and a wide range of animals including nematodes, insects, sea urchins, fish, amphibia and reptiles. YR retrotransposons can be divided into three major groups: the DIRS elements, PAT-like and the Ngaro elements. The three groups form distinct clades on phylogenetic trees based on alignments of reverse transcriptase/ribonuclease H (RT/RH) and YR sequences, and also having some structural distinctions. A group of eukaryote DNA transposons, cryptons, also carry tyrosine recombinases. These DNA transposons do not encode a reverse transcriptase. They have been detected in several pathogenic fungi and oomycetes. Sequence comparisons suggest that the crypton YRs are related to those of the YR retrotransposons. We suggest that the YR retrotransposons arose from the combination of a crypton-like YR DNA transposon and the RT/RH encoding sequence of a retrotransposon. This acquisition must have occurred at a very early point in the evolution of eukaryotes. PMID- 26104695 TI - The Integron: Adaptation On Demand. AB - The integron is a powerful system which, by capturing, stockpiling, and rearranging new functions carried by gene encoding cassettes, confers upon bacteria a rapid adaptation capability in changing environments. Chromosomally located integrons (CI) have been identified in a large number of environmental Gram-negative bacteria. Integron evolutionary history suggests that these sedentary CIs acquired mobility among bacterial species through their association with transposable elements and conjugative plasmids. As a result of massive antibiotic use, these so-called mobile integrons are now widespread in clinically relevant bacteria and are considered to be the principal agent in the emergence and rise of antibiotic multiresistance in Gram-negative bacteria. Cassette rearrangements are catalyzed by the integron integrase, a site-specific tyrosine recombinase. Central to these reactions is the single-stranded DNA nature of one of the recombination partners, the attC site. This makes the integron a unique recombination system. This review describes the current knowledge on this atypical recombination mechanism, its implications in the reactions involving the different types of sites, attC and attI, and focuses on the tight regulation exerted by the host on integron activity through the control of attC site folding. Furthermore, cassette and integrase expression are also highly controlled by host regulatory networks and the bacterial stress (SOS) response. These intimate connections to the host make the integron a genetically stable and efficient system, granting the bacteria a low cost, highly adaptive evolution potential "on demand". PMID- 26104694 TI - c-di-GMP and its Effects on Biofilm Formation and Dispersion: a Pseudomonas Aeruginosa Review. AB - Since its initial discovery as an allosteric factor regulating cellulose biosynthesis in Gluconacetobacter xylinus, the list of functional outputs regulated by c-di-GMP has grown. We have focused this article on one of these c di-GMP-regulated processes, namely, biofilm formation in the organism Pseudomonas aeruginosa. The majority of diguanylate cyclases and phosphodiesterases encoded in the P. aeruginosa genome still remain uncharacterized; thus, there is still a great deal to be learned about the link between c-di-GMP and biofilm formation in this microbe. In particular, while a number of c-di-GMP metabolizing enzymes have been identified that participate in reversible and irreversible attachment and biofilm maturation, there is a still a significant knowledge gap regarding the c di-GMP output systems in this organism. Even for the well-characterized Pel system, where c-di-GMP-mediated transcriptional regulation is now well documented, how binding of c-di-GMP by PelD stimulates Pel production is not understood in any detail. Similarly, c-di-GMP-mediated control of swimming, swarming and twitching also remains to be elucidated. Thus, despite terrific advances in our understanding of P. aeruginosa biofilm formation and the role of c-di-GMP in this process since the last version of this book (indeed there was no chapter on c-di-GMP!) there is still much to learn. PMID- 26104696 TI - The Integration and Excision of CTnDOT. AB - Bacteroides species are one of the most prevalent groups of bacteria present in the human colon. Many strains carry large, integrated elements including integrative and conjugative elements (ICEs). One such ICE is CTnDOT, which is 65 kb in size and encodes resistances to tetracycline and erythromycin. CTnDOT has been increasing in prevalence in Bacteroides spp., and is now found in greater than 80% of natural isolates. In recent years, CTnDOT has been implicated in the spread of antibiotic resistance among gut microbiota. Interestingly, the excision and transfer of CTnDOT is stimulated in the presence of tetracycline. The tyrosine recombinase IntDOT catalyzes the integration and excision reactions of CTnDOT. Unlike the well-characterized lambda Int, IntDOT tolerates heterology in the overlap region between the sites of cleavage and strand exchange. IntDOT also appears to have a different arrangement of active site catalytic residues. It is missing one of the arginine residues that is conserved in other tyrosine recombinases. The excision reaction of CTnDOT is complex, involving excision proteins Xis2c, Xis2d, and Exc, as well as IntDOT and a Bacteroides host factor. Xis2c and Xis2d are small, basic proteins like other recombination directionality factors (RDFs). Exc is a topoisomerase; however, the topoisomerase function is not required for the excision reaction. Exc has been shown to stimulate excision frequencies when there are mismatches in the overlap regions, suggesting that it may play a role in resolving Holliday junctions (HJs) containing heterology. Work is currently under way to elucidate the complex interactions involved with the formation of the CTnDOT excisive intasomes. PMID- 26104697 TI - History and Practice: Antibodies in Infectious Diseases. AB - Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s, when the use of serum from immunized animals provided the first effective treatment options against infections with Clostridium tetani and Corynebacterium diphtheriae. However, after the discovery of penicillin by Fleming in 1928, and the subsequent introduction of the much cheaper and safer antibiotics in the 1930s, serum therapy was largely abandoned. However, the broad and general use of antibiotics in human and veterinary medicine has resulted in the development of multi-resistant strains of bacteria with limited to no response to existing treatments and the need for alternative treatment options. The combined specificity and flexibility of antibody-based treatments makes them very valuable tools for designing specific antibody treatments to infectious agents. These attributes have already caused a revolution in new antibody-based treatments in oncology and inflammatory diseases, with many approved products. However, only one monoclonal antibody, palivizumab, for the prevention and treatment of respiratory syncytial virus, is approved for infectious diseases. The high cost of monoclonal antibody therapies, the need for parallel development of diagnostics, and the relatively small markets are major barriers for their development in the presence of cheap antibiotics. It is time to take a new and revised look into the future to find appropriate niches in infectious diseases where new antibody-based treatments or combinations with existing antibiotics, could prove their value and serve as stepping stones for broader acceptance of the potential for and value of these treatments. PMID- 26104699 TI - An Unexplored Diversity of Reverse Transcriptases in Bacteria. AB - Reverse transcriptases (RTs) are usually thought of as eukaryotic enzymes, but they are also present in bacteria and likely originated in bacteria and migrated to eukaryotes. Only three types of bacterial retroelements have been substantially characterized: group II introns, diversity-generating retroelements, and retrons. Recent work, however, has identified a myriad of uncharacterized RTs and RT-related sequences in bacterial genomes, which exhibit great sequence diversity and a range of domain structures. Apart from group II introns, none of these putative RTs show evidence of active retromobility. Instead, available information suggests that they are involved in useful processes, sometimes related to phages or phage resistance. This article reviews our knowledge of both characterized and uncharacterized RTs in bacteria. The range of their sequences and genomic contexts promises the discovery of new biochemical reactions and biological phenomena. PMID- 26104700 TI - Site-specific non-LTR retrotransposons. AB - Although most of non-long terminal repeat (non-LTR) retrotransposons are incorporated in the host genome almost randomly, some non-LTR retrotransposons are incorporated into specific sequences within a target site. On the basis of structural and phylogenetic features, non-LTR retrotransposons are classified into two large groups, restriction enzyme-like endonuclease (RLE)-encoding elements and apurinic/apyrimidinic endonuclease (APE)-encoding elements. All clades of RLE-encoding non-LTR retrotransposons include site-specific elements. However, only two of more than 20 APE-encoding clades, Tx1 and R1, contain site specific non-LTR elements. Site-specific non-LTR retrotransposons usually target within multi-copy RNA genes, such as rRNA gene (rDNA) clusters, or repetitive genomic sequences, such as telomeric repeats; this behavior may be a symbiotic strategy to reduce the damage to the host genome. Site- and sequence-specificity are variable even among closely related non-LTR elements and appeared to have changed during evolution. In the APE-encoding elements, the primary determinant of the sequence- specific integration is APE itself, which nicks one strand of the target DNA during the initiation of target primed reverse transcription (TPRT). However, other factors, such as interaction between mRNA and the target DNA, and access to the target region in the nuclei also affect the sequence specificity. In contrast, in the RLE-encoding elements, DNA-binding motifs appear to affect their sequence-specificity, rather than the RLE domain itself. Highly specific integration properties of these site-specific non-LTR elements make them ideal alternative tools for sequence-specific gene delivery, particularly for therapeutic purposes in human diseases. PMID- 26104701 TI - piggyBac Transposon. AB - The piggyBac transposon was originally isolated from the cabbage looper moth, Trichoplusia ni, in the 1980s. Despite its early discovery and dissimilarity to the other DNA transposon families, the piggyBac transposon was not recognized as a member of a large transposon superfamily for a long time. Initially, the piggyBac transposon was thought to be a rare transposon. This view, however, has now been completely revised as a number of fully sequenced genomes have revealed the presence of piggyBac-like repetitive elements. The isolation of active copies of the piggyBac-like elements from several distinct species further supported this revision. This includes the first isolation of an active mammalian DNA transposon identified in the bat genome. To date, the piggyBac transposon has been deeply characterized and it represents a number of unique characteristics. In general, all members of the piggyBac superfamily use TTAA as their integration target sites. In addition, the piggyBac transposon shows precise excision, i.e., restoring the sequence to its preintegration state, and can transpose in a variety of organisms such as yeasts, malaria parasites, insects, mammals, and even in plants. Biochemical analysis of the chemical steps of transposition revealed that piggyBac does not require DNA synthesis during the actual transposition event. The broad host range has attracted researchers from many different fields, and the piggyBac transposon is currently the most widely used transposon system for genetic manipulations. PMID- 26104702 TI - The Plasmidome of Firmicutes: Impact on the Emergence and the Spread of Resistance to Antimicrobials. AB - The phylum Firmicutes is one of the most abundant groups of prokaryotes in the microbiota of humans and animals and includes genera of outstanding relevance in biomedicine, health care, and industry. Antimicrobial drug resistance is now considered a global health security challenge of the 21st century, and this heterogeneous group of microorganisms represents a significant part of this public health issue.The presence of the same resistant genes in unrelated bacterial genera indicates a complex history of genetic interactions. Plasmids have largely contributed to the spread of resistance genes among Staphylococcus, Enterococcus, and Streptococcus species, also influencing the selection and ecological variation of specific populations. However, this information is fragmented and often omits species outside these genera. To date, the antimicrobial resistance problem has been analyzed under a "single centric" perspective ("gene tracking" or "vehicle centric" in "single host-single pathogen" systems) that has greatly delayed the understanding of gene and plasmid dynamics and their role in the evolution of bacterial communities.This work analyzes the dynamics of antimicrobial resistance genes using gene exchange networks; the role of plasmids in the emergence, dissemination, and maintenance of genes encoding resistance to antimicrobials (antibiotics, heavy metals, and biocides); and their influence on the genomic diversity of the main Gram-positive opportunistic pathogens under the light of evolutionary ecology. A revision of the approaches to categorize plasmids in this group of microorganisms is given using the 1,326 fully sequenced plasmids of Gram-positive bacteria available in the GenBank database at the time the article was written. PMID- 26104704 TI - Reverse Transcription of Retroviruses and LTR Retrotransposons. AB - The enzyme reverse transcriptase (RT) was discovered in retroviruses almost 50 years ago. The demonstration that other types of viruses, and what are now called retrotransposons, also replicated using an enzyme that could copy RNA into DNA came a few years later. The intensity of the research in both the process of reverse transcription and the enzyme RT was greatly stimulated by the recognition, in the mid-1980s, that human immunodeficiency virus (HIV) was a retrovirus and by the fact that the first successful anti-HIV drug, azidothymidine (AZT), is a substrate for RT. Although AZT monotherapy is a thing of the past, the most commonly prescribed, and most successful, combination therapies still involve one or both of the two major classes of anti-RT drugs. Although the basic mechanics of reverse transcription were worked out many years ago, and the first high-resolution structures of HIV RT are now more than 20 years old, we still have much to learn, particularly about the roles played by the host and viral factors that make the process of reverse transcription much more efficient in the cell than in the test tube. Moreover, we are only now beginning to understand how various host factors that are part of the innate immunity system interact with the process of reverse transcription to protect the host-cell genome, the host cell, and the whole host, from retroviral infection, and from unwanted retrotransposition. PMID- 26104703 TI - Integration, Regulation, and Long-Term Stability of R2 Retrotransposons. AB - R2 elements are sequence specific non-LTR retrotransposons that exclusively insert in the 28S rRNA genes of animals. R2s encode an endonuclease that cleaves the insertion site and a reverse transcriptase that uses the cleaved DNA to prime reverse transcription of the R2 transcript, a process termed target primed reverse transcription. Additional unusual properties of the reverse transcriptase as well as DNA and RNA binding domains of the R2 encoded protein have been characterized. R2 expression is through co-transcription with the 28S gene and self-cleavage by a ribozyme encoded at the R2 5' end. Studies in laboratory stocks and natural populations of Drosophila suggest that R2 expression is tied to the distribution of R2-inserted units within the rDNA locus. Most individuals have no R2 expression because only a small fraction of their rRNA genes need to be active, and a contiguous region of the locus free of R2 insertions can be selected for activation. However, if the R2-free region is not large enough to produce sufficient rRNA, flanking units - including those inserted with R2 - must be activated. Finally, R2 copies rapidly turnover within the rDNA locus, yet R2 has been vertically maintained in animal lineages for hundreds of millions of years. The key to this stability is R2's ability to remain dormant in rDNA units outside the transcribed regions for generations until the stochastic nature of the crossovers that drive the concerted evolution of the rDNA locus inevitably reshuffle the inserted and uninserted units, resulting in transcription of the R2 inserted units. PMID- 26104705 TI - Sleeping Beauty Transposition. AB - Sleeping Beauty (SB) is a synthetic transposon that was constructed based on sequences of transpositionally inactive elements isolated from fish genomes. SB is a Tc1/mariner superfamily transposon following a cut-and-paste transpositional reaction, during which the element-encoded transposase interacts with its binding sites in the terminal inverted repeats of the transposon, promotes the assembly of a synaptic complex, catalyzes excision of the element out of its donor site, and integrates the excised transposon into a new location in target DNA. SB transposition is dependent on cellular host factors. Transcriptional control of transposase expression is regulated by the HMG2L1 transcription factor. Synaptic complex assembly is promoted by the HMGB1 protein and regulated by chromatin structure. SB transposition is highly dependent on the nonhomologous end joining (NHEJ) pathway of double-strand DNA break repair that generates a transposon footprint at the excision site. Through its association with the Miz-1 transcription factor, the SB transposase downregulates cyclin D1 expression that results in a slowdown of the cell-cycle in the G1 phase, where NHEJ is preferentially active. Transposon integration occurs at TA dinucleotides in the target DNA, which are duplicated at the flanks of the integrated transposon. SB shows a random genome-wide insertion profile in mammalian cells when launched from episomal vectors and "local hopping" when launched from chromosomal donor sites. Some of the excised transposons undergo a self-destructive autointegration reaction, which can partially explain why longer elements transpose less efficiently. SB became an important molecular tool for transgenesis, insertional mutagenesis, and gene therapy. PMID- 26104698 TI - The Influence of LINE-1 and SINE Retrotransposons on Mammalian Genomes. AB - Transposable elements have had a profound impact on the structure and function of mammalian genomes. The retrotransposon Long INterspersed Element-1 (LINE-1 or L1), by virtue of its replicative mobilization mechanism, comprises ~17% of the human genome. Although the vast majority of human LINE-1 sequences are inactive molecular fossils, an estimated 80-100 copies per individual retain the ability to mobilize by a process termed retrotransposition. Indeed, LINE-1 is the only active, autonomous retrotransposon in humans and its retrotransposition continues to generate both intra-individual and inter-individual genetic diversity. Here, we briefly review the types of transposable elements that reside in mammalian genomes. We will focus our discussion on LINE-1 retrotransposons and the non autonomous Short INterspersed Elements (SINEs) that rely on the proteins encoded by LINE-1 for their mobilization. We review cases where LINE-1-mediated retrotransposition events have resulted in genetic disease and discuss how the characterization of these mutagenic insertions led to the identification of retrotransposition-competent LINE-1s in the human and mouse genomes. We then discuss how the integration of molecular genetic, biochemical, and modern genomic technologies have yielded insight into the mechanism of LINE-1 retrotransposition, the impact of LINE-1-mediated retrotransposition events on mammalian genomes, and the host cellular mechanisms that protect the genome from unabated LINE-1-mediated retrotransposition events. Throughout this review, we highlight unanswered questions in LINE-1 biology that provide exciting opportunities for future research. Clearly, much has been learned about LINE-1 and SINE biology since the publication of Mobile DNA II thirteen years ago. Future studies should continue to yield exciting discoveries about how these retrotransposons contribute to genetic diversity in mammalian genomes. PMID- 26104706 TI - Ecology of Bacillaceae. AB - Members of the family Bacillaceae are among the most robust bacteria on Earth, which is mainly due to their ability to form resistant endospores. This trait is believed to be the key factor determining the ecology of these bacteria. However, they also perform fundamental roles in soil ecology (i.e., the cycling of organic matter) and in plant health and growth stimulation (e.g., via suppression of plant pathogens and phosphate solubilization). In this review, we describe the high functional and genetic diversity that is found within the Bacillaceae (a family of low-G+C% Gram-positive spore-forming bacteria), their roles in ecology and in applied sciences related to agriculture. We then pose questions with respect to their ecological behavior, zooming in on the intricate social behavior that is becoming increasingly well characterized for some members of Bacillaceae. Such social behavior, which includes cell-to-cell signaling via quorum sensing or other mechanisms (e.g., the production of extracellular hydrolytic enzymes, toxins, antibiotics and/or surfactants) is a key determinant of their lifestyle and is also believed to drive diversification processes. It is only with a deeper understanding of cell-to-cell interactions that we will be able to understand the ecological and diversification processes of natural populations within the family Bacillaceae. Ultimately, the resulting improvements in understanding will benefit practical efforts to apply representatives of these bacteria in promoting plant growth as well as biological control of plant pathogens. PMID- 26104707 TI - Ty3, a Position-specific Retrotransposon in Budding Yeast. AB - Long terminal repeat (LTR) retrotransposons constitute significant fractions of many eukaryotic genomes. Two ancient families are Ty1/Copia (Pseudoviridae) and Ty3/Gypsy (Metaviridae). The Ty3/Gypsy family probably gave rise to retroviruses based on the domain order, similarity of sequences, and the envelopes encoded by some members. The Ty3 element of Saccharomyces cerevisiae is one of the most completely characterized elements at the molecular level. Ty3 is induced in mating cells by pheromone stimulation of the mitogen-activated protein kinase pathway as cells accumulate in G1. The two Ty3 open reading frames are translated into Gag3 and Gag3-Pol3 polyprotein precursors. In haploid mating cells Gag3 and Gag3-Pol3 are assembled together with Ty3 genomic RNA into immature virus-like particles in cellular foci containing RNA processing body proteins. Virus-like particle Gag3 is then processed by Ty3 protease into capsid, spacer, and nucleocapsid, and Gag3-Pol3 into those proteins and additionally, protease, reverse transcriptase, and integrase. After haploid cells mate and become diploid, genomic RNA is reverse transcribed into cDNA. Ty3 integration complexes interact with components of the RNA polymerase III transcription complex resulting in Ty3 integration precisely at the transcription start site. Ty3 activation during mating enables proliferation of Ty3 between genomes and has intriguing parallels with metazoan retrotransposon activation in germ cell lineages. Identification of nuclear pore, DNA replication, transcription, and repair host factors that affect retrotransposition has provided insights into how hosts and retrotransposons interact to balance genome stability and plasticity. PMID- 26104710 TI - Mutator and MULE Transposons. AB - The Mutator system of transposable elements (TEs) is a highly mutagenic family of transposons in maize. Because they transpose at high rates and target genic regions, these transposons can rapidly generate large numbers of new mutants, which has made the Mutator system a favored tool for both forward and reverse mutagenesis in maize. Low copy number versions of this system have also proved to be excellent models for understanding the regulation and behavior of Class II transposons in plants. Notably, the availability of a naturally occurring locus that can heritably silence autonomous Mutator elements has provided insights into the means by which otherwise active transposons are recognized and silenced. This chapter will provide a review of the biology, regulation, evolution and uses of this remarkable transposon system, with an emphasis on recent developments in our understanding of the ways in which this TE system is recognized and epigenetically silenced as well as recent evidence that Mu-like elements (MULEs) have had a significant impact on the evolution of plant genomes. PMID- 26104708 TI - Topological Behavior of Plasmid DNA. AB - The discovery of the B-form structure of DNA by Watson and Crick led to an explosion of research on nucleic acids in the fields of biochemistry, biophysics, and genetics. Powerful techniques were developed to reveal a myriad of different structural conformations that change B-DNA as it is transcribed, replicated, and recombined and as sister chromosomes are moved into new daughter cell compartments during cell division. This article links the original discoveries of superhelical structure and molecular topology to non-B form DNA structure and contemporary biochemical and biophysical techniques. The emphasis is on the power of plasmids for studying DNA structure and function. The conditions that trigger the formation of alternative DNA structures such as left-handed Z-DNA, inter- and intra-molecular triplexes, triple-stranded DNA, and linked catenanes and hemicatenanes are explained. The DNA dynamics and topological issues are detailed for stalled replication forks and for torsional and structural changes on DNA in front of and behind a transcription complex and a replisome. The complex and interconnected roles of topoisomerases and abundant small nucleoid association proteins are explained. And methods are described for comparing in vivo and in vitro reactions to probe and understand the temporal pathways of DNA and chromosome chemistry that occur inside living cells. PMID- 26104709 TI - Biofilm Matrix Proteins. AB - Proteinaceous components of the biofilm matrix include secreted extracellular proteins, cell surface adhesins, and protein subunits of cell appendages such as flagella and pili. Biofilm matrix proteins play diverse roles in biofilm formation and dissolution. They are involved in attaching cells to surfaces, stabilizing the biofilm matrix via interactions with exopolysaccharide and nucleic acid components, developing three-dimensional biofilm architectures, and dissolving biofilm matrix via enzymatic degradation of polysaccharides, proteins, and nucleic acids. In this article, we will review functions of matrix proteins in a selected set of microorganisms, studies of the matrix proteomes of Vibrio cholerae and Pseudomonas aeruginosa, and roles of outer membrane vesicles and of nucleoid-binding proteins in biofilm formation. PMID- 26104712 TI - Mating-type Gene Switching in Saccharomyces cerevisiae. AB - The budding yeast Saccharomyces cerevisiae has two alternative mating types designated MATa and MATalpha. These are distinguished by about 700 bp of unique sequences, Ya or Yalpha, including divergent promoter sequences and part of the open reading frames of genes that regulate mating phenotype. Homothallic budding yeast, carrying an active HO endonuclease gene, HO, can switch mating type through a recombination process known as gene conversion, in which a site specific double-strand break (DSB) created immediately adjacent to the Y region results in replacement of the Y sequences with a copy of the opposite mating type information, which is harbored in one of two heterochromatic donor loci, HMLalpha or HMRa. HO gene expression is tightly regulated to ensure that only half of the cells in a lineage switch to the opposite MAT allele, thus promoting conjugation and diploid formation. Study of the silencing of these loci has provided a great deal of information about the role of the Sir2 histone deacetylase and its associated Sir3 and Sir4 proteins in creating heterochromatic regions. MAT switching has been examined in great detail to learn about the steps in homologous recombination. MAT switching is remarkably directional, with MATa recombining preferentially with HMLalpha and MATalpha using HMRa. Donor preference is controlled by a cis-acting recombination enhancer located near HML. RE is turned off in MATalpha cells but in MATa binds multiple copies of the Fkh1 transcription factor whose forkhead-associated phosphothreonine binding domain localizes at the DSB, bringing HML into conjunction with MATa. PMID- 26104711 TI - The lambda Integrase Site-specific Recombination Pathway. AB - The site-specific recombinase encoded by bacteriophage lambda (Int) is responsible for integrating and excising the viral chromosome into and out of the chromosome of its Escherichia coli host. Int carries out a reaction that is highly directional, tightly regulated, and depends upon an ensemble of accessory DNA bending proteins acting on 240 bp of DNA encoding 16 protein binding sites. This additional complexity enables two pathways, integrative and excisive recombination, whose opposite, and effectively irreversible, directions are dictated by different physiological and environmental signals. Int recombinase is a heterobivalent DNA binding protein and each of the four Int protomers, within a multiprotein 400 kDa recombinogenic complex, is thought to bind and, with the aid of DNA bending proteins, bridge one arm- and one core-type DNA site. In the 12 years since the publication of the last review focused solely on the lambda site specific recombination pathway in Mobile DNA II, there has been a great deal of progress in elucidating the molecular details of this pathway. The most dramatic advances in our understanding of the reaction have been in the area of X-ray crystallography where protein-DNA structures have now been determined for of all of the DNA-protein interfaces driving the Int pathway. Building on this foundation of structures, it has been possible to derive models for the assembly of components that determine the regulatory apparatus in the P-arm, and for the overall architectures that define excisive and integrative recombinogenic complexes. The most fundamental additional mechanistic insights derive from the application of hexapeptide inhibitors and single molecule kinetics. PMID- 26104713 TI - Serine Resolvases. AB - Serine resolvases are an interesting group of site-specific recombinases that, in their native contexts, resolve large fused replicons into smaller separated ones. Some resolvases are encoded by replicative transposons and resolve the transposition product, in which the donor and recipient molecules are fused, into separate replicons. Other resolvases are encoded by plasmids and function to resolve plasmid dimers into monomers. Both types are therefore involved in the spread and maintenance of antibiotic-resistance genes. Resolvases and the closely related invertases were the first serine recombinases to be studied in detail, and much of our understanding of the unusual strand exchange mechanism of serine recombinases is owed to those early studies. Resolvases and invertases have also served as paradigms for understanding how DNA topology can be harnessed to regulate enzyme activity. Finally, their relatively modular structure, combined with a wealth of structural and biochemical data, has made them good choices for engineering chimeric recombinases with designer specificity. This chapter focuses on the current understanding of serine resolvases, with a focus on the contributions of structural studies. PMID- 26104715 TI - Everyman's Guide to Bacterial Insertion Sequences. AB - The number and diversity of known prokaryotic insertion sequences (IS) have increased enormously since their discovery in the late 1960s. At present the sequences of more than 4000 different IS have been deposited in the specialized ISfinder database. Over time it has become increasingly apparent that they are important actors in the evolution of their host genomes and are involved in sequestering, transmitting, mutating and activating genes, and in the rearrangement of both plasmids and chromosomes. This review presents an overview of our current understanding of these transposable elements (TE), their organization and their transposition mechanism as well as their distribution and genomic impact. In spite of their diversity, they share only a very limited number of transposition mechanisms which we outline here. Prokaryotic IS are but one example of a variety of diverse TE which are being revealed due to the advent of extensive genome sequencing projects. A major conclusion from sequence comparisons of various TE is that frontiers between the different types are becoming less clear. We detail these receding frontiers between different IS related TE. Several, more specialized chapters in this volume include additional detailed information concerning a number of these.In a second section of the review, we provide a detailed description of the expanding variety of IS, which we have divided into families for convenience. Our perception of these families continues to evolve and families emerge regularly as more IS are identified. This section is designed as an aid and a source of information for consultation by interested specialist readers. PMID- 26104716 TI - Division of Labor in Biofilms: the Ecology of Cell Differentiation. AB - The dense aggregation of cells on a surface, as seen in biofilms, inevitably results in both environmental and cellular heterogeneity. For example, nutrient gradients can trigger cells to differentiate into various phenotypic states. Not only do cells adapt physiologically to the local environmental conditions, but they also differentiate into cell types that interact with each other. This allows for task differentiation and, hence, the division of labor. In this article, we focus on cell differentiation and the division of labor in three bacterial species: Myxococcus xanthus, Bacillus subtilis, and Pseudomonas aeruginosa. During biofilm formation each of these species differentiates into distinct cell types, in some cases leading to cooperative interactions. The division of labor and the cooperative interactions between cell types are assumed to yield an emergent ecological benefit. Yet in most cases the ecological benefits have yet to be elucidated. A notable exception is M. xanthus, in which cell differentiation within fruiting bodies facilitates the dispersal of spores. We argue that the ecological benefits of the division of labor might best be understood when we consider the dynamic nature of both biofilm formation and degradation. PMID- 26104714 TI - P Transposable Elements in Drosophila and other Eukaryotic Organisms. AB - P transposable elements were discovered in Drosophila as the causative agents of a syndrome of genetic traits called hybrid dysgenesis. Hybrid dysgenesis exhibits a unique pattern of maternal inheritance linked to the germline-specific small RNA piwi-interacting (piRNA) pathway. The use of P transposable elements as vectors for gene transfer and as genetic tools revolutionized the field of Drosophila molecular genetics. P element transposons have served as a useful model to investigate mechanisms of cut-and-paste transposition in eukaryotes. Biochemical studies have revealed new and unexpected insights into how eukaryotic DNA-based transposons are mobilized. For example, the P element transposase makes unusual 17nt-3' extended double-strand DNA breaks at the transposon termini and uses guanosine triphosphate (GTP) as a cofactor to promote synapsis of the two transposon ends early in the transposition pathway. The N-terminal DNA binding domain of the P element transposase, called a THAP domain, contains a C2CH zinc coordinating motif and is the founding member of a large family of animal specific site-specific DNA binding proteins. Over the past decade genome sequencing efforts have revealed the presence of P element-like transposable elements or P element transposase-like genes (called THAP9) in many eukaryotic genomes, including vertebrates, such as primates including humans, zebrafish and Xenopus, as well as the human parasite Trichomonas vaginalis, the sea squirt Ciona, sea urchin and hydra. Surprisingly, the human and zebrafish P element transposase-related THAP9 genes promote transposition of the Drosophila P element transposon DNA in human and Drosophila cells, indicating that the THAP9 genes encode active P element "transposase" proteins. PMID- 26104717 TI - DNA Recombination Strategies During Antigenic Variation in the African Trypanosome. AB - Survival of the African trypanosome in its mammalian hosts has led to the evolution of antigenic variation, a process for evasion of adaptive immunity that has independently evolved in many other viral, bacterial and eukaryotic pathogens. The essential features of trypanosome antigenic variation have been understood for many years and comprise a dense, protective Variant Surface Glycoprotein (VSG) coat, which can be changed by recombination-based and transcription-based processes that focus on telomeric VSG gene transcription sites. However, it is only recently that the scale of this process has been truly appreciated. Genome sequencing of Trypanosoma brucei has revealed a massive archive of >1000 VSG genes, the huge majority of which are functionally impaired but are used to generate far greater numbers of VSG coats through segmental gene conversion. This chapter will discuss the implications of such VSG diversity for immune evasion by antigenic variation, and will consider how this expressed diversity can arise, drawing on a growing body of work that has begun to examine the proteins and sequences through which VSG switching is catalyzed. Most studies of trypanosome antigenic variation have focused on T. brucei, the causative agent of human sleeping sickness. Other work has begun to look at antigenic variation in animal-infective trypanosomes, and we will compare the findings that are emerging, as well as consider how antigenic variation relates to the dynamics of host-trypanosome interaction. PMID- 26104718 TI - Mechanisms of DNA Transposition. AB - DNA transposases use a limited repertoire of structurally and mechanistically distinct nuclease domains to catalyze the DNA strand breaking and rejoining reactions that comprise DNA transposition. Here, we review the mechanisms of the four known types of transposition reactions catalyzed by (1) RNase H-like transposases (also known as DD(E/D) enzymes); (2) HUH single-stranded DNA transposases; (3) serine transposases; and (4) tyrosine transposases. The large body of accumulated biochemical and structural data, particularly for the RNase H like transposases, has revealed not only the distinguishing features of each transposon family, but also some emerging themes that appear conserved across all families. The more-recently characterized single-stranded DNA transposases provide insight into how an ancient HUH domain fold has been adapted for transposition to accomplish excision and then site-specific integration. The serine and tyrosine transposases are structurally and mechanistically related to their cousins, the serine and tyrosine site-specific recombinases, but have to date been less intensively studied. These types of enzymes are particularly intriguing as in the context of site-specific recombination they require strict homology between recombining sites, yet for transposition can catalyze the joining of transposon ends to form an excised circle and then integration into a genomic site with much relaxed sequence specificity. PMID- 26104720 TI - Retraction: Targeting HMGB1 Inhibits Ovarian Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference. PMID- 26104719 TI - Modified mosquito landing boxes dispensing transfluthrin provide effective protection against Anopheles arabiensis mosquitoes under simulated outdoor conditions in a semi-field system. AB - BACKGROUND: Efforts to control malaria vectors have primarily focused on scaling up of long-lasting insecticidal nets (LLINs) and indoor residual spraying. Although highly efficient against indoor-biting and indoor-resting vectors, these interventions have lower impact on outdoor-biting mosquitoes. Innovative vector control tools are required to prevent outdoor human-mosquito contacts. In this work, the potential of spatial repellents, delivered in an active system that requires minimal user compliance, to provide personal protection against exophagic mosquitoes active in the early evening was explored. METHODS: A device previously used as an odour-baited lure and kill apparatus, the mosquito landing box (MLB), was modified to dispense the volatile synthetic pyrethroid, transfluthrin, as a spatial repellent. The MLB has an active odour-dispensing mechanism that uses a solar-powered fan and switches on at dusk to provide long duration dispensing of volatile compounds without the need for the user to remember to employ it. Two MLBs were located 5 m from a human volunteer to investigate the repellent effects of a transfluthrin 'bubble' created between the MLBs. Transfluthrin was emanated from polyester strips, hanging inside the MLB odour-dispensing unit. A fully randomized cross-over design was performed in a large, semi-field, screened cage to assess the effect of the repellent against laboratory-reared Anopheles arabiensis mosquitoes under ambient outdoor conditions. The knock-down capacity of the transfluthrin-treated strips was also evaluated at different time points up to 3 weeks after being impregnated to measure duration of efficacy. RESULTS: The protective transfluthrin bubble provided 68.9% protection against An. arabiensis bites under these simulated outdoor conditions. Volatile transfluthrin caused low mortality among mosquitoes in the semi-field system. Transfluthrin-treated strips continued to knock down mosquitoes in laboratory tests, 3 weeks after impregnation, although this effect diminished with time. CONCLUSION: Modified MLBs can be used as efficient and long lasting dispensers of volatile spatial repellents such as transfluthrin, thereby providing high levels of protection against outdoor-biting mosquitoes in the peri domestic space. They have a potential role in combatting outdoor malaria transmission without interfering with effective indoor interventions such as LLINs. PMID- 26104725 TI - Ir(III) complexes designed for light-emitting devices: beyond the luminescence color array. AB - In pursuing novel efficient lighting technologies and materials, phosphorescent cyclometallated Ir(iii) complexes have been prominent due to their wide color arrays and highly efficient electroluminescence. Their photophysical properties are strongly influenced by spin-orbit coupling exerted by the iridium core, usually resulting in intense, short-lived emission, which can be systematically tuned as a triumph of molecular engineering. This Perspective aims to present recent breakthroughs and state of the art on emissive Ir(iii) compounds, in particular a personal account on heteroleptic [Ir(N^C)2(L^X)](+) complexes, addressing the mechanistic concepts behind their luminescence. Their fascinating photophysical properties strengthen application in more-efficient light-emitting technologies, such as organic light-emitting diodes and light-emitting electrochemical cells. PMID- 26104726 TI - Erratum to: Ageing with HIV: a multidisciplinary review. PMID- 26104727 TI - Endocarditis caused by Streptococcus canis: an emerging zoonosis? AB - We report a human case of infective endocarditis caused by Streptococcus canis. Identification was carried out from positive blood culture using mass spectrometry and SodA gene sequencing. S. canis related zoonotic invasive infections may have been previously underdiagnosed due to inadequate identification of group G Streptococcus species. PMID- 26104728 TI - Non-transferrin-bound iron is associated with biomarkers of oxidative stress, inflammation and endothelial dysfunction in type 2 diabetes. AB - AIMS: To investigate the association between circulating non-transferrin-bound iron [NTBI], and markers of oxidative stress, endothelial function and inflammation in subjects with type 2 diabetes and non-diabetic subjects with varying degrees of obesity. METHODS: Plasma NTBI was measured by HPLC, together with total iron, iron-binding capacity, transferrin saturation and soluble transferrin receptor, together with total and reduced ascorbate, malondialdehyde [MDA], E-selectin and high-sensitivity c-reactive protein [hs-CRP] in groups of 28 subjects with type 2 diabetes, 28 non-obese controls and 17 obese non-diabetic subjects. RESULTS: Levels of NTBI were higher than controls in the diabetes group, but the total serum iron levels were lower. MDA levels were higher than controls in both the diabetes and obese groups, and this was associated with higher levels of oxidised ascorbate. hs-CRP levels were higher in both the diabetes and obese groups, and E-selectin was significantly higher in the diabetes group. There were strong positive correlations between HbA1c levels and NTBI [P<0.01], HbA1c and E-selectin [P<0.001] and NTBI and E-selectin [P<0.02] in the diabetes group. CONCLUSION: These results support the hypothesis that iron mediated oxidative stress may be a mechanism linking poor glycaemic control with vascular dysfunction in type 2 diabetes. PMID- 26104729 TI - Adverse event notifications implicating metformin with lactic acidosis in Australia. AB - OBJECTIVE: To summarise the reported lactic acidosis cases associated with metformin from the Australian Therapeutic Goods Administration (TGA) and estimate the incidence of metformin-associated lactic acidosis (MALA) in Australia. METHOD: All "lactic acidosis" cases associated with metformin and reported to the TGA between January 1971 and October 2014 were included. Data extracted included patient demographics, medical history and co-existing conditions, metformin dosage and relevant pathology results. RESULT: A total of 152 cases of suspected MALA were included in this study. For 20 patients the outcome was unknown. There were 23 patients (n=132, 17.4%) reported as deceased. Plasma lactate levels were higher in non-survivors (p=0.02). Thirty-five patients (n=132, 26.5%) were reported to have at least one pre-existing contraindication to the use of metformin; this proportion was not different between patients who died or survived. Renal impairment was the most common contraindication. Approximately 75% of patients were reported to have at least one clinical condition which might cause acidosis. Metformin dosage, plasma lactate and serum creatinine were not correlated. Based on the cases reported to the TGA, the incidence of MALA in Australia was estimated to be 2.3 (95% CI, 1.5-3.1) cases per 100,000 patient years between 1997 and 2011. CONCLUSION: Pre-existing clinical conditions, such as renal impairment, and acute illnesses associated with lactic acidosis were frequently reported in the cases of MALA. The estimated incidence of MALA was lower than in most previous studies in other countries, probably due to the nature of spontaneous reports to the TGA. PMID- 26104730 TI - Association between ApoA-II -265T/C polymorphism and oxidative stress in patients with type 2 diabetes mellitus. AB - BACKGROUND: Apolipoprotein A-II (ApoA-II) constitutes approximately 20% of the total HDL protein content. The results of various studies on the relationship between cardiovascular diseases (CVD) and the plasma ApoA-II level are contradictory. The aim of this study was to determine the relationship between ApoA-II polymorphism and oxidative stress (OS) as a risk factor for CVD. METHODS: The present comparative study was carried out on 180 obese and non-obese patients with type 2 diabetes, with equal numbers of CC, TC, and TT genotypes of ApoA-II 265T/C gene. The ApoA-II genotype was determined by the TaqMan assay method. The anthropometric measurements and serum levels of lipid profile, superoxide dismutase activity (SOD), total antioxidant capacity (TAC), and 8 isoprostaneF2alpha were measured. RESULTS: After adjusting for confounding factors, in the total study population and in obese and non-obese groups, the subjects with CC genotype had a lower mean serum SOD activity (p=0.002, p=0.007 and p=0.005, respectively) and higher mean 8-isoprostaneF2alpha concentration (p<0.001, p=0.003 and p=0.004, respectively) than the T-allele carriers. In the TT/TC group, the mean 8-isoprostanF2alpha concentration was significantly higher in the obese subjects than the non-obese subjects (p=0.009). In the CC group, no significant differences were found in the OS factors between obese and non-obese groups. CONCLUSION: The T allele in patients with type 2 diabetes is a protective factor against OS; obesity inhibits this protective effect. The results of this study represent the anti-atherogenic properties of ApoA-II. However, further studies are needed in this field. PMID- 26104731 TI - [Not Available]. PMID- 26104732 TI - [Not Available]. PMID- 26104733 TI - [Not Available]. PMID- 26104734 TI - [Not Available]. PMID- 26104735 TI - [VATS - technique and indications]. AB - Video-assisted thoracoscopic surgery (VATS) has revolutionized the practice of thoracic surgeons and improved patient experiences and outcomes worldwide. The VATS approach has matured over the past decades and now accounts for approximately 50 % of all operations in specialized thoracic surgery units. The VATS procedure is less invasive and therefore allows a faster recovery of patients. Over the last 20 years VATS has developed into a safe and effective technique for the diagnostics and therapy of many thoracic diseases. With increasing experience thoracic surgeons can carry out more advanced and technically challenging interventions. Nowadays, VATS is the superior technique in many cases of thoracotomy. PMID- 26104736 TI - A dinaphtho[8,1,2-cde:2',1',8'-uva]pentacene derivative and analogues: synthesis, structures, photophysical and electrochemical properties. AB - Dinaphtho[8,1,2-cde:2',1',8'-uva]pentacene and analogues as a new type of acene derivatives with scorpion-shaped structures were conveniently synthesized. Their structures, photophysical and electrochemical properties were experimentally and theoretically investigated. It was found that the pentacene derivative has a twisted configuration, but shows marked intermolecular pi-pi interactions, strong electronic delocalization, and a small HOMO-LUMO bandgap, which are different from those of pentacene and pentatwistacene derivatives with similar structures. PMID- 26104737 TI - Controlling pyridinic, pyrrolic, graphitic, and molecular nitrogen in multi-wall carbon nanotubes using precursors with different N/C ratios in aerosol assisted chemical vapor deposition. AB - Nitrogen-containing multi-wall carbon nanotubes (N-MWCNTs) were synthesized using aerosol assisted chemical vapor deposition (CVD) techniques in conjunction with benzylamine:ferrocene or acetonitrile:ferrocene mixtures. Different amounts of toluene were added to these mixtures in order to change the N/C ratio of the feedstock. X-ray photoelectron and near-edge X-ray absorption fine structure spectroscopy detected pyridinic, pyrrolic, graphitic, and molecular nitrogen forms in the N-MWCNT samples. Analysis of the spectral data indicated that whilst the nature of the nitrogen-containing precursor has little effect on the concentrations of the different forms of nitrogen in N-MWCNTs, the N/C ratio in the feedstock appeared to be the determining factor. When the N/C ratio was lower than ca. 0.01, all four forms existed in equal concentrations, for N/C ratios above 0.01, graphitic and molecular nitrogen were dominant. Furthermore, higher concentrations of pyridinic nitrogen in the outer shells and N2 molecules in the core of the as-produced N-MWCNTs suggest that the precursors were decomposed into individual atoms, which interacted with the catalyst surface to form CN and NH species or in fact diffused through the bulk of the catalyst particles. These findings are important for a better understanding of possible growth mechanisms for heteroatom-containing carbon nanotubes (CNTs) and therefore paving the way for controlling the spatial distribution of foreign elements in the CNTs using CVD processes. PMID- 26104738 TI - Focus on symptoms to improve early diagnosis, new cancer guidance says. PMID- 26104739 TI - Cross-vendor evaluation of key user-defined clinical decision support capabilities: a scenario-based assessment of certified electronic health records with guidelines for future development. AB - OBJECTIVE: Clinical decision support (CDS) is essential for delivery of high quality, cost-effective, and safe healthcare. The authors sought to evaluate the CDS capabilities across electronic health record (EHR) systems. METHODS: We evaluated the CDS implementation capabilities of 8 Office of the National Coordinator for Health Information Technology Authorized Certification Body (ONC ACB)-certified EHRs. Within each EHR, the authors attempted to implement 3 user defined rules that utilized the various data and logic elements expected of typical EHRs and that represented clinically important evidenced-based care. The rules were: 1) if a patient has amiodarone on his or her active medication list and does not have a thyroid-stimulating hormone (TSH) result recorded in the last 12 months, suggest ordering a TSH; 2) if a patient has a hemoglobin A1c result >7% and does not have diabetes on his or her problem list, suggest adding diabetes to the problem list; and 3) if a patient has coronary artery disease on his or her problem list and does not have aspirin on the active medication list, suggest ordering aspirin. RESULTS: Most evaluated EHRs lacked some CDS capabilities; 5 EHRs were able to implement all 3 rules, and the remaining 3 EHRs were unable to implement any of the rules. One of these did not allow users to customize CDS rules at all. The most frequently found shortcomings included the inability to use laboratory test results in rules, limit rules by time, use advanced Boolean logic, perform actions from the alert interface, and adequately test rules. CONCLUSION: Significant improvements in the EHR certification and implementation procedures are necessary. PMID- 26104740 TI - National Veterans Health Administration inpatient risk stratification models for hospital-acquired acute kidney injury. AB - OBJECTIVE: Hospital-acquired acute kidney injury (HA-AKI) is a potentially preventable cause of morbidity and mortality. Identifying high-risk patients prior to the onset of kidney injury is a key step towards AKI prevention. MATERIALS AND METHODS: A national retrospective cohort of 1,620,898 patient hospitalizations from 116 Veterans Affairs hospitals was assembled from electronic health record (EHR) data collected from 2003 to 2012. HA-AKI was defined at stage 1+, stage 2+, and dialysis. EHR-based predictors were identified through logistic regression, least absolute shrinkage and selection operator (lasso) regression, and random forests, and pair-wise comparisons between each were made. Calibration and discrimination metrics were calculated using 50 bootstrap iterations. In the final models, we report odds ratios, 95% confidence intervals, and importance rankings for predictor variables to evaluate their significance. RESULTS: The area under the receiver operating characteristic curve (AUC) for the different model outcomes ranged from 0.746 to 0.758 in stage 1+, 0.714 to 0.720 in stage 2+, and 0.823 to 0.825 in dialysis. Logistic regression had the best AUC in stage 1+ and dialysis. Random forests had the best AUC in stage 2+ but the least favorable calibration plots. Multiple risk factors were significant in our models, including some nonsteroidal anti-inflammatory drugs, blood pressure medications, antibiotics, and intravenous fluids given during the first 48 h of admission. CONCLUSIONS: This study demonstrated that, although all the models tested had good discrimination, performance characteristics varied between methods, and the random forests models did not calibrate as well as the lasso or logistic regression models. In addition, novel modifiable risk factors were explored and found to be significant. PMID- 26104742 TI - RobotReviewer: evaluation of a system for automatically assessing bias in clinical trials. AB - OBJECTIVE: To develop and evaluate RobotReviewer, a machine learning (ML) system that automatically assesses bias in clinical trials. From a (PDF-formatted) trial report, the system should determine risks of bias for the domains defined by the Cochrane Risk of Bias (RoB) tool, and extract supporting text for these judgments. METHODS: We algorithmically annotated 12,808 trial PDFs using data from the Cochrane Database of Systematic Reviews (CDSR). Trials were labeled as being at low or high/unclear risk of bias for each domain, and sentences were labeled as being informative or not. This dataset was used to train a multi-task ML model. We estimated the accuracy of ML judgments versus humans by comparing trials with two or more independent RoB assessments in the CDSR. Twenty blinded experienced reviewers rated the relevance of supporting text, comparing ML output with equivalent (human-extracted) text from the CDSR. RESULTS: By retrieving the top 3 candidate sentences per document (top3 recall), the best ML text was rated more relevant than text from the CDSR, but not significantly (60.4% ML text rated 'highly relevant' v 56.5% of text from reviews; difference +3.9%, [-3.2% to +10.9%]). Model RoB judgments were less accurate than those from published reviews, though the difference was <10% (overall accuracy 71.0% with ML v 78.3% with CDSR). CONCLUSION: Risk of bias assessment may be automated with reasonable accuracy. Automatically identified text supporting bias assessment is of equal quality to the manually identified text in the CDSR. This technology could substantially reduce reviewer workload and expedite evidence syntheses. PMID- 26104741 TI - Design and implementation of a privacy preserving electronic health record linkage tool in Chicago. AB - OBJECTIVE: To design and implement a tool that creates a secure, privacy preserving linkage of electronic health record (EHR) data across multiple sites in a large metropolitan area in the United States (Chicago, IL), for use in clinical research. METHODS: The authors developed and distributed a software application that performs standardized data cleaning, preprocessing, and hashing of patient identifiers to remove all protected health information. The application creates seeded hash code combinations of patient identifiers using a Health Insurance Portability and Accountability Act compliant SHA-512 algorithm that minimizes re-identification risk. The authors subsequently linked individual records using a central honest broker with an algorithm that assigns weights to hash combinations in order to generate high specificity matches. RESULTS: The software application successfully linked and de-duplicated 7 million records across 6 institutions, resulting in a cohort of 5 million unique records. Using a manually reconciled set of 11 292 patients as a gold standard, the software achieved a sensitivity of 96% and a specificity of 100%, with a majority of the missed matches accounted for by patients with both a missing social security number and last name change. Using 3 disease examples, it is demonstrated that the software can reduce duplication of patient records across sites by as much as 28%. CONCLUSIONS: Software that standardizes the assignment of a unique seeded hash identifier merged through an agreed upon third-party honest broker can enable large-scale secure linkage of EHR data for epidemiologic and public health research. The software algorithm can improve future epidemiologic research by providing more comprehensive data given that patients may make use of multiple healthcare systems. PMID- 26104743 TI - Improving prediction of fall risk among nursing home residents using electronic medical records. AB - OBJECTIVE: Falls are physically and financially costly, but may be preventable with targeted intervention. The Minimum Data Set (MDS) is one potential source of information on fall risk factors among nursing home residents, but its limited breadth and relatively infrequent updates may limit its practical utility. Richer, more frequently updated data from electronic medical records (EMRs) may improve ability to identify individuals at highest risk for falls. METHODS: The authors applied a repeated events survival model to analyze MDS 3.0 and EMR data for 5129 residents in 13 nursing homes within a single large California chain that uses a centralized EMR system from a leading vendor. Estimated regression parameters were used to project resident fall probability. The authors examined the proportion of observed falls within each projected fall risk decile to assess improvements in predictive power from including EMR data. RESULTS: In a model incorporating fall risk factors from the MDS only, 28.6% of observed falls occurred among residents in the highest projected risk decile. In an alternative specification incorporating more frequently updated measures for the same risk factors from the EMR data, 32.3% of observed falls occurred among residents in the highest projected risk decile, a 13% increase over the base MDS-only specification. CONCLUSIONS: Incorporating EMR data improves ability to identify those at highest risk for falls relative to prediction using MDS data alone. These improvements stem chiefly from the greater frequency with which EMR data are updated, with minimal additional gains from availability of additional risk factor variables. PMID- 26104744 TI - FoldNucleus: web server for the prediction of RNA and protein folding nuclei from their 3D structures. AB - MOTIVATION: To gain insight into how biopolymers fold as quickly as they do, it is useful to determine which structural elements limit the rate of RNA/protein folding. SUMMARY: We have created a new web server, FoldNucleus. Using this server, it is possible to calculate the folding nucleus for RNA molecules with known 3D structures-including pseudoknots, tRNAs, hairpins and ribozymes-and for protein molecules with known 3D structures, as long as they are smaller than 200 amino acid residues. Researchers can determine and understand which elements of the structure limit the folding process for various types of RNAs and protein molecules. Experimental F values for 21 proteins can be found and compared with those determined by our method: http://bioinfo.protres.ru/resources/phi_values.htm. AVAILABILITY AND IMPLEMENTATION: http://bioinfo.protres.ru/foldnucleus/. CONTACT: ogalzit@vega.protres.ru. PMID- 26104745 TI - MetaQuery: a web server for rapid annotation and quantitative analysis of specific genes in the human gut microbiome. AB - Microbiome researchers frequently want to know how abundant a particular microbial gene or pathway is across different human hosts, including its association with disease and its co-occurrence with other genes or microbial taxa. With thousands of publicly available metagenomes, these questions should be easy to answer. However, computational barriers prevent most researchers from conducting such analyses. We address this problem with MetaQuery, a web application for rapid and quantitative analysis of specific genes in the human gut microbiome. The user inputs one or more query genes, and our software returns the estimated abundance of these genes across 1267 publicly available fecal metagenomes from American, European and Chinese individuals. In addition, our application performs downstream statistical analyses to identify features that are associated with gene variation, including other query genes (i.e. gene co variation), taxa, clinical variables (e.g. inflammatory bowel disease and diabetes) and average genome size. The speed and accessibility of MetaQuery are a step toward democratizing metagenomics research, which should allow many researchers to query the abundance and variation of specific genes in the human gut microbiome. AVAILABILITY AND IMPLEMENTATION: http://metaquery.docpollard.org. CONTACT: snayfach@gmail.comS UPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26104746 TI - Living on a knife edge-the daily struggle of coping with symptomatic cardiac arrhythmias. AB - BACKGROUND: In 2010 a retrospective audit was undertaken to assess the viability of using PROMs in patients with symptomatic cardiac arrhythmias having undergone percutaneous arrhythmia ablation. A response rate of 74 % was achieved, with finding suggesting that arrhythmia patients reported a significant impact on their work, social and family life. AIMS: To conduct a qualitative cross sectional survey to understand patients' perspectives of how cardiac arrhythmias affect their daily lives, as part of a program to develop a Patient Reported Outcome Measure (PROM). METHOD: Twenty five patients aged 18 or over, diagnosed with a variety of symptomatic cardiac arrhythmias referred for a cardiac ablation procedure took part in cognitive interviews. These aimed to inform the development of a patient reported outcome measure and to determine factors important to this patient group. Common themes were identified using content analysis. RESULTS: Participants reported that symptoms of their arrhythmia caused them considerable problems and impacted adversely on their quality of life in many ways. This extended through daily routine, work and social activities and also to friends and family, with fear and anxiety being significant factors for most responders. Patients felt their illness was poorly understood, even by health professionals, and often reported that they felt isolated, lacking support and information. CONCLUSION: Symptomatic cardiac arrhythmias are a source of debilitating and life limiting symptoms, having a negative impact on quality of life. Symptoms and related complications are relevant across different arrhythmia substrates and patient groups. TRIAL REGISTRATION: The study is registered on the Clinical Trials website, Identifier NCT01672528. PMID- 26104747 TI - Improving prevalence estimation through data fusion: methods and validation. AB - BACKGROUND: Estimation of health prevalences is usually performed with a single survey. Some attempts have been made to integrate more than one source of data. We propose here to validate this approach through data fusion. Data Fusion is the process of integrating two sources of data into one combined file. It allows us to take even greater advantage of existing information collected in databases. Here, we use data fusion to improve the estimation of health prevalences for two primary health factors: cardiovascular diseases and diabetes. METHODS: We use a real data fusion operation on population health, where the imputation of basic health risk factors is used to enrich a large-scale survey on self-reported health status. We propose choosing the imputation methodology for this problem through a suite of validation statistics that assess the quality of the fused data. The compared imputation techniques have been chosen from among the main imputation methodologies: k-nearest neighbor, probabilistic modeling and regression. We use the 2006 Health Survey of Catalonia, which provides a complete report of the perceived health status. In order to deal with the uncertainty problem, we compare these methodologies under the single and multiple imputation frames. RESULTS: A suite of validation statistics allows us to discern the strengths and weaknesses of studied imputation methods. Multiple outperforms single imputation by providing better and much more stable estimates, according to the computed validation statistics. The summarized results indicate that the probabilistic methods preserve the multivariate structure better; sequential regression methods deliver greater accuracy of imputed data; and nearest neighbor methods end up with a more realistic distribution of imputed data. CONCLUSIONS: Data fusion allows us to integrate two sources of information in order to take grater advantage of the available data. Multiple imputed sequential regression models have the advantage of grater interpretability and can be used for health policy. Under certain conditions, more accurate estimates of the prevalences can be obtained using fused data (the original data plus the imputed data) than just by using only the observed data. PMID- 26104748 TI - Genomics in the renal clinic - translating nephrogenetics for clinical practice. AB - Genetic Renal Disease (GRD) presents to mainstream clinicians as a mixture of kidney-specific as well as multi-organ entities, many with highly variable phenotype-genotype relationships. The rapid increase in knowledge and reduced cost of sequencing translate to new and additional approaches to clinical care. Specifically, genomic technologies to test for known genes, the development of pathways to research potential new genes and the collection of registry data on patients with mutations allow better prediction of outcomes. The aim of such approaches is to maximise personal and health-system utility from genomics for those affected by nephrogenetic disorders. PMID- 26104749 TI - From trainee to tenure-track: ten tips. PMID- 26104750 TI - Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study. AB - OBJECTIVE: The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. METHODS: In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. RESULTS: A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). CONCLUSIONS: A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus. PMID- 26104752 TI - Incidence of fall-related injury among old people in mainland China. AB - BACKGROUND: The fall-related injuries of old people have attracted increasing attention particularly because of the continuous aging of the population. In this meta-analysis, we aim to present the incidence and sub-groups of fall-related injuries among old people in mainland China. METHODS: A systematic electronic literature search was performed using four Chinese and two English databases. The selected papers were cross-sectional studies in mainland China, the participants of which were recruited based on inclusion and exclusion criteria. Data were collected through face-to-face interviews using questionnaire. The risk of bias was assessed using the Reporting of Observational Studies in Epidemiology (STROBE), and the pooled rates were estimated by DerSimonian and Laird random effects model. RESULTS: A total of 40 cross-sectional studies that focused on 128,691 participants who were aged 60 years were included in this review. On the one hand, 54.95 per 1000 (overall), 45.94 per 1000 (males), 78.89 per 1000 (females), 25.95 per 1000 (60 years to 69 years), 33.03 per 1000 (70 years to 79 years), and 62.74 per 1000 (>=80 years) were estimated for the pooled incidence of fall-related injury. On the other hand, 91.72 per 1000 (overall), 94.54 per 1000 (males), and 144.93 per 1000 (females) were estimated for person-time incidence of fall-related injury. Higher incidence rates were observed in females compared with males, and these rates continued to increase along with age. CONCLUSIONS: A moderate level of fall-related injuries was observed among old people in mainland China. PMID- 26104753 TI - Pulmonary metastases in differentiated thyroid cancer: efficacy of radioiodine therapy and prognostic factors. AB - CONTEXT: Data from a large cohort of patients with pulmonary metastases from differentiated thyroid cancer (DTC) were retrospectively analyzed. OBJECTIVE: To assess the effect of radioiodine therapy and investigate the prognostic factors of survival for patients with pulmonary metastasis secondary to DTC. METHODS: A total of 372 patients with pulmonary metastasis from DTC treated with (131)I entered the study. According to the results of (131)I whole-body scan (WBS), pulmonary metastases were classified as (131)I-avid and non-(131)I-avid. For patients with (131)I-avid lung metastases, treatment response was measured by three parameters: serum thyroglobulin (Tg) levels, chest computed tomography (CT) and post-therapeutic (131)I-WBS. Overall survival was calculated by the Kaplan Meier method. Factors predictive of the outcome were determined by multivariate analyses. RESULTS: Among patients demonstrating (131)I-avid pulmonary metastases (256/372, 68.8%), 156 cases (156/256, 60.9%) showed a significant decrease in serum Tg levels after (131)I therapy and 138 cases (138/229, 60.3%) showed a reduction in pulmonary metastases on follow-up CT. A complete cure, however, was only achieved in 62 cases (62/256, 24.2%). Multivariate analysis showed that only age, the presence of multiple distant metastases and pulmonary metastatic node size were significant independent variables between the groups of (131)I-avid and non-(131)I-avid. CONCLUSION: This study indicated that, most (131)I-avid pulmonary metastases from DTC can obtain partial or complete remission after (131)I therapy. Younger patients (<40 years old) with only pulmonary metastases and small ('fine miliaric' or micronodular) metastases appear to have relative favorite outcomes. Patients who do not respond to (131)I treatment have a worse prognosis. PMID- 26104754 TI - A cost-effectiveness comparison between early surgery and non-surgical approach for incidental papillary thyroid microcarcinoma. AB - BACKGROUND: The issue of whether all incidental papillary thyroid microcarcinoma (PTMC) should be managed by early surgery (ES) has been questioned and there is a growing acceptance that a non-surgical approach (NSA) might be more appropriate. We conducted a cost-effectiveness analysis comparing the two strategies in managing incidental PTMC. METHODS: Our base case was a hypothetical 40-year-old female diagnosed with a unifocal intra-thyroidal 9 mm PTMC. The PTMC was considered suitable for either strategy. A Markov decision tree model was constructed to compare the estimated cost-effectiveness between ES and NSA after 20 years. Outcome probabilities, utilities and costs were derived from the literature. The threshold for cost-effectiveness was set at USD 50,000/quality adjusted life year (QALY). A further analysis was done for patients < 40 and >= 40 years. Sensitivity and threshold analyses were used to examine model uncertainty. RESULTS: Each patient who adopted NSA over ES cost an extra USD 682.54 but gained an additional 0.260 QALY. NSA was cost saving (i.e. less costly and more effective) up to 16 years from diagnosis and remained cost-effective from 17 years onward. In the sensitivity analysis, NSA remained cost-effective regardless of patient age (< 40 and >= 40 years), complications, rates of progression, year cycle and discount rate. In the threshold analysis, none of the scenarios that could have changed the conclusion appeared clinically likely. CONCLUSIONS: For a selected group of incidental PTMC, adopting NSA was not only cost saving in the initial 16 years but also remained cost effective thereafter. This was irrespective of patient age, complication rate or rate of PTMC progression. PMID- 26104751 TI - British Society of Gastroenterology/Association of Coloproctologists of Great Britain and Ireland guidelines for the management of large non-pedunculated colorectal polyps. AB - These guidelines provide an evidence-based framework for the management of patients with large non-pedunculated colorectal polyps (LNPCPs), in addition to identifying key performance indicators (KPIs) that permit the audit of quality outcomes. These are areas not previously covered by British Society of Gastroenterology (BSG) Guidelines.A National Institute of Health and Care Excellence (NICE) compliant BSG guideline development process was used throughout and the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to structure the guideline development process. A systematic review of literature was conducted for English language articles up to May 2014 concerning the assessment and management of LNPCPs. Quality of evaluated studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist System. Proposed recommendation statements were evaluated by each member of the Guideline Development Group (GDG) on a scale from 1 (strongly agree) to 5 (strongly disagree) with >80% agreement required for consensus to be reached. Where consensus was not reached a modified Delphi process was used to re evaluate and modify proposed statements until consensus was reached or the statement discarded. A round table meeting was subsequently held to finalise recommendations and to evaluate the strength of evidence discussed. The GRADE tool was used to assess the strength of evidence and strength of recommendation for finalised statements.KPIs, a training framework and potential research questions for the management of LNPCPs were also developed. It is hoped that these guidelines will improve the assessment and management of LNPCPs. PMID- 26104755 TI - Ag29(BDT)12(TPP)4: A Tetravalent Nanocluster. AB - The bottom-up assembly of nanoparticles into diverse ordered solids is a challenge because it requires nanoparticles, which are often quasi-spherical, to have interaction anisotropy akin to atoms and molecules. Typically, anisotropy has been introduced by changing the shape of the inorganic nanoparticle core. Here, we present the design, self-assembly, optical properties, and total structural determination of Ag29(BDT)12(TPP)4, an atomically precise tetravalent nanocluster (NC) (BDT, 1,3-benzenedithiol; TPP, triphenylphosphine). It features four unique tetrahedrally symmetrical binding surface sites facilitated by the supramolecular assembly of 12 BDT (wide footprint bidentate thiols) in the ligand shell. When each of these sites was selectively functionalized by a single phosphine ligand, particle stability, synthetic yield, and the propensity to self assemble into macroscopic crystals increased. The solid crystallized NCs have a substantially narrowed optical band gap compared to that of the solution state, suggesting strong interparticle electronic coupling occurs in the solid state. PMID- 26104756 TI - Parallel enzyme-linked immunosorbent assay screening for human immunodeficiency virus among blood donors in five Chinese blood centres: a retrospective analysis. AB - AIMS: To evaluate the strategy of parallel screening with different enzyme-linked immunosorbent assays (ELISA) among Chinese blood donors. BACKGROUND: Parallel screening with ELISA has been the main strategy to detect human immunodeficiency virus (HIV) in blood donations in China for more than a decade. The performance of the strategy should be analysed. METHODS: A total of 821,927 donations collected from five Chinese blood centres in 2008-2010 were tested using two third-generation ELISAs by different manufacturers licenced and confirmed by the Western blot (WB) in this study. The confirmatory positive predictive values (PPV), false positive rates (FPR), false negative rates (FNR) and potential risks for transfusion resulting from single or sequential ELISA screening were evaluated. RESULTS: A total of 5318 (0.647%) of donations screened HIV reactive and were discarded. WB confirmatory results on 1668 available samples suggested that PPVs for dual ELISA, one round ELISA reactive and grey zone samples were 75.1, 0.7 and 0.5%, respectively. Eight out of 1124 one round ELISA reactive and 1 out of 195 grey zone samples were WB confirmed positive. All but one ELISA assay displayed comparable PPVs but variable FPRs and FNRs that differed by blood centre. CONCLUSIONS: In the absence of nucleic acid testing (NAT), parallel ELISA screening prevented a substantial number of HIV infected donations from entering the Chinese blood supply. However, the loss of false positive donors should be re evaluated especially given the frequently reported blood supply shortage in China. PMID- 26104757 TI - Private firm gets L400m contract to run NHS administrative services in England. PMID- 26104758 TI - Variation of perioperative plasma mitochondrial DNA correlate with peak inflammatory cytokines caused by cardiac surgery with cardiopulmonary bypass. AB - BACKGROUD: Cardiac surgery with cardiopulmonary bypass (CPB) may cause inflammatory responses, which can deteriorate the outcomes. Inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6,-8 and 10, can act as both the effector and the predictor for post-operative inflammatory responses. Plasma mitochondrial DNA (mtDNA) was found as a pro inflammatory agent recently, which was released when cells were insulted. METHODS: In the present study, we included 38 patients undergoing coronary artery bypass graft (CABG) to analyze their perioperative plasma mtDNA and levels of inflammatory cytokines. Blood samples were collected before aortic cross-clamping (T1), at the end of CPB (T2), 6 h post-CPB (T3), 12 h post-CPB (T4), and 24 h post-CPB (T5). Rt-PCR and specific ELISA kits were used to quantify the plasma mtDNA and inflammatory cytokines, respectively. Bivariate correlations analysis was used to check the correlations between plasma mtDNA and inflammatory cytokines respectively. RESULTS: Results shown that plasma mtDNA elevated significantly at T2 and peaked at T4. Furthermore, plasma TNF-alpha, IL-6 and IL 8 levels significantly increased at T2 and peaked at T3 while IL-10 elevated and peaked at T2. Bivariate correlations analysis showed that the peak plasma mtDNA were positively correlated with the peak TNF-alpha (r = 0.677, P < 0.001), the peak IL-6 (r = 0.706, P < 0.001), the peak IL-8 (r = 0.584, P < 0.001) and the peak IL-10 (r = 0.565, P < 0.001). CONCLUSION: We found that plasma mtDNA might play a key role in CPB-induced post-operative inflammatory responses. PMID- 26104759 TI - HLA-DRalpha1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection. AB - BACKGROUND: DRalpha1-mouse(m)MOG-35-55, a novel construct developed in our laboratory as a simpler and potentially less immunogenic alternative to two domain class II constructs, was shown previously to target the MIF/CD74 pathway and to reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in DR*1501-Tg mice in a manner similar to the parent DR2beta1-containing construct. METHODS: In order to determine whether DRalpha1 mMOG-35-55 could treat EAE in major histocompatibility complex (MHC)-mismatched mice and to evaluate the treatment effect on central nervous system (CNS) inflammation, C57BL/6 mice were treated with DRalpha1-mMOG-35-55. In addition, gene expression profile was analyzed in spinal cords of EAE DR*1501-Tg mice that were treated with DRalpha1-mMOG-35-55. RESULTS: We here demonstrate that DRalpha1 mMOG-35-55 could effectively treat EAE in MHC-mismatched C57BL/6 mice by reducing CNS inflammation, potentially mediated in part through an increased frequency of M2 monocytes in the spinal cord. Microarray analysis of spinal cord tissue from DRalpha1-mMOG-35-55-treated vs. vehicle control mice with EAE revealed decreased expression of a large number of pro-inflammatory genes including CD74, NLRP3, and IL-1beta and increased expression of genes involved in myelin repair (MBP) and neuroregeneration (HUWE1). CONCLUSION: These findings indicate that the DRalpha1 mMOG-35-55 construct retains therapeutic, anti-inflammatory, and neuroprotective activities during treatment of EAE across MHC disparate barriers. PMID- 26104760 TI - High performing hospitals: a qualitative systematic review of associated factors and practical strategies for improvement. AB - BACKGROUND: High performing hospitals attain excellence across multiple measures of performance and multiple departments. Studying high performing hospitals can be valuable if factors associated with high performance can be identified and applied. Factors leading to high performance are complex and an exclusive quantitative approach may fail to identify richly descriptive or relevant contextual factors. The objective of this study was to undertake a systematic review of qualitative literature to identify methods used to identify high performing hospitals, the factors associated with high performers, and practical strategies for improvement. METHODS: Methods used to collect and summarise the evidence contributing to this review followed the 'enhancing transparency in reporting the synthesis of qualitative research' protocol. Peer reviewed studies were identified through Medline, Embase and Cinahl (Jan 2000-Feb 2014) using specified key words, subject terms, and medical subject headings. Eligible studies required the use of a quantitative method to identify high performing hospitals, and qualitative methods or tools to identify factors associated with high performing hospitals or hospital departments. Title, abstract, and full text screening was undertaken by four reviewers, and inter-rater reliability statistics were calculated for each review phase. Risk of bias was assessed. Following data extraction, thematic syntheses identified contextual factors important for explaining success. Practical strategies for achieving high performance were then mapped against the identified themes. RESULTS: A total of 19 studies from a possible 11,428 were included in the review. A range of process, output, outcome and other indicators were used to identify high performing hospitals. Seven themes representing factors associated with high performance (and 25 sub-themes) emerged from the thematic syntheses: positive organisational culture, senior management support, effective performance monitoring, building and maintaining a proficient workforce, effective leaders across the organisation, expertise-driven practice, and interdisciplinary teamwork. Fifty six practical strategies for achieving high performance were catalogued. CONCLUSIONS: This review provides insights into methods used to identify high performing hospitals, and yields ideas about the factors important for success. It highlights the need to advance approaches for understanding what constitutes high performance and how to harness factors associated with high performance. PMID- 26104762 TI - Correction for Sarkadi et al., High-Level Cellular and Humoral Immune Responses in Guinea Pigs Immunized Intradermally with a Heat-Inactivated Varicella-Zoster Virus Vaccine. PMID- 26104761 TI - SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing. AB - BACKGROUND: SIRT1 is likely to play a role in the extension in healthspan induced by dietary restriction. Actions of SIRT1 are pleiotropic, and effects on healthspan may include effects on DNA methylation. Polycomb group protein target genes (PCGTs) are suppressed by epigenetic mechanisms in stem cells, partly through the actions of the polycomb repressive complexes (PRCs), and have been shown previously to correspond with loci particularly susceptible to age-related changes in DNA methylation. We hypothesised that SIRT1 would affect DNA methylation particularly at PCGTs. To map the sites in the genome where SIRT1 affects DNA methylation, we altered SIRT1 expression in human intestinal (Caco-2) and vascular endothelial (HuVEC) cells by transient transfection with an expression construct or with siRNA. DNA was enriched for the methylated fraction then sequenced (HuVEC) or hybridised to a human promoter microarray (Caco-2). RESULTS: The profile of genes where SIRT1 manipulation affected DNA methylation was enriched for PCGTs in both cell lines, thus supporting our hypothesis. SIRT1 knockdown affected the mRNA for none of seven PRC components nor for DNMT1 or DNMT3b. We thus find no evidence that SIRT1 affects DNA methylation at PCGTs by affecting the expression of these gene transcripts. EZH2, a component of PRC2 that can affect DNA methylation through association with DNA methyltransferases (DNMTs), did not co-immunoprecipitate with SIRT1, and SIRT1 knockdown did not affect the expression of EZH2 protein. Thus, it is unlikely that the effects of SIRT1 on DNA methylation at PCGTs are mediated through direct intermolecular association with EZH2 or through effects in its expression. CONCLUSIONS: SIRT1 affects DNA methylation across the genome, but particularly at PCGTs. Although the mechanism through which SIRT1 has these effects is yet to be uncovered, this action is likely to contribute to extended healthspan, for example under conditions of dietary restriction. PMID- 26104764 TI - The expression of microRNA-34a is inversely correlated with c-MET and CDK6 and has a prognostic significance in lung adenocarcinoma patients. AB - We aimed to establish whether the expression of microRNA-34a (miR-34a) is correlated with that of c-MET and G1 phase regulators such as cyclin dependent kinase (CDK) 4, CDK6, and cyclin D (CCND) 1 in non-small cell lung cancer (NSCLC), and whether a relationship exists between miR-34a expression and both clinicopathologic factors and recurrence-free survival (RFS). For 58 samples archived from NSCLC patients, we measured the expression of miR-34a and c-MET, CDK4/6, and CCND1 by quantitative RT-PCR and assessed the relationship between miR-34a expression, clinicopathological factors, and RFS. The expression of miR 34a was significantly lower in squamous cell tumors (P < 0.001) and in tumors associated with lymphatic invasion (P = 0.001). We found significant inverse correlations between miR-34a and c-MET (R = -0.316, P = 0.028) and CDK6 expression (R = -0.4582, P = 0.004). RFS were longer in adenocarcinoma patients with high miR-34a expression than in those with low miR-34a expression (55.6 vs. 21.6 months; P = 0.020). With univariate analysis, statistically significant prognostic factors for RFS in adenocarcinoma patients were miR-34a expression (Relative risk (RR), 8.14; P = 0.049), TNM stage (RR, 13.55; P = 0.001), LN metastasis (RR, 4.19; P = 0.043), and the presence of lymphatic invasion (RR, 7.05; P = 0.015). In multivariate analysis, only miR-34a was prognostic for RFS (RR, 11.5; P = 0.027). miR-34a expression was inversely correlated with that of c MET and CDK6 in NSCLC, and had prognostic significance for RFS, especially in adenocarcinoma patients. PMID- 26104765 TI - Shikonin inhibits invasiveness of osteosarcoma through MMP13 suppression. AB - Osteosarcoma (OS) is the most common primary malignant bone tumor, notorious for its metastasis. We have recently shown that shikonin, an effective constituent extracted from Chinese medicinal herb, induces necroptosis in OS cells. Nevertheless, the effects of low-dose shikonin on the invasiveness of OS cells are unknown. Here, we showed that shikonin dose-dependently decreased OS cell invasiveness in both scratch wound healing assay and transwell cell migration assay. Moreover, the direct target of shikonin on cell invasiveness was found to be matrix metalloproteinase (MMP)-13. Further, the inhibitory effects of shikonin on cell invasiveness were completely abolished in MMP13-overexpressing OS cells. Together, these data suggest that shikonin may suppress OS invasiveness through MMP13 suppression. Thus, our data highlight a previous unappreciated role for shikonin in suppressing OS cell metastasis. PMID- 26104766 TI - Correlation between serum levels of vascular endothelial growth factor-C and sentinel lymph node status in early breast cancer. AB - Axillary lymph nodes status is the most important prognosis factor in early breast cancer. This status is known by a selective sentinel lymph node biopsy (SLNB) and/or lymphadenectomy. Immunohistochemical studies of breast cancer tumour tissue have reported a relation between the increased expression of vascular endothelial growth factor-C (VEGF-C) and the risk of lymph node metastasis. We researched whether serum levels of VEGF-C could be a predictor factor of sentinel lymph node status in these patients. A prospective analysis was performed on serum from 174 patients with early breast cancer who underwent SLNB. The level of VEGF-C was determined by enzyme-linked immunosorbent assay. Clinical-pathologic variables were collected. Univariate analysis and multivariate logistic regression were conducted, taking SLNB positivity as the segmentation variable. The predictive value of VEGF-C was assessed using ROC curves. Of the sample group of 167 patients, 64 (38.3 %) had affected lymph node. Eighteen patients (28.1 %) presented micrometastasis; there were isolated tumour cells in 11 cases (17.2 %) and macrometastasis in 35 (54.6 %). The median value of VEGF-C was 6561.5 pg/ml. These values did not correlate with any clinical variables, and there was no association between the level of VEGF-C and SLNB status (p = 0.626). In the multivariate analysis, tumour size (p = 0.009) and the presence of vascular invasion (p < 0.001) were independently associated with sentinel lymph node affected. Serum levels of VEGF-C do not appear to predict sentinel lymph node status in patients with early breast cancer who undergo SLNB. PMID- 26104767 TI - Stage-dependent changes of preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in colorectal cancer. AB - This study aims to assess the association of the preoperative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) with tumor stage in colorectal cancer (CRC) patients. A retrospective study was performed in 336 CRC patients. Preoperative whole blood counts, serum levels of carcinoembryonic antigen (CEA), and clinicopathologic data were collected. The correlations between laboratory parameters and the tumor, node, and metastasis (TNM) stages were analyzed. The clinicopathologic TNM stages among CRC patients were 12.8 % at stage I, 32.4 % at stage II, 44.6 % at stage III, and 10.1 % at stage IV. NLR, PLR, and CEA levels were higher in CRC patients compared to healthy controls (all P < 0.0001). Both NLR and PLR showed an early elevation as compared to CEA, with a higher area under curve (AUC) value (0.71 vs. 0.62) in predicting the presence of the tumor with stage I/II. Accordingly, significant elevations of NLR (P = 0.0018) and PLR (P < 0.0001) were firstly detected in stage I and stage II, respectively. In addition, NLR exhibited a second phase elevation in stage IV, with a significant higher level in M1 subgroup compared to M0 subgroup (P = 0.022). While PLR showed a T stage-dependent increase (P = 0.0003) and was identified as an independent factor for the T grade development (P < 0.0001). Our data indicated that both neutrophil- and platelet-mediated inflammatory reactions are predominantly involved in the different stages of CRC development. Determination of pretreatment levels of NLR and PLR might provide useful information for the early diagnosis or the therapeutic choices in CRC patients. PMID- 26104768 TI - TGIF1 promoted the growth and migration of cancer cells in nonsmall cell lung cancer. AB - Transforming growth factor beta-inducing factor 1 (TGIF1) was reported to be dysregulated in several types of cancer. However, its expression pattern and functions in nonsmall cell lung cancer (NSCLC) remained unknown. In the present study, the expression of TGIF1 was found to be elevated in the clinical NSCLC tissues. TGIF1 promoted the growth and migration of NSCLC cells, while knocking down the expression of TGIF1 inhibited the growth and migration of NSCLC cells. Moreover, downregulation of TGIF1 impaired the metastasis of NSCLC cells. In the study for the molecular mechanisms, it was found that TGIF1 positively regulated beta-catenin/TCF signaling. In summary, our study demonstrated the oncogenic role of TGIF1 in NSCLC, and TGIF1 might be a therapeutic target for NSCLC. PMID- 26104770 TI - Long-term spatio-temporal changes in a West African bushmeat trade system. AB - Landscapes in many developing countries consist of a heterogeneous matrix of mixed agriculture and forest. Many of the generalist species in this matrix are increasingly traded in the bushmeat markets of West and Central Africa. However, to date there has been little quantification of how the spatial configuration of the landscape influences the urban bushmeat trade over time. As anthropogenic landscapes become the face of rural West Africa, understanding the dynamics of these systems has important implications for conservation and landscape management. The bushmeat production of an area is likely to be defined by landscape characteristics such as habitat disturbance, hunting pressure, level of protection, and distance to market. We explored (SSG, tense) the role of these four characteristics in the spatio-temporal dynamics of the commercial bushmeat trade around the city of Kumasi, Ghana, over 27 years (1978 to 2004). We used geographic information system methods to generate maps delineating the spatial characteristics of the landscapes. These data were combined with spatially explicit market data collected in the main fresh bushmeat market in Kumasi to explore the relationship between trade volume (measured in terms of number of carcasses) and landscape characteristics. Over time, rodents, specifically cane rats (Thryonomys swinderianus), became more abundant in the trade relative to ungulates and the catchment area of the bushmeat market expanded. Areas of intermediate disturbance supplied more bushmeat, but protected areas had no effect. Heavily hunted areas showed significant declines in bushmeat supply over time. Our results highlight the role that low intensity, heterogeneous agricultural landscapes can play in providing ecosystem services, such as bushmeat, and therefore the importance of incorporating bushmeat into ecosystem service mapping exercises. Our results also indicate that even where high bushmeat production is possible, current harvest levels may cause wildlife depletion. PMID- 26104769 TI - Interaction analysis of IL-12A and IL-12B polymorphisms with the risk of colorectal cancer. AB - IL-12 is an antitumor cytokine with functions of inhibiting tumor growth, invasion, and metastasis, indicating that IL-12 is a promising candidate for cancer treatment. The aim of this study was to investigate the association of IL 12A rs568408, IL-12A rs2243115, and IL-12B rs3212227 with the susceptibility to colorectal cancer (CRC). Two hundred and fifty-seven histopathologically confirmed CRC patients and 236 age- and gender-matched controls were enrolled. The three polymorphisms were genotyped using a polymerase chain reaction restriction fragment length polymorphism assay. We found that the IL-12A rs568408 AG/AA genotypes were associated with an increased risk of CRC with an adjusted odds ratio (OR) of 1.66 (95 % confidence interval (CI), 1.11-2.48). Stratified analyses showed that patients carrying the IL-12B rs3212227AC/CC genotypes had a 1.97-fold increased risk of tumor metastasis (OR = 1.97; 95 % CI, 1.04-3.70). Gene-gene interaction analysis showed that subjects carrying the IL-12A rs568408AG/AA and IL-12B rs3212227AA genotypes had a 2.40-fold increased risk of CRC (OR = 2.40; 95 % CI, 1.14-5.07) and individuals carrying the IL-12A rs568408AG/AA and IL-12B rs3212227AC/CC genotypes had a 1.93-fold increased risk of CRC (OR = 1.93; 95 % CI, 1.10-3.41). These findings indicate that IL-12A rs568408 and IL-12B rs3212227 may be related to the development of CRC. PMID- 26104771 TI - Optogenetic probing of mitochondrial damage responses. AB - It is now possible to functionally impair mitochondria through light illumination with high specificity. These optogenetic tools permit precise control on the timing, location, and extent of mitochondrial damage within a cell population with subcellular resolution, allowing quantitative probing of the various types of mitochondrial damage responses within cells. This approach can generally be extended toward the probing of other organelle damage responses. PMID- 26104772 TI - Using Star Wars' supporting characters to teach about psychopathology. AB - OBJECTIVES: The pop culture phenomenon of Star Wars has been underutilised as a vehicle to teach about psychiatry. It is well known to students, registrars, and consultants alike. New Star Wars films are expected out in 2015, which will likely lead to further popularity. The purpose of this article is to illustrate psychopathology and psychiatric themes demonstrated by supporting characters, and ways they can be used to teach concepts in a hypothetical yet memorable way. CONCLUSIONS: Using the minor characters as a springboard for teaching has the benefit of students not having preconceived notions about them. Characters can be used to approach teaching about ADHD, anxiety, kleptomania and paedophilia. PMID- 26104773 TI - The importance of least restrictive care: the clinical implications of a recent High Court decision on negligence. AB - OBJECTIVE: This paper aims to explain the meaning and implications for practice of the High Court of Australia's finding in the negligence case, Hunter and New England Local Health District v McKenna [2014] HCA 44. METHOD: The facts of the case and the law of negligence are reviewed before reporting the Court's decision. RESULTS: The High Court found that the obligation upon doctors to provide the least restrictive option for care that was imposed by the, then applicable, Mental Health Act 1990 (NSW) was inconsistent with an obligation that might otherwise be imposed by a common law duty to have regard to the interests of those with whom a psychiatric patient may come into contact if not detained. CONCLUSIONS: The Court's finding underlines the importance of clinicians documenting their clinical reasoning around why their negotiated management plan was the option least restrictive of the patient's freedom and most protective of his or her human rights. PMID- 26104774 TI - Communication skills in psychiatry training. AB - OBJECTIVE: Mental health clinicians can experience problems communicating distressing diagnostic information to patients and their families, especially about severe mental illnesses such as schizophrenia. Evidence suggests that interpersonal communication skills can be effectively taught, as has been demonstrated in the specialty of oncology. However, very little literature exists with respect to interpersonal communication skills training for psychiatry. This paper provides an overview of the communication skills training literature. CONCLUSIONS: The report reveals significant gaps exist and highlights the need for advanced communication skills training for mental health clinicians, particularly about communicating a diagnosis and/or prognosis of schizophrenia. A new communication skills training framework for psychiatry is described, based on that used in oncology as a model. This model promotes applied skills and processes that are easily adapted for use in psychiatry, providing an effective platform for the development of similar training programs for psychiatric clinical practice. PMID- 26104775 TI - Treating OCD: what to do when first-line therapies fail. AB - OBJECTIVE: To provide a clinically-focused review of the biological treatment of treatment-resistant obsessive compulsive disorder (OCD). CONCLUSIONS: There is a paucity of research on how to manage OCD patients who fail to respond adequately to first line therapies. High-dose selective serotonin reuptake inhibitors (SSRIs) and clomipramine have good evidence-based data. Combinations of SSRIs have little support in clinical trials, but the combination of SSRIs and clomipramine can be helpful: careful clinical and cardiac monitoring is required. Certain adjunctive antipsychotics have a reasonable evidence base in OCD, but their use also needs to be weighed against the potential side effect burden. In patients with substantial generalised anxiety symptoms, clonazepam is worth considering. Of the other augmenting strategies, memantine and ondansetron appear useful in some cases, and are well tolerated. Topiramate might ameliorate compulsions to some degree, but it is less well tolerated. If all these strategies, along with expert psychological therapy, fail, careful consideration should be given to deep brain stimulation (DBS), which has an emerging evidence base and which can result in dramatic benefits for some individuals. For some patients, gamma radiosurgery might also still have a place. PMID- 26104776 TI - Psychological treatment of obsessive compulsive disorder: an update. AB - OBJECTIVE: The objective of this article is to provide an update on current psychological treatment for obsessive compulsive disorder (OCD). CONCLUSIONS: Cognitive behaviour therapy (CBT), incorporating exposure and response prevention, remains the non-pharmacological treatment of choice for OCD. Recent developments highlight the importance of family involvement in adult OCD treatment, and the use of alternative 'third-wave' interventions. Internet delivered CBT may provide an opportunity to overcome barriers to effective treatment, such as distance and lack of trained clinicians. PMID- 26104777 TI - Reactions to driving cessation: a qualitative study of people with dementia and their families. AB - OBJECTIVES: A proportion of older people with mild dementia are safe to drive. However, driving cessation is recommended at some point as the disease progresses. Driving cessation can have significant psychological and social consequences on people with dementia and their carers. This paper aims to explore the psychosocial and adjustment issues following driving cessation for people with dementia and their supporters. METHOD: Participants and their supporters were interviewed within 1 month of driving-cessation advice, and again 6 months later. Issues associated with driving cessation were explored in semi-structured interviews. RESULTS: Seven participants and their supporters were recruited. This has generated a total of 22 transcripts for qualitative analysis including follow up interviews. For those who could remember the details of driving cessation, most were unhappy with the decision. Carers who were supportive of driving cessation questioned the legality of it. Most participants minimised the impact of their driving cessation on their supporters. Most supporters were negatively affected by the decision. CONCLUSIONS: The preliminary findings highlight the need for a more comprehensive process for driving cessation in those with dementia, with closer links to regulatory bodies, and increased support for their families/carers. PMID- 26104778 TI - ECT and lithium in old age depression - cause or treatment of rapid cycling? AB - OBJECTIVE: This article presents the case of an elderly woman experiencing a depressive phase of Bipolar Affective Disorder 1 (BPAD1), who required electroconvulsive therapy (ECT), prior to which her lithium was ceased, and who developed ultra-ultra-rapid cycling (UURC) and ultra-rapid cycling (URC). This resolved with the recommencement of lithium and continuation of ECT. METHOD: Case report and review of the relevant literature. RESULTS: The patient's mood stabilized with recommencement of lithium and continuation of ECT. CONCLUSIONS: Ceasing lithium prior to ECT may carry a risk of URC or UURC in BPAD1. PMID- 26104779 TI - Examining Mental Health Act usage in an urban emergency department. AB - OBJECTIVE: In this study we aimed to examine the characteristics of Mental Health Act (MHA) usage in the Emergency Department (ED) of an urban teaching hospital in Sydney. METHODS: All MHA certificates written on individuals in the ED over a 12 week period in 2013 were collected. The medical record of each individual was reviewed by a member of the research team using an audit tool developed for the study. Any uncertainty over individual cases was addressed through research team consensus. RESULTS: A total of 172 MHA certificates were collected; 67 were written by police, 45 by ambulance, 54 by medical officers and three by accredited persons. Three magistrate orders for assessment were also received. Seventy percent of police and 60% of ambulance MHA certificates did not result in admission. Over a third were revoked by ED physicians. Forty-five people (32.4%) who presented voluntarily were subsequently detained. CONCLUSIONS: Police and ambulance MHA certification was a poor predictor of admission. Least restrictive measures were predominantly the outcome. Delegating ED physicians with authorised medical officer status assisted in facilitating this process. Formalised education and training on the principles and practicalities of MHA legislation should be ongoing for all professionals involved. PMID- 26104780 TI - Psychological treatments for trichotillomania: update and future directions. AB - OBJECTIVE: This paper aims to provide an overview of evidence-based psychological treatments for trichotillomania. CONCLUSIONS: Advances in the understanding of the phenomenology of trichotillomania has led to the augmentation of behavioural treatments with dialectical behaviour therapy and acceptance and commitment therapy. Further studies of treatment component efficacy and cognitive behavioural models are required. PMID- 26104781 TI - Families of returned defence force personnel: a changing landscape of challenges. AB - OBJECTIVE: This paper aims to identify the key challenges experienced by the families of defence force personnel following deployment. METHOD: We undertook a selective review of four post-deployment challenges to the families of defence force personnel: (1) changes to relationships; (2) changes to family member roles and responsibilities; (3) adjustment of children and parenting challenges; and (4) anger, family conflict and violence. Emerging issues in the area of post deployment adjustment are also discussed. RESULTS: Empirical studies of post deployment family adjustment are lacking. Each of the reviewed challenges can contribute to psychological difficulties and precipitate contact with mental health services. CONCLUSIONS: The challenges faced by defence force personnel when returning from deployment arise within a family context. Clinicians should thoroughly assess these factors in families following deployment, but also recognise family strengths and resilience to these challenges. PMID- 26104782 TI - Tension gastrothorax: acute life-threatening manifestation of late onset congenital diaphragmatic hernia (CDH) in children. AB - Tension gastrothorax in children is a life-threatening condition and presents dramatically with acute and severe respiratory distress. It develops when an intra-thoracic stomach herniated through a diaphragmatic defect is massively distended by trapped air and/or fluid causing mediastinal displacement. Tension gastrothorax is often misinterpreted as tension pneumothorax and managed as such leading to increased morbidity and mortality. We present a child with tension gastrothorax and a literature review of this phenomenon.Immediate clinical and radiographic evaluation should lead to accurate diagnosis followed by emergency decompression of the stomach before laparotomy with reduction of herniated viscera and repair of the diaphragmatic defect. PMID- 26104783 TI - Pancreatic mucinous cystic neoplasm in a transgender patient. AB - BACKGROUND: Cystic pancreatic lesions are increasingly more frequent detected clinical entities. Mucinous cystic neoplasm (MCN) is a hormone-related pancreatic tumor (HRTP) with a strong predominance in young and middle-aged females. CASE PRESENTATION: Here, we present the case of a 31-year-old surgically transgendered female-to-male patient with a history of alcoholic pancreatitis, on chronic testosterone therapy. He was found to have a pancreatic MCN and underwent distal pancreatectomy and splenectomy. CONCLUSION: To our knowledge, this is the first reported case of a transgender patient with a history of hormone replacement therapy (HRT) and pancreatic MCN. We consider possible mechanisms for the pathogenesis to explain this patient's neoplasm. PMID- 26104784 TI - Productivity loss and indirect costs associated with cardiovascular events and related clinical procedures. AB - BACKGROUND: The high acute costs of cardiovascular disease and acute cardiovascular events are well established, particularly in terms of direct medical costs. The costs associated with lost work productivity have been described in a broad sense, but little is known about workplace absenteeism or short term disability costs among high cardiovascular risk patients. The objective of this study was to quantify workplace absenteeism (WA) and short-term disability (STD) hours and costs associated with cardiovascular events and related clinical procedures (CVERP) in United States employees with high cardiovascular risk. METHODS: Medical, WA and/or STD data from the Truven Health MarketScan(r) Research Databases were used to select full-time employees aged 18 64 with hyperlipidemia during 2002-2011. Two cohorts (with and without CVERP) were created and screened for medical, drug, WA, and STD eligibility. The CVERP cohort was matched with a non-CVERP cohort using propensity score matching. Work loss hours and indirect costs were calculated for patients with and without CVERP and by CVERP type. Wages were based on the 2013 age-, gender-, and geographic region-adjusted wage rate from the United States Bureau of Labor Statistics. RESULTS: A total of 5,808 WA-eligible, 21,006 STD-eligible, and 3,362 combined WA and STD eligible patients with CVERP were well matched to patients without CVERP, creating three cohorts of patients with CVERP and three cohorts of patients without CVERP. Demographics were similar across cohorts (mean age 52.2-53.1 years, male 81.3-86.8%). During the first month of follow-up, patients with CVERP had more WA/STD-related hours lost compared with patients without CVERP (WA eligible: 23.4 more hours, STD-eligible: 51.7 more hours, WA and STD-eligible: 56.3 more hours) (p < 0.001). Corresponding costs were $683, $895, and $1,119 higher, respectively (p < 0.001). Differences narrowed with longer follow-up. In the first month and year of follow-up, patients with coronary artery bypass graft experienced the highest WA/STD-related hours lost and costs compared with patients with other CVERP. CONCLUSIONS: CVERP were associated with substantial work loss and indirect costs. Prevention or reduction of CVERP could result in WA and STD-related cost savings for employers. PMID- 26104785 TI - Human biting activity, spatial-temporal distribution and malaria vector role of Anopheles calderoni in the southwest of Colombia. AB - BACKGROUND: Anopheles calderoni was first recognized in Colombia in 2010 as this species had been misidentified as Anopheles punctimacula due to morphological similarities. An. calderoni is considered a malaria vector in Peru and has been found naturally infected with Plasmodium falciparum in Colombia. However, its biting behaviour, population dynamics and epidemiological importance have not been well described for Colombia. METHODS: To assess the contribution of An. calderoni to malaria transmission and its human biting behaviour and spatial/temporal distribution in the southwest of Colombia, human landing catches (HLC) and larval collections were carried out in a cross-sectional, entomological study in 22 localities between 2011 and 2012, and a longitudinal study was performed in the Boca de Prieta locality in Olaya Herrera municipality between July 2012 and June 2013. All mosquitoes determined as An. calderoni were tested by ELISA to establish infection with Plasmodium spp. RESULTS: Larvae of An. calderoni were found in four localities in 12 out of 244 breeding sites inspected. An. calderoni adults were collected in 14 out of 22 localities during the cross-sectional study and represented 41.3% (459 of 1,111) of the collected adult specimens. Other species found were Anopheles albimanus (54.7%), Anopheles apicimacula (2.1%), Anopheles neivai (1.7%), and Anopheles argyritarsis (0.2%). In the localities that reported the highest malaria Annual Parasite Index (>10/1,000 inhabitants) during the year of sampling, An. calderoni was the predominant species (>90% of the specimens collected). In the longitudinal study, 1,528 An. calderoni were collected by HLC with highest biting rates in February, May and June 2013, periods of high precipitation. In general, the species showed a preference to bite outdoors (p < 0.001). In Boca de Prieta, two specimens of An. calderoni were ELISA positive for Plasmodium circumsporozoite protein: one for P. falciparum and one for Plasmodium vivax VK-210. This represents an overall sporozoite rate of 0.1% and an annual entomological inoculation rate of 2.84 infective bites/human/year. CONCLUSIONS: This study shows that An. calderoni is a primary malaria vector in the southwest of Colombia. Its observed preference for outdoor biting is a major challenge for malaria control. PMID- 26104786 TI - Methods considerations for nystagmography. AB - OBJECTIVES: 1. To assess the reproducibility of eye movement velocity measurement using two methods: traditional electro-oculography (EOG) and infrared video oculography (VOG) and, 2. Determine whether the normal values for unilateral weakness and bilateral reduction of caloric responses vary according to method employed. BACKGROUND: Vestibular testing frequently involves measurement of eye movements. EOG has been the standard method for decades, but VOG and other methods have recently become popular. The assumption has been that all methods measure eye movements equally and accurately but this assumption has not been validated. In this paper we examine this assumption. METHODS: Eye movements were recorded simultaneously with commercially available EOG and VOG methods to evaluate differences in results for nineteen normal subjects undergoing caloric tests with warm and cold water. Examination of the records permitted identification and simultaneous measurement of 840 nystagmus beats. RESULTS: EOG and VOG measurements were correlated but the correlation was not strong (Spearman rho = 0.529, p < 0.01). Eye velocities recorded by the VOG system were greater than that for the EOG system. The mean VOG/EOG ratio was 1.71. Normal values used at our centre were adjusted to accommodate the use of video technology to account for the differences in sensitivity between EOG and VOG methods. CONCLUSION: The traditional EOG-based normal value for bilateral reduction of caloric response, 30 degree per second (d/s) based on traditional EOG measurements should be revised to 50 d/s for modern VOG testing in our lab. Normal values for vestibular testing may need to be re-evaluated when new technology is introduced. Each lab should verify normal values for their own methods and equipment. PMID- 26104787 TI - Circadian Arterial Blood Pressure Variation and Glaucoma Progression: More Questions Than Answers? PMID- 26104788 TI - Brachial Systolic Blood Pressure Fails to Predict Short-Term Outcome in Patients With Acute Ischemic Stroke: What About Central Systolic Pressure? PMID- 26104789 TI - Developing an industry-oriented safety curriculum using the Delphi technique. AB - In this study, we examined the development of industry-oriented safety degree curricula at a college level. Based on a review of literature on the practices and study of the development of safety curricula, we classified occupational safety and health curricula into the following three domains: safety engineering, health engineering, and safety and health management. We invited 44 safety professionals to complete a four-round survey that was designed using a modified Delphi technique. We used Chi-square statistics to test the panel experts' consensus on the significance of the items in the three domains and employed descriptive statistics to rank the participants' rating of each item. The results showed that the top three items for each of the three domains were Risk Assessment, Dangerous Machinery and Equipment, and Fire and Explosion Prevention for safety engineering; Ergonomics, Industrial Toxicology, and Health Risk Assessment for health engineering; and Industrial Safety and Health Regulations, Accident Investigation and Analysis, and Emergency Response for safety and health management. Only graduates from safety programmes who possess practical industry oriented abilities can satisfy industry demands and provide value to the existence of college safety programmes. PMID- 26104790 TI - The relationship between child- and parent-reported shared decision making and child-, parent-, and clinician-reported treatment outcome in routinely collected child mental health services data. AB - OBJECTIVE: Shared decision making (SDM) between service users and providers is increasingly being suggested as a key component of good healthcare. The aim of this research was to explore whether child- and parent-reported experience of SDM was associated with child- and parent-reported improvement in psychosocial difficulties and clinician-reported functioning at the end of treatment in child and adolescent mental health services (CAMHS). METHOD: The sample comprised N = 177 children (62% female; 31% aged 6-12 and 69% aged 13-18) with a variety of mental health problems from 17 services where routinely collected data consisted of presenting problems at outset, child- and parent-reported change in symptoms between Time 1 and Time 2 (Strengths and Difficulties Questionnaire; SDQ), clinician-reported change in functioning between Time 1 and Time 2 (Children's Global Assessment Scale; CGAS), and experience of SDM at Time 2 (as measured by responses to the Experience of Service Questionnaire; ESQ). RESULTS: Analysis revealed that both child- and parent-reported experience of SDM were associated with higher levels of child- and parent-reported improvement in psychosocial difficulties. However, child-reported experience of SDM was only associated with higher levels of child-reported improvement when their parents also reported higher levels of SDM. CONCLUSION: In CAMHS, involving both children and parents in decision making may contribute to enhanced treatment outcomes. PMID- 26104791 TI - The Rendez-vous technique for treatment of caesarean scar defects: a novel combined endoscopic approach. AB - BACKGROUND: A caesarean scar defect is a late complication of caesarean birth with a wide range of prevalence between 56 and 84% depending on which diagnostic tool and which definition is used. The referred symptoms which include postmenstrual spotting and infertility are fortunately rare. Moreover, severe complications such as caesarean scar pregnancy and uterine rupture in the following pregnancy may occur. Given the increasing incidence of caesarean births, the potential morbidity associated with caesarean scars is likely to become more important. Recently, a few repair techniques were described in the literature including the hysteroscopic resection of scarred tissue or the laparoscopic repair with or without robotic assistance. METHODS: Between June 2009 and February 2014, 21 women with caesarean scar defects were operated with the Rendez-vous technique, a minimally invasive surgery combining the laparoscopic and hysteroscopic approach. Data were retrospectively collected. The indications for this surgery included secondary infertility, previous caesarean scar pregnancy, recurrent miscarriage and postmenstrual spotting. Prior to operation, a transvaginal ultrasound was performed to examine the uterine wall defect. RESULTS: The patient characteristics are provided in Table 1. In all cases, the operation was successfully completed laparoscopically. The median operation time was 125 min. One case was complicated by recurrence of the scar defect 6 weeks after the operation. No other intra- or post-operative complications were observed, and the median in-patient stay was 3 days. CONCLUSIONS: The benefits of the technique include the feasibility and safety of the procedure, the "Halloween sign" (Fig. 1) which indicates the exact extent and localization of the scar defect and the immediate assessment of repair through the hysteroscopy at the end of the surgery. However, before further studies evaluate the efficacy of this method, the routine repair of caesarean scar defects cannot be recommended. A video of the technique is presented. PMID- 26104792 TI - Unidirectional barbed sutures as a novel technique for laparoscopic ventral hernia repair. AB - BACKGROUND: Incisional hernias remain a significant complication of abdominal surgeries. Primary closure of the hernia defect has been suggested to improve long-term abdominal wall function. However, this can be technically challenging and time consuming. This study describes laparoscopic use of non-absorbable barbed sutures in primary closure of hernia defects in addition to intraperitoneal mesh. METHODS: Patients who underwent laparoscopic primary ventral hernia repair with mesh were prospectively reviewed. Two groups were defined: Operations performed with barbed sutures for primary closure in addition to mesh and operations with only mesh without defect repair. The surgical technique involved running the hernia defect with a 2-polypropylene non absorbable unidirectional barbed suture and subsequently fixing the mesh intraperitoneally with tacks. In both groups, a single transfascial centering suture was also utilized. RESULTS: Twenty-eight cases with barbed suture and mesh reinforcement and 29 cases with mesh-only were identified. The average dimensions of the ventral hernia defects were 57.8 (6-187) and 44.6 cm(2) (9-156) in the barbed suture with mesh and mesh-only group, respectively, p = 0.23. Median operating time was 78 min (range 35-187 min) in the barbed suture with mesh group versus 62 min (34-155 min) in the mesh-only group, p = 0.44. The median suturing time of closing the ventral hernia defect was 16 min (11-24 min). There were no differences in the pain scores. Mean follow-up for both groups was 8.2 +/- 3.6 months (1-17 months) with one hernia recurrence in the mesh-only group, p = 0.41. CONCLUSIONS: The barbed suture closure system could be used for rapid and effective primary defect closure in laparoscopic ventral hernia repair in addition to intraperitoneal mesh placement. No significant difference in operating time was detected when compared to the mesh-only approach. Further evidence to support these findings and longer follow-up periods is warranted to evaluate short- and long-term complications. PMID- 26104793 TI - Development and implementation of the Structured Training Trainer Assessment Report (STTAR) in the English National Training Programme for laparoscopic colorectal surgery. AB - BACKGROUND: There is a lack of educational tools available for surgical teaching critique, particularly for advanced laparoscopic surgery. The aim was to develop and implement a tool that assesses training quality and structures feedback for trainers in the English National Training Programme for laparoscopic colorectal surgery. METHODS: Semi-structured interviews were performed and analysed, and items were extracted. Through the Delphi process, essential items pertaining to desirable trainer characteristics, training structure and feedback were determined. An assessment tool (Structured Training Trainer Assessment Report STTAR) was developed and tested for feasibility, acceptability and educational impact. RESULTS: Interview transcripts (29 surgical trainers, 10 trainees, four educationalists) were analysed, and item lists created and distributed for consensus opinion (11 trainers and seven trainees). The STTAR consisted of 64 factors, and its web-based version, the mini-STTAR, included 21 factors that were categorised into four groups (training structure, training behaviour, trainer attributes and role modelling) and structured around a training session timeline (beginning, middle and end). The STTAR (six trainers, 48 different assessments) demonstrated good internal consistency (alpha = 0.88) and inter-rater reliability (ICC = 0.75). The mini-STTAR demonstrated good inter-item reliability (alpha = 0.79) and intra-observer reliability on comparison of 85 different trainer/trainee combinations (r = 0.701, p = <0.001). Both were found to be feasible and acceptable. The educational report for trainers was found to be useful (4.4 out of 5). CONCLUSIONS: An assessment tool that evaluates training quality was developed and shown to be reliable, acceptable and of educational value. It has been successfully implemented into the English National Training Programme for laparoscopic colorectal surgery. PMID- 26104794 TI - Efficacy and safety of Hybrid-APC for the ablation of Barrett's esophagus. AB - BACKGROUND AND STUDY AIM: After thermal ablation of Barrett's esophagus (BE), stricture formation is reported in 5 to over 10% of patients. The question arises whether submucosal fluid injection prior to ablation may lower the risk of stricture formation. The aim of the present study was to evaluate the efficacy and safety of the new technique of Hybrid-APC which combines submucosal injection with APC. PATIENTS AND METHODS: Patients who had a residual BE segment of at least 1 cm after endoscopic resection of early Barrett's neoplasia underwent thermal ablation of BE by Hybrid-APC. Prior to thermal ablation, submucosal injection of sodium chloride 0.9% was carried out using a flexible water-jet probe (Erbejet 2; Erbe Elektromedizin, Tuebingen, Germany). Check-up upper GI endoscopy was carried out 3 months after macroscopically complete ablation including biopsies from the neo-Z-line and the former BE segment, and recording of stricture formation. RESULTS: From May 2011 to November 2012, a total of 60 patients (pt) were included in the study [55 pt male (92%); mean age 62 +/- 9 years, range 42-79]. Ten patients were excluded from the study. In the remaining 50 pt, Hybrid-APC ablation and check-up endoscopy at 3 months were carried out. Forty-eight out of 50 pt (96%; ITT: 49/60, 82%) achieved macroscopically complete remission after a median of 3.5 APC sessions [SD 2.4; range 1-10]. Freedom from BE was histopathologically observed in 39/50 patients (78%). There was one treatment-related stricture (2%). Minor adverse events of Hybrid-APC were observed in 11 patients (22%). CONCLUSIONS: According to this pilot series, Hybrid-APC was effective and safe for BE ablation in a tertiary referral center. The rate of stricture formation was only 2%. Further studies are required to confirm the present results. GERMAN CLINICAL TRIALS REGISTER: DRKS00003369. PMID- 26104795 TI - Length of Stay and Readmissions in Mastectomy Patients. AB - Interest is growing in preventing readmissions as payers start to link reimbursement to readmission rates. The purpose of this study was to assess factors that contribute to 30-day readmission rates for women undergoing mastectomy for breast cancer. Data from the Pennsylvania Health Care Cost Containment Council were queried for women undergoing mastectomy for breast cancer during 2011 (n = 2,919). The outcomes measured were length of stay (LOS) and 30-day readmission. Univariate comparisons between characteristics of readmitted (n = 172) and nonreadmitted patients were performed using t-tests and chi-square tests. Readmission was modeled using logistic regression; LOS was modeled using linear regression and controlled for potential confounders. In multivariate analyses, patients with peripheral vascular disease were more likely to be readmitted (OR 4.36, p = 0.002). Increased LOS was also associated with increased odds of readmission (OR 1.26, p = <0.0001). Since LOS was an important predictor of readmission we also estimated determinants of LOS using linear regression. The occurrence of reconstructive surgery (p = <0.0001) and renal disease (p < 0.0001) were highly predictive of longer LOS. This study showed peripheral vascular disease and longer lengths of stay were associated with higher odds of readmission in women undergoing mastectomy. Clinicians should be cognizant that optimizing a patient's vascular status before mastectomy may lead to lower rates of readmission. Additional research is needed to determine whether the relationship between readmissions and length of hospital stay is a causative versus associative phenomenon since LOS is a modifiable factor that may lead to lower readmissions. PMID- 26104796 TI - Calcitonin suppresses intervertebral disk degeneration and preserves lumbar vertebral bone mineral density and bone strength in ovariectomized rats. AB - We investigated the effect of calcitonin (CT) on lumbar intervertebral disk degeneration (LIDD) in rats with ovariectomy-induced osteopenia. CT protected ovariectomized rats from LIDD by, at least in part, modifying extracellular matrix metabolism of the disks and preserving the microarchitecture and biomechanical properties of adjacent vertebrae. INTRODUCTION: The present study aimed to investigate the effect of CT on lumbar vertebral bone mineral density and intervertebral disk degeneration in ovariectomized (OVX) rats. METHODS: We first subjected 50 3-month-old female rats to either OVX (n = 30) or sham (n = 20). Twelve weeks later, ten OVX and ten sham rats were necropsied. The remaining OVX rats began to receive either saline vehicle (OVX + V, n = 10), or salmon CT (OVX + CT, 16 IU/kg/2 days, n = 10). After 12 weeks of treatment, necropsy was conducted and bone mineral density was determined in L3-4 and L5-6 vertebrae. The microstructure and biomechanical properties of L3 vertebrae were detected by micro-computed tomography and compression test, respectively. L5-6 was also used to measure intervertebral disk height and observe intervertebral disk histological changes by Van Gieson staining and histological scores, as well as immunohistochemistry (IHC) analysis of matrix metalloprotease (MMP)-1, MMP-13, and collagen II expression. RESULTS: At 12 weeks post-OVX, OVX rats had lower BV/TV and Tb.N and higher intervertebral disk histological score than sham rats. After 24 weeks, OVX + CT rats had higher BMD, BV/TV, Tb.N, and bone biomechanical strength values than OVX + V rats. Histological analysis showed OVX + CT rats had significantly lower disk degeneration scores than OVX + V rats. IHC analysis revealed CT treatment decreased expression of MMP-1 and MMP-13 and increased expression of collagen II compared with OVX + V rats. CONCLUSIONS: Our data demonstrate that CT-treated OVX rats display less intervertebral disk degeneration and favorable changes in intervertebral disk metabolism, associated with higher trabecular bone mass, better trabecular microarchitecture, and better biomechanical strength when compared to vehicle-treated OVX rats. PMID- 26104797 TI - Spectacular improvement in vitamin D status in elderly osteoporotic women: 8-year analysis of an osteoporotic population treated in a dedicated fracture liaison service. AB - In a population of postmenopausal women with a fragility fracture, we found a drastic reduction in the proportion of women with severe (<25 nmol/L) and moderate (25 to 75 nmol/L) hypovitaminosis D, especially from 2009 onwards. These results show that supplementation has been very widely integrated into current practice. INTRODUCTION: Vitamin D (25(OH)D) is essential for bone health. In institutionalised osteoporotic women, it reduces the risk of fragility fractures. Numerous articles suggesting the possibility of extraosseous effects have generated a growing number of publications and recommendations on more widespread administration, to limit the risks of moderate or severe hypovitaminosis D. We assessed the impact on clinical practice of these recommendations concerning 25(OH)D supplementation in elderly at-risk populations. METHODS: A total of 1486 postmenopausal osteoporotic women were seen in the context of a fracture liaison service (i.e. a rheumatology consultation following a peripheral fragility fracture), between May 2005 and December 2012. Of these, 1107 had a 25(OH)D assay (femur, n = 520; humerus, n = 207; wrist, n = 380). RESULTS: The average age of the total population was 76.7 +/- 9.9 years, while for women with an available 25(OH)D assay, the average age was 75.1 +/- 11.8 years. The average 25(OH)D (nmol/L) level was similar for the three fracture sites: femur, 30 +/- 36.2; humerus, 27.5 +/- 24; and wrist, 31 +/- 26. A drastic reduction in the proportion of women with severe (<25 nmol/L) and moderate (25 to 75 nmol/L) hypovitaminosis D was observed, especially from 2009 onwards, with a mean prevalence of 69 and 30 % respectively before that year and 35 and 52 % thereafter. Conversely, the proportion of women with 25(OH)D at the threshold value of 75 nmol/L increased from 1.2 to 24 %. Overall, mean serum 25(OH)D levels were significantly higher when comparing the two periods 2005-2008 and 2009-1012 (17.6 +/- 14.6 and 48.4 +/ 39.2 nmol/L, respectively; p < 0.0001). CONCLUSION: These results show that supplementation has been very widely integrated into current practice. We can expect it to yield beneficial effects in osseous and extraosseous terms in osteoporotic women, particularly the very elderly. PMID- 26104798 TI - Pharmacological targeting of valosin containing protein (VCP) induces DNA damage and selectively kills canine lymphoma cells. AB - BACKGROUND: Valosin containing protein (VCP) is a critical mediator of protein homeostasis and may represent a valuable therapeutic target for several forms of cancer. Overexpression of VCP occurs in many cancers, and often in a manner correlating with malignancy and poor outcome. Here, we analyzed VCP expression in canine lymphoma and assessed its potential as a therapeutic target for this disease. METHODS: VCP expression in canine lymphomas was evaluated by immunoblotting and immunohistochemistry. The canine lymphoma cell lines CLBL-1, 17-71 and CL-1 were treated with the VCP inhibitor Eeyarestatin 1 (EER-1) at varying concentrations and times and were assessed for viability by trypan blue exclusion, apoptosis by TUNEL and caspase activity assays, and proliferation by propidium iodide incorporation and FACS. The mechanism of EER-1 action was determined by immunoblotting and immunofluorescence analyses of Lys48 ubiquitin and markers of ER stress (DDIT3), autophagy (SQSTM1, MAP1LC3A) and DNA damage (gammaH2AFX). TRP53/ATM-dependent signaling pathway activity was assessed by immunoblotting for TRP53 and phospho-TRP53 and real-time RT-PCR measurement of Cdkn1a mRNA. RESULTS: VCP expression levels in canine B cell lymphomas were found to increase with grade. EER-1 treatment killed canine lymphoma cells preferentially over control peripheral blood mononuclear cells. EER-1 treatment of CLBL-1 cells was found to both induce apoptosis and cell cycle arrest in G1. Unexpectedly, EER-1 did not appear to act either by inducing ER stress or inhibiting the aggresome-autophagy pathway. Rather, a rapid and dramatic increase in gammaH2AFX expression was noted, indicating that EER-1 may act by promoting DNA damage accumulation. Increased TRP53 phosphorylation and Cdkn1a mRNA levels indicated an activation of the TRP53/ATM DNA damage response pathway in response to EER-1, likely contributing to the induction of apoptosis and cell cycle arrest. CONCLUSIONS: These results correlate VCP expression with malignancy in canine B cell lymphoma. The selective activity of EER-1 against lymphoma cells suggests that VCP will represent a clinically useful therapeutic target for the treatment of lymphoma. We further suggest a mechanism of EER-1 action centered on the DNA repair response that may be of central importance for the design and characterization of VCP inhibitory compounds for therapeutic use. PMID- 26104799 TI - Cu(II) enhances the effect of Alzheimer's amyloid-beta peptide on microglial activation. AB - BACKGROUND: Aggregated forms of amyloid-beta (Abeta) peptides are important triggers for microglial activation, which is an important pathological component in the brains of Alzheimer's patients. Cu(II) ions are reported to be coordinated to monomeric Abeta, drive Abeta aggregation, and potentiate Abeta neurotoxicity. Here we investigated whether Cu(II) binding modulates the effect of Abeta on microglial activation and the subsequent neurotoxicity. METHODS: Abeta peptides were incubated with Cu(II) at an equimolar ratio to obtain the Cu(II)-Abeta complex. Primary and BV-2 microglial cells were treated with Cu(II)-Abeta, Abeta, or Cu(II). The tumor necrosis factor-alpha (TNF-alpha) and nitric oxide levels in the media were determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was detected by MitoSOX oxidation. RESULTS: Incubation of Cu(II) with Abeta confers different chemical properties on the resulting complex. At the subneurotoxic concentrations, Cu(II)-Abeta (but not Abeta or Cu(II) alone) treatment induced an activating morphological phenotype of microglia and induced the microglial release of TNF-alpha and nitric oxide as well as microglia-mediated neuronal damage. Cu(II)-Abeta-triggered microglial activation was blocked by nuclear factor (NF)-kappaB inhibitors and was accompanied with NF-kappaB activation. Moreover, Cu(II)-Abeta induced hydrogen peroxide release, which was not affected by NADPH oxidase inhibitors. Mitochondrial superoxide production was increased after Cu(II)-Abeta stimulation. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), inhibited Cu(II)-Abeta-elicited microglial release of TNF-alpha and nitric oxide as well as the microglia-mediated neurotoxic effect. CONCLUSION: Our observations suggest that Cu(II) enhances the effect of Abeta on microglial activation and the subsequent neurotoxicity. The Cu(II)-Abeta-triggered microglial activation involves NF-kappaB activation and mitochondrial ROS production. PMID- 26104800 TI - Health effects of fructose and fructose-containing caloric sweeteners: where do we stand 10 years after the initial whistle blowings? AB - Suspicion that fructose-containing caloric sweeteners (FCCS) may play a causal role in the development of metabolic diseases has elicited intense basic and clinical research over the past 10 years. Prospective cohort studies converge to indicate that FCCS, and more specifically sugar-sweetened beverages (SSBs), consumption is associated with weight gain over time. Intervention studies in which FCCS or SSB consumption is altered while food intake is otherwise left ad libitum indicate that increased FCCS generally increases total energy intake and body weight, while FCCS reduction decreases body weight gain. Clinical trials assessing the effects of SSB reduction as a sole intervention however fail to observe clinically significant weight loss. Many mechanistic studies indicate that excess FCCS can cause potential adverse metabolic effects. Whether this is associated with a long-term risk remains unknown. Scientific evidence that excess FCCS intake causes more deleterious effects to health than excess of other macronutrients is presently lacking. However, the large consumption of FCCS in the population makes it one out of several targets for the treatment and prevention of metabolic diseases. PMID- 26104804 TI - Effect of oxidation heat treatment on the bond strength between a ceramic and cast and milled cobalt-chromium alloys. AB - There is a dearth of dental scientific literature on the effect of different oxidation heat treatments (OHTs) (as surface pretreatments) on the bonding performance of cast and milled cobalt-chromium (CoCr) alloys. The objective of this study was to evaluate the effect of different OHTs on the bond strength between a ceramic and cast and milled CoCr alloys. Cobalt-chromium metallic specimens were prepared using either a cast or a milled method. Specimens were subjected to four different OHT methods: without OHT; OHT under normal atmospheric pressure; OHT under vacuum; and OHT under vacuum followed by sandblasting. The metal-ceramic bond strength was evaluated using a three-point bending test according to ISO9693. Scanning electron microscopy and energy dispersive spectroscopy were used to study the specimens' microstructure and elemental composition. The bond strength was not affected by the CoCr manufacturing method. Oxidation heat treatment performed under normal atmospheric pressure resulted in the highest bond strength. The concentration of oxygen on the alloy surfaces varied with the different pretreatment methods in the following order: OHT under normal atmospheric pressure > OHT under vacuum > without OHT ~ OHT under vacuum followed by sandblasting. PMID- 26104805 TI - Cellular Uptake Mechanism of Paclitaxel Nanocrystals Determined by Confocal Imaging and Kinetic Measurement. AB - Nanocrystal formulation has become a viable solution for delivering poorly soluble drugs including chemotherapeutic agents. The purpose of this study was to examine cellular uptake of paclitaxel nanocrystals by confocal imaging and concentration measurement. It was found that drug nanocrystals could be internalized by KB cells at much higher concentrations than a conventional, solubilized formulation. The imaging and quantitative results suggest that nanocrystals could be directly taken up by cells as solid particles, likely via endocytosis. Moreover, it was found that polymer treatment to drug nanocrystals, such as surface coating and lattice entrapment, significantly influenced the cellular uptake. While drug molecules are in the most stable physical state, nanocrystals of a poorly soluble drug are capable of achieving concentrated intracellular presence enabling needed therapeutic effects. PMID- 26104806 TI - Fatigue stipulation of bulk-fill composites: An in vitro appraisal. AB - OBJECTIVES: The aim of this study was to determine the Weibull and slow crack growth (SCG) parameters of bulk-fill resin based composites. The strength degradation over time of the materials was also assessed by strength-probability time (SPT) analysis. METHODS: Three bulk-fill [Tetric EvoCeram Bulk Fill (TBF); X tra fil (XTR); Filtek Bulk-fill flowable (BFL)] and a conventional one [Filtek Z250 (Z250)] were studied. Seventy five disk-shaped specimens (12mm in diameter and 1mm thick) were prepared by inserting the uncured composites in a stainless steel split mold followed by photoactivation (1200mW/cm(2)/20s) and storage in distilled water (37 degrees C/24h). Degree of conversion was evaluated in five specimens by analysis of FT-IR spectra obtained in the mid-IR region. The SCG parameters n (stress corrosion susceptibility coefficient) and sigmaf0 (scaling parameter) were obtained by testing ten specimens in each of the five stress rates: 10(-2), 10(-1), 10(0), 10(1) and 10(2)MPa/s using a piston-on-three-balls device. Weibull parameter m (Weibull modulus) and sigmaf0 (characteristic strength) were obtained by testing additional 20 specimens at 1MPa/s. Strength probability-time (SPT) diagrams were constructed by merging SCG and Weibull parameters. RESULTS: BFL and TBF presented higher n values, respectively (40.1 and 25.5). Z250 showed the highest (157.02MPa) and TBF the lowest (110.90MPa) sigmaf0 value. Weibull analysis showed m (Weibull modulus) of 9.7, 8.6, 9.7 and 8.9 for TBF, BFL, XTR and Z250, respectively. SPT diagram for 5% probability of failure showed strength decrease of 18% for BFL, 25% for TBF, 32% for XTR and 36% for Z250, respectively, after 5 years as compared to 1 year. SIGNIFICANCE: The reliability and decadence of strength over time for bulk-fill resin composites studied are, at least, comparable to conventional composites. BFL shows the highest fatigue resistance under all simulations followed by TBF, while XTR was at par with Z250. PMID- 26104807 TI - Apparent- and Tissue-Level Yield Behaviors of L4 Vertebral Trabecular Bone and Their Associations with Microarchitectures. AB - The precise quantification of vertebral trabecular bone strength and the associations between the microarchitecture and nonlinear mechanics of trabecular bone under various loading conditions may provide insights into trabecular bone quality and trabecular strength prediction based on microarchitectures. In this research, 44 cubic L4 vertebral trabecular bone specimens (5 * 5 * 5 mm(3)) were selected from six male Chinese donors aged 62-70 years. For each vertebral trabecular cube, micro-computed tomography image-based nonlinear micro-finite element analyzes were conducted under compressive and tensile loadings along two orthogonal directions. A bilinear tissue constitutive model was used to describe the nonlinearity of bone tissue material. In each analysis, apparent Young's modulus and initial apparent yield point were determined; the average tissue von Mises stress at the apparent yield point was also calculated, and the amount of tissue elements yielded was obtained. Principal components (PCs) analysis revealed three independent components of the microarchitectural parameters of the vertebral trabecular bones; these three PCs can account for 80.744% of the total variability of trabecular microarchitectures; the first PC (PC1) included bone volume fraction, connectivity density and trabecular number; the second PC (PC2) comprised structure model index and degree of anisotropy; and the third PC (PC3) represented trabecular thickness and age. Multivariate linear regression analysis showed that the PCs were strongly predictive of the apparent- and tissue-level mechanical parameters of the vertebral trabecular bone. To gain further insights into the mechanical properties of trabecular bone, we divided the six vertebral bodies into two groups based on the microarchitectural parameters: high-quality group and low-quality group. We then compared the differences in the mechanical parameters between tension and compression, as well as along longitudinal and transverse loading directions. Results showed that the apparent Young's moduli of the high-quality group were significantly greater than those of the low-quality group in longitudinal and transverse directions. Only the apparent yield strains of the two groups under the longitudinal compressive loading condition were significantly different. The apparent yield stresses and the average tissue von Mises stresses of the trabeculae in the trabecular cubes of the high-quality group were significantly greater than those of the low-quality group under the four loading conditions. This study provided quantitative information regarding the nonlinear mechanical properties of vertebral trabecular bone. This study also described the associations of these mechanical properties with microarchitectures. Our findings may help estimate vertebral strength and the related fracture risk. PMID- 26104808 TI - That's not it, either-neither polymorphisms in PHOX2B nor in MIF are involved in sudden infant death syndrome (SIDS). AB - The occurrence of sudden infant death syndrome (SIDS) has been linked to several genetic risk factors, e.g. genes involved in the neuroadrenergic system, variations in serotonin reporter genes or mutations in long-QT syndrome genes. Additionally, polymorphisms in genes with impact in sleep disorder syndromes have been proposed to be of importance as genetic risk factors for SIDS. In this study, we investigated the polyalanine length variation of PHOX2B and the -794 CATT repeat in the MIF promoter region as well as single nucleotide polymorphisms (rs28462174, rs28727473, rs16853571, rs755622, rs12485058, rs12485068, rs4822444, rs4822445, rs4822446, rs4822447 and rs2012124) in both genes in 278 SIDS cases and 240 controls. No significant differences were found in allele distribution of neither length polymorphisms nor single nucleotide polymorphisms between SIDS cases or controls. Therefore, an importance of these variations for the occurrence of SIDS could be ruled out. PMID- 26104809 TI - Motivators and deterrents to blood donation among Black South Africans: a qualitative analysis of focus group data. AB - BACKGROUND AND OBJECTIVES: South Africa has a markedly skewed representation where the majority of blood (62%) is presently collected from an ethnically White minority. This study seeks to identify culturally specific factors affecting motivation of donors in South Africa. MATERIALS AND METHODS: We performed a qualitative study to evaluate motivators and deterrents to blood donation among Black South Africans. A total of 13 focus groups, comprising a total of 97 Black South Africans, stratified by age and geographic location were conducted. Transcripts of the interviews were analysed using a coding framework by Bednall & Bove. RESULTS: Participants made 463 unique comments about motivators focusing primarily on promotional communications (28%), incentives (20%) and prosocial motivation (16%). Participants made 376 comments about deterrents which focused primarily on fear (41%), negative attitudes (14%) and lack of knowledge (10%). CONCLUSION: Although prosocial motivation (altruism) was the most frequently mentioned individual motivator, promotional communication elicited more overall comments by participants. As reported by many authors, fear and lack of awareness were strong deterrents, but scepticism engendered by perceived racial discrimination in blood collection were unique to the South African environment. PMID- 26104810 TI - How a patient advocacy group developed the first proposed draft guidance document for industry for submission to the U.S. Food and Drug Administration. AB - Among the challenges confronting patients with rare diseases is a dearth of treatment options. The development of safe and effective new therapies is hampered by challenges associated with conducting clinical trials in small populations. In this article, we describe how the Duchenne muscular dystrophy community-led by Parent Project Muscular Dystrophy-created a proposed draft guidance document for industry for submission to the U.S. Food and Drug Administration. This unprecedented undertaking involved a broad coalition of more than 80 stakeholders collaborating across nine time zones to produce a document in only 6 months. We hope that other rare disease communities and advocacy organizations can use our experience as a model for developing their own draft guidance documents. PMID- 26104811 TI - Pre-eclampsia in 2014: Seven ways to make a difference. PMID- 26104812 TI - Bilateral exudative retinal detachment in a patient with early onset severe preeclampsia. AB - This article describes a rare case of early onset severe preeclampsia presenting with loss of vision in both eyes due to retinal detachment. Retinal detachment has been mainly reported in late onset preeclampsia unlike in this case. Though, some authors believe that occurrence of maternal retinal detachment in cases of preeclampsia has no prognostic implication to the fetus, in this case, presence of retinal detachment was associated with foetal demise. PMID- 26104813 TI - Peptides do not prevent cleavage of endoglin to produce soluble endoglin. AB - MMP14 cleaves membrane bound endoglin to produce soluble endoglin (sEng), an anti angiogenic factor that causes endothelial dysfunction in preeclampsia. A recent publication proposed peptides with an amino acid sequence straddling the MMP14 cleavage site on endoglin decreases sEng release. This may be an exciting therapeutic approach and requires validation. We administered peptides to JAR cells, and primary placental explants and endothelial cells. The peptides had no effect on sEng production, and did not block sEng production in HEK293 with MMP14 and endoglin overexpressed. Peptides with an amino acid sequence encompassing the cleavage site do not prevent sEng production in vitro. PMID- 26104814 TI - Impact of non-steroidal anti-inflammatory drugs on hypertensive disorders of pregnancy. AB - OBJECTIVE: Non-steroidal anti-inflammatory drug (NSAID) use has the potential to adversely affect blood pressure in women with hypertensive disorders of pregnancy. We sought to evaluate this association. STUDY DESIGN: Women affected with severe hypertensive disorders of pregnancy were identified by retrospective chart review. The medication administration record was then used to identify controls (no NSAID exposure) until a sufficient number of patients were obtained, after which the cases (NSAID exposed) were identified in a chronological manner during the same study period until a 2:1 ratio was achieved. The primary outcome was the change in mean of all postpartum mean arterial pressures (MAP) throughout the hospital stay. Power analysis showed that 146 exposed and 73 unexposed subjects were necessary to obtain 90% power to detect a MAP difference of 10mmHg between the groups. Secondary outcomes included: initiation of anti-hypertensive medication, need for increased doses of anti-hypertension medication, and adverse events related to hypertension. RESULTS: 223 women had severe hypertensive disorders of pregnancy, of whom 75 (34%) were not exposed to NSAIDs and 148 (66%) were exposed. NSAID exposure was not associated with a difference in the average MAP postpartum (p=0.70), nor any of the secondary outcomes evaluated. Exposure to NSAIDs was less likely as serum creatinine increased (p=0.012). CONCLUSION: In women with severe hypertensive disorders of pregnancy, NSAIDs did not appear to increase the average postpartum MAP, increase the requirement for anti hypertensive medications, or increase the rate of adverse postpartum events. PMID- 26104815 TI - Cost-effectiveness analysis of cardiovascular risk factor screening in women who experienced hypertensive pregnancy disorders at term. AB - OBJECTIVES: To assess the cost-effectiveness of post-partum screening on cardiovascular risk factors and subsequent treatment in women with a history of gestational hypertension or pre-eclampsia at term. STUDY DESIGN: Two separate Markov models evaluated the cost-effectiveness analysis of hypertension (HT) screening and screening on metabolic syndrome (MetS), respectively, as compared to current practice in women with a history of term hypertensive pregnancy disorders. Analyses were performed from the Dutch health care perspective, using a lifetime horizon. One-way sensitivity analyses and Monte Carlo simulation evaluated the robustness of the results. RESULTS: Both screening on HT and MetS in women with a history of gestational hypertension or pre-eclampsia resulted in increase in life expectancy (HT screening 0.23year (95% CI -0.06 to 0.54); MetS screening 0.14years (95% CI -0.16 to 0.45)). The gain in QALYs was limited, with HT screening and MetS screening generating 0.04 QALYs (95% CI -0.12 to 0.20) and 0.03 QALYs (95% CI -0.14 to 0.19), resulting in costs to gain one QALY of ?4228 and ?28,148, respectively. Analyses for uncertainty showed a chance of 74% and 75%, respectively, that post-partum screening is cost-effective at a threshold of ?60,000/QALY. CONCLUSIONS: According to the available knowledge post-partum screening on cardiovascular risk factors and subsequent treatment in women with a history of gestational hypertension or pre-eclampsia at term is likely to be cost effective. PMID- 26104816 TI - Use of first or second trimester serum markers, or both, to predict preeclampsia. AB - OBJECTIVES: Preeclampsia is a serious complication of pregnancy, threatening fetal and maternal health. The aim of our study is to examine the association between preeclampsia and biochemical markers, in matched first and second trimester maternal serum samples. STUDY DESIGN: This is a nested case/control study derived from the cohort of pregnancies delivering at Women & Infants Hospital. Cases were identified at a clinic or by hospital codes, and individually confirmed by record review. Stored samples were available from 'integrated' Down syndrome screening. Results were expressed as multiples of the median (MoM). MAIN OUTCOME MEASURES: Preeclampsia was classified as early/severe, late/severe, or mild based on professional guidelines. An additional adverse outcome group had only gestational hypertension. RESULTS: Ninety-eight cases were each matched with five control pregnancies. Population distribution parameters and within and between trimester correlations were derived for cases and controls for six markers, as well as in case subgroups. The strongest associations were for early/severe preeclampsia with second trimester PAPP-A (rank sum test 2.30, p<0.01); PlGF (2.60, p<0.05) inhibin A (4.45, p<0.05) and endoglin (4.25, p<0.05). No strong associations were found for sVEGF-R and FLRG. Second trimester associations were stronger than those in the first (e.g., PAPP-A 2.45, p<0.01). No between-trimester associations were found that would provide important improvements in prediction. CONCLUSIONS: This matched analysis of the serum markers in early pregnancy allows for direct comparison of first and second trimester associations with preeclampsia. PAPP-A and PlGF are equally and highly predictive of early/severe preeclampsia. PMID- 26104817 TI - Adverse maternal and fetal outcomes and deaths related to preeclampsia and eclampsia in Haiti. AB - OBJECTIVE: The purpose of this study was to define the prevalence and clinical characteristics of preeclampsia and eclampsia at a hospital in rural Haiti. METHODS: This is a retrospective review of women presenting to Hopital Albert Schweitzer (HAS) in Deschapelles, Haiti with singleton pregnancy and diagnosis of preeclampsia or eclampsia from January 1, 2011 through December 31, 2012. Hospital charts were reviewed to obtain medical and prenatal history, hospital course, delivery information, and fetal/neonatal outcomes. The outcomes included placental abruption, antepartum eclampsia, postpartum eclampsia, maternal death, birthweight <2500g and stillbirth. Data are presented as median (quartile 1, quartile 3) or n (%) and risk ratios. RESULTS: During the study period, 1743 women were admitted to the maternity service at HAS and 290 (16.6%) were diagnosed with preeclampsia or eclampsia. Only singleton pregnancies were analyzed (N=270). Nearly all (95.0%) patients admitted with preeclampsia had severe preeclampsia. There were 83 patients with eclampsia (30.7%) of which 61 (73.4%) had antepartum eclampsia. There were 48 stillbirths (17.8%) and 5 maternal deaths (1.9%). Patients with antepartum eclampsia were younger, more likely to be nulliparous and had less prenatal care compared to women with antepartum preeclampsia. Antepartum eclampsia was associated with placental abruption and maternal death. CONCLUSIONS: The rates of preeclampsia and its associated complications, such as eclampsia, placental abruption, maternal death and stillbirth, are high at this facility in Haiti. Such data are essential to developing region-specific systems to prevent preeclampsia-related complications. PMID- 26104818 TI - Characterization of protocols for primary trophoblast purification, optimized for functional investigation of sFlt-1 and soluble endoglin. AB - OBJECTIVES: Soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) are the most studied molecules in preeclampsia. However, most trophoblast cell lines do not secrete both these factors. Thus, we set out to characterize protocols to functionally investigate sFlt-1 and sEng from primary trophoblast. STUDY DESIGN: Primary trophoblasts were isolated from term placenta by percoll gradient, then negative selection using a CD9 antibody. Purity was assessed by cytokeratin 7 immunostaining. We first examined the effects of CD9 negative selection on sFlt-1, sEng and hCG secretion and the ability of forskolin to enhance syncytialization. We then examined the effects of hypoxia on sFlt-1 production and assessed gene knockdown using siRNA. RESULTS: CD9 negative selection produced a pure population of primary trophoblasts. Secretion of sEng was 5-fold lower when CD9-positive cells were removed, sFlt1 was unchanged, and hCG was significantly increased. hCG analysis of the purified population indicated spontaneous syncytialization, which was not enhanced by forskolin. Forskolin similarly did not alter sFlt-1 secretion. Hypoxia significantly increased sFlt-1 secretion as expected. Importantly, high gene silencing efficiencies were readily achieved. CONCLUSION: In conclusion, we present a protocol that yields primary trophoblasts of high purity that produce abundant sFlt-1 and low but detectable levels of sEng. Furthermore, these cells are readily amenable to gene silencing by siRNAs and hence suitable for functional studies. PMID- 26104819 TI - Abnormal uterine artery Doppler velocimetry predicts adverse outcomes in patients with abnormal analytes. AB - OBJECTIVES: Our aim was to determine if uterine artery (UtA) Doppler studies would risk-stratify women with abnormal serum analytes on prenatal genetic screening into those at baseline and increased risk for preeclampsia and small for-gestational age (SGA). STUDY DESIGN: This retrospective cohort study examined outcomes of patients with ?one abnormal analyte (PAPP-A<0.3, hCG>3.0, AFP>2.5, inhibin>2.0, or unconjugated estriol<0.3MoM). At approximately 24weeks, we assessed UtA pulsatility index (PI). MAIN OUTCOME MEASURES: Preeclampsia, preterm preeclampsia, SGA (birthweight (BW) <10%) and intrauterine growth restriction (IUGR) (BW<3%). RESULTS: We identified 132 patients with ?one abnormal analyte, UtA Doppler screening, and delivery outcomes. Twenty-four (18%) had an elevated UtA PI (PI>1.6); preeclampsia occurred in 16 (12%) and 26 (20%) delivered a SGA neonate. Abnormal UtA Doppler PI increased the likelihood of a composite outcome of preeclampsia or SGA from 27% to 71% (LR 6.48 (2.93, 14.30)); a negative UtA Doppler PI reduced the likelihood to 18% (LR 0.57 (0.42, 0.78)). Abnormal UtA Doppler PI increased the likelihood of a more severe composite outcome of preterm preeclampsia or IUGR from 11% to 39% (LR 5.49 (3.03, 9.97)); a negative UtA Doppler study reduced the likelihood to 4% (LR 0.35 (0.16, 0.80)). CONCLUSIONS: In patients with abnormal serum analytes, abnormal UtA Doppler PI is significantly associated with preeclampsia or SGA and improves the prediction of these adverse outcomes by 9-15-fold. Providers can incorporate UtA Doppler PI into an abbreviated surveillance regimen; they can be reassured that a normal study markedly decreases the risk of a severe early adverse outcome. PMID- 26104820 TI - Lessons learned in using realist evaluation to assess maternal and newborn health programming in rural Bangladesh. AB - Realist evaluation furnishes valuable insight to public health practitioners and policy makers about how and why interventions work or don't work. Moving beyond binary measures of success or failure, it provides a systematic approach to understanding what goes on in the 'Black Box' and how implementation decisions in real life contexts can affect intervention effectiveness. This paper reflects on an experience in applying the tenets of realist evaluation to identify optimal implementation strategies for scale-up of Maternal and Newborn Health (MNH) programmes in rural Bangladesh. Supported by UNICEF, the three MNH programmes under consideration employed different implementation models to deliver similar services and meet similar MNH goals. Programme targets included adoption of recommended antenatal, post-natal and essential newborn care practices; health systems strengthening through improved referral, accountability and administrative systems, and increased community knowledge. Drawing on focused examples from this research, seven steps for operationalizing the realist evaluation approach are offered, while emphasizing the need to iterate and innovate in terms of methods and analysis strategies. The paper concludes by reflecting on lessons learned in applying realist evaluation, and the unique insights it yields regarding implementation strategies for successful MNH programming. PMID- 26104821 TI - Exploring corruption in the South African health sector. AB - Recent scholarly attention has focused on weak governance and the negative effects of corruption on the provision of health services. Employing agency theory, this article discusses corruption in the South African health sector. We used a combination of research methods and triangulated data from three sources: Auditor-General of South Africa reports for each province covering a 9-year period; 13 semi-structured interviews with health sector key informants and a content analysis of print media reports covering a 3-year period. Findings from the Auditor-General reports showed a worsening trend in audit outcomes with marked variation across the nine provinces. Key-informants indicated that corruption has a negative effect on patient care and the morale of healthcare workers. The majority of the print media reports on corruption concerned the public health sector (63%) and involved provincial health departments (45%). Characteristics and complexity of the public health sector may increase its vulnerability to corruption, but the private-public binary constitutes a false dichotomy as corruption often involves agents from both sectors. Notwithstanding the lack of global validated indicators to measure corruption, our findings suggest that corruption is a problem in the South African healthcare sector. Corruption is influenced by adverse agent selection, lack of mechanisms to detect corruption and a failure to sanction those involved in corrupt activities. We conclude that appropriate legislation is a necessary, but not sufficient intervention to reduce corruption. We propose that mechanisms to reduce corruption must include the political will to run corruption-free health services, effective government to enforce laws, appropriate systems, and citizen involvement and advocacy to hold public officials accountable. Importantly, the institutionalization of a functional bureaucracy and public servants with the right skills, competencies, ethics and value systems and whose interests are aligned with health system goals are critical interventions in the fight against corruption. PMID- 26104822 TI - Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings. AB - Corneal dystrophies are a heterogeneous group of bilateral, inherited, rare diseases characterized by slowly progressive corneal opacities, that lead to visual impairment. Most of them have an autosomal dominant pattern of inheritance with variable expressivity, but new mutations have been described. Many corneal dystrophies have been genetically characterized and the specific gene mutations identified, such as for the epithelial-stromal TGFBI dystrophies. Current classification systems identified four main groups of corneal dystrophies based on clinical, histologic, and genetic information. Diagnosis is performed during a routine ophthalmic examination that shows typical cellular abnormalities of the corneal epithelium, stroma, or endothelium. Disease progression should be carefully monitored to decide the proper clinical management. The treatment of corneal dystrophies is variable, depending on symptoms, clinical course, severity, and type of dystrophy. Management aimed to reduce symptoms and to improve vision, includes different surgical approaches. Novel cellular and genetic therapeutic approaches are under evaluation. J. Cell. Physiol. 231: 261 269, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26104823 TI - Effect of induction chemotherapy on survival in locally advanced head and neck squamous cell carcinoma treated with concurrent chemoradiotherapy: Single center experience. AB - BACKGROUND: Although induction chemotherapy can reduce distant metastases in locally advanced head and neck squamous cell carcinoma (HNSCC), overall survival (OS) improvement because of induction chemotherapy has not been confirmed. METHODS: We reviewed medical records of 224 patients diagnosed with locally advanced HNSCC who were treated with induction chemotherapy followed by concurrent chemoradiotherapy (CRT; induction chemotherapy/CRT; N = 144) and CRT alone (N = 80) from 2005 to 2013. We analyzed OS and progression-free survival (PFS). RESULTS: The 3-year OS rate was significantly higher in the induction chemotherapy/CRT group compared to the CRT group (74.0% vs 62.7%; p = .045). The 3-year PFS rate was 64.6% in the induction chemotherapy/CRT group and 54.1% in the CRT group (p = .060). Subgroup analysis showed patients with high N classification (N2 or N3) oropharyngeal cancer had greater benefits when treated with induction chemotherapy/CRT. CONCLUSION: Induction chemotherapy plus CRT improved OS, compared to CRT alone in locally advanced HNSCC, especially with high N classification. PMID- 26104825 TI - Borderline personality features and associated difficulty in emotion perception: An examination of accuracy and bias. AB - Research on borderline personality disorder (BPD) has consistently found that those with the disorder often experience volatile interpersonal interactions, and several areas of research have been dedicated to the understanding of the mechanisms behind these interpersonal struggles. One of the most common theories is that the emotional dysregulation that is characteristic of BPD may adversely impact these interpersonal interactions, perhaps through a resulting misperception of emotional states in others. The purpose of the current study was to examine perception of negative affect in those with borderline personality features using a signal detection paradigm, a modified version of the Reading the Mind in the Eyes Task. Results support the hypothesis of atypical perception of negative emotions in BPD, but with disinhibitory aspects of the disorder demonstrating the largest potential influence. This finding was obtained even after controlling for gender differences that were also observed on this task. These results suggest that an examination of trait components of BPD may be necessary for a complete understanding of the emotion perception abilities of those with the disorder. PMID- 26104824 TI - Composition, proteolysis indices and coagulating properties of ewe milk as affected by bulk tank somatic cell count. AB - The aim of this study was to assess the effect of ovine bulk tank somatic cell count (BTSCC) on composition, proteose-peptone (p-p) content and casein fractions as indicating parameters for proteolysis and coagulating properties of milk. A total of 97 samples of bulk tank milk from Manchega breed ewe flocks were grouped according to somatic cell count (SCC) into four classes: fewer than 500,000 cells/ml, from 500,000 to 10,00000 cells/ml, from 10,00000 to 15,00000 and more than 15,00000 cells/ml. The casein : protein ratio and lactose content decreased with BTSCC. Proteolysis increased with BTSCC, causing a drop in beta-casein and an increase in the gamma-caseins from a concentration of 500,000 cells/ml. Regarding coagulation behaviour, the rennet clotting time (RCT) and firming time (k20) rose from 10,00000-15,00000 cells/ml of milk. The results showed that the impairment of milk quality and milk ability to make cheese as affected by intramammary infection (IMI) can be inferred from the bulk tank milk of flocks with poor udder health. PMID- 26104827 TI - Satellite-based observations of unexpected coastal changes due to the Saemangeum Dyke construction, Korea. AB - Spatial and temporal changes around an area of conventional coastal engineering can be easily observed from field surveys because of the clear cause-and-effect observable in the before and after stages of the project. However, it is more difficult to determine environmental changes in the vicinity of tidal flats and coastal areas that are a considerable distance from the project. To identify any unexpected environmental impacts of the construction of Saemangeum Dyke in the area, we examined morphological changes identified by satellite-based observations through a field survey on Gomso Bay tidal flats (15km from Saemangeum Dyke), and changes in the suspended sediment distribution identified by satellite-based observations through a hydrodynamic analysis in the Saemangeum and Gomso coastal area. We argue that hydrodynamic changes due to conventional coastal engineering can affect the sedimentation pattern in the vicinity of tidal flats. We suggest that the environmental impact assessment conducted before a conventional coastal engineering project should include a larger area than is currently considered. PMID- 26104826 TI - In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept. AB - We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy ((1)H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology. PMID- 26104828 TI - Sand patties provide evidence for the presence of Deepwater Horizon oil on the beaches of the West Florida Shelf. AB - The ecological consequences of the Deepwater Horizon (DWH) oil spill are both long-term and pervasive. The distribution of toxicity and mutagenicity in the Gulf of Mexico suggests oil from the DWH spill could have contaminated the West Florida Shelf (WFS). We utilized polycyclic aromatic hydrocarbon (PAH) analysis to determine presence and potential origin of oil contaminants in beach sand patty samples. PAH profiles from WFS beaches were statistically significantly similar to DWH contaminated samples from the Northeast Gulf of Mexico (Gulf Shores, AL; Ft. Pickens, FL). Dioctyl sodium sulfosuccinate (DOSS), a major component of Corexit 9500 dispersant was also detected in the sediments. DOSS concentrations ranged from 1.6 to 5.5ngg(-1) dry weight. Additionally, two samples from DWH oil contaminated beaches were acutely toxic and one WFS beach sediment sample was mutagenic. These observations provide support for the theory that DWH oil made its way onto beaches of the WFS. PMID- 26104829 TI - Microtubule-associated proteins as direct crosslinkers of actin filaments and microtubules. AB - The cytoskeletal polymers--actin, microtubules, and intermediate filaments--are interlinked by coordinated protein interactions to form a complex three dimensional cytoskeletal network. Association of actin filaments with microtubules is important for various cellular processes such as cell division, migration, vesicle and organelle transport, and axonal growth. Several proteins including signaling molecules, motor proteins, and proteins directly or indirectly associated with microtubules and actin are involved in bridging the cytoskeletal components. Microtubule-associated proteins (MAPs) belonging to the MAP1, 2, 4 family and Tau proteins have been identified as key players that directly crosslink the two cytoskeletons. This review summarizes the current understanding of the interactions of these MAPs with actin filaments and their role in forming the actin-microtubule network and further discusses how the in vitro reconstitution assays can be used to study the dynamics of coordinated networks. Understanding the mechanisms by which actin and microtubules interact is key to decipher cancer, wound healing, and neuronal regeneration. PMID- 26104830 TI - Role of T-regulatory cells in the response to hepatitis B vaccine in hemodialysis patients. AB - Human disease elicits a complex array of biological processes that results in long-term protective immunological memory to infectious agents. Chronic kidney disease is known to impair induction of sustained immunological memory to hepatitis B vaccine (HBVax) antigens. We asked the question: Does end-stage renal disease promote changes in subtypes of regulatory T (Treg) cells that correlate with diminished amnestic response to HBVax antigen compared to healthy controls? The study design and setting was a prospective observational cohort at a veterans affairs medical center. End-stage renal disease patients on hemodialysis (HD) were compared with individuals with self-reported normal kidney function. All subjects received HBVax. Peripheral blood was sampled for assessment for Treg cells pre and post vaccination. CD4+ FOXP3 Treg numbers were similar between HD and healthy subjects during a 14-day time period post vaccination. HD subjcts had lower anti-HBSag antibody than CON (control) subjects (330 +/- 108.7 vs. 663.1 +/ 129.7 IU/mL; P = 0.063). Hemodialysis subjects with resting Tregs higher than the median value in our cohort demonstrated a significantly lower change in HBsAB at 30 days post booster vaccination (P = 0.030). No such relationship was found for the activated Treg subset among HD subjects, or either subset among CON subsets. In our limited comparison study of 11 HD and 8 CON subjects, Treg subsets did not differ between the two groups; but differences in the suppressive Treg numbers in the HD group could explain the altered antibody response to HBVax and is worthy of further study. PMID- 26104831 TI - The phenomenology of shame in the clinical encounter. AB - This article examines the phenomenology of body shame in the context of the clinical encounter, using the television program 'Embarrassing Bodies' as illustrative. I will expand on the insights of Aaron Lazare's 1987 article 'Shame and Humiliation in the Medical Encounter' where it is argued that patients often see their diseases and ailments as defects, inadequacies or personal shortcomings and that visits to doctors and medical professionals involve potentially humiliating physical and psychological exposure. I will start by outlining a phenomenology of shame in order to understand more clearly the effect shame about the body can have in terms of one's personal experience and, furthermore, one's interpersonal dynamics. I will then examine shame in the clinical encounter, linking body shame to the cultural stigma attached to illness, dysfunction and bodily frailty. I will furthermore explore how shame can be exacerbated or even incited by physicians through judgment and as a result of the power imbalance inherent to the physician-patient dynamic, compounded by the contemporary tendency to moralise about 'lifestyle' illnesses. Lastly, I will provide some reflections for how health care workers might approach patient shame in clinical practice. PMID- 26104832 TI - Temperament Dispositions, Problematic Eating Behaviours and Overweight in Adolescents. AB - Obesity, a common health condition in adolescence leading to severe medical complications, is assumed to be influenced by temperament factors. This paper investigates associations between reactive and regulative temperament, problematic eating behaviours and excess weight. Several self-report instruments were completed by 130 adolescents (mean age 14.13 +/- 0.61 years), including 27 overweight and obese individuals (20.8%). Bootstrap analysis revealed a mediating effect of restrained eating on the relation between reactive temperament and body mass index percentile, which differed according to gender: Restrained eating, which predicted weight gain, was more present in girls having a higher sensitivity to reward and in boys showing a higher sensitivity to punishment. No effect of regulative temperament was found. These results have important implications for weight management programmes, as they suggest that reducing restrained eating by working on temperament may help to control weight. PMID- 26104833 TI - Energy Level Tuning of Non-Fullerene Acceptors in Organic Solar Cells. AB - The use of non-fullerene acceptors in organic photovoltaic (OPV) devices could lead to enhanced efficiencies due to increased open-circuit voltage (VOC) and improved absorption of solar light. Here we systematically investigate planar heterojunction devices comprising peripherally substituted subphthalocyanines as acceptors and correlate the device performance with the heterojunction energetics. As a result of a balance between VOC and the photocurrent, tuning of the interface energy gap is necessary to optimize the power conversion efficiency in these devices. In addition, we explore the role of the charge transport layers in the device architecture. It is found that non-fullerene acceptors require adjusted buffer layers with aligned electron transport levels to enable efficient charge extraction, while the insertion of an exciton-blocking layer at the anode interface further boosts photocurrent generation. These adjustments result in a planar-heterojunction OPV device with an efficiency of 6.9% and a VOC above 1 V. PMID- 26104835 TI - Universal influenza vaccines, science fiction or soon reality? AB - Currently used influenza vaccines are only effective when the vaccine strains match the epidemic strains antigenically. To this end, seasonal influenza vaccines must be updated almost annually. Furthermore, seasonal influenza vaccines fail to afford protection against antigenically distinct pandemic influenza viruses. Because of an ever-present threat of the next influenza pandemic and the continuous emergence of drift variants of seasonal influenza A viruses, there is a need for an universal influenza vaccine that induces protective immunity against all influenza A viruses. Here, we summarize some of the efforts that are ongoing to develop universal influenza vaccines. PMID- 26104834 TI - Characterization of moose intestinal glycosphingolipids. AB - As a part of a systematic investigation of the species-specific expression of glycosphingolipids, acid and non-acid glycosphingolipids were isolated from three small intestines and one large intestine of the moose (Alces alces). The glycosphingolipids were characterized by binding of monoclonal antibodies, lectins and bacteria in chromatogram binding assays, and by mass spectrometry. The non-acid fractions were complex mixtures, and all had glycosphingolipids belonging to the lacto- and neolactoseries (lactotriaosylceramide, lactotetraosylceramide, neolactotetraosylceramide, Galalpha3-Le(x) hexaosylceramide, and lacto-neolactohexaosylceramide), globo-series (globotriaosylceramide and globotetraosylceramide), and isogloboseries (isoglobotriaosylceramide). Penta- and heptaglycosylceramides with terminal Galili determinants were also characterized. Furthermore, glycosphingolipids with terminal blood group O determinants (H triaosylceramide, H type 2 pentaosylceramide, H type 1 penta- and heptaosylceramide) were characterized in two of the moose small intestines, and in the one large intestine, while the third small intestine had glycosphingolipids with terminal blood group A determinants (A tetraosylceramide, A type 1 hexa- and octaosylceramide, A dodecaosylceramide). The acid glycosphingolipid fractions of moose small and large intestine contained sulfatide, and the gangliosides GM3, GD3, GD1a, GD1b, and also NeuGc and NeuAc variants of the Sd(a) ganglioside and the sialyl globopenta/SSEA-4 ganglioside. In humans, the NeuAc-globopenta/SSEA-4 ganglioside is a marker of embryonic and adult stem cells, and is also expressed in several human cancers. This is the first time sialyl-globopentaosylceramide/SSEA-4 has been characterized in a fully differentiated normal tissue, and also the first time NeuGc-globopentaosylceramide has been characterized. PMID- 26104836 TI - Space-time modelling of the spread of pancreas disease (PD) within and between Norwegian marine salmonid farms. AB - Infectious diseases are a constant threat to industrialised farming, which is characterised by high densities of farms and farm animals. Several mathematical and statistical models on spatio-temporal dynamics of infectious diseases in various farmed host populations have been developed during the last decades. Here we present a spatio-temporal stochastic model for the spread of a disease between and within aquaculture farms. The spread between farms is divided into several transmission pathways, including (i) distance related spread and (ii) other types of contagious contacts. The within-farm infection dynamics is modelled by a susceptible-infected-recovered (SIR) model. We apply this framework to model the spread of pancreas disease (PD) in salmon farming, using data covering all farms producing salmonids over 9 years in Norway. The motivation for the study was partly to unravel the spatio-temporal dynamics of PD in salmon farming and partly to use the model for scenario simulation of PD control strategies. We find, for example, that within-farm infection dynamics vary with season and we provide estimates of the timing from unobserved infection events to disease outbreaks on farms are detected. The simulations suggest that if a strategy involving culling of infectious cohorts is implemented, the number of detected disease outbreaks per year may be reduced by 57% after the full effect has been reached. We argue that the high detail and coverage of data on salmonid production and disease occurrence should encourage the use of simulation modelling as a means of testing effects of extensive control measures before they are implemented in the salmon farming industry. PMID- 26104837 TI - HbA2 : biology, clinical relevance and a possible target for ameliorating sickle cell disease. AB - HbA2 , a tetramer of alpha- and delta-globin chains, provides a diagnostic clue to the presence of beta-thalassaemia trait. This minor haemoglobin, which forms about 2-3% of the total, has no known physiological role, but has the interesting property of preventing polymerization of deoxy-sickle haemoglobin. If it were possible to increase the level of HbA2 sufficiently it could have a benefit in sickle cell disease similar to that of foetal haemoglobin. Moreover, HbA2 is present in all erythrocytes, an advantage not found with foetal haemoglobin, which is heterocellularly expressed. The molecular basis of HbA2 gene (HBD) expression is partially understood, and with new molecular tools, it might be possible to induce levels of HbA2 that could be clinically important. However, high concentrations of this positively charged haemoglobin might damage the erythrocyte membrane; also, the reciprocal relationship of delta- and gamma globin gene (HBD and HBG1/2, respectively) expression might negate any benefit of increasing transcription of the former. PMID- 26104838 TI - Mechanical circulatory support with impella to facilitate percutaneous coronary intervention for post-TAVI bilateral coronary obstruction. AB - One of the potential complications of transcatheter aortic valve implantation (TAVI) is coronary obstruction (CO), which can occur by displacement of heavily calcified native valve cusps against the coronary ostium. Treatment mandates immediate percutaneous coronary intervention (PCI) to restore coronary flow and improve hemodynamics and if unsuccessful, urgent implementation of circulatory support, commonly extracorporeal, with subsequent surgical revascularization. We report a case of post-TAVI CO for which successful emergent deployment of Impella percutaneous mechanical circulatory support to restore hemodynamic stability facilitated definitive treatment with bilateral PCI. Impella support represents an expeditious, effective, and widely available therapy to complement and facilitate PCI in the treatment of CO complicating TAVI, and may diminish requirement for urgent coronary artery bypass surgery. (c) 2015 Wiley Periodicals, Inc. PMID- 26104839 TI - Case of ketoacidosis in pregnancy. PMID- 26104840 TI - Effect of Serenoa Repens on Oxidative Stress, Inflammatory and Growth Factors in Obese Wistar Rats with Benign Prostatic Hyperplasia. AB - Serenoa repens has been widely used to treat benign prostatic hyperplasia and lower urinary tract symptoms; however, most of the studies have been conducted in individuals with normal weight and not obese. In this study, the effects of a lipidic extract of S. repens, in markers of oxidative stress, inflammation, and growth factors, in obese rats with testosterone-induced prostatic hyperplasia, were investigated. Total nitrites, malondialdehyde, total glutathione, superoxide dismutase (SOD), and catalase activity were measured; in addition, assays for inflammatory cytokines TNF-alpha, IL-1beta, IL-6 and the growth factors basic fibroblast growth factor (FGFb) and vascular endothelial growth factor (VEGF) were performed. The obese rats had a higher prostate weight compared with controls. S. repens significantly decreased prostate weight, total nitrites, and malondialdehyde; improved total glutathione, SOD, and catalase activity; and significantly reduced inflammatory (TNF-alpha, IL-1beta and IL-6) and growth factors (VEGF and FGFb). S. repens showed high antioxidant and antiinflammatory activity in obese rats, suggesting that their use could be beneficial in the treatment of benign prostatic hyperplasia. PMID- 26104843 TI - Unusual case of phakomatosis pigmentovascularis in a Japanese female infant associated with three phakomatoses: Port-wine stain, dermal melanocytosis and cutis marmorata telangiectatica congenita. PMID- 26104842 TI - Survival of African Swine Fever Virus in Excretions from Pigs Experimentally Infected with the Georgia 2007/1 Isolate. AB - African swine fever virus (ASFV) causes a lethal haemorrhagic disease of swine which can be transmitted through direct contact with infected animals and their excretions or indirect contact with contaminated fomites. The shedding of ASFV by infected pigs and the stability of ASFV in the environment will determine the extent of environmental contamination. The recent outbreaks of ASF in Europe make it essential to develop disease transmission models in order to design effective control strategies to prevent further spread of ASF. In this study, we assessed the shedding and stability of ASFV in faeces, urine and oral fluid from pigs infected with the Georgia 2007/1 ASFV isolate. The half-life of infectious ASFV in faeces was found to range from 0.65 days when stored at 4 degrees C to 0.29 days when stored at 37 degrees C, while in urine it was found to range from 2.19 days (4 degrees C) to 0.41 days (37 degrees C). Based on these half-lives and the estimated dose required for infection, faeces and urine would be estimated to remain infectious for 8.48 and 15.33 days at 4 degrees C and 3.71 and 2.88 days at 37 degrees C, respectively. The half-life of ASFV DNA was 8 to 9 days in faeces and 2 to 3 days in oral fluid at all temperatures. In urine, the half-life of ASFV DNA was found to be 32.54 days at 4 degrees C decreasing to 19.48 days at 37 degrees C. These results indicate that ASFV in excretions may be an important route of ASFV transmission. PMID- 26104844 TI - A Therapeutic Fast for Lymphoma Resulting in Wernicke Encephalopathy. AB - BACKGROUND: Wernicke encephalopathy is an acute neurological emergency caused by thiamine (vitamin B1) deficiency. The syndrome is associated with a significant morbidity and mortality, and prompt recognition and treatment of the syndrome in the emergency department (ED) is essential to improving patient outcomes. Numerous factors and clinical settings have been identified that predispose a patient to thiamine deficiency and subsequent Wernicke encephalopathy. CASE REPORT: We present the rare case of a 42-year-old man with a recent diagnosis of non-Hodgkin lymphoma who opted against chemotherapy in favor of a 60-day therapeutic water-only fast. On day 53 of his fast, the patient arrived to our ED in a coma and respiratory failure. Moments after the administration of thiamine, the patient's mental status and respiratory status improved significantly. Prior to admission and transport to the medical intensive care unit, the patient was awake, alert, and following basic commands. He was ultimately diagnosed with Wernicke encephalopathy. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: With the increasing incidence of patients choosing alternative medical therapies to treat a variety of diseases, numerous electrolyte, metabolic, and nutritional disorders are becoming increasingly more common in the ED setting. In some cases, patients may choose a therapeutic fast in an effort to combat a malignancy; the danger being that patients with cancers such as lymphoma are already at risk for thiamine deficiency as a result of the increased thiamine consumption associated with rapid cellular turnover. Wernicke encephalopathy is a life-threatening neurological emergency, and the emergency physician must be aware of the numerous predisposing factors to the condition, as early identification and treatment improves patient outcomes. PMID- 26104845 TI - Spinal Intramedullary Cysticercosis: A Rare Diagnostic Dilemma. PMID- 26104846 TI - Efficacy of Bolus-dose Phenylephrine for Peri-intubation Hypotension. AB - BACKGROUND: Intubation in hypotensive emergency department (ED) patients may increase the risk of life-threatening complications such as hypoperfusion and cardiovascular collapse. Peripherally administered, diluted "push-dose" phenylephrine has been advocated to treat peri-intubation hypotension, however, its effectiveness is unknown. STUDY OBJECTIVE: To investigate the efficacy and usage patterns of bolus-dose phenylephrine for peri-intubation hypotension at an academic medical center. METHODS: A retrospective chart review of all adult intubated, hypotensive patients (systolic blood pressure [SBP] < 90 mm Hg) over 12 months was conducted. During the peri-intubation period (30-min prior to/after intubation), the effect of phenylephrine was evaluated pre/post drug administration by comparing SBP, diastolic blood pressure (DBP), and heart rate (HR). RESULTS: A total of 119 patients met eligibility criteria. Phenylephrine was given to 29/119 (24%) patients and 20 (17%) were treated during the peri intubation period. Phenylephrine was given for many different conditions, and treatment timing varied greatly. Phenylephrine was given with other vasopressors 70% of the time (14/20), however, the timing of vasopressor infusion also varied greatly. When phenylephrine was given during the peri-intubation period, there were significant increases in SBP and DBP (p < 0.01) with no change in HR. CONCLUSION: In this academic ED, bolus-dose phenylephrine was used by practitioners without a systematic pattern. Although phenylephrine improved hemodynamics, it is possible that nonsystematic use of phenylephrine may cause inadvertent negative effects. Further studies will need to be conducted to better understand the best practices for use of phenylephrine. PMID- 26104847 TI - A highly reducing metal-free photoredox catalyst: design and application in radical dehalogenations. AB - Here we report the use of 10-phenylphenothiazine (PTH) as an inexpensive, highly reducing metal-free photocatalyst for the reduction of carbon-halogen bonds via the trapping of carbon-centered radical intermediates with a mild hydrogen atom donor. Dehalogenations were carried out on various substrates with excellent yields at room temperature in the presence of air. PMID- 26104848 TI - Transfemoral transcatheter aortic valve implantation in patients with small diseased peripheral vessels. AB - OBJECTIVES: The aim of this study was to assess the feasibility, safety and short term outcomes of transfemoral transcatheter aortic valve implantation (TF-TAVI) in patients with small diseased peripheral vessels. BACKGROUND: The transfemoral (TF) route for transcatheter aortic valve (TAVI) is the default option due to associated advantages. However, this is limited due to the high prevalence of significant peripheral arterial disease and increased risk of vascular complications. METHODS: Of 539 consecutive patients undergoing TAVI in a single Italian center, 23 patients underwent TF-TAVI in the presence of small peripheral vessels as defined by a minimal luminal diameter (MLD) of <=5.5mm [by computed tomography (CT)] and/or the inability to advance a large-bore sheath. Calcification was defined as being concentric if calcium extended more than 270 degrees around the circumference of the artery. All patients underwent 30-day clinical follow-up. RESULTS: 17 (73.9%) patients underwent peripheral vessel pre dilatation with a semi-compliant balloon and 6 (26.1%) patients with a Solopath sheath. 6 (26.1%) patients suffered a peri-procedural complication, with 1 patient requiring surgical embolectomy for thrombotic occlusion and the remaining patients successfully managed percutaneously in the catheter laboratory. No patient suffered a vessel perforation or required implantation of a covered stent. At 30-day follow-up, all patients were free of symptoms and signs or symptoms of peripheral vascular disease, with well-functioning TAVI prostheses as evaluated by echocardiography. CONCLUSIONS: Performing TF-TAVI is feasible in patients with no other viable vascular access option in the presence of small MLD and calcification of the peripheral vasculature, with any anticipated acute vascular complication managed in the catheter laboratory with established percutaneous techniques. PMID- 26104849 TI - Identifying efficient blue-phosphorescent polymer light-emitting diode host materials based on carbazole derivatives with C/Si-centered substituents using density functional theory. AB - Two series of carbazole derivatives were designed and studied that could potentially be used in polymer light-emitting diodes (PLEDs) as host molecules. These carbazole-based host molecules incorporated substituents with C or Si at their centers at the 3- and 6-positions on the carbazole moiety. Density functional theory calculations were performed to investigate the influence of the substituent on energy and charge transfer, and to predict whether each molecule could act as an effective host material in PLEDs. The results show that, for the series in which the carbazole moiety is linked to the substituent via the central C/Si atom ("cbz-sub series"), triplet-state electron transitions and triplet excitons arise from the carbazole moiety. Members of the cbz-sub series also exhibited higher triplet energies (ET) than the series in which the carbazole moiety is linked to the C/Si-centered substituent via an extra phenyl group ("cbz ph-sub series"). Moreover, members of the cbz-sub series presented strong molecular orbital interactions and suitable singlet and triplet energy differences (DeltaEST). Further investigations showed that, in each series, the presence of an Si atom was more likely to inhibit charge and exciton delocalization, and inserting a methyl or tert-butyl group at the 2- and 7 position, respectively, of the carbazole moiety in the cbz-ph-sub molecules improved their ET values and led to clear intramolecular charge-transfer character. A comparison of the energies of host and guest molecules showed that all of the molecules designed in this work are suitable for use with blue-light guest materials. PMID- 26104850 TI - In vivo detection of peripheral clefting in melanocytic lesions. PMID- 26104851 TI - Injectable tissue engineered pulmonary heart valve implantation into the pig model: A feasibility study. AB - BACKROUND: Transcatheter pulmonary valve replacement is currently performed in clinical trials, however limited by the use of glutaraldehyde treated bioprostheses. This feasibility study was performed to evaluate delivery-related tissue distortion during implantation of a tissue engineered (TE) heart valves. MATERIAL AND METHOD: The injectable TE heart valve was mounted on a self expanding nitinol stent (n=7) and delivered into the pulmonary position of seven pigs, (weight 26 to 31 kg), performing a sternotomy or limited lateral thoracotomy. Prior to implantation, the injectable TE heart valve was crimped and inserted into an applicator. Positioning of the implants was guided by fluoroscopy and after carefully deployment angiographic examination was performed to evaluate the correct delivered position. Hemodynamic measurements were performed by epicardial echocardiography. Finally, the animals were sacrificed and the injectable TE heart valves were inspected by gross examination and histological examination. RESULTS: Orthotopic delivery of the injectable TE heart valves were all successful performed, expect in one were the valve migrated due to a discrepancy of pulmonary and injectable TE valve size. Angiographic evaluation (n=6) showed normal valve function, supported by epicardial echocardiography in which no increase flow velocity was measured, neither trans- nor paravalvular regurgitation. Histological evaluation demonstrated absence of tissue damage due to the delivery process. CONCLUSIONS: Transcatheter implantation of an injectable TE heart valve seems to be possible without tissue distortion due to the delivery system. PMID- 26104852 TI - Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy? AB - OBJECTIVE: Hereditary transthyretin (ATTR) amyloidosis with increased left ventricular wall thickness could easily be misdiagnosed by echocardiography as hypertrophic cardiomyopathy (HCM). Our aim was to create a diagnostic tool based on echocardiography and ECG that could optimise identification of ATTR amyloidosis. METHODS: Data were analysed from 33 patients with biopsy proven ATTR amyloidosis and 30 patients with diagnosed HCM. Conventional features from ECG were acquired as well as two dimensional and Doppler echocardiography, speckle tracking derived strain and tissue characterisation analysis. Classification trees were used to select the most important variables for differentiation between ATTR amyloidosis and HCM. RESULTS: The best classification was obtained using both ECG and echocardiographic features, where a QRS voltage >30 mm was diagnostic for HCM, whereas in patients with QRS voltage <30 mm, an interventricular septal/posterior wall thickness ratio (IVSt/PWt) >1.6 was consistent with HCM and a ratio <1.6 supported the diagnosis of ATTR amyloidosis. This classification presented both high sensitivity (0.939) and specificity (0.833). CONCLUSION: Our study proposes an easily interpretable classification method for the differentiation between HCM and increased left ventricular myocardial thickness due to ATTR amyloidosis. Our combined echocardiographic and ECG model could increase the ability to identify ATTR cardiac amyloidosis in clinical practice. PMID- 26104853 TI - Vertebral compression fractures as the initial presentation of AL amyloidosis: case series and review of literature. AB - The clinical presentation of AL amyloidosis is highly variable. In this series, we describe five cases of AL amyloidosis with vertebral compression fractures as initial presentation. All five patients had evidence of bone marrow replacement on magnetic resonance imaging and bone marrow biopsies demonstrating diffuse interstitial amyloid deposition. Hepatomegaly and elevated liver enzymes, consistent with liver involvement with amyloidosis, were also seen in each case. All five patients responded well to anti-plasma cell chemotherapy, with normalization of serum free light chain levels, reduction in alkaline phosphatase and improvement in pain and functional status. Although rare, AL amyloidosis should be considered in the differential diagnosis of selected patients with spontaneous vertebral compression fractures. Moreover, there seems to be an association of vertebral compression fractures with liver involvement in AL amyloidosis. PMID- 26104855 TI - Selective inhibition by aspirin and naproxen of mainstream cigarette smoke induced genotoxicity and lung tumors in female mice. AB - The role of nonsteroidal anti-inflammatory drugs (NSAIDs) in smoke-related lung carcinogenesis is still controversial. We have developed and validated a murine model for evaluating the tumorigenicity of mainstream cigarette smoke (MCS) and its modulation by chemopreventive agents. In the present study, the protective effects of the nonselective cyclooxygenase inhibitors aspirin and naproxen were investigated by using a total of 277 Swiss H neonatal mice of both genders. Groups of mice were exposed whole-body to MCS during the first 4 months of life, followed by an additional 3.5 months in filtered air in order to allow a better growth of tumors. Aspirin (1600 mg/kg diet) and naproxen (320 mg/kg diet) were given after weanling until the end of the experiment. After 4 months of exposure, MCS significantly enhanced the frequency of micronucleated normochromatic erythrocytes in the peripheral blood of mice, and naproxen prevented such systemic genotoxic damage in female mice. After 7.5 months, exposure of mice to MCS resulted in the formation of lung tumors, both benign and malignant, and in several other histopathological lesions detectable both in the respiratory tract and in the urinary tract. Aspirin and, even more sharply, naproxen significantly inhibited the formation of lung tumors in MCS-exposed mice, but this protective effect selectively occurred in female mice only. These results lend support to the views that estrogens are involved in smoke-related pulmonary carcinogenesis and that NSAIDs have antiestrogenic properties. The two NSAIDs proved to be safe and efficacious in the experimental model used. PMID- 26104854 TI - Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. AB - Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this variability in susceptibility are still largely unknown. The aim of this study was to better understand this variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes (PHH) from several donors (n = 5) exposed in vitro to a non-toxic to toxic APAP dose range. To evaluate interindividual variation, gene expression data/levels of metabolites were plotted against APAP dose/donor. The correlation in APAP dose response between donors was calculated by comparing data points from one donor to the data points of all other donors using a Pearson-based correlation analysis. From that, a correlation score/donor for each gene/metabolite was defined, representing the similarity of the omics response to APAP in PHH of a particular donor to all other donors. The top 1 % highest variable genes were selected for further evaluation using gene set overrepresentation analysis. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Additionally, the interindividual variation in the expression of these genes could be associated with the variability in expression levels of hydroxyl/methoxy APAP and C8H13O5N-APAP-glucuronide. The before-mentioned metabolites or their derivatives have also been reported in blood of humans exposed to therapeutic APAP doses. Possibly these findings can contribute to elucidating the causative factors of interindividual susceptibility toward APAP. PMID- 26104856 TI - Wogonoside induces growth inhibition and cell cycle arrest via promoting the expression and binding activity of GATA-1 in chronic myelogenous leukemia cells. AB - GATA-1, a zinc finger transcription factor, has been demonstrated to play a key role in the progression of leukemia. In this study, we investigate the effects of wogonoside, a naturally bioactive flavonoid derived from Scutellaria baicalensis Georgi, on cell growth and cell cycle in chronic myeloid leukemia (CML) cells, and uncover its underlying mechanisms. The experimental design comprised CML cell lines K562, imatinib-resistant K562 (K562r) cells, and primary CML cells, treated in vitro or in vivo, respectively, with wogonoside; growth and cell cycle were then evaluated. We found that wogonoside could induce growth inhibition and G0/G1 cell cycle arrest in both normal and K562r cells. Wogonoside promotes the expression of GATA-1 and facilitates the binding to methyl ethyl ketone (MEK) and p21 promoter, thus inhibiting MEK/extracellular signal-regulated kinase signaling and cell cycle checkpoint proteins, including CDK2, CDK4, cyclin A, and cyclin D1, and increasing p21 expression. Furthermore, in vivo studies showed that administration of wogonoside decreased CML cells and prolonged survival in NOD/SCID mice with CML cell xenografts. In conclusion, these results clearly revealed the inhibitory effect of wogonoside on the growth in CML cells and suggested that wogonoside may act as a promising drug for the treatment of imatinib-resistant CML. PMID- 26104857 TI - Synergistic augmentation of ATP-induced interleukin-6 production by arsenite in HaCaT cells. AB - Chronic arsenic exposure causes cutaneous diseases such as hyperkeratosis and skin cancer. However, little information has been available regarding the molecular mechanisms underlying these symptoms. Because extracellular ATP and interleukin-6 (IL-6) are involved in pathological aspects of cutaneous diseases, we examined whether sodium arsenite (As(III)) affects ATP-induced IL-6 production in human epidermal keratinocyte HaCaT cells. The results showed that the addition of As(III) into the medium of HaCaT cells dose dependently increased the production of IL-6 induced by extracellular ATP, although As(III) alone had no effect on IL-6 production. To elucidate the mechanism of the synergistic effect of As(III) on IL-6 production by extracellular ATP, we next examined the phosphorylation of p38, ERK and epidermal growth factor receptor (EGFR), since we found that these signaling molecules were stimulated by exposure to extracellular ATP. The results indicated that ATP-induced phosphorylation of p38, ERK and EGFR was synergistically enhanced by co-exposure to As(III). To clarify the mechanisms underlying the enhanced phosphorylation of p38, ERK and EGFR by As(III), we explored two possible mechanisms: the inhibition of extracellular ATP degradation and the inhibition of protein tyrosine phosphatases (PTPs) activity by As(III). The degradation of extracellular ATP was not changed by As(III), whereas the activity of PTPs was significantly inhibited by As(III). Our results suggest that As(III) augments ATP-induced IL-6 production in HaCaT cells through enhanced phosphorylation of the EGFR and p38/ERK pathways, which is associated with the inhibition of PTPs activity. PMID- 26104858 TI - 'Am I covered?': an analysis of a national enquiry database on scope of practice. AB - AIM: Analysis of a national database of enquiries to a professional body pertaining to the scope of nursing and midwifery practice. BACKGROUND: Against a backdrop of healthcare reform is a demand for flexibility in nursing and midwifery roles with unprecedented redefinition of role boundaries and/or expansion. Guidance from professional regulatory bodies is being sought around issues of concern that are arising in practice. DESIGN: Qualitative thematic analysis. METHOD: The database of telephone enquiries (n = 9818) made by Registered Nurses and midwives to a national regulatory body (2001-2013) was subjected to a cleaning process and examined to detect those concerns that pertained to scope of practice. A total of 978 enquiries were subjected to thematic analysis. FINDINGS: Enquiries were concerned with three main areas: medication management, changing and evolving scope of practice and professional role boundaries. The context was service developments, staff shortages and uncertainty about role expansion and professional accountability. Other concerns related to expectations around responsibility and accountability for other support staff. CONCLUSION: Efforts by employers to maximize the skill mix of their staff and optimally deploy staff to meet service needs and/or address gaps in service represented the primary service context from which many enquiries arose. The greatest concern for nurses arises around medication management but innovation in healthcare delivery and the demands of service are also creating challenges for nurses and midwives. Maintaining and developing competence is a concern among nurses and midwives particularly in an environment of limited resources and where re-deployment is common. PMID- 26104859 TI - More rapid shift to a benthic niche in larger Gadus morhua juveniles. AB - Trophic use by Atlantic cod Gadus morhua juveniles was examined early and late in the shift from pelagic to benthic habitats. Changes in the proportion of pelagic copepods, estimates of benthic prey indicated by isotope mixing models and stable isotope values between sample periods suggested a gradual shift towards a benthic niche. Values of the trophic proxies, however, changed most markedly in the largest juvenile group, suggesting a more rapid trophic niche shift, and in turn competitive advantage, of larger juveniles. PMID- 26104860 TI - Effects of medetomidine and its active enantiomer dexmedetomidine on N demethylation of ketamine in canines determined in vitro using enantioselective capillary electrophoresis. AB - Cytochrome P450 (CYP) enzymes catalyze the metabolism of both, the analgesic and anesthetic drug ketamine and the alpha2 -adrenergic receptor-agonist medetomidine that is used for sedation and analgesia. As racemic medetomidine or its active enantiomer dexmedetomidine are often coadministered with racemic or S-ketamine in animals and dexmedetomidine together with S- or racemic ketamine in humans, drug drug interactions are likely to occur and have to be characterized. Enantioselective CE with highly sulfated gamma-cyclodextrin as chiral selector was employed for analyzing in vitro (i) the kinetics of the N-demethylation of ketamine mediated by canine CYP3A12 and (ii) interactions occurring with racemic medetomidine and dexmedetomidine during coincubation with ketamine and canine liver microsomes (CLM), canine CYP3A12, human liver microsomes (HLM), and human CYP3A4. For CYP3A12 without an inhibitor, Michaelis-Menten kinetics was determined for the single enantiomers of ketamine and substrate inhibition kinetics for racemic ketamine. Racemic medetomidine and dexmedetomidine showed an inhibition of the N-demethylation reaction in the studied canine enzyme systems. Racemic medetomidine is the stronger inhibitor for CLM, whereas there is no difference for CYP3A12. For CLM and CYP3A12, the inhibition of dexmedetomidine is stronger for the R- compared to the S-enantiomer of ketamine, a stereoselectivity that is not observed for CYP3A4. Induction is observed at a low dexmedetomidine concentration with CYP3A4 but not with CYP3A12, CLM, and HLM. Based on these results, S-ketamine combined with dexmedetomidine should be the best option for canines. The enantioselective CE assay with highly sulfated gamma-cyclodextrin as chiral selector is an effective tool for determining kinetic and inhibition parameters of metabolic pathways. PMID- 26104861 TI - Metallosupramolecular Ni2L3 and Ni4L6 complexes of bis-bidentate pyridine containing ligands: X-ray structures and catalytic proton reduction. AB - The pyridine-containing ligands and react with Ni(2+) ions to afford dinuclear triple-stranded helicate and tetrahedral cage supramolecular complexes, respectively; the two architectures exhibit contrasting reactivity towards electro- and photocatalytic proton reduction. PMID- 26104864 TI - In memoriam: Robert J. Arceci. PMID- 26104862 TI - Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date. AB - Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD. PMID- 26104865 TI - [Thoughts on the current euthanasia debate from the perspective of the German Society for Palliative Care]. PMID- 26104863 TI - Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice. AB - Pak1 plays an important role in various cellular processes, including cell motility, polarity, survival and proliferation. To date, its role in atherogenesis has not been explored. Here we report the effect of Pak1 on atherogenesis using atherosclerosis-prone apolipoprotein E-deficient (ApoE(-/-)) mice as a model. Disruption of Pak1 in ApoE(-/-) mice results in reduced plaque burden, significantly attenuates circulating IL-6 and MCP-1 levels, limits the expression of adhesion molecules and diminishes the macrophage content in the aortic root of ApoE(-/-) mice. We also observed reduced oxidized LDL uptake and increased cholesterol efflux by macrophages and smooth muscle cells of ApoE(-/ ):Pak1(-/-) mice as compared with ApoE(-/-) mice. In addition, we detect increased Pak1 phosphorylation in human atherosclerotic arteries, suggesting its role in human atherogenesis. Altogether, these results identify Pak1 as an important factor in the initiation and progression of atherogenesis. PMID- 26104866 TI - Structural basis for double cofactor specificity in a new formate dehydrogenase from the acidobacterium Granulicella mallensis MP5ACTX8. AB - Formate dehydrogenases (FDHs) are considered particularly useful enzymes in biocatalysis when the regeneration of the cofactor NAD(P)H is required, that is, in chiral synthesis with dehydrogenases. Their utilization is however limited to the recycling of NAD(+), since all (apart one) of the FDHs characterized so far are strictly specific for this cofactor, and this is a major drawback for their otherwise wide applicability. Despite the many attempts performed to modify cofactor specificity by protein engineering different NAD(+)-dependent FDHs, in the general practice, glucose or phosphite dehydrogenases are chosen for the recycling of NADP(+). We report on the functional and structural characterization of a new FDH, GraFDH, identified by mining the genome of the extremophile prokaryote Granulicella mallensis MP5ACTX8. The new enzyme displays a valuable stability in the presence of many organic cosolvents as well as double cofactor specificity, with NADP(+) preferred over NAD(+) at acidic pH values, at which it also shows the highest stability. The quite low affinities for both cofactors as well as for the substrate formate indicate, however, that the native enzyme requires optimization to be applied as biocatalytic tool. We also determined the crystal structure of GraFDH both as apoprotein and as holoprotein, either in complex with NAD(+) or NADP(+). Noticeably, the latter represents the first structure of an FDH enzyme in complex with NADP(+). This fine picture of the structural determinants involved in cofactor selectivity will possibly boost protein engineering of the new enzyme or other homolog FDHs in view of their biocatalytic exploitation for NADP(+) recycling. PMID- 26104867 TI - Biosynthesis of 2-deoxysugars using whole-cell catalyst expressing 2-deoxy-D ribose 5-phosphate aldolase. AB - 2-Deoxy-D-ribose 5-phosphate aldolase (DERA) accepts a wide variety of aldehydes and is used in de novo synthesis of 2-deoxysugars, which have important applications in drug manufacturing. However, DERA has low preference for non phosphorylated substrates. In this study, DERA from Klebsiella pneumoniae (KDERA) was mutated to increase its enzyme activity and substrate tolerance towards non phosphorylated polyhydroxy aldehyde. Mutant KDERA(K12) (S238D/F200I/DeltaY259) showed a 3.15-fold improvement in enzyme activity and a 1.54-fold increase in substrate tolerance towards D-glyceraldehyde compared with the wild type. Furthermore, a whole-cell transformation strategy using resting cells of the BL21(pKDERA12) strain, containing the expressed plasmid pKDERA12, resulted in increase in 2-deoxy-D-ribose yield from 0.41 mol/mol D-glyceraldehyde to 0.81 mol/mol D-glyceraldehyde and higher substrate tolerance from 0.5 to 3 M compared to in vitro assays. With further optimization of the transformation process, the BL21(pKDERA12) strain produced 2.14 M (287.06 g/L) 2-deoxy-D-robose (DR), with a yield of 0.71 mol/mol D-glyceraldehyde and average productivity of 0.13 mol/L.h (17.94 g/L.h). These results demonstrate the potential for large-scale production of 2-deoxy-D-ribose using the BL21(pKDERA12) strain. Furthermore, the BL21(pKDERA12) strain also exhibited the ability to efficiently produce 2-deoxy-D altrose from D-erythrose, as well as 2-deoxy-L-xylose and 2-deoxy-L-ribose from L glyceraldehyde. PMID- 26104868 TI - Environmental factors shaping the abundance and distribution of laccase-encoding bacterial community with potential phenolic oxidase capacity during composting. AB - Increasing molecular evidence points to a wide occurrence of laccase-like multicopper oxidase (LMCO)-encoding genes in bacteria. Most researches mainly focused on the bacterial LMCO diversity, whereas the processes and the environmental factors responsible for structuring bacterial LMCO communities remain relatively unknown in a composting system. Six gene libraries were constructed from samples in representative stages during composting. A total of 185 sequences obtained from sample DNA extracts were classified to 59 operational taxonomic units (OTUs) based on 10 % cutoff. The distribution profile of bacterial LMCO genes showed that proteobacterial- and actinobacterial-associated species were the dominant communities during composting. Pearson correlation analysis indicated that the pile temperature and water-soluble carbon (WSC) content were significantly positively correlated with bacterial LMCO gene OTU numbers, Chao1 and Shannon index, whereas the humic acid (HA)-like carbon content had the most significant effect on the distribution of the bacterial LMCO genes during composting by redundancy analysis. These findings will improve the understanding of the mutual relationship between environmental factors and bacterial LMCO community compositions in composting. PMID- 26104869 TI - "Paper Machine" for Molecular Diagnostics. AB - Clinical tests based on primer-initiated amplification of specific nucleic acid sequences achieve high levels of sensitivity and specificity. Despite these desirable characteristics, these tests have not reached their full potential because their complexity and expense limit their usefulness to centralized laboratories. This paper describes a device that integrates sample preparation and loop-mediated isothermal amplification (LAMP) with end point detection using a hand-held UV source and camera phone. The prototype device integrates paper microfluidics (to enable fluid handling) and a multilayer structure, or a "paper machine", that allows a central patterned paper strip to slide in and out of fluidic path and thus allows introduction of sample, wash buffers, amplification master mix, and detection reagents with minimal pipetting, in a hand-held, disposable device intended for point-of-care use in resource-limited environments. This device creates a dynamic seal that prevents evaporation during incubation at 65 degrees C for 1 h. This interval is sufficient to allow a LAMP reaction for the Escherichia coli malB gene to proceed with an analytical sensitivity of 1 double-stranded DNA target copy. Starting with human plasma spiked with whole, live E. coli cells, this paper demonstrates full integration of sample preparation with LAMP amplification and end point detection with a limit of detection of 5 cells. Further, it shows that the method used to prepare sample enables concentration of DNA from sample volumes commonly available from fingerstick blood draw. PMID- 26104870 TI - Deaths of older Australians related to their use of motorised mobility scooters. AB - This study describes motorized mobility scooter (MMS) rider-related fatalities in the older Australian population during the years 2000-2011, identified from the National Coronial Information System. Seventy-seven fatalities were identified, most aged 80 years or older (74.1%) and males predominated (76.6%). Most deaths (88.3%) resulted from collisions with motor vehicles or falling from the MMS. These findings are consistent with the reported morbidity data. Challenges to MMS case identification included lack of specification in reports to Coroners and inadequate codes. Improved specificity and coding are necessary to fully describe the extent of MMS-related injury. This study raises the issue of emerging largely unregulated consumer products. Further research is required to understand the uptake and use of MMS in the ageing population. Strategies are needed to decrease rider injuries whilst meeting community mobility needs. PMID- 26104871 TI - ROS-induced oxidative stress and apoptosis-like event directly affect the cell viability of cryopreserved embryogenic callus in Agapanthus praecox. AB - KEY MESSAGE: Oxidative stress and apoptosis-like programmed cell death, induced in part by H 2 O 2 , are two key factors that damage cells during plant cryopreservation. Their inhibition can improve cell viability. We hypothesized that oxidative stress and apoptosis-like event induced by ROS seriously impact plant cell viability during cryopreservation. This study documented changes in cell morphology and ultrastructure, and detected dynamic changes in ROS components (O 2 (.-) , H2O2 and OH.), antioxidant systems, and programmed cell death (PCD) events during embryonic callus cryopreservation of Agapanthus praecox. Plasmolysis, organelle ultrastructure changes, and increases in malondialdehyde (a membrane lipid peroxidation product) suggested that oxidative damage and PCD events occurred at several early cryopreservation steps. PCD events including autophagy, apoptosis-like, and necrosis also occurred at later stages of cryopreservation, and most were apoptosis. H2O2 is the most important ROS molecule mediating oxidative damage and affecting cell viability, and catalase and AsA-GSH cycle are involved in scavenging the intracellular H2O2 and protecting the cells against stress damage in the whole process. Gene expression studies verified changes of antioxidant system and PCD-related genes at the main steps of the cryopreservation process that correlated with improved cell viability. Reducing oxidative stress or inhibition of apoptosis-like event by deactivating proteases improved cryopreserved cell viability from 49.14 to 86.85 % and 89.91 %, respectively. These results verify our model of ROS-induced oxidative stress and apoptosis-like event in plant cryopreservation. This study provided a novel insight into cell stress response mechanisms in cryopreservation. PMID- 26104872 TI - Two novel alleles, HLA-B*46:01:11 and HLA-B*51:01:39 were identified in Chinese bone marrow donors. AB - HLA-B*46:01:11 has 219 G>A compared with HLA-B*46:01:01, and HLA-B*51:01:39 shows 561 G>A with HLA-B*51:01:01. PMID- 26104873 TI - Response to: spectral domain optical coherence tomography imaging of mucopolysaccharidoses I, II, IV A, and VI. PMID- 26104874 TI - Low concentrations of ethanol but not of dimethyl sulfoxide (DMSO) impair reciprocal retinal signal transduction. AB - BACKGROUND: The model of the isolated and superfused retina provides the opportunity to test drugs and toxins. Some chemicals have to be applied using low concentrations of organic solvents as carriers. Recently, E-/R-type (Cav2.3) and T-type (Cav3.2) voltage-gated Ca(2+) channels were identified as participating in reciprocal inhibitory retinal signaling. Their participation is apparent, when low concentrations of NiCl2 (15 MUM) are applied during superfusion leading to an increase of the ERG b-wave amplitude, which is explained by a reduction of amacrine GABA-release onto bipolar neurons. During these investigations, differences were observed for the solvent carrier used. METHODS: Recording of the transretinal receptor potentials from the isolated bovine retina. RESULTS: The pretreatment of bovine retina with 0.01 % (v/v) dimethylsulfoxide did not impair the NiCl2-mediated increase of the b-wave amplitude, which was 1.31-fold +/- 0.03 of initial value (n = 4). However, pretreatment of the retina with the same concentration of ethanol impaired reciprocal signaling (0.96-fold +/- 0.05, n = 4). Further, the implicit time of the b-wave was increased, suggesting that ethanol itself but not DMSO may antagonize GABA-receptors. CONCLUSION: Ethanol itself but not DMSO may block GABA receptors and cause an amplitude increase by itself, so that reciprocal signaling is impaired. PMID- 26104875 TI - Identification of novel Xanthomonas euvesicatoria type III effector proteins by a machine-learning approach. AB - The Gram-negative bacterium Xanthomonas euvesicatoria (Xcv) is the causal agent of bacterial spot disease in pepper and tomato. Xcv pathogenicity depends on a type III secretion (T3S) system that delivers effector proteins into host cells to suppress plant immunity and promote disease. The pool of known Xcv effectors includes approximately 30 proteins, most identified in the 85-10 strain by various experimental and computational techniques. To identify additional Xcv 85 10 effectors, we applied a genome-wide machine-learning approach, in which all open reading frames (ORFs) were scored according to their propensity to encode effectors. Scoring was based on a large set of features, including genomic organization, taxonomic dispersion, hypersensitive response and pathogenicity (hrp)-dependent expression, 5' regulatory sequences, amino acid composition bias and GC content. Thirty-six predicted effectors were tested for translocation into plant cells using the hypersensitive response (HR)-inducing domain of AvrBs2 as a reporter. Seven proteins (XopAU, XopAV, XopAW, XopAP, XopAX, XopAK and XopAD) harboured a functional translocation signal and their translocation relied on the HrpF translocon, indicating that they are bona fide T3S effectors. Remarkably, four belong to novel effector families. Inactivation of the xopAP gene reduced the severity of disease symptoms in infected plants. A decrease in cell death and chlorophyll content was observed in pepper leaves inoculated with the xopAP mutant when compared with the wild-type strain. However, populations of the xopAP mutant in infected leaves were similar in size to those of wild-type bacteria, suggesting that the reduction in virulence was not caused by impaired bacterial growth. PMID- 26104876 TI - Re-imaging malaria in the Philippines: how photovoice can help to re-imagine malaria. AB - BACKGROUND: This paper responds to a recent call for malaria to be re-imagined by: explaining why it needs to be re-imagined; offering one possible way in which this can be done; and describing some of benefits for malaria control when it is. METHODS: This study involved conducting a 15-week photovoice project with 44 predominantly ethnically Palawan school-going children in the municipality of Bataraza in the Philippines. The primary aim was to critically examine how facilitating children to take their own pictures of malaria could alter their understanding of it as well as the practices that they then engaged into prevent and treat it. RESULTS AND DISCUSSION: During the photovoice process, participants responded to the question, 'what does malaria mean to you?' by photographing multiple versions of malaria. Some of these versions align with biomedical conceptions and mirror common images of: its sources (e.g. mosquitoes); symptoms (e.g. fever); prevention practices (e.g. use of mosquito nets); diagnostic practices (e.g. use Rapid Diagnostic Tests) and treatment practices (e.g. use of anti-malarial drugs). However, in addition to these depictions, participants also took images of malaria that aligned with more local understanding of the body, health and well-being, which are often neglected by health practitioners. In the case of the Palawan, these versions of malaria are structured around the central tenet of balance. Participants therefore photographed themselves and members of their family and community engaging in a number of practices, which are orientated towards restoring and maintaining balance. As well being an effective means to illuminate multiple malarias and the practices that surround them, photovoice also enabled participants to learn new things and significantly, teach these things to others using their images. CONCLUSION: Photovoice is an effective method for re-imaging malaria. It allowed participants to depict and describe multiple versions of malaria and the practices that they engage in in context. Photovoice also had a potentially transformative effect. It acted as a means for participants and researchers to: visually depict everyday practices; collectively gain a deeper understanding of this doing; and then seek ways in which to make changes in line with this joint understanding. PMID- 26104877 TI - Chromium allergy and dermatitis: prevalence and main findings. AB - The history of chromium as an allergen goes back more than a century, and includes an interventional success with national legislation that led to significant changes in the epidemiology of chromium allergy in construction workers. The 2015 EU Leather Regulation once again put a focus on chromium allergy, emphasizing that the investigation of chromium allergy is still far from complete. Our review article on chromium focuses on the allergen's chemical properties, its potential exposure sources, and the allergen's interaction with the skin, and also provides an overview of the regulations, and analyses the epidemiological pattern between nations and across continents. We provide an update on the allergen from a dermatological point of view, and conclude that much still remains to be discovered about the allergen, and that continued surveillance of exposure sources and prevalence rates is necessary. PMID- 26104878 TI - Practical Guidance on the Use of Premix Insulin Analogs in Initiating, Intensifying, or Switching Insulin Regimens in Type 2 Diabetes. AB - INTRODUCTION: Premix insulin analogs are a well-established treatment for type 2 diabetes (T2D). However, there is a lack of simple, clear guidance on some aspects of their use. These include choosing a regimen for insulin initiation, recognizing when patients need intensification of therapy, and switching from basal-bolus to a premix insulin analog when appropriate. METHODS: An independent expert panel formulated recommendations on the use in T2D of the premix insulin analog formulations widely available in Australasia, based on the available evidence and their own experience. RESULTS: Results from trials in both initiation and intensification of insulin show that no single insulin or regimen is best on all endpoints, and that improved glycemic control can be expected regardless of which regimen is used. Thus, individual patient factors and preferences become more important. Guidance is presented to help the clinician choose between a premix insulin analog or basal analog for insulin initiation, and to intensify insulin therapy using premix insulin analogs. Recommendations are made on dosing, titration, the concomitant use of non-insulin glucose lowering drugs, and other practical issues, and on the special case of switching from basal-bolus to premix insulin analog therapy. CONCLUSION: This guidance is intended to help both general and specialist practitioners make informed choices and provide optimal care for patients with T2D. It emphasizes the importance of taking into account individual patient factors and preferences so that the choice of insulin regimen is individualized to the patient in the same way that glycemic targets are now individualized. FUNDING: Novo Nordisk Region IO A/S. PMID- 26104879 TI - [Familial hypertriglyceridemia: biochemical, clinical and molecular study in a Moroccan family]. AB - Familial hypertriglyceridemia is a rare autosomal recessive inborn error of metabolism. Mutation within the LPL gene constitutes the first cause of monogenic etiology. Lipoprotein lipase (LPL) is the key enzyme in triglyceride-rich lipoproteins catabolism. Familial LPL deficiency is expressed by eruptive xanthomatosis and acute pancreatitis. We report a Moroccan case with a monstrous hypertriglyceridemia caused by LPL gene mutation. We discuss pathophysiology aspects according to available investigations data and the relevance of familial screening. The proband is a 19-year-old woman originating from the village of Taourirt (South of Morocco). She was admitted in emergency for diabetic ketoacidosis. Clinical investigations and routine laboratory tests were performed upon admission. Then lipoprotein electrophoresis and sequencing of the LPL gene were practiced. A monstrous hypertriglyceridemia up to 199 mmol/L was found. Lipoprotein electrophoresis has objectified profound disturbances on chylomicrons, VLDL and IDL. The sequencing detected a missense mutation p.S286R at homozygous state in a consanguinity context. Discovery of this LPL gene mutation is the first indigenous and documented case, never related in any other ethnic group. It constitutes a novel proof of a founder effect in the south Moroccan population. Prevalence studies with familial screening should be done for preventative action which is the only acceptable way to limit the cardiovascular and pancreatitis risks in this population where inbreeding is a general rule. PMID- 26104882 TI - Physicochemical stability profile of Tulane virus: a human norovirus surrogate. AB - AIMS: Human norovirus (HuNoV) is estimated to cause 19-21 million illnesses each year in the US. A major limitation in HuNoV research is the lack of an in vitro culture system; therefore, surrogate viruses including murine norovirus (MNV) and feline calicivirus (FCV) are used to study HuNoV. Here, we aim to establish the physiochemical properties of Tulane virus (TV)-a newer HuNoV surrogate. METHODS AND RESULTS: For thermal inactivation, TV was exposed to 37 degrees C for 2 h, and 56, 63 and 72 degrees C for 30 min. For ethanol tolerance, TV was treated with 60, 70 and 90% ethanol at room temperature (RT) for 5 min. Tulane virus pH stability at pH 2, 3, 7, 9 and 10 was performed at RT for 90 min. At 37 degrees C, there was no significant reduction in TV after 2 h. However, at 56, 63 and 72 degrees C, D-values of 4.03, 1.18, and 0.24 min, were calculated respectively. The D-values obtained for TV ethanol tolerance were 1.46, 1.93, and 0.35 min at 60, 70 and 90% respectively. Less than 1 log10 plaque forming units (PFU) reduction was observed for TV at all pH levels except pH 10 where about a 2-log10 PFU reduction was observed. Tulane virus was also tolerant to chlorine disinfection on a solid surface with D-values of 15.82 and 5.42 min at 200 and 1000 ppm respectively. CONCLUSIONS: Tulane virus is likely a suitable surrogate to study HuNoV thermal stability as well as ethanol tolerance below 90%. Tulane virus also is a promising surrogate to study HuNoV pH stability and chlorine tolerance. SIGNIFICANCE AND IMPACT OF THE STUDY: Based on current work, in vitro studies demonstrate that TV is an overall more conservative and suitable surrogate for the study of HuNoV physicochemical properties. PMID- 26104881 TI - Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise. AB - Critical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued. Peripheral fatigue appears to be constant across O2 delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise. We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development and W '. Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O2 delivery conditions for small muscle mass exercise. W ' appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe-intensity exercise. The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ') have not been investigated. Six men (age: 25 +/- 4 years, body mass: 82 +/- 10 kg, height: 179 +/- 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post-exercise blood flow occlusion (Con + Occ), and Occ with 5 min post-exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements and W ' were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 +/- 5.1% vs. 22.7 +/- 6.0%) and central (42.6 +/- 3.9% vs. 4.9 +/- 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 +/- 4.2% vs. 69.0 +/- 6.2%) and central (65.5 +/- 14.6% vs. 18.6 +/- 4.1%) fatigue occurred for Occ + Occ than for Con + Occ. W ' was significantly related to the magnitude of global (r = 0.91) and peripheral (r = 0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest that W ' may be determined by the magnitude of fatigue accrued during exercise. PMID- 26104883 TI - Fetal outcome of trisomy 18 diagnosed after 22 weeks of gestation: Experience of 123 cases at a single perinatal center. AB - To investigate the pregnancy outcome of the fetuses with trisomy 18, we studied 123 cases of trisomy 18 who were born at our hospital from 1993 to 2009. Among them, 95.9% were diagnosed with trisomy 18 prenatally. Prenatal ultrasound findings showed fetal growth restriction in 77.2%, polyhydramnios in 63.4% and congenital heart defects in 95.1%. For 18 cases, cesarean section (C-section) was chosen, and for 75 cases, transvaginal delivery was chosen. Premature delivery occurred in 35.5%. Stillbirths occurred in 50 cases (40.7%). Fetal demise before onset of labor occurred in 30 cases and fetal demise during labor occurred in 20 cases which was 26.7% of vaginal deliveries. Among the 73 live-born infants, the survival rate for 24 h, 1 week, 1 month and 1 year were 63%, 43%, 33% and 3%. The median survival time was 3.5 days. There was no significant difference between the survival time of C-section and that of vaginal delivery. However, for the births involving breech presentation, the survival time of C-section was significantly longer than that of vaginal delivery. When the fetus is diagnosed with trisomy 18, the parents have to make many choices. These findings constitute critical information in prenatal counseling to the couples whose fetuses have been found to have trisomy 18, especially when they choose palliative approaches in the perinatal management. PMID- 26104880 TI - Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. AB - There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 * 10( 23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis. PMID- 26104884 TI - [Stereotactic Ablative Radiotherapy versus Lobectomy for Operable Stage I Non small -cell Lung Cancer: A Pooled Analysis of Two Randomized Trials ?- Interpretation of Thoracic Surgeons]. PMID- 26104885 TI - [Treatment for Stage I Non-small Cell Lung Cancer: ?Stereotactic Ablative Radiotherapy or Surgery?]. PMID- 26104886 TI - [Stereotactic Ablative Aadiotherapy?--A Better Choice for Operable Stage I Non small Cell Lung Cancer?]. PMID- 26104887 TI - [Early Stage Non-small Cell Lung Cancer: Surgery or Stereotactic Ablative Radiotherapy?]. PMID- 26104888 TI - [Methodology of Establishing and Identifying NCI-H2228/Crizotinib-resistant Cell Lines In Vitro]. AB - BACKGROUND AND OBJECTIVE: The mechanisms of small molecule targeting drug resistance and ways to overcome resistance are now both urgent need to improve the clinical efficacy. This study aimed to investigate the feasibility of using different methods to establish the crizotinib-resistant non-small cell lung cancer NCI-H2228/Crizotinib cell lines and to clarify the mechanisms of resistance to small molecule targeting drug, thus providing experimental and theoretical bases for further studies to overcome the mechanisms of Crizotinib resistance. METHODS: The study utilized stepwise increase of drug concentrations and chemical mutagen to induce Crizotinib-resistant NCI-H2228 cells. The drug 50% inhibitory concentration (IC50) values of parental and resistant cells and the population doubling time were determined by MTT assay. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) expression was evaluated by RT-PCR and Western blot. Full-length sequencing method was used to compare the EML4-ALK genes in the parent and drug-resistant cells and analyze the mechanisms of drug resistance. RESULTS: The method of gradually increasing drug concentration to induce Crizotinib-resistant NCI-H2228 cells was time-consuming because the cell growth recovery was extremely slow. Thus, this method was considered invalid. However, chemical mutagen ENU can effectively induce NCI H2228 cells resistant to crizotinib in a short time [IC50]= (3.810+/-1.100) MUmol/L, P=0.002,9 vs parental cells]. Furthermore, the gene mutation frequency of EML4-ALK in the resistant cells was significantly higher than that in the parent cells. CONCLUSIONS: Chemical mutagen-induced cell resistance was easily operated and had effectively shortened the experimental process. Preliminary technical methods and experimental evidence for in-depth study of drug resistance mechanisms and approaches to overcome the targeted drug resistance were also provided.?. PMID- 26104889 TI - [Screening of Highly Expressed CPEDeltaN Lung Cancer H1299 Cells]. AB - BACKGROUND AND OBJECTIVE: The N-terminal truncated carboxypeptidase E (CPEDeltaN) protein is a novel biomarker of tumor metastasis. This study screened the H1299 cell line with a highly expressed CPEDeltaN gene for in vivo imaging experiment. METHODS: Human CPEDeltaN gene was cloned into the luciferase lentiviral vector. H1299 cells transduced with CPEDeltaN or control lentiviral vectors were selected with 2 ug/mL puromycin. The expression of CPEDeltaN was identified through Western blot analysis, and luciferase activity was measured using luciferase reporters. RESULTS: The human CPEDeltaN lentiviral expression vector was successfully constructed. The transfection rate of H1299 cells by the lentivirus achieved 80%, with an infection multiplicity of 20. The H1299 cell line with high CPEDeltaN (H1299-CPEDeltaN) expression was established, with an increase in CPEDeltaN expression by four times compared with the control lentivirus transfected H1299 cell line (H1299-control). As H1299-CPEDeltaN and H1299-control can effectively decompose luciferase substrates, they can be applied in in vivo imaging. CONCLUSIONS: H1299-CPEDeltaN and H1299-control can be used in in vivo imaging experiment for further research on molecular mechanisms and signal transduction to elucidate the role of CPEDeltaN in lung cancer metastasis. PMID- 26104890 TI - PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer. AB - BACKGROUND: Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage. METHODS: We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of gamma-tubulin and pericentrin by IHC. RESULTS: The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and gamma-tubulin in Cul4A mouse lungs induced by AdenoCre. CONCLUSIONS: PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model. PMID- 26104891 TI - [Combined Chemotherapy with Vinorelbine and Ifosfamide as Third-line Treatment and Beyond of Advanced Non-small Cell Lung Cancer]. AB - BACKGROUND: Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) should be treated with first-line and second-line chemotherapy or target therapy according to the lung cancer guidelines. However, no recommended treatments are available after failure to these treatments. In our study, the efficacy and safety of combined chemotherapy of vinorelbine and ifosfamide as third-line therapy or beyond for advanced NSCLC was evaluated. METHODS: A total of 41 patients took a combination of vinorelbine and ifosfamide as third-line or above chemotherapy in Peking Union Hospital between May 2010 and May 2014. They were pathologically or cytologically confirmed as having locally advanced or metastatic NSCLC. Clinically measurable lesions existed, and Eastern Cooperative Oncology Group performance status ranged from 0 to 2. No serious complications were observed in the hematopoietic system, and liver and renal functions were normal. RESULTS: The 41 patients enrolled in this study were given 150 cycles of chemotherapy, of which 23 cycles (15.3%) were delayed or dose-adjusted. Results of the objective response evaluation showed that 3 cases had objective partial response (7.3%) and 25 cases were stable (61.0%). The median progression-free survival time was 5.5 months, and the median overall survival time was 10.5 months. Hematological toxicity was the most frequent adverse event. Grade 3/4 neutropenia had 10.7% occurrence; grade 3/4 white blood cell decrease had 8.7%; and grade 3/4 anemia had 8.7%. All adverse events were manageable, and no drug related death was found. CONCLUSIONS: Vinorelbine and ifosfamide as third-line treatment and beyond of NSCLC were well tolerated. Most patients can benefit from this combined chemotherapy. A clinical trial with large samples is necessary to prove whether overall survival will . PMID- 26104892 TI - [Variations in Serum CEA and CYFRA21-1 Levels Before and After Surgery Facilitate Prognosis of Non-small Cell Lung Cancer Patients]. AB - BACKGROUND AND OBJECTIVE: Serum carcinoembryonic antigen (CEA) and the soluble fragment of cytokeratin 19 (CYFRA21-1) are important tumor markers (TMs) in the preoperative examination of patients with non-small cell lung cancer (NSCLC). However, the prognostic role of these markers in NSCLC patients remains controversial. The aim of the study was to investigate the clinical significance of serum CEA variances and CYFRA21-1 levels for the prognosis of NSCLC patients following surgery. METHODS: This retrospective study investigated the clinical records and follow-up sessions of 175 patients with NSCLC who accepted surgery and adjuvant chemotherapy. Patients were subdivided into groups based on serum CEA and CYFRA21-1 levels. Survival analysis was conducted using Kaplan-Meier method for each group. The prognostic factor was evaluated using Cox proportional hazards model. RESULTS: The overall survival (OS) of patients with high preoperative CEA or CYFRA21-1 levels was lower than that of patients with normal preoperative CEA or CYFRA21-1 levels. The OS displayed a significant difference (P=0.001) between groups with high and normal preoperative CYFRA21-1. Compared with groups exhibiting normal preoperative and postoperative levels of CEA or CYFRA21-1, the OS was shorter for groups with high preoperative and postoperative levels of CEA or CYFRA21-1. The difference of the paired groups was significant (P<0.05). Compared with the groups with normal preoperative and postoperative levels of CEA and CYFRA21-1, the OS was lower for the groups with high preoperative and postoperative levels of CEA and CYFRA21-1, which indicated a significant difference (P<0.001). The CEACYFRA211 (HHHH), CEACYFRA211 (NNHH), CYFRA21-1 (HH), CEA (HH), and male gender were identified as independent prognostic factors (P<0.05). CONCLUSIONS: This study suggested that the prognosis of NSCLC patients was not significantly satisfactory if preoperative and postoperative level of serum CEA or CYFRA21-1 was higher than standard value, especially if the preoperative and postoperative levels of CYFRA21-1 and CEA were higher than the standard values. The measurement of preoperative and postoperative levels of CYFRA21-1 and CEA proved helpful for the prognosis of patients with NSCLC.?. PMID- 26104893 TI - [Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin ?in Patients with IIIa Lung Adenocarcinoma]. AB - BACKGROUND AND OBJECTIVE: Bevacizumab has showed its efficacy in advanced non squamous lung cancer. The aim of this study is to assess the safety of bevacizumab plus pemetrexed and carboplatin neoadjuvant chemotherapy in patients with lung adenocarcinoma. METHODS: 25 patients with IIIa lung adenocarcinoma undergoing lobectemy or pneumonectomy with mediastinal lymphadenectomy after induction bevacizumab (Bev) plus pemetrexed/carboplatin (PC) were selected. Toxicity of chemotherapy and postoperative complications were analyzed. RESULTS: Grade 3 or 4 neoadjuvant-related adverse events included fatigue (3 patients), neutropenia (3 patients), hypertension (1 patient). The adverse events thought to be related to bevacizumab included epistaxis in 2 patients (grade 1: 1; grade 2: 1) and hypertension in 3 patients (grade 1: 2; grade 3: 1). Postoperative complications included pneumonia in 2 patients, bronchial stump insufficiency in 1 case, atelectasis in 2 cases, and arrhythmia in 1 case. Hemorrhage events, thromboembolic events and wound-healing problems were not observed in the perioperative period. CONCLUSIONS: The treatment modality of neoadjuvant Bev-PC appears to be safe and tolerant in patients with stage IIIa lung adenocarcinoma. PMID- 26104894 TI - [Comparison of the Efficacy and Safety of Icotinib with Standard Second-line ?Chemotherapy in Previously Treated Advanced Non-small Cell Lung Cancer]. AB - BACKGROUND AND OBJECTIVE: This study compared the efficacy and safety of icotinib with standard second-line chemotherapy (single-agent docetaxel or pemetrexed) in previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Thirty two consecutive patients treated with icotinib and 33 consecutive patients treated with standard second-line chemotherapy in Xuanwu Hospital from January 2012 to July 2013 were enrolled in our retrospective research. The Response Evaluation Criteria in Solid Tumors were used to evaluate the tumor responses, and the progression-free survival (PFS) was evaluated by Kaplan-Meier method. RESULTS: Icotinib was comparable with standard second-line chemotherapy for advanced NSCLC in terms of overall response rate (ORR) (28.1% vs 18.2%, P=0.341), disease control rate (DFS)(43.8% vs 45.5%, P=0.890), and PFS (4.3 months vs 3.8 months, P=0.506). In the icotinib group, the ORR of epidermal growth factor receptor (EGFR) mutant was significantly higher than that of EGFR unknown or wild type (P=0.017). In multivariate analysis, age, gender, histology, and the optimum first-line treatment response were dependent prognostic factors based on the PFS of the icotinib group. The incidence of adverse events was significantly fewer in the icotinib group than in the chemotherapy group (P=0.001). CONCLUSIONS: Compared with the standard second-line chemotherapy, icotinib is active in the treatment of advanced NSCLC patients, especially with EGFR unknown in the second line, with an acceptable adverse event profile. PMID- 26104895 TI - [Progress of Postoperative Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer]. AB - The morbidity and mortality of lung cancer rank the first place among all the malignant tumor. According to the histopathological characteristics, lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer. Only 20% patients diagnosed with NSCLC have the chance for surgery while their 5 yr overall survival is about 30%-60%. The therapeutic outcome of surgery alone is not satisfying. Adjuvant chemotherapy after surgical resection in stage II-IIIa lung cancer showed efficacy in many randomized clinical trials, but its role in stage I disease remains controversial. The choice of appropriate chemotherapy candidates, the selection of chemotherapy regimens and the research progress on biomarker are mainly discussed in this review. PMID- 26104896 TI - [Role of RRM1 in the Treatment and Prognosis of Advanced Non-small Cell Lung Cancer]. AB - Lung cancer is one of the most common and highest mortality rates malignant tumors, further, 75%-80% is non-small cell lung cancer (NSCLC). For the majority of patients, lost the chance of radical operation or radiotherapy, chemotherapy is the main treatment. However, because of the diversities of tumor behavior and drug-resistant, the chemotherapy of advanced NSCLC is not optimistic. In recent years, with the application of molecular markers for individual chemotherapy, these patients have achieved prolong life and improved life quality. Individualized chemotherapy based on molecular markers to select the appropriate drug is the problem that needs to be solved. The paper gives a brief review on the role of ribonucleotide reductase subunit 1 (RRM1) in the treatment and prognosis of advanced NSCLC. Individualized chemotherapy by RRM1 can't become commonplace for advanced NSCLC and needs further research. PMID- 26104897 TI - [Progress in Tissue Specimens Alternative for the Driver Genes Testing of Non small Cell Lung Cancer]. AB - Target treatment based on driver genes in advanced non-small cell lung cancer is very important currently. Tumor tissues is the gold standard for driver genes testing. However, most of patients could not get the gene information for lack of enough tissues. To explore the tissue specimens alternatives is a hot spot in clinical work. This report reviews the tissue specimen alternatives of driver gene testing in non-small cell lung cancer. PMID- 26104898 TI - [Research Progress of Biomakers Proteomics-based in Lung Cancer]. AB - Proteomic technologies can be applied to cancer research to detect differential protein expression that could find cancer biomakers. Lung cancer biomarker discovery is significant due to its anticipated critical role in early diagnosis, therapy guidance, and prognosis monitoring of lung cancer. Therefore, there is an indeed need to identify new biomarkers for early diagnosis and prognosis that could serve to open novel therapeutic means. This article briefly introduces the latest reports in proteomic studies of lung cancer. It contains diagnostic, prognostic, and predictive biomarkers, and a summary based on the most recent literature and our own work. PMID- 26104899 TI - Removal, redistribution, and potential risks of soil Cd, Pb, and Zn after washing with various extractants. AB - The effectiveness of four different washing extractants--HCl, FeCl3, citric acid, and EDTA--in removing Cd, Pb, and Zn from polluted soil was studied. The removal of these metals, their redistribution between fractions, and the potential risks posed by them, in soils washed with the tested extractants, were examined. Although all the rounds of washing removed Cd, Pb, and Zn from soil, the first round removed more metals than subsequent rounds. Each of the four extractants had different effects on the removal of the metals. At the end of the first round of washing, HCl, EDTA, and FeCl3 were the most effective in removing Zn, Pb, and Cd, respectively. Both the single round and five successive rounds of washing with various extractants resulted in significant increases in Pb in the exchangeable/acid extractable fraction. Washing with HCl, EDTA, and FeCl3 significantly reduced potential risks (calculated as the Potential Risk Index, PRI) posed by Cd in washed soil. The first round of washing, using all extractants, increased the risks posed by Pb and Zn. However, five successive rounds of washing with FeCl3 and EDTA reduced the risk posed by Pb, and washing with citric acid and FeCl3 increased the risks posed by Zn. EDTA and HCl were better for reducing Zn risks, and successive washing with EDTA and FeCl3 were more effective in reducing Pb risks than the other extractants. Finally, five successive rounds of washing, with all the extractants, effectively reduced the potential risks posed by Cd. Among the four reagents, EDTA was advised to be the alternative of the washing reagent by significantly reducing the PRI values of Cd, Pb, and Zn. PMID- 26104900 TI - Exogenous NO depletes Cd-induced toxicity by eliminating oxidative damage, re establishing ATPase activity, and maintaining stress-related hormone equilibrium in white clover plants. AB - Various nitric oxide (NO) regulators [including the NO donor sodium nitroprusside (SNP), the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (cPTIO), the NO-synthase inhibitor N (G)-nitro-L-Arg-methyl ester (L NAME), and the SNP analogues sodium nitrite/nitrate and sodium ferrocyanide] were investigated to elucidate the role of NO in white clover (Trifolium repens L.) plants after long-term (5 days) exposure to cadmium (Cd). A dose of 100 MUM Cd stress significantly restrained plant growth and decreased the concentrations of chlorophyll and NO in vivo, whereas it disrupted the balance of stress-related hormones and enhanced the accumulation of Cd, thereby inducing reactive oxygen species (ROS) burst. However, the inhibition of plant growth was relieved by 50 MUM SNP through its stimulation of ROS-scavenging compounds (ascorbic acid, ascorbate peroxidase, catalase, glutathione reductase, non-protein thiol, superoxide dismutase, and total glutathione), regulation of H(+)-ATPase activity of proton pumps, and increasing jasmonic acid and proline but decreasing ethylene in plant tissues. Even so, the alleviating effect of SNP on plant growth was counteracted by cPTIO and L-NAME and was not observed with SNP analogues, suggesting that the protective roles of SNP are related to the induction of NO. These results suggest that NO may improve the Cd tolerance of white clover plants by eliminating oxidative damage, re-establishing ATPase activity, and maintaining hormone equilibrium. Improving our understanding of the role of NO in white clover plants is key to expanding the plantations to various regions and the recovery of pasture species in the future. PMID- 26104901 TI - Removal of sulfadimethoxine in soil mediated by extracellular oxidoreductases. AB - Sulfadimethoxine (SDM) is an antibiotic commonly used in concentrated animal feeding operations and released into the environment via manure application on agricultural lands. Transformation of antibiotics in soil impacts the likelihood of their entry to water bodies, uptake by plants, and thus their effect on terrestrial and aquatic organisms. We conducted experiments to incubate SDM in a sandy loam soil in the presence of humification enzymes commonly found in natural soil, laccase, horseradish peroxidase, and lignin peroxidase. Incubation with the enzymes led to significant reduction in the fraction of SDM extractable from soil, indicating the formation of bound residues. Such transformation was enhanced when the organic matter content in soil is increased or when certain chemical mediators were used along with laccase. The study provided a basis for understanding the environmental fate of sulfonamides and help with the development of remediation methods to mitigate the release of sulfonamides from soil to water. PMID- 26104902 TI - Ultra-high performance liquid chromatography-electrospray tandem mass spectrometry for the analysis of antibiotic residues in environmental waters. AB - An optimized solid-phase extraction (SPE) and ultra-high performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-MS/MS) method was developed for the effective analysis of 35 antibiotics including sulfonamides (SAs), quinolones (QLs), tetracyclines (TCs), macrolides (MALs), lincomycin (LIN), and chloramphenicol (CAP). The addition of 0.1% formic acid to the mobile phase was favorable for the formation of [M + H](+) and the enhancement in the detection signals, but using ammonium formate decreased [M + H](+) with a corresponding reduction in the response of CAP. The optimal pH range for the SPE was 4.5 ~ 5.0 with 6 mL aqueous ammonia/methanol (5/95, v/v) as the optimized eluent. An internal standard (IS) was selected for each type of analytes based on similarities in classification and retention time. The detection was completed in less than 10 min and was excellent with method detection limits (MDL) of 0.29 ~ 4.03 ng/L. The recoveries of the antibiotics in samples from ultrapure water and groundwater were 67.13 ~ 93.00% and 68.91 ~ 92.67%, respectively. The antibiotics in samples collected from wastewater, surface water, and groundwater were also effectively detected. This newly developed method has the advantages of short detection times, small sample consumption, excellent reproducibility, and high sensitivity. This provides a reliable and promising technique for the simultaneous detection and monitoring of various residual antibiotics in aqueous environmental samples. PMID- 26104903 TI - The dendroanalysis of oak trees as a method of biomonitoring past and recent contamination in an area influenced by uranium mining. AB - We reconstructed the contamination history of an area influenced by 40 years of uranium mining and subsequent remediation actions using dendroanalysis (i.e., the determination of the elemental content of tree rings). The uranium content in the tree rings of four individual oak trees (Quercus sp.) was determined by laser ablation with inductively coupled plasma mass spectrometry (LA-ICP-MS). This technique allows the investigation of trace metals in solid samples with a spatial resolution of 250 MUm and a detection limit below 0.01 MUg/g for uranium. The investigations show that in three of the four oaks sampled, there were temporally similar uranium concentrations. These were approximately 2 orders of magnitude higher (0.15 to 0.4 MUg/g) than those from before the period of active mining (concentrations below 0.01 MUg/g). After the mining was terminated and the area was restored, the uranium contents in the wood decreased by approximately 1 order of magnitude. The similar radial uranium distribution patterns of the three trees were confirmed by correlation analysis. In combination with the results of soil analyses, it was determined that there was a heterogeneous contamination in the forest investigated. This could be confirmed by pre-remediation soil uranium contents from literature. The uranium contents in the tree rings of the oaks investigated reflect the contamination history of the study area. This study demonstrates that the dendrochemical analysis of oak tree rings is a suitable technique for investigating past and recent uranium contamination in mining areas. PMID- 26104904 TI - Permeable reactive barrier of coarse sand-supported zero valent iron for the removal of 2,4-dichlorophenol in groundwater. AB - In this study, coarse sand-supported zero valent iron (ZVI) composite was synthesized by adding sodium alginate to immobilize. Composite was detected by scanning electron microscope (SEM), X-ray diffraction (XRD), and X-ray fluorescence (XRF). SEM results showed that composite had core-shell structure and a wide porous distribution pattern. The synthesized composite was used for degradation of 2,4-dichlorophenol (2,4-DCP) contamination in groundwater. Experimental results demonstrated that degradation mechanism of 2,4-DCP using coarse sand-supported ZVI included adsorption, desorption, and dechlorination. 2,4-DCP adsorption was described as pseudo-second-order kinetic model. It was concluded that dechlorination was the key reaction pathway, ZVI and hydrogen are prime reductants in dechlorination of 2,4-DCP using ZVI. PMID- 26104905 TI - Photocatalytic degradation of humic substances in aqueous solution using Cu-doped ZnO nanoparticles under natural sunlight irradiation. AB - In this study, Cu-doped ZnO nanoparticles were investigated as an efficient synthesized catalyst for photodegradation of humic substances in aqueous solution under natural sunlight irradiation. Cu-doped ZnO nanocatalyst was prepared through mild hydrothermal method and was characterized using FT-IR, powder XRD and SEM techniques. The effect of operating parameters such as doping ratio, initial pH, catalyst dosage, initial concentrations of humic substances and sunlight illuminance were studied on humic substances degradation efficiency. The results of characterization analyses of samples confirmed the proper synthesis of Cu-doped ZnO nanocatalyst. The experimental results indicated the highest degradation efficiency of HS (99.2%) observed using 1.5% Cu-doped ZnO nanoparticles at reaction time of 120 min. Photocatalytic degradation efficiency of HS in a neutral and acidic pH was much higher than that at alkaline pH. Photocatalytic degradation of HS was enhanced with increasing the catalyst dosage and sunlight illuminance, while increasing the initial HS concentration led to decrease in the degradation efficiency of HS. Conclusively, Cu-doped ZnO nanoparticles can be used as a promising and efficient catalyst for degradation of HS under natural sunlight irradiation. PMID- 26104906 TI - Differentiation syndrome in acute myeloid leukemia after treatment with azacitidine. AB - We report a case report of hyperleukocytosis, fever, hypotension, pulmonary and pericardial effusions, and acute kidney injury during initial treatment with azacitidine in a patient with AML-MRC. Collectively, the symptomatology resembled differentiation syndrome. Azacitidine has been previously associated with fever, peripheral edema, and hyperleukocytosis, but its side effect profile has never been described as similar to differentiation syndrome. The patient's deteriorating course quickly turned around after treatment with dexamethasone. This potential reaction, and potential treatment, is important for clinicians to be aware of. PMID- 26104908 TI - Persistent Disparities in Adult Hematopoietic Cell Transplantation. AB - The use of large databases has provided advancements in the understanding of racial, ethnic, and socioeconomic disparities in the field of adult hematopoietic cell transplants (HCT). Disparities exist on individual, institutional, and systemic levels for both allogeneic and autologous HCT. We reviewed the most recent publications that utilized large databases to elucidate disparities in HCT and placed them into historical context of the other major studies in the field. Two emerging themes were identified. These themes are persistent inequalities in both allogeneic HCT and autologous HCT for myeloma and the importance of improving homogeneity of care in HCT. Minimization of inequalities can be achieved only with an understanding of the persistent barriers that exist in the field. PMID- 26104907 TI - To Each Its Own: Linking the Biology and Epidemiology of NHL Subtypes. AB - Non-Hodgkin lymphoma (NHL) constitutes a diverse group of more than 40 subtypes, each characterized by distinct biologic and clinical features. Until recently, pinpointing genetic and epidemiologic risk factors for individual subtypes has been limited by the relative rarity of each. However, several large pooled case control studies have provided sufficient statistical power for detecting etiologic differences and commonalities between subtypes and thus yield new insight into their unique epidemiologic backgrounds. Here, we review the subtype specific medical, lifestyle, and biologic components identified in these studies, which suggest that a complex interplay between host genetics, autoimmune disorders, modifiable risk factors, and occupation contributes to lymphomagenesis. PMID- 26104909 TI - Cluster-Randomized Trial to Increase Hepatitis B Testing among Koreans in Los Angeles. AB - BACKGROUND: In the United States, Korean immigrants experience a disproportionately high burden of chronic hepatitis B (HBV) viral infection and associated liver cancer compared with the general population. However, despite clear clinical guidelines, HBV serologic testing among Koreans remains persistently suboptimal. METHODS: We conducted a cluster-randomized trial to evaluate a church-based small group intervention to improve HBV testing among Koreans in Los Angeles. Fifty-two Korean churches, stratified by size (small, medium, large) and location (Koreatown versus other), were randomized to intervention or control conditions. Intervention church participants attended a single-session small-group discussion on liver cancer and HBV testing, and control church participants attended a similar session on physical activity and nutrition. Outcome data consisted of self-reported HBV testing obtained via 6 month telephone follow-up interviews. RESULTS: We recruited 1,123 individuals, 18 to 64 years of age, across the 52 churches. Ninety-two percent of the sample attended the assigned intervention session and 86% completed the 6-month follow up. Sample characteristics included were as follows: mean age 46 years, 65% female, 97% born in Korea, 69% completed some college, and 43% insured. In an intent-to-treat analysis, the intervention produced a statistically significant effect (OR = 4.9, P < 0.001), with 19% of intervention and 6% of control group participants reporting a HBV test. CONCLUSION: Our intervention was successful in achieving a large and robust effect in a population at high risk of HBV infection and sequelae. IMPACT: The intervention was fairly resource efficient and thus has high potential for replication in other high-risk Asian groups. PMID- 26104910 TI - Estrogen Metabolites Are Not Associated with Colorectal Cancer Risk in Postmenopausal Women. AB - BACKGROUND: A potential protective role for estrogen in colon carcinogenesis has been suggested based on exogenous hormone use, but it is unclear from previous studies whether endogenous estrogens are related to colorectal cancer risk. These few prior studies focused on parent estrogens; none evaluated effects of estrogen metabolism in postmenopausal women. METHODS: We followed 15,595 women (ages 55-80 years) enrolled in the Breast and Bone Follow-up to the Fracture Intervention Trial (B~FIT) who donated blood between 1992 and 1993 for cancer through December 2004. A panel of 15 estrogen metabolites (EM), including estradiol and estrone, were measured in serum from 187 colorectal cancer cases and a subcohort of 501 women not using exogenous hormones at blood draw. We examined EM individually, grouped by pathway (hydroxylation at the C-2, C-4, or C-16 position) and by ratios of the groupings using Cox proportional hazards regression models. RESULTS: No significant associations were seen for estrone (HRQ4 vs. Q1 = 1.15; 95% CI, 0.69-1.93; Ptrend = 0.54), estradiol (HRQ4 vs. Q1 = 0.98; 95% CI, 0.58 1.64; Ptrend > 0.99), or total EM (the sum of all EM; HRQ4 vs. Q1 = 1.35; 95% CI, 0.81-2.24; Ptrend = 0.33). Most metabolites in the 2-, 4-, or 16-pathway were unrelated to risk, although a borderline trend in risk was associated with high levels of 17-epiestriol. CONCLUSION: Circulating estrogens and their metabolites were generally unrelated to colorectal cancer risk in postmenopausal women. IMPACT: Additional studies are needed to understand how exogenous estrogen may prevent colorectal cancer. PMID- 26104911 TI - [Glottis injection to improve voice function : Review of more than 500 operations]. AB - BACKGROUND: Hoarseness due to insufficient glottal closure can be treated by injection laryngoplasty (augmentation). Vocal fold injections can be performed as an in-office procedure or under general anesthesia. As injection materials have recently improved and different injection approaches are available, injection laryngoplasties are performed much more frequently. OBJECTIVES: Advantages and disadvantages of injection materials, laryngeal approaches, and differential indications are described. MATERIALS AND METHODS: Literature research and experience of more than 500 laryngeal injection procedures are provided. RESULTS AND CONCLUSIONS: Sophisticated use of available injection materials can provide a satisfying improvement of voice function with minimal patient discomfort. Adequate indication is mandatory for a favorable outcome. Further improvement regarding biocompatibility and the duration of injection materials is desirable. PMID- 26104912 TI - Cu(I) stabilizing crosslinked polyethyleneimine. AB - Polyethyleneimine (PEI) is known for its metal-coordinating properties and in its crosslinked form has applications in different areas ranging from drug delivery to waste water treatment and recovery of trace metals. With the aim to regulate the coordination environment of Cu(I) and Cu(II) ions in marine coatings, we have prepared a triazole cross-linking agent with 'soft' coordination that can crosslink PEI via indirect reductive amination. We have shown that this triazole crosslinker not only increases the Cu(II) absorption capacity of the crosslinked PEI in comparison to the traditionally used glutaraldehyde-crosslinked PEI (PEI GA), but also allows the crosslinked polymer network to stabilize the Cu(I) oxidation state more effectively. The Cu(II) uptake and Cu(I) stabilization of the polymer have been determined by elemental analysis and UV-vis spectroscopy. It was found that the triazole-crosslinked polymer (PEI-TA) could coordinate up to 12 wt% of Cu(II) before and 6 wt% Cu(II) after imine reduction. PMID- 26104913 TI - Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. AB - Elevated inflammatory cytokines (EMCs) at mucosal surfaces have been associated with HIV susceptibility, but the underlying mechanisms remain unclear. We characterized the soluble mucosal proteome associated with elevated cytokine expression in the female reproductive tract. A scoring system was devised based on the elevation (upper quartile) of at least three of seven inflammatory cytokines in cervicovaginal lavage. Using this score, HIV-uninfected Kenyan women were classified as either having EMC (n=28) or not (n=68). Of 455 proteins quantified in proteomic analyses, 53 were associated with EMC (5% false discovery rate threshold). EMCs were associated with proteases, cell motility, and actin cytoskeletal pathways, whereas protease inhibitor, epidermal cell differentiation, and cornified envelope pathways were decreased. Multivariate analysis identified an optimal signature of 16 proteins that distinguished the EMC group with 88% accuracy. Three proteins in this signature were neutrophil associated proteases that correlated with many cytokines, especially GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-1beta (interleukin-1beta), MIP-3alpha (macrophage inflammatory protein-3alpha), IL-17, and IL-8. Gene set enrichment analyses implicated activated immune cells; we verified experimentally that EMC women had an increased frequency of endocervical CD4(+) T cells. These data reveal strong linkages between mucosal cytokines, barrier function, proteases, and immune cell movement, and propose these as potential mechanisms that increase risk of HIV acquisition. PMID- 26104914 TI - Antigen-specific cytotoxic T lymphocytes target airway CD103+ and CD11b+ dendritic cells to suppress allergic inflammation. AB - Allergic airway inflammation is driven by the recognition of inhaled allergen by T helper type 2 (Th2) cells in the airway and lung. Allergen-specific cytotoxic T lymphocytes (CTLs) can strongly reduce airway inflammation, however, the mechanism of their inhibitory activity is not fully defined. We used mouse models to show that allergen-specific CTLs reduced early cytokine production by Th2 cells in lung, and their subsequent accumulation and production of interleukin (IL)-4 and IL-13. In addition, treatment with specific CTLs also increased the proportion of caspase(+) dendritic cells (DCs) in mediastinal lymph node (MLN), and decreased the numbers of CD103(+) and CD11b(+) DCs in the lung. This decrease required expression of the cytotoxic mediator perforin in CTLs and of the appropriate MHC-antigen ligand on DCs, suggesting that direct CTL-DC contact was necessary. Lastly, lung imaging experiments revealed that in airway-challenged mice XCR1-GFP(+) DCs, corresponding to the CD103(+) DC subset, and XCR1-GFP(-) CD11c(+) cells, which include CD11b(+) DCs and alveolar macrophages, both clustered in the areas surrounding the small airways and were closely associated with allergen-specific CTLs. Thus, allergen-specific CTLs reduce allergic airway inflammation by depleting CD103(+) and CD11b(+) DC populations in the lung, and may constitute a mechanism through which allergic immune responses are regulated. PMID- 26104915 TI - Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells. AB - Heat shock protein 90 (HSP90) regulates the stability of various proteins and plays an essential role in cellular homeostasis. Many client proteins of HSP90 are involved in cell growth, survival, and migration; processes that are generally accepted as participants in tumorigenesis. HSP90 is also up-regulated in certain tumors. Indeed, the inhibition of HSP90 is known to be effective in cancer treatment. Recently, studies showed that HSP90 regulates transforming growth factor beta1 (TGF-beta1)-induced transcription by increasing the stability of the TGF-beta receptor. TGF-beta signaling also has been implicated in cancer, suggesting the possibility that TGF-beta1 and HSP90 function cooperatively during the cancer cell progression. Here in this paper, we investigated the role of HSP90 in TGF-beta1-stimulated Mv1Lu cells. Treatment of Mv1Lu cells with the HSP90 inhibitor, 17-allylamino-demethoxy-geldanamycin (17AAG), or transfection with truncated HSP90 (DeltaHSP90) significantly reduced TGF-beta1-induced cell migration. Pretreatment with 17AAG or transfection with DeltaHSP90 also reduced the levels of phosphorylated Smad2 and Smad3. In addition, the HSP90 inhibition interfered the nuclear localization of Smads induced by constitutively active Smad2 (S2EE) or Smad3 (S3EE). We also found that the HSP90 inhibition decreased the protein level of importin-beta1 which is known to regulate R-Smad nuclear translocation. These data clearly demonstrate a novel function of HSP90; HSP90 modulates TGF-beta signaling by regulating Smads localization. Overall, our data could provide a detailed mechanism linking HSP90 and TGF-beta signaling. The extension of our understanding of HSP90 would offer a better strategy for treating cancer. PMID- 26104916 TI - Late Gadolinium Enhancement on Cardiac MRI Correlates with QT Dynamicity Represented by QT/RR Relationship in Patients with Ventricular Arrhythmias. AB - BACKGROUND: The distribution of late gadolinium enhancement (LGE) on the cardiac MRI (CMR) indicates myocardial fibrosis and provides information of possible reentry substrates. QT dynamicity reflecting repolarization abnormalities has gained attention as a potential prognostic predictive factor. OBJECTIVE: To clarify the correlation between the LGE distribution on CMR and QT dynamicity represented by the QT/RR relationship. METHODS: CMR and QT/RR analyses using Holter monitoring were performed in 34 patients (24 males, 60 +/- 11 years) with ventricular tachycardia (VT) and/or ventricular fibrillation (VF). The LGE on CMR was scored using a 4-point score in 17 left ventricular segments. The sum of the LGE scores was calculated for each patient. The QT/RR slope and daytime/nighttime QT/RR ratio (day/night ratio) were calculated. The correlation between the slope or the day/night QT/RR ratio and late enhancement findings was analyzed. RESULTS: All patients were divided into 23 LGE positive (LGE(+)) and 11 LGE negative (LGE( )) patients. The slopes of the QTe/RR and QTa /RR were significantly steeper in the LGE(+) than in LGE(-) patients (0.21 +/- 0.03 vs 0.13 +/- 0.02; P < 0.001, 0.19 +/- 0.03 vs 0.13 +/- 0.02; P < 0.001, respectively), and both slopes were significantly correlated with the total LGE scores (r = 0.83, P < 0.001; r = 0.71, P < 0.001, respectively). In the LGE(+) patients, the QTe day/night (1.37 +/- 0.38 vs 0.91 +/- 0.33; P = 0.002) and QTa day/night ratios (1.33 +/- 0.26 vs 1.06 +/- 0.30; P = 0.011) were significantly greater than those in the LGE(-) patients. CONCLUSION: The LGE distribution was closely related to the QT dynamicity, suggesting that a combination of these markers can be a powerful tool for understanding the background pathophysiology. PMID- 26104917 TI - Interleukin-6 reduces NMDAR-mediated cytosolic Ca2+ overload and neuronal death via JAK/CaN signaling. AB - Cytosolic Ca(2+) overload induced by N-methyl-D-aspartate (NMDA) is one of the major causes for neuronal cell death during cerebral ischemic insult and neurodegenerative disorders. Previously, we have reported that the cytokine interleukin-6 (IL-6) reduces NMDA-induced cytosolic Ca(2+) overload by inhibiting both L-type voltage-gated calcium channel (L-VGCC) activity and intracellular Ca(2+) store release in cultured cerebellar granule neurons (CGNs). Here we aimed to show that NMDA-gated receptor channels (i.e., NMDA receptors, NMDARs) are an inhibitory target of IL-6 via a mediation of calcineurin (CaN) signaling. As expected, IL-6 decreased NMDAR-mediated cytosolic Ca(2+) overload and inward current in cultured CGNs. The NMDAR subunits, NR1, NR2A, NR2B and NR2C, were expressed in CGNs. Blocking either of NR2A, NR2B and NR2C with respective antagonist reduced NMDA-induced extracellular Ca(2+) influx and neuronal death. Importantly, the reduced percentages in extracellular Ca(2+) influx and neuronal death by either NR2B or NR2C antagonist were weaker in the presence of IL-6 than in the absence of IL-6, while the reduced percentage by NR2A antagonist was not significantly different between the presence and the absence of IL-6. AG490, an inhibitor of Janus kinase (JAK), abolished IL-6 protection against extracellular Ca(2+) influx, mitochondrial membrane depolarization, neuronal death, and CaN activity impairment induced by NMDA. The CaN inhibitor FK506 reduced these IL-6 neuroprotective properties. Collectively, these results suggest that IL-6 exerts neuroprotection by inhibiting activities of the NMDAR subunits NR2B and NR2C (but not NR2A) via the intermediation of JAK/CaN signaling. PMID- 26104918 TI - Mitochondrial Ca2+ handling is crucial for generation of rhythmical Ca2+ waves in vascular interstitial cells from rabbit portal vein. AB - Vasomotion is the rhythmical changes in vascular tone of various blood vessels. It was proposed that in rabbit portal vein (RPV) the spontaneous contractile activity is driven by vascular interstitial cells (VICs), since RPV VICs generate rhythmical changes in intracellular Ca(2+) concentration ([Ca(2+)]i) associated with membrane depolarisation in these cells. In this work, using confocal imaging in Fluo-3 loaded RPV VICs we studied if generation of rhythmical [Ca(2+)]i changes is affected when Ca(2+) handling by mitochondria is compromised. We also visualised mitochondria in VICs using Mito Tracker Green fluorescent dye. Our results showed that freshly dispersed RPV VICs generated rhythmical [Ca(2+)]i oscillations with a frequency of 0.2-0.01 Hz. Imaging of VICs stained with Mito Tracker Green revealed abundant mitochondria in these cells with a higher density of the organelles in sub-plasmalemmar region compared to the central region of the cell. Oligomycin, an ATP synthase inhibitor, did not affect the amplitude and frequency of rhythmical [Ca(2+)]i oscillations. In contrast, two uncoupling agents, carbonylcyanide-3-chlorophenylhydrazone (CCCP) and carbonylcyanide-4 trifluoromethoxyphenylhydrazone (FCCP) effectively abolished rhythmical [Ca(2+)]i changes with simultaneous increase in basal [Ca(2+)]i in RPV VICs. These data suggest that in RPV VICs mitochondrial Ca(2+) handling is important for the generation of rhythmical [Ca(2+)]i changes which underlie the spontaneous rhythmical contractile activity in this vessel. PMID- 26104919 TI - Impact of vibration and agitation speed on dissolution of USP prednisone tablets RS and various IR tablet formulations. AB - Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1-4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation. PMID- 26104920 TI - Generalized vitiligo in a dog with primary hypoadrenocorticism. AB - BACKGROUND: Vitiligo is presumed to be an autoimmune disorder in the dog; primary adrenal insufficiency (Addison's disease) is associated with immune-mediated destruction of the adrenal cortex. HYPOTHESIS/OBJECTIVES: In this case report we describe a dog with primary hypoadrenocorticism that developed generalized vitiligo. CASE REPORT: A 4-year-old spayed female cross-bred dog developed signs of Addison's disease and this was confirmed by biochemical testing; the dog was treated with fludrocortisone acetate and then desoxycorticosterone pivalate. Three months after the diagnosis, the dog developed depigmentation of the whole hair coat and of several focal areas of the skin. Histopathological findings were consistent with vitiligo. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with immune mediated disease may develop other manifestations of immune-mediated disease, including a combination of Addison's disease and vitiligo. The cause in this case was not determined. PMID- 26104921 TI - Composite pheochromocytoma of the adrenal gland: a case series. AB - BACKGROUND: Composite pheochromocytoma is a rare pathological condition characterized by elements of both pheochromocytoma and neurogenic tumors. However, detailed clinical outcomes of this tumor have not been fully shown. From 2007 to 2013, we experienced three cases of adrenal composite pheochromocytoma. In this report, we investigate the clinicopathological features of these three cases of composite pheochromocytoma and compare them with previously reported cases. CASE PRESENTATIONS: Cases 1 and 2 were a 29-year-old Japanese woman and a 59-year-old Japanese man, respectively. They underwent laparoscopic left adrenalectomy, and pathological examination revealed composite pheochromocytoma ganglioneuroma. Case 3 was a 53-year-old Japanese man who had been receiving hemodialysis for 17 years. He underwent laparoscopic right adrenalectomy, and pathological examination revealed composite pheochromocytoma ganglioneuroblastoma. Although the Ki67-positive rates varied from 1.0 to 6.2% among the three cases, no clinical recurrences occurred. Despite the relatively high rate of Ki67 positivity, complete tumor resection resulted in favorable clinical outcomes. CONCLUSION: We experienced three cases of adrenal composite pheochromocytoma. Although the clinical findings and treatment outcomes of composite pheochromocytoma were similar to those of ordinary pheochromocytoma, further studies of the biological behavior and genetic profiles of composite pheochromocytoma are necessary to achieve a better understanding of this tumor. PMID- 26104922 TI - Molecular Biomarkers in Muscle-Invasive Bladder Cancer. PMID- 26104923 TI - Brazil's Challenges and Opportunities. PMID- 26104924 TI - Is Equipment Development Stifling Innovation in Radiation Oncology? PMID- 26104925 TI - Final Report of Radiation Therapy Oncology Group Protocol 9003: Provocative, but Limited Conclusions From Exploratory Analyses. PMID- 26104926 TI - What Is Reasonably Foreseeable? Lessons Learned From the SUPPORT Trial. PMID- 26104927 TI - Does Cancer Literature Reflect Multidisciplinary Practice? A Systematic Review of Oncology Studies in the Medical Literature Over a 20-Year Period. AB - PURPOSE: Quality cancer care is best delivered through a multidisciplinary approach requiring awareness of current evidence for all oncologic specialties. The highest impact journals often disseminate such information, so the distribution and characteristics of oncology studies by primary intervention (local therapies, systemic therapies, and targeted agents) were evaluated in 10 high-impact journals over a 20-year period. METHODS AND MATERIALS: Articles published in 1994, 2004, and 2014 in New England Journal of Medicine, Lancet, Journal of the American Medical Association, Lancet Oncology, Journal of Clinical Oncology, Annals of Oncology, Radiotherapy and Oncology, International Journal of Radiation Oncology, Biology, Physics, Annals of Surgical Oncology, and European Journal of Surgical Oncology were identified. Included studies were prospectively conducted and evaluated a therapeutic intervention. RESULTS: A total of 960 studies were included: 240 (25%) investigated local therapies, 551 (57.4%) investigated systemic therapies, and 169 (17.6%) investigated targeted therapies. More local therapy trials (n=185 [77.1%]) evaluated definitive, primary treatment than systemic (n=178 [32.3%]) or targeted therapy trials (n=38 [22.5%]; P<.001). Local therapy trials (n=16 [6.7%]) also had significantly lower rates of industry funding than systemic (n=207 [37.6%]) and targeted therapy trials (n=129 [76.3%]; P<.001). Targeted therapy trials represented 5 (2%), 38 (10.2%), and 126 (38%) of those published in 1994, 2004, and 2014, respectively (P<.001), and industry funded 48 (18.9%), 122 (32.6%), and 182 (54.8%) trials, respectively (P<.001). Compared to publication of systemic therapy trial articles, articles investigating local therapy (odds ratio: 0.025 [95% confidence interval: 0.012 0.048]; P<.001) were less likely to be found in high-impact general medical journals. CONCLUSIONS: Fewer studies evaluating local therapies, such as surgery and radiation, are published in high-impact oncology and medicine literature. Further research and attention are necessary to guide efforts promoting appropriate representation of all oncology studies in high-impact, broad readership journals. PMID- 26104928 TI - Underrepresentation of Local Therapy Trials in Leading Medical Journals: Cause for Outrage or Indifference? PMID- 26104929 TI - Medical Student--Reported Outcomes of a Radiation Oncologist--Led Preclinical Course in Oncology: A Five-Year Analysis. AB - PURPOSE: There is a recognized need for more robust training in oncology for medical students. At our institution, we have offered a core dedicated oncology block, led by a radiation oncologist course director, during the second year of the medical school curriculum since the 2008-2009 academic year. Herein, we report the outcomes of the oncology block over the past 5 years through an analysis of student perceptions of the course, both immediately after completion of the block and in the third year. METHODS AND MATERIALS: We analyzed 2 separate surveys. The first assessed student impressions of how well the course met each of the course's learning objectives through a survey that was administered to students immediately after the oncology block in 2012. The second was administered after students completed the oncology block during the required radiology clerkship in the third year. All questions used a 5-level Likert scale and were analyzed by use of a Wilcoxon signed-rank test. RESULTS: Of the 169 students who took the oncology course in 2012, 127 (75.1%) completed the course feedback survey. Over 73% of students agreed or strongly agreed that the course met its 3 learning objectives. Of the 699 medical students who took the required radiology clerkship between 2010 and 2013, 538 participated in the second survey, for a total response rate of 77%. Of these students, 368 (68.4%) agreed or strongly agreed that the course was effective in contributing to their overall medical education. CONCLUSION: Student perceptions of the oncology block are favorable and have improved across multiple categories since the inception of the course. Students self-reported that a dedicated preclinical oncology block was effective in helping identify the basics of cancer therapy and laying the foundation for clinical electives in oncology, including radiation oncology. PMID- 26104930 TI - Grade Inflation in Medical Student Radiation Oncology Clerkships: Missed Opportunities for Feedback? AB - PURPOSE: To test the hypothesis that medical student radiation oncology elective rotation grades are inflated and cannot be used to distinguish residency applicants. METHODS AND MATERIALS: The records of 196 applicants to a single radiation oncology residency program in 2011 and 2012 were retrospectively reviewed. The grades for each rotation in radiation oncology were collected and converted to a standardized 4-point grading scale (honors, high pass, pass, fail). Pass/fail grades were scored as not applicable. The primary study endpoint was to compare the distribution of applicants' grades in radiation oncology with their grades in medicine, surgery, pediatrics, and obstetrics/gynecology core clerkships. RESULTS: The mean United States Medical Licensing Examination Step 1 score of the applicants was 237 (range, 188-269), 43% had additional Masters or PhD degrees, and 74% had at least 1 publication. Twenty-nine applicants were graded for radiation oncology rotations on a pass/fail basis and were excluded from the final analysis. Of the remaining applicants (n=167), 80% received the highest possible grade for their radiation oncology rotations. Grades in radiation oncology were significantly higher than each of the other 4 clerkships studied (P<.001). Of all applicants, 195 of 196 matched into a radiation oncology residency. Higher grades in radiation oncology were associated with significantly higher grades in the pediatrics core clerkship (P=.002). However, other medical school performance metrics were not significantly associated with higher grades in radiation oncology. CONCLUSIONS: Although our study group consists of a selected group of radiation oncology applicants, their grades in radiation oncology clerkships were highly skewed toward the highest grades when compared with grades in other core clerkships. Student grading in radiation oncology clerkships should be re-evaluated to incorporate more objective and detailed performance metrics to allow for meaningful feedback to trainees and to better evaluate residency applicants to radiation oncology. PMID- 26104931 TI - Noncoplanar Beam Angle Class Solutions to Replace Time-Consuming Patient-Specific Beam Angle Optimization in Robotic Prostate Stereotactic Body Radiation Therapy. AB - PURPOSE: To investigate development of a recipe for the creation of a beam angle class solution (CS) for noncoplanar prostate stereotactic body radiation therapy to replace time-consuming individualized beam angle selection (iBAS) without significant loss in plan quality, using the in-house "Erasmus-iCycle" optimizer for fully automated beam profile optimization and iBAS. METHODS AND MATERIALS: For 30 patients, Erasmus-iCycle was first used to generate 15-, 20-, and 25-beam iBAS plans for a CyberKnife equipped with a multileaf collimator. With these plans, 6 recipes for creation of beam angle CSs were investigated. Plans of 10 patients were used to create CSs based on the recipes, and the other 20 to independently test them. For these tests, Erasmus-iCycle was also used to generate intensity modulated radiation therapy plans for the fixed CS beam setups. RESULTS: Of the tested recipes for CS creation, only 1 resulted in 15-, 20-, and 25-beam noncoplanar CSs without plan deterioration compared with iBAS. For the patient group, mean differences in rectum D1cc, V60GyEq, V40GyEq, and Dmean between 25-beam CS plans and 25-beam plans generated with iBAS were 0.2 +/- 0.4 Gy, 0.1% +/- 0.2%, 0.2% +/- 0.3%, and 0.1 +/- 0.2 Gy, respectively. Differences between 15- and 20-beam CS and iBAS plans were also negligible. Plan quality for CS plans relative to iBAS plans was also preserved when narrower planning target volume margins were arranged and when planning target volume dose inhomogeneity was decreased. Using a CS instead of iBAS reduced the computation time by a factor of 14 to 25, mainly depending on beam number, without loss in plan quality. CONCLUSIONS: A recipe for creation of robust beam angle CSs for robotic prostate stereotactic body radiation therapy has been developed. Compared with iBAS, computation times decreased by a factor 14 to 25. The use of a CS may avoid long planning times without losses in plan quality. PMID- 26104932 TI - Quality of Intensity Modulated Radiation Therapy Treatment Plans Using a 60Co Magnetic Resonance Image Guidance Radiation Therapy System. AB - PURPOSE: This work describes a commercial treatment planning system, its technical features, and its capabilities for creating (60)Co intensity modulated radiation therapy (IMRT) treatment plans for a magnetic resonance image guidance radiation therapy (MR-IGRT) system. METHODS AND MATERIALS: The ViewRay treatment planning system (Oakwood Village, OH) was used to create (60)Co IMRT treatment plans for 33 cancer patients with disease in the abdominal, pelvic, thorax, and head and neck regions using physician-specified patient-specific target coverage and organ at risk (OAR) objectives. Backup plans using a third-party linear accelerator (linac)-based planning system were also created. Plans were evaluated by attending physicians and approved for treatment. The (60)Co and linac plans were compared by evaluating conformity numbers (CN) with 100% and 95% of prescription reference doses and heterogeneity indices (HI) for planning target volumes (PTVs) and maximum, mean, and dose-volume histogram (DVH) values for OARs. RESULTS: All (60)Co IMRT plans achieved PTV coverage and OAR sparing that were similar to linac plans. PTV conformity for (60)Co was within <1% and 3% of linac plans for 100% and 95% prescription reference isodoses, respectively, and heterogeneity was on average 4% greater. Comparisons of OAR mean dose showed generally better sparing with linac plans in the low-dose range <20 Gy, but comparable sparing for organs with mean doses >20 Gy. The mean doses for all (60)Co plan OARs were within clinical tolerances. CONCLUSIONS: A commercial (60)Co MR-IGRT device can produce highly conformal IMRT treatment plans similar in quality to linac IMRT for a variety of disease sites. Additional work is in progress to evaluate the clinical benefit of other novel features of this MR-IGRT system. PMID- 26104933 TI - Automatic Segmentation of the Eye in 3D Magnetic Resonance Imaging: A Novel Statistical Shape Model for Treatment Planning of Retinoblastoma. AB - PURPOSE: Proper delineation of ocular anatomy in 3-dimensional (3D) imaging is a big challenge, particularly when developing treatment plans for ocular diseases. Magnetic resonance imaging (MRI) is presently used in clinical practice for diagnosis confirmation and treatment planning for treatment of retinoblastoma in infants, where it serves as a source of information, complementary to the fundus or ultrasonographic imaging. Here we present a framework to fully automatically segment the eye anatomy for MRI based on 3D active shape models (ASM), and we validate the results and present a proof of concept to automatically segment pathological eyes. METHODS AND MATERIALS: Manual and automatic segmentation were performed in 24 images of healthy children's eyes (3.29 +/- 2.15 years of age). Imaging was performed using a 3-T MRI scanner. The ASM consists of the lens, the vitreous humor, the sclera, and the cornea. The model was fitted by first automatically detecting the position of the eye center, the lens, and the optic nerve, and then aligning the model and fitting it to the patient. We validated our segmentation method by using a leave-one-out cross-validation. The segmentation results were evaluated by measuring the overlap, using the Dice similarity coefficient (DSC) and the mean distance error. RESULTS: We obtained a DSC of 94.90 +/- 2.12% for the sclera and the cornea, 94.72 +/- 1.89% for the vitreous humor, and 85.16 +/- 4.91% for the lens. The mean distance error was 0.26 +/- 0.09 mm. The entire process took 14 seconds on average per eye. CONCLUSION: We provide a reliable and accurate tool that enables clinicians to automatically segment the sclera, the cornea, the vitreous humor, and the lens, using MRI. We additionally present a proof of concept for fully automatically segmenting eye pathology. This tool reduces the time needed for eye shape delineation and thus can help clinicians when planning eye treatment and confirming the extent of the tumor. PMID- 26104934 TI - A Contralateral Esophagus-Sparing Technique to Limit Severe Esophagitis Associated With Concurrent High-Dose Radiation and Chemotherapy in Patients With Thoracic Malignancies. AB - PURPOSE: Severe (Radiation Therapy Oncology Group [RTOG] grade 3 or greater) esophagitis generally occurs in 15% to 25% of non-small cell lung cancer (NSCLC) patients undergoing concurrent chemotherapy and radiation therapy (CCRT), which may result in treatment breaks that compromise local tumor control and pose a barrier to dose escalation. Here, we report a novel contralateral esophagus sparing technique (CEST) that uses intensity modulated radiation therapy (IMRT) to reduce the incidence of severe esophagitis. METHODS AND MATERIALS: We reviewed consecutive patients with thoracic malignancies undergoing curative CCRT in whom CEST was used. The esophageal wall contralateral (CE) to the tumor was contoured as an avoidance structure, and IMRT was used to guide a rapid dose falloff gradient beyond the target volume in close proximity to the esophagus. Esophagitis was recorded based on the RTOG acute toxicity grading system. RESULTS: We identified 20 consecutive patients treated with CCRT of at least 63 Gy in whom there was gross tumor within 1 cm of the esophagus. The median radiation dose was 70.2 Gy (range, 63-72.15 Gy). In all patients, >=99% of the planning and internal target volumes was covered by >=90% and 100% of prescription dose, respectively. Strikingly, no patient experienced grade >=3 esophagitis (95% confidence limits, 0%-16%) despite the high total doses delivered. The median maximum dose, V45, and V55 of the CE were 60.7 Gy, 2.1 cc, and 0.4 cc, respectively, indicating effective esophagus cross-section sparing by CEST. CONCLUSION: We report a simple yet effective method to avoid exposing the entire esophagus cross-section to high doses. By using proposed CE dose constraints of V45 <2.5 cc and V55 <0.5 cc, CEST may improve the esophagus toxicity profile in thoracic cancer patients receiving CCRT even at doses above the standard 60- to 63-Gy levels. Prospective testing of CEST is warranted. PMID- 26104935 TI - Hypercellularity Components of Glioblastoma Identified by High b-Value Diffusion Weighted Imaging. AB - PURPOSE: Use of conventional magnetic resonance imaging (MRI) for target definition may expose glioblastomas (GB) to inadequate radiation dose coverage of the nonenhanced hypercellular subvolume. This study aimed to develop a technique to identify the hypercellular components of GB by using high b-value diffusion weighted imaging (DWI) and to investigate its relationship with the prescribed 95% isodose volume (PDV) and progression-free survival (PFS). METHODS AND MATERIALS: Twenty-one patients with GB underwent chemoradiation therapy post resection and biopsy. Radiation therapy (RT) treatment planning was based upon conventional MRI. Pre-RT DWIs were acquired in 3 orthogonal directions with b values of 0, 1000, and 3000 s/mm(2). Hypercellularity volume (HCV) was defined on the high b-value (3000 s/mm(2)) DWI by a threshold method. Nonenhanced signified regions not covered by the Gd-enhanced gross tumor volume (GTV-Gd) on T1-weighted images. The PDV was used to evaluate spatial coverage of the HCV by the dose plan. Association between HCV and PFS or other clinical covariates were assessed using univariate proportional hazards regression models. RESULTS: HCVs and nonenhanced HCVs varied from 0.58 to 67 cm(3) (median: 9.8 cm(3)) and 0.15 to 60 cm(3) (median: 2.5 cm(3)), respectively. Fourteen patients had incomplete dose coverage of the HCV, 6 of whom had >1 cm(3) HCV missed by the 95% PDV (range: 1.01-25.4 cm(3)). Of the 15 patients who progressed, 5 progressed earlier, within 6 months post-RT, and 10 patients afterward. Pre-RT HCVs within recurrent GTVs-Gd were 78% (range: 65%-89%) for the 5 earliest progressions but lower, 53% (range: 0%-85%), for the later progressions. HCV and nonenhanced HCV were significant negative prognostic indicators for PFS (P<.002 and P<.01, respectively). The hypercellularity subvolume not covered by the 95% PDV was a significant negative predictor for PFS (P<.05). CONCLUSIONS: High b-value DWI identifies the hypercellular components of GB and could aid in RT target volume definition. Future studies will allow us to investigate the role of high b-value DWI in identifying radiation boost volumes and diagnosing progression. PMID- 26104936 TI - The Effects of Pulsed Radiation Therapy on Tumor Oxygenation in 2 Murine Models of Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: To evaluate the efficacy of low-dose pulsed radiation therapy (PRT) in 2 head and neck squamous cell carcinoma (HNSCC) xenografts and to investigate the mechanism of action of PRT compared with standard radiation therapy (SRT). METHODS AND MATERIALS: Subcutaneous radiosensitive UT-SCC-14 and radioresistant UT-SCC-15 xenografts were established in athymic NIH III HO female mice. Tumors were irradiated with 2 Gy/day by continuous standard delivery (SRT: 2 Gy) or discontinuous low-dose pulsed delivery (PRT: 0.2 Gy * 10 with 3-min pulse interval) to total doses of 20 Gy (UT14) or 40 Gy (UT15) using a clinical 5-day on/2-day off schedule. Treatment response was assessed by changes in tumor volume, (18)F-fluorodeoxyglucose (FDG) (tumor metabolism), and (18)F fluoromisonidazole (FMISO) (hypoxia) positron emission tomography (PET) imaging before, at midpoint, and after treatment. Tumor hypoxia using pimonidazole staining and vascular density (CD34 staining) were assessed by quantitative histopathology. RESULTS: UT15 and UT14 tumors responded similarly in terms of growth delay to either SRT or PRT. When compared with UT14 tumors, UT15 tumors demonstrated significantly lower uptake of FDG at all time points after irradiation. UT14 tumors demonstrated higher levels of tumor hypoxia after SRT when compared with PRT as measured by (18)F-FMISO PET. By contrast, no differences were seen in (18)F-FMISO PET imaging between SRT and PRT for UT15 tumors. Histologic analysis of pimonidazole staining mimicked the (18)F-FMISO PET imaging data, showing an increase in hypoxia in SRT-treated UT14 tumors but not PRT-treated tumors. CONCLUSIONS: Differences in (18)F-FMISO uptake for UT14 tumors after radiation therapy between PRT and SRT were measurable despite the similar tumor growth delay responses. In UT15 tumors, both SRT and PRT were equally effective at reducing tumor hypoxia to a significant level as measured by (18)F-FMISO and pimonidazole. PMID- 26104937 TI - Personalized Medicine in Radiation Oncology--A Work in Progress. PMID- 26104938 TI - Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers. AB - PURPOSE: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. METHODS AND MATERIALS: Women aged >=55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease <=2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. RESULTS: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. CONCLUSIONS: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers. PMID- 26104940 TI - Consensus Guidelines and Contouring Atlas for Pelvic Node Delineation in Prostate and Pelvic Node Intensity Modulated Radiation Therapy. AB - PURPOSE: The purpose of this study was to establish reproducible guidelines for delineating the clinical target volume (CTV) of the pelvic lymph nodes (LN) by combining the freehand Royal Marsden Hospital (RMH) and Radiation Therapy Oncology Group (RTOG) vascular expansion techniques. METHODS AND MATERIALS: Seven patients with prostate cancer underwent standard planning computed tomography scanning. Four different CTVs (RMH, RTOG, modified RTOG, and Prostate and pelvIs Versus prOsTate Alone treatment for Locally advanced prostate cancer [PIVOTAL] trial) were created for each patient, and 6 different bowel expansion margins (BEM) were created to assess bowel avoidance by the CTV. The resulting CTVs were compared visually and by using Jaccard conformity indices. The volume of overlap between bowel and planning target volume (PTV) was measured to aid selection of an appropriate BEM to enable maximal LN yet minimal normal tissue coverage. RESULTS: In total, 84 nodal contours were evaluated. LN coverage was similar in all groups, with all of the vascular-expansion techniques (RTOG, modified RTOG, and PIVOTAL), resulting in larger CTVs than that of the RMH technique (mean volumes: 287.3 cm(3), 326.7 cm(3), 310.3 cm(3), and 256.7 cm(3), respectively). Mean volumes of bowel within the modified RTOG PTV were 19.5 cm(3) (with 0 mm BEM), 17.4 cm(3) (1-mm BEM), 10.8 cm(3) (2-mm BEM), 6.9 cm(3) (3-mm BEM), 5.0 cm(3) (4-mm BEM), and 1.4 cm(3) (5-mm BEM) in comparison with an overlap of 9.2 cm(3) seen using the RMH technique. Evaluation of conformity between LN-CTVs from each technique revealed similar volumes and coverage. CONCLUSIONS: Vascular expansion techniques result in larger LN-CTVs than the freehand RMH technique. Because the RMH technique is supported by phase 1 and 2 trial safety data, we proposed modifications to the RTOG technique, including the addition of a 3-mm BEM, which resulted in LN-CTV coverage similar to that of the RMH technique, with reduction in bowel and planning target volume overlap. On the basis of these findings, recommended guidelines including a detailed pelvic LN contouring atlas have been produced and implemented in the PIVOTAL trial. PMID- 26104941 TI - Defining the "Hostile Pelvis" for Intensity Modulated Radiation Therapy: The Impact of Anatomic Variations in Pelvic Dimensions on Dose Delivered to Target Volumes and Organs at Risk in Patients With High-Risk Prostate Cancer Treated With Whole Pelvic Radiation Therapy. AB - PURPOSE: The aim of this study was to evaluate the impact of variations in pelvic dimensions on the dose delivered to the target volumes and the organs at risk (OARs) in patients with high-risk prostate cancer (PCa) to be treated with whole pelvic radiation therapy (WPRT) in an attempt to define the hostile pelvis in terms of intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: In 45 men with high-risk PCa to be treated with WPRT, the target volumes and the OARs were delineated, the dose constraints for the OARs were defined, and treatment plans were generated according to the Radiation Therapy Oncology Group 0924 protocol. Six dimensions to reflect the depth, width, and height of the bony pelvis were measured, and 2 indexes were calculated from the planning computed tomographic scans. The minimum dose (Dmin), maximum dose (Dmax), and mean dose (Dmean) for the target volumes and OARs and the partial volumes of each of these structures receiving a specified dose (VD) were calculated from the dose-volume histograms (DVHs). The data from the DVHs were correlated with the pelvic dimensions and indexes. RESULTS: According to an overall hostility score (OHS) calculation, 25 patients were grouped as having a hospitable pelvis and 20 as having a hostile pelvis. Regarding the OHS grouping, the DVHs for the bladder, bowel bag, left femoral head, and right femoral head differed in favor of the hospitable pelvis group, and the DVHs for the rectum differed for a range of lower doses in favor of the hospitable pelvis group. CONCLUSIONS: Pelvimetry might be used as a guide to define the challenging anatomy or the hostile pelvis in terms of treatment planning for IMRT in patients with high-risk PCa to be treated with WPRT. PMID- 26104939 TI - Importance of Local Control in Early-Stage Prostate Cancer: Outcomes of Patients With Positive Post-Radiation Therapy Biopsy Results Treated in RTOG 9408. AB - PURPOSE: The purpose of this study was to assess the association between positive post-radiation therapy (RT) biopsy results and subsequent clinical outcomes in males with localized prostate cancer. METHODS AND MATERIALS: Radiation Therapy Oncology Group study 94-08 analyzed 1979 males with prostate cancer, stage T1b T2b and prostate-specific antigen concentrations of <= 20 ng/dL, to investigate whether 4 months of total androgen suppression (TAS) added to RT improved survival compared to RT alone. Patients randomized to receive TAS received flutamide with luteinizing hormone releasing hormone (LHRH) agonist. According to protocol, patients without evidence of clinical recurrence or initiation of additional endocrine therapy underwent repeat prostate biopsy 2 years after RT completion. Statistical analysis was performed to evaluate the impact of positive post-RT biopsy results on clinical outcomes. RESULTS: A total of 831 patients underwent post-RT biopsy, 398 were treated with RT alone and 433 with RT plus TAS. Patients with positive post-RT biopsy results had higher rates of biochemical failure (hazard ratio [HR] = 1.7; 95% confidence interval [CI] = 1.3 2.1) and distant metastasis (HR = 2.4; 95% CI = 1.3-4.4) and inferior disease specific survival (HR = 3.8; 95% CI = 1.9-7.5). Positive biopsy results remained predictive of such outcomes after correction for potential confounders such as Gleason score, tumor stage, and TAS administration. Prior TAS therapy did not prevent elevated risk of adverse outcome in the setting of post-RT positive biopsy results. Patients with Gleason score >= 7 with a positive biopsy result additionally had inferior overall survival compared to those with a negative biopsy result (HR = 1.56; 95% CI = 1.04-2.35). CONCLUSIONS: Positive post-RT biopsy is associated with increased rates of distant metastases and inferior disease-specific survival in patients treated with definitive RT and was associated with inferior overall survival in patients with high-grade tumors. PMID- 26104942 TI - Small Cell Carcinoma of the Urinary Bladder: A Retrospective, Multicenter Rare Cancer Network Study of 107 Patients. AB - PURPOSE: Small cell carcinomas of the bladder (SCCB) account for fewer than 1% of all urinary bladder tumors. There is no consensus regarding the optimal treatment for SCCB. METHODS AND MATERIALS: Fifteen academic Rare Cancer Network medical centers contributed SCCB cases. The eligibility criteria were as follows: pure or mixed SCC; local, locoregional, and metastatic stages; and age >=18 years. The overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis according to the Kaplan-Meier method. The log-rank and Wilcoxon tests were used to analyze survival as functions of clinical and therapeutic factors. RESULTS: The study included 107 patients (mean [+/-standard deviation, SD] age, 69.6 [+/-10.6] years; mean follow-up time, 4.4 years) with primary bladder SCC, with 66% of these patients having pure SCC. Seventy-two percent and 12% of the patients presented with T2-4N0M0 and T2-4N1-3M0 stages, respectively, and 16% presented with synchronous metastases. The most frequent curative treatments were radical surgery and chemotherapy, sequential chemotherapy and radiation therapy, and radical surgery alone. The median (interquartile range, IQR) OS and DFS times were 12.9 months (IQR, 7-32 months) and 9 months (IQR, 5-23 months), respectively. The metastatic, T2-4N0M0, and T2-4N1-3M0 groups differed significantly (P=.001) in terms of median OS and DFS. In a multivariate analysis, impaired creatinine clearance (OS and DFS), clinical stage (OS and DFS), a Karnofsky performance status <80 (OS), and pure SCC histology (OS) were independent and significant adverse prognostic factors. In the patients with nonmetastatic disease, the type of treatment (ie radical surgery with or without adjuvant chemotherapy vs conservative treatment) did not significantly influence OS or DFS (P=.7). CONCLUSIONS: The prognosis for SCCB remains poor. The finding that radical cystectomy did not influence DFS or OS in the patients with nonmetastatic disease suggests that conservative treatment is appropriate in this situation. PMID- 26104943 TI - Expert Consensus Contouring Guidelines for Intensity Modulated Radiation Therapy in Esophageal and Gastroesophageal Junction Cancer. AB - PURPOSE/OBJECTIVE(S): Current guidelines for esophageal cancer contouring are derived from traditional 2-dimensional fields based on bony landmarks, and they do not provide sufficient anatomic detail to ensure consistent contouring for more conformal radiation therapy techniques such as intensity modulated radiation therapy (IMRT). Therefore, we convened an expert panel with the specific aim to derive contouring guidelines and generate an atlas for the clinical target volume (CTV) in esophageal or gastroesophageal junction (GEJ) cancer. METHODS AND MATERIALS: Eight expert academically based gastrointestinal radiation oncologists participated. Three sample cases were chosen: a GEJ cancer, a distal esophageal cancer, and a mid-upper esophageal cancer. Uniform computed tomographic (CT) simulation datasets and accompanying diagnostic positron emission tomographic/CT images were distributed to each expert, and the expert was instructed to generate gross tumor volume (GTV) and CTV contours for each case. All contours were aggregated and subjected to quantitative analysis to assess the degree of concordance between experts and to generate draft consensus contours. The panel then refined these contours to generate the contouring atlas. RESULTS: The kappa statistics indicated substantial agreement between panelists for each of the 3 test cases. A consensus CTV atlas was generated for the 3 test cases, each representing common anatomic presentations of esophageal cancer. The panel agreed on guidelines and principles to facilitate the generalizability of the atlas to individual cases. CONCLUSIONS: This expert panel successfully reached agreement on contouring guidelines for esophageal and GEJ IMRT and generated a reference CTV atlas. This atlas will serve as a reference for IMRT contours for clinical practice and prospective trial design. Subsequent patterns of failure analyses of clinical datasets using these guidelines may require modification in the future. PMID- 26104944 TI - Image-Based Brachytherapy for the Treatment of Cervical Cancer. AB - Cervical cancer is a disease that requires considerable multidisciplinary coordination of care and labor in order to maximize tumor control and survival while minimizing treatment-related toxicity. As with external beam radiation therapy, the use of advanced imaging and 3-dimensional treatment planning has generated a paradigm shift in the delivery of brachytherapy for the treatment of cervical cancer. The use of image-based brachytherapy, most commonly with magnetic resonance imaging (MRI), requires additional attention and effort by the treating physician to prescribe dose to the proper volume and account for adjacent organs at risk. This represents a dramatic change from the classic Manchester approach of orthogonal radiographic images and prescribing dose to point A. We reviewed the history and currently evolving data and recommendations for the clinical use of image-based brachytherapy with an emphasis on MRI-based brachytherapy. PMID- 26104945 TI - SBRT Dose and Survival in Non-Small Cell Lung Cancer: In Regard to Koshy et al. PMID- 26104946 TI - In Reply to Levy et al. PMID- 26104947 TI - SRS With or Without Whole-Brain Radiation Therapy for Those With 1 to 4 Brain Metastases: In Regard to Sahgal et al. PMID- 26104948 TI - In Regard to Sahgal et al. PMID- 26104949 TI - In Reply to Gemici and Yaprak and Lowrey and Marcus. PMID- 26104952 TI - Regenerative medicine in otorhinolaryngology. AB - BACKGROUND: Tissue engineering using biocompatible scaffolds, with or without cells, can permit surgeons to restore structure and function following tissue resection or in cases of congenital abnormality. Tracheal regeneration has emerged as a spearhead application of these technologies, whilst regenerative therapies are now being developed to treat most other diseases within otolaryngology. METHODS AND RESULTS: A systematic review of the literature was performed using Ovid Medline and Ovid Embase, from database inception to 15 November 2014. A total of 561 papers matched the search criteria, with 76 fulfilling inclusion criteria. Articles were predominantly pre-clinical animal studies, reflecting the current status of research in this field. Several key human research articles were identified and discussed. CONCLUSION: The main issues facing research in regenerative surgery are translation of animal model work into human models, increasing stem cell availability so it can be used to further research, and development of better facilities to enable implementation of these advances. PMID- 26104953 TI - Dr. Charles J. Burstone (1928-2015). PMID- 26104954 TI - Creative adjuncts for clear aligners, part 2: Intrusion, rotation, and extrusion. PMID- 26104955 TI - Clinical applications of predictable force systems, part 1: One-couple and two couple systems. PMID- 26104956 TI - Early management of impacted maxillary incisors with skeletal anchorage. PMID- 26104957 TI - External inflammatory root resorption associated with a traumatic occlusion. PMID- 26104958 TI - Torque and intrusion control of the upper incisors with a modified posted archwire. PMID- 26104959 TI - Octanoic acid promotes branched-chain amino acid catabolisms via the inhibition of hepatic branched-chain alpha-keto acid dehydrogenase kinase in rats. AB - OBJECTIVE: It has been reported that administration of octanoic acid, one of medium-chain fatty acids (MCFAs), promoted leucine oxidation in vitro and in vivo, but it remained unclear how octanoic acid stimulated leucine oxidation. Therefore, the aim of this study was to elucidate the mechanism that octanoic acid facilitates branched-chain amino acid (BCAA) catabolism. MATERIALS/METHODS: In in vivo experiments, male rats were orally administered MCFAs as free fatty acids or triacylglycerol (trioctanoin), and then activities of hepatic branched chain alpha-ketoacid dehydrogenase (BCKDH) complex (BCKDC) and BCKDH kinase (BDK) and alterations in the concentration of blood components were analyzed. In in vitro experiments, purified BCKDC associated with BDK (BCKDH-BDK complex) was reacted with various concentrations of hexanoic, octanoic, and decanoic acids. RESULTS: Oral administration of trioctanoin in rats activated hepatic BCKDC via down-regulation of BDK activity in association with a decrease in plasma BCAA concentration and an increase in serum ketone body concentration. In vitro experiments using purified BCKDH-BDK complex showed that MCFAs (hexanoic, octanoic, and decanoic acids) inhibited BDK activity and that this inhibition was higher in hexanoic and octanoic acids than in decanoic acid. Oral administration of octanoic acid, but not decanoic acid, in rats activated hepatic BCKDC via down regulation of BDK activity by decreasing the amount of BDK bound to the complex. The serum ketone body level was elevated by both administration of octanoic acid and decanoic acid. CONCLUSION: These results suggest that octanoic acid promotes BCAA catabolism in vivo by activation of BCKDC via decreasing the bound form of BDK. PMID- 26104960 TI - Advances in imaging for diagnosis and management of cardiac sarcoidosis. AB - Sarcoidosis is a multisystem granulomatous disorder with a high prevalence of cardiac involvement. Cardiac sarcoidosis (CS) may be life threatening due to end stage cardiomyopathy and sudden cardiac death. The frequent absence of specific symptoms and lack of a diagnostic 'gold standard' pose challenges in the diagnosis of CS. Endomyocardial biopsy, although specific, has an unacceptably low sensitivity. Non-invasive cardiac imaging has a huge role in the assessment of patients with known or suspected CS. This comprehensive review compares the diagnostic accuracy, along with advantages and disadvantages, of established and emerging imaging modalities for CS. PMID- 26104961 TI - Pulmonary veins: an important side window into ventricular function. PMID- 26104962 TI - Ruptured mitral valve aneurysm due to infective endocarditis. PMID- 26104963 TI - Attenuation of dendritic spine density in the perirhinal cortex following 17beta Estradiol replacement in the rat. AB - Intraperirhinal cortex infusion of 17-beta estradiol (E2) impairs object recognition memory. However, it is not currently known whether this hormone modulates synaptic plasticity in this structure. Most excitatory synapses in the central nervous system are located on dendritic spines, and elevated E2 levels influence the density of these spines in several brain areas. The goal of the present study was to determine whether differences in dendritic spine density in the perirhinal cortex are observed following high E2 replacement in ovariectomized rats. The density of total spines, and mushroom-shaped (i.e. mature) spines were compared between a high E2 replacement (10 ug/kg/day, s.c.) and a no replacement condition. The perirhinal cortex is subdivided into Broadmann's area 35 and 36 and so group comparisons were made within each sub region separately. High E2 replacement resulted in lower density of mushroom shaped spines in area 35 relative to no replacement. There was no effect of high E2 replacement on dendritic spine density in area 36. These findings are consistent with the idea that higher E2 levels reduce dendritic spine density in area 35, which may result from spine shrinkage, or reduced synapse formation. This study provides preliminary evidence for a mechanism through which E2 may impair object-recognition memory. PMID- 26104965 TI - Factors affecting patterns of Amblyomma triste (Acari: Ixodidae) parasitism in a rodent host. AB - Here we offer a multivariable analysis that explores associations of different factors (i.e., environmental, host parameters, presence of other ectoparasites) with the interaction of Amblyomma triste immature stages and one of its main hosts in Argentina, the rodent Akodon azarae. Monthly and for two years, we captured and sampled rodents at 16 points located at 4 different sites in the Parana River Delta region. The analyses were conducted with Generalized Linear Mixed Models with a negative binomial response (counts of larvae or nymphs). The independent variables assessed were: (a) environmental: trapping year, season, presence of cattle; type of vegetation (natural grassland or implanted forest); rodent abundance; (b) host parameters: body length; sex; body condition; blood cell counts; natural antibody titres; and (c) co-infestation with other ectoparasites: other stage of A. triste; Ixodes loricatus; lice; mites; and fleas. Two-way interaction terms deemed a priori as relevant were also included in the analysis. Larvae were affected by all environmental variables assessed and by the presence of other ectoparasites (lice, fleas and other tick species). Host factors significantly associated with larval count were sex and levels of natural antibodies. Nymphs were associated with season, presence of cattle, body condition, body length and with burdens of I. loricatus. In most cases, the direction and magnitude of the associations were context-dependent (many interaction terms were significant). The findings of greater significance and implications of our study are two. Firstly, as burdens of A. triste larvae and nymphs were greater where cattle were present, and larval tick burdens were higher in implanted forests, silvopastoral practices developing in the region may affect the population dynamics of A. triste, and consequently the eco epidemiology of Rickettsia parkeri. Secondly, strong associations and numerous interactions with other ectoparasites suggest that co-infestations may be more important for tick dynamics than has so far been appreciated. PMID- 26104964 TI - Dose-dependent effects of experimental infection with the virulent Neospora caninum Nc-Spain7 isolate in a pregnant mouse model. AB - Pregnant BALB/c mice have been widely used as an in vivo model to study Neospora caninum infection biology and to provide proof-of-concept for assessments of drugs and vaccines against neosporosis. The fact that this model has been used with different isolates of variable virulence, varying infection routes and differing methods to prepare the parasites for infection, has rendered the comparison of results from different laboratories impossible. In most studies, mice were infected with similar number of parasites (2 * 10(6)) as employed in ruminant models (10(7) for cows and 10(6) for sheep), which seems inappropriate considering the enormous differences in the weight of these species. Thus, for achieving meaningful results in vaccination and drug efficacy experiments, a refinement and standardization of this experimental model is necessary. Thus, 2 * 10(6), 10(5), 10(4), 10(3) and 10(2) tachyzoites of the highly virulent and well characterised Nc-Spain7 isolate were subcutaneously inoculated into mice at day 7 of pregnancy, and clinical outcome, vertical transmission, parasite burden and antibody responses were compared. Dams from all infected groups presented nervous signs and the percentage of surviving pups at day 30 postpartum was surprisingly low (24%) in mice infected with only 10(2) tachyzoites. Importantly, infection with 10(5) tachyzoites resulted in antibody levels, cerebral parasite burden in dams and 100% mortality rate in pups, which was identical to infection with 2 * 10(6) tachyzoites. Considering these results, it is reasonable to lower the challenge dose to 10(5) tachyzoites in further experiments when assessing drugs or vaccine candidates. PMID- 26104966 TI - Stereotactic Body Radiotherapy for Pulmonary Metastases. PMID- 26104967 TI - Immunoregulatory functions and expression patterns of PE/PPE family members: Roles in pathogenicity and impact on anti-tuberculosis vaccine and drug design. AB - The Mycobacterium tuberculosis genome was sequenced more than 15 years ago. It revealed a lot of interesting information, one of which was that 10% of the total coding capacity of the M. tuberculosis genome is dedicated to the PE/PPE family. There is a gradual expansion of these proteins from nonpathogenic to pathogenic mycobacteria, and there is increasing evidence that PE/PPE proteins play important roles in mycobacterial pathogenesis. In this review, we discuss PE/PPE proteins, their close functional association with the ESX clusters, their immunomodulatory functions, and their important roles in mycobacterial virulence. In addition, we have attempted to review and compile information available in the literature detailing the expression patterns of PE/PPE family members in different mycobacterial species and also during infection. Our attempt has been to provide a succinct overview of this interesting family. PMID- 26104968 TI - Conditioned pain modulation is not decreased after partial sleep restriction. AB - BACKGROUND: Sleep problems have been identified as a risk factor for several chronic pain conditions. Reduced sleep has been related to increased pain perception and it has been hypothesized that reduced pain inhibition may explain this. The aim of this study was to determine if sleep restriction (SR) affects heat pain perception and conditioned pain modulation (CPM). METHODS: In a paired cross-over design with two conditions (2 nights habitual sleep (HS) vs. 2 nights 50% SR) CPM was tested in 22 healthy individuals (14 women, 8 men). The test stimulus (TS) was 2-min contact heat stimulation (47 +/- 1.3 degrees C) to the volar forearm. TS was delivered before and during a 7 degrees C cold pressor test (conditioning stimulus, CS) to the contralateral hand. RESULTS: TS was perceived as more painful after SR compared to after HS (p < 0.001). A stronger inhibitory CPM was found after SR versus after HS (p < 0.001). CONCLUSIONS: The results indicate that SR leads to increased heat pain perception, but not reduced inhibitory CPM. This contradicts general assumptions on the relation between SR and the CPM effect. PMID- 26104969 TI - Efficacy of losartan for improving insulin resistance and vascular remodeling in hemodialysis patients. AB - Insulin resistance and vascular remodeling are prevalent and predict cardiovascular mortality in hemodialysis patients. Angiotensin II (Ang II) may be involved in both pathogenesis. In the present study, we investigated the effects of the Ang II receptor blocker losartan on insulin resistance, arterial stiffness, and carotid artery structure in hemodialysis patients. Seventy-two hemodialysis patients were randomly assigned to receive either losartan 50 mg qd (n = 36) or beta-blocker bisoprolol 5 mg qd (n = 36). At the start and at month 12, ambulatory blood pressure (BP) monitoring, aortic pulse wave velocity (PWV) measurements, and carotid artery ultrasound were performed, and homeostasis model assessment index of insulin resistance (HOMA-IR) was determined. During the study period, bioimpedance method was used to evaluate volume status every 3 months. Home-monitored BPs were measured at least monthly. Ambulatory BP decreased significantly and similarly by either losartan or bisoprolol. Decreases in PWVs in losartan group at the end of month 12 were significantly greater than changes in PWV in bisoprolol group (0.9 +/- 0.3 vs. 0.4 +/- 0.5 m/s, P = 0.021). Common carotid artery intima-media cross-sectional area decreased significantly only in patients treated with losartan (20.3 +/- 4.9 vs. 19.1 +/- 5.1 mm(2) , P = 0.001), and HOMA-IR was also reduced in losartan group only (1.9 +/- 1.0 vs. 1.7 +/- 0.8, P = 0.003). Multiple regression analysis showed significant correlations between changes in PWV and changes in HOMA-IR. With comparable BP-lowering efficacy, losartan achieved better improvement in insulin sensitivity, arterial stiffness, and carotid artery hypertrophy in hemodialysis patients. The regression of arterial stiffness may be in part through attenuation in insulin resistance. PMID- 26104971 TI - Salidroside Mitigates Sepsis-Induced Myocarditis in Rats by Regulating IGF 1/PI3K/Akt/GSK-3beta Signaling. AB - Sepsis-induced myocardial injury (SIMI) is caused by various mechanisms. The aim of this study was to investigate the effects of salidroside (Sal) on SIMI and its mechanisms in rats. The sepsis model was established by intraperitoneal injection of lipopolysaccharide (LPS) (15 mg/kg in sterile saline). Sal decreased the serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), whereas the expressions of insulin-like growth factor-1 (IGF-1) signaling-related proteins, such as IGF-1 and its corresponding receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3K), p-PI3K, Akt, p-Akt, and glycogen synthase kinase-3beta (GSK-3beta), in the heart were decreased with Sal pretreatment. Mitigated myocardial cell swelling, degeneration, loss of transverse striations, and inflammatory cell infiltration were also observed in the LPS + Sal groups. Thus, Sal is assumed to exert pronounced cardioprotective effects in rats subjected to LPS, probably through regulation of IGF-1/PI3K/Akt/GSK-3beta signaling. PMID- 26104973 TI - Gastroesophageal reflux and lung disease. AB - Gastroesophageal reflux (GER) can cause respiratory symptoms and may trigger, drive and/or worsen airway disorders, interstitial lung diseases and lung allograft dysfunction. Whether lifestyle changes and acid suppression alone can counter and prevent the adverse effects of GER on the respiratory tract remains unclear. Recent data suggest that antireflux surgery may be more effective in preventing lung disease progression in patients with idiopathic pulmonary fibrosis or lung transplant recipients who have evidence of allograft dysfunction associated with the presence of excessive GER. Additional research and clinical trials are needed to determine the role of GER in various lung disorders and identify which interventions are most efficacious in preventing the respiratory consequences of gastroesophageal reflux disease. In addition, measuring biomarkers that indicate that gastric refluxate has been aspirated into the lower respiratory tract (e.g., pepsin and bile acid concentrations in bronchoalveolar lavage fluid) may prove helpful in both diagnosis and therapeutic decision making. PMID- 26104972 TI - Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alstrom Syndrome: an observational study. AB - BACKGROUND: Alstrom syndrome is a rare inherited ciliopathy with progressive multisystem involvement. Dilated cardiomyopathy is common in infancy and recurs or presents de novo in adults with high rates of premature cardiovascular death. Although Alstrom syndrome is characterised by fibrosis in solid organs such as the liver, the pathogenesis of related cardiomyopathy are not clear. To date it is not known whether diffuse interstitial myocardial fibrosis is present before the onset of heart failure symptoms or changes in conventional parameters of left ventricular function. METHODS: In this observational study, 26 patients with Alstrom syndrome (mean age 27 +/- 9 years, 65 % male, 24 h ABPM 130 +/- 14 / 77 +/- 9 mmHg) without symptomatic cardiovascular disease were recruited from a single centre and compared to matched healthy controls. All subjects underwent cardiac MRI (1.5 T) to assess ventricular function, diffuse interstitial myocardial fibrosis by measurement of extracellular volume on T1-mapping (MOLLI) and coarse replacement fibrosis using standard late gadolinium enhancement imaging. RESULTS: Global extracellular volume was increased in Alstrom syndrome with wider variation compared to controls (0.30 +/- 0.05 vs. 0.25 +/- 0.01, p < 0.05). Left ventricular long axis function and global longitudinal strain were impaired in Alstrom syndrome without change in ejection fraction, ventricular size or atrial stress (NT-proBNP) (p < 0.05). Global extracellular volume was associated with reduced peak systolic longitudinal strain (r = -0.73, p < 0.01) and strain rate (r = -0.57, p < 0.01), increased QTc interval (r = 0.49, p < 0.05) and serum triglycerides (r = 0.66, p < 0.01). Nine (35 %) patients had diffuse mid-wall late gadolinium enhancement in a non-coronary artery distribution. CONCLUSION: Diffuse interstitial myocardial fibrosis is common in Alstrom syndrome and is associated with impaired left ventricular systolic function. Serial studies are required to determine whether global extracellular volume may be an independent imaging biomarker of vulnerability to dilated cardiomyopathy and heart failure. PMID- 26104974 TI - Absence of leukaemic CD34+ cells in acute myeloid leukaemia is of high prognostic value: a longstanding controversy deciphered. AB - Primary resistance and relapses after initial successful treatment are common in acute myeloid leukaemia and therefore outcome remains poor. More accurate risk group stratification and effective personalized risk adapted treatment are necessary to improve outcome. In the last two decades, controversial results have been published concerning the prognostic relevance of CD34 expression. In this study of 706 acute myeloid leukaemia patients, we established a new flow cytometric-based CD34-definition, without use of cut-off values. We discriminated CD34-positive (n = 548) and CD34-negative (n = 158) patients by the presence or absence of neoplastic CD34+ cells, respectively. CD34-status was defined using aberrant immunophenotypes and validated using molecular phenotypes. This new definition of CD34 enables strong prediction of treatment outcome in the entire patient group and in several risk subgroups. Previously observed discrepancies in prognostic impact of CD34 protein expression using cut-offs (5-20%) can now entirely be explained by considering the number of CD34-negative cases. In the total patient group, the absence of neoplastic CD34-positive cells is paralleled by low levels of minimal residual disease, suggesting relative therapy sensitivity and explaining longer survival. Overall, we present CD34 surface expression as a relatively simple, powerful and independent predictor of clinical outcome, now warranting incorporation in acute myeloid leukaemia risk stratification. PMID- 26104975 TI - Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery. AB - OBJECTIVE: The aim was to develop a delineation guideline for target definition for APBI or boost by consensus of the Breast Working Group of GEC-ESTRO. PROPOSED RECOMMENDATIONS: Appropriate delineation of CTV (PTV) with low inter- and intra observer variability in clinical practice is complex and needs various steps as: (1) Detailed knowledge of primary surgical procedure, of all details of pathology, as well as of preoperative imaging. (2) Definition of tumour localization before breast conserving surgery inside the breast and translation of this information in the postoperative CT imaging data set. (3) Calculation of the size of total safety margins. The size should be at least 2 cm. (4) Definition of the target. (5) Delineation of the target according to defined rules. CONCLUSION: Providing guidelines based on the consensus of a group of experts should make it possible to achieve a reproducible and consistent definition of CTV (PTV) for Accelerated Partial Breast Irradiation (APBI) or boost irradiation after breast conserving closed cavity surgery, and helps to define it after selected cases of oncoplastic surgery. PMID- 26104976 TI - New dosimetry for childhood skin hemangioma treatments with (226)Ra needles or tubes. AB - BACKGROUND: The Stockholm Hemangioma Cohort is important for evaluation of late effects after exposure to ionizing radiation during childhood. Dose estimates in this cohort were based on both measurements and calculations using an old treatment planning system. METHODS: We compare previously published and calculated dose estimates with new ones, obtained by Monte Carlo simulations, which mimic the hemangioma treatments with (226)Ra needles and tubes. The distances between the (226)Ra sources and the thyroid and breasts, respectively, were reassessed. RESULT: The Monte Carlo calculations showed significantly lower dose values than those obtained earlier. The differences depended both on the modeling of the sources and on further individualized distances from the sources. The mean value of the new calculated doses was 25% of the old breast doses and 46% of the old thyroid doses. CONCLUSION: New dosimetry for hemangioma treatments gives significantly lower organ doses for the few cases receiving the highest absorbed dose values. This implies that radiation risk estimates will increase and have to be recalculated. For retrospective studies it is now possible to calculate organ doses from radium treatments using modern treatment planning systems by modeling the source geometry carefully and apply the TG-43 formalism. It is important to be aware of the large uncertainties in calculated absorbed dose values. PMID- 26104977 TI - Pregnancy associated nasopharyngeal carcinoma: A retrospective case-control analysis of maternal survival outcomes. AB - BACKGROUND: Pregnancy-associated nasopharyngeal carcinoma (PANPC) has been associated with poor survival. Recent advances in radiation technology and imaging techniques, and the introduction of chemotherapy have improved survival in nasopharyngeal carcinoma (NPC); however, it is not clear whether these changes have improved survival in PANPC. Therefore, the purpose of this study was to compare five-year maternal survival in patients with PANPC and non-pregnant patients with NPC. METHODS: After adjusting for age, stage and chemotherapy mode, we conducted a retrospective case-control study among 36 non-metastatic PANPC patients and 36 non-pregnant NPC patients (control group) who were treated at our institution between 2000 and 2010. RESULTS: The median age of both groups was 30years (range, 23-35years); median follow-up for all patients was 70months. Locoregionally-advanced disease accounted for 83.3% of all patients with PANPC and 92.9% of patients who developed NPC during pregnancy. In both the PANPC and control groups, 31 patients (86.1%) received chemotherapy and all patients received definitive radiotherapy. The five-year rates for overall survival (70% vs. 78%, p=0.72), distant metastasis-free survival (79% vs. 76%, p=0.77), loco regional relapse-free survival (97% vs. 91%, p=0.69) and disease-free survival (69% vs. 74%, p=0.98) were not significantly different between the PANPC and control groups. Multivariate analysis using a Cox proportional hazards model revealed that only N-classification was significantly associated with five-year OS. CONCLUSION: This study demonstrates that, in the modern treatment era, pregnancy itself may not negatively influence survival outcomes in patients with NPC; however, pregnancy may delay the diagnosis of NPC. PMID- 26104978 TI - Transfemoral approach with systematic use of FemoSealTM closure device compared to transradial approach in primary angioplasty. AB - OBJECTIVES: To compare the incidence of major adverse cardiac and cerebrovascular events (MACCE) and thrombolysis in myocardial infarction (TIMI) bleedings in primary percutaneous coronary intervention (pPCI) performed through transradial approach (TRA) or transfemoral approach (TFA) with systematic closure by FemoSealTM. BACKGROUND: Although the risk of bleeding can be reduced using vascular closure devices (VCD), there are few data comparing TRA and TFA with VCD, particularly in the setting of pPCI. METHODS: we included in this retrospective registry 777 patients who underwent pPCI at two centers from years 2010 to 2013. Exclusion criteria were implantation of intra-aortic balloon pump and achievement of femoral hemostasis by other means than FemoSealTM. We performed propensity-score matching and multivariate analysis to adjust for clinical and procedural confounders. RESULTS: We enrolled 511 patients in TRA group and 266 in TFA group. Both in the general population and in the propensity matched population, the incidence of MACCE was comparable in TRA vs. TFA patients (3.5 vs. 3.4% and 4.4 vs. 2.6%, respectively; P = ns). On the contrary, we observed a higher incidence of TIMI bleedings in TFA vs. TRA patients (5.6 vs. 2.2% in the general population and 6.6 vs. 1.3% in the propensity-matched population; P < 0.05); this difference was mainly driven by TIMI major bleedings. TFA was an independent predictor of bleeding at multivariate analysis. CONCLUSIONS: In pPCI the rate of TIMI major bleedings was higher in TFA with closure by FemoSealTM as compared to TRA, whereas the rates of minor bleedings and of MACCE were similar. PMID- 26104979 TI - Re: Asia, Australia and New Zealand Dyspnoea in Emergency Departments (AANZDEM) study: Rationale, design and analysis. PMID- 26104980 TI - Optimization of arterial spin labeling MRI for quantitative tumor perfusion in a mouse xenograft model. AB - Perfusion is an important biomarker of tissue function and has been associated with tumor pathophysiology such as angiogenesis and hypoxia. Arterial spin labeling (ASL) MRI allows noninvasive and quantitative imaging of perfusion; however, the application in mouse xenograft tumor models has been challenging due to the low sensitivity and high perfusion heterogeneity. In this study, flow sensitive alternating inversion recovery (FAIR) ASL was optimized for a mouse xenograft tumor. To assess the sensitivity and reliability for measuring low perfusion, the lumbar muscle was used as a reference region. By optimizing the number of averages and inversion times, muscle perfusion as low as 32.4 +/- 4.8 (mean +/- standard deviation) ml/100 g/min could be measured in 20 min at 7 T with a quantification error of 14.4 +/- 9.1%. Applying the optimized protocol, heterogeneous perfusion ranging from 49.5 to 211.2 ml/100 g/min in a renal carcinoma was observed. To understand the relationship with tumor pathology, global and regional tumor perfusion was compared with histological staining of blood vessels (CD34), hypoxia (CAIX) and apoptosis (TUNEL). No correlation was observed when the global tumor perfusion was compared with these pathological parameters. Regional analysis shows that areas of high perfusion had low microvessel density, which was due to larger vessel area compared with areas of low perfusion. Nonetheless, these were not correlated with hypoxia or apoptosis. The results suggest that tumor perfusion may reflect certain aspect of angiogenesis, but its relationship with other pathologies needs further investigation. PMID- 26104982 TI - Eradication of Transboundary Animal Diseases: Can the Rinderpest Success Story be Repeated? AB - A matrix system was developed to aid in the evaluation of the technical amenability to eradication, through mass vaccination, of transboundary animal diseases (TADs). The system involved evaluation of three basic criteria - disease management efficiency, surveillance and epidemiological factors - each in turn comprised of a number of elements (17 in all). On that basis, 25 TADs that have occurred or do occur in southern Africa and for which vaccines are available, in addition to rinderpest (incorporated as a yardstick because it has been eradicated worldwide), were ranked. Cluster analysis was also applied using the same criteria to the 26 diseases, creating division into three groups. One cluster contained only diseases transmitted by arthropods (e.g. African horse sickness and Rift Valley fever) and considered difficult to eradicate because technologies for managing parasitic arthropods on a large scale are unavailable, while a second cluster contained diseases that have been widely considered to be eradicable [rinderpest, canine rabies, the Eurasian serotypes of foot and mouth disease virus (O, A, C & Asia 1) and peste des petits ruminants] as well classical swine fever, Newcastle disease and lumpy skin disease. The third cluster contained all the other TADs evaluated with the implication that these constitute TADs that would be more difficult to eradicate. However, it is acknowledged that the scores assigned in the course of this study may be biased. The point is that the system proposed offers an objective method for assessment of the technical eradicability of TADs; the rankings and groupings derived during this study are less important than the provision of a systematic approach for further development and evaluation. PMID- 26104983 TI - Hypertensive disorders of pregnancy and future health and mortality: A record linkage study. AB - The objective of this register-based cohort study was to examine the relationship between hypertensive disorders of pregnancy and future hospital discharges from specified causes including cardiovascular disease, incident cancer registrations and mortality. From the Aberdeen Maternity and Neonatal Databank we identified 34,854 women who were born on or before 31st December 1967 and who had (i) preeclampsia/eclampsia, (ii) gestational hypertension or (iii) normal blood pressure in their first pregnancy. Hospital discharges from selected causes including cardiovascular disease, cancer registrations and deaths in these women were identified from the Scottish Morbidity Records. There were 2026 women who had preeclampsia, 8891 who had gestational hypertension and 23,937 who were normotensive during their first pregnancy. Compared to normotensive women, women with preeclampsia had a higher mortality from ischaemic heart disease (adj. IRR 1.38, 95% CI 1.03, 1.84) and circulatory disease (adj. IRR 1.30, 95% CI 1.06, 1.60). Similar trends were seen with gestational hypertension. There was no difference in all cause mortality in the three groups. The odds of a hypertensive episode were higher in women with preeclampsia (adj. OR 1.79, 95% CI 1.55, 2.05) and gestational hypertension (adj. OR 1.68, 95% CI 1.55, 1.82) compared to normotensives. Compared to normotensives, women with gestational hypertension (adj. IRR 0.91, 95% CI 0.85, 0.96) or preeclampsia (adj. IRR 0.86, 95% CI 0.77, 0.97) had lower incidences of cancer. Women with pregnancy induced hypertension are at a higher risk of incidence and mortality from ischaemic heart disease and a lower risk of cancer. PMID- 26104984 TI - A single rapid point-of-care placental growth factor determination as an aid in the diagnosis of preeclampsia. AB - OBJECTIVES: To evaluate the clinical performance of a rapid point-of-care test, Triage PLGF (Alere, San Diego) in the diagnosis of preeclampsia. STUDY DESIGN: For the reference range 2212 plasma samples were collected from 595 subjects with normotensive pregnancies, between week 17 of gestation and delivery. In the case control part, two cohorts of women with preeclampsia (80 women) were matched for maternal age, gestational age (GA) at sampling and parity with normotensive women who delivered at 37weeks or more. RESULTS: The areas under the receiver operating characteristic curves (GA<35weeks) were 1.0 and 0.994 (cohort 1 and 2, respectively). The clinical sensitivity of the Triage PLGF test for the pooled GA range of 21?GA<35, using a GA dependent cut-off, was 1.0 for both cohorts with specificities of 1.0 and 0.940. CONCLUSIONS: The Triage PLGF test distinguishes well between preterm pregnancies with and without preeclampsia. PMID- 26104985 TI - Transient gestational hypertension: Not always a benign event. AB - OBJECTIVE: Pregnancy outcome in women with transient gestational hypertension (TGH);defined as de novo blood pressure elevation after 20weeks gestation that normalizes by subsequent evaluation in a Day Assessment Unit. STUDY DESIGN: Retrospective cohort analysis of hypertensive pregnancies between 2003 and 2008. MAIN OUTCOME MEASURES: Final hypertensive delivery diagnosis and composites of adverse maternal and fetal outcome. RESULTS: Overall 1417 women were referred; 890 met criteria; 41% (65% of study population) had TGH. Twenty percent with TGH developed gestational hypertension and 19% preeclampsia. Women with TGH who developed preeclampsia had similar composite adverse maternal outcomes to other preeclamptic women (51% vs. 63%; p=0.24) but fewer adverse fetal outcomes (50% vs. 71%; p<0.01) due to less prematurity (30% vs. 45%; p=0.02) and small for gestational age babies (33% vs. 51%; p=0.02). Within the TGH population;developing gestational hypertension or preeclampsia was associated with referral at gestation <33weeks (RRR 2.8; p<0.01);initial average systolic blood pressure 130-139mmHg (RRR 2.1; p<0.01) and initial average diastolic blood pressure 80-89mmHg (RRR 3.2; p<0.01). CONCLUSION: TGH after 20weeks is common in pregnancy. Although initial assessment implies low risk;the risk of progression to gestational hypertension or preeclampsia is substantial and warrants appropriate clinical surveillance. PMID- 26104986 TI - Body mass index and hypertensive disorders of pregnancy. AB - OBJECTIVES: We compared the incidence of the hypertensive disorders of pregnancy in obese women with women of a normal body mass index (BMI). STUDY DESIGN: Prospective observational study in which BMI was calculated accurately early in pregnancy. Women were enrolled after a sonographic confirmation of an ongoing pregnancy. To reduce confounding variables the study was confined to white European women with a singleton pregnancy. MAIN OUTCOME MEASURES: Incidence of pre-eclampsia and gestational hypertension. RESULTS: In 2230 women, 16.8% were obese. Pre-eclampsia was diagnosed in 3.3% (n=74) and gestational hypertension in 3.0% (n=67). Both pre-eclampsia (p=0.01) and gestational hypertension (p<0.01) were common in obese women compared with normal weight women. Overall 13.1% of obese women developed a hypertensive disorder during pregnancy. When analysed by parity pre-eclampsia occurred in 2.1% of primigravidas and 0.3% of multigravidas. Pre-eclampsia was increased in obese multigravidas (p=0.001), but not obese primigravidas, suggesting that parity is more influential than obesity in the development of pre-eclampsia. CONCLUSIONS: Obese multigravidas are more likely to develop hypertensive disorders in pregnancy and obese primigravidas are more likely to develop gestational hypertension. This is important in clinical practice because maternal weight, unlike parity, is potentially modifiable before or during pregnancy. PMID- 26104987 TI - Treatment approaches for preeclampsia in low-resource settings: A randomized trial of the Springfusor pump for delivery of magnesium sulfate. AB - OBJECTIVE: To test the safety, efficacy, and acceptability of a simple, mechanically flow-controlled pump (Springfusor(r)) for the delivery of magnesium sulfate for the treatment of preeclampsia. DESIGN: Eligible women (n=300) had blood pressure ?140/100mmHg, and proteinuria ?1+ (30mgdL); the clinic team determined that they were likely to benefit from magnesium sulfate. Women were randomized to 24h of magnesium sulfate by either IV administered by the Springfusor(r) pump (n=147) or standard hospital practice - IV loading dose administered manually followed by maintenance therapy using an IM route of administration (n=153). MAIN OUTCOME MEASURES: Our primary outcome of interest was the safety and efficacy of the Springfusor pump including the side and adverse effects experienced during drug administration. Data on side effects, patient acceptability, delivery complications, and maternal and neonatal outcomes were collected. RESULTS: Fewer women stopped treatment due to side effects, toxicity, oliguria or renal failure, or women's request in the Springfusor arm (4% or 6 of 147 women) compared to the Standard of Care arm (6.5% or 10 of 153 women). Women in the Springfusor arm reported significantly less nausea, headache, and pain than women in the Standard of Care arm. Almost all women (97%) in the Springfusor arm reported their pain level as 'acceptable' or 'very acceptable' compared to only 30% of women given the Standard of Care. CONCLUSION: The Springfusor pump may offer an alternative to intramuscular administration of magnesium sulfate where electronic pumps are not available. PMID- 26104988 TI - Comparison of maternal serum levels of interleukin-10, interleukin-12, and interleukin-2 in normal and preeclamptic pregnancies. AB - OBJECTIVE: The aim of this study was 2 fold: (1) to compare the maternal serum levels of IL-10, IL-12, and IL-2 in preeclamptic and normal pregnant women, and (2) to study the serum levels of these cytokines in preeclamptic pregnancies with and without intrauterine growth retardation. STUDY DESIGN: Forty women with singleton pregnancies complicated by preeclampsia (32 severe and 8 mild) and 29 normotensive healthy pregnant women were included in the study. Preeclamptic patients were further divided into 2 groups according to the presence or absence of intrauterine growth retardation. Maternal serum levels of IL-10, IL 12, and IL 2 were compared between these groups using enzyme-linked immunosorbent assays. RESULTS: Maternal serum levels of IL-10 were significantly higher in the preeclampsia group than in controls (p<0.001). There were no statistically significant differences in maternal serum concentrations of IL-2 and IL-10 between the study and control groups (p>0.05). Serum levels of IL-2 and IL-10 in the patients with preeclampsia complicated by IUGR were elevated in comparison with the uncomplicated preeclampsia group. These differences were statistically significant (p<0.05 for both). CONCLUSIONS: IL-10 may be involved in the pathologic process of preeclampsia. Increased serum levels of IL-10 and IL-2 in preeclampsia complicated with IUGR suggests a possible role of these cytokines in IUGR. PMID- 26104989 TI - The role of podocytes in the early detection of pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia is a significant cause of maternal and neonatal mortality and morbidity in resource constrained countries. Because the exact aetiology is unknown, treatment of preeclampsia is empiric. Therefore, researchers have been investigating biomarkers for early detection of the syndrome to take steps to prevent complications. The kidney is reported to be affected by the preeclamptic process before clinical signs appear. Podocytes have been suggested as possible markers for this syndrome. However there is debate as to which is the best way to measure the amount of podocyturia. OBJECTIVE: To determine the best method to estimate podocyturia as a biomarker. METHODS: Midstream urine specimens were collected from 18 normotensive healthy primigravidae at their first antenatal visit. Urinary podocyte immunolabelling was performed by two techniques viz., culture and cytospin on urine from normotensive and clinically healthy pregnant women. MAIN OUTCOME MEASURED: Are the podocyte specific proteins, podocalyxin, podocin, nephrin and synaptopodin able to detect pre-eclampsia prior to the development of clinical signs as measured by two separate techniques. RESULTS: The results suggest that the expression of podocyte specific proteins, podocalyxin, podocin, nephrin and synaptopodin, is identifiable and quantifiable from midstream urine in healthy normotensive pregnant women. Cytospin was more efficient in determining the podocyte specific protein expression levels and podocalyxin was the most sensitive marker, with a Kappa coefficient of 0.23. CONCLUSIONS: These findings suggest that immuno-expression of podocyturia are best detected by the cytospin method. PMID- 26104990 TI - Plasma soluble corin and N-terminal pro-atrial natriuretic peptide levels in pregnancy induced hypertension. AB - OBJECTIVE: One of the theories involved in the pathogenesis of pregnancy induced hypertension involves salt and water retention. We aimed to measure the proenzyme convertase corin, responsible for pro-atrial natriuretic peptide (ANP) cleavage to active ANP, in plasma of hypertensive pregnant females. STUDY DESIGN: Sixty pregnant females suffering from pregnancy induced hypertension in second and third trimesters of pregnancy were compared to twenty eight healthy pregnant females of the same gestational period. Concomitant urine and plasma samples were collected for the determination of some biochemical parameters. Plasma soluble corin and N-terminal (NT) pro-ANP (1-98) values were determined in both groups using enzyme immunoassays. RESULTS: Plasma soluble corin mean value was significantly higher in the patient group compared to the control group. Upon dividing the patient group according to blood pressure, plasma NT pro-ANP showed significantly higher mean value in the group with blood pressure?140/90mmHg compared to the group with blood pressure<140/90mmHg and control group. CONCLUSIONS: High plasma soluble corin and NT pro-ANP values in hypertensive pregnant females particularly those with blood pressure?140/90mmHg speculates an ANP receptor/ post receptor signaling defect, which would aggravate the pregnancy induced hypertensive state. PMID- 26104991 TI - Effect of nitric oxide deficiency on tissue-type plasminogen activator expression in the umbilical cord in a pregnancy-induced hypertension rat model. AB - OBJECTIVES: Our study investigates the effects of nitric oxide (NO) deficiency during pregnancy on coagulation and fibrinolysis balance in fetal circulation. MAIN OUTCOME MEASURES: Pregnant rats were treated with or without oral N(G)-nitro l-arginine methyl ester (L-NAME). Systolic blood pressure (SBP) and urinary protein were measured. On gestational day 20, mRNA levels of tissue-type plasminogen activator (tPA), tissue factor (TF), and TF pathway inhibitor (TFPI) in the umbilical cord, placenta, and maternal aorta were evaluated. Immunohistochemical staining of the placenta for PA inhibitor-1 (PAI-1) was performed. RESULTS: L-NAME treatment in pregnant rats caused significant SBP elevation and severe proteinuria. In the L-NAME-treated group, weights of fetuses and placentae were diminished. tPA mRNA expression decreased in the umbilical cord and placenta, whereas TF and TFPI mRNA levels did not change. Intense PAI-1 immunoreactivity was observed in a part of degenerated placenta. In the aorta, tPA mRNA expression increased in the L-NAME-treated group, while TFPI mRNA levels were lower than in controls. CONCLUSIONS: NO deficiency during pregnancy decreased tPA mRNA expression in the umbilical cord and placenta but not in the maternal aorta. Imbalance between coagulation and fibrinolysis in fetal and maternal circulations may, at least in part, contribute to fetal growth restriction. PMID- 26104992 TI - Calcium-to-creatinine ratio in pregnancy-induced hypertension. AB - OBJECTIVES: Hypocalciuria has been correlated with preeclampsia. This study compared the calcium-to-creatinine ratio among the groups, and the correlation with the 24-h measurement of this ratio and a diagnosis of preeclampsia. STUDY DESIGN: Case-control study including mild and severe preeclampsia, chronic hypertension and normal pregnancy. MAIN OUTCOME MEASUREMENTS: The calcium-to creatinine ratio differentiates severe preeclampsia from mild preeclampsia, chronic hypertension and normal pregnancy. RESULTS: There were statistically significant differences between the groups when comparing severe preeclampsia and chronic hypertension, severe preeclampsia and normal pregnancy, and mild and severe preeclampsia (p<0.0001). The Spearman index between the calcium-to creatinine ratio and 24-h calciuria was 0.65 (high correlation). CONCLUSIONS: The calcium-to-creatinine ratio can reliably estimate 24-h calciuria, differentiating severe preeclampsia from mild preeclampsia, chronic hypertension and normal pregnancy. PMID- 26104993 TI - Question Prompt Lists in health consultations: A review. AB - OBJECTIVES: This review examines the use and effectiveness of Question Prompt Lists (QPL) as communication aids to enhance patient question asking, information provision to patients and patient participation in health and medical consultations. METHODS: A systematic search was undertaken to identify relevant literature concerning QPLs including academic databases, Google-based and snowball searching. Forty-two relevant studies reporting 50 interventions were identified. RESULTS: Although findings varied there was some evidence that a QPL endorsed by the physician increased total question asking. Using a QPL increased question asking concerning specific content areas (e.g. prognosis). There was some evidence that physicians provided more information during consultations. There were no consistent findings concerning effects on patient knowledge recall, anxiety and satisfaction or consultation time. Some interventions that increased question asking had longer consultation times. CONCLUSION: There is evidence that an appropriate QPL, endorsed by the physician and provided immediately before the consultation, may increase patient question asking and lead to more information being provided by the physician. PRACTICE IMPLICATIONS: There is increasing evidence to support QPL use in routine practice. Further trials might address the issues identified including an assessment of QPL optimal length and QPL adaptation for cultural and special needs groups. PMID- 26104994 TI - Development of a brief questionnaire to assess contraceptive intent. AB - OBJECTIVE: We sought to develop and validate an instrument that can enable providers to identify young women who may be at risk of contraceptive non adherence. METHODS: Item response theory based methods were used to evaluate the psychometric properties of the Contraceptive Intent Questionnaire, a 15-item self administered questionnaire, based on theory and prior qualitative and quantitative research. The questionnaire was administered to 200 women aged 15-24 years who were initiating contraceptives. We assessed item fit to the item response model, internal consistency, internal structure validity, and differential item functioning. RESULTS: All items fit a one-dimensional model. The separation reliability coefficient was 0.73. Participants' overall scores covered the full range of the scale (0-15), and items appropriately matched the range of participants' contraceptive intent. Items met the criteria for internal structure validity and most items functioned similarly between groups of women. CONCLUSION: The Contraceptive Intent Questionnaire appears to be a reliable and valid tool. Future testing is needed to assess predictive ability and clinical utility. PRACTICE IMPLICATIONS: The Contraceptive Intent Questionnaire may serve as a valid tool to help providers identify women who may have problems with contraceptive adherence, as well as to pinpoint areas in which counseling may be directed. PMID- 26104995 TI - Surface plasmons in quantum-sized noble-metal clusters: TDDFT quantum calculations and the classical picture of charge oscillations. AB - The localized surface-plasmon resonance of metal nanoparticles corresponds to a classical charge oscillation of the quasi-free conduction electrons. In the case of noble-metal nanoparticles, interband transitions from the d electrons influence the spectra strongly. In addition, the inhomogeneity of the nanoparticles at the atomistic level becomes important for small sizes. Using the time-evolution formulation of time-dependent density-functional theory, we show that in spherical 147-atom silver clusters, the localized surface-plasmon resonance corresponds indeed to a collective charge oscillation resembling the schematic picture, while the dynamics in a comparable gold cluster shows multiple modes which correspond to the spectra without strong resonance. Short nanorods show the same difference between Au and Ag. However, nanorods of high aspect ratio develop a silver-like charge oscillation. Monatomic silver chains behave similarly to the nanorods and show a clear transverse charge oscillation mode. The role of the d electrons in the screening of the localized surface-plasmon resonance is demonstrated. PMID- 26104996 TI - Fungal contamination of nebuliser devices used by people with cystic fibrosis. AB - BACKGROUND: Poor nebuliser hygiene can result in bacterial contamination and risk of infections. The aim of this study was to assess the prevalence of fungal contamination of nebulisers used by adults with cystic fibrosis. METHODS: A total of 170 nebulisers from 149 subjects were screened by wetting a sterile cotton swab with sterile water and swabbing each drug chamber. The swab was then plated out on Sabouraud and on Scel+agar and incubated at 27 degrees C for up to 2 weeks. RESULTS: Fungal cultures were positive in 86 (57.7%) patient's devices. In 28/149 (18.8%), 39/149 (26.2%), 47/149 (31.5%) and 20/149 (13.4%) of subjects Aspergillus species, yeasts, moulds and both yeasts and moulds were isolated respectively. There was no difference in contamination rates between different devices. CONCLUSION: Nebuliser devices are frequently contaminated by moulds and yeasts and emphasis should be placed on ensuring adequate nebuliser hygiene. PMID- 26104997 TI - Fear of Childbirth and Preference for Cesarean Delivery Among Young American Women Before Childbirth: A Survey Study. AB - BACKGROUND: Fear of birth and mode of delivery preferences are similar among pregnant and nonpregnant women, suggesting that attitudes toward birth are formed in young adulthood or earlier. Understanding why some young women fear birth and prefer obstetric interventions can inform public health initiatives aimed at reducing fear and promoting birth as a normal life event. METHODS: We conducted an online survey with 752 American nulliparous young women to assess their preferences and attitudes toward childbirth. We identified explanatory variables associated with reported fear of childbirth and cesarean delivery (CD) preferences. RESULTS: A preference for CD was reported by 14 percent of young women and 27 percent had scores indicating elevated fear of birth. Fear of birth increased the likelihood of cesarean preference (adjusted relative risk (ARR) 3.84 [95% CI 2.49-5.95]) as did a family history of CD (ARR 1.65 [95% CI 1.13 2.42]). The likelihood of reporting elevated childbirth fear was increased among young women who reported concerns about the physical changes pregnancy and birth have on women's bodies (ARR 2.04 [95% CI 1.50-2.78]). Young women who reported a high degree of confidence in their knowledge about childbirth were significantly less likely to report childbirth fear (ARR 0.61 [95% CI 0.42-0.87]). Access to childbirth information was also associated with a decreased likelihood of fear of birth (ARR 0.75 [95% CI 0.59-0.95]). CONCLUSIONS: Young women reporting high levels of childbirth fear are nearly four times more likely to prefer a CD. Specific fears, such as worries over the influence of pregnancy and birth on the female body, need to be addressed before pregnancy. PMID- 26104999 TI - Mechanochemical Reactions Reporting and Repairing Bond Scission in Polymers. AB - The past 10 years have seen a resurgence of interest in the field of polymer mechanochemistry. Whilst the destructive effects of mechanical force on polymer chains have been known for decades, it was only recently that researchers tapped into these forces to realize more useful chemical transformations. The current review discusses the strategic incorporation of weak covalent bonds in polymers to create materials with stress-sensing and damage-repairing properties. Firstly, the development of mechanochromism and mechanoluminescence as stress reporters is considered. The second half focuses on the net formation of covalent bonds as a response to mechanical force, via mechanocatalysis and mechanically unmasked chemical reactivity, and concludes with perspectives for the field. PMID- 26104998 TI - Sequential karyotyping in Burkitt lymphoma reveals a linear clonal evolution with increase in karyotype complexity and a high frequency of recurrent secondary aberrations. AB - Typical Burkitt lymphoma is characterized by an IG-MYC translocation and overall low genomic complexity. Clinically, Burkitt lymphoma has a favourable prognosis with very few relapses. However, the few patients experiencing disease progression and/or relapse have a dismal outcome. Here we report cytogenetic findings of seven cases of Burkitt lymphoma in which sequential karyotyping was performed at time of diagnosis and/or disease progression/relapse(s). After case selection, karyotype re-review and additional molecular analyses were performed in six paediatric cases, treated in Berlin-Frankfurt-Munster-Non-Hodgkin lymphoma study group trials, and one additional adult patient. Moreover, we analysed 18 cases of Burkitt lymphoma from the Mitelman database in which sequential karyotyping was performed. Our findings show secondary karyotypes to have a significant increase in load of cytogenetic aberrations with a mean number of 2, 5 and 8 aberrations for primary, secondary and third investigations. Importantly, this increase in karyotype complexity seemed to result from recurrent secondary chromosomal changes involving mainly trisomy 21, gains of 1q and 7q, losses of 6q, 11q, 13q, and 17p. In addition, our findings indicate a linear clonal evolution to be the predominant manner of cytogenetic evolution. Our data may provide a biological framework for the dismal outcome of progressive and relapsing Burkitt lymphoma. PMID- 26105000 TI - Value of Antral Nodularity for the Diagnosis of Helicobacter pylori Infection in Children. AB - BACKGROUND: The aim of this study was to confirm the role of antral nodularity in the diagnosis of Helicobacter pylori (H. pylori) infection in children. MATERIAL AND METHODS: This prospective study included 107 children (58 male; 54.2%), between the ages of 3 and 18 years, infected with H. pylori, which was confirmed if the patient had at least 2 of 4 positive test results (urea breath test, urease test in gastric biopsy, histopathology - positive hematoxylin and eosin and Giemsa staining, and/or monoclonal stool ELISA test - Amplified IDEIATM Hp StARTM). The control group consisted of 234 children with abdominal pain, of similar age, in whom urease test in gastric tissue and histopathology were negative. In both groups, photographs of the gastric antrum taken during endoscopy were evaluated for nodularity by 3 independent endoscopists, blinded to the results of other tests. Sensitivity, specificity, and negative and positive predictive value of nodularity were assessed. Indication for upper endoscopy was chronic abdominal pain not considered to be functional. RESULTS: There were no statistical differences between groups regarding sex (chi-square test with Yates's correction: p=0.8763) or age (mean +/-SD) 11.77+/-3.49 and 12.43+/-3.32, study and control groups, respectively (Mann-Whitney test: p=0.1352). The sensitivity of the presence of nodularity as an indication of H. pylori infection was 91.6% and specificity was 91%. PPV of gastric nodularity was 81% and NPV was 96%. CONCLUSIONS: Antral nodularity is reliable test. Physicians could start treatment of H. pylori infection whenever gastric nodularity is observed and the urease test result is positive, without waiting for histopathology results. PMID- 26105002 TI - Effects of new class III antiarrhythmic drug niferidil on electrical activity in murine ventricular myocardium and their ionic mechanisms. AB - A new class III antiarrhythmic drug niferidil has been recently introduced as a highly effective therapy cure for cases of persistent atrial fibrillation, but ionic mechanisms of its action are still unknown. Effects of niferidil on action potential (AP) waveform and major ionic currents were studied in mouse ventricular myocardium. APs were recorded with glass microelectrodes in multicellular preparations of right ventricular wall. Whole-cell patch-clamp technique was used to measure K(+), Ca(2+), and Na(+) currents in isolated mouse ventricular myocytes. While 10(-7) M niferidil failed to alter the AP configuration, 10(-6) M tended to prolong APs (by 12.05 +/- 1.8% at 50% of repolarization) and 10(-5) M induced significant slowing of repolarization (32.1 +/- 4.9% at 50% of repolarization). Among the potassium currents responsible for AP repolarization phase, IK1 was found to be almost insensitive to niferidil. Ito demonstrated low sensitivity to niferidil with IC50 = 2.03 * 10(-4) M. IKur, which was previously hypothesized to be the main target of the drug, was more sensitive with IC50 = 6 * 10(-5) M. However, sustained delayed rectifier potassium current Iss was inhibited with even lower IC50 = 2.8 * 10(-5) M. Therefore, suppression of Iss and, second, IKur by niferidil seems to underlie the AP prolongation in mouse ventricular tissue. Niferidil also produced a modest decrease in ICaL peak amplitude (IC50~10(-4) M), but failed to alter INa significantly. Niferidil prolongs APs in mouse ventricular myocardium mainly by inhibiting Iss and IKur K(+) currents, but not exclusively IKur, as was proposed earlier. Further investigations are required to reveal the mechanisms of niferidil action in human myocardium, where IKr is strongly expressed instead of Iss. PMID- 26105001 TI - Effect of thioridazine on antioxidant status of HEMn-DP melanocytes. AB - Thioridazine as an antipsychotic agent was extensively used to treat various psychotic disorders, e.g. schizophrenia. However, the therapy with this drug can induce serious side effects such as extrapyramidal symptoms or ocular and skin disorders, which mechanisms are still not fully established. To gain inside the molecular mechanisms underlying thioridazine toxicity, we examined the effect of this drug on cell viability, antioxidant defence system as well as melanogenesis in normal human melanocytes. It was demonstrated that thioridazine induces concentration-dependent loss in cell viability. The value of EC50 was calculated to be 2.24 MUM. To study the effect of thioridazine on antioxidant defence system in melanocytes, the level of hydrogen peroxide and the activities of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase were determined. The drug in concentrations of 0.1, 0.25, 1.0 and 2.5 MUM caused changes in cellular antioxidant defence system indicating the induction of oxidative stress. It was also shown that the analysed neuroleptic in concentrations of 1.0 and 2.5 MUM significantly inhibited melanogenesis. The observed changes in cell viability, antioxidant defence system and melanization in normal human melanocytes after thioridazine treatment may explain an important role of reactive oxygen species as well as melanin in mechanisms involved in this drug side effects directed on pigmented tissues. PMID- 26105003 TI - Anti-tumor properties of the cGMP/protein kinase G inhibitor DT3 in pancreatic adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Therefore, new therapeutic options are urgently needed to improve the survival of PDAC patients. Protein kinase G (PKG) conducts the interlude of cGMP signaling which is important for healthy as well as for cancer cells. DT3 is a specific inhibitor of PKG, and it has been shown to possess an anti-tumor cytotoxic activity in vitro. The main aim of this work was to investigate anti tumor effects of DT3 upon PDAC in vivo.Expression of PKG was assessed with real time PCR analysis in the normal and tumor pancreatic cells. In vitro cell viability, proliferation, apoptosis, necrosis, migration, and invasion of the murine PDAC cell line Panc02 were assessed after DT3 treatment. In vivo anti tumor effects of DT3 were investigated in the murine Panc02 orthotopic model of PDAC. Western blot analysis was used to determine the phosphorylation state of the proteins of interest.Functional PKGI is preferentially expressed in PDAC cells. DT3 was capable to reduce viability, proliferation, and migration of murine PDAC cells in vitro. At the same time, DT3 treatment did not change the viability of normal epithelial cells of murine liver. In vivo, DT3 treatment reduced the tumor volume and metastases in PDAC-bearing mice, but it was ineffective to prolong the survival of the tumor-bearing animals. In addition, DT3 treatment decreased phosphorylation of GSK-3, P38, and CREB in murine PDAC.Inhibition of PKG could be a potential therapeutic strategy for PDAC treatment which should be carefully validated in future pre-clinical studies. PMID- 26105004 TI - Effects of an in-hospital nursing intervention on changing illness perceptions in patients with injury. AB - AIM: The aim of this study was to evaluate the effectiveness of a nursing intervention in changing the illness perceptions of injured patients. BACKGROUND: Illness perceptions have been found to be among the important patient outcomes after an injury. Research has suggested that a designed intervention might be an effective means of shaping injured patients' illness perceptions. DESIGN: An experimental study design was employed. METHODS: A total of 82 injured patients completed this study, with 42 in the experimental group and 40 in the control group. Data were collected from 2011-2013. A trained nurse practitioner delivered an in-hospital nursing intervention according to self-regulatory theory. The outcome measure was the change in illness perceptions of injury among the patients as measured by the Chinese Illness Perception Questionnaire Revised Trauma (the Chinese IPQ-R-Trauma), which comprises eight subscales. The experimental and control groups were followed up via telephone survey 3 months after discharge. The generalized estimating equations were used to analyse the data. RESULTS: The results showed statistically significant differences on two subscales of the Chinese IPQ-R-Trauma, Identity and Controllability, before and after the intervention. Results for the remaining six subscales did not change significantly. The findings indicate that the intervention resulted in a decrease in injury-related physical symptoms and in increases in positive perceptions among patients about controlling their postinjury condition. CONCLUSIONS: This nursing intervention led to changes in patients' illness perceptions and potentially improved the patients' self-regulation after their injuries. Future research can be conducted to enhance the effectiveness of the intervention protocol. PMID- 26105005 TI - The studies of N-Octyl-N-Arginine-Chitosan coated liposome as an oral delivery system of Cyclosporine A. AB - OBJECTIVES: An amphiphilic polymer N-Octyl-N-Arginine-Chitosan (OACS) was synthesized to coat the Cyclosporine A (CsA) liposomes (CL) to decrease the destruction of liposomes in gastrointestinal tract (GI) tract and improve its oral absorption. METHODS: CL and OACS-CsA liposomes (OACS-CL) were prepared by rotary-film evaporation method, and characterized by dynamic light scattering, transmission electron microscopy, atomic force microscope and releasing properties. In-situ single pass perfusion experiment and in-vivo studies in rats were carried out to verify its absorption enhancement. KEY FINDINGS: The characterization results showed that its particle size, zeta potential and morphology changed before and after polymer coating. Release experiment indicated that OACS could slow down drug release and protect its degradation in the stomach. In-situ single pass perfusion proved that the absorption of OACS-CL at the jejunum was enhanced about 3 and 22 times compared with commercial preparation of microemulsions (Tianke) and CsA suspensions, respectively. In vivo, AUC0->infinity of three different OACS-CL groups (93.48 +/- 2.54, 100.98 +/ 13.08 and 99.01 +/- 19.02 h.MUg/ml, respectively) were higher than those of Tianke (69.34 +/- 7.93 h.MUg/ml), CL group (54.31 +/- 6.70 h.MUg/ml) and suspensions (31.14 +/- 1.30 h.MUg/ml). CONCLUSIONS: Therefore, OACS coated liposomes can be an effective strategy to promote drug's absorption and further reduce the anaphylactic reaction of abundant surfactants in commercial preparations. PMID- 26105006 TI - The RGD sequence present in IGFBP-2 is required for reduced glucose clearance after oral glucose administration in female transgenic mice. AB - Recent studies suggest that insulin-like growth factor-binding protein-2 (IGFBP 2) affects both growth and metabolism. Whereas negative growth effects are primarily due to negative interference with IGF-I, the mechanisms for metabolic interference of IGFBP-2 are less clear. As we demonstrate, overexpression of IGFBP-2 in transgenic mice is correlated with a decelerated clearance of blood glucose after oral administration. IGFBP-2 carries an integrin-binding domain (RGD motif), which has been shown to also mediate IGF-independent effects. We thus asked if higher serum levels of IGFBP-2 without an intact RGD motif would also partially block blood glucose clearance after oral glucose application. In fact, transgenic mice overexpressing mutated IGFBP-2 with higher levels of IGFBP 2 carrying an RGE motif instead of an RGD were not characterized by decelerated glucose clearance. Impaired glucose tolerance was correlated with lower levels of GLUT4 present in plasma membranes isolated from muscle tissues after glucose challenge. At the same time, activation of TBC1D1 was depressed in mice overexpressing wild-type but not mutated IGFBP-2. Although we do not have reason to assume altered activation of IGF-I receptor or PDK1/Akt activation in both models, we have identified increased levels of integrin-linked kinase and focal adhesion kinase dependent on the presence of the RGD motif. From our results we conclude that impaired glucose clearance in female IGFBP-2 transgenic mice is dependent on the presence of the RGD motif and that translocation of GLUT4 in the muscle may be regulated by IGFBP-2 via RGD-dependent mechanisms. PMID- 26105007 TI - Effect of lipopolysaccharides on adipogenic potential and premature senescence of adipocyte progenitors. AB - The elevation of circulating LPS has been associated with obesity and aging. However, whether and how LPS contributes to adipose tissue dysfunction is unclear. In this study, we investigated the effect of LPS on the adipogenic capacity and cellular senescence of adipocyte progenitors. Stromal-vascular cells were isolated from inguinal adipose tissue of C57BL/6 mice and treated with LPS during the different time periods of adipocyte differentiation. We found that LPS treatment for 24 h prior to the induction of differentiation led to the most profound effect on the inhibition of adipogenesis, as evidenced by the morphological changes and the decreased mRNA expression of adipocyte marker genes. In addition, LPS induced features of premature senescence of SV cells, including the activation of p53, the elevation of SA-beta-gal activity, and increased hydrogen peroxide production, but not telomere length. Upon LPS treatment, SV cells also developed senescence-associated secretory phenotype (SASP), as demonstrated by the increased expression of TNFalpha, IL-1beta, IL-6, MCP-1, and VEGFalpha. Blocking LPS-induced NF-kappaB activation and cytokine production by Bay 11-7082 failed to rescue the impaired adipogenesis and the reduction in PPARgamma and Zfp423 expression. On the contrary, rosiglitazone had little effect on cytokine production but corrected the defective adipogenic potential. In conclusion, we demonstrate that LPS inhibits adipogenesis by disrupting the differentiation of adipocyte progenitors in a NF-kappaB independent manner; LPS also induces premature senescence of adipocyte progenitors. Our data suggest that LPS could be a potential contributor to the defective adipogenesis and the development of cellular senescence in adipose tissue during obesity and aging. PMID- 26105008 TI - Effect of N-acetylcysteine infusion on exercise-induced modulation of insulin sensitivity and signaling pathways in human skeletal muscle. AB - -Reactive oxygen species (ROS) produced in skeletal muscle may play a role in potentiating the beneficial responses to exercise; however, the effects of exercise-induced ROS on insulin action and protein signaling in humans has not been fully elucidated. Seven healthy, recreationally active participants volunteered for this double-blind, randomized, repeated-measures crossover study. Exercise was undertaken with infusion of saline (CON) or the antioxidant N acetylcysteine (NAC) to attenuate ROS. Participants performed two 1-h cycling exercise sessions 7-14 days apart, 55 min at 65% Vo2peak plus 5 min at 85%Vo2peak, followed 3 h later by a 2-h hyperinsulinemic euglycemic clamp (40 mIU.min(-1).m(2)) to determine insulin sensitivity. Four muscle biopsies were taken on each trial day, at baseline before NAC infusion (BASE), after exercise (EX), after 3-h recovery (REC), and post-insulin clamp (PI). Exercise, ROS, and insulin action on protein phosphorylation were evaluated with immunoblotting. NAC tended to decrease postexercise markers of the ROS/protein carbonylation ratio by -13.5% (P = 0.08) and increase the GSH/GSSG ratio twofold vs. CON (P < 0.05). Insulin sensitivity was reduced (-5.9%, P < 0.05) by NAC compared with CON without decreased phosphorylation of Akt or AS160. Whereas p-mTOR was not significantly decreased by NAC after EX or REC, phosphorylation of the downstream protein synthesis target kinase p70S6K was blunted by 48% at PI with NAC compared with CON (P < 0.05). We conclude that NAC infusion attenuated muscle ROS and postexercise insulin sensitivity independent of Akt signaling. ROS also played a role in normal p70S6K phosphorylation in response to insulin stimulation in human skeletal muscle. PMID- 26105009 TI - Proteome profile of salt gland-rich epidermis extracted from a salt-tolerant tree species. AB - Preparation of proteins from salt-gland-rich tissues of mangrove plant is necessary for a systematic study of proteins involved in the plant's unique desalination mechanism. Extraction of high-quality proteins from the leaves of mangrove tree species, however, is difficult due to the presence of high levels of endogenous phenolic compounds. In our study, preparation of proteins from only a part of the leaf tissues (i.e. salt gland-rich epidermal layers) was required, rendering extraction even more challenging. By comparing several extraction methods, we developed a reliable procedure for obtaining proteins from salt gland rich tissues of the mangrove species Avicennia officinalis. Protein extraction was markedly improved using a phenol-based extraction method. Greater resolution 1D protein gel profiles could be obtained. More promising proteome profiles could be obtained through 1D-LC-MS/MS. The number of proteins detected was twice as much as compared to TUTS extraction method. Focusing on proteins that were solely present in each extraction method, phenol-based extracts contained nearly ten times more proteins than those in the extracts without using phenol. The approach could thus be applied for downstream high-throughput proteomic analyses involving LC-MS/MS or equivalent. The proteomics data presented herein are available via ProteomeXchange with identifier PXD001691. PMID- 26105010 TI - Modeling the magnetic properties of lanthanide complexes: relationship of the REC parameters with Pauling electronegativity and coordination number. AB - In a previous study, we introduced the Radial Effective Charge (REC) model to study the magnetic properties of lanthanide single ion magnets. Now, we perform an empirical determination of the effective charges (Zi) and radial displacements (Dr) of this model using spectroscopic data. This systematic study allows us to relate Dr and Zi with chemical factors such as the coordination number and the electronegativities of the metal and the donor atoms. This strategy is being used to drastically reduce the number of free parameters in the modeling of the magnetic and spectroscopic properties of f-element complexes. PMID- 26105011 TI - Product-Specific Regulatory Pathways to Approve Generic Drugs: The Need for Follow-up Studies to Ensure Safety and Effectiveness. AB - Generic drugs possessing the same active ingredients, dosage form, strength, route of administration, and labeling can be approved by the US Food and Drug Administration (FDA) as interchangeable with a brand-name drug without needing to repeat the formal Phase I, II, and III clinical trials conducted by the original manufacturers. In recent years, the FDA has approved several generic drugs using product-specific testing to determine therapeutic equivalence in accordance with the unique features of the particular drug. These have been used in two primary situations: (1) cases for which certain bioequivalence studies were not relevant; and (2) cases of complex molecules that may require specially tailored pharmaceutical equivalence studies. Examples include venlafaxine extended release, acarbose, vancomycin capsules, sodium ferric gluconate, salmon calcitonin nasal spray, and enoxaparin. Product-specific approaches to demonstrating therapeutic equivalence are essential to avoid delays in low-cost generic drug availability but can have important clinical implications; yet, currently, there is no formal process in place to monitor the safety and effectiveness of generic drugs approved using modified regulatory pathways. Several strategies can be used to monitor the safety and effectiveness of generic drugs approved via product-specific determinations of therapeutic equivalence. PMID- 26105012 TI - Aging mechanisms in amorphous phase-change materials. AB - Aging is a ubiquitous phenomenon in glasses. In the case of phase-change materials, it leads to a drift in the electrical resistance, which hinders the development of ultrahigh density storage devices. Here we elucidate the aging process in amorphous GeTe, a prototypical phase-change material, by advanced numerical simulations, photothermal deflection spectroscopy and impedance spectroscopy experiments. We show that aging is accompanied by a progressive change of the local chemical order towards the crystalline one. Yet, the glass evolves towards a covalent amorphous network with increasing Peierls distortion, whose structural and electronic properties drift away from those of the resonantly bonded crystal. This behaviour sets phase-change materials apart from conventional glass-forming systems, which display the same local structure and bonding in both phases. PMID- 26105013 TI - Sleep profiles in children with Down syndrome. AB - Down syndrome (DS) is the most common genetic cause of intellectual disability and results from an extra chromosome 21 (Trisomy 21). Sleep issues and/or obstructive sleep apnea (OSA) are assumed to be part of the DS phenotype with a high prevalence but are often under recognized. This cross-sectional study of children with DS examines the caregiver-reported sleep behaviors of 108 children with DS, ranging in age from 1.50 to 13.40 years (mean = 5.18 years) utilizing a standardized assessment tool, the Children's Sleep Habit Questionnaire (CSHQ). The CSHQ revealed 76% of children with DS had sleep problems, which began at a young age, and continue to persist and may recur with increasing age. Furthermore, children with DS who undergone adenoidectomy and tonsillectomy for OSA continued to have sleep problems suggesting that ongoing monitoring of sleep issues is needed in this population. Implications of sleep problems and recommended anticipatory guidance and intervention are discussed. PMID- 26105014 TI - High-resolution ultrasound of the posterior femoral cutaneous nerve: visualization and initial experience with patients. AB - OBJECTIVE: The posterior femoral cutaneous nerve (PFCN) is a sensory nerve originating from the sacral plexus. PFCN neuropathy leads to pain within the inferior gluteal region and the posterior aspect of the thigh. As electrophysiological assessment is challenging, diagnosis of PFCN neuropathy has been, thus far, primarily based on clinical findings, which can result in misdiagnosis. Therefore, alternative confirmatory assessments such as an imaging modality that could aid in the diagnosis of PFCN neuropathy would be desirable. The purpose of this study was to determine the feasibility of visualization of the PFCN with high-resolution ultrasound (HRUS) and to test this technique in our clinical routine. MATERIALS AND METHODS: The study consisted of two parts. In the first part, HRUS-guided perineural ink injections along the course of the PFCN were performed at the posterior aspect of the thigh in 26 lower limbs of 14 fresh non-embalmed cadavers. Subsequent dissection confirmed correct identification of the nerve. In the second part, patients with a suspected PFCN neuropathy were examined and a selective HRUS-guided nerve block was performed to verify the suspected diagnosis. RESULTS: The PFCN was correctly identified with HRUS in 96.2% (25/26) of cadavers. Further, six patients with a suspected lesion of the PFCN were examined, and the diagnosis was proven by successful HRUS-guided block in all cases. CONCLUSION: We confirmed the reliable visualization of the PFCN using HRUS. This offers a new technique for the assessment of the PFCN, which could also be demonstrated with the case series presented. PMID- 26105015 TI - Hamstring injuries: prevention and treatment-an update. AB - Despite increased knowledge of hamstring muscle injuries, the incidence has not diminished. We now know that not all hamstring injuries are the same and that certain types of injuries require prolonged rehabilitation and return to play. The slow stretch type of injury and injuries involving the central tendon both require longer times to return to play. A number of factors have been proposed as being indicators of time taken to return to play, but the evidence for these is conflicting. Recurrence rates remain high and it is now thought that strength deficits may be an important factor. Strengthening exercise should be performed with the hamstrings in a lengthened position. There is conflicting evidence regarding the efficacy of platelet-rich plasma injection in the treatment of hamstring injuries so at this stage we cannot advise their use. Various tests have been proposed as predictors of hamstring injury and the use of the Nordboard is an interesting addition to the testing process. Prevention of these injuries is the ultimate aim and there is increasing evidence that Nordic hamstring exercises are effective in reducing the incidence. PMID- 26105016 TI - Gait modifications to change lower extremity gait biomechanics in runners: a systematic review. AB - BACKGROUND: Abnormal biomechanics have been cited as a potential risk factor for running-related injury. Many modifiable biomechanical risk factors have also been proposed in the literature as interventions via gait retraining. AIM: To determine which interventions have successfully modified biomechanical variables linked to running-related injury. STUDY DESIGN: Systematic literature review. METHODS: MEDLINE, EMBASE, CINAHL, SportDiscus and PSYCINFO were searched using key terms related to running biomechanics and gait retraining. Quality of included studies was assessed using the modified Downs and Black Quality Index and a best evidence synthesis was performed. RESULTS: 27 studies investigating the effect of biomechanical interventions on kinetic, kinematic and spatiotemporal variables were included in this review. Foot strike manipulation had the greatest effect on kinematic measures (conflicting evidence for proximal joint angles; strong evidence for distal joint angles), real-time feedback had the greatest effect on kinetic measures (ranging from conflicting to strong evidence), and combined training protocols had the greatest effect on spatiotemporal measures (limited to moderate evidence). CONCLUSIONS: Overall, this systematic review shows that many biomechanical parameters can be altered by running modification training programmes. These interventions result in short term small to large effects on kinetic, kinematic and spatiotemporal outcomes during running. In general, runners tend to employ a distal strategy of gait modification unless given specific cues. The most effective strategy for reducing high-risk factors for running-related injury-such as impact loading-was through real-time feedback of kinetics and/or kinematics. PMID- 26105017 TI - Isokinetic muscle strength and readiness to return to sport following anterior cruciate ligament reconstruction: is there an association? A systematic review and a protocol recommendation. AB - INTRODUCTION: Following anterior cruciate ligament reconstruction (ACLR), strength is a key variable in regaining full function of the knee. Isokinetic strength is commonly used as part of the return to sport (RTS) criteria. AIM: We systematically reviewed the isokinetic strength evaluation protocols that are currently being used following ACLR. A secondary aim was to suggest an isokinetic protocol that could meet RTS criteria. METHOD: Articles were searched using ScienceDirect, PubMed and Sage Journals Online, combined with cross-checked reference lists of the publications. Protocol data and outcome measurements and RTS criteria were extracted from each article included in the review. RESULTS: 39 studies met the inclusion criteria and reported their isokinetic strength evaluation protocol following ACLR. The variables that were most commonly used were concentric/concentric mode of contraction (31 studies), angular velocity of 60 degrees /s (29 studies), 3-5 repetitions (24 studies), range of motion of 0-90 degrees (6 studies), and using gravity correction (9 studies). 8 studies reported strength limb symmetry index scores as part of their RTS criteria. CONCLUSIONS: There was no standardised isokinetic protocol following ACLR; isokinetic strength measures have not been validated as useful predictors of successful RTS. We propose a standard protocol to allow consistency of testing and accurate comparison of future research. PMID- 26105018 TI - The effect of strengthening interventions on strength and physical performance in people with cerebral palsy (PEDro synthesis). PMID- 26105019 TI - Method for (236)U Determination in Seawater Using Flow Injection Extraction Chromatography and Accelerator Mass Spectrometry. AB - An automated analytical method implemented in a flow injection (FI) system was developed for rapid determination of (236)U in 10 L seawater samples. (238)U was used as a chemical yield tracer for the whole procedure, in which extraction chromatography (UTEVA) was exploited to purify uranium, after an effective iron hydroxide coprecipitation. Accelerator mass spectrometry (AMS) was applied for quantifying the (236)U/(238)U ratio, and inductively coupled plasma mass spectrometry (ICPMS) was used to determine the absolute concentration of (238)U; thus, the concentration of (236)U can be calculated. The key experimental parameters affecting the analytical effectiveness were investigated and optimized in order to achieve high chemical yields and simple and rapid analysis as well as low procedure background. Besides, the operational conditions for the target preparation prior to the AMS measurement were optimized, on the basis of studying the coprecipitation behavior of uranium with iron hydroxide. The analytical results indicate that the developed method is simple and robust, providing satisfactory chemical yields (80-100%) and high analysis speed (4 h/sample), which could be an appealing alternative to conventional manual methods for (236)U determination in its tracer application. PMID- 26105020 TI - Good practices on cost - effective road infrastructure safety investments. AB - The paper presents the findings of a research project aiming to quantify and subsequently classify several infrastructure-related road safety measures, based on the international experience attained through extensive and selected literature review and additionally on a full consultation process including questionnaire surveys addressed to experts and relevant workshops. Initially, a review of selected research reports was carried out and an exhaustive list of road safety infrastructure investments covering all types of infrastructure was compiled. Individual investments were classified according to the infrastructure investment area and the type of investment and were thereafter analysed on the basis of key safety components. These investments were subsequently ranked in relation to their safety effects and implementation costs and on the basis of this ranking, a set of five most promising investments was selected for an in depth analysis. The results suggest that the overall cost effectiveness of a road safety infrastructure investment is not always in direct correlation with the safety effect and is recommended that cost-benefit ratios and safety effects are always examined in conjunction with each other in order to identify the optimum solution for a specific road safety problem in specific conditions and with specific objectives. PMID- 26105021 TI - Prevalence and distribution of colonic diverticula assessed with CT colonography (CTC). AB - OBJECTIVES: This study aimed to evaluate the prevalence of colonic diverticula according to age, gender, distribution, disease extension and symptoms with CT colonography (CTC). METHODS: The study population included 1091 consecutive patients who underwent CTC. Patients with diverticula were retrospectively stratified according to age, gender, clinical symptoms and colonic segment involvement. Extension of colonic diverticula was evaluated using a three-point quantitative scale. Using this data, a multivariate regression analysis was applied to investigate the existence of any correlation among variables. RESULTS: Colonic diverticula were observed in 561 patients (240 men, mean age 68 +/- 12 years). Symptomatic uncomplicated diverticular disease (SUDD) was present in 47.4% of cases. In 25.6% of patients <=40 years, at least one diverticulum in the colon was observed. Prevalence of right-sided diverticula in patients >60 years was 14.2% in caecum and 18.5% in ascending colon. No significant difference was found between symptomatic and asymptomatic patients regarding diverticula prevalence and extension. No correlation was present between diverticula extension and symptoms. CONCLUSION: The incidence of colonic diverticula appears to be greater than expected. Right colon diverticula do not appear to be an uncommon finding, with their prevalence increasing with patient age. SUDD does not seem to be related to diverticula distribution and extension. KEY POINTS: Incidence of colonic diverticula appears to be greater than expected. Right colon diverticula do not appear to be an uncommon finding. SUDD does not seem to be related to diverticula distribution and extension. PMID- 26105022 TI - Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium based contrast agent, gadobutrol. AB - OBJECTIVE: To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1 weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. RESULTS: Globus pallidus-to thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (rho = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). CONCLUSION: In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. KEY POINTS: Gadolinium deposition may occur within the human brain after multiple gadolinium contrast administrations. Increasing T1W signal intensity occurs within the dentate nucleus and globus pallidus. Increasing signal intensity may be a consequence of multiple administrations of gadobutrol. Administration of gadobutrol over a shorter period causes greater signal intensity increase. PMID- 26105023 TI - Breast cancer detection rates using four different types of mammography detectors. AB - OBJECTIVE: To compare the performance of different types of detectors in breast cancer detection. METHODS: A mammography image set containing subtle malignant non-calcification lesions, biopsy-proven benign lesions, simulated malignant calcification clusters and normals was acquired using amorphous-selenium (a-Se) detectors. The images were adapted to simulate four types of detectors at the same radiation dose: digital radiography (DR) detectors with a-Se and caesium iodide (CsI) convertors, and computed radiography (CR) detectors with a powder phosphor (PIP) and a needle phosphor (NIP). Seven observers marked suspicious and benign lesions. Analysis was undertaken using jackknife alternative free-response receiver operating characteristics weighted figure of merit (FoM). The cancer detection fraction (CDF) was estimated for a representative image set from screening. RESULTS: No significant differences in the FoMs between the DR detectors were measured. For calcification clusters and non-calcification lesions, both CR detectors' FoMs were significantly lower than for DR detectors. The calcification cluster's FoM for CR NIP was significantly better than for CR PIP. The estimated CDFs with CR PIP and CR NIP detectors were up to 15% and 22% lower, respectively, than for DR detectors. CONCLUSION: Cancer detection is affected by detector type, and the use of CR in mammography should be reconsidered. KEY POINTS: The type of mammography detector can affect the cancer detection rates. CR detectors performed worse than DR detectors in mammography. Needle phosphor CR performed better than powder phosphor CR. Calcification clusters detection is more sensitive to detector type than other cancers. PMID- 26105024 TI - The identification of a killer cell immunoglobulin-like receptor 3DL1*0150209 in an Asian population using molecular techniques. AB - Full-length sequences of KIR3DL1*0150209 differ from those of KIR3DL1*0150201 with seven single-nucleotide polymorphisms. PMID- 26105025 TI - Dexamethasone inhibits chondrocyte differentiation by suppression of Wnt/beta catenin signaling in the chondrogenic cell line ATDC5. AB - Glucocorticoids (GCs) regulate proliferation and differentiation in cultured mesenchymal cells through the modulation of various molecules. However, the relationship between growth factor signaling and GCs in differentiating chondrocytes has not been elucidated. In this study, we examined the effects of Wnt/beta-catenin signaling on chondrocyte differentiation and the effects of a GC analogue, dexamethasone (Dex), on Wnt/beta-catenin signaling activity by using a chondrocyte progenitor cell line ATDC5. Western blot analysis and TCF/LEF optimized promoter EGFP (TOPEGFP) assay showed that both beta-catenin protein levels and TCF/LEF transcription were up-regulated during insulin-transferrin sodium selenite (ITS)-induced chondrogenic differentiation. Morphological analysis showed that TCF/LEF transcription activity was most prominent in cartilage nodule-like structures. Furthermore, a beta-catenin mutant with constitutive transcriptional activity (DeltaN90) showed increased Alcian blue staining intensity and mRNA expression of Sox9, Col2a, aggrecan, Col10, and alkaline phosphatase, even in the absence of ITS stimulation. In contrast, Dex suppressed formation of ITS-induced cartilage nodule-like structures, TCF/LEF mediated transcription, and beta-catenin protein levels. Real-time PCR analysis showed that Dex increased the mRNA expression levels of secreted frizzled-related protein 1 (sFRP1) and Axin2. Furthermore, treatment with a sFRP1 inhibitor or the DeltaN90 beta-catenin mutant transfection attenuated Dex-induced suppression of cartilage matrix production by increasing Sox9 mRNA levels. These results suggest that Dex inhibits chondrocyte differentiation via down-regulation of Wnt/beta catenin signaling, which promotes chondrocyte differentiation in ATDC5 cells. PMID- 26105027 TI - To core, or not to core: the impact of coring on tree health and a best-practice framework for collecting dendrochronological information from living trees. AB - Trees are natural repositories of valuable environmental information that is preserved in the growth and structure of their stems, branches and roots. Dendrochronological analyses, based on the counting, crossdating and characterisation of incrementally formed wood rings, offer powerful insights for diverse fields including ecology, climatology and archaeology. The application of this toolset is likely to increase in popularity over coming decades due to advances in the field and a reduction in the cost of analyses. In research settings where the continued value of living trees subject to dendrochronological investigation is important, the use of an increment bore corer to extract trunk tissue is considered the best option to minimise negative impacts on tree health (e.g. stress and fitness). A small and fragmented body of literature, however, reports significant after-effects, and in some cases fatal outcomes, from this sampling technique. As it stands, the literature documenting increment bore coring (IBC) impacts lacks experimental consistency and is poorly replicated, making it difficult for prospective users of the method to assess likely tree responses to coring. This paucity of information has the potential to lead to destructive misuse of the method and also limits its safe implementation in circumstances where the risk of impacts may be appropriate. If IBC is to fulfil its potential as a method of choice across research fields, then we must first address our limited understanding of IBC impacts and provide a framework for its appropriate future use. Firstly, we review the historical context of studies examining the impacts of IBC on trees to identify known patterns, focal issues and biases in existing knowledge. IBC wound responses, particularly those that impact on lumber quality, have been the primary focus of prior studies. No universal treatment was identified that conclusively improved wound healing and few studies have linked wound responses to tree health impacts. Secondly, we build on literature insights using a theoretical approach to identify the most important factors to guide future research involving implementation of IBC, including innate tree characteristics and environmental factors. Thirdly, we synthesise and interrogate the quantitative data available through meta-analysis to identify risk factors for wound reactions. Although poor reporting standards, restricted scopes and a bias towards temperate ecosystems limited quantitative insight, we found that complete cambial wound closure could still harbour high rates of internal trunk decay, and that conditions favouring faster growth generally correlated with reduced indices of internal and external damage in broadleaved taxa. Finally, we propose a framework for guiding best-practice application of IBC to address knowledge gaps and maximise the utility of this method, including standardised reporting indices for identifying and minimising negative impacts on tree health. While IBC is an underutilised tool of ecological enquiry with broad applicability, the method will always incur some risk of negative impacts on the cored tree. We caution that the decision to core, or not to core, must be given careful consideration on a case-by-case basis. In time, we are confident that this choice will be better informed by evidence-based insight. PMID- 26105026 TI - Proteoglycans support proper granule formation in pancreatic acinar cells. AB - Zymogen granules (ZG) are specialized organelles in the exocrine pancreas which allow digestive enzyme storage and regulated secretion. The molecular mechanisms of their biogenesis and the sorting of zymogens are still incompletely understood. Here, we investigated the role of proteoglycans in granule formation and secretion of zymogens in pancreatic AR42J cells, an acinar model system. Cupromeronic Blue cytochemistry and biochemical studies revealed an association of proteoglycans primarily with the granule membrane. Removal of proteoglycans by carbonate treatment led to a loss of membrane curvature indicating a supportive role in the maintenance of membrane shape and stability. Chemical inhibition of proteoglycan synthesis impaired the formation of normal electron-dense granules in AR42J cells and resulted in the formation of unusually small granule structures. These structures still contained the zymogen carboxypeptidase, a cargo molecule of secretory granules, but migrated to lighter fractions after density gradient centrifugation. Furthermore, the basal secretion of amylase was increased in AR42J cells after inhibitor treatment. In addition, irregular-shaped granules appeared in pancreatic lobules. We conclude that the assembly of a proteoglycan scaffold at the ZG membrane is supporting efficient packaging of zymogens and the proper formation of stimulus-competent storage granules in acinar cells of the pancreas. PMID- 26105028 TI - Impact of a New Fusion Receptor on PD-1-Mediated Immunosuppression in Adoptive T Cell Therapy. AB - BACKGROUND: Adoptive T cell transfer (ACT) is currently under investigation for the treatment of metastatic cancer. Recent evidence suggests that the coinhibitory PD-1-PD-L1 axis plays a major role in ACT failure. We hypothesized that a new fusion receptor reverting PD-1-mediated inhibition into CD28 costimulation may break peripheral tolerance. METHODS: Different PD-1-CD28 fusion receptor constructs were created and retrovirally transduced into primary T cell receptor transgenic murine CD8(+) T cells specific for ovalbumin (OT-1). Cytokine release, proliferation, cytotoxicity, and tumor recognition were analyzed in vitro. Antitumor efficacy and mode of action were investigated in mice bearing subcutaneous tumors induced with the pancreatic carcinoma cell line Panc02 expressing the model antigen ovalbumin (Panc-OVA). For antitumoral efficacy, six to eight mice per group were used. All statistical tests are two-sided. RESULTS: Transduction of the PD-1-CD28 receptor constructs mediated enhanced cytokine release, T cell proliferation, and T cell-induced lysis of target tumor cells. The PD-1-CD28 receptor function was dependent on two of the CD28-signaling motifs and IFN-gamma release. Treatment of mice with established Panc-OVA tumors with fusion receptor-transduced OT-1 T cells mediated complete tumor regression. Mice rejecting the tumor were protected upon subsequent rechallenge with either ovalbumin-positive or -negative tumors, indicative of a memory response and epitope spreading in nine of 11 mice vs none of the six naive mice (P < .001). Treatment efficacy was associated with accumulation of IFN-gamma-producing T cells and an increased ratio of CD8(+) T cells to immunosuppressive myeloid derived suppressor cells in the tumors. CONCLUSIONS: Transduction of T cells with this new PD-1-CD28 receptor has the potential of breaking the PD-1-PD-L1 immunosuppressive axis in ACT. PMID- 26105030 TI - Effectiveness of community-based health services by nurse practitioners: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: To realise universal health coverage in an ageing society, adequate provision of appropriately trained human resources is essential. The nurse practitioner (NP) is an autonomous and independent, advanced practice nurse capable of providing treatment and care that can be substituted for some aspects of a medical doctor's (MD's) role, especially in a community setting. Previous systematic reviews found higher levels of patient satisfaction with services provided by NPs than those provided by MDs. As non-communicable diseases become a major health burden requiring long-term healthcare in community settings, this systematic review aims to assess the equivalence of NP services to standard care provided by MDs, and to determine whether their practice is an effective alternative to that of MDs in community settings. METHODS AND ANALYSIS: Relevant randomised controlled trials (RCTs) and cluster RCTs will be searched in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL and the British Nursing Index. We will assess patient and health system utilisation outcomes of interventions comparing treatment and care provided by NPs in community settings with that provided by MDs. Two authors will independently screen studies for inclusion, consulting with a third author where necessary to resolve discrepancies. The risk of bias of included studies will be assessed using the Cochrane Collaboration risk of bias tool, and quality of evidence using the GRADE approach. Meta-analysis of included studies will be conducted using fixed-effect or random-effects models depending on the degree of between-study heterogeneity. Results will be presented using risk ratios with 95% CI for dichotomous outcomes and standardised mean differences with 95% CI for continuous outcomes. ETHICS AND DISSEMINATION: This systematic review and meta-analysis protocol does not require ethical approval. We will disseminate the findings of this systematic review and meta-analysis via publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: PROSPEROCRD42014009627. PMID- 26105029 TI - Evaluation of the Methods and Management of Acute Coronary Events (EMMACE)-3: protocol for a longitudinal study. AB - INTRODUCTION: Patients with cardiovascular disease are living longer and are more frequently accessing healthcare resources. The Evaluation of the Methods and Management of Acute Coronary Events (EMMACE)-3 national study is designed to improve understanding of the effect of quality of care on health-related outcomes for patients hospitalised with acute coronary syndrome (ACS). METHODS AND ANALYSIS: EMMACE-3 is a longitudinal study of 5556 patients hospitalised with an ACS in England. The study collects repeated measures of health-related quality of life, information about medications and patient adherence profiles, a survey of hospital facilities, and morbidity and mortality data from linkages to multiple electronic health records. Together with EMMACE-3X and EMMACE-4, EMMACE-3 will assimilate detailed information for about 13 000 patients across more than 60 hospitals in England. ETHICS AND DISSEMINATION: EMMACE-3 was given a favourable ethical opinion by Leeds (West) Research Ethics committee (REC reference: 10/H131374). On successful application, study data will be shared with academic collaborators. The findings from EMMACE-3 will be disseminated through peer reviewed publications, at scientific conferences, the media, and through patient and public involvement. STUDY REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01808027. Information about the study is also available at EMMACE.org. PMID- 26105031 TI - Long-term effectiveness and outcome predictors of therapist-guided internet-based cognitive-behavioural therapy for social anxiety disorder in routine psychiatric care. AB - OBJECTIVES: Although the short-term outcome of therapist-guided internet-based cognitive-behavioural therapy (ICBT) for treating social anxiety disorder (SAD) has been well studied, little research has been undertaken on the sustainability of treatment gains, especially under clinically representative conditions. Further, there is some debate whether delivering psychological treatment via the internet may be suitable for more severely ill patients. DESIGN: Longitudinal multilevel growth-modelling of long-term (1-4 years) follow-up cohort data. SETTING: An outpatient psychiatric clinic specialised in internet interventions. PARTICIPANTS: 446 adults having been treated for SAD. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were estimated improvement rate and Cohen's d effect size on the self-rated Liebowitz Social Anxiety Disorder Scale. Secondary outcome measures were change in comorbid depressive symptoms and health-related quality of life. RESULTS: A large treatment effect was observed on the primary outcome measure after treatment (d=0.8 (95% CI 0.7 to 0.9)), with continued long term improvements (d=1.2 (95% CI 1.0 to 1.3)). However, the rate of change varied significantly between individuals over time. A faster rate of improvement was observed among patients with higher illness severity, whereas having a family history of social anxiety was related to worse response. Long-term improvements were also observed in comorbid depressive symptoms (d=0.7 (95% CI 0.5 to 0.8)) and health-related quality of life (d=-0.3 (95% CI -0.4 to -0.1)). CONCLUSIONS: These findings provide evidence for the long-term effectiveness of ICBT for SAD in routine clinical practice, even for more severe cases. PMID- 26105034 TI - An optimal control problem for ovine brucellosis with culling. AB - A mathematical model is used to study the dynamics of ovine brucellosis when transmitted directly from infected individual, through contact with a contaminated environment or vertically through mother to child. The model developed by Ainseba et al. [A model for ovine brucellosis incorporating direct and indirect transmission, J. Biol. Dyn. 4 (2010), pp. 2-11. Available at http://www.math.u-bordeaux1.fr/~pmagal100p/papers/BBM-JBD09.pdf. Accessed 3 July 2012] was modified to include culling and then used to determine important parameters in the spread of human brucellosis using sensitivity analysis. An optimal control analysis was performed on the model to determine the best way to control such as a disease in the population. Three time-dependent controls to prevent exposure, cull the infected and reduce environmental transmission were used to set up to minimize infection at a minimum cost. PMID- 26105033 TI - Prevalence and prognostic impact of chronic kidney disease in STEMI from a gender perspective: data from the SWEDEHEART register, a large Swedish prospective cohort. AB - OBJECTIVES: Gender differences in prevalence and prognostic impact of chronic kidney disease (CKD) in ST segment elevation myocardial infarction (STEMI) have been poorly evaluated. In STEMI, female gender has been independently associated with an increased risk of mortality. CKD has been found to be an important prognostic marker in myocardial infarction. The aim of this study was to evaluate gender differences in prevalence and prognostic impact of CKD on short-term and long-term mortality. DESIGN: Prospective observational cohort study. SETTING: The national quality register SWEDEHEART was used. In the beginning of the study period, 94% of the Swedish coronary care units contributed data to the register, which subsequently increased to 100%. The glomerular filtration rate was estimated (eGFR) according to Modification of Diet in Renal Disease Study (MDRD) and Cockcroft-Gault (CG). PARTICIPANTS: All patients with STEMI registered in SWEDEHEART from the years 2003-2009 were included (37,991 patients, 66% men). MAIN RESULTS: Women had 1.6 (MDRD) to 2.2 (CG) times higher multivariable adjusted risk of CKD. Half of the women had CKD according to CG. CKD was associated with 2-2.5 times higher risk of in-hospital mortality and approximately 1.5 times higher risk of long-term mortality in both genders. Each 10 mL/min decline of eGFR was associated with an increased risk of in-hospital and long-term mortality (22-33% and 9-16%, respectively) and this did not vary significantly by gender. Both in-hospital and long-term mortality were doubled in women. After multivariable adjustment including eGFR, there was no longer any gender difference in early outcome and the long-term outcome was better in women. CONCLUSIONS: Among patients with STEMI, female gender was independently associated with CKD. Reduced eGFR was a strong independent risk factor for short term and long-term mortality without a significant gender difference in prognostic impact and seems to be an important reason why women have higher mortality than men with STEMI. PMID- 26105032 TI - Clinical cardiovascular risk during young adulthood in offspring of hypertensive pregnancies: insights from a 20-year prospective follow-up birth cohort. AB - OBJECTIVES: Offspring of hypertensive pregnancies have increased cardiovascular risk factors during childhood. We hypothesised that offspring of hypertensive pregnancies would demonstrate increased clinical levels of hypertension by young adult life, which would be proportional to the severity of the pregnancy complication. DESIGN: Prospective birth cohort study SETTING: Tertiary obstetric hospital. PARTICIPANTS: 2868 young adult offspring of women enrolled during pregnancy into the Western Australia Pregnancy Cohort (Raine) Study. MAIN OUTCOME MEASURES: Cardiovascular risk, including incidence of hypertension and metabolic disease, in those born to hypertensive compared to normotensive pregnancies. RESULTS: Young adult offspring of hypertensive pregnancies were 2.5 times (95% CI 1.32 to 4.56, p=0.004) more likely to have global lifetime risk (QRISK) scores above the 75th centile. Thirty per cent of 20 year olds with hypertensive blood pressures were born following a hypertensive pregnancy. Pre-eclampsia or hypertension resulting in preterm birth associated with a threefold (95% CI 1.3 to 7.0, p=0.01) greater risk of being hypertensive by age 20 years, with no differences in body mass index. Whereas pregnancy-induced hypertension associated with a smaller 3 +/- 1 mm Hg blood pressure rise (p=0.001) and a twofold (95% CI 1.5 to 2.8, p=0.001) greater risk of being obese or overweight. Risk factor associations were consistent throughout early life and independent of other birth factors. CONCLUSIONS: Incidence of offspring hypertension was significantly increased in those whose mothers had a more complicated pregnancy history, including preterm birth and pre-eclampsia. PMID- 26105035 TI - Therapeutic efficacy of artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Enfranze, north-west Ethiopia. AB - BACKGROUND: Plasmodium falciparum accounts for approximately 60% of malaria cases in Ethiopia and artemether-lumefantrine has been used as a first-line treatment for uncomplicated P. falciparum malaria since 2004. The aim of this study was to assess the therapeutic efficacy of artemether-lumefantrine (AL) for the treatment of uncomplicated P. falciparum malaria in north-western Ethiopia. METHODS: A 28 day one-arm, prospective evaluation of the clinical and parasitological response to the first-line treatment for uncomplicated P. falciparum malaria was conducted in Enfranze Health Centre in accordance with the 2009 WHO efficacy study guidelines. Patients were treated with a 3-day course of AL and clinical and parasitological parameters were monitored over a 28-day follow-up. All data from recruited patients were imported into an electronic data base and Kaplan-Meier survival analysis was used for analysing primary [early treatment failures (ETF), late clinical failure (LCF), late parasitological failures (LPF), and adequate clinical and parasitological response (ACPR)] and secondary (PCT, GCT and FCT) outcomes. RESULTS: Eighty patients were enrolled and all of them completed the 28 day follow-up period. The PCR-corrected cure rate was 95.0% (95% CI 87.0-98.4%) and there were two ETF, one LCF and three LPF. Two of the LPF were classified as re infections by PCR. Seventy three point seven five percent, 91.25 and 95% of patients had cleared their parasitaemia by days 1, 2, and 3, respectively, and 75, 91.25 and 96.25% of patients had cleared their fever by days 1, 2, and 3. All patients completely cleared their gametocytes by day 7. CONCLUSION: The relatively high cure rate, low proportion of patients still positive on day 3 as well as parasite clearance times in this study would indicate no imminent threat of artemisinin resistance development in the region. However, the threat of spreading or de novo development of artemisinin resistance warrants regular monitoring of drug efficacy throughout the region. PMID- 26105037 TI - Body composition and the obesity paradox in coronary heart disease: can heavier really be healthier? PMID- 26105036 TI - Acute and recent air pollution exposure and cardiovascular events at labour and delivery. AB - OBJECTIVE: To study the relationship between acute air pollution exposure and cardiovascular events during labour/delivery. METHODS: The Consortium on Safe Labor (2002-2008), an observational US cohort with 223,502 singleton deliveries provided electronic medical records. Air pollution exposure was estimated by modified Community Multiscale Air Quality models. Cardiovascular events (cardiac failure/arrest, stroke, myocardial infarcts and other events) were recorded in the hospital discharge records for 687 pregnancies (0.3%). Logistic regression with generalised estimating equations estimated the relationship between cardiovascular events and daily air pollutant levels for delivery day and the 7 days preceding delivery. RESULTS: Increased odds of cardiovascular events were observed for each IQR increase in exposure to nitric oxides at 5 and 6 days prior to delivery (OR=1.17, 99% CI 1.04 to 1.30 and OR=1.15, 1.03 to 1.28, respectively). High exposure to toxic air pollution species such as ethylbenzene (OR=1.50, 1.08 to 2.09), m-xylene (OR=1.54, 1.11 to 2.13), o-xylene (OR=1.51, 1.09 to 2.09), p-xylene (OR=1.43, 1.03 to 1.99) and toluene (OR=1.42, 1.02 to 1.97) at 5 days prior to delivery were also associated with cardiovascular events. Decreased odds of events were observed with exposure to ozone. CONCLUSIONS: Air pollution in the days prior to delivery, especially nitrogen oxides and some toxic air pollution species, was associated with increased risk of cardiovascular events during the labour/delivery admission. PMID- 26105039 TI - External approach to rhinoplasty. AB - The technique of external rhinoplasty is outlined. Having reviewed 74 cases, its advantages and disadvantages are discussed. Reluctance to use this external approach seems to be based on emotional rather than radical grounds, for its seems to be the procedure of choice for many problems. PMID- 26105038 TI - Watchful observation versus early aortic valve replacement for symptomatic patients with normal flow, low-gradient severe aortic stenosis. AB - OBJECTIVES: The timing of aortic valve replacement (AVR) remains controversial in symptomatic patients with normal flow, low-gradient severe aortic stenosis (AS) and preserved LVEF. We sought to compare long-term mortality of early AVR versus a watchful observation strategy. METHODS: From 2000 to 2011, we prospectively evaluated 284 consecutive symptomatic patients (136 men, age 68+/-10 years) with normal flow, low-gradient severe AS and preserved LVEF who were potential candidates for early AVR. Normal flow, low-gradient severe AS was defined as indexed aortic valve area <0.6 cm(2)/m(2) with mean gradient <40 mm Hg and stroke volume index >=35 mL/m(2). Early AVR was performed on 98 patients (early AVR group), while the watchful observation strategy was selected for 186 patients (watchful observation group). Patients in the watchful observation group were referred for AVR if mean gradient was >=40 mm Hg during follow-up. RESULTS: There were no significant differences between the early AVR and the watchful observation groups for the risk of overall mortality (HR 0.94 for the early AVR; 95% CI 0.51 to 1.73) or for the estimated actuarial 8-year mortality rates (17+/ 5% vs 27+/-5%, p=0.84) in the overall cohort. Society of Thoracic Surgeons score, comorbidity index, age, coronary artery disease, aetiology of AS and performance of AVR were associated with overall survival. For 83 propensity-score-matched pairs, the risk of overall death was not significantly different between the two groups (HR 1.13 for the early AVR, 95% CI 0.55 to 2.35, p=0.74). CONCLUSIONS: Early AVR and watchful observation strategy show similar survival in symptomatic patients with normal flow, low-gradient severe AS and preserved LVEF. Watchful observation with timely performance of AVR should be considered a therapeutic option. PMID- 26105040 TI - Functional evaluation following microvascular oromandibular reconstruction of the oral cancer patient: A comparative study of reconstructed and nonreconstructed patients. PMID- 26105041 TI - Erratum. PMID- 26105043 TI - Microhydrated dihydrogen phosphate clusters probed by gas phase vibrational spectroscopy and first principles calculations. AB - We report infrared multiple photon dissociation (IRMPD) spectra of cryogenically cooled H2PO4(-)(H2O)n anions (n = 2-12) in the spectral range of the stretching and bending modes of the solute anion (600-1800 cm(-1)). The spectra cannot be fully understood using the standard technique of comparison to harmonic spectra of minimum-energy structures; a satisfactory assignment requires considering anharmonic effects as well as entropy-driven hydrogen bond network fluctuations. Aided by finite temperature ab initio molecular dynamics simulations, the observed changes in the position, width and intensity of the IRMPD bands with cluster size are related to the sequence of microsolvation. Due to stronger hydrogen bonding to the two terminal P[double bond, length as m-dash]O groups, these are hydrated before the two P-OH groups. By n = 6, all four end groups are involved in the hydrogen bond network and by n = 12, the cluster spectra show similarities to the condensed phase spectrum of H2PO4(-)(aq). Our results reveal some of the microscopic details concerning the formation of the aqueous solvation environment around H2PO4(-), provide ample testing grounds for the design of model solvation potentials for this biologically relevant anion, and support a new paradigm for the interpretation of IRMPD spectra of microhydrated ions. PMID- 26105042 TI - Hyperparathyroidism and Bone Health. AB - Bone pain, proximal muscle weakness, skeletal deformities, and pathological fractures are features of osteitis fibrosa cystica which occur in severe primary hyperparathyroidism (PHPT). In this condition, bone mineral density is usually extremely low, but may be reversible after parathyroidectomy. On X-ray, bone abnormalities are described as having a salt-and-pepper appearance in the skull, with bone erosions and resorption of the phalanges, brown tumors and cysts, as well as diffuse demineralization, along with pathological fractures, particularly in the long bones of the extremities. A marked elevation of the serum calcium and PTH concentrations is seen, and renal involvement is manifested by nephrolithiasis and nephrocalcinosis. In asymptomatic PHPT, the absence of clinically significant bone involvement has led to much more data on bone mineral density becoming available by dual X-ray absorptiometry (DXA) and also on new technologies such as trabecular bone score (TBS), which is a gray-level textural analysis of DXA images that provides an indirect index of trabecular microarchitecture. In addition, high-resolution peripheral computed tomography (HRpQCT), which has a low radiation exposure, provides further understanding of the microstructural skeletal features at both trabecular and cortical sites. PMID- 26105044 TI - Density Gradient Centrifugation for the Isolation of Cells of Multiple Lineages. AB - We recently developed a simple strategy for the enrichment of mesenchymal stem cells (MSCs) with the capacity for osteoblast, chondrocyte, and adipocyte differentiation. On transplantation, the progenitor-enriched fraction can regenerate bone with multiple lineages of donor origin. Although comprising multiple precursor cell types, the population is enriched >100-fold in osteoprogenitors, hence the name "highly purified osteoprogenitors" (HipOPs). To establish a new modified method of purifying pure MSCs, it is useful to know the expression patterns of surface markers on heterogeneous MSCs and committed cells such as osteoblasts, adipocytes, and chondrocytes. However, calcium deposition by osteoblasts is a critical obstacle in visualizing the expression patterns of surface markers. We now report a new method of separating differentiated osteoblastic HipOPs (OB-HipOPs) from calcium deposits using the Percoll density gradient centrifugation technique. After centrifuge separation, calcium deposits were observed at the bottom of the centrifuge tube, and living OB-HipOPs were harvested from the 10-70% fractions. However, there were no living cells in the 70-80% fraction. We concluded that living OB-HipOPs are separated by one 10-70% Percoll gradient. Furthermore, we analyzed the expression patterns of putative MSC markers on differentiated HipOPs. FACS analysis revealed that Sca-1, CD44, CD73, CD105, and CD106 were decreased in OB-HipOPs. In adipogenic- and chondrogenic-HipOPs, Sca-1, CD73, CD105, and CD106 were decreased. This new technique is a helpful tool to identify MSC surface markers and to clarify in more detail the differentiation stages of osteoblasts. PMID- 26105045 TI - The relationship between trauma, shame, and guilt: findings from a community based study of refugee minors in Germany. AB - BACKGROUND: The relationships between traumatic stress and self-conscious emotions, such as shame and guilt, remain to be fully explored, especially in refugees, who frequently are exposed to a multitude of stressors. OBJECTIVE: The aim of the present study was to investigate shame and guilt in refugee minors and to assess to what extent a greater cumulative exposure to traumatic stressors would result not only in more severe posttraumatic stress disorder (PTSD) symptoms but also in higher levels of shame and guilt. METHODS: Thirty-two male refugee minors, who were all below the age of 18 when they sought asylum in Germany, agreed to participate. At the time of the assessment, the age ranged from 11 to 20 years. Eighteen refugees had arrived without relatives in their host country ("unaccompanied minors"). In structured diagnostic interviews, a PTSD diagnosis was established using the UCLA PTSD Index. Posttraumatic guilt was assessed by means of the Trauma-related Guilt Inventory, and the Shame Variability Questionnaire was used to record the intensity, duration, and frequency of shame episodes. RESULTS: Feelings of guilt and shame as well as trauma symptoms were all associated with the number of traumatic event types subjects had experienced. Posttraumatic guilt and shame were both correlated with PTSD symptom severity. CONCLUSIONS: The findings indicate that cumulative stress such as exposure to multiple traumatic events poses a risk factor for the mental health including greater suffering and functional impairment due to shame and guilt. PMID- 26105046 TI - Food restriction alters energy allocation strategy during growth in tobacco hornworms (Manduca sexta larvae). AB - Growing animals must alter their energy budget in the face of environmental changes and prioritize the energy allocation to metabolism for life-sustaining requirements and energy deposition in new biomass growth. We hypothesize that when food availability is low, larvae of holometabolic insects with a short development stage (relative to the low food availability period) prioritize biomass growth at the expense of metabolism. Driven by this hypothesis, we develop a simple theoretical model, based on conservation of energy and allometric scaling laws, for understanding the dynamic energy budget of growing larvae under food restriction. We test the hypothesis by manipulative experiments on fifth instar hornworms at three temperatures. At each temperature, food restriction increases the scaling power of growth rate but decreases that of metabolic rate, as predicted by the hypothesis. During the fifth instar, the energy budgets of larvae change dynamically. The free-feeding larvae slightly decrease the energy allocated to growth as body mass increases and increase the energy allocated to life sustaining. The opposite trends were observed in food restricted larvae, indicating the predicted prioritization in the energy budget under food restriction. We compare the energy budgets of a few endothermic and ectothermic species and discuss how different life histories lead to the differences in the energy budgets under food restriction. PMID- 26105047 TI - Male ruff colour as a rank signal in a monomorphic-horned mammal: behavioural correlates. AB - Coexistence of individuals within a social group is possible through the establishment of a hierarchy. Social dominance is achieved through aggressive interactions, and, in wild sheep and goats, it is related mainly to age, body size and weapon size as rank signals. Adult male Himalayan tahr are much larger than females and subadult males. They have a prominent neck ruff, ranging in colour from yellow (5.5-9.5 years old, i.e. young adults, golden males) to brown (7.5-14.5 years old, i.e. older individuals, pale and dark brown males), with golden males being the most dominant. We investigated the social behaviour of male tahr and analysed the relationships between ruff colour, courtship and agonistic behaviour patterns during the rut. Colour classes varied in their use of several behaviour patterns (male dominance: approach, stare, horning vegetation; courtship: low stretch, naso-genital contact, rush). Golden-ruffed males used more threats than darker ones. Pale brown and dark brown males addressed threats significantly more often to males of lower or their own colour classes, respectively, whereas golden ones addressed threats to all colour classes, including their own. The courtship of dominant males was characterised by the assertive rush, whereas that of subordinates did not. Ruff colour of male Himalayan tahr may have evolved as a rank signal, homologous to horn size in wild sheep and goats. PMID- 26105048 TI - The South African Food Sensitisation and Food Allergy population-based study of IgE-mediated food allergy: validity, safety, and acceptability. AB - BACKGROUND: Few studies exist on food sensitization and challenge-proven food allergy in low- and middle-income countries. OBJECTIVE: To describe the study design and methodology to recruit infants from an African population for skin prick testing and oral food challenges and the use of preliminary data to investigate the extent to which the study sample is representative of the target population. METHODS: Children 12 to 36 months old were recruited from childcare education facilities in Cape Town. Children underwent skin prick testing to foods. Those with a reactive wheal of at least 1 mm larger than the negative control and not clearly tolerant according to history to a full age-appropriate portion to at least 1 food underwent oral food challenges. Parents who chose not to participate completed a nonparticipant questionnaire. Interim analysis of at least 500 respondents was performed. Demographic features of participating children were compared with those of nonparticipants and the population demographics of the most recent Cape Town census data. RESULTS: The response rate was 60.1%, with high participation and completion rates of 96.5% and 97.5%, respectively. Demographics of the completed participant sample were similar to those of the Cape Town census. Use of a nonrespondent questionnaire indicated no selection bias in favor of increased participation of participants with allergy. No ethnic differences in sensitization or food allergy were evident. CONCLUSION: The study was safe and feasible and the recruitment was effective and representative of the target population. Future studies will aim to increase the precision of the prevalence of food sensitization and allergy, describe environmental risk factors, and include a rural black African cohort. PMID- 26105049 TI - Do endothelial cells belong to the primitive stem leukemic clone in CML? Role of extracellular vesicles. AB - The expression of BCR-ABL in hematopoietic stem cells is a well-defined primary event in chronic myeloid leukemia (CML). Some reports have described the presence of BCR-ABL on endothelial cells from CML patients, suggesting the origin of the disease in a primitive hemangioblastic cell. On the other hand, extracellular vesicles (EVs) released by CML leukemic cells are involved in the angiogenesis modulation process. In the current work we hypothesized that EVs released from BCR-ABL(+) cells may carry inside the oncogene that can be transferred to endothelial cells leading to the expression of both BCR-ABL transcript and the oncoprotein. EVs from K562 cells and plasma of newly diagnosed CML patients were isolated by ultracentrifugation. RT-PCR analysis detected the presence of BCR-ABL RNA in the EVs isolated from both K562 cells and plasma of CML patients. The incorporation of these EVs into endothelial cells was demonstrated by flow cytometry and fluorescence microscopy showed that after 24h of incubation most EVs were incorporated. BCR-ABL transcripts were detected in all experiments on endothelial cells incubated with EVs from both sources. The presence of BCR-ABL on endothelial cells incubated with Philadelphia(+) EVs was also confirmed by Western blot assays. In summary, endothelial cells acquire BCR-ABL RNA and the oncoprotein after incubation with EVs released from Ph(+) positive cells (either from K562 cells or from plasma of newly diagnosed CML patients). This results challenge the hypothesis that endothelial cells may be part of the Philadelphia(+) clone in CML. PMID- 26105050 TI - G Protein-coupled Receptor 40 (GPR40) and Peroxisome Proliferator-activated Receptor gamma (PPARgamma): AN INTEGRATED TWO-RECEPTOR SIGNALING PATHWAY. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been widely used to treat type 2 diabetes mellitus. However, knowledge of PPARgamma signaling remains incomplete. In addition to PPARgamma, these drugs also activate G protein-coupled receptor 40 (GPR40), a Galphaq-coupled free fatty acid receptor linked to MAPK networks and glucose homeostasis. Notably, p38 MAPK activation has been implicated in PPARgamma signaling. Here, rosiglitazone (RGZ) activation of GPR40 and p38 MAPK was found to boost PPARgamma-induced gene transcription in human endothelium. Inhibition or knockdown of p38 MAPK or expression of a dominant negative (DN) p38 MAPK mutant blunted RGZ-induced PPARgamma DNA binding and reporter activity in EA.hy926 human endothelial cells. GPR40 inhibition or knockdown, or expression of a DN-Galphaq mutant likewise blocked activation of both p38 MAPK and PPARgamma reporters. Importantly, RGZ induction of PPARgamma target genes in primary human pulmonary artery endothelial cells (PAECs) was suppressed by knockdown of either p38 MAPK or GPR40. GPR40/PPARgamma signal transduction was dependent on p38 MAPK activation and induction of PPARgamma co activator-1 (PGC1alpha). Silencing of p38 MAPK or GPR40 abolished the ability of RGZ to induce phosphorylation and expression of PGC1alpha in PAECs. Knockdown of PGC1alpha, its essential activator SIRT1, or its binding partner/co-activator EP300 inhibited RGZ induction of PPARgamma-regulated genes in PAECs. RGZ/GPR40/p38 MAPK signaling also led to EP300 phosphorylation, an event that enhances PPARgamma target gene transcription. Thus, GPR40 and PPARgamma can function as an integrated two-receptor signal transduction pathway, a finding with implications for rational drug development. PMID- 26105051 TI - Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation. AB - Human studies have suggested that early undernutrition increases the risk of obesity, thereby explaining the increase in overweight among individuals from developing countries who have been undernourished as children. However, this conclusion is controversial, given that other studies do not concur. This study sought to determine whether rehabilitation after undernutrition increases the risk of obesity and metabolic disorders. We employed a published experimental food-restriction model. Wistar female rats subjected to severe food restriction since fetal stage and controls were transferred to a moderately high-fat diet (cafeteria) provided at 70 days of life to 6.5 months. Another group of undernourished rats were rehabilitated with chow. The energy intake of undernourished animals transferred to cafeteria formula exceeded that of the controls under this regime and was probably driven by hypothalamic disorders in insulin and leptin signal transduction. The cafeteria diet resulted in greater relative increases in both fat and lean body mass in the undernourished rats when compared with controls, enabling the former group to completely catch up in length and body mass index. White adipose tissues of undernourished rats transferred to the high-lipid regime developed a browning which, probably, contributed to avoid the obesigenic effect observed in controls. Nevertheless, the restricted group rehabilitated with cafeteria formula had greater accretion of visceral than subcutaneous fat, showed increased signs of macrophage infiltration and inflammation in visceral pad, dyslipidemia, and ectopic fat accumulation. The data indicate that early long-term undernutrition is associated with increased susceptibility to the harmful effects of nutritional rehabilitation, without causing obesity. PMID- 26105052 TI - Sialic Acids on Varicella-Zoster Virus Glycoprotein B Are Required for Cell-Cell Fusion. AB - Varicella-zoster virus (VZV) is a member of the human Herpesvirus family that causes varicella (chicken pox) and zoster (shingles). VZV latently infects sensory ganglia and is also responsible for encephalomyelitis. Myelin-associated glycoprotein (MAG), a member of the sialic acid (SA)-binding immunoglobulin-like lectin family, is mainly expressed in neural tissues. VZV glycoprotein B (gB) associates with MAG and mediates membrane fusion during VZV entry into host cells. The SA requirements of MAG when associating with its ligands vary depending on the specific ligand, but it is unclear whether the SAs on gB are involved in the association with MAG. In this study, we found that SAs on gB are essential for the association with MAG as well as for membrane fusion during VZV infection. MAG with a point mutation in the SA-binding site did not bind to gB and did not mediate cell-cell fusion or VZV entry. Cell-cell fusion and VZV entry mediated by the gB-MAG interaction were blocked by sialidase treatment. N glycosylation or O-glycosylation inhibitors also inhibited the fusion and entry mediated by gB-MAG interaction. Furthermore, gB with mutations in N-glycosylation sites, i.e. asparagine residues 557 and 686, did not associate with MAG, and the cell-cell fusion efficiency was low. Fusion between the viral envelope and cellular membrane is essential for host cell entry by herpesviruses. Therefore, these results suggest that SAs on gB play important roles in MAG-mediated VZV infection. PMID- 26105053 TI - Dickkopf Homolog 3 Induces Stem Cell Differentiation into Smooth Muscle Lineage via ATF6 Signalling. AB - Smooth muscle cells (SMCs) are a key component of healthy and tissue engineered vessels and play a crucial role in vascular development and the pathogenic events of vascular remodeling i.e. restenosis. However, the cell source from which they can be isolated is limited. Embryonic stem (ES) cells that have the remarkable capability to differentiate into vascular SMCs in response to specific stimuli provide a useful model for studying SMC differentiation. Previous studies suggested that dickkopf homolog 3 (DKK3) has a role in human partially induced pluripotent stem cell to SMC differentiation. Here, we demonstrate that the expression of DKK3 is essential for the expression of SMC markers and myocardin at both the mRNA and protein levels during mouse ES cell differentiation into SMCs (ESC-SMC differentiation). Overexpression of DKK3 leads to further up regulation of the aforementioned markers. Further investigation indicates that DKK3 added as a cytokine activates activating transcription factor 6 (ATF6), leading to the increased binding of ATF6 on the myocardin promoter and increased its expression. In addition, inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) promotes the expression of ATF6 and leads to further increase of myocardin transcription. Our findings offer a novel mechanism by which DKK3 regulates ESC-SMC differentiation by activating ATF6 and promoting myocardin expression. PMID- 26105054 TI - The Activation Pathway of Human Rhodopsin in Comparison to Bovine Rhodopsin. AB - Rhodopsin, the photoreceptor of rod cells, absorbs light to mediate the first step of vision by activating the G protein transducin (Gt). Several human diseases, such as retinitis pigmentosa or congenital night blindness, are linked to rhodopsin malfunctions. Most of the corresponding in vivo studies and structure-function analyses (e.g. based on protein x-ray crystallography or spectroscopy) have been carried out on murine or bovine rhodopsin. Because these rhodopsins differ at several amino acid positions from human rhodopsin, we conducted a comprehensive spectroscopic characterization of human rhodopsin in combination with molecular dynamics simulations. We show by FTIR and UV-visible difference spectroscopy that the light-induced transformations of the early photointermediates are very similar. Significant differences between the pigments appear with formation of the still inactive Meta I state and the transition to active Meta II. However, the conformation of Meta II and its activity toward the G protein are essentially the same, presumably reflecting the evolutionary pressure under which the active state has developed. Altogether, our results show that although the basic activation pathways of human and bovine rhodopsin are similar, structural deviations exist in the inactive conformation and during receptor activation, even between closely related rhodopsins. These differences between the well studied bovine or murine rhodopsins and human rhodopsin have to be taken into account when the influence of point mutations on the activation pathway of human rhodopsin are investigated using the bovine or murine rhodopsin template sequences. PMID- 26105055 TI - Structural Hot Spots Determine Functional Diversity of the Candida glabrata Epithelial Adhesin Family. AB - For host colonization, the human fungal pathogen Candida glabrata is known to utilize a large family of highly related surface-exposed cell wall proteins, the lectin-like epithelial adhesins (Epas). To reveal the structure-function relationships within the entire Epa family, we have performed a large scale functional analysis of the adhesion (A) domains of 17 Epa paralogs in combination with three-dimensional structural studies of selected members with cognate ligands. Our study shows that most EpaA domains exert lectin-like functions and together recognize a wide variety of glycans with terminal galactosides for conferring epithelial cell adhesion. We further identify several conserved and variable structural features within the diverse Epa ligand binding pockets, which affect affinity and specificity. These features rationalize why mere phylogenetic relationships within the Epa family are weak indicators for functional classification and explain how Epa-like adhesins have evolved in C. glabrata and related fungal species. PMID- 26105058 TI - Comparison of breastfeeding rates and health outcomes for infants receiving care from hospital outpatient clinic and community health centres in China. AB - Utilization of community health centres for child health care instead of hospital outpatient clinics is being promoted in China. To evaluate breastfeeding rates and health outcomes of infants who received health care from hospital outpatient clinic or community health centre, a prospective cohort study with six months follow-up was undertaken in Chengdu, China. Participants were 845 mothers and their infants, 417 receiving care from one hospital and 428 from five community health centres. The 'any breastfeeding' rates at one and three months post-partum were significantly lower (p < 0.01) in the hospital outpatient clinic (84% and 68%) than community health centres (92% and 78%). The presence of common illness problems was similar, though the prevalence of lower respiratory tract infection was significantly higher in the hospital group (14.6% vs. 6%, p < .01). No difference in infant growth was observed between the two groups. The results support continuing expansion of child health-care services through community health centres in China. PMID- 26105057 TI - A Simple Numerical Body Surface Mapping Parameter Signifies Successful Percutaneous Coronary Artery Intervention. AB - BACKGROUND: In coronary artery disease (CAD), body surface potential mapping (BSPM) may reveal minor electrical potential changes appearing in the depolarization phase even if pathological changes are absent on the conventional 12-lead ECG. We hypothesized that a simple BSPM parameter, Max/Min signifies successful percutaneous coronary intervention (PCI). METHODS: Ninety-two adult Caucasian patients with stable CAD and positive exercise test underwent coronary angiography. Seventy patients (age, 59 +/- 8; 46 males) were revascularized by PCI (left anterior descending [LAD] in 38, right [RCA] in 17 and left circumflex [LCX] coronary artery in 15). Control groups contained 22 patients (age, 60 +/- 8; 14 males) without intervention and 35 healthy subjects (age, 58 +/- 2; 15 males). Left ventricular ejection fraction (LVEF, transthoracic echocardiography) and Max/Min BSPM parameter (63-lead Montreal system) were evaluated before and 4 40 days following coronary angiography. Max/Min was defined by the ratio of the highest maximum to the deepest minimum potential of all leads recorded by BSPM. RESULTS: Before PCI, Max/Min value of patients with LAD lesion (0.83 [0.74; 0.93]) was significantly lower while that with RCA lesion (1.63 [1.35; 1.99]) was significantly higher than that of healthy group (1.01 [0.970; 1.13]) (P < 0.05) and LVEF was significantly lower in LAD lesion (46.50% [43.00; 51.00]) than in the healthy group (55.00% [50.00; 58.75]) (P < 0.01). Max/Min value significantly increased from 0.83 [0.74; 0.93] to 0.92 [0.82; 0.99] (P < 0.01) following LAD PCI while significantly decreased from 1.63 [1.35; 1.98] to 1.35 [1.21; 1.43] (P < 0.01) post-RCA PCI. It did not vary significantly, however, either following LCX PCI or without intervention. LVEF significantly increased (from 46.50% [43.00; 51.00] to 49.00% [46.00; 51.00]) only after LAD PCI. CONCLUSION: Max/Min parameter is suitable to follow patients after LAD and RCA PCI. PMID- 26105059 TI - Addressing childhood obesity at school entry: Qualitative experiences of school health professionals. AB - School entry provides an opportune moment for health professionals to intervene with children who are overweight, yet identification and management of childhood obesity presents challenges in practice. This multi-method qualitative study explored the experiences of 26 school health professionals in addressing childhood obesity at school entry. Methods included semi-structured interviews with service managers (n = 3); focus groups with school nurses (n = 12) and child health practitioners (n = 6); and open-ended questionnaires with school nurses (n = 4) and child health practitioners (n = 1) who were unable to attend the focus groups. A thematic analysis revealed agreement between service managers, school nurses and child health practitioners. Whilst it was felt school health professionals have an important role to play in managing childhood obesity, efforts to address child weight were limited by a lack of capacity, lack of clear protocols, challenges of engaging parents and insufficient training in childhood obesity and related lifestyle issues. School health policymakers need to recognize childhood obesity as a serious public health issue, allocate appropriate resources to nurse training and development and ensure clear pathways are established to ensure consistency of care. PMID- 26105056 TI - Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome. AB - The cerebellum is involved in sensorimotor operations, cognitive tasks and affective processes. Here, we revisit the concept of the cerebellar syndrome in the light of recent advances in our understanding of cerebellar operations. The key symptoms and signs of cerebellar dysfunction, often grouped under the generic term of ataxia, are discussed. Vertigo, dizziness, and imbalance are associated with lesions of the vestibulo-cerebellar, vestibulo-spinal, or cerebellar ocular motor systems. The cerebellum plays a major role in the online to long-term control of eye movements (control of calibration, reduction of eye instability, maintenance of ocular alignment). Ocular instability, nystagmus, saccadic intrusions, impaired smooth pursuit, impaired vestibulo-ocular reflex (VOR), and ocular misalignment are at the core of oculomotor cerebellar deficits. As a motor speech disorder, ataxic dysarthria is highly suggestive of cerebellar pathology. Regarding motor control of limbs, hypotonia, a- or dysdiadochokinesia, dysmetria, grasping deficits and various tremor phenomenologies are observed in cerebellar disorders to varying degrees. There is clear evidence that the cerebellum participates in force perception and proprioceptive sense during active movements. Gait is staggering with a wide base, and tandem gait is very often impaired in cerebellar disorders. In terms of cognitive and affective operations, impairments are found in executive functions, visual-spatial processing, linguistic function, and affective regulation (Schmahmann's syndrome). Nonmotor linguistic deficits including disruption of articulatory and graphomotor planning, language dynamics, verbal fluency, phonological, and semantic word retrieval, expressive and receptive syntax, and various aspects of reading and writing may be impaired after cerebellar damage. The cerebellum is organized into (a) a primary sensorimotor region in the anterior lobe and adjacent part of lobule VI, (b) a second sensorimotor region in lobule VIII, and (c) cognitive and limbic regions located in the posterior lobe (lobule VI, lobule VIIA which includes crus I and crus II, and lobule VIIB). The limbic cerebellum is mainly represented in the posterior vermis. The cortico-ponto-cerebellar and cerebello thalamo-cortical loops establish close functional connections between the cerebellum and the supratentorial motor, paralimbic and association cortices, and cerebellar symptoms are associated with a disruption of these loops. PMID- 26105060 TI - An empowerment health education program for children undergoing surgery for congenital heart diseases. AB - Since the surgery for congenital heart disease (CHD) is considered highly risky, appropriate postoperative care is crucial. After the surgery, children are often discharged with unhealed wounds, incomplete recovery, and continuing pain. Health education programs based on empowerment education model can assist clients to develop skills in self-management. This study aimed to evaluate the effectiveness of an empowerment health education program for improving caregiving knowledge, caring behaviors, and self-efficacy of parents caring for children after corrective surgery for CHD. This prospective clinical trial enrolled pediatric patients undergoing surgical correction for CHD. Patients were divided into two groups: the control group (n = 42), which received the standard education program, and the intervention group (n = 44), which participated in the empowerment theory-based education program. We collected data on left ventricular ejection fraction (LVEF); peripheral oxygen saturation (SpO2); New York Heart Association classification of the patients; and the parents' caregiving knowledge, caring behaviors, and self-efficacy before surgery and one month and three months after surgery. At one month and three months after surgery, the intervention group scored higher than the control group in caregiving knowledge, caring behavior, and self-efficacy. By the third month after surgery, the intervention group had significantly higher values of LVEF and SpO2 than the control group. PMID- 26105061 TI - Uncertainty: A little bit not sure. Parental concern about child growth or development. AB - Delays in child growth or development are significant problems for children, their families and population health. Eliciting parental concerns as early as possible to promote child growth and development requires close collaborative working with parents. There is evidence that parents delay expressing concern and that health-care professionals are not always effective at eliciting and attending to parental concerns. The aim of this study was to understand the experiences of parents of preschool children who had expressed a child growth or development concern. An Interpretative Phenomenological Analysis (IPA) study design was used with a purposive sample of parents of 15 preschool children in Ireland. Data were collected by semi-structured interviews and analysed using IPA. One key superordinate theme - Uncertainty - 'a little bit not sure' captured how parents made sense of their concerns about their child's growth and development. In addition to watching, comparing and wondering, parents assessed whether their child could 'do other things' or if something in particular could have caused the growth or development problem. Parents, particularly mothers, grapple with uncertainty associated with unfamiliar cues in the complex and multifaceted nature of child growth and development in their efforts to make sense of what is happening with their child. PMID- 26105062 TI - Protecting children in research: Safer ways to research with children who may be experiencing violence or abuse. AB - Children participating in research, like other children, may be being maltreated. There is also potential for exposure to abuse during research. Research training, practices and protocols to respond to disclosure and discovery of abuse to protect both researchers and children may not be sufficiently robust. Our aim was to compare and contrast research practices reported in the literature related to protecting children and to recommend safer ways to conduct research. The simultaneous increase in research with children, along with an increased willingness to listen to child victims of abuse, means that researchers must consider the protection of children in the research setting. Twenty-three papers were identified in a literature review. These studies reported a wide variation of ethical considerations, methods, methodology and came from different disciplines. From the 23 papers, two overarching themes were identified: social justice and research and safer research. To make research safer teams should consider training, safety protocols and support for child protection, which includes support to report safeguarding concerns to social care. Further work is required to ensure that training, protocols and support are effective in facilitating researchers to identify and make appropriate child abuse referrals. Ethics practices in abuse research need further debate. PMID- 26105063 TI - The road to retirement. PMID- 26105064 TI - Clinical applications of predictable force systems, part 2: Miniscrew anchorage. PMID- 26105065 TI - Changes in orthodontists' retirement planning and practice operations due to the recent recession. PMID- 26105066 TI - Creative adjuncts for clear aligners, part 3: Extraction and interdisciplinary treatment. PMID- 26105067 TI - Total TMJ reconstruction in cases of advanced idiopathic condylysis. PMID- 26105068 TI - Intrusion of palatally displaced maxillary lateral incisors using nickel titanium closed-coil springs. PMID- 26105069 TI - Guided eruption of multiple impacted teeth using a modified miniplate. PMID- 26105070 TI - VOLUME 31: HTA'S EVOLUTION: FROM CONSUMER TO HONEST BROKER TO ENGAGED COLLABORATOR. AB - In this issue, Facey and colleagues have eloquently summarized the product of the February 2015 HTAi Policy Forum discussion-the need for health technology assessment (HTA) to shift from a historically reactive role in both evaluating current evidence and requesting additional evidence generation to a more proactive role engaging with stakeholders to ensure that evidence produced is appropriate for any given intervention at different stages of the clinical development program. This makes logical a priori sense, of course, as proactive and engaged discussion is always superior to reactive and potentially adversarial interaction. PMID- 26105071 TI - Surface plasmon resonance imaging of pathogens: the Yersinia pestis paradigm. AB - BACKGROUND: Yersinia pestis, causing deadly plague, is classified as a group A bioterrorism bacterium. Some recent DNA-based methods were used for detection of bioterrorism agents. RESULTS: Y. pestis was used as a model organism to develop an immunosensor based on surface plasmon resonance imaging (SPRi) using monoclonal antibody against Y. pestis F1 antigen. The experimental approach included step-by-step detection of Y. pestis membrane proteins, lysed bacteria, intact bacteria, mock-infected powder and mock-infected clinical specimens. SPRi detected on average 10(6) intact Y. pestis organisms in buffer, in mock-infected powder and in a 1:4 mixture with HEL cells. CONCLUSIONS: This study offers the proof-of-concept of the SPRi-based detection of a human pathogen in both environmental and clinical specimens. PMID- 26105072 TI - Evaluation of an educational program for essential newborn care in resource limited settings: Essential Care for Every Baby. AB - BACKGROUND: Essential Care for Every Baby (ECEB) is an evidence-based educational program designed to increase cognitive knowledge and develop skills of health care professionals in essential newborn care in low-resource areas. The course focuses on the immediate care of the newborn after birth and during the first day or until discharge from the health facility. This study assessed the overall design of the course; the ability of facilitators to teach the course; and the knowledge and skills acquired by the learners. METHODS: Testing occurred at 2 global sites. Data from a facilitator evaluation survey, a learner satisfaction survey, a multiple choice question (MCQ) examination, performance on two objective structured clinical evaluations (OSCE), and pre- and post-course confidence assessments were analyzed using descriptive statistics. Pre-post course differences were examined. Comments on the evaluation form and post-course group discussions were analyzed to identify potential program improvements. RESULTS: Using ECEB course material, master trainers taught 12 facilitators in India and 11 in Kenya who subsequently taught 62 providers of newborn care in India and 64 in Kenya. Facilitators and learners were satisfied with their ability to teach and learn from the program. Confidence (3.5 to 5) and MCQ scores (India: pre 19.4, post 24.8; Kenya: pre 20.8, post 25.0) improved (p < 0.001). Most participants demonstrated satisfactory skills on the OSCEs. Qualitative data suggested the course was effective, but also identified areas for course improvement. These included additional time for hands-on practice, including practice in a clinical setting, the addition of video learning aids and the adaptation of content to conform to locally recommended practices. CONCLUSION: ECEB program was highly acceptable, demonstrated improved confidence, improved knowledge and developed skills. ECEB may improve newborn care in low resource settings if it is part of an overall implementation plan that addresses local needs and serves to further strengthen health systems. PMID- 26105073 TI - A large-scale functional screen identifies Nova1 and Ncoa3 as regulators of neuronal miRNA function. AB - MicroRNAs (miRNAs) are important regulators of neuronal development, network connectivity, and synaptic plasticity. While many neuronal miRNAs were previously shown to modulate neuronal morphogenesis, little is known regarding the regulation of miRNA function. In a large-scale functional screen, we identified two novel regulators of neuronal miRNA function, Nova1 and Ncoa3. Both proteins are expressed in the nucleus and the cytoplasm of developing hippocampal neurons. We found that Nova1 and Ncoa3 stimulate miRNA function by different mechanisms that converge on Argonaute (Ago) proteins, core components of the miRNA-induced silencing complex (miRISC). While Nova1 physically interacts with Ago proteins, Ncoa3 selectively promotes the expression of Ago2 at the transcriptional level. We further show that Ncoa3 regulates dendritic complexity and dendritic spine maturation of hippocampal neurons in a miRNA-dependent fashion. Importantly, both the loss of miRNA activity and increased dendrite complexity upon Ncoa3 knockdown were rescued by Ago2 overexpression. Together, we uncovered two novel factors that control neuronal miRISC function at the level of Ago proteins, with possible implications for the regulation of synapse development and plasticity. PMID- 26105075 TI - Brain network connectivity-behavioral relationships exhibit trait-like properties: Evidence from hippocampal connectivity and memory. AB - Despite a growing number of studies showing relationships between behavior and resting-state functional MRI measures of large-scale brain network connectivity, no study to our knowledge has sought to investigate whether intrinsic connectivity-behavioral relationships are stable over time. In this study, we investigated the stability of such brain-behavior relationships at two timepoints, approximately 1 week apart. We focused on the relationship between the strength of hippocampal connectivity to posterior cingulate cortex and episodic memory performance. Our results showed that this relationship is stable across samples of a different age and reliable over two points in time. These findings provide the first evidence that the relationship between large-scale intrinsic network connectivity and episodic memory performance is a stable characteristic that varies between individuals. PMID- 26105074 TI - The HDAC6/APOBEC3G complex regulates HIV-1 infectiveness by inducing Vif autophagic degradation. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) has evolved a complex strategy to overcome the immune barriers it encounters throughout an organism thanks to its viral infectivity factor (Vif), a key protein for HIV-1 infectivity and in vivo pathogenesis. Vif interacts with and promotes "apolipoprotein B mRNA editing enzyme-catalytic, polypeptide-like 3G" (A3G) ubiquitination and subsequent degradation by the proteasome, thus eluding A3G restriction activity against HIV-1. RESULTS: We found that cellular histone deacetylase 6 (HDAC6) directly interacts with A3G through its C-terminal BUZ domain (residues 841 1,215) to undergo a cellular co-distribution along microtubules and cytoplasm. The HDAC6/A3G complex occurs in the absence or presence of Vif, competes for Vif mediated A3G degradation, and accounts for A3G steady-state expression level. In fact, HDAC6 directly interacts with and promotes Vif autophagic clearance, thanks to its C-terminal BUZ domain, a process requiring the deacetylase activity of HDAC6. HDAC6 degrades Vif without affecting the core binding factor beta (CBF beta), a Vif-associated partner reported to be key for Vif- mediated A3G degradation. Thus HDAC6 antagonizes the proviral activity of Vif/CBF-beta associated complex by targeting Vif and stabilizing A3G. Finally, in cells producing virions, we observed a clear-cut correlation between the ability of HDAC6 to degrade Vif and to restore A3G expression, suggesting that HDAC6 controls the amount of Vif incorporated into nascent virions and the ability of HIV-1 particles of being infectious. This effect seems independent on the presence of A3G inside virions and on viral tropism. CONCLUSIONS: Our study identifies for the first time a new cellular complex, HDAC6/A3G, involved in the autophagic degradation of Vif, and suggests that HDAC6 represents a new antiviral factor capable of controlling HIV-1 infectiveness by counteracting Vif and its functions. PMID- 26105076 TI - A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia. AB - BACKGROUND: Grebe dysplasia, Hunter-Thompson dysplasia, and du Pan dysplasia constitute a spectrum of skeletal dysplasias inherited as an autosomal recessive trait characterized by short stature, severe acromesomelic shortening of the limbs, and normal axial skeleton. The majority of patients with these disorders have biallelic loss-of-function mutations of GDF5. In single instances, Grebe dysplasia and a Grebe dysplasia-like phenotype with genital anomalies have been shown to be caused by mutations in BMPR1B, encoding a GDF5 receptor. METHODS: We clinically and radiologically characterised an acromesomelic chondrodysplasia in an adult woman born to consanguineous parents. We sequenced GDF5 and BMPR1B on DNA of the proposita. We performed 3D structural analysis and luciferase reporter assays to functionally investigate the identified BMPR1B mutation. RESULTS: We extend the genotype-phenotype correlation in the acromesomelic chondrodysplasias by showing that the milder du Pan dysplasia can be caused by a hypomorphic BMPR1B mutation. We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia. CONCLUSIONS: The phenotypic severity gradient of the clinically and radiologically related acromesomelic chondrodysplasia spectrum of skeletal disorders may be due to the extent of functional impairment of the ligand-receptor pair GDF5-BMPR1B. PMID- 26105077 TI - Combating oil spill problem using plastic waste. AB - Thermoplastic polymers (such as polypropylene, polyethylene, polyethylene terephthalate (PET) and high density polyethylene (HDPE)) constitute 5-15% of municipal solid waste produced across the world. A huge quantity of plastic waste is disposed of each year and is mostly either discarded in landfills or incinerated. On the other hand, the usage of synthetic polymers as oil sorbents, in particular, polyolefins, including polypropylene (PP), and polyethylene (PE) are the most commonly used oil sorbent materials mainly due to their low cost. However, they possess relatively low oil absorption capacities. In this work, we provide an innovative way to produce a value-added product such as oil-sorbent film with high practical oil uptake values in terms of g/g from waste HDPE bottles for rapid oil spill remedy. PMID- 26105078 TI - Grape Marc Extract-Induced Defense Reactions and Protection against Phytophthora parasitica Are Impaired in NahG Tobacco Plants. AB - Grape marc extract (GME) acts as an elicitor of plant defense responses. This study analyzed GME-induced plant defense reactions in NahG transgenic tobacco. Leaf infiltration of NahG leaves revealed HR-like reactions with reduced lesions and weak deployment of autofluorescent compounds in the surrounding infiltrated tissues. The beta-1,3-glucanase PR2-, endochitinase PR3-, and osmotin PR5-target transcript levels were strongly lowered in NahG leaves, and the mutant failed to accumulate the antimicrobial PR1 transcripts. GME-induced protection against Phytophthora parasitica var. nicotianae (Ppn) was evaluated on tobacco leaves. The antimicrobial properties of GME against Ppn were evidenced using a range of in vitro tests. GME-sprayed wild-type leaves showed reduced infection areas, whereas GME failed to induce a protective effect against Ppn in NahG leaves. The results suggest that GME-induced plant defense reactions in tobacco plants was mediated by salicylic acid (SA) and that GME-induced protection against Ppn could be the combined result of antimicrobial and defense actions. PMID- 26105079 TI - Simultaneous transapical transcatheter aortic valve replacement and transcatheter mitral valve replacement for native valvular stenosis. AB - Transcatheter aortic valve replacement (TAVR) is well established for patients who cannot undergo surgery (Leon et al., N Engl J Med 2010;363:1597) or are high risk for surgery (Smith et al., N Engl J Med 2011;364:2187-2198). Experience with the TAVR procedure has led to recent reports of successful transcatheter mitral valve replacement (TMVR) procedures (Cheung et al., J Am Coll Cardiol 2014;64:1814; Seiffert et al., J Am Coll Cardiol Interv 2012;5:341-349) separately or simultaneously with the TAVR. However, these reports were of simultaneous valve-in-valve procedures (Cheung Anson, et al. J Am Coll Cardiol 2013;61:1759-1766). A recent report from Portugal also reported simultaneous transpical implantation of an inverted transcatheter aortic valve-in-ring in the mitral position and transcatheter aortic valve (Hasan et al., Circulation 2013;128:e74-e76). There has been an experience of TMVR only in native mitral valve for mitral valve stenosis, but none in both aortic and mitral valves. We report the first in human case of simultaneous transapical TAVR and TMVR in native valves secondary to valvular stenosis. Our patient was not a candidate for percutaneous balloon mitral valvuloplasty secondary to a high Wilkins Score. Sizing of the aortic valve was based on the transesophageal echocardiogram (TEE), whereas sizing of the mitral valve was based on TEE measurements and balloon inflation during left ventriculography. (c) 2015 Wiley Periodicals, Inc. PMID- 26105081 TI - Lumpy Skin Disease in Iraq: Study of the Disease Emergence. AB - This study intends to report the first emergence of lumpy skin disease (LSD) in Iraq, in addition to describing its related clinical signs. In August 2013, 21 cases of four outbreaks developed clinical signs suggestive of LSD in the Nineveh (Mosul) and Baghdad Governorates, which were considered as the first infected foci of LSD in Iraq. The disease was diagnosed tentatively, on the basis of clinical signs and epidemiological features, and it was confirmed as positive by the polymerase chain reaction and histopathological features. In September 2013, eight new outbreaks of LSD also appeared in Baghdad and Nineveh. In 2014, the disease spread rapidly to the governorates of Kirkuk, Salah Al-Din, Al-Anbar, Diyala, Wasit, Babil, Karbala, Najaf, Al-Diwaniyah, Muthanna, Maysan, DhiQar and Basra. The total number of infected cows and calves reported was 7396 and 227, respectively. The apparent morbidity and mortality rates were 9.11% and 0.51%, respectively, while the apparent case-fatality rate was 5.56%. Skin nodules, anorexia, reduce in milk production and decrease in bodyweight were the common clinical signs. Moreover, myiasis and mastitis were seen as complications in some infected animals. Attempts were made to stop the distribution of the disease including quarantine and treatment, control over animal movement and arthropod control. Ring vaccination was used in a 10 km radius zone around the outbreak with live sheep pox vaccine. The highly contagious transboundary nature of the LSD, its endemic distribution in the Iraqi neighbouring countries, and the current armed conflict in the area were the possible factors for the disease being introduced into the country. LSD had spread through the Middle East and Gulf peninsula and could be a cause of danger to the rest of Asia and Europe. International precaution, cooperation and exchange of information could guarantee the prevention and further spread of the disease to the rest of Asia and Europe. PMID- 26105082 TI - The Need for Cultural Safety in Injury Prevention. AB - Public health nurses are on the front line of injury prevention initiatives. However, within injury prevention interventions and research, issues pertaining to culture are often addressed through the employment of one of the three approaches: cultural competency, cultural appropriateness, and/or cultural sensitivity. When using these approaches, it is often suggested that it is only those who are the recipients of an intervention or the focus of research that "have" culture. The injury prevention designer's/provider's/researcher's own culture, as well as the ways in which it may influence the interventions or research, is typically rendered invisible. In this paper, we provide an overview and illustrations of the use of cultural competency, cultural appropriateness, and cultural sensitivity in injury prevention initiatives, as well as each approach's shortcomings. We then introduce cultural safety, an approach that has not yet gained traction in injury prevention but has had significant uptake within nursing in general, and argue that it has the potential to overcome many other approaches' shortcomings and thus may lead to more effective and socially just injury prevention initiatives. PMID- 26105083 TI - Urine biomarkers of schistosomiais and its associated bladder cancer. AB - Schistosomiasis (SCH) is the second only to malaria among the parasitic diseases affecting humans regarding the prevalence of infection worldwide. In this nonsystematic review, we summarize the existing data on commercially available and promising investigational urine markers for the detection of SCH and its associated bladder cancer (BC). We searched PubMed, Scopus and Cochran without time limits. We reviewed the recent literatures on urine-based markers for SCH and its associated BC. Many studies identified several urine biomarkers of Schistosoma haematobium and Schistosoma mansoni worms and their associated BC using automated, inexpensive, quantitative assays in urine. These markers may aid in early detection of bladder carcinoma and have the potential to reduce the number of follow-up cystoscopy, thus reducing healthcare costs and patient discomfort, at the same time. Nevertheless, clinical evidence is insufficient to warrant the substitution of the cystoscopic follow-up scheme by any of the currently available urine marker tests. PMID- 26105084 TI - Sodium NMR/MRI for anisotropic systems. AB - Sodium ((23)Na) plays a central role in many physiological processes, and its high NMR sensitivity makes it an attractive nucleus for biomedical NMR and MRI research. Many biological tissues contain structures such as fibers and membranes that impose anisotropic translational and rotational motions on the sodium ions. Translational motion can be studied by diffusion measurements. Anisotropic rotational motion results in non-vanishing quadrupolar interaction that it is best studied by exploiting multiple quantum coherences for (23)Na NMR spectroscopy and MRI. The current review covers the application of the various NMR techniques to the study of (23)Na in anisotropic compartments in cartilage, tendon, intervertebral discs, red blood cells, nervous system and muscles. PMID- 26105085 TI - Effect of high-protein supplemental therapy on subjective global assessment of CKD-5D patients. AB - Adequate nutrition in patients on hemodialysis is an important step for improving the quality of life. This prospective study was undertaken to monitor the nutritional status of patients who were given high-protein supplements on malnutrition inflammation score (MIS) and to correlate with biochemical parameters in maintenance hemodialysis (MHD) patients. This prospective study was conducted on 55 chronic kidney disease patients on MHD (37 women, 18 men), aged between 21 and 67 years. Of the 55 patients, 26 patients received high-protein commercial nutritional supplements, whereas 29 patients received high-protein kitchen feeding. Every patient had their MIS, 24-hour dietary recall, hand grip, mid arm circumference, triceps skin-fold thickness at 0, 3, and 6 months. Each of the above parameters was compared between the high-protein commercial nutritional supplement cohort and high-protein kitchen feeding cohort, and the data were analyzed. Of the 55 patients, 82.61% of patients on high-protein kitchen feeding group and 66.67% in high-protein commercial nutritional supplement group were nonvegetarian (P = 0.021). According to the MIS, improvement was observed in malnutrition status from 3- to 6-month period in 38.1% of patients in high protein commercial supplement group, whereas only in 8.7% in high-protein kitchen feeding group (P = 0.04). Assessment showed improvement in malnutrition status with high-protein commercial nutritional supplement, which was marked in patients with age group >65 years (P = 0.03) and in those in whom serum albumin is <35 g/L (P = 0.02). Both high-protein kitchen feeding and high-protein commercial nutritional supplement cohorts were observed to have improvement in overall nutritional status. Older patients >65 years with lower serum albumin levels (<3.5 g/dL) were observed to have significant improvement in nutritional status with high-protein commercial nutritional supplements. PMID- 26105086 TI - Brefeldin A exerts differential effects on anaplastic lymphoma kinase positive anaplastic large cell lymphoma and classical Hodgkin lymphoma cell lines. AB - To obtain further insights into the biological differences of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK+ ALCL) and classical Hodgkin lymphoma (HL), we screened microbial culture filtrates to search for compounds that would exert a significantly greater effect on the viability of ALK+ ALCL cell lines compared to HL cell lines and identified Brefeldin A (BFA) as a suitable candidate. BFA inhibited phosphorylation of ALK and its downstream molecule, signal transducer and activator of transcription 3 (STAT3), one of the central pathways for the survival of ALK+ ALCL cells. In HL cell lines BFA did not affect CD30 expression or constitutive nuclear factor (NF)-kappaB activity, both of which are critical for HL cell survival. BFA induced disruption of the Golgi apparatus in ALK+ ALCL cell lines, which was accompanied by a decrease in active ADP-ribosylation factor 1 (ARF1), whereas BFA had no significant effect on these parameters in HL cell lines. These results add extra insights into the biological distinction between ALK+ ALCL and HL cells and highlight the Golgi apparatus as a target for the treatment of ALK+ ALCL. PMID- 26105087 TI - Parinaud's oculoglandular syndrome revealing subclinical Rickettsia conorii infection. AB - The purpose of this study was to report a case of Parinaud's oculoglandular syndrome associated with subclinical Rickettsia conorii infection. We report a case of a 66-year-old male patient presented with unilateral persistent granulomatous conjunctivitis in the left eye and an ipsilateral preauricular lymphadenopathy without associated systemic features. Laboratory evaluation showed a positive indirect immunofluorescence antibody test for R. conorii. The patient received a 2-week course of oral doxycycline, with subsequent complete resolution of all his symptoms. Rickettsial disease should be considered in the differential diagnosis of oculoglandular syndrome with or without associated systemic symptoms in any patient living in or returning from a specific endemic area. PMID- 26105088 TI - Personality subtypes and chest pain in patients with nonobstructive coronary artery disease from the TweeSteden Mild Stenosis study: mediating effect of anxiety and depression. AB - BACKGROUND: Patients presenting with chest pain in nonobstructive coronary artery disease (CAD, luminal narrowing <60%) are at risk for emotional distress and future events. We aimed to examine the association of personality subtypes with persistent chest pain, and investigated the potential mediating effects of negative mood states. METHODS: Any chest pain in the past month was the primary outcome measure reported by 523 patients with nonobstructive CAD (mean age 61.4 years, SD = 9.4; 48% men), who participate in the TweeSteden Mild Stenosis (TWIST) observational cohort. Personality was categorized into a 'reference group', a high social inhibition ('SI only'), a high negative affectivity ('NA only') and a 'Type D' (NA and SI) group. Negative mood states included symptoms of depression and anxiety (Hospital Anxiety and Depression Scale) and cognitive and somatic depression (Beck Depression Inventory). The PROCESS macro was used to examine the relation between personality subtypes and chest pain presence, with the negative mood states as potential mediators. RESULTS: Persistent chest pain was present in 44% of the patients with nonobstructive CAD. Type D personality (OR = 1.91, 95% CI 1.24-2.95), but not the 'NA only' (OR = 1.48, 95% CI 0.89 2.44) or the 'SI only' (OR = 0.93, 95% CI 0.53-1.64) group was associated with chest pain, adjusted for age and sex. Negative mood states mediated the association between personality and chest pain. CONCLUSIONS: Type D personality, but not negative affectivity or social inhibition, was related to chest pain in nonobstructive CAD, which was mediated by negative mood states. PMID- 26105089 TI - Human herpesvirus 6 infection in a bone marrow biopsy specimen after allogeneic stem cell transplantation. PMID- 26105090 TI - Posterior Displacement of Supraspinatus Central Tendon Observed on Magnetic Resonance Imaging: A Useful Preoperative Indicator of Rotator Cuff Tear Characteristics. AB - PURPOSE: To characterize the orientation of the normal supraspinatus central tendon and describe the displacement patterns of the central tendon in rotator cuff tears using a magnetic resonance imaging (MRI)-based method. METHODS: We performed a retrospective MRI and chart review of 183 patients with a rotator cuff tear (cuff tear group), 52 with a labral tear but no rotator cuff tear (labral tear group), and 74 with a normal shoulder (normal group). The orientation of the supraspinatus central tendon relative to the bicipital groove was evaluated based on axial MRI and was numerically represented by the shortest distance from the lateral extension line of the central tendon to the bicipital groove. Tear size, fatty degeneration, and involvement of the anterior supraspinatus were evaluated to identify the factors associated with orientation changes. RESULTS: The mean distance from the bicipital groove to the central tendon line was 0.7 mm and 1.3 mm in the normal group and labral tear group, respectively. Full-thickness cuff tears involving the anterior supraspinatus showed a significantly greater distance (17.7 mm) than those sparing the anterior supraspinatus (4.9 mm, P = .001). Fatty degeneration of the supraspinatus was significantly correlated with the distance (P = .006). Disruption of the anterior supraspinatus and fatty degeneration of the supraspinatus were independent predictors of posterior displacement. CONCLUSIONS: The supraspinatus central tendon has a constant orientation toward the bicipital groove in normal shoulders, and the central tendon is frequently displaced posteriorly in full thickness rotator cuff tears involving the anterior leading edge of the supraspinatus. The degree of posterior displacement is proportional to tear size and severity of fatty degeneration of the supraspinatus muscle. A simple and quick assessment of the central tendon orientation on preoperative MRI can be a useful indicator of tear characteristics, potentially providing insight into the intraoperative repair strategy. LEVEL OF EVIDENCE: Level IV, diagnostic case control study. PMID- 26105091 TI - Incidence and Risk Factor Analysis of Symptomatic Venous Thromboembolism After Knee Arthroscopy. AB - PURPOSE: To (1) determine the incidence of symptomatic venous thromboembolic events (VTEs) after knee arthroscopy and arthroscopy-assisted procedures at a single institution and (2) determine associated risk factors for VTEs in these patients. METHODS: The records of patients who underwent knee arthroscopy at a single institution between 1988 and 2008 were reviewed. Chemoprophylaxis was not routinely used. Confirmed VTEs occurring within 4 weeks after the index arthroscopy procedure were included. A 2:1 matched control group was generated to include patients in whom knee arthroscopy was performed by the same surgeon either on the same day or immediately before each case resulting in a VTE. Preoperative and perioperative data were collected with respect to demographic data, medical history, medications, and surgical and anesthesia data. Univariate and multivariate analyses were performed. RESULTS: During the study period, 12,595 patients underwent knee arthroscopy. Among these patients, 43 cases of VTEs (35 deep venous thromboses [DVTs], 5 pulmonary embolisms [PEs], and 3 DVTs that progressed to PEs) occurred, resulting in an incidence of 0.30% (95% confidence interval [CI], 0.22% to 0.41%) for DVT, 0.06% (95% CI, 0.03% to 0.12%) for PE, and 0.34% (95% CI, 0.25% to 0.46%) for VTEs overall. Factors associated with an elevated risk of symptomatic postoperative VTEs included a history of malignancy (P = .01; odds ratio [OR], 6.3), a history of VTEs (P = .02; OR, 5.2), or the presence of more than 2 classic risk factors for VTEs (P = .01; OR, 13.6). CONCLUSIONS: In this study, symptomatic VTEs were rare and occurred infrequently, with an incidence of 0.34% (95% CI, 0.25% to 0.46%), after knee arthroscopy and arthroscopy-assisted cases in the absence of routine chemoprophylaxis. Patients with a history of VTEs, a history of malignancy, or 2 or more classic risk factors are at increased risk of VTEs after knee arthroscopy, and chemoprophylaxis should be considered in these select patients. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 26105092 TI - Hip Strength Deficits in Patients With Symptomatic Femoroacetabular Impingement and Labral Tears. AB - PURPOSE: To determine the prevalence of hip strength deficits in a consecutive cohort of patients with unilateral femoroacetabular impingement (FAI) compared with the asymptomatic contralateral hip. METHODS: Fifty consecutive patients undergoing hip arthroscopy for symptomatic FAI underwent preoperative hip strength dynamometer measurements and were included in the study. Manual isometric hip strength measurements were performed with a handheld dynamometer and included measurements of various hip strengths (flexion, extension, adduction, abduction, internal rotation, and external rotation). Weakness greater than or equal to 10% for any given measurement was defined as a strength deficit in this study. Clinical data including age, gender, size of labral tear, and preoperative outcome scores were recorded. Outcome scores included the modified Harris Hip Score and Short Form 12 Physical Component. RESULTS: The mean age of patients in the study was 32.0 years (range, 18.1 to 49.8 years). There were 32 male and 18 female patients. Hip abduction strength deficits were seen in 46% of patients and flexion strength deficits in 42% of patients. An 8% decrease in strength of the involved hip was seen in flexion, and an 8.7% decrease was seen in abduction. Patients with hip flexion strength deficits had a loss of function (mean modified Harris Hip Score, 57.8 v 66.1; P = .021) and larger labral tears (mean, 39 mm v 28 mm; P = .003). Hip flexion strength deficits correlated with loss of hip flexion (r = 0.373, P = .008). CONCLUSIONS: Hip strength deficits were common in patients presenting with unilateral symptomatic FAI and occurred most commonly in hip abduction and flexion. Strength deficits in hip flexion were associated with decreased function, loss of motion, and larger labral tears in patients with FAI and labral tears. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 26105093 TI - Editorial. PMID- 26105094 TI - Influence of so far neglected psychosomatic factors, BMI and smoking on pregnancy induced hypertension (PIH). AB - OBJECTIVE: Correlation of descriptive psychosomatic factors and birth parameters for pregnancy-induced hypertension (PIH). STUDY DESIGN: For this prospective study 508 pregnant (singleton) women from 16th-22nd gestational week (GW) were investigated by means of a semi-standardized questionnaire. Complete data concerning delivery were obtained from medical records. In addition to medical and sociodemographic risk factors, so far neglected parameters such as biographical information, personality factors, social environment, stress coping strategies and pregnancy-related anxieties were examined. A factor analysis was performed using a principal component method with subsequent varimax rotation. MAIN OUTCOME MEASURES: Main outcome measures were imminent preterm delivery, PIH, factual preterm delivery before 37GW and birth weight <10th percentile. RESULTS: Four hundred and eighty-eight qualified for evaluation and got included in the univariate logistic regression - 12.6% of them had PIH. The development of PIH showed a significant correlation with age (OR, 95% CI). Very young and older women were more likely to develop PIH. Development of PIH is significantly more frequent in women, whose parents adhered to an authoritarian educational style, had no emotional support of female friends, and a higher BMI. Women who always had been non-smokers and women who did not give up smoking during pregnancy, but only reduced the amount of cigarettes had the least probability of developing PIH, whereas total abandoning of smoking before and especially during pregnancy was associated with a significantly increased risk for the development of PIH. CONCLUSIONS: This study suggests psychosomatic factors, BMI and smoking behavior to be relevant for the development of PIH. PMID- 26105095 TI - Serum S100B in pregnancy complicated by preeclampsia: A case-control study. AB - BACKGROUND: Serum S100B is a protein produced and released primarily by astrocytes of the Central Nervous System (CNS). Elevated levels of serum S100B are associated with several types of pathological conditions of the brain, including the eclampsia in pregnant women. The aim of this study was to compare serum S100B concentrations in pregnant women with severe and mild preeclampsia (PE) with S100B serum levels in normotensive pregnant women. MATERIAL AND METHODS: Serum S100B protein was measured in normotensive pregnant women (n=15) and in women with mild PE (n=12) or severe PE (n=34). The serum S100B level (MUg/L) was determined by an luminometric assay. RESULTS: Sixty-one expectant mothers were studied, aged 26.6+/-8.7 (mean+/-SD) years and with a gestational age of 33.3+/-4.2 weeks. The severe PE group demonstrated higher S100B levels (0.20+/-0.19), as compared with mild PE (0.07+/-0.05) or normotensive groups (0.04+/-0.05). CONCLUSION: Elevated serum S100B levels in pregnant women with severe PE suggest that some kind of neural damage and subsequent astrocytic release of S100B is not dependent on the progression from severe preeclampsia to eclampsia. PMID- 26105096 TI - Association between placental growth factor levels in early onset preeclampsia with the occurrence of postpartum hemorrhage: A prospective cohort study. AB - OBJECTIVES: To determine the association between PlGF (placental growth factor) estimation in early second trimester (22-24weeks of gestation), with the occurrence of postpartum hemorrhage in pregnant women with early onset preeclampsia and whether the mode of delivery (cesarean or vaginal) has any association with increased risk of developing postpartum hemorrhage. STUDY DESIGN: A prospective cohort study was conducted on 788 pregnant women with singleton pregnancies diagnosed with early onset preeclampsia between March 2009 and June 2011. Maternal serum PlGF level estimation was done between 22 and 24weeks of gestation and a cut-off value of <122pg/ml was determined by receiver operating characteristic (ROC) curve analysis for identifying those at risk of developing postpartum hemorrhage. Association between serum PlGF level <122pg/ml and cesarean deliveries with the risk of developing postpartum hemorrhage was analyzed by logistic regression analysis and Odds ratio, which were computed. The results were considered statistically significant when P-value <0.05. MAIN OUTCOME MEASURES: Proportion of study population developing postpartum hemorrhage. RESULTS: Logistic regression analysis showed the association of serum PlGF <122pg/ml at 22-24weeks (Odds ratio 8.9516; 95% CI, 5.0728-15.7963) and that of cesarean delivery (Odds ratio 2.4252; 95% CI, 1.4573-4.0360) with the risk of developing postpartum hemorrhage. Both the associations were found to be statistically significant. CONCLUSION: Maternal serum PlGF level <122pg/ml at 22 24weeks of gestation and cesarean delivery are both strongly associated with the risk of developing postpartum hemorrhage in pregnant women with early onset preeclampsia. PMID- 26105097 TI - Folate transporter expression decreases in the human placenta throughout pregnancy and in pre-eclampsia. AB - The transport of folate across the placenta involves a number of different receptors including folate receptor-alpha (FR-alpha), reduced folate carrier (RFC) and proton coupled folate transporter (PCFT). In addition there are a number of ATP-dependent transporters which have also recently been shown to be involved in folate transport; these include ABCB1, ABCC2 and BCRP (ABCG2). The aim of the current study was to characterise the placental mRNA and protein expression of these folate transporters throughout gestation and also to see if expression is altered in pre-eclampsia. Placental tissue was collected from women undergoing termination of pregnancy (TOP) and from women undergoing elective Caesarean section. To investigate mRNA expression quantitative real time PCR was used with gene specific oligonucleotide primers to FR-alpha, RFC, PCFT, ABCB1, ABCC2, BCRP and the reference gene YWHAZ. Protein expression was also characterised using immunohistochemistry of paraffin embedded placental tissue. Both protein and mRNA expression of all transporters examined decreased as the gestation progressed. Expression of FR-alpha and PCFT mRNA and protein were decreased in pre-eclampsia compared with normal term pregnancy. The higher levels of expression of FR-alpha, RFC, PCFT, ABCB1, ABCC2 and BCRP in early pregnancy indicate that these transporters may have an important role in the establishment and development of the placenta, with expression reducing in preparation for parturition. Reductions in FR-alpha and PCFT in pre-eclampsia may be a mechanism involved in the pathogenesis of pre-eclampsia by limiting placental folate uptake resulting in reduced levels of angiogenesis, cell proliferation and antioxidant protection. PMID- 26105098 TI - Cardiac function at term in human pregnancy. AB - OBJECTIVES: We have previously demonstrated deterioration in cardiac function at term in human pregnancy. To explore further, we investigated central arterial hemodynamics and association with maternal weight during gestation. STUDY DESIGN: Primiparous women (n=32) were recruited in a tertiary referral obstetric hospital and a longitudinal cohort study with analyses at median 16 and 37weeks gestation undertaken. Subgroups of normal body mass index, <25kg/m(2), and overweight, ?25kg/m(2), at 16weeks were created. MAIN OUTCOME MEASURES: We performed 2D speckle tracking echocardiography strain analysis and tonometric measures of central arterial pressures, waveforms and pulse wave velocity. RESULTS: A reduction in cardiac strain (2P=0.002) from 16 to 37weeks gestation was associated with increased systemic vascular resistance (2P=0.008), reduced arterial compliance (2P=0.004) and increased central arterial pressures (2P<0.001) and augmentation index (2P=0.001). CONCLUSIONS: By 37weeks, compared with values in earlier pregnancy, overweight women had higher systemic vascular resistance (2P<0.05). Additionally, their central diastolic pressure was higher (2P<0.05) and their ventricular strain was lower (2P<0.05) than in normal weight pregnant women. An increase in systemic vascular resistance and central arterial pressures by term may contribute to the observed deterioration in cardiac function. This appears more prominent in overweight women. PMID- 26105099 TI - The maternal cardiovascular effect of carbetocin compared to oxytocin in women undergoing caesarean section. AB - OBJECTIVE: To compare haemodynamic changes, measured noninvasively using the USCOM monitor, after combined spino-epidural anaesthesia and after administration of two different uterotonic drugs, oxytocin and carbetocin, in a population of pregnant women during elective caesarean delivery. METHODS: Haemodynamic measurements were obtained with the USCOM system, by positioning a probe at maternal suprasternal notch (SSN) until the aortic valve flow's profile was optimally identified. Evaluations of the haemodynamic profile were obtained in seven different moments: before anaesthesia; during skin incision; 60, 180 and 300s after administration of uterotonic drug, at closure of the uterus, at closure of the skin. Doses of uterotonic drugs were: Oxytocin 5UI in 500cc NaCl eV, Carbetocin 100mcg in bolus eV. Main measured parameters were: heart rate, mean blood pressure, stroke volume, cardiac output and total vascular resistance. RESULTS: We enrolled 32 pregnant women. Patients were randomized in two groups: oxytocin and carbetocin. A reduction in mean blood pressure, a reduction of total vascular resistance and an increase of cardiac output and of stroke volume were seen, while heart rate values remained stable in both treatment groups. No statistically significant differences were found. DISCUSSION: Administration of carbetocin is associated with a substantial global haemodynamic stability in patients undergoing elective caesarean section without any difference with oxytocin. This observation allows us to consider carbetocin comparable to oxytocin, with minimum haemodynamic impact on the maternal circulation. This minimal effect on global haemodynamic stability might extend the use of this uterotonic drug in patients at high haemorrhagic risk with preeclampsia. PMID- 26105100 TI - Postpartum physical activity after preeclampsia. AB - OBJECTIVE: After mild and severe preeclampsia, to assess whether women meet the physical activity recommendation at 3 and 6months postpartum, and whether demographic, obstetric and anthropometric characteristics, mental health, and health-related quality of life are associated with less physical activity than recommended. STUDY DESIGN: Prospective cohort study. MAIN OUTCOME MEASURES: Self reported physical activity in MET-min/week, percentage of women who fail to meet the physical activity recommendation. METHODS: Of the 255 women diagnosed with preeclampsia invited to participate in this prospective cohort study, 174 (68%) provided informed consent. Analyses were restricted to 141 participants who completed the short form of the International Physical Activity Questionnaire at 3 and/or 6months postpartum. Logistic regression analysis was used to evaluate changes in physical activity level over time, and to establish which variables were associated with failure to meet the postpartum physical activity recommendation. RESULTS: At both 3 and 6months postpartum, 38% of women failed to meet the physical activity recommendation. Failure was associated with severe preeclampsia, cesarean section, admission to the neonatal intensive care unit, low gestational age at delivery, and low birth weight (all p<0.05). CONCLUSIONS: There seems to be a need to stimulate physical activity in about one third of women after a pregnancy complicated by preeclampsia, particularly in case of severe preeclampsia and other adverse pregnancy outcomes. Tailored lifestyle interventions are needed for women who fail to meet the recommendation. PMID- 26105101 TI - Lipid concentration in small for gestational age (SGA)pregnancies and hypertensive disorders. AB - OBJECTIVE: Low maternal serum lipid and high maternal serum lipid have both been associated with some complications in pregnancy. The lipid profiles in pregnancies complicated by small for gestational age (SGA) or hypertension disorders have been compared with those of normal pregnancies. METHOD: In a prospective study, 900 pregnant women between 13 and 23weeks of pregnancy were studied. Primarily, serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, were measured. Ultimately, the serum lipid levels at 13-23weeks of pregnancies were compared between the women who later suffered from hypertension disorders or SGA and the matched women with normal pregnancies. RESULTS: At 13-23weeks of pregnancy, the mean triglyceride levels were significantly higher in the women who later experienced preeclampsia when compared with normal, matched pregnancies with an appropriate weight for gestational age and women who had gestational hypertension (p=0.001 and p=0.014, respectively). Also, triglyceride levels were significantly higher in women with neonates with large for gestational age (LGA) in comparison with those who gave birth to neonates with SGA (p=0.012) and with uncomplicated matched pregnant women who gave birth to neonates with weight >10th and <90th percentile for their gestational age (p=0.007). CONCLUSION: Only the levels of TG and not any other lipids evaluated were found to be different in pregnancies complicated by preeclampsia when compared to pregnancies complicated by SGA. PMID- 26105102 TI - Maternal soluble human leukocyte antigen-G levels in pregnancies complicated by foetal intrauterine growth restriction with and without preeclampsia. AB - OBJECTIVE: The aim of this study was to investigate the maternal serum of soluble human leukocyte antigen-G (sHLA-G) levels in pregnant women with an isolated intrauterine growth restricted foetus (IUGR) and in preeclamptic pregnancies with and without IUGR. PATIENTS AND METHODS: The study was conducted on 31 normotensive patients with pregnancy complicated by IUGR, 17 preeclamptic patients with appropriate-for-gestational-age foetal intrauterine growth, 21 with preeclampsia complicated by IUGR, and 32 healthy pregnant controls. Maternal serum sHLA-G levels were calculated using the enzyme-linked immunosorbent assay. RESULTS: Maternal serum sHLA-G levels tended to be higher in both groups of preeclamptic patients, and were highest in patients with IUGR in the course of severe preeclampsia. Lower serum levels of sHLA-G were observed in the group of normotensive pregnant women with an intrauterine growth restricted foetus, but these differences were not statistically significant. The mean values were 22.759+/-14.151units/mL in the IUGR group, 25.948+/-18.888units/mL in preeclamptic patients with normal intrauterine foetal growth, 31.646+/ 27.576units/mL in preeclamptic pregnant women with IUGR, and 24.178+/ 24.828units/mL in the healthy controls. CONCLUSIONS: Our findings suggest that the increased levels of sHLA-G in the maternal serum may play a significant role in the pathogenesis of preeclampsia, especially in preeclampsia complicated by intrauterine foetal growth restriction. These associations may offer a better insight into the etiology and pathogenesis of preeclampsia with and without IUGR. It seems that sHLA-G does not play a clinically significant role in the pathogenesis of isolated intrauterine foetal growth restriction in normotensive pregnancies. PMID- 26105103 TI - Off-label and unlicenced medicine administration to paediatric emergency department patients. AB - OBJECTIVE: To determine the prevalence and nature of off-label and unlicenced (off-label/unlicenced) medicine administration to paediatric ED patients. METHODS: We undertook a retrospective, observational study in six EDs (July 2011 to June 2012, inclusive). Patients, aged 0-17 years, who were administered a medicine in the ED were included. At each site, 50 eligible patients were randomly selected each month of the study period. An explicit review of each patient's records was undertaken. Medicines were classified as on or off label/unlicenced according to categories of use approved by the Therapeutic Goods Administration. RESULTS: There were 3343 patients enrolled (56.5% men, mean +/- SD age 6.7 +/- 5.4 years). Of the 6786 medicine doses administered, 2072 (30.5%, 95% CI 29.4-31.7%) were off-label/unlicenced. The off-label/unlicenced doses were administered to 1213 (36.3%, 95% CI 34.7-37.9%) patients. Patients administered an off-label/unlicenced medicine were younger than those who were not (P < 0.01). Salbutamol, ondansetron, ipratropium, fentanyl and oxycodone were the medicines most commonly administered off-label. In 910 (44.0%) cases, the dose/frequency was not approved; in 592 (28.6%), there was an unapproved indication for treatment; in 158 (7.6%), the medicine was administered via an unapproved route; in 154 (7.4%) the medicine was not approved for the weight or age; and in 74 (3.5%) an unlicenced product was administered. The remaining cases had combinations of reasons. CONCLUSIONS: Off-label/unlicenced medicine administration is common. A registry of commonly used off-label medicines is recommended in which the safety and efficacy of their off-label use have been demonstrated by published evidence. PMID- 26105104 TI - Fluorination-dependent molecular orbital occupancy in ring-shaped perfluorocarbons. AB - Perfluorocarbons are a family of molecules consisting mainly of carbon and fluorine atoms. They have interesting chemical properties and have diverse applications in biomedicine, physical chemistry and polymer science. In this work, carbon K-edge absorption and emission spectra of liquid decalin are presented and compared to perfluorodecalin. A comprehensive picture of the electronic structure of decalin is provided based on soft X-ray absorption and emission spectroscopies. Experimental data are compared to theoretical time dependent density functional theory for the hydrocarbon, the perfluorocarbon and the stepwise fluorinated derivatives. We observed a molecular orbital change from unoccupied to occupied orbitals for perfluorodecalin, which was induced through the fluorination process. PMID- 26105105 TI - Anatomy of the bovine ascending aorta and brachiocephalic artery found unfavorable for total artificial heart implant. AB - The biocompatibility assessment of the Cleveland Clinic continuous-flow total artificial heart is an important part of the device developmental program. Surgical and postoperative management are key factors in achieving optimal outcomes. However, the presence of vascular anatomical abnormalities in experimental animal models is often unpredictable and may worsen the expected outcomes. We report a technical impediment encountered during total artificial heart implantation complicated by unfavorable bovine anatomy of the ascending aorta and brachiocephalic arterial trunk. PMID- 26105106 TI - A reoperation of thrombosed On-X valve detected by multidetector-row computed tomography. AB - A 62-year-old female patient underwent mitral valve replacement with a 31/33-mm On-X valve for ischemic mitral valve regurgitation. Three months later, transthoracic echocardiography incidentally showed a blocked leaflet with 6 mmHg of mean pressure gradient and 2.4 cm(2) of mitral valve orifice area. Transesophageal echocardiography could not detect thrombus. Electrocardiographically gated multidetector-row computed tomography (MDCT) clearly demonstrated a blocked leaflet in the close position and thrombus (2 cm in length, 0.4 cm(2) in area) attached onto the atrial aspect of the leaflet. These findings observed by MDCT were confirmed at reoperation. MDCT was useful diagnostic method for visualizing prosthetic valve thrombosis. PMID- 26105107 TI - Palliative parenteral nutrition use in patients with intestinal failure as a consequence of advanced pseudomyxoma peritonei: a case series. AB - Pseudomyxoma peritonei (PMP) is a rare condition complicated by intra-abdominal spread that can cause multilevel gastrointestinal (GI) obstruction. Parenteral nutrition (PN) use in the context of palliative care and malignancy remains controversial. We describe the use of palliative PN in three patients with progressive PMP causing multilevel GI obstruction and intestinal failure. All patients received > 90 days of PN. PN was safe in this cohort of patients. However, patient selection and the timing of intervention are important factors when considering the initiation of PN. PMID- 26105108 TI - Relatively high mortality risk in elderly Swedish subjects with low selenium status. AB - BACKGROUND/OBJECTIVES: The daily dietary intake of selenium (Se), an essential trace element, is still low in Sweden in spite of decades of nutritional information campaigns and the effect of this on the public health is presently not well known. The objective of this study was to determine the serum Se levels in an elderly Swedish population and to analyze whether a low Se status had any influence on mortality. SUBJECTS/METHODS: Six-hundred sixty-eight (n=668) elderly participants were invited from a municipality and evaluated in an observational study. Individuals were followed for 6.8 years and Se levels were re-evaluated in 98 individuals after 48 months. Clinical examination of all individuals included functional classification, echocardiography, electrocardiogram and serum Se measurement. All mortality was registered and endpoints of mortality were assessed by Kaplan-Meier plots, and Cox proportional hazard ratios adjusted for potential confounding factors were calculated. RESULTS: The mean serum Se level of the study population (n=668) was 67.1 MUg/l, corresponding to relatively low Se intake. After adjustment for male gender, smoking, ischemic heart disease, diabetes, chronic obstructive pulmonary disease and impaired heart function, persons with serum Se in the lowest quartile had 43% (95% confidence interval (CI): 1.02-2.00) and 56% (95% CI: 1.03-2.36) increased risk for all-cause and cardiovascular mortality, respectively. The result was not driven by inflammatory effects on Se concentration in serum. CONCLUSION: The mean serum Se concentration in an elderly Swedish population was 67.1 MUg/l, which is below the physiological saturation level for several selenoprotein enzymes. This result may suggest the value of modest Se supplementation in order to improve the health of the Swedish population. PMID- 26105110 TI - Surgical Anatomical Landmarks of the Thoracolumbar Vertebral Column on Magnetic Resonance Imaging in Dogs. AB - Magnetic resonance imaging (MRI) in veterinary medicine profoundly improved spinal cord disease investigation in canine patients. We aimed to further describe the anatomical landmarks of the thoracolumbar junction in sagittal MRI sequences. MRI studies from 90 dogs were reviewed retrospectively, representing a broad cross section of breeds and body weights. The ratio of the distance from the dorsal aspect of the vertebral canal to the dorsal aspect of the transverse process or rib articulation relative to the length of L2 vertebra was determined for T12, T13, L1 and L2 vertebrae. A statistically significant difference was noted with the transverse processes being more ventrally located than the cranial fovea costalis. The lumbar transverse processes and rib articulations dramatically varied in shape, being oval or round, respectively. The sagittal image at the level of the lateral margin of the articular facet joint proved to be the most consistent for review of these structures. PMID- 26105109 TI - DHEA metabolism to the neurosteroid androsterone: a possible mechanism of DHEA's antidepressant action. AB - BACKGROUND: Alterations in neurosteroid secretion have been implicated in the efficacy of antidepressants. In a previous study, the adrenal androgen DHEA, a precursor of the neurosteroid androsterone, produced antidepressant and libido enhancing effects in patients with midlife depression. To investigate the mechanisms underlying DHEA's behavioral effects in this same patient group, we examined plasma levels of four additional neurosteroids implicated in the regulation of affective behavior. METHODS: Blood samples were assayed for neurosteroids in men (n = 13) and women (n = 10) with midlife depression who previously participated in a crossover study in which DHEA and placebo were administered for 6 weeks each. Depression severity was measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma levels of androsterone (ADT), allopregnanolone, pregnanolone, and pregnenolone were measured by GC-MS at baseline and week 6 of each treatment phase. Data were analyzed with repeated measures analysis of variance (ANOVA-R) and Bonferroni t tests. RESULTS: ADT levels (but not allopregnanolone, pregnanolone, and pregnenolone) increased after DHEA but not after placebo (F 2,42 = 3.3, p < 0.05). Post-DHEA ADT levels were higher in women than men [t 63 = 2.9, p < 0.05]. However, in both men and women who met criteria for clinical response on the CES-D, baseline ADT levels significantly increased post-DHEA, and the magnitude of the ADT increase post DHEA treatment was similar in men and women. Consequently, it was the non responders who accounted for the sex difference in post-DHEA plasma ADT levels, a difference that was driven by values in two women (the only female non responders). CONCLUSIONS: The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA. PMID- 26105112 TI - Simultaneous and stereospecific analysis of warfarin oxidative metabolism using 2D LC/Q-TOF. AB - BACKGROUND: Warfarin is a widely used racemic anticoagulant with narrow therapeutic range and wide interindividual response to treatment. This is due to the extensive and differential clearance of R- and S-warfarin with the involvement of several polymorphic CYP450 enzymes resulting in the formation of several stereoisomeric oxidative metabolites. RESULTS: A stereospecific 2DLC/Q TOF method was developed for the simultaneous identification and quantitation of hydroxylated warfarin metabolites from a single sample analysis. Using this method metabolites from rat microsomal and plated hepatocyte incubations with R-, S- and (R/S)-warfarin were estimated. CONCLUSION: Multiheart cutting with high resolution MS and MS/MS analysis is suggested as a viable approach for achiral chiral separation of metabolites of warfarin and other chiral or prochiral drugs. PMID- 26105111 TI - Modulation of oxidative and inflammatory cardiac response by nonselective 1- and 2-cyclooxygenase inhibitor and benznidazole in mice. AB - OBJECTIVES: This study investigated the combined effects of benznidazole (BZ) and ibuprofen (IB) on the oxidative and inflammatory status of the cardiac tissue in vivo. METHODS: Swiss mice were randomized in groups receiving BZ (100 mg/kg) and IB (400 mg/kg) alone or combined (BZ + IB 200 or 400 mg/kg). Control animals were concurrently treated with 1% carboxymethyl cellulose. All treatments were administered orally for 7 days. KEY FINDINGS: BZ treatment increased cardiac production of nitrogen/oxygen-reactive species, malondialdeyde, carbonyl proteins, prostaglandins as well as the activities of catalase, superoxide dismutase and glutathione peroxidase. These parameters were attenuated by IB, with the best results at higher dose. Individually, BZ and IB significantly reduced the tissue levels of chemokine ligand 2, tumour necrosis factor-alpha and IL-10, but no reduction was observed when the treatments were combined. CONCLUSIONS: BZ triggers an oxidative and nitrosative route, which is associated with increased prostaglandin synthesis and marked damages to the lipids and proteins of the cardiac tissue. IB treatment attenuated reactive stresses triggered by BZ, which was an independent effects of this drug on the endogenous antioxidant enzymes. Individually, but not together, BZ and IB reduced the cardiac inflammatory status, indicating a beneficial and complex drug interaction. PMID- 26105113 TI - Research on drug-receptor interactions and prediction of drug activity via oriented immobilized receptor capillary electrophoresis. AB - Oriented covalent immobilized beta2 -adrenergic receptor (beta2 -AR) CE (OIRCE) was developed to determine the interactions between a set of natural extracts of Radix Paeoniae Rubra (NERPR) and beta2 -AR, and to predict the activity of NERPR. The inner capillary surface is chemically bonded with stable beta2 -AR coating via microwave-assisted technical synthesis. The modified capillaries were characterized via infrared spectroscopy and fluorescence microscopy. Furthermore, the bonding amounts of beta2 -AR were first obtained via fluorescence spectroscopy method. In determining the amount of bonded beta2 -AR, the regression equation A = 576 707C + 35.449 and the correlation coefficient 0.9995 were obtained. This result revealed an excellent linear relationship in the range of 2 * 10(-4) mg/mL to 1 * 10(-3) mg/mL. The normalized capacity factor (KRCE ) was obtained using OIRCE in evaluating drug-receptor interactions. Related theories and equations were used to calculate KRCE values from apparent migration times of a solute and EOF. The order of KRCE and the binding constant (Kb ) values between drugs and beta2 -AR was well consistent. The results confirmed that the OIRCE and KRCE values can be effectually used to investigate drug-receptor interactions, and OIRCE has the potential to predict drug activity and to select leading compounds from natural chemicals. PMID- 26105114 TI - Double [3 + 2]-dimerisation cascade synthesis of bis(triazolyl)bisphosphanes, a new scaffold for bidentate bisphosphanes. AB - A highly convergent synthesis of bis(triazolylphosphane oxides) was developed by a tandem copper-mediated Huisgen reaction-oxidative coupling. The phosphane oxides were reduced by trichlorosilane and the coordination of the resulting bisphosphanes was studied with various transition metals. PMID- 26105116 TI - Naltrexone ER/Bupropion ER: A Review in Obesity Management. AB - Oral naltrexone extended-release/bupropion extended-release (naltrexone ER/bupropion ER; Contrave((r)), Mysimba(TM)) is available as an adjunct to a reduced-calorie diet and increased physical activity in adults with an initial body mass index (BMI) of >= 30 kg/m(2) (i.e. obese) or a BMI of >= 27 kg/m(2) (i.e. overweight) in the presence of at least one bodyweight-related comorbidity, such as type 2 diabetes mellitus, hypertension or dyslipidaemia. In 56-week phase III trials in these patient populations, oral naltrexone ER/bupropion ER 32/360 mg/day was significantly more effective than placebo with regard to percentage bodyweight reductions from baseline and the proportion of patients who achieved bodyweight reductions of >= 5 and >= 10%. Significantly greater improvements in several cardiometabolic risk factors were also observed with naltrexone ER/bupropion ER versus placebo, as well as greater improvements in glycated haemoglobin levels in obese or overweight adults with type 2 diabetes. Naltrexone ER/bupropion ER was generally well tolerated in phase III trials, with nausea being the most common adverse event. Thus, naltrexone ER/bupropion ER 32/360 mg/day as an adjunct to a reduced-calorie diet and increased physical activity, is an effective and well tolerated option for chronic bodyweight management in obese adults or overweight adults with at least one bodyweight-related comorbidity. PMID- 26105115 TI - Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies. AB - The envelope spike of HIV-1 employs a 'glycan shield' to protect itself from antibody-mediated neutralization. Paradoxically, however, potent broadly neutralizing antibodies (bnAbs) that target this shield have been isolated. The unusually high glycan density on the gp120 subunit limits processing during biosynthesis, leaving a region of under-processed oligomannose-type structures, which is a primary target of these bnAbs. Here we investigate the contribution of individual glycosylation sites in the formation of this so-called intrinsic mannose patch. Deletion of individual sites has a limited effect on the overall size of the intrinsic mannose patch but leads to changes in the processing of neighbouring glycans. These structural changes are largely tolerated by a panel of glycan-dependent bnAbs targeting these regions, indicating a degree of plasticity in their recognition. These results support the intrinsic mannose patch as a stable target for vaccine design. PMID- 26105117 TI - Dalbavancin: A Review in Acute Bacterial Skin and Skin Structure Infections. AB - Intravenous dalbavancin (DalvanceTM; XydalbaTM) is approved for use in adult patients with acute bacterial skin and skin structure infections (ABSSSI), with the recommended regimen being a 1000 mg dose followed 1 week later by a 500 mg dose. In the multinational DISCOVER 1 and 2 trials in adult patients with ABSSSI, dalbavancin treatment was noninferior to vancomycin (for >= 3 days with an option to switch to oral linezolid to complete a 10- to 14-day course) in terms of early clinical success rates (assessed 48-72 h after initiation of treatment; primary endpoint required by the FDA to assess noninferiority in registration trials of ABSSSI). Clinical response rates were also similar in both treatment groups at the end of treatment (day 14-15), irrespective of geographic region or baseline characteristics, including by infection type, diabetes mellitus status, systemic inflammatory response syndrome status, causative pathogen and renal function. Dalbavancin was generally well tolerated, with adverse events generally being of mild to moderate intensity and transient. With its broad spectrum of activity against clinically relevant Gram-positive pathogens and its favourable pharmacokinetic profile that permits a convenient two-dose, once-weekly regimen with no requirement for therapeutic drug monitoring, dalbavancin is a promising emerging option for the treatment of ABSSSI in adult patients. PMID- 26105118 TI - Erratum. PMID- 26105120 TI - Pillion riders' cloth related injuries and helmet wearing patterns: a study of Lahore, Pakistan. AB - This study aims at investigating the burden and pattern of clothing related pillion riders' injuries and their helmet wearing pattern in Lahore, Pakistan. Data were collected for nine months (July 2013 to March 2014), reporting 13,248 motorcycle related injuries, out of which 8751 (66%) cases were related to the clothing related pillion riders' injuries. Out of these injuries 10.30% were severe injuries which can be prevented or reduced by proper safety measure, e.g. wearing helmet. It was also found that most of the fatalities were not wearing helmet. Injuries due to wearing of loose fitting clothes and absence of helmet are not uncommon in Pakistan and other underdeveloped parts of the world. Such accidents may be reduced by creating awareness and safety sense in the riders, where use of safe dress and helmet should be encouraged in order to avoid such fatal damages. PMID- 26105119 TI - Multi-contrast attenuation map synthesis for PET/MR scanners: assessment on FDG and Florbetapir PET tracers. AB - Positron Emission Tomography/Magnetic Resonance Imaging (PET/MR) scanners are expected to offer a new range of clinical applications. Attenuation correction is an essential requirement for quantification of PET data but MRI images do not directly provide a patient-specific attenuation map. Methods We further validate and extend a Computed Tomography (CT) and attenuation map (MU-map) synthesis method based on pre-acquired MRI-CT image pairs. The validation consists of comparing the CT images synthesised with the proposed method to the original CT images. PET images were acquired using two different tracers ((18)F-FDG and (18)F florbetapir). They were then reconstructed and corrected for attenuation using the synthetic MU-maps and compared to the reference PET images corrected with the CT-based MU-maps. During the validation, we observed that the CT synthesis was inaccurate in areas such as the neck and the cerebellum, and propose a refinement to mitigate these problems, as well as an extension of the method to multi contrast MRI data. Results With the improvements proposed, a significant enhancement in CT synthesis, which results in a reduced absolute error and a decrease in the bias when reconstructing PET images, was observed. For both tracers, on average, the absolute difference between the reference PET images and the PET images corrected with the proposed method was less than 2%, with a bias inferior to 1%. Conclusion With the proposed method, attenuation information can be accurately derived from MRI images by synthesising CT using routine anatomical sequences. MRI sequences, or combination of sequences, can be used to synthesise CT images, as long as they provide sufficient anatomical information. PMID- 26105121 TI - Direct High-Precision Measurements of the (87)Sr/(86)Sr Isotope Ratio in Natural Water without Chemical Separation Using Thermal Ionization Mass Spectrometry Equipped with 10(12) Omega Resistors. AB - Thermal ionization mass spectrometry (TIMS) allows excellent precision for determining Sr isotope ratios in natural water samples. Traditionally, a chemical separation procedure using cation exchange resin has been employed to obtain a high purity Sr fraction from natural water, which makes sample preparation time consuming. In this study, we present a rapid and precise method for the direct determination of the Sr isotope ratio of natural water using TIMS equipped with amplifiers with two 10(12) Omega resistors. To eliminate the (87)Rb isobaric interference, Re ribbons are used as filaments, providing a significant advantage over W ribbons in the inhibition of Rb(+) emission, based on systematically examining a series of NIST SRM987 standard doping with various amounts of Rb using Re and W ribbons. To validate the applicability of our method, twenty-two natural water samples, including different water types (rain, snow, river, lake and drinking water), that show a large range in Sr content variations (2.54-922.8 ppb), were collected and analyzed from North and South China. Analytical results show good precision (0.003-0.005%, 2 RSE) and the method was further validated by comparative analysis of the same water with and without chemical separation. The method is simple and rapid, eliminates sample preparation time, and prevents potential contamination during complicated sample-preparation procedures. Therefore, a high sample throughput inherent to the TIMS can be fully utilized. PMID- 26105122 TI - A novel HLA-B*27 allele, B*27:138, identified by sequence-based typing. AB - HLA-B*27:138 differs from B*27:06 by two nucleotide changes in exon 3. PMID- 26105123 TI - [Persisting lesion of the conjunctiva. A masquerade syndrome?]. AB - A 26-year-old female patient was referred because of a persisting swelling and redness of the conjunctiva for 4 months accompanied by pruritus. An ultrasound biomicroscopy showed hypoechogenic structures separated by multiple hyperechogenic septa. A biopsy was performed which revealed a marginal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type. A generalized lymphatic disease could be excluded by positron emission tomography-computed tomography (PET-CT). In agreement with the patient an extensive excision was performed followed by a wait and see strategy including close monitoring by ophthalmological and general internist control examinations. PMID- 26105124 TI - [Artificial iris after severe trauma of the orbit]. AB - INDICATIONS: Surgical revision of the eye of a 52-year-old female patient with iris replacement was carried out 1 year after severe injury of the globe. OBJECTIVE: The further surgical measures were necessary to improve not only the functional but also the cosmetic results. OPERATION TECHNIQUE: Due to the complex initial situation a combination of vitrectomy and peeling of the epiretinal membrane, perforating keratoplasty and finally iris and lens replacement was carried out. The complete surgical procedure is presented in a video accompanying this article. RESULTS: The best corrected vision increased to 0.25, 6 months after the intervention and the patient was satisfied with the functional and cosmetic results. The intraocular pressure remained in the normal range after 1 year of follow-up with no further therapy. PMID- 26105125 TI - The healthy worker effect: Do health problems predict participation rates in, and the results of, a follow-up survey? AB - PURPOSE: To determine the impact of the healthy worker effect (HWE) as a bias for the external and internal validity of the follow-up assessment in prospective survey research. Specifically, the study examined (1) whether the health status of respondents at the baseline measurement influenced response at the follow-up survey (external validity) and (2) whether HWE is a threat to internal validity by differential attrition, i.e., whether associations between work and health at baseline differ between stayers and dropouts. METHODS: In a two-wave questionnaire survey with a 2-year time lag comprising 6283 persons, 4392 responded at both time points (response rate 70%). Mental distress and somatic symptoms served as indicators of health. Role conflict and role clarity were indicators of work factors. RESULTS: There were few differences in response rate at follow-up between persons with and without health complaints at the baseline measurement. As response rate increased incrementally with educational level, there seems to be a socio-educational bias, rather than a HWE bias on survey participation. Baseline relationships between work factors and health indicators were equal in magnitude among stayers and dropouts. CONCLUSION: The health status of participants at baseline seems to have little impact on the external and internal validity of the follow-up assessment in prospective survey research. Hence, the findings provide little support to the HWE as a potential bias in prospective studies within occupational health research. A limitation of the study is that the findings do not inform about the impact of the HWE on participation in the baseline assessment. PMID- 26105126 TI - Virus ecology of fluvial systems: a blank spot on the map? AB - The ecology of viruses has been studied only in a limited number of rivers and streams. In light of a recent re-appraisal of the global fluvial surface area, issues such as abundance and production, host mortality and the influence of suspended particles and biofilms are addressed. Viral life cycles, potential impacts of viruses on water biochemistry and carbon flow, and viral diversity are considered. Variability in trophic levels along with the heterogeneous nature and hydrological dynamics of fluvial environments suggest a prevailingly physical control of virus-related processes under lotic conditions and more biological control under lentic conditions. Viral lysis likely contributes to a pool of rapidly cycling carbon in environments typically characterized by high proportions of recalcitrant terrestrial carbon. On average, 33.6% (equalling 0.605 Pg C year-1 ) of the globally respired carbon from fluvial systems may pass through a viral loop. Virus distribution and the proportion of organic material in horizontal transport versus processes in retention zones remain to be determined in detail. The need for up-scaling the contribution of virus-related processes in fluvial systems is of global relevance. Further, the role of climate change and the effect of anthropogenic alterations of fluvial systems on viruses require attention. The identification of these considerable knowledge gaps should foster future research efforts. PMID- 26105127 TI - Diagnostic test allergens used for in vivo diagnosis of allergic diseases are at risk: a European Perspective. AB - In the European Union (EU), allergens used for diagnostic tests (TAs) are defined as medicinal products and have to be registered by national authorities. The current situation is not homogeneous. Existing authorizations need to be kept in the market in some EU states, while others need complete new authorizations requiring clinical trials, quality assurance methods, stability studies, and periodic safety update reports. Allergen manufacturers argue that offering a comprehensive panel of TAs may be economically disastrous. Expenses for initiation and maintenance of TA authorizations far exceed their related revenues and manufacturers may be forced to significantly limit their allergen portfolios. The availability of a wide range of high-quality TAs is very important for in vivo diagnoses of IgE-mediated allergies. Increased regulatory demands induce costs that need to be covered by public health organizations or reimbursed by health insurance companies. PMID- 26105129 TI - The incidence of metastatic basal cell carcinoma (mBCC) in Denmark, 1997-2010. AB - BACKGROUND: Few data exist on the occurrence of metastatic basal cell carcinoma (mBCC). OBJECTIVE: To identify all cases of mBCC in Denmark over a 14-year period. METHODS: We searched the Danish National Patient Registry covering all Danish hospitals, the Danish Cancer Registry, the National Pathology Registry and the Causes of Death Registry during the period 1997 to 2010 for potential cases of mBCC registered according to the International classification of diseases ICD 10 and the International Systemized Nomenclature of Medicine (SNOMED). RESULTS: We identified 126,627 patients with a history of primary basal cell carcinoma (BCC) in the registries during the 14-year study period. Using case identifications from the four registries, a total of 170 potential mBCC cases were identified. However, after a pathology review, only five cases could be confirmed, of which three were basosquamous carcinomas. The 14-year cumulative incidence proportion of mBCC was 0.0039% (95% CI 0.0016-0.0083) among individuals with a history of previous BCC (n = 126,627) and 0.0001% (95% CI 0.0000-0.0002) in the general population. CONCLUSION: MBCC is a rare disease and only a small proportion of potential cases identified in automated clinical databases or registries can be confirmed by pathology and medical record review. PMID- 26105130 TI - The predictive value of multidetector CTA on outcomes in patients with below-the knee vascular injury. AB - BACKGROUND: Multidetector computed tomographic angiography (MDCTA) has become the gold standard for the early assessment of lower extremity vascular injury. The objective of this study was to evaluate the predictive value of MDCTA documented vessel run-off to the foot on limb salvage rates after lower extremity vascular injury. METHODS: All trauma patients undergoing lower extremity MDCTA for suspected vascular injury assessed at 2 high-volume Level I trauma centers between January 2009 and December 2012. Demographics, clinical data and outcomes (compartment syndrome requiring fasciotomy and limb salvage) were extracted. The predictive value of MDCTA vessel run-off was tested against an aggregate gold standard of operative intervention, clinical follow-up and all imaging obtained. RESULTS: During the 4-year study period, 398 patients sustained lower extremity trauma and were screened for inclusion into this study. Of those, 166 (41.7%) patients (72.9% at MHH and 27.1% at LAC+USC Medical Center) underwent initial evaluation with MDCTA, 86 (51.8%) had vascular injury below the knee identified by MDCTA. Among these, the average age was 38.0+/-15.8 years, 80.2% were men and 83.7% sustained a blunt injury mechanism. On admission, 8.1% were hypotensive and the median ISS was 10 (range 1-57). There was a direct correlation between the number of patent vessels to the foot and the need for operative intervention (86.4% with no patent vessels, 56.0% with 1 patent vessel, 33.3% with 2 and 0.0% with 3, p<0.001). When outcomes were analysed, the rates of fasciotomy for compartment syndrome decreased in a stepwise fashion as the number of patent vessels to the foot increased (63.6% with no patent vessels; 44.0% with 1; 21.2% with 2; and 0.0% with 3; p=0.003). No amputations occurred in patients with 2 or more patent vessels to the foot (68.2% for no patent vessel; 16.0% for 1; 0.0% for 2; and 0.0% for 3; p<0.001). CONCLUSIONS: In this multicenter evaluation of patients undergoing MDCTA for suspected below-the-knee vascular injury, there was a stepwise increase in the need for operative intervention, fasciotomy and amputation as the number of patent vessels to the foot decreased. PMID- 26105131 TI - Evaluation of diaphragm in penetrating left thoracoabdominal stab injuries: The role of multislice computed tomography. AB - INTRODUCTION: Penetrating left thoracoabdominal stab injuries are accompanied by diaphragmatic injury in 25-30% of cases, about 30% of which later develop into diaphragmatic hernia. This study aimed to determine the role of multislice computed tomography in the evaluation of left diaphragm in patients with penetrating left thoracoabdominal stab wounds. MATERIALS AND METHODS: This study reviewed penetrating left thoracoabdominal stab injuries managed in our clinic between April 2009 and September 2014. The thoracoabdominal region was defined as the region between the sternum, fourth intercostal space, and arcus costa anteriorly and the vertebra, lower tip of scapula, and the curve of the last rib posteriorly. Unstable cases and cases with signs of peritonitis were operated with laparotomy; the remaining patients were closely monitored. Forty-eight hours later, a diagnostic laparoscopy was applied to evaluate the left hemidiaphragma in asymptomatic patients who did not need laparotomy. The preoperatively obtained multislice thoracoabdominal computed tomography images were retrospectively examined for the presence of left diaphragm injury. Then, operative and tomographic findings were compared. RESULTS: This study included a total of 43 patients, 39 (91%) males and 4 (9%) females of mean age 30 years (range 15-61 years). Thirty patients had normal tomography results, whereas 13 had left diaphragmatic injuries. An injury to the left diaphragm was detected during the operation in 9 (1 in laparotomy and 8 in diagnostic laparoscopy) of 13 patients with positive tomography for left diaphragmatic injury and 2 (in diagnostic laparoscopy) of 30 patients with negative tomography. Multislice tomography had a sensitivity of 82% (95% CI: 48-98%), a specificity of 88% (71-96%), a positive predictive value of 69% (39-91%), and a negative predictive value of 93% (78-99%) for detection of diaphragmatic injury in penetrating left thoracoabdominal stab injury. CONCLUSIONS: Although diagnostic laparoscopy is the gold standard for diaphragmatic examination in patients with penetrating left thoracoabdominal stab wounds, multislice computed tomography is also valuable for detecting diaphragmatic injury. PMID- 26105128 TI - Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms. AB - Autism spectrum disorder (ASD) is a group of highly genetic neurodevelopmental disorders characterized by language, social, cognitive, and behavioral abnormalities. ASD is a complex disorder with a heterogeneous etiology. The genetic architecture of autism is such that a variety of different rare mutations have been discovered, including rare monogenic conditions that involve autistic symptoms. Also, de novo copy number variants and single nucleotide variants contribute to disease susceptibility. Finally, autosomal recessive loci are contributing to our understanding of inherited factors. We will review the progress that the field has made in the discovery of these rare genetic variants in autism. We argue that mutation discovery of this sort offers an important opportunity to identify neurodevelopmental mechanisms in disease. The hope is that these mechanisms will show some degree of convergence that may be amenable to treatment intervention. PMID- 26105132 TI - Mortuary based injury surveillance for low-mid income countries: process evaluation of pilot studies. AB - OBJECTIVE: Globally, injury is the fourth major cause of death and the third leading contributor to Disability Adjusted Life Years lost due to health conditions, with the greatest burden borne by low-middle income countries (LMICs) where injury data is scarce. In the absence of effective vital registration systems, mortuaries have been shown to provide an alternative source of cause of death information for practitioners and policy makers to establish strategic injury prevention policies and programs. This evaluation sought to assess the feasibility of implementing a standardised fatal injury data collection process to systematically collect relevant fatal injury data from mortuaries. The process evaluation is described. METHODS: A manual including a one page data collection form, coding guide, data dictionary, data entry and analysis program was developed through World Health Organization and Monash University Australia collaboration, with technical advice from an International Advisory Group. The data collection component was piloted in multiple mortuaries, in five LMICs (Egypt, India, Sri-Lanka, Tanzania and Zambia). Process evaluation was based on a questionnaire completed by each country's Principal Investigator. RESULTS: Questionnaires were completed for data collections in urban and rural mortuaries between September 2010 and February 2011. Of the 1795 reported fatal injury cases registered in the participating mortuaries, road traffic injury accounted for the highest proportion of cases, ranging from 22% to 87%. Other causes included burns, poisoning, drowning and falls. Positive system attributes were feasibility, acceptability, usefulness, timeliness, and simplicity and data field completeness. Some limitations included short duration of the pilot studies, limited injury data collector training and apparent underreporting of cases to the medico-legal system or mortuaries. CONCLUSION: The mortuary has been shown to be a potential data source for identifying injury deaths and their circumstances and monitoring injury trends and risk factors in LMICs. However, further piloting is needed, including in rural areas and training of forensic pathologists and data-recorders to overcome some of the difficulties experienced in the pilot countries. The key to attracting ongoing funding and support from governments and donors in LMICs for fatal injury surveillance lies in further demonstrating the usefulness of collected data. PMID- 26105133 TI - Comments to the paper "do we really need new medical information about the Turin Shroud?". AB - Following the interesting arguments raised in a recent letter to the editor, about a paper recently published in this journal, the authors are happy to take a cue from them to clarify some facts that have not been sufficiently treated for space. After a description of the methods used, arguments regarding a blunt trauma on the right shoulder with consequent dislocation, the position of the hands on the pubis with brachial plexus injury, and the wrist nailing that caused retracted thumbs are discussed in detail. PMID- 26105134 TI - Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption. AB - Local translation of mRNAs in the synapse has a major role in synaptic structure and function. Chronic alcohol use causes persistent changes in synaptic mRNA expression, possibly mediated by microRNAs localized in the synapse. We profiled the transcriptome of synaptoneurosomes (SN) obtained from the amygdala of mice that consumed 20% ethanol (alcohol) in a 30-day continuous two-bottle choice test to identify the microRNAs that target alcohol-induced mRNAs. SN are membrane vesicles containing pre- and post-synaptic compartments of neurons and astroglia and are a unique model for studying the synaptic transcriptome. We previously showed that chronic alcohol regulates mRNA expression in a coordinated manner. Here, we examine microRNAs and mRNAs from the same samples to define alcohol responsive synaptic microRNAs and their predicted interactions with targeted mRNAs. The aim of the study was to identify the microRNA-mRNA synaptic interactions that are altered by alcohol. This was accomplished by comparing the effect of alcohol in SN and total homogenate preparations from the same samples. We used a combination of unbiased bioinformatic methods (differential expression, correlation, co-expression, microRNA-mRNA target prediction, co-targeting, and cell type-specific analyses) to identify key alcohol-sensitive microRNAs. Prediction analysis showed that a subset of alcohol-responsive microRNAs was predicted to target many alcohol-responsive mRNAs, providing a bidirectional analysis for identifying microRNA-mRNA interactions. We found microRNAs and mRNAs with overlapping patterns of expression that correlated with alcohol consumption. Cell type-specific analysis revealed that a significant number of alcohol responsive mRNAs and microRNAs were unique to glutamate neurons and were predicted to target each other. Chronic alcohol consumption appears to perturb the coordinated microRNA regulation of mRNAs in SN, a mechanism that may explain the aberrations in synaptic plasticity affecting the alcoholic brain. PMID- 26105135 TI - Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex. AB - Cigarette smoking during pregnancy is associated with various disabilities in the offspring such as attention deficit/hyperactivity disorder, learning disabilities, and persistent anxiety. We have reported that nicotine exposure in female mice during pregnancy, in particular from embryonic day 14 (E14) to postnatal day 0 (P0), induces long-lasting behavioral deficits in offspring. However, the mechanism by which prenatal nicotine exposure (PNE) affects neurodevelopment, resulting in behavioral deficits, has remained unclear. Here, we report that PNE disrupted the proliferation of neuronal progenitors, leading to a decrease in the progenitor pool in the ventricular and subventricular zones. In addition, using a cumulative 5-bromo-2'-deoxyuridine labeling assay, we evaluated the rate of cell cycle progression causing the impairment of neuronal progenitor proliferation, and uncovered anomalous cell cycle kinetics in mice with PNE. Accordingly, the density of glutamatergic neurons in the medial prefrontal cortex (medial PFC) was reduced, implying glutamatergic dysregulation. Mice with PNE exhibited behavioral impairments in attentional function and behavioral flexibility in adulthood, and the deficits were ameliorated by microinjection of D-cycloserine into the PFC. Collectively, our findings suggest that PNE affects the proliferation and maturation of progenitor cells to glutamatergic neuron during neurodevelopment in the medial PFC, which may be associated with cognitive deficits in the offspring. PMID- 26105136 TI - Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala kappa-Opioid Receptors. AB - Chronic intermittent alcohol vapor exposure leads to increased dynorphin (DYN) A like peptide expression and heightened kappa-opioid receptor (KOR) signaling in the central nucleus of the amygdala (CeA) and these neuroadaptive responses differentiate alcohol-dependent from non-dependent phenotypes. Important for therapeutic development efforts is understanding the nature of the stimulus that drives dependence-like phenotypes such as escalated alcohol self-administration. Accordingly, the present study examined the impact of intra-CeA KOR antagonism on escalated operant alcohol self-administration and physiological withdrawal symptoms during acute withdrawal and protracted abstinence in rats previously exposed to chronic intermittent alcohol vapor. Following operant training, rats were implanted with intra-CeA guide cannula and exposed to long-term intermittent alcohol vapor exposure that resulted in escalated alcohol self-administration and elevated physiological withdrawal signs during acute withdrawal. Animals received intra-CeA infusions of the KOR antagonist nor-binaltorphimine (nor-BNI; 0, 2, 4, or 6 MUg) prior to operant alcohol self-administration sessions and physiological withdrawal assessment during acute withdrawal and protracted abstinence. The results indicated that site-specific KOR antagonism in the CeA ameliorated escalated alcohol self-administration during both acute withdrawal and protracted abstinence test sessions, whereas KOR antagonism had no effect on physiological withdrawal scores at either time point. These results dissociate escalated alcohol self-administration from physiological withdrawal symptoms in relation to KOR signaling in the CeA and help clarify the nature of the stimulus that drives escalated alcohol self-administration during acute withdrawal and protracted abstinence. PMID- 26105137 TI - Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains. AB - Antidepressant activity of N-methyl-D-aspartate (NMDA) receptor antagonists and negative allosteric modulators (NAMs) has led to increased investigation of their behavioral pharmacology. NMDA antagonists, such as ketamine, impair cognition in multiple species and in multiple cognitive domains. However, studies with NR2B subtype-selective NAMs have reported mixed results in rodents including increased impulsivity, no effect on cognition, impairment or even improvement of some cognitive tasks. To date, the effects of NR2B-selective NAMs on cognitive tests have not been reported in nonhuman primates. The current study evaluated two selective NR2B NAMs, CP101,606 and BMT-108908, along with the nonselective NMDA antagonists, ketamine and AZD6765, in the nonhuman primate Cambridge Neuropsychological Test Automated Battery (CANTAB) list-based delayed match to sample (list-DMS) task. Ketamine and the two NMDA NR2B NAMs produced selective impairments in memory in the list-DMS task. AZD6765 impaired performance in a non specific manner. In a separate cohort, CP101,606 impaired performance of the nonhuman primate CANTAB visuo-spatial Paired Associates Learning (vsPAL) task with a selective impairment at more difficult conditions. The results of these studies clearly show that systemic administration of a selective NR2B NAM can cause transient cognitive impairment in multiple cognitive domains. PMID- 26105138 TI - The Human BNST: Functional Role in Anxiety and Addiction. AB - The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region-the bed nucleus of the stria terminalis (BNST)-in the body's stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stress-related disorders and identify novel neural targets for treatment. PMID- 26105139 TI - Not All Antidepressants Are Created Equal: Differential Effects of Monoamine Uptake Inhibitors on Effort-Related Choice Behavior. AB - Motivated behavior can be characterized by behavioral activation and high work output. Moreover, people with depression and other disorders show effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue. Effort-based decision making is studied using tasks offering choices between high effort options leading to highly valued reinforcers vs low effort/low reward options, and such tasks could be useful as animal models of motivational symptoms. In the present studies the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine (TBZ) were investigated. TBZ blocks vesicular storage and also produces depressive symptoms in humans. Moreover, TBZ alters effort-based choice in rats, biasing animals toward low effort alternatives. The present studies investigated the ability of acute administration of various monoamine uptake inhibitors to reverse the effects of TBZ. Effort-related effects of TBZ were attenuated by the catecholamine uptake inhibitor and antidepressant bupropion, and this effect of bupropion was reversed by either D1 or D2 family antagonism. The effort-related effects of TBZ were also attenuated by the selective dopamine uptake blocker GBR12909. The 5-HT uptake inhibitor fluoxetine and the norepinephrine uptake inhibitor desipramine failed to reverse the effects of TBZ, and higher doses of these drugs, given alone or in combination with TBZ, led to further behavioral impairments. These results indicate that drugs acting on dopamine transmission are relatively effective at reversing the effort-related effects of TBZ, and are consistent with the hypothesis that drugs that enhance dopamine transmission may be effective at treating effort-related psychiatric symptoms in humans. PMID- 26105140 TI - Effects of Escitalopram Administration on Face Processing in Intermittent Explosive Disorder: An fMRI Study. AB - The neurobiological underpinnings of intermittent explosive disorder (IED) are traditionally linked to deficiencies in the serotonergic system. In this study, we investigated the effects of escitalopram, a selective serotonin reuptake inhibitor (SSRI), on brain activation during face processing. We expected that escitalopram would reduce amygdala activity in IED and in addition, we explored the effect in other social-emotional-related brain regions. A total of 17 subjects with current IED and 14 healthy controls participated in a randomized, double-blind, placebo-controlled, counterbalanced fMRI face processing study. The analysis focused on the faces compared to a fixation baseline contrast, and a factorial model with Group as between-subject and Drug as within-subject factor was tested. Group * Drug interaction effects were found in the amygdala (small volume corrected) and the left temporal parietal junction (TPJ; whole-brain corrected). Escitalopram increased amygdala activation in controls, but surprisingly not in IED. However, the TPJ showed increased activity in IED on escitalopram compared with placebo. The TPJ is associated with social-cognitive processes, such as perspective taking and empathy. The TPJ findings suggest that SSRI administration may reduce aggressive tendencies towards other people by enhancing these social-cognitive processes. Future research should further elucidate the long-term effects of SSRIs on various social-emotional tasks in IED. PMID- 26105141 TI - Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction. AB - MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 degrees C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID- 26105144 TI - Ureteral relaxation through calcitonin gene-related peptide release from sensory nerve terminals by hypotonic solution. AB - OBJECTIVES: To evaluate the influence of hypotonic solutions on ureteral relaxation mediated by the release of calcitonin gene-related peptide from intramural sensory nerve endings. METHODS: Urine osmolarity of Sprague-Dawley rats drinking water low in salt content (Fiuggi water) or a reference water for 7 days was measured. Release of calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter and urinary bladder by hypotonic solutions was assessed by an immunometric assay. The mechanism through which hypotonic solutions inhibit neurokinin A-induced phasic contractions of isolated rat ureters was evaluated by organ bath studies. RESULTS: A 7-day consumption of Fiuggi water in rats reduced urine osmolarity by ~40%. Exposure to hypotonic solutions released calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter. This response was abated in a calcium-free medium, after capsaicin desensitization, and in the presence of the unselective transient receptor potential channel antagonist, ruthenium red. Exposure of isolated rat ureteral preparations to a hypotonic solution inhibited neurokinin A-evoked phasic contraction. This response was attenuated by capsaicin desensitization and in the presence of the calcitonin gene-related peptide receptor antagonist, calcitonin gene-related peptide8-37 . Transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4 antagonists did not affect the neurogenic and calcitonin gene-related peptide-dependent relaxation. CONCLUSION: Present data show that hypotonic solution evokes calcitonin gene-related peptide release from capsaicin-sensitive intramural sensory nerves, thus inhibiting ureteral contractility, through a transient receptor potential-dependent mechanism. However, this mechanism does not involve transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4. Future studies with appropriate in vivo models should investigate the hypothesis that hypostenuric urine diffusing into the ureteral tissue might favor ureteral relaxation through this novel mechanism. PMID- 26105145 TI - Pharmacokinetics of sufentanil during long-term infusion in critically ill pediatric patients. AB - The aim of this study was to develop a population pharmacokinetic model of sufentanil and to assess the influence of covariates in critically ill children admitted to a pediatric intensive care unit. After institutional approval, 41 children were enrolled in the study. Blood samples for pharmacokinetic (PK) assessment were collected from routinely placed arterial catheters during and after discontinuation of infusion. Population nonlinear mixed-effects modeling was performed using NONMEM. A 2-compartment model described sufentanil PK sufficiently. Typical values of the central and peripheral volume of distribution and the metabolic and intercompartmental clearance for a theoretical patient weighing 70 kg were VC = 7.90 l, VT = 481 L, Cl = 5.3 L/h, and Q = 38.3 L/h, respectively. High interindividual variability of all PK parameters was noted. Allometric/isometric principles to scale sufentanil PK revealed that to achieve the same steady-state sufentanil concentrations in plasma for pediatric patients of different body weights, the infusion rate should follow the formula (infusion rate for a 70-kg adult patient, MUg/h) * (body weight/70 kg)(0.75). Severity of illness described by PRISM score, the monitored physiological and laboratory parameters, and coadministered drugs such as vasopressors were not found to be significant covariates. PMID- 26105143 TI - Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks. AB - Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Adverse early-life experiences provoke the release and modify the expression of several stress mediators and neurotransmitters within specific brain regions. The interaction of these mediators with developing neurons and neuronal networks may lead to long-lasting structural and functional alterations associated with cognitive and emotional consequences. Although a vast body of work has linked quantitative and qualitative aspects of stress to adolescent and adult outcomes, a number of questions are unclear. What distinguishes 'normal' from pathologic or toxic stress? How are the effects of stress transformed into structural and functional changes in individual neurons and neuronal networks? Which ones are affected? We review these questions in the context of established and emerging studies. We introduce a novel concept regarding the origin of toxic early-life stress, stating that it may derive from specific patterns of environmental signals, especially those derived from the mother or caretaker. Fragmented and unpredictable patterns of maternal care behaviors induce a profound chronic stress. The aberrant patterns and rhythms of early-life sensory input might also directly and adversely influence the maturation of cognitive and emotional brain circuits, in analogy to visual and auditory brain systems. Thus, unpredictable, stress-provoking early-life experiences may influence adolescent cognitive and emotional outcomes by disrupting the maturation of the underlying brain networks. Comprehensive approaches and multiple levels of analysis are required to probe the protean consequences of early-life adversity on the developing brain. These involve integrated human and animal-model studies, and approaches ranging from in vivo imaging to novel neuroanatomical, molecular, epigenomic, and computational methodologies. Because early-life adversity is a powerful determinant of subsequent vulnerabilities to emotional and cognitive pathologies, understanding the underlying processes will have profound implications for the world's current and future children. PMID- 26105146 TI - Dynamic CT perfusion image data compression for efficient parallel processing. AB - The increasing size of medical imaging data, in particular time series such as CT perfusion (CTP), requires new and fast approaches to deliver timely results for acute care. Cloud architectures based on graphics processing units (GPUs) can provide the processing capacity required for delivering fast results. However, the size of CTP datasets makes transfers to cloud infrastructures time-consuming and therefore not suitable in acute situations. To reduce this transfer time, this work proposes a fast and lossless compression algorithm for CTP data. The algorithm exploits redundancies in the temporal dimension and keeps random read only access to the image elements directly from the compressed data on the GPU. To the best of our knowledge, this is the first work to present a GPU-ready method for medical image compression with random access to the image elements from the compressed data. PMID- 26105142 TI - Stress and Fear Extinction. AB - Stress has a critical role in the development and expression of many psychiatric disorders, and is a defining feature of posttraumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies aimed at limiting pathological fear, such as exposure therapy. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiological basis of stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders. PMID- 26105147 TI - A laser Doppler system for monitoring cerebral microcirculation: implementation and evaluation during neurosurgery. AB - The aim of this study was to adapt and evaluate laser Doppler perfusion monitoring (LDPM) together with custom-designed brain probes and software for continuous recording of cerebral microcirculation in patients undergoing neurosurgery. The LDPM system was used to record perfusion and backscattered light (TLI). These parameters were displayed together with the extracted heart rate (HR), pulsatility index (PI) and signal trends from adjustable time intervals. Technical evaluation was done on skin during thermal provocation. Clinical measurements were performed on ten patients undergoing brain tumour surgery. Data from 76 tissue sites were captured with a length varying between 10 s to 15 min. Statistical comparisons were done using Mann-Whitney tests. Grey and tumour tissue could be separated from white matter using the TLI signal (p < 0.05). The perfusion was significantly higher in grey and tumour tissue compared to white matter (p < 0.005). LDPM was successfully used as an intraoperative tool for monitoring local blood flow and additional parameters linked to cerebral microcirculation (perfusion, TLI, HR and PI) during tumour resection. The systems stability opens up for studies in the postoperative care of patients with, for example, traumatic brain injury or subarachnoid haemorrhage. PMID- 26105148 TI - Influence of physical fitness and activity behavior on retinal vessel diameters in primary schoolchildren. AB - Retinal vessel alterations have been shown to be associated with cardiovascular risk factors and physical inactivity as early as childhood. In this context, the analysis of physical activity in children has solely been based on questionnaire assessments. The study aimed to examine the association of physical fitness performance and self-reported physical activity with retinal vessel diameters in young children. Three hundred ninety-one primary schoolchildren [7.3 years (SD 0.4)] were examined in this cross-sectional study. The primary outcome was endurance performance measured with the 20-m shuttle run. The additional tests consisted of a 20-m sprint, jumping sidewards and balancing backwards. Retinal microcirculation was assessed using a static retinal vessel analyzer. Parents completed questionnaires about physical and sedentary activities. Endurance performance was associated with narrower retinal venular diameters [-0.9 (95%CI: 1.8; -0.1) measuring units (mu)/ unit shuttle run, P = 0.04] and a higher arteriolar to venular ratio [0.003 (-0.001; 0.006)/unit shuttle run, P = 0.06]. The sprint performance was associated with narrower retinal arterioles [4.7 (0.8; 8.6) mu/unit sprint, P = 0.02]. Indoor playing activity correlated with narrower retinal venules [-0.04 (-0.07; -0.01) mu/per unit, P = 0.02]. Our data suggest that objectively measured endurance performance relates with better retinal vessel health in early childhood. PMID- 26105149 TI - Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). AB - We assessed the incidence, prognostic features, and outcomes associated with transformation of follicular lymphoma (FL) among 2652 evaluable patients prospectively enrolled in the National LymphoCare Study. At a median follow-up of 6.8 years, 379/2652 (14.3%) patients transformed following the initial FL diagnosis, including 147 pathologically confirmed and 232 clinically suspected cases. Eastern Cancer Oncology Group performance status >1, extranodal sites >1, elevated lactate dehydrogenase, and B symptoms at diagnosis were associated with transformation risk. Relative to observation, patients initiating treatment at diagnosis had a reduced risk of transformation (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.46-0.75). The risk of transformation was similar in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone compared with rituximab, cyclophosphamide, vincristine, and prednisone (adjusted HR, 0.94; 95% CI, 0.62-1.42). Maintenance rituximab was associated with reduced transformation risk (HR, 0.67; 95% CI, 0.46-0.97). Five-year survival from diagnosis was significantly worse for patients with vs without transformation (75%, 95% CI, 70-79 vs 85%, 95% CI, 83-86). The median overall survival post-transformation was 5 years. Forty-seven patients with evidence of transformation at the time of diagnosis shared similar prognostic factors and survival rates to those without transformation. Improved outcomes for transformation in the modern era are suggested by this observational study. This trial is registered at www.clinicaltrials.gov as #NCT00097565. PMID- 26105151 TI - Polyethylene Liner Dissociation Is a Complication of the DePuy Pinnacle Cup: A Report of 23 Cases. AB - BACKGROUND: Polyethylene liner dissociation is a rare but catastrophic event in total hip arthroplasty (THA), and certain implant designs are known to be at greater risk. Although the DePuy Pinnacle (Warsaw, IN, USA) modular acetabular construct has an excellent record of fixation and wear, an unexpectedly high number of liner dissociations has been noted. QUESTIONS/PURPOSES: The purposes of this study were (1) to characterize the clinical parameters observed in a large group of patients who have experienced liner dissociations with the DePuy Pinnacle acetabular component; (2) to describe the radiographic findings in this group of patients; and (3) to calculate a minimum frequency of this complication. METHODS: Since 2001, 23 patients with previously well-functioning THAs presented with sudden atraumatic polyethylene liner dissociation at four separate institutions. These THAs were performed between 2001 and 2013. Eight different arthroplasty specialists had performed the index hip arthroplasties using the DePuy Pinnacle acetabular component with a polyethylene liner. Polyethylene failures were evaluated for liner type and radiographic cup position. For three of the surgeons who contributed cases, institutional registries allowed the calculation of the number of components of this type that they used during the period in question, which provided a conservative estimate of the frequency of this type of failure. RESULTS: All 23 liner failures occurred atraumatically in previously asymptomatic THAs at a mean of 48 months (range, 3-138 months). Patients characteristically reported a new and sudden onset of discomfort with audible, reproducible squeaking. Surgical inspection of dissociated liners demonstrated displacement of polyethylene with shearing of the peripheral locking tabs. Radiographic evaluation demonstrated that 14 cups were well positioned and nine cups were malpositioned outside the so-called safe zone. Conservative estimates of the frequency of this complication from the three surgeons' practices whose institutional registries allowed calculation of the lowest possible frequency were 0.32% (six of 1888), 0.77% (three of 391), and 0.82% (three of 367). CONCLUSIONS: With this report of 23 additional liner dissociations, we suggest that surgeons should be aware of the problem and take extra precautions when using this implant to ensure locking mechanism integrity at the time of surgery. We caution that the frequency of liner dissociation may be higher than previously reported. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26105153 TI - CORR Insights((r)): Do Mesenchymal Stromal Cells Influence Microscopic Residual or Metastatic Osteosarcoma in a Murine Model? PMID- 26105154 TI - Concepts in bio-molecular spectroscopy: vibrational case studies on metalloenzymes. AB - Spectroscopic techniques play a major role in the elucidation of structure function relationships of biological macromolecules. Here we describe an integrated approach for bio-molecular spectroscopy that takes into account the special characteristics of such compounds. The underlying fundamental concepts will be exemplarily illustrated by means of selected case studies on biocatalysts, namely hydrogenase and superoxide reductase. The treatise will be concluded with an overview of challenges and future prospects, laying emphasis on functional dynamics, in vivo studies, and computational spectroscopy. PMID- 26105152 TI - What Is the Most Useful Questionnaire for Measurement of Coping Strategies in Response to Nociception? AB - BACKGROUND: There are several measures of coping strategies in response to nociception. These measures all correlate highly both with each other and with symptom intensity and magnitude of disability in patients with upper limb illness. This study aims to determine if distinct measures of coping strategies in response to nociception address the same underlying aspect of human illness behavior. QUESTIONS/PURPOSES: Our primary study question was: is there one common aspect of human illness behavior measured by (1) the Pain Catastrophizing Scale (PCS); (2) the Psychological Inflexibility in Pain Scale (PIPS); (3) the Patient Reported Outcomes Measurement Information System-Pain Interference (PROMIS-PI) Computer Adaptive Test (CAT); and (4) the Pain Self-Efficacy Questionnaire (PSEQ)? Secondarily, we aimed to determine which of the four questionnaires is most psychometrically sound. We measured correlations among questionnaires, coverage, reliability, completion time, and collinearity of these questionnaires when entered together in a multivariable model with the shortened version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) upper extremity disability questionnaire. METHODS: In this prospective study, 138 consecutive new or followup English-speaking patients aged 18 years or older presenting to a tertiary care referral center with traumatic and nontraumatic upper extremity conditions were invited to participate between March and May 2014. One hundred thirty-four (97%) patients agreed to participate and completed the four questionnaires in random order before their visit with the physician. We used exploratory factor analysis to assess whether there was a single common trait-an underlying aspect of human illness behavior-measured by these questionnaires. Interquestionnaire correlation was assessed using Spearman rank correlation coefficients; coverage by assessing floor and ceiling effect (proportion of scores at lower and upper limit); reliability by Cronbach's alpha measure of internal consistency; completion time in seconds using Kruskal-Wallis analysis; and collinearity statistics through a regression model with QuickDASH. RESULTS: Exploratory factor analysis identified a common trait measured by these four measures-coping strategies in response to nociception-indicated by a substantial correlation of every individual questionnaire with the underlying trait (PCS: 0.74, PIPS: 0.84, PROMIS-PI: 0.83, PSEQ: -0.86). All interquestionnaire correlations were also large to substantial and were highest for PROMIS-PI with PSEQ (rho = -0.84, p < 0.001) and lowest for PROMIS-PI with PCS (rho = 0.67, p < 0.001). Internal consistencies were high (PCS: 0.93, PIPS: 0.88, PSEQ: 0.92, and not determined for the PROMIS-PI as a result of its CAT administration). PROMIS PI was the quickest to complete (30 seconds [interquartile range, 24-44]) compared with the others (PCS: 91 seconds [66-122], p < 0.001; PIPS: 105 seconds [82-141], p < 0.001; PSEQ: 78 seconds [60-101], p < 0.001). The four coping questionnaires had a low partial r(2) and a relatively high variation inflation factor, indicating multicollinearity. PROMIS-PI was found to have the strongest correlation with QuickDASH (beta coefficient: 0.63; standard error: 0.10; p < 0.001). CONCLUSIONS: There is evidence that the four widely used measures of coping strategies in response to nociception address a single common aspect of human illness behavior, which negatively impacts upper extremity disability. Future studies assessing functional outcome should incorporate a measure of human illness behavior as it strongly relates to disability. CLINICAL RELEVANCE: Given that all of these measures address the same important aspect of human illness behavior, we recommend the PROMIS-PI CAT as the most efficient measure. PMID- 26105155 TI - Sequence-Based Predictive Models of Resistance to HIV-1 Integrase Inhibitors: An n-Grams Approach to Phenotype Assessment. AB - Amino acid substitutions in HIV-1 proteins critical to the viral replication cycle have the potential to undermine successful inhibition of those targets, with some mutations leading to either reduced susceptibility to certain medications or complete drug resistance. Phenotypic tests are best suited to quantify the effects of complex mutational patterns on drug resistance; however, the relatively high cost and long turnaround time associated with phenotyping has increased the demand for in silico drug-specific models capable of accurately predicting phenotype directly from the target protein sequences. The focus of this study is on the HIV-1 integrase (IN) enzyme, which mediates integration of reversibly transcribed viral DNA into the host cell genome, and the development of predictive statistical learning models of resistance to the IN inhibitors Raltegravir (RAL) and Elvitegravir (EVG). Models were trained using datasets of IN protein sequence variants each having a known phenotype, quantified as the fold change in susceptibility to the respective inhibitor, and obtained using an experimental assay. A sequence-based approach employing n-grams relative frequencies was implemented to uniquely characterize each IN variant as a feature vector of input attributes. Models for classifying IN variants as susceptible or resistant reach cross-validation balanced accuracy rates of 89% with RAL and 85% with EVG. Additionally, regression models achieve Pearson's correlation coefficients, between experimental and predicted log-transformed phenotypic fold change values, as high as r = 0.80 with RAL and r = 0.76 with EVG. Our results suggest that as additional training data are made publicly available, the models may hold promise as supplementary tools for making treatment decisions. PMID- 26105150 TI - Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. AB - Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low frequency (minor allele frequency [MAF] >=0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways. PMID- 26105156 TI - Pivotal Role of the Genital Epithelial Cells in HIV-1 Transmission. AB - AIDS remains one of the world's most serious health challenges, with 35 million people living with HIV worldwide at the end of 2013. HIV sexual transmission accounts for the overwhelming majority of people newly infected, making genital and rectal mucosal tissues the major sites of infection. This review focuses on the role of the female genital epithelial cells in the establishment of HIV infection. PMID- 26105157 TI - Mitochondrial responsibility in ageing process: innocent, suspect or guilty. AB - Ageing is accompanied by the accumulation of damaged molecules in cells due to the injury produced by external and internal stressors. Among them, reactive oxygen species produced by cell metabolism, inflammation or other enzymatic processes are considered key factors. However, later research has demonstrated that a general mitochondrial dysfunction affecting electron transport chain activity, mitochondrial biogenesis and turnover, apoptosis, etc., seems to be in a central position to explain ageing. This key role is based on several effects from mitochondrial-derived ROS production to the essential maintenance of balanced metabolic activities in old organisms. Several studies have demonstrated caloric restriction, exercise or bioactive compounds mainly found in plants, are able to affect the activity and turnover of mitochondria by increasing biogenesis and mitophagy, especially in postmitotic tissues. Then, it seems that mitochondria are in the centre of metabolic procedures to be modified to lengthen life- or health-span. In this review we show the importance of mitochondria to explain the ageing process in different models or organisms (e.g. yeast, worm, fruitfly and mice). We discuss if the cause of aging is dependent on mitochondrial dysfunction of if the mitochondrial changes observed with age are a consequence of events taking place outside the mitochondrial compartment. PMID- 26105159 TI - The Paradoxical Effects of AMPK on Insulin Gene Expression and Glucose-Induced Insulin Secretion. AB - The activation of AMP-activated protein kinase (AMPK) is known to repress the expression of the insulin gene and glucose-stimulated insulin secretion (GSIS). However, the mechanisms by which this occurs, as well as the effects of AMPK activation on glucolipotoxicity-induced beta-cell dysfunction, have not been elucidated. To investigate the effects of 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR) and peroxisome proliferator-activated receptorgamma coactivator-1alpha (PGC-1alpha) on beta-cell-specific genes under glucolipotoxic conditions, we performed real-time PCR and measured insulin secretion by primary islets. To study these effects in vivo, we administered AICAR for 10 days (1 mg/g body weight) to 90% pancreatectomized hyperglycemic mice. The exposure of isolated rat and human islets to glucolipotoxic conditions and the overexpression of PGC-1alpha suppressed insulin and NEUROD1 mRNA expression. However, the expression of these genes was preserved by AICAR treatment and by PGC-1alpha inhibition. Exposure of isolated islets to glucolipotoxic conditions for 3 days decreased GSIS, which was also well maintained by AICAR treatment and by PGC 1alpha inhibition. The administration of AICAR to 90% pancreatectomized hyperglycemic mice improved glucose tolerance and insulin secretion. These results indicate that treatment of islets with an AMPK agonist under glucolipotoxic conditions protects against glucolipotoxicity-induced beta-cell dysfunction. A better understanding of the functions of molecules such as PGC 1alpha and AMPK, which play key roles in intracellular fuel regulation, could herald a new era for the treatment of patients with type 2 diabetes mellitus by providing protection against glucolipotoxicity. PMID- 26105158 TI - Tumor Microenvironment Remodeling by 4-Methylumbelliferone Boosts the Antitumor Effect of Combined Immunotherapy in Murine Colorectal Carcinoma. AB - We have previously demonstrated that a low dose of cyclophosphamide (Cy) combined with gene therapy of interleukin-12 (AdIL-12) has a synergistic, although limited, antitumoral effect in mice with colorectal carcinoma. The main mechanism involved in the efficacy of Cy+AdIL-12 was the induction of a specific immune response mediated by cytotoxic T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment (TME) and to investigate how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure (TIP). As a consequence, tumor perfusion was improved allowing an increased adenoviral transgene expression. In addition, treatment with 4Mu boosted the number of cytotoxic T lymphocytes that reach the tumor after adoptive transfer resulting in a potent inhibition of tumor growth. Importantly, we observed complete tumor regression in 75% of mice when 4Mu was administrated in combination with Cy+AdIL-12. The triple combination 4Mu+Cy+AdIL 12 also induced a shift toward antiangiogenic factors production in tumor milieu. Our results showed that TME remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy. PMID- 26105160 TI - [Trauma and posttraumatic stress symptoms in patients in German primary care settings]. AB - BACKGROUND: Primary care settings have an important gatekeeping function to detect mental diseases, including trauma and posttraumatic stress disorders. OBJECTIVES: To assess the prevalence of trauma and posttraumatic symptoms in a first sample of northeast German primary care patients and to evaluate the diagnostic sensitivity and specificity of the general practitioners. MATERIAL AND METHODS: Traumatic experiences and posttraumatic stress disorders (PTSD) were assessed with self-rating questionnaires in a sample of N = 400 patients from 3 primary care facilities. Additionally, knowledge and diagnostic accuracy of the general practitioners were evaluated. RESULTS: According to the results of the patient health questionnaire (PHQ-15) data from all patients, the majority of patients questioned showed slight to moderate stress from somatic symptoms. Of the patients with complete data 7 % (n = 25) had a complete PTSD according to the results of the questionnaire, which was also identified in the medical assessment with a sensitivity of 40 %. The stress resulting from posttraumatic symptoms was closely associated with the extent of somatic complaints. CONCLUSION: Patients with a history of trauma and posttraumatic symptoms are prevalent in primary care settings. An early diagnosis by the general practitioner can help patients to receive adequate treatment. Patients with somatoform disorders in particular should be screened for trauma and posttraumatic symptoms. PMID- 26105161 TI - [Stroke - lifestyle and environment]. AB - Lifestyle modifications and environmental factors are important for stroke prevention and rehabilitation after stroke. The individual stroke risk may be modified by factors like physical activity, body weight and nutrition, special dietary supplements such as vitamins, smoking, consumption of tea, coffee and alcohol, psychological factors and by keeping a pet. The focus of this article lies on measures for stroke prevention. For certain topics, it also comments on factors that are important during rehabilitation after stroke. PMID- 26105162 TI - [Influence of lifestyle on neurodegenerative diseases]. AB - Lifestyle factors in midlife have an important influence on the risk of developing a neurodegenerative disease during later life. Data on lifestyle factors exist for Alzheimer's disease and Parkinson's disease. Continuous physical and cognitive activity, a balanced or Mediterranean diet with a high proportion of unsaturated fatty acids, the pharmacological treatment of arterial hypertension, sufficient and unfragmented sleep and possibly treatment with lipophilic statins reduce the risk of developing dementia later in life. Several studies in recent years have provided evidence that during the last decades the age-adjusted incidence of dementia has decreased. This is probably due to a healthier lifestyle and the treatment of risk factors. Continuous physical activity also decreases the likelihood of developing Parkinson's disease. Whether lifestyle factors also have an influence on the course and the progression of Alzheimer's and Parkinson's diseases in the symptomatic stages is unknown. PMID- 26105163 TI - [Psychiatric interventions for the unemployed]. AB - Unemployment is related to a higher risk for psychological distress and mental disorders, which cause individual suffering and socioeconomic costs for society in general. This selective review surveys the relationship between unemployment and psychological well-being and mental disorders. The most important programs for the improvement of the mental health of the unemployed are summarized: 1. Interventions for the unemployed with the aim of improving coping strategies reduce the risk of developing depressive symptoms. 2. The SUPPORT liaison outpatient unit collaborates closely with the unemployment agency and offers a low-threshold screening for mental disorders for unemployed subjects as well as counseling for those in need of treatment. 3. A group training based on cognitive behavioral therapy improves the psychological well-being of unemployed participants. 4. Supported employment is an effective means of placing severely mentally ill patients in a work-place accompanied by an extensive professional support. PMID- 26105164 TI - Childhood psychological maltreatment subtypes and adolescent depressive symptoms. AB - The aim of this study was to understand how subtypes and the timing of psychological maltreatment contribute to adolescent depressive symptoms at age 14. The sample included 638 youth from the Longitudinal Studies of Child Abuse and Neglect (LONGSCAN). At age 12, youth reported experiences of psychological maltreatment (degradation, isolating, and terrorizing), physical abuse (endangerment and physical injury), and sexual abuse that occurred before and during elementary school/last year. Multivariable regression models were conducted separately for females and males at each of the two time periods and accounted for demographics, primary caregiver depressive symptoms, other maltreatment subtypes, and youth-reported age 12 depressive symptoms. For girls, caregiver degradation was the only maltreatment subtype that contributed unique variance to depressive symptoms. Degradation before elementary school and chronic degradation had a stronger impact on depression symptoms. Only caregiver isolating behaviors during elementary school/last year and chronic isolation predicted depressive symptoms in boys. These results suggest that childhood psychological maltreatment is multi-dimensional and is implicated in the etiology of adolescent depressive symptoms. Future prevention efforts should consider parental psychological maltreatment in reducing risk for adolescent depression. PMID- 26105165 TI - Humane accomplishment of physicians and the philosophy of minimally-invasive and noninvasive medicine: A perspective. AB - The highest realm in clinical medicine is the harmonious unity of medical sciences and the humanistic spirit. Given that the beauty of human nature resides in humanity, a competent medical practitioner should be a sage that personifies the rigorous scientific spirit and the humanity. It is essential for a medical practitioner to learn to seek answers to medical inquiries at the philosophical level. Important as it is to study the organs, the cells and the functions of the body, medical practitioners need to be well-versed in the utmost beauty of mankind. The central tenet of minimally-invasive therapeutic medicine is to minimize harm to patients while effectively managing the lesion. The radical changes brought about by minimally-invasive technologies, exemplified by the non invasive high intensity focused ultrasound (HIFU) surgery, are to change the face of traditional surgery. PMID- 26105166 TI - Proceedings of the ASNC Cardiac PET Summit Meeting 12 May 2015, Baltimore, MD : 6. Recommendations for training and education for cardiac PET. PMID- 26105167 TI - Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic. AB - Tedizolid phosphate is the second commercially available oxazolidinone antibiotic, although the first one in class that is dosed once daily. It is a prodrug that is rapidly converted to the active compound tedizolid. Tedizolid has activity against a wide range of gram-positive pathogens, including methicillin resistant Staphylococcus aureus. It is approved to treat acute bacterial skin and skin structure infections (ABSSSIs). In 2 randomized controlled phase 3 trials, 6 days of tedizolid (200 mg once daily) has been proven to be noninferior to 10 days of linezolid (600 mg twice daily). These 2 ABSSSI studies have positioned tedizolid among the growing armamentarium of newer, novel, anti-gram-positive agents. Tedizolid appears to differ from linezolid in the incidence of gastrointestinal and hematologic side effects and appears to lack drug interactions with selective serotonin reuptake inhibitors. Conditions other than ABSSSI are currently being evaluated in clinical studies. PMID- 26105168 TI - Recent Updates on the Role of Pharmacokinetics-pharmacodynamics in Antimicrobial Susceptibility Testing as Applied to Clinical Practice. AB - Given current challenges in antimicrobial resistance and drug development, infectious diseases clinicians must rely on their own ingenuity to effectively treat infections while preserving the current antimicrobial armamentarium. An understanding of pharmacokinetics (PK), pharmacodynamics (PD), antimicrobial susceptibility testing (AST), and how these concepts relate, is essential to this task. In this review, we discuss how and why PK-PD impacts AST and the way infectious diseases are being treated, with a particular focus on vancomycin for methicillin-resistant Staphylococcus aureus, penicillin for Streptococcus pneumoniae, and an update on cephalosporins for Enterobacteriaceae. Finally, we address how new ideas to exploit PK-PD can promote innovative study design and bring about more rapid regulatory review of new antimicrobials. PMID- 26105169 TI - The Treatment of a Gangrenous Leg. PMID- 26105171 TI - Statistics and sovereignty: the workings of biopower in epidemiology. PMID- 26105170 TI - Pharmacokinetics of Raltegravir in HIV-Infected Patients on Rifampicin-Based Antitubercular Therapy. AB - BACKGROUND: Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) elimination, thereby potentially lowering RAL exposure. We examined the pharmacokinetics of RAL in human immunodeficiency virus (HIV)-infected patients on RIF-based antitubercular therapy in the French National Agency for HIV/AIDS and Viral Hepatitis Research 12 180 Reflate Tuberculosis trial. METHODS: Patients started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF (10 mg/kg/day). In arm 1 (n = 21), they received 400 mg RAL twice daily; in arm 2 (n = 16), they received RAL 800 mg twice daily initially then 400 mg twice daily 4 weeks after RIF discontinuation. Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of RAL together with RIF (period 1), 4 weeks after RIF discontinuation (period 2), and after the RAL dose reduction in arm 2 (period 3). RESULTS: In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI], .64-1.37) for the 12-hour area under the time concentration curve (AUC0-12), and 0.69 (90% CI, .42-1.13) for the concentration at 12 hours (C12). In arm 2, the corresponding GMRs were 0.75 (90% CI, .48-1.17) and 1.10 (90% CI, .61-2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88-3.23) for period 1 vs period 3. CONCLUSIONS: The double dose of RAL overcompensated for RIF induction, but the standard dose was associated with only small decreases in AUC0-12 and C12 during RIF coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection. CLINICAL TRIALS REGISTRATION: NCT0082231. PMID- 26105172 TI - Fashion victim: rhabdomyolysis and bilateral peroneal and tibial neuropathies as a result of squatting in 'skinny jeans'. PMID- 26105173 TI - Mutational spectrum and phenotypic variability of VCP-related neurological disease in the UK. PMID- 26105174 TI - Mid-Ventricular Obstructive Hypertrophic Cardiomyopathy and Apical Aneurysm Mimicking Acute ST-Elevation Myocardial Infarction. AB - Nonischemic ST-segment elevation may be confused as acute ST-elevation myocardial infarction (STEMI), especially in patients with atypical presenting symptoms. Among the possible differential diagnosis, hypertrophic cardiomyopathy (HCM) should be considered. Mid-ventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is a rare type of cardiomyopathy, accounting for approximately 5% of all HCM cases. ST-segment elevation on electrocardiogram (ECG) in patients with MVOHCM is a rare clinical presentation. We present a case of MVOHCM and apical aneurysm mimicking acute STEMI. PMID- 26105175 TI - Localization of CGRP receptor components and receptor binding sites in rhesus monkey brainstem: A detailed study using in situ hybridization, immunofluorescence, and autoradiography. AB - Functional imaging studies have revealed that certain brainstem areas are activated during migraine attacks. The neuropeptide calcitonin gene-related peptide (CGRP) is associated with activation of the trigeminovascular system and transmission of nociceptive information and plays a key role in migraine pathophysiology. Therefore, to elucidate the role of CGRP, it is critical to identify the regions within the brainstem that process CGRP signaling. In situ hybridization and immunofluorescence were performed to detect mRNA expression and define cellular localization of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), respectively. To define CGRP receptor binding sites, in vitro autoradiography was performed with [(3)H]MK-3207 (a CGRP receptor antagonist). CLR and RAMP1 mRNA and protein expression were detected in the pineal gland, medial mammillary nucleus, median eminence, infundibular stem, periaqueductal gray, area postrema, pontine raphe nucleus, gracile nucleus, spinal trigeminal nucleus, and spinal cord. RAMP1 mRNA expression was also detected in the posterior hypothalamic area, trochlear nucleus, dorsal raphe nucleus, medial lemniscus, pontine nuclei, vagus nerve, inferior olive, abducens nucleus, and motor trigeminal nucleus; protein coexpression of CLR and RAMP1 was observed in these areas via immunofluorescence. [(3)H]MK-3207 showed high binding densities concordant with mRNA and protein expression. The present study suggests that several regions in the brainstem may be involved in CGRP signaling. Interestingly, we found receptor expression and antagonist binding in some areas that are not protected by the blood-brain barrier, which suggests that drugs inhibiting CGRP signaling may not be able to penetrate the central nervous system to antagonize receptors in these brain regions. PMID- 26105176 TI - Pushing the extraction envelope. PMID- 26105177 TI - Asymmetrical mandibular molar protraction with conventional mechanics. PMID- 26105178 TI - Atypical extractions in adult treatment. PMID- 26105179 TI - Orthodontic movement of a lower incisor across the midline. PMID- 26105180 TI - Flowable resin for temporary fixation in bonding lingual retainers. PMID- 26105181 TI - 3D-printed orthodontic auxiliaries. PMID- 26105182 TI - Transcatheter device closure of perimembranous ventricular septal defect in children treated with prophylactic oral steroids: acute and mid-term results of a single-centre, prospective, observational study. AB - Background and Objective Although transcatheter closure of perimembranous ventricular septal defect is emerging as an accepted, viable alternative, conduction disturbances still remain a major concern. Although steroid treatment has shown encouraging results with complete recovery, efficacy of prophylactic use of steroids is still speculative. We aim to study the mid-term outcome of perimembranous ventricular septal defect closure in children who received prophylactic oral steroids. Materials and methods A prospective study was designed and antegrade device closure was attempted in eligible children who met the following inclusion criteria: age 3-18 years and weight >10 kg, defect diameter ?12 mm, and symptomatic, haemodynamic changes or history of infective endocarditis. Prophylactic steroid protocol consisted of 2 weeks oral prednisolone (1 mg/kg/day) initiated immediately after the procedure, and in the event of bradyarrhythmia it was escalated to 2 mg/kg. Patients were regularly followed-up at 1, 6, and 12 months and then annually. Patients with post procedure heart block underwent Holter monitoring after a minimum of 1 year interval. RESULTS: Between May, 2007 and August, 2012, successful device closure was accomplished in 290/297 patients. Mean age and weight were 9+/-3.12 years and 21+/-8.27 kg, respectively. The defect measured 5+/-1.38 mm on echocardiography. Mean fluoroscopy time was 12.98+/-8.64 minutes. Eight patients with major complications included one each with device embolisation, haemolysis, severe aortic regurgitation, and five with bradyarrhythmias, including complete atrioventricular block in three, Mobitz II in one, and bifascicular block in one. Patients with complete atrioventricular block responded to high-dose steroid and temporary pacemaker. Minor complications included post-procedure heart block (n=22) and blood loss (n=2). At 18.23+/-13.15 months follow-up, 8/27 (five major, 22 minor) with arrhythmia had persistent post-procedure heart block of no clinical consequences. CONCLUSION: In our patient population, transcatheter device closure of the perimembranous ventricular septal defect with prophylactic oral steroid resulted in excellent closure rate and acceptably low incidence of conduction disturbances at mid-term follow-up. PMID- 26105183 TI - Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment. AB - The circadian cycle is a genetically encoded clock that drives cellular rhythms of transcription, translation and metabolism. The circadian clock interacts with the diurnal environment that also drives transcription and metabolism during light/dark, sleep/wake, hot/cold and feast/fast daily and seasonal cycles. Epigenetic regulation provides a mechanism for cells to integrate genetic programs with environmental signals in order produce an adaptive and consistent output. Recent studies have revealed that DNA methylation is one epigenetic mechanism that entrains the circadian clock to a diurnal environment. We also review recent circadian findings in the epigenetic neurodevelopmental disorders Prader-Willi, Angelman and Rett syndromes and hypothesize a link between optimal brain development and intact synchrony between circadian and diurnal rhythms. PMID- 26105184 TI - WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish. AB - Bladder exstrophy, a severe congenital urological malformation when a child is born with an open urinary bladder, is the most common form of bladder exstrophy epispadias complex (BEEC) with an incidence of 1:30,000 children of Caucasian descent. Recent studies suggest that WNT genes may contribute to the etiology of bladder exstrophy. Here, we evaluated WNT-pathway genes in 20 bladder exstrophy patients using massively parallel sequencing. In total 13 variants were identified in WNT3, WNT6, WNT7A, WNT8B, WNT10A, WNT11, WNT16, FZD5, LRP1 and LRP10 genes and predicted as potentially disease causing, of which seven variants were novel. One variant, identified in a patient with a de novo nonsynonymous substitution in WNT3 (p.Cys91Arg), was further evaluated in zebrafish. Knock down of wnt3 in zebrafish showed cloaca malformations, including disorganization of the cloaca epithelium and expansion of the cloaca lumen. Our study suggests that the function of the WNT3 p.Cys91Arg variant was altered, since RNA overexpression of mutant Wnt3 RNA does not result in embryonic lethality as seen with wild-type WNT3 mRNA. Finally, we also mutation screened the WNT3 gene further in 410 DNA samples from BEEC cases and identified one additional mutation c.638G>A (p.Gly213Asp), which was paternally inherited. In aggregate our data support the involvement of WNT-pathway genes in BEEC and suggest that WNT3 in itself is a rare cause of BEEC. PMID- 26105185 TI - Dynamic distribution and the role of abscisic acid during seed development of a lady's slipper orchid, Cypripedium formosanum. AB - BACKGROUND AND AIMS: Although abscisic acid (ABA) is commonly recognized as a primary cause of seed dormancy, there is a lack of information on the role of ABA during orchid seed development. In order to address this issue, the localization and quantification of ABA were determined in developing seeds of Cypripedium formosanum. METHODS: The endogenous ABA profile of seeds was measured by enzyme linked immunosorbent assay (ELISA). Temporal and spatial distributions of ABA in developing seeds were visualized by immunohistochemical staining with monoclonal ABA antibodies. Fluoridone was applied to test the causal relationship between ABA content and seed germinability. KEY RESULTS: ABA content was low at the proembryo stage, then increased rapidly from 120 to 150 days after pollination (DAP), accompanied by a progressive decrease in water content and seed germination. Immunofluorescence signals indicated an increase in fluorescence over time from the proembryo stage to seed maturation. From immunogold labelling, gold particles could be seen within the cytoplasm of embryo-proper cells during the early stages of seed development. As seeds approached maturity, increased localization of gold particles was observed in the periplasmic space, the plasmalemma between embryo-proper cells, the surface wall of the embryo proper, and the inner walls of inner seed-coat cells. At maturity, gold particles were found mainly in the apoplast, such as the surface wall of the embryo proper, and the shrivelled inner and outer seed coats. Injection of fluoridone into capsules resulted in enhanced germination of mature seeds. CONCLUSIONS: The results indicate that ABA is the key inhibitor of germination in C. formosanum. The distinct accumulation pattern of ABA suggests that it is synthesized in the cytosol of embryo cells during the early stages of seed development, and then exported to the apoplastic region of the cells for subsequent regulatory processes as seeds approach maturity. PMID- 26105186 TI - Continent-wide distribution in mycorrhizal fungi: implications for the biogeography of specialized orchids. AB - BACKGROUND AND AIMS: Although mycorrhizal associations are predominantly generalist, specialized mycorrhizal interactions have repeatedly evolved in Orchidaceae, suggesting a potential role in limiting the geographical range of orchid species. In particular, the Australian orchid flora is characterized by high mycorrhizal specialization and short-range endemism. This study investigates the mycorrhizae used by Pheladenia deformis, one of the few orchid species to occur across the Australian continent. Specifically, it examines whether P. deformis is widely distributed through using multiple fungi or a single widespread fungus, and if the fungi used by Australian orchids are widespread at the continental scale. METHODS: Mycorrhizal fungi were isolated from P. deformis populations in eastern and western Australia. Germination trials using seed from western Australian populations were conducted to test if these fungi supported germination, regardless of the region in which they occurred. A phylogenetic analysis was undertaken using isolates from P. deformis and other Australian orchids that use the genus Sebacina to test for the occurrence of operational taxonomic units (OTUs) in eastern and western Australia. KEY RESULTS: With the exception of one isolate, all fungi used by P. deformis belonged to a single fungal OTU of Sebacina. Fungal isolates from eastern and western Australia supported germination of P. deformis. A phylogenetic analysis of Australian Sebacina revealed that all of the OTUs that had been well sampled occurred on both sides of the continent. CONCLUSIONS: The use of a widespread fungal OTU in P. deformis enables a broad distribution despite high mycorrhizal specificity. The Sebacina OTUs that are used by a range of Australian orchids occur on both sides of the continent, demonstrating that the short-range endemism prevalent in the orchids is not driven by fungal species with narrow distributions. Alternatively, a combination of specific edaphic requirements and a high incidence of pollination by sexual deception may explain biogeographic patterns in southern Australian orchids. PMID- 26105187 TI - Aluminium alleviates manganese toxicity to rice by decreasing root symplastic Mn uptake and reducing availability to shoots of Mn stored in roots. AB - BACKGROUND AND AIMS: Manganese (Mn) and aluminium (Al) phytotoxicities occur mainly in acid soils. In some plant species, Al alleviates Mn toxicity, but the mechanisms underlying this effect are obscure. METHODS: Rice (Oryza sativa) seedlings (11 d old) were grown in nutrient solution containing different concentrations of Mn(2+) and Al(3+) in short-term (24 h) and long-term (3 weeks) treatments. Measurements were taken of root symplastic sap, root Mn plaques, cell membrane electrical surface potential and Mn activity, root morphology and plant growth. KEY RESULTS: In the 3-week treatment, addition of Al resulted in increased root and shoot dry weight for plants under toxic levels of Mn. This was associated with decreased Mn concentration in the shoots and increased Mn concentration in the roots. In the 24-h treatment, addition of Al resulted in decreased Mn accumulation in the root symplasts and in the shoots. This was attributed to higher cell membrane surface electrical potential and lower Mn(2+) activity at the cell membrane surface. The increased Mn accumulation in roots from the 3-week treatment was attributed to the formation of Mn plaques, which were probably related to the Al-induced increase in root aerenchyma. CONCLUSIONS: The results show that Al alleviated Mn toxicity in rice, and this could be attributed to decreased shoot Mn accumulation resulting from an Al-induced decrease in root symplastic Mn uptake. The decrease in root symplastic Mn uptake resulted from an Al-induced change in cell membrane potential. In addition, Al increased Mn plaques in the roots and changed the binding properties of the cell wall, resulting in accumulation of non-available Mn in roots. PMID- 26105188 TI - Life cycle stage and water depth affect flooding-induced adventitious root formation in the terrestrial species Solanum dulcamara. AB - BACKGROUND AND AIMS: Flooding can occur at any stage of the life cycle of a plant, but often adaptive responses of plants are only studied at a single developmental stage. It may be anticipated that juvenile plants may respond differently from mature plants, as the amount of stored resources may differ and morphological changes can be constrained. Moreover, different water depths may require different strategies to cope with the flooding stress, the expression of which may also depend on developmental stage. This study investigated whether flooding-induced adventitious root formation and plant growth were affected by flooding depth in Solanum dulcamara plants at different developmental stages. METHODS: Juvenile plants without pre-formed adventitious root primordia and mature plants with primordia were subjected to shallow flooding or deep flooding for 5 weeks. Plant growth and the timing of adventitious root formation were monitored during the flooding treatments. KEY RESULTS: Adventitious root formation in response to shallow flooding was significantly constrained in juvenile S. dulcamara plants compared with mature plants, and was delayed by deep flooding compared with shallow flooding. Complete submergence suppressed adventitious root formation until up to 2 weeks after shoots restored contact with the atmosphere. Independent of developmental stage, a strong positive correlation was found between adventitious root formation and total biomass accumulation during shallow flooding. CONCLUSIONS: The potential to deploy an escape strategy (i.e. adventitious root formation) may change throughout a plant's life cycle, and is largely dependent on flooding depth. Adaptive responses at a given stage of the life cycle thus do not necessarily predict how the plant responds to flooding in another growth stage. As variation in adventitious root formation also correlates with finally attained biomass, this variation may form the basis for variation in resistance to shallow flooding among plants. PMID- 26105189 TI - Multidimensional Caregiving Burden of Female Family Caregivers in Korea. AB - The purpose of this study was to examine a staged theoretical model to explain cultural knowledge-based multidimensional burden of women family caregivers caring for community-dwelling older adults using a modified Poulshock and Deimling model. In the model, the antecedents included elders' impairment in activities of daily living (ADL), elders' cognitive impairment, caregivers' self efficacy, and caregivers' familism. The perception contained the disruptive behavior burden and social functioning burden of caregivers. The consequence variable included social activity restriction and negative changes in family relationships. The total sample was 157 primary women caregivers caring for community-dwelling older adults aged 65 and older. Instruments were General Self Efficacy Scale, Family Scale, and Burden Scale. Path analysis was done to analyze the model using multiple linear regression methods. This study showed that impairments of older adults (impairment in ADL, cognitive impairment) and caregiver beliefs (strong familism, low self-efficacy) had an indirect influence on negative changes in family relationship and social activity restriction through the perceived emotional distress. PMID- 26105190 TI - Targeted therapies in advanced differentiated thyroid cancer. AB - Differentiated thyroid cancer is the most common endocrine malignancy, and its incidence has been rising rapidly over the past 10 years. Although most patients with this disease have an excellent prognosis, a subset develops a more aggressive disease phenotype refractory to conventional therapies. Until recently, there was no effective therapy for these patients. With increasing knowledge of the molecular pathogenesis of thyroid cancer, novel targeted therapies are being developed for this group of patients. Sorafenib and lenvatinib, small-molecule multikinase inhibitors, were approved for the treatment of progressive, symptomatic, radioactive iodine refractory, advanced differentiated thyroid cancer in 2013 and 2015, respectively. This represents a major innovation in the therapy of patients with advanced thyroid cancer. However, these therapies still have many limitations and further research needs to be pursued with the ultimate goal of providing safe and effective personalized therapy for patients with advanced thyroid cancer. PMID- 26105191 TI - Adjunctive intracardiac echocardiography imaging from the left ventricle to guide percutaneous mitral valve repair with the MitraClip in patients with failed prior surgical rings. AB - OBJECTIVES: We evaluated intracardiac echocardiography (ICE) for adjunctively guiding the MitraClip procedure in patients with prior surgical rings. BACKGROUND: Transesophageal echocardiography (TEE) is the standard imaging modality used to guide the MitraClip procedure (Abbott Vascular, CA). However, in patients with post-surgical anatomy, clear imaging of the mitral valve leaflets may be complex because of shadowing from the surgical ring. In these patients, TEE may be suboptimal for guiding the procedure, even using three-dimensional imaging. METHODS: This retrospective analysis included data from 121 consecutive patients with mitral regurgitation who underwent MitraClip procedures at the University of Virginia. ICE was used adjunctively when there was difficulty with TEE, particularly for assessing the insertion of the posterior leaflet into the MitraClip's arms. The ICE catheter was introduced transarterially into the left ventricle and flexed to obtain the short-axis view. RESULTS: Six patients had prior surgical rings, and in five, we used adjunctive ICE. The etiology of the mitral regurgitation was prolapse of the posterior leaflet in one patient and restriction of the posterior leaflet due to ischemic tethering in the remainder. All images were obtained from the left ventricle, and were adequate for assessing posterior leaflet insertion and the perpendicularity of the MitraClip arms. The procedural success rate was 80%. There was no adverse event related to the ICE procedure. CONCLUSIONS: Mitral valve repair with the MitraClip system assisted by ICE is feasible in patients with prior surgical rings, achieving an excellent risk profile and satisfactory procedural success. PMID- 26105192 TI - Grid cells correlation structure suggests organized feedforward projections into superficial layers of the medial entorhinal cortex. AB - Navigation requires integration of external and internal inputs to form a representation of location. Part of this integration is considered to be carried out by the grid cells network in the medial entorhinal cortex (MEC). However, the structure of this neural network is unknown. To shed light on this structure, we measured noise correlations between 508 pairs of simultaneous previously recorded grid cells. We differentiated between pure grid and conjunctive cells (pure grid in Layers II, III, and VI vs. conjunctive in Layers III and V--only Layer III was bi-modal), and devised a new method to classify cell pairs as belonging/not belonging to the same module. We found that pairs from the same module show significantly more correlations than pairs from different modules. The correlations between pure grid cells decreased in strength as their relative spatial phase increased. However, correlations were mostly at 0 time-lag, suggesting that the source of correlations was not only synaptic, but rather resulted mostly from common input. Given our measured correlations, the two functional groups of grid cells (pure vs. conjunctive), and the known disorganized recurrent connections within Layer II, we propose the following model: conjunctive cells in deep layers form an attractor network whose activity is governed by velocity-controlled signals. A second manifold in Layer II receives organized feedforward projections from the deep layers, giving rise to pure grid cells. Numerical simulations indicate that organized projections induce such correlations as we measure in superficial layers. Our results provide new evidence for the functional anatomy of the entorhinal circuit-suggesting that strong phase-organized feedforward projections support grid fields in the superficial layers. PMID- 26105193 TI - Stabilization of the i-motif structure by the intra-strand cross-link formation. AB - The i-motif structures are formed by oligonucleotides containing cytosine tracts under acidic conditions. The folding of the i-motif under physiological conditions is of great interest because of its biological role. In this study, we investigated the effect of the intra-strand cross-link on the stability of the i motif structure. The 4-vinyl-substituted analog of thymidine (T-vinyl) was incorporated into the 5'-end of the human telomere complementary strand, which formed the intra-strand cross-link with the internal adenine. The intra-strand cross-linked i-motif displayed CD spectra similar to that of the natural i-motif at acidic pH, which was transformed into a random coil with the increasing pH. The pH midpoint for the transition from the i-motif to random coil increased from pH 6.1 for the natural one to pH 6.8 for the cross-linked one. The thermodynamic parameters were obtained by measuring the thermal melting behaviors by CD and UV, and it was determined that the intra-strand cross-linked i-motif is stabilized due to a favorable entropy effect. Thus, this study has clearly indicated the validity of the intra-strand cross-linking for stabilization of the i-motif structure. PMID- 26105194 TI - Design, synthesis and evaluation of MCH receptor 1 antagonists--Part III: Discovery of pre-clinical development candidate BI 186908. AB - Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development. PMID- 26105195 TI - Synthesis and biological evaluation of a series of fatty acid amides from Echinacea. AB - Alkylamides are lipophilic constituents of Echinacea and possess numerous biological activities. Although significant effort has been focused on the study of crude Echinacea extracts, very little is known regarding the activities of the individual constituents that make up these herbal treatments. Herein we explore the SAR of simple alkylamides found in Echinacea extracts with respect to their ability to decrease the production of the pro-inflammatory mediator TNF-alpha. Our results have revealed the key structural requirements for activity and provide lead compounds for further investigation of these poorly understood molecules. PMID- 26105196 TI - Sulfonamide bearing pyrazolylpyrazolines as potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII. AB - A series of pyrazolylpyrazolines was designed, synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against cytosolic human (h) isozymes hCA I and hCA II as well as transmembrane tumor associated isozymes, hCA IX and hCA XII. All the tested compounds exhibited an excellent CA activity profile against hCA I, hCA II and hCA XII when compared to the reference drug acetazolamide (AZA). Compounds 6d, 6f and 7a-7f have exhibited better inhibition profile against hCA XII (Ki = 0.47-5.1 nM) as compared with AZA (Ki = 5.7 nM) especially, compounds 6a, 7a, 7c and 7d which were nearly 10-fold better than reference drug. Against hCA II, all of the tested compounds were better than the standard drug especially compounds 6c, 6d, 7c and 7d (Ki = 1.1-1.7 nM) were many fold better inhibitors than AZA (Ki = 12.1 nM). In addition, they acted as selective CA inhibitors of isoform hCA XII over the physiological isoform hCA I. PMID- 26105198 TI - Patent foramen ovale closure following cryptogenic stroke or transient ischaemic attack: Long-term follow-up of 301 cases. AB - Patent foramen ovale has been identified as a conduit for paradoxical embolism resulting in cryptogenic stroke or transient ischemic attack (TIA). We aimed to establish rates of death, recurrent stroke or TIA among patients undergoing PFO closure for stroke or TIA at our unit. A retrospective analysis of all PFO closure patients was performed between May 2004 and January 2013. Follow up was performed by mortality tracing using the Medical Research Information Service of the Office of National Statistics. With regard to stroke or TIA recurrence, written consent forms and questionnaires were mailed with follow up telephone calls. Medical notes and imaging records were consulted where adverse events were noted. 301 patients aged 48.6 +/- 11.0 years, 54.4% male, with >=1 thromboembolic neurovascular event had percutaneous PFO closure with one of eight devices, with successful implantation in 99% of cases. Follow-up duration was 40.2 +/- 26.2 months (range 1.3-105.3); complete in 301 patients for mortality (100%) and 283 patients (94.0%) for neurovascular events. Two patients died during follow-up (respiratory failure n = 1; road traffic accident n = 1). Recurrent stroke (MRI or CT confirmed) was observed in five patients (0.5%; 0.55 per 100 person-years) and TIA in 9 (1.1%; 0.98 per 100 person-years). Atrial fibrillation requiring treatment was documented in 14 patients (1.7%). Percutaneous PFO closure in patients with cryptogenic stroke or TIA is a safe treatment with a low incidence of procedural complications and recurrent neurovascular events. Registry data like these may help to demonstrate the utility of PFO closure in stroke. PMID- 26105197 TI - South African HIV-1 subtype C transmitted variants with a specific V2 motif show higher dependence on alpha4beta7 for replication. AB - BACKGROUND: The integrin alpha4beta7 mediates the trafficking of immune cells to the gut associated lymphoid tissue (GALT) and is an attachment factor for the HIV gp120 envelope glycoprotein. We developed a viral replication inhibition assay to more clearly evaluate the role of alpha4beta7 in HIV infection and the contribution of viral and host factors. RESULTS: Replication of 60 HIV-1 subtype C viruses collected over time from 11 individuals in the CAPRISA cohort were partially inhibited by antibodies targeting alpha4beta7. However, dependence on alpha4beta7 for replication varied substantially among viral isolates from different individuals as well as over time in some individuals. Among 8 transmitted/founder (T/F) viruses, alpha4beta7 reactivity was highest for viruses having P/SDI/V tri-peptide binding motifs. Mutation of T/F viruses that had LDI/L motifs to P/SDI/V resulted in greater alpha4beta7 reactivity, whereas mutating P/SDI/V to LDI/L motifs was associated with reduced alpha4beta7 binding. P/SDI/V motifs were more common among South African HIV subtype C viruses (35%) compared to subtype C viruses from other regions of Africa (<8%) and to other subtypes, due in part to a founder effect. In addition, individuals with bacterial vaginosis (BV) and who had higher concentrations of IL-7, IL-8 and IL-1alpha in the genital tract had T/F viruses with higher alpha4beta7 dependence for replication, suggesting that viruses with P/SDI/V motifs may be preferentially transmitted in the presence of BV in this population. CONCLUSIONS: Collectively, these data suggest a role for alpha4beta7 in HIV infection that is influenced by both viral and host factors including the sequence of the alpha4beta7 binding motif, the cytokine milieu and BV in the genital tract. The higher frequency of P/SDI/V sequences among South African HIV-1 subtype C viruses may have particular significance for the role of alpha4beta7 in this geographical region. PMID- 26105200 TI - Contrast echocardiography for analysis of heart anatomy in tortoises. AB - OBJECTIVE: The cardiac anatomy in tortoises depicted on B-mode and color-Doppler should be better differentiated by additional contrast-echocardiography. MATERIAL AND METHODS: An intravenous contrast agent (INN-sulphur hexafluoride [SonoVue(r)]) was injected in four tortoises (three Testudo hermanni, one Agrionemys horsfieldii), via the coccygeal vein, with parallel B-mode echocardiographic examination. The results of the contrast-enhanced echocardiography were compared with the contrast-free B-mode recordings and color Doppler ultrasound. RESULTS: The use of SonoVue(r) enabled clearer distinction of the cardiac structures, differentiation of the arising major arteries, identification of wash-out-shunts, and visualization of blood flow patterns throughout the tortoise heart. CONCLUSION AND CLINICAL RELEVANCE: This study enables the accurate depiction and differentiation of cardiac anatomy in tortoises through the use of a combination of B-mode, color-Doppler and contrast echocardiography. Basic knowledge of blood flow in the reptile heart is essential to understand echocardiographic anatomy. Blood-flow-patterns and anatomy of the tortoise heart as found in this study will help to establish a basis for further echocardiographic examinations of these animals. PMID- 26105199 TI - Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts. AB - The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. PMID- 26105202 TI - Motivational Factors Predict Weight Loss in Rural Adults. AB - OBJECTIVE: The objective was to: (a) describe the changes over time in motivational factors of weight loss and (b) to examine predictors of weight loss in rural adults enrolled in a weight loss program. DESIGN AND SAMPLE: A longitudinal study was conducted in a convenience sample of 50 adults recruited from a rural Young Men's Christian Association. MEASURES: Questionnaires were completed at baseline (preprogram), 1, 2 and 3 months (end of program). RESULTS: Mean age was 42.4 (SD +/- 11.8); 84% were female and mean BMI was 32.9 (SD +/- 4.3). Individuals lost an average of 12.1 pounds. Barriers to healthy eating decreased significantly over time (p < .001). Significant predictors of weight loss included gender (beta = .501, p < .001), and the amount of change between baseline and 3 months in controlled regulation (beta = .270, p < .05), barriers to healthy eating (beta = -0.225, p < .05), and physical activity (beta = .238, p < .05) explaining 45% of the variance (F[(8, 41] = 5.92, p < .001) in weight loss. CONCLUSIONS: Rural adults were more likely to lose weight if they had higher levels of controlled regulation, if barriers were reduced, and if physical activity levels increased during the 3-month weight loss program. PMID- 26105201 TI - A comparison of resource utilization following chemotherapy for acute myeloid leukemia in children discharged versus children that remain hospitalized during neutropenia. AB - Comparisons of early discharge and outpatient postchemotherapy supportive care in pediatric acute myeloid leukemia (AML) patients are limited. We used data from the Pediatric Health Information System on a cohort of children treated for newly diagnosed AML to compare course-specific mortality and resource utilization in patients who were discharged after chemotherapy to outpatient management during neutropenia relative to patients who remained hospitalized. Patients were categorized at each course as early or standard discharge. Discharges within 3 days after chemotherapy completion were considered "early". Resource utilization was determined based on daily billing data and reported as days of use per 1000 hospital days. Inpatient mortality, occurrence of intensive care unit (ICU)-level care, and duration of hospitalization were compared using logistic, log-binomial and linear regression methods, respectively. Poisson regression with inpatient days as offset was used to compare resource use by discharge status. The study population included 996 patients contributing 2358 treatment courses. Fewer patients were discharged early following Induction I (7%) than subsequent courses (22-24%). Across courses, patients discharged early experienced high readmission rates (69-84%), yet 9-12 fewer inpatient days (all P < 0.001). Inpatient mortality was low across courses and did not differ significantly by discharge status. The overall risk for ICU-level care was 116% higher for early compared to standard discharge patients (adjusted risk ratio: 2.16, 95% confidence interval: 1.50, 3.11). Rates of antibiotic, vasopressor, and supplemental oxygen use were consistently elevated for early discharge patients. Despite similar inpatient mortality to standard discharge patients, early discharge patients may be at greater risk for life-threatening chemotherapy-related complications, including infections. PMID- 26105203 TI - Squamous cell carcinoma originating from cutaneous cysts: The Henry Ford Experience and review of the literature. AB - PURPOSE: Malignant transformation to squamous cell carcinoma (SCC) arising within cutaneous epidermal cysts is a very rare phenomenon. We provide a series of new cases and an overview of the literature. We sought to define the prevalence of and characterize SCC arising within epidermal and pilar cysts. PATIENT AND METHODS: We searched Henry Ford Health System (HFHS) non-melanoma skin cancer (NMSC) registry from 2005 to 2009 to identify cases of SCC arising from epidermal cysts. RESULTS: We identified 1904 cases of epidermal cysts at our institution between 2005 and 2014. Of these, three cases of SCC arose from an epidermal cyst and one case of SCC developed from a pilar cyst. All lesions occurred below the waist with the exception of the pilar cyst on the scalp. CONCLUSIONS: Given the extremely low incidence, propensity of malignant lesions to become symptomatic and efficacy of treatment, we do not recommend routine excision of all epidermal cysts. Instead, we recommend excision and pathology for all symptomatic epidermal cysts, or those that rapidly grow, or do not respond to medical therapy. PMID- 26105205 TI - Biologics and biosimilars. AB - Biological drugs are large, complex glycoprotein molecules produced in living organisms. Revolutionary treatments for many conditions, biologics used in dermatology will face patent expiration, opening opportunities for competitive versions. Biologic drugs are so complex such that it is impossible to reproduce them exactly. Biosimilars are designed to be highly similar, though not identical, to the innovator product. Because biosimilars are not exact replicates of innovator biologics, guidelines have suggested that biosimilars should be considered as unique therapeutic interventions, requiring unique names and physician notification prior to substitution. However, because biologics can never be replicated exactly, even innovator biologics have inherent batch-to batch variability; when the second batch of innovator products were released, physicians began prescribing non-identical variants of biologics to their patients, accepting the possibility of variation in clinical effects. Unlike the variants in innovator products, biosimilars will provide clinical trial data demonstrating similar clinical effects, though there will always be some degree of uncertainty in how much clinical impact will be result from the variation in both innovator and biosimilar products. How biosimilars are approved and how we use biosimilars will need to balance considerations of cost and development time with the possibility of variation in biological response. PMID- 26105204 TI - Meglumine antimoniate is more effective than sodium stibogluconate in the treatment of cutaneous leishmaniasis. AB - Sodium stibogluconate (SSG, Pentostam) and meglumine antimoniate (MA, Glucantime) are two antimonials that are widely used to treat cutaneous leishmaniasis (CL), but the relative efficacies of these treatments are not clear. The aim of this study is to compare the efficacy of intralesional SSG with intralesional MA therapy in the treatment of CL. One month after completion of the therapy, 1431 of 1728 patients (82%) who received intralesional MA showed complete clinical cure compared to 1157 of 1728 patients (67%) in the SSG group. Patients who did not respond to the first round of therapy were re-administered the same treatment but with twice weekly injections. Following completion of the second course of therapy, 237 of 297 patients (80%) in the MA group and 407 of 561 patients (72%) in the SSG group healed their lesions by 1-month post-treatment. At both times, the differences in cure rates between MA and SSG groups were statistically significant (p < 0.05). Cure rates in the MA group were always significantly higher than SSG groups irrespective of other parameters including age, gender, lesion site and type of lesion. Intralesional MA is more effective than intralesional SSG in the treatment of CL. PMID- 26105206 TI - Successful treatment of severe psoriasis with ustekinumab in a 13-year old girl. PMID- 26105208 TI - The Role of Early Language Difficulties in the Trajectories of Conduct Problems Across Childhood. AB - This study uses latent growth curve modelling to contrast the developmental trajectories of conduct problems across childhood for children with early language difficulties (LD) and those with typical language (TL). It also examines whether the presence of early language difficulties moderates the influence of child, parent and peers factors known to be associated with the development of conduct problems. Unconditional and language status conditional latent growth curves of conduct problems were estimated for a nationally representative cohort of children, comprising of 1627 boys (280 LD) and 1609 girls (159 LD) measured at ages 4-5, 6-7, 8-9 and 10-11. Multiple regression tested interaction between language status and predictors of the level and slope of the development of conduct symptoms. On average, children's conduct problems followed a curvilinear decrease. Compared to their TL peers, LD boys and girls had trajectories of conduct problems that had the same shape but with persistently higher levels. Among boys, LD amplified the contributions of parental hostility and SES and protected against the contributions of sociability and maternal psychological distress to a high level of conduct problems. In low SES boys, LD was a vulnerability to a slower rate of decline in conduct problems. Among girls, LD amplified the contributions of low pro-social behaviour to a higher level and sociability to a slower rate of decline of conduct problems while dampening the contribution of peer problems to a higher level of problems. PMID- 26105207 TI - Src family kinases differentially influence glioma growth and motility. AB - Src-family kinase (SFK) signaling impacts multiple tumor-related properties, particularly in the context of the brain tumor glioblastoma. Consequently, the pan-SFK inhibitor dasatinib has emerged as a therapeutic strategy, despite physiologic limitations to its effectiveness in the brain. We investigated the importance of individual SFKs (Src, Fyn, Yes, and Lyn) to glioma tumor biology by knocking down individual SFK expression both in culture (LN229, SF767, GBM8) and orthotopic xenograft (GBM8) contexts. We evaluated the effects of these knockdowns on tumor cell proliferation, migration, and motility-related signaling in culture, as well as overall survival in the orthotopic xenograft model. The four SFKs differed significantly in their importance to these properties. In culture, Src, Fyn, and Yes knockdown generally reduced growth and migration and altered motility-related phosphorylation patterns while Lyn knockdown did so to a lesser extent. However the details of these effects varied significantly depending on the cell line: in no case were conclusions about the role of a particular SFK applicable to all of the measures or all of the cell types examined. In the orthotopic xenograft model, mice implanted with non-target or Src or Fyn knockdown cells showed no differences in survival. In contrast, mice implanted with Yes knockdown cells had longer survival, associated with reduced tumor cell proliferation. Those implanted with Lyn knockdown cells had shorter survival, associated with higher overall tumor burden. Together, our results suggest that Yes signaling directly affects tumor cell biology in a pro tumorigenic manner, while Lyn signaling affects interactions between tumor cells and the microenvironment in an anti-tumor manner. In the context of therapeutic targeting of SFKs, these results suggest that pan-SFK inhibitors may not produce the intended therapeutic benefit when Lyn is present. PMID- 26105210 TI - Erratum to: Observing Interactions between Children and Adolescents and their Parents: The Effects of Anxiety Disorder and Age. PMID- 26105209 TI - Within-Person Changes in Individual Symptoms of Depression Predict Subsequent Depressive Episodes in Adolescents: a Prospective Study. AB - The current longitudinal study examined which individual symptoms of depression uniquely predicted a subsequent Major Depressive Episode (MDE) in adolescents, and whether these relations differed by sex. Adolescents (N = 240) were first interviewed in grade 6 (M = 11.86 years old; SD = 0.56; 54% female; 81.5% Caucasian) and then annually through grade 12 regarding their individual symptoms of depression as well as the occurrence of MDEs. Individual symptoms of depression were assessed with the Children's Depression Rating Scale-Revised (CDRS-R) and depressive episodes were assessed with the Longitudinal Interval Follow-up Evaluation (LIFE). Results showed that within-person changes in sleep problems and low self-esteem/excessive guilt positively predicted an increased likelihood of an MDE for both boys and girls. Significant sex differences also were found. Within-person changes in anhedonia predicted an increased likelihood of a subsequent MDE among boys, whereas irritability predicted a decreased likelihood of a future MDE among boys, and concentration difficulties predicted a decreased likelihood of an MDE in girls. These results identified individual depressive symptoms that predicted subsequent depressive episodes in male and female adolescents, and may be used to guide the early detection, treatment, and prevention of depressive disorders in youth. PMID- 26105211 TI - Risks, severity and timing of infections in patients with multiple myeloma: a longitudinal cohort study in the era of immunomodulatory drug therapy. AB - We defined the epidemiology and clinical predictors of infection in patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), proteasome inhibitors (PI) and autologous haematopoietic stem cell transplant (ASCT) in a large longitudinal cohort study. Clinical and microbiology records of patients with MM diagnosed between January 2008 and December 2012 were reviewed to capture patient demographics, characteristics of myeloma and infections (type, severity, outcomes). Conditional risk set modelling was used to determine clinical predictors of infection. One hundred and ninety-nine patients with MM with 771 episodes of infection were identified. 44.6% of infections were clinically defined, 35.5% were microbiologically defined and 19.9% were fever of unknown focus. There was a bimodal peak in incidence of bacterial (4-6 and 70-72 months) and viral infections (7-9 and 52-54 months) following disease diagnosis. Chemotherapy regimens high-dose melphalan [hazard ratio (HR) = 2.07], intravenous cyclophosphamide (HR = 1.96) and intensive combination systemic chemotherapy (HR = 1.86) and cumulative doses of corticosteroid (HR = 3.06 at highest dose) were independently associated with increased risk of infection overall (P < 0.05). IMiDs and PI and other clinical factors were not independently associated with increased risk of infection. New approaches to prevention and treatment of infection should focus upon identified periods of risk and treatment-related risk factors. PMID- 26105212 TI - Downregulation of Protection of Telomeres 1 expression in myelodysplastic syndromes with 7q deletion. PMID- 26105213 TI - About the RICA registry in patients with heart failure. PMID- 26105214 TI - The electronic properties of mixed valence hydrated europium chloride thin film. AB - We investigate the electronic properties of a model mixed-valence hydrated chloride europium salt by means of high resolution photoemission spectroscopy (HRPES) and resonant photoemission spectroscopy (RESPES) at the Eu 3d -> 4f and 4d -> 4f transitions. From the HRPES spectra, we have determined that the two europium oxidation states are homogeneously distributed in the bulk and that the hydrated salt film is exempt from surface mixed valence transition. From the RESPES spectra, the well separated resonant contributions characteristic of divalent and trivalent europium species (4f(6) and 4f(7) final states, respectively) are accurately extracted and quantitatively determined from the resonant features measured at the two edges. The partial absorption yield spectra, obtained by integrating the photoemission intensity in the valence-band region, can be well reproduced by atomic multiplet calculation at the M(4,5) (3d 4f) absorption edge and by an asymmetric Fano-like shape profile at the N(4,5) (4d-4f) absorption edge. The ratio of Eu(2+) and Eu(3+) species measured at the two absorption edges matches with the composition of the mixed valence europium salt as determined chemically. We have demonstrated that the observed spectroscopic features of the mixed valence salt are attributed to the mixed valence ground state rather than surface valence transition. HRPES and RESPES spectra provide reference spectra for the study of europium salts and their derivatives. PMID- 26105215 TI - Tyranny of distance and rural prehospital care: Is there potential for a national rural responder network? AB - Critical illness intersects with the workload of rural doctors in Australia, mostly via their on-call responsibilities to rural hospitals. A significant proportion of these are prehospital incidents - vehicle crashes, farming injuries, bushfire etc. Effective care for such patients requires an integration of prehospital ambulance services, retrieval services and tertiary level trauma services all the way through to rehabilitation. Ambulance services in rural areas are often volunteer based, and with increasing remoteness via the 'tyranny of distance' comes the likelihood of increased delay in arrival of specialist retrieval services. Potential exists to utilise rural clinicians to respond to prehospital incidents in certain defined circumstances, as suggested by a recent survey of rural doctors. PMID- 26105216 TI - OS001. Pregnancy outcome in subsequent pregnancies after eclampsia. AB - INTRODUCTION: Eclampsia in the previous pregnancy may have impact on future reproductive performance of the women. Few studies have been conducted in recent years to review the subsequent pregnancy outcome. In this study women with previous eclampsia were followed up in subsequent pregnancy and outcome was compared with normotensive control group. OBJECTIVES: To study the risk of recurrence of hypertension and associated complications in subsequent pregnancies following eclampsia. METHODS: Fifty-three pregnant women with previous history of eclampsia were supervised and delivered in PGIMER, Chandigarh, India (2001 April 2011 March) were studied prospectively. The pregnancy outcome was compared with 106 age and gravida matched controls who had remained normotensive in previous pregnancies. The data analysis was done by Chi-square test and Student 't' test. RESULTS: Amongst women with previous eclampsia eight women (15%) were found to have underlying chronic hypertension. The incidence of gestational hypertension and pre-eclampsia was 37.7% amongst these women, compared to 7.5% in control group (p=0.0001). Preterm deliveries mainly due to preterm inductions were higher (32%) amongst women with previous eclampsia compared to 12% amongst controls (p=0.0004). Incidence of intra uterine growth restriction was significantly higher amongst cases (15% vs 1.5%, p=0.0003). CONCLUSION: Women with previous eclampsia have higher incidence of chronic hypertension. These women are at significant risk to develop hypertensive disorders of pregnancy and its related complications. The recurrence of eclampsia is low with aggressive and vigilant antenatal care. PMID- 26105217 TI - OS002. Comparison TNF-alpha level and pathogen periodontal microorganismbetween normal pregnant women, periodontitis pregnant women, and lateonset severe preeclampsia women. AB - INTRODUCTION: Preeclampsia Morbidity and Mortality is still high because of unknown etiology and pathogenesis. One of the theory about pathogenesis of preeclampsia in developing country is infections. Periodontitis is found in 10 60% preeclampsia cases in our center. So we held this research to evaluate the association between preeclampsia, periodontal pathogen, and TNF-alpha level. OBJECTIVES: To compare and analyse the TNF-alpha level and pathogen periodontal microorganism between normal pregnant women, periodontitis pregnant women, and late onset severe preeclampsia women. Furthermore the research want to find any relationship between periodontitis and late onset severe preeclampsia. METHODS: Analytic observational research with cross sectional study design at Soetomo Hospital from November 2010 until February 2011. Thirty patients divided into 3 groups, normal pregnant women, periodontitis pregnant women, and late onset severe preeclampsia women group. All patients were evaluated whether any periodontitis. Periodontal swab were performed and blood samples were taken from all of the patients. TNF-alpha level and pathogen periodontal microorganism were evaluated and analysed. RESULTS: There is a significant difference TNF-alpha level between normal pregnant women, periodontitis pregnant women, and late onset severe preeclampsia p=0.000 (p<0.05). The highest TNF-alpha level is late onset preeclampsia, and the lowest is normal pregnant women. There is a significant difference pathogen periodontal microorganism between normal pregnant women, periodontitis pregnant women, and late onset severe preeclampsia p=0.001 (p<0.05). Porpyromonas ginggivalis is the most pathogen periodontal microorganism found at the samples. There is a significant difference TNF-alpha level between the samples with positive and negative pathogen periodontal microorganism p=0.04 (p<0.05). CONCLUSION: There is a significant difference about the TNF-alpha level and pathogen periodontal microorganism between normal pregnant women, periodontitis pregnant women, and late onset severe preeclampsia. Furthermore the TNF-alpha level between the samples with positive and negative pathogen periodontal microorganism is significantly difference. Maybe periodontitis has association with late onset severe preeclampsia. PMID- 26105218 TI - OS003. The influence of gestational weight gain on the development ofgestational hypertension in obese women. PMID- 26105219 TI - OS004. A link between the complement system and angiogenic imbalance inpreeclampsia: ficolin-2 deficiency. AB - INTRODUCTION: An excessive maternal systemic inflammatory response to pregnancy, as well as an imbalance between circulating angiogenic factors and their antagonists plays a central role in the pathogenesis of preeclampsia. The complement system, as part of innate immunity, is fundamental to the host's immune defense against microbial pathogens, apoptotic and necrotic cells. Both of its excessive activation and deficiencies can lead to various disorders. OBJECTIVES: The aim of this study was to determine circulating levels of components of the complement system and their relationship to those of angiogenic factors in normal pregnancy and preeclampsia. METHODS: Sixty preeclamptic patients, 60 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Circulating levels of C1rC1sC1-inh, C3bBbP, C4d, C3a, SC5b9, ficolin-2, ficolin-3, soluble fms-like tyrosine kinase-1 (sFlt 1) and placental growth factor (PlGF), as well as activity of the complex of mannose-binding lectin and mannose-binding lectin-associated serine protease 2 (MBL-MASP2 complex) were measured. For statistical analyses, non-parametric methods were applied. RESULTS: Circulating levels of C3bBbP, C4d, C3a, SC5b9, sFlt-1, PlGF, as well as MBL-MASP2 activity were significantly higher, while ficolin-2 concentrations were significantly lower in healthy pregnant than in healthy non-pregnant women. Furthermore, preeclamptic patients had significantly higher C1rC1sC1-inh, C3bBbP, C4d, C3a, SC5b9 and sFlt-1 levels and significantly lower ficolin-2, ficolin-3 and PlGF concentrations than healthy pregnant women. In the groups of healthy pregnant women and preeclamptic patients, plasma ficolin 2 levels showed a significant positive correlation with serum PlGF concentrations and a significant inverse correlation with serum levels of sFlt-1. There was no other relationship between complement components and angiogenic factors in either study group. CONCLUSION: Elevated levels of activation products in the systemic circulation indicate complement activation with increased terminal complex formation in preeclampsia, which seems to be independent from alterations in circulating angiogenic factors. Nevertheless, low ficolin-2 concentrations might contribute to the angiogenic imbalance in preeclampsia by impaired removal of the sFlt-1-containing trophoblast-derived material released into the maternal circulation by the hypoxic and oxidatively stressed preeclamptic placenta. PMID- 26105220 TI - OS005. Treatment with magnesium sulphate reduced the serum level of IL-6in preeclamptic women. AB - INTRODUCTION: Preeclampsia is one of the most common complications of pregnancy, affecting 2-7% of pregnant women. To prevent eclampsia from preeclampsia treatment with magnesium sulphate (MgSO4) is widely used. However the action of magnesium sulphate is unknown. OBJECTIVES: Although a RCT compared magnesium supplementation with placebo suggested there is no effect on the incidence of preeclampsia, a study showed treatment with MgSO4 reduced the level of IL-6 secretion in maternal circulation of preeclamptic placenta not fetal side [1]. In addition, a most recent study suggests that treatment with MgSO4 inhibited inflammatory cytokines such as IL-6 secretion induced by LPS [2]. Taken together these data suggest MgSO4 may be able to normalise IL-6 actions and secretion. IL 6 level is elevated in preeclamtic women, therefore in this study we investigated whether maternal MgSO4 treatment inhibit IL-6 secretion in women with preeclampsia. METHODS: Twenty two preeclamptic women and 71 gestation matched health women were included in this study. The definition of preeclampsia is followed by ACOG guideline. The gestation of preeclamptic women in this study was 26-38 weeks. The blood samples of preeclamptic women were taken before and after MgSO4 administration and the serum level of IL-6 was measured by ELISA kit (BD). RESULTS: The serum level of IL-6 in preeclamptic women (24.59pg/ml) was significantly increased before MgSO4 administration compared to gestation matched health pregnant women (11.1pg/ml). However the serum level of IL-6 was significantly reduced after MgSO4 administration (19.8pg/ml), but sill higher than gestation matched health pregnant women. CONCLUSION: Although the mechanism of magnesium sulphate is incompletely understood, our date consist with recent findings and suggest that it may act through the regulation of the level of IL-6 secretion which plays an important role in the pathogenesis of preeclampsia. PMID- 26105221 TI - OS006. Functional expression of endogenous ligands of Toll like receptor4 on monocytes and placentae from women during normal pregnancy andpre-eclampsia. AB - INTRODUCTION: Preeclampsia (PE) is characterized by an exaggerated systemic inflammatory response (ESIR). Several recent studies by our group and others have demonstrated up-regulation of Toll like receptor 4 (TLR4) in trophoblast, placenta and leukocytes in PE but the exact role of TLR4 in the pathogenesis of PE remains unclear. OBJECTIVES: We sought to determine the expression levels of endogenous ligands of TLR4 in plasma and placentas from women with PE vs normotensive pregnant women (NP), and to compare the inflammatory cytokine expression profiles of monocytes from women with PE to NP, in order to identify which of these endogenous ligands of TLR4 may play a functional role in the pathogenesis of PE for further study. METHODS: We recruited 16 PE (gestational age=33.6+/-3.0weeks), 10 normal pregnant (gestational age=31.6+/-3.8weeks) and 10 non-pregnant women. Plasma levels of endogenous TLR4 ligands-heparan sulfate, hyaluronan, fibronectin, fibrinogen and High mobility group box-1(HMGB1)-were measured by ELISA. Monocytes were isolated from peripheral blood, cultured and stimulated by lipopolysaccharide (LPS; TLR4 bacterial ligand) and endogenous TLR4 ligands, and inflammatory cytokines were measured in supernatant medium by cytometric array. Placental tissue from PE and NP were investigated for the different endogenous ligands by immunohistochemistry. RESULTS: Plasma levels of heparan sulfate and fibronectin did not differ between study groups, but HMGB1 was higher in PE (P<0.05) whilst fibrinogen was significantly lower in PE compared to NP (P<0.05). Stimulation of PE monocytes with LPS resulted in profound secretion of various cytokines: IL-6, IL-8, IL-1beta, TNFalpha and IL 10, in comparison with NP. Moreover, exposure to fibrinogen, but not to other endogenous TLR4 ligands, was also associated with significantly increased production of inflammatory cytokines in PE compared to NP. Also, we observed altered distribution levels of studied endogenous ligands in the placenta from PE vs NP. CONCLUSION: Our findings of increased inflammatory cytokine expression levels in PE in response to LPS are consistent with upregulation of TLR4 in PE. A similar response induced by fibrinogen suggests an important role for this endogenous ligand of TLR4 in the pathogenesis of PE. Whether our observation of decreased plasma levels of fibrinogen in PE is linked to this observation, or represents increased fibrinogenesis and fibrinolysis associated with the abnormal coagulopathy seen in this condition, is unclear. PMID- 26105222 TI - OS007. The apoptosis markers are altered in CD4(+)CD25(+)FOXP3(+) T regulatorylymphocytes in pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia (PE) is a common obstetric syndrome affecting about 5 10% of pregnant women. The etiology and pathogenesis of this syndrome are not fully understood. There are many studies describing alterations in the innate and adaptive immune system which may have an influence on the onset of this disorder. It was suggested that the activation of cell-mediated immunity may play the key role in the etiology of pre-eclampsia. It was proposed that inappropriate activation of the immune system can lead to pre-eclampsia. OBJECTIVES: The aim of our study was to estimate the surface expressions of CD95(APO-1/Fas) antigen and the intracellular expressions of anti-apoptotic proteinBcl-2 and pro-apoptotic proteinBax in CD4(+)CD25(+)FoxP3(+) T regulatory lymphocytes (Tregs) as well as the percentage of CD8(+)CD28(+) T cytotoxic cells in peripheral blood of patients with pre-eclampsia in comparison with healthy pregnant women in the third trimester of physiological pregnancy. METHODS: Twenty-four women with pre eclampsia and twenty normal third trimester pregnant women were included in the study. The lymphocytes were isolated from peripheral blood samples and labelled with monoclonal antibodies. The expressions of surface antigens and intracellular proteins were estimated using flow cytometry. RESULTS: The population of CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower in peripheral blood of patients with pre-eclampsia when compared to normal third trimester pregnant women. The percentages of CD4(+)CD25(+)FoxP3(+) Treg cells that express Bcl-2 protein were significantly lower in peripheral blood of patients with pre eclampsia when compared to healthy pregnant women, whereas the percentages of CD4(+)CD25(+)FoxP3(+) Treg cells with the expressions of Bax protein did not differ in both groups. Moreover, the mean fluorescence intensity (MFI) of Bcl-2 protein in CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower and MFI of Bax protein significantly higher in pre-eclampsia when compared to the control group. The percentage of CD8(+)CD28(+) T cells did not differ in both studied groups but MFI of CD28 antigen on T CD8(+) cells was significantly higher in pre eclampsia when compared to the control group. CONCLUSION: The obtained results suggest that the deficit of CD4(+)CD25(+)FoxP3(+) Treg lymphocytes which is observed in pre-eclampsia maybe associated with alterations in apoptosis markers. PMID- 26105223 TI - OS009. Second trimester serum hyperglycosylated human chorionic gonadotrophin and preeclampsia. AB - INTRODUCTION: Hyperglycosylated human chorionic gonadotrophin (hCG-h), produced by the placental trophoblast cells, is involved in placental development in early pregnancy. Decreased second trimester urine hCG-h is associated with later preeclampsia, which may be a sign of impaired trophoblastic invasion preceding symptoms of the disease. OBJECTIVES: To study whether maternal second trimester serum hCG-h concentrations predict later development of preeclampsia. METHODS: Fifty-five women with subsequent preeclampsia, 21 women with gestational hypertension, 30 normotensive women with small-for-gestational-age (SGA) infants and 83 controls with uneventful pregnancies were included in the study. Their serum hCG and hCG-h concentrations were analyzed by fluoroimmunoassay at 14 17weeks of gestation. The proportion of hCG-h of total hCG (%hCG-h) was calculated and converted to multiples of the median (MoMs) of the controls. MoMs of the groups were compared by Mann-Whitney U test. Pearson's correlation was used to analyze correlations between clinical characteristics and serum marker concentrations. The results are given as medians with 95% confidence intervals (95% CI). A two-tailed P<0.05 was considered significant. RESULTS: The concentrations of hCG-h and %hCG-h decreased with advancing gestational weeks in women with subsequent preeclampsia (r=-0.289, p=0.032 and r=-0.464, p<0.001), but not in women in the other groups. There was a tendency towards lower concentrations of hCG-h and %hCG-h in women with subsequent preeclampsia than in controls. The median MoMs of %hCG-h were 0.89 (95% CI,0.79-1.00) in women with subsequent preeclampsia and 1.00 (0.91-1.11) in controls. The corresponding values for women with subsequent gestational hypertension were 1.00 (0.86-1.16), for those with subsequent SGA infants they were 1.09 (0.89-1.23). The difference between preeclampsia and the other groups together was significant (p=0.029). CONCLUSION: Earlier studies suggest that decreased urine hCG-h concentrations reflect changes in placental function that precede the development of preeclampsia. At 14-17weeks of gestation, the serum concentrations of hCG-h showed moderate validity to predict later development of preeclampsia. Further studies on the utility of hCG-h for prediction of subsequent preeclampsia are warranted. PMID- 26105224 TI - OS010. Use of retinal imaging to characterise physiological vascularchanges throughout pregnancy. AB - INTRODUCTION: Visualisation of the microcirculation through retinal imaging can provide information on the health of systemic vasculature. Characterisation of the retinal vasculature throughout pregnancy using retinal imaging is a novel approach to examine physiological changes to the cardiovascular system, and may be useful to predict early pathophysiological signs of adverse maternal outcomes. OBJECTIVES: To characterise the retinal vascular and blood pressure (BP) changes that occur throughout a healthy pregnancy. METHODS: Data was collected from women recruited at 13+/-2 weeks of gestation from Royal Prince Alfred Hospital, a major tertiary referral hospital in Sydney, Australia. Retinal images centred on the optic disc and BP readings were collected throughout pregnancy. Postnatal data was collected from medical records, and women with hypertensive disorders of pregnancy and gestational diabetes mellitus were excluded. This left a final group of 19 women. Retinal images from 13+/-2, 19+/-2, 29+/-2 and 38+/-2 weeks gestation were graded using semi-automated retinal vascular calibre measurement (IVAN) software and the central retinal arteriolar equivalent (CRAE), and central retinal venular equivalent (CRVE). BP data was collected at the same time points as the retinal images. Analysis of data was performed using paired t-tests and repeated measures analysis of variance (ANOVA). Women with missing data points were excluded from the analysis at the relevant time points. RESULTS: Over the course of pregnancy, there was a significant dilatation of retinal arterioles between 13+/-2 and 19+/-2weeks (from 166.4 to 172.7MUm, SE: 3.7MUm, n=19, p=0.01), corresponding to a significant fall in diastolic BP during this time (from 64.6 to 60.2mmHg, SE: 1.5mmHg, p=0.01). No significant changes in venular diameter or systolic BP were noted. Between 19+/-2 and 29+/-2weeks (n=4), no significant changes to retinal arteriolar or venular diameter were seen although there were significant increases in both systolic and diastolic BP (SBP: from 100.3 to 109.9mmHg, SE: 1.9mmHg, p=0.01; DBP: from 59.3 to 64.6mmHg, SE: 6.9mmHg, p=0.01). Between 29+/-2 and 38+/-2weeks (n=3), no significant changes in retinal arteriolar, and venular diameter or BP were observed. CONCLUSION: An increase in retinal arteriolar diameter between 13+/-2 and 19+/-2 weeks gestation was observed, which corresponded to a decrease in both systolic and diastolic BP. However, between 19+/-2 and 29+/-2 weeks there was no change in vasculature, even though there was a significant increase in BP. By characterising the changes to retinal vessels that occur throughout a healthy pregnancy, we can further our understanding of the response of the systemic vasculature to pregnancy, which may provide clues to early vascular disease of pregnancies. PMID- 26105225 TI - OS011. Management of late preterm pregnancy complicated by mildpreeclampsia: A prospective randomized trial. AB - INTRODUCTION: In the absence of properly undertaken prospective randomized clinical trials, the optimal management of late preterm mild preeclampsia for best maternal and perinatal outcomes remains unclear for obstetricians worldwide. OBJECTIVES: We desired to determine if immediate or expectant management of the late preterm mother presenting with mild preeclampsia was more beneficial to her without compromise to her newborn. METHODS: This prospective randomized clinical trial of immediate versus expectant delivery for patients presenting with mild preeclampsia between the late preterm period of 34-0/7 to 36-6/7weeks gestation was undertaken using CONSORT guidelines. Patients were randomized to immediate delivery via induction of labor or cesarean delivery or inpatient expectant management with delivery at 37-0/7weeks gestation or earlier at onset of labor or progression to severe preeclampsia. The primary outcome was progression to severe preeclampsia; secondary outcomes were neonatal morbidity and mortality. Data were analyzed by appropriate tests for continuous or categorical outcomes with differences considered significant if p<0.05. RESULTS: One hundred and sixty nine patients during 2002-2008 satisfied and sustained protocol criteria in the immediate delivery (n=94) or inpatient expectant management (n=75) arms of the study. A third (33%) of expectantly managed patients developed severe preeclampsia during significantly longer hospitalization versus 3% in the immediately delivered patients (p=0.001). Cesarean delivery rates were similar. No significant neonatal morbidity differences were observed between groups; there were no maternal or neonatal deaths. The study was stopped in 2008 at 74% of the enrollment target when hospital policy changed to discourage inpatient hospitalization for uncomplicated mild preterm preeclampsia and in view of growing national concern for increased late preterm/early term neonatal morbidity and cost of care. CONCLUSION: Proceeding to delivery of the late preterm (?34weeks gestation) patient with mild preeclampsia lessens maternal risk without significantly increasing neonatal risk. PMID- 26105226 TI - OS012. Eclampsia with progressing disease correlates to severe diastolicblood pressure. AB - INTRODUCTION: Eclampsia is MRI-radiologically defined as posterior reversible encephalopathy syndrome (PRES), which indicate cases with eclampsia might improve spontaneously and reversibly. On the other hand the central nervous system is the main target organ affected by the disease of severe preeclampsia. Eclampsia is thought to be one of the severe states of this disease. We should recognise some eclamptic cases to grow worse resulting in disastrous stroke or poor prognosis. Especially the symptoms of long lasting unconsciousness or repeating seizures, or the sings with cerebrovascular vasospasms or brain stem lesion are considered as the progressing disease among the disease of eclampsia. We studied what factors among obstetrics features are related to this progressing disease of eclampsia. OBJECTIVES: Thirty six cases with eclampsia were entered in this study. All cases were managed in our hospital from 1995 to 2011. All cases had hypertensive disorders and 23 cases complicated with preeclampsia or superimposed preeclampsia. Four cases were antepartum eclampsia, 12 cases intrapartum and 10 cases postpartum. 20 cases were diagnosed as progressing disease of eclampsia, and 16 cases were no progressing disease. METHODS: As obstetric features, the peak values of hypertension at the onset of eclampsia, the proteinuria severity, the organ involvements such as HELLP syndrome or renal failure, parity and maternal age were studied. The values of systolic blood pressure (sBP) and diastolic blood pressure (dBP) were considered as independent parameters each other in this study. Statistical analysis was performed how these obstetric confounding features were to be correlated with progressing disease of eclampsia by logistic regression analysis (LRA). Univaiate and multivariate LRA were performed using with peak sBP, peak dBP, peak proteinuria, or other features as covariates, and progressive disease as dependent variable. RESULTS: Univariate analysis showed that ?210mmHg of sBP, ?105mmHg of dBP and ?10g/day of proteinuria were related to the progressing disease of eclampsia compared with the no progressing disease. And multivariate analysis showed that ?105mg of dBP had significantly the highest adjusted odds ratio of 10.0 (95%CI 0.96-103, p=0.05). CONCLUSION: We had shown previously CNS disorders such as eclampsia had the strongest correlation with severe sBP ?200mmHg among 108 cases of preeclampsia with severe hypertension and severe proteinuria, whereas other organ involvements such as HELLP syndrome had the strongest correlation with severe dBP ?110mmHg (now not in published, presented in ISSHP 2010). Other studies also strengthen the significance of high sBP in the management of eclampsia [1,2]. Controversially we noticed in this study that the progressing disease of eclampsia significantly related to severe dBP ?105mmHg. This indicates that severe dBP are the important marker as for predicting serious organ involvements either in central nervous system or in other organs in the disease of preeclampsia/eclampsia. PMID- 26105227 TI - OS013. Reduction of preeclampsia related complications with with theNO-donor penterythriltetranitrat (petn) in risk pregnancies - Aprospective randomized double-blind placebo pilot study. AB - INTRODUCTION: NO-donors reduce the impedance in uteroplacental vessels. Consequently Lees et al. pilot study demonstrated that transdermal nitroglycerin positively influences pregnancy outcome within a high-risk collective. Furthermore the NO-donor pentaerythriltetranitrate additionally expresses cell stabilizing effects in endothelial cells. OBJECTIVES: Hypothesizing an effect on endothelial health and uterine perfusion in pregnancies presented with pathological uterine perfusion at 20weeks of gestation we performed a randomized, prospective, and placebo-controlled, double-blind study implemented with the aim to investigate whether the oral NO-donor Pentalong((r)) (PETN) is suitable as a prophylactic drug in abnormal placentation. METHODS: We included 111 pregnancies presenting with abnormal placental perfusion (bilateral notch or mean RI>0.7) between the 19th and 24thweek of gestation (w.o.g.). Further risk factors (high risk group: history of HELLP/preeclampsia/IUGR/IUFD/placental abruption, type I diabetes mellitus, hypertension, thrombosis/thrombophilia) were identified in 78 study participants. Fifty-four women received PETN 57 received placebo. Doppler velocimetry measurements of uteroplacental and fetal vessels and fetal growth scans were monitored biweekly with primary endpoints being the occurrence of preeclampsia, IUGR and/or premature birth. RESULTS: Within the first week of intake, PETN improved uteroplacental perfusion significantly in comparison to placebo (mean PI 1.26+/-0.36 vs. 1.49+/-0.44; p< 0.01). Overall frequency of premature birth <32nd w.o.g.(4 vs. 12), IUGR <10th percentile (15 vs. 29) and preeclampsia (11 vs. 14) were reduced. Although reduction in preeclampsia was comparably low in those 25 patients developing preeclampsia the outcome was markedly improved in the PETN study group by reducing the frequency of IUGR (4 vs. 10), diagnosis of preeclampsia before 32 w.o.g. (3 vs. 7) and premature birth before 32 w.o.g. (1 vs. 6). Furthermore 4 fetal losses occurred in the study group all in the placebo group. CONCLUSION: NO-donors constitute an interesting option in the prophylaxis of adverse pregnancy outcome related to abnormal placentation. PMID- 26105228 TI - OS014. Which first-line drug to control severe hypertension in pregnancy? A pilot study. AB - INTRODUCTION: Severe hypertension is a common complication in pregnancy associated hypertensive disorders and there is no clear consensus on which first line antihypertensive drug to use in this setting. OBJECTIVES: To determine the efficacy and safety of four antihypertensive drugs (two intravenous and two oral) in pregnant women with severe hypertension. METHODS: Pilot prospective randomised study. INCLUSION CRITERIA: pregnant women with a gestational age >24weeks and admitted in the Obstetrics Department with severe hypertension defined as systolic blood pressure (SBP) ?165mmHg and/or diastolic blood pressure (DBP) ?105mmHg. The women were randomised in 4 groups to receive:-20mg intravenous labetalol;-5mg intravenous hydralazine;-10mg oral nifedipine tablets ;-10mg sublingual nifedipine. Treatment was repeated every 20mn until target SBP and DBP were reached (?150/?95mmHg). The primary endpoint was the time needed to achieve effective blood pressure control. Treatment failure was defined as the unability to reach the target BP within one hour. RESULTS: After giving informed consent, 41 pregnant women admitted with severe hypertension were randomised. Mean age was 35 years (SD 3.5), 65% were nulliparous and mean SBP and DBP at admission were 176 (SD 16) and 105 (SD 12)mmHg, respectively. Success to achieve target BP was reached in all patients within the oral 10mg nifedipine group (11 patients), in all but one patients with the 10mg sublingual group (12 patients), and only in 5 out of 9 patients and 6 out of 9 patients within the labetalol and hydralazine groups. They were only one hypotension (defined as SBP <120mmHg) in the two groups with intravenous drugs and 3 and 5 in the oral and sublingual nifedipine groups. CONCLUSION: These results indicate that oral nifedipine seems more effective than intravenous labetalol or hydralazine to reach BP control in pregnant patients with severe hypertension. A large scale randomized trial comparing oral nifedipine versus these commonly used intravenous antihypertensive drugs should be implemented in order to determine whether oral nifedipine is a more effective treatment in this population. PMID- 26105229 TI - OS015. What is the optimal time for delivery in women with gestationalhypertension? AB - INTRODUCTION: There is conflicting evidence regarding the treatment of women with gestational hypertension (GHTN). OBJECTIVES: To assess the optimal timing of delivery for women with GHTN by quantifying the risks of adverse maternal and fetal outcomes associated with ongoing pregnancy and with induction of labor at each gestational week 36-41 completed weeks. METHODS: The Consortium on Safe Labor electronic database from 19 hospitals across the US with 228,668 deliveries 2002-2008 was used to extract data on gravidas with GHTN, diagnosis assigned at delivery admission, using standard definitions. We only considered the first pregnancy to avoid intra-person correlation. Pregnancies complicated by diabetes mellitus, cardiac, pulmonary, or renal disease were excluded. The week-specific rates of maternal and neonatal morbidity/mortality (M/M) were calculated following induction of labor. Maternal outcomes included serious morbidity (composite defined as any of: ICU admission, abruption, large blood loss (>0.5L SVD, >1.0L CS), postpartum HTN) and mortality. Neonatal outcomes included SGA (?10th %tile), serious morbidity (composite defined as any of: seizures, severe respiratory morbidity or 5-min Apgar score ?3) and mortality. Pointwise 95% CI were calculated around each of these gestational age-specific rates. Statistical analyses were performed using FREQ, GLM and LOGISTIC procedures in SAS 9.2. RESULTS: Following induction of labor, the rate of maternal M/M reached a nadir of 89.6 per 1000 live births [95% CI 67.8,111.5], at 38-38 6/7 weeks gestation, while the rate of neonatal M/M fell to 10.5 per 1000 live births [95% CI 2.8,18.2], at 39-39 6/7 weeks. The rate of SGA ?10th 0/00decreased sharply between 36 and 37 weeks from 109.7 [95% CI 69.9,149.5], to 52.0 [95% CI 31.3,72.7]. CONCLUSION: In women with GHTN, induction of labor prior to 38weeks results in greater maternal M/M, but for the neonate induction at 39weeks results in lowest M/M. PMID- 26105230 TI - OS016. Retinal vascular changes in hypertensive disorders of pregnancy. AB - INTRODUCTION: Hypertensive disorders of pregnancy (HDP) are characterised by vascular dysfunction. Retinal vascular imaging is a novel, non-invasive way to characterise early microvascular changes in pregnancy, and as a result has the potential to be used to predict the onset of HDP. OBJECTIVES: To characterise retinal vascular changes that occur in HDP, and compare these changes to those in healthy pregnancies. METHODS: Women were recruited at 13+/-2 weeks of gestation from Royal Prince Alfred Hospital, a major metropolitan tertiary referral hospital in Sydney, Australia. Retinal images centred on the optic disc and blood pressure (BP) readings were collected at 13+/-2, 19+/-2, 29+/-2 and 38+/-2 weeks gestation. Retinal images were graded using semi-automated retinal vascular calibre measurement software (IVAN) and the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were calculated. Within and between subject repeat measures analysis was performed on images from each trimester, using paired t-tests and repeated measures analysis of variance (ANOVA). Multiple linear regressions were used to model the average arteriole diameter adjusted for age, tobacco consumption and body mass index (BMI). All tests were two-sided using a 5% level of significance. A clinical diagnosis of HDP was obtained from postnatal medical record data. Women with missing data points were excluded from the analysis at that time point. RESULTS: Of the 39 women included in the study, 6 (15%) were diagnosed with HDP. In the HDP cohort, repeated measures ANOVA revealed no significant changes in arteriolar or venular diameter measurements throughout pregnancy. Paired t-tests indicated no significant differences in any of the outcome measures between HDP and healthy pregnancies at 13+/-2 (n=36) and 19+/-2 (n=39)weeks. At 29+/-2weeks (n=39), there was a significantly smaller venular diameter in HDP pregnancies (220.4+/-6.9MUm vs 239.1+/- 5.4MUm in healthy pregnancies, p=0.03). At 38+/-2weeks (n=39), arteriolar diameter was significantly smaller in HDP pregnancies (148.6+/-6.0MUm vs 164.1+/-4.6MUm in healthy pregnancies, p=0.04). Similar results persisted following adjustments for cardiovascular risk factors (age, tobacco use and BMI). CONCLUSION: Significant differences in the retinal vasculature develop in HDP as compared to healthy pregnancies. These differences appear at29+/-2weeks gestation and persist throughout the rest of the pregnancy. Retinal vascular imaging is a promising tool for the detection of the early microvascular changes in HDP, prior to diagnosis. PMID- 26105231 TI - OS017. Maternal death risk factor score based on hospital reference pattern and maternal condition of eclamptic woman in Soetomo Hospital, Surabaya, Indonesia. AB - INTRODUCTION: Maternal Mortality Rate in Indonesia is still high, around 230/100,000 live birth in 2005. Eclampsia is the second most cause of maternal death (about 13%). We have a very high prevalence of eclampsia in our center (Surabaya) about 1.08% of all delivery. One of our main problem about eclampsia case is multiple referral hospital system, because we do not have many tertiary center for this case. We assumed that high incidence of maternal death because of eclampsia is caused by this factor. OBJECTIVES: To evaluate relationship between hospital referral system and maternal condition of eclamptic woman with maternal death event and develope scoring system to predict maternal death event on eclamptic woman. METHODS: This is a case control study with retrospective observational analytic design, involve all eclamptic woman whom reffered and admitted to Soetomo hospital (Indonesia) from 1 January 2005 until 31 December 2009. Total eclamptic woman was 160 cases, with 12 maternal death on case group and 148 survive maternal on control group. Research variable includes maternal condition (ages, parity, eclampsia type, complication) and hospital referral pattern (ANC, Magnesium Sulfate, anti-hypertensive drugs, multiple hospital referral, health workers accompanion during patient referral). Primary outcome includes maternal death. RESULTS: There is significant association between multiple hospital referral (RO 6.1, P=0.083), maternal age >35 (RO 17.4, P=0.032), lung oedema (RO 19.1, P=0.065), renal failure (RO 98.8, P=0.002), intra cranial hemorrhage (RO 6319.7, P?0.0001), Eclampsia type (RO 0.009), on eclamptic women with maternal death. No significant association between parity (RO 0.3 P=0.310), HELLP syndrome (RO 2.2 P=0.478), Magnesium Sulfate given before patient reffered (RO 0.7, P=0.685), ANC quantity (RO 0.9 P=0.844), health workers accompanion during referral (RO 0.9, P=0.901), on eclamptic women with maternal death event. CONCLUSION: There are 6 significant variable includes Maternal complication (ICH, renal failure, lung oedema), Maternal ages >35 years, antihypertensive drugs, multiple hospital referral, multiparity, and eclampsia type that can be made a scoring system. We develop scoring system based on risk factor that can be used to predict maternal death event on eclamptic woman. PMID- 26105232 TI - OS018. Maternal mortality and its mainly possible causepre-eclampsia/eclampsia in developing country (Surabaya-Indonesia as themodel). AB - INTRODUCTION: By slow decrease of Indonesia's 2010 highly maternal mortality rate (MMR) as 228/100,000 births mostly estimated to be out reach toward 2014 MDG target achievement of 118/100,000 births, even maternal deaths are notoriously under reported, possibly at least by as much as quarter. The population of Indonesia according to the 2010 national census is 237.6 million, with 58% living on the island of Java, the world's most populous island since it is only 6% of Indonesia total area. Despite risk approaching strategy and referral method in Indonesia national health system had already been formed but the application has not been optimal yet so that its achievement is still far from destination. OBJECTIVES: To study the correlationship between maternal mortality rate and its mainly possible cause pre-eclampsia/eclampsia METHODS: Retrospectively study was performed by using data Dr. Soetomo teaching hospital Surabaya and local government of East Java. RESULTS: Before the year 2008 the maternal deaths on our hospital Dr. Soetomo Surabaya was depicted very high as approximate 713/100,000 births (range 5.05-10.24 per 100,000 births) or 105 maternal deaths among 14,712 births. Pre-eclampsia/eclampsia was the most possible cause rate of 50-65%. Although at present tend to be improved situation but the year 2008 classic data indicated bad referral system application of severe pre-eclampsia and eclampsia cases that they came lately into our teaching hospital's intensive care unit with approximately 12.6% major complications consist of 50% lung oedema and the remain with placental abruption and cerebral bleeding. In more detailed description of maternal deaths as 29% died on the day 1 of intensive care unit treatment that some cases were death on arrival, 35% on the day 1-3 and >day 3 showed 36% of deaths. Even 40% our preeclampsia/eclampsia dominated ventilator use in hospital ICU due to >60% lung oedema that almost those 70% persist until 3 days (72h) in respiratory machine use. Our Dr. Soetomo hospital Surabaya as the tertiary hospital and referral center as well we observed 210 cases of severely pre eclampsia which divided into 40 cases of early onset and late onset type as 170 cases by the year 2010. Mainly the characteristic features in early onset type as follow 70% they were reproductive ages (20-35 years old), 60% was 24-32 gestational weeks, 12.5% got complication of Hellp syndrome, 25% with low albumin serum level (<3g%) and had renal failure as 40%. CONCLUSION: Despite Indonesia MMR apparently declined over last two decades but it did not slump as expected even it failed to achieve the 2014 MDG's target. PMID- 26105233 TI - OS019. External validation of the fullPIERS model in an existing dataset of women with severe pre-eclampsia, eclampsia or HELLP syndrome. PMID- 26105234 TI - OS020. Effects of exercise on maternal and neonatal outcomes in pregnantwomen with chronic hypertension and/or previous preecampsia: A randomized clinical trial. AB - INTRODUCTION: Chronic hypertension (CH) and previous preeclampsia (PE) are considered risk factors for developing PE. Physical activity (PA) has been proposed as an important part of hypertension's treatment and has been studied as a possibility for the prevention of PE and its complications.PA is recommended during pregnancy because it may be beneficial to maternal health.Furthermore, it is considered a safe activity for the mother and fetus. OBJECTIVES: The objective of this study was to assess the association between exercise in pregnant women with CH and/or previous PE and type of delivery, maternal and neonatal outcomes. METHODS: Randomized clinical trial performed between January, 2008 and November, 2011, at the Women's Hospital Dr.Jose Aristodemo Pinotti-CAISM/Unicamp, Brazil, enrolled 116 pregnant women presenting CH, previous PE or both factors associated.Women from 12 to 20 gestational weeks were selected from the prenatal outpatient clinic and randomly allocated to the study (SG) or non-interventional group (NIG). Women at the SG performed physical exercise using stationary bicycle (horizontal bench model) during 30min, once a week, under physical therapist supervision.The HR was maintained at 20% above resting heart rate and up to 140 beats per minute.The NIG followed regular prenatal routine.After birth the data related to type of delivery, maternal and neonatal outcomes were collected from medical records and analyzed comparing groups.The statistical analyzes was performed by Chi-square test and Fisher'sexact test.The program was SAS 9.1 version.Significance was assumed as p<0.5%. RESULTS: We had 6 drop-outs and 7 that did not deliver at our hospital and we could not retrieve the data.A total of 103 pregnant women were analyzed (53 in the SG and 50 in the NIG). The mean age was 31.4+/-5.9 and mean of Body Mass Index (BMI) was 34.9+/ 7.9kg/m(2).Considering the sociodemographic and clinical characteristics the SG and NIG were similar and homogeneous.The average exercise sessions conducted by the SG was 10.11 sessions.The cesarean rate was 69.9% in this study, and the most prevalent indication was cephalopelvic disproportion with 34.3%.However, no statistical differences was observed between groups on type of delivery (p= 0.1901), indications for cesarean delivery and maternal outcomes, including maternal morbidity, rate of PE events and admission in the Intensive Unit Care (ICU). The neonatal outcomes were no significant differences:newborn weigh (p=0.69), adequacy for gestational age (p=0.40), gestational age by recent ultrasound (p=0.20), Apgar 1 min scores (p=0.12), Apgar 5 min score (p=0.24), admission to the ICU (p=0.95) and neonatal morbidity (p=0.39). CONCLUSION: Exercise using stationary bicycle in pregnant women of high risk for PE (CH and/or previous PE) performed once a week, under physical therapist supervision does not seem to interfere in the type of delivery or maternal and neonatal outcomes. This study suggests that exercise with controlled intensity is safe, with no additional harm towards newborn health and with possible benefits to women's future health. PMID- 26105235 TI - OS021. Risk factors and outcomes of maternal obesity and excessive weight gain during pregnancy. AB - INTRODUCTION: The prevalence of overweight and obesity among women of reproductive age is increasing. Maternal obesity seems to be associated with short-term and long-term adverse outcomes. Excessive gestational weight gain might also influence the risk of adverse pregnancy outcomes. Not much is known about risk factors of maternal obesity and excessive gestational weight gain. Also, little is known about critical periods of gestational weight gain in relation to adverse pregnancy outcomes. OBJECTIVES: We aimed to determine risk factors and maternal, fetal and childhood consequences of maternal obesity and excessive gestational weight gain. Furthermore, we examined the associations of trimester-specific weight gain with the risk of adverse pregnancy outcomes. METHODS: The study was embedded in a population-based prospective cohort study among 6959 mothers and their children. Maternal anthropometrics were measured in each trimester of pregnancy. Information about maternal weight just before pregnancy, maximum weight during pregnancy and potential socio-demographic and lifestyle related determinants was obtained from questionnaire. Information about gestational hypertensive disorders and birth outcomes was obtained from medical records. Multivariate linear and logistic regression analyses were used. RESULTS: Maternal lower educational level, lower household income, multiparity, and FTO risk allel were associated with an increased risk of maternal obesity, whereas maternal European ethnicity, nulliparity, higher total energy intake, and smoking during pregnancy were associated with an increased risk of excessive gestational weight gain (all p-values <0.05). As compared to normal weight, maternal obesity was associated with increased risks of gestational hypertension (OR 6.31 (95% CI 4.30,9.26)), preeclampsia (OR (3.61 (95% CI 2.04,6.39)), gestational diabetes (OR 6.28 (95%CI 3.01,13.06)), caesarean delivery (OR 1.91 (95% CI 1.46,2.50)), delivering large size for gestational age infants (OR 2.97 (95% CI 2.16,4.08)), and childhood obesity (OR 5.02 (95% CI:2.97,8.45)). Weaker associations of excessive gestational weight gain with these outcomes were observed, with the strongest effects for first trimester weight gain. Weight gain in first and third trimester was associated with the risk of gestational hypertension (OR 1.24 (95% CI 1.12,1.39) and OR 1.27 (95% CI 1.06,1.51) per standard deviation of change in gestational weight gain per week, respectively), whereas weight gain in third trimester was associated with the risk of preeclampsia (OR 1.35 (95% CI 1.08,1.69), per standard deviation of change in gestational weight gain per week). CONCLUSION: Our study shows that maternal obesity and excessive weight gain during pregnancy are associated with socio-demographic, lifestyle, and genetic factors and with increased risks of adverse maternal, fetal and childhood health outcomes. As compared to prepregnancy overweight and obesity, excessive gestational weight gain has a limited influence on adverse pregnancy outcomes. PMID- 26105236 TI - OS022. Global use of ultrasound for maternal mortality reduction incountries with high maternal mortality ratios. AB - INTRODUCTION: Over a decade ago, the World Health Organization identified ultrasound as a low cost, portable technology and advocated for widespread teaching and application. Outcome data related to the use of ultrasound, however, is limited in low income countries. OBJECTIVES: We evaluated the global use of obstetric ultrasound for management of hypertensive disorders in pregnancies in countries with high maternal mortality ratios (MMR). METHODS: We performed a systematic review of the English language literature through PubMed, Global Health, CINAHL (Nursing and Allied Health) and Google Scholar, databases. We searched the terms "ultrasound", "obstetrics", "pregnancy", "maternal services", "extrauterine pregnancy", "embryo implantation", pregnancy toxemia", "eclampsia", and "pregnancy complications" to identify all published papers from 2000 to 2011. These terms were cross referenced with "Africa, Asia, Latin America, and the Caribbean". The maternal mortality report of 2005 from WHO, UNICEF, UNFPA and World Bank was used to identify all countries with MMR of ?100/100,000 live births. We systematically reviewed papers that described the use of obstetric ultrasound. We categorized usage into groups based on maternal mortality reduction, prenatal diagnosis/anomaly detection and ultrasound practice patterns. RESULTS: We identified 85 articles meeting the search criteria. The most commonly described obstetric categories included nomogram development, policy issues/social impact of ultrasound, and anomaly detection (Table 1). Six papers in the literature described maternal/perinatal outcomes, however, none described ultrasound use in the management of hypertensive diseases in pregnancy. CONCLUSION: Hypertensive diseases in pregnancy remain leading causes of maternal mortality worldwide. Few studies in the world's literature address the use of obstetric ultrasound for maternal and perinatal mortality reduction in high MMR regions. Further research and publications are needed in this area. PMID- 26105237 TI - OS023. Postpartum cardiovascular disease risk factors in women with ahistory of early onset preeclampsia, late onset preeclampsia and pregnancy induced hypertension. AB - INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in women. Epidemiological studies have shown an increased risk of a CVD event in women who have had a hypertensive disorder in one of their previous pregnancies. These data also suggest that these increased risks are associated with severity and time of onset of pre-eclampsia. Risk factors for CVD have not yet been compared between women who experienced early versus late and mild versus severe hypertensive disorders of pregnancy. OBJECTIVES: In this study we compared classic CVD risk factors of postpartum women with previous early-onset preeclampsia (EOPE), late onset pre-eclampsia (LOPE) and pregnancy induced hypertension (PIH). METHODS: A total of 81 women with previous EOPE (delivery required ?34weeks), 76 with LOPE (delivery ?36weeks) and 229 with PIH were included along with 79 healthy controls. Statistical analyses were performed using generalized linear models in PASW statistics 17.0, SPSS Inc. RESULTS: Adjusted means of blood pressure, fasting plasma glucose levels and LDL levels were significantly increased after all hypertensive disorders of pregnancy compared to controls. This increase of CVD risk factors was significantly correlated with severity and time of onset of the disease (Table 1). The prevalence of metabolic syndrome (BMI>30kg/m(2) and ?2 of the following; triglycerides ?150mg/dl, HDL cholesterol ?50mg/dl, systolic blood pressure ?130 or diastolic blood pressure ?85 and fasting plasma glucose levels ?100mg/dl) did not differ between the study groups; women who had PIH had the highest number of components of the metabolic syndrome (). CONCLUSION: These results further establish the predisposition to CVD in women with previous pre-eclampsia or PIH. EOPE is associated with a more pronounced CVD risk factor profile than LOPE or PIH, which may explain the previously described higher CVD event risk. PMID- 26105238 TI - OS024. Characteristics and outcomes of critically ill obstetric patientswith hypertensive disease of pregnancy in argentina: Multicenter study. AB - INTRODUCTION: Worldwide, hypertensive disease of pregnancy is one of the most frequent causes of admission of obstetric patients to the ICU. Maternal mortality risk related to Hypertension during pregnancy in Latin America is significantly higher than in developed countries. OBJECTIVES: To describe the characteristics and outcomes of pregnant-postpartum patients with hypertensive disease of pregnancy admitted to ICU METHODS: DESIGN: Multicenter case series study. POPULATION: pregnant-postpartum (<42days) patients with hypertensive disease of pregnancy admitted to ICU. SETTING: 3 ICUs in Argentina, 2 from the Public (P1) and 1 from the Private Health Sector (P2). STATISTICS: Continuous data are presented as mean+/-SD or median [IQR], and categorical data as number (%). Comparisons among continuous data were performed with unpaired t test or Mann Whitney U test. Categorical variables were analyzed by Chi-square test or Fisher exact test as appropriate. A two-sided alpha<0.05 was considered as significant. SPSS version 15 was used. RESULTS: One hundred and eighty four patients were included, 161(87.5%) from P1. General characteristics are shown in the Table. Gestational age was 34+/-5 weeks. Risk factors for preeclampsia not included in Charlson score were chronic hypertension (22;12%), Obesity (6;3%) and preeclampsia in previous pregnancy (5;3%). ICU admission was postpartum in 80%(145). Causes of admission were eclampsia (63;34%), severe preeclampsia (61;33%), HELLP (33;18%), Eclampsia-HELLP (18;10%), Chronic Hypertension (5;3%) and Gestational Hypertension (4;2%). Predictive mortality according with APACHEII was 14%. Antenatal care was present in 115/142(81%) patients; 97/124(78%) in P1 vs 18/18 (100%) in P2; p0.024. Antenatal care was appropriate in 77/108(71.3%) of patients; 59/90(65.5%) in P1 vs 18/18(100%) in P2; p0.001. Maternal deaths (6) occurred in the Public sector and none of the patients had received antenatal care. Causes of mortality were hemorrhagic stroke (3) and multiple organ dysfunction (3) Table 1. CONCLUSION: Most patients were from the public health sector and the majority did not have any comorbidity according with the Charlson score. Nevertheless, 18% presented risk factors for preeclampsia, not included in the mentioned score. Two-thirds of patients were admitted with eclampsia and severe preeclampsia. APACHEII overpredicted mortality. Half of deaths were related with hemorrhagic stroke, complication almost eradicated from developed countries. None of the patients who died had received antenatal care. PMID- 26105239 TI - OS025. Placental malaria infection as a risk factor for hypertensivedisorders of pregnancy in malaria endemic regions: A systematic review and meta-analysis. AB - INTRODUCTION: Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal mortality in low and middle income countries (LMICs). HDP complicates pregnancy in many malarial endemic areas with the greatest burden in sub-saharan Africa. It has been suggested that there is a link between placental malaria infection (PMI) caused by Plasmodium falciparum and HDP. To our knowledge, a systematic review has never been conducted on the relationship between PMI and HDP and the modification of that relationship with parity. OBJECTIVES: 1. To critically assess the association between PMI and HDP among a general obstetrical population in malarial endemic regions 2. To evaluate if the relationship between PMI and HDP is modified by parity. METHODS: We conducted a systematic review for any study reporting on placental malaria and hypertension. A literature search based on a prospectively prepared protocol was conducted in PubMed Central and EMBASE until 06/09/2011. Additional data on parity of study participants in each study group was requested from corresponding authors of included studies by personal contact through email. Studies were assessed using the Newcastle-Ottawa Scale. The Cochrane Revman 5.1 software was used for statistical analysis according to standardised methodology. Risk Ratios with 95% confidence interval were calculated. RESULTS: Seven studies met our inclusion criteria [1-7]. These included cross-sectional, case control and observational studies. Six were in English and one was translated internally from French. One study [2] was further excluded because it did not represent a general obstetrical population. Our meta analysis found no association between PMI and HDP in a general obstetric population in malaria endemic areas [RR of 1.00, 95% CI of 0.82,1.23]. Furthermore, we did not find that this relationship was modified by parity in two studies [RR (nulliparous) 0.92, 95% CI of 0.26,3.25)]. Events=women with HDP (). CONCLUSION: Although trends and associations have been reported in individual studies, we did not find a significant association between PMI and the risk of HDP. There is an apparent need for a large prospective cohort study to be conducted on PMI and the possible association with HDP. PMID- 26105240 TI - OS026. Study of neuroradiological and biochemical abnormalities in 100 women with preeclampsia-eclapmsia. AB - INTRODUCTION: The posterior reversible encephalopathy syndrome-PRES is recognised as the neuro radiologic abnormality in Eclampsia and with prompt treatment and delivery is usually reversible. OBJECTIVES: To study neuro radiological and biochemical abnormalities in severe preeclampsia and eclampsia and their reversibility following delivery. METHODS: 100 Women with severe pre-eclampsia and eclampsia admitted to High risk unit at Gandhi Hospital, Secunderabad were studied between September 2008 and September 2010. Preeclamptic women who presented with complications of pre eclampsia were included. Patients with convulsions in the absence of proteinuria and hypertension such as epileptics and other central nervous disorders and known intracranial pathology were excluded . All the women were investigated for laboratory parameters such as renal function tests, platelet counts, liver function tests, coagulation profile, fundoscopy, in antepartum period and abnormal results were re-evaluated one week after delivery and in cases with persistent abnormal results at one week postpartum were again evaluated at the end of two weeks. Fifty women with eclampsia among the study group underwent MR imaging of brain before delivery and thirty of these women who showed PRES underwent MR imaging postpartum. The different types images used are (i) T1 weighted image (ii) T2 weighted image - highly sensitive (iii) Flair image (iv) Diffusion Weighted image (DW) with Apparent Diffusion Co-efficient (ADC). MRI studies were performed in axial, coronal and sagittal axes in varying thickness of 5-10mm. The machine used was 1.5 Tesla Aves Siemens. The biochemical parameters and results of neuro imaging were studied antepartum and postpartum. RESULTS: Thirty six out of 50 women showed abnormal MRI findings. In 30 women (83%) findings were consistent with PRES. 3 cases (8%) showed infarction, 1 case showed CSVT , 1 cerebral hemorrhage and 1 showed glioma undiagnosed in antenatal period . Out of 30 cases of PRES, 18(77%) cases showed reversal within 1 week postpartum, and 9(33%) cases within 2 weeks postpartum. 80-90% of the abnormal laboratory parameters reversed to normal within 1 week post partum. Abnormal persistent parameters reversed to normal in all cases at the end of 2 weeks. CONCLUSION: Posterior Reversible Encephalopathy Syndrome (PRES) is a new clinico radiological entity resulting from vasogenic edema in almost all cases of eclampsia but rare with preeclampsia. In fact eclampsia may be considered as clinical manifestation of PRES. Though MRI brain is a valuable diagnostic tool in evaluation of eclampsia it is expensive, and less available. Repeat MRI investigations may not be necessary, as almost all cases of PRES are reversible. MRI brain in cases of eclampsia also help to identify rare pathologies in the brain other than PRES, wrongly attributed to eclampsia Though preeclampsia and eclampsia are reversible, duration required for reversal is 1-2week period, during which period pathology is resolving but not recovered completely and complications can still occur. Hence, close observation is required in the first 1-2week postpartum. PMID- 26105241 TI - OS027. Ethnicity and adverse pregnancy outcomes: A cohort study. AB - INTRODUCTION: Women who develop pregnancy complications are more likely to develop cardiovascular disorders later in life. A history of pre-eclampsia (PE) is associated with a four-fold increased risk of hypertension and twice the risk of future ischaemic heart disease and stroke. Early identification of women at risk of developing pregnancy complications is likely to facilitate targeted antenatal surveillance and possibly intervention. Maternal ethnicity affects the risk of developing some of these complications, and so is likely to be an important variable in the risk assessment. OBJECTIVES: The main aim of this study was to quantify the ethnicity-related risk of adverse pregnancy outcomes. METHODS: This was a multicentre cohort study in singleton pregnancies at 11(+0) 13(+6) weeks of gestation. Data on maternal characteristics, medical and obstetric history were collected and pregnancy outcomes ascertained. Racial origin was classified into Caucasian, African, South Asian, East Asian and mixed. The adverse pregnancy outcomes in this study included PE, gestational hypertension (GH), gestational diabetes (GDM), preterm delivery (PTD), small for gestational age (SGA), large for gestational age (LGA), stillbirth, obstetric cholestasis (OC) and emergency Caesarean section (CS). The diagnosis of PE and GH was made according to the guidelines of the International Society for the Study of Hypertension in Pregnancy. The neonate was considered SGA if the birthweight was less than the 5th percentile and LGA if the birthweight was more than the 90th percentile for gestation at delivery. The diagnosis of GDM was made if the fasting plasma glucose level was at least 6mmol/L or the plasma glucose level 2h after oral administration of 75g glucose was 7.8mmol/L or more (WHO). Stillbirth was defined as the death of a fetus before birth after the 24th week of pregnancy. The diagnosis of OC was made when there was pruritus in association with abnormal liver function in the absence of any other identifiable liver pathology which resolved after delivery. Multiple regression analysis was used to examine which maternal characteristics provided a significant contribution in the prediction of these adverse pregnancy outcomes. Crude and adjusted odds ratios (ORs) were derived for each pregnancy outcome. RESULTS: Seventy five thousand and four hundred women were included in the study, of whom 57,564 were Caucasian and 11,395 African. Compared to Caucasian ethnic origin, African women were more likely to develop PE [OR (95% CI): 2.77 (2.49-3.09), p<0.0001], GH [OR 1.38 (1.23 1.56), p<0.0001], SGA [OR 3.48 (3.16-3.83), p<0.0001], stillbirth [OR 2.42 (1.87 3.12), p<0.0001], GDM [OR 1.82 (1.59-2.07), p<0.0001], PTD prior to 37 weeks gestation [OR 1.33 (1.23-1.44), p<0.0001], and emergency CS [OR 2.42 (1.87-3.12), p<0.0001]. On the other hand, African women were less likely to develop LGA and OC [OR (95% CI): 0.63 (0.58-0.67) and 0.47 (0.32-0.69) respectively; p<0.0001 for both]. CONCLUSION: Compared to Caucasian ethnic background, women of African origin have a different risk profile for adverse pregnancy outcomes. This difference should be taken into account when calculating an individualised adjusted risk or when tailoring antenatal care. PMID- 26105242 TI - OS028. Hypertensive disease in pregnancy: An examination of ethnic differences and the Hispanic paradox. AB - INTRODUCTION: The "Hispanic Paradox" refers to the epidemiological finding that Hispanics in the US have better health outcomes than the average population despite what their aggregate socioeconomic determinants would predict. OBJECTIVES: The aim of this study was to evaluate obstetric outcomes for a multiethnic population with hypertensive diseases. METHODS: We performed a retrospective review of parturients with hypertensive disease delivering at Duke University Medical Center in 2005-2007. We analyzed maternal sociodemographic characteristics and ethnic differences in hypertensive disease types using Chi Square. We assessed the role of race and ethnicity on maternal and neonatal outcomes through a series of logistic regression analyses. RESULTS: Nine thousand eight hundred and thirteen women delivered during the study period, and 9% had hypertensive diseases in pregnancy. There were significant racial and ethnic differences in presentation (Chi-square=39.11, p<.001) with gestational hypertension more common in Whites, chronic hypertension in African Americans, and mild preeclampsia in Hispanics. The overall incidence of preeclampsia was lower in Hispanics. However, severe preeclampsia rates were equal across groups. Hispanics were more likely to be uninsured, younger, enter prenatal care later, and least likely to complete high school. There was no significant difference in smoking or parity. Stratified analyses by ethnicity showed that the relationship between severe preeclampsia and comorbidities (IUGR, LBW, ICN admission) were least pronounced in Hispanics and strongest in African American women. CONCLUSION: Despite similar rates of severe preeclampsia and adverse sociodemographic characteristics, Hispanic women with severe preeclampsia had better pregnancy outcomes than African-American or White women with the disease. PMID- 26105243 TI - OS029. Severe anemia, sickle cell disease, and thalassemia as riskfactors for preeclampsia in developing countries. AB - INTRODUCTION: Hypertensive disorders during pregnancy contribute greatly to maternal and perinatal morbidity and mortality in developing countries. The pathogenesis of such conditions may be illuminated by exploring their relationship to anemia. OBJECTIVES: To determine whether several types of anemia are risk factors for hypertensive disorders during pregnancy in developing countries. METHODS: Using data from the World Health Organization Global Survey for Maternal and Perinatal Health, collected in hospitals in six African and six Latin American countries from 2007 to 2008 and in four Asian countries from 2004 to 2005, we examined the associations between severe anemia, sickle cell disease and thalassemia and gestational hypertension or preeclampsia/eclampsia. After exclusions for comorbidities (chronic hypertension, diabetes, HIV infection) and missing data, the severe anemia, sickle cell disease, and thalassemia groups consisted of 219,627,117,383, and 9376 women, respectively. RESULTS: Multiparous women with severe anemia were at an increased risk of gestational hypertension (adjusted odds ratio (OR): 1.58; 95% confidence interval (CI): 1.15-2.19). Severe anemia had a significant association with preeclampsia/eclampsia for nulliparous (OR: 3.55; 95% CI: 2.87-4.41) and multiparous (OR: 3.94; 95% CI: 3.05-5.09) women. Sickle cell disease exhibited a significant association with gestational hypertension among nulliparous (OR: 2.49; 95% CI: 1.46-4.25) and multiparous (OR: 3.27; 95% CI: 2.33-4.58) women. No significant associations were found between sickle cell disease and preeclampsia/eclampsia, or between thalassemia and either gestational hypertension or preeclampsia/eclampsia. CONCLUSION: Severe anemia appears to be a risk factor for preeclampsia/eclampsia, while sickle cell disease appears to be a risk factor for gestational hypertension among women seeking hospital care in developing countries. PMID- 26105244 TI - OS030. Hypertension and labor duration: Does it take longer? AB - INTRODUCTION: Hypertensive disease in pregnancy carries higher maternal and fetal morbidity and mortality and often requires labor induction to minimize risk. It was previously taught that preeclampsia was associated with a more rapid progression through all stages of labor, while there is a paucity of data in other hypertensive categories. One investigation in preeclamptic women demonstrated that labor progress was prolonged with increased risk for cesarean delivery. OBJECTIVES: To study labor progression in induced nulliparas at term with hypertensive diseases in pregnancy. METHODS: Retrospective cohort study using data from the Consortium on Safe Labor; a multicenter project that abstracted labor and delivery information from electronic medical records in 19 hospitals across the US. A total of 32,276 women with singleton term gestation, induced labor, and vertex presentation were studied. Hypertensive women were grouped into 4 separate categories: chronic hypertension (cHTN), gestational hypertension (gHTN), preeclampsia (PreE) and superimposed preeclampsia (SIPreE) and compared to controls (no hypertensive disorder). For the first stage of labor, Interval-censored regression analysis was used to estimate median and 95th% duration of labor, centimeter by centimeter and from 4-10cm. RESULTS: Significant differences were noted in demographics between each group and controls including age, race, labor admission body mass index, gestational age at delivery, comorbidities, and admission cervical dilation (P<0.01 for all comparisons to the control group). As noted in the table, women with cHTN and SIPreE had a longer first stage of labor, gHTN had a shorter first stage of labor, and labor length was similar in PreE compared to controls. Second stage of labor was longer (5-41min) with epidural and varied among groups; however, the clinical significance is limited. 95th% for progression from 4-10cm in cHTN, SIPreE and gHTN were 27.4, 28.2 and 16.5h respectively (controls 20.1h) (). CONCLUSION: In nulliparas induced at term with hypertensive disease, labor progression in the first and second stage varies from controls. gHTN women have the shortest first stage of labor while PreE gravidas have labor patterns similar to controls. As cHTN and SIPreE women have a longer first stage, allowing labor to continue for a longer period in these gravidas may contribute to a reduced rate of cesarean delivery in the US, but will require further investigation. PMID- 26105245 TI - OS031. Lifestyle intervention after complicated pregnancy successfully improves cardiovascular and metabolic health: Results of the pro-active study. AB - INTRODUCTION: Women with a pregnancy complicated by preeclampsia, intra-uterine growth restriction and/or gestational diabetes are at increased risk of future cardiovascular and metabolic disease. Lifestyle intervention may help these women to effectively lower these risks. OBJECTIVES: To test if offering lifestyle intervention after a complicated pregnancy significantly reduces weight (primary objective) and/or other cardiovascular and metabolic risk factors (secondary objective). METHODS: The Pro-Active study (Postpartum Rotterdam Appraisal of Cardiovascular health and Tailored Intervention) is a feasibility study to develop and evaluate a postpartum lifestyle intervention program. In a prospective case-control setting we tested the effect of the lifestyle intervention. Women were included between April 2007 and August 2009. They were eligible if ?18 years old at time of inclusion, being able to understand and speak the Dutch language and not having pre-existing conditions that could interfere with the lifestyle intervention. Cases were offered lifestyle intervention by a trained counsellor between 6 and 10 months postpartum. During 3 private sessions, mainly exercise and fat-intake and to some extend smoking habits were discussed and aims were made to improve lifestyle. Controls did not receive these sessions, but were not restricted to improve lifestyle on their own. Anthropometric and laboratory measurements were taken at 6 and 10 months postpartum and again at 13 months postpartum to test for durability of the effects. RESULTS: During our study 1121 women gave birth after a complicated pregnancy. Four hundred and ninety Women were eligible for the study of which 240 women (49%) gave informed consent to participate. 56 Women (23%) were lost-to follow-up, leaving 186 women for the analysis. Between 6 and 13 months postpartum weight was significantly reduced in cases compared to controls by 2.1kg (95%>CI 0.4-3.7), resulting in a 0.7kg/m(2) (0.1-1.3) lower BMI. Also systolic blood pressure (5.0mmHg(0.3-9.7)), waist circumference (4.6cm(2.6-6.6)) and waist-to hip ratio (0.03(0.01-0.04)) were significantly improved in cases compared to controls. Heart rate, hip circumference and total cholesterol were significantly improved within cases, but not compared to controls. Diastolic blood pressure and fasting glucose were not improved. CONCLUSION: Lifestyle intervention after complicated pregnancy may be effective in lowering weight and improving other cardiovascular and metabolic risk factors. It suggests that now is prudent and justified to start a large-scale randomised controlled trial to validate our results. PMID- 26105246 TI - OS032. Pharmacotherapy for pre-eclampsia in low and middle income countries: An analysis of essential medicines lists (EMLS). AB - INTRODUCTION: Pre-eclampsia is the second leading cause of maternal mortality in low and middle income countries (LMIC). Pharmacological management of pre eclampsia has five major components including antihypertensive therapy for severe and non-severe hypertension, magnesium sulphate for prevention or treatment of eclampsia, treatment of pre-eclampsia-related end-organ complications, antenatal corticosteroids for acceleration of fetal pulmonary maturity given iatrogenic preterm delivery for maternal and/or fetal indications, and labour induction for such indicated deliveries. Essential medicines are defined by the World Health Organization (WHO) as "drugs that satisfy the health care needs of the majority of the population". Essential Medicines Lists (EMLs) detail these essential medicines within an individual country and support the argument that the medication should be routinely available. OBJECTIVES: To determine how many drugs required for comprehensive pre-eclampsia management are listed in national EMLs of LMIC. METHODS: We conducted a descriptive analysis of relevant drug prevalence on identified EMLs. We searched for the national EMLs of the 144 LMIC identified by the World Bank. EMLs were collected by broad based internet searches and in collaboration with the WHO. The EMLs were surveyed for therapies for the different aspects of pre-eclampsia management: hypertension (non-severe and severe with oral or parenteral agents), eclampsia, pre-eclampsia complications (e.g., pulmonary oedema, thrombosis), preterm birth, and labour induction. RESULTS: EMLs were located and reviewed for 58(40.3%) of LMIC. One or more parenteral antihypertensive agents were listed in 51(87.9%) EMLs. The most common agents were: hydralazine (67.2%), verapamil (58.6%), propranolol (39.7%) and sodium nitroprusside (37.9%); parenteral labetalol was listed by only 19.0% of EMLs. The most prevalent oral antihypertensive therapies listed were: nifedipine (96.6%, usually 10 or 20mg intermediate-acting tablets), methyldopa (94.8%), propranolol (89.7%), and atenolol (87.9%). Captopril, enalapril, hydrochlorothiazide and spironolactone were commonly listed. Magnesium sulphate for prevention and management of eclampsia was present in 86.2% of EMLs (and its antidote, calcium gluconate in 82.8%). To manage complications of pre-eclampsia, oral frusemide was listed in 94.8% of EMLs and parenteral heparin in 91.4%. Most EMLs listed parenteral dexamethasone (91.4%) for acceleration of fetal pulmonary maturity and oxytocin (98.3%) or a prostanoid (usually misoprostol, 39.7%) for labour induction. CONCLUSION: EMLs of LMIC provide comprehensive coverage of all aspects of recommended pre-eclampsia pharmacotherapy. These EMLs may be used as advocacy tools to ensure the availability of these therapies within each country. PMID- 26105247 TI - OS033. Correlates of maternal health outcomes associated with a low costintervention in secondary facilities across Kano state, Nigeria. AB - INTRODUCTION: Nigeria has one of the highest rates of maternal mortality in the world. Eclampsia is a major contributor to the deaths especially in Northern Nigeria where the culture of teenage marriage is common. Kano is the state with the highest population in Nigeria. Despite its effectiveness, magnesium sulphate was been used to treat eclampsia and severe preclampsia in only one of 35 general hospitals inthe state as at 2007. OBJECTIVES: In 2008, magnesium sulphate was introduced in 10 General Hospitals in Kano state of Northern Nigeria in a Population Council project funded by the MacArthur Foundation. The aim of the study was to determine if the maternal outcomes improved. METHODS: Doctors and midwives from the 10 hospitals were trained on the use of magnesium sulphate. The trained health workers later conducted step down trainings at their health facilities. Magnesium sulphate, treatment protocol, patella hammer and calcium gluconate were then supplied to the hospitals. Data was collected through structured data forms. The data was analysed using SPSS. RESULTS: Within a year of the project, 1045 patients with severe preeclampsia and eclampsia were treated. The case fatality rate for severe preeclampsia and eclampsia fell from 20.9% (95% CI 18.7-23.2) recorded before the project to 2.3% (95%CI 1.5-3.5) after the project. The perinatal mortality rate in those that received magnesium sulphate was 12.3% (CI 10.4-14.5) while the 5min APGAR score for 72.9% of the babies was 7 or more. CONCLUSION: Training of health workers on updated evidence based interventions and providing an enabling environment for their practice are key components to the attainment of the Millennium Development Goals in developing countries. PMID- 26105248 TI - OS034. Magnesium sulfate for prevention of eclampsia: Are intramuscularand intravenous regimens equivalent? AB - INTRODUCTION: Magnesium sulfate is the agent of choice for the treatment and prevention of eclampsia. Optimal loading and maintenance dosing has not been determined. OBJECTIVES: To compare the pharmacokinetic parameters if IM vs. IV magnesium sulfate. METHODS: A pharmacokinetic study was performed as part of a randomized trial that enrolled 300 women comparing IM and IV regimens of magnesium dosing in two low resource sites in India. Data from 258 enrolled women were analyzed in the pharmacokinetic study. Due to infrastructure available at the sites, a single sample was drawn per subject with the expectation of utilizing samples in a pooled data analysis. RESULTS: Magnesium clearance was estimated via pharmacokinetic modeling to be 48.1dL/h, volume of distribution 156dL and IM bioavailability 86.2%. The IM regimen produced higher initial serum concentrations, consistent with a substantially larger loading dose. At steady state, Mg concentrations in the IM and IV Groups were comparable. With either regimen, a substantial number of subjects would be expected to have serum concentrations lower than those generally expected to be therapeutic. CONCLUSION: A larger loading dose for the IV regimen should be considered. Where feasible, individualized higher doses of magnesium sulfate would yield a greater number of treated women with clinically effective magnesium concentrations. PMID- 26105249 TI - OS035. Blood pressure measurement by health professionals, comparison with American Heart Association Technique. AB - INTRODUCTION: It seems measurement of the blood pressure is always easy, although it is important and should be done by applying standard method. Even a few mistake can make difference between being prescribed medication or having the blood pressure monitored. OBJECTIVES: To compare the rate and accuracy of measuring blood pressure. METHODS: In this clinical trail study five hundred health professional consist of 179 nurses, 58 physicians, 99 medical and 118 nursing students and 46 association nurses were studied in 10 hospitals (3th of them were mother and child health centers) and health centers and five nursing and medical instructions when working with their students observed them. Two questioners were use for the data, demographic information and American Heart Association Standard questioner. RESULTS: The mean systolic-diastolic blood pressure for research samples in this study was 126+/-20.82/78.55+/-12.70mmHg and for the researcher's measurement was 120.15+/-20.56/72.08+/-12.24. The differences were-5.85mmHg for systolic and -6.47mmHg for diastolic BP. The most change of blood pressure before and after taking blood pressure were about pregnant women.Nurses and nursing students aided by 63% of the recommended procedures for taking blood pressure and other health professionals done by approximately 40%. CONCLUSION: Results indicated that health professional failed comply with the BP measurement guidelines, this may lead to a wrong diagnose. The importance of performing certain variables should be taken into account when teaching and assessing students in the future. Because hypertension is one of the leading causes of cardiovascular morbidity and mortality, the simple and accurate measurement of BP can be life saving. PMID- 26105250 TI - OS036. Ethnic differences in blood pressure and hypertensivecomplications during pregnancy; the generation R Study. AB - INTRODUCTION: Blood pressure levels during pregnancy are important risk factors for gestational hypertensive disorders. Non-pregnant women from ethnic minority groups are found to have higher blood pressure levels compared to white women. Little is known about variation in blood pressure development during pregnancy across different ethnic groups. OBJECTIVES: To investigate ethnic differences in blood pressure levels in each trimester of pregnancy and the risk of gestational hypertensive disorders and the degree to which such differences can be explained by education and lifestyle related factors. METHODS: The study included 6215 women participating in a population-based prospective cohort study from early pregnancy onwards in Rotterdam, The Netherlands. Ethnicity was assessed at enrolment. Blood pressure was measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Lifestyle factors included smoking, alcohol, caffeine intake, folic acid supplementation, sodium and energy intake, body mass index and maternal stress. Associations and explanatory pathways were investigated using linear and logistic regression analysis. RESULTS: Dutch pregnant women had higher systolic blood pressure levels as compared to women in other ethnic groups in each trimester of pregnancy. Compared to Dutch women, Turkish and Moroccan women had lower diastolic blood pressure levels in each trimester. These differences remained after adjusting for education and lifestyle factors. Turkish and Moroccan women had a lower risk of gestational hypertension as compared to Dutch women (OR 0.32; 95% CI: 0.18, 0.58 and OR 0.28; 95% CI: 0.14, 0.58) and Cape Verdean women had an elevated risk of preeclampsia (OR 2.22; 95% CI: 1.22, 4.07). Differences could not be explained by education or lifestyle. CONCLUSION: Substantial ethnic differences were observed in blood pressure levels in each trimester of pregnancy and risk of gestational hypertensive disorders. A wide range of potential explanatory variables could not explain these differences. PMID- 26105251 TI - OS037. Minipiers (pre-eclampsia integrated estimate of risk):Development of a clinical prediction model for use in low and middleincome countries (LMIC). PMID- 26105252 TI - OS038. Pre-conceptional preparation of women with chronic hypertensionof I-II stage II of the degree of risk of CHF 0-I and recurrent bacterial vaginosis. PMID- 26105253 TI - OS039. Early prediction of preeclampsia with maternal parameters,SVEGF-R1, PLGF, Inhibin-A and PAPP-A in general population: Results from the MSPE study. PMID- 26105254 TI - OS040. Effect of folic acid supplementation in pregnancy on preeclampsia- Folic acid clinical trial (FACT). AB - INTRODUCTION: Observational studies suggest that folic acid supplementation during pregnancy can reduce the risk of preeclampsia (PE). No randomized controlled trial has been conducted to demonstrate the effect of folic acid supplementation on PE. OBJECTIVES: FACT aims to determine efficacy on a new PE prevention strategy of high dose folic acid supplementation from early pregnancy (8(0/7) to 16(6/7)weeks of gestation) until delivery in women with high risk of developing PE. METHODS: DESIGN: FACT is an international, multi-centre, double blind, placebo controlled clinical trial of 3656 women. Eligible women will be randomised in a 1:1 ratio to folic acid 4.0mg or placebo. POPULATION: Pregnant women (8(0/7)and 16(6/7) weeks of gestation) ?18 years of age, taking ?1.1mg of folic acid supplementation who fulfill at least one of the following identified risk factors for PE. Pre-existing hypertension (blood pressure ?90mmHg on two separate occasions or at least 4h apart prior to randomization, or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to randomization), pre-pregnancy diabetes (Type I or Type II DM), twin pregnancy, history of PE in a previous pregnancy, BMI ?35kg/m(2) within 3 months prior this pregnancy or during the first trimester of this pregnancy. PRIMARY OUTCOME: PE is defined as blood pressure ?d90mmHg on two occasions ?4 h apart and proteinuria developed in women greater than 20 weeks of gestation. Or HELLP (Haemolysis, Elevated, Liver Enzymes, Low Platelets) syndrome Or superimposed PE, defined as history of pre-existing hypertension (diagnosed pre-pregnancy or before 20 weeks' gestation) with new proteinuria. Proteinuria is defined as: Analysis plan: Intent-to-Treat (ITT) population will be analyzed. Chi square test will be used in the comparison of incidence of PE between the intervention and placebo groups for analysis of the primary outcome. RESULTS: The Ottawa Hospital randomized the first FACT subject in April 2011. As of February 29th, 2012, 62 subjects have been randomized. There are currently 18 Canadian sites participating in FACT, of which 10 are actively recruiting and 8 are pending site activation. Internationally, Argentina, Australia and the United Kingdom are anticipating first recruits in the late spring of 2012. Israel and Holland are expected to begin enrolment as early as the fall of 2012. CONCLUSION: Recruitment is on target and expected to end August 2014. Results from this large scale trial will provide a definitive answer to the important question whether folic acid supplementation can prevent PE. PMID- 26105255 TI - OS041. Apolipoprotein A-I protects normal integration of the trophoblast into endothelial cellular networks in an in vitro model of preeclampsia. AB - INTRODUCTION: Failure of the trophoblast to appropriately invade uterine spiral arteries is thought to be an initiating event in preeclampsia, a disorder associated with endothelial dysfunction. A dyslipidemia characterised by low plasma levels of high density lipoproteins (HDL) and elevated triglycerides has also been described in preeclampsia. The pro-inflammatory cytokine TNF-alpha inhibits trophoblast invasion of uterine endothelial cells. Previous work using an in vitro JEG-3 cell/Uterine endothelial cell co-culture model investigated the effect of apoliopoprotein A-I, the main apolipoprotein component of HDL, on trophoblast incorporation into endothelial tubules in the presence and absence of TNF-alpha. These effects are now investigated using the human invasive trophoblast cell line HTR-8/SVneo. OBJECTIVES: This study asks if apoA-I, which has established anti-inflammatory properties, can protect against the deleterious effect of TNF-alpha on trophoblast-endothelial cell interactions. METHODS: The in vitro trophoblast-uterine endothelial cell co-culture model was used to investigate the effect of apoA-I on trophoblast incorporation into endothelial tubules in the presence and absence of TNF-alpha. Uterine endothelial cells were pre-incubated with lipid free apoA-I (final apoA-I concentration 1 mg/mL) for 16h prior to seeding on matrigel coated plates. Tubules formed within 4h. Fluorescence-labelled HTR-8/SVneo trophoblast cells were then co-cultured with the endothelial cells+/-TNF-alpha (final concentration of 0.2ng/mL). Bright field and fluorescent images were captured after 24h. The effect of TNF-alpha on HTR 8/SVneo cell invasion was quantified with Image J software. Integration of HTR 8/SVneo trophoblast cells into uterine endothelial tubular networks was also imaged using live cell imaging techniques (Zeiss Axiovert). RESULTS: TNF-alpha inhibited HTR-8/SVneo (trophoblast) cell integration into endothelial tubular structures by 24.1+/-3.7% p<0.001. This effect was reversed when the endothelial cells were pre-incubated for 16h with lipid free apoA-I (p<0.001 compared to non incubated cells). Live cell images of the co-culture clearly demonstrate a disruption to the normal integration of trophoblast into endothelial tubular structures in the presence of TNF-alpha. The protective effect conferred by pre incubation of endothelial cells with apoA-I against TNF-alpha is also clearly visible. CONCLUSION: Apolipoprotein A-I has been shown to enhance trophoblast endothelial cell integration in the presence of a pro-inflammatory stimulus. A healthy lipid profile may affect pregnancy outcomes by priming endothelial cells in preparation for trophoblast invasion. PMID- 26105256 TI - OS042. Discovery and characterization of antibody biomarkers ofpre-eclampsia and reagents for their detection. AB - INTRODUCTION: The effective management of pre-eclampsia (PE), a complex condition affecting 5% of pregnancies [1], would benefit from a clear diagnostic assay. Due to this need, great interest lies in the development and validation of objective biomarkers, among which antibodies remain attractive given their amplification by the immune system, stability, and current clinical use. Although several recent studies lend support to the idea that autoantibodies against the angiotensin II AT1 receptor (AT1-AAs) could be involved in PE [1], their presence is not highly specific for PE as measured by cell-based assays for AT1 agonism [2]. Given these results, we hypothesized that additional antibody biomarkers may exist in PE, and that a small panel of such biomarkers could provide an effective diagnostic tool. Furthermore, development of a simple binding assay will facilitate AT1-AA detection for larger-scale studies, while identifying other antibody biomarker(s) would enhance understanding of the immune component to PE pathogenesis. OBJECTIVES: The primary objective of this study was to identify a panel of peptide reagents that preferentially bind PE patients' serum antibodies. In addition, we sought to measure the frequency of AT1-AAs in a new patient cohort using a simplified assay. METHODS: Plasma samples were obtained from normal outcome pregnancies (n=28) as well as PE patients (n=25) and enriched for the antibody fraction. The seven amino acid AT1-AA epitope [1] was expressed on the surface of E. coli for reactivity analysis by flow cytometry. A bacteria displayed linear peptide library was screened against the antibody repertoires using a unique method of fluorescence activated cell sorting (FACS) to isolate peptides that react with multiple patients and show little reactivity with normal outcome pregnancies. FACS analysis was used to measure individual peptide reactivity, and statistical analyses included a Student's t-test and nonparametric tests to compare the means, medians, and normal scores. RESULTS: Using this simple binding assay, AT1-AAs were detected in a majority of PE patients and more rarely in normal-outcome pregnancies. Among the isolated peptide mimics, several unique peptides demonstrated significantly (p<0.03) higher reactivity with PE patients than with control samples but showed no sequence homology to the known AT1 epitope. Not only did our peptides perform well with the original set of samples used for discovery, but these peptides also reacted with antibodies from a small set of new PE (n=10) sera but not from new normal-outcome (n=10) pregnancies. CONCLUSION: Peptides distinct from the AT1 epitope and identified by library screening exhibited potential diagnostic utility for PE, suggesting that a panel of such peptides might provide a novel diagnostic test to distinguish PE from other conditions with similar symptoms. Also, this study demonstrated AT1-AA presence in an independent patient cohort with a simple binding assay, which can be easily expanded to evaluate larger cohorts. PMID- 26105257 TI - OS043. Identification and validation of novel markers for the predictionof pre eclampsia. AB - INTRODUCTION: Currently no test accurately predicts pre-eclampsia (PE) in a healthy nulliparous population. Unbiased protein biomarker discovery has the potential to identify novel markers but multimarker panels are required to achieve clinically relevant prediction of PE. To this purpose, single biomarker performances were obtained and multimarker panels developed in a significant subcohort of the international Screening fOr Pregnancy Endpoints study (SCOPE) study [1]. OBJECTIVES: To identify and validate novel protein markers for PE prediction using chromatographic and mass spectrometric techniques which enable the identification and quantification of plasma proteins present in plasma at sub ng/ml concentration (Pronota, Belgium). METHODS: Pre-disease plasma samples (22 26 weeks) from women who subsequently developed PE and those with uncomplicated pregnancies [2] were used to generate 30 plasma proteome profiles using the MASStermindTM pipeline. A set of novel protein candidates were validated using an antibody-free mass spectrometry method using multiple reaction monitoring (MASSterclassTM) in a subcohort of the SCOPE study (NZ & Aus) [1]. Relative abundance of 40+ proteins was determined in 20week plasma samples from 100 women who developed PE and 200 women who did not develop PE (included women with other pregnancy complications). Multivariate analyses were performed to identify algorithms with predictive performance using combinations confined to a maximum of 6 parameters (protein markers and clinical parameters) to avoid overfitting. Validation of the prediction panels was performed in an independent subcohort of SCOPE (Europe) comprising 50 PE and 150 no PE. RESULTS: From this large scale biomarker discovery effort a number of key results were obtained: a novel protein, i.e., Insulin-like growth factor binding protein, acid labile subunit (IGFALS), was identified. AUC for this marker for the prediction of all PE was 0.71 (CI 0.68-0.75) which was greater than both PlGF and s-Eng (respective AUCs: 0.64 and 0.61). IGFALS was also found to have predictive value for term (AUC 0.70) as well as preterm disease (AUC 0.75). Using multivariate analysis, marker panels were identified that achieved clinically relevant prediction (exemplary panel prediction of all PE cases AUC=0.79; prediction of preterm PE AUC=0.92). These multivariate models were successfully validated in the European SCOPE subcohort. In addition, predictive algorithms based on mass spectrometric read outs were largely invariant to interchanging the IGFALS mass spectrometry quantitation data with IGFALS ELISA data. CONCLUSION: This study demonstrates the capability of high level LC-MS technologies to discover candidate biomarkers and execute large scale multiplex validation to develop a predictive screening test for preeclampsia. PMID- 26105258 TI - OS044. Morphological differences in murine placenta detected by magneticresonance imaging measurements of T2 relaxation times in mouse models ofpreeclampsia. AB - INTRODUCTION: We have demonstrated that morphologically distinct regions of the murine placenta can be detected by magnetic resonance imaging (MRI), with image contrast arising from the variation in T2 relaxation times between regions and dependent upon blood flow. Previous studies of human placenta by other groups have shown a homogeneous tissue with correlation of relaxation times with gestational age and a trend for shorter relaxation times in pregnancies complicated by preeclampsia and fetal growth restriction. The ability to detect morphological changes and alterations in blood flow in experimental models of preeclampsia would be a significant boost in understanding the relationship between abnormal placental implantation, reduced placental perfusion, inflammatory cytokines, angiogenic molecules and other factors that may play a role in the syndrome. OBJECTIVES: The aim of this study was to investigate whether morphological changes or abnormalities can be detected by T2 mapping in the placenta of mice subject to two experimental models of preeclampsia (reduced uterine perfusion pressure (RUPP) model and TNF-alpha induced model). METHODS: Pregnant C57BL/6JArc mice were, on day 13.5 of gestation, either subject to a unilateral ligation of the right uterine artery (RUPP) (n=2) or given an infusion of TNF-alpha by subcutaneous insertion of a mini-osmotic pump primed to deliver 500ng/kg/day for 4days (n=2). Controls were normal pregnant (n=2), sham-operated (n=1) or saline infused animals(n=1). MRI images were acquired on anaesthetised mice on day 17.5 of gestation using a Bruker Avance 11.7 Tesla wide-bore spectrometer with micro-imaging probe capable of generating gradients of 0.45T/m. T2 measurements were acquired using an MSME sequence protocol (Bruker MSME-T2 map) with an in-plane resolution of 0.1-0.2mm. Matlab was used to generate R2 (i.e.,1/T2) maps from the acquired data with the T2 values being calculated from selected regions of interest from 2-6 individual placenta from each mouse. RESULTS: Differences in the pattern of the regions of T2 contrast in the placenta were observed between normal, TNF-alpha treated and RUPP mice. The ratio of T2 values from the inner two regions was also significantly altered in TNF-alpha treated 1.98+/-0.09 (p=0.007); RUPP 1.94+/-0.11 (p=0.006) compared to normal animals 2.5+/-0.1 . CONCLUSION: These results demonstrate that morphological differences or abnormalities can be detected by T2 mapping in the placenta of mice subject to experimental models of preeclampsia and may be used to analyse changes quantitatively. This technology has the potential to be used when studying the dynamic changes in the placenta of pregnancies complicated by preeclampsia. PMID- 26105259 TI - OS045. Multi-dimensional protein identification technology analysis of syncytiotrophoblast vesicles released from perfused preeclampsia placentas. AB - INTRODUCTION: In pre-eclampsia, the consequences of poor placentation lead to the second stage of pre-eclampsia, which involves activation of a maternal systemic inflammatory response (MSIR). Endothelial and other inflammatory cellular dysfunction cause the diverse features which characterise the disorder. We have previously shown that syncytiotrophoblast microvesicles (STBM) are pro inflammatory and circulate in increased amounts in pre-eclamptic women. We hypothesise that multiple placental "danger signals" are carried by STBM into the maternal circulation in increased amounts in PE with pro-inflammatory, anti angiogenic and pro-coagulant activity, implicating STBM in the pathophysiology of PE. OBJECTIVES: To characterise the proteins carried by STBM from normal and PE placentas. For the first time multi-dimensional protein identification technology (MudPIT) was used to derive the proteome profiles of normal and PE placenta STBM. METHODS: STBM were prepared from placentas (normal term: n=9 and PE: n=5) by dual lobe perfusion, isolated by ultracentrifugation and stored at -80 degrees C. Normal and PE derived placenta STBM pools were then subjected to MudPIT analysis. RESULTS: 538 proteins unique to PE STBM, 604 proteins unique to normal STBM and 1421 proteins common to both preparations were found. Preliminary analysis indicates the presence of alarmins (HSP70, and galectin 3), exosomal proteins (CD63,CD9,CD81), immunoregulatory molecules (CD26,CD200,CD47,Galectin 1), complement and complement regulatory molecules (C1q,C3,CD55,CD59 and vitronectin), amino acid transporters (CD98) and anti-angiogenic molecules (endoglin). Our analysis also reveals that proteins known to be elevated in blood before, or at, the time of pre-eclampsia are elevated or unique in STBM from PE placentas, including Fetuin A, Inter-alpha (globulin) inhibitor H4, Serum amyloid P component, Apolipoprotein H (or B2GP1) and Apolipoprotein AII. Thus, as predicted, a large number of circulating molecules are associated with STBM. The inter-relationships between proteins that are unique to either PE or normal pregnancy and the processes in which they are involved are being determined by Ingenuity Pathways Analysis software. In terms of biofunctions, preliminary analysis shows that proteins unique to PE STBM have a highly significant association (p<10(-11)) with 6 disease pathways including inflammatory, immunological, cardiovascular and reproductive system diseases and organ injury, whereas for proteins unique to normal STBM only protein synthesis was significant at the same level. CONCLUSION: STBM contain a heterogeneous population of vesicles that convey a large repertoire of placental proteins into the maternal circulation. The profound differences between PE and normal STBM indicate their pro-inflammatory potential. PMID- 26105260 TI - OS046. Genome-wide association scans identify novel maternalsusceptibility loci for preeclampsia. AB - INTRODUCTION: We have successfully utilized a family-based study design to localize several positional candidate preeclampsia susceptibility genes to chromosomes 2q22(ACVR2A,LCT,LRP1B,RND3,GCA),5q (ERAP2) and 13q(TNFSF13B). We now report on our continued positional cloning efforts using an alternative genome wide association (GWA) mapping strategy in large Caucasian case-control cohorts from Australia and Norway. OBJECTIVES: To identify maternal genetic risk loci for preeclampsia. METHODS: The unrelated Australian samples (545 cases,547 controls) were genotyped using Illumina BeadChip technology (700K loci) and have been analyzed using PLINK. All unrelated Norwegian samples were genotyped across several Illumina BeadChip substrates and consist of 847 cases (700K loci) and 638 controls. The Norwegian control samples originate from other HUNT studies pertaining to migraine (n=95,700K loci), lung cancer (n=89,370K loci) and normal brain pathology (n=454,2.5M loci). To analyze a concordant set of 2.5-3 million genotypes across all Norwegian samples we are currently using MaCH to impute those loci not directly genotyped. The Norwegian GWA data will be analyzed in SOLAR utilizing empirical kinship estimates to account for any distant relatedness. RESULTS: 1078 Australian samples (538 cases,540 controls) and 648, 175 SNPs passed our quality control metrics. Two SNP associations (rs7579169,p=3.6*10(-7); rs12711941,p=4.3*10(-7)) satisfied our genome-wide significant threshold (p<5.1*10(-7)). These SNPs reside less than 15kb downstream from the 3 terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. Sequencing of the INHBB locus in our patient cohort identified a third intergenic SNP to significantly associate with preeclampsia (rs7576192,p=1.5*10(-7)). These three SNPs confer risk (OR>1.56) and are in strong linkage disequilibrium with each other (r(2)>0.9) but not with any other genotyped SNP +/-200kb. The analysis of the Norwegian GWAS is underway. CONCLUSION: The Australian GWAS has identified a novel preeclampsia risk locus on chromosome 2q. The INHBB gene closest to our SNP associations is a plausible positional candidate susceptibility gene. There is a substantive body of evidence implicating inhibins, activins and other members of the TGF-betasuperfamily to have a role in the development of preeclampsia. The biological connection between ACVR2A and INHBB leads us to speculate that our linkage-based and GWA-based study designs, respectively, have identified a key biological pathway involved in susceptibility to preeclampsia. PMID- 26105261 TI - OS047. Quantification of placental vascularization in a rabbit model ofIUGR with three-dimensional power doppler angiography. AB - INTRODUCTION: Placental dysfunction is known to be a major cause of pregnancy complications, such as perinatal loss, preeclampsia, and intrauterine growth restriction (IUGR). Inadequate remodeling of the spiral arteries resulting in decreased blood flowto the placenta has been implicated in the pathophysiology of preeclampsia and IUGR. 3D power Doppler angiography (PDA) is a noninvasive and safe way to study blood flow within an organ or region of interest. The aim of this study was to evaluate PDA as a method to quantify placental perfusion in a pharmacological rabbit model of vascular IUGR induced by inhibition of NO synthesis. OBJECTIVES: Our objective was to evaluate the 3D power Doppler angiography (PDA) in terms of feasibility and ability to detect placental hypo perfusion in an experimental rabbit model of intrauterine growth restriction (IUGR). METHODS: Fourteen pregnant females were treated with NG-nitro-L-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, from day 24 to day 28 of gestation, to induce an IUGR. Concomitantly, 8 pregnant rabbits were used as controls. On day 28, 3D power Doppler indices were quantified in each uteroplacental unit. RESULTS: A total number of 180 live fetuses were obtained, 180 from the L-NAME group and 72 from the control group. G28 fetal weight was significantly lower in the L-NAME group than in the control group (27.40+/-0.55g vs 33.14+/-0.62g,p<0.0001). In the L-Name group the vascularization index (VI) was significantly lower than in the control group (2.6 [1.4;6.0] vs 7.6 [3.5;12.6],p<0.05). Similar results were obtained for the Flow Index (FI) and the Vascularization Flow Index (VFI). The number of fetuses considered as small for gestational age (SGA;weight<10th centile) was significantly higher in the L-NAME group than in the control group (47/108 vs 7/72,p<0.0001). The VI was significantly lower in the SGA group than in the eutrophic group (3.46 [0.46;5.9] vs 7.50 [4.22;10.9] p<0.05). Similar results were obtained for FI and VFI. CONCLUSIONS: This experiment study demonstrates that quantitative 3D PDA indices are sensitive enough to detect placental vascular insufficiency in an experimental model of IUGR. PMID- 26105262 TI - OS048 Mitochondrial content and function in placental cells and tissuesof preeclampsia and IUGR. AB - INTRODUCTION: Early onset placenta Preeclampsia (ePE) with Intrauterine Growth Restriction (IUGR) is associated with insufficient placental function, leading to decreased nutrient and oxygen (O2) availability for the fetus [1]. Mitochondria (mt) are the cell energy producers. Mt dysfunctions could be involved in altered placental metabolism leading to ePE and IUGR. We previously demonstrated higher levels of mtDNA in human IUGR placentas [2]. OBJECTIVES: Here we investigate mtDNA levels in ePE and PE without IUGR placentas, and we present an innovative technique, High Resolution Respirometry (HRR), on cytotrophoblast cells (CTC) from PE, IUGR and control placentas (C), measuring cell O2 consumption which represents respiratory chain efficiency. METHODS: mtDNA was measured by Real-Time PCR in 20 PE placentas, with (n=14) or without (n=6) IUGR, and 45 C. CTC were isolated from 4 PE, 4 IUGR and 6 C and characterized by flow cytometry, staining samples with anti-cytokeratin-7 and anti-vimentin antibodies. Cells were located in chambers with atmospheric O2levels; 2 different protocols were used, with or without digitonin permeabilization, allowing to measure the O2 consumption of the respiratory chain complexes singularly or all together. Substrates and inhibitors of different respiratory chain complexes were sequentially administered (succinate, ADP, oligomycin, FCCP, rotenone, antimycin A, glutamate, malate, myxothiazol, TMPD, ascorbate, pyruvate, cytochrome C, differently combined depending on the protocol) and O2 consumption levels were recorded. Data were normalized by Citrate Synthase (CS) activity and CTC mtDNA content. RESULTS: PE placentas: mtDNA content was significantly increased in ePE+IUGR (p=0.02) vs C; opposite to this, mtDNA was decreased in PE without IUGR (p=0.03). CTC: single mt O2 consumption (obtained by normalizing data both by CS activity and mtDNA) was slightly increased both in PE and IUGR. The global cell respiration was increased, though not significantly. The trend towards higher O2 consumption studied on permeabilized cells was confirmed for all the respiratory chain complexes. CONCLUSION: Our study showed that mtDNA is increased also in ePE with IUGR and added the novel observation that mtDNA is decreased in PE without IUGR. In both conditions placental mitochondria present an altered respiratory chain activity, with a trend to a higher respiratory capacity. This could lead to higher ATP production likely as an attempt to compensate for other aspects of placental disease due to small or inefficient exchange capabilities. Further data are needed to confirm these preliminary results, together with specific enzymatic assays to asses the respiratory chain complexes functionality. Supported by Fondazione Giorgio Pardi, Associazione Studio Malformazion(ASM) and by a Grant COFIN (Italian Ministry of Research) on: New markers for preterm deliveries. PMID- 26105263 TI - OS049. Exome sequencing identifies likely functional variantsinfluencing preeclampsia and CVD risk. AB - INTRODUCTION: Next-generation sequencing (NGS) in family-based study designs will be pivotal in unlocking the missing heritability of common complex diseases. Whilst our prior linkage- and association-based positional cloning studies in family- and population-based Australian cohorts, respectively, have discovered novel preeclampsia candidate genes (INHBB,ACVR2A,LCT,LRP1B,RND3,GCA,ERAP2,TNFSF13B), the full complement of causal genetic variation remains largely unknown. We have now sequenced the exomes of two Australian preeclampsia families in another step forward to unlocking preeclampsia's complex allelic architecture. OBJECTIVES: Identify family-specific exon-centric loci segregating in preeclamptic women only. METHODS: The exomes of 18 women (7 preeclamptics,11 controls) from two Australian families contributing to our chromosome 5q (Family 1) and 13q (Family 2) susceptibility loci, respectively, were sequenced using Illumina's TruSeq Exome Enrichment assay and NGS technology. Sequence alignments, quality control assessment and variant calling were conducted on our 8000 parallel processor compute server, MEDUSA. As a first pass, we prioritized exome sequence data to non-synonymous variants within the 1-LOD drop intervals of our 5q and 13q loci. Prioritized exonic variants were also genotyped in the Western Australian Pregnancy (Raine) Cohort to assess their significance against a plethora of cardiovascular disease (CVD) related traits. RESULTS: In Family 1 we identified two missense SNPs and in Family 2 we identified one missense SNP to segregate in the preeclamptic women but not in the unaffected women. The first SNP in Family 1 (rs62375061) resides within the LYSMD3 gene, is predicted to "possibly" damage the focal protein and the only public record of this SNP is within the Watson genome. The second SNP in Family 1 (rs111033530) resides within the GPR98 gene, is predicted to "probably" damage the focal protein and is rare (1.7% population prevalence). The SNP in Family 2 (rs1805388) resides within the LIG4 gene, is predicted to be highly deleterious (F-SNP FSS=0.849) and is common (?17% population prevalence). In the Raine cohort the LIG4 SNP was also significantly associated with weight (p=0.0085), total cholesterol (p=0.0007), HDL cholesterol (p=0.0067) and LDL cholesterol (p=0.0324). CONCLUSION: Our preliminary exome data documents the substantial potential to rapidly identify likely functional variants that influence preeclampsia risk. The GPR98 finding is of major interest to us as a recent genome-wide association study reported a significant association with diastolic blood pressure for a SNP at this same gene locus. Furthermore, our findings implicate LIG4 as a novel candidate susceptibility gene for CVD and add weight to the hypothesis of shared genetic risk factors for preeclampsia and CVD. PMID- 26105264 TI - OS050. Genetic variants in pre-eclampsia: a meta-analysis. AB - INTRODUCTION: Preeclampsia has a clear familial component, suggesting that the syndrome may be partly attributable to genetic susceptibility. The search for susceptibility genes has lead to a massive increase in the number of published studies involving genetic associations in preeclampsia. However, attempts to replicate these findings have yielded inconsistent results. This meta-analysis aims to assess the pooled effect of each genetic variant that is reproducibly associated with preeclampsia. OBJECTIVES: To create an overview of the genetic variants that are reproducibly associated with preeclampsia. METHODS: Studies assessing the association between genes and preeclampsia were searched in PubMed, EMBASE and Web of Science. We selected all genetic variants that were significantly associated with preeclampsia in an initial study and then independently reproduced in at least one additional study. Subsequently, all studies assessing these reproduced variants were included. The association between these variants and preeclampsia was calculated at the allele level and the main measure of effect was a pooled odds ratio. RESULTS: The literature search resulted in 2965 citations, of which 542 were genetic association studies investigating preeclampsia. We identified 23 replicated genetic variants, of which 8 remained significantly associated with preeclampsia in a random-effects meta-analysis. These variants were in or near the following genes: ACE,AGT,CTLA4,F2,FV (two variants),LPL and SERPINE1. CONCLUSION: This meta analysis found 8 genetic variants associated with preeclampsia. Most of these variants are in the renin-angiotensin and the coagulation system. Importantly, many of the variants that were associated with preeclampsia are known to be risk factors for the development of cardiovascular disease, indicating that preeclampsia and cardiovascular disease have shared genetic risk factors. The relative contribution and relevance of the identified genes in the pathogenesis of preeclampsia should be the focus of future studies. PMID- 26105265 TI - OS051. Web-based scientific data management and standardized specimencollection important tools for research and scientific exchange. AB - INTRODUCTION: Data management and specimen collection in scientific research underlie a number of challenges and often have to fit into daily routine as well as meet scientific standards. In the daily routine of E-science, data security combined with maximum user friendliness and autonomy have a clear positive impact on scientific efficiency.Using standardized specimen collection enables for exchanging material between research partners and helps answering scientific questions in shorter time period and with more scientific outcome. OBJECTIVES: We aim to establish SOP's for specimen collection and data management in obstetrics to ensure high quality and comparability in research. METHODS: We present a web based scientific platform for obstetrical data management and show SOP's for high quality specimen collection. RESULTS: The database was designed to administrate data concerning pregnancy, child-bed and the newborn and is by now fully integrated in clinical and scientific routine. It consists of documentation sheets that guarantee high quality data management and help administrating data protected by username and password. For answering scientific questions not only good data management but also SOPs for specimen collection are an important tool. Therefore we assessed protocols for standardized blood, urine and placenta collection which make material sampled on different study sites comparable. CONCLUSION: Standardized data and specimen collection are necessary for research co-operations and play an important role in answering scientific questions in a shorter time period and with enlarging sample size. PMID- 26105266 TI - OS052. Preeclampsia candidate genes differentially methylated in maternal leukocyte DNA. AB - INTRODUCTION: Altered gene expression in biomarkers associated with preeclampsia/ eclampsia (PE) could be explained in part by epigenetic phenomena such as variable methylation OBJECTIVES: We sought to characterize the methylation profiles of candidate genes known to be associated with the preeclampsia phenotype in maternal leukocyte DNA in preeclamptic cases and normotensive controls at the time of delivery. METHODS: Methylation profiles of maternal leukocyte DNA were evaluated in 14 PE cases and 14 normotensive controls. Subjects were nulliparous, non-smokers, age and BMI matched. Genomic DNA was run on a commercially available beadchip human methylation assay. Mean methylation at sites in genes from a well-defined preeclampsia gene set present on our platform were compared using a t-test. RESULTS: QC confirmed high correlation of replicates and detection p values >95%. Of the 39 genes in the "preeclampsia gene set", 34 were present on our platform with 73 CpG sites. Seven out of 34 tested in this gene set had differential methylation with p value <0.05. Two genes were found to be less methylated in PE which may result in more expression. AGT ( 3%;p= 0.027), angiotensin, is a potent vasoconstrictor with exaggerated effect in PE. DDAH1 (-6%;p=0.031) is involved in nitric oxide generation, via asymmetric dimethylarginine (ADMA), levels of which are known to be altered in PE. Five genes were more methylated and therefore may correlate with reduced transcription. CALCA (+4%;p=0.001) forms calcitonin-gene related peptide, a potent vasodilator decreased in the PE . F5 (+1%;p=0.016), coagulation Factor V, is a target of activated protein C, and increased resistance related to genetic variants (Factor V Leiden) or pregnancy have been associated with PE. MTHFR (+3%;p=0.041) regulates homocysteine; high levels are associated with a 20X increase in risk for PE. POMC (+4%;p=0.014) produces beta endorphin and through ACTH stimulates aldosterone, both decreased in PE. PTGS2 (+3%;p=0.03) is part of the COX 2 prostaglandin pathway involved in inflammation. CONCLUSION: Differential methylation of these 7 genes may affect transcription and explain known alterations in gene product associated with PE. PMID- 26105267 TI - OS053. Trophoblast invasion in the mesometrial triangle of atp infused pregnant rats. AB - INTRODUCTION: Poor placentation (disturbed and decreased trophoblast invasion) is a hallmark of preeclampsia (PE), which is a major complication of pregnancy. Unfortunately, the cause and mechanism of disturbed trophoblast invasion is still unknown. OBJECTIVES: The pro-inflammatory agent ATP has been shown to induce PE like signs, after a single infusion in pregnant rats. These PE-like characteristics include proteinuria and decreased fetal weight. Since purinergic ATP receptors are expressed on trophoblast cells, we aimed to study the effect of ATP infusion on trophoblast invasion in pregnant rats in this pilot study. METHODS: Pregnant rats received a single ATP (n=4) or saline (control,ni=5) infusion via a permanent jugular vein cannula on day 14 of pregnancy. At the time of maximal trophoblast invasion (day 17 of pregnancy) rats were sacrificed and placentas with mesometrial triangle were collected, fixed in zinc-buffer and embedded in paraffin. 4 MUm sections were stained with monoclonal alpha cytokeratin antibodies. In the mesometrial triangle, the maternal part of the rat placenta, the percentage of surface area of trophoblast invasion was evaluated using computerized image analysis. Also, the depth and width of invasion were analyzed by subdividing the mesometrial triangle in three concentric depth levels of equal width. In addition, trophoblast invaded versus non-invaded spiral arteries in the mesometrial triangle were quantified. RESULTS: In the mesometrial triangle, no changes in percentage of surface area of trophoblast invasion and percentage of invaded spiral arteries were observed after ATP infusion. However, the pattern of trophoblast invasion appeared to be disturbed in ATP infused rats, with a decreased depth of invasion and an increased width of invasion, resulting in a trend towards a decreased depth/width ratio of trophoblast invasion in ATP infused rats. CONCLUSION: In this (pilot) study we showed an altered trophoblast invasion pattern in the mesometrial triangle of the placenta, although no significant differences in the total surface area of trophoblast invasion were seen in experimental versus control pregnant animals. e mechanism by which ATP induces this altered trophoblast invasion pattern and its potential contribution to the pathophysiology of this experimental PE in the pregnant rat awaits further investigation. PMID- 26105268 TI - OS054. Differential strain sensitivities to ischemia/reperfusion in two mouse models of fetal growth restriction. AB - INTRODUCTION: Uterine ischemia/reperfusion (I/R) in rodents is a common model for the study of fetal growth restriction (FGR). It has been observed that different strains of mice vary in their response to uterine I/R. OBJECTIVES: Our objective was to characterize fetal and placental growth, and uterine and placental inflammation, in pregnant mice from 2 strains (C3H/HeOuJ and C57BL/6J), in response to different uterine I/R modalities. METHODS: Timed-pregnant mice (6-8 in each experimental group) were subjected to unilateral uterine I/R by either total flow restriction (TFR,right ovarian and uterine arterial clamping,5 or 30min) or partial flow restriction (PFR,right ovarian artery clamping,30min), or to sham-operation, on the 14th (for C57 mice) or 15th (for C3H mice) day of gestation. Four days later, fetal and placental weights and fetal loss were evaluated, and myeloperoxidase (MPO) activity was assayed in uterine and placental tissues. Data were analyzed by ANOVA with p<0.05 considered significant. RESULTS: In C3H/HeOuJ mice, TFR/30 min induced significantly (p<0.05) lower fetal and placental weights, and higher MPO activity in both uterus and placenta, compared to sham-operated controls. PFR/30min produced fetal but not placental growth restriction in the C3H mice. In contrast, C57BL/6J mice exhibited much greater sensitivity to uterine I/R: TFR/5 min was adequate to induce FGR in the C57 mice, which was equivalent in proportion to FGR caused by TFR/30min in C3H. C57 mice also exhibited significantly greater fetal loss and higher uterine, but not placental, MPO activity in response to I/R compared to sham-operated controls. CONCLUSION: Reliable FGR can be induced in different strains of mice by uterine I/R through adjustment of intensity, duration, and gestation day of the challenge. Mice of different strains have different tolerance to uterine I/R. These strain disparities would lend themselves to identifying the role of mouse strain-specific genetic determinants which form the bases for the observed differences in sensitivity to I/R-induced FGR. PMID- 26105269 TI - OS055. Sex-dependent differences in expression of FLT-1 variants andJMJD6 in mouse placenta. AB - INTRODUCTION: There is evidence for fetal sex-dependent differences in the way in which preeclamptic pregnancies proceed, and in maternal and neonatal outcomes. Mouse models are common in the study of preeclampsia and pooled tissue from multiple placentae is often used to obtain samples for expression studies. Potential concerns regarding this practice are the sex-dependent differences in placental expression of candidate factors. One biomolecule of interest is soluble fms-like tyrosine kinase 1 (sFLT-1) which is a known marker of preeclampsia and commonly used to determine the severity of the induced preeclampsia-like syndrome in rodent models. OBJECTIVES: It was the aim of this preliminary study to determine whether variation exists in the expression of different genes in murine placenta based on pup sex in C57BL/6JArc mice. A novel gene, Jumonji domain containing protein 6 (Jmjd6) that may prove to have a role in the pathogenesis of preeclampsia, mFLT-1 and sFLT-1 were selected as targets. METHODS: Seventeen pups were retrieved from three normal pregnant female mice euthanized via cervical dislocation (CD) on day 17.5 or 18.5. Tails and corresponding placentas were collected from the pups, snap frozen in liquid nitrogen and stored at -80 degrees C. Tails were used to accurately determine pup sex via PCR amplification of sex chromosome-specific sequences and revealed the presence of 3 females and 14 males. Quantitative PCR was used to determine the relative expression of the FLT 1 and Jmjd6 transcripts in each placenta. The placenta collected from the first pup of the first pregnant female served as the reference sample and transcript expression in the remaining samples was expressed relative to this sample. General linear modelling using linear regression with categorical variables was used to evaluate the difference in transcript expression between the sexes and Pearson's correlation coefficient used to examine relationships between variables. RESULTS: Pup sex was found to have a significant effect on the relative expression of sFLT-1 after controlling for litter, pup weight and gestational age (p=0.013), with 1.5 times more expression in the placentas of female pups. The expression of sFLT-1 was highly correlated with mFLT-1 (r=0.690,p=0.002). The relative expression of Jmjd6 was not significantly different in male and female placentas and sFlt-1 was not correlated with Jmjd6. CONCLUSION: This is the first study to demonstrate a link between fetal sex and placental sFLT-1 expression in mice, finding increased levels of this gene in the placentas of female pups. It is possible that in normal pregnancies, female placentas produce more sFLT-1 which acts to condition them and offer some protection during the sFLT-1 spike seen in preeclampsia. The findings of this study also highlight a possible need to consider sex as a variable in placental expression studies using mice to ensure the accuracy of results. PMID- 26105270 TI - OS056. Angiotensin II sensitivity and endothelial dysfunction afterexperimental preeclampsia. AB - INTRODUCTION: Women who suffered from preeclampsia (PE) have an increased risk for cardiovascular and renal diseases later in life. Although the exact mechanisms underlying this relationship are unknown, they may relate to an increased sensitivity to angiotensin II (Ang-II) and endothelial dysfunction during a preeclamptic pregnancy, which may persist after PE. Recently, we showed vascular hypersensitivity to Ang-II and disturbed endothelial cell function in experimental PE in rats as compared to healthy pregnant rats. OBJECTIVES: To study whether vascular hypersensitivity to Ang-II and endothelial dysfunction persist postpartum in experimental PE. METHODS: In this ongoing study, we thus far included non-pregnant rats (NP;n=9), formerly healthy pregnant rats (HP;n=9) and formerly experimental preeclamptic rats (PE; infusion of a low dose endotoxin; n=16). Six weeks after pregnancy, animals from each group were treated with Ang-II (osmotic minipump; 200ng/kg/min;NP: n=5;HP: n=6;PE: n=8) or were sham treated (NP: n=4;HP: n=3;PE: n=8). Blood pressure was measured in all rats one day before and weekly after Ang-II or sham treatment (for three weeks). At termination, the aortas of sham operated rats were obtained. Aortic rings (2mm) were mounted for isotonic measurement of vasotonus. Endothelium-dependent acetylcholine- (ACh) mediated vasodilation was studied in phenylephrine preconstricted rings in the presence of vehicle, N(G)-nitro-L-arginine methyl ester, indomethacin or both, followed by full concentration response curves for ACh (10(-8)M-10(-4)M). Ang-II sensitivity was assessed by obtaining full concentration response curves (10(-10)M-10(-6)M). AT-1 and AT-2 receptor sensitivity was determined by administration of Ang-II in the presence of the AT 1 receptor blocker losartan, or the AT-2 receptor blocker PD123319. RESULTS: Our results indicate no difference in mean (+/-SD) systolic blood pressure (SBP) between the three groups six weeks after delivery (NP: 129(+/-7);HP: 127(+/ 9);PE: 123(+/-10)mmHg;p=0.248). However, after three weeks of Ang-II treatment, a trend was found towards a stronger increase in SBP in PE rats as compared to HP rats (45.7(+/-18.9)% vs 63.4(+/-20.1)% respectively;p=0.081). Although we found no differences in in-vitro Ang-II sensitivity between the three groups, NP rats showed a trend towards an increased sensitivity of the AT-2 receptor to Ang-II compared to both groups of formerly pregnant rats. Total ACh-mediated endothelial relaxation was not different between the three groups. However, contribution of both NO and EDHF components to ACh-mediated relaxation seemed decreased in both groups of formerly pregnant rats as compared to the NP rats. CONCLUSION: These preliminary data suggest that healthy rats that suffered from preeclampsia during pregnancy have increased in-vivo sensitivity to Ang-II postpartum as compared to rats with an uncomplicated pregnancy. Whether these differences are related to in vitro- changes in Ang-II sensitivity or changes in endothelial function remains to be established. PMID- 26105271 TI - OS057. Pathophysiological role of elevated tissue transglutaminase in autoantibody-induced features of preeclampsia in pregnant mice. AB - INTRODUCTION: Preeclampsia (PE) is highly associated with the presence of autoantibodies that activate the major angiotensin receptor, AT1R. These autoantibodies (termed AT1-AA) cause most features of PE when introduced into pregnant mice and are believed to contribute to disease pathogenesis. Tissue transglutaminase (tTG) is a prominent member of a family of enzymes that crosslink proteins by catalyzing the formation of an isopeptide bond between the amide group of glutamine and the free amino group of lysine and is believed to play a role in AT1R activation. OBJECTIVES: To test the hypothesis that tTG plays a role in autoantibody-mediated AT1R activation and thereby contributes to the pathophyhsiology of PE. METHODS: Western blotting was used to quantify tTG in placentas of normotensive pregnant women and those with PE. Immunohistochemistry was used to determine cellular localization of tTG, AT1R and glutamyl-lysine isopeptides in placenta tissue. Co-immunoprecipitation experiments were used to explore the possible association of tTG and AT1R. Finally, in an effort to determine the role of tTG in AT1-AA-induced features of PE in vivo, we treated autoantibody-injected pregnant mice with cystamine, a potent tTG inhibitor. RESULTS: Western blot analysis showed elevated tTG in placentas of women with PE. Immunohistochemical analysis revealed that increased levels of tTG, glutamyl lysineisopeptides, AT1R co-localized in the microvillous membrane of PE placentas. Immunoprecipitation of tTG from human trophoblast cell (HTR) lysates resulted in the co-immunoprecipitation of AT1R, thereby providing evidence for an interaction between tTG and AT1R in HTR cells. Finally, we found that cystamine treatment significantly attenuated key features associated with PE including hypertension and proteinuria in the PE-IgG-injected pregnant mice. CONCLUSION: Taken together, we identified a previously unrecognized role of elevated tTG in PE likely by activating or stabilizing AT1Rs. These studies provide novel mechanisms of autoantibody-induced AT1R activation by elevated placental tTG, highlight the role of tTG in the pathogenesis of PE and suggest novel therapeutic strategies for the disease. PMID- 26105272 TI - OS058. Aldosterone deficiency adversely affects pregnancy outcome in mice. AB - INTRODUCTION: In pregnancy, plasma volume is expanded due to high aldosterone levels to support placental perfusion and fetal nutrition. Inadequately low aldosterone levels as present in preeclampsia, a life-threatening disease for both mother and child, are discussed to be involved in its pathogenesis or severity. OBJECTIVES: We used aldosterone synthase deficient (AS(-/-)) mice to test whether the absence of aldosterone is sufficient to impair pregnancy or even to cause preeclampsia. METHODS: AS(-/-) and AS(+/+) females were mated with AS(+/+) and AS(-/-) males, respectively, always generating AS(+/-) offspring. Blood pressure was measured by tail cuff, fetal and placental number and size as well as placental histology were assessed. Placental expression of HIF-1alphaand angiogenic factors was assessed by semiquantitative RT-PCR. RESULTS: With maternal aldosterone deficiency in AS(-/-) mice, systolic blood pressure was low before and further reduced during pregnancy and with no increase in proteinuria. Yet, AS(-/-) had smaller litters due to loss of fetuses as indicated by a high number of necrotic placentas with massive lymphocyte infiltrations at gestational day 18. Surviving fetuses and their placentas from AS(-/-) females were smaller. High salt diet before and during pregnancy increased systolic blood pressure only before pregnancy in both genotypes and reduced blood pressure during late pregnancy as compared to normal salt controls. Litter size from AS(-/-) was slightly improved and the differences in placental and fetal weights between AS(+/+) and AS(-/-) mothers disappeared. Overall an increased placental efficiency was observed in both groups. CONCLUSION: Our results demonstrate that aldosterone deficiency has profound adverse effects on placental function. High dietary salt intake improved placental function and lowered blood pressure in wild-type mice. In this animal model, aldosterone deficiency did not cause preeclampsia. PMID- 26105273 TI - OS059. Blockade of the bradykinin B2 receptor in early pregnancy reduces fetal growth and trophoblast invasion in guinea-pigs. AB - INTRODUCTION: Research in preeclampsia (PE) is hampered by the difficulty of sampling the placental bed in early pregnancies followed to delivery to be defined as normal or preeclamptic. Thus, animal models contribute to the understanding of its physiopathology. The guinea-pig shares with humans extensive vascular remodelling, a hemomonochorial placenta [1] and a vasodilator and angiogenic utero-placental repertoire [2]. In pregnancy it expresses bradykinin (BK) B1R and B2R receptors in cells related to invasion, angiogenesis and vasodilatation. In addition, in HTR-8/SVneo cells, BK induces a B2R-mediated increase in migration and invasion [3]. OBJECTIVES: To test whether blocking the B2R with a rodent-selective non-peptide antagonist Bradyzide (BDZ) from days 20 to 34 of an ~65 day gestation - period of maximal trophoblast invasion and placental development - induces PE-like morphological and functional alterations. METHODS: Virgin Pirbright guinea-pigs (Cavia Porcellus) after mating and echographic confirmation of pregnancy, were allocated in gestational day 20 to to subcutaneous implantation of Alzet pumps that delivered for 14 days saline (Control; n=7), BDZ0,875mg/kg/day (BDZ0,87; n=6) and BDZ 1,2mg/kg/day (BDZ1,2; n=7). Systolic pressure was acquired in the right hindlimb with a Power Lab 8 SP and analyzed with Labchart at day 34. On that day dams were sacrificed, vesical urine was extracted for protein determination, the fetuses and corresponding placentas weighed and the cephalo-caudal length measured. The placentas were studied by HE and immunohistochemistry for cytokeratin to identify trophoblasts. Results are expressed as means+/-SE. Statistical analysis was performed with Graphpad Prism 5.1, using one-way ANOVA, the recommended post hoc tests and chi2 test. RESULTS: Maternal systolic pressure tended to increase in BDZ0,875 and BDZ1,2 versus controls (63+/-567+/-6 versus 56+/-2,mm Hg respectively; NS). Proteinuria was not observed in any group. The number of viable fetuses tended to be reduced in both BZD treated groups (NS). The fetal weight (% maternal weight) was reduced in animals treated with BDZ0,875 and BDZ1,2 (042+/-002 and 045+/-001 versus 054+/-0,04 in controls; p (P<0.01 and 0.05 respectively). The cephalo caudal length was reduced in BDZ0,875 and BDZ1,2 (373+/-24 and 371+/-07 versus 422+/-21mm in controls; P<0.01). No differences were observed in placental weight. Spiral arteries surrounded by trophoblasts (%) were reduced in BDZ 0875 and BDZ1,2 versus controls (63 and 66.6 versus 100%, P=0.02). Invaded spiral arteries (%) were also reduced in the treated groups (80 and 43 versus 100%; P<0.002) No differences were observed in the depth of trophoblast decidual invasion. CONCLUSION: This study demonstrates that blocking the B2R in early pregnancy impairs fetal growth and transformation of the spiral arteries, and supports the role of the B2R in the local physiological adaptation. Further studies are needed to elucidate whether the early impairment translates to hypertension and proteinuria in the last third of pregnancy; if so, the guinea pig would provide a model to understand the physiopathology of the syndrome. Study financed by Fondecyt 1080228. PMID- 26105274 TI - OS060. Exercise training promotes placental growth and development in an animal model of preeclampsia superimposed on chronic hypertension. AB - INTRODUCTION: Chronic hypertension is an important risk factor for preeclampsia, increasing the prevalence of the disease to 15-25% in pregnant women. Unfortunately there are no known treatments for this disease aside from inducing delivery of the fetus. Nonetheless, several studies have found exercise training to have a protective effect on the risk of developing preeclampsia. OBJECTIVES: To determine the mechanisms implicated in the preventive effect of exercise training on preeclampsia, by focusing on the placenta. METHODS: Double transgenic mice, overexpressing both human renin and angiotensinogen (R(+)/A(+)), were used to investigate the effect of exercise training on an animal model of preeclampsia superimposed on chronic hypertension. Mice were placed in cages with free access to an exercise wheel 4 weeks prior to and during pregnancy. At gestational day 18, mice were sacrificed and their organs were collected. Real time PCR and Western Blot were performed to evaluate placental genes and proteins, respectively. Circulating sFlt-1(soluble Fms-like tyrosine kinase-1) levels were investigated by ELISA. Placental alterations were assessed by histology and immunohistochemistry, while blood pressure was measured by radiotelemetry. RESULTS: Sedentary R(+)/A(+) mice presented with significantly greater placental pathology, which was normalized with exercise training. This was characterized by a normalization of cytokeratin and histone H3 protein expression, thereby restoring placental development, specifically looking at trophoblasts and trophoblast giant cells, respectively. This exercise training effect appears to normalize placental growth primarily by promoting angiogenesis and development. Indeed, a pro-angiogenic shift could be detected which was characterized by an increase in placental growth factor gene expression, along with a decrease in sFlt-1 gene expression, which produced a decrease in circulating sFlt-1. Sedentary R(+)/A(+) mice also presented with a significant increase in VEGF protein, which was significantly decreased with exercise. Of interest, since it has been observed to be decreased with preeclampsia, insulin regulated aminopeptidase (IRAP) gene expression was significantly increased in the trained transgenic mice. Finally, exercise training prevented the increase in blood pressure normally observed at the end of gestation in sedentary R(+)A(+) mice. CONCLUSION: Exercise training both before and during gestation appears to promote placental growth and development by producing a pro-angiogenic placental environment. Put together, along with the lack in blood pressure increase, these factors may be responsible for preventing the development of preeclampsia in our animal model of preeclampsia superimposed on chronic hypertension. Identifying the mechanisms implicated in exercise-induced preeclampsia risk reduction will be critical to improve preeclampsia prophylaxis. PMID- 26105275 TI - OS061. Placental growth factor reduces blood pressure and proteinuria in experimental preeclampsia. AB - INTRODUCTION: Preeclampsia is a disorder related to an imbalance in the angiogenesis axis manifesting as endothelial dysfunction. Animal and human studies have shown that sFLT-1 (soluble fms like tyrosine kinase 1) is increased and PlGF (placental growth factor) reduced during the disease state. There are a paucity of studies investigating the clinical significance of normalising angiogenic axis. OBJECTIVES: To use a non-human primate uteroplacental ischemic (UPI) model of preeclampsia to assess if reversing the angiogenic imbalance, by increasing circulating PlGF, is able to ameliorate the hypertension and proteinuria. METHODS: Hypertensive proteinuria was induced in a non-human primate (Papio hamadryas) by ligation of a unilateral uterine artery at 130days of an 182day pregnancy. After two weeks of UPI, PlGF was administered by subcutaneous injection (100mg/kg/day) for 5 days (n=3) or normal saline in an equivalent volume (n=3). Blood pressure was monitored via intra-arterial radiotelemetry, sFLT-1 measured via ELISA and spot urinary protein:creatinine ratios were measured to monitor proteinuria. Data was analysed using SPSS by t-tests and analysis of repeated measures. Significance was set at p<0.05 and data expressed as the mean +/-SEM. RESULTS: After two weeks of UPI both groups demonstrated a significant elevation in blood pressure, proteinuria (p<0.05) and sFLT-1 (p<0.001). The systolic BP increased by 12.4+/-2.3mmHg and 11.7+/-2.9mmHg in the PlGF and control groups respectively compared to baseline (p<0.005). After PlGF administration, there was a significant reduction in blood pressure in the treated group (-5.2s+/-0.8mmHg) compared to the increase in BP in the control group (+6.5+/-3mmHg). Proteinuria also reduced in the treated group from 112+/ 51mg/mmol to 38+/-12mg/mmol whilst proteinuria in the control group was unchanged. The total circulating sFLT-1 was not significantly affected by the administration of PlGF after 5days. Although this study was not designed to assess fetal safety or outcomes, there was no adverse fetal outcome attributable to the administration of the PlGF. CONCLUSION: Administration of PlGF resulted in a reduction in BP and proteinuria without significantly affecting total sFLT-1 levels. Correcting the angiogenic axis imbalance may improve the clinical parameters in a non-human primate animal model of preeclampsia. PMID- 26105276 TI - OS062. Oxidative stress mediates podocyte injury in preeclampsia. AB - INTRODUCTION: Emerging evidence has shown that other than glomerular endotheliosis, podocyte injury plays a key role in kidney dysfunction in preeclampsia (PE). Podocyte shedding has been demonstrated in patients with PE, and proteinuria is signature of podocyte injury. We previously found altered distribution and reduced expression of podocyte protein nephrin and podoplanin in shed podocytes in PE. However, the mechanism of podocyte shedding and altered podocyte functional protein expression in shed podocytes in PE is not known. OBJECTIVES: To investigate if oxidative stress could induce podocyte injury in PE. METHODS: Kidney podocytes were isolated from urinary specimen from women with PE. Urinary podocytes were cultured with RPMI 1640 supplemented with 10% FBS and ITS liquid media. Podocyte expression and distribution of nephrin and superoxide dismutase-1 (CuZn-SOD) were determined by immunofluorescent staining. Images were captured by Apotome Observer and were reconstructed with Axiovision software. CuZn-SOD expression was used as an indicator of podocyte oxidative stress. Immortalized human podocytes (AB 8/13 cells) were used as control. Effects of oxidative stress on podocyte nephrin and CuZn-SOD expressions were induced by treating AB 8/13 cells with or without exposure to the hypoxic mimetic agent cobalt chloride. Protein expressions and distributions for nephrin and CuZn-SOD were determined by immunofluorescent staining and by Western blot. RESULTS: In differentiated podocytes (AB 8/13 cells), nephrin and CuZn-SOD were co-localized and expressed in the peripheral region of the foot process area. In contrast, nephrin and CuZn-SOD expressions were markedly reduced or lost in the foot process area in shed podocytes from PE patients. When AB 8/13 cells were treated with cobalt chloride, the patterns of nephrin and CuZn-SOD expressions and distributions were similar to that seen in shed podocytes from PE. Nephrin and CuZn-SOD expression and distribution were time-dependently decreased in AB 8/13 cells treated with cobalt chloride. We further found that after prolonged culture, shed podocytes differentiated into mature podocytes in vitro evidenced by the expression of nephrin and CuZn-SOD at the foot process area of the cells. CONCLUSION: Nephrin is a specific podocyte slit diaphragm protein. The findings of the co-localization of nephrin and CuZn-SOD in differentiated podocytes and a lack of nephrin and CuZn-SOD expressions in shed podocytes from PE suggest that sufficient antioxidant activity is required for maintaining the functional integrity of glomerular podocytes. The differentiation process was associated with functional protein rejuvenation including nephrin, podoplanin, and CuZn-SOD in shed podocytes from PE. The phenomenon of oxidative stress-induced reduced and altered nephrin and CuZn-SOD expression and distribution further suggests that increased oxidative stress contributes to podocyte injury in PE. PMID- 26105277 TI - OS064. Contribute of the L-cysteine/ H2S pathway in placenta homeostasisin hypertensive disorders. AB - INTRODUCTION: Hydrogen sulfide (H2S) is considered the third endogenous gas transmitter besides nitric oxide and carbon monoxide [1]. It is produced from L cysteine or L-methionine via the enzymes cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE). H2S is involved in the control of vascular homeostasis, having either relaxant or contractant effect on smooth muscle cells. The H2S involvement in rat and human intrauterine tissues has also been shown [2]. OBJECTIVES: The aim of our study was to investigate the L-cysteine/ H2S pathway in rat and human placenta in hypertensive state. METHODS: Placental samples were collected from spontaneous hypertensive rats (SHR) and normotensive rat (Wistar Kyoto; WKY). In parallel, placental samples were collected from 10 pre-eclamptic women and 5 controls after caesarean sections. Pre-eclamptic women were divided into two subgroups: Group1 (women who developed Early Preeclampsia, n=4); Group2 (women who developed Late Preeclampsia, n=6). The expression of CBS and CSE was evaluated in sample tissues by Western blotting analysis. The enzymatic activity was assessed in basal and stimulated (L- cysteine) condiction by a colorimetric assay. Statistical analysis was performed by using Student's t test. P<0,05 was considered as statistically significant. RESULTS: The expression of CBS and CSE in placenta of SHR rats were significantly reduced (p<0.05) compared to WKY. The H2S production resulted significantly (p<0,05) lower in SHR than WKY rats. In human placenta, the basal H2S production was similar in the three groups; interestingly the H2S production by adding L-cysteine, was higher in Late Preeclampsia compared to control group. CONCLUSION: H2S was produced in rat and human placenta. CBS and CSE, the enzymes involved in the production of H2S, were down-regulated in SHR rats and, as a consequence the H2S production was significantly reduced. Starting from these data, we tried to analyze the role of hydrogen sulfide in preeclampsia to assess the contribute of this gas transmitter in the development of this condition. Unexpectedly, preliminary data demonstrated that in women developing Late Preeclampsia there was an higher production of H2S after stimulation with L-cysteine, not revealed in Early Preeclampsia or in healthy control group. Our results indicated that the L-cysteine/H2S pathway could contribute to the development of preeclampsia condition. PMID- 26105278 TI - OS063. Vitamin D promotes endothelial progenitor cell differentiationand upregulates VEGF. AB - INTRODUCTION: Preeclampsia is multifactorial in origin but the primary trigger is thought to be related to impaired placentation which is followed by systemic maternal responses. Vitamin D3 deficiency is a worldwide problem and is associated with a substantial increase in preeclampsia risk. Endothelial progenitor cells, in particular their highly proliferative subpopulation of endothelial colony forming cells (ECFC), play an important role in placental vasculogenesis and endothelial repair capacity. However, the mechanisms of vitamin D3 influence on placental development are poorly understood. OBJECTIVES: Therefore we investigated the influence of vitamin D3 on the differentiation of endothelial progenitor cells (ECFCs) in a placental angiogenesis model and hypothesized that vitamin D3 stimulates the expression of vascular endothelial growth factor (VEGF) in ECFCs. METHODS: Umbilical cord blood was obtained from uncomplicated, term pregnancies, the mononuclear cells were isolated and seeded onto collagen-coated culture plates for outgrowth of ECFCs. After preincubation with 10 nM vitamin D3, ECFCs were plated onto Matrigel (BD Biosciences) in the presence of the treatment media. After 6 hours capillary-like tubules were fixed and their total length was determined per well and median values were calculated from n=38 experiments. For mRNA expression analyses total RNA isolation was performed. High capacity cDNA reverse transcription kit (Invitrogen) was used for cDNA synthesis and Real time RT-PCR was performed on the Rotor Gene 6000 PCR instrument (Corbett Research) using VEGF-A primers according to existing literature. Statistical analysis was performed using Wilcoxon signed rank test. RESULTS: Our experiments show a significant promoting effect of vitamin D3 on tubule formation in ECFCs. ECFCs treated with 10nM vitamin D3 showed a 1.27 times higher tubule formation compared to vehicle-treated controls (1.27+/-0.19, p<0.05, n=38). mRNA expression analysis showed a 1.8 times higher expression of VEGF-A mRNA in ECFCs treated with 10nM vitamin D3 compared to controls (1.82+/ 0.43, p<0.0001, n=18). CONCLUSION: Physiological concentrations of vitamin D3 significantly promote the formation of capillary-like structures by ECFCs in a cell culture model. This effect is mediated by an up-regulation of VEGF-mRNA in ECFCs by Vitamin D3. Since the de novo angiogenesis is a crucial step in development of the placenta, a vitamin D deficiency could play an important role in the pathophysiology of preeclampsia. This finding goes along with clinical studies in which vitamin D deficiency increases the risk of preeclampsia substantially. PMID- 26105279 TI - OS065. Placental growth factor as a diagnostic and prognostic test forplacental complications of pregnancy. AB - INTRODUCTION: Placental growth factor (PlGF) levels in maternal circulation are altered in pre-eclampsia and intrauterine growth restriction (IUGR) (Benton et al.) and may have utility in identifying cases associated with placental dysfunction and stratifying pregnancy survival. OBJECTIVES: We sought to determine if a positive PlGF test measured on the Triage PlGF rapid assay (Alere, San Diego) agrees with the clinical diagnosis and predicts preterm delivery. METHODS: EDTA-blood was collected from women admitted to the AMC Obstetrics Department after 20 weeks of gestation with informed consent and according to the protocol approved by the AMC Medical Ethical Board (10/127). Plasma free PlGF levels from women diagnosed with early-onset pre-eclampsia (n=28), normotensive IUGR (N=6) and pregnancy complications excluding pre-eclampsia and IUGR (n=18) were quantified using the Triage PlGF immunoassay. Samples were collected before GA 34+6 and analyzed in batch assay. Results were interpreted against GA dependent cutoffs set at the 5th centile for gestational age in normal pregnancy (Knudsen et al). PlGF levels below the cutoffs were assigned "positive" according to the product insert. The proportion of subjects with a positive PlGF test result was calculated for each group, together with the proportion of subjects requiring preterm delivery. RESULTS: Twenty-eight women developed early-onset pre eclampsia and, of these, 27/28 (96.4%) had a positive PlGF test. The woman with negative PlGF test presented to clinic at GA 34+3 with hypertension and suspected pre-eclampsia, but delivered at GA 39+4. Six women developed normotensive IUGR, of which 4 had a positive PlGF test, and in each the PlGF level was below the limit of detection of the test. The 2 women with a negative PlGF test had twin pregnancies. Eighteen women developed pregnancy complications excluding pre eclampsia and IUGR. Six had at least one serial sample with a positive PlGF test. Of these, one woman had partial placental abruption, 3 had PPROM, one had spontaneous labour at GA 33+3, and one had bleeding after elective embryo reduction and neonatal death during delivery at 23+3. The proportion of women with a positive PlGF test, where the date of delivery is known, requiring preterm delivery was 34/37 (91.9%). CONCLUSION: These preliminary data suggest that a positive PlGF test by Triage may identify placentally-mediated pregnancy complications and that a very low level of PlGF identifies women at increased risk for preterm delivery. PMID- 26105280 TI - OS066. Intrauterine CYP2J2 expression and circulatingepoxyeicosatrienoic acid levels in preeclampsia. AB - INTRODUCTION: The cytochrome P450 (CYP)-system regulates vascular functions, inflammation, and angiogenesis that are mechanistically important in preeclampsia. OBJECTIVES: The aim of this study was to analyze the dysregulation of the Cytochrome P450 in the pathogenesis of preeclampsia. METHODS: We performed microarray screening of placenta and decidua from 25 preeclamptic women and 23 controls. Results were confirmed by realtime RT-PCR, immunohistochemistry and Serum of patients were analyzed by HPLC tandem mass spectrometry. For functional testing we did cardiomyocyte contraction bioassay and myograph studies. The reduced uterine perfusion pressure (RUPP) rat model was proceed for interventional study. RESULTS: In microarray studies the CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic decidual tissue (3.9 fold, p<0.0001) and in preeclamptic placenta (1.55 fold, p<0.001). RT-PCR confirmed the upregulation and immunohistochemistry, localized CYP2J2 in trophoblasts of villi and deciduas at week 12 and term. The CYP2J2 metabolites were analyzed by HPLC tandem mass spectrometry. 5,6- epoxyeicosatrienoic acids (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids (DHET), were elevated in preeclamptic women compared to controls in the latter two-thirds of pregnancy and after delivery. Stimulation of the trophoblast-derived cell line SGHPL-4 with the preeclampsia-associated cytokine tumor necrosis factor-a enhanced CYP2J2 gene and protein expression. For functional testing, 5,6-EET increased the beating rate of neonatal cardiomyocytes in a bioassay and downregulated large-conductance calcium activated potassium channel KCa 1.1 activity. In the RUPP rat model of preeclampsia, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP inhibitor MsPPOH. Uterine arterial rings of rats also dilated in response to MsPPOH. CONCLUSION: Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction. PMID- 26105281 TI - OS067. VEGF, a novel stimulator of aldosterone production. AB - INTRODUCTION: Adrenal aldosterone production depends upon capillary integrity. Inadequately explained by increased renin secretion, aldosterone is high in pregnancy, a proangiogenic state. In preeclampsia, low aldosterone levels coincide with disturbed endothelial integrity due to disrupted VEGF signaling. OBJECTIVES: We hypothesized that the stimulation of adrenal aldosterone production is VEGF-sensitive. METHODS: We cultured endothelial cells (EC) in the presence and absence of VEGF. The supernatent was transferred to cultured adrenal cells, either the cell line H295R or isolated primary human adrenal cells from zona glomerulosa. aldosterone synthase mRNA and protein expression, aldosterone synthesis was assessed by adding radioactive labeled precursors or measuring aldosterone in the supernatent by Elisa. Cells were cultured either with angiotensin II (Ang II), VEGF or a combination hereof. Adenovirus-based overexpression of the soluble VEGF receptor type 1 (sFlt-1) was used to simulated conditions of preeclampsia in rats and its effect on the adrenocortical vasculature and circulating aldosterone levels. RESULTS: EC conditioning in the presence of VEGF enhanced aldosterone synthase activity in human adrenocortical cells. VEGF either alone or combined with Ang II increased aldosterone synthase transcription, enzyme availability and aldosterone production in adrenal cells. Neuropilin-1 and VEGF receptor expression differed only for Flt-1 which was present in ECs but not in adrenocortical cells. In contrast to Ang II, VEGF did not upregulate the steroidogenic acute regulatory protein. In line with this observation, Ang II stimulated both aldosterone and cortisol synthesis from progesterone whereas VEGF preferably the former. In rats, overexpression of sFlt 1 which traps VEGF led to adrenocortical capillary rarefaction. Serum aldosterone concentrations inversely correlated with sFlt-1 levels. CONCLUSION: In conclusion, VEGF stimulates aldosterone production indirectly via ECs and directlyin adrenocortical cells a finding explaining the increased aldosterone/renin ratio in normal pregnancy. It is reasonable to assume that the inappropriately low aldosterone availability in preeclampsia is a consequence of the known disturbed VEGF signaling. PMID- 26105282 TI - OS068. 25-Hydroxyvitamin D and angiogenic factors in early-onset severe preeclampsia. PMID- 26105283 TI - OS070. Shared genetic risk factors for preeclampsia and cardiovascular disease. AB - INTRODUCTION: There is compelling evidence to support the hypothesis that a maternal constitutional predisposition to cardiovascular disease (CVD) is a key component in development of preeclampsia. In particular, CVD and preeclampsia share pathological features such as endothelial dysfunction and inflammation, and have several metabolic abnormalities in common. In support of this hypothesis, our recent genetic dissection of the Australian preeclampsia susceptibility locus on chromosome 2q22 revealed shared novel genetic risk factors for preeclampsia and CVD-related traits. OBJECTIVES: To replicate association between our recently reported 2q22 preeclampsia risk variants and CVD-related traits in an independent Australian population based cohort. METHODS: Four independent SNPs from four genes, rs35821928 (LRP1B), rs17783344 (GCA), rs115015150 (RND3) and rs2322659 (LCT), were recently found to be significantly associated with preeclampsia susceptibility and CVD-related traits. These SNPs were genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of blood samples from 1246 mothers and 1461 adolescents and clinical measures such as, but not limited to, anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of these four potential preeclampsia susceptibility SNPs against the CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action. RESULTS: Several significant associations (p<0.05) for all four SNPs with a variety of CVD-related risk traits were detected, both for the mothers and the adolescents. The LRP1B SNP was associated with HDL/cholesterol ratio, LDL cholesterol, triglycerides, skinfold measures and weight. The GCA SNP was associated with total cholesterol, HDL cholesterol, serum insulin, hemoglobin, blood glucose, BMI and skinfold measures. The RND3 SNP was associated with triglycerides and waist-hip ratio. The LCT SNP was associated with hemoglobin, blood glucose and abdominal skinfold. CONCLUSION: We have recently identified genetic variants within the LRP1B, GCA, RND3 and LCT genes to be significantly associated with preeclampsia susceptibility and CVD-related risk traits. We have now demonstrated thatthese specific genetic variants are associated with CVD related risk traits in an independent population. Our collective findings provide substantial empirical data to support the hypothesis that genetic risk factors for preeclampsia and CVD are, at least in part, shared. PMID- 26105284 TI - OS069. Light, a TNF superfamily member, contributes to pathophysiology in a mouse model of preeclampsia. AB - INTRODUCTION: Preeclampsia (PE) is associated with alterations in the renin angiotensin system due to the presence of autoantibodies that activate the major angiotensin receptor, AT1R. The resulting chronic activation of the AT1 receptor is believed to contribute to a pro-inflammatory state that is also characteristic of PE. Microarray analysis revealed a pronounced increase in the abundance of LIGHT, a potent member of the TNF superfamily that has emerged as a key factor mediating strong T-cell inflammatory responses and a contributor to autoimmune disease pathogenesis. OBJECTIVES: The goal of research described here is to determine the contribution of LIGHT to the pathophysiology of PE. METHODS: An ELISA, specific for LIGHT was used to validate the results of the initial microarray analysis. Infusion experiments were used to determine the effects of elevated LIGHT in pregnant and non-pregnant mice. An adoptive transfer model of PE in pregnant mice was used to determine if AT1R agonistic autoantibodies (AT1AA) stimulate LIGHT production. The potential contribution of increased LIGHT to clinical features of PE in pregnant mice was evaluated by the use of neutralizing antibodies directed to the LIGHT receptors, HVEM and LTbetaR. RESULTS: The use of a LIGHT-specific ELISA showed that the cytokine was significantly increased in the circulation and placentas of women with PE. The infusion of recombinant LIGHT into pregnant mice induced major clinical features of PE, including hypertension and proteinuria. Such changes were not observed when LIGHT was infused into not non-pregnant mice. LIGHT was significantly elevated in a pregnant mouse model of PE based on the introduction of IgG from women with PE. In this autoantibody-injection model of PE, the use of neutralizing antibodies to the LIGHT receptors, HVEM and LTbetaR, blocked autoantibody-induced hypertension, proteinuria, elevated sFlt-1 production, impaired placental angiogenesis and endothelial dysfunction. CONCLUSION: Overall, our studies show that LIGHT is significantly elevated in women with PE and that elevated LIGHT contributes to pathophysiology of PE in an antibody-injection model of PE in pregnant mice. LIGHT-induced pathophysiology can be abrogated by the use of neutralizing antibodies directed at its receptors, HVEM and LTbetaR. These results indicate that LIGHT may have a previously unrecognized role in the pathophysiology of PE and that its detrimental effects are pregnancy-dependent. These findings immediately suggest novel therapeutic possibilities. PMID- 26105285 TI - OS071. Effect of methyldopa on the cerebral circulation in chronic hypertensive pregnancies. PMID- 26105286 TI - OS072. Regional distribution of cerebral white matter lesions years following (pre)eclampsia. PMID- 26105287 TI - OS074. Brachial artery flow-mediated dilatation as a predictor of pre-eclampsia in the first trimester of pregnancy. AB - INTRODUCTION: Increased vascular reactivity secondary to endothelial injury has been reported to be involved in the pathogenesis of pre-eclampsia (PE). However, whether these observations of vascular activity are the result or the cause of PE is still not fully understood. Some studies have shown that pregnant women who subsequently suffer from PE have an impaired flow-mediated dilatation in the brachial artery at the beginning of the second half of pregnancy. However this parameter has not been tested as a first trimester predictor of PE. OBJECTIVES: To investigate the role of maternal brachial artery reactivity during the first trimester of pregnancy (11-14 weeks) for the prediction of PE. METHODS: Prospective study with singleton pregnancies examined at 11-14 weeks of gestation, presenting consecutively for antenatal care in a tertiary Brazilian hospital. Maternal endothelial dysfunction was assessed by flow-mediated dilatation (FMD) of the brachial artery. FMD was assessed in 550 pregnant women by the same examiner. Obstetric and perinatal outcomes were available in 506 patients (92%). A total of 19 cases were excluded, because 6 miscarried, 12 presented isolated fetal growth restriction (FGR) and 1 was considered an "outlier" because of a significant inflammatory medical co-morbidity. The main outcome was PE based on the ISSHP classification, and we considered early-onset PE when delivery occurred before 34 weeks and late-onset PE when delivery occurred after 34 weeks. RESULTS: In a total of 487 patients, 31 cases developed PE (6.3%), with 9 cases (1.8%) of early-PE and 22 cases (4.5%) of late-PE. The mean gestational age of the study was 12 weeks (range 11-14 weeks).The diameter of the brachial artery at rest was similar between control and PE groups (2.83mm and 2.93mm; p = 0.60) and the resistance and pulsatility index measurements also showed no significant differences among these groups. The mean FMD was 7.4 +/- 8.2% in the control group and 7.3 +/- 8.2% in the PE group. Logistic regression analysis determined that FDM was not a predictor of PE (OR=0.99, CI 95% 0.94 1.04; p=0.90). Dividing the cases of PE in early and late-onset, it was also observed that the mean diameter of the brachial artery at rest was similar among these groups, and that after the shear stress test the diameter was not significantly different in patients who developed early-PE. CONCLUSION: Maternal brachial artery reactivity assessed by FMD in the first trimester of pregnancy is not a predictor of PE. PMID- 26105288 TI - OS073. Over-expression of MIRNA-203 results in increased inflammatory response in endothelial cells: a mechanism of increased endothelial inflammatory response in preeclampsia. AB - INTRODUCTION: MicroRNAs are small, non-coding RNAs that post-transcriptionally regulate gene expression and play important roles in various biological and pathological processes. Several miRNAs have been found to regulate endothelial cell (EC) function. Studies have shown that miR-203 plays an important role in the inflammatory response. OBJECTIVES: The present study was designed to specifically investigate miR-203 in the regulation of endothelial inflammatory responses and to determine if over-expression of miR-203 expression could lead to increased inflammatory response that is associated with endothelial activation/dysfunction in preeclampsia (PE). METHODS: Total RNA was isolated from ECs from 8 normal and 11 PE pregnancies. miR-203 expression was determined by real-time PCR. Relative miR-203 expression was calculated by comparative CT with formula 2(-DeltaDeltaCt). To determine if increased miR-203 expression is associated with increased EC inflammatory response, ECs were transfected with pre miR-203. Successful transfection of pre-miR-203 in ECs was confirmed by RT-PCR and U6 expression. EC production of ICAM, IL-6, and IL-8 were measured by ELISA. EC mRNA expressions for ICAM, IL-6, and IL-8 were determined by RT-PCR. miR-203 induced increased inflammatory response was also determined by leukocyte endothelial adhesion assay. Leukocyte myeloperoxidase (MPO) activity was measured as an indicator of leukocyte adhesion. RESULTS: (1) miR-203 expression was significantly increased in ECs from PE compared to normal pregnant controls (p<0.05) and the increased miR-203 expression was associated with increased ICAM expression in PE-ECs; (2) ICAM, IL-6, and IL-8 production and expression were significantly increased in ECs transfected with pre-miR-203, p<0.01; (3) MPO activity was significantly increased in ECs transfected with miR-203 compared to the controls, p<0.05. CONCLUSION: miR-203 expression is increased in PE-ECs. Over expression of miR-203 in ECs results in: (1) increased endothelial adhesion molecule ICAM production and expression; (2) increased inflammatory cytokine IL-6 and IL-8 productions and expressions; and (3) increased leukocyte and endothelial adhesion. Increased endothelial adhesion molecule expression and cytokine production are well-recognized endothelial inflammatory responses in PE. Therefore, our data provide strong evidence that increased miR-203 expression could be a molecular mechanism that leads to endothelial activation/dysfunction in PE. PMID- 26105289 TI - OS075. Endothelial-dependent vascular function is significantly impaired in obesity and restored by overexpression of DDAH1: Evidence for the role of ADMA. AB - INTRODUCTION: Obesity is a significant independent risk factor for preeclampsia. Vascular dysfunction is a central pathophysiological feature of preeclampsia. Vascular dysfunction is common in obesity. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and metabolized primarily by the enzyme DDAH1. ADMA is significantly elevated in obesity and preeclampsia. OBJECTIVES: The focus of this study was to investigate the role of elevated ADMA in obesity-mediated vascular dysfunction. METHODS: Endothelial-dependent and independent- vascular function of mesenteric arteries was assessed using an isometric myograph. Arteries from pregnant female C57/B6J control lean (n=7), control obese (n=12), DDAH1 overexpressing lean (n=6) and DDAH1 obese (n=10) mice were investigated. Obesity was induced by a high fat diet (42% fat, with adjusted calories, Harlan Teklad) for 8 weeks prior to mating. Data were analyzed by repeated measures ANOVA with significance at p<0.05. RESULTS: DDAH1 transgenic mice and control wild-type mice both increased body weight significantly on the high fat diet compared to lean mice (p<0.01). Obese mice also evidenced significantly elevated leptin concentrations (control obese= 4.1ng/ml and DDAH1 obese 3.9ng/ml) compared to lean mice (1.1ng/ml, p<0.05) reflecting increased adiposity. Contractile response to phenylephrine was not different between arteries from all groups of pregnant mice, however tension was greater in arteries from control obese mice compared to control lean mice (p<0.01). Methacholine-induced endothelial-dependent relaxation was significantly blunted in arteries from control obese mice (66+/-14%) compared to control lean mice (93+/-2%, p<0.001). In contrast, endothelial-dependent relaxation was intact in arteries from DDAH1 obese mice (90+/-8%). Endothelial-dependent relaxation was restored in arteries from control obese mice by ex-vivo incubation with L arginine (91+/-9%). Endothelial-dependent relaxation was not different between arteries from all groups of mice in the presence of the nitric oxide synthase inhibitor L-NAME. Similarly, endothelial-independent relaxation in response to nitroprusside was not different between arteries from all groups of mice. CONCLUSION: Overexpression of the ADMA metabolizing enzyme DDAH1 is protective of the obesity-mediated loss in endothelial-dependent relaxation. These data suggest that elevated ADMA is a significant contributor to vascular dysfunction in pregnancy. ACKNOWLEDGEMENT: This project supported by National Institutes of Health grant R01-HL091094. PMID- 26105290 TI - OS076. The effect of lectin-like oxidized low density lipoprotein receptor monoclonal antibody (LOX-1 MAb) on the expression of eNOS in preeclamptic HUVECs model. AB - INTRODUCTION: Preeclampsia is a major cause of fetal and maternal morbidity and mortality and it still occurs in 7-10% of all pregnancies worldwide. The pathophysiology remains unclear and so it was named "a disease of theories". Clinical and biochemical evidences assumed that disruption of normal endothelial cells may be the primary cause in the pathogenesis of preeclampsia. Factors that cause endothelial dysfunction are not certainly known, but the evidence suggests that factors related to the placenta. In a previous study conducted, HUVECs were found to significantly increase the uptaking of Ox-LDL by endothelial cells in response to the exposure to preeclampsia plasma when compared with non-pregnant women plasma and plasma of pregnant women. Ox-LDL binds to LOX-1 in vascular cells, including endothelial cells and smooth muscle cells, and is thought to cause endothelial dysfunction in patients with preeclampsia. One sign of endothelial dysfunction is the decline in biological activity of endothelial derived NO. NO biological half-time in vivo is less than 1 second. Nitric oxide is produced by the five-electron oxidation of L-arginine which is catalyzed by the enzyme eNOS. This research will observes the expression of eNOS in HUVECs PE model which were exposed to 5, 10, 20MUg/ml LOX-1 MAb (lectin-like oxidized LDL receptor monoclonal antibody). OBJECTIVES: To know the effect of LOX-1 MAb on the expression of eNOS in Preeclamptic HUVECs Model. METHODS: The study used HUVECs PE model which is HUVECs culture that was exposed with pre-eclamptic serum and it shown endothelial dysfunction. HUVECs culture was taken from the endothel of umbilical cord of newborn. HUVECs culture were divided into four groups: (1) HUVECs + Preeclamptic serum (HUVECs PE model), (2) HUVECs PE Model + LOX-1 MAb 5MUg/ml, (3) HUVECs PE Model + LOX-1 MAb 10;MUg/ml, 4) HUVECs PE Model + LOX-1 MAb 20MUg/ml. We performed immunocytochemistry study using primary antibody (anti eNOS) while eNOS expression was observed in each group. The data were analyzed using ANOVA, Tukey's test, Correlation and Regression test. RESULTS: eNOS expression in group 1 was significantly different with group 2, 3 and 4 (p<0.05). Group 2 was significantly different with group 1, 3 and 4 (p<0.05). In group 4 and 5 there were no significant difference each other, but both were significantly different with group 1 and 2 (p<0.05). About 72% of the expression of eNOS in HUVECs PE model were influenced by exposure LOX-1 MAb and the other 28% were influenced by other factors. In the observation of HUVECs PE model, we found that the higher dosage of LOX-1 MAb given on the model, the eNOS expression will increase proportionally. CONCLUSION: Exposure of LOX-1 MAb will significantly increase eNOS expression on HUVECs PE model. We concluded that the higher dosage of LOX-1 MAb given on the HUVECs PE model, the eNOS expression will increase proportionally. PMID- 26105291 TI - OS077. The chromosome 2q22 preeclampsia susceptibility locus reveals shared novel risk factors for CVD. AB - INTRODUCTION: We have previously localized a preeclampsia susceptibility locus on chromosome 2q22 in 34 Australian and New Zealand (AUS/NZL) families. Using an extended number of AUS/NZL families (n=74) we have now performed a comprehensive molecular genetics dissection of this locus. OBJECTIVES: Identify causal genetic risk factors for preeclampsia at the 2q22 risk locus. METHODS: To prioritize positional candidate genes for analysis we used a combination of bioinformatics, SNPing, whole-genome transcriptional profiling and proximity to the peak linkage signal. Prioritized genes were earmarked for exon-centric re-sequencing in 48 founder individuals from the 74 AUS/NZL families. All identified sequence variants were genotyped back in this extended familial cohort. Variants showing the strongest genetic association were genotyped in independent case-control cohorts from Australia (n=1095), Norway (n=3397) and Finland (n=1519), and in a large cohort of Mexican American families rich in quantitative cardiovascular disease (CVD) risk traits. RESULTS: We interrogated 1598 variants from 52 genes and identified four independent SNPs to be significantly associated with preeclampsia susceptibility in the 74 AUS/NZL families. These four SNPs reside in four novel preeclampsia candidate genes: LCT (rs2322659, p=0.002), LRP1B (rs35821928, p=0.0001), RND3 (rs115015150, p=0.002) and GCA (rs17783344, p=0.002). We could only replicate the LCT SNP association in the Australian case control population (p=0.04, combined p=0.001). These four SNPs are however, significantly associated with several quantitative CVD risk traits such as oxidative stress indicators, inflammatory biomarkers and obesity risk factors. CONCLUSION: Previous independent studies have reported significant genetic associations with total cholesterol levels and obesity risk factors for variants within LCT and LRP1B, respectively. RND3 inhibits the biological activity of a downstream effector protein, ROCK, which is known to affect endothelial dysfunction, inflammation, oxidative stress and vascular re-modeling. Grancalcin (GCA) is known to impact the adhesive properties of fibronectin, a marker for endothelial vascular injury. To our knowledge, data from the current study present for the first time empirical evidence of possible shared genetic risk factors underlying both preeclampsia and other CVD-related traits. PMID- 26105292 TI - OS078. Fetal growth restriction: A marker of severity of early-onset pre eclampsia? AB - INTRODUCTION: Pre-eclampsia (PE), particularly early-onset PE (PE requiring delivery before 34 weeks), is commonly associated with fetal growth restriction (FGR). The evidence for an association between FGR and a more severe PE phenotype is controversial. OBJECTIVES: The main aim of this study was to investigate whether the presence of FGR in women with early-onset PE is associated with more severe maternal disease compared to those with appropriately grown fetuses (AGA). METHODS: This was a retrospective cohort study of women with early-onset PE between 2001 and 2010 at University College London Hospital. The diagnosis of PE was made according to the criteria defined by the International Society of the Study of Hypertension in Pregnancy (ISSHP). PE was diagnosed when the systolic blood pressure was 140mmHg or more and/or the diastolic blood pressure 90mmHg or more on at least two occasions four hours apart developing after 20 weeks of gestation in previously normotensive women with proteinuria of 300 mg or more in 24h or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-h collection is available. FGR was defined as birthweight less than the 5th centile, with abnormal umbilical artery Doppler (raised pulsatility index, absent or reversed end-diastolic flow). Maternal, fetal and neonatal data were collected and study groups compared using Chi-square test or Fisher's exact test (categorical variables), and Mann Whitney-U test (continuous variables). Data analysis was performed using SPSS 16.0. RESULTS: In women with early-onset PE (n=134), FGR (n=66, 49%) was associated with significantly higher perinatal mortality (p=0.02). Gestational age at delivery was significantly lower in the FGR group (median, IQR: 29.0 weeks, 28.0-32.8 vs 32.0, 30.0-33.2, p=0.01). However, maternal indicators of PE severity, including blood pressure (3)160mmHg systolic or (3)110mmHg diastolic, ALT>100U/L, platelet count <100*10(9)/L, use of magnesium sulphate or use of antihypertensive therapy, were similar in the two groups. CONCLUSION: In women with early onset PE, FGR was associated with worse perinatal outcome, but was not associated with a more severe maternal PE phenotype. This may be because the presence of FGR in these women leads to earlier iatrogenic delivery, before the maternal condition deteriorates, but further studies are needed to investigate this. PMID- 26105293 TI - OS079. Fetal deglycosylated apolipoprotein C-III (Apo C-III0) concentration is altered in intrauterine growth restriction. AB - INTRODUCTION: We recently demonstrated that serum lipid levels are altered in growth restricted fetuses (IUGR) [1]. OBJECTIVES: We now aimed to analyse the proteome profile of umbilical cord blood in order to gain a greater understanding about metabolic changes in IUGR fetuses. METHODS: umbilical cord blood serum samples of IUGR (n=15) and of gestational age matched controls (CN; n=15) were subjected to fractionation by affinity chromatography using a bead system with hydrophobic interaction capabilities. So prepared protein mixtures were forwarded to MALDI-TOF mass spectrometric profiling. Assignment of ion signals in the mass spectra to specific proteins was substantiated by SDS-PAGE in conjunction with peptide mass fingerprint analysis. Concentrations of proteins of interest were additionally measured by ELISA. Statistical estimations were performed by Student's t-test and calculation of Spearman's correlation coefficient. RESULTS: MALDI mass spectra showed on average more than 60 protein ion signals between m/z 4000 and 25,000. The six best differentiating ion signals were found at m/z 8205, m/z 8766, m/z 13,945, m/z 15,129, m/z 15,308, and m/z 16,001. One of the constituent of this proteome signature is the deglycosylated form of apolipoprotein C-III, apo C-III0 (8766 m/z) that is known to prevent triglycerides from catabolism. While total Apo CIII concentration tended to be decreased (IUGR 22.54MUg/mL SD 10.25. CN 29.9MUg/mL SD 15.46. p=0.1355) calculated Apo C-III0 concentration levels has been found to be more abundant in the IUGR cord blood serum samples (IUGR 1.99MUg/mL SD 0.85. CN 1.15MUg/mL SD 0.55. p<0.0001). Moreover, fetal triglycerid levels were significantly increased in IUGR (IUGR 16.7mg/dL SD 7.58. CN 56.5mg/dL SD 49.92. p-value after log transformation =0.0008)and apo C-III0 was highly correlated to fetal triglyceride levels (rho=0.694). CONCLUSION: Using mass spectrometric approaches we successfully developed an IUGR specific proteome signature derived from human umbilical cord blood samples. Most interesting the deglycosylated form of the apolipoprotein C-III (apoC-III0) was found to be significantly increased in IUGR and thus might lead to reduced triglyceride catabolism. This observation is in agreement with the known observation of triglyceride levels being increased in IUGR fetuses. Our results indicate that subtle alterations in protein glycosylation need to be considered for improving our understanding of the pathomechanisms in IUGR. PMID- 26105294 TI - OS080. Maternal and fetal lipoprotein concentrations and expression of placental lipoprotein transporters in pre-eclampsia and normotensive controls. PMID- 26105295 TI - OS081. Novel KCNQ3/KCNE5 isoform protein and mRNA expression in first trimester human placentae. AB - INTRODUCTION: Potassium channel alpha-subunits encoded by KCNQ1-5 genes (Kv7) form voltage-dependent channels that can be modulated by KCNE1-5 encoded accessory proteins. These channels are known to play a role in the reactivity of blood vessels. We have previously shown that both mRNA and protein expression for the novel combination of KCNQ3 and KCNE5 are increased in term and preterm pre eclampsia (PE) compared to normotensive control placentae [1]. The expression of these isoforms in early placental tissue has not been examined. OBJECTIVES: The aims of this study were to determine whether KCNQ3 and KCNE5 mRNA and proteins are expressed in first trimester placental tissue. METHODS: Placental samples were obtained from women undergoing elective surgical termination of pregnancy between 6 and 12 weeks' gestation (n=7) following informed written consent. KCNQ3 and KCNE5 mRNA expression was measured by qRT-PCR and normalised to stably expressed GAPDH. Immunohistochemistry was used to assess protein expression and localisation of the isoforms. RESULTS: Both mRNA and protein expression of KCNQ3 and KCNE5 were detected in placental tissue at all gestations. KCNE5 mRNA expression remained constant between 6 and 10 weeks with a subsequent rise at 11 and 12 weeks. KCNQ3 mRNA expression was initially lower than KCNE5 but markedly increased at 7 weeks remaining high until 10 weeks and falling below KCNE5 levels by 12 weeks. Protein expression for both KCNQ3 and KCNE5 was localised mainly to the syncytiotrophoblast but was also evident in the mesenchyme; overall KCNQ3 intensity significantly increased with gestational age (p=0.044). CONCLUSION: KCNQ3 and KCNE5 channel isoforms are highly expressed in first trimester placenta. The temporal changes in mRNA expression mirror changes in the placental tissue oxygen tension which increases between 8 and 10 weeks. This would precede the dislocation of the spiral artery plugs enabling maternal blood to flow freely and continuously into the intervillous spaces. We speculate that the increase in mesenchymal protein expression may be related to angiogenesis during this critical window of feto-placental vascular development. Future work will characterise the complete KCNQ/KCNE isoforms in first trimester placental tissue and assess potential functional roles of these channels both in early placentation and in relation to PE. FUNDING: Tommy's Charity (Registered charity 1060508). PMID- 26105296 TI - OS082. CHIPS-Child: Testing the developmental origins hypothesis. AB - INTRODUCTION: CHIPS-Child is a natural test of the Developmental Origins of Health and Disease hypothesis (DOHaD) [1,2]. Reduced fetal growth rate is associated with adult cardiovascular risk markers (e.g., obesity) and disease [3,4]. Evidence worldwide indicates that this relationship is independent of birth weight. The leading theory describes 'developmental programming'in utero leading to permanent alteration of the fetal genome. While those changes are adaptive in utero, they may be maladaptive postnatally. OBJECTIVES: To directly test, for the first time in humans, whether differential blood pressure (BP) control in pregnancy has developmental programming effects, independent of birth weight. We predict that, like famine or protein malnutrition, 'tight' (vs. 'less tight') control of maternal BP will be associated with fetal under-nutrition and effects will be consistent with developmental programming. METHODS: CHIPS-Child is a parallel, ancillary study to the CHIPS randomized controlled trial (RCT). CHIPS is designed to determine whether 'less tight' control [target diastolic BP (dBP) 100mmHg] or 'tight' control [target dBP 85mmHg] of non-proteinuric hypertension in pregnancy is better for the baby without increasing maternal risk. CHIPS-Child will examine offspring of CHIPS participants non-invasively at 12m corrected post-gestational age (+/-2m) for anthropometry, hair cortisol, buccal swabs for epigenetic testing and a maternal questionnaire about infant feeding practices and background. Annual contact will be maintained in years 2-5 and will include annual parental measurement of the child's height, weight and waist circumference. CHIPS will recruit 1028 women. We estimate that 80% of CHIPS centres will participate in CHIPS-Child, approximately 97% of babies will survive, and 90% of children will be followed to 12m resulting in a sample size of 626. Power will be >80% to detect a between-group difference of ?0.25 in 'change in z-score for weight' between birth and 12m (2-sided alpha=0.05, SD 1). RESULTS: Recruitment has begun. The primary outcome will be the between-group difference in early postnatal weight gain ('change in z score for weight') between birth and 12m (p<0.05). Secondary:outcomes are (i) hypothalamic pituitary adrenal axis function (hair cortisol for overall cortisol production); and (ii) between-groups differences in DNA methylation, using targeted (genes associated with growth, obesity, cardiovascular disease, and/or a developmental programming effect) and global (genome-wide microarray) methods. CONCLUSION: CHIPS-Child offers a unique opportunity to both clarify whether differential dBP control in pregnancy has developmental programming effects and contribute to our understanding of human biology and diversity in a way that a cross-sectional or other observational studies cannot. PMID- 26105297 TI - OS084. Maternal haemodynamics at 11-13 weeks of gestation and adverse pregnancy outcomes. AB - INTRODUCTION: Women who develop adverse pregnancy outcomes are at increased risk of cardiovascular disease. In individuals with cardiovascular disorders there is increased central aortic systolic blood pressure (SBPAo) and arterial stiffness. OBJECTIVES: The hypothesis is that increased SBPAo and arterial stiffness are apparent before the clinical onset of adverse pregnancy outcomes. METHODS: This was a prospective study in singleton pregnancies at 11(+0)-13(+6) weeks' gestation. Pulse wave velocity (PWV), augmentation index (AIx) and SBPAo were measured. At the same visit, we recorded maternal characteristics and medical history and performed combined screening for aneuploidies. We also measured the uterine artery Doppler pulsatility index (PI). The study outcomes included preeclampsia (PE), gestational hypertension (GH), gestational diabetes (GDM), small for gestational age (SGA) and preterm delivery (PTD). The diagnosis of PE and GH was made according to the guidelines of the International Society for the Study of Hypertension in Pregnancy. The neonate was considered SGA if the birth weight was less than the 5th percentile for gestation at delivery. The diagnosis of GDM was made if the fasting plasma glucose level was at least 6 mmol/L or the plasma glucose level 2 h after oral administration of 75 g glucose was 7.8 mmol/L or more (WHO). We compared these parameters in those that developed PE (n=181), GDM (n=105), GH (n=137), SGA (n=337), PTD prior to 37 weeks' gestation (n=354) with unaffected controls (n=6,766). Multiple regression analysis was used to examine which maternal characteristics provided a significant contribution in the prediction of AIx-75, PWV and SBPAo. Each value was expressed as a multiple of the median (MoM) after adjustment for those characteristics. Pearson correlation analysis was used to examine the association between log10AIx-75 MoM, log10PWV MoM, log10 SBPAo MoM, log10uterine artery PI MoM and log10PAPP-A MoM with gestational age at delivery. RESULTS: In the PE group there was an increase in AIx-75 (1.13, IQR 0.96-1.33 MoM vs 1.00, IQR 0.87-1.16 MoM, p<0.0001), PWV (1.11, IQR 0.97-1.17 MoM vs 1.00, IQR 0.90-1.12 MoM, p<0.0001), and SBPAo (1.09, IQR 1.02-1.20 MoM vs. 1.00, IQR 0.94-1.08 MoM, p<0.0001). In those that subsequently developed GH, compared to unaffected controls, there was no significant difference in the uterine artery PI, PAPP-A or PWV but AIx-75 and SBPAo were increased (p<0.0001). In the GDM group there was an increase in PWV (1.06, IQR 0.96-1.19 MoM vs. 1.00, IQR 0.90-1.13 MoM, p=0.001) and SBPAo (1.03, IQR 0.98 1.14 vs. 1.00, IQR 0.94-1.08, p<0.0001), but no significant difference in the AIx 75 (1.02, IQR 0.89-1.22 MoM vs. 1.00, IQR 0.87-1.17 MoM, p=0.118). Compared to women who had term delivery, women who had iatrogenic PTD had significantly higher AIx-75 (1.08, IQR 0.91-1.27 MoM vs. 1.00, IQR 0.86-1.16 MoM, p<0.001) and SBPAo (1.06 MoM, IQR 0.98-1.15 vs. 1.00, IQR 0.93-1.07, p<0.001). CONCLUSION: A high proportion of women who develop PE, GDM or iatrogenic PTD have increased SBPAo and arterial stiffness that is apparent from the first trimester of pregnancy. PMID- 26105298 TI - OS083. Fetal growth and maternal vascular function in early pregnancy. AB - INTRODUCTION: Increasing evidence indicates that the rate of fetal growth is partly determined already in the first half of pregnancy. A number of authors have reported that if the fetus is smaller than expected at dating, the risk for a small for gestational age fetus increases. OBJECTIVES: To investigate if maternal vascular function in early pregnancy reflects fetal growth in the first trimester. METHODS: Fifty healthy women with singleton viable pregnancies were included in the study that were recorded the ultrasound department of UltraGyn Stockholm, Sweden for ultrasound dating in gestational week 11-14 . Of these, 25 women had their estimated date of delivery postponed ? 7 days at ultrasound dating compared to last menstrual period in gestational week 11-14. As controls 25 women were fetal size were in accordance with the last menstrual period (defined as expected date of delivery moved less than six days) were recruited. The dating examinations were performed by specially trained midwives. To assess gestational age, biparietal diameter was used. Exclusion criteria were the use of oral contraceptives within three months before conception, uncertain date of the last menstrual period, irregular menstrual periods, fetuses that were ? 21 days larger or smaller than expected, and fetal anomalies. Women that smoked were also excluded. Blood pressure was measured in the upper arm in a conventional way. The central blood pressure was calculated with a validated algorithm. Changes in skin microcirculation were measured using laser Doppler fluxmetri (LDF). Both endothelial dependent dilatation using assessment of acetylcholine (Ach) and local warming of skin to 44C for maximum micro vascular hyperaemia (MMH) and non endothelial dilatation using assessment of sodium nitroprusside (SNP) was examined. RESULTS: Fetuses that were smaller than expected at ultrasound dating compared to last menstrual period at gestational week 11-14, had an increased change in maximum micro vascular hyperaemia (p=0.034). There was no significant correlation between ACh-response (p=0.59) and SNP-response (p=0.23). No differences were seen in blood pressure. CONCLUSION: In the first trimester, changes in vascular function might reflect important adaptations that are required to facilitate normal fetal growth. This was highlighted by the findings of a positive correlation between fetal growth at 11-14 weeks gestation and changes in endothelial dependent microcirculation. Vascular function of these women will be followed longitudinally during pregnancy and related to obstetric outcome. If changes in microcirculation in the first trimester correlates to an increased risk for complications such as hypertensive disorders during pregnancy or intrauterine growth restriction this gives new insights into the early phase of these complications. PMID- 26105299 TI - OS085. Decreased maternal circulating PLGF is a significant predictor of length of pregnancy in women with hypertensive disorders of pregnancy. AB - INTRODUCTION: Diagnosis of the presence of disease and prediction of the rate of progression of disease in women with hypertensive disorders of pregnancy remains a clinical problem. Better methods are needed to determine the magnitude of risk to support patient counseling and clinical management. OBJECTIVES: To investigate whether the level of free PlGF is a significant predictor of length of pregnancy in women with hypertension. METHODS: In this case-control study a single sample was taken between the 22nd and 34th completed gestational weeks from 130 pregnant women with a final diagnosis of: pre-eclampsia (PE), HELLP-syndrome, superimposed pre-eclampsia (SIPE), chronic hypertension (CHT), gestational hypertension (GHT), and normal healthy pregnancy (Control). Plasma was analysed for PlGF using the Triage(r) PlGF assay (Alere, San Diego). A positive PlGF test was defined as below the 5th centile of normal healthy pregnancy. Hazard ratios for length-of pregnancy were calculated for a positive PlGF test in a multivariate Cox proportional hazards model adjusting for two covariates, the gestational age at sample collection and a final diagnosis of proteinuric hypertension (PE, HELLP, and SIPE). RESULTS: Median PlGF concentration was significantly lower in women with hypertension than in controls. Women with proteinuric hypertension had the lowest levels of PlGF. A positive PlGF test predicted delivery before 35 weeks in 93.7% women, and delivery before 37 weeks in 90.5% women. A positive PlGF test was associated with a significantly higher risk of imminent delivery. PlGF was a significant and independent predictor of women destined to deliver early because of maternal or fetal complication (adjusted Hazard Ratio of 3.43, 95%CI of 1.97 to 5.98). CONCLUSION: A positive PlGF test is significant predictor of length of pregnancy, independent of other diagnostic criteria. PlGF has the potential to identify increased risk without the limitation of non-specificity which exists with other diagnostic parameters. PMID- 26105300 TI - OS086. Methylation status of the HOXA13 promoter region in placental tissue of pregnancies complicated by early onset severe preeclampsia. AB - INTRODUCTION: Compromised placental function and morphology found in early onset preeclampsia as well as a modified phenotype of the fetus may derive from a deviation in the normal gene expression pattern. Previous studies demonstrated by experimental animal models, that the gene HOXA13 plays an essential role in the arrangement of the placental vascular net, identifying direct and indirect target functions this gene has on the endothelial component. Research in model systems and now expanding to human studies has suggested that the causes and consequences of a variety of pregnancy-related pathologies are connected to epigenetic regulation. OBJECTIVES: To evaluate the methylation status of the promoter region of HOXA13 within placental tissue and its association with specific clinical signs of severe early onset preeclampsia. METHODS: A prospective case - control study was performed to evaluate the methylation status of the promoter region of HOXA13 by pyrosequencing analysis within placental tissue and its association with specific clinical signs of severe early onset preeclampsia (EOSP). RESULTS: The group of preeclamptic patients reached a mean methylation degree of 27.06% (+/-8.94) and 30.56% (+/-8.08) on two CpG islands of HOXA13 5' promoter respectively. Conversely in the group of physiologic controls the mean degree of methylation resulted 15.12%(+/-3.64) (p<0.0016) and 18.25% (+/-3.45) (p<0.0005). CONCLUSION: This study firstly demonstrated that an hypermethylation of placental HOXA13 exists in preeclamptic placental tissues and concentrates only on the gene promoter. Additionally, the existence of a correspondence between themethylation process of the gene promoter HOXA 13 and the clinical manifestation of severe early onset preeclampsia supports the original hypothesis that this process may be at the base of the preeclamptic pathogenesis. PMID- 26105301 TI - OS087. Maternal characteristics, mean arterial pressure and PLGF in early prediction of preeclampsia. AB - INTRODUCTION: In a previous study, we described the predictive value of first trimester pregnancy-associated plasma protein-A (PAPP-A), free beta-subunit of human chorionic gonadotrophin (fb-hCG), Placental Growth Factor (PlGF) and A Desintegrin And Metalloproteinase 12 (ADAM12) for early onset preeclampsia (delivery <34 weeks) [1]. OBJECTIVES: The objective of the current study was to obtain the predictive value of these serum makers, for both early onset PE (EOPE) and late onset PE (LOPE), combined with maternal characteristics and first trimester maternal mean arterial blood pressure (MAP). METHODS: This was a nested case-control study, using stored first-trimester maternal serum from 167 women who subsequently developed PE, and 500 uncomplicated singleton pregnancies which resulted in a live birth =>37 weeks. Maternal characteristics (i.e. medical records, parity, weight, length) MAP and pregnancy outcome (i.e. gestational age at delivery, birthweight, fetal sex) were collected for each individual and used to calculate prior risks for PE in a multiple logistic regression model. MAP values and marker levels of PAPP-A, fb-hCG, PlGF and ADAM12 were expressed as multiples of the gestation-specific normal median (MoMs). Subsequently, MoMs were log-transformed and compared between PE and controls using Student's t-tests. Posterior risks were calculated using different combinations of variables;(1) maternal characteristics, serum markers, and MAP separately (2) maternal characteristics combined with serum markers or MAP (3) maternal characteristics combined with serum markers and MAP. The model-predicted detection rates (DR) for fixed 10% false-positive rates were obtained for EOPE and LOPE with or without intra-uterine growth restriction (IUGR,birth weight <10th centile). RESULTS: The maternal characteristics: maternal age, weight, length, smoking status and nulliparity were discriminative between PE and control groups and therefore incorporated in the multiple logistic regression model. MoM MAP was significantly elevated (1.10 p<0.001; 1.07 p<0.001) and MoM PlGF was significantly reduced (0.95 p=0.016; 0.90 p=0.029) in the EOPE and LOPE group, respectively. The differences in markers for IUGR groups were larger. The estimated DRs of the three different models are presented in the table. CONCLUSION: This study demonstrates that first-trimester MAP and PlGF combined with maternal characteristics are promising markers in risk assessment for PE. Combination of markers proved especially useful for risk assessment for term PE. Detection rates were higher in the presence of IUGR. PMID- 26105302 TI - OS089. Elevated levels of the heme scavenger alpha-1-microglobulin in maternal plasma at the end of first trimester in patients who subsequently develop preeclampsia. AB - INTRODUCTION: Resent research has revealed an increased concentration of free fetal hemoglobin (HbF) in maternal serum from patients who subsequently develops preeclampsia (PE). In a previous study of 96 patients we have shown that HbF in combination with the heme-scavenger alpha-1-microglobulin (A1M) are potential predictive biomarkers of PE. OBJECTIVES: In this validating case-control study we aimed to confirm the previous findings, that A1M is elevated in the maternal circulation at the end of first trimester in patients who subsequently develops PE. In this study A1M was measured in plasma instead of serum. METHODS: Patients were recruited from an ongoing prospective study of new biomarkers to predict and diagnose PE. In total we included 84 patients. 8 patients subsequently developed PE, 4 developed pregnancy induced hypertension (PIH) and 72 were controls with uncomplicated pregnancies. The plasma samples were all taken at 7+0-18+0 weeks of gestation (mean 12+1) and analyzed for concentrations of A1M with Radioimmuno Assay (RIA). This method has been previously described in details. Statistics was performed using one-way ANOVA. RESULTS: The mean plasma concentration of A1M in the PE group was 8.6mg/ml, 6.0 in the PIH group and 7.1mg/ml in the controls group. The PE group differed significantly from the controls group (p=0.004), whereas the PIH group did not differ significantly from the controls. CONCLUSION: Our findings in plasma confirm previous findings described for serum, i.e. A1M is significantly increased in in first trimester maternal plasma in patients who subsequently develops PE. Since A1M is the most efficient heme scavenger we suggest that A1M may be a physiological defense mechanism against the elevated levels of free HbF found in patients who subsequently develops PE or in patients with manifest PE. Furthermore, A1M did not increase in patients who develops PIH later in their pregnancies indicating its specificity for PE. PMID- 26105303 TI - OS088. First trimester triple vascular test for pre-eclampsia prediction. AB - INTRODUCTION: Although PE represents a major cause of maternal and fetal morbidity and mortality, the vascular mechanisms underlying this disorder have not been clearly identified. During the past three decades, while numerous clinical, biophysical, and biochemical screening tests have been proposed for the early detection of preeclampsia, maternal circulation changes during early pregnancy have yet to be fully evaluated for their contribution to PE prediction. OBJECTIVES: The aim of this study was to examine a combination of maternal risk factors, mean arterial blood pressure, uterine artery Doppler, brachial artery flow-mediated dilatation (FMD), and ophthalmic artery Doppler for pre-eclampsia prediction during the first trimester of pregnancy. METHODS: Prospective study with singleton pregnancies examined at 11-14 weeks of gestation, presenting consecutively for antenatal care in a tertiary Brazilian hospital. The base cohort population constituted of 487 singleton pregnancies, including 9 case subjects who developed pre-eclampsia (PE) requiring delivery before 34 weeks (early PE) and 22 with late PE, 47 with gestational hypertension, and 409 cases subjects (84%) who were unaffected by PE or gestational hypertension. Maternal history (nulliparity, previous and family history of PE), body mass index (BMI), mean arterial pressure (MAP), uterine artery pulsatility index, brachial artery FMD and ophthalmic artery Doppler were recorded in all of the cases. Univariate and logistic regression analysis was used to derive algorithms for the prediction of hypertensive disorders. RESULTS: Uterine artery percentile of mean PI was higher in the PE than in the control group (p<0.01). The mean brachial artery FMD was 7.4%+/-8.2% in the control group and 7.3%+/-8.2% in the PE group. Logistic regression analysis determined that FDM was not a predictor of PE (OR=0.99, CI 95% 0.94-1.04; p=0.90) and this test was withdrawn from the predictive model. The average of the first diastolic peak velocity in the ophthalmic artery was higher in the PE group compared with controls (24.56cm/s*21.13cm/s; p<0.01).It was estimated that, with the prediction algorithm for PE, a combination of maternal factors + MAP + uterine artery Doppler or ophthalmic artery Doppler can detect 78% of early-onset PE with 10% false-positive rate. CONCLUSION: Maternal ophthalmic artery Doppler in the first trimester of pregnancy is a novel predictive parameter for PE (especially early-onset PE), it has the same detection rate contribution in a multi-parameter predictive model as would be the case uterine artery Doppler was used instead. PMID- 26105304 TI - OS091. The origin of preeclampsia in diet-induced maternal endothelial stiffness. AB - INTRODUCTION: Despite research documenting variances in cellular hypoxia, angiogenesis, oxidative stress, endothelial signaling, and autoimmunity, the etiology of preeclampsia remains unknown. Women affected by preeclampsia show increased arterial stiffness and abnormal serum lipids when compared to unaffected mothers. Although enzymes modify and synthesize lipids, most acyl chains are incorporated into cell membranes unmodified from the form in which they were absorbed from the gastrointestinal tract. Therefore, diet plays a major role in determining the rheology and composition of cell membranes. OBJECTIVES: A To present a model of how diet might alter cell membrane composition and cause increased maternal membrane viscosity when lipids are actively transported across the placenta to the fetus. B-To demonstrate how rapidly changing maternal membrane composition and viscosity might cause the pathological elements of preeclampsia. METHODS: Literature search. RESULTS: Compared to diets of 10,000 years ago, modern diets have increased trans- and long-chain fatty acids, elevated omega-6 to -3 fatty acid ratios, and produce stiffer cell membranes, therefore might require increased membrane softening components such as cis polyunsaturated fatty acids (PUFA) to maintain homeoviscosity. High fetal requirements for essential PUFAs might deplete body stores of these molecules in mothers with decreased dietary intake, thereby causing increased maternal membrane stiffness. Native proteins are only marginally stable under physiological conditions. A 2005 study using artificial membranes and the receptor rhodopsin, demonstrated that alteration of membrane lipid composition to increase membrane stiffness caused lower rhodopsin activation [1]. Increased membrane stiffness arising from dietary lipid variances might alter membrane proteins and cause the endothelial signaling dysfunction of preeclampsia. Although primary amino acid sequences remain unchanged, the disruption of tertiary protein structure might yield proteins that appear foreign and thus evoke an immune response, giving rise to antibodies such as agonistic autoantibody angiotensin-1. In mitochondria, disruption of electron transport protein structures might interfere with electron tunneling and increase the production of free radicals and oxidative stress. Because oxygen diffuses more rapidly through flexible versus stiff membranes,stiff cell membranes might initiate the signaling cascade indicative of cellular hypoxia in preeclampsia with increased hypoxia inducible factor and angiogenic factors such as soluble endoglin and fms-like tyrosine kinase. The arterial intima acts as a sensor with blood pressure homeostatic responses modulated by the flexibility of endothelial membranes. Similarly to a diaphragm pressure transducer, if the diaphragm material is stiff, the signal is attenuated; conversely, a flexible diaphragm makes the instrument more sensitive to pressure. Thus, stiffened endothelium might cause hypertension. CONCLUSION: This paper presents a unifying molecular and cell membrane-based model of how diet-induced maternal cell membrane stiffness offers a coherent and unifying explanation for the pathological changes seen in preeclampsia. PMID- 26105305 TI - OS090. Performance of candidate clinical and biochemical markers in screening early in pregnancy to detect women at high risk to develop preeclampsia. AB - INTRODUCTION: The advent of early preventive measures, such as low-dose aspirin targeting women at high risk of preeclampsia (PE), emphasizes the need for better detection. Despite the emergence of promising biochemical markers linked to the pathophysiological processes, systematic reviews have shown that, until now, no single tests fulfill the criteria set by WHO for biomarkers to screen for a disease. However, recent literature reveals that by combining various clinical, biophysical and biochemical markers into multivariate algorithms, one can envisage to estimate the risk of PE with a performance that would reach clinical utility and cost-effectiveness, but this remains to be demonstrated in various environments and health care settings. OBJECTIVES: To investigate, in a prospective study, the clinical utility of candidate biomarkers and clinical data to detect, early in pregnancy, women at risk to develop PE and to propose a multivariate prediction algorithm combining clinical parameters to biochemical markers. METHODS: 7929 pregnant women prospectively recruited at the first prenatal visit, provided blood samples, clinical and sociodemographic information. 214 pregnant women developed hypertensive disorders of pregnancy (HDP) of which 88 had PE (1.2%), including 44 with severe PE (0.6%). A nested case-control study was performed including for each case of HDP two normal pregnancies matched for maternal age, gestational age at recruitment, ethnicity, parity, and smoking status. Based on the literature we selected the most promising markers in a multivariate logistic regression model: mean arterial pressure (MAP), BMI, placental growth factor (PlGF), soluble Flt-1, inhibin A and PAPP-A. Biomarker results measured between 10-18 weeks gestation were expressed as multiples of the median. Medians were determined for each gestational week. RESULTS: When combined with MAP at the time of blood sampling and BMI at the beginning of pregnancy, the four biochemical markers discriminate normal pregnancies from those with HDP. At a 5% false positive rate, 37% of the affected pregnancies would have been detected. However, considering the prevalence of HDP in our population, the positive predictive value would have been only 15%. If all the predicted positive women would have been proposed a preventive intervention, only one out 6.7 women could have potentially benefited. In the case of severe PE, performance was not improved, sensitivity was the same, but the positive predictive value decreased to 3% (lower prevalence of severe PE). CONCLUSION: In our low-risk Caucasian population, neither individual candidate markers nor multivariate risk algorithm using an a priori combination of selected markers reached a performance justifying implementation. This also emphasizes the necessity to take into consideration characteristics of the population and environment influencing prevalence before promoting wide implementation of such screening strategies. In a perspective of personalized medicine, it appears more than ever mandatory to tailor recommendations for HDP screening according not only to individual but also to population characteristics. PMID- 26105306 TI - OS092. qPCR-based analysis of podocyturia is a feasible diagnostic tool in preeclampsia. AB - INTRODUCTION: Preeclampsia affects 5% of all pregnancies and is a significant cause of maternal and fetal morbidity and mortalityworldwide. A clinically useful screening test that can predict the development of preeclampsia at an early stage is urgently needed. The detection of podocyturia by immunohistochemistry following cell culture has been noted as a sensitive and specific marker for preeclampsia. However, this method is laborious and carries the risk of cell culture contamination. OBJECTIVES: The aim of this study was to investigate the diagnostic value of qPCR as a rapid and sensitive method to detect podocyturia in women with preeclampsia. METHODS: Mid-stream urine samples were collected from preeclamptic [1] (n=35), healthy pregnant matched for gestational age (n=34), and healthy non-pregnant (n=12) women. mRNA was isolated using the Trizol method. qPCR analysis was performed for nephrin, VEGF, podocin, GAPDH and megalin transcripts. A ROC-curve analysis was performed. RESULTS: Significantly elevated mRNA expression levels of nephrin, podocin and VEGF were detected in preeclamptic women compared to healthy pregnant and healthy non-pregnant controls. A positive correlation (rho=0.82, p<0.0001) was observed between nephrin and VEGF mRNA expression in preeclamptic women. ROC curve analyses demonstrated a strong ability of this method to discriminate between the different study groups. CONCLUSION: qPCR analysis of podocyte-specific molecules in urine samples is a rapid and reliable method to quantify podocyturia. We demonstrate that this method distinguishes preeclamptic patients from healthy controls at disease onset. This method may be a tool for the detection of preeclampsia at an earlier stage, thereby preventing maternal and fetal morbidity and mortality. PMID- 26105307 TI - OS093. Prevalance of sleep disordered breathing in pregnancy. AB - INTRODUCTION: Snoring is a common symptom of Sleep Disordered Breathing (SDB), a condition that is present in 4% of the general population. SDB is identified by snoring and repetitive cessation of breathing during sleep accompanied by repetitive hypoxia and has been found to be associated with hypertension, stroke and heart attack.The general risk factors associated with severe preeclampsia significantly overlap with those reported to increase the risk of SDB syndromes. Further risk factors that need consideration include: multiple pregnancy, diabetes and chronic hypertension treatment. OBJECTIVES: To determine the prevalence of SDB in the pregnant population in a metropolitan hospital and to examine self-reported snoring against actual snoring as determined by Sonomat (c) studies and report fetal outcomes of those who snored compared to those who did not snore. METHODS: A questionnaire containing The Epworth Sleepiness Scale and the Berlin Questionnaire (which examines snoring and tiredness) was administered to 3000 pregnancies over a period of two years. Women were additionally recruited for detailed sleep studies, which entailed continuous night time blood pressure monitoring, encephalogram for sleep staging and continuous night time cardiotocographic monitoring. RESULTS: To date, 2206 surveys have been completed. Sleep studies have been undertaken by 280 women, of which half have continuous blood pressure readings. The detailed data provided through these studies is currently being examined and will be completed by June 2012. CONCLUSION: This study is unique and unprecedented in the scope of detailed data obtained through the variety of parameters measured. Coupled with pregnancy progression and comprehensive maternal and neonatal outcomes, it is anticipated that this multi faceted study will provide a wealth of knowledge on sleep patterns, SDB and its effect on pregnancy for both the mother and the fetus. PMID- 26105308 TI - OS094. Subclinical left ventricular dysfunction in preeclamptic women with preserved left ventricular ejection fraction: A 2D speckle tracking imaging study. AB - INTRODUCTION: Patients with preeclampsia are at risk for cardiovascular disease [1,2]. Changes in cardiac function are subtle in preeclampsia and are quantitatively difficult with conventional imaging. Strain measurements using speckle-tracking echocardiography have been used to sensitively quantifyabnormalities in other disease settings [3]. OBJECTIVES: The objective of this study was to evaluate changes in myocardial strain using speckle tracking echocardiography in women with and without preeclampsia. We hypothesized that global left systolic strain measures would prove more sensitive than conventional left ventricular ejection fraction in detecting early changes in systolic LV function manifesting as subclinical disease prior to overt progression. METHODS: We evaluated the feasibility and sensitivity of strain imaging using speckle tracking echocardiography. Thirty-six women were enrolled in this pilot study; 28 were analyzed: 11 with preeclampsia and 17 without preeclampsia. Echocardiographic Ejection fraction and global peak longitudinal ,radial and circumferential strain were measured. RESULTS: Global Median longitudinal strain was significantly worsened in women with preeclampsia compared to women without preeclampsia (P<0.0001). Similar results were observed for global radial strain (P=0.006) and circumferential strain (P=0.03). There was no significant difference in ejection fraction between the groups (P=0.52) (Table 1). Data are presented as median (interquartile range). CONCLUSION: Myocardial strain imaging using speckle tracking is more sensitive than left ventricular ejection fraction to detect differences in left ventricular systolic function in women with and without preeclampsia. PMID- 26105309 TI - OS095. Impedance cardiography: A straightforward and reliable tool to evaluate differences of cardiac reflex response between normal pregnancy and pre eclampsia. AB - INTRODUCTION: Reflex responses of cardiac cycle time intervals (CCTI) can be measured by echocardiography, and are reported to differ between uneventful pregnancy (UP) and pre-eclampsia (PE). It is unknown whether impedance cardiography (ICG) is a useful method to measure CCTI during pregnancy. OBJECTIVES: ICG measurements of CCTI before and after orthostatic challenge are evaluated in UP and in the clinical phase of PE. METHODS: Examinations were performed twice in 16 UP (30-36 weeks), and once in 30 early PE (EPE, <34 weeks) and in 32 late PE (LPE, ?34 weeks). A 3rd generation ICG device using a 4 electrode arrangement (NICCOMO, Medis, Germany) was used to measure CCTI in supine position and after moving to upright position. The pre-ejection period (PEP) is the time-interval between ventricular depolarisation and start of aortic flow. The left ventricular ejection time (LVET) is the time-interval between opening and closing of the aortic valve. Diastolic time (DT) is heart period duration - (PEP+LVET). Orthostatic-induced changes from supine to upright position (cardiac reflex response or CRR) were evaluated using One-sample Wilcoxon Signed Rank Tests. All CRRs in EPE and LPE were compared to UP using Mann-Whitney U tests. Data are represented as medians (interquartile ranges). RESULTS: Maternal age was comparable between all groups [29 (26-32) years; p?0.47]. Gestational age was comparable between both early [31 (28-32) vs 31 (27 33) weeks] and late [37 (36-39) vs 38 (36-39) weeks] third trimester UP and PE [p?0.38]. Pre-gestational BMI was higher in EPE compared to UP [26 (24-32) vs 23 (21-24); p<0.01]. This was not true for LPE [25 (23-28); p=0.06]. Birth weight percentiles were lower in both EPE and LPE compared to UP [UP: 44 (38-78), EPE: 18 (5-28), LPE: 31 (18-59); p<0.05], and also lower in EPE compared to LPE [p=0.03]. CRRs within each group are shown in Table 1. The CRRs of PEP were significantly different between UP and both EPE and LPE [p?0.01], due to orthostatic-induced increase in PE but not in UP . CONCLUSION: Our study confirms that orthostasis does not change PEP in UP but induces a significant increase of PEP in PE. The increased reflex-induced duration of isovolumetric contraction time can be explained by a decreased left ventricular performance in the clinical phase of PE as compared to UP. ICG turns out to be a straightforward and useful method to evaluate these hemodynamic features. PMID- 26105310 TI - OS096. Characteristics of hypertensive disorders in twin versus singleton pregnancies. AB - INTRODUCTION: Pre-eclampsia is well characterised in single pregnancies but less well in twin pregnancies, where the risks are higher. OBJECTIVES: The aim of this study, therefore, was to determine the characteristics of hypertensive disorders of pregnancy (HDP) in twin compared with singleton pregnancies. METHODS: We performed an analysis of 4976 prospectively recorded hypertensive pregnancies. These included pre-eclampsia (PE), gestational hypertension (GH) and chronic hypertension (CH). The rates and characteristics of these disorders were compared between singleton and twin pregnancies as was the progression of GH to PE for both groups. Maternal outcomes for severe hypertension (BP?170/?110mmHg), eclampsia, total antihypertensive medication requirements and maternal death were compared. Neonatal outcomes evaluated included birth weight, small for gestational age (SGA) and perinatal mortality. RESULTS: After exclusion of higher order pregnancies (triplets (n=2), a quadruplet pregnancy (n=1)), those with known secondary HT, white coat HT, or not fulfilling strict criteria for an accurate diagnosis (n=470) and those without an initial diagnosis recorded, there were 4156 women comprising 3942 singleton and 214 (5%) twin pregnancies.Hypertension (GH or PE) in twin pregnancy was diagnosed earlier than in singleton pregnancy (34+/-3 v 36+/-3 weeks, p<0.001). In the singleton pregnancies with de novo hypertension (n=3161), 60% had an initial diagnosis of GH and 40% had PE. In the twin pregnancies with de novo hypertension (n=199), 35% of women were initially diagnosed with GH and 65% with PE (p<0.001, single v twins). At delivery, 46% of the singletons had GH and 54% had PE, compared with twin pregnancies where 23% had GH and 77 % had PE (p<0.001). The progression from GH to PE for twins was greater than that for singleton pregnancies (34% v 15%, p<0.001). There were also781 singleton pregnancies and 15 twin pregnancies with CH. Twin pregnancies complicated by CH were more likely to progress to PE than singletons (54% v 18%, p<0.01). Women carrying twins were older (p<0.01) and they required less medication compared to those carrying singleton pregnancies(0.9+/ 1.2 v 1.3+/-1.5 medication score, p<0.05). Other maternal outcomes did not differ between the two groups. For neonatal outcomes, the gestation at delivery was earlier for twin than singleton pregnancies (36+/-2 v38+/-2 weeks, p<0.001) and SGA (less than 10th percentile) for twins was higher than singleton pregnancies (22% v 12%, p<0.001).No difference in perinatal mortality was noted. CONCLUSION: Women carrying twins who develop hypertension during pregnancy are more likely to present earlier, have initial PE rather than GH and to subsequently progress from GH to PE than in singleton pregnancy. Neonatal outcomes are worse in such pregnancies. It is thus reasonable for pregnant women with twins who develop de novo hypertension to be considered very high risk and possibly be managed in hospital. PMID- 26105311 TI - OS097. Hemodynamic assesment by applanation tonometry in women with early and late preeclampsia. AB - INTRODUCTION: Pre-eclampsia (PE) is associated with profound changes in the maternal cardiovascular system. The new concept of early and late preeclampsia established the hypothesis that these two entities may be associated with different models of vascular adaptation. Studies of central hemodynamics are limited. The applanation tonometry is able to evaluate, noninvasively, several vascular features and can be used to study the pathophyology of different forms of preeclampsia. OBJECTIVES: To compare vascular parameters of pulse wave analysis in pregnant women with early and late preeclampsia, determined by applanation tonometry. METHODS: This was a cross-sectional study involving pregnant women with 34 early-onset PE (<34 weeks) and 51 late-onset (?34 weeks) PE. Central blood pressure, peripheral and central pulse pressure, augmentation index, the augmentation pressure, subendocardial viability ratio and the ejection duration were assessed noninvasively using applanation tonometry (SphygmoCor (r)). Data were expressed as means+/-SD or as median and percentage. The mean was used for parameters with normal distribution and median for parameters that were not normally distribution. Comparisons between groups were performed using t test, Mann-Whitney test or chi-square(c(2)) for numerical and categorical data, respectively. It was considered a significance level of 5%. Statistical analysis were done using SPSS 10.5. RESULTS: Compared to late-onset PE group, women that developed early-onset PE had higher augmentation index (24.2+/-13.1 vs 18.8+/ 12.5; p=0.03). Any other paremeters presented significant differences between the groups. CONCLUSION: We found that early-onset PE is characterized by increased maternal arterial stiffness when compared late-onset PE, using applanation tonometry. PMID- 26105312 TI - OS098. Increased adiposity decreases the intensity myeloperoxidase in neutrophils from pregnant women at delivery. AB - INTRODUCTION: The cardiovascular risk factor myeloperoxidase (MPO) is a lysozomal enzyme found within azurophillic granules of inflammatory cells. Upon activation, inflammatory cells degranulate and release MPO. In the pregnancy disorder preeclampsia, MPO is elevated in the circulation and placenta and greater numbers of neutrophils are positive for hydrogen peroxide. OBJECTIVES: To determine if during preeclampsia, increases in circulating MPO result in losses of intracellular MPO within neutrophils. We also sought to determine if the degree by which neutrophil functionand intracellular MPO levels varies by BMI differsin women with preeclampsia compared to normal control pregnancies. METHODS: Reactive oxygen species (nitric oxide, superoxide and hydrogen preoxide) weredetermined in fresh whole blood samples from non-smoking women with normal pregnancies (n=8) and preeclampsia (n=9) by flow cytometry using intracellular fluorescent probes. Granulocytes were permeabilized (Dako, Glostrup, Denmark) and stained for MPO (anti-MPO, BD, San Jose, CA), and the number and percentage of CD15 and MPO positive cells and the intensity of MPO staining (MFI) was determined by flow cytometry. Student t-test or one-way ANOVA was used to test for significance. Dataare reported as mean+/-sem. RESULTS: There wasno significant difference in the number (percentage) orintensity of neutrophils staining for MPO between normal pregnancies and preeclampsia (MPO positive cells: 2816+/-981(39% positive) vs 2714+/-901(28% positive), Intensity: 3337+/-434 vs 3178+/-367 MFI units). However, there was a dramatic reduction in intensity of MPO staining in neutrophils from overweight women (BMI>27) compared to normal weight women regardless of pregnancy outcome (2508+/-160 vs 4091+/-376 MFI units, p=0.001). Among normal pregnancies, lean women had significantly more MFI of MPO than overweight women (4500+/-750 vs 2639+/-178 MFI units, p=0.04). The same trend was seen among women with preeclampsia (lean; 3845+/-428 vs overweight; 2344+/-292MFI units, p=0.07). CONCLUSION: The increased circulating levels of MPO in preeclampsia did not result in decreased intensity of MPO staining in circulating neutrophils. Neutrophils from normal weight women have greater amounts of intracellular MPO available upon activation than overweight and obese women. ACKNOWLEDGEMENT: This project was supported byNational Institutes of Health grant PO1-HD30367. PMID- 26105313 TI - OS099. The chips trial (control of hypertension in pregnancy study). PMID- 26105314 TI - OS100. Plasma placental growth factor (PLGF) measurement in women presenting with suspected pre-eclampsia: the pelican study. PMID- 26105315 TI - OS101. The brain study: cognition, quality of life and social functioning following preeclampsia. AB - INTRODUCTION: Previously preeclamptic women may express cognitive difficulties, which have largely been ignored or attributed to the stresses of a complicated pregnancy. OBJECTIVES: This study aimed to identify the scope of neurocognitive and psychosocial problems following preeclampsia. METHODS: Through website promotion and a mass e-mail members of the USA-based Preeclampsia Foundation who experienced preeclampsia in the past 20 years were invited to complete a web based survey, consisting of a questionnaire about current and past medical health, the Cognitive Failures Questionnaire (CFQ), the abbreviated WHO Quality Of Life questionnaire (WHOQOL-BREF), and the Social Functioning Questionnaire (SFQ). Participants were stimulated to ask a friend who had a normotensive pregnancy to complete the survey as well (controls). Women with current or past neurological conditions were excluded. Analysis was performed using Mann Whitney U test and linear regression. RESULTS: 966 cases and 342 controls were included. Median age was 34, median time since first pregnancy 4 and 5 years respectively. Cases scored significantly worse on all three questionnaires, and more often underwent psychiatric therapy, currently or in the past. There was a significant effect of migraine on all questionnaires and of eclampsia on CFQ score. Cronbach's alphas were >0.7, indicating good internal consistency of the questionnaires. Results are expressed as median (range) or number (percentage) (*)p<.001. CONCLUSION: Previously preeclamptic women report more cognitive and social problems, and worse quality of life compared to women who had normotensive pregnancies. Health care providers and patients should be aware of this so that affected women may receive recognition, psychological care and escape from the ignorance of their environment. Our findings may stimulate research relating to the origin and management of these important issues. PMID- 26105316 TI - OS102. Continuing pathology following a hypertensive pregnancy and the risk of future disease. AB - INTRODUCTION: New onset hypertension in pregnancy affects up to 6-8% of all pregnancies. For most women, hypertension and proteinuria settle following delivery. The National Institute for Health and Clinical Excellence (NICE) Hypertension in Pregnancy guideline recommends that this group of patients are reviewed by a medical professional postnatally [3]. However, studies have shown that blood pressure and urinalysis are often not checked in the postpartum period [4]. Women with a history of hypertension in pregnancy have a higher risk of future hypertension and cardiovascular disease (CVD) than women who have uncomplicated pregnancies [2]. Risk scores are available for assessing an individual's risk of CVD although they are not validated in women under 30. In UK, the most appropriate is QRISK2 score [1]. OBJECTIVES: To determine the frequency of ongoing problems following a new onset hypertensive pregnancy and assess the risk of future cardiovascular disease. METHODS: 351 women with new onset hypertension in pregnancy were reviewed 6 weeks postnatally. They were assessed for ongoing disease and cardiovascular risk. 10 year QRISK2 scores and heart age (the age at which a matched person has that score) were calculated. RESULTS: 211 women with pre-eclampsia (PE) and 140 with gestational hypertension (GH) were reviewed. 9% and 11% of women with previous PE and GH respectively still required antihypertensive agents at follow-up. Only 1 woman required more than one antihypertensive medication (PE group). 19 women with PE (9%) had ongoing proteinuria (PCR>30). 5% had an estimated GFR <60ml/min. In addition to those with a strong family history of hypertension, 23 patients (6.5%) required investigation for ongoing problems. Risk factors for CVD were common 6 weeks after delivery: Although the overall risk of CVD was low (median 10 year QRISK2 score 0.3, median relative risk 1.0), with 41% of women having the lowest possible heart age, 22% of women had a significantly elevated risk of CVD (QRISK2 heart age ?age+10). CONCLUSION: 16% of women had ongoing hypertension or proteinuria, evidence supporting the NICE guidance that all women with hypertension in pregnancy need follow-up after delivery. The overall risk of future CVD in women with previous hypertension in pregnancy is low but about one fifth of women are at very high risk. A program of risk assessment is required to allow preventative measures to be implemented. PMID- 26105318 TI - OS104. Are preeclampsia and adverse obstetrical outcomes predictors for longterm cardiovascular disease? AB - INTRODUCTION: Epidemiologic studies suggest that pregnancy complications such as preeclampsia, gestational diabetes, preterm delivery and low birth weight independently increase maternal risk for future development of cardiovascular disease. OBJECTIVES: To further investigate whether preeclampsia, gestational diabetes, and adverse obstetrical outcomes such as placental abruption, intrauterine growth restriction and preterm delivery, are independent risk factors for longterm cardiovascular disease. METHODS: This was a case-control study where 252 parous women (cases) with coronary artery disease were matched with a parous woman within 5 years of age with no known coronary artery disease (controls). Participants were recruited from the Royal Alexandra Hospital in cardiac catheterization lab recovery room in Edmonton, Canada. Women with significant angiographic coronary artery stenosis were eligible as cases and those without were eligible as controls. Participants were interviewed on their pregnancy histories and traditional cardiovascular risk factors, such as hypertension, diabetes etc. Descriptive statistics, chi-square tests and conditional regression analysis were performed. RESULTS: We recruited 244 cases and 246 controls. The average age was 66.3 and 65.8 respectively. Cases were more likely obese, had more pregnancies as well as traditional cardiovascular risk factors than controls. Adverse pregnancy outcomes were similar between the two groups except gestational hypertension. However, it was not statistically significant in the conditional logistic regression model. Independent risk factors for future cardiovascular diseases were: dyslipidemia (OR 12.8), hypertension (3.0), and being a current (OR 7.4) or former smoker (1.8). Adverse pregnancy outcomes CONCLUSION: In this study, adverse pregnancy outcomes were not independently associated with cardiovascular disorders. Our study was limited by recall bias, and ascertainment of diagnosis.Our study supports that dyslipidemia, hypertensiion and smoking increase future cardiovascular disease. Further studies are needed to examine a postpartum intervention model to proactively manage cardiovascular risk factors, such as lipids, in these at-risk women. PMID- 26105317 TI - OS103. Hypertensive disorders during pregnancy and cognitive decline of the offspring up to old age: the helsinki birth cohort study. AB - INTRODUCTION: Hypertensive disorders affect the fetal developmental milieu and may point to mechanisms by which prenatal adversity is associated with lower cognitive ability in subsequent life. OBJECTIVES: We tested whether hypertensive disorders during pregnancy predict age-related change in cognitive ability in the offspring up to old age. METHODS: Using mothers' blood pressure and urinary protein measurements from the maternity clinics and birth hospitals, we defined normotensive or hypertensive pregnancies in mothers of 398 men, who participated in the Helsinki Birth Cohort 1934-44 Study. The men underwent the Finnish Defense Forces basic ability test twice, first, during compulsory military service at age 20.1 (SD=1.4) years and, then, in a re-test at age 68.5 (SD=2.9) years. The test yields a total score and subscores for tests measuring verbal, arithmetic and visuospatial reasoning. Scores were standardized with a mean of 100 and standard deviation of 15. RESULTS: Men born after pregnancies complicated by a hypertensive disorder, compared with men born after normotensive pregnancies, scored 3.84 (95% Confidence Interval, 0.77 to 6.91) points lower on total cognitive ability at 68.5 years, and displayed a greater decline in total cognitive ability (2.31, 0.23 to 4.39) after 20.1 years. Of the subscores, associations were strongest for arithmetic reasoning. CONCLUSION: Maternal hypertensive disorders in pregnancy predict lower cognitive ability and greater cognitive decline up to old age. Multidisciplinary research is essential in order to uncover the mechanisms linking hypertensive pregnancy disorders with lower cognitive abilities in the offspring. PMID- 26105319 TI - OS105. Increased left ventricular mass index in normotensive formerly preeclamptic women is associated with the later development of chronic hypertension. AB - INTRODUCTION: A history of preeclampsia is associated with a 4-fold increased risk to develop chronic hypertension later in life. Interestingly, preeclampsia and chronic hypertension share the presence of increased left ventricular mass and increased left atrial diameter. Whether these increases are also present in the preclinical phase of chronic hypertension in women with a history of preeclampsia is still unknown. OBJECTIVES: To evaluate whether increased left ventricular mass index and/or left atrial widening in normotensive formerly preeclamptic women are associated with the development of chronic hypertension. METHODS: 324 Women with a history of preeclampsia, who were normotensive at the time of a diagnostic work-up 4 months postpartum, were included in this study. The tests employed included cardiac ultrasound and blood pressure measurements. Left ventricular mass was indexed (LVMi) for length in meters(2.7). To follow up on the health state, we send a health checklist to each screened former patient once every two years. The information of the diagnostic work-up and the one of the returned checklists were used for the statistical analysis by Uni- and Multivariate Cox regression analysis. RESULTS: Women who had developed chronic hypertension during a medium follow-up period of 6 years showed a significant Hazard Ratio (HR) of 1.11 (95% CI 1.03-1.18) for Left ventricular mass index, 1.13 (95% CI 1.06-1.20) for diastolic BP, 1.07 (95% CI 1.02-1.11) for systolic BP, 1.05 (95% CI 1.01-1.10) for Heart Rate and 0.215 (95% CI 0.055-0.848) for EA ratio. The multivariate top-down analysis showed a significant HR only for LVMi and diastolic BP, 1.08 (95% CI 1.00-1.18) and 1.10 (95% CI 1.02-1.19), respectively. CONCLUSION: Increased diastolic blood pressure and increased LVMi in normotensive formerly preeclamptic women are both associated with the development of chronic hypertension. PMID- 26105320 TI - OS107. Pregnancies involving hypertensive disorders of pregnancy are associated with posttraumatic stress disorder. AB - INTRODUCTION: Pregnancies complicated by hypertensive disorders of pregnancy (HDP) can result in adverse perinatal outcomes leading to additional and unexpected levels of stress for the families involved. OBJECTIVES: Our primary aim was to examine if HDP is associated with posttraumatic stress disorder (PTSD). METHODS: We analyzed data collected through an online survey by the Preeclampsia Foundation on PTSD symptoms using the Breslau Short Screening Scale for DSM-IV. We compared participant characteristics between women with and without PTSD using chi-square tests for discrete variables and t-tests for continuous variables. Univariate and multivariable logistic regression analyses were used to examine the outcome of PTSD and identify possible risk factors associated with HDP. RESULTS: We surveyed 1448 women (1076 HDP, 372 controls). After adjusting for psychiatric illness or mood disorder, parity, and age at affected pregnancy, we found that women with HDP were more than four times as likely to screen positive for PTSD (OR = 4.64, 95% CI: 3.37-6.39) when compared to women without HDP. Additionally, we found that PTSD symptoms increase with severity of HDP. When stratifying by severity, we found that women with gestational hypertension and preeclampsia were three and a half times more likely (OR=3.45, 95% CI: 1.70-7.00 and OR=3.48, 95% CI: 2.45-4.96, respectively); women with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome were nearly six times as likely (OR=5.76, 95% CI: 3.97-8.36), and women with eclampsia were almost ten times as likely to screen positive for PTSD (OR=9.76, 95% CI: 5.45-17.49) when compared to women without HDP. CONCLUSION: Pregnancies complicated by HDP are associated with increased risk of PTSD, with risk of PTSD increasing as severity of HDP increases. Medical practitioners should be aware of this association and consider screening women with HDP for signs of PTSD at their first postpartum visit. Those who screen positive could then be referred for a confirmatory diagnosis and, if needed, subsequent supportive care. PMID- 26105321 TI - OS106. The postpartum preeclampsia clinic (PPPEC) - an interdisciplinary clinic for cardiovascular risk reduction for women with preeclampsia. AB - INTRODUCTION: Preeclampsia (PEC) is a well-established risk factor for the development of future premature cardiovascular disease (CVD). However, women with PEC are not routinely counselled about these longterm risks, nor are their risk factors regularly assessed or treated for prevention of CVD. An interdisciplinary PPPEC clinic was recently established at the University of Alberta in order to address patient education and CVD risk factor management. OBJECTIVES: (1) To describe the implementation of a novel interdisciplinary clinic for postpartum women with PEC designed to both educate women of their CVD risk and manage their risk factors. (2) To describe our one-year experience with this clinic, identifying attendance issues common to postpartum clinics. METHODS: We performed a retrospective chart review using data obtained from standardized clinic booking lists. From these records, we extracted the following information: number of referrals, attendance dates (including adherence to visit) and patient demographics. Descriptive statistics were used to summarize patient demographics and percentages of missed visits were calculated. RESULTS: PPPEC Clinic Implemenation: All patients who attend this PPPEC clinic received education on PEC, its implications for future vascular health, and evidence-based strategies for CVD risk reduction through both a slide presentation, educational handouts as well as individualized CVD risk assessment by the interdisciplinary team (Obstetric Internist, nurse practitioner, pharmacist and dietician). Next, specific patient-directed lifestyle modification goals were developed in the form of an "Action Plan" for each CVD risk factor: blood pressure, cholesterol, glucose intolerance, physical activity level, weight, and smoking. These goals were reviewed at each follow-up visit. PPPEC Clinic Experience: From Sept 2010 to Feb 2012, there were 123 appointments in this bi-weekly clinic (63 new consults and 60 follow ups). The women's mean age was 29.4 years (range 17-43). Seventy four percent of scheduled apointments were attended. Of those that were missed, half were initial consultations and halfwere follow-up appointments. CONCLUSION: This interdisciplinary PPPEC addresses an important gap in clinical care for CVD prevention for these high-risk women. This study identified suboptimal attendance of scheduled postpartum visits. Future plans include: (1) identifying barriers to postpartum clinic attendance and strategies to overcome them, (2) examining the effectiveness of the educational and clinical intervention model in reducing cardiovascular risk factors in these women. PMID- 26105322 TI - OS108. Preeclamptic women display salt sensitivity and cardiovascular damage before their menopause. AB - INTRODUCTION: Salt sensitivity is an important cardiovascular risk factor. It has been shown that preeclamptic (PEC) women may not be totally cured after the delivery and keep a higher cardiovascular risk than nonPEC women. OBJECTIVES: We aimed to study the salt sensitivity of the blood pressure in women with a history of severe preeclamspia and women with no history of hypertensive complications.The design was a case control study with intervention, including 42 women recruited 5 to 17 years following delivery. METHODS: 21 women having suffered from a severe preeclampsia before 34 weeks of pregnancy and 19 age, race matched controls women,were randomized to follow for one week a low salt (LS) diet and a high salt (HS) diet (adding 6g NACL/d to usual diet). On day seven of each dietary period, 24h ambulatory blood pressure was recorded, and 24h urine collected in order to measure sodium excretion.Salt sensitivity was assigned if the mean 24h blood pressure increased by ? 3mmHg on a high- compared with a low salt diet. RESULTS: Preeclamptic women were aged 39.1(24-49) and controls 40.1(29 49), p=NS.Two of the PEC women already suffered from a cardiovascular event (2coronary events). The PEC women showed a significant increase of the BP and standard deviation (SD) of the BP compared to the controls.10 (47.6%) preeclamptic women showed salt sensitivity (odd ratio 5.4, 95% CI 0.972 30.601;P=0.042).Recurrent preeclampsia was associated with a significantly high risk to salt sensitivity status (OR 5; 95% confidence interval 1.1-31.6). CONCLUSION: Severe PEC women display already salt sensitivity of the blood pressure before their menopause and increased variability of the BP. Recurrent preeclampsia is a high risk factor for salt sensitivity and could allow to target this high-risk group at an early stage for preventive measures for cardiovascular disease. PMID- 26105323 TI - OS109. Lifestyle intervention after complicated pregnancy successfully improves saturated fat-intake, but not exercise and smoking habits: results of the pro active study. AB - INTRODUCTION: Women with a pregnancy complicated by preeclampsia, intra-uterine growth restriction and/or gestational diabetes are at increased risk of future cardiovascular and metabolic disease. Lifestyle intervention may help these women to effectively lower these risks. OBJECTIVES: To test if offering lifestyle intervention after a complicated pregnancy significantly improves saturated fat intake and exercise (primary objectives) and/or smoking habits (secondary objective). METHODS: The Pro-Active study (Postpartum Rotterdam Appraisal of Cardiovascular health and Tailored Intervention) is a feasibility study to develop and evaluate a postpartum lifestyle intervention program. In a prospective case-control setting we tested the effect of the lifestyle intervention. Women were included between April 2007 and August 2009. They were eligible if ?18 years old at time of inclusion, being able to understand and speak the Dutch language and not having pre-existing conditions that could interfere with the lifestyle intervention. Cases were offered lifestyle intervention by a trained counsellor between 6 and 10 months postpartum. During 3 private sessions, mainly exercise and fat-intake and to some extend smoking habits were discussed and aims were made to improve lifestyle. Controls did not receive these sessions, but were not restricted to improve lifestyle on their own. Lifestyle habits were scored at 6 and 13 months postpartum. For saturated fat-intake we used the Maastricht Fatlist. For exercise we used the International Physical Activity Questionnaire (IPAQ). For smoking habits we used a short version of the questionnaire of STIVORO (the Dutch anti-smoking association). We also performed a formative evaluation of the intervention program. RESULTS: During our study 1121 women gave birth after a complicated pregnancy. 490 Women were eligible for the study of which 240 women (49%) gave informed consent to participate. 56 Women (23%) were lost-to-follow-up, leaving 186 women for the analysis. Between 6 and 13 months postpartum saturated fat-intake was significantly reduced by 3.6g/day (95%>CI 1.8-5.4) in cases compared to controls. Exercise was improved in cases compared to controls, but it did not reach significance (277 MET's (-2699-3254)). Although smoking decreased from 14.5% to 10.4% in cases, it was not significant and comparable to the decrease in controls (15.0% to 8.4%). The formative evaluation showed that the most important motivator to improve lifestyle was the increased risk of future cardiovascular and metabolic disease (70%) and the increased risk for recurrence in a next pregnancy (57%). Main barriers were an already busy life (40%), distance (35%) and duration (38%) of travelling to the hospital and to early postpartum to pay attention to lifestyle (26%). CONCLUSION: Lifestyle intervention after complicated pregnancy may be effective in improving saturated fat-intake. Other interventions, specially aimed at postpartum women, are needed to improve exercise and smoking habits. More research is needed to develop lifestyle intervention program specifically aimed at these women. New possibilities of multimedia are promising. PMID- 26105324 TI - PP001. Variability in MRNA expression of Jmjd6 and FLT-1 variants in normal and preeclamptic human placenta. AB - INTRODUCTION: Biomolecules such as soluble fms-like tyrosine kinase 1 (sFLT-1) have been implicated in the pathogenesis of preeclampsia with many studies reporting on their expression in human placenta. OBJECTIVES: This study aimed to determine whether variation exists in the expression of different genes in human placenta based on collection site. Expression of different FLT-1 variants including the primate-specific sFLT-1e15a and a novel gene, Jumonji domain containing protein 6 (Jmjd6) that may prove to have a role in the pathogenesis of preeclampsia, was selected as targets. METHODS: Placental tissue was collected from one normotensive and one preeclamptic woman following caesarean section at 38 weeks. Twelve 1.5cm diameter*2mm thick samples were excised from various sites around the decidual surface. Quantitative PCR was used to determine the relative expression of the FLT-1 and Jmjd6 transcripts in the separate samples. Within a placenta, the first sample collected served as the reference and transcript expression in the remaining 11 samples was expressed relative to this sample. Between placentas, a pooled normal sample was used as a reference to determine the relative expression in preeclamptic compared to normal placental samples. One sample t -tests and coefficients of variation (CV) were used to explore the variation and Pearson's correlation coefficient was used to examine relationships. RESULTS: Within the normal placenta, significant variation was seen in the 12 collection sites for sFLT-1 e15a (CV=45.1% p=0.008) and Jmjd6 (CV=30.4% p=0.019). The CVs for sFLT-1 i13 and mFLT-1 were 25.6% and 23.7% respectively. Within the preeclamptic placenta, significant variation was seen in the expression of all FLT-1 variants; mFLT-1 (CV=66.9% p=0.023), sFLT-1 i13 (CV=64.8% p=0.033) and sFLT-1 e15a (CV=61.1% p=0.001) across different collection sites. Significant variation was also seen between preeclamptic placenta sites and a normotensive pool; mFLT-1 (CV=66.9% p=0.012), sFLT-1 e15a (CV=61.1% p=0.005) and Jmjd6(CV=65.2% p=0.029). Using cumulative moving means, the minimum number of samples required to obtain a zero difference in means for all transcripts in a data subset was 8 for the normal placenta and 6 for the preeclamptic placenta. Overall, the expression of Jmjd6 and all FLT-1 variants was increased in the samples from the preeclamptic placenta compared to normal. Expression of mFLT-1 was highly correlated with sFLT-1 i13 and sFLT-1 e15ain preeclamptic (r=0.808 p=0.001; r=0.841p=0.001) but not normal placenta, and Jmjd6 was not correlated with any transcript in either placenta. CONCLUSION: This study demonstrates significant variation in expression levels of several new and commonly investigated genes across sites in both normal and preeclamptic human placenta. These data show samples should be obtained from no less than 8 separate sites when pooling samples for expression analysis. Further, given that many studies examine relationships between different colocalised molecules, it may also be prudent to examine expression levels in each site separately to ensure that no relationships are missed. PMID- 26105325 TI - PP003. Antagonism in A2A and A2B adenosine receptor on fetal endothelium proliferation involves a nitric oxide-depended intracellular pathway in early and late-onset pre-eclampsia. AB - INTRODUCTION: Adenosine A2A and A2B receptor intracellular pathway is associated with either increasing endothelial nitric oxide (NO) synthase (eNOS) expression or eNOS activation (i.e., tyrosine 1177 phosphorylation); a mechanism linked to pro or anti-proliferative effects depending of the cell type. However, there are no reports in pre-eclampsia. OBJECTIVES: Investigate whether NO signaling pathway is involved in fetal endothelium proliferation induced by adenosine receptor activation in early and late-onset pre-eclampsia. METHODS: Human umbilical vein endothelial cells (HUVEC) were isolated from normal (n=25), late-onset pre eclampsia (n=11) and early-onset pre-eclampsia (n=22). Adenosine A2A and A2B expression was evaluated by immunocytochemistry and Western blot. Cell proliferation was analyzed using MTS-assay in absence or presence of non selective adenosine receptor agonist (NECA 10MUM), adenosine A2A receptor selective agonist (CGS-21680, 100nM), and/or the antagonists ZM-241385 (0-100MUM) or MRS-1754 (0-1MUM) for A2A and A2B receptors during 24h. In parallel experiments NOS inhibitor (L-NAME, 100MUM) was used in co-incubation by either adenosine receptor agonist or antagonists. Nitrite concentration in the culture medium and protein nitration assessed by Western blot were measured in cells exposed to CGS-21680 (30min). RESULTS: Early-onset pre-eclampsia was associated to low A2A (~70%), but high (~2-fold) A2B adenosine receptor protein abundance compared with normal or late-onset pre-eclampsia. Basally, HUVEC from early-onset showed a low (~42%), whereas late-onset exhibited high proliferation (~1.5-fold) compared with normal pregnancy. Cell proliferation was increased by CGS-21680 (~2 fold) in late-onset or normal pregnancy and ~5-fold in early-onset pre-eclampsia compared with respective control. NECA increased cell proliferation only in normal cells. Stimulatory effect of CGS-21680, was inhibited by ZM-241385 in normal pregnancies (Ki, 25nM) and late-onset (Ki 50nM) but not in early-onset (Ki ambiguous). Interestingly, MRS-1754 showed an increase in cell proliferation in a dose-response manner only in early-onset group. L-NAME partially blocked (~25%) the stimulatory effect of CGS-21680 in late-onset and normal pregnancy. Interestingly, L-NAME revert the maximal stimulatory effect of MRS-1754 observed in early-onset. Total and phosphorylated eNOS protein was reduced (~50%) in early onset pre-eclampsia compared to late-onset or normal pregnancy. In turn, cells from late-onset pre-eclampsia exhibited high (~2-fold) eNOS phosphorylation compared with normal pregnancy. In normal pregnancy, CGS-21680 (30min) increased (~2-fold) the eNOS phosphorylation and nitrotyrosine formation, without changes in nitrite levels, but non-significant changes were observed in early or late onset pre-eclamptic cells. CONCLUSION: Fetal endothelium from early-onset exhibits a predominant anti-proliferative effect mediated by adenosine A2B receptors activation, whereas the stimulatory effect of adenosine A2A receptors prevails in cells from late-onset pre-eclampsia. Both pro and anti-proliferative effects seem mediated by a nitric oxide-depended intracellular pathway. Supported by FONDECYT 1100684, Conicyt Anillo ACT73. PMID- 26105327 TI - PP004. Study of the methylenetetrahydrofolate reductase and the reduced-folate carrier-1 gene polymorphism in healthy and severe pre-eclamptic patients. AB - INTRODUCTION: One-carbon cycle is involved in two essential physiological processes: The synthesis of purins and pyrimidines required for DNA synthesis and repair. The other is the methylation with the methionine cycle. These one-carbon groups are served by the tetrahydrofolate and the S-adenosylmethionine. Deficiencies of the folate, or other abnormalities within the methionine pathway lead to elevated homocysteine levels. These disorders have been implicated in placental diseases. Earlier studies have shown that homocysteine levels are elevated by patients with severe pre-eclampsia than by healthy pregnant normotensive women. Methylenetetrahydrofolate reductase (MTHFR) gene C677T missense mutation has a high frequency by patients with HELLP syndrome and connected with elevated serum homocysteine levels. The reduced-folate carrier (RFC-1) facilitates the internalization of 5-methyltetrahydrofolate from the blood into peripheral cells. The mutation G80A this gene leads to higher plasma folate. OBJECTIVES: Our aim was to identify the polymorphism of these two genes in samples of severe pre-eclamptic patients and healthy controls. METHODS: Blood samples were collected from healthy pregnant normotensive women (n=82) and women with pre-eclampsia (n=75). DNA was isolated and quantitative real-time PCR method combined with melting curve analysis was performed for the detection of the two polymorphisms. Statistical analysis was performed with the STATISTICA software package. RESULTS: The frequency of the A allele in the RFC-1 gene was 46.57% by healthy pregnant and 41% by severe pre-eclamptic patients. The overall distribution of genotypes was not significantly different between the control and pre-eclamptic groups (p=0.58). In the study groups by the MTHFR gene the frequency of the T was 32% in pre-eclamptics, and 35.92% in controls. Similarly the overall distribution of genotypes was not significantly different between the two study groups (p=0.15). CONCLUSION: In hypertensive disorders of the pregnancy the one-carbon cycle is disturbed. We studied single nucleotide mutations in the genes of two enzymes involved in the cycle. We determined the allele and genotype frequencies in healthy control and pre-eclamptic patients and found no significant differences. Further examinations of other genetical compounds can help to understand the elevated homocysteine levels in pre-eclampsia. PMID- 26105326 TI - PP002. Study of polymorphisms of the adiponectin gene in women with gestational hypertension and preeclampsia. AB - INTRODUCTION: Adiponectin is involved in energy homeostasis by regulating glucose and lipid metabolism. Additionally, it presents anti-inflammatory and anti atherosclerotic functions. Polymorphisms in adiponectin gene (ADIPOQ) can modulate the concentrations of adiponectin. The influence of these polymorphisms on the development of gestational hypertension (GH) and preeclampsia (PE) is unknown. OBJECTIVES: The aim of this work was to examine the influence of polymorphisms in the gene ADIPOQ on the development of gestational hypertension and preeclampsia. METHODS: PATIENTS AND METHODS: We studied 401 pregnant women: 161 healthy pregnant (HP), 113 pregnant with gestational hypertension (GH) and 127 pregnant with preeclampsia (PE). Polymorphisms ADIPOQ -11391G>A (rs17300539), -11377C>G (rs266729), 45T>G (rs2241766) and 276G>T (rs1501299) were genotyped by allelic discrimination by PCR in real time. Haplotypes were inferred using the PHASE 2.1 program. RESULTS: There were no statistically significant differences in allele and genotype frequencies of the polymorphisms studied. In the analysis of haplotypes, we observed small differences in haplotype frequencies between groups, however, none of these differences was statistically significant (P>0.05). CONCLUSION: We found no association between the genotypic and allelic variants of the ADIPOQ gene polymorphisms with the development of gestational hypertension and preeclampsia. PMID- 26105328 TI - PP005. Natriuretic peptide precursor B gene (TTTC)N microsatellite polymorphism and elevated BNP levels in early onset pre-eclampsia. AB - INTRODUCTION: There is a variable tandem repeat (TTTC) polymorphism in the 5(') flanking region of the natriuretic peptide precursor B gene (NPPB), which shows association with severe pre-eclampsia. The 11-repeat carrier frequency is significantly higher in severe pre-eclamptic patients. The 11/11 genotype carriers in the pre-eclamptics has significantly higher BNP levels. OBJECTIVES: Our aim was to identify this polymorphism in samples of early onset pre-eclamptic (EOP) patients, late onset pre-eclamptic patients and healthy controls. We also compared the natriuretic peptide B (BNP) concentrations. METHODS: Blood samples were collected from healthy pregnant normotensive women (n=235) and women with pre-eclampsia (n=220). DNA was isolated and fluorescent PCR and DNA fragment analysis was performed for the detection of (TTTC) repeats. The plasma BNP concentration was measured by fluorescence immunoassay method using Triage BNP (Alere, San Diego). RESULTS: We detected 12 different repeats on the NPPB gene. The overall distribution of alleles and genotypes was significantly different between the control and pre-eclamptic groups. The 11/11 genotype carriers showed a significantly higher frequency in early onset pre-eclamptic patients than in the healthy pregnant controls (p=0.026). Calculated odds ratio (OR) was 1.694 (95% CI: 1.06-2.70). In contrast the 11/11 genotype carrier frequency was not significantly higher in the late onset pre-eclamptic group than in the control group (p=0.5308), adjusted OR 1.22 (95% CI: 0.7138-2.086). In the early onset pre eclamptics the 11/11 genotype showed a significantly higher frequency than in the late onset group (p=0.0039) OR: 6.00. The concentration of the BNP was 9.75pg/ml in the healthy controls and 32.40pg/ml in the pre-eclamptic group (p<0.0001). The 11/11 genotype carriers had significantly higher BNP levels in the pre-eclamptic group. The early onset pre-eclamptic patients had a significantly higher BNP concentration (40.55pg/ml) than in the late onset pre-eclamptic patients (24.1pg/ml) (p=0.013). CONCLUSION: The NPPB gene (TTTC) microsatellite polymorphism in the 5(')-flanking region showed a significant difference in the distribution of alleles and genotypes between early onset and late onset pre eclamptic patients in an ethnically homogeneous population. The concentration of the BNP was higher in early onset pre-eclamptic women, and it showed association with the genotypes. PMID- 26105329 TI - PP006. The comparison of serum VEGF and sFlt-1 on preeclampsia and eclampsia pregnant woman before and after delivery at Ulin Hospital, Banjarmasin, Indonesia. AB - INTRODUCTION: Preeclampsia is the main cause of maternal morbidity and mortality at Indonesia. In 2010, 228 maternal deaths occur in 100,000 live birth. Ulin Hospital, Banjarmasin, a tertiary care hospital has high prevalence of preeclampsia and eclampsia (22%). Vascular angiogenesis has a role on pathogenesis of preeclampsia, including angiogenic factor and anti-angiogenic factor like VEGF and sFlt-1. OBJECTIVES: To evaluate changes of sFlt-1 and VEGF levels on preeclampsia and eclampsia woman before and after delivery. METHODS: This is a cross sectional research, which include 30 pregnant women with preeclampsia and eclampsia at Ulin Hospital, Banjarmasin, whom pregnancy was terminated vaginaly or abdominaly. Every patient was checked for the serum level of sFlt-1 and VEGF before and 3days after delivery. RESULTS: There are significant changes of the serum level sFlt-1 and VEGF before and after delivery. Serum sFlt-1 mean value decrease significantly after delivery (18251.4pg/ml vs 1193.9pg/ml; p<0.0001). Serum VEGF mean value increase significantly after delivery (50.4pg/ml vs 836.1pg/ml; p<0.0001). Mean value of the angiogenic factor before and after delivery was not significantly different between early-onset PE, late-onset PE and eclampsia. CONCLUSION: There are significant changes of the angiogenic factors (sFlt-1 and VEGF) before and 3days after delivery. PMID- 26105330 TI - PP007. Effects of STAT1 suppression on ERK1/2 in trophoblastic cells. AB - INTRODUCTION: Migration and trophoblast invasion are controlled functionally along with the active participation of cytokines and growth factors. Two important intracellular signaling pathways are the Janus kinase/signal transducer and activator of transcription (JAK-STAT) and extracellular regulated kinase1/2 (ERK1/2). These pathways have been associated with the regulation of gene expression, cellular proliferation, differentiation, angiogenesis, embryo development and invasion in tumor and trophoblast cells. OBJECTIVES: The aim of our study is to characterize and analyze the regulation and crosstalks of STAT1 and ERK1/2 in trophoblast cells and the identification of activating cytokines. METHODS: The trophoblast derived cell line HTR-8/svneo and a choriocarcinoma cell line (JEG-3) were stimulated with interleukin-6 (IL-6), IL-11, granulocyte macrophage colony-stimulating factor (GMC-SF), leukemia inhibitory factor (LIF) or oncostatine M (OSM). The the expression and phosphorylation of STAT1(tyr705) and ERK1/2 were analyzed by gel electrophoresis and Western blotting. Expression of STAT1 was inhibited by administration of 50MUM fludarabine (2-fluoro-ara-AMP) for 2, 4, 8, 24, 48 or 72h or by using small interfering RNA (siRNA). The full activation of STAT1 was assessed by using an STAT1 DNA-binding assay. Finally, proliferation and invasion assays were performed (Grant Deutscher Akademischer Austausch Dienst A/10172477). RESULTS: LIF and OSM induce STAT1 and ERK1/2 phosphorylation in HTR-8 and JEG-3 cells. Fludarabine inhibits the so induced phosphorylation of STAT1 when administered 48 or 72h before stimulation. Simultaneously, ERK phosphorylation increases. In contrast, silencing of STAT1 by application of specific siRNA induces reduction of ERK1/2 phosphorylation. Fludarabine reduces STAT1 DNA-binding capacity. LIF and OSM increase proliferation. Silencing of STAT1 slightly decreases invasiveness of analyzed cells. CONCLUSION: STAT1 in trophoblast cells can be activated by placental cytokines. Suppression of STAT1 by fludarabine or siRNA influences activity of ERK1/2 which indicates a crosstalk between both pathways. Current studies will clarify the reason for the different effects on ERK1/2 in trophoblastic cells. PMID- 26105331 TI - PP008. Lipotoxicity and preeclampsia: A probable correlation (preliminary results). AB - INTRODUCTION: The impact of preeclampsia (PE) of pregnancy is seen as a global concern. Despite their importance, PE does not have well-established causes. Several studies point to obesity as a predisposing factor for PE [1]. In a systematic review Duckitt and Harrington showed that in women with BMI?30 the relative risk of developing PE is equal to 2.1 [2]. Bianco et al. demonstrated that the chance of patients with BMI?35 developing PE is more than 4 times [3]. Furthermore, it is believed that the intracellular accumulation of triglycerides cause mitochondrial dysfunction, more electron transport and generation of ROS (Reactive Oxygen Species) [4], causing a harmful effect on the endothelium. OBJECTIVES: To compare the incidence of potential lipotoxicity markers among normal pregnant women and with pre-eclampsia. METHODS: A case-control study, including pregnant women from October 2011 to January 2012 at Hospital Guilherme Alvaro in Santos/Brazil. The study group consisted of 27 mothers with pre eclampsia, according to the criteria of NHBPEP (2000) and the control group consisted of 27 mothers with normal pregnancy, who gave birth vaginally, at term without hypertension. The exclusion criteria were diagnosis of collagen diseases, smoking, diabetes, twin pregnancy and fetal malformations. Blood samples were collected immediately after delivery and the results were analyzed in conjunction with maternal data, according to the following variables: age, body mass index (BMI), serum cholesterol total and fractions, glucose, triglyceride and creative protein. Analysis of SF data was performed by calculating the odds ratio adopting an hypothesis rejection level of 0.05. RESULTS: The PE group had BMI>30 (or), serum triglycerides>150 (or) and LDL cholesterol>100 (or) more frequently than normal mothers, and as regards statistical significance comparing the age of the women, glucose level, HDS cholesterol, there was no significant difference between the groups. CONCLUSION: In pregnancy, lipotoxicity reduces the ability of trophoblastic invasion, causing maternal systemic endothelial and placental dysfunction causing alterations in metabolic functions. All such changes maintain a close relationship with the pathophysiology of PE. Monitoring pregestational period of obese patients or those with lipid disorders is part of the medical arsenal against PE by monitoring and advising on the best time to conceive. PMID- 26105332 TI - PP009. A follow-up study of Finnish pre-eclampsia families identifies a new fetal susceptibility locus on chromosome 18. AB - INTRODUCTION: According to the epidemiological research both maternal and fetal genes influence in predisposition to pre-eclampsia (PE). We have previously detected linkage signals in Finnish families on chromosomes 2p25, 4q32, and 9p13 using maternal phenotypes. OBJECTIVES: Our aim was to perform a follow-up linkage analysis using updated maternal phenotypes and an unprecedented linkage analysis using fetal phenotypes. METHODS: We performed a non-parametric linkage analysis using the same sample set and microsatellite markers as reported in the original linkage study (Laivuori et al., [1]). Markers genotyped were available from 237 individuals in 15 Finnish families including 72 affected mothers (pregnancy complicated by PE n=54, eclampsia n=1, or gestational hypertension [GHT] n=17), and 49 affected fetuses (born from a pregnancy complicated by PE n=45, or GHT n=4). MERLIN software (Abecasis et al., 2002) was used for sample and marker quality control and linkage analysis. Results from this study were compared against the original results obtained by using GENEHUNTER 2.1 software. RESULTS: The maximum nonparametric linkage (NPL) scores on chromosome 2 were at 21.70cM near marker D2S168 using maternal and fetal phenotypes (NPL score 3.79, p=0.00008, and NPL score 2.95, p=0.002, respectively). On chromosome 4 the highest peak was at 158.20 cM near marker D4S413 using maternal phenotypes (NPL score 3.13 p=0.0009), and at 109.60 cM near marker D4S1572 using fetal phenotypes (NPL score 2.50, p=0.006). On chromosome 9 the highest peaks using maternal phenotypes were at 38.90cM near marker D9S169 (NPL=3.76, p=0.00008), and at 120.80 cM near marker D9S1811 (NPL=2.74, p=0.003). The maximum peak on chromosome 9 using fetal phenotypes was found at 59.20cM near marker D9S175 (NPL=2.69, p=0.004). We found a suggestive linkage on chromosome 18 at 86.80cM near marker D18S64 using fetal phenotypes (NPL score of 2.51, p=0.006), but the highest peak using maternal phenotypes did not reach significance. CONCLUSION: In this follow up study we have confirmed the linkage signals identified in the original linkage analysis using maternal phenotypes. Linkage to chromosome 2 was also supported by analysis using fetal phenotypes. Chromosome 18 may harbour a new fetal susceptibility locus for PE. PMID- 26105333 TI - PP010. Does aldosterone participate in placental angiogenesis via PLGF? AB - INTRODUCTION: Angiogenic signals are a vital signal of placental integrity. Aldosterone has recently been shown to enhance placental growth factor (PlGF) expression in the peripheral vasculature [1] and to promote trophoblast growth [2]. The plgf gene possesses a functional mineralocorticoid receptor responsive element in the promoter region. OBJECTIVES: Thus, we hypothesized that aldosterone adapts placental angiogenesis to trophoblast growth by secreting PlGF. METHODS: The human choriocarcinoma cell line BeWo and first and third trimester human primary trophoblasts cells were subjected to several syncytialization signals. Upon visual confirmation, the cultured cells were subjected to either control conditions, the known stimulator forskolin, and increasing amounts of aldosterone (10(-9) to 10(-6)M) with and without the competitive aldosterone receptor blocker spironolactone. After 6 and 24h of incubation, RNA and protein were extracted. PlGF transcripts were quantified by Taqman PCR normalized to several housekeeping genes. Protein expression was quantified by ELISA. RESULTS: PlGF mRNA expression increased 3-fold with forskolin in BeWo cells. In this cell line, aldosterone could slightly stimulate PlGF production. In non-syncytialized primary human first trimester trophoblasts, aldosterone did not exert a specific effect. In contrast, the term primary human trophoblasts did respond with a 2.5-fold increase after incubation with aldosterone (10(-7)M) in the presence of forskolin to allow forming a syncytial layer. PlGF protein was already slightly upregulated following 6h of incubation with aldosterone. CONCLUSION: We concluded that aldosterone does regulate PlGF expression in specified conditions during pregnancy. Inappropriately low aldosterone levels such as in preeclampsia might such not only compromise plasma volume and trophoblast growth but also placental vascularization and systemic PlGF availability. These observations merit further investigation. PMID- 26105334 TI - PP011. Increased placental expression of angiogenin inhibitor (Ribonuclease inhibitor), a novel gene in pre-eclampsia. AB - INTRODUCTION: There is convincing evidence that imbalance between angiogenic and anti-angiogenic factors play an important role in the pathophysiology of pre eclampsia. Increased expression of soluble fms-like tyrosine kinase-1 (sFlt1), along with decreased placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) appear to play a key role in the abnormal placentation and vascular dysfunction of pre-eclampsia. Angiogenin is a potent inducer of angiogenesis and serum levels are elevated in pre-eclampsia. Angiogenin Inhibitor (also called placental Ribonuclease inhibitor) is a potent antagonist of both angiogenic and ribonucloetic activities of angiogenin. We demonstrate that placental expression of angiogenin inhibitor is altered in pre-eclampsia and may play a role in its pathophysiology. OBJECTIVES: The aim of the study was to assess the expression of angiogenin inhibitor in healthy normotensive and pre eclamptic placentas. METHODS: Placental expression of angiogenin inhibitor was measured in term placentae of 14 pre-eclamptic women and 16 normal pregnant controls. The women were matched for age, gestation and parity. Placental tissue was collected immediately after delivery and stored at -80 degrees C. The angiogenin inhibitor gene expression was measured using real-time quantitative polymerase chain reaction (rt-QPCR). The results were standardized using the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reference gene. RESULTS: mRNA expression of angiogenin inhibitor gene was significantly increased in pre eclamptic placentae (p=0.027) compared to normal pregnant controls; 0.44 (0.174 1.048) versus 0.091 (0.029-0.301), median and interquartile range, for pre eclampsia and normal controls, respectively. CONCLUSION: Placenta expression of angiogenin inhibitor gene is significantly increased in pre-eclampsia and may play a role in its pathophysiology. This finding may directly correlate with the reported ability of angiogenin inhibitor to protect from oxidative stress by its reactivity as an oxygen species scavenger. PMID- 26105335 TI - PP012. Morphometric analysis of the differences in placental angiogenesis during early and late-onset pre-eclampsia. PMID- 26105336 TI - PP013. Oxidized low density lipoprotein accumulation and the expression of the lectin-like oxLDL receptor (LOX-1) in placental tissue in preeclampsia and healthy controls. AB - INTRODUCTION: Oxidized Low Density Lipoproteins (oxLDL) and its receptor the lectin-like oxLDL receptor 1 (LOX-1) are key players in the development of atherosclerotic cardiovascular diseases. OBJECTIVES: Since preeclampsia is known to share similarities to the pathogenesis of atherosclerosis we hypothesized an increased accumulation of oxLDL and an increased expression of LOX-1 at the materno-fetal and feto-fetal interface within the placental tissue in preeclampsia in comparison to a control group. Second, we analyzed maternal and fetal serum lipid parameters including fetal oxLDL concentration. METHODS: OxLDL and LOX-1 intensity was determined via immunohistochemistry in placental paraffin sections of 11 women suffering from preeclampsia and compared to 11 gestational age matched preterm deliveries (29th to 36th week of gestation). Ten 'High Power Fields' were chosen randomly by the newCAST software and expression was analyzed via standardized methods by two independent and blinded observers. Maternal and fetal triglycerides, total cholesterol, LDL-cholesterol and HDL-cholesterol were measured by enzymatic colorimetric methods. Fetal oxLDL serum concentration was estimated by ELISA. Statistical examination was carried out by Student's t-test. Skewed variables were log-transformed. RESULTS: oxLDL and LOX-1 was predominantly found to be in villous trophoblast and placental endothelium. No significant differences could be observed in oxLDL expression intensities between preeclampsia and controls. LOX-1 expression tended to be increased in placental trophoblast and endothelium without being statistical significant (Table 1). Fetal triglyceride levels were significantly elevated in preeclampsia compared to controls while maternal triglyceride levels tend to be increased. No other significant differences in lipid concentrations could be observed (Table 2). CONCLUSION: We could not confirm our initial hypothesis of an accelerated oxLDL accumulation in placental tissue of preeclampsia. Though not statistically significant, placental endothelium seems to be activated in preeclampsia since LOX-1 expression is increased. Moreover, preeclampsia is a condition of dyslipidemia affecting both, maternal and fetal serum with implications for development of cardiovascular diseases in later life. PMID- 26105337 TI - PP014. Estimating fully and minimal oxidized low density lipoprotein accumulation in placental tissue in intrauterine growth restriction and healthy controls. AB - INTRODUCTION: We recently demonstrated that maternal serum LDL- and fetal serum HDL-cholesterol concentration is significantly reduced in intrauterine growth restriction (IUGR) [1]. OBJECTIVES: We now hypothesized that increased oxidative stress in IUGR placenta leads to an accumulation of oxidized LDL (oxLDL) particles which then become trapped within the placenta subsequently leading to reduced availability of cholesterol for mother and fetus. METHODS: Fully oxidized LDL (oxLDL) was determined via immunohistochemistry in placental paraffin sections of 18 women suffering from IUGR and 18 gestational age matched controls. Ten 'High Power Fields' were chosen randomly by the newCAST software and oxLDL expression was estimated via standardized methods by two independent and blinded observers. Minimal oxidatively modified LDL (MM-LDL) and non-modified Apolipoprotein B (ApoB) concentration was measured in full placental tissue lysates by ELISA. Values were correlated with maternal and fetal total cholesterol, LDL-, and HDL-cholesterol concentrations. Statistical examinations were carried out by Student's t-test and calculation of Pearson's correlation coefficient. RESULTS: oxLDL was found predominantly to be in villous trophoblast and placental endothelium. OxLDL intensity tended to be increased in IUGR (Table 1). We found MM-LDL concentrations in whole placental tissue lysates to be highly correlated to placental ApoB concentration (r=0.93). Both parameters were non significantly decreased in placenta of IUGR compared to controls (Table 1). Maternal serum LDL-C, and fetal serum LDL-C, TC, and HDL-C concentrations were significantly decreased in IUGR compared to controls (Table 2). OxLDL staining intensity was mildly negatively correlated to maternal LDL-C (r=-0.315) and much less to fetal HDL-C concentrations (r=-0.212). Placental ApoB and MM-LDL concentration were moderately positively correlated with fetal HDL-C concentrations (r=0.492 and r=0.447). CONCLUSION: Conformational changes of the ApoB lipoprotein during the process of oxidation might lead to an accumulation of oxLDL particles in placental tissue of IUGR and reduced fetal cholesterol bioavailability as evidenced by a decrease in fetal serum cholesterol levels. However, our analysis lacks in sufficient power and further studies are underway focussing on that subject. PMID- 26105338 TI - PP015. Differential expression of Nrf2 and VEGF in human placental beds from normal and pregnancies complicated with preeclampsia and IUGR. AB - INTRODUCTION: Impaired trophoblast invasion into the uteroplacental arteries is accompanied with an evidence of oxidative stress in the extravillous trophoblast in preeclampsia complicated with IUGR. OBJECTIVES: Preeclampsia is characterised by increased lipid oxidation and diminished antioxidant capacity; recently, we have shown that PE is associated with an increased expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) in villous cytotrophoblast. A possible relationship between the vascular endothelial growth factor (VEGF) and Nrf2 was established in vitro and the activation of Nrf2 pathway could lead to upregulation of VEGF synthesis through the induction of Nrf2-dependent Heme oxygenase-1 (HO-1). In this study the expression of Nrf2 and VEGF was determined in the interstitial and intramural extravillous trophoblast in normal pregnancies and those complicated by preeclampsia and intra-uterine growth restriction (IUGR). METHODS: Full-thickness uterine tissues were obtained from caesarean hysterectomies performed in 5 healthy normotensive women delivering term infants and from 5 women with severe early-onset preeclampsia and IUGR (29-34 week's gestation). The interstitial and intramural trophoblasts were studied by immunohistochemical analysis of paraffin sections stained with anti VEGF and anti Nrf2. RESULTS: Cases suffering from preeclampsia with IUGR were characterised by reduced invasion of extravillous trophoblast into uteroplacental arteries in the endometrial and myometrial segments. In addition, these cells showed an increased expression of Nrf2 in the pathological sections. The overexpression of Nrf2 in cases with preeclampsia was associated with restricted expression of VEGF in these cells compared to controls. CONCLUSION: Our data suggest that besides villous cytotrophoblast, also the extravillous trophoblast is a source of Nrf2 dependent genes. VEGF deficiency may cause higher oxidative stress in extravillous trophoblast in cases with preeclampsia with IUGR. The resulting reduced basal defence against oxidative stress and the higher vulnerability to oxidative damage may play a role in the limited trophoblast invasion into uteroplacental arteries in cases suffering from early onset preeclampsia and IUGR. PMID- 26105339 TI - PP016. Circulating lymphangiogenic factors in preeclampsia. AB - INTRODUCTION: Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state due to high levels of circulating soluble vascular endothelial growth factor 1 (sVEGFR1). However, the role of lymphangiogenesis in preeclampsia has not been investigated. Recently, impaired VEGF-C (factor that regulates lymphangiogenesis) signalling has been implicated in the pathogenesis of interstitial edema and salt-sensitive hypertension. OBJECTIVES: Therefore, we hypothesized that circulating VEGF-C and its circulating receptors (sVEGFR2 and sVEGFR3) may also be altered in preeclampsia and correlate with the severity of the phenotype. METHODS: We analyzed plasma levels of VEGF-C, sVEGFR1, sVEGFR2 and sVEGFR3 in women with gestational hypertension (GHTN, n=20), preeclampsia (PE, n=20) and normotensive pregnancies (NP, n=20) in the third trimester and values reported as mean+/-SD in pg/ml. RESULTS: As previously reported, sVEGFR1 levels were significantly higher in subjects with PE (19938 +/- 12973) than in GHTN (7156+/-5432), p<0.01 or NP (7760+/-6018), p<0.01. VEGF-C levels were lower in subjects with GHTN (676+/-323) than in PE (1335+/-625), p<0.01, but not statistically different than in NP (971+/-556), p=0.11. There was a trend towards lower sVEGFR-2 in PE as compared to GHTN or NP. Interestingly sVEGFR-3 was significantly lower in PE (54,371+/-21,107) as compared to NP (83,709+/-24,983), p<0.01, but not different as compared to GHTN (54,642+/-26,947). The ratio of sVEGFR-2+sVEGFR-3/VEGF-C was dramatically lower during PE (57+/-38) as compared to GHTN (113+/-72), p<0.01 or NP (133+/-91), p<0.01. CONCLUSION: Preeclampsia is characterized by circulating pro-lymphangiogenic state as evidenced by decreased sVEGFR-3, slightly decreased VEGFR-2, increased VEGF-C and a dramatically lower ratio of sVEGFR2+sVEGFR3/VEGF-C. Our data suggests that the circulating pro lymphoangiogenic state during preeclampsia may be a compensatory response to edema and hypertension. Additional studies are needed to evaluate the clinical relevance of the altered lymphangiogenic signalling pathway during preeclampsia. PMID- 26105340 TI - PP017 Comparison of vascular function in preeclamptic and normotensive pregnant women in the rural eastern Cape province of South Africa. AB - INTRODUCTION: Preeclampsia is associated with arterial stiffness and endothelial dysfunction. OBJECTIVES: The aim of the study was to compare vascular function of pregnant women with preeclampsia and normotensives by non-invasive techniques. METHODS: This was a comparative study where participants were recruited from Mthatha General Hospital complex Antenatal clinics. Fifty four (54) normotensive and 21 preeclamptic women were recruited into the study. Arterial stiffness was assessed using applanation tonometry with SphygmoCor device; central aortic pressures and peripheral and central augmentation index (Alx) and carotid-femoral pulse wave velocity were then calculated. Endothelial function was assessed by EndoPAT 2000 device; pneumatic probes were fitted to the index fingers; after baseline recordings a blood pressure cuff was inflated on the non-dominant arm then released after 5min to induce flow mediated reactive hyperemia; the ratio of the readings before and after occlusion was then used to calculate the score for endothelial function; the reactive hyperaemia index (RHI) RESULTS: RHI was significantly higher; p<0.001 among preeclamptic women compared to normotensives (1.76+/-0.5 vs 1.45+/-0.22) indicating good endothelial function. Pulse wave velocity was significantly higher; p<0.001 in preeclamptic than normotensive women (6.7+/-1.5 vs 5.1+/-0.7) indicating arterial stiffness. Alx measured by the EndoPAT 2000 correlated with peripheral Alx (r=0.623, p<0.0001) and central Alx (r=0.60, p<0.0001) was measured by the SphygmoCor. This means that either of these parameters can be used to assess arterial stiffness. CONCLUSION: In this interim analysis, we have demonstrated that women with preeclampsia have increased pulse wave velocity and peripheral augmentation index suggesting vascular stiffness. Low RHI values indicate endothelial dysfunction in the general population; however our results showed a higher value in preeclampsia than in normal pregnancy. Could there be other factors responsible for RHI in pregnancy? PMID- 26105341 TI - PP018 Cardiac reflex responses measured by impedance cardiography are different between low and high cardiac output pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia (PE) has been categorised into subtypes depending on low or high cardiac output (CO) states. Are cardiac reflex responses (CRR) different between these two subtypes? OBJECTIVES: Impedance cardiography (ICG) measurements of cardiac cycle time intervals (CCTI) before and after orthostatic challenge are evaluated in the clinical phase of PE with low and high CO (LPE and HPE, respectively). METHODS: Examinations were performed in 25 LPE (CO?7l/min) and 16 HPE (CO?9l/min). A third generation ICG device using a four electrode arrangement (NICCOMO, Medis, Germany) was used to measure CCTI in supine position and after moving to upright position. The pre-ejection period (PEP) is the time interval between ventricular depolarisation and start of aortic flow. The left ventricular ejection time (LVET) is the time-interval between opening and closing of the aortic valve. Systolic time ratio (STR) is PEP/LVET. Diastolic time (DT) is the heart period duration - (PEP+LVET). Time intervals were expressed as a percentage of the heart period duration, i.e. PEPi, LVETi and DTi. Orthostatic induced changes from supine to upright position (cardiac reflex response or CRR) were evaluated using One-sample Wilcoxon Signed Rank Tests. All CRRs were compared between LPE and HPE using Mann-Whitney U tests. Data are presented as medians (interquartile ranges). RESULTS: Maternal age was comparable between LPE and HPE [29 (26-34) vs 28 (26-33) years; p=0.55]. This was also true for gestational age [34 (30-38) vs 36 (31-39) weeks; p=0.50], and pre-gestational BMI [24 (22-30) vs 25 (24-32); p=0.21]. Birth weight percentiles were lower in LPE compared to HPE [18 (5-31) vs 44 (18-83); p<0.01]. CRRs within each group are shown in Table 1. CRRs of PEP, PEPi and DT were different between LPE and HPE [p?0.04], whereas changes in LVET, LVETi, DTi and STR were not [p?0.09]. Reflex induced changes of diastolic blood pressure and heart rate (HR) were not significantly different between LPE and HPE [p?0.41]. CONCLUSION: Orthostasis does not change PEP in HPE, but induces a significant increase of PEP in LPE. PEP is dependent on HR, preload, afterload and sympathetic activity. There is no difference in the reflex-induced response of HR, DBP (~afterload), and STR (~sympathetic activity) between the two groups. This suggests that the orthostatic-induced change in the isovolumetric contraction time in LPE is preload-induced. Our observations suggest that hemodynamic background mechanisms behind LPE and HPE are different, and support the view that these subtypes are two different clinical entities. PMID- 26105342 TI - PP019 The role of renal markers in women with and without preeclampsia: Evaluation of urinary excretion of podocytes and proteins. AB - INTRODUCTION: Preeclampsia (PE) is an important cause of glomerulopathy. Assessment of renal markers during pregnancy may have a predictive value for glomerular disease later in life. The early detection of PE may prevent the complications of this syndrome. OBJECTIVES: Assess the glomerular involvement in PE and in normal pregnancy by evaluating renal markers such as podocyturia and proteinuria. METHODS: Case-control study with 39 pregnant women after 20 weeks of gestation (control group - CG with n=25 and PE with n=14), we assessed podocyturia (cytospin method) and proteinuria (albuminuria, urine protein:creatinine - PCR, urinary retinol protein - RBP and albumin/creatinine ratio - ACR). (Grant FAPESP 08/56338-1) RESULTS: Mean+/-standard deviation of age and mean gestational age of CG were 26.9+/-6.4years and 37.1+/-5.0weeks and of PE, 26.4+/-6.9 and 30.6+/-5.6, respectively (p=0.001). No statistical differences were found between podocyturia in CG and PE although it was more frequent in this last group (p=0.258). Podocyte cells and parietal epithelial cells were detected in the slides. Mean+/-standard deviation of urinary RBP (p=0.017), albuminuria (p=0.002) and UAC ratio (p=0.006) of CG were 0.4+/-0.7mg/L, 7.3+/-6.9mg/L and 8.2+/-6.7mg/g and of PE, 2.0+/-4.4mg/L, 2267.4+/-2130.8mg/L (p=0.002) and 3778.9+/-4296.6mg/g (p=0.006), respectively. Mean value+/-standard deviation of urine PCR in PE was 6.7+/-6.1g/g (p=< 0.001). CONCLUSION: Urinary RBP, PCR, albuminuria and UAC ratio were elevated in PE in comparison to CG indicating its glomerular involvement but there was no correlation between those renal parameters and podocyturia. RPC and UAC ratios were good predictors of PE, but not podocyturia. Either podocyte cells as parietal epithelial cells were detected in the urine, these findings may indicate a non-invasive marker for renal disease activity but more studies are required to determine its role in PE. PMID- 26105343 TI - PP020 Association between renal dysfunction and angiogenic factors in preeclampsia. AB - INTRODUCTION: Hyperuricemia is a common finding in preeclamptic pregnancies and proteinuria, as well as hypertension are markers of preeclampsia. Production of anti-angiogenic proteins seems to be involved in the pathophysiology of hypertension and proteinuria in preeclampsia. OBJECTIVES: The purpose of this study was to evaluate whether there is an association between renal function and changes in serum levels of angiogenic factors in preeclamptic patients. METHODS: Serum was obtained from 83 preeclamptic patients in the last trimester of pregnancy for determination of uric acid. Placental growth factor (PlGF), vascular endothelial growth factor (VEGF) and soluble form of vascular endothelial growth factor receptor (sVEGFR-1) were evaluated in serum by an enzyme immunoassay. Proteinuria was determined in a 24-h urine collection. The concentration of angiogenic factors was compared with serum uric acid levels (<6mg/dL vs ?6mg/dL) and with proteinuria levels (<2g vs ?2g). Statistical analysis was performed using non-parametric tests with significance level set at 5%. RESULTS: In 40% of women with preeclampsia serum uric acid levels were ?6mg/dL, and proteinuria concentration ?2g was detected in 41% of patients. Positive correlation was observed between uric acid and proteinuria levels (r=0.7274; p<0.0001). Serum levels of PIGF were significantly lower in preeclamptic women with serum uric acid level ?6mg/dL compared with women with serum uric acid <6mg/dL (median 48.46 vs 117.32pg/mL). Significant difference between proteinuria ?2g and <2g was detected in relation to serum levels of PIGF (median 47.58 vs 114.24pg/mL), VEGF (median 25.35 vs 33.74pg/mL) and sVEGFR-1 (median 5386 vs 4605pg/mL). CONCLUSION: Elevation in circulating uric acid as well as proteinuria in preeclamptic women is associated with an altered angiogenic balance, suggesting that angiogenic factors may be involved in kidney dysfunction. PMID- 26105344 TI - PP021 Outcomes for adolescent women and their pregnancies in greater Western Sydney. AB - INTRODUCTION: Hypertensive disorders in pregnancy (HDP) are a common complication of pregnancy. It is widely believed that this is a more common complication of adolescent pregnancies. Adolescent pregnancies are generally primiparous and result in earlier delivery, and these factors put them at a greater risk of preeclampsia. However, the generally lower blood pressure of the group should act as a protective measure against this. OBJECTIVES: The aim of this investigation was to compare the adolescent age group (maternal age <20years at time of recruitment) to those in the 20-34years age group in terms of their change in blood pressure and diagnosis of HDP and preeclampsia. Immediate obstetric outcomes (gestation at delivery, birthweight and mode of delivery) were also compared. METHODS: Questionnaires were administered to pregnant women at Campbelltown and Liverpool hospitals as part of a much broader study looking at sleep disordered breathing in pregnancy. Data collected included demographic information, pregnancy blood pressure readings, pregnancy complications, delivery type and neonatal outcomes. Adolescents (Group 1 age <20years) were compared to older women (Group 2 aged 20-34years) utilizing Student's t-tests analysed with IBM SPSS v.19TM. RESULTS: Results were available on 2306 women, 108 in Group 1 and 2198 in Group 2. Adolescents had a lower booking systolic blood pressure (105mmHg and 109mmHg, p<0.005) and diastolic blood pressure (63mmHg and 65mmHG, p<0.002) than older women respectively. There was no statistical difference in the highest recorded systolic blood pressure antenatally (119mmHg and 121mmHg, p<0.06) nor the highest recorded diastolic blood pressure readings between Groups 1 and 2 respectively (74mmHg and 75mmHg, p=0.6). There was no difference in the rates of HDP between the groups (8.3% and 8.2%, p=0.8) nor the rates of preeclampsia (2.8% and 2.9%, p=1.0). CONCLUSION: Although adolescents have lower booking blood pressures than their older peers, their highest antenatal blood pressure readings are similar and they have the same incidence of HDP and preeclampsia. PMID- 26105345 TI - PP022 The haemostatic suture (technique of B-Lynch) may be an alternative to control uterine hemorrhage associated with hypertensive disorders. AB - INTRODUCTION: Postpartum haemorrhage is an important cause of maternal morbidity and mortality, uterine atony being responsible for most of the cases. Hypertensive disorders are supposed to increase the possibility of such complications, mainly when complicated by "abruptio placentae". The classical treatments for postpartum haemorrhage have been based on medications like oxytocin and misoprostol, but more recently a haemostatic uterine suture developed by Christopher B-Lynch has been indicated. Here, we describe our experience of performing such technique and investigate its results in patients complicated by hypertensive disorders. OBJECTIVES: Reporting a series of cases of postpartum haemorrhage treated with the B-Lynch suture. METHODS: This is a descriptive study including 39 patients treated with the B-Lynch suture after postpartum haemorrhage related to uterine atony. The period evaluated was between January 2005 and February 2012. Intravascular oxytocin was routinely used in all cases, with doses changing from 20 to 60 IU. The suture material used was chromed catgut 1.0mm. RESULTS: The mode of delivery was cesarean-section in all cases. Five patients (12.8%) had hypertensive disorder as additional complication and one of these patients had abruptio placentae followed by development of Couvelaire uterus. Overall, the B-Lynch technique helped to control haemorrhage in all cases evaluated. CONCLUSION: We believe that the B-Lynch technique appears as an important procedure to be indicated in cases of postpartum haemorrhage. Therefore, we recommend that this technique should be tried to control such complications before deciding for other more aggressive procedures like hysterectomy. It seems that this treatment may be used in patients complicated by hypertensive disorders. PMID- 26105346 TI - PP023. Unexpected random urinary protein: creatinine ratio results - Insightsfrom clinician-laboratory medicine collaboration. AB - INTRODUCTION: Proteinuria assessment is important in pregnancy, particularly in determining whether or not a woman has pre-eclampsia. The random protein to creatinine ratio (PrCr) has been recommended as a confirmatory test for dipstick proteinuria in pregnancy, defined as random PrCr ?30mg/mmol. However, it has been our clinical impression that women with normal pregnancy outcomes have fluctuating or persistently elevated PrCr values. OBJECTIVES: As the primary goal of proteinuria testing in pregnancy should be to identify women at increased risk of adverse outcomes, we sought to explore our clinical impression that an elevated PrCr is seen not infrequently in pregnancies with normal outcome. METHODS: In this prospective cohort study, consecutive inpatients or outpatients (attending high-risk maternity clinics) were evaluated at a tertiary care facility. Random midstream urine samples were obtained as part of normal clinical care. Urine protein was measured using a pyrocatechol violet molybdate dye binding method, and urine creatinine by an enzymatic method, both on an automated analyser (Vitros(r) 5.1 FS or Vitros(r) 5600, Ortho-Clinical Diagnostics, Rochester, NY) followed by PrCr calculation. Maternal and perinatal outcomes were abstracted from the hospital case notes. RESULTS: 160 women (81.9% outpatients) were screened at one/more antenatal visits providing a total of 233 samples for analysis. Ninety one (39.1%) samples had a random PrCr ?30 mg/mmol. This result was more common when urinary creatinine concentration was <3mM [64 (94.1%)] compared with ?3mM [27 (16.4%)], even among the 32 (20.0%) women with known normal pregnancy outcome [(13 (92.9%) vs. 0 (0%), respectively] (Panel A). In dilution studies using the same automated analyser, urinary protein (at a concentration of 0.12g/L) was 'detected' in deionised, double-distilled water. Method-specific re-analysis of data from two other published cohorts from our centre revealed substantially less inflation of PrCr values in dilute 24h urine samples tested using a pyrogallol red dye-binding based protein assay. When results were categorized according to urinary creatinine <3mM vs. ?3mM, PrCr ?30mg/mmol occurred in 12 (66.7%) vs. 99 (55.3%) respectively (p=0.35) in a 24-h urine completeness cohort and 92 (73.6%) vs. 313 (64.9%) respectively (p=0.07) in a cohort of women hospitalised for pre-eclampsia (Panel B). CONCLUSION: Random urinary PrCr results may be inflated in dilute urines because of overestimation of proteinuria in a common pyrocatechol violet dye-based method. This inflation was reduced but not eliminated when the dye used was pyrogallol red. Analytical methods do matter in the assessment of proteinuria in pregnant women. It may be prudent to consider the potential for falsely positive PrCr ?30mg/mmol in dilute urine, and to order PrCr testing on first voided (concentrated) urines whenever possible. PMID- 26105347 TI - PP024. Random urine albumin: Creatinine ratio in high-risk pregnancy - Is it clinically useful? AB - INTRODUCTION: The albumin:creatinine ratio (ACr) is the newest of available methods of proteinuria assessment in pregnancy. Published cut-offs for detection of ?0.3g/d proteinuria vary from 2mg/mmol to 8mg/mmol. Up to 20% of women have an elevated ACr in pregnancy but normal outcome. In addition, it is our impression that the urine albumin component of the ACr is frequently below the detection limit of the assay. OBJECTIVES: To evaluate the frequency with which a measurable ACr can be obtained in a high-risk outpatient maternity population. METHODS: In this prospective cohort study, consecutive inpatients or outpatients (attending primarily morning high-risk maternity clinics) were evaluated at a tertiary care facility. Random midstream urine samples were obtained as part of normal clinical care. In the hospital laboratory, urinary albumin was measured using an immunoturbidimetric method, and urinary creatinine by an enzymatic method, both on an automated analyser (Vitros(r) 5,1 FS or Vitros(r) 5600, Ortho-Clinical Diagnostics, Rochester NY). ACr was calculated for samples with measurable urine albumin, and for samples with albumin below the assay range, ACr was calculated using the assay cut-off for albumin of 6.00mg/L. RESULTS: One hundred and sixty women (81.9% outpatients) were screened at one/more antenatal visits, providing a total of 233 urine samples for analysis. 68 (29.2%) urine samples were dilute (i.e., had urinary creatinine <3mM); only 13 (19.1%) of these had measurable urinary albumin for calculation of the ACr. Overall, 117/233 samples (50.2%) had measurable urine albumin that could be used to calculate the ACr. 76 (65.0%) had ACr >2mg/mmol and 34 (29.1%) had ACr >8mg/mmol. For the 116/233 (49.8%) samples with urine albumin below the assay detection limit, ACr was calculated using 6.00mg/L as the value for urine albumin. All of the 55 dilute samples had an ACr >2mg/mmol and 3 (2.6%) had an ACr >8mg/mmol. If dilute samples were excluded, none of the remaining 61 samples had an ACr value >2mg/mmol. CONCLUSION: Among a population of pregnant women attending primarily morning high-risk maternity clinics, urine is often dilute and urine albumin is often below the assay detection limit. This combination may result in uninterpretable ACr values if an ACr cut-off of 2mg/mmol is used as the decision limit for proteinuria ?0.3g/d. ACr may be best performed on first voided (concentrated) urine if ACr is used to assess proteinuria in pregnancy. PMID- 26105348 TI - PP025. Urinary dipstick proteinuria testing - Does automated strip analysis offer an advantage over visual testing? AB - INTRODUCTION: The visual urinary test strip is widely accepted for screening for proteinuria in pregnancy, given the convenience of the method and its low cost. However, test strips are known to lack sensitivity and specificity. The 2010 NICE (National Institute for Health and Clinical Excellence) guidelines for management of pregnancy hypertension have recommended the use of an automated test strip reader to confirm proteinuria (http://nice.org.uk/CG107). Superior diagnostic test performance of an automated (vs. visual) method has been proposed based on reduced subjectivity. OBJECTIVES: To compare the diagnostic test properties of automated vs. visual read urine dipstick testing for detection of a random protein:creatinine ratio (PrCr) of ?30mg/mmol. METHODS: In this prospective cohort study, consecutive inpatients or outpatients (obstetric medicine and high risk maternity clinics) were evaluated at a tertiary care facility. Random midstream urine samples (obtained as part of normal clinical care) were split into two aliquots. The first underwent a point-of-care testing for proteinuria using both visual (Multistix 10SG, Siemens Healthcare Diagnostics, Inc., Tarrytown NY) and automated (Chemstrip 10A, Roche Diagnostics, Laval QC) test strips, the latter read by an analyser (Urisys 1100(r), Roche Diagnostics, Laval QC). The second aliquot was sent to the hospital laboratory for analysis of urinary protein using a pyrocatechol violet molybdate dye-binding method, and urinary creatinine using an enzymatic method, both on an automated analyser (Vitros(r) 5,1 FS or Vitros(r) 5600, Ortho-Clinical Diagnostics, Rochester NY); random PrCr ratios were calculated in the laboratory. Following exclusion of dilute samples with urinary creatinine concentration <3mM (given inflation of PrCr values in dilute urine by our method), diagnostic test properties were determined for visual and automated dipstick proteinuria testing (?1+) for detection of a random PrCr ?30mg/mmol. RESULTS: 160 women (81.9% outpatients) were screened at one/more antenatal visits, providing a total of 233 urine samples for analysis. Both visual and automated read urinary dipstick testing showed low sensitivity (56.0% and 53.9%, respectively). Positive likelihood ratios (LR+) and 95% CI were 15.0 [5.9,37.9] and 24.6 [7.6,79.6], respectively. Negative LR (LR-) were 0.46 [0.29,0.71] and 0.47 [0.31,0.72], respectively. CONCLUSION: Automated dipstick urinalysis is not more sensitive than visual read urinalysis for detection of proteinuria in a primarily outpatient setting in pregnancy. Both have excellent LR+ but only fair to poor LR- as previously recognised for visual dipstick testing. Performance of automated strip analysis testing may vary with the test strips and analyser used. PMID- 26105349 TI - PP026. Hyperuricemia in the prognosis of adverse perinatal outcomes. AB - INTRODUCTION: Elevated uric acid levels during the first or third trimester of gestation have been associated with poor perinatal outcomes in women with hypertensive pregnancies. OBJECTIVES: Investigate whether uric acid levels are related to adverse perinatal outcomes in Chilean hypertensive women. METHODS: It is a post-hoc analysis from a retrospective study including clinical records (n=416) of women with diagnosis of hypertension in pregnancy treated in the Hospital Clinico Herminda Martin, Chillan, Chile. From these records, 86 showed quantification of uric acid plasma levels at the moment of hypertension diagnosis ((3) 140/90mmHg; at 34+/-5weeks). Women were divided into three groups, considering uric acid levels below 25th percentile (Low group, n=27, <3.7mg/dl), from 25th to 75th percentile (Middle group, n=38, 3.8 to 5.7mg/dl) and above 75th percentile (High group, n=21, >5.8mg/dl) for the studied population. RESULTS: In the entire group of hypertensive women, the uric acid/creatinine ratio was positively related to hospitalization days (p=0.04), and negatively associated with newborn weight (p=0.02) and size (p=0.01). ANOVA analysis did not show statistical differences in age, parity, systolic, diastolic or media blood pressure, body mass index, proteinuria, hepatic enzymes or hypoxia perinatal in women with low, middle or high uric acid levels. However, women with high uric acid levels showed a longer-hospitalization period (~1.2days more), less platelet count (~40*10(3)/ml) and high creatinine plasma levels (~0.2mg/dl) and their babies showed less birth weight (~800g) and were smaller (~3cm) compared with women with low uric acid levels. Relative risk of intrauterine growth restriction in women with high levels of uric acid was 1.3 (CI, 0.96 to 1.73) compared with women with low levels. CONCLUSION: These data reinforce the general agreement about the utility of hyperuricemia in the prognosis of adverse perinatal outcomes in hypertensive pregnancies. PMID- 26105350 TI - PP027. Variation of urinary protein/creatinine ratio during the day in women suspected for preeclampsia. PMID- 26105351 TI - PP028. To assess maternal and neonatal outcomes of women on an antihypertensive agent with gestational hypertension, chronic hypertension or preeclampsia. AB - INTRODUCTION: There is a lack of evidence regarding antihypertensive medicine use in pregnancy. OBJECTIVES: To compare maternal and neonatal outcomes of women on an antihypertensive agent with gestational hypertension (GHTN), chronic hypertension (CHTN) and preeclampsia (preE). METHODS: The Consortium on Safe Labor electronic database from 19 hospitals across the US with 228,668 deliveries during 2002-2008 was used to extract data on gravidas with GHTN, CHTN, and preE on a calcium channel blocker, methyldopa, or beta blocker. Univariate and multivariate analyses were performed. RESULTS: There were 637 women on beta blockers, 207 on calcium channel blockers, 249 on Methyldopa, and 6869 women with hypertension on no agent (control group). Women on beta blockers had an increased risk of ICU admission, OR 3.74 (95% CI 1.8-7.6). Risk of thrombosis was increased in women on beta blockers, OR 3.6 (95% CI 1.4-9.2) and calcium channel blockers, OR 10.6 (95% CI 3.8-29.2). There was no increased risk of small for gestational age babies. There was a small, increased risk of NICU admission for babies of women on calcium channel blockers, OR 1.7 (95% CI 1.2-2.6) and methyldopa, OR 1.9 (95% CI 1.4-2.7). CONCLUSION: Beta and calcium channel blocker use was associated with significant risks of morbidity compared to Methyldopa use by gravid women with hypertensive disease. PMID- 26105352 TI - PP029. Gestational hypertension and birth weight in twin pregnancies. AB - INTRODUCTION: It is well known that hypertensive disorders of pregnancy are most frequent in twin pregnancies than in singleton ones. As demonstrated by a previous work of our group, twin pregnancies complicated by preeclampsia are associated with a higher rate of "small for gestational age" (SGA) neonates and inter-twin weight discordance than normotensive ones. OBJECTIVES: The present study investigates the effect of gestational hypertension (GH) on neonatal birth weight, inter-twin weight discordance and growth restriction rate among twin pregnancies. METHODS: A 26 year retrospective study was undertaken by examining 196 twin pregnancies complicated by GH, from January 1, 1980 to December 31, 2006, and comparing them to 912 normotensive twin pregnancies. RESULTS: No significant differences were observed between the two groups in relationship to birth weight, inter-twin weight discordance and growth restriction rate, with a trend towards a higher birth weight in GH group. In normotensive group, the discordance >25% was associated with a lower gestational age at the delivery (p<0.00001). Moreover, the rate of pregnancies with SGA second twin gradually rose while paralleling the degree of discordance. CONCLUSION: Contrary to preeclampsia in twin pregnancies the outcome of those complicated by GH is similar to normotensive ones. The trend towards a higher birth weight in GH seems apparently paradoxical, but it may reflect the role of uncomplicated hypertension in twin pregnancies: the increased blood pressure could be a physiologic response for more blood nutrient supply to the fetuses. PMID- 26105353 TI - PP030. Cardiovascular disease and risk in a pregnant woman's father as a risk factor for preeclampsia. AB - INTRODUCTION: In women experiencing their first pregnancy the assessment of risk of developing a hypertensive disorder of pregnancy (HDP) including preeclampsia is imprecise. Identification of women at higher than normal risk of developing preeclampsia may improve pregnancy management and lead to better outcomes. Previous studies, mostly retrospective, have indicated a possible link between cardiovascular history and risk of preeclampsia. OBJECTIVES: To evaluate the self reported family history of cardiovascular disease and risk (CVD/R) during an antenatal interview as a means of screening for risk of developing preeclampsia or other HDP. METHODS: Nulliparous women were recruited prospectively in early pregnancy before diagnosis of any HDP. Women reported on their maternal characteristics and the history of cardiovascular health in themselves, their parents and siblings and the father of the baby and his parents and siblings. Cardiovascular health was assessed as cardiovascular risk (high blood pressure, high cholesterol and diabetes) and cardiovascular disease (heart attack, stroke, angina and any major vascular surgery). Pregnancy outcomes were recorded after delivery, the diagnoses of gestational hypertension, preeclampsia and superimposed preeclampsia being assigned according to the criteria defined by SOMANZ, 2008. A nominal logistic regression analysis was used to evaluate the effects of family history on risk of developing HDP while adjusting for clinical risk factors known at the time of recruitment. RESULTS: Nine hundred and ninety seven women completed the study. Median gestational age at recruitment was 31.3weeks (Interquartile range [IQR] 24.4-35.9, range 5.6-39.1). Median age was 27.0years (IQR 23.0-32.0, range 16.0-45.0), median BMI was 28.6 (IQR 24.8-36.4, range 16.7-64.4) and 76.4% of the women did not smoke during the pregnancy. Preeclampsia was diagnosed in 12.6% of the women (103/997 preeclampsia, 23/997 superimposed) and 6.2% developed gestational hypertension (62/997). CVD/R was reported by 22.3% of mothers (including 1.7% of CVD alone) and in 9.3% of the partners (including 1.7% of CVD alone). Women reported CVD/R in 39.1% of their mothers (including 6.5% CVD alone) and in 42.2% (including 13.3% CVD alone) of their fathers. Women reported CVD/R in 30.3% (including 6.1% CVD alone) of the partners' mothers and in 38.9% (including 15.0% CVD alone) of the partners' fathers. Women who knew of CVD/R in their fathers had increased risk of preeclampsia (16.2% vs. 10.1%; Odds Ratio [OR]=.66 95% Confidence Interval [CI] 1.16-2.36, p=.005) that remained elevated after adjustments for maternal age, BMI, smoking in pregnancy and maternal CVD/R. No similar increase in risk of gestational hypertension was evident (7.4% vs. 5.4%; OR=1.31 95% CI0.81 2.10,p=0.272). CVD/R reported for any other family member did not significantly alter the woman's risk of developing preeclampsia or any other HDP. CONCLUSION: The presence of a history of CVD/R in the father of the pregnant woman indicated an increased risk of developing preeclampsia. The possibility of a similar association between CVD/R in other family members and HDP may exist however women in their first pregnancy may not have sufficient knowledge of family history. This lack of comprehensive information may limit the potential value of family history in determining the risk of preeclampsia and other hypertensive disorders in pregnancy. PMID- 26105354 TI - PP031. The prevalence of microalbuminuria following preeclampsia. AB - INTRODUCTION: About 7years after preeclampsia, the prevalence of microalbuminuria is reported to be around 30% [1]. As proteinuria resolves in most cases within two years of post partum, [2] this raises the question of whether microalbuminuria first regresses after preeclampsia or persists. OBJECTIVES: This cross-sectional study describes the prevalence of microalbuminuria in the years following preeclampsia. METHODS: Women with a history of preeclampsia (n=823) were evaluated 4-180months after delivery. Women with pre-existing hypertension, renal disease or diabetes mellitus were excluded (n=65). In a 24h urine collection we determined total protein (pyrogallol red), microalbuminuria (turbidometry, Cobas Bio and since 2007 nephelometry, BN ProSpec) and creatinine (Jaffe method). Microalbuminuria was considered to be present when there was ?3.5mg/mmol of creatinine. Proteinuria was defined as a total protein level of ?300mg/24h. RESULTS: Microalbuminuria was present in 12.0%, CI 9.7-14.6 and proteinuria in 2.7%, CI 1.7-4.1 of all cases. Microalbuminuria decreased up to 40months postpartum, but increased after that period of time (p=0.01 compared with 24-40months). CONCLUSION: This study suggests a U-shaped microalbuminuria pattern over time. Longitudinal research is necessary to confirm this. PMID- 26105355 TI - PP032. Unique features of long-term cardiovascular phenotype in young women with early-onset pre-eclampsia. AB - INTRODUCTION: Early-onset preeclampsia is associated with a greater risk of cardiovascular disease than late-onset preeclampsia. OBJECTIVES: We tested the hypothesis that young women, with previous early-onset preeclampsia, have unique differences in long term cardiovascular phenotype compared to late-onset preeclampsia or normal pregnancy. METHODS: 140 women (mean age 40 yrs) were followed up 6-13years following pregnancy. 90 had had preeclampsia (45 early onset (before 34 weeks of gestation), 45 late onset) and 50 had normotensive uncomplicated pregnancies. Women with cardiovascular risk factors present before pregnancy were excluded. Fasting lipids, glucose, insulin and circulating cytokines were measured. Central blood pressure (BP) and arterial stiffness (pulse wave velocity (PWV)/augmentation index (AI)) were assessed by applanation tonometry, common carotid intima media thickness (cIMT) by ultrasound and cutaneous capillary density by intravital microscopy. 46 women returned for assessment of cardiac structure and function by magnetic resonance and echocardiography as well as ambulatory blood pressure monitoring. RESULTS: All women with a previous history of preeclampsia had 5-10mmHg higher peripheral and central BP (P<0.001) as well as elevated total: HDL cholesterol (P<0.003), insulin resistance (P<0.04) and circulating TNFalpha (P<0.007). They also had increased arterial stiffness (P<0.04) and cIMT (P<0.005). Cardiac size and systolic function were preserved but there was evidence of abnormal diastolic relaxation (E/E' -P<0.04). In contrast early-onset preeclampsia was associated with characteristic differences in peri-pregnancy blood pressure, long term ambulatory measures and microvascular function. CONCLUSION: Early onset preeclampsia is associated with unique features in long term cardiovascular phenotype. Pregnancy disease characteristics may identify women at greatest potential benefit from monitoring and primary prevention. PMID- 26105356 TI - PP033. High blood pressure in pregnancy: an indicator of future health outcomes. AB - INTRODUCTION: Hypertensive disorders of pregnancy (HDP) remain a leading cause of maternal and perinatal morbidity and mortality worldwide. In Australia approximately 10% of all pregnancies are affected by HDP. There is growing evidence that endothelial damage caused by HDP remains after pregnancy and has long term consequences on maternal health. OBJECTIVES: The aim of our research was to determine the association between HDP and risk of having high blood pressure in later life. METHODS: Self-reported data regarding a physician's diagnosis of HDP and of high blood pressure later in life were obtained from women recruited from the 45 and Up Study, Australia. Relative risks (converted from odds ratios) and 99% confidence intervals were estimated using logistic regression, adjusting for demographic and lifestyle characteristics. RESULTS: A total of 82,164 women were included in the study, of which 9,845 reported having HDP. Women who had HDP had a significantly increased risk of having high blood pressure later in life compared to women who did not have HDP (adjusted relative risk of 2.05, 99% CI 1.99-2.11, p<0.001). The results showed that women who had HDP develop high blood pressure 6.3 years (99% CI 5.85-6.66, p<0.001) earlier compared to women without HDP. CONCLUSION: Women who have HDP are at a greater risk of future onset of high blood pressure compared to women who have a healthy pregnancy. Women with HDP should be monitored closely in the years following pregnancy for early identification and intervention of high blood pressure. PMID- 26105357 TI - PP035. Placental klotho protein in preeclampsia: A possible link to long term outcomes. AB - INTRODUCTION: An aging-suppressor gene, klotho, is a candidate factor for vascular disease because its deficiency leads to impaired endothelium-dependent vasodilation and impaired angiogenesis. Although klotho protein is predominantly expressed in the kidney, it is detected in a limited number of other tissues, such as the placenta, ovary, prostate gland, and small intestine. This protein is involved in several metabolic pathways such as calcium and phosphate homeostasis, the insulin-like growth factor 1 (IGF-1), apoptosis, angiotensin-II-induced events in the kidney and oxidative stress. OBJECTIVES: The aim was to assess the expression of the klotho gene in the placenta from pregnancies affected by severe preeclampsia. METHODS: Placentas were collected from normal pregnancies (n=12) and pregnancies complicated by preeclampsia (n=12), matched for gestational age. Klotho mRNA and protein were determined using real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. RESULTS: Real-Time PCR analyses demonstrated a significant (p=0.005) 83% down-regulation of Klotho in patients with Preeclampsia versus Controls. Results of Western Blot agreed with those from Real-Time PCR. CONCLUSION: Klotho mRNA expression in the placenta is decreased in preeclamptic pregnancies. Given its role in cardiovascular disease in aging, it may link preeclamptic mothers and their offsprings to long term cardiovascular outcomes. PMID- 26105358 TI - PP034. Cardiovascular outcomes remote from pregnancy in women with HDP: 23 32years following delivery. AB - INTRODUCTION: Cardiovascular disease (CVD) is a leading cause of mortality worldwide in women aged >54years. There is a strong association between HDP and the development of hypertension in later life. OBJECTIVES: To ascertain the current health profile of some of the women who were diagnosed with a HDP and participated in a trial during the time period of 1980-1989 and to examine the association between the two. METHODS: Women who delivered at a major teaching hospital during the designated time period and who were enrolled at that time in trials examining HDP treatments and outcomes were invited to participate in a health status evaluation. Their medical histories, time sequenced blood pressure readings, urinalysis, BMI and pulse wave analysis were compared using standard statistical techniques of Chi-square analysis and Student's t-tests obtained from IBM SPSS v.19TM. RESULTS: Thirty-nine women from the trials were available for follow-up. Of these women, 85% had current CVD, of which 88% had hypertension, 59% hypercholesterolaemia and 3% had experienced a CVA. Compared to the general female population of 22% for CVD this equates to a RR of 7.2 (CI 95% 3.042 15.13). CONCLUSION: HDP is associated with an increased risk of CVD compared to the general female population. Women who experience HDP in their pregnancy should be monitored regularly due to an increased risk of CVD and potentially early onset of the disease. PMID- 26105359 TI - PP036. Cardiovascular disease risk factors among women with a history of placental abruption. AB - INTRODUCTION: Several studies have shown that the risk of premature cardiovascular disease (CVD) is increased after maternal placental syndromes (MPS), including hypertensive disorders and placental abruption. Although a high prevalence of CVD risk factors has been observed for women with a history of preeclampsia and pregnancy-induced hypertension, it is unclear whether patients with previous placental abruption exhibit the same cardiovascular risk profile. OBJECTIVES: To investigate the association of placental abruption with the presence of modifiable CVD risk factors that may be of potential use for prevention programs. METHODS: We performed a case-control study of 75 women with a history of placental abruption and a control group of 79 women with uneventful pregnancies. At 6-9months postpartum we measured the following CVD risk factors: blood pressure, body-mass index (BMI), fasting blood glucose levels, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and CRP. Baseline variables in the two groups with and without a previous abruption were expressed as means and standard deviations (SD). Where appropriate, means were adjusted for potential confounders using a generalized linear model. Data were further stratified for women with or without additional MPS-related complications, i.e. preeclampsia, gestational hypertension and intrauterine growth restriction. RESULTS: Women who experienced placental abruption had a significantly higher systolic and diastolic blood pressures, BMI, fasting blood glucose levels, CRP, total cholesterol, HDL-cholesterol, LDL-cholesterol and cholesterol/HDL ratio, as compared to controls. These associations remained significant in women with previous placental abruption without concomitant other MPS only for plasma lipid profile, BMI and fasting blood glucose levels, but not for diastolic and systolic blood pressure. CONCLUSION: A history of placental abruption is independently associated with increased BMI, fasting blood glucose levels, total cholesterol and LDL-cholesterol postpartum. Early detection of CVD risk factors in women with previous placental abruption offers an attractive opportunity for primary and secondary prevention. PMID- 26105360 TI - PP037. Family history of cardiovascular disease and maternal vascular function during early pregnancy. AB - INTRODUCTION: Women with a family history of cardiovascular disease (CVD) have an increased risk of hypertensive disorders during pregnancy. Pregnancy is associated with increased physical demands on the cardiovascular system and hemodynamic changes. Cardiac output increases by about 40-50%, blood volume by 10 20% and vascular resistance decreases. OBJECTIVES: Our hypotheses was that women with a family history of CVD fail to have an adequate cardiovascular adaptation during pregnancy. METHODS: Fifty healthy women with singleton viable pregnancies were included in the study who were recorded in the Ultrasound Department of UltraGyn Stockholm, Sweden for ultrasound dating in gestational week of 11-14. Of these, 25 women had a family history of CVD which was defined as having at least one first degree relative with the diagnosis of premature hypertension, myocardial infarct or stroke before the age of 55 (men) or 65 (women). Twenty five healthy women without a family history were included as controls. Smokers were excluded. Blood pressure was measured in the upper left arm in a conventional way. The pulse wave was registered in the radial artery (SphygmoCor Px and Vx, PWV Medical). The central blood pressure was calculated with a validated algorithm. The pulse wave was then registered in the femoral artery, the velocity was calculated and the arterial stiffness estimated. Flow mediated vasodilation was studied in the radial artery through measurement with ultrasound of diameter changes and blood flow before and after ischemia (Vivid 7, GE, 10MHz transducer). RESULTS: Systolic blood pressure in the upper left arm was significantly higher in women with a family history of CVD (median 109.5mmHg versus 105mmHg, p=0.04). Diastolic blood pressure did not differ. Aortic blood pressure also differed significantly in women with a family history of CVD, both systolic (median 95mmHg versus 86.3mmHg, p=0.0005) and diastolic (median 66mmHg versus 59.3mmHg, p=0.0024). No other results were significantly different. All values refer to examinations at gestational weeks 11-14. CONCLUSION: Changes in vascular function during the first trimester reflect important adaptations that are necessary for a normal pregnancy. Women with a family history of CVD had a significantly higher blood pressure at 11-14weeks of gestation although the values were within normal range. The pregnancy related decrease of vascular resistance may be less pronounced in women with a family history of CVD. Vascular function will be followed longitudinally during pregnancy and related to obstetric outcome in this group. PMID- 26105361 TI - PP039. The importance of intentionally considering class 1 HELLP syndrome outcomes versus all other categories of HELLP syndrome or severe preeclampsia. AB - INTRODUCTION: Combining HELLP syndrome patient groups in publications and presentations may obfuscate any potential differences among patient groups with regard to maternal-perinatal outcomes and rendered therapies. OBJECTIVES: We explored the prevalence of major maternal morbidity (MMM) for patients with severe preeclampsia (SPRE) and each defined group of HELLP syndrome. METHODS: Retrospective cohort study 2000-2007 of patients categorized either as class 1 HELLP syndrome (HELLP1, platelets?50,000, AST?70,LDH?600), class 2 (HELLP2, platelets>50,000 to ?100,000), class 3 (HELLP3, platelets>100,000 to ?150,000), or partial/incomplete (HELLP4) with only 2 of 3 diagnostic parameters present. All SPRE patients (no HELLP) of 2005-2007 were also evaluated. Total MMM for each group was determined. MMM included cardiopulmonary [cardiogenic or noncardiogenic pulmonary edema, pleural or pericardial effusion, pulmonary embolus, indicated intubation, myocardial infarction or arrest], hematologic/coagulation [DIC, transfused blood products], central nervous system/visual [stroke, cerebral edema, hypertensive encephalopathy, vision loss], hepatic [subcapsular hematoma or rupture] or renal complications [acute tubular necrosis or renal failure]. All HELLP1 and HELLP2 patients received corticosteroids, magnesium sulfate and anti hypertensives. Comparison among groups was done using Chi-square or Fisher exact test at 95% CI. RESULTS: Four hundred and twenty patients had a form of HELLP syndrome 2000-2007; 688 patients had SPRE 2005-2007.The prevalence of MMM for each patient group was determined: HELLP1=41.5%; HELLP2=10.3%; HELLP3=20.0%; HELLP4=21.0%; and SPRE=17.7%. MMM in HELLP1 was significantly increased over all other groups (P<0.001). Combining MMM for HELLP1+HELLP2 produced a prevalence of 22.1% MMM, insignificantly different from all others including HELLP3, HELLP4 and SPRE (p=0.19), thereby obscuring the significantly elevated MMM of HELLP1 patients. CONCLUSION: Only patients with HELLP1 have significantly increased MMM compared to other HELLP groups or SPRE. Failing to separately evaluate patients with HELLP1 in studies of HELLP syndrome could lead to mistaken conclusions about the effectiveness of a treatment to reduce MMM. All publications reviewing HELLP syndrome management should address how well it functions to reduce patient development of HELLP1 and thus minimize MMM. PMID- 26105362 TI - PP038. Are women with gestational hypertension or preeclampsia at an increased long term risk of kidney function impairment? AB - INTRODUCTION: Preeclampsia is known to cause impairment of kidney function in pregnancy, which manifests as proteinuria. Previous studies have found an association between preeclampsia and kidney disease but were restricted in their numbers or had a short follow up time. OBJECTIVES: To assess the long term effects of hypertensive disorders of pregnancy on kidney function in later life. METHODS: From the Aberdeen maternity and neonatal databank (AMND), we identified the first singleton pregnancy of all women with date of birth on or before 30th June 1969. These women were linked by means of their identifying information to the local renal biochemistry database (GRBD). GRBD captures all kidney function tests from primary and secondary care in the health region. A cohort study design was used to assess the odds ratios with 95% confidence intervals for chronic kidney disease stage 1-5 (predefined based on internationally accepted KDOQI definition) occurring at least 1year following delivery. Those with gestational hypertension and preeclampsia were compared to normotensive women using multivariate logistic regression to adjust for potential confounders. RESULTS: A total of 14675 women who had been linked to the RBD and had complete information regarding age, socio-economic class, smoking category, and body mass index (BMI) were included in a multivariate model. The unadjusted odds ratio (95% confidence interval) of having chronic kidney disease (according to previously stated definition) in preeclamptic women was 2.04 (1.53,2.71) and that in women with gestational hypertension was 1.37 (1.15,1.65), while the adjusted odds ratio (95% confidence interval) of having chronic kidney disease was 1.93 (1.44,2.57) and 1.36 (1.13,1.63) in preeclamptic women and women with gestational hypertension respectively compared to women who were normotensive in their first pregnancy. CONCLUSION: Women who had gestational hypertension or preeclampsia in their first pregnancy had a higher risk of impairment of renal function compared to women who were normotensive. PMID- 26105363 TI - PP041. The effect of exercise in pregnant women with chronic hypertension and/or previous preeclampsia on blood pressure and heart rate variability. AB - INTRODUCTION: Hypertensive disorders during pregnancy are an important issue in global public health. Physical activity has been proposed as an important part of hypertension's treatment and has been studied as a possibility for the prevention of PE and its complications. OBJECTIVES: To assess the effect of exercise using stationary bicycle through blood pressure (BP) and heart rate (HR) measurements in pregnant women with CH, previous PE pregnancies or both factors associated. METHODS: This randomized clinical trial (preliminary data) performed at the Women's Hospital Dr. Jose Aristodemo Pinotti - CAISM/Unicamp, Brazil, enrolled 52 pregnant women presenting with CH, previous PE experience or both. Women from 12 to 20 gestational weeks were selected from the prenatal outpatient clinic and randomly allocated to the study (SG) or non-interventional group (NIG). Women at the SG performed physical exercise using stationary bicycle (horizontal bench model) during 30min, once a week, under a physical therapist supervision. The HR was maintained at 20% above resting heart rate and up to 140 beats per minute. BP and HR measurements were evaluated before and after exercise in sitting position. The NIG followed a regular prenatal routine with weekly returns for HR and BP measurements. The BP (systolic and diastolic) and HR were analyzed comparing groups. The BP measurement was analyzed comparing before and after exercise in the SG. Significance was assumed as p<5%. RESULTS: We had 6 drop-outs in the SG and 5 in the NIG. A total of 41 pregnant women were analyzed (16 in the SG and 25 in the NIG). The mean age was 32years and mean Body Mass Index (BMI) was 34.2+/ 7.0kg/m(2) in the SG and 34.5+/-8.4kg/m(2) in the NIG (p=0.91). Considering the sociodemographic and clinical characteristics the SG and NIG were similar and homogeneous. No statistical differences were observed between groups on systolic and diastolic BP and HR. However, BP at the end of the study in the interventional group was lower compared to pre-study BP. CONCLUSION: Pregnant women with CH, previous PE or both factors associated who did exercise using stationary bicycle, under supervision, once a week, did not present HR and BP changes in these preliminary data. PMID- 26105364 TI - PP040. Expression of RANTES (CCL5) in maternal plasma, fetal plasma and placenta in pre-eclampsia and normotensive controls. AB - INTRODUCTION: Studies have shown pre-eclampsia (PE) as an exacerbation of gestational inflammatory process. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted)/CCL5 is a chemokine, which is involved in chronic inflammation by the recruitment of inflammatory cells. It is secreted by many cell types such as endothelial cells, smooth muscle cells, macrophages, platelets and activated T-cells. Thus we hypothesized that RANTES expression is altered in PE and may be different in gestational tissues (maternal plasma, fetal plasma and placenta). OBJECTIVES: The purpose of the study is to analyze the expression of RANTES (CCL5) in three different tissues: maternal plasma, fetal plasma and placenta, in PE and normotensive controls (NC). METHODS: PE was diagnosed by the National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy guidelines. The patients were assisted in the Sao Lucas Hospital from PUCRS, Porto Alegre, Brazil. Following ethical approval and informed written consent, maternal and umbilical plasma and placental biopsies were taken from 33 PE and 35 NC. Samples were centrifuged immediately after blood collection and plasma was stored at -80 degrees C until assay. Placental Biopsies were taken midway between the cord and periphery, from the central region of cotyledons and were stored as well. RANTES expression was made by the ELISA test, in duplicates. They were also analyzed in each group: maternal age, maternal parity, gestational age on delivery, glucose, body mass index, proteinuria creatinuria ratio, systolic blood pressure (SBP), diastolic blood pressure (DBP), delivery method, birth weight, placental weight and Apgar index in 1st and 5th minute. RESULTS: Maternal age at the time of blood collection was not significantly different between the two groups. The women with preeclampsia delivered earlier and had smaller babies compared with the controls. Significant associations between groups (p<0.001) were seen in SBP, DBP, birth weight and delivery method. RANTES was increased in maternal plasma and placenta in patients with PE and decreased in fetus plasma in the same group (p<0.001). CONCLUSION: In this study, we have shown that RANTES expression in maternal plasma and placenta tissues, in women with established pre-eclampsia, is higher than in gestation matched women with a healthy pregnancy. It confirms the hypotheses that physiology of PE is associated with an increase of normal gestational inflammatory process. However in fetus tissue, the inflammatory chemokine is decreased in PE women. FUNDING: CAPES Foundation, Ministry of Education of Brazil, Brasilia - DF 70040-020, Brazil. PMID- 26105365 TI - PP042. Anti-hypertensive drugs hydralazine, clonidine and labetalol improve trophoblast integration into endothelial cellular networks in vitro. AB - INTRODUCTION: Preeclampsia is an exaggerated maternal inflammatory state with over-expression of placental soluble fms-like tyrosine kinase 1 (sFlt-1). It is also associated with shallow trophoblast invasion and inadequate transformation of uterine spiral arteries. Antihypertensive drugs administrated in preeclampsia to control blood pressure have been reported to regulate placental and circulating cytokine production from women with preeclampsia. Whether they could modulate the interaction between trophoblast and endothelial cells are not investigated. OBJECTIVES: This study is to examine the effect of pharmacological dose of anti-hypertensive hydralazine, clonidine and labetalol on trophoblast cell integration into inflammatory TNF-a pre-exposed endothelial cellular networks. METHODS: Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose (0.5ng/ml) inflammatory TNF-a or TNF-a plus sFlt-1 (100ng/ml) for 24hours. These cells were labelled with red fluorescence and seeded on a 24-well culture plate coated with Matrigel. Endothelial tubular structures appeared within 4hours. Green fluorescent-labelled HTR-8/SVneo trophoblast cells were then co-cultured with endothelial cells, with (or without) hydralazine (10MUg/ml), clonidine (1.0MUg/ml) or labetalol (0.5MUg/ml). Red and green fluorescent images were captured after 24hours. Drug effect on HTR-8 cells integration into endothelial cellular networks was quantified by Image Analysis software. The conditioned media were also collected to measure concentrations of free VEGF, PLGF and sFlt-1 by ELISA. RESULTS: When HTR-8/SVneo trophoblast cells were co-cultured with TNF-a pre-incubated endothelial cells, hydralazine and clonidine can significantly increase the trophoblast integration into endothelial cellular networks. This increase was not seen if co-cultured with normal endothelial cells (without TNF-a pre-incubation) or with TNF-a plus sFlt-1 treated endothelial cells. Labetalol could increase the HTR-8 cell integration into all endothelial cellular networks (with TNF-a and TNF a plus sFlt-1 treatment). There was no effect of any drug on the trophoblast invasion in the absence of TNF-a. In the conditioned medium, sFlt-1 was down regulated by hydralazine and clonidine but not by labetalol. A decrease in PLGF was seen in normal endothelial cell groups but not seen in pre-TNF-a or pre-TNF-a plus sFlt-1 endothelial cell groups. VEGF was not changed in all treatment groups. CONCLUSION: Some anti-hypertensive drugs may improve the cellular interaction between trophoblast and endothelial cells during pregnancy. An increase in sFlt-1 seen in human preeclampsia may deteriorate this effect. Hydralazine and clonidine can reduce the sFlt-1 concentration in the medium. Labetalol could increase trophoblast integration without decreasing sFlt-1, suggesting a mechanism independent of sFlt-1. Our in-vitrodata show that there is a potential effect of these agents on placental maternal arterial modelling. The drug effect on arterial/trophoblast interactions can be related to altered production of sFlt-1. PMID- 26105366 TI - PP043. Do women know what pre-eclampsia is? What is the level of knowledge of the disease in a small population connected to a social net? AB - INTRODUCTION: Pre-eclampsia is responsible for a great number of maternal deaths in our country. Even in urban areas that, theoretically, has more access to information and more medical assistance possibilities, much more women have very severe cases that could be avoided. Many initiatives to reduce this problem include effective women participation in that item, making us to believe that actual information access would allow precocious detection of the problem, leading to reduction of the maternal and perinatal risks. OBJECTIVES: To investigate a specific female population about how much they understand about the disease and its risks. METHODS: Using the social net Facebook(r), a survey was developed for online use, where direct questions related to pre-eclampsia were made. The questions involved information about age, times of pregnancy, knowledge about pre-eclampsia and their risks. It was considered an inclusion criterion the women who decided to participate in the survey spontaneously, and their identity was preserved. This form was sent to 1000 women, and 120 fully answered the questions and they were put under analysis. RESULTS: The studied group had average age between 22 and 35years. From the total, 107 (89.6%) had at least initiated high school, and the rest (11%) said that they had at least finished elementary school. From the analyzed data, it was found that 60 (50%) of the interviewed women, did not know anything about the subject. The rest said that they had some knowledge about the topic. From those, 14 (23%) had already heard about pre-eclampsia, but did not know what was it, 44 (73%) had a vaguely notion but did not know about the risks, and just 2 (4%) gave the entirely correct definition and knew about its implications. From all, 24 (20%) from the interviewed had at least once been pregnant, and 15 from those, had never heard about the pathology. CONCLUSION: Despite of the impact that pre-eclampsia represents on mother and baby's health, our results show that information in the studied group, is poor. The studied group has naturally more access to information, showing us that the situation is even more concerning. We believe that it is necessary to apply instruments that could redefine, in a greater way, the real information level to the female population in all levels of assistance. To enlarge the health politics, and increase its efficiency through informed women, seem to us, a fundamental strategy to qualify assistance and enhance maternal and prenatal safety. In an era that social nets had changed human behavior, why should not we use it as an efficient tool to promote life quality? PMID- 26105367 TI - PP044. Profile of pregnant women with pre-eclampsia treated in priority area. AB - INTRODUCTION: The maternity mortality rate in the Santos lowlands region, priority region of Sao Paulo/Brazil, is higher when compared to regions in the state of Sao Paulo. The hypertensive disorders are implicated in approximately 20% of death. Severe preeclampsia (PE) is recognized as the frequent diagnosis associated with maternal and fetal ominous outcomes. The recognition of potential risk support antenatal intervention which could anticipate the installation of catastrophic results. Identifying the epidemiological profile of women who may present with this evolution can guide public health policies and actions of the professionals involved in caring for these women avoiding preformed concepts and contributing to the recognition of local reality situation. OBJECTIVES: Identify the epidemiological profile of women affected by severe PE. METHODS: A descriptive study involving 46 pregnant women admitted to specialized hospital for high-risk pregnancy with the diagnosis of severe PE according to the criteria of NHBPEP (2000), as: blood pressure ?160/110mmHg, proteinuria 2.0g/24h or +2 dipstick, serum creatinine >1.2mg/dl (new onset), platelets <100,000/mm(3), microangiopathic hemolysis (increased lactate dehydrogenase), elevated alanine aminotransferase or aspartate aminotransferase, persistent headaches or other cerebral or visual disturbance, persistent epigastric pain or eclampsia in the period from January/2008 to November/2010. RESULTS: The average age of the pregnant women was 25.5years (+/-6.5), 11 women were multiparous and nulliparous and 35 (76.1%), the average gestational age at admission was 34 4/7, developing to eclampsia and/or HELLP syndrome were 07 women (15.2%), admission often occurred before the installation of labor in (93.5%) had a previous diagnosis of chronic hypertension (30.4%) and in all cases magnesium sulfate administration with an average length of 32h (+/-16.6h). CONCLUSION: The occurrence of severe PE was more common in nulliparous women at the age of 25years, admitted in prematurity and not in preterm labor. The outcome of seizure and/or HELLP has a considerable impact. The association of chronic hypertension with severe PE is more than 1/4 of the cases. These data are equivalent to other areas of Brazil and may contribute to emphasize the practice of prenatal acting that can recognize and pre-comment possible adverse developments and attitudes aimed at intercepting the process. PMID- 26105368 TI - PP046. Adherence to exercise with bicycle during pregnancy in women with risk of preeclampsia. AB - INTRODUCTION: Physical activity (PA) has been proposed as an important part of hypertension's treatment and has been studied as a possibility for the prevention of preeclampsia (PE) and its complications. PA is recommended during pregnancy because it may be beneficial to maternal health. However, some studies relate the difficulty in adherence to exercise during pregnancy. OBJECTIVES: The objective of this study was to evaluate the adherence to exercise with bicycle in pregnant women with risk of preeclampsia development and characterize these pregnants. METHODS: This is a secondary analysis of a randomized clinical trial at the Women's Hospital Dr. Jose Aristodemo Pinotti - CAISM/Unicamp, Brazil. We enrolled 116 pregnant women presenting with chronic hypertension (CH), previous PE or both factors associated (risk of PE development). Women from 12 to 20 gestational weeks were selected from the prenatal outpatient clinic and randomly allocated to the study (SG) or non-interventional group (NIG). Women at the SG performed exercise using stationary bicycle (horizontal bench model) during 30min, once a week, under a physical therapist supervision. The HR was maintained at 20% above resting heart rate and up to 140 beats per minute, and the BP was evaluated before and after exercise. The NIG followed regular prenatal routine with weekly returns for HR and BP measurements. We analyzed the adherence of the SG to exercise with bicycle and their sociodemographic and clinical characteristics. RESULTS: We invited 152 pregnants to participate and 33 (21.7%) refused. 116 pregnants were randomized and 58 were allocated to the SG. The mean age was 31.7+/-6.2 and mean of Body Mass Index (BMI) was 34.9+/-7.9kg/m(2). Previous PE were prevalent in 16 (27.6%) pregnant, CH in 51 (87.9%) pregnant and 9 (15.5(10.5%) pregnants relate to exercise before pregnancy. The average sessions performed by the SG using stationary bicycle were 9.24+/-7.03. That those who realized less than the mean session of the SG 14 had discontinued, 3 changed the prenatal city, 4 had TPP, 3 had difficulty in controlling blood pressure, 1 had autoimmune hepatitis diagnosis and 1 had fetal malformation. Considering the sociodemographic and clinical characteristics of these 27 the majority were obese and had had CH, they were not used to practice any type of exercise before pregnancy. Most of them were not primiparous, also had more children at home and found difficul to find time for exercise. The majority did not live next to our center. CONCLUSION: The majority of our population were obese, sedentary before pregnancy and with CH. In this study exercise, performed once a week, using stationary bicycle in pregnant women of high risk PE, seems to be difficult. PMID- 26105369 TI - PP045. Maternal mortality due to hypertension: A look at the puerperium. AB - INTRODUCTION: Maternal death is the death of a woman during pregnancy within 42days after delivery. It is one of the most serious violations of human rights of women, because it is a preventable tragedy in 92% of cases and occurs mainly in developing countries. Brazil, a country of continental dimensions has the challenge of reducing maternal deaths; one of the priority regions is Santos, a city in the state of Sao Paulo. It is felt that efforts are made to the adoption of care that can minimize risks during complicated pregnancy with hypertensive disorders, but not always this service is offered proportionally to postpartum. Perhaps the erroneous concept that the delivery is capable of quickly balancing the harm of maternal hypertensive disorders is implicated in reducing postpartum surveillance, exposing this group of women to undesirable outcomes. OBJECTIVES: Analyze the percentage of postpartum maternal deaths until 42days after delivery for hypertensive disorders in Santos in the period of 1999-2009. METHODS: Data were provided by the Ministry of Health of Brazil in www.datasus.gov.br (accessed February 2012). The number of maternal deaths was divided into maternal death in pregnancy, delivery and abortion and maternal death in puerperium up to 42, considering all causes of maternal death and identifying the proportion of deaths due to hypertensive syndromes. RESULTS: According to the general causes of death, more women die during pregnancy, delivery and abortion (69.7%) than postpartum (30.3%) and hypertensive disorders account for 20% of these outcomes. Analyzing the proportion of deaths due to hypertensive disorders in each period, we observed that during pregnancy the disorder accounts for 16.5% of all causes, however, the percentage reaches 30.3% in the puerperium. CONCLUSION: The increase of death in postpartum due to hypertensive syndromes, regarding all general causes, shows the necessary action to be done by the professional team to offer continuity care in and out of hospital in this period, considering that the challenges persist even after delivery. PMID- 26105370 TI - PP048. Questionnaire for obstetricians and neurosurgeons on brain stroke and hypertension in pregnancy in/around Nara Prefecture, Japan. AB - INTRODUCTION: Brain stroke in pregnancy, one of the most emergency features in hypertensive pregnancy, was surveyed nationwide (1582 hospitals) and 184 cases (1 2 in 10000 birth) including 10 maternal deaths were reported in Japan (2006). Also in a developed country, co-work of obstetricians (OB) and neurosurgeons (NS) is not always cooperative and the situation stresses clinical workers in emergency maternal transfer. OBJECTIVES: We performed a survey of obstetric and neurosurgery specialists in/around Nara Prefecture (1.3million population, placed in the middle of Japan and does not have remote rural area) about their understanding and preparation on brain stroke in pregnancy. A final aim of this study is to assess the problem in emergency care in pregnancy, especially in hypertensive disorder. METHODS: Fifty-seven OB answered the first questionnaire (executed by NS [S.Y.]) in January 2011 by post. After the analysis, a new questionnaire was executed by OB (K.N.) and 70 answers were given by NS in October 2011. Items in the questionnaire are shown below. Agreements for use of the answers in this research were given by each respondent. RESULTS: [Experience] Three OB (5.3%) and 32 NS (45.7%, 38 cases) experienced a brain stroke in pregnancy in their career. Four NS (10.5% of cases) faced maternal death, including brain hemorrhage after eclampsia. [Diagnosis] Symptoms that OB suspect of brain stroke were loss of consciousness > hemiplegia > headache, and hemiplegia > loss of consciousness > speech disorder in NS. [Hypertension and Brain Stroke] Sixty-four (92.8%) NS thought chronic hypertension as a risk factor of brain stroke in women in reproductive age, and 53 (75.7%) NS thought acute hypertension is. The target blood pressure in the treatment of brain stroke mostly indicated by NS was 140mm/Hg in systolic and 85mm/Hg in diastolic blood pressure. Medication for hypertension chosen by NS was calcium blocker (77.1%) and ARB (38.6%). [Emergency Transfer in Japan] In Japan, ER center to accept women with perinatal emergency is not enough stated. Once the transfer to the central hospital due to brain stroke in pregnancy is needed, a primary department to accept the patient must be decided. Forty-seven (82.7%) OB preferred the Obstetrics Department to be a primary receiver; on the other hand, 38 (56.7%) NS preferred the Neurosurgery Department and only 17 (25.3%) NS answered that obstetrics should be a primary department. Twelve (17.9%) NS answered that the both departments should work together from the beginning. CONCLUSION: Japanese maternal mortality rate is one of the lowest in the world (3.1 per 100,000 birth; 2007), but it was revealed in this study that the maternal emergency system in pregnancy-unrelated disease is not well arranged. Even though emergency system varies between each country, this knowledge in confliction between OB and NS in this area may be useful when other countries need to maintain the ER performance in hypertensive disorder in pregnancy. PMID- 26105371 TI - PP047. Outpatient management of pregnancy complicated by mild hypertensive disorders. AB - INTRODUCTION: Antenatal day care units have been experienced as an alternative to inpatient care for women with pregnancy complications including hypertensive disorders. OBJECTIVES: To assess the outcomes of outpatient management in women with gestational hypertension and mild preeclampsia and compare them to inpatient management. METHODS: Perinatal records of 294 patients (OUT group) attending the obstetric outpatient clinic were reviewed and compared with records of 398 women (IN group) attending the obstetric unit of the same tertiary referral center. The patients were divided as: GH, gestational hypertension (OUT: 194; IN: 244), GH with Intrauterine Growth Restriction (OUT: 52; IN: 78) and PE, mild preeclampsia (OUT: 48; IN: 76). The groups were comparable for age, parity, body mass index and gestational age at enrollment. RESULTS: When compared with patients treated in hospital, GH OUT women showed a higher gestational age at delivery (38+/-1.7 vs 35.5+/-2.3 weeks; p<0.001), longer time to delivery (62.0+/-4.8 vs 31.3+/ 5.4days; p<0.001), higher birthweight (3251+/-389 vs 2271+/-759.1g; p<0.001), and a lower admission to neonatal intensive care unit (21.3% vs 0%; p<0.001) (hospitalization rate: 25%). Similarly, Mild PE women treated as out patient showed later gestational age at delivery (37+/-1.2 vs 34.4+/-1.7weeks), longer time to delivery (55.4+/-6.9 vs 35.3+/-4.5days), higher birthweight (3168+/-363 vs 2196+/-685.17g), and a lower admission to NICU (15.6% vs 35.5%) (hospitalization rate: 55.6%), than the inpatient controls. In the gestational hypertension with IUGR no significant differences were observed between out- and in-patient management. CONCLUSION: Women attending day care units have better or comparable perinatal outcomes than inpatients. Ambulatory management at a day care unit is an option for monitoring and following up women with mild gestational hypertension or preeclampsia remote from term. Hospitalization remains an absolute indication if worsening of preeclampsia is diagnosed. PMID- 26105372 TI - PP050. Distribution of ABO and Rhesus blood groups in patients withpre-eclampsia. AB - INTRODUCTION: The ABO-system of antigens and the Rh-system (D-antigen) is genetically determined and remains the most important blood group systems clinically. Several studies have examined the association between ABO and Rhesus blood group systems and pre-eclampsia. At present there is no consensus to define this association, especially not in a Brazilian population. OBJECTIVES: The purpose of the present study was to evaluate the association between pre eclampsia versus ABO and Rhesus blood group systems in pregnant women hospitalized in a University Hospital in Porto Alegre, Brazil -Hospital Sao Lucas (HSL). METHODS: Pre-eclampsia/eclampsia (PE/E) was diagnosed by the National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy guidelines. This study consisted of 14,894 pregnant women admitted to the Maternity Department between 2005 and 2010. The patients were reviewed retrospectively for inclusion. Complications in pregnancy not related to pre eclampsia/eclampsia (PE/E) and those with uncompleted data were excluded. Medical records of 410 women were used to diagnose PE/E. The control group consisted of 8781 women. Each group was subdivided according to their blood groups. RESULTS: In comparison to the PE/E women and controls, no specific relation in blood groups was observed. With respect to ABO and Rh groups, no differences between PE/E and controls were observed (P=0.479 and P=0.169 respectively). When analyzed with both Rh and ABO Pearson Chi-Square also showed no differences (P=0.569). CONCLUSION: This study aimed to demonstrate some association between blood groups and PE/E using a large sample from the south of Brazil, a population not investigated before. In our study, no specific differences were observed between PE/E and controls in the distribution of the blood groups. In conclusion, the results of this study suggest no association between ABO and Rhesus blood group systems and PE/E in our population. FUNDING: CAPES Foundation-Ministry of Education of Brazil. PMID- 26105373 TI - PP049. Could the supplementation of L-arginine plus folic acid T improve reduced endothelial function seen in preeclampsia? AB - INTRODUCTION: Preeclampsia is characterized as an increase in vascular tone due to the disorder of endothelial cell function. It was found that action of nitric oxide (NO) derived from endothelial cell might be decreasing in preeclamptic women. OBJECTIVES: In the present study, we investigated whether or not the supplementation of L-arginine (LARG, NO synthase substrate) and folic acid (FA) might improve the reduced action of NO seen in preeclampsia. METHODS: Change in brachial artery diameter by hyperemia (%FMD) was measured to evaluate the endothelial function using ultrasound. Twelve of 25 normal pregnant women seen with reduced %FMD (<110) at less than 16weeks of gestation were given the supplementation of FA 0.8mg+LARG1g/day throughout pregnancy. The concentrations of FA+LARG in erythrocyte, and cGMP (a second messenger of NO) in serum were measured. The informed consent was obtained from each patient. This investigation was approved by the Ethics Committee of Nagoya City East and West Medical Center. RESULTS: Reduced % FMD was seen in 25 pregnant women. One of 12 pregnant women in the supplementation group developed mild, late onset preeclampsia, while 8 of 13 pregnant women in no supplement group developed onset preeclampsia (4 cases were severe). Following the supplementation, %FMD had been increasing as well as the concentrations of FA and LARG in erythrocyte, while the concentration of cGMP in serum had not changed. CONCLUSION: The supplementation of FA+LARG might prevent preeclampsia due to improvement of the reduced endothelial function in high risk pregnant women of preeclampsia. PMID- 26105374 TI - PP051. Prediction of preeclampsia with the sFlt-1/PLGF ratio: impact of the slope of repeated measurements. AB - INTRODUCTION: Patients with preeclampsia (PE) exhibit different serum concentrations of sFlt-1 and PlGF. The sFlt-1/PlGF ratio can be used as an aid in the diagnosis of preeclampsia. OBJECTIVES: The objective of this study was to explore the use of the sFlt-1/PlGF ratio as an aid in the prediction of preeclampsia in women with a high risk of the condition. METHODS: 150 patients with high risk of preeclampsia were included in this prospective study. Groups were compared according to the outcome of pregnancy: healthy pregnant women (controls, n=114), pregnancies complicated by intrauterine growth restriction without PE (IUGR, n=14), early PE<34 weeks of gestation (early PE, n=6) and late PE?34 weeks of gestation (late PE, n=16). Measurements of sFlt-1 and PlGF were performed on the automated Elecsys system. Statistical comparison of the sFlt 1/PlGF ratio in different outcome groups and multilevel analysis for logistic data using the random slope model was performed. RESULTS: We found significant differences in the sFlt-1/PlGF ratio between the outcome groups in weeks 24-36 of gestation (p=0,05). A significant difference in the sFlt-1/PlGF ratio between controls, IUGR and PE (early and late PE) could be measured up to six weeks before diagnosis (PE) or birth (IUGR, controls) (p=0,05). The random slope model showed significant different slopes (p=0,05) for individual outcome groups (controls 0,657; IUGR 1,786; early PE 1,951; late PE 0,881). CONCLUSION: The sFlt 1/PlGF ratio is able to identify pathologic pregnancy outcomes in gestational weeks 24-36. Prediction is feasible up to six weeks before clinical diagnosis (PE) or 6 weeks before birth (IUGR, controls). Repeated measurements are necessary beginning in 24 weeks of gestation with a maximum distance of six weeks. The slope between two measurements of the sFlt-1/PlGF ratio is predictive of further pregnancy outcome and the risk of developing preeclampsia. PMID- 26105375 TI - PP052. The course of sFlt-1 and PLGF reflects different progression pattern in early- versus late-onset preeclampsia and HELLP syndrome. AB - INTRODUCTION: Preeclampsia (PE), a serious multisystem disorder in pregnancy, is a leading cause of maternal and fetal morbidity and mortality worldwide and angiogenic factors like sFlt-1 and PlGF are closely related to the clinical course of preeclampsia. OBJECTIVES: We wondered, if these factors and the sFlt 1/PlGF ratio are a tool to differentiate the clinical progression pattern between early and late-onset PE and HELLP syndrome. METHODS: This retrospective study included 30 patients with PE out of which 7 patients had HELLP syndrome. Early onset PE was defined as patients with gestational age <34 weeks. Serial measurements of sFlt-1 and PlGF using the automated Elecsys platform (Roche(r)) were done from admission until delivery. RESULTS: Early-onset PE is characterized by an increase of sFlt-1 of 66% leading to an 137% increase of the sFlt-1/PlGF ratio. Late-onset PE shows a slower progression with an increase of the sFlt 1/PlGF ratio of only 39%. Patients with HELLP syndrome show comparable progression pattern. CONCLUSION: Angiogenic factors characterize PE and HELLP syndrome as continuously progressive diseases with a uniform development towards an antiangiogenic state. Early-onset subtypes show a more aggressive progression with a faster sFlt-1 increase. PMID- 26105376 TI - PP053. Development and validation of a model for prepregnant prediction of recurrence of early-onset preeclampsia. AB - INTRODUCTION: Women with a history of early-onset preeclampsia, requiring delivery before 34 weeks of gestation, often receive intensive surveillance with far more visits than routine antenatal care, additional testing such as the serial measurement of various fetal arterial Doppler blood flow velocity profiles, repetitive assessment of the fetal biometry, the amount of amniotic fluid, the fetal biophysical profile, and repetitive blood testing. Yet, recurrence risk is generally low. OBJECTIVES: To develop and validate a prepregnant prediction model to identify women at very low risk of recurrence of early-onset preeclampsia. These women may be reassured and offered routine antenatal care. METHODS: For the derivation of the model, we enrolled 407 pregnant women from 5 Dutch hospitals who had experienced early-onset preeclampsia in their previous pregnancy. Based on previous published evidence, we selected five predictor variables (gestational age at the time of previous birth, prior small-for-gestational-age (SGA) newborn, fasting blood glucose, body mass index (BMI) and the presence or absence of chronic hypertension) to be entered in a logistic regression model. Discrimination and calibration measures were evaluated after an internal validation step using standard bootstrapping techniques. After the model was built, we enrolled another 200 women to externally validate the model. For the external validation study, 6 more hospitals provided patients. RESULTS: The individual risk of recurrence of early onset preeclampsia using our formula can be calculated as follows: P(recurrence)=1/(1+e(-(linear predictor))), with linear predictor=0.29 0.42*fasting blood glucose (mmol/L) + 0.59* hypertension (yes/no) - 0.01*gestational age at the time of previous birth (days) - 0.41*prior SGA (yes/no)+0.01*BMI (kg/m(2)). After internal validation, the area under the receiver operating characteristic (ROC) curve of the model was 0.65 (95% CI: 0.56 0.74) in the development sample, and was higher in the external validation sample (AUC=0.76, 95% CI=0.58-0.96), indicating that the model discriminates well between women who will develop a recurrence and those who will not. Using a predicted risk threshold of, for example, 4.6%, about one-fourth of the population would be regarded low-risk with a negative predictive value of 100%. Calibration was satisfactory in both samples. CONCLUSION: Our model is helpful in the identification of women at very low risk of recurrent early-onset preeclampsia, and may be used to stratify women into normal care and intensified care groups. At present, we are conducting the PreCare study, in which we assess the effects and costs of introducing our prediction model into routine clinical practice. PMID- 26105377 TI - PP054. Predicting preeclampsia at late mid-term pregnancy before occurrence of clinical symptoms: Clinical utility of biomarkers and clinical parameters in a low-risk population. AB - INTRODUCTION: Despite research efforts and healthcare improvement, preeclampsia (PE) continues to be a leading cause of maternal and fetal morbidity and mortality. Early identification of women at risk of developing PE is the most promising approach to implement preventive measures such as low-dose aspirin to reduce negative outcomes. However, it is still relevant to evaluate pregnant women to detect PE before the occurrence of clinical symptoms and/or to have better tools to assist in its differential diagnosis. Recently, measurements of biomarkers such as soluble fms-like tyrosine kinase-1 (SFLT-1) and placental growth factor (PlGF) have been proposed and some manufacturers are already marketing reagents for this purpose. OBJECTIVES: To examine in a prospective study the performance of selected clinical and biochemical markers for identifying late mid-term pregnancy women at risk of developing PE within a few weeks. METHODS: Seven thousand nine hundred and twenty nine pregnant women prospectively recruited at the first routine prenatal visit, provided blood samples, clinical and sociodemographic information. Two hundred and fourteen pregnant women developed hypertensive disorders of pregnancy (HDP) of which 88 had PE (1.2%), including 44 who presented with severe PE (0.6%). We performed a nested case-control study from the whole cohort including for each case of HDP two normal pregnancies after matching for maternal age, gestational age at recruitment, ethnicity, parity, and smoking status. Based on the literature, we selected the most promising clinical and biochemical markers to be included in a multivariate logistic regression model: mean arterial pressure and body mass index (BMI), PlGF, SFLT-1, inhibin A, and PAPP-A. All markers were measured between 20 and 32 weeks of gestation except for BMI (early pregnancy). All biological marker results were transformed in multiples of median. Medians were established for each gestational week. Multivariate logistic regression analyses were performed to develop prediction algorithm. RESULTS: The resulting regression model discriminated the affected from normal pregnancies as indicated by an area under the receiver operating characteristics (ROC) curve of 0.8. But at a 5% false positive rate, only 28% of the women who have developed HDP would have been detected. Even when the statistical analyses were limited to severe PE, the performance was poor: sensitivity 30%, positive predictive value 2.7%. CONCLUSION: In our low-risk Caucasian population, neither individual candidate markers nor multivariate risk algorithm using an a priori combination of selected clinical and biochemical markers reached a performance justifying implementation as a screening procedure. These results emphasize the necessity to take into consideration the environment, population and health care settings influencing prevalence and characteristics of HDP before promoting wide implementation of such screening strategies. It is imperative to tailor future recommendations for HDP screening not only according to the individual but also to the population characteristics if clinical utility has to be reached. PMID- 26105378 TI - PP055. Preliminary results of the more prepared study (microparticle orientated risk evaluation in the prediction of preeclampsia among risk gravidas): A multicenter prospective prognostic marker study. AB - INTRODUCTION: Preeclampsia (PE) is a potentially dangerous pregnancy pathology contributing to a higher worldwide mortality and morbidity. The negative influence of syncytiotrophoblastic microparticles (STBMs) on the placenta and maternal endothelia is thought to play a key role in generating the inflammatory effects that lead to PE symptoms. Doppler sonography of the uterine arteries assists in identifying a risk population, however, the positive predictive value for this method is low. OBJECTIVES: Aim of this study is to evaluate whether STBMs can serve as an accessory marker to conventional Doppler sonography to better identify pregnant women who will actually develop PE. METHODS: Pregnant women between 19-21 gestational weeks (GW) with abnormal uterine perfusion were enrolled into this prospective study. Plasma samples were taken at inclusion (baseline) and at two further visits at 8 week intervals to follow STBM concentration alterations during pregnancy. The primary endpoint assessed is PE and/or hemolysis, elevated liver, low platelets (HELLP) syndrome. Other PE associated pathologies (intrauterine growth retardation [IUGR], intrauterine fetal demise [IUFD], placental abruption, premature delivery) constitute the secondary endpoints. Maternal STBM concentrations were measured using a home made Enzyme Linked Sorbent Assay (ELSA) which specifically measures STBMs. The receiver operating characteristics (ROC) for baseline measures are graphically displayed and area under curve (AUC) is estimated including 95% confidence levels. RESULTS: Of the 73 women included in the study, 16 developed PE (cases) and 56 did not (control). After analyses of mid-gestational probes, the ROC curve was in close proximity to the line of no-discrimination. CONCLUSION: Our preliminary results indicate that the maternal STBM concentration at mid gestation does not predict the development of PE or associated pregnancy pathologies. Further analysis is underway to assess whether STBM measurements at later gestational time points can predict PE shortly before onset of disease. PMID- 26105379 TI - PP056. Placental growth factor is a better predictor of preterm birth than uterine or umbilical artery doppler in hypertensive disorders of pregnancy. AB - INTRODUCTION: Diagnosis of the presence of disease and prediction of the rate of progression of disease in women with hypertensive disorders of pregnancy remains a clinical problem. OBJECTIVES: Adequate placentation and placental development are important for normal pregnancy. We determined whether PlGF is a better predictor of delivery before 34+0 and 37+0 weeks than uterine artery and umbilical artery doppler. METHODS: One hundred and four women presenting before the completed 34th week of pregnancy with hypertensive disorders of pregnancy were enrolled into the study. Final diagnosis was chronic hypertension (N=24), gestational hypertension (N=21), pre-eclampsia (N=24), HELLP-syndrome (N=15), superimposed preeclampsia (N=20). Blood draw occurred before the 34th week of pregnancy at the time of investigation for expedited delivery or expectant management. Plasma was analysed for PlGF by the Alere Triage(r) PlGF assay using fluorescently-labelled monoclonal antibodies against PlGF. A positive PlGF test was defined as below the 5th centile of normal healthy pregnancy. RESULTS: Of the 104 pregnant women, the level of PlGF was abnormal in 23 of 24 (96%) women with IUGR, compared to 10 of 24 (42%) and 14 of 24 (58%) for uterine artery doppler and umbilical artery doppler, respectively. In the case of pre-eclampsia, the level of PlGF was abnormal in 50 of 59 (85%), compared to 15 of 59 (25%) and 25 of 56 (45%) for uterine artery doppler and umbilical artery doppler, respectively. Forty four (42%) women required medical delivery before 34+0 weeks gestation and 68 (65%) before 37+0 weeks gestation (see Table). PlGF detected a higher number of women requiring early delivery than doppler. CONCLUSION: The new Triage(r) PlGF test provides useful information to inform clinical decisions in pregnancy-associated hypertensive disorders, before the 34th completed gestational week. PMID- 26105380 TI - PP057. The role of uterine artery pulsatility index for prediction of pregnancy outcome, in women affected by pre-eclampsia. AB - INTRODUCTION: Uterine artery (UtA) Pulsatility index assessed in the second trimester is known to be the best predictor of Pre-eclampsia (PE) in women with risk factors. The role of this index when PE occurs seems to be related with clinical outcome. OBJECTIVES: To detect if there does exist a correlation between mean UtA PI, assessed at diagnosis of PE, and: (A) Gestational Age (GA) at delivery; (B) birth weight (BW) percentile. To detect the predictive value of mean UtA PI and the development of adverse pregnancy outcome (APO). METHODS: Cohort study on 100 consecutive singleton pregnancies complicated with pre eclampsia referred to our Department from January 2010 and December 2011. Doppler evaluations were performed from diagnosis to delivery. Mean UtA PI obtained at time of diagnosis of PE were analysed. PE was defined according to ISSHP criteria. Clinical and perinatal outcomes were reviewed. APO was defined as Apgar score less than 7 at five minutes, pH <7.20; birth weight <5th percentile (SGA), stillbirth or neonatal death. Receiver-operating characteristics (ROC) curve was used to determine the predictive ability for subsequent development of APO. RESULTS: Maternal characteristics and main pregnancy outcomes are shown in Table 1. Fifty-six pregnancies developed APO. One case of stillbirth and four cases of neonatal death were observed. SGA occurred in 56/100 neonates; 52/95 (55%) live births were admitted to Neonatal Intensive Care Unit. Table 1. Mean UtA PI at diagnosis of PE was 1.40 (SD+/-0.28) in women that developed APO and 1.10 (SD+/ 0.41) in women that did not develop APO (p=0.02). Pearson's Correlation coefficient for mean UtA PI and GA at Delivery was -0.533 (p=0.002); while for mean UtA PI and BW percentile was -0.466 (p=0.007). The prediction of subsequent development of APO, expressed as the area under ROC curve, was 61.6 (95% CI 0.44 0.79) for UtA PI at Diagnosis of PE. CONCLUSION: Our data confirm that mean UtA PI, assessed at diagnosis of PE, represent a good independent predictor for GA at delivery end BW percentile. However the predictive value for development of APO seems to be poor. PMID- 26105381 TI - PP058. The additive effect of plasma levels of sFlt-1/PLGF ratio following the risk classification using both blood pressure levels and uterine artery blood flow impedance in the second trimester on the later occurrence of preeclampsia. AB - INTRODUCTION: The multivariate model including circulating levels of soluble fms like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratios, maternal factors, blood pressure (BP) levels and uterine artery (UtA) doppler in the first to second trimester has been reported to be clinically useful to predict PE more accurately. However, the effects of levels of sFlt-1/PlGF ratio after the stratification of women using two major risk factors for PE, BP levels and UtA blood flow imdedance (BFI) have not been evaluated. OBJECTIVES: Our aim was to evaluate the additive effect of plasma levels of sFlt-1/PlGF ratio following the risk classification using both mean blood pressure (MBP) levels and the combination of two UtABFI, mean pulsatility index (mPI) and mean notch depth index (mNDI), on the later occurrence of PE. METHODS: 1161 women were recruited into a prospective cohort study during 2004 and 2008. Clinical BPs were measured twice during 16 and 23 weeks, UtA doppler was performed twice during 16 and 23 weeks, and the mPI and mNDI was measured. Plasma samples were drawn once at 20 23weeks, and were stored at -20 degrees C until use. The levels of sFlt-1/PlGF ratio were measured by automated electrochemiluminescent immunoassay (Roche Diagnostics K.K.). The cutoff value of mean BP (MBP) was determined as 91.3mmHg using ROC curve, and that of sFlt-1/PlGF ratio was 13.0, the 97.5th percentile of log10(sFlt-1/PlGF) at 20-23 weeks in normal pregnant women. If the mPI was <90th percentile of the gestational-age specific reference range of mPI, or the mNDI was <90th percentile of the gestational-age specific reference range of mNDI, we defined that the UtABFI was low; if the mPI was ?90th percentile and the mNDI was ?90th percentile, we defined that the UtABFI was high. RESULTS: When women were stratified to 4 groups: low BP and low UtABFI, high BP but low UtABFI, high UtABFI but low BP, high BP and high UtABFI, the PPVs were 0.7%, 6.9%, 6.2% and 39.1%, respectively. In women with low BP and low UtABFI, the high sFlt-1/PlGF changed the PPV to 11.1%; the interval from the sampling to the onset of PE in women with high sFlt-1/PlGF ratio was significantly shorter than in those with low sFlt-1/PlGF ratio (mean+/-SD [weeks]: 5.9+/-1.5 vs. 16.5+/-2.1, p<0.01). In women with high BP but low UtABFI, the high sFlt-1/PlGF changed the PPV to 18.2%; the interval from the sampling to the onset of PE in women with high sFlt-1/PlGF ratio was significantly shorter than in those with low sFlt-1/PlGF ratio (8.0+/ 5.7 vs. 12.6+/-3.7, p<0.05). Although these effects of sFlt-1/PlGF ratio on the occurrence of PE were not confirmed in women with high BP and high UtABFI, PE occurred in all women with three risk factors (5/5), and the interval from the sampling to the onset of PE was6.8+/-4.1 weeks. CONCLUSION: Women with both high BP and high UtABFI, especially those with additional risk of high sFlt-1/PlGF ratio, were the highest risk of PE. In the lowest risk group of low BP and low UtABFI, the addition of sFlt-1/PlGF ratio improved the PPV and the interval from the sampling to the onset of PE. These results clearly indicated the clinical importance of measuring sFlt-1/PlGF ratio in addition to BP levels and UtABFI in all pregnant women in the second trimester. PMID- 26105382 TI - PP059. Angiogenic factors and risk of preeclampsia related adverse outcomes in twin pregnancies. AB - INTRODUCTION: Preeclampsia (PE) is a pregnancy specific hypertensive disorder with an overall incidence of 5-8% among all pregnancies.Incidence of PE in twins is about 2-4 fold higher compared to singletons.Angiogenic factors are implicated in pathogenesis of PE and related adverse outcomes.No studies exist evaluating angiogenic factor assessment in twin pregnancies complicated by PE or use of these proteins for prediction of PE-related adverse outcomes in twins. OBJECTIVES: Our objective was to evaluate whether angiogenic factor levels correlate with the diagnosis of PE and predict adverse maternal and perinatal outcomes in women with twin pregnancy. METHODS: This was a prospective cohort study of women with suspected PE and twin pregnancy from July 2009-August 2011.Antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) were measured at presentation on an automated platform.Diagnosis of hypertension PE during pregnancy was based on ACOG criteria.All diagnoses and outcomes were recorded 2 weeks later.An adverse outcome was defined as hemolysis elevated liver enzymes and low platelets (HELLP) syndrome; disseminated intravascular coagulation (DIC); abruption; pulmonary edema; cerebral hemorrhage; maternal, fetal and neonatal death; eclampsia; acute renal failure; small for gestational age; and indicated delivery.Data are presented as median (interquartile range).We computed the area under the curve (AUC) from the receiver operating characteristic curves to evaluate the ability of clinical values to discriminate between women who would and would not develop an adverse outcome within 2 weeks. RESULTS: There were 79 women with twin gestation who presented to triage for evaluation of PE. The median gestational age at enrollment was 33.9 (31.9-36.0) weeks.The incidence of PE was 58.2%, of which 60.9% was mild and 39.1% was severe.The median sFlt1/PlGF ratio was 72.2 (42.5-111.9) in women with PE compared to 47.4 (5.5-82.2) in women with no hypertensive disorder (P=0.052).Among the 52 (65.8%) women who experienced an adverse outcome within 2 weeks, the median sFlt1/PlGF ratio at presentation was elevated [74.2 (43.5-110.5)] compared to the 27 (34.2%) women without an adverse outcome [36.2 (7.1-71.3); P=0.0003].Among those presenting at <34 weeks (n=40), the difference in sFlt1/PlGF ratio was more striking [97.7 (76.6-178.1) versus 31.7 (6.5-48.7); P=0.001].When using only the highest systolic blood pressure at presentation and proteinuria the AUC was 0.61.Adding the sFlt1/PlGF ratio significantly improved the AUC to 0.77 (P=0.01).When restricting to women who presented at <34 weeks, a similar, although not statistically significant, improvement was seen when adding the sFlt1/PlGF ratio (AUC=0.85) compared with blood pressure and proteinuria alone(AUC=0.69;P=0.08). CONCLUSION: In women with twin pregnancy and suspected PE, the sFlt1/PlGF ratio at the time of initial evaluation is associated with subsequent diagnosis of PE and, more importantly, PE-related adverse maternal and perinatal outcomes. These findings are similar to singleton pregnancies and may implicate similar pathogenic pathways. PMID- 26105383 TI - PP060. Matrix metalloproteinases-2 and -9 and their inhibitors: A role in the development of pre-eclampsia? AB - INTRODUCTION: Pre-eclampsia (PE) is a common and potentially life-threatening condition, affecting 3-10% pregnancies[1]. Placentation has been shown to be deficient in PE and this may be a result of impaired trophoblast invasion [1]. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes which may be important in trophoblast invasion. The activity of MMPs is regulated by tissue inhibitors (TIMPs) and it has been proposed that alterations in MMP/TIMP levels may alter net MMP activity and play a part in both the early and late pathophysiology of pre-eclampsia [2]. Previous studies have largely looked at both active and latent MMP-9 and there is a need for more studies looking specifically at the active forms of these enzymes. OBJECTIVES: The aims of this study were to characterise active MMP-9 expression throughout normal gestation by immunohistochemical localisation, and to compare the levels of MMP-2, -9 (both pro and active) and TIMP-2 in normal and pre-eclamptic term placentae. METHODS: Immunohistochemical localisation of active MMP-9 was carried out on a gestational series of normal placentae from 6-41 weeks' gestation. Quantification of MMP and TIMP levels in term healthy (n=12), pre-eclamptic (n=16) and IUGR (n=12) placental homogenates was done by gelatin-substrate zymography and ELISA. Placentae from IUGR and healthy pregnancies were used as controls to allow us to identify and PE-specific alterations. RESULTS: Using immunohistochemical localisation, we demonstrated a negative relationship between gestational age and active MMP-9 expression throughout normal gestation (p=0.012). The zymographic and ELISA results showed no significant difference in MMP-2, MMP-9 or TIMP-2 levels in placenta from the healthy, pre-eclamptic and IUGR groups (p>0.05). CONCLUSION: To our knowledge, this is the first report using immunohistochemistry to specifically localise the active form of MMP-9 in a gestational series of this size. Our findings demonstrate that there may be high MMP-9 activity during early gestation, which is consistent with a key role for this enzyme in the process of placentation. Thus, it is important to determine if MMP-9 activity is abnormal in PE. In term placentae no difference was found in protein levels of MMPs and TIMPs between control and PE samples; further studies are ongoing to study the MMP and TIMP mRNA expression in these samples. PMID- 26105384 TI - PP061. The role of heat shock protein 60 and 70 in early- and late-onset preeclampsia differentiation. AB - INTRODUCTION: Preeclampsia is a human pregnancy-specific syndrome characterized by the onset of hypertension and proteinuria. These manifestations may occur before the 34th week of gestation or from this period on, being denominated early onset or late-onset preeclampsia respectively. The etiology of both disorders seems to differ qualitatively; therefore, different strategies of prevention and treatment must be studied. OBJECTIVES: The aim of the present study is to determine whether the plasma levels of heat-shock proteins Hsp60 and Hsp70 as well as specific antibodies anti-Hsp60 and anti-Hsp70 may differentiate early onset from late-onset preeclampsia. METHODS: We evaluated 175 pregnant women with PE (55 early-onset PE and 120 late-onset PE). Plasma was obtained from peripheral blood and Hsp60, Hsp70 as well as anti-Hsp60 and anti-Hsp70 antibody levels were determined by enzyme immunoassay. Uric acid levels were also determined in the plasma of patients. For statistical analyses, the Mann-Whitney U-test and the Spearman rank order correlation were applied with significance level set at 5%. RESULTS: Hsp70 levels obtained from early-onset PE group were significantly higher than the late-onset PE women and showed positive correlation with uric acid (r=0.4547; p=0.0028). The Hsp60 production was similar in both groups. Our results also indicate that there was no significant difference of anti-Hsp60 and anti-Hsp70 antibody levels between women with early- and late-onset PE. However,these antibody levels were high,indicating a strong relationship with the production of HSP60 and Hsp70 protein. CONCLUSION: Association between levels of Hsp70 and uric acid in plasma of patients with early-onset PE seems to reflect the oxidative stress in this group of patients. This study provides evidence that Hsp70 determination may be utilized to assess the differentiation between early- and late-onset PE. FINANCIAL SUPPORT: FAPESP 2010/09241-2. PMID- 26105385 TI - PP062. Silibinin modulates NF-kB pathway and proinflammatory cytokines production by mononuclear cells of preeclamptic women. AB - INTRODUCTION: Pre-eclampsia (PE) is a complication of human pregnancy characterized by hypertension and proteinuria after 20 weeks of gestation. In addition to increased activation of monocytes and granulocytes, there is an elevated production of proinflammatory cytokines in pregnant women with PE. The nuclear transcription factor-kB (NF-kB) is present in the cells of the immune system and is responsible for transcription of genes related to inflammation. Whereas the PE is associated with intense inflammatory response, the use of substances modulating the activity of NF-kB factor could be useful in alleviating the inflammation present in these patients. Silibinin is the main component of silymarin, a polyphenolic extract obtained from fruits and seeds of Sylibum marianum with potent hepatoprotective, anti-inflammatory and anti-fibrotic activities. OBJECTIVES: The objective of this study was to assess whether silibinin modulates the activity of NF-kB and the production of inflammatory cytokines by mononuclear cells of patients with PE. METHODS: We evaluated 34 pregnant women with PE, 20 normotensive pregnant women (NT) and 15 non-pregnant women (NP). Mononuclear cells (PBMC) were obtained from peripheral blood and cultured in the presence or absence of silibinin (50uM) and stimulated with 1ug/mL of lipopolysaccharide (LPS) for 18h. The supernatant was employed for determination of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL 1beta) by enzyme immunoassay. The cells were also cultured for 30min to perform the extraction and determination of the nuclear activity of NF-kB. RESULTS: The results showed increased endogenous activation of NF-kB in PBMC of the PE group compared with the NT and NP groups. We also observed increased production of TNF alpha and IL-1beta by non-stimulated PBMC in the PE group compared with NT and NP groups. A positive correlation between NF-kB activity and endogenous production of TNF-alpha (r=0.6509; p=0.0047) or IL-1 b (r=0.5106; p=0.0304) was observed in the PE group. Silibinin showed an anti-inflammatory activity by inhibiting the spontaneous and LPS-stimulated NF-kB activation as well as the production of inflammatory cytokines in all the groups studied. CONCLUSION: Patients with PE showed a greater activation of PBMC cells compared with NT women. Silibinin showed modulatory activity on the inflammatory response by downregulation of NF kB activation as well as TNF-alpha and IL-10 production. FINANCIAL SUPPORT: FAPESP 2010/00776-0. PMID- 26105386 TI - PP063. TLR-4 expression and pro-inflammatory cytokine production by peripheral blood monocytes from preeclamptic women. AB - INTRODUCTION: Toll-like receptor (TLR)-4 and TLR-2 are involved in inflammatory response of monocytes. These cells are activated in pregnant women with preeclampsia (PE), and over-produce inflammatory cytokines. TLR4 may recognize endogenous ligands, the so-called danger signals released by damaged cells, leading to production of pro-inflammatory cytokines. OBJECTIVES: This study investigated TLR2 and TLR4 expression and cytokine production by monocytes from women with PE before and after stimulation with TLR ligands. METHODS: Monocytes (5*10(5)cell/mL) were obtained from 32 preeclamptic (PE) and 20 normotensive (NT) pregnant women in the last trimester of pregnancy. TLR2 and TLR4 expression on monocyte surface was determined by flow cytometry in non-stimulated cells, and after 18h of culture with lipopysaccharide (LPS) and peptidoglycan (PG). TNF alpha, IL-10 and IL-12p70 production by these cells stimulated or not with LPS or PG was evaluated by enzyme immunoassay. Results were analyzed by non-parametric tests with significance level set at 5%. RESULTS: In the absence of stimulation, the basal TLR4 expression by monocytes detected by the median fluorescence intensity (MFI) was significantly higher in the PE group than in the NT group while no significant differences were observed between groups in relation to endogenous TLR2 expression. An increase in TLR4 MFIs was detected after monocytes from NT pregnant women were stimulated with LPS while TLR2 expression was increased after PG-stimulation. No alterations in TLR expression was detected after LPS or PG-stimulation in monocytes from patients with PE. Evaluation of endogenous cytokine levels in supernatant culture of monocytes showed higher concentrations of TNF-alpha and IL-12p70 in preeclamptic women in comparison with the NT group, whereas IL-10 values were significantly higher in NT pregnant women than in the PE group. In contrast, when monocytes were stimulated with the TLRs ligands LPS and PG, the release of TNF-alpha was significantly reduced, while IL 12p70 levels were significantly higher in women with PE compared to NT group. IL 10 production was similar in both groups studied. CONCLUSION: The basal up regulation of TLR4 expression associated with endogenous high TNF-alpha and IL 12p70 production by monocytes from preeclamptic women confirms the activated profile of these cells by the disease process. These findings provide new insights into possible roles for TLRs in the pathogenesis of systemic inflammation detected in PE. FINANCIAL SUPPORT: FAPESP 2009/11924-3 and 2010/20207-0. PMID- 26105387 TI - PP064. M1 Monocyte subpopulation is associated with pro-inflammatory cytokineproduction in pregnant women with preeclampsia. AB - INTRODUCTION: Monocytes from peripheral blood of pregnant women with preeclampsia are endogenously activated and secrete high levels of free radicals and inflammatory cytokines. OBJECTIVES: This study aimed at evaluating whether the inflammatory state of monocytes observed in preeclampsia is associated with the polarization of monocyte to M1 profile in peripheral blood, correlating the expression of surface receptors CD64, TLR2, TLR4, and CD163 and CD206 with cytokine production. METHODS: We studied 90 pregnant women, 30 normotensive and 60 with preeclampsia, matched for gestational age. Peripheral blood monocytes obtained from normotensive pregnant or preeclamptic pregnant women were cultured for 18h, and the expression of surface receptors on M1 inflammatory monocyte subpopulation (TLR2, TLR4 and CD64) and M2 suppressor monocyte subpopulation (CD163 and CD206) were evaluated by flow cytometry, using specific monoclonal antibodies, labeled with fluorochromes. The values were expressed as ??the mean fluorescence intensity. Moreover, the production of proinflammatory cytokines associated with M1 profile (TNF-alpha, IL-12p70 and IL-23) and the anti inflammatory cytokine associated with M2 profile (IL-10) were evaluated in the monocyte supernatant of culture by enzyme immunoassay. Results were analyzed using nonparametric tests with significance level set at 5%. RESULTS: The expression of CD4 and TLR4 on monocyte surface, from women with preeclampsia was significantly higher, while the expression of CD163 and CD206 was significantly decreased compared with normotensive pregnant women, suggesting the predominance of monocyte M1 profile. Endogenous production of TNF-alpha, IL-12p70 and IL-23 by monocytes was increased, while synthesis of IL-10 was lower in women with preeclampsia compared with normotensive pregnant women. Positive correlations between TLR4 and CD64 (r=0.5849), TLR4 and TNF-alpha (r=0.5126) or TLR4 and IL-23 (r=0.8095), as well as between CD64 and TNF-alpha (r = 0.7133) or CD64 and IL-23 (r = 0.6051) were observed in the preeclamptic group. The results confirm the activated state of monocytes from women with preeclampsia by increased production of proinflammatory cytokines and the expression of receptors characteristic of the M1 subpopulation. CONCLUSION: This study provides evidence that monocytes from women with preeclampsia are classically activated and the systemic inflammatory environment may differentiate and polarize these cells to the M1 profile. FINANCIAL SUPPORT: CNPq, FAPESP 2009/11924-3 and 2010/20207-0. PMID- 26105388 TI - PP065. dNK and dNK-CM mediated alterations of DNA methylation in extravillous cytotrophoblasts (EVTS). AB - INTRODUCTION: Placental DNA methylation is thought to be influenced by environmental exposure. Decidual natural killer cells (dNKs) directly contact with cytotrophoblasts in the early stage of pregnancy. dNKs may affect DNA methylation of extravillous cytotrophoblasts (EVTs) directly or indirectly through their secreted soluble factors. OBJECTIVES: Previously, we showed that EVT outgrowth and migration on collagen gel were restricted by exposure to dNK or dNK-derived conditioned medium (dNK-CM) (ref [1]). The aim of this study was to determine if EVT DNA methylation was altered by treating with dNK or dNK-CM. METHODS: Placental explants collected from 6 first-trimester healthy pregnancy terminations were cultured on a rat collagen gel model. Outgrowth EVTs from each subject were treated with medium or concordant dNK (trapped inside of hollow fibers) or dNK-CM. EVTs were harvested after 96-hour co-culturing and underwent DNA extraction. DNA methylation was quantified using the Infinium Human Methylation 450 BeadChip, which targets over 450,000 CpG sites in the human genome. Differential methylation was defined by having p<0.05 (Student's t-test) and average DNA methylation change >10% before and after treatments. Functional enrichment was assessed by gene ontology analysis with False Discovery Rate <10% defined as significantly enriched. RESULTS: Increased DNA methylation was observed for 360 loci and 572 loci by dNK or dNK-CM respectively, and decreased DNA methylation was shown for 62 loci and 188 loci by dNK or dNK-CM respectively. DNA methylation at 44 loci was altered by both dNK and dNK-CM. The common loci were overrepresented for associations with EVT differentiation, adhesion and migration. Examples of the relevant overlapped loci with increased DNA methylations were MYO15A and PRDM16 (PR domain zinc finger protein 16); and the overlapped loci with reduced DNA methylation were CDH9 and USP29 (ubiquitin specific protein 29). dNK but not dNK-CM reduced IL18 methylation and increased methylation on ITGAL (integrin, alpha L) and ITGB7. dNK-CM but not dNK reduced methylation of ITGAD and PCDH8 (protocadherin 8) and increased methylation of CDH4 and CDH6. CONCLUSION: DNA methylation of EVT was altered by exposure to surrounding dNK and their secreted soluble molecules. These results serve as a basis for further investigations on whether DNA methylation can mediate the changes in protein expression that influence EVT differentiation, adhesion and migration. PMID- 26105389 TI - PP066. Renal artery stenosis revealed by an early-onset preeclampsia: A series of 6 cases. AB - INTRODUCTION: Renovascular hypertension (HT) due to an renal artery stenosis (RAS) is uncommon. Therefore, it is actually very rare to diagnose RAS during a pregnancy; very few cases have been published. OBJECTIVES: We report here a series of RAS diagnosed after an early-onset preeclampsia (EOPE). METHODS: We reviewed the files of women who had been seen at our Obstetric Medicine Clinic after an EOPE over a 19-year period. EOPE was defined by occurrence of proteinuria ?0.30g/d before 32 weeks of gestation (WG) with permanent HT ? 140mmHg for systolic pressure and/or 90 for diastolic pressure. RESULTS: Six cases of RAS complicated with EOPE were included in the study (see table). Mean age at the time of EOPE was 27.8 years (24-35), mean term of appearance of EOPE was 22.8 WG (10-31) and mean parity was 1.5 (1-3). HELLP syndrome was found in one case, no patient had renal failure. Fetal death had occurred in three cases (two medical terminations of the pregnancy and one in utero fetal death). The mean birth weight of surviving neonates was 1235g (1070-1410). Physical examination revealed an abdominal bruit in two cases. RAS was suggested with duplex sonography in two cases, and evidenced with conventional percutaneous contrast angiography in five cases. RAS was secondary to a fibromuscular dysplasia in five cases and to atheromatosis in one case. Angioplasty was performed during conventional angiography procedure in four cases. During the follow-up, two women had a subsequent uneventful pregnancy. Restenosis was diagnosed in one case five years after angioplasty. PE: Pre-eclampsia. WG : Weeks of Gestation. MTP: Medical Termination of Pregnancy. IUFD : Intra-Uterine Fetal Death. RAS : Renal Artery Stenosis. NA : Not Applicable CONCLUSION: This series shows the necessity of exploring every case of HT with clinical features suggestive of secondary HT. Moreover, after an adverse obstetrical event, mainly after an EOPE and namely if it had occurred very early (before 28 WG), renovascular HT must be excluded before a subsequent pregnancy. Doppler ultrasound of the renal arteries is the first imaging modality to use since it is simple and noninvasive. Magnetic resonance angiography or computed axial tomography are also convenient. However, conventional percutaneous contrast angiography remains the gold standard for diagnosis of RAS, since it shows directly renal arteries and allows intervention in the same time with angioplasty and/or stent placement. PMID- 26105390 TI - PP068. Catastrophic antiphospholipid-syndrome (CAPS) - A severe pregnancy complication. AB - INTRODUCTION: Antiphospholipid syndrome (APS), is an autoimmune, hypercoagulable state caused by antibodies against cell-membrane phospholipids provoking arterial and venous thromboses as well as pregnancy-related complications such as miscarriage, stillbirth, preterm delivery, or severe preeclampsia. The syndrome occurs due to the autoimmune production of antibodies against phospholipid (aPL), a cell membrane substance. In particular, the disease is characterised by antibodies against cardiolipin (anti-cardiolipin antibodies) and beta2 glycoprotein I. In rare cases, APS can lead to rapid organ failure due to generalised thrombosis. This life-threatening complication is termed "catastrophic antiphospholipid syndrome" (CAPS) and is associated with a high maternal mortality. OBJECTIVES: To describe the characteristics of patients who developed catastrophic APS triggered during pregnancy and to possibly identify potential risk factors for the development of this complication. METHODS: Patients charts of women with autoimmune disorders (such as APS or systemic lupus erythematodes) observed and treated at the University of Graz and The University of Jena between 2007 and 2012 were evaluated. RESULTS: Four cases of CAPS were identified. In all women CAPS occurred as a severe early onset complication (<34 weeks of gestation) and all women had to be delivered by caesarean section between 27 and 32 weeks. With an "individualized" treatment including plasmapheresis, pregnancy can be prolonged for a short period to at least achieve lung maturation by steroids. Several specific features could be found: HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome-like symptoms, eclampsia-like symptoms (headache, amaurosis), abdominal pain resistent to conventional analgesic therapy, and intrauterine growth restriction. Histologic examination after delivery revealed placental infarctions. CONCLUSION: It is important to consider the possibility of the development of catastrophic APS in those patients with signs of HELLP syndrome and multiorgan failure during pregnancy or puerperium, especially in those patients with previous history of abortions and/or thrombosis. In specialised centers prolongation of pregnancy with an individualized treatment including plasmapheresis may be an option. PMID- 26105391 TI - PP069. The expressions of B7-H1 and B7-H4 co-stimulatory molecules on myeloid and lymphoid dendritic cells in pre-eclampsia and normal pregnancy. The expressions of B7-H1 and B7-H4 co-stimulatory moleculeson myeloid and lymphoid dendritic cells in pre-eclampsia and normal pregnancy. AB - INTRODUCTION: Pre-eclampsia (PE) is a common obstetric syndrome affecting about 5 10% of pregnant women. The syndrome is a leading cause of maternal and fetal morbidity and mortality, even in developed world. The etiology and pathogenesis of this syndrome are not fully understood. There are many studies describing alterations in the innate and adaptive immune system which may have an influence on the onset of this disorder. It was suggested that activation of cell-mediated immunity may play the key role in the etiology of pre-eclampsia. OBJECTIVES: The purpose of our study was to estimate the expressions of B7-H1 and B7-H4 costimulatory molecules on myeloid and lymphoid DCs (CD1c(+), BDCA-2(+)) in the peripheral blood of patients with pre-eclampsia and normal pregnant women in the third trimesters of physiological pregnancy. METHODS: Thirty three patients with pre-eclampsia and 26 normal pregnant women were included in the study. Dendritic cells were isolated from peripheral blood, stained with monoclonal antibodies against blood dendritic cell antigens and B7-H1 and B7-H4 molecules and estimated using flow cytometry. RESULTS: The expressions of B7-H1 molecule on CD1c(+) myeloid DCs and B7-H4 molecule on BDCA-2(+) lymphoid DCs did not differ in pre eclampsia and healthy third trimester pregnant women. The expressions of B7-H4 molecule on CD1c(+) myeloid DCs and B7-H1 molecule on BDCA-2(+) lymphoid DCs were significantly higher in peripheral blood of patients with pre-eclampsia in comparison with the control group. CONCLUSION: It seems possible that higher expressions of B7-H4 molecule on CD1c(+) myeloid DCs and B7-H1 molecule on lymphoid BDCA-2(+) DCs in pre-eclampsia may be the tolerogenic mechanism secondary to the pro-inflammatory response which is observed in this syndrome. PMID- 26105392 TI - PP070. Maternal flow-mediated dilation and nitrite concentration during third trimester of pregnancy and postpartum period. AB - INTRODUCTION: The vascular endothelium is thought to be responsible for cardiovascular adaptations in gestation, such as the decrease in peripheral vascular resistance and the decrease in arterial pressure. There is an increase of nitric oxide (NO) serum levels in normal gestation due to an increment in the activity of the enzyme endothelial nitric oxide synthase (eNOS). OBJECTIVES: To compare maternal flow-mediated dilation of the brachial artery (FMD) and the nitrite concentration between the third trimester of pregnancy and postpartum period. Additionally we want to evaluate whether FMD correlates with nitrite concentration. METHODS: Eligibility criteria were healthy pregnant women with single fetus, gestational age greater than 28 weeks, nonsmokers, and without personal or family history of vascular disease. Each pregnant woman was examined in the third trimester of pregnancy (3(rd)T) and between 8 and 12 weeks postpartum (PP) to evaluate FMD and nitrite concentrations in the whole blood. We excluded women who were not examined in both periods. We compared the values between the two periods using paired t tests. The correlation between FMD and nitrite concentration was examined by Pearson correlation coefficient. Significance level was set at p<0.05. RESULTS: 42 pregnant women were invited for the study. 35 healthy women were elected and 7 of them were excluded for not attending the postpartum evaluation. We found a trend of decreased FMD in the PP period (10.39+/-5.57 % vs. 8.42+/-4.21 %, p=0.11; 3(rd)T vs. PP respectively). No significant change was observed in the nitrite concentration (257.41+/ 122.95nmol/L vs.237.16+/-90.01nmol/L, p=0.28). We did not observe significant correlation between FMD and nitrite during 3(rd)T (r=-0.13, p=0.50) or PP (r=0.14, p=0.48). CONCLUSION: Although our sample size did not permit sufficient precision, FMD seems to decrease between the third trimester and postpartum period. Nitrite concentration did not change between the third trimester of pregnancy and the postpartum period, and it was not correlated to FMD. Studies evaluating larger samples are necessary to confirm these findings. PMID- 26105393 TI - PP071. Evaluation of maternal-fetal doppler parameters and of whole blood nitrite throughout gestation. AB - INTRODUCTION: The Doppler method is extensively applied today for the evaluation of pregnancies with involvement of the uteroplacental blood flow. Although increased nitric oxide (NO) formation plays an important role in regulation of systemic vascular resistance during pregnancy, growing evidence indicates that reduced NO formation is associated with hypertensive disorders of pregnancy, especially preeclampsia. OBJECTIVES: The studies were to assess the maternal and fetal Doppler parameters and to determine the whole blood nitrite levels during pregnancy. METHODS: Thirty-three healthy pregnant women were evaluated during the first (11-14 weeks), second (20-24 weeks) and third trimesters (34-36 weeks) of pregnancy. The maternal (uterine arteries) and fetal (cerebral and umbilical arteries) vessels were evaluated by Doppler velocimetry. venous blood was collected(15mL) for the determination of plasma nitrite by chemiluminescence. RESULTS: Regarding the Doppler parameters of the uterine arteries the mean pulsatility index was 1.73, 1.06 and 0.73 in the first, second and third trimesters of pregnancy, respectively. Fetal Doppler showed a mean resistance index of 0.82 and 0.81 for the middle cerebral artery, 0.73 and 0.60 for the umbilical artery in the second and third trimesters, respectively. The mean plasma nitrite concentration was 189.10, 178.28 and 199.57 nmol/ml in the first, second and third trimesters of pregnancy, respectively. CONCLUSION: The study demonstrated that a fall in flow resistance occurs in the uteroplacental vessels without changes in plasma nitrite concentrations during pregnancy. PMID- 26105394 TI - PP073. Gestational hypertension: A study on placental expression of endothelial and inducible nitric oxide synthase and no metabolism. AB - INTRODUCTION: Hypertension is one of the most common medical disorders in pregnancy and a major cause of maternal and perinatal morbidity and death. In primates adequate development of the embryo, and later of the fetus, depends on a successful hemomonochorial placentation. Nitric oxide (NO) a low molecular weight mediator, induces vasodilatation, inhibits platelet aggregation, and prevents the adhesion of platelets to endothelial cells. Till date, no data are available regarding gestational hypertension (GH) placenta and no metabolism and related enzyme expression and activity. OBJECTIVES: The present study aimed to evaluate eNOS and iNOS expression in the placentas of both normal and GH patients, by means of Real-Time quantitative PCR, measure placental nitric oxide and peroxynitrite levels in the same group of subjects, and correlate such findings with HELLP group already published. METHODS: Fifteen patients with gestational hypertension and thirty healthy pregnant controls comparable for maternal and gestational age were enrolled in the study. Placental tissue was taken immediately after delivery. eNOS and iNOS mRNA levels were evaluated Real-Time quantitative PCR, whereas nitric oxide and peroxynitrite production was measured by a commercially available kit. RESULTS: Placental eNOS and iNOS mRNA levels were significantly reduced in GH (2,02-fold reduction and 2,33-fold reduction, respectively) when compared to controls. Conversely, NO and ONOO(-) production were significantly higher in GH group compared to control group (31.56+/-4.15nmol NO/mg prot vs. 23.98+/-5.14nmol NO/mg prot and 68.49+/-8.57 arbitrary fluorescence units vs 17.31+/-2.25 arbitrary fluorescence units; p<0, 05). Such results were compared to HELLP group obtained in an already published study. CONCLUSION: As from results herein reported, we can hypothesize that complex mechanisms involving NO pathways cause a placental vasculature damage. However, it is not easy to understand if these changes could be interpreted as causes or consequences of this pathologic state. PMID- 26105395 TI - PP072. Features of intrarenal blood flow in patients with preeclampsia (PE). AB - INTRODUCTION: The pregnancy-associated complication preeclampsia is a leading cause of maternal and fetal morbidity and mortality. The classical clinical manifestations of preeclampsia are elevated blood pressure and proteinuria due to renal damage. In severe cases of preeclampsia, the only effective treatment is delivery, irrespective of gestational age. OBJECTIVES: To investigate renal perfusion in PE patients by ultrasound Doppler examination and to assess the possibility of strategy to identify renal blood flow changes to predict preeclampsia before the onset of disease. METHODS: We studied 31 pregnant women of 21-46 years without renal disease: 19 PE (gr.1) and 12 volunteers (gr.2 ). PE was defined as a combination of proteinuria >0.3g/24h and blood pressure >140/90mmHg. We used Vivid7. We measured systolic (Vps), diastolic (Ved) velocities in renal and segmental arteries, and in at 5 pulse beats of interlobar and arcuate arteries. The resistance parameter (RI)=(Vps-Ved )/Vps. RESULTS: Table 1. The intrarenal blood flow in distal arteries. There was no difference in velocities and RI in renal and segmental arteries in both groups. We noted decrease of arterial and increase of the venous flow (color Doppler) of distal arteries in gr.1 seems to be a marker of renal ischaemia. All volunteers have the same parameters from signals of all pulse beats in one area - in arcuate and interlobar arteries. The RI in gr.1 varied in all distal arteries pulse beats in comparison with gr.2, where RI was identical. CONCLUSION: The "patchy" decreasing of RI suggests the presence of thromo-occlusive lesions leading to arteriovenous blood flow bypassing. The doppler ultrasonography may be used as a method of early diagnostic PE. PMID- 26105396 TI - PP075. Endothelial dysfunction may be impaired by increased oxidative stress in preeclamptic women. AB - INTRODUCTION: The essential pathogenesis in preeclampsia is vasospasm induced by endothelial cell injury. The vascular endothelium regulates vascular smooth muscle tone by producing vasoconstrictors and vasodilators, such as nitric oxide (NO). Recently, it has been reported that the levels of oxidative stress are increased and they may impair endothelial NO production and induce endothelial dysfunction in preeclampsia. OBJECTIVES: To determine whether maternal release of oxygen free radical and antioxidants are associated with maternal vascular endothelial cell injury, we measured serum parameters of oxidative stress and endothelial function during pregnancy in women with or without preeclampsia. METHODS: We evaluated 20 participants with uncomplicated pregnancies, 15 with mild preeclampsia, and 18 with severe preeclampsia. Plasma concentrations were measured for derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) as markers of oxygen free radicals and antioxidants, respectively. Flow-mediated vasodilation (FMD) was also assessed as a marker of endothelial function. RESULTS: D-ROMs were increased in the maternal blood of the severe preeclamptic group compared with the control group (681.0+/-239.0 vs 478.6+/-101.4 CARR U, P<0.001), but not in the mild preeclamptic group (562.0+/ 106.5 CARR U). Plasma BAP levels did not change significant in all three groups. The proportion of d-ROMs to BAP was higher in the severe preeclamptic group than in controls (0.28+/-0.11 vs 0.21+/-0.05, P<0.01), but not in the mild preeclamptic group (0.24+/-0.08). FMD was significantly decreased in both preeclamptic groups (severe, 4.3+/-3.3%, P<0.001; mild, 6.5+/-3.6%, P<0.001) compared with controls (10.5+/-2.3%), but FMD in the severe preeclamptic group was significantly greater than in the mild preeclamptic group. A negative correlation between FMD and d-ROM concentrations was observed in all participants (r=-0.376, P<0.05), and the ratio of serum d-ROMsto BAP correlated negatively with FMD (r=-0.413, P<0.05) in all participants. CONCLUSION: We found that the production of oxygen free radicals increased, but not the production of antioxidants which decreased, as a result, an imbalance between reactive oxygen species formation and antioxidant defence mechanisms may have impaired endothelial function in preeclamptic women. PMID- 26105397 TI - PP074. Characteristic changes in endothelial function in uterine artery by administration of no synthase inhibitor during period of placental formation. AB - INTRODUCTION: Preeclampsia is characterized as an increased peripheral vascular resistance. It is found that the administration of the NOS inhibitor l-NAME at early pregnancy developed hypertension in rats similar to preeclampsia. Furthermore, we found action of endothelial NO was reduced due to possibly reactive oxygen species (ROS) in preeclamptic women. OBJECTIVES: We investigated whether this treatment modulates NO and ROS production in uterine artery endothelial cells at late pregnancy in rats. METHODS: l-NAME was continuously administered during the 8-14th day of gestation in Wistar rats. Blood pressure was meassured by use of tail-cuff method. The uterine artery was obtained at the 20th day of gestation. Acetylcholine (ACh)-induced endothelial NO production was estimated from DAF-2 fluorescence. Furthermore, ACh-induced endothelial cell ROS production was estimated from CM-H2 DCFDA by fluorescence imaging system. RESULTS: Blood pressure was higher and birth body weight was smaller in l-NAME treated rats than in saline-treated rats. Acetylcholine (ACh)-induced endothelial NO production was higher, while ACh-induced endothelial cell ROS production was similar, in l-NAME-treated rats when compared with those in control rats. CONCLUSION: It is suggested that the increased endothelial NO production in the uterine artery seen by a short term administration of l-NAME to rats during early pregnancy may function to protect the development of hypertension. PMID- 26105398 TI - PP076. Oscillation of blood pressure seen in eclamptic women. AB - INTRODUCTION: It was found that eclampsia might be caused by vasogenic edema as a result of breaking autoregulation of cerebral blood flow. The finding of PRES (posterior reversible encephalopathy syndrome) was seen on MRI (T2 FLAIR) in eclamptic women. PRES was also seen in women complicated by severe hypertension. Therefore, severity of hypertension might depend on the onset of eclampsia in pregnant women. However, it remains to be unclear with other factors except severity. OBJECTIVES: In the present study, we estimated the pathophysiological mechanisms focusing on changes of blood pressure in preeclamptic women. METHODS: From May to December 2011, 5 eclamptic women were present in Nagoya City West Medical center (795 pregnant women, including 22 preeclamptic women). Four of preeclamptic women developed eclampsia. We recorded changing blood pressure and analyzed them for 4 days (before and after 2 days). RESULTS: Three were severe hypertension (more than 160/110mmHg) before 2days. Just before, all showed wide oscillation of blood pressure (more than 30/15mmHg). One was severe preeclampsia in 37weeks of gestation. After cesarean section, blood pressure was decreasing (100/50mmHg), due to blood loss. Taking blood transfusion, blood pressure subsequently increased and disease occurred. Double product, which means a working index of heart function was low and was in turn low after it. Furthermore, shock index, which means a blood volume was upset. CONCLUSION: From these results, it was suggested that a wide-difference of blood pressure might induce elampsia in women complicated by preeclampsia. PMID- 26105399 TI - PP077. Effect of maternal antioxidant concentrations on expressions of angiogenesis-related genes in the villous trophoblasts from early pregnancy. AB - INTRODUCTION: The pathogenesis of preeclampsia is associated with oxidative stress of villous trophoblasts in early pregnancy. We have reported that antioxidant supplementations from 12weeks of gestation could prevent mild preeclampsia in pregnant women with oxidative stress. OBJECTIVES: To prove the effect of maternal antioxidant concentrations on expressions of angiogenesis related genes in the villous trophoblasts from early pregnancy. METHODS: Villous tissue and blood samples were obtained from pregnant women who had artificial abortions between 6 and 11weeks of gestation. RNA was extracted from villous tissue, and gene expression levels of fms-like tyrosine kinase-1 (FLT-1), endoglin (ENG), and placental growth factor (PGF) in villous tissue were measured by reverse transcription polymerase chain reaction. Serum vitamin C and E concentrations were measured by enzyme-linked immunosorbent assay. This study was approved by the Ethics Committee of Showa University Hospital. RESULTS: Negative correlations between maternal serum vitamin C levels and gene expressions of ENG (r=-0.856, p=0.007) and FLT-1 (r=-0.898, p=0.002) in the villous trophoblasts were observed. There was no correlation of maternal serum vitamin E concentration with any other gene expression in the villous trophoblasts. CONCLUSION: It is suggested that maternal oxidative stress may increase the gene expressions of anti-angiogenic factors in villous trophoblasts of early gestation, which may lead to the pathogenesis of preeclampsia. PMID- 26105400 TI - PP078. Total antioxidant capacity in patients with pregnancy induced hypertension: Its relation to maternal and/or perinatal complications. AB - INTRODUCTION: Pregnancy-induced hypertension (PIH) is a major cause of maternal and perinatal mortality and morbidity, particularly in under-resourced countries, like Mexico. Studies on PIH have shown increased oxidative stress products such as malondialdehyde and decrease of total antioxidant capacity (TAC). In this research we measured one marker of oxidative stress (OS) the TAC in patients with PIH and we associated it with the development of maternal and/or fetal complications. OBJECTIVES: Determine whether the plasma level of total antioxidant capacity (as a marker of oxidative stress) influences the development of maternal and/or perinatal complications in patients with PIH. METHODS: A observational, analytical, clinical study was conducted in patients with gestational hypertension (GH), mild preeclampsia (MP), severe preeclampsia (SP) and normal pregnancy (NP) > or = 28weeks gestational age. Serum samples were collected and stored at -70 degrees C until use for the determination of total antioxidant capacity. It was associated with the development of maternal and/or perinatal complications. RESULTS: TAC level in normotensive patients (NP) was mean of 2679 +/- 2014mEq/L while in hypertensive patients (GH, MP, SP) was on mean of 1502 +/-1340mEq/L (p<0.05), in the GH group was 1620 +/-1042mEq/L, in the MP group was 1977 +/-1865mEq/L, in the SP was 819 +/-305meq/L The mean TAC level in the 29 patients who had maternal and/or perinatal complications was 1521mEq/L, while in the 38 patients who showed no maternal and/or perinatal complications the mean was 2355mEq/L (p<0.05). Of the 29 patients who had complications 15 (52%) had greatly diminished TAC levels (less than 1000mEq/L), 9 (31%) had between 1000 and 2500mEq/L and only 5 (17%)>2500mEq/L. 72% (28/39) of PIH group had one or more maternal and/or perinatal complications, while only 1 patient (3.6%) of 28 patients with NP had one or more maternal and/or perinatal complications (p<0.05). CONCLUSION: Patients with decreased TAC level had a higher percentage of maternal and/or perinatal complications. Patients with PIH classified as mild preeclampsia, showing reduced TAC level should be in close observation as they have the risk of developing life-threatening complications since management is usually as outpatient. PMID- 26105401 TI - PP079. Evidence of placental and vascular endothelial apotosis and dysfunction by elevated serum human chorionic gonadotropin, soluble selectin and soluble Fas in HELLP syndrome. AB - INTRODUCTION: The etiology of Hemolysis, Elevated Liver enzyme, and Low Platelets (HELLP) syndrome remains unknown. We hypothesized that placental and vascular endothelial apoptosis and dysfunction might be the pathogenesis of HELLP syndrome. OBJECTIVES: To determine maternal serum levels and association among human chorionic gonadotropin (hCG), soluble Fas (sFas), and E-selectin (sE selectin) in HELLP syndrome. METHODS: Forty-two singleton pregnant women were studied. Fourteen patients were with HELLP syndrome and 28 patients were healthy gravidas. The serum levels of total beta-hCG, sFas, and sE-selectin were measured by enzyme-linked immunoassays. Mann-Whitney test and Spearman rank correlation were used for statistical analyses. Data were expressed as median and ranges. P value less than 0.05 is considered statistically significant. RESULTS: There were no significant differences in maternal age, gestational age, parity or race in patients with and without HELLP syndrome. The median levels of serum total beta hCG, sFas, and sE-selectin were significantly higher in women with HELLP syndrome than in healthy gravidas {total beta-hCG: 52,168 (14,936-213,445)mIU/mL vs. 17,942 (966-176,600)mIU/mL, p=0.016; sFas: 8.20 (3.0-22.6)U/ml vs. 5.8 (1.2 18.5)U/ml, p=0.001; sE-selectin: 107.7 (26.2-194.7)ng/mL vs. 23.0 (11.1 107.7)ng/mL, p<0.0001}. Moreover, serum total beta-hCG levels were significantly correlated with serum sFas (r=0.32, p=0.039) and sE-selectin levels (r=0.32, p=0.038). Serum sFas levels were also significantly correlated with serum sE slectin (r=0.47, p=0.003) CONCLUSION: Our data suggest that placental and vascular endothelial apoptosis in preeclampsia may further lead to placental and endothelial dysfunction as the possible pathogenesis in HELLP syndrome. PMID- 26105402 TI - PP080. Blood pressure in the offspring of experimental preeclamptic and normotensive baboon pregnancies. AB - INTRODUCTION: Experimental manipulation of the maternal environment in animal models has assisted with our understanding of the mechanisms contributing to fetal programming. Evidence suggests that individuals who experience a suboptimal intrauterine milieu have an increased risk of developing disease later in life. Preeclampsia is a complication of pregnancy known to alter the fetal environment. Such alterations lead to programming of the fetus for subsequent susceptibility to cardiovascular disease, including hypertension. Studies indicate that offspring from women with hypertensive disorders of pregnancy are at an increased risk of cardiovascular complications later in life. OBJECTIVES: To investigate whether offspring of experimental preeclamptic baboon pregnancies have higher blood pressure compared with offspring of their experimental controls and those of normotensive pregnancies. This is a pilot study to assess the feasibility of measuring health outcomes and risk factors for experimental preeclampsia offspring. METHODS: We have successfully developed two models of preeclampsia in the baboon (Papio hamadryas) through induction of uteroplacental ischemia in late pregnancy and TNFalpha infusion mid pregnancy. Systolic and diastolic blood pressure (SBP, DBP) were measured in baboon offspring from experimental preeclamptic (EPE, n=4), experimental preeclamptic control (EPE control, n=4) and normotensive pregnancies (Normal, n=12) using indirect sphygmomanometry (first and fourth Korotkoff sounds recorded). Each measurement was taken three times under identical anaesthetic and environmental conditions. Data are reported as the average +/- standard deviation. A generalized linear model was applied to the data and adjusted for age and sex. RESULTS: There was no significant difference in SBP of offspring from EPE (97.3+/-7.2mm Hg, P=0.21) or EPE control (108.4+/ 7.3mm Hg, P=0.16) when compared with offspring of normotensive pregnancies (102.6+/-7.3mm Hg). Similarly, there was no difference in DBP of offspring from EPE (67.5+/-15.4 mm Hg, P=0.72) or EPE control (61.5+/-15.7mm Hg, P=0.79) compared with normotensive offspring (63.9+/-16.7mm Hg). There was a significant difference in SBP and DBP of young (<5yrs) compared to older (?5yrs) animals (SBP: 96.4+/-7.9 versus 109.1+/-7.5mm Hg, P=0.003; DBP: 54.3+/-17.2 versus 74.4+/ 16.4mm Hg, P=0.009). There were no differences in SBP or DBP between male and female offspring (102.1+/-7.7 versus 103.4+/-8.3mm Hg, P=0.70; 63.9+/-16.8 versus 64.8+/-18.4mm Hg, P=0.90 respectively). CONCLUSION: This study has shown that offspring from experimental preeclamptic pregnancies survive and are able to undergo long-term testing of blood pressure. There does not appear to be any significant differences in blood pressure among EPE offspring and their controls. However, the opportunity to investigate offspring over an extended period of time is feasible. This will enable us to examine other parameters that affect BP of experimental preeclampsia offspring. PMID- 26105403 TI - PP081. Study group obstetrics - A platform for efficient collaboration and networking in obstetrical science. AB - INTRODUCTION: Modern medical science has to meet a series of challenges including the integration of new technologies and strategies to daily scientific routine. Biobanking is defined as 'a collection of biological material and the associated data and information stored in an organized system for a population or a large subset of a population' and plays a key role in these efforts. OBJECTIVES: The study group obstetrics aims to establish a platform for efficient collaboration and networking in obstetrical science. METHODS: Based on existing resources, technologies and expertise, autonomous data and sample collection in local biobanks shall be processed with uniformed SOPs to guarantee quality and compatibility. RESULTS: The study group obstetrics has created harmonized standards for sample and data management in biobanks as well as ethical and legal frameworks. Internet - based data management with uniform documentation sheets guarantee high data quality. Material and data are administrated autonomously and can be combined in the context of specific co-operations. CONCLUSION: Due to the outstanding dynamics over a limited period, the human pregnancy is an attractive field for biobanking and clinical case/control cohorts including disease focused cohorts. Harmonized standards and linkage in a network allow efficient scientific co-operations. Everyone interested is invited to join the study group obstetrics as an equitable member. PMID- 26105404 TI - PP082. Ophthalmic artery doppler for identification of severe preeclampsia in pregnancies complicated by hypertension. AB - INTRODUCTION: Hypertension is the most common disorder that occurs during pregnancy and one of the main causes of maternal mortality worldwide. Among the hypertensive disorders that affect pregnancy, preeclampsia (PE) is the major cause of maternal mortality, maternal morbidity, perinatal death, prematurity and intrauterine growth restriction. The acute cerebral complications in PE account for at least 75% of maternal death. Central nervous system hemodynamic modifications in PE are a controversial issue. Neurological involvement in PE eclampsia syndrome fulfills the criteria of posterior reversible encephalopathy syndrome (PRES). The pathophysiology of PRES is still under investigation. Assessment of cerebral circulation is challenging. Noninvasive techniques, especially transcranial Doppler sonography, are becoming more widely used to evaluate cerebral flow. Ophthalmic artery Doppler is a noninvasive examination used to study central vascular flow that has been shown to be a promising method in the evaluation of pregnant women with hypertension. OBJECTIVES: The aim of this study was to compare the ophthalmic artery Doppler indices observed in singleton pregnant women complicated by hypertension (study group) and to correlate the indices observed in hypertensive pregnant women with those observed in normal pregnant women (control group). METHODS: Ophthalmic artery Doppler indices of 30 mild and 30 severe pre-eclamptic women and 30 pregnant women with chronic hypertension (CH) at 20-40weeks of gestational age (GA) were compared. The control group consisted of 289 healthy pregnant women. Resistance index (RI), pulsatility index (PI), and peak ratio (PR) were determined in the right eye. The mean and SD were calculated for each group. Analysis of variance (ANOVA) was used to compare Doppler indexes means between groups. As significant differences were determined by ANOVA analysis, each group was compared by the Tukey method. Receiver operating characteristics (ROC) curves were used to determine the predictive power of ophthalmic artery Doppler indexes for the identification of severe pre-eclamptic women. P<0.05 was considered statistically significant. RESULTS: Significant differences were found between the values obtained for RI, PI, and PR in severe PE women compared to the other groups (study and control). The mean and SD for IR, IP and PR in mild PE, severe PE and CH groups were respectively 0.73 (+/-0.06), 1.63 (+/-0.35) and 0.65 (+/-0.10); 0.63 (+/-0.09), 1.13 (+/-0.31) and 0.89 (+/-0.12); 0.73 (+/-0.07), 1.66 (+/-0.49) and 0.66 (+/ 0.14). The mean and SD for IR, IP and PR in normotensive pregnant women were 0.75 (+/-0.05), 1.88 (+/-0.43), 0.52 (+/-0.10). The optimal cut-off values for IR, IP and PR for the identification of severe pre-eclamptic women determined by roc curves was 0.657, 1.318, 0.784 (sensitivity and specificity were 0.633 and 0.919, 0.733 and 0.888, 0.833 and 0.974, respectively). The area under the ROC curve for IR was 0.787(95% CI: 0.68-0.89), for IP was 0.797 (95% CI: 0.69-0.90) and for PR was 0.886 (95% CI: 0.80-0.96). CONCLUSION: Ophthalmic Doppler is a useful method in the identification of severe PE. PR was best ophthalmic Doppler index at discriminating between severe PE and pregnant women with mild PE or chronic hypertension as determined by roc curve. PMID- 26105405 TI - PP083. Clinic and out-of-clinic blood pressure changes during pregnancy by parity: Boshi study. AB - INTRODUCTION: Nulliparity is believed to be one of the risk factors for hypertension during pregnancy. However, the relationship between parity and out of-clinic blood pressure during pregnancy is still unknown. OBJECTIVES: The aim of this study was to evaluate clinic blood pressure and blood pressure measured at home during pregnancy among nulliparous and multiparous women. METHODS: This study was a prospective cohort study. We examined blood pressure measured in the clinic and at home among 530 normotensive pregnant women who received antenatal care at a maternity hospital in Japan. Clinic blood pressures were obtained by duplicate measurements at each antenatal care visit. The participants were also required to measure their own blood pressures every morning at home while they were pregnant. A linear mixed model was used for analysis of the blood pressure course throughout pregnancy [1]. The SAS package (version 9.2) was used for the statistical analyses. RESULTS: A total of 315 nulliparous and 215 multiparous women were entered into this study (mean ages 30.1+/-4.6years and 33.0+/ 4.1years, respectively). Clinic blood pressure during pregnancy among nulliparous women was significantly higher than that among multiparous women (P=0.02/P<0.0001 for systolic/diastolic blood pressure), whereas there were no significant differences in blood pressure measured at home during pregnancy between them (P=0.42/P=0.22 for systolic/diastolic blood pressure). CONCLUSION: Out-of-clinic blood pressure levels during pregnancy have been shown not to differ between nulliparous and multiparous women, while clinic blood pressure during pregnancy among nulliparous women is higher than that among multiparous women. PMID- 26105406 TI - PP084. Magnetic resonance imaging measurements of T2 relaxation times within contrasting regions of murine placenta is dependent upon blood flow. AB - INTRODUCTION: It has been postulated that reduced placental perfusion as a result of abnormal placental implantation is the initiating event that leads to the maternal symptoms of preeclampsia. To be able to directly measure blood flow and perfusion in the placenta in experimental models of preeclampsia would provide valuable insight into the structural abnormalities of this syndrome. Magnetic resonance imaging (MRI) offers visualization of anatomy and analysis of changes in tissue morphology and function including blood flow and perfusion. The major source of image contrast in MRI comes from the variation in relaxation times between tissues. Previously, human placenta has appeared as fairly homogeneous in studies of T1 and T2 relaxation times, with no internal morphology apparent. OBJECTIVES: The aim of this study was to investigate, using much higher field strengths (11.7Tesla) and much higher resolution than have been used previously, whether structural inhomogeneities in the placenta can be discerned by T2 mapping and whether T2 mapping is capable of detecting structural abnormalities that may affect blood flow in a preeclamptic placenta. METHODS: Magnetic resonance images were acquired on an anaesthetised C57BL/6JArc mouse placed in a vertical animal probe using a Bruker Avance 11.7Tesla wide-bore spectrometer with micro-imaging probe capable of generating gradients of 0.45T/m. T2 measurements were acquired using an MSME sequence protocol (Bruker MSME-T2-map) with an in-plane resolution of 0.1-0.2mm. Matlab was used to generate R2 (i.e., 1/T2) maps from the acquired data with the T2 values being calculated from selected regions of interest within 5 individual placenta. Additional T2 measurements were acquired on the same slices immediately after blood flow was reduced to zero. RESULTS: Three distinct regions of T2 contrast were discerned in the mouse placenta, likely correlating to the labrynthine, junctional and decidual zones. The contrast between the inner two regions was substantially abrogated when blood flow ceased upon euthanasia of the animal by anaesthetic overdose (p<0.005), whereas the decidual region remained unchanged (p=0.13). CONCLUSION: These results demonstrate that morphologically distinct regions of the mouse placenta can be detected through the mapping of T2 relaxation times. The contrast between regions is lost when blood flow ceases and the placenta becomes homogeneous in appearance, suggesting that differences in T2 relaxation times across regions of the placenta may be used to non-invasively examine structural abnormalities and blood flow in the placenta of experimental animal models of preeclampsia. PMID- 26105407 TI - PP085. Angiotensin II type 1 receptor antibodies increase angiotensin II sensitivity in pregnant rats. AB - INTRODUCTION: Pregnant women who subsequently develop preeclampsia are highly sensitive to infused angiotensin (Ang) II; the sensitivity persists postpartum. Activating autoantibodies against the Ang II type 1 (AT1) receptor are present in preeclampsia. In vitro and in vivo data suggest that they could be involved in the disease process. OBJECTIVES: The aim of the study was to show if AT1-AB generated by immunisation alters Ang II sensitivity in pregnant rats. METHODS: We generated and purified activating antibodies against the AT1 receptor (AT1-AB) by immunizing rabbits against the AFHYESQ epitope of the second extracellular loop, which is the binding epitope of endogenous activating autoantibodies against AT1 from patients with preeclampsia. We then purified AT1-AB using affinity chromatography with the AFHYESQ peptide. RESULTS: We were able to detect AT1-AB both by ELISA and a functional bioassay. We then passively transferred AT1-AB into pregnant rats, alone or combined with Ang II. AT1-AB activated protein kinase C-alpha and extracellular-related kinase 1/2. Passive transfer of AT1-AB alone or Ang II (435ng/kg per minute) infused alone did not induce a preeclampsia like syndrome in pregnant rats. However, the combination (AT1-AB plus Ang II) induced hypertension, proteinuria, intrauterine growth retardation, and arteriolosclerosis in the uteroplacental unit. We next performed gene-array profiling of the uteroplacental unit and found that hypoxia-inducible factor 1alpha was upregulated by Ang II plus AT1-AB, which we then confirmed by Western blotting in villous explants. Furthermore, endothelin 1 was upregulated in endothelial cells by Ang II plus AT1-AB. We show that AT1-AB induces Ang II sensitivity. CONCLUSION: Our mechanistic study supports the existence of an "autoimmune-activating receptor" that could contribute to Ang II sensitivity and possibly to preeclampsia. PMID- 26105408 TI - PP086. The modern search for possible predictors of preeclampsia in the first trimester of pregnancy (preliminary study). AB - INTRODUCTION: Preeclampsia is a major complication affecting at least 3-4% of all pregnancies and is globally responsible for approximately 50,000 maternal deaths annually. Currently the main cause of preeclampsia is a shallow placentation, with abnormal invasion of cytotrophoblasts and incomplete remodeling of placenta supplying maternal uterine spiral arteries. However, up to 20weeks, these processes are asymptomatic, although they are accompanied by the release of various macromolecules in the bloodstream of the mother, which are potential biomarkers of disease, needed to detect. Much progress has been made in recent years towards first-trimester models using combined factors that will be of realistic use in clinical practice.The ability to predict the most severe forms of preeclampsia would allow closer surveillance and earlier intervention to improve pregnancy outcomes. OBJECTIVES: To determine the significance of measuring the concentration of PlGF and sFlt-1 and their ratio in 11-13 weeks of pregnancy as early markers of preeclampsia. METHODS: The study included 85 pregnant women in 11-13 weeks with subsequent uncomplicated pregnancy and 11 patients which developed various hypertensive disorders, four of them have developed severe (n=2) and mild (n=2) preeclampsia later. Concentrations of markers were determined on automated analyzers Cobas E411 (Hoffmann La Roche) using test kits Elecsys PlGF and Elecsys sFlt-1. RESULTS: In the first trimester the concentration of sFlt-1 in healthy pregnant women was 1618,0+/-18,2pg/ml, PlGF - 47,5+/-3,5pg/ml, the sFlt-1/PLGF ratio - 35,9+/-3,2. In the second trimester parameters were as follows: sFlt-1 - 1898,0+/-29,8pg/ml, PlGF - 208,0+/ 11,0pg/ml, the sFlt-1/PLGF ratio-11,2+/-2,6. Two patients with severe preeclampsia had sFlt-1 concentration at 11-12 weeks of 2185 and 14923pg/ml, PlGF - 12,8 and 61.3pg/ml, the ratio sFlt-1/PLGF - 170,7 and 243.4. In two patients with mild preeclampsia, these figures were in 1700 and 2312pg/ml, 38.2 and 37,6pg/ml, 44,4 and 61,4, respectively. CONCLUSION: The optimal prediction biomarker does probably not exist. Our preliminary results confirm the feasibility of determining concentrations of sFlt-1 and PlGF, and their ratio in the 1st trimester of pregnancy to assess the risk of preeclampsia in order to reduce the frequency of obstetric complications and perinatal loss. Effective prediction of PE can be achieved at 11-13weeks' gestation. Further studies on the development and implementation a modified integrated screening program for early diagnosis of PE at 11-14weeks of gestation should be based on the assessment of maternal factors, biophysical, biochemical, and molecular genetic markers are needed. Better individualised patient prediction will allow us to target existing prevention, as it is, and to also develop new treatments in future. PMID- 26105409 TI - PP087. Deep trial secondary analysis: Digoxin immune fab fragment treatment has additional benefits in endogenous digitalis-like factor positive preeclamptic women. AB - INTRODUCTION: A double blinded placebo controlled clinical trial of a commercial digoxin immune Fab fragment (DIF) in preeclamptic (PE) women provided some benefit to treated subjects (1). In that study DIF, relative to placebo, prevented a decline in CrCl and lowered levels of endogenous digitalis-like factor (EDLF) activity as measured by sodium pump inhibition (SPI). However, some PE subjects had undetectable EDLF. OBJECTIVES: The hypothesis tested was that only PE women with measureable EDLF would respond to DIF treatment and analysis of EDLF positive women might reveal treatment effects masked by inclusion of EDLF negative, and hence non-responding, PE women. Accordingly, analyses of DIF effects in EDLF positive PE women were conducted. METHODS: Patient characteristics and study design have been published (1). In these subanalyses, subjects were considered to be EDLF positive if their plasma inhibited red cell sodium pump mediated Rb uptake. All analyses were redone for the EDLF positive subgroup by Covance Inc as in the original trial. Continuous data were analyzed by ANCOVA. Categorical data were analyzed by Barnard Exact Test. RESULTS: 45 subjects (23 DIF, 22 placebo) had baseline SPI evaluated. Of these 22% had undetectable SPI. EDLF positive PE women showed greater and more significant reductions of SPI in response to DIF at each time point (12, 24, 48 hr treatment) than in the original analysis. Subjects with undetectable EDLF showed no significant change in response to DIF or placebo. For CrCl, EDLF positive PE women showed greater and more significant preservation of CrCl compared with original analyses. Subjects absent EDLF showed deterioration of CrCl with or without DIF. Among EDLF positive PE women DIF treated women had significantly less maternal pulmonary edema (p=0.035) and significantly less intraventricular hemorrhage in their infants (p=0.015). There was the suggestion of reductions in the incidence of other maternal and neonatal abnormalities. CONCLUSION: These data indicate that EDLF positive PE women are those that responded to DIF and also raise the possibility of extended benefits of DIF treatment in this group. Results support further research in this area. PMID- 26105410 TI - PP088. Oral antihypertensive therapy for severe hypertension in pregnancy. AB - INTRODUCTION: The hypertensive disorders of pregnancy are among the leading causes of maternal mortality and morbidity. The vast majority occurs in low and middle income countries. It is widely accepted that women with severe hypertension are at increased risk of stroke and benefit from blood pressure (BP) reduction. Although traditionally, parenteral antihypertensive agents have been studied for treatment of severe hypertension in pregnancy, oral agents would be ideal for use in the community and in under-resourced settings. OBJECTIVES: To review the published evidence for the effectiveness of oral antihypertensive therapy for severe hypertension in pregnancy. METHODS: The following databases were searched (to May/11) for randomised controlled trials (RCT) of oral antihypertensive therapy for severe hypertension in pregnancy: MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews. Inclusion criteria were: severe hypertension [an inclusion criterion or average enrollment BP of: systolic BP ?160mmHg and/or diastolic BP ?110mmHg), use of oral or sublingual antihypertensive therapy in at least one of the treatment arms, and at least one relevant measure of maternal or perinatal outcome within a week of administration. Data were abstracted independently by two reviewers and discrepancies resolved by consensus. The Cochrane Revman 5.1 software was used for statistical analysis according to standardised methodology. RESULTS: We identified 14 eligible trials (796 women). Most compared oral/sublingual (SL) nifedipine 5-10mg (10 trials, 606 women, 8/10 trials specified capsule preparation), with either: intravenous (iv) hydralazine 5-20mg (6 trials, 282 women), oral nifedipine 10mg PA tablets (1 trial), oral prazosin 1mg (1 trial), iv labetalol (1 trial), or iv/intramuscular (im) chlorpromazine 12.5 (1 trial). Three trials (154 women) compared oral methyldopa (250-500mg initially) with either oral labetalol (100mg), atenolol (50-200mg) or kentanserin (80-120mg) (1 trial each). One trial (36 women) compared SL isosorbide 1.25mg with iv magnesium sulphate (4g iv then 1g/hr). No trials were identified that compared oral labetalol with either parenteral hydralazine or oral nifedipine. Nifedipine compared favourably with parenteral hydralazine with no differences seen in BP control or maternal or perinatal outcomes. Heterogeneity between trial results was seen within the oral/SL nifedipine vs. iv hydralazine subgroup in which one trial evaluated treatment success and side effects over 20min, and found that nifedipine was associated with relatively lower success and fewer side effects. The incidence of maternal hypotension in the nifedipine capsule arms of these trials was low (1/102, 3 trials), but hypotension was common in both arms of a trial of nifedipine 10mg capsule vs. 10mg PA tablet trial (i.e., 11/31 vs. 3/33, risk difference 26%, 95% CI7% to 46%). CONCLUSION: Given the available RCT data on which to base oral antihypertensive treatment of severe hypertension in pregnancy, the choice of antihypertensive agent may need to be driven by the availability of the drug, setting in which it is to be administered, and by whom. For facility use, the evidence supports oral nifedipine capsules. PMID- 26105411 TI - PP089. A new expectant management of early-onset preeclampsia. AB - INTRODUCTION: Early-onset and severe preeclampsia (PE) is a leading cause of maternal and prenatal morbidity and mortality. It has been challenging for doctors to produce good outcomes for both preeclamptic mothers and their babies. OBJECTIVES: To ameliorate this situation, a new expectant management was introduced in this study. METHODS: Umbilical blood velocity was monitored in 10 cases of early-onset preeclampsia patients who were treated continuously with magnesium sulfate accordingly. RESULTS: The average gestational age when PE initiated was 28+/-3 weeks (ranging from 23 to 31weeks). The mean days prolonged by expectant management were 32.5+/-23.6 days (ranging from 8 to 95days). The average gestational age at delivery was 34+/-1weeks (ranging from 31(+3) to 37weeks). The mean amount of magnesium sulfate used was 310.5+/-252.3g (ranging from 70 to 1000g). 10 pregnant women were all with abnormal umbilical blood velocity when admitted. All 10 babies were born alive. The mean birth weight was 1848+/-669g (ranging from 900 to 3120g). 9 (90%) babies were premature, and 6 (60%) babies had intrauterine growth restriction. There was no mortality or morbidity in both mothers and newborns. CONCLUSION: Early-onset preeclampsia is a process of stress injuries directly caused by feta-placental ischemia, which could be monitored by measuring the umbilical blood velocity by Doppler Ultrasound. Continuous use of magnesium sulfate may better maternal and prenatal outcomes by dilating placental blood vessels and increasing the umbilical blood. PMID- 26105412 TI - PP090. The contribution of podocyturia to the evaluation of ongoing glomerular disorder in pregnant women with kidney graft (preliminary results). AB - INTRODUCTION: Progressive proteinuria and glomerulosclerosis characterize chronic allograft nephropathy. However, the causes are not fully elucidated. Injury of parietal epithelial cells in glomeruli, the podocytes, is the initiating cause of many renal diseases, leading to proteinuria with possible progression to glomerulosclerosis. Podocytes are highly specialized cells, with an important role in maintaining the glomerular filtration barrier and producing growth factor for mesangial cells and endothelial cells. With their foot processes they cover the glomerular basement membrane, and form slit diaphragms with neighboring podocytes. The potential role of podocytes in the failing transplanted kidney is unknown. OBJECTIVES: To evaluate podocyturia as a functional marker in pregnant women with kidney grafts. METHODS: Twenty pregnant women with kidney grafts had their urine samples cytocentrifugated and evaluated by indirect immunofluorescence. The slide was incubated for 45' at room temperature with fluorescein (FITC) anti-rabbit IgG secondary antibody (Sigma-Aldrich, EUA). Then Vectashield (mounting medium for fluorescence) with DAPI (4'6-diamino-2 fenilindol dihidrocloreto) were applied H-1200 (Vector laboratories, inc, USA). The podocytes and the total number of cells were counted in 15 fields photographed under 400x magnification with a digital camera coupled to an epifluorescence microscope DM1000 (Leica, Germany) connected to a computer. The results were expressed as podocyte/total cells (%) per area of higher cell concentration (hot spots) in the field of 400x detected by staining of nuclei and cytoplasm. (Grant FAPESP 08/56338-1). RESULTS: The mean age of the women was 26years. The urinalysis was performed at the third trimester of gestation; 11 did not exhibit urinary podocytes and 9 had podocyturia. There was also a relationship between blood pressure levels, proteinuria and the excretion of podocytes. CONCLUSION: Urinary podocyte number, blood pressure and proteinuria were associated. We observed that urinary podocyte excretion occurs in pregnant women with kidney transplant almost synchronously with higher systolic and diastolic blood pressure and higher mean levels of proteinuria. The detection of podocyturia in these women could be useful for early diagnosis and follow-up of glomerular injury, eventually preeclampsia. It may be also associated to its severity or activity, although additional studies are necessary to confirm these aspects. PMID- 26105413 TI - PP091. Prematurity and hypertensive disorders in pregnancy. A major public health problem. AB - INTRODUCTION: Around the world each year 10% to 15% of direct maternal deaths are associated with hypertensive disorders in pregnancy. Not only it can be devastating and life threatening for the mothers but also for the babies. Risks for the baby include poor growth and prematurity [1]. In low and middle income countries many public hospitals have limited access to neonatal intensive care, and so the mortality and morbidity is likely to be considerably higher than in settings where such facilities are available. Thus, the approach to the problem preeclampsia should include issues related to prematurity and its impact, since many of these babies develop definitive complications, constituting a major public health problem with social and economic repercussions. OBJECTIVES: To evaluate the prevalence of preterm births in a public hospital health of the city of Sao Paulo, checking its main causal conditions, focusing in particular on the importance of hypertensive disorders in its determinism. METHODS: This was a retrospective study of a consecutive series of preterm infants, defined as gestational age less than 37 weeks born at Maternity School Vila Nova Cachoeirinha, situated at the north of Sao Paulo City, in the period from 01/04 to 31/12/2011. The study population was classified according to three main groups of causal factors: spontaneous labor, premature rupture of membranes and elective preterm delivery. In this group was evaluated the specific participation of hypertensive disorders. RESULTS: The number of live births during the study period was 5302 babies. Among these 433 had gestational age less than 37 weeks, corresponding to a prematurity rate of 8.16%. Of all infants, 385 cases were included in the analysis. Regarding the causes of the onset of preterm labor found that 140 cases (36.4%) presented with spontaneous labor, 128 cases (33.2%) had premature rupture of membranes and 117 (30.4%) cases were born as a result of elective preterm delivery. In the latter group 88 cases (75.2%) had complications related to hypertensive disorders. Regarding the general population of premature infants, hypertension accounted for 22.8% of cases. CONCLUSION: We conclude that among the various obstetric problems, hypertensive disorders represent an important impact on preterm birth in our setting, considering that our institution is a reference to this type of care across the city of Sao Paulo. This knowledge is a fundamental tool to support the adoption of interventions that can detect groups at risk for hypertension in pregnancy, the promotion of follow-up to intercept severe cases and provide an efficient network of maternity care that may have neonatal intensive care units. This set of measures is essential to minimize the impact of this serious problem. PMID- 26105414 TI - PP092. Satisfaction and experiences of pregnant hypertensive women participating in a feasibility study of guided imagery effects on blood pressure. AB - INTRODUCTION: Hypertensive disorders of pregnancy are associated with maternal and perinatal health risk. Some studies have demonstrated blood pressure reduction from the use of relaxation therapies, although previous study in pregnancy was limited. We undertook a RCT to determine the effects of guided imagery relaxation on BP and anxiety in hypertensive women during pregnancy, to answer feasibility questions for a larger trial. OBJECTIVES: This presentation will describe experiences and satisfaction with study participation, as reported by women in our study. METHODS: Pregnant women with hypertension (n=69) were randomized to two daily periods of guided imagery or quiet rest, for 4weeks or until delivery, whichever came first. Participants provided compliance data and evaluated guided imagery each week, and completed postpartum questionnaires about their satisfaction with study participation. RESULTS: Sixty women completed at least one week in the study. Compliance with allocated group conditions was high. Most women were satisfied with their allocation; 83.3% would choose to be in the study again. A greater proportion (42.4%) indicated that the study reassured them, compared to 3.4% who felt it added to their worry. Of those in the Guided Imagery group providing ratings, more than 75% reported enjoyment and ease of use. Most indicated they would use it for future hypertension in pregnancy and for stress, and would recommend it to others. CONCLUSION: Our results suggest that Guided Imagery may moderate BP increases in pregnant women with hypertension. However, success of any clinical intervention requires a high degree of patient compliance and acceptability. Guided imagery was acceptable, based on reported use and intent to use it for future stress and hypertension. Guided imagery can be used by hypertensive pregnant women to promote relaxation. Further research is required to determine whether it can improve physical and psychological health outcomes during pregnancy, birthing and postpartum. PMID- 26105415 TI - PP093 Maternal and fetal outcomes in oocyte donor pregnancies. AB - INTRODUCTION: The history of oocyte donation is relatively new in the framework of in vitro fertilization (IVF) techniques, and little has been discussed about the obstetric outcomes of such pregnancies. OBJECTIVES: The aim of this study is to assess the obstetric outcomes of pregnancy following in vitro fertilization with embryo transfer (IVF-ET) using donor oocytes and compare them to the outcomes from autologous IVF-ET and to spontaneous pregnancy in women with advanced age (AMA) to identify possible criticalities and help in counseling women and their doctors. METHODS: The study included a total of 70 delivered pregnancies. The study group included 14 oocyte donors IVF-ET (d-IVF-ET) from women aged 32-52years. The results from the study group were compared to the next two consecutive deliveries from the autologous IVF-ET (IVF-ET group) (n=28; age 30-46years) and with two more consecutive deliveries from women older than 40years (Advanced Maternal Age: AMA) (n=28, age 40-45years). We evaluated the occurrence of pregnancy-induced hypertension (PIH), preeclampsia (PE), fetal growth restriction (IUGR), the gestational age at birth, placental anomalies, the mode of delivery, birth weight and the neonatal Apgar score. The fetal weight was corrected with the gestational age at the time of delivery according to Gardosi. Statistical analysis was performed with the Chi-squared test. RESULTS: Oocyte donor pregnancies had significantly higher rates of PE (d-IVF-ET 21.4%, IVF-ET 0%, AMA 0%, p<0.011). They also had higher rates of PIH and IUGR (d- IVF-ET 21.4%, IVF-ET 0%, AMA 3.6% p<0.011) (d- IVF-ET 21.4%, IVF-ET 7.1%, AMA 3.6% p<0.011 respectively). We found placental anomalies only in the d-IVF-ET group; the incidence of placental accretism was 28.6%, (p<0.003). There are not significant differences in the gestational age at birth, placental anomalies, the mode of delivery, birth weight and the neonatal Apgar score between the groups. CONCLUSION: This is the first study that compares the obstetric outcomes of donor pregnancies to the outcomes of autologous IVF-ET pregnancies and to advanced maternal age. The advanced maternal age criterion assumes that most women requiring oocyte donation are older. Hypertensive disorders were surprisingly not related to maternal age or to the in vitro fertilization technique. Obstetricians that deal with pregnancies from oocyte donation need to be aware of the more severe obstetric outcomes, especially placenta accrete and pregnancy-related hypertensive disorders. This warrants close blood pressure monitoring and an accurate placenta ultrasound. All women who conceive through oocyte donation should be counselled as early as the pre-conception period and referred to specific centres for high-risk pregnancies. PMID- 26105416 TI - PP094. A comparison of gestational changes in urinary excretion of magnesium with those of calcium. AB - INTRODUCTION: Magnesium is one of the essential minerals required in various cellular functions. Some investigators have postulated that some aspects of pathophysiology in preeclampsia could be associated with alteration in regulatory mechanisms of the mineral. However, gestational changes in absorption, excretion and blood concentration of magnesium have remained less elucidated compared with those of calcium, which is another important mineral forming a divalent cation. OBJECTIVES: The purpose of this study was to clarify if urinary excretion of magnesium during pregnancy might be altered compared with those of calcium. METHODS: Sixty specimens of 24h urine and 586 samples of spot urine were collected from healthy pregnant women who gave consent. Determination of the minerals were according to Orthocresol-phthalein complexone method for calcium, and xylidyl blue method for magnesium. Urinary creatinine was determined by Jaffe Method. RESULTS: Daily excretions of magnesium determined with 24h samples were 60, 70, 81, 65, and 102mg in 1st, 2nd, and early 3rd trimesters, term, and postpartum 4weeks, respectively. There were no statistical differences among the values. Those of calcium were 174, 186, 139, 52, and 40mg, respectively. The values in term and in postpartum were significantly lower than those in 1st through early 3rd trimesters. The Mg/Cr ratios (mg/mg Cr) determined with spot urine samples were 0.064, 0.071, 0.066, 0.067, and 0.086, in 1st, 2nd, and early 3rd trimesters, term, and postpartum 4weeks, respectively. The value of Mg/Cr in postpartum was significantly higher than the values in pregnant period. The Ca/Cr ratios (mg/mg Cr) were 0.164, 0.163, 0.135, 0.118, and 0.090, respectively. There was a trend of decreasing pattern in changes of Ca/Cr from 2nd trimester to postpartum. CONCLUSION: It is suggested that there is a mechanism of preservation of calcium in the late phase of pregnancy or puerperal period by reducing urinary excretion of the mineral. However, human pregnancy does not seem to show such a function controlling magnesium metabolism. PMID- 26105417 TI - PP095. Guideline-based development of quality indicators for hypertensive diseases in pregnancy. AB - INTRODUCTION: Hypertensive disorders in pregnancy are one of the main causes of maternal morbidity and mortality. Internationally, several organizations have developed clinical guidelines to assist professionals and to supply patients with the best possible care. To improve the care for this group of patients, insight into the application of clinical guidelines in daily practice is needed. Valid quality indicators are necessary to estimate actual guideline adherence. In this study, we developed a set of valid guidelines based quality indicators for hypertensive diseases in pregnancy. OBJECTIVES: None. METHODS: A systematic RAND modified Delphi method was used to develop a set of quality indicators based on evidence-based guidelines and the literature, about hypertension and pregnancy. Experts' opinions were used to select the indicators regarding specific criteria such as efficacy, level of health gain and potential for care improvement. RESULTS: A representative set of 14 quality indicators was selected from 48 initial guideline recommendations. Indicators concerned both professional performance and organisation of care for patients with hypertension in pregnancy. CONCLUSION: This study describes the systematic, stepwise method used to develop quality indicators that can be used to monitor care for hypertensive diseases in pregnancy. PMID- 26105418 TI - PP096. The effect of preterm placental calcification on uteroplacental blood flow, fetal growth and perinatal outcome in hypertension complicating pregnancy. AB - INTRODUCTION: Placental calcification is often found in pregnancy at term and regarded as a physiological aging process. However, its earlier presence, before 36weeks' gestation (preterm placental calcification) may have an unusual pathological implication [1-3]. OBJECTIVES: This prospective cohort study aims to examine the effect of preterm placental calcification on uteroplacental blood flow, fetal growth and perinatal death (including intrauterine fetal death and neonatal death) in hypertension complicating pregnancy. METHODS: Monthly ultrasound was performed starting at 28weeks' gestation to establish the diagnosis of Grade III placental calcification, with measurement of fetal growth and uteroplacental blood flow by Doppler velocimetry on the umbilical vessels at 34weeks' gestation. Participants (n=105) were classified into Group A (n=44), a hypertensive study group with notable preterm placental calcification at 28 36weeks' gestation, and Group B (n=61), a hypertensive control group without notable preterm placental calcification prior to 36weeks' gestation. Women who smoked or drank alcohol during their pregnancies, had multifetal gestations, or major fetal congenital anomalies were all excluded. In addition to the measurement of S/D ratio, poor uteroplacental blood flow was confirmed by absent or reversed end-diastolic velocity (AREDV). Logistic regression analysis was used to estimate the risks of AREDV, poor fetal growth (IUGR) and perinatal death by calculating odds ratios (OR) and 95% confidence intervals (CI), adjusted by maternal age, body mass index, economic status, co-morbidities (e.g. diabetes, marked anemia and placenta previa), type of delivery, and parity. RESULTS: In Group A, there is significant higher mean S/D ratio (3.80 Vs 3.28), as well as higher incidences of AREDV (28.2% Vs 10.5%), IUGR (45.5% Vs 26.2%), and perinatal deaths (20.5% Vs 6.6%) than those in Group B (p<0.05). The risks of AREDV (OR 3.28; 95%CI 1.04-10.37), IUGR (OR 3.24; 95%CI 1.26-8.29), and perinatal death (OR 4.78; 95%CI 1.23-18.67) were greater in Group A than those in Group B (the control group). CONCLUSION: In hypertension complicating pregnancy, the presence of preterm placental calcification is associated with a higher incidence of poor uteroplacental blood flow, fetal growth and perinatal death. Being an ominous sign, it may precede poor uteroplacental blood flow, fetal growth and adverse fetal outcome and can serve as a predictor of such findings when noted on ultrasonography. The affected baby is at greater risk, thus requiring closer antepartum surveillance for fetal well-being. PMID- 26105419 TI - PP097. Cardiac output and systemic vascular resistance in normal pregnancy and in control non-pregnant women. AB - INTRODUCTION: Changes in cardiac output (CO) and systemic vascular resistance (SVR) have been shown to precede the clinical onset of pregnancy complications, such as pre-eclampsia and fetal growth restriction. CO and SVR undergo major changes during normal pregnancy. However, assessment of these vascular parameters requires intensive training and expensive techniques, so currently can be performed only in specialised centres. OBJECTIVES: The aim of this study was to investigate maternal cardiovascular function measured using an ultrasonic cardiac output monitor (USCOM), a simple non-invasive continuous wave Doppler device, in a cohort of pregnant women and non-pregnant controls. METHODS: This was a cross sectional study including 185 women with normal singleton pregnancies at 11 40weeks of gestation and 49 non-pregnant controls. Stroke volume (SV), CO and SVR were measured using the USCOM device. All measurements were performed with the patients in supine position. All women with a gestational age of >20weeks were in a left lateral position by placing a wedge-shaped pillow under their right side to prevent vena cava compression. In a group of 25 pregnant women, each measurement was repeated three times to evaluate the reproducibility of this technique. Cardiac index (CI), SV index (SVI) and SVR index (SVRI) relate CO, SV and SVR to the body surface area. The data were normally distributed after logarithmic transformation. Comparisons between pregnant and non-pregnant women were performed using Studentt-test, Chi-Square test or multiple regression analysis, when adjustment for potential confounders was necessary. Data analysis was performed using SPSS 16.0. RESULTS: In the first trimester, all of the following vascular parameters were higher in pregnant women compared to non pregnant controls: CO [median (IQR): 4.86 (4.45-5.57) vs 5.57 (4.76-6.52)L/min, P<0.001], CI [median (IQR): 2.69 (2.44-3.07) vs 3.25 (2.80-3.86)L/min/m(2), P<0.001], SV [median (IQR): 72.51 (68.10-80.18) vs 80.75 (74.50-99.74)mL/beat, P<0.001], SVI [median (IQR): 41.93 (37.53-46.57) vs 47.01 (43.85 53.79)mL/m(2)/beat, P<0.001]. Pregnant women had significantly lower SVR [median (IQR): 1458 (1261-1649) vs 1165 (1023-1406)sec/cm(-5), P<0.001] and SVRI [median (IQR): 2646 (2307-2963) vs 2006 (1179-2277)dynes-sec/cm(-5)/m(2), P<0.001] at 11 13weeks' gestation. CONCLUSION: Using USCOM, maternal cardiac function can be assessed in a simple, non-invasive and reproducible manner. This simple technique is likely to facilitate large scale studies of maternal cardiovascular function in pregnancy. PMID- 26105420 TI - PP098. Lipidic fingerprinting in women with early-onset preeclampsia: A first look. AB - INTRODUCTION: preeclampsia is characterized by intense inflammatory response and an anti-angiogenic state. Maternal obesity has been considered to have important impact on the genesis of preeclampsia as lipotoxicity leads to maternal endothelial dysfunction and chronic inflammation. Here we investigate the plasma lipid profile of preeclamptic women. OBJECTIVES: identify possible lipid biomarkers for preeclampsia. METHODS: this study included 8 pregnant women with early-onset preeclampsia (before 34weeks gestation) and 8 normal pregnant women. Each patient in the preeclampsia group was matched to a patient in the control group according to gestational age at the time of sample collection. All patients in the control group were followed until term and had normal outcomes. To investigate the lipid profile, lipids were extracted from plasma samples using the Bligh-Dyer protocol and the extracts were subjected to MALDI-TOF Mass Spectrometry. Data matrix was exported for partial least squares discriminant analysis. All the variables analysed were sorted by a score number named Variable Importance in the Projection. The major discriminant variables were selected and underwent to Mann-Whitney U test. RESULTS: a total of 1290 ions were initially identified during lipidomic assessment. Twelve m/z signals were highlighted as the most important lipids for the discrimination of patients with preeclampsia. The identification of these differential lipids was carried out through Lipid Database Search. The main classes identified were Glycerophosphocholines [GP01], Glycerophosphoserines [GP03], Glycerophosphoglycerols [GP04], Glycosyldiradylglycerols [GL05] and Glycerophosphates [GP10]. CONCLUSION: Our results suggest that some lipid species may be potential biomarkers for early onset preeclampsia. PMID- 26105421 TI - PP099. Chronic hypertension: follow-up of chronic hypertension pregnant women in 2008-2009. AB - INTRODUCTION: Chronic Hypertension (CH) is one of the most prevalent diseases in the world. Because women are getting pregnant in late ages, the incidence of Chronic Hypertension in pregnancy is raising (2-3%). As a long term disease in its essential form, with low repercussion in target-organs at reproductive age, the medical complications related to CH are not the main concern of the pregnant women. However, it influences the pregnancy and may result in serious maternal fetal complications, especially if a preeclampsia/eclampsia superimposes to pregnancy. The complications may be manifested as placental abruption, acute renal failure, cardiac decompensation, and cerebral accidents in the mother and of growth restriction and unexplained mid-trimester fetal death. The main goal in the follow-up of this pregnant women is to achieve controlled levels of blood pressure (Systolic - 110-140mmHg, Diastolic - 80-90mmHg) with anti-hypertensive drugs, and evaluate and early diagnose the most serious complication, preeclampsia/eclampsia(PE/E). OBJECTIVES: Review the cases of Chronic Hypertension followed in our institution in 2008-2009, with the analysis of population, anti-hypertensive drugs required to control HTA, fetal complications (growth restriction, preterm delivery and fetal death) and maternal/fetal complications (PE/E, Abruption placentae, Renal and Cardiac acute insufficiency, and cerebral accidents). METHODS: In a retrospective study, from January 2008 to December 2009, were analysed all files related with Chronic Hypertension followed in the obstetric department of Prof. Fernando Fonseca's Hospital. The statistic analysis was based on Excel 2007. RESULTS: The incidence of Chronic Hypertension was 40% of all hypertensive disorders in this period and of 1,5% in overall pregnant population. The maternal mean age of this group was 33,8 years (16;44) being the most prevalent pre-existing co-morbidities the endocrinologic disorders (obesity, Diabetes and thyroid pathology). 38% were previous medicated with anti hypertensive drugs, the majority of them needing only one drug to control blood pressure (BP) (64%). During the pregnancy follow up, 78% were medicated with one or more anti-hypertensive drugs, requiring only one drug to control BP in the majority of cases 66%. In terms of fetal complications 3 cases of growth restriction were signed (2%), preterm delivery in 26 cases (21%) and 2 interruptions of pregnancy in the second trimester before 24 weeks because of maternal complications (2%). There was one case of Abruption Placentae (1%). In terms of maternal complications there were 5 ICU internments (4%), and one situation of acute cardiac disfunction (1%). The CH was complicated by PE/E in 22 cases (18%). CONCLUSION: Chronic Hypertension is a prevalent disease, with an elevated incidence in pregnancy, and potential major fetal-maternal complications, obliging medical professionals to a straight and careful follow-up to control BP levels and early diagnose the adversely outcomes. PMID- 26105422 TI - PP100. Pre-eclampsia: Risk factors and outcomes - A two-year study. AB - INTRODUCTION: Pre-eclampsia (PE) is a hypertensive disorder responsible for major morbidity and mortality in both mother and fetus. There are some risk factors associated with this entity, but it remains very difficult to predict. OBJECTIVES: Study the incidence of PE and the related risk factors, as well as the maternal and fetal outcome. METHODS: We reviewed the clinical records of pregnant women admitted to Prof. Fernando Fonseca's Hospital from January 2008 to December 2009, with the diagnosis of pre-eclampsia. The statistic analysis was based on Excel 2007. RESULTS: There were 90 cases of PE, among the 308 hypertensive disorders reviewed, with an incidence of 1,1% in overall population of pregnant women. Risk factors with higher association were Chronic Hypertension before pregnancy (24,4%), maternal age above 35 years old (16,67%), maternal age under 20 years old (14,44%), and previous episode of pre-eclampsia (8,89%). Major maternal complications that determined Intensive Care Unit admission were recorded in 17 cases (18,89%), with 3 HELLP syndromes (Hemolysis, elevated liver enzymes, and low platelets)(3,33%). No maternal death was recorded. Preterm delivery (PTD) was seen in 61,1%, 32% before 34weeks and 6,67% before 28weeks. There were 19 cases of 1st minute Apgar Index below 7 and 5 cases of 5th minute Apgar Index below 7. There was one in utero death and two interruptions of pregnancy below 24 weeks due to serious PE. Three twin pregnancies. CONCLUSIONS: PE is a form of hypertensive pregnancy disorder, with a risk of recurrence in subsequent pregnancies. It has a catastrophic potential, mainly associated to PTD, and also with significant morbidity to the pregnant women, reflected in the incidence of admissions to ICU, HELLP syndrome and end-organ failure. In our study we confirmed the adverse outcomes related to this entity, and the risk factors associated. PMID- 26105423 TI - PP101. Preeclampsia and pregnancy induced hypertension and carotid artery atherosclerosis. AB - INTRODUCTION: Recent studies indicated preeclampsia (PE) and pregnancy-induced hypertension (PIH) as risk factors for cardiovascular diseases in young women. Women with a history of preeclampsia face double the risk of a heart disease during the 5-15years after pregnancy. We assessed the impact of these factors on endothelial function, atherosclerotic changes and lipid metabolism in young women with a history of preeclampsia and pregnancy-induced hypertension. OBJECTIVES: The aim of this study was to examine whether women with a history of preeclampsia more often show signs of atherosclerosis compared with control group METHODS: We analyzed serum levels of total cholesterol (TC), HDL-C, LDL-C and triglycerides (TG). Endothelium-dependent vasodilation and carotid artery intima-media thickness (CA-IMT) were evaluated in 18 patients with a history of PE, 16 with a history of PIH and 17 healthy controls (CN). Inter-group differences were calculated using Student's t-test. RESULTS: We found a worse lipid profile among women with PE and PIH. LDL-C was increased significantly in PE and PIH (PE: 3.17mmol/l [SD 0.50] and PIH: 3.37mmol/l [SD 0.48] vs CN: 2.83mmol/l [SD 0.35], p<0.05); TC and TG were higher in the PE and PIH groups, but not significantly (p>0.05). Compared to controls, endothelium-dependent vasodilation was significantly reduced in PE and PIH patients (10.5% [SD 4.3] and 8.8% [SD 3.1] vs 14.5% [SD 3.6], p<0.05). The mean combined CA-IMT was significantly higher in PE and PIH patients (0.66mm [SD 0.08] and 0.63mm [SD 0.09], respectively vs 0.52mm [SD 0.04]). CONCLUSION: We conclude that impaired endothelial vasoreactivity and increased CA-IMT are prevalent in women with a history of PE and PIH and are associated with traditional risk factors that strongly suggest that PE and PIH could be non-traditional cardiovascular risk factors. PMID- 26105424 TI - PP102. Hypertension in pregnancy and long term cardiovascular mortality outcomes. AB - INTRODUCTION: Hypertensive Disorders of Pregnancy (HDP) remain a leading cause of maternal morbidity and mortality worldwide affecting up to 10% of all pregnancies. Previous works inform that long term morbidity includes cardiovascular disease, including ischaemic heart disease, stroke and hypertension. The extent of long term mortality amongst women distant from the primary pregnancy event is not known. OBJECTIVES: To determine mortality rates and cause of death for women who had hypertension during pregnancy between the years 1980-86. METHODS: Women who had hypertension during pregnancy were identified via by ICD-9 coding. From record examination, there was an existing cohort of women who participated in clinical trials at Royal Prince Alfred Hospital in the 1980's. These trials included placebo controlled for blood pressure in pregnancy. The deaths among this cohort were identified by the NSW Registry of Birth Deaths and Marriages. The causes of death were verified from the International Classification of Diseases versions depending upon the year of death. RESULTS: There were a total of 332 women identified as participating in the various trials between the years 1980-86. Of these, there were 17 deaths reported by 2011. This gives an overall mortality rate of 5.1%. Five of these deaths were due to CVD. This equates to an RR of 44.6 (CI 95% 17.43-112.56). CONCLUSION: Women with hypertensive disorders in pregnancy have a higher mortality rate compared to the general female population. Further research is required to determine the relationship between HDP and future hypertension and whether the type of treatment and management women receive with HDP effects their risk of future long term health outcomes. PMID- 26105425 TI - PP103. Arterial stiffness in women with previous GDM - A follow up of Chinese HAPO study cohort. AB - INTRODUCTION: It is well known that women with history of gestational diabetes (GDM) are at risk of future DM. Whether they are at a higher risk of hypertension and cardiovascular risk remained to be determined. OBJECTIVES: To determine whether Chinese women who have been diagnosed GDM according to the new IADPSG criteria have a higher risk of hypertension & arterial stiffness than women with normal glucose tolerance (NGT) during pregnancy. METHODS: Chinese women who had participated in the HAPO study between 2001 and 2006 in Hong Kong were followed up at a median of 6years postpartum. All underwent anthropometric & BP measurements. Central systolic and diastolic blood pressures (SBP & DBP), augmentation index (AI) and pulse wave velocity (PWV) were assessed by using SphygmoCor((r)) PVx.A total of 608 women (494 NGT, 114 GDM) were followed up till early 2012. RESULTS: Although there was no significant difference in the rate of hypertension, the central SBP (106+/-12 vs 102+/-13mmHg, p=0.03), AI (22.1+/-8.3 vs 18.9+/-8.5%, p<0.001) and PWV (6.8+/-1.0 vs 6.6+/-0.8, p=0.03) were all higher in women with history of GDM. CONCLUSION: The findings suggest a higher risk of subclinical atherosclerosis amongst women with GDM despite the blood pressure may appear normal at the time of follow up. PMID- 26105426 TI - PP104. Pregnancy-induced hypertension is a strong risk factor for hypertension just 5 years after delivery: A double cohort study at the National Center for Child Health and Development and Showa University Hospital, Tokyo. AB - INTRODUCTION: Pregnancy-induced hypertension (PIH) is associated with increased risk for cardiovascular diseases later in life. OBJECTIVES: To assess the prevalence of subsequent hypertension and other life-style diseases five years after delivery in women who experienced pregnancy- induced hypertension. METHODS: A total of 1527 women who delivered singletons were registered at the National Center for Child Health and Development and Showa University Hospital Mother and child health center of integrated perinatal period between 2003 and 2005. After five years, these women were invited to participate in this study by mail, and 816 women completed the analysis. The women visited our hospital and underwent a medical examination. Women who were pregnant and nursing at the time when the physical examination was conducted were excluded from this survey. The outcomes assessed included the prevalences of hypertension, diabetes, and dyslipidemia. RESULTS: The number of PIH cases was 27 (3.3%: PIH group), whereas 787 women were used as controls subjects. The mean blood pressure five years after delivery was higher in the PIH group than in the control group (91.6+/-15.5mmHg vs 82.4+/ 8.8mmHg, respectively; p<0.001), and the prevalence of hypertension five years after labor was 18.5% in the PIH group and 2.9% in the controls (odds ratio UOR Y=6.2; 95% confidence interval (CI)=2.2-17.5; p=0.003). Moreover, regarding high normal blood pressure (>130/85mmHg), the prevalence was 33.4% in the PIH group and 6.1% in the control subjects (OR=7.2; 95% CI=3.1-16.3; p=0.003). No differences in the prevalences of subsequent diabetes or dyslipidemia were observed. CONCLUSION: Five years after the index pregnancy, women who experienced PIH exhibit an increased risk for subsequent hypertension. Therefore, the blood pressure of women with history of PIH should be regularly monitored after delivery. PMID- 26105427 TI - PP105. Mental health problems following preeclampsia or HELLP syndrome: Do we have a case? A systematic review. AB - INTRODUCTION: Women who suffered from pregnancy complications seem at higher risk for mental health problems. A common pregnancy complication is preeclampsia (PE) and the HELLP syndrome. OBJECTIVES: To review the literature and to investigate whether former PE/HELLP patients are more likely to have mental health problems or more severe mental health problems, as compared to women without a history of PE/HELLP, and to investigate whether PE/HELLP is an independent risk factor for developing mental health problems. METHODS: We performed a systematic search on PubMed and PsycInfo in July 2011. Studies had to present original data, consider postpartum depression, anxiety, or posttraumatic stress as outcomes, include both women with a history of PE/HELLP syndrome and at least one comparison group of women who had not experienced PE/HELLP, present the results for each group separately, or present the results of a multivariate regression analysis in which the diagnosis of PE/HELLP was considered as a factor, or both. Information on study design, participants and outcomes of interest for the current review were extracted using a prespecified form. Furthermore, a short critical appraisal checklist was used in order to evaluate the appropriateness of the studies in light of our specific review questions. For the purpose of the second review question, confounder control and handling of intermediate variables were specifically considered important. RESULTS: The search resulted in 227 articles, of which six were included. Four studies were historical cohort studies, two prospective. With respect to depression, the evidence is mixed. Out of the six studies addressing depression, all studies showed positive associations between PE/HELLP and the prevalence of depression or severity of depressive symptoms. However, the results of three of them were not statistically significant. The two studies addressing anxiety did not show a statistically significant association between PE and anxiety scores, although differences were in the expected direction (i.e. higher scores among women with PE). In the four studies addressing posttraumatic stress, associations were generally in the expected direction (i.e. higher prevalence and severity among women with PE/HELLP), but only a minority of them was statistically significant or partly significant. In most studies, confounder control was poor. CONCLUSION: Current evidence supporting a higher prevalence and an increased severity of mental health problems after PE/HELLP than after an uneventful pregnancy is inconclusive. Future studies should be prospective in design and should control for more possible confounders. PMID- 26105428 TI - PP106. Risk of long term renal graft loss after pregnancy in renal transplant recipients immunosuppressed with calcineurin inhibitors. AB - INTRODUCTION: Intron long-term graft function are uncertain. Although there have been a large number of successful pregnancies in renal graft recipients, the effects of pregnancy and type of immunosuppressant drugs. OBJECTIVES: To analyze (1) the impact of pregnancy on the long term renal function and graft survival of kidney transplant recipients (KTx), and (2) the impact og the pregnancy in (KTx) immunosupressed with calcineurin inhibitors (CNI). METHODS: Retrospective analysis of two cohorts: one (PG) formed by all the KTx recipients from our institution that became pregnant between 1973 and 2004, and the other one (NPG) formed by, when possible, up two KTx patients of similar demographic and clinical characteristics: patient age, donor source, donor age, interval between KTx and pregnancy (or a matched interval for NPG), baseline renal function before pregnancy, hypertension, proteinuria >1g, and CNI-based immunosuppression. but without pregnancies. Particular attention has been paid to long-term (5 and 10years) renal function and graft survival. Males were selected to complete NPG if no matched women were available. STATISTICAL ANALYSIS: Assessment of baseline homogeneity between the two cohorts was performed by appropriate analysis. Time of survival of kidney was estimated by means Kaplan-Meier method and the Cox proportional hazard model was used to perform adjusted analysis. RESULTS: Fifty five pregnancies in 43 patients (PG) and 68 paired controls (NPG) were included in the study. The basal and functional characteristics of PG before pregnancy and NPG were not statistical and clinical significantly different. In a univariate Cox regression analysis, 10 years graft survival after pregnancy/study entry was significantly better in CG (79.9%) than PG (60.9%) (P=0.02). Multivariate analysis of graft survival showed an increased risk of long-term graft loss in pregnant women that had been treated with CNI as immunosuppressant drug compared with NP KTx that received CNIs (HR: 2.4, 95% CI, 1.17-5.00; P=0.02). In a stratified analysis, evaluating separately the recipients that had received or not CNIs, the risk of graft loss was only increased among recipients that became pregnant post-transplantation treated with CNI compared with recipients that had received CNIs but had not become pregnant (HR: 3.3, 95% CI, 1.42-7.45; P=0.005), but not among recipients that became pregnant post-transplantation and received other immunosuppressant agents (HR: 0.9, 95% CI, 0.24-3.80; P=0.94). CONCLUSION: Pregnancy in women receiving baseline immunosuppression with CNI significantly increases the risk of long-term graft loss, non observed in KTx patients treated with CNI that not became pregnant, nor in KTx patients that became pregnant but are treated with other immunosuppressant drugs . At our knowledge, this observation has not been previously reported. PMID- 26105429 TI - PP107. Cardiovascular parameters 40 years after hypertensive pregnancies. AB - INTRODUCTION: Epidemiological data indicate an increased cardiovascular risk in women with previous hypertensive pregnancies. There are few clinical investigations regarding the mechanisms that could mediate this increased risk. OBJECTIVES: The aim of the present study was to clarify if any deterioration in the cardiovascular, metabolic or neuroendocrine status is present in women 40 years after pregnancies complicated by hypertension. METHODS: Three hundred and nineteen women were invited to take part in a follow up investigation regarding cardiovascular regulation. One hundred and five women accepted to participate - 50 with previously hypertensive pregnancies (HTP) and 55 with normotensive pregnancies (NTP). Office and ambulatory blood pressure levels, central blood pressure and pulse wave velocity, echocardiographic measurements (RWT, LVMI, LA, LA-RA, diastolic function, strain) and P-glucose, HbA1c, S-leptin, S-hsCRP, P renin, P-Noradrenaline and NT-proBNP were examined. Women who choose not to participate (n=214) were followed up with a questionnaire regarding their previous pregnancies and present cardiovascular health. RESULTS: The investigations did not reveal differences in any examined variables regarding blood pressure, echocardiographic parameters or blood analysis for metabolic and neurohumoral balance. Twenty-five individuals were diagnosed with hypertension in the HTP group (mean BP 145/86mmHg) and 17 subjects in the NTP group (mean BP 145/87mmHg). The questionnaire was answered by 79% of the participants and revealed that these women had an impaired cardiovascular health compared to the group investigated. CONCLUSION: Blood pressure, metabolic and neuroendocrine parameters are not permanently worsened in all women with previous hypertensive pregnancies. There exist disparities within the group of women with previous hypertensive pregnancies and there are women without obvious cardiovascular or metabolic dysfunction 40 years after the hypertensive manifestation during pregnancy. PMID- 26105430 TI - PP108. Post-partum evaluation of the blood pressure and the kidney function in pre-eclamptic women. AB - INTRODUCTION: Recent data have shown that preeclampsia is not just a disease of pregnancy that resolves with delivery. Preeclampsia may be considered a 'risk marker' for later-life diseases, including cardiovascular and renal diseases and the metabolic syndrome. OBJECTIVES: We aimed a longitudinal prospective study to analyze the renal abnormalities in the post-partum. METHODS: We studied 127 post preeclamptic women at 6 weeks post-partum. Twenty-four hour urine collection, ambulatory blood pressure and renal function were evaluated. RESULTS: The mean age (+/-SD) was 32+/-6years, BMI was 29.4+/-5.7, the race distribution was Caucasian 69%, Hispanic 14%, Black 12% and Orient 5%. Ten % were active smokers, 10% have been suffering from gestational diabetes. The mean duration of the pregnancy was 36 weeks 3/7+/-4. Our results show that the prevalence of hypertension defined by office blood pressure ?140/90 mmHg or ongoing antihypertensive treatment was 35%. The daytime ambulatory blood pressure (ABPM) was 122+/-16/85+/-11 mmHg, heart rate 84+/-8, and 111+/-20/75+/-11 mmHg at nighttime.Sixteen % had a daytime ABPM ?135/85mmHg corresponding to the definition of ambulatory hypertension. Ultrasensitive CRP was 4.9+/-5.1mg/ml, of them 31% had a frank elevation of the CRP >4. The glomerular filtration rate evaluated by the Gault-Cockroft equation showed a hyperfiltration with a mean value of 150+/-42ml/min. Eleven% had a decreased GFR < 90 ml/min. Microalbumine/creatinine ratio measured in the urine spot was 7 +/-4. Mean microalbuminuria was 225+/-529mg/d measured on the 24h urine collection.Urine 24h Na excretion rate was 204+/-48 mmol/d. CONCLUSION: In conclusion, after the post partum period, women having suffered from a pre-eclampsia display many cardiovascular risk factors with a high prevalence of hypertension, microalbuminuria, renal hyperfiltration and elevated CRP. These women should be carefully screened, and sub-groups with the higher risk have to be targeted for prevention and treatment, and close follow-up. PMID- 26105431 TI - PP109. Risk of preeclampsia in homologous and oocyte donation IVF pregnancies. AB - INTRODUCTION: Women who conceived by donor oocyte in vitro fertilization (IVF) are at high risk for placenta-related complications, because of advanced maternal age, nulliparity and maybe for an altered immune response. OBJECTIVES: The aim of this case-control study is to compare the incidence and the characteristics of preeclampsia in women who conceived by oocyte donor or by homologous IVF. METHODS: Data were collected from 65 consecutive women who conceived through oocyte donor IVF and 71 consecutive pregnancies from homologous IVF in women older than 35years (control group), who attended our institution between 2009 and 2011. Data are expressed as percentage, average and standard deviation (SD). Statistical analysis was performed by chi-square test for unpaired data and the results were considered significant with p<0.05. RESULTS: Thirteen women from the donor oocyte group were excluded because of first trimester miscarriage, ectopic pregnancy and lack of data. After the exclusion, 52 pregnancies from oocyte donation were compared to the control group. Baseline characteristics, such as maternal age, BMI, parity and prevalence of twin pregnancies were similar in the two groups. Preexisting hypertension was present only in the oocyte donor IVF group (n=6 cases). The risk of preeclampsia was significantly related to oocyte donor IVF (27% vs 5.6%, p=0.0024 OR=6.17), even when only singleton pregnancies were considered (16.7 vs 1.9%; p=0.02, OR=9). When women with preexisting hypertension were excluded, the incidence of severe preeclampsia remained significant (p=0.02). This result was not confirmed when both preexisting hypertension and twin pregnancies were excluded (p=0.09), even if the percentage of cases was higher in the oocyte donor IVF group (10.7% vs 1.85%). Three cases of life threatening severe preeclampsia occurred before the 24th week, two of which required interruption of pregnancy; one case was complicated by eclampsia. The two groups did not show significant differences in terms of prevalence of IUGR, both in multiple and singleton pregnancies, even if percentage values were higher in the donor IVF group (multiple: 21.2% vs 11.3%, p=0.21/ singleton 10% vs 5.6%, p=0.48). CONCLUSION: IVF with oocyte donation stands as an independent risk factor for preeclampsia. The risk of developing a severe and early preeclampsia may be increased when chronic hypertension occurs. PMID- 26105432 TI - PP110. The role of doppler to predict adverse pregnancy outcome in patients with pre-eclampsia. AB - INTRODUCTION: Recently Middle Cerebral Artery (MCA) to uterine artery (UtA) Pulsatility Index (PI) ratio and MCA to Umblical Artery (UA) PI ratio have been described to be good predictors of neonatal outcome in pre-eclamptic patients in the third trimester and have been proposed to identify fetuses at risk of morbidity and mortality. OBJECTIVES: To investigate the value of doppler indexes such as MCA PI, UA PI; MCA to UtA PI ratio and MCA to UA PI ratio to predict adverse pregnancy outcome (APO) in patients affected by Pre-eclampsia (PE). METHODS: Cohort study on 100 consecutive singleton pregnancies complicated with pre-eclampsia referred to our Department from January 2010 and December 2011.Doppler evaluations were performed from diagnosis to delivery.UtA, UA and ACM PI were assessed at each scan, Measurements obtained within one week from delivery were analysed, and MCA/UA PI ratio and MCA/UtA PI ratio calculated.PE was defined according to ISSHP criteria.Clinical and perinatal outcomes were reviewed.APO was defined as Apgar score less than 7 at five minutes, pH<7.20; birth weight <5th percentile (SGA), stillbirth or neonatal death. Receiver operating characteristics (ROC) curves were used to determine the predictive ability for subsequent development of APO. Logistic regression was run to assess the additional value to the routine indexes for both ratios. RESULTS: One case of stillbirth and four cases of neonatal death were observed.SGA was present in 56/100 neonates; 52/95 (55%) live births were admitted to Neonatal Intensive Care Unit.Maternal Age was 33years (mean, SD+/-5yy), mean maternal BMI was 23.6Kg/mq (SD+/-4.9Kg/mq), gestational age (GA at diagnosis of PE was 32+5w (mean, SD+/ 3+6w), GA at delivery was 33+4w (mean, SD+/-3+4w), birth weight percentile was 13.33 (mean, SD+/-18.23), pH was 7.26 (mean, SD+/-0.11)Fifty-six pregnancies developed APO. Doppler findings assessed within one week from delivery are shown in Table 1, values are expressed as mean (+/-SD). The prediction of subsequent development of APO, expressed as the area under ROC curve, was 0.695 (95% CI 0.59 0.80) for UtA PI; 0.730 (95% CI 0.62-0.81) for UAPI; 0.677 (95% CI 0.55-0.78) for MCA PI; 0.785 (95% CI 0.66-0.87) for MCA/UA PI; 0.774 (95% CI 0.66-0.86) for MCA/UtA PI. Moreover, a MCA/UA PI=1.28 showed a sensitivity of 74.4% and a specificity of 76.0% in predicting APO. Logistic regression analysis showed that the better index combination is represented by MCA/UA PI and MCA/UtA PI. CONCLUSION: In addition to UtA and UAPI, MCA/UA PI ratio and MCA/UtA PI ratio are useful predictors of neonatal outcome in pregnancies complicated with PE. PMID- 26105433 TI - PP111. The preceding features before onset of gestational hypertension and preeclampsia in home blood pressure monitoring: The existence of the inflection point and the rapid increased speed of blood pressure. AB - INTRODUCTION: It has not been clarified whether home blood pressure monitoring (HBPM) during pregnancy is useful to detect high risk pregnant women with later onset of gestational hypertension (GH) and preeclampsia (PE). OBJECTIVES: We thought to determine the preceding features of blood pressure (BP) in HBPM before the onset of GH and PE. We especially focused on the existence of the inflection point, its level, when it occurs, and the increased speed of BP after the inflection point. We compared these features in normal pregnant women (NP), women with GH, and women with PE. METHODS: In this prospective cohort study, 361 singleton pregnant women, among them 100 women recruited due to high risk for GH/PH in the second trimester, participated in a couple of tertiary perinatal centers between 2008 and 2010. HBPM were measured with the validated OMRON HEM 5001(R) automated digital oscillometric sphygmomanometer (OMRON Healthcare Japan). The device was programmed to take three consecutive readings at 15-second interval. HBPM was measured twice a day, at the time of awakening and sleep, through the first to third trimester, and the average systolic blood pressure (SBP) and diastolic blood pressure (DBP) of each gestational week (almost 42 times a week) were calculated. We defined the data of HBPM which started before 28 gestational weeks and continued until 2 weeks before the onset of GH/PE or delivery are eligible. The increased speed of systolic or diastolic BP after the inflection point was defined as ("BP at the onset in GH/PE or at delivery in NP" "BP at the inflection point") / ("Gestational weeks at the onset in GH/PE or at delivery in NP" - "Gestational weeks at the inflection point"). If there was no inflection point in HBPM, the increased speed of BP was defined as zero. The comparisons were performed using one-way analysis of variance (ANOVA) followed by multiple comparison. Data were shown as mean+/-SE. RESULTS: A total of 17 (4.7%) women developed PE, and 12 (3.3%) GH.The systolic blood pressure (SBP) levels at the inflection point in NP, GH and PE was 102.4+/-1.3, 118.7+/-2.9 and 117.4+/ 2.2mmHg, respectively (Significant pairs: NP < GH, PE); the diastolic blood pressure (DBP) levels at the inflection point was 59.2+/-1.0, 74.5+/-2.0 and 73.1+/-2.0mmHg, respectively (NP < GH, PE). The inflection point in NP, GH and PE occurred at 31.3+/-0.9, 28.4+/-1.5 and 22.3+/-1.4weeks, respectively (PE < GH, NP). The increased speed of SBP in NP, GH and PE was 1.2+/-0.1, 3.0+/-0.4 and 4.7+/-0.7mmHg/wk, respectively (NP < GH, PE); the increased speed of DBP was1.1+/ 0.1, 2.1+/-0.3 and 2.8+/-0.4mmHg/wk, respectively (NP < GH, PE). CONCLUSION: In women with later onset of GH/PE, the BP level at the inflection points was higher than in NP. The average inflection point in PE was earlier gestational weeks than in GH and NP. The average increased speed of blood pressure after the inflection point in GH/PE was faster than in NP. The preceding features of BP in HBPM may be clinically useful to detect high risk women with later onset of GH/PE. PMID- 26105434 TI - PP112. Prediction of preeclampsia based on clinical risk factors: A prospective high-risk cohort study. AB - INTRODUCTION: Early recognition of preeclampsia (PE) is crucial for better obstetric care. Clinical risk factors are easier to identify than biochemical markers and may be useful in the prediction of PE. OBJECTIVES: To evaluate which risk factors provide the best prediction for PE in a group at high-risk for developing PE. METHODS: A prospective cohort study of 100 pregnant women was performed. During the first trimester we included pregnant women who had at least one of the following risk factors for PE: previous history of PE, previous history of HELLP, pre-existing hypertension, diabetes mellitus, multiple pregnancy, obesity or autoimmune diseases. These women were monitored during their pregnancy and their medical data were used to set up a database. We focused on baseline characteristics (parity, maternal age, maternal smoking, ethnic origin, blood pressure at booking, risk factors mentioned above and medication use). Differences between groups were analysed using the Student's t test or the Mann-Whitney U test as applicable. Categorical data were analysed with chi(2) statistics. Subsequently, multivariable logistic regression analysis with a stepwise backward selection procedure of predictors was performed to identify independent risk factors for PE. RESULTS: Of the 100 women 22 (22.0%) developed PE and 13 (13.0%) developed gestational hypertension (GH). More women in the group with progression to PE had a history of PE (50.0% versus 26.2%, p=0.039), while less women had a multiple pregnancy (4.5% versus 27.7%, p=0.023) as compared with the group not progressing to either PE or GH. In the group of GH, no women were using antihypertensive medication while in the group of women not progressing to either PE or GH 32.3% were using antihypertensive medication (p=0.017). Multivariable logistic regression revealed that singleton pregnancy was the only independent predictor of PE (OR 8.04, 95% CI 1.01 - 64.3, p=0.045). CONCLUSION: In this prospective cohort study we evaluated clinical risk factors for the development of PE in pregnant high-risk women based on obstetric history and comorbidity. We found that a singleton pregnancy was the only independent predictor for PE in this group of high-risk women. The other risk factors for which the women were included were not strong enough to act as a predictor for PE in this relatively small cohort. Nonetheless, it is important to be alert for PE in this group of pregnant women with high-risk for PE, especially because most of them have more than one risk factor. PMID- 26105435 TI - PP114. First trimester multi-parameter prediction of pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia (PE), which affects about 3-5% of pregnant women, is the most frequent serious medical complication in pregnancy and a major cause of maternal and perinatal morbidity and mortality. During the past three decades, numerous clinical, biophysical, and biochemical screening tests have been proposed for the early detection of PE. Literature shows large variations in the sensitivity and predictive value of these tests. No single screening test used for PE prediction has gained widespread acceptance into clinical practice. Instead, panels of tests, which combine several clinical measurements, seem to be of more value for increasing the predictive value for PE. OBJECTIVES: The aim of this study was to examine a combination of maternal risk factors, mean arterial blood pressure, and uterine artery Doppler for pre-eclampsia prediction during the first trimester of pregnancy. METHODS: Prospective study with singleton pregnancies examined at 11-14 weeks of gestation, presenting consecutively for antenatal care in a tertiary Brazilian hospital. The base-cohort population was 487 singleton pregnancies, including nine case subjects who developed PE requiring delivery before 34 weeks (early PE) and 22 with late PE, 47 with gestational hypertension, and 409 cases subjects (84%) who were unaffected by PE or gestational hypertension. Maternal history, body mass index (BMI), mean arterial pressure (MAP), and uterine artery pulsatility index were recorded in all of the cases. Univariate and logistic regression analysis was used to derive algorithms for the prediction of hypertensive disorders. RESULTS: The maternal characteristics selected by regression analysis to be part of the final predictive model were nulliparity, previous personal and family history of PE. MAP was higher (86 versus 78 mmHg) in patients who developed PE (p<0.01). The uterine artery percentile of mean PI was higher in the PE than in the control group (50.3%+/-31.7% versus 37.4%+/-30.0%; p<0.01). It was estimated that, with the algorithm for PE, 78%, 45%, and 26% of early PE, late PE, and gestational hypertension, respectively, could be detected with a 10% false-positive rate. CONCLUSION: The traditional approach to screening for PE, which is based on maternal demographic characteristics and medical history, identifies ~60% of cases destined to develop early PE for a false-positive rate of 10%. This study proposes that a combination of maternal risk factors, mean arterial blood pressure, and uterine artery Doppler, for the same false-positive rate of 10%, could identify 78% of cases of early PE. PMID- 26105436 TI - PP113. NT-Pro-BNP: A predictor of adverse maternal outcomes in hypertensive gestational syndromes? AB - INTRODUCTION: BNP (brain-type natriuretic peptide) is released by cardiomyocytes, as a pro-hormone, in response to parietal stress augmentation and systemic endothelial dysfunction, and then Pro-BNP is cleaved into: NT-Pro-BNP and BNP fragment in 1:1 ratio. BNP is considered an important component of the adaptative mechanism that helps to reduce the load on the myocardium, through systemic vasodilatation, reduction in venous return and reduction in vascular volume. Hypertensive Gestational Syndromes (HGS) are considered to share those mechanisms, but the role of NT-Pro-BNP to evaluate maternal outcomes, is not well defined. OBJECTIVES: Evaluate the correlation between NT-Pro-BNP: in Normotensive Pregnant Women (NPW) and HGS with established markers of adverse maternal outcomes in HGS. METHODS: We performed a transversal case-control study to analyze NT-Pro-BNP in 68 patients with HGS vs 80 NPW admitted at a private hospital, and to evaluate its correlation with established clinical and blood markers of maternal outcomes at hospital admission. Patients with renal chronic failure, previous cardiac disease and mola were excluded. We used the Pearson and Kendall correlation test for quantitative variables and the non-parametrical Mann Whitney test for qualitative variables. RESULTS: The average maternal age was: NPW 33.2 years, HGS 33.8 years; average gestational age at delivery: NPW 38.5 weeks, HGS 35.3 weeks; first pregnancy: NPW 36%, HGS 56%; birth average weight: NPW 3351.6g, HGS 2615.5g; media NT-Pro-BNP: NPW 59.7pg/ml, HGS 704.8pg/ml. None of the NPW had high levels of NT-Pro-BNP. In the HGS group: 57% had preeclampsia, 10% HELLP, 25% gestational hypertension and 8% chronic hypertension. In the HGS media values for: proteinuria 1.5g/24h, glutamic-oxalacetic transaminase 86 UI/L, platelets 231,688/mm(3), glutamic-pyruvic transaminase 100 UI/L, uric acid 48mg/dl, hematocrit 33%, alkaline phosphatase 152 UI/L, lactic dehydrogenase 284 UI/L. In the HGS the following significant correlations were found: for NT-Pro BNP relation to: proteinuria (0.34 p=0.001), glutamic-oxalacetic transaminase (0.375 p=0.001), platelets (-0.353 p=0.001), glutamic-pyruvic transaminase (0.317 p=0.001), uric acid (0.398 p=0.001), hematocrit (-0.183 p=0.048), gestational age at delivery (-0.29 p=0.002), birth average weight (-0.23 p=0.018), cardiac failure ( p=0.001), number of used anti-hypertensive drugs (0.367 p=0.004), lactic dehydrogenase (0.65 p=0.001). The media NT-Pro-BNP was: 936pg/ml in preeclampsia , 1909pg/ml in HELLP, 150pg/ml in gestational hypertension and 107pg/ml in chronic hypertension. The highest NT-Pro-BNP level was 12,386pg/ml in a patient with systolic dysfunction (LVEF: 35%) associated with preeclampsia. After delivery, 13% HGS women had persistent hypertension post-partum, and this did not correlate with the level of NT-Pro-BNP at hospital admission. CONCLUSION: NT-Pro-BNP significantly correlates with established markers of adverse maternal outcomes in HGS, probing to be useful in routine maternal evaluation in this setting. PMID- 26105437 TI - PP115. Relationship between angiogenic factors and preeclampsia: Preliminary results. AB - INTRODUCTION: The pathogenesis of preeclampsia (PE) is complex and involves many mechanisms, including impaired placental angiogenesis. Endoglin (Eng) promotes angiogenesis, but in its soluble form (sEng) it is antiangiogenic and adiponectin has pro-angiogenic and anti-inflammatory effects on the endothelium. The combined analysis of these factors seems to better reflect maternal vascular damage. OBJECTIVES: We aimed to evaluate adiponectin and soluble endoglin levels, to analyze adiponectin (+45) gene polymorphism and its relation with adiponectin serum levels in patients with PE. METHODS: This case-control study included 24 PE patients and 20 healthy pregnant women (C: control). Adiponectin and sEng serum levels were determined by ELISA. Polymorphism genotyping was obtained by PCR RFLP. Data were analyzed by Mann-Whitney, Chi-square or Fisher's exact tests and significance was set at p<0.05. RESULTS: There were no differences in adiponectin levels between the groups (C*PE: 6772.4ng/mL*7763.2ng/mL, p=0.99), but women with PE had significantly higher sEng levels (23.45 ng/mL*3.35ng/mL, p<0.0001). Moreover, the ratio adiponectin/sEng was significantly lower in PE than in C women (325.02*2119.4, p<0.0001). There was no association between PE and the analyzed polymorphism, neither between adiponectin genotype/phenotype. CONCLUSION: Our findings confirm an association between PE and altered sEng levels. In addition, these results suggest that angiogenic mediators when analyzed together, can better reflect their involvement in the pathophysiology of PE. Financial support: FAPESP (09/54729-6 and 10/08082-8). PMID- 26105438 TI - PP116. Circulating PlGF can help predict preeclampsia and adverse outcome in patients with suspected preeclampsia or fetal growth restriction. AB - INTRODUCTION: The circulating concentration of PlGF is reported to be lower in patients experiencing preeclampsia and patients delivering a small for gestational age (SGA) neonate. OBJECTIVES: To evaluate the predictive value of circulating PlGF for preeclampsia and adverse outcome in patients with suspected preeclampsia or fetal growth restriction. METHODS: We prospectively enrolled 96 women who were included after 22 weeks gestation (WG) for suspected preeclampsia or suspected SGA, and measured plasma levels of PlGF (Triage(r) PLGF, Alere(c)) at enrollment. We studied outcome until delivery and one week postpartum, and defined adverse outcome as severe preeclampsia, SGA neonate (<10th centile) or elective delivery for maternal or fetal complication. Severe adverse outcome was studied among patients included <34WG and defined as eclampsia, HELLP syndrome, very SGA (<3rd centile) or elective delivery <34WG. RESULTS: The mean logtransformed PlGF level was lower for women who experienced preeclampsia than for those who did not (2.9 vs 3.7, p=0.02), and was markedly lower for patients who experienced adverse outcome (2.9 vs 4.3, p<0.001). The odds of presenting an adverse outcome were higher for the lowest tertile of PlGF compared to the higher (OR=12 , 95% CI [3-46] ). Among patients included <34WG, the odds of experiencing a severe adverse outcome were, respectively, for the lowest and intermediate tertile as compared with the higher tertile: OR=132 , 95% CI [14-1273]; and OR=20, 95% CI [4-106] . When included <34 WG, patients with a PlGF level <12pg/ml experienced a severe adverse outcome in 96% of cases (24/25), and only 1 of 28 patients with a PlGF level >50pg/ml experienced a severe adverse outcome within 15 days (4%). Among women with suspected SGA who were enrolled <32WG and whose PlGF level was <12pg/ml, 89% had an elective delivery before 34 WG (17/19). CONCLUSION: Among women with suspected preeclampsia or SGA, PlGF circulating levels differ between women who will experience an adverse outcome and those who will not. It can therefore be of help in the management of these patients, especially for those for whom the diagnosis is suspected early in pregnancy. PMID- 26105439 TI - PP117. Measurement of sFlt-1 and PlGF for prediction of pregnancy associated diseases. AB - INTRODUCTION: Severe preeclampsia is associated with characteristic changes of sFlt-1 and PlGF levels in the maternal serum. OBJECTIVES: The aim of our study is the determination of the predictive value of sFlt-1 and PlGF for preeclampsia and other pregnancy associated diseases in women with a pathological uterine Doppler measurement during the second trimester of pregnancy. METHODS: An updated analysis of an ongoing prospective trial will be presented. Criterion of inclusion was a bilateral pathological uterine Doppler measurement with an increase of the resistance index (RI) >95th percentile and/or a bilateral postsystolic notch during 19 and 24 weeks. Ratio of sFlt-1 and PlGF was repeatedly measured during pregnancy using a full-automated system (Elecsys(r), Roche). RESULTS: Presently, we recruited 36 patients. Full data are available from 17 patients. Out of these in 23.5% (n=4) a delivery before 37 weeks was indicated. 41% of all newborns (7/17) showed a birth weight <5th percentile. 23.5% of all patients developed a hypertensive pregnancy disorder but without fulfilling the criterions of preeclampsia. Only two patients had a sFlt-1/PlGF ratio >95th percentile. In both cases we found severe fetal growth retardation. One of them developed a pregnancy related hypertension based on an antiphospholipid syndrome. CONCLUSION: The additional measurement of the sFlt 1/PlGF ratio in a high risk group of pregnancies may improve the prediction of severe pregnancy related diseases during the second trimester. But keeping the low incidence of severe preeclampsia in mind, the measurements seem to be only usefulness in a high risk population. Although we reported presently only of a small part of our study population the sFlt-1/PlGF ratio did not revealed a good specificity for prediction of preeclampsia. Pathological values were also found in cases with fetal growth retardation without signs of preeclampsia. PMID- 26105440 TI - PP118. Is the placental mass associated with the severity of preeclampsia? AB - INTRODUCTION: Preeclampsia contributes to an increased perinatal morbidity and mortality of both the mother and the fetus. The exact pathogenesis of PE is unclear; it is generally believed, however, that the placenta plays a pivotal role in this process. OBJECTIVES: The aim of this study was to analyse the effect of the placental mass on the severity of PE. METHODS: Following PE placentae were analyzed and their weights were compared with those of normal pregnancies [1]. Moderate and severe PE as well as HELLP syndrome were defined according to international guidelines. To compare placental weights obtained at different gestational ages, a ratio between observed (O) and expected (E) weights were calculated. Chi(2)-test and Kruskal-Wallis-test were used for statistical analysis and significance was considered when p<0.05. RESULTS: Two hundred and eight placentae following singleton pregnancies complicated by preeclampsia were enrolled. The mean gestational age at birth was 31.8+/-3.8 weeks, 130 (62.5%) cases delivered before the 34th week. The group with severe PE delivered earlier than that with moderate PE (mean+/-SD, 32+/-3.9 vs. 34+/-3 weeks; p<0.01). Severe PE was found in 176 (84.6%) cases; 85 of this group were associated with a HELLP syndrome. Isolated HELLP were found in 4 (1.9%) cases. In 144 (69.2%) cases placental weight was below the 10th percentile. The mean of the weights was higher in the group with moderate PE than in those with severe PE, PE with HELLP and isolated HELLP (410+/-67g, respectively, 376+/-79g, 344+/-86g, 341+/-88g). When normalized using the O/E-ratio (in order to correct for gestational age) these differences were not significant (moderate PE 0.75+/-0.24; severe PE 0.74+/ 0.22, PE with HELLP 0.73+/-0.22; isolated HELLP 0.88+/-0.05; p=NS). CONCLUSION: Our data show that the placental mass is not associated with the severity of PE. We hypothesize that once the pathogenesis of PE is triggered (by placental factors), the severity of the disease is modulated mainly by the maternal response and not by the placental mass. PMID- 26105441 TI - PP119. The role of the nuclear factor erythroid 2-related factor 2 (Nrf2) in preeclampsia. AB - INTRODUCTION: Preeclampsia is a multi-organ syndrome characterized by maternal endothelial damage, is an independent long-term risk factor for hypertension and cardiovascular disease. OBJECTIVES: In animal models the administration of the Vascular Endothelial Growth Factor (VEGF) could reverse the hypertensive signs accompanying this disease. In addition VEGF is implicated in placental oxidative stress during preeclampsia. One of the major cellular defence mechanisms against oxidative stress is the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2). Therefore, the activation of Nrf2 up regulates the HO-1/CO system. The principal aim of this work is to investigate whether the activation of Nrf2 raises VEGF levels by up regulation of CO release. METHODS: This study took place in vitro, the choriocarcinoma cell line BeWo cells and the primary human umbilical vein endothelial cells (HUVECs) were used to study the relationship between VEGF and an Nrf2 inducer Sulforaphane, a naturally occurring compound derived from broccoli. ELISA, Western blot assay and the Dual Luciferase Assay were both mainly applied for protein and VEGF activity analysis. RESULTS: It was found that activation of HO-1 expression via Nrf2/ARE pathway augmented the production of CO, which in turn up-regulated the gene expression of VEGF, and down regulated the production of the antiangiogenic protein, the VEGF antagonist sFlt-1. CONCLUSION: Nrf2 driven HO-1 expression elevates the levels of VEGF via CO production. In particular, activating of Nrf2 via sulforaphane, may have therapeutic potential in preeclampsia. PMID- 26105442 TI - PP120. Hydatidiform mole as a cause of eclampsia in the first trimester: A case report. AB - INTRODUCTION: The occurrence of preeclampsia before the 20th week of gestation is rare and it has been associated with hydatidiform molar pregnancy. OBJECTIVES: We describe a case of first trimester eclampsia which occurred in a patient with hydatidiform mole. METHODS: Case report. RESULTS: A 16-year-old woman came to emergency service for abdominal pain and vaginal bleeding. She had been suffering of vomiting after meals and complaining for abdominal mass for 2months, without consulting her physician. The last reported period was 1month before; the patient told her periods were regular and the only disease she reported was chronic HBV hepatitis. Vital parameters were all normal. Urine pregnancy test resulted always negative. The gynecological exam reported an increased uterus and a little bleeding, so serum bhCG was performed because of the exam findings and resulted 110,5317UI/L. The transvaginal ultrasound showed images consistent with gestational trophoblastic disease. Computed tomography (CT) scan revealed the presence of an uterine mass and three lung nodules, reported as possibly metastatic. A few days later, the patient underwent dilation and curettage (D&C). Second grade hydatiform mole was diagnosed by histology. After D&C, the serum bhCG was 202,511UI/L. The day after, the patient presented bilateral acute blindness, followed by incoming general seizures, concurrent hypertension and tachycardia. Intravenous diazepam, levetiracetam and mannitol controlled the seizures, but the conscious state of the patient remained critical. Temperature reached 40 degrees C, with concurrent leukocytosis. Then, a lumbar puncture was performed but it resulted negative for inflammatory/infective processes. A head CT was performed the same day and showed a posterior reversible encephalopathy syndrome (PRES). Intravenous methylprednisolone was started. Long term therapy with methylprednisolone and levetiracetam was effective and the patient's status improved and stabilized. A subsequent chemotherapy with EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine) was performed for six cycles, until serum bhCG resulted negative and the abdomen/pelvis ultrasound, head NMR and chest X-ray resulted normal. CONCLUSION: Preeclampsia and eclampsia are regarded as common causes of PRES, which is considered to be the result of vasogenic brain edema. Clinical and imaging findings are usually reversible. Early diagnosis and elimination of possible causes are important in order to avoid permanent visual or brain injury. Imaging (especially MRI) should be carried out in eclamptic patients with visual disturbance in order to exclude other causes of blindness. Molar pregnancy is a rare but important cause of eclampsia, and it has always to be considered in case of early manifestations. PMID- 26105443 TI - PP121. Expression of PlGF, sFlt, MTF-1, HO-1 and HIF-1 alpha mRNAs in preeclampsia placenta and effect of preeclampsia sera on their expression of choriocarcinoma cells. AB - INTRODUCTION: Placenta growth factor (PlGF) is a growth factor originated from placenta. The sFlt-1 is soluble receptor for PlGF and suppresses PlGF function. It has been reported that in preeclampsia, serum level of PlGF decreased and sFlt 1 level increased and that preeclampsia placenta is in hypoxic condition. Metal responsive transcription factor (MTF)-1, Hemoxigenase 1 (HO-1) and Hypoxia responsive factor -1 (HIF-1) may be induced in hypoxic condition. OBJECTIVES: In order to investigate pathophysiology in preeclampsia, we studied the expression of PlGF, sFlt-1, MTF-1, HO-1 and HIF-1 alpha mRNAs in placenta taken from preeclampsia and the effect of preeclampsia sera on their expression of choriocarcinoma cells and analysed the effect of placental hypoxia and serum factor on the expression of PlGF and sFlt-1 mRNA. METHODS: Placenta and serum samples were taken from preeclampsia and normal pregnancy with informed consent. The choriocarcinoma cells (JEG-3) were cultured in 24-well tissue culture plate. The cells were cultured with preeclampsia and normal pregnant sera. The RNAs were purified from these cells 24h after and placenta. The expressions of these mRNA were measured by using the real time PCR method (Applied Biosystems-7500). RESULTS: The expression of PlGF mRNA decreased and that of sFlt-1mRNA increased in preeclampsia placenta. The expression of MTF-1 and HO-1 mRNA decreased. The correlation was found between the expression of PlGF and MTF-1 mRNA, PlGF and HO 1 mRNA and sFlt-1 and HO-1mRNA. Moreover, expression of sFlt-1mRNA increased and HO-1mRNA decreased in JEG-3 cells after incubation of preeclampsia sera. CONCLUSION: The changes of PlGFmRNA in preeclampsia placenta may relate to the expression of MTF-1 and HO-1 mRNA. The changes of sFlt-1mRNA may relate to the expression of HO-1 mRNA and serum factor. Not only hypoxia but also serum factor may play a role of the levels of PlGF and sFlt-1 in preeclampsia placenta. PMID- 26105444 TI - PP122. Lack of correlation between placental weight and circulating soluble fms like tyrosine kinase-1 and placental growth factor suggests trophoblastic activity as a major contributor to the serum pool. AB - INTRODUCTION: Serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in preeclampsia and fetal growth restriction. Whether the alterations result from mere variation in trophoblastic mass or trophoblastic activity in these diseases is still elusive. OBJECTIVES: Using placental weight as a surrogate for trophoblastic mass, we explored the relationship between placental weight at delivery and serum levels of sFlt-1 and PlGF at various gestational ages in normotensive pregnant Thai women. METHODS: One hundred and forty two serum samples from healthy, normotensive, singleton Thai pregnant women were prospectively collected from 6 gestational age intervals; 10-14, 15-19, 20-24, 25-29, 30-34, and 35-40weeks'. Analysis for the levels of sFlt-1 and PlGF was made from fresh specimens, using a commercially available automated system. Placental weight at delivery was followed in participants who remained unaffected with preeclampsia or fetal growth restriction until the time of delivery. RESULTS: Statistical analyses were achieved from 140 participants. Quartiles for these markers were calculated for each gestational age interval. Serum sFlt-1 levels continuously increased through the pregnancy. Serum PlGF levels reached its peak levels at menstrual period of 25-29weeks', and then declined. Serum sFlt-1/PlGF ratios were consistently lower than that of the European population throughout the pregnancy. No significant correlation is found between placental weight at delivery, and serum levels of either sFlt-1 or PlGF at any gestational age interval. CONCLUSION: Ethnic variation of serum angiogenic markers is shown in this study. Lack of correlation between placental weight and serum angiogenic markers in normotensive individuals suggest that trophoblastic activity, and not number of the trophoblast, contribute to the alterations in circulating pool. This may facilitate a better understanding for its potential clinical applications of these biomarkers for other placental related diseases. PMID- 26105445 TI - PP123. Evaluation of glycosaminoglycans in placental of pregnant women with and without preeclampsia. AB - INTRODUCTION: Preeclampsia (PE) is a major cause of maternal and perinatal mobility and mortality and its etiology is not yet completely understood. Recently studies have shown the association between increased expression of glycosaminoglycans (GAGs) in placental of women with PE and its physiopathology. OBJECTIVES: Identify and quantify GAGs in placental of pregnant women in healthy pregnancy and PE. METHODS: Case-control study with 44 patients, control group (CG) n=29 and n=15 PE group. All patients were submitted to placental tissue resection (sample size of 5*5cm with the umbilical cord insertion in the center). The tissue was conserved in acetone. The GAGs' analysis consisted of centrifugation, proteolysis, precipitation, and electrophoresis RESULTS: Average age and gestational age in CG and PE were 27.33years and 39.02weeks and 24.17 and 36.90, respectively. In CG 68.96% (20/29) were Caucasian and 80.00% (12/15) in PE. We found in CG 34.48% (10/29) of primiparous and 40.00% (6/15) in PE. The average 24-hour proteinuria in PE was 554.28g/24hs. The average birth weight was 3333.31g in CG and 2972.66 in PE. The mean +/- standard deviation of dermatan sulfate (DS), heparan sulfate (HS) and hyaluronic acid (HA) in CG and PE were: 0,100MUg/mg of tissue +/-0,005 and 0,144 +/-0,071; 0,077+/-0,041 and 0,113+/ 0,061; 1,281+/-1,857 and 3,076+/-4,930. CONCLUSION: GAGs are increased in PE when compared to normal pregnancy. The expression of HA and HS was twice higher in PE. More studies are needed to determine the correlation between GAGs and physiopathology of PE. PMID- 26105446 TI - PP124. Trofoblastic invasion: The role of subunits STAT1 and STAT3. AB - INTRODUCTION: The trophoblastic migration/invasion are controlled by cytokines and growth factors that use intracellular pathways of signal to promote the regulation of gene expression, proliferation, cells differentiation, angiogenesis and embryonic development. The most important mediator of cytokine in trophoblastic invasion is the Janus-Kinase/signal transducer and activator of transcription (JAK/STAT). STATs are amino acids, compounds of 700-850 variable long-chain with isoforms alpha and beta and molecular weight between 83-113kDa. The role of these factors in the pregnancy set up may contribute to adopt interventions that could contribute to prophylaxis and/or treatment of abnormalities in the course of gestation when installed early. OBJECTIVES: Search on database the role of STAT in the process of trophoblastic invasion with emphasis on subunits STAT1 and STAT3. METHODS: This is a review performed on PubMed database. Have been included Studies found from 1992 (the year of discovery of STATs) until July 2011, without language restriction. The descriptors were: "Signal transducers and activators of transcription "and" Trophoblast". In the end we excluded bibliographical review. RESULTS: Five of the six selected papers studied the role of STAT3 in the physiology of the trophoblastc invasion process. One of them, indirectly by selection process of lactobacilli of vaginal flora endogenous, during change of vaginal pH on pregnancy, altering the release of greater or lesser number of Interleukin-10 which modulates the activation JAK/STAT. Among them, one of the study refers to involvement of STAT1 in the immunomodulation of interface fetus-mother. CONCLUSION: STAT3 is directly involved in the process of trophoblast invasion either in its endometrium adherence to, angiogenesis, invasion and regulation of invasion. And STAT1 is involved in immunomodulation through its suppression by trophoblast STAT utron. Several soluble factors that are generally present in the decidua, especially hepatocyte growth factor, granulocyte macrophagocytic-colony stimulating factors, interleukin-6, interleukin-11 and inhibition leukemia factor , which have been described by using the JAK-STAT activating STAT1 and STAT3 for intracellular signaling and from this process may influence the invasion trophoblast. PMID- 26105447 TI - PP125. High mobility group box 1 protein (HMGB1): A pathogenic role in preeclampsia? AB - INTRODUCTION: A central pathogenic mechanism of preeclampsia is believed to be the production by the hypoxic placenta of various mediators which promote inflammation and oxidative stress when released into the maternal circulation. The high mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein. In conditions of hypoxic cellular stress or necrosis, HMGB1 is released into the extracellular milieu. Extracellular HMGB1 has proinflammatory effects, due to the engagement of various cell membrane receptors, notably the receptor for advanced glycation products (RAGE). OBJECTIVES: In preeclampsia, there is evidence for activation of RAGE, and enhanced amounts of HMGB1 have also been demonstrated in the placenta and amniotic fluid, but not, so far, in maternal blood. We hypothesize therefore that, in preeclampsia, the concentration of HMGB1 is abnormally high in maternal blood. METHODS: We enrolled 16 women in third trimester pregnancy and suffering from preeclampsia (blood pressure > 140/90mmHg with significant proteinuria), 16 women with normal pregnancies who were matched pairwise with the former for BMI and gestation week, and 16 non pregnant healthy women, matched for age with the other two groups. HMGB1 was assessed in peripheral blood with a commercial ELISA kit. The variance between the three groups was appreciated using an ANOVA analysis. Significance was considered for a probability value of < 0.5. RESULTS: The median [interquartile range] HMGB1 concentrations (in ng/mL) were 2.1 [1.1-3.2] in preeclamptic pregnancies, 1.1 [1.0-1.2] in normal pregnancies (p<0.05 vs preeclamptic group), and 0.6 [0.5-0.8] in non pregnant women (p<0.01 vs both other groups). CONCLUSION: In third trimester pregnancy, the presence of preeclampsia is associated with an approximately two-fold increase of HMGB1 concentration in maternal peripheral blood. Considering its known proinflammatory effects, HMGB1 could be one mediator responsible for the maternal manifestations of preeclampsia. PMID- 26105448 TI - PP126. Are placental fas and fas ligand gene polymorphisms associated with preeclampsia? AB - INTRODUCTION: Increased placental trophoblastic apoptosis has been reported in pregnancies complicated by preeclampsia. Fas-Fas ligand is one of the major signal transduction pathways of apoptosis. OBJECTIVES: To determine if placental Fas and Fas ligand gene polymorphisms differ between patients with and without preeclampsia. METHODS: Forty-five singleton placentas were studied. Twenty-three placentas were from preeclamptic pregnancies and 22 were from normotensive controls. The study was approved by IRB. Genotyping was performed for Fas-1377, Fas-691, Fas-670, Fas ligand-844, Fas ligand-1174, Fas ligand-2777. Chi-square and Fisher's exact tests were used for statistical analysis. RESULTS: There were no significant differences in maternal age, parity or race between the two groups. There were no significant differences in genotypes or allele frequencies for the placental Fas-1377, Fas-691, Fas-670, Fas ligand-844, Fas ligand-1174 and Fas ligand-2777. CONCLUSION: Immune intolerance of maternal and placental interaction plays an important role in the pathogenesis of preeclampsia. Our findings do not support the role of placental Fas and Fas ligand gene polymorphisms in the pathogenesis of preeclampsia. The heterogeneous and complex etiology of preeclampsia makes it unrealistic to expect a single nucleotide polymorphism to explain the pathogenesis of this pregnancy complication. This relatively understudied area warrants further investigation. PMID- 26105449 TI - PP127. CMV infection and TLR2 expression in HELLP syndrome. AB - INTRODUCTION: The HELLP syndrome is a serious complication in pregnancy characterized by haemolysis, elevated liver enzymes and low platelet count occurring in 10-20% of cases with severe preeclampsia and associated with metabolic disorders symptoms later in life. Emerging evidence indicated that cytomegalovirus (CMV) infection and TLR signaling activation are associated with severe preeclampsia and metabolic disorder conditions. OBJECTIVES: The aim of this study was to examine CMV sero-prevalence and its associated TLR signaling activation in patients with HELLPs. METHODS: A case-control study was performed. Subjects included women with HELLP syndrome (n=6) and normal pregnancy controls (n=20), who matched with cases for maternal age, gestational age and parity. Maternal serum CMV serology and cytokines response were measured by ELISA. TLR2 and TLR4 expression on peripheral Neutrophils were detected by real-time PCR. RESULTS: CMV IgG seropositivity was more prevalent among HELLP syndrome patients than normal pregnancy controls (85% versus 40%, p<0.01). Patients with HELLP syndrome also had elevated TLR2 (p<0.01) and IL-1beta mRNA expressions (p<0.05) and increased TNF-alpha: IL-10 (p<0.05) and IL-6: IL-10 (p<0.05) ratio compared with matched normal pregnancy controls. CONCLUSION: It is important to consider pregnancy CMV infection through TLR2 signaling in modulation of innate immune response in maternal HELLP syndrome, and may be linked with increased metabolic disorders later in life. PMID- 26105450 TI - PP128. Placental Caspase-3 gene polymorphisms is associated with preeclampsia. AB - INTRODUCTION: Increased placental trophoblastic apoptosis (programmed cell death) was previously reported in pregnancies complicated by preeclampsia. Caspase-3 is one of the key executioners of apoptosis. Caspase are expressed in many tissues including human placental trophoblast and other tissues. Variations in the promoter area of the Caspase genes may modulate apoptotic signaling, contributing to an increased risk of preeclampsia OBJECTIVES: To determine if gene polymorphisms of Caspase 3 proteins differ between patient with and without preeclampsia. METHODS: Forty-three singleton placentas were studied. Twenty-two placentas were with preeclampsia and 21 were normotensive controls. DNA was extracted from placentas using QIAAmp DNA Minikit. Genotyping of Caspase 3 +567 was determined by real-time PCR using the Applied Biosystems Prism 7900 HT SDS machine. Chi-square and Fisher's exact tests were used for statistical analysis. RESULTS: There were no significant differences in maternal age, parity or race between the two groups. Preeclamptic placentas had higher frequency of wild type TT of Caspase-3 SNP (+567) as compared with normotensive controls (59% versus 28.5%). Preeclamptic placentas expressed significantly more genotype of TT of Caspase-3 SNP (+567) than normotensive patients when compared to CC (p=0.02). The alle frequencies of the Caspase SNP (+567) in preeclampstic placentas were 0.77 and 0.23 for T and C, respectively, as compared to 0.52 and 0.48, respectively, in placentas from normotensive pregnancies. CONCLUSION: Immune intolerance of maternal and placental interaction plays an important role in the pathogenesis of preeclampsia. Increased of placental apoptosis was reported in pregnancy complicated with preeclamsia. Our findings indicate placental Caspase 3 (+567) gene polymorphisms is associated with preeclampsia. Altered placental alle frequencies and caspase-3 SNP (+567) in preeclampsia further suggests preeclampsia is a trophoblastic disorder. PMID- 26105451 TI - PP129. Assessment of oxidative status markers and no bioavailability in hypertensive disorders of pregnancy. AB - INTRODUCTION: Evidences point that an imbalance between overproduction of reactive oxygen species (ROS) and the lack of antioxidant mechanisms may contribute to endothelial dysfunction observed in hypertensives disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertensives (GH). OBJECTIVES: In the present study, we expanded these previous findings and evaluated systemically the plasma levels of oxidative stress markers (TBARS [2] and carbonyl [3]) and total antioxidant status (FRAP [1] and reduction of MTT (Medina et al., 2007)), as well as assessed the impact these markers on NO status in healthy pregnant, gestational hypertensive and preeclampsia pregnant. METHODS: A total of 99 pregnant were enrolled (38 HP, 33 GH and 28 PE. The lipid peroxidation was assessed by (TBARS, [2]). The determination of carbonyl was performed according to the method of [3] and FRAP assay by Benzie and Strain [1]). Nitrite levels were evaluated using chemiluminescence assay. RESULTS: We found similar values of TBARS among groups, and reduced carbonyl levels in HDP. Conversely, significant increases in plasma activity of antioxidant status of were observed in these groups (GH and PE) compared to healthy pregnant (using both MTT or FRAP method). CONCLUSION: Although antioxidant compensatory mechanism observed in HDP, the levels of nitrite remain reduced in these pregnant compared to healthy pregnant, suggesting that other mechanisms may be involved in the NO bioavailability. This study was funded by the Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil), the Conselho Nacional de Desenvolvimento Cienti'fico e Tecnologico (CNPq). PMID- 26105452 TI - PP130. ENOS tagging SNP haplotypes in hypertensive disorders of pregnancy. AB - INTRODUCTION: Haplotypes formed by polymorphisms (T-786C, rs2070744; a variable number of tandem repeats in intron 4, and Glu298Asp, rs1799983) of eNOS gene were associated previously with gestational hypertension (GH) and preeclampsia (PE). However, no study has explored the tagging SNPs rs743506 and rs7830 in these disorders. OBJECTIVES: The aim of the current study was to compare the distribution of the genotypes and haplotypes formed by the two tagging SNPs or by the five eNOS polymorphisms mentioned among healthy pregnant GH and PE. METHODS: We recruited 122 HP, 138 GH and 157 PE. Genotypes for the T-786C, the Glu298Asp and rs743506 polymorphisms were determined by Taqmana Allele Discrimination assays and fluorescence signals were measured on Chromo 4 Detector (Bio-Rad Laboratories, USA). Genotypes for the VNTR polymorphism in intron 4 and rs7830, however, were determined by PCR and fragment separation by electrophoresis in 8% polyacrylamide gels. Plasma aliquots were analyzed in triplicate for their nitrite content using an ozone-based chemiluminescence assay. RESULTS: The haplotype formed by the most common variants in each polymorphism "T b G A C" was more frequent in PE group compared to HP (P=0.00004), which may be explained by the higher linkage disequilibrium found in PE compared to GH and HP. Conversely, the haplotype "C b G G C" was more frequent in HP compared to PE (P=0.00113), which is supported by previous findings that demonstrated the association of the combination "C b G" with higher level of nitrite (NO marker). CONCLUSION: Our results suggest a protective effect of the haplotype "C b G G C" against the development of PE. This study was funded by the Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG-Brazil), the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP-Brazil). PMID- 26105453 TI - PP131. Regulation of heme oxygenase/carbon monoxide (ho/co) and l-arginine/nitric oxide (no) pathways by human chorionic gonadotropin (hcg) in human fetal endothelium. AB - INTRODUCTION: HO/CO and l-arginine/NO pathways are critical regulators of vascular function in early human pregnancy. HO is the rate-limiting enzyme in heme catabolism leading to the formation of biliverdin, which is subsequently reduced to bilirubin by biliverdin reductase, carbon monoxide, and free iron. HO 1, the inducible isoform of the enzyme, is essential to promote placental function and fetal development (1). HO-1 is also required to maintain nitric oxide synthesis (2). Human chorionic gonadotropin (hCG) is the first blastocyst derived hormonal signal playing a significant role in implantation and placentation (3). We hypothesized that hCG upregulates HO-1 and thus positively regulates early vascular events in human pregnancy. OBJECTIVES: In this study we used human umbilical vein endothelial cells (HUVECs) to demonstrate that hCG up regulates mRNA and protein abundance of HO-1. The effect of hCG on l-arginine transport and the expression of hCAT1, the main cationic amino acid transporter involved in endothelial nitric oxide synthesis were evaluated. METHODS: HUVEC were isolated from normal pregnancies (approval from the Institutional Review Board) by collagenase digestion and grown (37 degrees C, 5% CO2) in medium 199 supplemented with 20% newborn and fetal calf sera. Cells were treated with hCG (0.5-100IU/mL, 0-24hours and CoCl2 (150MUM, 6hours) as positive control. Total proteins were separated by SDS-PAGE electrophoresis, transferred to nitrocellulose membranes and incubated with monoclonal anti human HO-1 or anti beta-actin and respective secondary antibody conjugated with horseradish peroxidase. Protein bands were detected by enhanced chemiluminiscence. Total RNA was isolated and cDNA was obtained by reverse transcription. PCR assays were performed in a reaction mix containing 0.5MUM primers, dNTPs, Taq DNA polymerase, 2 mM MgCl2. Relative abundance of HO-1, hCAT-1 and 28S were determined. l [(3)H]Arginine transport (100MUM, 2 MUCi ml(-1), 37 degrees C, 1min) were determined in HUVECs exposed (30min) to hCG (0.5-100IU/mL) and CORM-2 (CO donor). RESULTS: The highest level of HO-1 protein were obtained at 5IU/mL of hCG and declined at higher concentrations. hCG increased HO-1 protein abundance and maximal response was observed at 6 hours (4-fold), decreasing at 24hours exposure. These effects of hCG on HO-1 protein abundance are well correlated with changes in HO-1 mRNA regarding time of exposure and concentration of hCG. L arginine transport and hCAT-1 mRNA were also increased (2.8-fold and 4.5-fold, respectively) by hCG. CONCLUSION: Upregulation of HO-1 as well as the increase in l-arginine transport and hCAT-1 mRNA in HUVECs are novel effects of hCG, which occur at physiological plasma concentrations of the hormone, as those found in the first weeks of pregnancy. These changes could be relevant for the maintenance of the NO synthesis in fetal and maternal vasculature, ensuring the predominance of the vasodilator tone. These effects could be also critical for vascular remodelling of uterine circulation and placental vascular development in early stages of pregnancy, the lack of which could result in abnormal placentation as described in preeclampsia and fetal growth restriction. PMID- 26105454 TI - PP132 Comparison between Early-onset and Late-onset Preeclampsia based on maternal cardiac output, Total Peripheral Vascular Resistance, and Uterine Artery Resistance Index. AB - INTRODUCTION: Earlier report show different maternal hemodynamic and uterine artery profile at early gestational ages between pregnant women that will develop Early-onset and Late onset Preeclampsia (PE) later. OBJECTIVES: The aim of this study is to compare maternal hemodynamic (Cardiac Output, Total Peripheral Vascular Resistance) and Uterine Perfusion (Uterine Artery Resistance Index) profile during onset of the disease between Early and Late-onset Preeclampsia. METHODS: A cross-sectional observational analytic study of 17 severe PE and 20 matched controls. The PE group was divided into early onset PE (<34weeks) and late onset PE (>34weeks). We examine doppler velocimetry ultrasound and echocardiography in 1-2days after the patient admitted to hospital. Primary outcome included uterine artery resistance index (UARI), cardiac output (CO), and total peripheral vascular resistance value (TVR). RESULTS: We found no significant difference of uterine artery resistance index value between early onset PE (0.68+/-0.079) and control (0.67+/-0.093) (p=0.620); late-onset PE (0.67+/-0.142) and control (0.67+/-0.084) (p=0.959). Maternal hemodynamic profile show Early-onset PE CO (6.06+/-1.172L/m) was higher than control (4.67+/ 1.739L/m) (p=0.079), and TVR (1.76+/-0.434dynes.s/cm(5)) was higher than control (1.58+/-0.498dynes.s/cm(5)) (p=0.481). Late onset PE show similar result, CO (5.17+/-1.433L/m) was higher than control (4.47+/-1.649L/m) (p=0.467) and TVR (2.29+/-0.796dynes.s/cm(5)) was also higher than control (1.82+/ 0.947dynes.s/cm(5)) (p=0.527). CONCLUSION: Maternal hemodynamic of Early onset and Late onset PE seem to have a complex process that cannot be differentiate strictly based on gestational ages, and the view that those two disease came from a different etiology should be reconsidered. PMID- 26105455 TI - PP133. Second and third trimester placental haemodynamics and the risks of pregnancy complications. The generation R study. PMID- 26105456 TI - PP134. l-Arginine supplementation induces the expression of genes related to antioxidant defense in cultures of human vascular endothelial cells: Protective role for preeclampsia. AB - INTRODUCTION: Recently, it has been proposed that supplementation with l-Arginine reduces the incidence of preeclampsia in high risk women, but the molecular mechanisms involved in the protective effect need to be determined. In addition, a critical role of l-Arginine in endothelial cell survival during oxidative stress, and the participation of neutrophils in the induction of oxidative stress during preeclampsia have been suggested. OBJECTIVES: To address if supplementation with l-arginine provides antioxidant defense in human vascular endothelial cells. METHODS: Human vascular endothelial cells (HUVECs) were isolated from umbilical cord veins obtained from healthy women underwent cesarean sections at term, with no evidence of hypertension disorders through the pregnancy. HUVECs were cultured in EndoGro media with LS supplement kit and 1% antibiotic with (n=10) or without 200uM l-Arginine (n=10). Confluent HUVECs were stimulated with neutrophils activated with 50umol/L arachidonic acid (1:16 ratio of neutrophil/cells). After incubation, cells were rinsed in PBS and harvested for RNA and protein extraction. Reverse transcription was performed using the RT(2) First Strand kit, and expression gene profiling was generated using the RT(2) Profiler PCR Array Human Oxidative Stress and Antioxidant Defense that includes the expression profile of 84 genes related to the oxidative pathway. Expression results were analyzed with the RT(2) Profiler PCR Array Data Analysis Template v3.0 and two different lists of fold change in gene expression were generated: (1) HUVEC+neutrophils vs HUVEC+l-Arginine + neutrophils and (2) HUVEC vs HUVEC+neutrophils. Validation of the expression assays was performed using western blots or ELISAS for proteins expressed by selected genes. RESULTS: Fold up- or down gene regulation are shown in Table 1. Forty six genes involved in oxidative stress defense were significantly up-regulated in HUVECs supplemented with l-arginine when were exposed to neutrophils. Interestingly, almost the same genes were down-regulated in non-supplemented HUVECs after neutrophil exposure. CONCLUSION: Supplementation with l-Arginine upregulates the expression of genes related to antioxidant defense in primary cultures of endothelial cells. This finding provides a novel insight about the molecular mechanisms involved in the protective role of l-Arginine during preeclampsia. PMID- 26105457 TI - PP135. Maternal serum levels of endothelial nitric oxide synthase and ADMA, an endogenous ENOS inhibitor in pregnancies complicated by severe preeclampsia. AB - INTRODUCTION: Preeclampsia is a major cause of maternal and fetal mortality and morbidity. Preeclampsia remains amongst the biggest challenges in obstetrics, but its aetiopathogenesis is still unclear. Recent observations support the hypothesis that imbalance between maternal angiogenic/anti-angiogenic factors concentrations is responsible for the clinical manifestations of the preeclampsia. It was also suggested that clinical manifestations of preeclampsia caused by endothelial malfunction including insufficient production of nitric oxide and that abnormality in nitric oxide synthesis or NO bioavailability may contribute to the development of preeclampsia. But the mechanism associated with alteration of nitric oxide formation in pregnancies complicated by preeclampsia is not well understood. OBJECTIVES: The aim of this study was to determine the maternal serum concentrations of endothelial nitric oxide synthase (eNOS) and its endogenous inhibitor, asymmetric dimethylarginine (ADMA) in pregnancies complicated by severe preeclampsia in comparison with healthy normotensive pregnant women. METHODS: A study was conducted including 29 uncomplicated women (the Control group) and 29 preeclamptic women (the Pre group). Preeclampsia was diagnosed by the increased blood pressure of >140mmHg systolic and >90mmHg diastolic in women who were normotensive before 20 weeks of gestation accompanied by proteinuria, defined as the urinary excretion of >0.3g protein in 24h specimen. Severe preeclampsia was defined as blood pressure >160/110mmHg on at least 2 occasions 6h apart with proteinuria >5g in a 24h urinary protein excretion. The maternal serum eNOS and ADMA concentrations were determined using a sandwich enzyme-linked immunosorbent assays. RESULTS: There were no statistically significant differences in gravidity, parity, maternal age and height in patient profiles between groups. Creatinine and urea levels were normal in all patients. Systolic and diastolic blood pressures were higher in preeclamptic pregnant women than in the control group. The mean systolic blood pressure values were 166.39+/-15.47mmHg in the Pre group and 115.72+/-10.34mmHg in the control group. The mean diastolic blood pressure values were 108.89+/ 10.45mmHg in the Pre group and 75.34+/-6.22mmHg in the healthy controls. These differences were statistically significant (p<0.000001). Our study revealed increased maternal serum levels of asymmetric dimethylarginine in preeclamptic patients (p=0.007223). The mean values of maternal serum ADMA were 0.597+/ 0.161mmol/L in the Pre group versus0.503+/-0.081mmol/L in the healthy pregnant patients. The levels of serum endothelial nitric oxide synthase were lower in women with pregnancies complicated by severe preeclampsia than in the healthy women from the control group, but these differences were not statistically significant (p=0.118770). The mean values of serum eNOS were 134.06+/-76.73U/ml in the Pre group and 187.70+/-165.41U/ml in the Control group. CONCLUSION: Elevated levels of ADMA and the unchanged levels of eNOS in pregnancies complicated by severe preeclampsia allow the conclusion that the nitric oxide deficiency in this pregnancy disorder result not from a reduced level or activity of eNOS, but from elevated levels of asymmetric dimethylarginine, an endogenous eNOS inhibitor. PMID- 26105458 TI - PP136. Blood pressure patterns in pregnant women who developed pre-eclampsia or hypertension. AB - INTRODUCTION: Early recognition of pregnant women at risk of pre-eclampsia (PE) in developing countries is essential to ensure timely transfer to the appropriate level of care. OBJECTIVES: Our aim was to determine the predictive value of blood pressure (BP) measurements taken in 4 week windows to identify women who will develop PE or new onset hypertension (NOHPT). METHODS: A prospective observational study.Women with one or more risk factors for PE presenting at a tertiary hospital for antenatal care before 14 weeks' gestation were approached to participate. After obtaining informed consent, a single researcher completed a comprehensive structured questionnaire regarding previous medical, pregnancy and contraceptive history, also including information of the patient's mother, siblings and the father. Clinical findings and the results of routine antenatal tests were documented. Subsequent care was according to existing management policies. The primary outcome was the development of PE (ISSHP definition). RESULTS: We enrolled 318 women, 9 of whom had uncomplicated deliveries elsewhere. There were 35 cases (12.6%) of PE and 39 cases of NOHPT amongst women who delivered after 20 weeks' gestation. Systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP) did not differ between groups at presentation. SBP was significantly higher in women in the PE group from 12-15 weeks' gestation (129.1+/-13.6 vs. 115.9+/-16.1mmHg) onwards, while the DBP became significantly higher from 24-27 weeks' gestation (84.0+/-13.3 vs. 69.3mmHg) onwards. MAP was also higher from 12-15 weeks' gestation (94.8+/ 8.5mmHg) onwards. PP was not of value. In women with NOHPT, SBP became significantly higher at 16-19 weeks' gestation (124.1+/-12.1 vs. 118.4+/-14.6), MAP became significantly higher at 24-27 weeks' gestation (89.8+/-14.6 vs. 85.7+/ 11.3mmHg) and DBP at 32-35 weeks' gestation (78.8+/-72 vs. 72.1+/-10.9mmHg). ROC curve analysis revealed poor ability of all four parameters to distinguish between women who will develop PE or NOHPT. CONCLUSION: SBP, DBP and MAP increases earlier in women who will develop PE compared with those who develop NOHPT. In both groups SBP and MAP changed earlier than DBP. PP did not differ between the various groups. There is no specific cut-off value of any parameter which will predict disease without an accompanying high false positive rate. SBP and DBP are only of clinical importance if specific threshold values as identified in existing classification systems are exceeded. PMID- 26105459 TI - PP137. Posterior reversible encephalopathy syndrome (PRES) is a constant component of eclampsia. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome (PRES) has been reported to occur in patients with eclampsia. In both conditions there is evidence to suggest disordered cerebral autoregulation. OBJECTIVES: We sought to investigate the concurrence of PRES with eclampsia and to describe the associated obstetric, radiologic and critical care correlates. METHODS: Single center 2001 2010 retrospective cohort study of all patients with eclampsia who underwent neuroimaging via magnetic resonance imaging (MRI) or computerized tomography (CT) with or without contrast. The medical records of all patients with eclampsia during the study interval were identified, evaluated and extracted for pertinent data; a diagnosis of PRES was made by radiologists using standard criteria. RESULTS: Forty-six of forty-seven (97.9%) patients with eclampsia revealed PRES on neuroimaging using one or more modalities: MRI without contrast=41 (87.2%), MRI with contrast=27 (57.4%), CT without contrast=16 (34%), CT with contrast=7 (14.8%) and/or MRA/MRV=2 (4.3%). PRES was identified within the parietal (36, 78.3%), occipital (35, 76.1%), frontal (29, 63%), temporal (13, 28.3%) and basal ganglia/ brainstem/cerebellum (12, 26.1%). Eclampsia occurred antepartum in 23 patients, postpartum in 24 patients with 22 vaginal/25 cesarean deliveries at a mean maternal age of 21.8 years (range 15-39) and a mean gestational age of 33.9 weeks (range 22.4-41.7 weeks). Ethnicity was African-American in 38 patients. Headache was the most common presenting symptom (87.2%) followed by altered mental status (51.1%), visual disturbances (34%) and nausea/vomiting (19.1%). Severe systolic hypertension was present in 22 (47%) of patients.Use of antihypertensives (87%), magnesium sulfate (100%), diuretics (66%) and corticosteroids (50%) facilitated maternal recovery in all cases with usually a brief hospitalization (mean 3.9 days, range 1-20 days). CONCLUSION: The common finding of PRES in patients with eclampsia suggests that PRES may be part of the pathogenesis of eclampsia. We speculate that therapy targeted at prevention or reversal of PRES pathogenesis will prevent or facilitate recovery from eclampsia. PMID- 26105460 TI - PP138. Human fetal malformations associated with the use of angiotensin II receptor antagonist. AB - INTRODUCTION: antagonists of angiotensin II receptor (AAR) are commonly used for the treatment of chronic hypertension in the general population. Some of these pharmacological agents are losartan, candesartan, valsartan and tasosartan. Despite the good response achieved with these drugs in the control of hypertension, all medications that act directly on the renin-angiotensin system should be contraindicated during pregnancy. These drugs have been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death.Here we report a case of fetal malformations and death associated with the use of losartan. OBJECTIVES: describing the association of fetal malformations and the use of losartan during first and second trimester of pregnancy. METHODS: this is a case report involving a 37-year-old pregnant woman at 26 gestational weeks. This patient had history of chronic hypertension for more than five years that was being regularly treated with Losartan 50mg/day. After her first consultation losartan was promptly discontinued and substituted for methyldopa. However, scan evaluation demonstrated severe oligohydramnios associated with altered fetal biophysical profile and altered Doppler fluxometry (absent diastolic flow at umbilical arteries). Therefore, a cesarean-section was performed after corticoid administration for fetal lung maturation. At first moment some characteristic alterations as fetal limb contractures and craniofacial deformation were detected at the 1007g new-born. This baby went to death 36h after delivery due to severe lung hypoplasia. RESULTS: the autopsy examination revealed renal tubular dysgenesis associated with changes secondary to nephropathy, probably induced by drug (Fig. 1). Associated findings were underdevelopment of bones of the skull with large fontanelles, thymus atrophy and signs of perinatal hypoxia. CONCLUSION: the difficulty of attending basic health assistance was attributed to be associated with this case, as this patient did not have opportunity and sufficient information about the necessity of changing her medication during pregnancy. Apart from this situation, this case report brings good information about the association between antagonists of angiotensin II receptor and human fetal malformations. PMID- 26105461 TI - PP139. The elective prematurity birth and its perinatal effects of syndromes in hypertensive pregnancy. AB - INTRODUCTION: The hypertensive pregnancy disorders affect 7.5% of Brazilian women, being a major cause of maternal and perinatal morbidity and mortality, affecting 6-10% of primigravidae. They represent a significant cause of prematurity birth, with elective responsible for 20-30% of premature births, with higher incidence of neonatal morbidity due to high rates of complications in short and long term. OBJECTIVES: Identify the repercussions in a short time, on caused by elective obstetric parity decisions in women with hypertensive neonatals pregnancy syndromes. METHODS: Retrospective analysis of medical records of pregnant women admitted to Hospital Guilherme Alvaro, in the city of Santos/SP - Brazil, between Jan/2005 to Jan/2012. Calculations were performed for dichotomous variables and an epidemiological analysis with data obtained on pregnant women with hypertension with a single fetus, subjected to delivery before 37 weeks. Classification of Hypertensive Syndromes followed the criteria of the NHBPEP - 2000, after blood pressure measurements were calibrated following standard technique: Chronic hypertension (CH), Pre-eclampsia, superimposed pre eclampsia and late gestational hypertension and multiple births were excluded, premature labor and fetal malformations, totaling 102 cases. RESULTS: Throughout the study, it was observed that 67.6% are appropriate for gestational age, birth weight 1500-2500grams (43.1%). Support in the neonatal were excluded ICU was necessary in the vast majority (75.7%), and length of stay exceeding 28 days in 29.3% of cases. The main indication was respiratory distress syndrome (63.6%) requiring intubation orotraquel and jaundice in 18.2% of premature infants was a common comorbidity (39.4%). Even with all the support in-hospital, the neonatal mortality was present in 8.1% of cases. The main indication of the resolution was for obstetric maternal complications (61.8%) where pre-eclampsia and preeclampsia superimposed were expressions which caused more frequent (42.2 and 40.2% respectively), showing the level of proteinuria between two -4.9g (32.1%). Gestational age at delivery was 32-34 weeks (43.1%), corticosteroid therapy was not performed (54.9%) and cesarean delivery was (94.1%). The most frequent age group was 20-34 years (53.9%), Caucasian (54.9%), primigravida (62.7%) and less than five prenatal visits (36.3%) were performed. CONCLUSION: The hypertensive pregnancy are risk factors for preterm elective delivery and is more frequent before 34 weeks, resulting in high perinatal morbidity and mortality, especially in cases of preeclampsia with severe clinical presentation and long hospital stays, with consequent costs and conducting excessive procedures in the neonate. Enable early referral to specialist services and consequent prenatal follow up, enables the adoption of early action, such as clinical support in a timely manner to facilitate the handling of cases which are still stable, optimizing the opportunity for administration of antenatal corticosteroids. It is necessary to review decisions about the mode of delivery in prematurity related to hypertension cases, with the aim of increasing the occurrence of vaginal deliveries. PMID- 26105462 TI - PP141. The lipid transporters ABCA1 and ABCG1 are differentially expressed in preeclamptic and IUGR placentas. AB - INTRODUCTION: The ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG1 are highly expressed in the placenta in various compartments, including the villous syncytiotrophoblast (V-STB) and foetal endothelial cells. Among other not yet characterized functions, they play a role in the foeto-maternal transport of cholesterol and other lipophilic molecules. In humans, preliminary data suggest expressional changes of ABCA1 and ABCG1 in pathologic gestation, particularly under hypoxic conditions, but a systematic expression analysis in common human pregnancy diseases has never been performed. OBJECTIVES: The aim of the present study was to characterize ABCA1 and ABCG1 expression in a large series of pathologic placentas, in particular from preeclampsia (PE) and intrauterine growth restriction (IUGR) which are associated with placental hypoxia. METHODS: Placentas from 152 pathological pregnancies, including PE and/or HELLP (n=24) and IUGR (n=21), and 20 normal control placentas were assessed for their ABCA1 and ABCG1 mRNA and protein expression with quantitative RT-PCR and semi-quantitative immunohistochemical analysis, respectively. RESULTS: ABCA1 protein expression in the V-STB was significantly less extensive in PE compared with normal controls (<10% of V-STB stained for ABCA1 in 58% PE placentas vs. 25% controls; p=0.035). Conversely, it was significantly more wide-spread in IUGR (>75% of V-STB stained in 57% IUGR placentas vs. 15% controls; p=0.009). Moreover, there was an insignificant trend for increased ABCA1 expression in fetal endothelial cells of stem villi in PE (p=0.0588). ABCA1 staining levels in V-STB were significantly associated with placental histopathological features related with hypoxia: they were decreased in placentas exhibiting syncytial knotting (p=0.033) and decidual vasculopathy (p=0.0437) and increased in low weight placentas (p=0.015). The significant and specific alterations in ABCA1 protein expression found at a specific cellular level were not paralleled by changes in ABCA1 mRNA abundance of total placental tissue. ABCG1 staining was universally extensive in the V-STB of normal placentas, always affecting more than 90% of V-STB surface. In comparison, ABCG1 staining of the V-STB was generally often reduced in pregnancy diseases. In particular, less than 90% of V-STB exhibited ABCG1 staining in 26% of PE placentas (p=0.022) and 35% of IUGR placentas (p=0.003). Similarly to ABCA1, ABCG1 mRNA expression in total placental tissue was not significantly different between controls and PE or IUGR. CONCLUSION: ABCA1 and ABCG1 proteins are differentially expressed, with either down- or up-regulation, in the V-STB of placentas exhibiting features of chronic hypoxia, such as in PE and IUGR. This suggests that other factors in addition to hypoxia regulate the expression of placental lipid transporters. The specific changes on a cellular level were masked when only total tissue mRNA was analysed underlining the importance of cell specific expression analysis. The potential effects of decreased placental ABCA1 and ABCG1 expression on foetal nutrition and development remain to be elucidated. PMID- 26105463 TI - PP142. Independent effects of pregnancy induced hypertension on childhood development: A retrospective cohort study. AB - INTRODUCTION: The effect of maternal pre-eclampsia on neurological and cognitive development of children is not well known. A literature search of Ovid MEDLINE, EMBASE and CINAHL revealed differing opinions in the current literature. It would appear that there is uncertainty regarding the independent effects of preterm birth, birth weight and pre-eclampsia on early childhood development, complicated by the fact that most pre-eclamptic mothers are delivered preterm, and many such babies are growth restricted. OBJECTIVES: To assess whether maternal hypertension in pregnancy was independently associated with additional support needs in children METHODS: STUDY DESIGN: Retrospective cohort study Setting: Grampian region of Scotland Main outcome measure: The primary outcome of interest was whether a child had developed a record in the Support Needs System (Grampian). Secondary outcomes included the development of a particular disorder or deficiency for example, autism. METHODS: Linkage of birth records of all singleton deliveries occurring in primigravidae between 1995 and 2008 in Aberdeen Maternity and Neonatal Databank with the Support Needs System (SNS) dataset in Grampian. The database from which the study population is derived - the Aberdeen Maternity and Neonatal Databank (AMND) has been in existence since 1950 The Support Needs System (SNS) is part of a Scottish-wide database recording information about children who have additional support needs for more than six months and has been utilised in Grampian since 1998. The first exposed cohort comprised children whose mothers had pre-eclampsia or eclampsia and the second, those whose mothers had gestational hypertension. Children with normotensive mothers formed the unexposed cohort. Hypertensive status in pregnancy was based on Davey and MacGillivray's classification of hypertensive disorders of pregnancy. Crude and adjusted odds ratios with 95% confidence Intervals of having a record in SNS in the presence of maternal pregnancy induced hypertension were calculated using logistic regression taking account of confounders such as preterm birth and low birth weight. RESULTS: After adjusting for confounding factors, neither pre-eclampsia {Adj OR 0.80 (95% CI 0.60,1.07)} nor gestational hypertension {Adj OR 1.16 (95% CI 0.99,1.36)} showed statistically significant associations with additional support needs. An association of pre-eclampsia with cerebral palsy seen on univariate analysis also disappeared on adjusting for confounders {Adj OR 1.26 (95% CI 0.43, 3.68)}. Birth before 32 weeks gestation and birthweight below 1500g were independently associated with additional support needs in children. CONCLUSION: While maternal hypertension was not found to be independently associated with special needs in children, very preterm birth and very low birthweight showed an association. PMID- 26105464 TI - PP143. Relationship between mid-pregnancy placenta growth factor and hemodynamics in the mother, fetus, and uterus. AB - INTRODUCTION: Placental Growth Factor (PlGF) is an angiogenic and vasoregulatory peptide member of the vascular endothelial growth factor family. Reduction of free, circulating PlGF is associated with preeclampsia and fetal growth restriction, and precedes the clinical manifestations of disease by several weeks. It is not known whether aberrant PlGF is related for alterations in endothelial vascular function that cause or exacerbate the placental syndromes of pregnancy. OBJECTIVES: We sought to determine if mid-pregnancy PlGF was related to, and possibly mediating, measures of maternal, fetal, or uterine hemodynamic function in women at risk for placenta-mediated complications of pregnancy. METHODS: We measured free plasma PlGF (Triage PlGF Assay, Alere, Inc.) between 22 and 25 weeks in high risk subjects referred for assessment of fetal growth and uterine artery Dopplers due to abnormalities of serum screening analytes or other risk factors for preeclampsia. Maternal hemodynamic parameters including mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance (SVR) and index of contractility (ICON) were measured in recumbent position with noninvasive electrical cardiography (Aesculon EC System, Cardiotronics, Inc.). Doppler measurements of blood flow in the uterine arteries (pulsatility index, PI) and umbilical artery (systolic:diastolic ratio, S/D) were obtained by ultrasound (Voluson E8, GE Healthcare, Inc.), along with the estimated fetal weight (EFW). PlGF was expressed as the log concentration, plotted against the hemodynamic measurements, and analyzed with Spearman's correlation coefficient, R. Statistical significance was set to p=0.05. RESULTS: Data from seventeen fully studied patients were analyzed. The median gestational age was 24.3 weeks. PlGF concentration ranged from 25 to 1180 with a median of 235pg/ml. PlGF was positively related to maternal cardiac index (R=0.56, p=0.02) and ICON (R=0.51, p=0.04) and negatively related to SVR (R=-0.48, p=0.05). There was a non significant negative correlation with MAP (R=-0.41, p=0.10). PlGF showed a positive correlation to EFW (R=0.52, p=0.03) and a negative relationship to umbilical artery S/D ratio (R=-0.42,p=0.06). There was no correlation between maternal PlGF and uterine artery Doppler PI (R=-0.19, p=0.46). CONCLUSION: The concentration of circulating free PlGF at mid-pregnancy is related to both maternal systemic hemodynamic function and fetal umbilical artery resistance (and growth) in high risk pregnancies prior to the onset of preeclampsia. It is not, however, related to vascular resistance in the uterine artery. PlGF may play a role in modulating the general vascular function of the fetus and mother after establishment of the uteroplacental circulation. PMID- 26105465 TI - PP144. Profile of lupus pregnancy in internal medecine practice. AB - INTRODUCTION: The pregnancies in systemic erythematous lupus (SLE) disease is a situation of high risk and involve both the mother and the fetus. The prematurity and the miscarriage are there more frequent, with increase risks of eclampsia, acute hypertension, HELP syndrome and of worsening renal disease. So the morbimortality is multiplied particularly when a anti-phospholipid syndrome 'APLS' is associated. The pregnancy remains however authorized when the SLE is in remission for more than 6 months with a validated treatment and successful means of monitoring. OBJECTIVES: To review the clinical profile of the pregnancies at the SLE patients with or without APLS in Internal Medicine Practice. METHODS: it's a retrospective study, in an internal medical centre over a period going from January, 2008 till December, 2011. The collection of the data is made from the index cards of clinical observations collecting items to interpret the data. All the patients are diagnosed referring to the criteria ACR (SLE/APLS) and all benefit from a follow-up in a obstetrics monitoring (ultrasounds to monitor growth and placental development). RESULTS: On a cohort of 80 SLE young patients hospitalized we brought together 20 patients answering eligibility criteria. The average age is of 26 years (21-41), SLE evolve with an average of 2.5years, the parity is estimated at 5 on average by patient. The pregnancies are programmed in only in 25% . The others cases of pregnancy remain the consequence of a not adapted contraception (50%). Lupus patients have history of renal damage (8) requiring immunosuppressive therapy (4) but renal function is preserved at all the patient's. The treatment is adapted to the clinical context and prophylactic doses of heparin and a baby aspirin are required in most situations. The cardiovascular and metabolic risk factors show an overweight (12), one dyslipemia (10), type 2 diabetes (2), and hypertension (3). The pregnancy is at the origin of a degradation of the renal function (4) with definitive chronic renal Insufficiency (1). The specific events observed are a HELLP syndrome (1), pre eclampsia (2), fetal losses (5), ischemic strokes (4) and post-partum cardiomyopathy (1). The pregnancies require caesarians (15) with ligature of trunks (2). We deplore fetal deaths (7) in tripled (1) and in twin (1) during the period of follow-up. We note a small birth weight (7), a preterm birth (5), a foetal distress (5) at the origin of a psychomotor disorders (1) and we observed a case of a transient skin lupus (1). CONCLUSION: The frequency of the maternal and fetal complications is partially understandable by the fact that the majority of the pregnancies neither are programmed, nor authorized by the treating physician. Indeed, between the denial of the disease and the desire of pregnancy in everything taken, the patients often take the risk and put the treating physician in front of pregnancies in top risks. PMID- 26105466 TI - PP145. Hypertensive disorders of pregnancy: A two year study (2008-2009). AB - INTRODUCTION: The hypertensive disorders of pregnancy are a leading cause of maternal mortality and morbidity. According to the group studies of NHPBEB 2000 four entities are defined: Chronic Hypertension (CH) previous to pregnancy, Gestational Hypertension (GH), Preeclampsia/Eclampsia (PE/E) and superimposed Preeclampisa/Eclampsia in Chronic Hypertension (PE/E CH). All this entities have different outcomes and require adequate follow-up and specific attitude. OBJECTIVES: Review all cases of hypertensive disorders in a two-year period, its incidences, and related maternal and fetal complications. METHODS: In a retrospective study, from January 2008 to December 2009, all files related with hypertensive disorders, seen in our department, were reviewed. The statistic analysis was based on Excel 2007. RESULTS: The global incidence of hypertensive disorders was 3.8% (309 cases), with each entity with an incidence of: 40% in CH, 40% GH, 25% PE/E and 7% PE/E CH. In terms of demographic characteristics the majority of the population were caucasian (46%) and black (40%), the mean age was of 31years (minimum of 12-maximum of 47), and mainly previous Chronic Hypertension and endocrinologic disorders as co-morbidities (Diabetes Mellitus, obesity and thyroid pathology). The fetal/maternal complications were mainly preterm delivery (26.2%), with a low percentage of Abruptio Placentae (1%). Maternal complications were analysed in terms of ICU admissions of 7%, cardiovascular/renal disorders of 1% and maternal bleeding 1%. No maternal death was described. Fetal outcomes were also studied, specifically in terms of birth weight, with an average of 2794 (500-5480g), apgar index in 1st and 5th minute below seven in respectively, 14% and 3.5%. CONCLUSION: The incidence of maternal complications in our analysis was lower than described in literature. The incidence of preterm delivery was similar to that reported in other studies, mostly due to late pre-terms (>32w). PMID- 26105467 TI - PP146. Psychological assessment of renal transplant recipients during pregnancy. AB - INTRODUCTION: Although many centers have reported their experience on maternal and perinatal outcomes in renal transplant recipients. Very few information can be found about the psychological aspects that may rise for these patients during pregnancy. Considering the importance of the psychological concerns for this kind of patients, we have developed a protocol to better assist renal transplant recipients during pregnancy and here we show what we have learnt. OBJECTIVES: To understand how the maternal concerns are seen from renal transplant recipients in terms of psychological aspects. METHODS: Fifteen pregnant kidney transplanted women with an average age of 27.5years were included in the study. All patients have been investigated beyond the 20th week of pregnancy to delivery. The study is cross-sectional, qualitative, and participation is based on developed phenomenological method. Final data analysis will be done through thematic analysis and hermeneutics of meaning. The only exclusion criteria were the current presence of psychiatric disorders or use of drugs that could influence cognitive and emotional aspects during the psychological evaluation. RESULTS: During the last two years we have observed in these women that all of them are aware of the risks of pregnancy after transplantation. Qualitative aspects were: Pregnant with kidney transplantation show: in relation to pregnancy, the desire to be mothers, to give a son to her husband, to become a healthy person again; they believe that conception is God's will, they have fear of pregnancy, ambivalence of feelings (fear and happiness). In relation to the graft, they reported fear of baby malformations, fear and anguish of graft loss, still consider it worth the risk of having the baby, and some women name the graft, if it were another infant. In relation to delivery, state anxiety and anguish at the proximity of labor (fear of labor pain, anesthesia, cesarean section, vaginal delivery and the "psychic pain"). CONCLUSION: Pending the final results of this study, we still observed that these patients and their husbands require multidisciplinary monitoring since the beginning of pregnancy. Factors religious, cultural and psychic are involved in the desire to be mothers. PMID- 26105468 TI - PP147. Prevalence of hypertensive syndromes according to pregnancy age. AB - INTRODUCTION: The decision of a woman to get pregnant at later age of her reproductive cycle has be a phenomenon around the world. Epidemiology data show frequent increase of clinical complications in direct proportion in advanced age motherhood, hypertensive disturbances being more prevalent. OBJECTIVES: Analyse the prevalence of hypertensive syndromes in pre-determined age groups at Hospital Guilherme Alvaro in Santos, Sao Paulo, Brazil showing the different segments in each one. METHODS: From data collected in the outpatient department of Hospital Guilherme Alvaro of High Risk Pre-natal between 04/06/2008 and 30/05/2011, a prevalence transversal study was carried out where data were obtained from 628 patients aged between 16 and 46years. Procedures of homogeny analysts were set out, always collecting data such as age and disorder for high risk gestation. According to age, patients were divided into groups: precocious (up to 19years old), middle age (between 20 and 34) and late pregnancies (over 35). RESULTS: In the precocious pregnancies, clinical illnesses/no hypertension (31%) were observed in first place, 25% (8) twin pregnancy in second place, 19% (6) showed hypertensive disturbances. Concerning pregnancies between 20 and 34years old, 36% (144 patients) showed hypertensive syndromes, 23% (92 patients) showed endocrine disturbances, 22% (90 patients) showed clinical illnesses/no hypertension, and 9% twin pregnancy. Regarding late pregnancies, the most frequent disturbance was isolated hypertensive syndromes: 44% (88 patients) in first place, only endocrine disturbances, 24% (47 patients) in second place followed by association between hypertensive syndromes and endocrinopathy with 13% (26 patients). CONCLUSION: About precocious pregnancies, greater prevalence showed clinical illnesses/no hypertension, whereas middle age and late pregnancies showed greater hypertensive syndrome prevalence, results, which are compatible with other studies, have been observed that due to advance of age, hypertensive syndromes are more frequent. For late pregnancies, the prevalence of clinical illnesses/no hypertension was a lower percentage regarding the other two groups: precocious pregnancies (31%=10 women), middle age pregnancies (22%=90 women), and late pregnancies (2%=7 women). Considering the fact that the occurrence of pregnancy is more and more late in life, it can be concluded that the professionals must be prepared to attend pregnancies on women with hypertensive disturbances and their eventual complications. PMID- 26105469 TI - PP148. Is there podocyturia in pregnant women with chronic hypertension? (Preliminary results). PMID- 26105470 TI - PP149. Hypertensive risk factors: Do they influence pregnancy outcome in women affected by new onset pre-eclampsia? AB - INTRODUCTION: Pre-eclampsia (PE) is a leading cause of maternal and foetal mortality and morbidity. Chronic Hypertension (CH) and a previous PE are well known risk factors for PE. If the prevalence of PE in nulliparous is about 2%, it raise up to 7-10% in women with CH or a previous PE. However, the role of these risk factors when PE occurs is still under discussion OBJECTIVES: To detect if maternal history of previous PE and/or Chronic Hypertension (CH) is associated with a worse clinical outcome in women affected by PE. METHODS: Cohort study on 100 consecutive singleton pregnancies complicated by PE referred to our Department from January 2010 to December 2011. PE and CH were defined according to ISSHP criteria. Small for Gestational Age (SGA) was defined as Birth Weight under the 5th percentile per Gestational Age. Patients were divided into two groups depending on positive (Group A, n=25) or negative (Group B, n=75) history for PE and/or Chronic Hypertension (CH). Patients assessed to group A were under prophylactic therapy with ASA 100mg oid. Clinical and perinatal outcomes were reviewed. Adverse Pregnancy Outcome (APO) was defined as Apgar score less than seven at five minutes, pH<7.20; birth weight<5th percentile (SGA), stillbirth or neonatal death. RESULTS: Groups were comparable for Maternal Age (Group A: 34years median, IQR 30-36yy; Group B: 34years, IQD 28-36yy ) and BMI (Group A: 23.7Kg/mq median, IQR 20.8-27.1Kg/mq; Group B: 22.4Kg/mq median IQR 20.3 26.0Kg/mq). One case of stillbirth (Group A) and four cases of neonatal death were observed, 1/25 in Group A (4%) and 3/75 (4%) in Group B. No differences were found in Gestational Age (GA) at diagnosis of PE (Group A: 32+2w median, IQR 28+0 35+4w; Group B: 33+2w median, IQR 30+0-36+1w); GA at delivery (Group A: 34+1w median, IQR 31+5-36+5w; Group B: 34+2w median, IQR 32+0-36+3w) Birth Weight percentile (Group A: 6th percentile median, IQR 2-21th percentile; Group B: 5th percentile median, IQR 1-15th percentile), prevalence of Small for Gestational Age (14/25 and 42/75, for Group A and B respectively), prevalence of APO (13/25 and 44/75, for Group A and B respectively). CONCLUSION: Our data suggest that a positive history for PE and/or CH does not influence clinical outcome in women affected by PE. This result could be explained by the administration of prophylactic ASA 100mg oid in this group of patients. PMID- 26105471 TI - PP150. Pregnancy outcome in women with heart disease in a single tertiary care center. AB - INTRODUCTION: The number of women presenting with cardiac disease during pregnancy is increasing because more women with repaired congenital heart disease are reaching childbearing age and because of more pregnancies occurring in women with ischemic heart disease. Cardiac disease is the leading cause of indirect maternal mortality in the Netherlands. OBJECTIVES: Clinical data of pregnant women with heart disease that received obstetric care and delivered in our center have been obtained with the intention to evaluate the cardiac and obstetric pregnancy outcomes and to provide data for local counseling and management guidelines. METHODS: Data were collected from all pregnant women with congenital or acquired heart disease who delivered between 2000 and 2010 in the VU University Medical Center Amsterdam. At least one consultation of a cardiologist during pregnancy was advised. The maternal outcomes of these pregnancies were evaluated. RESULTS: Data of 122 women with 160 pregnancies were obtained. In this study the main heart diseases in pregnancy were congenital heart disease (n=75.61%) and arrhythmia (n=22.18%). Rheumatic heart disease was accountable for 6% (n=7) and ischemic heart disease for 4% (n=5) of inclusions. Based on the functional criteria of the New York Heart Association (NYHA), 114/122 patients (93.4%) were classified NYHA Class I-II. Patients in NYHA Class III-IV (n=8/122, 6.6%), mainly had a history of myocardial infarction or pulmonary hypertension. Of all the women, 35 had cardiac surgery before pregnancy, mainly repair of congenital heart disease. In women with acquired heart disease the interventions before pregnancy included permanent cardiac pace-maker implantation (n=2), radiofrequency catheter ablation (RFCA) (n=4) and percutaneous transluminal coronary angioplasty or coronary artery bypass graft (n=4). There were 156 singleton and 4 twin pregnancies. Termination of pregnancy was performed in 3 cases; 1 for maternal cardiac and 2 for obstetric indications. There were 156 life-births of which 100 (64.1%) were spontaneous vaginal deliveries, 17 (10.9%) operative vaginal deliveries and 39 (25%) cesarean sections: 9 for maternal cardiac indication and 30 for obstetric reasons. 36 (36%) women received epidural analgesia during labor and delivery. Cesarean section under general anesthesia was performed in 14 cases (7 for maternal cardiac indication); 25 were performed under spinal/epidural anesthesia. Induction of labour occurred in 48 pregnancies: 10 for maternal cardiac indications and 38 for other maternal and fetal indications. 28 (17.5%) pregnancies were complicated by hypertensive disorders. Cardiac complications such as heart failure developed in 15 (9.4%) pregnancies. There were two maternal deaths (1.6%). CONCLUSION: Congenital heart disease is the type of heart disease that has the highest incidence in pregnancy, while main types of heart disease that lead to impaired cardiac function during pregnancy are ischemic disease and pulmonary hypertension. Incidence of pregnancy induced hypertensive disorders is increased in women with preexistent cardiac disorders. Maternal outcome is generally favourable for women with cardiac heart in NYHA class I/II. PMID- 26105472 TI - PP151. Hypertensive complications in pregnancy - Two year study (2008-2009). AB - INTRODUCTION: Hypertension affects 10% of all pregnancies and accounts for approximately a quarter of all antenatal admissions. Hypertension in pregnancy includes a wide spectrum of conditions, including pre-eclampsia, eclampsia, pre eclampsia superimposed on chronic hypertension, chronic hypertension, and gestational hypertension. Pregnancies complicated by hypertension are associated with increased risk of adverse fetal, neonatal and maternal outcomes, including preterm birth, fetal growth restriction, perinatal death, acute renal or hepatic failure, ante partum haemorrhage, postpartum haemorrhage and maternal death. Overall pre-eclampsia complicates 5-6% of pregnancies and eclampsia complicates 1 2% of pre-eclamptic pregnancies. OBJECTIVES: Analysis of the maternal complications (incidence of ICU admissions, preeclampsia/eclampsia, renal or cardiovascular acute dysfunction, HELLP syndrome, placental abruption, maternal death) and fetal/neonatal outcome. METHODS: In a retrospective study, from January 2008 to December 2009, all files related with complications of hypertensive disorders, seen in our institution, were analysed. The statistic analysis was based on Excel 2007. RESULTS: Of 309 cases, 123 patients (40%) were found to have gestational hypertension while 121 (40%) suffer chronic hypertension. Ninety patients (29%) have preeclampsia or eclampsia (4 cases). 22 patients with chronic hypertension had a superimposed preeclampsia. Fetal growth restriction, HELLP syndrome and placental abruption were the obstetric complications in 4%, 1% and 1% of the cases, respectively. Additionally, multiple pregnancy and gestational diabetes were noted in 2.6% and 10.7% of the patients. Delivery route was vaginal in 90 patients while 68.9% underwent caesarean section. 6.5% of the patients were admitted to ICU and no woman has died. Preterm delivery occurred in 26.2% of the cases and 2 interruptions of pregnancy before 24weeks were performed due to maternal complications. Intrauterine fetal demise was recorded in 2 cases on admission. CONCLUSION: Women with hypertensive disorders of pregnancy are more likely to have received medical or obstetric interventions such as caesarean section operations. Pregnancies complicated by preeclampsia and eclampsia may be associated with life-threatening complications for both the mother and infant. PMID- 26105473 TI - PP152. Eclampsia concurrent with HELLP syndrome - A sixteen-year clinical experience in an academic medical center. AB - INTRODUCTION: Hypertensive disorders represent the most common complication among pregnant women, affecting 6-8% of gestations in the United States [1]. In Asia, There are many pregnant women die of eclampsia and severe preeclampsia. And 99% of these deaths occur in low income countries [2]. Eclampsia is defined as the occurrence of seizures in a woman with preeclampsia that cannot be attributed to other causes. HELLP syndrome represents a severe form of preeclampsia/eclampsia characterized by hemolysis, elevated liver enzymes, and low platelets [3]. The reported incidence of HELLP syndrome in association with eclampsia ranges from 10.8% to 32.1%. [4,5] And the incidence of eclampsia in association with HELLP syndrome ranges from 6% to 52% [6,7]. OBJECTIVES: The purpose of this study was to determine the characteristics of eclampsia concurrent with HELLP syndrome and maternal complications during the study period. METHODS: We retrospectively collected the data from the log book of our birth center between January 1994 and December 2010. There were 22 eclampsia patients concurrent with HELLP syndrome as compared with 46 patients with eclampsia and without HELLP syndrome. We analyzed the characteristics of 22 patients concurrent with HELLP syndrome and investigated the maternal complications, as well as fetal prognosis of them. Fisher exact test and Chi-square test were used in categorized variables. The univariate analysis of neonatal outcome was used to calculate the odds ratio and 95% confidence interval. RESULTS: The significant maternal outcome variables in patient with eclampsia concurrent with HELLP syndrome included the following: disseminated intravascular coagulation (DIC) (OR, 9.214, 95% confidence interval, 2.19-38.86, p=0.002); hypoxic encephalopathy (OR,3.467, 95% confidence interval, 1.03-11.68, p=0.045) multiple organ dysfunction syndrome (MODS)( OR, 30.83, 95% confidence interval, 7.35-129.37, p<0.001) would associate with the contributions to the maternal complications. CONCLUSION: The complexity of maternal complications was associated with eclampsia patient concurrent with HELLP syndrome. PMID- 26105474 TI - PP153. Noninvasive assessment of maternal hemodynamic function by electrical impedance cardiography (EIC) and correlation with uterine and umbilical vascular resistance in mid-pregnancy. AB - INTRODUCTION: Maternal vascular adaptation to pregnancy involves the coordinated augmentation of both systemic and uteroplacental circulations, with the concomitant development of a new fetoplacental circuit. Disturbances of maternal hemodynamic adaptation in early pregnancy are often associated with compromise in the other circulations, although the assessment of maternal vascular function by conventional means is cumbersome and expensive. OBJECTIVES: We sought to assess maternal hemodynamic function with a noninvasive cardiographic monitor, and to correlate the findings to both uteroplacental and fetoplacental vascular resistance. METHODS: We measured cardiac output and index (CO,CI), systemic vascular resistance (SVR), mean arterial pressure (MAP) and an index of contractility (ICON) with a novel electrical impedance cardiograph (Aesculon EIC System, Cardiotronic, USA) that provides a volume independent estimate of cyclical blood flow velocity. We enrolled high-risk subjects between 22 and 25weeks who were referred for assessment of fetal growth and uterine artery Dopplers due to abnormalities of serum screening analytes or other risk factors for preeclampsia. Doppler measurements of blood flow in the uterine arteries (pulsatility index, PI) and umbilical artery (systolic: diastolic ratio, S/D) were obtained by ultrasound (Voluson E8, GE Healthcare, Inc.), along with the fetal weight percentile (FW%). Data were expressed as medians (+/- range), and analyzed with Spearman's correlation coefficient, R. Statistical significance was set to p=0.05. RESULTS: Electrical impedance cardiography (EIC) data was collected from seventeen subjects. There were no measurement failures. The median gestational age was 24.3weeks and the BMI was 26.4 (21-47). The median PI, S/D and FW% were 0.96 (0.47-2.1), 3.3 (2.6-7.1), and 53% (6-82%). EIC results and their relationship to uterine and umbilical Dopplers and fetal growth are shown in Table 1. There were no significant correlations between maternal systemic hemodynamic parameters and uterine artery PI. On the other hand, maternal cardiac function was strongly related to the umbilical artery S/D ratio, and SVR was uniquely related to the FW%. CONCLUSION: Maternal systemic hemodynamics can be conveniently acquired by EIC at the same time as routine obstetrical imaging. Our data suggest that maternal cardiovascular adaptation more closely reflects the fetoplacental circulation than the uteroplacental circulation in women at moderate risk of preeclampsia. EIC may be a useful adjunct in assessing risk of fetal compromise. PMID- 26105475 TI - PP154. Relationship between recorded and reported snoring during pregnancy: Objective measurement versus questionnaire responses. AB - INTRODUCTION: Snoring is a common symptom of sleep disordered breathing (SDB), a condition that is present in 4% of the general population. SDB is identified by snoring and repetitive cessation of breathing during sleep accompanied by repetitive hypoxia and has been found to be associated with hypertension, stroke and heart attack. There is not depth of knowledge examining the association between SDB and pregnancy outcomes. OBJECTIVES: To examine the prevalence of self reported snoring in pregnancy and the potential association between self reported snoring and the development of Hypertensive Disorders of Pregnancy (HDP) within a larger cohort from a prevalence of SDB in pregnancy study. METHODS: Questionnaires were administered to pregnant women attending an outpatient's antenatal clinic. The self reported snoring is a component of the Epworth scale. Pregnancy progression and outcome data were collected on all participants and analyse by IBM SPSS v.20TM utilising Chi-square analysis, Student T test and logistic regression analysis. HDP diagnoses were in alignment with the SOMANZ (2009) diagnostic criteria. RESULTS: Questionnaires were administered and outcomes collected on 2023 pregnancies. Snoring was reported by 49.2% of women. HDP affected 10.1% of the cohort, 3.3% of whom were preeclamptic. Of the pregnancies affected by HDP self reported snoring occurred in 57.7% in comparison to 43.3% who do not report snoring (p<0.001). CONCLUSION: This would indicate that there is an association between self reported snoring and the development of HDP. Further analysis will be undertaken to model the effect of other potential risk factors such as maternal age, parity, pre-pregnancy BMI and other co morbidities. PMID- 26105476 TI - PP155. Relationship between overnight blood pressure and snoring during pregnancy. AB - INTRODUCTION: Snoring increases during the last trimester of pregnancy and is linked with both gestational hypertension and gestational diabetes. Previous studies have used questionnaires to determine the presence and severity of snoring. OBJECTIVES: The purpose of this study was to compare self- reported and objectively measured snoring in pregnancy. METHODS: We studied 154 pregnant women. The results from the "Do you snore?" question of the Berlin questionnaire was compared with objectively measured snoring obtained during an at-home SonoMatTM study (a thin mattress overlay with sensors that measure breath sounds, breathing movement, heart sounds and body movement). RESULTS: Ninety eight women (mean gestation 28+/-7 weeks) answered "Yes" to the question "Do you snore?"; 48 women answered "No"; and 8 women answered "I don't know". In the group who answered "Yes", recorded snoring average was 20+/-19% of the night; in the "No" group, recorded snoring was 13+/-22% and in the "I don't know" group snoring was recorded as 22+/-21%. There was a significant difference between the percentages of snoring recorded in women who answered "yes" compared to those who answered "no" (p=0.04) but no other differences between groups. CONCLUSION: Snoring is very common in pregnancy, but questionnaire results provide only an approximate estimate of the presence of snoring. Importantly, significant snoring was present in 24% of women who denied snoring, and a significant number of women who reported snoring had minimal objectively recorded snoring. Objective measurement of snoring is needed to determine whether snoring is present in pregnant women. PMID- 26105477 TI - PP156. High prevalence of pre-pregnancy overweight and obesity associated with maternal and perinatal complications. AB - INTRODUCTION: High prevalence of pre-pregnancy weight excess, as well as evidence of increased risk of maternal and perinatal complications associated with nutritional states have been observed lately. Considering the possible ethnic and environmental influences few studies have assessed this risk in pregnant Brazilian women. OBJECTIVES: This study aimed at determining the prevalence of pre-pregnancy weight excess (overweight and obesity) and its association with maternal and perinatal complications in a Brazilian women population. METHODS: We conducted a prospective cross-sectional study with 3,300 women who had birth care at the Asa Sul Regional Hospital of Brasilia - Federal District (FD), from October 2009 to May 2010. Nutritional status was determined by body mass index (BMI), according to WHO criteria (2000): Low weight (BMI<18.5kg/m(2)), Normal weight (BMI between 18.5 and 24.9kg/m(2)), Weight excess (BMI?25kg/m(2)), Overweight (BMI between 25 and 29.9kg/m(2)) and obesity (BMI?30kg/m(2)). The outcome variables were: pre-clinical complications such as chronic hypertension and diabetes, manifestation of gestational hypertension/preeclampsia, pregnancy duration and resolution as well as perinatal outcomes. The association among these variables was assessed using chi-square (Pearson) and Fisher's exact test. Results were considered significant when p<0.05. RESULTS: In this population, weight excess before pregnancy had a prevalence of 27.2%, being 19.7% and 7.5% of pregnant women presenting, respectively, overweight and obesity. The prevalence of normal weight was 64.6% and low weight was 8.3%. Comparing the weight excess (BMI?25kg/m(2)) group with the normal weight group it was observed predominant hypertension (23% vs. 10%) and diabetes (10.1% vs. 3.6%), prolonged pregnancy (14.4% vs. 10.7%) and cesarean section rate (58.1% vs. 47.2%) in the weight excess group. Newborn weight equal to or greater than 4,000 g (9.5% vs. 4.5%) as well as fetal macrosomia (14.6% vs. 7.4%) also predominated in weight excess group. The comparison among the groups normal weight, overweight and obesity showed predominance of hypertension, diabetes cesarean section rate, newborns weight and fetal macrosomia in the obesity group. CONCLUSION: In the population analyzed, the prevalence of pre-pregnancy weight excess, particularly obesity, was high and associated with maternal and perinatal complications. Weight excess pre-pregnancy should be considered a risk to the pregnancy, demanding different obstetric care. Efforts should be made so that, in the pre-pregnancy period, women's weight can be as close to the normal weight as possible. PMID- 26105478 TI - PP157. Risk of preeclampsia in pregnant women with gestational diabetes in Alberta. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) may increase a woman's risk of developing preeclampsia (PET), a hypertensive (HTN) disorder of pregnancy associated with increased maternal and fetal morbidity and mortality [1-4]. The reported magnitude of the association between GDM and PET varies from no association to triple the risk [1-4]. OBJECTIVES: The objectives of this study were: first, to determine the association between GDM and PET; and second, to assess other factors that influence PET in a large cohort of pregnant women in Alberta. METHODS: A retrospective population-based cohort study was performed using the Alberta Perinatal Health Program (APHP) database. The APHP is a provincial clinical registry focused on the health of infants and their mothers. Women between the ages of 14 and 54 without preexisting diabetes (DM) who delivered between 2000 and 2009, were included in the primary analysis. Women with preexisting DM were included in the secondary analyses. Logistic regression was used to examine the association between GDM and PET after adjusting for baseline characteristics. RESULTS: A total of 430,012 women were included. The mean age was 28.5 years old (SD 5.6) and 42.9% were nulliparous. GDM was reported in 3.7% of women. Overall, 1.3% had PET, which was significantly higher in the GDM group (2.7% vs 1.3%; P<0.01). The unadjusted odds ratio (OR) (with 95% CI) for GDM as a risk factor for PET was 2.1 (1.9, 2.4). After adjustment for potential confounders, the OR remained significant at 1.9 (1.7, 2.1). Other significant risk factors for PET were: weight>91kg (2.6; 2.4, 2.7), nulliparity (3.3; 3.1, 3.5), preexisting HTN (5.6; 4.9, 6.4), and chronic kidney disease (5.8; 4.1, 8.2). When GDM was compared with preexisting DM, the risk of PET with GDM of 1.9 (1.4, 2.1) was in between that associated with DM on diet (1.4; 1.0, 2.9) and DM on insulin (3.3; 2.7, 3.9). CONCLUSION: Women with GDM in Alberta have a significantly higher risk of developing PET. Assessment of glycemic status in pregnancy may provide clinicians with a simple tool to assess risk that may guide PET surveillance. PMID- 26105479 TI - PP158. Hypertensive disorders in pregnant women affected by type I diabetes. AB - INTRODUCTION: Type I diabetes in pregnancy is associated with an increased incidence of hypertensive disorders. OBJECTIVES: The aim of the present study was to evaluate the incidence of hypertensive disorders in pregnant women affected by type I diabetes and pregnancy outcome in women with and without hypertension. METHODS: One hundred seventy two pregnancies in 150 women affected by type I diabetes were assessed. Twelve pregnancies were excluded (8 because of spontaneous abortions, 1 for voluntary abortion and 3 twin pregnancies), and 160 pregnancies were considered for the study. RESULTS: Twenty-five pregnancies (15.6%) were complicated by hypertensive disorders: 4.4% by chronic hypertension (CH), 5% by gestational hypertension (GH), 4.4% by preeclampsia (PE) and 1.8% by preeclampsia superimposed on chronic hypertension (PE+CH); 32% of the women presented a vascular disease (renal or retinal disease). The diabetic women with hypertensive complications were compared with diabetic women without hypertension. The main results are shown in Table 1. Significant differences in mean birth weight and mean gestational age were found. The group affected by preeclampsia showed 14.7% of small for gestational age (SGA) neonates (birth weight percentile less than 10th pc), and 57.1% of large for gestational age (LGA) neonates (birth weight percentile greater than 90th pc), two of them were over 4000 g. Only one case of very preterm delivery (<32 weeks) was observed in the sample. CONCLUSION: As expected, the incidence of hypertensive disorders in population affected by type 1 diabetes is higher than in general population and a poor pregnancy outcome was observed in this group of women. However, the neonatal outcome of women affected by preeclampsia is not different from that observed in women without hypertensive complications (diabetic controls) in terms of mean birth weight despite a significantly lower mean week gestation at delivery. PMID- 26105480 TI - PP159. In women with previous pregnancy hypertension, cardiovascular risk biomarkers may be modulated by haptoglobin genotype. AB - INTRODUCTION: Preeclampsia may affect the risk for future cardiovascular disease. Haptoglobin (Hp), an acute phase protein with genetic polymorphism (Hp1.1, 2.1 and 2.2) synthesized in the hepatocyte and in many tissues, may modulate the risk through the antioxidant and anti-inflammatory differential effects of their genotypes. OBJECTIVES: Evaluate some parameters of cardiovascular risk in association with genetic polymorphism of Hp in women with previous preeclampsia (HBP) compared to healthy women during gestation (NBP). METHODS: We studied 352 women aged 35+/-5.48 current year, taking these, 165 presented previous preeclampsia, 2-14 (+/-6.6) years ago. Genetic polymorphism of Hp was determined from plasma by electrophoresis. The different circulating biomarkers, myeloperoxidase ng/mL (MPO) and nitrates and nitrites (nmol/ml) by ELISA, transaminases - AST and ALT (U/L) and apolipoprotein A and B (mg/dL), uric acid (mg/dl) hs-CRP (mg/L) were determined by conventional methods as well as blood pressure (BP) and anthropometric parameters BMI and hip and waist circumference (WC).Statistical methods were Chi-square, ANOVA (Bonferroni) and t-Student. RESULTS: There were no differences in the distribution of phenotypes of Hp between NBP and those with previous hypertension in pregnancy. There were differences between NBP and HBP in the following parameters: Systolic BP (118.9+/ 13.4 vs 135.0+/-16.5, p<0.001); Diastolic BP (72.2+/-10.1 vs 85.9+/-12.0 p<0.001); MPO (62.3+/-30.9 vs 85.7+/-39.4, p=0.020); Nitrite (10.1+/-3.8 vs 19.1+/-7.0, p<0.001); ALT (18.0+/-8.0 vs 22.5+/-12.9, p=0.016); BMI (25.4+/-4.1 vs 27.1+/-4.8, p=0.031); WC (82.8+/-9.9 vs 89.5+/-15.6, p=0.002); Apo B (0.6+/ 0.1 vs 0.6+/-0.1, p=0.023). Those values vary with the genotypes of Hp and were observed Hp 1.1 and 2.1 in NBP and HBP respectively: [Systolic BP 119.2+/-13.7 vs 134.7+/-18.3 (p<0.001); Diastolic BP (72.8+/-11.9 vs 86.2+/-19.4 p<0.001); MPO (57.9+/-32.5 vs 94.2+/-42.1, p=0.008); Nitrites (9.6+/-3.2 vs 20.0+/-8.5, p<0.001); ALT(17.0+/-7.2 vs 20.4+/-8.0, p=0.033); WC (82.4+/-10.0 vs 90.8+/-17.6, p=0.004); Apo A (0.9+/-0.2 vs 1.0+/-0.2, p=0.011)] and Hp 2.2 in NBP and HBP respectively: [Systolic BP 118.2+/-13.1 vs 135.6+/-12.8 (p<0.001); Diastolic BP (70.9+/-7.2 vs 85.5+/-16.3 p<0.001); Nitrites (11.5+/-5.1 vs 18.0+/-4.4, p<0.001)]. CONCLUSION: Women with previous hypertension during pregnancy, presented significant differences in some classic cardiovascular risk biomarkers as well as in some others, associated with the inflammatory process, whose variation may be modulated by haptoglobin functional genetic polymorphism. The history of hypertensive disease in pregnancy may be relevant, in association with these biomarkers to the prevention of cardiovascular disease in particular of postmenopausal women. PMID- 26105481 TI - PP160. Endothelial dysfunction with obesity, pregnancy and preeclampsia. AB - INTRODUCTION: Preeclampsia, a pregnancy specific syndrome diagnosed clinically by new onset hypertension and proteinuria after twenty weeks of gestation, is a leading cause of maternal and fetal morbidity and mortality worldwide. The pathogenesis of preeclampsia is unknown but it is associated with a number of risk factors including past history of preeclampsia, diabetes, multiple pregnancies and obesity. The relationship between obesity and preeclampsia is not yet clear but endothelial dysfunction is implicated in both disorders. However, to date no studies have evaluated endothelial dysfunction in the presence of both obesity and preeclampsia. sE-selectin, a specific marker of endothelial dysfunction, has been shown to be increased in obese individuals and preeclamptic patients. We examined the relationship between concentrations of sE-selectin with respect to preeclampsia status (preeclampsia/no preeclampsia), BMI (obese/lean) and delivery status (preterm/term). OBJECTIVES: We hypothesized that endothelial dysfunction, as indicated by increased concentrations of sE-selectin, would be increased in obese patients. This increase would help to explain obesity as a risk factor in preeclampsia. METHODS: This was a retrospective case-control study of 91 Caucasian women enrolled in an ongoing investigation of preeclampsia at Magee-Womens Hospital. The women were grouped as preeclampsia lean preterms (n=14), control lean preterms (n=14), preeclampsia lean terms (n=10), control lean terms (n=7), preeclampsia obese preterms (n=9), control obese preterms (n=8), preeclampsia obese terms (n=14) and control obese terms (n=15). Preterm status was defined as delivery less than 37 weeks. Obese patients were defined as having a BMI >30 and lean patients were defined as having a BMI?18.5 but ?24. Controls were matched on race, gestational age of sample +/-2 weeks and age of mother +/-3 years. Serum samples were collected longitudinally across pregnancy from as early as 4weeks gestation through to 48h postpartum, and stored at -70 degrees C until assayed. sE-selectin concentrations were measured using an enzyme-linked immunosorbent assay, purchased from R&D Systems immunoassay. RESULTS: We conducted univariate comparison for subjects with and without preeclampsia, BMI and preterm birth, using a t-test and Wilcoxon/Krushal-Wallis test and linear regression to evaluate the association of sE-selectin and other factors. sE-selectin was higher in women with preeclampsia (p<0.05). Furthermore, lean preterm preeclamptics had higher sE-selectin concentrations than obese preterm preeclamptics (p=0.04), otherwise there was no effect of BMI. All the analyses were performed using SAS 9.2 (SAS Institute, Cary, NC) at a significance level of 0.05. CONCLUSION: sE-selectin is increased in preeclampsia but is not increased with obesity. Underlying endothelial dysfunction as defined by increased sE-selectin does not provide an explanation for obesity as a risk factor for preeclampsia. PMID- 26105482 TI - PP161. Association of maternal vitamin D and placenta growth factor with early onset severe preeclampsia. AB - INTRODUCTION: Decreased maternal 25-hydroxy vitamin D (25-OH-D) and placenta growth factor (PlGF) have both been associated with the diagnosis of early-onset severe preeclampsia (EOSPE). Prior investigations have identified these biomarkers to be decreased at the time of diagnosis of preeclampsia and prior to the onset of clinical diagnosis of preeclampsia. OBJECTIVES: This investigation aimed to define the association of these biomarkers with EOSPE. This will yield information concerning possible potential for these biomarkers to be used in diagnosis of preeclampsia. METHODS: Patients with EOSPE and healthy controls were recruited and demographics, outcomes, and plasma were collected at matched gestational age. 25-OH-D was assessed by radioimmunoassay and reported in ng/mL. PlGF was assessed by ELISA and reported in pg/mL. Receiver operator curves were constructed for each regression model and sensitivity and specificity were reported for each biomarker. RESULTS: In EOSPE, both 25-OH-D and PlGF were decreased significantly compared to controls. The combination of age, race, and PlGF or 25-OH-D performed well in discrimination of EOSPE and controls. The logistic regression model using both PlGF and 25-OH-D is shown below: CONCLUSION: PlGF and 25-OH-D are sensitive and specific markers for diagnosis of EOSPE. However, PlGF provided a higher sensitivity and specificity for EOSPE diagnosis. PMID- 26105483 TI - PP162. sFlt-1 controlled by CPAP in a pregnant patient with chronic hypertension. AB - INTRODUCTION: Preeclampsia is recognised as the leading cause of perinatal mortality and morbidity worldwide. Interest has been increasing recently as to the possible impact of sleep disordered breathing (SDB) on the mechanisms of preeclampsia, possibly by augmenting placental hypoxia during sleep. A biomarker of preeclampsia, sFlt-1, has also come to prominence in recent years and is postulated to be a good predictor of preeclampsia as well as a strong indicator of the severity of the disease. OBJECTIVES: The aim of this study was to investigate the effect of CPAP treatment for SDB on sFlt-1 concentrations during pregnancy. METHODS: Patients were recruited from the outpatients' clinic in Campbelltown Hospital, Campbelltown, NSW in the first half of 2011. The levels of sFlt-1 in four pregnant women, with or without hypertensive disorders of pregnancy, and with or without SDB were measured using ELISA. RESULTS: Women with SDB and chronic hypertension or preeclampsia had higher levels of sFlt-1 and a greater percentage increase of this marker, and CPAP treatment appeared to attenuate the rise of sFlt-1 as shown in the table below. CONCLUSION: Elevated sFlt-1 was associated with untreated SDB in those with chronic hypertension. This study provides feasibility for a larger scale study to occur, to further examine the validity of the hypothesis that CPAP treatment has a beneficial effect on sFLt-1 levels and therefore, may lower the risk and severity of preeclampsia. PMID- 26105484 TI - PP163. Are we using magnesium sulphate excessively for preeclamptic patients? AB - INTRODUCTION: There is now evidence that magnesium sulfate can prevent and control eclamptic seizures. For women with pre-eclampsia, magnesium sulfate reduces by more than one half the risk of eclampsia. After Magpie Trial [1] our clinical practice has been modified in terms of more liberal use of MgSO4, but the evidence regarding the benefit-to-risk ratio of MgSO4 prophylaxis in mild preeclampsia remains uncertain [2]. Thus we consider important to evaluate whether there are specific characteristics between patients who received the medicine that might signal risk and justify our decisions. OBJECTIVES: To identify in a group of hypertensive patients who used magnesium sulfate, clinical and/or laboratory characteristics that can be defined as specific risk factors and be useful to base clinical decisions. METHODS: The study was conducted at the Maternity School of Vila Nova Cachoeirinha, a public institution located in the north of the city of Sao Paulo (Baazil) between 01/07 and 31/12/2011. This is a retrospective study of a series of 103 pregnant women with hypertensive disorders, defined according to NHBPEP. We excluded patients admitted in labor. Patients were assigned into two groups according to the use of MgSO4. We compared clinical and laboratory characteristics between the two groups. RESULTS: Of 103 patients included, 31 (30.1%) received MgSO4. Among the outcomes analyzed, there were significant differences in the group that received MgSO4 in terms of blood pressure equal to or greater than 110mmHg, clinical symptoms (eg headache and visual disturbance) and at least some evidence of organ dysfunction (hepatic, renal, haematologic, or central nervous system) (Table 1). Table 1. Variables associated with theuse of magnesium sulfate. CONCLUSION: We can say that in our institution over the years was an increase in the use of magnesium sulfate. Our results support the hypothesis that about one in three patients treated at this institution receive the medication. Although our protocol admits that the decision may be based on subjective criteria, we identified some objective characteristics that supported their application, and that these criteria do not differ from the classic recommendations. We can also conclude that in our clinical experience we do not have identified a clear justification for support the routinely use of magnesium sulphate for all women with preeclampsia. PMID- 26105485 TI - PP164. Magnesium sulphate for prevention and treatment of eclampsia in low and middle income countries: Systematic review of tested regimens. AB - INTRODUCTION: Magnesium sulphate (MgSO4) is regarded as the most effective prophylactic and therapeutic agent for eclampsia. Although well studied and widely used in high income countries (HICs), MgSO4 is under utilized in low and middle income countries (LMICs) due to many factors including lack of adequately trained health care providers, supplies for administration, or the MgSO4 itself, in addition to fear of potential adverse effects. OBJECTIVES: To systematically review the dosing and effectiveness of MgSO4 regimens administered in LMICs to women with pre-eclampsia or eclampsia. METHODS: We searched Medline, EMBASE, IPA, CINAHL, CDSR and CENTRAL databases for English language randomized controlled trials (RCT) and observational studies of MgSO4 regimens administered in LMICs to women with pre-eclampsia or eclampsia. Two authors independently reviewed search results and extracted relevant data from eligible studies. No quality assessment was performed. RESULTS: Twenty two papers (7 RCT and 15 observational studies) from 12 LMIC met our inclusion criteria, of which 21 were conducted in hospital settings. Two studied MgSO4 for eclampsia prevention ,14 for eclampsia treatment and 6 studied MgSO4 for both. In 20 studies, both loading and maintenance MgSO4 dosing was administered, with intravenous (IV) or combined IV and intramuscular (IM) loading doses of 4-15g and IV or IM maintenance doses up to 2g/h. Five studies used only the IV route of administration, while the remainder coupled IV with IM administration. All studies were effective at preventing the initiation and/or recurrence of eclamptic seizures. One study of 265 women with eclampsia found that MgSO4 loading dose administration in the community (4g IV over 20min plus 3g IM in each buttock) before referral and administration of maintenance therapy in hospital was more effective in decreasing recurrent eclampsia compared with the standard practice of referral to hospital where the initial dose of MgSO4 was administered [RR of 0.23, 95% CI 0.11, 0.49]. The two studies of 4g IV plus 10g IM loading dose-only regimens did not show a significant reduction in eclamptic seizures compared with identical loading dose plus 5g/4h IM maintenance dose regimens [RR of 1.38, 95% CI of 0.23, 8.45]. However the combined sample size was small (N=180 women). CONCLUSION: In LMICs, most studies of MgSO4 for pre eclampsia or eclampsia were conducted in high level health care facilities and administered MgSO4 by the IV route, at least in part. The one study of community administration of a MgSO4 loading dose showed this approach to be effective. There are limited data to support loading dose-only regimens. PMID- 26105486 TI - PP165. Treatment approaches for preeclampsia: A sample from a big city of a developing country. AB - INTRODUCTION: Preeclampsia is a major cause of maternal morbidity and mortality worldwide, mainly in developing countries. Here we show an example of how is the clinical condition of these patients when they are referred from first care units to a tertiary care teaching maternity in the city of Sao Paulo, Brazil. OBJECTIVES: To evaluate how has been the approach for preeclamptic women in a big city of Brazil, an example of developing country. METHODS: This is a retrospective study that evaluated 41 patients that were referred to our hospital from August 2010 to December 2011. In most of the cases patients were referred due to elevations in blood pressure. The diagnosis of preeclampsia was based on the ISSHP recommendations. The diagnosis of severe preeclampsia was based either on clinical symptoms and/or laboratory parameters. Fetal distress was defined when Doppler velocimetry assessment demonstrated abnormal parameters (centralization with abnormal diastolic blood flow at umbilical arteries). RESULTS: Severe preeclampsia was diagnosed in 26 cases (63.4%) and 34 patients were treated with magnesium sulfate (82.9%). One case of eclampsia (2.4%) and five cases of "Abruptio Placentae" (12.1%) were registered. Fetal distress was diagnosed at the moment of admission in 13 cases (31.7%) and two of these fetuses ended in stillbirth (4.8%). Neonatal death occurred in three cases (7.3%), mainly due to extreme preterm delivery. Other outcomes are reported in the following table. ICU: Intensive Care Unit. CONCLUSION: This is a good example of how has been the approach of preeclamptic women in a big city of Brazil. Our results suggest that a special concern about the moment of referring these patients to tertiary care units should be taken by doctors at first care units. PMID- 26105487 TI - PP166. HELLP syndrome: Challenges for establishing diagnostic criteria. AB - INTRODUCTION: Preeclampsia is a public health problem which may manifest as pre eclampsia (hypertension, proteinuria and/or edema) and eclampsia (convulsive crises and rarely coma in pregnant women with previous pre-eclampsia). But the pathology of hypertensive disease of pregnancy can present different clinical forms. Within that spectrum is HELLP syndrome: hemolysis (H), elevated liver enzymes (EL) and thrombocytopenia (LP). OBJECTIVES: To assess the diagnostic criteria in the literature adopted for HELLP syndrome. METHODS: A literature review on the Virtual Health Library with the keywords "HELLP syndrome" and "diagnosis" found 674 citations. Six hundred and thirty-four dismissed for failing to engage with the proposed question, and 43 articles remained. Twenty seven articles were excluded because of the language, unable in Latin America, letters, case report and articles published prior to 1999. Sixteen original articles were included. Eleven reviews, one prospective study, two cohorts, one retrospective cohort study and a cross. Studies were classified according to degree of recommendation and level of evidence. RESULTS: The term clinical and laboratory markers were varied and their cut-off levels differ among the authors. The appearance of eclampsia, pain in the upper abdomen, nausea and significant proteinuria and other maternal morbidities were more frequent in patients with HELLP syndrome. The levels of lactic dehydrogenase, AST, and uric acid were further elevated in women with HELLP syndrome guarding correlation with the prognosis of the case. There is no consensus for the interpretation of laboratory values that may represent the most widespread occurrence of parameters: hemolytic anemia, elevated liver enzymes and thrombocytopenia. Other morbidities may have clinical signs, symptoms and laboratory abnormalities that mimic the syndrome. CONCLUSION: There are many questions to establish standard diagnostic criteria for all patients with HELLP syndrome, necessitating studies consistent with significant population numbers to establish the main signs and symptoms and try to reach consensus on the best markers for the diagnosis and its proper indexes cutting. PMID- 26105488 TI - PP167. A process evaluation of an innovative implementation strategy of the Dutch guidelines on hypertensive disorders in pregnancy using a computerized decision support system. AB - INTRODUCTION: Hypertensive disorders in pregnancy remain the leading cause of maternal mortality in the Netherlands. The Dutch Society of Obstetrics and Gynecology (NVOG) has developed evidence-based guidelines on the management of hypertension in pregnancy. Previous studies showed a low adherence rate to other NVOG guidelines and a large variation in usual care in different hospitals. In the BIG CHANGE trial an innovative implementation strategy of the NVOG guidelines on hypertension using a web-based application (BOS, by Giant Soft, Leeuwarden, The Netherlands) was compared to a common strategy of professional audit and feedback. In this study a process evaluation of BOS has been done, analyzing its efficiency, barriers and formulate improvement points. OBJECTIVES: Gynecologists, residents and clinical midwives from seven hospitals using BOS were asked to fill in the questionnaire. METHODS: A questionnaire was developed on the following items: efficiency, barriers and improvement. RESULTS: Thirty four completed questionnaires useful for analysis. 63.6% of the respondent also consulted the NVOG guideline or local protocol, mainly for confirmation of information, background information, medication. Technical problems were found in 44.1%. Positive opinions on user friendliness varied from 73.5% to 100%. No significant difference was found between the user frequency of BOS compared to the NVOG guidelines or local protocol, or between the time needed to consult them. Improvements mentioned by the respondents were mainly regarding the lay-out. Most respondents (85.3%) found it useful to make a computer based support system for other guidelines and 79.4% would also use this. CONCLUSION: BOS is regarded suitable as an instrument for implementing guidelines and respondents find it useful to develop it for other guidelines as well. Technical problems and poor implementation are important areas of improvement. PMID- 26105489 TI - PP168. The role of calcium supplementation in prevention endothelial cell activation, and possible relevance to preeclampsia. AB - INTRODUCTION: Preeclampsia remains a leading causing of maternal and perinatal mortality and morbidity. Preeclampsia is currently thought to be primarily a disease of endothelial activation and inflammation. OBJECTIVES: The deportation of trophoblast debris form the placenta was first linked to the pathogenesis of preeclampsia over a hundred years ago and it is hypothesised that deportation of necrotic trophoblast debris may contribute to maternal endothelial cell activation in preeclampsia. We have previously shown that treating placental explants with IL-6 results in shedding of more necrotic trophoblast debris from placental explants and that this debris when phagocytosed by endothelial cells results in activation of the endothelial cells. Although delivery remains the only definitive cure for preeclampsia a number of studies suggest that calcium supplementation may reduce the risk of developing preeclampsia by up to 50% but the protective mechanism of calcium supplementation is unclear. The aim of this work was to determine whether calcium supplementation affects either the production of necrotic trophoblast debris from the placenta or influences endothelial cell activation. METHODS: First trimester placental explants were cultured with IL-6 in the presence or absence of increasing concentrations of calcium (CaCl2) for 24h. Trophoblastic debris was collected from the explants and then exposed to monolayers of endothelial cell for 24h and endothelial cell activation measured by ICAM-1 ELISA. In other experiments, endothelial cells were treated with IL-6 or necrotic trophoblastic debris in the presence of increasing concentrations of CaCl2, ranging from 230MUg/mL to 700MUg/mL, for 24h. In some experiments, ebdothelial cells were treated with low concentration of CaCl2, ranging from 0MUg/mL to 230MUg/mL for 24h. Endothelial cell activation was measured by quantifying cell-surface ICAM-1 levels by ELISA. RESULTS: CONCLUSION: Our results demonstrate that calcium levels are important to endothelial cell activation and supplemental calcium may reverse the activation of the endothelium induced by proinflammatory mediators while having no effect on the production of trophoblast debris. These results may in part help to explain the benefits of calcium supplementation in the reduction of risk for developing preeclampsia. PMID- 26105490 TI - PP169. Management of fetal and maternal prognosis during severe toxemia. AB - INTRODUCTION: Severe gravidic toxemia gives heavy maternal and fetal morbidity and mortality. OBJECTIVES: The purpose of our data is to identify bad maternal and fetal factors during severe toxemia and the outcome of pregnancy. METHODS: It is a retrospective and comparative study about 200 cases of severe toxemia reported during 8 years 2004-2011 among 25,000 deliveries (control group). Toxemia is considered severe when blood pressure?160/100mHg, proteinuria ?2g/l, bad neurosensorial signs, hemostasis disorders, kidney and liver failure, some fetal tests: delay intra-uterine growth acute fetal suffering, fetal death. RESULTS: Frequency of severe toxemia 80/00, primiparous 58% vs. 35% control, gestational diabetes 12% vs. 10% control, oedema 87% vs. 45% control. Maternal morbidity is dominated by hemostasis disorders: low platelet count<80,000 23% vs. 8%, hypofibrinogenemia <4g/l 13% vs. 2%, HELLP syndrome eight cases vs. 0. We raised eight cases of eclampsia crises, 22 cases of retroplacental hematoma vs. 10 control. Blood transfusion 15% vs. 10% control, inhibitors of VII factor administered in two cases vs. 0. We do not deplore any maternal mortality. Fetal prognosis is very compromised ,the delay intra uterine growth 44% vs. 18% control, prematurity 66% vs. 15% control, perinatal mortality 600/00 vs 120/00 control CONCLUSION: More toxemia appears early during pregnancy more maternal and especially fetal prognosis is compromised. New drugs, predictive tests and preventives measurements improve maternal outcome better than fetals' one. PMID- 26105491 TI - PP170. Prenatal vitamin C and E supplementation is associated with a reduction in placental abruption and preterm birth in smokers. AB - INTRODUCTION: Maternal tobacco use increases the incidence of numerous adverse pregnancy outcomes including miscarriage, small for gestational age infants, spontaneous preterm birth and placental abruption. OBJECTIVES: We evaluated the relationship between prenatal vitamin C/E supplementation and perinatal outcomes by maternal smoking status. METHODS: Secondary analysis of a multicenter trial of vitamin C/E starting at 9-16 weeks in low-risk nulliparous women with singletons. We examined the effect of vitamin supplementation by reported smoker or non smoker at time of randomization. The primary outcomes were preeclampsia (new onset hypertension and proteinuria) and a composite outcome of severe pregnancy associated hypertension (severe hypertension OR mild or severe hypertension with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclamptic seizure, fetal growth restriction, medically indicated preterm birth or perinatal death). Perinatal outcomes included preterm birth and abruption. The Breslow-Day test was used to ascertain whether there was an interaction between smoking status and vitamin supplementation. RESULTS: Of 9969 women, 4993 received vitamins C/E and 4976 received placebo. The prevalence of smoking (15.6% overall; 788 vitamin, 763 placebo) was similar in treatment groups. The analysis of vitamin C/E by smoking status for perinatal outcomes is given (Table 1). The effect of prenatal vitamin C/E on the risk preeclampsia or pregnancy associated hypertension composite outcome did not differ by smoking status. Vitamin C/E was protective for placental abruption and preterm birth among smokers. CONCLUSION: The effect of vitamin C/E supplementation on preeclampsia/pregnancy associated hypertension did not differ by smoking status. However, vitamin C/E supplementation was associated with a >40% reduction in placental abruption and >30% reduction in preterm birth among smokers warranting further study. ACKNOWLEDGEMENT: This project supported in part by National Institutes of Health Grant PO1-HD30367. PMID- 26105492 TI - PP171. Hospitalized preterm mild preeclamptics: Is there a difference in outcomes between isolated or superimposed disease? AB - INTRODUCTION: Currently the standard of care is to admit and monitor patients with preterm mild preeclampsia. This is particularly important if the disease is superimposed in patients with chpt or with isolated disease if proteinuria is over 500mg in 24hours. Despite the common nature of this disease process little is known about the outcomes of these two groups. OBJECTIVES: The objective of this project is to compare the maternal and neonatal outcomes of patients hospitalized with isolated mild preterm preeclampsia to those with preterm superimposed preeclampsia. METHODS: All patients admitted between 1/2008 and 12/2011 that were expectantly managed with either mild isolated preterm preeclampsia or chpt with mild superimposed preeclampsia at our tertiary center were evaluated for inclusion in this retrospective cohort study. This study was IRB approved. To be included in the study a patient must have singleton gestation, no overt diabetes, no major chronic medical conditions, no major obstetrical complications, no congenital anomaly, or planned delivery before 37weeks. Patients with the following maternal complications were excluded: lupus, renal disease, and cardiac disease. Patients with the following obstetrical complications were excluded: multiple gestations, preterm labor, placenta previa, and preterm PROM. Mild preeclampsia and chpt were diagnosed using ACOG criteria. Patients were not included if they had severe disease being treated expectantly. Patients that met inclusion criteria were divided into two groups based on the presence of chpt. All patients were admitted to labor and delivery, treated with corticosteroids if indicated and were managed as inpatients until delivery. All patients had an ultrasound on admission, frequent laboratory evaluations, and daily antepartum testing. Outcomes of interest included latency period in days, incidence of IUGR, incidence of abruption, indication for delivery, maternal complications as well as neonatal morbidity and mortality. RESULTS: To date, we have identified 115 patients that met inclusion criteria and were included in this ongoing study. Fifty nine had isolated mild preeclampsia and 56 patients had chronic hypertension with superimposed preeclampsia. The following table compares the results of the two groups. Differences between the groups included age (24 vs. 30yrs, p<0.01), race with more whites having preeclampsia and more blacks having superimposed disease, days in hospital were longer in the superimposed group (9 vs. 13days, p<0.01) despite there being no significant difference in the latency period (6 vs. 9days, p=0.35). More superimposed patients developed pulmonary edema, (0% vs. 7%, p=0.05). A trend for increased abruptions was seen in the isolated group (9% vs. 0%, p=0.06). Vaginal delivery was more common in the preeclamptic group and repeat section more common in the superimposed group. No differences in neonatal outcomes were seen. CONCLUSION: Patients with preeclampsia were more likely younger, white and delivered vaginally when compared to patients with superimposed disease. While the superimposed patients were more likely older, black, had more pulmonary edema, were more likely treated with antihypertensives both antenatally and postpartum and were delivered by repeat section than patients with isolated disease. Neonatal outcomes were similar between the groups. PMID- 26105493 TI - PP172. Indian scenario of preeclampsia and its consequences and early prophylaxis. AB - INTRODUCTION: Preeclampsia remains one of the major obstetrical problems in less developed countries. The causes of this condition are still unknown, we have designed a prevention protocol with new concept to describe the etiology and cause of preeclampsia. OBJECTIVES: To study the effectiveness of the Jariwala's therapy and etiological causes of preeclapsia. we want to establish the new version of efficient prophylactic management to prevent the concequences of preeclampsia. METHODS: We have selected 800 cases who have developed preeclampsia during any phase of pregnancy and tried to prevent the developing preeclampsia (predicted with roll over test, color doppler and weight gain and or edema) by Jariwala's protocol. our aim is to reduce the severity of disease process by early prediction and treatment. we have not included the cases who may have completely treated after the inclusion criteria to predict the preclampsia and treated. the inclusion criteris is strictly followed by a protocol designed. RESULTS: Jariwala's therapy is effective in mild to moderate cases of preeclampsia. Till date we have successfully treated 800 cases of mild to moderate preeclapsia with 98% neonates delivered with birth weight of 2kg and more, 92% neonates sent directly to home without any complication; and developed well at home. CONCLUSION: If we try to treat the blood pressure (during pregnancy) by anti hypertensive we have noticeda IUGR and rebound increase of blood pressure, means decrease maternal blood pressure a decrease placental supplya deficient nutrienta rebound increase in toxin secretion (by fetus and placenta) a increase in blood pressure to supply more nutrient). So that it is my suggestion that the antihypertensive should be avoided if possible 2: increase permeability of placental membranes due to toxins secreted by fetus to supply more nutrient leads to increase permeability of placental membranes means increase protein loss from kidneys (due to toxins secreted from the fetus and placenta) increase third space leakage of fluid as nutrient leads to serum protein deficiency and increase permeability of endovascularities of all organs multi system disorder. so instead of treating the developing preeclampsia with routine treatment either terminate the pregnancy if it is severe and developing intensely or treat with the Jariwala's protocol. PMID- 26105494 TI - PP173. The role of mean artery blood pressure in the prediction of pre-eclampsia in pregnancies complicated with chronic hypertension. AB - INTRODUCTION: Chronic hypertension (CH) is a common disorder occurring in approximately 1-5% of pregnant women. Many studies emphasize that the development of superimposed preeclampsia (PE) is associated with high rates of adverse pregnancy outcome. Accurate prediction of women at risk for PE is crucial to judicious allocation of monitoring resources and use of preventive treatment, in order to improve maternal and neonatal outcome. Recent systematic review and meta analysis showed that mean arterial pressure (MAP) is a better predictor for pre eclampsia than systolic blood pressure and diastolic blood pressure OBJECTIVES: To detect the value of MAP in the first and second trimesters to predict PE in women with CH. To determine if MAP, assessed in the second trimester, can increase the predictive value for PE of II trimester UtA PI. METHODS: Cohort study on 100 consecutive singleton pregnancies complicated with CH referred to our Department from January 2008 to June 2011. Blood pressure was measured by a mercury sphygmomanometer at 11-14+6w and 23+0-25+6w, MAP was calculated. Doppler velocimetry was performed at 23+0-25+6w, mean UtA PI was calculated. PE and CH were defined according to ISSHP criteria. Clinical and perinatal outcomes were reviewed. Receiver-operating characteristic (ROC) curves were used to determine the predictive ability of I and II trimesters MAP and II trimester mean UtA PI for subsequent development of PE. Logistic regression analysis was run to assess the additional value of II trimester MAP to II trimester UtA PI. RESULTS: Mean maternal age was 36 years (SD +/-5yy); mean Body mass Index was 24Kg/mq (SD +/ 5Kg/mq); GA at I Trimester evaluation was 11+4w (SD +/-1+5w); I trimester MAP was 100.46mmHg (mean, SD +/-9.94mmHg); GA at Doppler and II trimester MAP was 24+4w (SD +/-4dd); II trimester MAP 97.53mmHg (mean, SD +/-10.27mmHg). Nineteen cases of PE were observed. Seventy patients were under prophylactic ASA 100mg oid. Fifty-two patients were under anti-hypertensive therapy from the first trimester. No differences in prevalence of PE were observed between patients in and out prophylactic treatment, as well as no differences in prevalence of PE were observed between patients under anti-hypertensive treatment or not. The prediction of subsequent development of PE, expressed as the area under ROC curve, was 0.469 (95% CI 0.34-0.59) for I trimester MAP; 0.659 (95% CI 0.55-0.76) for II trimester MAP; 0.748 (95% CI 0.65-0.83) for II trimester mean UtA PI; GA at delivery was 37+4w(mean, SD +/-3+2w); mean BW was 2958g (SD +/-735g); BW percentile was 38 (mean SD +/-29 percentiles); mean BW z-Score was -0.63 (SD +/ 1.6). Logistic regression analysis showed that MAP does not increase the predictive ability of II trimester UtA PI in women with CH. CONCLUSION: In our findings, MAP seems not to be a good predictor for subsequent development of PE in women with CH, moreover, it seems to be not useful to increase the predictive value for PE of II trimester UtA PI. II trimester UtA PI has been confirmed to be the best predictor for subsequent development of PE. PMID- 26105495 TI - PP174. Timely prediction of maternal complications in pre-eclampsia analysis of the fullPIERS model. PMID- 26105496 TI - PP175. Gestational hypertensive syndromes: Risk factors identification and complications in a primiparous population. AB - INTRODUCTION: Preeclampsia is a major cause of maternal and perinatal morbidity and mortality in Brazil and worldwide. It is a heterogeneous and multifactorial disorder, with no clear etiology and pathophysiology. The identification of risk factors for its development may help in prevention and early diagnosis of disease clinical onset. OBJECTIVES: To identify risk factors and complications of pre eclampsia (PE) and gestational hypertension (GH) in a population of primiparas, who had birth care at the Ceilandia Regional Hospital of Brasilia - Federal District. METHODS: Case-control study was conducted from November 2009 to December 2010 in a population of primiparas. We included all primiparas diagnosed with PE/GH, with random choice of normotensive primiparas in a ratio of 1:3. The variables studied as socio-demographic, obstetric, maternal and perinatal complications were collected using pre-tested questionnaire, after informed consent of the pregnant women. Chi-square and Fisher's multiple comparison were used in the data analysis, considering results significant when p <0.05. RESULTS: Among 1264 primiparas analyzed, 972 (76.9%) were normotensive and 292 (23.1%) hypertensive patients, being 64 (22%) with gestational hypertension and 228 (78%) with PE. Risk factors such as maternal age over 35years, women whose mother and/or sister with chronic hypertension history or who developed hypertension during pregnancy, use of male condom as a contraceptive method, obesity and excessive weight gain during pregnancy showed statistically significant correlation with development of the pathology. CONCLUSION: The development of gestational hypertensive syndrome in primiparous women is associated with family history and obesity, factors that can be used as screening for early identification of patients at risk of PE development. PMID- 26105497 TI - PP176. SFLT-1: A possibility of precocious diagnosis of preeclampsia. AB - INTRODUCTION: Preeclampsia (PE) affects 5-8% of all pregnant women and can trigger a severe gestational hypertension framework and eventually develop into eclampsia and HELLP syndrome. Anticipating the damage would be important in order to establish procedures that can reduce adverse outcomes. For this reason, many researches are undertaken to identify ways to make a diagnosis of preeclampsia as early as possible. It has been highlighted in literature the study: the sFlt1 (soluble fms-like tyrosine kinase-1) has been implicated in the precocious diagnosis of pre eclampsia. The sFlt1 is an anti-angiogenic factor produced in response to oxidative stress derived from the deleterious effects of pre eclampsia. OBJECTIVES: The objective of the study was to evaluate the role of Soluble fms-like tyrosine kinase-1 in the diagnosis of preeclampsia. METHODS: This is a review conducted in the database PubMed and Lilacs. For this purpose, we used the following MeSH, "Vascular Endothelial Growth Factor Receptor-1" OR "FLT1 protein, human" AND "Pre-Eclampsia/diagnosis" in PubMed and "Pre-eclampsia" AND "SFLT1A" in Lilacs, resulting in 84 papers. After reading the abstracts of these studies, we selected the articles analyzed taking into consideration the criteria for inclusion and exclusion. We excluded publications that were not in the period under study (2008 to July 2011) and by study design. Including only case-control, cohort and prospective observational. For a critical analysis of the material, we used the following indicators: researcher, years, central theme, participants, study design and primary outcome. RESULTS: The final results of this study were composed of seven articles and are shown for each target outcome. These vary according to gestational age at which PE is installed and the marker studied (sFlt1 alone or its relation to PlGF - sFlt1/PIGF). Six studies showed greater levels of sFlt1 for the preeclampsia groups when compared to the control group. Significantly differences in antiangiogenic factors seric levels were not found among preeclamptic and eclamptic patients. When associated with another factor, like PIGF, a greater efficacy in the diagnosis of early preeclampsia is shown. Of the studies analyzed, only one (Lynch et al) showed no significant difference between the values of sFlt-1 in groups of early PE, late PE and control for gestational ages between 10 and 15 weeks. As for the relation sFlt 1/PIGF, five studies have considered it even better for PE diagnosis when compared to sFlt-1 isolated. CONCLUSION: The dosage of sFlt1 may be a relevant resource for the early diagnosis of preeclampsia before the installation of target organ damage, especially if measured in the period between 12 and 28 weeks of gestational age. Whereas sFlt-1 manifests itself before the 20th week, that may be interesting clinical point of view since it is this phase that settles the most severe cases, when the adoption of care could prevent further risks. The relationship sFlt1/PIGF, was more appropriate than the measurement of sFlt1 alone. Additional studies are needed to: amplification of the number of women evaluated, establishing gestational age appropriate for study, serum standard and need to consider the relationship between sFlt1 and other factors pro and/or anti angiogenic. PMID- 26105498 TI - PP177. The usefulness of gestation-corrected hyperuricemia as a predictor of the development of preeclampsia on subsequent pregnancy. AB - INTRODUCTION: Hyperuricemia has been described commonly in preeclamptic pregnancies, often preceding the diagnosis of preeclampsia and historically was used as a diagnostic marker of preeclampsia. OBJECTIVES: The aim of this study was to determine the usefulness of uric acid to predict the preeclampsia on subsequent pregnancy. METHODS: The retrospective chart review was done. The pregnant women who had previous preeclampia or gestational hypertension and checked serum uric acid were enrolled in this study. Fifty-eight women were collected. Hyperuricemia was defined as being one standard deviation above the gestation-specific mean . And we used uric acid z-scores ([serum uric acid value gestation specific mean]/standard deviation of the population) to account for gestation-specific alterations in uric acid and tested this as a continuous variable. Linear regression analysis was used to assess the relationship between gestation-corrected hyperuricemia and development of preeclampsia on subsequent pregnancy. RESULTS: Of 58 women, nineteen had the development of recurrent preeclampsia (37.5%). Linear regression analysis showed that the absence or presence of gestation-corrected hyperuricemia was not associated with the development of preeclampsia on subsequent pregnancy (p=0.353, 95% CI 0.418 11.520). And gestation-specific uric acid z-score as a continuous variable did not show any association with the prediction of preeclampsia on subsequent pregnancy (p=0.353, 95% CI 0.087-2.394). CONCLUSION: Gestation-corrected hyperuricemia does not predict the development of preeclampsia on subsequent pregnancy. PMID- 26105499 TI - PP178. Antenatal sFlt1 and PlGF levels at 20-28weeks of gestation for prediction of the occurrence of preeclampsia: A preliminary report. AB - INTRODUCTION: Angiogenic and antiangiogenic factors substantially involve in the pathogenesis of preeclampsia. Levels of these biomarkers alter before the occurrence of disease. OBJECTIVES: To determine the potential of using antenatal serum levels of soluble fms-like tyrosine kinase (sFlt1) and placental growth factor (PlGF) at 20-28weeks of gestation for prediction of subsequent preeclampsia in non-selected population. METHODS: A reference range of serum sFlt1, PlGF level and sFlt1/PlGF ratio at 10-42weeks of gestation was determined from 291 healthy pregnant women using automated assays. Through antenatal visits at 20-28weeks of gestation, serum of 1,689 women who had singleton pregnancy were obtained and frozen at -80 degrees C. Serum of the mothers who subsequently develop preeclampsia were thawed and analyzed for sFlt1 and PlGF levels. RESULTS: At 48 hours postpartum, 21 of 1,689 mothers developed preeclampsia. Serum levels (mean+/-SEM) of sFlt1, PlGF and sFlt1/PlGF ratio obtained at 20-23(+6)weeks of gestation in preeclampsia (N=8) Vs. normal values were 1,845+/-697 Vs. 1807+/ 95pg/ml, 339+/-86 Vs. 542+/-26pg/ml and 33.9+/-29.5 Vs. 4.1+/-0.3 (P = 0.304,0.051 and 0.561) respectively. Serum levels of sFlt1, PlGF and sFlt1/PlGF ratio obtained at 24-27(+6)weeks of gestation in preeclampsia (N=13) Vs. normal values were 2,732+/-637 Vs. 1576+/-82pg/ml, 449+/-57 Vs. 718+/-52pg/ml and 8.9+/ 3.4 Vs. 2.6+/-0.2 (P = 0.081,0.006 and 0.017) respectively. CONCLUSION: In non selected population, automated assay of sFlt1 and PlGF levels and sFlt1/PlGF ratio during 20-28weeks of gestation appear to have potential in prediction of the occurrence of preeclampsia. PMID- 26105500 TI - PP179. The influence of prior abortion on rates of gestational hypertension/pre eclampsia and spontaneous preterm delivery in nulliparous women. AB - INTRODUCTION: Gestational hypertension/preeclampsia (GH) is clearly a heterogeneous condition of which the pathogenesis could be different in women with various risk factors. Nulliparity is a known risk factor for GH, however a previous abortion (spontaneous or induced) may be associated with a lower risk of GH. OBJECTIVES: To examine the effect of abortion history on rates of GH and spontaneous preterm delivery (SPTD) and in nulliparous women. METHODS: Nulliparous women with an initial prenatal screening at <13 weeks' gestation and a current singleton gestation delivering between 6/2006 and 6/2011 that voluntarily enrolled for risk assessment-case management services were identified from a database of clinical information. Excluded were women reporting a history of both spontaneous (SAB) and induced (IAB) abortions, or with a priori diagnosis of diabetes. Rates of SPTD and GH were compared between women with SAB or IAB history (AB group) and a reference group of primigravid women using Pearson's chi square, Student's t, Kruskal-Wallis H, and Mann-Whitney U statistics. RESULTS: Of the 75,487 women studied, 5.7% (n=4288) reported a history of IAB and 24.3% (n=18,328) reported a history of SAB. Overall, 301 women (0.4%) experienced a SAB at <20 weeks in the index pregnancy. Of those 75,186 with delivery ?20 weeks, the incidence of SPTD was 6.1% in controls vs. 6.0% in the IAB/SAB group (p=0.550). Rates of GH were 10.2% in controls vs. 8.0% (p<0.001) in the AB group despite the AB group having significantly (p<0.001) higher rates of women of African-American race (8.5% vs. 5.5%); age >34years (23.9% vs. 10.0%); and obesity (19.6% vs. 16.6%). For women with >2 AB's significant differences were observed in rates of SPTD vs. controls (8.2% vs. 6.0%, p<0.001), but rates of GH were similar (9.2% vs. 10.2%, p=0.188). (1)p<0.001 vs. 0 AB group. CONCLUSION: In nulliparous women, prior AB is associated with a reduction in risk for GH. Risk for SPTD increases only in those with >2 prior AB's. PMID- 26105501 TI - PP180. Maternal plasma endotoxin increases significantly across pregnancy with no association with obesity, inflammation, or insulin sensitivity. AB - INTRODUCTION: Endotoxin activates innate immunity, decreases insulin sensitivity and is associated with obesity. Recent data indicates that subclinical endotoxemia is associated with inflammation in obese women in late pregnancy. OBJECTIVES: The objective of this study was to quantify circulating endotoxin across pregnancy in lean and obese women, and assess the relationship between endotoxin and markers of inflammation and insulin sensitivity. METHODS: Endotoxin was measured in sterile maternal EDTA plasma samples from 24 lean pregnant women (BMI=22.4+/-1.9kg/m(2)) and 45 obese pregnant women (BMI= 32.6+/-2.1kg/m(2)), and 6 non-pregnant women. Samples were collected at 10.5+/-3.1, 21.3+/-4.6 and 35.2+/ 2.1weeks gestation. Endotoxin was quantified using the PyroGene Recombinant Factor C endotoxin detection assay from LONZA, inter-assay variability <10%. IL 6, myloperoxidase, uric acid, triglycerides, insulin and glucose were also measured. Statistical analysis was by repeated measures ANOVA and students t-test as appropriate. Correlation analysis was performed using Pearson product moment correlation coefficient. Statistical significance was accepted at p<0.05. RESULTS: Endotoxin was significantly increased in both lean (10.4+/-5.3EU/ml) and obese (9.1+/-5.3EU/ml) pregnant women compared to non-pregnant women (4.3+/ 2.6EU/ml, p<0.05). Endotoxin increased significantly across pregnancy in both lean and obese pregnant women (p<0.001), but was not different between these groups (table). Endotoxin was not associated with adiposity, IL-6, myloperoxidase, uric acid, triglycerides or insulin sensitivity as assessed by homeostasis model of insulin resistance (HOMA). Data are mean+/-SD. Repeated measures ANOVA p<0.001. CONCLUSION: Circulating endotoxin increases significantly during pregnancy, but endotoxin is not associated with markers of systemic inflammation or insulin resistance. Pregnancy may represent a condition of metabolic endotoxemia, however the causes and biologic activity of these increasing levels of endotoxin are unclear. PMID- 26105502 TI - PP181. The role of the JAK-STAT pathways and SOCS in preeclampsia. PMID- 26105503 TI - Radiology of Osteoporosis. AB - The radiologist has a number of roles not only in diagnosing but also in treating osteoporosis. Radiologists diagnose fragility fractures with all imaging modalities, which includes magnetic resonance imaging (MRI) demonstrating radiologically occult insufficiency fractures, but also lateral chest radiographs showing asymptomatic vertebral fractures. In particular MRI fragility fractures may have a nonspecific appearance and the radiologists needs to be familiar with the typical locations and findings, to differentiate these fractures from neoplastic lesions. It should be noted that radiologists do not simply need to diagnose fractures related to osteoporosis but also to diagnose those fractures which are complications of osteoporosis related pharmacotherapy. In addition to using standard radiological techniques radiologists also use dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) to quantitatively assess bone mineral density for diagnosing osteoporosis or osteopenia as well as to monitor therapy. DXA measurements of the femoral neck are also used to calculate osteoporotic fracture risk based on the Fracture Risk Assessment Tool (FRAX) score, which is universally available. Some of the new technologies such as high-resolution peripheral computed tomography (HR-pQCT) and MR spectroscopy allow assessment of bone architecture and bone marrow composition to characterize fracture risk. Finally radiologists are also involved in the therapy of osteoporotic fractures by using vertebroplasty, kyphoplasty, and sacroplasty. This review article will focus on standard techniques and new concepts in diagnosing and managing osteoporosis. PMID- 26105504 TI - Differential Diagnosis of Colonic Strictures: Pictorial Review With Illustrations from Computed Tomography Colonography. AB - Strictures of the colon can lead to significant morbidity requiring surgical management. The etiology of strictures is broad and generally categorized as benign, malignant, or pseudostrictures. Computed tomography (CT) is a crucial imaging modality in the assessment and characterization of colonic pathologies but colonoscopy remains the diagnostic gold standard. However, in the setting of incomplete colonoscopy due to strictures, the imaging features of CT will be relied on. This review will focus on the CT features of different colon pathologies leading to strictures and will be illustrated with images from 10 years of experience with CT colonography at our institutions from 2002-2012 (Hotel Dieu Hospital, Queen's University and Mount Sinai Hospital, University of Toronto). PMID- 26105506 TI - Epidemiology of deep cutaneous fungal infections in Korea (2006-2010). AB - Deep cutaneous fungal infections (DCFI) occur worldwide and their prevalence is influenced by personal factors of the affected patients and the geographic and cultural features. Surveillance studies of DCFI with respect to the various clinical backgrounds of affected patients can ultimately help to improve their outcome. Expanding on our previous study, we performed a retrospective analysis of patients with DCFI who were treated in a group of university teaching hospitals in Korea to determine the trends within a 5-year period. A retrospective medical record review of patients with DCFI treated between 2006 and 2010 at 16 university teaching hospitals located throughout Korea was performed. Among the 51 cases of DCFI (median patient age, 47.0 years), opportunistic infections in immunocompromised hosts accounted for half. Patients in this group included 11 who were transplant recipients and 12 with malignancies. Overall, Candida (13/51) was the most common causative organism, followed by Sporothrix (12) and Aspergillus (6). Papuloplaques and nodular lesions were the typical presentation, with maculopatches and ulcers also occurring in considerable numbers. Ten patients had systemic involvement. Eight immunocompromised patients did not recover from the disease despite systemic antifungal treatment. Our results highlight the equal involvement of opportunistic and primary pathogens in DCFI, as determined in cases from a 5-year period. Especially in immunocompromised hosts with non-specific skin findings, clinical suspicion is important because failure to diagnose a DCFI causes significant morbidity and possibly even death. PMID- 26105507 TI - Pleiotropic actions of the male pheromone cis-vaccenyl acetate in Drosophila melanogaster. AB - The male-specific lipid, cis-vaccenyl acetate (cVA) has multiple functions in intra-species communication in Drosophila melanogaster. The presence of cVA in a male suppresses courtship motivation of other males and averts male-male courtship. Meanwhile, aggression behaviors between males are promoted by a high amount of cVA caused by increased densities of male flies. cVA also works as a modifier of courtship memory, which is suppressed courtship motivation driven by previous unsuccessful courtship experience. Conversely, cVA in the courting male stimulates female reproductive motivation and increases the probability of copulation success. It also works as an aggregation pheromone, attracting both males and females at the gathering spot. Thus, cVA is a unique example of a single molecule leading to different behaviors in response to the social context. However, despite recent advances in understanding the molecular and neural machinery for cVA sensing, it is still largely unknown how cVA triggers a specific behavior as the situation demands. In this review article, I discuss two potential machineries that might determine cVA actions for behavior selection at the sensory level. PMID- 26105508 TI - Central nervous system inflammatory demyelinating diseases with stroke-like onset and their responses to thrombolysis. PMID- 26105509 TI - Teofilo Folengo's facial paralysis and unknown demise. PMID- 26105510 TI - Safety concerns related to modular/prefabricated building construction. AB - The US construction industry annually experiences a relatively high rate of fatalities and injuries; therefore, improving safety practices should be considered a top priority for this industry. Modular/prefabricated building construction is a construction strategy that involves manufacturing of the whole building or some of its components off-site. This research focuses on the safety performance of the modular/prefabricated building construction sector during both manufacturing and on-site processes. This safety evaluation can serve as the starting point for improving the safety performance of this sector. Research was conducted based on Occupational Safety and Health Administration investigated accidents. The study found 125 accidents related to modular/prefabricated building construction. The details of each accident were closely examined to identify the types of injury and underlying causes. Out of 125 accidents, there were 48 fatalities (38.4%), 63 hospitalized injuries (50.4%), and 14 non hospitalized injuries (11.2%). It was found that, the most common type of injury in modular/prefabricated construction was 'fracture', and the most common cause of accidents was 'fall'. The most frequent cause of cause (underlying and root cause) was 'unstable structure'. In this research, the accidents were also examined in terms of corresponding location, occupation, equipment as well as activities during which the accidents occurred. For improving safety records of the modular/prefabricated construction sector, this study recommends that future research be conducted on stabilizing structures during their lifting, storing, and permanent installation, securing fall protection systems during on-site assembly of components while working from heights, and developing training programmes and standards focused on modular/prefabricated construction. PMID- 26105511 TI - Novel chemiluminescent imaging microtiter plates for high-throughput detection of multiple serum biomarkers related to Down's syndrome via soybean peroxidase as label enzyme. AB - Novel chemiluminescent (CL) imaging microtiter plates with high-throughput, low cost, and simple operation for detection of four biomarkers related to Down's syndrome screening were developed and evaluated. To enhance the sensitivity of CL immunosensing, soybean peroxidase (SBP) was used instead of horseradish peroxide (HRP) as a label enzyme. The microtiter plates were fabricated by simultaneously immobilizing four capture monoclonal antibodies, anti-inhibin-A, anti unconjugated oestriol (anti-uE3), anti-alpha-fetoprotein (anti-AFP), and beta anti-HCG (anti-beta-HCG), on nitrocellulose (NC) membrane to form immunosensing microtiter wells. Under a sandwiched immunoassay, the CL signals on each sensing site of the microtiter plates were collected by a charge-coupled device (CCD), presenting an array-based chemiluminescence imaging method for detection of four target antigens in a well at the same time. The linear response to the analyte concentration ranged from 0.1 to 40 ng/mL for inhibin-A, 0.075 to 40 ng/mL for uE3, 0.2 to 400 ng/mL for AFP, and 0.4 to 220 ng/mL for beta-HCG. The proposed microtiter plates possessed high-throughput, good stability, and acceptable accuracy for detection of four antigens in clinical serum samples and demonstrated potential for practical applicability of the proposed method to Down's syndrome screening. Graphical Abstract Schematic evaluation of the microtiter plater for simultaneous detection of the four biomarkers. PMID- 26105512 TI - Data-independent-acquisition mass spectrometry for identification of targeted peptide site-specific modifications. AB - We present a novel strategy based on data-independent acquisition coupled to targeted data extraction for the detection and identification of site-specific modifications of targeted peptides in a completely unbiased manner. This method requires prior knowledge of the site of the modification along the peptide backbone from the protein of interest, but not the mass of the modification. The procedure, named multiplex adduct peptide profiling (MAPP), consists of three steps: 1) A fragment-ion tag is extracted from the data, consisting of the b-type and y-type ion series from the N and C-terminus, respectively, up to the amino acid position that is believed to be modified; 2) MS1 features are matched to the fragment-ion tag in retention-time space, using the isolation window as a pre filter to enable calculation of the mass of the modification; and 3) modified fragment ions are overlaid with the unmodified fragment ions to verify the mass calculated in step 2. We discuss the development, applications, and limitations of this new method for detection of unknown peptide modifications. We present an application of the method in profiling adducted peptides derived from abundant proteins in biological fluids with the ultimate objective of detecting biomarkers of exposure to reactive species. PMID- 26105513 TI - Multifunctional gold nanoparticles as signal transducers for fabrication of 1:2 molecular demultiplexer. AB - A label-free and enzyme-free demultiplexer system for the fabrication of 1:2 molecular demultiplexer with luminol functionalized gold nanoparticles (Lum AuNPs) as signal transducers was developed for the first time. The Lum-AuNPs had both chemiluminescence (CL) activity and surface plasmon resonance property. It was found that organothiols (RSH) could easily induce the aggregation of AuNPs via strong Au-S covalent interactions in the absence of hydrogen peroxide (H2O2), generating a red shift in the absorption band of AuNPs. However, the presence of H2O2 would readily oxidize RSH to disulfide (RS-SR), and the aggregation of Lum AuNPs did not occur due to lack of the sulfhydryl group. Meanwhile, H2O2 could react with Lum-AuNPs, producing a strong CL emission owing to the enhancement effect of RSH on AuNPs-luminol-H2O2 CL system. Thus, RSH, H2O2, absorbance ratio, and CL intensity served as the signal input, address input, and two different signal outputs of the 1:2 molecular demultiplexer, respectively. PMID- 26105514 TI - Refined association of melanoma differentiation-associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt. PMID- 26105515 TI - KPS/LDH index: a simple tool for identifying patients with metastatic melanoma who are unlikely to benefit from palliative whole brain radiotherapy. AB - PURPOSE: Low Karnofsky performance status (KPS) and elevated lactate dehydrogenases (LDHs) as a surrogate marker for tumor load and cell turnover may depict patients with a very short life expectancy. To validate this finding and compare it to other indices, namely, the recursive partitioning analysis (RPA) and diagnosis-specific graded prognostic assessment (DS-GPA), a multicenter analysis was undertaken. METHODS: A retrospective analysis of 234 metastatic melanoma patients uniformly treated with palliative whole brain radiotherapy (WBRT) was done. Univariate and multivariate analyses were used to determine the impact of patient-, tumor-, and treatment-related parameters on overall survival (OS). RESULTS: KPS and LDH emerged as independent factors predicting OS. By combining KPS and LDH values (KPS/LDH index), groups of patients with statistically significant differences in median OS (days; 95 % CI) after onset of WBRT were identified: group 1 (KPS >= 70/normal LDH) 234 (96-372), group 2 (KPS >= 70/elevated LDH) 112 (69-155), group 3 (KPS <70/normal LDH) 43 (12-74), and group 4 (KPS <70/elevated LDH) 29 (17-41). Between all four groups, statistically significant differences were observed. The RPA and DS-GPA indices failed to distinguish significantly between good and moderate prognosis and were inferior in predicting a very unfavorable prognosis. CONCLUSIONS: The parameters KPS and LDH independently impacted on OS. The combination of both (KPS/LDH index) identified patients with a very short life expectancy, who might be better served by recommending best supportive care instead of WBRT. The KPS/LDH index is simple and effective in terms of time and cost as compared to other prognostic indices. PMID- 26105516 TI - Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: a multi-institutional, randomized, exploratory trial (JORTC-CAM01). AB - PURPOSE: Cancer-related fatigue (CRF) is one of the most common symptoms reported by cancer patients. This randomized trial investigated the efficacy of the amino acid jelly Inner Power((r)) (IP), a semi-solid, orally administrable dietary supplement containing coenzyme Q10 and L-carnitine, in controlling CRF in breast cancer patients in Japan. METHODS: Breast cancer patients with CRF undergoing chemotherapy were randomly assigned to receive IP once daily or regular care for 21 days. The primary endpoint was the change in the worst level of fatigue during the past 24 h (Brief Fatigue Inventory [BFI] item 3 score) from day 1 (baseline) to day 22. Secondary endpoints were change in global fatigue score (GFS; the average of all BFI items), anxiety and depression assessed by the Hospital Anxiety and Depression Scale (HADS), quality of life assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific QLQ (EORTC QLQ-BR23), and adverse events. RESULTS: Fifty-nine patients were enrolled in the study, of whom 57 were included in the efficacy analysis. Median patient age was 50 years. Changes in the worst level of fatigue, GFS, and current feeling of fatigue were significantly different between the intervention and control groups, whereas the change in the average feeling of fatigue was not significantly different between groups. HADS, EORTC QLQ-C30, and EORTC QLQ-BR23 scores were not significantly different between the two groups. No severe adverse events were observed. CONCLUSION: IP may control moderate-severe CRF in breast cancer patients. TRIAL REGISTRATION: The registration number of this study in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) is UMIN000008646. PMID- 26105517 TI - MRI assessment of paraspinal muscles in patients with acute and chronic unilateral low back pain. AB - OBJECTIVE: To investigate the changes in paraspinal muscle cross-sectional area (CSA) and composition, using the digital data from lumbar spine MRIs of patients with acute and chronic low back pain (LBP). METHODS: In total, 178 patients with unilateral LBP who had lumbar MRI examination were recruited. The data were obtained by a retrospective documentation audit. The CSAs and mean signal intensities of the bilateral paraspinal muscles [psoas major (PM), quadratus lumborum, multifidus (MF) and erector spinae (ES)] were measured, and the percentage of fat infiltration was calculated. The data between the painful side and non-painful side were compared, and between-group comparisons were tested. 42 patients with chronic unilateral LBP could indicate the problem level, and the CSA and mean signal intensity of the MF muscle were analysed at the problem level, and one vertebral above and one vertebral level below the problem level. RESULTS: The CSAs of the PM and ES muscles were significantly decreased in the acute LBP group, while in the chronic LBP group, significant reduction in CSA was found in the MF and ES muscles on the painful side compared with the non-painful side. The mean signal intensity and fat content of the ES muscle on the painful side in the chronic LBP group was significantly higher than that on the painful side in the acute LBP group. The significant decrease of CSA in the MF muscle was found at multiple levels on the painful side. CONCLUSION: The present findings show that there is selective ipsilateral atrophy of paraspinal muscles, specific to the symptomatic side, in patients with acute and chronic LBP. The reduction of the muscle CSA and increased fatty infiltration occurred synchronously, and the extent of change is significantly greater in chronic LBP in the ES muscle. Atrophy of the MF muscle appears to be at multiple levels but side specific in relation to symptoms in patients with chronic LBP, and the decreased muscle CSA may occur prior to fatty infiltration. ADVANCES IN KNOWLEDGE: There are specific paraspinal muscles undergoing atrophy and fatty infiltration in patients with acute and chronic LBP on the symptomatic side. The CSA of the MF muscle decreased at multiple levels on the symptomatic side in patients with chronic unilateral LBP, which may occur prior to fatty infiltration. PMID- 26105518 TI - Development of an insect metalloproteinase inhibitor drug carrier system for application in chronic wound infections. AB - OBJECTIVES: The insect metalloproteinase inhibitor (IMPI) represents the first peptide capable of inhibiting virulence-mediating microbial M4-metalloproteinases and is promising as a therapeutic. The purpose of this study was to develop a suitable drug carrier system for the IMPI drug to enable treatment of chronic wound infections. Specifically, we studied on poloxamer 407 hydrogels, examining the influence of several additives and preservatives on the rheological parameters of the hydrogels, the bioactivity and release of IMPI. METHODS: The rheological characterisation of the hydrogel was performed by oscillatory measurements. The bioactivity of IMPI was evaluated in a Casein fluoresence quenching assay. KEY FINDINGS: In this study, a suitable application form for the dermal treatment of chronic wound infections with IMPI was designed. The influences of poloxamer 407 concentration and various additives on the viscoelastic properties and preservation of a thermosensitive hydrogel were investigated. The incorporation of the precursor drug IMPI-gluthathione-s transferase (GST) in the hydrogel had no influence on the rheological characteristics and will be released. The bioactivity of IMPI-GST is not influenced by the hydrogel and remains constant over 4 weeks of storage. CONCLUSIONS: This study reports the development of a poloxamer hydrogel as a suitable carrier system for the application of IMPI. PMID- 26105519 TI - The immunomodulating V and W proteins of Nipah virus determine disease course. AB - The viral determinants that contribute to Nipah virus (NiV)-mediated disease are poorly understood compared with other paramyxoviruses. Here we use recombinant NiVs (rNiVs) to examine the contributions of the NiV V and W proteins to NiV pathogenesis in a ferret model. We show that a V-deficient rNiV is susceptible to the innate immune response in vitro and behaves as a replicating non-lethal virus in vivo. Remarkably, rNiV lacking W expression results in a delayed and altered disease course with decreased respiratory disease and increased terminal neurological disease associated with altered in vitro inflammatory cytokine production. This study confirms the V protein as the major determinant of pathogenesis, also being the first in vivo study to show that the W protein modulates the inflammatory host immune response in a manner that determines the disease course. PMID- 26105520 TI - MicroRNAs expression in normal and malignant colon tissues as biomarkers of colorectal cancer and in response to pomegranate extracts consumption: Critical issues to discern between modulatory effects and potential artefacts. AB - SCOPE: MicroRNAs (miRs) are proposed as colorectal cancer (CRC) biomarkers. Pomegranate ellagic acid and their microbiota metabolites urolithins exert anticancer effects in preclinical CRC models, and target normal and malignant colon tissues in CRC patients. Herein, we investigated whether the intake of pomegranate extract (PE) modified miRs expression in surgical colon tissues versus biopsies from CRC patients. METHODS AND RESULTS: We conducted a randomized, double-blind, controlled trial. Thirty-five CRC patients consumed 900 mg PE daily before surgery. Control CRC patients (no PE intake, n = 10) were included. Our results revealed: (1) significant differences for specific miRs between malignant and normal tissues modifiable by the surgical protocols; (2) opposed trends between -5p and -3p isomolecules; (3) general induction of miRs attributable to the surgery; (4) moderate modulation of various miRs following the PE intake, and (5) no association between tissue urolithins and the observed miRs changes. CONCLUSION: PE consumption appears to affect specific colon tissue miRs but surgery critically alters miRs levels hindering the discrimination of significant changes caused by dietary factors and the establishment of genuine differences between malignant and normal tissues as biomarkers. The components responsible for the PE effects and the clinical relevance of these observations deserve further research. PMID- 26105521 TI - The "pear-shaped" bladder. PMID- 26105522 TI - Post-treated prostate cancer: normal findings and signs of local relapse on multiparametric magnetic resonance imaging. AB - The use of multiparametric magnetic resonance imaging (mp-MRI) for prostate cancer has increased over recent years, mainly for detection, staging, and active surveillance. However, suspicion of recurrence in the set of biochemical failure is becoming a significant reason for clinicians to request mp-MRI. Radiologists should be able to recognize the normal post-treatment MRI findings. Fibrosis and atrophic remnant seminal vesicles after prostatectomy are often found and must be differentiated from local relapse. Moreover, brachytherapy, external beam radiotherapy, cryosurgery, and hormonal therapy tend to diffusely decrease the signal intensity of the peripheral zone on T2-weighted images (T2WI) due to the loss of water content, consequently mimicking tumor and hemorrhage. The combination of T2WI and functional studies like diffusion-weighted imaging and dynamic contrast-enhanced improves the identification of local relapse. Tumor recurrence tends to restrict on diffusion images and avidly enhances after contrast administration either within or outside the gland. The authors provide a pictorial review of the normal findings and the signs of local tumor relapse after radical prostatectomy, external beam radiotherapy, brachytherapy, cryosurgery, and hormonal therapy. PMID- 26105523 TI - The target sign in colorectal liver metastases: an atypical Gd-EOB-DTPA "uptake" on the hepatobiliary phase of MR imaging. AB - PURPOSE: To describe the MRI findings in colorectal cancer liver metastases using gadoxetic acid (Gd-EOB-DTPA), with special emphasis on the target feature seen on the hepatobiliary phase. MATERIAL AND METHODS: The medical records of 45 colorectal cancer patients with an overall number of 150 liver metastases were reviewed. All patients underwent Gd-EOB-DTPA-enhanced MRI before any kind of treatment. We retrospectively evaluated, for each lesion, the signal intensity on the T1-weighted, T2-weighted, and diffusion-weighted images. Additionally, the enhancement pattern during the arterial-, portal-, equilibrium-, and hepatobiliary-phase was assessed. Fourteen lesions had a pathological correlation. RESULTS: Lesions size was 5-40 mm (mean 15 mm). All metastases were hypointense on T1-w imaging. Ninety-nine lesions (66%) had a central area of very high signal intensity on T2-w imaging. Fifty-one metastases (34%) were hyperintense on the T2-w images. In DWI, all lesions had a restricted diffusion. The mean ADC value was 1.31 * 10(-3) mm(2)/s (range 1.10-1.45 * 10(-3) mm(2)/s). During the arterial-phase imaging, 61 lesions (41%) showed a rim enhancement, while 89 lesions (59%) appeared as hypointense. All lesions had low signal intensity in the portal and equilibrium phase. Thirty-nine percent of the lesions also showed an enhancing rim on the portal-phase images. During the hepatobiliary phase, 80 lesions (53.3%) were hypointense, while 70 lesions (46.7%) had a target appearance. CONCLUSION: A number of metastases show an atypical contrast medium uptake during the hepatobiliary phase of gadoxetic acid-enhanced MRI, consisting in a target appearance. PMID- 26105524 TI - Limited utility of MRA for acute bowel ischemia after portal venous phase CT. AB - PURPOSE: Mesenteric ischemia and ischemic colitis are uncommon but potentially life-threatening causes of acute abdominal pain. Portal venous phase computed tomography (CT) is routinely ordered in the emergency room setting for abdominal pain, but subsequent MR angiography may be requested for additional evaluation of the mesenteric vasculature. We compare the concordance of CT and magnetic resonance angiography (MRA) for acute bowel ischemia. MATERIALS AND METHODS: Thirty-two patients who underwent contrast-enhanced MRA for bowel ischemia after having undergone CT evaluation within the preceding 2 weeks were identified. A retrospective review of imaging, treatment history, surgical, and pathology reports was conducted. Two radiologists each reviewed the imaging studies in a blinded fashion. RESULTS: Ten cases of bowel ischemia were confirmed by endoscopy and/or surgical pathology. CT correctly identified bowel findings in all cases. Intraobserver agreement between CT and MRA for all vessels was 0.68 and 0.63, highest for the superior mesenteric artery. Interobserver agreement was 0.74 for MRA and 0.78 for CT. Vascular findings were only directly mentioned in 10 of 32 CT reports (and 7 of 10 cases with confirmed bowel ischemia). MRA only detected two additional or alternative diagnoses. CONCLUSION: Portal venous phase CT and MRA demonstrate a high degree of concordance for vascular evaluation. Reviewed CT examinations were sufficient to assess the patency of the mesenteric vasculature, but vascular findings were not reported in most cases. A direct description within the report may have obviated the request for further MR imaging. MRA adds little value after portal venous CT in assessing bowel ischemia. PMID- 26105526 TI - Detection of Oxygen Vacancies in Oxides by Defect-Dependent Cataluminescence. AB - Oxygen vacancies can control a number of distinct properties of oxides. However, rapid and simple detection of oxygen vacancies is a great challenge owing to their elusive species and highly diluted contents. In this work, we have discovered that cataluminescence (CTL) intensity in diethyl ether oxidation reaction on the surface of TiO2 nanoparticles is proportional to the content of oxygen vacancies. The oxygen vacancy-dependent diethyl ether CTL is attributed to the fact that abundant chemisorbed O2 in oxygen vacancies could facilitate its contact reaction with chemisorbed diethyl ether molecules, resulting in an obvious improvement of CTL intensity. Therefore, diethyl ether CTL can be employed as a simple probe for oxygen vacancies in TiO2 nanoparticles. Its feasibility is validated by detecting the CTL intensity of diethyl ether on the surface of TiO2 with variable oxygen vacancies by metal ion-doped TiO2 nanoparticles (Cu, Fe, Co, and Cr) and hydrogen-treated TiO2 nanoparticles at different temperatures. The content of oxygen vacancies by the present CTL probe is in good agreement with that obtained by conventional X-ray photoelectron spectroscopy (XPS) technique. The superior properties of the developed CTL probe over already-developed methods include fast response, easy operation, low cost, long-term stability, and simple configuration. We believe that the oxygen vacancy sensitive CTL probe has a great potential in distinguishing oxygen vacancies in oxides. PMID- 26105525 TI - Dealing with Time in Health Economic Evaluation: Methodological Issues and Recommendations for Practice. AB - Time is an important aspect of health economic evaluation, as the timing and duration of clinical events, healthcare interventions and their consequences all affect estimated costs and effects. These issues should be reflected in the design of health economic models. This article considers three important aspects of time in modelling: (1) which cohorts to simulate and how far into the future to extend the analysis; (2) the simulation of time, including the difference between discrete-time and continuous-time models, cycle lengths, and converting rates and probabilities; and (3) discounting future costs and effects to their present values. We provide a methodological overview of these issues and make recommendations to help inform both the conduct of cost-effectiveness analyses and the interpretation of their results. For choosing which cohorts to simulate and how many, we suggest analysts carefully assess potential reasons for variation in cost effectiveness between cohorts and the feasibility of subgroup specific recommendations. For the simulation of time, we recommend using short cycles or continuous-time models to avoid biases and the need for half-cycle corrections, and provide advice on the correct conversion of transition probabilities in state transition models. Finally, for discounting, analysts should not only follow current guidance and report how discounting was conducted, especially in the case of differential discounting, but also seek to develop an understanding of its rationale. Our overall recommendations are that analysts explicitly state and justify their modelling choices regarding time and consider how alternative choices may impact on results. PMID- 26105527 TI - 'Fish' (Actinopterygii and Elasmobranchii) diversification patterns through deep time. AB - Actinopterygii (ray-finned fishes) and Elasmobranchii (sharks, skates and rays) represent more than half of today's vertebrate taxic diversity (approximately 33000 species) and form the largest component of vertebrate diversity in extant aquatic ecosystems. Yet, patterns of 'fish' evolutionary history remain insufficiently understood and previous studies generally treated each group independently mainly because of their contrasting fossil record composition and corresponding sampling strategies. Because direct reading of palaeodiversity curves is affected by several biases affecting the fossil record, analytical approaches are needed to correct for these biases. In this review, we propose a comprehensive analysis based on comparison of large data sets related to competing phylogenies (including all Recent and fossil taxa) and the fossil record for both groups during the Mesozoic-Cainozoic interval. This approach provides information on the 'fish' fossil record quality and on the corrected 'fish' deep-time phylogenetic palaeodiversity signals, with special emphasis on diversification events. Because taxonomic information is preserved after analytical treatment, identified palaeodiversity events are considered both quantitatively and qualitatively and put within corresponding palaeoenvironmental and biological settings. Results indicate a better fossil record quality for elasmobranchs due to their microfossil-like fossil distribution and their very low diversity in freshwater systems, whereas freshwater actinopterygians are diverse in this realm with lower preservation potential. Several important diversification events are identified at familial and generic levels for elasmobranchs, and marine and freshwater actinopterygians, namely in the Early Middle Jurassic (elasmobranchs), Late Jurassic (actinopterygians), Early Cretaceous (elasmobranchs, freshwater actinopterygians), Cenomanian (all groups) and the Paleocene-Eocene interval (all groups), the latter two representing the two most exceptional radiations among vertebrates. For each of these events along with the Cretaceous-Paleogene extinction, we provide an in-depth review of the taxa involved and factors that may have influenced the diversity patterns observed. Among these, palaeotemperatures, sea-levels, ocean circulation and productivity as well as continent fragmentation and environment heterogeneity (reef environments) are parameters that largely impacted on 'fish' evolutionary history, along with other biotic constraints. PMID- 26105528 TI - Estimating baseline toxicity of PAHs from marine chronically polluted sediments and bioaccumulation in target organs of fish hypothetically exposed to them: a new tool in risk assessment. AB - In soils and sediments contaminated by Hydrophobic Organic Compounds (HOCs), the total concentrations are less indicative of potential exposure and distribution than the associated freely dissolved concentrations (Cfree) or chemical activity. Therefore, these two parameters are increasingly used to assess sediment contamination with regard to their (1) partitioning into the water column, (2) bioaccumulation and (3) baseline toxic potential. In this work, sediments from a chronically polluted coastal area, with similar total PAH concentrations, were studied using PDMS coated glass jars (obtaining Cfree(SW) and chemical activity) to predict baseline toxicity and potential bioaccumulation from these sediments. The results indicate that, on the one hand, the chemical activity of the sediments differed by up to one order of magnitude and was below the level at which lethal baseline toxicity is expected, but is still a cause for concern due to the presence of other pollutants and different mechanisms of action. On the other hand, the combination of Cfree measurements and Biota to Sediment Accumulation Factors (BSAFs) allowed concentrations in different target organs of benthic flatfish, hypothetically exposed to these chronically polluted sediments, to be estimated. This new approach allows us to predict the concentration in biological tissues under the study of Cfree(SW) in sediments, as a useful tool in risk assessment. PMID- 26105529 TI - Ipsilateral resistance exercise prevents exercise-induced central sensitization in the contralateral limb: a randomized controlled trial. AB - PURPOSE: This study aimed to investigate the hypothesis that a repeated bout of eccentric exercise (ECC2) would result in smaller increase in the sensitivity of spinal nociceptive system, and smaller decrease in the local muscle blood oxygenation response in both the ipsilateral and the contralateral tibialis anterior muscle (TA) when compared with the initial bout (ECC1). It was hypothesized that the magnitude of the repeated bout effect (RBE) would be greater for the ipsilateral side than the contralateral side. METHODS: Twenty-six healthy young men performed two bouts of high-intensity eccentric exercise of TA separated by 2 weeks. Half of the participants used the same leg for both bouts (IPSI) and the other half used the contralateral leg for ECC2 (CONTRA). Nociceptive withdrawal reflex threshold (NWRT) and local muscle blood oxygenation were assessed for the exercised TA muscle before, immediately after, and one day after exercise. RESULTS: Significant decreases in NWRT and muscle oxygenation were observed after ECC1 (p < 0.05), but NWRT did not change after ECC2 in both groups. Smaller decreases in muscle oxygenation were observed after ECC2 than ECC1 in both groups with a similar magnitude of the difference between bouts, but an increase in muscle oxygen re-perfusion before ECC2 was only observed in the IPSI group. CONCLUSION: These results suggest that contralateral RBE was associated with spinal facilitation of the neuronal pathways situated at a homologous innervation level, and it is unlikely that oxygen re-perfusion improvement plays a major role in the contralateral RBE. PMID- 26105530 TI - Hot water immersion induces an acute cytokine response in cervical spinal cord injury. AB - PURPOSE: The dysfunctional sympathetic nervous system in individuals with cervical spinal cord injury (CSCI) impairs adrenergic responses and may, therefore, contribute to the blunted post-exercise cytokine response. The purpose of this study was to investigate an alternative way to exercise to induce an acute cytokine response by passive core temperature elevation in CSCI. METHODS: Seven male participants with a motor complete CSCI and 8 male able-bodied controls were immersed for 60 min in water set at a temperature 2 degrees C above the individuals' resting oesophageal temperature. Blood was collected pre, post, and every hour up to 4 h post-immersion. RESULTS: Hot water immersion resulted in an IL-6 plasma concentration mean increase of 133 +/- 144 % in both groups (P = 0.001). On a group level, IL-6 plasma concentrations were 68 +/- 38 % higher in CSCI (P = 0.06). In both groups, IL-8 increased by 14 +/- 11 % (P = 0.02) and IL-1ra by 18 +/- 17 % (P = 0.05). Catecholamine plasma concentrations were significantly reduced in CSCI (P < 0.05) and did not increase following immersion. CONCLUSIONS: Passive elevation of core temperature acutely elevates IL 6, IL-8 and IL-1ra in CSCI despite a blunted adrenergic response, which is in contrast to earlier exercise interventions in CSCI. The present study lays the foundation for future studies to explore water immersion as an alternative to exercise to induce an acute cytokine response in CSCI. PMID- 26105531 TI - Auditory function following post-dural puncture headache treated with epidural blood patch. A long-term follow-up. AB - BACKGROUND: Epidural analgesia is commonly used for pain management during labor. Sometimes, accidental dural puncture (ADP) occurs causing severely debilitating headache, which may be associated with transient hearing loss. We investigated if auditory function may be impaired several years after ADP treated with epidural blood patch (EBP). METHODS: Sixty women (ADP group) without documented hearing disability, who received EBP following ADP during labor between the years 2005 2011 were investigated in 2013 for auditory function using the following tests: otoscopic examination, tympanometry, pure tone audiometry, and transient-evoked otoacoustic emissions. Additionally, they responded to a questionnaire, the Speech, Spatial and Qualities (SSQ) of hearing, concerning perceived hearing impairment. The results were compared to a control group of 20 healthy, non pregnant women in the same age group. RESULTS: The audiometric test battery was performed 5.2 (1.9) years after delivery. No significant differences were found between the ADP and the control groups in tympanometry or otoacoustic emissions. Pure tone audiometry revealed a significant but small (< 5 dB) difference between the ADP and control groups (P < 0.05). The ability to hear speech in noise as measured by SSQ was significantly reduced in the ADP group compared to the control group (P < 0.05). CONCLUSIONS: A minor hearing loss was detected in the ADP group compared to the control group in pure tone audiometry in some women and during speech-in-noise component several years after accidental dural puncture treated with an epidural blood patch. This small residual hearing loss has minor clinical significance. PMID- 26105532 TI - In vivo comparison of biomineralized scaffold-directed osteogenic differentiation of human embryonic and mesenchymal stem cells. AB - Human pluripotent stem cells such as embryonic stem cells (hESCs) and multipotent stem cells like mesenchymal stem cells (hMSCs) hold great promise as potential cell sources for bone tissue regeneration. Comparing the in vivo osteogenesis of hESCs and hMSCs by biomaterial-based cues provides insight into the differentiation kinetics of these cells as well as their potential to contribute to bone tissue repair in vivo. Here, we compared in vivo osteogenic differentiation of hESCs and hMSCs within osteoinductive calcium phosphate (CaP) bearing biomineralized scaffolds that recapitulate a bone-specific mineral microenvironment. Both hESCs and hMSCs underwent osteogenic differentiation responding to the biomaterial-based instructive cues. Furthermore, hMSCs underwent earlier in vivo osteogenesis compared to hESCs, but both stem cell types acquired a similar osteogenic maturation by 8 weeks of implantation. PMID- 26105533 TI - Double dispersant-assisted ionic liquid dispersive liquid-liquid microextraction coupled with capillary electrophoresis for the determination of benzophenone-type ultraviolet filters in sunscreen cosmetic product. AB - In this work, double dispersant-assisted ionic liquid dispersive liquid-liquid microextraction coupled with micellar electrokinetic chromatography was developed to determine four UV filters (benzophenone, 4-hydroxybenzophenone, 2,4 dihydroxybenzophenone, and 2-hydroxy-4-methoxybenzophenone). 1-Hexyl-3 methylimidazolium hexafluorophosphate was used as the extraction solvent. The main novelty of the present work was that acetonitrile-Triton X-114 was used as double disperser solvent. Parameters affected the extraction efficiency were investigated and optimized. Under the optimum conditions, enrichment factors were in the range of 25.3-40.5. The limits of detection and quantitation, calculated at a S/N of three and ten, were 3.9-6.7 ng/mL and 13.0-22.3 ng/mL. The linearity of the method was in the range of 0.02-2 MUg/mL for 2, 4-dihydroxybenzophenone and 4-hydroxybenzophenone, 0.01-2 MUg/mL for benzophenone and 2-hydroxy-4 methoxybenzophenone, with correlation coefficient (R(2)) of 0.9984-0.9991. The proposed method was successfully applied to the determination of four benzophenone-type UV filters in six kinds of sunscreen cosmetic products, with yielded relative recoveries ranging from 80.2 to 117.7%. PMID- 26105534 TI - Isolated patchy heterochromia of the scalp hair. PMID- 26105535 TI - Physical fitness exercise versus cognitive behavior therapy on reducing the depressive symptoms among community-dwelling elderly adults: A randomized controlled trial. AB - BACKGROUND: Depression is a major health problem for community-dwelling elderly adults. Since limited resources are available to decrease the high prevalence of depressive symptoms among the elderly adults, improved support for them can be provided if we can determine which intervention is superior in ridding depressive symptoms. OBJECTIVE: To compare the effectiveness of the physical fitness exercise program and the cognitive behavior therapy program on primary (depressive symptoms) and secondary outcomes (6-min walk distance, quality of life, and social support) for community-dwelling elderly adults with depressive symptoms. DESIGN AND SETTINGS: A prospective randomized control trial was conducted in three communities in northern Taiwan. PARTICIPANTS: The elderly adults in the three communities were invited to participate by mail, phone calls, and posters. There were a total of 57 participants who had depressive symptoms and all without impaired cognition that participated in this trial. None of the participants withdrew during the 9 months of follow-up for this study. METHODS: Fifty-seven participants were randomly assigned to one of the three groups: the physical fitness exercise program group, the cognitive behavior therapy (CBT) group, or the control group. The primary (Geriatric Depression Scale-15, GDS-15), and secondary outcomes (6-min walk distance, SF-36, and Inventory of Socially Supportive Behaviors scales, ISSB) were collected immediately (T2), at 3 months (T3), and at 6 months after the interventions (T4). RESULTS: After the interventions, the CBT group participants demonstrated significantly lower symptoms of depression (p=0.009) at T2 and perceived more social support from those around them (p<0.001, <0.001 and =0.004, respectively) at three time-point comparisons than the control group. Moreover, after intervention, participants in the physical fitness exercise program group had decreased GDS-15 scores at three time-point comparisons (p=0.003, 0.012 and 0.037, respectively), had a substantially greater 6-min walk distance (p=0.023), a better quality of life (p<0.001), and a better perceived social support at T2 (p<0.001). CONCLUSIONS: Immediately after a 12-week intervention, there were significant decreases in depressive symptoms and more perceived social support amongst those in the CBT group. When considering the effectiveness in the decrease of depressive symptoms longer term, the increase in the 6-min walk distance and raising the patients' quality of life, physical fitness exercise program may be a better intervention for elderly adults with depressive symptoms. PMID- 26105536 TI - Haematological malignancies: Splicing the MDS genome. PMID- 26105537 TI - Forging a signature of in vivo senescence. AB - 'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumour suppression, loss of tissue regenerative capacity and ageing suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-associated biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiological responses to cellular stress. PMID- 26105540 TI - Where are we in laser corneal refractive surgery. PMID- 26105538 TI - The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. AB - Radiotherapy plays a central part in curing cancer. For decades, most research on improving treatment outcomes has focused on modulating radiation-induced biological effects on cancer cells. Recently, we have better understood that components within the tumour microenvironment have pivotal roles in determining treatment outcomes. In this Review, we describe vascular, stromal and immunological changes that are induced in the tumour microenvironment by irradiation and discuss how these changes may promote radioresistance and tumour recurrence. We also highlight how this knowledge is guiding the development of new treatment paradigms in which biologically targeted agents will be combined with radiotherapy. PMID- 26105542 TI - Editorial Comment from Dr Beyer to Identification of a subgroup with worse prognosis among patients with poor-risk testicular germ cell tumor. PMID- 26105539 TI - Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems. AB - Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes. PMID- 26105541 TI - Long-term results of corneal collagen crosslinking for progressive keratoconus. AB - PURPOSE: To evaluate long-term keratoconus stability after corneal crosslinking (CXL) with riboflavin. METHODS: In this prospective study, 57 eyes of 55 patients with progressive keratoconus, consecutively treated with ultraviolet A (UVA) - riboflavin CXL, were examined with the corneal topographer Pentacam, the biometer IOLMaster and the analyzer of corneal biomechanics Ocular Response Analyzer before and during a 24 months follow-up after CXL. RESULTS: Twenty-four months after CXL, there was a significant improvement in best corrected visual acuity (BCVA) (P<0.01), a significant decrease in corneal thinnest point (CTP), keratometry readings at the keratoconus apex (K max), and corneal volume (CV) (P<0.01), and a significant increase in axial eye length (AL) (P=0.01). No significant changes in anterior chamber volume (ACV) and depth (ACD), (P=0.8), corneal hysteresis (CH) (P=0.16) and corneal resistance factor (CRF) (P=0.06) were found. However, in the subgroup of patients with decreased K max readings 24 months after treatment, both CH and CRF showed a significant reduction (P<0.01). CONCLUSION: In the first month after the procedure, CXL induces a reduction in corneal volume. During the 24 months follow-up the cornea tends to recover its original volume with a persistence of the CXL efficacy. PMID- 26105543 TI - Inhibitory Effects of Lanthanum Chloride on Wear Particle-Induced Osteolysis in a Mouse Calvarial Model. AB - Osteolysis is a bone disorder associated with progressive destruction of bone tissues. However, the effects of lanthanum chloride (LaCl3) on osteolysis remain unknown. Therefore, the aim of this study was to determine the effects of LaCl3 on osteolysis in vivo. In a mouse calvarial model, C57BL/6J mice were injected with wear particles with or without LaCl3. Microcomputed tomography, hematoxylin and eosin staining, and tartrate-resistant acid phosphatase staining were performed for the pathological characterization of calvariae, and eight calvariae per group were prepared for the assay of TNF-alpha, IL-1beta, and RANKL secretion using quantitative enzyme-linked immunosorbent assay (ELISA). In mice treated with high-dose LaCl3, particle-induced osteolysis and inflammatory reaction were reduced compared with that in the vehicle-treated control. Moreover, treatment with high-dose LaCl3 suppressed the wear particle-induced decrease in bone mineral content, bone mineral density, and bone volume fraction. Bone destruction and resorption were higher in the LaCl3-treated group than in the saline-treated group but lower than those in the wear particle group. Finally, our results showed that treatment with a high dose of LaCl3 suppressed osteoclastogenesis. Thus, LaCl3 may represent a novel therapeutic agent for the treatment or prevention of wear particle-induced osteolysis and aseptic loosening. PMID- 26105544 TI - Effects of Single and Joint Subacute Exposure of Copper and Cadmium on Heat Shock Proteins in Common Carp (Cyprinus carpio). AB - Copper (Cu) and cadmium (Cd) are the most common heavy metals that are easily detected in aquatic environments on a global scale. In this paper, we investigated the messenger RNA (mRNA) and protein levels of HSPs (HSP60, HSP70, and HSP90) in the liver of the common carp exposed to Cu, Cd, and a combination of both metals by real-time quantitative PCR and Western blot. The results indicated that in each exposure group, the mRNA levels of HSP60, HSP70, and HSP90 were increased significantly compared to the corresponding controls after 96 h of exposure (P < 0.05). A significant increase was observed in the HSP70 protein level in the high-dose Cu group and all of the Cd groups. Significant increases were also observed in the protein levels of HSP60 and HSP90 in the high combination group and the low combination group, respectively. These results indicated that the dynamics of HSP expression observed in the common carp support the role of HSPs as biochemical markers in response to environmental pollution and provided valuable insights into the adaptive mechanisms used by the common carp to adapt to the challenges of stressful environments. PMID- 26105545 TI - Proanthocyanidin Protects Human Embryo Hepatocytes from Fluoride-Induced Oxidative Stress by Regulating Iron Metabolism. AB - To investigate whether grape seed proanthocyanidin extract (GSPE) antagonizes fluoride-induced oxidative injury by regulating iron metabolism, human embryo hepatic cells (L-02) were incubated with sodium fluoride (NaF, 80 mg/L) and/or GSPE (100 MUmol/L) for 24 h. Results showed the glutathione peroxidase (GSH-Px) content, superoxide dismutase (SOD) activity, and total antioxidant capacity (T AOC) level of the NaF group were significantly lower than that of the control group (P < 0.05), while malondialdehyde (MDA) content increased in the NaF group compared with the control group (P < 0.05). Moreover, the indexes mentioned above showed opposite changes in the NaF + GSPE group. In addition, iron content significantly increased in the NaF group compared to the control group(P < 0.05) and significantly decreased in the NaF + GSPE group compared to the NaF group (P < 0.05). Furthermore, hepcidin (coded by HAMP) messenger RNA (mRNA) expression significantly increased in the NaF group compared to the control group(P < 0.05) and significantly decreased in the NaF + GSPE group compared to the NaF group (P < 0.05). Ferroportin 1 (coded by FPN1) mRNA expression significantly decreased in the NaF group compared to the control group (P < 0.05) and significantly increased in the NaF + GSPE group compared to the NaF group (P < 0.05). These results indicate that GSPE provides significant cellular protection against oxidative stress induced by excessive fluoride via the iron metabolism regulation. PMID- 26105546 TI - The Co-Induced Effects of Molybdenum and Cadmium on the Trace Elements and the mRNA Expression Levels of CP and MT in Duck Testicles. AB - To investigate the chronic toxicity of molybdenum (Mo) and cadmium (Cd) on the trace elements and the mRNA expression levels of ceruloplasmin (CP) and metallothionein (MT) in duck testicles, 120 healthy 11-day-old male ducks were randomly divided into six groups with 20 ducks in each group. Ducks were treated with the diet containing different dosages of Mo or Cd. The source of Mo and Cd was hexaammonium molybdate ([(NH4)6Mo7O24.4H2O]) and cadmium sulfate (3CdSO4.8H2O), respectively, in this study. After being treated for 60 and 120 days, ten male birds in each group were randomly selected and euthanized and then testicles were aseptically collected for determining the mRNA expression levels of MT and CP, antioxidant indexes, and contents of trace elements in the testicle. In addition, testicle tissues at 120 days were subjected to histopathological analysis with the optical microscope. The results showed that co-exposure to Mo and Cd resulted in an increase in malondialdehyde (MDA) level while decrease in xanthine oxidase (XOD) and catalase (CAT) activities. The mRNA expression level of MT gene was upregulated while CP was decreased in combination groups. Contents of Mo, copper (Cu), iron (Fe), and zinc (Zn) decreased in combined groups while Cd increased in Cd and combined groups at 120 days. Furthermore, severe congestion, low sperm count, and malformation were observed in low dietary of Mo combined with Cd group and high dietary of Mo combined with Cd group. Our results suggested that Mo and Cd might aggravate testicular degeneration synergistically through altering the mRNA expression levels of MT and CP, increasing lipid peroxidation through inhibiting related enzyme activities and disturbing homeostasis of trace elements in testicles. Interaction of Mo and Cd may have a synergistic effect on the testicular toxicity. PMID- 26105547 TI - Effects of TiO2 NPs on Silkworm Growth and Feed Efficiency. AB - Silkworm (Bombyx mori) (B. mori) is an economically important insect and a model species for Lepidoptera. It has been reported that feeding of low concentrations of titanium dioxide nanoparticles (TiO2 NPs) can improve feed efficiency and increase cocoon mass, cocoon shell mass, and the ratio of cocoon shell. However, high concentrations of TiO2 NPs are toxic. In this study, we fed B. mori with different concentrations of TiO2 NPs (5, 10, 20, 40, 80, and 160 mg/L) and investigated B. mori growth, feed efficiency, and cocoon quality. We found that low concentrations of TiO2 NPs (5 and 10 mg/L) were more effective for weight gains, with significant weight gain being obtained at 72 h (P < 0.05). TiO2 NPs at 20 mg/L or higher had certain inhibitory effects, with significant inhibition to B. mori growth being observed at 48 h. The feed efficiency was significantly improved at low concentrations of 5 and 10 mg/L for 14.6 and 13.1 %, respectively (P < 0.05). All B. mori fed with TiO2 NPs showed increased cocoon mass and cocoon shell mass; at 5 and 10 mg/L TiO2 NPs, cocoon mass was significantly increased by 8.29 and 9.39 %, respectively (P < 0.05). We also found that low concentrations (5 and 10 mg/L) of TiO2 NPs promoted B. mori growth and development, improved feed efficiency, and increased cocoon production, while high concentrations (20 mg/L or higher) of TiO2 NPs showed inhibitory effect to the B. mori. Consecutive feeding of high concentrations of TiO2 NPs led to some degrees of adaptability. This study provides a reference for the research on TiO2 NPs toxicity and the basis for the development of TiO2 NPs as a feed additive for B. mori. PMID- 26105548 TI - Single-layer graphene-assembled 3D porous carbon composites with PVA and Fe3O4 nano-fillers: an interface-mediated superior dielectric and EMI shielding performance. AB - In this study, a novel composite of Fe3O4 nanofiller-decorated single-layer graphene-assembled porous carbon (SLGAPC) with polyvinyl alcohol (PVA) having flexibility and a density of 0.75 g cm(-3) is explored for its dielectric and electromagnetic interference (EMI) response properties. The composite is prepared by the solution casting method and its constituents are optimized as 15 wt% SLGAPC and 20 wt% Fe3O4 through a novel solvent relaxation nuclear magnetic resonance experiment. The PVA-SLGAPC-Fe3O4 composite shows high dielectric permittivity in the range of 1 Hz-10 MHz, enhanced by a factor of 4 as compared to that of the PVA-SLGAPC composite, with a reduced loss by a factor of 2. The temperature dependent dielectric properties reveal the activation energy behaviour with reference to the glass transition temperature (80 degrees C) of PVA. The dielectric hysteresis with the temperature cycle reveals a remnant polarization. The enhanced dielectric properties are suggested to be the result of improvement in the localized polarization of the integrated interface system (Maxwell-Wagner-Sillars (MWS) polarization) formed by the uniform adsorption of Fe3O4 on the surface of SLGAPC conjugated with PVA. The EMI shielding property of the composite with a low thickness of 0.3 mm in the X-band (8.2-12.4 GHz) shows a very impressive shielding efficiency of ~15 dB and a specific shielding effectiveness of 20 dB (g cm(-3))(-1), indicating the promising character of this material for flexible EMI shielding applications. PMID- 26105549 TI - Chronic exposure to higher BP in young adults is associated with cardiac dysfunction in middle age. PMID- 26105550 TI - Erratum to: Distilled Water Lavage During Surgery Improves Long-Term Outcomes of Patients with Ruptured Hepatocellular Carcinoma. PMID- 26105551 TI - Perioperative Microbiologic Monitoring of Sputum on Postoperative Day One as a Predictor of Pneumonia After Hepatectomy. AB - BACKGROUND: The purpose of this study was to retrospectively evaluate microbial examination of sputum on postoperative day one (POD1) and to determine risk factors for postoperative pneumonia (POP) after hepatectomy. METHODS: Two hundred ninety-four patients who expectorated sputum on POD1 after hepatectomy between 2003 and 2014 were investigated. Sputum samples were submitted for microbial examination. Risk factors for POP were identified using multivariable analysis. RESULTS: One hundred fifty-eight (53.7%) of 294 patients had bacteria in their sputum on POD1. POP was observed in 24 (8.2%) patients, with increased mortality in the patients with POP (0.74 vs 12.5%, p < 0.01). Multivariate analysis demonstrated that a Brinkman index of >400 and bacteria in sputum on POD1 were independent risk factors for POP. Bacterial homology in sputum obtained on POD1 and onset day of POP was found in 13 of the 24 (54.2%) patients with POP. In particular, in 13 patients with POP caused by methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa, homology was confirmed in 9 patients (69.2%). CONCLUSION: A Brinkman index >=400 and bacteria in sputum on POD1 increased the risk of POP. Presence of bacteria in sputum on POD1 may be useful in determining early treatment against POP after hepatectomy. PMID- 26105552 TI - Postoperative Ileus--More than Just Prolonged Length of Stay? AB - PURPOSE: Given that postoperative ileus is common in colectomy patients, we sought to examine the association of ileus with adverse events in this patient population. METHODS: The ACS NSQIP puf file from 2012 to 2013 was queried for non emergent colectomy cases. Predictors of other poor postoperative outcomes in patients who experienced postoperative ileus were assessed using chi-squared and multivariable regression analyses. Chi-squared analysis was used to assess for additive effects of ileus and other postoperative complications on mortality. p Values <0.05 were considered significant. RESULTS: We identified 32,392 patients who underwent non-emergent colectomy. Longer length of stay, higher complication, reoperation, readmission, and mortality rates were identified in patients with ileus (p < 0.001 for all). Overall, 59% of patients with ileus had at least one adverse outcome, compared with 25% of patients without ileus (p < 0.001). Patients who developed ileus in the absence of other complications had an identical mortality rate to patients without ileus (1%). Additional complications led to incremental increases in mortality rates. CONCLUSIONS: Patients with ileus and multiple complications are at significantly increased risk for adverse outcomes. Older patients with more comorbidity were found to be at risk for adverse outcomes in addition to ileus, begging the question of whether these patients may benefit from preoperative optimization. PMID- 26105553 TI - Differential sensitivity of lipegfilgrastim and pegfilgrastim to neutrophil elastase correlates with differences in clinical pharmacokinetic profile. AB - To assess the basis of the different half-lives of long-acting human granulocyte colony-stimulating factor (G-CSF) drugs, the effect of neutrophil elastase on lipegfilgrastim and pegfilgrastim was investigated. Sensitivity to human neutrophil elastase (HNE) was evaluated by incubating the drugs with HNE followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Drugs were also incubated with isolated human neutrophils followed by Western blot analysis. Lipegfilgrastim was more resistant to degradation with HNE or neutrophils than pegfilgrastim and appeared more intact on SDS-PAGE gels and Western blots. Lipegfilgrastim retained more functional activity than pegfilgrastim after incubation with HNE (67% vs ~ 9%, respectively) or neutrophils (80% vs ~ 4%, respectively) as assessed in an NFS-60 cell-based [(3) H]-thymidine incorporation assay. The binding and affinity of untreated lipegfilgrastim and pegfilgrastim for G-CSF receptors were evaluated using an NFS 60 competitive G-CSF receptor-binding assay and surface plasmon resonance. Untreated drugs were also evaluated in the functional NFS-60 thymidine incorporation assay. G-CSF receptor binding, receptor affinity, and functional activity were comparable between untreated drugs. The results showed a greater resistance to neutrophil elastase degradation and concomitant retention of functional activity of lipegfilgrastim compared with pegfilgrastim, which potentially explains the clinical observations of a longer half-life of lipegfilgrastim versus pegfilgrastim. PMID- 26105554 TI - Acute and chronic cytokine responses to resistance exercise and training in people with multiple sclerosis. AB - Exercise is a well-established part of rehabilitation for people with multiple sclerosis (PwMS), and it has been hypothesized to stimulate an anti-inflammatory environment that might be disease modifying. Yet, investigations on exercise induced immune responses are scarce and generally not paying attention to the medical treatments of the patient. At present, PwMS are routinely enrolled in immunosuppressive medication, but exercise-induced immunomodulatory effects have not been investigated under these circumstances. The objective of this study was to investigate the acute and chronic cytokines responses to resistance exercise training in medicated PwMS. Thirty-five people with relapsing-remitting multiple sclerosis (MS) treated with interferon (IFN)-beta, were randomized to a 24-week progressive resistance training (PRT) or control group. Plasma interleukin (IL) 1beta, IL-4, IL-10, IL-17F, IL-23, tumor necrosis factor-alpha and IFN-gamma were measured before and after 24 weeks of PRT. The acute effect was evaluated following standardized single-bout resistance exercise in the untrained and the trained state. No changes were observed in resting cytokine levels after PRT. However, an indication of reduced IL-17F secretion following resistance exercise was observed in the trained compared with the untrained state. This study suggests little acute and chronic effect of PRT on cytokine levels in IFN-treated PwMS. PMID- 26105555 TI - Effects of a Quasi-Randomized Web-Based Intervention on Risk Behaviors and Treatment Seeking Among HIV-Positive Men Who Have Sex With Men in Chengdu, China. AB - The men who have sex with men (MSM) population in China has experienced a recent increase in HIV incidence. Due to the dual stigma and discrimination towards homosexuality and HIV infection, most MSM living with HIV/AIDS are hard to reach by offline intervention initiatives. We recruited HIV-positive MSM participants in Chengdu, China and assessed whether they disclosed their HIV status to partners, motivated a partner to receive testing, used condoms consistently, or initiated antiretroviral therapy. Participants were quasi-randomized to either the intervention or control arm. The intervention group was given instructions for an online program with four modules: an information exchange website, a bulletin board system, individualized online counseling with trained peer educators, and an animation game. All participants were re-assessed at 6 months. The study enrolled 202 HIV-positive MSM. The intervention group had significant increases in disclosing their HIV status to their partners (76.0% vs 61.2%, P=0.0388) and motivating partners to accept HIV testing (42.3% vs 25.5%, P=0.0156) compared with the control group, but there were no between-group differences in receiving early treatment or using condoms consistently. We found that a web-based intervention targeting HIV-positive MSM was an effective tool in increasing the uptake of HIV testing within this high-risk population. PMID- 26105556 TI - Study of Iron oxide nanoparticles using Mossbauer spectroscopy with a high velocity resolution. AB - Iron oxide (magnetite and maghemite) nanoparticles developed for magnetic fluids were studied using Mossbauer spectroscopy with a high velocity resolution at 295 and 90K. The recorded Mossbauer spectra have demonstrated that usual physical models based on octahedral and tetrahedral sites were not suitable for fitting. Alternatively, the Mossbauer spectra were nicely fitted using a large number of magnetic sextets. The obtained results showed that the Mossbauer spectra and the assessed parameters were different for nanoparticles as-prepared and dispersed in the dispersing fluid at 295K. We claim that this finding is mainly due to the interaction of polar molecules with Iron cations at nanoparticle's surface or due to the surface coating using carboxylic-terminated molecules. It is assumed that the large number of spectral components may be related to complexity of the nanoparticle's characteristics and deviations from stoichiometry, including in the latter the influence of the oxidation of magnetite towards maghemite. PMID- 26105557 TI - Captive-rearing of Gunnison sage-grouse from egg collection to adulthood to foster proactive conservation and recovery of a conservation-reliant species. AB - Gunnison sage-grouse (Centrocercus minimus) are distributed across southwestern Colorado and southeastern Utah, United States. Their distribution has decreased over the past century and the species has been listed as threatened by the U.S. Fish and Wildlife Service. Reduced genetic diversity, small population size, and isolation may affect Gunnison sage-grouse population persistence. Population augmentation can be used to counteract or mitigate these issues, but traditional translocation efforts have yielded mixed, and mostly unsuccessful, results. Captive-rearing is a viable, although much debated, conservation approach to bolster wild conservation-reliant species. Although there have been captive rearing efforts with greater sage-grouse (C. urophasianus), to date, no information exists about captive-rearing methods for Gunnison sage-grouse. Therefore, we investigated techniques for egg collection, artificial incubation, hatch, and captive-rearing of chicks, juveniles, subadults, and adults for Gunnison sage-grouse. In 2009 we established a captive flock that produced viable eggs. From 2009-2011, we collected and artificially incubated 206 Gunnison sage grouse eggs from 23 wild and 14 captive females. Our hatchability was 90%. Wild produced eggs were heavier than captive-produced eggs and lost mass similarly during incubation. We produced 148 chicks in captivity and fed them a variety of food sources (e.g. invertebrates to commercial chow). Bacterial infections were the primary cause of chick mortality, but we successfully reduced the overall mortality rate during the course of our study. Conservationists and managers should consider the utility in developing a captive-rearing program or creating a captive population as part of a proactive conservation effort for the conservation-reliant Gunnison sage-grouse. PMID- 26105558 TI - [Pediatric thorax]. PMID- 26105559 TI - Functional expression of the human coagulation factor IX using heterologous signal peptide and propeptide sequences in mammalian cell line. AB - OBJECTIVE: To study the functions of pre-pro leader peptides of the human and porcine prothrombins on the human FIX (hFIX) expression. RESULTS: In silico analysis predicted higher secretion efficiencies for the prothrombins-derived signal peptides, in comparison with the native hFIX signal peptide. Replacements of the hFIX pre-pro sequence with those of the two prothrombins, led to increased levels of transcription of the chimeric transgenes, as compared to the native clone. This was in consistent with the lower minimum free energies, calculated for the recombinant transcripts, based on their secondary structures. Evaluation of secretion efficiency revealed that the highest and lowest FIX secretions belong to signal peptides derived from porcine' prothrombin and hFIX, respectively. Coagulation activities of the FIX expressed from chimeric variants could be increased up to tenfold, relative to the native clone. CONCLUSION: The feasibility of a leader-peptide replacement for the improvement of both transcription and post-transcriptional processes is described that can be relevant for production the vitamin-K dependent proteins. PMID- 26105560 TI - Thermal transport in phononic crystals and the observation of coherent phonon scattering at room temperature. AB - Large reductions in the thermal conductivity of thin silicon membranes have been demonstrated in various porous structures. However, the role of coherent boundary scattering in such structures has become a matter of some debate. Here we report on the first experimental observation of coherent phonon boundary scattering at room temperature in 2D phononic crystals formed by the introduction of air holes in a silicon matrix with minimum feature sizes >100 nm. To delaminate incoherent from coherent boundary scattering, phononic crystals with a fixed minimum feature size, differing only in unit cell geometry, were fabricated. A suspended island technique was used to measure the thermal conductivity. We introduce a hybrid thermal conductivity model that accounts for partially coherent and partially incoherent phonon boundary scattering. We observe excellent agreement between this model and experimental data, and the results suggest that significant room temperature coherent phonon boundary scattering occurs. PMID- 26105561 TI - Iatrogenic pneumothorax: What can we do? PMID- 26105562 TI - Iatrogenic acute cardiac tamponade during percutaneous removal of a fractured peripherally inserted central catheter in a premature neonate. AB - Acute cardiac tamponade (ACT) is a life-threatening complication associated with a peripherally inserted central catheter (PICC) in premature neonates. We present a case of ACT in a 4-day-old male infant. On the second admission day, a PICC was inserted. After 2.5 months, chest radiography showed PICC fracture, and its distal portion had migrated into the right pulmonary artery. Percutaneous removal through cardiac catheterization was attempted. However, right ventriculography demonstrated intrapericardial spillage of contrast agents, and iatrogenic ACT was confirmed. Cardiopulmonary resuscitation (CPR) was immediately started with open chest cardiac massage. Further surgical exploration revealed right atrial appendage perforation. After 25-min CPR, the patient restored spontaneous circulation, and removal of the foreign bodies was performed. The post-operative course was uneventful. PICC fracture is an uncommon complication, but may be life threatening. Precaution should be taken to avoid ACT during removal of a broken PICC. Once the tamponade is diagnosed, immediate interventions are mandatory. PMID- 26105563 TI - In Vivo Quantification of 5-HT2A Brain Receptors in Mdr1a KO Rats with 123I R91150 Single-Photon Emission Computed Tomography. AB - Our goal was to identify suitable image quantification methods to image 5 hydroxytryptamine2A (5-HT2A) receptors in vivo in Mdr1a knockout (KO) rats (i.e., P-glycoprotein KO) using 123I-R91150 single-photon emission computed tomography (SPECT). The 123I-R91150 binding parameters estimated with different reference tissue models (simplified reference tissue model [SRTM], Logan reference tissue model, and tissue ratio [TR] method) were compared to the estimates obtained with a comprehensive three-tissue/seven-parameter (3T/7k)-based model. The SRTM and Logan reference tissue model estimates of 5-HT2A receptor (5-HT2AR) nondisplaceable binding potential (BPND) correlated well with the absolute receptor density measured with the 3T/7k gold standard (r > .89). Quantification of 5-HT2AR using the Logan reference tissue model required at least 90 minutes of scanning, whereas the SRTM required at least 110 minutes. The TR method estimates were also highly correlated to the 5-HT2AR density (r > .91) and only required a single 20-minute scan between 100 and 120 minutes postinjection. However, a systematic overestimation of the BPND values was observed. The Logan reference tissue method is more convenient than the SRTM for the quantification of 5-HT2AR in Mdr1a KO rats using 123I-R91150 SPECT. The TR method is an interesting and simple alternative, despite its bias, as it still provides a valid index of 5 HT2AR density. PMID- 26105564 TI - The Effect of Diuresis on the Paced QRS Complexes in Pacing-Dependent Patients with Heart Failure. AB - BACKGROUND: Augmentation of the amplitude of QRS complexes with diuretic therapy for patients with congestive heart failure has been well documented. However, the effect of diuresis on the paced QRS complexes in pacing-dependent patients with heart failure is scarce. OBJECTIVE: To investigate the effect of diuresis on the paced QRS complexes in pacing-dependent patients with heart failure. METHOD: Thrity-two consecutive pacing-dependent patients with heart failure were enrolled in this study. Before and after diuresis, the sums of paced QRS amplitude of leads I+II (SigmapQRSI+II ), six limb leads (SigmapQRS6L ), leads V1 -V3 (SigmapQRSV1-V3 ), leads V4 -V6 (SigmapQRSV4-V6 ), leads V1 -V6 (SigmapQRSV1-V6 ), and lead aVR (pQRSaVR ), paced QRS duration (pQRSd ), paced QT intervals (pQT) and the body weight of each patient were measured, then the % changes (Delta%) in paced electrocardiogram (ECG) variables and the Delta% in body weight were evaluated. RESULTS: Compared with before diuresis, paced ECG variables significantly increased and body weight significantly decreased after diuresis, Delta% in paced QRS amplitude(s) in all ECG variables (SigmapQRSI+II, SigmapQRS6L, SigmapQRSV1-V3 , SigmapQRSV4-V6 , SigmapQRSV1-V6 , and pQRSaVR ) correlated well with Delta% in body weight (r = 0.416, r = 0.849, r = 0.901, r = 0.371, r = 0.837, r = 0.619, and P = 0.018, P < 0.001, P < 0.001, P = 0.037, P < 0.001, P < 0.001), while there was no correlation between Delta% in pQRSd and pQT and Delta% in body weight. CONCLUSIONS: The changes in amplitude of paced QRS complexes may be useful for the monitoring of therapy of pacing-dependent patients with heart failure. PMID- 26105565 TI - Grace under fire: aesthetic leadership in clinical nursing. AB - AIMS AND OBJECTIVES: This paper reports the results of an online descriptive survey that sought to determine nurses' perceptions of aesthetic leadership among clinical leaders in nursing. BACKGROUND: Clinical leadership has been identified as an essential component to ensuring the delivery of safe, high-quality health care. Leadership has been increasingly linked in the literature to aesthetics. However, little consideration has been given to aesthetics in relation to clinical leadership in nursing. DESIGN: A mixed-method, online descriptive survey. METHODS: Participants were recruited via e-learning platforms and social media. A total of 66 surveys were completed, including 31 written accounts of aesthetic leadership in practice. RESULTS: Aesthetic leadership characteristics in clinical leaders most valued are support, communication and the approach taken to colleagues. Taking risks and challenging processes were least likely to be evident among effective clinical leaders. CONCLUSION: Aesthetic leadership is multi-dimensional and a style of leadership to positively influence the clinical workplace. Support, effective communication and taking into consideration the feelings of colleagues are important dimensions of aesthetic leadership. RELEVANCE TO CLINICAL PRACTICE: Aesthetic leadership represents a way for clinical leaders to create and sustain a calm and positive clinical workplace. PMID- 26105566 TI - Distribution of histaminergic neurons and their modulatory effects on oscillatory activity in the olfactory center of the terrestrial slug Limax. AB - Terrestrial mollusks can form an odor aversion memory following the simultaneous presentation of a food odor and an aversive stimulus. The local field potential oscillation recorded on the surface of the procerebrum (PC; the higher olfactory center) exhibits a frequency change in response to the detection of a learned odor; such a change is thus considered to reflect the internal state of the brain during memory recall. Thus far, dopamine and serotonin have been demonstrated to change the oscillatory frequency. Other monoamines, however, have not yet been studied. In the present study, we investigated the possible involvement of histamine (HA). Immunohistochemical staining of HA and in situ hybridization against histidine decarboxylase revealed the location of the cell bodies of HAergic neurons in all ganglia of the brain. The majority of them were located at the medial aspect of the pedal ganglia, and the cerebral ganglia also contained numerous HAergic neurons in their posterior regions. The neuropil layers of the PC received HAergic innervation from the neurons in the cerebral ganglion, as well as from a few neurons located in the dorsomedial part of the cell mass layer of the PC. The HAergic fibers, however, innervated spatially limited regions of the PC, and seemed to affect a small fraction of the PC neurons. HA exerted accelerating effects on the LFP oscillation in a dose-dependent manner, and this effect was suppressed by an H2 blocker, cimetidine. Our results support the involvement of HA in the functioning of the PC. PMID- 26105567 TI - Impact of a Two-step Emergency Department Triage Model with START, then CTAS, on Patient Flow During a Simulated Mass-casualty Incident. AB - INTRODUCTION: A high influx of patients during a mass-casualty incident (MCI) may disrupt patient flow in an already overcrowded emergency department (ED) that is functioning beyond its operating capacity. This pilot study examined the impact of a two-step ED triage model using Simple Triage and Rapid Treatment (START) for pre-triage, followed by triage with the Canadian Triage and Acuity Scale (CTAS), on patient flow during a MCI simulation exercise. Hypothesis/Problem It was hypothesized that there would be no difference in time intervals nor patient volumes at each patient-flow milestone. METHODS: Physicians and nurses participated in a computer-based tabletop disaster simulation exercise. Physicians were randomized into the intervention group using START, then CTAS, or the control group using START alone. Patient-flow milestones including time intervals and patient volumes from ED arrival to triage, ED arrival to bed assignment, ED arrival to physician assessment, and ED arrival to disposition decision were compared. Triage accuracy was compared for secondary purposes. RESULTS: There were no significant differences in the time interval from ED arrival to triage (mean difference 108 seconds; 95% CI, -353 to 596 seconds; P=1.0), ED arrival to bed assignment (mean difference 362 seconds; 95% CI, -1,269 to 545 seconds; P=1.0), ED arrival to physician assessment (mean difference 31 seconds; 95% CI, -1,104 to 348 seconds; P=0.92), and ED arrival to disposition decision (mean difference 175 seconds; 95% CI, -1,650 to 1,300 seconds; P=1.0) between the two groups. There were no significant differences in the volume of patients to be triaged (32% vs 34%; 95% CI for the difference -16% to 21%; P=1.0), assigned a bed (16% vs 21%; 95% CI for the difference -11% to 20%; P=1.0), assessed by a physician (20% vs 22%; 95% CI for the difference -14% to 19%; P=1.0), and with a disposition decision (20% vs 9%; 95% CI for the difference -25% to 4%; P=.34) between the two groups. The accuracy of triage was similar in both groups (57% vs 70%; 95% CI for the difference -15% to 41%; P=.46). CONCLUSION: Experienced triage nurses were able to apply CTAS effectively during a MCI simulation exercise. A two-step ED triage model using START, then CTAS, had similar patient flow and triage accuracy when compared to START alone. PMID- 26105568 TI - [Recent onset cases of lead poisoning among painters]. PMID- 26105569 TI - IKr Impact on Repolarization and Its Variability Assessed by Dynamic Clamp. AB - BACKGROUND: Repolarization and its stability are exquisitely sensitive to IKr features. Information on the relative importance of specific IKr abnormalities is missing and would assist in the evaluation of arrhythmogenic risk. METHODS AND RESULTS: In single guinea-pig myocytes, endogenous IKr was replaced by modeled IKr (mIKr) by dynamic clamp (DC) at a cycle length of 1 s. mIKr parameters were systematically modified, and the resulting changes in action potential duration (APD) and its short term variability (SD1) were measured. We observed that (1) IKr blockade increased SD1 more than expected by its dependency on APD; (2) mIKr completely reversed APD and SD1 changes caused by IKr blockade; (3) repolarization was most sensitive to inactivation shifts, which affected APD and SD1 concordantly; (4) activation shifts of the same magnitude had marginal impact on APD, but only when reducing mIKr, they significantly increased SD1; (5) changes in maximal conductance resulted in a pattern similar to that of activation shifts. CONCLUSIONS: The largest effect on repolarization and its stability are expected from changes in IKr inactivation. APD is less sensitive to changes in other IKr gating parameters, which are better revealed by SD1 changes. SD1 may be more sensitive than APD in detecting IKr-dependent repolarization abnormalities. PMID- 26105570 TI - Transcaval puncture for access to the pulmonary venous atrium after the extracardiac total cavopulmonary connection operation. AB - BACKGROUND: Patients with surgically palliated total cavopulmonary connection are at risk for recurrent atrial arrhythmia requiring catheter ablation. Transcatheter procedures for those with extracardiac conduits (extracardiac-total cavopulmonary connection) are perhaps the most challenging because of exclusion of the venous circulation from the arrhythmia substrate. Puncture through the inferior vena cava to the pulmonary venous atrium may be an effective route for access in these patients. METHODS AND RESULTS: The pediatric and adult congenital surgical databases were explored for patients with extracardiac-total cavopulmonary connection and postoperative computed tomography imaging to assess for the presence of clinically relevant (>3 mm) apposition between the inferior vena cava and pulmonary venous atrium (cavoatrial overlap). The degree of overlap between the structures was measured by 2 blinded reviewers. Patients were stratified by surgical repair in childhood versus adult congenital heart disease. Thirty-seven patients were identified, with cavoatrial overlap observed in 9 (36%) of pediatric and 1 (9%) of adult congenital heart disease-repaired patients. Time elapsed after surgery was associated with cavoatrial overlap in the pediatric cohort (P=0.034) and was identified in all pediatric patients with computed tomography imaging >=8 years after surgery. Three patients underwent successful transcaval puncture during the study period without complication. CONCLUSIONS: Puncture through a region of overlap between the inferior vena cava and pulmonary venous atrium is feasible. Cavoatrial overlap is present in a substantial proportion of patients undergoing extracardiac-total cavopulmonary connection in childhood and is associated with a longer time elapsed since surgery. PMID- 26105571 TI - Capital Investment by Independent and System-Affiliated Hospitals. AB - Capital expenditures are a critical part of hospitals' efforts to maintain quality of patient care and financial stability. Over the past 20 years, finding capital to fund these expenditures has become increasingly challenging for hospitals, particularly independent hospitals. Independent hospitals struggling to find ways to fund necessary capital investment are often advised that their best strategy is to join a multi-hospital system. There is scant empirical evidence to support the idea that system membership improves independent hospitals' ability to make capital expenditures. Using data from the American Hospital Association and Medicare Cost Reports, we use difference-in-difference methods to examine changes in capital expenditures for independent hospitals that joined multi-hospital systems between 1997 and 2008. We find that in the first 5 years after acquisition, capital expenditures increase by an average of almost $16,000 per bed annually, as compared with non-acquired hospitals. In later years, the difference in capital expenditure is smaller and not statistically significant. Our results do not suggest that increases in capital expenditures vary by asset age or the size of the acquiring system. PMID- 26105572 TI - Is the Quebec provincial administrative database a valid source for research on chronic non-cancer pain? AB - PURPOSE: The objective of this study was to evaluate the validity of diagnostic codes recorded in the Regie de l'assurance maladie du Quebec (RAMQ) administrative database for identifying patients suffering from various types of chronic non-cancer pain. METHODS: The validity of published International Classification of Diseases, Ninth Revision, coding algorithms for identifying patients with particular chronic pain syndromes in the RAMQ database was tested using pain specialist-established diagnostic data of 561 patients enrolled in the Quebec Pain Registry, which was used as the reference standard. Modified versions of these algorithms (i.e., adaptation of the number of healthcare encounters) were also tested. For each algorithm, sensitivity, specificity, positive/negative predictive values, and their respective 95% confidence intervals (95%CI) were calculated. RESULTS: In the RAMQ database, some previously published algorithms and modified versions of these algorithms were found to be valid for identifying patients suffering from chronic lumbar pain (sensitivity: 0.65, 95%CI: 0.59-0.71; specificity: 0.83, 95%CI: 0.79-0.87), chronic back pain (sensitivity: 0.70, 95%CI: 0.64-0.76; specificity: 0.73, 95%CI: 0.68-0.78), and chronic neck/back pain (sensitivity: 0.71, 95%CI: 0.65-0.76; specificity: 0.78, 95%CI: 0.72-0.82). Algorithms to identify patients with other types of chronic pain showed low sensitivity: complex regional pain syndrome (<=0.07), fibromyalgia (<=0.42), and neuropathic pain (<=0.39). CONCLUSIONS: Our study provides evidence supporting the value of the RAMQ administrative database for conducting research on certain types of chronic pain disorders including back and neck pain. Users should, however, be cautious about the limitations of this database for studying other types of chronic pain syndromes such as complex regional pain syndrome, fibromyalgia, and neuropathic pain. PMID- 26105573 TI - A "cure" for preeclampsia: Improving neonatal outcomes by overcoming excess fetal placental vascular resistance. AB - From a broad perspective there are only three arterial systems that respond to relative hypoxia with vasoconstriction. They are the placental, the pulmonic and the renal vascular beds. The renal system's adaptation to hypoxia is markedly different from the other two circulatory beds and will not be further considered here. Regional vasoconstriction is adaptive in the placenta and lung because it redirects red blood cells from areas of relative hypoxia to more oxygenated areas thereby maximizing oxygen uptake for a given cardiac output. The fetal placental and pulmonary vascular systems are unique because their smooth muscle cells have a unique and possibly identical potassium channel that responds to hypoxia by closing, thereby depolarizing the cell membrane allowing calcium ion influx and muscle contraction. It may be that a variety of initial causes of temporary or local placental hypoxia initiate a cascade of first fetal placental then maternal vasoconstriction and endothelial activation leading to the clinical syndrome we call preeclampsia. The response cascades seen in preeclampsia, which for purposes of this article I will abbreviate as (PECL), after development of widespread vasoconstriction, will also be seen to be identical or at least parallel in pulmonary hypertension (PAH). This means that some or all of the pharmacotherapies presently used, tested or considered in early PAH may also have a therapeutic effect in PECL by reducing fetal placental arterial resistance thereby increasing fetal placental flow. This would allow increased oxygen and other nutrient uptake and possibly increased fetal cardiac output in the face of reduced fetal cardiac work. This may allow a delay in delivery in which fetuses grow and are better oxygenated in preterm PECL, improving neonatal outcomes. PMID- 26105574 TI - A PCT algorithm for discontinuation of antibiotic therapy is a cost-effective way to reduce antibiotic exposure in adult intensive care patients with sepsis. AB - OBJECTIVE: Procalcitonin (PCT) is a specific marker for differentiating bacterial from non-infective causes of inflammation. It can be used to guide initiation and duration of antibiotic therapy in intensive care unit (ICU) patients with suspected sepsis, and might reduce the duration of hospital stay. Limiting antibiotic treatment duration is highly important because antibiotic over-use may cause patient harm, prolonged hospital stay, and resistance development. Several systematic reviews show that a PCT algorithm for antibiotic discontinuation is safe, but upfront investment required for PCT remains an important barrier against implementation. The current study investigates to what extent this PCT algorithm is a cost-effective use of scarce healthcare resources in ICU patients with sepsis compared to current practice. METHODS: A decision tree was developed to estimate the health economic consequences of the PCT algorithm for antibiotic discontinuation from a Dutch hospital perspective. Input data were obtained from a systematic literature review. When necessary, additional information was gathered from open interviews with clinical chemists and intensivists. The primary effectiveness measure is defined as the number of antibiotic days, and cost-effectiveness is expressed as incremental costs per antibiotic day avoided. RESULTS: The PCT algorithm for antibiotic discontinuation is expected to reduce hospital spending by circa ? 3503 per patient, indicating savings of 9.2%. Savings are mainly due to reductions in length of hospital stay, number of blood cultures performed, and, importantly, days on antibiotic therapy. Probabilistic and one-way sensitivity analyses showed the model outcome to be robust against changes in model inputs. CONCLUSION: Proven safe, a PCT algorithm for antibiotic discontinuation is a cost-effective means of reducing antibiotic exposure in adult ICU patients with sepsis, compared to current practice. Additional resources required for PCT are more than offset by downstream cost savings. This finding is highly important given the aim of preventing widespread antibiotic resistance. PMID- 26105575 TI - Extracardiac Fontan fenestration using the SafeSept transseptal guidewire and snare-controlled diabolo-shaped covered-stent placement. AB - Transcatheter Fontan fenestration is a valuable option in situations of prolonged pleural drainage or low cardiac output in patients with failing Fontan circulation. This procedure relies on controlled baffle perforation without separation of the Fontan circuit from the pulmonary venous atrium, and placement of an accurately sized covered stent. We report a novel technique for transcatheter extracardiac Fontan fenestration using the SafeSept transseptal guidewire(r) and snare-controlled diabolo-shaped covered stent placement. PMID- 26105576 TI - The calcium-sensing receptor: one of a kind. PMID- 26105577 TI - Successful MitraClip(r) implantation after angioplasty of a chronic inferior vena cava filter thrombosis. AB - The MitraClip(r) has increasing use for severe, high surgical risk mitral regurgitation (MR). The MitraClip(r) is implanted percutaneously across the interatrial septum. Given the large diameter of the device delivery system, the femoral vein is the best option for central venous access. This is the first reported case of successful MitraClip(r) implantation through a chronically occluded IVC filter. (c) 2015 Wiley Periodicals, Inc. PMID- 26105578 TI - [Dermatomyositis in a family of Working Kelpies]. AB - Eight members of a family of Working Kelpies were presented with signs compatible with dermatomyositis. Alopecia, crusts, ulcerations of the skin, depigmentation of nasal planum and lips, onychodystrophy and atrophy of the masticatory muscles were present with varying degree. Histopathology of the skin, but not from muscles was performed in three dogs and confirmed the clinical diagnosis. Different immunomodulating drugs (steroids, cyclosporine, mycophenolate mofetil, pentoxifylline, doxycyline/niacinamid, omega-3 fatty acids and vitamin E) were used with variable success. Dermatomyositis is an immune-mediated disease and a genetic predisposition is known in humans and certain canine breeds, mainly Shetland Sheepdogs and Collies, but also for the Beauceron. The responsible genes have not been identified so far. It is assumed that the Working Kelpie derives from the Collie which could explain a hereditary predisposition in the Kelpie. PMID- 26105579 TI - Synthesis of a Class of Chiral-Bridged Phosphoramidite Ligands and Their Applications in the First Iridium-Catalyzed Asymmetric Addition of Arylboronic Acids to Isatins. AB - A series of novel chiral phosphoramidite ligands based on chiral-bridged biphenyl backbones have been prepared conveniently and characterized. The ligands complexed with [IrCodCl]2 provided the first iridium catalyst system for the asymmetric addition of arylboronic acids to N-protected isatins with high efficiency. When performed in THF/H2O at 80 degrees C with 2 equiv of the arylboronic acids, the transformations acquired good to excellent results (up to 98% yield and 95% ee). PMID- 26105580 TI - Scedosporium apiospermum Otitis Complicated by a Temporomandibular Arthritis: A Case Report and Mini-Review. AB - Scedosporium apiospermum is an ubiquitous fungus responsible for various infections in immunocompromised and immunocompetent patients. Ear infections are infrequent. We report an exceptional case of S. apiospermum external otitis complicated by temporomandibular joint arthritis. After 6 months of antibiotherapy, diagnosis was established by mycological analysis of external auditory canal and infratemporal fossae needle sampling. A satisfactory outcome was obtained after 2 months of voriconazole alone. We have reviewed 15 cases of S. apiospermum otitis. Seven of these patients were immunocompromised. Most common clinical presentation included a chronic external otitis lasting months or years before complication stage. Most common clinical features included recurrent unilateral otalgia (11/15) and purulent otorrhea (13/15). Diagnosis was often made at later stage (12/15) with local extension to bones and/or soft tissues (9/15) or cerebral lethal dissemination (3/15).The extremely low incidence of S. apiospermum otomycosis and its non-specific presentation results in a frequent diagnosis delay. A mycological investigation should be performed in case of persistent external otitis and/or osteolysis despite prolonged antibiotic treatment to prevent further extension of the disease. PMID- 26105581 TI - Spectral Doppler of the Hepatic Veins in Noncardiac Diseases: What the Echocardiographer Should Know. AB - In most instances, the flow profile in the hepatic veins (HVs) reflects the fluctuation of pressure within the right atrium. Thus, interrogation of blood flow in the HVs is highly useful for the evaluation of right heart hemodynamics and has become an integral part of any routine echocardiographic examination. However, flow in the HVs is also affected by the state of the liver parenchyma and by the fluctuation of pressure within the thoracic cavity. Therefore, liver and pulmonary pathologies influence the flow pattern in the HVs and may lead to its dissociation from right heart hemodynamics. Echocardiographers should familiarize themselves with the findings on HV Doppler in noncardiac diseases to avoid misinterpretation and incorrect diagnosis. PMID- 26105582 TI - Fenofibrate reduces inflammation in obese patients with or without type 2 diabetes mellitus via sirtuin 1/fetuin A axis. AB - AIMS: The aim of the current study is to investigate the effect of fenofibrate alone and in combination with pioglitazone on serum sirtuin 1 and fetuin A of obese patients with Type 2 Diabetes Mellitus (T2DM). METHODS: Intervention effect on inflammatory parameters was assessed before and after treatment. The study was conducted on 60 postmenopausal females of whom, only 44 patients completed the study. They were distributed as follows; obese patients without T2DM (n=15) who administered fenofibrate (160 mg/day) once for 8 weeks, obese patients with T2DM (n=15) who administered fenofibrate (160 mg/day) once for 8 weeks, obese patients with T2DM (n=14) who administered fenofibrate (160 mg/day) and pioglitazone (15 mg/day) combination once for 8 weeks. We measured fasting plasma glucose, glycated hemoglobin (HbA1c), serum lipids. Inflammatory markers (high sensitivity C-reactive protein "hs-CRP", interleukin-6 "IL-6", fetuin A, and sirtuin 1) of patients were measured in serum using enzyme-linked immunoassay (ELISA) kits. RESULTS: Sirtuin 1 levels in obese patients with T2DM were significantly lower than its levels in obese patients while fetuin A levels were significantly higher (P<0.001). Fenofibrate, alone and in combination with pioglitazone, significantly decreased triacylglycerol, hs-CRP, IL-6, fetuin A and increased sirtuin 1 levels (P<0.001) which suggests that it can be used to delay the complications of obesity and T2DM. There is a strong correlation between fetuin A, sirtuin 1, IL-6 and hs-CRP levels suggesting a shared common pathway. CONCLUSIONS: Fenofibrate was shown to increase serum sirtuin 1 and decrease serum fetuin A levels in obese patients. TRIAL NUMBER: PACTR201407000856135. PMID- 26105583 TI - Serial sampling of copeptin levels improves diagnosis and risk stratification in patients presenting with chest pain: results from the CHOPIN trial. AB - BACKGROUND: Copeptin has demonstrated a role in early rule out for acute myocardial infarction (AMI) in combination with a negative troponin. However, management of patients with chest pain with a positive copeptin in the setting of a negative troponin is unclear. METHODS: The multicentre CHOPIN trial enrolled 2071 patients with acute chest pain. Of these, 476 subjects with an initial negative troponin but an elevated copeptin (>14 pmol/L) were included in this study. Copeptin and troponin levels were rechecked at 2 h and the final diagnosis of AMI was made by two independent, blinded cardiologists. Follow-up at 30 days was obtained for major adverse cardiac events (MACEs), including death, AMI and urgent revascularisation. RESULTS: Of the 476 patients analysed, 365 (76.7%) had a persistently elevated copeptin at 2 h and 111 patients (23.3%) had a copeptin that fell below the cut-off of 14 pmol/L. When the second copeptin was elevated there were 18 AMIs (4.9%) compared with 0 (0%) when the second copeptin was negative (p=0.017), yielding a negative predictive value of 100% (95% CI 96.7% to 100%). On 30-day follow-up there were 36 MACEs (9.9%) in the positive second copeptin group and 2 (1.8%) MACEs in the negative second copeptin group (p=0.006). CONCLUSIONS: Patients with chest pain with an initial negative troponin but positive copeptin are common and carry an intermediate risk of AMI. A second copeptin drawn 2 h after presentation may help risk stratify and potentially rule out AMI in this cohort. PMID- 26105584 TI - I. Plenaries - Keynote Speakers. PMID- 26105585 TI - III. Finalist's Oral Communications. PMID- 26105586 TI - IV. Posters. PMID- 26105587 TI - II. Topic Sessions. PMID- 26105589 TI - Proton pump inhibitors are associated with lower gastrointestinal tract bleeding in low-dose aspirin users with ischaemic heart disease. AB - BACKGROUND: Impact of acid suppressants on lower gastrointestinal bleeding remains unclear in low-dose aspirin users; we aimed to investigate this relationship. METHODS: Retrospective cohort study of low-dose aspirin users who underwent coronary angiography for ischaemic heart disease in our institution between October 2005 and December 2006; patients were evaluated for upper or lower gastrointestinal bleedings within 3 years post-angiography. RESULTS: 538 patients were enrolled (males, 74.4%; mean age 67.4+/-10.6 years). Risk for upper gastrointestinal bleeding decreased with concomitant use of statins (HR, 0.37; 95% CI, 0.15-0.89), calcium channel blockers (HR, 0.29; 95% CI, 0.10-0.85), and histamine-2 receptor antagonists (HR, 0.26; 95% CI, 0.08-0.89). Concomitant use of proton pump inhibitors tended to decrease risk of upper gastrointestinal bleeding (HR, 0.27; 95% CI, 0.06-1.18). Risk for lower gastrointestinal bleeding increased with both concomitant use of warfarin (HR, 15.68; 95% CI, 4.43-55.53) and proton pump inhibitors (HR, 6.55; 95% CI, 2.01-21.32), but not with histamine 2 receptor antagonists. Hyperuricemia lowered risk for lower gastrointestinal bleeding (HR, 0.12; 95% CI, 0.02-0.88). CONCLUSIONS: In low-dose aspirin users, concomitant use of proton pump inhibitors increased lower gastrointestinal bleeding risk, independent from effects on upper gastrointestinal bleeding. PMID- 26105590 TI - Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry. AB - For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors. PMID- 26105591 TI - Clinical profile and recurrence rate in women with venous thromboembolism during combined hormonal contraceptive use: a prospective cohort study. PMID- 26105592 TI - A Qualitative Study of Autism Policy in Canada: Seeking Consensus on Children's Services. AB - Canadian autism policy has been unusually contentious, with parents resorting to litigation to secure services for their children in several provinces. To ascertain whether consensus was possible on improving services, we conducted an in-depth qualitative interview study with 39 parents, policymakers and researchers across the country. Parents vividly described the stresses of caring for their children, with considerable sympathy from researchers. Policymakers in turn struggled to balance the needs of all children. Yet participants agreed on the need for more comprehensive services across the spectrum and throughout the lifespan, and on the need to "do more for all" children. Our findings suggest that there is an emerging consensus on improving autism services in Canada-which should greatly benefit children. PMID- 26105593 TI - Extramedullary acute myeloid leukaemia: isolated leukaemic pleural and pericardial effusions without marrow disease. PMID- 26105594 TI - Evolution of Ecdysis and Metamorphosis in Arthropods: The Rise of Regulation of Juvenile Hormone. AB - Arthropods are the most successful group of animals, and are found in diverse habitats; they account for more than 80% of described animal species. A rigid exoskeleton is a common feature that is shared across the different groups of arthropods. The exoskeleton offers protection and is shed between developmental stages via a unique evolutionarily conserved process known as molting/ecdysis. Molting is triggered by steroid hormones, the ecdysteroids, and the regulation of their biosynthesis has long been proposed as a contributor to the success of arthropods during evolution. Nevertheless, how novelties arose that contributed to the diversifications of arthropods remain unclear. Juvenile hormones (JHs) are sequiterpenoids that were thought to be unique to insects, modulating the timing of metamorphosis in conjunction with the actions of ecdysteroids. Here, we revisit the old question of "the role that the sesquiterpenoids play in arthropod evolution" with a focus on the neglected non-insect arthropods. We hypothesize that the sesquiterpenoid, methyl farnesoate (MF), had already established regulatory functions in the last common ancestor of arthropods, and the difference in the regulation of biosynthesis and degradation of sesquiterpenoids, such as MF and JH, was another major driving force in the successful radiation of insects. PMID- 26105595 TI - Cnidarian Nerve Nets and Neuromuscular Efficiency. AB - Cnidarians are considered "nerve net animals" even though their nervous systems include various forms of condensation and centralization. Yet, their broad, two dimensional muscle sheets are innervated by diffuse nerve nets. Do the motor nerve nets represent a primitive organization of multicellular nervous systems, do they represent a consequence of radial symmetry, or do they offer an efficient way to innervate a broad, two-dimensional muscle sheet, in which excitation of the muscle sheet can come from multiple sites of initiation? Regarding the primitive nature of cnidarian nervous systems, distinct neuronal systems exhibit some adaptations that are well known in higher animals, such as the use of oversized neurons with increased speed of conduction, and condensation of neurites into nerve-like tracts. A comparison of neural control of two dimensional muscle sheets in a mollusc and jellyfish suggests that a possible primitive feature of cnidarian neurons may be a lack of regional specialization into conducting and transmitting regions. PMID- 26105596 TI - Self-assembly of NiTPP on Cu(111): a transition from disordered 1D wires to 2D chiral domains. AB - The growth and self-assembling properties of nickel-tetraphenyl porphyrins (NiTPP) on the Cu(111) surface are analysed via scanning tunnelling microscopy (STM), X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT). For low coverage, STM results show that NiTPP molecules diffuse on the terrace until they reach the step edge of the copper surface forming a 1D system with disordered orientation along the step edges. The nucleation process into a 2D superstructure was observed to occur via the interaction of molecules attached to the already nucleated 1D structure, reorienting molecules. For monolayer range coverage a 2D nearly squared self-assembled array with the emergence of chiral domains was observed. The XPS results of the Ni 2p(3/2) core levels exhibit a 2.6 eV chemical shift between the mono- and multilayer configuration of NiTPP. DFT calculations show that the observed chemical shifts of Ni 2p(3/2) occur due to the interaction of 3d orbitals of Ni with the Cu(111) substrate. PMID- 26105597 TI - Needle in a haystack: How to identify the sick febrile child. PMID- 26105598 TI - The additive effects of GS3 and qGL3 on rice grain length regulation revealed by genetic and transcriptome comparisons. AB - BACKGROUND: Grain length, as a critical trait for rice grain size and shape, has a great effect on grain yield and appearance quality. Although several grain size/shape genes have been cloned, the genetic interaction among these genes and the molecular mechanisms of grain size/shape architecture have not yet to be explored. RESULTS: To investigate the genetic interaction between two major grain length loci of rice, GS3 and qGL3, we developed two near-isogenic lines (NILs), NIL-GS3 (GS3/qGL3) and NIL-qgl3 (gs3/qgl3), in the genetic background of 93-11 (gs3/qGL3) by conventional backcrossing and marker-assisted selection (MAS). Another NIL-GS3/qgl3 (GS3/qgl3) was developed by crossing NIL-GS3 with NIL-qgl3 and using MAS. By comparing the grain lengths of 93-11, NIL-GS3, NIL-qgl3 and NIL GS3/qgl3, we investigated the effects of GS3, qGL3 and GS3 * qGL3 interaction on grain length based on two-way ANOVA. We found that GS3 and qGL3 had additive effects on rice grain length regulation. Comparative analysis of primary panicle transcriptomes in the four NILs revealed that the genes affected by GS3 and qGL3 partially overlapped, and both loci might be involved in brassinosteroid signaling. CONCLUSION: Our data provide new information to better understand the rice grain length regulation mechanism and help rice breeders improve rice yield and appearance quality by molecular design breeding. PMID- 26105599 TI - Results from a multicenter, open-label, pivotal phase II study of chidamide in relapsed or refractory peripheral T-cell lymphoma. AB - BACKGROUND: Chidamide is a novel benzamide type of subtype-selective histone deacetylase (HDAC) inhibitor with unique mechanisms of action compared with marketed HDAC inhibitors. This phase II study was to evaluate the efficacy and safety of chidamide in relapsed or refractory peripheral T-cell lymphoma (PTCL) in Chinese population. PATIENTS AND METHODS: Patients with relapsed or refractory PTCL of different subtypes received chidamide of 30 mg orally twice per week. The primary end point was overall response rate (ORR). Responding patients should be confirmed at least 4 weeks after the criteria of the response were first met, and were reviewed by an independent review committee. RESULTS: Eighty-three patients were enrolled and 79 patients with eligible PTCL histology were for efficacy assessments. Patients enrolled over 10% were with subtypes of PTCL not otherwise specified (34%), anaplastic large-cell lymphoma (22%), extranodal natural killer (NK)/T-cell lymphoma, nasal type (20%), or angioimmunoblastic T-cell lymphoma (AITL, 13%). The ORR was 28% (22 of 79) including 14% (11 of 79) with complete response/unconfirmed complete response (CR/CRu). Median progression-free survival and overall survival were 2.1 and 21.4 months, respectively. AITL patients tended to have higher ORR (50%) and CR/CRu rate (40%), as well as more durable responses, to chidamide treatment. Most adverse events (AEs) were grade 1 or 2, and AEs >=grade 3 that occurred in >=10% patients were thrombocytopenia (22%), leucopenia (13%) and neutropenia (11%), respectively. CONCLUSION: Chidamide represents a novel oral benzamide class of HDAC inhibitor with significant single agent activity and manageable toxicity in relapsed or refractory PTCL, and provides a much needed treatment option in this indication in China. Results led to China Food and Drug Administration approval of chidamide in this indication. PMID- 26105601 TI - Are antenatal weight management interventions effective in preventing pre eclampsia? Systematic review of randomised control trials. AB - INTRODUCTION: Pre-eclampsia, defined as the development of hypertension and proteinuria after 20weeks gestation, carries significant maternal and foetal risk. Pre-pregnancy BMI is the most useful predictor of pre-eclampsia. As the prevalence of obesity increases, prevention of pre-eclampsia by weight management strategies needs to be trialed. AIMS AND OBJECTIVES: To review the randomised controlled trials studying clinical effectiveness of antenatal weight management interventions compared to routine care in decreasing the incidence of pre eclampsia in women with BMI 26kg/m(2) or greater. METHODS: Electronic bibliographic databases were searched using a systematic search strategy to identify relevant trials. All trials involving weight management during pregnancy were considered. Using pre-determined inclusion criteria, six trials were included in this review and were independently assessed using standardised evaluation criteria. RESULTS: Three studies found a significant difference in gestational weight gain; amongst the intervention groups, the smallest was 5.0kg, whereas the largest was 13.6kg. In sub-group analysis, one trial found a significant difference in the incidence of pre-eclampsia between adherent (2/90) and non-adherent participants (5/26). However, no significant difference was found in the overall incidence of pre-eclampsia across all intervention and control groups. CONCLUSION: There was no evidence to suggest that antenatal weight management interventions were effective in reducing the incidence of pre eclampsia in women with a BMI?26kg/m(2). PMID- 26105600 TI - First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. AB - BACKGROUND: The phase III, randomized, open-label ENSURE study (NCT01342965) evaluated first-line erlotinib versus gemcitabine/cisplatin (GP) in patients from China, Malaysia and the Philippines with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients >=18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0-2 were randomized 1:1 to receive erlotinib (oral; 150 mg once daily until progression/unacceptable toxicity) or GP [G 1250 mg/m(2) i.v. days 1 and 8 (3-weekly cycle); P 75 mg/m(2) i.v. day 1, (3-weekly cycle) for up to four cycles]. Primary end point: investigator-assessed progression-free survival (PFS). Other end points include objective response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 217 patients were randomized: 110 to erlotinib and 107 to GP. Investigator-assessed median PFS was 11.0 months versus 5.5 months, erlotinib versus GP, respectively [hazard ratio (HR), 0.34, 95% confidence interval (CI) 0.22-0.51; log-rank P < 0.0001]. Independent Review Committee-assessed median PFS was consistent (HR, 0.42). Median OS was 26.3 versus 25.5 months, erlotinib versus GP, respectively (HR, 0.91, 95% CI 0.63 1.31; log-rank P = .607). ORR was 62.7% for erlotinib and 33.6% for GP. Treatment related serious adverse events (AEs) occurred in 2.7% versus 10.6% of erlotinib and GP patients, respectively. The most common grade >=3 AEs were rash (6.4%) with erlotinib, and neutropenia (25.0%), leukopenia (14.4%), and anemia (12.5%) with GP. CONCLUSION: These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC (NCT01342965). PMID- 26105602 TI - Preeclampsia: No longer solely a pregnancy disease. AB - Preeclampsia, the leading cause of maternal and perinatal morbidity and mortality, has been recently considered not only a pregnancy disease but also a risk factor for developing diseases later in life. Preeclampsia is becoming a disease of interest to internists and not just obstetricians. Women who have had preeclampsia seem to be at higher risk of premature death, mortality from ischemic heart disease, cardiovascular diseases including ischemic heart disease and hypertension, fatal and non-fatal stroke, venous thromboembolism, renal failure, type 2 diabetes mellitus, hypothyroidism, and cognitive defects, although they appear surprisingly protected from cancer. Furthermore, having had preeclampsia is a problem not only for the mother's future health, but it also affects the offspring's adult health. Children born from preeclamptic pregnancies are more prone to hypertension, insulin resistance and diabetes mellitus, neurological problems, stroke, and mental disorders along their life. Whether preeclampsia is a risk factor for disease later in life or it creates long-term organ damage is an intriguing question. This review analyzes recent epidemiological evidence of the long-term outcomes of preeclampsia and the background mechanisms of this phenomenon. Understanding the etiological background may provide guidance for the prevention and follow-up of women who experience preeclampsia. PMID- 26105603 TI - Soluble fms-like tyrosine kinase 1 and soluble endoglin are elevated circulating anti-angiogenic factors in pre-eclampsia. AB - Pre-eclampsia, characterized by hypertension and proteinuria, affects approximately 3-5% of all pregnancies worldwide and is a major cause of maternal and fetal morbidity and mortality. Maternal endothelial dysfunction is associated with disease pathogenesis. Recently, reports have shown that elevated levels of circulating soluble fms-like tyrosine kinase 1 [sFlt1] and soluble endoglin [sEng] are associated with pre-eclampsia. Flt1 is a receptor for vascular endothelial growth factor receptor [VEGF], whereas endoglin [Eng] is an auxiliary receptor for transforming growth factor-beta [TGF-beta] super-family members. Both signaling pathways modulate angiogenesis and are involved in vascular homeostasis. Increased levels of sFlt1 and sEng dysregulate VEGF and TGF-beta signaling respectively, resulting in endothelial dysfunction of maternal blood vessels. This review summarizes our current knowledge of Flt1 and endoglin and soluble forms in pre-eclampsia. Furthermore, it highlights the predictive and early-screening value of circulating levels of sFlt1 and sEng for the risk of developing pre-eclampsia. PMID- 26105604 TI - Limited value of angiogenic factors in obese women. AB - We performed a case-control study assessing the predictive value of sVEGFR and PlGF for preeclampsia in a population with high obesity prevalence. Body mass index and circulating mean concentrations of sVEGFR and PlGF were significantly higher in preeclamptic women. However, a two variable model associating sVEGFR and PlGF dosages was not better than the model including only age and BMI. When the prevalence of obesity is high, the extra benefit of the dosages of angiogenic factors appears to be of limited value. PMID- 26105605 TI - Flash pulmonary edema during cesarean section in a woman with preeclampsia. AB - BACKGROUND: Pulmonary edema may complicate preeclampsia. We report intraoperative flash pulmonary edema in a preeclamptic woman with Rendu-Osler-Weber syndrome. CASE: The patient was admitted at 33(+6) weeks gestation with preeclampsia. After rapid sequence induction and endotracheal intubation for cesarean section, flash pulmonary edema developed without evidence of cardiac dysfunction. She was mechanically ventilated and treated with furosemide. Following brisk diuresis she was extubated the next day and discharged on postoperative day 9 in good clinical condition. CONCLUSION: Endotracheal intubation for general anesthesia can cause acutely increased blood pressure, which, with concomitant low oncotic pressure, we believe contributed to intraoperative flash pulmonary edema. We present this case to raise awareness of this complication when general anesthesia is used for cesarean section in preeclampsia. PMID- 26105606 TI - Invasive versus non-invasive monitoring of acute severe hypertension in women with pre-eclampsia. AB - OBJECTIVE: To compare the accuracy of two non-invasive methods of blood-pressure measurement with intra-arterial measurement in women with pre-eclampsia and acute severe hypertension. METHODS: This descriptive, cross-sectional study prospectively enrolled 23 women with pre-eclampsia and acute severe hypertension for continuous intra-arterial blood-pressure monitoring. Simultaneous monitoring was performed with a manual and an automated, non-invasive device during episodes of severe hypertension. The paired T-test was used to compare measured values. The accuracy of a MAP?125mmHg in detecting a systolic blood pressure?160mmHg was determined. RESULTS: There was a weak correlation between intra-arterial and automated as well as intra-arterial and manual systolic values (r=0.34, p<0.01; r=0.41, p<0.00, respectively). Better correlation was found amongst diastolic values. The differences between the mean intra-arterial (94+/-11mmHg) and automated (96+/-12mmHg) diastolic values as well as intra-arterial and manual diastolic measurements (94+/-14mmHg) were not significant (p=0.20, 0.65, respectively). A mean arterial pressure?125mmHg was not accurate in detecting a systolic value?160mmHg, with low sensitivities (17.2-35.9%) and specificities (0 50%) for all three methods. CONCLUSIONS: When compared to intra-arterial monitoring, the automated and manual methods showed weak correlation with systolic but better correlation with diastolic values. A mean arterial pressure?125mmHg was not accurate in detecting systolic peaks. When protection against cerebral haemorrhage is paramount, intra-arterial measurement of systolic values is best. PMID- 26105607 TI - Capillary remodelling in normal pregnancy: Can it mediate the progressive but reversible rise in blood pressure? Novel insights into cardiovascular adaptation in pregnancy. AB - OBJECTIVE: To conduct a longitudinal study of skin capillary density changes throughout normal pregnancy and correlate them to changes in blood pressure. DESIGN: Prospective, longitudinal cohort study. SETTING: London teaching hospital. STUDY DESIGN: Two hundred and twenty-five Caucasian, Primigravid women with singleton pregnancy, normotensive throughout pregnancy, and with normal pregnancy outcomes. We used intra-vital video microscopy to measure basal (i.e. functional) and maximal (i.e. structural) skin capillary density (CD) according to a well-validated protocol. The subjects were studied at baseline (11-16weeks gestation) and at four consecutive visits (20-24weeks, 27-32weeks, 34-38weeks, and 5-15weeks postpartum). Blood pressure measurements were taken during the same visits. RESULTS: We found that normal pregnancy was associated with progressive capillary rarefaction, with the overall trend in the fall in both functional and structural CD being statistically significant (p<0.001). The fall in CD was a remarkable mirror image to a progressive rise in systolic and diastolic blood pressures, there being a significant correlation between systolic blood pressure and structural CD. Postpartum measurements of both CD and blood pressure were similar to base line levels. CONCLUSIONS: Progressive capillary rarefaction is a normal accompaniment of human pregnancy that may mediate the progressive rise in systolic and diastolic pressures. Both the CD and blood pressure changes are reversible, returning to baseline in the puerperium. PMID- 26105608 TI - Macular thickness measured by optical coherence tomography correlates with proteinuria in pre-eclampsia. AB - OBJECTIVES: Pre-eclampsia is associated with ocular changes. The aim of this study was to examine the macular changes of patients with early-onset severe pre eclampsia using optical coherence tomography (OCT). METHODS: This prospective study was performed at Tygerberg Academic Hospital, a secondary and tertiary referral centre in Cape Town, South Africa. Twenty women with early onset pre eclampsia and 20 women without hypertensive or vascular complications, matched for gestational age, were examined before and after delivery. RESULTS: There was a trend showing a positive correlation between increased central retinal thickness and increasing proteinuria in patients with pre-eclampsia antepartum (left eye r=0.52, p=0.04) and postpartum (left eye r=0.60, p=0.01). A positive correlation between average central 1mm and proteinuria was noted antepartum (left eye r=0.63, p=0.01) and postpartum (right eye r=0.52, p=0.03). There were no significant correlations between blood pressure and any of the retinal parameters. Two of the 23 patients with pre-eclampsia developed serous retinal detachments, both of which resolved completely postpartum. CONCLUSIONS: Macular thickness parameters measured using OCT correlated with the degree of proteinuria in pre-eclampsia. These changes reversed soon after delivery. PMID- 26105609 TI - Hypertension in pregnancy and endothelial activation: An emerging risk factor for cardiovascular disease. AB - OBJECTIVE: There is emerging evidence suggesting that women who develop hypertensive disorders of pregnancy should be considered at risk for cardiovascular disease (CVD). Our objective was to determine whether persistent endothelial activation, which represents the earliest step in atherogenesis, is present after delivery in women with a history of hypertensive pregnancies compared to women with normal pregnancies. STUDY DESIGN: Two matched case-control studies were conducted. In the first study, endothelial activation was assessed by the measurement of soluble intercellular adhesion molecules, namely, intercellular adhesion molecules-1 (ICAM-1), vascular cellular adhesion molecules 1 (V-CAM-1), E-selectin and P-selectin in 25 women with hypertensive pregnancies and in a matched control group with an uncomplicated pregnancy one month and three months after delivery. In the second study, adhesion molecules were measured in 20 patients with a history of HELLP syndrome several years after pregnancy and in 20 matched controls. RESULTS: Increased levels of soluble adhesion molecules were found in women with hypertensive complications compared to women with uncomplicated pregnancies shortly after delivery. Significant differences were still present, several years after delivery comparing levels of adhesion molecules in women with a history of HELLP syndrome with those found in control patients. CONCLUSIONS: Patients with hypertensive pregnancies showed an abnormal activation of the endothelium which persists after pregnancy. This activation was particularly marked in patients experiencing HELLP syndrome. These observations may represent an explanation to the increased risk of CVD later in life in patients experiencing hypertensive pregnancies, especially in women with a history of HELLP syndrome. PMID- 26105610 TI - Plasma levels of S100B during pregnancy in women developing pre-eclampsia. AB - OBJECTIVE: S100B is suggested to be a peripheral biomarker of central nervous system injury with increased blood-brain barrier permeability. The aim of this study was to investigate if there is a difference in plasma levels of S100B throughout pregnancy between women developing pre-eclampsia and those who did not. STUDY DESIGN: A nested case-control study within a longitudinal study cohort was performed. Healthy pregnant women were enrolled and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. Levels of S100B throughout pregnancy were analyzed with an ELISA assay. RESULTS: The levels of S100B did not change between gestational weeks 10 and 37 (0.047 vs. 0.052; p=0.71) in the healthy controls, but the S100B levels increased between corresponding weeks in women who developed pre-eclampsia (0.052 vs. 0.075; p<0.05). In gestational weeks 33 and 37 women who developed pre-eclampsia had higher levels of S100B than the controls (p=0.047 and p=0.010, respectively). CONCLUSION: S100B levels increase during pregnancy in women who develop pre-eclampsia and there is an increased S100B level in women who develop pre-eclampsia compared with healthy pregnancies several weeks before clinical symptoms of the disease. The increased amount of plasma S100B in women developing pre-eclampsia might be secondary to cerebral vascular damage and S100B is a potential peripheral biomarker reflecting cerebral involvement in pre-eclampsia. PMID- 26105611 TI - Cardiovascular risk markers in pregnancies complicated by diabetes mellitus or preeclampsia. AB - OBJECTIVE: To explore biomarkers indicating cardiovascular disease in pregnant women with diabetes or preeclampsia, since these women are at increased risk for future cardiovascular disease. STUDY DESIGN: EDTA-plasma from 262 women in gestational week 24-42 (healthy pregnancies n=71, preeclampsia n=105, type 2 diabetes n=17, gestational diabetes n=61, diabetes with preeclampsia n=8) was analyzed by immunoassay for neopterin, midregional pro-adrenomedullin (MR-proADM) and C-terminal pro-arginine vasopressin (CT-proAVP). The diabetes groups were also analyzed for midregional pro-atrial natriuretic peptide (MR-proANP), and compared to previously reported MR-proANP concentrations for healthy, normotensive and preeclamptic patients. RESULTS: In contrast to preeclampsia, median plasma MR-proANP was not increased in pregnancies complicated by diabetes, but in fact lower, compared to healthy pregnancies. Neopterin was increased in diabetic pregnancies and in late onset preeclampsia, compared to healthy pregnancies. Median plasma MR-proADM was increased in pregnancies complicated by gestational diabetes or preeclampsia, compared to healthy pregnancies. Median plasma MR-proANP was increased in diabetic pregnancies complicated by preeclampsia compared to pregnant women with diabetes only. CONCLUSION: Women with pregnancies complicated by diabetes mellitus or preeclampsia are at risk for future cardiovascular disease, but differ in circulating cardiovascular biomarker profile. A cardiovascular biomarker profiling during pregnancy might prove helpful in identifying women at risk for future cardiovascular disease, thus enabling targeted prophylactic interventions and follow-up. PMID- 26105612 TI - Clinical accuracy of inflationary oscillometry in pregnancy and pre-eclampsia: Omron-MIT Elite. AB - OBJECTIVE: To evaluate the accuracy of the Omron MIT Elite in pregnancy and pre eclampsia according to the British Hypertension Society protocol (BHS). DESIGN: Prospective observational study. SETTING: Antenatal clinics and wards at St. Thomas' Hospital (London, UK). POPULATION: Forty-five pregnant women including 15 with pre-eclampsia. METHODS: Nine sequential same arm blood pressure (BP) measurements were taken from each woman by trained observers, alternating between mercury sphygmomanometry and the test device. MAIN OUTCOME MEASURES: Grading criteria of the BHS protocol (A/B grade=pass; C/D=fail). RESULTS: The Omron MIT Elite achieved a grade A/A in both pregnancy and pre-eclampsia. The mean difference (SD) between the mercury standard and the device in pregnancy was -1.1 (5.2)mmHg and 1.5 (4.8)mmHg for systolic and diastolic BP respectively compared to 0.2 (5.3)mmHg and 2.2 (5.5)mmHg in pre-eclampsia. CONCLUSION: The Omron MIT Elite can be recommended for use in pregnancy and pre-eclampsia according to the BHS protocol. To date, this is the most accurate automated BP device validated in pre-eclampsia. PMID- 26105613 TI - Amino acid profile of plasma and cerebrospinal fluid in preeclampsia. AB - OBJECTIVES: To determine patterns in amino acids (arginine, GABA, glutamate and glutamine) and the diamine (agmatine) in plasma and cerebrospinal fluid (CSF) of mild and severe preeclampsia compared to control patients, using capillary zone electrophoresis to generate methods for refining diagnosis and prognosis and shed light on the pathophysiological mechanisms of preeclampsia. STUDY DESIGN: This is an observational case-control study in pregnant women that attended the emergency ward of the University Hospital, Merida, Venezuela, during the period April, 2009 April 2010. MAIN OUTCOME MEASURES: Molar concentration of amino acids and diamine in plasma and CSF in control, mild and severe preeclampsia patients. RESULTS: An increase in glutamate plasma levels was observed in mild preeclampsia and even higher in severe patients, while a biphasic response occurred in the CSF samples with a significant increment in mild preeclampsia patients and a decrease in severe preeclampsia patients. GABA significantly decreased both in plasma and CSF in mild preeclampsia with a tendency to return to normal levels in severe preeclampsia patients. Arginine CSF and plasma levels decreased in mild preeclampsia patients and even more in severe preeclampsia while agmatine significantly increased in plasma levels with no changes in CSF. CONCLUSIONS: The results are discussed in terms of molecules that could be used as biomarkers of the severity of the disease and the possible involvement of these substances in the pathophysiology of preeclampsia. PMID- 26105614 TI - Heterojunction synergies in titania-supported gold photocatalysts: implications for solar hydrogen production. AB - The mixed-phase nature of P25 TiO2 (85 % anatase/15 % rutile) plays a key role in the high H2 production rates shown by Au/P25 TiO2 photocatalysts in alcohol/water systems. However, a full understanding of the synergistic charge transfer mechanisms between the TiO2 polymorphs that drive the high rates is yet to be realised. Here, we deconstruct P25 TiO2 into its component phases, functionalise the phases with Au nanoparticles and explore charge transfer in Au/TiO2 systems using EPR spectroscopy. EPR spectroscopy and photocatalytic data provide direct evidence that electrons excited across the rutile band gap move to anatase lattice traps through interfacial surface sites, which decreases electron-hole pair recombination and increases charge carrier availability for photoreactions. In particular, three-phase interfacial sites between Au, anatase and rutile appear to be H2 evolution "hot spots". The results isolate the origin of high photocatalytic H2 production rates seen in Au/P25 TiO2 systems. PMID- 26105615 TI - Accuracy of Fluoroscopic Guided Acetabular Component Positioning During Direct Anterior Total Hip Arthroplasty. AB - Acetabular component malposition contributes to increased complications and early revision. Supine positioning during direct anterior approach (DAA) THA facilitates the use of fluoroscopy to improve component positioning. This study evaluated the accuracy of acetabular component orientation using intraoperative fluoroscopy in DAA THA. A total of 780 surgeries by two surgeons were retrospectively reviewed over a 3-year period. Ranges for abduction (30 degrees 50 degrees ) and version (5 degrees -250) were employed. Overall, 92% fell within the targeted abduction range, 93% fell within the targeted anteversion range, and 88% met both criteria. The accuracy of component positioning for combined abduction and anteversion improved yearly (79.2%, 2011; 90.9%, 2012; and 95.6%, 2013). Fluoroscopy in DAA THA is a useful tool to improve acetabular component orientation, though a learning curve exists with its interpretation. PMID- 26105616 TI - Optimal Irrigation and Debridement of Infected Total Joint Implants with Chlorhexidine Gluconate. AB - Previous study at our institution demonstrated that scrubbing a methicillin resistant Staphylococcus aureus (MRSA)-coated titanium disk with chlorhexidine gluconate (CG) solution achieved superior biofilm eradication compared to alternative solutions. The current study aimed to identify the minimum CG concentration for effective bacteria eradication of an in vitro periprosthetic joint infection (PJI) model. MRSA colony-forming units (CFUs) were counted following simulated irrigation and debridement with varying CG solutions before and after a 24-hour reincubation period. Significant decrease was noted on all disks before reincubation. Postreincubation, significant decrease in CFUs was found in the 4% and 2% groups. This study demonstrated that I+D of an infected PJI model with 4% CG solution was effective at treating MRSA biofilm at concentrations as low as 2%. PMID- 26105617 TI - Who Should Not Undergo Short Stay Hip and Knee Arthroplasty? Risk Factors Associated With Major Medical Complications Following Primary Total Joint Arthroplasty. AB - We retrospectively reviewed 1012 consecutive patients undergoing elective primary hip and knee arthroplasties to identify risk factors associated with postoperative complications. A total of 70 complications (6.9%) requiring additional physician interventions occurred following surgery and 59 (84%) occurred past 24 hours postoperatively. Independent multivariate risk factors for developing late (>24 hours) complications included COPD (adjusted OR 4.16), CHF (adjusted OR 9.71), CAD (adjusted OR 2.80), and cirrhosis (adjusted OR 8.43). These results suggest that most major medical complications requiring additional physician interventions occur greater than 24 hours following primary THA/TKA. Patients with history of COPD, CHF, CAD, and cirrhosis should not undergo short stay or outpatient TJA. PMID- 26105618 TI - Disseminated infection caused by Emmonsia pasteuriana in a renal transplant recipient. AB - Emmonsia pasteuriana is a thermally dimorphic fungus identified in very few human cases. Here, we report a case of a 43-year-old male renal transplant patient from China presenting with multiple painful skin eruptions on his head, nose and left thigh, later accompanied by respiratory failure. Histopathology of the biopsy collected from the left thigh upper ulcer and occipital nodule both demonstrated chronic inflammation with granuloma formation and yeast-like elements. Emmonsia pasteuriana was cultured from two biopsy specimens and their identity was confirmed by sequencing of the rDNA internal transcribed spacer. The patient in intensive care showed marked clinical improvement with antifungal treatment. PMID- 26105619 TI - Erratum to: Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction. PMID- 26105621 TI - Reply. PMID- 26105622 TI - Antibiotic susceptibility of Lactobacillus strains isolated from domestic geese. AB - The aim of this study was to determine the antibiotic susceptibility of 93 Lactobacillus strains isolated from domestic geese raised on Polish farms. The minimal inhibitory concentration (MIC) of 13 antimicrobial substances was determined by the broth microdilution method. All strains were sensitive to the cell wall inhibitors ampicillin and amoxicillin (MIC <= 8 MUg/ml). Resistance to inhibitors of protein synthesis and to fluoroquinolone inhibitors of replication was found in 44.1% and 60.2% of isolates, respectively; 26.9% strains were resistant to neomycin (MIC >= 64 MUg/ml), 23.6% to tetracycline (MIC >= 32 MUg/ml), 15% to lincomycin (MIC >= 64 MUg/ml), 18.3% to doxycycline (MIC >= 32 MUg/ml), 9.7% to tylosin (MIC >= 32 MUg/ml), 56% to flumequine (MIC >= 256 MUg/ml) and 22.6% to enrofloxacin (MIC >= 64 MUg/ml). Bimodal distribution of MICs indicative of acquired resistance and unimodal distribution of the high MIC values indicative of intrinsic resistance were correlated with Lactobacillus species. Eleven (11.8%) strains displayed multiple resistance for at least three classes of antibiotics. Data derived from this study can be used as a basis for reviewing current microbiological breakpoints for categorisation of susceptible and resistant strains of Lactobacillus genus and help to assess the hazards associated with the occurrence of drug resistance among natural intestinal microflora. PMID- 26105623 TI - Ionic transport in hybrid lead iodide perovskite solar cells. AB - Solar cells based on organic-inorganic halide perovskites have recently shown rapidly rising power conversion efficiencies, but exhibit unusual behaviour such as current-voltage hysteresis and a low-frequency giant dielectric response. Ionic transport has been suggested to be an important factor contributing to these effects; however, the chemical origin of this transport and the mobile species are unclear. Here, the activation energies for ionic migration in methylammonium lead iodide (CH3NH3PbI3) are derived from first principles, and are compared with kinetic data extracted from the current-voltage response of a perovskite-based solar cell. We identify the microscopic transport mechanisms, and find facile vacancy-assisted migration of iodide ions with an activation energy of 0.6 eV, in good agreement with the kinetic measurements. The results of this combined computational and experimental study suggest that hybrid halide perovskites are mixed ionic-electronic conductors, a finding that has major implications for solar cell device architectures. PMID- 26105620 TI - Molecular mechanisms underlying HBsAg negativity in occult HBV infection. AB - Although genomic detection is considered the gold standard test on HBV infection identification, the HBsAg investigation is still the most frequent clinical laboratory request to diagnose HBV infection in activity. However, the non detection of HBsAg in the bloodstream of chronic or acutely infected individuals has been a phenomenon often observed in clinical practice, despite the high sensitivity and specificity of screening assays standardized commercially and adopted in routine. The expansion of knowledge about the hepatitis B virus biology (replication/life cycle, genetic variability/mutability/heterogeneity), their biochemical and immunological properties (antigenicity and immunogenicity), in turn, has allowed to elucidate some mechanisms that may explain the occurrence of this phenomenon. Therefore, the negativity for HBsAg during the acute or chronic infection course may become a fragile or at least questionable result. This manuscript discusses some mechanisms that could explain the negativity for HBsAg in a serological profile of individuals with HBV infection in activity, or factors that could compromise its detection in the bloodstream during HBV infection. PMID- 26105624 TI - Zinc-containing yeast extract promotes nonrapid eye movement sleep in mice. AB - Zinc is an essential trace element for humans and animals, being located, among other places, in the synaptic vesicles of cortical glutamatergic neurons and hippocampal mossy fibers in the brain. Extracellular zinc has the potential to interact with and modulate many different synaptic targets, including glutamate and GABA receptors. Because of the central role of these neurotransmitters in brain activity, we examined in this study the sleep-promoting activity of zinc by monitoring locomotor activity and electroencephalogram after its administration to mice. Zinc-containing yeast extract (40 and 80 mg/kg) dose dependently increased the total amount of nonrapid eye movement sleep and decreased the locomotor activity. However, this preparation did not change the amount of rapid eye movement sleep or show any adverse effects such as rebound of insomnia during a period of 24 h following the induction of sleep; whereas the extracts containing other divalent cations (manganese, iron, and copper) did not decrease the locomotor activity. This is the first evidence that zinc can induce sleep. Our data open the way to new types of food supplements designed to improve sleep. PMID- 26105625 TI - A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. AB - Antigen-specific immunotherapy was studied in a multi-institutional phase 1/2 study by combining decitabine (DAC) followed by an autologous dendritic cell (DC)/MAGE-A1, MAGE-A3 and NY-ESO-1 peptide vaccine in children with relapsed/refractory solid tumors. Patients aged 2.5-15 years with relapsed neuroblastoma, Ewing's sarcoma, osteosarcoma and rhabdomyosarcoma were eligible to receive DAC followed by DC pulsed with overlapping peptides derived from full length MAGE-A1, MAGE-A3 and NY-ESO-1. The primary endpoints were to assess the feasibility and tolerability of this regimen. Each of four cycles consisted of week 1: DAC 10 mg/m(2)/day for 5 days and weeks 2 and 3: DC vaccine once weekly. Fifteen patients were enrolled in the study, of which 10 were evaluable. Generation of DC was highly feasible for all enrolled patients. The treatment regimen was generally well tolerated, with the major toxicity being DAC-related myelosuppression in 5/10 patients. Six of nine patients developed a response to MAGE-A1, MAGE-A3 or NY-ESO-1 peptides post-vaccine. Due to limitations in number of cells available for analysis, controls infected with a virus encoding relevant genes have not been performed. Objective responses were documented in 1/10 patients who had a complete response. Of the two patients who had no evidence of disease at the time of treatment, one remains disease-free 2 years post-therapy, while the other experienced a relapse 10 months post-therapy. The chemoimmunotherapy approach using DAC/DC-CT vaccine is feasible, well tolerated and results in antitumor activity in some patients. Future trials to maximize the likelihood of T cell responses post-vaccine are warranted. PMID- 26105626 TI - Sunitinib pretreatment improves tumor-infiltrating lymphocyte expansion by reduction in intratumoral content of myeloid-derived suppressor cells in human renal cell carcinoma. AB - Targeted therapy with sunitinib, pazopanib or everolimus has improved treatment outcome for patients with metastatic renal cell carcinoma patients (RCC). However, despite considerable efforts in sequential or combined modalities, durable remissions are rare. Immunotherapy like cytokine therapy with interleukin 2, T cell checkpoint blockade or adoptive T cell therapies can achieve long-term benefit and even cure. This raises the question of whether combining targeted therapy with immunotherapy could also be an effective treatment option for RCC patients. Sunitinib, one of the most frequently administered therapeutics in RCC patients has been implicated in impairing T cell activation and proliferation in vitro. In this work, we addressed whether this notion holds true for expansion of tumor-infiltrating lymphocytes (TILs) in sunitinib-treated patients. We compared resected primary RCC tumor material of patients pretreated with sunitinib with resection specimen from sunitinib-naive patients. We found improved TIL expansion from sunitinib-pretreated tumor digests. These TIL products contained more PD-1 expressing TIL, while the regulatory T cell infiltration was not altered. The improved TIL expansion was associated with reduced intratumoral myeloid-derived suppressor cell (MDSC) content. Depletion of MDSCs from sunitinib-naive RCC tissue-digest improved TIL expansion, proving the functional relevance of the MDSC alteration by sunitinib. Our in vivo results do not support previous in vitro observations of sunitinib inhibiting T cell function, but do provide a possible rationale for the combination of sunitinib with immunotherapy. PMID- 26105627 TI - Development of a bipolar disorder biobank: differential phenotyping for subsequent biomarker analyses. AB - BACKGROUND: We aimed to establish a bipolar disorder biobank to serve as a resource for clinical and biomarker studies of disease risk and treatment response. Here, we describe the aims, design, infrastructure, and research uses of the biobank, along with demographics and clinical features of the first participants enrolled. METHODS: Patients were recruited for the Mayo Clinic Bipolar Biobank beginning in July 2009. The Structured Clinical Interview for DSM IV was used to confirm bipolar diagnosis. The Bipolar Biobank Clinical Questionnaire and Participant Questionnaire were designed to collect detailed demographic and clinical data, including clinical course of illness measures that would delineate differential phenotypes for subsequent analyses. Blood specimens were obtained from participants, and various aliquots were stored for future research. RESULTS: As of September 2014, 1363 participants have been enrolled in the bipolar biobank. Among these first participants, 69.0 % had a diagnosis of bipolar disorder type I. The group was 60.2 % women and predominantly white (90.6 %), with a mean (SD) age of 42.6 (14.9) years. Clinical phenotypes of the group included history of psychosis (42.3 %), suicide attempt (32.5 %), addiction to alcohol (39.1 %), addiction to nicotine (39.8 %), obesity (42.9 %), antidepressant-induced mania (31.7 %), tardive dyskinesia (3.2 %), and history of drug-related serious rash (5.7 %). CONCLUSIONS: Quantifying phenotypic patterns of illness beyond bipolar subtype can provide more detailed clinical disease characteristics for biomarker research, including genomic-risk studies. Future research can harness clinically useful biomarkers using state-of-the-art research technology to help stage disease burden and better individualize treatment selection for patients with bipolar disorder. PMID- 26105628 TI - Dielectrophoresis-assisted 3D nanoelectroporation for non-viral cell transfection in adoptive immunotherapy. AB - Current transfection technologies lead to significant inter-clonal variations. Previously we introduced a unique electrotransfection technology, Nanochannel Electroporation (NEP), which can precisely and benignly transfect small cell populations (~100-200 cells) with single-cell resolution. Here we report on the development of a novel 3D NEP system for large scale transfection. A properly engineered array of nanochannels, capable of handling/transfecting ~60 000 cells cm(-2), was fabricated using cleanroom technologies. Positive dielectrophoresis was used to selectively position cells on the nanochannels, thus allowing highly efficient transfection. Single-cell dosage control was demonstrated using both small and large molecules, and different cell types. The potential clinical relevance of this system was tested with difficult-to-transfect natural killer cell suspensions, and plasmids encoding for the chimeric antigen receptor (CAR), a model of high relevance for adoptive immunotherapy. Our results show significantly higher CAR transfection efficiencies for the DEP-NEP system (>70% vs. <30%), as well as enhanced cell viabilities. PMID- 26105632 TI - Journal Club via social media: authors take note of the impact of #BlueJC. PMID- 26105633 TI - Common sense about prosecutions for female genital mutilation prevails-at least for now. PMID- 26105634 TI - Teens and young adults should be started on long-acting reversible contraceptives before sexual activity commences: AGAINST: Pre-emptive use without need or benefit may cause more harm than good. PMID- 26105635 TI - Teens and young adults should be started on long-acting reversible contraceptives before sexual activity commences: FOR: An opt-out programme would avoid teen pregnancy and associated costs. PMID- 26105636 TI - Episiotomy: navigating the evidence. PMID- 26105637 TI - Routine weighing of women during pregnancy is of limited value and should be abandoned: AGAINST: Routine weighing in pregnancy is the first step to preventing adverse birth outcomes. PMID- 26105638 TI - Routine weighing of women during pregnancy is of limited value and should be abandoned: FOR: Routine weighing does not solve the problem of obesity in pregnancy. PMID- 26105639 TI - Stillbirth: public/patient involvement in sensitive research and research ethics. PMID- 26105640 TI - The Hayman uterine compression suture. PMID- 26105641 TI - A new indication for trachelectomy. PMID- 26105642 TI - Re: Transverse vaginal septae: management and long-term outcomes. PMID- 26105643 TI - Re: The prevention and treatment of postpartum haemorrhage: what do we know, and where do we go next? PMID- 26105644 TI - Re: The Blue Journal Club: Preventable prematurity and fetal loss from IVF twins depend on embryo transfer policies. PMID- 26105645 TI - Authors' reply re: The Blue Journal Club. PMID- 26105646 TI - Re: Does preoperative urodynamics improve outcomes for women undergoing surgery for stress urinary incontinence? A systematic review and meta-analysis. PMID- 26105647 TI - Authors' reply re: Does preoperative urodynamics improve outcomes for women undergoing surgery for stress urinary incontinence? A systematic review and meta analysis. PMID- 26105648 TI - A report from #BlueJC: Can progestogens improve twin pregnancy outcomes? PMID- 26105649 TI - Multidisciplinary team training reduces the decision-to-delivery interval for emergency Caesarean section. AB - BACKGROUND: Emergency Caesarean section is performed when the life of the pregnant woman and/or the foetus is considered at risk. A 30-min standard for the decision-to-delivery interval (DDI) is a common practice and is supported by national organisations including The Danish Society of Obstetrics and Gynaecology. Danish obstetric departments report the DDI to a national database. A national arbitrarily set standard recommends that 95% of ECSs should be achieved within the 30-min DDI standard. In 2011, 34.4% of ECSs, performed at our hospital, were achieved within the 30-min time frame. This study aims to evaluate the effect of a simulation-based team training programme on the proportion of ECSs achieved within a 30-min time frame. METHOD: We performed an interventional before-and-after study. We evaluated a total of one hundred 30-min ECSs before and after the intervention. The primary outcome of interest was the proportion of 30-min ECSs achieved within a 30-min time frame. RESULTS: A total of 20 team training courses were held during May/June 2013. These courses trained 239 of 252 team members (comprised of: 36 obstetricians, 45 scrub nurses, 83 midwives, 38 anaesthesiologists, 37 nurse anaesthetists) in handling of 30-min ECS. This corresponds to 95% of staff. The proportion of 30-min ECSs achieved within a 30 min time frame was higher after team training (87.5%, 95% CI 79.2-93.4%) compared with before training (74.0%, 95% CI 64.0-82.4%) (P = 0.017). CONCLUSION: Team training may contribute positively to an increase in the proportion of ECSs achieved within a 30-min time frame. PMID- 26105650 TI - Seasonal variation in formation, structure, and chemical properties of phloem in Picea abies as studied by novel microtechniques. AB - MAIN CONCLUSION: Phloem production and structural development were interlinked with seasonal variation in the primary and secondary metabolites of phloem. Novel microtechniques provided new perspectives on understanding phloem structure and chemistry. To gain new insights into phloem formation in Norway spruce (Picea abies), we monitored phloem cell production and seasonal variation in the primary and secondary metabolites of inner bark (non-structural carbohydrates and phenolic stilbene glucosides) during the 2012 growing season in southern and northern Finland. The structure of developing phloem was visualised in 3D by synchrotron X-ray microtomography. The chemical features of developing phloem tissues isolated by laser microdissection were analysed by chemical microanalysis. Within-year phloem formation was associated with seasonal changes in non-structural carbohydrates and phenolic extractive contents of inner bark. The onset of phloem cell production occurred in early and mid-May in southern and northern Finland, respectively. The maximal rate of phloem production and formation of a tangential band of axial phloem parenchyma occurred in mid-June, when total non-structural carbohydrates peaked (due to the high amount of starch). In contrast, soluble sugar content dropped during the most active growth period and increased in late summer and winter. The 3D visualisation showed that the new axial parenchyma clearly enlarged from June to August. Sub-cellular changes appeared to be associated with accumulation of stilbene glucosides and soluble sugars in the newest phloem. Stilbene glucosides also increased in inner bark during late summer and winter. Our findings may indicate that stilbene biosynthesis in older phloem predominantly occurs after the formation of the new band(s) of axial parenchyma. The complementary use of novel microtechniques provides new perspectives on the formation, structure, and chemistry of phloem. PMID- 26105651 TI - Durum wheat dehydrin (DHN-5) confers salinity tolerance to transgenic Arabidopsis plants through the regulation of proline metabolism and ROS scavenging system. AB - MAIN CONCLUSION: The wheat dehydrin (DHN-5) gives birth to salinity tolerance to transgenic Arabidopsis plants by the regulation of proline metabolism and the ROS scavenging system. Dehydrins (DHNs) are involved in plant abiotic stress tolerance. In this study, we reported that salt tolerance of transgenic Arabidopsis plants overexpressing durum wheat dehydrin (DHN-5) was closely related to the activation of the proline metabolism enzyme (P5CS) and some antioxidant biocatalysts. Indeed, DHN-5 improved P5CS activity in the transgenic plants generating a significant proline accumulation. Moreover, salt tolerance of Arabidopsis transgenic plants was accompanied by an excellent activation of antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and peroxide dismutase (POD) and generation of a lower level of hydrogen peroxide (H2O2) in leaves compared to the wild-type plants. The enzyme activities were enhanced in these transgenic plants in the presence of exogenous proline. Nevertheless, proline accumulation was slightly reduced in transgenic plants promoting chlorophyll levels. All these results suggest the crucial role of DHN-5 in response to salt stress through the activation of enzymes implicated in proline metabolism and in ROS scavenging enzymes. PMID- 26105652 TI - The extreme Albino3 (Alb3) C terminus is required for Alb3 stability and function in Arabidopsis thaliana. AB - MAIN CONCLUSION: The extreme Alb3 C terminus is important for Alb3 stability in a light dependent manner, but is dispensable for LHCP insertion or D1 synthesis. YidC/Oxa1/Alb3 dependent insertion of membrane proteins is evolutionary conserved among bacteria, mitochondria and chloroplasts. Chloroplasts are challenged by the need to coordinate membrane integration of nuclear encoded, post-translationally targeted proteins into the thylakoids as well as of proteins translated on plastid ribosomes. The pathway facilitating post-translational targeting of the light-harvesting chlorophyll a/b binding proteins involves the chloroplast signal recognition particle, cpSRP54 and cpSRP43, as well as its membrane receptor FtsY and the translocase Alb3. Interaction of cpSRP43 with Alb3 is mediated by the positively charged, stromal exposed C terminus of Alb3. In this study, we utilized an Alb3 T-DNA insertion mutant in Arabidopsis thaliana lacking the last 75 amino acids to elucidate the function of this domain (alb3?C). However, the truncated Alb3 protein (Alb3?C) proved to be unstable under standard growth conditions, resulting in a reduction of Alb3?C to 20 % of wild-type levels. In contrast, accumulation of Alb3?C was comparable to wild type under low light growth conditions. Alb3?C mutants grown under low light conditions were only slightly paler than wild type, accumulated almost wild-type levels of light harvesting proteins and were not affected in D1 synthesis, therefore showing that the extreme Alb3 C terminus is dispensable for both, co- and post-translational, protein insertion into the thylakoid membrane. However, reduction of Alb3?C levels as observed under standard growth conditions resulted not only in a severely diminished accumulation of all thylakoid complexes but also in a strong defect in D1 synthesis and membrane insertion. PMID- 26105653 TI - DNA barcodes for the identification of Anoectochilus roxburghii and its adulterants. AB - MAIN CONCLUSION: Chinese medicinal herbs have a similar appearance and are easily confused, complicating identification via traditional methods. This study provided a scientific approach, based on DNA barcoding, to accurately and rapidly identify Anoectochilus roxburghii and its adulterants. This technology complements traditional methods of identification of medicinal herbs. A comparison of the DNA barcodes matK, psbA-trnH and ITS2 was performed to verify that the ITS2 sequence is an effective marker for rapidly and accurately identifying A. roxburghii and its closely related species. Genomic DNA extracted from A. roxburghii and its adulterants were used as templates and the ITS2 sequence was amplified using PCR amplification and sequencing. Species identification was conducted using BLAST1 and neighbor-joining trees. The 12 samples were successfully classified into four species based on the ITS2 sequence. The ITS2 sequence length of A. roxburghii was 253 bp. The average intra specific genetic distance of A. roxburghii was 0.0021, markedly lower than the inter-specific genetic distance between A. roxburghii and its adulterants (0.0380). Our findings illustrate that ITS2 sequence can accurately and efficiently distinguish A. roxburghii and its adulterants. In addition, the results provided reference for molecular identification of other Chinese herbal medicine. PMID- 26105655 TI - Foreword. Special issue on desiccation biology. PMID- 26105654 TI - Biochemical characterization of allene oxide synthases from the liverwort Marchantia polymorpha and green microalgae Klebsormidium flaccidum provides insight into the evolutionary divergence of the plant CYP74 family. AB - MAIN CONCLUSION: Allene oxide synthases (AOSs) were isolated from liverworts and charophytes. These AOSs exhibited enzymatic properties similar to those of angiosperms but formed a distinct phylogenetic clade. Allene oxide synthase (AOS) and hydroperoxide lyase (HPL) mediate the formation of precursors of jasmonates and carbon-six volatiles, respectively. AOS and HPL utilize fatty acid hydroperoxides and belong to the plant cytochrome P450 74 (CYP74) family that mediates plant defense against herbivores, pathogens, or abiotic stresses. Although members of the CYP74 family have been reported in mosses and other species, the evolution and function of multiple CYP74 genes in plants remain elusive. Here, we show that the liverwort Marchantia polymorpha belongs to a basal group in the evolution of land plants; has two closely related proteins (59% identity), MpAOS1 and MpAOS2, that are similar to moss PpAOS1 (49 and 47% identity, respectively); and exhibits AOS activity but not HPL activity. We also found that the green microalgae Klebsormidium flaccidum, consist of multicellular and non-branching filaments, contains an enzyme, KfAOS, that is similar to PpAOS1 (37% identity), and converts 13-hydroperoxide of linolenic acid to 12-oxo phytodienoic acid in a coupled reaction with allene oxide cyclase. Phylogenetic analysis showed two evolutionarily distinct clusters. One cluster comprised AOS and HPL from charophytic algae, liverworts, and mosses, including MpAOSs and KfAOS. The other cluster was formed by angiosperm CYP74. Our results suggest that plant CYP74 enzymes with AOS, HPL, and divinyl ether synthase activities have arisen multiple times and in the two different clades, which occurred prior to the divergence of the flowering plant lineage. PMID- 26105656 TI - Frontal extents in virtual environments are not immune to underperception. AB - Distance is commonly underperceived by up to 50 % in virtual environments (VEs), in contrast to relatively accurate real world judgments. Experiments reported by Geuss, Stefanucci, Creem-Regehr, and Thompson (Journal of Experimental Psychology: Human Perception and Performance, 38, 1242-1253, 2012) indicate that the exocentric distance separating two objects in a VE is underperceived when the objects are oriented in the sagittal plane (depth extents), but veridically perceived when oriented in a frontoparallel plane (frontal extents). The authors conclude that "distance underestimation in the [VE] generalizes to intervals in the depth plane, but not to intervals in the frontal plane." The current experiment evaluated an alternative hypothesis that the accurate judgments of frontal extents reported by Geuss et al. were due to a fortunate balance of underperception caused by the VE and overperception of frontal relative to depth extents. Participants judged frontal and depth extents in the classroom VE used by Geuss et al. and in a sparser VE containing only a grass-covered ground plane. Judgments in the classroom VE replicated findings by Geuss et al., but judgments in the grass VE show underperception of both depth and frontal extents, indicating that frontal extents are not immune to underperception in VEs. PMID- 26105658 TI - Two cases of erythroplasia of Queyrat with persistent post-treatment inflammation after histological remission of epithelial dysplasia. PMID- 26105657 TI - Modulation of spatial attention by goals, statistical learning, and monetary reward. AB - This study documented the relative strength of task goals, visual statistical learning, and monetary reward in guiding spatial attention. Using a difficult T among-L search task, we cued spatial attention to one visual quadrant by (i) instructing people to prioritize it (goal-driven attention), (ii) placing the target frequently there (location probability learning), or (iii) associating that quadrant with greater monetary gain (reward-based attention). Results showed that successful goal-driven attention exerted the strongest influence on search RT. Incidental location probability learning yielded a smaller though still robust effect. Incidental reward learning produced negligible guidance for spatial attention. The 95 % confidence intervals of the three effects were largely nonoverlapping. To understand these results, we simulated the role of location repetition priming in probability cuing and reward learning. Repetition priming underestimated the strength of location probability cuing, suggesting that probability cuing involved long-term statistical learning of how to shift attention. Repetition priming provided a reasonable account for the negligible effect of reward on spatial attention. We propose a multiple-systems view of spatial attention that includes task goals, search habit, and priming as primary drivers of top-down attention. PMID- 26105659 TI - Measurement of scapular dyskinesis using wireless inertial and magnetic sensors: Importance of scapula calibration. AB - Measurement of 3D scapular kinematics is meaningful in patients with shoulder pathologies showing scapular dyskinesis. This study evaluates the effect of single and double anatomical calibration (0 degrees and 120 degrees ) with a scapula locator compared to standard calibration (using sensor alignment with the spina scapulae and static upright posture, ISEO-protocol) on 3D scapular kinematics measured with an inertial and magnetic measurement system (IMMS). Ten patients with scapular dyskinesis performed humeral anteflexion and abduction movements while 3D scapular kinematics were measured using IMMS sensors. The sensor on the scapula was anatomically calibrated (i) according to the ISEO protocol, (ii) using single scapula locator calibration (0 degrees ) and (iii) double scapula locator calibration (0 degrees and 120 degrees ). For calibration, the scapula locator (with IMMS) was positioned on the scapula, while holding the humerus at several anteflexion and abduction postures. Single and double calibration resulted in a significant increase of scapular anterior tilt (14-30 degrees ) with respect to the skin-fixed sensor (ISEO). Protraction angles were not significantly different. During anteflexion, double calibration did not show a significant increase in lateral rotation compared to single calibration. During abduction of >90 degrees , double calibration showed 10-14 degrees increased lateral rotation with respect to single calibration, although this was not significant (P>0.06). Calibration with a scapula locator when applying IMMS is necessary, because measures of scapular anterior tilt are grossly underestimated with the ISEO-protocol. For shoulder movements that exceed 90 degrees elevation, a double calibration prevents small but relevant underestimation of lateral rotation angles of the scapula. PMID- 26105660 TI - Expedited patient-specific assessment of contact stress exposure in the ankle joint following definitive articular fracture reduction. AB - Acute injury severity, altered joint kinematics, and joint incongruity are three important mechanical factors linked to post-traumatic osteoarthritis (PTOA). Finite element analysis (FEA) was previously used to assess the influence of increased contact stress due to joint incongruity on PTOA development. While promising agreement with PTOA development was seen, the inherent complexities of contact FEA limited the numbers of subjects that could be analyzed. Discrete element analysis (DEA) is a simplified methodology for contact stress computation, which idealizes contact surfaces as a bed of independent linear springs. In this study, DEA was explored as an expedited alternative to FEA contact stress exposure computation. DEA was compared to FEA using results from a previously completed validation study of two cadaveric human ankles, as well as a previous study of post-operative contact stress exposure in 11 patients with tibial plafond fracture. DEA-computed maximum contact stresses were within 19% of those experimentally measured, with 90% of the contact area having computed contact stress values within 1MPa of those measured. In the 11 fractured ankles, maximum contact stress and contact area differences between DEA and FEA were 0.85 +/- 0.64 MPa and 22.5 +/- 11.5mm(2). As a predictive measure for PTOA development, both DEA and FEA had 100% concordance with presence of OA (KL grade >= 2) and >95% concordance with KL grade at 2 years. These results support DEA as a reasonable alternative to FEA for computing contact stress exposures following surgical reduction of a tibial plafond fracture. PMID- 26105661 TI - Tilted pillar array fabrication by the combination of proton beam writing and soft lithography for microfluidic cell capture: Part 1 Design and feasibility. AB - Design, fabrication, integration, and feasibility test results of a novel microfluidic cell capture device is presented, exploiting the advantages of proton beam writing to make lithographic irradiations under multiple target tilting angles and UV lithography to easily reproduce large area structures. A cell capture device is demonstrated with a unique doubly tilted micropillar array design for cell manipulation in microfluidic applications. Tilting the pillars increased their functional surface, therefore, enhanced fluidic interaction when special bioaffinity coating was used, and improved fluid dynamic behavior regarding cell culture injection. The proposed microstructures were capable to support adequate distribution of body fluids, such as blood, spinal fluid, etc., between the inlet and outlet of the microfluidic sample reservoirs, offering advanced cell capture capability on the functionalized surfaces. The hydrodynamic characteristics of the microfluidic systems were tested with yeast cells (similar size as red blood cells) for efficient capture. PMID- 26105662 TI - In situ imaging and proteome profiling indicate andrographolide is a highly promiscuous compound. AB - Natural products represent an enormous source of pharmacologically useful compounds, and are often used as the starting point in modern drug discovery. Many biologically interesting natural products are however not being pursued as potential drug candidates, partly due to a lack of well-defined mechanism-of action. Traditional in vitro methods for target identification of natural products based on affinity protein enrichment from crude cellular lysates cannot faithfully recapitulate protein-drug interactions in living cells. Reported herein are dual-purpose probes inspired by the natural product andrographolide, capable of both reaction-based, real-time bioimaging and in situ proteome profiling/target identification in live mammalian cells. Our results confirm that andrographolide is a highly promiscuous compound and engaged in covalent interactions with numerous previously unknown cellular targets in cell type specific manner. We caution its potential therapeutic effects should be further investigated in detail. PMID- 26105663 TI - Influence of electronic apex locators and a gutta-percha heating device on implanted cardiac devices: an in vivo study. AB - AIM: To evaluate the potential for electromagnetic interference (EMI) of electronic apex locators (EALs) and a gutta-percha heating device (HD) in patients with implantable cardiac pacemakers (ICPs) or cardioverter defibrillators (ICDs). METHODOLOGY: Two types of EALs (Romiapex A-15 and Novapex) and a HD (Touch'n Heat) were tested in patients followed in an outpatient clinic for cardiac arrhythmias. The heart rhythm was monitored on a computer screen during all experimental phases. After baseline data collection, the patient held each appliance (turned on) for 30 s, simulating their clinical use. If background noise was detected on the cardiac monitor, the sensitivity of the ICP/ICD was lowered by the cardiologist to evaluate the intensity of the detected EMI. RESULTS: Twelve patients were evaluated (5 female and 7 male), and in nine instances, background noise in their cardiac devices related to the use of the endodontic devices was detected (6 patients). After lowering the sensitivity of the cardiac implants, three patients had more severe EMI in six instances, including pauses in ICP function. The presence of a symptomatic or asymptomatic pause was related to the patient's underlying heart rhythm. The HD device produced background noise more often compared to EALs. These were associated with more severe types of EMI. CONCLUSION: The EALs and gutta-percha HD were capable of causing background noise detection or pauses in cardiac implants in vivo. The use of electronic dental devices nearby patients with cardiac implants should be carefully considered in clinical practice. PMID- 26105664 TI - Editorial Comment from Dr Zampieri to Varicocele is associated with varicose veins: A population-based case-control study. PMID- 26105666 TI - Inverted planar NH2CH=NH2PbI3 perovskite solar cells with 13.56% efficiency via low temperature processing. AB - In this work, NH2CH=NH2PbI3 (FAPbI3) was employed for light harvesting in inverted planer perovskite solar cells for the first time. Except for the silver cathode, all layers were solution-processed under or below 140 degrees C. The effect of the annealing process on device performance was investigated. The FAPbI3 solar cells based on a slowed-down annealing shows superior performance compared to the CH3NH3PbI3 (MAPbI3)-based devices, especially for the short circuit current density. A power conversion efficiency of 13.56% was obtained with high short circuit current density of 21.48 mA cm(-2). This work paves the way for low-temperature fabrication of efficient inverted planer structure FAPbI3 perovskite solar cells. PMID- 26105665 TI - Stem Cell Therapy for Myocardial Infarction 2001-2013 Revisited. AB - Stem cell therapy for ischemic heart disease was an emerging concept in the early 2000s. First hopes were largely overshadowed by rather inconsistent results in human trials conducted in the middle of the decade. We aimed at investigating how the field of stem cell research expanded worldwide over the years using scientometric methods. We performed a PubMed inquiry and screened a total of 2609 publications dealing with stem cell therapy for myocardial infarction in the years 2001-2013. Density equalizing maps were used to visualize important centres of stem cell research worldwide. This systematic bibliometric study revealed an increasing research interest in the field of stem cell research in the context of ischemic heart disease over the last decade. Though some of the large human trials failed to show significant effects of stem cell therapy, especially basic science represents an ever growing field that evolved promising new concepts over the last couple of years. The scientific principle of protective paracrine mediators released from transplanted stem cells seems to bear great potential for future cell-free therapeutic use. However, further mechanistic insights are needed before transition from bench to bedside should be attempted, taking the lessons learned from previous studies into account. PMID- 26105667 TI - Statewide Longitudinal Hospital Use and Charges for Pediatric and Adolescent Patients With Cancer. AB - PURPOSE: We investigated longitudinal hospitalization outcomes (total charges, hospital days and admissions) among pediatric and adolescent patients with cancer compared with individuals from the general population without cancer using a novel and efficient three-step regression procedure. METHODS: The statewide Utah Population Database, with linkages to the Utah Cancer Registry, was used to identify 1,651 patients who were diagnosed with cancer from 1996 to 2009 at ages 0 to 21 years. A comparison group of 4,953 same-sex and -age individuals was generated from birth certificates. Claims-based hospitalization data from 1996 to 2012 were retrieved from the Utah Department of Health. Using the regression method, we estimated survival (differences due to survival) and intensity (differences due to resource accumulation) effects of the cancer diagnosis on hospitalization outcomes within 10 years after diagnosis. RESULTS: At 10 years after diagnosis, on average, patients with cancer incurred $51,723 (95% CI, $48,100 to $58,284) more in charges, spent 30 additional days (95% CI, 27.7 to 36.1 days) in the hospital, and had 5.7 (95% CI, 5.4 to 6.4) more admissions than the comparison group. Our analyses showed that the highest hospitalization burden occurred during the first 4 years of diagnosis. Patients with leukemia incurred the greatest hospitalization burden throughout the 10 years from diagnosis. Intensity effects explained the majority of differences in hospital outcomes. CONCLUSION: Our results suggest that children and adolescents who were diagnosed with cancer in 2014 in the United States will incur over $800 million more in hospital charges than individuals without cancer by 2024. Interventions to reduce this burden should be explored in conjunction with improving health and survival outcomes. PMID- 26105668 TI - Use and Costs for Tumor Gene Expression Profiling Panels in the Management of Breast Cancer From 2006 to 2012: Implications for Genomic Test Adoption Among Private Payers. AB - PURPOSE: Tumor gene expression profiling (GEP) can be used to predict recurrence risk and the potential benefit of breast cancer treatment. Adoption of GEP among privately insured patients has not been well studied. Our objectives were to characterize trends in GEP use and to evaluate per-use patient and health plan payments from 2006 to 2012. METHODS: We used Truven Health Analytics MarketScan administrative claims database to examine GEP testing among women with breast cancer from 2006 to 2012 (N = 154,883). We estimated trends in the proportion of women who received GEP using segmented regression. We summarized average reimbursement for GEP, including insurer payments and patient out-of-pocket payments. RESULTS: Overall, 18,575 women received GEP. The average age was 53.6 years, and most were enrolled in a preferred provider organization health plan. The adjusted proportion of women with breast cancer who received GEP grew from 2.2% in 2006 to 18.8% in 2012 (adjusted risk ratio, 8.4; 95% CI, 7.6 to 9.3). Out of-pocket costs to the patient ranged from $0 to $4,752. Most patients paid nothing for GEP (median, $0; interquartile ratio, $4). Mean patient out-of-pocket costs were $175 (standard deviation [SD], $484). Private-insurer reimbursed amounts for GEP increased annually from an average of $3,125 (SD, $1,523) in 2006 to $3,680 (SD, $835) by 2012. CONCLUSION: GEP has rapidly diffused into clinical practice. Reimbursements by insurers have increased slowly, and average out-of pocket costs to patients have decreased, seemingly driven by improved coverage for testing over time. As more genetic tests become available, it will be important to understand how these technologies will affect cancer care costs across the US health care system. PMID- 26105669 TI - Changes in Medication Management After a Diagnosis of Cancer Among Medicare Beneficiaries With Diabetes. AB - PURPOSE: A new cancer diagnosis commonly initiates a cascade of health care decisions that have potentially important consequences for management of other chronic conditions such as diabetes. We sought to determine whether a new cancer diagnosis is associated with changes in medication adherence among Medicare beneficiaries with diabetes, and whether the relationship is affected by life expectancy and generosity of drug coverage. METHODS: The study population was drawn from a 5% random sample of Medicare beneficiaries with diabetes enrolled in Medicare Part D in 2007 and 2008. Patients had cancer newly diagnosed between January and December 2007 (n = 4,348) and were compared with a cancer-free control group (N = 28,507) assigned a pseudo-diagnosis date. Adherence (proportion of days covered [PDC]) with oral hypoglycemic agents, renin angiotensin-aldosterone system inhibitors, and statins was tracked for 6 months before and after the diagnosis date. Multivariable regression models assessed the independent impact of a cancer diagnosis, life expectancy (proxy measure: died 7 to 12 months after index date), and coverage generosity (proxy measure: low income subsidy recipient) on PDC, controlling for individual characteristics. RESULTS: Relatively larger declines in medication adherence (3 to 5 percentage points; P < .001) were observed overall for patients with cancer versus controls. Short life expectancy was associated with between 8% and 11% lower PDC (P < .001) in the cancer subgroup relative to controls. Low-income subsidy status had no differential effect on changes in drug adherence. CONCLUSION: A cancer diagnosis among patients with diabetes reduced adherence with evidence-based medications, particularly if patients' life expectancy was short. PMID- 26105670 TI - Measuring Comprehensiveness of Primary Care: Challenges and Opportunities. AB - Comprehensiveness of primary care (the extent to which the clinician, as part of the primary care team, recognizes and meets the majority of each patient's physical and mental health care needs) is an important element of primary care, but seems to be declining in the U.S. This is concerning, because more comprehensive primary care is associated with greater equity and efficiency in health care, improved continuity, less care fragmentation and better health outcomes. Without measurement and support for its improvement, comprehensiveness may further decline as other measured aspects of primary care (e.g. access, coordination) improve. To track, support and improve comprehensiveness, it is useful to have valid and reliable ways to measure it. This paper discusses challenges to measuring comprehensiveness for a primary care team's patient panel, presents survey and claims-based measures of comprehensiveness, and provides suggestions for future research. PMID- 26105672 TI - Methods of Observing Variations in Physicians' Decisions: The Opportunities of Clinical Vignettes. AB - To support their efforts to promote high quality and efficient care, policymakers need to better understand the key factors associated with variations in physicians' decisions, and in particular, physician deviations from evidence based care. Clinical vignette survey instruments hold potential for research in this area as an approach that both allows for practical, large-scale study and overcomes the data quality challenges posed by analysis of clinical data. These surveys present respondents with a narrative description of a hypothetical patient case and solicit responses to one or more questions regarding the care of the patient. In this review, we describe various methods for measuring variations in physicians' decisions and highlight a range of design features researchers should consider when developing a clinical vignette survey. We conclude by identifying areas for future research. PMID- 26105671 TI - Disentangling the Linkage of Primary Care Features to Patient Outcomes: A Review of Current Literature, Data Sources, and Measurement Needs. AB - Primary care plays a central role in the provision of health care, and is an organizing feature for health care delivery systems in most Western industrialized democracies. For a variety of reasons, however, the practice of primary care has been in decline in the U.S. This paper reviews key primary care concepts and their definitions, notes the increasingly complex interplay between primary care and the broader health care system, and offers research priorities to support future measurement, delivery and understanding of the role of primary care features on health care costs and quality. PMID- 26105673 TI - Factors Contributing to Variations in Physicians' Use of Evidence at The Point of Care: A Conceptual Model. AB - There is ample evidence that many clinical decisions made by physicians are inconsistent with current and generally accepted evidence. This leads to the underuse of some efficacious diagnostic, preventive or therapeutic services, and the overuse of others of marginal or no value to the patient. Evolving new payment and delivery models place greater emphasis on the provision of evidence based services at the point of care. However, changing physician clinical behaviors is likely to be difficult and slow. Policy makers therefore need to design interventions that are most effective in promoting greater evidence-based care. To help identify modifiable factors that can influence clinical decisions at the point of care, we present a conceptual model and literature review of physician decision making. We describe the multitude of factors--drawn from different disciplines--that have been shown to influence physician point-of-care decisions. We present a conceptual framework for organizing these factors, dividing them into patient, physician, practice site, physician organization, network, market, and public policy influences. In doing so, we review some of the literature that speak to these factors. We then identify areas where additional research is especially needed, and discuss the challenges and opportunities for health services and policy researchers to gain a better understanding of these factors, particularly those that are potentially modifiable by policymakers and organizational leaders. PMID- 26105674 TI - Measuring Changes in the Economics of Medical Practice. AB - For the latter third of the twentieth century, researchers have estimated production and cost functions for physician practices. Today, those attempting to measure the inputs and outputs of physician practice must account for many recent changes in models of care delivery. In this paper, we review practice inputs and outputs as typically described in research on the economics of medical practice, and consider the implications of the changing organization of medical practice and nature of physician work. This evolving environment has created conceptual challenges in what are the appropriate measures of output from physician work, as well as what inputs should be measured. Likewise, the increasing complexity of physician practice organizations has introduced challenges to finding the appropriate data sources for measuring these constructs. Both these conceptual and data challenges pose measurement issues that must be overcome to study the economics of modern medical practice. Despite these challenges, there are several promising initiatives involving data sharing at the organizational level that could provide a starting point for developing the needed new data sources and metrics for physician inputs and outputs. However, additional efforts will be required to establish data collection approaches and measurements applicable to smaller and single specialty practices. Overcoming these measurement and data challenges will be key to supporting policy-relevant research on the changing economics of medical practice. PMID- 26105676 TI - The Results Are Only as Good as the Sample: Assessing Three National Physician Sampling Frames. AB - BACKGROUND: Databases of practicing physicians are important for studies that require sampling physicians or counting the physician population in a given area. However, little is known about how the three main sampling frames differ from each other. OBJECTIVE: Our purpose was to compare the National Provider and Plan Enumeration System (NPPES), the American Medical Association Masterfile and the SK&A physician file. METHODS: We randomly sampled 3000 physicians from the NPPES (500 in six specialties). We conducted two- and three-way comparisons across three databases to determine the extent to which they matched on address and specialty. In addition, we randomly selected 1200 physicians (200 per specialty) for telephone verification. KEY RESULTS: One thousand, six hundred and fifty-five physicians (55 %) were found in all three data files. The SK&A data file had the highest rate of missing physicians when compared to the NPPES, and varied by specialty (50 % in radiology vs. 28 % in cardiology). NPPES and SK&A had the highest rates of matching mailing address information, while the AMA Masterfile had low rates compared with the NPPES. We were able to confirm 65 % of physicians' address information by phone. The NPPES and SK&A had similar rates of correct address information in phone verification (72-94 % and 79-92 %, respectively, across specialties), while the AMA Masterfile had significantly lower rates of correct address information across all specialties (32-54 % across specialties). CONCLUSIONS: None of the data files in this study were perfect; the fact that we were unable to reach one-third of our telephone verification sample is troubling. However, the study offers some encouragement for researchers conducting physician surveys. The NPPES and to a lesser extent, the SK&A file, appear to provide reasonably accurate, up-to-date address information for physicians billing public and provider insurers. PMID- 26105675 TI - Patient Use of Email, Facebook, and Physician Websites to Communicate with Physicians: A National Online Survey of Retail Pharmacy Users. AB - BACKGROUND: Patient-physician communication often occurs outside the clinic setting; many institutions discourage electronic communication outside of established electronic health record systems. Little empirical data are available on patient interest in electronic communication and Web-based health tools that are technically feasible but not widely available. RESEARCH OBJECTIVE: To explore patient behavior and interest in using the Internet to contact physicians. DESIGN: National cross-sectional online survey. PARTICIPANTS: A sample of 4,510 CVS customers with at least one chronic condition in the household was used to target patients with chronic conditions and their caregivers. Subjects were identified from a national panel of over 100,000 retail pharmacy customers. Of those sampled, 2,252 responded (50.0 % response rate). MAIN MEASURES: Survey measures included demographic and health information, patient use of email and Facebook to contact physicians, and patient interest in and use of Web-based tools for health. KEY RESULTS: A total of 37 % of patients reported contacting their physicians via email within the last six months, and 18 % via Facebook. Older age was negatively associated with contacting physicians using email (OR 0.57 [95 % CI 0.41-0.78]) or Facebook (OR 0.28 [0.17-0.45]). Non-white race (OR 1.61 [1.18-2.18] and OR 1.82 [1.24-2.67]) and caregiver status (OR 1.58 [1.27 1.96] and OR 1.71 [1.31- 2.23]) were positively associated with using email and Facebook, respectively. Patients were interested in using Web-based tools to fill prescriptions, track their own health, and access health information (37-57 %), but few were currently doing so (4-8 %). CONCLUSIONS: In this population of retail pharmacy users, there is strong interest among patients in the use of email and Facebook to communicate with their physicians. The findings highlight the gap between patient interest for online communication and what physicians may currently provide. Improving and accelerating the adoption of secure Web messaging systems is a possible solution that addresses both institutional concerns and patient demand. PMID- 26105677 TI - Making the Case for a New National Data Collection Effort on Physicians and Their Practices. PMID- 26105678 TI - Cotton Fever: Does the Patient Know Best? AB - Fever and leukocytosis have many possible etiologies in injection drug users. We present a case of a 22-year-old woman with fever and leukocytosis that were presumed secondary to cotton fever, a rarely recognized complication of injection drug use, after an extensive workup. Cotton fever is a benign, self-limited febrile syndrome characterized by fevers, leukocytosis, myalgias, nausea and vomiting, occurring in injection drug users who filter their drug suspensions through cotton balls. While this syndrome is commonly recognized amongst the injection drug user population, there is a paucity of data in the medical literature. We review the case presentation and available literature related to cotton fever. PMID- 26105679 TI - Small Talk. PMID- 26105680 TI - Facial Swelling and Rash Following Tooth Extraction. PMID- 26105681 TI - "Doctor, My Chest is on Fire". PMID- 26105683 TI - Risk factors of hand climbing-related injuries. AB - This study aimed to investigate the protective mechanisms or risk factors that can be related to the occurrence of hand climbing-related injuries (CRIH ). CRIH (tendon, pulley, muscle, and joint injuries) were retrospectively screened in 528 adult climbers. The questionnaire contained anthropometric items (e.g., body mass index - BMI), as well as items regarding climbing and basic training activities (warm-up, cool-down and session durations, number of session per week, hydration, practice level, climbing surface, and duration of the cardiovascular training). Higher skilled climbers and climbers with BMI above 21 kg/m(2) were more likely to have experienced CRIH (P < 0.01). Climbers with BMI above 20 kg/m(2) were more likely to have tendon injuries while those with a BMI above 21 kg/m(2) were more likely to have pulley injuries (P < 0.01). Skilled climbers, who climb more difficult routes, may use smaller grip size and a reduced number of fingers. Higher BMI will require a higher force to climb. Both high level and elevated BMI may increase the demands to the hands and fingers leading to CRIH . These risk factors are difficult to address as we cannot recommend the climbers to climb easier routes and decrease their BMI below 20 kg/m(2) . PMID- 26105684 TI - EEG background features that predict outcome in term neonates with hypoxic ischaemic encephalopathy: A structured review. AB - OBJECTIVES: Hypoxic ischaemic encephalopathy is a significant cause of mortality and morbidity in the term infant. Electroencephalography (EEG) is a useful tool in the assessment of newborns with HIE. This systematic review of published literature identifies those background features of EEG in term neonates with HIE that best predict neurodevelopmental outcome. METHODS: A literature search was conducted using the PubMed, EMBASE and CINAHL databases from January 1960 to April 2014. Studies included in the review described recorded EEG background features, neurodevelopmental outcomes at a minimum age of 12 months and were published in English. Pooled sensitivities and specificities of EEG background features were calculated and meta-analyses were performed for each background feature. RESULTS: Of the 860 articles generated by the initial search strategy, 52 studies were identified as potentially relevant. Twenty-one studies were excluded as they did not distinguish between different abnormal background features, leaving 31 studies from which data were extracted for the meta analysis. The most promising neonatal EEG features are: burst suppression (sensitivity 0.87 [95% CI (0.78-0.92)]; specificity 0.82 [95% CI (0.72-0.88)]), low voltage (sensitivity 0.92 [95% CI (0.72-0.97)]; specificity 0.99 [95% CI (0.88-1.0)]), and flat trace (sensitivity 0.78 [95% CI (0.58-0.91)]; specificity 0.99 [95% CI (0.88-1.0)]). CONCLUSION: Burst suppression, low voltage and flat trace in the EEG of term neonates with HIE most accurately predict long term neurodevelopmental outcome. SIGNIFICANCE: This structured review and meta analysis provides quality evidence of the background EEG features that best predict neurodevelopmental outcome. PMID- 26105685 TI - Individual variability in perceptual switching behaviour is associated with reversal-related EEG modulations. AB - OBJECTIVE: High individual variability is frequently observed in multistable perception, but few ERP studies have considered this factor. The present investigation evaluates the relation between individual perceptual switching and the modulation of reversal-related ERP components. METHODS: We used a bistable perception paradigm (Kornmeier and Bach, 2004), consisting of briefly flashed grid of nine Necker cubes, interspersed by a blank screen. The subject's task was to compare the previous stimulus with the latter one. The number of reversal perceptions was used as a measure of individual perceptual switching behaviour. RESULTS: As in previously reported findings, Reversal Negativity (RN, 180-300 ms) and Late Positive Component (LPC, 350-600 ms) were identified in response to reversal perception. In terms of individual differences, higher reversals were associated with reduced negativity of the RN and enhanced positivity of the LPC. CONCLUSION: The timing of the present results supports the hypothesis that individual variability in perceptual reversal is associated with different neural activations at later stage of processing, when the neural representation of ambiguous figure must be internalized to produce an appropriate response/behaviour. SIGNIFICANCE: Multistable perception can reveal crucial mechanisms underlying individual perceptual re-organization when inconsistent or incoherent stimuli come from the environment. PMID- 26105686 TI - A simple model for pollen-parent fecundity distributions in bee-pollinated forage legume polycrosses. AB - A simple Weibull distribution based empirical model that predicts pollen-parent fecundity distributions based on polycross size alone has been developed in outbred forage legume species for incorporation into quantitative genetic theory. Random mating or panmixis is a fundamental assumption in quantitative genetic theory. Random mating is sometimes thought to occur in actual fact, although a large body of empirical work shows that this is often not the case in nature. Models have been developed to explain many non-random mating phenomena. This paper measured pollen-parent fecundity distributions among outbred perennial forage legume species [autotetraploid alfalfa (Medicago sativa L.), autohexaploid kura clover (Trifolium ambiguum M. Bieb.), and diploid red clover (Trifolium pratense L.)] in ten polycrosses ranging in size (N) from 9 to 94 pollinated with bee pollinators [Bumble Bees (Bombus impatiens Cr.) and leafcutter bees (Megachile rotundata F.)]. A Weibull distribution best fit the observed pollen parent fecundity distributions. After standardizing data among the 10 polycrosses, a single Weibull distribution-based model was obtained with an R (2) of 0.978. The model is able to predict pollen-parent fecundity distributions based on polycross size alone. The model predicts that the effective polycross size will be approximately 9 % smaller than under random mating (i.e., N e/N ~ 0.91). The model is simple and can easily be incorporated into other models or simulations requiring a pollen-parent fecundity distribution. Further work is needed to determine how widely applicable the model is. PMID- 26105687 TI - CT for occult cancer is unnecessary in people with unexpected venous thromboembolism, study finds. PMID- 26105688 TI - Inhibition of ferric ion to oxalate oxidase shed light on the substrate binding site. AB - Oxalate oxidase (OxOx), a well known enzyme catalyzes the cleavage of oxalate to carbon dioxide with reduction of dioxygen to hydrogen peroxide, however its catalytic process is not well understood. To define the substrate binding site, interaction of Fe(3+) ions with OxOx was systemically investigated using biochemical method, circular dichrosim spectroscopy, microscale thermophoresis, and computer modeling. We demonstrated that Fe(3+) is a non-competitive inhibitor with a milder binding affinity to OxOx, and the secondary structure of the OxOx was slightly altered upon its binding. On the basis of the structural properties of the OxOx and its interaction with Fe(3+) ions, two residue clusters of OxOx were assigned as potential Fe(3+) binding sites, the mechanism of the inhibition of Fe(3+) was delineated. Importantly, the residues that interact with Fe(3+) ions are involved in the substrate orienting based on computer docking. Consequently, the interaction of OxOx with Fe(3+) highlights insight into substrate binding site in OxOx. PMID- 26105689 TI - Reply: To PMID 25597837. PMID- 26105690 TI - A scanning cavity microscope. AB - Imaging the optical properties of individual nanosystems beyond fluorescence can provide a wealth of information. However, the minute signals for absorption and dispersion are challenging to observe, and only specialized techniques requiring sophisticated noise rejection are available. Here we use signal enhancement in a high-finesse scanning optical microcavity to demonstrate ultra-sensitive imaging. Harnessing multiple interactions of probe light with a sample within an optical resonator, we achieve a 1,700-fold signal enhancement compared with diffraction limited microscopy. We demonstrate quantitative imaging of the extinction cross section of gold nanoparticles with a sensitivity less than 1 nm(2); we show a method to improve the spatial resolution potentially below the diffraction limit by using higher order cavity modes, and we present measurements of the birefringence and extinction contrast of gold nanorods. The demonstrated simultaneous enhancement of absorptive and dispersive signals promises intriguing potential for optical studies of nanomaterials, molecules and biological nanosystems. PMID- 26105691 TI - Presence of Fragmented QRS May Be Due to Higher Levels of Left Ventricle Mass in Patients with Severe Aortic Stenosis. PMID- 26105692 TI - Development of neuromuscular organization in the ctenophore Pleurobrachia bachei. AB - The phylogenetic position of the phylum Ctenophora and the nature of ctenphore nervous systems are highly debated topics in modern evolutionary biology. However, very little is known about the organization of ctenophore neural and muscular systems, and virtually nothing has been reported about their embryogenesis. Here we have characterized the neural and muscular development of the sea gooseberry, Pleurobrachia bachei, starting from the cleavage stages to posthatching larvae. Scanning electron microscopy and immunochemistry were used to describe the formation of the embryonic mouth, tentacles, combs, aboral organ, and putative sensory cells. The muscles started their specification at the end of the first day of Pleurobrachia development. In contrast, neurons appeared 2 days after myogenesis, just before the hatching of fully formed cydippid larvae. The first tubulin-immunoreactive neurons, a small group of four to six cells with neuronal processes, was initially recognized at the aboral pole during the third day of development. Surprisingly, this observed neurogenesis occurred after the emergence of distinct behavioral patterns in the embryos. Thus, the embryonic behavior associated with comb cilia beatings and initial muscle organization does not require morphologically defined neurons and their elongated neurites. This study provides the first description of neuromuscular development in the enigmatic ctenophores and establishes the foundation for future research using emerging genomic tools and resources. PMID- 26105694 TI - Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts. AB - Radiation-induced lung injury (RILI) limits the benefits of radiotherapy in patients with lung cancer. Radiation-induced differentiation of lung fibroblasts to myofibroblasts plays a key role in RILI. Recent studies have shown that mesenchymal stem cells (MSCs) can protect against lung fibrosis and that Wnt/beta catenin signaling is involved in fibrotic processes. In the present study, we explored the therapeutic potential of human umbilical cord MSCs (HUMSCs) for preventing radiation-induced differentiation of human lung fibroblasts (HLFs) to myofibroblasts. There are two advantages in the use of HUMSCs; namely, they are easily obtained and have low immunogenicity. Irradiated HLFs were co-cultured with HUMSCs. Expression of alpha-smooth muscle actin (alpha-SMA), a myofibroblast marker, was measured by Western blot analysis and immunohistochemistry. Irradiation (X-rays, 5 Gy) induced the differentiation of HLFs into myofibroblasts, which was inhibited by co-culture with HUMSCs. Irradiation also caused activation of the canonical Wnt/beta-catenin signaling in HLFs, as judged by increased phosphorylation of glycogen synthase kinase 3beta, nuclear accumulation of beta-catenin, and elevated levels of Wnt-inducible signaling protein-1 (WISP-1) in the conditioned medium. However, co-culture with HUMSCs attenuated the radiation-induced activation of the Wnt/beta-catenin signaling. We also measured the expression of FRAT1 that can enhance the Wnt/beta-catenin signaling by stabilizing beta-catenin. Co-culture with HUMSCs decreased FRAT1 protein levels in irradiated nHLFs. Thus, co-culture with HUMSCs attenuated the radiation-induced activation of Wnt/beta-catenin signaling in HLFs, thereby inhibiting myofibroblastic differentiation of HLFs. Wnt/beta-catenin signaling is a potential therapeutic target for limiting RILI in patients receiving radiotherapy for lung cancer. PMID- 26105695 TI - FokI Polymorphism of the Vitamin D Receptor Gene Is Associated with Susceptibility to Gastric Cancer: A Case-Control Study. AB - Vitamin D is a potential protective agent against cancer, and its activity is mediated mainly by vitamin D receptor (VDR). The FokI polymorphism (rs10735810) represents a T-to-C transition (ATG to ACG) in exon 2 of the VDR gene, and this ATG represents the translation-initiation codon, encoded by the f allele. The FokI polymorphism results in the generation of a protein shortened by three amino acids, translated from the downstream ATG codon (the F allele). We investigated the relationship between the FokI polymorphism and gastric cancer in a Chinese Han population. A total of 187 patients and 212 healthy controls were enrolled. The FokI polymorphism was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. The f allele frequency was higher in patients than that in controls (51.6% and 43.6%, P < 0.05). Multivariate logistics regression analysis revealed patients with the f allele (Ff + ff) showed a higher risk of gastric cancer [odds ratio (95% confidence interval) 2.73 (1.13~4.32)]. Patients with the f allele (Ff + ff) also presented a poorly differentiated type of gastric cancer (P < 0.05) and higher levels of C reactive protein on admission than the FF group (5.5 +/- 2.4 mg/L vs. 3.4 +/- 1.3 mg/L, P < 0.05). Here, we show an association between the VDR FokI polymorphism and the susceptibility to gastric cancer, which may be helpful for early detection of high-risk individuals with the f allele for gastric cancer. Conversely, the F allele may be a protective factor against gastric cancer. PMID- 26105693 TI - A Comprehensive View of the Neurotoxicity Mechanisms of Cocaine and Ethanol. AB - Substance use disorder is an emerging problem concerning to human health, causing severe side effects, including neurotoxicity. The use of illegal drugs and the misuse of prescription or over-the-counter drugs are growing in this century, being one of the major public health problems. Ethanol and cocaine are one of the most frequently used drugs and, according to the National Institute on Drug Abuse, their concurrent consumption is one of the major causes for emergency hospital room visits. These molecules act in the brain through different mechanisms, altering the nervous system function. Researchers have focused the attention not just in the mechanism of action of these drugs, but also in the mechanism by which they damage the nervous tissue (neurotoxicity). Therefore, the goal of the present review is to provide a global perspective about the mechanisms of the neurotoxicity of cocaine and ethanol. PMID- 26105696 TI - Lower serum soluble-EGFR is a potential biomarker for metastasis of HCC demonstrated by N-glycoproteomic analysis. AB - Hepatocellular carcinoma (HCC) is one of the most deadly cancers in the world due to its high metastatic potential. By using the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative N-glycoproteomic analysis, 26 differentially expressed serum glycoproteins derived from defined stages in orthotopic xenograft tumor model were identified. Among them, expression level of soluble EGFR (sEGFR) was verified in HCC cell lines. We found that non-metastasis HCC cell lines express significantly more sEGFR than HCC cell lines with metastasis potential both in cell lysates and culture media. Serum samples from 28 non-metastatic HCC patients and 28 metastatic HCC patients were assayed. Compared with the non-metastatic HCC group, serum level of sEGFR in metastatic HCC group was statistically lower (p<0.01). All these results provide evidence that sEGFR is a potential candidate for metastasis-associated biomarkers of HCC. The related molecular mechanism deserves to be further explored. PMID- 26105697 TI - Gut microbiota-derived outer membrane vesicles: under-recognized major players in health and disease? AB - The role of gut microbiota both in human health and in disease is the subject of intense investigation. The interactions between gut microbiota and the host involve a complex network of metabolic pathways and of biologically active molecules secreted by intestinal bacteria, some of which are packed into nanoparticles known as outer membrane vesicles (OMVs). OMVs can enter the systemic circulation and be delivered to different organs including the brain, eliciting a variety of immunological and metabolic responses. The resulting acute and chronic effects are largely unknown. However, recent studies suggest that OMVs could play a critical role in immune homeostasis and in acute inflammatory reactions. Moreover, the "leaky gut" hypothesis has recently emphasized the role of the brain-gut axis in the pathogenesis of major depressive disorders, pointing to the importance of bacteria and of bacterial products delivered into the circulation in eliciting the low-grade inflammatory response associated with this syndrome. Interestingly, experimental evidence suggests that OMVs can also affect the permeability of the blood-brain barrier. This review also highlights the importance of investigating possible influences of OMVs on the development of the immune system. PMID- 26105698 TI - Stem cell-derived liver cells for drug testing and disease modeling. AB - Differences between animals and humans in liver pathways now necessitate the use of in vitro models of the human liver for several applications such as drug screening. However, isolated primary human hepatocytes (PHHs) are a limited resource for building such models given shortages of donor organs. In contrast, human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) can be propagated nearly indefinitely and differentiated into hepatocyte-like cells in vitro using soluble factors inspired from liver development. Additionally, iPSCs can be generated from patients with specific genetic backgrounds to study genotype-phenotype relationships. While current protocols to differentiate hESCs and iPSCs into human hepatocyte-like cells (hESC-HHs and iPSC-HHs) still need improvement to yield cells functionally similar to the adult liver, proof-of concept studies have already shown utility of these cells in drug development and modeling liver diseases such as alpha1-antitrypsin deficiency, hepatitis B/C viral infections, and malaria. Here, we present an overview of hESC-HH and iPSC HH culture platforms that have been utilized for the aforementioned applications. We also discuss the use of semiconductor-driven microfabrication tools to precisely control the microenvironment around these cells to enable higher and longer-term liver functions in vitro. Finally, we discuss areas for improvement in creating next generation stem cell-derived liver models. In the future, stem cell-derived hepatocyte-like cells could provide a sustainable cell source for high-throughput drug screening, enabling better mechanistic understanding of human liver diseases for the development of more efficacious and safer therapeutics, and personalized cell-based therapies in the clinic. PMID- 26105700 TI - Genetics of autism spectrum disorder: an update on copy number variations leading to autism in the next generation sequencing era. AB - Autism spectrum disorder (ASD) is a large group of neurodevelopmental conditions that share common characteristics such as social and language impairment and repetitive and stereotypic behaviors. It is reported that ASD is on increase in recent years reaching ratios up to 1 in 68 children. The disease is seen four times more frequently in males than females. ASD is heritable with complex inheritance and genetic heterogeneity, and frequently coexists with other diseases such as intellectual disability, seizure disorders, and fragile-x. Recent advances in genomic technologies have led to a greater understanding of genetic mechanisms in ASD, discovery of novel genetic loci and risk factors, as well as submicroscopic chromosomal changes also known as copy number variations (CNVs). Here we review recent developments in the genetics field and hereditary and sporadic CNVs leading to ASD. PMID- 26105699 TI - Oncolytic immunotherapy through tumor-specific translation and cytotoxicity of poliovirus. AB - Achieving tumor-specific, robust, and durable effector cytotoxic immune responses is key to successful immunotherapy. This has been accomplished with adoptive cell transfer of ex vivo-expanded autologous tumor-infiltrating or engineered T cells, or with immune checkpoint inhibitors, enhancing inherent T cell reactivity. A natural ability to recruit effector responses makes tumor-targeting ('oncolytic') viruses attractive as immunotherapy vehicles. However, most viruses actively block inflammatory and immunogenic events; or, host innate immune responses may prevent immune initiating events in the first place. Moreover, the mechanisms of how virus infection can produce effector responses against host (tumor) neo antigens are unclear. We are pioneering oncolytic immunotherapy based on poliovirus, which has no specific mechanism to interfere with host immune activation, exhibits lytic cytotoxicity in the presence of an antiviral interferon response and pre-existing immunity, and engages a powerful innate immune sensor implicated in recruiting cytotoxic T cell responses. Central to this approach is a unique confluence of factors that drive tumor-specific viral translation and cytotoxicity. PMID- 26105702 TI - Anti-programmed cell death-1 (PD-1) monoclonal antibodies in treating advanced melanoma. AB - The anti-programmed cell death-1 (PD-1) monoclonal antibodies pembrolizumab and nivolumab have been contingently approved for the treatment of patients with advanced melanoma based on their durable response, high response rate, and favorable safety profile. Mature survival data from randomized phase III trials are eagerly awaited to confirm their position as the standard-of-care frontline or second-line therapy in advanced melanoma management algorithm. The immune related adverse events associated with these novel agents are somewhat different than those of ipilimumab, considering the manifestation of pneumonitis and acute renal failure. Active research is ongoing to identify biomarkers predictive of clinical benefit to the anti-PD1 monoclonal antibodies, to expand their utility in other disease settings, and to explore their safety and efficacy in combination with other therapeutic agents. Unanswered questions concerning optimal dosing schedule, treatment duration, and therapy sequencing will also need to be addressed in future investigations. PMID- 26105701 TI - Stroke induces a rapid adaptive autoimmune response to novel neuronal antigens. AB - Stroke affects millions of people worldwide every year. Despite this prevalence, mechanisms of long-term injury and repair within the ischemic brain are still understudied. Sterile inflammation occurs in the injured brain after stroke, with damaged tissue exposing central nervous system (CNS)-derived antigen that could initiate potential autoimmune responses. We used a standard immunology-based recall response assay for murine immune cells, isolated from the cervical lymph nodes and spleen after transient stroke, to determine if stroke induces autoreactivity to CNS target antigens. Our assays included novel neuronal peptides, in addition to myelin-, nuclear-, glial-, and endothelial-derived peptides. Autoimmune responses to an antigen were considered positive based on proliferation and activation over non-stimulated conditions. Stroke induced a significant increase in autoreactive CD4+ and CD8+ T cells, as well as autoreactive CD19+ B cells, as early as 4 days after stroke onset. Mice with large infarct volumes exhibited early T and B cell autoreactivity to NR2A, an NMDA receptor subunit, in cells isolated from lymph nodes but not spleen. Mice with small infarct volumes exhibited high autoreactivity to MAP2, a dendritic cytoskeletal protein, as well as myelin-derived peptides. This autoimmunity was maintained through 10 days post-stroke in both lymph nodes and spleen for all lymphocyte subsets. Sham surgery also induced early autoreactive B cell responses to MAP2 and myelin. Based on these observations, we hypothesize that stroke induces a secondary, complex, and dynamic autoimmune response to neuronal antigens with the potential to potentiate, or perhaps even ameliorate, long-term neuroinflammation. PMID- 26105703 TI - Breast-feeding and complementary feeding practices in the first 6 months of life among Norwegian-Somali and Norwegian-Iraqi infants: the InnBaKost survey. AB - OBJECTIVE: To examine breast-feeding and complementary feeding practices during the first 6 months of life among Norwegian infants of Somali and Iraqi family origin. DESIGN: A cross-sectional survey was performed during March 2013-February 2014. Data were collected using a semi-quantitative FFQ adapted from the second Norwegian national dietary survey among infants in 2006-2007. SETTING: Somali born and Iraqi-born mothers living in eastern Norway were invited to participate. SUBJECTS: One hundred and seven mothers/infants of Somali origin and eighty mothers/infants of Iraqi origin participated. RESULTS: Breast-feeding was almost universally initiated after birth. Only 7 % of Norwegian-Somali and 10 % of Norwegian-Iraqi infants were exclusively breast-fed at 4 months of age. By 1 month of age, water had been introduced to 30 % of Norwegian-Somali and 26 % of Norwegian-Iraqi infants, and infant formula to 44 % and 34 %, respectively. Fifty four per cent of Norwegian-Somali and 68 % of Norwegian-Iraqi infants had been introduced to solid or semi-solid foods at 4 months of age. Breast-feeding at 6 months of age was more common among Norwegian-Somali infants (79 %) compared with Norwegian-Iraqi infants (58 %; P=0.001). Multivariate analyses indicated no significant factors associated with exclusive breast-feeding at 3.5 months of age. Factors positively associated with breast-feeding at 6 months were country of origin (Somalia) and parity (>2). CONCLUSIONS: Breast-feeding initiation was common among Iraqi-born and Somali-born mothers, but the exclusive breast-feeding period was shorter than recommended in both groups. The study suggests that there is a need for new culture-specific approaches to support exclusive breast-feeding and complementary feeding practices among foreign-born mothers living in Norway. PMID- 26105704 TI - Sediment size distribution and composition in a reservoir affected by severe water level fluctuations. AB - The reservoir sediments are important sinks for organic carbon (OC), the OC burial being dependent on two opposite processes, deposition and mineralization. Hence factors such as severe water level fluctuations are expected to influence the rate of OC accumulation as they may affect both deposition and mineralization. The Barasona Reservoir has been historically threatened by siltation, whilst the use of water for irrigation involves a drastic decrease of the water level. In this context, we have studied the physical and chemical characteristics (grain size, major and minor elemental compositions, organic and inorganic carbon, and nitrogen) of the recent sediments of the Barasona Reservoir and the relationships among them in order to: a) elucidate the main processes governing OC accumulation, b) evaluate the rate of OC mineralization and c) approach the effect of drought on the sediment characteristics in this system. Our results indicated that Barasona sediments were dominated by fine silts (>60%) and clays (>20%), the mean particle size decreasing from tail to dam. Desiccation increased particle sorting and size distribution became bimodal, but no effect on average size was observed. Attending to the composition, Barasona sediments were very homogeneous with low concentrations of nitrogen (TN) and phosphorus (<1.2 g kg(-1) dw and <0.6 g kg(-1) dw, respectively) and high concentration of OC (~36 g kg(-1) dw). TN was negatively related to dry weight. Sediment mixing due to drastic changes in water level may have favoured the observed homogeneity of Barasona sediments affecting carbon, major ions and grain size. The high amount of OC deposited in Barasona sediment suggested that the adsorption of OC onto fine particles was more important than in boreal lakes. The rate of oxygen consumption by wet sediment ranged from 2.26 to 3.15 mg O2 m(-2) day(-1), values close to those compiled for Mediterranean running waters. PMID- 26105705 TI - Nutrients and contaminants in tissues of five fish species obtained from Shanghai markets: Risk-benefit evaluation from human health perspectives. AB - Shanghai is a Chinese megacity in the Yangtze River Delta area, one of the most polluted coastal areas in China. The inhabitants of Shanghai have very high aquatic product consumption rates. A risk-benefit assessment of the co-ingestion of fish nutrients and contaminants has not previously been performed for Shanghai residents. Samples of five farmed fish species (marine and freshwater) with different feeding habits were collected from Shanghai markets in winter and summer. Fatty acids, protein, mercury, cadmium, lead, copper, polychlorinated biphenyls, hexachlorocyclohexanes, and dichlorodiphenyltrichloroethanes were measured in liver, abdominal fat, and dorsal, abdominal, and tail muscles from fish. Tolerable daily intakes and benefit-risk quotients were calculated to allow the benefits and risks of co-ingesting n-3 long-chain polyunsaturated fatty acids and contaminants to be assessed according to the cancer slope factors and reference doses of selected pollutants. All of the contaminant concentrations in the muscle tissues were much lower than the national maximum limits, but the livers generally contained high Hg concentrations, exceeding the regulatory limit. The organic pollutant and n-3 long-chain polyunsaturated fatty acid concentrations correlated with the lipid contents of the fish tissues, and were higher in carnivorous marine fish than in omnivorous and herbivorous freshwater fish. The tolerable daily intakes, risk-benefit quotients, and current daily aquatic product intakes for residents of large Chinese cities indicated that the muscle tissues of most of the fish analyzed can be consumed regularly without significant contaminant-related risks to health. However, attention should be paid to the potential risks posed by dichlorodiphenyltrichloroethane in large yellow croaker and Hg in tilapia. Based on the results of this study, we encourage people to consume equal portions of marine and freshwater fish. PMID- 26105706 TI - Inequality of Opportunity: Reply to Pedro Rosa Dias and Erik Schokkaert. PMID- 26105707 TI - Treatment strategy profiles in substance use disorder treatment programs: A latent class analysis. AB - BACKGROUND: Modern treatment options for substance use disorder are diverse. While studies have analyzed the adoption of individual evidence-based practices in treatment centers, little is known about the specific make-up of treatment strategy profiles in treatment centers throughout the United States. The current study used latent class analysis to profile underlying treatment strategies and to evaluate philosophical and structural supports associated with each profile. METHODS: Utilizing three aggregated and secondary datasets of nationally representative samples of substance use disorder treatment centers (N=775), we employed latent class analysis to determine treatment strategy profiles. Using multinomial logistic regression, we then examined organizational characteristics associated with each profile. RESULTS: We found three distinct treatment strategy profiles: centers that primarily relied on motivational interviewing and motivational enhancement therapy, centers that utilized psychosocial and alternative therapies, and centers that employed comprehensive treatments including pharmacotherapy. The multinomial logistic regression revealed that philosophical and structural center characteristics were associated with membership in the comprehensive class. Centers with philosophical orientations conducive to holistic care and pharmacotherapy-acceptance, resource-rich infrastructures, and an entrepreneurial reliance on insured clients were more likely to offer diverse interventions. All associations were significant at the .05 level. PRINCIPLE CONCLUSION: The findings from this study help us understand the general strategies of treatment centers. From a practical perspective, practitioners and clients should be aware of the variation in treatment center practices where they may offer or receive treatment. PMID- 26105708 TI - Incidence and predictors of non-fatal drug overdose after release from prison among people who inject drugs in Queensland, Australia. AB - INTRODUCTION: Release from prison is a period of elevated risk for drug-related harms, particularly among people who inject drugs (PWID). Non-fatal overdose can cause serious morbidity and predicts future fatal overdose, however neither the incidence nor the risk factors for non-fatal overdose following release from prison are well understood. METHODS: Structured health-related interviews were conducted with 1051 adult prisoners in Queensland, Australia prior to release and approximately 1, 3 and 6 months post-release. Incidence of self-reported overdose in the community was calculated for PWID and all prisoners for three discrete time periods. Negative binomial regression with robust error variance was used to identify pre-release predictors of overdose among PWID. RESULTS: The incidence of reported overdose was highest between 1 and 3 months post-release (37.8 per 100 person-years (PY) among PWID; 24.5/100 PY among all ex-prisoners). In adjusted analyses, the risk of post-release non-fatal overdose was higher for PWID who reported: being unemployed for >6 months before prison, having been removed from family as a child, at least weekly use of benzodiazepines and/or pharmaceutical opiates in the 3 months prior to prison, and ever receiving opioid substitution therapy (OST). Pre-release psychological distress and a lifetime history of mental disorder also predicted overdose, whereas risky alcohol use in the year before prison was protective. CONCLUSIONS: PWID have a high risk of overdose following release from prison. Imprisonment is an opportunity to initiate targeted preventive interventions such as OST, overdose prevention training and peer-delivered naloxone for those with a high risk profile. PMID- 26105709 TI - Sensitive determination of enoxacin in pharmaceutical formulations by its quench effect on the fluorescence of glutathione-capped CdTe quantum dots. AB - A sensitive and simple method for the determination of enoxacin (ENX) was developed based on the fluorescence quenching effect of ENX for glutathione (GSH) capped CdTe quantum dots (QDs). Under optimum conditions, a good linear relationship was obtained from 4.333 * 10(-9) mol?L(-1) to 1.4 * 10(-5) mol?L( 1) with a correlation coefficient (R) of 0.9987, and the detection limit (3sigma/K) was 1.313 * 10(-9) mol?L(-1). The corresponding mechanism has been proposed on the basis of electron transfer supported by ultraviolet-visible (UV) light absorption, fluorescence spectroscopy, and the measurement of fluorescence lifetime. The method has been applied to the determination of ENX in pharmaceutical formulations (enoxacin gluconate injections and commercial tablets) with satisfactory results. The proposed method manifested several advantages such as high sensitivity, short analysis time, low cost and ease of operation. PMID- 26105710 TI - Reliability of new three-dimensional ultrasound technique for pelvic hiatal area measurement. AB - OBJECTIVE: To assess the reproducibility of a new technique for three-/four dimensional (3D/4D) ultrasound imaging of the pelvic floor: OmniViewTM volume contrast imaging (VCI) for measurement of the pelvic hiatal area on maximum contraction and Valsalva maneuver. In addition, we aimed to study the intermethod agreement between the new technique and the 3D/4D render method. METHODS: We acquired one static 3D and two dynamic 4D transperineal volumes (one obtained during contraction and one during Valsalva maneuver) from 35 nulliparous asymptomatic healthy volunteers and 35 women with symptoms of pelvic floor dysfunction. Each 3D dataset was analyzed using the OmniView-VCI technique to measure the pelvic hiatal area at rest, on maximum contraction and on maximum Valsalva. Analysis was performed twice by the same operator and once by another operator in order to assess intra- and interobserver reproducibility. All measurements were repeated by one operator using the 3D/4D render method to evaluate the intermethod agreement. Reproducibility and intermethod agreement were studied by means of intraclass correlation coefficients (ICC) and the Bland Altman method. RESULTS: Measurement of hiatal area using the OmniView-VCI technique showed excellent intraobserver and interobserver reproducibility in both asymptomatic and symptomatic women at rest, on contraction and on Valsalva maneuver. In addition, excellent agreement was demonstrated between OmniView-VCI and 3D/4D render in both groups (ICCs on Valsalva in asymptomatic and symptomatic women were 0.894 and 0.975, respectively). No systematic difference was noted in any of the reliability studies performed. CONCLUSIONS: OmniView-VCI is a reliable method for pelvic hiatal area measurement. Both rendering mode and OmniView-VCI can be used interchangeably for assessing pelvic hiatal area. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26105711 TI - In vitro evaluation and in silico screening of synthetic acetylcholinesterase inhibitors bearing functionalized piperidine pharmacophores. AB - A series of densely functionalized piperidine (FP) scaffolds was synthesized following a diastereoselective one-pot multicomponent protocol under eco-friendly conditions. The FPs were evaluated in vitro for their acetylcholinesterase (AChE) inhibitory activity, and in silico studies for all the target compounds were carried out using pharmacophore mapping, molecular docking and quantitative structure-activity relationship (QSAR) analysis in order to understand the structural features required for interaction with the AChE enzyme and the key active site residues involved in the intermolecular interactions. Halogenation, nitration or 3,4-methylenedixoxy-substitution at the phenyl ring attached to the 2- and 6-positions of 1,2,5,6-tetrahydropyridine nucleus in compounds 14-17, 19, 20, 24 and 26 greatly enhanced the AChE inhibitory activity. The docking analysis demonstrated that the inhibitors are well-fitted in the active sites. The in silico studies enlighten the future course of studies in modifying the scaffolds for better therapeutic efficacy against the deadly Alzheimer's disease. PMID- 26105712 TI - Selenorhodamine photosensitizers with the Texas-red core for photodynamic therapy of cancer cells. AB - We examined two selenorhodamines with amide and thioamide functionality at the 5 position of a 9-(2-thienyl) substituent on the selenoxanthylium analogue of the Texas-red core for their potential as photosensitizers for photodynamic therapy (PDT) in P-glycoprotein (P-gp)-expressing Colo-26 cells. These compounds were examined for their photophysical properties (absorption, fluorescence, and ability to generate singlet oxygen), for their uptake into Colo-26 cells in the absence or presence of verapamil, for their dark and phototoxicity toward Colo-26 cells, and for their co-localization with mitochondrial-specific agents in Colo 26 cells. Both compounds were extremely effective photosensitizers with values of EC50 ? 4 * 10(-8)M toward Colo-26 cells with 1.0 J cm(-2) laser light delivered at 630 +/- 2 nm. PMID- 26105713 TI - [Thyroid into the focus of attention]. PMID- 26105714 TI - [The importance of thyroid hormone transporters]. AB - Symptoms of a newly discovered X-chromosomal severe mental retardation disease were published by William Allan, Nash Herndon and Florence Dudley in 1944. Patients suffered from muscle weakness and a developmental delay not able to sit, walk and speak. In addition, they showed an endocrinological phenotype with abnormal thyroid hormone constellations. The reason for the Allan-Herndon-Dudley syndrome was found in a mutation of the monocarboxylate transporter 8 (MCT8, SLC16A2), a specific thyroid hormone transporter. PMID- 26105715 TI - Interaction of thyroid hormone with brown adipose tissue. Lessons learned from PET-CT. AB - Brown adipose tissue (BAT) plays an important role in regulating core-body temperature in various species including man. [18F]FDG-PET/CT imaging first revealed the presence of metabolically active BAT depots and that decreased BAT function is associated with various metabolic conditions. Thyroid hormone (TH) in concert with sympathetic nervous system signalling (SNS) stimulates BAT thermogenesis and thyroid disorders result in dysfunctional BAT. Currently, research is focussing not only on BAT regulation but also on browning of white adipose tissue (WAT) to BAT beige adipose tissue (BeAT) in order to develop novel treatments for human obesity and related conditions. While [18F]FDG-PET/CT imaging is continuing to provide valuable insights into BAT and BeAT function in health and disease, there is a pressing need to develop alternative radiotracers that reliably track their activity in vivo. As a result it is expected that preclinical micro PET/CT investigations of BAT and BeAT will gain in prominence. The aim of this short review is to i) describe fundamentals in BAT biology, ii) highlight some of the clinical and preclinical studies performed on humans and rodents with a focus on TH, BAT and PET/CT, and iii) bridge these data with our own studies within the DFG thyroid transact priority program. PMID- 26105716 TI - Systemic treatment of advanced differentiated and medullary thyroid cancer. Overview and practical aspects. AB - In the last few years, three new drugs for targeted systemic therapies have been approved for advanced and progressive thyroid cancer, namely vandetanib and cabozantinib for medullary and sorafenib for radioiodine refractory differentiated thyroid cancer. Patient selection by an interdisciplinary team and education of patients by the treating physicians play a major role when such a treatment is considered and initiated. Only patients with significant tumor burden and/or symptomatic disease or progression, which cannot be controlled by local therapies, should be treated. In order to preserve quality of life, the management of adverse effects is of utmost importance. Due to the mechanism of action of these tyrosine kinase inhibitors, the reliability of serum tumour markers, calcitonin and thyroglobulin, is limited for the assessment of response and follow-up, therefore morphological and metabolic imaging is of great importance. Minor or localized progression should not automatically trigger the termination of treatment or change of drug. In the near future, it is expected that additional drugs become available. PMID- 26105717 TI - Molecular genetic markers for thyroid FNAB. Established assays and future perspective. AB - AIM: Thyroid nodules > 1 cm are observed in about 12% of unselected adult employees aged 18-65 years screened by ultrasound scan (40). While intensive ultrasound screening leads to early detection of thyroid diseases, the determination of benign or malignant behaviour remains uncertain and may trigger anxieties in many patients and their physicians. A considerable number of thyroid resections are consecutively performed due to suspicion of malignancy in the detected nodes. Fine needle aspiration biopsy (FNAB) has been recommended for the assessment of thyroid nodules to facilitate detection of thyroid carcinomas but also to rule out malignancy and thereby avoid unnecessary thyroid resections. However, cytology results are dependent on experience of the respective cytologist and unfortunately inconclusive in many cases. METHODS: Molecular genetic markers are already used nowadays to enhance sensitivity and specificity of FNAB cytology in some centers in Germany. The most clinically relevant molecular genetic markers as pre-operative diagnostic tools and the clinical implications for the intraoperative and postoperative management were reviewed. RESULTS: Molecular genetic markers predominantly focus on the preoperative detection of thyroid malignancies rather than the exclusion of thyroid carcinomas. While some centers routinely assess FNABs, other centers concentrate on FNABs with cytology results of follicular neoplasia or suspicion of thyroid carcinoma. Predominantly mutations of BRAF, RET/PTC, RAS, and PAX8/PPARgamma or expression of miRNAs are analyzed. However, only the detection of BRAF mutations predicts the presence of (papillary) thyroid malignancy with almost 98% probability, indicating necessity of oncologic thyroid resections irrespective of the cytology result. Other genetic alterations are associated with thyroid malignancy with varying frequency and achieve less impact on the clinical management. CONCLUSION: Molecular genetic analysis of FNABs is increasingly performed in Germany. Standardization, quality controls, and validation of various methods need to be implemented in the near future to be able to compare the results. With increasing knowledge about the impact of genetic alterations on the prognosis of thyroid carcinomas, recommendations have to be defined that may lead to individually optimized treatment strategies. PMID- 26105718 TI - Is thyroid surgery performed too often in Germany? AB - Thyroid surgery is one of the more common surgical procedures in Germany. This is in contrast with the situation in some other countries, where this procedure is performed comparatively rarely. In this paper the number of thyroid surgeries in Germany is compared with other western countries (Netherlands, USA, England). In contrast to e. g. the USA and England the number of thyroid surgeries in Germany is declining, however with approximately 109/100,000/year in 2012 is still elevated (Netherlands: 16/100,000/year, USA: at least 42/100,000/year, England: at least 27/100,000/year). Possible contributing factors to this higher number of thyroid surgeries in Germany are explored. These factors include iodine deficiency, the frequent use of advanced diagnostics such as ultrasound, insufficient use of preoperative diagnostic measures such as fine needle biopsy and the practice of "defensive medicine". How much each of these factors contributes is however unclear. PMID- 26105719 TI - Graves'-Basedow disease in pregnancy. New trends in the management and guidance to reduce the risk of birth defects caused by antithyroid drugs. AB - Thyroid hormones are essential development factors and maternal thyroid dysfunction may cause pregnancy complications and diseases in the fetus/child. In the present review we discuss new data on the incidence of Graves'-Basedow disease (GBD) in and around pregnancy, and how hyperthyroidism may affect the risk of spontaneous abortion and stillbirth. A special concern in pregnant women is the potential side effects from the use of antithyroid drugs (ATDs). One type of side effects is the allergic/toxic reactions to the drugs, which seem to be similar in and outside pregnancy, and another is that ATDs tend to over treat the fetus when the mother with GBD is made euthyroid. To avoid fetal hypothyroidism, the lowest possible ATD dose should be used to keep maternal thyroid function at the upper limit of normality with low serum TSH. Birth defects after the use of methimazole (MMI) (or its prodrug carbimazole) have been considered to be very rare, and no risk has previously been associated with the use of propylthiouracil (PTU). However, a recent Danish national study found that 1/30 of children exposed to MMI in early pregnancy had birth defects associated with this, and many defects were severe. PTU exposure was associated with defects in 1/40, and these defects were less severe. Proposals are given on how to reduce the risk of ATD associated birth defects. PMID- 26105720 TI - Successful resection of TSH-secreting pituitary adenoma demonstrated by serial 99mTc-scintigraphy. PMID- 26105721 TI - Incidence and characteristics of patients presenting with acute myocardial infarction and non-obstructive coronary artery disease. AB - OBJECTIVES: This study aimed to characterize the etiologies of patients presenting with myocardial infarction (MI) and found to have non-obstructive coronary artery disease (NOCAD) and compare risk factors and in-hospital mortality to those with obstructive coronary artery disease (CAD). BACKGROUND: Patients presenting with an MI are often found to have NOCAD defined as less than 50% luminal diameter reduction by visual estimation on coronary angiography. METHODS: This study is a retrospective analysis of a total of 2,038 patients that presented to NorthShore University HealthSystem with MI and underwent coronary angiography from 2010 to 2013. RESULTS: 1,822 patients (89%) had CAD and 216 (11%) had NOCAD. Of the NOCAD patients, the most common etiologies were Takotsubo cardiomyopathy (28%), no alternative explanation (26%), demand ischemia (21%), myopericarditis (7%), coronary artery vasospasm (5%), and coronary artery dissection (3%). NOCAD patients were more likely to be younger and female. There was no significant difference between NOCAD and CAD patients in terms of in hospital mortality (3.7% vs. 4.0% respectively, OR = 1.1, 95% CI 0.5-2.3, P = 0.83 by univariate logistic regression, OR = 1.2, 95% CI 0.5-3.1, P = 0.74 by multivariable analysis). CONCLUSIONS: CAD patients were more likely to have traditional risk factors of diabetes, hypertension, hypercholesterolemia, previous MI, previous revascularization with percutaneous coronary intervention or coronary artery bypass graft surgery. Patients presenting with MI and NOCAD were found to have several different etiologies on coronary angiography with the most common being Takotsubo cardiomyopathy. PMID- 26105722 TI - Pathophysiology of diabetic ketoacidosis. PMID- 26105723 TI - From Light to Life. AB - The biogeochemical cycles of H, C, N, O and S are coupled via biologically catalyzed electron transfer (redox) reactions far from thermodynamic equilibrium. In this paper I examine the evolution of the structural motifs responsible for redox reactions (the biological "transistors") across the tree of life, and the photogeochemical reactions on minerals that ultimately came to be the driving force for these biological reactions. PMID- 26105724 TI - R-peaks detection based on stationary wavelet transform. AB - Automatic detection of the QRS complexes/R-peaks in an electrocardiogram (ECG) signal is the most important step preceding any kind of ECG processing and analysis. The performance of these systems heavily relies on the accuracy of the QRS detector. The objective of present work is to drive a new robust method based on stationary wavelet transform (SWT) for R-peaks detection. The decimation of the coefficients at each level of the transformation algorithm is omitted, more samples in the coefficient sequences are available and hence a better outlier detection can be performed. Using the information of local maxima, minima and zero crossings of the fourth SWT coefficient detail, the proposed algorithm identifies the significant points for detection and delineation of the QRS complexes, as well as detection and identification of the QRS individual waves peaks of the pre-processed ECG signal. Various experimental results show that the proposed algorithm exhibits reliable QRS detection as well as accurate ECG delineation, achieving excellent performance on different databases, on the MIT BIH database (Se=99.84%, P=99.88%), on the QT Database (Se=99.94%, P=99.89%) and on MIT-BIH Noise Stress Test Database, (Se=95.30%, P=93.98%). Reliability and accuracy are close to the highest among the ones obtained in other studies. Experiments results being satisfactory, the SWT may represent a novel QRS detection tool, for a robust ECG signal analysis. PMID- 26105725 TI - Validation of an Organizational Management Model of Remote Implantable Cardioverter-Defibrillator Monitoring Alerts. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are a standard means of sudden cardiac death prevention. Compared with ambulatory visits, remote monitoring (RM) of ICD recipients has improved the quality of health care and spared its resources. Few studies have addressed the organization of RM. We optimized and validated our institutional model of RM organization for ICD recipients. METHODS AND RESULTS: This observational study of 562 ICD recipients compared 2 RM periods consisting of iterative, qualitative, and quantitative (1) device diagnostic evaluations by nurses and cardiologists; and (2) selected decisional trees. The main study end points were the professional interventions prompted by, and times allocated to, RM alerts. During the first period, 1134 alerts occurred in 427 patients (286 patient-year), of which 376 (33%) were submitted to cardiologists' reviews, compared with, 1522 alerts in 562 patients (458 patient-year), of which 273 (18%) were submitted to cardiologists' reviews during the second period (P<0.001). An intervention was prompted by 73 of 376 (19.4%) alerts in the first versus 77 of 273 (28.2%) in the second period (P=0.009). The mean time to manage an alert was 4 minutes 31 s in the first versus 2 minutes 10 s in the second period (P<0.001). The annual numbers of alert related hospitalizations were 10.8 versus 8.1 per 100-patient-year (P=0.230), and annual numbers of alert-related visits were 9.8 and 6.1 per 100-patient-year (P=0.081), respectively. CONCLUSIONS: An optimized RM organization based on automated alerts and decisional trees enabled a focus on clinically relevant events and a decrease in the consumption of resources without compromising the quality of ICD recipients' care. PMID- 26105726 TI - Usability, learnability and performance evaluation of Intelligent Research and Intervention Software: A delivery platform for eHealth interventions. AB - Evaluation of an eHealth platform, Intelligent Research and Intervention Software was undertaken via cross-sectional survey of staff users and application performance monitoring. The platform is used to deliver psychosocial interventions across a range of clinical contexts, project scopes, and delivery modalities (e.g. hybrid telehealth, fully online self-managed, randomized control trials, and clinical service delivery). Intelligent Research and Intervention Software supports persuasive technology elements (e.g. tailoring, reminders, and personalization) as well as staff management tools. Results from the System Usability Scale involving 30 Staff and Administrative users across multiple projects were positive with overall mean score of 70 ("Acceptable"). The mean score for "Usability" sub-scale was 82 and for "Learnability" sub-scale 61. There were no significant differences in perceptions of usability across user groups or levels of experience. Application performance management analytics (e.g. Application Performance Index scores) across two test sites indicate the software platform is robust and reliable when compared to industry standards. Intelligent Research and Intervention Software is successfully operating as a flexible platform for creating, delivering, and evaluating eHealth interventions. PMID- 26105727 TI - What the neighbors say. PMID- 26105728 TI - Transcatheter pacemaker implantation in a patient with a bioprosthetic tricuspid valve. PMID- 26105729 TI - Not looking yourself: The cost of self-selecting photographs for identity verification. AB - Photo-identification is based on the premise that photographs are representative of facial appearance. However, previous studies show that ratings of likeness vary across different photographs of the same face, suggesting that some images capture identity better than others. Two experiments were designed to examine the relationship between likeness judgments and face matching accuracy. In Experiment 1, we compared unfamiliar face matching accuracy for self-selected and other selected high-likeness images. Surprisingly, images selected by previously unfamiliar viewers - after very limited exposure to a target face - were more accurately matched than self-selected images chosen by the target identity themselves. Results also revealed extremely low inter-rater agreement in ratings of likeness across participants, suggesting that perceptions of image resemblance are inherently unstable. In Experiment 2, we test whether the cost of self selection can be explained by this general disagreement in likeness judgments between individual raters. We find that averaging across rankings by multiple raters produces image selections that provide superior identification accuracy. However, benefit of other-selection persisted for single raters, suggesting that inaccurate representations of self interfere with our ability to judge which images faithfully represent our current appearance. PMID- 26105731 TI - Abstracts of the Medical Engineering and Bioinformatics 2015 (MEB 2015), China, 7 June 2015. PMID- 26105730 TI - Mesoporous SnO2 single crystals as an effective electron collector for perovskite solar cells. AB - Mesoporous single crystals are prized for their fast electron transport and high surface area. Here we report the first synthesis of mesoporous SnO2 single crystals (SnO2 MSCs) by a simple silica-templated hydrothermal method, and its application in solution-processed perovskite solar cells (PSCs). A relatively low efficiency (3.76%) was obtained due to the strong charge recombination at the SnO2/perovskite interface. However, by coating a thin TiO2 barrier layer on SnO2via TiCl4 treatment, we were able to achieve an 8.54% power conversion efficiency (PCE). A dynamics study using impedance spectroscopy revealed a much lower transport resistance for the SnO2 MSC-based solar cells than for the TiO2 nanocrystal PSCs, but a stronger recombination. Significantly, the thin TiO2 coating layer on SnO2 considerably reduced the recombination while largely maintaining the superior electron-transport properties. PMID- 26105732 TI - Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC Working Group Thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS). PMID- 26105733 TI - Differences in d-chiro-inositol-phosphoglycan expression between first and third trimester human placenta. PMID- 26105734 TI - Characteristics of hypertensive disorders in twin versus singleton pregnancies. AB - OBJECTIVE: To determine the characteristics of hypertensive disorders of pregnancy in twin compared with singleton pregnancies. STUDY DESIGN: Analysis of a prospectively recorded database of 4976 hypertensive pregnancies. MAIN OUTCOME MEASURES: Comparison of progression to pre-eclampsia and maternal and neonatal outcomes. RESULTS: There were 3942 singleton and 214 twin pregnancies. De novo hypertension in twin pregnancy was diagnosed earlier (p<0.001). In singleton pregnancies with de novo hypertension (n=3161), 60% had an initial diagnosis of gestational hypertension (GH) and 40% had pre-eclampsia (PE). In twin pregnancies with de novo hypertension (n=199), 35% of women were initially diagnosed with GH and 65% with PE (p<0.001). At delivery, 46% of the singletons had GH and 54% had PE, compared with twin pregnancies where 23% had GH and 77 % had PE (p<0.001). The progression from GH to PE for twins was twice that of singleton pregnancies (p<0.001). There were 781 singleton and 15 twin pregnancies with chronic hypertension (CH). Twin pregnancies complicated by CH were more likely to progress to PE than singletons (p<0.01). The gestation at delivery was earlier for twin pregnancies (p<0.001) and there were more twins that were smaller for gestational age (p<0.001). There were no differences in maternal outcomes. CONCLUSION: Women carrying twins with de novo hypertension are more likely to present earlier, have initial PE and to subsequently progress from GH to PE. Neonatal outcomes are worse in such pregnancies. PMID- 26105735 TI - Maternal hemodynamics influence fetal hemodynamics in normal and hypertensive pregnancy. AB - OBJECTIVES: This observational case-control study aims to test whether there is a relationship between maternal systemic hemodynamics, maternal renin-angiotensin system and fetal hemodynamics in normal and hypertensive pregnancy. STUDY DESIGN: Four groups of non-pregnant women (n=18), pregnant controls (n=25), women with gestational hypertension (n=21) and preeclampsia (n=10) were included. MAIN OUTCOME MEASURES: Maternal echocardiography parameters, plasma renin and aldosterone were correlated with fetal Doppler parameters in third trimester pregnancy. RESULTS: Higher maternal mean arterial pressure and total peripheral vascular resistance were associated with lower fetal middle cerebral artery pulsatility index (PI) (r=-.51, p<0.01 and r=-.49, p<0.01, respectively); mean arterial pressure correlated negatively with ductus venosus PI (r=-.35, p=0.01); higher maternal plasma aldosterone levels were associated with lower maternal uterine artery resistance (r=-0.33, p=0.03). CONCLUSIONS: It seems that maternal hemodynamics influence fetal hemodynamics with protective adaptation in fetal cerebral and ductus venosus blood flow observed as maternal blood pressure and vascular resistance increase. PMID- 26105736 TI - Higher plasma AOPP is associated with increased proteinuria excretion and decreased glomerular filtration rate in pre-eclamptic women. AB - BACKGROUND: Advanced oxidation protein products (AOPP) as a novel biomarker of oxidative stress has been demonstrated in chronic kidney disease (CKD) patients. The research was to investigate the plasma AOPP level in pre-eclamptic pregnant women and its correlation with 24-h proteinuria collection, cystatin C(CC), uric acid(UA) and creatinine(Cr). METHODS: Fifty pre-eclamptic women, including 22 mild and 28 severe preeclampsia were enrolled. Twentyfive healthy singleton pregnant women were selected as control. Blood samples were obtained from all groups to measure the levels of AOPP, CC, UA, Cr and other biochemical parameters at admission. Total protein in the 24h urine collection was measured. Pearson correlation was performed to evaluate the associations between plasma AOPP level and 24-h proteinuria collection, plasma cystatin C, uric acid and creatinine. RESULTS: The means of AOPP levels were significantly different among severe, mild pre-eclampsia and normotensive pregnant women (88.6+/-10.0MUmmol/L, 72.1+/ 11.1MUmmol/L and 48.7+/-11.3MUmmol/L). The means of cystatin C levels were significantly different among severe, mild pre-eclampsia and normotensive pregnant women (1.8+/-0.6MUmmol/L, 1.2+/-0.3MUmmol/L and 1.0+/-0.2MUmmol/L). Mild, severe pre-eclampsia and control groups did not differ significantly from each other with respect to uric acid and creatinine. Significant positive correlation between AOPP and 24-h proteinuria excretion in preeclamptic pregnant women was found in mild and severe preeclamptic pregnant women (r=0.792). Significant positive correlation between AOPP and cystatin C was found in normal and preeclamptic pregnant women (r=0.521). CONCLUSION: Plasma AOPP level had a significant positive correlation with 24-h proteinuria excretion and cystatin C. Further research about the relevance between the level of AOPP and the onset of preeclampsia was needed in order to have a profound prospective in oxidative stress and preeclampsia. PMID- 26105737 TI - Chlamydia trachomatis infection may increase the risk of preeclampsia. AB - BACKGROUND: Although the etiology of preeclampsia is not well understood, it has been suggested that excessive systemic inflammation may lead to oxidative stress, promoting the endothelial dysfunction characteristic of preeclampsia. Few prospective studies have examined the role of infection, an immune system stimulator, as a risk factor for preeclampsia. METHODS: We conducted a longitudinal study of the relationships between Chlamydia trachomatis (CT), Chlamydophila pneumoniae (CP), cytomegalovirus (CMV), herpes simplex virus (HSV) and preeclampsia among 509 preeclamptic cases and 336 normotensive controls nested within the Danish National Birth Cohort study. Antibodies were analyzed at a first prenatal visit (mean 17.0weeks) and at a late second/third trimester study visit. Prenatal infections were identified as IgG/IgM seroconversion or a fourfold rise in IgG antibody titers. Multiple regression models were adjusted for maternal age, BMI, smoking status, and time between blood draws. RESULTS: CT infection was associated with preeclampsia (ORadj 1.6, 95% CI 0.7, 3.6), severe preeclampsia (ORadj 1.8, 95% CI 0.6, 5.3), and preeclampsia resulting in preterm birth (ORadj 1.7, 95% CI 0.6-4.9) or birth of a small for gestational age infant (ORadj 2.1, 95% CI 0.6, 7.5), although CT infection was uncommon (n=33, 4.0%) and associations were not statistically significant. CP, CMV, and HSV infection were not associated with preeclampsia. CONCLUSIONS: Women with serological evidence of prenatal CT infection were more likely to develop preeclampsia, although infection was infrequent and confidence intervals were wide. Studies in populations at higher risk for STIs are needed to corroborate this association. PMID- 26105738 TI - Are placental Fas and Fas ligand gene polymorphisms associated with preeclampsia? AB - OBJECTIVE: Increased placental trophoblastic apoptosis has been reported in pregnancies complicated by preeclampsia. Fas-Fas ligand is one of the major signal transduction pathways of apoptosis. The objective of this study was to determine if placental Fas and Fas ligand gene polymorphisms differ between patients with and without preeclampsia. STUDY DESIGN: Forty-five singleton placentas were studied. Twenty-three placentas were from preeclamptic pregnancies and 22 were from normotensive controls. Genotyping was performed for Fas-1377, Fas-691, Fas-670, Fas ligand-844, Fas ligand-1174, Fas ligand-2777. Chi-square and Fisher's exact tests were used for statistical analysis. RESULTS: There were no significant differences in maternal age, parity or race between the two groups. There were no significant differences in genotypes or allele frequencies for the Fas-1377, Fas-691, Fas-670, Fas ligand-844, Fas ligand-1174 and Fas ligand-2777. CONCLUSION: Immune intolerance of maternal and placental interaction plays an important role in the pathogenesis of preeclampsia. Our findings do not support the role of placental Fas and Fas ligand gene polymorphisms in the pathogenesis of preeclampsia. PMID- 26105739 TI - Placental angiogenin inhibitor (ribonuclease inhibitor), a novel gene in pre eclampsia. AB - There is convincing evidence that imbalance between angiogenic and anti angiogenic factors play an important role in the pathophysiology of pre eclampsia. Angiogenin, a member of the RNase A super family, is a potent inducer of angiogenesis and serum levels are shown to be elevated in pre-eclampsia. We hypothesize that placental expression of angiogenin inhibitor which binds and blocks the activity of angiogenin is altered in pre-eclampsia and may play a role in its pathophysiology. Placental expression of angiogenin inhibitor was measured in term placentae of 15 women with preeclampsia and 16 normal pregnant controls. The women were matched for age, parity and gestational age. Placental tissue was collected immediately after delivery and stored at -80 degrees C until studied. Angiogenin inhibitor gene expression was measured using real-time quantitative polymerase chain reaction (rt-QPCR). The results were standardized using the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as reference gene. The mRNA expression of angiogenin inhibitor gene was significantly increased in preeclamptic placentae compared to normal pregnant controls [0.44 (0.174-1.048) versus 0.091 (0.029-0.301), median and interquatile range, p=0.027 for pre eclampsia and normal controls respectively]. There was no correlation between angiogenin inhibitor gene expression and maternal age, blood pressure, platelet count, gestation age, birth weight of the baby in pre-eclampsia and normal pregnancy. This study showed that placental expression of the angiogenin inhibitor gene is significantly increased in pre-eclampsia and may play a role in its pathophysiology. PMID- 26105740 TI - The definition of severe and early-onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). AB - OBJECTIVE: There is discrepancy in the literature on the definitions of severe and early-onset pre-eclampsia. We aimed to determine those definitions for clinical purposes and to introduce them in the classification of the hypertensive disorders of pregnancy for publication purposes. METHODS: We circulated a questionnaire to the International Committee of the International Society for the Study of Hypertension in Pregnancy focusing on the thresholds for defining severe preeclampsia and the gestation at which to define early-onset preeclampsia, and on the definition and inclusion of the HELLP syndrome or other clinical features in severe preeclampsia. The questions were closed, but all answers had space for more open detailed comments. RESULTS: There was a general agreement to define preeclampsia as severe if blood pressure was >160mmHg systolic or 110mmHg diastolic. There was scarce agreement on the amount of proteinuria to define severity. The HELLP syndrome was considered a feature to include in the severe classification. Most investigators considered early-onset preeclampsia as that occurring before 34weeks. CONCLUSIONS: A definition of pre-eclampsia is paramount for driving good clinical practice. Classifications on the other hand are useful to enable international comparisons of clinical data and outcomes. We used the results of this survey to update our previous classification for the purposes of providing clinical research definitions of severe and early onset pre-eclampsia that will hopefully be accepted in the international literature. PMID- 26105741 TI - Structure and function of cerebral and mesenteric resistance arteries in low-dose endotoxin-infused pregnant rats. AB - OBJECTIVE: Since the cerebrovasculature likely plays a prominent role in the pathophysiology of eclampsia, we assessed the effects of low-dose endotoxin induced experimental preeclampsia on the function and structure of rat posterior cerebral arteries (PCA) and mesenteric arteries (MA). METHODS: Nonpregnant (NP) and pregnant (P) rats were infused with saline (NP-CTL, n=9; P-CTL, n=9) or low dose endotoxin (NP-endotoxin, n=9; P-endotoxin, n=10). Myogenic activity, pressure of forced dilatation (FD) and structural properties were evaluated in PCA and MA. RESULTS: PCA underwent FD between 125 and 150mmHg in P-endotoxin (repeated measures ANOVA vs 75mmHg; P<0.05) and between 150 and 175mmHg in P-CTL and NP animals (repeated measures ANOVA vs 75mmHg; P<0.05). PCA myogenic tone was unaffected by pregnancy or endotoxin, however, pregnancy decreased the MA myogenic tone (P<0.05 vs NP). Passive characteristics of PCA and MA were unaffected by pregnancy or endotoxin. CONCLUSION: Low-dose endotoxin-infusion during pregnancy, but not pregnancy alone, decreased the pressure of FD in PCA. This may predispose to cerebral autoregulatory breakthrough and edema formation during increased blood pressure as seen in eclampsia. PMID- 26105743 TI - Toxic epidermal necrolysis co-existing with severe onset of ulcerative colitis- different condition or extraintestinal feature?--case report. PMID- 26105742 TI - The ARGOS gene family functions in a negative feedback loop to desensitize plants to ethylene. AB - BACKGROUND: Ethylene plays critical roles in plant growth and development, including the regulation of cell expansion, senescence, and the response to biotic and abiotic stresses. Elements of the initial signal transduction pathway have been determined, but we are still defining regulatory mechanisms by which the sensitivity of plants to ethylene is modulated. RESULTS: We report here that members of the ARGOS gene family of Arabidopsis, previously implicated in the regulation of plant growth and biomass, function as negative feedback regulators of ethylene signaling. Expression of all four members of the ARGOS family is induced by ethylene, but this induction is blocked in ethylene-insensitive mutants. The dose dependence for ethylene induction varies among the ARGOS family members, suggesting that they could modulate responses across a range of ethylene concentrations. GFP-fusions of ARGOS and ARL localize to the endoplasmic reticulum, the same subcellular location as the ethylene receptors and other initial components of the ethylene signaling pathway. Seedlings with increased expression of ARGOS family members exhibit reduced ethylene sensitivity based on physiological and molecular responses. CONCLUSIONS: These results support a model in which the ARGOS gene family functions as part of a negative feedback circuit to desensitize the plant to ethylene, thereby expanding the range of ethylene concentrations to which the plant can respond. These results also indicate that the effects of the ARGOS gene family on plant growth and biomass are mediated through effects on ethylene signal transduction. PMID- 26105744 TI - Severe metabolic acidosis: the presenting sign of an enterovesical fistula. PMID- 26105746 TI - Obstructive sleep apnea and acute respiratory failure due to pneumonia: Is truly a protective factor to mortality risk? PMID- 26105745 TI - Severity of inflammation as a risk factor for ileo-anal anastomotic leak after a pouch procedure in ulcerative colitis. AB - PURPOSE: The pelvic pouch procedure (PPP) carries significant post-operative complication risks including a 4-14 % risk of ileo-anal anastomotic (IAA) leak [1 4]. The aim of this study is to evaluate the severity of disease at the distal resection margin as an independent risk factor for an IAA leak following the PPP for patients with ulcerative colitis (UC). METHODS: A retrospective matched case control study was undertaken. The distal margin of each subject's specimen was reviewed by a blinded pathologist and the degree of inflammation was scored using a modified histological activity index (mHAI)--a 0 to 5 graded scale with HAI of 5 representing ulcerations >25 % the depth of bowel wall. RESULTS: Forty-nine patients with perioperative IAA leaks (mean 11 days +/-0.92) were identified and matched for gender, age and year of surgery. The case cohort had 33 males (67 %) of mean age at time of surgery of 36.3 years (+/-1.42). The severity of distal inflammation did not increase the risk of IAA leak. The presence of a diverting ileostomy was associated with a decreased incidence of an IAA leak (p = 0.01). CONCLUSION: Studies with greater power will be required to evaluate the association (if any) between histological severity of UC at the distal margin of a PPP procedure and IAA leak rate. This risk factor could influence preoperative management and post-operative outcome in patients requiring the PPP. PMID- 26105747 TI - Symptom burden and health-related quality of life among intensive care unit survivors in Argentina: A prospective cohort study. AB - PURPOSE: Our goal was to describe the evolution of selected physical and psychologic symptoms and identify the determinants of health-related quality of life (HRQOL) after intensive care unit (ICU) discharge. METHODS: The study is a prospective cohort of consecutive adult patients admitted to a mixed ICU in a university-affiliated hospital, mechanically ventilated for more than 48 hours. During ICU stay, epidemiological data and events probably associated to worsening outcomes were recorded. After discharge, patients were interviewed at 1, 3, 6, and 12 months. Health-related quality of life was assessed with EuroQoL Questionnaire-5 Dimensions, which includes the EQ-index and EQ-Visual Analogue Scale. RESULTS: One hundred twelve patients were followed up, aged 33 [24-49] years, 68% male, 76% previously healthy, and cranial trauma was the main diagnosis. Physical and psychologic symptoms and moderate/severe problems according to the EQ index progressively decreased after discharge, yet were still highly prevalent after 1 year. EQ index improved from 0.22 [0.01-0.69] to 0.52 [0.08-0.81], 0.66 [0.17-0.79], and 0.68 [0.26-0.86] (P < .001, for all vs month 1). EQ-Visual Analogue Scale remained stable, within acceptable values. Independent determinants of EQ-index were time, duration of mechanical ventilation, shock, weakness, and return to study/work. CONCLUSIONS: Determinants of HRQOL after ICU discharge were both related to late sequelae of critical illness and to some events occurring in the ICU. Notwithstanding the high symptom burden, patients still perceived their HRQOL as good. PMID- 26105748 TI - AlF3 surface-coated Li[Li0.2 Ni0.17 Co0.07 Mn0.56 ]O2 nanoparticles with superior electrochemical performance for lithium-ion batteries. AB - Li-rich layered cathode materials have already drawn considerable attention owing to their high capacity performance for Li-ion batteries (LIBs). In this work, layered Li-rich Li[Li0.2 Ni0.17 Co0.07 Mn0.56 ]O2 nanoparticles are surface modified with AlF3 through a facile chemical deposition method. The AlF3 surface layers have little impact on the structure of the material and act as buffers to prevent the direct contact of the electrode with the electrolyte; thus, they enhance the electrochemical performance significantly. The 3 wt % AlF3 -coated Li rich electrode exhibits the best cycling capability and has a considerably enhanced capacity retention of 83.1 % after 50 cycles. Moreover, the rate performance and thermal stability of the 3 wt % AlF3 -coated electrode are also clearly improved. Surface analysis indicates that the AlF3 coating layer can largely suppress the undesirable growth of solid electrolyte interphase (SEI) film and, therefore, stabilizes the structure upon cycling. PMID- 26105750 TI - Oro-hepatic link, endotoxemia, and systemic inflammation: The role of chronic periodontitis. PMID- 26105749 TI - Limitations on Monaural and Binaural Temporal Processing in Bilateral Cochlear Implant Listeners. AB - Monaural rate discrimination and binaural interaural time difference (ITD) discrimination were studied as functions of pulse rate in a group of bilaterally implanted cochlear implant users. Stimuli for the rate discrimination task were pulse trains presented to one electrode, which could be in the apical, middle, or basal part of the array, and in either the left or the right ear. In each two interval trial, the standard stimulus had a rate of 100, 200, 300, or 500 pulses per second and the signal stimulus had a rate 35% higher. ITD discrimination between pitch-matched electrode pairs was measured for the same standard rates as in the rate discrimination task and with an ITD of +/- 500 MUs. Sensitivity (d') on both tasks decreased with increasing rate, as has been reported previously. This study tested the hypothesis that deterioration in performance at high rates occurs for the two tasks due to a common neural basis, specific to the stimulation of each electrode. Results show that ITD scores for different pairs of electrodes correlated with the lower rate discrimination scores for those two electrodes. Statistical analysis, which partialed out overall differences between listeners, electrodes, and rates, supports the hypothesis that monaural and binaural temporal processing limitations are at least partly due to a common mechanism. PMID- 26105751 TI - Degraded expression of learned feedforward control in movements released by startle. AB - Recent work has shown that preplanned motor programs can be rapidly released via fast conducting pathways using a startling acoustic stimulus. Our question was whether the startle-elicited response might also release a recently learned internal model, which draws on experience to predict and compensate for expected perturbations in a feedforward manner. Our initial investigation using adaptation to robotically produced forces showed some evidence of this, but the results were potentially confounded by co-contraction caused by startle. In this study, we eliminated this confound by asking subjects to make reaching movements in the presence of a visual distortion. Results show that a startle stimulus (1) decreased performance of the recently learned task and (2) reduced after-effect magnitude. Since the recall of learned control was reduced, but not eliminated during startle trials, we suggest that multiple neural centers (cortical and subcortical) are involved in such learning and adaptation. These findings have implications for motor training in areas such as piloting, teleoperation, sports, and rehabilitation. PMID- 26105752 TI - Gain of postural responses increases in response to real and anticipated pain. AB - This study tested two contrasting theories of adaptation of postural control to pain. One proposes alteration to the postural strategy including inhibition of muscles that produce painful movement; another proposes amplification of the postural adjustment to recruit strategies normally reserved for higher load. This study that aimed to determine which of these alternatives best explains pain related adaptation of the hip muscle activity associated with stepping down from steps of increasing height adaptation of postural control to increasing load was evaluated from hip muscle electromyography (fine-wire and surface electrodes) as ten males stepped from steps of increasing height (i.e. increasing load). In one set of trials, participants stepped from a low step (5 cm) and pain was induced by noxious electrical stimulation over the sacrum triggered from foot contact with a force plate or was anticipated. Changes in EMG amplitude and onset timing were compared between conditions. Hip muscle activation was earlier and larger when stepping from higher steps. Although ground reaction forces (one of the determinants of joint load) were unchanged before, during and after pain, trials with real or anticipated noxious stimulation were accompanied by muscle activity indistinguishable from that normally reserved for higher steps (EMG amplitude increased from 9 to 17 % of peak). These data support the notion that muscle activation for postural control is augmented when challenged by real/anticipated noxious stimulation. Muscle activation was earlier and greater than that required for the task and is likely to create unnecessary joint loading. This could have long-term consequences if maintained. PMID- 26105753 TI - Self-touch modulates the somatosensory evoked P100. AB - It has recently been shown that contact between one's own limbs (self-touch) reduces the perceived intensity of pain, over and above the well-known modulation of pain by simultaneous colocalized tactile input Kammers et al. (Curr Biol 20:1819-1822, 2010). Here, we investigate how self-touch modulates somatosensory evoked potentials (SEPs) evoked by afferent somatosensory input. We show that the P100 SEP component, which has previously been implicated in the conscious perception of a tactile stimulus, is enhanced during self-touch, as compared to when one is touching nothing, an inanimate object, or another person. A follow-up experiment showed that there was no effect of self-touch on SEPs when the body parts in contact were not symmetric. Altogether, our findings suggest the interpretation that the secondary somatosensory cortex might underlie the specific analgesic effect of self-touch. PMID- 26105754 TI - Learning to predict is spared in mild cognitive impairment due to Alzheimer's disease. AB - Learning the statistics of the environment is critical for predicting upcoming events. However, little is known about how we translate previous knowledge about scene regularities to sensory predictions. Here, we ask whether patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) that are known to have spared implicit but impaired explicit recognition memory are able to learn temporal regularities and predict upcoming events. We tested the ability of MCI AD patients and age-matched controls to predict the orientation of a test stimulus following exposure to sequences of leftwards or rightwards oriented gratings. Our results demonstrate that exposure to temporal sequences without feedback facilitates the ability to predict an upcoming stimulus in both MCI-AD patients and controls. Further, we show that executive cognitive control may account for individual variability in predictive learning. That is, we observed significant positive correlations of performance in attentional and working memory tasks with post-training performance in the prediction task. Taken together, these results suggest a mediating role of circuits involved in cognitive control (i.e. frontal circuits) that may support the ability for predictive learning in MCI-AD. PMID- 26105755 TI - Visual-motor association learning in undergraduate students as a function of the autism-spectrum quotient. AB - We examined how performance on an associative learning task changes in a sample of undergraduate students as a function of their autism-spectrum quotient (AQ) score. The participants, without any prior knowledge of the Japanese language, learned to associate hiragana characters with button responses. In the novel condition, 50 participants learned visual-motor associations without any prior exposure to the stimuli's visual attributes. In the familiar condition, a different set of 50 participants completed a session in which they first became familiar with the stimuli's visual appearance prior to completing the visual motor association learning task. Participants with higher AQ scores had a clear advantage in the novel condition; the amount of training required reaching learning criterion correlated negatively with AQ. In contrast, participants with lower AQ scores had a clear advantage in the familiar condition; the amount of training required to reach learning criterion correlated positively with AQ. An examination of how each of the AQ subscales correlated with these learning patterns revealed that abilities in visual discrimination-which is known to depend on the visual ventral-stream system-may have afforded an advantage in the novel condition for the participants with the higher AQ scores, whereas abilities in attention switching-which are known to require mechanisms in the prefrontal cortex-may have afforded an advantage in the familiar condition for the participants with the lower AQ scores. PMID- 26105757 TI - Unified chromatography: Fundamentals, instrumentation and applications. AB - The concept of unified chromatography has been in existence for 50 years after the work of Giddings proposing that all modes of chromatography (gas chromatography, liquid chromatography, supercritical fluid chromatography and so on) may be treated together under a single unified theory. His idea was partially fulfilled 23 years later by Ishii, Takeuchi and colleagues, who demonstrated for the first time the possibility to analyze a complex sample containing substances with a wide range of boiling points and polarities in the same instrument and column, just by varying the mobile phase pressure and temperature to change from one chromatographic mode to another. This approach has been demonstrated through application to the separation of complex mixtures in several areas including crude oil, edible oils and polymers. Still, unified chromatography has not yet been fully developed. In the present work, we will review the fundamentals, instrumentation and several applications of the technique. Also discussed are the drawbacks that still hinder development, as well as the recent developments and trends in instrumentation and columns that suggest the most feasible ways forward to the full development of unified chromatography. PMID- 26105756 TI - Force-stabilizing synergies in motor tasks involving two actors. AB - We investigated the ability of two persons to produce force-stabilizing synergies in accurate multi-finger force production tasks under visual feedback on the total force only. The subjects produced a time profile of total force (the sum of two hand forces in one-person tasks and the sum of two subject forces in two person tasks) consisting of a ramp-up, steady-state, and ramp-down segments; the steady-state segment was interrupted in the middle by a quick force pulse. Analyses of the structure of inter-trial finger force variance, motor equivalence, anticipatory synergy adjustments (ASAs), and the unintentional drift of the sharing pattern were performed. The two-person performance was characterized by a dramatically higher amount of inter-trial variance that did not affect total force, higher finger force deviations that did not affect total force (motor equivalent deviations), shorter ASAs, and larger drift of the sharing pattern. The rate of sharing pattern drift correlated with the initial disparity between the forces produced by the two persons (or two hands). The drift accelerated following the quick force pulse. Our observations show that sensory information on the task-specific performance variable is sufficient for the organization of performance-stabilizing synergies. They suggest, however, that two actors are less likely to follow a single optimization criterion as compared to a single performer. The presence of ASAs in the two-person condition might reflect fidgeting by one or both of the subjects. We discuss the characteristics of the drift in the sharing pattern as reflections of different characteristic times of motion within the subspaces that affect and do not affect salient performance variables. PMID- 26105759 TI - Comparison of pulsatile and static pressures within the intracranial and lumbar compartments in patients with Chiari malformation type 1: a prospective observational study. AB - BACKGROUND: In Chiari malformation type 1 (CMI), the obstruction of cerebrospinal fluid (CSF) flow through the foramen magnum is believed to cause alterations of intracranial pressure (ICP) pulsations. Foramen magnum decompression (FMD) is therefore considered a treatment of choice. However, the pathophysiology of CMI is poorly understood and it remains unknown how ICP alterations relate to symptoms and radiological findings. This study was undertaken to measure pulsatile pressure and its gradient between intracranial and lumbar compartments, and to determine its relationship to clinical and radiological findings. METHOD: In patients with symptomatic CMI, we simultaneously measured ICP and lumbar CSF pressure, with particular focus on analysis of pulsatile pressure. Ventricular CSF volume (VV), intracranial volume (ICV) and posterior cranial fossa volume (PCFV) were calculated using volumetry software. RESULTS: In 26 patients (median 35 years), we found clearly abnormal or borderline values of pulsatile ICP in 18/26 patients (69 %; median 4.5 mmHg) and abnormal pulsatile pressure gradient in 17/24 patients (71 %; median 2.6 mmHg). The correlation between pulsatile ICP and the pulsatile pressure gradient was significantly positive (p < 0.001). We found no significant correlation between pulsatile or static pressure and extent of tonsillar ectopy, VV, ICV or PCFV. The pulsatile pressure gradient was significantly higher in patients with syringomyelia (p = 0.02). CONCLUSIONS: In this cohort, the pulsatile ICP was elevated in 69 %. The intracranial-lumbar pulsatile pressure gradient was abnormal in 71 % and significantly higher in patients with syringomyelia. The elevated pulsatile ICP significantly correlated with pulsatile pressure gradient; no similar correlation was found for static ICP. We interpret the results as providing evidence of impaired intracranial compliance as an important pathophysiological mechanism in CMI. PMID- 26105760 TI - Trauma- and distress-associated mental illness symptoms in close relatives of patients with severe traumatic brain injury and high-grade subarachnoid hemorrhage. AB - BACKGROUND: Close relatives (CR) of patients with severe traumatic brain injury (TBI) and high-grade subarachnoid hemorrhage (SAH) suffer extraordinary distress during the treatment: Distress may lead to persisting mental illness symptoms within the spectrum of post-traumatic stress disorder (PTSD), anxiety disorders, and depression. The primary goal of this study was to determine the prevalence and severity of these symptoms in CR. The secondary goal was identification of associated factors. METHOD: Standardized interviews were conducted with 53 CR (mean age of 57.7 +/- 11.4 years) of patients with TBI degrees III (n = 27) and high-grade SAH H&H degrees III-V (n = 26) between 5 and 15 months after the event. The interviews contained a battery of surveys to quantify symptoms of PTSD, anxiety disorders, and depression, i.e., Impact of Event Scale (IES-R), 36 item Short-Form General Health Survey (SF-36), and Hospital Anxiety and Depression Scale (HADS). Fixed and modifiable possibly influencing factors were correlated. RESULTS: Twenty-eight CR (53 %) showed IES-R scores indicating a probable diagnosis of PTSD. Twenty-five CR (47 %) showed an increased anxiety score and 18 (34 %) an increased depression score using HADS. Mean physical component summary of SF-36 was not abnormal (49.1 +/- 9.1), whereas mean mental component summary was under average (41.0 +/- 13.2), indicating a decreased quality of life caused by mental effects. Perception of the interaction quality with the medical staff and involvement into medical decisions correlated negatively with severity of mental illness symptoms. Evasive coping strategies were highly significantly associated with symptoms. CONCLUSIONS: This study quantifies an extraordinarily high prevalence of mental illness symptoms in CR of patients with critical acquired brain injury due to SAH and TBI. Modifiable factors were associated with severity of mental illness symptoms. Prospective studies testing efficiency of early psychotherapeutic interventions are needed. PMID- 26105758 TI - A genome-wide association study identifies multiple loci for variation in human ear morphology. AB - Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 * 10(-8) to 3 * 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1. PMID- 26105761 TI - Triple attack technique for non-union of femoral neck fractures. AB - PURPOSE: The purpose of this study was to describe the technique and clinical results following the utilization of biomechanical and biological means for adequate fracture healing in management of non-union of the neck of femur while preventing distortion of normal hip biomechanics. METHODS: Twenty-two patients with non-united fractures of femoral neck in adults were treated with what was termed the 'triple attack' procedure. This constituted iliac autogenous bone grafting, valgus subtrochanteric osteotomy together with static fixation across the non-union fracture site of the neck to avoid delayed femoral neck shortening. RESULTS: All patients were classified as Pauwel's type III fractures. The mean time interval between the last operation and the current procedure was 4.6 months. Average operative time was 58.6 minutes. Patients were followed up for an average of 43.6 months. Complete union was achieved in all cases at an average of 4.3 months. Significant improvement of all radiological parameters was noticed together with the Harris hip score from an average of 21.2 pre-operatively to 89.6 at the last follow-up. CONCLUSION: The present study provides encouraging clinical and functional results to suggest that this newly described procedure ('triple attack') might be a valuable option in the management of non-united femoral neck fractures. PMID- 26105762 TI - Validation of the Charlson comorbidity index in patients undergoing revision total hip arthroplasty. AB - PURPOSE: The Charlson comorbidity index (CCI) was developed to quantify the influence of comorbidities on survival. The age-related CCI respects patients' age as an additional risk factor. There are several studies available based on administrative data regarding functional outcome, implant survival, resource use and length of hospital stay in patients undergoing primary total hip arthroplasty (THA). To date, there is a lack of knowledge regarding the correlation of the CCI and the age-related CCI in case of revision total hip arthroplasty (RTHA). OBJECTIVE: Our objective was to validate the influence of the CCI and age-related CCI in patients undergoing RTHA regarding complication rate, resource use implant survival and mortality rate. METHODS: Between October 2007 and November 2012, 142 consecutive patients undergoing RTHA were included in this retrospective study. Routine clinical data were collected and analysed as anonymized aggregated data. In accordance to CCI and age-related CCI the rate of complications (internal medical and surgical complications), the length of hospital stay and the need for ICU treatment and the mortality rate was evaluated. Kaplan-Meier survivorship was used to determine implant survival. RESULTS: Twenty-one patients (15%) had a low risk CCI, 59 patients (41%) a moderate risk CCI and 62 patients (44%) a high risk CCI. The mean follow-up was 27 months (range 24-70 months). In total, we recorded 57 complications (40%), of which 45 were surgical (79%) and 12 were internal medical complications (21%). Twenty-four patients (17%) had to undergo revision surgery. CCI and age-related CCI had no influence regarding implant survival. We recorded a significant influence of the age-related CCI in regard to the necessity of postoperative intensive care unit stay and the length of total hospital stay. Further we recorded a significant influence of the CCI and the age related CCI regarding postoperative complications and internal complications, postoperative dislocation and the need for surgical revision. CONCLUSION: In summary, we conclude that the CCI and the age-related CCI are strong predictors regarding complication rate in patients undergoing RTHA. In a short- to mid-term follow-up, no influence on implant survival is detectable. PMID- 26105764 TI - Daniel Molliere (1848-1890): the French anatomist-surgeon who introduced Robin's pioneering osteoclast for the genu valgum observed in adolescents. AB - Inside the pages of the French medical treatises of the 19th century a forgotten osteoclast apparatus for the genu valgum observed in adolescents remained hidden waiting to be unearthed. It was Victor Robin's osteoclast, which has been used by the supreme French anatomist and surgeon Daniel Molliere. With the purpose to share a significant heritage on orthopaedics, a thorough research of the literature of the era was conducted. Our study resulted in the illumination of both Molliere's prolific figure and osteoclast's impact on orthopaedic surgery at that time. Having in mind Molliere's perseverance towards surgical apparatuses, his antiseptic measures inside his operating theatre, his published treatises, his surgical skills, we may effortlessly conclude that he stands among Lyon's best surgeons with an important contribution to orthopaedics. PMID- 26105763 TI - Meta-analysis suggests that reverse shoulder arthroplasty in proximal humerus fractures is a better option than hemiarthroplasty in the elderly. AB - PURPOSE: This systematic meta-analysis and review aims to critically compare the outcome of reverse shoulder arthroplasty versus hemiarthroplasty for the treatment of complex proximal humeral fracture. METHODS: Relevant original studies were searched in the electronic databases of Medline, Embase, Cochrane central database and China National Knowledge Infrastructure (CNKI) (all through December 2014). Studies that investigated and compared the effectiveness or complications in both groups and provided sufficient data of interest were included in this meta-analysis. Participants in both groups were significantly the same in the demography and injury mechanism. RESULTS: Eight studies that fulfilled inclusion and exclusion criteria were included in this meta-analysis, which included 421 participants in hemiarthroplasty (HA) and 160 in reverse shoulder arthroplasty (RSA). Patients were followed-up for at least one year in each study. Compared with HA, RSA was associated with a lower rate of total complications, higher American Shoulder and Elbow Surgeons (ASES) score, more healed tuberosities and improved active forward elevation. Both treatments were comparable in term of revision surgeries, mortality, subjective satisfaction and active external rotation. CONCLUSIONS: The present evidence from this meta analysis suggested that RSA was a more advantaged method for the treatment of complex proximal humeral fractures. Clinical decision should be preferred to RSA on the condition that patients' medical conditions are indicated. PMID- 26105765 TI - Loss of offset after pertrochanteric hip fractures affects hip function one year after surgery with a short intramedullary nail. A prospective cohort study. AB - PURPOSE: We hypothesised that protruding collum screws in intramedullary nails used for pertrochanteric fractures cause lateral pain/discomfort and that loss of offset relates to poorer hip function. METHODS: Seventy-six patients with an acute pertrochanteric femoral fracture AO types A1 and A2 were operated upon using a short intramedullary nail and were included in a prospective observational cohort study and followed-up for one year. The main outcome variables were lateral pain and hip function as evaluated with the Harris Hip Score. The main exposure was compression along the collum screw and lateral protrusion measured by anteroposterior X-ray images. Perioperative images were compared to images at the follow-up visit. Outcome variables were adjusted in regression models for reduction, fracture type, body mass index, sex and age. RESULTS: A total of 28 (36 %) patients experienced lateral pain at one year. We found a correlation between lateral protrusion and lateral pain, adjusted OR 4.5 per protruding centimetre (95 % CI, 1.1-17.5). Collum compression correlated with a poorer outcome with Harris Hip Score -14.2 per compressed centimetre (95 % CI, 21.8 to -6.7). CONCLUSIONS: In patients with type A1 and A2 pertrochanteric fractures operated on using intramedullary nailing, a large compression and lateral protrusion of the collum screw are associated with poorer hip function and lateral pain. New technical improvements for implants should focus on these factors to improve functional outcome after surgery. PMID- 26105766 TI - Are pre-operative anthropometric parameters helpful in predicting length and thickness of quadrupled hamstring graft for ACL reconstruction in adults? A prospective study and literature review. AB - PURPOSE: Cross-sectional diameter of 7 mm or more of graft in anterior cruciate ligament reconstruction is arguably the single most important factor determining the success of the operation. Pre-operative anthropometric parameters have been reported to correlate with diameter of quadrupled hamstring graft, which is the most popular graft choice today. We conducted this prospective study to determine the value of some anthropometric measurements to predict the length of harvested semitendinosus and gracilis tendons and quadrupled hamstring graft diameter. We also assessed the reliability of the mathematical equation in accurately predicting the graft diameter. METHODS: Height, weight, BMI and thigh length of 160 patients who underwent primary ACL reconstruction was measured before surgery. Using multivariate logistic regression analysis length of harvested semitendinous and gracilis tendons along with quadrupled graft diameter were correlated to height, weight, BMI and thigh length. RESULTS: Ninety-six percent had graft diameter of 7 mm or more. Height and thigh length were found to be most strongly correlating to both the length of harvested tendons and the quadrupled graft diameter (p <= 0.001, r = 0.25-0.39). Patients with height less than 147 cm were found to be at highest risk for inadequate graft diameter (less than 7 mm). Although the anthropometric parameters were found to be significantly related to height and thigh length, the strength of association is moderate. The mathematical equation for prediction of graft diameter using height was found to inaccurately over-predict the graft diameter in 33.1 % of cases, assessed using Bland-Altman plot. CONCLUSION: Anthropometric parameters, especially height and thigh length, can serve as a guide to plan hamstring graft diameter and length before ACL reconstruction. But, it is not advisable to rely on mathematical equations for absolute values of graft parameters as there is risk of over estimating hamstring length or graft thickness. PMID- 26105767 TI - New fracture pattern focusing on implant fracture for periprosthetic femoral fractures. AB - PURPOSE: The Vancouver Classification System (VCS) for assessing periprosthetic femoral fractures has become universally accepted. The Unified Classification System (UCS) has expanded upon and updated the VCS and applied treatment principles to all periprosthetic fractures. However, periprosthetic femoral fractures accompanied by stem fracture after hip arthroplasty were not classifiable under the original VCS or the UCS. RESULTS: Our new fracture pattern is based on the periprosthetic femoral fracture as well as stem fracture after hip arthroplasty, and its treatment is dependent upon the stability of the proximal portion of the fractured femoral prosthesis. CONCLUSION: We believe that our new fracture pattern, a supplement to the VCS and UCS, is useful in the establishment of a therapeutic strategy for periprosthetic femoral fractures. PMID- 26105768 TI - Fetal cell microchimerism in papillary thyroid cancer: A role in the outcome of the disease. AB - Fetal cell microchimerism (FCM) is defined as the persistence of fetal cells in maternal organs and circulation without any apparent rejection and it was hypothesized to protect toward the onset of some neoplastic diseases. To verify the role of FCM in papillary thyroid cancer (PTC), we enrolled 87 parous women with PTC and at least one male pregnancy preceding the diagnosis (PTC-P), 66 healthy women with 1 or more male children (HC-P) and 57 nonparous women with PTC (PTC-NP). The presence of circulating male DNA was assessed by the amplification of the Y chromosome-specific gene SRY, with a sensitivity of 1 male cell/1 million female cells. A significantly higher frequency of FCM was found in HC-P than PTC-P women (63.6% vs. 39.1%, p = 0.004). Among PTC-P patients, those positive for the presence of FCM (FMC+ve) had a lower prevalence of extrathyroidal extension (p = 0.027) and lymph node metastases (p = 0.044) than those without FCM (FMC-ve). Moreover, FMC+ve patients were more frequently in remission than FMC-ve cases (94.1 vs. 67.9%, p = 0.009). Interestingly, we showed for the first time that the positive effect on tumor presentation and outcome is specifically related to FCM and it is not an effect of pregnancy. In conclusion, circulating FCM is significantly more frequent in healthy parous women than in women with PTC. Moreover, the presence of circulating fetal male cells is associated with a significantly lower extrathyroidal extension and a good prognosis, suggesting a protective role of this phenomenon toward both the onset and the progression of thyroid cancer. PMID- 26105769 TI - An Elective in College Mental Health for Training Adult Psychiatry Residents in Young Adult Psychiatry. PMID- 26105770 TI - Duty Hours, Like Milestones, Were Not Studied Before Implementation. PMID- 26105771 TI - Clinical evaluation of quality of life: a survey among members of European Society of Thoracic Surgeons (ESTS). AB - OBJECTIVES: Quality of life (QoL) has been recognized as an important postoperative outcome. Despite the growing interest in this topic, there is almost no information about the daily use of QoL questionnaires within European Society of Thoracic Surgery (ESTS). The aim of this paper is to present the results of a survey launched to know the current practice of collecting and using QoL data within the Society. METHODS: The survey was designed by the members of the QoL and Patient Safety ESTS committee and included 13 questions about different aspects of QoL assessment: time points of data collection, type and method of administration of questionnaires, dropouts, surgical-related symptoms and definition of the target population. An electronic link was sent to invite 1250 ESTS members to complete the survey by e-mail. RESULTS: One hundred and fifty surgeons worldwide completed the survey. Of the total, 54.4% of the surgeons indicated that they never collect QoL data in their daily practice. Both SF-36 and EORTC C30 were the most commonly used questionnaires. They are considered as the most appropriate for thoracic surgery patients. Only 20% of the surgeons used the LC-13 module in addition. Most of the time (45.5%), questionnaires are completed through a face-to-face interview led by a physician. Only 21.2% of the responders collected data prior to surgery; 39.3% of the responders collect QoL data only from lung cancer patients and 16% add patients with oesophageal diseases. Postoperative complications, comorbidities, surgical and oncological baseline data and wound pain, healing disorders, arm mobility, oxygen dependency, return to work and postoperative medication were important items that responders suggested to include in future questionnaires. CONCLUSIONS: The obtained data showed a broad area for improvement in QoL. The ESTS has to lead this effort collaborating to standardize the research in this field, endorsing specific questionnaires, incorporating patient-reported outcomes more and more into guidelines and facilitating multicentre studies. PMID- 26105772 TI - Is it valuable and safe to perform reoperation for recurrent thymoma? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether it is valuable and safe to perform reoperation for recurrent thymoma. Altogether, more than 500 papers were found using the reported search, of which 15 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. This paper includes 1 level 1a study and 15 level 2b studies. The operative mortality was reported in six studies, ranging from 0 to 13.3%, and the operative morbidity in five studies, ranging from 0 to 32.1%. Most patients suffering from operative mortality (5/5) and morbidity (16/19) had myasthenia gravis. One meta-analysis demonstrated improved rates of long-term overall survival in patients with recurrent thymoma who were treated surgically compared with those treated non-surgically. Ten studies showed better survival after surgical treatment than after non-surgical treatment with the difference being statistically significant in 4 of them. Two studies reported that the prognosis in patients with complete reresection was comparable with that of patients without recurrence. One study found that patients with a thymus-related syndrome improved after re-resection. Another two studies revealed that debulking surgery for recurrent thymoma was associated with poorer survival and worse outcomes than both complete resection and non-surgical therapy. From the papers identified in our search, we can conclude that reoperation can be performed with acceptable morbidity and low mortality in appropriately selected patients with locally and/or regionally recurrent thymoma. Both survival and thymus-related syndromes are improved if the recurrence is surgically resected when compared with other medical treatments. Debulking surgery should be limited to those few selected patients in whom other treatment options are not available. In addition, morbidity and mortality most commonly occur in association with myasthenia gravis, and hence medical control of this should be optimized prior to reoperation. PMID- 26105773 TI - High-resolution manometry combined with impedance measurements discriminates the cause of dysphagia in children. AB - Pressure-flow analysis allows assessing esophageal bolus transport in relation to esophageal pressures. This study aimed to characterize pressure-flow metrics in relation to dysphagia in paediatric patients. We analysed esophageal pressure impedance recordings of 5 ml liquid and viscous swallows from 35 children (17 M, mean 10.5 +/- 0.8 years). Primary indication for referral was gastroesophageal reflux disease (GERD) (9), post-fundoplication dysphagia (5), idiopathic dysphagia (16), trachea-esophageal fistula (2) and other (3). Peristaltic function was assessed using the 20 mmHg iso-contour defect and the timing between bolus pressure and flow was assessed using the Pressure Flow Index, a metric elevated in relation to dysphagia. Patients were stratified in relation to dysphagia and to peristaltic defect size. Dysphagia was characterized by a weaker peristalsis for liquids and higher Pressure Flow Index for viscous. When patients were stratified based on weak or normal peristalsis, dysphagia with weak peristalsis related to a larger iso-contour defect size and dysphagia with normal peristalsis related to higher Pressure Flow Index. CONCLUSION: Pressure-flow analysis enables differentiation of patients with dysphagia due to weak peristalsis (poor bolus clearance) from abnormal bolus flow resistance (esophageal outflow obstruction). This new dichotomous categorization of esophageal function may help guide the selection of optimal treatment such as pharmacological or endoscopic therapy. WHAT IS KNOWN: * Pressure-flow analysis (PFA) can detect abnormalities in esophageal motility using integrated analysis of bolus propulsion and bolus flow during swallowing. * AIM analysis has recently been reported to be useful in identifying subtle pre-operative esophageal dysfunction in adult patients who developed post-fundoplication dysphagia as well as in patients with non-obstructive dysphagia. WHAT IS NEW: * Pressure-flow parameters can distinguish the cause of dysphagia in paediatric patients. * Combined high-resolution manometry and impedance measurements with pressure-flow analysis can differentiate paediatric patients with dysphagia symptoms in relation to either weak peristalsis (poor bolus clearance) or over-pressurization (abnormal bolus flow resistance). HOW MIGHT IT IMPACT ON CLINICAL PRACTICE IN THE FUTURE? * This study supports the use of a novel objective analysis method on recordings that are readily used in paediatric clinical practice. * The pressure flow approach allows discriminating esophageal dysfunction in relation to dysphagia symptoms in children. This has not been achieved in children with current analysis methods. * The new findings of this study allow a dichotomous categorization of esophageal function, which may help to guide the selection of the most optimal treatment such as pharmacological or endoscopic therapy. PMID- 26105774 TI - Patterning microfluidic device wettability with spatially-controlled plasma oxidation. AB - Microfluidic devices can form double emulsions with uniform properties, but require cumbersome fabrication steps to pattern their wettability. We demonstrate spatially-controlled plasma oxidation to create wettability patterns for forming double emulsions. Our method performs comparably to chemical techniques but is simpler, more reliable, and scalable to patterning large arrays of drop makers. PMID- 26105775 TI - Whole blood glutathione status and ICU morbidity in critically ill children. AB - BACKGROUND: A high reduced glutathione ratio is associated with high mortality in adult ICU patients. Whole blood glutathione status in critically ill children is less well characterized. In this study, whole blood glutathione status in pediatric intensive care (PICU) patients was determined and the relation between the redox status of whole blood glutathione and morbidity was investigated. METHODS: A prospective consecutive cohort of critically ill children (n = 146) admitted to the PICU of a tertiary university hospital, and a reference group of healthy children (n = 60) and healthy adults (n = 10) were included in the study. The concentrations of total and reduced whole blood were determined at admission and patient characteristics were recorded. RESULTS: A high fraction of reduced glutathione in the glutathione redox status was associated with longer dependency of mechanical ventilation and length of stay in the PICU (P = 0.02 and P = 0.03 respectively). In patients with a prolonged stay in the PICU (> 5 days), a more reduced state of glutathione was seen in patients who had more than two organ failures as compared to patients with one or two failing organs (P < 0.01 and P < 0.05), respectively. A positive correlation was also seen between numbers of organ failures and redox status of glutathione (r = 0.45, P < 0.001). CONCLUSION: A high reduced glutathione ratio was associated with longer PICU stay, duration of mechanical ventilation, and multiple organ failure. PMID- 26105777 TI - Analysis of 17 Y-STR loci haplotype and Y-chromosome haplogroup distribution in five Chinese ethnic groups. AB - To investigate genetic diversity in Chinese populations, 706 unrelated male individuals from five ethnic groups (Han, Korean, Hui, Mongolian, and Tibetan, respectively) were analyzed with 17 Y-chromosomal STRs. The haplotype diversity was 0.99985 in the combined data. A total of 675 distinct haplotypes were observed, of which 649 were unique. Y-chromosome haplogroups in the five groups were also predicted with Y-STR haplotypes. Genetic distance between the five studied ethnic groups and other published groups was analyzed by analysis of molecular variance and visualized in a multidimensional scaling plot. In conclusion, the 17 Y-STR loci are highly polymorphic markers in the five groups and hence are very useful in forensic application, population genetics, and human evolution studies. PMID- 26105776 TI - Anhedonia is associated with reduced incentive cue related activation in the basal ganglia. AB - Research has shown that reward incentives improve cognitive control in motivationally salient situations. Much previous work in this domain has focused on incentive cue-related activity in a number of brain regions, including the dorsolateral prefrontal cortex (DLPFC) and striatum. However, the more sustained changes in functional brain activity during task contexts with incentives have been relatively less explored. Here, we examined both the cue-related and sustained effects of rewards (i.e., monetary incentives) on cognitive control, with a particular focus on the roles of the DLPFC and striatum, using a mixed state-item design. We investigated whether variability in a reward-related trait (i.e., anhedonia) would modulate the sustained and/or the cue-related transient aspects of motivated cognitive control. Twenty-seven healthy individuals performed a modified response conflict task (Padmala & Pessoa, Journal of Cognitive Neuroscience, 23, 3419-3432, 2011) during scanning, in which participants were asked to categorize images as either houses or buildings with either congruent or incongruent overlaid words. Participants performed a baseline condition without knowledge of monetary incentives, followed by reward blocks with monetary incentives on some cued trials (reward cues) for fast and correct responses. We replicated previous work by showing increases in both sustained activity during reward versus baseline blocks and transient. cue-related activity in bilateral DLPFC and the basal ganglia. Importantly, healthy individuals with higher anhedonia showed less of an increase in trial-by-trial activity as a function of reward in the lateral globus pallidus. Together, our results suggest that reduced hedonic experience may be related to abnormality of reward cue related activity in the basal ganglia. PMID- 26105778 TI - Selective enzymatic cleavage and labeling for sensitive capillary electrophoresis laser-induced fluorescence analysis of oxidized DNA bases. AB - Oxidatively generated DNA damage is considered to be a significant contributing factor to cancer, aging, and age-related human diseases. It is important to detect oxidatively generated DNA damage to understand and clinically diagnosis diseases caused by oxidative damage. In this study, using selective enzymatic cleavage and quantum dot (QD) labeling, we developed a novel capillary electrophoresis-laser induced fluorescence method for the sensitive detection of oxidized DNA bases. First, oxidized DNA bases are recognized and removed by one DNA base excision repair glycosylase, leaving apurinic and apyrimidinic sites (AP sites) at the oxidized positions. The AP sites are further excised by the AP nicking activity of the chosen glycosylase, generating a nucleotide gap with 5'- and 3'- phosphate groups. After dephosphorylation with one alkaline phosphatase, a biotinylated ddNTP is introduced into the nucleotide space within the DNA strand by DNA polymerase I. The biotin-tagged DNA is further labeled with a QD streptavidin conjugate via non-covalent interactions. The DNA-bound QD is well separated from excess DNA-unbound QD by highly efficient capillary electrophoresis and is sensitively detected by online coupled laser-induced fluorescence analysis. Using this method, we can assess the trace levels of oxidized DNA bases induced by the Fenton reaction and UV irradiation. Interestingly, the use of the formamidopyrimidine glycosylase (FPG) protein and endonuclease VIII enables the detection of oxidized purine and pyrimidine bases, respectively. Using the synthesized standard DNA, the approach has low limits of detection of 1.1*10(-19)mol in mass and 2.9pM in concentration. PMID- 26105779 TI - The properties of capillary columns with sorbents based on poly-(1-trimethylsilyl 1-propyne) modified with nitrous oxide. AB - In this work, we report the study of properties of capillary columns with a porous layer of the functionalized polymer prepared via oxidation of poly-(1 trimethylsilyl-1-propyne) (PTMSP) by nitrous oxide. It was shown that the double CC bonds of polymer reacted with nitrous oxide with formation of ketone, carbonyl and hydroxyl groups. The increase in number of those groups in polymer changed a polarity of PTMSP. The change in polarity of polymer led to the selectivity of separations, including oxygen-containing substances. The polarity values were calculated for the prepared columns. It was shown that the total polarity according to McReynolds (DeltaI) was lower than that for known porous polymers. The examples of separations of aliphatic and aromatic hydrocarbons, oxygen- and halogen-containing substances were presented. PMID- 26105780 TI - Comparison of twin-cell centrifugal partition chromatographic columns with different cell volume. AB - Two twin-cell centrifugal partition chromatographic columns (SCPC 250 and SCPE 250-BIO, Armen Instrument, France) with the same column volume but different cell size and number were compared in terms of stationary phase retention and column efficiency. The columns were tested with two types of solvent systems: a commonly used organic solvent based biphasic system from the ARIZONA solvent system family and a polymer/salt based aqueous two phase system (ATPS). The efficiency of the columns was evaluated by pulse injection experiments of two benzenediols (pyrocatechol and hydroquinone) in the case of the ARIZONA system and a protein mixture (myoglobin and lysozyme) in the case of the ATPS. As result of high stationary phase retention, the column with the lower number of larger twin-cells (SCPE-250-BIO) is suitable for protein separations using ATPS. On the other hand, due to higher column efficiency, the column with the greater number of smaller cells (SCPC 250) is superior for batch elution separations performed with standard liquid-liquid chromatography organic solvent based biphasic systems. PMID- 26105781 TI - Matrix solid phase dispersion method for determination of polycyclic aromatic hydrocarbons in moss. AB - In this work a matrix solid-phase dispersion extraction method, followed by programmed temperature vaporization-gas chromatography-tandem mass spectrometry determination is proposed for the analysis of polycyclic aromatic hydrocarbons (PAHs) in moss samples. A devitalized, cultivated Sphagnum palustre L. moss clone obtained from the "Mossclone" EU-FP7 Project was used for the optimization and validation of the proposed method. Good trueness (84-116%), precision (intermediate precision lower than 11%) and sensitivity (quantitation limits lower than 1.7ngg(-1)) were obtained. The proposed method was compared with other procedures applied for this complex matrix, achieving a considerable reduction of sample amount, solvent volume and time consumption. The procedure was successfully tested for the analysis of PAHs in exposed moss clone samples for the monitoring of air pollution. Finally, the method was also tested for its suitability in the analysis of PAHs in other moss species as well as a lichen species. PMID- 26105782 TI - Homolog-focused profiling of ginsenosides based on the integration of step-wise formate anion-to-deprotonated ion transition screening and scheduled multiple reaction monitoring. AB - Homolog-focused profiling is a favored option to bridge targeted metabolomics toward non-targeted metabolomics. In current study, an attempt was made for the large-scale ginsenoside-specific analysis in ginseng (G) and American ginseng (AG). When formic acid (0.1%, v/v) was introduced as the mobile phase additive, formate anion-to-deprotonated ion transitions ([M+HCOO](-)>[M-H](-)) with an optimal collision energy (-32eV) could result in satisfactory responses for ginsenosides. Therefore, a step-wise multiple reaction monitoring (MRM)-based method employing [M+HCOO](-)>[M-H](-) ion pairs was constructed to screen ginsenosides among 501-1250u (for Q1) with a step-size of 2u, and MRM also served as a survey experiment to trigger enhanced product ion scans for MS(2) spectrum acquisition on a hybrid triple quadrupole-linear ion trap mass spectrometer; then, the identification of those observed ginsenosides was achieved on the basis of the well-defined mass cracking patterns for ginsenosides; afterwards, scheduled MRM was introduced for large-scale relatively quantitative analysis of all detected ginsenosides. Finally, comparative metabolomics were performed to differentiate G, AG, and their processed products. Method validation was carried out using thirteen authentic compounds. A total of 221 ginsenosides, among which 185 ones were annotated, were observed and relatively quantitated. All crude materials were obviously classified into groups I-III. Above all, the MRM-based homolog-focused profiling of ginsenosides could be used as a reliable tool to gain an in-depth view for ginsenoside-enriched herbal products. PMID- 26105783 TI - Methotrexate-associated lymphoproliferative disorder: Sequential development of angioimmunoblastic T-cell lymphoma-like lymphoproliferation in the lymph nodes and diffuse large B-cell lymphoma in the skin in the same patient. PMID- 26105785 TI - Study of the reactivity of silica supported tantalum catalysts with oxygen followed by in situ HEROS. AB - We report on the reactivity of grafted tantalum organometallic catalysts with molecular oxygen. The changes in the local Ta electronic structure were followed by in situ high-energy resolution off-resonant spectroscopy (HEROS). The results revealed agglomeration and formation of Ta dimers, which cannot be reversed. The process occurs independently of starting grafted complex. PMID- 26105784 TI - Heat stress induced apoptosis is triggered by transcription-independent p53, Ca(2+) dyshomeostasis and the subsequent Bax mitochondrial translocation. AB - In this study, We demonstrated that Bax mitochondrial translocation plays a vital role in the initiation of the mitochondrial signaling pathway upon activation by heat stress. In addition, both p53 mitochondrial translocation and Ca(2+) signal mediated MPTP opening activate Bax mitochondrial translocation. Employing pifithrin-alpha (a p53 mitochondrial translocation inhibitor) and CsA (a permeability transition pore (MPTP) inhibitor), we found that heat stress induced Bax mitochondrial translocation was significantly inhibited in cells pretreated with both PFT and CsA. Furthermore, we demonstrated that generation of reactive oxygen species (ROS) is a critical mediator in heat stress induced apoptosis and that the antioxidant MnTBAP significantly decreased heat stress induced p53 mitochondrial translocation and Ca(2+) signal mediated MPTP opening, as well as the subsequent Bax mitochondrial translocation and activation of the caspase cascade. Taken together, our results indicate that heat stress induces apoptosis through the mitochondrial pathway with ROS dependent mitochondrial p53 translocation and Ca(2+) dyshomeostasis, and the ensuing intro Bax mitochondrial translocation as the upstream events involved in triggering the apoptotic process observed upon cellular exposure to heat stress. PMID- 26105786 TI - Postmortem CT, gross and microscopic images of hemorrhage along the pulmonary artery sheath due to type A aortic dissection. PMID- 26105787 TI - The radiographic visibility of the root pulp of the third lower molar as an age marker. AB - PURPOSE: The aim of this work was to determine the usefulness of the visibility of the dental pulp in lower third molars in forensic age estimation. METHODS: Dental pulp visibility on lower third molars was assessed using a sample of 487 orthopantomograms. Intra and inter-observer agreement was determined using the Cohen's kappa test. A descriptive analysis of the stages according to age was done. The relationship between age and stage attainment was assessed using Chi square test and the strength and direction of the linear relationship between pulp visualization stage and chronological age was evaluated using Spearman rank order correlation (rho). Equations for predicting an age above 21 years were developed using logistic regression. The level of significance was defined at p < 0.05. RESULTS: The relationship between age and stage attainment had statistical significance for both sexes (p < 0.001). There was a medium positive correlation between the two variables for both genders (Spearman rho = 0.420, p < 0.001 and Spearman rho = 0.454, p < 0.001, for males and females respectively). The model built for age estimation successfully predicted age over 21 in 96.2% of the females and in 96.9% of the males. However, only 19.6 and 27.0% of predictions were accurate for the group that was younger than 21, for females and males, respectively. CONCLUSIONS: The accuracy of predictions for the group younger than 21 years of age was low, meaning that this methodology may not be suitable for age estimation. Still, stage 3 alone proved to be a suitable age marker for determining an age over 21 years. PMID- 26105788 TI - Dentures in dementia: the oral health management of patients in institutional care. PMID- 26105789 TI - Mediated Electron Transfer at Vertically Aligned Single-Walled Carbon Nanotube Electrodes During Detection of DNA Hybridization. AB - Vertically aligned single-walled carbon nanotube (VASWCNT) assemblies are generated on cysteamine and 2-mercaptoethanol (2-ME)-functionalized gold surfaces through amide bond formation between carboxylic groups generated at the end of acid-shortened single-walled carbon nanotubes (SWCNTs) and amine groups present on the gold surfaces. Atomic force microscopy (AFM) imaging confirms the vertical alignment mode of SWCNT attachment through significant changes in surface roughness compared to bare gold surfaces and the lack of any horizontally aligned SWCNTs present. These SWCNT assemblies are further modified with an amine terminated single-stranded probe-DNA. Subsequent hybridization of the surface bound probe-DNA in the presence of complementary strands in solution is followed using impedance measurements in the presence of Fe(CN)6 (3-/4-) as the redox probe in solution, which show changes in the interfacial electrochemical properties, specifically the charge-transfer resistance, due to hybridization. In addition, hybridization of the probe-DNA is also compared when it is attached directly to the gold surfaces without any intermediary SWCNTs. Contrary to our expectations, impedance measurements show a decrease in charge-transfer resistance with time due to hybridization with 300 nM complementary DNA in solution with the probe-DNA attached to SWCNTs. In contrast, an increase in charge-transfer resistance is observed with time during hybridization when the probe-DNA is attached directly to the gold surfaces. The decrease in charge transfer resistance during hybridization in the presence of VASWCNTs indicates an enhancement in the electron transfer process of the redox probe at the VASWCNT modified electrode. The results suggest that VASWCNTs are acting as mediators of electron transfer, which facilitate the charge transfer of the redox probe at the electrode-solution interface. PMID- 26105790 TI - Herd immunity and fatal cases of influenza among the population exposed to poultry and wild birds in Russian Asia in 2013-2014. AB - In total 1,525 blood serum samples were collected in October, 2013 in Russian Asia from people who reside in territories that are at high risk for emergence of influenza viruses with pandemic potential. Presence of antibodies to influenza viruses in the sera was tested in hemagglutination inhibition test. None of the samples produced positive results with the antigens A/H5 and A/H7. Twelve strains of influenza A(H1N1pdm09) virus were isolated from people who died presumably from influenza during 2013-2014 epidemic season. All strains were similar to vaccine strain A/California/07/09 according to their antigenic properties and sensitivity to anti-neuraminidase drugs (oseltamivir and zanamivir). Genetic analysis revealed that all strains belong to group 6, subgroup 6B of influenza A(H1N1)pdm09 virus. Substitutions in HA1: S164F add E235K as well as E47G, A86V, K331R, N386K, N397K in NA, and K131E, N29S in NS1, and N29S, R34Q in NEP separate investigated strains into two groups: 1st group-A/Chita/1114/2014, A/Chita/1115/2014, A/Chita/853/2014, A/Barnaul/269/2014 and 2nd group A/Chita/655/2014, A/Chita/656/2014, A/Chita/709/2014, A/Chita/873/2014. Mutation D222G in HA1, which is often associated with high morbidity of the illness, was present in strain A/Novosibirsk/114/2014. Substitution N386K in NA removes a potential N-glycosylation site in neuraminidases of A/Chita/1114/2014, A/Chita/1115/2014, A/Chita/853/2014, A/Barnaul/269/2014, A/Novosibirsk/114/2014, and A/Blagoveshensk/252/2014. PMID- 26105791 TI - Equilibrium and non-equilibrium dynamics simultaneously operate in the Galapagos islands. AB - Island biotas emerge from the interplay between colonisation, speciation and extinction and are often the scene of spectacular adaptive radiations. A common assumption is that insular diversity is at a dynamic equilibrium, but for remote islands, such as Hawaii or Galapagos, this idea remains untested. Here, we reconstruct the temporal accumulation of terrestrial bird species of the Galapagos using a novel phylogenetic method that estimates rates of biota assembly for an entire community. We show that species richness on the archipelago is in an ascending phase and does not tend towards equilibrium. The majority of the avifauna diversifies at a slow rate, without detectable ecological limits. However, Darwin's finches form an exception: they rapidly reach a carrying capacity and subsequently follow a coalescent-like diversification process. Together, these results suggest that avian diversity of remote islands is rising, and challenge the mutual exclusivity of the non equilibrium and equilibrium ecological paradigms. PMID- 26105793 TI - Quantitative ROESY analysis of computational models: structural studies of citalopram and beta-cyclodextrin complexes by (1) H-NMR and computational methods. AB - Complexation of racemic citalopram with beta-cyclodextrin (beta-CD) in aqueous medium was investigated to determine atom-accurate structure of the inclusion complexes. (1) H-NMR chemical shift change data of beta-CD cavity protons in the presence of citalopram confirmed the formation of 1 : 1 inclusion complexes. ROESY spectrum confirmed the presence of aromatic ring in the beta-CD cavity but whether one of the two or both rings was not clear. Molecular mechanics and molecular dynamic calculations showed the entry of fluoro-ring from wider side of beta-CD cavity as the most favored mode of inclusion. Minimum energy computational models were analyzed for their accuracy in atomic coordinates by comparison of calculated and experimental intermolecular ROESY peak intensities, which were not found in agreement. Several least energy computational models were refined and analyzed till calculated and experimental intensities were compatible. The results demonstrate that computational models of CD complexes need to be analyzed for atom-accuracy and quantitative ROESY analysis is a promising method. Moreover, the study also validates that the quantitative use of ROESY is feasible even with longer mixing times if peak intensity ratios instead of absolute intensities are used. PMID- 26105792 TI - BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK-PPARdelta-dependent pathway in mice. AB - AIMS/HYPOTHESIS: We explored the effects of beta-aminoisobutyric acid (BAIBA) on hyperlipidaemic-condition-induced insulin resistance and inflammation as mediated through a signalling pathway involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor delta (PPARdelta). METHODS: Mouse skeletal muscle C2C12 cells and C57BL/6J mice were treated with palmitate or a high-fat diet (HFD) and BAIBA. Inflammation and the expression of genes associated with insulin signalling were determined by western blot and quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si)RNA knockdown and specific inhibitors. RESULTS: BAIBA treatment ameliorated impairment of insulin receptor substrate (IRS)-1/Akt mediated insulin signalling in palmitate-treated C2C12 myocytes and in skeletal muscle of HFD-fed mice. In addition, BAIBA treatment reversed HFD-induced increases in body weight and improved impaired glucose tolerance in mice. In vitro and in vivo, inhibitory kappaBalpha (IkappaBalpha) phosphorylation, nuclear factor kappaB (NFkappaB) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPARdelta in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Ppardelta (also known as Ppard) siRNA abrogated the inhibitory effects of BAIBA on palmitate-induced inflammation and insulin resistance. BAIBA significantly induced the expression of genes associated with fatty acid oxidation, such as carnitine palmitoyltransferase 1 (Cpt1), acyl-CoA oxidase (Aco; also known as Acox1) and fatty acid binding protein 3 (Fabp3); this effect of BAIBA was significantly reduced by compound C and Ppardelta siRNA. CONCLUSIONS/INTERPRETATION: These results are the first to demonstrate that BAIBA attenuates insulin resistance, suppresses inflammation and induces fatty acid oxidation via the AMPK-PPARdelta pathway in skeletal muscle. PMID- 26105794 TI - Nanofiltration concentration of extracellular glutathione produced by engineered Saccharomyces cerevisiae. AB - This study aimed to optimize extracellular glutathione production by a Saccharomyces cerevisiae engineered strain and to concentrate the extracellular glutathione by membrane separation processes, including ultrafiltration (UF) and nanofiltration (NF). Synthetic defined (SD) medium containing 20 g L(-1) glucose was fermented for 48 h; the fermentation liquid was passed through an UF membrane to remove macromolecules. Glutathione in this permeate was concentrated for 48 h to 545.1 +/- 33.6 mg L(-1) using the NF membrane; this was a significantly higher concentration than that obtained with yeast extract peptone dextrose (YPD) medium following 96 h NF concentration (217.9 +/- 57.4 mg L(-1)). This higher glutathione concentration results from lower cellular growth in SD medium (final OD600 = 6.9 +/- 0.1) than in YPD medium (final OD600 = 11.0 +/- 0.6) and thus higher production of extracellular glutathione (16.0 +/- 1.3 compared to 9.2 +/- 2.1 mg L(-1) in YPD medium, respectively). Similar fermentation and membrane processing of sweet sorghum juice containing 20 g L(-1) total sugars provided 240.3 +/- 60.6 mg L(-1) glutathione. Increased extracellular production of glutathione by this engineered strain in SD medium and subsequent UF permeation and NF concentration in shortend time may help realize industrial recovery of extracellular glutathione. PMID- 26105796 TI - Erratum to: Quality assessment of estrogen receptor and progesterone receptor testing in breast cancer using a tissue microarray-based approach. PMID- 26105795 TI - CIB1 depletion impairs cell survival and tumor growth in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with generally poor prognosis and no available targeted therapies, highlighting a critical unmet need to identify and characterize novel therapeutic targets. We previously demonstrated that CIB1 is necessary for cancer cell survival and proliferation via regulation of two oncogenic signaling pathways, RAF-MEK-ERK and PI3K-AKT. Because these pathways are often upregulated in TNBC, we hypothesized that CIB1 may play a broader role in TNBC cell survival and tumor growth. Methods utilized include inducible RNAi depletion of CIB1 in vitro and in vivo, immunoblotting, clonogenic assay, flow cytometry, RNA-sequencing, bioinformatics analysis, and Kaplan-Meier survival analysis. CIB1 depletion resulted in significant cell death in 8 of 11 TNBC cell lines tested. Analysis of components related to PI3K-AKT and RAF-MEK-ERK signaling revealed that elevated AKT activation status and low PTEN expression were key predictors of sensitivity to CIB1 depletion. Furthermore, CIB1 knockdown caused dramatic shrinkage of MDA-MB 468 xenograft tumors in vivo. RNA sequence analysis also showed that CIB1 depletion in TNBC cells activates gene programs associated with decreased proliferation and increased cell death. CIB1 expression levels per se did not predict TNBC susceptibility to CIB1 depletion, and CIB1 mRNA expression levels did not associate with TNBC patient survival. Our data are consistent with the emerging concept of non-oncogene addiction, where a large subset of TNBCs depend on CIB1 for cell survival and tumor growth, independent of CIB1 expression levels. Our data establish CIB1 as a novel therapeutic target for TNBC. PMID- 26105797 TI - The predictive and prognostic role of phosphatase phosphoinositol-3 (PI3) kinase (PIK3CA) mutation in HER2-positive breast cancer receiving HER2-targeted therapy: a meta-analysis. AB - The association between PIK3CA mutation and resistance to anti-HER2 therapy (AHT) is not precisely defined. This meta-analysis intended to explore the clinical utility of PIK3CA mutation in HER2-positive breast cancer treated with AHT. Literature search identified 19 eligible studies. There were 1720 patients with advanced, 828 with early and 1290 patients treated in the neoadjuvant setting. In metastatic breast cancer, AHT showed no differential objective response benefit between the wild type (WT) and the mutated type (MT) PIK3CA subgroups (odds ratio [OR] = 1.09; 95 % CI 0.60-2.00; P = 0.78). AHT favorable affected progression free survival (PFS) irrespective of PIK3CA mutation. There was no PFS difference between WT and MT regardless of the offered therapy. In early breast cancer, trastuzumab combined with the same chemotherapy conferred consistent relapse-free survival benefit in WT and MT subgroups (WT: HR = 0.59; 95 % CI 0.44-0.80; P < 0.001 vs. MT: HR = 0.42; 95 % CI 0.24-0.74; P < 0.001). In the neoadjuvant setting, AHT-based therapy produced a 72 % higher pathologic complete response (pCR) rate in WT as compared with that in MT PIK3CA tumors (OR = 1.72; 95 % CI 1.29-2.13; P < 0.001). In that setting, there was no disease-free or overall survival difference based on PIK3CA mutational status. In this meta-analysis, AHT did not achieve differential benefit according to PIK3CA mutation in HER2 positive metastatic or early breast cancer; however, in the neoadjuvant setting, patients harboring WT PIK3CA tumors attained a higher pCR rate. PMID- 26105798 TI - Guidelines are advantageous, though not essential for improved survival among breast cancer patients. AB - The purpose of this retrospective multicenter study was to resolve the pseudo paradox that the clinical outcome of women affected by breast cancer has improved during the last 20 years irrespective of whether they were treated in accordance with clinical guidelines or not. This retrospective German multicenter study included 9061 patients with primary breast cancer recruited from 1991 to 2009. We formed subgroups for the time intervals 1991-2000 (TI1) and 2001-2009 (TI2). In these subgroups, the risk of recurrence (RFS) and overall survival (OS) were compared between patients whose treatment was either 100% guideline-conforming or, respectively, non-guideline-conforming. The clinical outcome of all patients significantly improved in TI2 compared to TI1 [RFS: p < 0.001, HR = 0.57, 95% CI (0.49-0.67); OS: p < 0.001, HR = 0.76, 95% (CI 0.66-0.87)]. OS and RFS of guideline non-adherent patients also improved in TI2 compared to TI. Comparing risk profiles, determined by Nottingham Prognostic Score reveals a significant (p = 0.001) enhancement in the time cohort TI2. Furthermore, the percentage of guideline-conforming systemic therapy (endocrine therapy and chemotherapy) significantly increased (p < 0.001) in the time cohort TI2 to TI for the non adherent group. The general improvement of clinical outcome of patients during the last 20 years is also valid in the subgroup of women who received treatments, which deviated from the guidelines. The shift in risk profiles as well as medical advances are major reasons for this improvement. Nevertheless, patients with 100% guideline-conforming therapy always had a better outcome compared to patients with guideline non-adherent therapy. PMID- 26105799 TI - A nationwide analysis of the use and outcomes of perioperative epidural analgesia in patients undergoing hepatic and pancreatic surgery. AB - BACKGROUND: We sought to define trends in the use of epidural analgesia (EA) for hepatopancreatic procedures, as well as to characterize inpatient outcomes relative to the use of EA. METHODS: The Nationwide Inpatient Sample database was queried to identify all elective hepatopancreatic surgeries between 2000 and 2012. In-hospital outcomes were compared among patients receiving EA vs conventional analgesia using propensity matching. RESULTS: EA utilization was 7.4% (n = 3,961). The use of EA among minimally invasive procedures increased from 3.8% in 2000 to 9.1% in 2012. The odds of sepsis (odds ratio [OR] .72, 95% confidence interval [CI] .56 to .93), respiratory failure (OR .79, 95% CI .69 to .91), and postoperative pneumonia (OR .77, 95% CI .61 to .98), as well as overall in-hospital mortality (OR .72, 95% CI .56 to .93) were lower in the EA cohort (all P < .05). In contrast, no association was noted between EA and postoperative hemorrhage (OR .81, 95% CI .65 to 1.01, P = .06). CONCLUSIONS: EA use among patients undergoing hepatopancreatic procedures remains low. After controlling for confounding factors, EA remained associated with a reduction in specific pulmonary-related complications, as well as in-hospital mortality. PMID- 26105800 TI - Clinical significance of preoperative neutrophil-lymphocyte vs platelet lymphocyte ratio in primary operable patients with non-small cell lung cancer. AB - BACKGROUND: Our aim was to determinate the prognostic value of neutrophil lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) in primary operable patients with non-small cell lung cancer (NSCLC). METHODS: Six hundred seventy eight NSCLC patients were enrolled in this study. The prognostic significance of both markers was determined by both univariate and multivariate Cox survival analysis. The cut-off value for NLR and PLR was selected by using receiver operating characteristic curve analysis. RESULTS: Multivariate analysis showed that NLR was an independent prognostic factor for disease-free survival (hazard ratio = 1.593, 95% confidence interval [CI] 1.277 to 1.988, P < .001) and overall survival (hazard ratio = 1.624, 95% CI 1.304 to 2.022, P < .001). The area under the curve was .640 (95% CI .599 to .682, P < .001) for NLR and .547 (95% CI .503 to .590, P = .036) for PLR, indicating that NLR was superior to PLR as a predictive factor in primary operable NSCLC patients. CONCLUSIONS: Preoperative NLR represents a significant independent prognostic indicator in primary operable NSCLC patients. Our results also demonstrate that high-risk patients based on the NLR do not benefit from adjuvant chemotherapy. PMID- 26105801 TI - Combined stoma reversal and liver resection: a matched case-control study. AB - BACKGROUND: Stoma reversal can be performed during liver resection (LR) in patients with colorectal liver metastases (CRCLM) whose primary colorectal tumor has been previously resected with a diverting loop ileostomy. This combined procedure is reputed to be associated with an increased morbidity. This study investigates the impact of simultaneous loop ileostomy closure (LIC) on the postoperative outcome of LR for CRCLM. METHODS: From November 1996 to April 2012, 408 patients who underwent LR for CRCLM were retrospectively studied from a prospective database. Patients who underwent simultaneous LR and LIC were matched for the type of the main liver procedure, the use of preoperative chemotherapy and the need for greater than or equal to 6 cycles of preoperative chemotherapy with LR only patients. Intraoperative and postoperative complications were recorded and compared. RESULTS: Twenty-four patients (6%) with simultaneous LR and LIC were matched with 72 patients with LR only. Both groups were comparable for patients' demographics and intraoperative findings. Liver related (P = .957) and overall postoperative morbidity (P = .643) rates did not differ between groups. CONCLUSION: The combined procedure appeared to be safe when strict surgical technique is used. PMID- 26105802 TI - What stress coping strategies are surgeons relying upon during surgery? AB - BACKGROUND: The objective of this study was to determine sources of intraoperative stress, impact on surgical outcomes, coping strategies, and surgeon interest in stress management training. METHODS: An anonymous survey was electronically distributed to surgeons at a tertiary care hospital. Respondents were asked to rate the perceived impact of 9 stressors on operative performance, identify stress coping strategies, list witnessed stress-related complications, and opine on the perceived need for stress management training. RESULTS: Seventy two responses were received (76% relative risk). Complex or rarely performed cases and poor assistance were associated with the highest stress, while personal life distractions were associated with the least. Importantly, 40% of surgeons indicated that they had witnessed an intraoperative complication directly related to surgeon stress. Respondents (82%) believed that formal stress management training is needed. CONCLUSIONS: Several stressors affect surgical performance and contribute to complications. Surgeons use a variety of stress coping strategies. Formal stress management training is needed. PMID- 26105803 TI - Distinct clinicopathological phenotype of hepatocellular carcinoma with ethoxybenzyl-magnetic resonance imaging hyperintensity: association with gene expression signature. AB - BACKGROUND: Although hepatocellular carcinoma (HCC) is mostly a lower intensity lesion in the hepatobiliary phase on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, some HCCs were shown as a higher intensity lesion (high HCC). This study aimed to reveal the clinicopathological and biological properties of high HCC. METHODS: Patients who underwent curative hepatectomy as the first treatment for HCC were included. HCC was defined as high HCC if the ratio between the signal intensity of the HCC and the background liver was greater than or equal to 1.0. We retrospectively performed clinicopathological and global gene expression analyses. RESULTS: Of the 77 patients, 14 had high HCC. Serum protein induced by vitamin K absence or antagonist II levels in high HCC were lower, and the high HCCs were well differentiated. The 3-year disease-free survival rates in high HCC and low HCC patients were 90% and 54%, respectively (P = .035). Overall survival did not differ significantly. Global gene expression analysis revealed that SLCO1B3 was upregulated in high HCC. CONCLUSIONS: Clinicopathological analysis revealed low grade malignancy in high HCCs compared with low HCCs. The expression of SLCO1B3 was key to the hyperintensity in the hepatobiliary phase of ethoxybenzyl diethylenetriamine pentaacetic acid magnetic resonance imaging. PMID- 26105804 TI - Imaging an aligned polyatomic molecule with laser-induced electron diffraction. AB - Laser-induced electron diffraction is an evolving tabletop method that aims to image ultrafast structural changes in gas-phase polyatomic molecules with sub Angstrom spatial and femtosecond temporal resolutions. Here we demonstrate the retrieval of multiple bond lengths from a polyatomic molecule by simultaneously measuring the C-C and C-H bond lengths in aligned acetylene. Our approach takes the method beyond the hitherto achieved imaging of simple diatomic molecules and is based on the combination of a 160 kHz mid-infrared few-cycle laser source with full three-dimensional electron-ion coincidence detection. Our technique provides an accessible and robust route towards imaging ultrafast processes in complex gas phase molecules with atto- to femto-second temporal resolution. PMID- 26105805 TI - Disease relevance of T11TS-induced T-cell signal transduction through the CD2 mediated calcineurin-NFAT pathway: Perspectives in glioma immunotherapy. AB - Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell - antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated "alternative pathway" of calcineurin-NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this "alternative pathway" of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-theta (PKC-theta), calcineurin and nuclear factor for activation of T-cells (NFAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door - one which is directed towards clinical studies for glioma-immunotherapy using T11TS. PMID- 26105807 TI - LPXRFa peptide system in the European sea bass: A molecular and immunohistochemical approach. AB - Gonadotropin-inhibitory hormone (GnIH) is a neuropeptide that suppresses reproduction in birds and mammals by inhibiting GnRH and gonadotropin secretion. GnIH orthologs with a C-terminal LPXRFamide (LPXRFa) motif have been identified in teleost fish. Although recent work also suggests its role in fish reproduction, studies are scarce and controversial, and have mainly focused on cyprinids. In this work we cloned a full-length cDNA encoding an LPXRFa precursor in the European sea bass, Dicentrarchus labrax. In contrast to other teleosts, the sea bass LPXRFa precursor contains only two putative RFamide peptides, termed sbLPXRFa1 and sbLPXRFa2. sblpxrfa transcripts were expressed predominantly in the olfactory bulbs/telencephalon, diencephalon, midbrain tegmentum, retina, and gonads. We also developed a specific antiserum against sbLPXRFa2, which revealed sbLPXRFa-immunoreactive (ir) perikarya in the olfactory bulbs-terminal nerve, ventral telencephalon, caudal preoptic area, dorsal mesencephalic tegmentum, and rostral rhombencephalon. These sbLPXRFa-ir cells profusely innervated the preoptic area, hypothalamus, optic tectum, semicircular torus, and caudal midbrain tegmentum, but conspicuous projections also reached the olfactory bulbs, ventral/dorsal telencephalon, habenula, ventral thalamus, pretectum, rostral midbrain tegmentum, posterior tuberculum, reticular formation, and viscerosensory lobe. The retina, pineal, vascular sac, and pituitary were also targets of sbLPXRFa-ir cells. In the pituitary, this innervation was observed close to follicle-stimulating hormone (FSH), luteinizing hormone (LH) and growth hormone (GH) cells. Tract-tracing retrograde labeling suggests that telencephalic and preoptic sbLPXRFa cells might represent the source of pituitary innervation. The immunohistochemical distribution of sbLPXRFa cells and fibers suggest that LPXRFa peptides might be involved in some functions as well as reproduction, such as feeding, growth, and behavior. PMID- 26105806 TI - Fatty acid-binding protein 5 limits the anti-inflammatory response in murine macrophages. AB - The beginning stages of liver damage induced by various etiologies (i.e. high fat diet, alcohol consumption, toxin exposure) are characterized by abnormal accumulation of lipid in liver. Alterations in intracellular lipid transport, storage, and metabolism accompanied by cellular insult within the liver play an important role in the pathogenesis of liver disease, often involving a sustained inflammatory response. The intracellular lipid transporter, fatty acid binding protein 5 (FABP5), is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin exposure in mice. This study tested the hypothesis that FABP5 regulates macrophage response to LPS in male C57bl/6 (wild type) and FABP5 knockout mice, both in vitro and in vivo. Treatment with LPS revealed that loss of FABP5 enhances the number of hepatic F4/80(+) macrophages in the liver despite limited liver injury. Conversely, FABP5 knock out mice display higher mRNA levels of anti-inflammatory cytokines IL-10, arginase, YM-1, and Fizz-1 in liver compared to wild type mice. Bone marrow derived macrophages stimulated with inflammatory (LPS and IFN-gamma) or anti inflammatory (IL-4) mediators also showed significantly higher expression of anti inflammatory/regulatory factors. These findings reveal a regulatory role of FABP5 in the acute inflammatory response to LPS-induced liver injury, which is consistent with the principle finding that FABP5 is a regulator of macrophage phenotype. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response. PMID- 26105808 TI - Normal range and genetic analysis of coagulation factor XII in the general Chinese population. AB - BACKGROUND: It has been reported that the average activity of coagulation factor XII depends on the ethnicity of the population under study but little information is available on Chinese. We here provide an analysis of the range of activities and antigenic levels of factor XII in healthy Han Chinese and correlate the measurements with polymorphisms and mutations in the corresponding gene. METHODS: Plasma samples were obtained from 549 healthy Chinese adults (264 men, 285 women; age 16-79years) undergoing routine check-ups. The samples were subjected to an activated partial thromboplastin time-based factor XII activity assay as well as an enzyme-linked immunosorbent assay. Partial gene sequence analyses were performed in subjects with low factor XII activity and in normal controls. RESULTS: Ninety-five percent of the subjects had factor XII activities between 47% and 160.25%, with no evidence for an influence of sex or age. Among 15 subjects with activity levels <=47%, we found one novel nonsense and two missense mutations that may lead to dysfunctional proteins. No mutations were found in a selection of subjects with activities above 47%. Interestingly, however, the particular sequence at a known C/T polymorphism at position 46 just upstream of the translational start codon was correlated with factor XII activity. Subjects homozygous for the T allele, which has an allelic frequency of 0.69, showed significantly lower factor XII activities compared to subjects homozygous for the C allele or those heterozygous for C/T. CONCLUSIONS: The survey determined the normal range of factor XII activities in healthy Chinese and identified mutations as well as a biased representation of a polymorphic nucleotide in subjects with abnormally low activities. The results provide an essential basis for the diagnosis of FXII deficiencies in Chinese. PMID- 26105809 TI - Health Consequences of Rural-to-Urban Migration: Evidence from Panel Data in China. AB - This paper provides new empirical evidence on the health consequences of rural-to urban migration in China. We use a panel dataset from 2003 to 2006 constructed by the Research Center on the Rural Economy at the Ministry of Agriculture in China to investigate the effects of short-term and medium-term migration on health status. By combining propensity-score matching and the difference-in-difference model, we attempt to overcome the migration endogeneity issue and estimate the average treatment effect on the treated. We find that the effect of short-term migration on health in China is significantly positive mostly because of the income effect. However, the effect of longer-term continuous migration on health is insignificant and close to zero. Our results are robust to several alternative estimation techniques and a series of robustness checks. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26105810 TI - How medicine is broken, and how we can fix it. PMID- 26105811 TI - Synthesis, characterization and thermoluminescence studies of Mn-doped ZnS nanoparticles. AB - ZnS:Mn nanoparticles were prepared by a chemical precipitation method and characterized by X-ray diffraction (XRD), field emission gun scanning electron microscope (FEGSEM), and high resolution transmission electron microscopy (HRTEM). Capping agent (mercaptoethanol) concentrations used were 0 M, 0.005 M, 0.01 M, 0.015 M, 0.025 M, 0.040 M, and 0.060 M, and resulted in nanoparticles sizes of 2.98 nm, 2.9 nm, 2.8 nm, 2.7 nm, 2.61 nm, 2.2 nm and 2.1 nm, respectively. The thermoluminescence (TL) glow curve was recorded by heating the sample exposed to UV-radiation, at a fixed heating rate 1 degrees C sec(-1). The TL intensity initially increased with temperature, attained a peak value Im for a particular temperature, and then decreased with further increase in temperature. The peak TL intensity increased with decreasing nanoparticle size, whereas the temperature corresponding to the peak TL intensity decreased slightly with reducing nanocrystal size. As a consequence of increase in surface-to-volume ratio and increased carrier recombination rates, the TL intensity increased with decreasing nanoparticle size. It was found that, whereas activation energy slightly decreased with decreasing nanoparticle size, the frequency factor decreased significantly with reduction in nanoparticle size. PMID- 26105812 TI - Effect of single point mutations in a form of systemic amyloidosis. AB - Amyloid deposits of light-chain proteins are associated with the most common form of systemic amyloidosis. We have studied the effects of single point mutations on amyloid formation of these proteins using explicit solvent model molecular dynamics simulations. For this purpose, we compare the stability of the wild-type immunoglobulin light-chain protein REI in its native and amyloid forms with that of four mutants: R61N, G68D, D82I, and A84T. We argue that the experimentally observed differences in the propensity for amyloid formation result from two effects. First, the mutant dimers have a lower stability than the wild-type dimer due to increase exposure of certain hydrophobic residues. The second effect is a shift in equilibrium between monomers with amyloid-like structure and such with native structures. Hence, when developing drugs against light-chain associated systemic amyloidosis, one should look for components that either stabilize the dimer by binding to the dimer interface or reduce for the monomers the probability of the amyloid form. PMID- 26105813 TI - Anaplastology in times of facial transplantation: Still a reasonable treatment option? AB - Optimum functional and aesthetic facial reconstruction is still a challenge in patients who suffer from inborn or acquired facial deformity. It is known that functional and aesthetic impairment can result in significant psychosocial strain, leading to the social isolation of patients who are affected by major facial deformities. Microvascular techniques and increasing experience in facial transplantation certainly contribute to better restorative outcomes. However, these technologies also have some drawbacks, limitations and unsolved problems. Extensive facial defects which include several aesthetic units and dentition can be restored by combining dental prostheses and anaplastology, thus providing an adequate functional and aesthetic outcome in selected patients without the drawbacks of major surgical procedures. Referring to some representative patient cases, it is shown how extreme facial disfigurement after oncological surgery can be palliated by combining intraoral dentures with extraoral facial prostheses using individualized treatment and without the need for major reconstructive surgery. PMID- 26105815 TI - Noncoding RNA in Mycobacteria. AB - Efforts to understand the molecular basis of mycobacterial gene regulation are dominated by a protein-centric view. However, there is a growing appreciation that noncoding RNA, i.e., RNA that is not translated, plays a role in a wide variety of molecular mechanisms. Noncoding RNA comprises rRNA, tRNA, 4.5S RNA, RnpB, and transfer-messenger RNA, as well as a vast population of regulatory RNA, often dubbed "the dark matter of gene regulation." The regulatory RNA species comprise 5' and 3' untranslated regions and a rapidly expanding category of transcripts with the ability to base-pair with mRNAs or to interact with proteins. Regulatory RNA plays a central role in the bacterium's response to changes in the environment, and in this article we review emerging information on the presence and abundance of different types of noncoding RNA in mycobacteria. PMID- 26105814 TI - Routine aspiration thrombectomy improves the diagnosis and management of embolic myocardial infarction. AB - OBJECTIVES: Assess the effect of aspiration thrombectomy on diagnosis and management of embolic acute myocardial infarction. BACKGROUND: Discrimination of embolic acute myocardial infarction from atherosclerotic plaque rupture/erosion prompts oral anticoagulation treatment of source of embolus, as well as avoiding unnecessary stenting and dual antiplatelet therapy. However, detection is difficult without aspiration. METHODS: We compared rates of diagnosis of embolic infarction for 2.5 years prior to (pre-RAT) and 2.5 years post routine aspiration thrombectomy (post-RAT). Baseline demographics, outcomes, and treatment strategies were also compared between the embolic infarction and atherosclerotic infarction. RESULTS: Diagnosed embolic infarction rose from 1.2% in the pre-RAT era to 2.8% in the post-RAT period (P < 0.05). In addition, more successful removal of thrombus by aspiration led to less stenting (20% vs. 55% P < 0.05) in the post-RAT period thus avoiding the hazards of "triple therapy." Embolic infarction was more frequently associated with atrial fibrillation (55% vs. 8%), had higher mortality (17% vs. 4%), and had higher rates of embolic stroke (13% vs. 0.3%) when compared with atherosclerotic MI (all P < 0.05). CONCLUSIONS: Routine aspiration thrombectomy more readily identifies embolic infarction allowing more specific therapy and avoidance of stenting and triple anticoagulant therapy. PMID- 26105816 TI - The Role of Complement in Antibody Therapy for Infectious Diseases. AB - The complement system is part of the innate immune system, eliciting central immunoregulatory functions. Detection of foreign surfaces is either achieved through complement-specific patternrecognition molecules or mediated by antigen recognition of antibodies. Immunoglobulin A (IgA), IgG, and IgM all have the potential to initiate a complement response, with the efficiency and response development closely related to the antibody isotype, multimeric state, and degree of glycosylation. A group of serum proteins constitutes the central effector functions of complement, thus allowing direct cell lysis, opsonization, and inflammation. These effector functions can be used in antibody therapies, especially against infectious diseases, as the target membranes lack complement regulatory proteins. The relative contribution of each function and the interplay with direct antibody-mediated clearance is not fully exploited, thus suggesting an option for further rational optimization of antibody therapies. PMID- 26105817 TI - Humanized Mice for Studying Human Immune Responses and Generating Human Monoclonal Antibodies. AB - The new-generation humanized (Hu) mouse models permit multilineage human hematopoiesis and generate T cells, B cells, macrophages, and dendritic cells required for a coordinated human immune response. Therefore, any desired antigen or human-specific pathogens that can infect humanized mice can be used to generate human antibody responses. Two leading humanized mouse models are currently being used. The Hu-HSC model uses the transplantation of human hematopoietic stem cells (HSCs), whereas the BLT mouse model is created by transplantation of human fetal liver, thymus, and HSC. A number of human pathogens such as HIV-1, dengue, Epstein-Barr virus, and hepatitis C virus have been studied in these systems. Responder antigen-specific B cells from these animals can be collected and used to generate human monoclonals by B-cell immortalization or by single-cell PCR methods to "rescue" antibody-producing genes for ectopic expression. Both models generate cellular and humoral immune responses. However, the antibodies generated are primarily of the IgM type because of the inefficient immunoglobulin class switch resulting in the suboptimal production of antigen-specific affinity-matured IgG. The current Hu mouse models thus far have permitted the analysis of human "antibodyome," and recent reports demonstrated their utility in generating human monoclonal antibodies. Ongoing efforts at further refinements are expected to make these systems more efficient in the near future. PMID- 26105818 TI - Antibody Structure. AB - A brief outline of antibody structure is followed by highlights from several recently determined crystal structures of human, antiviral Fabs. These Fabs all have novel structural features that allow them to potently and broadly neutralize their targets. PMID- 26105820 TI - Transcription Factor Binding Site Mapping Using ChIP-Seq. AB - Transcription factors (TFs) play a central role in regulating gene expression in all bacteria. Yet until recently, studies of TF binding were limited to a small number of factors at a few genomic locations. Chromatin immunoprecipitation followed by sequencing (ChIP-Seq) provides the ability to map binding sites globally for TFs, and the scalability of the technology enables the ability to map binding sites for every DNA binding protein in a prokaryotic organism. We have developed a protocol for ChIP-Seq tailored for use with mycobacteria and an analysis pipeline for processing the resulting data. The protocol and pipeline have been used to map over 100 TFs from Mycobacterium tuberculosis, as well as numerous TFs from related mycobacteria and other bacteria. The resulting data provide evidence that the long-accepted spatial relationship between TF binding site, promoter motif, and the corresponding regulated gene may be too simple a paradigm, failing to adequately capture the variety of TF binding sites found in prokaryotes. In this article we describe the protocol and analysis pipeline, the validation of these methods, and the results of applying these methods to M. tuberculosis. PMID- 26105821 TI - Molecular Genetics of Mycobacteriophages. AB - Mycobacteriophages have provided numerous essential tools for mycobacterial genetics, including delivery systems for transposons, reporter genes, and allelic exchange substrates, and components for plasmid vectors and mutagenesis. Their genetically diverse genomes also reveal insights into the broader nature of the phage population and the evolutionary mechanisms that give rise to it. The substantial advances in our understanding of the biology of mycobacteriophages including a large collection of completely sequenced genomes indicates a rich potential for further contributions in tuberculosis genetics and beyond. PMID- 26105822 TI - Cyclic AMP Signaling in Mycobacteria. AB - All cells must adapt to changing conditions, and many use cyclic AMP (cAMP) as a second messenger to sense and respond to fluctuations in their environment. cAMP is made by adenylyl cyclases (ACs), and mycobacteria have an unusually large number of biochemically distinct ACs. cAMP is important for gene regulation in mycobacteria, and the ability to secrete cAMP into host macrophages during infection contributes to Mycobacterium tuberculosis pathogenesis. This article discusses the many roles of cAMP in mycobacteria and reviews what is known about the factors that contribute to production, destruction, and utilization of this important signal molecule. Special emphasis is placed on cAMP signaling in M. tuberculosis complex bacteria and its importance to M. tuberculosis during host infection. PMID- 26105819 TI - Gene Transfer in Mycobacterium tuberculosis: Shuttle Phasmids to Enlightenment. AB - Infectious diseases have plagued humankind throughout history and have posed serious public health problems. Yet vaccines have eradicated smallpox and antibiotics have drastically decreased the mortality rate of many infectious agents. These remarkable successes in the control of infections came from knowing the causative agents of the diseases, followed by serendipitous discoveries of attenuated viruses and antibiotics. The discovery of DNA as genetic material and the understanding of how this information translates into specific phenotypes have changed the paradigm for developing new vaccines, drugs, and diagnostic tests. Knowledge of the mechanisms of immunity and mechanisms of action of drugs has led to new vaccines and new antimicrobial agents. The key to the acquisition of the knowledge of these mechanisms has been identifying the elemental causes (i.e., genes and their products) that mediate immunity and drug resistance. The identification of these genes is made possible by being able to transfer the genes or mutated forms of the genes into causative agents or surrogate hosts. Such an approach was limited in Mycobacterium tuberculosis by the difficulty of transferring genes or alleles into M. tuberculosis or a suitable surrogate mycobacterial host. The construction of shuttle phasmids-chimeric molecules that replicate in Escherichia coli as plasmids and in mycobacteria as mycobacteriophages-was instrumental in developing gene transfer systems for M. tuberculosis. This review will discuss M. tuberculosis genetic systems and their impact on tuberculosis research. PMID- 26105823 TI - Antibody Informatics: IMGT, the International ImMunoGeneTics Information System. AB - Antibody informatics, a part of immunoinformatics, refers to the concepts, databases, and tools developed and used to explore and to analyze the particular properties of the immunoglobulins (IG) or antibodies, compared with conventional genes and proteins. Antibody informatics is based on a unique ontology, IMGT ONTOLOGY, created in 1989 by IMGT, the international ImMunoGeneTics information system (http://www.imgt.org). IMGT-ONTOLOGY defined, for the first time, the concept of 'genes' for the IG and the T cell receptors (TR), which led to their gene and allele nomenclature and allowed their entry in databases and tools. A second IMGT-ONTOLOGY revolutionizing and definitive concept was the IMGT unique numbering that bridged the gap between sequences and structures for the variable (V) and constant (C) domains of the IG and TR, and for the groove (G) domains of the major histocompatibility (MH). These breakthroughs contributed to the development of IMGT databases and tools for antibody informatics and its diverse applications, such as repertoire analysis in infectious diseases, antibody engineering and humanization, and study of antibody/antigen interactions. Nucleotide sequences of antibody V domains from deep sequencing (Next Generation Sequencing or High Throughput Sequencing) are analyzed with IMGT/HighV-QUEST, the high-throughput version of IMGT/V-QUEST and IMGT/JunctionAnalysis. Amino acid sequences of V and C domains are represented with the IMGT/Collier-de-Perles tool and analyzed with IMGT/DomainGapAlign. Three-dimensional (3D) structures (including contact analysis and paratope/epitope) are described in IMGT/3Dstructure-DB. Based on a friendly interface, IMGT/mAb-DB contains therapeutic monoclonal antibodies (INN suffix-mab) that can be queried on their specificity, for example, in infectious diseases, on bacterial or viral targets. PMID- 26105824 TI - Structural Annotation of the Mycobacterium tuberculosis Proteome. AB - Efforts from the TB Structural Genomics Consortium together with those of tuberculosis structural biologists worldwide have led to the determination of about 350 structures, making up nearly a tenth of the pathogen's proteome. Given that knowledge of protein structures is essential to obtaining a high-resolution understanding of the underlying biology, it is desirable to have a structural view of the entire proteome. Indeed, structure prediction methods have advanced sufficiently to allow structural models of many more proteins to be built based on homology modeling and fold recognition strategies. By means of these approaches, structural models for about 2,877 proteins, making up nearly 70% of the Mycobacterium tuberculosis proteome, are available. Knowledge from bioinformatics has made significant inroads into an improved annotation of the M. tuberculosis genome and in the prediction of key protein players that interact in vital pathways, some of which are unique to the organism. Functional inferences have been made for a large number of proteins based on fold-function associations. More importantly, ligand-binding pockets of the proteins are identified and scanned against a large database, leading to binding site-based ligand associations and hence structure-based function annotation. Near proteome wide structural models provide a global perspective of the fold distribution in the genome. New insights about the folds that predominate in the genome, as well as the fold combinations that make up multidomain proteins, are also obtained. This chapter describes the structural proteome, functional inferences drawn from it, and its applications in drug discovery. PMID- 26105825 TI - Mycobacterium tuberculosis in the Proteomics Era. AB - The emerging field of proteomics has contributed greatly to improving our understanding of the human pathogen Mycobacterium tuberculosis over the last two decades. In this chapter we provide a comprehensive overview of mycobacterial proteome research and highlight key findings. First, studies employing a combination of two-dimensional gel electrophoresis and mass spectrometry (MS) provided insights into the proteomic composition, initially of the whole bacillus and subsequently of subfractions, such as the cell wall, cytosol, and secreted proteins. Comparison of results obtained under various culture conditions, i.e., acidic pH, nutrient starvation, and low oxygen tension, aiming to mimic facets of the intracellular lifestyle of M. tuberculosis, provided initial clues to proteins relevant for intracellular survival and manipulation of the host cell. Further attempts were aimed at identifying the biological functions of the hypothetical M. tuberculosis proteins, which still make up a quarter of the gene products of M. tuberculosis, and at characterizing posttranslational modifications. Recent technological advances in MS have given rise to new methods such as selected reaction monitoring (SRM) and data-independent acquisition (DIA). These targeted, cutting-edge techniques combined with a public database of specific MS assays covering the entire proteome of M. tuberculosis allow the simple and reliable detection of any mycobacterial protein. Most recent studies attempt not only to identify but also to quantify absolute amounts of single proteins in the complex background of host cells without prior sample fractionation or enrichment. Finally, we will discuss the potential of proteomics to advance vaccinology, drug discovery, and biomarker identification to improve intervention and prevention measures for tuberculosis. PMID- 26105826 TI - Bacillus subtilis Systems Biology: Applications of -Omics Techniques to the Study of Endospore Formation. AB - Endospore-forming bacteria, with Bacillus subtilis being the prevalent model organism, belong to the phylum Firmicutes. Although the last common ancestor of all Firmicutes is likely to have been an endospore-forming species, not every lineage in the phylum has maintained the ability to produce endospores (hereafter, spores). In 1997, the release of the full genome sequence for B. subtilis strain 168 marked the beginning of the genomic era for the study of spore formation (sporulation). In this original genome sequence, 139 of the 4,100 protein-coding genes were annotated as sporulation genes. By the time a revised genome sequence with updated annotations was published in 2009, that number had increased significantly, especially since transcriptional profiling studies (transcriptomics) led to the identification of several genes expressed under the control of known sporulation transcription factors. Over the past decade, genome sequences for multiple spore-forming species have been released (including several strains in the Bacillus anthracis/Bacillus cereus group and many Clostridium species), and phylogenomic analyses have revealed many conserved sporulation genes. Parallel advances in transcriptomics led to the identification of small untranslated regulatory RNAs (sRNAs), including some that are expressed during sporulation. An extended array of -omics techniques, i.e., techniques designed to probe gene function on a genome-wide scale, such as proteomics, metabolomics, and high-throughput protein localization studies, have been implemented in microbiology. Combined with the use of new computational methods for predicting gene function and inferring regulatory relationships on a global scale, these -omics approaches are uncovering novel information about sporulation and a variety of other bacterial cell processes. PMID- 26105827 TI - A purple acid phosphatase plays a role in nodule formation and nitrogen fixation in Astragalus sinicus. AB - The AsPPD1 gene from Astragalus sinicus encodes a purple acid phosphatase. To address the functions of AsPPD1 in legume-rhizobium symbiosis, its expression patterns, enzyme activity, subcellular localization, and phenotypes associated with its over-expression and RNA interference (RNAi) were investigated. The expression of AsPPD1 was up-regulated in roots and nodules after inoculation with rhizobia. Phosphate starvation reduced the levels of AsPPD1 transcripts in roots while increased those levels in nodules. We confirmed the acid phosphatase and phosphodiesterase activities of recombinant AsPPD1 purified from Pichia pastoris, and demonstrated its ability to hydrolyze ADP and ATP in vitro. Subcellular localization showed that AsPPD1 located on the plasma membranes in hairy roots and on the symbiosomes membranes in root nodules. Over-expression of AsPPD1 in hairy roots inhibited nodulation, while its silencing resulted in nodules early senescence and significantly decreased nitrogenase activity. Furthermore, HPLC measurement showed that AsPPD1 overexpression affects the ADP levels in the infected roots and nodules, AsPPD1 silencing affects the ratio of ATP/ADP and the energy charge in nodules, and quantitative observation demonstrated the changes of AsPPD1 transcripts level affected nodule primordia formation. Taken together, it is speculated that AsPPD1 contributes to symbiotic ADP levels and energy charge control, and this is required for effective nodule organogenesis and nitrogen fixation. PMID- 26105828 TI - Membrane targeting of MnSOD is essential for oxidative stress tolerance of nitrogen-fixing cultures of Anabaena sp. strain PCC7120. AB - The nitrogen-fixing cyanobacterium, Anabaena PCC7120 encodes for a membrane targeted 30 kDa Mn-superoxide dismutase (MnSOD) and a cytosolic FeSOD. The MnSOD is post-translationally processed to 27 and 24 kDa forms in the cytosol and periplasm/thylakoid lumen. The extent of cleavage of signal and linker peptides at the N-terminus is dependent on the availability of combined nitrogen during growth. While the 24 and 27 kDa forms are present in near equal proportions under nitrogen-fixing conditions, the 24 kDa form is predominant under nitrogen supplemented conditions. Individual contribution of these forms of MnSOD to total oxidative stress tolerance was analysed using recombinant Anabaena strains overexpressing either different molecular forms of MnSOD or MnSOD defective in the cleavage of signal/linker peptide. Targeting of MnSOD to the membrane and subsequent cleavage to release both the 24 and 27 kDa forms was essential for oxidative stress tolerance under nitrogen-fixing conditions. On the other hand, the cleavage of linker peptide was absolutely essential and the release of cytosolic 24 kDa form of MnSOD was obligatory for developing oxidative stress tolerance under nitrogen-supplemented conditions. Thus, a single MnSOD caters to the reduction of superoxide radical in both cytosol and thylakoid lumen/periplasm irrespective of the N-status of growth by regulating its cleavage. This is the first report on the physiological advantage of membrane-targeting and processing of MnSOD in either bacteria or plants. The higher oxidative stress tolerance offered by the cytosolic form of MnSOD has possibly resulted in retention of only the cytosolic form in bacterial non-nitrogen-fixers during evolution. PMID- 26105829 TI - Novel insights into red blood cell physiology using parasites as tools. AB - The mammalian red blood cell is a terminally differentiated cell that lacks a genetic programme and that has only a very limited metabolic capacity. Nonetheless, it serves as habitat for two parasites belonging to the monophyletic group of Apicomplexa, namely Plasmodium and Babesia. Studies of the parasitized red blood cell have revealed several properties that are unknown in the non infected cell and that are difficult to conceptualize based on our view of red blood cell function. Here we review the current knowledge on host cell invasion and nutrient acquisition by these parasites. We attempt to dissect the factors that are directly contributed by the parasites from those that exist but have remained undetected in the non-infected cell. PMID- 26105831 TI - Ambient preparation and reactions of gas phase silver cluster cations and anions. AB - Electrospray ionization of metal salt solutions followed by ambient heating transforms the resulting salt clusters into new species, primarily naked ionic metal clusters. The experiment is done by passing the clusters through a heated coiled loop outside the mass spectrometer which releases the counter-anion while generating the anionic or cationic naked metal cluster. The nature of the anion in the starting salt determines the type of metal cluster observed. For example, silver acetate upon heating generates only positive silver clusters, Ag(n)(+), but silver fluoride generates both positive and negative silver clusters, Ag(n)(+/-) (3 < n < 20). Both unheated and heated metal salt sprays yield ions with characteristic geometric and electronic magic numbers. There is also a strong odd/even effect in the cationic and anionic silver clusters. Thermochemical control is suggested as the basis for favored formation of the observed clusters, with anhydride elimination occurring from the acetates and fluorine elimination from the fluorides to give cationic and anionic clusters, respectively. Data on the intermediates observed as the temperature is ramped support this. The naked metal clusters react with gaseous reagents in the open air, including methyl substituted pyridines, hydrocarbons, common organic solvents, ozone, ethylene, and propylene. Argentation of hydrocarbons, including saturated hydrocarbons, is shown to occur and serves as a useful analytical ionization method. The new cluster formation methodology allows investigation of ligand-metal binding including in reactions of industrial importance, such as olefin epoxidation. These reactions provide insight into the physicochemical properties of silver cluster anions and cations. The potential use of the ion source in ion soft landing is demonstrated by reproducing the mass spectra of salts heated in air using a custom surface science instrument. PMID- 26105836 TI - Stress responses and pre-eclampsia. AB - Biological stress may affect individual cells, tissues or whole organisms, arising from disturbed homoeostasis of any cause. Stress is rarely localised. Because biological systems are closely integrated, it spreads to involve other systems. Stress responses are highly integrated and work to restore homoeostasis. Different response pathways overlap and interlink. If the responses fail or decompensate, distress ensues, of which the end-stage is death. Pre-eclampsia results from a series of biological stresses, possibly from conception, which become established by abnormal placentation and affect the mother, her foetus and her placenta. The stresses involve dialogue between mother and placenta. Even a normal placenta imposes substantial stress on maternal systems. When placental growth and perfusion is abnormal (poor placentation) then the placenta, particularly its outer trophoblast layer, becomes stressed - loosely denoted hypoxic damage or oxidative stress. Signals from the placenta spread the stress to the mother, who develops signs of pre-eclampsia. Cellular stress sensors initiate stress responses. Different stresses may trigger similar responses in specific cell types. The first cell response is reduced protein synthesis. However some synthetic pathways are spared or activated to produce stress signals. In relation to pre-eclampsia and the placenta, an excessive release of sFlt-1 a soluble decoy receptor for vascular endothelial growth factor (VEGF) is a trophoblast related stress signal. SFlt1 perturbs the angiogenic balance in the maternal circulation and is considered to cause many of the specific features of the maternal syndrome in pre-eclampsia. Three key points will be emphasised. First, multiple stressors, not simply hypoxia, stimulate the release of sFlt-1 from trophoblast. Second, sFlt-1 is only one of the group of stress signals delivered by trophoblast to the mother. Third, sFlt-1 is not the only trophoblast derived factor to perturb the maternal circulation in pre-eclampsia. PMID- 26105830 TI - Synthesis and characterization of image-able polyvinyl alcohol microspheres for image-guided chemoembolization. AB - Therapeutic embolization of blood vessels is a minimally invasive, catheter-based procedure performed with solid or liquid emboli to treat bleeding, vascular malformations, and vascular tumors. Hepatocellular carcinoma (HCC) affects about half a million people per year. When unresectable, HCC is treated with embolization and local drug therapy by transarterial chemoembolization (TACE). For TACE, drug eluting beads (DC Bead((r))) may be used to occlude or reduce arterial blood supply and deliver chemotherapeutics locally to the tumor. Although this treatment has been shown to be safe and to improve patient survival, the procedure lacks imaging feedback regarding the location of embolic agent and drug coverage. To address this shortcoming, herein we report the synthesis and characterization of image-able drug eluting beads (iBeads) from the commercial DC Bead((r)) product. Two different radiopaque beads were synthesized. In one approach, embolic beads were conjugated with 2,3,5-triiodobenzyl alcohol in the presence of 1,1'-carbonyldiimidazol to give iBead I. iBead II was synthesized with a similar approach but instead using a trimethylenediamine spacer and 2,3,5-triiodobenzoic acid. Doxorubicin was loaded into the iBeads II using a previously reported method. Size and shape of iBeads were evaluated using an upright microscope and their conspicuity assessed using a clinical CT and micro-CT. Bland and Dox-loaded iBeads II visualized with both clinical CT and microCT. Under microCT, individual bland and Dox loaded beads had a mean attenuation of 7904 +/- 804 and 11,873.96 +/- 706.12 HU, respectively. These iBeads have the potential to enhance image-guided TACE procedures by providing localization of embolic-particle and drug. PMID- 26105837 TI - Prediction and diagnosis of pre-eclampsia; the scientific basis. AB - The accurate prediction of women at risk of pre-eclampsia, and certain diagnosis are central to optimal management and treatment. Prediction has improved, particularly through measurement of angiogenic/antiangiogenic factors but sensitivity and specificity remains suboptimal, and the heterogeneity of underlying clinical risk confounds generalisability of a single early pregnancy test for all women. The 'omics' methodologies offer the potential for discovery of novel biomarkers and proteomics, metabolomics and transcriptomic approaches are beginning to identify multiple new candidates for evaluation. However, once pregnancy is established the potential for modification of established pathological processes, increasingly identifiable by accurate biomarkers, remains an unanswered and possibly unattainable challenge. The potential for more accurate pre-conceptional identification of risk, and subsequent modification of risk, presents an increasingly attractive alternative to prevention of pre eclampsia. Advances have certainly been made in diagnosis; the measurement of PlGF in women with suspected pre-eclampsia is likely to become an integral component of clinical care, improving detection and management of pre-eclampsia. PMID- 26105838 TI - Introduction to ISSHP new classification of preeclampsia. AB - The classification of the hypertensive disorders of pregnancy has always been a crucial point, especially in the scientific literature, to compare results from different series. Some of the classes have been reviewed during time, and some new ones have been added, paralleling the increased knowledge of the diseases and syndromes. Among the interests of a society there is the sharing of a common language and the guidance to give to scientific authors and editors for better presentation of their results and outcomes. Still leaving unchanged the definition of the five major classes of the hypertensive disorders of pregnancy (gestational hypertension, preeclampsia, chronic hypertension, preeclampsia superimposed on chronic hypertension, eclampsia) we realized that in the last years emerged a need to better define some forms of preeclampsia, especially in terms of severity and time of onset and indicated delivery. This is why the International Committee of the International Society for the Study of Hypertension in Pregnancy (ISSHP) was requested to come to a consensus, by responding to a questionnaire, on the thresholds to define "severe preeclampsia", and "early onset preeclampsia", and on which parameters to use to define the HELLP Syndrome and which other definitions may be added. There was an agreement to define "severe preeclampsia" by blood pressure values >160mmHg systolic or 110mmHg diastolic. The amount of proteinuria was considered not useful to define the severity. The HELLP syndrome was considered a feature to include in the severe classification, and that could be identified by a reduction of platelet count below <100,000/dl, an elevation of ALT or AST twofold the upper limit of normal, and an elevated LDH (twofold the upper reference limit or greater than 650IU/l). There was an agreement to define "early-onset preeclampsia" as that occurring before 34 weeks. The results of this survey can help in updating the previous ISSHP classification. PMID- 26105839 TI - Microvesicles and pre-eclampsia. AB - The maternal syndrome of pre-eclampsia is characterised by an excessive inflammatory response associated with endothelial dysfunction, brought about by the release of multiple factors from the placenta into the maternal circulation. While some of these factors are released as soluble molecules it is now apparent that many of them are associated with syncytiotrophoblast microvesicles and exosomes (collectively termed STBM), which are present in increased amounts in the circulation of women with pre-eclampsia. We have shown that STBM have proinflammatory, anti-endothelial and procoagulant activities in vitro, all of which are features of the maternal syndrome. We propose that the different effects of STBM result from different types of vesicles within the circulation the smaller exosomes being immunoregulatory and the larger microvesicles being proinflammatory, with a shift to the latter in pre-eclampsia. In support of this, we have demonstrated using a novel technique, Nanoparticle Tracking Analysis, that pre-eclampsia STBM are indeed larger than those from normal placentas. Furthermore, the range and types of factors they carry (and hence their functions) may differ in pre-eclampsia, where the syncytiotrophoblast is subjected to oxidative and inflammatory stress. We have carried out proteomic analysis on vesicles prepared from normal and pre-eclampsia placentas by perfusion and have identified differences in the repertoire of molecules they carry. Candidates include immunoregulatory molecules (B7-H1, CD200 and Galectin 1), complement and complement regulatory molecules (C1q, C3, CD55, CD59 and vitronectin), proinflammatory molecules (HSP70, HMGB1, Galectin 3 and Synctin 1), anti-angiogenic molecules (CD49e, CD51, CD26, Flt-1 and endoglin) and procoagulant molecules (tissue factor and phosphatidylserine). Characterising the molecular cargos of the STBM may lead to the discovery of new biomarkers for pre eclampsia and inform future treatments. PMID- 26105840 TI - Inflammatory mechanisms in preeclampsia. AB - Inflammation is a host response triggered by noxious stimuli arising during infection and/or tissue injury, and a controlled inflammatory response is beneficial to fighting infections and healing wounds. Normal pregnancy is characterised by a mild systemic inflammation, however, the inflammation may become detrimental if dysregulated, as seen in preeclampsia. Women with preeclamptic pregnancies have up to eightfold higher risk for cardiovascular diseases later in life, and genetic, clinical and molecular observations support shared underlying inflammatory mechanisms for these diseases. The discoveries that pattern recognition receptors (PRRs) directly sense inflammatory stimuli and activate innate immune cells have greatly increased our molecular understanding of inflammatory diseases. It is hypothesised that some of the clinical manifestations are caused by common underlying inflammatory mechanisms instrumented by PRRs. PRRs activate inflammatory responses by recognising endogenous damage-associated molecular patterns (DAMPs) released from injured tissues and stressed or dying cells; including degraded extracellular matrix components, heat-shock proteins, HMGB1 proteins, nucleic acids and crystalline structures such as cholesterol crystals. In preeclampsia, many such DAMPs are known to contribute to both the local placental inflammation and to systemic inflammation and endothelial dysfunction, but with largely unknown molecular action. Defining the role of PRRs in preeclampsia by learning from similar mechanisms associated with cardiovascular diseases will help us in improved understanding of this complex inflammatory syndrome. PMID- 26105841 TI - Developing potential biomarkers for preeclampsia: Why is the current strategy failing? AB - During the last decade major progress has been achieved in identifying new predictive biomarkers as well as setting up screening strategies for preeclampsia. A number of biochemical markers in combination with biophysical markers coupled to patients' demography and clinical history were identified and have been used in a number of studies. The combination of independent markers with various demographic and multivariate algorithms should have led to stratification of the risk to develop preeclampsia. However, today studies are still ongoing mostly focusing on a single marker and its performance for the early subtype of preeclampsia, which makes up only about 20% of all preeclampsia cases. While it is hard to forecast how medicine will progress, it has been the hope that a combination of risk stratification with large international randomised studies validating various prediction methods would enable new studies to identify preventive methods as well. This would have led to a significant revolution in the way pregnancy is managed to prevent preeclampsia. However, looking back on all the studies on markers such as soluble endoglin, placental protein 13 (PP13), placental growth factor (PlGF), vascular endothelial growth factor (VEGF) and soluble VEGF receptor-1 (sVEGF-R1 or sFlt-1) today pregnant women destined to develop preeclampsia are still suffering from the lack of any commonly accepted preventive therapy. Putative reasons for this failure of predictive biomarkers will be discussed in this talk. PMID- 26105842 TI - Update on genetics of pre-eclampsia. AB - Over half of the familial predisposition to pre-eclampsia can be attributed to genetic factors in the mother and/or fetus. The search for genetic susceptibility variants has progressed through candidate gene studies, family-based linkage studies, and most recently genome-wide association studies (GWAS). It is unlikely that any single variant has a large effect on pre-eclampsia susceptibility; studies involving thousands of samples are required to detect variants with small effect size. These exceed the resources of most individual research groups, and collaborative approaches are likely to be more fruitful. Collaboration has included meta-analysis of existing data, and recent publications offer some support to a role for thrombophilic polymorphisms in pre-eclampsia. A small number of GWAS have been published so far; the lack of replication of positive GWAS results in an independent population has been frustrating. This may be due to false positive results in the original GWAS, or lack of statistical power in the replication set. A further concern is that the pre-eclampsia syndrome is a common end-point to multiple pathologies with differing underlying genetic susceptibility, requiring ever larger sample sizes for their detection. In this climate, researchers should make every effort to record the phenotypic characteristics of their cohorts, to enable meta-analysis of independent GWAS results. The InterPregGen consortium of groups from Europe and Central Asia is conducting GWAS analysis of maternal and fetal genes in 13,000 pre-eclamptic pregnancies. This study will provide the opportunity to analyse maternal-fetal gene interactions in addition to their individual effects. Developments arising from the ever-falling costs of DNA sequencing include deep sequencing to identify rare variants with large effect sizes. The era of whole genome sequencing is likely to supplant the GWAS approach, creating challenges for data analysis, but with the potential to provide greater insights into the genetic basis of pre eclampsia. PMID- 26105843 TI - Maternal circulating PlGF concentrations and placenta-related pregnancy complications: First results from the CoLab AngF Study. AB - INTRODUCTION: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis. OBJECTIVE: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia. METHODS: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared. RESULTS: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility. CONCLUSIONS: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders. PMID- 26105844 TI - Pitfalls in setting up genetic studies on preeclampsia. AB - This presentation will consider approaches to discover susceptibility genes for a complex genetic disorder such as preeclampsia. The clinical disease presumably results from the additive effects of multiple sequence variants from the mother and the foetus together with environmental factors. Disease heterogeneity and underpowered study designs are likely to be behind non-reproducible results in candidate gene association studies. To avoid spurious findings, sample size and characteristics of the study populations as well as replication studies in an independent study population should be an essential part of a study design. In family-based linkage studies relationship with genotype and phenotype may be modified by a variety of factors. The large number of families needed in discovering genetic variants with modest effect sizes is difficult to attain. Moreover, the identification of underlying mutations has proven difficult. When pooling data or performing meta-analyses from different populations, disease and locus heterogeneity may become a major issue. First genome-wide association studies (GWAS) have identified risk loci for preeclampsia. Adequately powered replication studies are critical in order to replicate the initial GWAS findings. This approach requires rigorous multiple testing correction. The expected effect sizes of individual sequence variants on preeclampsia are small, but this approach is likely to decipher new clues to the pathogenesis. The rare variants, gene-gene and gene-environmental interactions as well as noncoding genetic variations and epigenetics are expected to explain the missing heritability. Next generation sequencing technologies will make large amount of data on genomes and transcriptomes available. Complexity of the data poses a challenge. Different depths of coverage might be chosen depending on the design of the study, and validation of the results by different methods is mandatory. In order to minimize disease heterogeneity in genetic studies of preeclampsia, identification of subtypes and intermediate phenotypes would be highly desirable. PMID- 26105845 TI - A multi-centre phase IIa clinical study of predictive testing for pre-eclampsia. IMproved PRegnancy Outcomes Via Early Detection (IMPROVED). AB - 1 in 20 first time pregnancies is complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful early pregnancy screening test exists, consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROVED Consortium members have pioneered a personalised medicine approach in identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The Consortium recently received funding under the auspices of the 7th Framework Programme of the European Union under the call: HEALTH- 2012-INNOVATION 1.2-1 (Grant Agreement no. Health-F5-2012-305169). The objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia. We report the design of a multicentre, phase IIa clinical study to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves serial maternal phlebotomy, collection of clinical data, and pregnancy outcome data. Participants will attend essential visits at 15 and 20 weeks' gestation, with optional 11 and 34 weeks' gestation. Blood samples will undergo a combination of proteomic and metabolomic tests, and diagnostic performance will be assessed in accord with a pre-approved statistical analysis plan which will report Receiver Operating Curves, and Positive Predictive Values. The study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If 'at risk' patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROVED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome. PMID- 26105846 TI - Long term cardiovascular outcomes for mother and child. AB - Preeclampsia is well established as one of the leading causes of maternal and fetal mortality and morbidity. Furthermore, it is now clear that women who have had preeclampsia have an increased risk of cardiovascular events over the next 10 15 years. Indeed, preeclampsia is associated with a fourfold increased risk of hypertension and double the risk of fatal and non fatal ischaemic heart disease and stroke. More recently, it has been emerging that offspring born to preeclampsia are also more likely to have a higher blood pressure from the childhood and stroke in the later life. Furthermore, the risk to mother and offspring is greatest when preeclampsia is diagnosed at an earlier gestation, suggesting a more severe form of preeclampsia. As the long term cardiovascular risk to both mother and child is known from delivery there is increasing interest in key phenotypic variations that are identifiable in mothers and children during the years between the episode of preeclampsia and the emergence of established cardiovascular disease. These might help explain the link between the two conditions, provide a means to identify subjects at greatest risk of later cardiovascular disease and establish intermediate endpoints for future preventative interventions. A range of studies from research groups around the world are beginning to unravel the links between preeclampsia and long term variations in cardiac and vascular structure and function, as well as persistent biological differences in both the mother and children. This increased understanding allows both better characterisation of long term cardiovascular outcomes and better identification of optimal approaches to improve long term outcomes. PMID- 26105847 TI - OP002. Impact of the NO-donor pentaerythrithyltetranitrate on perinatal outcome in high-risk pregnancies: A prospective randomized double blinded pilot study. AB - OBJECTIVE: To evaluate the effectiveness of the oral NO-donor PETN in secondary prevention of intrauterine growth restriction (IUGR), preterm birth and preeclampsia in high risk pregnancies. STUDY DESIGN: 111 women presenting with abnormal placental perfusion (bilateral notch or mean RI>0.7) at 19-24weeks of gestation were included in a prospective, randomized, placebo-controlled, double blinded study. Primary endpoint was IUGR and/or perinatal death, secondary endpoints were preterm birth, preeclampsia and placental abruption. RESULTS: 54 women received PETN and 57 placebo. PETN significantly decreased the risk of IUGR and/or perinatal death (adjusted RR 0.623 [95% - CI: 0.395-0.983]). Preterm birth before 32weeks was reduced (adjusted RR 0.359 [95% - CI 0.123-1.054]) and no placental abruption occurred in the PETN, but 5 in the placebo group. There was no reduction of preeclampsia. CONCLUSION: Significant reduction of adverse pregnancy outcome might be possible in pregnancies exhibiting abnormal placentation using PETN. PMID- 26105848 TI - OP001. A longitudinal study of maternal vascular reactivity, circulating endothelial progenitor cells and inflammatory response during the second half of pregnancy. AB - INTRODUCTION: Maternal endothelial dysfunction and inflammation are associated with hypertensive pregnancy disorders. OBJECTIVES: To investigate maternal endothelial function in normal pregnancy using two different methods and explore their association with markers of inflammatory response. METHODS: 53 women with uncomplicated pregnancies were examined at four-weekly intervals during 22 40weeks gestation. Maternal endothelial function was assessed using flow-mediated vasodilatation (FMD) of brachial artery. FMD was defined as the increase of brachial artery diameter in percent during reactive hyperemia compared to the resting diameter. Circulating EPC were defined as CD45low/CD34+/VEGFR2+ and quantified by flow cytometry. Concentration of the two markers of inflammatory response, i.e. leptin (immunoassay) and highly sensitive CRP (mCRP) (immunoturbidimetric method) were measured in the plasma samples. RESULTS: FMD decreased from 16.3% to 13.4% and concentration of EPC increased from 6.5 to 12.3 per million mononuclear cells during 22-40 weeks. Leptin increased from 18 to 22ng/L and mCRP did not change significantly (p=0.61). Significant associations were observed between FMD and mCRP (p=0.0016), and between FMD and leptin (p=0.0029). There was no significant association between EPC and FMD or between EPC and mCRP. CONCLUSION: FMD decreases, whereas the concentration of circulating EPC increases with advancing gestation during the second half of pregnancy. However, FMD was associated with biomarkers of inflammation but not with EPC. This suggests that the reduced NO-dependent vasodilatation observed in the third trimester of normal pregnancy is related to maternal inflammatory response. Mechanisms other than effective mobilization of EPC to repair endothelial damage are likely to be responsible for gestational age-associated increase in circulating EPC during pregnancy. PMID- 26105849 TI - OP004. A SNP associated with susceptibility to preeclampsia near the inhibin, beta B gene, is also associated with cardiovascular disease risk traits. AB - INTRODUCTION: It is well established that preeclampsia (PE) increases later life cardiovascular disease (CVD) risk. Consequently, PE has started to gain a role as an early screening criterion for CVD. PE and CVD share several risk factors, pathological features and metabolic abnormalities. These common antecedents have drawn attention to the likelihood of shared genetic susceptibility. OBJECTIVES: Results from our previous PE GWAS identified a significant association with the rs7579169 SNP and maternal PE susceptibility (odds ratio 1.57). This SNP resides near the Inhibin, beta B (INHBB) gene on chromosome 2q14. Therefore, this study sought to interrogate this PE susceptibility SNP against several CVD risk traits in an effort to highlight additional empirical evidence of likely shared PE/CVD genetic mechanisms. METHODS: The rs7579169 SNP was genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of fasting blood samples from 1246 mothers and 1461 adolescents (14- and 17-year-old) and clinical parameters pertaining, but not limited, to anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of rs7579169 against the Raine CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action. RESULTS: Significant associations (p<0.05) for rs7579169 with CVD-related risk traits were detected, both for the mothers and the adolescents. Specifically, the minor rs7579169-T allele (MAF 0.400) was found to be significantly associated with elevated levels of triglycerides, total and LDL cholesterol, a greater average waist:hip circumference ratio and a greater average hip circumference. CONCLUSION: We have previously identified rs7579169 located near the INHBB gene on chromosome 2q14 to significantly associate with maternal PE susceptibility. We have now demonstrated that this SNP is also significantly associated with several CVD-related risk traits in an independent Caucasian population. We hereby present additional empirical evidence of possible shared genetic risk factors underlying both PE and CVD related traits. PMID- 26105850 TI - OP003. Placental perfusion in normal pregnancy and in early and late preeclampsia: A magnetic resonance imaging study. AB - INTRODUCTION: Placental perfusion is of key interest for the understanding of the pathophysiology of different types of preeclampsia (PE). With magnetic resonance imaging (MRI) perfusion can be estimated non-invasively by calculation of the tissue perfusion fraction from a diffusion weighted sequence (DWI). OBJECTIVES: Our primary aim was to investigate if women with early or late PE have different placental perfusion compared with normal pregnancies. A secondary aim was to investigate if placental perfusion changes with increased gestational length in normal pregnancy. METHODS: 5 women with early PE (<34weeks), 8 women with late PE (?34weeks), and 19 women with normal pregnancies were included. All women underwent an MRI examination including a DWI sequence at 1.5T. The perfusion fraction was calculated. RESULTS: Women with early PE had a lower placental perfusion fraction (p=0.002) and women with late PE had a higher placental perfusion fraction (p=0.012) than gestational age matched women with normal pregnancies. The placental perfusion fraction decreased with increased gestational length in normal pregnancies (p=0.001). CONCLUSION: Our finding of reduced placental perfusion in early, but not late PE is in agreement with the hypothesis that early and late PE have partly different pathophysiology, where early PE is a mainly placental disease. The placental perfusion, as estimated by the perfusion fraction, decreased with increased gestational length in normal pregnancies. PMID- 26105851 TI - OP006. A preeclampsia genome-wide linkage scan in norwegian families. AB - INTRODUCTION: Several maternal susceptibility loci for preeclampsia (PE) have been discovered amongst Icelandic, Australian/New Zealand, Dutch and Finnish family cohorts, implicating locus heterogeneity. Through candidate gene studies, allele-specific heterogeneity in different populations is also evident. It is therefore likely that numerous population specific PE susceptibility variants exist, differing in their effect size. Despite on-going efforts to identify susceptibility genes for PE, the causal genetic variants still remain obscure. OBJECTIVES: The aim of this study is to interrogate the genetic architecture of PE susceptibility by performing a genome-wide linkage scan in a novel familial cohort from Norway. METHODS: A total of 480 DNA samples from The Norwegian PE Family Biobank were genotyped at Genomic Core Facility at NTNU. Genome-wide genotyping was performed with the Infinium HumanExome BeadChip (>240,000 markers) (Illumina, USA) that delivers focused coverage of exonic regions of the human genome. RESULTS: A total of 137 families are represented with 222 women with a valid PE diagnosis (SBP?140mmHg DBP?90mmHg, ?2 measurements at least 4h apart with documented proteinuria at ?2 occasions occurring after 20weeks of pregnancy), 44 with self-reported PE and 72 women with a healthy pregnancy. The genotyping has just recently been completed with an average call rate of 99.96%. Data and statistical analysis is now underway using MERLIN, R and SOLAR. A description of the Norwegian PE familial cohort plus preliminary results will be presented at the Congress. CONCLUSION: To our knowledge this is the first SNP based genome-wide linkage study on PE, and the first performed in a novel Norwegian PE family cohort. By using an approach focusing on functionally relevant markers we anticipate the identification of susceptibility loci that are of substantial importance for disease development. PMID- 26105852 TI - OP007. PLGF in combination with other commonly utilised tests and other biomarkers for predicting need for delivery for pre-eclampsia within 14days in women presenting prior to 35weeks' gestation. AB - INTRODUCTION: Current means of assessing women presenting with suspected pre eclampsia using BP and proteinuria are of limited use in predicting need for imminent delivery. OBJECTIVES/METHOD/DESIGN: We undertook a prospective multicentre study to determine diagnostic accuracy of PlGF <5th centile (Triage assay) and other candidate biomarkers in women presenting with suspected pre eclampsia at 20-35weeks' gestation, in determining need for delivery for pre eclampsia within 14days. We calculated ROC curves for predictive potential and undertook principal factor analysis to determine additional predictive ability for biomarker combinations. RESULTS: In 287 women enrolled prior to 35weeks, ROC area (0.88, SE 0.03) for PlGF <5th centile for pre-eclampsia requiring delivery within 14days was greater than all other commonly utilised tests (systolic and diastolic BP, urate, ALT), either singly (range 0.58-0.68), or in combination (0.69) (p<0.001 for all comparisons), and was greater than that of all other biomarkers; addition of 2 other biomarker panels (either procalcitonin, nephrin and BNP; or cystatin and PAPP-A) increased ROC area to 0.90 but these biomarkers had limited predictive ability on their own. CONCLUSION: In women presenting prior to 35weeks' gestation with suspected pre-eclampsia, low PlGF has a greater ROC area than other commonly utilised tests. Additional biomarkers add only a small increment to the predictive value of a single PlGF measurement. PMID- 26105854 TI - OP008. Different dysregulation of placental mirnas in early- and late-onset preeclampsia. AB - INTRODUCTION: miRNAs are small ~22nt RNAs, important in the fine-tuning of mRNA in many organs including placenta. Preeclampsia (PE) is a heterogenous disease which may be divided into early-onset PE, which is a more severe form with assumed placental origin, and late-onset PE, with assumed maternal origin. OBJECTIVES: The aim of this study was to investigate the differential expression of miRNAs in early and late-onset PE compared to controls using high throughput sequencing. METHODS: Placentas were obtained from an ongoing biobank collection at Oslo University Hospital. 23 normotensive controls, 23 early-onset PE (delivery at gestational week <34) and 26 late-onset PE (week?34) samples were sequenced using Illumina sequencing technology. Differential expressed miRNAs were identified by the EdgeR package in R and predicted targets were estimated by miRWalk. RESULTS: 3 placental miRNAs were differentially expressed between controls and late-onset PE, 4 miRNAs were differentially expressed between early- and late-onset PE and 51 miRNAs were differentially expressed between early-onset PE and controls. Combining with mRNA array data from a subgroup of the same patients, we identified predicted targets of some of these miRNAs with significant inverse correlation between the respective mRNAs/miRNAs. CONCLUSION: These preliminary results suggest that miRNAs in placenta could be more important in the dysregulation of mRNAs in early-onset PE than in late-onset of the disease. PMID- 26105853 TI - OP005. Preeclampsia is associated with the presence of transcriptionally active placental fragments in the maternal lung. AB - INTRODUCTION: Preeclampsia is associated with increased levels of the circulating anti-angiogenic factor sFlt-1 as well as with an excessive shedding of placenta derived multinucleated syncytial aggregates into the maternal circulation. However, it remains unclear whether these aggregates are transcriptionally active in the maternal organs and can therefore contribute to the systemic manifestations of preeclampsia. OBJECTIVES: We hypothesized that in preeclampsia, syncytial knots are the primary placental site of sFlt-1 production and that increased numbers of sFlt-1-containing syncytial aggregates are retained in the maternal lungs. METHODS: In this study, we measured placental sFlt-1 mRNA levels in preeclamptic- and control placentas and performed RNA in situ hybridization to localize the main placental expression site of sFlt-1 mRNA. Because the maternal lung is the first capillary bed that circulating syncytial aggregates traverse, we studied the presence and persistence of placental material in lungs of preeclamptic women and control subjects. To confirm the placental origin of suspected syncytial aggregates in these lungs, immunohistochemistry for the placenta-specific marker hCG and Y-chromosome in situ hybridization were performed. RESULTS: Using human placental tissue, we found that syncytial knots are the principal site of expression of the anti-angiogenic factor sFlt-1. In addition, in autopsy material obtained from women with preeclampsia (n=9), we observed significantly more placenta-derived syncytial aggregates in the lungs than in control subjects (n=26). Importantly, these placental aggregates still contained the anti-angiogenic factor sFlt-1 following their entrapment in the maternal lungs. CONCLUSION: The current study confirms the important role of syncytial knots in placental sFlt-1 mRNA production. Additionally, it shows a significant association between preeclampsia and larger quantities of sFlt-1 containing syncytial aggregates in maternal lungs, suggesting that the transfer of syncytial aggregates to the maternal compartment may contribute to the systemic endothelial dysfunction that characterizes preeclampsia. PMID- 26105855 TI - OP0010. Optimizing time from diagnosis to delivery in preeclampsia based on the future health prospects of offspring. AB - INTRODUCTION: Limited data exist on long-term health-consequences of maternal preeclampsia for offspring. OBJECTIVES: We investigated long-term offspring morbidity following preeclampsia and related these data to the time from diagnosis to delivery. METHODS: We performed a registry based retrospective cohort study in Denmark in the years 1977-2007. The primary exposure was preeclamptic days from diagnosis to delivery. We analyzed 6 gestational age groups separately. The outcomes were groups of later disease diagnoses in offspring. RESULTS: We included 758,524 singleton offspring who had accumulated 3,537,525 medical diagnoses. Offspring delivered by severely preeclamptic women between 28 and 33weeks had an increased risk of endocrine disorders (HR 1.46; 95% CI 1.09-1.96) compared to normotensive pregnancies, independent of days between diagnosis and delivery (HR 1.000; 95% CI 0.993-1.006). Offspring delivered by mildly preeclamptic women between 37 and 38 weeks had an increased risk of behavioral disorders (HR 1.19; 95% CI 1.05-1.37) and this risk was dependent on days since diagnosis (HR 1.006; 1.001-1.011). In general, after 37-38weeks, days from diagnosis to delivery increased the risk of later diagnoses in most disease groups. CONCLUSION: Offspring from preeclamptic pregnancies have increased risks of various later diseases. The time between diagnosis and delivery modified these risks only slightly, but it seems prudent not to prolong preeclamptic pregnancies after 38weeks. PMID- 26105856 TI - OP0011. Impaired autophagy in extravillous trophoblast may induce poor placentation in preeclampsia. AB - Shallow invasion of extravillous trophoblast (EVT) and inadequate vascular remodeling by EVT are the major cause of poor placentation in preeclampsia. In early pregnancy period, trophoblast experience hypoxic and low-nutrient condition. Autophagy is a cellular bulk degradation system to maintain cellular homeostasis under stress. We examined whether autophagy sustained the EVT functions under the harsh condition. An enhancement of autophagy was observed in primary cultured EVT and EVT cell line under 2% oxygen condition or cobalt treatment which induce HIF1alpha. The invasion and vascular remodeling under hypoxic condition were significantly reduced in autophagy-deficient EVT cells compared with wild-type EVT cells. Treatment of ATP partially rescued the poor invation under hypoxic condition suggesting that getting energy using autophagy play important role for cell invasion under hypoxia. Soluble endoglin (sENG), that is increased in sera in preeclamptic cases, suppressed EVT invasion and vascular remodeling by EVT by inhibiting autophagy. Next we have examined the impaired autophagy by immunohistochemical staining for p62. p62 is selectively degradated in autophagosome, so if impaired autophagy is present, p62 is accumulated in the cytoplasma. Enhanced imunostainings for p62 in interstitial EVT and endovascular EVT in preeclamptic cases were observed showing impaired autophagy in EVT of preeclamptic cases. sENG is known to inhibit TGFbeta that is a essential factor for differentiation of regulatory T cells. Impaired autophagy and decreased regulatory T cells by increased sENG may play important roles in pathophysiology of preeclampsia. PMID- 26105857 TI - Individual artery wall layer dimensions indicate increased cardiovascular risk in previous severe preeclampsia -an investigation using non-invasive high-frequency ultrasound. AB - BACKGROUND: Preeclampsia (PE) is associated with increased risk for cardiovascular disease later in life. Studies using gold standard of non-invasive estimation of atherosclerosis, the common carotid artery intima-media-thickness (CCA-IMT), have not indicated increased atherosclerosis in women with previous PE. That reason may be that with increasing age and degree of atherosclerosis the intima increases, while the media decreases. OBJECTIVES: To assess whether the individual thickness of the CCA intima and media layers and calculation of intima/media (I/M) ratio indicate an increased cardiovascular risk in women with previous severe PE. METHOD: Arterial intima- and media tthicknesses were obtained by non-invasive high-frequency ultrasound (22MHz) in 42 women with previous severe PE and 44 women with previous normal pregnancies. RESULTS: Women with previous severe PE had a thicker mean CCA intima and a higher I/M ratio, compared to women with previous normal pregnancies (both p<0.0001). In ROC curve analysis, intima thickness and I/M ratio discriminated strongly with regard to previous severe PE. CONCLUSION: The method using individual estimation of the CCA intima and media layers and calculating the I/M ratio, clearly showed an increased degree of atherosclerosis in women with previous severe PE. This method might become a clinically useful tool to stratify cardiovascular risk, enabling early intervention and hopefully reduce their long-term cardiovascular risk. PMID- 26105858 TI - PP002. Metabolomic biomarkers in serum and urine of preeclamptic women. AB - INTRODUCTION: Preeclampsia (PE) affects about 3% of pregnancies. The syndrome cannot be accurately predicted, and large variation complicates the search for early biomarkers. Metabolites are components of the metabolism; the chemical interactions in the body necessary for life. Metabolomics, the study of metabolism, has been used to characterize diabetes, cancer and cardiovascular disease (CVD). OBJECTIVES: Explore the use of magnetic resonance (MR) metabolomics on PE, and to elucidate potential clues to PE etiology and pathogenesis. METHODS: Serum and urine from non-pregnant women (n=10) and pregnant women with PE (n=10) or normal pregnancies (n=10), was analyzed with MR spectroscopy and subjected to multivariate analysis (MVA). Metabolites were quantified and compared between groups. RESULTS: Urine and serum samples revealed differences between PE and both control groups. Ten urine metabolites were significantly different between the three groups. Urine samples from women with early-onset PE clustered together in MVA. PE serum spectra had higher levels of low and very-low density lipoproteins, and lower high-density lipoproteins compared to control groups. CONCLUSION: PE and control samples were effectively discriminated using MR metabolomics, suggesting that MR metabolomics is a useful method for improved sub-phenotyping of PE in larger studies. Information relevant to the disease was found both for serum and urine samples, and indicated similarities between PE and CVD. PMID- 26105859 TI - PP001. The vascular tree during pregnancy and at follow-up - A longitudinal study of maternal vascular function. AB - INTRODUCTION: Normal maternal vascular function and optimal cardiovascular adaptation to the increasing demands of pregnancy is a prerequisite for a successful outcome of pregnancy. How different levels of the vascular tree react and interact during pregnancy has not been fully investigated previously but may be determined by genetic as well as maternal, fetal and environmental factors. OBJECTIVE: To investigate how different levels of vascular function change during the course of pregnancy and relate these levels to each other. METHODS: Healthy non smoking women with singleton pregnancies and a viable embryo recorded at the ultrasound departments of UltraGyn Stockholm, Sweden were recruited. The following cardiovascular examinations were performed: examination of structural changes of the heart: Echocardiography of the heart with Doppler examination and tissue Doppler. Examination of macrocirculation, vessel structure and function plus endothelial function: Intima-media thickness of the common carotid artery, pulse wave velocity, central blood pressure and flow mediated vasodilation. Examination of microvascular function in the skin and endothelial function: total circulation of the skin and capillary flow in nails. The microcirculation before, during and after iontophoresis with nitroprussid and acetylcholine. The investigations were performed in gestational week 11-14, 22-24, 36 and 9 months post partum. RESULTS: In total 35 participants had a normal course of pregnancy. Curves of the development of the various cardiovascular variables will be presented according to gestational age and their place in the vascular tree. CONCLUSIONS: These curves will be used to investigate how various determinants such as blood pressure, fetal growth and body mass index, as well as fetal sex affects and are affected by cardiovascular function in pregnancy. PMID- 26105860 TI - PP003. Heat shock protein 27 expression is spatially distributed in human placenta and selectively regulated during preeclampsia. AB - INTRODUCTION: Placental oxidative stress is a feature of the pregnancy syndrome preeclampsia. Heat shock proteins (HSPs) can be induced in cells as a protective mechanism to cope with cellular stress. We hypothesized that expression of HSP 27, a member of the small HSP family, would change in preeclampsia and that expression would vary in different placental zones. METHODS: Samples were obtained from eight sites within each placenta: four equally spaced apart pieces were sampled from 0 to 2cm from the cord insertion point and also between 2 and 4cm from the cord insertion point. Non-labor, labor preeclampsia and non-labor preeclampsia were studied. HSP 27 expression was investigated by Western blot analysis and real time PCR. RESULTS: HSP 27 was significantly increased in the preeclampsia labor group compared to the control labor group at the 2-4cm site (p=0.02). There was no change in phosphorylation at serine 82 and no changes at the mRNA level. CONCLUSIONS: The physiological and pathological significance of these remains to be elucidated but the results have important implications for how data obtained from studies in placental studies (and other organs) can be influenced by sampling methods. PMID- 26105861 TI - PP004. The polymorphism C677T of methylenetetrahydrofolate reductase (MTHFR), may increase risk for future higher blood pressure in women with previous hypertension in pregnancy. AB - INTRODUCTION: The MTHFR is a key enzyme in the folate cycle involved in homocysteine remethylation. The T allele of MTHFR C677T polymorphism is associated with lower activity inhibiting the DNA methylation and protecting from oxidative stress. OBJECTIVES: To evaluate the MTHFR genotype-phenotype relationship during and after pregnancy comparing hypertensive with normotensive women. METHOD: A sample of 380 women with 32.54+/-6.478 years old, 181 normotensive (NT) and 199 hypertensive (HBP) being 70.3% above 34 weeks of gestation. A subgroup 63 women with history of preeclampsia were studied 3-6 years postpartum and compared with 59 controls. The MTHFR was evaluated by PCR RFLP using DNA extracted from peripheral blood. Statistical analysis evaluated with appropriated tests. RESULTS: The distribution of genotypes of the MTHFR was different according to blood pressure (BP), it was observed that the TT genotype had lower frequency in HBP (p<0.001). In the subgroup CC+CT the MPO levels were higher in HBP as well as nitrites, leucocytes, neutrophils, Apo B, BMI, waist and ratio waist/hip compared with NT (p<0.001, p=0.04, p=0.042, p=0.035, p=0.03, p=0.022, p=0.026, respectively). There were differences between levels of BP systolic and diastolic between women previously HBP and NT of CC+CT compared with TT carriers (p<0.001). CONCLUSION: The MTHFR may modulate blood pressure (BP) and cardiovascular risk. TT genotype with increased expression of antioxidant enzymes, may be a protective factor for future hypertension and cardiovascular risk compared with women CC and CT genotypes with higher levels of circulating biomarkers of inflammation. PMID- 26105862 TI - PP006. Gene expression profiling of first trimester placentas from pregnancies at high risk of developing preeclampsia. AB - INTRODUCTION: Preeclampsia (PE) is an important cause of fetal and maternal morbidity and mortality. It is considered a two-stage disease, the first stage characterized by a defect placentation and the second stage by maternal manifestations. Details of the patho-physiology behind the transition from stage one to stage two remain unclear. OBJECTIVE: Was to study first trimester placental gene expression in patients identified as high risk for PE by either Doppler ultrasound or the biochemical markers cell free fetal hemoglobin (HbF) and alpha-1-microglobulin (A1M). METHODS: Placental samples were obtained from seven women at highrisk of PE as determined by Doppler ultrasound of the uterine arteries and eight women with normal uterine artery resistance who for other reasons terminated their pregnancies surgically. Maternal serum samples were analyzed for HbF and A1M. The patients were risk stratified according to two risk classifications: (I) High vs. low uterine artery resistance and (II) High HbF and A1M vs. low HbF and A1M. Total RNA from the placentas was used for whole genome microarray. The results were analyzed by bioinformatics and genes of interest confirmed with qPCR. RESULTS: A total of 453 and 332 significantly altered genes were identified in the two study groups. Bioinformatics revealed 12 genes of interest in study group I and 7 genes of interest in study group II. CONCLUSIONS: Genes related to vascular tonus regulation and inflammatory response were identified in study group I suggesting that a lack of tonus regulation and increased inflammation might contribute to the high uterine artery resistance seen in this group. Genes related to regulation of hematopoiesis was found in group II suggesting dysfunctional hematopoiesis as a factor explaining the high levels of cell-free HbF seen. PMID- 26105863 TI - PP005. Vitamin D depletion aggravates hypertension in transgenic rats. AB - INTRODUCTION: Vitamin D may ameliorate hypertension and kidney disease through genomic and extra-genomic pathways. OBJECTIVE: To investigate the impact of vitamin D in a transgenic rat model of angiotensin II-mediated hypertensive organ failure. METHODS: In 4-week-old age-matched rats overexpressing the human renin and angiotensinogen genes, group 1 (n=18) received vitamin D depleted chow; group 2 (n=15) standard chow and intraperitoneal paricalcitol at 800ng/kg thrice weekly; and group 3 (n=15) standard chow and vehicle injections. Blood pressure (tail cuff) and 24-h albuminuria were determined once weekly. After three weeks, animals were sacrificed. Heart tissue was examined for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) by RT-PCR. RESULTS: The vitamin D depleted group had higher blood pressure at week 1 (mean difference 23.4mmHg, 95% CI 9.1-37.7) and tended to have higher blood pressure in weeks 2 and 3 (mean difference 14.3mmHg 95% CI -0.02-28.7 and 15.2mmHg 95% CI -1.5-33). The depletion group had higher heart-to-body weight ratio, and a trend towards higher ANP and BNP levels. The group receiving paricalcitol did not perform better. No differences were found between groups in mortality or proteinuria. CONCLUSION: Short-term vitamin D depletion aggravated hypertension and end-organ damage in a rat model of angiotensin II-induced hypertension. Short-term interventions with high-dose vitamin D analogues had no protective effect. PMID- 26105864 TI - PP008. Placental klotho gene in preeclampsia. AB - INTRODUCTION: An aging-suppressor gene, klotho, is a candidate factor for vascular disease because its deficiency leads to impaired endothelium-dependent vasodilation and impaired angiogenesis. This protein is involved in several metabolic pathways such as the insulin-like growth factor 1 (IGF-1), apoptosis, angiotensin-II-induced events in the kidney and oxidative stress. OBJECTIVES: The aim of this study was to determine the difference of klotho genotiping and expression in the placentas of women with normal and preeclamptic pregnancies. METHOD/DESIGN: Placental tissue was collected from normal pregnancies (n=12) and pregnancies complicated by Preeclampsia (n=12), matched for gestational age. Klotho genotyping and expression was determined using real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. RESULTS: A polymorphism for -744 G/A mutation was significantly more common in the pathological group, with an odds ratio (OR) of 3.00 (1.02-8.81; 95% CI). The expression levels of both klotho isoforms and of the short klotho isoform were lower (80%) in the Preeclampsia group as compared to matched controls. Results of Western Blot agreed with those from Real-Time PCR. CONCLUSION: In preeclamptic pregnancies there are a genotyping polymorphism and a reduced expression of klotho gene. Given its role in cardiovascular disease in aging, it may link preeclamptic mothers and their offsprings to long term cardiovascular outcomes. PMID- 26105865 TI - PP009. Hypoxia alters syncytiotrophoblastic microparticles (STBM)-related coagulation capacities. AB - INTRODUCTION: Endothelial dysfunction is thought to be the cause of preeclampsia (PE) symptoms. Severe forms of PE are correlated to the release of syncytiotrophoblastic microparticles (STBM), which triggers inflammatory processes on the endothelium. The thrombogenic potential of STBMs is not well characterized. We investigated the pro-coagulant activity of STBMs. METHODS: STBMs were derived from placentae perfused under norm- and hypoxic conditions and quantified with our house-"ELISA". Surface phospholipid-dependent thrombin formation of microparticles was determined with a commercial ELISA. Rate and absolute platelet aggregation in platelet-rich plasma (PRP), while fibrin production in platelet free plasma, was measured in absence and presence of STBMs using a PAP-4 aggregometer. RESULTS: STBM concentration and STBM-induced thrombin formation is stable under normoxic and elevated under hypoxic conditions. STBMs derived from hypoxic placentae increase the rate of fibrinogenesis. Maximum platelet aggregation is stable under normoxic, while highly variable under hypoxic conditions. STBMs of hypoxic placentae cannot alter the rate of platelet aggregation, while normoxic STBMs adjust the rate according to need. CONCLUSION: Hypoxia negatively affects fibrinogenesis and the platelet aggregation-modulating effects of STBMs, which might be due to a phenotype alteration. All observed results may contribute to the impaired microcirculation seen in PE. PMID- 26105866 TI - PP010. Alpha-1-microglobulin protects from heme induced placenta and kidney damage in a pregnant ewe model for preeclampsia. AB - INTRODUCTION: Previous gene expression analysis have identified fetal hemoglobin (HbF) as a plausible etiological factor in preeclampsia. Free hemoglobin and its degradation products, e.g. heme, are known to cause oxidative stress, tissue damage, and vaso-constriction, typical findings in preeclampsia. OBJECTIVE: To study alpha-1-microglobulin (A1M), an endogenous radical scavenger and heme binder, as a potential treatment for preeclampsia using the pregnant ewe preeclampsia model. Free Hb and heme are known to take part in the pathology of this model and therefor well suited for evaluation of recombinant A1M as a therapy. METHODS: 11 pregnant ewes, at gestational age 125-131 days, were acclimatized for 36h and then starved for another 36h to induce preeclampsia symptoms. At the end of starvation period, they were treated either with placebo (n=6) or A1M injections (n=5). After injections, food was re-introduced and ewes further followed for 72h. The ewes were sacrificed the 6th day after beginning of acclimatization. Throughout the 6 days, the animals were monitored for blood pressure and different blood and urine parameters. Whole blood, kidney and placenta tissue samples were collected from the ewes. Gene expression analysis, blood analysis, histology and electron microscopy were used to evaluate the therapeutic effects of A1M. RESULTS: Starvation increased the amount of free heme in the blood. The ultrastructure of the placenta and kidney were damaged in a way similar to what previously have been described for PE. The glomeruli and the tubuli were damaged which was reflected by increased Ficol clearance and increased plasma creatinine levels. Treatment with A1M significantly normalized the kidney functions. The most profound changes on gene expression level were found in white blood cells in the starved animals. Starvation decreases mRNA expression for anti-oxidants such as CAT (P=0.04), SOD1 (P=0.008), SOD2 (1.8 fold) as well as angiogenetic factors such as VEGF (P=0.02) and HGF (1.6-fold). A1M treatment rescued the decreased expression of SOD2 (P=0.04) and HGF (2-fold). CONCLUSION: A1M is well tolerated and shows high potential as a treatment for PE like symptoms in the pregnant ewe model for PE. PMID- 26105867 TI - PP007. Nicotinic acetylcholine receptor subunits in the pre-eclamptic and cigarette smoke exposed human placenta. AB - INTRODUCTION: Cigarette smoking during pregnancy is associated with low birth weight, prematurity and neonatal morbidity and mortality. Nicotine, a major constituent of cigarette smoke, binds to nicotinic acetylcholine receptors (nAChRs). To date, 16 mammalian nAChR subunits have been identified. The effect of smoking on these subunits in human placenta has not yet been determined. Smoking is also associated with reduced pre-eclampsia (PE) risk and its protective effects may occur via changes in nAChRs. OBJECTIVES: This study aimed to determine which nAChR subunits are present in the normal human placenta, and whether any changes are occur from smoking or PE. METHODS: Using RT-qPCR, all 16 nAChR subunits were investigated in normal, healthy human placentas, and mRNA expression compared between controls (n=8), smokers (n=8) and PE (n=7). Results All 16 nAChR subunits were expressed in healthy placentas. Smoke exposure significantly increased alpha2 (p=0.006) and alpha9 (p=0.038), and decreased delta (p=0.013), subunit mRNA expression. In PE placentas, beta1 (p=0.048) and beta2 (p=0.031) subunit mRNA expression was increased. CONCLUSION: Nicotine exposure in pregnancy increases nAChR subunit mRNAs that play a role in vasoconstriction and amino acid uptake, possibly contributing to abnormalities in placentas from smoking mothers. Different subunits were affected in PE placentas, thus the hypoxic environment may induce changes in endogenous ACh levels, yielding compensatory increases in beta1 and beta2 subunits. PMID- 26105868 TI - PP011. Placental expression of the major protein components of caveolae, eNOS and iNOS in pre-eclampsia. AB - INTRODUCTION: Caveolins and Cavins are the major protein components of caveolae and regulate many cardiovascular functions. Caveolin-1 inhibits eNOS activity. The possible regulation of vascular reactivity/blood pressure by the caveolae are of interest in relation to pre-eclampsia (PE). We hypothesised that expression of Caveolin/Cavin genes would be reduced, paralleling the up-regulated eNOS in PE compared to normotensive controls (NC). OBJECTIVES: To analyse the placental mRNA expression of Caveolins1-3 and, Cavins1-4, eNOS and iNOS; and protein of caveolin 1, cavin-1 and eNOS in NC and PE placentae from White European women. METHODS: Following ethical approval and informed written consent, placental biopsies were taken midway between the cord and periphery, avoiding infarcts, from 24 NC and 23 PE patients. Gene expression was measured by qRT-PCR. Protein localization was identified by immunohistochemistry and expression semi-quantitatively assessed. RESULTS: Results of mRNA/proteins are shown on table below. Protein expression was localised to the cytotrophoblast and syncytiotrophoblast. No differences were found for any other gene/protein. CONCLUSION: As well as their known effects on eNOS expression, caveolae mediate internalisation of numerous hormone receptors, thus potentially changing pressor and depressor responsiveness. This is the first time that structural determinants of caveolae have been studied in NC and PE pregnancy. FUNDING: Tommy's, CAPES. PMID- 26105869 TI - PP012. Abnormal vascular umbilical cord morphology in vascular-related pregnancy complications. AB - BACKGROUND: Preeclampsia (PE), foetal growth restriction (FGR) and preterm birth (PTB) are associated with an increased risk on the development of cardiovascular disease in offspring. Abnormal programming of the embryonic and extra-embryonic vasculature may be involved. The umbilical cord could be a good model for studying foetal vascular development. OBJECTIVES: We examined the morphology of the umbilical cord vasculature in complicated (PE, FGR, PTB) and uncomplicated pregnancies. METHODS: In a case-control study, we included 105 patients consisting of PE (n=31), FGR (n=26), PTB (n=24) and controls (n=24). Macroscopic measurements were performed and tissue samples were formalin-fixed within 1 hour after birth, for microscopic analysis of digitised paraffin sections. RESULTS: The macroscopic evaluation showed shorter umbilical cords in PE than in controls. Microscopic measurements revealed a smaller total cord area in all complicated pregnancies compared to controls. The artery wall area was smaller in PE and IUGR, and a smaller vein wall area was present in PE only, compared to controls. The percentage of elastic fibres in the vein was lower in PE and IUGR than in controls (Table 1). CONCLUSION: Our study demonstrates umbilical cord vascular abnormalities in PE, FGR and PTB, suggesting early vascular damage. Future studies should focus on similar structural changes in foetal vasculature and associations with cardiovascular disease in later life. PMID- 26105870 TI - PP014. A pioneer explore of PTZ-induced eclampsia in preeclampsia rats. AB - INTRODUCTION: Eclampsia is the most serious state of hypertensive disorder in pregnancy, but the pathogenesis of eclampsia seizures is poorly understood. OBJECTIVES: An eclampsia animal model was developed by PTZ injection on preeclampsia rats. METHOD: Rats received endotoxin (1.0MUg/kg body weight) form tail vein in an hour on GD14 to build the preeclampsia (PE) model. PTZ i.p injection were given to PE rats on GD16, 17, 18 to induce seizures and build an eclampsia model. All experiment rats were divided into three groups, PE, normal, pregnant (P), non-pregnant (NP) group (n=18 in each group). Each group gave two doses of PTZ (40 or 35mg/kg) as subgroups. Blood pressure, urinary albumin, biochemical indexes (AST, ALT, SCr, Urea) were measured. Seizure severity was defined by Racine' standard and seizure time were recorded. RESULTS: PTZ-induced eclampsia shows a increasing blood pressure, urinary albumin, liver function damage and different stages of seizures. The latency of seizure in PE rats with 40mg/kg PTZ is obviously shortened when compared with the P and NP group (p<0.05) and the duration is prolonged (p<0.05). The same trend is still existence at the low dose of PTZ injection. Rate of tonic-clonic seizures is elevated in PE and P group when compared with NP group, but nonsignificantly. CONCLUSION: We use 40mg/kg PTZ to endotoxin induced preeclampsia model to build an eclampsia model, which mimicked the multiple organ function disorder in human eclampsia. Meanwhile, we found the PE status may decreases threshold for PTZ induced seizures. PMID- 26105871 TI - PP013. Single nucleotide polymorphisms of the maternal cystathionine-b-synthase gene are associated with preeclampsia (PE). AB - INTRODUCTION: Cystathionine-b-synthase (CBS) produces the vasodilatory and anti inflammatory hydrogen sulfide (H2S) by conversion of homocysteine (Hcy). H2S is involved in placental vascular tone regulation. Previously, we showed that woman with PE have hyperhomocysteinemia and decreased placental CBS gene expression. OBJECTIVES: Aberrant CBS gene expression may play a role in hyperhomocysteinemia and decreased H2S and could be involved in pathogenesis of PE. We studied whether the presence of CBS single nucleotide polymorphisms (SNPs) is associated with the development of PE. METHODS: Six CBS SNPs (rs12329764, rs2851391, rs234713, rs234706, rs1789953, rs11203172) were genotyped in 99 controls, 60 severe, and 39 mild PE cases. Severe and mild PE cases were additionally subdivided into late- (>34 weeks) and early-onset (<34 weeks) PE. The association of the alleles with development PE was tested with logistic regression. RESULTS: Two of the six SNPs are associated with PE. The minor allele for rs11203172 reduces the risk for developing severe PE (OR[95% CI]=0.54[0.21-0.94], p=0.023). The minor allele for rs234706, which is associated with low Hcy, increased the risk to develop mild, late-onset PE (2.10[1.15-3.85], p=0.016). CONCLUSION: SNPs in the CBS gene are associated with risk of developing PE. Within the CBS gene, SNPs associated with both a decreased and an increased risk to develop PE were found. Altered effectiveness of CBS may affect PE through decreased H2S production or Hcy accumulation. PMID- 26105872 TI - PP016. Relation of apoptosis, proliferation and angiogenesis in early and late onset of preeclampsia. AB - INTRODUCTION: The placental bed plays a key role in placentation during gestation. Most studies investigated the expression of angiogenic factors in the placenta, but their expression and potential role in the placental bed have not been investigated adequately. OBJECTIVES: The aim of the study was to examine the expression of the fact is that Apo-Cas is apoptotic marker and VEGF in placental bed of pregnancy with early, late-onset PE and without PE. METHODS: Placental bed biopsy tissues obtained during Cesarean Section from patients with early-onset (n=15), late-onset (n=15) and without (n=15) PE. The normotensive controls without PE were matched for gestational age at delivery with patients with PE. The expression of Apo-Cas and VEGF in placental bed tissues were evaluated using reverse transcriptase PCR, real-time PCR, immunohistochemistry and Western blot. RESULTS: There was no statistical difference between the PE group and normotensive control group in age and body mass index. The level of apoptotic marker Apo-Cas was higher in early-compared to late-onset of PE (5%+/-1.4, and 15%+/-2.7). The expression of VEGF was significantly decreased in both PE groups compare to control (p<0.05), but not statistically significant between groups with PE. We also revealed reduction of VEGF receptors in endometrial stroma and its absence in endothelial cells. CONCLUSION: This study showed the prevalence of apoptosis and decreased expression of VEGF in the placental bed of pregnancies complicated by PE compared with control. Further research will help to create the pathogenetic basis for early prediction, recognition and management of PE. PMID- 26105873 TI - PP017. Withdrawn. PMID- 26105874 TI - PP015. Plasma levels and placental expression of BNP/NT-proBNP in early and late onset preeclampsia. AB - INTRODUCTION: Women with preeclampsia (PE) have elevated plasma levels of NT proBNP. We hypothesized that the placenta may be a source to these elevated levels. OBJECTIVES: Our objectives were to study the plasma levels of NT-proBNP and the protein and mRNA expression of placental BNP in women with early and late onset PE and controls. METHODS: Plasma levels of NT-proBNP were measured in women with early (n=18) and late (n=20) onset PE, in two groups of healthy pregnant women in gestational week 24-32 (n=22) and 36-42 (n=14), and in non-pregnant women (n=20). Placental BNP protein and mRNA was studied with immunohistochemistry and qPCR. Placental release of NT-proBNP was studied with tissue culturing. RESULTS: Women with early (365 (14-9815) pg/ml) and late (176 (33-2547) pg/ml) onset PE had higher levels of NT-proBNP in plasma than their respective controls (p<0.001). A tendency towards higher plasma levels in early compared to late onset PE was observed (p=0.057). 20 out of 25 placental tissue samples had proBNP mRNA, no differences between the study groups were found. BNP protein was found in maternal spiral arteries and syncytiotrophoblasts. NT-proBNP peptide (6-7pg/ml) was present in medium used for placenta cultures. CONCLUSIONS: Our results suggest that there may be a placental source of NT-proBNP. If this source is responsible for the elevated plasma levels of NT-proBNP in preeclamptic women and what role, if any, BNP/NT-proBNP play in PE pathophysiology remains to be elucidated. PMID- 26105875 TI - PP020. Evidence of a preventive role of Nrf2 in preeclampsia. AB - INTRODUCTION: Smoking during pregnancy is associated with lower preeclampsia risk. This has been mainly explained through the effect of carbon monoxide CO. OBJECTIVES: Recent studies showed that the activation of heme oxygenase-1 HO-1 and consequently its metabolite CO in cultured cells mediated an inhibition of sFlt-1 and sEng release, and an up-regulation of the endogenous VEGF. The transcriptional regulation of the HO-1 gene is majorly regulated through the transcription factor Nrf2. The aim of this study was to investigate in vitro the effect of HO-1-activation via Nrf2 on the pro- and anti-angiogenic factors. METHODS: BeWo cells and HUVECs endothelial cells were used to study the angiogenic effect of Nrf2-activation. ELISA, scratch and tube formation assay were mainly applied. RESULTS: The activation of HO-1 via Nrf2 lead to an increase in the protein levels of VEGF (control 64.75pg/ml+/-4.3; Sulforaphane-treated cells 128.2pg/ml+/-6.5 p<0.005) and decrease in the augmented sFlt-1 in the supernatant of the treated cells (control 186.3pg/ml+/-28.7; H2O2-treatment 2026pg/ml+/-64, co-treatment with H2O2 and Sulforaphane 1200pg/ml+/-19.7 p<0.01). Up-regulation of HO-1/CO enhanced tube formation and migration of the endothelial cells. CONCLUSION: The activation of HO-1/CO via Nrf2 inducer such as sulforaphane inhibited in vitro the release of sFlt-1, thus the activation of Nrf2 during the first trimester may improve the balance of the pro- and anti angiogenic factors. PMID- 26105876 TI - PP021. The role of the transcription factor Nrf2 in the murine placental development. AB - INTRODUCTION: The placenta is the key organ for successful pregnancy and fetal growth. Oxidative stress during early human placental development is associated with pregnancy-related disorders. The transcription of many antioxidative-genes is mediated mainly through the transcription factor Nrf2. Furthermore, a link between Nrf2, vascular homeostasis and extravillous trophoblast invasion has been discussed. OBJECTIVES: Here, we investigated the placental phenotype, placental and fetal weight of the Nrf2 knockout (Nrf2(-/-)) and wild type (Nrf2(+/+)) mice and the vascular function of these placentas around embryonic day 18.5. METHODS: We performed H&E, Periodic Acid Schiff (PAS) and immunohistochemistry of paraffin embedded mouse placenta samples. RESULTS: There is no significant difference in both placental and fetal weight of both geno types (Nrf2(-/-) and Nrf2(+/+)). Phenotypic analysis of ED 18.5 placentas showed presence of trophoblast clusters in the labyrinth and frequent enlarged maternal blood lacunae. Furthermore, Nr2( /-) showed increased levels in the lipid peroxidation product 4-hydroxinonoeal (4 HNE), which is a sensitive marker of oxidative damage and lipid peroxidation. CONCLUSION: This data point out the necessity of a functional Nrf2 for placental development, as it may interact with the differentiation of the trophoblast lineage from one side and to diminish the oxidative damage during pregnancy from the other side. PMID- 26105877 TI - PP018. Does altitude affect the placental renin angiotensin system (RAS) in pre eclampsia (PE)? AB - INTRODUCTION: We have previously shown the activation of placental RAS in high altitude normotensive (NT) pregnancies [1], presumably related to hypoxia during placental development. PE incidence is increased at high altitude; hypoxia reoxygenation injury contributes to the elevated oxidative stress seen in this condition. Binding of Angiotensin II to its type I receptor (AT1R) increases generation of reactive oxygen species and we have shown an increase in AT1R in PE [2]. Therefore we investigated whether the RAS is further augmented in PE at high altitudes. METHODS: Biopsies were collected, with informed, written consent, from NT and PE women (ISSHP guidelines) at sea-level (UK) and high altitude, 3100m (Leadville, Colorado) immediately after vaginal delivery or elective non-laboured Caesarean section. mRNA expression of the RAS components (angiotensinogen (AGT), prorenin, prorenin receptor, AT1R and angiotensin type 2 receptor) was determined by qRT-PCR and normalised to 3 stably-expressed housekeeping genes using geNorm. Protein expression was semi-quantitatively assessed by immunohistochemistry (H score) and compared between groups (Mann Whitney U test). RESULTS: mRNA expression of all RAS components was unaffected by altitude in NT, but significantly lower for all in PE (P=0.026-<0.0001). However, in NT, protein expression of all components except AGT was significantly increased at altitude (P=0.037-<0.001). Protein expression of AGT and AT1R was also increased in altitude PE (P<0.004 for both). CONCLUSION: We have shown the placental RAS to be activated at altitude, with apparent differences in transcription/translation. Hypoxia-inducible transcription factors such as HIF-1 enhance transcription and translation of many genes encoding "rescue" proteins; this might explain the effects of altitude in NTs. HIF-1 is increased in PE, which might allow increased protein expression at altitude in spite of lower mRNA. PMID- 26105878 TI - PP019. A new player in preeclampsia: The NF-E2-related factor 2 (NRF2). AB - INTRODUCTION: Preeclampsia PE is characterized by diminished antioxidant capacity. These enzymes are mainly regulated via the transcription factor Nrf2. OBJECTIVES: PE is associated with an increase in Nrf2 activity. Nrf2 involves also in the vascular homeostasis during PE. Respective hemodisturbances have been associated with impaired invasion of the extravillous trophoblast EVT in early onset IUGR associated with PE. To test this link, we studied in vitro the interaction between Nrf2 and VEGF, then their expression was determined in third trimester placental beds in cases of severe early onset IUGR/PE. METHODS: BeWo cells were used in the in vitro study.Western blot; ELISA and Dual Luciferase assay were applied. Full-thickness uterine tissues from 6 healthy and 6 women with severe early onset IUGR/PE were used to study the expression of VEGF, Nrf2 and 4-HNE in the EVT. RESULTS: Nrf2-activation and its downstream target protein HO-1 augmented CO production, which in turn up-regulated the expression of VEGF. EVT in cases with IUGR/PE showed increased expression of Nrf2 and decreased VEGF intensity. CONCLUSION: In early onset IUGR/PE the EVT experience oxidative stress and try to counteract this by increased expression of Nrf2. However, since these cells fail to up-regulate VEGF, Nrf2-activation does not occur, leading to further trophoblast damage. At the same time, in vitro data show a protective role of the Nrf2/HO-1 pathway, which may have a therapeutic potential in PE. PMID- 26105879 TI - PP022. An animal model for eclampsia. AB - BACKGROUND/AIMS: Eclampsia, a leading cause of maternal mortality. Little is known about the causes of eclampsia and there is no effective treatment. Development of an animal model may help to expand our understanding and may hold great potential for the design of effective treatment. METHODS: Experimental preeclampsia model was build first, rats were received a infusion of endotoxin (LPS) (1.0MUg/kg body weight) or saline solution through the tail vein during 1h on gestational day 14, blood pressure and albuminuria were measured. On gestational day 18 all experimental rats were received electric stimulation, the seizure behaviors were observed and EEG were recorded in these rats. Terminations of pregnancy were performed on day 21 of gestation, resorptions and pups birth weights were recorded. RESULTS: PE model rats develop many features of human PE that correlates with bad pregnancy outcomes. Both clinical behavior and EEG records documented seizure activity developed in 100% of pregnancy rats and 58.3% of non-pregnancy rats (P=0.01). The PE model rats had a 31.25% decrease of the latency (3.3+/-1.4min) to evoke a full motor seizure compared with normal pregnancy rats (4.8+/-2.2min), and had a significant decrease contrast to non pregnancy rats (10.6+/-7.1min), LP<0.05). EEG recordings showed seizure activities when rats had clinically generalized tonic-clonic convulsions. CONCLUSION: We described a rat model of eclampsia, were the relevant predominant features of human eclampsia. PMID- 26105880 TI - PP023. Soluble Fms-like tyrosine kinase-1 and placental growth factor expression in a rat model of pre-eclampsia. AB - BACKGROUND/AIMS: Soluble Fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PIGF) have been used clinically to predict preeclampsia (PE). This study investigated these factors in a rat model of preeclampsia induced by ultra-low dose endotoxin. METHODS: The experimental PE rat model was generated on gestational day 14. Rats were anesthetized and divided into a normal pregnancy group (NP, n=7) (which received a normal saline infusion) and a PE model group (n=9) (which received an infusion of lipopolysaccharide (LPS) endotoxin (1.0MUg/kg body weight). Infusions were given through the tail vein for 1 hour. Blood pressure was monitored and albuminuria, serum ALT, AST, creatinine and BUN were measured. As well, concentrations of sFlt-1 and PIGF in serum and amniotic fluid were measured by enzyme-linked immuno sorbent assay (ELISA). RESULTS: Arterial pressure was increased (135+/-7 versus 116+/-3mmHg; P<0.03) in the PE model rats compared with the NP rats. The concentration of sFlt-1 in the PE model group (162.7+/-73.9pg/ml) was significantly higher than NP group (123+/-64pg/ml) (P<0.05). The serum level of PIGF in PE model group (9.7+/-6.2pg/ml) was significantly lower compared to the NP group (23.4+/-12.4) (P<0.05). The plasma sFlt-1/PIGF ratio in the PE model group (18.3+/-5.6) was greater than that in the NP group (6.7+/-2.1) (P<0.05). Similar changes were also present in the amniotic fluid. CONCLUSION: sFlt-1 and PIGF levels in this rat PE model induced by ultra low-dose endontoxin showed changes consistent with findings in preeclamptic patients, indicating that this animal model mimics human preeclampsia well in these aspects of the disorder. PMID- 26105881 TI - PP025. Measurement of the activity of the circulating and intrarenal renin angiotensin system (iRAS) in pregnant and non-pregnant subjects. AB - OBJECTIVES: To see if urinary angiotensinogen (uAGT)/creatinine and other urinary components of the RAS could be used to detect renal disease in pregnancy, as renal disease predisposes to preeclampsia. METHODS: Plasma and urinary prorenin, ACE and AGT (iRAS) were measured by ELISA. Urinary active renin levels were measured enzymatically (9 males, 10 non pregnant, 61 Australian Indigenous pregnant women). RESULTS: No relationships between plasma RAS and iRAS were found. In non-pregnant females plasma AGT levels were inversely related to protein and albumin/creatinine (r=-0.72, P=0.019, n=10; r=-0.65, P=0.042, n=10). In pregnancy, plasma ACE levels were related to protein/creatinine (r=0.29, P=0.036, n=54). Urinary protein/creatinine was not related to iRAS activity (males and non-pregnant females) but in pregnancy was related to prorenin and active renin/creatinine (r=0.45, P=0.02, n=26 r=0.47, P<0.001, n=50). Urinary albumin/creatinine was related to uAGT and active renin/creatinine in pregnancy (r=0.39, P=0.005, n=51; r=0.37, P=0.008, n=51). uACE/creatinine and uAGT/creatinine were related (r=0.52, P<0.001, n=51). CONCLUSION: Excretion of components of the iRAS is independent of plasma levels. Not only is uAGT/creatinine related to albumin/creatinine but there are similar relationships with other iRAS components. Measurement of the iRAS in human pregnancy may detect early stage renal disease, endemic in Indigenous Australians. PMID- 26105882 TI - PP027. Alterations in maternal antioxidant micronutrient concentrations in women prior to developing pre-eclampsia. AB - INTRODUCTION: Changes in plasma antioxidant trace elements during pregnancy are closely related to mortality and morbidity in the newborn. Deficiencies of specific micronutrient antioxidant activities, associated with copper, selenium, zinc and manganese have previously been associated with pre-eclampsia (PE) at term. The purpose of the present study was to investigate these maternal plasma micronutrient concentrations with associated enzyme activities, specifically the copper-related caeruloplasmin, in a subcohort of the international SCreening fOr Pregnancy Endpoints (SCOPE) study, in early pregnancy, prior to disease onset. METHODS: Pre-disease plasma samples (14-16+6 weeks') collected from women who subsequently developed PE (n=245) and age- and BMI-matched uncomplicated normotensive controls (NC; n=471) were used following written informed consent. Micronutrient concentrations were measured by inductively-coupled mass spectrometry and caeruloplasmin activity by colorimetric activity assay. RESULTS: Plasma copper concentrations at 15 weeks' gestation were significantly elevated in women who subsequently developed PE; no differences were seen for all other micronutrients (Table). No differences were seen in caeruloplasmin activity between the two groups. However, a positive association between copper concentration and caeruloplasmin activity was observed (r=0.305; R2=0.093; P<0.0001). CONCLUSION: Copper has a dual function in pregnancy, while it may be beneficial as a cofactor for numerous antioxidant enzymes, it also a redox-active transition metal, which catalyses the formation of free radicals and increased levels may contribute to oxidative stress status in PE. These data indicate that although women with PE show significantly higher copper, the caeruloplasmin activity is not significantly higher. It seems that during PE, the activity does not increase proportionally with the levels of copper and may indicate a dysfunction of the antioxidant enzyme. Work is underway to characterise copper dependent antioxidant superoxide dismutase activity and markers of oxidative stress in these women. FUNDING: British Heart Foundation (Charity No. 225971). PMID- 26105883 TI - PP024. Effects of intravenous magnesium sulfate on the characteristics of eclamptic seizures induced by electrical stimuli in a rat preeclampsia/eclampsia model. AB - BACKGROUND/AIMS: Eclampsia is a serious complication of pregnancy and remains a leading cause of maternal mortality worldwide. Magnesium sulfate is commonly used in the prophylaxis and treatment of eclampsia. However, uncertainty remain regarding its anticonvulsant mechanism(s) of action. This study examined the effects of intravenous magnesium sulfate on the characteristics of eclamptic seizures in a rat preeclampsia/eclampsia model. METHODS: All rats were implanted with stainless nickel-cadmium alloy bipolar electrodes one week before fertilization. Next, an experimental rat preeclampsia (PE) model was induced on gestational day 14 by anaesthetising rats and infusing over 1 hour into their tail veins lipopolysaccharide (LPS) (1.0MUg/kg body weight) (with control rats receiving normal saline). The rats were then divided into three groups: a normal pregnancy (NP) group (n=6) which received a continuous infusion of saline; a control PE model group (n=7) (which had previously received the LPS treatment) which also received a continuous infusion of saline; and a treated PE model group (n=8) (which had previously received the LPS treatment) which received a continuous infusion of magnesium sulfate (60mg/kg/day). The continuous infusions in all three groups were delivered by implanted osmotic minipumps . Measurements were made of blood pressure, albuminuria, serum ALT, AST, and creatinine, BUN and serum magnesium concentrations. On gestational day 18, all experimental rats received a standardized electrical stimulus. Seizure activity was assessed using electroencephalogram (EEG) recordings. Terminations of pregnancy were performed on gestational day 21. Resorptions and pup birth weights were recorded. RESULTS: The pregnant LPS treated rats developed many features of human PE (e.g. hypertension, proteinuria, liver and kidney dysfunctions). The mean concentration of Mg(2+) in the magnesium sulfate therapy group (0.86+/-0.24mmol/L) was significantly higher (p<0.05) than in both the control PE model group (0.61+/ 0.12mmol/L) and the NP group (0.62+/-0.09mmol/L). The magnesium sulfate therapy group had a significantly (p<0.05) increased latency period (21.7+/-8.9min) to evoke a full motor seizure compared to both the NP group (4.8+/-2.2min)and the control PE model group (3.3+/-1.4min), there being no significant difference (p>0.05) between the latency periods of the NP group and the control PE model group. Overall, the magnesium sulfate therapy regimen completely prevented seizure activity in 3/8 (37.5%) of the treated PE model rats compared to 6/6 (100%) of the NP rats and 7/7 (100%) of the control PE rats. The treated PE model group also had significantly (p<0.05) reduced seizure duration (26+/-4s) compared to both the NP (40+/-7s) and the control PE model (45+/-9s) groups. As well, there was a significantly (p<0.05) shorter EEG seizure amplitude change in the treated PE model group (58+/-6MUv). CONCLUSION: In this rat preeclamsia/eclampsia model, the anticonvulsant characteristics of magnesium sulfate have been shown to include significantly increasing seizure latency period, reducing seizure duration and decreasing seizure EEG amplitude. PMID- 26105884 TI - PP028. Serum cytokine profile in relation to the clinical features and laboratory parameters in women with preeclampsia. AB - INTRODUCTION: Preeclampsia is characterized by an excessive maternal systemic inflammatory response. OBJECTIVES: To determine circulating levels of cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia, and to investigate their relationship to the clinical features and laboratory parameters of the patients. METHODS: Serum levels of IL-1beta, IL-1ra, IL-2, IL-4, IL-6, IL 8, IL-10, IL-12p40, IL-12p70, IL-18, IFN-gamma, TNF-alpha, TGF-beta1, IP-10, MCP 1, ICAM-1 and VCAM-1 were measured in 60 preeclamptic, 60 healthy pregnant and 59 healthy non-pregnant women. RESULTS: In addition to a shift towards Th1-type immunity (increased IL-2/IL-4 and IFN-gamma/IL-4 ratios), levels of the pro inflammatory cytokines IL-6 and TNF-alpha, the chemokines IL-8, IP-10 and MCP-1, as well as the adhesion molecules ICAM-1 and VCAM-1, were raised in preeclampsia, resulting in an overall pro-inflammatory systemic environment. Increased IP-10, MCP-1, ICAM-1 and VCAM-1 concentrations of preeclamptic patients showed significant correlations with blood pressure values, renal and liver function parameters, as well as with CRP, malondialdehyde, von Willebrand factor antigen and fibronectin levels. CONCLUSION: Elevated amounts of pro-inflammatory cytokines, chemokines and adhesion molecules in the maternal circulation might play a central role in the excessive systemic inflammatory response, as well as in the generalized endothelial dysfunction characteristics of preeclampsia. PMID- 26105885 TI - PP029. Genetic change of adipose tissue related to inflammation in preeclampsia: Findings under novel culture method. AB - INTRODUCTION: Recently, adipose tissue is suggested to contribute to the inflammatory action in preeclampsia(PE), from peripheral increase of cytokines. However, the mechanism of the action in adipose tissue was not clarified yet. OBJECTIVES: In this study, we performed "Gel bottom-captured" adipose tissue culture with PE to show that the adipose tissue is the inflammatory focus in the pathophysiology of PE. METHODS: Under informed consent of the patients, omentum from probe laparotomy for ovarian cancer was captured in Peptide Hydrogel(r). After 24h starvation, tissues were cultured with medium containing 10% of severe PE and healthy pregnant maternal serum (n=5 each). M30 (Apoptosis) and M65 (all cell death) were measured with ELISA. After mRNA extraction from tissue, quantitative PCR array (Qiagen, Inc.) was performed on all samples. RESULTS: No significant histological differences were found between each culture. However, M30/M65 ratio was increased in PE (p=0.053). In PCR array, under 2-fold decrease in OSM (p=0.019) was found, and over 2-fold increase in TLR (p<0.01) and other inflammatory genes were defined in PE. CONCLUSION: Inflammatory action in PE via TLR pathway was defined by adipose tissue culture. Apoptosis were shown in PE condition, but total tissue injury include necrosis were suggested to be stronger in normal pregnancy. Increase of inflammatory gene suggested that adipose tissue is one of a main organ of systemic inflammation in PE. PMID- 26105886 TI - PP033. Oxidized LDL particles in the placenta of intrauterine growth restriction (IUGR) subgroups. AB - INTRODUCTION: Maternal serum LDL concentrations are lower in IUGR pregnancies as compared to controls (CTRL). We now hypothesized that an increased oxidative stress results in the formation of oxidized LDL (oxLDL) particles which than accumulates within the placenta. This is particularly hypothesized for the severe early onset subgroup of IUGR with preeclampsia (PE). METHODS: OxLDL (minimal modified and fully oxidized LDL) levels in placental biopsies from term IUGR (>37 weeks, t-IUGR, n=5), preterm IUGR (<34 weeks, p-IUGR, n=5), and preterm IUGR with PE (PE-IUGR, n=5) were compared to a CTRL group consisted of gestational age matched preterm (p-CTRL, n=10) and term (t-CTRL, n=5) placentas by ELISA and immunohistochemistry (IHC). RESULTS: Fully oxidized LDL but not minimally oxidized LDL concentrations were higher in p-IUGR and tend to be increased in PE IUGR when compared to p-CTRL (p=0.040 and p=0.075). There was virtually no difference of fully oxidized LDL levels between p-CTRL, t-CTRL, and t-IUGR. We confirmed a higher oxLDL accumulation in trophoblasts of p-IUGR and PE-IUGR as compared to both CTRL groups by IHC though this was not statistically significant. CONCLUSION: Conformational changes of LDL during the process of oxidation might lead to an accumulation of oxLDL particles in placental tissue of IUGR. The pathogenesis of early onset IUGR might differ from those of late onset IUGR. PMID- 26105887 TI - PP032. Apolipoprotein profiling in umbilical cord blood of intrauterine growth restricted (IUGR) neonates. AB - INTRODUCTION: Fetal umbilical cord HDL concentration is lower in IUGR neonates as compared to gestational age matched controls (CTRL). The causes by now are unknown. A full apolipoprotein analysis of cord blood might help in understanding the changes in lipid metabolism seen in IUGR. OBJECTIVE: To characterize cord blood apolipoprotein profile of IUGR neonates. METHODS: Serum of venous umbilical cord blood (15 IUGR vs. 15 CTRL) was analyzed by Multiple Reaction Monitoring (MRM). 15 different known apolipoproteins were profiled. HDL and LDL were measured by colorimetric methods in fetal cord blood and their corresponding mothers. RESULTS: Fetal HDL (p<0.0001), ApoC1 (p<0.0001), and ApoE (p=0.0001) levels were lower in IUGR as compared to CTRL. Fetal HDL levels were positive correlated to ApoE, ApoC1, and ApoA2 (r=0.79, r=0.74, r=0.56). Fetal LDL levels were positive correlated to ApoB, ApoE, ApoA2, and ApoC3 (r=0.74, r=0.67, r=0.57, r=0.55). Maternal LDL concentrations correlated positive to fetal ApoC1, ApoC2, and LCAT-concentration (r=0.54, r=0.52, r=0.52). DISCUSSION: The results underlines the relevance of ApoE in fetal development. Moreover, we speculate that maternal lipid profile has an impact on fetal lipid metabolisms as evidenced by the association of maternal LDL levels and fetal ApoC1, ApoC2, and LCAT concentrations. This observation requires further confirmation and is worth to be analyzed since it provides a mechanistic link for therapeutic options. PMID- 26105888 TI - PP031. The fetal cholesterol acceptor potential in cord sera of intrauterine growth restricted (IUGR) neonates. AB - INTRODUCTION: The fetal umbilical cord blood cholesterol concentration is lower in IUGR neonates as compared to gestational age matched controls (CTRL). One possible explanation is an alteration of cholesterol acceptor concentration or functionality and a disturbed interaction with reverse cholesterol transport (RCT) mechanisms at the placentofetal interface. OBJECTIVE: To study receptor specific mechanisms of RCT in response to fetal sera of IUGR and CTRL neonates. METHODES: Different cell lines were used to determine the fractional efflux of (3)H-cholesterol in response to whole fetal serum (IUGR n=25; CTRL n=25) in the absence or presence of ABCA1 overexpression. Efflux values were correlated to serum concentrations of possible cholesterol acceptors like HDL, apoA1, and apoE. RESULTS: The main finding was a significant over all reduction of fractional cholesterol efflux in response to IUGR serum as compared to CTRL (p<0.001). The differences were abolished after overexpression of ABCA1. Cholesterol efflux over all was highly correlated to HDL and ApoE concentration (n~=0.777 and n~=0.60). CONCLUSION: The reduced cholesterol efflux acceptor capacity appears to diminish cholesterol availability and transplacental cholesterol transport to IUGR fetuses. Moreover, disturbances of RCT are involved in the pathomechanisms of atherosclerosis. Our results represent a link between the known association of being born small for gestational age and risk of developing CVD later in life. PMID- 26105889 TI - PP030. Transmission electron microscopy reveals leakage of laeverin into the villous capillaries and ectopic expression in the cytoplasm instead of cell membrane of the trophoblasts in preeclamptic placentas. AB - INTRODUCTION: Laeverin, a membrane-bound aminopeptidase is specifically expressed in human placenta. We previously reported that mRNA levels of laeverin-gene are up-regulated in the placentas of severely preeclamptic women compared to healthy controls. Furthermore, immunofluorescence studies indicated that laeverin is expressed in the cytoplasm rather than the cell membrane of preeclamptic placentas. OBJECTIVE: To study differences in size and integrity of laeverin protein expressed in preeclamptic and normal placentas, and to investigate sub cellular localization of laeverin, in the trophoblasts. METHODS: Proteins from placental tissue of three severely preeclamptic women and three healthy controls were extracted using Magnabeads in MagNaLyser in T-PER solution. Western blot analysis was done by SDS-polyacrylamide gel electrophoresis and electro-blotting on PVDP membranes. Membranes were developed by Tropix CDP-Star and immuno reactive bands were visualised. Immuno-electronmicroscopy was performed on high pressure freezed (Tokyasu method) tissue samples of three placentas (from1 healthy and 2 severely preeclamptic women). Ultrathin sections were fixed and labeled with primary antibody raised against laeverin, followed by antibody conjugated with 5nm gold particles (PAG5). Experiments were performed in triplicates and images were taken using a JEM-1010 transmission electron microscope at 50,000 and 70,000 magnifications. RESULTS: Western blot analysis detected laeverin-protein of normal size (approximately 100kDa) both in normal and preeclamptic placentas. However, laeverin was overexpressed in preeclamptic placentas compared to healthy controls. Immuno-electronmicroscopy revealed presence of laeverin within the capillaries in preeclamptic placentas which was not seen in healthy controls. At a sub-cellular level laeverin was localized on the cell membrane of trophoblasts in healthy placentas. However, in preeclamptic placentas, laeverin was localized in the cytoplasm and in particular in the Golgi apparatus. CONCLUSIONS: In preeclamptic placentas, laeverin is overexpressed and it appears to leak into the villous capillaries and localize in the cytoplasm instead of cell membrane of the trophoblasts. PMID- 26105890 TI - PP035. Genome-wide expression profile of first and second trimester human uterine natural killer cells. AB - INTRODUCTION: Uterine Natural Killer (uNK) cells are key regulators of the placental bed during early placental development and account for 40% of decidual cells. uNK cells have been suggested to play a role in pregnancy complications including maternal placental syndromes, such as preeclampsia. Furthermore uNK cells are involved in angiogenesis, immunomodulation, trophoblast invasion and spiral artery remodeling. These temporal processes are essential for normal placentation and may suggest a time dependent role for uNK cells. OBJECTIVE: To determine uNK cell phenotypic changes during early human placental development. METHODS: uNK cells were isolated from first (7-8 wks, n=6) and second trimester decidual tissue (13-14wks, n=6) by enzymatic digestion and flow sorting, based on uNK cell specific surface marker expression (CD56(high)CD16-CD3-). Total RNA was isolated and subjected to genome-wide gene expression profiling. Expression patterns were validated by quantitative rt-PCR. RESULTS: Using purified uNK cells we identified 140 transcripts that are differentially expressed between the first and second trimester of pregnancy. Many of these transcripts cluster into promising novel and established NK cell functional characteristics. CONCLUSION: The uNK cell phenotype changes over the course of early pregnancy. We propose that these phenotypic changes of NK cells may be dictated by the "uterine niche" to promote the orderly and precisely timed process of placentation. PMID- 26105891 TI - PP034. Renal histology in preeclampsia: A special role for the podocyte. AB - INTRODUCTION: In preeclampsia (PE), the kidney is one of the major target organs. Growing evidence suggests PE increases the risk of subsequent microalbuminuria and end-stage renal disease (ESRD). Endotheliosis and podocyte changes due to anti-angiogenic factors seem to be salient features of PE. However, it is unknown whether chronic lesions are present in PE patients that could contribute to this increased risk. OBJECTIVES: We hypothesized that women with PE and young women with chronic hypertension might show similarity in renal lesions. Furthermore, we investigated if the number of podocytes within the kidney is decreased under these different circumstances. Methods We performed a search for renal autopsy tissues using a nationwide computerized database (PALGA) to collect a unique large cohort of preeclamptic patients (n=11). Three control groups were included consisting of young women who died during pregnancy without hypertension (n=25) and non-pregnant controls with (n=14) and without (n=13) chronic hypertension. WT 1 staining was used to quantify the number of podocytes. Results Women with PE had MPGN-like lesions without immune-deposits. Tram tracking and podocyte changes were exclusively observed in these patients. Endotheliosis was significantly more present in PE, but sporadically seen in pregnant- and hypertensive controls. Chronic ischaemic lesions were predominantly found in young women with chronic hypertension, and not in PE and other controls. No differences were found in glomerular podocyte number between the study groups. CONCLUSION: All women with PE had MPGN-like lesions in their kidneys which was therefore regarded characteristic for PE. In contrast, no chronic lesions were observed in PE which could explain the increased risk of impaired renal function later in life. Interestingly, we demonstrated no difference in podocyte number between study groups. These results might suggest that neither persistent hypertension or dysbalance in angiogenic factors (i.e. preeclampsia) cause an observable change in podocyte number within the kidney. PMID- 26105892 TI - PP036. The intrarenal renin-angiotensin system and pregnancy outcome. AB - OBJECTIVES: The intrarenal renin angiotensin system (iRAS) may be activated in normal pregnancy. Failure of activation may predispose to preeclampsia. METHODS: Urinary angiotensinogen/creatinine (uAGT/creat), albumin and protein/creat were measured in 10 non-pregnant and 17 pregnant non-Indigenous women and 61 Indigenous pregnant women (in whom other components of iRAS were also measured). RESULTS: uAGT/creat was higher in pregnancy (18.2+/-3.2MUg/mmol, n=9 vs. 1.1+/ 0.3MUg/mmol, P=0.001, n=10). Women with clinical proteinuria and/or preeclampsia had low uAGT/creat (n=3). Hypertensive women had normal high uAGT/creat (n=4). Indigenous pregnant women had higher protein/creat (P=0.01) and lower uAGT/creat (2.9+/-1.0MUg/mmol, P=0.010, n=51) than non-Indigenous pregnant women. Indigenous women were classified based on a uAGT/creat of <2MUg/mmol (n=37) or >2.0MUg/mmol (n=12). Only low uAGT/creat Indigenous pregnant women had correlations between uAGT/creat and albumin/creat (r=0.367, P=0.027), renin/creat and albumin or protein/creat (r=0.493, P=0.002, r=0.603, P<0.001). uAGT/creat levels fell with gestation (r=-0.329, P=0.047) while Cystatin C increased (r=0.592, P=0.000). CONCLUSION: The iRAS is activated in normal pregnancy. This is not the case in women with proteinuria/preeclampsia or in many Indigenous women who have higher urinary protein/creat. Therefore a low uAGT/creat in pregnancy may indicate impaired renal function and be associated with an increased risk of preeclampsia. PMID- 26105893 TI - PP037. Relationship of serum leptin levels to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in women with preeclampsia. AB - INTRODUCTION: Serum leptin levels are known to be increased in preeclampsia. OBJECTIVES: To determine circulating levels of leptin along with those of several cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia, and to investigate whether serum leptin levels are related to the clinical features and measured laboratory parameters of the patients. METHODS: Serum levels of leptin, IL-1beta, IL-1ra, IL-2, IL-4, IL-6, IL 8, IL-10, IL-12p40, IL-12p70, IL-18, IFN-gamma, TNF-alpha, TGF-beta1, IP-10, MCP 1, ICAM-1, VCAM-1, sFlt-1 and PlGF were determined in 60 preeclamptic, 60 healthy pregnant and 59 healthy non-pregnant women. RESULTS: There were significant differences in most of the measured laboratory parameters among the three study groups except for serum IL-1beta and TGF-beta1 levels. Preeclamptic patients had significantly higher leptin levels than healthy pregnant women. A significant positive correlation was observed between serum leptin and IP-10 concentrations of preeclamptic patients. Furthermore, elevated serum leptin level and sFlt 1/PlGF ratio had an additive effect in the risk of preeclampsia, as shown by the substantially higher odds ratios of their combination than of either alone. CONCLUSION: Increased serum levels of leptin are related to those of IP-10 in preeclampsia, suggesting that circulating leptin might contribute to the development of endothelial dysfunction through the anti-angiogenic effect of IP 10. PMID- 26105894 TI - PP038. Renal ETK/BMX activation decreased in preeclampsia. AB - INTRODUCTION: Vascular endothelial growth factors (VEGF's) are essential to angiogenesis and play a central role in the pathophysiology of preeclampsia. Specifically, antagonists of VEGFR2 cause a preeclampsia-like syndrome, in humans and rats[1]. ETK/BMX is a receptor tyrosine kinase (RTK) which induces VEGF expression and forms a complex with VEGFR2, whereby VEGF and TNF can induce a reciprocal activation of both kinases. OBJECTIVES: To determine the levels of phosphorylation, and thus activation, of VEGFR2 and ETK/BMX in renal tissue from women with preeclampsia and with healthy pregnancies. METHODS: Renal tissue was obtained with consent from six preeclamptic and six healthy pregnant women included in a previous renal needle biopsy study[2] and a RayBio(r) Phosphorylation Antibody Array was used according to instructions. RESULTS: Phosphorylated ETK/BMX was significantly reduced in the preeclamptic women compared to in the healthy pregnant women. There was no difference in phosphorylated VEGFR2 between groups. CONCLUSION: These data suggest that ETK/BMX could be an important mediator of VEGF function in healthy pregnancy, in the kidneys more so than VEGFR2, and that absence of the positive feedforward signalling that ETK/BMX and VEGF together accomplish, and/or a TNF induced activation of this, may play a role in the pathophysiology of preeclampsia. PMID- 26105895 TI - PP041. The underlying mechanisms in reduced action of endothelial nitric oxide in resistance artery in preeclampsia. AB - OBJECTIVE: In preeclampsia (PE), the action of endothelial nitric oxide (eNO) is reduced by in vitro investigation of characteristic changes using vascular strips of resistance artery. We studied underlying mechanisms in the reduced action of it. METHODS: The vascular strips of omental resistance arteries were obtained from PE and normotensive pregnant women. Informed consent was obtained from each patient. This study was permitted by ethical board. (1) The various isometric tension by NO were measured by bradykinin (BK), sodium nitroprusside (SNP) and the inhibition of 8-pCPT-cGMPVert@during the STA2 (a stable analogue of thromboxane A2)-induced contraction. (2) The [Ca(2+)]i were measured in the endothelium-intact strip loaded cell-permeable form of Fura 2 (Fura 2-AM). (3) The concentrations of cGMP and eNO synthase (eNOS) were measured in endothelial cell intact strips. RESULTS: (1) In PE, endothelium-dependant (by BK) and independent (by SNP) relaxation of NO in the STA2-induced contractions were significantly smaller, while the action of c GMP was also reduced. (2) BK increased the concentration of [Ca(2+)]i, although the increase was not reduced in PE. (3) The concentrations of cGMP with BK and without BK and eNOS were not reduced in PE. CONCLUSION: These results revealed that the action of endothelial NO might be reduced not due to decrease in the production of NO in the endothelium but rather to reduced action of cGMP itself. PMID- 26105896 TI - PP040. Activation of endosomal toll-like receptors in first trimester trophoblasts. AB - INTRODUCTION: A mild systemic inflammation may be beneficial to normal pregnancy, however exaggerated inflammation may contribute to pregnancy complications. Infections and cell stress or damage may evoke placental inflammation by activation of Toll-like receptors (TLRs). TLR3, TLR7, TLR8 and TLR9 are located intracellulary on endosomes and are activated by nucleic acids from microbes and damaged cells. Trophoblasts play a crucial role during placentation, and the role of TLRs in first trimester trophoblasts needs to be determined. OBJECTIVES: To characterize endosomal TLR gene expression and activation in first trimester trophoblasts, to extend knowledge of endosomal TLR involvement in placental inflammation. METHODS: Primary trophoblasts were isolated from six first trimester placentas by enzyme degradation and gradient centrifugation. Gene expression of TLR3, TLR7, TLR8 and TLR9 in primary first trimester trophoblasts and the trophoblast cell line BeWo was quantified by RT-qPCR. The trophoblasts were stimulated with ligands for endosomal TLRs, and release of pro-inflammatory cytokines was analyzed by multiplex. RESULTS: Primary first trimester trophoblasts showed gene expression of all endosomal TLRs, and endosomal TLR activation gave increased production of the pro-inflammatory cytokines IL-6, IL 8, and IP-10. CONCLUSION: Primary first trimester trophoblasts express functional endosomal TLRs, indicating TLR-mediated trophoblast involvement in early placental inflammation. PMID- 26105897 TI - PP039. ETK/BMX and renin-angiotensin system (RAS) components are differentially expressed in renal tissue in both normal and preeclamptic pregnancy. AB - INTRODUCTION: Renal ETK/BMX activity is reduced in preeclampsia. Systemic RAS has been studied in preeclampsia; the renal RAS has not. None of the proteins in either pathway have previously been located in renal tissue from human pregnancy. OBJECTIVES: To determine renal expression and distribution of proteins involved in the ETK/BMX and RAS pathways in normal and preeclamptic pregnancy. METHODS: Limited residual tissue was available from renal biopsies in eight preeclamptic and seven healthy pregnant women. Immunohistochemistry was performed for AT1R, AT2R, angiotensinogen (AGT), prorenin, unphosphorylated ETK/BMX (uBMX) and phosphorylated ETK/BMX (pBMX). Immunohistochemical scoring was performed semiquantatively by a nephropathologist blinded to the original diagnosis. Results All proteins were renally expressed, AT1R equally in glomeruli and tubules, AT2R and prorenin more strongly in the tubules. If at all, uBMX was weakly expressed in glomeruli, and no glomerular pBMX expression was detected. Both uBMX and pBMX were strongly expressed in distal tubules. The material was too limited to detect differences between groups. CONCLUSION: The presence of prorenin, and both angiotensin receptors in the proximal tubule may indicate activation of the intra-renal RAS. Angiotensin II promotes sodium retention at the proximal tubule independently of aldosterone. Activated ETK/BMX in injured tubular epithelial cells is associated with cell repair and regeneration, proliferation and motility. PMID- 26105898 TI - PP042. Cell surface toll-like receptors in primary first trimester trophoblasts. AB - INTRODUCTION: The first trimester of pregnancy is characterised by a mild pro inflammatory environment, however excessive inflammation threatens placental development and function. Toll-like receptors (TLRs) are crucial in initiating inflammation. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are expressed on the cell surface, and respond to microbial infection and cell damage and stress signals. Recent findings of TLRs in trophoblasts indicate a role in inflammation during pregnancy, but further studies are warranted. OBJECTIVES: To investigate gene expression and function of cell surface TLRs in first trimester trophoblasts, to extend knowledge on the role of trophoblast TLRs during placental development. METHODS: Primary trophoblasts were isolated from first trimester placentas (n=6) by enzyme degradation and density gradient centrifugation. Gene expression of TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 was quantified by RT-qPCR in primary first trimester trophoblasts and the trophoblast cell line BeWo. Trophoblasts were stimulated with cell surface TLR ligands and pro-inflammatory cytokine release was analysed by multiplex immunoassay. RESULTS: Primary first trimester trophoblasts expressed all cell surface TLR mRNAs, and activation of TLR2/1, TLR4 and TLR5 induced IL-6 and/or IL-8. CONCLUSION: The broad expression of functional cell surface TLRs in primary first trimester trophoblasts suggests a central role for trophoblasts in placental inflammation and immune activation. PMID- 26105899 TI - PP044. Differential expression of trophoblast-, endothelial- and embryonic stem cell-associated transcription factors in 1st trimester, and in 3rd trimester preeclampsia and intrauterine growth restriction. AB - OBJECTIVES: Trophoblast progenitor cells express stem cells markers (SCM) to maintain the proliferative characteristic of stem cells. Beyond blastocyst stage or in preeclampsia (PE) or intrauterine growth restriction (IUGR) little is known about expression of SCMs. We examined the expression of trophoblast and other SCMs in 1st and 3rd trimester placenta and in preeclampsia (PE) and intrauterine growth restriction (IUGR) in order to discriminate if these markers might be involved in progenitor cell functions. METHODS: 8 samples each of 1st trimester placentae (elective abortions), 3rd trimester IUGR, PE and control (normal term pregnancy placentae) were stained by immunoperoxidase to detect the SCMs: CDX2 (trophectoderm SCM), SOX2, NANOG and OCT4A (embryonic SCMs) and NOTCH1 (endothelial SCM). RESULTS: In 1st trimester all SCM were detected, expressed homogenous in syncytio- and cytotrophoblast, and grow increasingly mosaic-like towards the end of 1st trimester. These signals are lost or diminished in 3rd trimester, whereby the syncytiotrophoblast loses these signals first. NOTCH1, however, remains highly expressed in all trophoblast subtypes of both IUGR and PE pregnancies. CONCLUSION: Both embryonic and trophoblast SCMs are expressed in 1st trimester trophoblast and appear most vivid among the villous trophoblast of very early pregnancy. Loss of stem cell transcription factor expression in term placentae indicates temporal regulation, and a so far unknown specific function. PMID- 26105900 TI - PP045. Different associations between phenotypes of preeclampsia and thrombophilias. AB - INTRODUCTION: Studies on the association of preeclampsia (PE) with thrombophilias (TRPH) are conflicting. Clinical heterogeneity of PE may be one of the explanations. OBJECTIVES: The present study addresses the question whether different phenotypes of PE are associated with subtypes of TRPH. METHODS: In this retrospective cohort study between 1985 until 2010 women with PE were offered postpartum screening for the following TRPH: anti-phospholipid antibodies (APA), APC-resistance, protein C deficiency and protein S deficiency (PSD), hyperhomocysteinemia (HCY), factor V Leiden and Prothrombin gene mutation. RESULTS: 890 Women with PE were screened for TRPH. 49% Also had HELLP, 60% had IUGR, 71% delivered before the 34th week. One or more TRPH factors were present in 31% of the women. Severe PE was associated with PSD (p=0.01). IUGR (p<0.01) was associated with APA (p<0.01) and PSD (P=0.03). Early onset PE was associated with APA (P, 0.01). More than 10% of placental infarction was associated with APA (p<0.01). Placental weight below the 5th percentile was associated with HCY (p=0.03). Other phenotypes of PE and TRPH were not associated. CONCLUSION: Severe and early onset PE, especially if complicated by IUGR, are associated with APA and PSD. Other phenotypes of PE, especially HELLP syndrome, were not associated with TRPH. We advise to screen for APA and PSD after severe and early onset PE, especially if complicated by IUGR. We do not recommend screening for TRPH in other phenotypes of PE. PMID- 26105901 TI - PP043. Oxidative stress in the maternal body also affects the fetus in preeclamptic women with fetal growth restriction. AB - The purpose of the present study was to determine whether oxidative stress occurring in the maternal body also affects the fetus in preeclamptic women with FGR. We ?@consecutively recruited 17 preeclamptic women with FGR, 16 preeclamptic women without FGR, and 16 healthy pregnant women with uncomplicated pregnancy. We measured concentrations of derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxygen free radicals in a maternal vein, umbilical artery, and umbilical vein. ?@Maternal d-ROM levels were higher in preeclamptic groups compared to the control group. Umbilical artery and vein d-ROM levels were elevated in preeclamptic women with FGR compared to the control group. Umbilical artery d-ROM levels were significantly higher than in the vein in preeclamptic women with FGR, but not in those without FGR. Umbilical arterial blood pH was significantly lower in preeclamptic women with FGR. The partial pressure of oxygen (PaO2) in umbilical arterial blood tended to be lower in preeclamptic women with FGR (p=0.08). The partial pressure of carbon dioxide (PaCO2) in umbilical arterial blood was significantly higher in preeclamptic women with FGR. These results indicate that oxidative stress occurring in the maternal body also affects the fetus in preeclamptic women with FGR. PMID- 26105902 TI - PP046. A unique urinary proteome profile at 15 weeks' gestation in low-risk women with subsequent pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia remains one of the leading causing of maternal and perinatal morbidity and mortality. Recent plasma biomarker discovery has improved the diagnosis of pre-eclampsia; however no factors which are quantitatively different remote from disease onset have been identified. Urine represents an ideal non-invasive fluid for analysis and potentially rich source of biomarker detection. Proteomics is a rapidly developing technique which allows the detection and identification of individual proteins. We propose that early glomerular changes will result in significant differences in the urinary proteome of women destined to develop pre-eclampsia, prior to detection of the clinical syndrome. OBJECTIVES: To define a urinary profile at 15 weeks' gestation, predictive of subsequent pre-eclampsia, in low risk nulliparous women. METHODS: Urine samples from twelve women at 15 weeks' gestation who subsequently developed pre-eclampsia (cases) and twelve gestation-, BMI- and age-matched controls were selected from the SCreening Of Pregnancy Endpoints (SCOPE) cohort. A proteome profile was established using a validated workflow, involving selective immunodepletion, 1D SDS-PAGE gel fractionation, in-gel digestion of gel sections, LC-MS/MS analysis and normalised spectral analysis. RESULTS: More than 900 proteins were identified using minimal stringency in Scaffold. Spectral counts revealed 24 proteins were significantly upregulated in cases and absent in controls and 3 proteins were absent in cases but present in controls. For protection of intellectual property protein identities are omitted. CONCLUSIONS: A urinary proteomic signature can be identified in the urine of women at 15 weeks' gestation who subsequently develop pre-eclampsia. Formal quantitative analysis will be performed with selective reactive-monitoring analysis, followed by subsequent validation of this differential proteomic profile using a larger number samples per groups. PMID- 26105903 TI - PP049. The arterio-venous ratio of retinal vessels in the first trimester as a predictor for preeclampsia. AB - INTRODUCTION: Retinal changes are known in severe preeclampsia (PE). This is the first study evaluating static retinal vessel analysis in pregnancy to measure retinal vessel diameter and in women destined to develop preeclampsia. METHODS: 51 non-pregnant controls (29+/-4 years) and 601 pregnant women (30+/-6 years) arterio-venous ratio (AVR) of retinal arterioles and venules was measured with Dynamic Vessel Analyzer in 1. (12.1+/-2.5 weeks; T1), 2. (22.6+/-2.3 weeks; T2), 3. (33.1+/-3.8 weeks; T3) trimester and postpartum (19.1+/-15.3 weeks; pp). RESULTS: 38 women developed gestational hypertension (GH), while 143 developed PE. AVR [mean+/-SD] in the PE-group (28+/-6 years) was lower (p<0,02) in T1, T2, and pp compared to 420 women who remained normotensive during pregnancy (T1: 0.80+/-0.06 vs. 0.9+/-0.08; T2: 0.86+/-0.06 vs. 0.9+/-0.11; T3: 0.88+/-0.09 vs. 0.89+/-0.1; pp: 0.83+/-0.08 vs. 0.87+/-0.1). Non-pregnant controls (0.86+/-0.1) as well as normotensive pregnancies did not show any differences in AVR-values when compared to those who developed GH later in pregnancy (T1: 0.42+/-0.20; T2: 0.35+/-0.18; T3: 0.49+/-0.09; pp: 0.44+/-0.19). With a defined cut-off value of <0.83 AVR in the first trimester we were able to predict PE with a positive predictive value of 43.2% and a sensitivity of 86%. CONCLUSION: AVR is lower in women susceptible for PE. These data are the first to provide evidence that microvascular changes of retinal vessels predate PE and even persist after delivery. PMID- 26105904 TI - PP047. Fetal gender specific differences in markers of placentation and maternal adaptation to pregnancy - The generation R study. AB - INTRODUCTION: Evidence indicates a gender specific interaction between the mother, placenta and fetus in which maternal adaptation to pregnancy and outcome partly depends on fetal gender. OBJECTIVES: This study assesses fetal gender specific differences in placental biomarkers and uteroplacental vascular resistance. Methods Within the Generation R Study, in 1st and 2nd trimester (median 13.3 and 20.4 wks) blood samples were drawn to assess soluble fms-like tyrosine kinase (s-Flt1), placental growth factor (PLGF) and plasminogen activator inhibitor 2 (PAI-2). Uteroplacental resistance was assessed by mean pulsatility index (PI) of the uterine and umbilical arteries in the 2nd trimester. Mann-Whitney U and Student's t-test were performed to assess associations of gender on the above mentioned factors. RESULTS: In total 8631 women were included (4274 female and 4357 male fetuses). From these women, 172 had a pregnancy complicated by pre-eclampsia (1.9%). Fetal sex related differences in placental biomarkers, being most pronounced in non pre-eclamptic pregnancies (Table 1). Differences were also observed between early (<34wks) and late onset pre-eclamptic women (>34wks). CONCLUSION: This study shows that maternal adaptation to pregnancy varies by fetal gender, suggesting gender specific differences in placentation and placental function. The differences between pre-eclamptic and non pre-eclamptic women, and among pre-eclamptic women, suggest that different mechanisms apply to pre-eclamptic pregnancies. PMID- 26105905 TI - PP048. Carotid intima-media-thickness in the first trimester as a predictor of preeclampsia. AB - INTRODUCTION: Carotid intima media thickness (IMT) is an established marker for endothelial dysfunction and cardiovascular risk. The aim of this study was to assess IMT in the first trimester and it's predictive value for preeclampsia. METHOD: We measured IMT on 51 non-pregnant controls (29+/-4 years) and 601 pregnant women (30+/-6 years) in the 1. (12.1+/-2.5 wks; T1), 2. (22.6+/-2.3 wks; T2), 3. (33.1+/-3.8 wks; T3) trimester, and postpartum (19.1+/-15.3 wks; pp) with high-resolution ultrasound. RESULTS: 38 pregnant women developed gestational hypertension (GH) and 143 preeclampsia (PE). IMT [mean (mm)+/-SD] of women who later developed PE (28+/-6 years) was significantly greater (p<0,03) at all visits compared to 420 women who remained normotensive during pregnancy (T1: 0.58+/-0.1 vs. 0.34+/-0.16; T2: 0,.3+/-0.1 vs. 0.34+/-0.1; T3: 0.49+/-0.09 vs. 0.34+/-0.13; pp: 0.56+/-0.31 vs. 0.39+/-0.14) and non-pregnant controls (0.44+/ 0.08). IMT of women who later developed GH was not different compared to normotensive pregnant and non-pregnant controls (T1: 0.42+/-0.20; T2: 0.35+/ 0.18; T3: 0.49+/-0.09; pp: 0.44+/-0.19). Using a cut-off value of >0.5 mm we would be able to predict PE already in the first trimester with a positive predictive value of 45.5 % and a sensitivity of 76.9 %. CONCLUSION: IMT is increased starting from first trimester onwards in women who later developed preeclampsia but not in women developing gestational hypertension. In high risk pregnancies measurement of IMT could represent an easy to use early detection method to predict preeclampsia noninvasively. PMID- 26105906 TI - PP050. NT-Pro-BNP: Correlation with adverse outcome markers in hypertensive gestational syndromes. AB - INTRODUCTION: Brain-type natriuretic peptide is released by cardiomyocites in response to parietal stress augmentation and systemic endothelial dysfunction. Hypertensive Gestational Syndromes (HGS) share this mechanism, but the correlation between NT-Pro-BNP and maternal/fetal outcomes is not yet clear enough. OBJECTIVES: Evaluate the correlation between NT-Pro-BNP in HGS and Normotensive Pregnant Women (NPW), with clinical and biological markers of adverse maternal/fetal outcome. METHODS: We performed a transversal case-control study to analyze NT-Pro-BNP and established markers in 87 patients with HGS and 95 NPW. RESULTS: The average gestational age at delivery (GAD) was: HGS 35.5 weeks, NPW 38.1 weeks; birth average weight (BAW): HGS 2616.2 gr, NPW 3281.6 gr; average maternal age (AMA): HGS 33.7 years, NPW 33.5 years; media NT-Pro-BNP (pg/ml): HGS 626.5, NPW 60.6. In the HGS media NT-Pro-BNP (pg/ml): HELLP 1342.3, Preeclampsia 686.7, Gestational hypertension 171.1, Chronic hypertension 108.5, the following significant correlations were found for NT-Pro-BNP relation to: Proteinuria p0.001, GOT p0.001, GPT p0.001, Platelets p0.001, Hematocrit p0.026,Uric acid p0.001, Alkaline phosphatase p0.001, LDH p0.001, GAD p0.004, BAW p0.010, AMA p0.042, cardiac failure p0.002, number of used anti-hypertensive drugs p0.004. CONCLUSIONS: NT-Pro-BNP significantly correlates with markers of adverse maternal/fetal outcome in HGS and identify a high risk subgroup in these Syndromes. PMID- 26105907 TI - PP052. Diagnosis of pre-eclampsia and prediction of time to delivery in women with suspected pre-eclampsia presenting before 36 weeks' gestation. AB - INTRODUCTION: The pro-angiogenic factor PlGF has an important role in the development and maintenance of the placenta. Incomplete remodelling of uterine spiral arteries is associated with placental oxidative stress, placental dysfunction, and the complications of pre-eclampsia and fetal growth restriction. Abnormally low PlGF levels identify placental dysfunction and an increased risk for pregnancy complication. OBJECTIVE: To evaluate the correlation between abnormally low PlGF concentration, a diagnosis of pre-eclampsia or IUGR, and a short interval to delivery. METHODS: We recruited a total of 45 pregnant women with suspected pre-eclampsia between 23+0 to 36+0 weeks of gestation. The concentration of PlGF was measured in maternal EDTA plasma samples (Alere, Triage(r) PlGF), a rapid assay using monoclonal antibodies raised against free PlGF. RESULTS: Pre-eclampsia was diagnosed clinically in 25 women. PlGF was abnormal (<100pg/mL) in all 25 women (100% sensitivity). Eighteen women (72%) had a PlGF level <12pg/mL (very abnormal) and, of these, 14 (78%) had IUGR and a birthweight below the 10th centile. The mean time to delivery in women with a PlGF level <12pg/mL was 7.5 days (0-18d), compared with 23 days (0-67d) for a PlGF level in the range ?12<100pg/mL, in agreement with data recently reported by Chappell [1]. CONCLUSION: The high sensitivity of PlGF for pre-eclampsia with/without IUGR and its strong prediction of time-to-delivery allows PlGF to be a valuable diagnostic tool. PlGF has the potential to remove the uncertainty in clinical decision-making in women with suspected pre-eclampsia. PMID- 26105908 TI - PP051. Budget impact analysis of maternal plasma PIGF concentrations in women with suspected pre-eclampsia: The potential for improved health service usage. AB - INTRODUCTION: Existing methods of assessing women with suspected pre-eclampsia are expensive and labour intensive, yet perform poorly. OBJECTIVES AND METHODS: The PELICAN multi-centre observational cohort study demonstrated that PlGF predicts need for delivery for pre-eclampsia within 14 days. We constructed a decision analytical model using outcome data from 100 women comparing resource use by final diagnosis and PlGF level. Costs were obtained from 2012-2013 NHS tariffs. RESULTS: Of the 100 women, 40 had a final diagnosis of pre-eclampsia and delivered within 14 days of the PlGF test; 10 were healthy pregnancies with normal PlGF levels. 82% of women with pre-eclampsia were admitted during the final 2 weeks of pregnancy, with a 5-day (SD=5) length of stay, compared with 30% of healthy pregnancies with normal PlGF (1 day; SD=0.58). Resource use for outpatient appointments, scans and day unit admissions was similar for the two groups although higher in the group with a final diagnosis of pre-eclampsia. Total costs, excluding delivery, were approximately a third higher in the pre eclampsia group. CONCLUSIONS: This interim analysis suggests pre-eclampsia is associated with significantly higher resource use, although there is some inappropriate resource use in healthy women. PlGF can assist diagnosis and identify women requiring increased care and could be used to direct appropriate resource allocation in women over 37 weeks. PMID- 26105909 TI - PP053. The role of peroxisome proliferator-activated receptor gamma co-activator 1-alpha in pregnancy. AB - INTRODUCTION: PGC-1alpha is a transcriptional co-activator that drives mitochondrial biogenesis in many tissues, including cardiac. PGC-1alpha is a powerful regulator of angiogenesis, a process of fundamental importance to the development of a healthy placenta in normal pregnancy. While the angiogenic role of PGC-1alpha has previously been described in the heart, its function and expression in the placenta is unknown. It may be possible that PGC-1alpha plays a key role in the imbalance of angiogenic factors observed in the pregnancy specific condition of pre-eclampsia. OBJECTIVES: To determine if PGC-1alpha is expressed in placental tissue and its implications for pathophysiological disorders of pregnancy. METHODS: Human placental samples were obtained from normal healthy pregnant women for processing and immunohistochemical analysis using an anti-PGC-1alpha rabbit polyclonal antibody. In addition, PGC-1alpha expression was examined in placental tissue from normal pregnant and reduced uterine perfusion pressure (RUPP) rats. RESULTS: Positive staining for PGC-1alpha was noted in both human and rat placental tissue with varying levels of expression. Staining appeared to be localised to the vascular endothelial cells, trophoblasts and syncytiotrophoblasts, with some minor staining in the maternal decidua and stroma. Moreover, intensity of staining for PGC-1alpha appeared reduced in placental tissue from RUPP rats. CONCLUSION: This study indicates that PGC-1alpha strongly localised to endothelial cells in both human and rat placental tissue. Furthermore, our data may implicate PGC-1alpha in the pathogenesis of pre-eclampsia, but further research is needed. Future studies could suggest the use of PGC-1alpha as a future drug target for treatment of complicated pregnancies. PMID- 26105910 TI - PP054. Elevated maternal plasma glycogen phosphorylase isoenzyme BB as time of disease biomarker of pre-eclampsia and small-for-gestational-age. AB - INTRODUCTION: Glycogen phosphorylase isoenzyme BB (GPBB) is a marker of acute coronary syndromes. Pre-eclampsia (PE) and coronary syndrome share several aetiological and pathophysiological features. GPBB levels have previously been found to be elevated in pregnancy and preterm PE. OBJECTIVES: We conducted 6 case control studies within the SCOPE Ireland cohort to investigate whether plasma GPBB levels are altered at time of disease presentation and to examine if GPBB has any power as a predictive biomarker at earlier gestations. Methods Blood samples were taken at time of presentation with PE (n=25) and SGA (n=23) and also at 15 and 20 weeks gestation for PE with no SGA (n=33), PE and SGA (n=18), SGA no PE with gestational hypertension (GH) (n=25) and no GH (n=25). All were matched to uncomplicated pregnancy controls. GPBB plasma concentration was measured with GPBB-ELISA kits (Diagenics, Germany). RESULTS: The plasma GPBB concentration at disease presentation with PE and SGA was significantly higher than in normal uncomplicated pregnancies. There was no difference in plasma GPBB levels at 15 or 20 weeks' gestation in women who subsequently developed PE or SGA compared with controls. CONCLUSION: Plasma GPBB is increased at time of presentation with PE and SGA suggesting that plasma GPBB is a biomarker of uteroplacental insufficiency. However, we found no evidence to support its use as an early pregnancy biomarker as it was not significantly elevated at 15 or 20 weeks' gestation. PMID- 26105911 TI - PP055. Uric acid correlates with uterine artery vascular resistance, but not with uterine artery pulsatility index. AB - INTRODUCTION: Studies indicate that uric acid is involved in the development of hypertensive diseases of pregnancy, and that uric acid might influence the remodeling of the spiral arteries. OBJECTIVE: To investigate the relationship with uric acid and utero-placental hemodynamics in the second half of pregnancy. METHODS: 53 women with uncomplicated pregnancies were examined longitudinally at 4-weekly intervals from 22 to 40 weeks of gestation. Blood samples for plasma uric acid were analyzed (enzymatic colorimetric method. INSTRUMENT: Modular P, Roche Diagnostic), and blood pressure (BP) was measured. Uterine artery Doppler velocity waveforms were obtained, and vessel diameter was measured bilaterally. Uterine artery volume blood flow (Quta) was calculated as the product of mean velocity and cross-sectional area of the vessel. Mean arterial pressure (MAP) was calculated as: diastolic BP+(systolic BP - diastolic BP)/3. Uterine artery resistance (Rquta) was calculated as: MAP/Quta. Uterine artery pulsatility index (UtaPI) was calculated as: (peak systolic velocity - end-diastolic velocity)/time averaged maximum velocity. Linear mixed models and linear regression models were used for statistical analysis. RESULTS: 242 blood samples were analyzed. Uric acid increased from 176 to 238MUmol/L. Rquta and UtaPI decreased from 0.26 to 0.13mmHg/ml/min and 0.8-0.6 respectively. Uric acid was significantly correlated to Rquta (p=0.005), but not to Uta PI (p=0.178). CONCLUSION: There is a strong association between uric acid and uterine artery vascular resistance during the second half of pregnancy indicating that uric acid might play a role in establishing low resistance blood flow in the uteroplacental compartment. PMID- 26105912 TI - PP056. Cardiac adaptation in the preclinical phase of recurrent preeclampsia in women with a history of early preeclampsia. AB - INTRODUCTION: Preeclampsia is thought to be preceded by first trimester circulatory maladaptation. Early and late onset PE may exhibit two different cardiac and hemodynamic states. Moreover, early PE relates to postpartum impaired cardiac function. Incomplete resolved or impaired cardiac function may influence the pattern of cardiac adaptation in the next pregnancy and may relate to recurrent disease. We postulate that in women with a history of early PE, the pattern of early cardiac adaptation differs between those that do and those that do not develop recurrent disease. OBJECTIVES: We hypothesize that after early onset PE, in the subsequent gestation, the pattern of cardiac adaptation differs between those that do and those that do not develop recurrent disease. METHODS: In this cohort study, we included 84 women with a history of early-onset PE. Former PE patients who concomitantly experienced HELLP-syndrome, fetal growth restriction and/or fetal demise, were excluded. The remaining 51 women underwent serial cardiac ultrasound and automated blood pressure and heart rate recordings, once before, and again at gestational age 12, 16 and 20 weeks. Post hoc, women were subdivided into those who did (RECUR) or did not develop recurrent PE (CONTR). We analyzed data using repeated measures analysis of variance. RESULTS: 14/51 (27%) women developed recurrent PE. Pre-pregnant heart rate was higher (71 vs 64 bpm, p<0.05) and stroke volume lower (68 vs 77mL, p<0.05) in RECUR as compared to CONTR. Even though LVM index was consistently lower in the RECUR group, the two subgroups responded to the next pregnancy with a comparable pattern of cardiac adaptation. CONCLUSION: Despite consistently lower LVM and SV and higher HR, after early onset PE, the pattern of subsequent early pregnancy cardiac adaptation is comparable in those that do and do not develop recurrent disease. PMID- 26105913 TI - PP058. Cradle: Community blood pressure monitoring in rural Africa: Detection of underlying pre-eclampsia. AB - INTRODUCTION: In many developing countries pre-eclampsia is under-detected partly due to inadequate training in accurate blood pressure (BP) measurements and insufficient, poorly functioning equipment. OBJECTIVE: To evaluate whether the introduction of easy to use, low cost novel BP devices (Microlife 3AS1-2; designed by our research group specifically for use in developing countries and validated in pregnancy (B/A grade) according to BHS criteria) into rural clinics in Tanzania, Zimbabwe and Zambia increases referrals for suspected pre-eclampsia to a central referral hospital (as reflected by an increase in mean BP in pregnant women seen in the central referral site). METHODS: International prospective longitudinal pre- and post-intervention pilot study. BP measurements were taken from consecutive women ?20 weeks' gestation who accessed care at a referral site (N=694). 20 BP devices were distributed to 20 rural antenatal clinics in each country. Post-intervention data was collected the following year (N=547). RESULTS: After adjustment for confounders, there was a significant increase in primary outcome; post-intervention mean diastolic BP for all women (2.39mmHg, p<0.001, 95% CI 0.97-3.8), implying an increased proportion of referred hypertensive women; and a reduction in proportion of women (median gestation 35 weeks') who had never previously had a BP taken in pregnancy (25.1% to 16.9%, OR 0.58, p=0.001, CI 0.42-0.79). CONCLUSION: Equipping community healthcare providers with this novel validated BP device is feasible, widely accepted and results in increased referrals for suspected pre-eclampsia. A cluster RCT to evaluate the effect of these monitors equipped with a traffic light 'early warning system' is planned. PMID- 26105914 TI - PP057. ENOSI4 and EPHX1 polymorphisms affect maternal susceptibility topreeclampsia - Analysis of five polymorphisms predisposing tocardiovascular disease in 279 caucasian and 241 african women. AB - OBJECTIVES: Clinical studies have documented a familiar tendency to develop preeclampsia and patients with impaired endothelial health are at increased risk. We studied genetic polymorphisms associated to cardiovascular disease and impaired endothelial function in women with and without preeclampsia. METHODS: 241 African and 279 Caucasian women were recruited for genetic testing of the polymorphisms epoxide hydrolase 1 (EPXH1), endothelial nitric oxide synthase (NOS3) on exon 7 and variable nucleotide tandem repeats in intron 4 (NOS3I4a/b), angiotensinogen and the estrogen receptor1 polymorphism in intron 1. RESULTS: Of 241 African women, 95 developed preeclampsia and out of the 279 Caucasian women 81 had preeclampsia. Carriers of the NOS3I4a/b polymorphism had a 1.7-fold increased risk to develop preeclampsia. There was no difference in distribution of the other tested polymorphism. Furthermore we could show a fourfold reduction to encounter severe course of preeclampsia (defined as occurrence of HELLP syndrome or eclampsia) in carriers of the EPHX1 polymorphism encoding histidine. CONCLUSIONS: Our data reveal a highly significant association of the NOS3I4a/b polymorphism with increased risk to develop preeclampsia in pregnancy. The shown association of EPXH1 polymorphism with the severity of preeclampsia strengthen the concept, that individual susceptibility determines the capability of the maternal organism to deal with the pregnancy derived agents causing preeclampsia. PMID- 26105915 TI - PP059. Characteristics of body inflammatory reaction during the implementation of differentiated therapy of preeclampsia in perioperative care. AB - OBJECTIVES: To learn features of the electrolyte balanced starch solution of Tetraspan in comparison with standard starch solutions in therapy of preeclampsia. The advantages of Tetraspan (B Braun(r)) application were the composition, which is due to electrolyte composition near to blood plasma absence of negative influence on kidneys and on curtailing system of blood. MATERIAL AND METHODS: 220 puerperal women with preeclampsia after cesarean section were investigated. They were divided into two groups: In the basic group n=110, the composition of infusion therapy included Tetraspan, in comparison group n=110 one of the well known hydroxyethylstarch solution. The control group include puerperal women (n=100) without preeclampsia infusion therapy of this group did not include starch solutions. Efficiency of therapy was estimated on a clinical picture, body fluid's sectors examination in dynamics and cytokine profile (proinflammatory IL1a, IL 6 and anti-inflammatory IL 10) immunological examination. Inspections were spent on 1st and 5th days after Cesarean section. RESULTS: The cytokines profile: the 1st day in the basic group: IL1 a-124+/-13.1, IL 6 - 56.2+/-19.1, IL 10 62+/-11. At 5th day: IL1 a 109+/-13.5, IL 6 - 41.6+/ 17.3, IL 10 52+/-13. At comparison group -1st day: IL1 a-123+/-10.9, IL 6 - 51.3+/-28.2, IL1 a 10 63.4+/-14.1. At 5th day: IL1 a 112+/-24, IL 6 - 47+/-26.3, IL 10 61+/-18.4. CONTROL GROUP: At 1st day: IL1 a -82+/-15.2, IL 6 - 33.3+/-21.1, IL10 98.7+/-13.6. At 5th day: IL1 a - 114+/-12.6, IL 6 - 27.1+/-18.3, IL 10 - 64.9+/-12.6. CONCLUSION: The cytokines dynamic profile examination from the first to fifth day in basic group (in comparison with the second group) shows timely minimization of proinflammatory cytokines level and increase of the anti inflammatory cytokines, which has good prognostic indication in recovery period. Modeling influence of Tetraspan at the inflammatory answer provides early decrease of proinflammatory and increase of anti-inflammatory markers level. Thus, on the basis of clinical and laboratory inspection results proved the efficiency of Tetraspan and recommends to apply this electrolyte balanced starch solution in perioperative therapy of average and heavy preeclampsia. PMID- 26105916 TI - PP063. Carotid artery stiffness and elasticity in gestational diabetes. AB - INTRODUCTION: Gestational diabetes (GMD) is gaining in importance in prenatal care due to it's increasing prevalence. These women do have a higher risk for disrupted elasticity and stiffening of the carotid artery. Aim of this study was to assess carotid intima media thickness (IMT) and vessel wall changes during pregnancy and postpartum. METHODS: IMT and vessel wall parameters of the carotid artery were evaluated with high resolution ultrasound during pregnancy and postpartum on 84 women with gestational diabetes and 106 gestational age matched controls. RESULTS: Carotid elasticity (mean (%)+/-SD) was significantly lower in women with GDM than healthy pregnant women (9.48 (103/kPa)+/-3.21 vs. 11.01+/ 3.17, p<0.047), whereas blood pressure independent beta-stiffness (mean+/-SD) was significantly increased in women with GDM (6.08+/-3.15 vs. 4.68+/-1.57; p=0.007). Pregnancies complicated by GDM had higher mean arterial pressure then matched controls (93+/-12 vs. 86+/-10mmHg, p<0.015). Postpartum, both groups did not show any significant changes. CONCLUSION: Carotid stiffening and rigidity is present in gestational diabetes mellitus during pregnancy and shows postpartal recovery. Therefore GDM dependent vessel wall changes seem to be only temporary and not pre existing. PMID- 26105917 TI - PP062. Characteristic changes of systemic blood pressure in eclampsia. AB - AIM: It was found that eclampsia might be caused by vasogenic edema of brain as the results of breaking autoregulation of cerebral blood flow due to possibly the systemic increase in blood pressure (BP). In the present study, we investigated characteristic changes of systemic BP just after the onset of eclampsia. METHOD: Four eclamptic women during pregnancy were participated. Two had labor pains. Two were given anti-hypertensive drugs due to severe hypertension. BP in both systolic and diastolic, and mean arterial pressure (MAP), before and after onset of eclampsia were evaluated. RESULT: Basal BP in systolic, diastolic and MAP before eclampsia were 132+/-13, 79+/-24, 90+/-20mmHg. Maximum BP in systolic, diastolic and MAP before eclampsia were 172+/-10, 96+/-13 and 121+/-10mmHg. BP in systolic, diastolic and MAP after eclampsia were 124+/-23, 74+/-14 and 91+/ 12mmHg. An increase in MAP was 24+/-11mmHg before eclampsia, while a decrease was 31+/-2mmHg after onset of eclampsia. CONCLUSION: In eclampsia, an increase in BP was seen just before eclampsia, while a severe decrease in BP (more than 30mmHg of MAP) was seen after it. PMID- 26105918 TI - PP065. Assessment of total vascular resistance and total body water in normotensive women during the first trimester of pregnancy in order to predict hypertensive complications. AB - INTRODUCTION: In pregnancy there is an increase in maternal cardiac output (CO) and a reduction in total vascular resistance (TVR). Abnormalities of this adaptive mechanisms lead to numerous disorders of pregnancy. Moreover the mother's body water composition undergoes important modifications in total body water (TBW), extracellular and intracellular body water (EBW, IBW). OBJECTIVES: Aim of the study is to identify a group of patients at high risk of developing hypertensive complications of pregnancy in frist trimester. METHOD: To investigate hemodynamic changes and distribution of body water during the frist trimester of pregnancy, we conducted an observational study. We evaluated CO, TVR and Time Flow Corrected (TFc) with the USCOM system, a non invasive method. Patients were, also, subjected to BIA (Body Impedance Assessment). RESULTS: We enrolled 120 healthy pregnant women. 20 patients, were excluded for bad signal. Absolute values of haemodynamic and body impedance measures are shown in Fig. 1. Patients were divided in two groups:Group A with TVR>1200 dyne and Group B with TVR<1200 dyne. CO values were higher in group B. There wasn't significant differences in TBW, haematocrit, TFc and WBI (water balance index: TBW/Hct) between the two groups. CONCLUSION: Our results show that at costant values of TBW, Hct and WBI,we can find difference in term of TVR and CO in the first trimester of pregnancy. These parameters may improve the accuracy of screening in clinical practice. PMID- 26105919 TI - PP064. Total vascular resistances in early pregnancy: A key to understand abnormal cardiovascular adaptation associated with spontaneous abortion. AB - INTRODUCTION: From early pregnancy, maternal hemodynamic profile begins to change. The absence of these changes leads to increased risk of complication during the gestation. OBJECTIVES: Aim of this study is to understand in early pregnancy the behaviour of total vascular resistances (TVR) as a sign of maternal cardiovascular adaptation to pregnancy. METHOD: A cross section study was conducted. We followed 160 healthy women with singleton pregnancy during the first trimester of gestation. We evaluated cardiac output (CO) and TVR at 7, 9 and 11 weeks of gestation. We obtained the following haemodynamic measurements with the USCOM system, a non invasive method: heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), CO and TVR. RESULTS: 160 healthy pregnant women were selected, 8 patients, were excluded for a bad signal. Absolute values of the haemodynamic measures are shown in Fig. 1. 41 patients underwent spontaneous embryonic demise. This last group of patients showed in 54% (group A) TVR values within the normal limits (TVR<1200), while 46% patients (group B) showed TVR values well above the normal limits (TVR>1200) and CO values below the normal adaptation to pregnancy. Table 1 shows hemodynamic measures for the group A and group B; we found differences in term of CO, TVR and PAS between the two groups. CONCLUSION: Elevated TVR might indicate an abnormal vascular adaptation already in first weeks of pregnancy. Moreover, in women who undergo to abortion, elevated TVR could be use to distinguish genetic or environmental causes of miscarriage. PMID- 26105920 TI - PP066. Withdrawn. PMID- 26105921 TI - PP068. Evaluation of cardiovascular health in previously preeclamptic women. AB - INTRODUCTION: Women with a history of preeclampsia have an increased risk of developing cardiovascular disease (CVD) later in life. Classical risk scores are not suitable as risk estimates of CVD in this young population. Recent recommendations from the American Heart Association are aimed to improve cardiovascular health (CVH). OBJECTIVES: Examining CVH by Health Life Check (HLC) (http://mylifecheck.heart.org/) in previously severe preeclamptic women is part of our cardiovascular risk follow-up program. Final score is a scale from 1 to 10, where 10 represents ideal CVH. RESULTS: Since 2011 HLC is offered to all women in this program. So far, 213 women were included, 148 (70%) underwent a CVH assessment by performing HLC between three months and one year after delivery. The overall HLC score was 7.4 (median; range: 0.8-10.0) at 3.6 months after the delivery. Only 2 out of 148 women (1.4%) had an ideal score. HLC score was 7.1 (median; range: 0.8-10.0) for 48 women who had a HLC score within 6 months after delivery versus 8.2 (median; range: 2.6-9.8) in the second half of the first year after delivery. CONCLUSION: These are the first data on CVH in women after severe preeclampsia. Only 1.4% of these women had an ideal score. Active counselling of these women could be the reason of the improved score over time. We showed that CVH as assessed by HLC is an excellent tool for cardiovascular risk management in this specific group of women. PMID- 26105922 TI - PP067. Third trimester prediction of late PE. AB - INTRODUCTION: It is well known that a multiparametric model including epidemiological maternal factors, uterine Doppler and biochemical parameters could be useful at 1st and 2nd Trimester for the prediction of early PE (<34 weeks of gestation) but less accurate for late PE (?34 weeks of gestation). Different physiopathologies have been suggested for these two entities. A new approach based in a 3rd trimester screening has been suggested for the predicton of late PE. OBJECTIVES: To define the prediction capacity of maternal characteristics at 3rd trimester for late PE. MATERIAL AND METHODS: 4724 pregnancies followed up and delivered in our centre from July 2010 to December 2012 were included in a cross sectional study. Out of these, 59 cases developed a late preeclampsia (1.2%). Controls were gestations with no diagnosis of PE nor gestational hypertension. All patients made a 3rd trimester visit at 31-33 weeks, where systolic and diastolic blood pressure and the absolute weight gain since the beginning of pregnancy were measured. Parity, maternal age and body mass index at the beginning of the pregnancy were also recorded. A multivariate logistic regression analysis was made to define the predictive capacity of these variables for late PE. RESULTS: MAP was significantly higher in those patients who developped PE (78.8 vs 88.8 mmHg, p<0.05). Although cases had a higher BMI at first visit ( BMI 25.9 vs 23, p<0.05), the total weight gain during pregnancy up to the 3rd trimester was similar among groups (9.3 vs 10.3kg, p>0.05). The mean GA at delivery of cases was 38 (range 35-41 weeks) and of controls 39.1 (range 34 42 weeks). In a multivariate logistic regression analysis, MAP and BMI were independent and significant predictors of late PE at 3rd Trimester. The model including BMI and MAP has an AUC of 0.76 (0.683-0.837). CONCLUSIONS: A 3rd trimester screening could be useful in the prediction of late-onset PE. PMID- 26105923 TI - PP069. Hypertension evaluated by 24-hour ambulatory blood pressure measurements in previously preeclamptic women one year postpartum. AB - INTRODUCTION: Women with a history of preeclampsia have an increased risk of developing cardiovascular disease (CVD) later in life. 24-hour ambulatory blood pressure measurement is considered to be the gold-standard for diagnosing hypertension. Data on 24-hour ambulatory blood pressure measurement in women with a history of preeclampsia are scarce. OBJECTIVES: To evaluate hypertension in previously severe preeclamptic women, 24-hour ambulatory blood pressure measurements were performed one year after delivery as part of our cardiovascular risk follow-up program. RESULTS: Since 2011 213 women were included in this program. 24-hour ambulatory blood pressure measurement was performed in 90 out of 121 women (74%) who completed follow-up one year after delivery. Systolic blood pressure was 121 mm Hg (median; range 96-157) and diastolic blood pressure 78mm Hg (median; range 62-114). Twenty-three women (26.0%) used antihypertensive medication one year postpartum. Blood pressure levels were not significantly different between women with and without medication. Five women (5/67, 7.5%) of those not using antihypertensives, were diagnosed as having hypertension by this measurement. CONCLUSION: These data show that 30% of these previously severe preeclamptic women have persisting hypertension one year postpartum. These data stress the importance of close monitoring of blood pressure in these women. PMID- 26105924 TI - PP070. Maternal cardiovascular profiling in the first trimester ofpregnancies complicated with gestation induced hypertension or fetal growth restriction. AB - INTRODUCTION: Maternal cardiovascular (CV) profiling is useful in the assessment of gestational hypertensive disorders (GHD)(1). The onset of GHD occurs during the first weeks of gestation(2). OBJECTIVE: To evaluate whether CV profiling can detect first trimester differences between women with uncomplicated pregnancies (UP) and those who will develop GHD or fetal growth restriction (FGR). METHODS: CV function was evaluated according to standardised protocols in 242 pregnant women around 12 weeks of gestation, using impedance cardiography (ICG) and combined ECG - Doppler ultrasonography. Outcome was evaluated after delivery and categorized as UP (n=218), GHD with or without proteinuria (n=13), and pregnancies complicated with FGR (n=11). Measurements were compared between groups using Mann-Whitney U test for continuous data or Fisher's Exact test for categorical variables. RESULTS: As compared to UP, women destined to develop GHD showed increased systolic blood pressure, diastolic blood pressure and mean arterial pressure; and decreased ICG aortic velocity - and acceleration index. Pregnancies complicated with FGR showed decreased stroke volume and cardiac output when compared to UP. No differences were found concerning the maternal veins. CONCLUSION: First trimester maternal CV function differs between women with uncomplicated pregnancies and those destined to develop GHD or FGR. Non invasive CV profiling enables the identification of these differences. PMID- 26105925 TI - PP071. suPAR levels in normal- and preeclamptic pregnancies. AB - INTRODUCTION: Preeclampsia (PE) has been considered to be a maternal inflammatory response to pregnancy and may be hazardous for mother and child. Soluble urokinase Plasminogen Activator receptor (suPAR) is a non-specific marker that reflects overall systemic inflammation and immune activation. OBJECTIVES: We examined the levels of suPAR in first and third trimesters of normal- and preeclamptic pregnancies. METHODS: Two clinical studies were conducted. The first study included 43 women who subsequently developed PE and 86 control women not developing PE. Blood samples were collected during the first trimester. The two groups were matched with respect to gestational age. In the second study, 13 cases of PE and 8 controls were enrolled and blood samples were collected during the third trimester. Serum suPAR were analyzed by the commercially availably suPARnostic(r) assay kit (ELISA, Virogates, Copenhagen, Denmark). RESULTS: There were no significant differences in first trimester suPAR level between women who subsequently developed PE and those who completed a normal pregnancy (4.5 [3.7 5.4] ng/mL versus 4.3 [3.8-5.0] ng/mL, p=0.49, median [interquartile range]). In the third trimester, suPAR levels were significantly elevated in the preeclamptic group compared to the control group (2.5 [2.2-3.5] ng/mL versus 1.9 [1.5-2.1] ng/mL, p=0.008). After adjustment for gestational age (38.6 (0.7) and 31 (3.1) weeks in the control- and the PE-group respectively, p<0.001, mean (SD)), the group difference did not remain statistically significant (p=0.064). CONCLUSION: suPAR is not a suitable marker for detecting the systemic maternal inflammatory response in women with established PE nor a useful pre-clinical marker of the disorder. The observation of the higher suPAR level in first trimester of pregnancy compared to third trimester suPAR level alludes to a possible physiological function that needs to be clarified. PMID- 26105926 TI - PP072. Development of polyphenols-containing nanoparticles for the treatment of vaginal inflammation. AB - INTRODUCTION: Vaginal inflammation during pregnancy is linked to miscarriage, preterm labour, placental dysfunction and perinatal complications. Despite the availability of several anti-inflammatory drugs, there is no general consensus regarding safe formulation especially for use in early pregnancy. On the other hand, polyphenols especially "curcumin" from Turmeric (powdered rhizome of Curcuma longa) and "catechins" from green tea have been traditionally used and widely discussed (>16,000 citations for curcumin and >24,000 for catechin in SciFinder) as pharmacologically active anti-inflammatory components and considered as safe. However, due to their poor solubility, low bioavailability and stability, their clinical application remains to be limited. OBJECTIVES: Our aim was to develop a non-teratogenic and non-toxic polyphenol-bearing nanoparticles which can be safely used in early pregnancy for the treatment of vaginal inflammation. METHODS: Vesicle-based liposomal formulations for polyphenols (curcumins and catechins) were developed and standardized. Liposomal curcumins and catechins were characterized in respect to their stability, size and entrapment efficiency. Antioxidant activities were evaluated by DPPH/ABTS+/O2.- and SOD activities. Anti-inflammatory activities were evaluated by measuring LPS-induced NO and pro-inflammatory cytokines such as IL-1B and TNF A in macrophages (J774.1) and LPG-induced cytokines IL-8 in human vaginal cells lines (End1/E6E7, Ect1/E6E7, VK2/E6E7). Antioxidant and anti-inflammatory activities of curcumin/catechin and their corresponding vesicle-based formulation were compared. RESULTS: Phospholipid-based nanoparticles (approx. 200 nm) were found to be stable and incorporating high amount of curcumins or catechins. Liposomal curcumin was found to be 2- to 6-folds more potent than curcumin in inhibiting NO production and pro-inflammatory cytokines in macrophages. IL-8 was inhibited up to 67% by the liposomal curcumin in human vaginal cell lines (End1/E6E7, Ect1/E6E7, VK2/E6E7) as compared to curcumin. However, similar vesicle formulations of catechins were not significantly superior to non-vesicle formulations of catechins. CONCLUSION: Standardized liposomal curcuminoids have potential as an effective and safe topical formulation for the treatment of vaginal inflammation in early pregnancy. PMID- 26105927 TI - PP073. The diagnostics potential of integral rheography during the dynamic examination of body fluid sectors at puerperal women with preeclampsia. AB - OBJECTIVES: correction of infusion intravenous therapy to avoid body hyperhydration during the infusion therapy by estimating body's water sectors condition at puerperal women with preeclampsia, which were delivered by caesarian section and received infusion intravenous therapy. MATERIAL AND METHODS: 220 women with average and severe preeclampsia were analyzed. Due to the infusion therapy composition women were divided into 2 groups: 1- the basic group (n=110) in which the infusion solution was new hydroxyethylstarch solution (Tetraspan), which consist of starch at isooncotic solution, which electrolyte structure is similar to blood plasma and contains Na, K, Cl, Mg, Ca ions, also malats and lactats. At the 2-nd (n=110), the comparison group, we applied the standart hydrocyethylstarch solutions, starch in physiologic saline. So during the application of Tetraspan, our attention was focused on its isoionic structure, that excludes negative influence on kidneys and is the unique balanced solution for hypovolemia elimination. The third group of puerperal women - control group (n=100) includes puerperal women without preeclampsia, after Cesarean section due to other indications. The infusion therapy in this group did not include hydroxyethylstarch solution. Water sectors were investigated by integral dual frequency impedometry, method which integrated two-frequency impedometry defining volumes of liquid sectors of an organism (the general, extracellular - intravascular and intersitial, endocellular) and equilibration of liquids between sectors in time dynamic with <> rheography apparatus. Body liquid sectors were examined at first day and fifth day after C-section. RESULTS: At first day after delivery in the basic group (n=110): the evident increase of the extracellular liquid's volume revealed at 59 women (53.6%), tempered increase of the extracellular liquid at 43 women (39%) and normal values of fluid sectors conditions were observed at 8 women (7.3%). In second group (n=110): at 57 (51.8%) the evident increase of the extracellular liquid's volume was revealed; at 46 (41.8%) - tempered increase and normal results were observed in 7 (6.4%) puerperal women. In control group (n=100) it was not marked the significant changes in water sectors. On 5 days in first group (n=110) it was revealed: evident at 12 (10.9%), tempered increases at 51 (46.3%), normal indicators at 47 (42.7%). In comparison group (n=110): the evident increase of extracellular liquid was revealed in 20 (18%), tempered in 59 (53.6%), normal at 31 (28%) women. At control group (n=100) the delivered results mainly shows practically up to normal values of body liquid's sector was defined. CONCLUSION: The results analysis shows that at heavy preeclampsia the body liquids sectors normalization occurs gradually from evident to temper and then becomes normal and this adaptation depends of the infusion therapy composition. As it comes from the basic group, where at fifth day the amount of patients with temper and normal values of extracellular water appreciably increased, in comparison with the 2nd group where the normalization of liquid's sectors occurs but the process is more torpid, not as exponential as the 1st group results shows. The normalization of body hyper hydration in 1st group where Tetraspan was applied is going more optimal that is probably connected with optimal correction of hypovolemy up to the balanced structure and the improved bioavailability of Tetraspan. The growth of women with temper hyper hydration amount at 5th day in first and in second groups, occur due to the infusion therapy and liquidation of the evident hyper hydration. As the research shows the technique for diagnosis of body liquid sectors, being noninvasive and accessible, is either informative, gives the opportunity to supervise the quantity and efficiency of the infusion therapy. PMID- 26105928 TI - PP075. Poor renal function following hypertensive pregnancy: Older mothers and smaller babies. AB - INTRODUCTION: There is increasing evidence that hypertensive pregnancy is a risk factor for renal disease [1]. OBJECTIVES: To examine the correlation between maternal and offspring characteristics and impaired glomerular filtration rate following a hypertensive pregnancy. METHOD: We calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula corrected for body surface area in a cohort of 422 women at 6 weeks following a pregnancy complicated by all types of hypertension (pre-eclampsia, gestational hypertension, essential hypertension with and without superimposed pre eclampsia). We performed statistical analysis using Spearmans rho to examine for correlations with maternal and fetal characteristics. RESULTS: 2.1% women had poor renal function at 6 weeks after delivery with a GFR <60ml/min/1.73m(2). Older mothers were more likely to have a lower GFR (p=0.001). Women with poor renal function at 6 weeks were more likely to have had a low birth weight baby (p=0.002). The median birth weight for women with GFR<60ml/min/1.73m(2) was 2.85kg as opposed to 3.23kg for women with a GFR >60ml/min/1.73m(2). CONCLUSIONS: Clinically significant renal impairment following a hypertensive pregnancy is a rare. Advancing maternal age represents an important risk factor for on-going renal disease in this population. Small babies are more likely in a hypertensive pregnancy [2] and may also represent a marker for poorer maternal health after birth in this population. PMID- 26105929 TI - PP074. Persistent proteinuria after a pre-eclamptic pregnancy. AB - INTRODUCTION: There is increasing evidence to suggest that both preeclampsia and microalbuminuria are linked to long term cardiovascular and renal disease [1,2]. OBJECTIVES: To identify the proportion and characteristics of women with persistent significant proteinuria at 6 weeks following delivery. METHOD: We examined the blood pressure, serum electrolytes and urine protein creatinine ratio (PCR) in a cohort of 219 women who were seen following a pre-eclamptic pregnancy in a postnatal clinic at a minimum of 6 weeks following delivery. RESULTS: A PCR>50mg/mmol (considered to be clinically significant) was seen in 4.1% women at 6 weeks after delivery. Women with a higher antenatal PCR were more likely to have a PCR>50mg/mmol at 6 weeks postnatal (p=0.003). Antenatal or postnatal blood pressure was not correlated with persistent significant proteinuria. Neither estimated nor calculated glomerular filtration rate (eGFR) at 6 weeks correlated with those having persistent proteinuria, however there was a trend towards lower eGFR and higher serum creatinine antenatally in this group (p=0.138 and p=0.088). CONCLUSION: There are a small but worrying number of women who still have clinically significant proteinuria at 6 weeks after a pre eclamptic pregnancy. This represents a group of women who may have a higher risk of cardiovascular and renal disease. PMID- 26105930 TI - PP077. New prognostic marker for the risk to develop early-onset preeclampsia. AB - INTRODUCTION: ESM-1 plays a role in the regulation of angiogenesis and is released by activated endothelial cells. OBJECTIVE: To test the hypothesized that ESM-1 is increased in preeclampsia (PE). METHODS: Plasma samples from high risk pregnancies divided in 23 healthy (CON), 11 severe early-onset PE (SE) and 7 severe late-onset PE (SL) pregnancies were collected at regular intervals between week 12 and birth. ESM-1 was measured by ELISA. RESULTS: (see figure) Between GA week 24 and birth, ESM-1 concentrations were significantly increased in both early and late preeclampsia compared to controls (Mann Whitney, p<0.05). Surprisingly, the concentration of ESM-1 also differed between the three groups at weeks 12 and 16. The ESM-1 concentration of healthy pregnancies (mean+/ SEM:1857+/-861pg/ml) and those that developed severe late-onset PE (1298+/ 371pg/ml) are comparable, but in those pregnancies that develop severe early onset PE, the concentration (410+/-355pg/ml) is significantly lower as compared with healthy pregnancies. CONCLUSIONS: ESM-1 concentrations are increased during early and late severe preeclampsia, which may be due to endothelial cell activation in these conditions. Interestingly, since ESM-1 is decreased at 12-16 weeks in patients that later on develop early onset severe PE, it might be a prognostic marker which can determine the risk of women to develop severe early onset PE already as early as 12 to 16 weeks of gestation. PMID- 26105931 TI - PP076. Gender differences in fetal growth and fetal-placental ratio in preeclamptic and normal pregnancies. AB - INTRODUCTION: Boys have higher morbidity and mortality than girls,particularly when born prematurely, despite higher birthweight. Adaptation to poor intrauterine environment by reducing fetal growth is more prevalent in female than male fetuses. Differences in reponses between the genders might be mediated by placental functions, as illustrated by the fetal-placental ratio. OBJECTIVES: To study the fetal-placental ratio in normal and preeclamptic pregnancies and compare this ratio in boys and girls. METHODS: The STORK study (n=1031) is a prospective, longitudinal study of fetal growth. We calculated fetal-placental ratio for boys and girls in normal and preeclamptic pregnancies. Differences between groups were analysed by independent t-tests. RESULTS: Boys had a higher fetal-placental ratio than girls (5.26 vs 5.1 g, p=0.015) in normal pregnancies. 39 women (3.8%) developed preeclampsia. Boys had the same ratio in both groups. Girls in preeclamptic pregnancies had a lower ratio than in normal pregnancies (4.5 vs 5.1 g, p=0.05). CONCLUSION: Boys appear to invest more in their own growth than in placental growth. In preeclampsia they maintain the same fetal placental ratio. In girls, birthweight is lower whereas placental weight is maintained, giving a reduced fetal-placental ratio. This pattern is more pronounced in preeclampsia. #Birthweight according to gestational age * corrected for gestational age. PMID- 26105932 TI - PP079. Ovarian reserve and function is preserved following severe preeclampsia. AB - INTRODUCTION: Preeclampsia is a multi-organ disorder that predominantly affects renal, cardiovascular, and endocrine systems with long-term consequences for the women's health. As advanced age and history of subfertility increase the risk of developing preeclampsia, reduced ovarian reserve may be associated with preeclampsia. However, long-term effect of preeclampsia on the ovarian function and reserve is not known. We hypothesized that the ovarian reserve and function are reduced in women with a previous history of severe preeclampsia. OBJECTIVE: To compare the plasma levels of markers of ovarian function (FSH, LH, SHBG, testosterone) and reserve (anti-Mullerian hormone, AMH) in women who previously had preeclampsia with their matched controls. METHOD: Twenty women who had severe preeclampsia (PE group) requiring delivery before 36 weeks of gestation and 20 controls were matched for age, parity, height and weight were included in the study. Women were not breast-feeding, they were having regular menstrual periods and were not using any hormonal contraception. Fasting blood samples were taken during the follicular phase. Plasma was separated and frozen at -70 degrees until analyzed. Comparison between groups was performed using paired sample t-test for parametric and Wilcoxon T-test for nonparametric data. A two-tailed p-value <0.05 was considered significant. RESULTS: The mean age was 36.4 years, height 164cm and weight 72kg in PE group, compared to 37.0 years, 165cm and 69kg, respectively in control group. The mean AMH was 1.34ng/mL in PE group compared to 1.55ng/mL in controls (p=NS). No significant differences were found in the levels of LH (6.72 versus 6.53 IU/L), FSH (5.27 versus 7.16 IU/L), LH/FSH ratio (1.39 versus 1.11), SHBG (63.65 versus 52.90 versus 52.90nmol/L), and testosterone (0.72 versus 1.01nmol/L) between groups. CONCLUSION: Ovarian reserve and function is not altered significantly in women with a previous history of preeclampsia. PMID- 26105933 TI - PP078. The influence of maternal position on gestational hemodynamics. AB - INTRODUCTION: Cardiovascular profiling is useful for gestational hemodynamic studies. Conflicting results of cardiac output evolution from third trimester pregnancy to term are frequently reported. OBJECTIVES: To stress the effect of maternal position in the assessment of maternal cardiac and arterial parameters during normal pregnancy. METHODS: Impedance cardiography measurements were executed during 16 normal pregnancies using a standard protocol with known reproducibility. Gestational evolution of stroke volume, cardiac output, cardiac cycle time intervals, aortic flow parameters and total peripheral vascular resistance was measured in supine, standing and sitting positions. SAS procedure MIXED for linear mixed models was used for each parameter separately. RESULTS: Evolution of stroke volume and cardiac output in supine position differed from standing (p<0.01) and sitting positions (p<0.05). Next to this, pre-ejection period, left ventricular ejection time index, systolic time ratio and total peripheral vascular resistance also showed a different evolution between supine and standing positions (p<0.05); no differences were observed between standing and sitting positions (p?0.19). CONCLUSION: Next to the frequently reported cardiac output, gestational evolutions of other pre-load dependent parameters are influenced by maternal position. This study shows the importance of a standardized protocol for the measurement of cardiovascular parameters in pregnancy. PMID- 26105934 TI - PP080. First trimester umbilical artery end-diastolic flow and pulsatility index: Comparison between preeclampsia and control. AB - INTRODUCTION: The appearance of end-diastolic flow velocities (EDF) in the umbilical artery (UA), usually between 10 and 14 weeks of gestation, has been associated with the opening of the spiral arteries and consequently of the intervillous space. OBJECTIVES: The aim of our study was to compare first trimester UA pulsatility index (PI) and EDF between women who developed preeclampsia (cases) and controls. METHODS: Our database was searched for cases who had UA Doppler between 10-14 weeks. UA PI and EDF were compared between cases and two gestational age (GA) matched controls. RESULTS: 15 cases with severe preeclampsia (PE) were matched to 30 controls. GA with negative EDF was lower than with positive EDF (12.1+/-0.79 vs. 12.8+/-0.34; p=0.001). UA PI in cases was higher than in controls, although not significant (cases: 2.18+/-0.6 vs. CONTROLS: 1.92+/-0.48; p=0.12). However, comparing groups with negative EDF, the difference became significant (PI cases: 2.45+/-0.57 vs. PI controls: 1.94+/ 0.56; p=0.038), while no difference was found comparing groups with positive EDF. CONCLUSION: First trimester UA PI is significantly higher in women which will develop PE than in controls. Interestingly, the timing of screening for PE by UA Doppler seems to play an important issue. PMID- 26105935 TI - PP082. Eclampsia in flanders: A comparative study between flanders, United Kingdom and The Netherlands. AB - INTRODUCTION: Eclampsia fulfills the European criteria of "uncommon medical conditions". OBJECTIVES: To describe eclampsia in Flanders and compare the results with data of United Kingdom Obstetric Surveillance System (UKOSS) and a similar study in the Netherlands. Methods Between January and December 2012 each maternity hospital in Flanders was contacted monthly to learn whether a case of eclampsia had occurred. For each reported case an extensive questionnaire was completed. The obtained data were analyzed using the IBM-SPSSvs20 and BMJ-CIA programs. RESULTS: Over 95% of all maternity hospitals in Flanders participated. In 2012, 16 eclampsia cases were reported (incidence 2.3/10,000). Data of 14/16 cases could be used for analysis. No maternal or perinatal death occurred. In 71.4% (10/14;95%CI:45.4-88.3%) the gestational age at time of delivery was <37 weeks; in 28.6% (4/14;95%CI:11.7-54.6%) the insult occurred after the delivery; 50.00% (7/14;95%CI:26.8-73.2%) of the patients was primigravida and 28.6% (4/14;95%CI:11.7-54.6%) was negroid. Data presented in the table below summarize the findings of the last medical examination preceding the insult (n=13, insufficient data in 1 case). CONCLUSIONS: The incidence of eclampsia in Flanders is comparable to that of the UK (2.7/10,000) and is 2.7 times smaller than that of the Netherlands (6.2/10.000). Proteinuria was not tested in 9. In 5 of 14 no clear alert sign was seen at the last observation compared to 10.8% and 21% in Ndl and UK. PMID- 26105936 TI - PP081. Predictors of pregnancy induced hypertension in an urban low resource setting. AB - INTRODUCTION: Hypertensive disorders in pregnancy, including Pregnancy Induced Hypertension (PIH), are important causes of morbidity and mortality in pregnancy. Identifying women at high risk will allow for early management to reduce complications of PIH. OBJECTIVES: The objectives were to determine the incidence of PIH among pregnant women and develop risk prediction models for early detection of women at increased risk of PIH. METHODS: A longitudinal cohort study involving 2539 pregnant women attending antenatal clinic in the Greater Accra region of Ghana was conducted between February and May 2010. The outcome, PIH, was defined as systolic or diastolic blood pressure BP of 140mmHg or 90mmHg respectively. Logistic regression was used to derive the prediction models and bootstrapping technique was used to internally validate them. A score chart was used to classify pregnant women into low, moderate and high risk of developing PIH. RESULTS: The incidence of PIH was 8.0% (95% C.I: 7.98-8.02%) and 10.9% (95% C.I:10.89-10.91%) in nulliparous and multiparous women respectively. Systolic blood pressure, diastolic blood pressure, history of hypertension in parents, family history of diabetes, proteinuria, body mass index (BMI) were among independent predictors in early pregnancy of subsequent PIH. The prognostic performance, estimated by the area under the Receiver Operating Characteristic (ROC) curve, ranged between 0.64 and 0.84 for the models for nulliparous and multiparous. CONCLUSION: Using a limited set of maternal characteristics, pregnant women at increased risk of developing PIH can be identified. Categorizing women by risk of PIH and providing tailored antenatal care will minimize complications of PIH. PMID- 26105937 TI - PP084. Hypertension after preeclampsia in women with C1114G polymorphism in rgs2 (the regulator of g protein signaling 2). AB - INTRODUCTION: Women with preeclampsia have increased risk of developing hypertension later in life. We recently demonstrated an association between preeclampsia and the CG or GG genotype of the rs4606 in the regulator of G protein signaling 2 (RGS2) gene. RGS2 negatively regulates several vasoconstrictors. OBJECTIVES: To explore the potential association between the rs4606 and hypertension after pregnancy in women with previous preeclampsia or controls. METHODS: DNA from 933 women with a history of preeclampsia and 2010 women without a history of preeclampsia was analyzed for the rs4606 in RGS2. RESULTS: Preeclampsia, but not the rs4606, was significantly associated with hypertension (systolic blood pressure ?140mmHg and/or diastolic blood pressure ?90mmHg and/or taking antihypertensive drugs) in both univariate and multivariate analyses, including adjustment for classical cardiovascular risk factors. For women with hypertension defined as blood pressure above 160/100mmHg and/or taking antihypertensive drugs, the rs4606 was significantly associated with hypertension in multivariate analysis. Our data further suggested an association between the rs4606 and physical activity in relation to hypertension. CONCLUSIONS: Women with the rs4606 CG or GG genotype may be at elevated risk for severe hypertension. However, a history of preeclampsia remained an independent predictor of hypertension after accounting for this polymorphism and classical cardiovascular risk factors. PMID- 26105938 TI - PP083. Maternal pre-eclampsia and bone mineral density of the adult offspring. AB - INTRODUCTION: Preterm birth at very low birth weight (VLBW; <1500g) is associated with cardiometabolic risk factors and reduced bone mineral density (BMD) in the adult offspring. Pre-eclampsia (PE) is a frequent cause of preterm birth and is also associated with cardiometabolic risk factors in the offspring. Whether it is associated with BMD is not known. OBJECTIVE: To study BMD in adult offspring of mothers with pre-eclampsia. METHODS: We studied participants of the Helsinki Study of Very Low Birth Weight Adults: 144 born at VLBW and 139 born at term. From the VLBW and term offspring a respective 32 and 11 were born from pregnancy complicated by preeclampsia. We measured BMD at age 18-27 years by dual X-ray absorptiometry. We express BMD in Z scores which indicate the difference in SD units from the value expected for sex and age. RESULTS: VLBW adults exposed to maternal pre-eclampsia had higher lumbar spine Z score (mean -0.44 SD units, compared to -1.07 in unexposed VLBW adults, p=0.002) and femoral neck Z score ( 0.05 vs. -0.53, p=0.003). Corresponding Z scores for those born at term were 0.02 (PE) and -0.45 (no PE) for lumbar spine (p=0.2), 0.78 and 0.08 for femoral neck (p=0.02). The Table shows mean differences after adjustment for offspring current body size and potential confounders. CONCLUSIONS: Young adults exposed to maternal PE have higher BMD than those not exposed. This suggests that preeclampsia has a long-term protective effect on offspring bone health. PMID- 26105939 TI - PP085. Hypertensive complication in pregnancy - HELLP syndrome - One year study (2012). AB - INTRODUCTION: HELLP syndrome is characterized by hemolysis with a microangiopathic blood smear, elevated liver enzymes, and low platelet count. It develops in 10-20% of women with severe preeclampsia/eclampsia. The syndrome is associated with maternal morbidities - DIC, renal failure, pulmonary edema and hepatic hematoma/rupture. Some need transfusions and others require laparotomies for intraabdominal bleeding. OBJECTIVES: Study the incidence and related risk factors of HELLP syndrome in Pregnancy, as well as the maternal/fetal outcome. METHODS: A retrospective study of admissions for HELLP syndrome in 2012.The statistical analysis was based on Excel 2007. RESULTS: In 55 admissions for hypertensive complications in pregnancy, 3 women had HELLP syndrome - 2 were black race and 1 was caucasian. The average maternal age was 29. None had relevant medical history. 2 of the women developed HELLP syndrome after severe preeclampsia. The fetal/neonatal outcomes were prematurity in 2 cases, birth weight average was 1798g and none had apgar-index below 7. There was no fetal death. Premature delivery occurred in 2 cases and all were by cesarean. Maternal complications that determined Intensive Care Unit Admission was recorded in one case - laparotomy for internal bleeding and transfusions were needed. No maternal death occured. CONCLUSIONS: HELLP syndrome is associated with many morbidities which risk increases with severity of symptoms/lab results. We had no aggresive/fatal outcomes. PMID- 26105941 TI - PP088. The role of microRNA in pathogenesis of preeclampsia-miRNA network analysis. AB - INTRODUCTION: Preeclampsia (PE) is a leading cause of maternal and fetal mortality and morbidity, affecting least 5-8% of all pregnancies worldwide. Several theories (e.g., immunological, placental ischemia, and genetic) have been described to explain pathogenesis of PE. The analysis of different contributing factors (proteins, mRNA, miRNA) are in the higlight of preeclampsia research, leading to an increasing pool of data. Recently, microRNA-s seems to provide feasible biochemical mechanism playing key role in protein translation regulation. MATERIALS AND METHODS: The aim of our strudy was to collect datas from literature regarding to different subset of miRNA-s connected to pathways playing role in pathogenesis of preeclampsia. miRNA expression datas were analysied by biostatistical methods, connections in miRNA gene network and graphical representation of connections and crosspoints of supposed pathways were performed. CONCLUSIONS: In more than a hundered miRNA-s analysed in different studies most of the reserches concentrate on angiogenesis, trophoblast cell invasion, vascular developement, oxiadtive stress and blood presure regulation. This condition resulting as major crosspoints miRNA-s involved in this pathways: miR-29b, miR-155, miR-195, miR-16, miR-20a, miR-20b. Complex network analysis and graphical presentation in dynamic manner of miRNA pathways and possible consecquences of aletartion in miRNA expression could help in setting of major directions in PE research. PMID- 26105940 TI - PP087. Multicenter external validation and recalibration of a model for preconceptional prediction of recurrent early-onset preeclampsia. AB - INTRODUCTION: In an earlier paper we reported on the development of a model aimed at the prediction of preeclampsia recurrence, based on variables obtained before the next pregnancy (fasting glucose, BMI, previous birth of a small-for gestational-age infant, duration of the previous pregnancy, and the presence of hypertension). OBJECTIVE: To externally validate and recalibrate the prediction model for the risk of recurrence of early-onset preeclampsia. METHODS: We collected data about course and outcome of the next ongoing pregnancy in 229 women with a history of early-onset preeclampsia. Recurrence was defined as preeclampsia requiring delivery before 34 weeks. We computed risk of recurrence and assessed model performance. In addition, we constructed a table comparing sensitivity, specificity, and predictive values for different suggested risk thresholds. RESULTS: Early-onset preeclampsia recurred in 6.6% of women. The model systematically underestimated recurrence risk. The model's discriminative ability was modest, the area under the receiver operating characteristic curve was 58.9% (95% CI: 45.1 - 72.7). Using relevant risk-thresholds, the model created groups that were only moderately different in terms of their average risk of recurrent preeclampsia (Table 1). CONCLUSION: Compared to an AUC of 65% in the development cohort, the discriminate ability of the model was diminished. It had inadequate performance to classify women into clinically relevant risk groups. PMID- 26105942 TI - PP089. Analytical aspects of marinobufagenin and its applications in the diagnosis of preeclampsia. AB - INTRODUCTION: Marinobufagenin (MBG), a bufadienolide cardiac inotrope, enjoys a growing interest in the early diagnosis of volume expansion-mediated hypertensive states such as preeclampsia (PE). This endogenous mammalian vasoconstrictive compound, is a selective inhibitor of the alpha1 subunit of Na+,K+-ATPase, leading to hypertension and natriuresis. Enhanced production of MBG has been described in preeclamptic patients prior the development of hypertension and proteinuria, leading to consider MBG as a biomarker for PE [1-3]. However, the role of MBG as a biomarker remains to be fully understood as well as his biosynthetic pathway. The need has arisen for an accuracy and sensitive analytical method of MBG plasma levels in order to further investigate the implications of MBG in PE, and to help to establish a diagnosis for this syndrome. OBJECTIVE: Our aim is to develop a sensitive and robust analytical MBG dosage method allowing quantifications as low as possible. A critical threshold value may be established in order to discriminate normal pregnant from preeclamptic women. METHODS: Nowadays, the MBG standard compound is not commercially available. It forced us to develop an extraction method of MBG from the crystallized toad Bufo Marinus venom. A pre-extraction step on rat and human plasma is performed in order to clean and to concentrate samples. Several liquid chromatography (LC) strategies coupled with different detection methods are considered and performed. RESULTS AND DISCUSSION: Pure MBG has been successfully extracted from the crystallized toad venom. The identity of the compound has been confirmed by different spectral techniques. The pre-extraction step from plasma samples spiked with MBG has been carried out through a solid phase extraction HLB cartridge with an extraction yield of 88%. Preliminary reversed-phase LC method allows quantifications of MBG between 6MUg/mL and 11MUg/mL. PMID- 26105943 TI - PP086. Severe hypertensive complications in pregnancy - Two years study (2011 2012). AB - INTRODUCTION: There are major hypertensive disorders related to pregnancy preeclampsia,eclampsia and HELLP syndrome. These women are at an increased risk for placental abruption,renal failure, cerebral hemorrhage,hepatic failure/rupture,pulmonary edema, DIC and of long-term cardiovascular disease. OBJECTIVES: Study the incidence, risk factors, maternal/fetal outcome of hypertensive complications that determined Intensive Care Unit admission. METHODS: A retrospective study of admissions in Intensive Care Unit for preeclampsia, HELLP syndrome and eclampsia in 2011-2012. RESULTS: There were 8 admissions in Intensive Care - 88% black women, average age was 20 years and all were nulliparous. 1 had an hypertension induced by pregnancy, but 63% had increased blood pressure in hospital admission. 50% had elevated liver enzymes, 25% proteinuria, 1 low platelet count and 1 had normal blood results. 50% of the admissions were due to eclampsia, 38% due to severe preeclampsia and 1 due to HELLP. Fetal/neonatal outcomes were prematurity in 25%, birth weight average was 2759g and none had apgar below 7. There was no fetal death. Vaginal delivery occurred in 25% and caesarian in 75%. Maternal complications were elevated blood pressure (75%), cardiorespiratory disorders (38%), encephalopathy (25%), renal disorder (13%) and convulsions (13%). There was no maternal death. CONCLUSION: The risk of adverse outcome increases with the severity of hypertension and organ damage. Early detection and appropriate management are essential. PMID- 26105944 TI - Effects of pregnancy on endothelial function and cardiovascular disease risk in HIV-infected women. AB - OBJECTIVE: This study assessed flow-mediated vasodilation (FMD) and brachial artery diameter (BAD) in HIV-infected pregnant women compared to healthy pregnant controls, and determined their relationships to variables of interest, including the HIV status. METHODS: Subjects were enrolled prospectively for this longitudinal, observational study. Body mass index (BMI), blood pressure (BP), fasting lipoprotein profiles, homeostasis model assessment of insulin resistance (HOMA-IR), FMD, and BAD were assessed at 10-12, 20-22, and 32-35weeks gestation in HIV-infected women and healthy controls aged 18-45years with singleton pregnancies. RESULTS: Fourteen HIV-infected women and 19 controls were enrolled. Groups were similar at baseline except there were more Caucasians in the control group (P<0.01). FMD and BAD did not change during pregnancy in either group, and there were no differences between groups. In multivariable regression analysis, FMD was associated with BAD (P=0.002), but not with age, BMI, BP, TC, TG, HOMA IR, or HIV status. No variables were associated with BAD. CONCLUSION: No differences were observed in FMD or BAD between HIV-infected and healthy pregnant women, and neither measure changed significantly during pregnancy. HIV status did not affect endothelial function or brachial artery diameter. Pregnancy does not appear to further increase the CVD risk associated with HIV infection. PMID- 26105945 TI - Pre-eclampsia in swine flu. PMID- 26105946 TI - Random urine albumin:creatinine ratio in high-risk pregnancy - Is it clinically useful? AB - We evaluated the frequency of measurable albuminuria (?6.00mg/L) for albumin:creatinine ratios (ACr) among 160 consecutive women attending high-risk clinics. Of last urine samples before delivery, 76 had measurable albuminuria and 41/76 (53.9%) had ACr ?2mg/mmol of which 7.3% had normal pregnancy outcome. 84 samples had albuminuria <6.00mg/L and 43/84 (51.2%) had ACr ?2mg/mmol of which 25.6% had normal pregnancy outcome (p=0.025). Excluding 48/160 (30.0%) dilute samples (urinary creatinine <3mM), no samples with unmeasurable albuminuria had ACr ?2mg/mmol. In pregnancy, urine is often dilute and without measurable albuminuria, leading to a clinically relevant proportion of false positive results by ACr. PMID- 26105947 TI - Measurement of sST2 is comparable to PlGF in the diagnosis of early-onset pre eclampsia. AB - A diagnostic test to confirm pre-eclampsia would be beneficial for the clinical management of the syndrome. The Triage PlGF test is able to confirm pre-eclampsia with high accuracy, with the greatest efficacy at <35weeks gestation. We recently found that the anti-inflammatory protein sST2 is elevated in the plasma of pre eclamptic women compared to normal controls. Here sST2 and PlGF are compared in early-onset and late-onset pre-eclamptic women. sST2 was found to be an equally good diagnostic tool for early-onset (sST2 AUC 0.944 versus PlGF AUC 0.995; not significant) but not late-onset disease. PMID- 26105948 TI - Early-pregnancy asymmetric dimethylarginine (ADMA) levels in women prone to develop recurrent hypertension. AB - OBJECTIVE: To evaluate early-pregnancy levels of ADMA (asymmetric dimethylarginine) in recurrent hypertensive pregnancy. STUDY DESIGN: In this retrospective observational study, blood samples from 35 normotensive women with a previous hypertensive pregnancy were obtained preconceptionally and at 12, 16 and 20weeks in their next pregnancy. We assessed ADMA, symmetric dimethylarginine (SDMA), l-arginine and l-citrulline. We analyzed differences in longitudinal patterns between normotensive (NT, n=18) and recurrent hypertensive (HT, n=17) pregnancies by linear mixed models, with a sub-analysis for preeclampsia (PE, n=6). MAIN OUTCOME MEASURES: ADMA, SDMA, l-arginine and l-citrulline. RESULTS: Pre-pregnant SDMA and l-citrulline were lower in HT. At 12weeks, ADMA and ADMA/SDMA ratio correlated inversely with PAPP-A and beta-hCG, respectively. In both groups, ADMA-related compounds changed inconsistently with advancing (mid trimester) pregnancy, although in HT, l-arginine tended to decrease between 16 and 20weeks, a decline consistent in PE. CONCLUSION: These data support a modest role for ADMA and related metabolites in the pathogenesis of hypertensive pregnancy. PMID- 26105949 TI - Determination of placental growth factor (PlGF) levels in healthy pregnant women without signs or symptoms of preeclampsia. AB - OBJECTIVE: To identify a reference range for placental growth factor (PlGF) in normotensive women without symptoms or signs of preeclampsia. STUDY DESIGN: Comprising the study cohort were 247 term pregnancies without preeclampsia or adverse neonatal outcomes from 16 sites in the US and Canada. Serial plasma samples were collected in 6 gestational age (GA) intervals between 20+0 and 40+0weeks. Non-parametric percentiles of the distribution of PlGF were estimated in each GA interval and a parametric model was developed to describe the distribution of PlGF as a continuous smooth function of GA (from 20 to 40weeks) in normal healthy pregnancy. Demographic and clinical factors influencing PlGF levels were also examined. RESULTS: There were 1366 evaluable samples collected from 247 subjects (242, 238, 226, 223, 222, and 215 samples in each GA interval, 20-24, 24-29, 29-32, 32-35, 35-37, and 37-40weeks, respectively). The 5th percentile of PlGF was 76.4, 141.1, 139.3, 65.5, 31.7, and 23.4pg/mL in each respective GA interval. The distribution of PlGF is approximately log normal with parameters that vary continuously as a function of GA. PlGF distribution is weakly dependent on maternal age, race/ethnicity, parity, and maximum systolic blood pressure (taken between weeks 20 and 24). Although statistically significant, these factors did not modify PlGF levels by more than +/-15%. CONCLUSION: These data provide a valid reference range for PlGF in normal pregnancy. PMID- 26105950 TI - The unfavorable slope from mild preeclampsia through severe preeclampsia, to eclampsia. AB - OBJECTIVE: To compare the risk factors as well as maternal and perinatal outcomes between women with eclampsia to those with mild and severe preeclampsia. METHODS: A retrospective study comparing pregnancy outcomes of women with preeclampsia (mild and severe) with those who were complicated with eclampsia was conducted. Statistical analysis included chi-square test for trend (the linear-by-linear association test). RESULTS: The study population consisted of 10,018 women, 0.5% (n=52) suffered from eclampsia, 24% (n=2,409) had severe preeclampsia and 75.4% (n=7,557) had mild preeclampsia. A significant linear association was noted between the three groups (eclampsia, severe preeclampsia and mild preeclampsia) and risk factors such as nulliparity, young maternal age and oligohydramnios. A significant linear association was also documented between the three groups and adverse obstetric and perinatal outcomes such as post-partum hemorrhage, the need for blood transfusion, non reassuring fetal heart rate (NRFHR) patterns, low Apgar score at 5min and perinatal mortality. CONCLUSIONS: An unfavorable slope was noted in the rate of certain risk factors and adverse perinatal outcomes between women with eclampsia through patients with severe preeclampsia to those with mild preeclampsia. PMID- 26105951 TI - Health-related quality of life changes in patients undergoing repeated catheter ablation for atrial fibrillation. AB - OBJECTIVE: Pulmonary vein isolation (PVI) for paroxysmal or non-paroxysmal atrial fibrillation (AF) should increase health-related quality of life (QOL). DESIGN: Retrospective cohort study of consecutive patients scheduled for PVI. SETTING: University Medical Center. MAIN OUTCOME MEASURES: QOL was assessed using the physical (PCS) and mental (MCS) component summary scores from the SF-12v2 in patients undergoing PVI (mean 50, range 0-100, with higher scores indicating greater QOL). SF-12v2 was obtained at initial presentation (3-months) before PVI and after PVI at the end of follow-up (mean 1.7 +/- 1.4 years) which included: (1) Clinical status, ECG, and 24-h ECG every 3 months, (2) trans-telephonic ECGs for 4 weeks every 3 months, or (3) continuous ECG via implanted devices. A recurrence was any atrial arrhythmia >30 s. RESULTS: Out of 229 patients (73% males; 58 +/- 11 years), 72% returned SF-12v2 regarding 187 PVI procedures: 56% for 1st PVI, 48% for 2nd PVI, 71% for 3rd PVI, and 44% for 4th PVI. The mean difference between before and after PVI was 10 for PCS and 9 for MCS. History of paroxysmal or non-paroxysmal AF did not influence QOL (p = 0.724). Patients with an estimated PCS improvement >= 10 or an estimated MCS improvement >= 9 had the best outcome after repeated PVI. Success rates were 72 or 82% after 1 year compared to 20 and 22% in patients not achieving this improvement, respectively (p < 0.0001). CONCLUSION: Improvement in QOL correlates with success of AF ablation after single and repeated PVI. Assessment of QOL pre- and post-PVI can complement ECG techniques for PVI success monitoring. PMID- 26105952 TI - Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents. AB - The sodium glucose cotransporter (SGLT) 1 plays a major role in glucose absorption and incretin hormone release in the gastrointestinal tract; however, the impact of SGLT1 inhibition on plasma glucagon-like peptide-1 (GLP-1) levels in vivo is controversial. We analyzed the effects of SGLT1 inhibitors on GLP-1 secretion in normoglycemic and hyperglycemic rodents using phloridzin, CGMI [3-(4 cyclopropylphenylmethyl)-1-(beta-d-glucopyranosyl)-4-methylindole], and canagliflozin. These compounds are SGLT2 inhibitors with moderate SGLT1 inhibitory activity, and their IC50 values against rat SGLT1 and mouse SGLT1 were 609 and 760 nM for phloridzin, 39.4 and 41.5 nM for CGMI, and 555 and 613 nM for canagliflozin, respectively. Oral administration of these inhibitors markedly enhanced and prolonged the glucose-induced plasma active GLP-1 (aGLP-1) increase in combination treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in normoglycemic mice and rats. CGMI, the most potent SGLT1 inhibitor among them, enhanced glucose-induced, but not fat-induced, plasma aGLP-1 increase at a lower dose compared with canagliflozin. Both CGMI and canagliflozin delayed intestinal glucose absorption after oral administration in normoglycemic rats. The combined treatment of canagliflozin and a DPP4 inhibitor increased plasma aGLP-1 levels and improved glucose tolerance compared with single treatment in both 8- and 13-week-old Zucker diabetic fatty rats. These results suggest that transient inhibition of intestinal SGLT1 promotes GLP-1 secretion by delaying glucose absorption and that concomitant inhibition of intestinal SGLT1 and DPP4 is a novel therapeutic option for glycemic control in type 2 diabetes mellitus. PMID- 26105953 TI - AB-CHMINACA, AB-PINACA, and FUBIMINA: Affinity and Potency of Novel Synthetic Cannabinoids in Producing Delta9-Tetrahydrocannabinol-Like Effects in Mice. AB - Diversion of synthetic cannabinoids for abuse began in the early 2000s. Despite legislation banning compounds currently on the drug market, illicit manufacturers continue to release new compounds for recreational use. This study examined new synthetic cannabinoids, AB-CHMINACA (N-[1-amino-3-methyl-oxobutan-2-yl]-1 [cyclohexylmethyl]-1H-indazole-3-carboxamide), AB-PINACA [N-(1-amino-3-methyl-1 oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide], and FUBIMINA [(1-(5 fluoropentyl)-1H-benzo[d]imadazol-2-yl)(naphthalen-1-yl)methanone], with the hypothesis that these compounds, like those before them, would be highly susceptible to abuse. Cannabinoids were examined in vitro for binding and activation of CB1 receptors, and in vivo for pharmacological effects in mice and in Delta(9)-tetrahydrocannabinol (Delta(9)-THC) discrimination. AB-CHMINACA, AB PINACA, and FUBIMINA bound to and activated CB1 and CB2 receptors, and produced locomotor suppression, antinociception, hypothermia, and catalepsy. Furthermore, these compounds, along with JWH-018 [1-pentyl-3-(1-naphthoyl)indole], CP47,497 [rel-5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol], and WIN55,212-2 ([(3R)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de] 1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone, monomethanesulfonate), substituted for Delta(9)-THC in Delta(9)-THC discrimination. Rank order of potency correlated with CB1 receptor-binding affinity, and all three compounds were full agonists in [(35)S]GTPgammaS binding, as compared with the partial agonist Delta(9)-THC. Indeed, AB-CHMINACA and AB-PINACA exhibited higher efficacy than most known full agonists of the CB1 receptor. Preliminary analysis of urinary metabolites of the compounds revealed the expected hydroxylation. AB-PINACA and AB-CHMINACA are of potential interest as research tools due to their unique chemical structures and high CB1 receptor efficacies. Further studies on these chemicals are likely to include research on understanding cannabinoid receptors and other components of the endocannabinoid system that underlie the abuse of synthetic cannabinoids. PMID- 26105954 TI - Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma. AB - The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P1-5) play critical roles in many pathologic processes, including cancer. The S1P axis has become a bona fide therapeutic target in cancer. JTE-013 [N-(2,6-dichloro-4 pyridinyl)-2-[1,3-dimethyl-4-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl] hydrazinecarboxamide], a known S1P2 antagonist, suffers from instability in vivo. Structurally modified, more potent, and stable S1P2 inhibitors would be desirable pharmacological tools. One of the JTE-013 derivatives, AB1 [N-(1H-4-isopropyl-1 allyl-3-methylpyrazolo[3,4-b]pyridine-6-yl)-amino-N'-(2,6-dichloropyridine-4-yl) urea], exhibited improved S1P2 antagonism compared with JTE-013. Intravenous pharmacokinetics indicated enhanced stability or slower clearance of AB1 in vivo. Migration assays in glioblastoma showed that AB1 was slightly more effective than JTE-013 in blocking S1P2-mediated inhibition of cell migration. Functional studies in the neuroblastoma (NB) cell line SK-N-AS showed that AB1 displayed potency at least equivalent to JTE-013 in affecting signaling molecules downstream of S1P2. Similarly, AB1 inhibition of the growth of SK-N-AS tumor xenografts was improved compared with JTE-013. Cell viability assays excluded that this enhanced AB1 effect is caused by inhibition of cancer cell survival. Both JTE-013 and AB1 trended to inhibit (C-C motif) ligand 2 expression and were able to significantly inhibit subsequent tumor-associated macrophage infiltration in NB xenografts. Interestingly, AB1 was more effective than JTE-013 in inhibiting the expression of the profibrotic mediator connective tissue growth factor. The terminal deoxynucleotidyl transferase-mediated digoxigenin deoxyuridine nick-end labeling assay and cleaved caspase-3 detection further demonstrated that apoptosis was increased in AB1-treated NB xenografts compared with JTE-013. Overall, the modification of JTE-013 to produce the AB1 compound improved potency, intravenous pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clinical and experimental applicability. PMID- 26105955 TI - Deciphering the Epigenetic Code of Cardiac Myocyte Transcription. AB - RATIONALE: Epigenetic mechanisms are crucial for cell identity and transcriptional control. The heart consists of different cell types, including cardiac myocytes, endothelial cells, fibroblasts, and others. Therefore, cell type-specific analysis is needed to gain mechanistic insight into the regulation of gene expression in cardiac myocytes. Although cytosolic mRNA represents steady state levels, nuclear mRNA more closely reflects transcriptional activity. To unravel epigenetic mechanisms of transcriptional control, cell type-specific analysis of nuclear mRNA and epigenetic modifications is crucial. OBJECTIVE: The aim was to purify cardiac myocyte nuclei from hearts of different species by magnetic- or fluorescent-assisted sorting and to determine the nuclear and cellular RNA expression profiles and epigenetic marks in a cardiac myocyte specific manner. METHODS AND RESULTS: Frozen cardiac tissue samples were used to isolate cardiac myocyte nuclei. High sorting purity was confirmed for cardiac myocyte nuclei isolated from mice, rats, and humans. Deep sequencing of nuclear RNA revealed a major fraction of nascent, unspliced RNA in contrast to results obtained from purified cardiac myocytes. Cardiac myocyte nuclear and cellular RNA expression profiles showed differences, especially for metabolic genes. Genome wide maps of the transcriptional elongation mark H3K36me3 were generated by chromatin-immunoprecipitation. Transcriptome and epigenetic data confirmed the high degree of cardiac myocyte-specificity of our protocol. An integrative analysis of nuclear mRNA and histone mark occurrence indicated a major impact of the chromatin state on transcriptional activity in cardiac myocytes. CONCLUSIONS: This study establishes cardiac myocyte-specific sorting of nuclei as a universal method to investigate epigenetic and transcriptional processes in cardiac myocytes of different origins. These data sets provide novel insight into cardiac myocyte transcription. PMID- 26105956 TI - Crossed Cerebellar Diaschisis Due to Rasmussen Encephalitis. PMID- 26105957 TI - Screen-Printing of ZnO Nanostructures from Sol-Gel Solutions for Their Application in Dye-Sensitized Solar Cells. AB - Diblock copolymers have been used in sol-gel synthesis to successfully tailor the nanoscale morphology of thin ZnO films. As the fabrication of several-micron thick mesoporous films such as those required in dye-sensitized solar cells (DSSCs) was difficult with this approach, we exploited the benefits of diblock copolymer-directed synthesis that made it compatible with screen printing. The simple conversion of the diblock copolymer ZnO precursor sol to a screen-printing paste was not possible as it resulted in poor film properties. To overcome this problem, an alternative route is proposed in which the diblock copolymer ZnO precursor sol is first blade coated and calcined, then converted to a screen printing paste. This allows the benefits of diblock-copolymer-directed particle formation to be compatible with printing methods. The morphologies of the ZnO nanostructures were studied by SEM and correlated with the current density voltage characteristics. PMID- 26105959 TI - Prevalence and burden of osteoarthritis amongst older people in Ireland: findings from The Irish LongituDinal Study on Ageing (TILDA). AB - OBJECTIVE: To investigate the prevalence of osteoarthritis (OA) in a population aged >=50 years in Ireland, and to determine its relationship with demographic and health-related variables. METHODS: Cross-sectional data from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA), a population-based study of 8175 people aged >=50 years were analyzed. Logistic regression was used to determine associations between the presence of OA and a range of demographic and health related variables. RESULTS: A total of 8175 people >=50 years in Ireland were identified from the TILDA database of whom 45.7% (n = 2941) were male and 54.3% (n = 4431) were female. The overall prevalence of OA was 12.9% (women-17.3%; men 9.4%). Prevalence increased with age, with prevalence in those aged >= 80 years twice that [17.7%; 95% confidence interval (CI) 13.97, 21.54] of those aged 50-60 years (8.23, 95% CI 7.32, 9.13). On multivariable analysis, OA was significantly associated (P < 0.02) with female gender, older age, pain severity, higher body mass index (BMI), fear of falling, greater number of physical limitations and medication use. In particular, there was a strong association between the use of NSAIDS and the presence of OA [adj odd ratio (OR) = 5.88, 95% CI 4.16, 8.31]. A significant association was also found between OA and increasing number of chronic diseases (adj OR = 2.75 9, 95% CI = 2.44, 3.09). CONCLUSIONS: OA is a common and multifaceted condition, with comparable prevalence of self-reported OA in Ireland with similar populations. Assessment and management should focus on potentially modifiable factors such as BMI, pain, physical limitations, polypharmacy and fear of falling. More research is required to understand the complex inter-relationships between these and other risk-associated variables. PMID- 26105958 TI - Negative modulation of alpha5 GABAA receptors in rats may partially prevent memory impairment induced by MK-801, but not amphetamine- or MK-801-elicited hyperlocomotion. AB - Reportedly, negative modulation of alpha5 GABAA receptors may improve cognition in normal and pharmacologically-impaired animals, and such modulation has been proposed as an avenue for treatment of cognitive symptoms in schizophrenia. This study assessed the actions of PWZ-029, administered at doses (2, 5, and 10 mg/kg) at which it reached micromolar concentrations in brain tissue with estimated free concentrations adequate for selective modulation of alpha5 GABAA receptors, in three cognitive tasks in male Wistar rats acutely treated with the noncompetitive N-methyl-d-aspartate receptor antagonist, MK-801 (0.1 mg/kg), as well in tests of locomotor activity potentiated by MK-801 (0.2 mg/kg) or amphetamine (0.5 mg/kg). In a hormetic-like manner, only 5 mg/kg PWZ-029 reversed MK-801-induced deficits in novel object recognition test (visual recognition memory), whereas in the Morris water maze, the 2 mg/kg dose of PWZ-029 exerted partial beneficial effects on spatial learning impairment. PWZ-029 did not affect recognition memory deficits in social novelty discrimination procedure. Motor hyperactivity induced with MK-801 or amphetamine was not preventable by PWZ-029. Our results show that certain MK-801-induced memory deficits can be ameliorated by negative modulation of alpha5 GABAA receptors, and point to the need for further elucidation of their translational relevance to cognitive deterioration in schizophrenia. PMID- 26105960 TI - Phase-field modelling of the dynamics of Z-ring formation in liposomes: Onset of constriction and coarsening. AB - We propose a model for the dynamics of the formation of rings of FtsZ on tubular liposomes which produce constriction on the corresponding membrane. Our phase field model is based on a simple bending energy that captures the dynamics of the interplay between the protein and the membrane. The short-time regime is analyzed by a linear dispersion relation, with which we are able to predict the number of rings per unit length on a tubular liposome. We study numerically the long-time dynamics of the system in the non-linear regime where we observe coarsening of Z rings on tubular liposomes. In particular, our numerical results show that, during the coarsening process, the number of Z-rings decreases as the radius of tubular liposome increases. This is consistent with the experimental observation that the separation between rings is proportional to the radius of the liposome. Our model predicts that the mechanism for the increased rate of coarsening in liposomes of larger radius is a consequence of the increased interface energy. PMID- 26105961 TI - Laser-induced capillary effect in thin layers of water-alcohol mixtures. AB - The effect of droplet formation in thin layers of water-alcohol mixtures upon laser heating was studied. The droplet growth in the laser beam is governed by the surface tension gradient, which induces solutocapillary flows from the periphery to the center of the heated area. This gradient arises due to the local increase in surface tension caused by the evaporation of alcohol from the heated area of the layer. The experimental results have shown that the increase in the initial concentration of water in the mixture gives rise to the increase in droplet size. However, the increase in the power of laser irradiation leads to a decrease in the droplet growth rate. A simplified one-dimensional model of droplet growth is developed. The model involves the dependence of surface tension on both the temperature and concentration of components in the mixture, as well as the evaporation and condensation of alcohol. The experimental results are compared with those obtained using numerical simulations. A reasonable agreement between experimental and numerical results was shown. PMID- 26105962 TI - Polymorphisms in melanoma differentiation-associated gene 5 are not associated with clearance of hepatitis C virus in a European American population. PMID- 26105963 TI - Characteristics of medication schedules used by elderly ambulatory patients. AB - PURPOSE: We investigated the prevalence and quality of medication schedules of elderly ambulatory patients and assessed factors associated with the availability of a medication schedule. In particular, we evaluated whether sending out a blank medication schedule template would increase the chances to use such a document. METHODS: Data originate from the ESTHER study, a cohort study conducted in Saarland, Germany, in which trained study physicians performed home visits. They scanned all medication schedules, recorded the participants' medication, and performed thorough geriatric assessments. As part of the intervention, a blank medication schedule template along with a brochure was mailed to half of the participants (intervention group) 4 weeks prior to the home visits. RESULTS: In total, 553 of 2470 participants (22.4 %) had a medication schedule. Almost two thirds of the schedules were issued by health care professionals (n = 353, 63.8 %). These schedules offered a higher quality, although important information such as over-the-counter (OTC) medication was regularly missing. Self-reported adherence was higher in participants who used self-issued medication schedules; however, self-reported medication adherence in patients with any medication schedule was poorer compared to those patients not using a schedule. Factors associated with the availability of a medication schedule were male sex, a higher number of medicines to take, and a more complex drug regimen. The intervention did not increase the number of patients having a medication schedule. CONCLUSION: Only a minority of elderly ambulatory patients had a medication schedule at home. Sending out a brochure along with a blank medication schedule template did not increase the prevalence of medication schedules. PMID- 26105964 TI - Influence of point estimates and study power of bioequivalence studies on establishing bioequivalence between generics by adjusted indirect comparisons. AB - PURPOSE: Adjusted indirect comparisons can be used to investigate bioequivalence between generic products that are bioequivalent with a common reference product. In previous work with generic tuberculosis medicines prequalified by the WHO, it was observed that although indirect comparisons are an effective approach for confirming the interchangeability of generics, the approach is subject to less precision than direct comparisons. The objective of this investigation was to explore this by examining the influence of point estimates and power of bioequivalence studies versus the reference on the ability to show equivalence in indirect comparisons. METHODS: Power was considered as a determining factor instead of variability and sample size, because sample size is calculated based on variability and desired power. Scenarios were computed combining a range of point estimate differences (0-14 %) and statistical power of the studies (50 99.99 %). RESULTS: The indirect comparisons could conclude equivalence between generics only when (a) point estimate differences between generics were low (<= 5.5 %) for any sufficiently powered study (> 80 %), or (b) the differences were large (but less than 14 %) and both bioequivalence studies were overpowered (e.g., 10 % difference and power >= 95 %). CONCLUSIONS: In summary, the ability to demonstrate interchangeability between generics is dependent not only on the real differences between the products but also on the design of the original generic vs. reference bioequivalence studies being combined, as earmarked by their respective power. PMID- 26105965 TI - Optimizing the relationship between chromatographic efficiency and retention times in temperature-programmed gas chromatography. AB - A methodology that can maximise the chromatographic efficiency that can be achieved within a defined time frame in temperature-programmed gas chromatography is described. The efficiency can be defined as the inverse of peak widths measured in retention index units. This parameter can be described by a model similar to the van Deemter equation, which is expanded to account for the effect of the temperature rate in addition to the effect of carrier gas velocity. The model of efficiency is found by response surface methodology, where the temperature rates and the carrier gas velocities are systematically varied in the experiments. A second model that accurately explains the retention time of the last eluting compound can be found from the same experiments, and optimal conditions are found by combining the two models. The methodology has been evaluated with four capillary columns and three carrier gases, using fatty acid methyl esters as analytes. All experiments showed that there is a fairly linear decrease in efficiency with increasing temperature rates. At any temperature rate, optimal velocity is only marginally higher than the velocity that maximises chromatographic efficiency, since the carrier gas velocity has a limited effect on the retention times. PMID- 26105966 TI - Linking megathrust earthquakes to brittle deformation in a fossil accretionary complex. AB - Seismological data from recent subduction earthquakes suggest that megathrust earthquakes induce transient stress changes in the upper plate that shift accretionary wedges into an unstable state. These stress changes have, however, never been linked to geological structures preserved in fossil accretionary complexes. The importance of coseismically induced wedge failure has therefore remained largely elusive. Here we show that brittle faulting and vein formation in the palaeo-accretionary complex of the European Alps record stress changes generated by subduction-related earthquakes. Early veins formed at shallow levels by bedding-parallel shear during coseismic compression of the outer wedge. In contrast, subsequent vein formation occurred by normal faulting and extensional fracturing at deeper levels in response to coseismic extension of the inner wedge. Our study demonstrates how mineral veins can be used to reveal the dynamics of outer and inner wedges, which respond in opposite ways to megathrust earthquakes by compressional and extensional faulting, respectively. PMID- 26105967 TI - Detection of water-soluble disease-associated PrP species in blood and brain of scrapie-infected hamster. AB - The high-speed supernatant (S(HS)) of scrapie-infected hamster brain homogenate contains a soluble infectivity similar to that of the plasma that escapes leukodepletion and can transmit prion infection. This recent finding highlights the fact that soluble prion infectivity could be relevant for prion disease propagation and progression. PrP(Sc) is essential in prion disease pathogenesis, but little to nothing is known about the PrP(Sc) species that may be associated with this form of prion infectivity. Scrapie-infected hamster plasma and S(HS) were subjected to biochemical analysis, and the results demonstrate for the first time that soluble infectivity is associated with a water-soluble PrP(Sc) species with substantially different properties from classical PrP(Sc), the concentration of which seems to correlate with the magnitude and efficiency of the soluble infectivity. Such characteristics suggest that this species might represent the soluble prion agent itself or its vehicle, highlighting the need to adequately revise the strategies involved in prion removal, diagnosis, and therapy. PMID- 26105968 TI - Planning for Production of Freshwater Fish Fry in a Variable Climate in Northern Thailand. AB - Provision of adequate numbers of quality fish fry is often a key constraint on aquaculture development. The management of climate-related risks in hatchery and nursery management operations has not received much attention, but is likely to be a key element of successful adaptation to climate change in the aquaculture sector. This study explored the sensitivities and vulnerability of freshwater fish fry production in 15 government hatcheries across Northern Thailand to climate variability and evaluated the robustness of the proposed adaptation measures. This study found that hatcheries have to consider several factors when planning production, including: taking into account farmer demand; production capacity of the hatchery; availability of water resources; local climate and other area factors; and, individual species requirements. Nile tilapia is the most commonly cultured species of freshwater fish. Most fry production is done in the wet season, as cold spells and drought conditions disrupt hatchery production and reduce fish farm demand in the dry season. In the wet season, some hatcheries are impacted by floods. Using a set of scenarios to capture major uncertainties and variability in climate, this study suggests a couple of strategies that should help make hatchery operations more climate change resilient, in particular: improving hatchery operations and management to deal better with risks under current climate variability; improving monitoring and information systems so that emerging climate-related risks are known sooner and understood better; and, research and development on alternative species, breeding programs, improving water management and other features of hatchery operations. PMID- 26105969 TI - Reconciling Biodiversity Conservation and Timber Production in Mixed Uneven-Aged Mountain Forests: Identification of Ecological Intensification Pathways. AB - Mixed uneven-aged forests are considered favorable to the provision of multiple ecosystem services and to the conciliation of timber production and biodiversity conservation. However, some forest managers now plan to increase the intensity of thinning and harvesting operations in these forests. Retention measures or gap creation are considered to compensate potential negative impacts on biodiversity. Our objectives were to assess the effect of these management practices on timber production and biodiversity conservation and identify potential compensating effects between these practices, using the concept of ecological intensification as a framework. We performed a simulation study coupling Samsara2, a simulation model designed for spruce-fir uneven-aged mountain forests, an uneven-aged silviculture algorithm, and biodiversity models. We analyzed the effect of parameters related to uneven-aged management practices on timber production, biodiversity, and sustainability indicators. Our study confirmed that the indicators responded differently to management practices, leading to trade-offs situations. Increasing management intensity had negative impacts on several biodiversity indicators, which could be partly compensated by the positive effect of retention measures targeting large trees, non-dominant species, and deadwood. The impact of gap creation was more mitigated, with a positive effect on the diversity of tree sizes and deadwood but a negative impact on the spruce-fir mixing balance and on the diversity of the understory layer. Through the analysis of compensating effects, we finally revealed the existence of possible ecological intensification pathways, i.e., the possibility to increase management intensity while maintaining biodiversity through the promotion of nature-based management principles (gap creation and retention measures). PMID- 26105970 TI - Bioenergy and Biodiversity: Key Lessons from the Pan American Region. AB - Understanding how large-scale bioenergy production can affect biodiversity and ecosystems is important if society is to meet current and future sustainable development goals. A variety of bioenergy production systems have been established within different contexts throughout the Pan American region, with wide-ranging results in terms of documented and projected effects on biodiversity and ecosystems. The Pan American region is home to the majority of commercial bioenergy production and therefore the region offers a broad set of experiences and insights on both conflicts and opportunities for biodiversity and bioenergy. This paper synthesizes lessons learned focusing on experiences in Canada, the United States, and Brazil regarding the conflicts that can arise between bioenergy production and ecological conservation, and benefits that can be derived when bioenergy policies promote planning and more sustainable land management systems. We propose a research agenda to address priority information gaps that are relevant to biodiversity concerns and related policy challenges in the Pan American region. PMID- 26105971 TI - Influence of Removal of a Non-native Tree Species Mimosa caesalpiniifolia Benth. on the Regenerating Plant Communities in a Tropical Semideciduous Forest Under Restoration in Brazil. AB - Exotic species are used to trigger facilitation in restoration plantings, but this positive effect may not be permanent and these species may have negative effects later on. Since such species can provide a marketable product (firewood), their harvest may represent an advantageous strategy to achieve both ecological and economic benefits. In this study, we looked at the effect of removal of a non native tree species (Mimosa caesalpiniifolia) on the understory of a semideciduous forest undergoing restoration. We assessed two 14-year-old plantation systems (modified "taungya" agroforestry system; and mixed plantation using commercial timber and firewood tree species) established at two sites with contrasting soil properties in Sao Paulo state, Brazil. The experimental design included randomized blocks with split plots. The natural regeneration of woody species (height >=0.2 m) was compared between managed (all M. caesalpiniifolia trees removed) and unmanaged plots during the first year after the intervention. The removal of M. caesalpiniifolia increased species diversity but decreased stand basal area. Nevertheless, the basal area loss was recovered after 1 year. The management treatment affected tree species regeneration differently between species groups. The results of this study suggest that removal of M. caesalpiniifolia benefited the understory and possibly accelerated the succession process. Further monitoring studies are needed to evaluate the longer term effects on stand structure and composition. The lack of negative effects of tree removal on the natural regeneration indicates that such interventions can be recommended, especially considering the expectations of economic revenues from tree harvesting in restoration plantings. PMID- 26105972 TI - EU Sanitary Regulation on Livestock Disposal: Implications for the Diet of Wolves. AB - Sanitary and environmental regulations may have indirect effects on the wildlife and ecosystem services beyond their regulatory scope. To illustrate such effects, this paper examines how EU sanitary measures, in conjunction with additional regulations and socio-economic changes, have caused wolf diet to shift in Galicia, northwestern Spain. Prior to the bovine spongiform encephalopathy (BSE) crisis in Europe in 2000, livestock carcasses used to be left on the field and were eaten by scavengers and carnivores. As a result of the BSE crisis, sanitary regulations regarding the disposal of livestock carcasses were introduced. These regulations affected the populations of avian scavengers. We hypothesize that wolf ecology has also been affected by the aforementioned regulations. We analysed wolf diet for the period 2003-2006 and compared the results with those of a previously published study (1974-1978). We found a shift in wolf feeding habits following the implementation of these EU regulations. A decrease in carrion consumption was registered, and wolves increased their feeding on the rising population of wild ungulates, especially on roe deer, and on wild pony. Future regulations should assess their potential indirect effects in the early stages of drafting to allow for the design of proper mitigation measures. PMID- 26105973 TI - Efficacy and safety of oral insulin compared to subcutaneous insulin: a systematic review and meta-analysis. AB - INTRODUCTION: A systematic review and meta-analysis of interventional studies was conducted to compare the efficacy and safety of oral insulin versus subcutaneous (SC) insulin in diabetic patients. METHODS: Medline, Scopus, ISI Web of Knowledge and Cochrane Central Register of Controlled Trials were searched. Two independent reviewers evaluated studies for eligibility and quality and extracted the data. The primary outcomes were fasting blood glucose (FBG), 1h and 2h postprandial blood glucose, HbA1c, AUC of insulin, C max and T max of insulin, and T max of glucose infusion rate. Secondary outcomes were adverse events. RESULTS: Eleven studies (n = 373) met the inclusion criteria. Meta-analyses showed that there is no significant difference between oral and SC insulin in controlling HbA1c, FBG, 1 and 2 h postprandial blood glucose and producing C max of insulin (P > 0.05); however oral insulin had faster action as indicated by the shorter T max, compared to SC insulin (P < 0.05). The most included studies were varied in their methodological quality. CONCLUSION: This systematic review and meta-analysis showed that oral insulin is comparable to SC insulin with regard to glycemic efficacy and safety. However, is necessary to conduct additional studies in which oral insulin administered to large number of patients for long enough periods of time. PMID- 26105974 TI - Bisphenol A environmental exposure and the detrimental effects on human metabolic health: is it necessary to revise the risk assessment in vulnerable population? AB - In the last decades, many reports have focused the attention on deleterious effects of novel environmental chemical compounds, including bisphenol A (BPA), on human health. BPA, a common and widely chemical contaminant acting as endocrine disruptor, accumulates in adipose tissue and may affect adipocyte metabolic and inflammatory functions. BPA, at low chronic doses, is now considered as an obesogen compound, and might contribute to the rise of metabolic syndrome, visceral adiposity and diabetes epidemics. The BPA worldwide presence in the environment is responsible for chronic exposure during vulnerable periods, such as foetal and neonatal life. The BPA source of contamination can occur via food, beverage, wastewater, air, dust and soil. BPA, as lipophilic compound, may accumulate into the adipose tissue already during foetal life and may affect adulthood health, through adverse effects on the growth and development of organs and tissues. Thus, based on several studies, it would be crucial to consider further actions aimed to refine risk assessment at least in vulnerable population, such as foetuses, infants and young children, to prevent metabolic diseases and obesity. PMID- 26105975 TI - Association between nonalcoholic fatty liver disease and bone mineral density: a systematic review and meta-analysis. PMID- 26105976 TI - List blocking and longer retention intervals reveal an influence of gist processing for lexically ambiguous critical lures. AB - In two experiments, we examined veridical and false memory for lists of associates from two meanings (e.g., stumble, trip, harvest, pumpkin, etc.) that converged upon a single, lexically ambiguous critical lure (e.g., fall), in order to compare the activation-monitoring and fuzzy-trace false memory accounts. In Experiment 1, we presented study lists that were blocked or alternated by meaning (within subjects), followed by a free recall test completed immediately or after a 2.5-min delay. Correct recall was greater for blocked than for alternated lists. Critical-lure false recall was greater for blocked lists on an immediate test, whereas both list types produced equivalent false recall on a delayed test. In Experiment 2, lists blocked and alternated by meaning were presented via a between-subjects design, in order to eliminate possible list-type carryover effects. Correct recall replicated the result from Experiment 1; however, blocking lists increased false recall on delayed, but not on immediate, tests. Across the experiments, clustering correct recall by meaning increased across the delay selectively for the alternated lists. Our results suggest that thematic (i.e., gist) processes are influential for false recall, especially following a delay, a pattern consistent with fuzzy-trace theory. PMID- 26105977 TI - Variations of secretome profiles according to conditioned medium preparation: The example of human mesenchymal stem cell-derived adipocytes. AB - One challenging point in analyzing cellular secretome collected as conditioned medium is cross-contamination by cell culture media components, especially bovine serum proteins. A common approach for serum removal is to wash the cells, an alternative is to grow cells using serum-free conditions. Given that the sample processing may influence the phenotype of cells and thus the secretome, it is important to establish the optimal protocol for each cell type. In this study, we compared two methods for preparing conditioned medium from human adipocytes derived from mesenchymal stem cells. Cells were either washed twice with PBS or cultured the last four days of differentiation in serum-free adipogenic medium. Gene expression of the cells was evaluated by using real-time PCR and 1D LC-MS/MS was used to compare secreted proteins present in the culture supernatants. Surprisingly, results showed significant differences in gene expression patterns of the cells and in protein content of the conditioned media and suggested that PBS washes induced severe modifications of the phenotype of cells and thus changes in protein secretion profiles. These data emphasize the significant variations in protein species related to cell manipulations and underline the importance of procedure optimization prior to any proteomic investigation. PMID- 26105978 TI - Young children contrast their behavior to that of out-group members. AB - The tendency for children to overimitate and conform to unanimous majorities is pervasive. Here we tested whether social factors are powerful enough to lead children to overcome this tendency and contrast their behavior to that of others. In one condition, children were shown a video of three out-group members performing the same action on a novel toy. In this condition, 5-year-olds, but not 4-year-olds, were significantly more likely to produce the contrasting action than the action demonstrated by the group. On the other hand, children who saw the same actions performed by neutral individuals typically matched their actions to those of the group regardless of their age. By demonstrating that 5-year-olds actively contrast their behavior to that of out-group members, these results provide an important comparison with previous research on imitation and conformity and demonstrate the profound influence that social motivations exert over children's copying behavior. PMID- 26105979 TI - Achieving synchronization with active hybrid materials: Coupling self-oscillating gels and piezoelectric films. AB - Lightweight, deformable materials that can sense and respond to human touch and motion can be the basis of future wearable computers, where the material itself will be capable of performing computations. To facilitate the creation of "materials that compute", we draw from two emerging modalities for computation: chemical computing, which relies on reaction-diffusion mechanisms to perform operations, and oscillatory computing, which performs pattern recognition through synchronization of coupled oscillators. Chemical computing systems, however, suffer from the fact that the reacting species are coupled only locally; the coupling is limited by diffusion as the chemical waves propagate throughout the system. Additionally, oscillatory computing systems have not utilized a potentially wearable material. To address both these limitations, we develop the first model for coupling self-oscillating polymer gels to a piezoelectric (PZ) micro-electro-mechanical system (MEMS). The resulting transduction between chemo mechanical and electrical energy creates signals that can be propagated quickly over long distances and thus, permits remote, non-diffusively coupled oscillators to communicate and synchronize. Moreover, the oscillators can be organized into arbitrary topologies because the electrical connections lift the limitations of diffusive coupling. Using our model, we predict the synchronization behavior that can be used for computational tasks, ultimately enabling "materials that compute". PMID- 26105980 TI - Association between low serum magnesium concentration and hyperuricemia. AB - OBJECTIVES: To examine the cross-sectional associations between serum magnesium (Mg) and hyperuricemia (HU). METHODS: 2904 subjects were included in this study. HU was defined as uric acid >=416 MUmol/L for the male population and >=360 MUmol/L for the female population. A multivariable logistic analysis model was applied to test the associations after adjusting for a number of potential confounding factors. RESULTS: The relative odds of the prevalence of HU were significantly decreased by 0.65 times in the third quintile of serum Mg (OR 0.65, 95% CI 0.47-0.89), and 0.61 times in the fifth quintile (OR 0.61, 95% CI 0.45 0.83), compared with the lowest quintile: P for trend was 0.002. For males, the relative odds for HU were significantly decreased by 0.61 times in the third quintile of serum Mg (OR 0.61, 95% CI 0.42-0.89), 0.68 times in the fourth quintile (OR 0.68, 95% CI 0.47-0.97), and 0.59 times in the fifth quintile (OR 0.59, 95% CI 0.41-0.84) compared with the lowest quintile: P for trend was 0.003. However, no significant association was observed between serum Mg and HU for females. CONCLUSION: Serum Mg is inversely associated with HU. This association remains valid for the male subgroup, but not for the female subgroup. PMID- 26105981 TI - Intrinsic half-metallicity in fractal carbon nitride honeycomb lattices. AB - Fractals are natural phenomena that exhibit a repeating pattern "exactly the same at every scale or nearly the same at different scales". Defect-free molecular fractals were assembled successfully in a recent work [Shang et al., Nature Chem., 2015, 7, 389-393]. Here, we adopted the feature of a repeating pattern in searching two-dimensional (2D) materials with intrinsic half-metallicity and high stability that are desirable for spintronics applications. Using first-principles calculations, we demonstrate that the electronic properties of fractal frameworks of carbon nitrides have stable ferromagnetism accompanied by half-metallicity, which are highly dependent on the fractal structure. The ferromagnetism increases gradually with the increase of fractal order. The Curie temperature of these metal-free systems estimated from Monte Carlo simulations is considerably higher than room temperature. The stable ferromagnetism, intrinsic half-metallicity, and fractal characteristics of spin distribution in the carbon nitride frameworks open an avenue for the design of metal-free magnetic materials with exotic properties. PMID- 26105982 TI - Interferon-inducible Protein 6-16 (IFI-6-16, ISG16) promotes Hepatitis C virus replication in vitro. AB - Interferon-inducible protein 6-16 (IFI-6-16, ISG16) is one of the interferon stimulated genes (ISGs) whose expression levels can be induced by type I interferons. Previous studies from our group indicated that higher expression levels of ISG16 were detected in the pre-treatment liver tissues of patients chronically infected with hepatitis C virus (HCV) who do not respond to interferon-based therapy. However, its role in HCV production is not well defined. This study is to test the effect of over-expression of ISG16 on HCV RNA replication and IFN anti-HCV activity in both HCV replicon cells and JFH-1 HCV culture system (HCVcc). Expression plasmid of ISG16 was constructed and transfected into HCV replicon cells or JFH-1 HCV culture system. After confirmation of the successful expression of ISG16 at mRNA (real-time PCR) and protein (Western Blot) levels, HCV RNA level was analyzed by real-time quantitative PCR in the absence or presence of interferon-alpha. Over-expression of ISG16 promoted HCV RNA replication in both the Con1b replicon and the HCV JFH 1-based cell culture system and blunted the anti-HCV activity of IFN-alpha. In conclusion, Over-expression of ISG16 promotes HCV RNA replication and rescues the IFNalpha-mediated anti-HCV activity. PMID- 26105983 TI - Management of Excessive Weight Loss Following Laparoscopic Roux-en-Y Gastric Bypass: Clinical Algorithm and Surgical Techniques. AB - BACKGROUND: There are no clinical guidelines or published studies addressing excessive weight loss and protein calorie malnutrition following a standard Roux en-Y gastric bypass (RYGB) to guide nutritional management and treatment strategies. This study demonstrates the presentation, clinical algorithm, surgical technique, and outcomes of patients afflicted and successfully treated with excessive weight loss following a standard RYGB. METHODS: Three patients were successfully reversed to normal anatomy after evaluation, management, and treatment by multidisciplinary team. Lowest BMI (kg/m(2)) was 18.9, 17.9, and 14.2, respectively. RESULTS: Twelve-month post-operative BMI (kg/m(2)) was 28.9, 22.8, and 26.1, respectively. Lowest weight (lbs) was 117, 128, and 79, respectively. Twelve-month post-operative weight (lbs) was 179, 161, and 145, respectively. Pre-reversal gastrostomy tube was inserted into the remnant stomach to demonstrate weight gain and improve nutritional status prior to reversal to original anatomy. CONCLUSION: We propose a practical clinical algorithm for the work-up and management of patients with excessive weight loss and protein calorie malnutrition after standard RYGB including reversal to normal anatomy. PMID- 26105985 TI - The New Dimension in Aortic Measurements - Use of the Inner Edge Measurement for the Thoracic Aorta in Australian Patients. AB - BACKGROUND: Historically, aortic measurements were established using M-mode echocardiography, measuring from the leading edge to leading edge. Improvements in echocardiographic imaging now permit accurate assessment using the blood tissue interface. Normal values have not been established using this technique. METHODS: A prospective analysis of consecutive patients without pathology was conducted. Measurements of aortic dimensions were made using the blood-tissue interface and the leading edge methods at end-diastole, and at end-systole using the blood-tissue interface. Data collected included BSA, and aortic measurements (LVOT, root, ST junction, mid ascending aorta, aortic arch). RESULTS: The echocardiograms of 512 patients were evaluated. The mean age was 56 years, with 304 males (59%) and 208 females (41%). The average measurements (blood tissue interface) were: aortic root 31.2mm, sinotubular junction 25.9mm, mid ascending aorta 30.6 and aortic arch 23.4. On average, the leading edge method measurements were 1.5mm larger (p<0.0001), consistent with the added thickness of the anterior aortic wall. Ratios to BSA were also estimated. Tables have been created suggesting normal and abnormal values. CONCLUSIONS: Improvements in echocardiographic imaging permit the blood-tissue interface to be readily visualised. Reference ranges for the estimation of aortic sizes using this method are provided. More accurate and anatomical estimation of the aortic dimensions can now be achieved. PMID- 26105986 TI - Acquired Large Calcified Unruptured Sinus of Valsalva Aneurysm. AB - Acquired aneurysms of the sinus of Valsalva are rare. They are caused by infections such as tuberculosis, syphilis and endocarditis, as well as atherosclerosis and traumatic injury. They may be asymptomatic and incidentally discovered. We present a rare case of a large acquired calcified unruptured aneurysm of the right coronary sinus of Valsalva that was compressing the right ventricular outflow tract. PMID- 26105987 TI - Slow Heart Rate Predicts New Occurrence of Atrial Fibrillation. AB - BACKGROUND: This study aims to investigate the relation between baseline heart rate and new occurrence of AF in patients with mild symptoms. METHODS: Patients without pre-existing AF or structural heart disease who underwent 24-hour electrocardiogram (ECG) monitoring for palpitations, dizziness or syncope were followed up for new-onset AF. RESULTS: 428 patients (mean age 66.6+/-10.2 years, 43.7% male) were classified according to the average heart rate into four quartiles (1(st) quartile: <63 beat per minute (bpm); 2(nd) quartile: 63-70 bpm; 3(rd) quartile 70-77 bpm; and 4(th) quartile: >77 bpm). There were no significant differences in gender, prevalence of diabetes, hypertension, left ventricular ejection fraction, or medications but a higher prevalence of coronary artery disease was noted among patients in the lower quartiles of average heart rate. After a mean follow-up of 5.8+/-1.8 years, 60 patients (14.0%) developed new onset AF. The annual incidence of new-onset AF was highest amongst those at the lowest quartile of average heart rate (9.39%/year) as compared to those amongst other quartiles. Cox regression analysis revealed that increasing age, decreasing quartile of average heart rate, and the use of calcium channel blocker were associated with increased risk of new-onset AF. CONCLUSIONS: Average heart rate predicts new AF. PMID- 26105988 TI - Adjustment and Coping Mechanisms for Individuals with Genetic Aortic Disorders. AB - BACKGROUND: Advances in diagnosis and management of Genetic Aortic (GA) Disorders have improved prognosis for affected individuals, yet many do not adhere to key management recommendations, and some may experience clinically significant levels of psychological distress. These issues are often not communicated to treating clinicians. Poor adjustment and coping may adversely impact on prognosis, but little is known about the processes contributing to negative outcomes. This study investigated adjustment to GA disorders to determine which processes facilitated or hindered good adherence and psychological outcomes. METHODS: Semi-structured interviews involving 21 individuals (12M, 9 F; age 19-62 years) with a GA Disorder and psychosocial measures of depression/stress/anxiety (DASS), coping (COPE) and involvement in treatment (CPS) were used. Qualitative data were analysed using grounded theory and a model of adjustment was developed. RESULTS: Although most participants adhered to physician management recommendations and experienced minimal emotional distress, a subset reported poor adherence and/or sub/clinical levels of depression/anxiety/stress (29%). Dysfunctional coping mechanisms were infrequent, however 22% participants reported 'little or no' acceptance and 43% avoided life planning in response to a diagnosis of GA disorder. Interviews revealed an overarching theme: Negotiating perception of self and GA disorder, supported by five sub-themes: Restrictions upon Lifestyle, Destabilisation, Future, Support, and Unmet Needs. Accepting restrictions and having support were conducive to better adherence, whilst destabilisation and loss of control had a negative impact. A model of adjustment is proposed to explain how patients reached one of four outcomes relating to psychological distress and adherence to physician recommendations. The central tenet of the model is founded on how realistically patients appraise their vulnerability to GA threat and whether they are able to integrate their perceptions of illness with their sense of self-identity. CONCLUSIONS: This study indicates that individuals with GA are at risk of experiencing psychosocial distress and coping difficulties, even years after diagnosis. Key factors likely to be associated with impaired coping among GA patients include inability to integrate the illness into one's identity/life, or to follow physician recommendations. Potential unmet needs were identified, including the provision of more relevant information and opportunities for peer support. These findings may also be applicable to other inherited cardiac disorders. PMID- 26105989 TI - Supplements and Cardiovascular Health. PMID- 26105990 TI - Analysis of Lipoprotein Subfractions in Chinese Han Patients with Stable Coronary Artery Disease. AB - BACKGROUND: The relation of lipoprotein subfractions with stable coronary artery disease (CAD) has not been fully investigated in the Chinese Han population. METHODS: Four-hundred-and-thirteen consecutive patients without any lipid lowering drug treatment were investigated. Patients were classified into two groups according to the angiographic results: CAD group (n=293) and non-CAD group (n=120). The high-density lipoprotein (HDL) and low-density lipoprotein (LDL) subfractions were analysed using the Quantimetrix Lipoprint system. RESULTS: The data showed that the large HDL-cholesterol (HDL-C) level, large HDL subfraction percentage, and mean LDL particle size were significantly lower, while the small HDL-C level and HDL subfraction percentage, intermediate and small LDL cholesterol (LDL-C) levels, and LDL subfraction percentages were higher in the CAD group compared with those in the non-CAD group. Interestingly, our results suggested that the small HDL-C level and HDL subfraction percentage as well as mean LDL particle size were independently associated with the presence of CAD assessed by logistic regression analysis (OR=1.136, 95%CI=1.018-1.268, p=0.022; OR=1.076, 95%CI=1.021-1.134, p=0.007; OR=0.946, 95%CI=0.898-0.997, p=0.040; respectively). CONCLUSIONS: Similar to previous Western population studies, our data suggested a clear association between the lipoprotein subfractions and stable CAD presented as higher small HDL subfraction and smaller mean LDL particle size in Chinese Han patients. PMID- 26105992 TI - Orbital reconstruction in nonpolar tetravalent transition-metal oxide layers. AB - A promising route to tailoring the electronic properties of quantum materials and devices rests on the idea of orbital engineering in multilayered oxide heterostructures. Here we show that the interplay of interlayer charge imbalance and ligand distortions provides a knob for tuning the sequence of electronic levels even in intrinsically stacked oxides. We resolve in this regard the d level structure of layered Sr2IrO4 by electron spin resonance. While canonical ligand-field theory predicts g||-factors less than 2 for positive tetragonal distortions as present in Sr2IrO4, the experiment indicates g|| is greater than 2. This implies that the iridium d levels are inverted with respect to their normal ordering. State-of-the-art electronic-structure calculations confirm the level switching in Sr2IrO4, whereas we find them in Ba2IrO4 to be instead normally ordered. Given the nonpolar character of the metal-oxygen layers, our findings highlight the tetravalent transition-metal 214 oxides as ideal platforms to explore d-orbital reconstruction in the context of oxide electronics. PMID- 26105991 TI - Hairy and Enhancer of Split 6 (Hes6) Deficiency in Mouse Impairs Neuroblast Differentiation in Dentate Gyrus Without Affecting Cell Proliferation and Integration into Mature Neurons. AB - Hes6 is a member of the hairy-enhancer of split homolog (Hes) family of transcription factors and interacts with other Hes family genes. During development, Hes genes are expressed in neural stem cells and progenitor cells. However, the role of Hes6 in adult hippocampal neurogenesis remains unclear. We therefore investigated the effects of Hes6 on adult hippocampal neurogenesis, by comparing Hes6 knockout and wild-type mice. To this end, we immunostained for markers of neural stem cells and progenitor cells (nestin), proliferating cells (Ki67), post-mitotic neuroblasts and immature neurons (doublecortin, DCX), mature neuronal cells (NeuN), and astrocyte (S100beta). We also injected 5-bromo-2' deoxyuridine (BrdU) to trace the fate of mitotic cells. Nestin- and Ki67-positive proliferating cells did now show any significant differences between wild and knockout groups. Hes6 knockout negatively affects neuroblast differentiation based on DCX immunohistochemistry. On the contrary, the ratio of the BrdU and NeuN double-positive cells did not show any significance, even though it was slightly higher in the knockout group. These results suggest that Hes6 is involved in the regulation of neuroblast differentiation during adult neurogenesis, but does not influence integration into mature neurons. PMID- 26105993 TI - The Expression of Tubb2b Undergoes a Developmental Transition in Murine Cortical Neurons. AB - The development of the mammalian brain requires the generation, migration, and differentiation of neurons, cellular processes that are dependent on a dynamic microtubule cytoskeleton. Mutations in tubulin genes, which encode for the structural subunits of microtubules, cause detrimental neurological disorders known as the tubulinopathies. The disease spectra associated with different tubulin genes are overlapping but distinct, an observation believed to reflect functional specification of this multigene family. Perturbation of the beta tubulin TUBB2B is known to cause polymicrogyria, pachygyria, microcephaly, and axon guidance defects. Here we provide a detailed analysis of the expression pattern of its murine homolog Tubb2b. The generation and characterization of BAC transgenic eGFP reporter mouse lines has revealed that it is highly expressed in progenitors and postmitotic neurons during cortical development. This contrasts with the 8-week-old cortex, in which Tubb2b expression is restricted to macroglia, and expression is almost completely absent in mature neurons. This developmental transition in neurons is mirrored in the adult hippocampus and the cerebellum but is not a universal feature of Tubb2b; its expression persists in a population of postmitotic neurons in the 8-week-old retina. We propose that the dynamic spatial and temporal expression of Tubb2b reflects specific functional requirements of the microtubule cytoskeleton. PMID- 26105994 TI - China rejects patent on hepatitis C drug sofosbuvir. PMID- 26105996 TI - Beyond the meristems: similarities in the CLAVATA3 and INFLORESCENCE DEFICIENT IN ABSCISSION peptide mediated signalling pathways. AB - Plants form new organs throughout their lives; this requires a balance between cell proliferation and differentiation, and between the generation and loss of organs. To do this, plants must maintain a population of stem cells within the meristems, and at the same time, closely control the identity and position of cells at the meristem boundaries as they differentiate to new leaf or flower primordia. Once developed, organs may need to be shed, either as a controlled developmental decision-such as floral abscission after pollination, or as a response to disease, environmental stress, and predators. Cell wall degradation at specialized abscission zone (AZ) cells needs to occur for this to take place, but since there is little cell rearrangement in plants, cell separation events are also important for plant architecture. In this Opinion paper we discuss the role of two peptide ligand signalling systems that control stem cell homeostasis and cell separation, respectively. We draw parallels between the signalling pathways and explore on the commonalities of the downstream components activated and controlled by the signalling peptides. We provide evidence for AZ cells having a meristem identity and discuss the role of identical KNOTTED-LIKE HOMEOBOX (KNOX) transcription factors in meristem maintenance and abscission. Lastly we explore the evolutionary relationship between the pathways. PMID- 26105995 TI - Developmentally regulated HEART STOPPER, a mitochondrially targeted L18 ribosomal protein gene, is required for cell division, differentiation, and seed development in Arabidopsis. AB - Evidence is presented for the role of a mitochondrial ribosomal (mitoribosomal) L18 protein in cell division, differentiation, and seed development after the characterization of a recessive mutant, heart stopper (hes). The hes mutant produced uncellularized endosperm and embryos arrested at the late globular stage. The mutant embryos differentiated partially on rescue medium with some forming callus. HES (At1g08845) encodes a mitochondrially targeted member of a highly diverged L18 ribosomal protein family. The substitution of a conserved amino residue in the hes mutant potentially perturbs mitoribosomal function via altered binding of 5S rRNA and/or influences the stability of the 50S ribosomal subunit, affecting mRNA binding and translation. Consistent with this, marker genes for mitochondrial dysfunction were up-regulated in the mutant. The slow growth of the endosperm and embryo indicates a defect in cell cycle progression, which is evidenced by the down-regulation of cell cycle genes. The down regulation of other genes such as EMBRYO DEFECTIVE genes links the mitochondria to the regulation of many aspects of seed development. HES expression is developmentally regulated, being preferentially expressed in tissues with active cell division and differentiation, including developing embryos and the root tips. The divergence of the L18 family, the tissue type restricted expression of HES, and the failure of other L18 members to complement the hes phenotype suggest that the L18 proteins are involved in modulating development. This is likely via heterogeneous mitoribosomes containing different L18 members, which may result in differential mitochondrial functions in response to different physiological situations during development. PMID- 26105997 TI - High-resolution quantification of root dynamics in split-nutrient rhizoslides reveals rapid and strong proliferation of maize roots in response to local high nitrogen. AB - The plant's root system is highly plastic, and can respond to environmental stimuli such as high nitrogen (N) in patches. A root may respond to an N patch by selective placement of new lateral roots, and therewith increases root N uptake. This may be a desirable trait in breeding programmes, since it decreases NO3(-) leaching and N2O emission. Roots of maize (Zea mays L.) were grown without N in split-nutrient rhizoslides. One side of the slides was exposed to high N after 15 d of root development, and root elongation was measured for another 15 d, described in a time course model and parameterized. The elongation rates of crown axile roots on the N-treated side of the plant followed a logistic increase to a maximum of 5.3cm d(-1); 95% of the maximum were reached within 4 d. At the same time, on the untreated side, axile root elongation dropped linearly to 1.2cm d( 1) within 6.4 d and stayed constant thereafter. Twice as many lateral roots were formed on the crown axis on the N side compared to the untreated side. Most strikingly, the elongation rates of laterals of the N side increased linearly with most of the roots reaching an asymptote ~8 d after start of the N treatment. By contrast, laterals on the side without N did not show any detectable elongation beyond the first day after their emergence. We conclude that split nutrient rhizoslides have great potential to improve our knowledge about nitrogen responsiveness and selection for contrasting genotypes. PMID- 26105998 TI - Comparative glycopattern analysis of mucins in the Brunner's glands of the guinea pig and the house mouse (Rodentia). AB - The mucins secreted by the Brunner's glands and the duodenal goblet cells of the Guinea-pig and the house mouse were compared by conventional and FITC-conjugated lectin histochemistry. Methylation/saponification and sialidase digestion were performed prior to lectin binding to detect the residues subterminal to sulfated groups and sialic acid, respectively. In the Guinea-pig the Brunner's glands produce class-III stable sulfosialomucins. Sialic acid is mostly 2,6-linked to galactose or to N-acetylgalactosamine and is in part O-acetylated in C7, C8, and C9. Sulfated groups are probably linked to sialic acid and N-acetylgalactosamine. Terminal residuals of N-acetylglucosamine, galactose, N-acetylgalactosamine and fucose linked in alpha1,2, alpha1,3, and alpha1,4 are also present. Duodenal goblet cells of the Guinea-pig present a lower number of residuals in respect to the Brunner's glandular ones, with sialic acid and N-acetylgalactosamine subterminal to sulfated groups. In the house mouse the Brunner's glands produce class-III stable neutral mucins, binding to same lectins as in the Guinea-pig except for those specific to sialic acid. A diversity of fucosylated residuals higher than in the Guinea-pig is observed. The mouse duodenal goblet cells lack stable class-III mucins, have little sialic acid and present a lower number of residuals in respect to the correspondent Brunner's glands. Regulation of the acidic intestinal microenvironment, prevention of pathologies and hosting of microflora can explain the observed results and the differences observed between the two rodents. PMID- 26105999 TI - Age-Dependent Decrease of DNA Hydroxymethylation in Human T Cells. AB - Hydroxymethylcytosine (hmC) is a natural nucleobase, which is converted from methylcytosine (mC) by tet methylcytosine dioxygenase (TET) family (TET1-3) enzymes. Decrease of genomic hmC is postulated to confer a risk for myeloid lineage as well as T-cell neoplasms, based on the fact that loss-of-function mutations in the TET2 gene were frequently identified in these diseases. The relationship between hmC and aging remains to be elucidated. Here, we demonstrated that hmC content decreased with age in the peripheral blood T cells of 53 human volunteers. We further identified that the mRNA expression levels of TET1 and TET3 decreased with age, while those of TET2 were not influenced by age. The genomic hmC content was correlated with the mRNA expression level of TET3, but not those of TET1 and TET2. Our study suggests the presence of new epigenetic regulatory mechanisms in aging T cells. PMID- 26106000 TI - Histopathological Characteristics of Lymphomas in the Upper Aerodigestive Tract. A Single-Institute Study in Japan. AB - We analyzed the histopathological characteristics of lymphomas biopsied from the upper aerodigestive tract between 2000 and 2014 at the National Cancer Center Hospital in Japan. Of a total of 309 consecutive cases, the following incidences were observed: mature B-cell neoplasms, 77% (n = 239); mature T- and NK-cell neoplasms, 20% (n = 63); classical Hodgkin lymphomas, 0.7% (n = 2); and lymphoblastic lymphomas, 2% (n = 5). Lymphomas were most frequently (57%) detected in the oropharynx. The majority of cases (89%) were mature B-cell neoplasms (diffuse large B-cell lymphoma, 60%; follicular lymphoma, 10%), and 10% of cases were mature T-cell neoplasms. Six cases of plasma cell neoplasm (4 primary and 2 secondary involvement) and 2 cases of plasmablastic lymphoma in the upper aerodigestive tract were observed. Two out of 3 cases of extraosseous plasmacytoma with available biopsy material were positive for EBER1. All 3 patients received irradiation and achieved complete response; 1 had not relapsed after 17 months and the remaining 2 relapsed as plasma cell myeloma and solitary plasmacytoma of the bone. Of 47 extranodal NK/T-cell lymphoma, nasal-type cases in the upper aerodigestive tract, 38 (81%) were present in the sinonasal region and the remaining 9 (19%) were in the oropharynx (n = 4), nasopharynx (n = 3), and oral cavity (n = 2). In conclusion, since both primary lymphoma and secondary involvement of lymphoma are often diagnosed using biopsied materials from the upper aerodigestive tract, pathologists and hematologists should recognize the characteristics of lymphoma in this tissue. PMID- 26106001 TI - Mutation Analysis for TP53 in Chronic-Type Adult T-Cell Leukemia/Lymphoma. AB - Adult T-cell leukemia/lymphoma (ATLL) is a T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). ATLL is classified into four clinical subtypes based on the clinical manifestation: acute, lymphoma, chronic and smoldering. Approximately half of chronic type ATLL cases progressed to the acute type. We previously demonstrated that genomic alterations related to the cell cycle de regulation such as CDKN2A and immune escape such as CD58 alteration can serve as predictive biomarkers for acute transformation of the chronic type. Although alteration of TP53, which is known to be a major regulator of cell cycle, has been identified in several types of cancers including acute type ATLL, no copy number alteration of TP53 was found in the chronic type by array comparative genomic hybridization. In the present study, mutation of TP53 was further analyzed by sequencing for these cases as well as HTLV-I carriers with oligo clonality. However, no TP53 mutation was identified. These results suggested that TP53 mutation plays a role for the later stage of ATLL development. PMID- 26106002 TI - T-Cell Prolymphocytic Leukemia, Small Cell Variant, Possibly at the Stage of Intracytoplasmic Expression of CD3 in T-Cell Ontogenesis. AB - T-cell prolymphocytic leukemia, small cell variant (T-PLL-s), is a rare lymphoid neoplasm associated with a poor prognosis. We encountered a case of T-PLL-s with a characteristic phenotype. A 67-year-old female was referred to our hospital because of lymphocytosis in August 2013. Hepatosplenomegaly, lymphadenopathy, and skin lesions were absent. Hematologic examination revealed a white blood cell count of 17.9 * 10(9)/L with 81.2% mature lymphocytes, which were small with a high nuclear/cytoplasmic ratio, lacking a nucleolus and cytoplasmic granules. Anemia and thrombocytopenia were not observed. Flow cytometric analysis showed that these lymphocytes were positive for CD2, cyCD3, CD4, CD5, CD7, CD21, and CD38 (partially), but negative for smCD3, smTCR-alphabeta and -gammadelta, cyTCR beta, CD1a, CD8, CD25, HLA-DR, and terminal deoxynucleotidyl transferase. Polymerase-chain reaction analysis of cells from both the peripheral blood and the bone marrow demonstrated monoclonal rearrangement of TCR-gamma. A possible rearranged band of the TCR-beta gene was observed by Southern blot analysis. The karyotype of the marrow cells was 46, XX. A diagnosis of T-PLL-s, possibly at the stage of cytoplasmic CD3 expression in the ontogenesis of T-cells, was made. The patient has been asymptomatic, and the white blood cell count has gradually increased during one-year observation, being 69.0 * 10(9)/L with 89.7% lymphocytes in August 2014. PMID- 26106003 TI - Lymphocyte-Rich Classical Hodgkin Lymphoma. A Case with Difficulty in Distinguishing from Nodular Lymphocyte-Predominant Hodgkin Lymphoma. AB - A 35-year-old man was referred to our hospital because of left supraclavicular and cervical lymphadenopathies. Histopathological examination of the lymph nodes revealed reactive lymphadenopathy. He visited our hospital three years after the initial diagnosis because of enlarged left cervical lymph nodes. Histopathologically, both Hodgkin/Reed-Sternberg (H/RS) and lymphocyte predominant (LP) cells were found in the lymph node. We first suspected nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), because these cells were CD15(-) and CD30(-). However, the diagnosis of lymphocyte-rich classical Hodgkin lymphoma (LRCHL) was finally confirmed, because these cells were found to be CD20(-), Bob.1(+), Oct.2(-), and BCL6(-) by additional immunostaining. The patient was treated with six cycles of ABVD chemotherapy, and a complete response was achieved. However, he underwent autologous stem-cell transplantation after high dose chemotherapy owing to a relapse 10 months after primary treatment. Distingushing LRCHL from NLPHL was difficult in this patient, because histopathological examination showed both H/RS and LP cells, and immunostaining revealed these cells to be triple negative (CD15(-), CD30(-) and CD20(-)). Accumulation of such cases are necessary to establish better criteria for the differential diagnosis and assessment of clinical behavior. PMID- 26106004 TI - Acute Myeloid Leukemia Diagnosed 5 Years after Adult T-Cell Leukemia/Lymphoma. AB - A case of secondary acute myeloid leukemia (AML) was identified following adult T cell leukemia/lymphoma (ATL), for which combination chemotherapy had been administered, including epipodophyllotoxin, anthracycline, and alkylating agents. AML with maturation was diagnosed by the cytological findings, cell surface markers, and chromosomal abnormalities. We previously reported two cases of AML accompanied by ATL. In this case of AML after chemotherapy for ATL, we considered that the AML was probably associated with previous chemotherapy for ATL. Although the ATL remained in remission, the therapy-related AML with complex chromosomal abnormalities proved resistant to chemotherapy, and the patient died from complications associated with AML. PMID- 26106005 TI - Complete Remission in Systemic Skin Interdigitating Dendritic Cell Sarcoma after ABVD Chemotherapy. AB - Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm that is thought to arise from dendritic cells. This disease usually involves the lymph nodes and, rarely, extra-nodal sites. We report a 62-year-old man presenting skin nodules in the head, body, and extremities, as well as bone marrow involvement. Morphologic analysis of a biopsied specimen from the skin lesion was consistent with IDCS. Immunohistochemical staining demonstrated that the tumor cells were positive for IDCS-associated antigens such as CD4, CD45, CD68 (KP-1), and S-100 protein. Complete remission was achieved by treatment with 6 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) chemotherapy. Although the optimal treatment of IDSC remains unknown, the experience in the current case supports the notion that ABVD chemotherapy may be effective for IDCS, and further extends this idea to rare patients presenting multiple skin lesions. PMID- 26106006 TI - Intravascular Large B-Cell Lymphoma Complicated by Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis that was Successfully Treated with Rituximab Containing Chemotherapy. AB - A 64-year-old woman had suffered from painful livedo reticularis for 2 years and was referred to us due to fever, anasarca and paresthesia of the lower limbs. Serum proteinase-3-anti-neutrophil cytoplasmic antibody (ANCA) was positive. Abnormal lymphocytes were found in the cerebrospinal fluid and bone marrow. Skin biopsy revealed large atypical lymphoid cells with CD20 positivity lodged in the small vessels and neutrophilic infiltration into the arterial vascular wall with fibrinoid degeneration. A diagnosis of intravascular large B-cell lymphoma complicated by ANCA-associated vasculitis was made, and rituximab-containing chemotherapy followed by prednisolone was quite effective for both lymphoma and ANCA-associated vasculitis. PMID- 26106007 TI - Histiocytic Sarcoma Originating in the Lung in a 16-Year-Old Male. AB - We report a 16-year-old male with histiocytic sarcoma (HS) originating in the lung. Partial resection of the lung was performed for a 3-cm mass with a clear boundary detected in the right inferior pulmonary lobe on a health checkup. Histologically, the tumor infiltrated into the surrounding tissue, and was comprised of spindle cells, mainly, and foam cells accompanied by mild nuclear atypia. The tumor cells were immunohistochemically positive for CD68 and CD163, indicating histiocytic lineage and the MIB-1-positive rate was low. Spindle cell morphology of HS is quite rare and only 3 cases of pulmonary HS have previously been reported. PMID- 26106008 TI - Double-Hit Lymphoma. PMID- 26106009 TI - Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. AB - BACKGROUND: Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. METHODS AND RESULTS: We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.97 and HR, 0.84; 95%, CI 0.67-1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61-1.04 and HR, 0.65; 95% CI, 0.55-0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84 1.22 and HR, 0.84; 95% CI, 0.73-0.96; interaction P=0.10). CONCLUSIONS: More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. PMID- 26106011 TI - Dyslipidemia testing: Why, for whom and when. AB - Dyslipidemia is a major risk factor for cardiovascular disease. This review addresses why, who and when to test for dyslipidemia. The essence why to test lipids is that those individuals recognized to potentially benefit from primary cardiovascular risk prevention, have a complete cardiovascular risk assessment. Who and when to test lipids differs among the major European, English and American guidelines regarding the recommended age and approach. It is important to note that the threshold and the frequency in whom to perform risk assessment is not established. Most important in decisions concerning lipid testing is communication and to involve individual circumstances. PMID- 26106010 TI - The relationship between cognitive function and high-resolution diffusion tensor MRI of the cingulum bundle in multiple sclerosis. AB - BACKGROUND: Imaging can provide noninvasive neural markers of disease progression in multiple sclerosis (MS) that are related to behavioral and cognitive symptoms. Past work suggests that diffusion tensor imaging (DTI) provides a measure of white matter pathology, including demyelination and axonal counts. OBJECTIVES: In the current study, the authors investigate the relationship of DTI measures in the cingulum bundle to common deficits in MS, including episodic memory, working memory, and information processing speed. METHODS: Fifty-seven patients with MS and 17 age- and education-matched controls underwent high-spatial resolution diffusion scans and cognitive testing. Probabilistic tracking was used to generate tracks from the posterior cingulate cortex to the entorhinal cortex. RESULTS: Radial and axial diffusivity values were significantly different between patients and controls (p < 0.031), and in patients bilateral diffusion measures were significantly related to measures of episodic memory and speed of processing (p < 0.033). CONCLUSIONS: The tractography-based measures of posterior cingulum integrity reported here support further development of DTI as a viable measure of axonal integrity and cognitive function in patients with MS. PMID- 26106012 TI - Palliative care: From oncology to all nursing arenas - Good practice or scaring the patients? AB - The aim of this paper is to encourage critical discussion of an individual's understanding of palliative care and compare this with a health care professional's understanding of palliative care. In doing this, the paper serves to illustrate the importance of words attached to services - so with palliative care - are we providing good care, or scaring the patients? The paper touches on the historical origins of palliative care as an adjunct of oncology, to a specialism in its own right and now as an integral part of all care - in a 'generalist palliative care nurse'. However, it is unlikely that patients and their families are aware of such developments and will see palliative care services as immediate end of life care. It is argued that whatever your thoughts on the use of the term 'palliative care', it is important to understand what has resonance for patients. You may not agree with this paper, and I do not expect all of you to agree, but I hope it has made you think. For those who strongly disagree, take heart from a quote by Frank A. Clark (1860-1936) 'We find comfort among those who agree with us - growth among those who don't'. PMID- 26106013 TI - Defining the minimum anatomical coverage required to protect the axilla and arm against penetrating ballistic projectiles. AB - INTRODUCTION: Defining the minimum anatomical structural coverage required to protect from ballistic threats is necessary to enable objective comparisons between body armour designs. Current protection for the axilla and arm is in the form of brassards, but no evidence exists to justify the coverage that should be provided by them. METHOD: A systematic review was undertaken to ascertain which anatomical components within the arm or axilla would be highly likely to lead to either death within 60 min or would cause significant long-term morbidity. RESULTS: Haemorrhage from vascular damage to the axillary or brachial vessels was demonstrated to be the principal cause of mortality from arm trauma on combat operations. Peripheral nerve injuries are the primary cause of long-term morbidity and functional disability following upper extremity arterial trauma. DISCUSSION: Haemorrhage is managed through direct pressure and the application of a tourniquet. It is therefore recommended that the minimum coverage should be the most proximal extent to which a tourniquet can be applied. Superimposition of OSPREY brassards over these identified anatomical structures demonstrates that current coverage provided by the brassards could potentially be reduced. PMID- 26106014 TI - Hundreds are arrested for Medicare fraud totalling $712m. PMID- 26106015 TI - Reply. PMID- 26106016 TI - Creation of a 3D printed temporal bone model from clinical CT data. AB - PURPOSE: Generate and describe the process of creating a 3D printed, rapid prototype temporal bone model from clinical quality CT images. MATERIALS AND METHODS: We describe a technique to create an accurate, alterable, and reproducible rapid prototype temporal bone model using freely available software to segment clinical CT data and generate three different 3D models composed of ABS plastic. Each model was evaluated based on the appearance and size of anatomical structures and response to surgical drilling. RESULTS: Mastoid air cells had retained scaffolding material in the initial versions. This required modifying the model to allow drainage of the scaffolding material. External auditory canal dimensions were similar to those measured from the clinical data. Malleus, incus, oval window, round window, promontory, horizontal semicircular canal, and mastoid segment of the facial nerve canal were identified in all models. The stapes was only partially formed in two models and absent in the third. Qualitative feel of the ABS plastic was softer than bone. The pate produced by drilling was similar to bone dust when appropriate irrigation was used. CONCLUSION: We present a rapid prototype temporal bone model made based on clinical CT data using 3D printing technology. The model can be made quickly and inexpensively enough to have potential applications for educational training. PMID- 26106017 TI - External-beam radiation therapy for malignant paraganglioma of the head and neck. AB - BACKGROUND: Malignant paragangliomas of the head and neck are very rare tumors of the neuroendocrine cells associated with the peripheral nervous system. There are limited data available to help guide treatment of these tumors and the role of radiation therapy (RT) is not well-defined. This article briefly reviews the pathology, clinical presentation, and treatment modalities of these tumors and reviews our institutional experience in treating this malignancy. PATIENTS AND METHODS: From November 1993 through May 2005, 5 patients with 5 malignant paragangliomas of the jugular bulb and carotid body were treated with RT at the University of Florida to a median dose of 70 Gy at 1.8 Gy per fraction. Mean and median follow-up times are 12.8 years and 14.4 years, respectively. RESULTS: We were able to achieve significant disease-free intervals of >10 years for 3 of 5 patients and >5 years for 4 of 5 patients. Of the 2 patients who failed treatment, 1 recurred 7.3 years after the RT salvage treatment following combination surgery and RT at another institution, and 1 experienced distant metastasis 2.8 years after treatment without obvious recurrence of local disease. CONCLUSION: Malignant paragangliomas are a very rare entity whose main treatment modality has yet to be well established. Overall, data concerning outcomes are sparse, but particularly data on the role of RT in the treatment of these difficult tumors. We recommend doses to 70 Gy at 2 Gy per once-daily fraction as an adjuvant treatment with surgery to both remove the source of disease and provide microscopic control. Patients with incompletely resectable tumors are treated with RT alone. PMID- 26106018 TI - Thermal desorption gas chromatography with mass spectrometry study of outgassing from polymethacrylimide foam (Rohacell(r)). AB - Polymethacrylimide foams are used as light structural materials in outer-space devices; however, the foam closed cells contain volatile compounds that are outgassed even at low temperatures. These compounds ignite as plasmas under outer space radiation and the intense radio-frequency fields used in communications. Since plasmas may cause spacecraft fatal events, the conditions in which they are ignited should be investigated. Therefore, qualitative and quantitative knowledge about polymethacrylimide foam outgassing should be established. Using thermogravimetric analysis, weight losses reached 3% at ca. 200 degrees C. Thermal desorption gas chromatography with mass spectrometry detection was used to study the offgassed compounds. Using successive 4 min heating cycles at 125 degrees C, each one corresponding to an injection, significant amounts of nitrogen (25.3%), water (2.6%), isobutylene (11.3%), tert-butanol (2.9%), 1 propanol (11.9%), hexane (25.3%), propyl methacrylate (1.4%), higher hydrocarbons (11.3%), fatty acids (2.2%) and their esters (1.3%), and other compounds were outgassed. Other compounds were observed during the main stage of thermal destruction (220-280 degrees C). A similar study at 175 degrees C revealed the extreme difficulty in fully outgassing polar compounds from polymethacrylimide foams by baking and showed the different compositions of the offgassed atmosphere that can be expected in the long term. PMID- 26106023 TI - GP leaders unite in calling for inspections of surgeries to be suspended. PMID- 26106024 TI - Recurrent cerebral ischemia after patent foramen ovale percutaneous closure in older patients: A two-center registry study. AB - OBJECTIVES: The aim of this study is to describe the cerebral ischemia recurrence rate after percutaneous patent foramen ovale (PFO) closure in patients older than 55 years and their outcomes, compared with younger patients. BACKGROUND: The registries data and the recent randomized trials about PFO closure are focused on patients younger than 55 years. Little is known about older patients' long-term outcome. METHODS: In total, 458 patients underwent PFO closure for cryptogenic cerebral ischemia and were stratified into an "older" (>= 55 years, 151 patients) and a "younger" (<55 years, 307 patients) group. RESULTS: Older patients had mean age of 63 +/- 6 years and more atrial septum aneurysm (P = 0.05), hypertension, diabetes, and dyslipidemia (P = 0.001). Mean followup was 4.5 +/- 2.8 years. Older patients had a higher rate of ischemic recurrence (0.3 vs. 4.0%, P = 0.002), after a mean time of 3.1 +/- 2.6 years. The Kaplan-Meier curve confirmed higher event-free survival in the youngers (P = 0.008). None of the patients with ischemic recurrence had significant residual shunt. Age and hypertension were correlated to ischemic recurrence, but age was the only independent predictor at multivariate analysis. CONCLUSIONS: Recurrent cerebral ischemia after PFO closure is more frequent in older patients and could most likely be associated to conditions related to age (atherosclerosis, atrial fibrillation), than to paradoxical embolism. The procedure is as safe as in younger patients. PMID- 26106025 TI - Correlation between the different therapeutic properties of Chinese medicinal herbs and delayed luminescence. AB - In the practice and principle of Chinese medicine, herbal materials are classified according to their therapeutic properties. 'Cold' and 'heat' are the most important classes of Chinese medicinal herbs according to the theory of traditional Chinese medicine (TCM). In this work, delayed luminescence (DL) was measured for different samples of Chinese medicinal herbs using a sensitive photon multiplier detection system. A comparison of DL parameters, including mean intensity and statistic entropy, was undertaken to discriminate between the 'cold' and 'heat' properties of Chinese medicinal herbs. The results suggest that there are significant differences in mean intensity and statistic entropy and using this method combined with statistical analysis may provide novel parameters for the characterization of Chinese medicinal herbs in relation to their energetic properties. PMID- 26106026 TI - A clinicopathologic study of 11 rosette-forming meningiomas: a rare and potentially confusing pattern. PMID- 26106027 TI - Depleted mitochondrial DNA content in peripheral blood of women with a history of HELLP syndrome. AB - OBJECTIVE: To test the hypothesis that a quantitative defect of maternal cellular mitochondria would play a role in the pathogenesis of HELLP syndrome. STUDY DESIGN: Peripheral blood mitochondrial DNA (MtDNA) was measured in 20 non pregnant women with a history of HELLP syndrome, 40 non-pregnant control subjects who had previous physiologic pregnancies, 59 subjects carrying physiologic pregnancies, seven pregnant women with a history of HELLP syndrome and five women in the active phase of the disease. MAIN OUTCOME MEASURE: Peripheral blood Mt DNA. RESULTS: The median (interquartile range) mtDNA in women with a history of HELLP syndrome, in non-pregnant women who had previous physiologic pregnancies, in subjects carrying physiologic pregnancies, in pregnant women with a history of HELLP syndrome and in women in the active phase of the disease was 115 (81-194), 229 (199-319), 174 (136-211), 101 (82-178) and 92 (39-129) copies per nuclear DNA, respectively. Non-pregnant women with a history of HELLP syndrome had significantly lower levels than non-pregnant controls (p<0.001). Moreover, blood mtDNA was lower in pregnant women with a history of HELLP syndrome and in those in the active phase of the disease when compared to pregnant controls (p=0.002 and p=0.025, respectively). CONCLUSIONS: Attenuated maternal mitochondrial function may favor HELLP syndrome development. PMID- 26106028 TI - Clinical significance of proteinuria determined with dipstick test, edema, and weekly weight gain ?500g at antenatal visit. AB - OBJECTIVE: To determine how urine dipstick test, edema, and/or excessive weight gain (EWG, defined as ?500g/week) at antenatal visits predict significant proteinuria (defined as a protein-to-creatinine ratio [P/Cr, mg/mg] ?0.27) and preeclampsia. METHODS: Data from 3279 antenatal visits between 30 and 36weeks of gestation were studied in 783 women with singleton pregnancies. In 24 preeclamptic pregnancies, data from 89 antenatal visits at and before diagnosis of preeclampsia were used. Spot P/Cr was determined in women with repeated positive dipstick test results in two successive antenatal visits or in those with a positive dipstick test result tested in the presence of hypertension. RESULTS: Proteinuria on dipstick test, edema, and EWG appeared often in both women with and without preeclampsia; 66.7% vs. 27.7%, 83.3% vs. 44.1%, and 91.7% vs. 81.6%, respectively. However, repeated positive dipstick test results in two successive antenatal visits yielded sensitivity of 45.5%, specificity of 95.2%, and positive and negative predictive values of 30.0% and 97.4%, respectively, for detection of significant proteinuria and corresponding figures of 33.3%, 94.1%, 14.0%, and 98.0% for prediction of preeclampsia. CONCLUSION: Repeated positive dipstick test results in two successive antenatal visits warrant a need for a confirmation test of significant proteinuria. PMID- 26106029 TI - An assessment of predictive value of the biophysical profile in women with preeclampsia using data from the fullPIERS database. AB - INTRODUCTION: Pre-eclampsia is associated with increased risk to both the mother and fetus. Effective monitoring of the fetal condition is essential to the management of women with pre-eclampsia. The biophysical profile (BPP) is one monitoring tool available to clinicians. AIMS AND OBJECTIVES: To compare the BPP test with cardiotocography/non-stress test (CTG/NST) alone for their ability to predict fetal acidemia at birth or a composite adverse perinatal outcome among women with preeclampsia and to estimate the effect of BPP assessment on mode of delivery and birth outcome. METHODS: Secondary analysis of a prospective cohort of women with preeclampsia. The predictive ability of the tests was assessed based on sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-). Women assessed with the BPP were compared with matched controls not assessed with the BPP to determine the odds of Cesarean delivery or adverse perinatal outcomes after adjustment for potential confounders. RESULTS: Five out of 89 women (5.6%) had an abnormal BPP; 18 out of 89 (20.2%) had an abnormal CTG/NST. Fetal acidemia was diagnosed in 13 fetuses (14.6%); composite adverse perinatal outcome in 68 fetuses/infants (76.4%). Both tests had relatively poor predictive performance for both outcomes (LR+ between 2.50 and 3.90 and LR- between 0.64 and 0.93). Assessment with the BPP was positively associated with fetal acidemia (adjusted OR 4.84; 95% CI 1.33-17.66). CONCLUSION: The BPP and CTG/NST alone were poor predictors of perinatal outcome in this cohort; multiple tests should be considered when assessing fetal risk in women with preeclampsia. PMID- 26106030 TI - Changes in d-dimer levels in pregnant women according to gestational week. AB - We performed a retrospective review of medical charts regarding blood d-dimer levels determined cross-sectionally by the latex agglutination assay in 1952 samples from 1185 women to determine changes in d-dimer levels according to the stage of pregnancy. Three of 17 women in whom further investigations were performed were found to have clinical venous thromboembolism (VTE). The median and 95th percentile values of d-dimer (MUg/mL) in the 1182 women without clinical VTE, 0.54 and 2.41 at gestational week (GW) 4-13, increased gradually to 1.22 and 5.03 at GW 14-27, 1.81 and 6.18 at GW 28-35, and 2.13 and 5.85 at GW 36-42, respectively. A total of nine women (0.76%), including three women with clinical VTE, exhibited a d-dimer level >14.0MUg/mL, which was well above the 99th percentile for any stage of pregnancy. Thus, 3 (33%) of the nine with a d-dimer level >14MUg/mL developed clinical VTE, while none of the remaining 1176 women with a d-dimer level ?14MUg/mL developed clinical VTE. Although further prospective studies are required, our results suggested that there is a certain cut-off d-dimer value that would allow us to differentiate between pregnant women with and without clinical VTE. PMID- 26106031 TI - Postpartum alterations in circulating endothelial progenitor cells in women with a history of pre-eclampsia. AB - OBJECTIVE: To characterize persistent postpartum maternal endothelial dysfunction following pre-eclampsia (PE) through the assessment of endothelial progenitor cells as markers of endothelial reparative capacity. STUDY DESIGN: Maternal circulating endothelial progenitor cells were measured at 2months and 6months postpartum in women who had recently experienced PE pregnancies (n=17). Normotensive controls (n=13) with uncomplicated pregnancies served for comparison at the same time points. Progenitor cells were measured by flow cytometry and by colony forming units. Maternal cardiovascular risk was measured at 6months postpartum. MAIN OUTCOME MEASURES: Levels of maternal circulating endothelial progenitor cells and cardiovascular risk in the early postpartum period of uncomplicated and PE pregnancies. RESULTS: CD34+VEGFR-2+ and CD133+VEGFR-2+ cells were elevated in PE subjects at 2months postpartum compared to healthy control subjects, although reduced by 6months postpartum. PE was associated with reduced colony forming units at 2 and 6months postpartum. Cardiovascular risk scores were increased in PE compared to normotensive controls. CONCLUSIONS: We have demonstrated that there is a physiological alteration in the number and function of circulating progenitor cells following PE pregnancies. Furthermore, this population of women exhibited elevated cardiovascular risk profiles compared to those with uncomplicated pregnancies. Pregnancy and the development of PE identify an early window for cardiovascular risk screening in women. Cellular markers of vascular health offer an approach to the investigation of postpartum endothelial dysfunction. PMID- 26106032 TI - Eclampsia: Maternal and neonatal outcomes. AB - The objective of our study is to define the maternal and neonatal outcomes associated with eclampsia. This retrospective cohort study was performed using the Consortium on Safe Labor, database from 12 clinical centers, including 19 hospitals, from 2002-2008. All patients admitted with a diagnosis of eclampsia or seizure in labor and delivery or postpartum were included in the analysis. Patients with history of seizure disorder were excluded. Maternal and neonatal outcomes were compared to outcomes of women with preeclampsia and their neonates. Statistical analyses were performed using SAS. Chi square and t-test were used for categorical and continuous variables, respectively. Logistic regression and general linear regression were used to calculate odds ratios and 95% confidence intervals. p<0.05 was considered significant. The eclampsia prevalence was 0.08% (n=191) in our population; the preeclampsia cohort had 7012 women. There were significantly more eclamptic women (49%) delivered by cesarean section, as compared to preeclamptic women (36%), OR 1.7 (1.28-2.28). These women were more likely to have an ICU admission OR 12.9 (7.0-23.7). The mean gestational ages and birthweights were lower in the neonates of the eclampsia group. A multivariate analysis revealed that low cord arterial pH, low 5min Apgar score, respiratory distress syndrome OR 5.5, (1.11-27.66) and seizures OR 10.3 (3.12-33.68), p<0.05, were significantly elevated in the eclampsia cohort. The prevalence of eclampsia in our contemporary obstetrics population was 0.08%. Both mothers as well as neonates of eclamptics are at significant risk for complications due to their illness. PMID- 26106033 TI - sFlt-1/PlGF ratio as a prognostic marker of adverse outcomes in women with early onset preeclampsia. AB - Soluble fms-like tyrosine kinase 1 (sFlt-1) is an anti-angiogenic factor released in higher amounts by preeclamptic placentas and it has been implicated in the endothelial dysfunction observed in the disease. In this study we evaluated if circulating sFlt-1/PlGF ratio is useful to predict adverse outcomes in women with early-onset preeclampsia. This is a cohort study of 88 preeclamptic women with singleton pregnancies at ?35weeks of gestation. According to definitions used, adverse outcomes occurred in 46.5% (N=43) of the patients. The median sFlt1/PlGF ratio (25th-75th centile) for all patients evaluated was of 42.26 (13.1-226.1). The median sFlt-1/PlGF ratio among women who had any adverse outcome (N=43) versus no adverse outcomes (N=45) was of 227.6 (80.3-346.1) versus 14.4 (3.35 30.0), (P<0.0001). According to our analyses a sFlt-1/PlGF ratio cut-point of ?85 gave a sensitivity of 74.0% and specificity of 97.0%. The positive predictive value and the negative predictive value were 96.0% and 80.0%, respectively. The median sFlt-1/PlGF ratio (25th-75th centile) for patients who delivered within <7days was 260.0 (127.7-404.7) as compared to 14.4 (3.35-34.97) for those patients who delivered within two weeks or more (P<0.0001). Our results suggest that sFlt-1/PlGF ratio is a promising marker for adverse outcomes in women with early-onset preeclampsia. PMID- 26106034 TI - Correspondence related to "Flash pulmonary edema during cesarean section in a woman with preeclampsia." Pregnancy hypertension: 371-373. PMID- 26106035 TI - Evaluation and utilization of preassembled frozen commercial fast real-time qPCR master mixes for detection of cytomegalovirus and BK virus. AB - Quantitative DNA detection of cytomegalovirus (CMV) and BK virus (BKV) is critical in the management of transplant patients. Quantitative laboratory developed procedures for CMV and BKV have been described in which much of the processing is automated, resulting in rapid, reproducible, and high-throughput testing of transplant patients. To increase the efficiency of such assays, the performance and stability of four commercial preassembled frozen fast qPCR master mixes (Roche FastStart Universal Probe Master Mix with Rox, Bio-Rad SsoFast Probes Supermix with Rox, Life Technologies TaqMan FastAdvanced Master Mix, and Life Technologies Fast Universal PCR Master Mix), in combination with in-house designed primers and probes, was evaluated using controls and standards from standard CMV and BK assays. A subsequent parallel evaluation using patient samples was performed comparing the performance of freshly prepared assay mixes versus aliquoted frozen master mixes made with two of the fast qPCR mixes (Life Technologies TaqMan FastAdvanced Master Mix, and Bio-Rad SsoFast Probes Supermix with Rox), chosen based on their performance and compatibility with existing PCR cycling conditions. The data demonstrate that the frozen master mixes retain excellent performance over a period of at least 10 weeks. During the parallel testing using clinical specimens, no difference in quantitative results was observed between the preassembled frozen master mixes and freshly prepared master mixes. Preassembled fast real-time qPCR frozen master mixes perform well and represent an additional strategy laboratories can implement to reduce assay preparation times, and to minimize technical errors and effort necessary to perform clinical PCR. PMID- 26106036 TI - Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. AB - Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1(mut/+)) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency. PMID- 26106037 TI - Computational study of the W260A activating mutant of Src tyrosine kinase. AB - Tyrosine kinases are enzymes playing a critical role in cellular signaling. Mutations causing increased in kinase activity are often associated with cancer and various pathologies. One example in Src tyrosine kinases is offered by the substitution of the highly conserved tryptophan 260 by an alanine (W260A), which has been shown to cause an increase in activity. Here, molecular dynamics simulations based on atomic models are carried out to characterize the conformational changes in the linker region and the catalytic (kinase) domain of Src kinase to elucidate the impact of the W260A mutation. Umbrella sampling calculations show that the conformation of the linker observed in the assembled down-regulated state of the kinase is most favored when the kinase domain is in the inactive state, whereas the conformation of the linker observed in the re assembled up-regulated state of the kinase is favored when the kinase domain is in the unphosphorylated active-like state. The calculations further indicate that there are only small differences between the WT and W260A mutant. In both cases, the intermediates states are very similar and the down-regulated inactive conformation is the most stable state. However, the calculations also show that the free energy cost to reach the unphosphorylated active-like conformation is slightly smaller for the W260A mutant compared with WT. A simple kinetic model is developed and submitted to a Bayesian Monte Carlo analysis to illustrate how such small differences can contribute to accelerate the trans-autophosphorylation reaction and yield a large increase in the activity of the mutant as observed experimentally. PMID- 26106038 TI - An appraisal of the Functional Movement ScreenTM grading criteria--Is the composite score sensitive to risky movement behavior? AB - OBJECTIVE: To examine the relationship between the composite Functional Movement Screen (FMS) score and performers' spine and frontal plane knee motion. DESIGN: Examined the spine and frontal plane knee motion exhibited by performers who received high (>14) and low (<14) composite FMS scores. Participants' body motions were quantified while they performed the FMS. SETTING: Biomechanics laboratory. PARTICIPANTS: Twelve men who received composite FMS scores greater than 14 were assigned to a high-scoring group. Twelve age-, height- and weight matched men with FMS scores below 14 were assigned to a low-scoring group. OUTCOME MEASURES: Composite FMS scores and peak lumbar spine flexion/extension, lateral bend and axial twist, and left and right frontal plane knee motion. RESULTS: Significant differences (p < 0.05) and large effect sizes (>0.8) were noted between the high- and low-scoring groups when performing the FMS tasks; high-scorers employed less spine and frontal plane knee motion. Substantial variation was also observed amongst participants. CONCLUSIONS: Participants with high composite FMS scores exhibited less spine and frontal plane knee motion while performing the FMS in comparison to their low-scoring counterparts. However, because substantial variation was observed amongst performers, the FMS may not provide the specificity needed for individualized injury risk assessment and exercise prescription. PMID- 26106039 TI - Mapping malaria in municipalities of the Coffee Triangle region of Colombia using Geographic Information Systems (GIS). AB - Geographical Information Systems (GIS) have been used extensively for the development of epidemiological maps of malaria but not in the Coffee Triangle region of Colombia, endemic for P. vivax, P. falciparum and P. malariae. Surveillance case data (2007-2011) were used to estimate annual incidence rates per Plasmodium spp. (cases/100,000 pop) to develop the first malaria maps in the 53 municipalities of this region (departments Caldas, Quindio, Risaralda). The GIS software used was Kosmo Desktop 3.0RC1((r)). Thirty thematic maps were developed according to the municipalities, years, parasite etiology, and uncomplicated and complicated cases. A total of 6582 cases were reported (6478 uncomplicated and 104 complicated, 77.8% Risaralda), for a cumulated rate of 269.46 cases/100,000 pop. Among uncomplicated cases, 5722 corresponded to P. vivax (234.25 cases/100,000 pop), 475 to P. falciparum (19.45 cases/100,000 pop), 8 to P. malariae (0.33 cases/100,000 pop) and 273 mixed (P. falciparum/P. vivax) (11.18 cases/100,000 pop). The highest rate reported was in the more undeveloped and rural municipality of Risaralda (Pueblo Rico, 57.7 cases/1000 pop, 2009). The burden of disease was concentrated in one department (>75% of the region). The use of GIS-based epidemiological maps helps to guide decision-making for the prevention and control of this public health problem that still represents a significant issue in the region and the country, particularly in children. PMID- 26106040 TI - The epidemiology of Dengue fever in Saudi Arabia: A systematic review. AB - Dengue fever (DF) is the most serious mosquito-borne viral disease worldwide. DF is an acute febrile illness caused by Aedes aegypti and Aedes albopictus, which are endemic in certain cities of Saudi Arabia, such as Jeddah and Makkah (Mecca). An online literature search was conducted using relevant keywords to retrieve DF studies conducted in Saudi Arabia. Forty-five articles were identified initially. After screening for exclusion and retrieving full texts, a total of 10 articles were used for this review. Four studies were cross-sectional, and three observed a seroprevalence ranging from 31.7% to 56.9%, either among clinically suspected cases or among patients visiting the hospital for other reasons. Evidence extracted from risk factors and distribution studies indicated that young males are commonly affected. Fever, vomiting, thrombocytopenia and leukopoenia were the common features of the three studies related to clinical presentation of DF. One cross-sectional study concerning an educational program for DF demonstrated that a positive family history of DF, literate mothers, and age over 17 years were the predictors of a high DF knowledge score. However, the paucity of large epidemiological studies limits the generalizability of such evidence. Future studies in Saudi Arabia should focus upon the expansion of DF to other cities in the Kingdom. Larger epidemiological studies are needed for estimating the true burden and incidence of DF in the Saudi population, as they are limited to seroprevalence among clinically suspected cases and hospital-based patients. PMID- 26106042 TI - Magnesium intervention studies -methodological aspects. PMID- 26106044 TI - The Origin, Expression, Function and Future Research Focus of a G Protein-coupled Receptor, Mas-related Gene X2 (MrgX2). AB - Mas-related genes (Mrgs) belong to a large family of G protein-coupled receptor genes found in rodents. Human MRGX proteins are G protein-coupled 7-transmembrane proteins sharing 41-52% amino acid identity with each other, but have no orthologs in rodents. MrgX2 is a member of the MrgX family. MRGX2 is expressed in the small neurons of sensory ganglia and mast cells. It can interact with a series of factors and genes such as the peptides substance P, vasoactive intestinal peptide, cortistatin (CST), proadrenomedullin N-terminal peptide (PAMP), LL-37, PMX-53 and beta-defensins. MRGX2 is related to nociception, adrenal gland secretion and mast cell degranulation. Recent research on MrgX2 provides insights into its role in nociception and anti-microbial activities. This article reviewed the origin, expression and function of MrgX2, and discussed possible future research focus. PMID- 26106045 TI - Pol I-transcribed hepatitis C virus genome RNA replicates, produces an infectious virus and leads to severe hepatic steatosis in transgenic mice. AB - Patients chronically infected with hepatitis C virus (HCV) are at risk of developing end-stage liver disease and hepatocellular carcinoma. Development of drugs to inhibit hepatocyte damage and a vaccine against HCV is hampered by the lack of a small animal model. We generated mice in which the viral genome RNA was always present in the hepatocytes using a special transgene. Here we show that the HCV genome RNA transcribed by Pol I polymerase can replicate and produce infectious viruses in mice. We obtained a transgenic mouse with 200 copies per haploid which we named the A line mouse. It produced ~ 3 * 10(6) HCV RNA copies/mL serum, which is at the comparable level as patients with chronic HCV infection. This mouse was immunotolerant to HCV and showed hepatic steatosis without any necroinflammation at the age of 6 months or hepatocellular carcinoma at the age of 15 months. Thus, the A line mouse can be used as an animal model for chronic HCV infection. This will enable better study of the abnormalities in metabolism and signal transduction in infected hepatocytes, and development of drugs that cure abnormalities. PMID- 26106046 TI - Blood pressure, renal biochemical parameters and histopathology in an original rat model of essential hypertension (SHRSP/Kpo strain). AB - Hypertensive nephropathy, a consequence of chronic high blood pressure, is increasingly a cause of end-stage renal diseases and its correct management is very important for clinical outcome. Spontaneously hypertensive rat (SHR/Kpo) and stroke-prone SHR (SHRSP/Kpo) strains represent models of human essential hypertension. However, the kidney injuries in SHR/Kpo and SHRSP/Kpo are not well defined. We therefore characterized the renal pathophysiology of SHR/Kpo and SHRSP/Kpo compared with normotensive control (WKY/Kpo) rats. The SHRSP/Kpo exhibited increased systolic blood pressure at 10 weeks of age, and proteinuria and increased blood urea nitrogen (BUN) and serum creatinine levels at 20 weeks. We simultaneously detected mononuclear cell infiltration, tubular injuries, accumulation of extracellular matrix and marked expression of alpha-SMA in the tubulointerstitium. Additionally, TGF-beta1 and CTGF were up-regulated in the kidney of SHRSP/Kpo. We lastly focused on changes in glomerular cells of SHRSP/Kpo. Nestin, a podocyte marker, was detected but decreased slightly in 20 week-old SHRSP/Kpo. PECAM-1 expression was increased in SHRSP/Kpo glomeruli, indicating the thickening of glomerular endothelial cells. Moreover, we found that alpha-SMA, a myofibroblast marker, was also upregulated in the glomeruli of SHRSP/Kpo at 20 weeks. These findings suggest that SHRSP/Kpo could be a valuable animal model for human hypertensive nephropathy. PMID- 26106047 TI - Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) are a promising cell source for cartilage regenerative medicine. Meanwhile, the risk of tumorigenesis should be considered in the clinical application of human iPSCs (hiPSCs). Here, we report in vitro chondrogenic differentiation of hiPSCs and maturation of the differentiated hiPSCs through transplantation into mouse knee joints. Three hiPSC clones showed efficient chondrogenic differentiation using an established protocol for human embryonic stem cells. The differentiated hiPSCs formed hyaline cartilage tissues at 8 weeks after transplantation into the articular cartilage of NOD/SCID mouse knee joints. Although tumors were not observed during the 8 weeks after transplantation, an immature teratoma had developed in one mouse at 16 weeks. In conclusion, hiPSCs are a potent cell source for regeneration of hyaline articular cartilage. However, the risk of tumorigenesis should be managed for clinical application in the future. PMID- 26106048 TI - Increased expression of 5-HT(2A) and 5-HT(2B) receptors in detrusor muscle after partial bladder outlet obstruction in rats. AB - Serotonin (5-hydroxytryptamine; 5-HT)-induced bladder contraction is enhanced after partial bladder outlet obstruction (pBOO) in rats. We investigated time dependent changes in bladder contraction and expression of 5-HT(2A) and 5-HT(2B) receptor mRNA in bladder tissue to elucidate the mechanism of this enhancement. On day 3 and 7 after pBOO, contractile responses of isolated rat bladder strips to 5-HT were increased compared with that in sham-operated rats; on day 14, the response had decreased to the same level as that in sham rat bladders. In contrast, carbacholinduced contraction was not enhanced by pBOO at any time point. In sham rats, 5-HT(2A) receptor mRNA was expressed in the urothelium, and 5-HT(2B) receptor mRNA was expressed in the detrusor muscle layer. In pBOO rats, both receptor mRNAs were increased in the detrusor muscle and subserosal layers, but not in the urothelium. The increase of 5-HT(2A) receptor mRNA was maintained from day 3 to day 14 after pBOO, and 5-HT(2B) receptor mRNA was increased on day 7 after pBOO. These results suggested that pBOO induced up-regulation of the 5 HT(2A) and 5-HT(2B) receptors in the detrusor muscle and subserosal layers of the bladder, and such up-regulation may be related to the enhanced bladder contractile response to 5-HT. PMID- 26106049 TI - Three-dimensional reconstruction of serial sections for analysis of the microvasculature of the white pulp and the marginal zone in the human spleen. AB - Although a number of papers have given useful information on splenic microcirculation by light and/or scanning electron microscopy, controversies remain as to the vascular arrangement, especially in the human spleen. The present study re-examined the microvasculature of the human spleen using a three dimensional reconstruction of immunohistochemically stained tissue sections, and showed that the central artery does not directly issue follicular arteries in the human spleen; follicular arteries are derived from penicillar arteries outside the follicle and end in the white pulp. We found that the splenic follicle is surrounded by an elaborate system of anastomosed capillaries in both the marginal zone and the superficial layer of the white pulp. Most of these capillaries are also branches of the penicillar arterioles that are issued from the central artery in the same, or a different, white pulp system. Because the endothelia of these capillaries are widely open in the marginal zone, this vascular network may play a major role in supplying blood to the marginal zone. The accumulation of sialoadhesin-positive macrophages was also observed around the vascular network, suggesting an important role for this structure as the front line of immune response. PMID- 26106050 TI - A systematic analysis for localization of predominant growth factors and their receptors involved in murine tooth germ differentiation using in situ hybridization technique. AB - Tooth development is regulated by various growth factors and their receptors. However, the overall mechanism of growth factor-mediated odontogenesis remains to be elucidated. The present study examined expression sites and intensities of major growth factors and receptors in the tooth germ of murine fetuses and neonates. Signals of TGF-beta and CTGF in fetuses were released from the enamel epithelium, while their neonatal signals arose in odontoblasts. Moreover, BMP/Smad signaling may affect the differentiation of ameloblasts, in contrast to PDGFalpha whose signals may cause odontoblast differentiation. Growth factors associated with the formation of the periodontium were IGF1, IGF2, IGFBP3, CTGF, and PDGFalpha. Concerning cusp formation, the enamel knot selectively expressed FGF4, BMP2, and BMP4 with an expression of PDGFalpha in the enamel-free area. It is concluded that many molecules play critical roles in the epithelium-mesenchyme interaction of tooth germ differentiation, and their expressions are precisely controlled. PMID- 26106051 TI - Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean. AB - Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase which is highly homologous to angiotensin-converting enzyme (ACE). ACE2 produces vasodilator peptides angiotensin 1-7 from angiotensin II. In the present study, we synthesized various internally quenched fluorogenic (IQF) substrates (fluorophore Xaa-Pro-quencher) based on the cleavage site of angiotensin II introducing N terminal fluorophore N-methylanthranilic acid (Nma) and C-terminal quencher N(epsilon)-2,4- dinitrophenyl-lysine [Lys(Dnp)]. The synthesized mixed substrates "Nma-Xaa-Pro-Lys(Dnp)" were hydrolyzed by recombinant human (rh) ACE2. The amount of each product was determined by liquid chromatography mass spectrometry (LC-MS) with fluorescence detection and it was found that Nma-His-Pro-Lys(Dnp) is the most suitable substrate for rhACE2. The K(m), k(cat), and k(cat)/K(m) values of Nma-His-Pro-Lys(Dnp) on rhACE2 were determined to be 23.3 MUM, 167 s(-1), and 7.17 MUM(-1) s(-1), respectively. Using the rhACE2 and the newly developed IQF substrate, we found rhACE2 inhibitory activity in soybean and isolated the active compound soybean ACE2 inhibitor (ACE2iSB). The physicochemical data on the isolated ACE2iSB were identical to those of nicotianamine. ACE2iSB strongly inhibited rhACE2 activity with an IC50 value of 84 nM. This is the first demonstration of an ACE2 inhibitor from foodstuffs. PMID- 26106052 TI - High levels of vitamin D in relation to reduced risk of schizophrenia with elevated C-reactive protein. AB - There is growing evidence on the novel role of vitamin D in reducing inflammation. This study aimed to examine the hypothesis that vitamin D is inversely associated with C-reactive protein (CRP) in patients with schizophrenia, and high levels of vitamin D may be linked to reduced risk of schizophrenia with elevated CRP. Ninety-three patients with schizophrenia and 93 family-matched controls were recruited in this cross-sectional study. Plasma concentrations of CRP and 25-hydroxyvitamin D [25(OH)D] were measured using commercial kits. Information about demographic characteristics and clinic data were obtained by interviews or medical records. Mean levels of CRP and 25(OH)D were 43.3% higher and 26.7% lower for patients compared to controls, respectively. 25(OH)D were inversely associated with CRP in the patients, but not in the controls. The proportions of patients significantly increased with increasing quartiles of CRP, while significantly decreased with increasing quartiles of 25(OH)D. Among individuals with high CRP, participants with high 25(OH)D have significantly lower proportion (adjusted OR =0.217, 95% CI 0.063, 0.751) of schizophrenia compared to those with low 25(OH)D. The evidence suggested that high levels of vitamin D may be linked to reduced risk of schizophrenia with elevated CRP. PMID- 26106054 TI - Sustained reduction in health care costs after adjunctive treatment of graded intensive short-term dynamic psychotherapy in patients with psychotic disorders. AB - The aim of this pilot study was to evaluate the changes in symptom severity and long-term health care cost after intensive short-term dynamic psychotherapy (ISTDP) individually tailored and administered to patients with psychotic disorders undergoing standard psychiatric care. Eleven therapists with different levels of expertise delivered an average of 13 one-hour sessions of graded ISTDP to 38 patients with psychotic disorders. Costs for health care services were compiled for a one-year period prior to the start of ISTDP (baseline) along with four one-year periods after termination. Two validated self-report scales, the Brief Symptom Inventory and the Inventory of Interpersonal Problems, were administered at intake and termination of ISTDP. Results revealed that health care cost reductions were significant for the one-year post-treatment period relative to baseline year, for both physician costs and hospital costs, and the reductions were sustained for the follow-up period of four post-treatment years. Furthermore, at treatment termination self-reported symptoms and interpersonal problems were significantly reduced. These preliminary findings suggest that this brief adjunctive psychotherapy may be beneficial and reduce costs in selected patients with psychotic disorders, and that gains are sustained in long-term follow-up. Future research directions are discussed. PMID- 26106055 TI - Maturation in patients with borderline personality disorder. AB - Patients with borderline personality disorder have a characteristic and extreme personality associated with psychopathology. The aim was to investigate personality change in relation to suicidality following treatment. 21 patients were assessed before and after psychotherapy on personality (NEO PI-R) and suicidality (SUAS). At follow-up, Neuroticism and Conscientiousness normalized along with six lower-order facets; Depression, Impulsiveness, Competence, Achievement Striving, Self-Discipline and Deliberation. Thirteen patients showed a positive personality development paralleled by a lesser degree of suicidality. PMID- 26106053 TI - Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa. AB - Oxytocin is a peptide hormone important for social behavior and differences in psychological traits have been associated with variants of the oxytocin receptor gene in healthy people. We examined whether single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene (OXTR) correlated with clinical symptoms in women with anorexia nervosa, bulimia nervosa, and healthy comparison (HC) women. Subjects completed clinical assessments and provided DNA for analysis. Subjects were divided into four groups: HC, subjects currently with anorexia nervosa (AN C), subjects with a history of anorexia nervosa but in long-term weight recovery (AN-WR), and subjects with bulimia nervosa (BN). Five SNPs of the oxytocin receptor were examined. Minor allele carriers showed greater severity in most of the psychiatric symptoms. Importantly, the combination of having had anorexia and carrying either of the A alleles for two SNPS in the OXTR gene (rs53576, rs2254298) was associated with increased severity specifically for ED symptoms including cognitions and behaviors associated both with eating and appearance. A review of psychosocial data related to the OXTR polymorphisms examined is included in the discussion. OXTR polymorphisms may be a useful intermediate endophenotype to consider in the treatment of patients with anorexia nervosa. PMID- 26106056 TI - Relationships between posttraumatic stress disorder (PTSD), dissociation, quality of life, hopelessness, and suicidal ideation among earthquake survivors. AB - Researches have demonstrated that Posttraumatic stress disorder (PTSD) is one of the most common stress reactions in the face of disasters and significantly associated with a broad range of trauma-induced sequelaes including anxiety, depression, suicidality as well as functional impairments. To date, though many aspects of risk factors with respect to the development and maintenance of PTSD have been addressed, mediating role of dissociation has received relatively less attention. In the present study, we examined relations of PTSD with quality of life, hopelessness, suicidal ideation, and mediational effect of pathological dissociation in these connections. 583 subjects most of whom experienced a severe earthquake participated in the study after two years of the disaster. We found that being female, being single, earthquake exposure, and having greater suicidal ideation were significant predictors of PTSD symptom severity. Role-Physical, Bodily-Pain, General Health and Role-Emotional subscales of the SF-36 were inversely associated with PTSD symptom severity. Pathological dissociation significantly mediated the substantial associations between predictors and PTSD symptom clusters. Chronic dissociation appears to put trauma exposed individuals in jeopardy of prolonged posttraumatic reactions by mediating the negative influences of risk factors in the face of experienced earthquake. PMID- 26106057 TI - Task frequency influences stimulus-driven effects on task selection during voluntary task switching. AB - Task selection during voluntary task switching involves both top-down (goal directed) and bottom-up (stimulus-driven) mechanisms. The factors that shift the balance between these two mechanisms are not well characterized. In the present research, we studied the role that task frequency plays in determining the extent of stimulus-driven task selection. In two experiments, we used the basic paradigm adapted from Arrington (Memory & Cognition, 38, 991-997, 2008), in which the effect of stimulus availability serves as a marker of stimulus-driven task selection. A number and letter appeared on each trial with varying stimulus onset asynchronies, and participants performed either a consonant/vowel or an even/odd judgment. In Experiment 1, participants were instructed as to the relative frequency with which each task was to be performed (i.e., 50/50, 60/40, or 75/25) and were further instructed to make their transitions between tasks unpredictable. In Experiment 2, participants were given no instructions about how to select tasks, resulting in naturally occurring variation in task frequency. With both instructed (Exp. 1) and naturally occurring (Exp. 2) relative task frequencies, the less frequently performed task showed a greater effect of stimulus availability on task selection, suggestive of a larger influence of stimulus-driven mechanisms during task performance for the less frequent task. When goal-directed mechanisms of task choice are engaged less frequently, the relative influence of the stimulus environment increases. PMID- 26106058 TI - The helpfulness of category labels in semi-supervised learning depends on category structure. AB - The study of semi-supervised category learning has generally focused on how additional unlabeled information with given labeled information might benefit category learning. The literature is also somewhat contradictory, sometimes appearing to show a benefit to unlabeled information and sometimes not. In this paper, we frame the problem differently, focusing on when labels might be helpful to a learner who has access to lots of unlabeled information. Using an unconstrained free-sorting categorization experiment, we show that labels are useful to participants only when the category structure is ambiguous and that people's responses are driven by the specific set of labels they see. We present an extension of Anderson's Rational Model of Categorization that captures this effect. PMID- 26106059 TI - Perceptual expertise improves category detection in natural scenes. AB - There is much debate about how detection, categorization, and within-category identification relate to one another during object recognition. Whether these tasks rely on partially shared perceptual mechanisms may be determined by testing whether training on one of these tasks facilitates performance on another. In the present study we asked whether expertise in discriminating objects improves the detection of these objects in naturalistic scenes. Self-proclaimed car experts (N = 34) performed a car discrimination task to establish their level of expertise, followed by a visual search task where they were asked to detect cars and people in hundreds of photographs of natural scenes. Results revealed that expertise in discriminating cars was strongly correlated with car detection accuracy. This effect was specific to objects of expertise, as there was no influence of car expertise on person detection. These results indicate a close link between object discrimination and object detection performance, which we interpret as reflecting partially shared perceptual mechanisms and neural representations underlying these tasks: the increased sensitivity of the visual system for objects of expertise - as a result of extensive discrimination training - may benefit both the discrimination and the detection of these objects. Alternative interpretations are also discussed. PMID- 26106060 TI - Qualitative attentional changes with age in doing two tasks at once. AB - Does practice reduce, or even eliminate, aging effects on the attentional limitations responsible for dual-task interference? The studies reviewed in this article show that age differences reliably persist after extensive practice. Strikingly, dual-task interference remains larger among older adults even in training conditions that allow them to achieve single-task performance as fast as younger adults. These findings demonstrate that age deficits in attentional functioning are robust. Advancing age also can be accompanied by improvements in cognitive functioning, such as in the ability to access the lexicon without attention (i.e., automatically), due to lifelong experience with word reading. Future research needs to establish whether age deficits in central attention are due to structural changes that are irreversible or reversible to some extent. PMID- 26106061 TI - Contrasting vertical and horizontal representations of affect in emotional visual search. AB - Independent lines of evidence suggest that the representation of emotional evaluation recruits both vertical and horizontal spatial mappings. These two spatial mappings differ in their experiential origins and their productivity, and available data suggest that they differ in their saliency. Yet, no study has so far compared their relative strength in an attentional orienting reaction time task that affords the simultaneous manifestation of both types of mapping. Here, we investigated this question using a visual search task with emotional faces. We presented angry and happy face targets and neutral distracter faces in top, bottom, left, and right locations on the computer screen. Conceptual congruency effects were observed along the vertical dimension supporting the 'up = good' metaphor, but not along the horizontal dimension. This asymmetrical processing pattern was observed when faces were presented in a cropped (Experiment 1) and whole (Experiment 2) format. These findings suggest that the 'up = good' metaphor is more salient and readily activated than the 'right = good' metaphor, and that the former outcompetes the latter when the task context affords the simultaneous activation of both mappings. PMID- 26106062 TI - Shuffling your way out of change blindness. AB - Change detection is typically discussed in the literature as a 2-state phenomenon. Small differences between otherwise identical images are easy to detect when the images are superimposed in space and alternated in time ("shuffled"). However, change blindness results from any disruption that prevents the critical change from generating the sole salient transient. Here we show that different presentation strategies produce different degrees of change blindness for the same change. Specifically, shuffling the images supports faster change detection than viewing the same 2 images side by side, even when the images contain a number of distracting differences. In Experiment 1, pairs of photographs having a 50 % chance of containing a difference were viewed either in alternation, in a "Shuffle" condition, or simultaneously, in a "Side-by-Side" condition. Change detection was about 6 seconds faster when the images were viewed in the "Shuffle" mode. In Experiment 2, we presented two images that were slightly laterally shifted relative to each other (0-48 pixels). The RT benefit for the Shuffle viewing mode was very strong when the relative shift was small, to insignificant when there was a large difference between the two images. However, at large shifts, Shuffle maintained an accuracy advantage. It seems that changes are easier to detect when comparing images in a Shuffle condition rather than Side-by-Side. This has important implications for real world tasks like radiology where detection of change is critical. PMID- 26106063 TI - Design and discovery of a novel half-Heusler transparent hole conductor made of all-metallic heavy elements. AB - Transparent conductors combine two generally contradictory physical properties, but there are numerous applications where both functionalities are crucial. Previous searches focused on doping wide-gap metal oxides. Focusing instead on the family of 18 valence electron ternary ABX compounds that consist of elements A, B and X in 1:1:1 stoichiometry, we search theoretically for electronic structures that simultaneously lead to optical transparency while accommodating intrinsic defect structures that produce uncompensated free holes. This leads to the prediction of a stable, never before synthesized TaIrGe compound made of all metal heavy atom compound. Laboratory synthesis then found it to be stable in the predicted crystal structure and p-type transparent conductor with a strong optical absorption peak at 3.36 eV and remarkably high hole mobility of 2,730 cm(2) V(-1) s(-1) at room temperature. This methodology opens the way to future searches of transparent conductors in unexpected chemical groups. PMID- 26106064 TI - Optimization of microwave-assisted extraction for six inorganic and organic arsenic species in chicken tissues using response surface methodology. AB - Response surface methodology was applied to optimize the parameters for microwave assisted extraction of six major inorganic and organic arsenic species (As(III), As(V), dimethyl arsenic acid, monomethyl arsenic acid, p-arsanilic acid, and roxarsone) from chicken tissues, followed by detection using a high-performance liquid chromatography with inductively coupled mass spectrometry detection method, which allows the simultaneous analysis of both inorganic and organic arsenic species in the extract in a single run. Effects of extraction medium, solution pH, liquid-to-solid ratio, and the temperature and time of microwave assisted extraction on the extraction of the targeted arsenic species were studied. The optimum microwave-assisted extraction conditions were: 100 mg of chicken tissue, extracted by 5 mL of 22% v/v methanol, 90 mmol/L (NH4 )2 HPO4 , and 0.07% v/v trifluoroacetic acid (with pH adjusted to 10.0 by ammonium hydroxide solution), ramping for 10 min to 71 degrees C, and holding for 11 min. The method has good extraction performance for total arsenic in the spiked and nonspiked chicken tissues (104.0 +/- 13.8% and 91.6 +/- 7.8%, respectively), except for the ones with arsenic contents close to the quantitation limits. Limits of quantitation (S/N = 10) for As(III), As(V), dimethyl arsenic acid, monomethyl arsenic acid, p-arsanilic acid, and roxarsone in chicken tissues using this method were 0.012, 0.058, 0.039, 0.061, 0.102, and 0.240 mg/kg (dry weight), respectively. PMID- 26106065 TI - Early malfunction of polyvinyl alcohol membrane of septal occluder. AB - Percutaneous device closure of atrial septal defect (ASD) is now considered the choice of treatment. Numerous devices with advantages/disadvantages are currently available and under development. Cardia Ultrasept II ASD occluder has a nitinol frame covered with polyvinyl alcohol (PVA) membrane. Here, a well-documented case of early malfunction of PVA membrane detected in the first week of implantation in a 4-year-old male patient, who underwent an uneventful device closure with 20 mm Cardia Ultrasept II ASD Occluder, is presented. One week after implantation left-to-right shunt through the device was detected and the explantation of device revealed PVA membrane with multiple perforations. PMID- 26106066 TI - Pteropine orthoreovirus infection among out-patients with acute upper respiratory tract infection in Malaysia. AB - This study aims to assess the incidence rate of Pteropine orthreovirus (PRV) infection in patients with acute upper respiratory tract infection (URTI) in a suburban setting in Malaysia, where bats are known to be present in the neighborhood. Using molecular detection of PRVs directly from oropharyngeal swabs, our study demonstrates that PRV is among one of the common causative agents of acute URTI with cough and sore throat as the commonest presenting clinical features. Phylogenetic analysis on partial major outer and inner capsid proteins shows that these PRV strains are closely related to Melaka and Kampar viruses previously isolated in Malaysia. Further study is required to determine the public health significance of PRV infection in Southeast Asia, especially in cases where co-infection with other pathogens may potentially lead to different clinical outcomes. PMID- 26106067 TI - Engineering trypsin for inhibitor resistance. AB - The development of effective protease therapeutics requires that the proteases be more resistant to naturally occurring inhibitors while maintaining catalytic activity. A key step in developing inhibitor resistance is the identification of key residues in protease-inhibitor interaction. Given that majority of the protease therapeutics currently in use are trypsin-fold, trypsin itself serves as an ideal model for studying protease-inhibitor interaction. To test the importance of several trypsin-inhibitor interactions on the prime-side binding interface, we created four trypsin single variants Y39A, Y39F, K60A, and K60V and report biochemical sensitivity against bovine pancreatic trypsin inhibitor (BPTI) and M84R ecotin. All variants retained catalytic activity against small, commercially available peptide substrates [kcat /KM = (1.2 +/- 0.3) * 10(7) M(-1 ) s(-1) . Compared with wild-type, the K60A and K60V variants showed increased sensitivity to BPTI but less sensitivity to ecotin. The Y39A variant was less sensitive to BPTI and ecotin while the Y39F variant was more sensitive to both. The relative binding free energies between BPTI complexes with WT, Y39F, and Y39A were calculated based on 3.5 us combined explicit solvent molecular dynamics simulations. The BPTI:Y39F complex resulted in the lowest binding energy, while BPTI:Y39A resulted in the highest. Simulations of Y39F revealed increased conformational rearrangement of F39, which allowed formation of a new hydrogen bond between BPTI R17 and H40 of the variant. All together, these data suggest that positions 39 and 60 are key for inhibitor binding to trypsin, and likely more trypsin-fold proteases. PMID- 26106068 TI - Biological effect of food additive titanium dioxide nanoparticles on intestine: an in vitro study. AB - Titanium dioxide nanoparticles (TiO2 NPs) are widely found in food-related consumer products. Understanding the effect of TiO2 NPs on the intestinal barrier and absorption is essential and vital for the safety assessment of orally administrated TiO2 NPs. In this study, the cytotoxicity and translocation of two native TiO2 NPs, and these two TiO2 NPs pretreated with the digestion simulation fluid or bovine serum albumin were investigated in undifferentiated Caco-2 cells, differentiated Caco-2 cells and Caco-2 monolayer. TiO2 NPs with a concentration less than 200 ug ml(-1) did not induce any toxicity in differentiated cells and Caco-2 monolayer after 24 h exposure. However, TiO2 NPs pretreated with digestion simulation fluids at 200 ug ml(-1) inhibited the growth of undifferentiated Caco 2 cells. Undifferentiated Caco-2 cells swallowed native TiO2 NPs easily, but not pretreated NPs, implying the protein coating on NPs impeded the cellular uptake. Compared with undifferentiated cells, differentiated ones possessed much lower uptake ability of these TiO2 NPs. Similarly, the traverse of TiO2 NPs through the Caco-2 monolayer was also negligible. Therefore, we infer the possibility of TiO2 NPs traversing through the intestine of animal or human after oral intake is quite low. This study provides valuable information for the risk assessment of TiO2 NPs in food. PMID- 26106069 TI - Speech Range Profile (SRP) Findings Before and After Mutational Falsetto (Puberphonia). AB - INTRODUCTION: Mutational falsetto is a temporary adolescent voice. Voice therapy support in mutational falsetto helps the individual to regain a healthy voice. Speech Range Profile (SRP) is considered to be a method requiring less time in the pretherapy and posttherapy evaluations of voice patients. OBJECTIVE: The purpose of this study was to determine the differences between the SRP results of male subjects experiencing mutational falsetto before and after therapy. METHODS: Sixteen male participants have been included in this study. F0, MinF0, MaxF0, F0Range, F0Range (st), MindB SPL, and MaxdB SPL have been taken to evaluation. SRP recordings of all subjects have been performed. All the recordings have been repeated before and after therapy. RESULTS: A statistically significant difference has been observed between the F0 and MinF0 values before and after therapy (P < 0.001). CONCLUSIONS: SRP provides important information about frequency and intensity. In mutational falsetto, SRP is a useful technique in terms of evaluating success in therapy. PMID- 26106070 TI - Comparison of Two Perceptual Methods for the Evaluation of Vowel Perturbation Produced by Jitter. AB - OBJECTIVES: To explore perceptual evaluation of jitter produced by fundamental frequency (F0) variation in a sustained vowel /a/, using two different methods. One is based on listener's internal references and the other is based on external references provided by the experimenter. METHODS: We used two methods: one is magnitude estimation-converging limits (ME-CL), which is close to the standard approach used by speech therapists when they use numerical estimations and their own standards, and other is intramodal matching procedure (IMP), where each matched stimulus is to be compared with a fixed-set matching stimuli. Systematic variations were introduced in vowel /a/ by Linear Prediction Coding synthesis using an F0 contour function obtained from a statistical jitter model. Six jitter values were used for each of two reference F0 values. Three groups of listeners were tested: expert speech therapists, speech therapy students, and naive listeners. RESULTS: Perceptual functions appear to be similar and linear for both methods as the theory predicts. The answers of all groups of listeners tested with ME-CL present higher standard deviations than for IMP. When subjects were tested with IMP, intrareliability and interreliability measurements show a significant improvement for both expert and naive listeners. CONCLUSIONS: Both intraindividual and interindividual differences for expert speech therapists could be better managed when tested with an IMP than when they use numerical estimations and internal standards to evaluate vowel perturbation produced by jitter. This procedure could be the basis for the development of a clinical evaluation tool. PMID- 26106071 TI - Effect of Noise on Vocal Loudness and Pitch in Natural Environments: An Accelerometer (Ambulatory Phonation Monitor) Study. AB - PURPOSE: This study investigated the effects of environmental noise on the production of vocal intensity and fundamental frequency using an accelerometer. METHODS: Twenty-four vocally healthy young adults (12 men and 12 women, aged 19 22 years) recorded a monologue passage using KayPENTAX (Montvale, NJ, USA) Ambulatory Phonation Monitor (model 3200) under three natural environmental conditions in a randomized order: a quiet room (mean noise, 35.5 dBA), room with moderate level of noise (mean noise, 54.5 dBA), and a room with high noise (mean noise, 67.5 dBA). RESULTS: Both gender groups showed significant increases in the mean vocal intensity, fundamental frequency, and perceived vocal effort in the high-noise environment than in the other two conditions. No significant difference was found in the vocal intensity between the quiet and moderately noisy environment except in the fundamental frequency in the female group. CONCLUSIONS: This study showed that the use of accelerometer for laryngeal signal recordings could be a useful tool for measuring phonation without being affected by the background noise. The findings also support the recommendation that noise levels for conversation should be kept <50-55 dB to maintain speech intelligibility. PMID- 26106072 TI - Phase II Study of the AKT Inhibitor MK-2206 plus Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer Who Previously Progressed on Erlotinib. AB - PURPOSE: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the EGFR inhibitor erlotinib in erlotinib-sensitive cell lines. Inhibitors of AKT signaling mitigated this HGF mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK-2206, a highly selective inhibitor of AKT, in NSCLC patients. EXPERIMENTAL DESIGN: Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg orally every day + MK-2206 45 mg orally every alternate day on a 28-day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20% at 12 weeks (stratum 2: EGFR wild-type). RESULTS: Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were, respectively, 9% and 40% in stratum 1; 3% and 47% in stratum 2. Median progression-free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2. CONCLUSIONS: Combination MK-2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild-type NSCLC. Although activity was seen in EGFR-mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild-type NSCLC. PMID- 26106073 TI - Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2-SN-38 Antibody Conjugate (Sacituzumab Govitecan). AB - PURPOSE: This study examined the delivery of SN-38 to Trop-2-expressing tumors and assessed the constitutive products in the serum, liver, and small intestine in nude mice bearing human tumor xenografts (Capan-1 or NCI-N87) given a single injection of irinotecan (40 mg/kg; ~ 0.8 mg/mouse, containing ~ 460 MUg SN-38 equivalents) or sacituzumab govitecan (IMMU-132), an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG coupled site specifically with an average of 7.6 molecules of SN-38. EXPERIMENTAL DESIGN: At select times, tissues were extracted and concentrations of the products measured by reversed-phase high performance liquid chromatography (HPLC). RESULTS: In serum, >98% irinotecan cleared within 5 minutes; peak levels of SN-38 and SN-38G (glucuronidated SN-38) were detected in equal amounts at this time, and no longer detected after 6 to 8 hours. IMMU-132 was detected in the serum over 3 days, and at each interval, >= 95% of total SN-38 was bound to the antibody. Intact IMMU-132 cleared with a half life of 14 hours, which closely reflected the in vitro rate of SN-38 released from the conjugate in mouse serum (i.e., 17.5 hours), whereas the IgG portion of the conjugate cleared with a half-life of 67.1 hours. In vitro and in vivo studies disclosed IgG-bound SN-38 was protected from glucuronidation. Area under the curve (AUC) analysis indicated that IMMU-132 delivers 20-fold to as much as 136-fold more SN-38 to tumors than irinotecan, with tumor:blood ratios favoring IMMU-132 by 20- to 40-fold. Intestinal concentrations of SN-38/SN-38G also were 9 fold lower with IMMU-132. CONCLUSIONS: These studies confirm a superior SN-38 tumor delivery by IMMU-132 compared with irinotecan. PMID- 26106074 TI - Macitentan, a Dual Endothelin Receptor Antagonist, in Combination with Temozolomide Leads to Glioblastoma Regression and Long-term Survival in Mice. AB - PURPOSE: The objective of the study was to determine whether astrocytes and brain endothelial cells protect glioma cells from temozolomide through an endothelin dependent signaling mechanism and to examine the therapeutic efficacy of the dual endothelin receptor antagonist, macitentan, in orthotopic models of human glioblastoma. EXPERIMENTAL DESIGN: We evaluated several endothelin receptor antagonists for their ability to inhibit astrocyte- and brain endothelial cell induced protection of glioma cells from temozolomide in chemoprotection assays. We compared survival in nude mice bearing orthotopically implanted LN-229 glioblastomas or temozolomide-resistant (LN-229(Res) and D54(Res)) glioblastomas that were treated with macitentan, temozolomide, or both. Tumor burden was monitored weekly with bioluminescence imaging. The effect of therapy on cell division, apoptosis, tumor-associated vasculature, and pathways associated with cell survival was assessed by immunofluorescent microscopy. RESULTS: Only dual endothelin receptor antagonism abolished astrocyte- and brain endothelial cell mediated protection of glioma cells from temozolomide. In five independent survival studies, including temozolomide-resistant glioblastomas, 46 of 48 (96%) mice treated with macitentan plus temozolomide had no evidence of disease (P < 0.0001), whereas all mice in other groups died. In another analysis, macitentan plus temozolomide therapy was stopped in 16 mice after other groups had died. Only 3 of 16 mice eventually developed recurrent disease, 2 of which responded to additional cycles of macitentan plus temozolomide. Macitentan downregulated proteins associated with cell division and survival in glioma cells and associated endothelial cells, which enhanced their sensitivity to temozolomide. CONCLUSIONS: Macitentan plus temozolomide are well tolerated, produce durable responses, and warrant clinical evaluation in glioblastoma patients. PMID- 26106075 TI - siRNA Lipid Nanoparticle Potently Silences Clusterin and Delays Progression When Combined with Androgen Receptor Cotargeting in Enzalutamide-Resistant Prostate Cancer. AB - PURPOSE: Lipid nanoparticle (LNP) formulations facilitate tumor uptake and intracellular processing through an enhanced permeation and retention effect (EPR), and currently multiple products are undergoing clinical evaluation. Clusterin (CLU) is a cytoprotective chaperone induced by androgen receptor (AR) pathway inhibition to facilitate adaptive survival pathway signaling and treatment resistance. In our study, we investigated the efficacy of siRNA tumor delivery using LNP systems in an enzalutamide-resistant (ENZ-R) castration resistant prostate cancer (CRPC) model. EXPERIMENTAL DESIGN: Gene silencing of a luciferase reporter gene in the PC-3M-luc stable cell line was first assessed in subcutaneous and metastatic PC-3 xenograft tumors. Upon validation, the effect of LNP siRNA targeting CLU in combination with AR antisense oligonucleotides (ASO) was assessed in ENZ-R CRPC LNCaP in vitro and in vivo models. RESULTS: LNP LUC siRNA silenced luciferase expression in PC-3M-luc subcutaneous xenograft and metastatic models. LNP CLU-siRNA potently suppressed CLU and AR ASO-induced CLU and AKT and ERK phosphorylation in ENZ-R LNCaP cells in vitro, more potently inhibiting ENZ-R cell growth rates and increased apoptosis when compared with AR ASO monotherapy. In subcutaneous ENZ-R LNCaP xenografts, combinatory treatment of LNP CLU-siRNA plus AR-ASO significantly suppressed tumor growth and serum PSA levels compared with LNP LUC-siRNA (control) and AR-ASO. CONCLUSIONS: LNP siRNA can silence target genes in vivo and enable inhibition of traditionally non druggable genes like CLU and other promising cotargeting approaches in ENZ-R CRPC therapeutics. PMID- 26106077 TI - A renin-ssance in primary aldosteronism testing: obstacles and opportunities for screening, diagnosis, and management. PMID- 26106076 TI - Nonblocking Monoclonal Antibody Targeting Soluble MIC Revamps Endogenous Innate and Adaptive Antitumor Responses and Eliminates Primary and Metastatic Tumors. AB - PURPOSE: The human tumor-derived soluble MHC I-chain-related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model. EXPERIMENTAL DESIGN: We treated the engineered MIC-expressing "humanized" TRAMP/MIC bitransgenic mice at advanced disease stages with a sMIC-neutralizing nonblocking anti-MIC mAb and assessed the therapeutic efficacy and associated mechanisms. RESULTS: A sMIC-neutralizing nonblocking anti-MIC mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous antitumor immune responses, exemplified by restoring natural killer (NK) cell homeostasis and function, enhancing susceptibility of MIC(+)-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T-cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive. CONCLUSIONS: Therapy with a sMIC neutralizing nonblocking anti-MIC mAb can effectuate antitumor immune responses against advanced MIC(+) tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies. PMID- 26106078 TI - siRNA Screening Identifies the Host Hexokinase 2 (HK2) Gene as an Important Hypoxia-Inducible Transcription Factor 1 (HIF-1) Target Gene in Toxoplasma gondii Infected Cells. AB - Although it is established that oxygen availability regulates cellular metabolism and growth, little is known regarding how intracellular pathogens use host factors to grow at physiological oxygen levels. Therefore, large-scale human small interfering RNA screening was performed to identify host genes important for growth of the intracellular protozoan parasite Toxoplasma gondii at tissue oxygen tensions. Among the genes identified by this screen, we focused on the hexokinase 2 (HK2) gene because its expression is regulated by hypoxia-inducible transcription factor 1 (HIF-1), which is important for Toxoplasma growth. Toxoplasma increases host HK2 transcript and protein levels in a HIF-1-dependent manner. In addition, parasite growth at 3% oxygen is restored in HIF-1-deficient cells transfected with HK2 expression plasmids. Both HIF-1 activation and HK2 expression were accompanied by increases in host glycolytic flux, suggesting that enhanced HK2 expression in parasite-infected cells is functionally significant. Parasite dependence on host HK2 and HIF-1 expression is not restricted to transformed cell lines, as both are required for parasite growth in nontransformed C2C12 myoblasts and HK2 is upregulated in vivo following infection. While HK2 is normally associated with the cytoplasmic face of the outer mitochondrial membrane at physiological O2 levels, HK2 relocalizes to the host cytoplasm following infection, a process that is required for parasite growth at 3% oxygen. Taken together, our findings show that HIF-1-dependent expression and relocalization of HK2 represent a novel mechanism by which Toxoplasma establishes its replicative niche at tissue oxygen tensions. IMPORTANCE: Little is known regarding how the host cell contributes to the survival of the intracellular parasite Toxoplasma gondii at oxygen levels that mimic those found in tissues. Our previous work showed that Toxoplasma activates the expression of an oxygen-regulated transcription factor that is required for growth. Here, we report that Toxoplasma regulates the abundance and activity of a key host metabolic enzyme, hexokinase 2, by activating HIF-1 and by promoting dissociation of hexokinase 2 from the mitochondrial membrane. Collectively, our data reveal HIF-1/hexokinase 2 as a novel target for an intracellular pathogen that acts by reprograming the host cell's metabolism to create an environment conducive for parasite replication at physiological oxygen levels. PMID- 26106080 TI - Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers. AB - Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved. PMID- 26106079 TI - Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids. AB - Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N'-(3 bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3 bromo-N'-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE: Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals. PMID- 26106081 TI - Accuracy of Self-Report of Sexual Activity among Adolescent Girls: Implications for Interpretation of Vaginal Flora Patterns. PMID- 26106083 TI - Reply to "Accuracy of Self-Report of Sexual Activity among Adolescent Girls: Implications for Interpretation of Vaginal Flora Patterns". PMID- 26106082 TI - Functional Analysis of the Human Antibody Response to Meningococcal Factor H Binding Protein. AB - Two licensed serogroup B meningococcal vaccines contain factor H binding protein (FHbp). The antigen specifically binds human FH, which downregulates complement. In wild-type mice whose mouse FH does not bind to FHbp vaccines, the serum anti FHbp antibody response inhibited binding of human FH to FHbp. The inhibition was important for eliciting broad anti-FHbp serum bactericidal activity. In human FH transgenic mice and some nonhuman primates, FHbp was able to form a complex with FH and FHbp vaccination elicited anti-FHbp antibodies that did not inhibit FH binding. To investigate the human anti-FHbp repertoire, we cloned immunoglobulin heavy- and light-chain-variable-region genes of individual B cells from three adults immunized with FHbp vaccines and generated 10 sequence-distinct native anti-FHbp antibody fragments (Fabs). All 10 Fabs bound to live meningococci; only 1 slightly inhibited binding of human FH, while 4 enhanced FH binding. Affinity purified anti-FHbp antibody from serum of a fourth immunized adult also enhanced binding of human FH to live meningococcal bacteria. Despite the bound FH, the affinity-purified serum anti-FHbp antibodies elicited human complement-mediated bactericidal activity that was amplified by the alternative pathway. The lack of FH inhibition by the human anti-FHbp Fabs and serum antibodies suggests that binding of human FH to the vaccine antigen skews the anti-FHbp antibody repertoire to epitopes outside the FH-binding site. Mutant FHbp vaccines with decreased FH binding may represent a means to redirect the human antibody repertoire to epitopes within the FH binding site, which can inhibit FH binding and, potentially, increase safety and protective activity. IMPORTANCE: Two meningococcal vaccines contain factor H binding protein (FHbp). Immunized mice whose mouse factor H (FH) does not bind to FHbp develop serum anti-FHbp antibodies that block binding of human FH to the bacteria. With less bound FH, the bacteria become more susceptible to complement killing. To investigate human responses, we isolated 10 recombinant anti-FHbp antibody fragments (Fabs) from immune cells of three immunized adults. One slightly inhibited binding of FH to the bacteria, and four enhanced FH binding. Purified serum anti-FHbp antibodies from a fourth immunized adult also enhanced FH binding. Although bound FH would be expected to block the alternative pathway, the human anti-FHbp antibodies retained bactericidal activity and the ability to activate the alternative pathway. Mutant FHbp vaccines with decreased binding to human FH may redirect the human antibody repertoire to epitopes within the FH binding site that inhibit FH binding, which are expected to increase protective activity. PMID- 26106084 TI - Evaluation of Protein Profiles From Treated Xenograft Tumor Models Identifies an Antibody Panel for Formalin-fixed and Paraffin-embedded (FFPE) Tissue Analysis by Reverse Phase Protein Arrays (RPPA). AB - Reverse phase protein arrays (RPPA) are an established tool for measuring the expression and activation status of multiple proteins in parallel using only very small amounts of tissue. Several studies have demonstrated the value of this technique for signaling pathway analysis using proteins extracted from fresh frozen (FF) tissue in line with validated antibodies for this tissue type; however, formalin fixation and paraffin embedding (FFPE) is the standard method for tissue preservation in the clinical setting. Hence, we performed RPPA to measure profiles for a set of 300 protein markers using matched FF and FFPE tissue specimens to identify which markers performed similarly using the RPPA technique in fixed and unfixed tissues. Protein lysates were prepared from matched FF and FFPE tissue specimens of individual tumors taken from three different xenograft models of human cancer. Materials from both untreated mice and mice treated with either anti-HER3 or bispecific anti-IGF-1R/EGFR monoclonal antibodies were analyzed. Correlations between signals from FF and FFPE tissue samples were investigated. Overall, 60 markers were identified that produced comparable profiles between FF and FFPE tissues, demonstrating significant correlation between the two sample types. The top 25 markers also showed significance after correction for multiple testing. The panel of markers covered several clinically relevant tumor signaling pathways and both phosphorylated and nonphosphorylated proteins were represented. Biologically relevant changes in marker expression were noted when RPPA profiles from treated and untreated xenografts were compared. These data demonstrate that, using appropriately selected antibodies, RPPA analysis from FFPE tissue is well feasible and generates biologically meaningful information. The identified panel of markers that generate similar profiles in matched fixed and unfixed tissue samples may be clinically useful for pharmacodynamic studies of drug effect using FFPE tissues. PMID- 26106085 TI - Identification of the Population Structure of Myzus persicae (Hemiptera: Aphididae) on Peach Trees in China Using Microsatellites. AB - In this study, we characterized the genetic structure of Myzus persicae (Sulzer) (Hemiptera: Aphididae) populations in China using microsatellites. We expected that these data will reveal the genetic relationships among various populations of M. persicae and will be of value in the development of better methods for pest control. Four hundred sixty individuals from 23 areas over 13 provinces were collected in the early spring of 2010, all from their primary host, Prunus persicae. The markers analyzed were highly polymorphic, as demonstrated by the expected heterozygosity value (He = 0.861) and the Polymorphism Information Content (PIC = 0.847), which indicated that M. persicae maintains a high level of genetic diversity. Analysis of molecular variance revealed an intermediate level of population differentiation among M. persicae populations (F(ST) = 0.1215). Geographic isolation existed among these populations, and, consequently, the genetic structure of the populations was split into a southern group and a northern group divided by the Yangtse River. PMID- 26106086 TI - Sitona lineatus (Coleoptera: Curculionidae) Larval Feeding on Pisum sativum L. Affects Soil and Plant Nitrogen. AB - Adults of Sitona lineatus (pea leaf weevil, PLW) feed on foliage of several Fabaceae species but larvae prefer to feed on nodules of Pisum sativum L. and Vicia faba L. Indirectly, through their feeding on rhizobia, weevils can reduce soil and plant available nitrogen (N). However, initial soil N can reduce nodulation and damage by the weevil and reduce control requirements. Understanding these interactions is necessary to make integrated pest management recommendations for PLW. We conducted a greenhouse study to quantify nodulation, soil and plant N content, and nodule damage by weevil larvae in relation to soil N amendment with urea, thiamethoxam insecticide seed coating and crop stage. PLWs reduced the number of older tumescent (multilobed) nodules and thiamethoxam addition increased them regardless of other factors. Nitrogen amendment significantly increased soil available N (>99% nitrate) as expected and PLW presence was associated with significantly lower levels of soil N. PLW decreased plant N content at early flower and thiamethoxam increased it, particularly at late flower. The study illustrated the complexity of interactions that determine insect herbivory effects on plant and soil nutrition for invertebrates that feed on N-fixing root nodules. We conclude that effects of PLW on nodulation and subsequent effects on plant nitrogen are more pronounced during the early growth stages of the plant. This suggests the importance of timing of PLW infestation and may explain the lack of yield depression in relation to this pest observed in many field studies. Also, pea crops in soils with high levels of soil N are unlikely to be affected by this herbivore and should not require insecticide inputs. PMID- 26106087 TI - The Insecticide Susceptibility Status of Aedes aegypti (Diptera: Culicidae) in Farm and Nonfarm Sites of Lagos State, Nigeria. AB - Nigeria is one of the malaria-endemic countries. In Lagos State, Nigeria, various malaria vector control programs including the use of chemical insecticides are currently being implemented. This study was designed to provide information on the susceptibility status of some nontargeted vectors such as Aedes aegypti. Adult Ae. aegypti mosquitoes from two farm sites and a nonfarm site were exposed to World Health Organization test papers impregnated with Deltamethrin (0.05%), Permethrin (0.75%), and DDT (4%) insecticides. The Knockdown time (KdT50 and KdT95) and percentage mortality after 24 h post exposure were determined. In all the exposed mosquito populations to permethrin, mortality rate > 98% (susceptibility) was recorded, whereas mortality rates < 95.8% (resistance) and > 98% (susceptibility) to deltamethrin were observed in the nonfarm site and farm sites mosquito populations, respectively. All the mosquito populations were resistant to DDT in 2 yr. The KdT50 of the populations to DDT increased (60.2 69.6) in one of the farm sites and the nonfarm site (68.9-199.96), while a decrease (243-63.4) in another farm site in 2 yr. Significant difference (P < 0.05) in KdT50 was recorded between the farm and nonfarm sites Ae. aegypti mosquitoes in the second year after exposure to deltamethrin and DDT. An increase in KdT95 after exposure to deltamethrin in the first year was recorded. Higher KdT values and lower mortality rates in Ae. aegypti populations in the nonfarm sites are indications there are existing factors selecting for insecticide resistance outside agricultural use of insecticides. PMID- 26106088 TI - Adult Behavior of Tirumala limniace (Lepidoptera: Danaidae). AB - Tirumala limniace Cramer as an ornamental butterfly is utilized in butterfly garden, in this article we study their adult activities include flight, foraging, courtship, mating, and oviposition. We found that males spent 22.1% of its time flying, 14.1% foraging, 63.8% in courtship and mating. And females spent 30.8% of its time flying, 10.1% foraging, 57.1% in courtship and mating, and 2% ovipositing. Adults emerged from pupae when temperatures were above 23.5 degrees C and eclosion took only ~1 min, typically followed by a small amount of flight on the first day. Flight activity peaked from the ninth to the thirteenth day after eclosion, and there were two daily peak flight times: 10:00-13:00 and 15:00 18:00. The peak of flower-visiting activity was from the eighth to the thirteenth day after eclosion, and there were two daily peak foraging times: 11:00-12:00 and 16:00-17:00. Flight and foraging frequency and time were positively correlated and both were closely related to temperature, with very little flight or foraging below 18 degrees C and an increase at temperatures above 22 degrees C. Courtship and mating took place on the sixth day after eclosion, while oviposition occurred the following day. Oviposition occurred over 8 d, and the shortest time of a single oviposition was 2 s. The average life expectancy of males was 16.5 d, while that of females was 15 d. PMID- 26106089 TI - Reduction of Optimal Thermal Range in Aging Western Cherry Fruit Flies (Diptera: Tephritidae). AB - The western cherry fruit fly is an economically important pest of sweet cherries in the western United States. The potential of this pest to establish and spread in areas in which it is not currently present has been the focus of recent research. Most published information on the thermal tolerance and optimal thermal range of this pest has focused primarily on the diapausing pupae and predictive phenology models. Microrespirometry and differential calorimetry can be useful tools in describing the thermotolerance and optimal thermal range of insects. This methodology was employed to investigate the effects of western cherry fruit fly adult age on the optimal thermal range. Newly emerged flies exhibited the widest optimal thermal range spanning from 6.6 to 42.2 degrees C for a total range of 35.8 degrees C during heating scans of 0.4 degrees C/min from 2 to 50 degrees C. This range diminished as the flies aged, with the shortest span observed with 28-d-old flies ranging from 10.5 to 37.8 degrees C, a span of 27.2 degrees C. Measurements of heat rate and oxygen consumption at isothermal, or static, temperatures indicated that all flies could survive exposure to 40 degrees C for at least 20 min, and that metabolism was greatly reduced, with a concomitant reduction in oxygen consumption rate at 40 to 42 degrees C. All flies exhibited a heat rate and oxygen consumption rate of zero when exposed to 45 and 50 degrees C. The loss of thermotolerance in adult flies can influence its ability to establish and spread in climates where daily temperatures exceed the optimal thermal range of this species. PMID- 26106090 TI - Developmental Biology and Effects of Adult Diet on Consumption, Longevity, and Fecundity of Colaspis crinicornis (Coleoptera: Chrysomelidae). AB - The chrysomelid beetle Colaspis crinicornis Schaeffer (Coleoptera: Chrysomelidae) occurs primarily in the Great Plains region of the United States. Little is known about the biology and ecology of this species, but over the last decade, it has become increasingly common in the corn, Zea mays L., and soybean, Glycine max (L.) Merrill, agroecosystem of southeastern Nebraska. As part of a larger comprehensive project to understand the natural history and pest potential of this species, laboratory experiments were conducted to study the developmental biology, morphological characters of immature stages, and the effect of adult diet on consumption, longevity, and fecundity. Females readily deposited egg clusters in the soil, and percentage egg hatch was high under laboratory conditions. Larvae and pupae were confirmed to be soil-dwelling stages. C. crinicornis has relatively short egg, pupal, and adult stages with the majority of its life cycle spent in the larval stage. Results of choice and no-choice adult feeding experiments indicate that diets of corn or soybean leaves did not significantly affect consumption, longevity, or fecundity of adult C. crinicornis, suggesting that corn and soybean leaves are similarly suitable food sources for adults. The ability to effectively utilize tissues from very different plant families as adult food sources suggests that C. crinicornis is polyphagous in the field. PMID- 26106091 TI - Does religion deserve a place in secular medicine? AB - Biggar (2015) argues that "religion" deserves a place in secular medicine. Against this view, I argue that religion (as most people would understand the term) should not play a role in shaping secular health policy, and I provide some illustrations of the potential dangers of the contrary. However, I also suggest that-upon closer inspection-Biggar seems to be using the term "religion" to refer to obliquely to what most people would call "moral philosophy." On this less controversial interpretation, Biggar's proposal is inoffensive-but also unoriginal. PMID- 26106092 TI - Brain. Editorial. PMID- 26106093 TI - Brain stimulation and memory. PMID- 26106094 TI - From Time is brain to Physiology is brain: a case for reflection in acute stroke treatment decisions. PMID- 26106095 TI - Progranulin protects against the tissue damage of acute ischaemic stroke. PMID- 26106096 TI - Oculomotor abnormalities in posterior cortical atrophy: are they different from those in Alzheimer's disease after all? PMID- 26106097 TI - Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases. AB - Memory loss after brain injury can be a source of considerable morbidity, but there are presently few therapeutic options for restoring memory function. We have previously demonstrated that burst stimulation of the fornix is able to significantly improve memory in a rodent model of traumatic brain injury. The present study is a preliminary investigation with a small group of cases to explore whether theta burst stimulation of the fornix might improve memory in humans. Four individuals undergoing stereo-electroencephalography evaluation for drug-resistant epilepsy were enrolled. All participants were implanted with an electrode into the proximal fornix and dorsal hippocampal commissure on the language dominant (n = 3) or language non-dominant (n = 1) side, and stimulation of this electrode reliably produced a diffuse evoked potential in the head and body of the ipsilateral hippocampus. Each participant underwent testing of verbal memory (Rey Auditory-Verbal Learning Test), visual-spatial memory (Medical College of Georgia Complex Figure Test), and visual confrontational naming (Boston Naming Test Short Form) once per day over at least two consecutive days using novel test forms each day. For 50% of the trials, the fornix electrode was continuously stimulated using a burst pattern (200 Hz in 100 ms trains, five trains per second, 100 us, 7 mA) and was compared with sham stimulation. Participants and examiners were blinded to whether stimulation was active or not, and the order of stimulation was randomized. The small sample size precluded use of inferential statistics; therefore, data were analysed using descriptive statistics and graphic analysis. Burst stimulation of the fornix was not perceived by any of the participants but was associated with a robust reversible improvement in immediate and delayed performance on the Medical College of Georgia Complex Figure Test. There were no apparent differences on either Rey Auditory-Verbal Learning Test or Boston Naming Test. There was no apparent relationship between performance and side of stimulation (language dominant or non-dominant). There were no complications. Preliminary evidence in this small sample of patients with drug-resistant epilepsy suggests that theta burst stimulation of the fornix may be associated with improvement in visual-spatial memory. PMID- 26106098 TI - Corrigendum. PMID- 26106099 TI - Corrigendum. PMID- 26106102 TI - Abortion: a disunited Europe. PMID- 26106103 TI - Barriers and facilitators of access to first-trimester abortion services for women in the developed world: a systematic review. AB - OBJECTIVES: To identify the barriers and facilitators to accessing first trimester abortion services for women in the developed world. METHODS: Systematic review of published literature. CINAHL, PubMed, Proquest, MEDLINE, InformIT, Scopus, PsycINFO and Academic Search Premier were searched for papers written in the English language, from the developed world, including quantitative and qualitative articles published between 1993 and 2014. RESULTS: The search initially yielded 2511 articles. After screening of title, abstract and removing duplicates, 38 articles were reviewed. From the provider perspective, barriers included moral opposition to abortion, lack of training, too few physicians, staff harassment, and insufficient hospital resources, particularly in rural areas. From the women's perspective, barriers included lack of access to services (including distance and lack of service availability), negative attitudes of staff, and the associated costs of the abortion procedure. Service access could be enhanced by increasing training, particularly for mid-level practitioners; by increasing the range of service options, including the use of telehealth; and by creating clear guidelines and referral procedures to alternative providers when staff have a moral opposition to abortion. CONCLUSION: Despite fewer legal barriers to accessing abortion services, the evidence from this review suggests that women in developed countries still face significant inequities in terms of the level of quality and access to services as recommended by the World Health Organization. PMID- 26106104 TI - Do women seeking termination of pregnancy need pre-abortion counselling? AB - BACKGROUND: Pre-termination counselling is currently voluntary in the UK; however, there has been political debate regarding the introduction of mandatory pre-termination counselling as well as who should be providing the abortion counselling services. OBJECTIVE: To quantify the proportion of women who use pre termination counselling services and to evaluate their experience. METHOD: An anonymous self-administered questionnaire of women requesting an abortion at Chalmers Sexual Health Centre and the Royal Infirmary of Edinburgh NHS Lothian from 6 October to 2 December 2014. RESULTS: Only 18 (9%) of the 201 women surveyed reported using pre-termination counselling. The majority of women did not feel counselling was necessary because they were already certain of their decision. Nearly a quarter (22%) of women claimed to not know counselling was available. Women who did use counselling were satisfied with the services they received. The majority of counselling services were provided by the National Health Service and only one woman used a 'pro-life' charity. Women stated that they would prefer face-to-face counselling rather than telephone or Internet based counselling. CONCLUSIONS: Most women do not seem to want or need pre termination counselling therefore policies aimed at mandatory counselling, would be contrary to women's wishes. Counselling should be targeted at women with risk factors for psychological complications post-termination. PMID- 26106105 TI - Medical abortion: the hidden revolution. AB - While the medical abortion (MA) drugs, mifepristone and misoprostol, have radically altered reproductive health practices around the world, there has been little field research on the sales and use of these drugs, especially in developing countries. This leaves the family planning community with many unanswered questions. While good profiles of contraceptive use are available for many countries and we have good technical data on the MA drugs' efficacy, dosages and regimens such as home dosage of misoprostol versus clinic dosage, we have very little information about the quantities of MA drugs sold, how they are used, where they are used, and, in the case of misoprostol, for what purposes. Sales data are available from one excellent commercial survey and from social marketing sales of mifepristone and misoprostol and these are presented. Acknowledging the sensitivity of the issue, especially in countries where abortion is severely restricted, the author makes a plea for careful additional research to shed light on an important and growing part of the international reproductive health picture. PMID- 26106106 TI - Poisson regression. PMID- 26106107 TI - Female genital mutilation: three questions for us to consider. PMID- 26106108 TI - MEDFASH (Medical Foundation for HIV & Sexual Health). PMID- 26106109 TI - Incomplete removal of an intrauterine system. PMID- 26106110 TI - Comment on 'Continuing need for and provision of a service for non-standard implant removal'. PMID- 26106111 TI - Comment on 'Continuing need for and provision of a service for non-standard implant removal': author's response. PMID- 26106112 TI - The Role of Emotional Intelligence in Predicting Postpartum Depression. AB - This study examines the direct and moderating effects of emotional intelligence on postpartum depression (PPD), while taking into account social support and stressful life events. Using a prospective cohort design, 165 women were surveyed in their third trimester and again at 9 weeks postpartum. Results support the direct effects of emotional intelligence (beta = -.20, p = .01), social support (beta = -.17, p = .04), and stressful life events (beta = .17, p = .04) on PPD. Moderating effects are also supported with significant effects on PPD: stressful life events * emotional intelligence (beta = -.17, p = .04) and stressful life events * social support (beta = -.21, p = .01). PMID- 26106113 TI - Effect of Intravenous Recombinant Tissue-Type Plasminogen Activator in Patients With Mild Stroke in the Third International Stroke Trial-3: Post Hoc Analysis. AB - BACKGROUND AND PURPOSE: Randomized trial evidence on the risk/benefit ratio of thrombolysis for mild stroke is limited. We sought to determine the efficacy of intravenous recombinant tissue-type plasminogen activator (IV r-tPA) in a subset of patients with mild deficit in the third International Stroke Trial (IST-3). METHODS: IST-3 compared IV r-tPA with control within 6 hours of onset in patients for whom IV r-tPA was considered promising but unproven. Analysis was restricted to subjects randomized within 3 hours of onset with a baseline National Institutes of Health Stroke Scale <=5, pretreatment blood pressure <185/110, and no other r-tPA exclusion criteria. We compared r-tPA and control arms for primary (Oxfordshire Handicap Score [OHS] 0-2) and secondary (ordinal OHS and OHS 0-1) outcomes at 6 months. RESULTS: Among 3035 IST-3 subjects, 612 (20.2%) had an National Institutes of Health Stroke Scale <=5; of these 106 (17.6%) met the restricted criteria. Allocation to r-tPA was associated with an increase in OHS 0 to 2 (84% r-tPA versus 65% control; adjusted odds ratio, 3.31; 95% confidence interval, 1.24-8.79) and a favorable shift in OHS distribution (adjusted odds ratio, 2.38; 95% confidence interval, 1.17-4.85). There was no significant effect of r-tPA on OHS 0 to 1 (60% versus 51%; adjusted odds ratio, 1.92; 95% confidence interval, 0.83-4.43). CONCLUSIONS: This post hoc analysis in a highly selected sample of IST-3 supports the rationale of A Study of the Efficacy and Safety of Activase (Alteplase) in Patients With Mild Stroke (PRISMS) trial-a randomized, phase IIIb study to evaluate IV r-tPA in mild ischemic stroke. PMID- 26106114 TI - Intensive Versus Distributed Aphasia Therapy: A Nonrandomized, Parallel-Group, Dosage-Controlled Study. AB - BACKGROUND AND PURPOSE: Most studies comparing different levels of aphasia treatment intensity have not controlled the dosage of therapy provided. Consequently, the true effect of treatment intensity in aphasia rehabilitation remains unknown. Aphasia Language Impairment and Functioning Therapy is an intensive, comprehensive aphasia program. We investigated the efficacy of a dosage-controlled trial of Aphasia Language Impairment and Functioning Therapy, when delivered in an intensive versus distributed therapy schedule, on communication outcomes in participants with chronic aphasia. METHODS: Thirty-four adults with chronic, poststroke aphasia were recruited to participate in an intensive (n=16; 16 hours per week; 3 weeks) versus distributed (n=18; 6 hours per week; 8 weeks) therapy program. Treatment included 48 hours of impairment, functional, computer, and group-based aphasia therapy. RESULTS: Distributed therapy resulted in significantly greater improvements on the Boston Naming Test when compared with intensive therapy immediately post therapy (P=0.04) and at 1 month follow-up (P=0.002). We found comparable gains on measures of participants' communicative effectiveness, communication confidence, and communication-related quality of life for the intensive and distributed treatment conditions at post therapy and 1-month follow-up. CONCLUSIONS: Aphasia Language Impairment and Functioning Therapy resulted in superior clinical outcomes on measures of language impairment when delivered in a distributed versus intensive schedule. The therapy progam had a positive effect on participants' functional communication and communication-related quality of life, regardless of treatment intensity. These findings contribute to our understanding of the effect of treatment intensity in aphasia rehabilitation and have important clinical implications for service delivery models. PMID- 26106115 TI - Short History of Confidence Intervals: Or, Don't Ask "Does the Treatment Work?" but "How Sure Are You That It Works?". PMID- 26106116 TI - Intima-Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults: Findings From the Coronary Artery Risk Development in Young Adults Study. AB - BACKGROUND AND PURPOSE: The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants. METHODS: At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z scores, with negative values indicating worse performance. RESULTS: Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (z scores) in unadjusted linear regression models (verbal memory, -0.16; 95% confidence interval [CI], -0.20 to -0.13; processing speed, -0.23; 95% CI, -0.27 to -0.19; and executive function, -0.17; 95% CI, -0.20 to -0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (-0.06; 95% CI, -0.09 to -0.02; P, 0.003) and borderline associated with executive function (-0.03; 95% CI, -0.07 to 0.00; P, 0.07) but not with verbal memory. CONCLUSIONS: We observed an association between greater IMT and worse processing speed-a key component of cognitive functioning-at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging. PMID- 26106117 TI - Futile Interhospital Transfer for Endovascular Treatment in Acute Ischemic Stroke: The Madrid Stroke Network Experience. AB - BACKGROUND AND PURPOSE: The complexity of endovascular revascularization treatment (ERT) in acute ischemic stroke and the small number of patients eligible for treatment justify the development of stroke center networks with interhospital patient transfers. However, this approach might result in futile transfers (ie, the transfer of patients who ultimately do not undergo ERT). Our aim was to analyze the frequency of these futile transfers and the reasons for discarding ERT and to identify the possible associated factors. METHODS: We analyzed an observational prospective ERT registry from a stroke collaboration ERT network consisting of 3 hospitals. There were interhospital transfers from the first attending hospital to the on-call ERT center for the patients for whom this therapy was indicated, either primarily or after intravenous thrombolysis (drip and shift). RESULTS: The ERT protocol was activated for 199 patients, 129 of whom underwent ERT (64.8%). A total of 120 (60.3%) patients required a hospital transfer, 50 of whom (41%) ultimately did not undergo ERT. There were no differences in their baseline characteristics, the times from stroke onset, or in the delays in interhospital transfers between the transferred patients who were treated and those who were not treated. The main reasons for rejecting ERT after the interhospital transfer were clinical improvement/arterial recanalization (48%) and neuroimaging criteria (32%). CONCLUSIONS: Forty-one percent of the ERT transfers were futile, but none of the baseline patient characteristics predicted this result. Futility could be reduced if repetition of unnecessary diagnostic tests was avoided. PMID- 26106119 TI - New Additions to Multimedia Manual of Cardio-Thoracic Surgery. PMID- 26106118 TI - Stem Cell-Based Tissue Replacement After Stroke: Factual Necessity or Notorious Fiction? PMID- 26106120 TI - eComment. When and why is it reasonable to perform a pleural lavage cytology in non-small-cell lung cancer patients? PMID- 26106123 TI - Science and Culture: Charting the history of Western art with math. PMID- 26106121 TI - eComment. The wide spectrum of thoracic approaches on a learning curve basis. PMID- 26106125 TI - Alterations of oxidative phosphorylation in meningiomas and peripheral nerve sheath tumors. AB - BACKGROUND: Changes in the mode of aerobic energy production are observed in many solid tumors, though the kinds of changes differ among tumor types. We investigated mitochondrial energy metabolism in meningiomas and peripheral nerve sheath tumors, taking into consideration the histologic heterogeneity of these tumors. METHODS: Oxidative phosphorylation (OXPHOS) complexes and porin (a marker for mitochondrial mass) were analyzed by immunohistochemical staining of meningiomas (n = 76) and peripheral nerve sheath tumors (schwannomas: n = 10; neurofibromas: n = 4). The enzymatic activities of OXPHOS complexes and citrate synthase were determined by spectrophotometric measurement. Western blot analysis of OXPHOS complexes, porin, and mitochondrial transcription factor A was performed. Furthermore, mitochondrial DNA copy number was determined. RESULTS: The tumors differed with regard to mitochondrial energy metabolism. Low levels of a subset of OXPHOS complexes were frequently observed in World Health Organization grade I meningiomas (percent of cases with a reduction; complex I: 63%; complex II: 67%; complex IV: 56%) and schwannomas (complex III: 40%, complex IV: 100%), whereas in neurofibromas a general reduction of all complexes was observed. In contrast, expression of complexes III and V was similar to that in normal brain tissue in the majority of tumors. Mitochondrial mass was comparable or higher in all tumors compared with normal brain tissue, whereas mitochondrial DNA copy number was reduced. CONCLUSIONS: The reduction of OXPHOS complexes in meningiomas and peripheral nerve sheath tumors has potential therapeutic implications, since respiratory chain-deficient tumor cells might be selectively starved by inhibitors of glycolysis or by ketogenic diet. PMID- 26106126 TI - Correlates of dietary behavior in adults: an umbrella review. AB - CONTEXT: Multiple studies have been conducted on correlates of dietary behavior in adults, but a clear overview is currently lacking. OBJECTIVE: An umbrella review, or review-of-reviews, was conducted to summarize and synthesize the scientific evidence on correlates and determinants of dietary behavior in adults. DATA SOURCES: Eligible systematic reviews were identified in four databases: PubMed, PsycINFO, The Cochrane Library, and Web of Science. Only reviews published between January 1990 and May 2014 were included. STUDY SELECTION: Systematic reviews of observable food and dietary behavior that describe potential behavioral determinants of dietary behavior in adults were included. After independent selection of potentially relevant reviews by two authors, a total of 14 reviews were considered eligible. DATA EXTRACTION: For data extraction, the importance of determinants, the strength of the evidence, and the methodological quality of the eligible reviews were evaluated. Multiple observers conducted the data extraction independently. DATA SYNTHESIS: Social-cognitive determinants and environmental determinants (mainly the social-cultural environment) were included most often in the available reviews. Sedentary behavior and habit strength were consistently identified as important correlates of dietary behavior. Other correlates and potential determinants of dietary behavior, such as motivational regulation, shift work, and the political environment, have been studied in relatively few studies, but results are promising. CONCLUSIONS: The multitude of studies conducted on correlates of dietary behavior provides mixed, but sometimes quite convincing, evidence. However, because of the generally weak research design of the studies covered in the available reviews, the evidence for true determinants is suggestive, at best. PMID- 26106127 TI - Workability and mental wellbeing among therapeutic prison officers. AB - BACKGROUND: Previous research has examined how age and health can shape workability (WA). This study seeks to explore how a lack of WA (inability) may affect the health of the employee. AIMS: To explore the effects of work inability on mental wellbeing among therapeutic prison officers. METHODS: An anonymous cross-sectional study of prison officers conducted in a category B English prison using the Work Ability Index (WAI) and General Health Questionnaire-28 (GHQ). RESULTS: Fifty-seven officers (59%) participated and of those 95% achieved GHQ caseness. Officers with poorer WA reported significantly higher GHQ scores. Work inability for mental demands had significant associations with anxiety (beta = 0.58, 95% CI -4.21 to -1.88, particularly sleep loss; Pearson's r = -0.66). CONCLUSIONS: Our findings present clear associations between poor WA and its impact upon mental wellbeing. The results of this study may help to focus on areas for intervention such as improving WA and promoting mental wellbeing. PMID- 26106134 TI - Cause and Prevention of Human Cancer. PMID- 26106136 TI - The effect of environmental chemicals on the tumor microenvironment. AB - Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis. PMID- 26106135 TI - The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis. AB - The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial-mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis. PMID- 26106137 TI - Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis. AB - One of the important 'hallmarks' of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential. PMID- 26106138 TI - Disruptive chemicals, senescence and immortality. AB - Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? What are the underlying mechanisms responsible for chemical carcinogen-induced cellular immortality? Here, we explore the possible mechanisms of cellular immortalization, the contribution of immortalization to tumorigenesis and the mechanisms by which chemical carcinogens may contribute to these processes. PMID- 26106139 TI - Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression. AB - As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks. PMID- 26106140 TI - Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis? AB - Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low dose chemical mixtures and the fact that exposures can influence multiple cancer associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested. PMID- 26106141 TI - Environmental immune disruptors, inflammation and cancer risk. AB - An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented. PMID- 26106143 TI - The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. AB - The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span. PMID- 26106147 TI - Genome-wide association studies and contribution to cardiovascular physiology. AB - The study of family pedigrees with rare monogenic cardiovascular disorders has revealed new molecular players in physiological processes. Genome-wide association studies of complex traits with a heritable component may afford a similar and potentially intellectually richer opportunity. In this review we focus on the interpretation of genetic associations and the issue of causality in relation to known and potentially new physiology. We mainly discuss cardiometabolic traits as it reflects our personal interests, but the issues pertain broadly in many other disciplines. We also describe some of the resources that are now available that may expedite follow up of genetic association signals into observations on causal mechanisms and pathophysiology. PMID- 26106146 TI - Dopamine's Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders. AB - The prefrontal cortex (PFC) elaborates and differentiates in primates, and there is a corresponding elaboration in cortical dopamine (DA). DA cells that fire to both aversive and rewarding stimuli likely project to the dorsolateral PFC (dlPFC), signaling a salient event. Since 1979, we have known that DA has an essential influence on dlPFC working memory functions. DA has differing effects via D1 (D1R) versus D2 receptor (D2R) families. D1R are concentrated on dendritic spines, and D1/5R stimulation produces an inverted U-shaped dose response on visuospatial working memory performance and Delay cell firing, the neurons that generate representations of visual space. Optimal levels of D1R stimulation gate out "noise," whereas higher levels, e.g., during stress, suppress Delay cell firing. These effects likely involve hyperpolarization-activated cyclic nucleotide-gated channel opening, activation of GABA interneurons, and reduced glutamate release. Dysregulation of D1R has been related to cognitive deficits in schizophrenia, and there is a need for new, lower-affinity D1R agonists that may better mimic endogenous DA to enhance mental representations and improve cognition. In contrast to D1R, D2R are primarily localized on layer V pyramidal cell dendrites, and D2/3R stimulation speeds and magnifies the firing of Response cells, including Response Feedback cells. Altered firing of Feedback neurons may relate to positive symptoms in schizophrenia. Emerging research suggests that DA may have similar effects in the ventrolateral PFC and frontal eye fields. Research on the orbital PFC in monkeys is just beginning and could be a key area for future discoveries. PMID- 26106148 TI - SWP73 Subunits of Arabidopsis SWI/SNF Chromatin Remodeling Complexes Play Distinct Roles in Leaf and Flower Development. AB - Arabidopsis thaliana SWP73A and SWP73B are homologs of mammalian BRAHMA associated factors (BAF60s) that tether SWITCH/SUCROSE NONFERMENTING chromatin remodeling complexes to transcription factors of genes regulating various cell differentiation pathways. Here, we show that Arabidopsis thaliana SWP73s modulate several important developmental pathways. While undergoing normal vegetative development, swp73a mutants display reduced expression of FLOWERING LOCUS C and early flowering in short days. By contrast, swp73b mutants are characterized by retarded growth, severe defects in leaf and flower development, delayed flowering, and male sterility. MNase-Seq, transcript profiling, and ChIP-Seq studies demonstrate that SWP73B binds the promoters of ASYMMETRIC LEAVES1 and 2, KANADI1 and 3, and YABBY2, 3, and 5 genes, which regulate leaf development and show coordinately altered transcription in swp73b plants. Lack of SWP73B alters the expression patterns of APETALA1, APETALA3, and the MADS box gene AGL24, whereas other floral organ identity genes show reduced expression correlating with defects in flower development. Consistently, SWP73B binds to the promoter regions of APETALA1 and 3, SEPALLATA3, LEAFY, UNUSUAL FLORAL ORGANS, TERMINAL FLOWER1, AGAMOUS-LIKE24, and SUPPRESSOR OF CONSTANS OVEREXPRESSION1 genes, and the swp73b mutation alters nucleosome occupancy on most of these loci. In conclusion, SWP73B acts as important modulator of major developmental pathways, while SWP73A functions in flowering time control. PMID- 26106149 TI - Genome Sequencing of Arabidopsis abp1-5 Reveals Second-Site Mutations That May Affect Phenotypes. AB - Auxin regulates numerous aspects of plant growth and development. For many years, investigating roles for AUXIN BINDING PROTEIN1 (ABP1) in auxin response was impeded by the reported embryo lethality of mutants defective in ABP1. However, identification of a viable Arabidopsis thaliana TILLING mutant defective in the ABP1 auxin binding pocket (abp1-5) allowed inroads into understanding ABP1 function. During our own studies with abp1-5, we observed growth phenotypes segregating independently of the ABP1 lesion, leading us to sequence the genome of the abp1-5 line described previously. We found that the abp1-5 line we sequenced contains over 8000 single nucleotide polymorphisms in addition to the ABP1 mutation and that at least some of these mutations may originate from the Arabidopsis Wassilewskija accession. Furthermore, a phyB null allele in the abp1 5 background is likely causative for the long hypocotyl phenotype previously attributed to disrupted ABP1 function. Our findings complicate the interpretation of abp1-5 phenotypes for which no complementation test was conducted. Our findings on abp1-5 also provide a cautionary tale illustrating the need to use multiple alleles or complementation lines when attributing roles to a gene product. PMID- 26106142 TI - Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. AB - Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. PMID- 26106152 TI - Correction for Gursoy-Yuzugullu et al., Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair. PMID- 26106145 TI - Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death. AB - Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of pro-survival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of pro-apoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis. PMID- 26106150 TI - DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice. AB - Fibrosis is caused by scar tissue formation in internal organs and is associated with 45% of deaths in the United States. Two closely related human serum proteins, serum amyloid P (SAP) and C-reactive protein (CRP), strongly affect fibrosis. In multiple animal models, and in Phase 1 and Phase 2 clinical trials, SAP affects several aspects of the innate immune system to reduce fibrosis, whereas CRP appears to potentiate fibrosis. However, SAP and CRP bind the same Fcgamma receptors (FcgammaR) with similar affinities, and why SAP and CRP have opposing effects is unknown. Here, we report that SAP but not CRP binds the receptor DC-SIGN (SIGN-R1) to affect the innate immune system, and that FcgammaR are not necessary for SAP function. A polycyclic aminothiazole DC-SIGN ligand and anti-DC-SIGN antibodies mimic SAP effects in vitro. In mice, the aminothiazole reduces neutrophil accumulation in a model of acute lung inflammation and, at 0.001 mg/kg, alleviates pulmonary fibrosis by increasing levels of the immunosuppressant IL-10. DC-SIGN (SIGN-R1) is present on mouse lung epithelial cells, and SAP and the aminothiazole potentiate IL-10 production from these cells. Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics. PMID- 26106151 TI - Ocean stoichiometry, global carbon, and climate. PMID- 26106144 TI - Causes of genome instability: the effect of low dose chemical exposures in modern society. AB - Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis. PMID- 26106153 TI - Correction to Supporting Information for Talantova et al., Abeta induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. PMID- 26106154 TI - Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. AB - Alternative splicing of proteins gives rise to different isoforms that play a crucial role in regulating several cellular processes. Notably, splicing profiles are altered in several cancer types, and these profiles are believed to be involved in driving the oncogenic process. Although the importance of alternative splicing alterations occurring during cancer is increasingly appreciated, the underlying regulatory mechanisms remain poorly understood. In this study, we use both biochemical and physical tools coupled with engineered models, patient samples, and a murine model to investigate the role of the mechanical properties of the tumor microenvironment in regulating the production of the extra domain-B (EDB) splice variant of fibronectin (FN), a hallmark of tumor angiogenesis. Specifically, we show that the amount of EDB-FN produced by endothelial cells increases with matrix stiffness both in vitro and within mouse mammary tumors. Matrix stiffness regulates splicing through the activation of serine/arginine rich (SR) proteins, the splicing factors involved in the production of FN isoforms. Activation of the SR proteins by matrix stiffness and the subsequent production of EDB-FN are dependent on intracellular contractility and PI3K-AKT signaling. Notably, matrix stiffness-mediated splicing is not limited to EDB-FN, but also affects splicing in the production of PKC betaII and the VEGF 165b splice variant. Together, these results demonstrate that the mechanical properties of the microenvironment regulate alternative splicing and establish a previously unidentified mechanism by which cells can adapt to their microenvironment. PMID- 26106155 TI - Trp triad-dependent rapid photoreduction is not required for the function of Arabidopsis CRY1. AB - Cryptochromes in different evolutionary lineages act as either photoreceptors or light-independent transcription repressors. The flavin cofactor of both types of cryptochromes can be photoreduced in vitro by electron transportation via three evolutionarily conserved tryptophan residues known as the "Trp triad." It was hypothesized that Trp triad-dependent photoreduction leads directly to photoexcitation of cryptochrome photoreceptors. We tested this hypothesis by analyzing mutations of Arabidopsis cryptochrome 1 (CRY1) altered in each of the three Trp-triad tryptophan residues (W324, W377, and W400). Surprisingly, in contrast to a previous report all photoreduction-deficient Trp-triad mutations of CRY1 remained physiologically and biochemically active in Arabidopsis plants. ATP did not enhance rapid photoreduction of the wild-type CRY1, nor did it rescue the defective photoreduction of the CRY1(W324A) and CRY1(W400F) mutants that are photophysiologically active in vivo. The lack of correlation between rapid flavin photoreduction or the effect of ATP on the rapid flavin photoreduction and the in vivo photophysiological activities of plant cryptochromes argues that the Trp triad-dependent photoreduction is not required for the function of cryptochromes and that further efforts are needed to elucidate the photoexcitation mechanism of cryptochrome photoreceptors. PMID- 26106156 TI - Engineered cellular gene-replacement platform for selective and inducible proteolytic profiling. AB - Cellular demolition during apoptosis is completed by executioner caspases, that selectively cleave more than 1,500 proteins but whose individual roles are challenging to assess. Here, we used an optimized site-specific and inducible protease to examine the role of a classic apoptotic node, the caspase-activated DNase (CAD). CAD is activated when caspases cleave its endogenous inhibitor ICAD, resulting in the characteristic DNA laddering of apoptosis. We describe a posttranscriptional gene replacement (PTGR) approach where endogenous biallelic ICAD is knocked down and simultaneously replaced with an engineered allele that is susceptible to inducible cleavage by tobacco etch virus protease. Remarkably, selective activation of CAD alone does not induce cell death, although hallmarks of DNA damage are detected in human cancer cell lines. Our data strongly support that the highly cooperative action of CAD and inhibition of DNA repair systems are critical for the DNA laddering phenotype in apoptosis. Furthermore, the PTGR approach provides a general means for replacing wild-type protein function with a precisely engineered mutant at the transcriptional level that should be useful for cell engineering studies. PMID- 26106157 TI - Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA. AB - Platelets are anucleated blood elements highly potent at generating extracellular vesicles (EVs) called microparticles (MPs). Whereas EVs are accepted as an important means of intercellular communication, the mechanisms underlying platelet MP internalization in recipient cells are poorly understood. Our lipidomic analyses identified 12(S)-hydroxyeicosatetranoic acid [12(S)-HETE] as the predominant eicosanoid generated by MPs. Mechanistically, 12(S)-HETE is produced through the concerted activity of secreted phospholipase A2 IIA (sPLA2 IIA), present in inflammatory fluids, and platelet-type 12-lipoxygenase (12-LO), expressed by platelet MPs. Platelet MPs convey an elaborate set of transcription factors and nucleic acids, and contain mitochondria. We observed that MPs and their cargo are internalized by activated neutrophils in the endomembrane system via 12(S)-HETE. Platelet MPs are found inside neutrophils isolated from the joints of arthritic patients, and are found in neutrophils only in the presence of sPLA2-IIA and 12-LO in an in vivo model of autoimmune inflammatory arthritis. Using a combination of genetically modified mice, we show that the coordinated action of sPLA2-IIA and 12-LO promotes inflammatory arthritis. These findings identify 12(S)-HETE as a trigger of platelet MP internalization by neutrophils, a mechanism highly relevant to inflammatory processes. Because sPLA2-IIA is induced during inflammation, and 12-LO expression is restricted mainly to platelets, these observations demonstrate that platelet MPs promote their internalization in recipient cells through highly regulated mechanisms. PMID- 26106159 TI - Backbones of evolutionary history test biodiversity theory for microbes. AB - Identifying the ecological and evolutionary mechanisms that determine biological diversity is a central question in ecology. In microbial ecology, phylogenetic diversity is an increasingly common and relevant means of quantifying community diversity, particularly given the challenges in defining unambiguous species units from environmental sequence data. We explore patterns of phylogenetic diversity across multiple bacterial communities drawn from different habitats and compare these data to evolutionary trees generated using theoretical models of biodiversity. We have two central findings. First, although on finer scales the empirical trees are highly idiosyncratic, on coarse scales the backbone of these trees is simple and robust, consistent across habitats, and displays bursts of diversification dotted throughout. Second, we find that these data demonstrate a clear departure from the predictions of standard neutral theories of biodiversity and that an alternative family of generalized models provides a qualitatively better description. Together, these results lay the groundwork for a theoretical framework to connect ecological mechanisms to observed phylogenetic patterns in microbial communities. PMID- 26106158 TI - CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance. AB - Dimerization of Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD2) heterodimers is critical for both MyD88- and TIR-domain-containing adapter inducing IFN-beta (TRIF)-mediated signaling pathways. Recently, Zanoni et al. [(2011) Cell 147(4):868-880] reported that cluster of differentiation 14 (CD14) is required for LPS-/Escherichia coli- induced TLR4 internalization into endosomes and activation of TRIF-mediated signaling in macrophages. We confirmed their findings with LPS but report here that CD14 is not required for receptor endocytosis and downstream signaling mediated by TLR4/MD2 agonistic antibody (UT12) and synthetic small-molecule TLR4 ligands (1Z105) in murine macrophages. CD14 deficiency completely ablated the LPS-induced TBK1/IRF3 signaling axis that mediates production of IFN-beta in murine macrophages without affecting MyD88 mediated signaling, including NF-kappaB, MAPK activation, and TNF-alpha and IL-6 production. However, neither the MyD88- nor TRIF-signaling pathways and their associated cytokine profiles were altered in the absence of CD14 in UT12- or 1Z105-treated murine macrophages. Eritoran (E5564), a lipid A antagonist that binds the MD2 "pocket," completely blocked LPS- and 1Z105-driven, but not UT12 induced, TLR4 dimerization and endocytosis. Furthermore, TLR4 endocytosis is induced in macrophages tolerized by exposure to either LPS or UT12 and is independent of CD14. These data indicate that TLR4 receptor endocytosis and the TRIF-signaling pathway are dissociable and that TLR4 internalization in macrophages can be induced by UT12, 1Z105, and during endotoxin tolerance in the absence of CD14. PMID- 26106160 TI - A retro-biosynthetic approach to the prediction of biosynthetic pathways from position-specific isotope analysis as shown for tramadol. AB - Tramadol, previously only known as a synthetic analgesic, has now been found in the bark and wood of roots of the African medicinal tree Nauclea latifolia. At present, no direct evidence is available as to the biosynthetic pathway of its unusual skeleton. To provide guidance as to possible biosynthetic precursors, we have adopted a novel approach of retro-biosynthesis based on the position specific distribution of isotopes in the extracted compound. Relatively recent developments in isotope ratio monitoring by (13)C NMR spectrometry make possible the measurement of the nonstatistical position-specific natural abundance distribution of (13)C (delta(13)Ci) within the molecule with better than 10/00 precision. Very substantial variation in the (13)C positional distribution is found: between delta(13)Ci = -11 and -530/00. Distribution is not random and it is argued that the pattern observed can substantially be interpreted in relation to known causes of isotope fractionation in natural products. Thus, a plausible biosynthetic scheme based on sound biosynthetic principals of precursor-substrate relationships can be proposed. In addition, data obtained from the (18)O/(16)O ratios in the oxygen atoms of the compound add support to the deductions made from the carbon isotope analysis. This paper shows how the use of (13)C NMR at natural abundance can help with proposing a biosynthetic route to compounds newly found in nature or those difficult to tackle by conventional means. PMID- 26106161 TI - Less than the sum of its parts, a leinamycin precursor has superior properties. PMID- 26106162 TI - Structural analysis of a class III preQ1 riboswitch reveals an aptamer distant from a ribosome-binding site regulated by fast dynamics. AB - PreQ1-III riboswitches are newly identified RNA elements that control bacterial genes in response to preQ1 (7-aminomethyl-7-deazaguanine), a precursor to the essential hypermodified tRNA base queuosine. Although numerous riboswitches fold as H-type or HLout-type pseudoknots that integrate ligand-binding and regulatory sequences within a single folded domain, the preQ1-III riboswitch aptamer forms a HLout-type pseudoknot that does not appear to incorporate its ribosome-binding site (RBS). To understand how this unusual organization confers function, we determined the crystal structure of the class III preQ1 riboswitch from Faecalibacterium prausnitzii at 2.75 A resolution. PreQ1 binds tightly (KD,app 6.5 +/- 0.5 nM) between helices P1 and P2 of a three-way helical junction wherein the third helix, P4, projects orthogonally from the ligand-binding pocket, exposing its stem-loop to base pair with the 3' RBS. Biochemical analysis, computational modeling, and single-molecule FRET imaging demonstrated that preQ1 enhances P4 reorientation toward P1-P2, promoting a partially nested, H-type pseudoknot in which the RBS undergoes rapid docking (kdock ~ 0.6 s(-1)) and undocking (kundock ~ 1.1 s(-1)). Discovery of such dynamic conformational switching provides insight into how a riboswitch with bipartite architecture uses dynamics to modulate expression platform accessibility, thus expanding the known repertoire of gene control strategies used by regulatory RNAs. PMID- 26106163 TI - Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. AB - Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D3-vitamin A) impedes the dimerization rate of vitamin A--by approximately fivefold for the vitamin A dimer A2E--and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D3-vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D3-vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina. PMID- 26106164 TI - Ongoing dynamics in large-scale functional connectivity predict perception. AB - Most brain activity occurs in an ongoing manner not directly locked to external events or stimuli. Regional ongoing activity fluctuates in unison with some brain regions but not others, and the degree of long-range coupling is called functional connectivity, often measured with correlation. Strength and spatial distributions of functional connectivity dynamically change in an ongoing manner over seconds to minutes, even when the external environment is held constant. Direct evidence for any behavioral relevance of these continuous large-scale dynamics has been limited. Here, we investigated whether ongoing changes in baseline functional connectivity correlate with perception. In a continuous auditory detection task, participants perceived the target sound in roughly one half of the trials. Very long (22-40 s) interstimulus intervals permitted investigation of baseline connectivity unaffected by preceding evoked responses. Using multivariate classification, we observed that functional connectivity before the target predicted whether it was heard or missed. Using graph theoretical measures, we characterized the difference in functional connectivity between states that lead to hits vs. misses. Before misses compared with hits and task-free rest, connectivity showed reduced modularity, a measure of integrity of modular network structure. This effect was strongest in the default mode and visual networks and caused by both reduced within-network connectivity and enhanced across-network connections before misses. The relation of behavior to prestimulus connectivity was dissociable from that of prestimulus activity amplitudes. In conclusion, moment to moment dynamic changes in baseline functional connectivity may shape subsequent behavioral performance. A highly modular network structure seems beneficial to perceptual efficiency. PMID- 26106165 TI - Correction for Balakrishnan et al., Novel pathways for fuels and lubricants from biomass optimized using life-cycle greenhouse gas assessment. PMID- 26106166 TI - Reply to Toker and Pavlidis: Blood biomarkers for Parkinson's disease. PMID- 26106167 TI - Metaanalysis of flawed expression profiling data leading to erroneous Parkinson's biomarker identification. PMID- 26106168 TI - beta-lactam-associated eosinophilic colitis. AB - A 42-year-old man with a history of childhood asthma presented with a 2-week history of watery diarrhoea and marked peripheral eosinophilia in the setting of recent use of cephalexin. His colonoscopy revealed patchy colitis. Biopsies were consistent with eosinophilic colitis. Two months later he received a course of amoxicillin resulting in recurrence of peripheral eosinophilia. Given the time frame of beta-lactam administration to symptom onset and elimination of all other precipitating causes, he was diagnosed with beta-lactam-associated eosinophilic colitis. The patient's symptoms resolved and peripheral eosinophil count decreased with no specific treatment. Eosinophilic colitis is a rare heterogeneous condition, the pathogenesis of which is likely to be an interplay between environmental and genetic factors. It can be secondary to a helminthic infection or a drug reaction and has been associated with ulcerative colitis. If secondary causes of eosinophilic colitis have been excluded, the mainstay of treatment is with corticosteroids. PMID- 26106169 TI - Takayasu's or tuberculous arteritis? AB - Takayasu's arteritis (TA) is a large vessel vasculitis of unknown aetiology characterised by involvement of the aorta and its major branches. Tuberculous arteritis of the aorta is an uncommon condition usually secondary to the dissemination of Mycobacterium tuberculosis infection from the mediastinum and/or lung to the adjacent aorta; this may mimic TA. We report a case of a 23-year-old woman with cutaneous granulomatous vasculitis and saccular aneurysmal dilation of the aorta and large vessels, and highlight the findings shared by TA and tuberculous arteritis. PMID- 26106170 TI - Kidney transplantation in an adult patient with VACTERL association. AB - The vertebral, anal, cardiac, tracheoesophageal, renal, and limb birth defects (VACTERL) association is a rare, non-random constellation of congenital abnormalities among which urinary tract anomalies can be included. In the presence of these anomalies, patients are suspected to have a higher rate of renal failure than average. We report a case of a 22-year-old woman with VACTERL association and consequent end stage renal failure. A live-related kidney transplant was carried out successfully and the postoperative course was uncomplicated. The patient had immediate graft function. Risk factors that may complicate kidney transplant surgery in this patient population as well as considerations relevant to peritransplant management are discussed. PMID- 26106171 TI - Stroke and patent foramen ovale: intervene or wait. AB - A 33-year-old woman presented to the emergency department with an acute left partial anterior circulation ischaemic stroke. Thrombolysis was not administered due to a rapidly improving National Institutes of Health Stroke Scale (NIHSS) score and she was thereafter given appropriate treatment for secondary prevention. CT and MRI demonstrated a left basal ganglia infarct with haemorrhagic transformation. Initial investigations revealed no evidence of atrial fibrillation or large vessel disease. Further investigation with transthoracic, bubble contrast and transoesophageal echocardiogram all indicated the presence of a grade 1 tunnel-shaped patent foramen ovale (PFO) with some aneurysmal interatrial septum. No other cause for her stroke was found. There is no current evidence to support the routine use of percutaneous PFO closure in prevention of stroke or transient ischaemic attack. National guidelines advise transcatheter closure of PFO should only be considered for patients with recurrent cryptogenic stroke on optimal medical management. PMID- 26106172 TI - Broncholithiasis presenting as bronchiectasis and recurrent pneumonias. AB - A broncholith is defined as the presence of calcified material within a bronchus or within a cavity communicating with a bronchus. It is most frequently caused by Histoplasmosis or tuberculosis (TB) spp. Bronchial distortion, irritation and erosion by broncholiths can cause bronchiectasis, recurrent pneumonias and haemoptysis. We present a case of recurrent pneumonia due to a broncholith, which resolved conservatively with antibiotics. Owing to recurrent fevers and post obstructive pneumonias, a lobectomy or rigid bronchoscopic removal were considered but the patient was deemed not to be a candidate for general anaesthesia due to her comorbidities. Broncholiths are an uncommon cause of bronchiectasis and recurrent pneumonias. However, the wide range of symptoms and low clinical suspicion are the main reasons why a diagnosis can be delayed. Various treatment options are available and the choice of therapy should be made depending on the broncholith's size, mobility, location and local surgical expertise. PMID- 26106173 TI - Covered stents for exclusion of iatrogenic common carotid artery-internal jugular vein fistula and brachiocephalic artery pseudoaneurysm. AB - Covered stents have rarely been used in neuroendovascular procedures. We report the case of a 74-year-old woman with a complex iatrogenic vascular injury from attempted insertion of a hemodialysis catheter: concurrent brachiocephalic artery pseudoaneurysm and common carotid artery to internal jugular vein fistula. Both lesions were excluded successfully by using two balloon-expandable covered stents with a satisfactory short-term clinical and angiographic outcome. PMID- 26106174 TI - An 11-year-old boy with silico-tuberculosis attributable to secondary exposure to sandstone mining in central India. AB - Silicosis from secondary exposure is not often reported. This is the first such report of a child with possible silicosis attributable to secondary exposure to sandstone mining in India. Silicosis from secondary exposure has been reported in the gem polishing and slate pencil manufacturing industries in India; however, the stone-mining industry is severely under-researched. No preventive measures have been instituted in the stone-mining industry and children are exposed to respirable silica dust when their mothers take them to their work places. Poverty and lack of accessibility to modern medical facilities promote malnutrition and tuberculosis, two known co-morbid conditions. Stone mining, an export-oriented industry, produces billions of dollars of foreign currency every year. Although there is legislation to protect workers from exploitation, employers disregard the law and the state turns a blind eye by not implementing proper enforcement mechanisms. Silicosis from environmental exposure affects the entire community that lives in stone-mining areas. PMID- 26106175 TI - Successful living donor liver transplantation of fulminant liver failure due to isoniazid prophylaxis. AB - Progressive liver failure is rarely seen in tuberculosis chemoprophylaxis with isoniazid. We present a case of a 32-year-old woman admitted to our clinic reporting abdominal pain, nausea and vomiting for 2 days. The initial diagnosis was fulminant toxic hepatitis due to isoniazid chemoprophylaxis, which was treated successfully with living donor transplantation. Tuberculosis continues to be a significant public health problem. Isoniazid-related hepatotoxicity is extremely rare in adults. The only treatment in cases of fulminant liver failure is orthotopic liver transplantation from a deceased or living donor. If a deceased donor is not available or the patient refuses this treatment, living donor transplantation is the only choice. Although rare, isoniazid used as protective therapy for pulmonary tuberculosis can lead to fulminant liver failure. When cadaveric liver transplantation is not available, living donor liver transplantation is vital. PMID- 26106176 TI - Diffuse idiopathic skeletal hyperostosis and isotretinoin in cystic acne. AB - We present the case of a 35-year-old man with thoracic back pain and stiffness, whose only medical history was cystic acne treated with repeated courses of retinoids. His thoracic spine was severely limited in range of movement and was found, on X-ray, to have unilateral hyperostosis typical of diffuse idiopathic skeletal hyperostosis (DISH)--an often asymptomatic condition rarely found in those under 50. Back stiffness in young patients with prolonged retinoid exposure should be investigated. PMID- 26106177 TI - Bony non-union in a patient receiving androgen deprivation therapy for prostate cancer. AB - We present a case of a 76-year-old man who underwent a corrective femoral osteotomy for a varus deformity and stress fractures. The patient was on androgen deprivation therapy (ADT) for prostate cancer and the osteotomy failed to heal. At 13 months, the ADT was stopped and bony union was achieved in 3 months. Orthopaedic surgeons treating fractures in this patient population need to aware of the problems associated with ADT and closely liaise with oncologists and urologists to stop ADT or start alternative treatment until bony union has been achieved. PMID- 26106178 TI - From a fish tank injury to hospital haemodialysis: the serious consequences of drug interactions. AB - We present the case of a 68-year-old man admitted to hospital with severe acute kidney injury secondary to statin-induced rhabdomyolysis. Five weeks previously, the patient started a course of clarithromycin for infection of a finger wound with Mycobacterium marinum. His current medications included simvastatin, which he continued along with clarithromycin. The severity of the acute kidney injury necessitated initial continuous venovenous haemofiltration followed by 12 haemodialysis sessions before a spontaneous improvement in renal function occurred. Statins are widely prescribed and we report this case to encourage increased vigilance in avoiding drug interactions known to increase the risk of statin-induced myopathy, including macrolide antibiotics, calcium channel antagonists and amiodarone. The authors would also like to highlight recent guidance on atorvastatin as the statin of choice in patients with chronic kidney disease, and of the need for dose adjustment in those with an estimated glomerular filtration rate less than 30 mLs/min/1.73 m2. PMID- 26106179 TI - Incomplete peripheral facial nerve palsy and ulnar neuropathy due to leprosy mistaken as faciobrachial stroke. AB - A middle-aged woman was referred to our hospital emergency ward in view of acute onset left faciobrachial weakness. An urgent MRI of the brain was performed, which did not reveal any abnormality and hence a neurology consultation was arranged in order to rule out acute stroke. However, examination and retrospective history taking proved to be a valuable aid in this patient's diagnosis. The incomplete lower motor neuron facial nerve palsy and hand weakness due to leprosy in reaction was confused by the general practitioner as a faciobrachial stroke. PMID- 26106180 TI - Post-transfusion breathlessness in a patient with acute myeloid leukaemia. AB - We present a case of a 38-year-old man with acute myeloid leukaemia (AML) in remission who developed sudden-onset chest pain and shortness of breath 30 min after receiving a blood transfusion. His condition deteriorated and required transferring him to the intensive care unit. The initial differential diagnosis was wide given his immunosuppression, recent chemotherapy, hospitalised status and receipt of blood products. Extensive work up concluded Coxsackie virus induced myopericarditis as the cause of his symptoms. He was treated with colchicine monotherapy for 3 months and remained without recurrence of pericarditis at 3 months of follow-up. PMID- 26106181 TI - Entrapment of the brachial artery following supracondylar fracture reduction. PMID- 26106182 TI - Postpartum onset and subsequent relapse of eosinophilic granulomatosis with polyangiitis. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) can affect women of childbearing age. However, reports of the disease in the postpartum period are limited. We present a case of postpartum-onset EGPA that went into clinical remission before relapsing in the subsequent postpartum period. Our patient presented with dyspnoea, arthralgia and rash, shown to be eosinophilic vasculitis, 3 days following the birth of her second child. CT of the thorax showed alveolar shadowing and mediastinal lymphadenopathy. She was treated successfully for EGPA with glucocorticoid therapy. She declined maintenance treatment during remission. Off treatment, she remained disease free throughout her next pregnancy. In the postpartum period she relapsed in an almost identical manner, requiring prolonged glucocorticoid therapy, cyclophosphamide and rituximab. This case highlights the importance of maintenance therapy around pregnancy in individuals with EGPA, and the need for careful monitoring of women with a history of EGPA in the postpartum period. PMID- 26106183 TI - Bowhunter's syndrome. PMID- 26106184 TI - PROLIFICA: a story of West African clinical and research collaborations to target hepatitis B-related hepatocellular carcinoma in West Africa. PMID- 26106187 TI - Biologic Responses to Weight Loss and Weight Regain: Report From an American Diabetes Association Research Symposium. PMID- 26106188 TI - Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism. AB - Individuals with metabolic syndrome and frank type 2 diabetes are at increased risk of atherosclerotic cardiovascular disease, partially due to the presence of lipid and lipoprotein abnormalities. In these conditions, the liver and intestine overproduce lipoprotein particles, exacerbating the hyperlipidemia of fasting and postprandial states. Incretin-based, antidiabetes therapies (i.e., glucagon-like peptide [GLP]-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) have proven efficacy for the treatment of hyperglycemia. Evidence is accumulating that these agents also improve fasting and postprandial lipemia, the latter more significantly than the former. In contrast, the gut-derived peptide GLP-2, cosecreted from intestinal L cells with GLP-1, has recently been demonstrated to enhance intestinal lipoprotein release. Understanding the roles of these emerging regulators of intestinal lipoprotein secretion may offer new insights into the regulation of intestinal lipoprotein assembly and secretion and provide new opportunities for devising novel strategies to attenuate hyperlipidemia, with the potential for cardiovascular disease reduction. PMID- 26106186 TI - Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity. AB - Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic beta-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications. PMID- 26106189 TI - GLP-1R Agonists and Endothelial Dysfunction: More Than Just Glucose Lowering? PMID- 26106190 TI - Hypoglycemia-Associated Autonomic Failure in Diabetes: Maladaptive, Adaptive, or Both? PMID- 26106191 TI - Defective Glucagon-Like Peptide 1 Secretion in Prediabetes and Type 2 Diabetes Is Influenced by Weight and Sex. Chicken, Egg, or None of the Above? PMID- 26106192 TI - Interaction of Adipogenesis and Angiogenesis in Dietary-Induced Obesity. PMID- 26106193 TI - An Innate Disposition for a Healthier Gut: GLP-1R Signaling in Intestinal Epithelial Lymphocytes. PMID- 26106194 TI - PET Measurements of Organ Metabolism: The Devil Is in the Details. PMID- 26106195 TI - Evidence for Residual and Partly Reparable Insulin Secretory Function and Maintained beta-Cell Gene Expression in Islets From Patients With Type 1 Diabetes. PMID- 26106196 TI - Intestinal Lipoprotein Secretion: Incretin-Based Physiology and Pharmacology Beyond Glucose. PMID- 26106197 TI - New Piece in the Jigsaw Puzzle: Adipose Tissue-Derived Stem Cells From Obese Subjects Drive Th17 Polarization. PMID- 26106198 TI - Blood Lipids and Type 2 Diabetes Risk: Can Genetics Help Untangle the Web? PMID- 26106199 TI - Erratum. PD-L1-Driven Tolerance Protects Neurogenin3-Induced Islet Neogenesis to Reverse Established Type 1 Diabetes in NOD Mice. Diabetes 2015;64:529-540. PMID- 26106201 TI - Comment on Vandal et al. Insulin Reverses the High-Fat Diet-Induced Increase in Brain Abeta and Improves Memory in an Animal Model of Alzheimer Disease. Diabetes 2014;63:4291-4301. PMID- 26106202 TI - Response to Comment on Vandal et al. Insulin Reverses the High-Fat Diet-Induced Increase in Brain Abeta and Improves Memory in an Animal Model of Alzheimer Disease. Diabetes 2014;63:4291-4301. PMID- 26106203 TI - An Asthma Protocol Improved Adherence to Evidence-Based Guidelines for Pediatric Subjects With Status Asthmaticus in the Emergency Department. AB - BACKGROUND: In our institution's pediatric emergency department, adherence to evidence-based asthma guidelines was noted to be suboptimal for patients with asthma exacerbations. We hypothesized that an evidence-based asthma protocol would improve time to treatment and adherence to National Institutes of Health guidelines for patients presenting to the emergency department with status asthmaticus. METHODS: Subjects at our institution were retrospectively identified through an electronic medical record search following institutional review board approval. The asthma protocol was initiated in February 2012. All pediatric subjects who received continuous albuterol in the emergency department before (February 26, 2009, to February 22, 2012, n = 193) and after (February 23, 2012, to December 31, 2012, n = 68) protocol initiation were analyzed. The post protocol data were collected as part of routine quality assurance monitoring with a target of 60 post-protocol subjects. Subjects were identified at the end of each month, which resulted in a total of 68 subjects being included. Primary outcomes measured included time to initial treatment with inhaled bronchodilator therapy, time to treatment with systemic corticosteroids, and total number of ipratropium bromide treatments delivered. RESULTS: Two-hundred sixty-one subjects (7.1 +/- 4.6 y of age, 66% male) were included. Demographics were similar in the pre- and post-protocol groups. Compared with the pre-protocol group, more subjects in the post-protocol group received bronchodilators within 30 min (60% vs 77%, P = .02), at least one dose of ipratropium bromide (55% vs 87%, P < .001), 3 doses of ipratropium bromide (14% vs 54%, P < .001), and corticosteroids within 60 min (62% vs 77%, P = .04). There were no statistically significant differences between the pre- and post-protocol cohorts in the mean time to first bronchodilator treatment (32 +/- 41 vs 26 +/- 52 min, P = .34), mean time to corticosteroid administration (74 +/- 68 vs 54 +/- 63 min, P = .06), or mean emergency department length of stay (342 +/- 143 vs 364 +/- 183 min, P = .31). CONCLUSIONS: An asthma protocol resulted in improved adherence to National Institutes of Health guidelines in children with status asthmaticus and improved efficiency in the administration of rescue bronchodilator and systemic corticosteroid therapy. PMID- 26106204 TI - High-Flow Nasal Cannula and Aerosolized beta Agonists for Rescue Therapy in Children With Bronchiolitis: A Case Series. AB - Asthma and bronchiolitis are episodic obstructive pulmonary diseases characterized by bronchoconstriction, airway wall inflammation, increased mucus production, and air-flow obstruction. We present the cases of 5 infants treated for acute bronchiolitis with respiratory distress using a combination of high flow nasal cannula oxygen (HFNC) and an Aerogen nebulizer to deliver aerosolized beta-agonist therapy. In all infants, we found that HFNC resulted in a greater heart rate increase than delivery via a facemask. We also found that patients tolerated inhaled therapy better with HFNC than a facemask. PMID- 26106205 TI - Diagnostic Utility of Biomarkers in COPD. AB - BACKGROUND: COPD will become the third leading cause of death by 2020. There are many situations in which spirometry, the primary tool for diagnosis of COPD, cannot be performed, and thus, the staging and status of these patients cannot be determined. To date, there is no known biochemical marker used for diagnosing COPD. This study aimed to explore the utility of biomarkers for diagnosis of COPD. METHODS: This was an observational study composed of 96 stable subjects with COPD and 96 subjects with normal lung function. Each group contained an equal number of smokers and nonsmokers. Serum levels of superoxide dismutase 3, glutathione peroxidase, catalase, ceruloplasmin ferroxidase activity, C-reactive protein, and surfactant protein D (SPD) were estimated. Ferroxidase activity was estimated by a kinetic method, whereas the other analytes were measured by enzyme linked immunosorbent assay. The cutoff value, sensitivity and specificity at the cutoff value, and area under the curve for each analyte were determined from receiver operating characteristic curve. RESULTS: Significantly decreased superoxide dismutase 3 and increased ferroxidase activity, SPD, glutathione peroxidase, and C-reactive protein levels were found in subjects with COPD. For all subjects and nonsmoking subjects with COPD, the area under the curve was highest for ferroxidase activity, followed by glutathione peroxidase, SPD, and C reactive protein, with a sensitivity and specificity of > 73%. For smoking subjects with COPD, the area under the curve was highest for SPD, followed by glutathione peroxidase, ferroxidase activity, and C-reactive protein, with a sensitivity and specificity > 67%. Some combinations of markers were found to give either a sensitivity or specificity of > 95%, which can be utilized to rule in and rule out COPD. CONCLUSIONS: Biomarkers can be reliably utilized in the diagnosis of COPD. Of all the markers, SPD appears to be the most promising in smokers, whereas ferroxidase activity shows promise in nonsmokers. To rule out COPD, ferroxidase activity or glutathione peroxidase can be potentially useful, whereas to rule in COPD, ferroxidase activity and glutathione peroxidase appear to be the most promising combination in both nonsmoking and smoking subjects. PMID- 26106206 TI - Efficacy of High-Flow Nasal Cannula Therapy in Acute Hypoxemic Respiratory Failure: Decreased Use of Mechanical Ventilation. AB - BACKGROUND: We evaluated the efficacy of high-flow nasal cannula (HFNC) therapy, a promising respiratory support method for acute hypoxemic respiratory failure (AHRF). METHODS: We conducted a retrospective single-center cohort study comparing the periods before (June 2010 to May 2012) and after (June 2012 to May 2014) HFNC introduction (pre- and post-HFNC periods). During these periods, we retrieved cases of AHRF treated with any respiratory support (invasive ventilation, noninvasive ventilation [NIV], and HFNC) and compared in-hospital mortality, ICU/intermediate care unit/hospital stay, and need for mechanical ventilation. RESULTS: Eighty-three subjects (65 treated with NIV, and 18 treated with invasive ventilation) and 89 subjects (33 treated with HFNC, 43 treated with NIV, and 13 treated with invasive ventilation) identified from 782 pre-HFNC and 930 post-HFNC records of acute respiratory failure who required emergent admissions to the respiratory care department were analyzed. Overall, the in hospital mortality rate was similar, although there was a non-significant and slight decrease from 35 to 27% (P = .26). There was no significant difference among ICU, intermediate care unit (P = .80), and hospital (P = .33) stay. In the post-HFNC period, significantly fewer subjects required mechanical ventilation (NIV or invasive ventilation) (100% vs 63%, P < .01). Additionally, there were significantly fewer ventilator days (median [interquartile range] of 5 [2-11] vs 2 [1-5] d, P < .05) and more ventilator-free days (median [interquartile range] of 18 [0-25] vs 26 [20-27] d, P < .01). CONCLUSIONS: HFNC might be an alternative for AHRF subjects with NIV intolerance. PMID- 26106207 TI - Radioaerosol Pulmonary Deposition Using Mesh and Jet Nebulizers During Noninvasive Ventilation in Healthy Subjects. AB - BACKGROUND: In vivo deposition studies of aerosol administration during noninvasive ventilation (NIV) are scarce in the literature. The aim of this study was to compare radioaerosol pulmonary index and radioaerosol mass balance in the different compartments (pulmonary and extrapulmonary) of radio-tagged aerosol administered using vibrating mesh nebulizers and conventional jet nebulizers during NIV. METHODS: This was a crossover clinical trial involving 10 healthy subjects (mean age of 33.7 +/- 10.0 y) randomly assigned to both treatment arms of this study: group 1 (NIV + vibrating mesh nebulizer, n = 10) and group 2 (NIV + jet nebulizer, n = 10). All subjects inhaled 3 mL of technetium-99m diethylenetriaminepentaacetic acid (25 mCi) and 0.9% saline solution via vibrating mesh and jet nebulizers during NIV through a face mask secured with straps while receiving positive inspiratory and expiratory pressures of 12 and 5 cm H2O, respectively. Scintigraphy was performed to count radioaerosol particles deposited in the regions of interest to determine radioaerosol mass balance from the lungs, upper airways, stomach, nebulizer, ventilator circuit, inspiratory and expiratory filters, and mask as a percentage. RESULTS: Vibrating mesh nebulizers deposited 972,013 +/- 214,459 counts versus jet nebulizer with 386,025 +/- 130,363 counts (P = .005). In a determination of mass balance, vibrating mesh nebulizers showed a higher deposition of inhaled radioaerosol compared with jet nebulizers (23.1 +/- 5.8% vs 6.1 +/- 2.5%, P = .005) and a higher proportion of radioaerosol deposited into the lungs (5.5 +/- 0.9% versus 1.5 +/- 0.6%, respectively, P = .005). The residual drug volume was lower with vibrating mesh nebulizers (5.1 +/- 1.5%) compared with jet nebulizers (41.3 +/- 4.2%, P = .005). CONCLUSIONS: During NIV in healthy subjects, vibrating mesh nebulizers delivered > 2-fold more radiolabeled drug into the respiratory tract compared with conventional jet nebulizers. Additional studies are recommended in subjects with asthma, COPD, bronchiectasis, and cystic fibrosis to better understand differences in both aerosol delivery and response. (ClinicalTrials.gov registration NCT01889524.). PMID- 26106209 TI - Chronic periaortitis with thoracic aorta and epiaortic artery involvement: a systemic large vessel vasculitis? AB - OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by fibro inflammatory tissue surrounding the abdominal aorta and the iliac arteries. Anecdotal reports have shown that CP may also involve other vascular districts, particularly the thoracic aorta. The aim of this study was to investigate the thoracic aorta and epiaortic artery involvement in CP. METHODS: Patients were eligible if they had undergone imaging studies assessing inflammatory involvement of the thoracic aorta and its major branches (e.g. contrast CT, MRI or PET-CT). We explored the patterns of thoracic vessel involvement and compared the clinical characteristics of patients with and without thoracic disease. Where available, we also reviewed the thoracic vascular/perivascular tissue biopsies. RESULTS: Of 153 CP patients seen between 1999 and 2012, 77 were eligible. Of these, 28 (36%) had thoracic involvement: 15 (54%) had thoracic periaortitis, with 7 also showing epiaortic artery involvement; 6 (21%) had periaortitis surrounding a thoracic aortic aneurysm, 2 of them with epiaortic artery involvement; 7 (25%) had a thoracic aortic aneurysm without periaortitis. Patients with thoracic disease were more frequently female (P = 0.01), were older (P = 0.001) and had a higher frequency of pain and constitutional symptoms (P = 0.02). Thoracic (peri)vascular biopsies revealed adventitial and peri-adventitial fibro-inflammatory patterns similar to those observed in abdominal CP. CONCLUSION: In about one-third of patients, CP also involves the thoracic aorta and the epiaortic arteries, which supports the hypothesis of a systemic inflammatory disease of the large arteries. PMID- 26106208 TI - First report of FIP1L1-PDGFRalpha-positive eosinophilic granulomatosis with polyangiitis. PMID- 26106210 TI - Ultrasonographic predictors for clinical and radiological progression in knee osteoarthritis after 2 years of follow-up. AB - OBJECTIVE: The aim of this study was to investigate the association between a set of US features and radiographic and clinical progression of knee OA after 2 years of follow-up. METHODS: A total of 125 patients fulfilling ACR clinical criteria for knee OA underwent US examination of the most symptomatic knee. The US protocol included assessment of synovial hypertrophy, joint effusion, infrapatellar bursitis, Baker's cyst, medial meniscus protrusion and cartilage thickness. Clinical progression was defined using the inverse Osteoarthritis Research Society International responder criteria or progression to total knee replacement. Radiological progression was defined as a >=2 point increase in Altman score or progression to total knee replacement. Regression analyses were performed with baseline ultrasonographic features as independent variables and progression (two separate models for clinical progression and radiographic progression) as the dependent variable. RESULTS: A total of 31 (25%) patients fulfilled the criteria of clinical progression and 60 (48%) patients fulfilled the criteria of radiological progression. The presence of Baker's cyst showed a statistically significant association with clinical [odds ratio (OR) 3.07 (95% CI 1.21, 7.78)] as well as radiological [OR 2.84 (95% CI 1.17, 6.90)] progression. Synovial hypertrophy showed a weaker but consistent association with clinical as well as radiological progression [OR 2.11 (95% CI 0.80, 5.57)]. CONCLUSION: We demonstrated a longitudinal association between Baker's cyst (and to a lesser extent synovial hypertrophy) at baseline and radiological and clinical progression after 2 years. PMID- 26106211 TI - Tumour-associated antigens in systemic sclerosis patients with interstitial lung disease: association with lung involvement and cancer risk. AB - OBJECTIVE: To evaluate the serum levels of tumour-associated antigens (TAAs) in patients with SSc and interstitial lung disease (ILD) and to define whether their levels mirror the severity and the progression of lung damage. METHODS: Data from 80 SSc patients with ILD were collected at baseline and after 2 years as well as from 40 SSc controls without ILD. The occurrence of any malignancy was recorded. RESULTS: At baseline, an increase of at least one TAA was present in 35 SSc patients with ILD compared with 6 SSc patients without ILD (P < 0.0001); this was associated with lower forced vital capacity (FVC) and higher interstitial and alveolar scores. Levels of carbohydrate antigen 15-3 and carcinoembryonic antigen inversely correlated with FVC and directly correlated with alveolar and interstitial scores and their levels were higher in patients who presented a progression of lung damage after 2 years. During 4 years of follow-up, a malignancy was detected in seven patients who already had an increase of at least one TAA. Values of TAAs increased over time in patients who developed cancer, while their trend remained stable in the others. At multivariate analysis, to have three or more TAAs emerged as a strong independent predictor of the development of malignancies [relative risk 24.1 (95% CI 1.8, 315.0), P = 0.02]. CONCLUSION: TAAs can be elevated in the sera of SSc patients and correlate with the degree of lung damage, suggesting a role as severity biomarkers. Close follow up is necessary in SSc patients because of the increased cancer risk overall in patients with increased TAAs. PMID- 26106212 TI - Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients. AB - OBJECTIVE: To characterize the clinical features of IgG4-related disease (IgG4 RD) in China. METHODS: A prospective cohort study of IgG4-RD was carried out in Peking Union Medical College Hospital between 2011 and 2013. Patients with newly diagnosed IgG4-RD were enrolled. RESULTS: A total of 118 patients with IgG4-RD were enrolled, including 82 males and 36 females, aged 53.1 (s.d. 13.6) years. The most common symptom at onset was lacrimal gland swelling (38/32.2%). A range of organs were involved: 77 patients (65.3%) had lymphadenopathy, 76 (64.4%) had sialadenitis, 60 (50.8%) had dacryoadenitis, 45 (38.1%) had autoimmune pancreatitis, 32 (27.1%) had pulmonary involvement, 31 (26.3%) had periaortitis/retroperitoneal fibrosis, 29 (35.4% of male patients) had prostatitis and 29 (24.6%) had renal involvement. In addition, there were 21 (17.8%) cases of sclerosing cholangitis, 15 (12.7%) of sinusitis and 10 (8.5%) of inflammatory pseudotumour. Uncommon manifestations included mediastinal fibrosis, skin involvement, sclerosing thyroiditis, hypophysitis, orchitis and colitis. Multiple organ involvement was observed in 93 patients, whereas only 4.2% had only a single organ involved. A history of allergy was reported in 73 (61.9%) patients. The serum IgG4 level was elevated in 97.5% and was correlated with the number of organs involved. Most patients were treated with glucocorticoids alone or in combination with immunosuppressive drugs, and the majority usually improved within 3 months. CONCLUSION: IgG4-RD is a systemic inflammatory and sclerosing disease. Parotid and lacrimal involvement (formerly called Mikulicz's disease), lymphadenopathy and pancreatitis are the most common manifestations. Patients with IgG4-RD showed favourable responses to treatment with glucocorticoids and immunosuppressive agents. PMID- 26106213 TI - Coronary calcification in SLE: comparison with the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: Accelerated atherosclerosis is a major cause of morbidity and death in SLE. The purpose of this study was to determine whether the prevalence and extent of coronary artery calcium (CAC) is higher in female SLE patients compared with a non-SLE sample from the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: CAC was measured in 80 female SLE patients and 241 female MESA controls from the Baltimore Field Centre, ages 45-64 years, without evidence of clinical cardiovascular disease. Binary regression was used to estimate the ratio of CAC prevalence in SLE vs MESA controls, controlling for demographic and cardiovascular risk factors. To compare the groups with respect to the quantity of CAC among those with non-zero Agatston scores, we used linear models in which the outcome was a log-transformed Agatston score. RESULTS: The prevalence of CAC was substantially higher in SLE. The differences were most pronounced and statistically significant in those aged 45-54 years (58% vs 20%, P < 0.0001), but were still observed among those aged 55-65 years (57% vs 36%, P = 0.069). After controlling for age, ethnicity, education, income, diabetes mellitus, hypertension, hyperlipidaemia, high-density lipoprotein levels, smoking, education and BMI, SLE patients still had a significantly higher prevalence of CAC than controls. Among those with CAC, the mean log Agatston score did not differ significantly between SLE and MESA participants. CONCLUSION: Women with SLE have a higher prevalence of CAC than comparable women without SLE, even after adjusting for traditional cardiovascular risk factors, especially among those aged 45-54 years. PMID- 26106214 TI - Inflammatory bowel diseases in anti-neutrophil cytoplasmic antibody-associated vasculitides: 11 retrospective cases from the French Vasculitis Study Group. AB - OBJECTIVE: Coexistence of ANCA-associated vasculitis (AAV) and IBD is a rare condition that is rarely described in the literature. The aim of the study was to describe the main characteristics of patients presenting with both IBD and AAV. METHODS: A retrospective study of AAV patients in the French Vasculitis Study Group cohort who also had a diagnosis of IBD was conducted. We reviewed the medical records and outcomes of these patients. RESULTS: We identified 11 patients with AAV and IBD. Four patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) also had ulcerative colitis and seven patients with granulomatosis with polyangiitis (GPA) had Crohn's disease. No Crohn's disease was observed in eosinophilic GPA and no ulcerative colitis in GPA. IBD started before AAV manifestations in six cases, simultaneously in two cases and after AAV manifestations in three cases. CONCLUSION: Coexistence of IBD and AAV is a rare condition. The therapeutic management of these patients includes corticosteroids in all cases and immunosuppressive drugs in some patients. Coexistence of IBD and AAV might be explained by common underlying inflammatory responses and cytokine profiles polarized towards either Th1 or Th2. Finally, in the presence of digestive manifestations in the context of AAV, the hypothesis of IBD should be assessed. PMID- 26106215 TI - Insights into transcription termination of Hfq-binding sRNAs of Escherichia coli and characterization of readthrough products. AB - The genes encoding Hfq-dependent sRNAs possess a typical Rho-independent transcription terminator. Here, we have studied the molecular events occurring at Rho-independent terminators of sRNA genes, focusing on two well-characterized Hfq binding sRNAs, SgrS and RyhB. We constructed several hybrid genes in which the DNA sequence corresponding to a strong Rho-independent terminator was placed just downstream from the Rho-independent terminators of sRNA genes. By using this system, we demonstrate that transcripts frequently read through the Rho independent terminators of sgrS and ryhB in normally growing cells. We show that Hfq does not affect the transcriptional readthrough event itself. We also find that the readthrough products no longer bind to Hfq in vivo. We have developed a competition assay based on a biotin-streptavidin system to analyze the interaction of Hfq and a particular RNA molecule in vitro. By using this method, we verify that the 3'-extended form of SgrS does not bind to Hfq in vitro. Finally, we demonstrate that transcription termination is significantly enhanced under stress conditions where transcription initiation of sRNA genes on the chromosome is induced. We conclude that the production of sRNAs is regulated not only at the step of transcription initiation but also at the step of transcription termination. The mechanism by which transcription termination is enhanced under stress conditions remains to be understood. PMID- 26106216 TI - Increased efficiency of evolved group I intron spliceozymes by decreased side product formation. AB - The group I intron ribozyme from Tetrahymena was recently reengineered into a trans-splicing variant that is able to remove 100-nt introns from pre-mRNA, analogous to the spliceosome. These spliceozymes were improved in this study by 10 rounds of evolution in Escherichia coli cells. One clone with increased activity in E. coli cells was analyzed in detail. Three of its 10 necessary mutations extended the substrate binding duplexes, which led to increased product formation and reduced cleavage at the 5'-splice site. One mutation in the conserved core of the spliceozyme led to a further reduction of cleavage at the 5'-splice site but an increase in cleavage side products at the 3'-splice site. The latter was partially reduced by six additional mutations. Together, the mutations increased product formation while reducing activity at the 5'-splice site and increasing activity at the 3'-splice site. These results show the adaptation of a ribozyme that evolved in nature for cis-splicing to trans splicing, and they highlight the interdependent function of nucleotides within group I intron ribozymes. Implications for the possible use of spliceozymes as tools in research and therapy, and as a model for the evolution of the spliceosome, are discussed. PMID- 26106217 TI - Spatial Variance in Resting fMRI Networks of Schizophrenia Patients: An Independent Vector Analysis. AB - Spatial variability in resting functional MRI (fMRI) brain networks has not been well studied in schizophrenia, a disease known for both neurodevelopmental and widespread anatomic changes. Motivated by abundant evidence of neuroanatomical variability from previous studies of schizophrenia, we draw upon a relatively new approach called independent vector analysis (IVA) to assess this variability in resting fMRI networks. IVA is a blind-source separation algorithm, which segregates fMRI data into temporally coherent but spatially independent networks and has been shown to be especially good at capturing spatial variability among subjects in the extracted networks. We introduce several new ways to quantify differences in variability of IVA-derived networks between schizophrenia patients (SZs = 82) and healthy controls (HCs = 89). Voxelwise amplitude analyses showed significant group differences in the spatial maps of auditory cortex, the basal ganglia, the sensorimotor network, and visual cortex. Tests for differences (HC SZ) in the spatial variability maps suggest, that at rest, SZs exhibit more activity within externally focused sensory and integrative network and less activity in the default mode network thought to be related to internal reflection. Additionally, tests for difference of variance between groups further emphasize that SZs exhibit greater network variability. These results, consistent with our prediction of increased spatial variability within SZs, enhance our understanding of the disease and suggest that it is not just the amplitude of connectivity that is different in schizophrenia, but also the consistency in spatial connectivity patterns across subjects. PMID- 26106218 TI - Postinfarction Functional Recovery Driven by a Three-Dimensional Engineered Fibrin Patch Composed of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells. AB - Considerable research has been dedicated to restoring myocardial cell slippage and limiting ventricular remodeling after myocardial infarction (MI). We examined the ability of a three-dimensional (3D) engineered fibrin patch filled with human umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) to induce recovery of cardiac function after MI. The UCBMSCs were modified to coexpress luciferase and fluorescent protein reporters, mixed with fibrin, and applied as an adhesive, viable construct (fibrin-cell patch) over the infarcted myocardium in mice (MI UCBMSC group). The patch adhered well to the heart. Noninvasive bioluminescence imaging demonstrated early proliferation and differentiation of UCBMSCs within the construct in the postinfarct mice in the MI-UCBMSC group. The implanted cells also participated in the formation of new, functional microvasculature that connected the fibrin-cell patch to both the subjacent myocardial tissue and the host circulatory system. As revealed by echocardiography, the left ventricular ejection fraction and fractional shortening at sacrifice were improved in MI UCBMSC mice and were markedly reduced in mice treated with fibrin alone and untreated postinfarction controls. In conclusion, a 3D engineered fibrin patch composed of UCBMSCs attenuated infarct-derived cardiac dysfunction when transplanted locally over a myocardial wound. PMID- 26106220 TI - IRE1 prevents endoplasmic reticulum membrane permeabilization and cell death under pathological conditions. AB - The endoplasmic reticulum (ER) has emerged as a critical regulator of cell survival. IRE1 is a transmembrane protein with kinase and RNase activities that is localized to the ER and that promotes resistance to ER stress. We showed a mechanism by which IRE1 conferred protection against ER stress-mediated cell death. IRE1 signaling prevented ER membrane permeabilization mediated by Bax and Bak and cell death in cells experiencing ER stress. Suppression of IRE1 signaling triggered by its kinase activity led to the accumulation of the BH3 domain containing protein Bnip3, which in turn triggered the oligomerization of Bax and Bak in the ER membrane and ER membrane permeabilization. Consequently, in response to ER stress, cells deficient in IRE1 were susceptible to leakage of ER contents, which was associated with the accumulation of calcium in mitochondria, oxidative stress in the cytosol, and ultimately cell death. Our results reveal a role for IRE1 in preventing a cell death-initializing step that emanates from the ER and provide a potential target for treating diseases characterized by ER stress, including diabetes and Wolfram syndrome. PMID- 26106219 TI - DNA methylation regulates neuronal glutamatergic synaptic scaling. AB - Enhanced receptiveness at all synapses on a neuron that receive glutamatergic input is called cell-wide synaptic upscaling. We hypothesize that this type of synaptic plasticity may be critical for long-term memory storage within cortical circuits, a process that may also depend on epigenetic mechanisms, such as covalent chemical modification of DNA. We found that DNA cytosine demethylation mediates multiplicative synaptic upscaling of glutamatergic synaptic strength in cultured cortical neurons. Inhibiting neuronal activity with tetrodotoxin (TTX) decreased the cytosine methylation of and increased the expression of genes encoding glutamate receptors and trafficking proteins, in turn increasing the amplitude but not frequency of miniature excitatory postsynaptic currents (mEPSCs), indicating synaptic upscaling rather than increased spontaneous activity. Inhibiting DNA methyltransferase (DNMT) activity, either by using the small-molecule inhibitor RG108 or by knocking down Dnmt1 and Dnmt3a, induced synaptic upscaling to a similar magnitude as exposure to TTX. Moreover, upscaling induced by DNMT inhibition required transcription; the RNA polymerase inhibitor actinomycin D blocked upscaling induced by DNMT inhibition. Knocking down the cytosine demethylase TET1 also blocked the upscaling effects of RG108. DNMT inhibition induced a multiplicative increase in mEPSC amplitude, indicating that the alterations in glutamate receptor abundance occurred in a coordinated manner throughout a neuron and were not limited to individual active synapses. Our data suggest that DNA methylation status controls transcription-dependent regulation of glutamatergic synaptic homeostasis. Furthermore, covalent DNA modifications may contribute to synaptic plasticity events that underlie the formation and stabilization of memories. PMID- 26106221 TI - Identification of small-molecule inhibitors of calcineurin-NFATc signaling that mimic the PxIxIT motif of calcineurin binding partners. AB - Calcineurin (CN), a serine and threonine protein phosphatase that depends on Ca(2+) and calmodulin for its activity, is the target of the immunosuppressant drugs cyclosporin A (CsA) and tacrolimus (FK506). CN dephosphorylates and activates members of the NFATc (nuclear factor of activated T cells) family of transcription factors in T cells by binding to their conserved PxIxIT motif. Upon dephosphorylation, NFATc proteins translocate to the nucleus, where they stimulate the expression of genes encoding cytokines and chemokines that are required for T cell proliferation and the immune response. We performed a pharmacophore-based virtual screening of ~5.5 million commercially available, "drug-like" compounds to identify nonpeptidic compounds that inhibited the CN dependent activation of NFATc signaling and that could serve as potential drug candidates for immunosuppressive therapy. Of 32 compounds that mimicked the PxIxIT motif, 7 competed with NFATc for binding to CN in vitro without interfering with the phosphatase activity of CN. Furthermore, in activated human CD4(+) T cells, four of the seven compounds inhibited the expression of NFATc dependent genes, cytokine production, and cell proliferation, suggesting that these may have therapeutic potential as immunosuppressive agents. PMID- 26106224 TI - Erratum. The Relative and Combined Ability of High-Sensitivity Cardiac Troponin T and N-Terminal Pro-B-Type Natriuretic Peptide to Predict Cardiovascular Events and Death in Patients With Type 2 Diabetes. Diabetes Care 2014;37:295-303. PMID- 26106223 TI - Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation. AB - Glucokinase-maturity-onset diabetes of the young (GCK-MODY), also known as MODY2, is caused by heterozygous inactivating mutations in the GCK gene. GCK gene mutations are present in ~1 in 1,000 of the population, but most are not diagnosed. They are common causes of MODY (10-60%): persistent incidental childhood hyperglycemia (10-60%) and gestational diabetes mellitus (1-2%). GCK MODY has a unique pathophysiology and clinical characteristics, so it is best considered as a discrete genetic subgroup. People with GCK-MODY have a defect in glucose sensing; hence, glucose homeostasis is maintained at a higher set point resulting in mild, asymptomatic fasting hyperglycemia (5.4-8.3 mmol/L, HbA1c range 5.8-7.6% [40-60 mmol/mol]), which is present from birth and shows slight deterioration with age. Even after 50 years of mild hyperglycemia, people with GCK-MODY do not develop significant microvascular complications, and the prevalence of macrovascular complications is probably similar to that in the general population. Treatment is not recommended outside pregnancy because glucose-lowering therapy is ineffective in people with GCK-MODY and there is a lack of long-term complications. In pregnancy, fetal growth is primarily determined by whether the fetus inherits the GCK gene mutation from their mother. Insulin treatment of the mother is only appropriate when increased fetal abdominal growth on scanning suggests the fetus is unaffected. The impact on outcome of maternal insulin treatment is limited owing to the difficulty in altering maternal glycemia in these patients. Making the diagnosis of GCK-MODY through genetic testing is essential to avoid unnecessary treatment and investigations, especially when patients are misdiagnosed with type 1 or type 2 diabetes. PMID- 26106225 TI - Erratum. The Relationship Between Alcohol Consumption and Vascular Complications and Mortality in Individuals With Type 2 Diabetes. Diabetes Care 2014;37:1353 1359. PMID- 26106226 TI - Erratum. Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1). Diabetes Care 2014;37:2159-2167. PMID- 26106228 TI - Role of Peroxynitrite in the Development of Diabetic Peripheral Neuropathy. PMID- 26106229 TI - Small Fiber Neuropathy in Patients With Latent Autoimmune Diabetes in Adults. PMID- 26106230 TI - Gastric Bypass Surgery in Severely Obese Women With Type 1 Diabetes: Anthropometric and Cardiometabolic Effects at 1 and 5 Years Postsurgery. PMID- 26106231 TI - Comment on Thomsen et al. Incretin-Based Therapy and Risk of Acute Pancreatitis: A Nationwide Population-Based Case-Control Study. Diabetes Care 2015;38:1089 1098. PMID- 26106232 TI - Response to Comment on Thomsen et al. Incretin-Based Therapy and Risk of Acute Pancreatitis: A Nationwide Population-Based Case-Control Study. Diabetes Care 2015;38:1089-1098. PMID- 26106233 TI - Low Levels of Unmodified Insulin Glargine in Plasma of People With Type 2 Diabetes Requiring High Doses of Basal Insulin. PMID- 26106234 TI - Food Order Has a Significant Impact on Postprandial Glucose and Insulin Levels. PMID- 26106235 TI - Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450. AB - Benzbromarone (BBR) is a hepatotoxic drug, but the detailed mechanism of its toxicity remains unknown. We identified 2,6-dibromohydroquinone (DBH) and mono debrominated catechol (2-ethyl-3-(3-bromo-4,5-dihydroxybenzoyl)benzofuran; CAT) as novel metabolites of BBR in rat and human liver microsomal systems by comparison with chemically synthesized authentic compounds, and we also elucidated that DBH is formed by cytochrome P450 2C9 and that CAT is formed mainly by CYP1A1, 2D6, 2E1, and 3A4. Furthermore, CAT, DBH, and the oxidized form of DBH are highly cytotoxic in HepG2 compared with BBR. Taken together, our data demonstrate that DBH, a novel reactive metabolite, may be relevant to BBR-induced hepatotoxicity. PMID- 26106236 TI - PILL Series. Deliberate self-harm in adolescents. AB - Deliberate self-harm refers to an intentional act of causing physical injury to oneself without wanting to die. It is frequently encountered in adolescents who have mental health problems. Primary care physicians play an important role in the early detection and timely intervention of deliberate self-harm in adolescents. This article aims to outline the associated risk factors and possible aetiologies of deliberate self-harm in adolescents, as well as provide suggestions for clinical assessment and appropriate management within the primary care setting. PMID- 26106237 TI - Ministry of Health Clinical Practice Guidelines: Anxiety Disorders. AB - The Ministry of Health (MOH) has developed the clinical practice guidelines on Anxiety Disorders to provide doctors and patients in Singapore with evidence based treatment for anxiety disorders. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on anxiety disorders, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guideline /cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines. PMID- 26106238 TI - Review of sleep studies of patients with chronic insomnia at a sleep disorder unit. AB - INTRODUCTION: Chronic insomnia is associated with many physical and psychiatric illnesses, and its underlying aetiology needs to be identified in order to achieve safe and effective treatment. Obstructive sleep apnoea (OSA) and periodic limb movement disorder (PLMD) are common primary sleep disorders that can lead to chronic insomnia. Patients with these conditions are evaluated using polysomnography (PSG). METHODS: The PSG records of 106 patients with chronic insomnia who presented to a multidisciplinary sleep clinic in Singapore over a five-year period were reviewed. To examine the utility of PSG in the evaluation of chronic insomnia, the clinical diagnoses of the patients before and after the sleep studies were compared. RESULTS: Among the 106 patients, 69 (65.4%) were suspected to have primary sleep disorders based on clinical history and examination alone. Following PSG evaluation, 42.5% and 4.7% of the study population were diagnosed with OSA and PLMD, respectively. OSA was found in 35.9% of the 39 patients who had underlying psychiatric conditions. CONCLUSION: This study illustrates that many patients with chronic insomnia have underlying primary sleep disorders. It also highlights the danger of attributing chronic insomnia in psychiatric patients to their illness, without giving due consideration to other possible aetiologies. Clinicians should maintain a high index of suspicion for the presence of other aetiologies, and make timely and targeted referrals for sleep studies where appropriate. PMID- 26106239 TI - The clinical profile of patients with anorexia nervosa in Singapore: a follow-up descriptive study. AB - INTRODUCTION: The prevalence rate of anorexia nervosa is lower in Asia than in the West, although studies have found that it is on the rise in Asia. This study aims to present the clinical profile of patients presenting with anorexia nervosa in Singapore. METHODS: The present study used archival data from the Eating Disorder Programme registry of the Department of Psychiatry, Singapore General Hospital, Singapore. Patient records from 2003 to 2010 were collected and analysed. Presenting characteristics of the patients were also compared with those of another local study conducted eight years earlier. RESULTS: From 2003 to 2010, a total of 271 patients were diagnosed with anorexia nervosa by a psychiatrist in our hospital. Of these, 251 (92.6%) were female and 238 (87.8%) were Chinese. Our patients had a lower mean weight (36.83 kg, p < 0.001) and a lower mean body mass index (BMI) (14.43 kg/m(2), p < 0.001) than patients from the previous local study. Almost half of all our patients (n = 135, 49.8%) were diagnosed with at least one psychiatric comorbidity and 50 (18.5%) had a history of self-harm. CONCLUSION: The presenting characteristics of our study cohort were similar to those of the Western population. However, the lower presenting weight and BMI in our cohort indicates that cases seen today are more severe than those seen eight years ago. Therefore, it is important to put in place prevention programmes to help adolescents cultivate a healthy body image as well as early intervention programmes to improve detection rates and treatment outcomes. PMID- 26106240 TI - A prospective study of epidemiological risk factors for ingestion of fish bones in Singapore. AB - INTRODUCTION: Ingestion of fish bones is a common clinical complaint among adult patients. The aim of this study was to evaluate the epidemiological and behavioural risk factors for fish bone ingestion. METHODS: Between 2009 and 2010, a physician-administered questionnaire was administered to 112 consecutive patients who presented to the emergency department of an adult tertiary hospital with the complaint of fish bone ingestion. RESULTS: The wearing of dentures, the use of utensils to eat fish and the practice of deboning fish in one's mouth were found to be associated with an increased risk of fish bone ingestion. CONCLUSION: To prevent the occurrence of fish bone ingestion and its possible complications, at-risk populations should be advised on the precautions to take when eating boned fish. PMID- 26106241 TI - High-grade culprit lesions are a common cause of ST-segment elevation myocardial infarction. AB - INTRODUCTION: Conventional knowledge holds that the majority of ruptured atherosclerotic plaques causing ST-segment elevation myocardial infarction (STEMI) are found in moderate stenoses that produce < 50% loss of arterial diameter. This study aimed to analyse the culprit lesions in patients who presented with STEMI and underwent primary percutaneous coronary intervention (PPCI) at our institution. METHODS: Patients who underwent PPCI between June 2008 and August 2010 at our institution were included in the analysis. Quantitative coronary angiography was performed for the culprit lesions immediately after antegrade flow was restored by thrombectomy, low-profile balloon predilatation or guidewire crossing. RESULTS: A total of 1,021 patients were included in the study. The mean age was 57 +/- 12 years and 85.2% were male. Lesion measurement was done after coronary flow was restored by thrombectomy (73.1%), balloon dilatation (24.1%) and following guidewire passage across the lesion (2.8%). Mean minimal luminal diameter was 1.1 +/- 0.5 mm, mean reference vessel diameter was 2.8 +/- 0.6 mm, mean diameter stenosis was 61 +/- 16% and mean lesion length was 16 +/- 6 mm. Most (80.2%) of the culprit lesions had diameter stenoses > 50% (p < 0.01). Although balloon angioplasty was performed in 24.1% of the patients, the majority (64.2%) still had diameter stenoses > 50%. High-grade stenoses (> 50%) were more frequently observed in male patients (p = 0.04). CONCLUSION: Contrary to the existing paradigm, we found that most of the patients with STEMI in our institution had culprit lesions with diameter stenosis > 50%. PMID- 26106242 TI - Comment on: The assessment of combined first trimester screening in women of advanced maternal age in an Asian cohort. PMID- 26106243 TI - Authors' Reply: The assessment of combined first trimester screening in women of advanced maternal age in an Asian cohort. PMID- 26106244 TI - Non-asbestos Causes of mesothelioma and translocation of asbestos fibres. PMID- 26106245 TI - An unusual presentation of recurrent uterine rupture during pregnancy. AB - We describe a case of recurrent uterine rupture at the site of a previous rupture. Our patient had a history of right interstitial pregnancy with spontaneous uterine fundal rupture at 18 weeks of pregnancy. During her subsequent pregnancy, she was monitored closely by a senior consultant obstetrician. The patient presented at 34 weeks with right hypochondriac pain. She was clinically stable and fetal monitoring showed no signs of fetal distress. Ultrasonography revealed protrusion of the intact amniotic membranes in the abdominal cavity at the uterine fundus. Uterine rupture is a rare but hazardous obstetric complication. High levels of caution should be exercised in patients with a history of prior uterine rupture, as they may present with atypical symptoms. Ultrasonography could provide valuable information in such cases where there is an elevated risk of uterine rupture at the previous rupture site. PMID- 26106246 TI - Toxic leucoencephalopathy after 'chasing the dragon'. AB - Toxic leucoencephalopathy (TLE) is a rare neurological complication of heroin abuse. 'Chasing the dragon' is an inhalational mode of heroin abuse that originated in Southeast Asia. Intriguingly, no cases of TLE have been reported from this region, although the inhalational mode of heroin abuse is common. We herein report the case of a middle-aged man with a history of polysubstance abuse who presented with progressive neurological symptoms and progressed to an uncommunicative state. While the initial impression was that of iatrogenic parkinsonism, diffuse leucoencephalopathy with sparing of the cerebellum was noted on magnetic resonance imaging. In view of his history of inhalational heroin abuse close to the onset of the neurological symptoms, a diagnosis of TLE was made. No clinical improvement was noted with administration of a dopaminergic agent. This is the first known case of delayed TLE following heroin inhalation from Southeast Asia with the unusual feature of cerebellar sparing. PMID- 26106247 TI - Isolated and bilateral simultaneous facial palsy disclosing early human immunodeficiency virus infection. AB - Bilateral lower motor neuron type facial palsy is an unusual neurological disorder. There are few reports that associate it with the human immunodeficiency virus (HIV) infection on initial presentation. A 51-year-old married woman, who was previously healthy and had no risk of HIV infection, presented solely with bilateral simultaneous facial palsy. A positive HIV serology test was confirmed by an enzyme-linked immunosorbent assay test. Following a short course of oral prednisolone, the patient recovered completely from facial palsy in three months, even though an antiretroviral treatment was suspended. Exclusion of HIV infection in patients with bilateral facial palsy is essential for early diagnosis and management of HIV. PMID- 26106248 TI - Congenital midline sinus of the upper lip. AB - A congenital lip sinus is a rare condition that has been reported to occur in both the upper and lower lips, either in isolation or in association with congenital deformities such as a cleft lip and palate in Van der Woude syndrome. The prevalence of lower lip sinuses has been estimated to be about 0.00001% of the white population. Upper lip sinuses are even more uncommon. To date, there have been several case reports of upper lip sinuses and fistulas, but no similar cases have been described in Singapore. We herein report a case of congenital upper lip sinus presenting as a recurring upper lip abscess and review the current literature on this condition. PMID- 26106249 TI - Ellis-van Creveld syndrome in adulthood: extending the clinical spectrum. AB - Ellis-van Creveld (EvC) syndrome is a rare autosomal recessive malformation disorder. Cardiac defects are observed in about 50% of EvC cases. Surgical data is lacking on the prognosis and life expectancy of EvC patients. Herein, we report the case of a 38-year-old man with EvC syndrome who underwent two surgical corrections for cardiac anomalies. This report supplements the available information on the clinical course of EvC syndrome in older patients. PMID- 26106250 TI - Multimodality imaging of splenic sclerosing angiomatoid nodular transformation. AB - Sclerosing angiomatoid nodular transformation (SANT) is an exceedingly rare, benign and proliferative vascular lesion that arises from the splenic red pulp. It is often an incidental finding on imaging. The diagnosis of SANT is confirmed via histopathological examination of the resected spleen. Herein, we present a case of SANT and describe its typical imaging characteristics. An asymptomatic 39 year-old man was found to have a 3.1 cm * 2.7 cm * 2.3 cm hypoechoic splenic lesion during abdominal ultrasonography, which was performed to investigate his elevated gamma-glutamyl transpeptidase and alanine transaminase levels. Contrast enhanced computed tomography suggested a vascular splenic lesion, while magnetic resonance imaging demonstrated features consistent with SANT. In view of the increasing size of the lesion on follow-up imaging, the patient elected for splenectomy. Histopathological examination confirmed SANT, and the lesion was completely resected by laparoscopic splenectomy. PMID- 26106251 TI - Serum Levels of Progranulin Are Closely Associated with Microvascular Complication in Type 2 Diabetes. AB - OBJECTIVE: Progranulin (PGRN) was recently introduced as a novel marker of chronic inflammatory response in obesity and type 2 diabetes capable of directly affecting the insulin signaling pathway. This study aimed to investigate the correlation between PGRN and type 2 diabetics with microvascular complications. METHODS: PGRN serum levels and glucose metabolism related substance were measured in 84 type 2 diabetic patients with or without microangiopathies and 12 health persons. Further analyses of serum PGRN in different stages of diabetic microangiopathies were conducted. RESULTS: Serum levels of PGRN were markedly higher in type 2 diabetic patients with microangiopathies. PGRN serum levels increased with the progress of diabetic microangiopathies with significantly highest values detectable in clinical diabetic nephropathy (CDN) and proliferative diabetic retinopathy (PDR) groups. Serum PGRN concentrations in all individuals positively and markedly correlated with systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), triglyceride (TG), urinary albumin excretion rate (UAER), blood urea nitrogen (BUN), creatinine (CRE), white blood cell (WBC), disease duration, IL-6, and TNF-alpha, while correlating negatively and significantly with eGFR. Multiple linear regression analysis showed that only UAER and CRE were independently associated with serum PGRN. CONCLUSION: PGRN might be considered as a marker for diabetic microangiopathy and its severity. PMID- 26106252 TI - Uric Acid as a Marker of Kidney Disease: Review of the Current Literature. AB - Uric acid has been implicated in the pathophysiology of renal disease; however renal clearance makes a causal relationship difficult to prove. We examine the current literature to support a potential role of uric acid in the development of kidney disease and to determine the potential to use uric acid as a marker for future renal decline. After review, we conclude that uric acid is definitively linked to the development of chronic kidney disease and can be a poor prognostic factor for the development of acute renal failure, as well. However, further human research is needed before predictive models utilizing uric acid can be developed and used in the clinical setting. PMID- 26106253 TI - Hyperoxia-Induced Protein Alterations in Renal Rat Tissue: A Quantitative Proteomic Approach to Identify Hyperoxia-Induced Effects in Cellular Signaling Pathways. AB - INTRODUCTION: In renal tissue as well as in other organs, supranormal oxygen pressure may lead to deleterious consequences on a cellular level. Additionally, hyperoxia-induced effect in cells and related free radicals may potentially contribute to renal failure. The aim of this study was to analyze time-dependent alterations of rat kidney protein expression after short-term normobaric hyperoxia using proteomics and bioinformatic approaches. MATERIAL AND METHODS: N = 36 Wistar rats were randomized into six different groups: three groups with normobaric hyperoxia (exposure to 100% oxygen for 3 h) and three groups with normobaric normoxia (NN; room air). After hyperoxia exposure, kidneys were removed immediately, after 3 days and after 7 days. Kidney lysates were analyzed by two-dimensional gel electrophoresis followed by peptide mass fingerprinting using tandem mass spectrometry. Statistical analysis was performed with DeCyder 2D software (p < 0.01). Biological functions of differential regulated proteins were studied using functional network analysis (Ingenuity Pathways Analysis and PathwayStudio). RESULTS: Expression of 14 proteins was significantly altered (p < 0.01): eight proteins (MEP1A_RAT, RSSA_RAT, F16P1_RAT, STML2_RAT, BPNT1_RAT, LGMN_RAT, ATPA_RAT, and VDAC1_RAT) were downregulated and six proteins (MTUS1_RAT, F16P1_RAT, ACTG_RAT, ACTB_RAT, 2ABA_RAT, and RAB1A_RAT) were upregulated. Bioinformatic analyses revealed an association of regulated proteins with inflammation. CONCLUSIONS: Significant alterations in renal protein expression could be demonstrated for up to 7 days even after short-term hyperoxia. The identified proteins indicate an association with inflammation signaling cascades. MEP1A and VDAC1 could be promising candidates to identify hyperoxic injury in kidney cells. PMID- 26106254 TI - Assessment of Liver Remnant Using ICG Clearance Intraoperatively during Vascular Exclusion: Early Experience with the ALIIVE Technique. AB - Background. The most significant risk following major hepatectomy is postoperative liver insufficiency. Current preoperative assessment of the future liver remnant relies upon assumptions which may not be valid in the setting of advanced resection strategies. This paper reports the feasibility of the ALIIVE technique which assesses the liver remnant with ICG clearance intraoperatively during vascular exclusion. Methods. 10 patients undergoing planned major liver resection (hemihepatectomy or greater) were recruited. Routine preoperative assessment included CT and standardized volumetry. ICG clearance was measured noninvasively using a finger spectrophotometer at various time points including following parenchymal transection during inflow and outflow occlusion before vascular division, the ALIIVE step. Results. There were one case of mortality and three cases of posthepatectomy liver failure. The patient who died had the lowest ALIIVE ICG clearance (7.1%/min versus 14.4 +/- 4.9). Routine preoperative CT and standardized volumetry did not predict outcome. Discussion/Conclusion. The novel ALIIVE technique is feasible and assesses actual future liver remnant function before the point of no return during major hepatectomy. This technique may be useful as a check step to offer a margin of safety to prevent posthepatectomy liver failure and death. Further confirmatory studies are required to determine a safety cutoff level. PMID- 26106255 TI - Detecting Migraine in Patients with Mild Traumatic Brain Injury Using Three Different Headache Measures. AB - Posttraumatic migraine may represent an important subtype of headache among the traumatic brain injury (TBI) population and is associated with increased recovery times. However, it is underdiagnosed in patients with mild traumatic brain injury (mTBI). This study examined the effectiveness of the self-administered Nine-Item Screener (Nine-Item Screener-SA), the Headache Impact Test- 6 (HIT-6), the 3-Item Migraine Screener, and the Rivermead Post-Concussion Questionnaire (RPQ) at discriminating between mTBI patients with (n = 23) and without (n = 20) migraines. The Nine-Item Screener demonstrated significant differences between migraine patients with and without migraine on nearly every question, especially on Question 9 (disability), sensitivity: 0.95 and specificity: 0.65 (95% CI, 0.64 0.90). The HIT-6 demonstrated significant differences between migraine and no migraine patients on disability and pain severity, with disability having a sensitivity of 0.70 and specificity of 0.75 (95% CI, 0.54-0.83). Only Question 3 of the 3-Item ID Migraine Screener (photosensitivity) showed significant differences between migraine and no-migraine patients, sensitivity: 0.84 and specificity: 0.55 (CI, 0.52-0.82). The RPQ did not reveal greater symptoms in migraine patients compared with those without. Among headache measures, the Nine Item Screener-SA best differentiated between mTBI patients with and without migraine. Disability may best identify migraine sufferers among the TBI population. PMID- 26106256 TI - Impaired Fracture Healing after Hemorrhagic Shock. AB - Impaired fracture healing can occur in severely injured patients with hemorrhagic shock due to decreased soft tissue perfusion after trauma. We investigated the effects of fracture healing in a standardized pressure controlled hemorrhagic shock model in mice, to test the hypothesis that bleeding is relevant in the bone healing response. Male C57/BL6 mice were subjected to a closed femoral shaft fracture stabilized by intramedullary nailing. One group was additionally subjected to pressure controlled hemorrhagic shock (HS, mean arterial pressure (MAP) of 35 mmHg for 90 minutes). Serum cytokines (IL-6, KC, MCP-1, and TNF alpha) were analyzed 6 hours after shock. Fracture healing was assessed 21 days after fracture. Hemorrhagic shock is associated with a significant increase in serum inflammatory cytokines in the early phase. Histologic analysis demonstrated a significantly decreased number of osteoclasts, a decrease in bone quality, and more cartilage islands after hemorrhagic shock. MUCT analysis showed a trend towards decreased bone tissue mineral density in the HS group. Mechanical testing revealed no difference in tensile failure. Our results suggest a delay in fracture healing after hemorrhagic shock. This may be due to significantly diminished osteoclast recruitment. The exact mechanisms should be studied further, particularly during earlier stages of fracture healing. PMID- 26106257 TI - iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants. AB - There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS) in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS(-/-)) and wild-type (WT) mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS(-/-) mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS(-/-) mice. In contrast, the iNOS(-/-) implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS(-/-) mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice. PMID- 26106258 TI - Serum Levels of Lipopolysaccharide and 1,3-beta-D-Glucan Refer to the Severity in Patients with Crohn's Disease. AB - OBJECTIVES: Interactions between the host and gut microbial community contribute to the pathogenesis of Crohn's disease (CD). In this study, we aimed to detect lipopolysaccharide (LPS) and 1,3-beta-D-glucan (BG) in the sera of CD patients and clarify the potential role in the diagnosis and therapeutic approaches. MATERIALS AND METHODS: Serum samples were collected from 46 patients with active CD (A-CD), 22 CD patients at remission stage (R-CD), and 20 healthy controls, and the levels of LPS, BG, and TNF in sera were determined by ELISA. Moreover, sixteen patients with A-CD received anti-TNF monoclonal antibody therapy (infliximab, IFX) at a dose of 5 mg/kg body weight at weeks 0, 2, and 6, and the levels of LPS and BG were also tested at week 12 after the first intravenous infusion. RESULTS: Serum levels of LPS and BG were found to be markedly increased in A-CD patients compared with R-CD patients and healthy controls (P < 0.05). They were also observed to be positively correlated with CDAI, ESR, and SES-CD, respectively (P < 0.05). Furthermore, the levels of TNF in sera had a significant correlation with LPS and BG, respectively. The concentrations of LPS and BG were demonstrated to be significantly downregulated in the sera of A-CD patients 12 weeks after IFX treatment (P < 0.05), suggesting that blockade of TNF could inhibit bacterial endotoxin absorption, partially through improving intestinal mucosal barrier. CONCLUSIONS: Serum levels of LPS and BG are significantly increased in A-CD patients and positively correlated with the severity of the disease. Blockade of intestinal mucosal inflammation with IFX could reduce the levels of LPS and BG in sera. Therefore, this study has shed some light on measurement of serum LPS and BG in the diagnosis and treatment of CD patients. PMID- 26106259 TI - MITOSCISSOR: A Useful Tool for Auto-Assembly of Mitogenomic Datasets in the Evolutionary Analysis of Fishes. AB - As a result of the development of rapid and efficient sequencing technologies, complete sequences of numerous mitochondrial genomes are now available. Mitochondrial genomes have been widely used to evaluate relationships between species in several fields, including evolutionary and population genetics, as well as in forensic identification and in the study of mitochondrial diseases in humans. However, the creation of mitochondrial genomes is extremely time consuming. In this paper, we present a new tool, MITOSCISSOR, which is a rapid method for parsing and formatting dozens of complete mitochondrial genome sequences. With the aid of MITOSCISSOR, complete mitochondrial genome sequences of 103 species from Tetraodontiformes (a difficult-to-classify order of fish) were easily parsed and formatted. It typically takes several days to produce similar results when relying upon manual editing. This tool could open the .gb file of Genbank directly and help us to use existing mitogenomic data. In the present study, we established the first clear and robust molecular phylogeny of 103 tetraodontiform fishes, a goal that has long eluded ichthyologists. MITOSCISSOR greatly increases the efficiency with which DNA data files can be parsed and annotated, and thus has the potential to greatly facilitate evolutionary analysis using mitogenomic data. This software is freely available for noncommercial users at http://www.filedropper.com/mitoscissor. PMID- 26106260 TI - Synthetic Extracellular Microenvironment for Modulating Stem Cell Behaviors. AB - The innate ability of stem cells to self-renew and differentiate into multiple cell types makes them a promising source for tissue engineering and regenerative medicine applications. Their capacity for self-renewal and differentiation is largely influenced by the combination of physical, chemical, and biological signals found in the stem cell niche, both temporally and spatially. Embryonic and adult stem cells are potentially useful for cell-based approaches; however, regulating stem cell behavior remains a major challenge in their clinical use. Most of the current approaches for controlling stem cell fate do not fully address all of the complex signaling pathways that drive stem cell behaviors in their natural microenvironments. To overcome this limitation, a new generation of biomaterials is being developed for use as three-dimensional synthetic microenvironments that can mimic the regulatory characteristics of natural extracellular matrix (ECM) proteins and ECM-bound growth factors. These synthetic microenvironments are currently being investigated as a substrate with surface immobilization and controlled release of bioactive molecules to direct the stem cell fate in vitro, as a tissue template to guide and improve the neo-tissue formation both in vitro and in vivo, and as a delivery vehicle for cell therapy in vivo. The continued advancement of such an intelligent biomaterial system as the synthetic extracellular microenvironment holds the promise of improved therapies for numerous debilitating medical conditions for which no satisfactory cure exists today. PMID- 26106261 TI - Medicinal Plants: A Potential Source of Compounds for Targeting Cell Division. AB - Modern medicinal plant drug discovery has provided pharmacologically active compounds targeted against a multitude of conditions and diseases, such as infection, inflammation, and cancer. To date, natural products from medicinal plants remain a solid niche as a source from which cancer therapies can be derived. Among other properties, one favorable characteristic of an anticancer drug is its ability to block the uncontrollable process of cell division, as cancer cells are notorious for their abnormal cell division. There are numerous other documented works on the potential anticancer activity of drugs derived from medicinal plants, and their effects on cell division are an attractive and growing therapeutic target. Despite this, there remains a vast number of unidentified natural products that are potentially promising sources for medical applications. This mini review aims to revise the current knowledge of the effects of natural plant products on cell division. PMID- 26106262 TI - Novelty Seeking as a Phenotypic Marker of Adolescent Substance Use. AB - Trait novelty seeking has been consistently implicated in substance use, yet the origins and mechanisms of novelty seeking in substance use proneness are unclear. We aimed to characterize novelty seeking as a phenotypic marker of substance use proneness in adolescence, a critical period for drug use experimentation. To this end, we parsed novelty seeking's two constituent subdimensions - exploratory excitability (drive for novel experience) and impulsiveness (careless decision making) - and explored the individual relations of these dimensions to: (1) the use of a variety of licit and illicit substances, (2) family history of substance use, and (3) subjective drug effects. Five hundred eighty five adolescents (mean age = 14.5 years) completed surveys of key variables. Results indicated that, when accounting for the covariation among exploratory excitability and impulsiveness, impulsiveness emerged as the more salient correlate of substance use and was independently associated with initiation of nearly all drug classes. Mediation analyses of the mechanisms of novelty seeking-related risk illustrated that impulsiveness mediated the association of family history of substance use with both initiation and past 30-day frequency of use. Both impulsiveness and exploratory excitability were associated with increased positive and negative subjective drug effects, and the analyses supported a significant indirect pathway from impulsiveness to a more frequent use via positive subjective effects. Although limited by a cross-sectional design, these findings suggest that impulsiveness-like aspects of the novelty seeking construct may represent a useful phenotypic marker for early substance use proneness that potentially (1) increases initiation risk, (2) has familial origins, and (3) promotes more frequent use by altering subjective drug response. PMID- 26106263 TI - Accuracies and Contrasts of Models of the Diffusion-Weighted-Dependent Attenuation of the MRI Signal at Intermediate b-values. AB - The diffusion-weighted-dependent attenuation of the MRI signal E(b) is extremely sensitive to microstructural features. The aim of this study was to determine which mathematical model of the E(b) signal most accurately describes it in the brain. The models compared were the monoexponential model, the stretched exponential model, the truncated cumulant expansion (TCE) model, the biexponential model, and the triexponential model. Acquisition was performed with nine b-values up to 2500 s/mm(2) in 12 healthy volunteers. The goodness-of-fit was studied with F-tests and with the Akaike information criterion. Tissue contrasts were differentiated with a multiple comparison corrected nonparametric analysis of variance. F-test showed that the TCE model was better than the biexponential model in gray and white matter. Corrected Akaike information criterion showed that the TCE model has the best accuracy and produced the most reliable contrasts in white matter among all models studied. In conclusion, the TCE model was found to be the best model to infer the microstructural properties of brain tissue. PMID- 26106264 TI - Blood Pressure and Heart Rate Alterations through Music in Patients Undergoing Cataract Surgery in Greece. AB - INTRODUCTION: Music has been proposed as a safe, inexpensive, nonpharmacological antistress intervention. The purpose of this study was to determine whether patients undergoing cataract surgery while listening to meditation music experience lower levels of blood pressure and heart rate. METHODS: Two hundred individuals undergoing cataract surgery participated in the study. Hundred individuals listened to meditation music, through headphones, before and during the operation (intervention group) and 100 individuals received standard care (control group). Patients stress coping skills were measured by the Sense of Coherence Scale (SOC Scale). Systolic and diastolic blood pressure and heart rate were defined as outcome measures. RESULTS: According to the SOC Scale, both groups had similar stress coping skills (mean score: 127.6 for the intervention group and 127.3 for the control group). Before entering the operating room (OR) as well as during surgery the rise in systolic and diastolic pressures was significantly lower in the intervention group (P < 0.001). Among patients receiving antihypertensive therapy, those in the intervention group presented a lower increase only in systolic pressure (P < 0.001) at both time recordings. For those patients in the intervention group who did not receive antihypertensive treatment, lower systolic blood pressure at both time recordings was recorded (P < 0.001) while lower diastolic pressure was observed only during entry to the OR (P = 0.021). Heart rate was not altered between the two groups in any of the recordings. CONCLUSIONS: Meditation music influenced patients' preoperative stress with regard to systolic blood pressure. This kind of music can be used as an alternative or complementary method for blood pressure stabilizing in patients undergoing cataract surgery. PMID- 26106265 TI - Similarity of Serum and Plasma Insulin-like Growth Factor Concentrations. AB - BACKGROUND: Insulin-like growth factors (IGFs) are implicated in many normal physiological processes and pathological states, including cancer. For large consortia projects, it may be necessary to make comparisons among studies with different specimens that were not collected specifically to optimize the measurement of IGFs. OBJECTIVE: This study aimed to compare IGFs in matched serum and plasma samples. METHODS: We measured IGF-I, IGF-II, insulin-like growth factor-binding protein (IGFBP)-3, C-peptide, and leptin in serum and ethylenediaminetetraacetic-containing-plasma samples obtained concurrently from 30 healthy women aged 64-80 years in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial using chemiluminescent or colorimetric enzyme-linked immune assays. Coefficients of variation (CVs) and correlations were determined. RESULTS: Intraassay CVs ranged from 0.4% for IGFBP-3 to 10% for IGF-II. Mean concentrations of all analytes were higher in the serum, but the differences in mean concentrations of the analytes between serum and plasma were all <11%. Concordance correlation coefficients of matched serum/plasma specimens were 0.92, 0.91, 0.82, 0.96, and 0.99 for IGF-I, IGFBP-3, IGF-II, C-peptide, and leptin, respectively. CONCLUSION: IGF concentrations measured in serum and plasma are highly correlated but are consistently slightly higher in serum, suggesting that IGF values should be corrected for systematic bias, particularly in consortial efforts when pooling data derived from different specimens. PMID- 26106266 TI - Combination of PAPPA, fhCGbeta, AFP, PlGF, sTNFR1, and Maternal Characteristics in Prediction of Early-onset Preeclampsia. AB - OBJECTIVE: To evaluate the efficacy of first-trimester markers-pregnancy associated plasma protein A (PAPPA), free human chorionic gonadotropin beta (fhCGbeta), alpha-fetoprotein (AFP), placental growth factor (PlGF), and soluble tumor necrosis factor receptor-1 (sTNFR1) together with maternal characteristics (MC) for prediction of early-onset preeclampsia (EOPE). METHODS: During 2005 2010, the abovementioned biomarkers were analyzed with logistic regression analysis in 64 EOPE and 752 control subjects to determine whether these biomarkers separately and in combination with MC would predict development of EOPE. RESULTS: PAPPA, fhCGbeta, and PlGF levels were lower, whereas AFP and sTNFR1 levels were higher in mothers with EOPE compared to controls. The combination of all markers with MC (age, weight, and smoking status) detected 48% of the mothers with EOPE, with a 10% false-positive rate (FPR). CONCLUSIONS: First-trimester maternal serum levels of PAPPA, fhCGbeta, AFP, PlGF, and sTNFR1, together with MC, are predictive of development of subsequent EOPE. These markers, along with MC, form a suitable panel for predicting EOPE. PMID- 26106267 TI - Bioinformatics Data Mining Approach Suggests Coexpression of AGTPBP1 with an ALS linked Gene C9orf72. AB - BACKGROUND: Expanded GGGGCC hexanucleotide repeats located in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene represent the most common genetic abnormality for familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Formation of nuclear RNA foci, accumulation of repeat-associated non-ATG-translated dipeptide-repeat proteins, and haploinsufficiency of C9orf72 are proposed for pathological mechanisms of C9ALS/FTD. However, at present, the physiological function of C9orf72 remains largely unknown. METHODS: By searching on a bioinformatics database named COXPRESdb composed of the comprehensive gene coexpression data, we studied potential C9orf72 interactors. RESULTS: We identified the ATP/GTP binding protein 1 (AGTPBP1) gene alternatively named NNA1 encoding a cytosolic carboxypeptidase whose mutation is causative of the degeneration of Purkinje cells and motor neurons as the most significant gene coexpressed with C9orf72. We verified coexpression and interaction of AGTPBP1 and C9orf72 in transfected cells by immunoprecipitation and in neurons of the human brain by double-labeling immunohistochemistry. Furthermore, we found a positive correlation between AGTPBP1 and C9orf72 mRNA expression levels in the set of 21 human brains examined. CONCLUSIONS: These results suggest that AGTPBP1 serves as a C9orf72 interacting partner that plays a role in the regulation of neuronal function in a coordinated manner within the central nervous system. PMID- 26106268 TI - Pharmaceutical research in the Kingdom of Saudi Arabia: A scientometric analysis during 2001-2010. AB - Studies on the performance of Saudi Arabia in the pharmaceutical science research using quantitative and qualitative measures. They analyze the productivity and global publication share and rank of the top 15 countries. The author studies Saudi Arabia's publications output, growth and citation quality, international collaborative publication share and most important the collaborating partners, contribution and citation impact of its top 15 organizations and authors, productivity patterns of its top publishing journals and characteristics of its highly cited papers. PMID- 26106269 TI - Alternatives to animal testing: A review. AB - The number of animals used in research has increased with the advancement of research and development in medical technology. Every year, millions of experimental animals are used all over the world. The pain, distress and death experienced by the animals during scientific experiments have been a debating issue for a long time. Besides the major concern of ethics, there are few more disadvantages of animal experimentation like requirement of skilled manpower, time consuming protocols and high cost. Various alternatives to animal testing were proposed to overcome the drawbacks associated with animal experiments and avoid the unethical procedures. A strategy of 3 Rs (i.e. reduction, refinement and replacement) is being applied for laboratory use of animals. Different methods and alternative organisms are applied to implement this strategy. These methods provide an alternative means for the drug and chemical testing, up to some levels. A brief account of these alternatives and advantages associated is discussed in this review with examples. An integrated application of these approaches would give an insight into minimum use of animals in scientific experiments. PMID- 26106270 TI - Consumers' perceptions on the contribution of community pharmacists in the dispensing process at Dawadmi. AB - BACKGROUND: Community pharmacies are widely distributed and developments in this sector will greatly improve pharmaceutical health care delivery. OBJECTIVES: To provide consumer's perceptions towards the contribution of community pharmacists in the dispensing process. METHOD: The study was performed from mid-October to mid-November 2013 in Dawadmi, KSA. Data were carried out using a structured face to-face questionnaire with randomly selected 100 consumers at different community pharmacies. The questionnaire composed of nine closed questions about consumer's perceptions towards the pharmacist's role, counselling quality and dispensing errors in community pharmacies. RESULTS: Consumers perceive that pharmacists are not committed to dispense medications with prescription (72%), it is embarrassing to ask questions to the pharmacist in the current pharmacy premises (48%), pharmacists do not give enough counselling about their medications (48%) and they previously encountered a dispensing error (26%). CONCLUSION: The professional performance of community pharmacists in dispensing is below expectation. Majority of consumers perceive that community pharmacists are violating pharmacy law and giving them insufficient medicine information while dispensing. Authorities should stimulate both pharmacist's and consumer's awareness by educational campaign, improve standards for the profession and penalise violators. It is a necessity for community pharmacies to develop consultation areas to assure privacy, improve counselling quality, and reduce dispensing errors. PMID- 26106271 TI - Perception of community pharmacists toward their current professional role in the healthcare system of Dubai, United Arab Emirates. AB - The new paradigm to pharmacy profession has changed the focus of pharmacists from product-centered to patient-oriented. This change has brought new set of beliefs and assumptions on the way services should be delivered to pharmacy clients. The main aim of this study was to explore the perception of community pharmacists on their current professional role in Dubai. Key findings show that community pharmacists are more directed toward business than patients. They almost dispense all categories of medicines over-the-counter without the need of prescriptions. However, a new trend of pharmacists in Dubai is to provide enhanced pharmacy services such as consultation to patients upon request. PMID- 26106272 TI - Utilization of model-based meta-analysis to delineate the net efficacy of taspoglutide from the response of placebo in clinical trials. AB - The objective of this study was to develop quantitative models to delineate the net efficacy of taspoglutide on fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) from the response of placebo in type 2 diabetes patients, and further find pharmacodynamic potency of taspoglutide and FPG for half of maximum reduction responses of FPG and HbA1c, respectively. Several PD data about taspoglutide treatments for type 2 diabetes patients were digitalized from the published papers related with the clinical development of taspoglutide. The model based meta-analysis (MBMA) studies for FPG and HbA1c were performed with Monolix 4.2 software. The MBMA successfully described the effects of placebo and taspoglutide on pharmacological indexes of FPG and HbA1c through mono and multiple combination therapies in clinical trials. The pharmacodynamic potency (25.3 pmol/l) produced 50% of maximum responses of FPG (-2.39 mmol/l) from the responses of placebo for FPG (-0.371 mmol/l); the response change of FPG (-1.81 mmol/l) affected 50% of maximum response change (-1.74%) for HbA1c from the response of placebo (-0.253%). The leveraging prior knowledge from the longitudinal MBMA will be utilized to guide clinical development of taspoglutide and further support study designs including optimization of dose and duration of therapy. PMID- 26106273 TI - Adiponectin serum levels correlate with insulin resistance in type 2 diabetic patients. AB - The adipose tissue is not only an inert storage depot for lipids, but also it secretes a variety of bioactive molecules, known as adipokines, which affect whole-body homeostasis. Adiponectin is the most abundant of these adipocytokines and is known to have a regulatory effect on the metabolism of glucose and lipid. The main objectives of this study were to evaluate the serum levels of adiponectin and to establish a correlation between adiponectin serum levels and the degree of insulin resistance in type 2 diabetic patients. Eighty participants were enrolled in this study; 61 type 2 diabetic patients and 19 apparently healthy subjects. Serum level of adiponectin was measured by enzyme-linked immunosorbent assay (ELISA) for each participant. Data collection sheet was filled with all required information for each participant. Adiponectin level in the diabetic patients (5.05 +/- 2.61 MUg/ml) was lower than in non-diabetic healthy controls (5.71 +/- 2.35 MUg/ml). When the results were compared according to gender, diabetic females showed significantly higher adiponectin levels (5.76 +/- 2.64 MUg/ml) than diabetic males (4.366 +/- 2.43 MUg/ml, P = 0.035). In addition, female diabetic patients with abdominal obesity (waist circumference (WC) ? 88 cm) had lower adiponectin levels (5.58 +/- 2.58 MUg/ml) than diabetic females without abdominal obesity (6.96 +/- 3.12 MUg/ml). The correlation analysis indicated that adiponectin had a significant positive correlation with age (r = -0.450, P < 0.001). In conclusion, female diabetic patients had a statistically significant higher adiponectin level than male diabetic patients which could indicate a gender effect. Adiponectin levels were inversely related to insulin resistance; as patients with abdominal obesity had lower serum levels of adiponectin. PMID- 26106274 TI - Hospital pharmacists' self-evaluation of their competence and confidence in conducting pharmacy practice research. AB - OBJECTIVES: Research is essential to the advancement of pharmacy practice and healthcare. Pharmacists have a pivotal role to play in this strategy. However, there is a paucity of data about hospital pharmacists' competence and ability in conducting health-related research. This study primarily aims to determine the research demographics of hospital pharmacists in Qatar and to assess the pharmacists' perceptions of their competence and confidence to conduct research. METHODS: A multi-centered survey using a 70-item piloted questionnaire was conducted among a randomly selected sample of pharmacists practicing at seven Hamad Medical Corporation-managed hospitals. Both descriptive and inferential statistical analyses were applied using IBM-SPSS(r) version 20. KEY FINDINGS: A total of 120 participants responded to the survey (67% response rate). About 70% of the participants did not have any previous research experience. At least 20% of the respondents self-reported inadequate competence and/or confidence in developing research protocols, critically appraising the literature, undertaking and applying appropriate statistical techniques, and interpreting research findings. The level of education along with the current hospital of practice had significant effects on pharmacists' self-assessed competence (p < 0.05). Overall, 85% of the participants were interested in pursuing postgraduate studies or research-related training. CONCLUSIONS: A large proportion of hospital pharmacists in Qatar self-assessed themselves as having deficiencies in several domains of research process or competencies, although they recognized the value of research in advancing pharmacy practice. These findings have important implications for developing informal research training programs and promoting the pursuit of formal postgraduate programs to bridge the knowledge gaps found among hospital-practicing pharmacists. PMID- 26106275 TI - Does self-reflection and peer-assessment improve Saudi pharmacy students' academic performance and metacognitive skills? AB - BACKGROUND: The patient-centered focus of clinical pharmacy practice which demands nuanced application of specialized knowledge and skills targeted to meeting patient-specific therapeutic needs warrant that the training strategy used for PharmD graduates must empower with the ability to use the higher level cognitive processes and critical thinking effectively in service delivery. However, the historical disposition to learning in the Middle East and among Saudi students appeared heavily focused on rote memorization and recall of memorized facts. OBJECTIVES: To assess the impact of active pedagogic strategies such as self-reflection and peer assessment on pharmacy students' academic performance and metacognitive skills, and evaluate students' feedback on the impact of these active pedagogic strategies on their overall learning experience. METHOD: An exploratory prospective cohort study was conducted among 4th year students at the College of Clinical Pharmacy, King Faisal University, Saudi Arabia to assess the impact of self-reflection and peer-assessment in a semester wide assessment tasks in two compulsory first semester 4th year courses (Therapeutics-3 and Pharmacoeconomics). An end-of-course evaluation survey with a pre-tested 5-item open-ended questionnaire was also conducted to evaluate students' feedback on the impact of active pedagogic strategies on their overall learning experience. RESULT: Male students (study group) constituted 40.7% of the cohort while 59.3% were females (control group) with mean +/- SD age of 23.2 +/- 5.6 and 22.1 +/- 4.9 years respectively. The mean +/- SD scores for quizzes, mid term and final exams, and the overall percentage pass were significantly higher in the study group for both courses (P < 0.001). The majority of the students in the study group opined that the exposure to active pedagogic strategies enabled them to improve their use of critical thinking, facilitated deeper engagement with their learning and improved their clinical decision-making and discussion skills. CONCLUSION: The use of active pedagogic strategies such as self reflection and peer-assessment appeared to significantly improve examination performance, facilitate deep and constructive engagement with learning and fostered students' confidence in the use of critical thinking and clinical decision-making. PMID- 26106276 TI - Self nanoemulsifying drug delivery system of stabilized ellagic acid-phospholipid complex with improved dissolution and permeability. AB - Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid-phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid phospholipid complex was verified through solubility studies. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid-phospholipid complex showed mean globule size of 106 +/- 0.198 nm and cloud point at 83-85 degrees C. The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA. PMID- 26106277 TI - Stealth Amphotericin B nanoparticles for oral drug delivery: In vitro optimization. AB - PURPOSE: Amphotericin B (AmB) is an effective anti-fungal and anti-leishmanial agent. However, AmB has low oral bioavailability (0.3%) and adverse effects (e.g., nephrotoxicity). The objectives of this study were to improve the oral bioavailability by entrapping AmB in pegylated (PEG) poly lactide co glycolide copolymer (PLGA-PEG) nanoparticles (NPs). The feasibility of different surfactants and stabilizers on the mean particle size (MPS) and entrapment efficiency were also investigated. MATERIALS AND METHODS: NPs of AmB were prepared by a modified emulsification diffusion method employing a vitamin E derivative as a stabilizer. Physicochemical properties and particle size characterization were evaluated using Fourier Transform Infra-Red spectroscopy (FTIR), differential scanning calorimetry, scanning electron microscopy and transmission electron microscopy. Moreover, in vitro dissolution profiles were performed for all formulated AmB NPs. RESULTS: MPS of the prepared spherical particles of AmB ranged from 26.4 +/- 2.9 to 1068 +/- 489.8 nm. An increased stirring rate favored AmB NPs with a smaller MPS. There was a significant reduction in MPS, drug content and drug release, when AmB NPs were prepared using the diblock polymer PLGA-PEG with 15% PEG. Addition of three emulsifying agents poly vinyl pyrrolidone (PVP), Vitamin E (TPGS) and pluronic F-68 to AmB formulations led to a significant reduction in particle size and increase in drug entrapment efficiency (DEE) compared to addition of PVP alone. FTIR spectroscopy demonstrated a successful loading of AmB to pegylated PLGA-PEG copolymers. PLGA PEG copolymer entrapment efficiency of AmB was increased up to 56.7%, with 92.7% drug yield. After a slow initial release, between 20% and 54% of AmB was released in vitro within 24 h phosphate buffer containing 2% sodium deoxycholate and were best fit Korsmeyer-Peppas model. In conclusion, PLGA-PEG diblock copolymer with 15% PEG produced a significant reduction (>70%) in MPS with highest drug content. The percentage of PEG in the copolymer and the surfactant/stabilizer used had a direct effect on AmB release in vitro, entrapment efficiency and MPS. These developed formulations are feasible, effective and improved alternatives to other carriers for oral delivery of AmB. PMID- 26106278 TI - Microbiological quality of non-sterile pharmaceutical products. AB - In microbiological terms, pharmaceutical products can be divided into two groups: sterile and non-sterile. Non-sterile drugs must satisfy the appropriate microbiological purity criteria which are included in pharmacopoeial monographs. Pharmacopoeial studies are prepared specifically with a view to ensuring that the medicinal product is therapeutically effective and safe for the patient. The analysis comprised the results of microbiological purity tests performed before the products are marketed. Total of 1285 samples of non-sterile drugs manufactured by different pharmaceutical plants in Polish were taken into study. The microbiological quality of drugs was assessed in accordance with the criteria included in the European Pharmacopoeia (EP). An analysis of test results demonstrated that the percentage of non-compliant samples was 1.87%. The groups of drugs, which the most often did not satisfy EPs' requirements, were drugs containing raw materials of natural origin (5.7%). The samples of studied drugs that did not meet the criteria contained in EP, exceed the maximum allowable microbiological count limits and contained microbes whose presence is prohibited. The most common non-compliance was the excessive levels of the maximum acceptable fungal count (n = 12) and the excessive the maximum acceptable aerobic microbial count (n = 10). PMID- 26106279 TI - Formulation and characterization of 5-Fluorouracil enteric coated nanoparticles for sustained and localized release in treating colorectal cancer. AB - 5-Fluorouracil is used in the treatment of colorectal cancer along with oxaliplatin as first line treatment, but it is having lack of site specificity and poor therapeutic effect. Also toxic effects to healthy cells and unavailability of major proportion of drug at the colon region remain as limitations. Toxic effects prevention and drug localization at colon area was achieved by preparing enteric-coated chitosan polymeric nanoparticles as it can be delivered directly to large bowel. Enteric coating helps in preventing the drug degradation at gastric pH. So the main objective was to prepare chitosan polymeric nanoparticles by solvent evaporation emulsification method by using different ratios of polymer (1:1, 1:2, 1:3, 1:4). Optimized polymer ratio was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), entrapment efficiency and particle size and further subjected to enteric coating. In vitro drug release studies were done using dialysis bag technique using simulated fluids at various pH (1.2, 4.5, 7.5, 7.0) to mimic the GIT tract. 5-FU nanoparticles with drug: polymer ratio of 1:2 and 1:3 has shown better particle size (149 +/- 1.28 nm and 138 +/- 1.01 nm respectively), entrapment efficiency (48.12 +/- 0.08% and 69.18 +/- 1.89 respectively). 5-FU E1 has shown better drug release after 4 h and has shown 82% drug release till 24 h in a sustained manner comparable to the non-enteric coated tablets, which released more than 50% of the drug before entering the colon region. So we can conclude that nanoparticles prepared by this method using the same polymer with the optimized ratio can represent as potential drug delivery approach for effective delivery of the active pharmaceutical ingredient to the colorectal tumors. PMID- 26106280 TI - Effect of HPMC and mannitol on drug release and bioadhesion behavior of buccal discs of buspirone hydrochloride: In-vitro and in-vivo pharmacokinetic studies. AB - Delivery of orally compromised therapeutic drug molecules to the systemic circulation via buccal route has gained a significant interest in recent past. Bioadhesive polymers play a major role in designing such buccal dosage forms, as they help in adhesion of designed delivery system to mucosal membrane and also prolong release of drug from delivery system. In the present study, HPMC (release retarding polymer) and mannitol (diluent and pore former) were used to prepare bioadhesive and controlled release buccal discs of buspirone hydrochloride (BS) by direct compression method. Compatibility of BS with various excipients used during the study was assessed using DSC and FTIR techniques. Effect of mannitol and HPMC on drug release and bioadhesive strength was studied using a 3(2) factorial design. The drug release rate from delivery system decreased with increasing levels of HPMC in formulations. However, bioadhesive strength of formulations increased with increasing proportion of HPMC in buccal discs. Increased levels of mannitol resulted in faster rate of drug release and rapid in vitro uptake of water due to the formation of channels in the matrix. Pharmacokinetic studies of designed bioadhesive buccal discs in rabbits demonstrated a 10-fold increase in bioavailability in comparison with oral bioavailability of buspirone reported. PMID- 26106281 TI - Vancomycin therapy in critically ill patients on continuous renal replacement therapy; are we doing enough? AB - BACKGROUND: Recommendations regarding vancomycin dosing and monitoring in critically ill patients on continuous renal replacement therapy (CRRT) are limited. This is a retrospective study to assess the adequacy of current vancomycin dosing and monitoring practice for patients on CRRT in a tertiary hospital in Riyadh, Saudi Arabia. METHODS: A retrospective chart review of adult patients admitted between 1 April 2011 and 30 March 2013 to critical care and received intravenous vancomycin therapy whilst on CRRT was performed. RESULTS: A total of 68 patients received intravenous vancomycin therapy whilst on CRRT, of which 32 met the inclusion criteria. Fifty-one percent were males and median (range) age was 62.5 (19 - 90) years. Median APACHE II score was 33.5 (22-43) and median Charlson Comorbidity Score was 4 (0-8). The mean (+/- standard deviation) dose of vancomycin was 879.9 mg (+/- 281.2 mg) for an average duration of 5.9 days (+/- 3.7 days). All patients received continuous veno-venous haemofiltration (CVVH). A total of 55 vancomycin level readings were available from the study population, ranging from 6.6 to 41.3, with wide variations within the same sampling time frames. Vancomycin levels of > 15 mg/L or were achieved at least once in 24 patients (75.0%), but only 11 patients (34.3%) had 2 or more serum vancomycin level readings of 15 mg/L or more. CONCLUSION: Therapeutic vancomycin levels are difficult to maintain in critically ill patients who are receiving IV vancomycin therapy whilst on CRRT. Aggressive dosing schedules and frequent monitoring are required to ensure adequate vancomycin therapy in this setting. PMID- 26106282 TI - Shorter and sturdier bridges between traditional Chinese medicines and modern pharmacology. PMID- 26106283 TI - MicroRNA-24 inhibits growth, induces apoptosis, and reverses radioresistance in laryngeal squamous cell carcinoma by targeting X-linked inhibitor of apoptosis protein. AB - BACKGROUND: Increasing evidence indicates that dysregulation of microRNAs is involved in tumor progression and development. The aim of this study was to investigate the expression of microRNA-24 (miR-24) and its function in laryngeal squamous cell carcinoma (LSCC). METHODS: Quantitative RT-PCR (qRT-PCR) was used to detect miR-24 expression in LSCC cell lines and tissue samples. MTT, colony formation, and flow cytometry was performed to analyze the effects of miR-24 expression on growth, apoptosis, and radiosensitivity of LSCC cells. Dual luciferase reporter assays were performed to examine regulation of putative miR 24 targets. Expression of X-linked inhibitor of apoptosis protein (XIAP) mRNA and protein, cleaved or total caspase-3, and cleaved or total PARP protein were detected by qRT-PCR and western blotting assays, respectively. RESULTS: miR-24 expression levels in LSCC cell lines or tissue were significantly lower than in a normal human keratinocyte cell line or adjacent normal tissues. Functional analyses indicated that re-expression of miR-24 inhibits growth, reduces colony formation, and enhances apoptosis in LSCC cells. In addition, miR-24 upregulation increases LSCC sensitivity to irradiation by enhancing irradiation-induced apoptosis, and luciferase activity indicated that miR-24 binds to the 3' untranslated region (3'-UTR) of XIAP mRNA. Upregulation of miR-24 inhibits XIAP protein expression in LSCC cells, and silencing of XIAP mimics the effects of miR 24 upregulation on LSCC cells. In addition, XIAP mRNA expression significantly increases in LSCC tissues and is inversely correlated with miR-24 expression. CONCLUSIONS: Our data suggest that miR-24 inhibits growth, increases apoptosis, and enhances radiosensitivity in LSCC cells by targeting XIAP. Therefore, miR-24 may be a potential molecular target for the treatment of human LSCC. PMID- 26106284 TI - Biologic versus Synthetic Mesh Reinforcement: What are the Pros and Cons? AB - Preserving patients' native tissues has posed many challenges for surgeons. Increased life expectancy is leading to a proportionately older surgical population with weaker tissues. The growing population of morbidly obese patients in addition to those with multiple comorbidities which influence the native strength and perfusion of tissues compounds the surgeon's challenge. Certainly, there is a rising demand for materials to replace or augment a patient's native tissue when it has been compromised. Over time, the number of products available has increased substantially. The ideal substitute, however, is debatable. The manufacturing and processing of these materials has become more complex and this has resulted in a significant increase in cost. The composition of the mesh, clinical scenario, and operative technique all interact to impact the long-term results. Surgeons require a thorough understanding of these products to guide proper selection and use, to ensure optimal outcomes for patients, and to properly steward financial resources. This review will outline the properties of commonly used materials, highlighting the strength and weakness of each. It will then discuss recommendations regarding mesh selection, coding, and reimbursement. While general principles and trends can be highlighted, further studies of biologic versus synthetic meshes are clearly necessary. PMID- 26106285 TI - Synthesis and Characterization of Bioactive Acylpyrazolone Sulfanilamides and Their Transition Metal Complexes: Single Crystal Structure of 4-Benzoyl-3-methyl 1-phenyl-2-pyrazolin-5-one Sulfanilamide. AB - Two Schiff base ligands Ampp-Sn 1 and Bmpp-Sn 2, afforded by a condensation reaction between sulfanilamide and the respective acylpyrazolone carbonyl precursors, their Mn(II), Co(II), Ni(II), and Cu(II) complexes prepared by the reaction of ligands and corresponding metal salts in aqueous solutions, were synthesized and then characterized by both analytical and spectroscopic methods, in a view to developing new improved bioactive materials with novel properties. On the basis of elemental analysis, spectroscopic and TGA results, transition metal complexes, with octahedral geometry having two molecules of the bidentate keto-imine ligand each, have been proposed. The single crystal structure of Bmpp Sn according to X-ray crystallography showed a keto-imine tautomer type of Schiff base, having three intramolecular bonds, one short N2?H2?O3 hydrogen bond of 1.90 A and two long C13?H13?O2 and C32?H32?O3 hydrogen bonds of 2.48 A. A moderate to low biological activities have been exhibited by synthesized compounds when compared with standard antimicrobial agents on screening the synthesized compounds against Staphylococcus aureus, Bacillus pumilus, Proteus vulgaris, and Aeromonas hydrophila for antibacterial activity and against free radical 1, 1 diphenyl-2-picryl-hydrazyl (DPPH) for antioxidant activity. PMID- 26106286 TI - Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? AB - Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator activated receptor gamma (PPAR-gamma) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-gamma, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism. PMID- 26106287 TI - Current conceptual challenges in the study of rhythm processing deficits. AB - Interest in the study of rhythm processing deficits (RPD) is currently growing in the cognitive neuroscience community, as this type of investigation constitutes a powerful tool for the understanding of normal rhythm processing. Because this field is in its infancy, it still lacks a common conceptual vocabulary to facilitate effective communication between different researchers and research groups. In this commentary, we provide a brief review of recent reports of RPD through the lens of one important empirical issue: the method by which beat perception is measured, and the consequences of method selection for the researcher's ability to specify which mechanisms are impaired in RPD. This critical reading advocates for the importance of matching measurement tools to the putative neurocognitive mechanisms under study, and reveals the need for effective and specific assessments of the different aspects of rhythm perception and synchronization. PMID- 26106288 TI - Breaking the millisecond barrier on SpiNNaker: implementing asynchronous event based plastic models with microsecond resolution. AB - Spike-based neuromorphic sensors such as retinas and cochleas, change the way in which the world is sampled. Instead of producing data sampled at a constant rate, these sensors output spikes that are asynchronous and event driven. The event based nature of neuromorphic sensors implies a complete paradigm shift in current perception algorithms toward those that emphasize the importance of precise timing. The spikes produced by these sensors usually have a time resolution in the order of microseconds. This high temporal resolution is a crucial factor in learning tasks. It is also widely used in the field of biological neural networks. Sound localization for instance relies on detecting time lags between the two ears which, in the barn owl, reaches a temporal resolution of 5 MUs. Current available neuromorphic computation platforms such as SpiNNaker often limit their users to a time resolution in the order of milliseconds that is not compatible with the asynchronous outputs of neuromorphic sensors. To overcome these limitations and allow for the exploration of new types of neuromorphic computing architectures, we introduce a novel software framework on the SpiNNaker platform. This framework allows for simulations of spiking networks and plasticity mechanisms using a completely asynchronous and event-based scheme running with a microsecond time resolution. Results on two example networks using this new implementation are presented. PMID- 26106289 TI - Reporter cell lines to evaluate the selectivity of chemicals for human and zebrafish estrogen and peroxysome proliferator activated gamma receptors. AB - Zebrafish is increasingly used as an animal model to study the effects of environmental nuclear receptors (NRs) ligands. As most of these compounds have only been tested on human NRs, it is necessary to measure their effects on zebrafish NRs. Estrogen receptors (ER) alpha and beta and peroxysome proliferator activated receptor (PPAR) gamma are main targets of environmental disrupting compounds (EDCs). In humans there are two distinct nuclear ERs (hERalpha and hERbeta), whereas the zebrafish genome encodes three ERs, zfERalpha, zfERbeta1, and zfERbeta2. Only one isoform of PPARgamma is expressed in both humans and zebrafish. In this review, we described reporter cell lines that we established to study the interaction of EDCs with human and zebrafish ERs and PPARgamma. Using these cell lines, we observed that zfERs are thermo-sensitive while zfPPARgamma is not. We also showed significant differences in the ability of environmental and synthetic ligands to modulate activation of zfERs and zfPPARgamma in comparison to hERs and hPPARgamma. Some environmental estrogens (bisphenol A, mycoestrogens) which are hER panagonists displayed greater potency for zfERalpha as compared to zfERbetas. hERbeta selective agonists (8betaVE2, DPN, phytoestrogens) also displayed zfERalpha selectivity. Among hERalpha selective synthetic agonists, 16alpha-LE2 was the most zfERalpha selective compound. Almost all zfPPARgamma environmental ligands (halogenated bisphenol A derivatives, phthalates, perfluorinated compounds) displayed similar affinity for human and zebrafish PPARgamma while pharmaceutical hPPARgamma agonists like thiazolidones are not recognized by zfPPARgamma. Altogether, our studies show that all hERs and hPPARgamma ligands do not control in a similar manner the transcriptional activity of zfERs and zfPPARgamma and point out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. PMID- 26106290 TI - Therapeutic potential of mGluR5 targeting in Alzheimer's disease. AB - Decades of research dedicated toward Alzheimer's disease (AD) has culminated in much of the current understanding of the neurodegeneration associated with disease. However, delineating the pathophysiology and finding a possible cure for the disease is still wanting. This is in part due to the lack of knowledge pertaining to the connecting link between neurodegenerative and neuroinflammatory pathways. Consequently, the inefficacy and ill-effects of the drugs currently available for AD encourage the need for alternative and safe therapeutic intervention. In this review we highlight the potential of mGluR5, a metabotropic glutamatergic receptor, in understanding the mechanism underlying the neuronal death and neuroinflammation in AD. We also discuss the role of mGlu5 receptor in mediating the neuron-glia interaction in the disease. Finally, we discuss the potential of mGluR5 as target for treating AD. PMID- 26106291 TI - Divalent metal transporter 1 (DMT1) in the brain: implications for a role in iron transport at the blood-brain barrier, and neuronal and glial pathology. AB - Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail. PMID- 26106292 TI - Wide-field Ca(2+) imaging reveals visually evoked activity in the retrosplenial area. AB - Due to recent advances of genetic manipulation, mouse brain has become a useful model for studying brain function, which demands whole brain functional mapping techniques in the mouse brain. In the present study, to finely map visual responsive areas in the mouse brain, we combined high-resolution wide-field optical imaging with transgenic mice containing the genetically encoded Ca(2+) indicator, GCaMP3. With the high signal amplitude of GCaMP3 expressing in excitatory neurons, this system allowed neural activity to be observed with relatively fine spatial resolution and cell-type specificity. To evaluate this system, we examined whether non-visual areas exhibited a visual response over the entire surface of the mouse hemisphere. We found that two association areas, the retrosplenial area (RS) and secondary motor/anterior cingulate area (M2/AC), were significantly responsive to drifting gratings. Examination using gratings with distinct spatiotemporal frequency parameters revealed that the RS strongly responded to high-spatial and low-temporal frequency gratings. The M2/AC exhibited a response property similar to that of the RS, though it was not statistically significant. Finally, we performed cellular imaging using two photon microscopy to examine orientation and direction selectivity of individual neurons, and found that a minority of neurons in the RS clearly showed visual responses sharply selective for orientation and direction. These results suggest that neurons in RS encode visual information of fine spatial details in images. Thus, the present study shows the usefulness of the functional mapping method using a combination of wide-field and two-photon Ca(2+) imaging, which allows for whole brain mapping with high spatiotemporal resolution and cell-type specificity. PMID- 26106293 TI - Age-dependent increase of brain copper levels and expressions of copper regulatory proteins in the subventricular zone and choroid plexus. AB - Our recent data suggest a high accumulation of copper (Cu) in the subventricular zone (SVZ) along the wall of brain ventricles. Anatomically, SVZ is in direct contact with cerebrospinal fluid (CSF), which is secreted by a neighboring tissue choroid plexus (CP). Changes in Cu regulatory gene expressions in the SVZ and CP as the function of aging may determine Cu levels in the CSF and SVZ. This study was designed to investigate the associations between age, Cu levels, and Cu regulatory genes in SVZ and plexus. The SVZ and CP were dissected from brains of 3-week, 10-week, or 9-month old male rats. Analyses by atomic absorption spectroscopy revealed that the SVZ of adult and old animals contained the highest Cu level compared with other tested brain regions. Significantly positive correlations between age and Cu levels in SVZ and plexus were observed; the SVZ Cu level of old animals was 7.5- and 5.8-fold higher than those of young and adult rats (p < 0.01), respectively. Quantitation by qPCR of the transcriptional expressions of Cu regulatory proteins showed that the SVZ expressed the highest level of Cu storage protein metallothioneins (MTs), while the CP expressed the high level of Cu transporter protein Ctr1. Noticeably, Cu levels in the SVZ were positively associated with type B slow proliferating cell marker Gfap (p < 0.05), but inversely associated with type A proliferating neuroblast marker Dcx (p < 0.05) and type C transit amplifying progenitor marker Nestin (p < 0.01). Dmt1 had significant positive correlations with age and Cu levels in the plexus (p < 0.01). These findings suggest that Cu levels in all tested brain regions are increased as the function of age. The SVZ shows a different expression pattern of Cu-regulatory genes from the CP. The age-related increase of MTs and decrease of Ctr1 may contribute to the high Cu level in this neurogenesis active brain region. PMID- 26106295 TI - Nitric oxide releases Cl(-) from acidic organelles in retinal amacrine cells. AB - Determining the factors regulating cytosolic Cl(-) in neurons is fundamental to our understanding of the function of GABA- and glycinergic synapses. This is because the Cl(-) distribution across the postsynaptic plasma membrane determines the sign and strength of postsynaptic voltage responses. We have previously demonstrated that nitric oxide (NO) releases Cl(-) into the cytosol from an internal compartment in both retinal amacrine cells and hippocampal neurons. Furthermore, we have shown that the increase in cytosolic Cl(-) is dependent upon a decrease in cytosolic pH. Here, our goals were to confirm the compartmental nature of the internal Cl(-) store and to test the hypothesis that Cl(-) is being released from acidic organelles (AO) such as the Golgi, endosomes or lysosomes. To achieve this, we made whole cell voltage clamp recordings from cultured chick retinal amacrine cells and used GABA-gated currents to track changes in cytosolic Cl(-). Our results demonstrate that intact internal proton gradients are required for the NO-dependent release of internal Cl(-). Furthermore, we demonstrate that increasing the pH of AO leads to release of Cl(-) into the cytosol. Intriguingly, the elevation of organellar pH results in a reversal in the effects of NO. These results demonstrate that cytosolic Cl(-) is closely linked to the regulation and maintenance of organellar pH and provide evidence that acidic compartments are the target of NO. PMID- 26106294 TI - Reactive oxygen species trigger motoneuron death in non-cell-autonomous models of ALS through activation of c-Abl signaling. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell-autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1(G93A) (ACM-hSOD1(G93A)) quickly enhances Nav channel mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1(G93A), but not ACM-hSOD1(WT), increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60 min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1(G93A)-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1(G86R) or TDP43(A315T). We further find that co-application of ACM-SOD1(G93A) with blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, or tiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1(G93A) induces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death. PMID- 26106296 TI - Facial stimulation induces long-term depression at cerebellar molecular layer interneuron-Purkinje cell synapses in vivo in mice. AB - Cerebellar long-term synaptic plasticity has been proposed to provide a cellular mechanism for motor learning. Numerous studies have demonstrated the induction and mechanisms of synaptic plasticity at parallel fiber-Purkinje cell (PF-PC), parallel fiber-molecular layer interneurons (PF-MLI) and mossy fiber-granule cell (MF-GC) synapses, but no study has investigated sensory stimulation-evoked synaptic plasticity at MLI-PC synapses in the cerebellar cortex of living animals. We studied the expression and mechanism of MLI-PC GABAergic synaptic plasticity induced by a train of facial stimulation in urethane-anesthetized mice by cell-attached recordings and pharmacological methods. We found that 1 Hz, but not a 2 Hz or 4 Hz, facial stimulation induced a long-term depression (LTD) of GABAergic transmission at MLI-PC synapses, which was accompanied with a decrease in the stimulation-evoked pause of spike firing in PCs, but did not induce a significant change in the properties of the sensory-evoked spike events of MLIs. The MLI-PC GABAergic LTD could be prevented by blocking cannabinoid type 1 (CB1) receptors, and could be pharmacologically induced by a CB1 receptor agonist. Additionally, 1 Hz facial stimulation delivered in the presence of a metabotropic glutamate receptor 1 (mGluR1) antagonist, JNJ16259685, still induced the MLI-PC GABAergic LTD, whereas blocking N-methyl-D-aspartate (NMDA) receptors during 1 Hz facial stimulation abolished the expression of MLI-PC GABAergic LTD. These results indicate that sensory stimulation can induce an endocannabinoid (eCB) dependent LTD of GABAergic transmission at MLI-PC synapses via activation of NMDA receptors in cerebellar cortical Crus II in vivo in mice. Our results suggest that the sensory stimulation-evoked MLI-PC GABAergic synaptic plasticity may play a critical role in motor learning in animals. PMID- 26106297 TI - Emerging roles of Axin in cerebral cortical development. AB - Proper functioning of the cerebral cortex depends on the appropriate production and positioning of neurons, establishment of axon-dendrite polarity, and formation of proper neuronal connectivity. Deficits in any of these processes greatly impair neural functions and are associated with various human neurodevelopmental disorders including microcephaly, cortical heterotopias, and autism. The application of in vivo manipulation techniques such as in utero electroporation has resulted in significant advances in our understanding of the cellular and molecular mechanisms that underlie neural development in vivo. Axin is a scaffold protein that regulates neuronal differentiation and morphogenesis in vitro. Recent studies provide novel insights into the emerging roles of Axin in gene expression and cytoskeletal regulation during neurogenesis, neuronal polarization, and axon formation. This review summarizes current knowledge on Axin as a key molecular controller of cerebral cortical development. PMID- 26106298 TI - Network-timing-dependent plasticity. AB - Bursts of activity in networks of neurons are thought to convey salient information and drive synaptic plasticity. Here we report that network bursts also exert a profound effect on Spike-Timing-Dependent Plasticity (STDP). In acute slices of juvenile rat somatosensory cortex we paired a network burst, which alone induced long-term depression (LTD), with STDP-induced long-term potentiation (LTP) and LTD. We observed that STDP-induced LTP was either unaffected, blocked or flipped into LTD by the network burst, and that STDP induced LTD was either saturated or flipped into LTP, depending on the relative timing of the network burst with respect to spike coincidences of the STDP event. We hypothesized that network bursts flip STDP-induced LTP to LTD by depleting resources needed for LTP and therefore developed a resource-dependent STDP learning rule. In a model neural network under the influence of the proposed resource-dependent STDP rule, we found that excitatory synaptic coupling was homeostatically regulated to produce power law distributed burst amplitudes reflecting self-organized criticality, a state that ensures optimal information coding. PMID- 26106299 TI - Deep brain stimulation of the subthalamic nucleus preferentially alters the translational profile of striatopallidal neurons in an animal model of Parkinson's disease. AB - Deep brain stimulation targeting the subthalamic nucleus (STN-DBS) is an effective surgical treatment for the motor symptoms of Parkinson's disease (PD), the precise neuronal mechanisms of which both at molecular and network levels remain a topic of debate. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively identify changes in translational gene expression in either Drd1a-expressing striatonigral or Drd2-expressing striatopallidal medium spiny neurons (MSNs) of the striatum following STN-DBS. 6 hydroxydopamine lesioned mice received either 5 days stimulation via a DBS electrode implanted in the ipsilateral STN or 5 days sham treatment (no stimulation). Striatal polyribosomal RNA was selectively purified from either Drd2 or Drd1a MSNs using the TRAP method and gene expression profiling performed. We identified eight significantly altered genes in Drd2 MSNs (Vps33b, Ppp1r3c, Mapk4, Sorcs2, Neto1, Abca1, Penk1, and Gapdh) and two overlapping genes in Drd1a MSNs (Penk1 and Ppp1r3c) implicated in the molecular mechanisms of STN-DBS. A detailed functional analysis, using a further 728 probes implicated in STN-DBS, suggested an increased ability to receive excitation (mediated by increased dendritic spines, increased calcium influx and enhanced excitatory post synaptic potentials) accompanied by processes that would hamper the initiation of action potentials, transport of neurotransmitters from soma to axon terminals and vesicular release in Drd2-expressing MSNs. Finally, changes in expression of several genes involved in apoptosis as well as cholesterol and fatty acid metabolism were also identified. This increased understanding of the molecular mechanisms induced by STN-DBS may reveal novel targets for future non-surgical therapies for PD. PMID- 26106300 TI - Response: "Commentary: Comparison of spike parameters from optically identified GABAergic and glutamatergic neurons in sparse cortical cultures". PMID- 26106301 TI - Functional response properties of VIP-expressing inhibitory neurons in mouse visual and auditory cortex. AB - Despite accounting for about 20% of all the layer 2/3 inhibitory interneurons, the vasoactive intestinal polypeptide (VIP) expressing neurons remain the least thoroughly studied of the major inhibitory subtypes. In recent studies, VIP neurons have been shown to be activated by a variety of cortico-cortical and neuromodulatory inputs, but their basic sensory response properties remain poorly characterized. We set out to explore the functional properties of layer 2/3 VIP neurons in the primary visual (V1) and primary auditory cortex (A1), using two photon imaging guided patch recordings. We found that in the V1, VIP neurons were generally broadly tuned, with their sensory response properties resembling those of parvalbumin (PV) expressing neurons. With the exception of response latency, they did not exhibit a significant difference from PV neurons across any of the properties tested, including overlap index, response modulation, orientation selectivity, and direction selectivity. In the A1, on the other hand, VIP neurons had a strong tendency to be intensity selective, which is a property associated with a subset of putative pyramidal cells and virtually absent in PV neurons. VIP neurons had a best intensity that was significantly lower than that of PV and putative pyramidal neurons. Finally, sensory evoked spike responses of VIP neurons were delayed relative to pyramidal and PV neurons in both the V1 and A1. Combined, these results demonstrate that the sensory response properties of VIP neurons do not fit a simple model of being either PV-like broadly tuned or pyramidal-like narrowly tuned. Instead, the selectivity pattern varies with sensory area and can even be, as in the case of low sound intensity responsiveness, distinct from both PV and pyramidal neurons. PMID- 26106302 TI - Phenotype overlap in glial cell populations: astroglia, oligodendroglia and NG 2(+) cells. AB - The extent to which NG-2(+) cells form a distinct population separate from astrocytes is central to understanding whether this important cell class is wholly an oligodendrocyte precursor cell (OPC) or has additional functions akin to those classically ascribed to astrocytes. Early immuno-staining studies indicate that NG-2(+) cells do not express the astrocyte marker GFAP, but orthogonal reconstructions of double-labeled confocal image stacks here reveal a significant degree of co-expression in individual cells within post-natal day 10 (P10) and adult rat optic nerve (RON) and rat cortex. Extensive scanning of various antibody/fixation/embedding approaches identified a protocol for selective post-embedded immuno-gold labeling. This first ultrastructural characterization of identified NG-2(+) cells revealed populations of both OPCs and astrocytes in P10 RON. NG-2(+) astrocytes had classic features including the presence of glial filaments but low levels of glial filament expression were also found in OPCs and myelinating oligodendrocytes. P0 RONs contained few OPCs but positively identified astrocytes were observed to ensheath pre-myelinated axons in a fashion previously described as a definitive marker of the oligodendrocyte lineage. Astrocyte ensheathment was also apparent in P10 RONs, was absent from developing nodes of Ranvier and was never associated with compact myelin. Astrocyte processes were also shown to encapsulate some oligodendrocyte somata. The data indicate that common criteria for delineating astrocytes and oligodendroglia are insufficiently robust and that astrocyte features ascribed to OPCs may arise from misidentification. PMID- 26106303 TI - Transient receptor potential cation channel subfamily V member 1 expressing corneal sensory neurons can be subdivided into at least three subpopulations. AB - The cornea is innervated by three main functional classes of sensory neurons: polymodal nociceptors, pure mechano-nociceptors and cold-sensing neurons. Here we explored transient receptor potential cation channel subfamily V member 1 (TRPV1) expression in guinea pig corneal sensory neurons, a widely used molecular marker of polymodal nociceptors. We used retrograde tracing to identify corneal afferent neurons in the trigeminal ganglion (TG) and double label in situ hybridization and/or immunohistochemistry to determine their molecular profile. In addition, we used immunohistochemistry to reveal the neurochemistry and structure of TRPV1 expressing nerve endings in the corneal epithelium. Approximately 45% of corneal afferent neurons expressed TRPV1, 28% expressed Piezo2 (a marker of putative pure mechano-nociceptors) and 8% expressed the transient receptor potential cation channel subfamily M member 8 (TRPM8; a marker of cold-sensing neurons). There was no co-expression of TRPV1 and Piezo2 in corneal afferent neurons, but 6% of TRPV1 neurons co-expressed TRPM8. The TRPV1 expressing corneal afferent neurons could be divided into three subpopulations on the basis of calcitonin gene-related peptide (CGRP) and/or or glial cell line-derived neurotrophic factor family receptor alpha3 (GFRalpha3) co-expression. In the corneal epithelium, the TRPV1 axons that co-expressed CGRP and GFRalpha3 ended as simple unbranched endings in the wing cell layer. In contrast, those that only co-expressed GFRalpha3 had ramifying endings that branched and terminated in the squamous cell layer, whereas those that only co-expressed CGRP had simple endings in the basal epithelium. This study shows that the majority of TRPV1 expressing corneal afferent neurons (>90%) are likely to be polymodal nociceptors. Furthermore, TRPV1 expressing corneal afferent neurons can be subdivided into specific subpopulations based on their molecular phenotype, nerve terminal morphology and distribution in the corneal epithelium. PMID- 26106305 TI - Response: New neurons from old beliefs in the adult piriform cortex? A Commentary on: "Occurrence of new neurons in the piriform cortex". PMID- 26106304 TI - Unraveling the multiscale structural organization and connectivity of the human brain: the role of diffusion MRI. AB - The structural architecture and the anatomical connectivity of the human brain show different organizational principles at distinct spatial scales. Histological staining and light microscopy techniques have been widely used in classical neuroanatomical studies to unravel brain organization. Using such techniques is a laborious task performed on 2-dimensional histological sections by skilled anatomists possibly aided by semi-automated algorithms. With the recent advent of modern magnetic resonance imaging (MRI) contrast mechanisms, cortical layers and columns can now be reliably identified and their structural properties quantified post-mortem. These developments are allowing the investigation of neuroanatomical features of the brain at a spatial resolution that could be interfaced with that of histology. Diffusion MRI and tractography techniques, in particular, have been used to probe the architecture of both white and gray matter in three dimensions. Combined with mathematical network analysis, these techniques are increasingly influential in the investigation of the macro-, meso-, and microscopic organization of brain connectivity and anatomy, both in vivo and ex vivo. Diffusion MRI-based techniques in combination with histology approaches can therefore support the endeavor of creating multimodal atlases that take into account the different spatial scales or levels on which the brain is organized. The aim of this review is to illustrate and discuss the structural architecture and the anatomical connectivity of the human brain at different spatial scales and how recently developed diffusion MRI techniques can help investigate these. PMID- 26106306 TI - 7-Tesla MRI demonstrates absence of structural lesions in patients with vestibular paroxysmia. AB - Vestibular parxoysmia (VP) is a rare vestibular disorder. A neurovascular cross compression (NVCC) between the vestibulochochlear nerve and an artery seems to be responsible for short attacks of vertigo in this entity. An NVCC can be seen in up to every fourth subject. The significance of these findings is not clear, as not all subjects suffer from symptoms. The aim of the present study was to assess possible structural lesions of the vestibulocochlear nerve by means of high field magnetic resonance imaging (MRI), and whether high field MRI may help to differentiate symptomatic from asymptomatic subjects. 7 Tesla MRI was performed in six patients with VP and confirmed NVCC seen on 1.5 and 3.0 MRI. No structural abnormalities were detected in any of the patients in 7 Tesla MRI. These findings imply that high field MRI does not help to differentiate between symptomatic and asymptomatic NVCC and that the symptoms of VP are not caused by structural nerve lesions. This supports the hypothesis that the nystagmus associated with VP has to be conceived pathophysiologically as an excitatory vestibular phenomenon, being not related to vestibular hypofunction. 7 Tesla MRI outperforms conventional MRI in image resolution and may be useful in vestibular disorders. PMID- 26106307 TI - Cortical signature of patients with HBV-related cirrhosis without overt hepatic encephalopathy: a morphometric analysis. AB - Previous studies have shown that patients with hepatitis B virus-related cirrhosis (HBV-RC) without overt hepatic encephalopathy (OHE) are associated with a varying degree of cognitive dysfunction. Several resting-state functional magnetic resonance imaging (fMRI) studies have been conducted to explore the neural correlates of such cognitive deficits, whereas little effort has been made to investigate the cortical integrity in cirrhotic patients without OHE. Here, using cortical thickness, surface area and local gyrification index (lGI), this study performed a comprehensive analysis on the cortical morphometry of patients with HBV-RC without OHE (HBV-RC-NOHE) vs. matched healthy controls. Compared with healthy controls, we found significantly increased cortical thickness in the bilateral lingual and parahippocampal gyrus, right posterior cingulate cortex, precuneus, peri-calcarine sulcus and fusiform gyrus in patient with HBV-RC-NOHE, which may closely relate to be the low-grade brain edema. Cortical gyrification analysis showed significantly increased lGI in the left superior and inferior parietal cortex as well as lateral occipital cortex, which was speculated to be associated with disruptions in white matter connectivity and sub-optimal intra cortical organization. In addition, the mean cortical thickness/lGI of the regions with structural abnormalities was shown to be negatively correlated with psychometric hepatic encephalopathy score (PHES) of the patients with HBV-RC NOHE. These morphological changes may serve as potential markers for the preclinical diagnosis and progression of HBV-RC-NOHE. PMID- 26106308 TI - Pre-adaptation to noisy Galvanic vestibular stimulation is associated with enhanced sensorimotor performance in novel vestibular environments. AB - Performance on a visuomotor task in the presence of novel vestibular stimulation was assessed in nine healthy subjects. Four subjects had previously been adapted to 120 min exposure to noisy Galvanic vestibular stimulation (GVS) over 12 weekly sessions of 10 min; the remaining five subjects had never experienced GVS. Subjects were seated in a flight simulator and asked to null the roll motion of a visual bar presented on a screen using a joystick. Both the visual bar and the simulator cabin were moving in roll with a pseudorandom (sum of sines) waveform that were uncorrelated. The cross correlation coefficient, which ranges from 1 (identical waveforms) to 0 (unrelated waveforms), was calculated for the ideal (perfect nulling of bar motion) and actual joystick input waveform for each subject. The cross correlation coefficient for the GVS-adapted group (0.90 [SD 0.04]) was significantly higher (t[8] = 3.162; p = 0.013) than the control group (0.82 [SD 0.04]), suggesting that prior adaptation to GVS was associated with an enhanced ability to perform the visuomotor task in the presence of novel vestibular noise. PMID- 26106309 TI - fMRI neurofeedback facilitates anxiety regulation in females with spider phobia. AB - BACKGROUND: Spider phobics show an exaggerated fear response when encountering spiders. This fear response is aggravated by negative and irrational beliefs about the feared object. Cognitive reappraisal can target these beliefs, and therefore has a fear regulating effect. The presented study investigated if neurofeedback derived from functional magnetic resonance imaging (fMRI) would facilitate anxiety regulation by cognitive reappraisal, using spider phobia as a model of anxiety disorders. Feedback was provided based on activation in left dorsolateral prefrontal cortex and right insula, as indicators of engagement and regulation success, respectively. METHODS: Eighteen female spider phobics participated in a randomized, controlled, single-blinded study. All participants completed a training session in the MRI scanner. Participants assigned to the neurofeedback condition were instructed to shape their regulatory strategy based on the provided feedback. Participants assigned to the control condition were asked to adapt their strategy intuitively. RESULTS: Neurofeedback participants exhibited lower anxiety levels than the control group at the end of the training. In addition, only neurofeedback participants achieved down-regulation of insula activation levels by cognitive reappraisal. Group differences became more pronounced over time, supporting learning as a mechanism behind this effect. Importantly, within the neurofeedback group, achieved changes in insula activation levels during training predicted long-term anxiety reduction. CONCLUSIONS: The conducted study provides first evidence that fMRI neurofeedback has a facilitating effect on anxiety regulation in spider phobia. PMID- 26106310 TI - Dscam2 affects visual perception in Drosophila melanogaster. AB - Dscam2, a cell surface protein that mediates cellular repulsion, plays a crucial role in the development of the Drosophila melanogaster visual system. Dscam2 generates boundaries between neighboring modules in the fly optic lobe; in Dscam2 mutants this visual system modularity is compromised. Although developmental wiring defects have been well described in the Dscam2 mutant, behavioral consequences have not been investigated. To address this, we examined the visual behavior of Dscam2 mutant flies. Using a phototaxis assay, we ascertained that these flies are not blind, but have a reduced phototaxic response. Through population-based and single fly optomotor assays, we found that Dscam2 mutant flies can track motion but that their response is opposite to control flies under defined experimental conditions. In a fixation paradigm, which allows tethered flies to control the angular position of a visual stimulus, mutant flies' responses were diametrically opposed to those seen in control flies. These data suggest that modest changes in the modularity of the fly visual system in the Dscam2 mutant can dramatically change the perception of specific visual cues and modify behavior. PMID- 26106311 TI - Threat affects risk preferences in movement decision making. AB - Emotional states such as sadness, anger, and threat have been shown to play a critical role in decision-making processes. Here we addressed the question of whether risk preferences are influenced by postural threat and whether this influence generalizes across motor tasks. We examined risk attitudes in the context of arm-reaching (ARM) and whole-body (WB) leaning movements, expecting that increased postural threat would lead to proportionally similar changes in risk-sensitivity for each motor task. Healthy young adults were shown a series of two-alternative forced-choice lotteries, where they were asked to choose between a riskier lottery and a safer lottery on each trial. Our lotteries consisted of different monetary rewards and target sizes. Subjects performed each choice task at ground level and atop an elevated platform. In the presence of this postural threat, increased physiological arousal was correlated with decreased movement variability. To determine risk-sensitivity, we quantified the frequency with which a subject chose the riskier lottery and fit lottery responses to a choice model based on cumulative prospect theory (CPT). Subjects exhibited idiosyncratic changes in risk-sensitivity between motor tasks and between elevations. However, we found that overweighting of small probabilities increased with postural threat in the WB task, indicating a more cautious, risk-averse strategy is ascribed to the possibility of a fall. Subjects were also more risk-seeking in the WB movements than in ARM at low elevation; this behavior does not seem to derive from consistent distortions in utility or probability representations but may be explained by subjects' inaccurate estimation of their own motor variability. Overall, our findings suggest that implicit threat can modify risk attitudes in the motor domain, and the threat may induce risk-aversion in salient movement tasks. PMID- 26106312 TI - Artworks as dichotomous objects: implications for the scientific study of aesthetic experience. AB - This paper addresses an issue that has been studied from both scientific and art theoretical perspectives, namely the dichotomous nature of representational artworks. Representational artworks are dichotomous in that they present us with two distinct aspects at once. In one aspect we are aware of what is represented while in the other we are aware of the material from which the representation is composed. The dichotomy arises due the incompatibility, indeed contradiction, between these aspects of awareness, both of which must be present if we are to fully appreciate the artwork. Examples from art history are given to show how artists have exploited this dichotomy in a way that conditions our response to their work. I hypothesize that the degree of manifest dichotomy in a work determines the strength of its aesthetic effect, and propose this could be experimentally tested. I conclude that scientific studies of aesthetic experience should take the dichotomous nature of artworks into account. PMID- 26106313 TI - Differences in gaze anticipation for locomotion with and without vision. AB - Previous experimental studies have shown a spontaneous anticipation of locomotor trajectory by the head and gaze direction during human locomotion. This anticipatory behavior could serve several functions: an optimal selection of visual information, for instance through landmarks and optic flow, as well as trajectory planning and motor control. This would imply that anticipation remains in darkness but with different characteristics. We asked 10 participants to walk along two predefined complex trajectories (limacon and figure eight) without any cue on the trajectory to follow. Two visual conditions were used: (i) in light and (ii) in complete darkness with eyes open. The whole body kinematics were recorded by motion capture, along with the participant's right eye movements. We showed that in darkness and in light, horizontal gaze anticipates the orientation of the head which itself anticipates the trajectory direction. However, the horizontal angular anticipation decreases by a half in darkness for both gaze and head. In both visual conditions we observed an eye nystagmus with similar properties (frequency and amplitude). The main difference comes from the fact that in light, there is a shift of the orientations of the eye nystagmus and the head in the direction of the trajectory. These results suggest that a fundamental function of gaze is to represent self motion, stabilize the perception of space during locomotion, and to simulate the future trajectory, regardless of the vision condition. PMID- 26106314 TI - Changes in task-based effective connectivity in language networks following rehabilitation in post-stroke patients with aphasia. AB - In this study, we examined regions in the left and right hemisphere language network that were altered in terms of the underlying neural activation and effective connectivity subsequent to language rehabilitation. Eight persons with chronic post-stroke aphasia and eight normal controls participated in the current study. Patients received a 10 week semantic feature-based rehabilitation program to improve their skills. Therapy was provided on atypical examples of one trained category while two control categories were monitored; the categories were counterbalanced across patients. In each fMRI session, two experimental tasks were conducted: (a) picture naming and (b) semantic feature verification of trained and untrained categories. Analysis of treatment effect sizes revealed that all patients showed greater improvements on the trained category relative to untrained categories. Results from this study show remarkable patterns of consistency despite the inherent variability in lesion size and activation patterns across patients. Across patients, activation that emerged as a function of rehabilitation on the trained category included bilateral IFG, bilateral SFG, LMFG, and LPCG for picture naming; and bilateral IFG, bilateral MFG, LSFG, and bilateral MTG for semantic feature verification. Analysis of effective connectivity using Dynamic Causal Modeling (DCM) indicated that LIFG was the consistently significantly modulated region after rehabilitation across participants. These results indicate that language networks in patients with aphasia resemble normal language control networks and that this similarity is accentuated by rehabilitation. PMID- 26106315 TI - Accurately decoding visual information from fMRI data obtained in a realistic virtual environment. AB - Three-dimensional interactive virtual environments (VEs) are a powerful tool for brain-imaging based cognitive neuroscience that are presently under-utilized. This paper presents machine-learning based methods for identifying brain states induced by realistic VEs with improved accuracy as well as the capability for mapping their spatial topography on the neocortex. VEs provide the ability to study the brain under conditions closer to the environment in which humans evolved, and thus to probe deeper into the complexities of human cognition. As a test case, we designed a stimulus to reflect a military combat situation in the Middle East, motivated by the potential of using real-time functional magnetic resonance imaging (fMRI) in the treatment of post-traumatic stress disorder. Each subject experienced moving through the virtual town where they encountered 1-6 animated combatants at different locations, while fMRI data was collected. To analyze the data from what is, compared to most studies, more complex and less controlled stimuli, we employed statistical machine learning in the form of Multi Voxel Pattern Analysis (MVPA) with special attention given to artificial Neural Networks (NN). Extensions to NN that exploit the block structure of the stimulus were developed to improve the accuracy of the classification, achieving performances from 58 to 93% (chance was 16.7%) with six subjects. This demonstrates that MVPA can decode a complex cognitive state, viewing a number of characters, in a dynamic virtual environment. To better understand the source of this information in the brain, a novel form of sensitivity analysis was developed to use NN to quantify the degree to which each voxel contributed to classification. Compared with maps produced by general linear models and the searchlight approach, these sensitivity maps revealed a more diverse pattern of information relevant to the classification of cognitive state. PMID- 26106316 TI - Tai Chi Training may Reduce Dual Task Gait Variability, a Potential Mediator of Fall Risk, in Healthy Older Adults: Cross-Sectional and Randomized Trial Studies. AB - BACKGROUND: Tai Chi (TC) exercise improves balance and reduces falls in older, health-impaired adults. TC's impact on dual task (DT) gait parameters predictive of falls, especially in healthy active older adults, however, is unknown. PURPOSE: To compare differences in usual and DT gait between long-term TC-expert practitioners and age-/gender-matched TC-naive adults, and to determine the effects of short-term TC training on gait in healthy, non-sedentary older adults. METHODS: A cross-sectional study compared gait in healthy TC-naive and TC-expert (24.5 +/- 12 years experience) older adults. TC-naive adults then completed a 6 month, two-arm, wait-list randomized clinical trial of TC training. Gait speed and stride time variability (Coefficient of Variation %) were assessed during 90 s trials of undisturbed and cognitive DT (serial subtractions) conditions. RESULTS: During DT, gait speed decreased (p < 0.003) and stride time variability increased (p < 0.004) in all groups. Cross-sectional comparisons indicated that stride time variability was lower in the TC-expert vs. TC-naive group, significantly so during DT (2.11 vs. 2.55%; p = 0.027); by contrast, gait speed during both undisturbed and DT conditions did not differ between groups. Longitudinal analyses of TC-naive adults randomized to 6 months of TC training or usual care identified improvement in DT gait speed in both groups. A small improvement in DT stride time variability (effect size = 0.2) was estimated with TC training, but no significant differences between groups were observed. Potentially important improvements after TC training could not be excluded in this small study. CONCLUSION: In healthy active older adults, positive effects of short- and long-term TC were observed only under cognitively challenging DT conditions and only for stride time variability. DT stride time variability offers a potentially sensitive metric for monitoring TC's impact on fall risk with healthy older adults. PMID- 26106317 TI - Time-based prospective memory functioning in mild cognitive impairment associated with Parkinson's disease: relationship with autonomous management of daily living commitments. AB - OBJECTIVE: Prospective memory (PM), that is, the ability to keep in memory and carry out intentions in the future, is reported to be impaired in individuals with Parkinson's disease (PD). PM failure may be also associated with reduced daily living functioning in these patients. Little is known, however, about the relationship between mild cognitive impairment (MCI) and time-based PM functioning in PD patients and the possible impact of PM deficits on patients' autonomy in daily living. Here we aimed to investigate whether MCI associated with PD affects time-based PM. We also wished to determine whether PM impairment accounts for reduced autonomous management of medication in these patients. METHOD: The study included 48 PD patients with MCI, 33 PD patients without cognitive disorders (PDN) and 20 healthy controls. The time-based PM procedure required that subjects perform an action after a fixed time. The PM procedure was incorporated in the standard neuropsychological assessment. One score was computed for the ability to retrieve the intention (prospective component) and one for remembering the action to be executed (retrospective component). The Pill Questionnaire was administered to assess the ability to manage medication. RESULTS: PD patients with MCI performed less accurately in the PM procedure than HC and tended to perform poorer than PDN. Moreover, in PD patients with MCI, accuracy on the prospective component of the PM task and performance on the Modified Card Sorting Test significantly predicted the ability to manage medication. CONCLUSIONS: RESULTS document that reduced efficiency of time-based PM processes in PD is specifically related to the presence of MCI. The same data indicate that PM weakness may be associated with impaired daily living functioning and decreased autonomy. PMID- 26106318 TI - Facing Challenges in Differential Classical Conditioning Research: Benefits of a Hybrid Design for Simultaneous Electrodermal and Electroencephalographic Recording. AB - Several challenges make it difficult to simultaneously investigate central and autonomous nervous system correlates of conditioned stimulus (CS) processing in classical conditioning paradigms. Such challenges include, for example, the discrepant requirements of electroencephalography (EEG) and electrodermal activity (EDA) recordings with regard to multiple repetitions of conditions and sufficient trial duration. Here, we propose a MultiCS conditioning set-up, in which we increased the number of CSs, decreased the number of learning trials, and used trials of short and long durations for meeting requirements of simultaneous EEG-EDA recording in a differential aversive conditioning task. Forty-eight participants underwent MultiCS conditioning, in which four neutral faces (CS+) were paired four times each with aversive electric stimulation (unconditioned stimulus) during acquisition, while four different neutral faces (CS-) remained unpaired. When comparing after relative to before learning measurements, EEG revealed an enhanced centro-posterior positivity to CS+ vs. CS- during 368-600 ms, and subjective ratings indicated CS+ to be less pleasant and more arousing than CS-. Furthermore, changes in CS valence and arousal were strong enough to bias subjective ratings when faces of CS+/CS- identity were displayed with different emotional expression (happy, angry) in a post experimental behavioral task. In contrast to a persistent neural and evaluative CS+/CS- differentiation that sustained multiple unreinforced CS presentations, electrodermal differentiation was rapidly extinguished. Current results suggest that MultiCS conditioning provides a promising paradigm for investigating pre post-learning changes under minimal influences of extinction and overlearning of simple stimulus features. Our data also revealed methodological pitfalls, such as the possibility of occurring artifacts when combining different acquisition systems for central and peripheral psychophysiological measures. PMID- 26106319 TI - Commentary: Viewing photos and reading nouns of natural graspable objects similarly modulate motor responses. PMID- 26106321 TI - Boundaries and potentials of traditional and alternative neuroscience research methods in music therapy research. PMID- 26106320 TI - Retinotopic patterns of background connectivity between V1 and fronto-parietal cortex are modulated by task demands. AB - Attention facilitates the processing of task-relevant visual information and suppresses interference from task-irrelevant information. Modulations of neural activity in visual cortex depend on attention, and likely result from signals originating in fronto-parietal and cingulo-opercular regions of cortex. Here, we tested the hypothesis that attentional facilitation of visual processing is accomplished in part by changes in how brain networks involved in attentional control interact with sectors of V1 that represent different retinal eccentricities. We measured the strength of background connectivity between fronto-parietal and cingulo-opercular regions with different eccentricity sectors in V1 using functional MRI data that were collected while participants performed tasks involving attention to either a centrally presented visual stimulus or a simultaneously presented auditory stimulus. We found that when the visual stimulus was attended, background connectivity between V1 and the left frontal eye fields (FEF), left intraparietal sulcus (IPS), and right IPS varied strongly across different eccentricity sectors in V1 so that foveal sectors were more strongly connected than peripheral sectors. This retinotopic gradient was weaker when the visual stimulus was ignored, indicating that it was driven by attentional effects. Greater task-driven differences between foveal and peripheral sectors in background connectivity to these regions were associated with better performance on the visual task and faster response times on correct trials. These findings are consistent with the notion that attention drives the configuration of task-specific functional pathways that enable the prioritized processing of task-relevant visual information, and show that the prioritization of visual information by attentional processes may be encoded in the retinotopic gradient of connectivty between V1 and fronto-parietal regions. PMID- 26106322 TI - On the distinguishability of HRF models in fMRI. AB - Modeling the Hemodynamic Response Function (HRF) is a critical step in fMRI studies of brain activity, and it is often desirable to estimate HRF parameters with physiological interpretability. A biophysically informed model of the HRF can be described by a non-linear time-invariant dynamic system. However, the identification of this dynamic system may leave much uncertainty on the exact values of the parameters. Moreover, the high noise levels in the data may hinder the model estimation task. In this context, the estimation of the HRF may be seen as a problem of model falsification or invalidation, where we are interested in distinguishing among a set of eligible models of dynamic systems. Here, we propose a systematic tool to determine the distinguishability among a set of physiologically plausible HRF models. The concept of absolutely input distinguishable systems is introduced and applied to a biophysically informed HRF model, by exploiting the structure of the underlying non-linear dynamic system. A strategy to model uncertainty in the input time-delay and magnitude is developed and its impact on the distinguishability of two physiologically plausible HRF models is assessed, in terms of the maximum noise amplitude above which it is not possible to guarantee the falsification of one model in relation to another. Finally, a methodology is proposed for the choice of the input sequence, or experimental paradigm, that maximizes the distinguishability of the HRF models under investigation. The proposed approach may be used to evaluate the performance of HRF model estimation techniques from fMRI data. PMID- 26106323 TI - Self-organizing neural integration of pose-motion features for human action recognition. AB - The visual recognition of complex, articulated human movements is fundamental for a wide range of artificial systems oriented toward human-robot communication, action classification, and action-driven perception. These challenging tasks may generally involve the processing of a huge amount of visual information and learning-based mechanisms for generalizing a set of training actions and classifying new samples. To operate in natural environments, a crucial property is the efficient and robust recognition of actions, also under noisy conditions caused by, for instance, systematic sensor errors and temporarily occluded persons. Studies of the mammalian visual system and its outperforming ability to process biological motion information suggest separate neural pathways for the distinct processing of pose and motion features at multiple levels and the subsequent integration of these visual cues for action perception. We present a neurobiologically-motivated approach to achieve noise-tolerant action recognition in real time. Our model consists of self-organizing Growing When Required (GWR) networks that obtain progressively generalized representations of sensory inputs and learn inherent spatio-temporal dependencies. During the training, the GWR networks dynamically change their topological structure to better match the input space. We first extract pose and motion features from video sequences and then cluster actions in terms of prototypical pose-motion trajectories. Multi-cue trajectories from matching action frames are subsequently combined to provide action dynamics in the joint feature space. Reported experiments show that our approach outperforms previous results on a dataset of full-body actions captured with a depth sensor, and ranks among the best results for a public benchmark of domestic daily actions. PMID- 26106324 TI - The Role of Information and Communication Technologies in Clinical Trials with Patients with Alzheimer's Disease and Related Disorders. PMID- 26106325 TI - Non-monotonic reorganization of brain networks with Alzheimer's disease progression. AB - BACKGROUND: Identification of stage-specific changes in brain network of patients with Alzheimer's disease (AD) is critical for rationally designed therapeutics that delays the progression of the disease. However, pathological neural processes and their resulting changes in brain network topology with disease progression are not clearly known. METHODS: The current study was designed to investigate the alterations in network topology of resting state fMRI among patients in three different clinical dementia rating (CDR) groups (i.e., CDR = 0.5, 1, 2) and amnestic mild cognitive impairment (aMCI) and age-matched healthy subject groups. We constructed density networks from these 5 groups and analyzed their network properties using graph theoretical measures. RESULTS: The topological properties of AD brain networks differed in a non-monotonic, stage specific manner. Interestingly, local and global efficiency and betweenness of the network were rather higher in the aMCI and AD (CDR 1) groups than those of prior stage groups. The number, location, and structure of rich-clubs changed dynamically as the disease progressed. CONCLUSIONS: The alterations in network topology of the brain are quite dynamic with AD progression, and these dynamic changes in network patterns should be considered meticulously for efficient therapeutic interventions of AD. PMID- 26106327 TI - Age-related hearing impairment and frailty in Alzheimer's disease: interconnected associations and mechanisms. PMID- 26106326 TI - Biomarkers of postoperative delirium and cognitive dysfunction. AB - Elderly surgical patients frequently experience postoperative delirium (POD) and the subsequent development of postoperative cognitive dysfunction (POCD). Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers. PMID- 26106329 TI - Modeling transportation of efavirenz: inference on possibility of mixed modes of transportation and kinetic solubility. AB - Understanding drug transportation mechanisms in the human body is of paramount importance in modeling Pharmacokinetic-Pharmacodynamic relationships. This work gives a novel general model of efavirenz transportation projections based on concentrations simulated from patients on a dose of 600 mg. The work puts forward a proposition that transportation can wholly be modeled by concentration and time in a uniform volumetric space. Furthermore, movement entities are used to inform the state of "kinetic solubility" of a solution. There is use of Ricker's model, and forms of the Hill's equation in modeling transportation. Characterization on the movement rates of solution particle are suggested in relation to advection rate of solution particle. At turning points on the transportation rate of solution particle vs. concentration curve, a suggestion of possibly change of dominance in the mode of transportation and saturation is made. There are four movement rates postulated at primary micro-level transportation, that are attributed to convection, diffusion [passive transportation (EI )] and energy dependent system transportation (ED ) in relation to advection. Furthermore, a new parameter is introduced which is defined as an advection rate constant of solution particle. It is postulated to be dependent on two rate constants of solution particle, that is a convection rate constant of solution particle and a saturable transportation rate constant of solution particle. At secondary micro level transportation, the results show convection as sum of advection and saturable transportation. The kinetics of dissolution of efavirenz in the solution space is postulated. Relatively, a good level of kinetics of dissolution is projected in the concentration region 0 - 32.82 MUg/ml. PMID- 26106331 TI - Semantic processing of English sentences using statistical computation based on neurophysiological models. AB - Computer programs that can accurately interpret natural human language and carry out instructions would improve the lives of people with language processing deficits and greatly benefit society in general. von Neumann in theorized that the human brain utilizes its own unique statistical neuronal computation to decode language and that this produces specific patterns of neuronal activity. This paper extends von Neumann's theory to the processing of partial semantics of declarative sentences. I developed semantic neuronal network models that emulate key features of cortical language processing and accurately compute partial semantics of English sentences. The method of computation implements the MAYA Semantic Technique, a mathematical technique I previously developed to determine partial semantics of sentences within a natural language processing program. Here I further simplified the technique by grouping repeating patterns into fewer categories. Unlike other natural language programs, my approach computes three partial semantics. The results of this research show that the computation of partial semantics of a sentence uses both feedforward and feedback projection which suggest that the partial semantic presented in this research might be a conscious activity within the human brain. PMID- 26106330 TI - Gender differences in pharmacokinetics and pharmacodynamics of methadone substitution therapy. AB - Gender-related differences in the pharmacological effects of drug are an emerging topic. This review examines gender differences in both pharmacokinetic and pharmacodynamic aspects of methadone, a long-acting opioid agonist that is prescribed as a treatment for opioid dependence and the management of chronic pain. METHOD: We performed a search in the Medline database from 1990 to 2014 in order to find published literature related to gender differences in pharmacokinetics (PK) and pharmacodynamics (PD) of methadone. RESULTS: None of the studies were carried out with the primary or secondary aim to identify any gender differences in the pharmacokinetic profile of methadone. Importantly; high inter-subjects variability in PK parameters was found also intra female population. The reported differences in volume of distribution could be ascribed to the physiological differences between men and women in body weight and composition, taking into account that the dose of methadone was established irrespective of body weight of patients (Peles and Adelson, 2006). On the other hand, the few studies present in literature found no gender difference in some direct pharmacodynamic parameters. Some reports have suggested that female gender is associated with an increased risk for long-QT-related cardiac arrhythmias in methadone maintenance subjects. CONCLUSION: Even though it may be too simplistic to expect variability only in one parameter to explain inter-individual variation in methadone response, we believe that a better knowledge of gender-related differences might have significant implications for better outcomes in opioid dependence substitution therapy in women. PMID- 26106328 TI - Mesothelial cells in tissue repair and fibrosis. AB - Mesothelial cells are fundamental to the maintenance of serosal integrity and homeostasis and play a critical role in normal serosal repair following injury. However, when normal repair mechanisms breakdown, mesothelial cells take on a profibrotic role, secreting inflammatory, and profibrotic mediators, differentiating and migrating into the injured tissues where they contribute to fibrogenesis. The development of new molecular and cell tracking techniques has made it possible to examine the origin of fibrotic cells within damaged tissues and to elucidate the roles they play in inflammation and fibrosis. In addition to secreting proinflammatory mediators and contributing to both coagulation and fibrinolysis, mesothelial cells undergo mesothelial-to-mesenchymal transition, a process analogous to epithelial-to-mesenchymal transition, and become fibrogenic cells. Fibrogenic mesothelial cells have now been identified in tissues where they have not previously been thought to occur, such as within the parenchyma of the fibrotic lung. These findings show a direct role for mesothelial cells in fibrogenesis and open therapeutic strategies to prevent or reverse the fibrotic process. PMID- 26106332 TI - Angiotensin II inhibitor facilitates epidermal wound regeneration in diabetic mice. AB - Tissue regeneration and wound healing are severely impaired in diabetes and are associated with poor circulation and dysfunctional blood vessels. Angiotensin II inhibitors are anti-hypertensive drugs used in clinical practice to regulate blood pressure and could affect tissue remodeling. We hypothesize that blocking angiotensin II, using Losartan, could facilitate tissue regeneration in diabetic mice. To this end, we established an experimental model of wound healing in streptozotocin-induced diabetic mice. Our data demonstrated that Losartan accelerates wound repair and normalizes wound stromal responses, having a beneficial role in wounds of diabetic individuals. Our findings highlight a potential therapeutic use of Losartan in improving wound repair in diabetic conditions. PMID- 26106333 TI - Antenatal maternal hypoxia: criterion for fetal growth restriction in rodents. AB - Rodents are a useful model for life science research. Accumulating evidence suggests that the offspring of mice and rats suffer from similar disorders as humans when exposed to hypoxia during pregnancy. Importantly, with antenatal hypoxic exposure, human neonates demonstrate low birth weight or growth restriction. Similarly, with antenatal hypoxic exposure rodents also demonstrate the fetal growth restriction (FGR). Surprisingly, there is no consensus on the minimum duration or degree of hypoxic exposure required to cause FGR in rodents. Thus, we have reviewed the available literature in an attempt to answer these questions. Based on studies in rats, birth weight reduction of 31% corresponded to 10th percentile reduction in birth weight curve. With the similar criterion (10th percentile), in mice 3 days or more and in rats 7 days or more of 14% or lower hypoxia administration was required to produce statistically significant FGR. PMID- 26106334 TI - Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels. AB - Cyclic nucleotide gated (CNG) channels are a critical component of the visual transduction cascade in the vertebrate retina. Mutations in the genes encoding these channels have been associated with a spectrum of inherited retinal disorders. To gain insight into their pathophysiological mechanisms, we have investigated the functional consequences of several CNGB3 mutations, previously associated with macular degeneration (Y469D and L595F) or complete achromatopsia (S156F, P309L, and G558C), by expressing these subunits in combination with wild type CNGA3 in Xenopus oocytes and characterizing them using patch-clamp recordings in the inside-out configuration. These mutations did not prevent the formation of functional heteromeric channels, as indicated by sensitivity to block by L-cis-diltiazem. With the exception of S156F, each of the mutant channels displayed electrophysiological properties reflecting enhanced channel activity at physiological concentrations of cGMP (i.e., a gain-of-function phenotype). The increased channel activity produced by these mutations resulted from either increased functional expression levels, or increased sensitivity to cyclic nucleotides. Furthermore, L595F increased the spontaneous open probability in the absence of activating ligand, signifying a ligand independent gain-of function change. In addition to the CNGB3 disease-associate mutations, we characterized the effects of several common CNGB3 and CNGA3 single-nucleotide polymorphisms (SNPs) on heteromeric CNGA3+CNGB3 channel function. Two of the SNPs examined (A3-T153M, and B3-W234C) produced decreased ligand sensitivity for heteromeric CNG channels. These changes may contribute to background disease susceptibility when combined with other genetic or non-genetic factors. Together, these studies help to define the underlying molecular phenotype for mutations relating to CNG channel disease pathogenesis. PMID- 26106336 TI - A Commentary on "A New Initiative on Precision Medicine". PMID- 26106335 TI - The Detrimental Impact of Maladaptive Personality on Public Mental Health: A Challenge for Psychiatric Practice. AB - Experts in personality psychology and personality disorders have long emphasized the pervasive and persistent detrimental impact of maladaptive personality traits on mental health and functioning. However, in routine psychiatric practice, maladaptive personality is readily ignored and personality traits are seldom incorporated into clinical guidelines. The aim of this narrative review is to outline how pervasively personality influences public mental health and how personality thereby challenges common psychiatric practice. A comprehensive search and synthesis of the scientific literature demonstrates that maladaptive personality traits and personality disorders, in particular high neuroticism and negative affectivity, first, are risk factors for divorce, unemployment, and disability pensioning; second, relate to the prevalence, incidence, and co occurrence of common mental disorders; third, impair functioning, symptom remission, and recovery in co-occurring common mental disorders; and fourth, predispose to treatment resistance, non-response and poor treatment outcome. In conclusion, maladaptive personality is not only involved in the development and course of mental disorders but also predisposes to chronicity and re-occurrence of psychopathology and reduces the efficacy of psychiatric treatments. The pernicious impact of maladaptive personality on mental health and functioning demands that careful assessment and thorough consideration of personality should be compulsory in psychiatric practice. PMID- 26106337 TI - Teasing apart retrieval and encoding interference in the processing of anaphors. AB - Two classes of account have been proposed to explain the memory processes subserving the processing of reflexive-antecedent dependencies. Structure-based accounts assume that the retrieval of the antecedent is guided by syntactic tree configurational information without considering other kinds of information such as gender marking in the case of English reflexives. By contrast, unconstrained cue-based retrieval assumes that all available information is used for retrieving the antecedent. Similarity-based interference effects from structurally illicit distractors which match a non-structural retrieval cue have been interpreted as evidence favoring the unconstrained cue-based retrieval account since cue-based retrieval interference from structurally illicit distractors is incompatible with the structure-based account. However, it has been argued that the observed effects do not necessarily reflect interference occurring at the moment of retrieval but might equally well be accounted for by interference occurring already at the stage of encoding or maintaining the antecedent in memory, in which case they cannot be taken as evidence against the structure-based account. We present three experiments (self-paced reading and eye-tracking) on German reflexives and Swedish reflexive and pronominal possessives in which we pit the predictions of encoding interference and cue-based retrieval interference against each other. We could not find any indication that encoding interference affects the processing ease of the reflexive-antecedent dependency formation. Thus, there is no evidence that encoding interference might be the explanation for the interference effects observed in previous work. We therefore conclude that invoking encoding interference may not be a plausible way to reconcile interference effects with a structure-based account of reflexive processing. PMID- 26106338 TI - Age of second language acquisition in multilinguals has an impact on gray matter volume in language-associated brain areas. AB - Numerous structural studies have established that experience shapes and reshapes the brain throughout a lifetime. The impact of early development, however, is still a matter of debate. Further clues may come from studying multilinguals who acquired their second language at different ages. We investigated adult multilinguals who spoke three languages fluently, where the third language was learned in classroom settings, not before the age of 9 years. Multilinguals exposed to two languages simultaneously from birth (SiM) were contrasted with multinguals who acquired their first two languages successively (SuM). Whole brain voxel based morphometry revealed that, relative to SuM, SiM have significantly lower gray matter volume in several language-associated cortical areas in both hemispheres: bilaterally in medial and inferior frontal gyrus, in the right medial temporal gyrus and inferior posterior parietal gyrus, as well as in the left inferior temporal gyrus. Thus, as shown by others, successive language learning increases the volume of language-associated cortical areas. In brains exposed early on and simultaneously to more than one language, however, learning of additional languages seems to have less impact. We conclude that - at least with respect to language acquisition - early developmental influences are maintained and have an effect on experience-dependent plasticity well into adulthood. PMID- 26106339 TI - Unconscious deception detection measured by finger skin temperature and indirect veracity judgments-results of a registered report. AB - A pre-registered experiment was conducted to examine psychophysiological responses to being lied to. Bridging research on social cognition and deception detection, we hypothesized that observing a liar compared to a truth-teller would decrease finger skin temperature of observers. Participants first watched two targets while not forewarned that they would later be asked to judge (direct and indirect) veracity, and then watched another two targets while forewarned about this. During both these phases finger skin temperature was measured. Findings pertaining to temperature partly confirmed our main hypothesis. When participants were observing a liar, irrespective of being forewarned, on average finger skin temperature declined over time. In the forewarned phase, temperature trajectories of truth-tellers were higher than those of liars, however, in the not forewarned phase, this pattern was reversed. Results confirmed our further hypotheses that participants judge liars as less likeable and less trustworthy than truth-tellers an indication of indirect deception detection. Our hypothesis that the effect size for trustworthiness would be bigger than that of liking was not supported by the data. Additionally, and also confirming our hypothesis, participants performed around chance level when directly judging whether the target person was lying. Exploratory analyses are reported with regard to truth bias and dependency between direct and indirect veracity judgments. Limitations and directions for future work related to the existence of psychophysiological indicators of deception detection are discussed. PMID- 26106340 TI - Sensorimotor strategies for recognizing geometrical shapes: a comparative study with different sensory substitution devices. AB - The sensorimotor approach proposes that perception is constituted by the mastery of lawful sensorimotor regularities or sensorimotor contingencies (SMCs), which depend on specific bodily characteristics and on actions possibilities that the environment enables and constrains. Sensory substitution devices (SSDs) provide the user information about the world typically corresponding to one sensory modality through the stimulation of another modality. We investigate how perception emerges in novice adult participants equipped with vision-to-auditory SSDs while solving a simple geometrical shape recognition task. In particular, we examine the distinction between apparatus-related SMCs (those originating mostly in properties of the perceptual system) and object-related SMCs (those mostly connected with the perceptual task). We study the sensorimotor strategies employed by participants in three experiments with three different SSDs: a minimalist head-mounted SSD, a traditional, also head-mounted SSD (the vOICe) and an enhanced, hand-held echolocation device. Motor activity and fist-person data are registered and analyzed. Results show that participants are able to quickly learn the necessary skills to distinguish geometric shapes. Comparing the sensorimotor strategies utilized with each SSD we identify differential features of the sensorimotor patterns attributable mostly to the device, which account for the emergence of apparatus-based SMCs. These relate to differences in sweeping strategies between SSDs. We identify, also, components related to the emergence of object-related SMCs. These relate mostly to exploratory movements around the border of a shape. The study provides empirical support for SMC theory and discusses considerations about the nature of perception in sensory substitution. PMID- 26106341 TI - Time series analysis for psychological research: examining and forecasting change. AB - Psychological research has increasingly recognized the importance of integrating temporal dynamics into its theories, and innovations in longitudinal designs and analyses have allowed such theories to be formalized and tested. However, psychological researchers may be relatively unequipped to analyze such data, given its many characteristics and the general complexities involved in longitudinal modeling. The current paper introduces time series analysis to psychological research, an analytic domain that has been essential for understanding and predicting the behavior of variables across many diverse fields. First, the characteristics of time series data are discussed. Second, different time series modeling techniques are surveyed that can address various topics of interest to psychological researchers, including describing the pattern of change in a variable, modeling seasonal effects, assessing the immediate and long-term impact of a salient event, and forecasting future values. To illustrate these methods, an illustrative example based on online job search behavior is used throughout the paper, and a software tutorial in R for these analyses is provided in the Supplementary Materials. PMID- 26106342 TI - Fairness requires deliberation: the primacy of economic over social considerations. AB - While both economic and social considerations of fairness and equity play an important role in financial decision-making, it is not clear which of these two motives is more primal and immediate and which one is secondary and slow. Here we used variants of the ultimatum game to examine this question. Experiment 1 shows that acceptance rate of unfair offers increases when participants are asked to base their choice on their gut-feelings, as compared to when they thoroughly consider the available information. In line with these results, Experiments 2 and 3 provide process evidence that individuals prefer to first examine economic information about their own utility rather than social information about equity and fairness, even at the price of foregoing such social information. Our results suggest that people are more economically rational at the core, but social considerations (e.g., inequality aversion) require deliberation, which under certain conditions override their self-interested impulses. PMID- 26106343 TI - Accelerated forgetting? An evaluation on the use of long-term forgetting rates in patients with memory problems. AB - The main focus of this review was to evaluate whether long-term forgetting rates (delayed tests, days, to weeks, after initial learning) are more sensitive measures than standard delayed recall measures to detect memory problems in various patient groups. It has been suggested that accelerated forgetting might be characteristic for epilepsy patients, but little research has been performed in other populations. Here, we identified eleven studies in a wide range of brain injured patient groups, whose long-term forgetting patterns were compared to those of healthy controls. Signs of accelerated forgetting were found in three studies. The results of eight studies showed normal forgetting over time for the patient groups. However, most of the studies used only a recognition procedure, after optimizing initial learning. Based on these results, we recommend the use of a combined recall and recognition procedure to examine accelerated forgetting and we discuss the relevance of standard and optimized learning procedures in clinical practice. PMID- 26106344 TI - What makes space-time interactions in human vision asymmetrical? AB - The interaction of space and time affects perception of extents: (1) the longer the exposure duration, the longer the line length is perceived and vice versa; (2) the shorter the line length is, the shorter the exposure duration is perceived. Previous studies have shown that space-time interactions in human vision are asymmetrical; spatial cognition has a larger effect on temporal cognition rather than vice versa (Merritt et al., 2010). What makes the interactions asymmetrical? In this study, participants were asked to judge exposure duration of lines that differed in length or to judge the lengths of the lines with different exposure time; to judge the task-relevant stimulus extents that also varied in the task-irrelevant stimulus extents. Paired spatial and temporal tasks in which the ranges of task-relevant and -irrelevant stimulus values were common, were conducted. In our hypothesis, the imbalance in saliency of spatial and temporal information would cause asymmetrical space-time interaction. To assess the saliency, task difficulty was rated. If saliency of relevant stimuli is high, the difficulty of discrimination task would be low, and vice versa. The saliency of irrelevant stimuli in one task would be reflected in the difficulty of the other task, in the pair of tasks. If saliency of irrelevant stimuli is high, the difficulty of paired task would be low, and vice versa. The result supports our hypothesis; spatial cognition asymmetrically affected on temporal cognition when the difficulty of temporal task was significantly higher than that of spatial task. PMID- 26106346 TI - Cognitive functioning in socially anxious adults: insights from the NIH Toolbox Cognition Battery. AB - Theory suggests that individuals with social anxiety manifest unique patterns of cognition with less efficient fluid cognition and unperturbed crystallized cognition; however, empirical support for these ideas remains inconclusive. The heterogeneity of past findings may reflect unreliability in cognitive assessments or the influence of confounding variables. The present study examined the relations among social anxiety and performance on the reliable, newly established NIH Toolbox Cognition Battery. Results indicate that high socially anxious adults performed as well as low anxious participants on all measures of fluid cognition. However, high socially anxious adults demonstrated enhanced crystallized cognitive abilities relative to a low socially anxious comparison group. PMID- 26106347 TI - Does interpersonal behavior of psychotherapy trainees differ in private and professional relationships? AB - AIM: The present study aimed to evaluate the effect of trainees' interpersonal behavior on work involvement (WI) and compared their social behavior within professional and private relationships as well as between different psychotherapeutic orientations. METHODS: The interpersonal scales of the Intrex short-form questionnaire and the Work Involvement Scale (WIS) were used to evaluate two samples of German psychotherapy trainees in psychoanalytic, psychodynamic, and cognitive behavioral therapy training. Trainees from Sample 1 (N = 184) were asked to describe their interpersonal behavior in relation to their patients when filling out the Intrex, whereas trainees from Sample 2 (N = 135) were asked to describe the private relationship with a significant other. RESULTS: Interpersonal affiliation in professional relationships significantly predicted the level of healing involvement, while stress involvement was predicted by interpersonal affiliation and interdependence in trainees' relationships with their patients. Social behavior within professional relationships provided higher correlations with WI than private interpersonal behavior. Significant differences were found between private and professional relation settings in trainees' interpersonal behavior with higher levels of affiliation and interdependence with significant others. Differences between therapeutic orientation and social behavior could only be found when comparing trainees' level of interdependence with the particular relationship setting. CONCLUSION: Trainees' interpersonal level of affiliation in professional relationships is a predictor for a successful psychotherapeutic development. Vice versa, controlling behavior in professional settings can be understood as a risk factor against psychotherapeutic growth. Both results strengthen an evidence based approach for competence development during psychotherapy training. PMID- 26106345 TI - Interoception, contemplative practice, and health. AB - Interoception can be broadly defined as the sense of signals originating within the body. As such, interoception is critical for our sense of embodiment, motivation, and well-being. And yet, despite its importance, interoception remains poorly understood within modern science. This paper reviews interdisciplinary perspectives on interoception, with the goal of presenting a unified perspective from diverse fields such as neuroscience, clinical practice, and contemplative studies. It is hoped that this integrative effort will advance our understanding of how interoception determines well-being, and identify the central challenges to such understanding. To this end, we introduce an expanded taxonomy of interoceptive processes, arguing that many of these processes can be understood through an emerging predictive coding model for mind-body integration. The model, which describes the tension between expected and felt body sensation, parallels contemplative theories, and implicates interoception in a variety of affective and psychosomatic disorders. We conclude that maladaptive construal of bodily sensations may lie at the heart of many contemporary maladies, and that contemplative practices may attenuate these interpretative biases, restoring a person's sense of presence and agency in the world. PMID- 26106348 TI - The independence of expression and identity in face-processing: evidence from neuropsychological case studies. AB - The processing of facial identity and facial expression have traditionally been seen as independent-a hypothesis that has largely been informed by a key double dissociation between neurological patients with a deficit in facial identity recognition but not facial expression recognition, and those with the reverse pattern of impairment. The independence hypothesis is also reflected in more recent anatomical models of face-processing, although these theories permit some interaction between the two processes. Given that much of the traditional patient based evidence has been criticized, a review of more recent case reports that are accompanied by neuroimaging data is timely. Further, the performance of individuals with developmental face-processing deficits has recently been considered with regard to the independence debate. This paper reviews evidence from both acquired and developmental disorders, identifying methodological and theoretical strengths and caveats in these reports, and highlighting pertinent avenues for future research. PMID- 26106349 TI - A face detection bias for horizontal orientations develops in middle childhood. AB - Faces are complex stimuli that can be described via intuitive facial features like the eyes, nose, and mouth, "configural" features like the distances between facial landmarks, and features that correspond to computations performed in the early visual system (e.g., oriented edges). With regard to this latter category of descriptors, adult face recognition relies disproportionately on information in specific spatial frequency and orientation bands: many recognition tasks are performed more accurately when adults have access to mid-range spatial frequencies (8-16 cycles/face) and horizontal orientations (Dakin and Watt, 2009). In the current study, we examined how this information bias develops in middle childhood. We recruited children between the ages of 5-10 years-old to participate in a simple categorization task that required them to label images according to whether they depicted a face or a house. Critically, children were presented with face and house images comprised either of primarily horizontal orientation energy, primarily vertical orientation energy, or both horizontal and vertical orientation energy. We predicted that any bias favoring horizontal information over vertical should be more evident in faces than in houses, and also that older children would be more likely to show such a bias than younger children. We designed our categorization task to be sufficiently easy that children would perform at near-ceiling accuracy levels, but with variation in response times that would reflect how they rely on different orientations as a function of age and object category. We found that horizontal bias for face detection (but not house detection) correlated significantly with age, suggesting an emergent category-specific bias for horizontal orientation energy that develops during middle childhood. These results thus suggest that the tuning of high-level recognition to specific low-level visual features takes place over several years of visual development. PMID- 26106350 TI - Optic-flow selective cortical sensory regions associated with self-reported states of vection. AB - Optic flow is one of the most important visual cues to the estimation of self motion. It has repeatedly been demonstrated that a cortical network including visual, multisensory, and vestibular areas is implicated in processing optic flow; namely, visual areas middle temporal cortex (MT+), V6; multisensory areas ventral intra-parietal area (VIP), cingulate sulcus visual area, precuneus motion area (PcM); and vestibular areas parieto-insular vestibular cortex (PIVC) and putative area 2v (p2v). However, few studies have investigated the roles of and interaction between the optic-flow selective sensory areas within the context of self-motion perception. When visual information (i.e., optic flow) is the sole cue to computing self-motion parameters, the discrepancy amongst the sensory signals may induce an illusion of self-motion referred to as 'vection.' This study aimed to identify optic-flow selective sensory areas that are involved in the processing of visual cues to self-motion, by introducing vection as an index and assessing activation in which of those areas reflect vection, using functional magnetic resonance imaging. The results showed that activity in visual areas MT+ and V6, multisensory area VIP and vestibular area PIVC was significantly greater while participants were experiencing vection, as compared to when they were experiencing no vection, which may indicate that activation in MT+, V6, VIP, and PIVC reflects vection. The results also place VIP in a good position to integrate visual cues related to self-motion and vestibular information. PMID- 26106352 TI - Construal level and free will beliefs shape perceptions of actors' proximal and distal intent. AB - Two components of lay observers' calculus of moral judgment are proximal intent (the actor's mind is focused on performing the action) and distal intent (the actor's mind is focused on the broader goal). What causes observers to prioritize one form of intent over the other? The authors observed whether construal level (Studies 1-2) and beliefs about free will (Studies 3-4) would influence participants' sensitivity to the actor's proximal vs. distal intent. In four studies, participants read scenarios in which the actor's proximal and distal intent were independently manipulated. In Study 1, when only distal intent was present in the actor's mind, participants rated the psychologically distant actor more responsible than the psychologically near actor. In Study 2, when only distal intent was in the actor's mind, participants with a chronic high level of action identification rated the actor more responsible than did those with a low level of action identification. In both studies, when only proximal intent was in the actor's mind, construal level did not predict judgments of responsibility. In Study 3, when only proximal intent was present in the actor's mind, the more participants believed in free will, the more they rated the actor responsible. When only distal intent was in the actor's mind, free will belief did not influence ratings of responsibility. In Study 4, the same pattern emerged when free will/determinism beliefs were manipulated and the actor performed a positive (life-saving) act. The authors discuss how these results shed new light on the literatures on moral reasoning and psycho-legal theory. PMID- 26106351 TI - The default mode network as a biomarker for monitoring the therapeutic effects of meditation. AB - The default mode network (DMN) is a group of anatomically separate regions in the brain found to have synchronized patterns of activation in functional magnetic resonance imaging (fMRI). Mentation associated with the DMN includes processes such as mind wandering, autobiographical memory, self-reflective thought, envisioning the future, and considering the perspective of others. Abnormalities in the DMN have been linked to symptom severity in a variety of mental disorders indicating that the DMN could be used as a biomarker for diagnosis. These correlations have also led to the use of DMN modulation as a biomarker for assessing pharmacological treatments. Concurrent research investigating the neural correlates of meditation, have associated DMN modulation with practice. Furthermore, meditative practice is increasingly understood to have a beneficial role in the treatment of mental disorders. Therefore we propose the use of DMN measures as a biomarker for monitoring the therapeutic effects of meditation practices in mental disorders. Recent findings support this perspective, and indicate the utility of DMN monitoring in understanding and developing meditative treatments for these debilitating conditions. PMID- 26106353 TI - Relatively effortless listening promotes understanding and recall of medical instructions in older adults. AB - Communication success under adverse conditions requires efficient and effective recruitment of both bottom-up (sensori-perceptual) and top-down (cognitive linguistic) resources to decode the intended auditory-verbal message. Employing these limited capacity resources has been shown to vary across the lifespan, with evidence indicating that younger adults out-perform older adults for both comprehension and memory of the message. This study examined how sources of interference arising from the speaker (message spoken with conversational vs. clear speech technique), the listener (hearing-listening and cognitive-linguistic factors), and the environment (in competing speech babble noise vs. quiet) interact and influence learning and memory performance using more ecologically valid methods than has been done previously. The results suggest that when older adults listened to complex medical prescription instructions with "clear speech," (presented at audible levels through insertion earphones) their learning efficiency, immediate, and delayed memory performance improved relative to their performance when they listened with a normal conversational speech rate (presented at audible levels in sound field). This better learning and memory performance for clear speech listening was maintained even in the presence of speech babble noise. The finding that there was the largest learning-practice effect on 2nd trial performance in the conversational speech when the clear speech listening condition was first is suggestive of greater experience dependent perceptual learning or adaptation to the speaker's speech and voice pattern in clear speech. This suggests that experience-dependent perceptual learning plays a role in facilitating the language processing and comprehension of a message and subsequent memory encoding. PMID- 26106354 TI - Gender roles and traits in stress and health. AB - Women have a life-expectancy advantage over men, but a marked disadvantage with regards to morbidity. This is known as the female-male health-survival paradox in disciplines such as medicine, medical sociology, and epidemiology. Individual differences in physical and mental health are further notably explained by the degree of stress individuals endure, with women being more affected by stressors than men. Here, we briefly examine the literature on women's disadvantage in health and stress. Beyond biological considerations, we follow with socio cognitive explanations of gender differences in health and stress. We show that gender roles and traits (masculinity in particular) explain part of the gender differences in stress, notably cognitive appraisal and coping. Stress in turn degrades health. Implications are discussed. In conclusion, traditional socialization is advantageous for men in terms of health. PMID- 26106355 TI - Facial expression at retrieval affects recognition of facial identity. AB - It is well known that memory can be modulated by emotional stimuli at the time of encoding and consolidation. For example, happy faces create better identity recognition than faces with certain other expressions. However, the influence of facial expression at the time of retrieval remains unknown in the literature. To separate the potential influence of expression at retrieval from its effects at earlier stages, we had participants learn neutral faces but manipulated facial expression at the time of memory retrieval in a standard old/new recognition task. The results showed a clear effect of facial expression, where happy test faces were identified more successfully than angry test faces. This effect is unlikely due to greater image similarity between the neural training face and the happy test face, because image analysis showed that the happy test faces are in fact less similar to the neutral training faces relative to the angry test faces. In the second experiment, we investigated whether this emotional effect is affected by the expression at the time of learning. We employed angry or happy faces as learning stimuli, and angry, happy, and neutral faces as test stimuli. The results showed that the emotional effect at retrieval is robust across different encoding conditions with happy or angry expressions. These findings indicate that emotional expressions do not only affect the stages of encoding and consolidation, but also the retrieval process in identity recognition. PMID- 26106356 TI - How are personality trait and profile agreement related? AB - It is argued that if we compute self-other agreement on some personality traits then we possess no or very little information about the individuals who are the targets of this judgment. This idea is largely based on two separate ways of computing self-other agreement: trait agreement (rT ) and profile agreement (rP ), which are typically associated with two different trait-centered and person centered approaches in personality research. Personality traits of 4115 targets from Czech, Belgian, Estonian, and German samples were rated by themselves and knowledgeable informants. We demonstrate that trait agreement can be partialled into individual contributions so that it is possible to show how much each individual pair of judges contributes to agreement on a particular trait. Similarly, it is possible to decompose agreement between two personality profiles into the individual contributions of traits from which these profiles are assembled. If normativeness is separated from distinctiveness of personality scores and individual profiles are ipsatized, then mean profile agreement rP becomes identical to mean trait agreement r T . The views that trait-by-trait analysis does not provide information regarding accuracy level of a particular pair of judges and profile analysis does not permit assessment of the relative contributions of traits to overall accuracy are not supported. PMID- 26106357 TI - Automatic imitation in a rich social context with virtual characters. AB - It has been well established that people respond faster when they perform an action that is congruent with an observed action than when they respond with an incongruent action. Here we propose a new method of using interactive Virtual Characters (VCs) to test if social congruency effects can be obtained in a richer social context with sequential hand-arm actions. Two separate experiments were conducted, exploring if it is feasible to measure spatial congruency (Experiment 1) and anatomical congruency (Experiment 2) in response to a VC, compared to the same action sequence indicated by three virtual balls. In Experiment 1, we found a robust spatial congruency effect for both VC and virtual balls, modulated by a social facilitation effect for participants who felt the VC was human. In Experiment 2 which allowed for anatomical congruency, a form by congruency interaction provided evidence that participants automatically imitate the actions of the VC but do not imitate the balls. Our method and results build a bridge between studies using minimal stimuli in automatic interaction and studies of mimicry in a rich social interaction, and open new research venue for future research in the area of automatic imitation with a more ecologically valid social interaction. PMID- 26106358 TI - Commentary on: People search for meaning when they approach a new decade in chronological age. PMID- 26106359 TI - Commentary: Development of magnitude processing in children with developmental dyscalculia: space, time, and number. PMID- 26106360 TI - Corrigendum: Task-dependency and structure-dependency in number interference effects in sentence comprehension. AB - [This corrects the article on p. 349 in vol. 6, PMID: 25914652.]. PMID- 26106361 TI - Construct labeling: public trust and scientific credibility. PMID- 26106363 TI - Loss of Autonoetic Awareness of Recent Autobiographical Episodes and Accelerated Long-Term Forgetting in a Patient with Previously Unrecognized Glutamic Acid Decarboxylase Antibody Related Limbic Encephalitis. AB - We describe a 35-year-old male patient presenting with depressed mood and emotional instability, who complained about severe anterograde and retrograde memory deficits characterized by accelerated long-term forgetting and loss of autonoetic awareness regarding autobiographical memories of the last 3 years. Months before he had experienced two breakdowns of unknown etiology giving rise to the differential diagnosis of epileptic seizures after various practitioners and clinics had suggested different etiologies such as a psychosomatic condition, burnout, depression, or dissociative amnesia. Neuropsychological assessment indicated selectively impaired figural memory performance. Extended diagnostics confirmed accelerated forgetting of previously learned and retrievable verbal material. Structural imaging showed bilateral swelling and signal alterations of temporomesial structures (left >right). Video-EEG monitoring revealed a left temporal epileptic focus and subclincal seizure, but no overt seizures. Antibody tests in serum and liquor were positive for glutamic acid decarboxylase antibodies. These findings led to the diagnosis of glutamic acid decarboxylase antibody related limbic encephalitis. Monthly steroid pulses over 6 months led to recovery of subjective memory and to intermediate improvement but subsequent worsening of objective memory performance. During the course of treatment, the patient reported de novo paroxysmal non-responsive states. Thus, antiepileptic treatment was started and the patient finally became seizure free. At the last visit, vocational reintegration was successfully in progress. In conclusion, amygdala swelling, retrograde biographic memory impairment, accelerated long-term forgetting, and emotional instability may serve as indicators of limbic encephalitis, even in the absence of overt epileptic seizures. The monitoring of such patients calls for a standardized and concerted multilevel diagnostic approach with repeated assessments. PMID- 26106362 TI - Thalamocortical Dysrhythmia: A Theoretical Update in Tinnitus. AB - Tinnitus is the perception of a sound in the absence of a corresponding external sound source. Pathophysiologically it has been attributed to bottom-up deafferentation and/or top-down noise-cancelling deficit. Both mechanisms are proposed to alter auditory -thalamocortical signal transmission, resulting in thalamocortical dysrhythmia (TCD). In deafferentation, TCD is characterized by a slowing down of resting state alpha to theta activity associated with an increase in surrounding gamma activity, resulting in persisting cross-frequency coupling between theta and gamma activity. Theta burst-firing increases network synchrony and recruitment, a mechanism, which might enable long-range synchrony, which in turn could represent a means for finding the missing thalamocortical information and for gaining access to consciousness. Theta oscillations could function as a carrier wave to integrate the tinnitus-related focal auditory gamma activity in a consciousness enabling network, as envisioned by the global workspace model. This model suggests that focal activity in the brain does not reach consciousness, except if the focal activity becomes functionally coupled to a consciousness enabling network, aka the global workspace. In limited deafferentation, the missing information can be retrieved from the auditory cortical neighborhood, decreasing surround inhibition, resulting in TCD. When the deafferentation is too wide in bandwidth, it is hypothesized that the missing information is retrieved from theta-mediated parahippocampal auditory memory. This suggests that based on the amount of deafferentation TCD might change to parahippocampocortical persisting and thus pathological theta-gamma rhythm. From a Bayesian point of view, in which the brain is conceived as a prediction machine that updates its memory-based predictions through sensory updating, tinnitus is the result of a prediction error between the predicted and sensed auditory input. The decrease in sensory updating is reflected by decreased alpha activity and the prediction error results in theta-gamma and beta-gamma coupling. Thus, TCD can be considered as an adaptive mechanism to retrieve missing auditory input in tinnitus. PMID- 26106364 TI - Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding. AB - Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological levels, upon reuptake of DA into presynaptic terminals. DA translocation involves the co-transport of two sodium ions and the channeling of a chloride ion, and it is achieved via alternating access between outward-facing (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent quantitative systems pharmacology study suggested that orphenadrine (ORPH), an anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like cocaine modulate the function of DAT in different ways. However, the molecular mechanisms of modulation remained elusive due to the lack of structural data on DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way to a deeper understanding of the mechanism and time evolution of DAT-drug/ligand interactions. Using a combination of homology modeling, docking analysis, molecular dynamics simulations, and molecular biology experiments, we performed a comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and their modulation of hDAT function. Simulations demonstrate that binding DA or AMPH drives a structural transition toward a functional form predisposed to translocate the ligand. In contrast, ORPH appears to inhibit DAT function by arresting it in the OF open conformation. The analysis shows that cocaine and ORPH competitively bind DAT, with the binding pose and affinity dependent on the conformational state of DAT. Further assays show that the effect of ORPH on DAT uptake and endocytosis is comparable to that of cocaine. PMID- 26106365 TI - Early Trabecular Development in Human Vertebrae: Overproduction, Constructive Regression, and Refinement. AB - Early bone development may have a significant impact upon bone health in adulthood. Bone mineral density (BMD) and bone mass are important determinants of adult bone strength. However, several studies have shown that BMD and bone mass decrease after birth. If early development is important for strength, why does this reduction occur? To investigate this, more data characterizing gestational, infant, and childhood bone development are needed in order to compare with adults. The aim of this study is to document early vertebral trabecular bone development, a key fragility fracture site, and infer whether this period is important for adult bone mass and structure. A series of 120 vertebrae aged between 6 months gestation and 2.5 years were visualized using microcomputed tomography. Spherical volumes of interest were defined, thresholded, and measured using 3D bone analysis software (BoneJ, Quant3D). The findings showed that gestation was characterized by increasing bone volume fraction whilst infancy was defined by significant bone loss (~2/3rds) and the appearance of a highly anisotropic trabecular structure with a predominantly inferior-superior direction. Childhood development progressed via selective thickening of some trabeculae and the loss of others; maintaining bone volume whilst creating a more anisotropic structure. Overall, the pattern of vertebral development is one of gestational overproduction followed by infant "sculpting" of bone tissue during the first year of life (perhaps in order to regulate mineral homeostasis or to adapt to loading environment) and then subsequent refinement during early childhood. Comparison of early bone developmental data in this study with adult bone volume values taken from the literature shows that the loss in bone mass that occurs during the first year of life is never fully recovered. Early development could therefore be important for developing bone strength, but through structural changes in trabecular microarchitecture rather than bone mass. PMID- 26106366 TI - Crosstalk of the Insulin-Like Growth Factor Receptor with the Wnt Signaling Pathway in Breast Cancer. AB - The insulin-like growth factor system has long been considered a pathway that promotes cell proliferation, survival, and transformation, and is thus a promoter of tumorigenesis. However, recent failure of clinical trials for IGF-1R inhibitors reveals the need for a better understanding of how this pathway functions in specific tumor subtypes. Ongoing studies are designed to uncover biomarkers and downstream targets to enhance therapeutic strategies. Other approaches in specific tumor models reveal complex interactions between IGF signaling and other tumor initiating pathways. Here, we review relevant background and recent studies suggesting that inhibiting the IGF-1R can amplify Wnt and Notch signaling pathways in a model of triple negative breast cancer. PMID- 26106367 TI - Novel Insights into the Genetics and Pathophysiology of Adrenocortical Tumors. AB - Adrenocortical tumors (ACTs) are typically unilateral and can be classified as benign adrenocortical adenomas (ACAs) or malignant adrenocortical cancers (ACCs). In rare cases, tumors may occur in both adrenal glands as micronodular hyperplasia (primary pigmented nodular adrenal dysplasia) or as macronodular hyperplasia (primary bilateral macronodular adrenal hyperplasia, PBMAH). The study of certain tumor predisposition syndromes has improved our understanding of sporadic ACTs. Most ACAs are associated with abnormalities of the cAMP signaling pathway, whereas most ACCs are linked to alterations in IGF2, TP53, or the Wnt/betacatenin pathways. Over the past year, single-nucleotide polymorphism array technology and next-generation sequencing have identified novel genetic alterations in ACTs that shed new light on the molecular mechanisms of oncogenesis. Among these are somatic mutations of PKA catalytic subunit alpha gene (PRKACA) in ACA, germline, and somatic mutations of armadillo repeat containing 5 gene (ARMC5) in primary bilateral macronodular adrenal hyperplasia and somatic alterations of the E3 ubiquitin ligase gene ZNRF3 in ACC. This review focuses on the recent discoveries and their diagnostic, prognostic, and therapeutic implications. PMID- 26106368 TI - Corrigendum: "Cancer Cell Gene Expression Modulated from Plasma Membrane Integrin alphavbeta3 by Thyroid Hormone and Nanoparticulate Tetrac". AB - [This corrects the article on p. 240 in vol. 5, PMID: 25628605.]. PMID- 26106369 TI - S-layers at second glance? Altiarchaeal grappling hooks (hami) resemble archaeal S-layer proteins in structure and sequence. AB - The uncultivated "Candidatus Altiarchaeum hamiconexum" (formerly known as SM1 Euryarchaeon) carries highly specialized nano-grappling hooks ("hami") on its cell surface. Until now little is known about the major protein forming these structured fibrous cell surface appendages, the genes involved or membrane anchoring of these filaments. These aspects were analyzed in depth in this study using environmental transcriptomics combined with imaging methods. Since a laboratory culture of this archaeon is not yet available, natural biofilm samples with high Ca. A. hamiconexum abundance were used for the entire analyses. The filamentous surface appendages spanned both membranes of the cell, which are composed of glycosyl-archaeol. The hami consisted of multiple copies of the same protein, the corresponding gene of which was identified via metagenome-mapped transcriptome analysis. The hamus subunit proteins, which are likely to self assemble due to their predicted beta sheet topology, revealed no similiarity to known microbial flagella-, archaella-, fimbriae- or pili-proteins, but a high similarity to known S-layer proteins of the archaeal domain at their N-terminal region (44-47% identity). Our results provide new insights into the structure of the unique hami and their major protein and indicate their divergent evolution with S-layer proteins. PMID- 26106370 TI - Automated quantification of the phagocytosis of Aspergillus fumigatus conidia by a novel image analysis algorithm. AB - Studying the pathobiology of the fungus Aspergillus fumigatus has gained a lot of attention in recent years. This is due to the fact that this fungus is a human pathogen that can cause severe diseases, like invasive pulmonary aspergillosis in immunocompromised patients. Because alveolar macrophages belong to the first line of defense against the fungus, here, we conduct an image-based study on the host pathogen interaction between murine alveolar macrophages and A. fumigatus. This is achieved by an automated image analysis approach that uses a combination of thresholding, watershed segmentation and feature-based object classification. In contrast to previous approaches, our algorithm allows for the segmentation of individual macrophages in the images and this enables us to compute the distribution of phagocytosed and macrophage-adherent conidia over all macrophages. The novel automated image-based analysis provides access to all cell cell interactions in the assay and thereby represents a framework that enables comprehensive computation of diverse characteristic parameters and comparative investigation for different strains. We here apply automated image analysis to confocal laser scanning microscopy images of the two wild-type strains ATCC 46645 and CEA10 of A. fumigatus and investigate the ability of macrophages to phagocytose the respective conidia. It is found that the CEA10 strain triggers a stronger response of the macrophages as revealed by a higher phagocytosis ratio and a larger portion of the macrophages being active in the phagocytosis process. PMID- 26106372 TI - Methods to identify the unexplored diversity of microbial exopolysaccharides. AB - Microbial exopolysaccharides (EPS) are a structurally very diverse class of molecules. A number of them have found their application in rather diverging fields that extend from medicine, food, and cosmetics on the one side to construction, drilling, and chemical industry on the other side. The analysis of microbial strains for their competence in polysaccharide production has therefore been a major issue in the past, especially in the search for new polysaccharide variants among natural strain isolates. Concerning the fact that nearly all microbes carry the genetic equipment for the production of polysaccharides under specific conditions, the naturally provided EPS portfolio seems to be still massively underexplored. Therefore, there is a need for high throughput screening techniques capable of identifying novel variants of bacterial EPS with properties superior to the already described ones, or even totally new ones. A great variety of different techniques has been used in screening approaches for identifying microorganisms that are producing EPS in substantial amounts. Mucoid growth is often the method of choice for visual identification of EPS producing strains. Depending on the thickening characteristics of the polysaccharide, observation of viscosity in culture broth can also be an option to evaluate EPS production. Precipitation with different alcohols represents a common detection, isolation, and purification method for many EPS. A more quantitative approach is found in the total carbohydrate content analysis, normally determined, e.g., by phenol sulfuric-acid-method. In addition, recently a new and reliable method for the detailed analysis of the monomeric composition and the presence of rare sugars and sugar substitutions has become available, which could give a first hint of the polymer structure of unknown EPS. This minireview will compare available methods and novel techniques and discuss their benefits and disadvantages. PMID- 26106371 TI - Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions. AB - Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles. PMID- 26106373 TI - Reflux esophagitis triggered after Helicobacter pylori eradication: a noteworthy demerit of eradication therapy among the Japanese? AB - In the February 2013 Revision of Insured Medical Treatment, bacterial eradication for all Helicobacter pylori-positive individuals in Japan was covered under the insurance scheme. However, reflux esophagitis is believed to occur in approximately 10% of Japanese patients who undergo eradication therapy. Hence, the risk of reflux esophagitis among such cases should be carefully considered, particularly in the treatment for H. pylori-positive patients who are otherwise healthy. The eradication of H. pylori in cases of H. pylori-positive gastritis markedly suppresses gastric inflammation, and inhibits gastric mucosal atrophy and its progression to intestinal metaplasia. In a long-term follow-up study (10 20 years), eradication treatment was found to reduce the risk of subsequent gastric cancer. However, the fact that eradication-induced reflux esophagitis could increase the long-term risk of Barrett's esophagus and esophageal adenocarcinoma should also be considered in the Japanese population. Appropriate treatment with proton pump inhibitors should be taken into consideration for patients undergoing eradication therapy in clinical practice. PMID- 26106376 TI - Revealing the unexplored fungal communities in deep groundwater of crystalline bedrock fracture zones in Olkiluoto, Finland. AB - The diversity and functional role of fungi, one of the ecologically most important groups of eukaryotic microorganisms, remains largely unknown in deep biosphere environments. In this study we investigated fungal communities in packer-isolated bedrock fractures in Olkiluoto, Finland at depths ranging from 296 to 798 m below surface level. DNA- and cDNA-based high-throughput amplicon sequencing analysis of the fungal internal transcribed spacer (ITS) gene markers was used to examine the total fungal diversity and to identify the active members in deep fracture zones at different depths. Results showed that fungi were present in fracture zones at all depths and fungal diversity was higher than expected. Most of the observed fungal sequences belonged to the phylum Ascomycota. Phyla Basidiomycota and Chytridiomycota were only represented as a minor part of the fungal community. Dominating fungal classes in the deep bedrock aquifers were Sordariomycetes, Eurotiomycetes, and Dothideomycetes from the Ascomycota phylum and classes Microbotryomycetes and Tremellomycetes from the Basidiomycota phylum, which are the most frequently detected fungal taxa reported also from deep sea environments. In addition some fungal sequences represented potentially novel fungal species. Active fungi were detected in most of the fracture zones, which proves that fungi are able to maintain cellular activity in these oligotrophic conditions. Possible roles of fungi and their origin in deep bedrock groundwater can only be speculated in the light of current knowledge but some species may be specifically adapted to deep subsurface environment and may play important roles in the utilization and recycling of nutrients and thus sustaining the deep subsurface microbial community. PMID- 26106375 TI - Apolipoprotein L1 (APOL1) Variants (Vs) a possible link between Heroin-associated Nephropathy (HAN) and HIV-associated Nephropathy (HIVAN). AB - In 1970s, Heroin-associated Nephropathy (HAN), one form of focal and segmental glomerulosclerosis (FSGS), was a predominant cause of End-stage Kidney Disease (ESKD) in African-Americans (AAs). In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS) in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN) markedly increased. Recent studies in AAs have identified APOL1 variants (Vs) as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of occurrence of both HAN and HIVAN in AAs. AAs with APOL1Vs develop idiopathic FSGS at four-fold higher rate compared to European Americans (EAs). Similarly, HIV infected AAs with APOL1Vs (if not on antiviral therapy), risk a 50% (10-fold greater) chance of developing HIVAN. It has been suggested that APOL1Vs expression may render podocytes more vulnerable to various types of injury: bacterial, viral, and others. However, in addition to genetic variants, additional factors such as persistence of a second hit may determine the nature and severity of glomerular disease. In patients with HAN, heroin or contaminants may have been the offending second insult(s) which caused renal disease in susceptible AA patients. In the 80's, since heroin-induced second hit was neither consistent nor sustained (depending on drug availability in the street), the disease was masked or replaced HIV infected patients (especially in untreated subjects), by an overwhelming second hit by the virus which was both intense as well as persistent. It appears that APOL1Vs may be one of the links between the disappearance of HAN and emergence of HIVAN in AA patients. PMID- 26106374 TI - Diversity of the Epsilonproteobacteria Dsb (disulfide bond) systems. AB - The bacterial proteins of the Dsb family-important components of the post translational protein modification system-catalyze the formation of disulfide bridges, a process that is crucial for protein structure stabilization and activity. Dsb systems play an essential role in the assembly of many virulence factors. Recent rapid advances in global analysis of bacteria have thrown light on the enormous diversity among bacterial Dsb systems. While the Escherichia coli disulfide bond-forming system is quite well understood, the mechanisms of action of Dsb systems in other bacteria, including members of class Epsilonproteobacteria that contain pathogenic and non-pathogenic bacteria colonizing extremely diverse ecological niches, are poorly characterized. Here we present a review of current knowledge on Epsilonproteobacteria Dsb systems. We have focused on the Dsb systems of Campylobacter spp. and Helicobacter spp. because our knowledge about Dsb proteins of Wolinella and Arcobacter spp. is still scarce and comes mainly from bioinformatic studies. Helicobacter pylori is a common human pathogen that colonizes the gastric epithelium of humans with severe consequences. Campylobacter spp. is a leading cause of zoonotic enteric bacterial infections in most developed and developing nations. We focus on various aspects of the diversity of the Dsb systems and their influence on pathogenicity, particularly because Dsb proteins are considered as potential targets for a new class of anti-virulence drugs to treat human infections by Campylobacter or Helicobacter spp. PMID- 26106377 TI - Characterization and evaluation of antimicrobial and cytotoxic effects of Streptomyces sp. HUST012 isolated from medicinal plant Dracaena cochinchinensis Lour. AB - A highly potent secondary metabolite producing endophytic strain, Streptomyces sp. HUST012 was isolated from the stems of the medicinal plant Dracaena cochinchinensis Lour. Strain HUST012 showed antimicrobial and antitumor activities which were significantly much higher than those of dragon's blood extracted from D. cochinchinensis Lour. On further analysis, the strain was found to produce two metabolites, SPE-B11.8 (elucidated to be a novel metabolite (Z) tridec-7-ene-1,2,13-tricarboxylic acid) and SPE-B5.4 (elucidated as Actinomycin D). The Minimum Inhibitory Concentration values of SPE-B11.8 against a set of test bacterial organisms (Methicillin-resistant Staphylococcus epidermis ATCC 35984, Methicillin-resistant Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, and Klebsiella pneumoniae ATCC 13883) ranged between 15.63 and 62.5 MUg/ml while that for SPE-B5.4 ranged between 0.04 and 2.24 MUg/ml. The compound SPE-B11.8 showed cytotoxic effect at 41.63 and 29.54 MUg/ml IC 50-values against Hep G2 and MCF-7, respectively, while the compound SPE-B5.4 exhibited stronger activities against them at 0.23 and 0.18 MUg/ml IC 50-values. PMID- 26106378 TI - Integrative conjugative elements of the ICEPan family play a potential role in Pantoea ananatis ecological diversification and antibiosis. AB - Pantoea ananatis is a highly versatile enterobacterium isolated from diverse environmental sources. The ecological diversity of this species may be attributed, in part, to the acquisition of mobile genetic elements. One such element is an Integrative and Conjugative Element (ICE). By means of in silico analyses the ICE elements belonging to a novel family, ICEPan, were identified in the genome sequences of five P. ananatis strains and characterized. PCR screening showed that ICEPan is prevalent among P. ananatis strains isolated from different environmental sources and geographic locations. Members of the ICEPan family share a common origin with ICEs of other enterobacteria, as well as conjugative plasmids of Erwinia spp. Aside from core modules for ICEPan integration, maintenance and dissemination, the ICEPan contain extensive non-conserved islands coding for proteins that may contribute toward various phenotypes such as stress response and antibiosis, and the highly diverse ICEPan thus plays a major role in the diversification of P. ananatis. An island is furthermore integrated within an ICEPan DNA repair-encoding locus umuDC and we postulate its role in stress induced dissemination and/or expression of the genes on this island. PMID- 26106379 TI - Mechanism of antibacterial action of the alcoholic extracts of Hemidesmus indicus (L.) R. Br. ex Schult, Leucas aspera (Wild.), Plumbago zeylanica L., and Tridax procumbens (L.) R. Br. ex Schult. AB - Herbal products derived from Hemidesmus indicus (L.) R. Br. ex Schult, Leucas aspera (Wild.), Plumbago zeylanica L., and Tridax procumbens (L.) R. Br. ex Schult. are widely used in traditional medicine. Though the extracts of these plants were found to be antimicrobial in nature and have the potential to be used in clinics, the mechanism of action of is not reported. The ethanolic extracts of Hemidesmus indicus (L.) R. Br. ex Schult, Hemidesmus indicus ethanolic extract (HIEE), Leucas aspera (Wild.), Leucas aspera ethanolic extract (LAEE), Plumbago zeylanica L., Plumbago zeylanica ethanolic extract (PZEE), and Tridax procumbens (L.) R. Br. ex Schult, Tridax procumbens ethanolic extract (TPEE) were tested for their antibacterial activity against E. coli. Antibacterial activity was analyzed by CFU assay and the effect on the bacterial membrane by fluorescence activated cell sorting and scanning electron microscopy. LAEE, PZEE, and HIEE displayed potent bacterial killing activity in a time and concentration dependent manner. TPEE did not display appreciable antibacterial activity. The antibacterial action involved disruption of membrane potential, inner membrane permeabilization, blebbing and leakage of cellular contents. Our results contribute to the understanding of the antibacterial mechanism of alcoholic extracts of the medicinal plants used in this study. PMID- 26106380 TI - Allergies, Helicobacter pylori and the continental enigmas. AB - Helicobacter pylori, a gastric pathogen, is known to be associated with gastric and duodenal ulcers, and is also a strong risk factor for the development of gastric cancer and lymphoma of the mucosal-associated lymphoid tissue. Ordinarily, this should make a strong case for its eradication at par with any other infectious disease. However, the unique biology of H. pylori and the complexity of its interactions with humans, its only known natural host, do not permit the recommendation of unambiguous preventive and therapeutic measures. Moreover, this organism has co-evolved with humans as a practically universal member of the natural gastric microbiota over at least 100,000 years. H. pylori persists for a lifetime in mostly asymptomatic hosts, and causes clinical disease only in a minority of infections. Therefore, its potential contribution to the maintenance of human immune homeostasis, as is the case with the better-studied members of the intestinal microbiota, is certainly worthy of serious investigation. In this paper, we summarize some interesting and often anecdotal data drawn from recent studies, and examine their significance in the context of the hygiene hypothesis. We also examine whether the lower incidence of gastric cancer over large parts of the world in spite of a high prevalence of infection (the Asian and African enigmas) may be re-interpreted in terms of the hygiene hypothesis. Finally, it is suggested that an evolutionary-ecological approach to the study of H. pylori infection may help in the formulation of strategies for the management of this infection. This may well be an infectious disease wherein medical interventions may have to be personalized to ensure optimal outcomes. PMID- 26106382 TI - Effect of age on the pathogenesis of duck tembusu virus in Cherry Valley ducks. AB - The effect of host age on the outcome of duck tembusu virus (DTMUV) infection was studied in ducks. Three groups of Cherry Valley ducks at 1, 3, and 7 weeks of age were intramuscularly infected with DTMUV to systematically observe the clinical symptoms, pathological changes, tissue viral loads, and immune responses. Severe clinical symptoms and neurological dysfunction were observed in 1-week-old ducks as early as 2 days post infection (dpi) and some died at 5-7 dpi. Three weeks-old ducks showed similar but milder symptoms and no deaths. However, 7-weeks-old ducks showed only transient loss of appetite. Gross lesions gradually reduced in severity as ducks matured. One-week-old ducks showed endocardial hemorrhage, splenomegaly, swelling in the lymph follicles of the ileum, liver, and kidney swelling with degeneration, and meningeal hyperemia. Three-weeks-old ducks showed only mild pathological lesions. No visible lesions were observed in 7-weeks-old ducks. However, pathological histology analysis demonstrated all infected ducks displayed viral encephalitis. DTMUV could be detected in the brains of 1-week-old ducks as early as 1 dpi and virus titers of most organs in 1-week-old ducks were significantly higher than that of 3- and 7-weeks-old ducks at 3-5 dpi. The patterns of IFN-gamma, IL-2, and serum neutralizing antibodies were similar, and there were significant difference between the youngest ducks and the older ducks at early infection stage (P < 0.05). More important is that although the antibody titers of all infected ducks were similar from 9 to 17 dpi, reduced clearance of virus was observed in the youngest groups comparing with the other two groups, indicating that immune system maturity was more important than the presence of neutralizing antibody. In summary, this study demonstrates that viral pathogenesis is strongest in 1-week-old ducks and the age-related immune response plays an important role in the pathogenesis of DTMUV in ducks. PMID- 26106381 TI - Molecular mechanisms for the evolution of bacterial morphologies and growth modes. AB - Bacteria exhibit a rich diversity of morphologies. Within this diversity, there is a uniformity of shape for each species that is replicated faithfully each generation, suggesting that bacterial shape is as selectable as any other biochemical adaptation. We describe the spatiotemporal mechanisms that target peptidoglycan synthesis to different subcellular zones to generate the rod-shape of model organisms Escherichia coli and Bacillus subtilis. We then demonstrate, using the related genera Caulobacter and Asticcacaulis as examples, how the modularity of the core components of the peptidoglycan synthesis machinery permits repositioning of the machinery to achieve different growth modes and morphologies. Finally, we highlight cases in which the mechanisms that underlie morphological evolution are beginning to be understood, and how they depend upon the expansion and diversification of the core components of the peptidoglycan synthesis machinery. PMID- 26106383 TI - Isolation and characterization of a beta-propeller gene containing phosphobacterium Bacillus subtilis strain KPS-11 for growth promotion of potato (Solanum tuberosum L.). AB - Phosphate-solubilizing and phytate-mineralizing bacteria collectively termed as phosphobacteria provide a sustainable approach for managing P-deficiency in agricultural soils by supplying inexpensive phosphate to plants. A phosphobacterium Bacillus subtilis strain KPS-11 (Genbank accession no. KP006655) was isolated from potato (Solanum tuberosum L.) rhizosphere and characterized for potato plant growth promoting potential. The strain utilized both Ca-phosphate and Na-phytate in vitro and produced 6.48 MUg mL(-1) indole-3-acetic acid in tryptophan supplemented medium. P-solubilization after 240 h was 66.4 MUg mL(-1) alongwith the production of 19.3 MUg mL(-1) gluconic acid and 5.3 MUg mL(-1) malic acid. The extracellular phytase activity was higher (4.3 * 10(-10) kat mg( 1) protein) than the cell-associated phytase activity (1.6 * 10(-10) kat mg(-1) protein). B. subtilis strain KPS-11 utilized 40 carbon sources and showed resistance against 20 chemicals in GENIII micro-plate system demonstrating its metabolic potential. Phytase-encoding gene beta-propeller (BPP) showed 92% amino acid similarity to BPP from B. subtilis (accession no.WP_014114128.1) and 83% structural similarity to BPP from B. subtilis (accession no 3AMR_A). Potato inoculation with B. subtilis strain KPS-11 increased the root/shoot length and root/shoot weight of potato as compared to non-inoculated control plants. Moreover, rifampicin-resistant derivative of KPS-11 were able to survive in the rhizosphere and on the roots of potato up to 60 days showing its colonization potential. The study indicates that B. subtilis strain KPS-11 can be a potential candidate for development of potato inoculum in P-deficient soils. PMID- 26106384 TI - Hyaluronan, Inflammation, and Breast Cancer Progression. AB - Breast cancer-induced inflammation in the tumor reactive stroma supports invasion and malignant progression and is contributed to by a variety of host cells including macrophages and fibroblasts. Inflammation appears to be initiated by tumor cells and surrounding host fibroblasts that secrete pro-inflammatory cytokines and chemokines and remodel the extracellular matrix (ECM) to create a pro-inflammatory "cancerized" or tumor reactive microenvironment that supports tumor expansion and invasion. The tissue polysaccharide hyaluronan (HA) is an example of an ECM component within the cancerized microenvironment that promotes breast cancer progression. Like many ECM molecules, the function of native high molecular weight HA is altered by fragmentation, which is promoted by oxygen/nitrogen free radicals and release of hyaluronidases within the tumor microenvironment. HA fragments are pro-inflammatory and activate signaling pathways that promote survival, migration, and invasion within both tumor and host cells through binding to HA receptors such as CD44 and RHAMM/HMMR. In breast cancer, elevated HA in the peri-tumor stroma and increased HA receptor expression are prognostic for poor outcome and are associated with disease recurrence. This review addresses the critical issues regarding tumor-induced inflammation and its role in breast cancer progression focusing specifically on the changes in HA metabolism within tumor reactive stroma as a key factor in malignant progression. PMID- 26106385 TI - The Role of Infection and Inflammation in Stillbirths: Parallels with SIDS? AB - It has been suggested that stillbirths are part of the spectrum of infant deaths that includes sudden infant death syndrome (SIDS). This paper examines the hypothesis that risk factors associated with stillbirths might contribute to dysregulation of inflammatory responses to infections that could trigger the physiological responses leading to fetal loss. These include genetic factors (ethnic group, sex), environmental (infection, cigarette smoke, obesity), and developmental (testosterone levels) factors. Interactions between the genetic, environmental, and developmental risk factors are also considered, e.g., the excess of male stillborn infants in relation to the effects of testosterone levels during development on pro-inflammatory responses. In contrast to SIDS, inflammatory responses of both mother and fetus need to be considered. Approaches for examining the hypothesis are proposed. PMID- 26106386 TI - Differential Cytotoxicity but Augmented IFN-gamma Secretion by NK Cells after Interaction with Monocytes from Humans, and Those from Wild Type and Myeloid Specific COX-2 Knockout Mice. AB - The list of genes, which augment NK cell function when knocked out in neighboring cells is increasing, and may point to the fundamental function of NK cells targeting cells with diminished capability to differentiate optimally since NK cells are able to target less differentiated cells, and aid in their differentiation. In this paper, we aimed at understanding the effect of monocytes from targeted knockout of COX-2 in myeloid cells (Cox-2(flox/flox);LysM(Cre/) (+)) and from control littermates (Cox-2(flox/flox);LysM (+) (/) (+)) on ex vivo function of NK cells. Furthermore, we compared the effect of monocytes treated with and without lipopolysaccharide (LPS) on NK cells from mice and humans. NK cells purified from Cox-2(flox/flox);LysM(Cre/) (+) mice had heightened cytotoxic activity when compared to those obtained from control littermates. In addition, NK cells cultured with autologous Cox-2(flox/flox);LysM(Cre/) (+) monocytes and DCs, mouse embryonic fibroblasts from global knockout COX-2, but not with knockout of COX-2 in T cells, had increased cytotoxic function as well as augmented IFN-gamma secretion when compared to NK cells from control littermates cultured with monocytes. LPS inhibited NK cell cytotoxicity while increasing IFN gamma secretion when cultured in the presence of monocytes from either Cox 2(flox/flox);LysM(Cre/) (+) or control littermates. In contrast to mice, NK cells from humans when cultured with monocytes lost cytotoxic function and gained ability to secrete large amounts of IFN-gamma, a process, which we had previously coined as "split anergy." Similar to mice, LPS potentiated the loss of human NK cell cytotoxicity while increasing IFN-gamma secretion in the presence of monocytes. Greater loss of cytotoxicity and larger secretion of IFN-gamma in NK cells induced by gene knockout cells may be important for the greater need of these cells for differentiation. PMID- 26106388 TI - AMD3100/CXCR4 Inhibitor. PMID- 26106389 TI - Finding Fusin/CXCR4, the First "2nd Receptor" for HIV Entry. PMID- 26106391 TI - CXCL8 - The First Chemokine. PMID- 26106390 TI - NKG2D is a Key Receptor for Recognition of Bladder Cancer Cells by IL-2-Activated NK Cells and BCG Promotes NK Cell Activation. AB - Intravesical instillation of bacillus Calmette-Guerin (BCG) is used to treat superficial bladder cancer, either papillary tumors (after transurethral resection) or high-grade flat carcinomas (carcinoma in situ), reducing recurrence in about 70% of patients. Initially, BCG was proposed to work through an inflammatory response, mediated by phagocytic uptake of mycobacterial antigens and cytokine release. More recently, other immune effectors such as monocytes, natural killer (NK), and NKT cells have been suggested to play a role in this immune response. Here, we provide a comprehensive study of multiple bladder cancer cell lines as putative targets for immune cells and evaluated their recognition by NK cells in the presence and absence of BCG. We describe that different bladder cancer cells can express multiple activating and inhibitory ligands for NK cells. Recognition of bladder cancer cells depended mainly on NKG2D, with a contribution from NKp46. Surprisingly, exposure to BCG did not affect the immune phenotype of bladder cells nor increased NK cell recognition of purified IL-2-activated cell lines. However, NK cells were activated efficiently when BCG was included in mixed lymphocyte cultures, suggesting that NK activation after mycobacteria treatment requires the collaboration of various immune cells. We also analyzed the percentage of NK cells in peripheral blood of a cohort of bladder cancer patients treated with BCG. The total numbers of NK cells did not vary during treatment, indicating that a more detailed study of NK cell activation in the tumor site will be required to evaluate the response in each patient. PMID- 26106392 TI - TCR-Signaling Events in Cellular Metabolism and Specialization. AB - Engaging the T cell receptor (TCR) with peptide:MHC complexes initiates a cascade of signaling events that activates T cells in an antigen-specific manner. It is now clear that multiple inputs, including the strength of TCR signaling, co stimulation, and the cytokine environment, impact T cell specialization decisions in the context of specific pathogenic encounters. Additionally, it is now appreciated that these same stimuli direct cellular metabolism programs. In this review, we will discuss how TCR-signaling events coordinate cellular metabolism and specialization gene programs in T cells. PMID- 26106393 TI - Chemokines and HIV: The First Close Encounter. PMID- 26106394 TI - CCR5 and HIV Infection, a View from Brussels. PMID- 26106395 TI - CXCR5, the Defining Marker for Follicular B Helper T (TFH) Cells. PMID- 26106387 TI - Pathogenesis of Systemic Sclerosis. AB - Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc. PMID- 26106396 TI - In vivo TCR Signaling in CD4(+) T Cells Imprints a Cell-Intrinsic, Transient Low Motility Pattern Independent of Chemokine Receptor Expression Levels, or Microtubular Network, Integrin, and Protein Kinase C Activity. AB - Intravital imaging has revealed that T cells change their migratory behavior during physiological activation inside lymphoid tissue. Yet, it remains less well investigated how the intrinsic migratory capacity of activated T cells is regulated by chemokine receptor levels or other regulatory elements. Here, we used an adjuvant-driven inflammation model to examine how motility patterns corresponded with CCR7, CXCR4, and CXCR5 expression levels on ovalbumin-specific DO11.10 CD4(+) T cells in draining lymph nodes. We found that while CCR7 and CXCR4 surface levels remained essentially unaltered during the first 48-72 h after activation of CD4(+) T cells, their in vitro chemokinetic and directed migratory capacity to the respective ligands, CCL19, CCL21, and CXCL12, was substantially reduced during this time window. Activated T cells recovered from this temporary decrease in motility on day 6 post immunization, coinciding with increased migration to the CXCR5 ligand CXCL13. The transiently impaired CD4(+) T cell motility pattern correlated with increased LFA-1 expression and augmented phosphorylation of the microtubule regulator Stathmin on day 3 post immunization, yet neither microtubule destabilization nor integrin blocking could reverse TCR imprinted unresponsiveness. Furthermore, protein kinase C (PKC) inhibition did not restore chemotactic activity, ruling out PKC-mediated receptor desensitization as mechanism for reduced migration in activated T cells. Thus, we identify a cell-intrinsic, chemokine receptor level-uncoupled decrease in motility in CD4(+) T cells shortly after activation, coinciding with clonal expansion. The transiently reduced ability to react to chemokinetic and chemotactic stimuli may contribute to the sequestering of activated CD4(+) T cells in reactive peripheral lymph nodes, allowing for integration of costimulatory signals required for full activation. PMID- 26106398 TI - Fructans and other water soluble carbohydrates in vegetative organs and fruits of different Musa spp. accessions. AB - The water soluble carbohydrates (WSC) glucose, fructose, and sucrose are well known to the great public, but fructans represent another type of WSC that deserves more attention given their prebiotic and immunomodulatory properties in the food context. Although the occurrence of inulin-type fructo-oligosaccharides (FOS) was proposed in the fruit of some banana accessions, little or no information is available neither on the exact identity of the fructan species, nor on the fructan content in different parts of banana plants and among a broader array of banana cultivars. Here, we investigated the WSC composition in leaves, pulp of ripe fruits and rhizomes from mature banana plants of 11 accessions (I to XI), including both cultivated varieties and wild Musa species. High performance anion exchange chromatography with integrated pulsed amperometric detection (HPAEC-IPAD) showed the presence of 1-kestotriose [GF2], inulobiose [F2], inulotriose [F3], 6-kestotriose and 6G-kestotriose (neokestose) fructan species in the pulp of mature fruits of different accessions, but the absence of 1,1-nystose and 1,1,1 kestopentaose and higher degree of polymerization (DP) inulin-type fructans. This fructan fingerprint points at the presence of one or more invertases that are able to use fructose and sucrose as alternative acceptor substrates. Quantification of glucose, fructose, sucrose and 1-kestotriose and principal component analysis (PCA) identified related banana groups, based on their specific WSC profiles. These data provide new insights in the biochemical diversity of wild and cultivated bananas, and shed light on potential roles that fructans may fulfill across species, during plant development and adaptation to changing environments. Furthermore, the promiscuous behavior of banana fruit invertases (sucrose and fructose as acceptor substrates besides water) provides a new avenue to boost future work on structure-function relationships on these enzymes, potentially leading to the development of genuine banana fructosyltransferases that are able to increase fructan content in banana fruits. PMID- 26106399 TI - Emerging roles of long non-coding RNA in root developmental plasticity and regulation of phosphate homeostasis. AB - Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression in a variety of biological process and in multiple species. In plants, they are transcribed by different RNA polymerases and show diverse structural features. With the aid of next-generation sequencing technologies, a large number of lncRNA have been identified in model plants as well as in crops. This review focuses on the demonstration that lncRNAs control root system architecture, notably in response to phosphate availability, through regulation of transcription, alternative splicing, microRNA activity, messenger RNA stability and translation, illustrating remarkable diversity in their roles in regulating developmental plasticity. PMID- 26106397 TI - Biotechnological strategies and tools for Plum pox virus resistance: trans-, intra-, cis-genesis, and beyond. AB - Plum pox virus (PPV) is the etiological agent of sharka, the most devastating and economically important viral disease affecting Prunus species. It is widespread in most stone fruits producing countries even though eradication and quarantine programs are in place. The development of resistant cultivars and rootstocks remains the most ecologically and economically suitable approach to achieve long term control of sharka disease. However, the few PPV resistance genetic resources found in Prunus germplasm along with some intrinsic biological features of stone fruit trees pose limits for efficient and fast breeding programs. This review focuses on an array of biotechnological strategies and tools, which have been used, or may be exploited to confer PPV resistance. A considerable number of scientific studies clearly indicate that robust and predictable resistance can be achieved by transforming plant species with constructs encoding intron-spliced hairpin RNAs homologous to conserved regions of the PPV genome. In addition, we discuss how recent advances in our understanding of PPV biology can be profitably exploited to develop viral interference strategies. In particular, genetic manipulation of host genes by which PPV accomplishes its infection cycle already permits the creation of intragenic resistant plants. Finally, we review the emerging genome editing technologies based on ZFN, TALEN and CRISPR/Cas9 engineered nucleases and how the knockout of host susceptibility genes will open up next generation of PPV resistant plants. PMID- 26106400 TI - AtPGL3 is an Arabidopsis BURP domain protein that is localized to the cell wall and promotes cell enlargement. AB - The BURP domain is a plant-specific domain that has been identified in secretory proteins, and some of these are involved in cell wall modification. The tomato polygalacturonase I complex involved in pectin degradation in ripening fruits has a non-catalytic subunit that has a BURP domain. This protein is called polygalacturonase 1 beta (PG1beta) and the Arabidopsis genome encodes three proteins that exhibit strong amino acid similarities with PG1beta? We generated Arabidopsis lines in which expression levels of AtPGLs are altered in order to investigate the biological roles of the Arabidopsis PG1beta-like proteins (AtPGLs). Among the three AtPGLs (AtPGL1-3), AtPGL3 exhibited the highest transcriptional activity throughout all developmental stages. AtPGL triple mutant plants have smaller rosette leaves than those of wild type plants because the leaf cells are smaller in the mutant plants. Interestingly, when we overexpressed AtPGL3 using a 35S promoter, leaf cells in transgenic plants grew larger than those of the wild type. A C-terminal GFP fusion protein of AtPGL3 complemented phenotypes of the triple mutant plants and it localized to the cell wall. A truncated AtPGL3-GFP fusion protein lacking the BURP domain failed to rescue the mutant phenotypes even though the GFP protein was targeted to the cell wall, indicating that the BURP domain is required for the protein's effect on cell expansion. Quantitative RT-PCR and immunoblot analyses indicated that the alpha expansin 6 gene is up-regulated in the overexpressor plants. Taken together, these results indicate that AtPGL3 is an apoplastic BURP domain protein playing a role in cell expansion. PMID- 26106401 TI - Closing the loop on the GABA shunt in plants: are GABA metabolism and signaling entwined? AB - gamma-Aminobutyric acid (GABA) is a non-proteinogenic amino acid that is found in uni- and multi-cellular organisms and is involved in many aspects of plant life cycle. GABA metabolism occurs by the action of evolutionary conserved enzymes that constitute the GABA shunt, bypassing two steps of the TCA cycle. The central position of GABA in the interface between plant carbon and nitrogen metabolism is well established. In parallel, there is evidence to support a role for GABA as a signaling molecule in plants. Here we cover some of the recent findings on GABA metabolism and signaling in plants and further suggest that the metabolic and signaling aspects of GABA may actually be inseparable. PMID- 26106402 TI - Re-analysis of RNA-seq transcriptome data reveals new aspects of gene activity in Arabidopsis root hairs. AB - Root hairs, tubular-shaped outgrowths from root epidermal cells, play important roles in the acquisition of nutrients and water, interaction with microbe, and in plant anchorage. As a specialized cell type, root hairs, especially in Arabidopsis, provide a pragmatic research system for various aspects of studies. Here, we re-analyzed the RNA-seq transcriptome profile of Arabidopsis root hair cells by Tophat software and used Cufflinks program to mine the differentially expressed genes. Results showed that ERD14, RIN4, AT5G64401 were among the most abundant genes in the root hair cells; while ATGSTU2, AT5G54940, AT4G30530 were highly expressed in non-root hair tissues. In total, 5409 genes, with a fold change greater than two-fold (FDR adjusted P < 0.05), showed differential expression between root hair cells and non-root hair tissues. Of which, 61 were expressed only in root hair cells. One hundred and thirty-six out of 5409 genes have been reported to be "core" root epidermal genes, which could be grouped into nine clusters according to expression patterns. Gene ontology (GO) analysis of the 5409 genes showed that processes of "response to salt stress," "ribosome biogenesis," "protein phosphorylation," and "response to water deprivation" were enriched. Whereas only process of "intracellular signal transduction" was enriched in the subset of 61 genes expressed only in the root hair cells. One hundred and twenty-one unannotated transcripts were identified and 14 of which were shown to be differentially expressed between root hair cells and non-root hair tissues, with transcripts XLOC_000763, XLOC_031361, and XLOC_005665 being highly expressed in the root hair cells. The comprehensive transcriptomic analysis provides new information on root hair gene activity and sets the stage for follow-up experiments to certify the biological functions of the newly identified genes and novel transcripts in root hair cell morphogenesis. PMID- 26106404 TI - Transcriptome analysis of the compatible interaction of tomato with Verticillium dahliae using RNA-sequencing. AB - Tomato Verticillium wilt is a soil-borne vascular disease caused by the necrotrophic fungus Verticillium dahliae. Although some understanding of plant defense mechanisms against V. dahliae infection has been gained for incompatible interactions, including identification of inducible resistant genes and defense signaling pathways, the genes and signaling pathways involved in the compatible interaction remain unclear. To investigate the molecular basis of the compatible interaction between tomato and V. dahliae, transcriptomes of V. dahliae infected tomatoes were compared to those of a control group. A total of approximately 25 million high-quality reads were generated by means of the RNA sequencing (RNA seq) method. The sequence reads were aligned to the tomato reference genome and analyzed to measure gene expression levels, and to identify alternative splicing events. Comparative analysis between the two samples revealed 1,953 significantly differentially expressed genes (DEGs), including 1,281 up-regulated and 672 down regulated genes. The RNA-Seq output was confirmed using RT-qPCR for 10 selected genes. The Nr, Swiss-Prot, Gene Ontology (GO), Clusters of Orthologous Groups (COG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to annotate DEG functions. Of the 1,953 DEGs identified, 1,953, 1,579, 1,739, 862, and 380 were assigned by Nr, Swiss-Prot, GO, COG, and KEGG, respectively. The important functional groups identified via GO and COG enrichment were those responsible for fundamental biological regulation, secondary metabolism, and signal transduction. Of DEGs assigned to 87 KEGG pathways, most were associated with phenylpropanoid metabolism and plant-pathogen interaction pathways. Most of the DEGs involved in these two pathways were up-regulated, and may be involved in regulating the tomato-V. dahliae compatible interaction. The results will help to identify key susceptible genes and contribute to a better understanding of the mechanisms of tomato susceptible response to V. dahliae. PMID- 26106403 TI - Interactions between plant endomembrane systems and the actin cytoskeleton. AB - Membrane trafficking, organelle movement, and morphogenesis in plant cells are mainly controlled by the actin cytoskeleton. Not all proteins that regulate the cytoskeleton and membrane dynamics in animal systems have functional homologs in plants, especially for those proteins that form the bridge between the cytoskeleton and membrane; the membrane-actin adaptors. Their nature and function is only just beginning to be elucidated and this field has been greatly enhanced by the recent identification of the NETWORKED (NET) proteins, which act as membrane-actin adaptors. In this review, we will summarize the role of the actin cytoskeleton and its regulatory proteins in their interaction with endomembrane compartments and where they potentially act as platforms for cell signaling and the coordination of other subcellular events. PMID- 26106405 TI - Construction of chromosome segment substitution lines enables QTL mapping for flowering and morphological traits in Brassica rapa. AB - Chromosome segment substitution lines (CSSLs) represent a powerful method for precise quantitative trait loci (QTL) detection of complex agronomical traits in plants. In this study, we used a marker-assisted backcrossing strategy to develop a population consisting of 63 CSSLs, derived from backcrossing of the F1 generated from a cross between two Brassica rapa subspecies: "Chiifu" (ssp. pekinensis), the Brassica "A" genome-represented line used as the donor, and "49caixin" (ssp. parachinensis), a non-heading cultivar used as the recipient. The 63 CSSLs covered 87.95% of the B. rapa genome. Among them, 39 lines carried a single segment; 15 lines, two segments; and nine lines, three or more segments of the donor parent chromosomes. To verify the potential advantage of these CSSL lines, we used them to locate QTL for six morphology-related traits. A total of 58 QTL were located on eight chromosomes for all six traits: 17 for flowering time, 14 each for bolting time and plant height, six for plant diameter, two for leaf width, and five for flowering stalk diameter. Co-localized QTL were mainly distributed on eight genomic regions in A01, A02, A05, A06, A08, A09, and A10, present in the corresponding CSSLs. Moreover, new chromosomal fragments that harbored QTL were identified using the findings of previous studies. The CSSL population constructed in our study paves the way for fine mapping and cloning of candidate genes involved in late bolting, flowering, and plant architecture related traits in B. rapa. Furthermore, it has great potential for future marker aided gene/QTL pyramiding of other interesting traits in B. rapa breeding. PMID- 26106406 TI - Potential for bias and low precision in molecular divergence time estimation of the Canopy of Life: an example from aquatic bird families. AB - Uncertainty in divergence time estimation is frequently studied from many angles but rarely from the perspective of phylogenetic node age. If appropriate molecular models and fossil priors are used, a multi-locus, partitioned analysis is expected to equally minimize error in accuracy and precision across all nodes of a given phylogeny. In contrast, if available models fail to completely account for rate heterogeneity, substitution saturation and incompleteness of the fossil record, uncertainty in divergence time estimation may increase with node age. While many studies have stressed this concern with regard to deep nodes in the Tree of Life, the inference that molecular divergence time estimation of shallow nodes is less sensitive to erroneous model choice has not been tested explicitly in a Bayesian framework. Because of available divergence time estimation methods that permit fossil priors across any phylogenetic node and the present increase in efficient, cheap collection of species-level genomic data, insight is needed into the performance of divergence time estimation of shallow (<10 MY) nodes. Here, we performed multiple sensitivity analyses in a multi-locus data set of aquatic birds with six fossil constraints. Comparison across divergence time analyses that varied taxon and locus sampling, number and position of fossil constraint and shape of prior distribution showed various insights. Deviation from node ages obtained from a reference analysis was generally highest for the shallowest nodes but determined more by temporal placement than number of fossil constraints. Calibration with only the shallowest nodes significantly underestimated the aquatic bird fossil record, indicating the presence of saturation. Although joint calibration with all six priors yielded ages most consistent with the fossil record, ages of shallow nodes were overestimated. This bias was found in both mtDNA and nDNA regions. Thus, divergence time estimation of shallow nodes may suffer from bias and low precision, even when appropriate fossil priors and best available substitution models are chosen. Much care must be taken to address the possible ramifications of substitution saturation across the entire Tree of Life. PMID- 26106407 TI - The role of INDY in metabolism, health and longevity. AB - Indy (I'm Not Dead Yet) encodes the fly homolog of a mammalian SLC13A5 plasma membrane transporter. INDY is expressed in metabolically active tissues functioning as a transporter of Krebs cycle intermediates with the highest affinity for citrate. Decreased expression of the Indy gene extends longevity in Drosophila and C. elegans. Reduction of INDY or its respective homologs in C. elegans and mice induces metabolic and physiological changes similar to those observed in calorie restriction. It is thought that these physiological changes are due to altered levels of cytoplasmic citrate, which directly impacts Krebs cycle energy production as a result of shifts in substrate availability. Citrate cleavage is a key event during lipid and glucose metabolism; thus, reduction of citrate due to Indy reduction alters these processes. With regards to mammals, mice with reduced Indy (mIndy(-/-)) also exhibit changes in glucose metabolism, mitochondrial biogenesis and are protected from the negative effects of a high calorie diet. Together, these data support a role for Indy as a metabolic regulator, which suggests INDY as a therapeutic target for treatment of diet and age-related disorders such as Type II Diabetes and obesity. PMID- 26106408 TI - PPAR-Alpha Agonist Used at the Acute Phase of Experimental Ischemic Stroke Reduces Occurrence of Thrombolysis-Induced Hemorrhage in Rats. AB - The impact of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, on the risk of thrombolysis-induced hemorrhage during the acute phase of stroke in a rat model of stroke was studied. One-hour middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator was made in rats receiving either fenofibrate or vehicle for 72 h after stroke. Evaluation of infarct, hemorrhage, middle cerebral artery vasoreactivity, and immunochemistry (CD11b for microglial activation, myeloperoxidase, and ICAM-1 for neutrophil infiltration) was performed. The PPAR-alpha agonist significantly reduced the risk of hemorrhage after thrombolysis in parallel with a decrease in the infarct volume and in the stroke-induced vascular endothelial dysfunction. These effects are concomitant with a reduction in microglial activation and neutrophil infiltration in infarct area. Our results strengthen the idea that using drugs such as fenofibrate, with pleiotropic properties due to PPAR-alpha agonism, may be of value to reduce thrombolysis-induced hemorrhage during acute stroke. PMID- 26106409 TI - A Fuzzy Computing Model for Identifying Polarity of Chinese Sentiment Words. AB - With the spurt of online user-generated contents on web, sentiment analysis has become a very active research issue in data mining and natural language processing. As the most important indicator of sentiment, sentiment words which convey positive and negative polarity are quite instrumental for sentiment analysis. However, most of the existing methods for identifying polarity of sentiment words only consider the positive and negative polarity by the Cantor set, and no attention is paid to the fuzziness of the polarity intensity of sentiment words. In order to improve the performance, we propose a fuzzy computing model to identify the polarity of Chinese sentiment words in this paper. There are three major contributions in this paper. Firstly, we propose a method to compute polarity intensity of sentiment morphemes and sentiment words. Secondly, we construct a fuzzy sentiment classifier and propose two different methods to compute the parameter of the fuzzy classifier. Thirdly, we conduct extensive experiments on four sentiment words datasets and three review datasets, and the experimental results indicate that our model performs better than the state-of-the-art methods. PMID- 26106410 TI - Energy Consumption Forecasting Using Semantic-Based Genetic Programming with Local Search Optimizer. AB - Energy consumption forecasting (ECF) is an important policy issue in today's economies. An accurate ECF has great benefits for electric utilities and both negative and positive errors lead to increased operating costs. The paper proposes a semantic based genetic programming framework to address the ECF problem. In particular, we propose a system that finds (quasi-)perfect solutions with high probability and that generates models able to produce near optimal predictions also on unseen data. The framework blends a recently developed version of genetic programming that integrates semantic genetic operators with a local search method. The main idea in combining semantic genetic programming and a local searcher is to couple the exploration ability of the former with the exploitation ability of the latter. Experimental results confirm the suitability of the proposed method in predicting the energy consumption. In particular, the system produces a lower error with respect to the existing state-of-the art techniques used on the same dataset. More importantly, this case study has shown that including a local searcher in the geometric semantic genetic programming system can speed up the search process and can result in fitter models that are able to produce an accurate forecasting also on unseen data. PMID- 26106411 TI - Rescue Therapy with a Proton Pump Inhibitor Plus Amoxicillin and Rifabutin for Helicobacter pylori Infection: A Systematic Review and Meta-Analysis. AB - Background. To conduct a systematic review and meta-analysis of clinical trials for eradication of Helicobacter pylori (H. pylori) that included a treatment arm with a proton pump inhibitor, rifabutin, and amoxicillin. Materials and Methods. We selected clinical trials that examined the efficacy of H. pylori eradication therapies and included a study arm using the test regimen from major medical literature databases and abstracts from major gastroenterology meetings. We also did subgroup and sensitivity analyses. Results. Twenty-one studies were included in systematic review. The total eradication rates of the test regimen were 70.4% by intent-to-treat (ITT) and 72.0% by per-protocol (PP) analyses. The pooled odds ratio (OR) was 0.55 using fixed effects model (P = 0.283) for the test regimen versus other triple regimens. The total eradication rates were 68.4% for the test regimen and 81.9% in the control group by ITT, while the OR was 1.08 using random effects model (P = 0.019). The pooled eradication rate was 66.4% for the test regimen and 67.4% for the control group by ITT. The total adverse effects incidence were 25.1% for the test regimen. Conclusions. The test regimen for H. pylori rescue therapy may be not superior to control regimens in efficacy. PMID- 26106412 TI - Short-Term Efficacy of Exclusive Enteral Nutrition in Pediatric Crohn's Disease: Practice in China. AB - Aims. The objective of this study was to compare the efficacy of exclusive enteral nutrition (EEN) and corticosteroids in inducing remission in pediatric Crohn's disease (CD) and the effects of the treatment on growth improvements. Methods. Data was retrospectively collected for children and adolescents newly diagnosed with CD in a referral center. Patients who were followed up for more than 2 months with mild to moderate disease were included. Basic demographics, history, physical examination, the pediatric Crohn disease activity index (PCDAI), laboratory findings, endoscopic findings, and adverse effects were recorded. Remission was defined as PCDAI < 10 points. Results. Ten subjects received EEN and 18 patients received corticosteroids. The median follow-up in EEN group and steroid group was 9.2 weeks and 9.6 weeks, respectively. The remission rate in EEN group was significantly higher than that in steroid group (90.0% versus 50.0%, resp., P < 0.05). Growth improvement, which was evaluated by changes in height for age z-score, was more apparent in EEN group than that in steroids group (P < 0.05). No adverse effects were observed in EEN group. Conclusions. In children with mild to moderate CD, EEN is more effective than corticosteroids in improving disease severity and growth deficiency, as well as providing less side effects. PMID- 26106413 TI - Advances in the Endoscopic Management of Obesity. AB - Obesity has become a worldwide epidemic with significant impact on quality of life, morbidity, and mortality rates. Over the past two decades, bariatric surgery has established itself as the most effective and durable treatment for patients with obesity and its associated comorbidities. However, despite the use of minimally invasive techniques, bariatric surgery is associated with complications in approximately 15% of patients, has a substantial cost, and is used by only 1% of patients who are eligible. Therefore, there is a need for effective minimally invasive therapies, which will be utilized by the large proportion of obese patients who are in desperate need of treatment but are not receiving any. Endoscopic approaches to the management of obesity have been developed, with the aim of delivering more effective, durable, and safer methods of weight reduction. In this paper, we review currently available and future endoscopic therapies that will likely join the armamentarium used in the management of obesity. PMID- 26106414 TI - Temozolomide Therapy for Aggressive Pituitary Tumors: Results in a Small Series of Patients from Argentina. AB - We evaluated results of temozolomide (TMZ) therapy in six patients, aged 34-78 years, presenting aggressive pituitary tumors. In all the patients tested O(6) methylguanine-DNA methyltransferase (MGMT) immunoexpression in surgical specimens was absent. Patients received temozolomide 140-320 mg/day for 5 days monthly for at least 3 months. In two patients minimum time for evaluation could not be reached because of death in a 76-year-old man with a malignant prolactinoma and of severe neutro-thrombopenia in a 47-year-old woman with nonfunctioning pituitary adenoma. In two patients (a 34-year-old acromegalic woman and a 39-year old woman with Nelson's syndrome) no response was observed after 4 and 6 months, respectively, and the treatment was stopped. Conversely, two 52- and 42-year-old women with Cushing's disease had long-term total clinical and radiological remissions which persisted after stopping temozolomide. We conclude that TMZ therapy may be of variable efficacy depending on-until now-incompletely understood factors. Cooperative work on a greater number of cases of aggressive pituitary tumors should be crucial to establish the indications, doses, and duration of temozolomide administration. PMID- 26106415 TI - Serum IGFBP-2 and Risk of Atypical Hyperplasia of the Breast. AB - Atypical hyperplasia of the breast (AH) is associated with increased risk of subsequent invasive breast cancer, yet little is known about the etiology of AH. Insulin-like growth factor binding protein 2 (IGFBP-2) may contribute to the development of AH due to its proliferative effects on mammary tissue. We conducted a nested case-control study of postmenopausal women enrolled in Women's Health Initiative-Clinical Trial. Cases were 275 women who developed incident AH during follow-up, individually (1 : 1) matched to controls. Levels of IGFBP-2 were determined from fasting serum collected at baseline. Multivariable conditional logistic regression models were used to estimate odds ratios for the association of IGFBP-2 with risk of AH. Serum IGFBP-2 was associated with a nonsignificant decrease in risk for AH, when comparing the highest quartile to lowest quartile (OR = 0.65; 95% CI = 0.32-1.31). This decrease in risk was most evident when analyses were restricted to nondiabetic, nonusers of hormone therapy (OR = 0.33, 95% CI = 0.13-0.86, p trend = 0.06) and nondiabetic women who were overweight or obese (OR = 0.43, 95% CI = 0.18-1.03, p trend = 0.05). Results from this study provide some support for an inverse association between serum IGFBP2 levels and risk of AH, particularly in nondiabetic women who are overweight or obese. Further studies are required to confirm these results. PMID- 26106416 TI - Caries Experience Differs between Females and Males across Age Groups in Northern Appalachia. AB - Sex disparities in dental caries have been observed across many populations, with females typically exhibiting higher prevalence and more affected teeth. In this study we assessed the sex disparities in two Northern Appalachian populations from West Virginia (WV, N = 1997) and Pennsylvania (PA, N = 1080) by comparing caries indices between males and females across four phases of dental development: primary dentition in children aged 1-5 years, mixed dentition in children aged 6-11 years, permanent dentition in adolescents aged 12-17 years, and permanent dentition in adults aged 18-59 years. No significant sex differences were observed for children aged 1-5 years. Contrary to national and international trends, WV girls aged 6-11 years had 1.5 fewer affected teeth than boys (p < 0.001). However, by ages 12-17, caries indices in the WV girls matched those in boys. In both WV and PA adults, women and men had similar total counts of affected teeth (i.e., DMFT), although women had more dental restorations (p < 0.001) and men had more current decay (p < 0.001). These results suggest that in some Appalachian populations, young girls benefit from protection against caries that is lost during adolescence and that adult women utilize dental health care to a greater degree than men. PMID- 26106417 TI - Intermittent Compressive Stress Enhanced Insulin-Like Growth Factor-1 Expression in Human Periodontal Ligament Cells. AB - Mechanical force was shown to promote IGF-1 expression in periodontal ligament both in vitro and in vivo. Though the mechanism of this effect has not yet been proved, here we investigated the molecular mechanism of intermittent mechanical stress on IGF-1 expression. In addition, the role of hypoxia on the intermittent compressive stress on IGF-1 expression was also examined. In this study, human periodontal ligament cells (HPDLs) were stimulated with intermittent mechanical stress for 24 hours. IGF-1 expression was examined by real-time polymerase chain reaction. Chemical inhibitors were used to determine molecular mechanisms of these effects. For hypoxic mimic condition, the CoCl2 supplementation was employed. The results showed that intermittent mechanical stress dramatically increased IGF-1 expression at 24 h. The pretreatment with TGF-beta receptor I or TGF-beta1 antibody could inhibit the intermittent mechanical stress-induced IGF-1 expression. Moreover, the upregulation of TGF-beta1 proteins was detected in intermittent mechanical stress treated group. Correspondingly, the IGF-1 expression was upregulated upon being treated with recombinant human TGF-beta1. Further, the hypoxic mimic condition attenuated the intermittent mechanical stress and rhTGF-beta1-induced IGF-1 expression. In summary, this study suggests intermittent mechanical stress-induced IGF-1 expression in HPDLs through TGF beta1 and this phenomenon could be inhibited in hypoxic mimic condition. PMID- 26106418 TI - Prognostic Value of Residual Disease after Interval Debulking Surgery for FIGO Stage IIIC and IV Epithelial Ovarian Cancer. AB - Although complete debulking surgery for epithelial ovarian cancer (EOC) is more often achieved with interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT), randomized evidence shows no long-term survival benefit compared to complete primary debulking surgery (PDS). We performed an observational cohort study of patients treated with debulking surgery for advanced EOC to evaluate the prognostic value of residual disease after debulking surgery. All patients treated between 1998 and 2010 in three Dutch referral gynaecological oncology centres were included. The prognostic value of residual disease after surgery for disease specific survival was assessed using Cox regression analyses. In total, 462 patients underwent NACT-IDS and 227 PDS. Macroscopic residual disease after debulking surgery was an independent prognostic factor for survival in both treatment modalities. Yet, residual tumour less than one centimetre at IDS was associated with a survival benefit of five months compared to leaving residual tumour more than one centimetre, whereas this benefit was not seen after PDS. Leaving residual tumour at IDS is a poor prognostic sign as it is after PDS. The specific prognostic value of residual tumour seems to depend on the clinical setting, as minimal instead of gross residual tumour is associated with improved survival after IDS, but not after PDS. PMID- 26106419 TI - Neural Differentiation of Human Adipose Tissue-Derived Stem Cells Involves Activation of the Wnt5a/JNK Signalling. AB - Stem cells are a powerful resource for cell-based transplantation therapies, but understanding of stem cell differentiation at the molecular level is not clear yet. We hypothesized that the Wnt pathway controls stem cell maintenance and neural differentiation. We have characterized the transcriptional expression of Wnt during the neural differentiation of hADSCs. After neural induction, the expressions of Wnt2, Wnt4, and Wnt11 were decreased, but the expression of Wnt5a was increased compared with primary hADSCs in RT-PCR analysis. In addition, the expression levels of most Fzds and LRP5/6 ligand were decreased, but not Fzd3 and Fzd5. Furthermore, Dvl1 and RYK expression levels were downregulated in NI hADSCs. There were no changes in the expression of beta-catenin and GSK3beta. Interestingly, Wnt5a expression was highly increased in NI-hADSCs by real time RT PCR analysis and western blot. Wnt5a level was upregulated after neural differentiation and Wnt3, Dvl2, and Naked1 levels were downregulated. Finally, we found that the JNK expression was increased after neural induction and ERK level was decreased. Thus, this study shows for the first time how a single Wnt5a ligand can activate the neural differentiation pathway through the activation of Wnt5a/JNK pathway by binding Fzd3 and Fzd5 and directing Axin/GSK-3beta in hADSCs. PMID- 26106420 TI - In Vitro Studies of Bacterial Cellulose and Magnetic Nanoparticles Smart Nanocomposites for Efficient Chronic Wounds Healing. AB - The quality of life of patients with chronic wounds can be extremely poor and, therefore, over the past decades, great efforts have been made to develop efficient strategies to improve the healing process and the social impact associated with these conditions. Cell based therapy, as a modern tissue engineering strategy, involves the design of 3D cell-scaffold bioconstructs obtained by preseeding drug loaded scaffolds with undifferentiated cells in order to achieve in situ functional de novo tissue. This paper reports on the development of bionanocomposites based on bacterial cellulose and magnetic nanoparticles (magnetite) for efficient chronic wounds healing. Composites were obtained directly in the cellulose bacterial culture medium by dispersing various amounts of magnetite nanoparticles during the biosynthesis process. After purification and drying, the membranes were characterized by Raman spectroscopy and X-ray diffraction to reveal the presence of magnetite within the bacterial cellulose matrix. Morphological investigation was employed through SEM and TEM analyses on bionanocomposites. The biocompatibility of these innovative materials was studied in relation to human adipose derived stem cells in terms of cellular morphology, viability, and proliferation as well as scaffolds cytotoxic potential. PMID- 26106421 TI - Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. The poor prognosis of colorectal cancer patients is due to development of chemoresistance and cancer metastasis. Recently osteopontin (OPN) has been associated with stem-like properties in colorectal cancer. This study further examined the clinicopathological significance of OPN in CRC and its effect on chemoresistance and transcription of stem cell markers. We examined the transcription level of OPN in 84 CRC patients and correlated the expression with their clinicopathological parameters. The associations of OPN overexpression with transcription of stem cell markers and response to chemotherapy in DLD1-OPN overexpressing clones and CRC patients were also investigated. Our results showed that OPN was significantly overexpressed in CRC, and its overexpression correlated with tumor stage and poor prognosis. Overexpression of CRC induced OCT4 and SOX2 expression in vitro and correlated with SOX2 overexpression in CRC patients. In addition, DLD1-OPN overexpressing cells showed enhanced ability to survive upon oxaliplatin treatment, and OPN expression was higher in CRC patients who were resistant to oxaliplatin-involved chemotherapy treatment. Thus, CRC cells overexpressing OPN demonstrated stem-like properties and OPN inhibition is a potential therapeutic approach to combat CRC progression and chemoresistance. PMID- 26106422 TI - A 3D Porous Gelatin-Alginate-Based-IPN Acts as an Efficient Promoter of Chondrogenesis from Human Adipose-Derived Stem Cells. AB - Cartilage has limited regeneration potential. Thus, there is an imperative need to develop new strategies for cartilage tissue engineering (CTE) amenable for clinical use. Recent CTE approaches rely on optimal cell-scaffold interactions, which require a great deal of optimization. In this study we attempt to build a novel gelatin- (G-) alginate- (A-) polyacrylamide (PAA) 3D interpenetrating network (IPN) with superior performance in promoting chondrogenesis from human adipose-derived stem cells (hADSCs). We show that our G-A-PAA scaffold is capable of supporting hADSCs proliferation and survival, with no apparent cytotoxic effect. Moreover, we find that after exposure to prochondrogenic conditions a key transcription factor known to induce chondrogenesis, namely, Sox9, is highly expressed in our hADSCs/G-A-PAA bioconstruct, along with cartilage specific markers such as collagen type II, CEP68, and COMP extracellular matrix (ECM) components. These data suggest that our G-A-PAA structural properties and formulation might enable hADSCs conversion towards functional chondrocytes. We conclude that our novel G-A-PAA biomatrix is a good candidate for prospective in vivo CTE applications. PMID- 26106423 TI - Protective Effect of Neuropeptide Substance P on Bone Marrow Mesenchymal Stem Cells against Apoptosis Induced by Serum Deprivation. AB - Substance P (SP) contributes to bone formation by stimulating the proliferation and differentiation of bone marrow stromal cells (BMSCs); however, the possible involved effect of SP on apoptosis induced by serum deprivation (SD) in BMSCs is unclear. To explore the potential protective effect of SP and its mechanism, we investigated the relationships among SP, apoptosis induced by SD, and Wnt signaling in BMSCs. SP exhibited a protective effect, as indicated by a reduction in the apoptotic rate, nuclear condensation, caspase-3 and caspase-9 activation, and the ratio of Bax/Bcl-2 that was observed after 24 h of SD. This protective effect was blocked by the inhibition of Wnt signaling or antagonism of the NK-1 receptor. Moreover, SP promoted the mRNA and protein expression of Wnt signaling molecules such as beta-catenin, p-GSK-3beta, c-myc, and cyclin D1 in addition to the nuclear translocation of beta-catenin, indicating that active Wnt signaling is involved in SP inhibition of apoptosis. Our results revealed that mediated by the NK-1 receptor, SP exerts an inhibitory effect on serum deprivation induced apoptosis in BMSCs that is related to the activation of canonical Wnt signaling. PMID- 26106424 TI - Renal Stem Cells, Tissue Regeneration, and Stem Cell Therapies for Renal Diseases. PMID- 26106425 TI - Recent Advances in Hydroxyapatite Scaffolds Containing Mesenchymal Stem Cells. AB - Modern day tissue engineering and cellular therapies have gravitated toward using stem cells with scaffolds as a dynamic modality to aid in differentiation and tissue regeneration. Mesenchymal stem cells (MSCs) are one of the most studied stem cells used in combination with scaffolds. These cells differentiate along the osteogenic lineage when seeded on hydroxyapatite containing scaffolds and can be used as a therapeutic option to regenerate various tissues. In recent years, the combination of hydroxyapatite and natural or synthetic polymers has been studied extensively. Due to the interest in these scaffolds, this review will cover the wide range of hydroxyapatite containing scaffolds used with MSCs for in vitro and in vivo experiments. Further, in order to maintain a progressive scope of the field this review article will only focus on literature utilizing adult human derived MSCs (hMSCs) published in the last three years. PMID- 26106426 TI - Endothelial Differentiation of Human Adipose-Derived Stem Cells on Polyglycolic Acid/Polylactic Acid Mesh. AB - Adipose-derived stem cell (ADSC) is considered as a cell source potentially useful for angiogenesis in tissue engineering and regenerative medicine. This study investigated the growth and endothelial differentiation of human ADSCs on polyglycolic acid/polylactic acid (PGA/PLA) mesh compared to 2D plastic. Cell adhesion, viability, and distribution of hADSCs on PGA/PLA mesh were observed by CM-Dil labeling, live/dead staining, and SEM examination while endothelial differentiation was evaluated by flow cytometry, Ac-LDL/UEA-1 uptake assay, immunofluorescence stainings, and gene expression analysis of endothelial related markers. Results showed hADSCs gained a mature endothelial phenotype with a positive ratio of 21.4 +/- 3.7% for CD31+/CD34- when induced in 3D mesh after 21 days, which was further verified by the expressions of a comprehensive range of endothelial related markers, whereas hADSCs in 2D induced and 2D/3D noninduced groups all failed to differentiate into endothelial cells. Moreover, compared to 2D groups, the expression for alpha-SMA was markedly suppressed in 3D cultured hADSCs. This study first demonstrated the endothelial differentiation of hADSCs on the PGA/PLA mesh and pointed out the synergistic effect of PGA/PLA 3D culture and growth factors on the acquisition of mature characteristic endothelial phenotype. We believed this study would be the initial step towards the generation of prevascularized tissue engineered constructs. PMID- 26106427 TI - Osteogenic Potential of Dental Mesenchymal Stem Cells in Preclinical Studies: A Systematic Review Using Modified ARRIVE and CONSORT Guidelines. AB - Background and Objective. Dental stem cell-based tissue engineered constructs are emerging as a promising alternative to autologous bone transfer for treating bone defects. The purpose of this review is to systematically assess the preclinical in vivo and in vitro studies which have evaluated the efficacy of dental stem cells on bone regeneration. Methods. A literature search was conducted in Ovid Medline, Embase, PubMed, and Web of Science up to October 2014. Implantation of dental stem cells in animal models for evaluating bone regeneration and/or in vitro studies demonstrating osteogenic potential of dental stem cells were included. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were used to ensure the quality of the search. Modified ARRIVE (Animal research: reporting in invivo experiments) and CONSORT (Consolidated reporting of trials) were used to critically analyze the selected studies. Results. From 1914 citations, 207 full-text articles were screened and 137 studies were included in this review. Because of the heterogeneity observed in the studies selected, meta-analysis was not possible. Conclusion. Both in vivo and in vitro studies indicate the potential use of dental stem cells in bone regeneration. However well-designed randomized animal trials are needed before moving into clinical trials. PMID- 26106428 TI - Atherogenic Cytokines Regulate VEGF-A-Induced Differentiation of Bone Marrow Derived Mesenchymal Stem Cells into Endothelial Cells. AB - Coronary artery stenting or angioplasty procedures frequently result in long-term endothelial dysfunction or loss and complications including arterial thrombosis and myocardial infarction. Stem cell-based therapies have been proposed to support endothelial regeneration. Mesenchymal stem cells (MSCs) differentiate into endothelial cells (ECs) in the presence of VEGF-A in vitro. Application of VEGF-A and MSC-derived ECs at the interventional site is a complex clinical challenge. In this study, we examined the effect of atherogenic cytokines (IL-6, TNFalpha, and Ang II) on EC differentiation and function. MSCs (CD44(+), CD73(+), CD90(+), CD14(-), and CD45(-)) were isolated from the bone marrow of Yucatan microswine. Naive MSCs cultured in differentiation media containing VEGF-A (50 ng/mL) demonstrated increased expression of EC-specific markers (vWF, PECAM-1, and VE-cadherin), VEGFR-2 and Sox18, and enhanced endothelial tube formation. IL 6 or TNFalpha caused a dose-dependent attenuation of EC marker expression in VEGF A-stimulated MSCs. In contrast, Ang II enhanced EC marker expression in VEGF-A stimulated MSCs. Addition of Ang II to VEGF-A and IL-6 or TNFalpha was sufficient to rescue the EC phenotype. Thus, Ang II promotes but IL-6 and TNFalpha inhibit VEGF-A-induced differentiation of MSCs into ECs. These findings have important clinical implications for therapies intended to increase cardiac vascularity and reendothelialize coronary arteries following intervention. PMID- 26106429 TI - Effects of Artificial Ligaments with Different Porous Structures on the Migration of BMSCs. AB - Polyethylene terephthalate- (PET-) based artificial ligaments (PET-ALs) are commonly used in anterior cruciate ligament (ACL) reconstruction surgery. The effects of different porous structures on the migration of bone marrow mesenchymal stem cells (BMSCs) on artificial ligaments and the underlying mechanisms are unclear. In this study, a cell migration model was utilized to observe the migration of BMSCs on PET-ALs with different porous structures. A rabbit extra-articular graft-to-bone healing model was applied to investigate the in vivo effects of four types of PET-ALs, and a mechanical test and histological observation were performed at 4 weeks and 12 weeks. The BMSC migration area of the 5A group was significantly larger than that of the other three groups. The migration of BMSCs in the 5A group was abolished by blocking the RhoA/ROCK signaling pathway with Y27632. The in vivo study demonstrated that implantation of 5A significantly improved osseointegration. Our study explicitly demonstrates that the migration ability of BMSCs can be regulated by varying the porous structures of the artificial ligaments and suggests that this regulation is related to the RhoA/ROCK signaling pathway. Artificial ligaments prepared using a proper knitting method and line density may exhibit improved biocompatibility and clinical performance. PMID- 26106430 TI - Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Acute Myocardial Ischemic Injury. AB - This study is aimed at investigating whether human umbilical cord mesenchymal stem cell- (hucMSC-) derived exosomes (hucMSC-exosomes) have a protective effect on acute myocardial infarction (AMI). Exosomes were characterized under transmission electron microscopy and the particles of exosomes were further examined through nanoparticle tracking analysis. Exosomes (400 MUg protein) were intravenously administrated immediately following ligation of the left anterior descending (LAD) coronary artery in rats. Cardiac function was evaluated by echocardiography and apoptotic cells were counted using TUNEL staining. The cardiac fibrosis was assessed using Masson's trichrome staining. The Ki67 positive cells in ischemic myocardium were determined using immunohistochemistry. The effect of hucMSC-exosomes on blood vessel formation was evaluated through tube formation and migration of human umbilical vein endothelial cells (EA.hy926 cells). The results indicated that ligation of the LAD coronary artery reduced cardiac function and induced cardiomyocyte apoptosis. Administration of hucMSC exosomes significantly improved cardiac systolic function and reduced cardiac fibrosis. Moreover, hucMSC-exosomes protected myocardial cells from apoptosis and promoted the tube formation and migration of EA.hy926 cells. It is concluded that hucMSC-exosomes improved cardiac systolic function by protecting myocardial cells from apoptosis and promoting angiogenesis. These effects of hucMSC-exosomes might be associated with regulating the expression of Bcl-2 family. PMID- 26106431 TI - Mesenchymal Stem Cells and Cutaneous Wound Healing: Current Evidence and Future Potential. AB - Human skin is a remarkable organ that sustains insult and injury throughout life. The ability of skin to expeditiously repair wounds is paramount to survival. With an aging global population, coupled with a rise in the prevalence of conditions such as diabetes, chronic wounds represent a significant biomedical burden. Mesenchymal stem cells (MSC), a progenitor cell population of the mesoderm lineage, have been shown to be significant mediators in inflammatory environments. Preclinical studies of MSC in various animal wound healing models point towards a putative therapy. This review examines the body of evidence suggesting that MSC accelerate wound healing in both clinical and preclinical studies and also the possible mechanisms controlling its efficacy. The delivery of a cellular therapy to the masses presents many challenges from a safety, ethical, and regulatory point of view. Some of the issues surrounding the introduction of MSC as a medicinal product are also delineated in this review. PMID- 26106432 TI - Study on the Dynamic Biological Characteristics of Sca-1(+) Hematopoietic Stem and Progenitor Cell Senescence. AB - The researches in the dynamic changes of the progress of HSCs aging are very limited and necessary. In this study, male C57BL/6 mice were divided into 5 groups by age. We found that the superoxide damage of HSPCs started to increase from the middle age (6 months old), with notably reduced antioxidation ability. In accordance with that, the senescence of HSPCs also started from the middle age, since the self-renewal and differentiation ability remarkably decreased, and senescence-associated markers SA-beta-GAL increased in the 6-month-old and the older groups. Interestingly, the telomere length and telomerase activity increased to a certain degree in the 6-month-old group. It suggested an intrinsic spontaneous ability of HSPCs against aging. It may provide a theoretical and experimental foundation for better understanding the senescence progress of HSPCs. And the dynamic biological characteristics of HSPCs senescence may also contribute to the clinical optimal time for antiaging drug intervention. PMID- 26106434 TI - Shrinkage of Prostate and Improved Quality of Life: Management of BPH Patients with Croton membranaceus Ethanolic Root Extract. AB - Benign prostatic hyperplasia (BPH) is an enlargement of the prostate. The study aimed at validating the use of freeze-dried Croton membranaceus ethanolic root extract for BPH management. Thirty-three patients were observed before and after 3-month administration of 20 mg t.i.d orally. The International Prostate Symptom Score (IPSS), and the International Index of Erectile Function (IIEF) questionnaires were used. Total/free PSA (tPSA, fPSA), renal, liver function, lipid tests, and ultrasonographic imaging were performed. Thirty (30) patients (66 +/- 11 years) completed the study. IPSS results showed 37% had severe, 40% moderate, and 23% mild symptoms before; 57% and 43% had moderate and mild symptoms, respectively, after treatment. IIED of patients' results showed 30% with severe, 40% moderate, 24% mild-moderate, 3% mild, and 3% no erectile dysfunction before treatment and 20% severe, 43% moderate, and 37% mild-moderate dysfunction, after treatment. Quality of life (QoL) improved (P = 0.001). Significant but non-pathological increases in total and indirect bilirubin as well as apolipoprotein A occurred. Mean tPSA reduced from 27.9 +/- 19.0 to 16.2 +/- 11.8 ng/mL (P = 0.002); fPSA from 6.1 +/- 4.8 to 3.9 +/- 2.9 ng/mL (P = 0.045); and prostate volume from 101.8 +/- 41.3 to 54.5 +/- 24.8 cm(3) (P = 0.023). C. membranaceus shrinks the prostate and improves QoL. PMID- 26106435 TI - Supplementation of Citrus maxima Peel Powder Prevented Oxidative Stress, Fibrosis, and Hepatic Damage in Carbon Tetrachloride (CCl4) Treated Rats. AB - Citrus maxima peel is rich in natural phenolic compounds and has a long use in the traditional medicine. HPLC-DAD analysis on Citrus maxima peel powder exhibited the presence of various phenolic compounds such as caffeic acid and (-) epicatechin. To determine the plausible hepatoprotective activity of Citrus maxima peel powder, we used carbon tetrachloride (CCl4) treated rat model. Liver damage in rats was confirmed by measuring the AST, ALT, and ALP enzyme activities. In addition, lipid peroxidation products (MDA), nitric oxide, advanced protein oxidation products level (APOP), and catalase activities were also analyzed along with the histological profiling for the inflammatory cell infiltration, collagen, and iron deposition in liver. Dietary supplementation of Citrus maxima peel powder exhibited significant reduction of serum AST, ALT, and ALP activities in carbon tetrachloride treated rats. Moreover, Citrus maxima peel powder also showed a significant reduction of the oxidative stress markers (MDA, NO, and APOP level) and restored the catalase activity in CCl4 treated rats. Histological examination of the liver section revealed reduced inflammatory cells infiltration, collagen, and iron deposition in CCl4 treated rats. The results from this study demonstrated that Citrus maxima peel powder produced significant hepatoprotective action in CCl4 administered rats. PMID- 26106433 TI - Propolis: A Complex Natural Product with a Plethora of Biological Activities That Can Be Explored for Drug Development. AB - The health industry has always used natural products as a rich, promising, and alternative source of drugs that are used in the health system. Propolis, a natural resinous product known for centuries, is a complex product obtained by honey bees from substances collected from parts of different plants, buds, and exudates in different geographic areas. Propolis has been attracting scientific attention since it has many biological and pharmacological properties, which are related to its chemical composition. Several in vitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolated compounds, as well as to evaluate and validate its potential. Yet, there is a lack of information concerning clinical effectiveness. The goal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerning the chemical composition and the biological properties of this natural compound from different geographic origins. PMID- 26106436 TI - The Use of Complementary and Alternative Medicine among Lebanese Adults: Results from a National Survey. AB - Objective. To examine the prevalence and correlates of Complementary and Alternative Medicine (CAM) use in Lebanon. Methods. A cross-sectional survey was conducted through face to face interviews on a nationally representative sample of 1,475 Lebanese adults. The survey questionnaire explored the sociodemographic and health related characteristics as well as the types and modes of CAM use. The main outcome in this study was the use of CAM during the last 12 months. Results. Prevalence of CAM use was 29.87% with "folk herbs" being the most commonly used (75%). Two out of five CAM users indicated using it as alternative to conventional therapies and only 28.4% of users disclosed the use of CAM to their physician. CAM use was significantly associated with higher income, presence of a chronic disease, and lack of access to needed health care. Lower odds of CAM use were observed among older adults and those with a higher education level. Conclusions. This study revealed a high prevalence of CAM use in Lebanon. Health policy and decision makers need to facilitate proper regulation and integration of CAM into mainstream medicine and educate health care providers and the public alike on the safe and effective use of CAM therapies. PMID- 26106437 TI - Fucoxanthin: A Promising Medicinal and Nutritional Ingredient. AB - Fucoxanthin, an allenic carotenoid, can be isolated from edible brown seaweeds. Recent studies have reported that fucoxanthin has many physiological functions and biological properties, such as antiobesity, antitumor, antidiabetes, antioxidant, anti-inflammatory, and hepatoprotective activities, as well as cardiovascular and cerebrovascular protective effects. Therefore, fucoxanthin can be used as both medicinal and nutritional ingredient to prevent and treat chronic diseases. Although fucoxanthin possesses many medicinal ingredient and nutritional qualities, studies indicated that its structure was unstable. In this paper, we consulted the current documents and reviewed structural properties and factors affecting the stability of fucoxanthin. We also reported the metabolism, safety, pharmacological activities, and the methods of improving the bioavailability of fucoxanthin. Based on these studies providing essential background knowledge, fucoxanthin can be developed into marine drugs and nutritional products. PMID- 26106438 TI - Unmanned aerial platform-based multi-spectral imaging for field phenotyping of maize. AB - BACKGROUND: Recent developments in unmanned aerial platforms (UAP) have provided research opportunities in assessing land allocation and crop physiological traits, including response to abiotic and biotic stresses. UAP-based remote sensing can be used to rapidly and cost-effectively phenotype large numbers of plots and field trials in a dynamic way using time series. This is anticipated to have tremendous implications for progress in crop genetic improvement. RESULTS: We present the use of a UAP equipped with sensors for multispectral imaging in spatial field variability assessment and phenotyping for low-nitrogen (low-N) stress tolerance in maize. Multispectral aerial images were used to (1) characterize experimental fields for spatial soil-nitrogen variability and (2) derive indices for crop performance under low-N stress. Overall, results showed that the aerial platform enables to effectively characterize spatial field variation and assess crop performance under low-N stress. The Normalized Difference Vegetation Index (NDVI) data derived from spectral imaging presented a strong correlation with ground-measured NDVI, crop senescence index and grain yield. CONCLUSION: This work suggests that the aerial sensing platform designed for phenotyping studies has the potential to effectively assist in crop genetic improvement against abiotic stresses like low-N provided that sensors have enough resolution for plot level data collection. Limitations and future potential uses are also discussed. PMID- 26106439 TI - Optimization and Corroboration of the Regulatory Pathway of p42.3 Protein in the Pathogenesis of Gastric Carcinoma. AB - AIMS: To optimize and verify the regulatory pathway of p42.3 in the pathogenesis of gastric carcinoma (GC) by intelligent algorithm. METHODS: Bioinformatics methods were used to analyze the features of structural domain in p42.3 protein. Proteins with the same domains and similar functions to p42.3 were screened out for reference. The possible regulatory pathway of p42.3 was established by integrating the acting pathways of these proteins. Then, the similarity between the reference proteins and p42.3 protein was figured out by multiparameter weighted summation method. The calculation result was taken as the prior probability of the initial node in Bayesian network. Besides, the probability of occurrence in different pathways was calculated by conditional probability formula, and the one with the maximum probability was regarded as the most possible pathway of p42.3. Finally, molecular biological experiments were conducted to prove it. RESULTS: In Bayesian network of p42.3, probability of the acting pathway "S100A11->RAGE->P38->MAPK->Microtubule-associated protein->Spindle protein->Centromere protein->Cell proliferation" was the biggest, and it was also validated by biological experiments. CONCLUSIONS: The possibly important role of p42.3 in the occurrence of gastric carcinoma was verified by theoretical analysis and preliminary test, helping in studying the relationship between p42.3 and gastric carcinoma. PMID- 26106441 TI - A multivariate analysis on the comparison of raw notoginseng (Sanqi) and its granule products by thin-layer chromatography and ultra-performance liquid chromatography. AB - BACKGROUND: Granule products produced from medicinal herbs are gaining popularity. However, there have been few studies comparing the quality or efficacy of granules with those of herbal formulations. This study aims to compare commercially available notoginseng (Sanqi in Chinese) in both raw and granule forms by thin layer chromatography (TLC) and ultra-performance liquid chromatography with photodiode array detection (UPLC-PDA) using multivariate analysis. METHODS: Aqueous extracts of the raw herb (collected from six different sources in China) and granule products (purchased in China, Taiwan and Australia) were re-extracted with methanol to remove water-soluble excipients. Five compounds (ginsenosides Rg1, Rg2, Rd and Rb1 and notoginsenoside NR1) in the methanolic extracts were quantified by TLC and UPLC-PDA. Multivariate statistical analysis using hierarchical component analysis (HCA) and principal component analysis (PCA) was used to determine the similarities between the granule products and raw herbs. A 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay was used to measure the antioxidant capacities of the extracts. RESULTS: HCA and PCA of the TLC analysis clustered the granule products into one group. By UPLC analysis, the raw herbs and two of the granule products (G7 and G12) were allocated into Group 1 and the rest of the granule products into Group 2. The contents of the five marker compounds in Group 1 were higher than Group 2 and also exhibited stronger ABTS activity (P = 0.005). By Pearson correlation, the contents of the five compounds in the samples were positively and significantly correlated to their antioxidant activities. CONCLUSIONS: UPLC was more efficient than TLC for the simultaneous determination of the five major compounds in Sanqi products in terms of linearity, higher sensitivity and repeatability. The statistical analysis of the samples by HCA and PCA revealed that the contents of the marker compounds were significantly higher in the raw herb group than the granule group. PMID- 26106440 TI - Statistical and Computational Methods for Genetic Diseases: An Overview. AB - The identification of causes of genetic diseases has been carried out by several approaches with increasing complexity. Innovation of genetic methodologies leads to the production of large amounts of data that needs the support of statistical and computational methods to be correctly processed. The aim of the paper is to provide an overview of statistical and computational methods paying attention to methods for the sequence analysis and complex diseases. PMID- 26106442 TI - Life events, emotional responsiveness, and the functional prognosis of patients with rheumatoid arthritis. AB - BACKGROUND: Stressors may differently affect human physiological systems according to the host properties relevant to psycho-behavioral processes that the stressors invoke. In a Japanese multicenter cohort study of patients with rheumatoid arthritis (RA), we examined if major life events differently contribute to the patients' functional prognosis according to their ability to identify emotions as manifest feelings when encountering the events (emotional responsiveness). METHODS: 460 patients with RA completed a self-administered baseline questionnaire about psychosocial factors including emotional responsiveness. Two years later, they checked on a list of positive/negative personal events that happened during the two-year study period. Rheumatologists evaluated their functional status at baseline and follow-up using the ACR classification system. RESULTS: In a multiple logistic regression model that included baseline demographic, disease activity/severity-related, therapeutic, and socioeconomic factors as covariates, none of the counts of positive, negative, or all life events was associated with the functional status at follow up. In the subgroup with poor emotional responsiveness, however, these life event counts were all associated with a poorer functional prognosis (odds ratio of ACR class 3-4 vs. 1-2 associated with one increment in the all life-event count = 2.39, 95 % confidence interval = 1.27-4.48, p = .007), while no such relationship was evident for the rest of the patients. CONCLUSIONS: Major life events, whether positive or negative in nature, may have an impact on the disease course of patients with RA when the patient has poor emotional responsiveness to the event(s). PMID- 26106443 TI - Assessments of health services availability in humanitarian emergencies: a review of assessments in Haiti and Sudan using a health systems approach. AB - BACKGROUND: Assessing the availability of health services during humanitarian emergencies is essential for understanding the capacities and weaknesses of disrupted health systems. To improve the consistency of health facilities assessments, the World Health Organization has proposed the use of the Health Resources Availability Mapping System (HeRAMS) developed in Darfur, Sudan as a standardized assessment tool for use in future acute and protracted crises. This study provides an evaluation of HeRAMS' comprehensiveness, and investigates the methods, quality and comprehensiveness of health facilities data and tools in Haiti, where HeRAMS was not used. METHODS AND FINDINGS: Tools and databases containing health facilities data in Haiti were collected using a snowball sampling technique, while HeRAMS was purposefully evaluated in Sudan. All collected tools were assessed for quality and comprehensiveness using a coding scheme based on the World Health Organization's health systems building blocks, the Global Health Cluster Suggested Set of Core Indicators and Benchmarks by Category, and the Sphere Humanitarian Charter and Minimum Standards in Humanitarian Response. Eight assessments and databases were located in Haiti, and covered a median of 3.5 of the 6 health system building blocks, 4.5 of the 14 Sphere standards, and 2 of the 9 Health Cluster indicators. None of the assessments covered all of the indicators in any of the assessment criteria and many lacked basic data, limiting the detail of analysis possible for calculating standardized benchmarks and indicators. In Sudan, HeRAMS collected data on 5 of the 6 health system building blocks, 13 of the 14 Sphere Standards, and collected data to allow the calculation of 7 of the 9 Health Cluster Core Indicators and Benchmarks. CONCLUSIONS: There is a need to agree upon essential health facilities data in disrupted health systems during humanitarian emergencies. Although the quality of the assessments in Haiti was generally poor, the large number of platforms and assessment tools deployed suggests that health facilities data can be collected even during acute emergencies. Further consensus is needed to establish essential criteria for data collection and to establish a core group of health systems assessment experts to be deployed during future emergencies. PMID- 26106444 TI - Structural and spectral investigations of the recently synthesized chalcone (E)-3 mesityl-1-(naphthalen-2-yl) prop-2-en-1-one, a potential chemotherapeutic agent. AB - BACKGROUND: Chalcones (1,3-diaryl-2-propen-1-ones, represent an important subgroup of the polyphenolic family, which have shown a wide spectrum of medical and industrial application. Due to their redundancy in plants and ease of preparation, this category of molecules has inspired considerable attention for potential therapeutic uses. They are also effective in vivo as anti-tumor promoting, cell proliferating inhibitors and chemo preventing agents. RESULTS: Synthesis and molecular structure investigation of (E)-3-mesityl-1-(naphthalen-2 yl) prop-2-en-1-one (3) is reported. The structure of the title compound 3 is confirmed by X-ray crystallography. The optimized molecular structure of the studied compound is calculated using DFT B3LYP/6-311G (d,p) method. The calculated geometric parameters are in good agreement with the experimental data obtained from our reported X-ay structure. The calculated IR fundamental bands were assigned and compared with the experimental data. The electronic spectra of the studied compound have been calculated using the time dependant density functional theory (TD-DFT). The longest wavelength band is due to H -> L (79 %) electronic transition which belongs to pi-pi* excitation. The (1)H- and (13)C-NMR chemical shifts were calculated using gauge independent atomic orbitals (GIAO) method, which showed good correlations with the experimental data (R(2) = 0.9911 0.9965). The natural bond orbital (NBO) calculations were performed to predict the natural atomic charges at different atomic sites. The molecular electrostatic potential (MEP) was used to visualize the charge distribution on the molecule. Molecular docking results suggest that the compound might exhibit inhibitory activity against GPb and may act as potential anti-diabetic compound. CONCLUSIONS: (E)-3-Mesityl-1-(naphthalen-2-yl) prop-2-en-1-one single crystal is grown and characterized by single crystal X-ray diffraction, FT-IR, UV-vis, DFT and optimized geometrical parameters are close to the experimental bond lengths and angles. Molecular stability was successfully analyzed using NBO and electron delocalization is confirmed by MEP. Prediction of Activity Spectra Analysis of the title compound, predicts anti-diabetic activity with probability to have an active value of 0.348. Graphical Abstract(E)-3-Mesityl-1-(naphthalen-2-yl) prop-2 en-1-one: a crystal structure and computational studies. PMID- 26106445 TI - Simultaneous extraction, optimization, and analysis of flavonoids and polyphenols from peach and pumpkin extracts using a TLC-densitometric method. AB - BACKGROUND: The use of medicinal plants has been reported throughout human history. In the fight against illnesses, medicinal plants represent the primary health care system for 60 % of the world's population. Flavonoids are polyphenolic compounds with active anti-microbial properties; they are produced in plants as pigments. Quercetin, myricetin, and rutin are among the most well known and prevalent flavonoids in plants, with an antioxidant activity capable of decreasing the oxidation of low density lipoproteins [LDLs]. To date, this research is the first of its kind to employ a coupled thin-layer chromatography (TLC) and a densitometric quantification method with a Box-Behnken design (BBD) response surface methodology (RSM) for optimization of ultrasonic-assisted extraction and determination of rutin and quercetin from peach and ellagic acid and myricetin from pumpkin fruits. RESULTS: The effect of process variables (extraction temperature ( degrees C), extraction power (%) and extraction time (min)) on ultrasound-assisted extraction (UAE) were examined by using BBD and RSM. TLC followed by Quantity-OneTM (BioRad) image analysis as a simple and rapid method was used for identification and quantification of the compounds in complex mixtures. The results were consistent under optimal conditions among the experimental values and their predicted values. A mass spectrometry (MALDI-TOF MS) technique was also used to confirm the identity of the natural products in the TLC spots resolved. CONCLUSION: The results show that the coupled TLC densitometric methods & BBD can be a very powerful approach to qualitative and quantitative analysis of; rutin and quercetin from peach extracts; and ellagic acid and myricetin contents from pumpkin extracts. PMID- 26106446 TI - Clinical supervision for clinical psychology students in Uganda: an initial qualitative exploration. AB - BACKGROUND: Burn out in clinical psychologists working in low income countries has been reported. Clinical supervisory structures do not yet exist in Uganda. A way to decrease levels of burn out and increase quality of care for people with mental illness is through clinical supervision. The aim of this study was to explore the initial experiences of supervision for clinical psychology students in Uganda to ascertain whether or not clinical supervision is culturally appropriate, and what aspects of supervision had been helpful and unhelpful. METHODS: A qualitative design with thematic analysis was utilized. A focus group was held with 12 second year clinical psychology students to ask their experiences of receiving supervision. RESULTS: Data analysis created five themes. Firstly, the negative emotions that resulted from the training processed were discussed, and how supervision helped and did not help the students to manage these. Secondly, the students voiced that supervision helped them to learn through observational experiences, co-therapist roles and parallel processes within the supervisory relationship. Thirdly, supervision had taught the clinical psychology students their role as a clinical psychology student, how to act within the Ugandan mental health system and skills to conduct therapy. Fourthly, suggestions for the future of supervision were given, with the students requesting for it to start earlier in the training, for supervisors who can meet with the students on a regular basis to be selected and for the training the students receive at university to match the skills required on their placements, with a request for more practical techniques rather than theory. The final theme related to left over miscellaneous data, such as the students agreeing with each other. CONCLUSIONS: The students stated that supervision was helpful overall, implying that clinical supervision is culturally appropriate for clinical psychology students in Uganda. Suggestions for future supervision were given. In order to decrease high levels of staff burn out in the mental health systems in Uganda, supervisory structures with an emphasis on self care need to be established. PMID- 26106447 TI - Engineering pH responsive fibronectin domains for biomedical applications. AB - BACKGROUND: Engineered antibodies with pH responsive cell surface target antigen binding affinities that decrease at the acidic pH (5.5-5.8) within the endosomes have been found to have reduced susceptibility to degradation within the lysosomes and increased serum half-life. Such pH responsive recombinant antibodies have been developed for the treatment of cancer and cardiovascular disease. Engineered tenth type III human fibronectin (Fn3) domains are emerging as a class of target antigen-binding biopharmaceuticals that could complement or be superior to recombinant antibodies in a number of biomedical contexts. As such, there is strong motivation for demonstrating the feasibility of engineering Fn3s with pH responsive antigen binding behavior that could lead to improved Fn3 pharmacokinetics. RESULTS: A yeast surface-displayed Fn3 histidine (His) mutant library screening approach yielded epidermal growth factor receptor (EGFR) binding Fn3 domains with EGFR binding affinities that markedly decrease at endosomal pH; the first reported case of engineering Fn3s with pH responsive antigen binding. Yeast surface-displayed His mutant Fn3s, which contain either one or two His mutations, have equilibrium binding dissociation constants (KDs) that increase up to four-fold relative to wild type when pH is decreased from 7.4 to 5.5. Assays in which Fn3-displaying yeast were incubated with soluble EGFR after ligand-free incubation in respective neutral and acidic buffers showed that His mutant Fn3 pH responsiveness is due to reversible changes in Fn3 conformation and/or EGFR binding interface properties rather than irreversible unfolding. CONCLUSIONS: We have established a generalizable method for efficiently constructing and screening Fn3 His mutant libraries that could enable both our laboratory and others to develop pH responsive Fn3s for use in a wide range of biomedical applications. PMID- 26106448 TI - Metabolic modeling of synthesis gas fermentation in bubble column reactors. AB - BACKGROUND: A promising route to renewable liquid fuels and chemicals is the fermentation of synthesis gas (syngas) streams to synthesize desired products such as ethanol and 2,3-butanediol. While commercial development of syngas fermentation technology is underway, an unmet need is the development of integrated metabolic and transport models for industrially relevant syngas bubble column reactors. RESULTS: We developed and evaluated a spatiotemporal metabolic model for bubble column reactors with the syngas fermenting bacterium Clostridium ljungdahlii as the microbial catalyst. Our modeling approach involved combining a genome-scale reconstruction of C. ljungdahlii metabolism with multiphase transport equations that govern convective and dispersive processes within the spatially varying column. The reactor model was spatially discretized to yield a large set of ordinary differential equations (ODEs) in time with embedded linear programs (LPs) and solved using the MATLAB based code DFBAlab. Simulations were performed to analyze the effects of important process and cellular parameters on key measures of reactor performance including ethanol titer, ethanol-to-acetate ratio, and CO and H2 conversions. CONCLUSIONS: Our computational study demonstrated that mathematical modeling provides a complementary tool to experimentation for understanding, predicting, and optimizing syngas fermentation reactors. These model predictions could guide future cellular and process engineering efforts aimed at alleviating bottlenecks to biochemical production in syngas bubble column reactors. PMID- 26106449 TI - Divergent evolutionary behavior of H3 histone gene and rDNA clusters in venerid clams. AB - BACKGROUND: Histone H3 gene clusters have been described as highly conserved chromosomal markers in invertebrates. Surprisingly, in bivalves remarkable interspecific differences were found among the eight mussels and between the two clams in which histone H3 gene clusters have already been located. Although the family Veneridae comprises 10 % of the species of marine bivalves, their chromosomes are poorly studied. The clams belonging to this family present 2n = 38 chromosomes and similar karyotypes showing chromosome pairs gradually decreasing in length. In order to assess the evolutionary behavior of histone and rRNA multigene families in bivalves, we mapped histone H3 and ribosomal RNA probes to chromosomes of ten species of venerid clams. RESULTS: In contrast with the reported conservation of histone H3 gene clusters and their intercalary location in invertebrates, these loci varied in number and were mostly subterminal in venerid clams. On the other hand, while a single 45S rDNA cluster, highly variable in location, was found in these organisms, 5S rDNA clusters showed interspecific differences in both number and location. The distribution patterns of these sequences were species-specific and mapped to different chromosomal positions in all clams but Ruditapes decussatus, in which one of the minor rDNA clusters and the major rDNA cluster co-located. CONCLUSION: The diversity in the distribution patterns of histone H3 gene, 5S rDNA and 28S rDNA clusters found in venerid clams, together with their different evolutionary behaviors in other invertebrate taxa, strongly suggest that the control of the spreading of these multigene families in a group of organisms relies upon a combination of evolutionary forces that operate differently depending not only on the specific multigene family but also on the particular taxa. Our data also showed that H3 histone gene and rDNA clusters are useful landmarks to integrate nex-generation sequencing (NGS) and evolutionary genomic data in non-model species. PMID- 26106450 TI - Metrabase: a cheminformatics and bioinformatics database for small molecule transporter data analysis and (Q)SAR modeling. AB - ABSTRACT: Both metabolism and transport are key elements defining the bioavailability and biological activity of molecules, i.e. their adverse and therapeutic effects. Structured and high quality experimental data stored in a suitable container, such as a relational database, facilitates easy computational processing and thus allows for high quality information/knowledge to be efficiently inferred by computational analyses. Our aim was to create a freely accessible database that would provide easy access to data describing interactions between proteins involved in transport and xenobiotic metabolism and their small molecule substrates and modulators. We present Metrabase, an integrated cheminformatics and bioinformatics resource containing curated data related to human transport and metabolism of chemical compounds. Its primary content includes over 11,500 interaction records involving nearly 3,500 small molecule substrates and modulators of transport proteins and, currently to a much smaller extent, cytochrome P450 enzymes. Data was manually extracted from the published literature and supplemented with data integrated from other available resources. Metrabase version 1.0 is freely available under a CC BY-SA 4.0 license at http://www-metrabase.ch.cam.ac.uk. PMID- 26106451 TI - Nasal paraganglioma: A case report and literature review. AB - INTRODUCTION: Paragangliomas are neuroendocrine tumors that most commonly originate in the adrenal gland, a type that is called pheochromocytoma; however, 5-10% of paragangliomas are extra-adrenal and may arise in any area between the neck and pelvic region along the sympathetic nervous system. Those located in the head and neck comprise 3% of extra-adrenal tumors, with the majority originating in the tympanic-jugular region and carotid body. OBJECTIVE: To present a rare case of nasal paraganglioma and review the literature. CASE REPORT: The patient was submitted to medial subtotal maxillectomy, and her clinical findings, diagnostic data, and treatment outcome were recorded. CONCLUSION: Paragangliomas are considered benign tumors, but they occasionally display a malignant character. The most important finding in this case was the need for total resection of the tumor to avoid recurrence. PMID- 26106452 TI - Clinical and fiberoptic endoscopic assessment of swallowing in patients with chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease is characterized by progressive and partially reversible obstruction of pulmonary airflow. AIM: To characterize swallowing in patients with chronic obstructive pulmonary disease and correlate the findings with the degree chronic obstructive pulmonary disease, heart and respiratory rate, oxygen saturation, and smoking. METHOD: We conducted a prospective cohort study of 19 patients (12 men and 7 women; age range, 50-85 years) with confirmed medical diagnosis of chronic obstructive pulmonary disease. This study was performed in 2 stages (clinical evaluation and functional assessment using nasolaryngofibroscopy) on the same day. During both stages, vital signs were checked by medical personnel. RESULTS: Clinical evaluation of swallowing in all patients showed the clinical signs of cough. The findings of nasolaryngofibroscopy highlighted subsequent intraoral escape in 5 patients (26.5%). No patient had tracheal aspiration. There was no association of subsequent intraoral escape with degree of chronic obstructive pulmonary disease, heart and respiratory rate, oxygen saturation, or smoking. CONCLUSION: In patients with chronic obstructive pulmonary disease, there was a prevalence of oral dysphagia upon swallowing and nasolaryngofibroscopy highlighted the finding of subsequent intraoral escape. There was no correlation between intraoral escape and the degree of chronic obstructive pulmonary disease, heart and respiratory rate, oxygen saturation, or smoking. PMID- 26106453 TI - Augmentation in Restless Legs Syndrome: Treatment with Gradual Medication Modification. AB - Dopaminergic drugs can cause augmentation during the treatment of restless legs syndrome (RLS). We previously reported that sudden withdrawal of dopaminergic treatment was poorly tolerated. We now report our experience with gradual withdrawal of the dopaminergic drug during the drug substitution process using a retrospective chart review with comparison to previous data. Seven patients with RLS and dopaminergic drug-induced augmentation were treated with a gradual withdrawal of the offending drug and replacement with an alternative medication. Compared to sudden withdrawal, measured outcomes were similar but gradual tapering was better tolerated. We conclude that for augmentation in RLS, gradual tapering of the augmentation-inducing dopaminergic drug is better tolerated than sudden withdrawal. The optimal approach to treating augmentation has not been established and may differ between patients. Further study with direct comparison of strategies and a larger patient population is needed to confirm our preliminary observations. PMID- 26106454 TI - Withdrawal-Emergent Dyskinesias following Varenicline Therapy. AB - Varenicline (Chantix[R]) is a nicotinic acetylcholine receptor partial agonist used to aid smoking cessation. Adverse psychiatric and behavioral effects of the drug are recognized and national drug monitoring has included reports of tardive dyskinesia, but no cases have been described in the literature. We now report the first two cases of varenicline-related withdrawal emergent dyskinesias. PMID- 26106456 TI - Diagnosis and Treatment of Acute Gout at a University Hospital Emergency Department. AB - BACKGROUND: Acute gout attacks account for a substantial number of visits to the emergency department (ED). Our aim was to evaluate acute gout diagnosis and treatment at a University Hospital ED. METHODS: Our study was a retrospective chart review of consecutive patients with a diagnosis of acute gout seen in the ED 1/01/2004 - 12/31/2010. We documented: demographics, clinical characteristics, medications given, diagnostic tests, consultations and whether patients were hospitalized. Descriptive and summary statistics were performed on all variables. RESULTS: We found 541 unique ED visit records of patients whose discharge diagnosis was acute gout over a 7 year period. 0.13% of ED visits were due to acute gout. The mean patient age was 54; 79% were men. For 118 (22%) this was their first attack. Attack duration was <= 3 days in 75%. Lower extremity joints were most commonly affected. Arthrocentesis was performed in 42 (8%) of acute gout ED visits. During 355 (66%) of ED visits, medications were given in the ED and/or prescribed. An anti-inflammatory drug was given during the ED visit during 239 (44%) visits. Medications given during the ED visit included: NSAIDs: 198 (56%): opiates 190 (54%); colchicine 32 (9%) and prednisone 32 (9%). During 154 (28%) visits an anti-inflammatory drug was prescribed. Thirty two (6%) were given no medications during the ED visit nor did they receive a prescription. Acute gout rarely (5%) led to hospitalizations. CONCLUSION: The diagnosis of acute gout in the ED is commonly clinical and not crystal proven. Anti-inflammatory drugs are the mainstay of treatment in acute gout; yet, during more than 50% of ED visits, anti-inflammatory drugs were not given during the visit. Thus, improvement in the diagnosis and treatment of acute gout in the ED may be required. PMID- 26106455 TI - The Three A's in Asthma - Airway Smooth Muscle, Airway Remodeling & Angiogenesis. AB - Asthma affects more than 300 million people worldwide and its prevalence is still rising. Acute asthma attacks are characterized by severe symptoms such as breathlessness, wheezing, tightness of the chest, and coughing, which may lead to hospitalization or death. Besides the acute symptoms, asthma is characterized by persistent airway inflammation and airway wall remodeling. The term airway wall remodeling summarizes the structural changes in the airway wall: epithelial cell shedding, goblet cell hyperplasia, hyperplasia and hypertrophy of the airway smooth muscle (ASM) bundles, basement membrane thickening and increased vascular density. Airway wall remodeling starts early in the pathogenesis of asthma and today it is suggested that remodeling is a prerequisite for other asthma pathologies. The beneficial effect of bronchial thermoplasty in reducing asthma symptoms, together with the increased potential of ASM cells of asthmatics to produce inflammatory and angiogenic factors, indicate that the ASM cell is a major effector cell in the pathology of asthma. In the present review we discuss the ASM cell and its role in airway wall remodeling and angiogenesis. PMID- 26106457 TI - An Unusual Mimicker of Systemic Lupus Erythematosus: A Case Report. AB - We present a case of a 47 year-old African American female with 15 pack-years of tobacco use and heavy alcohol use who presented with arthritis and was found to have a positive antinuclear antibodies (ANA), anti double stranded DNA antibodies (anti-dsDNA), and anti-Sjogren's syndrome-related antigen A and antigen B (anti SSA and anti-SSB). She was subsequently found to have a lung adenocarcinoma associated with hypertrophic pulmonary osteoarthropathy (HPO). This demonstrates a case of positive antinuclear antibodies and arthritis in a patient with lung adenocarcinoma, which can be falsely diagnosed as systemic lupus erythematosus. PMID- 26106460 TI - BOG: R-package for Bacterium and virus analysis of Orthologous Groups. AB - BOG (Bacterium and virus analysis of Orthologous Groups) is a package for identifying groups of differentially regulated genes in the light of gene functions for various virus and bacteria genomes. It is designed to identify Clusters of Orthologous Groups (COGs) that are enriched among genes that have gone through significant changes under different conditions. This would contribute to the detection of pathogens, an important scientific research area of relevance in uncovering bioterrorism, among others. Particular statistical analyses include hypergeometric, Mann-Whitney rank sum, and gene set enrichment. Results from the analyses are organized and presented in tabular and graphical forms for ease of understanding and dissemination of results. BOG is implemented as an R-package, which is available from CRAN or can be downloaded from http://www.stat.osu.edu/~statgen/SOFTWARE/BOG/. PMID- 26106458 TI - Inflammation, Iron, Energy Failure, and Oxidative Stress in the Pathogenesis of Multiple Sclerosis. AB - Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Different trigger pathologies have been suggested by the primary cytodegenerative "inside-out" and primary inflammation-driven "outside-in" hypotheses. Recent data indicate that mitochondrial injury and subsequent energy failure are key factors in the induction of demyelination and neurodegeneration. The brain weighs only a few percent of the body mass but accounts for approximately 20% of the total basal oxygen consumption of mitochondria. Oxidative stress induces mitochondrial injury in patients with multiple sclerosis and energy failure in the central nervous system of susceptible individuals. The interconnected mechanisms responsible for free radical production in patients with multiple sclerosis are as follows: (i) inflammation-induced production of free radicals by activated immune cells, (ii) liberation of iron from the myelin sheets during demyelination, and (iii) mitochondrial injury and thus energy failure-related free radical production. In the present review, the different sources of oxidative stress and their relationships to patients with multiple sclerosis considering tissue injury mechanisms and clinical aspects have been discussed. PMID- 26106459 TI - Quercetin Affects Erythropoiesis and Heart Mitochondrial Function in Mice. AB - Quercetin, a dietary flavonoid used as a food supplement, showed powerful antioxidant effects in different cellular models. However, recent in vitro and in vivo studies in mammals have suggested a prooxidant effect of quercetin and described an interaction with mitochondria causing an increase in O2 (?-) production, a decrease in ATP levels, and impairment of respiratory chain in liver tissue. Therefore, because of its dual actions, we studied the effect of quercetin in vivo to analyze heart mitochondrial function and erythropoiesis. Mice were injected with 50 mg/kg of quercetin for 15 days. Treatment with quercetin decreased body weight, serum insulin, and ceruloplasmin levels as compared with untreated mice. Along with an impaired antioxidant capacity in plasma, quercetin-treated mice showed a significant delay on erythropoiesis progression. Heart mitochondrial function was also impaired displaying more protein oxidation and less activity for IV, respectively, than no-treated mice. In addition, a significant reduction in the protein expression levels of Mitofusin 2 and Voltage-Dependent Anion Carrier was observed. All these results suggest that quercetin affects erythropoiesis and mitochondrial function and then its potential use as a dietary supplement should be reexamined. PMID- 26106461 TI - Comparative genomics for biodiversity conservation. AB - Genomic approaches are gathering momentum in biology and emerging opportunities lie in the creative use of comparative molecular methods for revealing the processes that influence diversity of wildlife. However, few comparative genomic studies are performed with explicit and specific objectives to aid conservation of wild populations. Here I provide a brief overview of comparative genomic approaches that offer specific benefits to biodiversity conservation. Because conservation examples are few, I draw on research from other areas to demonstrate how comparing genomic data across taxa may be used to inform the characterisation of conservation units and studies of hybridisation, as well as studies that provide conservation outcomes from a better understanding of the drivers of divergence. A comparative approach can also provide valuable insight into the threatening processes that impact rare species, such as emerging diseases and their management in conservation. In addition to these opportunities, I note areas where additional research is warranted. Overall, comparing and contrasting the genomic composition of threatened and other species provide several useful tools for helping to preserve the molecular biodiversity of the global ecosystem. PMID- 26106462 TI - Computational Methods for Modification of Metabolic Networks. AB - In metabolic engineering, modification of metabolic networks is an important biotechnology and a challenging computational task. In the metabolic network modification, we should modify metabolic networks by newly adding enzymes or/and knocking-out genes to maximize the biomass production with minimum side-effect. In this mini-review, we briefly review constraint-based formalizations for Minimum Reaction Cut (MRC) problem where the minimum set of reactions is deleted so that the target compound becomes non-producible from the view point of the flux balance analysis (FBA), elementary mode (EM), and Boolean models. Minimum Reaction Insertion (MRI) problem where the minimum set of reactions is added so that the target compound newly becomes producible is also explained with a similar formalization approach. The relation between the accuracy of the models and the risk of overfitting is also discussed. PMID- 26106463 TI - Using Stem Cells to Model Diseases of the Outer Retina. AB - Retinal degeneration arises from the loss of photoreceptors or retinal pigment epithelium (RPE). It is one of the leading causes of irreversible blindness worldwide with limited effective treatment options. Generation of induced pluripotent stem cell (IPSC)-derived retinal cells and tissues from individuals with retinal degeneration is a rapidly evolving technology that holds a great potential for its use in disease modelling. IPSCs provide an ideal platform to investigate normal and pathological retinogenesis, but also deliver a valuable source of retinal cell types for drug screening and cell therapy. In this review, we will provide some examples of the ways in which IPSCs have been used to model diseases of the outer retina including retinitis pigmentosa (RP), Usher syndrome (USH), Leber congenital amaurosis (LCA), gyrate atrophy (GA), juvenile neuronal ceroid lipofuscinosis (NCL), Best vitelliform macular dystrophy (BVMD) and age related macular degeneration (AMD). PMID- 26106464 TI - Repository of Human Blood Derivative Biospecimens in Biobank: Technical Implications. AB - Human biorepositories are collection of biological samples and health information from a large number of participants generally in the cohort studies. The main purpose of established biobanks is organization of biomedical research for upgrading the knowledge of human disorders from cancer to infectious and rare disease. The studies of generation relationships and understanding the preclinical stages of ageing are also from the solution of bitobank. This review overview the significance and storage condition of biospecimens including whole blood, red blood cells (RBC), buffy coat, plasma, serum, DNA and RNA that derived from blood in human biobanks. These biological samples provide valuable information on the prevalence of germline mutations, epigenetic modifications or interaction between genes and proteins in associated with the development of certain types of disease. The quality of biospecimen in biobanks is a powerful tool for valid identification of biomarkers. Therefore optimum qualities of human biological samples in long time storage that have been assessed in several studies also indicate in this review. PMID- 26106465 TI - Epidemiologic Features of Inflammatory Bowel Disease in Guilan Province, North of Iran, During 2002-2012. AB - BACKGROUND The geographical incidence of IBD varies considerably. This study aimed to survey the epidemiologic features of IBD in Guilan province, North of Iran, during ten years duration. METHODS In this retrospective cross-sectional study, we assessed the documents of 868 patients with IBD referred to private and governmental clinics of Guilan province between 2002 and 2012. Variables such as demographic data, risk factors, diagnosis, extraintestinal manifestations and type of treatment were collected. RESULTS Among 868 patients with IBD, 756 patients (87.1%) diagnosed as UC and 112 patients (12.9%) as CD. The mean age of patients with UC and CD was 46.73+/-15.79 and 40.15+/-14.27 years respectively. Male/female ratio in UC and CD was 0.92:1 and 0.75:1 respectively. The most common age of disease initiation in UC was 40-59 years and in CD 20-39 years (p<0.001). Extraintestinal manifestations were seen in 25.4 percent of patients with IBD. Most of patients were treated with combination of two drugs: salicylates and azathioprine (p<0.04). The incidence of IBD gradually increased during the past 4 years in Guilan province. CONCLUSION This study showed that CD were presented significantly more common in younger patients than UC and totally the disease was slightly more common in female. PMID- 26106466 TI - Efficacy of Clarithromycin Containing Bismuth-Based Regimen as a Second-Line Therapy in Helicobacter Pylori Eradication. AB - BACKGROUND The eradication of Helicobacter pylori infection, commonly prevailing in the stomach, has been important since its introduction. Adequate preparations should be made in finding alternatives when faced with first-line treatment failures. Currently, ideal second-line treatments are indistinct and varied among countries as result of different antibiotic resistance patterns. We aimed to evaluate the safety and efficacy of a clarithromycin-containing bismuth-based quadruple regimen as a second-line treatment. METHODS Forty-eight H.pylori positive patients with proven gastric or duodenal ulcers and/or erosions who had previously failed to respond to furazolidone-containing regimens were enrolled. They received pantoprazole (40 mg-bid), amoxicillin (1gr-bid), bismuth subcitrate (240 mg-bid), and clarithromycin (500mg-bid) for 10 days. Eight weeks after treatment, a (14)C-urea breath test was performed for the re-evaluation of H. pylori eradication. RESULTS Forty-three patients completed the study. H.pylori eradication rates were 79.2% (95% CI=65.00-89.53) and 88.4% (95% CI=74.91-96.11) according to intention-to-treat and per-protocol analyses, respectively. All patients had excellent compliance to treatment and one did not continue therapy because of adverse effects. CONCLUSION In developing countries such as Iran, a ten-day clarithromycin-containing bismuth-based quadruple regimen is encouraged as a second-line treatment because of the acceptable rate of eradication and low adverse effects. PMID- 26106467 TI - Is the Prevalence of Celiac Disease Higher than the General Population in Inflammatory Bowel Diseaese? AB - BACKGROUND In some studies inflammatory bowel disease (IBD) and celiac disease were considered to be associated and some belive that this association may influence the prognosis of IBD. However, there is a cosiderable controversy regarding this association. Therefore ,we aimed to assess the association of these two common digestive diseases and evaluate the complications of this association. METHODS In this comparative study, 200 patients with ulceritive colitis (UC) and 206 patients with Crohn's disease (CD) were evaluated for celiac disease using relevant diagnostic tests and pathologic studies. Total IgA, IgA tissue transgulaminase antibody and specific IgA anti endomysial antibody were asseyed. In cases of IgA deficiency, total IgG and IgG tissue TG and IgG anti endomyseal Ab were measured. Patients with increased specific IgA and IgG antibodies for celiac disease, underwent endoscopy and 4 standard samples were obtained. Our results were compared with the results of the prevalence study of celiac disease in the general population. Data were analyzed using analytic and descriptive statistics at a significance level of 5%. RESULTS Among the studied patients, 1 patient with UC had elevated IgA anti tTG antibody and IgA anti endomysial antibody who underwent endoscopy and celiac was confirmed on pathology. Hence, of the 200 patientswith UC, the diagnosis of celiac disease was confirmed in 1 patient (1:200) with no significant difference with the prevalence of celiac disease in the general population (1:166). However, none of our patients with Crohn's disease had celiac disease (0:206). CONCLUSION We found no significant difference in the prevalence of celiac disease between patients with UC and the general population. Since most of our participants had a mild level of Crohn's activation, none of those with Crohn's disease had celiac disease. Complications of IBD including sclerosing cholangitis, may be more common in patients with concurrent celiac disease. Therefore, it is recommended that celiac disease be considered in patients with severe and complicated IBD. PMID- 26106468 TI - Clarithromycin vs. Gemifloxacin in Quadruple Therapy Regimens for Empiric Primary Treatment of Helicobacter pylori Infection: A Randomized Clinical Trial. AB - BACKGROUND Eradication of Helicobacter pylori infection plays a crucial role in the treatment of peptic ulcer. Clarithromycin resistance is a major cause of treatment failure. This randomized clinical trial aimed at evaluating the efficacy of a clarithromycin versus gemifloxacin containing quadruple therapy regimen in eradication of H.pylori infection. METHODS In this randomized double blind clinical trial (RCT 2012102011054N2), a total of 120 patients were randomized to two groups of 60 patients each. Patients with proven H.pylori infection were consecutively assigned into two groups to receive OBAG or OBAC in gastroenterology clinic in Rasoul-e- Akram General Hospital in Tehran, Iran. The patients in the OBAG group received omeprazole (20 mg) twice daily, bismuth subcitrate (240 mg) twice daily, amoxicillin (1 gr) twice daily, and gemifloxacin (320 mg) once daily, and those in the OBAC group received omeprazole (20 mg) twice daily, 240 mg of bismuth subcitrate twice daily, amoxicillin (1 gr) twice daily, and clarithromycin (500 mg) twice daily for 10 days. RESULTS Five patients from each group were excluded from the study because of poor compliance, so 110 patients completed the study. The intention-to-treat eradication rate was 61.6% and 66.6% for the OBAC and OBAG groups, respectively. According to the per protocol analysis, the success rates of eradication of H.pylori infection were 67.2% and 72.7% for OBAC and OBAG groups, respectively (p=0.568). CONCLUSION The results of this study suggest that gemifloxacin containing regimen is at least as effective as clarithromycin regimen; hence, this new treatment could be considered as an alternative for the patients who cannot tolerate clarithromycin. PMID- 26106469 TI - Incidental Diagnosis of Appendiceal Abscess by Colonoscopy; A Case Report and Review of the Literature. AB - Although complicated acute appendicitis is occasionally observed in general practice, the diagnosis of appendiceal abscess by colonoscopy is unusual. We report a case of appendiceal abscess with spontaneous drainage into the lumen of colon diagnosed during colonoscopy and resolved by the time of surgery. PMID- 26106470 TI - Serological Evaluation of Celiac Disease in Children with Congenital Heart Defect; A Case Control Study. AB - BACKGROUND Due to the increased prevalence of celiac disease in chromosomal anomalies and other congenital anomalies, this study was conducted to evaluate the seroprevalence of celiac disease (CD) in patients with congenital heart defects (CHD). METHODS This case-control study was done on 1002 children in two groups of CHD patients (n=402) and controls (n=600). The serum tissue transglutamianse (TTG) levels were investigated. The two groups were compared in terms of TTG IgA levels and p<0.05 was considered as the significant level. RESULTS The means of serum TTG IgA levels in children with CHD and the control groups were 19.17+/-46.67 and 7.77+/-10.02 u/mL respectively (p=0.001). After ANOVA analysis a significant difference between two cyanotic and acyanotic subgroups of cases and control groups was observed (p=0.000). The follow up tukey test showed only non-significant difference between the cyanotic and acyanotic cases. The frequency of TTG IgA with the consideration of 20 u/mL as cut-off point showed a significant association with groups (X2=28.31 and p=0.000). CONCLUSION According to the results the serum TTG IgA levels were significantly higher in patients with CHD than normal children and screening for CD in children with CHD is recommended. PMID- 26106471 TI - Report of a Rare Case of Nasal Mucosa Pyoderma Vegetans in a Patient with Ulcerative Colitis. AB - Some dermatologic manifestations are common in ulcerative colitis (UC). Herein, we present a 36-year-old woman with ulcerative colitis and uncommon nasal mucosa pyoderma vegetans. The patient presented to our hospital with symptoms of active colitis and a concomitant 3*4*5 cm dermato-mucosal lesion in her left nasal lumen. After surgery of the mucosal lesion, the treatment for her active colitis was initiated with intravenous infliximab and oral asacol. After a 1-year follow up, no sign of recurrence favoring mucosal lesion was noted and symptoms of ulcerative colitis were managed properly. PMID- 26106472 TI - A Rare Cause of Recurrent Abdominal Pain. PMID- 26106473 TI - Furazolidone and Helicobacter pylori Treatment. PMID- 26106474 TI - Mesenchymal stromal cells of osteosarcoma patients do not show evidence of neoplastic changes during long-term culture. AB - BACKGROUND: In vitro expanded mesenchymal stromal cells (MSCs) are increasingly used as experimental cellular therapy. However, there have been concerns regarding the safety of their use, particularly with regard to possible oncogenic transformation. MSCs are the hypothesized precursor cells of high-grade osteosarcoma, a tumor with often complex karyotypes occurring mainly in adolescents and young adults. METHODS: To determine if MSCs from osteosarcoma patients could be predisposed to malignant transformation we cultured MSCs of nine osteosarcoma patients and five healthy donors for an average of 649 days (range 601-679 days). Also, we compared MSCs derived from osteosarcoma patients at diagnosis and from healthy donors using genome wide gene expression profiling. RESULTS: Upon increasing passage, increasing frequencies of binucleate cells were detected, but no increase in proliferation suggestive of malignant transformation occurred in MSCs from either patients or donors. Hematopoietic cell specific Lyn substrate 1 (HLCS1) was differentially expressed (fold change 0.25, P value 0.0005) between MSCs of osteosarcoma patients (n = 14) and healthy donors (n = 9). CONCLUSIONS: This study shows that although HCLS1 expression was downregulated in MSCs of osteosarcoma patients and binucleate cells were present in both patient and donor derived MSCs, there was no evidence of neoplastic changes to occur during long-term culture. PMID- 26106476 TI - Risk factors for acquisition of carbapenem resistant Enterobacteriaceae in an acute tertiary care hospital in Singapore. AB - BACKGROUND: Carbapenem resistant Enterobacteriaceae (CRE) is increasingly reported worldwide. A similar increase is seen in Singapore since identification of its first case in 2008. The aim of this study was to identify local risk factors for carriage of CRE in patients from an acute tertiary care hospital in Singapore. METHOD: A matched case-control study was conducted on inpatients treated from January 1, 2011 till December 31, 2013. Two hundred and three cases of CRE infection or colonization were matched with 203 controls. CRE types were identified by PCR. Statistical analysis of data including a multivariate logistic regression analysis was done using SPSS 21.0. RESULTS: CREs were commonly seen in Klebsiella pneumoniae (42.2 %), Escherichia coli (24.3 %) and Enterobacter cloacae complex (17.2 %) in the 268 isolates. NDM-1 was the commonest CRE type seen (44.4 %), followed by KPC (39.9 %) whilst OXA-48 only constituted (7.8 %). Univariate analysis identified key risk factors associated with CRE as history of previous overseas hospitalization (OR: 33.667; 95 % CI: 4.539-259.700), admission to ICU (OR: 11.899; 95 % CI: 4.986-28.399) and HD/ICA (OR: 6.557; 95 % CI: 4.057 10.596); whilst a multivariate analysis revealed exposure to antibiotics penicillin (OR: 4.640; 95 % CI: 1.529-14.079] and glycopeptide (OR: 5.162; 95 % CI: 1.377-19.346) and presence of central line device (OR: 3.117; 95 % CI: 1.167 8.330) as significant independent predictors. CONCLUSIONS: The identification of risk factors amongst our local population helped to refine the criteria used for target active surveillance screening for CRE amongst inpatients at time of hospital admission. PMID- 26097685 TI - Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity. AB - OBJECTIVE: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs) based on evidences reported in the published literature. METHODS: We extensively reviewed the literature concerning nelfinavir (NFV) as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. CONCLUSIONS: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS), decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes. PMID- 26106477 TI - The effects of exercise and diet on olfactory capability in detection dogs. AB - A previous work suggests that dietary fat may influence canine olfaction. The present study evaluated whether olfactory performance could be influenced by forms of dietary fat and exercise. Seventeen certified detection dogs were fed three different diets (high fat, low fat or high polyunsaturated fat) for 12 weeks. After 12 weeks, olfactory testing was performed using a scent wheel in an olfaction laboratory using three explosive materials. The dogs completed eight to twelve scent trials before and after a 30 min treadmill exercise on five consecutive days. A mixed-effect logistic regression model was used to examine how diet, pre- or post-exercise, trial number, odourant, mass of target and target position influenced the probability of dogs alerting on the target odour. There were no significant changes in the dog's ability to find a target odour at threshold amounts. Dogs were 1.42 (1.08, 1.87; 95 % CI) times as likely to find a target on the high polyunsaturated fat diet relative to the high-fat diet (P = 0.009). The low-fat diet was not significantly different from either the high-fat diet or the high polyunsaturated fat diet (P = 0.12). Dogs were 1.49 (1.26, 1.76; 95 % CI) times as likely to find a target prior to exercise relative to after exercise (P < 0.001). Dogs on the high PUFA diet utilising maize oil showed mild improvement in olfaction. The exact reasons are unknown; however, the higher relative amount of linoleic acid in the diet may play a role in olfactory sensation which warrants further examination of optimal diets for detection dogs. PMID- 26106479 TI - Disordered eating behavior among group fitness instructors: a health-threatening secret? AB - BACKGROUND: The present study aimed to examine disordered eating behavior (DE) and self-reported eating disorders (ED) among Norwegian group fitness instructors. METHODS: Group fitness instructors from Norway (n = 685 females and 152 males, response rate: 57 %) completed an online survey. The survey included the instruments Eating Disorders Inventory (EDI) and the Exercise Dependence Scale (EDS). RESULTS: A total of 22 % of the male and 59 % of the female respondents were classified with DE. The respondents classified with DE had higher BMI, more weight loss attempts, and higher total EDI score compared to the respondents with no DE. A correlation between EDI total score and EDS total score was found among both male and female group fitness instructors. No males and four percent of the females reported having a current ED. The instructors with self reported current ED had higher weekly volume of instructing classes compared to the other instructors. None of the respondents with self-reported ED had informed their center manager about it. CONCLUSION: The high prevalence of DE behavior calls for concern. The reported secrecy regarding self-reported ED might decrease the possibility for early recognition and intervention. The findings reveal implications for the instructors' physical and mental health, for their reputation and impact as important healthy role models and health/fitness authorities, and for the importance of prevention, identification and management of such behavior in fitness center settings. PMID- 26106478 TI - Linear growth faltering in infants is associated with Acidaminococcus sp. and community-level changes in the gut microbiota. AB - BACKGROUND: Chronic malnutrition, termed stunting, is defined as suboptimal linear growth, affects one third of children in developing countries, and leads to increased mortality and poor developmental outcomes. The causes of childhood stunting are unknown, and strategies to improve growth and related outcomes in children have only had modest impacts. Recent studies have shown that the ecosystem of microbes in the human gut, termed the microbiota, can induce changes in weight. However, the specific changes in the gut microbiota that contribute to growth remain unknown, and no studies have investigated the gut microbiota as a determinant of chronic malnutrition. RESULTS: We performed secondary analyses of data from two well-characterized twin cohorts of children from Malawi and Bangladesh to identify bacterial genera associated with linear growth. In a case control analysis, we used the graphical lasso to estimate covariance network models of gut microbial interactions from relative genus abundances and used network analysis methods to select genera associated with stunting severity. In longitudinal analyses, we determined associations between these selected microbes and linear growth using between-within twin regression models to adjust for confounding and introduce temporality. Reduced microbiota diversity and increased covariance network density were associated with stunting severity, while increased relative abundance of Acidaminococcus sp. was associated with future linear growth deficits. CONCLUSIONS: We show that length growth in children is associated with community-wide changes in the gut microbiota and with the abundance of the bacterial genus, Acidaminococcus. Larger cohorts are needed to confirm these findings and to clarify the mechanisms involved. PMID- 26106480 TI - Vitamin D receptor expression levels determine the severity and complexity of disease progression among leprosy reaction patients. AB - We studied the roles of vitamin D and its receptor, VDR, in the progression of leprosy. The majority of individuals with leprosy from Kolkata, India, with a type 1 or type 2 reaction have low levels of vitamin D3 in serum samples. Interestingly, individuals with a type 2 reaction associated with neuritis/erythema nodosum leprosum had very low VDR mRNA expression levels, ranging from 5% to 10%, compared to that of healthy control subjects; these patients also had a high bacilli index, ranging from 3+ to 5+. This is the first report to indicate that VDR expression levels may determine the complexity and severity of the progression of leprosy. PMID- 26106481 TI - Evolution of antimicrobial resistance and serotype distribution of Streptococcus pneumoniae isolated from children with invasive and noninvasive pneumococcal diseases in Algeria from 2005 to 2012. AB - Pneumococcal infections are a major cause of morbidity and mortality in developing countries. The introduction of pneumococcal conjugate vaccines (PCVs) has dramatically reduced the incidence of pneumococcal diseases. PCVs are not currently being used in Algeria. We conducted a prospective study from 2005 to 2012 in Algeria to determine antimicrobial drug resistance and serotype distribution of Streptococcus pneumoniae from children with pneumococcal disease. Among 270 isolated strains from children, 97 (36%) were invasive disease; of these, 48% were not susceptible to penicillin and 53% not susceptible to erythromycin. A high rate of antimicrobial nonsusceptibility was observed in strains isolated from children with meningitis. The serotype distribution from pneumococci isolated from children with invasive infections was (by order of prevalence): 14, 1, 19F, 19A, 6B, 5, 3, 6A and 23F. Multidrug resistance was observed in serotypes 14, 19F, 19A and 6B. The vaccine coverage of serotypes isolated from children aged <5 years was 55.3% for PCV7, 71.1% for PCV10 and 86.8% for PCV13. Our results highlight the burden of pneumococcal disease in Algeria and the increasing S. pneumoniae antibiotic resistance. The current pneumococcal vaccines cover a high percentage of the circulating strains. Therefore, vaccination would reduce the incidence of pneumococcal disease in Algeria. PMID- 26106482 TI - Persistence of anti-chikungunya virus-specific antibodies in a cohort of patients followed from the acute phase of infection after the 2007 outbreak in Italy. AB - Chikungunya is a mosquito-borne infection of humans, and its diffusion has increased worldwide. In 2007 an outbreak occurred in Italy. In this study, the antibody response of 133 patients followed up starting from the acute phase of infection was investigated. Antibody titres were periodically scored up to 1 year since the infection: 82.7% of the IgM antibody disappeared within 12 months, and the IgG response lasted longer than 12 months. Nevertheless, the IgG mean titre was lower in 95.5% of patients at the end of follow-up, thus suggesting a decrease within a relatively short period. PMID- 26106483 TI - Increases in intravenous magnesium use among hospitalized patients: an institution cross-sectional experience. AB - BACKGROUND: Among hospitalized patients, indications for the measurement of magnesium levels and treatment of hypomagnesemia with intravenous magnesium are not well defined. Recently, there have been reports of worldwide shortages of intravenous magnesium sulphate. OBJECTIVE: To examine secular trends in the administration of intravenous magnesium on hospital wards at a tertiary care institution. The secondary objective is to identify factors associated with magnesium use among admitted patients. METHODS: Retrospective cross-section review of hospitalized patients at a single Canadian tertiary care center. Utilization of non-parental nutrition intravenous magnesium from 2003 to 2013 stratified by hospital ward was examined. In addition, patient level data from select wards (including medical and surgical services) was examined at early and more recent time period (4/2006 versus 4/2013). RESULTS: Among the 248,329 hospitalized patients, intravenous magnesium use increased by 2.86 fold from 2003 to 2013. Not all wards had an increase whereas some had nearly a 10 fold increase in use. In the sample (n = 769), (adjusting for admission magnesium level, presence of an indication for intravenous magnesium, ward location, comorbidity and demographics) intravenous magnesium administration was higher (25.8 % versus 5.5 %) in 2013 versus 2006 (OR 13.91 (95 % CI, 6.21-31.17, p < 0.001). Despite this increase in intravenous magnesium administration, <3 % of patients were admitted on oral magnesium in 2006 and 2013. For patients receiving intravenous magnesium only a minority were discharged on oral therapy despite low levels. CONCLUSIONS: This center has witnessed a considerable increase in the use of in hospital intravenous magnesium over the last 6 years that cannot be explained for by medical indications. The risks and benefits of this therapy deserve further study. If this change in practice is representative of other North American hospitals, it may be responsible for recent drug shortages. PMID- 26106484 TI - Critical Appraisal of Clinical Practice Guidelines for Age-Related Macular Degeneration. AB - Purpose. To evaluate the methodological quality of age-related macular degeneration (AMD) clinical practice guidelines (CPGs). Methods. AMD CPGs published by the American Academy of Ophthalmology (AAO) and Royal College of Ophthalmologists (RCO) were appraised by independent reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, which comprises six domains (Scope and Purpose, Stakeholder Involvement, Rigor of Development, Clarity of Presentation, Applicability, and Editorial Independence), and an Overall Assessment score summarizing methodological quality across all domains. Results. Average domain scores ranged from 35% to 83% for the AAO CPG and from 17% to 83% for the RCO CPG. Intraclass correlation coefficients for the reliability of mean scores for the AAO and RCO CPGs were 0.74 and 0.88, respectively. The strongest domains were Scope and Purpose and Clarity of Presentation. The weakest were Stakeholder Involvement (AAO) and Editorial Independence (RCO). Conclusions. Future AMD CPGs can be improved by involving all relevant stakeholders in guideline development, ensuring transparency of guideline development and review methodology, improving guideline applicability with respect to economic considerations, and addressing potential conflict of interests within the development group. PMID- 26106485 TI - Ophthalmologic Psychophysical Tests Support OCT Findings in Mild Alzheimer's Disease. AB - Purpose. To analyze in mild Alzheimer's disease (MAD) patients, GDS-4 (Reisberg Scale), whether or not some psychophysical tests (PTs) support OCT macular findings in the same group of MAD patients reported previously. Methods. Twenty three MAD patients and 28 age-matched control subjects with mean Mini Mental State Examination of 23.3 and 28.2, respectively, with no ocular disease or systemic disorders affecting vision were included. Best-corrected visual acuity (VA), contrast sensitivity (CS) (3, 6, 12, and 18 cpds), color perception (CP), and perception digital test (PDT) were tested in one eye of each patient. Results. In comparison with the controls, MAD patients presented (i) a significant decrease in VA, PDT, and CS for all spatial frequencies analyzed, especially the higher ones, and (ii) a significant increase in unspecific errors on the blue axis (P < 0.05 in all instances). In MAD patients, a wide aROC curve was plotted in all PTs. Conclusions. In MAD, CS, VA, and the tritan axis in CP were impaired. The PTs with the greatest predictive value are the higher spatial frequencies in CS and tritan unspecific errors in CP. PT abnormalities are consistent with the structural findings reported in the same MAD patients using OCT. PMID- 26106486 TI - Factors Associated with Anemia among Children Aged 6-23 Months Attending Growth Monitoring at Tsitsika Health Center, Wag-Himra Zone, Northeast Ethiopia. AB - Background. Globally, about 47.4% of children under five are suffering from anemia. In Ethiopia, 60.9% of children under two years are suffering from anemia. Anemia during infancy and young childhood period is associated with poor health and impaired cognitive development, leading to reduced academic achievement and earnings potential in their adulthood life. However, there is scarcity of information showing the magnitude of iron deficiency anemia among young children in Ethiopia. Therefore, this study aimed at assessing prevalence and associated factors of iron deficiency anemia among children under two (6-23 months). Methods. Institution based cross-sectional study was carried out from March to May, 2014, at Tsitsika Health Center in Wag-Himra Zone, Northeast Ethiopia. Systematic random sampling technique was employed. Automated hemoglobin machine was used to determine the hemoglobin level. Socioeconomic and demographic data were collected by using a pretested and structured questionnaire. Binary logistic regression analysis was used to identify associated factors and odds ratio with 95% CI was computed to assess the strength of association. Results. Total of 347 children participated in this study. The overall prevalence of anemia was 66.6%. In multivariate logistic regression analysis, male sex (AOR = 3.1 (95% CI: 1.60 5.81)), 9-11 months of age (AOR = 9.6 (95% CI: 3.61-25.47)), poor dietary diversity (AOR = 3.2 (95% CI: 1.35-7.38)), stunting (AOR = 2.7 (95% CI: 1.20 6.05)), diarrhea (AOR = 4.9 (1.63-14.59)), no formal education (AOR = 2.6 (95% CI: 1.26-5.27)), early initiation of complementary food (AOR = 11.1 (95% CI: 4.08 30.31)), and lowest wealth quintile (AOR = 3.0 (95% CI: 1.01-8.88)) were significantly associated with anemia. Conclusion. The overall prevalence of anemia among children who aged 6-23 months has sever public health importance in the study area. Integrated efforts need to be prioritized to improve health as well as appropriate infant and young child feeding practice among children under. PMID- 26106487 TI - The Clinical Efficacy and Safety of Ertapenem for the Treatment of Complicated Urinary Tract Infections Caused by ESBL-Producing Bacteria in Children. AB - Background. Urinary tract infections (UTIs) are common and important clinical problem in childhood, and extended-spectrum-beta-lactamase- (ESBL-) producing organisms are the leading cause of healthcare-related UTIs. In this study, we aimed to evaluate the clinical efficacy and safety of ertapenem therapy in children with complicated UTIs caused by ESBL-producing organisms. Methods. Seventy-seven children with complicated UTIs caused by ESBL-producing organisms were included in this retrospective study, and all had been treated with ertapenem between January 2013 and June 2014. Results. Sixty-one (79%) females and sixteen (21%) males with a mean +/- standard deviation (SD) age of 76.6 +/- 52 months (range 3-204, median 72 months) were enrolled in this study. Escherichia coli (E. coli) (n = 67; 87%) was the most common bacterial cause of the UTIs followed by Klebsiella pneumoniae (K. pneumoniae) (n = 9; 11.7%) and Enterobacter cloacae (E. cloacae) (n = 1; 1.3%). The mean duration of the ertapenem therapy was 8.9 +/- 1.6 days (range 4-11). No serious drug-related clinical or laboratory adverse effects were observed, and the ertapenem therapy was found to be safe and well tolerated in the children in our study. Conclusion. Ertapenem is a newer carbapenem with the advantage of once-daily dosing and is highly effective for treating UTIs caused by ESBL-producing microorganisms. PMID- 26106489 TI - Undifferentiated Intimal Sarcoma of the Inferior Vena Cava with Extension to the Right Atrium and Renal Vasculature. AB - Primary sarcomas of the great vessels (aorta, pulmonary artery, and inferior vena cava (IVC)) are exceedingly rare. We report a rare case of an undifferentiated intimal sarcoma of the IVC with extension to the right atrium, adrenal, and renal veins. The patient underwent extensive resection, reconstruction of the IVC, and subsequent adjuvant chemotherapy. Patient has tolerated chemotherapy and, at 17 months after resection, the patient remains free of tumor recurrence. Undifferentiated intimal sarcomas remain a rare entity with only five cases of venous undifferentiated intimal sarcomas reported in the literature, two of which occurred in the IVC. Intimal sarcomas tend to carry a poor prognosis with the limited literature available on treatment approaches. Our objective is to highlight this rare entity and possible treatment approach which we utilized. Primary sarcomas of IVC need to be included as part of a complete differential diagnosis in patients with atrial masses or recurrent pulmonary emboli. PMID- 26106488 TI - Relationship between Zinc (Zn (2+) ) and Glutamate Receptors in the Processes Underlying Neurodegeneration. AB - The results from numerous studies have shown that an imbalance between particular neurotransmitters may lead to brain circuit dysfunction and development of many pathological states. The significance of glutamate pathways for the functioning of the nervous system is equivocal. On the one hand, glutamate transmission is necessary for neuroplasticity, synaptogenesis, or cell survival, but on the other hand an excessive and long-lasting increased level of glutamate in the synapse may lead to cell death. Under clinical conditions, hyperactivity of the glutamate system is associated with ischemia, epilepsy, and neurodegenerative diseases such as Alzheimer's, Huntington's, and many others. The achievement of glutamate activity in the physiological range requires efficient control by endogenous regulatory factors. Due to the fact that the free pool of ion Zn(2+) is a cotransmitter in some glutamate neurons; the role of this element in the pathophysiology of a neurodegenerative diseases has been intensively studied. There is a lot of evidence for Zn(2+) dyshomeostasis and glutamate system abnormalities in ischemic and neurodegenerative disorders. However, the precise interaction between Zn(2+) regulative function and the glutamate system is still not fully understood. This review describes the relationship between Zn(2+) and glutamate dependent signaling pathways under selected pathological central nervous system (CNS) conditions. PMID- 26106490 TI - Raghib Syndrome Presenting as a Cryptogenic Stroke: Role of Cardiac MRI in Accurate Diagnosis. AB - Raghib Syndrome is a rare developmental complex, which consists of persistence of the left superior vena cava (PLSVC) along with coronary sinus ostial atresia and atrial septal defect. This Raghib complex anomaly has also been associated with other congenital malformations including ventricular septal defects, enlargement of the tricuspid annulus, and pulmonary stenosis. Our case demonstrates an isolated PLSVC draining into the left atrium along with coronary sinus atresia in a young patient presenting with cryptogenic stroke without the atrial septal defect. Majority of the cases reported in the literature were found to have the lesion during the postmortem evaluation or were characterized at angiography and/or echocardiography. We stress the importance of modern day imaging like the computed tomography (CT) angiography and cardiac MRI in diagnosis and surgical management of such rare lesions leading to cryptogenic strokes. PMID- 26106491 TI - Telescopic Overdenture and Implant Supported Fixed Partial Denture: A Pragmatic Treatment Approach. AB - This case report presents a patient who had been rehabilitated with a telescopic overdenture and implant supported fixed partial denture (ISFPD). The treatment process was as follows: (1) fabricating telescopic crowns and overdenture prosthesis for the lower jaw and a temporary complete denture for the upper jaw, (2) using the temporary denture as diagnostic and surgical guide to optimize dental implant placement, and (3) fabricating ISFPD for the upper jaw. Using the patient's existing or temporary denture not only serves as an alternative surgical guide to calibrate the dental implant locations but also helps to finish the restoration at desired dimension, size, and anatomic form. PMID- 26106492 TI - A Case of Fulminant Hepatitis due to Echovirus 9 in a Patient on Maintenance Rituximab Therapy for Follicular Lymphoma. AB - Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have been described as complicating Rituximab therapy. We report an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. We also describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment and thus may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future. PMID- 26106493 TI - Three Cases of West Nile Encephalitis over an Eight-Day Period at a Downtown Los Angeles Community Hospital. AB - Since its introduction in New York City in 1999, the virus has spread throughout the entire North American continent and continues to spread into Central and Latin America. Our report discusses the signs and symptoms, diagnostics, and treatment of West Nile disease. It is important to recognize the disease quickly and initiate appropriate treatment. We present three cases of West Nile encephalitis at White Memorial Medical Center in East Los Angeles that occurred over the span of eight days. All three patients live within four to six miles from the hospital and do not live or work in an environment favorable to mosquitoes including shallow bodies of standing water, abandoned tires, or mud ruts. All the patients were Hispanic. Physicians and other health care providers should consider West Nile infection in the differential diagnosis of causes of aseptic meningitis and encephalitis, obtain appropriate laboratory studies, and promptly report cases to public health authorities. State governments should establish abatement programs that will eliminate sources that allow for mosquito reproduction and harboring. The public needs to be given resources that educate them on what entails the disease caused by the West Nile virus, what the symptoms are, and, most importantly, what they can do to prevent themselves from becoming infected. PMID- 26106494 TI - Stiff Person Syndrome: A Rare Neurological Disorder, Heterogeneous in Clinical Presentation and Not Easy to Treat. AB - Background. Stiff person syndrome (SPS) is a rare neurological disorder characterized by progressive rigidity of axial and limb muscles associated with painful spasms. SPS can be classified into classic SPS, paraneoplastic SPS, and SPS variants. Its underlying pathogenesis is probably autoimmune, as in most cases antibodies against glutamic acid decarboxylase (GAD) are observed. Similarly, paraneoplastic SPS is usually linked to anti-amphiphysin antibodies. Treatment is based on drugs enhancing gamma-aminobutyric acid (GABA) transmission and immunomodulatory agents. Case Series. Patient 1 is a 45-year-old male affected by the classic SPS, Patient 2 is a 73-year-old male affected by paraneoplastic SPS, and Patient 3 is a 68-year-old male affected by the stiff limb syndrome, a SPS variant where symptoms are confined to the limbs. Symptoms, diagnostic findings, and clinical course were extremely variable in the three patients, and treatment was often unsatisfactory and not well tolerated, thus reducing patient compliance. Clinical manifestations also included some unusual features such as recurrent vomiting and progressive dysarthria. Conclusions. SPS is a rare disorder that causes significant disability. Because of its extensive clinical variability, a multitask and personalized treatment is indicated. A clearer understanding of uncommon clinical features and better-tolerated therapeutic strategies are still needed. PMID- 26106495 TI - Posterior Reversible Encephalopathy Syndrome Secondary to CSF Leak and Intracranial Hypotension: A Case Report and Literature Review. AB - Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical neuroradiological condition characterized by insidious onset of neurological symptoms associated with radiological findings indicating posterior leukoencephalopathy. PRES secondary to cerebrospinal fluid (CSF) leak leading to intracranial hypotension is not well recognized etiology of this condition. Herein, we report a case of PRES that occurred in the setting of CSF leak due to inadvertent dural puncture. Patient underwent suturing of the dural defect. Subsequently, his symptoms resolved and a repeated brain MRI showed resolution of brain lesions. The pathophysiology and mechanistic model for developing PRES in the setting of intracranial hypotension were discussed. We further highlighted the importance of tight blood pressure control in patients with CSF leak and suspected intracranial hypotension because they are more vulnerable to develop PRES with normal or slightly elevated bleed pressure values. PMID- 26106496 TI - Synchronous Multicentric Giant Cell Tumour of Distal Radius and Sacrum with Pulmonary Metastases. AB - Giant cell tumour (GCT) is an uncommon primary bone tumour, and its multicentric presentation is exceedingly rare. We report a case of a 45-year-old female who presented to us with GCT of left distal radius. On the skeletal survey, osteolytic lesion was noted in her right sacral ala. Biopsy confirmed both lesions as GCT. Pulmonary metastasis was also present. Resection-reconstruction arthroplasty for distal radius and thorough curettage and bone grafting of the sacral lesion were done. Multicentric GCT involving distal radius and sacrum with primary sacral involvement is not reported so far to our knowledge. PMID- 26106497 TI - Epithelial Downgrowth after Intraocular Surgery Treated with Intracameral 5 Fluorouracil. AB - Purpose. To present the clinical and histopathologic correlation of two cases of epithelial downgrowth (EDG) after prior intraocular surgery. Methods. Observational case reports. Results. We present two cases of EDG occurring after intraocular surgery. In both cases, after two anterior chamber injections of 5 fluorouracil (5FU), the area of EDG initially regressed. In Case 1, a limited area of EDG eventually recurred, and penetrating keratoplasty with cryotherapy was curative. In Case 2, subsequent corneal edema required Descemet-stripping automated endothelial keratoplasty, and the patient remained clinically free of EDG without further treatment. Conclusion. Intracameral 5FU may have a role in the treatment of EDG after intraocular surgery, though its precise utilization and impact remain to be defined. PMID- 26106498 TI - Pleomorphic Adenoma of the External Auditory Canal: A Rare Presentation. AB - A 55-year-old male presented with a nine-month history of gradually enlarging, painless mass in the right external auditory canal associated with hearing loss and occasional bleeding. Examination demonstrated complete obstruction of the outer 1/3 of the external auditory canal by a firm, pink, rubbery mass. CT scan of the temporal bone showed tumor mass with no evidence of bone destruction. The tumor was excised and histopathology confirmed a diagnosis of ceruminous pleomorphic adenoma of the external auditory canal. Six months following the surgery, patient is free of any recurrent disease. PMID- 26106499 TI - Metastasis of Malignant Melanoma to Urinary Bladder: A Case Report and Review of the Literature. AB - Aims. Metastatic malignant melanoma of the urinary bladder is a rare clinical entity, with only twenty-three published cases to date. We present a case of this rare entity, a thorough review of the literature, and differential diagnosis of melanoma in the bladder. Methods and Results. A 55-year-old woman with a history of malignant melanoma of the right thigh, excised eight years ago, presented with back pain, fatigue, and hematuria. She underwent computed tomography (CT) scan and was found to have metastases within the liver, spleen, lungs, and urinary bladder. She underwent cystoscopy and transurethral resection of three polypoid lesions. Histologic and immunohistochemical examination revealed metastatic malignant melanoma involving bladder mucosa. Conclusions. This case illustrates the importance of including malignant melanoma in the differential diagnosis of high grade neoplasms of bladder, especially in cases where the relevant clinical history is not available. PMID- 26106500 TI - An Unusual Cause of Abdominal Pain: Three Lead Pellets within the Appendix Vermiformis. AB - Most ingested foreign bodies usually pass out in the feces uneventfully. Complications such as intestinal perforation and bleeding usually occur with sharp, thin, stiff, long, and pointed objects. This case describes the management of three lead pellets within the appendix vermiformis. A 45-year-old male visited our clinic complaining of a 4-month history of abdominal pain. The patient inquiry revealed that he had eaten hunted rabbit meat on numerous occasions and had unintentionally ingested three lead pellets. Plain abdominal films and a barium enema showed foreign bodies in the right lower abdominal quadrant. Since the lead pellets were thought to have migrated extraluminally, they were removed through laparotomy under fluoroscopic guidance. An appendectomy was performed. Pathologically, three lead pellets were embedded in the appendix, which showed signs of intramucosal inflammation. Foreign bodies causing appendicitis are rare. However, if stiff or pointed objects enter the appendicular lumen, there is a high risk of appendicitis, perforation, or abdominal pain. An appendectomy was required to remove the ingested lead pellets in the appendix. PMID- 26106501 TI - Life-Threatening Postpneumonectomy Syndrome Complicated with Right Aortic Arch after Left Pneumonectomy. AB - A 54-year-old man with right aortic arch underwent left lower lobectomy and lingular segmentectomy, followed by complete pneumonectomy, for refractory nontuberculous mycobacterial infection. Three months after the pneumonectomy, he developed acute respiratory distress. Computed tomography showed an excessive mediastinal shift with an extremely narrowed bronchus intermedius and right lower bronchus compressed between the right pulmonary artery and the right descending aorta. Soon after the nearly obstructed bronchus intermedius was observed by bronchoscopy, he began to exhibit frequent hypoxic attacks, perhaps due to mucosal edema. Emergent surgical repositioning of the mediastinum and decompression of the bronchus was indicated. After complete adhesiolysis of the left thoracic cavity was performed, to maintain the proper mediastinal position, considering the emergent setting, an open wound thoracostomy was created and piles of gauze were inserted, mildly compressing the heart and the mediastinum to the right side. Thoracoplasty was performed three months later, and he was eventually discharged without any dressings needed. Mediastinal repositioning under thoracostomy should be avoided in elective cases because of its extremely high invasiveness. However, in the case of life-threatening postpneumonectomy syndrome in an emergent setting, mediastinal repositioning under thoracostomy may be an option to save life, which every thoracic surgeon could attempt. PMID- 26106502 TI - Adenomatoid Tumor of the Tunica Albuginea in a Boy: A Case Report and Literature Review. AB - Adenomatoid tumors (AT) are the most common paratesticular neoplasms and account for approximately 30% of all paratesticular masses. Most of them occur in the third or fourth decade and present as well-defined firm and painless masses. We report here a case of adenomatoid tumor from tunica albuginea. This patient is a 12-year-old boy with left testicular pain for 6 months. Scrotal ultrasonography revealed a solid mass of paratesticular origin. The histology and immunohistochemistry confirmed the final diagnosis. A right tumor resection was performed. Because of its rarity, the clinical and histopathologic appearance is seldom illustrated. Here we present a case report and a comprehensive literature review with the objective of providing useful information on this entity. PMID- 26106503 TI - A Proposed Maneuver to Guide Transseptal Puncture Using Real-Time Three Dimensional Transesophageal Echocardiography: Pilot Study. AB - Aim of Study. To assess the feasibility of a new proposed maneuver "RATLe-90" using real-time three-dimensional transesophageal echocardiography (RT-3DTEE) for anatomically oriented visualization of the interatrial septum (IAS) in guiding the transseptal puncture TSP. Methods. The study included 20 patients (mean age, 60.2 +/- 6.7 years; 60% males) who underwent TSP for different indications. RT 3DTEE was used to guide TSP. The proposed maneuver RATLe-90 (Rotate-Anticlockwise Tilt-Left-90) was applied in all cases to have the anatomically oriented en face view of the IAS from the right atrial (RA) aspect. Having this anatomically oriented view, we guided the TSP catheter towards the proper puncture site according to the planned procedure. Results. Using the RATLe-90 maneuver, the anatomically oriented en face view of the IAS from the RA was obtained in all patients. We were able to guide the puncture catheter to the proper puncture site on the IAS. The 3D images obtained were clearly understood by both echocardiographers and interventionists. The RATLe-90 maneuver acquisition time was 19.9 +/- 1.6 seconds. The time-to-tent was 64.8 +/- 16.3 seconds. Less TEE probe manipulations were needed while guiding the TSP. Conclusions. Application of RT3D-TEE during TSP using RATLe-90 maneuver is feasible with shorter fluoroscopy time and minimizing TEE probe manipulations. PMID- 26106504 TI - Factors Associated with the Use of Drug-Eluting Stents in Patients Presenting with Acute ST-Segment Elevation Myocardial Infarction. AB - Background. Drug-eluting stents (DES) have proven clinical superiority to bare metal stents (BMS) for the treatment of patients with ST-segment elevation myocardial infarction (STEMI). Decision to implant BMS or DES is dependent on the patient's ability to take dual antiplatelet therapy. This study investigated factors associated with DES placement in STEMI patients. Methods. Retrospective analysis was performed on 193 patients who presented with STEMI and were treated with percutaneous coronary intervention at an urban, tertiary care hospital. Independent factors associated with choice of stent type were determined using stepwise multivariate logistic regression. Odds ratio (OR) was used to evaluate factors significantly associated with DES and BMS. Results. 128 received at least one DES, while 65 received BMS. BMS use was more likely in the setting of illicit drug or alcohol abuse ([OR] 0.15, 95% CI 0.05-0.48, p <= 0.01), cardiogenic shock (OR 0.26, 95% CI 0.10-0.73, p = 0.01), and larger stent diameter (OR 0.28, 95% CI 0.11-0.68, p <= 0.01). Conclusions. In this analysis, BMS implantation was associated with illicit drug or alcohol abuse and presence of cardiogenic shock. This study did not confirm previous observations that non-White race, insurance, or income predicts BMS use. PMID- 26106505 TI - An Efficient Taguchi Approach for the Performance Optimization of Health, Safety, Environment and Ergonomics in Generation Companies. AB - BACKGROUND: A unique framework for performance optimization of generation companies (GENCOs) based on health, safety, environment, and ergonomics (HSEE) indicators is presented. METHODS: To rank this sector of industry, the combination of data envelopment analysis (DEA), principal component analysis (PCA), and Taguchi are used for all branches of GENCOs. These methods are applied in an integrated manner to measure the performance of GENCO. The preferred model between DEA, PCA, and Taguchi is selected based on sensitivity analysis and maximum correlation between rankings. To achieve the stated objectives, noise is introduced into input data. RESULTS: The results show that Taguchi outperforms other methods. Moreover, a comprehensive experiment is carried out to identify the most influential factor for ranking GENCOs. CONCLUSION: The approach developed in this study could be used for continuous assessment and improvement of GENCO's performance in supplying energy with respect to HSEE factors. The results of such studies would help managers to have better understanding of weak and strong points in terms of HSEE factors. PMID- 26106506 TI - A Comparison between the Second Korean Working Conditions Survey (KWCS) and the First KWCS. AB - BACKGROUND: The study was designed to assess the changes in working conditions through a comparative analysis of the characteristics of working conditions in 2006 and 2010. METHODS: We performed a comparative analysis of the data related to the first Korean Working Conditions Survey (KWCS) and the second KWCS in the categories of demographic characteristics, quality of labor, exposure to hazards, and health problems. RESULTS: From our analysis of the demographic characteristics, we saw an increase in labor force participation rate of women and elderly people. As a result of the investigation with regards to working hours, the ratio of employees who worked for >= 49 hours per week was decreased and the ratio of employees who worked for >= 40 h/wk increased. As for exposure to hazards, exposure to tobacco smoke notably decreased in 2010 compared with 2006. With regards to health problems, there was a sharp increase in the number of people who complained of muscle pain in their arms and legs. CONCLUSION: KWCS data included many aspects of working conditions as a nationwide sample. In addition, because this is a periodic nationwide survey, the labor force, working hours, harmful factor exposure, and the change in health problems characteristics according to the flow of time could be investigated. The information comparing the main results of the first survey conducted in 2006 and the second survey conducted in 2010 obtained through this study can be used as an important base material for the establishment of the national policy. PMID- 26106507 TI - Use of Ergonomic Measures Related to Musculoskeletal Complaints among Construction Workers: A 2-year Follow-up Study. AB - BACKGROUND: The physical work demands of construction work can be reduced using ergonomic measures. The aim of this study was to evaluate the use of ergonomic measures related to musculoskeletal disorders (MSDs) among construction workers. METHODS: A questionnaire was sent at baseline and 2 years later to 1,130 construction workers. We established (1) the proportion of workers reporting an increase in their use of ergonomic measures, (2) the proportion of workers reporting a decrease in MSDs, (3) the relative risk for an increase in the use of ergonomic measures and a decrease in MSDs, and (4) workers' knowledge and opinions about the use of ergonomic measures. RESULTS: At follow-up, response rate was 63% (713/1,130). The proportion of workers using ergonomic measures for vertical transport increased (34%, 144/419, p < 0.01); for measures regarding horizontal transport and the positioning of materials, no change was reported. The proportion of workers reporting shoulder complaints decreased (28%, 176/638, p = 0.02). A relationship between the use of ergonomic measures and MSDs was not found; 83% (581/704) of the workers indicated having sufficient knowledge about ergonomic measures. Lightening the physical load was reported to be the main reason for using them. CONCLUSION: Only the use of ergonomic measures for vertical transport increased over a 2-year period. No relationship between the use of ergonomic measures and MSDs was found. Strategies aimed at improving the availability of ergonomic equipment complemented with individualized advice and training in using them might be the required next steps to increase the use of ergonomic measures. PMID- 26106508 TI - Development and Validation of a Safety Climate Scale for Manufacturing Industry. AB - BACKGROUND: This paper describes the development of a scale for measuring safety climate. METHODS: This study was conducted in six manufacturing companies in Iran. The scale developed through conducting a literature review about the safety climate and constructing a question pool. The number of items was reduced to 71 after performing a screening process. RESULTS: The result of content validity analysis showed that 59 items had excellent item content validity index (>= 0.78) and content validity ratio (> 0.38). The exploratory factor analysis resulted in eight safety climate dimensions. The reliability value for the final 45-item scale was 0.96. The result of confirmatory factor analysis showed that the safety climate model is satisfactory. CONCLUSION: This study produced a valid and reliable scale for measuring safety climate in manufacturing companies. PMID- 26106509 TI - Surveying the Impact of Work Hours and Schedules on Commercial Motor Vehicle Driver Sleep. AB - BACKGROUND: Given the long hours on the road involving multiple and interacting work stressors (i.e., delivery pressures, irregular shifts, ergonomic hazards), commercial drivers face a plethora of health and safety risks. Researchers goal was to determine whether and to what extent long-haul trucker work schedules influence sleep duration and quality. METHODS: Survey and biometric data collected from male long-haul truck drivers at a major truckstop in central North Carolina over a six month period. RESULTS: Daily hours worked (mean = 11 hours, 55 minutes) and frequency of working over government-mandated daily HOS regulations (23.8% "frequently or always") were statistically significant predictors of sleep duration. Miles driven per week (mean = 2,812.61), irregular daily hours worked (63.8%), and frequency of working over the daily hour limit (23.8% "frequently or always") were statistically significant predictors of sleep quality. CONCLUSION: Implications of findings suggest a comprehensive review of the regulations and operational conditions for commercial motor vehicle drivers be undertaken. PMID- 26106510 TI - The Impact of Multiple Roles on Psychological Distress among Japanese Workers. AB - BACKGROUND: There has been considerable interest in Japanese society in the problem of work-related stress leading to depressive symptoms, and an increasing number of primary houseworkers maintain paid employment. The purpose of this study was to examine the differential impact of multiple roles associated with psychological distress among Japanese workers. METHODS: We studied 722 men and women aged 18-83 years in a cross-sectional study. The K10 questionnaire was used to examine psychological distress. RESULTS: The proportion of participants with psychological distress was higher in women (17.8%) compared with men (11.5%). Having three roles significantly decreased the risk of psychological distress [women: odds ratio (OR), 0.37-fold; men: OR, 0.41] compared with only one role. In working married women, there was significantly less psychological distress (OR, 0.27), and those with childrearing or caregiving responsibilities for elderly parents had significantly less psychological distress (OR, 0.38) than those with only an employment role. Similarly, working married men who had childrearing or caregiving responsibilities for elderly parents had significantly less psychological distress (OR, 0.41) than those who had only an employment role. CONCLUSION: The present study demonstrated that participants who had only an employment role had an increased risk of psychological distress. The degree of psychological distress was not determined solely by the number of roles. It is important to have balance between work and family life to reduce role conflict and/or role submersion, which in turn may reduce the risk of psychological distress. PMID- 26106511 TI - Psychosocial Factors and Musculoskeletal Pain Among Rural Hand-woven Carpet Weavers in Iran. AB - BACKGROUND: Musculoskeletal pain (MSP) is a common and disabling problem among carpet weavers and is linked to physical and psychosocial factors of work. This study aimed to determine the prevalence of MSP, its psychosocial risk factors, and association of pain in each pair of anatomical sites among carpet weavers. METHODS: A cross-sectional study was performed among 546 hand-woven carpet weavers in rural small-scale workshops of Iran. Data were collected by using parts of a standardized CUPID (Cultural and Psychosocial Influences on Disability) questionnaire focused on MSP in 10 body sites, including the low back, neck, both right and left shoulders, elbows, wrists/hands, individual, physical and psychosocial risk factors. Statistical analysis was performed applying logistic regression models. RESULTS: Prevalence of MSP in at least one body site was 51.7% over the past month. The most common sites were low back and right shoulder pain 27.4% and 20.1%, respectively. A significant difference was found between the mean number of painful anatomical sites and the level of education, age, physical loading at work, time pressure, lack of support, and job dissatisfaction. In pairwise comparisons, strongest association was found between pain in each bilateral anatomical site (odds ratio = 11.6-35.3; p < 0.001). CONCLUSION: In home-based workshops of carpet weaving, psychosocial factors and physical loading were associated with MSP. This finding is consistent with studies conducted among other jobs. Considering the preventive programs, the same amount of attention should be paid to psychosocial risk factors and physical loading. Also, further longitudinal studies are needed to investigate the relationship of psychological factors. PMID- 26106512 TI - Relationship between Comorbid Health Problems and Musculoskeletal Disorders Resulting in Musculoskeletal Complaints and Musculoskeletal Sickness Absence among Employees in Korea. AB - BACKGROUND: To investigate the relationship between musculoskeletal disorders and comorbid health problems, including depression/anxiety disorder, insomnia/sleep disorder, fatigue, and injury by accident, and to determine whether certain physical and psychological factors reduce comorbid health problems. METHODS: In total, 29,711 employees were selected from respondents of the Third Korean Working Conditions Survey and categorized into two groups: Musculoskeletal Complaints or Musculoskeletal Sickness Absence. Four self-reported health indicators (overall fatigue, depression/anxiety, insomnia/sleep disorder, and injury by accident) were selected as outcomes, based on their high prevalence in Korea. We used multiple logistic regression analysis to determine the relationship between comorbid health problems, musculoskeletal complaints, and sickness absence. RESULTS: The prevalence of musculoskeletal complaints and musculoskeletal sickness absence due to muscular pain was 32.26% and 0.59%, respectively. Compared to the reference group, depression/anxiety disorder and overall fatigue were 5.2-6.1 times more prevalent in the Musculoskeletal Complaints Group and insomnia/sleep disorder and injury by accident were 7.6-11.0 times more prevalent in the Sickness Absence Group. When adjusted for individual and work-related physical factors, prevalence of all four comorbid health problems were slightly decreased in both groups. CONCLUSION: Increases in overall fatigue and depression/anxiety disorder were observed in the Musculoskeletal Complaints Group, while increases in insomnia/sleep disorder and injury by accident were observed in the Sickness Absence Group. For management of musculoskeletal complaints and sickness absence in the workplace, differences in health problems between employees with musculoskeletal complaints and those with sickness absence as well as the physical and psychological risk factors should be considered. PMID- 26106513 TI - Noise-Induced Hearing Loss in the Police Force. AB - BACKGROUND: Noise-induced hearing loss (NIHL) is a major preventable occupational health problem with 250 million people worldwide known to have disabling impairment of moderate to greater severity. The aims of the study are to estimate the prevalence of NIHL in the police force; and study its association with age, sex, duration of service (years), smoking and alcohol habits, use of hearing protective devices, as well as preexisting chronic diseases. METHODS: A cross sectional study was conducted on 543 police personnel who had undergone periodic medical examination over a 12-month period. The diagnostic criteria for NIHL were (1) history of occupational noise exposure, (2) bilateral hearing loss, (3) hearing loss of >= 25 dBA at 4,000 Hz in two consecutive audiograms, and (4) no significant medical history affecting hearing. Severity of NIHL was based on the World Health Organization grading. RESULTS: Males (74.8%) made up the majority of the police force. The mean age for police personnel was 35.55 +/- 9.57 years, and the mean duration of service was 14.75 +/- 9.39 years. Compliance with the usage of hearing protective devices was seen in 64.4%. The prevalence of NIHL in this study population was 34.2%, with a higher prevalence in males (37.7%) than in females (23.9%). The study also showed strong associations between NIHL and male sex (odds ratio, 1.9; P < 0.05), and hypertension (odds ratio, 3.3; P < 0.001). Overall, 93% were found to have mild NIHL, 3.5% had moderate NIHL, and 3.5% had severe NIHL. No police personnel were found to have profound hearing loss. CONCLUSION: The prevalence of NIHL in this study is high compared to other similar studies among police personnel. This study shows that increasing age, male, presence of hypertension, diabetes, and longer duration of service are significant associated factors for NIHL. Preventative strategies include health surveillance, implementation of a hearing conservation program, and legislation. PMID- 26106514 TI - Predictors of Hepatitis B Preventive Behavioral Intentions in Healthcare Workers. AB - BACKGROUND: Healthcare workers' practices regarding hepatitis B have an important effect on the control of this problem in workplaces. METHODS: A questionnaire based cross-sectional study was used to investigate the role of knowledge, cues to action, and risk perceptions as predictors of preventive behavioral intentions for hepatitis B among healthcare works in Broujen, Iran (n = 150). History of hepatitis B vaccination, hepatitis B surface antigen test, and demographic characteristics were investigated. The psychometric properties of the questionnaire were established. RESULTS: Those who had a history of hepatitis B surface antigen test had a statistically significant higher level of risk perceptions (30.89 +/- 4.08 vs. 28.41 +/- 3.93, p < 0.01) and preventive behavioral intentions (5.05 +/- 1.43 vs. 4.45 +/- 1.29, p < 0.01). The mean score of cues to action was significantly correlated with age and work history (r = 0.20, p = 0.02 and r = 0.19, p = 0.02). Preventive behavioral intentions were significantly correlated with cues to action and risk perceptions but not with knowledge level. Cognitional factors were responsible for a 17% change in observed variance of preventive behavioral intentions, which was statistically significant. CONCLUSION: Risk perceptions were the most important determinant of preventive behavioral intentions for hepatitis B among health personnel; thus, emphasizing risk perceptions is recommended in educational programs aimed at increasing health personnel's practices regarding hepatitis B. PMID- 26106515 TI - Occupational Safety and Health Activities Conducted across Countries in Asia. AB - Three occupational safety and health (OSH) activities, one international and two national workshops, were documented as part of OSH activities conducted under the International Labor Organization/Korea Partnership Program in the year 2011-2012. This study aimed to provide information on what the three OSH activities were implemented and how they contributed to the improvement of OSH in Asian countries. The international workshop was useful for the participants to understand a variety of information on OSH as well as participatory action oriented training (PAOT) approaches at the regional and global levels. The two national workshops were practical for participants to strengthen their knowledge and skills on the PAOT at the enterprise and national levels. The study shows that the three OSH activities contributed to the understanding of the participants on OSH and PAOT, and that the activities promoted the improvement of OSH across countries in Asia. PMID- 26106516 TI - A Call for Action to Improve Occupational Health and Safety in Ghana and a Critical Look at the Existing Legal Requirement and Legislation. AB - Occupational health and safety (OHS) is a broad field of professional practice, which involves specialists from different disciplines including but not limited to engineers, occupational health physicians, physical and biological scientists, economists, and statisticians. The preventive systems required to ensure workers are protected from injuries and illnesses dwell heavily on engineers; however, the extent to which the engineer can go regarding planning and implementing preventive measures is dependent on specific legal requirements, leadership commitment from the company, organization, and nation. The objective of this paper is to identify the areas of opportunities for improvements in OHS management in Ghana with regard to the nation's legal requirements, commitment of the Ghana government, and Ghanaian leadership as well as appropriate structuring of Ghanaian institutions responsible for monitoring and managing OHS in Ghana. This paper identified Ghana's fragmented legal requirements concerning OHS, which are under different jurisdictions with unclear responsibilities and accountabilities. The paper also highlights the training needs of Ghanaian academic institutions regarding OHS. Among other recommendations made including structuring of Ghanaian institutions to manage OHS in line with the ILO-OSH 2001, this paper aligns the recommendations with the articles and elements of International Labour Organization convention number 155 and OHSAS 18001 elements. PMID- 26106517 TI - Aging Workers and Trade-Related Injuries in the US Construction Industry. AB - The study was designed to identify any trends of injury type as it relates to the age and trade of construction workers. The participants for this study included any individual who, while working on a heavy and highway construction project in the Midwestern United States, sustained an injury during the specified time frame of when the data were collected. During this period, 143 injury reports were collected. The four trade/occupation groups with the highest injury rates were laborers, carpenters, iron workers, and operators. Data pertaining to injuries sustained by body part in each age group showed that younger workers generally suffered from finger/hand/wrist injuries due to cuts/lacerations and contusion, whereas older workers had increased sprains/strains injuries to the ankle/foot/toes, knees/lower legs, and multiple body parts caused by falls from a higher level or overexertion. Understanding these trade-related tasks can help present a more accurate depiction of the incident and identify trends and intervention methods to meet the needs of the aging workforce in the industry. PMID- 26106518 TI - Corrigendum to "Identification of Knowledge Gaps Regarding Healthcare Workers' Exposure to Antineoplastic Drugs: Review of Literature, North America versus Europe" [Saf Health Work 5 (4) (2014) 169-174]. AB - [This corrects the article DOI: 10.1016/j.shaw.2014.06.001.]. PMID- 26106519 TI - Erratum to "Obesity as a Possible Risk Factor For Lost-Time Injury In Registered Nurses: A Literature Review" [Saf Health Work 6 (1) (2015) 1-8]. AB - [This corrects the article DOI: 10.1016/j.shaw.2014.12.006.]. PMID- 26106520 TI - Identification of distinctive interdomain interactions among ZP-N, ZP-C and other domains of zona pellucida glycoproteins underlying association of chicken egg coat matrix. AB - The vertebrate egg coat, including mammalian zona pellucida, is an oocyte specific extracellular matrix comprising two to six zona pellucida (ZP) glycoproteins. The egg coat plays important roles in fertilization, especially in species-specific interactions with sperm to induce the sperm acrosome reaction and to form the block to polyspermy. It is suggested that the physiological functions of the egg coat are mediated and/or regulated coordinately by peptide and carbohydrate moieties of the ZP glycoproteins that are spatially arranged in the egg coat, whereas a comprehensive understanding of the architecture of vertebrate egg-coat matrix remains elusive. Here, we deduced the orientations and/or distributions of chicken ZP glycoproteins, ZP1, ZP3 and ZPD, in the egg coat matrix by confocal immunofluorescent microscopy, and in the ZP1-ZP3 complexes generated in vitro by co-immunoprecipitation assays. We further confirmed interdomain interactions of the ZP glycoproteins by far-Western blot analyses of the egg-coat proteins and pull-down assays of ZP1 in the serum, using recombinant domains of ZP glycoproteins as probes. Our results suggest that the ZP1 and ZP3 bind through their ZP-C domains to form the ZP1-ZP3 complexes and fibrils, which are assembled into bundles through interactions between the repeat domains of ZP1 to form the ZP1-ZP3 matrix, and that the ZPD molecules self associate and bind to the ZP1-ZP3 matrix through its ZP-N and ZP-C domains to form the egg-coat matrix. Based on these results, we propose a tentative model for the architecture of the chicken egg-coat matrix that might be applicable to other vertebrate ones. PMID- 26106521 TI - Blockage of TGFbeta-SMAD2 by demethylation-activated miR-148a is involved in caffeic acid-induced inhibition of cancer stem cell-like properties in vitro and in vivo. AB - Current standard practices for treatment of cancers are less than satisfactory because of recurrence mediated by cancer stem cells (CSCs). Caffeic acid (CaA) is a novel anti-tumor agent that inhibits proliferation, migration, and invasion in human cancer cells. However, little is known about the functions of CaA in regulating CSCs-like properties and the potential molecular mechanisms. Here, we found that CaA attenuated the CSCs-like properties by the microRNA-148a (miR 148a)-mediated inhibition of transforming growth factor beta (TGFbeta)-SMAD2 signaling pathway both in vitro and in vivo. CaA enhanced the expression of miR 148a by inducing DNA methylation. MiR-148a, which targeted the SMAD2-3'UTR, decreased the expression of SMAD2. Knockdown of miR-148a abolished the CaA induced inhibition of TGFbeta-SMAD2 signal pathway and the CSCs-like properties. Our study found a novel mechanism that CaA inhibits the CSCs-like properties via miR-148a-mediated inhibition of TGFbeta-SMAD2 signaling pathway, which may help to identify a new approach for the treatment of human cancers. PMID- 26106522 TI - Hyaluronic acid regulates a key redox control factor Nrf2 via phosphorylation of Akt in bovine articular chondrocytes. AB - One important pharmacological function of hyaluronic acid (HA) in chondrocytes is reduction of cellular superoxide generation and accumulation. Here we demonstrated a relationship between HA supplementation and accumulation of Nuclear factor-erythroid-2-related factor 2 (Nrf2), which is a master transcription factor in cellular redox reactions, in cultured chondrocytes derived from bovine joint cartilage. In HA-treated chondrocytes, expression of Nrf2 and its downstream genes was upregulated. In HA-treated chondrocytes, Akt was phosphorylated, and inhibition of Akt activity or suppression of HA receptors CD44 and/or RHAMM with siRNAs prevented HA-mediated Nrf2 accumulation. Furthermore, Nrf2 siRNA inhibited the HA effect on antioxidant enzymes. These results show that HA might contribute to ROS reduction through Nrf2 regulation by activating Akt. Our study suggests a new mechanism for extracellular matrix (ECM) mediated redox systems in chondrocytes. PMID- 26106523 TI - Enhanced oleate uptake and lipotoxicity associated with laurate. AB - Free fatty acids have been reported to induce cell death (lipotoxicity), but the effects depend on the carbon chain length and number of double bonds. Medium chain saturated fatty acids (MC-SFAs), such as laurate, have less lipotoxicity than long-chain saturated fatty acids (LC-SFAs), such as palmitate. Monounsaturated fatty acids, such as oleate, have also been reported not only to exert cytotoxic effects, but also to reduce the lipotoxicity of LC-SFA. However the interaction between MC-SFA and oleate with respect to cell death is unclear. In this report, we found that lipotoxicity was enhanced by a combination of laurate and oleate relative to either fatty acid alone. The possible mechanisms involved were examined by measuring the production of reactive oxygen species, mitochondrial depolarization, caspase-3 activity, and lipid droplet formation. Although the stress signals and cell death pathways were distinct among different cell types, we found a common phenomenon of enhanced lipid droplet formation in all cells tested. Using fluorescent- or radioisotope-labeled fatty acids, we found that oleate, but not laurate, increased the uptake of fluorescent-labeled fatty acids, and the combinatory effect was more efficient than with oleate alone. We also found that laurate increased oleate uptake, but the effect of oleate on laurate uptake varied among cell types. These results suggest that laurate enhances the influx rate of oleate, the increased intracellular concentration of which not only enhances lipid storage, but also induces cell death by lipotoxic stress responses, which vary according to cell type. PMID- 26106524 TI - Thalamic-hippocampal-prefrontal disruption in relapsing-remitting multiple sclerosis. AB - BACKGROUND: Cortical, thalamic and hippocampal gray matter atrophy in relapsing remitting MS (RRMS) is associated cognitive deficits. However, the role of interconnecting white matter pathways including the fornix, cingulum, and uncinate fasciculus (UF) is less well studied. OBJECTIVE: To assess MS damage to a hippocampal-thalamic-prefrontal network and the relative contributions of its components to specific cognitive domains. METHODS: We calculated diffusion tensor fractional anisotropy (FA) in the fornix, cingulum and UF as well as thalamic and hippocampal volumes in 27 RRMS patients and 20 healthy controls. A neuropsychological battery was administered and 4 core tests known to be sensitive to MS changes were used to assess cognitive impairment. To determine the relationships between structure and cognition, all tests were grouped into 4 domains: attention/executive function, processing speed, verbal memory, and spatial memory. Univariate correlations with structural measures and depressive symptoms identified potential contributors to cognitive performance and subsequent linear regression determined their relative effects on performance in each domain. For significant predictors, we also explored the effects of laterality and axial versus radial diffusivity. RESULTS: RRMS patients had worse performance on the Symbol Digit Modalities Test, but no significant impairment in the 4 cognitive domains. RRMS had reduced mean FA of all 3 pathways and reduced thalamic and hippocampal volumes compared to controls. In RRMS we found that thalamic volume and BDI predicted attention/executive function, UF FA predicted processing speed, thalamic volume predicted verbal memory, and UF FA and BDI predicted spatial memory. CONCLUSIONS: Hippocampal-thalamic-prefrontal disruption affects cognitive performance in early RRMS with mild to minimal cognitive impairment, confirming both white and gray matter involvement in MS and demonstrating utility in assessing functional networks to monitor cognition. PMID- 26106525 TI - Psychopathic traits modulate microstructural integrity of right uncinate fasciculus in a community population. AB - Individuals with psychopathy possess emotional and behavioral abnormalities. Two neural regions, involved in behavioral control and emotion regulation, are often implicated: amygdala and ventromedial prefrontal cortex (VMPFC). Recently, in studies using adult criminal populations, reductions in microstructural integrity of the white matter connections (i.e., uncinate fasciculus (UF)) between these two neural regions have been discovered in criminals with psychopathy, supporting the notion of neural dysfunction in the amygdala-VMPFC circuit. Here, a young adult, community sample is used to assess whether psychopathic traits modulate microstructural integrity of UF, and whether this relationship is dependent upon levels of trait anxiety, which is sometimes used to distinguish subtypes of psychopathy. Results reveal a negative association between psychopathic traits and microstructural integrity of UF, supporting previous findings. However, no moderation of the relationship by trait anxiety was discovered. Findings provide further support for the notion of altered amygdala-VMPFC connectivity in association with higher psychopathic traits. PMID- 26106526 TI - Conflict anticipation in alcohol dependence - A model-based fMRI study of stop signal task. AB - BACKGROUND: Our previous work characterized altered cerebral activations during cognitive control in individuals with alcohol dependence (AD). A hallmark of cognitive control is the ability to anticipate changes and adjust behavior accordingly. Here, we employed a Bayesian model to describe trial-by-trial anticipation of the stop signal and modeled fMRI signals of conflict anticipation in a stop signal task. Our goal is to characterize the neural correlates of conflict anticipation and its relationship to response inhibition and alcohol consumption in AD. METHODS: Twenty-four AD and 70 age and gender matched healthy control individuals (HC) participated in the study. fMRI data were pre-processed and modeled with SPM8. We modeled fMRI signals at trial onset with individual events parametrically modulated by estimated probability of the stop signal, p(Stop), and compared regional responses to conflict anticipation between AD and HC. To address the link to response inhibition, we regressed whole-brain responses to conflict anticipation against the stop signal reaction time (SSRT). RESULTS: Compared to HC (54/70), fewer AD (11/24) showed a significant sequential effect - a correlation between p(Stop) and RT during go trials - and the magnitude of sequential effect is diminished, suggesting a deficit in proactive control. Parametric analyses showed decreased learning rate and over-estimated prior mean of the stop signal in AD. In fMRI, both HC and AD responded to p(Stop) in bilateral inferior parietal cortex and anterior pre-supplementary motor area, although the magnitude of response increased in AD. In contrast, HC but not AD showed deactivation of the perigenual anterior cingulate cortex (pgACC). Furthermore, deactivation of the pgACC to increasing p(Stop) is positively correlated with the SSRT in HC but not AD. Recent alcohol consumption is correlated with increased activation of the thalamus and cerebellum in AD during conflict anticipation. CONCLUSIONS: The current results highlight altered proactive control that may serve as an additional behavioral and neural marker of alcohol dependence. PMID- 26106527 TI - Tract shape modeling detects changes associated with preterm birth and neuroprotective treatment effects. AB - Preterm birth is associated with altered connectivity of neural circuits. We developed a tract segmentation method that provides measures of tract shape and integrity (probabilistic neighborhood tractography, PNT) from diffusion MRI (dMRI) data to test the hypotheses: 1) preterm birth is associated with alterations in tract topology (R), and tract-averaged mean diffusivity () and fractional anisotropy (FA); 2) neural systems are separable based on tract averaged dMRI parameters; and 3) PNT can detect neuroprotective treatment effects. dMRI data were collected from 87 preterm infants (mean gestational age 29(+1) weeks, range 23(+2) -34(+6)) at term equivalent age and 24 controls (mean gestational age 39(+6) weeks). PNT was used to segment eight major fasciculi, characterize topology, and extract tract-averagedand FA. Tract topology was altered by preterm birth in all tracts except the splenium (p < 0.05, false discovery rate [FDR] corrected). After adjustment for age at scan, tract averagedwas increased in the genu and splenium, right corticospinal tract (CST) and the left and right inferior longitudinal fasciculi (ILF) in preterm infants compared with controls (p < 0.05, FDR), while tract-averaged FA was decreased in the splenium and left ILF (p < 0.05, FDR). Specific fasciculi were separable based on tract-averagedand FA values. There was a modest decrease in tract-averagedin the splenium of preterm infants who had been exposed to antenatal MgSO4 for neuroprotection (p = 0.002). Tract topology is a biomarker of preterm brain injury. The data provide proof of concept that tract-averaged dMRI parameters have utility for evaluating tissue effects of perinatal neuroprotective strategies. PMID- 26106528 TI - Reward salience and risk aversion underlie differential ACC activity in substance dependence. AB - The medial prefrontal cortex, especially the dorsal anterior cingulate cortex (ACC), has long been implicated in cognitive control and error processing. Although the association between ACC and behavior has been established, it is less clear how ACC contributes to dysfunctional behavior such as substance dependence. Evidence from neuroimaging studies investigating ACC function in substance users is mixed, with some studies showing disengagement of ACC in substance dependent individuals (SDs), while others show increased ACC activity related to substance use. In this study, we investigate ACC function in SDs and healthy individuals performing a change signal task for monetary rewards. Using a priori predictions derived from a recent computational model of ACC, we find that ACC activity differs between SDs and controls in factors related to reward salience and risk aversion between SDs and healthy individuals. Quantitative fits of a computational model to fMRI data reveal significant differences in best fit parameters for reward salience and risk preferences. Specifically, the ACC in SDs shows greater risk aversion, defined as concavity in the utility function, and greater attention to rewards relative to reward omission. Furthermore, across participants risk aversion and reward salience are positively correlated. The results clarify the role that ACC plays in both the reduced sensitivity to omitted rewards and greater reward valuation in SDs. Clinical implications of applying computational modeling in psychiatry are also discussed. PMID- 26106529 TI - Attention in spina bifida myelomeningocele: Relations with brain volume and integrity. AB - This study investigated the relations of tectal volume and superior parietal cortex, as well as alterations in tectocortical white matter connectivity, with the orienting and executive control attention networks in individuals with spina bifida myelomeningocele (SBM). Probabilistic diffusion tractography and quantification of tectal and superior parietal cortical volume were performed on 74 individuals aged 8-29 with SBM and a history of hydrocephalus. Behavioral assessments measured posterior (covert orienting) and anterior (conflict resolution, attentional control) attention network functions. Reduced tectal volume was associated with slower covert orienting; reduced superior parietal cortical volume was associated with slower conflict resolution; and increased axial diffusivity and radial diffusivity along both frontal and parietal tectocortical pathways were associated with reduced attentional control. Results suggest that components of both the orienting and executive control attention networks are impaired in SBM. Neuroanatomical disruption to the orienting network appears more robust and a direct consequence of characteristic midbrain dysmorphology; whereas, executive control difficulties may emerge from parietal cortical anomalies and reduced frontal and parietal cortical-subcortical white matter pathways susceptible to the pathophysiological effects of congenital hydrocephalus. PMID- 26106530 TI - The associations of depression and hypertension with brain volumes: Independent or interactive? AB - Independent studies on major depressive disorder (MDD) and hypertension, suggest overlapping abnormalities in brain regions associated with emotional and autonomic processing. However, the unique and interactive effects of MDD and hypertension have never been studied in a single sample. Brain volume in these areas may be an explanatory link in the comorbidity between MDD and hypertension. Voxel-based morphometry was used to test for main effects of MDD (N = 152) and hypertension (N = 82) and their interactions on gray and white matter volumes. Voxel-wise results are reported at p < .05 FWE corrected for the spatial extent of the whole brain and a-priori regions of interest (ROIs: hippocampus, anterior cingulate cortex (ACC) and inferior frontal gyrus (IFG)). In addition, analyses on the extracted total volumes of our ROIs were performed. Interactive effects in the mid-cingulate cortex (MCC) (p FWE = .01), cerebellum (p FWE = .01) and in the ACC total ROI volume (p = .02) were found. MDD in the presence, but not in the absence of hypertension was associated with lower volumes in the ACC and MCC, and with a trend towards larger gray matter volume in the cerebellum. No associations with white matter volumes were observed. Results suggest that the combination of MDD and hypertension has a unique effect on brain volumes in areas implicated in the regulation of emotional and autonomic functions. Brain volume in these regulatory areas may be an explanatory link in the comorbidity between hypertension and MDD. PMID- 26106531 TI - Variability in blood oxygen level dependent (BOLD) signal in patients with stroke induced and primary progressive aphasia. AB - Although fMRI is increasingly used to assess language-related brain activation in patients with aphasia, few studies have examined the hemodynamic response function (HRF) in perilesional, and contralesional areas of the brain. In addition, the relationship between HRF abnormalities and other variables such as lesion size and severity of aphasia has not been explored. The objective of this study was to investigate changes in HRF signal during language-related neural activation in patients with stroke-induced aphasia (SA). We also examined the status of the HRF in patients with aphasia due to nonvascular etiology, namely, primary progressive aphasia (PPA). Five right handed SA patients, three PPA patients, and five healthy individuals participated in the study. Structural damage was quantified with T1-weighted MR images. Functional MR imaging was performed with long trial event-related design and an overt naming task to measure BOLD signal time to peak (TTP) and percent signal change (DeltaS). In SA patients, the average HRF TTP was significantly delayed in the left hemisphere regions involved in naming compared to healthy participants and PPA patients. However, DeltaS was not different in SA patients compared to the other two groups. Delay in HRF TTP in the left hemisphere naming network of SA patients was correlated with lesion size and showed a negative correlation with global language function. There were no significant differences in the HRF TTP and DeltaS in the right hemisphere homologues of the naming network or in the left and the right occipital control regions across the three groups. In PPA patients, HRF had a normal pattern. Our results indicate that abnormal task-related HRF is primarily found in the left hemisphere language network of SA patients and raise the possibility that abnormal physiology superimposed on structural damage may contribute to the clinical deficit. Follow-up investigations in a larger sample of age-matched healthy individuals, SA, and PPA patients will be needed to further confirm and extend our findings. PMID- 26106532 TI - Three dysconnectivity patterns in treatment-resistant schizophrenia patients and their unaffected siblings. AB - Among individuals diagnosed with schizophrenia, approximately 20%-33% are recognized as treatment-resistant schizophrenia (TRS) patients. These TRS patients suffer more severely from the disease but struggle to benefit from existing antipsychotic treatments. A few recent studies suggested that schizophrenia may be caused by impaired synaptic plasticity that manifests as functional dysconnectivity in the brain, however, few of those studies focused on the functional connectivity changes in the brains of TRS groups. In this study, we compared the whole brain connectivity variations in TRS patients, their unaffected siblings, and healthy controls. Connectivity network features between and within the 116 automated anatomical labeling (AAL) brain regions were calculated and compared using maps created with three contrasts: patient vs. control, patient vs. sibling, and sibling vs. CONTROL: To evaluate the predictive power of the selected features, we performed a multivariate classification approach. We also evaluated the influence of six important clinical measures (e.g. age, education level) on the connectivity features. This study identified abnormal significant connectivity changes of three patterns in TRS patients and their unaffected siblings: 1) 69 patient-specific connectivity (PCN); 2) 102 shared connectivity (SCN); and 3) 457 unshared connectivity (UCN). While the first two patterns were widely reported by previous non-TRS specific studies, we were among the first to report widespread significant connectivity differences between TRS patient groups and their healthy sibling groups. Observations of this study may provide new insights for the understanding of the neurophysiological mechanisms of TRS. PMID- 26106533 TI - Validity of semi-quantitative scale for brain MRI in unilateral cerebral palsy due to periventricular white matter lesions: Relationship with hand sensorimotor function and structural connectivity. AB - AIM: To provide first evidence of construct validity of a semi-quantitative scale for brain structural MRI (sqMRI scale) in children with unilateral cerebral palsy (UCP) secondary to periventricular white matter (PWM) lesions, by examining the relationship with hand sensorimotor function and whole brain structural connectivity. METHODS: Cross-sectional study of 50 children with UCP due to PWM lesions using 3 T (MRI), diffusion MRI and assessment of hand sensorimotor function. We explored the relationship of lobar, hemispheric and global scores on the sqMRI scale, with fractional anisotropy (FA), as a measure of brain white matter microstructure, and with hand sensorimotor measures (Assisting Hand Assessment, AHA; Jebsen-Taylor Test for Hand Function, JTTHF; Melbourne Assessment of Unilateral Upper Limb Function, MUUL; stereognosis; 2-point discrimination). RESULTS: Lobar and hemispheric scores on the sqMRI scale contralateral to the clinical side of hemiplegia correlated with sensorimotor paretic hand function measures and FA of a number of brain structural connections, including connections of brain areas involved in motor control (postcentral, precentral and paracentral gyri in the parietal lobe). More severe lesions correlated with lower sensorimotor performance, with the posterior limb of internal capsule score being the strongest contributor to impaired hand function. CONCLUSION: The sqMRI scale demonstrates first evidence of construct validity against impaired motor and sensory function measures and brain structural connectivity in a cohort of children with UCP due to PWM lesions. More severe lesions correlated with poorer paretic hand sensorimotor function and impaired structural connectivity in the hemisphere contralateral to the clinical side of hemiplegia. The quantitative structural MRI scoring may be a useful clinical tool for studying brain structure-function relationships but requires further validation in other populations of CP. PMID- 26106534 TI - The impact of isolated lesions on white-matter fiber tracts in multiple sclerosis patients. AB - Infratentorial lesions have been assigned an equivalent weighting to supratentorial plaques in the new McDonald criteria for diagnosing multiple sclerosis. Moreover, their presence has been shown to have prognostic value for disability. However, their spatial distribution and impact on network damage is not well understood. As a preliminary step in this study, we mapped the overall infratentorial lesion pattern in relapsing-remitting multiple sclerosis patients (N = 317) using MRI, finding the pons (lesion density, 14.25/cm(3)) and peduncles (13.38/cm(3)) to be predilection sites for infratentorial lesions. Based on these results, 118 fiber bundles from 15 healthy controls and a subgroup of 23 patients showing lesions unilaterally at the predilection sites were compared using diffusion tensor imaging to analyze the impact of an isolated infratentorial lesion on the affected fiber tracts. Fractional anisotropy, mean diffusion as well as axial and radial diffusivity were investigated at the lesion site and along the entire fiber tract. Infratentorial lesions were found to have an impact on the fractional anisotropy and radial diffusivity not only at the lesion site itself but also along the entire affected fiber tract. As previously found in animal experiments, inflammatory attack in the posterior fossa in multiple sclerosis impacts the whole affected fiber tract. Here, this damaging effect, reflected by changes in diffusivity measures, was detected in vivo in multiple sclerosis patients in early stages of the disease, thus demonstrating the influence of a focal immune attack on more distant networks, and emphasizing the pathophysiological role of Wallerian degeneration in multiple sclerosis. PMID- 26106535 TI - Poorer frontolimbic white matter integrity is associated with chronic cannabis use, FAAH genotype, and increased depressive and apathy symptoms in adolescents and young adults. AB - BACKGROUND: The heaviest period of cannabis use coincides with ongoing white matter (WM) maturation. Further, cannabis-related changes may be moderated by FAAH genotype (rs324420). We examined the association between cannabis use and FAAH genotype on frontolimbic WM integrity in adolescents and emerging adults. We then tested whether observed WM abnormalities were linked with depressive or apathy symptoms. METHODS: Participants included 37 cannabis users and 37 healthy controls (33 female; ages 18-25). Multiple regressions examined the independent and interactive effects of variables on WM integrity. RESULTS: Regular cannabis users demonstrated reduced WM integrity in the bilateral uncinate fasciculus (UNC) (MD, right: p = .009 and left: p = .009; FA, right: p = .04 and left: p = .03) and forceps minor (fMinor) (MD, p = .03) compared to healthy controls. Marginally reduced WM integrity in the cannabis users was found in the left anterior thalamic radiation (ATR) (FA, p = .08). Cannabis group * FAAH genotype interaction predicted WM integrity in bilateral ATR (FA, right: p = .05 and left: p = .001) and fMinor (FA, p = .02). In cannabis users, poorer WM integrity was correlated with increased symptoms of depression and apathy in bilateral ATR and UNC. CONCLUSIONS: Consistent with prior findings, cannabis use was associated with reduced frontolimbic WM integrity. WM integrity was also moderated by FAAH genotype, in that cannabis-using FAAH C/C carriers and A carrying controls had reduced WM integrity compared to control C/C carriers. Observed frontolimbic white matter abnormalities were linked with increased depressive and apathy symptoms in the cannabis users. PMID- 26106536 TI - Aberrant functional connectivity within the basal ganglia of patients with Parkinson's disease. AB - Resting state functional MRI (rs-fMRI) has been previously shown to be a promising tool for the assessment of early Parkinson's disease (PD). In order to assess whether changes within the basal ganglia network (BGN) are disease specific or relate to neurodegeneration generally, BGN connectivity was assessed in 32 patients with early PD, 19 healthy controls and 31 patients with Alzheimer's disease (AD). Voxel-wise comparisons demonstrated decreased connectivity within the basal ganglia of patients with PD, when compared to patients with AD and healthy controls. No significant changes within the BGN were seen in AD, when compared to healthy controls. Moreover, measures of functional connectivity extracted from regions within the basal ganglia were significantly lower in the PD group. Consistent with previous radiotracer studies, the greatest change when compared to the healthy control group was seen in the posterior putamen of PD subjects. When combined into a single component score, this method differentiated PD from AD and healthy control subjects, with a diagnostic accuracy of 81%. Rs-fMRI can be used to demonstrate the aberrant functional connectivity within the basal ganglia of patients with early PD. These changes are likely to be representative of patho-physiological basal ganglia dysfunction and are not associated with generalised neurodegeneration seen in AD. Further studies are necessary to ascertain whether this method is sensitive enough to detect basal ganglia dysfunction in prodromal PD, and its utility as a potential diagnostic biomarker for premotor and early motoric disease. PMID- 26106537 TI - Brain and behavior in 48, XXYY syndrome. AB - The phenotype of 48, XXYY syndrome (referred to as XXYY) is associated with characteristic but variable developmental, cognitive, behavioral and physical abnormalities. To discern the neuroanatomical phenotype of the syndrome, we conducted quantitative and qualitative analyses on MRI brain scans from 25 males with XXYY and 92 age and SES matched typically developing XY males. Quantitatively, males in the XXYY group had smaller gray and white matter volumes of the frontal and temporal lobes. Conversely, both gray and white matter volumes of the parietal lobe as well as lateral ventricular volume were larger in the XXYY group. Qualitatively, males in the XXYY group had a higher incidence of colpocephaly (84% vs. 34%, p <= 0.001), white matter lesions (25% vs. 5%, p = 0.007), and thin posterior body of the corpus callosum (28% vs. 3%, p = 0.001). The specificity of these findings may shed light on the role of the X and Y chromosomes in typical and atypical brain development and help provide direction for future studies of brain-behavior relationships in males with XXYY syndrome. PMID- 26106538 TI - Multiple sclerosis, cannabis, and cognition: A structural MRI study. AB - OBJECTIVE: A subset of patients with multiple sclerosis (MS) smoke cannabis to relieve symptoms including spasticity and pain. Recent evidence suggests that smoking cannabis further impairs cognition in people with MS and is linked to impaired functional brain changes. No such association, however, has been reported between cannabis use and structural brain changes, hence the focus of the present study. METHODS: Twenty patients with MS who smoke cannabis for symptom relief, and 19 matched non-cannabis-smoking MS patients were given the Brief Repeatable Neuropsychological Battery and structural MRI scans. Images were segmented into gray matter and white matter, and subsequently analysed with Partial Least Squares, a data-driven multivariate technique that explores brain behaviour associations. RESULTS: In both groups, the Partial Least Squares analysis yielded significant correlations between cognitive scores and both gray matter (33% variance, p < .0001) and white matter (17% variance, p < .05) volume. Gray matter volume in the thalamus, basal ganglia, medial temporal, and medial prefrontal regions, and white matter volume in the fornix correlated with cognitive deficits. Crucially, the analysis indicated that brain volume reductions were associated with more extensive cognitive impairment in the cannabis versus the non-cannabis MS group. INTERPRETATION: These results suggest that cannabis use in MS results in more widespread cognitive deficits, which correlate with tissue volume in subcortical, medial temporal, and prefrontal regions. These are the first findings demonstrating an association between cannabis use, cognitive impairment and structural brain changes in MS patients. PMID- 26106539 TI - The nature of white matter abnormalities in blast-related mild traumatic brain injury. AB - Blast-related traumatic brain injury (TBI) has been a common injury among returning troops due to the widespread use of improvised explosive devices in the Iraq and Afghanistan Wars. As most of the TBIs sustained are in the mild range, brain changes may not be detected by standard clinical imaging techniques such as CT. Furthermore, the functional significance of these types of injuries is currently being debated. However, accumulating evidence suggests that diffusion tensor imaging (DTI) is sensitive to subtle white matter abnormalities and may be especially useful in detecting mild TBI (mTBI). The primary aim of this study was to use DTI to characterize the nature of white matter abnormalities following blast-related mTBI, and in particular, examine the extent to which mTBI-related white matter abnormalities are region-specific or spatially heterogeneous. In addition, we examined whether mTBI with loss of consciousness (LOC) was associated with more extensive white matter abnormality than mTBI without LOC, as well as the potential moderating effect of number of blast exposures. A second aim was to examine the relationship between white matter integrity and neurocognitive function. Finally, a third aim was to examine the contribution of PTSD symptom severity to observed white matter alterations. One hundred fourteen OEF/OIF veterans underwent DTI and neuropsychological examination and were divided into three groups including a control group, blast-related mTBI without LOC (mTBI - LOC) group, and blast-related mTBI with LOC (mTBI + LOC) group. Hierarchical regression models were used to examine the extent to which mTBI and PTSD predicted white matter abnormalities using two approaches: 1) a region specific analysis and 2) a measure of spatial heterogeneity. Neurocognitive composite scores were calculated for executive functions, attention, memory, and psychomotor speed. Results showed that blast-related mTBI + LOC was associated with greater odds of having spatially heterogeneous white matter abnormalities. Region-specific reduction in fractional anisotropy (FA) in the left retrolenticular part of the internal capsule was observed in the mTBI + LOC group as the number of blast exposures increased. A mediation analysis revealed that mTBI + LOC indirectly influenced verbal memory performance through its effect on white matter integrity. PTSD was not associated with spatially heterogeneous white matter abnormalities. However, there was a suggestion that at higher levels of PTSD symptom severity, LOC was associated with reduced FA in the left retrolenticular part of the internal capsule. These results support postmortem reports of diffuse axonal injury following mTBI and suggest that injuries with LOC involvement may be particularly detrimental to white matter integrity. Furthermore, these results suggest that LOC-associated white matter abnormalities in turn influence neurocognitive function. PMID- 26106540 TI - MEG-based detection and localization of perilesional dysfunction in chronic stroke. AB - Post-stroke impairment is associated not only with structural lesions, but also with dysfunction in surviving perilesional tissue. Previous studies using equivalent current dipole source localization of MEG/EEG signals have demonstrated a preponderance of slow-wave activity localized to perilesional areas. Recent studies have also demonstrated the utility of nonlinear analyses such as multiscale entropy (MSE) for quantifying neuronal dysfunction in a wide range of pathologies. The current study utilized beamformer-based reconstruction of signals in source space to compare spectral and nonlinear measures of electrical activity in perilesional and healthy cortices. Data were collected from chronic stroke patients and healthy controls, both young and elderly. We assessed relative power in the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta (15-30 Hz) frequency bands, and also measured the nonlinear complexity of electrical activity using MSE. Perilesional tissue exhibited a general slowing of the power spectrum (increased delta/theta, decreased beta) as well as a reduction in MSE. All measures tested were similarly sensitive to changes in the posterior perilesional regions, but anterior perilesional dysfunction was detected better by MSE and beta power. The findings also suggest that MSE is specifically sensitive to electrophysiological dysfunction in perilesional tissue, while spectral measures were additionally affected by an increase in rolandic beta power with advanced age. Furthermore, perilesional electrophysiological abnormalities in the left hemisphere were correlated with the degree of language task-induced activation in the right hemisphere. Finally, we demonstrate that single subject spectral and nonlinear analyses can identify dysfunctional perilesional regions within individual patients that may be ideal targets for interventions with noninvasive brain stimulation. PMID- 26106541 TI - The autism puzzle: Diffuse but not pervasive neuroanatomical abnormalities in children with ASD. AB - Autism Spectrum Disorder (ASD) is a clinically diagnosed, heterogeneous, neurodevelopmental condition, whose underlying causes have yet to be fully determined. A variety of studies have investigated either cortical, subcortical, or cerebellar anatomy in ASD, but none have conducted a complete examination of all neuroanatomical parameters on a single, large cohort. The current study provides a comprehensive examination of brain development of children with ASD between the ages of 4 and 18 years who are carefully matched for age and sex with typically developing controls at a ratio of one-to-two. Two hundred and ten magnetic resonance images were examined from 138 Control (116 males and 22 females) and 72 participants with ASD (61 males and 11 females). Cortical segmentation into 78 brain-regions and 81,924 vertices was conducted with CIVET which facilitated a region-of-interest- (ROI-) and vertex-based analysis, respectively. Volumes for the cerebellum, hippocampus, striatum, pallidum, and thalamus and many associated subregions were derived using the MAGeT Brain algorithm. The study reveals cortical, subcortical and cerebellar differences between ASD and Control group participants. Diagnosis, diagnosis-by-age, and diagnosis-by-sex interaction effects were found to significantly impact total brain volume but not total surface area or mean cortical thickness of the ASD participants. Localized (vertex-based) analysis of cortical thickness revealed no significant group differences, even when age, age-range, and sex were used as covariates. Nonetheless, the region-based cortical thickness analysis did reveal regional changes in the left orbitofrontal cortex and left posterior cingulate gyrus, both of which showed reduced age-related cortical thinning in ASD. Our finding of region-based differences without significant vertex-based results likely indicates non-focal effects spanning the entirety of these regions. The hippocampi, thalamus, and globus pallidus, were smaller in volume relative to total cerebrum in the ASD participants. Various sub-structures showed an interaction of diagnosis-by-age, diagnosis-by-sex, and diagnosis-by-age-range, in the case where age was divided into childhood (age < 12) and adolescence (12 < age < 18). This is the most comprehensive imaging-based neuro-anatomical pediatric and adolescent ASD study to date. These data highlight the neurodevelopmental differences between typically developing children and those with ASD, and support aspects of the hypothesis of abnormal neuro-developmental trajectory of the brain in ASD. PMID- 26106543 TI - Cortical morphometry and IQ in VLBW children without cerebral palsy born in 2003 2007. AB - Children born prematurely with very low birth weight (VLBW: bw <= 1500 g) have an increased risk of preterm perinatal brain injury, which may subsequently alter the maturation of the brain, including the cerebral cortex. The aim of study was to assess cortical thickness and surface area in VLBW children compared with term born controls, and to investigate possible relationships between cortical morphology and Full IQ. In this cross-sectional study, 37 VLBW and 104 term children born between the years 2003-2007 were assessed cognitively at 5-10 years of age, using age appropriate Wechsler tests. The FreeSurfer software was used to obtain estimates of cortical thickness and surface area based on T1-weighted MRI images at 1.5 Tesla. The VLBW children had smaller cortical surface area bilaterally in the frontal, temporal, and parietal lobes. A thicker cortex in the frontal and occipital regions and a thinner cortex in posterior parietal areas were observed in the VLBW group. There were significant differences in Full IQ between groups (VLBW M = 98, SD = 9.71; controls M = 108, SD = 13.57; p < 0.001). There was a positive relationship between IQ and surface area in both groups, albeit significant only in the larger control group. In the VLBW group, reduced IQ was associated with frontal cortical thickening and temporo-parietal thinning. We conclude that cortical deviations are evident in childhood even in VLBW children born in 2003-2007 who have received state of the art medical treatment in the perinatal period and who did not present with focal brain injuries on neonatal ultrasonography. The cortical deviations were associated with reduced cognitive functioning. PMID- 26106542 TI - Increased cortico-striatal connectivity during motor practice contributes to the consolidation of motor memory in writer's cramp patients. AB - Sensorimotor representations of movements are created in the sensorimotor network through repeated practice to support successful and effortless performance. Writer's cramp (WC) is a disorder acquired through extensive practice of finger movements, and it is likely associated with the abnormal acquisition of sensorimotor representations. We investigated (i) the activation and connectivity changes in the brain network supporting the acquisition of sensorimotor representations of finger sequences in patients with WC and (ii) the link between these changes and consolidation of motor performance 24 h after the initial practice. Twenty-two patients with WC and 22 age-matched healthy volunteers practiced a complex sequence with the right (pathological) hand during functional MRI recording. Speed and accuracy were measured immediately before and after practice (day 1) and 24 h after practice (day 2). The two groups reached equivalent motor performance on day 1 and day 2. During motor practice, patients with WC had (i) reduced hippocampal activation and hippocampal-striatal functional connectivity; and (ii) overactivation of premotor-striatal areas, whose connectivity correlated with motor performance after consolidation. These results suggest that patients with WC use alternative networks to reach equiperformance in the acquisition of new motor memories. PMID- 26106544 TI - Brain activation during self- and other-reflection in bipolar disorder with a history of psychosis: Comparison to schizophrenia. AB - OBJECTIVES: Reflecting on the self and on others activates specific brain areas and contributes to metacognition and social cognition. The aim of the current study is to investigate brain activation during self- and other-reflection in patients with bipolar disorder (BD). In addition, we examined whether potential abnormal brain activation in BD patients could distinguish BD from patients with schizophrenia (SZ). METHODS: During functional magnetic resonance imaging (fMRI), 17 BD patients, 17 SZ patients and 21 healthy controls (HCs) performed a self reflection task. The task consisted of sentences divided into three conditions: self-reflection, other-reflection and semantic control. RESULTS: BD patients showed less activation in the posterior cingulate cortex (PCC) extending to the precuneus during other-reflection compared to HCs (p = 0.028 FWE corrected on cluster-level within the regions of interest). In SZ patients, the level of activation in this area was in between BD patients and HCs, with no significant differences between patients with SZ and BD. There were no group differences in brain activation during self-reflection. Moreover, there was a positive correlation between the PCC/precuneus activation during other-reflection and cognitive insight in SZ patients, but not in BD patients. CONCLUSIONS: BD patients showed less activation in the PCC/precuneus during other-reflection. This may support an account of impaired integration of emotion and memory (evaluation of past and current other-related information) in BD patients. Correlation differences of the PCC/precuneus activation with the cognitive insight in patients with BD and SZ might reflect an important difference between these disorders, which may help to further explore potentially distinguishing markers. PMID- 26106545 TI - Filling in the gaps: Anticipatory control of eye movements in chronic mild traumatic brain injury. AB - A barrier in the diagnosis of mild traumatic brain injury (mTBI) stems from the lack of measures that are adequately sensitive in detecting mild head injuries. MRI and CT are typically negative in mTBI patients with persistent symptoms of post-concussive syndrome (PCS), and characteristic difficulties in sustaining attention often go undetected on neuropsychological testing, which can be insensitive to momentary lapses in concentration. Conversely, visual tracking strongly depends on sustained attention over time and is impaired in chronic mTBI patients, especially when tracking an occluded target. This finding suggests deficient internal anticipatory control in mTBI, the neural underpinnings of which are poorly understood. The present study investigated the neuronal bases for deficient anticipatory control during visual tracking in 25 chronic mTBI patients with persistent PCS symptoms and 25 healthy control subjects. The task was performed while undergoing magnetoencephalography (MEG), which allowed us to examine whether neural dysfunction associated with anticipatory control deficits was due to altered alpha, beta, and/or gamma activity. Neuropsychological examinations characterized cognition in both groups. During MEG recordings, subjects tracked a predictably moving target that was either continuously visible or randomly occluded (gap condition). MEG source-imaging analyses tested for group differences in alpha, beta, and gamma frequency bands. The results showed executive functioning, information processing speed, and verbal memory deficits in the mTBI group. Visual tracking was impaired in the mTBI group only in the gap condition. Patients showed greater error than controls before and during target occlusion, and were slower to resynchronize with the target when it reappeared. Impaired tracking concurred with abnormal beta activity, which was suppressed in the parietal cortex, especially the right hemisphere, and enhanced in left caudate and frontal-temporal areas. Regional beta-amplitude demonstrated high classification accuracy (92%) compared to eye-tracking (65%) and neuropsychological variables (80%). These findings show that deficient internal anticipatory control in mTBI is associated with altered beta activity, which is remarkably sensitive given the heterogeneity of injuries. PMID- 26106546 TI - Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures. AB - OBJECTIVE: White matter hyperintensities (WMHs) are common with age, grow over time, and are associated with cognitive and motor impairments. Mechanisms underlying WMH growth are unclear. We aimed to determine the presence and extent of decreased normal appearing white matter (NAWM) cerebral blood flow (CBF) surrounding WMHs to identify 'WM at risk', or the WMH CBF penumbra. We aimed to further validate cross-sectional finding by determining whether the baseline WMH penumbra CBF predicts the development of new WMHs at follow-up. METHODS: Sixty one cognitively intact elderly subjects received 3 T MPRAGE, FLAIR, and pulsed arterial spin labeling (PASL). Twenty-four subjects returned for follow-up MRI. The inter-scan interval was 18 months. A NAWM layer mask, comprised of fifteen layers, 1 mm thick each surrounding WMHs, was generated for periventricular (PVWMH) and deep (DWMH) WMHs. Mean CBF for each layer was computed. New WMH and persistent NAWM voxels for each penumbra layer were defined from follow-up MRI. RESULTS: CBF in the area surrounding WMHs was significantly lower than the total brain NAWM, extending approximately 12 mm from both the established PVWMH and DWMH. Voxels with new WMH at follow-up had significantly lower baseline CBF than voxels that maintained NAWM, suggesting that baseline CBF can predict the development of new WMHs over time. CONCLUSIONS: A CBF penumbra exists surrounding WMHs, which is associated with future WMH expansion. ASL MRI can be used to monitor interventions to increase white matter blood flow for the prevention of further WM damage and its cognitive and motor consequences. PMID- 26106547 TI - Diagnostic classification of intrinsic functional connectivity highlights somatosensory, default mode, and visual regions in autism. AB - Despite consensus on the neurological nature of autism spectrum disorders (ASD), brain biomarkers remain unknown and diagnosis continues to be based on behavioral criteria. Growing evidence suggests that brain abnormalities in ASD occur at the level of interconnected networks; however, previous attempts using functional connectivity data for diagnostic classification have reached only moderate accuracy. We selected 252 low-motion resting-state functional MRI (rs-fMRI) scans from the Autism Brain Imaging Data Exchange (ABIDE) including typically developing (TD) and ASD participants (n = 126 each), matched for age, non-verbal IQ, and head motion. A matrix of functional connectivities between 220 functionally defined regions of interest was used for diagnostic classification, implementing several machine learning tools. While support vector machines in combination with particle swarm optimization and recursive feature elimination performed modestly (with accuracies for validation datasets <70%), diagnostic classification reached a high accuracy of 91% with random forest (RF), a nonparametric ensemble learning method. Among the 100 most informative features (connectivities), for which this peak accuracy was achieved, participation of somatosensory, default mode, visual, and subcortical regions stood out. Whereas some of these findings were expected, given previous findings of default mode abnormalities and atypical visual functioning in ASD, the prominent role of somatosensory regions was remarkable. The finding of peak accuracy for 100 interregional functional connectivities further suggests that brain biomarkers of ASD may be regionally complex and distributed, rather than localized. PMID- 26106548 TI - The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia. AB - BACKGROUND AND PURPOSE: Elevated levels of amyloid deposition as well as white matter damage are thought to be risk factors for Alzheimer Disease (AD). Here we examined whether qualitative ratings of white matter damage predicted cognitive impairment beyond measures of amyloid. MATERIALS AND METHODS: The study examined 397 cognitively normal, 51 very mildly demented, and 11 mildly demented individuals aged 42-90 (mean 68.5). Participants obtained a T2-weighted scan as well as a positron emission tomography scan using (11)[C] Pittsburgh Compound B. Periventricular white matter hyperintensities (PVWMHs) and deep white matter hyperintensities (DWMHs) were measured on each T2 scan using the Fazekas rating scale. The effects of amyloid deposition and white matter damage were assessed using logistic regressions. RESULTS: Levels of amyloid deposition (ps < 0.01), as well as ratings of PVWMH (p < 0.01) and DWMH (p < 0.05) discriminated between cognitively normal and demented individuals. CONCLUSIONS: The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels. PMID- 26106549 TI - Cortical thickness, surface area, and folding alterations in male youths with conduct disorder and varying levels of callous-unemotional traits. AB - PURPOSE: Previous studies have reported changes in gray matter volume in youths with conduct disorder (CD), although these differences are difficult to interpret as they may have been driven by alterations in cortical thickness, surface area (SA), or folding. The objective of this study was to use surface-based morphometry (SBM) methods to compare male youths with CD and age and sex-matched healthy controls (HCs) in cortical thickness, SA, and folding. We also tested for structural differences between the childhood-onset and adolescence-onset subtypes of CD and performed regression analyses to assess for relationships between CD symptoms and callous-unemotional (CU) traits and SBM-derived measures. METHODS: We acquired structural neuroimaging data from 20 HCs and 36 CD participants (18 with childhood-onset CD and 18 with adolescence-onset CD) and analyzed the data using FreeSurfer. RESULTS: Relative to HCs, youths with CD showed reduced cortical thickness in the superior temporal gyrus, reduced SA in the orbitofrontal cortex (OFC), and increased cortical folding in the insula. There were no significant differences between the childhood-onset and adolescence-onset CD subgroups in cortical thickness or SA, but several frontal and temporal regions showed increased cortical folding in childhood-onset relative to adolescence-onset CD participants. Both CD subgroups also showed increased cortical folding relative to HCs. CD symptoms were negatively correlated with OFC SA whereas CU traits were positively correlated with insula folding. CONCLUSIONS: Cortical thinning in the superior temporal gyrus may contribute to the social cognitive impairments displayed by youths with CD, whereas reduced OFC SA may lead to impairments in emotion regulation and reward processing in youths with CD. The increased cortical folding observed in the insula may reflect a maturational delay in this region and could mediate the link between CU traits and empathy deficits. Altered cortical folding was observed in childhood-onset and adolescence-onset forms of CD. PMID- 26106550 TI - Injury to white matter tracts in relapsing-remitting multiple sclerosis: A possible therapeutic window within the first 5 years from onset using diffusion tensor imaging tract-based spatial statistics. AB - DTI studies in multiple sclerosis (MS) reveal white matter (WM) injury that occurs with disease progression. In the present study we aimed to elucidate the relationship of microstructural WM damage in patients with varying periods of disease duration. DTI scans were acquired from 90 MS patients and 25 healthy controls. Patients were grouped to short (<1 year), moderate (1 up to 6 years) and long (6-10 years) disease duration periods. Statistical analyses of the fractional anisotropy (FA) data were performed using tract-based spatial statistics (TBSS). Whole-brain skeletal FA measurements showed a significant decrease between healthy controls and the short MS disease duration group, as well as between moderate disease duration and long disease duration groups, but failed to show a significant difference between short and moderate disease duration groups. Voxelwise analysis revealed clusters of diffuse FA reductions in 40 WM tracts when comparing healthy controls and MS short disease duration group, with the point of maximal significant difference located in the left inferior longitudinal fasciculus. Comparing short with long disease duration groups, progressive FA reduction was demonstrated across 30 WM tracts, with the point of maximal significant difference migrating to the body of the corpus callosum. A non-linear pattern of WM microstructure disruption occurs in RRMS. Alterations are seen early in the disease course within 1 year from onset, reach a plateau within the next 5 years, and only later additional WM changes are detected. An important period of a possible therapeutic window therefore exists within the early disease stage. PMID- 26106551 TI - A greater involvement of posterior brain areas in interhemispheric transfer in autism: fMRI, DWI and behavioral evidences. AB - A small corpus callosum (CC) is one of the most replicated neurobiological findings in autism spectrum (AS). However, its effect on interhemispheric (IH) communication is unknown. We combined structural (CC area and DWI), functional (task-related fMRI activation and connectivity analyses) as well as behavioral (Poffenberger and Purdue tasks) measures to investigate IH integration in adult AS individuals of typical intelligence. Despite similar behavioral IH transfer time and performances in bimanual tasks, the CC sub-regions connecting frontal and parietal cortical areas were smaller in AS than in non-AS individuals, while those connecting visual regions were similar. The activation of visual areas was lower in AS than in non-AS individuals during the presentation of visual stimuli. Behavioral IH performances were related to the properties of CC subregions connecting motor areas in non-AS individuals, but to the properties of posterior CC regions in AS individuals. Furthermore, there was greater functional connectivity between visual areas in the AS than in the non-AS group. Levels of connectivity were also stronger in visual than in motor regions in the autistic subjects, while the opposite was true for the non-autistic group. Thus, visual IH transfer plays an important role in visuo-motor tasks in AS individuals. These findings extend the well established enhanced role of perception in autistic cognition to visuo-motor IH information transfer. PMID- 26106552 TI - Functional connectivity underlying postural motor adaptation in people with multiple sclerosis. AB - A well-characterized neural network is associated with motor learning, involving several brain regions known to have functional and structural deficits in persons with multiple sclerosis (PwMS). However, it is not known how MS affects postural motor learning or the neural networks involved. The aim of this study was to gain a better understanding of the neural networks underlying adaptation of postural responses within PwMS. Participants stood on a hydraulically driven, servo controlled platform that translated horizontally forward and backward in a continuous sinusoidal pattern across multiple trials over two consecutive days. Our results show similar postural adaptation between PwMS and age-matched control participants despite overall deficits in postural motor control in PwMS. Moreover, PwMS demonstrated better retention the following day. PwMS had significantly reduced functional connectivity within both the cortico-cerebellar and cortico-striatal motor loops; neural networks that subserve implicit motor learning. In PwMS, greater connectivity strength within the cortico-cerebellar circuit was strongly related to better baseline postural control, but not to postural adaptation as it was in control participants. Further, anti-correlated cortico-striatal connectivity within the right hemisphere was related to improved postural adaptation in both groups. Taken together with previous studies showing a reduced reliance on cerebellar- and proprioceptive-related feedback control in PwMS, we suggest that PwMS may rely on cortico-striatal circuitry to a greater extent than cortico-cerebellar circuitry for the acquisition and retention of motor skills. PMID- 26106553 TI - Negative symptoms in schizophrenia are associated with aberrant striato-cortical connectivity in a rewarded perceptual decision-making task. AB - BACKGROUND: Negative symptoms in schizophrenia have been associated with structural and functional changes in the prefrontal cortex. They often persist after treatment with antipsychotic medication which targets, in particular, the ventral striatum (VS). As schizophrenia has been suggested to arise from dysfunctional connectivity between neural networks, it is possible that residual aberrant striato-cortical connectivity in medicated patients plays a role in enduring negative symptomology. The present study examined the relationship between striato-cortical connectivity and negative symptoms in medicated schizophrenia patients. METHODS: We manipulated motivation in a perceptual decision-making task during functional magnetic resonance imaging. Comparing healthy controls (n = 21) and medicated patients with schizophrenia (n = 18) we investigated how motivation-mediated changes in VS activation affected functional connectivity with the frontal cortex, and how changes in connectivity strength from the neutral to motivated condition related to negative symptom severity. RESULTS: A pattern of aberrant striato-cortical connectivity was observed in the presence of intact VS, but altered left inferior frontal gyrus (IFG) motivation mediated activation in patients. The more severe the patient's negative symptoms, the less the connectivity strength between the right VS and left IFG changed from the neutral to the motivated condition. Despite aberrant striato-cortical connectivity and altered recruitment of the left IFG among patients, both patients and healthy controls adopted a more liberal response strategy in the motivated compared to the neutral condition. CONCLUSIONS: The present findings suggest that there is a link between dysfunctional striato-cortical connectivity and negative symptom severity, and offer a possible explanation as to why negative symptoms persist after treatment with antipsychotics. PMID- 26106554 TI - Quantifying motor recovery after stroke using independent vector analysis and graph-theoretical analysis. AB - The assessment of neuroplasticity after stroke through functional magnetic resonance imaging (fMRI) analysis is a developing field where the objective is to better understand the neural process of recovery and to better target rehabilitation interventions. The challenge in this population stems from the large amount of individual spatial variability and the need to summarize entire brain maps by generating simple, yet discriminating features to highlight differences in functional connectivity. Independent vector analysis (IVA) has been shown to provide superior performance in preserving subject variability when compared with widely used methods such as group independent component analysis. Hence, in this paper, graph-theoretical (GT) analysis is applied to IVA-generated components to effectively exploit the individual subjects' connectivity to produce discriminative features. The analysis is performed on fMRI data collected from individuals with chronic stroke both before and after a 6-week arm and hand rehabilitation intervention. Resulting GT features are shown to capture connectivity changes that are not evident through direct comparison of the group t-maps. The GT features revealed increased small worldness across components and greater centrality in key motor networks as a result of the intervention, suggesting improved efficiency in neural communication. Clinically, these results bring forth new possibilities as a means to observe the neural processes underlying improvements in motor function. PMID- 26106555 TI - Altered resting brain connectivity in persistent cancer related fatigue. AB - There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = -0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As the DMN is a network involved in self-referential thinking we speculate that enhanced connectivity between the DMN and the frontal gyrus may be related to mental fatigue and poor sleep quality. In contrast, enhanced connectivity between the DMN and regions in the subgenual cingulate and brainstem may serve a protective function in the non-fatigued group. PMID- 26106556 TI - Cerebellar infarct patterns: The SMART-Medea study. AB - OBJECTIVE: Previous studies on cerebellar infarcts have been largely restricted to acute infarcts in patients with clinical symptoms, and cerebellar infarcts have been evaluated with the almost exclusive use of transversal MR images. We aimed to document the occurrence and 3D-imaging patterns of cerebellar infarcts presenting as an incidental finding on MRI. METHODS: We analysed the 1.5 Tesla MRI, including 3D T1-weighted datasets, of 636 patients (mean age 62 +/- 9 years, 81% male) from the SMART-Medea study. Cerebellar infarct analyses included an assessment of size, cavitation and gliosis, of grey and white matter involvement, and of infarct topography. RESULTS: One or more cerebellar infarcts (mean 1.97; range 1-11) were detected in 70 out of 636 patients (11%), with a total amount of 138 infarcts identified, 135 of which showed evidence of cavitation. The average mean axial diameter was 7 mm (range 2-54 mm), and 131 infarcts (95%) were smaller than 20 mm. Hundred-thirty-four infarcts (97%) involved the cortex, of which 12 in combination with subcortical white matter. No infarcts were restricted to subcortical branches of white matter. Small cortical infarcts involved the apex of a deep (pattern 1) or shallow fissure (pattern 2), or occurred alongside one (pattern 3) or opposite sides (pattern 4) of a fissure. Most (87%) cerebellar infarcts were situated in the posterior lobe. CONCLUSIONS: Small cerebellar infarcts proved to be much more common than larger infarcts, and preferentially involved the cortex. Small cortical infarcts predominantly involved the posterior lobes, showed sparing of subcortical white matter and occurred in characteristic topographic patterns. PMID- 26106557 TI - Structural connectivity changes in temporal lobe epilepsy: Spatial features contribute more than topological measures. AB - BACKGROUND: Previous studies reported reduced volumes of many brain regions for temporal lobe epilepsy (TLE). It has also been suggested that there may be widespread changes in network features of TLE patients. It is not fully understood, however, how these two observations are related. METHODS: Using magnetic resonance imaging data, we perform parcellation of the brains of 22 patients with left TLE and 39 non-epileptic controls. In each parcellated region of interest (ROI) we computed the surface area and, using diffusion tensor imaging and deterministic tractography, infer the number of streamlines and their average length between each pair of connected ROIs. For comparison to previous studies, we use a connectivity 'weight' and investigate how ROI surface area, number of streamlines & mean streamline length contribute to such weight. RESULTS: We find that although there are widespread significant changes in surface area and position of ROIs in patients compared to controls, the changes in connectivity are much more subtle. Significant changes in connectivity weight can be accounted for by decreased surface area and increased streamline count. CONCLUSION: Changes in the surface area of ROIs can be a reliable biomarker for TLE with a large influence on connectivity. However, changes in structural connectivity via white matter streamlines are more subtle with a relatively lower influence on connection weights. PMID- 26106558 TI - Sensory cortical re-mapping following upper-limb amputation and subsequent targeted reinnervation: A case report. AB - This case study demonstrates the change of sensory cortical representations of the residual parts of the arm in an individual who underwent a trans-humeral amputation and subsequent targeted reinnervation (TR). As a relatively new surgical technique, TR restores a direct neural connection from amputated sensorimotor nerves to specific target muscles. This method has been successfully applied to upper-limb and lower-limb amputees, and has shown effectiveness in regaining control signals via the newly re-innervated muscles. Correspondingly, recent study results have shown that motor representations for the missing limb move closer to their original locations following TR. Besides regaining motor control signals, TR also restores the sensation in the re-innervated skin areas. We therefore hypothesize that TR causes analogous cortical sensory remapping that may return closer to their original locations. In order to test this hypothesis, cortical activity in response to sensory-level electrical stimulation in different parts of the arm was studied longitudinally in one amputated individual before and up to 2 years after TR. Our results showed that 1) before TR, the cortical response to sensory electrical stimulation in the residual limb showed a diffuse bilateral pattern without a clear focus in either the time or spatial domain; and 2) 2 years after TR, the sensory map of the reinnervated median nerve reorganized, showing predominant activity over the contralateral S1 hand area as well as moderate activity over the ipsilateral S1. Therefore, this work provides new evidence for long-term sensory cortical plasticity in the human brain after TR. PMID- 26106559 TI - A multimodal MRI approach to identify and characterize microstructural brain changes in neuropsychiatric systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 +/- 13 years, all females), 9 SLE patients without NP symptoms (44 +/- 11 years, all females), and 14 healthy controls (HC) (40 +/- 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage. PMID- 26106560 TI - Longitudinal gray matter contraction in three variants of primary progressive aphasia: A tenser-based morphometry study. AB - The present study investigated the pattern of longitudinal changes in cognition and anatomy in three variants of primary progressive aphasia (PPA). Eight patients with the non-fluent variant of PPA (nfvPPA), 13 patients with the semantic variant (svPPA), seven patients with the logopenic variant (lvPPA), and 29 age-matched, neurologically healthy controls were included in the study. All participants underwent longitudinal MRI, neuropsychological and language testing at baseline and at a 1-year follow-up. Tenser-based morphometry (TBM) was applied to T1-weighted MRI images in order to map the progression of gray and white matter atrophy over a 1-year period. Results showed that each patient group was characterized by a specific pattern of cognitive and anatomical changes. Specifically, nfvPPA patients showed gray matter atrophy progression in the left frontal and subcortical areas as well as a decline in motor speech and executive functions; svPPA patients presented atrophy progression in the medial and lateral temporal lobe and decline in semantic memory abilities; and lvPPA patients showed atrophy progression in lateral/posterior temporal and medial parietal regions with a decline in memory, sentence repetition and calculations. In addition, in all three variants, the white matter fibers underlying the abovementioned cortical areas underwent significant volume contraction over a 1-year period. Overall, these results indicate that the three PPA variants present distinct patterns of neuroanatomical contraction, which reflect their clinical and cognitive progression. PMID- 26106561 TI - An unbiased Bayesian approach to functional connectomics implicates social communication networks in autism. AB - Resting-state functional magnetic resonance imaging (rsfMRI) studies reveal a complex pattern of hyper- and hypo-connectivity in children with autism spectrum disorder (ASD). Whereas rsfMRI findings tend to implicate the default mode network and subcortical areas in ASD, task fMRI and behavioral experiments point to social dysfunction as a unifying impairment of the disorder. Here, we leverage a novel Bayesian framework for whole-brain functional connectomics that aggregates population differences in connectivity to localize a subset of foci that are most affected by ASD. Our approach is entirely data-driven and does not impose spatial constraints on the region foci or dictate the trajectory of altered functional pathways. We apply our method to data from the openly shared Autism Brain Imaging Data Exchange (ABIDE) and pinpoint two intrinsic functional networks that distinguish ASD patients from typically developing controls. One network involves foci in the right temporal pole, left posterior cingulate cortex, left supramarginal gyrus, and left middle temporal gyrus. Automated decoding of this network by the Neurosynth meta-analytic database suggests high level concepts of "language" and "comprehension" as the likely functional correlates. The second network consists of the left banks of the superior temporal sulcus, right posterior superior temporal sulcus extending into temporo parietal junction, and right middle temporal gyrus. Associated functionality of these regions includes "social" and "person". The abnormal pathways emanating from the above foci indicate that ASD patients simultaneously exhibit reduced long-range or inter-hemispheric connectivity and increased short-range or intra hemispheric connectivity. Our findings reveal new insights into ASD and highlight possible neural mechanisms of the disorder. PMID- 26106562 TI - Automatic segmentation and volumetry of multiple sclerosis brain lesions from MR images. AB - The location and extent of white matter lesions on magnetic resonance imaging (MRI) are important criteria for diagnosis, follow-up and prognosis of multiple sclerosis (MS). Clinical trials have shown that quantitative values, such as lesion volumes, are meaningful in MS prognosis. Manual lesion delineation for the segmentation of lesions is, however, time-consuming and suffers from observer variability. In this paper, we propose MSmetrix, an accurate and reliable automatic method for lesion segmentation based on MRI, independent of scanner or acquisition protocol and without requiring any training data. In MSmetrix, 3D T1 weighted and FLAIR MR images are used in a probabilistic model to detect white matter (WM) lesions as an outlier to normal brain while segmenting the brain tissue into grey matter, WM and cerebrospinal fluid. The actual lesion segmentation is performed based on prior knowledge about the location (within WM) and the appearance (hyperintense on FLAIR) of lesions. The accuracy of MSmetrix is evaluated by comparing its output with expert reference segmentations of 20 MRI datasets of MS patients. Spatial overlap (Dice) between the MSmetrix and the expert lesion segmentation is 0.67 +/- 0.11. The intraclass correlation coefficient (ICC) equals 0.8 indicating a good volumetric agreement between the MSmetrix and expert labelling. The reproducibility of MSmetrix' lesion volumes is evaluated based on 10 MS patients, scanned twice with a short interval on three different scanners. The agreement between the first and the second scan on each scanner is evaluated through the spatial overlap and absolute lesion volume difference between them. The spatial overlap was 0.69 +/- 0.14 and absolute total lesion volume difference between the two scans was 0.54 +/- 0.58 ml. Finally, the accuracy and reproducibility of MSmetrix compare favourably with other publicly available MS lesion segmentation algorithms, applied on the same data using default parameter settings. PMID- 26106563 TI - Rotation-invariant multi-contrast non-local means for MS lesion segmentation. AB - Multiple sclerosis (MS) lesion segmentation is crucial for evaluating disease burden, determining disease progression and measuring the impact of new clinical treatments. MS lesions can vary in size, location and intensity, making automatic segmentation challenging. In this paper, we propose a new supervised method to segment MS lesions from 3D magnetic resonance (MR) images using non-local means (NLM). The method uses a multi-channel and rotation-invariant distance measure to account for the diversity of MS lesions. The proposed segmentation method, rotation-invariant multi-contrast non-local means segmentation (RMNMS), captures the MS lesion spatial distribution and can accurately and robustly identify lesions regardless of their orientation, shape or size. An internal validation on a large clinical magnetic resonance imaging (MRI) dataset of MS patients demonstrated a good similarity measure result (Dice similarity = 60.1% and sensitivity = 75.4%), a strong correlation between expert and automatic lesion load volumes (R(2) = 0.91), and a strong ability to detect lesions of different sizes and in varying spatial locations (lesion detection rate = 79.8%). On the independent MS Grand Challenge (MSGC) dataset validation, our method provided competitive results with state-of-the-art supervised and unsupervised methods. Qualitative visual and quantitative voxel- and lesion-wise evaluations demonstrated the accuracy of RMNMS method. PMID- 26106564 TI - Differentiating SCT and inattentive symptoms in ADHD using fMRI measures of cognitive control. AB - Attention Deficit/Hyperactivity Disorder (ADHD) is associated with different impairment profiles in the symptom domains of hyperactivity/impulsivity and/or inattention. An additional symptom domain of sluggish cognitive tempo (SCT) has also been proposed. Although there is a degree of correlation between the SCT symptom domain and inattention, it has been proposed as a distinct disorder independent of ADHD. The objective of this study was to examine the neural substrates of cue-related preparatory processes associated with SCT symptoms versus inattentive symptoms in a group of adolescents with ADHD. We also compared cue-related effects in the entire ADHD group compared with a group of typically developing (TD) peers. A modified cued flanker paradigm and fMRI examined brain activity associated with attention preparation and motor response preparation. Between group contrasts between the ADHD and TD group revealed significant hypoactivity in the ADHD group during general attention preparation in the supplementary motor area (SMA) and in the right superior parietal lobe (SPL) during response preparation. In the ADHD group, greater numbers of SCT symptoms were associated with hypoactivity in the left SPL to cues in general whereas greater numbers of inattentive symptoms were associated with greater activity in the SMA to cues that provided no information and less activity in the thalamus during response preparation. Hypoactivity in the SPL with increasing SCT symptoms may be associated with impaired reorienting or shifting of attention. Altered activity in the SMA and thalamus with increasing inattention may be associated with a general problem with response preparation, which may also reflect inefficient processing of the response preparation cue. Our results support a degree of differentiation between SCT and inattentive symptom profiles within adolescents with ADHD. PMID- 26106565 TI - Functional and structural brain correlates of risk for major depression in children with familial depression. AB - Despite growing evidence for atypical amygdala function and structure in major depression, it remains uncertain as to whether these brain differences reflect the clinical state of depression or neurobiological traits that predispose individuals to major depression. We examined function and structure of the amygdala and associated areas in a group of unaffected children of depressed parents (at-risk group) and a group of children of parents without a history of major depression (control group). Compared to the control group, the at-risk group showed increased activation to fearful relative to neutral facial expressions in the amygdala and multiple cortical regions, and decreased activation to happy relative to neutral facial expressions in the anterior cingulate cortex and supramarginal gyrus. At-risk children also exhibited reduced amygdala volume. The extensive hyperactivation to negative facial expressions and hypoactivation to positive facial expressions in at-risk children are consistent with behavioral evidence that risk for major depression involves a bias to attend to negative information. These functional and structural brain differences between at-risk children and controls suggest that there are trait neurobiological underpinnings of risk for major depression. PMID- 26106566 TI - Contrasting brain patterns of writing-related DTI parameters, fMRI connectivity, and DTI-fMRI connectivity correlations in children with and without dysgraphia or dyslexia. AB - Based on comprehensive testing and educational history, children in grades 4-9 (on average 12 years) were diagnosed with dysgraphia (persisting handwriting impairment) or dyslexia (persisting word spelling/reading impairment) or as typical writers and readers (controls). The dysgraphia group (n = 14) and dyslexia group (n = 17) were each compared to the control group (n = 9) and to each other in separate analyses. Four brain region seed points (left occipital temporal gyrus, supramarginal gyrus, precuneus, and inferior frontal gyrus) were used in these analyses which were shown in a metaanalysis to be related to written word production on four indicators of white matter integrity and fMRI functional connectivity for four tasks (self-guided mind wandering during resting state, writing letter that follows a visually displayed letter in alphabet, writing missing letter to create a correctly spelled real word, and planning for composing after scanning on topic specified by researcher). For those DTI indicators on which the dysgraphic group or dyslexic group differed from the control group (fractional anisotropy, relative anisotropy, axial diffusivity but not radial diffusivity), correlations were computed between the DTI parameter and fMRI functional connectivity for the two writing tasks (alphabet and spelling) by seed points. Analyses, controlled for multiple comparisons, showed that (a) the control group exhibited more white matter integrity than either the dysgraphic or dyslexic group; (b) the dysgraphic and dyslexic groups showed more functional connectivity than the control group but differed in patterns of functional connectivity for task and seed point; and (c) the dysgraphic and dyslexic groups showed different patterns of significant DTI-fMRI connectivity correlations for specific seed points and written language tasks. Thus, dysgraphia and dyslexia differ in white matter integrity, fMRI functional connectivity, and white matter gray matter correlations. Of clinical relevance, brain differences were observed in dysgraphia and dyslexia on written language tasks yoked to their defining behavioral impairments in handwriting and/or in word spelling and on the cognitive mind wandering rest condition and composition planning. PMID- 26106567 TI - Postural sway and regional cerebellar volume in adults with attention deficit/hyperactivity disorder. AB - OBJECTIVE: Motor abnormalities, including impaired balance and increased postural sway, are commonly reported in children with ADHD, but have yet to be investigated in adults with ADHD. Furthermore, although these abnormalities are thought to stem from cerebellar deficits, evidence for an association between the cerebellum and these motor deficits has yet to be provided for either adults or children with ADHD. METHOD: In this study, we measured postural sway in adults with ADHD and controls, examining the relationship between sway and regional cerebellar gray matter volume. Thirty-two ADHD and 28 control participants completed various standing-posture tasks on a Wii balance board. RESULTS: Postural sway was significantly higher for the ADHD group compared to the healthy controls. Higher sway was positively associated with regional gray matter volume in the right posterior cerebellum (lobule VIII/IX). CONCLUSION: These findings show that sway abnormalities commonly reported in children with ADHD are also present in adults, and for the first time show a relationship between postural control atypicalities and the cerebellum in this group. Our findings extend the literature on motor abnormalities in ADHD and contribute to our knowledge of their neural substrate. PMID- 26106568 TI - Altered resting-state network connectivity in stroke patients with and without apraxia of speech. AB - Motor speech disorders, including apraxia of speech (AOS), account for over 50% of the communication disorders following stroke. Given its prevalence and impact, and the need to understand its neural mechanisms, we used resting state functional MRI to examine functional connectivity within a network of regions previously hypothesized as being associated with AOS (bilateral anterior insula (aINS), inferior frontal gyrus (IFG), and ventral premotor cortex (PM)) in a group of 32 left hemisphere stroke patients and 18 healthy, age-matched controls. Two expert clinicians rated severity of AOS, dysarthria and nonverbal oral apraxia of the patients. Fifteen individuals were categorized as AOS and 17 were AOS-absent. Comparison of connectivity in patients with and without AOS demonstrated that AOS patients had reduced connectivity between bilateral PM, and this reduction correlated with the severity of AOS impairment. In addition, AOS patients had negative connectivity between the left PM and right aINS and this effect decreased with increasing severity of non-verbal oral apraxia. These results highlight left PM involvement in AOS, begin to differentiate its neural mechanisms from those of other motor impairments following stroke, and help inform us of the neural mechanisms driving differences in speech motor planning and programming impairment following stroke. PMID- 26106569 TI - [(18)F]-fluoro-L-thymidine PET and advanced MRI for preoperative grading of gliomas. AB - PURPOSE: Conventional MRI based on contrast enhancement is often not sufficient in differentiating grade II from grade III and grade III from grade IV diffuse gliomas. We assessed advanced MRI, MR spectroscopy and [(18)F]-fluoro-l-thymidine ([(18)F]-FLT) PET as tools to overcome these limitations. METHODS: In this prospective study, thirty-nine patients with diffuse gliomas of grades II, III or IV underwent conventional MRI, perfusion, diffusion, proton MR spectroscopy ((1)H MRS) and [(18)F]-FLT-PET imaging before surgery. Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), Cho/Cr, NAA/Cr, Cho/NAA and FLT-SUV were compared between grades. RESULTS: Cho/Cr showed significant differences between grade II and grade III gliomas (p = 0.03). To discriminate grade II from grade IV and grade III from grade IV gliomas, the most relevant parameter was the maximum value of [(18)F]-FLT uptake FLTmax (respectively, p < 0.001 and p < 0.0001). The parameter showing the best correlation with the grade was the mean value of [(18)F]-FLT uptake FLTmean (R(2) = 0.36, p < 0.0001) and FLTmax (R(2) = 0.5, p < 0.0001). CONCLUSION: Whereas advanced MRI parameters give indications for the grading of gliomas, the addition of [(18)F]-FLT-PET could be of interest for the accurate preoperative classification of diffuse gliomas, particularly for identification of doubtful grade III and IV gliomas. PMID- 26106570 TI - Dysfunction of ventrolateral prefrontal cortex underlying social anxiety disorder: A multi-channel NIRS study. AB - Social anxiety disorder (SAD) is characterized by strong fear and anxiety during social interactions. Although ventrolateral prefrontal cortex (VLPFC) activity in response to emotional stimuli is related to pathological anxiety, little is known about the relationship between VLPFC activity and social anxiety. This study aimed to investigate whether VLPFC activity was involved in SAD and whether VLPFC activity was related to the level of social anxiety. Twenty-four drug-naive patients with SAD and 35 healthy controls underwent near-infrared spectroscopy (NIRS) scanning while performing a verbal fluency task (VFT). Results indicated that, compared to the healthy controls, the SAD patients exhibited smaller changes of oxygenated hemoglobin (oxy-Hb) concentrations in the VLPFC during the VFT. Furthermore, the right VLPFC activation was negatively correlated with social avoidance. In contrast to the latter, the healthy controls exhibited a positive correlation between changes of oxy-Hb concentrations in the bilateral VLPFC and social fear. Our findings provide evidence for VLPFC dysfunction in SAD, and indicate that the VLPFC dysfunction may contribute to the difference between normal and abnormal social anxiety. PMID- 26106571 TI - Developmental synergy between thalamic structure and interhemispheric connectivity in the visual system of preterm infants. AB - Thalamic structural co-variation with cortical regions has been demonstrated in preterm infants, but its relationship to cortical function and severity of non cystic white matter injury (non-cystic WMI) is unclear. The relationship between thalamic morphology and both cortical network synchronization and cortical structural connectivity has not been established. We tested the hypothesis that in preterm neonates, thalamic volume would correlate with primary cortical visual function and microstructural integrity of cortico-cortical visual association pathways. A total of 80 term-equivalent preterm and 44 term-born infants underwent high-resolution structural imaging coupled with visual functional magnetic resonance imaging or diffusion tensor imaging. There was a strong correlation between thalamic volume and primary visual cortical activation in preterms with non-cystic WMI (r = 0.81, p-value = 0.001). Thalamic volume also correlated strongly with interhemispheric cortico-cortical connectivity (splenium) in preterm neonates with a relatively higher severity of non-cystic WMI (p-value < 0.001). In contrast, there was lower correlation between thalamic volume and intrahemispheric cortico-cortical connectivity, including the inferior longitudinal fasciculus and inferior frontal orbital fasciculus. This study shows distinct temporal overlap in the disruption of thalamo-cortical and interhemispheric cortico-cortical connectivity in preterm infants suggesting developmental synergy between thalamic morphology and the emergence of cortical networks in the last trimester. PMID- 26106572 TI - Brain structural, functional, and cognitive correlates of recent versus remote autobiographical memories in amnestic Mild Cognitive Impairment. AB - Deficits in autobiographical memory appear earlier for recent than for remote life periods over the course of Alzheimer's disease (AD). The present study aims to further our understanding of this graded effect by investigating the cognitive and neural substrates of recent versus remote autobiographical memories in patients with amnestic Mild Cognitive Impairment (aMCI) thanks to an autobiographical fluency task. 20 aMCI patients and 25 Healthy elderly Controls (HC) underwent neuropsychological tests assessing remote (20-to-30 years old) and recent (the ten last years) autobiographical memory as well as episodic and semantic memory, executive function and global cognition. All patients also had a structural MRI and an FDG-PET scan. Correlations were assessed between each autobiographical memory score and the other tests as well as grey matter volume and metabolism. Within the aMCI, performances for the remote period correlated with personal semantic memory and episodic memory retrieval whereas performances for the recent period only correlated with episodic memory retrieval. Neuroimaging analyses revealed significant correlations between performances for the remote period and temporal pole and temporo-parietal cortex volumes and anterior cingulate gyrus metabolism, while performances for the recent period correlated with hippocampal volume and posterior cingulate, medial prefrontal and hippocampus metabolism. The brain regions related with the retrieval of events from the recent period showed greater atrophy/hypometabolism in aMCI patients compared to HC than those involved in remote memories. Recall of recent memories essentially relies on episodic memory processes and brain network while remote memories also involve other processes such as semantic memory. This is consistent with the semanticization of memories with time and may explain the better resistance of remote memory in AD. PMID- 26106573 TI - Abnormal structural connectivity in the brain networks of children with hydrocephalus. AB - Increased intracranial pressure and ventriculomegaly in children with hydrocephalus are known to have adverse effects on white matter structure. This study seeks to investigate the impact of hydrocephalus on topological features of brain networks in children. The goal was to investigate structural network connectivity, at both global and regional levels, in the brains in children with hydrocephalus using graph theory analysis and diffusion tensor tractography. Three groups of children were included in the study (29 normally developing controls, 9 preoperative hydrocephalus patients, and 17 postoperative hydrocephalus patients). Graph theory analysis was applied to calculate the global network measures including small-worldness, normalized clustering coefficients, normalized characteristic path length, global efficiency, and modularity. Abnormalities in regional network parameters, including nodal degree, local efficiency, clustering coefficient, and betweenness centrality, were also compared between the two patients groups (separately) and the controls using two tailed t-test at significance level of p < 0.05 (corrected for multiple comparison). Children with hydrocephalus in both the preoperative and postoperative groups were found to have significantly lower small-worldness and lower normalized clustering coefficient than controls. Children with hydrocephalus in the postoperative group were also found to have significantly lower normalized characteristic path length and lower modularity. At regional level, significant group differences (or differences at trend level) in regional network measures were found between hydrocephalus patients and the controls in a series of brain regions including the medial occipital gyrus, medial frontal gyrus, thalamus, cingulate gyrus, lingual gyrus, rectal gyrus, caudate, cuneus, and insular. Our data showed that structural connectivity analysis using graph theory and diffusion tensor tractography is sensitive to detect abnormalities of brain network connectivity associated with hydrocephalus at both global and regional levels, thus providing a new avenue for potential diagnosis and prognosis tool for children with hydrocephalus. PMID- 26106574 TI - Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study. AB - Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing. PMID- 26106576 TI - A retrospective study of Babesia macropus associated with morbidity and mortality in eastern grey kangaroos (Macropus giganteus) and agile wallabies (Macropus agilis). AB - This is a retrospective study of 38 cases of infection by Babesia macropus, associated with a syndrome of anaemia and debility in hand-reared or free-ranging juvenile eastern grey kangaroos (Macropus giganteus) from coastal New South Wales and south-eastern Queensland between 1995 and 2013. Infection with B. macropus is recorded for the first time in agile wallabies (Macropus agilis) from far north Queensland. Animals in which B. macropus infection was considered to be the primary cause of morbidity had marked anaemia, lethargy and neurological signs, and often died. In these cases, parasitised erythrocytes were few or undetectable in peripheral blood samples but were sequestered in large numbers within small vessels of visceral organs, particularly in the kidney and brain, associated with distinctive clusters of extraerythrocytic organisms. Initial identification of this piroplasm in peripheral blood smears and in tissue impression smears and histological sections was confirmed using transmission electron microscopy and molecular analysis. Samples of kidney, brain or blood were tested using PCR and DNA sequencing of the 18S ribosomal RNA and heat shock protein 70 gene using primers specific for piroplasms. The piroplasm detected in these samples had 100% sequence identity in the 18S rRNA region with the recently described Babesia macropus in two eastern grey kangaroos from New South Wales and Queensland, and a high degree of similarity to an unnamed Babesia sp. recently detected in three woylies (Bettongia penicillata ogilbyi) in Western Australia. PMID- 26106575 TI - What graph theory actually tells us about resting state interictal MEG epileptic activity. AB - Graph theory provides a useful framework to study functional brain networks from neuroimaging data. In epilepsy research, recent findings suggest that it offers unique insight into the fingerprints of this pathology on brain dynamics. Most studies hitherto have focused on seizure activity during focal epilepsy, but less is known about functional epileptic brain networks during interictal activity in frontal focal and generalized epilepsy. Besides, it is not clear yet which measures are most suitable to characterize these networks. To address these issues, we recorded magnetoencephalographic (MEG) data using two orthogonal planar gradiometers from 45 subjects from three groups (15 healthy controls (7 males, 24 +/- 6 years), 15 frontal focal (8 male, 32 +/- 16 years) and 15 generalized epileptic (6 male, 27 +/- 7 years) patients) during interictal resting state with closed eyes. Then, we estimated the total and relative spectral power of the largest principal component of the gradiometers, and the degree of phase synchronization between each sensor site in the frequency range [0.5-40 Hz]. We further calculated a comprehensive battery of 15 graph-theoretic measures and used the affinity propagation clustering algorithm to elucidate the minimum set of them that fully describe these functional brain networks. The results show that differences in spectral power between the control and the other two groups have a distinctive pattern: generalized epilepsy presents higher total power for all frequencies except the alpha band over a widespread set of sensors; frontal focal epilepsy shows higher relative power in the beta band bilaterally in the fronto-central sensors. Moreover, all network indices can be clustered into three groups, whose exemplars are the global network efficiency, the eccentricity and the synchronizability. Again, the patterns of differences were clear: the brain network of the generalized epilepsy patients presented greater efficiency and lower eccentricity than the control subjects for the high frequency bands, without a clear topography. Besides, the frontal focal epileptic patients showed only reduced eccentricity for the theta band over fronto-temporal and central sensors. These outcomes indicate that functional epileptic brain networks are different to those of healthy subjects during interictal stage at rest, with a unique pattern of dissimilarities for each type of epilepsy. Further, when properly selected, three network indices suffice to provide a comprehensive description of these differences. Yet, since such uniqueness in the pattern of differences is also evident in the power spectrum, we conclude that the added value of the graph theory approach in this context should not be overestimated. PMID- 26106577 TI - A change in electrographic activity and blood flow during interictal and postictal psychotic states in a patient with epilepsy. AB - We report a patient with epilepsy who experienced interictal and postictal psychoses. Her psychiatric symptoms consisted of grandiose and fantastic delusions during both psychotic states. During remission, electroencephalography showed bitemporal epileptiform discharges that were predominant in the right temporal region. Epileptiform discharges present during the psychotic states were predominant in the left temporal region. Single-photon emission computed tomography showed hyperperfusion in the left basal ganglia during the interictal psychotic state and hyperperfusion in the right temporal lobe and left basal ganglia during the postictal psychotic state. We suggest that the occurrence of postictal and interictal psychotic states in this patient were associated with a common change in electrographic activity and blood flow. PMID- 26106578 TI - Nonconvulsive status epilepticus secondary to paclitaxel administration. AB - Nonconvulsive status epilepticus (NCSE) can be triggered by metabolic disturbances and drugs in adults without previous epilepsy. We present the case of a 51-year-old woman without previous history of epilepsy and recently diagnosed with infiltrating lobular breast carcinoma. Following the administration of paclitaxel-cremophor, she presented a striking disinhibited behavior with episodic spatial disorientation, emotional indifference, and irritability. Urgent EEG was consistent with NCSE. Clinical improvement and resolution of EEG abnormalities were observed following the administration of intravenous levetiracetam and lacosamide. Other causes of NCSE were ruled out, and antiepileptic drugs were slowly tapered off without new episodes of abnormal behavior after three months of follow-up. We have reported the first case of NCSE secondary to paclitaxel-cremophor. Neurologists and oncologists should consider NCSE as an unusual complication of treatment with paclitaxel-cremophor in patients without a history of epilepsy. PMID- 26106579 TI - A case study of voltage-gated potassium channel antibody-related limbic encephalitis with PET/MRI findings. AB - Preclinical and clinical studies have demonstrated the significance of inflammation and autoantibodies in epilepsy, and the use of immunotherapies in certain situations has become an established practice. Temporal lobe epilepsy can follow paraneoplastic or nonparaneoplastic limbic encephalitis associated with antibodies directed against brain antigens. Here, we focus on a patient with worsening confusion and temporal lobe seizures despite treatment with antiepileptic medications. Serial brain MRIs did not conclusively reveal structural abnormalities, so the patient underwent brain PET/MRI to simultaneously evaluate brain structure and function, revealing bitemporal abnormalities. The patient was diagnosed with voltage-gated potassium channel antibody-related limbic encephalitis based on clinical presentation, imaging findings, and antibody testing. Treatment included the addition of a second antiepileptic agent and oral steroids. His seizures and cognitive deficits improved and stabilized. PMID- 26106580 TI - Impact of polymorphisms of the GGCX gene on maintenance warfarin dose in Chinese populations: Systematic review and meta-analysis. AB - The meta-analysis was conducted to investigate the impact of gamma-glutamyl carboxylase (GGCX) on maintenance warfarin dose. 8 studies were included, focusing on the impact of GGCX single nucleotide polymorphisms (SNPs) on mean daily warfarin dose (MDWD). GGCX (rs699664; AA versus GG, GA versus GG, A versus GG) and GGCX (rs12714145; GA versus GG, AA versus GG, A versus GG) showed no significant differences on mean daily warfarin dose (MDWD). This meta-analysis was the first to report the relationship between GGCX SNPs and MDWD in Chinese populations. No evidence could be found in the relationship between SNPs of GGCX (rs699664 and rs12714145) and maintenance warfarin dose. PMID- 26106581 TI - Proteomic analysis of differentially expressed protein in hemocytes of wild giant freshwater prawn Macrobrachium rosenbergii infected with infectious hypodermal and hematopoietic necrosis virus (IHHNV). AB - Epizootic diseases cause huge mortality and economical loses at post larvae stages in freshwater prawn aquaculture industry. These prawns seem less susceptible to viral diseases except for infectious hypodermal and hematopoietic necrosis virus (IHHNV). During viral infection in prawns, hemocytes are the primary organ that shows immunological response within the early stages of infection. We applied proteomic approaches to understand differential expression of the proteins in hemocytes during the viral disease outbreak. To aid the goal, we collected Macrobrachium rosenbergii broodstocks from the local grow out hatchery which reported the first incidence of IHHNV viral outbreak during larvae stage. Primarily, application of the OIE primer targeting 389 bp fragments of IHHNV virus was used in identification of the infected and non-infected samples of the prawn breeding line. Analysis of two-dimensional gel electrophoresis showed specific down-regulation of Arginine kinase and Sarcoplasmic calcium binding protein and up/down-regulation of Prophenoloxidase1 and hemocyanin isoforms. These proteins were validated using semi quantitative RT-PCR and gene transcripts at mRNA level. These identified proteins can be used as biomarkers, providing a powerful approach to better understanding of the immunity pathway of viral disease with applications in analytic and observational epidemiology diagnosis. Proteomic profiling allows deep insight into the pathogenesis of IHHNV molecular regulation and mechanism of hemocyte in freshwater prawns. PMID- 26106582 TI - The complete mitochondrial genome of Papilio glaucus and its phylogenetic implications. AB - Due to the intriguing morphology, lifecycle, and diversity of butterflies and moths, Lepidoptera are emerging as model organisms for the study of genetics, evolution and speciation. The progress of these studies relies on decoding Lepidoptera genomes, both nuclear and mitochondrial. Here we describe a protocol to obtain mitogenomes from Next Generation Sequencing reads performed for whole genome sequencing and report the complete mitogenome of Papilio (Pterourus) glaucus. The circular mitogenome is 15,306 bp in length and rich in A and T. It contains 13 protein-coding genes (PCGs), 22 transfer-RNA-coding genes (tRNA), and 2 ribosomal-RNA-coding genes (rRNA), with a gene order typical for mitogenomes of Lepidoptera. We performed phylogenetic analyses based on PCG and RNA-coding genes or protein sequences using Bayesian Inference and Maximum Likelihood methods. The phylogenetic trees consistently show that among species with available mitogenomes Papilio glaucus is the closest to Papilio (Agehana) maraho from Asia. PMID- 26106585 TI - Single-Cell Phenotypic Characterization of Human Pituitary GHomas and Non Functioning Adenomas Based on Hormone Content and Calcium Responses to Hypothalamic Releasing Hormones. AB - Human pituitary tumors are generally benign adenomas causing considerable morbidity due to excess hormone secretion, hypopituitarism, and other tumor mass effects. Pituitary tumors are highly heterogeneous and difficult to type, often containing mixed cell phenotypes. We have used calcium imaging followed by multiple immunocytochemistry to type growth hormone secreting (GHomas) and non functioning pituitary adenomas (NFPAs). Individual cells were typed for stored hormones and calcium responses to classic hypothalamic releasing hormones (HRHs). We found that GHomas contained growth hormone cells either lacking responses to HRHs or responding to all four HRHs. However, most GHoma cells were polyhormonal cells responsive to both thyrotropin-releasing hormone (TRH) and GH-releasing hormone. NFPAs were also highly heterogeneous. Some of them contained ACTH cells lacking responses to HRHs or polyhormonal gonadotropes responsive to LHRH and TRH. However, most NFPAs were made of cells storing no hormone and responded only to TRH. These results may provide new insights on the ontogeny of GHomas and NFPAs. PMID- 26106584 TI - STAT3-Mediated Metabolic Reprograming in Cellular Transformation and Implications for Drug Resistance. AB - Signal transducer and activator of transcription (STAT)3 mediates the signaling downstream of cytokine and growth factor receptors, regulating the expression of target genes. It is constitutively phosphorylated on tyrosine (Y-P) in many tumors, where its transcriptional activity can induce a metabolic switch toward aerobic glycolysis and down-regulate mitochondrial activity, a prominent metabolic feature of most cancer cells, correlating with reduced production of ROS, delayed senescence, and protection from apoptosis. STAT3 can, however, also localize to mitochondria, where its serine-phosphorylated (S-P) form preserves mitochondrial oxidative phosphorylation and controls the opening of the mitochondrial permeability transition pore, also promoting survival and resistance to apoptosis in response to specific signals/oncogenes such as RAS. Thus, downstream of different signals, both nuclear, Y-P STAT3, and mitochondrial, S-P STAT3, can act by promoting cell survival and reducing ROS production. Here, we discuss these properties in the light of potential connections between STAT3-driven alterations of mitochondrial metabolism and the development of drug resistance in cancer patients. PMID- 26106583 TI - 4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity. AB - Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co receptors, which can be targeted to boost tumor immunity. Among these, the co stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB's expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized. PMID- 26106586 TI - Hedgehog Inhibitors in Rhabdomyosarcoma: A Comparison of Four Compounds and Responsiveness of Four Cell Lines. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and is divided into two major histological subgroups, i.e., embryonal (ERMS) and alveolar RMS (ARMS). RMS can show HEDGEHOG/SMOOTHENED (HH/SMO) signaling activity and several clinical trials using HH inhibitors for therapy of RMS have been launched. We here compared the antitumoral effects of the SMO inhibitors GDC 0449, LDE225, HhA, and cyclopamine in two ERMS (RD, RUCH-2) and two ARMS (RMS-13, Rh41) cell lines. Our data show that the antitumoral effects of these SMO inhibitors are highly divers and do not necessarily correlate with inhibition of HH signaling. In addition, the responsiveness of the RMS cell lines to the drugs is highly heterogeneous. Whereas some SMO inhibitors (i.e., LDE225 and HhA) induce strong proapoptotic and antiproliferative effects in some RMS cell lines, others paradoxically induce cellular proliferation at certain concentrations (e.g., 10 MUM GDC-0449 or 5 MUM cyclopamine in RUCH-2 and Rh41 cells) or can increase HH signaling activity as judged by GLI1 expression (i.e., LDE225, HhA, and cyclopamine). Similarly, some drugs (e.g., HhA) inhibit PI3K/AKT signaling or induce autophagy (e.g., LDE225) in some cell lines, whereas others cannot (e.g., GDC-0449). In addition, the effects of SMO inhibitors are concentration-dependent (e.g., 1 and 10 MUM GDC-0449 decrease GLI1 expression in RD cells whereas 30 MUM GDC-0449 does not). Together these data show that some SMO inhibitors can induce strong antitumoral effects in some, but not all, RMS cell lines. Due to the highly heterogeneous response, we propose to conduct thorough pretesting of SMO inhibitors in patient-derived short-term RMS cultures or patient-derived xenograft mouse models before applying these drugs to RMS patients. PMID- 26106588 TI - Combined association of physical activity and diet with C-reactive protein among smokers. AB - BACKGROUND: In the general population, both physical activity and dietary behavior are independently associated with less systemic inflammation, with this relationship less examined among smokers. To our knowledge, no study has examined the combined association of both physical activity and dietary behavior on systemic inflammation among daily smokers, which was the purpose of this study. METHODS: Data from the 2003-2006 NHANES were employed. 810 adult smokers provided C-reactive protein data (CRP; a marker of inflammation), and sufficient physical activity (accelerometry) and dietary data (healthy eating index). RESULTS: The fully adjusted model showed that participants meeting physical activity guidelines and eating a healthy diet (beta = -0.34, p = 0.03) had lower CRP levels when compared to those not engaging in these health behaviors, but only having one health behavior was not a significant predictor of CRP (beta = -0.19, p = 0.14). CONCLUSIONS: Smokers engaging in regular physical activity while consuming a healthy diet demonstrate lower CRP levels than their counterparts. When taken together, these behaviors may mitigate inflammation associated with various chronic diseases, which is of particular importance as very few smokers successfully quit smoking. PMID- 26106587 TI - The role of autophagy in intracellular pathogen nutrient acquisition. AB - Following entry into host cells intracellular pathogens must simultaneously evade innate host defense mechanisms and acquire energy and anabolic substrates from the nutrient-limited intracellular environment. Most of the potential intracellular nutrient sources are stored within complex macromolecules that are not immediately accessible by intracellular pathogens. To obtain nutrients for proliferation, intracellular pathogens must compete with the host cell for newly imported simple nutrients or degrade host nutrient storage structures into their constituent components (fatty acids, carbohydrates, and amino acids). It is becoming increasingly evident that intracellular pathogens have evolved a wide variety of strategies to accomplish this task. One recurrent microbial strategy is to exploit host degradative processes that break down host macromolecules into simple nutrients that the microbe can use. Herein we focus on how a subset of bacterial, viral, and eukaryotic pathogens leverage the host process of autophagy to acquire nutrients that support their growth within infected cells. PMID- 26106589 TI - Applying Biotechnology and Bioengineering to Pediatric Lung Disease: Emerging Paradigms and Platforms. AB - Pediatric lung diseases remain a costly worldwide health burden. For many children with end-stage lung disease, lung transplantation remains the only therapeutic option. Due to the limited number of lungs available for transplantation, alternatives to lung transplant are desperately needed. Recently, major improvements in tissue engineering have resulted in newer technology and methodology to develop viable bioengineered lungs. These include critical advances in lung cell biology, stem cell biology, lung extracellular matrix, microfabrication techniques, and orthotopic transplantation of bioartificial lungs. The goal of this short review is to engage the reader's interest with regard to these emerging concepts and to stimulate their interest to learn more. We review the existing state of the art of lung tissue engineering, and point to emerging paradigms and platforms in the field. Finally, we summarize the challenges and unmet needs that remain to be overcome. PMID- 26106590 TI - Immune Thrombocytopenia in Two Unrelated Fanconi Anemia Patients - A Mere Coincidence? AB - Thrombocytopenia and pancytopenia, occurring in patients with Fanconi anemia (FA), are interpreted either as progression to bone marrow failure or as developing myelodysplasia. On the other hand, immune thrombocytopenia (ITP) represents an acquired and often self-limiting benign hematologic disorder, associated with peripheral, immune-mediated, platelet destruction requiring different management modalities than those used in congenital bone marrow failure syndromes, including FA. Here, we describe the clinical course of two independent FA patients with atypical - namely immune - thrombocytopenia. While in one patient belonging to complementation group FA-A, the ITP started at 17 months of age and showed a chronically persisting course with severe purpura, responding well to intravenous immunoglobulins (IVIG) and later also danazol, a synthetic androgen, the other patient (of complementation group FA-D2) had a self-limiting course that resolved after one administration of IVIG. No cytogenetic aberrations or bone marrow abnormalities other than FA-typical mild dysplasia were detected. Our data show that acute and chronic ITP may occur in FA patients and impose individual diagnostic and therapeutic challenges in this rare congenital bone marrow failure/tumor predisposition syndrome. The management and a potential context of immune pathogenesis with the underlying marrow disorder are discussed. PMID- 26106591 TI - Current Updates on Choanal Atresia. AB - Choanal atresia (CA) is a relatively uncommon but well-recognized condition characterized by the anatomical closure of the posterior choanae in the nasal cavity. Since the original description back in the early eighteenth century, there have been controversies regarding its exact pathogenesis, the optimal surgical approach, and the use of adjunct treatments such as post-surgical stenting and anti-neoplastic agents, despite of abundant literature available. The emergence and development of new technologies play a significant role in the management of this condition. This review provides a comprehensive clinical update on CA and identifies areas for future study based on the existing available literature. PMID- 26106592 TI - Editorial: Emerging Zoonoses: Eco-Epidemiology, Involved Mechanisms, and Public Health Implications. PMID- 26106593 TI - Is it Time to Consider the "Burnout Syndrome" A Distinct Illness? AB - The "burnout syndrome" has been defined as a combination of emotional exhaustion, depersonalization, and reduced personal accomplishment caused by chronic occupational stress. Although there has been increasing medical interest in burnout over the last decades, it is argued in this paper that the syndrome cannot be elevated to the status of diagnostic category, based on (1) an analysis of the genesis of the burnout construct, (2) a review of the latest literature on burnout-depression overlap, (3) a questioning of the three-dimensional structure of the burnout syndrome, and (4) a critical examination of the notion that burnout is singularized by its job-related character. It turns out that the burnout construct is built on a fragile foundation, both from a clinical and a theoretical standpoint. The current state of science suggests that burnout is a form of depression rather than a differentiated type of pathology. The inclusion of burnout in future disorder classifications is therefore unwarranted. The focus of public health policies dedicated to the management of "burnout" should not be narrowed to the three definitional components of the syndrome but consider its depressive core. PMID- 26106595 TI - Fast Growing Plantations for Wood Production - Integration of Ecological Effects and Economic Perspectives. AB - Biomass crops are perceived as a feasible means to substitute sizeable amounts of fossil fuel in the future. A prospect of CO2 reduction (resp. CO2 neutrality) is credited to biomass fuels, and thus a potential contribution to mitigate climate change. Short rotation coppices (SRCs) with fast growing poplar and willow trees are an option for producing high yields of woody biomass, which is suitable for both energetic and material use. One negative effect that comes along with the establishment of SRC may be a decrease in groundwater recharge, because high rates of transpiration and interception are anticipated. Therefore, it is important to measure, analyze, and model the effects of SRC-planting on landscape water budgets. To analyze the effects on the water budget, a poplar SRC plot was studied by measuring hydrological parameters to be used in the hydrological model WaSim. Results reveal very low or even missing ground water recharge for SRC compared to agricultural land use or grassland, especially succeeding dry years. However, this strong effect on plot level is moderated on the larger spatial scale of catchment level, for which the modeling was also performed. In addition to water, nutrient fluxes and budgets were studied. Nitrogen is still a crucial issue in today's agriculture. Intensive fertilization or increased applications of manure from concentrated livestock breeding are often leading to high loads of nitrate leaching, or enhanced N2O emissions to the atmosphere on arable crop fields. SRC or agroforestry systems on former crop land may offer an option to decrease such N losses, while simultaneously producing woody biomass. This is mainly due to the generally smaller N requirements of woody vegetation, which usually entail no need for any fertilization. The trees supply deep and permanent rooting systems, which can be regarded as a "safety net" to prevent nutrient leaching. Thus, SRC altogether can help to diminish N eutrophication. It is important to offer viable and attractive economic perspectives to farmers and other land managers besides of the potential ecological benefits of SRCs. For this reason, an integrated tool for scenario analysis was developed within the BEST project ("BEAST - Bio-Energy Allocation and Scenario Tool"). It combines ecological assessments with calculations of economic revenue as a basis for a participative regional dialog on sustainable land use and climate protection goals. Results show a substantial capacity for providing renewable energy from economically competitive arable SRC sites while generating ecological synergies. PMID- 26106594 TI - Transposable Element Insertions in Long Intergenic Non-Coding RNA Genes. AB - Transposable elements (TEs) are abundant in mammalian genomes and appear to have contributed to the evolution of their hosts by providing novel regulatory or coding sequences. We analyzed different regions of long intergenic non-coding RNA (lincRNA) genes in human and mouse genomes to systematically assess the potential contribution of TEs to the evolution of the structure and regulation of expression of lincRNA genes. Introns of lincRNA genes contain the highest percentage of TE-derived sequences (TES), followed by exons and then promoter regions although the density of TEs is not significantly different between exons and promoters. Higher frequencies of ancient TEs in promoters and exons compared to introns implies that many lincRNA genes emerged before the split of primates and rodents. The content of TES in lincRNA genes is substantially higher than that in protein-coding genes, especially in exons and promoter regions. A significant positive correlation was detected between the content of TEs and evolutionary rate of lincRNAs indicating that inserted TEs are preferentially fixed in fast-evolving lincRNA genes. These results are consistent with the repeat insertion domains of LncRNAs hypothesis under which TEs have substantially contributed to the origin, evolution, and, in particular, fast functional diversification, of lincRNA genes. PMID- 26106596 TI - 3D Printing of Octacalcium Phosphate Bone Substitutes. AB - Biocompatible calcium phosphate ceramic grafts are able of supporting new bone formation in appropriate environment. The major limitation of these materials usage for medical implants is the absence of accessible methods for their patient specific fabrication. 3D printing methodology is an excellent approach to overcome the limitation supporting effective and fast fabrication of individual complex bone substitutes. Here, we proposed a relatively simple route for 3D printing of octacalcium phosphates (OCP) in complexly shaped structures by the combination of inkjet printing with post-treatment methodology. The printed OCP blocks were further implanted in the developed cranial bone defect followed by histological evaluation. The obtained result confirmed the potential of the developed OCP bone substitutes, which allowed 2.5-time reducing of defect's diameter at 6.5 months in a region where native bone repair is extremely inefficient. PMID- 26106597 TI - Conserved Functional Motifs and Homology Modeling to Predict Hidden Moonlighting Functional Sites. AB - Moonlighting functional centers within proteins can provide them with hitherto unrecognized functions. Here, we review how hidden moonlighting functional centers, which we define as binding sites that have catalytic activity or regulate protein function in a novel manner, can be identified using targeted bioinformatic searches. Functional motifs used in such searches include amino acid residues that are conserved across species and many of which have been assigned functional roles based on experimental evidence. Molecules that were identified in this manner seeking cyclic mononucleotide cyclases in plants are used as examples. The strength of this computational approach is enhanced when good homology models can be developed to test the functionality of the predicted centers in silico, which, in turn, increases confidence in the ability of the identified candidates to perform the predicted functions. Computational characterization of moonlighting functional centers is not diagnostic for catalysis but serves as a rapid screening method, and highlights testable targets from a potentially large pool of candidates for subsequent in vitro and in vivo experiments required to confirm the functionality of the predicted moonlighting centers. PMID- 26106598 TI - Overcoming Recruitment Barriers in Urban Older Adults Residing in Congregate Living Facilities. AB - Background. Participation of minority older adults in mental health research has been limited by mistrust, transportation difficulties, lack of knowledge, and insufficient community partnership. We describe strategies utilized to overcome these recruitment barriers. Methods. Our target population included 553 public housing residents of older adult high-rise buildings in Rochester, NY. We had a two-stage cross-sectional study: Stage 1 was a health survey for all residents and Stage 2 was a psychiatric interview of English-speaking residents aged 60 years and older. Recruitment occurred through mailings, onsite activities, and resident referrals. Results. Stage 1 had 358 participants (64.7% response) and Stage 2 had 190 (61.6% target population response), with higher participation among African Americans. We found some strategies effective for overcoming recruitment barriers. First, we partnered with a community agency and organized onsite educational activities to improve residents' trust. Second, the study occurred entirely onsite, which facilitated participation of functionally impaired residents. Third, onsite activities allowed the residents to learn about the study and complete surveys in person. Fourth, we provided immediate incentives that resulted in many study referrals. Conclusions. Although recruitment of minority older adults presents unique challenges, a multifaceted community-tailored approach mitigated several recruitment barriers in this mental health study. PMID- 26106600 TI - Comparison of Malated Ringer's with Two Other Balanced Crystalloid Solutions in Resuscitation of Both Severe and Moderate Hemorrhagic Shock in Rats. AB - In preclinical treatment of polytraumatized patients crystalloids are preferentially used. To avoid metabolic acidosis, metabolizable anions like lactate or acetate are used to replace chloride in these solutions. We here studied the effects of malated Ringer's in resuscitation of both shock severities in comparison to lactated and acetated Ringer's. Male Wistar rats underwent severe (mean arterial blood pressure (MAP) of 25-30 mmHg) or moderate (MAP 40-45 mmHg) hemorrhagic shock. Adjacent to the shock period animals were resuscitated with acetated (AR), lactated (LR), or malated Ringer's (MR) and observed for 150 min. MR improved survival compared with LR and AR in severe hemorrhagic shock whereas it was equally effective to LR and superior to AR in moderate hemorrhagic shock. In all other parameters tested, MR was also effective similar to the other solutions under these conditions. We conclude that MR is preferable to AR and LR in resuscitation of hemorrhagic shock independent of shock depth. The positive effects of MR may stem from the absence of any adverse impact on energy metabolism under both conditions. PMID- 26106599 TI - Colorectal Cancer Biomarkers: Where Are We Now? AB - Colorectal cancer is one of the major causes of cancer-related death in the Western world. Patient survival is highly dependent on the tumor stage at the time of diagnosis. Reduced sensitivity to chemotherapy is still a major obstacle in effective treatment of advanced disease. Due to the fact that colorectal cancer is mostly asymptomatic until it progresses to advanced stages, the implementation of screening programs aimed at early detection is essential to reduce incidence and mortality rates. Current screening and diagnostic methods range from semi-invasive procedures such as colonoscopy to noninvasive stool based tests. The combination of the absence of symptoms, the semi-invasive nature of currently used methods, and the suboptimal accuracy of fecal blood tests results in colorectal cancer diagnosis at advanced stages in a significant number of individuals. Alterations in gene expression leading to colorectal carcinogenesis are reflected in dysregulated levels of nucleic acids and proteins, which can be used for the development of novel, minimally invasive molecular biomarkers. The purpose of this review is to discuss the commercially available colorectal cancer molecular diagnostic methods as well as to highlight some of the new candidate predictive and prognostic molecular markers for tumor, stool, and blood samples. PMID- 26106602 TI - Lack of Association between Membrane-Type 1 Matrix Metalloproteinase Expression and Clinically Relevant Molecular or Morphologic Tumor Characteristics at the Leading Edge of Invasive Colorectal Carcinoma. AB - Colorectal cancer (CRC) is one of the leading causes of death from cancer in the western world, but tumor biology and clinical course show great interindividual variation. Molecular and morphologic tumor characteristics, such as KRAS/BRAF mutation status, mismatch repair (MMR) protein expression, tumor growth pattern, and tumor cell budding, have been shown to be of key therapeutic and/or prognostic relevance in CRC. Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-anchored zinc-binding endopeptidase that is expressed at the leading edge of various invasive carcinomas and promotes tumor cell invasion through degradation of the extracellular matrix. The aim of this study was to investigate possible associations between MT1-MMP expression and molecular tumor characteristics as well as morphologic features of tumor aggressiveness in a consecutive series of 79 CRC tissue samples. However, although MT1-MMP was expressed in 41/79 samples (52%), there was no significant association between MT1-MMP expression and KRAS/BRAF mutation status, MMR protein expression, presence of lymphovascular invasion, tumor growth pattern, tumor-infiltrating lymphocytes, or tumor cell budding in our sample cohort (P > 0.05). Thus, we conclude that although MT1-MMP may play a role in CRC invasion, it is not of key relevance to the current models of CRC invasion and aggressiveness. PMID- 26106603 TI - Nontuberculous Mycobacteria in Noncystic Fibrosis Bronchiectasis. AB - During the past decades, a growing interest has been raised in evaluating nontuberculous mycobacteria (NTM) in patients with noncystic fibrosis bronchiectasis (NCFBE). This paper reviews several aspects of the correlations between NTM and NCFBE, including pathogenesis, radiological features, diagnosis, and management. Bronchiectasis and NTM lung disease are connected, but which one comes first is still an unresolved question. The rate of NTM lung disease in NCFBE varies through the studies, from 5% to 30%. The most frequent species isolated is MAC. NCFBE patients affected by NTM infection frequently present coinfections, including both other different NTM species and microorganisms, such as P. aeruginosa. Once a diagnosis of NTM disease has been reached, the initiation of therapy is not always mandatory. NTM species isolated, patients' conditions, and disease severity and its evolution should be considered. Risk factors for disease progression in NCFBE patients with NTM are low body mass index, cavitary disease, consolidations, and macrolide resistance at presentation. PMID- 26106601 TI - Nontuberculous Mycobacterial Ocular Infections: A Systematic Review of the Literature. AB - Nontuberculous or atypical mycobacterial ocular infections have been increasing in prevalence over the past few decades. They are known to cause periocular, adnexal, ocular surface and intraocular infections and are often recalcitrant to medical therapy. These infections can potentially cause detrimental outcomes, in part due to a delay in diagnosis. We review 174 case reports and series on nontuberculous mycobacterial (NTM) ocular infections and discuss etiology, microbiology, risk factors, diagnosis, clinical presentation, and treatment of these infections. History of interventions, trauma, foreign bodies, implants, contact lenses, and steroids are linked to NTM ocular infections. Steroid use may prolong the duration of the infection and cause poorer visual outcomes. Early diagnosis and initiation of treatment with multiple antibiotics are necessary to achieve the best visual outcome. PMID- 26106604 TI - In Pursuit of New Imprinting Syndromes by Epimutation Screening in Idiopathic Neurodevelopmental Disorder Patients. AB - Alterations of epigenetic mechanisms, and more specifically imprinting modifications, could be responsible of neurodevelopmental disorders such as intellectual disability (ID) or autism together with other associated clinical features in many cases. Currently only eight imprinting syndromes are defined in spite of the fact that more than 200 genes are known or predicted to be imprinted. Recent publications point out that some epimutations which cause imprinting disorders may affect simultaneously different imprinted loci, suggesting that DNA-methylation may have been altered more globally. Therefore, we hypothesised that the detection of altered methylation patterns in known imprinting loci will indirectly allow identifying new syndromes due to epimutations among patients with unexplained ID. In a screening for imprinting alterations in 412 patients with syndromic ID/autism we found five patients with altered methylation in the four genes studied: MEG3, H19, KCNQ1OT1, and SNRPN. Remarkably, the cases with partial loss of methylation in KCNQ1OT1 and SNRPN present clinical features different to those associated with the corresponding imprinting syndromes, suggesting a multilocus methylation defect in accordance with our initial hypothesis. Consequently, our results are a proof of concept that the identification of epimutations in known loci in patients with clinical features different from those associated with known syndromes will eventually lead to the definition of new imprinting disorders. PMID- 26106605 TI - DNA Methylation Levels of Melanoma Risk Genes Are Associated with Clinical Characteristics of Melanoma Patients. AB - In melanoma development, oncogenic process is mediated by genetic and epigenetic mutations, and few studies have so far explored the role of DNA methylation either as predisposition factor or biomarker. We tested patient samples for germline CDKN2A methylation status and found no evidence of inactivation by promoter hypermethylation. We have also investigated the association of clinical characteristics of samples with the DNA methylation pattern of twelve genes relevant for melanomagenesis. Five genes (BAP1, MGMT, MITF, PALB2, and POT1) presented statistical association between blood DNA methylation levels and either CDKN2A-mutation status, number of lesions, or Breslow thickness. In tumors, five genes (KIT, MGMT, MITF, TERT, and TNF) exhibited methylation levels significantly different between tumor groups including acral compared to nonacral melanomas and matched primary lesions and metastases. Our data pinpoint that the methylation level of eight melanoma-associated genes could potentially represent markers for this disease both in peripheral blood and in tumor samples. PMID- 26106606 TI - Over-the-Counter Drugs and Complementary Medications Use among Children in Southern Italy. AB - The use of nonprescription medicines (NPDs) for children illnesses without a doctor's suggestion can lead to unnecessary medication use and is not free of risks. The aim of our study was to examine attitudes and practice of parents towards NPDs use for their children. We also investigated the conditions that may predict NPDs use. A cross-sectional survey was conducted on parents of children attending Community Based Pediatrician (CBP) consultation and data were collected through structured interviews. Positive attitude on NPDs use was reported by 71.4% of parents, and 61.5% of them had administered NPDs in the previous 6 months. Antipyretic drugs were the most frequently used medication class without the supervision of the CBP. A positive attitude towards NPDs was significantly more frequent in parents who did not use the CBP as the sole source of information about drugs. The study demonstrated a widespread use of NPDs in children in our context, supported by a substantial positive attitude towards their safety. However, considering potential harms related to some NPDs and the finding that most parents rely on CBP advice, role of CBP on appropriate use of NPDs by parents should be emphasized. PMID- 26106607 TI - miRNA Profiles of Tubular Cells: Diagnosis of Kidney Injury. AB - MicroRNAs (miRNAs) are small noncoding RNAs of 18-23 nucleotides that regulate gene expression. Recently, plasma miRNAs have been investigated as biomarkers for various physiological and pathological conditions. The present study details the conserved miRNA expression profiles of tubular tissues, and discusses whether they could be used to distinguish between proximal tubule injury, diagnose acute kidney injury (AKI), and the early-stage renal tubular dysfunction. miRNA expression was assessed with miRNA array and real-time reverse transcription polymerase chain reaction using the TaqMan system. The expression profiles of miR 200a/b/c, miR-145, miR-192, miR-194, miR-216a/b, miR-217, and miR-449a in human and rat tubular tissues such as the kidneys, lung, small intestine, and various exocrine glands were adequate for discriminating tubular tissues. In the kidney, miR-192 and miR-194 were highly expressed, whereas miR-145 and miR-449a were absent. miR-145 and miR-449a were relatively specifically expressed in small intestine and lung, respectively. Therefore, the combined levels of miR-200a/b/c, miR-192, and miR-194 in plasma were very useful in diagnosing AKI induced by contact freezing in mice. Moreover, urinary miR-200a levels were useful for the diagnosis of renal tubular dysfunction in Dahl salt-sensitive rat with high salt administration. Our results indicate that miRNA expression profiles are useful as biomarkers for identification of various kidney injuries. PMID- 26106608 TI - Theranostic Imaging of Yttrium-90. AB - This paper overviews Yttrium-90 ((90)Y) as a theranostic and nuclear medicine imaging of (90)Y radioactivity with bremsstrahlung imaging and positron emission tomography. In addition, detection and optical imaging of (90)Y radioactivity using Cerenkov luminescence will also be reviewed. Methods and approaches for qualitative and quantitative (90)Y imaging will be briefly discussed. Although challenges remain for (90)Y imaging, continued clinical demand for predictive imaging response assessment and target/nontarget dosimetry will drive research and technical innovation to provide greater clinical utility of (90)Y as a theranostic agent. PMID- 26106610 TI - HMGB1-Induced Cross Talk between PTEN and miRs 221/222 in Thyroid Cancer. AB - High mobility group box 1 (HMGB1) is an ubiquitous protein that plays different roles in the nucleus, cytoplasm, and extracellular space. It is an important DAMP molecule that allows communication between damaged or tumor cells and the immune system. Tumor cells exploit HMGB1's ability to activate intracellular pathways that lead to cell growth and migration. Papillary thyroid cancer is a well differentiated tumor and is often used to study relationships between cells and the inflammatory microenvironment as the latter is characterized by high levels of inflammatory cells and cytokines. Anaplastic thyroid cancer is one of the most lethal human cancers in which many microRNAs and tumor suppressor genes are deregulated. Upregulation of microRNAs 221 and 222 has been shown to induce the malignant phenotype in many human cancers via inhibition of PTEN expression. In this study we suggest that extracellular HMGB1 interaction with RAGE enhances expression of oncogenic cluster miR221/222 that in turn inhibits tumor suppressor gene PTEN in two cell lines derived from human thyroid anaplastic and papillary cancers. The newly identified pathway HMGB1/RAGE/miR221/222 may represent an effective way of tumor escape from immune surveillance that could be used to develop new therapeutic strategies against anaplastic tumors. PMID- 26106609 TI - Molecular Mechanoneurobiology: An Emerging Angle to Explore Neural Synaptic Functions. AB - Neural synapses are intercellular asymmetrical junctions that transmit biochemical and biophysical information between a neuron and a target cell. They are very tight, dynamic, and well organized by many synaptic adhesion molecules, signaling receptors, ion channels, and their associated cytoskeleton that bear forces. Mechanical forces have been an emerging factor in regulating axon guidance and growth, synapse formation and plasticity in physiological and pathological brain activity. Therefore, mechanical forces are undoubtedly exerted on those synaptic molecules and modulate their functions. Here we review current progress on how mechanical forces regulate receptor-ligand interactions, protein conformations, ion channels activation, and cytoskeleton dynamics and discuss how these regulations potentially affect synapse formation, stabilization, and plasticity. PMID- 26106611 TI - Transcriptomic and Immunohistochemical Profiling of SLC6A14 in Pancreatic Ductal Adenocarcinoma. AB - We used a target-centric strategy to identify transporter proteins upregulated in pancreatic ductal adenocarcinoma (PDAC) as potential targets for a functional imaging probe to complement existing anatomical imaging approaches. We performed transcriptomic profiling (microarray and RNASeq) on histologically confirmed primary PDAC tumors and normal pancreas tissue from 33 patients, including five patients whose tumors were not visible on computed tomography. Target expression was confirmed with immunohistochemistry on tissue microarrays from 94 PDAC patients. The best imaging target identified was SLC6A14 (a neutral and basic amino acid transporter). SLC6A14 was overexpressed at the transcriptional level in all patients and expressed at the protein level in 95% of PDAC tumors. Very little is known about the role of SLC6A14 in PDAC and our results demonstrate that this target merits further investigation as a candidate transporter for functional imaging of PDAC. PMID- 26106612 TI - Endoscopic Raman Spectroscopy for Molecular Fingerprinting of Gastric Cancer: Principle to Implementation. AB - Currently, positive endoscopic biopsy is the standard criterion for gastric cancer diagnosis but is invasive, often inconsistent, and delayed although early detection and early treatment is the most important policy. Raman spectroscopy is a spectroscopic technique based on inelastic scattering of monochromatic light. Raman spectrum represents molecular composition of the interrogated volume providing a direct molecular fingerprint. Several investigations revealed that Raman spectroscopy can differentiate normal, dysplastic, and adenocarcinoma gastric tissue with high sensitivity and specificity. Moreover, this technique can indentify malignant ulcer and showed the capability to analyze the carcinogenesis process. Automated on-line Raman spectral diagnostic system raised possibility to use Raman spectroscopy in clinical field. Raman spectroscopy can be applied in many fields such as guiding a target biopsy, optical biopsy in bleeding prone situation, and delineating the margin of the lesion. With wide field technology, Raman spectroscopy is expected to have specific role in our future clinical field. PMID- 26106613 TI - Use of Contrast-Enhanced Ultrasound to Study Relationship between Serum Uric Acid and Renal Microvascular Perfusion in Diabetic Kidney Disease. AB - PURPOSE: To investigate the relationship between uric acid and renal microvascular perfusion in diabetic kidney disease (DKD) using contrast-enhanced ultrasound (CEUS) method. MATERIALS AND METHODS: 79 DKD patients and 26 healthy volunteers were enrolled. Renal function and urine protein markers were tested. DKD patients were subdivided into two groups including a normal serum uric acid (SUA) group and a high SUA group. Contrast-enhanced ultrasound (CEUS) was performed, and low acoustic power contrast-specific imaging was used for quantitative analysis. RESULTS: Normal controls (NCs) had the highest levels of AUC, AUC1, and AUC2. Compared to the normal SUA DKD group, high SUA DKD patients had significantly higher IMAX, AUC, and AUC1 (P < 0.05). DKD patients with low urinary uric acid (UUA) excretion had significantly higher AUC2 compared to DKD patients with normal UUA (P < 0.05). CONCLUSION: Hyperuricemia in DKD patients was associated with a renal ultrasound image suggestive of microvascular hyperperfusion. The CEUS parameter AUC1 holds promise as an indicator for renal microvascular hyperperfusion, while AUC2 might be a useful indicator of declining glomerular filtration rate in DKD patients with decreased excretion of uric acid. PMID- 26106614 TI - The Role of Overweight and Obesity in In Vitro Fertilization Outcomes of Poor Ovarian Responders. AB - OBJECTIVE: Obesity is a worldwide concern with detrimental health effects including decreased fecundity. However, obesity's impact on in vitro fertilization (IVF) is inconclusive and there is little data concerning poor ovarian responders (POR). This study explored the effects of overweight and obesity on IVF outcomes of POR. Design. We retrospectively evaluated 188 POR undergoing IVF cycles. METHODS: Patients were categorized into three groups. Group 1 was normal weight POR (18.5-24.9 kg/m(2), n = 96); Group 2 was overweight POR (25.0-29.9 kg/m(2), n = 52); and Group 3 was obese POR (>=30.0 kg/m(2), n = 40). Main measured outcomes included IVF outcomes. RESULTS: The oocyte maturity, total gonadotropin dose-duration, and cycle cancellation rates were similar. Obese women had significantly decreased LH levels. LH < 4 mIU/mL had a sensitivity (62%) and a specificity (86%) for IVF failure (AUC: 0.71). Fertilization rates of obese subjects were significantly lower than normal and overweight subjects (p = 0.04). Obese women's clinical pregnancy rates were significantly lower (15%) than normal weight women (33.3%, p = 0.01). CONCLUSIONS: Despite similar counts of recruited mature oocytes, obese POR women had decreased fertilization and clinical pregnancy rates. Obesity rather than overweight significantly decreased IVF outcomes in POR. PMID- 26106615 TI - The Kampo Medicine Yokukansan Decreases MicroRNA-18 Expression and Recovers Glucocorticoid Receptors Protein Expression in the Hypothalamus of Stressed Mice. AB - It is well known that glucocorticoid receptor (GR) signaling regulates the hypothalamic-pituitary-adrenal (HPA) axis, and GR expression level is associated with HPA axis activity. Recent studies revealed that microRNA- (miR-) 18 and/or 124a are candidate negative regulators of GR in the brain. The Kampo medicine Yokukansan (YKS) can affect psychological symptoms such as depression and anxiety that are associated with stress responses. In this study, we evaluated the effect of YKS on miR-18 and 124a and GR levels in mice exposed to stress. We found that YKS pretreatment normalized elevated plasma corticosterone levels in stress exposed mice. In addition, GR mRNA levels were downregulated in the brain following stress exposure. While miR-124a expression levels were not altered in the hypothalamus of stress-exposed mice, miR-18 levels decreased in the hypothalamus of YKS-pretreated mice after stress exposure. Finally, GR protein levels in the paraventricular nucleus (PVN) of the hypothalamus after stress exposure recovered in YKS-pretreated mice. Collectively, these data suggest that YKS normalizes GR protein levels by regulating miR-18 expression in the hypothalamus, thus normalizing HPA axis activity following stress exposure. PMID- 26106616 TI - An Open Multicenter Study of Clinical Efficacy and Safety of Urolastic, an Injectable Implant for the Treatment of Stress Urinary Incontinence: One-Year Observation. AB - The prevalence of stress urinary incontinence rises and affects up to 30% of women after 50 years of age. Midurethral slings are currently the mainstay of surgical anti-incontinence therapy. Some patients experience recurrent SUI (RSUI) which is defined as a failure of anti-incontinence surgery after a period of time or persistence of SUI after the procedure aimed at correcting it. The urethral bulking agent application decreases invasiveness of treatment and meets patients requirements. The objective of this study was to assess the safety and clinical efficacy of Urolastic injection. One hundred and five patients with SUI (including 91 patients with RSUI) were treated with Urolastic in three tertiary gynecological clinics. The efficacy of the procedure was assessed objectively at each follow-up visit by means of cough test and a standard 1-hour pad test. Objective success rate after 12 months after primary procedure in RSUI patients was found in 59.3% of patients. In 14 patients with primary SUI improvement after 1 year was found in 71.4% of patients. Although cure rates after MUS are up to 90% there is still place for less invasive treatment option like periurethral injection of bulking agents, especially in patients with previous SUI surgical management. PMID- 26106617 TI - Use of MALDI-TOF MS for Identification of Nontuberculous Mycobacterium Species Isolated from Clinical Specimens. AB - The aim of this study was to compare the results obtained for identification by MALDI-TOF of nontuberculous mycobacteria (NTM) isolated in clinical samples with those obtained by GenoType Mycobacterium CM/AS (common mycobacteria/additional species). A total of 66 Mycobacterium isolates from various clinical specimens (mainly respiratory) were tested in this study. They were identified using MALDI TOF Bruker from strains isolated in Lowenstein, following the recommended protocol of heat inactivation and extraction, and were simultaneously analyzed through hybridization by GenoType Mycobacterium from liquid culture MGIT. Our results showed that identification by MALDI-TOF was correct in 98.4% (65/66) of NTM isolated in our clinical practice (M. avium, M. intracellulare, M. abscessus, M. chelonae, M. fortuitum, M. mucogenicum, M. kansasii, and M. scrofulaceum). MALDI-TOF was found to be an accurate, rapid, and cost-effective system for identification of mycobacteria species. PMID- 26106618 TI - Contrast-Enhanced Ultrasound. PMID- 26106619 TI - Identifying Highly Penetrant Disease Causal Mutations Using Next Generation Sequencing: Guide to Whole Process. AB - Recent technological advances have created challenges for geneticists and a need to adapt to a wide range of new bioinformatics tools and an expanding wealth of publicly available data (e.g., mutation databases, and software). This wide range of methods and a diversity of file formats used in sequence analysis is a significant issue, with a considerable amount of time spent before anyone can even attempt to analyse the genetic basis of human disorders. Another point to consider that is although many possess "just enough" knowledge to analyse their data, they do not make full use of the tools and databases that are available and also do not fully understand how their data was created. The primary aim of this review is to document some of the key approaches and provide an analysis schema to make the analysis process more efficient and reliable in the context of discovering highly penetrant causal mutations/genes. This review will also compare the methods used to identify highly penetrant variants when data is obtained from consanguineous individuals as opposed to nonconsanguineous; and when Mendelian disorders are analysed as opposed to common-complex disorders. PMID- 26106620 TI - Improved Diagnostic Multimodal Biomarkers for Alzheimer's Disease and Mild Cognitive Impairment. AB - The early diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) is very important for treatment research and patient care purposes. Few biomarkers are currently considered in clinical settings, and their use is still optional. The objective of this work was to determine whether multimodal and nonpreviously AD associated features could improve the classification accuracy between AD, MCI, and healthy controls, which may impact future AD biomarkers. For this, Alzheimer's Disease Neuroimaging Initiative database was mined for case control candidates. At least 652 baseline features extracted from MRI and PET analyses, biological samples, and clinical data up to February 2014 were used. A feature selection methodology that includes a genetic algorithm search coupled to a logistic regression classifier and forward and backward selection strategies was used to explore combinations of features. This generated diagnostic models with sizes ranging from 3 to 8, including well documented AD biomarkers, as well as unexplored image, biochemical, and clinical features. Accuracies of 0.85, 0.79, and 0.80 were achieved for HC-AD, HC-MCI, and MCI-AD classifications, respectively, when evaluated using a blind test set. In conclusion, a set of features provided additional and independent information to well-established AD biomarkers, aiding in the classification of MCI and AD. PMID- 26106621 TI - Specific Proteins in Nontuberculous Mycobacteria: New Potential Tools. AB - Nontuberculous mycobacteria (NTM) have been isolated from water, soil, air, food, protozoa, plants, animals, and humans. Although most NTM are saprophytes, approximately one-third of NTM have been associated with human diseases. In this study, we did a comparative proteomic analysis among five NTM strains isolated from several sources. There were different numbers of protein spots from M. gordonae (1,264), M. nonchromogenicum type I (894), M. nonchromogenicum type II (935), M. peregrinum (806), and M. scrofulaceum/Mycobacterium mantenii (1,486) strains, respectively. We identified 141 proteins common to all strains and specific proteins to each NTM strain. A total of 23 proteins were selected for its identification. Two of the common proteins identified (short-chain dehydrogenase/reductase SDR and diguanylate cyclase) did not align with M. tuberculosis complex protein sequences, which suggest that these proteins are found only in the NTM strains. Some of the proteins identified as common to all strains can be used as markers of NTM exposure and for the development of new diagnostic tools. Additionally, the specific proteins to NTM strains identified may represent potential candidates for the diagnosis of diseases caused by these mycobacteria. PMID- 26106623 TI - Triglyceride High-Density Lipoprotein Ratios Predict Glycemia-Lowering in Response to Insulin Sensitizing Drugs in Type 2 Diabetes: A Post Hoc Analysis of the BARI 2D. AB - Glycemic management is central in prevention of small vessel and cardiovascular complications in type 2 diabetes. With the plethora of newer medications and recommendations for a patient centered approach, more information is necessary to match the proper drug to each patient. We showed that BARI 2D, a five-year trial designed to compare two different glycemic treatment strategies, was suitable for assessing different responses according to different phenotypic characteristics. Treatment with insulin sensitizing medications such as thiazolidinediones and metformin was more effective in improving glycemic control, particularly in the more insulin resistant patient, when compared to the insulin provision strategy using insulin and or sulfonylureas. Triglyceride and high density lipoprotein ratio (TG/HDL-cholesterol ratio) was found to be a readily available and practical biomarker that helps to identify the insulin resistant patient. These results support the concept that not all medications for glycemic control work the same in all patients. Thus, tailored therapy can be done using phenotypic characteristics rather than a "one-size-fits-all approach." PMID- 26106622 TI - Could Histoplasma capsulatum Be Related to Healthcare-Associated Infections? AB - Healthcare-associated infections (HAI) are described in diverse settings. The main etiologic agents of HAI are bacteria (85%) and fungi (13%). Some factors increase the risk for HAI, particularly the use of medical devices; patients with severe cuts, wounds, and burns; stays in the intensive care unit, surgery, and hospital reconstruction works. Several fungal HAI are caused by Candida spp., usually from an endogenous source; however, cross-transmission via the hands of healthcare workers or contaminated devices can occur. Although other medically important fungi, such as Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Histoplasma capsulatum, have never been considered nosocomial pathogens, there are some factors that point out the pros and cons for this possibility. Among these fungi, H. capsulatum infection has been linked to different medical devices and surgery implants. The filamentous form of H. capsulatum may be present in hospital settings, as this fungus adapts to different types of climates and has great dispersion ability. Although conventional pathogen identification techniques have never identified H. capsulatum in the hospital environment, molecular biology procedures could be useful in this setting. More research on H. capsulatum as a HAI etiologic agent is needed, since it causes a severe and often fatal disease in immunocompromised patients. PMID- 26106625 TI - Evacuation after the Fukushima Daiichi Nuclear Power Plant Accident Is a Cause of Diabetes: Results from the Fukushima Health Management Survey. AB - The Great East Japan Earthquake and Fukushima Daiichi nuclear disaster in 2011 forced the evacuation of a large number of residents and created changes in the lifestyle of the evacuees. These changes may have affected the evacuees' glucose metabolism, thereby leading to an increase in the incidence of diabetes. This study included Japanese men and women who were living near the Fukushima Daiichi Nuclear Power Plant in Fukushima prefecture before the disaster. Subjects subsequently underwent annual health checkups with a focus on metabolic syndromes, which were conducted under the Health Care Insurers. Using the Comprehensive Health Check survey, we analyzed changes in the glucose metabolism before and after the disaster. A total of 27,486 subjects underwent follow-up examinations after the disaster, with a mean follow-up period of 1.6 years. After the disaster, the prevalence of diabetes increased significantly, and we observed that the incidence of diabetes was significantly greater among evacuees than among nonevacuees. Furthermore, multivariate logistic regression analysis revealed that evacuation was significantly associated with the incidence of diabetes. In conclusion, this is the first study to demonstrate that evacuation is associated with the incidence of diabetes. This information may be used to guide follow-up recommendations for evacuees. PMID- 26106624 TI - Epigenetic Changes in Endothelial Progenitors as a Possible Cellular Basis for Glycemic Memory in Diabetic Vascular Complications. AB - The vascular complications of diabetes significantly impact the quality of life and mortality in diabetic patients. Extensive evidence from various human clinical trials has clearly established that a period of poor glycemic control early in the disease process carries negative consequences, such as an increase in the development and progression of vascular complications that becomes evident many years later. Importantly, intensive glycemic control established later in the disease process cannot reverse or slow down the onset or progression of diabetic vasculopathy. This has been named the glycemic memory phenomenon. Scientists have successfully modelled glycemic memory using various in vitro and in vivo systems. This review emphasizes that oxidative stress and accumulation of advanced glycation end products are key factors driving glycemic memory in endothelial cells. Furthermore, various epigenetic marks have been proposed to closely associate with vascular glycemic memory. In addition, we comment on the importance of endothelial progenitors and their role as endogenous vasoreparative cells that are negatively impacted by the diabetic milieu and may constitute a "carrier" of glycemic memory. Considering the potential of endothelial progenitor based cytotherapies, future studies on their glycemic memory are warranted to develop epigenetics-based therapeutics targeting diabetic vascular complications. PMID- 26106626 TI - Glucose Metabolism Effects of Vitamin D in Prediabetes: The VitDmet Randomized Placebo-Controlled Supplementation Study. AB - Epidemiological evidence suggests a role for vitamin D in type 2 diabetes prevention. We investigated the effects of vitamin D3 supplementation on glucose metabolism and inflammation in subjects with prediabetes. A 5-month randomized, double-blind, placebo-controlled intervention with three arms (placebo, 40 MUg/d, or 80 MUg/d vitamin D3) was carried out among sixty-eight overweight (BMI 25-35) and aging (>=60 years) subjects from Finland, with serum 25-hydroxyvitamin D3 [25(OH)D3] < 75 nmol/L and either impaired fasting glucose or impaired glucose tolerance. Analyses included 66 subjects who completed the trial. Glucose metabolism was evaluated by fasting and 2-hour oral glucose tolerance test derived indices and glycated hemoglobin. Inflammation was evaluated by high sensitive C-reactive protein and five cytokines. Although a dose-dependent increase in serum 25(OH)D3 over the supplementation period was observed (P trend < 0.001), there were no other statistically significant differences in changes in the 13 glucose homeostasis indicators between the study groups other than increase in the 120 min glucose concentration (P trend = 0.021) and a decreasing trend both in 30 min plasma insulin (P trend = 0.030) and glycated hemoglobin (P trend = 0.024) concentrations. A borderline statistically significant decreasing trend in interleukin-1 receptor antagonist concentration was observed (P = 0.070). Vitamin D3 supplementation does not improve glucose metabolism in ageing subjects with prediabetes but may have modest anti-inflammatory effects. PMID- 26106628 TI - Polyamide as a Denture Base Material: A Literature Review. AB - The purpose of this article was to review the biocompatibility, physical, and mechanical properties of the polyamide denture base materials. An electronic search of scientific papers from 1990-2014 was carried out using PubMed, Scopus and Wiley Inter Science engines using the search terms "nylon denture base" and "polyamide denture base". Searching the key words yielded a total of 82 articles. By application of inclusion criteria, the obtained results were further reduced to 24 citations recruited in this review. Several studies have evaluated various properties of polyamide (nylon) denture base materials. According to the results of the studies, currently, thermo-injectable, high impact, flexible or semi flexible polyamide is thought to be an alternative to the conventional acrylic resins due to its esthetic and functional characteristics and physicochemical qualities. It would be justifiable to use this material for denture fabrication in some cases such as severe soft/ hard tissue undercuts, unexplained repeated fracture of denture, in aesthetic-concerned patients, those who have allergy to other denture base materials, and in patients with microstomia. Although polyamide has some attractive advantages, they require modifications to produce consistently better properties than the current polymethyl methacrylate (PMMA) materials. Moreover, since there is a very limited knowledge about their clinical performance, strict and careful follow-up evaluation of the patients rehabilitated with polyamide prosthesis is recommended. PMID- 26106627 TI - Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis. AB - In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4(+) regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naive CD4(+) T cells to CD4(+) regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4(+) regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance. . PMID- 26106629 TI - Immunohistochemical Expression of Mast Cell in Oral Reactive Lesions. AB - STATEMENT OF THE PROBLEM: Soft tissue reactive lesions are the most common lesions of the oral cavity. Although many studies have shown the interaction of mast cells with fibroblasts and their participation in fibrosis, the role of mast cells in these lesions is not well understood. PURPOSE: The aim of this study was to evaluate the mast cells (MCs) count in oral soft-tissue reactive lesions including peripheral giant cell granuloma (PGCG), peripheral ossifying fibroma (POF), irritation fibroma (IF) and normal oral mucosa. MATERIALS AND METHOD: In this cross-sectional study, 50 samples including IF, PGCG, POF (14 cases for each group) and 8 cases of normal oral mucosa were stained with tryptase antibody through immunohistochemistry. The number of mast cells was counted in 5HPF containing maximum counts for each section stained with tryptase. Statistical analysis including Chi-square test and Tukey test with a significance level of 0.05 were considered. RESULTS: The number of MCs was found to have increased in reactive lesions compared with normal oral mucosa. MCs count in the POF group was higher than the others. CONCLUSION: These findings suggest a possible role of mast cells in the pathogenesis of reactive oral lesions and induction of fibrous tissues. Chemical mediators released from mast cells might influence other cells, especially fibroblasts, to induce fibrosis. PMID- 26106630 TI - Resistance to Sliding in Clear and Metallic Damon 3 and Conventional Edgewise Brackets: an In vitro Study. AB - STATEMENT OF THE PROBLEM: Frictional forces are considered as important counterforce to orthodontic tooth movement. It is claimed that self-ligating brackets reduce the frictional forces. PURPOSE: The aim of this study was to compare the resistance to sliding in metallic and clear Damon brackets with the conventional brackets in a wet condition. MATERIALS AND METHOD: The samples included 4 types of brackets; metallic and clear Damon brackets and metallic and clear conventional brackets (10 brackets in each group). In this study, stainless steel wires sized 0.019*0.025 were employed and the operator's saliva was used to simulate the conditions of oral cavity. The tidy-modified design was used for simulation of sliding movement. The resistance to sliding and static frictional forces was measured by employing Testometric machine and load cell. RESULTS: The mean (+/-SD) of resistance to sliding was 194.88 (+/-26.65) and 226.62 (+/-39.9) g in the esthetic and metallic Damon brackets, while these values were 187.81(+/ 27.84) and 191.17(+/-66.68) g for the clear and metallic conventional brackets, respectively. Static frictional forces were 206.4(+/-42.45) and 210.38(+/-15.89) g in the esthetic and metallic Damon brackets and 220.63(+/-49.29) and 215.13(+/ 62.38) g in the clear and metallic conventional brackets. According to two-way ANOVA, no significant difference was observed between the two bracket materials (clear and metal) and the two types of bracket (self-ligating versus conventional) regarding resistance to sliding (p= 0.17 and p= 0.23, respectively) and static frictional forces (p= 0.55 and p= 0.96, respectively). CONCLUSION: Neither the type of bracket materials nor their type of ligation made difference in resistance to sliding and static friction. PMID- 26106631 TI - Video-based Learning Versus Traditional Method for Preclinical Course of Complete Denture Fabrication. AB - STATEMENT OF THE PROBLEM: Advances in computer science and technology allow the instructors to use instructional multimedia programs to enhance the process of learning for dental students. PURPOSE: The purpose of this study was to determine the effect of a new educational modality by using videotapes on the performance of dental students in preclinical course of complete denture fabrication. MATERIALS AND METHOD: This quasi-experimental study was performed on 54 junior dental students in Shahid Beheshti University of Medical Sciences (SBMU). Twenty five and 29 students were evaluated in two consecutive semesters as controls and cases, respectively for the same course. The two groups were matched in terms of "knowledge about complete denture fabrication" and "basic dental skills" using a written test and a practical exam, respectively. After the intervention, performance and clinical skills of students were assessed in 8 steps. Eventually, a post-test was carried out to find changes in knowledge and skills of students in this regard. RESULTS: In the two groups with the same baseline level of knowledge and skills, independent T-test showed that students in the test group had a significantly superior performance in primary impression taking (p= 0.001) and primary cast fabrication (p= 0.001). In terms of anterior teeth set up, students in the control group had a significantly better performance (p= 0.001). CONCLUSION: Instructional videotapes can aid in teaching fabrication of complete denture and are as effective as the traditional teaching system. PMID- 26106632 TI - The Efficacy of Two Intravenous Sedative Drugs in Management of Uncooperative Children for Dental Treatments. AB - STATEMENT OF THE PROBLEM: Some children do not show an appropriate cooperation with their dentist. A number of them cannot be managed by local anesthesia and the usual techniques used to control behaviors, so further steps are required to control their pain and anxiety. Pharmaceutical control is recommended through sedation or general anesthesia. PURPOSE: This study was aimed to evaluate two groups of drugs in intravenous sedation method. MATERIALS AND METHOD: In this clinical trial intervention study, patients were randomly divided into two groups of 18 and 20 and each group received either intravenous midazolam-ketamine or midazolam-fentanyl. During the procedure, 0.25mg midazolam was administered to both groups if needed. The scores of intraoperative sedation and operation conditions were evaluated and recorded by dental sedation teacher groups (DSTG) system in the 10(th), 20(th), 30(th) and 40(th) minutes of the operation. The results were analyzed by SPSS (version 16) using independent T-test, Wilcoxon, Mann-Whitney and Pearson Chi-Square tests as appropriated. RESULTS: There was no significant difference between the two groups in sedation period (p= 0.55), recovery time (p= 0.18), Frankl score (p= 0.83(, score of intraoperative sedation and operating conditions (p> 0.05), and sedation complications (p= 0.612). In addition, no complication occurred in recovery. CONCLUSION: There was no significant difference between the two drug groups; both were appropriate in controlling children's behavior. PMID- 26106633 TI - The Effect of Thyroid Hormone, Prostaglandin E2, and Calcium Gluconate on Orthodontic Tooth Movement and Root Resorption in Rats. AB - STATEMENT OF THE PROBLEM: A major objective of investigators is to clarify the role of metabolites in achievement of maximum tooth movement with minimal root damage during orthodontic tooth movement (OTM). PURPOSE: The aim of this study was to determine the effect of administration of thyroid hormone, prostaglandin E2, and calcium on orthodontic tooth movement and root resorption in rats. MATERIALS AND METHOD: Sixty four male Wistar rats were randomly divided into 8 groups of eight rats each: 1- 20ug/kg thyroxine was injected in traperitoneally after installation of the orthodontic appliance. 2- 0.1 ml of 1 mg/ml prostaglandin E2 was injected submucosally. 3- 10% (200 mg/kg) calcium gluconate was injected. 4- Prostaglandin E2 was injected submucosally and 10% calcium was injected intraperitoneally. 5- Thyroxine was injected intraperitoneally and prostaglandin E2 was injected submucosally. 6- 20ug/kg thyroxine with calcium was injected. 7- Prostaglandin E2 was injected submucosally with calcium and thyroxine. 8- Distilled water was used in control group. The orthodontic appliances comprised of a NiTi closed coil were posteriorly connected to the right first molar and anteriorly to the upper right incisor. OTM was measured with a feeler gauge. The mid-mesial root of the first molar and the adjacent tissues were histologically evaluated. The Data were analyzed by one-way ANOVA and Student-Newman-Keuls test. RESULTS: The highest mean OTM was observed in the thyroxine and prostaglandin E2 group (Mean+/-SD = 0.7375+/-0.1359 mm) that was significantly different (p< 0.05). A significant difference (p< 0.05) in root resorption was observed between the prostaglandin E2 (0.0192+/-0.0198 mm(2)) and the other groups. CONCLUSION: It seems that the combination of thyroxine and prostaglandin E2, with a synergistic effect, would decrease the root resorption and increase the rate of orthodontic tooth movement in rats. PMID- 26106634 TI - Orthognathic Surgery Patients (Maxillary Impaction and Setback plus Mandibular Advancement plus Genioplasty) Need More Intensive Care Unit (ICU) Admission after Surgery. AB - STATEMENT OF THE PROBLEM: Due to shortage of ICU beds in hospitals, knowing what kind of orthognathic surgery patients more need ICU care after surgery would be important for surgeons and hospitals to prevent unnecessary ICU bed reservation. PURPOSE: The aim of the present study was to determine what kinds of orthognathic surgery patients would benefit more from ICU care after surgery. MATERIALS AND METHOD: 210 patients who were admitted to Chamran Hospital, Shiraz, for bimaxillary orthognathic surgery (2008-2013) were reviewed based on whether they had been admitted to ICU or maxillofacial surgery ward. Operation time, sex, intraoperative Estimated Blood Loss (EBL), postoperative complications, ICU admission, and unwanted complications resulting from staying in ICU were assessed. RESULTS: Of 210 patients undergoing bimaxillary orthognathic surgery, 59 patients (28.1%) were postoperatively admitted to the ICU and 151 in the maxillofacial ward (71.9%). There was not statistically significant difference in age and sex between the two groups (p> 0.05). The groups were significantly different in terms of operation time (p< 0.001). Blood loss For ICU admitted patients was 600.00+/-293.621mL and for those who were hospitalized in the ward was 350.00+/-298.397 mL. Statistically significant differences were found between the two groups (p< 0.001). Moreover, there was a direct linear correlation between operation time and intraoperative estimated blood loss and this relationship was statistically significant (r=0.42, p< 0.001). Patients with maxillary impaction and setback plus mandibular advancement plus genioplasty were among the most ICU admitted patients (44%), while these patients were only 20% of all patients who were admitted to the ward. As a final point, the result illustrated that patients who were admitted to the ICU experienced more complication such as bleeding, postoperative nausea, and pain (p< 0.001). CONCLUSION: Orthognathic surgery patients (maxillary impaction and setback plus mandibular advancement plus genioplasty) due to more intraoperative bleeding and postoperative nausea and pain would benefit from ICU admission after surgery. PMID- 26106635 TI - Effect of Different Instrumentation Techniques on Vertical Root Fracture Resistance of Endodontically Treated Teeth. AB - STATEMENT OF THE PROBLEM: Vertical root fractures are catastrophic events that often result in tooth extraction. Many contributing factor are associated with increasing incidence of vertical root fracture. Root canal preparation is one of the predisposing factors which can increase the root susceptibility to vertical fracture. PURPOSE: The aim of this study was to compare the effects of three different instrumentation techniques on vertical root fracture resistance of endodontically treated teeth. MATERIALS AND METHODS: In this study, 120 freshly extracted mandibular premolar teeth of similar dimensions were decoronated and randomly divided into control (n=30), nickel-titanium hand K-file (HF, n=30), BioRaCe rotary file (BR, n=30), and WaveOne reciprocating single-file (WO, n=30) groups. After cleaning and shaping the root canals, AH26 was used as canal sealer, and obturation was completed using the continuous wave technique. The root canals were embedded vertically in standardised autopolymerising acrylic resin blocks, and subjected to a vertical load to cause vertical root fracture. The forces required to induce fractures were measured using a universal testing machine. ANOVA and Tukey's post-hoc test were used to analyse the data. RESULTS: All experimental groups showed statistically significant reductions in fracture resistance as compared with the control group. There was a statistically significant difference between the HF and BR groups. The WO group did not differ significantly from the HF group or the BR group. CONCLUSION: All three instrumentation techniques caused weakening of the structure of the roots, and rendered them susceptible to fracture under lesser load than unprepared roots. The fracture resistance of roots prepared with the single-file reciprocating technique was similar to that of those prepared with NiTi hand and rotary instrumentation techniques. PMID- 26106636 TI - Management of Post-orthodontic White Spot Lesions and Subsequent Enamel Discoloration with Two Microabrasion Techniques. AB - STATEMENT OF THE PROBLEM: Demineralization of enamel adjacent to orthodontic appliances frequently occurs, commonly due to insufficient oral hygiene. PURPOSE: The aim of this study was to compare two microabrasion techniques on improving the white spot lesions as well as subsequent enamel discoloration. MATERIALS AND METHOD: Sixty extracted premolar teeth without caries and hypoplasia were selected for this study. White spot lesions were artificially induced on the buccal surface of each tooth. Teeth were randomly assigned to three treatment groups, each treated with pumice powder as the control, microabrasion with 18% HCl, and microabrasion with 37% H3PO4. Subsequently, the three groups were daily immersed for five minutes in a tea-coffee solution for a period of one week. Colorimetric evaluation was done before and after formation of white spot lesions, after microabrasion, and after immersion in the colored solution; then the color differences (?E) were calculated. Statistical analysis was performed by multiple measurement analysis and the Tukey's test. RESULTS: This study showed that ?E between the stages of white spot formation and microabrasion for H3PO4 was more than other groups and for the pumice powder group it was less than the others. Furthermore, there was a significant difference between ?E of the three study groups (p= 0.017). Additionally, ?E after placing the teeth in the colored solution and microabrasion was the highest for the HCl group and the lowest for the pumice powder group. There was also a significant difference between the three groups (p= 0.000). CONCLUSION: Pumice powder alone had similar effects as 18% HCl on removing the white spot lesions. Nevertheless, 18% HCl makes the enamel susceptible for subsequent color staining more than the other microabrasion methods. PMID- 26106637 TI - The Effects of New Design of Access Hole on Porcelain Fracture Resistance of Implant-Supported Crowns. AB - STATEMENT OF THE PROBLEM: One disadvantage of cement-retained crowns is the lack of predictable irretrievability. This problem can be overcome through designing a screw access hole in the metal substructure of cement-retained restoration and using porcelain stain to define this area. PURPOSE: This study aimed to evaluate the influence of existence of screw access hole on porcelain fracture resistance of metal-ceramic implant-supported crowns. MATERIALS AND METHOD: Thirty six standardized metal-ceramic crowns were fabricated and divided into 3 groups (n=12); group 1 conventional cement-retained metal-ceramic crowns as control group, group 2 cement-retained MC crowns in which porcelain stain was used to define the location of screw access channel, and group 3 cement-retained metal ceramic crowns in the metal substructure of which a hole and ledge was designed in the location of screw access channel. The specimens were cemented (TempBond, Kerr) to their dedicated abutments. A hole was made in the location of screw access channel in group 2 and 3 and filled with photo-polymerized composite resin (3M; ESPE). All specimens were thermocycled and loaded in universal testing machine at crosshead speed of 2mm/min until fracture. Mean values of load at fracture were calculated in each group and compared with One-way ANOVA (alpha=0.05). RESULTS: Mean value of the load required to fracture the restorations was 1947+/-487 N in group 1, 1927+/-539 N in group 2, and 2170+/-738 N in group 3. No statistically significant difference was found between the fracture resistance values of the three groups (p> 0.05). CONCLUSION: Presence of screw access channel in cement-retained implant restorations does not compromise fracture resistance. PMID- 26106638 TI - The Effects of Denture Cleansing Solutions on the Retention of Attachments of Implant Supported Overdentures. AB - STATEMENT OF THE PROBLEM: Implant-retained overdenture can improve the stability of dentures and prevent bone loss. Overdenture-wearing patients need special hygiene care. PURPOSE: The aim of this study was to evaluate the effects of various denture cleansers on the retention of Dio orange O-rings. METHOD AND MATERIALS: In this experimental study, 40 Dio orange O-rings were divided into 4 groups (10 O-rings each) and each group was soaked for equivalent of 6 months in the following solutions: 5.25% NaOCl (1:10 dilution), Corega cleanser tabs, Professional cleanser tabs and water (as the control group). After 6 months, O rings were tested for 2inch/minutes of tensile force. The peak load-to dislodgement was recorded. Data were imported to SPSS18 and were analyzed by One Way ANOVA and Tukey HSD test (p<= 0.05). RESULTS: Denture cleansing solutions have significant effects on the reduction of retentive value of O-rings (p<= 0.001). Corega tabs caused the reduction of 15.7% (9.91+/-0.53 N) in the retentive value of O-rings and Professional tabs caused 15% (10.00+/-0.86 N). NaOCl caused significant decrease (48%) in retentive value of O-rings (6.10+/ 0.91 N in comparison with the control group (11.76+/-1 N). CONCLUSION: This in vitro study demonstrated that the retention of O-rings was affected when soaked in cleansing solutions. NaOCl caused more reduction in retentive value compared to effervescent cleansers and would not be recommended for cleansing O-rings. These results should be interpreted clinically and the role of other factors in the retention of O-rings should be considered in order to recommend the best cleanser for O-ring overdentures. PMID- 26106639 TI - Elastofibroma of the Face: A Case Report. AB - Elastofibroma is a rare neoplasm that characteristically occurs in subscapular area in response to microtrauma. There are some reports of this tumor in other sites of the body but, up till now, there has been no report of elastofibroma in the face. A 20-year-old man presented with a slow growing painless mass in the face without any history of trauma. Histopathologic examination revealed a soft tissue mass composed of eosinophilic fibers admixed with aggregation of fat cells, capillary blood vessels, and fibroblasts. Elastic stain and Masson's trichrome stain confirmed the nature of elastic and collagen fibers. It was a case of elastofibroma in the face. PMID- 26106640 TI - Multidimensional QoE of Multiview Video and Selectable Audio IP Transmission. AB - We evaluate QoE of multiview video and selectable audio (MVV-SA), in which users can switch not only video but also audio according to a viewpoint change request, transmitted over IP networks by a subjective experiment. The evaluation is performed by the semantic differential (SD) method with 13 adjective pairs. In the subjective experiment, we ask assessors to evaluate 40 stimuli which consist of two kinds of UDP load traffic, two kinds of fixed additional delay, five kinds of playout buffering time, and selectable or unselectable audio (i.e., MVV-SA or the previous MVV-A). As a result, MVV-SA gives higher presence to the user than MVV-A and then enhances QoE. In addition, we employ factor analysis for subjective assessment results to clarify the component factors of QoE. We then find that three major factors affect QoE in MVV-SA. PMID- 26106642 TI - Effects of Organized Physical Activity on Selected Health Indices among Women Older than 55 Years. AB - The main aim of this study was to determine health benefits among women older than 55 years who participated in organized, group-based physical activity (OPA). Thirty-five women aged 65.0 +/- 7.3 years volunteered for this study. The classical and nonclassical cardiovascular (CVD) risk factors were measured before and after a 2-week OPA camp in a remote location and 3 months of OPA. Self-guided physical activity was analyzed 18 months after OPA. Two-week effects included significant decreases in body mass index, waist and hip circumferences, resting systolic and diastolic blood pressure (BP) and resting heart rate, improved exercise capacity (EC), improved low-density lipoprotein and high-density lipoprotein (HDL-C), cholesterol, and other atherogenic lipid indices (ALI), and a reduction in 10-year estimated risk of death from CVD. Three-month effects included a further decrease in systolic BP, improvements in EC and HDL-C, and maintenance of lower levels of ALI, as well as lower CVD risk. The implementation of the OPA programme had a positive impact on somatic features, exercise capacity, biochemical indices, and risk for death from CVD. The presented programme can be regarded as an effective element of primary prevention of cardiovascular diseases among women older than 55 years. PMID- 26106643 TI - Comparison of the Anesthetic Techniques. PMID- 26106645 TI - Stroboscopic Surface Thermal Lensing for Fast Detection of Thermal Defects in Large-Scaled Coating Films. AB - A stroboscopic surface thermal lensing (SSTL) system for the fast detection of thermal-induced defects in large-scaled optical coating films was constructed. The SSTL signal was generated by a set of double-modulators and captured by a high speed matrix camera, respectively. The spot size of both pump laser and probe laser expanded for larger detection area was finished in a single step. Based on the STL technique, both the mapping of amplitude and the phase of SSTL signal on the whole area of the coatings can be achieved simultaneously. PMID- 26106641 TI - Exhaled Breath Condensate: Technical and Diagnostic Aspects. AB - PURPOSE: The aim of this study was to evaluate the 30-year progress of research on exhaled breath condensate in a disease-based approach. METHODS: We searched PubMed/Medline, ScienceDirect, and Google Scholar using the following keywords: exhaled breath condensate (EBC), biomarkers, pH, asthma, gastroesophageal reflux (GERD), smoking, COPD, lung cancer, NSCLC, mechanical ventilation, cystic fibrosis, pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis, interstitial lung diseases, obstructive sleep apnea (OSA), and drugs. RESULTS: We found 12600 related articles in total in Google Scholar, 1807 in ScienceDirect, and 1081 in PubMed/Medline, published from 1980 to October 2014. 228 original investigation and review articles were eligible. CONCLUSIONS: There is rapidly increasing number of innovative articles, covering all the areas of modern respiratory medicine and expanding EBC potential clinical applications to other fields of internal medicine. However, the majority of published papers represent the results of small-scale studies and thus current knowledge must be further evaluated in large cohorts. In regard to the potential clinical use of EBC analysis, several limitations must be pointed out, including poor reproducibility of biomarkers and absence of large surveys towards determination of reference normal values. In conclusion, contemporary EBC-analysis is an intriguing achievement, but still in early stage when it comes to its application in clinical practice. PMID- 26106644 TI - A Review on Pharmacological Properties of Zingerone (4-(4-Hydroxy-3 methoxyphenyl)-2-butanone). AB - Humans have been using natural products for medicinal use for ages. Natural products of therapeutic importance are compounds derived from plants, animals, or any microorganism. Ginger is also one of the most commonly used condiments and a natural drug in vogue. It is a traditional medicine, having some active ingredients used for the treatment of numerous diseases. During recent research on ginger, various ingredients like zingerone, shogaol, and paradol have been obtained from it. Zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) is a nontoxic and inexpensive compound with varied pharmacological activities. It is the least pungent component of Zingiber officinale. Zingerone is absent in fresh ginger but cooking or heating transforms gingerol to zingerone. Zingerone closely related to vanillin from vanilla and eugenol from clove. Zingerone has potent anti-inflammatory, antidiabetic, antilipolytic, antidiarrhoeic, antispasmodic, and so forth properties. Besides, it displays the property of enhancing growth and immune stimulation. It behaves as appetite stimulant, anxiolytic, antithrombotic, radiation protective, and antimicrobial. Also, it inhibits the reactive nitrogen species which are important in causing Alzheimer's disease and many other disorders. This review is written to shed light on the various pharmacological properties of zingerone and its role in alleviating numerous human and animal diseases. PMID- 26106646 TI - Human Leucocyte Antigen Profile and Transmission of Mutans Streptococci in Mother Child Pairs. AB - PURPOSE: To investigate possible association between the transmission of mutans streptococci and sharing the immune system component Human Leucocyte Antigen (HLA) class II in mother-child pairs. MATERIAL AND METHODS: Plaque samples from 43 mother-child pairs were cultivated and screened for mutans streptococci. In 14 pairs where both mother and child harboured the bacteria, the strains were genotyped by Random Amplified Polymorphic DNA and samples were run on PAGE gels. Analysis of genetic identity between mother and child strains was performed with help of software and Dice similarity index. The distribution of HLA of serogroup DR4 (HLA DR4) was studied in relation to maternal transmission and mutans streptococci colonisation in children. The study hypothesis was that in pairs where both mother and child were HLA DR4 positive, transmission of mutans streptococci was more likely. RESULTS: No correlation between the presence of HLA DR4 in mother and child and maternal transmission of mutans streptococci was established. However, the results showed no linkage between mutans streptococci colonisation and HLA DR 4. Of 15 children with mutans streptococci, 12 were HLA DR4 positive. CONCLUSION: The result suggests that presence of HLA DR4 could be a predisposing factor for colonisation with mutans streptococci in children. PMID- 26106647 TI - Bisphosphonates: Clinical Applications and Adverse Events in Dentistry. AB - PURPOSE: To review the mechanisms of action and clinical applications of bisphosphonate drugs, which are widely used in the management of metastatic bone cancer and systemic metabolic bone diseases, as well as the complications related to bisphosphonate treatment, emphasising the occurrence and management of bisphosphonate-related osteonecrosis of the jaws (BRONJ). MATERIALS AND METHODS: A search of the medical and dental literature was conducted in Medline and Embase using a combination of the key words bisphosphonates, jaw, complications, osteonecrosis, osteoporosis and periodontal disease. A manual search of the references of the retrieved articles was also performed. RESULTS: BRONJ predominantly affects cancer patients being treated with high-dose intravenous bisphosphonates and is characterised by the appearance of necrotic bone in the oral cavity either spontaneously or following an invasive surgical procedure such as dental extraction. The severity of this condition warrants a thorough medical and dental history in every patient in order to identify high risk patients. CONCLUSION: It is important that dental practitioners be aware of the association between bisphosphonate treatment and osteonecrosis of the jaws. Clinicians should perform a thorough oral examination in cancer patients before they begin intravenous bisphosphonate treatment. Optimal oral hygiene and regular dental care can lower BRONJ risk. Further clinical research is necessary to unveil the full therapeutic potential of bisphosphonates, their mechanisms of action and the factors that induce unwanted side-effects. PMID- 26106648 TI - Caries Experience and Distribution by Tooth Surfaces in Primary Molars in the Pre school Child Population of Lodz, Poland. AB - PURPOSE: To evaluate caries experience in primary molars as well as the differences in caries prevalence and caries lesion location on individual tooth surfaces between first and second primary molars in pre-school children. MATERIALS AND METHODS: A cross-sectional study was conducted on 307 children, aged 3 to 5 years, from randomly chosen kindergartens in Lodz, Poland. Caries experience was scored according to WHO recommendations. The caries intensity (dmft, dmfts) for first and second primary molars was calculated. In addition, the percentage of particular surfaces with caries was counted for each molar separately. RESULTS: The mean dmft for primary molars was 1.84 (dmfts=2.47) and dmft>0 was seen in 53.09% of the study subjects. While in the entire examined population dmft and dmfts for first and second molars did not differ significantly, in 5-year-old children, the left mandibular first molar was associated with a higher caries intensity than the left mandibular second molar (dmfts=0.465 vs 0.344, Z=-1.98, p=0.04). However, in 5-year-olds, higher caries occurrence was seen for occlusal surfaces of the tooth 85 than 84 (33.62% vs 20.68%, chi2=4.09, p=0.03). The distal surface was more frequently affected in first molars than in second molars in children aged 4 (85 vs 84, chi2=17.1, p<0.001; 75 vs 74, chi2=11.5, p=0.007, 55 vs 54; chi2=4.6, p=0.03) and 5 years (54 vs 55, chi2=20.09; 64 vs 65, chi2=16.75; 74 vs 75, chi2=21.6; 84 vs 85, chi2=31.07; all comparisons p<0.001). In contrast, the mesial surfaces of mandibular second molars demonstrated more caries than the homologous surfaces of first molars, both in 4-year-olds (85 vs 84, chi2=6.15, p=0.01) and 5-year-olds (75 vs 74, chi2=3.9, p=0.04). CONCLUSION: In 5-year-old children, caries of occlusal and mesial surfaces was more common in primary second molars. However, distal surfaces were affected more in first than second molars. PMID- 26106649 TI - Antibacterial Efficacy of a Propolis Toothpaste and Mouthrinse Against a Supragingival Multispecies Biofilm. AB - PURPOSE: To determine in vitro the antibacterial properties of propolis toothpaste and mouthrinse against an in vitro multispecies biofilm model. MATERIALS AND METHODS: Six-species biofilms grown anaerobically on pellicle coated hydroxyapatite disks were fed with glucose/sucrose-supplemented medium 3 times daily for 45 min and incubated in 37 degrees C saliva between feedings for up to 64.5 h. At each interval, biofilms were exposed to six different slurries and solutions, including: 1) toothpaste without propolis, 2) toothpaste with propolis, 3) toothpaste with chlorhexidine, 4) mouthrinse with propolis, 5) mouthrinse with chlorhexidine, 6) saline solution (control). Afterwards, biofilms were harvested and the number of colony forming units were determined (CFU). The results were analysed using ANOVA, followed by the Bonferroni test at a 5% significance level. RESULTS: The strongest CFU reduction was shown after treatment with 0.12% chlorhexidine (p<0.0004). When comparing the different toothpastes, there was no statistically significant difference (p<0.05) in CFU reduction. However, they all showed a significant reduction in CFU of more than one log-step vs the saline control group. Nevertheless, the propolis-containing mouthrinse showed no significant reduction in CFU. CONCLUSION: All toothpastes under investigation displayed some growth inhibition in this supragingival biofilm model, which accounted for an approximately 80%-88% linear reduction. However, the propolis mouthwash had no effect. PMID- 26106650 TI - Fluoride Varnishes--Is There a Correlation Between Fluoride Release and Deposition on Enamel? AB - PURPOSE: Fluoride uptake of enamel after application of fluoride varnishes was compared with fluoride release into artificial saliva. The hypothesis was that fluoride uptake is higher for products exhibiting faster fluoride release. MATERIALS AND METHODS: Fluoride varnishes, i.e. Fluor Protector S, Duraphat, MI Varnish, Clinpro White Varnish, Profluorid Varnish and Enamel Pro Varnish were applied on bovine enamel specimens. Subsequently, specimens were incubated in artificial saliva. After removal of the varnishes, surface bound fluoride was extracted with potassium hydroxide and measured with an ion-selective electrode. Structurally bound fluoride was etched from the same specimens with perchloric acid. Fluoride release of varnish films into artificial saliva was measured for comparison. RESULTS: After 4 h in artificial saliva, the highest total enamel fluoride uptake of 47.9 MUg F.cm-2 was found with Fluor Protector S, followed by Enamel Pro Varnish with 22.1 MUg F.cm-2. The other products ranged between 12-16 MUg F.cm-2. This was several times higher than the negative control. Fluoride uptake did not correlate with release into artificial saliva. During the first 4 h, Duraphat released the lowest and MI Varnish the highest amount of fluoride with 7.7 and 249 MUg F.cm-2, respectively. The fluoride uptake of these two products was not statistically different. CONCLUSION: Enamel fluoride uptake cannot be predicted from the fluoride release rate of a product. Hence, based on the results of this study, fluoride release into artificial saliva is no measure for the efficacy of a fluoride varnish. PMID- 26106651 TI - Perception of Personal Dental Appearance and Dental Aesthetic Index Score Among 18- to 20-year-old College Students in Rural South India. AB - PURPOSE: To assess the correlation between self-perceived dental appearance and dental malocclusion among 18- to 20-year-old college students in Virajpet, Karnataka. MATERIALS AND METHODS: A stratified random sample consisting of 280 18 to 20-year-old college students in Virajpet were recruited for the study. A pretested Oral Aesthetic Subjective Impact Scale (OASIS) and Visual Analogue Scale (VAS) were used to assess the subjects' perception of dental aesthetics. Malocclusion was clinically assessed using the Dental Aesthetic Index (DAI). The data were tabulated and analysed using SPSS version 16. The Spearman rankorder correlation coefficient was employed to determine the correlation between self perceived dental appearance and dental malocclusion. RESULTS: Of the 280 students, 41.8% were females and 58.2% were males. The mean OASIS score was 23.93 (+/-3.72), the VAS score was 69.61 (+/-15.78) and DAI 24.80 (+/-6.29). CONCLUSION: There was a negative correlation between perception of personal dental appearance and the DAI scores in this group. PMID- 26106652 TI - Self-reported Use of Dental Floss over 13 Years: Relationship with Family Income, Mother's Age and Educational Level. AB - PURPOSE: To determine whether family income, age and educational level of the mother of the family are associated with self-reported use of dental floss over a 13-year period in a city in southern Brazil. MATERIALS AND METHODS: A comparison of two household surveys was carried out where mothers of the family were interviewed using a structured questionnaire in order to obtain demographic, behavioural and socioeconomic information. In total, 852 and 984 households were included in 1996 and 2009, respectively. Self-reported use of dental floss was assessed dichotomously (yes/no). Poisson regression models were fitted to study the association between sociodemographic variables with the use of dental floss. Proportion ratios (PR) and 95% confidence intervals (95% CI) were reported. RESULTS: The proportion of dental floss use increased from 48% to 59% over 13 years. The probability of dental floss use increased 1.23 times from 1996 to 2009 (PR = 1.23; 95% CI 1.13-1.34). Households with mothers >=50 years old presented a 28% lower probability of using dental floss than households with mothers <=35 years old. In households with higher family income and higher educational level of the mother, probabilities of flossing were 90% and 97% higher. CONCLUSION: Family income, age and educational level of the mother of the family are associated with self-reported use of dental floss over 13 years. PMID- 26106653 TI - Oral Infections and Pregnancy: Knowledge of Gynecologists/Obstetricians, Midwives and Dentists. AB - PURPOSE: To establish an inventory of knowledge, attitudes and daily pratice of dental and medical practitioners in France regarding oral health care and its relationship to pregnancy, particularly to preterm delivery and low birth-weight infants. MATERIALS AND METHODS: A questionnaire was distributed to health-care professionals (n= 460), consisting of 100 prenatal care practitioners (obstetricians, midwives) and 360 dentists, about their knowledge of oral alterations during pregnancy, the possible association between periodontal disorders and preterm/low birth weight, and their conduct toward their patients. RESULTS: Bleeding gums and pregnancy gingivitis were the oral manifestations most often cited by all the practitioners. In contrast, prenatal care practitioners were unaware of epulis and a greater percentage of them than dentists believed caries risk to increase during pregnancy. The most adverse pregnancy outcomes cited were risk of premature delivery and chorioamniotis. Only dentists had received initial training on pregnancy complications. Finally, all health professionals point out the lack of continuing education on this topic. CONCLUSION: The present results underline the need for a better initial professional education and continuing education regarding pregnancy and oral health conditions and emphasise the need to update the guidelines in health care practices for pregnant women for a more effective prevention of risk-related adverse pregnancy outcomes, such as pre-term birth or pre-eclampsia. PMID- 26106654 TI - Oral Impacts on Quality of Life in Adult Patients with Class I, II and III Malocclusion. AB - PURPOSE: To compare the social impact of malocclusion on quality of life between adult patients with Angle Class I, II and III malocclusion. MATERIALS AND METHODS: A total of 222 adult patients (139, 42 and 41 with Angle Class I, II and III malocclusion, respectively) were recruited voluntarily from those attending the Orthodontic Clinic of Khyber College of Dentistry in Pesh awar, Pakistan. Participants were asked to complete the Urdu version of the short form of the Oral Health Impact Profile (OHIP-14), which was previously validated for this study. Multivariate analysis of variance (MANOVA) was used to compare the seven OHIP-14 domains scores and the total score between patients with malocclusion Class I, II and III. RESULTS: Adults with Class III malocclusion had a significantly higher OHIP-14 total score than those with Class I malocclusion (a mean difference of 5 units between groups), but there were no differences between other Angle malocclusion groups. In addition, adults with Class III malocclusion reported greater impacts on the three OHIP-14 disability domains (physical, psychological and social) than those with Class I malocclusion. No significant interactions with sex and age were found. CONCLUSION: These findings suggest that adult patients with Class III malocclusion had a poorer quality of life than those with Class I malocclusion. Differences were mainly found in the physical, psychological and social disability domains of the OHIP-14 instrument. PMID- 26106655 TI - Microheterogeneity within conformational states of ubiquitin revealed by high resolution trapped ion mobility spectrometry. AB - The present work employs trapped ion mobility spectrometry (TIMS) for the analysis of ubiquitin ions known to display a multitude of previously unresolved interchangeable conformations upon electrospray ionization. The conformational distributions of ubiquitin [M + 6H](6+) through [M + 13H](13+) ions observed by TIMS are nearly identical to numerous drift tube ion mobility spectrometry studies reported in the literature. At an experimental resolving power up to ~300, many of the congested conformations within the well-known compact, partially folded, and elongated [M + 7H](7+) states are separated. Minimizing the voltages (RF and DC) in the entrance funnel results in exclusive observation of compact [M + 7H](7+) conformers. However, under these conditions, the mobility dependent pseudopotential coefficient may discriminate against ions having larger collision cross sections-a universal effect for all RF ion guides, funnels, and traps operating in the presence of a gas. The data presented underscore the complications associated with direct comparison of collision cross section values that represent an ensemble average of multiple underlying conformations. As illustrated herein, the microheterogeneity within a particular conformational family and the relative state-to-state abundance can be altered by solvent memory, energetic, and kinetic effects. PMID- 26106656 TI - A one-pot domino C-H, C-C activation in coumarins: a fast track to 2,3-diaryl benzo[b]furans. AB - An approach to synthesize 2,3-diaryl benzo[b]furans using coumarins and aryl bromides is developed. This state-of-the-art strategy capitalizes on a palladium catalyzed one-pot decarbonylative diarylation of coumarins, paving the way to achieve biologically interesting 2,3-diaryl benzo[b]furans. PMID- 26106657 TI - Behavioral Hyperventilation and Central Sleep Apnea in Two Children. AB - Behavioral hyperventilation is a rarely recognized cause of central sleep apnea (CSA) among children. We report two pediatric patients who presented with prolonged central sleep apnea secondary to behavioral hyperventilation. One patient also had a prolonged corrected QT (QT(C)) interval resulting from hyperventilation PMID- 26106658 TI - An Alternative Cause for Long Term Changes with Mandibular Advancement Devices. PMID- 26106659 TI - Obituary. Yves Gerard Illouz, MD: 1929 to 2015. PMID- 26106660 TI - Epilepsy-related clinical characteristics and mortality: a systematic review and meta-analysis. PMID- 26106661 TI - Epilepsy-related clinical characteristics and mortality: a systematic review and meta-analysis. PMID- 26106662 TI - Proceedings of the AAAM's 58th Annual Scientific Conference, October 12-15, 2014, Munich, Germany. PMID- 26106663 TI - Proceedings of the 17th International Carotenoid Symposium, June 29-July 4, 2014, Park City, Utah, USA. PMID- 26106664 TI - Proceedings of the 3rd International Conference on Biomedical Engineering and Biotechnology (iCBEB 2014), September 25-28, 2014, Beijing, China. PMID- 26106665 TI - Proceedings of he Power of Programming 2014: International Conference on Developmental Origins of Adiposity and Long-Term Health, March 13-15, 2014, Munich, Germany. PMID- 26106666 TI - Proceedings from the 7th Probiotics, Prebiotics and New Foods Meeting, September 8-12, 2014, Rome, Italy. PMID- 26106667 TI - Special issue as a tribute to Dick Heinegard. PMID- 26106669 TI - Prevention, Use of Health Services, and Genes: Implications of Genetics for Policy Formation. AB - We evaluate the hypothesis that genetic factors influence the use of health services and prevention behaviors in a national sample of adult twins in the United States. The analysis compares the correlation of these outcomes between identical twins, who share all their genes, to the correlation between nonidentical twins, who share, on average, only one-half of their genes. Because the environmental similarities of twins are assumed to be the same for identical and nonidentical twin pairs, researchers can partition the variance in behavioral outcomes that are due to genetic and environmental factors. Using established methods in this field, we find evidence of significant genetic influences on preferences toward prevention, overall prevention effort, routine checkups, and prescription drug use. Use of curative services does not appear to be influenced by genes. Our findings offer several implications for policymakers and researchers and suggest that genetics could be informative for health services and policy research. PMID- 26106670 TI - Intended And Unintended Effects Of The War On Poverty: What Research Tells Us And Implications For Policy. AB - During the mid-1960s, the United States adopted a series of cash and in-kind transfer programs, as well as human capital investment strategies, as part of the War on Poverty. A number of other programs were first proposed as part of this "war" but were not implemented until the mid-1970s. These programs had noble goals: to increase incomes at the bottom of the income distribution, reduce poverty, and improve nutrition, heath, and human capital. However, various features of the programs also had the potential to produce unintended consequences: for example, means-tested programs can discourage work. In this paper, we comprehensively evaluate the main War on Poverty programs that were aimed at the low-income nonelderly population along with several follow-on programs. We focus on both intended and unintended consequences, drawing on the most compelling causal evidence. We conclude with a series of lessons learned and questions that are outstanding. PMID- 26106668 TI - Can Genetics Predict Response to Complex Behavioral Interventions? Evidence from a Genetic Analysis of the Fast Track Randomized Control Trial. AB - Early interventions are a preferred method for addressing behavioral problems in high-risk children, but often have only modest effects. Identifying sources of variation in intervention effects can suggest means to improve efficiency. One potential source of such variation is the genome. We conducted a genetic analysis of the Fast Track randomized control trial, a 10-year-long intervention to prevent high-risk kindergarteners from developing adult externalizing problems including substance abuse and antisocial behavior. We tested whether variants of the glucocorticoid receptor gene NR3C1 were associated with differences in response to the Fast Track intervention. We found that in European-American children, a variant of NR3C1 identified by the single-nucleotide polymorphism rs10482672 was associated with increased risk for externalizing psychopathology in control group children and decreased risk for externalizing psychopathology in intervention group children. Variation in NR3C1 measured in this study was not associated with differential intervention response in African-American children. We discuss implications for efforts to prevent externalizing problems in high risk children and for public policy in the genomic era. PMID- 26106671 TI - Checklist of the earthworm fauna of Croatia (Oligochaeta: Lumbricidae). AB - A checklist of the Croatian earthworm fauna (Oligochaeta: Lumbricidae) is presented, including published records and authors' personal data. This is the first checklist for Croatia only, with comprehensive information for each earthworm species regarding ecological category, habitat, distribution type and distribution in Croatia. The currently known earthworm fauna of Croatia comprises 68 species belonging to 17 genera, with Octodrilus being the species-richest genus (15 species). Chorologically these species can be allocated to 13 different types of distribution. Nineteen species are endemic of which 10 species are endemic to Croatia and 9 species are endemic to Croatia and neighbouring countries (Italy, Slovenia, Hungary, and Montenegro). The endemic earthworms are distributed in the areas of higher altitudes in the Continental and Alpine biogeographic region, mostly covered with forest or autochtonous vegetation. PMID- 26106672 TI - A new shrub frog in the genus Platymantis (Ceratobatrachidae) from the Nakanai Mountains of eastern New Britain Island, Bismarck Archipelago. AB - We describe a new-species of high elevation rainforest shrub frog (genus Platymantis) from the Nakanai Mountains of eastern New Britain (Bismarck Archipelago), Papua New Guinea. The distinctive new species possesses a moderate body size (29.5-32.2 mm in four males), widely expanded finger and toe disks, smooth to slightly granular dorsal skin, low but distinctly protuberant supraocular and tarsal tubercles, a conspicuous series of bright yellow flank areolations, a low but distinct intraocular sagittal crest, bronze-brown iris, and a unique advertisement call. We compare the new species with congeneric New Britain taxa and to other phenotypically similar species from the Solomon Bismarck-Admiralty archipelagos. The new species is phenotypically most similar to P macrosceles Zweifel 1975, and has been collected at only one high elevation site (Tompoi Camp). The available data suggest that the new species, known from 1700 m, is elevationally segregated from P. macroscles (to date, only recorded from 800-900 m in the Nakanai Mountains). New Britain Island has emerged as a major center of endemic ceratobatrachid species diversity. Additional species are anticipated to result from ongoing field work, especially in the western portion of the island, which remains largely unexplored. PMID- 26106673 TI - Intraspecific variation in Typhlocharis Dieck, 1869 (Coleoptera, Carabidae, Anillini): the case of two new species of the baetica group. AB - Two new species of Typhlocharis Dieck, 1869 from the southwest of the Iberian Peninsula included in baetica species group are described: T acutangula n. sp. and T. mixa n. sp. The new species can be easily recognized by the presence of an anterodistal dentiform projection in metatibia (T. acutangula sp.n) and pseudotetramery and a medial tooth in clypeus (T mixta sp.n), features not observed in any other species of the group, but present in quadridentata and gomezi groups respectively. An updated key of baetica group is provided. The large series of T. mixta n. sp. allowed a good study of intraspecific variation, which is detailed and compared within the genus. Implications for the systematics and relations of the baetica group are discussed. Intraspecific variations are grouped in four categories: individual variations in shape, size and proportions, alterations in chaetotaxy, asymmetries, and teratologies or malformations. Finally, implications and problems of intraspecific variability for the systematics of the genus are discussed. PMID- 26106674 TI - Feather mites of the genus Zachvatkinia Dubinin, 1949 (Astigmata: Analgoidea: Avenzoariidae) from Saudi Arabia: A new species and two new records. AB - Feather mites of the family Avenzoariidae (Acari: Astigmata: Analgoidea) are recorded for the first time in Saudi Arabia. A new avenzoariid species, Zachvatkinia (Zachvatkinia) repressae sp. n. (Avenzoariidae: Bonnetellinae), is described from the White-cheeked Tern, Sterna repressa Hartert, 1916 (Charadriiformes: Stemidae). The new species belongs to the sternae group and is closely related to Z (Z.) chlidoniae Mironov, 1989a. Two more species, Z. (Z.) dromae Mironov, 1992 and Z. (Z.) sternae (Canestrini & Fanzago, 1876), were collected from the Crab Plover Dromas ardeola Paykull, 1805 (Charadriiformes: Dromadidae) and the Sooty Gull Ichthyaetus hemprichii (Bruch, 1853) (Charadriiformes: Laridae), respectively. Among the 18 described species of Zachvatkinia Dubinin, 1949, including the new species, this is the fifth species recorded from a sternid host. The remaining 13 nominal species are associated with birds of the families Diomedeidae, Dromadidae, Hydrobatidae, Laridae, Pelecanoididae, Procellariidae and Stercorariidae. A checklist of world species of Zachvatkinia with data on their distribution and type hosts is also provided. PMID- 26106675 TI - Revision of the genus Hemitrachys Gorham, with discovery of a second species (Coleoptera: Cleridae: Clerinae). AB - The genus Hemitrachys Gorham, 1876 is revised and a new species Hemitrachys tubericollis n. sp. from China is described as the second species of this genus. Thirty-eight illustrations of habitus, genital and external characters are provided. PMID- 26106676 TI - The first Triassic dipteran (Insecta) from South America, with review of Hennigmatidae. AB - The first Triassic dipteran from South America is described based on an isolated wing from the lower Upper Triassic deposits of Argentina (Mendoza Province, Potrerillos Formation, Quebrada del Durazno locality). Trihennigma zavattierii gen. et sp. nov. is a member of the Mesozoic family Hennigmatidae, previously recorded only from Eurasia. A key for the genera and species of Hennigmatidae is provided and systematic position of the taxa is discussed. PMID- 26106677 TI - A new species of Gymnocnemia Schneider, 1845 from Morocco with additional diagnostic data for the genus (Neuroptera, Myrmeleontidae). AB - Gymnnocnemia editaerevayae nov. sp. is described from the High Atlas Mountains in Morocco and compared to Gymnocneinia variegata Schneider, 1845. Descriptions of male genitalia and male and female terminalia of G. variegata are provided. Both species are illustrated. PMID- 26106678 TI - Correction to "Nomenclature of African species of the genus Stenodactylus (Squamata: Gekkonidae)" by Metallinou and Crochet (2013). PMID- 26106679 TI - Systematics of interstitial encrusting bryozoans from southeastern Brazil. AB - This paper describes 22 species of marine bryozoans found in the sand-grain encrusting interstitial epifauna of the northeast coast of Sao Paulo state, Brazil: one new cyclostome, Disporella calcitrapa sp. nov., and 21 cheilostomes. Sixteen of the cheilostomes are new species, and three represent new genera. They are Ammatophora arenacea sp. nov., Discoporella gemmulifera sp. nov., Puellina caraguata sp. nov., Puellina tuba sp. nov., Rosulapelta rosetta gen. et sp. nov., Collarina spicata sp. nov., Hippothoa calcicola sp. nov., Trypostega ilhabelae sp. nov., Reptadeonella granulosa sp. nov., Drepanophora irregularis sp. nov., Allotherenia sabulosa gen. et sp. nov., Bryopesanser tilbrooki sp. nov., Psammocleidochasma tridentatum gen. et sp. nov., Celleporina abstrusa sp. nov., Hippoporella castellana sp. nov., and Hippoporella sabulonis sp. nov. Other species found in this habitat, Alderina smitti, Cymulopora uniserialis, Vibracellina laxibasis, Akatopora leucocypha, and Smittipora sawayai, have previously been described. The family Cymuloporidae fam. nov. is erected for Cymulopora and Crepis. The occurrence in this habitat of living colonies of bryozoans more characteristic of larger subtidal shell substrata indicates the potential importance of an interstitial refuge in maintaining and dispersing encrusting bryozoan populations along continental shelves where larger substrata are absent or rare. PMID- 26106680 TI - Checklist of earthworms (Oligochaeta: Lumbricidae) from Montenegro: Diversity and biogeographical review. AB - A checklist of the lumbricid earthworms in Montenegro is presented. Comprehensive information on the distribution and habitats of all earthworms is given in order to establish the definitive list of known taxa from Montenegro. The complete list of earthworm taxa of Montenegro comprises 40 species and subspecies, belonging to 12 genera of the family Lumbricidae. The list underlines the diversity of earthworms and provides a general overview of their distribution and zoogeographical type. Our study shows that the degree of endemism is comparatively high, exceeding 20%. Summing up the endemics and the Balkanic species, 42.5% of the total lumbricid fauna shows an autochthonous character. PMID- 26106681 TI - A new species of Kaloula (Amphibia: Anura: Microhylidae) from southern Guangxi, China. AB - A new species of narrow-mouthed frog of Kaloula is described in the Nonggang National Nature Reserve, Sino-Vietnamese border region of southern China. Kaloula nonggangensis sp. nov. is distinguished from its congeners by a combination of the following characters: medium size (SVL 41.4-52.7 mm in 18 adult males, 52.2 mm in 1 female); smooth or slightly rough olive dorsum with irregular dark-green marks and brown spots; tips of the fingers widely dilated and truncated; males with nearly fully webbed toes; males with two side protuberant osseous tubercles on the upper surface of the tips of fingers and chest beige with small lemon colored spots. K. nonggangensis sp. nov. is found in habitats ranging from cultivated fields adjacent to the forest to primary evergreen forest in karst habitats. Based upon a 16S ribosomal RNA mitochondrial gene fragment, K. nonggangensis sp. nov. is embedded within the K. verrucosa group (including K borealis, K. rugifera and K. verrucosa), and displays a low genetic distance to these species (< 3%). Considering the distinct morphology and karyotype we nevertheless suggest a status as separate species for these allopatrically distributed lineages. PMID- 26106682 TI - Description of nymphal instars of Ornithodoros mimon Kohls, Clifford & Jones, 1969 (Acari: Argasidae). AB - Ornithodoros mimon is an argasid tick common on Chiroptera in the Neotropical region, where it also bites humans aggressively. Here we describe for the first time all nymphal instars (N1, N2 and N3) of O. mimon based on optical and scanning electron microscopy. Although the nymphal instars of O. mimon resemble each other closely, there are characters that differentiate them: the N3 are taller that N1 and N2; the genital primordium occurs in some N2 and all N3; the spiracular plate in N1 and N2 is cone-like, but in N3 it is semicircular; and the submarginal dorsal groove is less distinct in N1 but more evident in N3. Nymphs of 0. mimon closely resemble the bat-associated species of the genus Ornithodoros included in the Alectorobius group. We review prior descriptions of nymphs of the Alectorobius group and make comparisons with nymphs of O. minon, highlighting characters with diagnostic information, such as the idiosomal shape, presence of discs and hood and absence subapical protuberance of tarsus I. The description of nymphal instars of O. mimon herein presented, improves the taxonomy of the family Argasidae, performing a work more detailed about the immature stage of this species. PMID- 26106683 TI - The identity of Cancer thunborgii Euphras6n, 1795, a senior synonym of Cronius ruber (Lamarck, 1818) (Crustacea: Brachyura: Portunidae). PMID- 26106684 TI - Advertisement and aggressive calls of Ischnocnema oea (Heyer, 1984) (Anura, Brachycephalidae). PMID- 26106685 TI - Revision of Neotropical aphrophorine spittlebugs, part 2: tribe Orthoraphini (Hemiptera, Cercopoidea). AB - The tribe Orthoraphini is validated by diagnosis to include the new-world fauna of Orthorapha Westwood with 21 species from Brazil and 2 newly recorded from Bolivia, including 9 new species: boliviana from an unknown locality in Bolivia and decorata, inscripta, inflata, invidia, irregularis, oculata, sagittata and sphaerata from Brazil. There are also 10 new combinations from Lepyronia Amyot & Serville: bufo Walker; concinna Stal, frontalis Stal, fusconotata Stal, geminata Jacobi, obscurata Amyot & Serville, obliqua Jacobi, quadrimaculata Lallemand, rana Walker and subfasciata Amyot & Serville. Keys are presented to the new-world species and 3 subgenera, including Lepyronoxia Melichar, stat.nov. (= Balsana Metcalf, syn.nov.) and Balsania subg.nov. In addition, the tribe contains 15 genera of old-world Aphrophorinae with an estimated 290 species from Pacific islands; of these, the previously undescribed male genitalia from 25 species in 8 genera are illustrated and antennal characters for Orthorapha and 14 Pacific island genera of Orthoraphini are compared to those of Cloviini, Philaenini and Aphrophorini. This is the first tribe of Cercopoidea to be described as limited to the Southern Hemisphere. PMID- 26106686 TI - Copelatus cessaima sp. nov. (Coleoptera: Dytiscidae: Copelatinae): first record of a troglomorphic diving beetle from Brazil. AB - Copelatus cessaima sp. nov. is described from Brazil. The new species was collected in water puddles inside of caves found in an ironstone formation and has typical troglomorphic characters: the eyes and metathoracic wings are absent, the elytra are fused and the body has long setae. This is the second species of Copelatinae reported as troglomorphic and the first record of a troglomorphic Dytiscidae species in Brazil. The modified morphology of the new species and the lack of elytral striae make the placement of C. cessaima sp. nov. in one of the 15 recognized Copelatus species groups difficult. Thus, we assign the new species to a "group unknown" as defined in Nilsson's world catalogue of the family Dytiscidae. PMID- 26106687 TI - Species of Bicellaria (Diptera: Hybotidae) from Asia. AB - Bicellaria amankutanensis sp. nov. (Uzbekistan), B. chimganensis sp. nov. (Uzbekistan), B. farkaci sp. nov. (China), B. globulicauda sp. nov. (Uzbekistan), B. koreana sp. nov. (North Korea, Russia), B. kovalevi sp. nov. (Georgia), B. setitibia sp. nov. (Georgia), B. shatalkini sp. nov. (Russia), B. thailandica sp. nov. (Thailand), and B. woodi sp. nov. (Japan) are described and illustrated. Bicellaria montana Kato is newly synonymised with B. uvens Melander. Bicellaria spuria ingrata Collin is considered a distinct species. A key to all known Asian species of Bicellaria is provided. PMID- 26106688 TI - Globorentonium, a new genus of rentoniine Trogossitidae (Coleoptera: Cleroidea) from Australia and Brazil. AB - A new genus of Rentoniini, Globorentonium gen. n., is described including three new species: G globulum sp. n. (type species) from Tasmania, Victoria, ACT and southern New South Wales; G lescheni sp. n. from northern New South Wales and G plaumanni sp. n. from southern Brazil. The new genus is compared with other known genera of Rentoniinae, and a key to world genera is provided. PMID- 26106689 TI - Four new African turriform gastropods (Mollusca: Conoidea). AB - Four new species, belonging to four distinct conoidean families, are described from east Africa and Mozambique Channel. Iredalea adenensis sp. nov. (Drilliidae Olsson, 1964), from Gulf of Aden, and Buchema shearmani sp. nov. (Horaiclavidae Bouchet et al., 2011), from off Mogadishu (Somalia), both trawled by local fishermen, represent the first record of their respective genera in eastern Africa. Crassispira somalica sp. nov. (Pseudomelatomidae Morrison, 1965), also collected offshore from Modagishu (Somalia), represents the first eastern Africa species bearing "typical" Crassispira features. Tropidoturris vizcondei sp. nov. (Borsoniidae Bellardi, 1875), from the Mozambique Channel, increases the knowledge of a genus considered endemic to southeastern Africa. PMID- 26106690 TI - Chondropyga insignicosta, a new species of Cetoniinae (Coleoptera: Scarabaeidae) from Queensland, Australia. AB - Chondropyga insignicosta, new species (Coleoptera: Scarabaeidae: Cetoniinae) is described from Queensland, Australia. PMID- 26106691 TI - The nursery-web spider Hygropoda tanganus (Roewer, 1955) comb. nov. (Araneae: Lycosoidea: Pisauridae); generic transfer, first description of the female and redescription of the male. PMID- 26106692 TI - New and little known species of the genus Orphnus MacLeay (Coleoptera: Scarabaeidae: Orphninae) from the East African Rift. PMID- 26106693 TI - The lysianassid genus Pseudambasia in Australian waters (Crustacea, Amphipoda, Lysianassidae, Lysianassinae). AB - Pseudambasia appears to be an Indo-West Pacific endemic, comprising mostly tropical and temperate species but also one from the New Zealand subantarctic. In this paper the genus Pseudambasia Stephensen is diagnosed against all other genera of the Lysianassinae. Six new species of Pseudambasia (P. dartnalli sp. nov.; P. lochi sp. nov.; P. ponderi sp. nov.; P. poorei sp. nov.; P. sheardi sp. nov.; and P. springthorpei sp. nov.) are described from Australian waters. PMID- 26106694 TI - Notes on the taxonomy of the Holarctic Corynoptera Winnertz sensu lato (Diptera, Sciaridae), with description of six new species. AB - Six new species of Corynoptera Winnertz from northern Finland, Japan and North America are newly described and illustrated: Corynoptera captiosa sp. n., C. cracentis sp. n., C. inari sp. n., C. salmelai sp. n., C. spiciforceps sp. n. and C. tuomikoskii sp. n.. Corynoptera subvariegata Rudzinski, 1992 is redescribed and C. perochaeta (Mohrig & Menzel, 1990) and C. variegata Mohrig, 1985 are illustrated and their characters discussed. The new species studied show unusual characters for the genus, and do not fit well into currently defined species groups. PMID- 26106695 TI - New species and records of Trypetinae (Diptera: Tephritidae) from China. AB - Eight new species of Trypetinae (Diptera: Tephritidae) from China are described and illustrated. The new species are Cornutrypeta chishuiensis Chen sp. nov., C. motuonia Chen sp. nov., Hoplandromyia hubeiensis Chen sp. nov., H. motuonica Chen sp. nov., Magnimyiolia disrupta Chen sp. nov., M tengchongnica Chen sp. nov., M tibetana Chen et Wang sp. nov. and M. yunnanica Chen et Wang sp. nov. Keys to the known species of the genera Cornutrypeta Han et Wang and Hoplandromyia Bezzi from the World, and the genera Magnimyiolia Shiraki from East Asia are updated and provided. C. spinifrons (Schroeder) is newly recorded from China, and the female of C. hunanica Chen et Wang is recorded, described and illustrated for the first time. Illustrations of the type of M huanana Wang and a new distribution of C. hunanica Chen et Wang are provided. PMID- 26106696 TI - Speleonectes cokei, new species of Remipedia (Crustacea: Speleonectidae) from a submerged ocean cave near Caye Chapel, Belize. AB - Speleonectes cokei n. sp. is the 15th species of Speleonectes to be described. It is the first remipede described from a submerged cave off the mainland of Belize. The species is the third found along the Caribbean coast of the Yucatan Peninsula. S. cokel can be distinguished from S. tulumensis Yager, 1987 and S. fuchscockburni Neiber et al., 2012 by the number of antenna 1 segments, number of antenna 2 exopod setae, spines on maxilla 1 segment 2, and caudal rami to anal segment length. PMID- 26106697 TI - Description of the octopunctata-group species of Protaphorura from China (Collembola: Onychiuridae). AB - Protaphorura species of the octopunctata-group are recorded in China for the first time. Two new species, Protaphorura jiamusiensis sp. nov. and Protaphorura maoerensis sp. nov., and one species new to China, Protaphorura nutak, are reported. Protaphorura jiamusiensis sp. nov. is diagnosed mainly by the formula of pso on the body and subcoxae 1, the psx formula, the ratio of M/sp on Abd. V and the number of chaetae on Th. I-III sterna between the legs. Protaphorura maoerensis sp. nov. is similar to P. mongolica and P. sakatoi, but it can be easily distinguished from them by the dorsal pso formula. PMID- 26106698 TI - A remarkable new Nilotonia species (Acari, Hydrachnidia, Anisitsiellidae) from percolating water of a cave in Cat Ba island in Halong Bay, Vietnam. AB - Both sexes of Nilotonia sketi sp. nov. are described from percolating water of a cave in Cat Ba island in Halong Bay, Vietnam. The IV-L-6 of the new species is characterized by a line of longer ventral setae, and presence of two longer distoventral setae. The systematic position of Nilotonia species attributed to the subgenera Dartiella K. Viets, 1929 and Dartonia K. Viets, 1929 are discussed. The latter subgenus is re-defined and Dartiella is proposed as its junior synonym. Two new subgenera, Gereckonia (type species: Nilotonia turcica Ozkan & Soysal, 1989 from Turkey) and Davetonia (type species: Nilotoniaperplexa Cook, 1967 from India) are erected. PMID- 26106699 TI - A checklist of the species under the genus Monocystis Von Stein, 1848 (Apicomplexa: Sporozoa: Monocystidae) described from oligochaete hosts. AB - A checklist of 24 species of the genus Monocystis is presented and includes the salient features of each species, type host and site of infection. PMID- 26106700 TI - Taxonomic notes on two species of bush katydids (Orthoptera: Tettigoniidae: Phaneropterinae) from Bukit Fraser, Malay Peninsula. AB - Material based on a taxonomic collection in Bukit Fraser, Pahang of Malay Peninsula enables the review of two genera of bush katydid (Phaneropterinae). The female of Elimaea (Rhaebelimaea) pseudochloris Ingrisch, 1998 is described and recorded for the first time outside its type locality, Thailand. One new species of Pseudopsyra from Bukit Fraser is described: Pseudopsyra bispina sp. n. PMID- 26106701 TI - Tapajos cristinae gen. n., sp. n. (Diptera: Chironomidae: Chironominae) from the Neotropical region. AB - A new genus of non-biting midges, Tapajos gen. n., is erected for T cristinae sp. n. from the Neotropical region, and placed in the subfamily Chironominae, tribe Chironomini. Adult males are characterized by the combination of bare eyes; antenna with 11 flagellomeres; antepronotal lobes fused medially; fore tibia with inner scale broad and rounded; superior volsella with a long sickle shaped, bare part arising from the distal lateral corner of a globose, densely trichiose base; inferior volsella sub-cylindrical, surpassing the anal point, distally setose and slightly expanded. PMID- 26106702 TI - Simple rules on adjectival endings in zoological nomenclature and their use in scale insect names (Hemiptera: Sternorrhyncha: Coccoidea), with some corrections to combinations in common use. AB - We give some simple rules on Latin grammar to help scale insect systematists to apply the correct adjectival gender endings to species names. We list some common errors that have occurred when species names have either been proposed with a wrong gender ending or when they have been transferred from one genus to another. We also correct the gender endings to several species names in a few families. PMID- 26106703 TI - A new species of Lygodactylus (Squamata: Gekkonidae) endemic to Mount Namuli, an isolated 'sky island' of northern Mozambique. AB - A new species of high elevation dwarf gecko (Gekkonidae: Lygodactylus) is described from Mount Namuli, northern Mozambique. This new species is distinguished from other closely related species in the genus Lygodactylus by body size, scalation, and color, and is genetically divergent from congeners. The species is most similar genetically and morphologically to Lygodactylus rex, the King Dwarf Gecko, which is endemic to Mount Mulanje, Malawi. Mount Mulanje and Mount Namuli are two of several understudied inselbergs forming the southern limit of the Afromontane archipelago in Malawi and Mozambique. The sister taxon relationship of the dwarf gecko species on Mount Mulanje and Mount Namuli illustrates the historical biogeographic connections between these inselbergs, a pattern which is emerging with continued work in this region. The discovery of this new species adds to a growing list of species unique to Mount Namuli, and further establishes this montane region as a conservation priority. PMID- 26106704 TI - Two new species of the coffinfish genus Chaunax (Lophiiformes: Chaunacidae) from the Indian Ocean. AB - Two new coffinfishes, Chaunax nebulosus n. sp. and Chaunax africanus n. sp., are described from the Indian Ocean. Both species belong to the C.fimbriatus-species group which is characterised by having filaments on the dorsal head and a complex color pattern on the dorsal surface. They are morphometrically and meristically conservative but differ in coloration. Chaunax nebulosus can be distinguished from its closest relatives by its dense covering of very small, irregular grayish green spots and having 5 small blackish markings on its dorsal surface. Chaunax africanus can be distinguished from other members in having a colour pattern of long narrow brown bars on the dorsal-fin base and head (forming a radiate pattern around the eye), and a complex white reticulate pattern (often double-lined) over the entire dorsal surface. Comments on species occurring in Indian Ocean and the status of members of C. fimbriatus-species group are also provided. PMID- 26106705 TI - Two new species and records of Stenochironomus Kieffer from Brazilian Amazon region, with description of immature stages (Diptera: Chironomidae). AB - Two new species of Stenochironomus Kieffer, 1919 are described in Brazil. New records of Stenochironomus nudipupa Borkent, 1984 and S. gladius Borkent, 1984 from Brazil, new data on geographical distribution of S. jubatus Borkent, 1984 and S. triannulatus Borkent, 1984 from the State of Roraima, and S. bacrionis Borkent, 1984 recorded from the State of Amazonas, as well as emended descriptions of immature stages of S. triannulatus Borkent, 1984 and S. reissi Borkent, 1984 are also presented. PMID- 26106706 TI - Rediscovery and range extension of Ciliopagurus liui Forest, 1995 and description of a new species of Pagurus Fabricius, 1775 (Crustacea: Decapoda: Anomura: Paguroidea) from the Kerala State, southwestern India. AB - Two species of paguroid hermit crabs, Ciliopagurus liui Forest, 1995 (Diogenidae) and Pagurus spinossior n. sp. (Paguridae), are reported from the Kerala State, southwestern India. Ciliopagurus liui, is first recorded from the Indian Ocean. This species was originally described on the basis of a single male specimen from the Tonkin Gulf in the South China Sea, though its geographical range also included Japan, based on literature. Supplemental description and illustrations are provided for better understanding of the diagnostic features of this little known species. Pagurus spinossior n. sp., described on the basis of a single male specimen, appears closest to P. spinulentus (Henderson, 1888), known only by the holotype from the Philippines, but the lack of spinules on the dorsal margins of the dactyli of the second pereopods, the different shape of the anterior lobe of the thoracic stemite 6, and the more numerous spines on the terminal to posterior margins of the telson distinguish the new species from P. spinulentus. PMID- 26106707 TI - New species of the scale worm genus Pholoe (Polychaeta: Pholoidae) from southeast Brazil. AB - Exploration of poorly known regions of the Brazilian coast has resulted in the discovery of a new species in the scale worm family Pholoidae. Pholoe microantennata sp. nov. occurs at the Campos Basin (states of Espirito Santo and Rio de Janeiro) and along the northern coast of Sao Paulo State. It differs from other species in the genus because it has numerous large and conical marginal papillae on the elytra and two small lateral antenna attached to the distal portion of the prostomium. The family Pholoidae remains species-poor compared with most polychaete families, and it currently comprises 24 species worldwide. In Brazil, only three species of this family have been recorded. PMID- 26106708 TI - A comment on the oral dermal flaps of Elachistocleis Parker, 1927 (Anura: Microhylidae) larvae. PMID- 26106709 TI - Taxonomic study of the genus Myrmarachne of Borneo (Araneae: Salticidae). AB - Twenty-two species of the genus Myrmarachne are reported from Borneo in the present study. Among those, eight are new to science, M. acromegalis sp. nov., M. alticephalon sp. nov., M. brevichelicera sp. nov., M. crassembolus sp. nov., M. cyrtodens sp. nov., M. endoi sp. nov., M. lambirensis sp. nov. and M. sabahna sp. nov. The following synonymies are proposed: Myrmarachne topali Zabka, 1985 syn. nov. as a junior synonym of M. hanoii Zabka, 1985, M. gigantea Zabka, 1985 syn. nov. as a junior synonym of M. maxillosa (C. L. Koch, 1846). The females of M. assimilis Banks, 1930, M. biseratensis Badcock, 1918, M. gedongensis Badcock, 1918, M. markaha Barrion & Litsinger, 1995 and M. shelfordii Peckham & Peckham, 1907 are described for the first time. PMID- 26106710 TI - New species of Neuronema McLachlan, 1869 from China (Neuroptera, Hemerobiidae). AB - Two new species of Neuronema McLachlan are described from China: Neuronemaypsilum sp. nov., which was found in Beijing and Shaanxi provinces, and Neuronema maculosum sp. nov., which was found in Chongqing and Gansu provinces. Keys are given to identify the species of Neuronema in China. PMID- 26106711 TI - Review of the genus Allochotes (Coleoptera: Cleridae: Neorthopleurinae) from Taiwan. AB - The Taiwanese species of the genus Allochotes are reviewed with descriptions of two new species, A. forniculatus sp. n. and A. piceus sp. n. A new synonymy is proposed: A. violaceipennis Schenkling syn. n. (= A. sauteri Schenkling). The Taiwanese Allochotes species are divided into three species groups based on the male genital structures. PMID- 26106712 TI - Podocoryna martinicana, a new species of athecate hydroid (Cnidaria: Hydrozoa: Hydractiniidae) from the Caribbean. AB - A new species of hydroid, Podocoryna martinicana sp. nov., is described from the Lesser Antilles. It lives symbiotically with Iridopagurus caribbensis (A. Milne Edwards & Bouvier, 1893) (Decapoda: Paguridae) inhabiting various gastropod shells. Its colonies are highly organized and develop exclusively around the aperture of the host shell. A few large, columnar gastrozooids provided with numerous tentacles arise from a perisarc-covered stolonal mat on the inner lip of the shell, and appear to form a gate when the hermit is withdrawn, while numerous, small, highly prolific gonozooids dress a line on the edge of the outer lip. Slender, very contractile tentaculozooids occur variably among the colonies. The dispersive stage, a free-swimming medusa with four well-developed marginal tentacles and no ocelli, is solely described based on young, sexually immature specimens. The species is further characterized by the peculiar bright white tinge of the core of both hydroid and medusa tentacles. Rich illustrations, data on the nematocyst complement, as well as comparisons with related congeners are provided. PMID- 26106713 TI - New fossil mesoserphid wasps (Insecta, Hymenoptera, Proctotrupoidea) from the Jehol Biota, China. AB - A new genus with two new species, Codoserphus calophlebius gen. et sp. nov. and Codoserphus euneurus gen. et sp. nov., assigned to the subfamily Mesoserphinae of Mesoserphidae, are described from the Jehol Biota, Early Cretaceous Yixian Formation of Huangbanjigou Village in Liaoning, China. Codoserphus gen. nov. is characterized by its fore wing with all major veins present, not reduced, and l cu-a distal to 1-M in fore wing. An updated key is given for the genera of Mesoserphidae from around the world. PMID- 26106714 TI - First checklist of the chrysidid wasps (Hymenoptera: Chrysididae) of Iran. AB - A first checklist of the Iranian Chrysididae is proposed. The list includes 184 species in 20 genera. Seventy species and genera Spinolia Dahlbom, 1854, Spintharina Semenov, 1892, Trichrysis Lichtenstein, 1876 are newly recorded from Iran. New combination is proposed for Chrysura laconiae (Arens, 2001), comb. nov. (from Chrysis) and Chrysurapyrogaster turca (Linsenmaier, 1997), comb. nov. (from Chrysis). New synonymy is proposed for Chrysura barbatula (Linsenmaier, 1968) = Chrysura barbatica Bohart, 1991, syn. nov. The status of Chrysis transcaspica Mocsary, 1889 is resurrected. Historical data with the comments of current taxonomic position and the specific validity of some species are given. PMID- 26106715 TI - A new Psammogammarus (Amphipoda: Eriopisidae) from anchialine pools on the Exuma Cays, Bahamas. AB - Psammogammarus lucayensis sp. nov. is described from anchialine pools on Little Iguana Cay (Exuma Cays, Great Bahama Bank). It can be easily distinguished from the other 14 members of the genus by the combination of: 1) carpus of G2 longer than broad; 2) male G2 palm margin non-excavated, evenly convex and devoid of strong mid-palmar robust setae; 3) basis of P7 with subparallel margins; 4) armature arrangement of ventral margin of epimeral plates as 0-2-3; 5) posteroventral angle of epimeral plate III strongly produced; 6) protopod of U2 with distomedial angle armed with comb of 3-4 robust setae; 7) U3 endopod as long as exp1; and 8) telson with robust setae on tip. The generic diagnosis is amended in order to allow the precise characterization of members of Psammogammarus compared to other eriopisids. PMID- 26106716 TI - Review of amphipods of the Melita group (Amphipoda: Melitidae) from the costal waters of Sakhalin Island (Far East of Russia). I. Genera Megamoera Bate, 1862 and Armatomelita gen. nov. AB - A review of Melita group (fam. Melitidae) from the shelf of Sakhalin Island based on literature and own data is provided. Based on new material, four new species of the genus Megamoera are described: M. similidentata sp. nov. and M. striata sp. nov. from north-east shelf of Sakhalin Island; M falsomikulitschae sp. nov. and M. aequidentatum sp. nov. from Aniva Bay (southern Sakhalin). The new genus Armatomelita gen. nov. and new species A. tshayensis sp. nov. are described from Aniva Bay (southern Sakhalin). A key to the world species of the genus Megamoera is provided. Cladistic analysis of morphological relationships within the genus Megamoera is implemented. PMID- 26106717 TI - The phylogenetic position of Lepidopygopsis typus (Teleostei: Cyprinidae), a monotypic freshwater fish endemic to the Western Ghats of India. AB - Lepidopygopsis, known as the peninsular-Indian hill trout, is a monotypic genus endemic to the Periyar stream-reservoir system, in the Western Ghats. Due to the morphological similarity of its only species, L. typus, with the Himalayan schizothoracine fishes, it was considered to be a relict species and a classic example of disjunct distribution. Using mitochondrial and nuclear gene sequence datasets, we show that L. typus is not allied to the schizothoracine fishes. Phylogenetic hypothesis-testing unequivocally supports a scenario in which L. typus and a clade comprising various genera of Asian and African barbins such as Tor Gonoproktopterus, Kosswigobarbus and Varicorhinus are sister groups. Based on our results, we suggest that the sheath of tile-like scales covering the anal-fin base of schizothoracine fishes and Lepidopygopsis typus could be a symplesiomorphy or a homoplasy. PMID- 26106718 TI - The genus Odontophrynus (Anura: Odontophrynidae): a larval perspective. AB - The genus Odontophrynus consists of 11 species of medium-sized frogs distributed across south and east South America. This study examines and describes the chondrocrania and oral cavities of O. americanus, O. maisuma, O. carvalhoi, and O. cultripes, and review current knowledge about the larval external morphology of the genus. Twenty-one tadpoles were cleared and double-stained for chondrocranium description and five tadpoles were dissected for analysis in a scanning electron microscope. The presence of a tectum parientale may be considered here as a putative synapomorphy of the genus. The O. americanus and O. cultripes species groups were partially differentiated by the length of the processus pseudopterigoideus, shape of divergence of the hypobranchial plates, number of postnarial papillae, and number of projections of the lateral ridge papillae. The larvae of O. occidentalis species group, in turn, differed from others by presenting a greater total length. PMID- 26106719 TI - Mantacaprella macaronensis, a new genus and species of Caprellidae (Crustacea: Amphipoda) from Canary Islands and Cape Verde. AB - Mantacaprella macaronensis new genus, new species, is described based on specimens collected from Canary Islands and Cape Verde. Mantacaprella is close to the genera Parambus, Pseudolirius, Propodalirius and Paracaprella, but can be distinguished by the combination of the following characteristics: pereopods 3, 4 and 5 two-articulate; pereopods 6 and 7 six-articulate; mandibular molar present and palp absent; male abdomen with a pair of well-developed appendages. The new species has been found living in Cymodocea nodosa meadows and Caulerpa prolifera beds from 8.8 to 14.6 m depth in Gran Canaria (Canary Islands), and in natural rocky and artificial habitats (shipwrecks) at 25 m in Sal Island (Cape Verde). Even though the new species is one of the dominant amphipods inhabiting meadows of Cymodocea nodosa in Gran Canaria and in Cape Verde, it had not been described so far. This reflects the lack of knowledge on Macaronesian invertebrates, such as amphipods, and the need of further taxonomical studies to better characterise the whole biodiversity of this region and to design adequate programmes of management and conservation. PMID- 26106720 TI - Pethia aurea (Teleostei: Cyprinidae), a new species of barb from West Bengal, India, with redescription of P. gelius and P. canius. AB - Fishes currently assigned to Pethia gelius Hamilton from West Bengal are shown to belong to a closely-related group of three species: P gelius, its erstwhile synonym P canius Hamilton and a new species, P aurea. The three species are distinguished from all other species of Pethia by having the lateral line incomplete, with 3-4 pored scales; 20-26 scales in lateral series on body; 1/24 5/l/2-31/2 scales in transverse line on body; 8-9 predorsal scales; barbels absent and by a unique colour pattern consisting of two or three black blotches on the body (which, however, fade on preservation), the first behind the opercle, the second beneath the origin of the dorsal fin, extending to the mid-lateral region, and the third above the origin of the anal fin. A black spot is also present at the base of the dorsal and anal fins. Additionally, P gelius is distinguished by having the last unbranched dorsal-fin ray thick, straight, serrated, with 20-25 serrae on its posterior margin; a snout length of 6.1-8.4% standard length (SL); a body depth of 32.6-37.7% SL; and a dorsal-fin height of 19.4-22.8% SL. Pethia canius is additionally distinguished by having a snout length of 8.9-11.8% SL; a body depth of 28.1-32.2% SL; and dorsal-fin height of 26.9-32.8% SL. Pethia aurea, new species, is additionally distinguished from all its congeners by having 1/25/1/3-31/2 scales in transverse line on body; 9 pre dorsal scales; and last unbranched dorsal-fin ray slender, serrated, with 19-22 serrae on posterior margin. PMID- 26106721 TI - Neohydatothrips (Thysanoptera: Thripidae) from China: new species and records, with a key to species. AB - Three new species of Neohydatothrips (Thripidae: Sericothripinae) are described and illustrated from China: N. concavus sp. n., N. flavicingulus sp. n. and N. luteolipes sp. n.; and two species previously recorded from Taiwan are here reported for mainland China for the first time: N. plynopygus (Karny) and N. tabulifer (Priesner). A key to the 16 Neohydatothrips species recorded from China (including Taiwan) is provided. PMID- 26106722 TI - Ochthebius hivae (Coleoptera: Hydraenidae) from western Iran, a new species of the O. metallescens group with remarkable aedeagal variability. AB - Ochthebius hivae is described from western Iran (Ilam and Khuzestan Provinces). It belongs to the O. metallescens Rosenhauer, 1847 species group. The aedeagal distal lobe of this species is remarkably variable. PMID- 26106723 TI - Hypogean pseudoscorpions (Arachnida) from Jaen province (Andalusia, Spain), with descriptions of four new species and a new synonymy. AB - Four new hypogean species are described from the Jaen province (southern Spain): Chthonius (Ephippiochthonius) espa- nyoli sp. nov., C. (E.) giennensis sp. nov., C. (E.) villacarrillo sp. nov. and Neobisium (Ommatoblothrus) perezruizi sp. nov. New records are given for the species Chthonius (E.) cazorlensis, C. (E.) perezi, C. (E.) tetrachelatus, Neobisium (O.) perezi, Microcreagrella caeca caeca and Allochernes masi. Chthonius (E.) verai and C. (E.) minutus are removed from the list of the Andalusian fauna. A new synonymy is proposed: Neobisium (O.) gev Carabajal Marquez, Garcia Carrillo & Rodriguez Fernandez, 2011, is a junior subjective synonym of N. (O.) perezi Carabajal Marquez, Garcia Carrillo & Rodriguez Fernandez, 2011. PMID- 26106724 TI - A new species of Astyanax from headwater streams of southern Brazil (Characiformes: Characidae). AB - Astyanax pirabitira, new species, is described from the upper portion of the rio das Antas, laguna dos Patos system, and from the rio Pelotas, upper rio Uruguay drainage, Rio Grande do Sul State, Brazil. The new species belongs to the A. scabripinnis species complex and differs from its congeners by a combination of characters, viz., body depth (27.1-34.0% of standard length), narrow interorbital width (22.2-28.7% of head length), head depth (72.9-97.0% of HL), number of branched anal-fin rays (15-20), number of lateral line scales (37-40), one or two maxillary teeth, two humeral spots and absence of secondary sexual characters (bony hooks in the fins or other differences in the morphology). Comments on the endemic fish fauna of the region are presented. PMID- 26106725 TI - Telopathes magna gen. nov., spec. nov. (Cnidaria: Anthozoa: Antipatharia: Schizopathidae) from deep waters off Atlantic Canada and the first molecular phylogeny of the deep-sea family Schizopathidae. AB - A new genus and species of deep-sea antipatharian, Telopathes magna gen. nov., spec. nov., is described from the western North Atlantic off the coast of Canada. Five additional paratypes, consisting ofjuvenile to adult forms, are reported from the New England and Corner Rise Seamounts (NW Atlantic). Preliminary sequencing of a subsection of the nuclear ribosomal cistron confirmed the phylogenetic affinity of T. magna to the order Antipatharia, and in particular the family Schizopathidae. Subsequent sequencing of three mitochondrial DNA segments from nine of the 11 currently-recognized genera within the Schizopathidae revealed a well-supported phylogenetic relationship between T. magna and Stauropathes. This is the first study to use molecular techniques to elucidate the evolutionary relationships of the Schizopathidae, a family of black corals almost exclusively found in the deep sea (depths > 200 m). Telopathes is distinguished from other genera within the family Schizopathidae by its largely pinnulated stalk, sparse branching pattern to the second degree that is not restricted to a single plane, two anterolateral rows of long, simple primary pinnules, arranged alternately to sub-opposite, and colony with an adhesive base. This record of T. magna brings the total number of nominal species of Antipatharia reported to occur off eastern Canada to 12 and represents the third new genus added to the Schizopathidae since a critical review of the family by Dennis Opresko in 2002. PMID- 26106726 TI - New taxa and new records of oribatid mites of the family Galumnidae (Acari: Oribatida) from Ecuador. AB - The new genus Neoctenogalumna gen. nov. with Ctenogalumna moresonensis Engelbrecht, 1972 as a type species and the new subgenus Neoctenogalumna (Paractenogalumna) subgen. nov. with Neoctenogalumna (Paractenogalumna) longiciliata sp. nov. as a type species are proposed. Four new species Allogalumna ampla sp. nov., Galumna miniporosa sp. nov., Pergalumna ornamenta sp. nov. and Neoctenogalumna (Paractenogalumna) longiciliata sp. nov. are described from Ecuadorian soils. Neoctenogalumna moresonensis (Engelbrecht, 1972) comb. nov. and N. congoensis (Stary, 2005) comb. nov. are transferred in the genus Neoctenogalumna gen. nov. from Ctenogalumna. An identification key to known species of Neoctenogalumna gen. nov. is provided. An annotated checklist of identified Ecuadorian Galumnidae is presented. Four species Allogalumna borhidii Balogh & Mahunka, 1979, A. cubana Balogh & Mahunka, 1979, Pergalumna australis Perez-Inigo & Baggio, 1980, Galumna laselvae Balogh, 1997--are recorded for the first time from Ecuador. One genus and one species Trichogalumna Balogh, 1960 and Trichogalumna nipponica (Aoki, 1966) are recorded for the first time from the Neotropical region. PMID- 26106727 TI - Three new species of scale mites (Acari: Pterygosomatidae) parasitizing Agama sankaranica (Sauria: Agamidae). AB - Three new species of pterygosomatid mites Pterygosoma engai sp. nov. P. indare sp. nov. and P olape sp. nov. (Acari: Pterygosomatidae) are described from the agamid lizard Agama sankaranica (Sauria: Agamidae) from Kenya. P. engai sp. nov. is similar to P annectans circularis Jack, 1962 but in the new species, the anterior paddle-shaped setae with spicules on the apical margin of the idiosomal dorsum and three pairs of the postero-lateral setae are present, setae dm1 are paddle-shaped, peripheral setae and setae dGIV are absent, the pseudoanal setal series is represented by three pairs of setae ps. P indare sp. nov. is most closely related to P. agamae agamae Peters, 1849 but differs by the absence of eyes and setae dGI, the presence of the flattened hypostomal apex and 12-14 pairs of the peripheral setae and some of them are tapered. P olape sp. nov. is similar to P engai sp. nov. but differs by the presence of the hypostome with a smooth rounded apex and 16 pairs of the peripheral setae inserted ventrally, the genital series is represented by one pair of setae g situated ventrally and four pairs of setae ps situated ventrally and terminally. PMID- 26106728 TI - Biodiversity of hillstream fishes in Bangladesh. AB - Bangladesh is a country of 1,47,570 km2 of mostly flat topography, but about 12 percent is hilly. The hilly areas are confined to the northeast and the southeastern parts of the country bordering India and Myanmar. Hill streams are highly variable and very important for the study and understanding of the aquatic biodiversity of Bangladesh. Hillstream ecosystems include a variety of habitats including those with sand, clay, cobble, gravel, mud, and rock substrates. In a recent field survey, 82 species of fishes have been identified from those habitats. The ichthyofauna belongs to the following families (numbers of species in parentheses) Notopteridae (1), Engraulidae (1), Cyprinidae (32), Psilorhynchidae (3), Nemacheilidae (2), Cobitidae (6), Bagridae (6), Schilbeidae (5), Amblycipitidae (1), Akysidae (1), Sisoridae (4), Erethistidae (1), Clariidae (1), Olyridae (1), Aplocheilidae (1), Ambassidae (2), Badidae (1), Mugilidae (1), Gobiidae (2), Osphronemidae (2), Channidae (3), Mastacembelidae (3), Belonidae (1) and Tetraodontidae (1). This paper provides a checklist of the hillstream fish species with their habitat preferences and associated fauna. PMID- 26106729 TI - Overview of the species of Aphelocheirus (Hemiptera: Heteroptera: Aphelocheiridae) of India, with description of a new species from West Bengal. AB - An overview and a key to the species of Aphelocheirus of India are given. Aphelocheirus (Aphelocheirus) thirumalaii sp. nov. from Gorumara National Park of Jalpaiguri district, West Bengal, is described. With this new species, eight other species of benthic water bugs (Aphelocheiridae) are reported from India. A distribution map of all known Indian species is also provided. PMID- 26106730 TI - Phytoseiidae (Acari: Mesostigmata) from natural ecosystems in the State of Sao Paulo, Brazil. AB - This work describes the results of a study of the phytoseiid mites collected from plants in two natural ecosystems in the State of Sao Paulo, Brazil-Cerrado and Atlantic Forest. In this study, 40 phytoseiid species are reported. Measurements of different structures are given for species for which measurements for the respective Sao Paulo populations were not previously provided. This study also includes the description of two new genera, Breviseius g. n. and Serraseius g. n., and ten new species, Amblydromalus macroatrium n. sp., Amblyseius atlanticus n. sp., Breviseius sennae n. sp., Cocoseius paucisetis n. sp., Proprioseiospsis pariquerassuensis n. sp., Serraseius caicara n. sp., Typhlodromalus ingae n. sp., Typhlodromalus feresisimilis n. sp., Typhlodromips corniformis n. sp. and Typhlodromips robustisetus n. sp. PMID- 26106731 TI - A new synonymy of Graptocleptes bicolor (Burmeister), with taxonomical notes (Hemiptera: Heteroptera: Reduviidae: Harpactorinae: Harpactorini). AB - Hiranetis coleopteroides (Walker, 1873) is here found to be conspecific with Graptocleptes bicolor (Burmeister, 1838). Graptocleptes bicolor is redescribed and the male genitalia characters are illustrated for the first time. Intraspecific morphological, color and male genitalia variability are discussed. Furthermore, the species is recorded from Paraguay for the first time. PMID- 26106732 TI - Review of the Leafhopper Genus Macrosteles Fieber (Hemiptera: Cicadellidae: Deltocephalinae) from China. AB - The leafhopper genus Macrosteles Fieber in China comprises 25 species including ten new species: Macrosteles brochus Zhang & Lu, M. brunneus Zhang & Lu, M. choui Zhang & Lu, M. ehensis Zhang & Lu, M. gracilis Zhang & Lu, M. falcatus Zhang & Lu, M. haperatus Zhang & Lu, M. nabiae Kwon, M. parastriifrons Zhang & Lu and M. spinosus Kwon. Five species are newly recorded from China, including M. abludens Anufriev, M. albicostalis Vilbaste, M. alpinus (Zetterstedt), M. lividus (Edwards) and M. sordidipennis (Stal). One taxon previously treated as a subspecies of M fascifrons (Stal) is elevated to species rank: M. lindbergi Dlabola, n. stat. The following six new synonyms are proposed: M. bimaculatus Dai, Li & Chen, 2008 = M. lividus (Edwards, 1894), M heiseles Kuoh, 1981 = M. guttatus (Matsumura, 1915); M. huangxionis Kuoh, 1981 = M. heitiacus Kuoh, 1981; M. latiaedeagus Dai et al., 2008 = M. cristatus Ribaut, 1927; and M. serrata Dai et al., 2011 = M. striifrons Anufriev, 1968 and also a junior homonym of M. serratus Kwon, 2010; and M. symphorosus Yang, 1996 = M. viridigriseus (Edwards, 1924). A checklist to the Macrosteles species from China is provided together with a key for separation of males. PMID- 26106733 TI - New species of Nymphites Haase (Neuroptera: Nymphidae) from the Middle Jurassic of China, with a redescription of the type species of the genus. AB - Nymphites priscus (Weyenbergh, 1869) from the Late Jurassic of Solnhofen (Germany), type species of the genus Nymphites Haase, 1890, is redescribed. The genus is assigned to the Nymphidae. The taxon Nymphitidae is not valid; it is an artificial aggregation of fossil genera. Two species new to science, one named, of Nymphites from the Middle Jurassic locality of Daohugou (Inner Mongolia, China) are described. PMID- 26106734 TI - Epiplatys atratus (Cyprinodontiformes: Nothobranchiidae), a new species of the E. multifasciatus species group from the Lulua Basin (Kasai drainage), Democratic Republic of Congo. AB - Epiplatys atratus, a new species of the E. multifasciatus group, is described from specimens collected from several tributaries of the middle Lulua River, a tributary of the Kasai River, south of Kananga (Democratic Republic of the Congo, Kasai Occidental Province). Epiplatys atratus is the south-eastern most representative of the genus. Large adult E. atratus males differ from all congeners in displaying a dark grey to black pigmentation of body and fins. In contrast to other Epiplatys species, with a fully exposed laterosensory system of the head, the lobes surrounding the supra-orbital part of the laterosensory system almost completely cover the system in large males of E. atratus. Also in males of E. atratus the dorsal fin is positioned on average more anteriorly than in other members of the E. multifasciatus group. Small males and females show a unique pattern of three fine oblique dark bars just behind the pectoral fin. PMID- 26106735 TI - Two New Species of Black Flies (Diptera: Simuliidae) from the High Andes of Colombia. AB - The females, males, pupae, and larvae of two new species of Simulium are described and illustrated from a small stream 3950 m above sea level in the Lake Otun area of the Colombian Andes Mountains. Simulium (Pternaspatha) quimbayium n. sp. represents a 630-km northeastern extension of the distributional range of previously known members of the subgenus Pternaspatha, and Simulium (Psilopelmia) machetorum n. sp. represents the highest altitude recorded for a species of the subgenus Psilopelmia. These species illustrate the unique simuliid biodiversity in the paramo ecosystem of the high northern Andes. PMID- 26106736 TI - Pamphagidae (Orthoptera: Caelifera) of North Africa: key to genera and the annotated check-list of species. AB - At least 95 species of Pamphagidae belonging to 17 genera are known in North Africa. Taxonomic status is fairly known, with some exception, mainly due to scarcity of available specimens of some genera in museums and collections. In this paper, the author proposes a new key to genera and reports the annotated list of all the known species, based on specimens examined in different European museums. Concerning the subfamily Thrinchinae, he proposes to consider only the following species of the genus Tmethis: T. cisti, T. harterti new status, T. maroccanus and T. pulchripennis. He also considers Neotmethis bidentatus synonym of T. harterti, and the three newly described species of the genus Tuarega as synonyms of T. insignis. In addition, he proposes to remove Batrachotettix elephas from the synonyms of T. insignis, because its description consents to establish that it belongs to a South African Porthetinae, not to a Thrinchinae. With regard to the subfamily Pamphaginae, the author recognizes the presence in North Africa of three tribes, until now containing 90 species: Finotiini, Pamphagini and Euryparyphini; Amigus is definitively considered a valid genus within the tribe Pamphagini, with the only species A. nigroadspersus. Additionally, he proposes a new key to species of the genus Paracinipe. He considers Paracinipe theryi as a valid species; previously it has been listed as subspecies of P. dolichocera. He also establishes that Acinipe calabra of Italy is the same taxon living in North Africa. Further, he describes Euryparyphes rungsi new species from Middle Atlas, and Paraeumigus lopezi new species from West Morocco, and synonymizes Eunapiodes granosus rungsi with E. atlantis. Finally, he reports biometric data of the genera Tmethis, Paracinipe, Paraeumigus and Eunapiodes. PMID- 26106737 TI - Fungus-feeding thrips from Australia in the worldwide genus Hoplandrothrips (Thysanoptera, Phlaeothripinae). AB - From Australia, 16 species of Hoplandrothrips are here recorded, of which 11 are newly described. An illustrated key is provided to 15 species, but Phloeothrips leai Karny cannot at present be recognised from its description. The generic relationships between Hoplandrothrips, Hoplothrips and some other Phlaeothripinae that live on freshly dead branches are briefly discussed. PMID- 26106739 TI - Crossodactylodinae Fouquet, Blotto, Maronna, Verdade, Junca, de Sa & Trefaut Rodrigues, 2013 is an invalid junior synonym of Paratelmatobiinae Ohler & Dubois, 2012 (Amphibia, Anura). PMID- 26106738 TI - Description of a new unusual Pselaphodes Westwood, 1870 (Coleoptera: Staphylinidae: Pselaphinae) from Nepal. PMID- 26106740 TI - Systematic revision of the Parvoscincus decipiens (Boulenger, 1894) complex of Philippine forest skinks (Squamata: Scincidae: Lygosominae) with descriptions of seven new species. AB - Analysis of external morphological characters, color pattern, and DNA sequence data, plus consideration of biogeographical patterns, leads us to the hypothesis that the Parvoscincus decipiens complex of Philippine forest skinks consists of a minimum of eight highly divergent, phenotypically distinct, cohesive evolutionary lineages. We rectify this taxonomic underestimation of species diversity with formal descriptions of seven new species (P. abstrusus sp. nov., P. agtorum sp. nov., P. arvindiesmosi sp. nov., P aurorus sp. nov., P banahaoensis sp. nov., P. jimmymcguirei sp. nov., and P. palaliensis sp. nov.) and highlight geographical sampling deficiencies, which, if addressed with additional fieldwork, should lead to additional new species discoveries. Due to the difficulty of identifying non overlapping differences in scalation on similarly sized, small-bodied skinks, species level diversity in diminutive Philippine forest skinks is undoubtedly substantially underestimated. PMID- 26106741 TI - A new species of Macrobrachium Spence Bate, 1868 (Decapoda, Palaemonidae), M. pantanalense, from the Pantanal, Brazil. AB - The neotropical species Macrobrachium amazonicum (Heller, 1862) is considered a particularly successful species, showing an extremely wide range of distribution (ca 4.000 km across). Populations assigned to this species live in estuaries along the northern and northeastern coasts of South America as well as in fresh water habitats in the Amazon, Orinoco and Parana-Paraguay river basins. Following recent comparative studies that showed differential ecological, reproductive, developmental and physiological traits in geographically separated populations from the Amazon delta and the Pantanal region, Brazil, we examined the morphology of adult shrimps from these two regions. Based on significant differences, we conclude that the Pantanal population constitutes a new species, which is described here as Macrobrachium pantanalense. The main differences between M. amazonicum and the new species have been found in the morphology of the second pereiopod, the telson, and in the color patterns of both males and females. A modification on the key of American species of Macrobrachium is provided to accommodate the new species. PMID- 26106742 TI - New water mite species (Acari, Hydrachnidia) from Vietnam. AB - Descriptions of four new water mite species, Torrenticola vietnamica sp. nov. (female), Limnesia vietnamensis sp. nov. (female, deutonymph), Hygrobates gusakovi sp. nov. (male), Albaxona gusevi sp. nov. (female) from running waters of Vietnam are presented. PMID- 26106743 TI - Description of Schistonchus altissimus n. sp. (Nematoda: Aphelenchoididae), an associate of Ficus altissima in China. AB - A new nematode species was recovered from the syconia of Ficus altissima from the residential area of Huajingxincheng, Guangzhou, Guangdong Province, China during a survey of nematode diversity. Schistonchus altissimus n. sp. is characterised by having females with a short post-uterine sac, an ovoid spermatheca and a conoid tail with a mucron in the female, excretory pore located near the lip; and males with amoeboid sperm, a conoid tail without a mucron and three pairs of subventral papillae, no gubernaculum, and hook-shaped spicules with a cucullus and a thorn-shaped rostrum. Schistonchus altissimus n. sp. is typologically differentiated from all other described species in this genus, except for S. microcarpus, by having a spicule with cucullus on the male tail tip. Schistonchus altissimus n. sp. is easily differentiated from other sequenced species by the partial small subunit rRNA gene (SSU), D3 expansion segment of the large subunit rRNA gene (LSU) and mitochondrial DNA subunit I (mtCOI). Phylogenetic analysis with partial SSU sequences suggests that S. altissimus n. sp. is in a highly supported monophyletic clade with two Chinese species (S. microcarpus and S. centerae) and two neotropical species (S. aureus and Schistonchus sp. ex Ficus colubrinae Standl.). Based on inferences using LSU D3 sequence data, S. altissimus n. sp. has a closer relationship with four Chinese species (S. centerae, S. fistulosus, S. guangzhouensis and S. microcarpus) than with S. hirtus and S. superbus, also from China. PMID- 26106744 TI - Four new species of Haplosclerida (Porifera, Demospongiae) from the Aleutian Islands, Alaska. AB - Four new species of Haplosclerida are described from the Aleutian Islands, Alaska: Callyspongia mucosa n.sp., Cladocroce infundibulum n. sp., Cladocroce attu n. sp. and Cladocroce kiska n. sp. The new species are described and compared to congeners of the region. This is the northernmost record of the genus Callyspongia and the first record of the subgenus Callyspongia from the North Pacific Ocean. To accommodate Cladocroce kiska in its genus the definition has to be broadened to allow sigmas. PMID- 26106745 TI - A new species and new records of microcaddisflies (Trichoptera: Hydroptilidae) from northeastern Brazil. AB - The Hydroptilidae constitute the most diverse and widespread family of Trichoptera in the world. About 90 species of microcaddisflies have been recorded from Brazil, but the northeastern region is one of the least-sampled. In this work we describe a new species of Metrichia from Pernambuco State. Furthermore, we present the first records of Flintiella andreae Angrisano 1995 and Oxyethira bettyae Thomson & Holzenthal 2012 from Brazil, and four other new records from the northeastern region. PMID- 26106746 TI - Morphological and biological observations on the stick insect Tithonophasma tithonus (Gray, 1835) (Phasmida: Pseudophasmatidae: Pseudophasmatinae). PMID- 26106747 TI - On the advertisement call of Dermatonotus muelleri (Boettger, 1885) (Anura, Microhylidae). PMID- 26106748 TI - First record of Damiria Keller, 1891 from Brazil, with the description of a new species (Poeciloscierida; Demospongiae; Porifera). PMID- 26106749 TI - [Reactive (psychogenic) depressions]. AB - In this literature review, authors analyzed the history of studies on psychogenic (stress-included) depressions and the current state of the problem. The status of these diseases in classification systems, main directions of current research, proposed conceptions and perspectives of future studies in the filed are considered. PMID- 26106750 TI - Farewell and thanks to Dave Sackett, Cochrane's first pilot. PMID- 26106751 TI - Psychosocial interventions for benzodiazepine harmful use, abuse or dependence. AB - BACKGROUND: Benzodiazepines (BZDs) have a sedative and hypnotic effect upon people. Short term use can be beneficial but long term BZD use is common, with several risks in addition to the potential for dependence in both opiate and non opiate dependent patients. OBJECTIVES: To evaluate the effectiveness of psychosocial interventions for treating BZD harmful use, abuse or dependence compared to pharmacological interventions, no intervention, placebo or a different psychosocial intervention on reducing the use of BZDs in opiate dependent and non-opiate dependent groups. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL- the Cochrane Library issue 12, 2014) which includes the Cochrane Drugs and Alcohol Group Specialized Register; PubMed (from 1966 to December 2014); EMBASE (from 1988 to December 2014); CINAHL Cumulative Index to Nursing and AlliedHealth Literature (1982 to September 2013); PsychINFO (1872 to December 2014); ERIC (Education Resources Information Centre, (January 1966 to September 2013); All EBM Reviews (1991 to September 2013, Ovid Interface); AMED (Allied & Alternative Medicine) 1985 to September 2013); ASSIA (Applied Social Sciences Index & Abstracts (1960 to September 2013); LILACS (January 1982 to September 2013);Web of Science (1900 to December 2014);Electronic Grey Literature Databases: Dissertation Abstract; Index to Theses. SELECTION CRITERIA: Randomised controlled trials examining the use of a psychosocial intervention to treat BZDs versus pharmacological interventions,no intervention, placebo or a different psychosocial intervention on reducing the use of BZDs in opiate dependent and non-opiate dependent groups. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures outlined in Cochrane Guidelines. MAIN RESULTS: Twenty-five studies including 1666 people met the inclusion criteria. The studies tested many different psychosocial interventions including cognitive behavioural therapy (CBT) (some studies with taper, other studies with no taper), motivational interviewing (MI),letters to patients advising them to reduce or quit BZD use, relaxation studies, counselling delivered electronically and advice provided by a general practitioner (GP). Based on the data obtained, we performed two meta-analyses in this Cochrane review: one assessing the effectiveness of CBT plus taper versus taper only (575 participants), and one assessing MI versus treatment as usual (TAU) (80 participants).There was moderate quality of evidence that CBT plus taper was more likely to result in successful discontinuation of BZDs within four weeks post treatment compared to taper only (Risk ratio (RR) 1.40, 95% confidence interval (CI) 1.05 to 1.86; nine trials, 423 participants) and moderate quality of evidence at three month follow-up (RR 1.51, 95% CI 1.15 to 1.98) in favour of CBT (taper)for 575 participants. The effects were less certain at 6, 11, 12, 15 and 24 months follow-up. The effect of CBT on reducing BZDs by> 50% was uncertain for all time points examined due to the low quality evidence. There was very low quality evidence for the effect on drop-outs at any of the time intervals; post treatment (RR 1.05, 95% CI 0.66 to 1.66), three month follow-up (RR 1.71, 95% CI0.16 to 17.98) and six month follow-up (RR 0.70, 95% CI 0.17 to 2.88).Based on the very low quality of evidence available, the effect of MI versus TAU for all the time intervals is unclear; post treatment(RR 4.43, 95% CI 0.16 to 125.35; two trials, 34 participants), at three month follow-up (RR 3.46, 95% CI 0.53 to 22.45; four trials,80 participants), six month follow-up (RR 0.14, 95% CI 0.01 to 1.89) and 12 month follow-up (RR 1.25, 95% CI 0.63 to 2.47).There was very low quality of evidence to determine the effect of MI on reducing BZDs by > 50% at three month follow-up (RR 1.52,95% CI 0.60 to 3.83) and 12 month follow-up (RR 0.87, 95% CI 0.52 to 1.47). The effects on drop-outs from treatment at any of e time intervals between the two groups were uncertain due to the wide CIs; post treatment (RR 0.50, 95% CI 0.04 to 7.10), three month follow-up (RR 0.46, 95% CI 0.06 to 3.28), six month follow-up (RR 8.75, 95% CI 0.61 to 124.53) and 12 month follow-up(RR 0.42, 95% CI 0.02 to 7.71).The following interventions reduced BZD use - tailored GP letter versus generic GP letter at 12 month follow-up (RR 1.70, 95%CI 1.07 to 2.70; one trial, 322 participants), standardised interview versus TAU at six month follow-up (RR 13.11, 95% CI 3.25 to 52.83; one trial, 139 participants) and 12 month follow-up (RR 4.97, 95% CI 2.23 to 11.11), and relaxation versus TAU at three month follow-up (RR 2.20, 95% CI 1.23 to 3.94).There was insufficient supporting evidence for the remaining interventions.We performed a 'Risk of bias' assessment on all included studies. We assessed the quality of the evidence as high quality for random sequence generation, attrition bias and reporting bias; moderate quality for allocation concealment, performance bias for objective outcomes, and detection bias for objective outcomes; and low quality for performance bias for subjective outcomes and detection bias for subjective outcomes. Few studies had manualised sessions or independent tests of treatment fidelity; most follow-up periods were less than 12 months.Based on decisions made during the implementation of protocol methods to present a manageable summary of the evidence we did not collect data on quality of life, self-harm or adverse events. AUTHORS' CONCLUSIONS: CBT plus taper is effective in the short term (three month time period) in reducing BZD use. However, this is not sustained at six months and subsequently. Currently there is insufficient evidence to support the use of MI to reduce BZD use. There is emerging evidence to suggest that a tailored GP letter versus a generic GP letter, a standardised interview versus TAU, and relaxation versus TAU could be effective for BZD reduction. There is currently insufficient evidence for other approaches to reduce BZD use. PMID- 26106752 TI - Chelation for autism spectrum disorder (ASD). AB - BACKGROUND: It has been suggested that the severity of autism spectrum disorder (ASD) symptoms is positively correlated with the level of circulating or stored toxic metals, and that excretion of these heavy metals, brought about by the use of pharmaceutical chelating agents, results in improved symptoms. OBJECTIVES: To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms. SEARCH METHODS: We searched the following databases on 6 November 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase,PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including three trials registers. In addition we checked references lists and contacted experts. SELECTION CRITERIA: All randomised controlled trials of pharmaceutical chelating agents compared with placebo in individuals with ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data. We did not conduct a meta-analysis, as only one study was included. MAIN RESULTS: We excluded nine studies because they were non-randomised trials or were withdrawn before enrolment.We included one study, which was conducted in two phases. During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three-day course of oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms. AUTHORS' CONCLUSIONS: This review included data from only one study, which had methodological limitations. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed. PMID- 26106753 TI - Extrapontine Myelinolysis in a patient with Primary Adrenal Insufficiency. AB - PURPOSE: To report the development of estrapontine myelinolysis (EPM) in a patient with adrenal insufficiency and review similar in the literature. CASE REPORT: A 49-year-old female with insufficiency presented with acute dysarthria, stuttering, and parkinsonism. She received isotonic saline hydration for adrenal crisis and hyponatremia 18 days before the onset of symtoms. The brain MRI and MRS showed demyelination at bilateral basal ganglia and the thalamus, which was compatible with EPM and resolved within 3 months after steroid treatment. CONCLUSION: Development of acute parkinsonism after rapid correction of hyponatremia may indicate the occurrence of EPM and underlying adrenal insufficiency should be excluded in these patients. PMID- 26106754 TI - Photosynthesis in variable environments. PMID- 26106755 TI - Huge arachnoid Cyst Presenting as Cough Headache. PMID- 26106756 TI - Obituary: John Michael Thresh - On lifelong war with plant viruses. PMID- 26106757 TI - [In Process Citation]. PMID- 26106758 TI - [In Process Citation]. PMID- 26106759 TI - [In Process Citation]. PMID- 26106760 TI - [In Process Citation]. PMID- 26106761 TI - Leaf-litter thrips of the genus Adraneothrips from Asia and Australia (Thysanoptera, Phlaeothripinae). AB - The Oriental genus Stigmothrips Ananthakrishnan is synonymised with A draneothrips Hood, a genus in which most species have been described from the Neotropics. Problems with descriptions by T.N. Ananthakrishnan of species from India are discussed, but cannot be fully resolved without access to the holotypes. A key is provided to 23 species of Adraneothrips from Asia and Australia, including four new species: darwini sp. n. from Northern Territory, Australia; hani sp. n. from Taiwan, China; yunnanensis sp. n. from Yunnan, China as well as Java, Indonesia; and waui sp. n. from Papua New Guinea. One species from the Philippines, Adraneothrips makilingensis (Reyes) comb. n., is transferred from Apelaunothrips, and the male of Adraneothrips russatus (Haga) is described and illustrated for the first time, from Yunnan, China. Two species are newly recorded from Australia: coloratus (Mound) previously known only from the Solomon Islands, and russatus (Haga) previously known from southern Japan and southern China but with one female recorded here from Fiji. Further new records are, coloratus from Java, and chinensis (Zhang & Tong) from Malaysia. Colonies of species in this genus are commonly found living on dead leaves, as fungus feeders, and many species are brightly coloured or bicoloured in patterns of yellow and brown. PMID- 26106762 TI - A new species of the genus Tropiocolotes Peters, 1880 from western Iran (Squamata: Sauria: Gekkonidae). AB - The genus Tropiocolotes comprises small, naked toed, ground dwelling and nocturnal desert geckos, ranging from Morocco and Mauritania in northern Africa to south and central Arabia as well as coastal Iran. Herein, we describe a new species of the genus Tropiocolotes from western Iran based on five specimens from Nayband region. This new taxon is described with a statistical approach based on 34 meristic, metric and qualitative morphological characters of more than 300 individuals of related species. PMID- 26106763 TI - The South American wolf spider genus Birabenia Mello-Leitao, 1941 (Araneae: Lycosidae: Lycosinae). AB - The wolf spider genus Birabenia Mello-Leitao, 1941 is revalidated, comprising B. birabenae Mello-Leitao (type species) and B. vittata (Mello-Leitao) comb. n. The monotypic genus Melloicosa Roewer is synonymised with Birabenia by the transfer of its type species Gnatholycosa vittata Mello-Leitao. Three species, Hogna taeniata (Mello-Leitao), Geolycosa sanogastensis (Mello-Leitao) and Paratrochosina murina (Mello-Leitao) are considered junior synonyms of B. birabenae. Representatives of Birabenia show affinities with Trochosa C. L. Koch but can be distinguished by the presence of one pair of apical spines or none on the ventral side of tibia I of females, the presence of four teeth on the cheliceral retromargin, a shorter furrow on the prolateral side of the tegulum on the male bulb and by having more than seven macrosetae at the tip of cymbium. Birabenia is distributed from north-western Argentina to southern Uruguay. PMID- 26106764 TI - A review of Amblypalpus and Priscapalpus (Acari: Trombidiformes: Tenuipalpidae), including two new species of Amblypalpus from Iran. AB - Two new species of Amblypalpus (Acari: Trombidiformes: Tenuipalpidae) are described from Iran: Amblypalpus iraniensis sp. nov., from Wild Almond, Amygdalus scoparia (Rosaceae), and Amblypalpus thymus sp. nov., from Common Thyme, Thymus vulgaris (Lamiaceae). The new species are classified tentatively in Amblypalpus. The species Priscapalpus thomissus Meyer, 1979 is transferred to Amblypalpus and the genus concept of Priscapalpus is narrowed and therefore redefined. Similarly, we present an expanded concept of Amblypalpus. A key to brevipalpine genera and Amblypalpus species is provided. PMID- 26106765 TI - Uirassubrillia beckeri gen. n., sp. n. (Diptera: Chironomidae, Orthocladiinae) from northeastern Brazil. AB - Uirassubrillia beckeri gen. n., sp. n. is described and illustrated based on male and female imagines from Bahia State in Brazil. The new genus is placed in the Brillia-group as the adults have a strongly setose body and setose wing membrane, RM is long and oblique, and the eye has a long, parallel-sided dorsomedian extension. The male hypopygium has a characteristic digitiform superior volsella and a bifurcate gonostylus. The female has three seminal capsules, two large and a third, smaller one. PMID- 26106766 TI - Two new species of Pseudonannolene Silvestri, 1895 from Brazilian iron ore caves (Spirostreptida: Pseudonannolenidae). AB - Pseudonannolene gogo sp. n. and Pseudonannolene rolamossa sp. n. are described from individuals collected from Brazilian iron ore caves, Minas Gerais state. The family Pseudonannolenidae is exclusively Neotropical and frequently found in caves of Brazil, from which 23 species are known. The new species are compared with its congeners and with other Brazilian cave-dwelling species. PMID- 26106767 TI - Molecular evidence of the taxonomic status of western Mexican populations of Pliaethornis longirostris (Aves: Trochilidae). AB - Species diversity is largely underestimated by current taxonomy, precluding a precise understanding of evolutionary processes. Genetic data have increased our understanding of that cryptic diversity, and multilocus studies are now desirable. In this study, we used mitochondrial and nuclear DNA sequences to evaluate the taxonomic status of the western Mexico's populations of Phaethornis longirostris. We found differences of 4.2 % in mtDNA and different alleles for one nDNA locus between western and eastern Mexican populations. Molecular and morphological evidence support the separation of these populations (P. 1. mexicanus and P. 1. griseoventer) as the species Phaethornis mexicanus Hartert 1897. Phaethornis mexicanus is endemic to western Mexico and sister to the remaining populations of P. longirostris. The speciation of P mexicanus probably occurred around 880,000 years ago by a vicariant event involving climatic vegetational changes. PMID- 26106768 TI - Redescription of the tadpole of Kaloula taprobanica (Anura: Microhylidae) from Sri Lanka. PMID- 26106769 TI - Australian species of the ant genus Dolichoderus (Hymenoptera: Formicidae). AB - The Australian species of the ant genus Dolichoderus are revised. The fauna contains 27 species belonging to four species goups, the australis group (5 species, 2 newly described), the doriae group (6 species, 2 newly described), the scabridus poup (6 species, 1 newly described) and the scrobiculatus group (10 species, 4 newly described). The former subspecies niger Crawley and rufotibialis Clark are raised to species-level. The following nine new species are described: albamaculus sp. n., canopus sp. n., etus sp. n., gordoni sp. n., inferus sp. n., kathae sp. n., omicron sp. n., rutilus sp. n. and semiorbis sp. n. Four new synonyms are proposed: armstrongi McAreavey with reflexus Clark, glauerti Wheeler with parvus Clark, occidentalis Clark withformosus Clark and ruficornis Santschi with scabridus Roger. A neotype is designated for D. clusor Forel. The majority of species are found in southern forested areas with only a few species known from arid and tropical regions. PMID- 26106770 TI - Oligochaeta (Annelida) of the profundal of Lake Hazar (Turkey), with description of Potamothrix alatus hazaricus n. ssp.. AB - Lake Hazar is an alkaline oligotrophic lake of tectonic origin, located in the Eastern Anatolia region in Turkey, 1248 a a.s.l. Its surface area is 80 km2, the average depth 93 m and maximum depth 205 m. The lake and its surroundings an under protection as a region of historical value. During the present study (2007 2012), samples were taken from 15 stations located at a depth of 2-200 m. Oligochaeta comprised 69% of the total invertebrate abundance. The profundal olgochaete fauna was found to consist of only three tubificid taxa, all of the subfamily Tubificinae. Potamothrix alatus hazaricus Timm & Arslan, n. ssp. was dominating anywhere down to maximum depths while Psammoryctides barbatus (Grube) and Ilyodrilus(?) sp. occurred seldom. All three are new records for Lake Hazar. Potamothrix alatus hazaricus shares the "winged" body shape in its genital region with the nominal, brackish-water subspecies P. a. alatus Finogenova, 1972, and the lateral position of the spermathecal pores and the shape of the ventral chaetae with the freshwater subspecies P. a. paravanicus Poddubnaja & Pataridze, 1989 known from Transcaucasian lakes. The mitochondrial COI barcoding gene suggests long separation between the two taxa, but the nuclear ITS region shows no variation. The generic position of Ilyodrilus (?) sp. remains obscure since its internal genitalia could not be studied. PMID- 26106771 TI - A revision of the Schinia volupia (Fitch) species complex (Lepidoptera: Noctuidae: Heliothinae). AB - DNA barcode analysis of cytochrome oxidase I (COI) could not differentiate between the species of the Schinia volupia (Fitch, 1868) complex including S. volupia, S. masoni Smith, S. fulleri (McElvare, 1961); S. sanrafaeli Opler, 2004; S. miniana (Grote, 1881); and S. biforma Smith, 1906. Genitalic characters could only differentiate S. biforma from the S. volupia complex. Based on forewing color and pattern, larval host plant utilization, and geographic distribution, S. volupia, S. sanrafaeli, S. fulleri, and S. miniana are recognized as valid species and S. masoni is considered a new synonym of S. volupia. Schinia volupia, S.fulleri, S. sanrafaeli, S. miniana, and S. biforma are diagnosed and described. A variety of adult images are presented to show the range of variation among these species. Male and female genitalia of all included taxa are illustrated. Host plant utilization is discussed and illustrated. Distribution maps for examined specimens are provided. PMID- 26106772 TI - Catalog of type specimens of invertebrates in the collection of the Instituto Nacional de Pesquisas da Amazonia, Manaus, Brazil. VI. Hexapoda: Hemiptera: Heteroptera. AB - A catalog of type specimens of Heteroptera (Insecta: Hemiptera) deposited in the Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, Brazil, is presented and updated to May, 2012. A total of 37 holotypes and 61 lots of paratypes of 78 species are listed in their families: Miridae and Reduviidae (infraorder: Cimicomorpha); Mesoveliidae and Velfidae (Gerromorpha); Belostomatidae, Naucoridae, and Notonectidae (Nepomorpha); and Coreidae, Geocoridae [the older sense of "Lygaeidae"], and Pentatomidae (Pentatomomorpha). The taxa are presented alphabetically by infraorders, families, and genera, followed by epithet, bibliographic citation, type category, collection number, method of preservation, and present data on the labels. When necessary, we added localities data, and changes in taxonomic status of some species PMID- 26106773 TI - New records of water mites mainly from Vogelkop, New Guinea (Acari: Hydrachnidia), with the description of one new genus and thirteen new species. AB - New records are given of water mites from Vogelkop, New Guinea. A total of 33 species is recorded, including the descriptions of a representative of a new genus, i.e. Dropursides aberratus, and of twelve further species new to science, i.e. Hydrobaumia purpurea, Oxus manokwariensis, Limnesia multiscutata, Limnesia vogelkop, Australiobates elongatus, Unionicola novaeguineae, Neumania silvestris, Recifella jluviatilis, Koenikea sentaniensis, Albia ilikensis, Albia papuaensis and Axonopsella bisetosa. The female of Albia wauensis Wiles and the male of Axonopsella ovalis Wiles are described for the first time. PMID- 26106774 TI - First fossil larvae of Berothidae (Neuroptera) from Baltic amber, with notes on the biology and termitophily of the family. AB - Four fossil larvae of Berothidae (Neuroptera) from Baltic amber are described in detail, and the main characters of a fifth larva are discussed briefly. Two first instars very probably belong to the Berothinae; the subfamilial affinities of three othe (probably full-grown) larvae are unclear. The latter are characterized by features not found so far in extant taxa of Berothi dae: antennae and labial palps with six to seven segments; ecdysial cleavage lines consist of only frontal and coronal sutures (the lateral suture is absent); pronotal sclerites large and very close to each other along midline. However, these larvae belong with certainty to Berothidae as indicated by the structure of their mouthparts, and their general appearance. Morphological and biological data on the larvae of Berothidae are summarized and analyzed. It is presumed that termitophily might have evolved during the Cretaceous (or in the early Cenozoic), and only in Berothinae (or in subfamilies closely related to this group). The Baltic amber berothid assemblage apparently included both termitophilous and noni termitophilous larvae. PMID- 26106775 TI - On some brachypterous Encyrtidae (Hymenoptera: Chalcidoidea) from India, with description of four new species. AB - Four new species of brachypterous Encyrtidae (Hymenoptera: Chalcidoidea) are described. These are: Cheiloneurus mandyanus Hayat, sp. nov., Encyrtus coorgensis Hayat & Zeya, sp. nov., Microterys atturensis Hayat, sp. nov. and Pseudectroma indicum Hayat & Zeya, sp. nov. The following species that exist either in brachypterous forms only or in both brachypterous and macropterous forms are recorded: Anomalicornia tenuicornis Mercet, Cheiloneurus bangalorensis (Subba Rao), C. quadricolor (Girault), Diversinervus cervantesi (Girault), Globulencyrtus politus (Hoffer), Indaphycus planus Hayat, Neodusmetia sangwani (Subba Rao), Prochiloneurus bolivari Mercet, Rhopus atys Noyes & Hayat and Sakencyrtus mirus Hayat. Globulencyrtus politus and P bolivari are newly recorded from India. A diagnosis of Globulencyrtus, and redescriptions of G politus, P bolivari based on the Indian specimens and of the brachypterous forms of R. atys are given. The occurrence of brachyptery in the Encyrtidae is briefly noted together with a list of brachypterous species recorded from India. PMID- 26106776 TI - Ciimaerocyon gen. nov., a morphologically aberrant myrmecophilous genus of water scavenger beetle (Coleoptera: Hydrophilidae: Sphaeridiinae). AB - Anew hydrophilid genus Chimaerocyon gen. nov. containing two species, C. shimadai sp. nov. (Malaysia: Pahang) and C. sumatranus sp. nov. (Indonesia: Sumatra), is described. Specimens of C. shimadai were collected from brood cells in anest of Pheidole singaporensis Ozdikmen, 2010. The biology of C. sumatranus remains unknown. A molecular phylogeny based on four genes (cox1, cox2, 18S and 28S) supports the placement of the genus as deeply nested within the Cercyon-group of the tribe Megasternini. This position is supported by the subdistal position of the median spur in the hind wing (unique to Megasternini) and the presence of sucking disc on male maxilla (unique for Megastemini+Sphaeridiini). The remaining external morphology differs substantially from other representatives of Megasternini. The hypothesis that the aberrant morphology of Chimaerocyon gen. nov. is a consequence of myrmecophily is discussed. PMID- 26106777 TI - Two new species of the batfish genus Malthopsis (Lophiiformes: Ogcocephalidae) from the Western Indian Ocean. AB - Two new species of the triangular batfishes, genus Malthopsis, are described from the western Indian Ocean. Both belong to a species group with minute prickles on the ventral surface. Malthopsis bradburyae n. sp. differs from its congeners by having the body covered by blunt, flat bucklers; subopercular buckler dull, without well-developed spines, its ventral surface covered by minute prickles and a few large bucklers anterior to the pelvic-fin base; rostrum moderately long, directed forward rather than upward; eye relatively small. Malthopsis austrafricana n. sp. differs from its congeners by having a long forward and horizontally directed rostrum; subopercular bucklers dull, without well-developed spines; ventral surface evenly covered by minute prickles and small bucklers; small black patches on dorsal surface; and a strong tail. Comments and a key to the Western Indian Ocean species of Malthopsis are provided. PMID- 26106778 TI - The genus Macrostemum Kolenati 1859 (Trichoptera: Hydropsychidae) in the Neotropical Region: Description of two new species, taxonomic notes, distributional records and key to males. AB - The genus Macrostemum Kolenati contains 105. described species, with 15 valid species in the Neotropical region. The Adults are recognized principally by wing membranes strongly marked with dark and light colors. The Neotropical species Of Macrostemum were described based on the wing colors patterns and body morphology. In this paper we present a taxonomic study of the Neotropical species, descriptions of two new species from Brazil, distributional records and a key to males. The male of Macrostemum negrense Flint 1978 is described for the first time, Names of three Neotropical species, M. ramosum (Navas 1916), M. trigramma (Navas 1916), and M. triste (Navas 1916) are designated nomina dubia. PMID- 26106779 TI - A new, riparian, species of Allobates Zimmermann and Zimmermann, 1988 (Anura: Aromobatidae) from southwestern Amazonia. AB - We describe Allobatesflaviventris sp. nov., a medium-sized (SVL 16.7-19.7 mm in males; 19.3-21.1 mm in females) aromobatid frog with Finger III not swollen in adult males from eastern state of Acre, Brazil. It inhabits open forests with bamboo, usually along small streams and rivers. it has golden-yellow belly and a unique advertisement call as a distinctive character. Notes on natural history are also provided. PMID- 26106780 TI - Taxonomic revision of Drymoluber Amaral, 1930 (Serpentes: Colubridae). AB - The present study is a taxonomic revision of the genus Drymoluber Amaral, 1930, using meristic and morphometric characters, aspects of external hemipenial morphology and body coloration. Sexual dimorphism occurs in D. dichrous and D. brazili but was not detected in D. apurimacensis. Morphological variation within D. dichrous is related to geographic distance between populations. Furthermore, variation in the number of ventrals and subcaudals in D. dichrous and D. brazili follows latitudinal and longitudinal clinal patterns. Drymoluber dichrous is diagnosed by the presence of 15-15-15 smooth dorsal scale rows with two apical pits, and 157-180 ventrals and 86-110 subcaudals; it occurs along the eastern versant of the Andes, in the Amazon forest, on the Guiana Shield, in the Atlantic forest, and its transitional areas with the Caatinga and Cerrado. Drymoluber brazili has 17-17-15 smooth dorsal scale rows with two apical pits, 182-202 ventrals and 109-127 subcaudals, and ranges throughout the Caatinga, Cerrado, Atlantic forest and transitional areas between these last two domains. Drymoluber apurimacensis has 13-13-13 smooth dorsal scale rows without apical pits, 158-182 ventrals and 84-93 subcaudals, and occurs in the Apurimac Valley, south of the Apurimac and Pampas rivers in Peru. PMID- 26106781 TI - Paraedessa, a new genus of Edessinae (Hemiptera: Heteroptera: Pentatomidae). AB - The new genus Paraedessa is proposed, to include four species previously placed in Edessa. The new genus is characterized by males with the pygophore showing a lateral expansion of proctiger, and females with gonocoxites 8 reduced; gonapophyses 8 exposed and sclerotized. The species are very similar and their identification is possible only by comparing genitalia. New combinations proposed are Paraedessa stolida (Linnaeus) from Suriname and Brazil; P. heymonsi (Breddin) from Peru and Bolivia; P verhoeffi (Breddin) from Venezuela, Colombia, Peru and Brazil and P paravinula (Barber) from Puerto Rico. New species proposed are P. albomaculata from Suriname; P. cyanodorsata from Costa Rica, Panama and Venezuela; P. ecuadoriensis from Colombia and Ecuador; P. silvicola from French Guiana; P. subretangulata from Nicaragua, Costa Rica, Colombia and Venezuela. The species were illustrated and photographed. Descriptions were made using mostly male and female genitalia external morphological characters. A key and distribution map for the species are also provided. PMID- 26106782 TI - The genus Gelanes Horstmann (Hymenoptera: Ichneumonidae: Tersilochinae) from South Korea, with description of four new species. AB - The genus Gelanes Horstmann is recorded from South Korea for the first time. Eight species of the genus are found to occur in this country. Four species, G dentator sp. nov., G protritus sp. nov., G provectus sp. nov. and G verendus sp. nov., are described as new, three species, G belokobylskii, G cuspidatus and G simillimus, also occur in the Russian Far East, and G gubarevae was previously known only from Europe. A key to the South Korean species of Gelanes is provided. PMID- 26106783 TI - Species status of Bombus monticola Smith (Hymenoptera: Apidae) supported by DNA barcoding. AB - Certain species of bumblebees are difficult to distinguish based on morphology alone due to a lack of diagnostic characters and extensive intraspecific variation in colour patterns. The discussion concerning whether Bombus lapponicus and Bombus monticola are the same species or not, seems to be ongoing. We present a study of 16 speciemens of B. monticola/B. lapponicus from Norway, identified with previously published morphological characters and with DNA barcoding. The results showed a match with the examination of the morphological characters and the DNA sequence data. These results confirm that B. lapponicus and B. monticola appear as separate species in Norway, which supports earlier conclusions based on both morphological differences and differences in cephalic marking pheromones in males. The wide sympatric range of the two taxa in Scandinavia also strongly support their species status. PMID- 26106784 TI - Taxonomic revision of the African genus Trechosiella Jeannel (Coleoptera: Carabidae: Trechinae). AB - The genus Trechosiella Jeannel, 1960 (Carabidae: Trechinae) is revised. In addition to the known species T. laetula (Peringuey, 1898), T. scotti (Jeannel, 1937), T. basilewskyi Jeannel, 1960 and T. katicola Jeannel, 1964, T. endroedyyoungai spec. nov., T. oligophthalma spec. nov. and T. scotti swartbergensis subspec. nov. are newly described. Trechosiella laetulaperingueyi (Jeannel, 1926) is recognized as a new synonym of T. laetula sensu stricto. Trechosiella macroptera Casale, 1986 is demoted to become a subspecies of T. scotti, as T scotti macroptera status demotus. An identification key to the known species and subspecies of Trechosiella and a distribution map of the southern African taxa are provided. PMID- 26106785 TI - New unidentate jumping spider genera (Araneae: Salticidae) from Australia. AB - The Australian fauna includes large numbers of undescribed, tiny, litter-living, jumping spiders. In this paper four monotypic new genera (Ananeon howardensis n. g. n. sp., Barraina anfracta n. g. n.sp., Frewena maculata n.g. n.s., and Pungalina weiri n.g, n.sp.) are described. Two species (Neon taylori n.sp. and Neon australis n. sp.) representing the two distinctive morphological patterns found in Australian species of this genus are also described. The former, similar in the morphology of the palp and genitalia to that found in many species from eastern Australia, is most similar in morphology to N. sumatranus Logunov 1998 from Indonesia and N. kovblyuki Logunov 2004 from the Crimea. The latter, and other similar species from South Australia and Western Australia, has palp morphology and fringing on L1 very similar to that seen in N. nojimai Ikeda 1995 from Japan. PMID- 26106786 TI - New species of Tenuipalpus (Acari: Tenuipalpidae) from Semidecidual Forest remnants in the State of Sao Paulo, Brazil. AB - Three new species of the genus Tenuipalpus (Acariformes: Tenuipalpidae), T tapiae sp. nov., T. apichai sp. nov., and T. nambii sp. nov. collected in Semidecidual Forest native plants in the northwest of the state of Sao Paulo, Brazil are described and illustrated. A key of the Brazilian species of Tenuipaipus based on females is presented. PMID- 26106787 TI - The nomenclatural status of the two "spiny-wristed" fiddler crabs: Uca spinicarpa Rathbun, 1900, and U. hesperiae Crane, 1975 (Crustacea: Brachyura: Ocypodidae). AB - A secondary homonymy is documented for Gelasimus [= Uca] tetragonon var. spinicarpa Kossmann, 1877 (a species from the Red Sea), and Uca spinicarpa Rathbun, 1900 (a species from the Gulf of Mexico). Although Kossmann's usage of the nomen spinicarpa has chronological priority, a reversal of precedence is required by Article 23.9 of the Code since Kossmann's use has not been applied as a valid name since the original publication in 1877, while Rathbun's use of the name has been applied over 50 times in the last half century. The species Kossmann was most likely referring to is today known as Uca hesperiae Crane, 1975, a name which may be retained in light of the reversal of precedence. PMID- 26106788 TI - Further contribution to the knowledge of Ityphilus calinus Chamberlin, 1957, a poorly known ballophilid centipede from Colombia, with description of Ityphilus bonatoi, a new diminutive geophilomorph species from Brazil (Myriapoda: Chilopoda, Geophilomorpha). AB - Ityphilus calinus Chamberlin, 1957 (Chilopoda: Geophilomorpha, Ballophilidae), a poorly known centipede from Cauca Valley, Colombia, is herein redescribed and illustrated after the male holotype, revealing the condition of the forcipular tarsungulum (which is completely smooth), also giving new data on many other morphological features of specific value until now unknown. A new diminutive species named Ityphilus bonatoi sp. nov. is herein proposed after the holotype female from Rio de Janeiro State, Brazil. The new species is characterized by having the internal edge of the forcipular tarsungulum serrate; among the other Neotropical members of the genus having the same trait, it only shares with I. donatellae Pereira, 2012 (from Central Amazon) a very small body size and a low number of leg-bearing segments. The new species represents the first record of the genus Ityphilus from the Atlantic Rainforest biome, and the southernmost representative of the genus in the Continent. A key for identification of the Neotropical species currently included in Ityphilus is also given. PMID- 26106789 TI - New species of high elevation cloud forest butterflies of the genus Pedaliodes Butler from the northern Colombian Andes (Lepidoptera, Nymphalidae, Satyrinae). AB - Four new species of Pedaliodes Butler (i.e., P. adrianae, n. sp., P. haydoni, n. sp., P. philinae, n. sp. and P. rodriguezi, n. sp.) are described from the high elevation cloud forests in the Frontino massif in the Colombian Western Cordillera and the northern part of the Central and Eastern Cordilleras. The affinities of these new species with other congeners are discussed. The total number of described species of Colombian Pronophilina is increased to 208, with a particularly high total number of species (88) and proportion of endemic species (26%) in the Western Cordillera. PMID- 26106790 TI - The Hemiptera type-material housed in the "Museu de Ciencias Naturais, Fundacao Zoobotanica do Rio Grande do Sul" of Porto Alegre, Brazil. AB - We provide a commented and referenced list on the type material deposited in the "Museu de Ciencias Naturais, Fundacao Zoobotanica do Rio Grande do Sul", Porto Alegre, Brazil. Geographic coordinates are available on a digital repository for free access. High-resolution images of the specimens are available under request. PMID- 26106791 TI - Neotripyla vulgaris gen. n., sp. n. and Semitobrilus andrassyi sp. n. (Nematoda, Triplonchida) from freshwater bodies of Vietnam. AB - A new genus and two new species are described and illustrated from Vietnam. Neotripyla gen. n. has distinctive morphological characters of both Tripylidae and Tobrilidae. The presence of three lips, a narrow stoma with no sclerotized walls, and the arrangement of outer labial and cephalic setae are characteristic of nematodes of the family Tripylidae. The presence of vesiculate precloacal supplements in males and the absence of a muscular pouch for the spicular apparatus are characteristic of nematodes of the family Tobrilidae. Accordingly a new family, Neotripylidae fam. n., is established. Neotripyla vulgaris gen. n., sp. n. is designated the type and only species of the new genus and family. Semitobrilus andrassyi sp. n. is closely related to S. gagarini (Ebsary, 1982), but differs in the longer spicules (71-80 um vs 65 um long in S. gagarini) and in the presence of keel-like projection and lateral ribs at distal part of spicules. S. gagarini (Ebsary, 1982) is considered a valid species of the genus Semitobrilus. A list of all valid species of the genus Semitobrilus and key for their determination are given. PMID- 26106792 TI - A new species of Atrichopleura Bezzi (Diptera, Empididae, Empidinae) from Ceara, Brazil. AB - Atrichopleura Bezzi, 1909 occurs in different regions of the Southern Hemisphere (24 Neotropical species, 2 Afrotropical species and 2 Australasian species). A new species collected in the Brazilian state of Ceara, A. acuminata sp. nov. is described and illustrated. This is the first record of the genus from northeastern Brazil. A modified key to the five Brazilian species is presented. PMID- 26106793 TI - A new and possibly critically endangered species of casque-headed tree frog Aparasphenodon Miranda-Ribeiro, 1920 (Anura, Hylidae) from southeastern Brazil. AB - A new species of casque-headed tree frog of the genus Aparasphenodon is described from the municipality of Cataguases (21 degrees 20'S, 42 degrees 45'W; 288 m a.s.l.) in the Atlantic Rain Forest of Minas Gerais State, southeastern Brazil. Aparasphenodon pomba sp. nov. is characterized by medium size (males, snout-vent length, SVL 51.6-60.5 mm; females, SVL 58.7-62.1 mm); snout almost round in dorsal view; dorsum and limbs with cream-colored reticulation on dark-brown background; spots on ventral surface cream-colored; lips white; cream-colored dorsolateral stripe originating on the snout, crossing the upper eyelid and extending posteriorly to the axilla level; and red iris. PMID- 26106794 TI - First record of the genus Chvalaea Papp & Fo1dvari from Northern Europe (Diptera: Hybotidae). PMID- 26106795 TI - New and interesting Peritelini of the Western Mediterranean fauna. XX. A novel Meira (Jacquelin du Val, 1852) species from the Ligurian Alps. AB - Meira diottii, nov.sp. from the Ligurian Alps is described. Relevant anatomical characters are detailed and illustrated with drawings and photography. Characteristic sensilla on the penis are identified and illustrated with scanning electron microscopy. Relationships with other Meira species are proposed. PMID- 26106796 TI - A new species of Evonima Walker, 1865 (Lepidoptera: Nolidae: Nolinae) from China. PMID- 26106798 TI - SERS and NMR Studies of Typical Aggregation-Induced Emission Molecules. AB - Over recent decades, aggregation-induced emission (AIE) molecules have attracted increasing attention. Restriction of intramolecular rotation (RIR) has been widely accepted as the cause of the emission when AIE molecules aggregate into clusters. The intramolecular rotation of AIE molecules can be monitored by molecular vibration spectra such as nuclear magnetic resonance (NMR), infrared, and Raman, especially surface-enhanced Raman scattering (SERS) which has high sensitivity down to a single molecule. We employed SERS and NMR to study the AIE emission mechanism and compared experimental results with simulation data to monitor the RIR. Interestingly, we found that intramolecular rotation was also restricted for individual AIE molecules loaded onto SERS substrate surfaces due to the laid-down configuration. PMID- 26106797 TI - Shrapnel nanoparticles loading docetaxel inhibit metastasis and growth of breast cancer. AB - Metastasis is one of the major obstacles for the successful therapy of breast cancer. To inhibit the metastasis and growth of breast cancer simultaneously, a new docetaxel (DTX) loaded shrapnel nano delivery system with the reduction- and enzyme-sensitive properties was designed and developed. Firstly, methoxy polyethylene glycol-peptide-vitamin E succinate (PPV), a matrix metalloproteinases (MMPs)-sensitive copolymer, was synthesized by conjugating mPEG and vitamin E succinate (VES) using an enzyme-sensitive peptide. Then, DTX loaded methoxy polyethylene glycol-s-s-vitamin E succinate (PSV) micelles (DPM) @ PPV-based liposomes (DPM@PL) were prepared by the incorporation of DPM into the PPV-based liposomes. DPM@PL showed a shrapnel structure with average particle size 113.3 +/- 2.7 nm. The drug loading and encapsulation efficiency of DPM@PL were 1.93% and 99.02%, respectively. An obvious burst release (>90%) of drug was observed in the simulated tumor microenvironment with MMPs and reductive glutathione. The cellular uptake and cytotoxicity of DPM@PL in 4T1 cells were significantly enhanced after the pre-treatment of activated MMP-9. Compared with Taxotere((r)), DPM@PL remarkably increased the distribution of DTX in lung and tumor of 4T1 tumor-bearing mice, and inhibited the in situ tumor growth and pulmonary metastasis formation effectively through the enhanced DTX-induced apoptosis and the reduced metastasis-promoting proteins expression. Compared with saline group, the inhibitory rates of DPM@PL against tumor volume and lung metastasis were about 81% and 92%, respectively, and it didn't produce the significant systemic toxicity. As a result, DPM@PL could be a promising nano delivery system for the successful therapy of breast cancer. PMID- 26106799 TI - Chiral Lewis Acid-Catalyzed Enantioselective Cycloadditions between Indoles and Cyclic Carbonyl Ylides Derived from Diazodiketone or Diazoketoester Derivatives. AB - Asymmetric 1,3-dipolar cycloaddition reactions between N-methylindoles and several cyclic carbonyl ylides that were derived from diazodiketone or diazoketoester precursors in the presence of both achiral Rh and chiral lanthanoid metal catalysts are described. For the six-membered cyclic carbonyl ylides derived from 1-diazo-5-aryl-2,5-pentanedione precursors, the cycloaddition reactions were carried out using Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2 Lu(OTf)3 complex (10 mol %) as catalysts, resulting in high enantioselectivities (83% to >98% ee (exo)) along with relatively good exo-selectivities (exo:endo = 65:35 to 94:6) and yields (63-85%). For the five-membered cyclic carbonyl ylide derived from 1-diazo-2,4-pentandione precursor, the cycloaddition reaction with 5 bromo-1-methylindole was carried out in the presence of Rh2(OAc)4 (2 mol %) and the chiral Pybox-Ph2-Er(OTf)3 complex (30 mol %) as catalysts, resulting in relatively good enantioselectivity (78% ee) and endo-selectivity (endo:exo = 81:19). PMID- 26106800 TI - Evaluation of sterol transport from the endoplasmic reticulum to mitochondria using mitochondrially targeted bacterial sterol acyltransferase in Saccharomyces cerevisiae. AB - To elucidate the mechanism of interorganelle sterol transport, a system to evaluate sterol transport from the endoplasmic reticulum (ER) to the mitochondria was constructed. A bacterial glycerophospholipid: cholesterol acyltransferase fused with a mitochondria-targeting sequence and a membrane-spanning domain of the mitochondrial inner membrane protein Pet100 and enhanced green fluorescent protein was expressed in a Saccharomyces cerevisiae mutant deleted for ARE1 and ARE2 encoding acyl-CoA:sterol acyltransferases. Microscopic observation and subcellular fractionation suggested that this fusion protein, which was named mito-SatA-EGFP, was localized in the mitochondria. Steryl esters were synthesized in the mutant expressing mito-SatA-EGFP. This system will be applicable for evaluations of sterol transport from the ER to the mitochondria in yeast by examining sterol esterification in the mitochondria. PMID- 26106801 TI - Speciation Matters: Bioavailability of Silver and Silver Sulfide Nanoparticles to Alfalfa (Medicago sativa). AB - Terrestrial crops are directly exposed to silver nanoparticles (Ag-NPs) and their environmentally transformed analog silver sulfide nanoparticles (Ag2S-NPs) when wastewater treatment biosolids are applied as fertilizer to agricultural soils. This leads to a need to understand their bioavailability to plants. In the present study, the mechanisms of uptake and distribution of silver in alfalfa (Medicago sativa) were quantified and visualized upon hydroponic exposure to Ag NPs, Ag2S-NPs, and AgNO3 at 3 mg total Ag/L. Total silver uptake was measured in dried roots and shoots, and the spatial distribution of elements was investigated using transmission electron microscopy (TEM) and synchrotron-based X-ray imaging techniques. Despite large differences in release of Ag(+) ions from the particles, Ag-NPs, Ag2S-NPs, and Ag(+) became associated with plant roots to a similar degree, and exhibited similarly limited (<1%) amounts of translocation of silver into the shoot system. X-ray fluorescence (XRF) mapping revealed differences in the distribution of Ag into roots for each treatment. Silver nanoparticles mainly accumulated in the (columella) border cells and elongation zone, whereas Ag(+) accumulated more uniformly throughout the root. In contrast, Ag2S-NPs remained largely adhered to the root exterior, and the presence of cytoplasmic nano-SixOy aggregates was observed. Exclusively in roots exposed to particulate silver, NPs smaller than the originally dosed NPs were identified by TEM in the cell walls. The apparent accumulation of Ag in the root apoplast determined by XRF, and the presence of small NPs in root cell walls suggests uptake of partially dissolved NPs and translocation along the apoplast. PMID- 26106802 TI - EFFECTS OF SELF-SELECTED MUSIC ON MAXIMAL BENCH PRESS STRENGTH AND STRENGTH ENDURANCE. AB - Listening to music during strength workouts has become a very common practice. The goal of this study was to assess the effect of listening to self-selected music on strength performances. Thirty-one resistance-trained men (M age = 24.7 yr., SD = 5.9; M height = 178.7 cm, SD = 4.7; M body mass = 83.54 kg, SD = 12.0) were randomly assigned to either a Music group (n = 19) or to a Control group (n = 12). Both groups took part in two separate sessions; each session consisted in a maximal strength test (1-RM) and a strength-endurance test (repetitions to failure at 60% 1-RM) using the bench press exercise. The music group listened to music in the second assessment session, while the control group performed both tests without music. Listening to music induced a significant increase of strength endurance performance and no effects on maximal strength. These findings have implications for the use of music during strength workouts. PMID- 26106803 TI - RELIABILITY AND CRITERION VALIDITY OF A NOVEL CLINICAL TEST OF SIMPLE AND COMPLEX REACTION TIME IN ATHLETES. AB - Slowed reaction time (RT) represents both a risk factor for and a consequence of sport concussion. The purpose of this study was to determine the reliability and criterion validity of a novel clinical test of simple and complex RT, called RT(clin), in contact sport athletes. Both tasks were adapted from the well-known ruler drop test of RT and involve manually grasping a falling vertical shaft upon its release, with the complex task employing a go/no-go paradigm based on a light cue. In 46 healthy contact sport athletes (24 men; M = 16.3 yr., SD = 5.0; 22 women: M age = 15.0 yr., SD = 4.0) whose sports included soccer, ice hockey, American football, martial arts, wrestling, and lacrosse, the latency and accuracy of simple and complex RT(clin) had acceptable test-retest and inter rater reliabilities and correlated with a computerized criterion standard, the Axon Computerized Cognitive Assessment Tool. Medium to large effect sizes were found. The novel RT(clin) tests have acceptable reliability and criterion validity for clinical use and hold promise as concussion assessment tools. PMID- 26106805 TI - Ethanol-Associated Cardiomyocyte Apoptosis and Left Ventricular Dilation Are Unrelated to Changes in Myocardial Telomere Length in Rats. AB - AIM: The aim of this work was to determine whether ethanol-associated myocardial apoptosis and cardiac dilation are related to myocardial telomere shortening in rats. METHODS AND RESULTS: Sprague-Dawley (SD) rats received either drinking water with (ethanol: n = 19) or without (control: n = 19) 5% (v/v) ethanol ad libitum, for 4 months. Left ventricular (LV) dimensions and function (echocardiography and isolated perfused heart preparations), cardiomyocyte apoptosis (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling), and leukocyte and myocardial telomere length (real-time polymerase chain reaction) were determined at the end of the study. Ethanol administration resulted in a marked increase in cardiomyocyte apoptosis (ethanol 0.85 +/- 0.13% vs control 0.36 +/- 0.06%; P = .0021) and LV dilation (LV end-diastolic diameter: ethanol 8.20 +/- 0.14 mm vs control 7.56 +/- 0.11 mm [P = .0014]; volume intercept at 0 mm Hg (V0) of the LV end-diastolic pressure-volume relationship: ethanol 0.40 +/- 0.03 mL vs control 0.31 +/- 0.02 mL [P = .020]). However, there were no changes in systolic chamber function as indexed by LV endocardial fractional shortening or the slope of the LV systolic pressure-volume relationship (end systolic elastance). The percentage of myocardial apoptosis was correlated with the degree of LV dilation (% apoptosis vs LV EDD: r = 0.39; n = 38; P = .021; vs V0: r = 0.44; n = 19; P = .046). No differences in leukocyte or cardiac telomere length were noted between the ethanol and control groups. Furthermore, cardiac telomere length was not associated with indexes of LV dilation (LVEDD and V0) or cardiomyocyte apoptosis. CONCLUSIONS: Chronic ethanol associated myocardial apoptosis and adverse remodeling occurs independently from changes in cardiac telomere length. Telomere shortening may not be a critical mechanism responsible for cardiomyocyte apoptosis and adverse cardiac remodeling. PMID- 26106806 TI - Trends in Heart Failure Clinical Trials From 2001-2012. AB - BACKGROUND: A systematic assessment of the temporal trends in heart failure (HF) clinical trials is lacking. METHODS AND RESULTS: A total of 154 phase II-IV HF trials including 162,725 patients published from 2001 to 2012 in 8 high-impact factor journals were reviewed. The median number of participants and sites per trial were 367 (interquartile range [IQR] 133-1450) and 38 (5-101), respectively. Median enrollment duration was 2.2 (1.5-3.3) years. The majority of studies investigated treatment for chronic HF (82.5%) and investigated HF with reduced ejection fraction (EF) (71.4%), whereas 27 trials (17.5%) enrolled patients with mixed EF and 9 (5.8%) enrolled HF with preserved EF patients alone. Enrollment rates did not significantly change over time (median 0.49 patients site(-1) month(-1), IQR 0.34-0.98; P = .53). Trials meeting their primary end point decreased over time from 73.5% in 2001-2003 to 52.5% in 2010-2012 (P = .08) and were more often smaller and used nonmortality end points. Industry trials were larger with shorter enrollment duration, more concentrated in North America, and more likely to be positive. Trials conducted exclusively outside North America and Western Europe had the highest enrollment rates (median 1.95 patients site( 1) month(-1), IQR 1.34-4.11). CONCLUSIONS: Contemporary HF clinical trials display slow enrollment rates and decreased rates of positive outcomes over time. Positive trials tended to be smaller size with a higher proportion of surrogate end points. PMID- 26106807 TI - Timing and Duration of Traffic-related Air Pollution Exposure and the Risk for Childhood Wheeze and Asthma. AB - RATIONALE: The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. OBJECTIVES: We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. METHODS: Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants' time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. MEASUREMENTS AND MAIN RESULTS: High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04-2.57 and aOR = 2.31; 95% CI, 1.28-4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01-2.88). CONCLUSIONS: Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development. PMID- 26106809 TI - Rational Re-engineering of a Transcriptional Silencing PreQ1 Riboswitch. AB - Re-engineered riboswitches that no longer respond to cellular metabolites, but that instead can be controlled by synthetic molecules, are potentially useful gene regulatory tools for use in synthetic biology and biotechnology fields. Previously, extensive genetic selection and screening approaches were employed to re-engineer a natural adenine riboswitch to create orthogonal ON-switches, enabling translational control of target gene expression in response to synthetic ligands. Here, we describe how a rational targeted approach was used to re engineer the PreQ1 riboswitch from Bacillus subtilis into an orthogonal OFF switch. In this case, the evaluation of just six synthetic compounds with seven riboswitch mutants led to the identification of an orthogonal riboswitch-ligand pairing that effectively repressed the transcription of selected genes in B. subtilis. The streamlining of the re-engineering approach, and its extension to a second class of riboswitches, provides a methodological platform for the creation of new orthogonal regulatory components for biotechnological applications including gene functional analysis and antimicrobial target validation and screening. PMID- 26106808 TI - Identification of determinants for tRNA substrate recognition by Escherichia coli C/U34 2'-O-methyltransferase. AB - Post-transcriptional modifications bring chemical diversity to tRNAs, especially at positions 34 and 37 of the anticodon stem-loop (ASL). TrmL is the prokaryotic methyltransferase that catalyzes the transfer of the methyl group from S-adenosyl L-methionine to the wobble base of tRNA(Leu)CAA and tRNA(Leu)UAA isoacceptors. This Cm34/Um34 modification affects codon-anticodon interactions and is essential for translational fidelity. TrmL-catalyzed 2'-O-methylation requires its homodimerization; however, understanding of the tRNA recognition mechanism by TrmL remains elusive. In the current study, by measuring tRNA methylation by TrmL and performing kinetic analysis of tRNA mutants, we found that TrmL exhibits a fine-tuned tRNA substrate recognition mechanism. Anticodon stem-loop minihelices with an extension of 2 base pairs are the minimal substrate for EcTrmL methylation. A35 is a key residue for TrmL recognition, while A36-A37-A38 are important either via direct interaction with TrmL or due to the necessity for prior isopentenylation (i(6)) at A37. In addition, TrmL only methylates pyrimidines but not purine residues at the wobble position, and the 2'-O methylation relies on prior N(6)-isopentenyladenosine modification at position 37. PMID- 26106810 TI - Crystallite Size Effect on Thermal Conductive Properties of Nonwoven Nanocellulose Sheets. AB - The thermal conductive properties, including the thermal diffusivity and resultant thermal conductivity, of nonwoven nanocellulose sheets were investigated by separately measuring the thermal diffusivity of the sheets in the in-plane and thickness directions with a periodic heating method. The cross sectional area (or width) of the cellulose crystallites was the main determinant of the thermal conductive properties. Thus, the results strongly indicate that there is a crystallite size effect on phonon conduction within the nanocellulose sheets. The results also indicated that there is a large interfacial thermal resistance between the nanocellulose surfaces. The phonon propagation velocity (i.e., the sound velocity) within the nanocellulose sheets was estimated to be ~800 m/s based on the relationship between the thermal diffusivities and crystallite widths. The resulting in-plane thermal conductivity of the tunicate nanocellulose sheet was calculated to be ~2.5 W/mK, markedly higher than other plastic films available for flexible electronic devices. PMID- 26106811 TI - Can Disorder Enhance Incoherent Exciton Diffusion? AB - Recent experiments aimed at probing the dynamics of excitons have revealed that semiconducting films composed of disordered molecular subunits, unlike expectations for their perfectly ordered counterparts, can exhibit a time dependent diffusivity in which the effective early time diffusion constant is larger than that of the steady state. This observation has led to speculation about what role, if any, microscopic disorder may play in enhancing exciton transport properties. In this article, we present the results of a model study aimed at addressing this point. Specifically, we introduce a general model, based upon Forster theory, for incoherent exciton diffusion in a material composed of independent molecular subunits with static energetic disorder. Energetic disorder leads to heterogeneity in molecule-to-molecule transition rates, which we demonstrate has two important consequences related to exciton transport. First, the distribution of local site-specific hopping rates is broadened in a manner that results in a decrease in average exciton diffusivity relative to that in a perfectly ordered film. Second, since excitons prefer to make transitions that are downhill in energy, the steady state distribution of exciton energies is biased toward low-energy molecular subunits, those that exhibit reduced diffusivity relative to a perfectly ordered film. These effects combine to reduce the net diffusivity in a manner that is time dependent and grows more pronounced as disorder is increased. Notably, however, we demonstrate that the presence of energetic disorder can give rise to a population of molecular subunits with exciton transfer rates exceeding those of subunits in an energetically uniform material. Such enhancements may play an important role in processes that are sensitive to molecular-scale fluctuations in exciton density field. PMID- 26106812 TI - Instructional Simulation Integrates Research, Education, and Practice. AB - Instructional simulation is widely used in clinical education. Examples include the use of inanimate models meant to imitate humans, standardized patients who are actors portraying patients with certain conditions, and role-play where learners experience the disease through props and circumstances. These modalities are briefly described, and then case examples are provided of simulation curricula in use that integrate research findings and clinical practice expertise to guide development and implementation steps. The cases illustrate how formative and summative feedback from two legs of the "three-legged stool" can be potent integrating forces in development of simulation curricula. In these examples, the educational outputs benefit from purposeful inclusion of research and practice inputs. Costs are outlined for instructor and learner time commitments, space considerations, and expendables. The authors' data and experience suggest that instructional simulation that is supported by a solid scientific base and clinical expertise is appreciated by teachers and learners. PMID- 26106813 TI - Adsorption of ozone and plasmonic properties of gold hydrosol: the effect of the nanoparticle size. AB - The impact of the size of gold nanoparticles on the magnitude of the bathochromic shift of their plasmon resonance peak upon ozone adsorption is revealed and analyzed. Namely, the plasmon band position of 7, 10, 14 and 32 nm nanoparticles shifts toward longer wavelengths by 51, 35, 23 and 9 nm respectively, i.e. the smaller the nanoparticles, the greater the shift of the band. Thus, the sensor efficiency of gold hydrosol increases with a decrease in the nanoparticle size. The shift of the Fermi level is a linear function of the inverse radius of nanoparticles. The observed alterations in the gold nanoparticle plasmonic properties and the Fermi level position are explained by a decrease in the electron density of nanoparticles caused by the electrons' partial binding by adsorbed O3 molecules. The insignificance of oxygen and nitrous oxide effects on plasmonic properties of gold hydrosol is observed. PMID- 26106814 TI - Highly Regio- and Diastereoselective Formation of Tetrasubstituted (Z)-1,2 Dihaloalkenes from the Halogenation of Trimethylsilyl Alkynes with ICl. AB - The stereoselective anti addition of diatomic halogens to alkynes has been well studied. A method is reported that utilizes the beta-silyl effect to override this typically observed anti selectivity and provides halogenation products that result from syn addition. The reaction involves the addition of iodine monochloride to trialkylsilyl-substituted alkynes to produce tetrasubstituted (Z) dihaloalkenes in good to excellent yields and with excellent regio- and diastereoselectivity. PMID- 26106815 TI - Combined orthodontic and restorative treatment of avulsed maxillary central incisors. PMID- 26106816 TI - Modified Alt-RAMEC treatment of Class III malocclusion in young patients with Down syndrome. PMID- 26106817 TI - The Hot Seat: Clear aligners. PMID- 26106818 TI - A centennial for the profession. PMID- 26106819 TI - Creative adjuncts for clear aligners, part 1: Class II treatment. PMID- 26106820 TI - Orthodontic management of unerupted transposed canines. PMID- 26106821 TI - Functional Connectivity-Based Parcellation of the Thalamus: An Unsupervised Clustering Method and Its Validity Investigation. AB - Node definition or delineating how the brain is parcellated into individual functionally related regions is the first step to accurately map the human connectome. As a result, parcellation of the human brain has drawn considerable attention in the field of neuroscience. The thalamus is known as a relay in the human brain, with its nuclei sending fibers to the cortical and subcortical regions. Functional magnetic resonance imaging techniques offer a way to parcellate the thalamus in vivo based on its connectivity properties. However, the parcellations from previous studies show that both the number and the distribution of thalamic subdivisions vary with different cortical segmentation methods. In this study, we used an unsupervised clustering method that does not rely on a priori information of the cortical segmentation to parcellate the thalamus. Instead, this approach is based on the intrinsic resting-state functional connectivity profiles of the thalamus with the whole brain. A series of cluster solutions were obtained, and an optimal solution was determined. Furthermore, the validity of our parcellation was investigated through the following: (1) identifying specific resting-state connectivity patterns of thalamic parcels with different brain networks and (2) investigating the task activation and psychophysiological interactions of specific thalamic clusters during 8-Hz flashing checkerboard stimulation with simultaneous finger tapping. Together, the current study provides a reliable parcellation of the thalamus and enhances our understating of thalamic. Furthermore, the current study provides a framework for parcellation that could be potentially extended to other subcortical and cortical regions. PMID- 26106822 TI - Detection of huntingtin exon 1 phosphorylation by Phos-Tag SDS-PAGE: Predominant phosphorylation on threonine 3 and regulation by IKKbeta. AB - Expansion of a CAG triplet repeat within the first exon of the HUNTINGTIN gene encoding for a polyglutamine tract is the cause of a progressive neurodegenerative disorder known as Huntington's disease. N-terminal fragments of mutant huntingtin have a strong propensity to form oligomers and aggregates that have been linked to the Huntington's disease pathology by different mechanisms, including gain of toxic functions. The biological and biophysical properties of the polyglutamine expansion within these huntingtin fragments are influenced by neighboring domains, in particular by the first 17 amino acids of huntingtin (N17), which precede the polyglutamine expansion. It has been suggested that N17 phosphorylation modulate mutant huntingtin aggregation and toxicity, but the study of its functional and pathological relevance requires the capacity to detect this modification in biological samples in a simple, robust way, that ideally provides information on the abundance of a phosphorylated species relative to the total pool of the protein of interest. Using a modified SDS-PAGE protocol (Phos-Tag) followed by Western blotting with specific anti-HUNTINGTIN antibodies, we efficiently resolved huntingtin fragments expressed in cellular contexts based on the presence of phosphorylated residues, we defined threonine 3 as the major site of huntingtin N17 phosphorylation and, finally, we identified IKK-beta as a kinase capable of phosphorylating threonine 3 in N-terminal hungtingtin fragments. PMID- 26106823 TI - A wheat salinity-induced WRKY transcription factor TaWRKY93 confers multiple abiotic stress tolerance in Arabidopsis thaliana. AB - Wheat is an important crop in the world. But most of the cultivars are salt sensitive, and often adversely affected by salt stress. WRKY transcription factors play a major role in plant responses to salt stress, but the effective salinity regulatory WRKYs identified in bread wheat are limited and the mechanism of salt stress tolerance is also not well explored. Here, we identified a salt (NaCl) induced class II WRKY transcription factor TaWRKY93. Its transcript level was strongly induced by salt (NaCl) and exogenous abscisic acid (ABA). Over expression of TaWRKY93 in Arabidopsis thaliana enhanced salt (NaCl), drought, low temperature and osmotic (mannitol) stress tolerance, mainly demonstrated by transgenic plants forming longer primary roots or more lateral roots on MS plates supplemented with NaCl and mannitol individually, higher survival rate under drought and low temperature stress. Further, transgenic plants maintained a more proline content, higher relative water content and less electrolyte leakage than the wild type plants. The transcript abundance of a series of abiotic stress related genes was up-regulated in the TaWRKY93 transgenic plants. In summary, TaWRKY93 is a new positive regulator of abiotic stress, it may increase salinity, drought and low temperature stress tolerance through enhancing osmotic adjustment, maintaining membrane stability and increasing transcription of stress related genes, and contribute to the superior agricultural traits of SR3 through promoting root development. It can be used as a candidate gene for wheat transgenic engineering breeding against abiotic stress. PMID- 26106824 TI - Bradykinin increased the permeability of BTB via NOS/NO/ZONAB-mediating down regulation of claudin-5 and occludin. AB - After demonstrating bradykinin (BK) could increase the permeability of blood tumor barrier (BTB) via opening the tight junction (TJ), and that the possible mechanism is unclear, we demonstrated that BK could increase the expressions of eNOS and nNOS and promote ZONAB translocation into nucleus. NOS inhibitors l-NAME and 7-NI could effectively block the effect of BK on increasing BTB permeability, decreasing the expressions of claudin-5 and occludin and promoting the translocation of ZONAB. Overexpression of ZONAB could significantly enhance BK mediating BTB permeability. Meanwhile, chromatin immunoprecipitation verified ZONAB interacted with the promoter of claudin-5 and occludin respectively. This study indicated NOS/NO/ZONAB pathway might be involved in BK's increasing the permeability of BTB. PMID- 26106825 TI - Czech Republic: health system review. AB - This analysis of the Czech health system reviews recent developments in organization and governance, health financing, health-care provision, health reforms and health system performance. The Czech health-care system is based on compulsory statutory health insurance providing virtually universal coverage and a broad range of benefits, and doing so at 7.7 % of GDP in 2012 - well below the EU average - of which a comparatively high 85 % was publicly funded. Some important health indicators are better than the EU averages (such as mortality due to respiratory disease) or even among the best in the world (in terms of infant mortality, for example). On the other hand, mortality rates for diseases of the circulatory system and malignant neoplasms are well above the EU average, as are a range of health-care utilization rates, such as outpatient contacts and average length of stay in acute care hospitals. In short, there is substantial potential in the Czech Republic for efficiency gains and to improve health outcomes. Furthermore, the need for reform in order to financially sustain the system became evident again after the global financial crisis, but there is as yet no consensus about how to achieve this. PMID- 26106826 TI - Buruli Ulcer Successfully Treated With Negative-Pressure Wound Therapy. PMID- 26106827 TI - Vitamin D and asthma: current perspectives. AB - PURPOSE OF REVIEW: To review the current evidence on the relationship between vitamin D and asthma. RECENT FINDINGS: The rising morbidity and tremendous socioeconomic burden of asthma have prompted efforts to seek modifiable environmental and nutritional factors that contribute to the asthma epidemic. The association between low levels of vitamin D and asthma has been supported by many, but not all observational and epidemiologic studies. Recently, several controlled clinical trials have been undertaken to explore the effect of vitamin D supplementation on asthma control and respiratory tract infections. While some trials support the beneficial role of vitamin D supplementation in reducing asthma severity in children, several trials have found no beneficial role in adults. SUMMARY: Given the high prevalence of vitamin D insufficiency in children and adults worldwide and recent randomized controlled trials of vitamin D in asthma, supplementation with vitamin D cannot be recommended as adjunctive therapy for asthma. PMID- 26106828 TI - Diagnostic and therapeutic management of hereditary angioedema due to C1 inhibitor deficiency: the Italian experience. AB - PURPOSE OF REVIEW: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease, with a reported prevalence of about 1 : 50 000. C1-INH-HAE causes disabling symptoms, which may be life-threatening if swelling affects upper airways. Diagnostic procedures are now well established and the role of bradykinin as the main mediator of plasma outflow eliciting angioedema formation has been clearly elucidated. RECENT FINDINGS: Increased understanding of the pathogenesis of C1-INH-HAE allowed in recent years the development of new drugs targeted to inhibit bradykinin synthesis (Ecallantide) or activity (Icatibant). At the same time, a recombinant C1-INH concentrate (Ruconest) was produced from the milk of transgenic rabbits and two plasma derived C1-INHs (Berinert, Cinryze) underwent controlled trials to obtain marketing authorization. In 2012, an Italian network for C1-INH-HAE (ITACA) was established by physicians of 17 HAE reference centres to collect data from Italian patients and to homogenize and improve the diagnostic and therapeutic approach to the disease. SUMMARY: Although there is a widespread agreement on therapeutic goals and treatment of C1-INH-HAE acute attacks, different approaches to prophylaxis are still present among HAE experts. The clinical experience of ITACA on a large population of C1-INH-HAE patients followed for several years may help in identifying the most effective strategies for the management of the disease. PMID- 26106830 TI - Reframing Surgical Care: Understanding Complexity and Promoting Teaming. AB - Reframing healthcare delivery in terms of the principles of complex adaptive systems has practical implications for addressing the challenges in improving surgical care. In an Integrated Practice Unit (IPU) - such as a surgical service line, a surgical in-patient floor, or an acute care unit - a diverse group of caregivers must interact in a highly interdependent fashion in an environment characterized by ambiguity, uncertainty, and time constraints. Understanding of the concept of teaming and the tenets of relational coordination are crucial to the promotion of a successful patient-centric approach to surgical care. PMID- 26106831 TI - Ketorolac Use and Postoperative Complications in Gastrointestinal Surgery. AB - OBJECTIVE: To study the association between ketorolac use and postoperative complications. BACKGROUND: Nonsteroidal anti-inflammatory drugs may impair wound healing and increase the risk of anastomotic leak in colon surgery. Studies to date have been limited by sample size, inability to identify confounding, and a focus limited to colon surgery. METHODS: Ketorolac use, reinterventions, emergency department (ED) visits, and readmissions in adults (>= 18 years) undergoing gastrointestinal (GI) operations was assessed in a nationwide cohort using the MarketScan Database (2008-2012). RESULTS: Among 398,752 patients (median age 52, 45% male), 55% underwent colorectal surgery, whereas 45% had noncolorectal GI surgery. Five percent of patients received ketorolac. Adjusting for demographic characteristics, comorbidities, surgery type/indication, and preoperative medications, patients receiving ketorolac had higher odds of reintervention (odds ratio [OR] 1.20, 95% confidence interval [CI] 1.08-1.32), ED visit (OR 1.44, 95% CI 1.37-1.51), and readmission within 30 days (OR 1.11, 95% CI 1.05-1.18) compared to those who did not receive ketorolac. Ketorolac use was associated with readmissions related to anastomotic complications (OR 1.20, 95% CI 1.06-1.36). Evaluating only admissions with <= 3 days duration to exclude cases where ketorolac might have been used for complication-related pain relief, the odds of complications associated with ketorolac were even greater. CONCLUSIONS: Use of intravenous ketorolac was associated with greater odds of reintervention, ED visit, and readmission in both colorectal and noncolorectal GI surgery. Given this confirmatory evaluation of other reports of a negative association and the large size of this cohort, clinicians should exercise caution when using ketorolac in patients undergoing GI surgery. PMID- 26106836 TI - Diffusion-weighted MRI for Early Prediction of Treatment Response on Preoperative Chemoradiotherapy for Patients With Locally Advanced Rectal Cancer: A Feasibility Study. AB - OBJECTIVE: This study investigates the predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) for good pathological response at different time points during and after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. BACKGROUND: Preoperative CRT followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer. The use of standard radical surgery in good treatment responders after CRT is being questioned. METHODS: Patients with locally advanced rectal adenocarcinoma were treated with preoperative CRT followed by surgery. DW-MRI scans were performed before CRT, during the third week of CRT, 4 weeks post-CRT and presurgery. Tumor apparent diffusion coefficient (ADC) values were acquired from the DW-MRI scans. After surgery the pathological tumor regression grade was assessed according to the classification by Mandard et al [Cancer. 1994;73:2680-2686]. Patients with pathological complete or near-complete response (tumor regression grade 1-2) were classified as good responders (GRs). RESULTS: Twenty-two patients participated of which 9 were GRs (41%). Pre-CRT ADC values were lower in good versus moderate/poor responders (P = 0.04). ADC values during CRT and four weeks post CRT were higher in GR. ADC values presurgery did not differ between response groups. For all time points the relative ADC increase (DeltaADC) compared to the ADC pre-CRT was higher in GR (P < 0.001). The DeltaADC during CRT and four weeks post-CRT were the best predictive parameters for pathological good response. CONCLUSIONS: This study shows that DW-MRI is feasible to select good treatment responders during preoperative CRT for locally advanced rectal cancer. PMID- 26106842 TI - Live Donor Liver Transplantation With Older (>=50 Years) Versus Younger (<50 Years) Donors: Does Age Matter? AB - OBJECTIVE: To compare the outcome of adult live donor liver transplantation (LDLT) with grafts from older versus younger donors. INTRODUCTION: Using older donor grafts for adult LDLT may help expand the donor pool. However, the risks of LDLT with older donors remain controversial, and many centers are reluctant to use live donors aged 45 years or older for adult LDLT. METHODS: Outcomes of patients receiving a LDLT graft from donors aged 50 years or older (n = 91) were compared with those receiving a live donor graft from donors younger than 50 years (n = 378). RESULTS: Incidences of biliary (LDLT <50: 24% vs LDLT >=50: 23%; P = 0.89) and major complications (LDLT <50: 24% vs LDLT >=50: 24%; P = 1) were similar between both groups of recipients. No difference was observed in 30-day recipient mortality (LDLT <50: 3% vs LDLT >=50: 0%; P = 0.13). The 1- (90% vs 90%), 5- (82% vs 73%), and 10- (71% vs 58%) year graft survival was statistically similar between both groups (P = 0.075). Likewise, patient survival after 1- (92% vs 96%), 5- (83% vs 79%), and 10- (76% vs 69%) years was also similar (P = 0.686). Overall, donors rate of major complications (Dindo-Clavien >=3b) within 30 days was low (n = 2.3%) and not different in older versus younger donors (P = 1). Donor median hospital stay in both groups was identical [LDLT <50: 6 (4-17) vs LDLT >=50: 6 (4-14) days; P = 0.65]. No donor death occurred and all donors had full recovery and returned to baseline activity. CONCLUSIONS: Right lobe LDLT with donors aged 50 years or older results in acceptable recipient outcome without increased donor morbidity or mortality. Potential live donors should not be declined on the basis of age alone. PMID- 26106845 TI - Risk Factors for Marginal Ulcer After Gastric Bypass Surgery for Obesity: A Population-based Cohort Study. AB - OBJECTIVE: This study aimed to assess risk factors for developing marginal ulcer (MU) after gastric bypass (GBP) surgery for obesity. BACKGROUND: MU is a common and potentially serious complication of GBP surgery, little is known about its etiology. METHODS: This population-based cohort study of GBP in 2006-2011 evaluated MU in relation to diabetes, hyperlipidemia, hypertension, chronic obstructive pulmonary disease (COPD), ulcer history, use of proton pump inhibitors (PPIs), aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and selective serotonin reuptake inhibitors (SSRIs). Multivariable Cox proportional hazard regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for confounding. RESULTS: Among 20,294 GBP patients, diabetes and peptic ulcer history entailed statistically significantly increased risk of MU (HR = 1.26, 95% CI 1.03-1.55 and HR = 2.70, 95% CI 1.81-4.03), although hyperlipidemia, hypertension, and COPD did not. PPI users had an increased HR of MU (HR = 1.37, 95% CI 1.17-1.60). Aspirin and NSAID consumption less than or equal to median entailed decreased HRs of MU (HR = 0.56, 95% CI 0.37-0.86 and HR = 0.30, 95% CI 0.24-0.38), although aspirin and NSAID users more than median had an increased risk and no association with MU, respectively (HR = 1.90, 95% CI 1.41-2.58 and HR = 0.90, 95% CI 0.76-1.87). The use of SSRI less than or equal to median had a decreased risk of MU (HR = 0.50, 95% CI 0.37-0.67), although use more than median entailed increased HR (HR = 1.26, 95% CI 1.01-1.56). CONCLUSIONS: Diabetes and peptic ulcer history seem to be risk factors for MU, but not hyperlipidemia, hypertension, or COPD. Limited doses of aspirin, NSAIDs, and SSRIs might not increase the risk, although higher doses of aspirin do. The association with PPI could be due to confounding by indication. PMID- 26106846 TI - Diet, Obesity, and Political Involvement. AB - This essay is an opinion article addressed to the busy practitioner. It provides information on nutrition, diet, nutritional science, and obesity to serve as a reference in teaching his patients on these issues. It is composed by a gastroenterologist who has been engaged in clinical gastroenterology and nutrition, research, and teaching in an academic medical center for 35 years. It also relates the information to conclusions on reasonable involvement of the national government in these topics. Finally, its audience might include the interested, well-educated, lay public. Hence, excessive scientific parlance and referencing have been avoided. PMID- 26106847 TI - Metal binding spectrum and model structure of the Bacillus anthracis virulence determinant MntA. AB - The potentially lethal human pathogen Bacillus anthracis expresses a putative metal import system, MntBCA, which belongs to the large family of ABC transporters. MntBCA is essential for virulence of Bacillus anthracis: deletion of MntA, the system's substrate binding protein, yields a completely non-virulent strain. Here we determined the metal binding spectrum of MntA. In contrast to what can be inferred from growth complementation studies we find no evidence that MntA binds Fe(2+) or Fe(3+). Rather, MntA binds a variety of other metal ions, including Mn(2+), Zn(2+), Cd(2+), Co(2+), and Ni(2+) with affinities ranging from 10(-6) to 10(-8) M. Binding of Zn(2+) and Co(2+) have a pronounced thermo stabilizing effect on MntA, with Mn(2+) having a milder effect. The thermodynamic stability of MntA, competition experiments, and metal binding and release experiments all suggest that Mn(2+) is the metal that is likely transported by MntBCA and is therefore the limiting factor for virulence of Bacillus anthracis. A homology-model of MntA shows a single, highly conserved metal binding site, with four residues that participate in metal coordination: two histidines, a glutamate, and an aspartate. The metals bind to this site in a mutually exclusive manner, yet surprisingly, mutational analysis shows that for proper coordination each metal requires a different subset of these four residues. ConSurf evolutionary analysis and structural comparison of MntA and its homologues suggest that substrate binding proteins (SBPs) of metal ions use a pair of highly conserved prolines to interact with their cognate ABC transporters. This proline pair is found exclusively in ABC import systems of metal ions. PMID- 26106848 TI - Mortality Among Injured Children Treated at Different Trauma Center Types. AB - IMPORTANCE: Trauma is the leading cause of death among US children. Whether pediatric trauma centers (PTCs), mixed trauma centers (MTCs), or adult trauma centers (ATCs) offer a survival benefit compared with one another when treating injured children is controversial. Ascertaining the optimal care environment will better inform quality improvement initiatives and accreditation standards. OBJECTIVE: To evaluate the association between type of trauma center (PTC, MTC, or ATC) and in-hospital mortality among young children (5 years and younger), older children (aged 6-11 years), and adolescents (aged 12-18 years). DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, injured children aged 18 years or younger who were hospitalized in the United States from January 1, 2010, to December 31, 2013, were observed for the duration of their admission until discharge or death. We included patients with an Abbreviated Injury Score of 2 or greater in at least 1 body region. Random-intercept multilevel regression was used to evaluate the association between center type and in-hospital mortality after adjusting for confounders. Stratified analyses in young children, older children, and adolescents were performed. We conducted secondary analyses limited to patients with severe injuries (Injury Severity Score >=25). Both analyses were performed between January 1 and August 31, 2014. Data were derived from 252 US level I and II trauma centers voluntarily participating in the American College of Surgeons adult or pediatric Trauma Quality Improvement Program. MAIN OUTCOME AND MEASURE: In-hospital mortality. RESULTS: We identified 175 585 injured children. Crude mortality rates were 2.3% for children treated at ATCs, 1.8% for children treated at MTCs, and 0.6% for children treated at PTCs. After adjustment, children had higher odds of dying when treated at ATCs (odds ratio [OR], 1.57; 95% CI, 1.15-2.14) and MTCs (OR, 1.45; 95% CI, 1.05-2.01) compared with those treated at PTCs. In stratified analyses, young children had higher odds of death when treated at ATCs vs PTCs (OR, 1.78; 95% CI, 1.05-3.40), but there was no association between center type and mortality among older children (OR, 1.17; 95% CI, 0.65-2.11) and adolescents (OR, 1.23; 95% CI, 0.82 1.85). Results were similar in analyses of severely injured children: those treated at ATCs (OR, 1.75; 95% CI, 1.25-2.44) and MTCs (OR, 1.62; 95% CI, 1.15 2.29) had higher odds of death when compared with those treated at PTCs. CONCLUSIONS AND RELEVANCE: Injured children treated at ATCs and MTCs had higher in-hospital mortality compared with those treated at PTCs. This association was most evident in younger children and remained significant in severely injured children. Quality improvement initiatives geared toward ATCs and MTCs are required to provide optimal care to injured children. PMID- 26106853 TI - Is (18)F-FDG PET/CT an accurate tool for identifying metastases of lobular breast cancer? PMID- 26106854 TI - A 30-year experience in using oral methotrexate as initial treatment for gestational trophoblastic neoplasia regardless of risk group. AB - BACKGROUND: Treatment of postmolar gestational trophoblastic neoplasia (GTN) is often stratified according to FIGO score using methotrexate (MTX) for low-risk patients and first-line multi-agent chemotherapy (e.g. EMA-CO) for high-risk patients. In contrast, oral MTX may be given as first-line therapy to all GTN patients regardless of risk group. The aim was to examine the efficacy of oral MTX and a response-adapted treatment policy, which has been used for three decades at Aarhus University Hospital (AUH). MATERIAL AND METHODS: Seventy-one consecutive postmolar GTN patients treated 1981-2011 were included. Data were obtained from medical records, using histopathology and human choriogonadotropin (hCG) to verify the diagnosis. All patients received oral MTX as first-line chemotherapy. Second- and third-line chemotherapy was given according to response. RESULTS: Sixty-four (90%) patients were retrospectively categorized as FIGO low-risk disease, whereas seven patients (10%) had high-risk disease. Complete response to first-line oral MTX chemotherapy was observed in 35/71 (49%) patients, while 62/71 (87%) had complete remission on MTX (first-line) and/or MTX plus dactinomycin (second-line), without the use of multi-agent therapy. Nine patients (13%) received third-line multi-agent chemotherapy, six low-risk (67%) and three high-risk (33%) patients. There were no recurrences and no patients died as a consequence of toxicity or disease. CONCLUSION: Fifty percent of all patients can be cured on oral MTX alone. By adding dactinomycin, about 90% are cured without use of multi-agent chemotherapy. The use of oral MTX as initial treatment can minimize the number of patients receiving multi-agent chemotherapy. PMID- 26106856 TI - Cancer: Diagnosis by extracellular vesicles. PMID- 26106855 TI - The architecture of the spliceosomal U4/U6.U5 tri-snRNP. AB - U4/U6.U5 tri-snRNP is a 1.5-megadalton pre-assembled spliceosomal complex comprising U5 small nuclear RNA (snRNA), extensively base-paired U4/U6 snRNAs and more than 30 proteins, including the key components Prp8, Brr2 and Snu114. The tri-snRNP combines with a precursor messenger RNA substrate bound to U1 and U2 small nuclear ribonucleoprotein particles (snRNPs), and transforms into a catalytically active spliceosome after extensive compositional and conformational changes triggered by unwinding of the U4 and U6 (U4/U6) snRNAs. Here we use cryo electron microscopy single-particle reconstruction of Saccharomyces cerevisiae tri-snRNP at 5.9 A resolution to reveal the essentially complete organization of its RNA and protein components. The single-stranded region of U4 snRNA between its 3' stem-loop and the U4/U6 snRNA stem I is loaded into the Brr2 helicase active site ready for unwinding. Snu114 and the amino-terminal domain of Prp8 position U5 snRNA to insert its loop I, which aligns the exons for splicing, into the Prp8 active site cavity. The structure provides crucial insights into the activation process and the active site of the spliceosome. PMID- 26106857 TI - Hallucigenia's head and the pharyngeal armature of early ecdysozoans. AB - The molecularly defined clade Ecdysozoa comprises the panarthropods (Euarthropoda, Onychophora and Tardigrada) and the cycloneuralian worms (Nematoda, Nematomorpha, Priapulida, Loricifera and Kinorhyncha). These disparate phyla are united by their means of moulting, but otherwise share few morphological characters--none of which has a meaningful fossilization potential. As such, the early evolutionary history of the group as a whole is largely uncharted. Here we redescribe the 508-million-year-old stem-group onychophoran Hallucigenia sparsa from the mid-Cambrian Burgess Shale. We document an elongate head with a pair of simple eyes, a terminal buccal chamber containing a radial array of sclerotized elements, and a differentiated foregut that is lined with acicular teeth. The radial elements and pharyngeal teeth resemble the sclerotized circumoral elements and pharyngeal teeth expressed in tardigrades, stem-group euarthropods and cycloneuralian worms. Phylogenetic results indicate that equivalent structures characterized the ancestral panarthropod and, seemingly, the ancestral ecdysozoan, demonstrating the deep homology of panarthropod and cycloneuralian mouthparts, and providing an anatomical synapomorphy for the ecdysozoan supergroup. PMID- 26106859 TI - Palaeontology: Hallucigenia's head. PMID- 26106858 TI - Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. AB - Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy. PMID- 26106860 TI - Erratum: A strong ultraviolet pulse from a newborn type Ia supernova. PMID- 26106862 TI - Erratum: No signature of ejecta interaction with a stellar companion in three type Ia supernovae. PMID- 26106861 TI - The core spliceosome as target and effector of non-canonical ATM signalling. AB - In response to DNA damage, tissue homoeostasis is ensured by protein networks promoting DNA repair, cell cycle arrest or apoptosis. DNA damage response signalling pathways coordinate these processes, partly by propagating gene expression-modulating signals. DNA damage influences not only the abundance of messenger RNAs, but also their coding information through alternative splicing. Here we show that transcription-blocking DNA lesions promote chromatin displacement of late-stage spliceosomes and initiate a positive feedback loop centred on the signalling kinase ATM. We propose that initial spliceosome displacement and subsequent R-loop formation is triggered by pausing of RNA polymerase at DNA lesions. In turn, R-loops activate ATM, which signals to impede spliceosome organization further and augment ultraviolet-irradiation-triggered alternative splicing at the genome-wide level. Our findings define R-loop dependent ATM activation by transcription-blocking lesions as an important event in the DNA damage response of non-replicating cells, and highlight a key role for spliceosome displacement in this process. PMID- 26106864 TI - Corrigendum: In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system. PMID- 26106863 TI - Distinct lineages of Ebola virus in Guinea during the 2014 West African epidemic. AB - An epidemic of Ebola virus disease of unprecedented scale has been ongoing for more than a year in West Africa. As of 29 April 2015, there have been 26,277 reported total cases (of which 14,895 have been laboratory confirmed) resulting in 10,899 deaths. The source of the outbreak was traced to the prefecture of Gueckedou in the forested region of southeastern Guinea. The virus later spread to the capital, Conakry, and to the neighbouring countries of Sierra Leone, Liberia, Nigeria, Senegal and Mali. In March 2014, when the first cases were detected in Conakry, the Institut Pasteur of Dakar, Senegal, deployed a mobile laboratory in Donka hospital to provide diagnostic services to the greater Conakry urban area and other regions of Guinea. Through this process we sampled 85 Ebola viruses (EBOV) from patients infected from July to November 2014, and report their full genome sequences here. Phylogenetic analysis reveals the sustained transmission of three distinct viral lineages co-circulating in Guinea, including the urban setting of Conakry and its surroundings. One lineage is unique to Guinea and closely related to the earliest sampled viruses of the epidemic. A second lineage contains viruses probably reintroduced from neighbouring Sierra Leone on multiple occasions, while a third lineage later spread from Guinea to Mali. Each lineage is defined by multiple mutations, including non-synonymous changes in the virion protein 35 (VP35), glycoprotein (GP) and RNA-dependent RNA polymerase (L) proteins. The viral GP is characterized by a glycosylation site modification and mutations in the mucin-like domain that could modify the outer shape of the virion. These data illustrate the ongoing ability of EBOV to develop lineage-specific and potentially phenotypically important variation. PMID- 26106865 TI - A Middle Triassic stem-turtle and the evolution of the turtle body plan. AB - The origin and early evolution of turtles have long been major contentious issues in vertebrate zoology. This is due to conflicting character evidence from molecules and morphology and a lack of transitional fossils from the critical time interval. The ~220-million-year-old stem-turtle Odontochelys from China has a partly formed shell and many turtle-like features in its postcranial skeleton. Unlike the 214-million-year-old Proganochelys from Germany and Thailand, it retains marginal teeth and lacks a carapace. Odontochelys is separated by a large temporal gap from the ~260-million-year-old Eunotosaurus from South Africa, which has been hypothesized as the earliest stem-turtle. Here we report a new reptile, Pappochelys, that is structurally and chronologically intermediate between Eunotosaurus and Odontochelys and dates from the Middle Triassic period (~240 million years ago). The three taxa share anteroposteriorly broad trunk ribs that are T-shaped in cross-section and bear sculpturing, elongate dorsal vertebrae, and modified limb girdles. Pappochelys closely resembles Odontochelys in various features of the limb girdles. Unlike Odontochelys, it has a cuirass of robust paired gastralia in place of a plastron. Pappochelys provides new evidence that the plastron partly formed through serial fusion of gastralia. Its skull has small upper and ventrally open lower temporal fenestrae, supporting the hypothesis of diapsid affinities of turtles. PMID- 26106866 TI - Sub-micron lateral topography affects endothelial migration by modulation of focal adhesion dynamics. AB - Through the interaction with topographical features, endothelial cells tune their ability to populate target substrates, both in vivo and in vitro. Basal textures interfere with the establishment and maturation of focal adhesions (FAs) thus inducing specific cell-polarization patterns and regulating a plethora of cell activities that govern the overall endothelial function. In this study, we analyze the effect of topographical features on FAs in primary human endothelial cells. Reported data demonstrate a functional link between FA dynamics and cell polarization and spreading on structured substrates presenting variable lateral feature size. Our results reveal that gratings with 2 um lateral periodicity maximize contact guidance. The effect is linked to the dynamical state of FAs. We argue that these results are readily applicable to the rational design of active surfaces at the interface with the blood stream. PMID- 26106867 TI - Label-free microRNA detection based on terbium and duplex-specific nuclease assisted target recycling. AB - In this paper, we describe a novel label-free fluorescence method for microRNA-21 (miR-21) detection based on terbium (Tb(3+)) and duplex-specific nuclease (DSN) assisted target recycling. Capture probes (Cps), containing a target-binding part and a signal-output part, are immobilized on magnetic beads (MBs). In the presence of the target miR-21, it hybridizes with the target-binding part of a Cp to form a DNA-RNA heteroduplex. Due to the considerable cleavage preference for DNA in DNA-RNA hybrids, DSN hydrolyzes the target-binding part of the Cp while liberating the intact target miR-21 to hybridize with a new Cp and initiate the second cycle of hydrolysis. Eventually, through magnetic separation, only the signal-output part of the Cp could remain in solution and function as a signalling flare to increase the fluorescence intensity of Tb(3+) dramatically. By employing the above strategy, this approach can gain an amplified fluorescent signal and detect as low as 8 fM miR-21 under the optimized conditions. Moreover, due to the high selectivity of DSN, the method shows little cross-hybridization among the closely related miRNA family members even at the single-base-mismatched level. Successful attempts were made in applying the approach to detect miR-21 in human cell lysate samples of breast cancer patients. PMID- 26106868 TI - The Effect of Stress and Speech Rate on Vowel Coarticulation in Catalan Vowel Consonant-Vowel Sequences. AB - PURPOSE: The goal of this study was to ascertain the effect of changes in stress and speech rate on vowel coarticulation in vowel-consonant-vowel sequences. METHOD: Data on second formant coarticulatory effects as a function of changing /i/ versus /a/ were collected for five Catalan speakers' productions of vowel consonant-vowel sequences with the fixed vowels /i/ and /a/ and consonants: the approximant /delta/, the alveolopalatal nasal /n/, and /l/, which in the Catalan language differs in darkness degree according to speaker. RESULTS: In agreement with predictions formulated by the degree-of-articulation-constraint model of coarticulation, the size of the vowel coarticulatory effects was inversely related to the degree of articulatory constraint for the consonant, and the direction of those effects was mostly carryover or anticipatory in vowel consonant-vowel sequences with highly constrained consonants (/n/, dark /l/) and more variable whenever the intervocalic consonant was less constrained (/delta/, clear /l/). Stress and speech-rate variations had an effect on overall vowel duration, second formant frequency, and coarticulation size but not on the consonant-specific patterns of degree and direction of vowel coarticulation. CONCLUSION: These results indicate that prosodically induced coarticulatory changes conform to the basic principles of segmental coarticulatory organization. PMID- 26106869 TI - Electron transport in carbon wires in contact with Ag electrodes: a detailed first principles investigation. AB - The structure and electronic properties of carbon atom chains Cn in contact with Ag electrodes are investigated in detail with first principles means. The ideal Ag(100) surface is used as a model for binding, and electron transport through the chains is studied as a function of their length, applied bias voltage, presence of capping atoms (Si, S) and adsorption site. It is found that the metal molecule bond largely influences electronic coupling to the leads. Without capping atoms the quality of the electric contact improves when increasing the carbon atom coordination number to the metal (1, 2 and 4 for adsorption on a top, bridge and hollow position, respectively) and this finding translates almost unchanged in more realistic tip-like contacts which present one, two or four metal atoms at the contact. Current-voltage characteristics show Ohmic behaviour over a wide range of bias voltages and the resulting conductances change only weakly when increasing the wire length. The effect of a capping species is typically drastic, and either largely reduces (S) or largely increases (Si) the coupling of the wire to the electrodes. Comparison of our findings with recent experimental results highlights the limits of the adopted approach, which can be traced back to the known gap problem of density-functional-theory. PMID- 26106870 TI - Hyperbaric oxygen therapy for chronic wounds. AB - BACKGROUND: Chronic wounds are common and present a health problem with significant effect on quality of life. Various pathologies may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing. OBJECTIVES: To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb. SEARCH METHODS: For this second update we searched the Cochrane Wounds Group Specialised Register (searched 18 February 2015); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2015, Issue 1); Ovid MEDLINE (1946 to 17 February 2015); Ovid MEDLINE (In-Process & Other Non Indexed Citations, 17 February 2015); Ovid EMBASE (1974 to 17 February 2015); and EBSCO CINAHL (1982 to 17 February 2015). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy). DATA COLLECTION AND ANALYSIS: Three review authors independently evaluated the risk of bias of the relevant trials using the Cochrane methodology and extracted the data from the included trials. We resolved any disagreement by discussion. MAIN RESULTS: We included twelve trials (577 participants). Ten trials (531 participants) enrolled people with a diabetic foot ulcer: pooled data of five trials with 205 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 2.35, 95% confidence interval (CI) 1.19 to 4.62; P = 0.01) with HBOT at six weeks but this benefit was not evident at longer term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We identified one trial (30 participants) which enrolled patients with non-healing diabetic ulcers as well as venous ulcers ("mixed ulcers types") and patients were treated for 30 days. For this "mixed ulcers" there was a significant benefit of HBOT in terms of reduction in ulcer area at the end of treatment (30 days) (MD 61.88%, 95% CI 41.91 to 81.85, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers. AUTHORS' CONCLUSIONS: In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias. PMID- 26106875 TI - Dual-targeting organometallic ruthenium(II) anticancer complexes bearing EGFR inhibiting 4-anilinoquinazoline ligands. AB - We have recently demonstrated that complexation with (eta(6)-arene)Ru(II) fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4 anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9 ethylguanine (Chem. Commun., 2013, 49, 10224-10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(eta(6)-arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4 anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)Ru(II) fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(eta(6)-arene)Ru(N,N-L13)Cl]PF6 (, IC50 = 1.36 MUM, = 4-(3'-chloro-4'-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy) 7-methoxyquinazoline) is 29-fold more active than its analogue, [(eta(6) arene)Ru(N,N-ethylenediamine)Cl]PF6, and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules. PMID- 26106877 TI - (Ag,Cu)-Ta-O ternaries as high-temperature solid-lubricant coatings. AB - Ternary oxides have gained increasing attention due to their potential use as solid lubricants at elevated temperatures. In this work, the tribological properties of three ternary oxides-AgTaO3, CuTaO3, and CuTa2O6-were studied using a combination of density-functional theory (DFT), molecular dynamics (MD) simulations with newly developed empirical potential parameters, and experimental measurements (AgTaO3 and CuTa2O6 only). Our results show that the MD-predicted friction force follows the trend AgTaO3 < CuTaO3 < CuTa2O6, which is consistent with the experimentally measured coefficients of friction. The wear performance from both MD and experiment exhibits the opposite trend, with CuTa2O6 providing the best resistance to wear. The sliding mechanisms are investigated using experimental characterization of the film composition after sliding, quantification of Ag or Cu cluster formation at the interface during the evolution of the film in MD, and DFT energy barriers for atom migration on the material surface. All our observations are consistent with the hypothesis that the formation of metal (or metal oxide) clusters on the surface are responsible for the friction and wear behavior of these materials. PMID- 26106876 TI - The Edible Marine Alga Gracilariopsis chorda Alleviates Hypoxia/Reoxygenation Induced Oxidative Stress in Cultured Hippocampal Neurons. AB - Age-related neurological disorders are of growing concern among the elderly, and natural products with neuroprotective properties have been attracting increasing attention as candidates for the prevention or treatment of neurological disorders induced by oxidative stress. In an effort to explore natural resources, we collected some common marine seaweed from the Korean peninsula and Indonesia and screened them for neuroprotective activity against hypoxia/reoxygenation (H/R) induced oxidative stress. Of the 23 seaweeds examined, the ethanol extract of Gracilariopsis chorda (GCE) provided maximum neuroprotection at an optimum concentration of 15 MUg/mL, followed by Undaria pinnatifida. GCE increased cell viability after H/R, decreased the formation of reactive oxygen species (measured by 2',7'-dichlorodihydrofluorescein diacetate [DCF-DA] staining), and inhibited the double-stranded DNA breaks (measured by H2AX immunocytochemistry), apoptosis (measured by Annexin V/propidium iodide staining), internucleosomal DNA fragmentation (measured by DNA laddering), and dissipation of mitochondrial membrane potential (measured by JC-1 staining). Using reverse-phase high-pressure liquid chromatography, we quantitated the arachidonic acid (AA) in GCE, which provides neuroprotection against H/R-induced oxidative stress. This neuroprotective effect of AA was comparable to that of GCE. These findings suggest that the neuroprotective effect of GCE against H/R-induced neuronal death is due, at least in part, to the AA content that suppresses neuronal apoptosis. PMID- 26106878 TI - Fluorescent recognition of uranyl ions by a phosphorylated cyclic peptide. AB - Fluorescent recognition of uranyl ions was achieved using a phosphorylated cyclic peptide, which can be used as a fluorescent sensor for the detection of uranyl ions with high selectivity and sensitivity. PMID- 26106879 TI - Mapping surface tension induced menisci with application to tensiometry and refractometry. AB - In this work, we discuss an optical method for measuring surface tension induced menisci. The principle of measurement is based upon the change in the background pattern produced by the curvature of the meniscus acting as a lens. We measure the meniscus profile over an inclined glass plate and utilize the measured meniscus for estimation of surface tension and refractive index. PMID- 26106880 TI - Ukraine: health system review. AB - This analysis of the Ukrainian health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. Since the country gained independence from the Soviet Union in 1991, successive governments have sought to overcome funding shortfalls and modernize the health care system to meet the needs of the population's health. However, no fundamental reform of the system has yet been implemented and consequently it has preserved the main features characteristic of the Semashko model; there is a particularly high proportion of total health expenditure paid out of pocket (42.3 % in 2012), and incentives within the system do not focus on quality or outcomes. The most recent health reform programme began in 2010 and sought to strengthen primary and emergency care, rationalize hospitals and change the model of health care financing from one based on inputs to one based on outputs. Fundamental issues that hampered reform efforts in the past re-emerged, but conflict and political instability have proved the greatest barriers to reform implementation and the programme was abandoned in 2014. More recently, the focus has been on more pressing humanitarian concerns arising from the conflict in the east of Ukraine. It is hoped that greater political, social and economic stability in the future will provide a better environment for the introduction of deep reforms to address shortcomings in the Ukrainian health system. PMID- 26106881 TI - CT attenuation features of individual calcified coronary plaque: differences among asymptomatic, stable angina pectoris, and acute coronary syndrome groups. AB - BACKGROUND: Coronary artery calcium (CAC) assessed by non-contrast cardiac CT has been shown to be an independent factor from the Framingham risk factors in predicting cardiovascular events. However, many patients with acute coronary syndrome (ACS) have low CAC score. A recent study that re-analyzed the previous CAC CT scan of MESA cohort showed that in subjects with global lower density, CAC was associated with higher risk of ACS. We aimed to further evaluate the characteristics of CAC attenuation features in ACS subjects, in comparison to asymptomatic and stable angina pectoris (SAP) groups. METHODS: In a period of 18 months, 524 consecutive subjects received standard CAC CT scans in our department; 278 of 524 subjects with presence of CAC (225 men, age = 60.6+/-9.5 years; ACS = 41, SAP = 78, asymptomatic = 159) were enrolled. Agatston score, number of plaques (NP) per subject and mean (HMEAN) and standard deviation (HSD) of attenuation of each calcified plaque were measured. Three regression models to distinguish the groups were built: model 1, conventional risk factors only; model 2, Agatston score plus model 1; model 3, plaque attenuation features plus model 2. RESULTS: Agatston score in ACS group (median = 112.9) was higher than in the asymptomatic group (median = 54.4, P = 0.028) and similar to the SAP group (median = 237.8, P = 0.428). Calcified plaques in the ACS group showed lower (HMEAN = 180.5) and more homogenous (HSD = 31.2) attenuation than those of the asymptomatic group (HMEAN = 205.9, P = 0.002; HSD = 52.4, P = 0.006) and the SAP group (HMEAN = 204.1, P = 0.016; HSD = 54.4, P = 0.011). Model 3 significantly improved the distinction between ACS and asymptomatic groups (area under curve [AUC] = 0.93) as compared to model 2 (AUC = 0.83, P = 0.003) and model 1 (AUC = 0.79, P = 0.001). CONCLUSIONS: Calcified plaques in the ACS group were characteristically of low and homogenous CT attenuation. With validation in a large cohort, analysis of CT attenuation features may improve risk stratification of ACS using CAC CT scan. PMID- 26106882 TI - Impacts of different grades of tropical cyclones on infectious diarrhea in Guangdong, 2005-2011. AB - OBJECTIVE: Guangdong province is one of the most vulnerable provinces to tropical cyclones in China. Most prior studies concentrated on the relationship between tropical cyclones and injuries and mortality. This study aimed to explore the impacts of different grades of tropical cyclones on infectious diarrhea incidence in Guangdong province, from 2005 to 2011. METHODS: Mann-Whitney U test was firstly used to examine if infectious diarrhea were sensitive to tropical cyclone. Then unidirectional 1:1 case-crossover design was performed to quantitatively evaluate the relationship between daily number of infectious diarrhea and tropical cyclone from 2005 to 2011 in Guangdong, China. Principal component analysis (PCA) was applied to eliminate multicollinearity. Multivariate logistic regression model was used to estimate the hazard ratios (HRs) and the 95% confidence intervals (CI). RESULTS: There were no significant relationships between tropical cyclone and bacillary dysentery, amebic dysentery, typhoid, and paratyphoid cases. Infectious diarrhea other than cholera, dysentery, typhoid and paratyphoid significantly increased after tropical cyclones. The strongest effect were shown on lag 1 day (HRs = 1.95, 95%CI = 1.22, 3.12) and no lagged effect was detected for tropical depression, tropical storm, severe tropical storm and typhoon, with the largest HRs (95%CI) of 2.16 (95%CI = 1.69, 2.76), 2.43 (95%CI = 1.65, 3.58) and 2.21 (95%CI = 1.65, 2.69), respectively. Among children below 5 years old, the impacts of all grades of tropical cyclones were strongest at lag 0 day. And HRs were 2.67 (95%CI = 1.10, 6.48), 2.49 (95%CI = 1.80, 3.44), 4.89 (95%CI = 2.37, 7.37) and 3.18 (95%CI = 2.10, 4.81), respectively. CONCLUSION: All grades of tropical cyclones could increase risk of other infectious diarrhea. Severe tropical storm has the strongest influence on other infectious diarrhea. The impacts of tropical cyclones on children under 5 years old were higher than total population. PMID- 26106883 TI - Polymorphisms in Ion Transport Genes Are Associated with Eggshell Mechanical Property. AB - Eggshell mechanical property traits such as eggshell breaking strength (ESS), eggshell thickness (EST) and eggshell weight (ESW) are most common and important indexes to evaluate eggshell quality in poultry industry. Uterine ion transporters involve in eggshell formation and might be associated with eggshell mechanical property traits. In this study, 99 SNPs in 15 ion transport genes were selected to genotype 976 pedigreed hens of Rhode Island Red. ESS, EST and ESW were measured for each bird at 55 weeks of age. The association study showed that 14 SNPs in 8 genes were significantly related (p < 0.05) with at least one trait, and their contributions to phenotypic variance ranged from 0.23% to 4.14%. Both ATP2A3 and SLC4A5 had a significant effect on all the three traits. Strong linkage disequilibrium (LD) was detected among SNPs in four genes: ATP2A3, ITPR1, SLC8A3, SCNN1a. The significant effects of those diplotypes on eggshell mechanical property traits were found, and their contributions to phenotypic variance ranged from 0.50% to 0.70%. It was concluded that the identified SNPs and diplotypes in this study were potential markers influencing the eggshell mechanical properties, which could contribute to the genetic improvement of eggshell quality. PMID- 26106884 TI - A New Combinatorial Optimization Approach for Integrated Feature Selection Using Different Datasets: A Prostate Cancer Transcriptomic Study. AB - BACKGROUND: The joint study of multiple datasets has become a common technique for increasing statistical power in detecting biomarkers obtained from smaller studies. The approach generally followed is based on the fact that as the total number of samples increases, we expect to have greater power to detect associations of interest. This methodology has been applied to genome-wide association and transcriptomic studies due to the availability of datasets in the public domain. While this approach is well established in biostatistics, the introduction of new combinatorial optimization models to address this issue has not been explored in depth. In this study, we introduce a new model for the integration of multiple datasets and we show its application in transcriptomics. METHODS: We propose a new combinatorial optimization problem that addresses the core issue of biomarker detection in integrated datasets. Optimal solutions for this model deliver a feature selection from a panel of prospective biomarkers. The model we propose is a generalised version of the (alpha,beta)-k-Feature Set problem. We illustrate the performance of this new methodology via a challenging meta-analysis task involving six prostate cancer microarray datasets. The results are then compared to the popular RankProd meta-analysis tool and to what can be obtained by analysing the individual datasets by statistical and combinatorial methods alone. RESULTS: Application of the integrated method resulted in a more informative signature than the rank-based meta-analysis or individual dataset results, and overcomes problems arising from real world datasets. The set of genes identified is highly significant in the context of prostate cancer. The method used does not rely on homogenisation or transformation of values to a common scale, and at the same time is able to capture markers associated with subgroups of the disease. PMID- 26106886 TI - Correction: a modular analysis of the auxin signalling network. PMID- 26106887 TI - Testing the Role of Climate Change in Species Decline: Is the Eastern Quoll a Victim of a Change in the Weather? AB - To conserve a declining species we first need to diagnose the causes of decline. This is one of the most challenging tasks faced by conservation practitioners. In this study, we used temporally explicit species distribution models (SDMs) to test whether shifting weather can explain the recent decline of a marsupial carnivore, the eastern quoll (Dasyurus viverrinus). We developed an SDM using weather variables matched to occurrence records of the eastern quoll over the last 60 years, and used the model to reconstruct variation through time in the distribution of climatically suitable range for the species. The weather model produced a meaningful prediction of the known distribution of the species. Abundance of quolls, indexed by transect counts, was positively related to the modelled area of suitable habitat between 1990 and 2004. In particular, a sharp decline in abundance from 2001 to 2003 coincided with a sustained period of unsuitable weather over much of the species' distribution. Since 2004, abundance has not recovered despite a return to suitable weather conditions, and abundance and area of suitable habitat have been uncorrelated. We suggest that fluctuations in weather account for the species' recent decline, but other unrelated factors have suppressed recovery. PMID- 26106885 TI - Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes. AB - Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1) deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo 1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes. PMID- 26106888 TI - Portlandemys gracilis n. sp., a New Coastal Marine Turtle from the Late Jurassic of Porrentruy (Switzerland) and a Reconsideration of Plesiochelyid Cranial Anatomy. AB - BACKGROUND: Several groups of stem cryptodires became adapted to coastal marine environments as early as the Late Jurassic, 40 million years before the Pan Chelonioidea. The Plesiochelyidae are a major component of this first radiation of crown-group turtles into marine habitats. They are abundant in many European localities, but their systematics is still greatly confused. Only three species are represented by cranial material: Plesiochelys etalloni, Plesiochelys planiceps, and Portlandemys mcdowelli. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we describe a cranium and a mandible from the Kimmeridgian of Porrentruy (Switzerland), which we refer to a new species, Portlandemys gracilis n. sp. This new taxon differs from Portlandemys mcdowelli in several aspects of the cranium and mandible, notably in being generally more gracile, but the two species share a narrow skull, a more acute angle between the labial ridges on the mandible, and a unique configuration of the anterodorsal part of the basicranium. The cranial anatomy of plesiochelyid turtles is discussed in details based primarily on these new specimens and new cranial material of Plesiochelys etalloni from Solothurn, Switzerland. CONCLUSIONS/SIGNIFICANCE: Several characters (e.g., the contribution of the parietal to the foramen nervi trigemini, the configuration of the dorsum sellae and sella turcica, the presence of an infolding ridge on the posterior surface of the quadrate) appear as potential candidates to help elucidate plesiochelyid relationships. Some of these characters are included in a previously published phylogenetic dataset and help to stabilize the relationships of plesiochelyid turtles and closely related taxa. For the first time, our results suggest that plesiochelyids, 'Thalassemys' moseri, and Solnhofia parsonsi (representing the Eurysternidae) form a clade at the base of Eucryptodira. PMID- 26106889 TI - The relationship between cranial structure, biomechanical performance and ecological diversity in varanoid lizards. AB - Skull structure is intimately associated with feeding ability in vertebrates, both in terms of specific performance measures and general ecological characteristics. This study quantitatively assessed variation in the shape of the cranium and mandible in varanoid lizards, and its relationship to structural performance (von Mises strain) and interspecific differences in feeding ecology. Geometric morphometric and linear morphometric analyses were used to evaluate morphological differences, and finite element analysis was used to quantify variation in structural performance (strain during simulated biting, shaking and pulling). This data was then integrated with ecological classes compiled from relevant scientific literature on each species in order to establish structure function relationships. Finite element modelling results showed that variation in cranial morphology resulted in large differences in the magnitudes and locations of strain in biting, shaking and pulling load cases. Gracile species such as Varanus salvadorii displayed high strain levels during shaking, especially in the areas between the orbits. All models exhibit less strain during pull back loading compared to shake loading, even though a larger force was applied (pull =30N, shake = 20N). Relationships were identified between the morphology, performance, and ecology. Species that did not feed on hard prey clustered in the gracile region of cranial morphospace and exhibited significantly higher levels of strain during biting (P = 0.0106). Species that fed on large prey clustered in the elongate area of mandible morphospace. This relationship differs from those that have been identified in other taxonomic groups such as crocodiles and mammals. This difference may be due to a combination of the open 'space-frame' structure of the varanoid lizard skull, and the 'pull back' behaviour that some species use for processing large prey. PMID- 26106890 TI - Transcriptome response signatures associated with the overexpression of a mitochondrial uncoupling protein (AtUCP1) in tobacco. AB - Mitochondrial inner membrane uncoupling proteins (UCP) dissipate the proton electrochemical gradient established by the respiratory chain, thus affecting the yield of ATP synthesis. UCP overexpression in plants has been correlated with oxidative stress tolerance, improved photosynthetic efficiency and increased mitochondrial biogenesis. This study reports the main transcriptomic responses associated with the overexpression of an UCP (AtUCP1) in tobacco seedlings. Compared to wild-type (WT), AtUCP1 transgenic seedlings showed unaltered ATP levels and higher accumulation of serine. By using RNA-sequencing, a total of 816 differentially expressed genes between the investigated overexpressor lines and the untransformed WT control were identified. Among them, 239 were up-regulated and 577 were down-regulated. As a general response to AtUCP1 overexpression, noticeable changes in the expression of genes involved in energy metabolism and redox homeostasis were detected. A substantial set of differentially expressed genes code for products targeted to the chloroplast and mainly involved in photosynthesis. The overall results demonstrate that the alterations in mitochondrial function provoked by AtUCP1 overexpression require important transcriptomic adjustments to maintain cell homeostasis. Moreover, the occurrence of an important cross-talk between chloroplast and mitochondria, which culminates in the transcriptional regulation of several genes involved in different pathways, was evidenced. PMID- 26106892 TI - Correction: tigers of sundarbans in India: is the population a separate conservation unit? PMID- 26106891 TI - High-Frequency Heart Rate Variability Linked to Affiliation with a New Group. AB - This study tests the hypothesis that high levels of high-frequency heart rate variability (HF-HRV) predisposes individuals to affiliate with new groups. Resting cardiac physiological recordings were taken before and after experimental sessions to measure trait high-frequency heart rate variability as an index of dispositional autonomic influence on heart rate. Following an experimental manipulation of priming of caring-related words, participants engaged in a minimal group paradigm, in which they imagined being a member of one of two arbitrary groups, allocated money to members of the two groups, and rated their affiliation with the groups. High levels of HF-HRV were associated with ingroup favouritism while allocating money, an effect largely attributable to a positive relationship between HF-HRV and allocation of money to the ingroup, and less due to a negative relationship between HF-HRV and money allocation to the outgroup. HF-HRV was also associated with increased self-reported affiliation feelings for the ingroup but was unrelated to feelings towards the outgroup. These effects remained substantial even after controlling for age, gender, BMI, mood, caffeine consumption, time of day of data collection, smoking and alcohol behaviour, and respiration rate. Further, the effects were observed regardless of whether participants were primed with caring-related words or not. This study is the first to bridge a long history of research on ingroup favouritism to the relatively recent body of research on cardiac vagal tone by uncovering a positive association between HF-HRV and affiliation with a novel group. PMID- 26106893 TI - Evaluating the impact of abrupt changes in forest policy and management practices on landscape dynamics: analysis of a Landsat image time series in the Atlantic Northern Forest. AB - Sustainable forest management is based on functional relationships between management actions, landscape conditions, and forest values. Changes in management practices make it fundamentally more difficult to study these relationships because the impacts of current practices are difficult to disentangle from the persistent influences of past practices. Within the Atlantic Northern Forest of Maine, U.S.A., forest policy and management practices changed abruptly in the early 1990s. During the 1970s-1980s, a severe insect outbreak stimulated salvage clearcutting of large contiguous tracts of spruce-fir forest. Following clearcut regulation in 1991, management practices shifted abruptly to near complete dependence on partial harvesting. Using a time series of Landsat satellite imagery (1973-2010) we assessed cumulative landscape change caused by these very different management regimes. We modeled predominant temporal patterns of harvesting and segmented a large study area into groups of landscape units with similar harvest histories. Time series of landscape composition and configuration metrics averaged within groups revealed differences in landscape dynamics caused by differences in management history. In some groups (24% of landscape units), salvage caused rapid loss and subdivision of intact mature forest. Persistent landscape change was created by large salvage clearcuts (often averaging > 100 ha) and conversion of spruce-fir to deciduous and mixed forest. In groups that were little affected by salvage (56% of landscape units), contemporary partial harvesting caused loss and subdivision of intact mature forest at even greater rates. Patch shape complexity and edge density reached high levels even where cumulative harvest area was relatively low. Contemporary practices introduced more numerous and much smaller patches of stand-replacing disturbance (typically averaging <15 ha) and a correspondingly large amount of edge. Management regimes impacted different areas to different degrees, producing different trajectories of landscape change that should be recognized when studying the impact of policy and management practices on forest ecology. PMID- 26106895 TI - Visual perception of procedural textures: identifying perceptual dimensions and predicting generation models. AB - Procedural models are widely used in computer graphics for generating realistic, natural-looking textures. However, these mathematical models are not perceptually meaningful, whereas the users, such as artists and designers, would prefer to make descriptions using intuitive and perceptual characteristics like "repetitive," "directional," "structured," and so on. To make up for this gap, we investigated the perceptual dimensions of textures generated by a collection of procedural models. Two psychophysical experiments were conducted: free-grouping and rating. We applied Hierarchical Cluster Analysis (HCA) and Singular Value Decomposition (SVD) to discover the perceptual features used by the observers in grouping similar textures. The results suggested that existing dimensions in literature cannot accommodate random textures. We therefore utilized isometric feature mapping (Isomap) to establish a three-dimensional perceptual texture space which better explains the features used by humans in texture similarity judgment. Finally, we proposed computational models to map perceptual features to the perceptual texture space, which can suggest a procedural model to produce textures according to user-defined perceptual scales. PMID- 26106894 TI - Disgust versus Lust: Exploring the Interactions of Disgust and Fear with Sexual Arousal in Women. AB - Sexual arousal is a motivational state that moves humans toward situations that inherently pose a risk of disease transmission. Disgust is an emotion that adaptively moves humans away from such situations. Incongruent is the fact that sexual activity is elementary to human fitness yet involves strong disgust elicitors. Using an experimental paradigm, we investigated how these two states interact. Women (final N=76) were assigned to one of four conditions: rate disgust stimuli then watch a pornographic clip; watch a pornographic clip then rate disgust stimuli; rate fear stimuli then watch a pornographic clip; or watch a pornographic clip then rate fear stimuli. Women's genital sexual arousal was measured with vaginal photoplethysmography and their disgust and fear reactions were measured via self-report. We did not find that baseline disgust propensity predicted sexual arousal in women who were exposed to neutral stimuli before erotic content. In the Erotic-before-Disgust condition we did not find that sexual arousal straightforwardly predicted decreased image disgust ratings. However, we did find some evidence that sexual arousal increased self-reported disgust in women with high trait disgust and sexual arousal decreased self reported disgust in women with low trait disgust. Women who were exposed to disgusting images before erotic content showed significantly less sexual arousal than women in the control condition or women exposed to fear-inducing images before erotic content. In the Disgust-before-Erotic condition the degree of self reported disgust was negatively correlated with genital sexual arousal. Hence, in the conflict between the ultimate goals of reproduction and disease avoidance, cues of the presence of pathogens significantly reduce the motivation to engage in mating behaviors that, by their nature, entail a risk of pathogen transmission. PMID- 26106897 TI - Will Passive Protection Save Congo Forests? AB - Central Africa's tropical forests are among the world's largest carbon reserves. Historically, they have experienced low rates of deforestation. Pressures to clear land are increasing due to development of infrastructure and livelihoods, foreign investment in agriculture, and shifting land use management, particularly in the Democratic Republic of Congo (DRC). The DRC contains the greatest area of intact African forests. These store approximately 22 billion tons of carbon in aboveground live biomass, yet only 10% are protected. Can the status quo of passive protection - forest management that is low or nonexistent - ensure the preservation of this forest and its carbon? We have developed the SimCongo model to simulate changes in land cover and land use based on theorized policy scenarios from 2010 to 2050. Three scenarios were examined: the first (Historical Trends) assumes passive forest protection; the next (Conservation) posits active protection of forests and activation of the national REDD+ action plan, and the last (Agricultural Development) assumes increased agricultural activities in forested land with concomitant increased deforestation. SimCongo is a cellular automata model based on Bayesian statistical methods tailored for the DRC, built with the Dinamica-EGO platform. The model is parameterized and validated with deforestation observations from the past and runs the scenarios from 2010 through 2050 with a yearly time step. We estimate the Historical Trends trajectory will result in average emissions of 139 million t CO2 year-1 by the 2040s, a 15% increase over current emissions. The Conservation scenario would result in 58% less clearing than Historical Trends and would conserve carbon-dense forest and woodland savanna areas. The Agricultural Development scenario leads to emissions of 212 million t CO2 year-1 by the 2040s. These scenarios are heuristic examples of policy's influence on forest conservation and carbon storage. Our results suggest that 1) passive protection of the DRC's forest and woodland savanna is insufficient to reduce deforestation; and 2): enactment of a REDD+ plan or similar conservation measure is needed to actively protect Congo forests, their unique ecology, and their important role in the global carbon cycle. PMID- 26106896 TI - Dissection of a Complex Disease Susceptibility Region Using a Bayesian Stochastic Search Approach to Fine Mapping. AB - Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1D associated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r2 ? 0:3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4+ T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data. PMID- 26106898 TI - Temperature Dependence of Photodegradation of Dissolved Organic Matter to Dissolved Inorganic Carbon and Particulate Organic Carbon. AB - Photochemical transformation of dissolved organic matter (DOM) has been studied for more than two decades. Usually, laboratory or "in-situ" experiments are used to determine photodegradation variables. A common problem with these experiments is that the photodegradation experiments are done at higher than ambient temperature. Five laboratory experiments were done to determine the effect of temperature on photochemical degradation of DOM. Experimental results showed strong dependence of photodegradation on temperature. Mathematical modeling of processes revealed that two different pathways engaged in photochemical transformation of DOM to dissolved inorganic carbon (DIC) strongly depend on temperature. Direct oxidation of DOM to DIC dominated at low temperatures while conversion of DOM to intermediate particulate organic carbon (POC) prior to oxidation to DIC dominated at high temperatures. It is necessary to consider this strong dependence when the results of laboratory experiments are interpreted in regard to natural processes. Photodegradation experiments done at higher than ambient temperature will necessitate correction of rate constants. PMID- 26106899 TI - Childhood Learning Disabilities and Atypical Dementia: A Retrospective Chart Review. AB - OBJECTIVE: To further our understanding of the association between self-reported childhood learning disabilities (LDs) and atypical dementia phenotypes (Atypical Dementia), including logopenic primary progressive aphasia (L-PPA), Posterior Cortical Atrophy (PCA), and Dysexecutive-type Alzheimer's Disease (AD). METHODS: This retrospective case series analysis of 678 comprehensive neuropsychological assessments compared rates of self-reported LD between dementia patients diagnosed with Typical AD and those diagnosed with Atypical Dementia. 105 cases with neuroimaging or CSF data available and at least one neurology follow-up were identified as having been diagnosed by the neuropsychologist with any form of neurodegenerative dementia. These cases were subject to a consensus diagnostic process among three dementia experts using validated clinical criteria for AD and PPA. LD was considered Probable if two or more statements consistent with prior LD were documented within the Social & Developmental History of the initial neuropsychological evaluation. RESULTS: 85 subjects (Typical AD n=68, Atypical AD n=17) were included in the final analysis. In logistic regression models adjusted for age, gender, handedness, education and symptom duration, patients with Probable LD, compared to patients without Probable LD, were significantly more likely to be diagnosed with Atypical Dementia vs. Typical AD (OR 13.1, 95% CI 1.3 128.4). All three of the L-PPA cases reporting a childhood LD endorsed childhood difficulty with language. By contrast, both PCA cases reporting Probable childhood LD endorsed difficulty with attention and/or math. CONCLUSIONS: In people who develop dementia, childhood LD may predispose to atypical phenotypes. Future studies are required to confirm whether atypical neurodevelopment predisposes to regional-specific neuropathology in AD and other dementias. PMID- 26106900 TI - Toward the Identification of Two Glycoproteins Involved in the Stomatal Deregulation of Downy Mildew-Infected Grapevine Leaves. AB - Stomata remain abnormally opened and unresponsive to abscisic acid in grapevine leaves infected by downy mildew. This deregulation occurs from 3 days postinoculation and increases concomitantly with leaf colonization by the pathogen. Using epidermal peels, we demonstrated that the active compound involved in this deregulation is located in the apoplast. Biochemical assays showed that the active compound present in the apoplastic fluids isolated from Plasmopara viticola-infected grapevine leaves (IAF) is a CysCys bridge independent, thermostable and glycosylated protein. Fractionation guided assays based on chromatography coupled to stomatal response and proteomic analysis allowed the identification of both plant and pathogen proteins in the active fraction obtained from IAF. Further in silico analysis and discriminant filtrations based on the comparison between predictions and experimental indications lead to the identification of two Vitis vinifera proteins as candidates for the observed stomatal deregulation. PMID- 26106901 TI - Bradyrhizobium BclA Is a Peptide Transporter Required for Bacterial Differentiation in Symbiosis with Aeschynomene Legumes. AB - Nodules of legume plants are highly integrated symbiotic systems shaped by millions of years of evolution. They harbor nitrogen-fixing rhizobium bacteria called bacteroids. Several legume species produce peptides called nodule-specific cysteine-rich (NCR) peptides in the symbiotic nodule cells which house the bacteroids. NCR peptides are related to antimicrobial peptides of innate immunity. They induce the endosymbionts into a differentiated, enlarged, and polyploid state. The bacterial symbionts, on their side, evolved functions for the response to the NCR peptides. Here, we identified the bclA gene of Bradyrhizobium sp. strains ORS278 and ORS285, which is required for the formation of differentiated and functional bacteroids in the nodules of the NCR peptide producing Aeschynomene legumes. The BclA ABC transporter promotes the import of NCR peptides and provides protection against the antimicrobial activity of these peptides. Moreover, BclA can complement the role of the related BacA transporter of Sinorhizobium meliloti, which has a similar symbiotic function in the interaction with Medicago legumes. PMID- 26106902 TI - New Approaches to Measuring Sticky Molecules: Improvement of Instrumental Response Times Using Active Passivation. AB - A novel method has been developed to improve sampling system response times for nominally "sticky" molecules such as HNO3 and NH3. The method reported here makes use of active, continuous passivation, where the instrument interfaces are continuously exposed to 0.01-1 ppm of fluorinated acidic or basic surfactants. To reduce HNO3 response times, perfluoroheptanoic acid and perfluorobutanesulfonic acid vapors are evaluated as passivation species. 1H,1H-perfluorooctylamine is used to improve NH3 response times. The resulting time responses using the perfluoroalkanoic acids are on the order of 0.4-0.7 s for a 75% quantitative recovery of HNO3, and 1-5 s for 90% recovery. Similar response time improvements are seen in detection of NH3 using perfluorooctylamine (<1 s for a 75% recovery, ~ 2 s for 90% recovery). This generally applicable methodology significantly improves the capability of eddy covariance flux and real-time plume-based measurements of highly polar molecules that have historically been hampered by slow response times due to adsorption on sampling system surfaces. The utility of this approach is demonstrated by field measurements of HNO3 eddy covariance fluxes in a central U.S. prairie. PMID- 26106903 TI - Alternative and Legacy Perfluoroalkyl Substances: Differences between European and Chinese River/Estuary Systems. AB - The production and use of long-chain perfluoroalkyl substances (PFASs) must comply with national and international regulations. Driven by increasingly stringent regulations, their production has been outsourced to less regulated countries in Asia. In addition, the fluoropolymer industry started to use fluorinated alternatives, such as 2,3,3,3-tetrafluoro-2-(1,1,2,2,3,3,3 heptafluoropropoxy)propanoic acid (HFPO-DA). Between August 2013 and September 2014, we investigated the occurrence and distribution of HFPO-DA and legacy PFASs in surface waters of the following river/estuary systems: the Elbe and Rhine Rivers in Germany, the Rhine-Meuse delta in The Netherlands, and the Xiaoqing River in China. Distinct differences were revealed among the study areas; notably, the Chinese samples were highly polluted by an industrial point source discharging mainly perfluorooctanoic acid (PFOA). This particular point source resulted in concentrations more than 6000 times higher than an industrial point source observed in the Scheur River, where HFPO-DA was the dominant compound with a concentration of 73.1 ng/L. Moreover, HFPO-DA was detected in all samples along the coastline of the North Sea, indicating that the compound may be transported from the Rhine-Meuse delta into the German Bight via the water current. To the best of our knowledge, the fluorinated alternative, HFPO-DA, was detected for the first time in surface waters of Germany and China. PMID- 26106904 TI - Understanding the Effect of Monomeric Iridium(III/IV) Aquo Complexes on the Photoelectrochemistry of IrO(x).nH2O-Catalyzed Water-Splitting Systems. AB - Soluble, monomeric Ir(III/IV) complexes strongly affect the photoelectrochemical performance of IrO(x).nH2O-catalyzed photoanodes for the oxygen evolution reaction (OER). The synthesis of IrO(x).nH2O colloids by alkaline hydrolysis of Ir(III) or Ir(IV) salts proceeds through monomeric intermediates that were characterized using electrochemical and spectroscopic methods and modeled in TDDFT calculations. In air-saturated solutions, the monomers exist in a mixture of Ir(III) and Ir(IV) oxidation states, where the most likely formulations at pH 13 are [Ir(OH)5(H2O)](2-) and [Ir(OH)6](2-), respectively. These monomeric anions strongly adsorb onto IrO(x).nH2O colloids but can be removed by precipitation of the colloids with isopropanol. The monomeric anions strongly adsorb onto TiO2, and they promote the adsorption of ligand-free IrO(x).nH2O colloids onto mesoporous titania photoanodes. However, the reversible adsorption/desorption of electroactive monomers effectively short-circuits the photoanode redox cycle and thus dramatically degrades the photoelectrochemical performance of the cell. The growth of a dense TiO2 barrier layer prevents access of soluble monomeric anions to the interface between the oxide semiconductor and the electrode back contact (a fluorinated tin oxide transparent conductor) and leads to improved photoanode performance. Purified IrO(x).nH2O colloids, which contain no adsorbed monomer, give improved performance at the same electrodes. These results explain earlier observations that IrO(x).nH2O catalysts can dramatically degrade the performance of metal oxide photoanodes for the OER reaction. PMID- 26106905 TI - Polysaccharide-Based Conjugates for Biomedical Applications. AB - Polysaccharides contain different functional groups (such as hydroxyl, amino, carboxylic acid, aldehydes) that make them ideal for conjugation. They are biodegradable, biocompatible, and hydrophilic. Polysaccharide conjugates have been used in drug, gene, and macromolecule delivery, tissue engineering, and other biomedical applications. Polysaccharide conjugates have also been used primarily for solubilization and controlled release of hydrophobic moieties. The advent of nanotechnology, gene therapy, and tissue engineering influenced the way these conjugates are now used. Modern day conjugates are modulated to be thermoresponsive, pH-responsive, photoresponsive, or target-specific (receptor mediated targeting). This Review briefly introduces different polysaccharides followed by different synthetic strategies used for conjugation; finally, recent applications were compiled. PMID- 26106906 TI - Antioxidative Reaction of Carotenes against Peroxidation of Fatty Acids Initiated by Nitrogen Dioxide: A Theoretical Study. AB - In this study, we investigated the antioxidative functions of carotenes (CARs) against the peroxidation of lipids initiated by nitrogen dioxide using density functional theory. The hydrogen-atom transfer (HAT), radical adduct formation (RAF), and electron transfer (ET) mechanisms were investigated. We chose beta carotene (beta-CAR) and lycopene (LYC) and compared their NO2(*) initiations and peroxidations with those of linoleic acid (LAH), the model of the lipid. We found that for CARs ET is more likely to occur in the most polar (water) environment than are HAT and RAF. In less polar environments, CARs react more readily with NO2(*) via HAT and RAF than does the lipid model, LAH. Comparatively, reaction barriers for the RAF between CARs and NO2(*) are smaller than those for the HAT. The additions of O2 to the radical intermediates O2N-CAR(*) and CAR(-H)(*) involve sizable barriers and are endergonic. Other than HAT of LAH, we revealed that lipid peroxidation is likely to be initiated by -NO2 addition and the subsequent barrierless addition of O2. Finally, LYC is a more effective antioxidative agent against NO2(*)-initiated lipid peroxidation than is beta-CAR. PMID- 26106907 TI - Efficacy of stannous, fluoride and their their combination in dentin erosion prevention in vitro. AB - The aim of this study was to compare the protective effects of solutions containing stannous (Sn), fluoride (F) and their combination in the prevention of dentin erosion. Forty bovine root dentin specimens (4'4'2 mm(3)) were prepared and randomly assigned to 4 groups (n = 10): SnCl2 (800 ppm/6.7 mM Sn), NaF (250 ppm/13 mM F), NaF/SnCl2 (800 ppm/6.7 mM Sn; 250 ppm/13 mM F), and deionized water (DIW) as a negative control. An acquired pellicle was formed on dentin samples by incubation in clarified, pooled, stimulated human saliva for 24 hours. The specimens were subjected to 5 daily cycles, each consisting of 5 of min demineralization (0.3%/15.6 mM citric acid, pH 2.6, 6'/day) and 60 min of re mineralization in clarified human saliva. Thirty minutes after the 1st, 3rd and 5th demineralization episodes of each day, the specimens were treated with one of the test solutions for 2 min. Surface loss was measured via optical profilometry. Mixed-model ANOVA followed by Tukey's test were used for the statistical analysis. Sn, F, and their combination significantly reduced the dentin surface loss by 23%, 36%, and 60% compared with DIW, respectively. All groups were significantly different (p < 0.05). The combination of Sn and F significantly reduced the amount of dentin surface loss compared with all other groups. The F group also significantly reduced surface loss compared with Sn and DIW, followed by the Sn group, which showed significantly greater protection compared with the DIW control. The daily use of a combined fluoride and stannous solution is promising for preventing dentin erosion. PMID- 26106908 TI - Colloidal Quantum Dot Solar Cells. PMID- 26106910 TI - Total synthesis of two potent anti-inflammatory macrolactones of the oxacyclododecindione type. AB - An esterification/Friedel-Crafts-cyclization approach permitted the first successful synthetic entry into the oxacyclododecindione subclass of the dihydroxyphenylacetic acid lactone-type natural products. This route allowed the preparation of two highly active anti-inflammatory fungal secondary metabolites 14-deoxyoxacyclododecindione and 14-deoxy-4-dechlorooxacyclododecindione as well as their 14-desmethyl analogues. PMID- 26106909 TI - Microarray Determination of the Expression of Drug Transporters in Humans and Animal Species Used for the Investigation of Nasal Absorption. AB - Mice and rats are commonly used to investigate in vivo nasal drug absorption, yet their small nasal cavities limit their use for in vitro investigations. Bovine tissue explants have been used to investigate drug transport through the nasal respiratory and olfactory mucosae, yet limited information is available regarding the similarities and differences among these animal models compared to humans. The aim of this study was to compare the presence of a number of important drug transporters in the nasal mucosa of these species. DNA microarray results for nasal samples from humans, rats, and mice were obtained from GenBank, while DNA microarray and RT-PCR were performed on bovine nasal explants. The drug transporters of interest include multidrug resistance, cation, anion, peptide, and nucleoside transporters. Each of the species (mouse, rat, cattle, and human) shows similar patterns of expression for most of the important drug transporters. Several transporters were highly expressed in all the species, including MRP1, OCTN2, PEPT2, and y+LAT2. While some differences in transporter mRNA and protein expression were observed, the transporter expression patterns were quite similar among the species. The differences suggest that it is important to be aware of any specific differences in transporter expression for a given compound being investigated, yet the similarities support the continued use of these animal models during preclinical investigation of intranasally administered therapeutics. PMID- 26106912 TI - The Use of Conjunctival Rotational Autograft in the Management of Pterygium. PMID- 26106911 TI - Association of Height With Pattern Reversal Visual Evoked Potentials. AB - PURPOSE: This study was conducted to investigate whether pattern reversal visual evoked potential parameters in a large sample of healthy subjects are influenced by height of the subjects. DESIGN: It was an institutional, cross-sectional study. METHODS: Pattern reversal visual evoked potential (PRVEP) recordings from 400 eyes from 200 normal subjects were performed in the Neurophysiology unit of the Department of Physiology in accordance to the standardized methodology and montages were kept as per 10-20 International System of electroencephalogram electrode placements. VEP latencies, duration and amplitude were measured in all subjects. The correlation of all the electrophysiological parameters with height was evaluated by Pearson's correlation co-efficient (r) and its statistical significance was evaluated. RESULTS: On correlating mean height with mean VEP parameters of both eyes in the subjects it was found that there is a positive correlation of P100 latency and N155 latency in the subjects and a highly significant negative correlation of P100 amplitude with height in the subjects of various age groups. N70 latency was found to be significantly positively correlated with height whereas P100 Duration showed a non-significant negative correlation with height of the subjects. CONCLUSION: Our findings suggest that VEP latencies, duration and amplitude are influenced by the height of the individual. The positive correlation between VEP latencies and increasing height may all reflect the increase in length between the optic nerve head and the visual processing areas-the striate and the extra striate cortex which are the main generators of the various PRVEP waveforms. PMID- 26106913 TI - Age-Related Macular Degeneration: From Genetics to Epigenetics. PMID- 26106914 TI - The Evolution of Cataract Surgery: Controversies Through the Ages. AB - Cataracts have been in public consciousness since ancient times. Throughout the ages, the comfort of established practices, at times, has obstructed the implementation of improved policies. The opposition to lensectomy, hygiene practices, intraocular lenses, and phacoemulsification (phaco) are explored. As femtosecond laser cataract surgery attempts to secure a foothold in cataract treatment, we consider whether it is destined to be a forgotten footnote or if, like other contributions to the history books, the difficulties of establishing a new technique are abstracting the benefits represented. PMID- 26106915 TI - Aggressive Debridement Improves Outcome of Fungal Keratitis. AB - PURPOSE: To study surgical debridement in the management of fungal keratitis in 44 patients. DESIGN: A prospective randomized study. METHODS: Patients with presumed fungal keratitis were randomized into 2 groups. The first group had diagnostic corneal scraping with a Kimura spatula while the second group underwent surgical debridement utilizing a motorized drill with attached diamond burr. Material obtained from both methods was plated on Sabaurauds medium, blood agar and stained for bacteria and fungi. Topical and systemic antifungal therapy was instituted, and patients were examined until resolution. RESULTS: Pathogens were identified to a greater degree in the aggressive debridement group than in the Kimura spatula group. Patients who had aggressive debridement had a significant reduction in time to re-epithelialization and keratitis resolution (9.4 days) compared with the scraping group (17.1 days, P < 0.001). Mean uncorrected visual acuity (UCVA) in the surgical group was 1.02 logarithm of the minimal angle of resolution (logMAR) preoperatively and 0.43 logMAR postoperatively (P < 0.001). Mean UCVA in the Kimura spatula group was 1.20 logMAR before and 0.58 logMAR after scraping (P = 0.03). A single incidence of perforation occurred in the scraping group with the diagnosis of Fusarium made from the corneal button. CONCLUSIONS: Aggressive debridement and debulking of fungal keratitis provides a faster clinical resolution with no reduction in visual potential. The acquisition of pathogens is more accurate with surgical debridement as compared with conventional scraping. Aggressive surgical debridement of keratitis not only aids in diagnosis but may also be therapeutic. PMID- 26106916 TI - Conjunctival Rotation Autograft for Pterygium: An Alternative to Conventional Conjunctival Autografting. AB - PURPOSE: To determine the safety and efficacy of conjunctival rotation autograft (CRA) as an alternative to conventional conjunctival autograft after pterygium excision and its complications and rate of recurrence. DESIGN: A prospective non comparative interventional case study. METHODS: Conjunctival rotation autograft was performed under peribulbar block in 50 eyes with primary pterygium as well as recurrent pterygium of grade 1, 2 and 3 according to a morphological grading system. Patients were followed up for 12 months for complications like graft retraction, injection, recurrence, etc. RESULTS: A total of 55 CRAs were done in 50 eyes of 47 subjects in the study wherein grafts were attached by using the 10 0 nylon sutures in primary and recurrent pterygia. Mean follow up period was 11.67 months (Range 9-12 months). The most commonly found complications were graft injection in 16 (29.09%) cases and graft pigmentation in 5 (9.0%) cases. Injection was not associated with pterygium grade and was found to be statistically insignificant (P = 0.27). Recurrence was found only in 1 (1.8%) case in grade T3 recurrent pterygium. CONCLUSIONS: Conjunctival rotation autograft appears to be a successful and safe alternative to conjunctival autograft, with a relatively low rate of pterygium recurrence in this uncontrolled series. We advocate the use of CRA for cases of pterygium in which a conventional autograft is contraindicated or difficult. In addition, the procedure can be used as a primary surgical option in primary and recurrent pterygia. PMID- 26106917 TI - Twenty-Three-Gauge Pars Plana Vitrectomy With Inferior Retinectomy and Postoperative Perfluoro-n-Octane Retention for Retinal Detachment Repair. AB - PURPOSE: The objective of this article was to study outcomes following use of perfluoro-n-octane (PFO) as a short-term postoperative vitreous substitute in patients undergoing pars plana vitrectomy for a recurrent rhegmatogenous retinal detachment (RRD) with advanced proliferative vitreoretinopathy requiring an inferior retinectomy. DESIGN: A retrospective consecutive chart review. METHODS: The charts of subjects who underwent RRD repair by pars plana vitrectomy with short-term postoperative PFO, vitreous substitution were retrospectively reviewed. The primary outcome was the anatomic success rate following retinectomy and short-term PFO retention. The secondary outcomes were change in best corrected visual acuity (BCVA) and occurrence of complications related to short term PFO retention. RESULTS: The anatomic success rate at the final follow-up was 91.7% (11/12). A total of 7 (58.3%; confidence interval, 32%-80.7%) of 12 patients achieved a final BCVA better than initial BCVA. There were no significant complications related to short-term PFO retention. CONCLUSIONS: Perfluoro-n-octane is efficacious and safe as a short-term vitreous substitute for repair of a recurrent RRD with advanced proliferative vitreoretinopathy requiring an inferior retinectomy. PMID- 26106918 TI - Corneal Debridement Update: Adjuvant Therapies and Wound Healing. AB - Corneal debridement techniques have seen evolution in instrumentation and indication. Although the techniques themselves are simple and usually effective, there is often the need for adjuvant topical therapies to augment healing and/or prevent recurrence of disease. To better understand the requirement for adjuvant therapies, the current theories of corneal wound healing are reviewed. PMID- 26106919 TI - Recent Innovations in Medical and Surgical Retina. AB - PURPOSE: To highlight recent innovations in the medical and surgical treatment of retinal disease. DESIGN: Retrospective literature review. METHODS: The peer reviewed, published (during 2012) English literature was searched using the Medline database. Articles deemed relevant were selected and highlighted. RESULTS: A number of important innovations in the treatment of retinal disease have occurred during the past year. We review developments in regenerative medicine (e.g., retinal prosthesis, optogenetics, cell-based therapy), diagnostics (e.g., swept source optical coherence tomography [OCT], intraoperative OCT, multimodal imaging), surgical innovations (e.g., chemical vitreolysis with ocriplasmin, 27-gauge vitrectomy), and pharmacological therapy of retinal vascular disease (e.g., use of ranibizumab and aflibercept in the treatment of macular edema associated with diabetic retinopathy and retinal vein occlusion). CONCLUSIONS: Many important innovations in regenerative medicine, diagnostic and surgical instrumentation, and pharmacological therapy for retinal vascular disease have occurred during the past year. In view of the number of agents in early phase clinical trials (e.g., treatments for dry age-related macular degeneration) as well as technologies under development (e.g., microrobots for vitreous surgery), this trend will continue. PMID- 26106920 TI - Retinal Prostheses Development in Retinitis Pigmentosa Patients-Progress and Comparison. AB - PURPOSE: Since 2000, several groups have initiated chronic studies, implanting electronic retinal prostheses into the blind eyes of patients with retinitis pigmentosa to produce formed vision. DESIGN: A review and comparison of their techniques and results. METHODS: The 4 groups reviewed comprise 2 epiretinal and 2 subretinal groups. Visual function results reported in their publications during approximately the past 2 years are compared. RESULTS: Serious adverse effects occurred in both epiretinal groups but none in the 2 subretinal groups. Phosphenes with some similarity to the multielectrode stimulation pattern were induced by 1 group (EpiRet GmbH), and a somewhat higher phosphene pattern was created by another group (Second Sight). In 1 subretinal group (Retina Implant AG), an even higher phosphene pattern allowed recognition of letters and objects such as a cup or saucer. In the second subretinal group (Optobionics), besides perceived phosphenes, a neurotrophic rescue of visual function produced a marked improvement of visual acuity, color and contrast perception, visual field size, and improved darkness perception. In some subjects, recognition of facial features and household objects was restored. CONCLUSIONS: Both epiretinal and subretinal prostheses created phosphene-type patterned vision in some subjects. The phosphene resolution of Retina Implant AG's subretinal device was substantially greater than both epiretinal devices. Of the 4 groups, only Optobionic's paracentrally placed subretinal Artificial Silicon Retina implant induced an unexpected neurotrophic rescue and return of lost visual function resulting in the greatest return of visual acuity, color and contrast perception, visual field enlargement, and darkness perception. PMID- 26106921 TI - Letter to the Editor: Bacterial Species and Surgical Sites Involved in Contamination During Strabismus Surgery. PMID- 26106922 TI - Reply Regarding Bacterial Species and Surgical Sites Involved in Contamination During Strabismus Surgery. PMID- 26106923 TI - Letter to the Editor Regarding Scleral Buckling for Rhegmatogenous Retinal Detachment Using Vitrectomy-Based Visualization Systems and Chandelier Illumination. PMID- 26106924 TI - Reply to Letter Regarding Scleral Buckling for Rhegmatogenous Retinal Detachment Using Vitrectomy-Based Visualization and Chandelier Illumination. PMID- 26106925 TI - Impact of Preexisting Mental Illnesses on Receipt of Guideline-Consistent Breast Cancer Treatment and Health Care Utilization. AB - This study determined the impact of preexisting mental illnesses on guideline consistent breast cancer treatment and breast cancer-related health care utilization. This was a retrospective, longitudinal, cohort study conducted using data from the 2006-2008 Medicaid Analytic Extract files. The target population for the study consisted of female Medicaid enrollees who were aged 18-64 years and were newly diagnosed with breast cancer in 2007. Guideline-consistent breast cancer treatment was defined according to established guidelines. Breast cancer related health care use was reported in the form of inpatient, outpatient, and emergency room visits. Statistical analyses consisted of multivariable hierarchical regression models. A total of 2142 newly diagnosed cases of breast cancer were identified. Approximately 38% of these had a preexisting mental illness. Individuals with any preexisting mental illness were less likely to receive guideline-consistent breast cancer treatment compared to those without any preexisting mental illness (adjusted odds ratio: 0.793, 95% confidence interval [CI]: 0.646-0.973). A negative association was observed between preexisting mental illness and breast cancer-related outpatient (adjusted incident rate ratio (AIRR): 0.917, 95% CI: 0.892-0.942) and emergency room utilization (AIRR: 0.842, 95% CI: 0.709-0.999). The association between preexisting mental illnesses and breast cancer-related inpatient utilization was statistically insignificant (AIRR: 0.993, 95% CI: 0.851-1.159). The findings of this study indicate that breast cancer patients with preexisting mental illnesses experience disparities in terms of receipt of guideline-consistent breast cancer treatment and health care utilization. The results of this study highlight the need for more focused care for patients with preexisting mental illness. PMID- 26106926 TI - Membrane-reinforced three-dimensional electrospun silk fibroin scaffolds for bone tissue engineering. AB - Electrospun silk fibroin (SF) scaffolds have drawn much attention because of their resemblance to natural tissue architecture such as extracellular matrix, and the biocompatibility of SF as a candidate material to replace collagen. However, electrospun scaffolds lack the physical integrity of bone tissue scaffolds, which require resistance to mechanical loadings. In this work, we propose membrane-reinforced electrospun SF scaffolds by a serial process of electrospinning and freeze-drying of SF solutions in two different solvents: formic acid and water, respectively. After wet electrospinning followed by replacement of methanol with water, SF nanofibers dispersed in water were mixed with aqueous SF solution. Freeze-drying of the mixed solution resulted in 3D membrane-connected SF nanofibrous scaffolds (SF scaffolds) with a thickness of a few centimeters. We demonstrated that the SF concentration of aqueous SF solution controlled the degree of membrane reinforcement between nanofibers. It was also shown that both increase in degree of membrane reinforcement and inclusion of hydroxyapatite (HAP) nanoparticles resulted in higher resistance to compressive loadings of the SF scaffolds. Culture of human osteoblasts on collagen, SF, and SF-HAP scaffolds showed that both SF and SF-HAP scaffolds had biocompatibility and cell proliferation superior to that of the collagen scaffolds. SF-HAP scaffolds with and without BMP-2 were used for in vivo studies for 4 and 8 weeks, and they showed enhanced bone tissue formation in rat calvarial defect models. PMID- 26106928 TI - Dignity in Practice: Day-to-Day Life in Intensive Care Units in Western Europe. AB - Dignity is a key concept in contemporary health care ethics, but the practical meaning of dignity in care remains unclear. In this article, I show that in practice, different and possibly conflicting notions of what dignity means are engaged simultaneously in the care of critical patients. The empirical data is based on ethnographic fieldwork conducted in three separate intensive care units in three European countries, Spain, Norway, and France, in the spring of 2014. Four weeks were spent at each site. Using participant observations and semi structured interviews with 24 intensive care unit staff, I illustrate how the ideal of patient dignity is carried out in practice in the daily life of these units. PMID- 26106927 TI - Crystal structures of CRISPR-associated Csx3 reveal a manganese-dependent deadenylation exoribonuclease. AB - In prokaryotes, the CRISPR/Cas system is known to target and degrade invading phages and foreign genetic elements upon subsequent infection. However, the structure and function of many Cas proteins remain largely unknown, due to the high diversity of Cas proteins. Here we report 3 crystal structures of Archaeoglobus fulgidus Csx3 (AfCsx3) in free form, in complex with manganese ions and in complex with a single-stranded RNA (ssRNA) fragment, respectively. AfCsx3 harbors a ferredoxin-like fold and forms dimer both in the crystal and in solution. Our structure-based biochemical analysis demonstrates that the RNA binding sites and cleavage sites are located at 2 separate surfaces within the AfCsx3 dimer, suggesting a model to bind, tether and cleave the incoming RNA substrate. In addition, AfCsx3 displays robust 3'-deadenylase activity in the presence of manganese ions, which strongly suggests that AfCsx3 functions as a deadenylation exonuclease. Taken together, our results indicate that AfCsx3 is a Cas protein involved in RNA deadenylation and provide a framework for understanding the role of AfCsx3 in the Type III-B CRISPR/Cas system. PMID- 26106929 TI - The Pain Reliever and Heroin Epidemic in the United States: Shifting Winds in the Perfect Storm. AB - AIMS: The abuse of prescription pain relievers and/or heroin is a significant public health concern. This article identifies the changes in this epidemic and estimates the extent of the gap between treatment availability and need. METHOD: This article uses the national data on opioid and heroin abuse to identify at risk groups. RESULT: Findings include shifting from narcotic analgesics to heroin and demographic changes as well as changes in supply and new medication-assisted therapies. CONCLUSIONS: The number of persons dependent on pain relievers or heroin and new initiates is more than three times greater than the current capacity to deliver treatment. PMID- 26106932 TI - Unilateral baroreceptor activation therapy: the beauty of asymmetry. AB - With respect to paired internal organs, we commonly think that these are symmetrical and have identical physiological functions. This, however, appears not to be the case. A particular organ where asymmetry comes to expression is the baroreceptor system. Clinical data in patients with resistant hypertension who are treated with device-based baroreceptor activation clearly show that there are functional differences between the left and the right baroreceptor systems. This has implications for our understanding of certain diseases. PMID- 26106933 TI - Liraglutide for Type 2 diabetes and obesity: a 2015 update. AB - Subcutaneous liraglutide (Victoza((r)), Novo Nordisk) was approved for the treatment of Type 2 diabetes mellitus (T2DM) in Europe in 2009 and in the USA in 2010. In December 2014, liraglutide 3.0 mg was approved by the Food and Drug Administration (FDA) and in March 2015 by the European Medicines Agency (EMA) for the treatment of chronic weight management under the brand name Saxenda((r)) Novo Nordisk. Liraglutide causes a glucose-dependent increase in insulin secretion, decreases glucagon secretion and promotes weight loss by inhibiting appetite. Liraglutide probably induces satiety through activation of different areas in the hind brain and possibly by preserving free leptin levels. Recently, liraglutide has been suggested to protect against prediabetes and seems to prevent bone loss by increasing bone formation following diet-induced weight loss in obesity. This article not only covers the major clinical trials evaluating the effects of liraglutide in obesity and T2DM but also provides novel insights into the pharmacological mechanisms of liraglutide. PMID- 26106930 TI - Characterizing Resting-State Brain Function Using Arterial Spin Labeling. AB - Arterial spin labeling (ASL) is an increasingly established magnetic resonance imaging (MRI) technique that is finding broader applications in studying the healthy and diseased brain. This review addresses the use of ASL to assess brain function in the resting state. Following a brief technical description, we discuss the use of ASL in the following main categories: (1) resting-state functional connectivity (FC) measurement: the use of ASL-based cerebral blood flow (CBF) measurements as an alternative to the blood oxygen level-dependent (BOLD) technique to assess resting-state FC; (2) the link between network CBF and FC measurements: the use of network CBF as a surrogate of the metabolic activity within corresponding networks; and (3) the study of resting-state dynamic CBF BOLD coupling and cerebral metabolism: the use of dynamic CBF information obtained using ASL to assess dynamic CBF-BOLD coupling and oxidative metabolism in the resting state. In addition, we summarize some future challenges and interesting research directions for ASL, including slice-accelerated (multiband) imaging as well as the effects of motion and other physiological confounds on perfusion-based FC measurement. In summary, this work reviews the state-of-the art of ASL and establishes it as an increasingly viable MRI technique with high translational value in studying resting-state brain function. PMID- 26106934 TI - Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists. AB - Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality. PMID- 26106935 TI - Current applications of biomarkers in cardiomyopathies. AB - Cardiomyopathies are an important cause of sudden cardiac death in young people and are responsible for arrhythmias and premature heart failure in all age groups. Although many cardiomyopathies are inherited, biochemical markers are a fundamental part of the diagnostic work-up and are useful in the prognostic assessment of disease. In this article, the authors review the rationale and evidence for important biomarkers according to their role in patient management. Emerging biomarkers are briefly reviewed, alongside modern scientific approaches to biomarker discovery. PMID- 26106936 TI - A clinical study of sudden deafness. AB - CONCLUSIONS: Sudden Sensorineural Hearing Loss (SSHL) was commonly seen in middle aged people. Tinnitus was reported by 87.2% of the patients, and dizziness or vertigo were reported by 48.5%. The most common concomitant disorder of SSHL was hyperlipidemia. OBJECTIVE: A retrospective register study with SSHL was performed in Xi'an, China, from 2000-2009. RESULTS: Of 617 inpatients, the right ear was affected in 267 cases, the left ears in 282 cases, and both ears in 68 cases. The most common age of patients was 41-50 years. There were 20.4% SSHL patients with hypertension, coronary artery disease, or diabetes, and 49.6% patients with hyperlipidemia. Auditory Brainstem Responses (ABR) were performed in 460 patients (504 ears) before treatment, and the ABR threshold of 56.4% ears was > 90 dB. The constituent ratio of patients with an ABR threshold over 90 dB was greater in the vertigo group than the other group. CT and/or MRI scans were available in 277 cases, of which 40 cases (14.4%) were abnormal. PMID- 26106937 TI - Enhanced Molecular Recognition between Nucleobases and Guanine-5'-monophosphate disodium (GMP) by Surfactant Aggregates in Aqueous Solution. AB - Only specific base pairs on DNA can bind with each other through hydrogen bonds, which is called the Watson-Crick (W/C) pairing rule. However, without the constraint of DNA chains, the nucleobases in bulk aqueous solution usually do not follow the W/C pairing rule anymore because of the strong competitive effect of water and the multi-interaction edges of nucleobases. The present work applied surfactant aggregates noncovalently functionalized by nucleotide to enhance the recognition between nucleobases without DNA chains in aqueous solution, and it revealed the effects of their self-assembling ability and morphologies on the recognition. The cationic ammonium monomeric, dimeric, and trimeric surfactants DTAB, 12-3-12, and 12-3-12-3-12 were chosen. The surfactants with guanine-5' monophosphate-disodium (GMP) form micelles, vesicles, and fingerprint-like and plate-like aggregates bearing the hydrogen-bonding sites of GMP, respectively. The binding parameters of these aggregates with adenine (A), uracil (U), guanine (G), and cytosine(C) indicate that the surfactants can promote W/C recognitions in aqueous solution when they form vesicles (GMP/DTAB) or plate-like aggregates (GMP/12-3-12) with proper molecular packing compactness, which not only provide hydrophobic environments but also shield non-W/C recognition edges. However, the GMP/12-3-12 micelles with loose molecular packing, the GMP/12-3-12 fingerprint like aggregates where the hydrogen bond sites of GMP are occupied by itself, and the GMP/12-3-12-3-12 vesicles with too strong self-assembling ability cannot promote W/C recognition. This work provides insight into how to design self assemblies with the performance of enhanced molecule recognition. PMID- 26106940 TI - The Canadian Assessment of Physical Literacy: Development of a Model of Children's Capacity for a Healthy, Active Lifestyle Through a Delphi Process. AB - BACKGROUND: The Canadian Assessment of Physical Literacy (CAPL) was conceptualized as a tool to monitor children's physical literacy. The original model (fitness, activity behavior, knowledge, motor skill) required revision and relative weights for calculating/interpreting scores were required. METHODS: Nineteen childhood physical activity/fitness experts completed a 3-round Delphi process. Round 1 was open-ended questions. Subsequent rounds rated statements using a 5-point Likert scale. Recommendations were sought regarding protocol inclusion, relative importance within composite scores and score interpretation. RESULTS: Delphi participant consensus was achieved for 64% (47/73) of statement topics, including a revised conceptual model, specific assessment protocols, the importance of longitudinal tracking, and the relative importance of individual protocols and composite scores. Divergent opinions remained regarding the inclusion of sleep time, assessment/ scoring of the obstacle course assessment of motor skill, and the need for an overall physical literacy classification. CONCLUSIONS: The revised CAPL model (overlapping domains of physical competence, motivation, and knowledge, encompassed by daily behavior) is appropriate for monitoring the physical literacy of children aged 8 to 12 years. Objectively measured domains (daily behavior, physical competence) have higher relative importance. The interpretation of CAPL results should be reevaluated as more data become available. PMID- 26106941 TI - One year in review 2015: systemic lupus erythematosus. AB - Systemic lupus erythematosus is a multiorgan autoimmune disease with a highly variable clinical course, typically involving women in childbearing age. At present, many aspects of its pathogenesis still remain unclear. Moreover, although a significant increase of patient survival has been observed in the last decades, morbidity and mortality remain high. Finally, SLE impacts negatively on the health-related quality-of-life of patients. Therefore, multiple aspects of SLE still remain challenging and it continues to be the object of both clinical and translational clinical research. Herewith, we provide a critical digest of the recent literature on this topic. PMID- 26106942 TI - Comprehensive Multispectroscopic Analysis on the Interaction and Corona Formation of Human Serum Albumin with Gold/Silver Alloy Nanoparticles. AB - In the present investigation, we have systematically studied the binding mechanism of model protein human serum albumin (HSA) with gold/silver alloy nanoparticles (Au/Ag NPs) using multiple spectroscopic techniques. Absorption spectral studies of Au/Ag NPs in the presence of increasing concentrations of HSA resulted in a slight red shift of the surface plasmon resonance band (SPR) of Au/Ag NPs, suggesting changes in the refractive index around the nanoparticle surface owing to the adsorption of HSA. The results from high-resolution transmission electron microscopy (HR-TEM), dynamic light scattering (DLS), and zeta potential analysis substantiated the formation of a dense layer of HSA on the surface of Au/Ag NPs. The formation of a ground-state complex between HSA and Au/Ag NPs was evident from the outcome of the steady-state emission titration experiments of the HSA-Au/Ag NPs system. The binding parameters computed from corrected emission quenching data revealed that HSA exhibited a significant binding affinity toward Au/Ag NPs. The identical fluorescence lifetime values of HSA and HSA-Au/Ag NPs from time-resolved fluorescence spectroscopic analysis further authenticated the findings of steady-state emission measurements. The formation of HSA corona on the Au/Ag NPs surface was established on the basis of experimental quenching data and theoretical values. The occurrence of partial unfolding of HSA upon its interaction with the Au/Ag NPs surface was established by using an extrinsic fluorophore 1-anilino-8-naphthalenesulfonic acid (ANS). Absorption, Fourier transform infrared (FT-IR), Raman, circular dichroism (CD), and excitation-emission matrix (3D) spectral studies were also carried out to explore Au/Ag NPs-induced tertiary and secondary conformational changes of HSA. The influence of Au/Ag NPs on the esterase-like activity of HSA was established by probing the hydrolysis of p-nitrophenyl acetate. PMID- 26106944 TI - Uranium Binding Mechanisms of the Acid-Tolerant Fungus Coniochaeta fodinicola. AB - The uptake and binding of uranium [as (UO2)(2+)] by a moderately acidophilic fungus, Coniochaeta fodinicola, recently isolated from a uranium mine site, is examined in this work in order to better understand the potential impact of organisms such as this on uranium sequestration in hydrometallurgical systems. Our results show that the viability of the fungal biomass is critical to their capacity to remove uranium from solution. Indeed, live biomass (viable cells based on vital staining) were capable of removing ~16 mg U/g dry weight in contrast with dead biomass (autoclaved) which removed ~45 mg U/g dry weight after 2 h. Furthermore, the uranium binds with different strength, with a fraction ranging from ~20-50% being easily leached from the exposed biomass by a 10 min acid wash. Results from X-ray absorption spectroscopy measurements show that the strength of uranium binding is strongly influenced by cell viability, with live cells showing a more well-ordered uranium bonding environment, while the distance to carbon or phosphorus second neighbors is similar in all samples. When coupled with time-resolved laser fluorescence and Fourier transformed infrared measurements, the importance of organic acids, phosphates, and polysaccharides, likely released with fungal cell death, appear to be the primary determinants of uranium binding in this system. These results provide an important progression to our understanding with regard to uranium sequestration in hydrometallurgical applications with implications to the unwanted retention of uranium in biofilms and/or its mobility in a remediation context. PMID- 26106943 TI - High Aspect Ratio Carbon Nanotube Membranes Decorated with Pt Nanoparticle Urchins for Micro Underwater Vehicle Propulsion via H2O2 Decomposition. AB - The utility of unmanned micro underwater vehicles (MUVs) is paramount for exploring confined spaces, but their spatial agility is often impaired when maneuvers require burst-propulsion. Herein we develop high-aspect ratio (150:1), multiwalled carbon nanotube microarray membranes (CNT-MMs) for propulsive, MUV thrust generation by the decomposition of hydrogen peroxide (H2O2). The CNT-MMs are grown via chemical vapor deposition with diamond shaped pores (nominal diagonal dimensions of 4.5 * 9.0 MUm) and subsequently decorated with urchin like, platinum (Pt) nanoparticles via a facile, electroless, chemical deposition process. The Pt-CNT-MMs display robust, high catalytic ability with an effective activation energy of 26.96 kJ mol(-1) capable of producing a thrust of 0.209 +/- 0.049 N from 50% [w/w] H2O2 decomposition within a compact reaction chamber of eight Pt-CNT-MMs in series. PMID- 26106945 TI - First-Principles Study on Structural, Electronic, and Spectroscopic Properties of gamma-Ca2SiO4:Ce(3+) Phosphors. AB - In the present work, geometric structures, electronic properties, and 4f -> 5d transitions of gamma-Ca2SiO4:Ce(3+) phosphors have been investigated by using first-principles calculations. Four categories of typical substitutions (i.e., the doping of the Ce(3+) without the neighboring dopants/defects and with the neighboring VO(**), AlSi', and VCa") are taken into account to simulate local environments of the Ce(3+) located at two crystallographically different calcium sites in the gamma-Ca2SiO4. Density functional theory (DFT) geometry optimization calculations are first performed on the constructed supercells to obtain the information about the local structures and preferred sites for the Ce(3+). On the basis of the optimized crystal structures, the electronic properties of gamma Ca2SiO4:Ce(3+) phosphors are calculated with the Heyd-Scuseria-Ernzerhof screened hybrid functional, and the energies and relative oscillator strengths of the 4f > 5d transitions of the Ce(3+) are derived from the ab initio embedded cluster calculations at the CASSCF/CASPT2/RASSI-SO level. A satisfactory agreement with the available experimental results is thus achieved. Moreover, the relationships between the dopants/defects and the electronic as well as spectroscopic properties of gamma-Ca2SiO4:Ce(3+) phosphors have been explored. Such information is vital, not least for the design of Ce(3+)-based phosphors for the white light emitting diodes (w-LEDs) with excellent performance. PMID- 26106947 TI - Threading the Needle--How to Stop the HIV Outbreak in Rural Indiana. PMID- 26106948 TI - Rapid Macrocycle Threading by a Fluorescent Dye-Polymer Conjugate in Water with Nanomolar Affinity. AB - A macrocyclic tetralactam host is threaded by a highly fluorescent squaraine dye that is flanked by two polyethylene glycol (PEG) chains with nanomolar dissociation constants in water. Furthermore, the rates of bimolecular association are very fast with k(on) ~ 10(6)-10(7) M(-1) s(-1). The association is effective under cell culture conditions and produces large changes in dye optical properties including turn-on near-infrared fluorescence that can be imaged using cell microscopy. Association constants in water are ~1000 times higher than those in organic solvents and strongly enthalpically favored at 27 degrees C. The threading rate is hardly affected by the length of the PEG chains that flank the squaraine dye. For example, macrocycle threading by a dye conjugate with two appended PEG2000 chains is only three times slower than threading by a conjugate with triethylene glycol chains that are 20 times shorter. The results are a promising advance toward synthetic mimics of streptavidin/biotin. PMID- 26106949 TI - Development of Injectable Hyaluronic Acid/Cellulose Nanocrystals Bionanocomposite Hydrogels for Tissue Engineering Applications. AB - Injectable hyaluronic acid (HA)-based hydrogels compose a promising class of materials for tissue engineering and regenerative medicine applications. However, their limited mechanical properties restrict the potential range of application. In this study, cellulose nanocrystals (CNCs) were employed as nanofillers in a fully biobased strategy for the production of reinforced HA nanocomposite hydrogels. Herein we report the development of a new class of injectable hydrogels composed of adipic acid dihydrazide-modified HA (ADH-HA) and aldehyde modified HA (a-HA) reinforced with varying contents of aldehyde-modified CNCs (a CNCs). The obtained hydrogels were characterized in terms of internal morphology, mechanical properties, swelling, and degradation behavior in the presence of hyaluronidase. Our findings suggest that the incorporation of a-CNCs in the hydrogel resulted in a more organized and compact network structure and led to stiffer hydrogels (maximum storage modulus, E', of 152.4 kPa for 0.25 wt % a-CNCs content) with improvements of E' up to 135% in comparison to unfilled hydrogels. In general, increased amounts of a-CNCs led to lower equilibrium swelling ratios and higher resistance to degradation. The biological performance of the developed nanocomposites was assessed toward human adipose derived stem cells (hASCs). HA CNCs nanocomposite hydrogels exhibited preferential cell supportive properties in in vitro culture conditions due to higher structural integrity and potential interaction of microenvironmental cues with CNC's sulfate groups. hASCs encapsulated in HA-CNCs hydrogels demonstrated the ability to spread within the volume of gels and exhibited pronounced proliferative activity. Together, these results demonstrate that the proposed strategy is a valuable toolbox for fine tuning the structural, biomechanical, and biochemical properties of injectable HA hydrogels, expanding their potential range of application in the biomedical field. PMID- 26106950 TI - BSA-directed synthesis of CuS nanoparticles as a biocompatible photothermal agent for tumor ablation in vivo. AB - Photothermal therapy as a physical therapeutic approach has greatly attracted research interest due to its negligible systemic effects. Among the various photothermal agents, CuS nanoparticles have been widely used due to their easy preparation, low cost, high stability and strong absorption in the NIR region. However, the ambiguous biotoxicity of CuS nanoparticles limited their bio application. So it is highly desirable to develop biocompatible CuS photothermal agents with the potential of clinical translation. Herein, we report a novel method to synthesize biocompatible CuS nanoparticles for photothermal therapy using bovine serum albumin (BSA) as a template via mimicking biomaterialization processes. Owing to the inherent biocompatibility of BSA, the toxicity assays in vitro and in vivo showed that BSA-CuS nanoparticles possessed good biocompatibility. In vitro and in vivo photothermal therapies were performed and good results were obtained. The bulk of the HeLa cells treated with BSA-CuS nanoparticles under laser irradiation (808 nm) were killed, and the tumor tissues of mice were also successfully eliminated without causing any obvious systemic damage. In summary, a novel strategy for the synthesis of CuS nanoparticles was developed using BSA as the template, and the excellent biocompatibility and efficient photothermal therapy effects of BSA-CuS nanoparticles show great potential as an ideal photothermal agent for cancer treatment. PMID- 26106952 TI - Chiral Phosphine-Silver(I) Complex Catalyzed Enantioselective Interrupted Feist Benary Reaction with Ynones: The Aldol-Cycloisomerization Cascade. AB - Silver-catalyzed interrupted Feist-Benary reaction is described for the efficient enantioselective synthesis of dihydrofuran heterocycles. A new method has been developed for the silver(I)-(R)-BINAP complex mediated aldol-cycloisomerization cascade reaction between ynones and 1,3-diketones to provide functionalized dihydrofurans with moderate to good yields (up to 95%) and good to excellent enantiomeric excess (up to 98%). The presence of an exocyclic double bond and hydroxy group in the dihydrofuran products provides wide scope for further structural manipulation. PMID- 26106951 TI - Crystallization of Probucol in Nanoparticles Revealed by AFM Analysis in Aqueous Solution. AB - The crystallization behavior of a pharmaceutical drug in nanoparticles was directly evaluated by atomic force microscopy (AFM) force curve measurements in aqueous solution. A ternary spray-dried sample (SPD) was prepared by spray drying the organic solvent containing probucol (PBC), hypromellose (HPMC), and sodium dodecyl sulfate (SDS). The amorphization of PBC in the ternary SPD was confirmed by powder X-ray diffraction (PXRD) and solid-state 13C NMR measurements. A nanosuspension containing quite small particles of 25 nm in size was successfully prepared immediately after dispersion of the ternary SPD into water. Furthermore, solution-state 1H NMR measurements revealed that a portion of HPMC coexisted with PBC as a mixed state in the freshly prepared nanosuspension particles. After storing the nanosuspension at 25 degrees C, a gradual increase in the size of the nanoparticles was observed, and the particle size changed to 93.9 nm after 7 days. AFM enabled the direct observation of the morphology and agglomeration behavior of the nanoparticles in water. Moreover, AFM force-distance curves were changed from (I) to (IV), depending on the storage period, as follows: (I) complete indentation within an applied force of 1 nN, (II) complete indentation with an applied force of 1-5 nN, (III) partial indentation with an applied force of 5 nN, and (IV) nearly no indentation with an applied force of 5 nN. This stiffness increase of the nanoparticles was attributed to gradual changes in the molecular state of PBC from the amorphous to the crystal state. Solid-state 13C NMR measurements of the freeze-dried samples demonstrated the presence of metastable PBC Form II crystals in the stored nanosuspension, strongly supporting the AFM results. PMID- 26106953 TI - Visualization of polar nanoregions in lead-free relaxors via piezoresponse force microscopy in torsional dual AC resonance tracking mode. AB - Polar nanoregions (PNRs) play a key role in the functionality of relaxor ferroelectrics; however, visualizing them in lead-free relaxor ferroelectrics with high lateral resolution is still challenging. Thus, we studied herein the local ferroelectric domain distribution of the lead-free bismuth-based (1 x)(Bi1/2Na1/2TiO3-Bi1/2K1/2TiO3) -x(Bi1/2Mg1/2TiO3) piezoceramics which show a relaxor behavior using dual AC resonance tracking (DART) piezoresponse force microscopy (PFM). By using excitation frequencies at either side of the contact resonance peak of the torsional cantilever vibration, an enhanced contrast in the amplitude and phase images of the piezoresponse can be achieved. Additionally, this tracking technique reduces the topographical crosstalk while mapping the local electromechanical properties. The true drive amplitude, drive phase, contact resonant frequency and quality factor can be estimated from DART-PFM data obtained with vertically or torsionally vibrating cantilevers. This procedure yields a three-dimensional quantitative map of the local piezoelectric properties of the relaxor ferroelectric samples. With this approach, torsional DART allowed for the visualization of fine substructures within the monodomains, suggesting the existence of PNRs in relaxor ferroelectrics. The domain structures of the PNRs were visualized with high precision, and the local electromechanical characteristics of the lead-free relaxor ferroelectrics were quantitatively mapped. PMID- 26106954 TI - Rh-catalyzed oxidizing group-directed ortho C-H vinylation of arenes by vinylstannanes. AB - An efficient method for the synthesis of functionalized vinyl arenes from the reaction of N-methoxybenzamides or N-phenoxyacetamides with vinylstannanes via rhodium(iii)-catalyzed C-H activation is described. The application of the methodology for the synthesis of a natural product thalactamine and a 7-membered ring oxepine are also demonstrated. PMID- 26106955 TI - New concepts and outcomes for children with hepatoblastoma based on the experience of a tertiary center over the last 21 years. AB - OBJECTIVE: The aim of this study was to summarize the experience of a tertiary center in treating hepatoblastoma for the last 21 years. PATIENTS AND METHODS: Fifty-eight cases were included. The tumor extent and prognosis were assessed using the PRETEXT system. The following data were analyzed: age at diagnosis, comorbidities, prematurity, treatment modalities, histopathological findings, surgical details and complications, treatment outcomes, chemotherapy schedules, side effects and complications. Treatment outcomes included the occurrence of local or distant recurrence, the duration of survival and the cause of death. The investigation methods were ultrasonography, CT scan, serum alpha-fetoprotein level measurement and needle biopsy. Chemotherapy was then planned, and the resectability of the tumor was reevaluated via another CT scan. RESULTS: The mean numbers of neoadjuvant cycles and postoperative cycles of chemotherapy were 6+/-2 and 1.5+/-1.7, respectively. All children except one were submitted for surgical resection, including 50 partial liver resections and 7 liver transplantations. Statistical comparisons demonstrated that long-term survival was associated with the absence of metastasis (p=0.04) and the type of surgery (resection resulted in a better outcome than transplantation) (p=0.009). No associations were found between vascular invasion, incomplete resection, histological subtype, multicentricity and survival. The overall 5-year survival rate of the operated cases was 87.7%. CONCLUSION: In conclusion, the experience of a Brazilian tertiary center in the management of hepatoblastoma in children demonstrates that long survival is associated with the absence of metastasis and the type of surgery. A multidisciplinary treatment involving chemotherapy, surgical resection and liver transplantation (including transplantations using tissue from living donors) led to good outcomes and survival indexes. PMID- 26106946 TI - Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. AB - BACKGROUND: The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. METHODS: In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention. RESULTS: The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention. CONCLUSIONS: Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541.). PMID- 26106956 TI - High-fidelity simulation versus case-based discussion for teaching medical students in Brazil about pediatric emergencies. AB - OBJECTIVE: To compare high-fidelity simulation with case-based discussion for teaching medical students about pediatric emergencies, as assessed by a knowledge post-test, a knowledge retention test and a survey of satisfaction with the method. METHODS: This was a non-randomized controlled study using a crossover design for the methods, as well as multiple-choice questionnaire tests and a satisfaction survey. Final-year medical students were allocated into two groups: group 1 participated in an anaphylaxis simulation and a discussion of a supraventricular tachycardia case, and conversely, group 2 participated in a discussion of an anaphylaxis case and a supraventricular tachycardia simulation. Students were tested on each theme at the end of their rotation (post-test) and 4 6 months later (retention test). RESULTS: Most students (108, or 66.3%) completed all of the tests. The mean scores for simulation versus case-based discussion were respectively 43.6% versus 46.6% for the anaphylaxis pre-test (p=0.42), 63.5% versus 67.8% for the post-test (p=0.13) and 61.5% versus 65.5% for the retention test (p=0.19). Additionally, the mean scores were respectively 33.9% versus 31.6% for the supraventricular tachycardia pre-test (p=0.44), 42.5% versus 47.7% for the post-test (p=0.09) and 41.5% versus 39.5% for the retention test (p=0.47). For both themes, there was improvement between the pre-test and the post-test (p<0.05), and no significant difference was observed between the post-test and the retention test (p>0.05). Moreover, the satisfaction survey revealed a preference for simulation (p<0.001). CONCLUSION: As a single intervention, simulation is not significantly different from case-based discussion in terms of acquisition and retention of knowledge but is superior in terms of student satisfaction. PMID- 26106957 TI - Septic pulmonary embolism caused by a Klebsiella pneumoniae liver abscess: clinical characteristics, imaging findings, and clinical courses. AB - OBJECTIVES: Septic pulmonary embolism caused by a Klebsiella (K.) pneumoniae liver abscess is rare but can cause considerable morbidity and mortality. However, clinical information regarding this condition is limited. This study was conducted to elucidate the full disease spectrum to improve its diagnosis and treatment. METHOD: We reviewed the clinical characteristics, imaging findings, and clinical courses of 14 patients diagnosed with septic pulmonary embolism caused by a K. pneumoniae liver abscess over a period of 9 years. RESULTS: The two most prevalent symptoms were fever and shortness of breath. Computed tomography findings included a feeding vessel sign (79%), nodules with or without cavities (79%), pleural effusions (71%), peripheral wedge-shaped opacities (64%), patchy ground-glass opacities (50%), air bronchograms within a nodule (36%), consolidations (21%), halo signs (14%), and lung abscesses (14%). Nine (64%) of the patients developed severe complications and required intensive care. According to follow-up chest radiography, the infiltrates and consolidations were resolved within two weeks, and the nodular opacities were resolved within one month. Two (14%) patients died of septic shock; one patient had metastatic meningitis, and the other had metastatic pericarditis. CONCLUSION: The clinical presentations ranged from insidious illness with fever and respiratory symptoms to respiratory failure and septic shock. A broad spectrum of imaging findings, ranging from nodules to multiple consolidations, was detected. Septic pulmonary embolism caused by a K. pneumoniae liver abscess combined with the metastatic infection of other vital organs confers a poor prognosis. PMID- 26106958 TI - The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis. AB - OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions. PMID- 26106959 TI - Model for End-Stage Liver Disease, Model for Liver Transplantation Survival and Donor Risk Index as predictive models of survival after liver transplantation in 1,006 patients. AB - OBJECTIVES: Liver transplantation has not increased with the number of patients requiring this treatment, increasing deaths among those on the waiting list. Models predicting post-transplantation survival, including the Model for Liver Transplantation Survival and the Donor Risk Index, have been created. Our aim was to compare the performance of the Model for End-Stage Liver Disease, the Model for Liver Transplantation Survival and the Donor Risk Index as prognostic models for survival after liver transplantation. METHOD: We retrospectively analyzed the data from 1,270 patients who received a liver transplant from a deceased donor in the state of Sao Paulo, Brazil, between July 2006 and July 2009. All data obtained from the Health Department of the State of Sao Paulo at the 15 registered transplant centers were analyzed. Patients younger than 13 years of age or with acute liver failure were excluded. RESULTS: The majority of the recipients had Child-Pugh class B or C cirrhosis (63.5%). Among the 1,006 patients included, 274 (27%) died. Univariate survival analysis using a Cox proportional hazards model showed hazard ratios of 1.02 and 1.43 for the Model for End-Stage Liver Disease and the Model for Liver Transplantation Survival, respectively (p<0.001). The areas under the ROC curve for the Donor Risk Index were always less than 0.5, whereas those for the Model for End-Stage Liver Disease and the Model for Liver Transplantation Survival were significantly greater than 0.5 (p<0.001). The cutoff values for the Model for End-Stage Liver Disease (>=29.5; sensitivity: 39.1%; specificity: 75.4%) and the Model for Liver Transplantation Survival (>=1.9; sensitivity 63.9%, specificity 54.5%), which were calculated using data available before liver transplantation, were good predictors of survival after liver transplantation (p<0.001). CONCLUSIONS: The Model for Liver Transplantation Survival displayed similar death prediction performance to that of the Model for End-Stage Liver Disease. A simpler model involving fewer variables, such as the Model for End-Stage Liver Disease, is preferred over a complex model involving more variables, such as the Model for Liver Transplantation Survival. The Donor Risk Index had no significance in post transplantation survival in our patients. PMID- 26106960 TI - Risk factors for surgical site infection of pilon fractures. AB - OBJECTIVES: Pilon fracture is a complex injury that is often associated with severe soft tissue damage and high rates of surgical site infection. The goal of this study was to analyze and identify independent risk factors for surgical site infection among patients undergoing surgical fixation of a pilon fracture. METHODS: The medical records of all pilon fracture patients who underwent surgical fixation from January 2010 to October 2012 were reviewed to identify those who developed a surgical site infection. Then, we constructed univariate and multivariate logistic regressions to evaluate the independent associations of potential risk factors with surgical site infection in patients undergoing surgical fixation of a pilon fracture. RESULTS: A total of 519 patients were enrolled in the study from January 2010 to October 2012. A total of 12 of the 519 patients developed a surgical site infection, for an incidence of 2.3%. These patients were followed for 12 to 29 months, with an average follow-up period of 19.1 months. In the final regression model, open fracture, elevated postoperative glucose levels (>=125 mg/dL), and a surgery duration of more than 150 minutes were significant risk factors for surgical site infection following surgical fixation of a pilon fracture. CONCLUSIONS: Open fractures, elevated postoperative glucose levels (>=125 mg/dL), and a surgery duration of more than 150 minutes were related to an increased risk for surgical site infection following surgical fixation of a pilon fracture. Patients exhibiting the risk factors identified in this study should be counseled regarding the possible surgical site infection that may develop after surgical fixation. PMID- 26106961 TI - Naming ability in patients with mild to moderate Alzheimer's disease: what changes occur with the evolution of the disease? AB - OBJECTIVES: Naming deficit is a linguistic symptom that appears in the initial phase of Alzheimer's disease, but the types of naming errors and the ways in which this deficit changes over the course of the disease are unclear. We analyzed the performance of patients with Alzheimer's disease on naming tasks during the mild and moderate phases and verified how this linguistic skill deteriorates over the course of the disease. METHODS: A reduced version of the Boston Naming Test was administered to 30 patients with mild Alzheimer's disease, 30 patients with moderate Alzheimer's disease and 30 healthy controls. Errors were classified as verbal semantic paraphasia, verbal phonemic paraphasia, no response (pure anomia), circumlocution, unrelated verbal paraphasia, visual errors or intrusion errors. RESULTS: The patients with moderate Alzheimer's disease had significantly fewer correct answers than did both the control group and the group with mild Alzheimer's disease. With regard to the pattern of errors, verbal semantic paraphasia errors were the most frequent errors in all three groups. Additionally, as the disease severity increased, there was an increase in the number of no-response errors (pure anomia). The group with moderate Alzheimer's disease demonstrated a greater incidence of visual errors and unrelated verbal paraphasias compared with the other two groups and presented a more variable pattern of errors. CONCLUSIONS: Performance on nominative tasks worsened as the disease progressed in terms of both the quantity and the type of errors encountered. This result reflects impairment at different levels of linguistic processing. PMID- 26106962 TI - Comparison of the safety and efficacy of a fixed-dose combination regimen and separate formulations for pulmonary tuberculosis treatment. AB - OBJECTIVES: Fixed-dose combination formulations, which simplify the administration of drugs and prevent the development of drug resistance, have been recommended as a standard anti-tuberculosis treatment regimen. However, the composition and dosage recommendations for fixed-dose combination formulations differ from those for separate formulations. Thus, questions about the effectiveness and side effects of combination formulations remain. The aim of this study was to compare the safety and efficacy of these two types of anti tuberculosis regimens for pulmonary tuberculosis treatment. METHOD: A prospective, randomized controlled study was conducted using the directly observed treatment short-course strategy. Patients were randomly allocated to one of two short-course regimens. One year after completing the treatment, these patients' outcomes were analyzed. ClinicalTrials.gov: NCT00979290. RESULTS: A total of 161 patients were enrolled, 142 of whom were evaluable for safety assessment. The two regimens had a similar incidence of adverse effects. In the per-protocol population, serum bilirubin concentrations at the peak level, at week 4, and at week 8 were significantly higher for the fixed-dose combination formulation than for the separate formulations. All patients had negative sputum cultures at the end of the treatment, and no relapse occurred after one year of follow-up. CONCLUSIONS: In this randomized study, transient higher serum bilirubin levels were noted for the fixed-dose combination regimen compared with the separate formulations during treatment. However, no significant difference in safety or efficacy was found between the groups when the directly observed treatment short-course strategy was used. PMID- 26106963 TI - Developing a new endograft for the treatment of juxtarenal aortic aneurysms: definition and experimentation. AB - OBJECTIVES: To analyze angiotomographic parameters of juxtarenal aneurysms to assess the applicability of an endograft model to patients and to create in vitro and in vivo models to assess the new endograft. METHODS: A total of 49 patients with juxtarenal aneurysms were submitted to angiotomographic evaluation, and parameters such as the aortic diameter, the length of the neck, and the angulations of the celiac trunk, superior mesenteric artery and renal arteries; the distances between them; and anatomic variations were analyzed. Based on these parameters, an endograft model was developed and tested in a newly created in vitro model of juxtarenal aneurysm. An experimental model of juxtarenal aneurysm was then established in six pigs weighing 50-60 kg to assess the new endograft model. RESULTS: The angiotomographic parameters of juxtarenal aneurysm measured in this study were similar to those reported in the literature and allowed the development of an endograft based on the hourglass concept, which was applicable to 85.8% of the patients. The in vitro model of juxtarenal aneurysm evidenced good radiopacity and functionality and permitted adjustments in the new device and technical improvements in the procedures for treating these aneurysms. In addition, the porcine model of juxtarenal aneurysm was successfully created in all six animals using a bovine pericardial patch, and use of the new endograft in three pilot procedures evidenced its feasibility. CONCLUSIONS: The Hourglass endograft was rendered applicable to treatment of the majority of patients with juxtarenal aneurysms simply by changing its diameter. Moreover, the new in vitro and in vivo models were shown to be effective for assessing both the presented endograft and experiments assessing the endovascular treatment of juxtarenal aneurysms. PMID- 26106964 TI - Assessments of the associations of thrombus localization with accompanying disorders, risk factors, D-dimer levels, and the red cell distribution width in pulmonary embolism. AB - OBJECTIVE: Pulmonary embolisms occur as a wide spectrum ranging from clinically asymptomatic thrombi to massive thrombi that lead to cardiogenic shock. The purpose of this study was to determine the associations of thrombus localization with risk factors, accompanying disorders, D-dimer levels and the red blood cell distribution width in patients with pulmonary embolism. MATERIAL AND METHODS: In 148 patients diagnosed with pulmonary embolism, the presence and anatomical localization of the thrombus were assessed via computed tomographic pulmonary angiography. The accompanying disorders, risk factors, serum D-dimer levels, and red blood cell distribution width of the patients were retrospectively evaluated. ClinicalTrials.gov: NCT02388841. RESULTS: The mean age of the patients was 54+/ 16.0 years, and 48 patients were >=65 years of age. The most frequent accompanying disorders were chronic obstructive pulmonary disease (22%) and malignancy (10.1%), and the most frequent risk factors were recent operation (14.1%) and immobilization (18.2%). Thrombi were most frequently observed in the right pulmonary artery (37.8%). In 31% of the patients, the thrombus was localized to the main pulmonary arteries. Immobile patients exhibited a higher proportion of thrombi in the main pulmonary arteries than mobile patients. The mean D-dimer level and the mean red blood cell distribution width in the patients with thrombi in the main pulmonary arteries were higher than those in the patients with thrombi in more distal pulmonary arterial branches. CONCLUSION: Significant associations of proximally localized thrombi with immobilization, the D-dimer levels, and the red blood cell distribution width were observed. PMID- 26106965 TI - Mesenteric hypoperfusion and inflammation induced by brain death are not affected by inhibition of the autonomic storm in rats. AB - OBJECTIVES: Brain death is typically followed by autonomic changes that lead to hemodynamic instability, which is likely associated with microcirculatory dysfunction and inflammation. We evaluated the role of the microcirculation in the hemodynamic and inflammatory events that occur after brain death and the effects of autonomic storm inhibition via thoracic epidural blockade on mesenteric microcirculatory changes and inflammatory responses. METHODS: Male Wistar rats were anesthetized and mechanically ventilated. Brain death was induced via intracranial balloon inflation. Bupivacaine (brain death-thoracic epidural blockade group) or saline (brain death group) infusion via an epidural catheter was initiated immediately before brain death induction. Sham-operated animals were used as controls (SH group). The mesenteric microcirculation was analyzed via intravital microscopy, and the expression of adhesion molecules was evaluated via immunohistochemistry 180 min after brain death induction. RESULTS: A significant difference in mean arterial pressure behavior was observed between the brain death-thoracic epidural blockade group and the other groups, indicating that the former group experienced autonomic storm inhibition. However, the proportion of perfused small vessels in the brain death-thoracic epidural blockade group was similar to or lower than that in the brain death and SH groups, respectively. The expression of intercellular adhesion molecule 1 was similar between the brain death-thoracic epidural blockade and brain death groups but was significantly lower in the SH group than in the other two groups. The number of migrating leukocytes in the perivascular tissue followed the same trend for all groups. CONCLUSIONS: Although thoracic epidural blockade effectively inhibited the autonomic storm, it did not affect mesenteric hypoperfusion or inflammation induced by brain death. PMID- 26106966 TI - Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis. AB - To evaluate the association of either propylthiouracil or methimazole treatment for hyperthyroidism during pregnancy with congenital malformations, relevant studies were identified by searching Medline, PubMed, the Cochrane Library and EMBASE. We intended to include randomized controlled trials, but no such trials were identified. Thus, we included cohort studies and case-control studies in this meta-analysis. A total of 7 studies were included in the meta-analyses. The results revealed an increased risk of birth defects among the group of pregnant women with hyperthyroidism treated with methimazole compared with the control group (odds ratio 1.76, 95% confidence interval 1.47-2.10) or the non-exposed group (odds ratio 1.71, 95% confidence interval 1.39-2.10). A maternal shift between methimazole and propylthiouracil was associated with an increased odds ratio of birth defects (odds ratio 1.88, 95% confidence interval 1.27-2.77). An equal risk of birth defects was observed between the group of pregnant women with hyperthyroidism treated with propylthiouracil and the non-exposed group (odds ratio 1.18, 95% confidence interval 0.97-1.42). There was only a slight trend towards an increased risk of congenital malformations in infants whose mothers were treated with propylthiouracil compared with in infants whose mothers were healthy controls (odds ratio 1.29, 95% confidence interval 1.07-1.55). The children of women receiving methimazole treatment showed an increased risk of adverse fetal outcomes relative to those of mothers receiving propylthiouracil treatment. We found that propylthiouracil was a safer choice for treating pregnant women with hyperthyroidism according to the risk of birth defects but that a shift between methimazole and propylthiouracil failed to provide protection against birth defects. PMID- 26106967 TI - High order forces and nonlocal operators in a Kohn-Sham Hamiltonian. AB - Real space pseudopotentials have a number of advantages in solving for the electronic structure of materials. These advantages include ease of implementation, implementation on highly parallel systems, and great flexibility for describing partially periodic systems. One limitation of this approach, shared by other electronic structure methods, is the slow convergence of interatomic forces when compared to total energies. For real space methods, this requires a fine grid to converge a solution of the Kohn-Sham problem, which is accompanied by concurrent increase in memory and additional matrix-vector multiplications. Here we introduce a method to expedite the computation of interatomic forces by employing a high order integration technique. We demonstrate the usefulness of this technique by calculating accurate bond lengths and vibrational frequencies for molecules and nanocrystals without using fine real space grids. PMID- 26106968 TI - Surface-enhanced Raman spectroscopy for DNA detection by the self-assembly of Ag nanoparticles onto Ag nanoparticle-graphene oxide nanocomposites. AB - A novel surface-enhanced Raman scattering (SERS) sensing system which operates by the self-assembly of Ag nanoparticles (AgNPs) onto the nanocomposite of AgNPs and graphene oxide (AgNP-GO) in the presence of two complementary DNAs has been developed. In this system, AgNP-GO serves as a SERS-active substrate. The AgNPs with the modification of non-fluorescent 4-mercaptobenzoic acid (4-MBA) act as highly efficient Raman probes for DNA hybridization. When probe DNAs on AgNP-GO are complementary to target DNAs on AgNPs functionalized with 4-MBA, the DNA hybridization occurring directs the self-assembly of AgNPs onto AgNP-GO, leading to the creation of SERS hot spots. Due to the fact that partial 4-MBA molecules are located in the region of the hot spots, their SERS signals are greatly enhanced, indicating successful DNA hybridization. It is noteworthy that the size of AgNPs contributes significantly to the enhancement of SERS activity. The detection limit of the target DNAs at the pM level can be achieved through the self-assembly of large sized AgNPs onto AgNP-GO. More importantly, the AgNP-AgNP GO system shows reproducible SERS signals in proportion to the logarithm of the target DNA concentrations spanning from 10(-6) to 10(-12) M and the excellent capability for multiplex DNA detection. PMID- 26106969 TI - Glass-like dynamics in confined and congested ant traffic. AB - The collective movement of animal groups often occurs in confined spaces. As animal groups are challenged to move at high density, their mobility dynamics may resemble the flow of densely packed non-living soft materials such as colloids, grains, or polymers. However, unlike inert soft-materials, self-propelled collective living systems often display social interactions whose influence on collective mobility are only now being explored. In this paper, we study the mobility of bi-directional traffic flow in a social insect (the fire ant Solenopsis invicta) as we vary the diameter of confining foraging tunnels. In all tunnel diameters, we observe the emergence of spatially heterogeneous regions of fast and slow traffic that are induced through two phenomena: physical obstruction, arising from the inability of individual ants to interpenetrate, and time-delay resulting from social interaction in which ants stop to briefly antennate. Density correlation functions reveal that the relaxation dynamics of high density traffic fluctuations scale linearly with fluctuation size and are sensitive to tunnel diameter. We separate the roles of physical obstruction and social interactions in traffic flow using cellular automata based simulation. Social interaction between ants is modeled as a dwell time (Tint) over which interacting ants remain stationary in the tunnel. Investigation over a range of densities and Tint reveals that the slowing dynamics of collective motion in social living systems are consistent with dynamics near a fragile glass transition in inert soft-matter systems. In particular, flow is relatively insensitive to density until a critical density is reached. As social interaction affinity is increased (increasing Tint) traffic dynamics change and resemble a strong glass transition. Thus, social interactions play an important role in the mobility of collective living systems at high density. Our experiments and model demonstrate that the concepts of soft-matter physics aid understanding of the mobility of collective living systems, and motivate further inquiry into the dynamics of densely confined social living systems. PMID- 26106974 TI - Bioengineered multilayered human corneas from discarded human corneal tissue. AB - Corneal transplantation has become a common procedure to improve visual acuity by replacing the opaque or distorted host tissue with clear healthy donor corneal tissue. However, globally its wide spread clinical utility is limited due to a lack of supply of high quality corneas. Bioengineered neo-corneas using discarded human corneas to isolate corneal endothelial and epithelial cells, as well as corneal stroma as a scaffolding material, could help address this shortage. The objective of this study was to fabricate multilayered corneal equivalents that could be suitable for full thickness cornea transplantation. To achieve this goal human corneal endothelial cells (hCEC) and human limbal epithelial cells (hLEC) were isolated from discarded human corneas and expanded in vitro, maintaining their phenotype for at least 3 passages. We used our previously described process of human cornea decellularization to create corneal scaffolds that preserve the native extracellular matrix of the corneal stroma. The corneal scaffolds were seeded with hCEC and hLEC, using a special apparatus that enabled seeding both sides of the scaffold. The cell-seeded corneal constructs supported hCEC and hLEC growth and multi-cellular organization for 2 weeks in vitro. Immunohistochemical analysis showed expression of typical hCEC and hLEC markers on their corresponding sides. Importantly, the cell-seeded corneal constructs were more transparent than non-seeded corneal scaffolds. Taken together, this study demonstrates the feasibility of creating multilayered cornea equivalents, exclusively from human donor-derived materials. These constructs may be suitable for corneal transplantation, and as a short-term application, may serve for ophthalmological drug testing purposes. PMID- 26106975 TI - Alkaloids from the Traditional Chinese Medicine ChanSu: synthesis-enabled structural reassignment of bufopyramide to bufoserotonin C. AB - A synthesis of putative bufopyramide has shown the structure assigned to the natural product to be incorrect. The spectroscopic data for the natural product bufopyramide matches that obtained from a synthetic sample of bufoserotonin C, confirming that the two natural products are not distinct, but instead the same compound. PMID- 26106976 TI - Is it the end of the nervous breakdown on avian influenza? PMID- 26106977 TI - Evidence for the negative impact of reward on self-regulated learning. AB - The undermining effect refers to the detrimental impact rewards can have on intrinsic motivation to engage in a behaviour. The current study tested the hypothesis that participants' self-regulated learning behaviours are susceptible to the undermining effect. Participants were assigned to learn a set of Swahili English word pairs. Half of the participants were offered a reward for performance, and half were not offered a reward. After the initial study phase, participants were permitted to continue studying the words during a free period. The results were consistent with an undermining effect: Participants who were not offered a reward spent more time studying the words during the free period. The results suggest that rewards may negatively impact self-regulated learning behaviours and provide support for the encouragement of intrinsic motivation. PMID- 26106978 TI - Early origin and adaptive evolution of the GW182 protein family, the key component of RNA silencing in animals. AB - The GW182 proteins are a key component of the miRNA-dependent post transcriptional silencing pathway in animals. They function as scaffold proteins to mediate the interaction of Argonaute (AGO)-containing complexes with cytoplasmic poly(A)-binding proteins (PABP) and PAN2-PAN3 and CCR4-NOT deadenylases. The AGO-GW182 complexes mediate silencing of the target mRNA through induction of translational repression and/or mRNA degradation. Although the GW182 proteins are a subject of extensive experimental research in the recent years, very little is known about their origin and evolution. Here, based on complex functional annotation and phylogenetic analyses, we reveal 448 members of the GW182 protein family from the earliest animals to humans. Our results indicate that a single-copy GW182/TNRC6C progenitor gene arose with the emergence of multicellularity and it multiplied in the last common ancestor of vertebrates in 2 rounds of whole genome duplication (WGD) resulting in 3 genes. Before the divergence of vertebrates, both the AGO- and CCR4-NOT-binding regions of GW182s showed significant acceleration in the accumulation of amino acid changes, suggesting functional adaptation toward higher specificity to the molecules of the silencing complex. We conclude that the silencing ability of the GW182 proteins improves with higher position in the taxonomic classification and increasing complexity of the organism. The first reconstruction of the molecular journey of GW182 proteins from the ancestral metazoan protein to the current mammalian configuration provides new insight into development of the miRNA dependent post-transcriptional silencing pathway in animals. PMID- 26106979 TI - Lack of Transcription Factor p53 Exacerbates Elastase-Induced Emphysema in Mice. AB - The transcription factor p53 is overexpressed in the lung of patients with emphysema, but it remains unclear if it has a deleterious or protective effect in disease progression. We investigated the role of p53 in the elastase-induced emphysema model and the molecular underlining mechanisms. Wild-type (WT) and p53( /-) mice were instilled with pancreatic porcine elastase. We quantified emphysema (morphometric analysis), chemokine (C-C motif) ligand 2 (CCL2), and TNF-alpha in bronchoalveolar lavage (BAL) (ELISA), oxidative stress markers [heme oxygenase 1 (HO1), NAD(P)H dehydrogenase quinone 1 (NQO1), and quantitative RT-PCR], matrix metalloproteinase 12 (MMP12) expression, and macrophage apoptosis (cleaved caspase-3, immunofluorescence). p53 gene expression was up-regulated in the lung of elastase-instilled mice. p53 deletion aggravated elastase-induced emphysema severity, pulmonary inflammation (macrophage and neutrophil numbers and CCL2 and TNF-alpha levels in BAL), and lung oxidative stress. These findings, except for the increase in CCL2, were reproduced in WT mice transplanted with p53(-/-) bone marrow cells. The increased number of macrophages in p53(-/-) mice was not a consequence of reduced apoptosis or an excess of chemotaxis toward CCL2. Macrophage expression of MMP12 was higher in p53(-/-) mice compared with WT mice after elastase instillation. These findings provide evidence that p53(-/-) mice and WT mice grafted with p53(-/-) bone marrow cells are more prone to developing elastase-induced emphysema, supporting a protective role of p53, and more precisely p53 expressed in macrophages, against emphysema development. The pivotal role played by macrophages in this phenomenon may involve the MMP12-TNF alpha pathway. PMID- 26106981 TI - What Does the Evidence Reveal Regarding Home- and Community-Based Nutrition Services for Older Adults? PMID- 26106982 TI - Outcomes Matter: The Need for Improved Data Collection and Measurement in Our Nation's Home-Delivered Meals Programs. AB - The nation's home-delivered meals program is an important service strategy to provide nutrition and socialization to hundreds of thousands of homebound older adults. However, data limitations have prevented the formation of an evidence base for these programs beyond measuring outputs. This article discusses our need to have a better way to measure and analyze need, unmet need, and outcomes associated with receipt of services in order to ensure that this valuable program receives the level of support required to continue to serve homebound older adults. In order to shape the discussion about the best ways to provide evidence of these programs' impact, it is important to think about what outcomes could and should be measured, the best possible sources of data, and how providers can collect this information effectively and uniformly. PMID- 26106980 TI - Lavandin (Lavandula * intermedia Emeric ex Loiseleur) essential oil from Spain: determination of aromatic profile by gas chromatography-mass spectrometry, antioxidant and lipoxygenase inhibitory bioactivities. AB - Lavandin (Lavandula * intermedia Emeric ex Loiseleur) essential oils (EOs), from Abrial, Super and Grosso cultivars, cultivated and extracted in the South East of Spain, were analysed by using GC/MS to determine their composition, in both relative (peak area) and absolute (using standard curves) concentrations. Linalool (34-47%), linalyl acetate (17-34%), camphor (4-9%) and eucalyptol (3-7%) were determined as the main molecules. This characterisation was completed with the enantioselective gas chromatography, where ( - )-linalool, (+)-camphor and ( )-linalyl acetate were determined as the main components. Antioxidant activity was evaluated positively by several methods: activity against free radicals, chelating and reducing power, probably due to linalool and linalyl acetate. Mild inhibitory activity on lipoxygenase was observed supporting potential anti inflammatory activity, mainly due to linalool and camphor. These properties support the potential use of L. * intermedia essential oils as natural cosmetic and natural pharmaceutical ingredient to fight several skin diseases. PMID- 26106983 TI - Older Americans Act Nutrition Programs: A Community-Based Nutrition Program Helping Older Adults Remain at Home. AB - Nutrition interventions are important as the older population, most of whom live in the community, increases in size and diversity. They are key to leading a healthy, functional life and mitigating chronic health conditions. The Older Americans Act Nutrition Program served 86.3 million congregate and 137.4 million home-delivered meals to 1.6 million and 850,000 older adults, respectively (2012). Congregate and home-delivered participants were older, poorer, sicker, more functionally impaired, and at a greater risk of institutionalization than the general U.S. older population. The Nutrition Program is publically and privately funded. About 44% of congregate and 30% of home-delivered expenditures are from federal sources, which dropped from $25 per older adult in 1990 to $12 in 2013. Despite multiple funding sources, funding is insufficient for the expanding older population. Health, nutrition, and social service professionals need to coordinate their community-based services to truly help older adults remain in their homes. PMID- 26106984 TI - Meeting the Training Needs of Aging Network Nutrition Program Professionals: Past, Present, and Future. AB - Aging network nutrition professionals must continuously adapt knowledge and skills in order to maintain the provision of high quality, appropriate, and targeted services able to address the evolving demographic, home- and health care needs of the older Americans of today and tomorrow. This evolution must be supported by ready access to contemporary training and technical assistance. Since the passage of the Older Americans Act in 1972, the Administration on Aging has provided a diverse and contemporary array of supportive program development modalities for aging network nutrition professionals, ranging from the establishment of nutrition training centers and institutes, to the formation of action learning collaboratives. A sustainable and broad funding base is needed to support the training needs of aging network professionals and assure their continued acquisition of the skills, knowledge, and business acumen needed to integrate food and nutrition services into home and community-based social, health, and long-term care systems. PMID- 26106986 TI - Characteristics of Older Georgians Receiving Older Americans Act Nutrition Program Services and Other Home- and Community-Based Services: Findings from the Georgia Aging Information Management System (GA AIMS). AB - This descriptive study examined characteristics of older Georgians receiving Older Americans Act Nutrition Program Services and other home- and community based services (HCBS) using state aging administrative data (N = 31,341, mean age: 76.6 +/- 9.2 y, 71.2% female, 52.3% White). Home-delivered meals (HDM) was used most frequently. The characteristics of older Georgian HCBS participants varied by the type and number of HCBS received. Those receiving HDM and other in home and caregiving services were more likely to show poorer sociodemographic, economic, and functional characteristics, and food insecurity. Those receiving multiple HCBS were most vulnerable, but showed lower level of food insecurity than those receiving single HCBS, suggesting potential combined benefits of receiving multiple programs. This study underscores the importance of documenting dynamic needs for HCBS, especially HDM, among vulnerable older adults as part of standard administrative process to identify those at high risk of institutionalization, optimize HCBS delivery and coordination, and maximize HCBS benefits. PMID- 26106985 TI - Does Participation in Home-Delivered Meals Programs Improve Outcomes for Older Adults? Results of a Systematic Review. AB - Participation in home-delivered meals programs may contribute to the health and independence of older adults living in the community, especially those who are food insecure or those who are making transitions from acute, subacute, and chronic care settings to the home. The purpose of this study was to conduct a comprehensive and systematic review of all studies related to home-delivered meals in order to shed light on the state of the science. A complete review of articles appearing in PubMed using the keyword "Meal" was conducted; and titles, abstracts, and full-texts were screened for relevance. Included in this review are 80 articles. Most studies are descriptive and do not report on outcomes. Frequently reported outcomes included nutritional status based on self-reported dietary intake. Additionally, most studies included in this review are cross sectional, have a small sample size, and/or are limited to a particular setting or participant population. More rigorous research is needed to (1) gain insight into why so few eligible older adults access home-delivered meals programs, (2) support expansion of home-delivered meals to all eligible older adults, (3) better identify what home-delivered meals models alone and in combination with other services works best and for whom, and (4) better target home-delivered meals programs where and when resources are scarce. PMID- 26106987 TI - Benchmarking a Home-Delivered Meal Program's Annual Satisfaction Survey: A Metropolitan Area Neighborhood Nutrition Alliance (MANNA) Initiative in Philadelphia. AB - The Metropolitan Area Neighborhood Nutrition Alliance (MANNA) is a community based organization providing home-delivered meals in Philadelphia, Pennsylvania to individuals at acute nutritional risk and experiencing a life-threatening illness, independent of age or income. The challenge MANNA faces, like other community-based organizations, is to demonstrate effective services by benchmarking with other organizations. This article reports how MANNA benchmarked results of their annual satisfaction survey against the 2013 National Survey of Older Americans Act Program. Overall, MANNA recipients were more often satisfied with the taste and variety of food, and more MANNA recipients rated the program as excellent. However, more MANNA recipients reported not having enough money to buy food, skipping meals because of money, needing to choose between food and medications or food and utilities. MANNA is using these findings as an impetus to better understand the needs of their clients, especially as they transition off the meal program, and to identify additional resources to support transitional programming. PMID- 26106988 TI - A Model Home-Delivered Meals Program to Support Transitions from Hospital to Home. AB - Meals On Wheels, Inc. of Tarrant County (MOWI) collaborated with local community based organizations and hospitals to provide home-delivered meals and an evidence based medication management intervention as a care transition service. The model program was designed to address risk factors commonly associated with preventable hospital readmissions. MOWI staff provided meals to 121 patients recently discharged from an inpatient hospitalization or emergency department visit from March 2013 through March 2014. A total of 18,010 meals were delivered to the 121 clients. On average, clients received 6.25 meals per week with meal delivery starting, on average, 8.95 days postdischarge. Ninety-three of the 121 clients also elected to receive the HomeMeds program. Client self-report of health care utilization (e.g., hospital readmission) at three months and six months was lower than expected given client characteristics. Positive changes in the Emergent Care Assessment and resolution of medication alerts provide additional evidence of a positive effect of the home-delivered meals program. More research is needed to document the benefits of home-based care supports following hospitalization. PMID- 26106989 TI - The Impact of a Home-Delivered Meal Program on Nutritional Risk, Dietary Intake, Food Security, Loneliness, and Social Well-Being. AB - Maintaining independence and continuing to live at home is one solution to manage the rising health care costs of aging populations in the United States; furthermore, seniors are at risk of malnutrition and food insecurity. Home delivered meal programs are a tool to address food, nutrition, and well-being concerns of this population. Few studies have identified outcomes from these programs; this pilot study reviews the nutritional status, dietary intake, well being, loneliness, and food security levels of seniors participating in a Meals on Wheels delivery service. Clients, new to the meal program, participated in pre and postphone interviews, and 51 seniors completed the study. The survey was composed of five scales or questionnaires, and statistical analyses were conducted using SPSS. Improvements across all five measures were statistically significant after participating two months in the home-delivered meal program. Implications for further research, practice, and the Older Americans Act are discussed. PMID- 26106990 TI - Factors Associated with Inpatient Hospital (Re)admissions in Medicare Beneficiaries in Need of Food Assistance. AB - Little is known about pathways underlying inpatient hospital (re)admissions in older adults unable to meet basic needs. This study examined the factors associated with (re)admissions in a sample of low-income older Medicare beneficiaries in need of food assistance in Georgia in 2008 (N = 892, mean age 75.4 +/- 8.8 years, 30.3% Black, 68.5% female). About 35.3% of the sample experienced 1 + hospital (re)admissions. (Re)admissions were significantly more likely in individuals who requested Older Americans Act Nutrition Program Home Delivered Meals services (OR 2.3; 95% CI 1.4, 3.8), had more outpatient emergency room visits (1 visit: OR 2.1; 95% CI 1.4, 3.1; 2+ visits: OR 3.6; 95% CI 2.4, 5.4), and experienced greater multimorbidity (OR 1.6; 95% CI 1.4, 3.1). Support for home and community-based services may be critical in reducing potentially avoidable inpatient hospital (re)admissions. PMID- 26106992 TI - Association of Home-Delivered Meals on Daily Energy and Nutrient Intakes: Findings from the National Health and Nutrition Examination Surveys. AB - This study examines the impact of a home-delivered meal program on daily energy and nutrient intakes using nationally representative data from the National Health and Nutrition Examination Survey 2003-2012 waves. First-difference estimator addressed selection bias by using within-individual variations in diet and service use status between two nonconsecutive 24-hour dietary recalls among 145 home-delivered meal service users. Service use was found to be associated with a net increase in daily intake of protein by 8.39 g, fiber 3.39 g, calcium 145.94 mg, copper 0.16 mg, magnesium 45.37 mg, potassium 317.39 mg, selenium 14.04 mcg, and sodium 327.52 mg; whereas the effects on daily intake of total energy, fat, and vitamin D were not statistically significant. Home-delivered meals improve nutrient intakes among participants, but currently the program may be too limited in scale and capacity to best capitalize its beneficial impact on healthy aging and health care cost containment at the national level. PMID- 26106991 TI - Food Anxiety Is Associated with Poor Health Status Among Recently Hospital Discharged Older Adults. AB - Older adults returning home from the hospital may encounter health issues that cause anxiety about their ability to obtain enough food. Home-delivered meal (HDM) programs support nutritional needs and improve food security of those who cannot provide for themselves. A study conducted in six states examined feelings of anxiety about getting enough food in older adults (aged 60 years and older), comparing three time points: prior to hospitalization, at hospitalization (n = 566) and after receiving HDMs for two months posthospitalization (n = 377). Food anxiety during hospitalization was significantly higher among Hispanic ethnicity, current and former smokers, diabetics, and those who eat alone or have difficulty shopping. Food anxiety was significantly lower from baseline to two months follow up (P < 0.0001), and participants showed improvements in certain coping strategies they used to get their meals. Indicators of food anxiety can help the health care system and community nutrition programs target those at highest risk of negative health outcomes. PMID- 26106993 TI - Computer-Aided Design and Computer-Aided Manufacturing Hydroxyapatite/Epoxide Acrylate Maleic Compound Construction for Craniomaxillofacial Bone Defects. AB - The aim of this study was to investigate the use of computer-aided design and computer-aided manufacturing hydroxyapatite (HA)/epoxide acrylate maleic (EAM) compound construction artificial implants for craniomaxillofacial bone defects. Computed tomography, computer-aided design/computer-aided manufacturing and three dimensional reconstruction, as well as rapid prototyping were performed in 12 patients between 2008 and 2013. The customized HA/EAM compound artificial implants were manufactured through selective laser sintering using a rapid prototyping machine into the exact geometric shapes of the defect. The HA/EAM compound artificial implants were then implanted during surgical reconstruction. Color-coded superimpositions demonstrated the discrepancy between the virtual plan and achieved results using Geomagic Studio. As a result, the HA/EAM compound artificial bone implants were perfectly matched with the facial areas that needed reconstruction. The postoperative aesthetic and functional results were satisfactory. The color-coded superimpositions demonstrated good consistency between the virtual plan and achieved results. The three-dimensional maximum deviation is 2.12 +/- 0.65 mm and the three-dimensional mean deviation is 0.27 +/- 0.07 mm. No facial nerve weakness or pain was observed at the follow-up examinations. Only 1 implant had to be removed 2 months after the surgery owing to severe local infection. No other complication was noted during the follow-up period. In conclusion, computer-aided, individually fabricated HA/EAM compound construction artificial implant was a good craniomaxillofacial surgical technique that yielded improved aesthetic results and functional recovery after reconstruction. PMID- 26106994 TI - U-shaped Osteotomy Around the Descending Palatine Artery to Prevent Posterior Osseous Interference for Superior/Posterior Repositioning of the Maxilla in Le Fort I Osteotomy. AB - In maxillary orthognathic surgery, superior repositioning of the maxilla is sometimes difficult, and removal of bony interference, especially around the descending palatine artery (DPA), is very time-consuming in cases of severe maxillary impaction. Posterior repositioning of the maxilla for removal of bony interference between the posterior maxilla and the pterygoid process is also technically difficult. Because the most common site of hemorrhage in Le Fort I osteotomy is the posterior maxilla, this bone removal is a source of frustration for surgeons in DPA injury. When the DPA is injured during bone removal and ligation is performed, aseptic necrosis of the maxilla may occur. Therefore, a simple and safe method for maxillary superior/posterior repositioning is required to remove osseous interference around the DPA. The authors describe here U-shaped osteotomy around the DPA to prevent posterior osseous interference for superior/posterior repositioning of the maxilla in Le Fort I osteotomy. PMID- 26106996 TI - Pediatric Facial Fractures: Interpersonal Violence as a Mechanism of Injury. AB - PURPOSE: Interpersonal violence is a relatively infrequent cause of injury to the craniofacial skeleton in the pediatric population. The presentation of fractures as a result of different causes varies dramatically and can have a direct impact on management. The current study compares facial fractures in a pediatric population as a result of interpersonal violence with other mechanisms of injury. METHODS: A retrospective review of all of the facial fractures at a level 1 trauma center in an urban environment was performed for the years 2000 to 2012. Patients <=18 years were included. Patient demographics were collected, as well as location of fractures, concomitant injuries, services consulted, and surgical management strategies. Patients were placed into 2 groups, those sustaining an injury as a result of interpersonal violence and all others. A significance value of 5% was used. RESULTS: During this period, there were 3147 facial fractures treated at our institution, 353 of which were in pediatric patients. Upon further review, 68 patients were excluded because of insufficient data for analysis, leaving 285 patients for review. There were 124 (43.5%) patients identified as sustaining a fracture as a result of interpersonal violence. Those sustaining a fracture as a result of interpersonal violence were statistically (P < 0.05) more likely to be boys and to have sustained a fracture of the mandible. The most common services consulted for this group of patients was plastic surgery and oral and maxillofacial surgery. This group of patients was statistically (P < 0.05) more likely to be admitted specifically for management of a facial fracture and statistically (P < 0.05) more likely to be treated operatively with rigid internal fixation. Those sustaining a fracture as a result of interpersonal violence were significantly less likely to have other systemic injuries such as spinal fractures, intracranial fractures, long bone fractures, and pelvic/thoracic fractures. This group was also more likely to undergo treatment via conservative means. In addition, a significantly higher Glasgow Coma Scale (14.7 vs 12.8) and age (16.0 vs 12.8 years) and a significantly lower hospital length of stay (2.9 vs 7.9 days) was observed in the group subjected to interpersonal violence. CONCLUSIONS: Pediatric patients experiencing facial facture as a result of interpersonal violence show a very distinctive pattern of presentation. The energy associated with the injury is likely focused directly at the craniofacial skeleton and therefore other organ systems are spared. This allows more directed fracture management resulting in a shorter hospital stay when necessitating admission. The findings of the current study are important in that such a large proportion of the patients reviewed experienced interpersonal violence, more so than most other similar studies. PMID- 26106995 TI - Extradural Ossification Following Epidural Hematoma in Children: A Rare But Significant Entity. AB - There has been a profound increase in the number of patients undergoing head computed tomography after minor injuries and the identification of epidural hematomas has risen concurrently. Although emergent craniotomy and evacuation has been the conventional standard for management, some epidural hematomas can be managed nonoperatively in carefully selected patients. Because of the difficulty in clinically monitoring epidural hematoma absorption and resolution because of the attributed risks of imaging radiation exposure in pediatric patients, the exact incidence of epidural hematoma ossification is unknown. Integrating epidural hematoma calcification into management algorithms is not clearly defined in the literature. The authors report a case of a 2-year-old girl with a calcified epidural hematoma requiring surgical treatment. With the incidence of epidural hematomas rising, providers should be aware of the rare but consequential incidence of epidural hematoma ossification. After literature review and discussion of the pathophysiology, the authors present an algorithmic approach to account for this rare entity. For conservative management of asymptomatic epidural hematomas, providers should consider follow-up magnetic resonance imaging to evaluate resolution in 2 to 3 months. If the magnetic resonance imaging indicates a failure to resolve, a computed tomography scan should then be performed to evaluate ossification and possible need for surgical intervention. PMID- 26106997 TI - The Effect of Nasal Septal Deviation on Frontal and Maxillary Sinus Volumes and Development of Sinusitis. AB - The purpose of this study was to determine the possible role of nasal septal deviation on volume of maxillary and frontal sinuses. Between February 2011 and October 2013, paranasal sinus computed tomography (CT) findings of 732 patients (410 males, 322 females) who were admitted to Ear Nose and Throat Department of Kayseri Research and Training Hospital were retrospectively analyzed. By excluding the other coexistent sinonasal pathologies, 83 consecutive patients with nasal septal deviations were included in the study. The volume of each maxillary and frontal sinus (ipsi- and contralateral to the deviation side) was also calculated using the computer program. There was no statistically significant difference between ipsilateral and contralateral maxillary sinus volumes in group 1 and group 3 (P > 0.05). There was a statistically significant difference between ipsilateral and contralateral maxillary sinus volumes in group 2 (P < 0.05). There was no statistically significant difference between ipsilateral and contralateral frontal sinus volumes in group 1, group 2, and group 3 (P > 0.05). Moderate septal deviation significantly affects the volume of maxillary sinus. Mild and severe septal deviation does not significantly affect the volume of maxillary sinus. Effect of septal deviation on frontal sinus volume was not detected. The probability to encounter maxillary and frontal sinusitis ipsilateral to the all septum deviation groups was significantly increased in both right- and left-sided subjects. PMID- 26106999 TI - Cutaneous Metastasis on Scalp of Hepatocellular Carcinoma. PMID- 26106998 TI - Customized "In-Office" Three-Dimensional Printing for Virtual Surgical Planning in Craniofacial Surgery. AB - BACKGROUND: Virtual surgical planning using three-dimensional (3D) printing technology has improved surgical efficiency and precision. A limitation to this technology is that production of 3D surgical models requires a third-party source, leading to increased costs (up to $4000) and prolonged assembly times (averaging 2-3 weeks). The purpose of this study is to evaluate the feasibility, cost, and production time of customized skull models created by an "in-office" 3D printer for craniofacial reconstruction. METHODS: Two patients underwent craniofacial reconstruction with the assistance of "in-office" 3D printing technology. Three-dimensional skull models were created from a bioplastic filament with a 3D printer using computed tomography (CT) image data. The cost and production time for each model were measured. RESULTS: For both patients, a customized 3D surgical model was used preoperatively to plan split calvarial bone grafting and intraoperatively to more efficiently and precisely perform the craniofacial reconstruction. The average cost for surgical model production with the "in-office" 3D printer was $25 (cost of bioplastic materials used to create surgical model) and the average production time was 14 hours. CONCLUSIONS: Virtual surgical planning using "in office" 3D printing is feasible and allows for a more cost-effective and less time consuming method for creating surgical models and guides. By bringing 3D printing to the office setting, we hope to improve intraoperative efficiency, surgical precision, and overall cost for various types of craniofacial and reconstructive surgery. PMID- 26107000 TI - Acellular Dermal Matrix Use in Cleft Palate and Palatal Fistula Repair: A Potential Benefit? AB - BACKGROUND: In cleft palate repair, anatomically oriented, tension free, atraumatic total closure is the key to achieve a normal speech consecutive to a sufficient velopharyngeal closure and also to prevent postoperative fistula development. In this clinical study, we review our experience with acellular dermal matrix (ADM) which was used as an adjunct to facilitate difficult cleft palate and palatal fistula closure. METHODS: From October 2009 till December 2013, primary cleft palate and fistula repairs in which ADM was used were culled from the cleft surgery files. Acellular dermal matrix was used as an extra layer in between palatal flaps of primary repairs and as a sandwiched sheet separating the flaps used to repair fistulas. In addition to patient, cleft and fistula demographics, records were evaluated for sizes, fistula development, fistula recurrence, extrusion, exposure, and infection. RESULTS: Acellular dermal matrix was used in 35 patients with palatal clefts of mean size 15 +/- 4 mm and in 15 palatal fistulas. Two-flap palatoplasty technique was the dominant technique for the palate repair. Fistula rate for the palate repair was 8.5% and fistula recurrence rate was 20%. Mean follow-up for the palate and fistula repair patients was 29 +/- 15 months and 32 +/- 11 months, respectively. In two cases of palatoplasty group and in four cases of fistula repair group, ADM was exposed resulting in total extrusion in two fistula cases. CONCLUSIONS: In this ongoing experience of application, ADM has been shown to be a simple, safe, and helpful tool to reduce fistula rate mainly in relatively wide and high tension tenuous cleft palate repairs but less favorable in challenging fistula closure attempts particularly along with poorly vascularized surrounding tissues. However, study design and its results are yet far from strongly recommending routine ADM use in cleft palate surgery. PMID- 26107001 TI - Mandibular Bone Exposure and Osteonecrosis in a Patient With an Uncomplicated Medical History. PMID- 26107002 TI - Circular Excision and Purse-String Closure for Pediatric Facial Skin Lesions. AB - Standard resection of pediatric facial skin lesions consists of lenticular excision and linear closure. This one-stage procedure for circular lesions results in a linear scar 3 times longer than the diameter of the removed specimen. Circular excision and purse-string closure has been described for infantile hemangiomas to reduce the length of scar. The purpose of this study was to analyze the application of this technique for any type of circular facial skin lesion in the pediatric population. Records of consecutive pediatric patients with facial skin lesions treated with circular excision and purse-string closure from 2007-2014 were reviewed. Patient age, sex, type of lesion, location, and size were recorded. Number of stages necessary to remove the area and complications were analyzed. Seventy-seven children (74% female) underwent circular excision and purse-string closure for an infantile hemangioma (46%), pigmented nevus (27%), Spitz nevus (7%), pilomatrixoma (5%), pyogenic granuloma (5%), vascular malformation (4%), or another type of skin lesion (6%). Age at the time of resection was 6.0 years (range 4 months-17 years) and mean lesion area was 3.9 cm (range 0.2-19.6); 30% of patients underwent a second procedure and no infection or wound dehiscence occurred. Circular excision and purse-string closure is an effective technique to manage any type of circular skin lesion in the pediatric population. It is particularly useful for lesions on the face because it limits the length of a scar. A subset of patients may benefit from second procedure to convert the circular scar from a circle into a line. PMID- 26107003 TI - Attomolar Level Detection of Raman Molecules with Hierarchical Silver Nanostructures Including Tiny Nanoparticles between Nanosized Gaps Generated in Silver Petals. AB - We developed a route for synthesizing Ag nanostructures with tunable morphologies for ultrasensitive surface-enhanced Raman spectroscopy. Through the consecutive addition of three reducing agents (i.e., 4-mercaptobenzoic acid, trisodium citrate, and ascorbic acid) to an aqueous solution of silver nitrate, hierarchical flower-like Ag nanostructures were produced. The nanostructures had Ag petals in which nanosized gaps were generated, and small Ag nanoparticles were incorporated within the gaps. Theoretically, the nanostructures exhibited highly enhanced electric fields in the outer-shell regions where the small Ag nanoparticles were densely located. Combining the enhanced field effect with resonance effect of a Raman-active molecule (methylene blue) at a specific wavelength, measurable Raman signals were obtained at concentrations as low as 100 attomolar (10(-16) M; corresponding to 10(-21) mol). Key factors were discussed for the synthesis of the Ag nanostructures while finely controlling the morphologies of hierarchical Ag nanostructures, thereby modulating the intensity of surface-enhanced resonance Raman spectroscopy (SERRS) signals. Therefore, this synthetic method produces highly promising nanostructures for SERRS-based applications. PMID- 26107004 TI - Changes in Tinnitus After Middle Ear Implant Surgery: Comparisons With the Cochlear Implant. AB - OBJECTIVES: Tinnitus is a very common symptom in patients with hearing loss. Several studies have confirmed that hearing restoration using hearing aids or cochlear implants (CIs) has a suppressive effect on tinnitus in users. The aim of this study was to analyze the effect of other hearing restoration devices, specifically the middle ear implant (MEI), on changes in tinnitus severity. DESIGN: From 2012 to October 2014, 11 adults with tinnitus and hearing loss underwent MEI surgery. Pure-tone audiometry, tinnitus handicap inventory (THI), and visual analog scale scores for loudness, awareness, and annoyance and psychosocial instruments were measured before, immediately after, and 6 months after surgery. Changes in hearing thresholds and THI scores were analyzed and compared with those of 16 CI recipients. RESULTS: In both MEI and CI groups, significant improvements in tinnitus were found after the surgery. The THI scores improved in 91% of patients in the MEI group and in 56% of those in the CI group. Visual analog scale scores and psychosocial scale scores also decreased after surgery, but there were no statistical differences between the groups. CONCLUSIONS: The results indicate that the MEI may be as beneficial as the CI in relieving tinnitus in subjects with unilateral tinnitus accompanying hearing loss. Furthermore, this improvement may manifest as hearing restoration or habituation rather than a direct electrical nerve stimulation, which was previously considered as the main mechanism underlying tinnitus suppression by auditory implants. PMID- 26107005 TI - Quality Improvement Targets for Regional Variation in Surgical End-Stage Renal Disease Care. AB - IMPORTANCE: Arteriovenous fistula (AVF) access improves survival in patients with end-stage renal disease (ESRD) compared with other modalities when used at first hemodialysis. Use varies between locations, but, to our knowledge, no study has related this finding to mortality on a national scale. OBJECTIVE: To quantify regional variation in AVF access at first hemodialysis, as well as the associated effect on mortality in the US Renal Data System. DESIGN, SETTING, AND PARTICIPANTS: The US Renal Data System tracks all patients with ESRD in the United States. A retrospective analysis of the population from January 1, 2006, to December 31, 2010, was performed. Univariate analyses (chi2 test; 2-tailed, unpaired t test; and analysis of variance) as well as multivariable logistic regressions were carried out to compare patient characteristics, incident AVF frequencies, and corrected mortality hazards between ESRD Network Programs, which comprise 18 states, commonwealths, and protectorates in which residents receive hemodialysis. Of the patients receiving hemodialysis in these networks, the data on 464,547 individuals who were beginning renal replacement therapy were analyzed. Analysis was started April 1, 2013, and ended August 3, 2014. MAIN OUTCOMES AND MEASURES: Mortality hazard variation between ESRD Network Programs in the United States and incident AVF frequency. RESULTS: Of the 464,547 patients beginning hemodialysis in this cohort, first hemodialysis with an AVF ranged from 11.1% to 22.2% depending on the ESRD Network in which they maintained residency (P < .001). Similarly, corrected mortality hazard varied by 28% (hazard ratios from 0.99 [95% CI, 0.96-1.03] to 1.27 [95% CI, 1.22-1.31]; P < .001). Logistic regression determined nephrology care to increase the odds of a patient beginning hemodialysis using an AVF by 11-fold (odds ratio, 11.42 [95% CI, 10.93-11.93]; P < .001); congestive heart failure was a negative correlatefold (odds ratio, 0.65 [95% CI, 0.64-0.67]; P < .001). No region achieved the 50% Fistula First Breakthrough Initiative (now known as Fistula First Catheter Last) target for incident AVF access. CONCLUSIONS AND RELEVANCE: Marked regional variation in functional incident AVF frequency and risk-adjusted ESRD mortality exists across the United States. Differences in access to preoperative nephrology care and patient comorbidities may explain some of these variations, but an opportunity to implement best-practice guidelines exists. PMID- 26107006 TI - Phenomenon of individual difference in human monocyte activation. AB - Macrophages play an important role in the pathogenesis of atherosclerosis, including the early pre-clinical stages of the disease development. We have explored the possibility that the disease onset could be associated with altered monocyte/macrophage response to activating pro- and anti-inflammatory stimuli. We evaluated the susceptibility of circulating monocytes from healthy individuals and patients with asymptomatic carotid atherosclerosis to M1 and M2 activation. The obtained data indicated the existence of a remarkable individual difference in susceptibility to activation among monocytes isolated from the blood of different subjects, regardless of the presence or absence of atherosclerosis. The identified differences in susceptibility to activation between monocytes may explain the individual peculiarities of the immune response in different subjects. PMID- 26107007 TI - Porcine reproductive and respiratory syndrome virus (PRRSV) from the first outbreak of India shows close relationship with the highly pathogenic variant of China. AB - BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is an economically important viral disease of pigs worldwide. India has reported the first outbreak of PRRS in the pig population of Mizoram state to the Office International des Epizooties on the 26 June 2013. HYPOTHESIS/OBJECTIVES: The aim of the present study was to determine the genotype and origin of porcine reproductive and respiratory syndrome virus (PRRSV) from the first outbreak in the pig population of Mizoram state, India, in 2013. ANIMALS AND METHODS: A total of 880 affected pigs from the outbreak were clinically examined, 51 animals were necropsied and tested by reverse transcription polymerase chain reaction (RT-PCR) to detect PRRSV and 148 serum samples were tested to detect PRRSV-specific antibodies. The full open reading frame 5 (ORF5) gene sequences from 12 and ORF7 gene sequences from three clinical cases were sequenced and analysed for genomic characterization, respectively. RESULTS: The outbreak was confirmed by the detection of PRRSV-specific antibodies in 109 out of 148 serum samples (74%) and also by RT-PCR in 46 out of 51 necropsy samples (90%). Notably, ORF5 and ORF7 genes of Indian strain shares the same nucleotide positions i.e. 13,698-14,300 and 14,799-15,170, respectively, with the highly pathogenic (HP) strain of China and were grouped together in a phylogenetic tree. CONCLUSIONS AND CLINICAL IMPORTANCE: Sequence and phylogenetic analysis of ORF5 and ORF7 confirmed that the Indian strain has a close link with the HP-PRRSV of China. The current study forms an essential step for better understanding of the epidemiology as well as the movement and spread of the disease in India. PMID- 26107008 TI - Aspire to Inspire: The Launch of the Asia-Pacific Journal of Ophthalmology. PMID- 26107010 TI - Femtosecond Laser Cataract Surgery: An Experience From Australia. AB - Cataract surgery remains the most widely performed intraocular procedure throughout the world. Safety and accuracy of the procedure are paramount and techniques should remain under constant review. Recently, the introduction of the femtosecond laser to assist cataract surgery has provided ophthalmologists with an exciting tool that may further improve outcomes. We review the existing literature, discuss the potential implications for a variety of stakeholders and discuss our initial experience with the femtosecond laser. PMID- 26107009 TI - Femtosecond Laser: Is It the Way Forward for Cataract Surgery? PMID- 26107011 TI - Intravitreal Bevacizumab, Plasminogen, and Pneumatic Retinopexy for Subfoveal Hemorrhage in Age-Related Macular Degeneration. AB - PURPOSE: To evaluate the therapeutic effect of intravitreal bevacizumab combined with intravitreal plasminogen and pneumatic retinopexy as treatment of subfoveal hemorrhages due to exudative age-related macular degeneration. DESIGN: Clinical interventional case series study. METHODS: Ten patients (10 eyes) with exudative age-related macular degeneration, presented with a subfoveal hemorrhage larger than 1 disc size and smaller than 5 disc sizes. They received an intravitreal injection of 50 MUg of plasminogen and 0.3 mL of 100% sulfur hexafluoride gas combined with intravitreal 1.5 mg of bevacizumab, followed by 2 additional intravitreal injections of 1.5 mg of bevacizumab in an interval of 6 weeks. RESULTS: Mean visual acuity improved slightly, although not statistically significant (P = 0.24), from 1.56 +/- 0.47 to 1.48 +/- 0.60 logMAR at 1 month after the procedure and to 1.35 +/- 0.54 logMAR at 3 months after baseline. Subfoveal hemorrhage recurred in none of the patients during the follow-up. In all patients, the subfoveal hemorrhage had at least partially been moved to the infrafoveal region. Pronounced degenerative subfoveal changes were the main reason for a lack of a marked increase in visual acuity after the procedure. CONCLUSIONS: For some patients with exudative age-related macular degeneration and a subfoveal hemorrhage larger than 1 disc size and smaller than 5 disc sizes, the combined intravitreal injection of bevacizumab, plasminogen, and gas followed by 2 additional intravitreal bevacizumab injections can lead to a stabilization or slight improvement in visual acuity, unless subfoveal degenerative changes are not too marked to prevent a gain in vision. PMID- 26107012 TI - International Values of Central Pachymetry in Normal Subjects by Rotating Scheimpflug Camera. AB - PURPOSE: In corneal refractive surgery, postoperative ectasia risk assessment routinely includes pachymetric analysis at the apex and thinnest point. We examined whether these data differ worldwide and constructed preliminary country specific normative thresholds. DESIGN: This was a multicenter, cross-sectional study. METHODS: Using the Pentacam Eye Scanner (OCULUS GmbH, Wetzlar, Germany), we examined 1 randomly selected eye from each of 555 normal adults (8 countries, 6 continents), measuring the thinnest point location, central pachymetry (thinnest point, pupillary center, and apex), and the apex-thinnest point difference. International differences were assessed by 1-way analysis of variance. Normative thresholds were defined by 2- and 3-SD gates or Tukey method. RESULTS: The thinnest point averaged 0.44 mm temporal and 0.29 mm inferior to the apex. Individual thinnest points located more than 1.0 mm inferior represented fewer than 0.5% of normal corneas (>0.76 mm in the US subgroup). The mean thinnest-point pachymetry was 536 MUm overall, and values less than 469 or 435 MUm (-2 or -3 SD, respectively) would be expected in less than 2.5% or 0.15% of normal corneas, respectively. The thinnest-point pachymetry averaged 2 to 3 MUm thinner than apical (range, 0-32 MUm). Differences of greater than 8.5 MUm would be expected in less than 0.5% of normal corneas overall. CONCLUSIONS: International differences were largely clinically insignificant. Nevertheless, it remains preferable to establish racial/geographic-specific normative values. We defined preliminary generalized and country-specific thresholds useful to the corneal refractive surgeon for identifying potentially abnormal corneas based on common pachymetric parameters, particularly the thinnest point by tomography. PMID- 26107013 TI - Retinal Nerve Fiber Layer Imaging with Spectral-Domain Optical Coherence Tomography: Impact of Signal Strength on Analysis of the RNFL Map. AB - PURPOSE: The objective of the study was to investigate the influence of signal strength (SS) on retinal nerve fiber layer (RNFL) measurement and interpretation of the RNFL thickness deviation map obtained with a spectral-domain optical coherence tomography. DESIGN: Cross-sectional study. METHODS: Thirty-seven eyes from 37 normal subjects were included. Six cube scans, each with 200 * 200 RNFL measurement pixels covering an area of 6 * 6 mm at the optic disc region with SS from 5 to 10, were collected with the Cirrus HD-optical coherence tomography (Carl Zeiss Meditec Inc, Dublin, Calif) by varying the level of polarization. The differences in RNFL measurements and the number of abnormal (outside 95% of the centile ranges) superpixels (1 superpixel = 4 * 4 pixels) at different levels of SS were compared with repeated-measures analysis of variance. RESULTS: The RNFL thickness generally increased with the SS. There were significant differences in RNFL thickness between images with SS of 10 and those with SS of 5 to 7 at the superonasal (1-3 o'clock) and inferotemporal (7-9 o'clock) sectors. One o'clock was the most frequent location that showed abnormal RNFL measurement. The average number of abnormal superpixels ranged between 99 (SS = 5) and 34 (SS = 10). There was no significant difference in the number of abnormal superpixels between images with SS of 10 and those with SS of 8 or 9. CONCLUSIONS: Although SS changes induced by polarization adjustment may not be the same as those induced by media opacity or corneal irregularity, it is evident that the level of SS has a significant impact on RNFL measurement. PMID- 26107014 TI - New Compact Accommodometer to Measure Accommodation Amplitude as a Biomarker. AB - PURPOSE: This study aimed to evaluate a newly designed compact accommodometer (CA) and compare this with a conventional accommodometer for measuring accommodation as a biomarker for aging and lifestyle. DESIGN: This is an observational case series. METHODS: Accommodative amplitude was measured using 2 different accommodometers in 114 patients. We obtained the data of the near-point accommodation amplitude. Subsequently, we used smoking habit as an example of lifestyle-related factor to evaluate its effect on the accommodative power. RESULTS: The first part of the study included 60 eyes of 60 men and 54 eyes of 54 women, with a mean (SD) age of 43.8 (12.9) years (range, 18-58 years). There was a consistency within each measuring method despite a significant difference between the 2 devices (P < 0.01). Measuring accommodation by CA was significantly faster than by conventional modality (190.9 +/- 58.1 seconds for CA and 371.8 +/- 123.6 seconds for D'ACOMO, P < 0.0001, paired t test). In the second part of the study, we found a significant correlation between age and accommodative amplitude both in smokers and in nonsmokers. The accommodative amplitude of the smoker group was significantly lower than that of the nonsmoker group (P < 0.001). CONCLUSIONS: Compact accommodometer may work as an alternative and convenient method in place of the conventional accommodometer for measuring accommodative amplitude as an aging biomarker. Lifestyle factors can affect the magnitude of accommodation, which can be measured by this newly developed CA. PMID- 26107015 TI - Recent Advances and Future Challenges in Ocular Surface Reconstruction: On the Road to Translational Medicine. AB - Severe ocular surface diseases are some of the most challenging entities currently facing ophthalmologists. The purpose of this review was to describe the recent advances, current developments, and future challenges related to ocular surface reconstruction from both the basic science and clinical aspects. To date, many candidate corneal epithelial stem-cell markers for tissue-engineered culture transplants have been proposed worldwide. Several groups have reported the long term clinical results of cultivated epithelial transplantation for treating severe ocular surface disease. In an attempt to further develop the surgical procedures of ocular surface reconstruction, several groups recently reported using cells obtained from novel sources, surrounding cell substrates, and safer culture processes. As a result of the basic research and breakthroughs in the field of corneal regenerative medicine, great progress has been made in the basic understanding and development of new therapeutic tools. PMID- 26107016 TI - Acute Postoperative Endophthalmitis Following Cataract Surgery: A Review. AB - Endophthalmitis following cataract surgery is rare but continues to be a serious complication following cataract surgery. Over the years, the incidence of endophthalmitis has declined because of various preoperative and perioperative measures. They include use of antiseptic and appropriate surgical draping techniques. In this review, we have focused on the incidence, existing risk factors, various clinical features, management strategies, and prophylaxis pertaining to postoperative endophthalmitis following cataract surgery. Outcomes and pitfalls of 2 landmark studies, namely, the Endophthalmitis Vitrectomy Study and the European Society of Cataract and Refractive Surgeons Endophthalmitis Study, are briefly mentioned.Infectious endophthalmitis following cataract surgery is a dreaded complication. Preoperative identification of risk factors and effective prophylaxis could help in reducing its incidence. Early diagnosis followed by management of these patients either with vitreous tap or vitrectomy coupled with intravitreal antibiotics holds the key. PMID- 26107017 TI - An Update on Intravitreal Injections for Macular Diseases: Friend or Foe? AB - The purpose of this article is to review the role of intravitreal injections of medications in the treatment of the two common macular diseases, macular edema and age related macular degeneration (AMD). We perform literature search by search engine Pubmed till May 2011, using keywords 'intravitreal injections', 'age-related macular degeneration' and 'macular edema' to retrieve relevant review articles and original papers. To conclude, with advance in technology, intravitreal injections of medications may have become an integral part of our ability to treat a wide range of macular diseases. The use of ranibizumab, pegaptanib in the treatment of neovascular AMD and TA in the treatment of various causes of macular edema have shown promising results in a number of prospective randomized controlled trials, with low risk of complications reported. PMID- 26107018 TI - HTRA1 in Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of severe visual impairment and irreversible blindness in most developed countries, affecting more than 50 million of elderly people worldwide. Current treatments, such as intravitreal injection of antiangiogenic agents, mitigate the effect of advanced AMD but cannot completely cure the disease. Comprehensive understanding of the AMD pathological mechanisms is important for the development of new therapies. Previously, we identified a single-nucleotide polymorphism (rs11200638) in the promoter region of the high temperature requirement factor A1 (HTRA1) gene on chromosome 10q26 to be associated with exudative AMD. In further biological studies, we have provided evidence that HTRA1 could be a potential disease causing gene within the 10q26 locus. In this review, we summarize the pathology of AMD and the molecular function of the HtrA1 protein. Also evaluated are the genetic effects of HTRA1 polymorphism on AMD in different populations and interactions with other AMD-associated genes, especially with the complement factor H (CFH) gene, which was identified for nonexudative AMD. The biological roles of HtrA1 are exhaustively examined on its contribution to the multifactorial pathogenic mechanism of AMD. Although HtrA1 should play a part in AMD pathogenesis, a host of other genetic and environmental factors, known and unknown, is involved and warrants intensive future research. PMID- 26107020 TI - Quantification of hearing loss in patients with posterior semicircular canal dehiscence. AB - CONCLUSION: Patients with posterior semicircular canal dehiscence (PSCD) have low frequency conductive hearing loss similar to patients with superior semicircular canal dehiscence (SSCD) secondary to a pathologic third window. OBJECTIVES: PSCD can result in conductive hearing loss, but the magnitude of this hearing loss remains to be quantified. Patients with SSCD have been shown to have low frequency conductive hearing loss. The underlying pathophysiology of hearing loss from PSCD and SSCD is similar and related to a pathologic third window. METHOD: A PubMed search was completed for a meta-analysis of patients with PSCD. Articles with quality audiograms were obtained. Air conduction thresholds for ears with posterior semicircular canal dehiscence were compared to the opposite ear as well as normal control data. RESULTS: Eight articles with 21 patients with PSCD and quality audiograms were included. Two patients had bilateral PSCD and one of those was excluded because hearing thresholds were at the limit of the audiometer. Patients with posterior semicircular canal dehiscence have statistically significant lower air conduction thresholds in frequencies at and below 2000 Hz. PMID- 26107021 TI - Trametinib in metastatic melanoma. AB - The treatment of metastatic melanoma is rapidly changing. In 2002, the BRAF mutation was described in over 50% of melanomas and led to the first BRAF inhibitor, vemurafenib, being approved for clinical use in 2011. Clinical responses are often rapid but duration of response is limited due to the development of resistance. MEK is the next downstream target from BRAF in the MAP kinase pathway. Trametinib was the first MEK inhibitor to be approved for clinical use in 2013. Preclinical studies demonstrated a delay in resistance and a reduction in cutaneous toxicity by combined BRAF and MEK inhibition. Here, we review the rationale for clinical development of trametinib and give an update on recent clinical trials of trametinib alone and in combination with braf inhibition in melanoma. PMID- 26107022 TI - Reliability of a Single Light Source Purkinjemeter in Pseudophakic Eyes. AB - PURPOSE: To study the reliability of Purkinje image analysis for assessment of intraocular lens tilt and decentration in pseudophakic eyes. METHODS: The study comprised 64 eyes of 39 patients. All eyes underwent phacoemulsification with intraocular lens implanted in the capsular bag. Lens decentration and tilt were measured multiple times by an infrared Purkinjemeter. A total of 396 measurements were performed 1 week and 1 month postoperatively. Lens tilt (Tx, Ty) and decentration (Dx, Dy) in horizontal and vertical directions, respectively, were calculated by dedicated software based on regression analysis for each measurement using only four images, and afterward, the data were averaged (mean values, MV) for repeated sequence of measurements. New software was designed by us for recalculating lens misalignment parameters offline, using a complete set of Purkinje images obtained through the repeated measurements (9 to 15 Purkinje images) (recalculated values, MV'). MV and MV' were compared using SPSS statistical software package. RESULTS: MV and MV' were found to be highly correlated for the Tx and Ty parameters (R2 > 0.9; p < 0.001), moderately correlated for the Dx parameter (R2 > 0.7; p < 0.001), and weakly correlated for the Dy parameter (R2 = 0.23; p < 0.05). Reliability was high (Cronbach alpha > 0.9) for all measured parameters. Standard deviation values were 0.86 +/- 0.69 degrees, 0.72 +/- 0.65 degrees, 0.04 +/- 0.05 mm, and 0.23 +/- 0.34 mm for Tx, Ty, Dx, and Dy, respectively. CONCLUSIONS: The Purkinjemeter demonstrated high reliability and reproducibility for lens misalignment parameters. To further improve reliability, we recommend capturing at least six Purkinje images instead of three. PMID- 26107023 TI - Comparison of Topical Cyclosporine and Diquafosol Treatment in Dry Eye. AB - PURPOSE: To compare the treatment effects of topical cyclosporine A (CsA) and diquafosol sodium (DQS) for the treatment of moderate to severe dry eye disease (DED). METHODS: This prospective, nonrandomized, comparative study involved 60 eyes of 60 patients with moderate to severe DED who were treated with topical CsA 0.05% (group 1, 31 patients) or DQS 3% (group 2, 29 patients) in addition to artificial tears for 3 months. Before treatment, and at 1 and 3 months after treatment, the Ocular Surface Disease Index, tear breakup time, Schirmer score, tear clearance rate, and corneal and conjunctival staining scores were compared. RESULTS: Significant improvements in Ocular Surface Disease Index score, tear clearance rate, and corneal staining score were observed 1 month after treatment in group 2 (p = 0.014, p = 0.002, and p < 0.001, respectively), when compared with group 1. However, no significant differences were observed between the two groups 3 months after treatment (p > 0.05). Tear breakup times were significantly higher in group 2 compared with group 1 for the duration of the study (p < 0.001). Three months after treatment, Schirmer score was significantly higher and conjunctival staining score was significantly lower in group 1 compared with group 2 (p < 0.001). CONCLUSIONS: Both topical CsA 0.05% and DQS 3% are effective in patients with moderate to severe DED. However, the timing and degree of therapeutic effects on tear film and ocular surface parameters, as well as symptoms, can be different between the two treatments. PMID- 26107024 TI - Macular Abnormalities in Chinese Patients with Uveitis. AB - PURPOSE: To investigate the prevalence of macular abnormalities in Chinese patients affected by uveitis. METHODS: A retrospective study was performed by reviewing the medical records and high-definition spectral domain optical coherence tomography (SD-OCT) scans in a cohort of 413 uveitis eyes to assess the presence of macular abnormalities. RESULTS: Macular abnormalities were observed in 242 (58.6%) of the 413 examined eyes with uveitis. The observed macular abnormalities include diffuse macular edema, cystoid macular edema (CME), and serous retinal detachment. In addition, vitreoretinal abnormalities in the patients with uveitis were evaluated through SD-OCT. The evaluated vitreoretinal abnormalities include epiretinal membrane, tractional CME, macular adhesions, macular hole, and choroidal neovascularization. The most frequent abnormality in the uveitis patients was CME, observed in 105 eyes (25.4%), and followed by epiretinal membrane, observed in 52 eyes (12.6%). Moreover, the percentage of uveitis patients with vitreoretinal abnormalities (23.1%) was significantly high. CONCLUSIONS: Macular abnormalities were more frequently observed in uveitis compared with those in the general population. Multiple patterns of macular abnormalities indicate lesions of multilayer of cells. Therefore, when following up uveitis patients, it is highly recommended to screen with SD-OCT to evaluate the macular alterations of those patients. Careful observation of the macular abnormalities using SD-OCT may help to identify patients who are at risk for visual loss secondary to foveal changes and provide preventive treatment. PMID- 26107026 TI - Analgesic management of acute pain in the opioid-tolerant patient. AB - PURPOSE OF REVIEW: The management of acute pain in the opioid-tolerant patient is an area in perioperative medicine that is growing, as the use of opioids for chronic noncancer pain has been tolerated in the USA. Adding to this population is an increase in opioid abusers, addicts and those in recovery and maintenance programmes. These patients will continue to present for surgery and with acute pain that anaesthesiologists and other members of the healthcare team must become more adept at managing. RECENT FINDINGS: This review covers some of the strategies that may be used by practitioners in the management of acute pain in the opioid-tolerant patient. It is important to collect a detailed history of opioid and drugs of abuse, including the timing of the last dose in order to avoid precipitation of withdrawal. The use of multimodal anaesthetic and analgesic strategies is important for both patient safety and satisfaction and can enhance recovery and discharge home. SUMMARY: There is a need for more high level evidence-based guidelines to help practitioners achieve the best care of this growing high-risk population of patients. PMID- 26107025 TI - Influence of Near Tasks on Posture in Myopic Chinese Schoolchildren. AB - PURPOSE: To investigate near-vision posture in Chinese myopic schoolchildren and compare near-vision posture during different near-vision tasks (i.e., playing video games, reading, and writing). METHODS: The study investigated 120 myopic children (grades 1 through 6 and aged 6 to 13 years). An electromagnetic motion tracking system was used for continuous measurements of the working distance and head declination of the subjects while they were playing video games or reading or writing at a desk. The reading and writing documents were adjusted by grade level (i.e., grades 1 to 2, 3 to 4, and 5 to 6). For analysis, the subjects were grouped in two refractive groups according to their median spherical equivalent refractive error (-1.50D). RESULTS: The myopic schoolchildren used close working distances for all tasks: 21.3 +/- 5.2 cm (video games), 27.2 +/- 6.4 cm (reading), and 24.9 +/- 5.8 cm (writing). The mean head declinations were 63.5 +/ 12.2 deg (video games), 37.1 +/- 12.8 deg (reading), and 44.5 +/- 14.1 deg (writing). Working distance decreased significantly across time for the reading and writing tasks (p < 0.001). Head declination increased significantly across time only for the reading task (p < 0.001). Grade level significantly influenced working distance, but the difference was not significant when working distance was adjusted by the subject's size. No differences were observed within the refractive or the accommodative lag groups in terms of the posture data (p > 0.05). Working distance was negatively correlated with head declination (r = 0.53, p < 0.001). CONCLUSIONS: Close working distances were observed for Chinese myopic schoolchildren. The attention dedicated to each task, the task difficulty, and the page/screen size may affect near working distance and head declination. Handheld video games were associated with the closest working distance, which may be a risk factor for myopia progression, according to previous studies. PMID- 26107027 TI - The Role of Goniosynechialysis in the Management of Chronic Angle-Closure Glaucoma. PMID- 26107028 TI - What's New and Important in Refractive Surgery? A Year in Review. PMID- 26107029 TI - Formative Assessment of Ophthalmology Problem-Based Learning Tutorials During Undergraduate Medical Training. AB - PURPOSE: One of the major challenges lies in the use of strategies to assess students working in small groups. The assessment by tutors and peers, and self assessment by students appear to be integral parts of problem-based-learning (PBL) tutorials. Our study aimed to analyze the formative assessment scores by students themselves, their tutor and peers during undergraduate ophthalmology tutorials. DESIGN: A cross sectional study. METHODS: One hundred undergraduate students' self-assessment made during ophthalmology PBL tutorials were compared with that made by their tutor and student peers. At the end of every session, each student and student peers were given an assessment form dealing with criteria like responsibility, information processing, communication, critical analysis and self-awareness. The questionnaires were filled using the 5-point Likert scale. The tutor's assessment was made using the same criteria. RESULTS: There were significant positive correlations between self-assessment and tutor assessment in regard to participation in PBL session (P = 0.01), punctuality for each session (P <= 0.001) and bring new information (P = 0.001). There was a positive correlation between self-assessment and peer assessment regarding active participation (P = 0.02) and bringing new information (P = 0.003). However, there was no significant correlation between the overall scores given by selves and those by peers and the tutor. CONCLUSIONS: Students tended to overrate themselves. The self-assessment scores were generally higher than those given by their tutor and peers. To foster evidence-based practice of ophthalmology, the information acquisition skills need to be improved. PMID- 26107030 TI - Comparison of Combined Phacoemulsification, Intraocular Lens Implantation, and Goniosynechialysis With Phacotrabeculectomy in the Treatment of Primary Angle Closure Glaucoma and Cataract. AB - PURPOSE: This study aimed to compare the efficacy and safety of combined phacoemulsification, intraocular lens implantation, and goniosynechialysis with phacotrabeculectomy in the treatment of primary angle-closure glaucoma (PACG) and cataract. DESIGN: A comparative case series. METHODS: Sixty-five patients (65 eyes) with PACG and cataract from the Fifth Affiliated Hospital of Sun Yat-Sen University were enrolled for this study between October 2009 and July 2011. Of these, 33 underwent combined phacoemulsification, intraocular lens implantation, and goniosynechialysis (treatment group), and 32 underwent phacotrabeculectomy (control group). The effects on intraocular pressure, best-corrected visual acuity, anterior chamber angle, number of antiglaucoma medications, and complications were evaluated. RESULTS: Both the treatment group and the control group had lowered intraocular pressure, reduced the use of antiglaucoma medications, and improved vision in patients with PACG and cataract. Complications were 8 (24.2%) of 33 in the treatment group and 12 (37.5%) of 32 in the control group. CONCLUSIONS: Combined phacoemulsification, intraocular lens implantation, and goniosynechialysis appears to be a preferred method for the treatment of PACG and cataract because it seems to have the same efficacy as phacotrabeculectomy and has much less surgical complications. PMID- 26107031 TI - Management of Rheumatoid Arthritis-Related Peripheral Ulcerative Keratitis Using Glycerol-Preserved Corneas. AB - PURPOSE: This study aimed to report the surgical outcome of patch grafts using glycerol-preserved corneas in perforated or near-perforated rheumatoid arthritis related peripheral ulcerative keratitis (PUK). DESIGN: This is a retrospective chart review of a case series. METHODS: The medical records at a single institution were reviewed between July 2004 and July 2011. Of the 19 patients with PUK, 7 (36.8%) underwent glycerol-preserved cornea patch grafts for rheumatoid arthritis-related PUK. The clinical features, precipitating factors, adjuvant therapy, and therapeutic outcomes were analyzed. RESULTS: The age of patients ranged from 49 to 82 years (mean [SD], 64.43 [13.53] years) for the 4 women and 3 men with perforated or near-perforated PUK who were managed with systemic and local immunosuppressive therapy. A wound culture revealed 1 Staphylococcus aureus and 1 filamentary fungal infection. The mean (SD) area of the graft was 13.28 (6.11) mm; the mean (SD) time to reepithelializaiton was 7.0 (1.60) days. One patient had high intraocular pressure managed by topical medication; another had a complicated cataract formation. One graft melting was successfully managed by topical and systemic medication. CONCLUSIONS: Glycerol preserved cornea patch grafts were successful in all patients and may be a viable option in perforated or near-perforated PUK, particularly when fresh donor corneas are neither available nor indicted. PMID- 26107032 TI - Characteristics of Patients Who Drop Out From Ranibizumab Therapy. AB - PURPOSE: Anti-vascular endothelial growth factor therapy is a first-line treatment for age-related macular degeneration, but frequent visits and injections can be a burden for patients. This study aimed to estimate the dropout rate and tolerability of ranibizumab therapy in a clinical setting. DESIGN: A retrospective case-control study. METHODS: We investigated 250 eyes with choroidal neovascular membranes who underwent anti-vascular endothelial growth factor therapy in a single practice from July 1, 2008, to June 30, 2010. Clinical characteristics of patients who dropped out of treatment (n = 85) were recorded and compared with patients who continued with follow-up (n = 165). RESULTS: The dropout rate from follow-up was 34.5%. The dropout rate was not significantly different between age groups, but there was a trend increasing dropout with increasing age. Dropout rate did not differ between sexes. Dropout rate was significantly higher (50.0%) in those living farther than 100 km from the clinic, compared with those who lived within 100 km (28.0%; odds ratio, 2.48). Patients with no other systemic diseases were also seen to drop out at a significantly higher rate (48.7%; P < 0.04). Financial status did not appear to affect dropout rate. CONCLUSIONS: Dropout of ranibizumab therapy was higher among patients who lived far from the clinic, those referred with a diagnosis of age-related macular degeneration, and patients with other health problems. The dropout rate from this clinic was 34.5%. These findings have implications in the planning of interventions to improve the follow-up of patients with blinding eye disease. PMID- 26107033 TI - Specialist Nurse Screening for Retinopathy of Prematurity-A Pilot Study. AB - PURPOSE: To compare the accuracy of retinopathy of prematurity (ROP) screening between nurse specialists and an expert pediatric ophthalmologist. DESIGN: A comparative case series of ROP screening in a level 2 neonatal intensive care unit setting where there is a higher threshold for accepting very premature or unwell neonates. METHODS: Trained specialist ROP nurses acquired wide-field digital images, graded ROP, and proposed a follow-up plan. This was compared with the findings by an ROP expert ophthalmologist. Outcomes include sensitivity, specificity, positive predictive value, and negative predictive value of ROP grading by trained ROP nurses. RESULTS: Mean gestational age was 28.6 weeks, and mean birth weight was 1184 g of the 64 consecutive neonates included. A total 316 eye screens was performed. Image acquisition, grading, and a management plan by the ROP nurse were possible in all screens. In right eyes, the presence of any ROP (stage >0) was 15%. Sensitivity, specificity, positive predictive value, and negative predictive value of ROP grading were 91.7% (95% CI, 73%-99%), 80.6% (95% CI, 72.9%-86.9%), 45.8% (95% CI, 31.4%-60.80%), and 98.2% (95% CI, 93.6%-99.8%), respectively. Agreement on the management plan occurred in 84.8% of cases. In virtually all circumstances of disagreement, ROP nurses exaggerated the ROP grading present and/or recommended a repeat screen when discharge from service was more appropriate. CONCLUSIONS: Our preliminary findings demonstrated good agreement between ROP nurses and the ROP expert ophthalmologist. Further research in expanding the role of utilizing nonphysician health workers in ROP screening is suggested. PMID- 26107034 TI - Tapping of Macular Hole Edges: The Outcomes of a Novel Technique for Large Macular Holes. AB - PURPOSE: To describe the novel technique of tapping macular hole edges for holes with low macular hole index (MHI) and assess its outcomes. DESIGN: A prospective interventional study. METHODS: Twenty-eight consecutive eyes with idiopathic large macular holes (MHI < 0.5) were enrolled. A standardized surgical protocol was performed using vitrectomy with brilliant blue G dye-assisted large internal limiting membrane peeling, intraocular gas tamponade with 18% C3F8, and strict postoperative prone positioning for 5 days. Tapping of macular hole edges was performed on all sides using 23-gauge GreenTip soft tip cannula. Hole closure was examined postoperatively using optical coherence tomography. RESULTS: There were 16 females and 12 males aged 63 +/- 14.38 years. The mean MHI was 0.32. Hole closure was seen in 25 eyes (89.29%). MHI was less than 0.25 in the 3 eyes with failed macular hole surgery. Epiretinal membrance (ERM) was present in 22 eyes (78.57%). The presence of ERM did not correlate with hole closure (P = 1.00). Continuity of external limiting membrane was a better predictor of functional success than inner segment/outer segment continuity (P < 0.05). Type I hole closure was seen in 20 (80%) of 25 eyes while the remaining 5 eyes (20%) had type II hole closure on optical coherence tomography. Corrected distance visual acuity improved significantly from 0.86 +/- 0.2 logMAR preoperatively 0.43 +/- 0.22 logMAR postoperatively (P < 0.0001). CONCLUSIONS: Newer technique of tapping macular hole edges provides acceptable anatomical and functional success rates even in large macular holes (MHI< 0.5). PMID- 26107035 TI - Screening and Referral of Diabetic Retinopathy: A Comparative Review of the Practice Guidelines. AB - Diabetic retinopathy (DR) is a leading cause of preventable visual impairment in the working age group. The major risk factors for development and progression are duration of disease and the severity of hyperglycemia. The Global Diabetic Retinopathy Project developed a new classification system for DR and macular edema to enhance communication and coordination among the multidisciplinary team of physicians taking care of diabetic patients. Diabetic retinopathy progresses from nonproliferative DR to proliferative DR through a series of stages. Early detection and timely referral are critical for timely interventions to prevent further deterioration. Primary care physicians have an integral role in the community as they are the first point of contact for patients. Guidelines from various associations provide recommendations to physicians taking care of diabetic patients on how to screen and situations where referral to an ophthalmologist is needed. Dilated direct ophthalmoscopy is a convenient method to assess the fundus, but it does not replace retinal photography in the screening of DR. All patients with proliferative DR and diabetic macular edema should be referred to an ophthalmologist, whereas the situation for nonproliferative DR remains unclear as no consensus was drawn from the various guidelines. PMID- 26107036 TI - Advances in Refractive Surgery. AB - PURPOSE: The objective of this study was to review advances in the field of refractive surgery as reported in the peer-reviewed literature over the previous year. DESIGN: This was a literature review. METHODS: We conducted a PubMed search for terms related to refractive surgery and reviewed prominent international ophthalmic journals published from May 2012 through April 2013. All pertinent articles were reviewed, and selected articles with the greatest relevance were included. RESULTS: Many studies over the previous year have highlighted progress in the field of refractive surgery; topics included keratoconus screening, photorefractive keratectomy and laser in situ keratomileusis, corneal cross linking, small-incision lenticule extraction, phakic intraocular lenses, corneal inlays, presbyopic corneal treatments, and femtosecond laser-assisted astigmatic keratotomy. CONCLUSIONS: The field of refractive surgery continues to provide exciting developments. Improvements in established procedures and promising new surgical options make the current climate an appealing one for refractive surgeons and patients. PMID- 26107037 TI - Recent Advances in Ophthalmic Plastic Surgery: Part 1-Eyelid. AB - PURPOSE: The objective of this study was to provide an update of the current literature in ophthalmic and facial plastic surgery, specifically related to disorders of the eyelid. DESIGN: This was a review of published literature from January 2012 to June 2013 METHODS: The authors conducted a PubMed literature search of English-language articles published between January 2012 and June 2013 using the following search terms: eyelid, congenital, acquired, infection, inflammation, trauma, tumor, ptosis, entropion, ectropion, lagophthalmos, botulinum toxin, fillers, blepharoplasty, and miscellaneous topics related to the disorders of the eyelid. The authors included original articles, review articles, and case reports with relevant new information that is of potential clinical use to a comprehensive ophthalmologist as well as to the subspecialist. RESULTS: Current literature on the disorders of the eyelid is replete with useful clinical information of relevance to a practicing ophthalmologist. Major advances have been reported in understanding of the surgical anatomy and its applications, ptosis, entropion, ectropion, lagophthalmos, infection, inflammation, trauma, and tumors. CONCLUSIONS: There seems to be tremendous excitement in revisiting the anatomy and pathology and modifying the management protocols and surgical procedures to achieve optimal results, as the subspecialty continues to advance at a brisk pace. PMID- 26107038 TI - Letter to the Editor Regarding "Conjunctival Rotation Autograft: An Alternative to Conventional Conjunctival Autografting". PMID- 26107039 TI - Authors' Reply. PMID- 26107040 TI - Letter to the Editor Regarding the Article Entitled "Association of Height With Pattern Reversal Visual Evoked Potentials". PMID- 26107041 TI - Reply to the Letter to the Editor Regarding the Article Entitled "Association of Height With Pattern Reversal Visual Evoked Potentials". PMID- 26107042 TI - Impact of Varying the Parameters of Stimulation of 2 Commonly Used Waveforms on Muscle Force Production and Fatigue. AB - STUDY DESIGN: Laboratory-based experimental study using a repeated-measures design. OBJECTIVES: To determine the effect of varying stimulation parameters of burst-modulated alternating current (BMAC) and pulsed current (PC) on quadriceps femoris muscle force output and fatigue. BACKGROUND: The impact of altering stimulation parameters on muscle force and fatigue using PC has been well described; however, less is known regarding BMAC. METHODS: Quadriceps femoris muscle force was measured during a series of neuromuscular electrical stimulation induced muscle contractions, with varying combinations of pulse duration and frequency, using PC or varying duty cycles and burst frequencies using BMAC. Additionally, muscle fatigue tests were conducted bilaterally with different stimulation waveforms and parameters. RESULTS: For PC, the product of pulse duration and frequency was strongly predictive of muscle force output (R(2) = 0.85, P<.05). When using BMAC, the duty cycle was a strong predictor of force output (R(2) = 0.91, P<.05). Altering the frequency during BMAC had no effect on muscle force production, as opposed to the classic force-frequency relationship consistently observed with PC. Waveform type significantly impacts muscle fatigue, the BMAC resulted in a more rapid rate of fatigue irrespective of stimulation frequency, and it was confirmed again that lower frequencies of PC result in less fatigue during repeated muscle contractions. CONCLUSION: In this study, altering the burst frequency of BMAC did not influence muscle force or fatigue, whereas the duty cycle significantly impacted muscle force production. Frequency of PC impacted both force and fatigue as expected, demonstrating increased muscle force and fatigue with increased frequency. PMID- 26107043 TI - Dynamic Balance Deficits 6 Months Following First-Time Acute Lateral Ankle Sprain: A Laboratory Analysis. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVE: To utilize kinematic and stabilometric measures to compare dynamic balance during performance of the Star Excursion Balance Test between persons 6 months following first-time lateral ankle sprain (LAS) and a noninjured control group. BACKGROUND: Biomechanical evaluation of dynamic balance in persons following first-time LAS during performance of the Star Excursion Balance Test could provide insight into the mechanisms by which individuals proceed to recover fully or develop chronic ankle instability. METHODS: Sagittal plane kinematics of the lower extremity and the center-of-pressure path during the performance of the anterior, posterolateral, and posteromedial reach directions of the Star Excursion Balance Test were obtained from 69 participants 6 months following first-time acute LAS and from a control group of 20 noninjured participants. RESULTS: Compared to the control group, the LAS group displayed lower normalized reach distances in all 3 reach directions on the injured and noninjured limbs, with the largest observed effect size in the posterolateral direction (P = .001, etap(2) = 0.07). The performance impairment was associated with less hip and knee flexion and ankle dorsiflexion at the point of maximum reach (P<.02), and coincided with less complexity of the center-of-pressure path (P<.05). CONCLUSION: Participants with a 6-month history of LAS exhibit a persistence of deficits previously established in the acute phase of injury. PMID- 26107044 TI - Diagnostic Accuracy of the Slump Test for Identifying Neuropathic Pain in the Lower Limb. AB - STUDY DESIGN: Diagnostic accuracy study with nonconsecutive enrollment. OBJECTIVES: To assess the diagnostic accuracy of the slump test for neuropathic pain (NeP) in those with low to moderate levels of chronic low back pain (LBP), and to determine whether accuracy of the slump test improves by adding anatomical or qualitative pain descriptors. BACKGROUND: Neuropathic pain has been linked with poor outcomes, likely due to inadequate diagnosis, which precludes treatment specific for NeP. Current diagnostic approaches are time consuming or lack accuracy. METHODS: A convenience sample of 21 individuals with LBP, with or without radiating leg pain, was recruited. A standardized neurosensory examination was used to determine the reference diagnosis for NeP. Afterward, the slump test was administered to all participants. Reports of pain location and quality produced during the slump test were recorded. RESULTS: The neurosensory examination designated 11 of the 21 participants with LBP/sciatica as having NeP. The slump test displayed high sensitivity (0.91), moderate specificity (0.70), a positive likelihood ratio of 3.03, and a negative likelihood ratio of 0.13. Adding the criterion of pain below the knee significantly increased specificity to 1.00 (positive likelihood ratio = 11.9). Pain-quality descriptors did not improve diagnostic accuracy. CONCLUSION: The slump test was highly sensitive in identifying NeP within the study sample. Adding a pain-location criterion improved specificity. Combining the diagnostic outcomes was very effective in identifying all those without NeP and half of those with NeP. Limitations arising from the small and narrow spectrum of participants with LBP/sciatica sampled within the study prevent application of the findings to a wider population. LEVEL OF EVIDENCE: Diagnosis, level 4-. PMID- 26107045 TI - Validity of Activity Monitor Step Detection Is Related to Movement Patterns. AB - BACKGROUND: There is a need to examine step-counting accuracy of activity monitors during different types of movements. The purpose of this study was to compare activity monitor and manually counted steps during treadmill and simulated free-living activities and to compare the activity monitor steps to the StepWatch (SW) in a natural setting. METHODS: Fifteen participants performed laboratory-based treadmill (2.4, 4.8, 7.2 and 9.7 km/h) and simulated free-living activities (eg, cleaning room) while wearing an activPAL, Omron HJ720-ITC, Yamax Digi- Walker SW-200, 2 ActiGraph GT3Xs (1 in "low-frequency extension" [AGLFE] and 1 in "normal-frequency" mode), an ActiGraph 7164, and a SW. Participants also wore monitors for 1-day in their free-living environment. Linear mixed models identified differences between activity monitor steps and the criterion in the laboratory/free-living settings. RESULTS: Most monitors performed poorly during treadmill walking at 2.4 km/h. Cleaning a room had the largest errors of all simulated free-living activities. The accuracy was highest for forward/rhythmic movements for all monitors. In the free-living environment, the AGLFE had the largest discrepancy with the SW. CONCLUSION: This study highlights the need to verify step-counting accuracy of activity monitors with activities that include different movement types/directions. This is important to understand the origin of errors in step-counting during free-living conditions. PMID- 26107046 TI - Improvement of Parameters of the AMBER Potential Force Field for Phospholipids for Description of Thermal Phase Transitions. AB - In this study, we improved parameters of the AMBER potential force field for phospholipids in order to describe the thermal phase transition using molecular dynamic (MD) simulations. To estimate the errors of the main phase transition temperature (Tm), first, MD simulations using the GAFFlipid and Gaff parameters were performed for six phospholipid bilayers, 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-distearoyl-sn-glycero-3 phosphocholine (DSPC), 1-palmitoyl,2-oleoyl-sn-glycero-3-phosphocholine (POPC), and 1-palmitoyl,2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), with increasing temperature. The Tm values were characterized according to the structural parameter, area per lipid, and gauche ratio in alkyl chains. The Tm values of the six lipids showed ~50 K differences from the experimentally measured values. To reduce these errors, the well-depth values in the Lennard-Jones potential of the alkyl chains were modified to fit the Tm values of the simulation to the experimental values in a single DPPC bilayer. After the fitting procedure, the Tm values of the six lipids improved, and the errors of Tm improved from ~50 to ~15 K. We show that the simulation applying the improved parameters provides more accurate results than the original parameters. These modified parameters were also found to be useful for performing MD simulation of transmembrane proteins with membrane models. PMID- 26107047 TI - Age and Gender Effects on Wideband Absorbance in Adults With Normal Outer and Middle Ear Function. AB - PURPOSE: This study examined the effects of age and gender on wideband energy absorbance in adults with normal middle ear function. METHOD: Forty young adults (14 men, 26 women, aged 20-38 years), 31 middle-aged adults (16 men, 15 women, aged 42-64 years), and 30 older adults (20 men, 10 women, aged 65-82 years) were assessed. Energy absorbance (EA) data were collected at 30 frequencies using a prototype commercial instrument developed by Interacoustics. RESULTS: Results showed that the young adult group had significantly lower EA (between 400 and 560 Hz) than the middle-aged group. However, the middle-aged group showed significantly lower EA (between 2240 and 5040 Hz) than the young adult group. In addition, the older adult group had significantly lower EA than the young adult group (between 2520 and 5040 Hz). No significant difference in EA was found at any frequency between middle-aged and older adults. Across age groups, gender differences were found with men having significantly higher EA values than women at lower frequencies, whereas women had significantly higher EA at higher frequencies. CONCLUSIONS: This study provides evidence of the influence of gender and age on EA in adults with normal outer and middle ear function. These findings support the importance of establishing age- and gender-specific EA norms for the adult population. PMID- 26107048 TI - Arm Ischemia and Posterior Stroke in a Patient With a Pulsatile Mass in the Right Upper Side of Chest. Innominate artery pseudoaneurysm. PMID- 26107050 TI - Comparison of Redox Activity between 2-Aminothioether and 2-Aminothiophenol: Redox-Induced Dimerization of 2-Aminothioether via C-C Coupling. AB - Three chemical reactions of two 2-aminothioethers and 2-aminothiophenol with CpRu(II)Cl(PPh3)2 (Cp(-) = cyclopentadienyl anion), under identical reaction conditions, are reported. While 2-(methylthio)aniline, H2L(1) and an analogous substrate, 2-(phenylthio)aniline yielded dicationic dinuclear complexes [(PPh3)CpRu(II)(L(3/)L(4))Ru(II)Cp(PPh3)]Cl2 (where L(3) = (4E)-4-(4-imino-3 (methylthio)cyclohexa-2,5-dienylidene)-2-(methylthio)cyclohexa-2,5-dienimine ([1a]Cl2) and L(4) = (4E)-4-(4-imino-3-(phenylthio)cyclohexa-2,5-dienylidene)-2 (phenylthio)cyclohexa-2,5-dienimine ([1b]Cl2)), the reaction with 2 aminothiophenol (H2L(2)) produced a mononuclear complex [(PPh3)CpRu(II)(L(2))]Cl (where L(2) = 6-iminocyclohexa-2,4-dienethione) ([2]Cl). All these complexes are obtained in high yields (65%-75%). Formations of the products from the above reactions involve a similar level of oxidation of the respective substrate, although their courses are completely different. A comparison between the above two chemical transformations are scrutinized thoroughly. Characterizations of these complexes were made using a host of physical methods: X-ray crystallography, nuclear magnetic resonance (NMR), cyclic voltammetry, ultraviolet-visible (UV-vis), electron paramagnetic resonance (EPR) spectroscopy, and density functional theory (DFT). The complexes [1a]Cl2 and [1b]Cl2 showed intense metal-to-ligand charge transfer transition in the long wavelength region of the spectrum, at 860 and 895 nm, respectively, and displayed two reversible electron transfer (ET) processes at [1a](2+): -0.28 and -0.52 V; [1b](2+): -0.13 and -0.47 V, along with an irreversible ET process at 0.76 and 0.54 V, respectively. The ET processes at negative potentials are due to successive reductions of the bridging ligand, which are characterized by EPR and UV-vis spectroscopy. The one-electron reduced compound, [1a](+), showed a intraligand charge transfer transition (ILCT) at 1530 nm. The complex [2](+) showed a reversible ET process at -0.36 V and two irreversible ET processes at -1.04 and 1.18 V, respectively. DFT calculations were used to support the spectral and redox properties of the complexes and also to throw light on the difference of redox behavior between thioether and thiophenol substrates. PMID- 26107049 TI - Using Edge Voxel Information to Improve Motion Regression for rs-fMRI Connectivity Studies. AB - Recent fMRI studies have outlined the critical impact of in-scanner head motion, particularly on estimates of functional connectivity. Common strategies to reduce the influence of motion include realignment as well as the inclusion of nuisance regressors, such as the 6 realignment parameters, their first derivatives, time shifted versions of the realignment parameters, and the squared parameters. However, these regressors have limited success at noise reduction. We hypothesized that using nuisance regressors consisting of the principal components (PCs) of edge voxel time series would be better able to capture slice specific and nonlinear signal changes, thus explaining more variance, improving data quality (i.e., lower DVARS and temporal SNR), and reducing the effect of motion on default-mode network connectivity. Functional MRI data from 22 healthy adult subjects were preprocessed using typical motion regression approaches as well as nuisance regression derived from edge voxel time courses. Results were evaluated in the presence and absence of both global signal regression and motion censoring. Nuisance regressors derived from signal intensity time courses at the edge of the brain significantly improved motion correction compared to using only the realignment parameters and their derivatives. Of the models tested, only the edge voxel regression models were able to eliminate significant differences in default-mode network connectivity between high- and low-motion subjects regardless of the use of global signal regression or censoring. PMID- 26107051 TI - Medical Facts versus Value Judgments--Toward Preference-Sensitive Guidelines. PMID- 26107052 TI - Breaking the Silence of the Switch--Increasing Transparency about Trainee Participation in Surgery. PMID- 26107054 TI - IMAGES IN CLINICAL MEDICINE. Nevus Comedonicus. PMID- 26107053 TI - CLINICAL PRACTICE. Advanced Dementia. PMID- 26107055 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 20-2015. A Newborn Girl with Hypotension, Coagulopathy, Anemia, and Hyperbilirubinemia. PMID- 26107056 TI - The Elusive Right to Health Care under U.S. Law. PMID- 26107057 TI - TREM2 and Risk of Alzheimer's Disease--Friend or Foe? PMID- 26107058 TI - A 9-Valent HPV Vaccine in Women. PMID- 26107059 TI - A 9-Valent HPV Vaccine in Women. PMID- 26107060 TI - A 9-Valent HPV Vaccine in Women. PMID- 26107061 TI - A 9-Valent HPV Vaccine in Women. PMID- 26107062 TI - A 9-Valent HPV Vaccine in Women. PMID- 26107063 TI - A 9-Valent HPV Vaccine in Women. PMID- 26107064 TI - Viscosupplementation for Osteoarthritis of the Knee. PMID- 26107065 TI - Viscosupplementation for Osteoarthritis of the Knee. PMID- 26107066 TI - Viscosupplementation for Osteoarthritis of the Knee. PMID- 26107067 TI - Viscosupplementation for Osteoarthritis of the Knee. PMID- 26107068 TI - IMAGES IN CLINICAL MEDICINE. Ping-Pong Gaze. PMID- 26107069 TI - INTERACTIVE MEDICAL CASE. A Stinging Sensation. PMID- 26107070 TI - Ruthenium-Catalyzed Asymmetric Hydrohydroxyalkylation of Butadiene: The Role of the Formyl Hydrogen Bond in Stereochemical Control. AB - The catalyst generated in situ from RuH2(CO)(PPh3)3, (S)-SEGPHOS, and a chiral phosphoric acid promotes asymmetric hydrohydroxyalkylation of butadiene and affords enantioenriched alpha-methyl homoallylic alcohols. The observed diastereo and enantioselectivities are determined by both the chiral phosphine and chiral phosphate ligands. Density functional theory calculations (M06/SDD-6-311G(d,p) IEFPCM(acetone)//B3LYP/SDD-6-31G(d)) predict that the product distribution is controlled by the kinetics of carbon-carbon bond formation, and this process occurs via a closed-chair Zimmerman-Traxler-type transition structure (TS). Chiral-phosphate-dependent stereoselectivity arising from this TS is enabled through a hydrogen bond between the phosphoryl oxygen and the aldehyde formyl proton present in TADDOL-derived catalysts. This interaction is absent in the corresponding BINOL-derived systems, and the opposite diastereo- and enantioselectivity is observed. Additional factors influencing the stereochemical control are determined. PMID- 26107072 TI - Thermodynamic parameters of cation exchange in MOF-5 and MFU-4l. AB - We present a method for approximating thermodynamic parameters DeltaG(P,T) degrees , DeltaH, and DeltaS for the cation exchange process in metal-organic frameworks, as exemplified by Ni(2+) exchange into Zn4O(1,4 benzenedicarboxylate)3 (MOF-5) and Co(2+) exchange into MOF-5 and Zn5Cl4(bis(1H 1,2,3-triazolo-[4,5-b],[4',5'-i])dibenzo-[1,4]-dioxin)3 (MFU-4l). For these examples, we find that the cation exchange process is endergonic and that parameters such as solvent and cation identity impact the thermodynamics. PMID- 26107071 TI - Predicting the Solubility Advantage of Amorphous Pharmaceuticals: A Novel Thermodynamic Approach. AB - For the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) to be improved, the transformation of crystalline APIs to the amorphous state has often been shown to be advantageous. As it is often difficult to measure the solubility of amorphous APIs, the application of thermodynamic models is the method of choice for determining the solubility advantage. In this work, the temperature-dependent solubility advantage of an amorphous API versus its crystalline form was predicted for five poorly soluble APIs in water (glibenclamide, griseofulvin, hydrochlorothiazide, indomethacin, and itraconazole) based on modeling the API/solvent phase diagrams using the perturbed-chain statistical associating fluid theory (PC-SAFT). Evaluation of the performance of this approach was performed by comparing the predicted solubility advantage to experimental data and to the solubility advantage calculated by the commonly applied Gibbs-energy-difference method. For all of the systems considered, PC-SAFT predictions of the solubility advantage are significantly more accurate than the results obtained from the Gibbs-energy-difference method. PMID- 26107073 TI - CoDAS. Editorial. PMID- 26107074 TI - Screening for oropharyngeal dysphagia. PMID- 26107075 TI - Comparison of students from private and public schools on the spelling performance. AB - OBJECTIVE: To compare the spelling ability of schoolchildren from the fourth to sixth grades of the elementary schools in the private and public schools of Bauru, Sao Paulo, and to verify whether errors are overcome as studies progress and the hierarchy of errors as to how often they occur. METHODS: A dictation was applied to 384 schoolchildren: 206 from the private schools: 74 were at the fourth grade, 65 at the fifth grade, and 67 at the sixth grade; and 178 from the public schools; 56 at the fourth grade, 63 at the fifth grade, and 59 at the sixth grade of elementary school. Student's t test was used. RESULTS: In comparison of total spelling errors score, difference was found among the fourth and sixth grades of the private and public schools. Spelling errors decreased as education progressed, and those related to language irregularities were more common. CONCLUSION: Spelling ability and performance of students from the private and public schools are not similar in the fourth and sixth grades, but it is in the fifth grade. Spelling errors are gradually overcome as education progresses; however, this overcome rate was considerable between the fourth and fifth grades in the public schools. Decrease in the types of spelling errors follows a hierarchy of categories: phoneme/grapheme conversion, simple contextual rules, complex contextual rules, and language irregularities. Finally, the most common type of spelling error found was that related to language irregularities. PMID- 26107076 TI - Language evaluation protocol for children aged 2 months to 23 months: analysis of sensitivity and specificity. AB - PURPOSE: To establish cutoff points for the analysis of the Behavior Observation Form (BOF) of children in the ages of 2 to 23 months and evaluate the sensitivity and specificity by age group and domains (Emission, Reception, and Cognitive Aspects of Language). METHODS: The sample consisted of 752 children who underwent BOF. Each child was classified as having appropriate language development for the age or having possible risk of language impairment. Performance Indicators (PI) were calculated in each domain as well as the overall PI in all domains. The values for sensitivity and specificity were also calculated. The cutoff points for possible risk of language impairment for each domain and each age group were obtained using the receiver operating characteristics curve. RESULTS: The results of the study revealed that one-third of the assessed children have a risk of language impairment in the first two years of life. The analysis of BOF showed high sensitivity (>90%) in all categories and in all age groups; however, the chance of false-positive results was higher than 20% in the majority of aspects evaluated. It was possible to establish the cutoff points for all categories and age groups with good correlation between sensitivity and specificity, except for the age group of 2 to 6 months. CONCLUSION: This study provides important contributions to the discussion on the evaluation of the language development of children younger than 2 years. PMID- 26107077 TI - Efficacy of a perceptual and visual-motor skill intervention program for students with dyslexia. AB - PURPOSE: To verify the efficacy of a perceptual and visual-motor skill intervention program for students with dyslexia. METHODS: The participants were 20 students from third to fifth grade of a public elementary school in Marilia, Sao Paulo, aged from 8 years to 11 years and 11 months, distributed into the following groups: Group I (GI; 10 students with developmental dyslexia) and Group II (GII; 10 students with good academic performance). A perceptual and visual motor intervention program was applied, which comprised exercises for visual motor coordination, visual discrimination, visual memory, visual-spatial relationship, shape constancy, sequential memory, visual figure-ground coordination, and visual closure. In pre- and post-testing situations, both groups were submitted to the Test of Visual-Perceptual Skills (TVPS-3), and the quality of handwriting was analyzed using the Dysgraphia Scale. RESULTS: The analyzed statistical results showed that both groups of students had dysgraphia in pretesting situation. In visual perceptual skills, GI presented a lower performance compared to GII, as well as in the quality of writing. After undergoing the intervention program, GI increased the average of correct answers in TVPS-3 and improved the quality of handwriting. CONCLUSION: The developed intervention program proved appropriate for being applied to students with dyslexia, and showed positive effects because it provided improved visual perception skills and quality of writing for students with developmental dyslexia. PMID- 26107078 TI - Communication skills in individuals with spastic diplegia. AB - PURPOSE: To assess communication skills in children with spastic diplegia. METHODS: The study included 20 subjects, 10 preschool children with spastic diplegia and 10 typical matched according to gender, mental age, and socioeconomic status. Assessment procedures were the following: interviews with parents, Stanford - Binet method, Gross Motor Function Classification System, Observing the Communicative Behavior, Vocabulary Test by Peabody Picture, Denver Developmental Screening Test II, MacArthur Development Inventory on Communicative Skills. Statistical analysis was performed using the values of mean, median, minimum and maximum value, and using Student's t-test, Mann-Whitney test, and Paired t-test. RESULTS: Individuals with spastic diplegia, when compared to their peers of the same mental age, presented no significant difference in relation to receptive and expressive vocabulary, fine motor skills, adaptive, personal social, and language. The most affected area was the gross motor skills in individuals with spastic cerebral palsy. The participation in intervention procedures and the pairing of participants according to mental age may have approximated the performance between groups. CONCLUSION: There was no statistically significant difference in the comparison between groups, showing appropriate communication skills, although the experimental group has not behaved homogeneously. PMID- 26107079 TI - Comparative study of the imitation ability in Specific Language Impairment and Autism Spectrum Impairment. AB - PURPOSE: To compare abilities of imitating generic and sequential motion gesture schemes in family routines among children with Autism Spectrum Disorder (ASD) and Specific Language Impairment (SLI) and to analyze the relation between imitation index and verbal production in the ASD group. METHODS: The sample was constituted by 2:1 pairing of 36 children, according to gender and age. All of them were diagnosed by a multidisciplinary team as belonging to the ASD group (n=24) or SLI group (n=12) and were under direct and indirect intervention in a school clinic. We have used the stage of imitation of the Assessment of Symbolic Maturity, which entails the imitation of nine generic and three sequential motion gesture schemes. RESULTS: There was a tendency to a better performance of the SLI group at imitating both generic and sequential gesture schemes. As we have related the ability of imitation to the verbal production in the ASD group, a direct relation between the production of phrases and the imitation of sequential schemes was detected. CONCLUSION: The ability to imitate gesture and sequential schemes could be compared, and a more prominent impairment was identified in children with autism. Among them, a direct significant relationship between the ability of imitating sequential gesture schemes in family routine and verbal production of words and sentences was verified. PMID- 26107080 TI - Proposal for implementing the Sentence Recognition Index in individuals with hearing disorders. AB - PURPOSE: To present and describe a new strategy and protocol for obtaining the Sentences Recognition Indexes (SRI), using the Lists of Phrases in Portuguese test (LPP), considering words in the analysis of responses; to analyze and compare the results using the previous and the new strategies by checking their applicability and suitability. METHODS: To consider each word of the sentence, words were classified according to their importance: functional and content words, assigning them, respectively, two and one points. SRI were obtained in 33 normal hearing adults, and results were compared using the two strategies. RESULTS: A new protocol was established. Each point corresponds to the following percentages in each list: 1B, 1.11%; 2B, 1.13%; 3B, 1.17%; 4B, 1.16%; 5B, 1.20%; and 6B, 1.11%. The median SRI obtained through usual and new strategies were, respectively, for the list 1B: 60 and 82.57%; 2B: 70 and 80.79%; 3B: 50 and 76.60%; 4B: 70 and 82.60%; 5B: 50 and 77.20%; and 6B: 60 and 82.14%. A significant difference was found when these strategies were compared. CONCLUSION: New strategy and protocol for evaluating the SRI were developed using the LPP test, considering each word of the sentence. When comparing the responses it was noticed that when considering each word in the sentence it is possible to scale, more detailed and less variability, the actual ability to recognize speech of each individual, the new strategy and protocol developed confirmed its applicability and suitability to assess Sentence Recognition Indexes in Quiet in individuals with hearing disorders in a specific listening condition. PMID- 26107081 TI - Auditory brainstem response in gerbils submitted to ischemia and sepsis. AB - INTRODUCTION: An ischemic stroke is a clinical condition that affects thousands of people worldwide. As a result of this injury, neuronal death can be observed, and in the natural course of recovery, the individual may develop sepsis. Sepsis is a systemic inflammatory response that can lead the patient to death. To assess the clinical condition of a patient with this condition, the Auditory Brainstem Response (ABR) can be useful, since it is not an invasive procedure, it is a fast technique and it can be done at the bedside. PURPOSE: To assess auditory brainstem response (ABR) latency values in gerbils subjected to ischemia and sepsis. METHODS: ABR values were collected from 72 adult male gerbils, which were divided into six groups: control, sepsis, ischemia, sham, ischemia with sepsis, and sham with sepsis. For the induction of sepsis, lipopolysaccharide (LPS) was applied intraperitoneally in gerbils. The animals were anesthetized with a ketamine/xylazine combination before collection; their ABR were collected before any procedure (base collection), after ischemia, and 24 hours after the application of LPS. The absolute latency of wave IV was evaluated, and the values were compared between groups. RESULTS: There were significant differences in the groups submitted to sepsis in the latency value of wave IV in relation with the other groups. CONCLUSION: ABR was sensitive to sepsis with the increase in latency of wave IV during the development of the disease in the experimental model used. PMID- 26107082 TI - Executives' speech expressiveness: analysis of perceptive and acoustic aspects of vocal dynamics. AB - PURPOSE: To analyze speech expressiveness in a group of executives based on perceptive and acoustic aspects of vocal dynamics. METHODS: Four male subjects participated in the research study (S1, S2, S3, and S4). The assessments included the Kingdomality test to obtain the keywords of communicative attitudes; perceptive-auditory assessment to characterize vocal quality and dynamics, performed by three judges who are speech language pathologists; perceptiveauditory assessment to judge the chosen keywords; speech acoustics to assess prosodic elements (Praat software); and a statistical analysis. RESULTS: According to the perceptive-auditory analysis of vocal dynamics, S1, S2, S3, and S4 did not show vocal alterations and all of them were considered with lowered habitual pitch. S1: pointed out as insecure, nonobjective, nonempathetic, and unconvincing with inappropriate use of pauses that are mainly formed by hesitations; inadequate separation of prosodic groups with breaking of syntagmatic constituents. S2: regular use of pauses for respiratory reload, organization of sentences, and emphasis, which is considered secure, little objective, empathetic, and convincing. S3: pointed out as secure, objective, empathetic, and convincing with regular use of pauses for respiratory reload and organization of sentences and hesitations. S4: the most secure, objective, empathetic, and convincing, with proper use of pauses for respiratory reload, planning, and emphasis; prosodic groups agreed with the statement, without separating the syntagmatic constituents. CONCLUSION: The speech characteristics and communicative attitudes were highlighted in two subjects in a different manner, in such a way that the slow rate of speech and breaks of the prosodic groups transmitted insecurity, little objectivity, and nonpersuasion. PMID- 26107083 TI - Association between readiness for behavior change and complaints of vocal problems in teachers. AB - PURPOSE: To verify the association between readiness to behavioral change and self-reported vocal problems of teachers in schools from the municipal education network of Montes Claros, Minas Gerais, Brazil. METHODS: The URICA-VOICE scale was used to measure the motivational stages of 138 teachers. Readiness to change was the variable outcome, whereas the independent variables referred to sociodemographic, economic, occupational, lifestyle, general health, and teacher's own voice factors. RESULTS: The majority (59.4%) of teachers were in the pre-contemplation stage of the URICA-VOICE scale. The variables use of medication, perception of voice failure, and demand for speech and language therapy were retained for the final model. CONCLUSION: The low readiness to change showed the need for increased awareness of the risks and benefits related to the voice and general health. The results can provide public health intervention strategies that deal with individuals at various stages in the decision-making process. PMID- 26107084 TI - Characteristics of voice and personality of patients with vocal fold immobility. AB - PURPOSE: To examine the voice and personality characteristics of patients diagnosed with organic dysphonia secondary to vocal fold immobility. METHODS: The study comprised patients of both genders, attending the Clinic School of Speech Therapy of the Federal University of Paraiba, with otorhinolaryngological diagnosis of vocal fold immobility and speech therapy diagnosis of dysphonia. The self-assessment of voice was measured through a Vocal Screening Protocol and Voice Symptoms Scale (VoiSS), the voice was collected for auditory-perceptive evaluation, and the Factorial Personality Battery (FPB) was used. Descriptive statistical analysis was performed to determine the frequency, mean, and standard deviation of the studied variables. RESULTS: Eight patients participated in the study, of both genders, with average age of 40.4 +/- 16.9 years. The more frequent risk factors were the personal ones (4.7 +/- 2.1). In the VoiSS, the patients presented a higher average in the limitation score (34.1 +/- 15.7). From the auditory-perceptive evaluation, moderate intensity of vocal deviation was obtained, with predominant vocal roughness (57.7 +/- 25.2). In the FPB, the patients had an average higher than the cutoff scores in neuroticism (3.8 +/- 1.4) and accomplishment (5.2 +/- 1.0). CONCLUSION: The predominant vocal parameter was roughness. The patients referred to a few risk factors that compromise the vocal behavior and presented the neuroticism and realization factors as a highlight in their personality. Thus, individuals with vocal fold immobility show personality characteristics that may be a reflection of their voice disorder, not a factor that determines their dysphonia. PMID- 26107085 TI - Comparison between clinical and videofluoroscopic evaluation of swallowing in children with suspected dysphagia. AB - PURPOSE: To verify the accuracy of clinical evaluation compared with videofluoroscopic swallowing studies in the detection of isolated laryngeal penetration and laryngeal aspiration in children with suspected dysphagia; to identify clinical signs and symptoms associated with isolated laryngeal penetration and laryngeal aspiration; and to determine the sensitivity and specificity of the clinical signs and symptoms identified. METHODS: Retrospective analysis of data from clinical and videofluoroscopic evaluations carried out in 55 children from 1 month to 7 years and 11 months old. For clinical assessment, the Protocol for Clinical Assessment of Pediatric Dysphagia was used. The sensitivity, specificity, and positive and negative predictive values of clinical evaluation were analyzed. For statistical analysis, the Fisher's exact and chi2 tests were used. RESULTS: Clinical evaluation showed, in general, a sensitivity of 86% and a specificity of 32%. For isolated laryngeal penetration, clinical evaluation showed a sensitivity of 88%. For laryngeal aspiration, clinical evaluation showed a sensitivity of 86%. However, the specificity values were low for both alterations. There was no association between clinical evaluation and videofluoroscopic findings. Choking was the only clinical sign associated with isolated laryngeal penetration thin fluid and showed a sensitivity of 53% and a specificity of 77%. CONCLUSIONS: Clinical evaluation was sensible to detect isolated laryngeal penetration and laryngeal aspiration in children with suspected dysphagia. However, it showed a low specificity. Choking was the only clinical sign associated with isolated laryngeal penetration of thin fluid. More prospective studies are needed to confirm these findings in this population. PMID- 26107086 TI - Proposal and content validation of an orofacial myofunctional assessment protocol for individuals with cleft lip and palate. AB - PURPOSE: To create and validate the content of an orofacial myofunctional assessment protocol for individuals with cleft lip and palate. METHODS: The first version of an orofacial myofunctional assessment protocol for individuals with cleft lip and palate was created by two speech-language pathologists, who contemplated the structural and functional aspects of the stomatognathic system. This version was analyzed by other two speech-language pathologists experienced in cleft lip and palate assessment, who suggested changes that led to the second version of the protocol. Dynamic and static images necessary for performing the orofacial myofunctional examination were recorded from three individuals with cleft lip and palate, who represented three life stages: childhood, adolescence, and adulthood. Five examiners evaluated the images, applied the proposed protocol, and judged each item regarding its clarity to validate the content, from Content Validity Index. RESULTS: The assessment protocol was finalized with 13 items, ten related to structural aspects and three related to functional aspects, with their corresponding sub-items. The general agreement in the validation of its content was 100%, so that only one stage was required. CONCLUSION: A protocol to evaluate the orofacial myofunctional aspects of individuals with cleft lip and palate was created with 13 items, as well as their corresponding sub-items, and its content was validated. PMID- 26107087 TI - Respiratory mode, nasal patency and palatine dimensions. AB - PURPOSE: To investigate the influence of breathing mode and nasal patency in the dimensions of the hard palate by comparing mouth breathing (MB) and nasal breathing (NB) adults. METHODS: Seventy-seven individuals, distributed into the MB group (n=38) and the NB group (n=39), of both genders and aged between 18 and 30 years old, took part in the study. The respiratory mode diagnosis was based on anamnesis, physical characteristics, and otorhinolaryngological examination. The volunteers were evaluated in terms of nasal patency, with a peak nasal inspiratory flow (PNIF) meter, and obstruction symptoms, by a Nasal Obstruction Symptom Evaluation (NOSE) scale, and had their transversal and vertical hard palate dimensions measured with a digital caliper in plaster models. RESULTS: Comparing both groups, the MB group presented significantly higher values in the NOSE scale, lower values in the PNIF, lower values in the transversal distance of the palate in the intercanine region, and significantly higher values in the vertical distance in the regions of the first and second premolars and molars. There was a negative correlation between PNIF and NOSE, and a positive correlation between PNIF and transversal distance of the palate in the region of the first premolars. CONCLUSION: MB adults presented reduced nasal patency and a higher degree of nasal obstruction symptoms. The hard palate was morphologically narrower and deeper in adults with the MB mode compared to the NB mode. Moreover, it was concluded that the smaller the nasal patency, the greater the obstruction symptoms and the narrower the hard palate. PMID- 26107088 TI - The use of superficial heat for treatment of temporomandibular disorders: an integrative review. AB - PURPOSE: To perform an integrative review of scientific bibliographic production on the use of superficial heat treatment for temporomandibular disorders. Research strategy : Literature review was accomplished on PubMed, LiLACS, SciELO, Bireme, Web of Science, and BBO databases. The following descriptors were used: hot temperature, hyperthermia induced, heat transference, temporomandibular joint, temporomandibular joint disorders, temporomandibular joint dysfunction syndrome, and their equivalents in Portuguese and Spanish. SELECTION CRITERIA: Articles that addressed the superficial heat for the treatment of temporomandibular disorders, published in English, Spanish, or Portuguese, between 1980 and 2013. DATA ANALYSIS: The following data were collected: technique of applying superficial heat, duration of application, stimulated body area, temperature of the stimulus, frequency of application, and benefits. RESULTS: initially, 211 studies were found, but just 13 contemplated the proposed selection criteria. Data were tabulated and presented in chronological order. CONCLUSION: Several techniques for superficial heat application on treatment of temporomandibular disorders were found in the literature. The moist heat was the most widely used technique. Many studies suggested the application of heat for at least 20 minutes once a day. Most authors recommended the application of heat in facial and cervical regions. The heat treatment resulted in significant relief of pain, reduced muscle tension, improved function of the mandible, and increased mouth opening. PMID- 26107089 TI - A New Metabolite with a Unique 4-Pyranone-gamma-Lactam-1,4-Thiazine Moiety from a Hawaiian-Plant Associated Fungus. AB - An endophytic fungus Paraphaeosphaeria neglecta FT462 isolated from the Hawaiian plant Lycopodiella cernua (L.) Pic. Serm produced one unusual compound (1, paraphaeosphaeride A) with the 4-pyranone-gamma-lactam-1,4-thiazine moiety, along with two new compounds (2 and 3, paraphaeosphaerides B and C, respectively) and the known compound (4). Compounds 1-3 were characterized by NMR and MS spectroscopic analysis. The absolute configuration of the 3-position of compound 1 was determined as S by electronic circular dichroism (ECD) calculations. Compound 3 also showed STAT3 inhibition at 10 MUM. PMID- 26107090 TI - Quantum Dynamics of Vinylidene Photodetachment on an Accurate Global Acetylene Vinylidene Potential Energy Surface. AB - Vinylidene is a high-energy isomer of acetylene, and the rearrangement of bonds in the two species serves as a prototype for isomerization reactions. Here, a full-dimensional quantum mechanical study of the vinylidene vibration is carried out on a recently developed global acetylene-vinylidene potential energy surface by simulating the photodetachment dynamics of the vinylidene anion. Several low lying vibrational levels of the anion were first determined on a new ab initio based potential energy surface, and their photoelectron spectra were obtained within the Condon approximation. The vibrational features of the vinylidene isomer are found to agree well with the experiment in both positions and intensities, validating the global acetylene-vinylidene potential energy surface. PMID- 26107091 TI - Solid-liquid critical behavior of a cylindrically confined Lennard-Jones fluid. AB - Extensive molecular dynamics simulations have been performed to study the phase behavior of Lennard-Jones particles confined in a quasi-one-dimensional hydrophobic nanopore. We provide unambiguous evidence for a solid-liquid critical point by investigating (i) isotherms in the pressure-volume plane, (ii) the spontaneous solid-liquid phase separation below a certain temperature, (iii) diverging heat capacity and isothermal compressibility as a certain point is approached, (iv) continuous change of dynamical and structural properties above the point, (v) the finite-size scaling analysis of the density distribution below and above the point. The result combined with earlier studies of confined water suggests that the solid-liquid critical point is not uncommon in quasi-one- and quasi-two-dimensional fluids. PMID- 26107092 TI - Addiction. PMID- 26107093 TI - The hijacked brain. PMID- 26107094 TI - Genetics: No more addictive personality. PMID- 26107095 TI - Neuroscience: Rewiring the brain. PMID- 26107096 TI - Pharmacotherapy: Quest for the quitting pill. PMID- 26107097 TI - Perspective: Beyond the neural circuits. PMID- 26107098 TI - Contingency management: Why it pays to quit. PMID- 26107099 TI - Technology: Barriers to misuse. PMID- 26107100 TI - Perspective: Behavioural addictions matter. PMID- 26107101 TI - Addiction: 4 big questions. PMID- 26107102 TI - Toward an understanding of the thermosensitive behaviour of pH-responsive hydrogels based on cyclodextrins. AB - The molecular mechanism responsible for the thermosensitive behaviour exhibited by pH-responsive cyclodextrin-based hydrogels is explored here with the twofold aim of clarifying some basic aspects of H-bond interactions in hydrogel phases and contributing to a future engineering of cyclodextrin hydrogels for targeted delivery and release of bioactive agents. The degree of H-bond association of water molecules entrapped in the gel network and the extent of intermolecular interactions involving the hydrophobic/hydrophilic moieties of the polymer matrix are probed by UV Raman and IR experiments, in order to address the question of how these different and complementary aspects combine to determine the pH dependent thermal activation exhibited by these hydrogels. Complementary vibrational spectroscopies are conveniently employed in this study with the aim of safely disentangling the spectral response arising from the two main components of the hydrogel systems, i.e. the polymer matrix and water solvent. The experimental evidence suggests that the dominant effects in the mechanism of solvation of cyclodextrin-based hydrogels are due to the changes occurring, upon increasing of temperature, in the hydrophobicity character of specific chemical moieties of the polymer, as triggered by pH variations. The achievements of this work corroborate the potentiality of the UV Raman scattering technique, in combination with more conventional IR experiments, to provide a "molecular view" of complex macroscopic phenomena exhibited in hydrogel phases. PMID- 26107103 TI - [(11)C]CO2 to [(11)C]CO conversion mediated by [(11)C]silanes: a novel route for [(11)C]carbonylation reactions. AB - A novel chemical methodology is described for the conversion of [(11)C]CO2 to [(11)C]CO. Diphenylmethyl silanes trap [(11)C]CO2 and release [(11)C]CO rapidly when triggered by TBAF. Released [(11)C]CO was used to produce [(11)C]N benzylbenzamide and AMPA receptor ligand, [(11)C], in radiochemical yields >90% within 6 min from [(11)C]CO2 production. PMID- 26107104 TI - Thin film field-effect transistors of 2,6-diphenyl anthracene (DPA). AB - An anthracene derivative, 2,6-diphenyl anthracene (DPA), was successfully synthesized with three simple steps and a high yield. The compound was determined to be a durable high performing semiconductor with thin film device mobility over 10 cm(2) V(-1) s(-1). The efficient synthesis and high performance indicates its great potential in organic electronics. PMID- 26107105 TI - Enhanced angiogenesis and osteogenesis in critical bone defects by the controlled release of BMP-2 and VEGF: implantation of electron beam melting-fabricated porous Ti6Al4V scaffolds incorporating growth factor-doped fibrin glue. AB - Electron beam melting (EBM)-fabricated porous titanium implants possessing low elastic moduli and tailored structures are promising biomaterials for orthopedic applications. However, the bio-inert nature of porous titanium makes reinforcement with growth factors (GFs) a promising method to enhance implant in vivo performance. Bone-morphogenic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) are key factors of angiogenesis and osteogenesis. Therefore, the present study is aimed at evaluating EBM-fabricated porous titanium implants incorporating GF-doped fibrin glue (FG) as composite scaffolds providing GFs for improvement of angiogenesis and osteogenesis in rabbit femoral condyle defects. BMP-2 and VEGF were added into the constituent compounds of FG, and then this GF doped FG was subsequently injected into the porous scaffolds. In five groups of implants, angiogenesis and osteogenesis were evaluated at 4 weeks post implantation using Microfil perfusion and histological analysis: eTi (empty scaffolds), cTi (containing undoped FG), BMP/cTi (containing 50 MUg rhBMP-2), VEGF/cTi (containing 0.5 MUg VEGF) and Dual/cTi (containing 50 MUg rhBMP-2 and 0.5 MUg VEGF). The results demonstrate that these composite implants are biocompatible and provide the desired gradual release of the bioactive growth factors. Incorporation of GF delivery, whether a single factor or dual factors, significantly enhanced both angiogenesis and osteogenesis inside the porous scaffolds. However, the synergistic effect of the dual factors combination was observable on angiogenesis but absent on osteogenesis. In conclusion, fibrin glue is a biocompatible material that could be employed as a delivery vehicle in EBM fabricated porous titanium for controlled release of BMP-2 and VEGF. Application of this method for loading a porous titanium scaffold to incorporate growth factors is a convenient and promising strategy for improving osteogenesis of critical-sized bone defects. PMID- 26107106 TI - MERS - A cautionary tale. PMID- 26107107 TI - New PKS-NRPS tetramic acids and pyridinone from an Australian marine-derived fungus, Chaunopycnis sp. AB - Chemical analysis of a marine-derived fungus, Chaunopycnis sp. (CMB-MF028), isolated from the inner tissue of a pulmonate false limpet Siphonaria sp., collected from rock surfaces in the intertidal zone of Moora Park, Shorncliffe, Queensland, yielded the tetramic acid F-14329 (1) and new analogues, chaunolidines A-C (2-4), together with the new pyridinone chaunolidone A (5), and pyridoxatin (6). Structures inclusive of absolute configurations were assigned to 1-6 on the basis of detailed spectroscopic analysis, X-ray crystallography, electronic circular dichroism (ECD), biosynthetic considerations and chemical interconversion. Chaunolidine C (4) exhibits modest Gram-positive antibacterial activity (IC50 5-10 MUM), while chaunolidone A (5) is a selective and potent inhibitor (IC50 0.09 MUM) of human non-small cell lung carcinoma cells (NCI H460). Tetramic acids 1-4 form metal chelates with Fe(III), Al(III), Cu(II), Mg(II) and Zn(II). PMID- 26107108 TI - EXAMINING THE EFFECT OF SMILE INTENSITY ON AGE PERCEPTIONS. AB - Research has demonstrated the positive effects of smiles on interpersonal perceptions of attractiveness, likability, and friendliness. A possible mechanism underlying the effects of smiles is babyfacedness. Four studies were conducted with 1,235 participants. In Study 1, 646 participants were assigned to one of the six levels of smile intensity and responded to the measures of age perception and perceived babyfacedness. Compared to the neutral expression, the maximal smile reduced age estimations and this effect was mediated by perceived babyfacedness. In Study 2, 59 respondents' responses indicated that a maximal smile reduced the perception of age. In Study 3, 318 respondents estimated the age of models in different sex and levels of smile intensity. Maximal smiles reduced age estimations. In Study 4, 125 students and 87 non-students were randomly assigned to one of the three levels of smile intensity and provided age estimations. Replicating previous findings, maximal smiles reduced age estimations. Consistent results emerged from the various contexts, models, and samples, as well as in a pooled analysis. PMID- 26107109 TI - RORSCHACH SPACE RESPONSES AND ANGER. AB - In this study, three different subtypes of Space responses to the Rorschach test were hypothesized: S-fusion, S-reversal, and S-integration. The relationship between these subtypes and feelings of anger and aggression was investigated. The Rorschach test, the State-Trait Anxiety Inventory-2 (STAXI-2), and the Aggression Questionnaire (AQ) were administered to 50 university students. Scores on the STAXI-2 were positively associated with S-fusion and negatively associated with S integration. No significant associations of S subtypes with aggression were found. The findings support the hypothesis that different figure-ground relationships, shown in the subtypes of S responses, indicate different psychological processes. PMID- 26107110 TI - RABGTPases in MT1-MMP trafficking and cell invasion: Physiology versus pathology. AB - The matrix metalloproteinase MT1-MMP is a central regulator of cell invasion in both physiological and pathological settings, such as tissue surveillance by immune cells and cancer cell metastasis. MT1-MMP cleaves a plethora of intra- and extracellular proteins, including extracellular matrix proteins, matrix receptors, and also other MMPs, and thus enables modification of both the cell surface proteome and the pericellular environment. Despite its importance for cell invasion, the pathways regulating MT1-MMP exposure on the cell surface are largely unknown. Recently, our groups discovered that a specific subset of RABGTPases, most notably RAB5a, is critical for MT1-MMP trafficking in primary human macrophages and carcinoma cells. Here, we discuss and contrast our findings for both cell types, pointing out common features and differences in the RABGTPase-dependent trafficking of MT1-MMP in health and disease. PMID- 26107111 TI - Novel dialkylphosphorylhydrazones: Synthesis, leishmanicidal evaluation and theoretical investigation of the proposed mechanism of action. AB - As part of a program to develop new drugs for the treatment of neglected diseases, new dialkylphosphorylhydrazones were synthesized and evaluated against the trypanosomatid parasites Leishmania braziliensis and Leishmania amazonensis. The synthesis of these compounds proved satisfactory with yields ranging from moderate to good. The most active compounds against L. braziliensis presented IC50 values in the 10(-2) MUM range, similar to that of the reference drug pentamidine. Two compounds, 4m and 4n, showed a significant dose dependent decrease in the infection index of L. amazonensis infected macrophages and caused a complete healing of nodules and ulcers when tested in vivo against L. amazonensis-infected mice, but the control of parasite burden at the inoculation site was statistically significant only in the case of treatment with 4n. A target fishing (reverse docking) approach using molecular docking with 15 enzymes of L. braziliensis indicated that the probable target of the active compounds was hexokinase, the first enzyme of the glycolytic pathway. PMID- 26107112 TI - Recent prospective of surface engineered Nanoparticles in the management of Neurodegenerative disorders. AB - Clinically, the therapeutic outcomes in neurodegenerative disorders (NDs) by drug treatment are very limited, and the most insurmountable obstacle in the treatment of NDs is the blood-brain barrier (BBB), which provides the highest level of protection from xenobiotics. A great deal of attention still needs to be paid to overcome these barriers, and surface-engineered polymeric nanoparticles are emerging as innovative tools that are able to interact with the biological system at a molecular level for the desired response. The present review covers the potential importance of surface-structure-engineered nanoparticles to overcome the BBB for good bioavailability, and the evaluation of drug therapy in NDs. PMID- 26107113 TI - Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to deposition of fibrin in the bloodstream. It may occur in patients with acute and chronic leukemia and is particularly associated with acute promyelocytic leukemia (a subtype of acute myeloid leukemia). OBJECTIVES: To assess the clinical benefits and harms of any pharmacological intervention for treating DIC in patients with acute or chronic leukemia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 05), MEDLINE (1946 to 7 May 2015), LILACS (1982 to 7 May 2015) and African Index Medicus (7 May 2015). There was no language restrictions. We sought additional randomized controlled trials (RCTs) from the World Health Organization International Clinical Trials Registry Platform and the reference lists of primary studies identified. SELECTION CRITERIA: RCTs assessing the clinical benefits and harms of interventions for treating DIC in patients with acute and chronic leukemia. DATA COLLECTION AND ANALYSIS: Two review authors independently performed trial selection, 'Risk of bias' assessment and data extraction. Primary outcomes were overall mortality, in-hospital mortality from any cause (15-day and 30-day) and adverse events. MAIN RESULTS: In this Cochrane Review update we did not include any new RCT compared with the first review version. Accordingly, four RCTs (388 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included trials reported data on mortality and bleeding. The studies were conducted in Japan, Italy and the Netherlands. We classified the included trials as: 1) including patients with or without leukemia which did not report data for the leukemia subgroup (366 participants); and 2) only including patients with leukemia (22 participants). Overall, the risk of bias of the included trials was high, since the trial authors did not provide a detailed description about trial design and execution.According to the GRADE recommendations, we judged the overall quality of the body of evidence for all prefixed outcomes as 'very low', due to methodological limitations and very small sample size.One trial, including 10 participants with leukemia and comparing dermatan sulphate with heparin, reported no deaths during trial treatment.In terms of bleeding data, we were unable to pool results from two studies that were only conducted with leukemia patients due to the inconsistency in the measurement and reporting of this outcome. One trial, including 12 participants with leukemia, found very low quality evidence that tranexamic acid can reduce the cumulative hemorrhagic score in participants compared with those assigned to placebo (P = 0.0015, very low quality evidence). On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis (1/5 (20%) versus 2/5 (40%); RR 0.50; 95% CI 0.06 to 3.91; P = 0.51, very low quality evidence).No thromboembolic complications were reported in either trial that included patients with leukemia only (very low quality evidence). The safety profile was inconclusive.The included trials did not assess overall mortality, resolution of respiratory failure, renal failure or shock. AUTHORS' CONCLUSIONS: Due to a lack of new RCTs, our conclusions in this Cochrane Review update are the same as the previous review version. We included four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The quality of the evidence was low to very low. Therefore, prescription of these interventions for treating DIC in patients with acute and chronic leukemia can neither be supported nor rejected, unless new evidence from a large high-quality trial alters this conclusion. PMID- 26107114 TI - Successful Replacement of Artemia salina nauplii with Marine Rotifers (Brachionus plicatilis) in the Diet of Preadult Zebrafish (Danio rerio). AB - Previously established rearing protocols for zebrafish begin feeding with marine rotifers (Brachionus plicatilis), followed by Artemia nauplii until the fish reach subadult stage, the developmental time point at which they can be most easily transitioned onto a processed diet. However, the inclusion of Artemia is less than ideal, given its fluctuating availability and high costs. We tested whether or not we could replace Artemia with rotifers during our normal rearing sequence and still meet published performance standards for (i) weaning fish onto a processed diet by 25 days postfertilization (dpf) and (ii) successful breeding by 60 dpf. Here, we present the results of trials where wild-type and casper zebrafish were fed exclusively with rotifers (R) or rotifers followed by Artemia (RA) for the first 25 dpf after which point all fish were transitioned to a processed diet (Gemma Micro 300). We measured growth and survival at days 25 and 60, and tested for reproductive capability at 60 dpf. While growth performance was significantly better in the RA groups, we were still able to meet goals for both weaning and generation time in the R groups without compromising survival or sex ratios. PMID- 26107116 TI - TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors. AB - Chronic stress is a potent risk factor for depression, but the mechanism by which stress causes depression is not fully understood. To investigate the molecular mechanism underlying stress-induced depression, C57BL/6 inbred mice were treated with repeated restraint to induce lasting depressive behavioral changes. Behavioral states of individual animals were evaluated using the forced swim test, which measures psychomotor withdrawals, and the U-field test, which measures sociability. From these behavioral analyses, individual mice that showed depression-like behaviors in both psychomotor withdrawal and sociability tests, and individuals that showed a resiliency to stress-induced depression in both tests were selected. Among the neuropeptides expressed in the amygdala, thyrotropin-releasing hormone (TRH) was identified as being persistently up regulated in the basolateral amygdala (BLA) in individuals exhibiting severe depressive behaviors in the two behavior tests, but not in individuals displaying a stress resiliency. Activation of TRH receptors by local injection of TRH in the BLA in normal mice produced depressive behaviors, mimicking chronic stress effects, whereas siRNA-mediated suppression of either TRH or TRHR1 in the BLA completely blocked stress-induced depressive symptoms. The TRHR1 agonist, taltirelin, injection in the BLA increased the level of p-ERK, which mimicked the increased p-ERK level in the BLA that was induced by treatment with repeated stress. Stereotaxic injection of U0126, a potent inhibitor of the ERK pathway, within the BLA blocked stress-induced behavioral depression. These results suggest that repeated stress produces lasting depression-like behaviors via the up-regulation of TRH and TRH receptors in the BLA. PMID- 26107118 TI - Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice. AB - We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID- 26107119 TI - Attitudes Regarding Palliative Sedation and Death Hastening Among Swiss Physicians: A Contextually Sensitive Approach. AB - In Switzerland, where assisted suicide but not euthanasia is permitted, the authors sought to understand how physicians integrate palliative sedation in their practice and how they reflect on existential suffering and death hastening. They interviewed 31 physicians from different care settings. Five major attitudes emerged. Among specialized palliative care physicians, convinced, cautious and doubtful attitudes were evident. Within unspecialized settings, palliative sedation was more likely to be considered as death hastening: clinicians either avoid it with an inexperienced attitude or practice it with an ambiguous attitude, raising the issue of unskilled and abusive uses of sedatives at the end of life. PMID- 26107120 TI - Significance of Diurnal Intraocular Pressure Measurement. PMID- 26107117 TI - Histamine receptor signaling in energy homeostasis. AB - Histamine modulates several aspects of energy homeostasis. By activating histamine receptors in the hypothalamus the bioamine influences thermoregulation, its circadian rhythm, energy expenditure and feeding. These actions are brought about by activation of different histamine receptors and/or the recruitment of distinct neural pathways. In this review we describe the signaling mechanisms activated by histamine in the hypothalamus, the evidence for its role in modulating energy homeostasis as well as recent advances in the understanding of the cellular and neural network mechanisms involved. This article is part of the Special Issue entitled 'Histamine Receptors'. PMID- 26107121 TI - Intravitreal Bevacizumab, Plasminogen, and Pneumatic Retinopexy for Subfoveal Hemorrhage in Age-Related Macular Degeneration. PMID- 26107122 TI - Author Reply. PMID- 26107123 TI - New Compact Accommodometer to Measure Accommodation Amplitude. PMID- 26107124 TI - Author Reply. PMID- 26107125 TI - Prevention of Cataract Blindness in Rural China. AB - China has undergone dramatic economic and social reforms during last 30 years, leading to a notably higher level of living standards and health care access for Chinese citizens. However, China's cataract surgical rate of 780 cases/y per million population trails Asian neighbors with lower income levels such as India and Vietnam. Eye care providers and patients encounter many barriers in gaining access to one another.Hands-on training programs conducted by international nongovernmental organizations and the government have helped to increase the number of qualified cataract surgeons in rural area, but establishing a residency training system that produces ophthalmologists capable of performing independent surgery is the only sustainable way to meet the increasing demand for surgery from an aging population. The New Rural Cooperative Medical System has successfully reduced the financial burden of cataract surgery for the rural population; however, reimbursement for outpatient treatment of leading eye diseases is needed.Community outreach screening combined with education is essential in rural areas' increased demand for surgery. Methods to optimize the yield from such screening must still be devised and proven, however. Improvements in the hospital administration and management structure are also needed to improve the efficiency of China's rural hospitals in delivering high-quality, low cost cataract surgical services. PMID- 26107126 TI - Prospective Randomized Comparative Study of the Effect of Pupil Dilation or Miosis in Intraocular Lens Pupillary Capture After Combined Phacoemulsification and Vitrectomy With Intraocular Tamponade. AB - PURPOSE: The objective of the study was to compare the safety and efficacy of postoperative pharmacological pupil dilation, miosis, and alternate-day pupil dilation and miosis after combined phacoemulsification (phaco), intraocular lens (IOL) implantation, and pars plana vitrectomy (PPV) with intraocular tamponade. DESIGN: This was a prospective, randomized controlled clinical trial. METHODS: Patients who were indicated for phaco with IOL implantation, PPV, and intraocular tamponade were randomly assigned into 3 different groups: (1) pupil dilation using 4% homatropine (dilation group), (2) pupil miosis using 1% pilocarpine (miosis group), and (3) alternate-day pupil miosis and dilation starting with 1% pilocarpine on the first day postoperatively and switched to 4% homatropine thereafter on alternate days (alternate-day group). The main outcome measured was the rate of IOL capture postoperatively. The secondary measurable outcomes were the complication rates, visual acuity, and ease of fundal examination with binocular indirect ophthalmoscopy. RESULTS: Twenty-two, 21, and 20 eyes were allocated to the dilation, miosis, and alternate-day groups, respectively. Intraocular lens capture was found in 7 (11.1%) of 63 eyes. Intraocular lens was captured in 6 (27.3%) of 22 eyes in the dilation, 1 (4.5%) of 21 eyes in the miosis, and none in the alternate-day groups (P = 0.0133). The difference of the visual acuity among the 3 groups was not statistically significant (P = 0.650). Anterior chamber reaction of more than +1 cell in the first week was found in 6 (27.3%) of 22, 13 (61.9%) of 21, and 10 (50%) of 20 eyes in the dilation, miosis, and alternate-day groups, respectively (P = 0.074). Although more eyes were found with posterior synechia in the miosis group, the difference was not statistically significant (P = 0.478). The number of eyes that had suboptimal binocular indirect ophthalmoscopy view was 3 (13.6%) of 22, 12 (57.1%) of 21, and 6 (30%) of 20 in the dilation, miosis, and alternate-day groups, respectively (P = 0.01). CONCLUSIONS: Pupil dilation after combined phaco with IOL implantation, PPV, and intraocular tamponade could lead to a higher chance of IOL capture. Pupil miosis may lead to more anterior chamber inflammation. The regimen of alternate pupil dilation and miosis may cause less chance of IOL capture. PMID- 26107127 TI - Preoperative Antisepsis With Povidone-Iodine 5% in Cataract Surgery. AB - PURPOSE: This study aimed to evaluate the efficacy of povidone-iodine (PI) 5% as the only preoperative antiseptic in cataract surgery. DESIGN: Prospective interventional case series. METHODS: Fifty patients undergoing phacoemulsification under topical anesthesia in an outpatient surgery setting in a teaching hospital participated in the study. The preoperative antiseptic regimen consisted of instillation into the conjunctival sac and periorbital scrub with PI 5%. No topical antibiotic was given. Eyelid margin swabs were obtained for bacteriological culture before and after PI antisepsis and at the conclusion of surgery. The number of bacterial species isolated was compared with the Wilcoxon test. Anterior chamber aspirates were taken immediately before and after surgery to determine the rate of contamination. RESULTS: Bacteria were isolated from the eyelid margins of 48 patients (96%; 95% exact confidence interval, 86.3% 99.5%) before surgery, from the eyelid margins of 28 patients (56%) after antisepsis with PI 5%, and from the eyelid margins of 26 patients (56%; 95% exact confidence interval, 41.3%-70.0%) at the conclusion of surgery. The reduction of positive eyelid margin culture was statistically significant (P < 0.0001). Anterior chamber aspirates were positive in 3 patients. One patient with negative growth from anterior chamber aspirates developed culture-negative postoperative endophthalmitis. CONCLUSIONS: Because 56% of eyelids still have positive culture after PI 5% antisepsis, it might not be relied on as the sole preoperative antiseptic measure. Meticulous surgical technique, together with other modalities of preoperative and intraoperative antisepsis, should be used to prevent postoperative endophthalmitis. PMID- 26107128 TI - Diurnal Intraocular Pressure Profiles in Chronic Open-Angle Glaucoma. AB - PURPOSE: To evaluate day-and-night intraocular pressure (IOP) profiles in normal and glaucomatous eyes. DESIGN: Hospital-based clinical observational study. METHODS: The study included 3561 day-and-night profiles of IOP measurements performed by Goldmann applanation tonometry on 1408 eyes of 720 normal Caucasian subjects or chronic open-angle glaucoma patients. RESULTS: For all groups except the secondary open-angle glaucoma group, IOP was highest at 7 a.m., followed by noon and 5 p.m., and finally at 9 p.m. or midnight. In secondary open-angle glaucoma, mean measurements did not vary significantly during day and night. The profile amplitude (mean: 5.5 2.8 mm Hg) was significantly (P < 0.001) higher in the secondary open-angle glaucoma group than in the normal-pressure glaucoma group and the normal group. The two latter groups did not vary significantly (P = 0.47) in profile amplitude. Expressed as percentage of the mean IOP, the IOP amplitude did not vary significantly between any of the study groups. The inter eye IOP difference for any measurement time was significantly (P < 0.001) smaller than the IOP profile amplitude. CONCLUSIONS: Treated secondary open-angle glaucoma eyes did not exhibit the normal day-and-night pressure profile which was usually shown in normal eyes and eyes treated for other types of chronic open angle glaucoma. The day-and-night IOP amplitude in absolute terms is highest in secondary open-angle glaucoma. In relative terms, the IOP amplitude did not vary significantly between the various types of chronic open-angle glaucoma. Inter-eye IOP differences were significantly (P < 0.001) smaller than the IOP profile amplitude. PMID- 26107129 TI - Long-Term Follow-Up Study of Autosomal Dominant Optic Atrophy in an Australian Population. AB - PURPOSE: This study aimed to describe the phenotype of Australian patients with a clinical diagnosis of dominant optic atrophy (DOA) and provide long-term follow up data on its natural history. DESIGN: Retrospective analysis. METHODS: All patients with the clinical diagnosis of DOA observed during a 30-year period at a single tertiary referral center (Save Sight Institute, Sydney Eye Hospital, Sydney, Australia) with at least 12 months of follow-up were included in the study. Clinical characteristics were assessed with particular attention to change in visual acuity (VA). RESULTS: There were 36 patients with DOA from 26 different Australian families. The most common clinical presentation of DOA was insidious onset of visual difficulties beginning in childhood. Mean (SD) age at diagnosis of DOA was 16 (14) years. During a mean follow-up period of 10.6 years (median, 10 years), 44% of study eyes had no change in VA, 35% had reduction of VA by 1 Snellen line, 13% had a reduction of VA by 2 Snellen lines, and 8% of the study eyes had a VA reduction of more than 2 Snellen lines. Six of 36 patients were legally blind at last follow-up. CONCLUSIONS: There is considerable heterogeneity in the presenting VA and natural history of DOA between individual patients and within families with DOA, with VA ranging from 6/6 to hand motion perception. This study provides valuable information to aid the clinician counseling the long term visual outcome in patients with DOA and their families. PMID- 26107130 TI - Comparison of Outcomes of Suprabrow Single-Stab and 3-Stab Incision Frontalis Sling Surgery. AB - PURPOSE: This study aimed to compare functional and cosmetic outcomes of suprabrow single-stab (SBSS) versus conventional 3-stab incision frontalis sling surgery. DESIGN: Comparative case series. METHODS: Twenty-one eyes of 17 patients for the study group and 21 eyes of 16 patients for the control group were included. All patients underwent thorough ptosis evaluation before surgery. Using Seiff silicone suspension set, the study group underwent SBSS, whereas the control group underwent suprabrow 3-stab surgery. The SBSS surgery modified conventional suprabrow 3-stab surgery by decreasing the number of suprabrow incisions to only a single one while still in the form of Fox pentagon.Functional outcomes were assessed in both groups using parameters like vertical fissure height, margin reflex distance 1, lagophthalmos, and lid closure. Vertical fissure height, lid crease height, lagophthalmos, symmetry of lids, and presence of scars were used to evaluate the cosmetic outcome of surgery. All patients were followed up for 15 months. RESULTS: The study group and the control group were comparable at all points of time in functional outcome measures. On comparing the cosmetic outcomes, the study group fared significantly better than the control group (P = 3.092 * 10 in adults and P = 4.113 * 10 in children, Mann-Whitney U test), predominantly as a result of reduced scarring and fewer number of suprabrow scars. CONCLUSIONS: The SBSS frontalis suspension technique, while retaining the usual advantages and functional results of standard sling procedures, is associated with decreased intraoperative bleeding, reduced postoperative edema and scarring, and a better aesthetic outcome. PMID- 26107131 TI - An Update in Laser and Pharmaceutical Treatment for Polypoidal Choroidal Vasculopathy. AB - Polypoidal choroidal vasculopathy (PCV) is a condition characterized by multiple, recurrent, serosanguineous pigment epithelium detachment and neurosensory retinal detachment due to abnormal choroidal polypoidal lesions. Polypoidal choroidal vasculopathy is particularly prevalent in Asians and occurs in up to 30% of patients presenting with neovascular age-related macular degeneration. In recent years, various treatment modalities have been described in the literature for the treatment of PCV. This review article aims to provide an overview and to summarize the current nonsurgical treatment for PCV. PMID- 26107132 TI - Predictive Factors Within the Optic Nerve Complex for Glaucoma Progression: Disc Hemorrhage and Parapapillary Atrophy. AB - The optic nerve complex (ONC) is a new term we have created to describe the clinically and non-clinically visible portions of the optic nerve and surrounding tissues. Recent advances in imaging technologies have created a need to provide a unified and comprehensive view of the structure and function of the components of ONC to assess various risk factors for glaucoma development and progression. Despite a great deal remaining to elucidate their underlying pathogenesis, disc hemorrhages and beta-zone parapapillary atrophy have been consistently shown in different study designs to be significant risk factors for glaucoma progression. Given their easy visibility as components of the ONC, disc hemorrhage and beta zone parapapillary atrophy are widely underscored glaucoma features that should be thoroughly investigated and documented with the purpose of stratifying patients under risk categories along with other intraocular pressure-dependent and -independent factors. This review provides an update on these 2 features and their relationship to glaucoma progression. PMID- 26107133 TI - Manual Small Incision Cataract Surgery: A Review. AB - We aim at reviewing published peer-reviewed studies that evaluate the safety and efficacy of manual small incision cataract surgery (MSICS). Literature searches of the PubMed and the Cochrane Library databases were conducted with no date restrictions; the searches were limited to articles published in English only. All publications with at least level II and III evidence were studied and surgical techniques were analyzed. MSICS was also compared with phacoemulsification and large incision extracapsular cataract surgery (ECCE) with respect to visual outcome, surgery time, cost, intra and postoperative complications and suitability for high volume surgical practices in the developing world.The overall safety profile of MSICS was found to be excellent with intra and postoperative complication rates comparable to phacoemulsification and ECCE. Multiple studies reported the safety and efficacy of MSICS for complicated cases, such as brunescent and white cataract and cataracts associated with phacolytic and phacomorphic glaucoma. Compared to phacoemulsification MSICS was associated with lower and shorter operative times. Visual outcomes were excellent and comparable to phacoemulsification with up to 6 months follow up.The literature provides outcome analysis of a variety of different MSICS techniques. As a whole, MSICS provides excellent outcomes with a low rate of surgical and postoperative complications. Particularly in the developing world, MSICS appears to provide outcomes that are of comparable quality to phacoemulsification at a much lower cost. PMID- 26107134 TI - Efficacy of Topical Levofloxacin 0.5% in Treating Levofloxacin-Resistant Pseudomonas aeruginosa-Induced Keratitis. AB - PURPOSE: To evaluate the efficacy of topical levofloxacin 0.5% in treating levofloxacin-resistant Pseudomonas aeruginosa-induced keratitis. DESIGN: Longitudinal study. METHODS: The study was conducted in 21 New Zealand White rabbits whose corneas were inoculated with 0.1 mL of 1000 colony-forming units of levofloxacin-resistant P. aeruginosa. After 24 hours, the rabbits were randomized into 3 groups: 9 were treated with levofloxacin 0.5%, 6 were treated with ceftazidime 50 mg/mL, and 6 were treated with a placebo. The rabbits were given a loading dose once every 5 minutes in the first hour and continued to receive a dose once an hour in the next 11 hours. Afterward, 3 rabbits treated with levofloxacin were killed. Their corneas were examined for levofloxacin concentration. The remaining rabbits continued to receive 6 regular doses for 4 more days, each of which was administered at a 2-hour interval. Levofloxacin concentration was examined. Treatment efficacy was evaluated based on 4 clinical characteristics: corneal infiltrate, conjunctival edema, conjunctival injection, and discharge. RESULTS: All clinical characteristics, except conjunctival edema, improved significantly in rabbits treated with either levofloxacin or ceftazidime, compared to the placebo group. At the last follow-up (120 hours), all clinical characteristics improved significantly in both treatment groups. Mean corneal levofloxacin concentration in the treatment groups was 6.25 (0.32) MUg/g, which declined significantly to a mean of 2.15 (1.23) MUg/g after another 120 hours. CONCLUSIONS: Topical levofloxacin 0.5% improved the clinical characteristics of keratitis induced by levofloxacin-resistant P. aeruginosa. Such improvement could be attributed to a high concentration of levofloxacin that was above the minimum inhibitory level. PMID- 26107135 TI - Lingual-occlusal surface position predicts retroglossal obstruction in patients with obstructive sleep apnea hypopnea syndrome. AB - CONCLUSION: Lingual-occlusal surface position was significantly related to retroglossal obstruction, and lingual-occlusal surface position may be an available reference in clinical practice for the preliminary assessment of retroglossal obstruction. OBJECTIVE: To investigate the relationship between lingual-occlusal surface position and retroglossal obstruction in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). MATERIALS AND METHODS: A total of 140 patients with OSAHS diagnosed by polysomnography (PSG) were enrolled. Lingual-occlusal surface position was evaluated and classified into three types. Airway computed tomograpy (CT) was performed to measure the retroglossal cross sectional area and inner diameter. The PSG was repeated after the nasopharyngeal tube insertion (NPT-PSG). The NPT-PSG results, CT-measured data and incidence of retroglossal obstruction were compared among the different lingual-occlusal surface positions groups. RESULTS: The demographics of OSAHS patients with different lingual-occlusal surface positions was similar. As lingual-occlusal surface position type varied from type I to type III, retroglossal cross sectional area and inner diameter decreased, retroglossal airway obstruction rate increased, apnea hypopnea index (AHI) measured by NPT-PSG increased, and lowest oxygen saturation (LaSO2) decreased. PMID- 26107137 TI - MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1. AB - OBJECTIVES: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance. DESIGN AND METHODS: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip. RESULTS: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change >= 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375. CONCLUSION: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor. PMID- 26107138 TI - A sole multi-analyte receptor responds with three distinct fluorescence signals: traffic signal like sensing of Al(3+), Zn(2+) and F(-). AB - A dialdehyde-based multi-analyte sensor renders distinctive emission spectra for Al(3+), Zn(2+) and F(-) ions. The ligand exhibited different types of interactions with these three different ions resulting in the enhancement of fluorescence intensity at three different wavelengths. All the sensing processes were studied in detail by absorption spectroscopy, emission spectroscopy and (1)H NMR titration experiment. The ligand has the working ability in a wide pH range including the physiological pH. The ligand is non-toxic and amicable for sensing intracellular Al(3+) and Zn(2+) in live HeLa cells. PMID- 26107139 TI - The Vibrant Soundbridge in Children and Adolescents: Preliminary European Multicenter Results. AB - OBJECTIVE: Evaluation of safety and efficacy of the Vibrant Soundbridge in the treatment of hearing loss in children and adolescents with primary focus on improvement in speech discrimination. STUDY DESIGN: Prospective, single-subject repeated-measures design in which each subject serves as his/her own control. SETTING: Tertiary referral center. PATIENTS: Nineteen patients aged 5 to 17 years. INTERVENTION: Implantation of an active middle ear implant. MAIN OUTCOME MEASURE: Improvement in word recognition scores, speech reception thresholds, and signal-to-noise ratios (SNRs) were evaluated, in addition to air and bone conduction. Oldenburger Kids Satztest/Oldenburger Satztest sentences and Gottinger/Freiburger monosyllables at 65-dB hearing level were tested in two age groups. RESULTS: Significant speech discrimination improvement was seen in all patients after 6 months. In children 5 to 9 years old, mean monosyllable recognition improved from 28.9% (unaided) to 95.5% (Soundbridge-aided). Aided 50% sentence discrimination at 44.1 dB and SNR of -4.9 dB were measured. In patients 10 to 17 years old, mean word recognition improved from 18.5% to 89.0%, sentence reception threshold improved to 40.2 dB, and SNR to -3.6 dB. Comparison between age groups indicated a slight trend toward quicker adaptation by older subjects. However, after initial adjustment, a higher level of overall benefit was seen at 6 months in younger children. CONCLUSIONS: Currently, the only middle ear implant approved for pediatric patients, the Vibrant Soundbridge, provides an option in cases of congenital aural atresia or disease-induced defects, when surgical intervention and reconstruction is indicated. The 6-month results in this comparatively large study population validated conclusions found in previous trials. PMID- 26107140 TI - Letter to the Editor RE: Cochlear Implantation in Children with Congenital and Noncongenital Unilateral Deafness: A Case Series. PMID- 26107141 TI - Symbiotics in irritable bowel syndrome--better than probiotics alone? AB - PURPOSE OF REVIEW: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder associated with significant physical and psychological comorbidity. The etiology of the condition is uncertain but recent research suggests that the gut bacterial composition may play a role in its development. Therefore, manipulation of the intestinal microbiome by using probiotics and symbiotics has the potential to improve patient outcomes in IBS. RECENT FINDINGS: Numerous randomized controlled trials suggest a benefit of probiotics in the management of IBS, with a significant reduction in the likelihood of symptoms persisting after therapy, and improvements in abdominal pain, bloating and flatulence when probiotics are compared with placebo. Evidence for the effect of probiotics on quality of life is conflicting. Relatively few randomized controlled trials have examined the effect of symbiotics on outcomes in IBS, but results thus far are promising. SUMMARY: Probiotics appear to be beneficial in IBS. Data supporting the use of symbiotics is sparse. Whether symbiotics are superior to probiotics is unclear. PMID- 26107142 TI - Variety, Enjoyment, and Physical Activity Participation Among High School Students. AB - BACKGROUND: Federal guidelines state that youth should participate in a variety of physical activity (PA) they find enjoyable. Little is known, however, about how variety and enjoyment are associated with PA participation among adolescents. METHODS: Data came from the 2010 National Youth Physical Activity and Nutrition Survey, a nationally representative survey of adolescents. Path analysis was used to examine the association of a variety of self-reported PA, defined as the number of activities and activity types (ie, team sports/weightlifting, individual activities, and other competitive/recreational sports), on self reported PA enjoyment and participation. The analysis also examined whether enjoyment mediates the association between a variety of PA and participation. Separate models were estimated for boys and girls. RESULTS: Number of activities was associated with increased PA enjoyment and participation. For boys and girls, team sports/weightlifting was associated with increased participation, and individual activities were indirectly associated with increased participation through enjoyment. For boys, team sports/weightlifting was indirectly related with participation. CONCLUSIONS: These findings suggest that participation in a variety of PA is associated with increased PA enjoyment and participation. Providing opportunities for adolescents to engage in a variety of activities might help them identify PA they enjoy and facilitate lifelong PA habits. PMID- 26107144 TI - Retinoblastoma: Recent Update and Management Frontiers. PMID- 26107143 TI - Variable Patterns of Continuous Morphine Infusions at End of Life. AB - BACKGROUND: Continuous morphine infusions (CMIs) treat pain and dyspnea at the end of life (EOL). CMIs may be initiated at an empiric rate and/or are rapidly escalated without proper titration. OBJECTIVE: The study objective was to evaluate CMI patterns at the EOL. METHODS: This single-center, retrospective chart review evaluated adult patients who died while receiving CMI at EOL. Patient demographics and opioid dosing information were extracted from an electronic medical record. Twenty-four hour IV morphine equivalent was calculated prior to CMI initiation and at the time of death. RESULTS: Of the 190 patient charts, 63.2% (n=120) received no bolus doses prior to CMI initiation. Mean 24 hour IV morphine equivalent prior to CMI initiation was 49.3 mg (range: 0-1200 mg, SD 384.9) and at time of death was 267.1 mg (12.0-5193.2 mg, SD 442.2), representing an increase of +442%. Mean CMI starting rate was 3.3 mg/hour (0.4 30.0 mg/hour, SD 3.6) with titration at time of death to a mean of 7.7 mg/hour (0.4-70.0 mg/hour, SD 9.4), representing an increase of +130%. Mean number of CMI rate adjustments was 2.5 (0-5, SD 3.3); and number of bolus doses administered between titrations was 4.2 (0-27, SD 4.8). Mean time from CMI initiation to death was 15.5 hours (0.05-126.9 hours, SD 21.7). There was a negative association between rate of infusion increase per hour and total number of hours on CMI (r= 0.2, p=0.0062). CONCLUSIONS: Hospitalized patients at EOL had a much higher 24 hour IV morphine equivalents and CMI rates at time of death compared to CMI initiation. Variability was observed in the number of CMI rate adjustments and the number of bolus doses administered. PMID- 26107145 TI - Medication Adherence in Glaucoma Patients. PMID- 26107146 TI - Adherence and Persistence: The Challenges for Glaucoma Medical Therapy. AB - Suboptimal adherence and persistence to therapy are major challenges for patients treated with ocular hypotensive medications. The problem affects 5% to 80% of glaucoma patients from all nations, ethnicities, socioeconomic backgrounds, and education levels. Although health care providers are generally poor at detecting suboptimal or poor adherence in the clinical setting, several strategies to systematically assess adherence and persistence rates are available. One strategy involves electronic monitoring of patient dosing, which provides useful insights into specific patterns of adherence behavior among glaucoma patients. Adherence behavior is complex with multiple interrelated determinants; these can be broadly grouped into provider factors, environmental factors, medication factors, and patient factors. Targeted patient education strategies, counseling, electronic monitors, alarms, and reminders have all been used in efforts to improve adherence. These interventions probably work best in combination. Identifying tangible barriers to adherence and simple strategies to overcome these through an open, discursive relationship between clinician and patient is key to optimizing adherence. PMID- 26107147 TI - The Endophthalmitis Kit. AB - PURPOSE: This study aimed to provide essential first-intervention material for treatment of bacterial and fungal endophthalmitis in a ready-to-use kit. DESIGN: A prospective investigational study. METHODS: We have developed the Endophthalmitis Kit (E-kit), which contains most essential devices and antibacterial and antifungal antibiotics for initial treatment of bacterial and fungal endophthalmitis. The easy-to-prepare antibiotics includes vancomycin, ceftazidime, and voriconazole. We used visual analog scale to score the health personnel comfort of each content of the kit in 20 consecutive patients with endophthalmitis where the E-Kit was used. RESULTS: The visual analog scale score was highest for the antibiotics and least for eye speculum. The 2-step preparation of antibiotics was easier than the current 4-step preparation. CONCLUSIONS: The E-Kit benefit included accurate and easy preparation of antibiotics and antifungal, safe vitreous biopsy and intravitreal injection, and reduced ordering time and inventory cost. PMID- 26107148 TI - Comparison of Type of Species and Antibacterial Susceptibility Profile of Staphylococci Isolated From Normal Healthy Conjunctiva and Ocular Infections. AB - PURPOSE: To compare the prevalence of various staphylococcal species in ocular infections [OIs (n = 105)] and in normal healthy conjunctiva [NC (n = 51)]. Antibacterial susceptibility profile of the isolates and prevalence of mecA gene among the isolates were also compared. DESIGN: A prospective, comparative, experimental study. METHODS: Antibiotic susceptibility was determined against chloramphenicol, ciprofloxacin, gatifloxacin, moxifloxacin, ofloxacin, cefazolin, vancomycin and cefoxitin by disc diffusion technique as per Clinical and Laboratory Standards Institute guidelines. Methicillin resistance was confirmed by detection of mecA gene by polymerase chain reaction. RESULTS: The prevalence of Staphylococcus aureus was significantly higher (P < 0.0001) in OIs compared with NC (48.6%, 9.8%), whereas the prevalence of Staphylococcus epidermidis was higher (P = 0.02) in NC (22.9%, 41.2%). Overall methicillin resistance was higher in S. epidermidis (66.7% each in OIs and NC) compared with S. aureus (OIs: 7.8%; NC: 0%), which was statistically significant (P < 0.0001). Methicillin resistance was also high among other coagulase-negative staphylococci in both groups [OIs: 40% (12/30); NC: 28% (7/25)]. Vancomycin was effective against all the isolates from both groups. Cefazolin was equally effective. CONCLUSIONS: This study found S. aureus to be a major pathogen in OIs, although it is not common conjunctival flora. The data caution that prevalence of methicillin resistance in coagulase negative staphylococci is more than S. aureus in OIs and must be considered in their treatment. Despite methicillin resistance, staphylococci from OIs and NC remain sensitive to vancomycin and cefazolin. PMID- 26107149 TI - Feasibility of the New Torsional Phacoemulsification Software Phacoemulsification (Ozil IP) in Hard Cataracts. AB - PURPOSE: To assess the feasibility of using the new torsional intelligent phacoemulsification software (Ozil IP) phacoemulsification in hard cataracts of N3+. DESIGN: A cohort study. METHODS: Eighty patients were recruited and randomized into 2 groups, the study group and the control group. Each group consisted of 40 eyes. Routine cataract surgeries were performed using standard torsional software (Ozil) and Ozil IP in hard cataracts of N3+. Main outcome measures included cumulative dissipated energy (CDE), amount of balanced salt solution (BSS) used, and changes in central corneal thickness (CCT). RESULTS: The mean CDE was significantly less in the study group compared with the control group (P = 0.05). The mean time in foot pedal position 3 (FP3) for varying grades of cataract density ranged from 16.3 to 30.2 seconds in the study group and from 19.1 to 39.7 seconds in the control group, which was statistically significant (P = 0.03). The amount of BSS used was 34.19 mL in the study group and 44.05 mL in the control group. On the first postoperative day, CCT was significantly different between the study and the control group (P = 0.005). CONCLUSIONS: The 3 parameters (CDE, FP3 and BSS amount) were found to be effective with no significant complications. The new Ozil IP required less CDE and less FP3 time with less postoperative corneal edema, and thus patients had a more rapid visual recovery. PMID- 26107150 TI - Review of Intermediate Uveitis. AB - The purpose of this article is to highlight evidence about the medical and surgical management of intermediate uveitis (IU). Updated understandings of the immunopathology of IU were reviewed in this retrospective literature review. Literature selection for this review was based on the PubMed database (National Library of Medicine) and OVID database (Wolters Kluwer). Articles deemed relevant were selected and highlighted. Intermediate uveitis is most often a benign form of uveitis. Since intermediate uveitis has been described in association with different systemic disorders, the initial diagnostic evaluation should serve to exclude masquerade syndromes and infectious diseases in which immunosuppression may be ineffective or contraindicated. Although the pathogenesis of intermediate uveitis is not fully understood, identification of proinflammatory molecules involved in the IU has contributed to the development and implementation of new therapies. Studies about the use of various immunosuppressants, biological agents and surgical treatment on IU have provided more evidence for managing IU. Nevertheless, corticosteroids remain the mainstay of treatment. The treatment options of intermediate uveitis are evolving, with the development of various immunosuppressants and biological agents. The management of intermediate uveitis should be tailored individually, based on specific causes of the disease and associated complications. PMID- 26107151 TI - One Year of Pediatric Ophthalmology and Strabismus Research in Review. AB - PURPOSE: To highlight recent advances in amblyopia and strabismus. DESIGN: Literature review. METHODS: A literature search of articles published in the English language was performed in PubMed or MEDLINE between May 2012 and April 2013 using the terms amblyopia or strabismus. Articles deemed relevant were selected. RESULTS: The review highlights articles that increase our understanding of strabismus and amblyopia as well as newer treatment strategies. CONCLUSIONS: The review highlights some new information and possible future advances in amblyopia and strabismus. PMID- 26107152 TI - One Year of Cornea Research in Review-2012. AB - PURPOSE: The purpose of this study was to provide an update of significant cornea literature published in the past 1 year. DESIGN: This was a literature review. METHODS: The authors conducted a 1-year English-language literature search on PubMed, from January 1, 2012, to December 31, 2012, using the following terms: corneal transplantation, anterior lamellar keratoplasty, penetrating keratoplasty, endothelial keratoplasty, Descemet stripping automated endothelial keratoplasty, Descemet membrane endothelial keratoplasty, Descemet membrane endothelial transfer, ocular surface epithelial transplantation, limbal epithelial transplantation, cultivated oral mucosal epithelial transplantation, keratoprosthesis, infectious keratitis, cross-linking, keratoconus, corneal neovascularization, corneal imaging, optical coherence tomography, Pentacam Scheimpflug imaging, and in vivo confocal microscopy. RESULTS: This review includes original articles and review articles that contain significant updates and novel aspects in the field of cornea from the following journals: American Journal of Ophthalmology, British Journal of Ophthalmology, Ophthalmology, Investigative Ophthalmology and Visual Science, and Cornea. Letters to the editor, unpublished work, manuscripts not in English, and abstracts were not included. CONCLUSIONS: This review highlights significant literature that is applicable to the practicing ophthalmologist. PMID- 26107154 TI - Letter to the Editor Regarding "Specialist Nurse Screening for Retinopathy of Prematurity-A Pilot Study". PMID- 26107153 TI - Genetic and Epigenetic Profile of Retinoblastoma in a Chinese Population: Analysis of 47 Patients. AB - PURPOSE: To report genetic findings of retinoblastoma gene RB1 in a Chinese ethnic group with retinoblastoma. DESIGN: A retrospective noncomparative case series. METHODS: Genomic DNA was extracted from peripheral blood samples, and tumor tissue samples were collected from 47 patients (37 patients with unilateral retinoblastoma). The 27 known RB1 coding exons, splicing boundaries, and promoters were screened for point mutations or small mutations by polymerase chain reaction-single-strand conformation polymorphism-DNA sequencing. Microsatellite analysis was applied to 30 patients with both blood samples and retinoblastoma tumor tissues available to examine loss of heterozygosity according to microsatellite markers within or adjacent to the RB1 locus. Methylation of the RB1 gene was investigated in retinoblastoma tissue samples of 40 patients by methylation-specific polymerase chain reaction. RESULTS: Mutations in the RB1 gene were identified in 10 patients (21%). A loss of heterozygosity was detected at locus D13S153 in 14 of 26 patients, at locus D13S262 in 13 of 28 patients, and at locus D13S284 in 8 of 27 patients. Altogether, loss of heterozygosity was detected in 18 (60%) of 30 patients. Loss of heterozygosity at the RB1 locus was associated with a loss of pRb expression (P = 0.01). Hypermethylation in the promoter CpG island in the RB1 gene was found in 4 (10%) of 40 examined patients. CONCLUSIONS: The localization and type of mutations identified in Chinese patients with retinoblastoma fit well into the pattern observed in previous studies on other ethnic groups. No new mutations were found. Future studies may examine whether these results are helpful for genetic counseling of Chinese patients. PMID- 26107155 TI - Safety of Specialist Nurse Screening for Retinopathy of Prematurity-Response to Letter. PMID- 26107156 TI - Effect of Polymethylene Spacer of Cationic Gemini Surfactants on Solvation Dynamics and Rotational Relaxation of Coumarin 153 in Aqueous Micelles. AB - The present work demonstrates the solvation dynamics and rotational relaxation of Coumarin 153 (C-153) in the micelles of a series of cationic gemini surfactants, 12-s-12, 2Br(-) containing a hydrophobic polymethylene spacer with s = 3, 4, 6, 8, 12. Steady-state and time-correlated single-photon counting (TCSPC) fluorescence spectroscopic techniques have been used to carry out this study. Steady-state and TCSPC fluorescence data suggest that C-153 molecules are located at the Stern layer of micelles. While probe molecules feel more or less the same micropolarity in the micellar phase, the microviscosity of micelles decreases with spacer chain length. Solvation dynamics at the Stern layer is bimodal in nature with fast solvation as a major component. Counter ions and water molecules bonded with the polar headgroups of surfactant molecules are responsible for the slow component. Average solvation time increases with spacer chain length because of the increased degree of counter ion dissociation. Some water molecules are involved in the solvation of counter ions themselves, resulting in the decrease in "free" water molecules to be available for the solvation of C-153. The hydrophobic spacer chain also has an effect on increasing the solvation time with increasing chain length. The average rotational relaxation time for C-153 decreases with spacer chain length with a rapid decrease at s > 4. The anisotropy decay of C-153 in micelles is biexponential in nature. The slow rotational relaxation is due to the lateral diffusion of C-153 in micelles. Lateral diffusion is much faster than the rotational motion of a micelle as a whole. The rotational motion of the micelle as a whole becomes faster with the decreasing size of micelles. PMID- 26107157 TI - Expanding Therapy With Long-Acting Antipsychotic Medication in Patients With Schizophrenia. PMID- 26107158 TI - Pneumomediastinum Following Blunt Trauma: Are We Closer to Unlocking Its Significance? PMID- 26107159 TI - Cognitive effects of deep brain stimulation in patients with obsessive-compulsive disorder. AB - BACKGROUND: Deep brain stimulation (DBS) is a promising treatment for treatment refractory obsessive-compulsive disorder (OCD). However, the effects of DBS on cognitive functioning remain unclear. Therefore, we aimed to assess cognitive safety of DBS for treatment-refractory OCD and the association between clinical changes and cognitive functioning. METHODS: Patients with treatment-refractory OCD treated with DBS targeted at the nucleus accumbens (NAcc) were compared with a control group of 14 patients with treatment-refractory OCD treated with care as usual. We assessed cognitive functioning at baseline, 3 weeks postoperatively and following 8 months of DBS. We compared change in clinical symptoms with cognitive changes. RESULTS: There were 16 patients in the DBS group and 14 patients in the control group. Three weeks postoperatively, the DBS group showed a significantly reduced performance on measures of visual organization and verbal fluency and a trend toward reduced performance on measures of visual memory and abstract reasoning. Cognitive functioning was found to be stable on all other measures. After 8 months of DBS, reduced performances persisted, except for a significant improvement in verbal fluency. Cognitive functioning in all other domains remained unaffected. We found no correlation between improvement of clinical symptoms and cognitive changes. LIMITATIONS: A limitation of this study was its relatively small sample size. CONCLUSION: Deep brain stimulation targeted at the NAcc may be considered a safe method in terms of cognition because cognitive functioning was unaffected on most neuropsychological measures. Nevertheless, we observed some minor reduced performance on specific measures of executive functioning that were possibly associated with surgical intervention. Our results suggest that severity of OCD symptoms is independent of cognitive functioning. PMID- 26107160 TI - Valence and agency influence striatal response to feedback in patients with major depressive disorder. AB - BACKGROUND: Reduced sensitivity to positive feedback is common in patients with major depressive disorder (MDD). However, findings regarding negative feedback are ambiguous, with both exaggerated and blunted responses being reported. The ventral striatum (VS) plays a major role in processing valenced feedback, and previous imaging studies have shown that the locus of controls (self agency v. external agency) over the outcome influences VS response to feedback. We investigated whether attributing the outcome to one's own action or to an external agent influences feedback processing in patients with MDD. We hypothesized that depressed participants would be less sensitive to the feedback attribution reflected by an altered VS response to self-attributed gains and losses. METHODS: Using functional MRI and a motion prediction task, we investigated the neural responses to self-attributed (SA) and externally attributed (EA) monetary gains and losses in unmedicated patients with MDD and healthy controls. RESULTS: We included 21 patients and 25 controls in our study. Consistent with our prediction, healthy controls showed a VS response influenced by feedback valence and attribution, whereas in depressed patients striatal activity was modulated by valence but was insensitive to attribution. This attribution insensitivity led to an altered ventral putamen response for SA - EA losses in patients with MDD compared with healthy controls. LIMITATIONS: Depressed patients with comorbid anxiety disorder were included. CONCLUSION: These results suggest an altered assignment of motivational salience to SA losses in patients with MDD. Altered striatal response to SA negative events may reinforce the belief of not being in control of negative outcomes contributing to a cycle of learned helplessness. PMID- 26107161 TI - Elevated cognitive control over reward processing in recovered female patients with anorexia nervosa. AB - BACKGROUND: Individuals with anorexia nervosa are thought to exert excessive self control to inhibit primary drives. METHODS: This study used functional MRI (fMRI) to interrogate interactions between the neural correlates of cognitive control and motivational processes in the brain reward system during the anticipation of monetary reward and reward-related feedback. In order to avoid confounding effects of undernutrition, we studied female participants recovered from anorexia nervosa and closely matched healthy female controls. The fMRI analysis (including node-to-node functional connectivity) followed a region of interest approach based on models of the brain reward system and cognitive control regions implicated in anorexia nervosa: the ventral striatum, medial orbitofrontal cortex (mOFC) and dorsolateral prefrontal cortex (DLPFC). RESULTS: We included 30 recovered patients and 30 controls in our study. There were no behavioural differences and no differences in hemodynamic responses of the ventral striatum and the mOFC in the 2 phases of the task. However, relative to controls, recovered patients showed elevated DLPFC activity during the anticipation phase, failed to deactivate this region during the feedback phase and displayed greater functional coupling between the DLPFC and mOFC. Recovered patients also had stronger associations than controls between anticipation-related DLPFC responses and instrumental responding. LIMITATIONS: The results we obtained using monetary stimuli might not generalize to other forms of reward. CONCLUSION: Unaltered neural responses in ventral limbic reward networks but increased recruitment of and connectivity with lateral-frontal brain circuitry in recovered patients suggests an elevated degree of selfregulatory processes in response to rewarding stimuli. An imbalance between brain systems subserving bottom-up and top-down processes may be a trait marker of the disorder. PMID- 26107162 TI - Olfactory performance segregates effects of anhedonia and anxiety on social function in patients with schizophrenia. AB - BACKGROUND: Social dysfunction is common among individuals with schizophrenia. While often attributed to anhedonia, social dysfunction could also result from unrecognized anxiety. We examined the contributions of anhedonia and anxiety to social function using olfactory function to examine whether the domains had separate underpinnings. METHODS: We assessed anhedonia, anxiety and social function as well as olfactory function in well-characterized patients with schizophrenia or schizoaffective disorder and healthy controls. RESULTS: We included 56 patients and 37 controls in our study. Patients exhibited significantly higher levels of anhedonia and anxiety than controls, and the domains were highly correlated in patients. The combination of anhedonia and anxiety more strongly predicted social dysfunction than either measure alone. Smell identification was differentially related to the symptoms, with better performance predicting less anhedonia but more social fear in male patients. LIMITATIONS: The use of self-report measures precludes differentiation between recollected or recounted experience. Aside from smell identification and odour threshold, additional measures of olfaction may be considered for future studies. CONCLUSION: Anhedonia and anxiety were strongly correlated and both negatively impacted social function. The olfactory biomarker results support the conclusion that these domains are separate. Social function in patients with schizophrenia may improve with interventions for anxiety, even in the presence of marked negative symptoms. PMID- 26107164 TI - Correction: the tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury. PMID- 26107163 TI - Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases. AB - BACKGROUND: Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. METHODS: We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. RESULTS: We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS-) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. LIMITATIONS: Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. CONCLUSION: The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS- responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine. PMID- 26107165 TI - Social Support in Two Cultures: Everyday Transactions in the U.S. and Empathic Assurance in Japan. AB - We studied received social support using the cross-cultural method of situation sampling. College students from the US and Japan described and rated recent examples of received social support, both everyday support as well as support in response to stress. Middle class, European-American (EuA) students' situations fit a model in which support is frequent and offered freely in interactions, even for relatively minor issues. Even when it's unrequested, EuA support makes recipients feel in control, and support-givers are perceived to have acted by free choice. In contrast, results suggest that middle-class Japanese (Jpn) contexts favor support that is empathic and responsive to the recipients' degree of need. Japanese support was experienced positively when it was emotional support, when it was in more serious situations and when the support was rated as needed by the recipient. In Japan, although problem-based support is most common, it is not particularly positive, apparently because it is less likely to be perceived as needed. PMID- 26107166 TI - Identification of miR-26a as a target gene of bile acid receptor GPBAR-1/TGR5. AB - GPBAR1/TGR5 is a G protein-coupled receptor of bile acids. TGR5 is known to regulate the BA homeostasis and energy metabolism. Recent studies highlight an important role of TGR5 in alleviating obesity and improving glucose regulation, however, the mechanism of which is still unclear. Here we report that TGR5 is involved in mediating the anti-obesity and anti-hyperglycemia effect of a natural compound, oleanolic acid. By comparing the miRNA profiles between wild type and TGR5-/- livers after OA treatment, we identified miR-26a as a novel downstream target gene of TGR5 activation. The expression of miR-26a in the liver was induced in a TGR5-dependent manner after feeding the mice with a bile acid diet. TGR5 activation strongly increased the expression of miR-26a in macrophages, including the Kupffer cells in the liver. We further demonstrated that JNK pathway was required for miR-26a induction by TGR5 activation. Interestingly, we located the TGR5-responsive DNA element to a proximal region of miR-26's promoter, which was independent of the transcription of its host genes. These results unravel a new mechanism by which bile acid receptor TGR5 activates a miRNA gene expression. PMID- 26107167 TI - Hiccups Associated with Aripiprazole in an Adolescent with Bipolar Disorder. PMID- 26107168 TI - Correction: Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers. PMID- 26107170 TI - A DPSIR model for ecological security assessment through indicator screening: a case study at Dianchi Lake in China. AB - Given the important role of lake ecosystems in social and economic development, and the current severe environmental degradation in China, a systematic diagnosis of the ecological security of lakes is essential for sustainable development. A Driving-force, Pressure, Status, Impact, and Risk (DPSIR) model, combined with data screening for lake ecological security assessment was developed to overcome the disadvantages of data selection in existing assessment methods. Correlation and principal component analysis were used to select independent and representative data. The DPSIR model was then applied to evaluate the ecological security of Dianchi Lake in China during 1988-2007 using an ecological security index. The results revealed a V-shaped trend. The application of the DPSIR model with data screening provided useful information regarding the status of the lake's ecosystem, while ensuring information efficiency and eliminating multicollinearity. The modeling approach described here is practical and operationally efficient, and provides an attractive alternative approach to assess the ecological security of lakes. PMID- 26107169 TI - Effects of Different Maturation Systems on Bovine Oocyte Quality, Plasma Membrane Phospholipid Composition and Resistance to Vitrification and Warming. AB - The objective of this study was to evaluate the effects of different maturation systems on oocyte resistance after vitrification and on the phospholipid profile of the oocyte plasma membrane (PM). Four different maturation systems were tested: 1) in vitro maturation using immature oocytes aspirated from slaughterhouse ovaries (CONT; n = 136); 2) in vitro maturation using immature oocytes obtained by ovum pick-up (OPU) from unstimulated heifers (IMA; n = 433); 3) in vitro maturation using immature oocytes obtained by OPU from stimulated heifers (FSH; n = 444); and 4) in vivo maturation using oocytes obtained from heifers stimulated 24 hours prior by an injection of GnRH (MII; n = 658). A sample of matured oocytes from each fresh group was analyzed by matrix associated laser desorption-ionization (MALDI-TOF) to determine their PM composition. Then, half of the matured oocytes from each group were vitrified/warmed (CONT VIT, IMA VIT, FSH VIT and MII VIT), while the other half were used as fresh controls. Afterwards, the eight groups underwent IVF and IVC, and blastocyst development was assessed at D2, D7 and D8. A chi-square test was used to compare embryo development between the groups. Corresponding phospholipid ion intensity was expressed in arbitrary units, and following principal components analyses (PCA) the data were distributed on a 3D graph. Oocytes obtained from superstimulated animals showed a greater rate of developmental (P<0.05) at D7 (MII = 62.4+/-17.5% and FSH = 58.8+/-16.1%) compared to those obtained from unstimulated animals (CONT = 37.9+/-8.5% and IMA = 50.6+/-14.4%). However, the maturation system did not affect the resistance of oocytes to vitrification because the blastocyst rate at D7 was similar (P>0.05) for all groups (CONT VIT = 2.8+/-3.5%, IMA VIT = 2.9+/ 4.0%, FSH VIT = 4.3+/-7.2% and MII VIT = 3.6+/-7.2%). MALDI-TOF revealed that oocytes from all maturation groups had similar phospholipid contents, except for 760.6 ([PC (34:1) + H]+), which was more highly expressed in MII compared to FSH (P<0.05). The results suggest that although maturation systems improve embryonic development, they do not change the PM composition nor the resistance of bovine oocytes to vitrification. PMID- 26107171 TI - Pesticides and Ostreid Herpesvirus 1 Infection in the Pacific Oyster, Crassostrea gigas. AB - Since 2008, mass mortality outbreaks have been reported in all French regions producing Pacific oysters, and in several Member States of the European Union. These mass mortality events of Pacific oysters are related to OsHV-1 infection. They occur during spring and summer periods leaving suspect the quality of the marine environment and the role of seasonal use of pesticides associated with the arrival of freshwater in oyster rearing areas. Pesticides have been also detected in French coastal waters, especially in areas of oyster production. Using PMA real-time PCR we showed that a mixture of 14 pesticides has no effect on the integrity of virus capsids from viral suspension in the conditions tested. A contact of oysters with this pesticide mixture was related to higher mortality rates among experimentally infected animals in comparison with control ones (no previous pesticide exposure before experimental infection). We therefore suggest that pesticides at realistic concentration can exert adverse effects on Pacific oysters and causes an increased susceptibility to the viral infection in experimental conditions. PMID- 26107172 TI - Role of Areca Nut Induced TGF-beta and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis. AB - Areca nut consumption has been implicated in the progression of Oral Submucous fibrosis (OSF); an inflammatory precancerous fibrotic condition. Our previous studies have demonstrated the activation of TGF-beta signaling in epithelial cells by areca nut components and also propose a role for epithelial expressed TGF-beta in the pathogenesis of OSF. Although the importance of epithelial cells in the manifestation of OSF has been proposed, the actual effectors are fibroblast cells. However, the role of areca nut and TGF-beta in the context of fibroblast response has not been elucidated. Therefore, to understand their role in the context of fibroblast response in OSF pathogenesis, human gingival fibroblasts (hGF) were treated with areca nut and/or TGF-beta followed by transcriptome profiling. The gene expression profile obtained was compared with the previously published transcriptome profiles of OSF tissues and areca nut treated epithelial cells. The analysis revealed regulation of 4666 and 1214 genes by areca nut and TGF-beta treatment respectively. The expression of 413 genes in hGF cells was potentiated by areca nut and TGF-beta together. Further, the differentially expressed genes of OSF tissues compared to normal tissues overlapped significantly with areca nut and TGF-beta induced genes in epithelial and hGF cells. Several positively enriched pathways were found to be common between OSF tissues and areca nut +TGF-beta treated hGF cells. In concordance, areca nut along with TGF-beta enhanced fibroblast activation as demonstrated by potentiation of alphaSMA, gammaSMA and collagen gel contraction by hGF cells. Furthermore, TGF-beta secreted by areca nut treated epithelial cells influenced fibroblast activation and other genes implicated in fibrosis. These data establish a role for areca nut influenced epithelial cells in OSF progression by activation of fibroblasts and emphasizes the importance of epithelial-mesenchymal interaction in OSF. PMID- 26107174 TI - High-Throughput 3-D Monitoring of Agricultural-Tree Plantations with Unmanned Aerial Vehicle (UAV) Technology. AB - The geometric features of agricultural trees such as canopy area, tree height and crown volume provide useful information about plantation status and crop production. However, these variables are mostly estimated after a time-consuming and hard field work and applying equations that treat the trees as geometric solids, which produce inconsistent results. As an alternative, this work presents an innovative procedure for computing the 3-dimensional geometric features of individual trees and tree-rows by applying two consecutive phases: 1) generation of Digital Surface Models with Unmanned Aerial Vehicle (UAV) technology and 2) use of object-based image analysis techniques. Our UAV-based procedure produced successful results both in single-tree and in tree-row plantations, reporting up to 97% accuracy on area quantification and minimal deviations compared to in field estimations of tree heights and crown volumes. The maps generated could be used to understand the linkages between tree grown and field-related factors or to optimize crop management operations in the context of precision agriculture with relevant agro-environmental implications. PMID- 26107173 TI - Core and Shell Song Systems Unique to the Parrot Brain. AB - The ability to imitate complex sounds is rare, and among birds has been found only in parrots, songbirds, and hummingbirds. Parrots exhibit the most advanced vocal mimicry among non-human animals. A few studies have noted differences in connectivity, brain position and shape in the vocal learning systems of parrots relative to songbirds and hummingbirds. However, only one parrot species, the budgerigar, has been examined and no differences in the presence of song system structures were found with other avian vocal learners. Motivated by questions of whether there are important differences in the vocal systems of parrots relative to other vocal learners, we used specialized constitutive gene expression, singing-driven gene expression, and neural connectivity tracing experiments to further characterize the song system of budgerigars and/or other parrots. We found that the parrot brain uniquely contains a song system within a song system. The parrot "core" song system is similar to the song systems of songbirds and hummingbirds, whereas the "shell" song system is unique to parrots. The core with only rudimentary shell regions were found in the New Zealand kea, representing one of the only living species at a basal divergence with all other parrots, implying that parrots evolved vocal learning systems at least 29 million years ago. Relative size differences in the core and shell regions occur among species, which we suggest could be related to species differences in vocal and cognitive abilities. PMID- 26107175 TI - Characterizing the DNA Damage Response by Cell Tracking Algorithms and Cell Features Classification Using High-Content Time-Lapse Analysis. AB - Traditionally, the kinetics of DNA repair have been estimated using immunocytochemistry by labeling proteins involved in the DNA damage response (DDR) with fluorescent markers in a fixed cell assay. However, detailed knowledge of DDR dynamics across multiple cell generations cannot be obtained using a limited number of fixed cell time-points. Here we report on the dynamics of 53BP1 radiation induced foci (RIF) across multiple cell generations using live cell imaging of non-malignant human mammary epithelial cells (MCF10A) expressing histone H2B-GFP and the DNA repair protein 53BP1-mCherry. Using automatic extraction of RIF imaging features and linear programming techniques, we were able to characterize detailed RIF kinetics for 24 hours before and 24 hours after exposure to low and high doses of ionizing radiation. High-content-analysis at the single cell level over hundreds of cells allows us to quantify precisely the dose dependence of 53BP1 protein production, RIF nuclear localization and RIF movement after exposure to X-ray. Using elastic registration techniques based on the nuclear pattern of individual cells, we could describe the motion of individual RIF precisely within the nucleus. We show that DNA repair occurs in a limited number of large domains, within which multiple small RIFs form, merge and/or resolve with random motion following normal diffusion law. Large foci formation is shown to be mainly happening through the merging of smaller RIF rather than through growth of an individual focus. We estimate repair domain sizes of 7.5 to 11 um2 with a maximum number of ~15 domains per MCF10A cell. This work also highlights DDR which are specific to doses larger than 1 Gy such as rapid 53BP1 protein increase in the nucleus and foci diffusion rates that are significantly faster than for spontaneous foci movement. We hypothesize that RIF merging reflects a "stressed" DNA repair process that has been taken outside physiological conditions when too many DSB occur at once. High doses of ionizing radiation lead to RIF merging into repair domains which in turn increases DSB proximity and misrepair. Such finding may therefore be critical to explain the supralinear dose dependence for chromosomal rearrangement and cell death measured after exposure to ionizing radiation. PMID- 26107176 TI - Should We Stop Looking for a Better Scoring Algorithm for Handling Implicit Association Test Data? Test of the Role of Errors, Extreme Latencies Treatment, Scoring Formula, and Practice Trials on Reliability and Validity. AB - Since the development of D scores for the Implicit Association Test, few studies have examined whether there is a better scoring method. In this contribution, we tested the effect of four relevant parameters for IAT data that are the treatment of extreme latencies, the error treatment, the method for computing the IAT difference, and the distinction between practice and test critical trials. For some options of these different parameters, we included robust statistic methods that can provide viable alternative metrics to existing scoring algorithms, especially given the specificity of reaction time data. We thus elaborated 420 algorithms that result from the combination of all the different options and test the main effect of the four parameters with robust statistical analyses as well as their interaction with the type of IAT (i.e., with or without built-in penalty included in the IAT procedure). From the results, we can elaborate some recommendations. A treatment of extreme latencies is preferable but only if it consists in replacing rather than eliminating them. Errors contain important information and should not be discarded. The D score seems to be still a good way to compute the difference although the G score could be a good alternative, and finally it seems better to not compute the IAT difference separately for practice and test critical trials. From this recommendation, we propose to improve the traditional D scores with small yet effective modifications. PMID- 26107177 TI - Tantalum Nitride-Decorated Titanium with Enhanced Resistance to Microbiologically Induced Corrosion and Mechanical Property for Dental Application. AB - Microbiologically induced corrosion (MIC) of metallic devices/implants in the oral region is one major cause of implant failure and metal allergy in patients. Therefore, it is crucial to develop practical approaches which can effectively prevent MIC for broad clinical applications of these materials. In the present work, tantalum nitride (TaN)-decorated titanium with promoted bio-corrosion and mechanical property was firstly developed via depositing TaN layer onto pure Ti using magnetron sputtering. The microstructure and chemical constituent of TaN coatings were characterized, and were found to consist of a hard fcc-TaN outer layer. Besides, the addition of TaN coatings greatly increased the hardness and modulus of pristine Ti from 2.54 +/- 0.20 to 29.88 +/- 2.59 GPa, and from 107.19 +/- 6.98 to 295.46 +/- 19.36 GPa, respectively. Potentiodynamic polarization and electrochemical impedance spectroscopy studies indicated that TaN coating exhibited higher MIC resistance in comparison to bare Ti and TiN-coated coating in two bacteria-containing artificial saliva solutions. Moreover, the biofilm experiment showed that the TaN-decorated Ti sample possessed good antibacterial performance. The SEM and XPS results after biofilm removal demonstrated that TaN film remained its integrity and stability, while TiN layer detached from Ti surface in the bio-corrosion tests, demonstrating the anti-MIC behavior and the strong binding property of TaN coating to Ti substrate. Considering all these results, TaN-decorated Ti material exhibits the optimal comprehensive performance and holds great potential as implant material for dental applications. PMID- 26107178 TI - Limitations of climatic data for inferring species boundaries: insights from speckled rattlesnakes. AB - Phenotypes, DNA, and measures of ecological differences are widely used in species delimitation. Although rarely defined in such studies, ecological divergence is almost always approximated using multivariate climatic data associated with sets of specimens (i.e., the "climatic niche"); the justification for this approach is that species-specific climatic envelopes act as surrogates for physiological tolerances. Using identical statistical procedures, we evaluated the usefulness and validity of the climate-as-proxy assumption by comparing performance of genetic (nDNA SNPs and mitochondrial DNA), phenotypic, and climatic data for objective species delimitation in the speckled rattlesnake (Crotalus mitchellii) complex. Ordination and clustering patterns were largely congruent among intrinsic (heritable) traits (nDNA, mtDNA, phenotype), and discordance is explained by biological processes (e.g., ontogeny, hybridization). In contrast, climatic data did not produce biologically meaningful clusters that were congruent with any intrinsic dataset, but rather corresponded to regional differences in atmospheric circulation and climate, indicating an absence of inherent taxonomic signal in these data. Surrogating climate for physiological tolerances adds artificial weight to evidence of species boundaries, as these data are irrelevant for that purpose. Based on the evidence from congruent clustering of intrinsic datasets, we recommend that three subspecies of C. mitchellii be recognized as species: C. angelensis, C. mitchellii, and C. Pyrrhus. PMID- 26107179 TI - Matrix Intensification Affects Body and Physiological Condition of Tropical Forest-Dependent Passerines. AB - Matrix land-use intensification is a relatively recent and novel landscape change that can have important influences on the biota within adjacent habitat patches. While there are immediate local changes that it brings about, the influences on individual animals occupying adjacent habitats may be less evident initially. High-intensity land use could induce chronic stress in individuals in nearby remnants, leading ultimately to population declines. We investigated how physiological indicators and body condition measures of tropical forest-dependent birds differ between forest adjacent to surface mining sites and that near farmlands at two distances from remnant edge in southwest Ghana. We used mixed effects models of several condition indices including residual body mass and heterophil to lymphocyte (H/L) ratios (an indicator of elevated chronic stress) to explore the effect of matrix intensity on forest-dependent passerines classed as either sedentary area-sensitive habitat specialists or nomadic generalists. Individual birds occupying tropical forest remnants near surface mining sites were in poorer condition, as indicated by lower residual body mass and elevated chronic stress, compared to those in remnants near agricultural lands. The condition of the sedentary forest habitat specialists white-tailed alethe, Alethe diademata and western olive sunbird, Cyanomitra obscura was most negatively affected by high-intensity surface mining land-use adjacent to remnants, whereas generalist species were not affected. Land use intensification may set in train a new trajectory of faunal relaxation beyond that expected based on habitat loss alone. Patterns of individual condition may be useful in identifying habitats where species population declines may occur before faunal relaxation has concluded. PMID- 26107180 TI - Evidence for a Role of the Transcriptional Regulator Maid in Tumorigenesis and Aging. AB - Maid is a helix-loop-helix protein that is involved in cell proliferation. In order to further elucidate its physiological functions, we studied Maid activity in two small fish model systems. We found that Maid expression was greatest in zebrafish liver and that it increased following partial hepatectomy. Maid levels were also high in hepatic preneoplastic foci induced by treatment of zebrafish with diethylnitrosamine (DEN), but low in hepatocellular carcinomas (HCC), mixed tumors, and cholangiocarcinomas developing in these animals. In DEN-treated transgenic medaka overexpressing Maid, hepatic BrdU uptake and proliferation were reduced. After successive breedings, Maid transgenic medaka exhibited decreased movement and a higher incidence of abnormal spine curvature, possibly due to the senescence of spinal cord cells. Taken together, our results suggest that Maid levels can influence the progression of liver cancer. In conclusion, we found that Maid is important regulator of hepatocarconogenesis and aging. PMID- 26107181 TI - Phytohormone Involvement in the Ustilago maydis- Zea mays Pathosystem: Relationships between Abscisic Acid and Cytokinin Levels and Strain Virulence in Infected Cob Tissue. AB - Ustilago maydis is the causative agent of common smut of corn. Early studies noted its ability to synthesize phytohormones and, more recently these growth promoting substances were confirmed as cytokinins (CKs). Cytokinins comprise a group of phytohormones commonly associated with actively dividing tissues. Lab analyses identified variation in virulence between U. maydis dikaryon and solopathogen infections of corn cob tissue. Samples from infected cob tissue were taken at sequential time points post infection and biochemical profiling was performed using high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS). This hormone profiling revealed that there were altered levels of ABA and major CKs, with a marked reduction in CK glucosides, increases in methylthiol CKs and a particularly dramatic increase in cisZ CK forms, in U. maydis infected tissue. These changes were more pronounced in the more virulent dikaryon relative to the solopathogenic strain suggesting a role for cytokinins in moderating virulence during biotrophic infection. These findings highlight the fact that U. maydis does not simply mimic a fertilized seed but instead reprograms the host tissue. Results underscore the suitability of the Ustilago maydis- Zea mays model as a basis for investigating the control of phytohormone dynamics during biotrophic infection of plants. PMID- 26107182 TI - Circulating Lipids Are Associated with Alcoholic Liver Cirrhosis and Represent Potential Biomarkers for Risk Assessment. AB - Liver disease is the greatest cause of death related to alcohol and a major public health problem. While excessive alcohol intake results in hepatosteatosis in most individuals, this can progress in some to more severe forms of liver disease including fibrosis and cirrhosis. An ongoing challenge in the management of alcoholic liver disease is the identification of liver injury early in the disease process such that intervention strategies can prevent serious long term outcomes. Given that excessive alcohol consumption results in dysregulation of lipid metabolism we applied lipid profiling technology to characterise and compare serum lipid profiles from excessive chronic drinkers with no liver disease to those with advanced alcoholic cirrhosis. In a cohort of 59 excessive drinkers (31 with liver cirrhosis and 28 with no evidence of liver disease) we used electrospray ionisation tandem mass spectrometry to measure over 300 individual lipid species in serum, including species of the major phospholipid, sphingolipid, glycerolipid and sterol classes. Six of the 25 lipid classes and subclasses were significantly associated with alcoholic liver cirrhosis; these included dihexosylceramide, trihexosylceramide, alkylphosphatidylcholine, lysoalkylphosphatidylcholine, phosphatidylinositol and free cholesterol. Multivariate classification models created with only clinical characteristics gave an optimal model with an AUC of 0.847 and an accuracy of 79.7%. The addition of lipid measurements to the clinical characteristics resulted in models of improved performance with an AUC of 0.892 and accuracy of 81.8%. The gain in AUC and accuracy of the combined models highlight the potential of serum lipids as markers of liver injury in alcoholic liver disease. PMID- 26107184 TI - Heteroligand o-Semiquinonato-Formazanato Cobalt Complexes. AB - Two novel heteroligand o-semiquinonato-formazanato cobalt complexes [Co(3,6 SQ)(Form)] (1) and [Co(3,6-SQ)2(Form)] (2) (3,6-SQ is 3,6-di-tert-butyl-o benzosemiquinonate radical anion; Form is 1,3,5-triphenylformazanate anion) were synthesized and characterized in detail. The molecular structures of [Co(3,6 SQ)(Form)] and [Co(3,6-SQ)2(Form)] were determined by X-ray analysis. Magnetic susceptibility measurements and spectroscopic studies have shown that square planar complex 1 is diamagnetic with a residual paramagnetism due to antiferromagnetic exchange metal-ligand. Complex 2 includes cobalt(III) in the low-spin state and two anionic-radical o-semiquinonato and one formazanate ligand. PMID- 26107183 TI - Invasive Breast Cancer Incidence in 2,305,427 Screened Asymptomatic Women: Estimated Long Term Outcomes during Menopause Using a Systematic Review. AB - BACKGROUND: Earlier studies of breast cancer, screening mammography, and mortality reduction may have inflated lifetime and long-term risk estimates for invasive breast cancer due to limitations in their data collection methods and interpretation. OBJECTIVE: To estimate the percentage of asymptomatic peri/postmenopausal women who will be diagnosed with a first invasive breast cancer over their next 25 years of life. METHODS: A systematic review identified peer-reviewed published studies that: 1) enrolled no study participants with a history of invasive breast cancer; 2) specified the number of women enrolled; 3) reported the number of women diagnosed with a first invasive breast cancer; 4) did not overcount [count a woman multiple times]; and, 5) defined the length of follow-up. Data sources included PubMed, Cochrane Library, and an annotated library of 4,409 full-text menopause-related papers collected and reviewed by the first author from 1974 through 2008. Linear regression predicted incidence of first invasive breast cancer, based on follow-up duration in all studies that met the our inclusion criteria, and in a subset of these studies that included only women who were 1) at least 50 years old and 2) either at least 50 or less than 50 but surgically menopausal at enrollment. RESULTS: Nineteen studies met the inclusion criteria. They included a total of 2,305,427 peri/postmenopasual women. The mean cumulative incidence rate of first invasive breast cancer increased by 0.20% for each year of age (95% CI: 0.17, 0.23; p < 0.01; R2 = 0.90). Over 25 years of follow-up, an estimated 94.55% of women will remain breast cancer-free (95% CI: 93.97, 95.13). In the 12 studies (n = 1,711,178) that enrolled only postmenopausal women, an estimated 0.23% of women will be diagnosed with a first invasive breast cancer each year (95% CI: 0.18, 0.28; p < 0.01, R2 = 0.88). CONCLUSION: The vast majority (99.75%) of screened asymptomatic peri/postmenopasual women will not be diagnosed with invasive breast cancer each year. Approximately 95% will not be diagnosed with invasive breast cancer during 25 years of follow-up. Women who receive clinical examinations, but do not have mammograms, will have higher cancer-free rates because innocuous positives (comprising 30-50% of mammography diagnoses) will remain undetected. Informed consent to asymptomatic women should include these results and consideration of the benefits of avoiding mammograms. PMID- 26107185 TI - VUV Photodissociation Dynamics of Nitrous Oxide: The O((1)SJ=0) and O((3)PJ=2,1,0) Product Channels. AB - Vacuum ultraviolet photodissociation dynamics of nitrous oxide was investigated using the time-sliced velocity ion imaging technique. Images of the O((1)SJ=0) and the O((3)PJ=2,1,0) products were measured at nine photolysis wavelengths from 124.44 to 133.20 nm, respectively. Three main dissociation channels: O((1)S0) + N2(X(1)Sigmag(+)), O((3)PJ=2,1,0) + N2(A(3)Sigmau(+)), and O((3)PJ=2,1,0) + N2(B(3)Pig) were observed and identified in the product images where vibrational states of N2 were fully resolved. Product total kinetic energy releases and angular distributions were acquired. In all product channels, the branching ratios of vibrational states of N2 products were determined. In addition, the O((3)PJ=2,1,0) + N2(A(3)Sigmau(+))/O((3)PJ=2,1,0) + N2(B(3)Pig) branching ratios were determined. We found that in the O((3)PJ=2,1,0) channels the O((3)PJ=2,1,0) + N2(B(3)Pig) channel becomes dominant at long photolysis wavelength, indicating a strong coupling between the singlet D((1)Sigmag(+)) state and the triplet (3)Pi state. For both O((1)S0) and O((3)PJ=2,1,0) products, the derived angular anisotropy parameters (beta values) are very close to 2 at lower vibrational states of the correlated N2 electronic states and gradually decrease with the increasing vibrational quantum number. These behaviors suggest that the photodissociation processes are primarily governed by a fast dissociation in a linear geometry, while the N2 products at excited vibrational states are very likely produced via a more bent transition state. PMID- 26107187 TI - Trypanocidal, trichomonacidal and cytotoxic components of cultivated Artemisia absinthium Linnaeus (Asteraceae) essential oil. AB - Artemisia absinthium is an aromatic and medicinal plant of ethnopharmacological interest and it has been widely studied. The use ofA. absinthium based on the collection of wild populations can result in variable compositions of the extracts and essential oils (EOs). The aim of this paper is the identification of the active components of the vapour pressure (VP) EO from a selected and cultivated A. absinthium Spanish population (T2-11) against two parasitic protozoa with different metabolic pathways: Trypanosoma cruzi and Trichomonas vaginalis. VP showed activity on both parasites at the highest concentrations. The chromatographic fractionation of the VP T2-11 resulted in nine fractions (VLC1-9). The chemical composition of the fractions and the antiparasitic effects of fractions and their main compounds suggest that the activity of the VP is related with the presence of trans-caryophyllene and dihydrochamazulene (main components of fractions VLC1 and VLC2 respectively). Additionally, the cytotoxicity of VP and fractions has been tested on several tumour and no tumour human cell lines. Fractions VLC1 and VLC2 were not cytotoxic against the nontumoural cell line HS5, suggesting selective antiparasitic activity for these two fractions. The VP and fractions inhibited the growth of human tumour cell lines in a dose-dependent manner. PMID- 26107186 TI - T-cell receptor Vbeta repertoire of CD8+ T-lymphocyte subpopulations in cutaneous leishmaniasis patients from the state of Rio de Janeiro, Brazil. AB - In human cutaneous leishmaniasis (CL), the immune response is mainly mediated by T-cells. The role of CD8+ T-lymphocytes, which are related to healing or deleterious functions, in affecting clinical outcome is controversial. The aim of this study was to evaluate T-cell receptor diversity in late-differentiated effector (LDE) and memory CD8+ T-cell subsets in order to create a profile of specific clones engaged in deleterious or protective CL immune responses. Healthy subjects, patients with active disease (PAD) and clinically cured patients were enrolled in the study. Total CD8+ T-lymphocytes showed a disturbance in the expression of the Vbeta2, Vbeta9, Vbeta13.2, Vbeta18 and Vbeta23 families. The analyses of CD8+T-lymphocyte subsets showed high frequencies of LDE CD8+T lymphocytes expressing Vbeta12 and Vbeta22 in PAD, as well as effector-memory CD8+ T-cells expressing Vbeta22. We also observed low frequencies of effector and central-memory CD8+ T-cells expressing Vbeta2 in PAD, which correlated with a greater lesion size. Particular Vbeta expansions point to CD8+ T-cell clones that are selected during CL immune responses, suggesting that CD8+ T-lymphocytes expressing Vbeta12 or Vbeta22 are involved in a LDE response and that Vbeta2 contractions in memory CD8+T-cells are associated with larger lesions. PMID- 26107188 TI - Corynebacterium diphtheriae putative tellurite-resistance protein (CDCE8392_0813) contributes to the intracellular survival in human epithelial cells and lethality of Caenorhabditis elegans. AB - Corynebacterium diphtheriae, the aetiologic agent of diphtheria, also represents a global medical challenge because of the existence of invasive strains as causative agents of systemic infections. Although tellurite (TeO32-) is toxic to most microorganisms, TeO32--resistant bacteria, including C. diphtheriae, exist in nature. The presence of TeO32--resistance (TeR) determinants in pathogenic bacteria might provide selective advantages in the natural environment. In the present study, we investigated the role of the putative TeR determinant (CDCE8392_813gene) in the virulence attributes of diphtheria bacilli. The disruption of CDCE8392_0813 gene expression in the LDCIC-L1 mutant increased susceptibility to TeO32- and reactive oxygen species (hydrogen peroxide), but not to other antimicrobial agents. The LDCIC-L1 mutant also showed a decrease in both the lethality of Caenorhabditis elegans and the survival inside of human epithelial cells compared to wild-type strain. Conversely, the haemagglutinating activity and adherence to and formation of biofilms on different abiotic surfaces were not regulated through the CDCE8392_0813 gene. In conclusion, the CDCE8392_813 gene contributes to the TeR and pathogenic potential of C. diphtheriae. PMID- 26107190 TI - 'Drawing' a Molecular Portrait of CIN and Cervical Cancer: a Review of Genome Wide Molecular Profiling Data. AB - In this review we summarize the results of studies employing high-throughput methods of profiling of HPV-associated cervical intraepithelial neoplasia (CIN) and squamous cell cervical cancers at key intracellular regulatory levels to demonstrate the unique identity of the landscape of molecular changes underlying this oncopathology, and to show how these changes are related to the 'natural history' of cervical cancer progression and the formation of clinically significant properties of tumors. A step-wise character of cervical cancer progression is a morphologically well-described fact and, as evidenced by genome wide screenings, it is indeed the consistent change of the molecular profiles of HPV-infected epithelial cells through which they progressively acquire the phenotypic hallmarks of cancerous cells. In this sense, CIN/cervical cancer is a unique model for studying the driving forces and mechanisms of carcinogenesis. Recent research has allowed definition of the whole-genome spectrum of both random and regular molecular alterations, as well as changes either common to processes of carcinogenesis or specific for cervical cancer. Despite the existence of questions that are still to be investigated, these findings are of great value for the future development of approaches for the diagnostics and treatment of cervical neoplasms. PMID- 26107189 TI - Influence of Endosomal Escape and Degradation of alpha-Galactosylceramide Loaded Liposomes on CD1d Antigen Presentation. AB - Alpha-galactosylceramide (GC), a lipid antigen present on CD1d molecules, is a unique adjuvant that enables a strong antitumor effect to be induced via activation of natural killer T cells. We previously reported that a liposomal formulation of GC significantly enhanced GC presentation via CD1d and antitumor immunity. However, the influence of the intracellular fate of liposomes controlled by the lipid composition on GC presentation using GC-loaded liposomes (GC-Lip) remains unclear. In this study, we prepared a GC-Lip formulation by incorporating dioleoyl-phosphatidylethanolamine (DOPE)/cholesterol, egg phosphatidylcholine (EPC)/cholesterol, and distearoyl phosphocholine (DSPC)/cholesterol, and investigated the relationship between the intracellular trafficking of GC-Lip and GC presentation in antigen-presenting cells. When GC Lip was prepared using DOPE, a fusogenic lipid, the endosomal escape of liposomes was enhanced, resulting in a decrease in GC presentation of CD1d, compared to the EPC based GC-Lip (EPC/GC-Lip). The stability of liposomes in endosomes/lysosomes had no influence on GC presentation. The DSPC based GC-Lip (DSPC/GC-Lip) induced GC presentation without any detectable degradation in liposomal structure, although the EPC/GC-Lip induced GC presentation with degradation of liposomal structure. The efficiency of GC presentation between EPC/GC-Lip and DSPC/GC-Lip was comparable. These GC presentations that were independent of the degradation of liposomes were dominated by saposins, sphingolipid activator proteins. Our findings reveal that GC presentation on CD1d from the fluid liposomes involves the action of saposins, regardless of whether liposome degradation occurs. This insight can be of use in terms of developing GC-Lip formulation for efficient GC presentation. PMID- 26107191 TI - Current Status and Future Perspectives of Sonodynamic Therapy and Sonosensitiers. AB - The precaution and treatment for cancer become inevitable with the rising of morbidity and mortality. In this article, a promising new methodology for cancer treatment, sono-dynamic therapy (SDT) was introduced. In addition, we extensively reviewed the molec-ular mechanisms of SDT killing cancer and summarized the classification of sonosensi-tizers. At the same time, research progress of SDT indicates that it is possible to become a developing field for cancer treatment in clinical application. PMID- 26107192 TI - Are PIK3CA Mutation and Amplification Associated with Clinicopathological Characteristics of Gastric Cancer? AB - Alterations in mitochondrial DNA (mtDNA) have been studied in various cancers. However, the clinical value of mtDNA copy number (mtCN) alterations in gastric cancer (GC) is poorly understood. In the present study, we investigated whether alterations in mtCNs might be associated with clinicopathological parameters in GC cases. mtCN was measured in 109 patients with GC by real-time PCR. Then, correlations with clinicopathological characteristics were analyzed. mtCN was elevated in 64.2% of GC tissues compared with paired, adjacent, non- cancerous tissue. However, the observed alterations in mtCN were not associated with any clinicopathological characteristics, including age, gender, TN stage, Lauren classification, lymph node metastasis, and depth of invasion. Moreover, Kaplan Meier survival curves revealed that mtCN was not significantly associated with the survival of GC patients. In this study, we demonstrated that mtCN was not a significant marker for predicting clinical characteristics or prognosis in GC. PMID- 26107193 TI - Comparative Study of Carcinoembryonic Antigen Tumor Marker in Stomach and Colon Cancer Patients in Khyber Pakhtunkhwa. AB - BACKGROUND: Due to the increase in morbidity and mortality rate, cancer has become an alarming threat to the human population worldwide. Since cancer is a progressive disorder, timely diagnosis would be helpful to prevent/stop cancer from progressing to severe stage. In Khyber Pakhtunkhwa, Pakistan, most of the time, tumors are diagnosed with endoscopy and biopsy; therefore rare studies exist regarding the diagnosis of gastrointestinal (GIT) carcinomas based on tumor markers, especially CEA. OBJECTIVES: This study made a comparative analysis of CEA in admitted hospitalized stomach and colon cancer patients diagnosed as GIT with biopsy. MATERIALS AND METHODS: In this study, a total of 66 cases were included. The level of CEA was determined in the blood of these patients using ELISA technique. RESULTS: Out of 66 patients, the level of CEA was high in 59.1% of the total, 60.7% in colon cancer patients and 57.9 % in stomach cancer patients. Moreover, the incidence of colorectal and stomach cancer was greater in males as compared to females. Patients were more of the age group of 40- 60 and the level of CEA was comparatively higher in patients (51.5%) with histology which was moderately differentiated, than patients with well differentiated and poorly differentiated tumor histology. CONCLUSIONS: CEA level was high in more than 50% of the total patients. Moreover, CEA exhibited higher sensitivity for colon than stomach cancer. PMID- 26107194 TI - Relations of Serum Visfatin and Resistin Levels with Endometrial Cancer and Factors Associated with its Prognosis. AB - BACKGROUND: The aims of this study were compare the serum visfatin and resistin levels between endometrial cancer (EC) patients and controls and evaluate their power to predict prognosis. MATERIALS AND METHODS: This prospective study was conducted between March 2013 to June 2014 on the Gynecologic Oncology Department of the University of Selcuk, Konya, Turkey. A total of 42 EC patients and 42 controls were included and assessed for differences in serum visfatin and resistin levels, along with prognostic factors. RESULTS: Endometrial cancer patients had significantly higher visfatin levels than control s (p: 0.011), associated with deep myometrial invasion (p: 0.019). In contrast the serum level of resistin did not significantly differ between EC patients and controls (p: 0.362). However, high resistin level in EC patients was associated with increase lymph node metastasis (p: 0.009). On logistic regression analysis, we found that serum visfatin elevation was associated with risk of myometrial invasion (OR: 1,091; 95%CI: 1.021- 1.166; p: 0.010) and serum resistin with risk of lymph node metastasis (OR: 1.018; 95%CI: 1.000- 1.035; p: 0.046). For myometrial invasion prediction, a serum visfatin level greater than 26.8 ng/mL demonstrated a sensitivity and specificity of 66.6 % and 96.4%, respectively. For lymph node metastasis prediction, the best cut-off for serum resistin level was 599ng/mL. A serum resistin level greater than this demonstrated a sensitivity and specificity of 87.5% and 77.1%, respectively. CONCLUSIONS: Our data suggest that serum visfatin is elevated in patients with EC and serum visfatin and resistin levels could be used to predict the risk of advance stage lesions. PMID- 26107195 TI - miR-9 Modulates Osteosarcoma Cell Growth by Targeting the GCIP Tumor Suppressor. AB - Osteosarcoma is the most common primary bone tumor in humans, especially in childhood. However, the genetic etiology for its pathogenesis remains elusive. It is known that microRNAs (miRNAs) are involved in the development of tumor progression. Here we show that microRNA-9 (miR-9) is a potential oncogene upregulated in osteosarcoma cells. Knockdown of miR-9 in osteosarcoma resulted in suppressed colony formation and cell proliferation. Further study identified GCIP, a Grap2 and cyclin D interacting protein, as a direct target of miR- 9. In addition, GCIP overexpression activated retinoblastoma 1 (Rb) and suppressed E2F transcriptional target expression in osteosarcoma cells. Moreover, GCIP depletion reversed miR-9 knockdown induced colony formation and cell proliferation suppression. In sum, these results highlight the importance of miR-9 as an oncogene in regulating the proliferation of osteosarcoma by directly targeting GCIP and may provide new insights into the pathogenesis of osteosarcoma. PMID- 26107196 TI - Ki-67 Can Predict the Response to the Gemcitabine, Oxaliplatin And L-asparaginase Regimen (GELOX) and Prognosis in Patients with Nasal Natural Killer/T-cell Lymphoma. AB - GELOX (gemcitabine, oxaliplatin and L-asparaginase) regimen showed an impressive result in our previous study, but the effect of this new regimen is still dissatisfying for some patients, so it is necessary to identify which patients will benefit from this regimen. A total of fifty-one cases with nasal natural killer/T-cell lymphoma receiving initial GELOX chemotherapy were enrolled in this study. The ki-67 expression detected by immunohistochemistry (IHC) in the specimens ranged from 10% to 90%, with a median value of 70%, so cases higher than the median value (>=70%) were defined as high ki-67 expression, and the others were designated as low ki-67 expression. The response rate had no statistical difference between low ki-67 expression group and high ki-67 expression group (P=0.291) though the value in the former group was relatively high. After a median follow-up of 18.03 months, the 3-year progression-free survival (PFS) for patients with low ki-67 expression was significantly higher than those with high ki-67 expression (83.8% vs. 47.9%, P=0.038). In the stage I/II subgroup, 3-year PFS and overall survival (OS) were statistically higher in the patients with low ki-67 expression than those with high ki- 67 expression. Multivariate analysis revealed high ki-67 expression was an independent prognostic factor for PFS. These results suggest that low ki-67 expression can predict a good response of GELOX in these patients, and the combination of ki-67 expression and early stage is helpful to identify an excellent prognosis subgroup from patients receiving GELOX in this disease. PMID- 26107197 TI - Role of exon 7 PTEN Gene in Endometrial Carcinoma. AB - BACKGROUND: Endometrial carcinoma is the most common malignant tumor of the female genital tract and the fourth most common cancer in Iranian women after breast, colorectal and lung cancers. Various genetic alterations appear to be early events in the pathogenesis of endometrial carcinoma and it seems that PTEN is the most commonly mutated gene in the endometrioid subtype. The aim of the present study was to investigate the correlation between mutations in exon 7 of PTEN gene and endometrial carcinoma. MATERIALS AND METHODS: Seventy-five patients with endometrial carcinoma and 75 females whose underwent hysterectomy for non tumoral indication were selected for evaluation of PTEN mutations in exon 7 by PCR-SSCP and sequencing. Correlations between the frequency and type of mutation and the pathologic findings of the cancer (tumor subtype, stage and grade) were assessed. RESULTS: All of the samples were obtained from Iranian patients. 60 % (45 cases) of the tumors were endometriod and 40% (30 cases) were of serous type. The grade distributions of the 75 cases according to the FIGO staging system were as follows: low grade, 20 cases; high grade 55 cases, low stage, 41 cases; high stage 34 cases. For exon 7 of the PTEN gene, the analysis showed that there were no mutations in our cases. CONCLUSIONS: Our findings in the present study suggest that exon 7 of PTEN does not play any significant role in the development of endometrial carcinoma in Iranian cases. PMID- 26107198 TI - Association between MTHFR C677T Polymorphism and Risk of Prostate Cancer: Evidence from 22 Studies with 10,832 Cases and 11,993 Controls. AB - BACKGROUND: The MTHFR C677T polymorphism is a genetic alteration affecting an enzyme involved in folate metabolism, but its relationship to host susceptibility to prostate cancer remains uncertain. The aim of this study was to investigate the association between MTHFR C677T polymorphism and prostate cancer by performing a meta-analysis. MATERIALS AND METHODS: Pubmed and Web of Science databases were searched for case-control studies investigating the association between MTHFR C677T polymorphism and prostate cancer. Odds ratios (OR) and 95% confidence intervals (95%CI) were used to assess any link. RESULTS: A total of 22 independent studies were identified, including 10,832 cases and 11,993 controls. Meta-analysis showed that there was no obvious association between MTHFR C677T polymorphism and risk of prostate cancer under all five genetic models. There was also no obvious association between MTHFR C677T polymorphism and risk of prostate cancer in the subgroup analyses of Caucasians. In contrast, MTHFR C677T polymorphism was associated with increased risk for prostate cancer in Asians with the allele model (C vs G: OR=1.299, 95 %CI =1.121-1.506, P=0.001, Pheterogeneity =0.120, I2=45%), additive genetic model (CC vs TT: OR =1.925, 95 % CI= 1.340-2.265, P=0.00, Pheterogeneity =0.587, I2=0.00%), recessive model (CC vs TT+TC: OR= 1.708, 95 % CI= 1.233-2.367, P=0.001, Pheterogeneity =0.716, I2=0.00%), and heterozygote genetic model (CT vs TT: OR=2.193, 95 % CI =1.510 3.186, P=0.000, Pheterogeneity =0.462, I2=0.00%). CONCLUSIONS: These results suggest that the MTHFR C677T polymorphism does not contribute to the risk of prostate cancer from currently available evidence in populations overall and Caucasians. However, the meta analysis indicates that it may play a role in prostate cancer development in Asians. PMID- 26107199 TI - Effects of Offspring-Related Characteristics on Depressive Disorder among Cancer Patients and Survivors. AB - OBJECTIVE: To investigate the influence of offspring-related characteristics on the prevalence of depressive disorders among cancer patients and those who survived cancer for at least 45 years. MATERIALS AND METHODS: Data were obtained from the Korean Longitudinal Study of Aging (KLoSA). To investigate the association between offspring and depressive disorder among cancer patients and survivors, we analyzed data from 292 cancer patients and survivors drawn from a total subject pool of 16,613 individuals at baseline. RESULTS: According to our results, the odds ratio (OR) for subjects with five or more offspring developing depressive disorder was -0.794 (p-value: 0.039, SE: 0.329) compared with that of those with two offspring. In addition, the adjusted effect of the number of male and female offspring on the presence of depressive disorder showed that the OR for those with three or more female offspring for developing depressive disorder was -0.958 lower (SE: 0.305, p-value: 0.012) than it was for those with no female offspring. CONCLUSIONS: This article provides evidence for an association between offspring-related characteristics and depressive disorders among cancer patients and survivors. Therefore, offspring may be important contributors to the emotional status of cancer patients and survivors. Further study should precisely need to measure depressive disorders because of self-reported data. PMID- 26107200 TI - OK-432 Suppresses Proliferation and Metastasis by Tumor Associated Macrophages in Bladder Cancer. AB - OK-432, a Streptococcus-derived anticancer immunotherapeutic agent, has been applied in clinic for many years and achieved great progress in various cancers. In the present study, we investigated its anticancer effect on bladder cancer through tumor associated macrophages (TAMs). MTS assay validated OK-432 could inhibit proliferation in both T24 and EJ bladder cell lines. OK-432 also induced apoptosis of bladder cancer cells in vitro. Consequently, we demonstrated that OK 432 could suppress the bladder cancer cells migration and invasion by altering the EMT-related factors. Furthermore, using SD rat model, we revealed that OK-432 inhibited tumor growth, suppressed PCNA expression and inhibited metastasis in vivo. Taken together, these findings strongly suggest that OK-432 inhibits cell proliferation and metastasis through inducing macrophages to secret cytokines in bladder cancer. PMID- 26107201 TI - The Effects of ASMase Mediated Endothelial Cell Apoptosis in Multiple Hypofractionated Irradiations in CT26 Tumor Bearing Mice. AB - BACKGROUND: To investigate the effects of ASMase mediated endothelial cell apoptosis in multiple hypofractionated irradiations in CT26 tumor bearing mice. MATERIALS AND METHODS: Thirty-five CT26 tumor bearing mice were subjected to single ionizing radiation (IR) of 0, 3, 6, 9, 12, 15, 18 Gy. Eight hours after IR, the mice were sacrificed and tumor tissues were used for CD31 immunohistochemistry staining, TUNEL and CD31 double staining, ASMase activity assay. Then 6 and 12 Gy were chosen for multiple hypofractionated IR experiments according to the above results. Each time after IR, 5 mice were sacrificed and assayed as above. RESULTS: The ASMase activities were increased significantly after a single IR of 12 Gy or higher which was accompanied with remarkable increased endothelial cell apoptosis and decreased MVD. For 6 Gy which was not high enough to trigger ASMase activation, after 2 or more times of IR, the ASMase activities were significantly increased accompanied with remarkable increased endothelial cell apoptosis and decreased MVD. While for 12 Gy, after 2 or more times of IR, the ASMase activities and endothelial cell apoptosis rates were maintained without remarkable increase; however, the MVD was significantly decreased. What's more, the cancer cell apoptosis rates were significantly increased after multiple IR for both 6 Gy and 12 Gy. CONCLUSIONS: ASMase mediated endothelial cell apoptosis may play an important role in the process of multiple hypofractionated IR for CT26 colorectal carcinoma. PMID- 26107202 TI - Endothelial Cell Proliferation and Vascular Endothelial Growth Factor Expression in Primary Colorectal Cancer and Corresponding Liver Metastases. AB - BACKGROUND: . Colorectal carcinoma (CRC) is one of the major causes of cancer death worldwide. Data from the literature indicate differences between the proliferation rate of endothelial cells relative to the morphology growth type, possibly due to origin of specimens (autopsy material, surgery fragments) or quantification methods. Vascular endothelial growth factor (VEGF) is a factor that stimulates the proliferation of endothelial cells. It is expressed in more than 90% of cases of metastatic CRC. AIM: The aim of this study was to evaluate the endothelial cell proliferation and VEGF expression in primary tumors and corresponding liver metastases. MATERIALS AND METHODS: Our study included 24 recent biopsies of primary tumors and corresponding liver metastases of CRC cases. CD34/ Ki67 double immunostaining and RNA scope assay for VEGF were performed. RESULTS: In the primary tumors analysis of VEGFmRNA expression indicated no significant correlation with differentiation grade, proliferative and non-proliferative vessels in the intratumoral and peritumoral areas. In contrast, in the corresponding liver metastases, VEGFmRNA expression significantly correlated with the total number of non- proliferative vessels and total number of vessels. CD34/ Ki67 double immunostaining in the cases with poorly differentiated carcinoma indicated a high number of proliferating endothelial cells in the peritumoral area and a low number in the intratumoral area for the primary tumor. Moderately differentiated carcinomas of colon showed no proliferating endothelial cells in the intratumoral area in half of the cases included in the study, for both, primary tumor and liver metastasis. In well differentiated CRCs, in primary tumors, a high proliferation rate of endothelial cells in the intratumoral area and a lower proliferation rate in the peritumoral area were found. A low value was found in corresponding liver metastasis. CONCLUSIONS: The absence of proliferative endothelial cells in half of the cases for the primary tumors and liver metastases in moderately differentiated carcinoma suggest a vascular mimicry phenomenon. The mismatch between the total number of vessels and endothelial proliferation in primary tumors indicate that a functional vascular network is already formed or the existence of some mechanisms influenced by other angiogenic factors. PMID- 26107203 TI - Participation of the Women Covered by Family Physicians in Breast Cancer Screening Program in Kerman, Iran. AB - BACKGROUND: Mammography screening is a method for reducing breast cancer mortality in women over 40 years old . A participation rate of at least 70% is a prerequisite for screening programs. This study aimed at determining the participation rate of women in breast cancer screening in Iran. MATERIALS AND METHODS: The study population in this prospective research consisted of 35 to 69 years old women in the villages and towns Kerman District, in 2013. The data were collected by a well-validated risk assessment questionnaire. The questionnaires were completed with the help of health workers and technicians in the health centers, who were trained on breast cancer screening program. RESULTS: As a whole, 19,651 women were invited to complete the questionnaire, of whom 15,794 women (80.37%) completed it. In the urban region, of 3150 eligible women 2728 women (86.60%) participated in the study. The acceptance rates for mammography in rural and urban regions were 34.95% and 8.75%, respectively. CONCLUSIONS: Finally, 3.8% and 16.34% of 35 to 69 years old women in the urban regions were mammographed, respectively. CONCLUSION: The low participation of eligible women in breast cancer screening program alerts us against including the program in the health insurance package. PMID- 26107204 TI - Smoking among Secondary School Students in Kota Tinggi, Johor, Malaysia--Findings from a Cross-Sectional Study. AB - BACKGROUND: Smoking is a learnt behavior during adolescence and understanding the factor/s associated with smoking will assist in identifying suitable measures in combating the rising prevalence of smoking among adolescents. This research aimed to identify the factor/s associated with smoking among form four students in Kota Tinggi, Johor. Multistage sampling was used to select a representative sample of students in 2008 and data were collected using a self-administered validated questionnaire. This study revealed that the overall smoking prevalence was 19.0% with a significantly higher proportion of male smokers (35.8%) as compared to females (3.15%). Adolescents who were male (aOR 6.6, 95%CI 2.61-16.4), those who had peer/s who smoked (aOR 4.03, 95% CI 1.31-12.4), and those who studied in rural areas and Felda Settlements ( aOR 4.59, 95 CI 1.11-18.0; aOR 9.42, 95%CI 3.91-29.1) were more likely to smoke in the past one week. On the other hand, adolescents with better knowledge on the hazards of smoking and negative attitudes towards smoking were less likely to smoke (aOR 0.51, 95%CI 0.37-0.72; aOR 0.67, 95%CI 0.46-0.99). Future promotional and interventional programmes on smoking should be considered and the above identified risk factors integrated to reduce smoking prevalence among students of school-going ages in Kota Tinggi. Johor. PMID- 26107205 TI - The Inhibition Effect of Triptolide on Human Endometrial Carcinoma Cell Line HEC 1B: a in vitro and in vivo Studies. AB - BACKGROUND: To investigate the inhibitory effect and the underlying mechanism of triptolide on cultured human endometrial carcinoma HEC-1B cells and corresponding xenograft. MATERIALS AND METHODS: For in vitro studies, the inhibition effect of proliferation on HEC-1B cell by triptolide was determined by MTT assay; cell cycle and apoptosis of the triptolide-treated and untreated cells were detected by flow cytometry. For in vivo studies, a xenograft tumor model of human endometrial carcinoma was established using HEC-1B cells, then the tumor-bearing mice were treated with high, medium, and low-dose (8 MUg, 4 MUg and 2 MUg/day) triptolide or cisplatin at 40 MUg/day or normal saline as control. The mice were treated for 10-15 days, during which body weight of the mice and volume of the xenograft were weighted. Then expression of Bcl-2 and vascular endothelial growth factor (VEGF) was analyzed by SABC immunohistochemistry. RESULTS: Cell growth was significantly inhibited by triptolide as observed by an inverted phase contrast microscope; the results of MTT assay indicated that triptolide inhibits HEC-1B cell proliferation in a dose and time-dependent manner; flow cytometry showed that low concentration (5 ng/ml) of triptolide induces cell cycle arrest of HEC 1B cells mainly at S phase, while higher concentration (40 or 80 ng/ml) induced cell cycle arrest of HEC-1B cells mainly at G2/M phase, and apoptosis of the cells was also induced. High-dose triptolide showed a similar tumor-inhibitory effect as cisplatin (-50%); high-dose triptolide significantly inhibited Bcl-2 and VEGF expression in the xenograft model compared to normal saline control (P<0.05). CONCLUSIONS: triptolide inhibits HEC-1B cell growth both in vitro and in mouse xenograft model. Cell cycle of the tumor cells was arrested at S and G2/M phase, and the mechanism may involve induction of tumor cell apoptosis and inhibition of tumor angiogenesis. PMID- 26107206 TI - Breast Cancer Inpatients Undergoing Mastectomy from a Hospital in Guangzhou, China: A Retrospective Analysis 2004- 2013. AB - BACKGROUND: To explore the hospitalizations of breast cancer patients undergoing mastectomy, and to provide a basis for management, clinical prevention and treatment. MATERIALS AND METHODS: We conducted an investigation by means of the retrospective survey and the medical records retrieval system, and made out the data of patients suffered from breast cancer in a hospital in Guangzhou from 2004 to 2013, including age, medical payment methods, pathological type, treatment, treatment results, complications, hospitalization days, cost and so on. RESULTS: The average age of the inpatients was 50.14 years old. The main histologic types were infiltrating duct carcinoma (88.06%). The main surgery was modified radical mastectomy (80.41%). The cure rate was 90.80% during the 10 years. The main medical payment method was self-paying (57.28%). The average hospital stay was 13.51 days, and average hospitalization cost was RMB 23,083.66 yuan, proportion of drug fees up to 39.70%. Postoperative complication rate was 0.79%. The self paying group was with the highest proportion of drug fees (P<0.05), while the free medical service group was with the longest hospitalization days (P<0.05). CONCLUSIONS: The payment methods significantly affected the proportion of drug fees and hospitalization days. The therapeutic effect was satisfactory with less complications and reasonable proportion of drug fees in our hospital. PMID- 26107207 TI - Prognostic Value of a CYP2B6 Gene Polymorphism in Patients with Acute Myeloid Leukemia. AB - BACKGROUND: The objectives of this study aimed to detect a CYP2B6 polymorphism in de novo cases of acute myeloid leukemia patients and identify any role in disease progression and outcome. MATERIALS AND METHODS: DNA was isolated from peripheral blood of 82 newly diagnosed acute myeloid leukemia cases and the CYP2B6 G15631T gene polymorphism was assayed by PCR restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of the GG genotype (wild type) was 48 (58.5%) and that of the mutant type T allele was 34 (41.9%). GT genotype heterozygous variants were found in 28 (34%), and TT genotype homozygous variants in 6 (7.3%) cases. We found no significant association between the CYP2B6 G15631T polymorphism and complete response (CR) (p-value=0.768), FAB classification (p value=0.51), cytogenetic analysis (p-value=0.673), and overall survival (p value=0.325). Also, there were no significant links with early toxic death (p value=0.92) or progression- free survival (PFS) (p-value=0.245). CONCLUSIONS: Our results suggest that the CYP2B6 polymorphism has no role in disease progression, therapeutic outcome, patient free survival, early toxic death and overall survival in acute myeloid leukemia patients. PMID- 26107208 TI - Mutation Analysis of the Dimer Forming Domain of the Caspase 8 Gene in Oral Submucous Fibrosis and Squamous Cell Carcinomas. AB - BACKGROUND: Missense and frame-shift mutations within the dimer forming domain of the caspase 8 gene have been identified in several cancers. However, the genetic status of this region in precancerous lesions, like oral submucous fibrosis (OSMF), and well differentiated oral squamous cell carcinomas (OSCCs) in patients from southern region of India is not known, and hence the present study was designed to address this issue. MATERIALS AND METHODS: Genomic DNA isolated from biopsy tissues of thirty one oral submucous fibrosis and twenty five OSCC samples were subjected to PCR amplification with intronic primers flanking exon 7 of the caspase 8 gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the status of mutation. RESULTS: Sequence analysis identified a frame-shift and a novel missense mutation in two out of twenty five OSCC samples. The frame-shift mutation was due to a two base pair deletion (c.1225_1226delTG), while the missense mutation was due to substitution of wild type cysteine residue with phenylalanine at codon 426 (C426F). The missense mutation, however, was found to be heterozygous as the wild type C426C codon was also present. None of the OSMF samples carried mutations. CONCLUSIONS: The identification of mutations in OSCC lesions but not OSMF suggests that dimer forming domain mutations in caspase 8 may be limited to malignant lesions. The absence of mutations in OSMF also suggests that the samples analyzed in the present study may not have acquired transforming potential. To the best of our knowledge this is the first study to have explored and identified frame-shift and novel missense mutations in OSCC tissue samples. PMID- 26107209 TI - Risk factors for Opisthorchis viverrini Infection in Nong Khai Province, Thailand. AB - BACKGROUND: Opisthorchis viverrini (OV) infection is the main risk factor for cholangiocarcinoma and is often found in Northeastern Thailand. The prevalence of OV infection and the incidence of cholangiocarcinoma are major public health problems in this region. OBJECTIVES: The objectives of this study were to identify factors associated with OV infection among people in Nong Khai Province in order to develop a prevention programme in the community. MATERIALS AND METHODS: The data were collected in July 2013. Stool specimens were examined for intestinal parasites within hours after collection using a normal saline wet preparation and the modified Kato- Katz technique. A case-control study was conducted to collect information about demographic data, the habit of eating unsafely prepared fish, the safe disposal of waste food, and the practice of defaecating in fields. Structured questionnaires were used to interview 351 participants (117 cases and 234 controls) in a random selection of 30 villages across Nong Khai Province. Multiple logistic regression was used to identify risk factors for OV infection. RESULTS: In the multivariate analysis, the results showed that the factors which had a statistically significant association with OV infection were the habit of consuming unsafely prepared fish (ORadj=5.17, 95%CI=2.49- 10.74), the similar habit of family members (ORadj=3.25, 95%CI=1.63 6.49) , a history of O. viverrini infection (ORadj=5.64, 95%CI=2.10-15.18), a history of taking praziquantel (ORadj=5.66, 95%CI=3.11-10.29), and the unsafe disposal of waste food (ORadj=2.1, 95%CI=1.10-3.80). CONCLUSIONS: The findings of this study highlight the features on which a community programme should focus in order to reduce the prevalence of opisthorchiasis and incidence of bile duct cancer. PMID- 26107210 TI - Contribution of Macrophage Migration Inhibitory Factor -173G/C Gene Polymorphism to the Risk of Cancer in Chinese Population. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF) -173G/C (rs755622) gene polymorphism has been associated with cancer risk. Previous studies have revealed that MIF -173G/C gene polymorphism may increase cancer in the Chinese population, while results of individual published studies remain inconsistent and inconclusive.We performed this meta-analysis to derive a more precise estimation of the relationship. MATERIALS AND METHODS: We conducted a search on PubMed, Embase, MEDLINE, Cochrane Library ,Chinese National Knowledge Infrastructure (CNKI), Wanfang, Weipu on Dec 31, 2014.Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the association. A total of eight studies including 2,186 cases and 2,285 controls were involved in this meta-analysis. RESULTS: The pooled results indicated the significant association between MIF 173G/C polymorphism and the risk of cancer for Chinese population (CC + CG vs GG: OR=1.14, 95%CI=1.02-127, pheterogeneity<0.01; P =0.023; CC vs CG+GG: OR=1.12, 95%CI=1.02- 1.23, pheterogeneity< 001; P =0.017;CC vs GG: OR=1.18, 95%CI=1.04 1.33, pheterogeneity<001; P =0.008; CG vs GG:OR=1.03, 95%CI=0.91-1.15, pheterogeneity<001; P =0.656; C vs G:OR=1.24, 95%CI=1.14-1.25, pheterogeneity<001; P <001). Subgroup analysis showed that in patients with "solid tumors", heterogeneity was very large (OR=0.94,95%CI=0.83 1.06,pheterogeneity=0.044; p=0.297). Within "non-solid tumors", the association became even stronger (OR=6.62, 95 % CI=4.32-10.14, pheterogeneity<0.001; p <0.001). CONCLUSIONS: This study suggested that MIF ?173G/C gene polymorphism may increase increase cancer in the Chinese population.Furthermore, more larger sample and representative population-based casees and well-matched controls are needed to validate our results. PMID- 26107211 TI - Serum Tumor Marker Levels might have Little Significance in Evaluating Neoadjuvant Treatment Response in Locally Advanced Breast Cancer. AB - BACKGROUND: To determine the potential value of serum tumor markers in predicting pCR (pathological complete response) during neoadjuvant chemotherapy. MATERIALS AND METHODS: We retrospectively monitored the pro-, mid-, and post- neoadjuvant treatment serum tumor marker concentrations in patients with locally advanced breast cancer (stage II-III) who accepted pre-surgical chemotherapy or chemotherapy in combination with targeted therapy at Fudan University Shanghai Cancer Center between September 2011 and January 2014 and investigated the association of serum tumor marker levels with therapeutic effect. Core needle biopsy samples were assessed using immunohistochemistry (IHC) prior to neoadjuvant treatment to determine hormone receptor, human epidermal growth factor receptor 2(HER2), and proliferation index Ki67 values. In our study, therapeutic response was evaluated by pCR, defined as the disappearance of all invasive cancer cells from excised tissue (including primary lesion and axillary lymph nodes) after completion of chemotherapy. Analysis of variance of repeated measures and receiver operating characteristic (ROC) curves were employed for statistical analysis of the data. RESULTS: A total of 348 patients were recruited in our study after excluding patients with incomplete clinical information. Of these, 106 patients were observed to have acquired pCR status after treatment completion, accounting for approximately 30.5% of study individuals. In addition, 147patients were determined to be Her-2 positive, among whom the pCR rate was 45.6% (69 patients). General linear model analysis (repeated measures analysis of variance) showed that the concentration of cancer antigen (CA) 15-3 increased after neoadjuvant chemotherapy in both pCR and non-pCR groups, and that there were significant differences between the two groups (P=0.008). The areas under the ROC curves (AUCs) of pre-, mid-, and post-treatment CA15-3 concentrations demonstrated low-level predictive value (AUC=0.594, 0.644, 0.621, respectively). No significant differences in carcinoembryonic antigen (CEA) or CA12-5 serum levels were observed between the pCR and non-pCR groups (P=0.196 and 0.693, respectively). No efficient AUC of CEA or CA12-5 concentrations were observed to predict patient response toward neoadjuvant treatment (both less than 0.7), nor were differences between the two groups observed at different time points. We then analyzed the Her-2 positive subset of our cohort. Significant differences in CEA concentrations were identified between the pCR and non-pCR groups (P=0.039), but not in CA15-3 or CA12-5 levels (p=0.092 and 0.89, respectively). None of the ROC curves showed underlying prognostic value, as the AUCs of these three markers were less than 0.7. The ROC-AUCs for the CA12-5 concentrations of inter-and post neoadjuvant chemotherapy in the estrogen receptor negative HER2 positive subgroup were 0.735 and 0.767, respectively. However, the specificity and sensitivity values were at odds with each other which meant that improving either the sensitivity or specificity would impair the efficiency of the other. CONCLUSIONS: Serum tumor markers CA15-3, CA12-5, and CEA might have little clinical significance in predicting neoadjuvant treatment response in locally advanced breast cancer. PMID- 26107212 TI - Outcome of Childhood Acute Lymphoblastic Leukemia Treated Using the Thai National Protocols. AB - BACKGROUND: In recent decades, the prognosis for childhood leukemia has improved, especially for acute lymphoblastic leukemia (ALL). In Thailand, though, the survival rate for ALL is unimpressive. In 2006, standard national protocols for childhood leukemia treatment were implemented. We herein report the outcome of the ALL national protocols and explanations behind discrepancies in outcomes between institutions. MATERIALS AND METHODS: Between March 2006 and February 2008, 486 children with ALL from 12 institutions were enrolled in the Thai national protocols. There were 3 different protocols based on specific criteria: one each for standard risk, high risk and Burkitt's ALL. We classified participating centers into 4 groups of institutions, namely: medical schools in Bangkok, provincial medical schools, hospitals in Bangkok and provincial hospitals. We also evaluated supportive care, laboratory facilities in participating centers, socioeconomics, and patient compliance. Overall and event free survival were determined for each group using the Kaplan Meier method. Statistical differences were determined using the log-rank test. Previous outcomes of Thai childhood ALL treatment between 2003 and 2005 served as the historic control. RESULTS: Five-year overall survival of ALL treated using the Thai national protocol was 67.2%; an improvement from the 63.7% of the 12 institute historical control (p-value=0.06). There were discrepancies in event free survival of ALL between centers in Bangkok and up-country provinces (69.9% vs 51.2%, p-value <0.01). Socioeconomics and patient compliance were key elements in determining the outcome (65.5% vs 47.5%, 59.4% vs 42.9%) (p-value < 0.02). CONCLUSIONS: Implementation of standard national protocols for childhood leukemia in Thailand did not significantly improve the outcome of ALL. Factors leading to better outcomes included (a) improvement of treatment compliance (b) prevention of treatment abandonment and PMID- 26107213 TI - Perceptions of Turkish University Students about the Effects of Water Pipe Smoking on Health. AB - BACKGROUND: The popularity of the water pipe, also referred to as hookah, narghile, shisha or hubble-bubble, has increased tremendously during the past few decades. This study was conducted to determine student water pipe smoking status and perceptions about the effects of water pipe smoking on health in a state university in Ankara. MATERIALS AND METHODS: This cross-sectional study was conducted between September 2014 and January 2015. The data were collected with a questionnaire and "The Scale of Perception about the Effects of Water Pipe Smoking on Health". The data obtained were evaluated in IBM SPSS (version 20.0) statistical package program in computer. One-way analysis of variance (ANOVA) was used for the analyses by checking homogeneity of variances and Student's t-test. Values of p<0.05 were considered statistically significant. RESULTS: The total mean score obtained by young people who took part in the study was determined as (X_=65.20+/-1.25, min=33, max=75). Upon comparison of the total mean scores obtained by young people from the Scale of Perception about the effects of water pipe smoking on health and gender variable, the scores obtained by the females students were higher than those of the male students with a statistically significant difference (t=7.525, p<0.05). A statistically significant difference was observed between the total mean scores obtained by young people with cigarette and water pipe smoking status (for each, t=-3.731, p<0.05; t=-13.987, p<0.05). CONCLUSIONS: In conclusion, university students have wrong knowledge on the dangers of water pipe smoking. There was a high prevalence of using water pipes among university students. Gender significantly affected the perceptions about the effect of water pipe smoking on health in our sample. PMID- 26107214 TI - Cancer/Testis OIP5 and TAF7L Genes are Up-Regulated in Breast Cancer. AB - Breast cancer still remains as the most frequent cancer with second mortality rate in women worldwide. There are no validated biomarkers for detection of the disease in early stages with effective power in diagnosis and therapeutic approaches. Cancer/testis antigens are recently promising tumor antigens and suitable candidates for targeted therapies and generating cancer vaccines. We conducted the present study to analyze transcript changes of two cancer/testis antigens, OIP5 and TAF7L, in breast tumors and cell lines in comparison with normal breast tissues by quantitative real time RT-PCR for the first time. Significant over-expression of OIP5 was observed in breast tumors and three out of six cell lines including MDA-MB-468, T47D and SKBR3. Not significant expression of TAF7L was evident in breast tumors but significant increase was noted in three out of six cell lines including MDA-MB-231, BT474 and T47D. OIP5 has ssignificant role in chromatin organization and cell cycle control during cell cycle exit and normal chromosome segregation during mitosis and TAF7L is a component of the transcription factor ??D, which is involved in transcription initiation of most protein coding genes. TAF7Lis located at X chromosome and belongs to the CT-X gene family of cancer/testis antigens which contains about 50% of CT antigens, including those which have been used in cancer immunotherapy. PMID- 26107215 TI - A clinical Comparison of Lobaplatin or Cisplatin with Mitomycine and Vincristine in Treating Patients with Cervical Squamous Carcinoma. AB - BACKGROUND: The research was to compare the efficacy and side effects of cisplatin or lobaplatin in combination with mitomycine (MMC) and vincristine in treating patients with cervical squamous carcinoma. MATERIALS AND METHODS: Cervical squamous carcinoma patients who were pathologically diagnosed with stage Ib-IIb from April 2012 to May 2013 in the general hospital of Chinese People's Libration Amy were enrolled. All patients were confirmed without prior treatment and were randomly divided into two groups, Group A and B. Efficacy and side effects were evaluated after one cycle of chemotherapy. RESULTS: Group A (n=42) were treated with Loubo(r) (Lobaplatin) 50mg/m2, MMC 16mg/m2 and Vincristine 2mg/m2 every 21 days. Group B (n=44) were treated with Cisplatin 100mg/m2, MMC 16mg/m2 and Vincristine 2mg/m2 every 21 days. All 86 patients completed one cycle of chemotherapy with cisplatin or lobaplatin in combination with MMC and vincristine. No difference was observed regardiing short-term effect between two groups. Main side effects were bone marrow suppression and gastrointestinal reactions including decrease of white blood cells, platelet and nausea/vomiting. Grade III-VI liver and kidney impairment was not reported in two groups. In group A the incidence of uterine artery spasm in the process of drug delivery was significantly lower than the group B. CONCLUSIONS: Cisplatin or lobaplatin with MMC and Vincristine in the interventional treatment of cervical squamous carcinoma were effective, especially after uterine artery perfusion chemotherapy at tumor reduction and tumor downstaging period. The adverse reactions of concurrent chemotherapy are tolerable, and low physical and mental pressure even more less stimulation of vascular in treatment with lobaplatin. However, the long term effects of this treatment need further observation. PMID- 26107216 TI - Meta-Analysis of the Association between H63D and C282Y Polymorphisms in HFE and Cancer Risk. AB - BACKGROUND: Previous studies suggested that the H63D and C282Y polymorphisms in the HFE genes were susceptible to many cancer types, nevertheless, the present results were inconclusive. Thus, the present study was aimed to evaluate the association between the HFE polymorphisms (H63D and C282Y) and cancer risk via meta-analysis. MATERIALS AND METHODS: We retrieved PubMed, Google Scholar, Embase and Web of Science databases for all eligible studies up to April 1, 2015. All the statistical analysis was conducted by STATA 12.0. RESULTS: Finally, a total of 20 publications including 24 case-control studies, comprising 6,524 cases and 31,080 controls for HFE-C282Y polymorphism and 19 publications including 21 case control studies, comprising 5,648 cases and 14,257 controls for HFE-H63D polymorphism were enrolled in our analysis. An increased risk for overall cancer risk was identified in HFE-H63D polymorphism under allele contrast (D vs H: OR=1.153; 95%CI=1.031- 1.289, Pheterogeneity=0.002), homozygotes vs wide type (DD vs HH: OR=1.449; 95%CI=1.182-1.777, Pheterogeneity=0.391), dominant model (DD+HD vs HH: OR=1.145; 95%CI=1.007-1.301, Pheterogeneity=0.002) and recessive model (DD vs HD+HH: OR=1.416 ; 95%CI=1.156-1.735, Pheterogeneity=0.549), as well as HFE- C282Y under homozygotes vs wide type (YY vs CC: OR=1.428, 95%CI=1.017-2.006, Pheterogeneity=0.220). In addition, in the stratified analysis by cancer type, an increased risk was identified in hepatocellular carcinoma and breast cancer in C282Y polymorphism, as well as pancreatic cancer in H63D polymorphism, whereas a decreased risk of colorectal cancer was identified in C282Y polymorphism. CONCLUSIONS: Present study suggested that H63D and C282Y polymorphisms associated with an increased risk of overall cancer. Nevertheless, well- designed study with large sample size will be continued on this issue of interest. PMID- 26107217 TI - Cytotoxicity Assessment of Six Different Extracts of Abelia triflora leaves on A 549 Human Lung Adenocarcinoma Cells. AB - The present investigation was designed to assess the anticancer activity of six different leaf extracts (ethyl acetate, methanol, chloroform, petroleum ether, n butanol, and water soluble) of Abelia triflora on A-549 human lung adenocarcinoma epithelial cells. A-549 cells were exposed to 10-1000 MUg/ml concentrations of the leaf extracts of A. triflorafor 24 h and then percentage cell viability was assessed by 3-(4,5-dimethylthiazol-2yl)-2,5-biphenyl tetrazolium bromide (MTT) assay. The results showed that leaf extracts of A. triflora significantly reduced the viability of A-549 cells in a concentration-dependent manner. Decrease was recorded as 31% with ethyl acetate, 36% with methanol, 46% with chloroform, 54% with petroleum ether, 62% with n-butanol, and 63% with water soluble extracts at 1000 MUg/ml each. Among the various plant extracts, ethyl acetate extract showed the highest decrease in the percentage cell viability, followed by methanol, chloroform, petroleum ether, n-butanol, and water soluble extracts. Our results demonstrated preliminary screening of anticancer activity of different soluble extracts of A. triflora extracts against A-549 cells, which can be further used for the development of a potential therapeutic anticancer agents. PMID- 26107218 TI - Epidemioclinical Feature of Early-Onset Colorectal Cancer at-Risk for Lynch Syndrome in Central Iran. AB - BACKGROUND: Colorectal cancer (CRC) is becoming one of the most complicated challenges of human health, particularly in developing countries like Iran. In this paper, we try to characterize CRC cases diagnosed < age 50 at-risk for Lynch syndrome within central Iran. MATERIALS AND METHODS: We designed a descriptive retrospective study to screen all registered CRC patients within 2000-2013 in Poursina Hakim Research Center (PHRC), a referral gastroenterology clinic in central Iran, based on being early-onset (age at diagnosis <=50 years) and Amsterdam II criteria. We calculated frequencies and percentages by SPSS 19 software to describe clinical and family history characteristics of patients with early-onset CRC. RESULTS: Overall 1,659 CRC patients were included in our study of which 413 (24.9%) were <=50 years at diagnosis. Of 219/413 successful calls 67 persons (30.6%) were reported deceased. Family history was positive for 72/219 probands (32.9%) and 53 families (24.2%) were identified as familial colorectal cancer (FCC), with a history of at-least three affected members with any type of cancer in the family, of which 85% fulfilled the Amsterdam II Criteria as hereditary non-polyposis colorectal cancer (HNPCC) families (45/219 or 20.5%). Finally, 14 families were excluded due to proband tumor tissues being unavailable or unwillingness for incorporation. The most common HNPCC-associated extracolonic cancer among both males and females of the families was stomach, at respectively 31.8 and 32.7 percent. The most common tumor locations among the 31 probands were rectum (32.3%), sigmoid (29.0%), and ascending colon (12.9%). CONCLUSIONS: Given the high prevalence of FCC (~1/4 of early-onset Iranian CRC patients), it is necessary to establish a comprehensive cancer genetic counseling and systematic screening program for early detection and to improve cancer prognosis among high risk families. PMID- 26107219 TI - Evaluation of Managerial Needs for Palliative Care Centers: Perspectives of Medical Directors. AB - BACKGROUND: Palliative therapies have an important role in increasing the quality of healthcare and in dealing with physical and psychosocial problems due to cancer. We here aimed to evaluate the managerial perspectives and opinions of the hospital managers and clinical directors about specialized palliative care centers. MATERIALS AND METHODS: This study was conducted in two large-scale hospitals in which oncology care is given with medical directors (n:70). A questionnaire developed by the researchers asking about demographic characteristics and professional experience, opinions and suggestions of medical directors about providing and integrating palliative care into healthcare was used and responses were analyzed. RESULTS: Potential barriers in providing palliative care (PC) and integrating PC into health systems were perceived as institutional by most of the doctors (97%) and nurses (96%). Social barriers were reported by 54% of doctors and 82% of nurses. Barriers due to interest and knowledge of health professionals about PC were reported by 76% of doctors and 75% of nurses. Among encouragement ideas to provide PC were dealing with staff educational needs (72%), improved working conditions (77%) and establishing a special PC unit (49)%. An independent PC unit was suggested by 27.7% of participants and there was no difference between the hospitals. To overcome the barriers for integration of PC into health systems, providing education for health professionals and patient relatives, raising awareness in society, financial arrangements and providing infrastructure were suggested. The necessity for planning and programming were emphasized. CONCLUSIONS: In our study, the opinions and perspectives of hospital managers and clinical directors were similar to current approaches. Managerial needs for treating cancer in efficient cancer centers, increasing the capacity of health professionals to provide care in every stage of cancer, effective education planning and patient care management were emphasized. PMID- 26107220 TI - Quantitative Assessment of the Association between ABC Polymorphisms and Osteosarcoma Response: a Meta-analysis. AB - BACKGROUND: ABC proteins are one key type of transport superfamilies which undertake majority of drug transport, which affect the osteosarcoma response to chemotherapeutics. Previous studies have suggested the association between ABC polymorphisms and osteosarcoma response. However, the results of previous studies remain controversial. Therefore, we perform a meta-analysis to get a more precise estimation of this association. The association between ABC polymorphisms and osteosarcoma response was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). Three polymorphisms of ABC including ABCB1 rs1128503, ABCC3 rs4148416 and ABCC2 rs717620 polymorphism were investigated. Overall, significant association was observed between ABCC3 rs4148416 polymorphism and osteosarcoma response under allele contrast (T vs. C: OR=1.73, 95%CI=1.09-2.74, P=0.019), homozygote comparison (TT vs. CC: OR=2.00, 95%CI=1.25-3.23, P=0.004), recessive genetic model (TT vs. TC/CC: OR=1.80, 95%CI=1.14-2.84, P=0.011) and dominant genetic model (TT/TC vs. CC: OR=1.70, 95%CI=1.20-2.42, P=0.003). Moreover, significant association was also observed in Caucasian population rather than Asian population for ABCB1 rs1128503 polymorphism. We conclude that ABCC3 rs4148416 polymorphism was significantly associated with poor osteosarcoma response and ABCB1 rs1128503 polymorphism was significantly associated with good osteosarcoma response in Caucasian population rather than Asian population. PMID- 26107221 TI - Aberrant Methylation of RASSF1A gene Contribute to the Risk of Renal Cell Carcinoma: a Meta-Analysis. AB - The aim of this study was to assess the diagnostic value of RASSF1A methylation in renal cell carcinoma. Systematically search were performed using the Pubmed, ProQest and Web of Science for all articles on the association between RASSF1A methylation and renal cell carcinoma before 15 April 2015. After the filtration, 13 studies involving 677 cases and 497 controls met our criteria. Our meta analysis suggested that hypermethylation of RASSF1A gene was associated with the increased risk of RCC(OR:4.14, 95%CI:1.06-16.1). Stratified analyses showed a similar risk in qualitative detection method(OR:28.4, 95%CI:10.2-79.6), body fluid sample(OR:12.8, 95%CI:5.35-30.8), and American(OR:10.5, 95%CI:1.97-55.9). Our result identified that RASSF1A methylation had a strong potential in prediction the risk of Renal cell carcinoma. PMID- 26107222 TI - In vitro Evaluation of Cytotoxic Activities of Essential Oil from Moringa oleifera Seeds on HeLa, HepG2, MCF-7, CACO-2 and L929 Cell Lines. AB - Moringa oleifera Lam. (Moringaceae) is widely consumed in tropical and subtropical regions for their valuable nutritional and medicinal characteristics. Recently, extensive research has been conducted on leaf extracts of M. oleifera to evaluate their potential cytotoxic effects. However, with the exception of antimicrobial and antioxidant activities, little information is present on the cytotoxic activity of the essential oil obtained from M. oleifera seeds. Therefore, the present investigation was designed to investigate the potential cytotoxic activity of seed essential oil obtained from M. oleifera on HeLa, HepG2, MCF-7, CACO-2 and L929 cell lines. The different cell lines were subjected to increasing oil concentrations ranging from 0.15 to 1 mg/mL for 24h, and the cytotoxicity was assessed using MTT assay. All treated cell lines showed a significant reduction in cell viability in response to the increasing oil concentration. Moreover, the reduction depended on the cell line as well as the oil concentration applied. Additionally, HeLa cells were the most affected cells followed by HepG2, MCF-7, L929 and CACO-2, where the percentages of cell toxicity recorded were 76.1, 65.1, 59.5, 57.0 and 49.7%, respectively. Furthermore, the IC50 values obtained for MCF-7, HeLa and HepG2 cells were 226.1, 422.8 and 751.9 MUg/mL, respectively. Conclusively, the present investigation provides preliminary results which suggest that seed essential oil from M. oleifera has potent cytotoxic activities against cancer cell lines. PMID- 26107223 TI - Probability Sampling Method for a Hidden Population Using Respondent-Driven Sampling: Simulation for Cancer Survivors. AB - When there is no sampling frame within a certain group or the group is concerned that making its population public would bring social stigma, we say the population is hidden. It is difficult to approach this kind of population survey methodologically because the response rate is low and its members are not quite honest with their responses when probability sampling is used. The only alternative known to address the problems caused by previous methods such as snowball sampling is respondent-driven sampling (RDS), which was developed by Heckathorn and his colleagues. RDS is based on a Markov chain, and uses the social network information of the respondent. This characteristic allows for probability sampling when we survey a hidden population. We verified through computer simulation whether RDS can be used on a hidden population of cancer survivors. According to the simulation results of this thesis, the chain-referral sampling of RDS tends to minimize as the sample gets bigger, and it becomes stabilized as the wave progresses. Therefore, it shows that the final sample information can be completely independent from the initial seeds if a certain level of sample size is secured even if the initial seeds were selected through convenient sampling. Thus, RDS can be considered as an alternative which can improve upon both key informant sampling and ethnographic surveys, and it needs to be utilized for various cases domestically as well. PMID- 26107224 TI - Cosmetic Outcomes and Quality of Life in Thai Women Post Breast Conserving Therapy for Breast Cancer. AB - PURPOSE: To evaluate the correlation between cosmetic outcome (CO), body image, and quality of life in post breast-conserving therapy (BCT) women. MATERIALS AND METHODS: This cross-sectional study concerned one-year post-completed BCT Thai women. The data included subjective and objective CO with a questionnaire covering demographic and clinical data, anti-hormonal treatment status, Eastern Cooperative Oncology Group (ECOG) performance status, Self-Reported Cosmetic Outcomes (SRCO), Self-Reported Breast Symmetry (SRBS), Body Image Scale (BIS), and the Functional Assessment of Cancer Therapy with Breast Cancer subscale (FACT B). Participants had breast photographs taken for the evaluation of objective cosmetic outcome (OCO) after breast cancer conservation treatment. The relationship between CO and FACT-B was tested using Spearman's rank correlation Results: A total 127 participants volunteered for the study. The participant characteristics were age 52(+/-9), Buddhist 87%, married 65%, body mass index 25.0(+/-4.6), breast cup size A-C 91%, college educated 60%, employed 66%, ECOG 0 1 95%, tumor size less than or equal to 2 cm 55%, no lymph node metastasis 98%, and taking tamoxifen 57%. Two percent of the participants regretted their decision to undergo BCT. The SRCO was excellent in 2%, good in 68%, fair in 30%, and poor in 0%. For SRBS, rates were 17%, 58%, 24% and 1% for excellent, good, fair and poor cosmetic outcomes, respectively. The BCCT scores were excellent 24%, good 39%, fair 32%, and poor 6%. The median total QOL score of the participants was 130 (93-144). There was no significant correlation between CO and FACT-B scores. CONCLUSIONS: The significance of CO for FACT-B in Thai women with breast cancer could not be assessed in detail because of a very low level of correlation. The results may be due to the effects of cultural background. PMID- 26107225 TI - Loss of Expression of PTEN is Associated with Worse Prognosis in Patients with Cancer. AB - BACKGROUND: The tumor suppressor phosphatase and tensin homolog (PTEN) is an important negative regulator of cell-survival signaling. However, available results for the prognostic value of PTEN expression in patients with cancer remain controversial. Therefore, a meta-analysis of published studies investigating this issue was performed. MATERIALS AND METHODS: A literature search via PubMed and EMBASE databases was conducted. Statistical analysis was performed by using the STATA 12.0 (STATA Corp., College, TX). Data from eligible studies were extracted and included into the meta-analysis using a random effects model. RESULTS: A total of 3,810 patients from 27 studies were included in the meta-analysis, 22 investigating the relationship between PTEN expression and overall survival (OS) using univariate analysis, and nine with multivariate analysis. The pooled hazard ratio (HR) for OS was 1.64 (95% confidence interval (CI): 1.32-2.05) by univariate analysis and 1.56 (95% CI: 1.20-2.03) by multivariate analysis. In addition, eight papers including two disease-free survival analyses (DFSs), four relapse-free-survival analyses (RFSs), three progression-free-survival analyses (PFSs) and one metastasis-free-survival analysis (MFS) reported the effect of PTEN on survival. The results showed that loss of PTEN expression was significant correlated with poor prognosis, with a combined HR of 1.74 (95% CI: 1.24-2.44). Furthermore, in the stratified analysis by the year of publication, ethnicity, cancer type, method, cut- off value, median follow-up time and neoadjuvant therapy in which the study was conducted, we found that the ethnicity, cancer type, method, median follow-up time and neoadjuvant therapy are associated with prognosis. CONCLUSIONS: Our study shows that negative or loss of expression of PTEN is associated with worse prognosis in patients with cancer. However, adequately designed prospective studies need to be performed for confirmation. PMID- 26107226 TI - Nested Case-control Study of Occupational Radiation Exposure and Breast and Esophagus Cancer Risk among Medical Diagnostic X Ray Workers in Jiangsu of China. AB - Medical diagnostic X-ray workers are one occupational group that expose to the long-term low-dose external radiation over their working lifetime, and they may under risk of different cancers. This study aims to determine the relationship between the occupational X-ray radiation exposure and cancer risk among these workers in Jiangsu, China. We conducted Nested case-control study to investigate the occupational X-ray radiation exposure and cancer risk. Data were collected through self-administered questionnaire, which includes but not limits to demographic data, personal behaviors and family history of cancer. Retrospective dose reconstruction was conducted to estimate the cumulative doses of the x-ray workers. Inferential statistics, t-test and 2 tests were used to compare the differences between each group. We used the logistic regression model to calculate the odds ratio (OR) and 95% confidence interval (CI) of cancer by adjusting the age, gender. All 34 breast cancer cases and 45 esophageal cancer cases that detected in a cohort conducted among health workers between 1950~2011 were included in this presented study, and 158 cancer-free controls were selected by frequency-matched (1:2). Our study found that the occupational radiation exposure was associated with a significantly increased cancer risk compared with the control, especially in breast cancer and esophageal cancer (adjusted OR=2.90, 95% CI: 1.19-7.04 for breast cancer; OR=4.19, 95% CI: 1.87-9.38 for esophageal cancer, and OR=3.43, 95% CI: 1.92-6.12 for total cancer, respectively). The occupational X-ray radiation exposure was associated with increasing cancer risk, which indicates that proper intervention and prevention strategies may be needed in order to bring down the occupational cancer risk. PMID- 26107227 TI - Short Sleep Duration and Its Correlates among Cancer Survivors in Korea: the Korea National Health and Nutrition Examination Surveys. AB - BACKGROUND: Though a large proportion of cancer survivors are assumed to be commonly affected by sleep disturbance, few studies have focused on short sleep problems and its correlates among Korean cancer survivors. The purpose of this study was to evaluate the prevalence of short sleep in adult cancer survivors from a nationwide population-based sample and to identify risk factors for short sleep duration. MATERIALS AND METHODS: Based on the fourth and fifth Korea National Health and Nutrition Examination Surveys (2007-2012), 1,045 cancer survivors and 33,929 non-cancer controls were analyzed. The prevalence of short sleep was compared between these two groups. Associations between short sleep and its correlates were evaluated using multiple logistic regression among cancer survivors: odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated after adjusting for sociodemographic factors, lifestyle factors, psychological conditions, and cancer-related factors. RESULTS: About 8.1% of cancer survivors slept for less than 5 hours per day (6.2% men and 9.3% women), whereas this was the case for only 3.7% of non-cancer controls. Cancer survivors who had the lowest household income level showed a significantly higher likelihood for short sleep (adjusted OR 2.82, 95%CI 1.06-7.54). Self-reported poor health and depressive symptoms were found to be associated with significantly increased likelihood for short sleep in cancer survivors (adjusted OR 3.60, 95%CI 1.40-9.26 and adjusted OR 2.00, 95%CI 1.17-3.42). Gastric cancer survivors had a 3.97-fold increased risk for short sleep (95%CI 1.60-9.90). CONCLUSIONS: The prevalence of short sleep occurs at a high rate among the Korean cancer survivors, which may indicate a poorer quality of life and a higher risk of future complications in survivorship. Targeted interventions that can assist cancer survivors to cope with sleep disturbances as well as ensuring psychological stability are warranted to reduce the latent disease burden. PMID- 26107228 TI - Radical Oncological Surgery and Adjuvan Therapy in Non- Small Cell Lung Cancer Patients over 70 years of Age. AB - BACKGROUND: The incidence of lung cancer increases with age. Approximately 50% of non-small cell lung cancer (NSCLC) patients are over 70 years old. Because of the increasing elderly population, treatment approaches in this age group continue to be studied similar to groups of young people. MATERIALS AND METHODS: In the current study, 26 patients who underwent radical surgery and adjuvan chemoradiation at Ataturk Chest Diseases and Chest Surgery Training and Research Hospital were evaluated retrospectively. RESULTS: Of 21 patients (81%) were male and the average age was 74.4. Lobectomy was performed in 18 cases, pneumonectomy in 3, sleeve lobectomy in 3 and bilobectomy in 2. There was no perioperative or early period mortality. Overall survival was 24.5 months. CONCLUSIONS: From our study, lung cancer surgery and adjuvant therapy can be performed safely with low morbidity in the elderly. PMID- 26107229 TI - A Pilot Study on Factors Associated with Presentation Delay in Patients Affected with Head and Neck Cancers. AB - BACKGROUND: Patient delay can contribute to a poor outcome in the management of head and neck cancers (HNC). The main objective of the present study was to investigate the factors associated with patient delay in our population. MATERIALS AND METHODS: Patients with cancers of the head and neck attending a regional cancer center of North East India were consecutively interviewed during the period from June 2014 to November 2014. The participation of patients was voluntary. The questionnaire included information on age, gender, residential status, educational qualification, monthly family income, any family history of cancer, and history of prior awareness on cancer from television (TV) program and awareness program. RESULTS: Of 311 (n) patients, with an age range of 14-88 years (mean 55.4 years), 81.7% were males and 18.3% females (M:F=4.4). The overall median delay was 90 days (range=7 days-365 days), in illiterate patients the median delay was 90 days and 60 days in literate patients (P=0.002), the median delay in patients who had watched cancer awareness program on TV was 60 days and in patients who were unaware about cancer information from TV program had a median delay of 90 days (p=0.00021) and delay of <10 weeks was seen in 139 (44.6%) patients, a delay of 10-20 weeks in 98 (31.5%) patients, and a delay of 20-30 weeks in 63 (20.2%) patients. CONCLUSIONS: Education and awareness had a significant impact in reduction of median patient delay in our HNC cases. PMID- 26107230 TI - The Level of Squamous Cell Carcinoma Antigen and Lymph Node Metastasis in Locally Advanced Cervical Cancer. AB - BACKGROUND: This study aimed to determine the utility and a cut-off level of serum squamous cell carcinoma antigen (SCC-Ag) to predict lymph node metastasis in locally advanced cervical cancer cases. We also investigated the correlation between SCC-Ag level and lymph node status. MATERIALS AND METHODS: From June 2009 to June 2014, 232 patients with cervical cancer stage IB2-IVA, who were treated at Ramathibodi Hospital, were recruited. Receiver operating characteristic (ROC) curves were used to identify the best cut-off point of SCC-Ag level to predict lymph node metastasis. Quantile regression was performed to evaluate the correlation between SCC-Ag levels and pelvic lymph node metastasis, paraaortic lymph node metastasis, and parametrial involvement as well as tumor size. RESULTS: Pelvic lymph node metastasis and paraaortic lymph node metastasis were diagnosed in 46.6% and 20.1% of the patients, respectively. The median SCC-Ag level was 6 ng/mL (range, 0.5 to 464.6 ng/ mL). The areas under ROC curves between SCC-Ag level and pelvic lymph node metastasis, paraaotic lymph node metastasis, parametrial involvements were low. SCC-Ag level was significantly correlated with paraaortic lymph node status (p=0.045) but not with pelvic lymph node status and parametrial involvement. SCC-Ag level was also related to the tumor diameter (p<0.05). CONCLUSIONS: SCC-Ag level is not a good predictor for pelvic and paraaortic lymph node metastasis. However, it is still beneficial to assess the tumor burden of squamous cell carcinoma of the cervix. PMID- 26107231 TI - Radiotherapy and Concurrent Chemo-Radiotherapy in Locally Advanced Hypopharyngeal Cancers--A Hospital Registry Based Analysis. AB - BACKGROUND: The survival of patients with hypopharyngeal cancer is low amongst head and neck cancer cases. The incidence rates of hypopharyngeal cancers in our population are amongst the highest in the world and there are limited data available on the literature on varied responses to first course of treatment with radiotherapy (RT) and concurrent chemo-radiotherapy (CRT) in our population. MATERIALS AND METHODS: Clinical characteristics and initial responses to treatment in patients who had received radiotherapy and chemo-radiotherapy in a regional cancer center from January 2010 to December 2013 were evaluated. The data were obtained from the hospital cancer registry, and analysis was carried using descriptive statistics. Pearson's chi-square was used to test for differences in the variables and p<0.05 was considered statistically significant. RESULTS: A total of 554 patients were included in the analysis, 411 (74.2%) receiving RT and 143 (25.8%) being given CRT. There was significantly lower number of patients above 70 years with a higher proportion of patients below 50 years who had received CRT (p<0.05). Some 79.3% and 84.6% of patients in the RT and CRT groups respectively presented with a favorable performance status, and in the RT group 240 (58.4%) showed complete response (CR), and in the CRT group 103 (72.0%) showed CR at the first follow-up (p<0.05). CONCLUSIONS: Concurrent chemo radiotherapy gives better short term response to treatment in locally advanced hypopharyngeal cancers. PMID- 26107232 TI - Mutation Screening and Association Study of the Folylpolyglutamate Synthetase (FPGS) Gene with Susceptibility to Childhood Acute Lymphoblastic Leukemia. AB - BACKGROUND: Folylpolyglutamate synthetase (FPGS), an important enzyme in the folate metabolic pathway, plays a central role in intracellular accumulation of folate and antifolate in several mammalian cell types. Loss of FPGS activity results in decreased cellular levels of antifolates and consequently to polyglutamatable antifolates in acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: During May 1997 and December 2003, 134 children diagnosed with ALL were recruited from one hospital in Thailand. We performed a mutation analysis in the coding regions of the FPGS gene and the association between single nucleotide polymorphisms (SNPs) within FPGS in a case-control sample of childhood ALL patients. Mutation screening was conducted by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and subsequently with direct sequencing (n=72). Association analysis between common FPGS variants and ALL risk was done in 98 childhood ALL cases and 95 healthy volunteers recruited as controls. RESULTS: Seven SNPs in the FPGS coding region were identified by mutation analysis, 3 of which (IVS13+55C>T, g.1297T>G, and g.1508C>T) were recognized as novel SNPs. Association analysis revealed 3 of 6 SNPs to confer significant increase in ALL risk these being rs7039798 (p= 0.014, OR=2.14), rs1544105 (p=0.010, OR= 2.24), and rs10106 (p=0.026, OR= 1.99). CONCLUSIONS: These findings suggested that common genetic polymorphisms in the FPGS coding region including rs7039789, rs1544105, and rs10106 are significantly associated with increased ALL risk in Thai children. PMID- 26107233 TI - Quantitative Review of Oral Cancer Research Output from Pakistan. AB - BACKGROUND: Oral cancer is the most common cancer among men and second only to breast cancer among women in Pakistan. For the effective control and prevention of oral cancer, Pakistan needs to recognize the importance of research and generation of the evidence-base which can inform policy making and planning and implementation of intervention programs. The objective of this review was to quantify oral cancer research output in Pakistan. MATERIALS AND METHODS: A systematic electronic search in "Medline", "ISI-Web of Science" and "Pakmedinet", supplemented by a Google search, was carried out in January and February, 2014, to identify literature from Pakistan relevant to oral cancer. The selection of publications for the review was carried out according to preset criteria. Data were recorded and analyzed using Microsoft Excel. RESULTS: A total of 166 publications comprising 62 case series, 36 cross sectional, 31 case control, 10 basic laboratory research, eleven reviews and two trials, were included in this review. Some 35 % of the publications focused on risk factors for oral cancer. COMSATS Institute of Information Technology was the institution with the highest contribution. CONCLUSIONS: There is a lack of research in the field of oral cancer research in Pakistan. Focused efforts should be put in place to improve both quality and quantity of oral cancer research in the country. PMID- 26107234 TI - Knowledge, Attitudes and Practice of Testicular Self- examination among Male University Students from Bangladesh, Madagascar, Singapore, South Africa and Turkey. AB - The aim of this study was to investigate the knowledge, attitude and practice of testicular self-examination (TSE) among male university students from low income (Bangladesh, Madagascar), middle income (South Africa, Turkey) and emerging economy (Singapore) countries. Using anonymous questionnaires, data were collected from 2,061 male undergraduate university students aged 16-30 (mean age 21.4, SD=2.4) from 5 universities in 5 countries across Asia and Africa. Overall, 17.6% of the male students indicated that they knew how to perform TSE; this knowledge proportion was above 20% in Bangladesh and Singapore, while it was the lowest (12.2%) in Madagascar. Among all men, 86.4% had never practiced TSE in the past 12 months, 7.1% 1-2 times, 3.5% 3-10 times, and monthly TSE was 3.1%. The proportion of past 12 month TSE was the highest (17.6%) among male university students in South Africa and the lowest (7.3%) among students in Singapore. Logistic regression found that TSE importance or positive attitude was highly associated with TSE practice. TSE practices were found to be inadequate and efforts should be made to develop programmes that can increase knowledge related to testicular cancer as well as the practice of testicular self-examination. PMID- 26107235 TI - Secondary Circulating Tumor Cells (CTCs) but not Primary CTCs are Associated with the Clinico-Pathological Parameters in Chilean Patients With Colo-Rectal Cancer. AB - BACKGROUND: The aim of this study was to assess detection of circulating tumor cells (CTC) using anti-CEA pre and post surgery in Chilean patients with colo rectal cancer. MATERIALS AND METHODS: The presence of CTCs was evaluated in 80 colorectal cancer patients pre and post surgery using standard immunocytochemistry and the results were compared with findings for standard clinico-pathological parameters. RESULTS: In patients pre- surgery CEA (+) CTCs were frequently found, with no relation to tumor size or nodal status. After surgery, the presence of CTCs was associated with such clinico-pathological parameters. The frequency of CTC detection in node positive patients did not change after surgery. In patients with metastasis there was also no change in the frequency of CTC detection, and clusters of 3 or more CTCs were evident. CONCLUSIONS: Secondary CTCs are associated with clinico-pathological parameters only after surgical removal of the primary tumor, and might be important in identifying patients at high risk of relapse. Primary CTCs detected before surgical removal are frequently found, are not associated with the clinico pathological parameters and might have a role in cancer screening. These findings suggest the need for studies with a larger population of patients. PMID- 26107236 TI - Metastatic Inhibitory and Radical Scavenging Efficacies of Saponins Extracted from the Brittle Star (Ophiocoma erinaceus). AB - Echinodermata use saponins in chemical defense against pathogens and predators. The molecular mechanisms of antimetastatic effects of brittle star saponins are still unknown. The present study examined antioxidant capacity and invasive ability in HeLa carcinoma cells exposed to brittle star crude saponins. Discolorating methods with DPPH and ABTS and expression of SOD-2 with RT-PCR were used to estimate the antioxidant activity. The anti-invasive activity of extracted saponins was examined through adhesion of HeLa cells to extracellular matrix, wound healing and evaluation of the mRNA levels of MMP-2 and MMP-9 by real time-PCR. The results showed that extracted saponins had cytotoxicity against cervical cancer cells and ABTS and DPPH scavenging properties with IC50 values of 604.5, 1012 MUg/ml, respectively. Further, we found that, in wound healing assay, brittle star saponins could prevent invasion of HeLa cells in a concentration dependent manner. Furthermore, cell adhesion assay demonstrated blockage of cell attachment to extracellular matrix with an IC50 concentration of 16.1MUg/ml. The significant dose dependent down regulation of MMP-2 and MMP-9 in treated cells demonstrated that isolated saponins can decline tumor metastasis in vitro. The brittle star saponins remarkably prevented cervical cancer invasion and migration associated with down regulation of matrix metalloproteinase expression. Therefore, saponins could be suggested as an anti-invasive candidate against cervical cancer and an antioxidant as well. PMID- 26107237 TI - Predictive and Prognostic Biomarkers for Patients Treated with Anti-EGFR Agents in Lung Cancer: A Systemic Review and Meta-Analysis. AB - BACKGROUND: Several studies have investigated predictive and prognostic biomarkers for patients treated with anti-epidermal growth factor receptor (EGFR) agents in lung cancer. However, the conclusion is controversial. MATERIALS AND METHODS: A meta-analysis was conducted to evaluate the associations of mutant K ras, PIK3CA and PTEN deficiency with the efficacy of anti-EGFR agents in lung cancer. The primary endpoint was objective response rate (ORR). The secondary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 61 studies were included in the final meta-analysis. The result showed that K-ras mutation was a good predictor for ORR (RR=0.42, 95%CI, 0.33-0.55, p=0.000) and an effective prognostic marker for OS (HR=1.37, 95%CI, 1.15-1.65, p=0.001) and PFS (HR=1.33, 95%CI, 1.05-1.69, p=0.019). However, PTEN deficiency or PIK3CA mutation did not show any significance predictive value for ORR (PTEN, RR=0.82, 95%CI, 0.56-1.19, p=0.286; PIK3CA, RR=1.08, 95%CI, 0.17-6.66, P=0.938). And PTEN deficiency or expression of PIK3CA did not show significance prognostic value for OS (PTEN, HR=0.88, 95%CI, 0.31-2.46,P=0.805; PIK3CA, HR=0.79, 95%CI: 0.23-2.68, P=0.706). CONCLUSIONS: Our meta-analysis showed that K ras mutation may be an effective predictor in lung cancer patients treated with anti-EGFR agents. Whereas, the predictive and prognostic value of PTEN deficiency and PIK3CA mutation need to be further investigated. PMID- 26107238 TI - Roles of Combined Glypican-3 and Glutamine Synthetase in Differential Diagnosis of Hepatocellular Lesions. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and thirdly leading cause of cancer-related death worldwide. The estimated risk of hepatocellular carcinoma is 15 to 20 times as high among persons infected with HCV as it is among those who are not infected, with most of the excess risk limited to those with advanced hepatic fibrosis or cirrhosis. Glypican3 (GPC3) plays a key role in relation to signaling with growth factors, regulating the proliferative activity of cancer cells. Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia in the mammalian liver. GS was suggested as a specific marker for tracing cell lineage relationships during hepatocarcinogenesis. In normal liver, GS expression is seen in pericentral hepatocytes, but not by midzonal or periportal hepatocytes. In HCC, strong and diffuse GS expression in seen in tumor cells. RESULTS: Glypican3 immunopositvity was highly specific and sensitive indicator for hepatocellular carcinoma as well as glutamine synthetase which was found to be a sensitive and specific indicator for development of hepatocellular carcinoma when compared to cirrhosis, liver cell dyspalsia and metastatic carcinomas. Statistical analysis revealed a significant association between GPC3 and GS with tumor size (P=0.003, p=0.006, respectively). Diffuse staining significantly associated with large tumor size while, focal and mixed staining was detected more with small tumor size. Studying the relation with tumor grade also revealed significant association between diffuse GPC3 and GS staining with high tumor grade. Diffuse staining was detected in 91.7% and 100% respectively of poorly differentiated specimens and only in 33.3% and 22.2% of well differentiated specimens. CONCLUSIONS: While using GPC3 and GS to screen for premalignant hepatic lesions remains controversial, our data suggest that GPC3 and GS may be a reliable diagnostic immunomarkers to distinguish HCC from benign hepatocellular lesions. However, negative immunostaining should not exclude the diagnosis of HCC. PMID- 26107239 TI - Adult Urological Soft Tissue Sarcomas: A Multicenter Study of the Anatolian Society of Medical Oncology (ASMO). AB - OBJECTIVE: To analyze clinicopathological characteristics, prognostic factors and survival rates of the patients with urological soft tissue sarcomas treated and followed up in Turkey. MATERIALS AND METHODS: For overall survival analyses the Kaplan-Meier method was used. From medical records, nine prognostic factors on overall survival were analysed. RESULTS: For the 53 patients (34 males, 19 females) whose charts were reviewed, the median age was 53 (range 22 to 83) years. Most frequently renal location (n=30; 56.6%) was evident and leiomyosarcoma (n=20, 37.7%) was the most frequently encountered histological type. Median survival time of all patients was 40.3 (95% CI, 14.2-66.3) months. In univariate analysis, male gender, advanced age (>=50 years), metastatic stage, unresectability, grade 3, renal location were determined as worse prognostic factors. In multivariate analysis, metastatic stage, unresectability and grade 3 were determined as indicators of worse prognosis. CONCLUSIONS: Urological soft tissue sarcomas are rarely seen tumours in adults. The most important factors in survival are surgical resection, stage of the tumour at onset, grade and location of the tumour, gender and age of the patients. PMID- 26107240 TI - Proliferative and Inhibitory Activity of Siberian ginseng (Eleutherococcus senticosus) Extract on Cancer Cell Lines; A-549, XWLC-05, HCT-116, CNE and Beas 2b. AB - Siberian ginseng (Eleutherococcus senticosus) is used primarily as an adaptogen herb and also for its immune stimulant properties in Western herbal medicine. Another closely related species used in East Asian medicine systems i.e. Kampo, TCM (Manchuria, Korea, Japan and Ainu of Hokkaido) and also called Siberian ginseng (Acanthopanax senticosus) also displays immune-stimulant and anti-cancer properties. These may affect tumour growth and also provide an anti-fatigue effect for cancer patients, in particular for those suffering from lung cancer. There is some evidence that a carbohydrate in Siberian ginseng may possess not only immune stimulatory but also anti-tumour effects and also display other various anti-cancer properties. Our study aimed to determine the inhibitory and also proliferative effects of a methanol plant extract of Siberan ginseng (E. senticosus) on various cancer and normal cell lines including: A-549 (small cell lung cancer), XWLC-05 (Yunnan lung cancer cell line), CNE (human nasopharyngeal carcinoma cell line), HCT-116 (human colon cancer) and Beas-2b (human lung epithelial). These cell lines were treated with an extract from E. senticosus that was evaporated and re- constituted in DMSO. Treatment of A-549 (small cell lung cancer) cells with E. senticosus methanolic extract showed a concentration dependent inhibitory trend from 12.5 - 50MUg/mL, and then a plateau, whereas at 12.5 and 25 MUg/mL, there is a slight growth suppression in QBC-939 cells, but then a steady suppression from 50, 100 and 200MUg/mL. Further, in XWLC-05 (Yunnan lung cancer cell line), E. senticosus methanolic extract displayed an inhibitory effect which plateaued with increasing dosage. Next, in CNE (human nasopharyngeal carcinoma cell line) there was a dose dependent proliferative response, whereas in Beas-2 (human lung epithelial cell line), an inhibitory effect. Finally in colon cancer cell line (HCT-116) we observed an initially weak inhibitory effect and then plateau. PMID- 26107241 TI - Ovarian Cancer in Children and Adolescents: Treatment and Reproductive Outcomes. AB - OBJECTIVE: To review ovarian cancer cases in children and adolescents in Siriraj Hospital and assess the prognosis, recurrence of disease, and reproductive outcomes after treatment. MATERIALS AND METHODS: A retrospective descriptive study was conducted in ovarian cancer patients 21 years and younger who had been treated at Siriraj Hospital between January 1990 and December 2009. Medical records were reviewed and relevant data were recorded. RESULTS: A total of 48 cases met the criteria; their mean age was 16.4 years. Abdominal distension was the major symptom. 91.6% were germ cell tumors and the remaining cases were sex cord-stromal and epithelial tumors. More than half (25/48 cases) presented with stage I disease. The most common used chemotherapy regimen for germ cell tumors was BEP (bloemycin, etoposide, cisplatin). Most of patients had favorable outcomes; 46/48 cases had complete remission and retained their good health at the time of the review. We had only one recurrent case and one dead case. Ten of contacted patients had married and 3 of them had successful full-term pregnancies. CONCLUSIONS: Ovarian malignancy in children and adolescents is a rare disease. The authors reported 48 cases in 20 year-period of work. Most of them have favorable outcomes. Return of ovarian function and fertility are the topics of interest. PMID- 26107242 TI - Study of Pemetrexed-based Chemotherapy for Patients with Locally Advanced or Metastatic Cancers. AB - PURPOSE: This study was conducted to observe the efficacy and safety of pemetrexed based chemotherapy in treating patients with locally advanced or metastatic cancers as first-line, second-line or third-line therapy. MATERIALS AND METHODS: From May 2011 to January 2015, we recruited 29 patients with advanced breast cancer, 19 patients with advanced ovary cancer, 17 patients with advanced esophageal cancer,5 patients with advanced gallbladder cancer,5 patients with advanced cervical cancer and 1 patient with advanced tongue cancer in Jiangsu Cancer Hospital and Research Institute.All of them were pathologically confirmed and treated with pemetrexed based chemotherapy. After two cycles of treatment,efficacy and safety can be evaluated. RESULTS: For pemetrexed based regimens,including 76 patients with 6 kinds of advanced cancer were considered eligible for inclusion. Complete remission represents CR, partial remission represents PR, stable disease represents SD, progressive disease represents PD. Among 29 patients with advanced breast cancer, 4 patients chose pemetrexed based regimens as second-line treatment,1 of them was PR,the other 3 got SD. The last 25 patients made use of this chemotherapy as third-line treatment, except one patient could not be assessed, 2 of them got PR,6 of them got SD,the remaining 16 of them finally were PD.19 patients with advanced ovary cancer,5 patients used this regimens as second-line treatment, 3 of them got PD,the remaining patients got SD, respectively. The last 14 patients made use of pemetrexed based regimens as third-line treatment,. RR (CR+PR) was 28.5%. Among 17 patients with advanced esophageal cancer, 2 patients made use of pemetrexed based regimens as first-line treatment,both of them got PR.4 of them used this chemotherapy as second-line regimen, except 2 patients could not be assessed,the remaining 2 was PD at last. The last 11 patients was third-line users, RR (CR+PR) was 18.2%. Among 5 patients with advanced gallbladder cancer, pemetrexed based regimens was used in 1 patient as first- line treatment and 1 patient as second-line treatment. The curative effect was SD and PD, respectively. 3 patients accepted pemetrexed based regimens as third-line treatment, 2 of them got PD as results and another was SD. Among 5 patients with advanced cervical cancer, just 1 patient adopted pemetrexed based regimens as first-line treatment, whose curative effect was PR.2 patients chose this chemotherapy regimens as second-line treatment. Both of them got PD as their consequence. The last 2 patients made use of the regimens as third-line treatment, the effect of them was PD and SD, respectively. The one who with advanced tongue cancer, pemetrexed based regimens was used as second-line treatment, and the consequence was PD. About 71.1% patients experienced bone marrow suppression. Among them, 5 patients reached 4 grade. Other toxicity of pemetrexed were neurotoxicity, fatigue, diarrhea, dysphagia and vomiting. No treatment related death occurred with pemetrexed-based treatment. CONCLUSIONS: Pemetrexed based chemotherapy has considerable effect in patients with advanced cancers such as breast cancer,esophageal cancer and ovary cancer. More randomly clinical trials are needed to verify the results. PMID- 26107243 TI - A Pooled Analysis on Crizotinib in Treating Chinese Patients with EML4-ALK Positive Non-small-cell Lung Cancer. AB - BACKGROUND: This analysis was conducted to evaluate the efficacy and safety of crizotinib based regimens in treating Chinese patients with EML4-ALK positive non small-cell lung cancer. MATERIALS AND METHODS: Clinical studies evaluating the efficacy and safety of crizotinib based regimens on response and safety for Chinese patients with EML4-ALK positive non-small-cell lung cancer were identified by using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. RESULTS: In crizotinib based regimens, 3 clinical studies which including 128 Chinese patients with EML4-ALK positive non-small cell lung cancer and treated with crizotinib based regimen were considered eligible for inclusion. Pooled analysis suggested that, in all patients, the pooled RR was 59.3% (76/128) in crizotinib based regimens. ALT/AST mild visual disturbances, nausea, and vomiting were the main side effects. No treatment related death occurred in these crizotinib based treatments. CONCLUSIONS: This pooled analysis suggests that crizotinib based regimens are associated with good response rate and accepted toxicities in treating Chinese patients with EML4-ALK positive non-small-cell lung cancer. PMID- 26107244 TI - Are Rogerofenib and Nilotinib Effective for Advanced Gastrointestinal Stromal Tumor (GIST) Patients who have Already been Given Main Treatments? PMID- 26107245 TI - Structure-based design of potent HIV-1 protease inhibitors with modified P1 biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies. AB - We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy 1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV 1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease. PMID- 26107247 TI - Improving Hospital Quality and Costs in Nonoperative Traumatic Brain Injury: The Role of Acute Care Surgeons. AB - IMPORTANCE: The role of acute care surgeons is evolving; however, no guidelines exist for the selective treatment of patients with traumatic brain injury (TBI) exclusively by acute care surgeons. We implemented the Brain Injury Guidelines (BIG) for managing TBI at our institution on March 1, 2012. OBJECTIVE: To compare the outcomes in patients with TBI before and after implementation of the BIG protocol. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 2-year analysis of our prospectively maintained database of all patients with TBI (findings of skull fracture and/or intracranial hemorrhage on an initial computed tomographic scan of the head) who presented to our level I trauma center. The pre-BIG group included patients with TBI from March 1, 2011, through February 29, 2012, and the post-BIG group included patients from July 1, 2012, through June 30, 2013. MAIN OUTCOMES AND MEASURES: The primary outcome measures were patients with repeated computed tomography of the head and neurosurgical consultations. Secondary outcome measures were findings of progression of intracranial hemorrhage on repeated computed tomographic scans, neurosurgical intervention, hospital admission, intensive care unit admission, hospital and intensive care unit length of stay, 30-day readmission rate, and hospital costs per patient. RESULTS: A total of 796 patients (415 in the pre-BIG group and 381 in the post-BIG group) were included. There was a significant reduction (19.0%) in the rate of neurosurgical consultation (post-BIG group, 273 patients [71.7%]; pre-BIG group, 376 [90.6%]; P < .001), repeated computed tomography of the head (post-BIG group, 255 patients [66.9%]; pre-BIG group, 381 patients [91.8%]; P < .001), hospital (post-BIG group, 330 [86.6%]; pre-BIG group, 398 [95.9%]; P < .001) and intensive care unit admission (post-BIG group, 202 [53.0%]; pre-BIG group, 257 [61.9%]; P = .01), hospital length of stay (post-BIG group, 5.4 [4.5] days; pre-BIG group, 6.1 [4.8] days; P = .03), and hospital costs per patient ($4772 per patient; P = .03) with implementation of BIG. There was no difference in the in-hospital mortality rate (post-BIG group, 62 patients [16.3%]; pre-BIG group, 69 patients [16.6%]; P = .89), progression of intracranial hemorrhage on repeated scans (post-BIG group, 41 patients [10.8%]; pre-BIG group, 59 patients [14.2%]; P = .14), neurosurgical intervention (post-BIG group, 61 patients [16.0%]; pre-BIG group, 59 patients [14.2%]; P = .48), and 30-day readmission rate (post-BIG group, 31 patients [8.1%]; pre-BIG group, 37 patients [8.9%]; P = .69) after implementation of BIG. CONCLUSIONS AND RELEVANCE: Implementation of BIG is safe and cost-effective. BIG defines the management of TBI without the need for neurosurgical consultation and unnecessary imaging. Establishing a national, multi-institutional study implementing the BIG protocol is warranted. PMID- 26107248 TI - Correction: Casein Kinase 1 and Phosphorylation of Cohesin Subunit Rec11 (SA3) Promote Meiotic Recombination through Linear Element Formation. PMID- 26107249 TI - Persistence, isolation and diversification of a naturally fragmented species in local refugia: the case of Hydromantes strinatii. AB - The study of the European plethodontid salamander Hydromantes strinatii using allozyme and mitochondrial markers showed a strong geographical genetic structure. This was likely the outcome of different evolutionary mechanisms leaving their signature despite the effects of the genetic drift due to the low population size typical of this species. Two highly divergent clades were identified in the eastern and central-western part of the range, with further geographic sub-structure. Nuclear and mitochondrial markers substantially recovered the same population groups but were conflicting in reconstructing their relationships. This apparent incongruence highlighted the action of different mechanisms such as secondary contacts and incomplete lineage sorting in originating the observed genetic variation. The troglophilic habit of this species provided the opportunity to show the importance of caves as local refugia in maintaining the genetic diversity through the persistence of local populations. Accordingly, high nucleotide and haplotype diversity, strong geographic genetic structuring and lack of expansion were evidenced. This signature was found in the populations from the Ligurian and Maritime Alps, in agreement with the complex orography and paleoclimatic history of this Mediterranean hotspot. PMID- 26107250 TI - Antigen-specific tolerogenic dendritic cells ameliorate the severity of murine collagen-induced arthritis. AB - Dendritic cells (DCs) play important roles in initiation of the pathogenic processes of autoimmune disorders, such as rheumatoid arthritis (RA). Tolerogenic dendritic cells (tolDCs) are generated from naive DCs and induce T cell tolerance; thus, they represent a promising strategy for specific cellular therapy for autoimmune diseases. In this study, we generated green fluorescent protein (GFP)-labeled tolDCs and confirmed their phenotypes and biological functions. We found that tolDCs suppressed the memory lymphocyte response and exhibited strong tolerogenic potential; thus, these cells show promise for the treatment of autoimmune diseases. Additionally, a collagen-induced arthritis (CIA) mouse model was used to test the role of tolDCs in vivo. The results of a further mechanistic experiment revealed that tolDCs suppressed inflammatory arthritis at least partially by up-regulating regulatory T (Treg) cells. Collectively, our data suggest that tolDCs may be used as a promising alternative therapy for inflammatory arthritis. PMID- 26107251 TI - Spatial-Temporal Dynamics of High-Resolution Animal Networks: What Can We Learn from Domestic Animals? AB - Animal social network is the key to understand many ecological and epidemiological processes. We used real-time location system (RTLS) to accurately track cattle position, analyze their proximity networks, and tested the hypothesis of temporal stationarity and spatial homogeneity in these networks during different daily time periods and in different areas of the pen. The network structure was analyzed using global network characteristics (network density), subgroup clustering (modularity), triadic property (transitivity), and dyadic interactions (correlation coefficient from a quadratic assignment procedure) at hourly level. We demonstrated substantial spatial-temporal heterogeneity in these networks and potential link between indirect animal environment contact and direct animal-animal contact. But such heterogeneity diminished if data were collected at lower spatial (aggregated at entire pen level) or temporal (aggregated at daily level) resolution. The network structure (described by the characteristics such as density, modularity, transitivity, etc.) also changed substantially at different time and locations. There were certain time (feeding) and location (hay) that the proximity network structures were more consistent based on the dyadic interaction analysis. These results reveal new insights for animal network structure and spatial-temporal dynamics, provide more accurate descriptions of animal social networks, and allow more accurate modeling of multiple (both direct and indirect) disease transmission pathways. PMID- 26107253 TI - Differential Survival for Men and Women with HIV/AIDS-Related Neurologic Diagnoses. AB - OBJECTIVES: Neurologic complications of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) frequently lead to disability or death in affected patients. The aim of this study was to determine whether survival patterns differ between men and women with HIV/AIDS-related neurologic disease (neuro-AIDS). METHODS: Retrospective cohort data from a statewide surveillance database for HIV/AIDS were used to characterize survival following an HIV/AIDS-related neurologic diagnosis for men and women with one or more of the following conditions: cryptococcosis, toxoplasmosis, primary central nervous system lymphoma, progressive multifocal leukoencephalopathy, and HIV associated dementia. A second, non-independent cohort was formed using university based cases to confirm and extend the findings from the statewide data. Kaplan Meier analysis was used to compare the survival experiences for men and women in the cohorts. Cox regression was employed to characterize survival while controlling for potential confounders in the study population. RESULTS: Women (n=27) had significantly poorer outcomes than men (n=198) in the statewide cohort (adjusted hazard ratio=2.31, 95% CI: 1.22 to 4.35), and a similar, non significant trend was observed among university-based cases (n=17 women, 154 men). Secondary analyses suggested that this difference persisted over the course of the AIDS epidemic and was not attributable to differential antiretroviral therapy responses among men and women. CONCLUSIONS: The survival disadvantage of women compared to men should be confirmed and the mechanisms underlying this disparity elucidated. If this relationship is confirmed, targeted clinical and public health efforts might be directed towards screening, treatment, and support for women affected by neuro-AIDS. PMID- 26107252 TI - Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA PK and Akt. AB - The inflammasome activates caspase-1 and the release of interleukin-1beta (IL 1beta) and IL-18, and several inflammasomes protect against intestinal inflammation and colitis-associated colon cancer (CAC) in animal models. The absent in melanoma 2 (AIM2) inflammasome is activated by double-stranded DNA, and AIM2 expression is reduced in several types of cancer, but the mechanism by which AIM2 restricts tumor growth remains unclear. We found that Aim2-deficient mice had greater tumor load than Asc-deficient mice in the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colorectal cancer. Tumor burden was also higher in Aim2(-/-)/Apc(Min/+) than in APC(Min/+) mice. The effects of AIM2 on CAC were independent of inflammasome activation and IL-1beta and were primarily mediated by a non-bone marrow source of AIM2. In resting cells, AIM2 physically interacted with and limited activation of DNA-dependent protein kinase (DNA-PK), a PI3K related family member that promotes Akt phosphorylation, whereas loss of AIM2 promoted DNA-PK-mediated Akt activation. AIM2 reduced Akt activation and tumor burden in colorectal cancer models, while an Akt inhibitor reduced tumor load in Aim2(-/-) mice. These findings suggest that Akt inhibitors could be used to treat AIM2-deficient human cancers. PMID- 26107254 TI - Primed Immune Responses Triggered by Ingested Bacteria Lead to Systemic Infection Tolerance in Silkworms. AB - In the present study, we examined whether microorganisms collaterally ingested by insects with their food activate the innate immune system to confer systemic resistance against subsequent bacterial invasion. Silkworms orally administered heat-killed Pseudomonas aeruginosa cells showed resistance against intra hemolymph infection by P. aeruginosa. Oral administration of peptidoglycans, cell wall components of P. aeruginosa, conferred protective effects against P. aeruginosa infection, whereas oral administration of lipopolysaccharides, bacterial surface components, did not. In silkworms orally administered heat killed P. aeruginosa cells, P. aeruginosa growth was inhibited in the hemolymph, and mRNA amounts of the antimicrobial peptides cecropin A and moricin were increased in the hemocytes and fat body. Furthermore, the amount of paralytic peptide, an insect cytokine that activates innate immune reactions, was increased in the hemolymph of silkworms orally administered heat-killed P. aeruginosa cells. These findings suggest that insects sense bacteria present in their food by peptidoglycan recognition, which activates systemic immune reactions to defend the insects against a second round of infection. PMID- 26107255 TI - Multivariate Analysis of Prognostic Biomarkers in Surgically Treated Endometrial Cancer. AB - OBJECTIVE: The aim of this study was to identify biomarkers with prognostic value in the setting of surgically treated endometrial cancer. METHODS: Medical data for 282 patients with surgically treated endometrial cancer were reviewed retrospectively. Preoperative concentrations of six serum biomarkers (CA125, CA15 3, C-reactive protein [CRP], D-dimer [D-D], platelet-to-lymphocyte ratio [PLR], and neutrophil-to-lymphocyte ratio [NLR]) were analysed to determine potential associations with clinicopathologic characteristics and to assess prognostic values separately via Kaplan-Meier method and multivariate Cox regression. RESULTS: In univariate analyses, the 5-year overall survival (OS) rate was 86.5% for a maximum follow-up period of 75 months. High concentrations of CA125, CA15 3, CRP, D-D, PLR, and NLR each proved significantly predictive of poor survival (log-rank test, P<0.01). CRP and D-D were identified as independent prognosticators, using a Cox regression model. Study patients were then stratified (based on combined independent risk factors) into three tiers (P<0.001), marked by 5-year OS rates of 92.1%, 78.4%, and 33.3%. CONCLUSIONS: All serum biomarkers assessed (CA125, CA15-3, CRP, D-D, PLR, and NLR) proved to be valid prognostic indices of surgically treated endometrial cancer. A novel prognostic grouping system, incorporating independent risk factors (CRP and D-D Concentrations), may have merit in assessing these patients preoperatively, providing a biologic basis for improved clinical staging. PMID- 26107256 TI - Ashtanga-Based Yoga Therapy Increases the Sensory Contribution to Postural Stability in Visually-Impaired Persons at Risk for Falls as Measured by the Wii Balance Board: A Pilot Randomized Controlled Trial. AB - OBJECTIVE: Persons with visual impairment (VI) are at greater risk for falls due to irreparable damage to visual sensory input contributing to balance. Targeted training may significantly improve postural stability by strengthening the remaining sensory systems. Here, we evaluate the Ashtanga-based Yoga Therapy (AYT) program as a multi-sensory behavioral intervention to develop postural stability in VI. DESIGN: A randomized, waitlist-controlled, single-blind clinical trial. METHODS: The trial was conducted between October 2012 and December 2013. Twenty-one legally blind participants were randomized to an 8-week AYT program (n = 11, mean (SD) age = 55(17)) or waitlist control (n=10, mean (SD) age = 55(10)). AYT subjects convened for one group session at a local yoga studio with an instructor and two individual home-based practice sessions per week for a total of 8 weeks. Subjects completed outcome measures at baseline and post-8 weeks of AYT. The primary outcome, absolute Center of Pressure (COP), was derived from the Wii Balance Board (WBB), a standalone posturography device, in 4 sensory conditions: firm surface, eyes open (EO); firm surface, eyes closed (EC); foam surface, EO; and foam surface, EC. Stabilization Indices (SI) were computed from COP measures to determine the relative visual (SIfirm, SIfoam), somatosensory (SIEO, SIEC) and vestibular (SIV, i.e., FoamEC vs. FirmEO) contributions to balance. This study was not powered to detect between group differences, so significance of pre-post changes was assessed by paired samples t-tests within each group. RESULTS: Groups were equivalent at baseline (all p > 0.05). In the AYT group, absolute COP significantly increased in the FoamEO (t(8) = -3.66, p = 0.01) and FoamEC (t(8) = -3.90, p = 0.01) conditions. Relative somatosensory SIEO (t(8) = -2.42, p = 0.04) and SIEC (t(8) = -3.96, p = 0.01), and vestibular SIV (t(8) = -2.47, p = 0.04) contributions to balance increased significantly. As expected, no significant changes from EO to EC conditions were found indicating an absence of visual dependency in VI. No significant pre-post changes were observed in the control group (all p > 0.05). CONCLUSIONS: These preliminary results establish the potential for AYT training to develop the remaining somatosensory and vestibular responses used to optimize postural stability in a VI population. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT01366677. PMID- 26107257 TI - Polymorphisms in CaSR and CLDN14 Genes Associated with Increased Risk of Kidney Stone Disease in Patients from the Eastern Part of India. AB - Kidney stone disease (KSD) is a major clinical problem imposing a large burden for both healthcare and economy globally. In India, the prevalence of kidney stone disease is rapidly increasing. This study aimed to evaluate the association between genetic defects in vitamin D receptor (VDR), calcium sensing receptor (CaSR) and claudin 14 (CLDN14) genes and kidney stone disease in patients from eastern India. We enrolled 200 consecutive kidney stone patients (age 18-60 years) (cases) and their corresponding sex and age matched 200 normal individuals (controls). To identify genetic variants responsible for KSD, we performed sequence analysis of VDR, CaSR and CLDN14 genes. Four non-synonymous (rs1801725, rs1042636, rs1801726 and rs2228570), one synonymous (rs219780) and three intronic single nucleotide polymorphisms (SNPs) (rs731236, rs219777 and rs219778) were identified. Genotype and allele frequency analysis of these SNPs revealed that, rs1801725 (Ala986Ser), rs1042636 (Arg990Gly) of CaSR gene and rs219778, rs219780 (Thr229Thr) of CLDN14 gene were significantly associated with KSD. Serum calcium levels were significantly higher in subjects carrying 986Ser allele and calcium excretion was higher in subjects bearing 990Gly allele. In conclusion, rs1801725, rs1042636, rs219778 and rs219780 SNPs were associated with kidney stone risk in patients from the eastern part of India. PMID- 26107259 TI - Trajectories of Sensory Over-Responsivity from Early to Middle Childhood: Birth and Temperament Risk Factors. AB - Sensory over-responsivity, a subtype of sensory modulation disorder, is characterized by extreme negative reactions to normative sensory experiences. These over-reactions can interfere with daily activities and cause stress to children and their families. The etiology and developmental course of sensory over-responsivity is still largely unknown. We measured tactile and auditory over responsivity in a population-based, typically developing sample of twins (N=978) at age two years via a caregiver report temperament questionnaire and again at age seven years via a sensory over-responsivity symptom inventory. Participating twins were treated as singletons although all analyses controlled for clustering within families. Children were divided into four trajectory groups based on risk status at both ages: low symptom (N=768), remitted (N=75), late-onset (N=112), and chronic (N=24). A subset of children who screened positive for SOR in toddlerhood (N = 102) took part in a pilot study focused on sensory over responsivity at four years of age. Children in the chronic group had more severe symptoms of sensory sensitivity at age four years, including more motion sensitivity, than the other trajectory groups. Children in the chronic group had a younger gestational age and were more likely to be low birth-weight than the low symptom group. Differences between remitted and late-onset groups and the low symptoms group were inconsistent across measures. Sensory over-responsivity was modestly correlated across ages (r = .22 for tactile over-responsivity and r = .11 for auditory over-responsivity), but symptoms were more stable among children born prematurely or who had more fearful and less soothable temperaments. A clear implication is that assessment over development may be necessary for a valid sensory processing disorder diagnosis, and a speculative implication is that sensory over-responsivity symptoms may be etiologically heterogeneous, with different causes of transient and stable symptoms. PMID- 26107260 TI - Cranial Morphology of the Brachystelechid 'Microsaur' Quasicaecilia texana Carroll Provides New Insights into the Diversity and Evolution of Braincase Morphology in Recumbirostran 'Microsaurs'. AB - Recumbirostran 'microsaurs,' a group of early tetrapods from the Late Carboniferous and Early Permian, are the earliest known example of adaptation to head-first burrowing in the tetrapod fossil record. However, understanding of the diversity of fossorial adaptation within the Recumbirostra has been hindered by poor anatomical knowledge of the more divergent forms within the group. Here we report the results of MUCT study of Quasicaecilia texana, a poorly-known recumbirostran with a unique, broad, shovel-like snout. The organization of the skull roof and braincase of Quasicaecilia is found to be more in line with that of other recumbirostrans than previously described, despite differences in overall shape. The braincase is found to be broadly comparable to Carrolla craddocki, with a large presphenoid that encompasses much of the interorbital septum and the columella ethmoidalis, and a single compound ossification encompassing the sphenoid, otic, and occipital regions. The recumbirostran braincase conserves general structure and topology of braincase regions and cranial nerve foramina, but it is highly variable in the number of ossifications and their extent, likely associated with the reliance on braincase ossifications to resist compression during sediment compaction and mechanical manipulation by epaxial and hypaxial musculature. Expansion of the deep ventral neck musculature in Quasicaecilia, autapomorphic among recumbirostrans, may reflect unique biomechanical function, and underscores the importance of future attention to the role of the cervical musculature in contextualizing the origin and evolution of fossoriality in recumbirostrans. PMID- 26107258 TI - Taxonomic resolutions based on 18S rRNA genes: a case study of subclass copepoda. AB - Biodiversity studies are commonly conducted using 18S rRNA genes. In this study, we compared the inter-species divergence of variable regions (V1-9) within the copepod 18S rRNA gene, and tested their taxonomic resolutions at different taxonomic levels. Our results indicate that the 18S rRNA gene is a good molecular marker for the study of copepod biodiversity, and our conclusions are as follows: 1) 18S rRNA genes are highly conserved intra-species (intra-species similarities are close to 100%); and could aid in species-level analyses, but with some limitations; 2) nearly-whole-length sequences and some partial regions (around V2, V4, and V9) of the 18S rRNA gene can be used to discriminate between samples at both the family and order levels (with a success rate of about 80%); 3) compared with other regions, V9 has a higher resolution at the genus level (with an identification success rate of about 80%); and 4) V7 is most divergent in length, and would be a good candidate marker for the phylogenetic study of Acartia species. This study also evaluated the correlation between similarity thresholds and the accuracy of using nuclear 18S rRNA genes for the classification of organisms in the subclass Copepoda. We suggest that sample identification accuracy should be considered when a molecular sequence divergence threshold is used for taxonomic identification, and that the lowest similarity threshold should be determined based on a pre-designated level of acceptable accuracy. PMID- 26107261 TI - Control of Pierce's Disease by Phage. AB - Pierce's Disease (PD) of grapevines, caused by Xylella fastidiosa subsp. fastidiosa (Xf), is a limiting factor in the cultivation of grapevines in the US. There are presently no effective control methods to prevent or treat PD. The therapeutic and prophylactic efficacy of a phage cocktail composed of four virulent (lytic) phages was evaluated for control of PD. Xf levels in grapevines were significantly reduced in therapeutically or prophylactically treated grapevines. PD symptoms ceased to progress one week post-therapeutic treatment and symptoms were not observed in prophylactically treated grapevines. Cocktail phage levels increased in grapevines in the presence of the host. No in planta phage-resistant Xf isolates were obtained. Moreover, Xf mutants selected for phage resistance in vitro did not cause PD symptoms. Our results indicate that phages have great potential for biocontrol of PD and other economically important diseases caused by Xylella. PMID- 26107262 TI - Collective waves in dense and confined microfluidic droplet arrays. AB - Excitation mechanisms for collective waves in confined dense one-dimensional microfluidic droplet arrays are investigated by experiments and computer simulations. We demonstrate that distinct modes can be excited by creating specific 'defect' patterns in flowing droplet trains. Excited longitudinal modes exhibit a short-lived cascade of pairs of laterally displacing droplets. Transversely excited modes obey the dispersion relation of microfluidic phonons and induce a coupling between longitudinal and transverse modes, whose origin is the hydrodynamic interaction of the droplets with the confining walls. Moreover, we investigate the long-time behaviour of the oscillations and discuss possible mechanisms for the onset of instabilities. Our findings demonstrate that the collective dynamics of microfluidic droplet ensembles can be studied particularly well in dense and confined systems. Experimentally, the ability to control microfluidic droplets may allow the modulation of the refractive index of optofluidic crystals, which is a promising approach for the production of dynamically programmable metamaterials. PMID- 26107263 TI - We Should Expect More out of Our Sewage Sludge. AB - Sewage sludge and biosolids production and management are a central component of water and sanitation engineering. The culmination of previous incremental technologies and regulations aimed at solving a current treatment problem, rather than developing the practice for the higher goals of sustainability have resulted in sludge becoming an economic and social liability. Sludge management practice must shift from treatment of a liability toward recovery of the embedded energy and chemical assets, while continuing to protect the environment and human health. This shift will require new research, treatment technologies and infrastructure and must be guided by the application of green engineering principles to ensure economic, social, and environmental sustainability. PMID- 26107264 TI - Peptide-MHC-I from Endogenous Antigen Outnumber Those from Exogenous Antigen, Irrespective of APC Phenotype or Activation. AB - Naive anti-viral CD8+ T cells (TCD8+) are activated by the presence of peptide MHC Class I complexes (pMHC-I) on the surface of professional antigen presenting cells (pAPC). Increasing the number of pMHC-I in vivo can increase the number of responding TCD8+. Antigen can be presented directly or indirectly (cross presentation) from virus-infected and uninfected cells, respectively. Here we determined the relative importance of these two antigen presenting pathways in mousepox, a natural disease of the mouse caused by the poxvirus, ectromelia (ECTV). We demonstrated that ECTV infected several pAPC types (macrophages, B cells, and dendritic cells (DC), including DC subsets), which directly presented pMHC-I to naive TCD8+ with similar efficiencies in vitro. We also provided evidence that these same cell-types presented antigen in vivo, as they form contacts with antigen-specific TCD8+. Importantly, the number of pMHC-I on infected pAPC (direct presentation) vastly outnumbered those on uninfected cells (cross presentation), where presentation only occurred in a specialized subset of DC. In addition, prior maturation of DC failed to enhance antigen presentation, but markedly inhibited ECTV infection of DC. These results suggest that direct antigen presentation is the dominant pathway in mice during mousepox. In a broader context, these findings indicate that if a virus infects a pAPC then the presentation by that cell is likely to dominate over cross presentation as the most effective mode of generating large quantities of pMHC-I is on the surface of pAPC that endogenously express antigens. Recent trends in vaccine design have focused upon the introduction of exogenous antigens into the MHC Class I processing pathway (cross presentation) in specific pAPC populations. However, use of a pantropic viral vector that targets pAPC to express antigen endogenously likely represents a more effective vaccine strategy than the targeting of exogenous antigen to a limiting pAPC subpopulation. PMID- 26107265 TI - Effectiveness of a Treatment Switch to Nevirapine plus Tenofovir and Emtricitabine (or Lamivudine) in Adults with HIV-1 Suppressed Viremia. AB - BACKGROUND: Switching subjects with persistently undetectable HIV-1 viremia under antiretroviral treatment (ART) to once-daily tenofovir/emtricitabine (or lamivudine) + nevirapine is a cost-effective and well-tolerated strategy. However, the effectiveness of this approach has not been established. METHODS: We performed a retrospective study evaluating the rates of treatment failure, virological failure (VF), and variables associated, in all subjects initiating this switch combination in our clinic since 2001. Analyses were performed by a modified intention to treat, where switch due to toxicity equalled failure. The main endpoint was plasma HIV-RNA < 50 copies/mL. RESULTS: 341 patients were treated for a median of 176 (57; 308) weeks. At week 48, 306 (89.7%) subjects had HIV-1 RNA <50 copies/mL, 10 (2.9%) experienced VF, and 25 (7.4%) discontinued the treatment due to toxicity. During the whole follow-up 23 (6.7%) individuals (17 on lamivudine, 6 on emtricitabine; p = 0.034) developed VF and treatment modification due to toxicity occurred in 36 (10.7%). Factors independently associated with VF in a multivariate analysis were: intravenous drug use (HR 1.51; 95%CI 1.12, 2.04), time with undetectable viral load before the switch (HR 0.98; 0.97, 0.99), number of prior NRTIs (HR 1.49; 1.15, 1.93) or NNRTIs (HR 3.22; 1.64, 6.25), and previous NVP (HR 1.54; 1.10, 2.17) or efavirenz (HR 5.76; 1.11, 29.87) unscheduled interruptions. VF was associated with emergence of usual nevirapine mutations (Y181C/I/D, K103N and V106A/I), M184V (n = 16; 12 with lamivudine vs. 4 with emtricitabine, p = 0.04), and K65R (n = 7). CONCLUSIONS: The rates of treatment failure at 48 weeks, or long-term toxicity or VF with this switch regimen are low and no unexpected mutations or patterns of mutations were selected in subjects with treatment failure. PMID- 26107266 TI - Experienced and Perceived Risks of Mycobacterial Diseases: A Cross Sectional Study among Agropastoral Communities in Northern Tanzania. AB - OBJECTIVE: The current study was conducted to assess experienced risk factors and perceptions of mycobacterial diseases in communities in northern Tanzania. METHODS: We conducted a cross-sectional study in Arusha and Manyara regions in Northern Tanzania. We enrolled tuberculosis (TB) patients attending Mount Meru Hospital, Enduleni Hospital and Haydom Lutheran Hospitals in Arusha municipality, Ngorongoro and Mbulu districts, respectively. Patient addresses were recorded during their first visit to the hospitals. Patients with confirmed diagnosis of TB by sputum smear microscopy and/or culture at central laboratory were followed up and interviewed using pre-tested questionnaires, and selected relatives and neighbors were also interviewed. The study was conducted between June 2011 and May 2013. RESULTS: The study involved 164 respondents: 41(25%) were TB patients, 68(41.5%) were their relatives and 55(33.5%) their neighbors. Sixty four (39%) knew a risk factor for mycobacterial disease. Overall, 64(39%) perceived to be at risk of mycobacterial diseases. Exposure to potential risks of mycobacterial diseases were: keeping livestock, not boiling drinking water, large family, smoking and sharing dwelling with TB patients. Rural dwellers were more often livestock keepers (p<0.01), more often shared dwelling with livestock (p<0.01) than urban dwellers. More primary school leavers reported sharing dwelling with TB patients than participants with secondary and higher education (p = 0.01). CONCLUSION: Livestock keeping, sharing dwelling with livestock, sharing household with a TB patient were perceived risk factors for mycobacterial diseases and the participants were exposed to some of these risk factors. Improving knowledge about the risk factors may protect them from these serious diseases. PMID- 26107267 TI - Acute on/off effects and chronic blood pressure reduction after long-term baroreflex activation therapy in resistant hypertension. AB - BACKGROUND: Baroreflex activation therapy (BAT) by electrical stimulation of baroreceptors at the carotid sinus is a promising therapeutic approach to reduce elevated blood pressure (BP). To assess the efficacy of long-term BAT, we investigated acute BP alterations after device deactivation and reactivation (on/off effects) in patients on chronic BAT, as well as chronic BP reductions. METHOD: Resistant hypertension patients (n = 17) were enrolled in an open-label, single-arm evaluation of unilateral BAT after exclusion of secondary hypertension. Initial eligibility criteria were SBP>= 140 mmHg, despite stable medical therapy with at least three antihypertensive drugs including at least one diuretic. For on/off testing, several office cuff BP measurements were performed: at rest with activated device, 4-6 min after deactivation, and 4-6 min after reactivation. RESULTS: Before BAT, mean office cuff BP was 179 +/- 25 over 98 +/- 18 mmHg. At the time of on/off testing (15.1 +/- 8.7 months after initial activation and before deactivation), BP was reduced to 147 +/- 29 over 84 +/- 20 mmHg. On deactivation, SBP increased to 158 +/- 38 mmHg (P = 0.004) and DBP to 89 +/- 23 mmHg (P = 0.04). After reactivation, SBP decreased to 144 +/- 34 mmHg (P = 0.002 vs. deactivation) and DBP to 83 +/- 23 mmHg (P = 0.009). There was no correlation between duration of chronic BAT and systolic or diastolic acute on/off response. CONCLUSION: Unilateral BAT reduces BP in patients with resistant hypertension in the long term. There is a significant on/off effect on BP, supporting the efficacy of BAT. The acute on/off response to BAT does not depend on treatment duration. Thus, no evidence of tolerance over time to chronic BAT was found. PMID- 26107268 TI - Courage and character, leaders and legends: an interview with Giuseppe Orlando, MD, PhD. PMID- 26107269 TI - Practical protocol for management of severe hyponatremia in patients undergoing liver transplant surgery. PMID- 26107270 TI - Development and initial evaluation of the psychometric properties of self efficacy and adherence scales for patients with a left ventricular assist device. AB - CONTEXT: No tools exist to measure patients' self-efficacy for and adherence to the complex home-care regimen after having a left ventricular device (LVAD) implanted. OBJECTIVE: To develop 2 new instruments, the LVAD Patient Self Efficacy Scale (LPSES) and the LVAD Patient Home Management Adherence Scale (LPHMAS), and evaluate their psychometric properties. METHODS: This multistage instrumentation study recruited 102 patients (77.5% men and 22.5% women) aged 20 to 82 years, predominantly from the Midwest (34.3%) and the Northeast (26.5%) regions of the United States. Main indications for LVAD were bridge-to-transplant (69.6%) and destination therapy (21.6%), with mean implant duration of 19.9 (SD, 15.5) months. Study participants completed the following instruments: LPSES, LPHMAS, General Self-Efficacy Scale (GSES), Medical Outcomes Study General Adherence (MOSGA), and Self-Care Heart Failure Index (SCHFI) confidence and maintenance subscales. Item analyses, psychometric properties including factorial and convergent validities, and internal consistency reliability were tested. RESULTS: Factor analyses showed that the variances for the 20-item LPSES and 9 item LPHMAS were 60.2% and 53.6%, respectively. Convergent validity of the newly developed instruments was supported by the following correlations: LPSES and GSES (r = 0.34); LPSES and SCHFI-confidence (r = 0.60); LPHMAS and MOSGA (r = 0.33); LPHMAS and SCHFI-maintenance (r = 0.40). Internal consistency reliability coefficients were 0.94 (LPSES) and 0.84 (LPHMAS). Based on these data, the LPSES and LPHMAS are valid and reliable measures of self-efficacy and adherence specific for LVAD patients. Confirmatory testing is needed to further support the validity of these instruments for use in research and clinical practice. PMID- 26107271 TI - Evaluation of the psychometric properties of self-efficacy and adherence scales for caregivers of patients with a left ventricular assist device. AB - CONTEXT: No published instrument has been designed to measure caregivers' self efficacy for and adherence to the complex home-care regimen of patients with a left ventricular assist device (LVAD). OBJECTIVE: To evaluate the psychometric properties of 2 newly developed instruments: the LVAD Caregiver Self-Efficacy Scale (LCSS) and the LVAD Caregiver Home Management Adherence Scale (LCAS). METHODS: A multistage design was employed for this instrumentation study. Of the 125 LVAD caregivers recruited from online support groups, 98 (78.4%) provided complete data. Participants were predominantly female (80%), aged 18 to 79 years, from 4 regions of the United States. They completed the following instruments: LCSS, LCAS, General Self-Efficacy Scale (GSE), and the confidence and maintenance subscales of the Caregiver Contribution to Self-Care of Heart Failure Index (CC SCHFI). Item analyses, factorial construct validity, convergent validity, and internal consistency reliability of the scales were evaluated. RESULTS: The analysis of the LCSS (21 items) revealed a 2-factor solution, which consisted of a 17-item routine factor and a 4-item anticipatory factor. Convergent validity of the LCSS was supported by moderate correlations among LCSS, GSE, and CC-SCHFI confidence. The analysis of LCAS (17 items) revealed a 1-factor solution. Its convergent validity was supported by moderate correlation between LCAS and CC SCHFI-maintenance. Internal consistency reliability coefficients of the LCSS and LCAS were alpha = 0.93 and alpha = 0.96, respectively. These data suggest that the 2 instruments are adequately valid and reliable measures of self-efficacy and adherence in the context of LVAD patient care managed by home caregivers. Further research is needed to support the applicability of these instruments in other research and practice settings. PMID- 26107272 TI - Interactions between health care personnel and parents approached for organ and/or tissue donation: influences on parents' adjustment to loss. AB - CONTEXT: The effect of loss on those approached for organ and/or tissue donation, particularly in the years thereafter, has received little attention. OBJECTIVE: To assess whether adjustment of a parent to loss of a child is influenced by interactions with health care personnel. METHODS: A self-administered questionnaire was completed by the parents of 216 decedents. Interactions in the hospital were assessed by examining the experience in the hospital, physical separation from the child, and the relationship with health care professionals. Adjustment to loss was defined by 4 components: grief, personal growth after loss, meaning of life after loss, and the meaning of organ donation. RESULTS: A positive experience in the hospital was significantly associated with the meaning of donation. Increased satisfaction with the separation process was associated with better adjustment on all components. Finally, a better relationship with health care professionals was associated with less grief and with greater personal growth. These results were characterized after adjustment for time since loss, which was from 6 months to 27 years. CONCLUSIONS: Interactions in the hospital appear to influence adjustment to loss significantly. Appropriate interventions may aid parents in their adjustment to life. PMID- 26107273 TI - Transition to adult care in pediatric solid-organ transplant: development of a practice guideline. AB - BACKGROUND: Transition to adult-centered care is becoming an increasingly important area of practice in pediatric organ transplant. Standardized, best practice guidelines are needed to assist transplant practitioners in providing optimal transitional care for this population of patients. OBJECTIVE: To describe the development and implementation of a practice guideline for the transitional care of pediatric transplant recipients. METHODS: A quality improvement project was undertaken in a pediatric multiorgan transplant program setting. Strategies employed included (1) creation of an interdisciplinary working group, (2) survey of transition-related practices and learning needs of transplant practitioners, (3) review of the literature and existing transition-related materials, and (4) creation of transition guidelines. RESULTS: An interdisciplinary survey of transplant practitioners at our institution identified practice strengths related to transitional care and learning needs. Review of relevant literature and other materials revealed limited but emerging research related to the transition of pediatric transplant recipients from pediatric to adult care. Existing transition tools were examined and applicable items identified. A practice guideline for use with pediatric transplant recipients transitioning to adult care was developed. Strategies to educate staff about the guideline and promote ongoing guideline use were implemented. CONCLUSION: Preparing pediatric transplant recipients and their families for transition to adult-centered care is an emerging challenge for transplant teams. These guidelines provide practitioners with a developmentally sensitive overview of important transition-related domains and strategies directed toward patients and their caregivers, who may experience the process of transition differently. Dissemination of the pediatric transplant transition guideline will make transition information more widely available to transplant practitioners. PMID- 26107274 TI - Vulnerability and chronic illness management in pediatric kidney and liver transplant recipients. AB - CONTEXT: Solid-organ transplant is the treatment of choice for end-stage organ failure and requires a transition from management of a life-threatening condition to a chronic illness. Despite research focusing on quality of life after transplant, there is a gap addressing the role of managing a chronic illness focusing on vulnerability and impact on family. OBJECTIVE: Identify patient and family patterns of adaptation among kidney and liver transplant recipients in regard to (1) vulnerability, (2) impact of illness on the family, (3) family functioning, and (4) quality of life (parent and child report). DESIGN: Cross sectional study enrolling children 5 to 18 years old and their parent at a single time point after kidney or liver transplant. Validated self-report tools were completed. RESULTS: In all, 47 participants (24 kidney and 23 liver) were recruited. Mean age at transplant was 4.0 (kidney) and 2.1 (liver) years. Mean age at report was 12.1 (kidney) and 7.1 (liver) years. Child vulnerability correlated negatively with (1) family impact in the kidney (P < .05) and liver (P < .05) transplant groups, (2) PedsQL subscales including Parent Emotional (P< .05), Parent Social (P< .01), Parent Psychosocial (P < .01), Parent Physical (P < .05), Parent School (P < .05), and Child Social (P < .01) in the kidney transplant group, (3) PedsQL Parent Emotional subscale (P< .01) in the liver transplant group, and (4) Functional status (P < .01) in the liver transplant group. CONCLUSIONS: Child vulnerability provides insight into quality of life and the impact of illness on the family and family functioning. PMID- 26107275 TI - Bortezomib-containing regimen for primary treatment of early antibody-mediated cardiac allograft rejection: a case report. AB - Evidence regarding the use of bortezomib-containing schemes in primary treatment of antibody-mediated rejection in heart transplant recipients is scarce. This case report presents the clinical experience with upstream use of bortezomib in primary treatment of early antibody-mediated rejection in an adult heart transplant recipient. Two cycles of bortezomib together with methylprednisolone, immunoadsorption, rituximab, and supplementary doses of intravenous immunoglobulin G reversed signs of heart failure, production of donor-specific antibodies, and findings of antibody-mediated rejection in biopsy. This treatment regimen was tolerated with only mild hematologic toxicity and proved to be successful during a 12-month follow-up. Primary treatment with a bortezomib containing regimen appears to be a new therapeutic option for severe antibody mediated rejection in heart transplant recipients. However, the efficacy and safety of this treatment need to be tested in prospective trials. PMID- 26107276 TI - Getting used to being a patient: the postoperative experience of living liver transplant donors. AB - CONTEXT: Living donor liver transplant is a viable option for eligible persons in need of a liver transplant, but little is known about the hospitalization experience of patients undergoing hepatectomy for transplant donation. OBJECTIVE: To explore the hospital experience of patients recovering from donor hepatectomy. DESIGN: A qualitative interpretive descriptive design was used to understand the hospital experience of patients recovering from donor hepatectomy. Semistructured interviews, conducted before discharge, were audiotaped and transcribed verbatim. Coding was performed independently, then jointly by investigators to reach consensus on emerging themes. Setting-Major university hospital in the Northeastern United States. Sample-Adults (>18 years of age) whose primary language was English or Spanish and who could provide written informed consent. RESULTS: The sample consisted of 15 participants who had a mean age of 34.6 years; half were women. Most were white and college educated. The relationship of the donors to recipients varied from immediate family to altruistic donors. "Getting used to being a patient" was the major theme that captured the patients' postoperative experience. Four subthemes explained the experience: regaining consciousness, all those tubes, expecting horrible pain, and feeling special and cared for. These were described in the context of an "amazing and impressive" transplant team. CONCLUSION: As healthy donors are getting used to being patients, these results provide clinicians with a deeper understanding of the transplant experience from the donor's perspective so that care can be tailored to meet their unique needs. PMID- 26107277 TI - Exploring the success of Good Samaritan organ donation in New Zealand. AB - The rate of living kidney donation from 2006 to 2012 was roughly the same in Australia and New Zealand, but the rate of Good Samaritan donation was significantly higher in New Zealand (1.49 donors/million) than in Australia (0.23 donors/million). Three possible reasons for New Zealand's high rate of Good Samaritan donation are explored: (1) since 2005, New Zealand has offered a tax free financial safety net for living donors; (2) unlike Australia, New Zealand is not carved into jurisdictional segments with multiple policies on Good Samaritan donation, lending to a streamlined approach; (3) New Zealand embraces e technology to communicate the concept of Good Samaritan donation to the public. Additionally, New Zealand's recent initiatives to increase the rate of living donation are described. PMID- 26107278 TI - African American kidney transplant patients' perspectives on challenges in the living donation process. AB - CONTEXT: The increasing shortage of deceased donor kidneys suitable for African Americans highlights the critical need to increase living donations among African Americans. Little research has addressed African American transplant recipients' perspectives on challenges and barriers related to the living donation process. OBJECTIVE: To understand the perspectives of African American recipients of deceased and living donor kidney transplants on challenges, barriers, and educational needs related to pursuing such transplants. PARTICIPANTS AND DESIGN: A mixed-method design involved 27 African American kidney recipients (13 male) in 4 focus groups (2 per recipient type: 16 African American deceased donor and 11 living donor recipients) and questionnaires. Focus group transcripts were evaluated with NVivo 10.0 (QSR, International) by using inductive and deductive qualitative methods along with crystallization to develop themes of underlying barriers to the living donor kidney transplant process and were compared with the questionnaires. RESULTS: Four main themes were identified from groups: concerns, knowledge and learning, expectations of support, and communication. Many concerns for the donor were identified (eg, process too difficult, financial burden, effect on relationships). A general lack of knowledge about the donor process and lack of behavioral skills on how to approach others was noted. The latter was especially evident among deceased donor recipients. Findings from the questionnaires on myths and perceptions supported the lack of knowledge in a variety of domains, including donors' surgical outcomes risks, costs of surgery, and impact on future health. Participants thought that an educational program led by an African American recipient of a living donor kidney transplant, including practice in approaching others, would increase the likelihood of transplant eligible patients pursuing living donor kidney transplant. PMID- 26107279 TI - Promoting organ donation through challenge campaigns. AB - CONTEXT: Four challenge campaigns in 2012 and 2013 were undertaken to promote organ donor registrations in New York State. Challenge campaigns relied on community advocates statewide to initiate month-long outreach efforts with top teams earning monetary rewards and public recognition. OBJECTIVE: To significantly increase the number and proportion of New York residents who have consented to donation through the electronic registry. DESIGN: Four month-long campaigns undertaken in fall and spring of 2012 and 2013. SETTING: Statewide recruitment efforts organized by New York Alliance for Donation and the 4 organ procurement organizations in New York State. PARTICIPANTS: Adult residents of New York State. INTERVENTION: Project staff recruited team leaders across New York State and used online and offline resources to recruit teams, educate team leaders, and bolster outreach efforts. MAIN OUTCOME MEASURES: Number of completed registration forms within month-long campaign periods. Also investigated were statistics on website use (eg, page views, new visitors) and interviews with team leaders regarding campaign activities after the campaign. RESULTS: Across 4 campaigns, 107 teams were recruited and 2286 persons registered their consent to donate through the state system. Each team recruited a mean of 21 persons; 40% of teams registered 0 persons. PMID- 26107280 TI - Immunosuppressant-driven de novo malignant neoplasms after solid-organ transplant. AB - Solid-organ transplant recipients are at a 3- to 5-fold increased risk of a de novo malignant neoplasm developing compared with the general population. The most frequently developed virus-associated malignant neoplasms are Kaposi sarcoma (standardized incidence ratio [SIR], 208.0), nonmelanoma skin cancer (SIR, 28.6), and posttransplant lymphoproliferative disorder, primarily non-Hodgkin lymphoma (SIR, 8.1). Immunosuppressive agents such as corticosteroids, antimetabolites, calcineurin inhibitors, and mammalian target of rapamycin (mTOR) inhibitors play a key role in either causing or preventing this complication. It is hypothesized that some of these regimens can impair cancer surveillance, facilitate the action of oncogenic viruses, and promote direct oncogenic activity. Evolving research has shown promising dual antitumor and immunosuppressive properties of the mTOR inhibitor class. The effective management of posttransplant neoplasms most likely involves the use of these medications among other preventative options. These measures include monitoring certain viral loads as well as immunosuppressant drug levels. Reducing these levels to as low as possible for healthy engraftment and altering regimens when appropriate are management strategies that could lessen this complication of solid-organ transplant. More studies examining the effects of therapeutic drug monitoring are needed to determine specific plasma drug concentrations that will ensure organ engraftment without the development of de novo malignant neoplasms. PMID- 26107281 TI - Indolent, Potentially Inconsequential Lung Cancers in the Pittsburgh Lung Screening Study. AB - RATIONALE: The finding of indolent, potentially inconsequential cancers (overdiagnosis) is inherent to cancer screening in general, and there is a growing body of literature about this concept in lung cancer screening. OBJECTIVES: We report on indolent, potentially inconsequential lung cancers in the Pittsburgh Lung Screening Study (PLuSS) population screened for lung cancer with annual low-dose computed tomography. METHODS: We identified 93 subjects with screen-detected prevalence cancers in PLuSS. We defined indolent, potentially inconsequential cancers as stage I prevalence lung cancer cases that had volumetric doubling time >400 days (when available) and maximal standardized uptake value max on positron emission tomography (PET) scan <=1 (when available). MEASUREMENTS AND MAIN RESULTS: Approximately 18.5% (n = 17) of all 93 screen detected prevalence lung cancers in PLuSS were indolent, potentially inconsequential cancers. All such cancers except for one were adenocarcinomas by histology. Median tumor size of such cancers at the time of final diagnosis was 10 mm (range, 7-22 mm). Median doubling time was significantly longer in this group when compared with the rest of the prevalence stage 1 cancers (752 vs. 284.5 d). CONCLUSIONS: Although the precise definitions may vary, the existence of indolent, potentially inconsequential cancers in low-dose computed tomography lung cancer screening is real. Clinicians involved in managing patients with low dose computed tomography-detected slow-growing nodules, especially with a standardized uptake value <=1 on PET scan, should consider the possibility of indolent, potentially inconsequential cancer in the longitudinal management of these nodules. PMID- 26107282 TI - Spectral Diversity and Regulation of Coral Fluorescence in a Mesophotic Reef Habitat in the Red Sea. AB - The phenomenon of coral fluorescence in mesophotic reefs, although well described for shallow waters, remains largely unstudied. We found that representatives of many scleractinian species are brightly fluorescent at depths of 50-60 m at the Interuniversity Institute for Marine Sciences (IUI) reef in Eilat, Israel. Some of these fluorescent species have distribution maxima at mesophotic depths (40 100 m). Several individuals from these depths displayed yellow or orange-red fluorescence, the latter being essentially absent in corals from the shallowest parts of this reef. We demonstrate experimentally that in some cases the production of fluorescent pigments is independent of the exposure to light; while in others, the fluorescence signature is altered or lost when the animals are kept in darkness. Furthermore, we show that green-to-red photoconversion of fluorescent pigments mediated by short-wavelength light can occur also at depths where ultraviolet wavelengths are absent from the underwater light field. Intraspecific colour polymorphisms regarding the colour of the tissue fluorescence, common among shallow water corals, were also observed for mesophotic species. Our results suggest that fluorescent pigments in mesophotic reefs fulfil a distinct biological function and offer promising application potential for coral-reef monitoring and biomedical imaging. PMID- 26107283 TI - Impact of SDS surfactant on the interactions of Cu(2+) ions with the amyloidogenic region of human prion protein. AB - Prion diseases, known as Transmissible Spongiform Encephalopathies (TSEs), are a group of fatal neuronal, and to some extent infectious disorders, associated with a pathogenic protein agent called prion protein (PrP). The human prion protein (hPrP) fragment encompassing the 91-127 region, also known as the amyloidogenic domain, comprises two copper-binding sites corresponding to His-96 and His-111 residues that act as anchors for Cu(2+) binding. In this work, we investigated Cu(2+) interaction with hPrP91-127 in the presence of the anionic surfactant sodium dodecyl sulfate (SDS), which induces a partial alpha-helix folding of the peptide. Our data indicate that the Cu(2+) coordination ability of the amyloidogenic fragment in the presence of SDS micelles is significantly different to that observed in aqueous solution. This is mainly due to the fact that SDS micelles strongly stabilize the formation of the alpha-helical structure of the peptide backbone, which is well conserved also upon Cu(2+) binding, contrary to the random coil conformation mainly assumed by hPrP91-127 in aqueous solutions. Potentiometric and spectroscopic studies clearly indicate that in the case of SDS containing solutions, Cu(2+) ions coordinate simultaneously to both imidazoles, while in the case of water solutions, metal ion coordination involves only a single His side chain, which individually acts as an independent Cu(2+) anchoring site. PMID- 26107284 TI - Quantifying the Short-Term Costs of Conservation Interventions for Fishers at Lake Alaotra, Madagascar. AB - Artisanal fisheries are a key source of food and income for millions of people, but if poorly managed, fishing can have declining returns as well as impacts on biodiversity. Management interventions such as spatial and temporal closures can improve fishery sustainability and reduce environmental degradation, but may carry substantial short-term costs for fishers. The Lake Alaotra wetland in Madagascar supports a commercially important artisanal fishery and provides habitat for a Critically Endangered primate and other endemic wildlife of conservation importance. Using detailed data from more than 1,600 fisher catches, we used linear mixed effects models to explore and quantify relationships between catch weight, effort, and spatial and temporal restrictions to identify drivers of fisher behaviour and quantify the potential effect of fishing restrictions on catch. We found that restricted area interventions and fishery closures would generate direct short-term costs through reduced catch and income, and these costs vary between groups of fishers using different gear. Our results show that conservation interventions can have uneven impacts on local people with different fishing strategies. This information can be used to formulate management strategies that minimise the adverse impacts of interventions, increase local support and compliance, and therefore maximise conservation effectiveness. PMID- 26107285 TI - Differences in Arbuscular Mycorrhizal Fungal Community Composition in Soils of Three Land Use Types in Subtropical Hilly Area of Southern China. AB - Land use type is key factor in restoring the degraded soils due to its impact on soil chemical properties and microbial community. In this study, the influences of land use type on arbuscular mycorrhizal fungal (AMF) community and soil chemical properties were assessed in a long-run experimental station in subtropical hilly area of southern China. Soil samples were collected from forest land, orchard and vegetable field. Soil chemical properties were analyzed, and PCR-DGGE was performed to explore the AMF community structure. Cloning and sequencing of DGGE bands were conducted to monitor AMF community composition. Results indicate that the contents of total P, available P and available K were the highest while the contents of soil organic matter, total N, total K and available N were the lowest in vegetable field soils, with forest land soils vice versa. According to DGGE profiling, AMF community in forest soils was more closely related to that in orchard soils than that in vegetable field soils. Sequencing indicated that 45 out of 53 excised bands were AMF and 64.4% of AMF belonged to Glomeraceae, including some "generalists" present in all soils and some "specialists" present only in soils of particular land use. Category principle component analysis demonstrated that total N, soil organic matter and available P were the most important factors affecting AMF community, and some AMF phylotypes were closely associated with particular soil chemical properties. Our data suggest that AMF communities are different with different land use types. PMID- 26107286 TI - Polymorphisms in the TOLLIP Gene Influence Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis in the Amazonas State of Brazil. AB - INTRODUCTION: The clinical outcome to Leishmania-infection is determined by the individual adaptive immune T helper cell responses and their interactions with parasitized host cells. An early development of a proinflammatory immune response (Th1 response) is necessary for Leishmania-infection resolution. The Toll interacting protein (TOLLIP) regulates human Toll-like receptors signaling pathways by down regulating the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) and inducing the ant-inflammatory cytokine interleukin-10 (IL-10). Polymorphisms in the TOLLIP gene are associated with infectious diseases. MATERIAL AND METHODS: The polymorphisms rs5743899 and rs3750920 in the TOLLIP gene were genotyped by polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis in 631 patients with cutaneous leishmaniasis (CL) caused by L. guyanensis and 530 individuals with no history of leishmaniasis. RESULTS: The G and T alleles of the rs5743899 and rs3750920 were more common in patients with CL than in healthy individuals (P = 2.6 x10(-8) ; odds ratio [OR], 1.7 [ 95% confidence interval (CI) 1.4-2.0] and P = 1.9 x10(-8) ; OR, 1.6 [95% CI 1.4-1.9] respectively). The r2 and D' linkage disequilibrium between the two polymorphisms are 0.05 and 0.473 with a confidence bounds of 0.37 to 0.57 respectively. CONCLUSION: The two polymorphisms are independently associated with an increased risk of developing CL. PMID- 26107287 TI - Mechanical environmental transport of actinides and 137Cs from an arid radioactive waste disposal site. AB - Aeolian and pluvial processes represent important mechanisms for the movement of actinides and fission products at the Earth's surface. Soil samples taken in the early 1970's near a Department of Energy radioactive waste disposal site (the Subsurface Disposal Area, SDA, located in southeastern Idaho) provide a case study for studying the mechanisms and characteristics of environmental actinide and (137)Cs transport in an arid environment. Multi-component mixing models suggest actinide contamination within 2.5 km of the SDA can be described by mixing between 2 distinct SDA end members and regional nuclear weapons fallout. The absence of chemical fractionation between (241)Am and (239+240)Pu with depth for samples beyond the northeastern corner and lack of (241)Am in-growth over time (due to (241)Pu decay) suggest mechanical transport and mixing of discrete contaminated particles under arid conditions. Occasional samples northeast of the SDA (the direction of the prevailing winds) contain anomalously high concentrations of Pu with (240)Pu/(239)Pu isotopic ratios statistically identical to those in the northeastern corner. Taken together, these data suggest flooding resulted in mechanical transport of contaminated particles into the area between the SDA and a flood containment dike in the northeastern corner, following which subsequent contamination spreading in the northeastern direction resulted from wind transport of discrete particles. PMID- 26107288 TI - Limitations of In Vivo Reprogramming to Dopaminergic Neurons via a Tricistronic Strategy. AB - Parkinson's disease is one of the most common neurodegenerative disorders characterized by cell death of dopaminergic neurons in the substantia nigra. Recent research has focused on cellular replacement through lineage reprogramming as a potential therapeutic strategy. This study sought to use genetics to define somatic cell types in vivo amenable to reprogramming. To stimulate in vivo reprogramming to dopaminergic neurons, we generated a Rosa26 knock-in mouse line conditionally overexpressing Mash1, Lmx1a, and Nurr1. These proteins are characterized by their role in neuronal commitment and development of midbrain dopaminergic neurons and have previously been shown to convert fibroblasts to dopaminergic neurons in vitro. We show that a tricistronic construct containing these transcription factors can reprogram astrocytes and fibroblasts in vitro. However, cassette overexpression triggered cell death in vivo, in part through endoplasmic reticulum stress, while we also detected "uncleaved" forms of the polyprotein, suggesting poor "cleavage" efficiency of the 2A peptides. Based on our results, the cassette overexpression induced apoptosis and precluded reprogramming in our mouse model. Therefore, we suggest that alternatives must be explored to balance construct design with efficacious reprogramming. It is evident that there are still biological obstacles to overcome for in vivo reprogramming to dopaminergic neurons. PMID- 26107289 TI - Protein value of cereals and cereal by-products for ruminants: a comparison between crude protein and protein-based estimates. AB - In situ estimates of ruminal undegraded fraction (RU) and effective intestinal digestibility (EID, corrected for microbial colonisation) of dry matter (DM), crude protein (CP) and total analysed amino acids (TAA) of rye, wheat and corn grains, wheat bran, wheat and barley distillers' dried grains with solubles (DDGS) and corn gluten feed were measured on three rumen and duodenum cannulated wethers using (15)N labelling techniques and considering ruminal rates of particle comminution (kc) and outflow. Results indicate that not considering kc and microbial colonisation led to considerable overestimations of RU which increased with feed ruminal degradation. Microbial colonisation may be also associated with overestimations of EID, whose estimates for DM, CP and TAA were predicted from parameters related with the ruminal escape of intestinally indigestible materials. The RU estimates were higher for TAA than for CP in grains, but the opposite was observed in by-products, whereas EID estimates were higher for TAA in all feeds. To obtain accurate protein values in these feedstuffs, it is required to consider both kc and ruminal microbial colonisation. The CP-based results underestimate the intestinally digested protein in grains and the opposite is evidenced in cereal by-products. Microbial protein synthesised in the rumen is largely the major fraction of the feedstuff protein value with the exception of DDGS. PMID- 26107290 TI - Using in vitro/in silico data for consumer safety assessment of feed flavoring additives--A feasibility study using piperine. AB - Consumer health risk assessment for feed additives is based on the estimated human exposure to the additive that may occur in livestock edible tissues compared to its hazard. We present an approach using alternative methods for consumer health risk assessment. The aim was to use the fewest possible number of animals to estimate its hazard and human exposure without jeopardizing the safety upon use. As an example we selected the feed flavoring substance piperine and applied in silico modeling for residue estimation, results from literature surveys, and Read-Across to assess metabolism in different species. Results were compared to experimental in vitro metabolism data in rat and chicken, and to quantitative analysis of residues' levels from the in vivo situation in livestock. In silico residue modeling showed to be a worst case: the modeled residual levels were considerably higher than the measured residual levels. The in vitro evaluation of livestock versus rodent metabolism revealed no major differences in metabolism between the species. We successfully performed a consumer health risk assessment without performing additional animal experiments. As shown, the use and combination of different alternative methods supports animal welfare consideration and provides future perspective to reducing the number of animals. PMID- 26107291 TI - Quantitative risk assessment of the aggregate dermal exposure to the sensitizing fragrance geraniol in personal care products and household cleaning agents. AB - A quantitative risk assessment was performed to establish if consumers are at risk for being dermally sensitized by the fragrance geraniol. Aggregate dermal exposure to geraniol was estimated using the Probabilistic Aggregate Consumer Exposure Model, containing data on the use of personal care products and household cleaning agents. Consumer exposure to geraniol via personal care products appeared to be higher than via household cleaning agents. The hands were the body parts receiving the highest exposure to geraniol. Dermal sensitization studies were assessed to derive the point of departure needed for the estimation of the Acceptable Exposure Level (AEL). Two concentrations were derived, one based on human studies and the other from dose-response analysis of the available murine local lymph node assay data. The aggregate dermal exposure assessment resulted in body part specific median exposures up to 0.041 MUg/cm(2) (highest exposure 102 MUg/cm(2)) for hands. Comparing the exposure to the lowest AEL (55 MUg/cm(2)), shows that a range of 0.02-0.86% of the population may have an aggregated exposure which exceeds the AEL. Furthermore, it is demonstrated that personal care products contribute more to the consumer's geraniol exposure compared to household cleaning agents. PMID- 26107292 TI - Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies. AB - Current regulatory policies of both the US Food and Drug Administration and Drug Enforcement Administration do not delineate automatic exceptions for biologics with respect to preclinical assessments for abuse liability of all new entities. As defined in current guidance documents and drug control policies, an exception may be given upon thorough review of available data, therapeutic target and in consultation with the Controlled Substances Staff within the Center for Drug Evaluation and Research of the FDA, but a blanket exception for all biological entities is not currently available. We review the abuse liability testing of four known biologics with definitive positive abuse liability signals in the three core abuse liability assays, self-administration, drug discrimination, and dependence potential described in the FDA draft guidance document. Interestingly, while all four examplars have positive abuse liability signals in all three assays, two of these biologics are controlled under the Comprehensive Drug Abuse and Control Act (CSA, 1970) and the other two are not currently controlled. Admittedly, these four biologics are small molecule entities. However, there is no reference to "molecular size" in the legally-binding statutory definition of biologics under the FD&C act or in the Controlled Substances Act. Neither of these drug control policy mandates have a bifurcated control status in which to make exceptions based solely on molecular size. With the current pharmaceutical focus on new technologies, such as "Trojan Horses", targeting the active transport of large molecule entities directly into the CNS, an argument to automatically exempt new molecular entities solely on molecular size is untenable. We argue that for the safety and health of general public the current regulatory control status be maintained until definitive criteria for exceptions can be identified and amended to both the FD&CA and CSA, if warranted. PMID- 26107293 TI - The toxicological evaluation of repetitive 2- and 4-week intravenous injection of Activin A/BMP-2 chimera (AB204) into rats. AB - The subchronic (28-days) toxicity of an Activin A/BMP-2 chimera (AB204) was assessed in rats. Sprague-Dawley rats received repetitive intravenous injection of AB204 in doses of 0, 0.25 and 0.5 mg/kg for two weeks and in doses of 0, 0.08, 0.16 and 0.32 mg/kg/day for four weeks. No animal was dead and no change caused by the AB204 was observed in general symptoms, weight variation, and food and water intake as well as blood test and autopsy findings. In conclusion, the no observed adverse effects level (NOAEL) of the AB204 on rats was determined to be 0.32 mg/kg/day. PMID- 26107294 TI - Dietary supplements: International legal framework and adulteration profiles, and characteristics of products on the Brazilian clandestine market. AB - The objectives of this work were to evaluate current legislation on dietary supplements in the United States, the European Union and Brazil, and the profile of adulterated and/or irregular products on these markets. Due to a less restrictive legal framework, a supplement product that is freely available in the US may be considered a drug or even be proscribed in the EU and Brazil, thus giving rise to a clandestine market based on smuggling. From 2007 to 2014, the United States Food and Drug Administration reported 572 cases of supplement adulterations in the country, mainly products for sexual enhancement (41.6%). Data from the European Union Rapid Alert System for Food and Feed showed 929 adulterations during the same period, over 40% due to unauthorized ingredients or undeclared medicines. From 2007 to 2013, the Brazilian Federal Police Department seized 5470 supplement products, 92.2% with an American-declared origin. Qualitative chemical analyses performed on 2898 products found 180 adulterations, 41.1% due to undeclared drugs, mainly anabolic steroids, anorectics and products for erectile dysfunction, all considered medicines in Brazil. Educating the public regarding the potential risks they are taking when consuming adulterated or irregular products is necessary to protect the health of consumers. PMID- 26107295 TI - 3D computational mechanics elucidate the evolutionary implications of orbit position and size diversity of early amphibians. AB - For the first time in vertebrate palaeontology, the potential of joining Finite Element Analysis (FEA) and Parametrical Analysis (PA) is used to shed new light on two different cranial parameters from the orbits to evaluate their biomechanical role and evolutionary patterns. The early tetrapod group of Stereospondyls, one of the largest groups of Temnospondyls is used as a case study because its orbits position and size vary hugely within the members of this group. An adult skull of Edingerella madagascariensis was analysed using two different cases of boundary and loading conditions in order to quantify stress and deformation response under a bilateral bite and during skull raising. Firstly, the variation of the original geometry of its orbits was introduced in the models producing new FEA results, allowing the exploration of the ecomorphology, feeding strategy and evolutionary patterns of these top predators. Secondly, the quantitative results were analysed in order to check if the orbit size and position were correlated with different stress patterns. These results revealed that in most of the cases the stress distribution is not affected by changes in the size and position of the orbit. This finding supports the high mechanical plasticity of this group during the Triassic period. The absence of mechanical constraints regarding the orbit probably promoted the ecomorphological diversity acknowledged for this group, as well as its ecological niche differentiation in the terrestrial Triassic ecosystems in clades as lydekkerinids, trematosaurs, capitosaurs or metoposaurs. PMID- 26107296 TI - From Research to Practice: Which Research Strategy Contributes More to Clinical Excellence? Comparing High-Volume versus High-Quality Biomedical Research. AB - The question when and to what extent academic research can benefit society is of great interest to policy-makers and the academic community. Physicians in university hospitals represent a highly relevant test-group for studying the link between research and practice because they engage in biomedical academic research while also providing medical care of measurable quality. Physicians' research contribution to medical practice can be driven by either high-volume or high quality research productivity, as often pursuing one productivity strategy excludes the other. To empirically examine the differential contribution to medical practice of the two strategies, we collected secondary data on departments across three specializations (Cardiology, Oncology and Orthopedics) in 50 U.S.-based university hospitals served by 4,330 physicians. Data on volume and quality of biomedical research at each department was correlated with publicly available ratings of departments' quality of care, demonstrating that high-quality research has significantly greater contribution to quality of care than high-volume research. PMID- 26107297 TI - Reply: To PMID 24486408. PMID- 26107299 TI - Eye Care for the Developing World: The Next Frontier. PMID- 26107298 TI - Effect of chondrocyte-derived early extracellular matrix on chondrogenesis of placenta-derived mesenchymal stem cells. AB - The extracellular matrix (ECM) surrounding cells contains a variety of proteins that provide structural support and regulate cellular functions. Previous studies have shown that decellularized ECM isolated from tissues or cultured cells can be used to improve cell differentiation in tissue engineering applications. In this study we evaluated the effect of decellularized chondrocyte-derived ECM (CDECM) on the chondrogenesis of human placenta-derived mesenchymal stem cells (hPDMSCs) in a pellet culture system. After incubation with or without chondrocyte-derived ECM in chondrogenic medium for 1 or 3 weeks, the sizes and wet masses of the cell pellets were compared with untreated controls (hPDMSCs incubated in chondrogenic medium without chondrocyte-derived ECM). In addition, histologic analysis of the cell pellets (Safranin O and collagen type II staining) and quantitative reverse transcription-PCR analysis of chondrogenic markers (aggrecan, collagen type II, and SOX9) were carried out. Our results showed that the sizes and masses of hPDMSC pellets incubated with chondrocyte-derived ECM were significantly higher than those of untreated controls. Differentiation of hPDMSCs (both with and without chondrocyte-derived ECM) was confirmed by Safranin O and collagen type II staining. Chondrogenic marker expression and glycosaminoglycan (GAG) levels were significantly higher in hPDMSC pellets incubated with chondrocyte-derived ECM compared with untreated controls, especially in cells precultured with chondrocyte-derived ECM for 7 d. Taken together, these results demonstrate that chondrocyte-derived ECM enhances the chondrogenesis of hPDMSCs, and this effect is further increased by preculture with chondrocyte-derived ECM. This preculture method for hPDMSC chondrogenesis represents a promising approach for cartilage tissue engineering. PMID- 26107300 TI - Addressing Glaucoma in the Developing Countries of the Asia Pacific Region: An Opportunity to Transition From Disease-Specific Responses to Integration of Eye Care. AB - The Asia Pacific region accounts for more than 50% of global blindness. Although most attention has appropriately been focused on cataract, the most prevalent and treatable cause of global blindness, other conditions including glaucoma contribute significantly to visual impairment. The population attributable risk percentage for glaucoma suggests that it is a significant public health problem, and generally, case detection rather than population-based screening is the most appropriate strategy to identify disease. Glaucoma management requires the full range of comprehensive ophthalmic examination skills and therefore allows the diagnosis of most other potentially blinding conditions as well: these skills should be part of residency training in all developing countries in the region. A comprehensive examination on all patients presenting to an eye clinic not only detects glaucoma but also provides the opportunity to expand existing cataract centered programs toward the larger goal of prevention of blindness from any cause. Local efforts to improve residency training can be supplemented by regional support such as assistance in curriculum development and assessment of trainees. Assistance in glaucoma training would involve in-country diagnostic and surgical training with extended stays to teach postoperative care, supplemented by possible fellowships in developed countries. Although these changes will not have a large impact on blindness from glaucoma in the short term, they have the potential to develop a framework and skill set that is required for long-term reduction in morbidity from blindness of all causes, including glaucoma. PMID- 26107301 TI - Comparison of Toric Intraocular Lenses and Arcuate Corneal Relaxing Incisions to Correct Moderate to High Astigmatism in Cataract Surgery. AB - PURPOSE: To compare toric intraocular lens (IOL) implantation with arcuate corneal relaxing incisions for moderate to high corneal astigmatism during cataract surgery. DESIGN: A retrospective comparison study. METHODS: This 12 month single-surgeon study compared eyes with cataract and preexisting astigmatism of 1.75 diopters (D) or greater (range, 1.75-5.25 D) receiving corneal arcuate relaxing incisions or toric IOL implantation. Main outcome measures were visual acuity, refractive results, and IOL axis determination. RESULTS: There were 45 and 20 eyes in the toric IOL and arcuate incision groups, respectively. Preoperative data were not significantly different between the 2 groups; the mean preoperative astigmatism was 2.16 +/- 0.93 D in the toric IOL group and 2.41 +/- 0.76 D in the incisional group. At 6 months postoperatively, the mean residual astigmatism was 0.75 and 1.33 D (P = 0.000), respectively; 82.2% and 44.4% of eyes were 1.00 D or less (P = 0.000), and 35.7% and 16.7% of eyes were 0.50 D or less (P = 0.000), respectively. Uncorrected distance visual acuity improved in both groups; eyes in the toric IOL group were more likely to be 20/30 or better (87% vs 29%, P = 0.008). Following surgery, all eyes had best corrected visual acuity of 20/40 or greater, and no eye lost a line of vision. The mean toric IOL rotation was 2.6 +/- 1.7 degrees (range, 0-6 degrees). CONCLUSIONS: Both toric IOLs and arcuate corneal incisions reduce moderate to high preexisting corneal astigmatism during cataract surgery; however, toric IOL implantation was more effective and predictable. PMID- 26107302 TI - Near Vision Impairment Is Associated With Cognitive Impairment in Type 2 Diabetes. AB - PURPOSE: The objective of this study was to assess the relationship between vision and cognitive impairment in patients with type 2 diabetes mellitus (DM) who are at risk of both conditions. DESIGN: This was a cross-sectional study. METHODS: Persons with type 2 DM underwent a comprehensive clinical examination. Distance and near vision tests were performed, and presence and severity of diabetic retinopathy and diabetic macular edema, indicators of DM control such as fasting plasma glucose and glycosylated hemoglobin, and anthropometric measures were assessed using standardized protocols. Depression status and level of physical activity were measured using validated questionnaires. Adjusted logistic regression models were used to examine the association between near and distance vision impairment and cognitive impairment tested with a 6-item cognitive impairment test. RESULTS: Participants (n = 501) were aged 66 +/- 11 (mean +/- SD) years, and their mean duration of DM was 14 +/- 10 years. In adjusted models, near (P = 0.016) but not distance (P = 0.984) vision impairment was associated with cognitive impairment. Persons with near vision impairment were almost 4 times more likely to have cognitive impairment (odds ratio 3.90; 95% confidence interval, 1.31-12.56; P = 0.023), after adjusting for age, sex, and other covariables. CONCLUSIONS: Our findings suggest common risk factors and pathways may exist between near vision impairment and cognitive dysfunction in patients with type 2 DM. Future studies need to further assess this link. PMID- 26107303 TI - Single-Segment Intacs Severe Keratoconus 80% Stromal Depth Insertion With a Femtosecond Laser for Asymmetric Keratoconus: A Case Series. AB - PURPOSE: To study the efficacy of inferior, single-segment, 80% stromal depth Intacs severe keratoconus (SK) intracorneal ring segment implantation. DESIGN: A prospective case series. METHODS: Eighteen eyes from 15 patients with asymmetric keratoconus underwent 80% stromal depth Intacs SK single inferior segment implantation, using an IntraLase femtosecond laser for tunnel creation. Parameters studied included preoperative and postoperative uncorrected and best corrected visual acuity (VA), manifest refraction and elevation-based computerized corneal topography. RESULTS: Patients' VA was tested with Early Treatment Diabetic Retinopathy Study (ETDRS) chart. All the eyes demonstrated a significant ETDRS line improvement of 5.4 +/- 2.0 after a follow-up period of 8.9 +/- 3.9 months. Thirteen eyes (72%) showed a line improvement of 4 or more. Best corrected VA remained unchanged in 8 eyes (44%) while 7 eyes (39%) showed a line improvement of 1 to 8. Sixteen eyes (89%) had a significant change in manifest cylinder [3.0 +/- 2.2 diopters (D)]. Of the 18 eyes, astigmatism reduction was 3.44 +/- 1.98 D, from 5.6 +/- 2.2 D preoperatively to 2.5 +/- 1.5 D postoperatively (P < 0.05). Implant placement reduced both preexisting hyperopic and myopic spheres in 14 cases (78%). Although one case showed a significant postoperative regression of the obtained correction, Intacs SK implantation was safe and effective in all the other cases. CONCLUSIONS: Femtosecond laser assisted single-segment Intacs SK (80% depth intrastromal placement) is a safe and effective technique for improving uncorrected and best-corrected VA and correcting both spherical and cylindrical refractive errors in eyes with severe asymmetric keratoconus. PMID- 26107304 TI - Role of Lacrimal Canalicular Trephination and Mini-Monoka Stent in the Management of Idiopathic Distal Canalicular Obstructions: Our Experience of 23 Cases. AB - PURPOSE: Different techniques have been mentioned in literature for management of idiopathic lacrimal canalicular obstructions. The aim of this study was to report surgical outcomes with use of Sisler's lacrimal trephine and role of Mini-Monoka monocanalicular stent in patients of idiopathic distal canalicular obstructions. DESIGN: This was a prospective, interventional case series. METHODS: Twenty-three patients of idiopathic distal canalicular obstruction were managed surgically from August 2011 to October 2012. Lacrimal canalicular trephination was done in all followed by on-table syringing and Mini-Monoka stent insertion. RESULTS: There were 15 women and 8 men. Mean age of patients was 50.33 +/- 12.06 years. Average duration of complaints was 20.58 +/- 23.01 months. Twenty-four eyes were included in the study. Common canalicular obstruction was present in 15 eyes (62.5%), whereas 9 (37.5%) had distal lower canalicular obstruction. Mini-Monoka stent was kept in place for a minimum of 8 weeks. Twenty eyes (83.33%) reported absent epiphora, whereas 2 eyes (8.33%) reported improvement at average post stent removal follow-up of 8.66 +/- 3.17 months. No significant complication was observed in intraoperative and postoperative period except for 2 spontaneous tube extrusions, which were managed with tube reinsertion. CONCLUSIONS: Lacrimal canalicular trephination with Mini-Monoka stent insertion is an easy, monocanalicular and lesser invasive technique, which has never been reported earlier in literature. We conclude that this repeatable procedure has good anatomical and functional success rates with minimal complications as compared with the other available treatment modalities for lacrimal canalicular obstructions. PMID- 26107305 TI - No Evidence for Genetic Contribution of Ocular Dominance: The Guangzhou Twin Eye Study. AB - PURPOSE: The purpose of this study was to explore the heritability of ocular dominance in a classic twin study. DESIGN: A classical twin study. METHODS: Twins aged 7 to 19 years enrolled from the Guangzhou Twin Registry received comprehensive eye examinations. Ocular dominance was assessed by the "hole-in-the card test" by trained optometrists. Zygosity of the participants was confirmed by genotyping in all same-sex twin pairs. The pairwise concordance rate was calculated as the main outcome. RESULTS: After excluding 110 children with anisometropia of 2.0 diopters or greater and 24 children with alternating ocular dominance, a total of 941 twin pairs were identified in the analysis, including 596 monozygotic and 345 dizygotic pairs. Right-eye dominance was present in 59.3% of twins with available data. The pairwise concordance rate was 0.529 and 0.530 in monozygotic and dizygotic twin pairs, respectively (P > 0.5). The tetrachoric correlation was 0.043 and 0.035, respectively. When comparing the young twins and their parents, no significant difference in the percentage of offspring with left eye dominance was found between right * right parent mating group and non-right * right parent mating groups. CONCLUSIONS: Genetic factors may not be involved in ocular dominance in Chinese teens and children. PMID- 26107306 TI - Urgent Vitrectomy/Phacovitrectomy for Bullous Macula-Off Retinal Detachment: Implications for Optimal Timing of Surgery. AB - PURPOSE: Recently, an increasing number of ophthalmologists are using vitrectomy as the first line of treatment for retinal detachment (RD). The purpose of the present study was to determine the cutoff time of duration of macular detachment (DMD) after which postoperative best corrected visual acuity (BCVA) decreases sharply in eyes treated with primary vitrectomy. DESIGN: This was a retrospective, noncomparative, interventional case series. METHODS: Fifty-six eyes with macula-on RD and 126 eyes with bullous macula-off RD. RESULTS: Mean postoperative BCVA showed a statistically significant decrease when DMD exceeded 10 days (P = 0.009) with vitrectomy/phacovitrectomy as the primary mode of treatment, which was comparable to previous studies using scleral buckling. Approximately 90% (88%-93%) of eyes achieved a postoperative 20/40 BCVA when DMD was 2 days or less, after which the ratio decreased (P = 0.008) but plateaued around 40% until DMD reached 10 days. On the other hand, only 5.6% of (7/126) eyes with DMD of 3 days or less achieved a postoperative 20/20 BCVA. CONCLUSIONS: As with scleral buckling, the mean postoperative BCVA in eyes with bullous macula off RD treated with primary vitrectomy/phacovitrectomy dropped significantly when DMD exceeded 10 days. To achieve a good postoperative visual acuity (20/40), urgent surgery with a DMD of 2 days or less is desired. Operative repair within this period, rather than outright emergency surgery, may be appropriate for most cases. PMID- 26107307 TI - Effectiveness of Topical Antifungal Drugs in the Management of Fungal Keratitis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Fungal keratitis (FK) typically requires intensive therapy with topical antifungal agents. To date, evidence from clinical trials has been conflicting with respect to the most effective topical antifungal drug in the treatment of FK. Therefore, a systematic review and meta-analysis of randomized controlled trials (RCTS) using the Cochrane methodology was undertaken to evaluate the effectiveness of topical antifungals in management of FK. Outcomes included time to cure, treatment failure, complications of infection, visual acuity and adverse effects. A comprehensive search for studies was undertaken resulting in inclusion of 8 RCTs, predominantly from India, involving a total of 793 participants, the majority of whom were infected with filamentous fungi. Topical voriconazole was more likely to result in therapeutic keratoplasty compared with natamycin [relative risk (RR) 1.89 95% CI: 1.14, 3.12] with a number needed to treat of 13 (95% CI: 7, 50). Final visual acuity was significantly better with natamycin compared with voriconazole [weighted mean difference (WMD) 0.13, 95% CI 0.00, 0.27]. There was no difference in risk of treatment failure across all topical antifungal treatments studied (chlorhexidine gluconate, econazole, miconazole, natamycin, silver sulphadiazine and voriconazole). This study suggests treatment failure was comparable among antifungal treatments reviewed. However, natamycin resulted in better visual acuity following acute infection, compared with voriconazole. Voriconazole had a significantly greater risk of therapeutic keratoplasty compared with natamycin in the populations studied. PMID- 26107308 TI - Electroporating Human Corneal Epithelial Cells With Interleukin 10 and Fas Ligand pDNA. AB - PURPOSE: To develop an optimal electroporation protocol for plasmid (pDNA) transfection of a human corneal epithelial cell (hCEC) line and investigate the immunomodulatory capacity of interleukin 10 and Fas ligand (FasL) transfection on hCECs. DESIGN: A controlled experimental study. METHODS: Human corneal epithelial cells were electroporated with pDNA encoding enhanced green fluorescent protein, interleukin 10, or FasL. Supernatants were analyzed for cytokine secretion using enzyme-linked immunosorbent assay. To test potential immunosuppression, electroporated hCECs were cocultured with allogeneic peripheral blood mononuclear cells, and the supernatants analyzed for interferon gamma production. RESULTS: Maximum transfection efficiencies were obtained using optimized settings, and transgene expression was detected up to 13 days following transfection. Interleukin 10 levels peaked at day 4 and FasL at day 2 following electroporation. Coculture supernatants showed significantly lower levels of interferon gamma in the modulated groups compared with control. CONCLUSIONS: Our results demonstrate highly efficient transfection of hCECs using an optimized electroporation protocol. Interleukin 10 and FasL may provide a means of immune modulation of corneal epithelial cells. PMID- 26107309 TI - Letter to the Editor Regarding "Comparison of Combined Phacoemulsification, Intraocular Lens Implantation, and Goniosynechialysis With Phacotrabeculectomy in the Treatment of Primary Angle-Closure Glaucoma and Cataract". PMID- 26107310 TI - Understanding the Highly Varying pKa of Arylamines. A Perspective from the Average Local Ionization Condensed-to-Atom Framework. AB - The highly varying experimental pKa values for 36 arylamines spanning 7 orders of magnitude is carefully examined. Within this framework, a valence condensed-to atom model for the average ionization energy is introduced and tested. The theoretical approach is connected to orbital Fukui functions directly mapped into semilocal or regional site-specific responses. It is revealed that the average local ionization energies associated with the amino nitrogen atom is linearly correlated to the basicity of the substituted arylamines, properly reproducing the experimental ordering of basicity. The condensed-to-atom descriptor exhibits a high predictive power, providing a new direct reactivity evaluation of significant value. PMID- 26107311 TI - Gender Influences Radicular Pain Perception in Patients with Lumbar Disc Herniation. AB - BACKGROUND: Previous studies have demonstrated gender differences in pain perception in quantitative sensory testing. Thus, we hypothesized that there are differences in men and women with lumbar disc herniation awaiting lumbar sequestrectomy. To elucidate the differences in pain perception between men and women, we carried out a prospective clinical monocentric trial using quantitative sensory testing. METHODS: With institutional ethical approval, patients with radiculopathy awaiting lumbar sequestrectomy were examined the day before surgery. Preoperative pain was assessed using quantitative sensory testing and a series of questionnaires including Beck Depression Inventory and a numeric rating scale (NRS) for back and leg pain. Statistical analysis was performed using the Kolmogorov-Smirnov test for normal distribution. The unpaired Student's t-test, Mann-Whitney U test, and Fisher's exact test were used to analyze intergroup differences in the clinical and demographic characteristics and in clinical outcome variables. RESULTS: Fifty patients (20 women and 30 men) were included in the study. The groups did not differ in NRS for back and leg pain. Heat and pressure pain thresholds were found to be lower in women than in men (p<=0.05). Subgroup analyses revealed decreased wind-up ratio in male patients with prior periradicular steroid application (p<=0.05). CONCLUSIONS: Our results clearly indicate that sex differences in pain perception not only exist in healthy subjects, but also in patients with lumbar disc herniation. Therefore, it is essential to provide different treatment modalities to women and men. PMID- 26107312 TI - Stem cell therapy in multiple sclerosis: a future perspective. PMID- 26107314 TI - UK Parkinson's Excellence Network: empowering service improvement across the UK. AB - Parkinson's UK, together with leading Parkinson's professionals, has set up the UK Parkinson's Excellence Network to bring together the passion and expertise of leading clinicians with the strategic leadership and resources of Parkinson's UK underpinned by the voice of people affected by Parkinson's. Launched in London in February 2015, the Excellence Network aims to drive sustainable improvements in health and social care services. It will provide a more strategic approach to clinical development so that Parkinson's services across health and social care can be transformed to provide the best quality care across the UK. PMID- 26107315 TI - UK Parkinson's Excellence Network: time for a paradigm shift in Parkinson's care. PMID- 26107316 TI - A spotlight on microneurotrophins: the future of amyotrophic lateral sclerosis treatment? PMID- 26107317 TI - Current research in aging: a report from the 2015 Ageing Summit. AB - Ageing Summit, London, UK, 10-12 February 2015 The Ageing Summit 2015 held on 10 12 February 2015 in London (UK) provided an extensive update to our knowledge of the 'Biology of Ageing' and a forum to discuss the participants' latest research progress. The meeting was subdivided into four thematic sessions: cellular level research including the aging brain; slowing down progression, rejuvenation and self-repair; genetic and epigenetic regulation; and expression and pathology of age-related diseases. Each session included multiple key presentations, three to five short research communications and ongoing poster presentations. The meeting provided an exciting multidisciplinary overview of the aging process from cellular and molecular mechanisms to medico-social aspects of human aging. PMID- 26107318 TI - Neuropsychological tests for predicting cognitive decline in older adults. AB - AIM: To determine neuropsychological tests likely to predict cognitive decline. METHODS: A sample of nonconverters (n = 106) was compared with those who declined in cognitive status (n = 24). Significant univariate logistic regression prediction models were used to create multivariate logistic regression models to predict decline based on initial neuropsychological testing. RESULTS: Rey Osterrieth Complex Figure Test (RCFT) Retention predicted conversion to mild cognitive impairment (MCI) while baseline Buschke Delay predicted conversion to Alzheimer's disease (AD). Due to group sample size differences, additional analyses were conducted using a subsample of demographically matched nonconverters. Analyses indicated RCFT Retention predicted conversion to MCI and AD, and Buschke Delay predicted conversion to AD. CONCLUSION: Results suggest RCFT Retention and Buschke Delay may be useful in predicting cognitive decline. PMID- 26107320 TI - Are we providing the best possible care for dementia patients? AB - Healthcare for patients with dementia is often reactive, poorly organized and fragmented. We discuss opportunities for improvements in the care of individuals living with dementia at home that can be implemented by physicians in their practices today. In particular, we argue that systematic identification and diagnosis of cognitive impairment and dementia in their early stages, coupled with a coherent, evidence-informed management framework, would benefit patients with dementia substantially and ease the burden of their caregivers. We emphasize that dementia influences all aspects of patient care, and each medical decision must be passed through the filter of knowledge that patients with dementia have special needs that can be identified and addressed. PMID- 26107319 TI - Testing family-centered, function-focused care in hospitalized persons with dementia. AB - AIM: Hospital-acquired disability causes decreased quality of life for patients with dementia and family caregivers, and increased societal costs. MATERIALS & METHODS: A comparative, repeated measures study tested the feasibility and preliminary efficacy of the family-centered, function-focused care intervention (Fam-FFC) in dyads of hospitalized, medical patients with dementia and family caregivers (FCGs). RESULTS: The intervention group demonstrated better activities of daily living and walking performance, and less severity/duration of delirium and hospital readmissions, but no significant differences in gait/balance. FCGs showed increased preparedness for caregiving and less anxiety but no significant differences in depression, strain and mutuality. CONCLUSION: Fam-FFC presents a possible pathway to meeting the Triple Aim of improved patient care, improved patient health and reduced costs for persons with dementia. PMID- 26107321 TI - Alemtuzumab in multiple sclerosis: an update. AB - Since the introduction of IFN-beta, disease-modifying treatments, acting through various immune mechanisms, have been shown to reduce disease activity and severity in relapsing multiple sclerosis. Nevertheless, there remain patients for whom these treatments are incompletely effective, poorly tolerated or contraindicated. Alemtuzumab is a humanized monoclonal antibody that works by selectively depleting circulating lymphocytes. It is given as an intravenous infusion of 12 mg daily for 5 days, then a year later for 3 days. Effectiveness in patients with active relapsing-remitting multiple sclerosis has been demonstrated in two Phase III clinical trials, where it outperformed IFN-beta-1a 44 mcg on clinical and radiographic efficacy measures. Its side effect profile, including infusion-associated reactions, infections and secondary autoimmunity, coupled with its long-lasting biological effect, requires patients to commit to close monitoring while on the drug and for 4 years after the final infusion. For select patients with active disease, alemtuzumab offers a powerful therapeutic option. PMID- 26107322 TI - Behavioral treatments for speech in Parkinson's disease: meta-analyses and review of the literature. AB - Parkinson's disease (PD) results from neurodegenerative processes leading to alteration of motor functions. Most motor symptoms respond well to pharmacological and neurosurgical treatments, except some axial symptoms such as speech impairment, so-called dysarthria. However, speech therapy is rarely proposed to PD patients. This review aims at evaluating previous research on the effects of speech behavioral therapies in patients with PD. We also performed two meta-analyses focusing on speech loudness and voice pitch. We showed that intensive therapies in PD are the most effective for hypophonia and can lead to some improvement of voice pitch. Although speech therapy is effective in handling PD dysarthria, behavioral speech rehabilitation in PD still needs further validation. PMID- 26107323 TI - Diagnosing dementia in adults with Down's syndrome. AB - Individuals with Down's syndrome (DS) are living longer and many will survive into their fifth or sixth decade of life. Among the DS population, the prevalence of dementia in Alzheimer's disease increases from 9.4% in age group 30-39 years to 54.5% age group 60-69 years. The psychopathology of dementia in Alzheimer's disease is similar to that seen in the general population although differences are apparent due to the underlying intellectual disability in DS and on the reliance on collateral information from informants. The diagnostic workup follows accepted practice although neuropsychological tests and neuroimaging will only be adjuncts to the clinical assessment; such investigations have limited diagnostic value. Presently, research is focused on identifying genetic and biological measures of Alzheimer's disease in DS. PMID- 26107324 TI - New insights into the management of chronic inflammatory demyelinating polyradiculoneuropathy. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variants can be challenging to diagnose and treat. A combination of clinical, electrophysiological and laboratory features is often required to reach a diagnosis. New data are emerging about potential biomarkers and factors that may indicate treatment needs in individual patients. High-quality evidence exists for the efficacy of intravenous immunoglobulin (IVIG) in the treatment of CIDP, including quality of life (QoL) benefits. Besides pharmacological treatment, psychological factors must also be addressed to improve patients' QoL. Home-based IVIG infusion therapy is currently a well-established approach in some countries. A 6-month pilot study conducted in Ontario, Canada, provided proof of safety and patient acceptance of home-based IVIG therapy, although some logistical issues emerged. PMID- 26107326 TI - Visual Field Progression in Treated Glaucoma Patients. PMID- 26107327 TI - Three Generations of Eminent American Chinese: Lives Intertwined With History. AB - This article describes the lives of 3 generations of a remarkable American Chinese family, who all excelled in their achievements. Grandfather Chan Loon Teung was the first Chinese Harvard graduate; the father, Eugene Chan, and his wife, Winifred Mao, were famous ophthalmologists, working in the United States and in China, and their daughter, Chi-Chao Chan, is a specialist in ophthalmic pathology and uveitis at the National Institutes of Health in the United States. Although the different generations all encountered dramatic situations caused by political turmoil, such as the Xinhai Revolution, World War II, and the cultural revolution in China, this did not prevent them from making major contributions to their home countries and ophthalmology. The history of this family as depicted in this article illustrates what perseverance and passion can achieve. PMID- 26107328 TI - Comparison of PROGRESSOR and Glaucoma Progression Analysis 2 to Detect Visual Field Progression in Treated Glaucoma Patients. AB - PURPOSE: We compared the abilities of PROGRESSOR and Glaucoma Progression Analysis 2 (GPA2) to detect glaucomatous visual field (VF) progression. DESIGN: Retrospective cohort. METHODS: We reviewed the charts of glaucoma patients with repeatable VF loss and >= 8 SITA-Standard 24-2 VFs. Progression was evaluated using 3 methods: (1) PROGRESSOR pointwise linear regression (Medisoft, Inc), (2) GPA2 VF index (VFI) regression (GPA-VFI), and (3) GPA Early Manifest Glaucoma Trial (EMGT) criteria (Carl Zeiss Meditec, Inc; GPA-EMGT). For PROGRESSOR, progression was determined when at least 2 adjacent test points in the same hemifield progressed by more than 1.0 dB/y, P < 0.01. For GPA-VFI, progression was defined when VFI rate was more than 1.0%/y, P < 0.01. RESULTS: A total of 130 eyes [130 patients; mean (SD) age, 63.6 (12.7) years; mean (SD) number of VF, 11.2 (3.6); mean follow-up time, 7.3 (1.8) years] were enrolled. There was a significant correlation between VFI and PROGRESSOR rates of change (r = 0.81, P < 0.01). The number of eyes progressing based on PROGRESSOR, GPA-VFI, and the GPA EMGT criteria was 55, 37, and 46, respectively (P = 0.06). There was a moderate agreement between PROGRESSOR and the GPA-EMGT (kappa = 0.43), between PROGRESSOR and GPA-VFI (kappa = 0.57), and between GPA-VFI and GPA-EMGT (kappa = 0.45). PROGRESSOR and GPA-EMGT tended to detect similar numbers of progressing points per eye [3.7 (5.8) vs 3.1 (4.4), P = 0.50, respectively]. CONCLUSIONS: The 3 methods showed statistically similar sensitivities for the detection of VF progression. In addition, the EMGT and PROGRESSOR criteria revealed good spatial consistency. PMID- 26107329 TI - Intravitreal Bevacizumab After Intravitreal Triamcinolone for Exudative Age Related Macular Degeneration. AB - PURPOSE: This study aimed to assess the effect of intravitreal bevacizumab on visual acuity after a previously unsuccessful intravitreal triamcinolone acetonide injection for the treatment of exudative age-related macular degeneration. DESIGN: This is a clinically interventional case series study. METHODS: This study included patients with exudative age-related macular degeneration who had previously received an intravitreal injection of approximately 25 mg of triamcinolone without an increase in visual acuity. Patients received 3.5 (2.3) injections [mean (SD)] of 1.5 mg of bevacizumab. RESULTS: The study consisted of 36 patients (38 eyes) with a mean (SD) age of 77.9 (7.4) years. The mean (SD) visual acuity before the injection of bevacizumab was 0.84 (0.46) logMAR. After a mean (SD) follow-up of 10.1 (5.8) months (range, 2-21.9 months), the mean visual acuity was 0.94 (0.47) logMAR, without a statistically significant difference between the baseline value and the posttreatment value (P = 0.06; 95% confidence interval for the difference, -0.22 to 0.01 logMAR). CONCLUSIONS: Intravitreal bevacizumab injections may not markedly improve vision in exudative age-related macular degeneration if previous intravitreal triamcinolone failed to increase visual acuity. PMID- 26107330 TI - Mitomycin C-Augmented Trabeculectomy Combined With Single-Site Manual Small Incision Cataract Surgery Through a Tunnel Flap Technique. AB - PURPOSE: The objective of this study was to analyze short-term outcomes of mitomycin C-augmented trabeculectomy combined with manual small-incision cataract surgery (MSICS/Trab). DESIGN: This was a retrospective, noncomparative single center case series. METHODS: Records of eyes that underwent MSICS/Trab with mitomycin C performed between January 2006 and May 2007 were reviewed. Manual small-incision cataract surgery was done through a superior scleral tunnel; a Kelly punch was used for the trabeculectomy through the tunnel flap, and after a peripheral iridectomy, the scleral tunnel was opposed with two 10-0 nylon sutures. RESULTS: Of the 103 patients, 64 (62.1%) had primary open-angle glaucoma (POAG), 23 (22.3%) had secondary open-angle glaucoma (SOAG), and 16 (15.5%) had chronic angle closure glaucoma (CACG). The minimum follow-up was 6 months, and mean follow-up was 12.6 months. Demographics and mean intraocular pressure (IOP) at the time of surgery (30.4 +/- 10.3 mm Hg) were comparable in all 3 groups. Significant visual improvement and reduction in IOP levels from baseline were observed at 6 months (16.64 +/- 4.75 mm Hg) irrespective of the type of glaucoma (P = 0.035). Subgroup analysis showed a significant difference in IOP levels of CACG group compared with the SOAG group (P = 0.035) at 6 months. However, no statistically significant difference was observed in IOP comparisons between POAG and CACG groups or POAG and SOAG groups. CONCLUSIONS: Mitomycin C-augmented MSICS/Trab appears to be safe and effective technique in tackling coexistent cataract and glaucoma in developing world. PMID- 26107331 TI - Long-Term Comparison of Endothelial Changes Between Torsional and Longitudinal Phacoemulsification. AB - PURPOSE: The objective of this study was to evaluate endothelial changes between torsional and longitudinal phacoemulsification 2 years after cataract surgery. DESIGN: This was a prospective, randomized, controlled clinical trial. METHODS: We enrolled 200 patients with senile cataract between August 2008 and December 2009 for surgery using either torsional (group A, n = 100) or longitudinal (group B, n = 100) phacoemulsification. Outcomes were central endothelial cell density and corrected distance visual acuity (CDVA) 3 months and in this follow-up 2 years after surgery. Statistical evaluation of endothelial cell loss (ECL) was performed according to statistical guidelines by creating a primary analysis (substitution of missing values by the median) and a secondary analysis (actual data). RESULTS: The mean age was 71 (SD, 7.3) years. We were able to reexamine 46 patients in group A and 54 in group B 2 years after surgery. The median CDVA before surgery was 0.3 logMAR in group A and 0.35 logMAR in group B, improving to 0 logMAR postoperatively in both groups. The median ECL in the primary analysis was 6.9% after 3 months and 10.3% 2 years after surgery in group A. In group B, we found a loss of 6.6% after 3 months and 8.6% 2 years postoperatively. In the secondary analysis, the loss was 10.0% in group A and 8.5% in group B after 2 years. The difference was statistically not significant. CONCLUSIONS: There is no difference between the ECL between torsional and longitudinal phacoemulsification up to 2 years after cataract surgery. PMID- 26107332 TI - Anomalous Vascular Patterns of the Optic Disc in Amblyopia. AB - PURPOSE: To evaluate the presence of anomalies of the optic disc vascular patterns in subjects with amblyopia. DESIGN: Case controlled study. The outcome measure is temporal deviation of central retinal vessels and / or vascular pattern asymmetry. METHODS: A total of 342 hyperopic amblyopic patients were evaluated. An additional 88 subjects with equal visual acuity with strabismus, and 108 subjects with equal visual acuity and anisometropia were evaluated. RESULTS: In this study, more than 50% of amblyopic patients had optic disc deformities. Sixty-five percent of subjects with amblyopia, orthophoria, and anisometropia exceeding 1.5 D had these anomalies compared with less than 7% of the groups without amblyopia or strabismus. CONCLUSIONS: These disc anomalies may be associated with disorganization of optic nerve axons. This finding indicates the possibility of a peripheral cause for impaired vision and could provide an explanation for the variability in visual defects associated with amblyopia. Optic nerve imaging should be incorporated into clinical protocols for amblyopia research. PMID- 26107333 TI - Simultaneous Interface Candida Keratitis in 2 Hosts Following Descemet Stripping Endothelial Keratoplasty With Tissue Harvested From a Single Contaminated Donor and Review of Clinical Literature. AB - PURPOSE: The objective of this study was to report 2 cases of interface fungal keratitis in 2 separate patients following Descemet stripping automated endothelial keratoplasty (DSAEK) with tissue harvested from the same donor. DESIGN: This was a retrospective simultaneous interinstitutional hosptial-based case reports. METHODS: Two patients with corneal infections following DSAEK were identified from 2 individual practices. Both patients had undergone DSAEK from the same donor. Preoperative and postoperative eye examination included visual acuity, anterior and posterior segment evaluations, and clinical follow-up course from the time of surgery. Methods of medical therapy and surgical intervention are additionally discussed. RESULTS: The 2 patients presented in our series present with interface fungal keratitis postoperatively in the face of the original source coming from a single donor (patient 1: 7 days postoperatively and patient 2: 7 weeks postoperatively). As medical treatment failed in both cases, surgery was undertaken in both cases (therapeutic penetrating keratoplasty). With prompt recognition as well as medical and surgical treatment, patient 1 achieved best corrected visual acuity of 20/30 at 6 months postoperatively, and patient 2 had best corrected visual acuity of 20/80 at 10 months postoperatively. CONCLUSIONS: Fungal keratitis following DSAEK occurs in a sequestered space and therefore represents a treatment challenge with potentially devastating outcome. We recommend an aggressive surgical approach with early removal of the donor button and irrigation with intracameral antifungal agents. PMID- 26107334 TI - High Altitude and the Eye. AB - The purpose of this study was to review the available data on the effect of high altitude on the eyes. We carried out electronic literature search on www.pubmed.com for articles published through year 2011. The search terms included high altitude and the eye, high-altitude retinopathy, eye problems in the Himalayas, and eye diseases in Tibet. Other terms like visual functions, intraocular pressure, corneal thickness, tear function, and ocular motility, at high altitude, were searched separately and in combination. Data were retrieved from both prospective and retrospective studies published in the English language.High altitude has both short-term and long-term effects on the eyes. The short-term effects include high-altitude retinopathy, change in corneal thickness, and photokeratitis. Long-term effects include pterygium, cataract, and dry eye syndrome. High-altitude retinopathy of mild degree does not affect vision but has a predictive value for the development of high-altitude cerebral edema. Change in corneal thickness at altitude induces refractive changes in eyes with radial keratotomy and in eyes with LASIK. High altitude does not adversely affect visual acuity and contrast sensitivity; scotopic vision may be affected if supplemental oxygen is not used. PMID- 26107335 TI - Systematic Review of Peribulbar Anesthesia Versus Sub-Tenon Anesthesia for Cataract Surgery. AB - Commonly used anesthetic techniques for cataract surgery include peribulbar and sub-Tenon anesthesia. This evidence-based review compares these techniques, with a particular focus on patient comfort, akinesia, and anesthetic complications. A systematic search of the literature revealed that there is a paucity of robust evidence comparing sub-Tenon and peribulbar anesthesia. Based on the best available evidence, there is no significant difference in the efficacy of peribulbar compared with sub-Tenon anesthesia for cataract surgery; however, the potential complications of peribulbar anesthesia are more serious. PMID- 26107336 TI - Horner Syndrome: A Practical Approach to Investigation and Management. AB - Horner syndrome is typically described by the classic triad of blepharoptosis, miosis, and anhydrosis resulting from disruption along the oculosympathetic pathway. Because of the complex and extensive course of this pathway, there are a large number of causes of Horner syndrome ranging from benign to life-threatening diseases. This review article aims to provide a practical approach to investigation and management, including evaluation of the more recent use of apraclonidine for pharmacological testing. PMID- 26107337 TI - Mitochondrial Changes in Aging Orbicularis Oculi Muscles: Histologic and Genetic Analyses in Elderly Asian Patients. AB - PURPOSE: We aimed to determine whether there was underlying mitochondrial myopathy in some aging patients diagnosed with involutional ptosis. We compared orbicularis oculi muscle from patients with ptosis and patients with dermatochalasis without ptosis, using histochemical and mitochondrial DNA (mtDNA) analysis. DESIGN: This was a case-control study. METHODS: We studied 10 patients with ptosis who underwent correction surgery, and 10 patients without ptosis, who had dermatochalasis surgery, all in 1 institution. Orbicularis oculi muscle was examined with standard muscle histochemistry; modified Gomori trichrome, nicotinamide adenine dinucleotide (NADH), succinyl dehydrogenase (SDH), cytochrome c oxidase (COX), and Congo red. Genetic analysis was performed for deletions of mtDNA. RESULTS: The mean age of the group with ptosis was 67.6 years and that of the dermatochalasis group was 65.2 years. Inflammation, fibrosis, or amyloid was not present in the orbicularis of either ptosis or dermatochalasis group. There was no significant difference in ragged red fibers, NADH, SDH, or COX staining patterns between ptosis and dermatochalasis groups. One of 10 specimens in the ptosis group and 1 of 10 in the dermatochalasis group showed deletion of mtDNA. CONCLUSIONS: Our study of orbicularis oculi muscle found no difference between patients with and without involutional ptosis. We conclude that the presence of ragged red fibers, subsarcolemmal NADH and SDH accentuation, and COX-negative staining patterns in orbicularis muscle could represent age related involutional changes. The significance of deletion of mtDNA needs further investigation. PMID- 26107338 TI - Comparison of Outcomes of Suprabrow Single-Stab and 3-Stab Incision Frontalis Sling Surgery. PMID- 26107339 TI - Author Reply. PMID- 26107340 TI - Predictive Factors Within the Optic Nerve Complex for Glaucoma Progression: Disc Hemorrhage and Parapapillary Atrophy. PMID- 26107341 TI - Author Reply. PMID- 26107342 TI - Diagnostic Tests for Childhood Tuberculosis: Past Imperfect, Present Tense and Future Perfect? PMID- 26107343 TI - Species C is Predominant in Chinese Children with Acute Respiratory Adenovirus Infection. PMID- 26107344 TI - Differences in Norovirus-Associated Hospital Visits Between Jewish and Bedouin Children in Southern Israel. AB - Population-based surveillance during 2006-2013 showed that norovirus hospitalization rates among Bedouin (low-middle income settings) children <5 years old were 13.9/10,000 person-years compared with 7.1/10,000 among Jewish (high-income settings) children who were <5 years (rate ratio: 2.0, 95% confidence interval: 1.6-2.3). Differences were most prominent among infants (59.7 vs. 19.7/10,000, respectively; rate ratio: 3.0, 95% confidence interval: 2.5-3.8). GII.3 and GII.4 strains dominated (67%) in both populations. PMID- 26107345 TI - An Overview of Quadrivalent Human Papillomavirus Vaccine Safety: 2006 to 2015. AB - BACKGROUND: A quadrivalent human papillomavirus (HPV4) type 6/11/16/18 vaccine (GARDASIL/SILGARD(r)) has been licensed in many countries around the world for the prevention of cervical, vulvar, vaginal, and anal cancers and precancers, as well as external genital warts causally related to HPV types 6/11/16/18. Across 7 phase 3 clinical trials involving more than 29,000 males and females ages 9-45 years, vaccination was generally well tolerated. Because of its expected public health benefit in reducing cervical cancer and other HPV-related diseases, the vaccine has been implemented in the national vaccination programs of several countries, with over 178 million doses distributed worldwide. METHODS: Extensive efforts to assess the safety of the vaccine in routine practice have been conducted over the past 9 years since licensure, including more than 15 studies in more than 1 million preadolescents, adolescents and adults from various countries. Most have been performed in the general population although there have been some in special populations (pregnant women, HIV-infected individuals and those with systemic lupus erythematosus). RESULTS: We present a summary of the published, postlicensure safety data from active and passive surveillance. Only syncope, and possibly skin infections were associated with vaccination in the postlicensure setting. Serious adverse events, such as adverse pregnancy outcomes, autoimmune diseases (including Guillain-Barre Syndrome and multiple sclerosis), anaphylaxis, venous thromboembolism and stroke, were extensively studied, and no increase in the incidence of these events was found compared with background rates. CONCLUSIONS: These results, along with the safety data from the prelicensure clinical trials, confirm that the HPV4 vaccine has a favorable safety profile. Key policy, medical and regulatory organizations around the world have independently reviewed these data and continue to recommend routine HPV vaccination. PMID- 26107346 TI - Acute Adrenal Failure in a Term Newborn with Congenital Cytomegalovirus Infection. PMID- 26107347 TI - Re-evaluating the New Committee on Infectious Diseases Recommendations for Palivizumab Use in Premature Infants. PMID- 26107348 TI - Why is depression more prevalent in women? PMID- 26107349 TI - Acute renal and neurotoxicity in older lithium users: How can we manage and prevent these events in patients with late-life mood disorders? PMID- 26107350 TI - Galleria mellonella as a host model to study Aspergillus terreus virulence and amphotericin B resistance. AB - The aim of this study was to investigate if the alternative in vivo model Galleria mellonella can be used (i) to determine differences in pathogenicity of amphotericin B (AMB) resistant and susceptible A. terreus isolates, (ii) to evaluate AMB efficacy in vivo (iii) and to correlate outcome to in vitro susceptibility data. Larvae were infected with 2 A. terreus AMB resistant (ATR) and 3 AMB susceptible (ATS) isolates and survival rates were correlated to physiological attributes and killing ability of larval haemocytes. Additionally, infected larvae were treated with different concentrations of L-AMB. Haemocyte density were ascertained to evaluate the influence of L-AMB on the larval immune cells. Larvae were sensitive to A. terreus infection in an inoculum-size and temperature dependent manner. In vitro susceptibility to L-AMB correlated with in vivo outcome of antifungal treatment, defining an AMB susceptible strain cluster of A. terreus. Susceptibility to L-AMB increased virulence potential in the larval model, but this increase was also in accordance with faster growth and less damage caused by larval haemocytes. L-AMB treatment primed the larval immune response by increasing haemocyte density. G. mellonella provides a convenient model for the in vivo screening of A. terreus virulence and treatment options, contributing to the generation of a hypothesis that can be further tested in refined experiments in mammalian models. PMID- 26107351 TI - Annotation of the Protein Coding Regions of the Equine Genome. AB - Current gene annotation of the horse genome is largely derived from in silico predictions and cross-species alignments. Only a small number of genes are annotated based on equine EST and mRNA sequences. To expand the number of equine genes annotated from equine experimental evidence, we sequenced mRNA from a pool of forty-three different tissues. From these, we derived the structures of 68,594 transcripts. In addition, we identified 301,829 positions with SNPs or small indels within these transcripts relative to EquCab2. Interestingly, 780 variants extend the open reading frame of the transcript and appear to be small errors in the equine reference genome, since they are also identified as homozygous variants by genomic DNA resequencing of the reference horse. Taken together, we provide a resource of equine mRNA structures and protein coding variants that will enhance equine and cross-species transcriptional and genomic comparisons. PMID- 26107352 TI - Exercising: the more, the better? PMID- 26107353 TI - Article published in the U.S. News Health: "Top-Rated Diets Overall". PMID- 26107356 TI - Treatment of isolated lesions of the posterior cruciate ligament. PMID- 26107357 TI - Treatment of abdominal tumors using radiotherapy. PMID- 26107358 TI - Typical case: herpes zoster. AB - The varicella zoster virus is the causative agent of herpes zoster and varicella. In herpes zoster, the virus dormant within dorsal root ganglia is reactivated, resulting in painful vesicular lesions overlying an erythematous base. PMID- 26107359 TI - Retinol, beta-carotene and oxidative stress in systemic inflammatory response syndrome. AB - OBJECTIVE: patients suffering systemic inflammatory response syndrome (SIRS) constitute a group susceptible to elevated levels of oxidative stress. This study's aim is to evaluate the state of oxidative stress and levels of serum retinol and beta-carotene in these patients. METHODS: forty-six patients were divided into 2 groups: those those without diet (G1; n=18) and those with enteral nutritional support (G2; n=28). Serum levels of retinol and total carotenoids were measured. C-reactive protein (CRP) levels and Apache scores were also calculated. Oxidative stress was estimated by measuring thiobarbituric acid reactive substance (TBARS) levels. RESULTS: the patients' median age was 66.9 (SD=19.3) years. Lower concentrations of retinol and carotenoids were found in 68.6 and 66.7% of G1, respectively. In G2, despite average vitamin A levels being 8078 + 4035, retinol and beta-carotene were considered insufficient (31.2 and 33.4%, respectively). No difference was noted between the 2 groups, according to the variables studied, with the exception being PCR and beta-carotene (p=0.002; p=0.01). CONCLUSION: the data presented in this study supports the need to establish/revise clinical practices in treating SIRS patients, in light of this micronutrient's role in the immune system and antioxidant defense without it interfering with its toxicity. PMID- 26107360 TI - The effects of pre-op trainning on the anxiety levels of children in Corum/Turkey. AB - OBJECTIVE: all individuals regardless of their age or level of development require physical, emotional and cognitive preparation before an operation. It is known that the attitudes of pediatric nurses towards pediatric patients are influential on the anxiety levels of children awaiting an operation. This study aims to determine the effect of pre-op trainning on the anxiety levels of pediatric patients hospitalized for hernioplasty surgery. METHODS: this cross sectional and quasi-experimental study included a total of 100 patients aged 7-12 years admitted for inguinal hernia surgery, 50 of which were the control group and 50 the experiment group. The data was gathered using the patients' identification forms and a child steady state anxiety scale. Research data was evaluated with appropriate statistical methods. RESULTS: the groups showed similar socio-demographic features and no statistically significant difference was observed (p>0.05). During the pre-op period neither of the groups showed any statistically significant difference in terms of both state and trait anxiety levels (p>0.05), however the experiment group showed a statistically significant drop in their anxiety levels during the post-op period (p<0.05). CONCLUSION: the state anxiety levels of children receiving a planned pre-op trainning are lower compared to children who did not receive such trainning. Reducing the anxiety levels of sick children is possible through giving visual and tangible information appropriate with the age and developmental level of the sick child during the pre-op period. PMID- 26107361 TI - Quality of life of patients with rheumatoid arthritis under biological therapy. AB - OBJECTIVE: assessing health-related quality of life (HRQL) in patients with rheumatoid arthritis (RA), before and after treatment with biological therapy. METHODS: a longitudinal study, conducted from November 2010 to September 2011, with implementation of the instruments HAQ II (health assessment questionnaire) and SF-36 (medical outcomes short-from health survey). Barlett test, Anova, Friedman and paired t-test were performed for multiple extracts. RESULTS: 30 patients were evaluated, mean age of 47.6 (SD: 12.25) years and prevalence of females (90%). The mean score of HAQ II before treatment was 1.97, with significant reduction of up to 1.23 after six months of biological therapy (p<0.01). Most of the SF-36 domains showed significant improvement after six months of treatment (p<0.01), highlighting the social aspects, pain, physical functioning, emotional issues, vitality and physical aspects. CONCLUSION: the use of biologic therapy in patients with RA refractory to standard therapies proved to be an important pharmacological strategy for improving HRQL. PMID- 26107362 TI - Relationship between vitamin D and lung function, physical performance and balance on patients with stage I-III chronic obstructive pulmonary disease. AB - OBJECTIVES: vitamin D is important for muscle function and it affects different aspects of muscle metabolism. This study aim to determine whether serum 25(OH) D levels are related to lung functions, physical performance and balance in patients with chronic obstructive pulmonary disease (COPD). METHODS: in 90 patients with COPD and 57 healthy controls lung function tests, physical performance tests (time up and go, gait velocity test, sit-to-stand test, isometric strength, isokinetic strength), static (functional reach test) and dynamic (time up and go) balance tests and the association of 25(OH)D levels with lung functions, physical performance and balance were evaluated. RESULTS: the COPD patients had significantly more deficit in physical function and balance parameters, and in dynamic balance test (p<0.005). Isokinetic knee muscle strength (flexor and extensor) in COPD patients was significantly lower than in the controls (p<0.05); FEV1 (p=0.008), FVC (p=0.02), FEV1/FVC (p=0.04), TLC (p=0.01) were lower in COPD patients with vitamin D deficiency [25(OH) D less than 15 ng/mL] than in COPD patients without vitamin D deficiency. Hand grip test (p=0.000) and isokinetic knee muscle strength (flexor and extensor) (p<0.05) were also lower in COPD patients with vitamin D deficiency. Vitamin D deficiency was more pronounced in patients with stage III COPD (p<0.05). CONCLUSION: patients with COPD had worst physical functioning, poor balance and less muscle strength. Severe disturbed lung and peripheral muscle functions are more pronounced in COPD patients with vitamin D deficiency. PMID- 26107363 TI - Obese patients lose weight independently of nutritional follow-up after bariatric surgery. AB - OBJECTIVE: to examine the association between preoperative body weight, adherence to postsurgical nutritional follow-up, length of postoperative period, and weight loss during the first 18 months among adults who have undergone bariatric surgery. METHODS: a retrospective cohort study was conducted on 241 consecutive patients who underwent open Roux-en-Y gastric bypass (RYGBP) from January 2006 to December 2008, in a teaching hospital in Sao Paulo (Brazil). Data were collected through hospital records review and the variables analyzed included sex, age, immediate preoperative weight, adherence to postsurgical nutritional visits and length of postoperative period. Proportional body weight reductions during the 18 month follow-up period were examined using generalized estimating equations. RESULTS: 81% (n = 195) of participants were female, with overall mean age of 44.4 +/- 11.6 years, mean preoperative weight of 123.1 +/- 21.2 kg and mean preoperative body mass index of 47.2 +/- 6.2 kg/m2. The overall adherence to postoperative follow- up schedule was 51% (95%CI: 44.5-57.5%). Preoperative body weight and adherence were not associated with proportional weight reduction (Wald's test p > 0.18). Weight loss leveled off at the end of the 18-month follow up period for both compliant and non-compliant patients (Wald's test p = 0.00). CONCLUSIONS: our study showed that weight loss occurred steadily over the first 18 months after RYGBP, leveling off at around 40% weight reduction. It was associated with neither presurgical weight, nor nutritional follow-up and it may be primarily dependent on the surgical body alterations themselves. This finding may have implications for intervention strategies aimed at motivating patients to comply with early postsurgical and life-long follow-up. PMID- 26107364 TI - In-hospital mortality risk factors in community acquired pneumonia: evaluation of immunocompetent adult patients without comorbidities. AB - OBJECTIVE: several scores were developed in order to improve the determination of community acquired pneumonia (CAP) severity and its management, mainly CURB-65 and SACP score. However, none of them were evaluated for risk assessment of in hospital mortality, particularly in individuals who were non-immunosuppressed and/or without any comorbidity. In this regard, the present study was carried out. METHODS: we performed a cross-sectional study in 272 immunocompetent patients without comorbidities and with a diagnosis of CAP. Performance of CURB- 65 and SCAP scores in predicting in-hospital mortality was evaluated. Also, variables related to death were assessed. Furthermore, in order to design a model of in-hospital mortality prediction, sampled individuals were randomly divided in two groups. The association of the variables with mortality was weighed and, by multiple binary regression, a model was constructed in one of the subgroups. Then, it was validated in the other subgroup. RESULTS: both scores yielded a fair strength of agreement, and CURB-65 showed a better performance in predicting in hospital mortality. In our casuistry, age, white blood cell counts, serum urea and diastolic blood pressure were related to death. The model constructed with these variables showed a good performance in predicting in-hospital mortality; moreover, only one patient with fatal outcome was not correctly classified in the group where the model was constructed and in the group where it was validated. CONCLUSION: our findings suggest that a simple model that uses only 4 variables, which are easily accessible and interpretable, can identify seriously ill patients with CAP. PMID- 26107365 TI - Profile of cystic fibrosis in two reference centers in southern Brazil. AB - OBJECTIVE: to compare the characteristics of cystic fibrosis patients treated in two reference centers in southern Brazil in order to observe trends in the treatment and clinical outcomes that may produce changes in clinical conduct. METHODS: cross-sectional, retrospective study with 83 patients diagnosed with cystic fibrosis, aged one month to eighteen years. The variables analyzed were obtained through review of medical records, including: demographic and clinical characteristics, socioeconomic status, pulmonary function test, bacterial colonization profile, medication and physiotherapy. RESULTS: between the two centers there was significant difference in the variables, including admissions in the previous year (p<0.001), lifetime hospital admissions (p<0.001), use of Dornase alpha (p=0.003) and inhaled antibiotic therapy (p=0.006), which were higher at the Santo Antonio Children's Hospital (HCSA), while age at first colonization with Staphylococcus aureus (p=0.008), maternal age (p=0.030), clinical score (p=0.001), socioeconomic score (p=0.021) and use of hypertonic saline (p<0.001) were lower at HCSA compared to Sao Lucas Hospital (HSL). CONCLUSION: the study centers seem to receive a different population of patients, both in socioeconomic terms, as well as disease severity, which interferes with the choice of medication treatment. At the HCSA, preventive actions against infection due to the high incidence of Burkholderia cepacia Complex and careful research into early lung changes will be encouraged. PMID- 26107366 TI - Clinical profile of patients with myasthenia gravis followed at the University Hospital, Federal University of Minas Gerais. AB - OBJECTIVE: to determine the clinical profile of patients with myasthenia gravis (MG); followed at the Neuromuscular Diseases Clinic of the University Hospital, Federal University of Minas Gerais, Brazil, and to compare it with other Brazilian case series. METHODS: sociodemographic and clinical data were collected from patients, and a systematic literature review performed, focusing on national studies on the clinical profile of MG patients. RESULTS: sixty nine patients were enrolled in the study. Fifty five (91%) subjects were female and the mean age (SD) was 37.6 (+/- 11.4) years. The mean disease duration was 14.1 years. Regarding treatment, prednisone was the most used strategy (64%), followed by the use of azathioprine (43%). There was no difference between thymectomized (42) and non-thymectomized (27) patients regarding disease severity and medication use. CONCLUSION: clinical and socio-demographic features of this MG sample from a University-based clinic resemble those reported in other Brazilian series and in the international literature. PMID- 26107367 TI - Metabolic syndrome resolution by Roux-en-Y gastric bypass in a real world: a case control study. AB - OBJECTIVES: the aim of this study was to evaluate the efficacy of Roux-en-Y Gastric Bypass (RYGB), compared with nonsurgical treatment (NS group), as an instrument for inducing remission of co-morbidities related to Metabolic Syndrome (MetS) in patients with Obesity, grades 2 and 3 (Ob2,3). METHODS: two hundred and fifty eight Ob2,3 patients were selected in a retrospective analysis and included in a case control study. MetS was defined as described by the International Diabetes Federation. One hundred and twenty-nine of these patients underwent RYGB (S group), and 129 were assessed as an NS group. RESULTS: at baseline, S and NS groups did not differ in BMI, age, female sex and prevalence of MetS (p>0.05). For the S group the outcomes were a reduction in BMI of 38.1% (p<0.001), waist circumference of 28.6% (p<0.001), fasting plasma glucose of 10.5% (p<0.001), serum LDL-cholesterol of 21.9% (p<0.001) and of 85% in the number of patients with MetS (p<0.001). For the NS group, only a decrease of 4.12%(p=0.047) in triglyceride levels and of 5.9%(p=0.031) in Diastolic Blood Pressure was observed. In the NS group, 98.6% of the patients continued to have MetS. The number needed to treat (NNT) with surgery to resolve one case of MetS was 1.2 (CI 95%: 1.1 - 1.4). CONCLUSION: in the real world, in the South of Brazil, compared with NS treatment and after 1 year of observation, RYGB is highly effective for decreasing the prevalence of MetS. PMID- 26107368 TI - Acute appendicitis in pregnancy: literature review. AB - INTRODUCTION: suspected appendicitis is the most common indication for surgery in non-obstetric conditions during pregnancy and occurs in about one in 500 to one in 635 pregnancies per year. This occurs more often in the second trimester of pregnancy. Acute appendicitis is the most common general surgical problem encountered during pregnancy. METHODS: a literature review on research of scientific articles, under the terms "acute appendicitis" and "pregnancy", in PubMed, Lilacs/SciELO, Scopus, Cochrane Library and Uptodate databases. RESULTS: the clinical manifestations of appendicitis are similar to non-pregnant women, however, without a classic presentation, which often occurs, diagnosis is difficult and must be supported by imaging. DISCUSSION: clinical diagnosis should be strongly suspected in pregnant women with classic findings such as abdominal pain that migrates to the right lower quadrant. The main purpose of imaging is to reduce delays in surgical intervention due to diagnostic uncertainty. A secondary objective is to reduce, but not eliminate, the negative appendectomy rate. Differential diagnosis of suspected acute appendicitis usually includes pathologies considered in non-pregnant people. CONCLUSION: the imaging study of choice is ultrasound, MRI may be used when the former is not conclusive and, as a last resort, a CT scan can be performed. The treatment remains appendectomy by laparotomy, since the feasibility of video- assisted surgery in these cases remains controversial. PMID- 26107369 TI - Quality of life in women with urinary incontinence. AB - The aim of this study is to examine the relationship among psychological, clinical and sociodemographic variables, and quality of life in women with urinary incontinence. The sample consisted of 80 women diagnosed with urinary incontinence (UI) followed in a Northern Central Hospital in Portugal. Participants answered the Incontinence Quality of Life (I-QOL); Satisfaction with Sexual Relationship Questionnaire (SSRQ); Hospital Anxiety and Depression Scales (HADS) and the Brief Cope. The results revealed that women with higher quality of life considered their symptoms of urine loss as mild or moderated compared to those with severe urine loss. The less severe urine loss was associated with greater sexual satisfaction and less use of religion and self-blame as coping strategies. In terms of coping, women who considered the loss of urine as severe expressed more feelings regarding UI. Stress urinary incontinence, high sexual satisfaction, and less use of denial, distraction, and religion as coping strategies, predicted higher quality of life. According to the results, UI has an impact on women's sexual satisfaction and quality of life. Therefore, intervention programs should target these women, including their partners, helping them to adjust to their condition and teaching effective coping strategies in order to improve their sexual satisfaction and quality of life. PMID- 26107370 TI - Acute pericarditis. AB - Acute pericarditis is a common disease caused by inflammation of the pericardium, usually benign and self-limited and can occur as an isolated or as a manifestation of a systemic disease entity. Represents 5% of all causes of chest pain in the emergency room. The main etiology are viral infections, although it can also be secondary to systemic diseases and infections. The main complication of acute pericarditis is pericardial effusion, triggering a cardiac tamponade. The first line of treatment is the use of anti-inflammatory and or acetylsalicylic acid. Most patients have a good initial response to an NSAID associated to colchicine and became asymptomatic within a few days. This review article seeks to contemplate the main clinical findings and armed investigation to optimize the diagnosis of this important disease, as well as addressing their therapeutic management. PMID- 26107371 TI - Oral sex and risk of oral cancer: a meta-analysis of observational studies. AB - OBJECTIVE: Association between oral sex and oral cancer is a highlighted topic all the time; however, many published epidemiological studies remain failed to obtain a consistent conclusion. We performed this meta-analysis to ascertain whether oral sex is a risk factor or a risk marker for oral cancer. METHOD: The PubMed database was searched up to 30 August 2013 (latest updated on 21 December 2014) for relevant observational studies that tested the association between oral sex and oral cancer risk. After data extraction from eligible studies, the meta analysis was conducted using the Comprehensive Meta-Analysis software. RESULTS: Finally we yielded six case-control studies and one cross-sectional study with 5553 individuals. The results based on random-effects model indicated that there was no significant association between oral sex and risk of oral cancer (OR 1.15, 95% CI 0.86 to 1.54; P = 0.33). Sensitivity analysis showed that the result was robust and subgroups analyses also revealed similar results. Publication bias was not detected. CONCLUSION: Current evidence suggests that oral sex is a risk marker rather than an independent risk factor for oral cancer. However, the practitioners should assure they are without sexually transmitted diseases and with good oral health, and at least cleaned carefully and thoroughly before oral sex. PMID- 26107372 TI - The ACTN3 R577X Polymorphism Is Associated with Cardiometabolic Fitness in Healthy Young Adults. AB - Homozygosity for a premature stop codon (X) in the ACTN3 "sprinter" gene is common in humans despite the fact that it reduces muscle size, strength and power. Because of the close relationship between skeletal muscle function and cardiometabolic health we examined the influence of ACTN3 R577X polymorphism over cardiovascular and metabolic characteristics of young adults (n = 98 males, n = 102 females; 23 +/- 4.2 years) from our Assessing Inherent Markers for Metabolic syndrome in the Young (AIMMY) study. Both males and females with the RR vs XX genotype achieved higher mean VO2 peak scores (47.8 +/- 1.5 vs 43.2 +/-1.8 ml/O2/min, p = 0.002) and exhibited higher resting systolic (115 +/- 2 vs 105 +/- mmHg, p = 0.027) and diastolic (69 +/- 3 vs 59 +/- 3 mmHg, p = 0.005) blood pressure suggesting a role for ACTN3 in the maintenance of vascular tone. We subsequently identified the expression of alpha-actinin 3 protein in pulmonary artery smooth muscle, which may explain the genotype-specific differences in cardiovascular adaptation to acute exercise. In addition, we utilized targeted serum metabolomics to distinguish between RR and XX genotypes, suggesting an additional role for the ACTN3 R577X polymorphism in human metabolism. Taken together, these results identify significant cardiometabolic effects associated with possessing one or more functional copies of the ACTN3 gene. PMID- 26107374 TI - Segmentation and Classification of Bone Marrow Cells Images Using Contextual Information for Medical Diagnosis of Acute Leukemias. AB - Morphological identification of acute leukemia is a powerful tool used by hematologists to determine the family of such a disease. In some cases, experienced physicians are even able to determine the leukemia subtype of the sample. However, the identification process may have error rates up to 40% (when classifying acute leukemia subtypes) depending on the physician's experience and the sample quality. This problem raises the need to create automatic tools that provide hematologists with a second opinion during the classification process. Our research presents a contextual analysis methodology for the detection of acute leukemia subtypes from bone marrow cells images. We propose a cells separation algorithm to break up overlapped regions. In this phase, we achieved an average accuracy of 95% in the evaluation of the segmentation process. In a second phase, we extract descriptive features to the nucleus and cytoplasm obtained in the segmentation phase in order to classify leukemia families and subtypes. We finally created a decision algorithm that provides an automatic diagnosis for a patient. In our experiments, we achieved an overall accuracy of 92% in the supervised classification of acute leukemia families, 84% for the lymphoblastic subtypes, and 92% for the myeloblastic subtypes. Finally, we achieved accuracies of 95% in the diagnosis of leukemia families and 90% in the diagnosis of leukemia subtypes. PMID- 26107373 TI - CX3CR1 Is Expressed in Differentiated Human Ciliated Airway Cells and Co Localizes with Respiratory Syncytial Virus on Cilia in a G Protein-Dependent Manner. AB - Respiratory syncytial virus (RSV) is the principal cause of bronchiolitis in infants and a significant healthcare problem. The RSV Glycoprotein (G) mediates attachment of the virus to the cell membrane, which facilitates interaction of the RSV Fusion (F) protein with nucleolin, thereby triggering fusion of the viral and cellular membranes. However, a host protein ligand for G has not yet been identified. Here we show that CX3CR1 is expressed in the motile cilia of differentiated human airway epithelial (HAE) cells, and that CX3CR1 co-localizes with RSV particles. Upon infection, the distribution of CX3CR1 in these cells is significantly altered. Complete or partial deletion of RSV G results in viruses binding at least 72-fold less efficiently to cells, and reduces virus replication. Moreover, an antibody targeting an epitope near the G protein's CX3CR1-binding motif significantly inhibits binding of the virus to airway cells. Given previously published evidence of the interaction of G with CX3CR1 in human lymphocytes, these findings suggest a role for G in the interaction of RSV with ciliated lung cells. This interpretation is consistent with past studies showing a protective benefit in immunizing against G in animal models of RSV infection, and would support targeting the CX3CR1-G protein interaction for prophylaxis or therapy. CX3CR1 expression in lung epithelial cells may also have implications for other respiratory diseases such as asthma. PMID- 26107375 TI - East Asian monsoon signals reflected in temperature and precipitation changes over the past 300 years in the middle and lower reaches of the Yangtze River. AB - Based on observational data and Asian monsoon intensity datasets from China, the relationships between the East Asian winter monsoon index and winter temperature, the East Asian summer monsoon index and Meiyu precipitation over the middle and lower reaches of the Yangtze River, were analyzed. We found that the monsoon signals were reflected in the temperature and Meiyu precipitation variations. Thus, we used the reconstructed Meiyu precipitation and winter temperature series for the past 300 years and detected the summer/winter monsoon intensity signals using multi-taper spectral estimation method and wavelet analysis. The main periodicities of Meiyu precipitation and winter temperature, such as interannual cycle with 2-7-year, interdecadal-centennial cycles with 30-40-year and 50-100 year, were found. The good relationships between the East Asian summer and winter monsoons suggested that they were in phase at 31-year cycle, while out of phase at 100-year cycle, but with 20-year phase difference. In addition, the winter monsoon intensity may be regulated by the North Atlantic Oscillation, the Arctic Oscillation and the Atlantic Multidecadal Oscillation, and the summer monsoon is closely related to the signal intensities of the Pacific Decadal Oscillation. PMID- 26107376 TI - Trends in anemia management practices in patients receiving hemodialysis and peritoneal dialysis: a retrospective cohort analysis. AB - BACKGROUND/AIMS: Recent changes in clinical practice guidelines and reimbursement policies may have affected the use of anemia-related medications and red blood cell (RBC) transfusions in peritoneal dialysis (PD) and hemodialysis (HD) patients. We sought to compare patterns of erythropoiesis-stimulating agents (ESA) and intravenous (IV) iron use, achieved hemoglobin levels, and RBC transfusion use in PD and HD patients. METHODS: In quarterly cohorts of prevalent dialysis patients receiving persistent therapy (>3 months), 2007-2011, with Medicare Parts A and B coverage, we assessed ESA and IV iron use and dose, RBC transfusions, and hemoglobin levels. Quarterly transfusion rates were calculated. RESULTS: Observable PD and HD patients numbered 14,958 and 221,866 in Q1/2007 and 17,842 and 256,942 in Q4/2011. Adjusted ESA use was lower in PD (71.4-80.1%) than in HD (86.9-92.0%) patients, decreasing from 80.1% (Q1/2010) to 71.4% (Q4/2011) in PD patients, and from 92.0 to 86.9% in HD patients. The mean adjusted ESA dose decreased by 67.5% in PD and 58.4% in HD patients. IV iron use tended to increase, peaking at 39.3% for PD (Q3/2011) and 80.5% for HD (Q2/2011) patients. Adjusted mean hemoglobin levels fell from 11.7 to 10.6 mg/dl in PD and from 12.0 to 10.7 mg/dl in HD ESA users; adjusted transfusion rates increased from 2.4 to 3.0 per 100 patient-months in PD and from 2.6 to 3.3 in HD patients. CONCLUSIONS: In patients receiving persistent dialysis, dose and frequency of ESA administrations decreased during the period 2007-2011. Mean hemoglobin levels decreased by more than 1 g/dl, while transfusion rates increased by approximately 25%. PMID- 26107377 TI - Brain Injury Guidelines for Small Head Injuries. PMID- 26107378 TI - Safety and Efficacy of Human Wharton's Jelly-Derived Mesenchymal Stem Cells Therapy for Retinal Degeneration. AB - PURPOSE: To investigate the safety and efficacy of subretinal injection of human Wharton's Jelly-derived mesenchymal stem cells (hWJ-MSCs) on retinal structure and function in Royal College of Surgeons (RCS) rats. METHODS: RCS rats were divided into 2 groups: hWJ-MSCs treated group (n = 8) and placebo control group (n = 8). In the treatment group, hWJ-MSCs from healthy donors were injected into the subretinal space in one eye of each rat at day 21. Control group received saline injection of the same volume. Additional 3 animals were injected with nanogold-labelled stem cells for in vivo tracking of cells localisation using a micro-computed tomography (microCT). Retinal function was assessed by electroretinography (ERG) 3 days before the injection and repeated at days 15, 30 and 70 after the injection. Eyes were collected at day 70 for histology, cellular and molecular studies. RESULTS: No retinal tumor formation was detected by histology during the study period. MicroCT scans showed that hWJ-MSCs stayed localised in the eye with no systemic migration. Transmission electron microscopy showed that nanogold-labelled cells were located within the subretinal space. Histology showed preservation of the outer nuclear layer (ONL) in the treated group but not in the control group. However, there were no significant differences in the ERG responses between the groups. Confocal microscopy showed evidence of hWJ-MSCs expressing markers for photoreceptor, Muller cells and bipolar cells. CONCLUSIONS: Subretinal injection of hWJ-MSCs delay the loss of the ONL in RCS rats. hWJ-MSCs appears to be safe and has potential to differentiate into retinal-like cells. The potential of this cell-based therapy for the treatment of retinal dystrophies warrants further studies. PMID- 26107379 TI - Intermittent Androgen Suppression: Estimating Parameters for Individual Patients Based on Initial PSA Data in Response to Androgen Deprivation Therapy. AB - When a physician decides on a treatment and its schedule for a specific patient, information gained from prior patients and experience in the past is taken into account. A more objective way to make such treatment decisions based on actual data would be useful to the clinician. Although there are many mathematical models proposed for various diseases, so far there is no mathematical method that accomplishes optimization of the treatment schedule using the information gained from past patients or "rapid learning" technology. In an attempt to use this approach, we integrate the information gained from patients previously treated with intermittent androgen suppression (IAS) with that from a current patient by first fitting the time courses of clinical data observed from the previously treated patients, then constructing the prior information of the parameter values of the mathematical model, and finally, maximizing the posterior probability for the parameters of the current patient using the prior information. Although we used data from prostate cancer patients, the proposed method is general, and thus can be applied to other diseases once an appropriate mathematical model is established for that disease. PMID- 26107381 TI - Computed Tomographic Findings and Mortality in Patients With Pneumomediastinum From Blunt Trauma. AB - IMPORTANCE: The care of most patients with pneumomediastinum (PNM) due to trauma can be managed conservatively; however, owing to aerodigestive tract injury and other associated injuries, there is a subset of patients with PNM who are at higher risk of mortality but can be difficult to identify. OBJECTIVE: To characterize computed tomographic (CT) findings associated with mortality in patients with PNM due to blunt trauma. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of medical records from January 1, 2002, to December 31, 2011, was conducted at a university-based urban trauma center. The patients evaluated were those injured by blunt trauma and found to have PNM on initial chest CT scanning. Data analysis was performed July 2, 2013, to June 18, 2014. MAIN OUTCOMES AND MEASURES: In-hospital mortality. RESULTS: During the study period, 3327 patients with blunt trauma underwent chest CT. Of these, 72 patients (2.2%) had PNM. Patients with PNM had higher Injury Severity Scores (P < .001) and chest Abbreviated Injury Scale scores (P < .001) compared with those without PNM. Pneumomediastinum was associated with higher mortality (9 [12.5%] vs 118 [3.6%] patients; P < .001) and longer mean (SD) hospital stays (11.3 [14.6] vs 5.1 [8.8] days; P < .001), intensive care unit stays (5.4 [10.2] vs 1.8 [5.7] days; P < .001), and ventilator days (1.7 [4.2] vs 0.6 [4.0] days; P < .03). We evaluated several chest CT findings that may have predictive value. Pneumomediastinum size was not associated with in-hospital mortality (P = .22). However, location of air in the posterior mediastinum was associated with increased mortality of 25% (7 of 28 patients; P = .007). Air in all mediastinal compartments was also associated with increased mortality of 40.0% (4 of 10 patients; P = .01). Presence of hemothorax along with PNM was associated with mortality of 22.2% (8 of 36 patients; P = .01). CONCLUSIONS AND RELEVANCE: Pneumomediastinum is uncommon in patients with injury from blunt trauma; however, CT findings of posterior PNM, air in all mediastinal compartments, and concurrent hemothorax are associated with increased mortality. These CT findings could be used as a triage tool to alert the trauma surgeon to a potentially lethal injury. PMID- 26107380 TI - High expression levels of BLyS/BAFF by blood dendritic cells and granulocytes are associated with B-cell dysregulation in SIV-infected rhesus macaques. AB - Dendritic cells (DCs) modulate B-cell survival and differentiation, mainly through production of growth factors such as B lymphocyte stimulator (BLyS/BAFF). In recent longitudinal studies involving HIV-1-infected individuals with different rates of disease progression, we have shown that DCs were altered in number and phenotype in the context of HIV-1 disease progression and B-cell dysregulations were associated with increased BLyS/BAFF expression in plasma and by blood myeloid DCs (mDCs) in rapid and classic progressors but not in HIV-1 elite controllers (EC). Suggesting that the extent to which HIV-1 disease progression is controlled may be linked to BLyS/BAFF expression status and the capacity to orchestrate B-cell responses. Herein, longitudinal analyses of simian immunodeficiency virus (SIV)-infected rhesus macaques also revealed increased expression of BLyS/BAFF by blood mDCs as soon as day 8 and throughout infection. Strikingly, granulocytes presented the highest BLyS/BAFF expression profile in the blood of SIV-infected macaques. BLyS/BAFF levels were also increased in plasma and correlated with viral loads. Consequently, these SIV-infected animals had plasma hyperglobulinemia and reduced blood B-cell numbers with altered population frequencies. These data underscore that BLyS/BAFF is associated with immune dysregulation in SIV-infected rhesus macaques and suggest that BLyS/BAFF is a key regulator of immune activation that is highly conserved among primates. These findings emphasize the potential importance of this SIV-infected primate model to test whether blocking excess BLyS/BAFF has an effect on the overall inflammatory burden and immune restoration. PMID- 26107382 TI - Determining a Cut-Off Point for Scores of the Breastfeeding Self-Efficacy Scale Short Form: Secondary Data Analysis of an Intervention Study in Japan. AB - BACKGROUND: Breastfeeding self-efficacy can be measured with the Breastfeeding Self-Efficacy Scale-Short Form (BSES-SF). Mothers with low BSES-SF scores stop exclusive breastfeeding prematurely, but specific interventions can prevent that undesirable outcome. Because those interventions can be expensive, often one must decide which mothers will receive them. For that purpose, a cut-off BSES-SF score would be useful, but none is available. Therefore, we aimed to assess the overall accuracy of BSES-SF scores as predictors of not practicing post-discharge exclusive breastfeeding, and to choose an appropriate cut-off score for making that prediction. METHODS: This is a secondary data analysis of an intervention study. Data from 378 women in two non-Baby-Friendly Hospitals were analyzed. Participants were women in their third trimester who were 16 years of age or older, were able to read and write Japanese, were expected to have a singleton birth, and had completed the BSES-SF before discharge. BSES-SF scores were measured before discharge. Breastfeeding status was assessed 4 weeks and 12 weeks postpartum. Receiver Operating Characteristic (ROC) curves were used to assess the predictive ability of the BSES-SF and to inform the choice of a cut-off point. RESULTS: For both of the ROC curves (4 and 12 weeks postpartum) the area under the curve was 0.74. To obtain a high sensitivity, a cut-off score of 50 was chosen. With that cut-off score the sensitivity was 79% and the specificity was 52% 4 weeks postpartum, and they were 77% and 52%, respectively, 12 weeks postpartum. CONCLUSION: In conclusion, the BSES-SF has moderate overall accuracy to distinguish women who will not practice exclusive breastfeeding after discharge from those who will. At non-Baby-Friendly hospitals in Japan, interventions to support exclusive breastfeeding might be considered for new mothers who have BSES-SF scores that are less than or equal to 50. PMID- 26107384 TI - Dramatic vapor-phase modulation of the characteristics of graphene field-effect transistors. AB - Here we report on dramatic and favorable changes to the operating characteristics in monolayer graphene field-effect transistors (FETs) exposed to vapor-phase, polar organic molecules in ambient. These changes include significant reduction of the Dirac voltage, accompanied by both an increase in electron and hole mobility, MU, and a decrease in residual carrier density, N0, to < 3 * 10(11) cm( 2). In contrast to graphene FET modulation with various liquid- and solid-phase dielectric media present in the literature, we attribute these changes to screening by polar vapor-phase molecules of fields induced by charged impurities and defects, n(imp), in or near the active layer. The magnitude of the changes produced in the graphene FET parameters scales remarkably well with the dipole moment of the delivered molecules. These effects are reversible, a unique advantage of working in the vapor phase. The changes observed upon polar molecule delivery are analogous to those produced by depositing and annealing fluoropolymer coatings on graphene that have been reported previously, and we attribute these changes to similar charge screening or neutralization phenomena. PMID- 26107383 TI - Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression. AB - Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the "stemness" marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease. PMID- 26107385 TI - Between power and powerlessness: a meta-ethnography of sources of resilience in young refugees. AB - OBJECTIVE: This article reviews available qualitative studies that report young refugees' ways of dealing with adversity to address their sources of resilience. DESIGN: We searched five electronic databases. Twenty-six empirical studies were included in the review. A meta-ethnography approach was used to synthesize these qualitative studies. RESULTS: Six sources of resilience emerged: (1) social support, (2) acculturation strategies, (3) education, (4) religion, (5) avoidance, and (6) hope. These sources indicated social as well as personal factors that confer resilience in young refugees, but most of them also had counterproductive aspects. CONCLUSION: The results, from an ecological developmental perspective, stressed the interplay between protective and risk processes in the mental health of young refugees who had resettled in Western countries, and they emphasized the variability as well as the universality of resilience-promoting processes. Further research is needed to explore the cultural shape of resilience and the long-term consequences of war and migration on young refugees. PMID- 26107386 TI - Linking Dynamic Habitat Selection with Wading Bird Foraging Distributions across Resource Gradients. AB - Species distribution models (SDM) link species occurrence with a suite of environmental predictors and provide an estimate of habitat quality when the variable set captures the biological requirements of the species. SDMs are inherently more complex when they include components of a species' ecology such as conspecific attraction and behavioral flexibility to exploit resources that vary across time and space. Wading birds are highly mobile, demonstrate flexible habitat selection, and respond quickly to changes in habitat quality; thus serving as important indicator species for wetland systems. We developed a spatio temporal, multi-SDM framework using Great Egret (Ardea alba), White Ibis (Eudocimus albus), and Wood Stork (Mycteria Americana) distributions over a decadal gradient of environmental conditions to predict species-specific abundance across space and locations used on the landscape over time. In models of temporal dynamics, species demonstrated conditional preferences for resources based on resource levels linked to differing temporal scales. Wading bird abundance was highest when prey production from optimal periods of inundation was concentrated in shallow depths. Similar responses were observed in models predicting locations used over time, accounting for spatial autocorrelation. Species clustered in response to differing habitat conditions, indicating that social attraction can co-vary with foraging strategy, water-level changes, and habitat quality. This modeling framework can be applied to evaluate the multi annual resource pulses occurring in real-time, climate change scenarios, or restorative hydrological regimes by tracking changing seasonal and annual distribution and abundance of high quality foraging patches. PMID- 26107387 TI - Correction: Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004549.]. PMID- 26107388 TI - Modeling the Origin and Possible Control of the Wealth Inequality Surge. AB - The rapid increase of wealth inequality in the past few decades is a most disturbing social and economic issue of our time. In order to control, and even reverse that surge, its origin and underlying mechanisms should be revealed. One of the challenges in studying these mechanisms is to incorporate realistic individual dynamics in the population level in a self-consistent manner. Our theoretical approach meets the challenge by using interacting multi-agent master equations to model the dynamics of wealth inequality. The model is solved using stochastic multi-agent iterated maps. Taking into account growth rate, return on capital, private savings and economic mobility, we were able to capture the historical dynamics of wealth inequality in the United States during the course of the 20th century. We show that the fraction of capital income in the national income and the fraction of private savings are the critical factors that govern the wealth inequality dynamics. In addition, we found that economic mobility plays a crucial role in wealth accumulation. Notably, we found that the major decrease in private savings since the 1980s could be associated primarily with the recent surge in wealth inequality and if nothing changes in this respect we predict further increase in wealth inequality in the future. However, the 2007-08 financial crisis brought an opportunity to restrain the wealth inequality surge by increasing private savings. If this trend continues, it may lead to prevention, and even reversing, of the ongoing inequality surge. PMID- 26107389 TI - Effect of Ethanol, Sulfur Dioxide and Glucose on the Growth of Wine Spoilage Yeasts Using Response Surface Methodology. AB - Response surface methodology (RSM) was used to study the effect of three factors, sulfur dioxide, ethanol and glucose, on the growth of wine spoilage yeast species, Zygosaccharomyces bailii, Schizosaccharomyces pombe, Saccharomycodes ludwigii and Saccharomyces cerevisiae. Seventeen central composite rotatable design (CCRD) trials were designed for each test yeast using realistic concentrations of the factors (variables) in premium red wine. Polynomial regression equations were fitted to experimental data points, and the growth inhibitory conditions of these three variables were determined. The overall results showed Sa. ludwigii as the most resistant species growing under high ethanol/free sulfur dioxide concentrations, i.e., 15% (v/v)/20 mg L-1, 14% (v/v)/32 mg L-1 and 12.5% (v/v)/40 mg L-1, whereas other yeasts did not survive under the same levels of ethanol/free sulfur dioxide concentrations. The inhibitory effect of ethanol was primarily observed during longer incubation periods, compared with sulfur dioxide, which showed an immediate effect. In some CCRD trials, Sa. ludwigii and S. cerevisiae showed growth recovery after a short death period under the exposure of 20-32 mg L-1 sulfur dioxide in the presence of 11% (v/v) or more ethanol. However, Sc. pombe and Z. bailii did not show such growth recovery under similar conditions. Up to 10 g L-1 of glucose did not prevent cell death under the sulfur dioxide or ethanol stress. This observation demonstrates that the sugar levels commonly used in wine to sweeten the mouthfeel do not increase wine susceptibility to spoilage yeasts, contrary to the anecdotal evidence. PMID- 26107390 TI - Inflammation in acute and chronic pancreatitis. AB - PURPOSE OF REVIEW: This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis. RECENT FINDINGS: Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation. SUMMARY: Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression. PMID- 26107391 TI - Urinary kidney injury molecule-1 rapid test predicts acute kidney injury in extremely low-birth-weight neonates. AB - BACKGROUND: The new urinary and serum biomarkers are discovered and are being investigated. With them we can diagnose acute kidney injury (AKI) faster and more precisely and they also have a significant role in the outcome prediction. METHODS: The study included 22 extremely low-birth-weight neonates who were hospitalized in the neonatal intensive care units. They were divided into two groups based on serum creatinine (SCr) level-with and without AKI. Detection and quantification of urinary kidney injury molecule-1 (uKIM-1) was done on the third day of life, using commercially available KIM-1 rapid test. Subsequently, measurements were repeated only in subjects who were diagnosed with AKI, at different values of SCr. RESULTS: Logistic regression analysis showed that AKI is an independent risk factor for mortality. In a group of neonates with AKI, 50% of neonates administered the KIM-1 rapid test showed positive findings. KIM-1 rapid test was positive in patients with a wide range of SCr levels (range of 78.73-385 umol/l), but all subjects had oliguria and died in the next 24 h. CONCLUSION: KIM 1 is a significant predictor of death. On the other hand, our study failed to prove that KIM-1 rapid test has any significance for early prediction of AKI. PMID- 26107392 TI - Relating plaque morphology to respiratory syncytial virus subgroup, viral load, and disease severity in children. AB - BACKGROUND: Viral culture plaque morphology in human cell lines are markers for growth capability and cytopathic effect, and have been used to assess viral fitness and select preattenuation candidates for live viral vaccines. We classified respiratory syncytial virus (RSV) plaque morphology and analyzed the relationship between plaque morphology as compared to subgroup, viral load and clinical severity of infection in infants and children. METHODS: We obtained respiratory secretions from 149 RSV-infected children. Plaque morphology and viral load was assessed within the first culture passage in HEp-2 cells. Viral load was measured by polymerase chain reaction (PCR), as was RSV subgroup. Disease severity was determined by hospitalization, length of stay, intensive care requirement, and respiratory failure. RESULTS: Plaque morphology varied between individual subjects; however, similar results were observed among viruses collected from upper and lower respiratory tracts of the same subject. Significant differences in plaque morphology were observed between RSV subgroups. No correlations were found among plaque morphology and viral load. Plaque morphology did not correlate with disease severity. CONCLUSION: Plaque morphology measures parameters that are viral-specific and independent of the human host. Morphologies vary between patients and are related to RSV subgroup. In HEp-2 cells, RSV plaque morphology appears unrelated to disease severity in RSV infected children. PMID- 26107393 TI - Surfactant protein B and A concentrations are increased in neonatal pneumonia. AB - BACKGROUND: Term newborns with pneumonia show a reduced pulmonary compliance due to multiple and ill-defined factors. Surfactant proteins' (SPs) changes could have a role in the reduced compliance but the matter is still unsettled. The aim of this study was to clarify the meaning of SPs changes during pneumonia in term newborns. METHODS: In 28 term ventilated newborns, 13 with pneumonia and 15 with no lung disease, we measured SP-B, SP-A, disaturated-phosphatidylcholine (DSPC), and total phospholipids (PL) concentrations in tracheal aspirates at intubation and close to extubation. We also measured DSPC kinetics using (U-(13)C PA)dipalmitoyl-phosphatidylcholine. RESULTS: At baseline, SP-B, expressed as % of PL, was significantly different between the groups, being 3.5-fold higher in pneumonia than controls. Conversely, SP-A did not vary between the groups. At extubation, SP-B and SP-A concentrations had decreased significantly in newborns with pneumonia, while there was no significant change in controls. DSPC t1/2 was significantly shorter in the pneumonia group (11.8 (5.5-19.8) h vs. 26.6 (19.3 63.6) h, P = 0.011). CONCLUSION: In term newborns with pneumonia, SP-B increases with respect to PL, and DSPC is turned over at a faster rate. Disease's resolution is associated with the restoration of the normal ratio between SP-B and PL. PMID- 26107394 TI - Oxidized proportion of muscle coenzyme Q10 increases with age in healthy children. AB - BACKGROUND: Coenzyme Q10 (CoQ10) is synthesized in most human tissues, with high concentration in the skeletal muscle. CoQ10 functions in the mitochondrial respiratory chain and serves as a potent liphophilic antioxidant in membranes. CoQ10 deficiency impairs mitochondrial ATP synthesis and increases oxidative stress. It has been suggested that plasma CoQ10 status is not a robust proxy for the diagnosis of CoQ10 deficiency. METHODS: We determined the concentration and redox-status of CoQ10 in plasma and muscle tissue from 140 healthy children (0.8 15.3 y) by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: There was no correlation between CoQ10 concentration or redox status between plasma and muscle tissue. Lipid-related CoQ10 plasma concentrations showed a negative correlation with age (Spearman's, P <= 0.02), but there was no significant age-related correlation for muscle concentration. In muscle tissue, we found a distinct shift in the redox status in favor of the oxidized proportion with increasing age (Spearman's, P <= 0.00001). Reference values for muscle CoQ10 concentration (40.5 +/- 12.2 pmol/mg wet tissue) and CoQ10 redox status (46.8 +/- 6.8% oxidized within total) were established for healthy children. CONCLUSION: The age-related redox shift in muscle tissue suggests changes in antioxidative defense during childhood. The reference values established here provide a necessary prerequisite for diagnosing early CoQ10 deficiency. PMID- 26107395 TI - Free reaction enthalpy profile of the Schrock cycle derived from density functional theory calculations on the full [Mo(HIPT)N3N] catalyst. AB - A series of density functional theory (DFT) calculations on the full [Mo(HIPT)N3N] catalyst are performed to obtain an energy profile of the Schrock cycle. This is a continuation of our earlier investigation of this cycle in which the bulky hexaisopropyterphenyl (HIPT) substituents of the ligand were replaced by hydrogen atoms (Angew. Chem., Int. Ed. 2005, 44, 5639). In an effort to provide a treatment that is as converged as possible from a quantum-chemical point of view, the present study now fully takes the HIPT moieties into account. Moreover, structures and energies are calculated with a near-saturated basis set, leading to models with 280 atoms and 4850 basis functions. Solvent and scalar relativistic effects have been treated using the conductor-like screening model and zeroth-order regular approximation, respectively. Free reaction enthalpies are evaluated using the PBE and B3LYP functionals. A comparison to the available experimental data reveals much better agreement with the experiment than preceding DFT treatments of the Schrock cycle. In particular, free reaction enthalpies of reduction steps and NH3/N2 exchange are now excellently reproduced. PMID- 26107396 TI - Computer-Assisted Drug Formulation Design: Novel Approach in Drug Delivery. AB - We hypothesize that, by using several chemo/bio informatics tools and statistical computational methods, we can study and then predict the behavior of several drugs in model nanoparticulate lipid and polymeric systems. Accordingly, two different matrices comprising tripalmitin, a core component of solid lipid nanoparticles (SLN), and PLGA were first modeled using molecular dynamics simulation, and then the interaction of drugs with these systems was studied by means of computing the free energy of binding using the molecular docking technique. These binding energies were hence correlated with the loadings of these drugs in the nanoparticles obtained experimentally from the available literature. The obtained relations were verified experimentally in our laboratory using curcumin as a model drug. Artificial neural networks were then used to establish the effect of the drugs' molecular descriptors on the binding energies and hence on the drug loading. The results showed that the used soft computing methods can provide an accurate method for in silico prediction of drug loading in tripalmitin-based and PLGA nanoparticulate systems. These results have the prospective of being applied to other nano drug-carrier systems, and this integrated statistical and chemo/bio informatics approach offers a new toolbox to the formulation science by proposing what we present as computer-assisted drug formulation design (CADFD). PMID- 26107397 TI - Worthless and Nutritive Nuptial Gifts: Mating Duration, Sperm Stored and Potential Female Decisions in Spiders. AB - In nuptial gift-giving species females sometimes select their potential mates based on the presence and size of the gift. But in some species, such as the Neotropical polyandrous spider Paratrechalea ornate male gifts vary in quality, from nutritive to worthless, and this male strategy can be in conflict with female nutritional benefits. In this species, males without gifts experience a reduction in mating success and duration, while males that offer worthless or genuine nutritive gifts mate with similar frequencies and durations. The female apparently controls the duration of copulation. Thus, there is scope for females to favour males offering gifts and further if these are nutritious, via post copulatory processes. We first tested whether females differentially store sperm from males that offer the highest nutritional benefits by experimentally presenting females with males that offer either nutritive or worthless gifts (uninterrupted matings). Second, we carried out another set of experiments to examine whether females can select sperm based only on gift presence. This time we interrupted matings after the first pedipalp insertion, thus matching number of insertions and mating duration for males that: offered and did not offer gift. Our results showed that the amount of sperm stored is positive related to mating duration in all groups, except in matings with worthless gifts. Gift presence itself did not affect the sperm stored by females, while they store similar number of sperm in matings with males offering either nutritive or worthless gifts. We discuss whether females prefer males with gifts regardless, if content, because it represents an attractive and/or reliable signal. Or alternatively, they prefer nutritive nuptial gifts, as they are an important source of food supply and/or signal of male donor ability. PMID- 26107398 TI - Addressing Depression and Suicide Among Physician Trainees. PMID- 26107399 TI - Correction: A Multi-country Study of the Household Willingness-to-Pay for Dengue Vaccines: Household Surveys in Vietnam, Thailand, and Colombia. PMID- 26107400 TI - Delivery of Topically Applied Calpain Inhibitory Peptide to the Posterior Segment of the Rat Eye. AB - We developed an inhibitory peptide that specifically acts against mitochondrial MU-calpain (Tat-MUCL, 23 amino acid, 2857.37 Da) and protects photoreceptors in retinal dystrophic rats. In the present study, we topically administered Tat-MUCL to the eyes of Sprague-Dawley rats for 7 days to determine both the delivery route of the peptide to the posterior segment of the eye and the kinetics after topical application in adult rats. Distribution of the peptide was determined by immunohistochemical analysis, and enzyme-linked immune-absorbent assay was used to quantify the accumulation in the retina. Peptides were prominently detected in both the anterior and posterior segments of the eye at 1 h after the final eye drop application. Immunohistochemically positive reactions were observed in the retina, optic nerve, choroid, sclera and the retrobulbar tissues, even in the posterior portion of the eye. Immunoactivities gradually diminished at 3 and 6 h after the final eye drop. Quantitative estimations of the amount of peptide in the retina were 15.3, 5.8 and 1.0 pg/MUg protein at 1, 3 and 6 h after the final instillation, respectively. Current results suggest that while the topically applied Tat-MUCL peptide reaches the posterior segment of the retina and the optic nerve, the sufficient concentration (> IC50) is maintained for at least 6 h in the rat retina. Our findings suggest that delivery of topically applied peptide to the posterior segment and optic nerve occurs through the conjunctiva, periocular connective tissue, sclera and optic nerve sheath. PMID- 26107401 TI - Predicting the Rejection of Major Seawater Ions by Spiral-Wound Nanofiltration Membranes. AB - Seawater nanofiltration (SWNF) generates a softened permeate stream and a retentate stream in which the multivalent ions accumulate, offering opportunities for practical utilization of both streams. This study presents an approach to simulation of SWNF including all major seawater ions (Na(+), Cl(-), Ca(2+), Mg(2+), and SO4(2-)) based on the Nernst-Planck equation, and uses it for permeate and retentate streams composition prediction. The number of degrees of freedom in the system was reduced by assuming a very high ionic permeability for Na(+), which only weakly affected the other parameters in the system. Two alternatives were examined to analyze the importance of concentration dependence of ion permeabilities: The assumption of constant ion permeabilities resulted in a reasonable fit with experimental data. However, for the permeate composition the overall fit was significantly improved (P < 0.0001) when the permeabilities of Ca(2+) and Mg(2+) were allowed to depend on the ratio of their total concentration to Na(+). This type of dependence emphasizes the strong interaction of divalent ions with the membrane and its effect on the membrane fixed charge through screening or charge reversal. When this effect was included, model predictions closely matched the experimental results obtained, corroborating the phenomenological approach proposed in this study. PMID- 26107402 TI - Medical diagnoses associated with substance dependence among inpatients at a large urban hospital. AB - BACKGROUND: There are limited data on reasons for hospital admission among patients dependent on substances other than alcohol. We compared primary discharge diagnoses for heroin- or cocaine-dependent patients to non-dependent patients. MATERIAL AND METHODS: We evaluated a cohort of patients admitted to a general medicine service at a public teaching hospital during July 2005-June 2008. Through bedside interviews, we identified patients who had substance-use disorders. We categorized patients by substance used, route of administration, and dependent or non-dependent use. We grouped diagnostic codes (i.e., ICD-9) using Healthcare Utilization Project categories. We excluded HIV-infected patients. RESULTS: Of 11,397 patients, 341 (3.0%) were dependent on inhalational heroin, 260 (2.3%) on non-injection cocaine, and 106 (0.9%) on injection heroin. Compared to non-dependent patients, inhalational heroin-dependent patients were over three-fold more likely to have been admitted for respiratory diseases (28% vs. 8%, p<0.01); this association was strongest for asthma exacerbation (OR=7.0; 95% CI, 4.7 to 70.4, p<0.01). Of the 225 admissions for an asthma exacerbation, 44 (19.6%) had co-occurrent heroin-dependence. The most frequent diagnostic category among cocaine-dependent patients was circulatory, which was similar to non-dependent patients (22% vs. 21%, p=0.92). DISCUSSION: There is a strong association between heroin dependence and hospital admission for an asthma exacerbation. Provision of specialized substance-use treatment for inhalational heroin users will be necessary to reduce the frequency of exacerbations and repeat hospital admissions. PMID- 26107404 TI - The role of curvature anisotropy in the ordering of spheres on an ellipsoid. AB - Non-spherical emulsion droplets can be stabilized by densely packed colloidal particles adsorbed at their surface. In order to understand the microstructure of these surface packings, the ordering of hard spheres on ellipsoidal surfaces is determined through large scale computer simulations. Defects in the packing are shown generically to occur most often in regions of strong curvature; however, the relationship between defects and curvature is nontrivial, and the distribution of defects shows secondary maxima for ellipsoids of sufficiently high aspect ratio. As with packings on spherical surfaces, additional defects beyond those required by topology are observed as chains or "scars". The transition point, however, is found to be softened by the anisotropic curvature which also partially orients the scars. A rich library of symmetric commensurate packings are identified for low particle number. We verify experimentally that ellipsoidal droplets of varying aspect ratio can be arrested by surface-adsorbed colloids. PMID- 26107405 TI - Physical Activity Level and Associated Factors Among Higher Secondary School Students in Banke, Nepal: A Cross-Sectional Study. AB - BACKGROUND: This study was carried out to assess physical activity level and identify associated factors among higher secondary school students in Banke district, Nepal. METHODS: A school-based, cross-sectional descriptive study was conducted among 405 students studying in grades 11 and 12 in 7 higher secondary schools selected randomly. A self-administered questionnaire based on the International Physical Activity Questionnaire was used to measure physical activity level. RESULTS: Only 5% of students were found to be inactive, and domestic and transport-related activities were major contributors to total physical activity score. No significant difference existed for total physical activity and domain-specific and activity-specific scores across different age groups when males and females were tested separately. Being male (P = .046), lower economic status (P = .026), living at a distance of less than 30 minutes (P = .007), walking/cycling to school (P < .001), and studying in government school (P < .001) were associated with increased physical activity scores on multivariate logistic regression analysis. CONCLUSION: Routine activities such as transport and household chores contributed greatly to total physical activity among students. This study highlights the need for physical activity promotion interventions at school addressing the associated factors and a need for greater focus on leisure-time physical activities. PMID- 26107406 TI - Rapid Endolysosomal Escape and Controlled Intracellular Trafficking of Cell Surface Mimetic Quantum-Dots-Anchored Peptides and Glycopeptides. AB - A novel strategy for the development of a high performance nanoparticules platform was established by means of cell surface mimetic quantum-dots (QDs) anchored peptides/glycopeptides, which was developed as a model system for nanoparticle-based drug delivery (NDD) vehicles with defined functions helping the specific intracellular trafficking after initial endocytosis. In this paper, we proposed a standardized protocol for the preparation of multifunctional QDs that allows for efficient cellular uptake and rapid escaping from the endolysosomal system and subsequent cytoplasmic molecular delivery to the target cellular compartment. Chemoselective ligation of the ketone-functionalized hexahistidine derivative facilitated both efficient endocytic entry and rapid endolysosomal escape of the aminooxy/phosphorylcholine self-assembled monolayer coated QDs (AO/PCSAM-QDs) to the cytosol in various cell lines such as human normal and cancer cells, while modifications of these QDs with cell-penetrating arginine-rich peptides showed poor cellular uptake and induced self-aggregation of AO/PCSAM-QDs. Combined use of hexahistidylated AO/PCSAM-QDs with serglycine like glycopeptides, namely synthetic proteoglycan initiators (PGIs), elicited the entry and controlled intracellular trafficking, Golgi localization, and also excretion of these nanoparticles, which suggested that the present approach would provide an ideal platform for the design of high performance NDD systems. PMID- 26107407 TI - White matter hyperintensities are associated with the severity of late-life somatoform disorders and executive functions. AB - BACKGROUND: Medically unexplained symptoms are often seen in the elderly. Recently, correlations between medically unexplained symptoms and somatoform disorders (SDs) have been reported. The existence of many interactive psychiatric aetiologies is known among SDs. Late-life SDs might be influenced by some aetiological factors caused by ageing processes, such as structural changes in the brain and cognitive dysfunctions. AIMS: Under such circumstances, we investigated the presence of subcortical white matter hyperintensities (WMHs), which increase with ageing, and hypothesized that subcortical WMHs are related to the disease severity of late-life SDs. Furthermore, we confirmed whether cognitive dysfunction influences this process. METHODS: To evaluate these hypotheses, we examined patients with medically unexplained symptoms who met the criteria for undifferentiated somatoform disorder and divided the patients into three groups according to the degree of subcortical WMHs: grade 0, grade 1, and grade 2. The subcortical WMHs were rated using Fazekas grading. Differences in symptom severity and cognitive functions were compared among the three groups. RESULTS: The grade 2 group had the severest symptoms. Furthermore, the grade 2 group had lower cognitive function scores than the other groups. CONCLUSIONS: The present study showed that the presence of subcortical WMHs in patients with late life SDs was a predictor of disease severity. Moreover, cognitive dysfunction appeared to play a role in the advancement of disease severity. PMID- 26107408 TI - Assessment of co-morbidity of adult separation anxiety in patients with bipolar disorder. AB - OBJECTIVE: The aim of this study was to assess the co-morbidity of adult separation anxiety in bipolar patients and evaluate its effects on the course of disorder and functionality. METHOD: A total of 70 patients who have been regularly followed in the Bipolar Disorder Unit were included in the study. The Structured Clinical Interview for DSM-IV - Axis I and Axis II disorders and demographic form were used. Separation anxiety was investigated by the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS) and the Hamilton Anxiety Rating Scale (HAM-A) was filled out by an interviewer. In addition, all patients completed the Bipolar Disorder Functioning Questionnaire (BDFQ), Separation Anxiety Symptom Inventory (SASI) and Adult Separation Anxiety Questionnaire (ASA). RESULTS: The prevalence rate of co-morbid adult separation anxiety disorder (A-SepAD) was 54% (n = 38) in our sample. Age of onset was in adulthood among 36% of patients with a diagnosis of A-SepAD and the others (64%) were childhood-onset. Co-morbidity of personality disorders was more common in bipolar patients with childhood-onset separation anxiety disorder (C-SepAD). The lifetime prevalence of co-morbidity of specific phobias and number of suicide attempts were significantly higher in the group with A-SepAD. Functionality loss due to feeling of stigmatization was higher, and total functionality as measured by the BDFQ was found to be lower in bipolar patients with A-SepAD. CONCLUSION: The results of this study have shown that 54% of bipolar patients had a diagnosis of A-SepAD. A-SepAD seems to increase the number of suicide attempts and have negative effects on functionality. A-SepAD should be assessed in regular interviews of patients with bipolar disorder. PMID- 26107409 TI - Exploratory factor analysis of a 16D Health-Related Quality of Life instrument with adolescents seeking help for early psychiatric symptoms. AB - BACKGROUND: Health-related quality of life (HRQoL) is a widely studied phenomenon in health care. This study aimed to identify which factors can be extracted from a generic 16-dimension (16D) HRQoL instrument in a sample of adolescents seeking help for early psychiatric symptoms. METHODS: Data were collected at the Helsinki University Central Hospital (HUCH), Finland, by an early intervention team. In total, 394 help-seeking adolescents (mean age 15.3 years, SD 2.14 years, 183 boys and 211 girls) completed a 16D HRQoL questionnaire. RESULTS: Exploratory factor analysis (generalized least squares method, promax rotation) identified four factors in the 16D instrument. The first factor of "psychophysiological health" included the dimensions of vitality, breathing, distress, sleeping, physical appearance, mental functioning and depression. The second factor, "physical and social health", consisted of the items discomfort and symptoms, friends and elimination. The items hearing, eating and speech were loaded on factor three, "health in somatosensory functioning". Moreover, the single item of school and hobbies was loaded on factor four, "health in functioning ability". However, the items of vision and mobility were not loaded on any factor. Since the 16D instrument was originally designed for 11-15-year-old adolescents, analysis was repeated using a subsample of this age group (n = 245). CONCLUSIONS: The results here suggest that the 16D instrument consists of four factors and forms its own latent variable structure in this specific sample of adolescents seeking help for early psychiatric symptoms. However, items such as vision, mobility and school and hobbies should be interpreted with caution as a part of the factor structure of a 16D instrument among this population. PMID- 26107410 TI - Immuno-metabolism and adipose tissue: The key role of hematopoietic stem cells. AB - The field of immunometabolism has come a long way in the past decade, leading to the emergence of a new role for white adipose tissue (WAT) that is now recognized to stand at the junction of immune and metabolic regulations. Interestingly, a crucial role of the abundant and heterogeneous immune population present in WAT has been proposed in the induction and development of metabolic diseases. Although a large body of data focused on mature immune cells, only few scattered studies are dedicated to leukocyte production, and the activity of hematopoietic stem cells (HSC) in these pathological states. Considering that blood cell production and the differentiation of HSCs and their progeny is orchestrated, in part, by complex interacting signals emanating from their microenvironment, it thus seems worth to better understand the relationships between metabolism and HSC. This review discusses the alterations of hematopoietic process described in metabolic diseases and focused on the emerging data concerning HSC present in WAT. PMID- 26107411 TI - Vascular endothelial growth factor from Trimeresurus jerdonii venom specifically binds to VEGFR-2. AB - Vascular endothelial growth factors (VEGFs) play important roles in angiogenesis. In this study, a vascular endothelial growth factor named TjsvVEGF was purified from the venom of Trimeresurus jerdonii by gel filtration, affinity, ion-exchange and high-performance liquid chromatography. TjsvVEGF was a homodimer with an apparent molecular mass of 29 kDa. The cDNA encoding TjsvVEGF was obtained by PCR. The open reading frame of the cloned TjsvVEGF was composed of 432 bp coding for a signal peptide of 24 amino acid residues and a mature protein of 119 amino acid residues. Compared with other snake venom VEGFs, the nucleotide and deduced protein sequences of the cloned TjsvVEGF were conserved. TjsvVEGF showed low heparin binding activity and strong capillary permeability increasing activity. The KD of TjsvVEGF to VEFGR-2 is 413 pM. However, the binding of TjsvVEGF to VEGFR-1 is too weak to detect. Though TjsvVEGF had high sequence identities (about 90%) with Crotalinae VEGFs, the receptor preference of TjsvVEGF was similar to Viperinae VEGFs which had lower sequence identities (about 60%) with it. TjsvVEGF might serve as a useful tool for the study of structure-function relationships of VEGFs and their receptors. PMID- 26107412 TI - Camelina sativa: An ideal platform for the metabolic engineering and field production of industrial lipids. AB - Triacylglycerols (TAG) containing modified fatty acids with functionality beyond those found in commercially grown oil seed crops can be used as feedstocks for biofuels and bio-based materials. Over the years, advances have been made in transgenically engineering the production of various modified fatty acids in the model plant Arabidopsis thaliana. However, the inability to produce large quantities of transgenic seed has limited the functional testing of the modified oil. In contrast, the emerging oil seed crop Camelina sativa possesses important agronomic traits that recommend it as an ideal production platform for biofuels and industrial feedstocks. Camelina possesses low water and fertilizer requirements and is capable of yields comparable to other oil seed crops, particularly under stress conditions. Importantly, its relatively short growing season enables it to be grown as part of a double cropping system. In addition to these valuable agronomic features, Camelina is amenable to rapid metabolic engineering. The development of a simple and effective transformation method, combined with the availability of abundant transcriptomic and genomic data, has allowed the generation of transgenic Camelina lines capable of synthesizing high levels of unusual lipids. In some cases these levels have surpassed what was achieved in Arabidopsis. Further, the ability to use Camelina as a crop production system has allowed for the large scale growth of transgenic oil seed crops, enabling subsequent physical property testing. The application of new techniques such as genome editing will further increase the suitability of Camelina as an ideal platform for the production of biofuels and bio-materials. PMID- 26107414 TI - Prenatally Diagnosed Hemophilia in a Newborn: a Case Report. AB - Hemophilia is the most common inherited coagulation disorder, and approximately one-half of patients are diagnosed as newborns. For prenatal diagnosis of hemophilia A, genetic tests are performed using chorionic villi (biopsy PCR chorionic villi sampling [CVS]) at 10 weeks' of gestation. The result in this fetus demonstrated an inversion within intron 1 in part for hemophilia A. This male infant, who was his parents' first offspring, was born after an uneventful pregnancy. An uncle suffered from hemophilia A. This report describes a newborn who was prenatally diagnosed with hemophilia A. The timely diagnosis of hemophilia in a newborn enabled the provision of adequate therapy, which led to a favorable outcome. PMID- 26107413 TI - How Lovebirds Maneuver Rapidly Using Super-Fast Head Saccades and Image Feature Stabilization. AB - Diurnal flying animals such as birds depend primarily on vision to coordinate their flight path during goal-directed flight tasks. To extract the spatial structure of the surrounding environment, birds are thought to use retinal image motion (optical flow) that is primarily induced by motion of their head. It is unclear what gaze behaviors birds perform to support visuomotor control during rapid maneuvering flight in which they continuously switch between flight modes. To analyze this, we measured the gaze behavior of rapidly turning lovebirds in a goal-directed task: take-off and fly away from a perch, turn on a dime, and fly back and land on the same perch. High-speed flight recordings revealed that rapidly turning lovebirds perform a remarkable stereotypical gaze behavior with peak saccadic head turns up to 2700 degrees per second, as fast as insects, enabled by fast neck muscles. In between saccades, gaze orientation is held constant. By comparing saccade and wingbeat phase, we find that these super-fast saccades are coordinated with the downstroke when the lateral visual field is occluded by the wings. Lovebirds thus maximize visual perception by overlying behaviors that impair vision, which helps coordinate maneuvers. Before the turn, lovebirds keep a high contrast edge in their visual midline. Similarly, before landing, the lovebirds stabilize the center of the perch in their visual midline. The perch on which the birds land swings, like a branch in the wind, and we find that retinal size of the perch is the most parsimonious visual cue to initiate landing. Our observations show that rapidly maneuvering birds use precisely timed stereotypic gaze behaviors consisting of rapid head turns and frontal feature stabilization, which facilitates optical flow based flight control. Similar gaze behaviors have been reported for visually navigating humans. This finding can inspire more effective vision-based autopilots for drones. PMID- 26107415 TI - Preparation of poly(L-lactic acid) nanofiber scaffolds with a rough surface by phase inversion using supercritical carbon dioxide. AB - Phase inversion using supercritical carbon dioxide (SC-CO2) has been widely used in the development of tissue engineering scaffolds, and particular attention has been given to obtaining desired morphology without additional post-treatments. However, the main challenge of this technique is the difficulty in generating a three-dimensional (3D) nanofiber structure with a rough surface in one step. Here, a poly(L-lactic acid) (PLLA) 3D nanofiber scaffold with a rough surface is obtained via phase inversion using SC-CO2 by carefully choosing fabrication conditions and porogens. It is found that this method can effectively modulate the structure morphology, promote the crystallization process of semicrystalline polymer, and induce the formation of rough structures on the surface of nanofibers. Meanwhile, the porogen of ammonium bicarbonate (AB) can produce a 3D structure with large pores, and porogen of menthol can improve the interconnectivity between the micropores of nanofibers. A significant increase in the fiber diameter is observed as the menthol content increases. Furthermore, the menthol may affect the mutual transition between the alpha' and alpha crystals of PLLA during the phase separation process. In addition, the results of protein adsorption, cell adhesion, and proliferation assays indicate that cells tend to have higher viability on the nanofiber scaffold. This process combines the characteristic properties of SC-CO2 and the solubility of menthol to tailor the morphology of polymeric scaffolds, which may have potential applications in tissue engineering. PMID- 26107416 TI - Differential expression of id genes and their potential regulator znf238 in zebrafish adult neural progenitor cells and neurons suggests distinct functions in adult neurogenesis. AB - Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas. Interestingly, znf238 was also detected in these regions, its expression overlapping with id2a, id3 and id4 expression. Further detailed characterization of the id-expressing cells demonstrated that (a) id1 is expressed in type 1 and type 2 neural progenitors as previously published, (b) id2a in type 1, 2 and 3 neural progenitors, (c) id3 in type 3 neural progenitors and (d) id4 in postmitotic neurons. Our data provide a detailed map of id and znf238 expression in the brain of adult zebrafish, supplying a framework for studies of id genes function during adult neurogenesis and brain regeneration in the zebrafish. PMID- 26107420 TI - Soybean oil and beef tallow in dry extruded diets for adult dogs. AB - The aim of the study was to determine the effects of two different fat sources (soybean oil (SO) and beef tallow (BT)) in dry extruded dog diets on the intake of food and metabolizable energy (ME), on faecal characteristics and apparent total tract digestibility (ATTD) of nutrients and energy. Ten adult dogs of different breeds were used in a Latin square design. Five experimental diets were designed from a basal diet. A Control diet was coated with 1% SO and four other diets were obtained by coating the basal diet with 6.5% and 13% of SO or BT. The Control, 6.5% and 13% coated diets contained approximately 8.5%, 15% and 20% fat, respectively. The dogs had similar dry matter (DM) intakes and, consequently, higher ME intakes with an increased fat content for both sources (p < 0.05). Fat digestibility was highest for Diet SO13% (p < 0.05). The ATTD of DM and organic matter was highest (p < 0.05) for Diets SO13% and BT13%. Fat coating improved the faecal score, especially for Diet BT13%. The dietary ratios of protein:fat:carbohydrate [% of ME] were close to AAFCO's estimates. For SO a higher ATTD (99.1%) and ME content (38.88 MJ/kg) was estimated than for BT (ATTD 92.9% and 36.37 MJ ME/kg). Both SO and BT can comprise up to 13% of the diet. However, SO was more susceptible to leaking from the kibbles with the coating method applied. PMID- 26107421 TI - Particles at Oil-Air Surfaces: Powdered Oil, Liquid Oil Marbles, and Oil Foam. AB - The type of material stabilized by four kinds of fluorinated particles (sericite and bentonite platelet clays and spherical zinc oxide) in air-oil mixtures has been investigated. It depends on the particle wettability and the degree of shear. Upon vigorous agitation, oil dispersions are formed in all the oils containing relatively large bentonite particles and in oils of relatively low surface tension (gammala < 26 mN m(-1)) like dodecane, 20 cS silicone, and cyclomethicone containing the other fluorinated particles. Particle-stabilized oil foams were obtained in oils having gammala > 26 mN m(-1) where the advancing air-oil-solid contact angle theta lies between ca. 90 degrees and 120 degrees . Gentle shaking, however, gives oil-in-air liquid marbles with all the oil particle systems except for cases where theta is <60 degrees . For oils of tension >24 mN m(-1) with omniphobic zinc oxide and sericite particles for which advancing theta >= 90 degrees , dry oil powders consisting of oil drops in air which do not leak oil could be made upon gentle agitation up to a critical oil:particle ratio (COPR). Above the COPR, catastrophic phase inversion of the dry oil powders to air-in-oil foams was observed. When sheared on a substrate, the dry oil powders containing at least 60 wt % of oil release the encapsulated oil, making these materials attractive formulations in the cosmetic and food industries. PMID- 26107422 TI - Dopamine-Induced Changes in Serum Erythropoietin and Creatinine Clearance Reflect Risk Factors for Progression of IgA Nephropathy. AB - INTRODUCTION: The infusion of low-dose dopamine is normally associated with an increase in creatinine clearance, thereby allowing one to assess renal functional reserve. Increased renal blood flow is also associated with a reduction in erythropoietin (EPO) levels. OBJECTIVES: We evaluated the use of dopamine infusion in subjects with IgA nephropathy to determine if these functional changes correlate with risk factors for progression and compared this to the renal biopsy findings. PATIENTS AND METHODS: Changes in creatinine clearance and EPO levels were determined in 46 non-nephrotic IgA patients with relative preserved renal function after the infusion of low dose dopamine. Control subjects (n = 15) were evaluated using similar protocols. RESULTS: Subjects with IgA nephropathy could be separated into those who showed a fall in EPO levels (n = 24) and those who showed no change or a rise in EPO levels (n = 22). Subjects showing the expected fall in EPO demonstrated a higher increase in creatinine clearance, similar to that observed in control subjects. Most importantly, subjects who showed a fall in EPO had less proteinuria, less N-acetyl-beta-D glucosaminidase excretion, lower serum uric acid, blood pressure, and less features of metabolic syndrome despite similar inflammation and fibrosis on biopsy as compared to the others. CONCLUSIONS: A decrease in EPO in response to dopamine is associated with a clinical phenotype that is less likely to develop progressive renal disease. These studies suggest that a fall in EPO in response to dopamine likely reflects preserved tubulointerstitial function that cannot be assessed by renal biopsy alone. PMID- 26107424 TI - Prediction by Low Plasma HbA1c of Mortality, Cardiac and Noncardiac Disease Risk: Modulation by Diabetic Status and Sex. AB - AIM: The aim of the study was to evaluate the predictive value of HbA(1c) for risk of overall mortality or a composite endpoint of death and nonfatal events. METHODS: Logistic regression retrospectively assessed the longitudinal association of measured HbA(1c) with outcome in 746 middle-aged adults, recruited from a tertiary health center and stratified to absence or presence of type 2 diabetes, using the recent American Diabetes Association criteria. RESULTS: A total of 70 deaths and additional incident nonfatal events in 82 cases were recorded at a median of 3.1-year follow-up. Multivariable linear regression revealed among nondiabetic individuals HbA(1c) to be significantly associated- independent of fasted glucose--inversely with triglycerides and high-density lipoprotein cholesterol, distinct from the diabetic sample. Sex and diabetes status differed in baseline HbA1c values with respect to the development of outcome. Nondiabetic men who subsequently died exhibited significantly lower HbA(1c), as did men and women with incident coronary heart disease. Similar difference was observed for incident hypothyroidism and nondiabetic subjects developing malignancy. In logistic regression analysis, adjusted for sex, age, and fasting glucose, each 0.7% (SD, 1) decrement of baseline HbA(1c) predicted the composite endpoint in the nondiabetic sample (risk estimates, 1.49%; 95% confidence interval, 1.07-2.04), but not in the diabetic sample, whereas overall mortality in the whole sample was increased (risk estimates, 1.51%; 95% confidence interval, 1.05-2.17). CONCLUSIONS: Inverse association of HbA(1c) with adverse outcomes in men and nondiabetic people indicates the involvement of HbA(1c) levels in autoimmune activation. The weaker inverse association with prevalent diabetes and in women is consistent with the operation of more pronounced confounding autoimmune processes. PMID- 26107423 TI - Red Blood Cells Store and Release Interleukin-33. AB - Interleukin-33 (IL-33) is a member of the IL-1 cytokine superfamily that potently drives production of a variety of cytokines and contributes to the pathogenesis of inflammatory diseases. The IL-33 is a nuclear protein and is released from apoptotic or necrotic cells. Serum IL-33 levels are increased in various diseases, such as atopic dermatitis, chronic hepatitis C infection, and asthma. Here, we show that red blood cells (RBCs) are one of the major sources of plasma IL-33. The IL-33 levels are significantly increased in supernatants from lysed RBCs. Plasma IL-33 levels are increased in patients during hemolysis, and plasma IL-33 levels show a positive correlation with degree of hemolysis. The IL-33 protein and messenger RNA levels were detected in the late stages of differentiation in ex vivo primary human erythroid progenitor cell cultures, suggesting that IL-33 is expressed during maturation of RBCs. Furthermore, hemoglobin depleted red cell lysates induced IL-8 expression in human epithelial cells. This effect was attenuated in IL-33 decoy receptor expressing cells and was enhanced in IL-33 receptor expressing cells. These results suggest that erythroid progenitor cells produce IL-33 and circulating RBCs represent a major source of IL-33 that is released upon hemolysis. PMID- 26107425 TI - Alkoxy substituted halogenated closo-dodecaborates as anions for ionic liquids. AB - Halogenated and alkoxylated closo-dodecaborates [B12X11OR](2-) (X = Cl, Br; R = propyl, octyl, dodecyl) have been synthesized by halogenation of the known [B12H11OH](2-) anion followed by alkylation in the superbasic medium DMSO/KOH. The obtained sodium salts were transformed by simple metathesis reactions in aqueous solution to the tetrabutylammonium ([NBu4](+)) and 1-hexyl-3 methylimidazolium ([C6mim](+)) salts. All compounds were fully characterized by heteronuclear NMR, IR and Raman spectroscopy, ESI mass spectrometry, and thermal analytical measurements. Selected anions were also structurally characterized as their [Ph4P](+) salts by single crystal X-ray diffraction. The [C6mim](+) salts are thermally stable up to more than 300 degrees C and show clear melting points. Surprisingly, the compound [C6mim]2[B12Cl11O-propyl] having the short propyl group bound to the boron cluster shows the lowest melting point (96 degrees C) of all the investigated compounds. Thus this compound is a rare member of the class of ionic liquids consisting of dianions. PMID- 26107426 TI - Crossed and uncrossed acoustic reflex growth functions in normal-hearing adults, typically developing children, and children with suspected auditory processing disorder. AB - OBJECTIVE: Previous data suggested that children with suspected auditory processing disorders (APD) often show elevated or absent acoustic reflex thresholds, especially in crossed conditions (e.g. Allen & Allan, 2014 ). This study further explored these effects by measuring acoustic reflex growth functions (ARGF). DESIGN: Crossed and uncrossed ARGF slopes were obtained by linear fits between reflex amplitudes and increases in activator level from threshold to 15 dB above it. STUDY SAMPLE: Normal-hearing adults, typically developing children and children with reported listening difficulties and suspected of having an APD, participated. RESULTS: The ARGF slopes were shallower in crossed than in uncrossed conditions for all groups but the magnitude of the effect was significantly greater in the children with suspected APD. There were no differences between the typically developing children and the adults. CONCLUSIONS: The results suggest shallower ARGFs in children with suspected APD. Given the role of the acoustic reflex in facilitating hearing speech in noise these findings may begin to shed light on physiologic explanations for some of the difficulties that are reported by children with suspected APD. PMID- 26107427 TI - The impact of tinnitus on cognitive performance in normal-hearing individuals. AB - OBJECTIVE: The aim of this study was to investigate whether the previously reported differences in cognitive performance as assessed using a Stroop paradigm between individuals with and without tinnitus is present in normal-hearing individuals. DESIGN: Participants completed audiometric evaluation, a visual Stroop test, as well as the Swedish version of the hospital anxiety and depression scale (HADS) questionnaire. In addition individuals with tinnitus participated in a short interview regarding tinnitus characteristics as well as a follow up data collection of the tinnitus questionnaire (TQ). STUDY SAMPLE: Forty individuals participated in this study. Twenty had tinnitus (tinnitus group) and 20 had not (control group). The groups were age- and sex-matched and all participants had normal hearing thresholds (20 dB HL or better). RESULTS: No differences in terms of cognitive performances were found between individuals with tinnitus compared to individuals without tinnitus. CONCLUSION: In contrast to previous studies of hearing-impaired subjects with tinnitus, the results of the present found no signs of cognitive interference in normal-hearing subjects with tinnitus when assessed using intensive short duration tasks. PMID- 26107429 TI - Correlation Between Exposure Rate and Residual Activity in Felines Undergoing 131I Thyroid Ablation Therapy. AB - Radioiodine thyroid ablation therapy is a common method for treatment of felines exhibiting hyperthyroidism. Due to the high gamma-ray emission rate of radioiodine (I), patients following treatment must be held in isolation for several days before release to prevent unnecessary dose to owners and members of the public. Dose rate measurement on the external surface of the patient of <= 20 MUSv h is maintained as the patient release criterion without regard to residual activity. However, the Texas Department of State Health Services regulatory guide recommends a release limit of 3.7 MBq to households with non-pregnant women and children over the age of 18 y, and a limit of 925 kBq to households of pregnant women and children who can be supervised. In this paper, Monte Carlo computational radiation transport techniques are employed to predict and standardize the patient isolation time at the clinic by correlating the thyroid burden and surface dose rates of felines. Measurements of patient dose rate as a function of time are used to determine the patient-specific effective half-life experimentally and to validate the model results. Results show that an average holding time of 8 to 9 d is sufficient to reduce the residual activity to 3.7 MBq levels. Additionally, contact dose rate measurements of 20 MUSv h or less correlate to residual activity levels of approximately 925 kBq. Based on the model and measurements, a protocol was developed for clinical use at Texas A&M University Veterinary Medical Teaching Hospital to allow estimation of residual activity following injection. This in turn confirms that the surface dose rates used as the release criteria follow the release limits recommended in the regulatory guide. PMID- 26107428 TI - Evaluation of Aquaporin-3 Role in Nonmelanoma Skin Cancer: An Immunohistochemical Study. AB - Aquaporin-3 (AQP3), is an aquaglyceroporin, that plays a role in cell proliferation, tumorigenesis, and cell migration. This study aimed at evaluating the possible role of AQP3 in nonmelanoma skin cancer (NMSC) pathogenesis through its immunohistochemical expression in skin biopsies of these diseases. One hundred and thirty cutaneous specimens were studied. These included 60 cases of NMSC and 40 normal skin and 30 psoriasis samples, from age- and gender-matched subjects, as a control group. AQP3 was expressed in 66.7% of basal cell carcinoma (BCC) cases and in 93.3% of squamous cell carcinoma (SCC) cases. Higher AQP3 expression (p = .01), expression percentage (p = .01), and H score (p = .04) were significantly associated with SCC compared to BCC. Normal skin and psoriasis showed significantly higher AQP3 expression (p = .001, p < .001, respectively), expression percentage (p < .001 for both), and H score values (p < .001, p = .001, respectively) compared to NMSC. Higher H score values in BCC were significantly associated with female gender (p = .02) and with nodular lesions (p > .001). Higher H score values in SCC were significantly associated with grade III tumors (p = .04) and AQP3 percentage of expression was significantly correlated with grade III tumors (r = .48, p = .009). In conclusion, AQP3 may play a role in NMSC pathogenesis. This probably occurs through aquaporin-mediated glycerol transport and ATP generation. Its downregulation, observed in the current work, is mostly a result of excessive proliferation. Further studies are needed to investigate the therapeutic effect of its inhibition in NMSC treatment. PMID- 26107430 TI - Numerical Analysis of Organ Doses Delivered During Computed Tomography Examinations Using Japanese Adult Phantoms with the WAZA-ARI Dosimetry System. AB - A dosimetry system for computed tomography (CT) examinations, named WAZA-ARI, is being developed to accurately assess radiation doses to patients in Japan. For dose calculations in WAZA-ARI, organ doses were numerically analyzed using average adult Japanese male (JM) and female (JF) phantoms with the Particle and Heavy Ion Transport code System (PHITS). Experimental studies clarified the photon energy distribution of emitted photons and dose profiles on the table for some multi-detector row CT (MDCT) devices. Numerical analyses using a source model in PHITS could specifically take into account emissions of x rays from the tube to the table with attenuation of photons through a beam-shaping filter for each MDCT device based on the experiment results. The source model was validated by measuring the CT dose index (CTDI). Numerical analyses with PHITS revealed a concordance of organ doses with body sizes of the JM and JF phantoms. The organ doses in the JM phantoms were compared with data obtained using previously developed systems. In addition, the dose calculations in WAZA-ARI were verified with previously reported results by realistic NUBAS phantoms and radiation dose measurement using a physical Japanese model (THRA1 phantom). The results imply that numerical analyses using the Japanese phantoms and specified source models can give reasonable estimates of dose for MDCT devices for typical Japanese adults. PMID- 26107431 TI - Determination of 226Ra Activity Using Gamma Spectrometry with 226Ra-222Rn Disequilibrium. AB - Radium-226 (Ra) activity is normally determined indirectly by gamma spectrometry, in particular by measuring the characteristic gamma-ray emitted from its progeny (Pb and Bi) when Ra-Rn secular equilibrium is reached. This article describes a measurement method involving the measurement of Pb ingrowth. The activity of Ra determined by this method agrees with that measured after Ra-Rn equilibrium. The method of Pb ingrowth allows rapid and sufficiently accurate determination of Ra activity without the need to wait for Ra-Rn equilibrium. PMID- 26107432 TI - Public Exposure from Indoor Radiofrequency Radiation in the City of Hebron, West Bank-Palestine. AB - This work presents the results of measured indoor exposure levels to radiofrequency (RF) radiation emitting sources in one of the major cities in the West Bank-the city of Hebron. Investigated RF emitters include FM, TV broadcasting stations, mobile telephony base stations, cordless phones [Digital Enhanced Cordless Telecommunications (DECT)], and wireless local area networks (WLAN). Measurements of power density were conducted in 343 locations representing different site categories in the city. The maximum total power density found at any location was about 2.3 * 10 W m with a corresponding exposure quotient of about 0.01. This value is well below unity, indicating compliance with the guidelines of the International Commission on Non-ionizing Radiation Protection (ICNIRP). The average total exposure from all RF sources was 0.08 * 10 W m. The relative contributions from different sources to the total exposure in terms of exposure quotient were evaluated and found to be 46% from FM radio, 26% from GSM900, 15% from DECT phones, 9% from WLAN, 3% from unknown sources, and 1% from TV broadcasting. RF sources located outdoors contribute about 73% to the population exposure indoors. PMID- 26107433 TI - Estimating Annual Individual Doses for Evacuees Returning Home to Areas Affected by the Fukushima Nuclear Accident. AB - To contribute to the reconstruction and revitalization of Fukushima Prefecture following the 2011 nuclear power disaster, annual individual doses were estimated for evacuees who will return home to Tamura City, Kawauchi Village, and Iitate Village in Fukushima. Ambient external dose rates and individual doses obtained with personal dosimeters were measured at many residential and occupational sites throughout the study areas to obtain fundamental data needed for the estimation. The measurement results indicated that the ratio of individual dose based on a personal dosimeter to the ambient external dose measurement was 0.7 with 10% uncertainty. Multiplying the ambient external dose by 0.7 may be an appropriate measure of the effective dose to an individual in the investigated area. Annual individual doses were estimated for representative lifestyles and occupations based on the ambient external dose rates at the measurement sites, taking into account the relationship between the ambient external dose and individual dose. The results were as follows: 0.6-2.3 mSv y in Tamura, 1.1-5.5 mSv y in Kawauchi, and 3.8-17 mSv y in Iitate. For all areas investigated, the estimated dose to outdoor workers was higher than that to indoor workers. Identifying ways to reduce the amount of time that an outdoor worker spends outdoors would provide an effective measure to reduce dose. PMID- 26107434 TI - Experimental Quantification of Delayed Radiation-Induced Organ Damage in Highly Irradiated Rats With Bone Marrow Protection: Effect of Radiation Dose and Organ Sensitivity. AB - The evolution of organ damage following extensive high-dose irradiation remains largely unexplored and needs further investigation. Wistar rats [with or without partial bone marrow protection (~20%)] were irradiated at lethal gamma-ray doses (12, 14, and 16 Gy) and received antibiotic support. While total-body-irradiated rats did not survive, bone marrow protection (achieved by protecting hind limbs behind a lead wall) combined with antibiotic support allowed survival of 12-Gy and 14-Gy irradiated rats for more than 3 mo, with a late phase of body weight loss and altered clinical status. Histological analysis of radiation-induced damages in visceral organs (liver, kidney, and ileum), performed 64 and 104 d after high-dose body irradiation, indicates that the extent and the evolution of damage depend on both the irradiation dose and organ. A dose-related aggravation of lesions was observed in the liver and kidney but not in the ileum. In contrast to the liver, alterations in the kidney and ileum aggravate with time, emphasizing the need to develop new efficient countermeasures to protect both the gastrointestinal tract and kidney from late-occurring radiation effects. Specifically, the complex evolution of organ damage presented in this paper offers the possibility to explore and then validate specific therapeutic windows using candidate drugs targeted to each injured visceral organ. PMID- 26107435 TI - Assessing the Effectiveness of Risk Communication for Maintenance Workers Who Deal With Induced Radioactivity Management of Medical Linear Accelerators. AB - In Japan, an amended law that mandates levels of unintended induced radioactivity has been in effect since 1 April 2012. According to the new regulation, if the concentration of induced radioactivity in affected parts is above the clearance level, the parts must be regarded as radioactive even if they weigh less than 1 kg. This regulation reform raises several new issues concerning medical linear accelerators, including how to determine the decay period for induced radioactivity before maintenance can be performed and how to identify what parts should be considered radioactive waste. The authors performed several risk communication (RC) activities aimed at improving the understanding of maintenance workers at medical accelerator manufacturers and establishing good guidelines by involving stakeholders. For this purpose, a working group was established and conducted RC activities, such as holding opinion exchange meetings between medical staff and maintenance workers and creating a booklet to answer questions from maintenance workers. To evaluate these activities, three questionnaire surveys were conducted between 2011 and 2014. According to the results of this study, the ratio of maintenance workers who accepted "The decay period is within one week" was approximately 60% at the third survey and significantly increased (P < 0.0001) during the survey period. Approximately 25% of the maintenance workers felt that not enough information was provided about the decay period, and approximately 63% thought that the information provided on the health effects of radiation was sufficient. These results suggest that the present RC was successful. PMID- 26107437 TI - Evaluating the Radiation From Accidental Exposure During a Nondestructive Testing Event. AB - Industrial radiography is a common nondestructive testing (NDT) method used in various industries. An investigation was conducted for a 1999 incident in Taiwan where two workers (Operators A and B) were accidently exposed to an unshielded Ir source while conducting industrial radiography. Operators A and B experienced acute close-range radiation exposure to a source of Ir for 3 h at a strength of 2.33 * 10 Bq. The health of mammary glands, bone marrow, thyroid glands, eyes, and genital organs of these two workers after radiation exposure was examined. Subsequently, Operator A experienced severe radiation injury, including tissue necrosis and keratinization in the fingers, chromosomal abnormalities, reduced blood cell count, diffuse hyperplasia of the thyroid gland, opaque spots in the crystalline lens, and related radiation effects. The results showed that the left index finger and thumb, eyes, and gonads of Operator A were exposed to a radiation dose of about 369-1,070, 23.1-67.4, 2.4-5.3, and 4.2-11.6 Gy, respectively. Effective dose for Operator A was estimated to range from 6.9 to 18.9 Sv. The left fingers, thumb, eyes, and gonads of Operator B were exposed to a radiation dose of 184.9-646.2, 11.8-40.7, 0.49-3.33, and 0.72-7.18 Gy, respectively, and his effective dose was between 2.5 and 11.5 Sv. This accident indicated a major flaw in the control and regulation of radiation safety for conducting NDT industrial radiography in 1999; however, similar problems still exist. Modifications of the Ionizing Radiation Protection Act in Taiwan are suggested in this study to regulate the management of NDT industries, continually educate the NDT workers in radiation safety, and enact notification provisions for medical care systems toward acute radiation exposure events. PMID- 26107436 TI - Linking Gamma-H2AX Foci and Cancer in Rat Skin Exposed to Heavy Ions and Electron Radiation. AB - This study uses acute doses of three test radiations, [Ar ions (L = 125 keVMU), Ne ions (L = 25 keVMU) and electron radiation] to examine a potential quantitative link between rat skin cancer induction and gamma-H2AX foci in rat keratinocytes exposed in vitro to radiations with comparable L values. Theory provided a testable link between cancer yield and gamma-H2AX foci yields: YCa(D,L)rat = (NF)2YAX(D,L)keratinocyte (eqn 1), where YCa(D,L) is cancers(rat) at 1.0 y, YAX(D,L) is in vitro gamma-H2AX foci(keratinocyte) , D is radiation dose, L is linear energy transfer, N is irradiated keratinocytes in vivo, and F is the error rate of end joining. An explicit expression for cancer yield was derived based on cancers arising in the ion track region in proportion to D and L (first term) and independently in proportion to D in the delta ray region in between the ion tracks (second term): YCa(D,L) = CCaLD + BCaD (eqn 1a). Parameters quantified include: CCa = 0.000589 +/- 0.000150 cancers micron[rat(kev)Gy]; BCa = 0.0088 +/- 0.0035 cancers(ratGy), F = (8.18 +/- 0.91) * 10; N = (8.8 +/- 1.2) * 10 and (NF)2 = 0.036 +/- 0.006 cancer keratinocyte(rat H2AX foci). Verification of eqns (1) and (1a) and the constancy of F support the hypothesis that end-rejoining errors play a major role in radiation carcinogenesis in rat skin. Cancer yields per rat were consistently predictable based on gamma-H2AX foci yields in keratinocytes in vitro such that 27.8 H2AXfoci(keratinocyte) predicted 1.0 cancer(rat) at 1 y. PMID- 26107438 TI - New ANSI Standard for Thyroid Phantom. PMID- 26107443 TI - An investigation of nitrile transforming enzymes in the chemo-enzymatic synthesis of the taxol sidechain. AB - Paclitaxel (taxol) is an antimicrotubule agent widely used in the treatment of cancer. Taxol is prepared in a semisynthetic route by coupling the N-benzoyl (2R,3S)-3-phenylisoserine sidechain to the baccatin III core structure. Precursors of the taxol sidechain have previously been prepared in chemoenzymatic approaches using acylases, lipases, and reductases, mostly featuring the enantioselective, enzymatic step early in the reaction pathway. Here, nitrile hydrolysing enzymes, namely nitrile hydratases and nitrilases, are investigated for the enzymatic hydrolysis of two different sidechain precursors. Both sidechain precursors, an openchain alpha-hydroxy-beta-amino nitrile and a cyanodihydrooxazole, are suitable for coupling to baccatin III directly after the enzymatic step. An extensive set of nitrilases and nitrile hydratases was screened towards their activity and selectivity in the hydrolysis of two taxol sidechain precursors and their epimers. A number of nitrilases and nitrile hydratases converted both sidechain precursors and their epimers. PMID- 26107442 TI - An immunoinformatic approach for identification of Trypanosoma cruzi HLA-A2 restricted CD8(+) T cell epitopes. AB - Chagas disease is a major neglected tropical disease caused by persistent chronic infection with the protozoan parasite Trypanosoma cruzi. An estimated 8 million people are infected with T. cruzi, however only 2 drugs are approved for treatment and no vaccines are available. Thus there is an urgent need to develop vaccines and new drugs to prevent and treat Chagas disease. In this work, we identify T cell targets relevant for human infection with T. cruzi. The trans sialidase (TS) gene family is a large family of homologous genes within the T. cruzi genome encoding over 1,400 members. There are 12 highly conserved TS gene family members which encode enzymatically active TS (functional TS; F-TS), while the remaining TS family genes are less conserved, enzymatically inactive and have been hypothesized to be involved in immune evasion (non-functional TS; NF-TS). We utilized immunoinformatic tools to identify HLA-A2-restricted CD8(+) T cell epitopes conserved within F-TS family members and NF-TS gene family members. We also utilized a whole-genome approach to identify T cell epitopes present within genes which have previously been shown to be expressed in life stages relevant for human infection (Non-TS genes). Thirty immunogenic HLA-A2-restricted CD8(+) T cell epitopes were identified using IFN-gamma ELISPOT assays after vaccination of humanized HLA-A2 transgenic mice with mature dendritic cells pulsed with F-TS, NF TS, and Non-TS peptide pools. The immunogenic HLA-A2-restricted T cell epitopes identified in this work may serve as potential components of an epitope-based T cell targeted vaccine for Chagas disease. PMID- 26107445 TI - Stratification of complexity in congenital heart surgery: comparative study of the Risk Adjustment for Congenital Heart Surgery (RACHS-1) method, Aristotle basic score and Society of Thoracic Surgeons-European Association for Cardio- Thoracic Surgery (STS-EACTS) mortality score. AB - OBJECTIVE: To determine whether stratification of complexity models in congenital heart surgery (RACHS-1, Aristotle basic score and STS-EACTS mortality score) fit to our center and determine the best method of discriminating hospital mortality. METHODS: Surgical procedures in congenital heart diseases in patients under 18 years of age were allocated to the categories proposed by the stratification of complexity methods currently available. The outcome hospital mortality was calculated for each category from the three models. Statistical analysis was performed to verify whether the categories presented different mortalities. The discriminatory ability of the models was determined by calculating the area under the ROC curve and a comparison between the curves of the three models was performed. RESULTS: 360 patients were allocated according to the three methods. There was a statistically significant difference between the mortality categories: RACHS-1 (1) - 1.3%, (2) - 11.4%, (3)-27.3%, (4) - 50 %, (P<0.001); Aristotle basic score (1) - 1.1%, (2) - 12.2%, (3) - 34%, (4) - 64.7%, (P<0.001); and STS-EACTS mortality score (1) - 5.5 %, (2) - 13.6%, (3) - 18.7%, (4) - 35.8%, (P<0.001). The three models had similar accuracy by calculating the area under the ROC curve: RACHS-1- 0.738; STS-EACTS-0.739; Aristotle- 0.766. CONCLUSION: The three models of stratification of complexity currently available in the literature are useful with different mortalities between the proposed categories with similar discriminatory capacity for hospital mortality. PMID- 26107444 TI - Simplified method for esophagus protection during radiofrequency catheter ablation of atrial fibrillation--prospective study of 704 cases. AB - INTRODUCTION: Although rare, the atrioesophageal fistula is one of the most feared complications in radiofrequency catheter ablation of atrial fibrillation due to the high risk of mortality. OBJECTIVE: This is a prospective controlled study, performed during regular radiofrequency catheter ablation of atrial fibrillation, to test whether esophageal displacement by handling the transesophageal echocardiography transducer could be used for esophageal protection. METHODS: Seven hundred and four patients (158 F/546M [22.4%/77.6%]; 52.8 +/- 14 [17-84] years old), with mean EF of 0.66 +/- 0.8 and drug-refractory atrial fibrillation were submitted to hybrid radiofrequency catheter ablation (conventional pulmonary vein isolation plus AF-Nests and background tachycardia ablation) with displacement of the esophagus as far as possible from the radiofrequency target by transesophageal echocardiography transducer handling. The esophageal luminal temperature was monitored without and with displacement in 25 patients. RESULTS: The mean esophageal displacement was 4 to 9.1cm (5.9 +/- 0.8 cm). In 680 of the 704 patients (96.6%), it was enough to allow complete and safe radiofrequency delivery (30W/40oC/irrigated catheter or 50W/60oC/8 mm catheter) without esophagus overlapping. The mean esophageal luminal temperature changes with versus without esophageal displacement were 0.11 +/- 0.13oC versus 1.1 +/- 0.4oC respectively, P<0.01. The radiofrequency had to be halted in 68% of the patients without esophageal displacement because of esophageal luminal temperature increase. There was no incidence of atrioesophageal fistula suspected or confirmed. Only two superficial bleeding caused by transesophageal echocardiography transducer insertion were observed. CONCLUSION: Mechanical esophageal displacement by transesophageal echocardiography transducer during radiofrequency catheter ablation was able to prevent a rise in esophageal luminal temperature, helping to avoid esophageal thermal lesion. In most cases, the esophageal displacement was sufficient to allow safe radiofrequency application without esophagus overlapping, being a convenient alternative in reducing the risk of atrioesophageal fistula. PMID- 26107446 TI - Study of novel coating strategy for coronary stents: simutaneous coating of VEGF and anti- CD34 antibody. AB - INTRODUCTION: Intravascular coronary stenting has been used in the treatment of coronary artery disease (CAD), with a major limitation of in-stent restenosis (ISR). The 316 stainless steel has been widely used for coronary stents. In this study, we developed a novel coating method to reduce ISR by simultaneously coating vascular endothelial growth factor (VEGF) and anti-CD34 antibody on 316L stainless steel. METHODS: Round 316L stainless steel sheets in the D-H group were polymerized with compounds generated from condensation reaction of dopamine and heparin using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and N hydroxysuccinimide (NHS). Sixteen sheets from the D-H group were further immersed into 1ug/ml VEGF165 and 3mg/ml heparin sodium one after another for 10 times, and named as the D-(H-V)10 group. Eight sheets from the D-(H-V)10 group were coated with anti-CD34 antibody and termed as the D-(H-V)10-A group. Immunofluorescence assay and ELISA were used to evaluate whether the 316L stainless steel disks were successfully coated with VEGF and anti-CD34 antibody. RESULTS: The results of immunofluorescence assay and ELISA showed that VEGF could be detected in the D-(H V)10 and D-(H-V)10-A group, suggesting the steel sheets were successfully covered with VEGF. Anti-CD34 antibody could only be observed in the D-(H-V)10-A group, which was the only group coated with CD34 antibody. Both results suggested that the 316L stainless steel sheets were successfully coated with VEGF and anti-CD34 antibody. CONCLUSION: Our study developed a method to simultaneously coat VEGF and anti-CD34 antibody to stainless metal steel. This research serves as a fundamental role for a novel coating strategy. PMID- 26107447 TI - Atrioventricular block in coronary artery bypass surgery: perioperative predictors and impact on mortality. AB - INTRODUCTION: Disturbances of the cardiac conduction system are frequent in the postoperative period of coronary artery bypass surgery. They are mostly reversible and associated with some injury of the conduction tissue, caused by the ischemic heart disease itself or by perioperative factors. OBJECTIVE: Primary: investigate the association between perioperative factors and the emergence of atrioventricular block in the postoperative period of coronary artery bypass surgery. Secondary: determine the need for temporary pacing and of a permanent pacemaker in the postoperative period of coronary artery bypass surgery and the impact on hospital stay and hospital mortality. METHODS: Analysis of a retrospective cohort of patients submitted to coronary artery bypass surgery from the database of the Postoperative Heart Surgery Unit of the Sao Lucas Hospital of the Pontifical Catholic University of Rio Grande do Sul, using the logistic regression method. RESULTS: In the period from January 1996 to December 2012, 3532 coronary artery bypass surgery were carried out. Two hundred and eighty-eight (8.15% of the total sample) patients had atrioventricular block during the postoperative period of coronary artery bypass surgery, requiring temporary pacing. Eight of those who had atrioventricular block progressed to implantation of a permanent pacemaker (0.23% of the total sample). Multivariate analysis revealed a significant association of atrioventricular block with age above 60 years (OR=2.34; CI 95% 1.75-3.12; P<0.0001), female gender (OR=1.37; CI 95% 1.06-1.77; P=0.015), chronic kidney disease (OR=2.05; CI 95% 1.49-2.81; P<0.0001), atrial fibrillation (OR=2.06; CI 95% 1.16-3.66; P=0.014), functional class III and IV of the New York Heart Association (OR=1.43; CI 95% 1.03-1.98; P=0.031), perioperative acute myocardial infarction (OR=1.70; CI 95% 1.26-2.29; P<0.0001) and with the use of the intra-aortic balloon in the postoperative period of coronary artery bypass surgery (OR=1.92; CI 95% 1.21-3.05; P=0.006). The presence of atrioventricular block resulted in a significant increase in mortality (17.9% vs. 7.3% in those who did not develop atrioventricular block) (OR=2.09; CI 95% 1.46-2.99; P<0.0001) and a longer hospital stay (12.75 days x 10.53 days for those who didn't develop atrioventricular block) (OR=1.01; CI 95% 1.00-1.02; P=0.01). CONCLUSIONS: In most cases, atrioventricular block in the postoperative period of coronary artery bypass surgery is transient and associated with several perioperative factors: age above 60 years, female sex, chronic kidney disease, atrial fibrillation, New York Heart Association functional class III or IV, perioperative acute myocardial infarction and use of an intra-aortic balloon. Its occurrence prolongs hospitalization and, above all, doubles the risk of mortality. PMID- 26107448 TI - Effect of N-acetylcysteine in hearts of rats submitted to controlled hemorrhagic shock. AB - INTRODUCTION: Pharmacological therapy is a strategy for the prevention of complications associated with ischemia and reperfusion injury that occurs after volume replacement in the treatment of hemorrhagic shock. OBJECTIVE: The aim of this study was to evaluate the effect of N-acetylcysteine associated with fluid resuscitation in cardiac injury in a rat hemorrhagic shock model. METHODS: Mice Wister male rats were randomly and subjected to controlled hemorrhagic shock for 60 min. and then, subjected to resuscitation with Ringer lactate. In a group of six animals, 150 mg/kg of N-acetylcysteine were added to fluid volume replacement. The animals were observed for 120 min and after this period, were euthanized and cardiac tissue was collected for histopathological analysis and measurement of thiobarbituric acid reactive substances and pro-and anti inflammatory interleukin. RESULTS: Cardiac tissue of the group treated with N acetylcysteine showed lower concentrations of thiobarbituric acid reactive substances (0.20 +/- 0.05 vs. 0.27 +/- 0.05, P = 0.014) and reduced histopathological damage and edema when compared to the group whose volume replacement occurred only with Ringer lactate. There was no difference in the expression of cytokines interleukin 6 (2,138.29 +/- 316.89 vs. 1,870.16 +/- 303.68, P = 0.091) and interleukin 10 (1.019,83 +/- 262,50 vs. 848.60 +/- 106.5, P = 0.169) between the treated groups. CONCLUSION: The association of N acetylcysteine on volume replacement attenuates oxidative stress in the heart, as well myocardial damage and edema, but does not modify the expression of inflammatory cytokines. PMID- 26107449 TI - Predictors of mortality in cardiac surgery: brain natriuretic peptide type B. AB - OBJECTIVE: We evaluated whether the preoperative serum concentration of brain natriuretic peptide (BNP) is a predictor of in-hospital mortality in patients that underwent cardiac surgery. METHODS: We continuously evaluated 488 patients that underwent cardiac valve surgery or coronary artery bypass grafting (CABG) between January of 2009 and July of 2012. Follow up of these patients were done prospectively for 30 days postoperatively. RESULTS: Data analysis showed that the overall mortality rate was equal to 9.6%, Receiver Operating Charactheristic (ROC) curve analysis found the optimal cut-off value of BNP equal to 382 pg/mL for overall mortality (AUC=0.73, 95% CI=0.66 to 0.81, P<0.001). Multivariate analysis showed that the value of BNP higher than 382 pg/mL (P=0.033, HR=2.05, 95% CI=1.6 to 3.98) was an independent predictor of overall mortality at 30 days postoperatively. CONCLUSION: We concluded that the preoperative serum concentration of BNP is an independent predictor of mortality in patients undergoing valve surgery or coronary artery bypass graft. PMID- 26107450 TI - A propose of pulmonary dysfunction stratification after valve surgery by physiotherapeutic assistance level. AB - OBJECTIVE: a) to propose and implement an evaluation system; b) to classify the pulmonary involvement and determine levels of physical therapy; c) to check the progress postoperatively. METHODS: Patients underwent physiotherapy assessment preoperatively, postoperatively and after 5 days of intervention. They were classified into three levels of care: level 1 - low risk of complication; Level 2 - medium risk; Level 3 - high risk. We used analysis of variance and Kruskal Wallis and analysis of variance for repeated measures or Friedman. Chi-square test or Fisher for proportions. We considered statistical significance level P<0.05. RESULTS: We studied 199 patients, 156 classified within level 1, 32 at level 2 and 11 at level 3. Thoracoabdominal motion and auscultation changed significantly postoperatively, persisting at levels 2 and 3 (P<0.05). Oxygenation and respiratory rate changed at levels 2 and 3 postoperatively (P<0.05) with recovery at the end. Significant decrease in lung volumes occurred in three levels (P<0.05) with partial recovery at level 1, lung collapse occurred at all levels, with recovery by 56% at level 1, 47% at level 2, 27% at level 3. CONCLUSION: The proposed assessment identified valve surgery patients who require differentiated physical therapy. Level 1 patients had rapid recovery, while the level 2 showed significant changes with functional gains at the end. Level 3 patients, more committed and prolonged recovery, should receive greater assistance. PMID- 26107451 TI - Factors associated with moderate or severe left atrioventricular valve regurgitation within 30 days of repair of incomplete atrioventricular septal defect. AB - INTRODUCTION: Left atrioventricular valve regurgitation is the most concerning residual lesion after surgical correction of atrioventricular septal defect. OBJECTIVE: To determine factors associated with moderate or greater left atrioventricular valve regurgitation within 30 days of surgical repair of incomplete atrioventricular septal defect. METHODS: We assessed the results of 51 consecutive patients 14 years-old and younger presenting with incomplete atrioventricular septal defect that were operated on at our practice between 2002 and 2010. The following variables were considered: age, weight, absence of Down syndrome, grade of preoperative left atrioventricular valve regurgitation, abnormalities on the left atrioventricular valve and the use of annuloplasty. The median age was 4.1 years; the median weight was 13.4 Kg; 37.2% had Down syndrome. At the time of preoperative evaluation, there were 23 cases with moderate or greater left atrioventricular valve regurgitation (45.1%). Abnormalities on the left atrioventricular valve were found in 17.6%; annuloplasty was performed in 21.6%. RESULTS: At the time of postoperative evaluation, there were 12 cases with moderate or greater left atrioventricular valve regurgitation (23.5%). The variation between pre- and postoperative grades of left atrioventricular valve regurgitation of patients with atrioventricular valve malformation did not reach significance (P=0.26), unlike patients without such abnormalities (P=0.016). During univariate analysis, only absence of Down syndrome was statistically significant (P=0.02). However, after a multivariate analysis, none of the factors reached significance. CONCLUSION: None of the factors studied was determinant of a moderate or greater left atrioventricular valve regurgitation within the first 30 days of repair of incomplete atrioventricular septal defect in the sample. Patients without abnormalities on the left atrioventricular valve benefit more of the operation. PMID- 26107452 TI - Surgical treatment of complex aneurysms and thoracic aortic dissections with the Frozen Elephant Trunk technique. AB - OBJECTIVE: Report initial experience with the Frozen Elephant Trunk technique. METHODS: From July 2009 to October 2013, Frozen Elephant Trunk technique was performed in 21 patients (66% male, mean age 56 +/- 11 years). They had type A aortic dissection (acute 9.6%, chronic 57.3%), type B (14.3%, all chronic) and complex aneurysms (19%). It was 9.5% of reoperations and 38% of associated procedures (25.3% miocardial revascularization, 25.3% replacement of aortic valve and 49.4% aortic valved graft). Aortic remodeling was evaluated comparing preoperative and most recent computed tomography scans. One hundred per cent of complete follow-up, mean time of 28 months. RESULTS: In-hospital mortality of 14.2%, being 50% in acute type A aortic dissection, 8.3% in chronic type A aortic dissection, 33.3% in chronic type B aortic dissection and 0% in complex aneurysms. Mean times of cardiopulmonary bypass (152 +/- 24 min), myocardial ischemia (115 +/- 31 min) and selective cerebral perfusion (60 +/- 15 min). Main complications were bleeding (14.2%), spinal cord injury (9.5%), stroke (4.7%), prolonged mechanical ventilation (4.7%) and acute renal failure (4.7%). The need for second-stage operation was 19%. False-lumen thrombosis was obtained in 80%. CONCLUSION: Frozen Elephant Trunk is a feasible technique and should be considered. The severity of the underlying disease justifies high mortality rates. The learning curve is a reality. This approach allows treatment of more than two segments at once. Nonetheless, if a second stage is made necessary, it is facilitated. PMID- 26107453 TI - Analysis of immunostaining and western blotting of endothelin 1 and its receptors in mitral stenosis. AB - INTRODUCTION: Rheumatic Fever represents a serious public health problem in developing countries, with thousands of new cases each year. It is an autoimmune disease, which occurs in response to infection by streptococcus A. OBJECTIVE: The aim of this study was to evaluate the immunolabeling and protein expression for endothelin-1 and 3 (ET-1, ET-3) and its receptors (ETA, ETB) in rheumatic mitral valves. METHODS: Immunohistochemistry was used to identify ET-1/ET-3 and ETA/ETB receptors in rheumatic and control mitral valves. Quantitative analysis of immunostaining for ET-1/ET-3 and ETA/ETB receptors was performed. In addition, western blot analysis was carried out to assess protein levels in tissue samples. RESULTS: ET-1 and ETA receptor immunostaining predominated in stenotic valves, mainly associated with fibrotic regions, inflammatory areas and neovascularization. Quantitative analysis showed that the average area with positive expression of ET-1 was 18.21 +/- 14.96%. For ETA and ETB, the mean expressed areas were respectively 15.06 +/- 13.13% and 9.20 +/- 11.09%. ET-3 did not have a significant expression. The correlation between the expression of both endothelin receptors were strongly positive (R = 0.74, P = 0.02), but the correlation between ET-1 and its receptor were negative for both ETA (R = -0.37, P = 0.25), and ETB (R = -0.14, P = 0.39). This data was supported by western blot analysis. CONCLUSION: The strong correlation between ET-1 and its receptors suggests that both play a role in the pathophysiology of rheumatic mitral valve stenosis and may potentially act as biomarkers of this disease. PMID- 26107454 TI - Epidemiology of congenital heart disease in Brazil. AB - INTRODUCTION: Congenital heart disease is an abnormality in the structure or cardiocirculatory function, occurring from birth, even if diagnosed later. It can result in intrauterine death in childhood or in adulthood. Accounted for 6% of infant deaths in Brazil in 2007. OBJECTIVE: To estimate underreporting in the prevalence of congenital heart disease in Brazil and its subtypes. METHODS: The calculations of prevalence were performed by applying coefficients, giving them function rates for calculations of health problems. The study makes an approach between the literature and the governmental registries. It was adopted an estimate of 9: 1000 births and prevalence rates for subtypes applied to births of 2010. Estimates of births with congenital heart disease were compared with the reports to the Ministry of Health and were studied by descriptive methods with the use of rates and coefficients represented in tables. RESULTS: The incidence in Brazil is 25,757 new cases/year, distributed in: North 2,758; Northeast 7,570; Southeast 10,112; South 3,329; and Midwest 1,987. In 2010, were reported to System of Live Birth Information of Ministry of Health 1,377 cases of babies with congenital heart disease, representing 5.3% of the estimated for Brazil. In the same period, the most common subtypes were: ventricular septal defect (7,498); atrial septal defect (4,693); persistent ductus arteriosus (2,490); pulmonary stenosis (1,431); tetralogy of Fallot (973); coarctation of the aorta (973); transposition of the great arteries (887); and aortic stenosis 630. The prevalence of congenital heart disease, for the year of 2009, was 675,495 children and adolescents and 552,092 adults. CONCLUSION: In Brazil, there is underreporting in the prevalence of congenital heart disease, signaling the need for adjustments in the methodology of registration. PMID- 26107456 TI - Cardiopulmonary bypass: development of John Gibbon's heart-lung machine. AB - OBJECTIVE: To provide a brief review of the development of cardiopulmonary bypass. METHODS: A review of the literature on the development of extracorporeal circulation techniques, their essential role in cardiovascular surgery, and the complications associated with their use, including hemolysis and inflammation. RESULTS: The advancement of extracorporeal circulation techniques has played an essential role in minimizing the complications of cardiopulmonary bypass, which can range from various degrees of tissue injury to multiple organ dysfunction syndrome. Investigators have long researched the ways in which cardiopulmonary bypass may insult the human body. Potential solutions arose and laid the groundwork for development of safer postoperative care strategies. CONCLUSION: Steady progress has been made in cardiopulmonary bypass in the decades since it was first conceived of by Gibbon. Despite the constant evolution of cardiopulmonary bypass techniques and attempts to minimize their complications, it is still essential that clinicians respect the particularities of each patient's physiological function. PMID- 26107457 TI - Endnote Web tutorial for BJCVS/RBCCV. AB - At present, many useful tools for reference management are available for use. They can be either off-line softwares or accessible Websites to all users in the internet. Their target is to facilitate the production of scientific text. But, to accomplish that, the featured bibliographic style should be effectively inserted, and the program has to be free. Here in this tutorial, we present Endnote Web(r), a bibliographic reference management program comprising these two requirements: it contains the Brazilian Journal of Cardiovascular Surgery reference format and its use is free for charge after sign-in in IP registered terminal in Web of Science(r). PMID- 26107455 TI - Stroke of a cardiac myxoma origin. AB - OBJECTIVE: The clinical features of cardiac myxoma stroke have not been sufficiently described. Debates remain concerning the options and timing of treatment and the clinical outcomes are unknown. This article aims to highlight the pertinent aspects of this rare condition. METHODS: Data source of the present study came from a comprehensive literature collection of cardiac myxoma stroke in PubMed, Google search engine and Highwire Press for the year range 2000-2014. RESULTS: Young adults, female predominance, single cerebral vessel (mostly the middle cerebral artery), multiple territory involvements and solitary left atrial myxoma constituted the outstanding characteristics of this patient setting. The most common affected cerebral vessel (the middle cerebral artery) and areas (the basal ganglion, cerebellum and parietal and temporal regions) corresponded well to the common manifestations of this patient setting, such as conscious alteration, ataxia, hemiparesis and hemiplegia, aphasia and dysarthria. Initial computed tomography scan carried a higher false negative rate for the diagnosis of cerebral infarction than magnetic resonance imaging did. A delayed surgical resection of cardiac myxoma was associated with an increased risk of potential consequences in particular otherwise arterial embolism. The mortality rate of this patient population was 15.3%. CONCLUSION: Cardiac myxoma stroke is rare. Often does it affect young females. For an improved diagnostic accuracy, magnetic resonance imaging of the brain and echocardiography are imperative for young stroke patients in identifying the cerebral infarct and determining the stroke of a cardiac origin. Immediate thrombolytic therapy may completely resolve the cerebral stroke and improve the neurologic function of the patients. An early surgical resection of cardiac myxoma is recommended in patients with not large territory cerebral infarct. PMID- 26107458 TI - Bibliometric indexes, databases and impact factors in cardiology. AB - Bibliometry is a quantitative statistical technique to measure levels of production and dissemination of knowledge, as well as a useful tool to track the development of an scientific area. The valuation of production required for recognition of researchers and magazines is accomplished through tools called bibliometric indexes, divided into quality indicators and scientific impact. Initially developed for monographs of statistical measures especially in libraries, today bibliometrics is mainly used to evaluate productivity of authors and citation repercussion. However, these tools have limitations and sometimes provoke controversies about indiscriminate application, leading to the development of newer indexes. It is important to know the most common search indexes and use it properly even acknowledging its limitations as it has a direct impact in their daily practice, reputation and funds achievement. PMID- 26107459 TI - Andreas Vesalius 500 years--A Renaissance that revolutionized cardiovascular knowledge. AB - The history of medicine and cardiology is marked by some geniuses who dared in thinking, research, teaching and transmitting scientific knowledge, and the Italian Andreas Vesalius one of these brilliant masters. His main scientific work "De Humani Corporis Fabrica" is not only a landmark study of human anatomy but also an artistic work of high aesthetic quality published in 1543. In the year 2014 we celebrated 500 years since the birth of the brilliant professor of Padua University, who with his courage and sense of observation changed the understanding of cardiovascular anatomy and founded a school to date in innovative education and research of anatomy. By identifying "the anatomical errors" present in Galen's book and speech, he challenged the dogmas of the Catholic Church, the academic world and the doctors of his time. However, the accuracy of his findings and his innovative way to disseminate them among his students and colleagues was essential so that his contributions are considered by many the landmark of modern medicine. His death is still surrounded by mysteries having different hypotheses, but a certainty, suffered sanctions of the Catholic Church for the spread of their ideas. The cardiologists, cardiovascular surgeons, interventional cardiologists, electrophysiologists and cardiovascular imaginologists must know the legacy of genius Andreas Vesalius that changed the paradigm of human anatomy. PMID- 26107461 TI - Prognostic prediction of troponins in cardiac myxoma: case study with literature review. AB - OBJECTIVE: It was supposed that troponins in cardiac myxoma patients might be in a same fashion as in the conditions without myocardial injury. In order to verify this hypothesis, troponins in cardiac myxoma patients were discussed by presenting a comprehensive retrieval of the literature with incorporating the information of a recent patient. METHODS: Postoperative detections of troponin I, creatine kinase isoenzyme MB (CK-MB) and N-terminal pro-B-type natriuretic peptide revealed elevated troponin I and CK-MB and normal N-terminal pro-B-type natriuretic peptide. Postoperative troponin I and CK-MB shared a same trend, reaching a peak value at postoperative hour 2, gradually decreased on postoperative day 1, and reached a plateau on postoperative days 7 and 13. A significant correlation could be noted between the postoperative values of the two indicators (Y = 0.0714X + 0.6425, r2 = 0.9111, r=0.9545, P=0.0116). No significant linear correlation between troponin I and N-terminal pro-B-type natriuretic peptide were found. Literature review of troponins in cardiac myxoma patients revealed the uncomplicated patients had a normal or only slightly elevated troponin before open heart surgery. However, the complicated patients (with cerebral or cardiac events) showed a normal preoperative troponin in 3 (23.1%) and an elevated troponin in 10 (76.9%) patients (chi2 = 7.54, P = 0.0169, Fisher's exact test). The overall quantitative result of troponin I was 2.45 +/- 2.53 ug/L, and that of troponin T was 3.10 +/- 4.29 mg/L, respectively. CONCLUSION: Troponins are not necessarily elevated in patients with a cardiac myxoma without coronary syndrome. By contrast, patients with a cardiac myxoma with an elevated troponin may herald the presence of an associated coronary event. An old cerebral infarct does not necessarily cause an elevation of troponin or B-type natriuretic peptide, or new neurological events, but might lead to a delayed awakening. PMID- 26107462 TI - Geraldo Verginelli, the search for elegance and perfectionism in cardiovascular surgery. PMID- 26107460 TI - Effects of ischemia and omeprazole preconditioning on functional recovery of isolated rat heart. AB - OBJECTIVE: The aim of this study was to compare protective effects of ischemic and potential protective effects of pharmacological preconditioning with omeprazole on isolated rat heart subjected to ischemia/reperfusion. METHODS: The hearts of male Wistar albino rats were excised and perfused on a Langendorff apparatus. In control group (CG) after stabilization period, hearts were subjected to global ischemia (perfusion was totally stopped) for 20 minutes and 30 minutes of reperfusion. Hearts of group II (IPC) were submitted to ischemic preconditioning lasting 5 minutes before 20 minutes of ischemia and 30 minutes of reperfusion. In third group (OPC) hearts first underwent preconditioning lasting 5 minutes with 100 MUM omeprazole, and then submitted 20 minutes of ischemia and 30 minutes of reperfusion. RESULTS: Administration of omeprazole before ischemia induction had protective effect on myocardium function recovery especially regarding to values of systolic left ventricular pressure and dp/dt max. Also our findings are that values of coronary flow did not change between OPC and IPC groups in last point of reperfusion. CONCLUSION: Based on our results it seems that ischemic preconditioning could be used as first window of protection after ischemic injury especially because all investigated parameters showed continuous trend of recovery of myocardial function. On the other hand, preconditioning with omeprazole induced sudden trend of recovery with positive myocardium protection, although less effective than results obtained with ischemic preconditioning not withstand, we must consider that omeprazole may be used in many clinical circumstances where direct coronary clamping for ischemic preconditioning is not possible. PMID- 26107463 TI - ERRATUM. PMID- 26107465 TI - Clinical value of BNP as an independent predictor of mortality following heart surgery. PMID- 26107466 TI - Exploring Second-Order Nonlinear Optical Properties and Switching Ability of a Series of Dithienylethene-Containing, Cyclometalated Platinum Complexes: A Theoretical Investigation. AB - The second-order nonlinear optical (NLO) properties of a series of dithienylethene- (DTE-) containing Pt(II) complexes have been investigated by density functional theory calculations. The first hyperpolarizabilities beta of studied systems can be greatly enhanced by simple ligand substitutions. Because of the nature of DTE units, the beta values also can be varied by the use of lights in the studied systems. The highest beta difference between photoisomers can over 1000 * 10(-30) esu, with the contrast around five times. Thus, the studied systems can act as effective photoswitchable second-order NLO materials. The time-dependent density functional theory calculations revealed that the charge transfer patterns of studied systems have special characters compared to other reported DTE-containing NLO switched chromogens, the DTE units mainly act as electron-donors in studied systems, and the variation of beta can be viewed as alternation of donor abilities of DTE units; thus, our work also proposed a new mechanism for designing photoswitched NLO multifunctional materials. PMID- 26107467 TI - Modeling the Health and Economic Burden of Hepatitis C Virus in Switzerland. AB - BACKGROUND: Chronic hepatitis C virus infection is a major cause of liver disease in Switzerland and carries a significant cost burden. Currently, only conservative strategies are in place to mitigate the burden of hepatitis C in Switzerland. This study expands on previously described modeling efforts to explore the impact of: no treatment, and treatment to reduce HCC and mortality. Furthermore, the costs associated with untreated HCV were modeled. METHODS: Hepatitis C disease progression and mortality were modeled. Baseline historical assumptions were collected from the literature and expert interviews and strategies were developed to show the impact of different levels of intervention (improved drug cure rates, treatment and diagnosis) until 2030. RESULTS: Under the historical standard of care, the number of advanced stage cases was projected to increase until 2030, at which point the annual economic burden of untreated viremic infections was projected to reach ?96.8 (95% Uncertainty Interval: ?36 - ?232) million. Scenarios to reduce HCV liver-related mortality by 90% by 2030 required treatment of 4,190 >=F2 or 3,200 >=F3 patients annually by 2018 using antivirals with a 95% efficacy rate. Delaying the implementation of these scenarios by 2 or 5 years reduced the impact on mortality to 75% and 57%, respectively. CONCLUSIONS: With today's treatment efficacy and uptake rates, hepatitis C disease burden is expected to increase through 2030. A substantial reduction in disease burden can be achieved by means of both higher efficacy drugs and increased treatment uptake. However, these efforts cannot be undertaken without a simultaneous effort to diagnose more infections. PMID- 26107469 TI - Keratoprostheses-The Challenge. PMID- 26107468 TI - Carbon Nanotube Nanocomposites with Highly Enhanced Strength and Conductivity for Flexible Electric Circuits. AB - Carbon nanotubes (CNTs) have an important role in nanotechnology due to their unique properties, retaining the inherent material flexibility, superior strength, and electrical conductivity, unless the bottleneck of CNTs persists and the aggregated structure is overcome. Here, we report on the highly enhanced mechanical and electrical properties of the CNT-chitosan nanocomposites through homogeneous dispersion of CNTs into chitosan solution using a high-pressure homogenizer. The optimal condition is a 50% (w/w) chitosan-CNT film, providing about 7 nm thickness of homogeneous chitosan layer on CNTs, a good tensile strength of 51 MPa, high electrical conductivity under 16 Omega/sq, and a stable bending and folding performance. This CNT-chitosan nanocomposite with highly enhanced properties is an amenable material to fabricate structures of various shapes such as films, sensors, and circuits and also enables a simple and cost effective approach to improve the performance of a device that presents the first flexible and soft electric circuits yet reported using only CNT-chitosan as the conductor. PMID- 26107470 TI - APAO's Commitment to Ophthalmic Education. AB - The Asia-Pacific Academy of Ophthalmology (APAO) is a supranational organization set up in 1960 with the aims to advance the science and art of ophthalmology and eliminate preventable blindness in the Asia-Pacific region through teaching, research, and service. Being the major driving force of ophthalmologic development in the region, the APAO is dedicated to providing education opportunities to ophthalmologists and visual scientists in the region and beyond. Since its inception in 1960, ophthalmic education has topped the APAO's priority list. Accordingly, the APAO organizes an annual congress, organizes scientific meetings and conferences, publishes its official journal and newspaper, recognizes ophthalmologists' achievements, and offers training and learning opportunities to young and aspiring ophthalmologists. This perspective reviews efforts the APAO has made in advancing ophthalmic education and its future plans to further expand the scopes of its service to help push back the frontiers of knowledge. PMID- 26107471 TI - Childhood Vascular Risk Factors and Retinal Vessel Caliber. AB - PURPOSE: Variations in retinal vessel caliber have been associated with risk of ocular and systemic vascular diseases in adults. In this study, we examined the relationships between childhood vascular risk factors and retinal vessel caliber in young healthy adolescents. DESIGN: This was a cross-sectional study of 1225 adolescents recruited from 3 community-based schools in Singapore. METHODS: Blood pressure and anthropometry measurements were obtained through standardized examinations. Birth weight was ascertained from health records completed by medical personnel soon after birth. Retinal vessel caliber was measured from retinal photographs using a semiautomated computer-based program following a validated standardized protocol. RESULTS: After adjusting for age, sex, and other relevant factors, each SD increase in blood pressure levels (systolic or diastolic) was associated with narrower arteriolar caliber (1.61 MUm; P < 0.001); each SD increase in body mass index was associated with narrower arteriolar caliber (1.49 MUm; P < 0.001) and wider venular caliber (2.68 MUm; P < 0.001), and each SD decrease in birth weight was associated with narrower arteriolar caliber (1.31 MUm; P = 0.001). CONCLUSIONS: Young adolescents with elevated blood pressure, obesity, or low birth weight have changes in retinal vessel caliber that are associated with ocular and systemic vascular diseases in adulthood. These findings provide evidence of possible adverse effects of childhood vascular risk factors on the retinal microvasculature early in life. PMID- 26107472 TI - Eye Popping Disease: Common Characteristics and Management of Spontaneous Globe Subluxation. AB - PURPOSE: The objective of this study was to describe the clinical features, predisposing factors, and management of 8 new cases of spontaneous globe subluxation (SGS) and provide a review of the relevant literature. DESIGN: Patient demographics, clinical presentations, investigations, management, complications, and outcomes were measured. METHODS: This was a retrospective, case-note analysis of 8 patients with SGS and a major review of the English language literature. RESULTS: Eight new cases of spontaneous globe subluxation were identified with varying clinical manifestations and treatments. Literature review has shown less than 50 cases. Space-occupying lesions such as thyroid eye disease, shallow orbits, and floppy eyelids were major contributors to predisposition to SGS. CONCLUSIONS: Orbital congestion, shallow orbits, and floppy eyelids can all play a role in predisposing patients to SGS. Successful surgical management of SGS, when required, should be tailored to the individual patient profile for best results. PMID- 26107473 TI - Outcome of Boston Keratoprosthesis in a Developing Country-Importance of Patient Selection, Education, and Perioperative Care: The Indian Experience. AB - PURPOSE: We aim to analyze the results of Boston type 1 keratoprosthesis from the Indian subcontinent, with particular emphasis on patient education and perioperative care. DESIGN: Retrospective interventional case series. METHODS: This was a retrospective study of patients operated on for Boston type 1 keratoprosthesis between January 2008 and April 2011. RESULTS: Of 20 patients who underwent surgery, the indications included silicone oil-induced keratopathy (8 eyes; 40%), chemical injury (7 eyes; 35%), repeated graft failures (3 eyes, 15%), and 2 pediatric eyes (10%)-1 sclerocornea and 1 congenital anterior staphyloma. The mean follow-up was 21.8 months ranging from 6 to 45 months. Best corrected postoperative visual acuity was noted to be greater than 20/200 in 16 (80%) of 20 eyes. Anatomic integrity was maintained in 18 eyes (90%). Repeated corneal melt necessitated removal of the prosthesis with corneal transplant in 2 eyes. There was no infection or endophthalmitis in any of the 20 eyes. CONCLUSIONS: The good anatomic and functional results, with no postoperative infection in our experience with Boston keratoprosthesis over a 3-year period, are encouraging. Strict inclusion criteria and ensuring good patient compliance are important factors in determining good results with a low risk of infection in a tropical developing country. PMID- 26107474 TI - The Effects of Fixed Combination of Bimatoprost-Timolol and Travoprost-Timolol on Intraocular Pressure in Patients With Primary Open-Angle Glaucoma or Ocular Hypertension, Previously on Nonfixed Combination of Latanoprost and Timolol. AB - PURPOSE: To compare the effects of fixed combination of bimatoprost-timolol and travoprost-timolol on intraocular pressure (IOP) in patients with primary open angle glaucoma or ocular hypertension. DESIGN: This was a prospective, randomized, observer-masked, crossover parallel comparison trial. METHODS: Forty one patients with primary open-angle glaucoma or ocular hypertension on nonfixed combination of latanoprost and timolol with IOP of 21 mm Hg or less were randomized to either bimatoprost-timolol or travoprost-timolol fixed combinations for 8-week treatment period. Intraocular pressure was measured at 8 AM, 12 PM, 4 PM, and 8 PM at the baseline and at the end point. Conjunctiva hyperemia and superficial punctate keratopathy after treatment with each fixed combination therapy were assessed and compared with the baseline. Patients were then switched to the opposite drug without a medication-free period for another 8-week, and diurnal IOP measurement was repeated. RESULTS: Bimatoprost-timolol fixed combination reduced the baseline mean diurnal IOP statistically significantly from 17.3 mm Hg [95% confidence interval (CI), 16.8-17.7 mm Hg] to 16.4 mm Hg (95% CI, 15.9-17.0 mm Hg) (P = 0.036). Travoprost-timolol fixed combination lowered the mean diurnal IOP to 17.1 mm Hg (95% CI, 16.5-17.7 mm Hg), but it was not significant. Direct comparison between the 2 fixed combinations showed no significant difference. Both fixed combinations had no significant effect on conjunctiva hyperemia. Interestingly, patients on travoprost-timolol fixed combination had significantly less superficial punctuate keratopathy (P = 0.012). CONCLUSIONS: Both fixed combination of bimatoprost-timolol and travoprost-timolol had no significantly different ocular hypotensive effect. However, bimatoprost timolol fixed combination produced additional IOP lowering in patients previously treated with nonfixed combination of latanoprost and timolol. PMID- 26107475 TI - Correlation Between Axial Length and Anterior Chamber Depth in Normal Eyes, Long Eyes, and Extremely Long Eyes. AB - PURPOSE: The objective of this study was to investigate the correlation between axial length (AL) and anterior chamber depth (ACD) in normal to long eyes and in extremely long eyes. DESIGN: This was an observational cross-sectional study in a single-center, private hospital. METHODS: Axial length and ACD data were retrieved from the intraocular lens (IOL) Master database of patients who presented for IOL or phakic lens implantation. Only left eyes were included. The correlation between AL and ACD was tested with Pearson correlation coefficient in all eyes, normal to long eyes (AL < 27.5 mm), and extremely long eyes (AL >= 27.5 mm). P < 0.01 was statistically significant. RESULTS: The cohort was composed of 1184 eyes of 1184 Chinese patients. The mean age was 65.8 +/- 13.3 years (range, 19-98 years). The mean AL and ACD were 24.73 +/- 2.48 mm (range, 20.51-36.20 mm) and 3.09 +/- 0.44 mm (range, 1.95-4.68 mm), respectively. Pearson correlation coefficients in all eyes, normal to long eyes (1026 eyes, 87%), and extremely long eyes (158 eyes, 13%) were 0.56 (P < 0.001), 0.59 (P < 0.001), and -0.15 (P = 0.67), respectively. CONCLUSIONS: There was a statistically significant positive correlation between AL and ACD in normal and long eyes but not in extremely long eyes. No correlation between AL and ACD in extremely long eyes requires newer generation IOL formulas (ACD included) to increase the accuracy of IOL implantation. PMID- 26107476 TI - Pars Plana Vitrectomy With or Without Silicone Oil Endotamponade in Surgical Management of Endophthalmitis. AB - PURPOSE: To compare outcomes of pars plana vitrectomy (PPV) with and without silicone oil injection (SOI) in surgical management of endophthalmitis. DESIGN: This was a prospective, randomized, interventional, comparative study. METHODS: This is a prospective, randomized, interventional, comparative study comprising 129 eyes with endophthalmitis (postsurgical and traumatic) that underwent PPV. Group 1 (n = 65) eyes, which underwent vitrectomy alone, were compared with group 2 (n = 64) eyes, in whom complete PPV with SOI was done for visual and anatomical outcomes and additional subsequent interventions. RESULTS: Mean best corrected visual acuity improvement was 0.867 +/- 1.13 and 1.140 +/- 0.88 in groups 1 and 2, respectively (P < 0.005). In the posttraumatic subgroup, difference between groups 1 and 2 in mean change in best corrected visual acuity was statistically significant (0.580 +/- 1.10 and 1.132 +/- 0.8 respectively, P < 0.05). Rate of retinal detachment was 6.2% in group 2 as compared with 25.5% in group 1. Groups 1 and 2 required additional subsequent procedures in 27 eyes (41.54%) and 5 eyes (7.8%), respectively (P < 0.0001). CONCLUSIONS: Overall, complete vitrectomy with SOI resulted in significantly better anatomical outcomes and significantly less need for additional surgery as compared with PPV. In addition, in the posttraumatic subgroup, statistically better visual outcomes were noted in group 2 than in group 1. PMID- 26107477 TI - Initial Experience With the Wavelight Refractive Suite for Myopic Laser In Situ Keratomileusis. AB - PURPOSE: The objective of this study was to describe our initial experience with the newest refractive platform, the Wavelight Refractive Suite. DESIGN: This was a consecutive case series of first 50 eyes that underwent myopic laser in situ keratomileusis. METHODS: A total of 50 myopic eyes (28 patients) were included in this study. Uncorrected distance visual acuity, manifest refraction, and keratometry readings were taken preoperatively and 3 months postoperatively. Emmetropia was targeted with an optical zone of 6.5 mm, and flap dimensions were of 130-MUm thickness and 9-mm diameter with a superior hinge in all eyes. Flap thickness was measured with optical coherence tomography postoperatively. RESULTS: At 3 months postoperatively, 82% (41/50) of eyes achieved uncorrected distance visual acuity of 6/6 or better, 98% (49/50) achieved 6/9 or better, and all eyes achieved 6/12 or better. Eighty-four percent of eyes were within 0.5 diopter (D) of target of emmetropia, and 98% of eyes were within 1 D. Mean postoperative flap thickness was 124 +/- 7.8 MUm. CONCLUSIONS: The Wavelight Refractive Suite consisting of the femtosecond laser FS200 and Excimer laser EX500 is the newest integrated refractive surgical platform available and can offer good refractive predictability as shown by the results in our initial 50 myopic eyes. PMID- 26107478 TI - Encephalotrigeminal Angiomatosis (Sturge-Weber Syndrome, Klippel-Trenaunay-Weber Syndrome): A Review. AB - Sturge-Weber syndrome (SWS) (encephalotrigeminal angiomatosis) is a phakomatosis associated with port-wine stains of the face, seizures, mental retardation, and usually ipsilateral meningeal vascular malformations. The classic form affects leptomeninges, eyes, and face. Although the precise etiology and pathogenesis are unclear, the postulated defect is primary venous dysplasia with failure of the primordial embryonic venous plexus to regress. A spontaneous somatic mutation in fibroblast fibronectin gene expression in the vascular malformation may occur during embryonic development. Ocular involvement is characterized by conjunctival, episcleral, retinal, and choroidal vascular abnormalities. The vascular lesions have been inconsistently described as angiomas, hemangiomas, and vascular malformations. Based on the endothelial cellular activity, they can be considered vascular malformations (or port-wine stains), which never regress spontaneously. Congenital, developmental, and adult-onset glaucoma are often seen when the malformations involve the distribution of the first branch of the trigeminal nerve.Both mechanical and vascular causes have been proposed to account for the development of glaucoma. The mechanical theory is based on obstruction of aqueous outflow secondary to developmental anterior chamber angle abnormalities, and the vascular theory is based primarily on elevated episcleral venous pressure. Management of glaucoma in patients with SWS is often challenging and is aimed at controlling intraocular pressure and preventing progressive visual loss and blindness. It also carries an increased risk for surgical complications. This review summarizes the literature regarding the genetics, clinical features, and management of ocular complications of SWS with special focus on glaucoma. PMID- 26107479 TI - Refractive Surgery in Children. AB - Refractive surgery in children is controversial. The main indications are bilateral high ametropia and anisometropia where conventional treatment with spectacles or contact lens is not tolerated. Other reported indications include accommodative strabismus and previous cataract surgery. The most commonly performed procedures currently are surface ablation procedures using excimer laser. The main disadvantage of surface ablation procedures is refractive regression, which is more pronounced in higher degrees of ametropia. More recently, there is a growing number of studies evaluating the safety and effectiveness of phakic intraocular lenses (IOLs) as an alternative surgical management for children who are noncompliant with conventional treatment and unsuitable for laser ablative procedures. The advantages of phakic IOLs are reversibility, predictability, and lack of regression. The principal concern with phakic IOL insertion is long-term endothelial cell loss. Clear lens extraction has been performed in patients with shallow anterior chambers beyond the range of corneal laser refractive procedures; however, major drawbacks include loss of accommodation and significant risk of retinal detachment. In summary, results to date show that refractive surgery can be successfully performed in children and meets an important need in a select subgroup of patients who are recalcitrant to traditional therapy. Issues that remain controversial are the age at which to perform surgery, choice of procedure, need for anesthesia, instability of refractive errors in children, and long-term safety considerations. PMID- 26107480 TI - Retinal Vessel Analysis as a Tool to Quantify Risk of Diabetic Retinopathy. AB - Diabetic retinopathy remains a leading cause of visual impairment and blindness worldwide. Identifying high-risk asymptomatic individuals who will likely develop the sight-threatening forms of diabetic retinopathy is an important clinical goal as it allows early, targeted implementation of preventive strategies to reduce their risk of vision loss. However, diabetic retinopathy is not a linear disease. Predicting the risk of diabetic retinopathy is challenging, and the current approach simply based on an assessment of traditional risk factors lacks precision. Retinal vessel analysis may offer a novel and noninvasive tool to improve risk prediction for diabetic retinopathy. With the use of this technology, studies have shown that a spectrum of structural alterations in the retinal vasculature can now be reliably quantified. In particular, variations in retinal vessel caliber have been consistently associated with the risks of retinopathy development and progression and shown to have prognostic predictive value above and beyond the conventional risk factors. Despite the promising results, there remain several unresolved issues that need to be addressed before the research findings on retinal vessel analysis are translated into clinical application. Coupling with standard clinical assessment, the additional information obtained from this technology could potentially guide clinical decision making, patient prognostication, and possibly monitor therapeutic response. PMID- 26107481 TI - Aqueous Humor Levels of TGF-beta2 and TNF-alpha in Indonesian Eyes With Acute Primary Angle Closure. AB - PURPOSE: To measure aqueous humor levels of TGF-beta2 and TNF-alpha in Indonesian eyes with acute primary angle closure (APAC) and to investigate their relationship to response to treatment. DESIGN: A prospective observational study. METHODS: On presentation, aqueous humor samples were taken from APAC eyes by paracentesis. All APAC eyes then underwent laser peripheral iridotomy (LPI). Two weeks following LPI, trabeculectomy was performed if the intraocular pressure (IOP) was still high. Alternatively, phacoemulsification was performed in cases of normal IOP. Aqueous humor samples were taken again at the time of both surgical procedures. Age-matched cataract patients were included as a control group. Cytokine samples were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Forty-three Indonesian APAC subjects were recruited in this study. The mean presenting IOP was 56.4 +/- 0.52 mmHg and 53% underwent trabeculectomy. Comparison of the APAC eyes to the control group showed there was a significant difference in the mean levels of TGF-beta2 (2007.7 +/- 827.2 pg/mL vs 466.1 +/- 219.3 pg/mL, p < 0.001) and TNF-alpha (0.714 +/- 0.33 pg/mL vs 0.228 +/- 0.16 pg/mL, p < 0.001). There was no significant difference in the presented TGF-beta2 and TNF-alpha levels between the trabeculectomy and phacoemulsification groups (p:0.391 and p:0.494). Between presentation and surgery in the trabeculectomy subgroup, both cytokine levels appeared to be significantly different (p < 0.035 and p < 0.038). CONCLUSIONS: This study showed the aqueous humor levels of TGF-beta2 and TNF-alpha appeared high at presentation but decreased subsequently, with no difference detected between groups with persistently high IOP and those with normalized IOP. PMID- 26107482 TI - Donor Infection After Endothelial Keratoplasty: Potential Issues. PMID- 26107483 TI - Simultaneous Interface Candida Keratitis in 2 Hosts Following Descemet Stripping Endothelial Keratoplasty With Tissue Harvested From a Single Contaminated Donor. PMID- 26107484 TI - Comparison of PROGRESSOR Versus Glaucoma Progression Analysis 2 to Detect Visual Field Progression in Treated Glaucoma Patients. PMID- 26107485 TI - Re: Manuscript Comparison of PROGRESSOR Versus Glaucoma Progression Analysis 2 to Detect Visual Field Progression in Treated Glaucoma Patients. PMID- 26107487 TI - Keratoconus Citations: Battle of the Bulge. PMID- 26107486 TI - Oxime ether lipids containing hydroxylated head groups are more superior siRNA delivery agents than their nonhydroxylated counterparts. AB - AIM: To evaluate the structure-activity relationship of oxime ether lipids (OELs) containing modifications in the hydrophobic domains (chain length, degree of unsaturation) and hydrophilic head groups (polar domain hydroxyl groups) toward complex formation with siRNA molecules and siRNA delivery efficiency of resulting complexes to a human breast cancer cell line (MDA-MB-231). MATERIALS & METHODS: Ability of lipoplex formation between oxime ether lipids with nucleic acids were examined using biophysical techniques. The potential of OELs to deliver nucleic acids and silence green fluorescent protein (GFP) gene was analyzed using MDA-MB 231 and MDA-MB-231/GFP cells, respectively. RESULTS & CONCLUSION: Introduction of hydroxyl groups to the polar domain of the OELs and unsaturation into the hydrophobic domain favor higher transfection and gene silencing in a cell culture system. PMID- 26107488 TI - Citation Analysis of Keratoconus 1900-2013: The Most Influential Publications, Authors, Institutions, and Journals. AB - PURPOSE: The objectives of this study were to identify the 250 most highly cited publications on keratoconus and to identify trends in topics and distinguish the most influential authors, journals, and institutions in the field. DESIGN: This was a database study. METHODS: The authors searched the Web of Science database using the keyword "keratoconus." The results were refined to articles and reviews only, years 1900 to 2013, and sorted by citation count. The 250 most cited, relevant publications to keratoconus were identified, and citation analysis of the authors, topics, journals, institutions, and countries was performed. RESULTS: From the 3030 records identified, the most cited 250 publications were all published in the last 60 years. Publication numbers rose exponentially from the early 1960s, and citation rates have mirrored this. For the 250 most cited publications, the top 25 authors contributed to 60.2% (mean, 6.1 +/- 2.3 publications per author), and the top 25 institutions contributed to 57.6%. The mean citation count per article was 80.7 +/- 62.4. Twelve journal titles contained 89.2% of the 250 most cited articles, and greater than 47.6% of publications originated from the United States. The major subtopics were corneal transplantation (31.2%), diagnostic instruments (17.6%), and structural and molecular analyses (17.6%). CONCLUSIONS: There has been an exponential increase in the body of knowledge on keratoconus in the last 60 years. This interest has been driven by refractive surgery related keratectasia, the emergence of better imaging technologies, and effective treatments. PMID- 26107489 TI - Status of Ophthalmic Education and the Eye Health Workforce in South Asian Association for Regional Cooperation Countries. AB - PURPOSE: This study aimed to assess the capacity for ophthalmic education in the 8 South Asian Association for Regional Cooperation (SAARC) countries and to determine the need and future projections of eye health professionals in the region. DESIGN: This was a retrospective study and comprised desk review and Web based questionnaire. METHODS: Developed in the Asia Pacific region, the Capacity Assessment Tool for SAARC Eye Care Education, a Web-based survey mechanism derived from a 12-point framework, was used to collect data on the number of ophthalmologists and other eye care personnel, training institutions, and capacity for training in each SAARC country. RESULTS: There are an estimated 17,568 practicing ophthalmologists and 4086 ophthalmic subspecialists in the SAARC region. The population per ophthalmologist is approximately 92,270. Allied eye health professionals constitute an important element of the eye health workforce and have a population per allied eye health professional of approximately 99,852; the ophthalmologist to doctor (physician) ratio is 1:61. There are more than 510 centers providing ophthalmology training and more than 32 centers providing subspecialty training; ophthalmic subspecialty training varies from a 3-month observership to a 12-month hands-on training. CONCLUSIONS: In the SAARC region, the challenge is to sustain and increase the eye health workforce to meet the needs of a growing and aging population. The demographic transitions, improved child survival and life expectancy rates, and emerging noncommunicable disease trends require training of ophthalmic subspecialists and supporting eye care teams to meet the service delivery demands of changing eye health paradigms. PMID- 26107490 TI - Patients' Short-term Satisfaction With Cataract Surgery and Long-Term Sustainability of Improved Visual-Related Quality of Life Over 3 Postoperative Years. AB - PURPOSE: This study aimed to assess self-reported satisfaction following cataract surgery, and the sustainability of improved visual function and health-related quality of life in a cataract surgical cohort over 3 years post phacoemulsification surgery. DESIGN: A clinic-based cohort study. METHODS: Cataract surgical patients were recruited and followed up annually after surgery. Logarithm of the minimum angle of resolution (LogMAR) visual acuity, visual function (using the VF-14 questionnaire), and health-related quality of life (using the Short-Form Health Survey [SF-36] questionnaire) were assessed preoperatively and at 1, 2, and 3 years postoperatively. RESULTS: Of the 2029 patients recruited, 1924 (94.8%) had at least 1 postoperative visit, and 1229 (63.9%) had the 3-year follow-up examination performed. The mean age was 75.1 +/- 6 years, and 54.1% were female. Of the 1229, 439 (35.7%) and 286 (23.3%) had completed the VF-14 and SF-36 questionnaires, respectively, at all 3 follow-up visits. The majority (92.1%) of patients reported being satisfied with the outcome of the surgery 6 months postoperatively. The overall VF-14 scores were significantly improved at the 12-month postoperative visits compared with preoperative scores (P < 0.01), independent of age and sex. The improved VF-14 mean scores were sustained for up to 3 years postoperatively. Health-related quality of life (SF-36 scores) showed no significant changes between preoperative and 1-, 2-, and 3-year postoperative examinations. CONCLUSIONS: We documented the sustainability of improvement in visual function-related quality of life associated with cataract surgery over 3 postoperative years. Cataract surgery was not associated with improvement in health-related quality-of-life scores. PMID- 26107491 TI - Evaluation of Wound Morphology of Sclerotomy Sites of Sutureless Vitrectomy Using Spectralis Anterior Segment Optical Coherence Tomography. AB - PURPOSE: The aim of the study was to evaluate wound morphology in vivo in eyes undergoing sutureless vitrectomy. DESIGN: This was a prospective consecutive case series. METHODS: Twenty eyes undergoing sutureless vitrectomy were evaluated using anterior segment optical coherence tomography on days 1, 15, and 30. Ten eyes each belonged to 23-gauge (group A) and 25-gauge (group B). Scans were taken on the incision sites. Group A cases were further divided into group A1 and A2 on the basis of the surgical time of less than 15 minutes' and more than 15 minutes' duration, respectively. RESULTS: On day 1, the mean outer and inner incision diameters in group A were 236.6 and 146 um, and those for group B were 118.6 and 90 um. A significant decrease (P < 0.0001) in both the port sizes was observed in both groups' follow-up. Group B showed significant decrease (P < 0.0001) in the port sizes on l follow-up as compared with group A. Group A1 had smaller incision size as compared with group A2 on the first postoperative day, although not statistically significant(P > 0.05). CONCLUSIONS: In both groups, the sclerotomy incisions showed good healing at 1-month duration. The 25-gauge sclerotomies showed better healing characteristics of wound morphology as compared with the 23 gauge sclerotomies. PMID- 26107492 TI - Management of Choroidal Neovascularization Secondary to Pathological Myopia: The Era of Changes. AB - Choroidal neovascularization (CNV) secondary to pathological myopia is an important cause of significant visual impairment in young adults. High myopia is particularly prevalent in Asian population. New scientific contributions have been made to the understanding of high myopia and myopic CNV. Treatment for myopic CNV has previously relied on photodynamic therapy, laser photocoagulation, and submacular surgery. The treatment outcomes from these modalities are, however, controversial. The introduction of antiangiogenic agents including bevacizumab and ranibizumab has brought the treatment of myopic CNV into a new era. The purpose of this review was to provide an overview of the natural history of myopic CNV, the prognostic factors, and the various treatment options including laser photocoagulation and photodynamic therapy, with particular attention on antiangiogenic agents. PMID- 26107493 TI - Neuro-Ophthalmology Annual Review. AB - The aim of this study was to update the practicing ophthalmologist on the English language neuro-ophthalmology literature from the prior year. This study is a review of English-language literature from August 1, 2012, to August 1, 2013. The authors searched PubMed articles published from August 1, 2012, to August 1, 2013, limited to English-language publications including original articles, review articles, and case reports and excluding letters to the editor, unpublished work, and abstracts. We researched the following topics: pupillary abnormalities, eye movement dysfunction, neuromuscular diseases, optic neuropathies, optic neuritis and demyelinating disease including multiple sclerosis, lesions of the chiasm and posterior primary visual pathways, elevated intracranial pressure, tumors and aneurysms affecting the visual pathways, vascular diseases, higher visual functions, and neuroimaging advances. We intend to share clinically relevant literature of the past year with the practicing ophthalmologist. We aimed to highlight remarkable and interesting literature rather than exhaustively including all new neuro-ophthalmological publications of the year. We reviewed literature in the past year with a focus on relevance and novelty. This review updates the comprehensive ophthalmologist on neuro ophthalmic topics. PMID- 26107494 TI - Ghrelin Levels in Patients With Primary Open-Angle Glaucoma. AB - PURPOSE: This study was aimed to assess the levels of ghrelin in aqueous humor and plasma of human eyes with primary open-angle glaucoma (POAG) and to correlate their concentrations with the severity of glaucoma. DESIGN: This was a case control, prospective study. METHODS: Fifty patients with POAG and 35 patients with senile nonpathologic cataract (control group) were enrolled in the study prospectively. Aqueous humor samples were obtained by paracentesis from patients with glaucoma and cataract who underwent elective surgery. Aqueous humor and corresponding plasma samples were analyzed for ghrelin concentrations by radioimmunoassay diagnostic kits assay. RESULTS: Ghrelin levels were significantly lower in aqueous humor of patients with POAG with respect to the comparative group of patients with cataract (P < 0.001). There was no significant difference in the levels of ghrelin in the plasma of patients with POAG and that of patients with cataract. A positive correlation was found between plasma/aqueous humor ghrelin concentration in patients with POAG versus the control group (P < 0.001). No significant correlation was found between the levels of ghrelin and the severity of visual field loss. CONCLUSIONS: Lower levels of aqueous humor ghrelin may be associated with POAG and may be a consequence of glaucomatous damage. PMID- 26107495 TI - Letter to the Editor Regarding "The Endophthalmitis Kit". PMID- 26107496 TI - Species-Specific Chromosome Engineering Greatly Improves Fully Human Polyclonal Antibody Production Profile in Cattle. AB - Large-scale production of fully human IgG (hIgG) or human polyclonal antibodies (hpAbs) by transgenic animals could be useful for human therapy. However, production level of hpAbs in transgenic animals is generally very low, probably due to the fact that evolutionarily unique interspecies-incompatible genomic sequences between human and non-human host species may impede high production of fully hIgG in the non-human environment. To address this issue, we performed species-specific human artificial chromosome (HAC) engineering and tested these engineered HAC in cattle. Our previous study has demonstrated that site-specific genomic chimerization of pre-B cell receptor/B cell receptor (pre-BCR/BCR) components on HAC vectors significantly improves human IgG expression in cattle where the endogenous bovine immunoglobulin genes were knocked out. In this report, hIgG1 class switch regulatory elements were subjected to site-specific genomic chimerization on HAC vectors to further enhance hIgG expression and improve hIgG subclass distribution in cattle. These species-specific modifications in a chromosome scale resulted in much higher production levels of fully hIgG of up to 15 g/L in sera or plasma, the highest ever reported for a transgenic animal system. Transchromosomic (Tc) cattle containing engineered HAC vectors generated hpAbs with high titers against human-origin antigens following immunization. This study clearly demonstrates that species-specific sequence differences in pre-BCR/BCR components and IgG1 class switch regulatory elements between human and bovine are indeed functionally distinct across the two species, and therefore, are responsible for low production of fully hIgG in our early versions of Tc cattle. The high production levels of fully hIgG with hIgG1 subclass dominancy in a large farm animal species achieved here is an important milestone towards broad therapeutic applications of hpAbs. PMID- 26107497 TI - Evaluation of Copan FLOQSwab for the molecular detection of Chlamydia trachomatis by Abbott RealTime CT PCR. AB - OBJECTIVES: We evaluated Copan FLOQSwabs next to Abbott swabs for the detection of Chlamydia trachomatis (CT) by Abbott RealTime PCR. METHODS: We collected 1062 paired swabs from female sex workers. The study was divided in two arms, according to the order of swab collection. RESULTS: If the Abbott swab was collected first, 501 couples were concordant and two discordant (Abbott negative and Copan positive). If the Copan swab was collected first, 537 couples were concordant and 10 discordant (eight Abbott negative and Copan positive and two Abbott positive and Copan negative). All discordant samples contained low levels of C. trachomatis. Technical issues lead to retesting of 64 Copan and 21 Abbott swabs. CONCLUSION: Our results show that Copan FLOQSwabs can be used interchangeably with Abbott swabs. While appearing to have an advantage in detecting more positive samples, the use of Copan swabs led to a higher retesting rate due to technical errors. PMID- 26107499 TI - Improving the Measurement of Cognitive Ability in Geriatric Patients. AB - BACKGROUND/AIMS: No single tool is available in geriatric clinical settings to quantitatively measure global cognitive ability at different stages ranging from normal functioning to severe impairment. We developed an adaptive test to measure cognitive ability in geriatric populations (Geriatric Rapid Adaptive Cognitive Estimate, GRACE); however, the test failed to discriminate between high functioning individuals. This study aimed to estimate the extent to which adding more difficult items to the GRACE would improve measurement precision in the upper range of cognitive ability. METHODS: The original data used to develop the GRACE was merged with newly collected data of patients who presented at local geriatric clinics. The Rasch analysis was used to estimate the difficulty level of the newly added items and evaluate whether the psychometric properties of the GRACE were improved. RESULTS: One newly added item (Sequencing 5) had a higher difficulty level than all of the previous items in the GRACE. The rest of the new items were located in the high difficulty range. CONCLUSION: The psychometric properties of our adaptive screening tool were improved, and we were able to distinguish between individuals who had higher levels of cognitive functioning. PMID- 26107498 TI - An Interspecies Comparative Analysis of the Predicted Secretomes of the Necrotrophic Plant Pathogens Sclerotinia sclerotiorum and Botrytis cinerea. AB - Phytopathogenic fungi form intimate associations with host plant species and cause disease. To be successful, fungal pathogens communicate with a susceptible host through the secretion of proteinaceous effectors, hydrolytic enzymes and metabolites. Sclerotinia sclerotiorum and Botrytis cinerea are economically important necrotrophic fungal pathogens that cause disease on numerous crop species. Here, a powerful bioinformatics pipeline was used to predict the refined S. sclerotiorum and B. cinerea secretomes, identifying 432 and 499 proteins respectively. Analyses focusing on S. sclerotiorum revealed that 16% of the secretome encoding genes resided in small, sequence heterogeneous, gene clusters that were distributed over 13 of the 16 predicted chromosomes. Functional analyses highlighted the importance of plant cell hydrolysis, oxidation-reduction processes and the redox state to the S. sclerotiorum and B. cinerea secretomes and potentially host infection. Only 8% of the predicted proteins were distinct between the two secretomes. In contrast to S. sclerotiorum, the B. cinerea secretome lacked CFEM- or LysM-containing proteins. The 115 fungal and oomycete genome comparison identified 30 proteins specific to S. sclerotiorum and B. cinerea, plus 11 proteins specific to S. sclerotiorum and 32 proteins specific to B. cinerea. Expressed sequence tag (EST) and proteomic analyses showed that 246 S. sclerotiorum secretome encoding genes had EST support, including 101 which were only expressed in vitro and 49 which were only expressed in planta, whilst 42 predicted proteins were experimentally proven to be secreted. These detailed in silico analyses of two important necrotrophic pathogens will permit informed choices to be made when candidate effector proteins are selected for function analyses in planta. PMID- 26107500 TI - Establishment of plasma microRNA detection method by using taqman probe based quantitative reverse transcription PCR. AB - MicroRNAs (miRNAs) are a kind of short non—coding RNAs that regulate gene expression at the post—transcriptional level. Recently, many studies have found that circulating miRNAs have the potential to sever as diagnostic biomarkers for many diseases. However, the methods for the quantification of circulating miRNAs still need more adjustment. In this study, we tried to establish a reliable method to quantify the plasma miRNAs. We used quantitative real—time PCR with taqman probes to detect the plasma miR—153 level. Three controls were used in this study, including two external miRNAs control from C. elegans miRNAs (cel—miR—54 and cel—miR—238) and one internal control (hsa—miR—486). All of these controls were stable in plasma and the cel—miR—238/cel—miR—54/hsa—miR—486 combination could improve the normalization process. The expression level of the target miRNA, human plasma miR—153, could be quantified accurately with taqman probes .The assay has high accuracy, high sensitivity and a large dynamic range from 100 copies to 10(13) copies in the PCR reaction. Our study provided a standardized quantification method for plasma miRNAs which might be used as biomarker in many diseases research. PMID- 26107501 TI - Effect of Lead stress on phosphatase activity and reducing power assay of Triticum aestivum. AB - Lead (Pb) is a highly toxic heavy metal for both plants and animals; the environment is increasingly polluted with heavy metals and reduces crop productivity. Plants possess homeostatic mechanisms that allow them to keep correct concentrations of essential metal ions in cellular compartments and to minimize the damaging effects of an excess of nonessential ones. One of their adverse effects on plants are the generation of harmful active oxygen species, leading to oxidative stress and the antioxidative activity seems to be of fundamental importance for adaptive response of plant against environmental stress. The present study explores the effects of lead (soil treated twice/ week) with (10, 30 and 60 mM) on the specific activities of phosphatases which might lead to reducing power assay in (Triticum aestivum PBW344) seedling. A significant decrease in the redox potential of shoot compared to root was observed at the similar concentration of lead. A similar trend on leaves was also noted. Acid and alkaline phosphatase activities were significantly higher in roots than in shoot at all the three concentration of lead i.e. 10, 30 and 60 mM, compared to controls. The above mentioned changes were more pronounced at 60 mM concentration of lead than two other concentrations. These results lead us to suggest that increased lead concentration in soil might lead to adverse effects on plant growth and phosphatase activities. PMID- 26107502 TI - AIM2 inflammasome is dispensable for the host defense against Pseudomonas aeruginosa infection. AB - Respiratory tract infection with Pseudomonas aeruginosa is a major cause of hospital—acquired pneumonia in immune—compromised individuals. Lung infection with P. aeruginosa is often associated with production of various inflammatory cytokines including IL—1β. Production of IL—1β requires proteolytic cleavage by a multiprotein complex termed inflammasome. AIM2 inflammasome recognizes foreign cytosolic double stranded DNA. A role of AIM2 in P. aeruginosa infection has not been reported previously. In this study, we found that P. aeruginosa infection induced degradation of AIM2 protein in macrophages and induction of AIM2 mRNA expression in macrophages and in the lung of mice. Interestingly, P. aeruginosa infection induced a similar level of IL—1β, IL—6 and TNF production in wild—type and AIM2—deficient mice. Similarly, no significant differences in bacterial clearance, neutrophil infiltration and NF—κB activation were observed between wild—type and AIM2—deficient mice following P. aeruginosa lung infection. Our data suggest that AIM2 inflammasome is dispensable for the host defense against P. aeruginosa infection. PMID- 26107503 TI - Highly nitrogen doped carbon nanosheets as an efficient electrocatalyst for the oxygen reduction reaction. AB - In this work, highly nitrogen doped carbon nanosheets (HNCNSs) have been successfully prepared by annealing EDTA calcium disodium salt. They exhibited a direct four-electron reaction pathway and high stability as an efficient metal free catalyst for the oxygen reduction reaction. PMID- 26107504 TI - Recombinant Soluble Respiratory Syncytial Virus F Protein That Lacks Heptad Repeat B, Contains a GCN4 Trimerization Motif and Is Not Cleaved Displays Prefusion-Like Characteristics. AB - The respiratory syncytial virus (RSV) fusion protein F is considered an attractive vaccine candidate especially in its prefusion conformation. We studied whether recombinant soluble RSV F proteins could be stabilized in a prefusion like conformation by mutation of heptad repeat B (HRB). The results show that soluble, trimeric, non-cleaved RSV F protein, produced by expression of the furin cleavage site-mutated F ectodomain extended with a GCN4 trimerization sequence, is efficiently recognized by pre- as well as postfusion-specific antibodies. In contrast, a similar F protein completely lacking HRB displayed high reactivity with prefusion-specific antibodies recognizing antigenic site O, but did not expose postfusion-specific antigenic site I, in agreement with this protein maintaining a prefusion-like conformation. These features were dependent on the presence of the GCN4 trimerization domain. Absence of cleavage also contributed to binding of prefusion-specific antibodies. Similar antibody reactivity profiles were observed when the prefusion form of F was stabilized by the introduction of cysteine pairs in HRB. To study whether the inability to form the 6HB was responsible for the prefusion-like antibody reactivity profile, alanine mutations were introduced in HRB. Although introduction of alanine residues in HRB inhibited the formation of the 6HB, the exposure of postfusion-specific antigenic site I was not prevented. In conclusion, proteins that are not able to form the 6HB, due to mutation of HRB, may still display postfusion-specific antigenic site I. Replacement of HRB by the GCN4 trimerization domain in a non-cleaved soluble F protein resulted, however, in a protein with prefusion-like characteristics, suggesting that this HRB-lacking protein may represent a potential prefusion F protein subunit vaccine candidate. PMID- 26107505 TI - Impact of long-term exposure to the tyrosine kinase inhibitor imatinib on the skeleton of growing rats. AB - The tyrosine kinase (TK) inhibitor imatinib provides a highly effective therapy for chronic myeloid leukemia (CML) via inhibition of the oncogenic TK BCR-ABL1. However, off-target TKs like platelet-derived growth factor receptors (PDGF-R) and colony-stimulating factor-1 receptor (c-fms), involved in bone remodeling, are also inhibited. Thus, pediatric patients with CML on imatinib exhibit altered bone metabolism, leading to linear growth failure. As TKI treatment might be necessary for a lifetime, long-term effects exerted on bone in children are of major concern. Therefore, we studied the skeletal long-term effects of continuous and intermittent imatinib exposure in a juvenile rat model. Four-weeks-old male Wistar rats were chronically exposed to imatinib via drinking water over a period of 10 weeks. Animals were exposed to a standard and high imatinib dosage continuously and to the high imatinib dose intermittently. Bone mass and strength were assessed using pQCT, micro-computed tomography (MUCT), and biomechanical testing at the prepubertal, pubertal, and postpubertal age. Bone length and vertebral height as well as biochemical markers of bone turnover were analyzed. Femoral and tibial bone length were dose-dependently reduced by up to 24% (p<0.0001), femoral and tibial trabecular bone mass density (BMD) were reduced by up to 25% (p<0.01), and femoral breaking strength was lowered by up to 20% (p<0.05). Intermittent exposure mitigated these skeletal effects. Long-term exposure resulted in reduced vertebral height by 15% and lower trabecular BMD by 5%. Skeletal changes were associated with suppressed serum osteocalcin (p<0.01) and non-significantly elevated serum CTX-I and PINP levels. In conclusion, imatinib mainly impaired longitudinal growth of long bones rather than the vertebrae of growing rats. Interestingly, intermittent imatinib exposure has less skeletal side effects, which may be beneficial in pediatric patients taking imatinib. PMID- 26107506 TI - Public Reporting of Patient Satisfaction vs Objective Quality Measures: Why Must We Choose? Can Patients Have Both? PMID- 26107508 TI - Diagnosis of breast tumor using thermal tomography q-r curve. AB - Metabolic heat, the product following the metabolism of cells, is closely related to the pathological information of living organisms, which means there are strong connections between the heat distribution and the pathological state of the living organism. The mathematical function delta is introduced in the classical Pennes bioheat transfer equation as a point heat source, and by simplifying the boundary condition, a bioheat transfer model is established. Based on the temperature distribution of the human body surface, the q-r curve of heat intensity q varying with depth r is acquired while combining the fitting method of the Lorentz curve. According to 34,977 clinical confirmed cases and the corresponding classified statistics, diagnostic criteria (for breast diseases) for judging diseases by the q-r curve are proposed. The P -value of our statistics is <0.05 , which means our classified statistics are reliable. Six typical clinical examinations are performed, and the diagnosis results are very consistent with those of B-ultrasonic images, molybdenum target x-ray, and pathological examination, which suggests that the method of diagnosing diseases with a q-r curve has very good prospects for application. It is radiation free and noninvasive to the human body. PMID- 26107507 TI - Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis. AB - Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or beta-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA. PMID- 26107509 TI - Evaluation of Four Commercial Multiplex Molecular Tests for the Diagnosis of Acute Respiratory Infections. AB - Acute Respiratory Infections (ARIs) are responsible for considerable morbidity and mortality worldwide. Documentation of respiratory specimens can help for an appropriate clinical management with a significant effect on the disease progress in patient, the antimicrobial therapy used and the risk of secondary spread of infection. Here, we compared the performances of four commercial multiplex kits used in French University Hospital diagnostic microbiology laboratories for the detection of ARI pathogens (i.e., the xTAG Respiratory Viral Panel Fast, RespiFinder SMART 22, CLART PneumoVir and Fast Track Diagnostics Respiratory Pathogen 33 kits). We used a standardised nucleic acids extraction protocol and a comprehensive comparative approach that mixed reference to well established real time PCR detection techniques and analysis of convergent positive results. We tested 166 respiratory clinical samples and identified a global high degree of correlation for at least three of the techniques (xTAG, RespiFinder and FTD33). For these techniques, the highest Youden's index (YI), positive predictive (PPV) and specificity (Sp) values were observed for Core tests (e.g., influenza A [YI:0.86-1.00; PPV:78.95-100.00; Sp:97.32-100.00] & B [YI:0.44-1.00; PPV:100.00; Sp:100.00], hRSV [YI:0.50-0.99; PPV:85.71-100.00; Sp:99.38-100.00], hMPV [YI:0.71 1.00; PPV:83.33-100.00; Sp:99.37-100.00], EV/hRV [YI:0.62-0.82; PPV:93.33-100.00; Sp:94.48-100.00], AdV [YI:1.00; PPV:100.00; Sp:100.00] and hBoV [YI:0.20-0.80; PPV:57.14-100.00; Sp:98.14-100.00]). The present study completed an overview of the multiplex techniques available for the diagnosis of acute respiratory infections. PMID- 26107510 TI - Effect Modifying Role of Serum Calcium on Mortality-Predictability of PTH and Alkaline Phosphatase in Hemodialysis Patients: An Investigation Using Data from the Taiwan Renal Registry Data System from 2005 to 2012. AB - Predicting mortality in dialysis patients based on low intact parathyroid hormone levels is difficult, because aluminum intoxication, malnutrition, older age, race, diabetes, or peritoneal dialysis may influence these levels. We investigated the clinical implications of low parathyroid hormone levels in relation to the mortality of dialysis patients using sensitive, stratified, and adjusted models and a nationwide dialysis database. We analyzed data from 2005 to 2012 that were held on the Taiwan Renal Registry Data System, and 94,983 hemodialysis patients with valid data regarding their intact parathyroid levels were included in this study. The patient cohort was subdivided based on the intact parathyroid hormone and alkaline phosphatase levels. The mean hemodialysis duration within this cohort was 3.5 years. The mean (standard deviation) age was 62 (14) years. After adjusting for age, sex, diabetes, the hemodialysis duration, serum albumin levels, hematocrit levels, calcium levels, phosphate levels, and the hemodialysis treatment adequacy score, the single-pool Kt/V, the crude and adjusted all-cause mortality rates increased when alkaline phosphatase levels were higher or intact parathyroid hormone levels were lower. In general, at any given level of serum calcium or phosphate, patients with low intact parathyroid hormone levels had higher mortality rates than those with normal or high iPTH levels. At a given alkaline phosphatase level, the hazard ratio for all-cause mortality was 1.33 (p < 0.01, 95% confidence interval 1.27-1.39) in the group with intact parathyroid hormone levels < 150 pg/mL and serum calcium levels > 9.5 mg/dL, but in the group with intact parathyroid hormone levels > 300 pg/mL and serum calcium levels > 9.5 mg/dL, the hazard ratio was 0.92 (95% confidence interval 0.85-1.01). Hence, maintaining albumin-corrected high serum calcium levels at > 9.5 mg/dL may correlate with poor prognoses for patients with low intact parathyroid hormone levels. PMID- 26107511 TI - Evidence for the dimerization-mediated catalysis of methionine sulfoxide reductase A from Clostridium oremlandii. AB - Clostridium oremlandii MsrA (CoMsrA) is a natively selenocysteine-containing methionine-S-sulfoxide reductase and classified into a 1-Cys type MsrA. CoMsrA exists as a monomer in solution. Herein, we report evidence that CoMsrA can undergo homodimerization during catalysis. The monomeric CoMsrA dimerizes in the presence of its substrate methionine sulfoxide via an intermolecular disulfide bond between catalytic Cys16 residues. The dimeric CoMsrA is resolved by the reductant glutaredoxin, suggesting the relevance of dimerization in catalysis. The dimerization reaction occurs in a concentration- and time-dependent manner. In addition, the occurrence of homodimer formation in the native selenoprotein CoMsrA is confirmed. We also determine the crystal structure of the dimeric CoMsrA, having the dimer interface around the two catalytic Cys16 residues. A central cone-shaped hole is present in the surface model of dimeric structure, and the two Cys16 residues constitute the base of the hole. Collectively, our biochemical and structural analyses suggest a novel dimerization-mediated mechanism for CoMsrA catalysis that is additionally involved in CoMsrA regeneration by glutaredoxin. PMID- 26107512 TI - Accuracy of Lung Ultrasonography versus Chest Radiography for the Diagnosis of Adult Community-Acquired Pneumonia: Review of the Literature and Meta-Analysis. AB - Lung ultrasonography (LUS) is being increasingly utilized in emergency and critical settings. We performed a systematic review of the current literature to compare the accuracy of LUS and chest radiography (CR) for the diagnosis of adult community-acquired pneumonia (CAP). We searched in Pub Med, EMBASE dealing with both LUS and CR for diagnosis of adult CAP, and conducted a meta-analysis to evaluate the diagnostic accuracy of LUS in comparison with CR. The diagnostic standard that the index test compared was the hospital discharge diagnosis or the result of chest computed tomography scan as a "gold standard". We calculated pooled sensitivity and specificity using the Mantel-Haenszel method and pooled diagnostic odds ratio using the DerSimonian-Laird method. Five articles met our inclusion criteria and were included in the final analysis. Using hospital discharge diagnosis as reference, LUS had a pooled sensitivity of 0.95 (0.93 0.97) and a specificity of 0.90 (0.86 to 0.94), CR had a pooled sensitivity of 0.77 (0.73 to 0.80) and a specificity of 0.91 (0.87 to 0.94). LUS and CR compared with computed tomography scan in 138 patients in total, the Z statistic of the two summary receiver operating characteristic was 3.093 (P = 0.002), the areas under the curve for LUS and CR were 0.901 and 0.590, respectively. Our study indicates that LUS can help to diagnosis adult CAP by clinicians and the accuracy was better compared with CR using chest computed tomography scan as the gold standard. PMID- 26107513 TI - Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases. AB - The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity. PMID- 26107514 TI - Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97. AB - Patients with type 1 diabetes (T1D) suffer from beta-cell destruction by CD8+ T cells that have preproinsulin as an important target autoantigen. It is of great importance to understand the molecular mechanism underlying the processing of preproinsulin into these CD8+ T-cell epitopes. We therefore studied a pathway that may contribute to the production of these antigenic peptides: degradation of proinsulin via ER associated protein degradation (ERAD). Analysis of the MHC class I peptide ligandome confirmed the presentation of the most relevant MHC class I-restricted diabetogenic epitopes in our cells: the signal peptide-derived sequence A15-A25 and the insulin B-chain epitopes H29-A38 and H34-V42. We demonstrate that specific silencing of Derlin-2, p97 and HRD1 by shRNAs increases steady state levels of proinsulin. This indicates that these ERAD constituents are critically involved in proinsulin degradation and may therefore also play a role in subsequent antigen generation. These ERAD proteins therefore represent interesting targets for novel therapies aiming at the reduction and possibly also prevention of beta-cell directed auto-immune reactions in T1D. PMID- 26107515 TI - Noise-Induced Frequency Modifications of Tamarin Vocalizations: Implications for Noise Compensation in Nonhuman Primates. AB - Previous research suggests that nonhuman primates have limited flexibility in the frequency content of their vocalizations, particularly when compared to human speech. Consistent with this notion, several nonhuman primate species have demonstrated noise-induced changes in call amplitude and duration, with no evidence of changes to spectral content. This experiment used broad- and narrow band noise playbacks to investigate the vocal control of two call types produced by cotton-top tamarins (Saguinus Oedipus). In 'combination long calls' (CLCs), peak fundamental frequency and the distribution of energy between low and high frequency harmonics (spectral tilt) changed in response to increased noise amplitude and bandwidth. In chirps, peak and maximum components of the fundamental frequency increased with increasing noise level, with no changes to spectral tilt. Other modifications included the Lombard effect and increases in chirp duration. These results provide the first evidence for noise-induced frequency changes in nonhuman primate vocalizations and suggest that future investigations of vocal plasticity in primates should include spectral parameters. PMID- 26107517 TI - HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures. AB - Cervical cancer is a multi-stage disease caused by human papillomaviruses (HPV) infection of cervical epithelial cells, but the mechanisms regulating disease progression are not clearly defined. Using 3-dimensional organotypic cultures, we demonstrate that HPV16 E6 and E7 proteins alter the secretome of primary human keratinocytes resulting in local epithelial invasion. Mechanistically, absence of the IGF-binding protein 2 (IGFBP2) caused increases in IGFI/II signalling and through crosstalk with KGF/FGFR2b/AKT, cell invasion. Repression of IGFBP2 is mediated by histone deacetylation at the IGFBP2 promoter and was reversed by treatment with histone deacetylase (HDAC) inhibitors. Our in vitro findings were confirmed in 50 invasive cancers and 79 cervical intra-epithelial neoplastic lesions caused by HPV16 infection, where IGFBP2 levels were reduced with increasing disease severity. In summary, the loss of IGFBP2 is associated with progression of premalignant disease, and sensitises cells to pro-invasive IGF signalling, and together with stromal derived factors promotes epithelial invasion. PMID- 26107516 TI - Measuring Faecal Epi-Androsterone as an Indicator of Gonadal Activity in Spotted Hyenas (Crocuta crocuta). AB - Enzyme immunoassays (EIA) that measure faecal testosterone metabolites (fTM) are useful tools to monitor gonadal activity. The aim of this study was to validate an "in-house" epiandrosterone EIA to monitor fTM in spotted hyenas. FTM were characterised in a male and a female hyena that each received an injection of 3H testosterone. High-performance liquid chromatography (HPLC) analyses revealed a cluster of highly polar enzyme-hydrolysable hormone metabolite conjugates. We performed hydrolysis using beta-glucuronidase to deconjugate metabolites and improve sensitivity of the assay. Because beta-glucuronidase from Helix pomatia has been reported to bias testosterone measurements in some species, we compared the enzymatic activity of the commonly used beta-glucuronidase extracted from H. pomatia with the same enzyme from Escherichia coli. Our results showed that beta glucuronidases from both sources produced similar results from spotted hyena faeces. We therefore hydrolysed samples with H. pomatia enzymes. HPLC analyses also demonstrated that following hydrolysis the epiandrosterone EIA measured significant amounts of immunoreactive metabolites corresponding to radiolabelled metabolites in both sexes. Additionally, HPLC and GC-MS analyses confirmed the presence of epiandrosterone in faeces of spotted hyenas. The biological relevance of the epiandrosterone EIA was validated by demonstrating (1) a significant increase in fTM levels in response to a testosterone injection within 16 h, (2) no biological responsiveness to an adrenocorticotropic hormone (ACTH) injection and (3) significant differences in fTM levels between juvenile males and adult immigrant males in a free-ranging wild population. Our results clearly demonstrate that the epiandrosterone EIA is a reliable non-invasive method to monitor gonadal activity in spotted hyenas. PMID- 26107518 TI - Antenna Mechanism of Length Control of Actin Cables. AB - Actin cables are linear cytoskeletal structures that serve as tracks for myosin based intracellular transport of vesicles and organelles in both yeast and mammalian cells. In a yeast cell undergoing budding, cables are in constant dynamic turnover yet some cables grow from the bud neck toward the back of the mother cell until their length roughly equals the diameter of the mother cell. This raises the question: how is the length of these cables controlled? Here we describe a novel molecular mechanism for cable length control inspired by recent experimental observations in cells. This "antenna mechanism" involves three key proteins: formins, which polymerize actin, Smy1 proteins, which bind formins and inhibit actin polymerization, and myosin motors, which deliver Smy1 to formins, leading to a length-dependent actin polymerization rate. We compute the probability distribution of cable lengths as a function of several experimentally tuneable parameters such as the formin-binding affinity of Smy1 and the concentration of myosin motors delivering Smy1. These results provide testable predictions of the antenna mechanism of actin-cable length control. PMID- 26107519 TI - Development and First Phase Evaluation of a Maternity Leave Educational Tool for Pregnant, Working Women in California. AB - BACKGROUND: Despite the provision of maternity leave offered to mothers, many American women fail to take leave. METHODS: We developed an evidence-based maternity leave educational tool for working women in California using participatory design. We tested its short-term efficacy with a randomized controlled trial of pregnant English-speakers (n=155). RESULTS: Among intervention participants exposed to the tool, 65% reported that they learned something new; 38% were motivated to seek more information; and 49% said it helped them plan their maternity leave. Among participants who delivered at >= 37 weeks gestation and said the tool helped them plan their leave, 89% took more than one week of prenatal leave, a significantly higher proportion than among controls who did not receive the tool (64%, p=0.049). Other findings favored trial participants, but were not statistically significant in this small sample. More intervention participants took some prenatal leave (80%) vs. controls (74%, p=0.44). Among participants who had returned to work when surveyed (n=50), mean postnatal leave uptake was on average 1 week longer for intervention participants vs. controls (13.3 vs. 12.2 weeks, p=0.54). CONCLUSIONS: The first-phase evaluation of this tool shows that it successfully informed women about maternity leave options, clarified complex regulations, encouraged women to seek further information and helped plan maternity leave. Compared to controls, trial participants who used the tool to plan their leave were far more likely to take prenatal leave close to term. Future evaluation of the tool when mediated by a health provider or employer is warranted. PMID- 26107520 TI - Correction: Harnessing Case Isolation and Ring Vaccination to Control Ebola. PMID- 26107521 TI - Impaired Glucose Metabolism in Mice Lacking the Tas1r3 Taste Receptor Gene. AB - The G-protein-coupled sweet taste receptor dimer T1R2/T1R3 is expressed in taste bud cells in the oral cavity. In recent years, its involvement in membrane glucose sensing was discovered in endocrine cells regulating glucose homeostasis. We investigated importance of extraorally expressed T1R3 taste receptor protein in age-dependent control of blood glucose homeostasis in vivo, using nonfasted mice with a targeted mutation of the Tas1r3 gene that encodes the T1R3 protein. Glucose and insulin tolerance tests, as well as behavioral tests measuring taste responses to sucrose solutions, were performed with C57BL/6ByJ (Tas1r3+/+) inbred mice bearing the wild-type allele and C57BL/6J-Tas1r3tm1Rfm mice lacking the entire Tas1r3 coding region and devoid of the T1R3 protein (Tas1r3-/-). Compared with Tas1r3+/+ mice, Tas1r3-/- mice lacked attraction to sucrose in brief-access licking tests, had diminished taste preferences for sucrose solutions in the two bottle tests, and had reduced insulin sensitivity and tolerance to glucose administered intraperitoneally or intragastrically, which suggests that these effects are due to absence of T1R3. Impairment of glucose clearance in Tas1r3-/- mice was exacerbated with age after intraperitoneal but not intragastric administration of glucose, pointing to a compensatory role of extraoral T1R3 dependent mechanisms in offsetting age-dependent decline in regulation of glucose homeostasis. Incretin effects were similar in Tas1r3+/+ and Tas1r3-/- mice, which suggests that control of blood glucose clearance is associated with effects of extraoral T1R3 in tissues other than the gastrointestinal tract. Collectively, the obtained data demonstrate that the T1R3 receptor protein plays an important role in control of glucose homeostasis not only by regulating sugar intake but also via its extraoral function, probably in the pancreas and brain. PMID- 26107522 TI - The dose-dependent effect of nesiritide on renal function in patients with acute decompensated heart failure: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Conflicting renal effects of nesiritide have been reported in patients with acute decompensated heart failure. To answer this controversy, we performed a meta-analysis of randomized controlled trials to evaluate the influence of nesiritide on renal function in patients with acute decompensated heart failure. METHODS: Articles were obtained from PubMed, Medline, Cochrane Library and reference review. Randomized controlled studies that investigated the effects of continuous infusion of nesiritide on renal function in adult patients with acute decompensated heart failure were included and analyzed. Fixed-effect model was used to estimate relative risk (RR) and weight mean difference (WMD). The quality assessment of each study, subgroup, sensitivity, and publication bias analyses were performed. RESULTS: Fifteen randomized controlled trials were eligible for inclusion. Most of included studies had relatively high quality and no publication bias was found. Overall, compared to control therapies, nesiritide might increase the risk of worsening renal function in patients with acute decompensated heart failure (RR 1.08, 95% CI 1.01-1.15, P = 0.023). In subgroup analysis, high-dose nesiritide strongly associated with renal dysfunction (RR 1.54, 95% CI 1.19-2.00, P = 0.001), but no statistical differences were observed in standard-dose (RR 1.04, 95% CI 0.98-1.12, P = 0.213), low-dose groups (RR 1.01, 95% CI 0.74-1.37, P = 0.968) and same results were identified in the subgroup analysis of placebo controlled trials. Peak mean change of serum creatinine from baseline was no significant difference (WMD -2.54, 95% CI -5.76 0.67, P = 0.121). CONCLUSIONS: In our meta-analysis, nesiritide may have a dose dependent effect on renal function in patients with acute decompensated heart failure. High-dose nesiritide is likely to increase the risk of worsening renal function, but standard-dose and low-dose nesiritide probably have no impact on renal function. These findings could be helpful to optimize the use of nesiritide in clinical practice. PMID- 26107523 TI - The acceptability of PEGASUS: an intervention to facilitate shared decision making with women contemplating breast reconstruction. AB - Good practice guidelines recommend that women who undergo mastectomy are offered reconstructive surgery. However, many who choose this option report a degree of decisional regret and dissatisfaction because their pre-surgical expectations were not met. This paper reports an acceptability study of a new intervention (PEGASUS) that aims to support shared decision-making by eliciting women's pre surgical expectations and setting patient-centred goals. Eighteen women contemplating breast reconstruction completed the PEGASUS intervention. Semi structured interviews were conducted with 12 women and 3 health professionals to explore their experiences of using PEGASUS. Interview transcripts were subjected to a thematic analysis, and a content analysis was conducted on 79 goals that the 18 women identified. Feedback was extremely positive--women found that completing PEGASUS alongside a discussion with a specially trained health professional helped them prepare for the surgical consultation and increased their trust in their surgeon. Staff reported that PEGASUS facilitated patient-centred discussions and informed the decisions made about potential surgery. This preliminary study suggests that this novel intervention is acceptable to patients and health professionals alike. Further work is needed to evaluate its efficacy and then its effectiveness with a larger sample of women, and its potential use with other patient groups. PMID- 26107524 TI - Does neuroimaging help to deliver better recovery of movement after stroke? AB - PURPOSE OF REVIEW: This review examines recent brain imaging studies that might contribute to delivering better recovery of motor function after stroke. RECENT FINDINGS: Most recent studies characterize differences in structural and functional organization of the poststroke brain in relation to impairment, or measure alterations in brain organization as the result of one form of therapy or another. These studies have not altered clinical practice. New approaches can test specific models of motor recovery after stroke. Firstly, anatomical assessment of key motor pathways, particularly corticospinal tract, may be useful in predicting long-term outcomes if used in combination with early clinical scores. Secondly, assessment of neuronal oscillations with electro or magneto encephalography may provide a novel way of assessing the balance between excitatory and inhibitory cortical processes and thereby provide biomarkers of the potential for experience-dependent plasticity. SUMMARY: Most recent studies are observational and do not test a plausible model of motor recovery after stroke. Brain imaging studies of stroke recovery need to consider how to provide tools to aid prediction of long-term outcome or response to treatment, or describe potential therapeutic targets for novel recovery promoting interventions, if they are to be clinically useful. PMID- 26107525 TI - Updated views of movement disorders. PMID- 26107526 TI - Computer-based analysis of brain images: how close are we to clinical applications? PMID- 26107528 TI - Microscopic segregation of hydrophilic ions in critical binary aqueous solvents. AB - Solid surfaces suspended in critical aqueous binary mixtures containing hydrophilic salt have recently been found to exhibit anomalous interactions, and a possible mechanism is provided by the asymmetric solvation preferences of weakly and strongly hydrophilic cations and anions, respectively. Here we address this mechanism by studying interfacial ion distributions in a critical binary mixture of water and 2,6-dimethylpyridine containing potassium chloride at temperatures below the lower critical point, using grazing-incidence X-ray fluorescence from the liquid-vapour interface. Our data provide direct and unambiguous experimental evidence for microscopic segregation of hydrophilic ions in critical aqueous binary mixtures, thereby supporting the important role of asymmetric ion solvation in the above mentioned anomalous force. However, the experimental data are only qualitatively reproduced by state-of-the-art theoretical calculations, demonstrating the need of a microscopic theoretical model including asymmetric ion solvation. PMID- 26107527 TI - Erylivingstone A-C with antioxidant and antibacterial activities from Erythrina livingstoniana. AB - The chemical study of Erythrina livingstoniana has led to the isolation of three new flavanones namely 5,7,3'-trihydroxy-4'-methoxy-5'-formylflavanone (erylivingstone A) (1), 5,7,3'-trihydroxy-5'-(2-hydroxy-3-methylbut-3-enyl)-4' methoxyflavanone (erylivingstone B) (2) and 5,7,3'-trihydroxy-5'-(3-hydroxy-3 methyl-trans-but-1-enyl)-4'-methoxyflavanone (erylivingstone C) (3) together with three known compounds (4-6). Their structures were elucidated on the basis of NMR data, HRMS(n) fragmentation pathway and by comparison with literature data. We evaluated the antibacterial efficacies and free-radical scavenging potential of the isolated compounds (1-6). The typical environmental strains of Gram-positive Bacillus subtilis, Gram-negative Escherichia coli, as well as against the clinically important Staphylococcus aureus, Streptococcus pyogenes and E. coli (risk-group 2) were used for the antibacterial assay. Compounds 5 and 6 exhibited the most pronounced efficacy against tested environmental bacteria as well as against the pathogenic strain of E. coli. Compound 3 was also quite active against these three bacterial strains. The isolated compounds showed weak radical scavenging properties with compound 6 being the most active, followed by compounds 2, 3 and 5. PMID- 26107529 TI - Ebola Virus Disease Outbreak in Isiro, Democratic Republic of the Congo, 2012: Signs and Symptoms, Management and Outcomes. AB - Data collected during the 2012 Ebola virus disease (EVD) epidemic in the Democratic Republic of the Congo were analysed for clinical signs, symptoms and case fatality of EVD caused by Bundibugyo virus (BDBV), establishment of differential diagnoses, description of medical treatment and evaluation of the quality of clinical documentation. In a quantitative observational prospective study, global epidemiological data from 52 patients (34 patients within the community, 18 patients treated in the Ebola Treatment Centre) were entered anonymously into a database, subsequently matched and analysed. Relevant findings include an over-representation of females among community EVD cases (85.3%) and of community EVD cases in the age group of 15-54 years (82.4%). All ETC patients had fever (55.6% of all 18 ETC patients during their hospital stay) or self reported fever (88.2% upon admission) at some point of time during their illness. Major symptoms of ETC patients during hospital stay included asthenia (82.4%), anorexia (82.4%), myalgia (70.6%), sore throat/difficulty swallowing (70.6%), arthralgia (76.5%) and nausea (70.6%). Gastrointestinal signs and symptoms (nausea, diarrhoea, vomiting) (76.4%) as well as general pain (94.1%) were frequent in ETC patients. The median duration of EVD was 18 days, while the mean incubation period was 11.3 days. Differential diagnosis of EVD included malaria (28.3%), intestinal parasitosis (10.9%), and infectious syndrome (10.9%). There was also an important variation in clinical evolvement. Quality of documentation was adversely affected by the way patient file contents were transferred from inside to outside the high-risk zone, entailing a mean mismatch value of 27.3% between patient file contents inside vs. outside the high-risk zone. This study adds further description of EVD (frequently non-specific signs and symptoms, non frequent bleeding, a long incubation period, long duration of disease) and emphasizes the need for improving clinical monitoring and documentation in EVD outbreak settings. PMID- 26107530 TI - Relaxation dynamics of liposomes in an aqueous solution. AB - The gel-liquid crystal phase transition has been studied by the temperature and frequency dependent dielectric relaxation behavior of liposomes in an aqueous solution (40 g L(-1) DPPC-water mixture). Four relaxation processes were observed in the frequency range from 40 Hz to 30 GHz which were ascribed to different molecular mechanisms, related to the structural units of the system. The gel liquid crystal phase transition was also described very accurately from the temperature-dependent dielectric relaxation strength, relaxation time and symmetric shape parameter of the relaxation functions obtained from the fitting procedure. Relaxation process 3, obtained from the dielectric fitting procedure, was confirmed by dielectric modulus analysis. A comparison of the lipid membrane with non-biological systems like liquid crystals was performed. It was determined that the lipid membrane has a ferroelectric liquid crystal like behavior. Process 3 is comparable to the soft mode relaxation process observed in ferroelectric liquid crystals which was detected close to the smectic-C*-smectic-A phase transition. Differential scanning calorimetry was also used to confirm the gel liquid crystal phase transition of this mixture. PMID- 26107531 TI - Selective Extraction of Rare Earth Elements from Permanent Magnet Scraps with Membrane Solvent Extraction. AB - The rare earth elements (REEs) such as neodymium, praseodymium, and dysprosium were successfully recovered from commercial NdFeB magnets and industrial scrap magnets via membrane assisted solvent extraction (MSX). A hollow fiber membrane system was evaluated to extract REEs in a single step with the feed and strip solutions circulating continuously through the MSX system. The effects of several experimental variables on REE extraction such as flow rate, concentration of REEs in the feed solution, membrane configuration, and composition of acids were investigated with the MSX system. A multimembrane module configuration with REEs dissolved in aqueous nitric acid solutions showed high selectivity for REE extraction with no coextraction of non-REEs, whereas the use of aqueous hydrochloric acid solution resulted in coextraction of non-REEs due to the formation of chloroanions of non-REEs. The REE oxides were recovered from the strip solution through precipitation, drying, and annealing steps. The resulting REE oxides were characterized with XRD, SEM-EDX, and ICP-OES, demonstrating that the membrane assisted solvent extraction is capable of selectively recovering pure REEs from the industrial scrap magnets. PMID- 26107532 TI - Findings From the EASY Minds Cluster Randomized Controlled Trial: Evaluation of a Physical Activity Integration Program for Mathematics in Primary Schools. AB - BACKGROUND: To evaluate the impact of a primary school-based physical activity (PA) integration program delivered by teachers on objectively measured PA and key educational outcomes. METHODS: Ten classes from 8 Australian public schools were randomly allocated to treatment conditions. Teachers from the intervention group were taught to embed movement-based learning in their students' (n = 142) daily mathematics program in 3 lessons per week for 6 weeks. The control group (n = 98) continued its regular mathematics program. The primary outcome was accelerometer determined PA across the school day. Linear mixed models were used to analyze treatment effects. RESULTS: Significant intervention effects were found for PA across the school day (adjusted mean difference 103 counts per minute [CPM], 95% confidence interval [CI], 36.5-169.7, P = .008). Intervention effects were also found for PA (168 CPM, 95% CI, 90.1-247.4, P = .008) and moderate-to-vigorous PA (2.6%, 95% CI, 0.9-4.4, P = .009) in mathematics lessons, sedentary time across the school day (-3.5%, 95% CI, -7.0 to -0.13, P = .044) and during mathematics ( 8.2%, CI, -13.0 to -2.0, P = .010) and on-task behavior (13.8%, 95% CI, 4.0-23.6, P = .011)-but not for mathematics performance or attitude. CONCLUSION: Integrating movement across the primary mathematics syllabus is feasible and efficacious. PMID- 26107533 TI - The dynamic association processes leading from a silica precursor to a mesoporous SBA-15 material. AB - During the last two decades, the synthesis of silica with an ordered mesoporous structure has been thoroughly explored. The basis of the synthesis is to let silica monomers polymerize in the presence of an amphiphilic template component. In the first studies, cationic surfactants were used as structure inducer. Later it was shown that pluronic copolymers also could have the role. One advantage with the pluronics copolymers is that they allow for a wider variation in the radius of pores in the resulting silica material. Another advantage lies in the higher stability resulting from the thicker walls between the pores. Mesoporous silica has a very high area to volume ratio, and the ordered structure ensures surface homogeneity. There are a number of applications of this type of material. It can be used as support for catalysts, as templates to produces other mesoporous inorganic materials, or in controlled release applications. The synthesis of mesoporous silica is, from a practical point of view, simple, but there are significant possibilities to vary synthesis conditions with a concomitant effect on the properties of the resulting material. It is clear that the structural properties on the nanometer scale are determined by the self assembly properties of the amphiphile, and this knowledge has been used to optimize pore geometry and pore size. To have a practical functional material it is desirable to also control the structure on a micrometer scale and larger. In practice, one has largely taken an empirical approach in optimizing reaction conditions, paying less attention to underlying chemical and physicochemical mechanisms that lead from starting conditions to the final product. In this Account, we present our systematic studies of the processes involved not only in the formation of the mesoporous structure as such, but also of the formation of structures on the micrometer scale. The main point is to show how the ongoing silica polymerization triggers a sequence of structural changes through the action of colloidal interactions. Our approach is to use a multitude of experimental methods to characterize the time evolution of the same highly reproducible synthesis process. It is the silica polymerization reactions that set the time scale, and the block copolymer self-assembly responds to the progress of the polymerization through a basically hydrophobic interaction between silica and ethylene oxide units. The progression of the silica polymerization leads to an increased hydrophobicity triggering an aggregation process resulting in the formation of silica-copolymer composite particles of increasing size. The particle growth occurs in a stepwise way caused by intricate shifts between colloidal stability and instability. By tuning reaction conditions one can have an end product of hexagonal prism composite particles with single crystal 2D hexagonal order. PMID- 26107534 TI - Probing cell-matrix interactions in RGD-decorated macroporous poly (ethylene glycol) hydrogels for 3D chondrocyte culture. AB - Macroporous hydrogels have shown great promise as scaffolds for cartilage engineering by facilitating nutrition transport and tissue in growth. Cell-matrix adhesion-a fundamental process in tissue engineering-has shown a profound effect on subsequent cell phenotype, extracellular matrix (ECM) accumulation, and tissue reorganization. In this study, arginine-glycine-aspartic acid (RGD) was introduced to macroporous hydrogels of poly (ethylene glycol) (PEG) to fabricate PEG-G400 (with 0.4mM RGD) and PEG-G2000 (2mM RGD) to probe the cell-matrix interactions within hydrogels. Primary chondrocytes demonstrated a slightly stretched morphology with increasing RGD concentration and PEG-G2000 hydrogels boosted cell viability, proliferation, and deposition of collagen II and GAG, in comparison to the PEG-G400 and PEG-RED groups. Results also revealed chondrocytes within the cell aggregates underwent dedifferentiation and hypertrophy within RGD incorporated hydrogels, as evidenced by the high level of gene expression of collagen I on day 14 and strong immunohistological staining of collagen X and collagen I on day 35. Evidently, a high concentration of RGD (2mM RGD) enhanced cell-matrix interactions through elevating the expression of integrin beta1 and vinculin. Thus, the integration of RGD in macroporous hydrogels with a concentration of 2 mM may be sufficient for improving cell functionality, with a slight probability of dedifferentiation and hypertrophy of chondrocytes. PMID- 26107537 TI - Addressing Depression and Suicide Among Physician Trainees--Reply. PMID- 26107538 TI - A Randomized Controlled Trial of the Effects of Isolated Lumbar Extension Exercise on Lumbar Kinematic Pattern Variability During Gait in Chronic Low Back Pain. AB - BACKGROUND: Chronic low back pain (CLBP) is a multifactorial condition with a variety of symptoms, one of which is abnormal gait. The lumbar spine and its musculature are important in controlling gait, and in CLBP the lumbar extensors are often deconditioned. Because of this specific isolated lumbar extension, exercise often is recommended. It was therefore of interest to examine its effects of upon gait variability. OBJECTIVE: To examine the effects of isolated lumbar extension resistance training on lumbar kinematic variability during gait in participants with CLBP. DESIGN: Randomized controlled trial. SETTING: University Health, Exercise and Sport Science Laboratory. PARTICIPANTS: Twenty four participants with nonspecific CLBP. INTERVENTIONS: Participants were randomly allocated to a 12-week isolated lumbar extension exercise intervention (1*/week performing a single set to momentary muscular failure using a load equal to 80% max tested torque) or nontraining control period. MAIN OUTCOME MEASUREMENTS: Lumbar kinematics during gait, including angular displacement, kinematic waveform pattern (CVp), and offset (CVo) variability, were examined via 3-dimensional analyses. RESULTS: No significant changes in displacement or CVo were found as a result of the intervention; however, a small but significant reduction in sagittal plane CVp (-20.90 +/- 3.53%, effect size = 0.48, P = .044) occurred, indicating improved motor pattern replication through this movement plane. CONCLUSIONS: Considering the role of the lumbar extensors in gait, and their common deconditioning in CLBP, an isolated lumbar extension resistance exercise intervention may reduce gait variability. These results suggest isolated lumbar extension exercise may specifically reduce sagittal plane variability, indicating improved motor pattern replication through this movement plane, perhaps attributable to the plane of movement used during the exercise. PMID- 26107539 TI - Evidence for Intensive Aphasia Therapy: Consideration of Theories From Neuroscience and Cognitive Psychology. AB - Treatment intensity is a critical component to the delivery of speech-language pathology and rehabilitation services. Within aphasia rehabilitation, however, insufficient evidence currently exists to guide clinical decision making with respect to the optimal treatment intensity. This review considers perspectives from 2 key bodies of research, the neuroscience and cognitive psychology literature, with respect to the scheduling of aphasia rehabilitation services. Neuroscience research suggests that intensive training is a key element of rehabilitation and is necessary to achieve functional and neurologic changes after a stroke occurs. In contrast, the cognitive psychology literature suggests that optimal long-term learning is achieved when training is provided in a distributed or nonintensive schedule. These perspectives are evaluated and discussed with respect to the current evidence for treatment intensity in aphasia rehabilitation. In addition, directions for future research are identified, including study design, methods of defining and measuring treatment intensity, and selection of outcome measures in aphasia rehabilitation. PMID- 26107540 TI - Physical Activity Level Among Stroke Patients Hospitalized in a Rehabilitation Unit. AB - BACKGROUND: The current literature contains little information about the level of physical activity of hospitalized patients who have had a stroke. Improving knowledge in the area could help optimize rehabilitation. OBJECTIVES: To determine the level of physical activity of hospitalized patients who have had a stroke to discover if they achieved the recommended 30 minutes of physical activity per day (equivalent to 142 kcal) during sessions of 10 consecutive minutes. SETTING: Physical and Rehabilitation Medicine Unit of the Jean Rebeyrol Hospital, Limoges, France. PARTICIPANTS: All patients (N = 88) who had sustained a stroke within the previous 6 months were included over a period of 7 months. MAIN OUTCOME MEASURES: The duration of physical activity and related energy expenditure were estimated using a SenseWear armband (BodyMedia [Jawbone]). Subjects wore the sensor on the nonparetic arm for 2 consecutive days from 9 am to 4:30 pm, corresponding to the period spent daily on rehabilitation. The Fisher simple correlation test and Mann-Whitney nonparametric test were performed. RESULTS: A total of 88 patients aged 66 +/- 17 years with a mean poststroke period of 43 +/- 34 days and a mean Barthel Index of 61 +/- 25/100 were enrolled in the study. Between 9 am and 4:30 pm, patients took part in an average of 23 +/ 30 minutes of physical activity (equivalent to 91 +/- 122 kcal). Correlations were found between physical activity time in the hospital and physical activity before the stroke occurred (r = 0.345, P < .0001), the Barthel Index (r = 0.284, P = .0002), body mass index (r = -0.440, P < .0001), and time to hospital release (r = -0.183, P = .0194). CONCLUSION: It was found that 62% of patients did not achieve the recommended amount of physical activity. Sessions dedicated to physical activity could motivate patients who have had a stroke and help them meet recommendations before leaving the rehabilitation unit. PMID- 26107541 TI - Dying matters, still. PMID- 26107542 TI - What is the evidence for evidence? PMID- 26107543 TI - Prevention and management of chemotherapy-induced nausea and vomiting. AB - Nausea and vomiting are among the most frequently experienced toxic side-effects associated with chemotherapy. Although nausea and vomiting can result from surgery or radiotherapy, chemotherapy-induced nausea and vomiting (CINV) is potentially the most severe and most distressing. Estimates regarding the incidence of CINV vary depending on the treatment administered and individual patient characteristics.The impact of CINV on quality of life (QoL) and daily activities is considerable. Pharmacological treatments are considered routine for CINV. Clinical guidelines now recommend that patients receiving moderate emetic chemotherapy (MEC) regimens be preferentially treated with palonosetron, the 5 hydroxytryptamine type 3 (5-HT3) receptor antagonist, in combination with dexamethasone. In addition, it has shown that single-dose fosaprepitant is equivalent to the standard 3-day aprepitant regimen (the neurokinin 1 (NK1) receptor antagonist). Despite these advances in antiemetic management, approximately 50% of patients receiving chemotherapy still experience nausea and/or vomiting. Further improvements are still desirable, particularly in the prevention and treatment of delayed CINV. Non-pharmacological interventions can be possible adjuncts to standard anti-emetic therapy. Using new technologies to collect patient-reported outcomes may improve the accuracy of assessment, provide a better picture of the patient's experience of these symptoms, and provide a means to simultaneously monitor symptoms, educate patients, and collect longitudinal data. PMID- 26107544 TI - Evidence-based guidelines for pressure ulcer management at the end of life. AB - It is important to develop an individualised plan of care for people at the end of life to prevent pressure ulcers, and to treat them if they do occur. This article discusses patient and risk assessment, prevention and care for pressure ulcers for the palliative care patient and the recommendations given in the palliative care section of the Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline (National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel and Pan Pacific Pressure Injury Alliance, 2014). PMID- 26107545 TI - Why diversity matters in advance care planning. PMID- 26107546 TI - When dying at home is not an option: exploration of hostel staff views on palliative care for homeless people. AB - BACKGROUND: The Department of Health in the UK suggest that hostel staff are the most appropriate key workers for their dying homeless residents and that hostel based palliative care may be the best way forward. However, little is known about the views of hostel staff with regard to this. METHODS: Semi-structured qualitative interviews were conducted with seven participants from hostels distributed across three counties. A total of 37 specific case studies were discussed involving homeless residents with a wide range of life-limiting or palliative conditions. FINDINGS: Eight main themes emerged: understanding palliative care; working with limited medical information; taking responsibility; building rapport; upholding residents' dignity; recognising physical deterioration; managing environmental challenges; role limitations and support needs of hostel staff. CONCLUSION: Discussion centred around the following four topics: policy, principles and practice of palliative care; professional boundaries as a threat to holism and a hindrance to dignity; the social undesirability and invisibility of homeless people; 'community living' as a barrier to hostel-based palliative care and a new concept of family. PMID- 26107547 TI - Hospice to home: a patient-centric multi professional community approach. AB - As people live longer with multidimensional health and end-of-life care needs, palliative care provision is becoming increasingly complex. Demands on hospice services are increasing, therefore new models of care are needed that are accessible to a wider range of patients. Most people prefer to die at home (Gomes et al, 2013a); however, evidence reports that the most common place of death is hospital (53%) (Marie Curie, 2013). This article describes how one hospice developed a model of care working in partnership with statutory services that provided patient-centred care, achieved preferences and prevented unnecessary admissions into hospital. It describes each element of the model and how they work seamlessly together. The evaluation of the model suggests that maximal impact can be gained by focusing service development on expanding and improving care at home. Preventing unnecessary hospital admissions, while simultaneously improving the quality of care, remains the fundamental driver for high-quality end-of-life care. PMID- 26107548 TI - Assisting patients with motor neurone disease to make decisions about their care. AB - Motor neurone disease (MND), is a progressive terminal illness affecting the central nervous system, causing paralysis of the muscles affecting limb movement, breathing and bulbar function, with an average life expectancy of 2-4 years. Patients are presented with repeated loss and the constant need to make adjustments to their lifestyle and expectations. Within palliative care there has been a move to formalise planning by undertaking advance care planning, giving the patient the opportunity to plan whether they would consider medical interventions and how they would like their care and death to be managed. There are now a multitude of forms and documents to complete if the patient is willing to do so. Advance care planning may not be something all patients wish to embrace, and this poses the question of whether there are cases where the repeated demand to think forward to a time when further losses are experienced is serving the agenda of the health professional at the expense of the patient. Nevertheless, health professionals might be concerned that a delay in decision making could impact on the patient's future care. There is potential for conflict between the wish of the patient--to remain focused on the positive--and the health professional's perception of the benefits of completing an advance care plan or discussing interventions which, if persued, might lead to a breakdown of the therapeutic relationship. A more flexible approach, focusing on the agenda set by the patient, underpinned by a therapeutic and trusting relationship, can avoid distress for the patient, while ensuring good care and the best outcome for the patient. PMID- 26107550 TI - Isolated Ileal Pancreatic Heterotopia Causing Intussusception with Gangrene. AB - Isolated ileal heterotopic pancreatic tissue as a lead point of intussusception in children is extremely rare. We report a 6-month-old female with ileoileal intussusception and a 4-year-old female with ileocolic intussusception both associated with gangrene. A review of literature suggests a higher prevalence of gangrene probably secondary to the pancreatic exocrine tissue. PMID- 26107551 TI - Insight on Tricalcium Silicate Hydration and Dissolution Mechanism from Molecular Simulations. AB - Hydration of mineral surfaces, a critical process for many technological applications, encompasses multiple coupled chemical reactions and topological changes, challenging both experimental characterization and computational modeling. In this work, we used reactive force field simulations to understand the surface properties, hydration, and dissolution of a model mineral, tricalcium silicate. We show that the computed static quantities, i.e., surface energies and water adsorption energies, do not provide useful insight into predict mineral hydration because they do not account for major structural changes at the interface when dynamic effects are included. Upon hydration, hydrogen atoms from dissociated water molecules penetrate into the crystal, forming a disordered calcium silicate hydrate layer that is similar for most of the surfaces despite wide-ranging static properties. Furthermore, the dynamic picture of hydration reveals the hidden role of surface topology, which can lead to unexpected water tessellation that stabilizes the surface against dissolution. PMID- 26107553 TI - Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non Small-Cell Lung Cancer. AB - Approximately half of all patients with non-small-cell lung cancer (NSCLC) develop brain metastases (BM) during the course of their disease, leading to significant challenges in treatment. Molecular targeted tyrosine kinase inhibitors have proven effective for patients with activating mutations in the epidermal growth factor receptor gene and chromosomal rearrangements involving the anaplastic lymphoma kinase gene. Despite their efficacy in systemic disease control, their effectiveness in patients with BM is not well established. In this article, we review recent data on the use of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for treatment of patients with NSCLC and BM. These data highlight the potential for meaningful disease control within the central nervous system and the inherent challenges in treating patients with NSCLC and BM. PMID- 26107552 TI - Key concepts that people need to understand to assess claims about treatment effects. AB - OBJECTIVE: People are confronted with claims about the effects of treatments and health policies daily. Our objective was to develop a list of concepts that may be important for people to understand when assessing claims about treatment effects. METHODS: An initial list of concepts was generated by the project team by identifying key concepts in literature and tools written for the general public, journalists, and health professionals, and consideration of concepts related to assessing the certainty of evidence for treatment effects. We invited key researchers, journalists, teachers and others with expertise in health literacy and teaching or communicating evidence-based health care to patients to act as the project's advisory group. RESULTS: Twenty-nine members of the advisory group provided feedback on the list of concepts and judged the list to be sufficiently complete and organised appropriately. The list includes 32 concepts divided into six groups: (i) Recognising the need for systematic reviews of fair tests, (ii) Judging whether a comparison of treatments is fair comparison, (iii) Understanding the role of chance, (iv) Considering all the relevant fair comparisons, (v) Understanding the results of fair comparisons of treatments, (vi) Judging whether fair comparisons of treatments are relevant. CONCLUSION: The concept list provides a starting point for developing and evaluating resources to improve people's ability to assess treatment effects. The concepts are considered to be universally relevant, and include considerations that can help people assess claims about the effects of treatments, including claims that are found in mass media reports, in advertisements and in personal communication. PMID- 26107554 TI - Stereoselective formation and catalytic activity of hydrido(acylphosphane)(chlorido)(pyrazole)rhodium(III) complexes. Experimental and DFT studies. AB - The reaction of [{RhCl(COD)}2] (COD = 1,5-cyclooctadiene) with L = pyrazole (Hpz), 3(5)-methylpyrazole (Hmpz) or 3,5-dimethylpyrazole (Hdmpz) and PPh2(o C6H4CHO) (Rh : L : P = 1 : 2 : 1) gives hydridoacyl complexes [RhHCl{PPh2(o C6H4CO)}(L)2] (). Stereoselective formation of and with pyrazoles trans to hydrido and phosphorus and hydrogen bond formation with O-acyl and chlorido occur. is a mixture of two linkage isomers in a 9 : 1 ratio, with two 5 methylpyrazole ligands or with one 3- and one 5-methylpyrazole ligand, respectively. Fluxional undergoes metallotropic tautomerization and is a mixture of equal amounts of and , with hydrido trans to pyrazole or chlorido, respectively. Complexes readily exchange hydrido by chlorido to afford [RhCl2{PPh2(o-C6H4CO)}(L)2] (, and ) as single isomers with cis chloridos and two N-HCl hydrogen bonds. The reaction of with PPh3 or PPh2OH affords static [RhHCl{PPh2(o-C6H4CO)}(PPh3)L] () or [RhHCl{PPh2(o-C6H4CO)}(PPh2OH)L] () respectively with trans P-atoms and pyrazoles forming N-HCl hydrogen bonds. and contain single species with hydrido cis to chlorido, while is a mixture of equal amounts of and . Complexes , with an additional O-HO hydrogen bond, selectively contain only the cis-H,Cl species with all the three ligands. The reaction of [{RhCl(COD)}2] with L and PPh2(o-C6H4CHO) (Rh : L : P = 1 : 1 : 2) led to complexes with trans P-atoms, [RhHCl{PPh2(o-C6H4CO)}{PPh2(o-C6H4CHO)-kappaP}L] (, and ), at room temperature, and to [RhCl{PPh2(o-C6H4CO)}{PPh2(o-C6H4CHOH)}(Hmpz)] () or [RhCl{PPh2(o-C6H4CO)}2L] () with hydrogen evolution in refluxing benzene. DFT calculations were used to predict the correct isomers, their ratios and the particular intramolecular hydrogen bonds in these complexes. Single crystal X-ray diffraction analysis was performed on , and . Complexes are efficient homogeneous catalysts (0.5 mol% loading) in the hydrolysis of amine- or ammonia-borane (AB) to generate up to 3 equivalents of hydrogen in the presence of air. PMID- 26107555 TI - The Ultrastructure of MCF-7 Breast Cancer Cells after Vasodilator-Stimulated Phosphoprotein Knockdown. AB - Inhibition of vasodilator-stimulated phosphoprotein (VASP) expression could modulate the adhesion and proliferation of breast cancer cells. However, the underlying mechanisms are not well defined. Here, we show that knockdown of the VASP changes the ultrastructure of human MCF-7 breast cancer cells. Transfection of VASP shRNA significantly lowered the expression of VASP protein in MCF-7 cells. In the shRNA-VASP group, immunofluorescence showed diminished presence of F-actin, and it was lower in the nucleus than in the cytoplasm. After VASP was inhibited, the MCF-7 cells were oval in shape with blunt lamellipodium, disappearance of the cristae of mitochondria, decreased microvilli and more vacuoles. Collectively, our findings elucidated the morphological mechanism that knockdown of the VASP changed the ultrastructure of MCF-7 cells. PMID- 26107557 TI - Unfolding the story of chromatin organization in senescent cells. AB - Cell senescence, the permanent withdrawal of a cell from the cell cycle, is characterized by dramatic, cytological scale changes to DNA condensation throughout the genome. While prior emphasis has been placed on increases in heterochromatin, such as the formation of compact Senescent Associated Heterochromatin Foci (SAHF) structures, our recent findings showed that SAHF formation is preceded by the unravelling of constitutive heterochromatin into visibly extended structures, which we have termed Senescent Associated Distension of Satellites or SADS. Interestingly, neither of these marked changes in DNA condensation appear to be mediated by changes in canonical, heterochromatin associated histone modifications. Rather, several observations suggest that these events may be facilitated by changes in LaminB1 levels and/or other factors that control higher-order chromatin architecture. Here, we review what is known about senescence-associated chromatin reorganization and present preliminary results using high-resolution microscopy techniques to show that each peri/centromeric satellite in senescent cells is comprised of several condensed domains connected by thin fibrils of satellite DNA. We then discuss the potential importance of these striking changes in chromatin condensation for cell senescence, and also as a model to provide a needed window into the higher-order packaging of the genome. PMID- 26107558 TI - Serous Tubal Intraepithelial Carcinoma (STIC)-like Lesions Arising in Ovarian Serous Cystadenofibroma: Report of 2 Cases. AB - Recent studies have demonstrated that most so-called ovarian high-grade serous carcinomas are likely to arise from the epithelium of the distal fimbrial portion of the fallopian tube from a precursor lesion known as serous tubal intraepithelial carcinoma (STIC). We report 2 cases in patients aged 56 and 71 of lesions morphologically identical to STIC (referred to as STIC-like lesions) arising from the benign ciliated epithelium of ovarian serous cystadenofibromas. In 1 case, 2 glands within the serous cystadenofibroma exhibited high-grade nuclear atypia and mitotic activity and in the other similar changes were multifocal. No invasion of the stroma was seen. In both cases, the STIC-like lesion exhibited aberrant "mutation-type" staining with p53 (1 diffuse intense positivity, 1 null pattern). As far as we are aware, a STIC-like lesion involving the epithelium of a benign ovarian serous neoplasm has not been reported previously. Both patients were followed up without adjuvant treatment. One case is recent, and follow-up in the other patient is uneventful at 12 mo. PMID- 26107559 TI - Pelvic Ependymoma With Clinical Response to GnRH Analog Therapy: A Case Report With an Overview of Primary Extraneural Ependymomas. AB - Extraneural ependymomas are rare tumors that occur in sacrococcygeal, pelvic and extra pelvic regions. While sacrococcygeal extraneural ependymomas are equally distributed among males and females, pelvic and extra pelvic ependymomas have been exclusively reported in women, mainly of child bearing age. We present a case of extraneural, pelvic ependymoma that showed clinical response to GnRH therapy with its immunohistochemical and electron microscopic analysis, and an overview of primary extraneural ependymomas based on a review of all such cases published in English literature. PMID- 26107560 TI - Immunophenotypic Analysis in Early Mullerian Serous Carcinogenesis. AB - Studies on the immunophenotypes of early forms of serous carcinoma arising from female genital tract are limited. We aimed to examine p53, p16(Ink4a), estrogen receptor (ER), progesterone receptor (PR), ERBB2, WT1, and Ki-67 protein expression in endometrial intraepithelial carcinoma (n=29), serous tubal intraepithelial lesion (n=4) and carcinoma (STIC, n=10), and the putative precursor p53 signature (n=11). Among endometrial intraepithelial carcinoma, 80% demonstrated p53 overexpression and 10% were consistent with a null phenotype. p16(Ink4a) immunostaining were observed in all endometrial intraepithelial carcinoma cases. ER, PR, ERBB2, and WT1 were positive in 54%, 25%, 11%, and 18% of cases, respectively. STIC cases demonstrated p53 overexpression and null phenotype in 90% and 10%, respectively. All STIC cases were p16(Ink4a) and WT1 positive, whereas ER and PR were positive in 70% and 20%, respectively. All STICs were negative for ERBB2. Among serous tubal intraepithelial lesion cases, 75% demonstrated p53 overexpression and 25% a null phenotype. p53 was positive in all 11 p53 signature cases, whereas p16(Ink4a) was universally negative. Finally, ER and PR were positive in 100% and 73% of p53 signature cases, respectively. These results suggest that p16(Ink4a) has a role in early Mullerian serous carcinogenesis but is absent in the earliest noncommitted lesion. p16(Ink4a) immunohistochemistry can be used as an adjunct confirmatory tool in p53-null cases with limited surface area. PMID- 26107561 TI - Collision of Ductal Carcinoma In Situ of Anogenital Mammary-like Glands and Vulvar Sarcomatoid Squamous Cell Carcinoma. AB - A spectrum of invasive adenocarcinomas presumably arising from the anogenital mammary-like glands of the vulva has been reported. Even rarer are the cases of pure ductal carcinoma in situ that originated from these unique glandular structures. Herein, we report an 81-yr-old woman presented with an invasive well differentiated squamous cell carcinoma of the vulva. Unexpectedly, the underlying dermis demonstrated a cystically dilated structure that displayed a layer of malignant squamous cells in the periphery, and a second centrally located population of neoplastic cells exhibiting glandular differentiation. In addition, a spindle and pleomorphic malignant cell population consistent with a sarcomatoid carcinoma was identified around the cystic structure. Scattered benign anogenital mammary-like glands were present in the adjacent dermis. The histologic and immunohistochemical findings were consistent with those of vulvar squamous cell carcinoma that has undergone sarcomatoid transformation after spreading in a pagetoid fashion into an underlying focus of ductal carcinoma in situ of anogenital mammary-like gland origin. PMID- 26107562 TI - Pseudorosette-Like Proliferations of the Endometrium. AB - The endometrium displays a wide spectrum of appearances in both neoplastic and non-neoplastic tissue. Unusual proliferations are not infrequently encountered and may lead to misinterpretation. In this study, we investigated pseudorosette like proliferations (PLPs) found within the endometrial stroma which, to our knowledge, have not been previously reported. Nineteen endometrial samples with PLPs were identified over a period of 5 yr. Characteristics of the endometrium in which the PLPs were arising as well as patient information were recorded for each case. In addition, residual tissue from 10 of the cases was immunostained for cytokeratin, CD10, smooth muscle actin, S-100, and caldesmon to better characterize the lesions. In all cases the endometrium was in the proliferative phase and none of the patients reported the use of exogenous hormones. In 89% (17 of 19) of the cases, PLPs were present as a single focus; 2 cases showed multiple PLPs. Of the 10 immunostained cases, 90% (9 of 10) showed strong/diffuse staining for smooth muscle actin. Six cases showed negative or weak (1+) staining for CD10, whereas 3 showed moderate (2+) and 1 showed strong (3+) staining. In all cases the PLPs were negative for cytokeratin AE1/AE3, S-100, and caldesmon. These studies suggest that PLPs are benign proliferations with smooth muscle differentiation. PMID- 26107563 TI - Expression of Transcription Factors and Nuclear Receptors in Mixed Germ Cell-Sex Cord Stromal Tumor and Related Tumors of the Gonads. AB - In this study, we compare the expression of OCT4, SALL4, and TSPYL1 in mixed germ cell-sex cord stromal tumor (MGC-SCST) of either gonad to that of normal adult testis, classic and spermatocytic seminoma, intratubular germ cell neoplasia, unclassified, gonadoblastoma, and dysgerminoma to determine the entity or entities that most closely resemble MGC-SCST by immunohistochemistry of germ cells. The most useful transcription factor was OCT4. In addition, to its already described value in distinguishing germinoma and embryonal carcinoma from yolk sac tumor and in differentiating classic from spermatocytic seminoma, we found that OCT4 is useful in confirming or ruling out potential malignancy in MGC-SCST of either gonad. Expression of OCT4 in most ovarian MGC-SCSTs resembles that of dysgerminoma, whereas most testicular examples resemble that of spermatocytic seminoma and normal adult testis. Thus, most MGC-SCSTs of the ovary are potentially malignant, and corresponding tumors of the testis are mostly benign; however, exceptions likely can be detected by the use of OCT4, potentially leading to more appropriate clinical management in some cases. SALL4 is an underutilized transcription factor that is useful in distinguishing testicular MGC-SCST from sex cord stromal tumor, unclassified in those neoplasms where the germ cells are sparse or unevenly distributed. Compared with other transcription factors studied, TSPY and its congener TSPYL1 have little value in the assessment of germ cell tumors because of their relatively wide range of expression in normal adult testis and in germ cell tumors. PMID- 26107564 TI - Solitary Fibrous Tumor of the Uterus Presenting With Lung Metastases: A Case Report. AB - We describe the case of an 81-yr-old woman who presented with bilateral pulmonary nodules in the setting of a large uterine mass, concerning for a gynecologic malignancy such as leiomyosarcoma. However, fine-needle aspiration of a lung nodule revealed a spindle cell neoplasm consistent with solitary fibrous tumor (SFT), a rare mesenchymal neoplasm characterized by a patternless architecture of spindle cells and branching ectatic vessels. Total abdominal hysterectomy demonstrated a primary SFT of the uterus. Both the lung lesion and uterine mass were positive for STAT6, a sensitive and specific biomarker for SFT. SFT infrequently metastasizes and only rarely occurs in the uterus. These tumors are considered to have uncertain malignant potential, and the diagnosis of "malignant" SFT requires the presence of >4 mitoses per 10 high-power fields. The uterine SFT we report did not meet this criterion for malignancy, emphasizing that this entity can behave aggressively even without increased mitoses or atypical histology. To our knowledge, this is the first reported case of a uterine SFT with metastasis to the lung. We discuss the differential diagnosis for the finding of multiple pulmonary spindle cell lesions in the setting of a uterine mass. PMID- 26107565 TI - Diagnosis of Ovarian Carcinoma Histotype Based on Limited Sampling: A Prospective Study Comparing Cytology, Frozen Section, and Core Biopsies to Full Pathologic Examination. AB - Growing insights into the biological features and molecular underpinnings of ovarian cancer has prompted a shift toward histotype-specific treatments and clinical trials. As a result, the preoperative diagnosis of ovarian carcinomas based on small tissue sampling is rapidly gaining importance. The data on the accuracy of ovarian carcinoma histotype-specific diagnosis based on small tissue samples, however, remains very limited in the literature. Herein, we describe a prospective series of 30 ovarian tumors diagnosed using cytology, frozen section, core needle biopsy, and immunohistochemistry (p53, p16, WT1, HNF-1beta, ARID1A, TFF3, vimentin, and PR). The accuracy of histotype diagnosis using each of these modalities was 52%, 81%, 85%, and 84% respectively, using the final pathology report as the reference standard. The accuracy of histotype diagnosis using the Calculator for Ovarian Subtype Prediction (COSP), which evaluates immunohistochemical stains independent of histopathologic features, was 85%. Diagnostic accuracy varied across histotype and was lowest for endometrioid carcinoma across all diagnostic modalities (54%). High-grade serous carcinomas were the most overdiagnosed on core needle biopsy (accounting for 45% of misdiagnoses) and clear cell carcinomas the most overdiagnosed on frozen section (accounting for 36% of misdiagnoses). On core needle biopsy, 2/30 (7%) cases had a higher grade lesion missed due to sampling limitations. In this study, we identify several challenges in the diagnosis of ovarian tumors based on limited tissue sampling. Recognition of these scenarios can help improve diagnostic accuracy as we move forward with histotype-specific therapeutic strategies. PMID- 26107566 TI - Microcystic Stromal Tumor of the Ovary: A Case Report of a Newly Described Ovarian Neoplasm With a beta-catenin (CTNNB1) G34E Mutation. AB - Microcystic stromal tumor of the ovary (MSTO) is an exceedingly rare, unusual, and recently described entity with unique genetic alterations that assist in its diagnosis. We describe the case of a 50-year-old woman who presented with a complex right ovarian mass. A hysterectomy with bilateral salpingo-oophorectomy was performed and revealed an ovarian mass consistent with MSTO by histomorphology and immunohistochemical studies. Tumor cells were immunohistochemically reactive for vimentin, CD10, beta-catenin, and Wilms tumor 1. In addition, we detected a missense mutation c.101 G>A, p.G34E in exon 3 of the beta-catenin (CTNNB1) gene, which leads to an amino acid substitution of glycine at codon 34 by glutamic acid. The utility of genetic testing of this tumor and additional reporting of alterations detected is needed to verify pathogenicity of variants detected, as well as their potential roles with prognosis, behavior, and therapeutic targets. The overall clinical course of MSTO appears to be nonaggressive, although the number of reported cases are limited thus far. PMID- 26107567 TI - Immunohistochemical Expression and Prognostic Significance of CD97 and its Ligand DAF in Human Cervical Squamous Cell Carcinoma. AB - Accumulating evidences had demonstrated that the CD97, a member of the epidermal growth factor 7-transmembrane family, and its cellular ligand decay accelerating factor (DAF) both play important roles in tumor dedifferentiation, migration, invasiveness, and metastasis. However, the roles of CD97 and DAF in human cervical squamous cell carcinoma (CSCC) have not been investigated. The purpose of this study was to observe the expression profile of CD97 and DAF in CSCC and evaluate their clinical significance. Immunohistochemistry was used to investigate the expression of CD97 and DAF proteins in 97 patients with CSCC and 53 patients with cervical intraepithelial neoplasia, a precursor lesion of CSCC. CD97 and DAF were absent or only weakly expressed in the normal epithelium of the cervix but were present in 83.5% (81/97) and 90.7% (88/97) of CSCC samples, respectively. Overexpression of CD97 was significantly associated with a high International Federation of Gynecology and Obstetrics stage (P=0.010) and lymph node metastasis (P=0.026). The majority of CSCCs, irrespective of staging/grading classification, displayed strong DAF immunostaining. Kaplan-Meier survival analysis revealed that overexpression of CD97 was associated with a worse prognosis. Multivariate analyses showed that the International Federation of Gynecology and Obstetrics stage (P=0.000), lymph node metastasis (P=0.004), and CD97 expression (P=0.040) were independent risk factors for overall survival. The present study suggested that the expressions of CD97 and DAF were both upregulated in CSCC. The expression level of CD97 in CSCC was associated with the severity of the tumor. Furthermore, CD97 might be an independent poor prognostic factor for CSCC patients. PMID- 26107568 TI - A Novel Synthesized Sulfonamido-Based Gallate-JEZ-C as Potential Therapeutic Agents for Osteoarthritis. AB - Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on osteoarthritis (OA). However, GA has much weaker anti-oxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel compound named JEZ-C and analyzed its anti-arthritis and chondro-protective effects. Comparison of JEZ C with its sources i.e. GA and Sulfamethoxazole (SMZ) was also performed. Results showed that JEZ-C could effectively inhibit the IL-1-mediated induction of MMP-1 and MMP-13 and could induce the expression of TIMP-1, which demonstrated its ability to reduce the progression of OA. JEZ-C can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Meanwhile, expression of the collagen I gene was effectively downregulated, revealing the inhibition of chondrocytes dedifferentiation by JEZ-C. Hypertrophy that may lead to chondrocyte ossification was also undetectable in JEZ-C groups. The recommended dose of JEZ-C ranges from 6.25*10-7 MUg/ml to 6.25*10-5 MUg/ml, among which the most profound response was observed with 6.25*10-6 MUg/ml. In contrast, its source products of GA and SMZ have a weak effect not only in the inhibition of OA but also in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed JEZ-C as a promising novel agent in the treatment of chondral and osteochondral lesions. PMID- 26107569 TI - [Aspects of early sexual activity]. PMID- 26107570 TI - [Frequency of Human Papillomavirus in the placenta, in the colostrum and in the umbilical cord blood]. AB - PURPOSE: To determine the frequency of Human Papillomavirus (HPV) in the placenta, in the colostrum and in the umbilical cord blood of parturient women and their newborns assisted at the Clinic of Gynecology and Obstetrics of the University Hospital of Rio Grande (RS), Brazil. METHODS: Biopsies were collected from 150 placentas on the maternal side, 150 on the fetal side, 138 samples of umbilical cord blood and 118 of the colostrum. The placenta biopsies were collected from the central and peripheral portions. DNA was extracted according to the manufacturer's protocol and to a reference found in the literature. HPV was detected by the nested polymerase chain reaction (PCR-Nested) using primers MY09/11 and GP5/GP6. Genotyping was performed by direct sequencing. The participants responded to a self-applied questionnaire with demographic and clinical data, in order to characterize the sample. RESULTS: HPV was detected in 4% (6/150) of cases on the mother's side of the placentas, in 3.3% (5/150) on the fetal side, in 2.2% (3/138) in umbilical cord blood and in 0.84% (1/118) in colostrum samples. The vertical transmission rate was 50%. HPV-6 was the low-risk genotype found (60%) and the high-risk genotypes were HPV-16 and HPV-18 (20% each). CONCLUSIONS: These results suggest that HPV can infect the placenta, the colostrum and the umbilical cord blood. PMID- 26107571 TI - [Temporal evolution of anemia prevalence in pregnant adolescents of a public maternity of Rio de Janeiro]. AB - PURPOSE: To describe the evolution of the prevalence of anemia in pregnant adolescents attended at a public maternity in the city of Rio de Janeiro from 2004 to 2013. METHODS: A retrospective cross-sectional study with 628 pregnant/postpartum women divided into 3 groups: Group A (2004-2006), Group B (2007-2010) and Group C (2013). Information about anthropometric, clinical, sociodemographic data and obstetric and prenatal care of adolescents was obtained from medical records of the pregnant women. A hemoglobin concentration n<11 g/dL was considered to be anemia. Data were analyzed statistically by the chi-square test, Student's t-test and ANOVA, and the post hoc Tukey test. RESULTS: The prevalence of gestational anemia over the years was 43% (GA=138), 36% (GB=80) and 47.1% (GC=40) and the overall prevalence for the 2004-2013 period was 41.1% (n=258). The occurrence of anemic pregnant women increased with the progression of pregnancy; however, in the 3rd quarter there was a decrease in the prevalence of anemia in GB (29.3%) compared to GA (38.7%; p=0.04). Factors associated with anemia were number of prenatal visits and prenatal nutritional assistance, place of residence, pre-pregnancy BMI, and gestational weight gain. CONCLUSION: The results showed that the prevalence of anemia among pregnant adolescents seen at a public maternity is high. There was no reduction of anemia during the study period and other factors in addition to iron deficiency were involved in the genesis of anemia in this population. PMID- 26107572 TI - Do induced twin pregnancies influence the obstetric and neonatal results of multiple births born before 32 weeks? Comparison to spontaneous gestation. AB - PURPOSE: To compare obstetric outcomes of induced preterm twin births (under 32 weeks gestation) with those spontaneously conceived. METHODS: Prospective study of twin pregnancies (25 induced and 157 spontaneously conceived) developed over a period of 16 years in a tertiary obstetric center. Demographic factors, obstetric complications, gestational age at delivery, mode of delivery, birth weight and immediate newborn outcome were compared. RESULTS: The analysis of obstetrical complications concerning urinary or other infections, hypertensive disorders of pregnancy, gestational diabetes, fetal malformations, intrauterine fetal death, intrauterine growth restriction and intrauterine discordant growth reveal no significant statistical differences between the two groups. First trimester bleeding was higher in the induced group (24 versus 8.3%, p=0.029). The cesarean delivery rate was 52.2% in spontaneous gestations and 64% in induced gestations. Gestational age at delivery, birth weight, Apgar scores at first and fifth minutes, admissions to Neonatal Intensive Care Unit and puerperal complications show no statistically significant differences between the two groups. These results were independent of chorionicity and induction method. CONCLUSION: The mode of conception did not influence obstetric and neonatal outcomes. Although induced pregnancies have higher risk of first trimester bleeding, significant differences were not observed regarding other obstetric and puerperal complications and neonatal results. PMID- 26107573 TI - [Abnormal vaginal secretion: sensitivity, specificity and concordance between clinical and cytological diagnosis]. AB - PURPOSE: To estimate the prevalence of bacterial vaginosis (BV), candidiasis and trichomoniasis and compare the findings of physical examination of the vaginal secretion with the microbiological diagnosis obtained by cytology study of a vaginal smear using the Papanicolaou method. METHODS: A cross-sectional study of 302 women aged 20 to 87 years, interviewed and submitted to a gynecology test for the evaluation of vaginal secretion and collection of a cytology smear, from June 2012 to May 2013. Sensitivity analyses were carried out and specificity, positive predictive value (PPV) and negative predictive value (NPV) with their respective 95%CI were determined to assess the accuracy of the characteristics of vaginal secretion in relation to the microbiological diagnosis of the cytology smear . The kappa index (k) was used to assess the degree of agreement between the clinical features of vaginal secretion and the microbiological findings obtained by cytology. RESULTS The prevalence of BV, candidiasis and trichomoniasis was 25.5, 9.3 and 2.0%, respectively. The sensitivity, specificity, PPV and NPV of the clinical characteristics of vaginal secretion for the cytological diagnosis of BV were 74, 78.6, 54.3 and 89.9%, respectively. The sensitivity, specificity, PPV and the NPV of the clinical characteristics of vaginal secretion for the cytological diagnosis of candidiasis were 46.4, 86.2, 25.5 and 94%, respectively. The correlation between the clinical evaluation of vaginal secretion and the microbiological diagnosis of BV, candidiasis and trichomoniasis, assessed by the kappa index, was 0.47, 0.23 and 0.28, respectively. CONCLUSION The most common cause of abnormal vaginal secretion was BV. The clinical evaluation of vaginal secretion presented amoderate to weak agreement with the microbiological diagnosis, indicating the need for complementary investigation of the clinical findings of abnormal vaginal secretion. PMID- 26107574 TI - [Frequency of atypical squamous cells of undetermined significance (ASCUS) for pregnant and non-pregnant women]. AB - PURPOSE: To compare the frequency of an ASCUS Pap Smear result in pregnant and non-pregnant women, stratified by age group. METHODS: We analyzed the results of 1,336,180 cytopathologyc exams of Pap smears performed between 2000 and 2009 (ten years) with the purpose of screening for cervical carcinoma. Comparisons were made between pregnant and non-pregnant women, and the sample was stratified into three age groups (20-24, 25-29 and 30-34 years). The chi2 test was used and the magnitude of association was determined by the by Odds Ratio (OR) with the 95% confidence interval (95%CI). RESULTS: A Total of 447,489 samples were excluded on the basis of the criteria adopted, for a total final sample of 37,137 pregnant women and 851,554 non-pregnant women. An ASCUS result was detected in 1.2% of cases, with a significant difference between pregnant and non-pregnant women in the age groups of 20-24 years (OR=0.85; 95%CI 0.75-0.97) and 25-29 years (OR=0.78; 95%CI 0.63-0.96). There was no difference in the group between 30-34 years (OR=0.76; 95%CI 0.57-1.03). CONCLUSIONS: This study suggested that non pregnant women have a higher frequency of ASCUS, most evident in the age group of 20 to 29 years. The collection of cervical cancer screening should not be a compulsory part of the prenatal routine. PMID- 26107575 TI - [Effects of tibolone on the breast parenchyma: experimental study]. AB - OBJECTIVE: To assess the effect of tibolone on mammary tissue of castrated rats over 3 different periods of time. METHODS: Sixty virgin female Wistar rats were submitted to oophorectomy. Twenty-one days after surgery, with hypoestrogenism confirmed, the experimental rats were randomly assigned to six groups: Tibolone 1 (n=10) received tibolone 1 mg/day for 23 days, tibolone 2 (n=10) for 59 days and tibolone 3 (n=10) for 118 days. The groups control 1 (n=8), control 2 (n=7) and control 2 (n=10) received distilled water for 23, 59 and 118 days, respectively. After treatment, all six pairs of mammary glands were removed and stained with hematoxylin and eosin (HE) for histological analysis after euthanasia. The histological parameters evaluated were: epithelial cell proliferation and secretory activity. The variables were analyzed statistically, with the level of significance set at 0.05. RESULTS: Histological changes were observed in 20/55 rats, mild epithelial hyperplasia in 7/55, moderate epithelial hyperplasia in 5/55, alveolar-nodular hyperplasia in 7/55, atypia without epithelial proliferation in 1/55, and no cases of severe epithelial hyperplasia were found. Secretory activity was observed in 31/55 rats. The secretory activity was significantly higher in the tibolone groups compared to control at all the time points assessed (p=0,001). The histological changes were did not show significance when the control and tibolone groups were compared. The time of exposure to tibolone did not show significance when the three different periods of evaluation were compared. CONCLUSION: No relation between histological modification and tibolone treatment was verified after short-, medium- and long term treatment. PMID- 26107576 TI - Medico-legal litigation in Obstetrics: a characterization analysis of a decade in Portugal. AB - PURPOSE: It was to analyse the most critical areas in Obstetrics and to suggest measures to reduce or avoid the situations most often involved in these disputes. METHODS: Obstetrics cases submitted to the Medico-legal Council since the creation of the National Institute of Legal Medicine and Forensic Sciences in 2001 until 2011 were evaluated. A comprehensive characterization, determination of absolute/relative frequencies, hypothesis of a linear trend over the years and the association between each parameter was done. RESULTS: The analysis has shown no significantly linear trend. The most common reasons for disputes were perinatal asphyxia (50%), traumatic injuries of the newborn (24%), maternal sequelae (19%) and issues related to prenatal diagnosis and/or obstetric ultrasound (5.4%). Perinatal asphyxia showed no significantly linear trend (p=0.58) and was usually related to perinatal deaths or permanent neurologic sequelae in newborn children. Traumatic injuries of the newborn, mostly related to instrumented deliveries, shoulder dystocia or vaginal delivery in breech presentation, has shown a significantly increased linear trend (p<0.001), especially related to instrumented deliveries. The delay/absence of cesarean section was the clinical procedure questioned in a significantly higher number of cases of perinatal asphyxia (68.7%) and of traumatic lesions of the newborn due to instrumented deliveries (20.5%). CONCLUSION: It is important to improve and correct theoretical/practical daily clinical performance in these highlighted areas, in order to reduce or even avoid situations that could end up in medico legal litigations. PMID- 26107579 TI - Psychological and cortisol reactivity to experimentally induced stress in adults with ADHD. AB - Individuals with ADHD suffer from increased vulnerability to environmental and mental stressors and may be at increased risk for chronic stress in everyday life. The Hypothalamic-Pituitary-Adrenal (HPA) axis is a critical physiological system that mediates responses to stress. The present study seeks to examine test performance, test anxiety, self-reported psychological stress and cortisol reactivity to mental-cognitive stress in adults with ADHD when compared with healthy controls. Stress was induced by an arithmetic ability test. Psychological stress was assessed repeatedly throughout the experimental session. Salivary cortisol, an indicator of the HPA axis function, was evaluated immediately upon arrival, as well as 1 min and 20 min post-test completion. Results revealed higher levels of test anxiety and poorer performance on the test in the ADHD group. The ADHD and control groups showed no difference in base-line levels of subjective stress and in subjective stress levels 20 min after the test. In contrast, individuals with ADHD reported significantly higher levels of stress at the test anticipation phase and 1 min post-test completion. Cortisol response to stress differed according to group: in the ADHD group, 20 min post-test cortisol levels were significantly higher than base-line cortisol levels. This was not evident in the control group. These results suggest greater activation of the HPA axis in response to stress in adults with ADHD when compared with healthy controls. Adults with ADHD do not differ from controls in basal levels of subjective stress and cortisol, but do have stronger psychophysiological reactions in response to stressful challenges. The present findings are among the first to demonstrate significant alterations in cortisol reactivity to stress in adults with ADHD. PMID- 26107580 TI - The Nanotechnology Revolution. PMID- 26107577 TI - Obesity and Aging: Consequences for Cognition, Brain Structure, and Brain Function. AB - OBJECTIVES: This review focuses on the relationship between obesity and aging and how these interact to affect cognitive function. The topics covered are guided by the Scaffolding Theory of Aging and Cognition (STAC [Park and Reuter-Lorenz. Annu Rev Psychol 2009;60:173-96]-a conceptual model designed to relate brain structure and function to one's level of cognitive ability. METHODS: The initial literature search was focused on normal aging and was guided by the key words, "aging, cognition, and obesity" in PubMed. In a second search, we added key words related to neuropathology including words "Alzheimer's disease," "vascular dementia," and "mild cognitive impairment." RESULTS: The data suggest that being overweight or obese in midlife may be more detrimental to subsequent age-related cognitive decline than being overweight or obese at later stages of the life span. These effects are likely mediated by the accelerated effects obesity has on the integrity of neural structures, including both gray and white matter. Further epidemiological studies have provided evidence that obesity in midlife is linked to an increased risk for Alzheimer's disease and vascular dementia, most likely via an increased accumulation of Alzheimer's disease pathology. CONCLUSIONS: Although it is clear that obesity negatively affects cognition, more work is needed to better understand how aging plays a role and how brain structure and brain function might mediate the relationship of obesity and age on cognition. Guided by the STAC and the STAC-R models, we provide a roadmap for future investigations of the role of obesity on cognition across the life span. PMID- 26107578 TI - A tug-of-war between the host and the pathogen generates strategic hotspots for the development of novel therapeutic interventions against infectious diseases. AB - Microbial pathogens are known to express an array of specific signaling molecules referred as Pathogen Associated Molecular Patterns (PAMPs), which are recognized by Pattern Recognition Receptors (PRRs), present on the surface of the host cells. Interactions between PAMPs and PRRs on the surface of the host cells lead to signaling events which could culminate into either successful infection or clearance of the pathogens. Here, we summarize how these events may generate novel host based as well as pathogen based molecular targets for designing effective therapeutic strategies against infections. PMID- 26107581 TI - Objective Sounds Better Than Subjective: Is It? Issues of Validity, Relevance, and Cost in Diagnostic Testing. AB - There has been a push in medical diagnostics and treatment to move toward objective testing and away from subjective testing. However, it is not certain that the superiority of one over the other is as clear cut as is usually considered to be the case. This issue is raised because there are advantages and disadvantages to every testing modality. The important considerations are degree of validity, of relevance, and of ease of obtaining the test, regardless of the type of testing. When a clinical diagnosis is certain or virtually certain, there is no need to use a test for diagnostic purposes. There still might be a justification for testing, however, even in such situations. In most instances, meaningful interpretation of a test result requires clinical information. Such clinical information is, of course, subjective, but still necessary. The use of tests in the clinic has to be directed by the "subjective" clinical examination, else the results make no sense. Subjective is "subjective" and as such open to biased interpretation. "Objective tests" also are often open to as much bias and misinterpretation as are subjective evaluations; they can seduce us into a false sense of security. It is essential to remember that the need for clinical evaluation will remain, and that the quality of the clinical evaluation is what is most critical to appropriate evaluation of any test result. PMID- 26107582 TI - Scheimpflug Analysis of Centration and Bending of Posterior Chamber Phakic Intraocular Lenses. AB - PURPOSE: The aim of the study was to present a novel technique for the assessment of postoperative centration and bending in phakic intraocular lens (PIOL), illustrated through 4 patient examples. DESIGN: This was a prospective observational study. METHODS: Four patients (7 eyes) who presented with complaints of reduced quality of vision after implantation with a Staar Collamer plate haptic PIOL were recruited for assessment. Scheimpflug images were obtained and analyzed with respect to the apical axis and the crystalline lens by means of an in-house-developed algorithm. The program provides an estimate for the PIOL centration and bending through an analysis of the distance between the PIOL and the crystalline lens. RESULTS: The algorithm detected PIOL bending in 5 of the 7 eyes and PIOL decentration in 3 eyes. The PIOL bending or decentration detected corresponded, in all cases, with the axis of the astigmatism-like complaints in the patient. In 2 eyes of the same patient, the analysis could not be performed because the distance between PIOL and crystalline lens was too short for reliable analysis. CONCLUSIONS: This algorithm is a useful tool to objectively assess the postoperative complaints of patients implanted with a posterior chamber PIOL. Bending and decentration due to anatomical variations of the sulcus lens position can be measured and in many cases correlated with patients' complaints. PMID- 26107583 TI - Quick Referral and Urgent Surgery to Preempt Foveal Detachment in Retinal Detachment Repair. AB - PURPOSE: This study aimed to evaluate the consultation and referral pathway and benefit of urgent surgery within 24 hours of outpatient clinic presentation on increasing the ratio of eyes with fovea-on at surgery and visual outcomes in retinal detachment cases. DESIGN: This is a retrospective, interventional case series. METHODS: A total of 106 eyes underwent an operation for rhegmatogenous retinal detachment. Standard vitrectomy or explant scleral buckling was performed. The ratio of eyes with fovea-on at the time of operation, anatomical success rate, and postoperative best corrected visual acuity were measured. RESULTS: Of the106 eyes, 46 (43.4%) already were fovea-off at initial eye clinic visit, and 9 eyes became fovea-off during referral. Consequently, 55 patients (51.9%) were fovea-off when presenting to our outpatient clinic. Retinal detachment was within 1 disc diameter of the fovea in 9 of 51 eyes with fovea-on at outpatient clinic presentation, but surgery within 24 hours spared 6 eyes from foveal involvement. The anatomical success rate of primary surgery was 98.8% (81/82 eyes) by vitrectomy and 83.3% (20/24 eyes) by scleral buckling. Postoperative best corrected visual acuity of the fovea-on group was significantly higher (mean [SD], -0.019 [0.22] logarithm of the minimal angle of resolution) than that of the fovea-off group (mean [SD], 0.32 [0.45] logarithm of the minimal angle of resolution; P = 0.002). CONCLUSIONS: More than half (51.9%) of our cohort had already been fovea-off by outpatient presentation. Therefore, efforts to urge patients to visit operating facilities promptly seem to be as important as the urgent surgeries themselves. PMID- 26107584 TI - A 31/2-Year Study of Bacterial Keratitis From Odisha, India. AB - PURPOSE: To report the clinical and microbiological characteristics and treatment outcome of bacterial keratitis at a tertiary eye care center in eastern India. DESIGN: Retrospective analysis of medical and microbiology records. METHODS: All patients had undergone complete clinical and microbiological evaluation for microbial keratitis. Patients with laboratory-proven bacterial keratitis were included in the study. RESULTS: Between July 2006 and December 2010, 1417 microbial keratitis was clinically diagnosed in the patients. Whereas no organisms were found in 27.8% (394/1417) of cases, 21.4% (303/1417) were bacterial. From 303 patients, 347 bacterial isolates were cultured, 260 (74.9%) of which were gram-positive, 67 were gram-negative, and 20 were acid-fast. Streptococcus pneumoniae was the predominant isolate (86/347 [24.7%]), followed by Staphylococcus species [64/347 (18.4%)]. Pseudomonas aeruginosa (29/347 [8.3%]) was the most common gram-negative bacterial isolate. High level of susceptibility to cefazolin (96.2%) and vancomycin (96.5%) was found in gram positive cocci, whereas susceptibility of Pseudomonas species to gatifloxacin was 95.1%. Fifty-three patients (17.5%) required tissue adhesive, and 47 (15.5%) needed penetrating keratoplasty. Healed corneal scar was achieved in 188 patients (62%), whereas 34 (11.2%) were lost to follow-up. Large stromal infiltrate size, older age group, and poor presenting visual acuity were significant factors that adversely affected final outcome (P < 0.05). CONCLUSIONS: Proportion of bacterial keratitis was low compared with other studies from India. Gram-positive bacteria were a common cause of bacterial keratitis with high susceptibility to cefazolin and vancomycin. Gram-negative bacteria were sensitive to gatifloxacin with overall good treatment outcome. PMID- 26107585 TI - Predicted Trends in the Incidence of Retinoblastoma in the Asia-Pacific Region. AB - PURPOSE: The aim of this study is to predict the incidence trends of retinoblastoma in the Asia-Pacific region. DESIGN: Statistical prediction is based on the assumption of uniform incidence among live-born children. METHODS: The number of live births was projected from population sizes and birth rates, corrected for infant mortality, and taken from the 2012 Revision of the World Population Prospects by the United Nations. The uniform incidence of 1:16,642 was derived from an earlier birth cohort analysis. Western Asia was excluded from calculations. RESULTS: Six of 15 countries with over 100 retinoblastomas annually and responsible for 43% of 8099 retinoblastomas predicted for 2013 are Asia Pacific nations. The predicted incidence of retinoblastoma in the Asia-Pacific peaked in 1988 at 4772 children and is 4167 and 3859, respectively, in 2012 and 2023. The 10 countries that account for 90% of retinoblastomas in the Asia Pacific are India (1486 and 1435 children in 2013 and 2023, respectively), China (1103 and 911), Indonesia (277 and 265), Pakistan (260 and 261), Bangladesh (184 and 172), the Philippines (142 and 152), Iran (87 and 74), Vietnam (85 and 72), Japan (64 and 58), and Afghanistan (59 and 59). Largest relative decreases are predicted for China (-17%), Vietnam and Iran (-15%), and Sri Lanka (-13%). CONCLUSIONS: Reported retinoblastomas during the last decade in the Asia-Pacific account for less than half of predicted numbers, which can be used as surrogates for evaluating completeness of registration and for advocacy toward reducing deaths and blindness from retinoblastoma. PMID- 26107586 TI - Superior Oblique Palsy: Epidemiology and Clinical Spectrum From a Tertiary Eye Care Center in South India. AB - PURPOSE: The objective of this study was to describe the epidemiologic characteristics and clinical spectrum of superior oblique palsy (SOP) at a tertiary eye care center. DESIGN: This was a retrospective case review. METHODS: Retrospective analysis of case records of 181 consecutive patients diagnosed with SOP seen from January 2001 to December 2008 was performed. RESULTS: The mean age of the patients was 31.78 +/- 19.28 years (range, 1-85 years). One hundred thirty six (75.1%) were males, and 45 (24.9%) were females. Most common presenting symptom was manifest vertical deviation (81.7%). Most common etiology was trauma (33.7%) followed by a congenital (32.6%), idiopathic (23.7%), and ischemic (8.8%) etiology. One patient each had multiple myeloma and central nervous system tuberculoma. Bilateral SOP was noted in 11 cases; 7 (63.4%) of them were posttraumatic, 3 (27.3%) were congenital, and 1 developed after cerebrovascular accident. Neuroimaging performed in 67 patients (37%) with suspected central nervous system pathology was positive in 10 (14.9%) of patients. The distribution of neuroimaging abnormalities was traumatic sequelae in 5 patients (50%), intracranial space-occupying lesion in 1 (10%), granuloma in dorsal midbrain in 1 (10%), and ischemic lesions (lacunar infarcts, occipital lobe infarcts) in 3 (30%) patients. CONCLUSIONS: Superior oblique palsy etiology tends to show an age and sex distribution. Trauma and congenital etiologies are the most common in young males and females, respectively, whereas ischemic etiology is more frequent in middle-aged and elderly people. Detailed history, meticulous ocular and systemic examination, appropriate neuroimaging, and systemic investigations help elucidate the etiology. PMID- 26107587 TI - Diabetes, Diabetic Retinopathy, and Retinal Vascular Alterations: A Systematic Review. AB - The aim of this review is to summarize the available findings from previous research that has focused on retinal vascular caliber characteristics in diabetes and diabetic retinopathy and identify any gaps that exist in the current literature. A systematic Medline, EMBASE, and PubMed search of relevant articles was conducted with coverage up to the 30th of September, 2012. The search was not restricted by language but was limited to studies conducted in humans. The majority of articles conducted on children and adolescents with type 1 diabetes have reported that arterioles with larger caliber were present in the early stages of diabetic retinopathy (n = 5). Only a few studies conducted on older individuals with type 1 diabetes (n = 2) suggest that smaller retinal arteriolar caliber is associated with increased severity of diabetic retinopathy. Much stronger trends have been identified between venular caliber and older individuals with diabetes, with the vast majority of studies reporting that retinal venular dilation represents a later sign of severe diabetic retinopathy (n = 6), with only 1 study highlighting associations with incident diabetes (n = 1). Significant developments have occurred to better understand the relationship between retinal vascular caliber and the onset and progression of diabetes and diabetic retinopathy. Recent evidence suggests that retinal arteriolar dilation may be a possible risk factor in the early development diabetic retinopathy and retinal venules are dilated in persons with severe diabetic retinopathy. Despite this, the clinical significance of these findings requires further evaluation. PMID- 26107588 TI - Nanotechnology-Based Approaches for Ophthalmology Applications: Therapeutic and Diagnostic Strategies. AB - PURPOSE: The purpose of this article was to review recent advances in applications of nanotechnology in ophthalmology. DESIGN: Literature review. METHODS: Research articles about nanotechnology-based treatments for particular eye diseases and diagnostic technologies were searched through Web of Science, and the most recent advances were reported. RESULTS: Nanotechnology enabled to improve drug and gene delivery systems, medicine solubility and short half-life in biological systems, controlled release, targeted delivery, bioavailability, diffusion limitations, and biocompatibility so far. These promising achievements are the assurance of next-generation treatment technologies. As well as treatment, nanofabrications systems such as microelectromechanical manufacturing systems removed the limitations of nanodevice generations and led the development of diagnostic tools such as intraocular pressure monitors and biosensors. CONCLUSIONS: The pursuit of personalized medicine approaches for combating ocular diseases may be possible only through the development of nanotechnology platforms that include molecular-level engineering. Nanoparticle engineering is a common thread; herein, we attempt to show unmodified nanoparticles as well as interesting and representative biomimetic strategies can be used for specific diseases. Finally, through combining microelectromechanical and nanoelectromechanical manufacturing system strategies, interesting manufacturing and sensor development can be accomplished for early detection and, in some cases, treatment of ocular diseases. PMID- 26107589 TI - A Study Investigating a Possible Link Between Lens Protein in the Vitreous Fluid of Eyes After Uncomplicated Cataract Surgery and Chronic Cystoid Macular Edema. AB - PURPOSE: This study aimed to determine if the lens protein aquaporin 0 (AQP0) is present in the vitreous of pseudophakic eyes of patients presenting with chronic cystoid macular edema (CME). DESIGN: A case-control study was conducted. METHODS: Ten patients undergoing therapeutic vitrectomy for chronic CME after uncomplicated cataract surgery were enrolled in this study. Fourteen patients with pseudophakia undergoing vitrectomy surgery for indications other than CME acted as the comparison group.The vitreous fluid from the 2 groups was analyzed for the presence of the lens protein AQP0 and type II collagen (used as a positive control). RESULTS: Type II collagen was detected in all the vitreous samples, whereas AQP0 was documented in 50% of eyes with chronic CME but was not found in the vitreous of any eyes without a documented history of CME. CONCLUSIONS: Aquaporin 0 is found in some eyes with chronic CME after uncomplicated cataract surgery, suggesting contamination of the vitreous by lens protein may have a role in the pathogenesis of this disorder. PMID- 26107590 TI - Letter to the Editor Regarding the "Evaluation of Wound Morphology of Sclerotomy Sites of Sutureless Vitrectomy Using Spectralis Anterior Segment Optical Coherence Tomography". PMID- 26107591 TI - Evaluation of Wound Morphology of Sclerotomy Sites of Sutureless Vitrectomy Using Spectralis Anterior Segment Optical Coherence Tomography. PMID- 26107592 TI - In-Depth Electrochemical Investigation of Surface Attachment Chemistry via Carbodiimide Coupling. AB - Aminoferrocene is used as an electroactive indicator to investigate carbodiimide coupling reactions on a carboxylic acid-functionalized self-assembled monolayer. The commonly used attachment chemistry with 1-ethyl-3-(3 (dimethylamino)propyl)carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) is used for surface activation. A number of conditions are investigated, including EDC and NHS concentration, buffer solutions, incubation timing, and aminoferrocene concentration. Ferrocene is a well-documented electroactive species, and the number of surface-bound ferrocene species can be calculated using electrochemical methods. This capability allows determination of optimal conditions, as well as providing a method for comparing and investigating novel carboxylated surfaces. An EDC-mediated procedure with ~5 mM EDC and NHS (1:1) made in water, with a full acid monolayer, with 250 MUM aminoferrocene for 40 min was found to give the highest ferrocene attachment. An application of this is demonstrated for preparing a probe-DNA-coated surface for DNA sensing. By backfilling with aminoferrocene, a differential quantification of the amount of probe DNA available for sensing can be obtained. This provides an elegant method to monitor an important aspect, namely, probe surface characterization, which will be highly useful for biosensing purposes. PMID- 26107593 TI - Selective Lamellar Keratoplasty: Surgical Strategy to Prevent Corneal Blindness in Asia Pacific Region. PMID- 26107594 TI - International Council of Ophthalmology: Refocusing Ophthalmic Education in the Asia-Pacific Region and Beyond. AB - The International Council of Ophthalmology (ICO) is a global organization with a regional focus. Working in partnership with supranational and ICO member societies, the ICO is building a "World Alliance for Sight" to improve access to the highest-quality eye care worldwide. Designed to preserve and restore vision on an international scale, the ICO initiative, "Refocusing Ophthalmic Education," enhances ophthalmic education of residents, subspecialists, medical students, and allied eye care personnel by redefining the most effective ways to teach and in creating beneficial educational opportunities. The "Teaching the Teachers" program helps ophthalmic educators incorporate more effective methods of training and continuing professional development to meet societal needs, achieved in part through regional courses for residency program directors; symposia, and keynote talks presented by ICO's World Ophthalmology Educational Colloquium, Conferences for Ophthalmic Educators, and ophthalmic surgical competency rubrics. Recognizing that standardized curricula are essential for consistent ophthalmic education, the ICO has developed a curricular framework whereby goals, expectations, knowledge base, competencies, and technical training are delineated. The ICO is defining worldwide models of team training and compiling best practice, which will include training-program accreditation to ensure improvement in the education of ophthalmologists. International Council of Ophthalmology Web-based teaching courses, a Webinar Network, and a technology blog further support information and communication technologies for teaching and learning. At the ICO's Center for Ophthalmic Educators (educators.icoph.org), trainers will find valuable teaching resources in multiple languages as well as ways to share ideas and collaborate with peers and other ophthalmic educators. PMID- 26107595 TI - Comparison of the Surgical Outcomes of Various Methods of Endothelial Keratoplasty. AB - PURPOSE: The objective of this study was to evaluate the outcomes of various techniques of endothelial keratoplasty (EK) including deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), and Descemet stripping automated endothelial keratoplasty (DSAEK). DESIGN: This was a retrospective comparative case series. METHODS: The medical records of 48 consecutive patients who have undergone EK in a tertiary eye center between January 2005 and June 2011 were reviewed. Information related to demographics, visual acuity, corneal endothelial cell count, and postoperative complications was recorded. RESULTS: The series included 11 eyes with DLEK, 11 eyes with DSEK, and 26 eyes with DSAEK. There was no significant difference in visual outcomes, endothelial cell loss, and postoperative complications between the 3 groups 1 year after surgery. The mean logMAR visual acuity at 12 months was 0.54 (SD, 0.26) for DLEK, 0.55 (SD, 0.47) for DSEK, and 0.63 (SD, 0.48) for DSAEK, respectively. The 6-month endothelial cell density loss was 48.4%, 39.2%, and 47.5% for the DLEK, DSEK, and DSAEK groups, respectively. Early postoperative graft dislocation occurred in 1 (9%) of the DLEK cases, 2 (18%) of the DSEK cases, and 1 (4%) of the DSAEK cases. All of these cases were successfully repositioned. CONCLUSIONS: Despite the various evolution and surgical modifications and development in EK in the past few years, the visual outcomes and postoperative complications between DLEK, DSEK, and DSAEK were comparable. PMID- 26107596 TI - Pediatric Orbital Blow-Out Fractures: Surgical Outcomes. AB - PURPOSE: The objective of this study was to evaluate the features, timing of intervention, complications, and outcomes of patients who underwent surgery for pediatric orbital blow-out fractures. DESIGN: This was a retrospective case review studying all cases of pediatric orbital blow-out fractures that underwent surgical intervention from 2000 to 2009 in a tertiary ophthalmic center in Singapore. METHODS: Case notes review of all cases of pediatric orbital blow-out fractures repaired surgically was carried out for demographics, time to intervention, and outcome. How the various factors may affect the outcome was statistically analyzed. RESULTS: A total of 23 patients were reviewed. There were 21 patients (91.3%) with floor fractures, 1 (4.3%) with medial wall fracture, and 1 (4.3%) with combined medial wall and floor fracture. Of the 21 cases of floor fracture, 20 cases had radiological images available for review, 17 (85%) were linear, and 3 (15%) were open. Patients with open fractures were older with a mean age of 14.0 years as compared with 12.6 years in those with linear fractures. The mean duration from injury to intervention was 13.0 days. Preoperatively, 14 (60.9%) had diplopia, but only 4 cases (17.4%) had diplopia in extreme gaze at the last follow-up after surgery (18 months). Outcome was not affected by age, duration between injury and intervention, type of fracture, and nature of implants used. CONCLUSIONS: Our study demonstrated that pediatric orbital blow-out fractures had good outcomes. It might also suggest the possibility of not having to manage all linear fractures as a surgical emergency. PMID- 26107597 TI - Clinical Features of Central Retinal Vein Occlusion With Inflammatory Etiology. AB - PURPOSE: The purpose of this study was to characterize central retinal vein occlusion (CRVO) with inflammatory etiology. DESIGN: A retrospective study. METHODS: We retrospectively reviewed 51 eyes of 48 patients with CRVO between 2004 and 2009 and investigated whether they had inflammatory findings related to retinal vasculitis, that is, severe peripheral retinal vascular changes based on fluorescein angiography and anterior vitreous cells. The extent of vascular leakage was classified as "mild," "moderate," and "severe" in angiographic images. RESULTS: Six eyes of 5 patients (11.8%) had both inflammatory criteria. All patients were male and with a diagnosis of ischemic CRVO. No causative etiology was detected in any patient. The mean age was 46.4 (SD, 23.3) years. The age range was not limited to young generation. These patients received systemic corticosteroid therapy with a mean follow-up period of 41.8 months. The mean logMAR visual acuity [1.29 (SD, 0.77)] and central retinal thickness [1290.5 (SD, 399.0) MUm)] at the initial visit were significantly (P = 0.004 and P = 0.001) improved at the final visit [0.94 (SD, 0.69) and 266.7 (SD, 135.4) MUm, respectively]. CONCLUSIONS: Central retinal vein occlusion with idiopathic inflammatory conditions appears to have clinical characteristics of broad age range and good response to systemic corticosteroid therapy. PMID- 26107598 TI - Epipolis-Laser In Situ Keratomileusis Discarding Epithelium Versus Laser In Situ Keratomileusis for Myopia and Myopic Astigmatism in Asian Eyes. AB - PURPOSE: To compare long-term safety, efficacy, predictability, and visual outcomes of epipolis-laser in situ keratomileusis (epi-LASIK) discarding epithelium versus LASIK in Asian eyes. DESIGN: This was a prospective, randomized, bilateral case series. METHODS: This study included 166 eyes of 83 patients with myopia and myopic astigmatism who received epi-LASIK in 1 eye and LASIK in the contralateral eye. Automated separation of the epithelium was performed with epi-KTM, and LASIK was performed with M2 microkeratome using 90 MUm calibrated heads. Patients were seen post-operatively at 1 and 3 days, 1 week, and on days 1, 3, 7 at 1, 3, 6, and 12 months. Uncorrected visual acuity, best corrected visual acuity, spherical equivalent (SE), contrast sensitivity, total higher-order aberration, corneal sensitivity, and clarity were analyzed. RESULTS: Mean preoperative SE was -4.26 (SD, 1.64) diopters (D) in epi-LASIK and 4.27 (SD, 1.63) D in the LASIK group. Twelve months after surgery, mean SE was 0.04 (SD, 0.40) and 0.11 (SD, 0.30) D, respectively. There was no significant difference in uncorrected visual acuity (P = 0.451), SE (P = 0.157) and contrast sensitivity between groups at the 1-year follow-up (P > 0.05). During 6 months after operation, corneal sensitivity values were significantly lower in the LASIK group (P < 0.05). No eye lost line of best corrected visual acuity in both groups. In epi-LASIK eyes, there was no haze in 97.5% and haze grade 1 in 2.5% at 3 months postoperatively. From 6 months onward, alls corneas were clear. CONCLUSIONS: Epi-LASIK was safe, predictable, and effective and may be considered an alternative for LASIK. PMID- 26107599 TI - A Japanese Survey of Perioperative Antibiotic Prophylaxis in Cataract Surgery. AB - PURPOSE: The objective of this study was to identify trends in the use of perioperative antibiotic prophylaxis in cataract surgery in Japan. DESIGN: This was a national survey by mail or interview. METHODS: The use of perioperative antibiotic prophylaxis in cataract surgery was evaluated by conducting a survey in 6 regions within Japan from October 1, 2011, to March 1, 2012. RESULTS: Responses were received from 285 (75%) of the 387 surgeons who were surveyed. The results revealed that 89% (255/285) administered ophthalmic antibiotic ointment. Forty-seven percent (133/285) used antibiotics in forms other than ophthalmic ointments within 6 hours after surgery, 7% (19/285) used eyedrops, 24% (67/285) used antibiotics via an irrigation bottle, 1% (2/285) used intracameral injections, and 24% (69/285) used subconjunctival injections. CONCLUSIONS: Although poor intraocular penetration of ophthalmic ointments has been reported, ophthalmic ointments are widely used. The fact that antibiotics should ideally be administered within 6 hours after surgery is not widely recognized. However, intracameral injection, which achieves much higher antibiotic concentration in the anterior chamber than other methods, is a technique that should be widely acknowledged. PMID- 26107600 TI - Clinical Features, Investigations, Management, and Prognosis of Serpiginous Choroiditis. AB - Serpiginous choroiditis is an inflammatory form of posterior uveitis that affects the choroid, retinal pigment epithelium, and choriocapillaries. Known to be recurrent and progressive in nature, this bilateral disease can result in severe visual loss both during the active and healed stages. The age at onset is 40 to 50 years, but it can affect younger Indian population. It can be further classified into 3 types based on its clinical presentation, and they are, namely, peripapillary, macular, and ampiginous. Histological features further qualify the site of inflammation as evidenced by lymphocytic infiltration within the choroid and atrophy of choriocapillaries and retinal pigment epithelium. Despite a multitude of etiologies such as autoimmunity, infection, and degeneration, autoimmune causes remain the mainstay. Laboratory investigations can help rule out infections, whereas angiography can provide further insights into the progression of the disease. Newer investigations such as optical coherence tomography and fundus autofluorescence can help locate the lesion and identify the phase of the disease. Corticosteroids with immunosuppressives are the major management modality. Treatment of complications may require intravitreal injections, laser photocoagulation, or even vitreoretinal surgery. PMID- 26107601 TI - An Update on the Diagnosis and Management of Central Serous Chorioretinopathy. AB - Central serous chorioretinopathy (CSC) is a complicated disease with still unclear causes, pathogenesis and management strategy despite active research. CSC has been traditionally considered as a self-limiting disease where spontaneous recovery occurs in 90% of the patients within a few months. This proclaimed "benign" nature of CSC, however, has been queried by increasing scientific evidence that permanent photoreceptors damage and neurosensory-cystoid degeneration of macula occur in the event of chronic CSC. CSC is probably not a benign disease. Treatments for CSC are still evolving. It is very difficult to define the proper timing for active treatment of CSC because it is not easy to define a universally accepted cut-off time point for active intervention. There is a recent suggestion that active CSC treatment should be considered if symptoms last longer than 3 months as atrophy of photoreceptors may occur as early as 4 months after initial presentation. The CSC patients may be stratified into two groups based on the initial presenting visual acuity and duration of symptom: the good visual prognosis group and the dubious visual prognosis group. The management may then be tailor-made based on the visual prognosis group. "Safety enhanced'" photodynamic therapy (PDT) using lower doses and reduced fluence is still the mainstay of treatment. Newer treatment modalities like intravitreal anti-VEGF therapy, micropulsed diode laser treatment, and the use of corticosteroid antagonists do warrant further investigation. Combination therapies involving two or more of the above modalities of treatments may have a role to play in this actively researched area. PMID- 26107602 TI - The Immunology of Glaucoma. AB - The presence of specific antibodies and T cells that are specific in patients with glaucoma supports the idea that the immune system may play an important role in the initiation and/or sustainment of glaucomatous optic neuropathy, at least in some patients. At present, our understanding regarding immunological mechanisms associated with glaucomatous optic neuropathy is far from satisfactory. In this review, we examined evidence suggesting involvement of autoimmune responses in the pathogenesis of glaucoma. These include detection of autoantibodies and T cells and expression of cytokines and stress proteins in patients with glaucoma. Although immune responses are thought to be detrimental, some responses may exert a protective effect against neurodegenerative damage. Likely, the balance between positive and negative regulators determines the survival or demise of cells. It is vital that research continues to elucidate the roles of the immune system in glaucomatous neurodegeneration and the possibility of alternative modalities of treatment. These studies may also provide valuable molecular biomarkers for the diagnosis and identification of a specific cohort of patients with glaucoma, that is, those with normal-tension glaucoma. PMID- 26107603 TI - Genetics in Age-Related Macular Degeneration: Current Research and Implications for Future Treatment. AB - Age-related macular degeneration (AMD) remains a leading cause of visual loss in the developed world, and genetic factors are known risks for disease development, as well as affecting response to therapy. Here, we review genetic factors associated with AMD and the influence of genetics on the understanding of AMD pathogenesis. The potential role of genetics in assisting in the management of AMD and future research avenues are also discussed. PMID- 26107604 TI - Childhood Vascular Risk Factors and Retinal Vessel Caliber. PMID- 26107605 TI - Childhood Vascular Risk Factors and Retinal Vessel Caliber: Author Reply. PMID- 26107606 TI - Suprabrow Single-Stab and Three-Stab Incision Frontalis Sling Surgery. PMID- 26107607 TI - Author Reply. PMID- 26107608 TI - Femtosecond Laser Cataract Surgery: An Experience From Australia. PMID- 26107609 TI - Author Reply. PMID- 26107610 TI - Examining Ligand-Based Stabilization of Proteins in Cells with MEK1 Kinase Inhibitors. AB - In this study, we describe the evaluation of a cell-based protein stability assay using beta-galactosidase fragment complementation technology performed in two independent laboratories. The assay is based on the ability of certain ligands to bind to a protein leading to a ligand-protein complex that has a different stability than the free protein. The assay employed a prolabeled-tagged MEK1 kinase stably expressed in A549 cells and this was used to evaluate focused sets of compounds containing known MEK1inhibitors as well as a random set of compounds. An assay using a prolabeled-tagged lysine methyltransferase known as G9a expressed in A549 cells was used as a counterscreen. In one study, it was found that the majority of MEK1 inhibitors were either found as inactive (52%) or showed a selective inhibitory response (18%) in the cell-based MEK1 assay; however, eight compounds showed a specific activation response consistent with stabilization of MEK1 in cells. Examination of these stabilizing compounds showed that three of these were analogs of hypothemycin, a known covalent allosteric MEK1 inhibitor, while the remaining compounds covered one structural class. Both laboratories were able to confirm activity in the cell-based MEK1 assay for known MEK1 inhibitors and found that this activity was highly selective over the G9a counterscreen assay. Screening of a mechanism of action library containing compounds with bioactivity annotations against the cell-based MEK1 assay did not reveal any mechanisms leading to an increase in signal other than inhibitors of MEK1. This study supports that the MEK1 cellular protein stability assay is sensitive to certain MEK1 inhibitors, often noncompetitive inhibitors with respect to ATP. The cellular stability assay format could be useful to rapidly filter kinase inhibitor hit lists for allosteric kinase inhibitors and support target engagement in cells. PMID- 26107611 TI - Orthogonal Injection Ion Funnel Interface Providing Enhanced Performance for Selected Reaction Monitoring-Triple Quadrupole Mass Spectrometry. AB - The electrodynamic ion funnel facilitates efficient focusing and transfer of charged particles in the higher-pressure regions (e.g., ion source interfaces) of mass spectrometers, thus providing increased sensitivity. An "off-axis" ion funnel design has been developed to reduce the source contamination and interferences from, e.g. ESI droplet residue and other poorly focused neutral or charged particles with very high mass-to-charge ratios. In this study, a dual ion funnel interface consisting of an orthogonal higher pressure electrodynamic ion funnel (HPIF) and an ion funnel trap combined with a triple quadrupole mass spectrometer was developed and characterized. An orthogonal ion injection inlet and a repeller plate electrode was used to direct ions to an ion funnel HPIF at a pressure of 9-10 Torr. Key factors for the HPIF performance characterized included the effects of RF amplitude, the DC gradient, and operating pressure. Compared to the triple quadrupole standard interface more than 4-fold improvement in the limit of detection for the direct quantitative MS analysis of low abundance peptides was observed. The sensitivity enhancement in liquid chromatography selected reaction monitoring (LC-SRM) analyses of low-abundance peptides spiked into a highly complex mixture was also compared with that obtained using both a commercial S-lens interface and an in-line dual-ion funnel interface. PMID- 26107612 TI - The Cognitive Decline of Marshal Philippe Petain. AB - In 1940, at the age of 84, Marshal Petain was appointed the head of state and government of France. His health was excellent but he tired easily. He felt unable to learn and his memory was weak. During a crisis situation in 1942, he did not lead, plan and decide and he was replaced as head of government. From 1943 on, he was increasingly apathetic. In 1945/1946 he had difficulty finding words after a short conversation. A parliamentary committee concluded in 1947 that he was senile. His mental condition worsened in the years thereafter. In retrospect, it is clear that the final responsibility for the policies of the French government in the Second World War had rested on a man who was going through a predementia process of cognitive decline. PMID- 26107613 TI - Rh(III)-Catalyzed C-H Amidation of Indoles with Isocyanates. AB - The rhodium(III)-catalyzed direct amidation of indoles and pyrroles with aryl and alkyl isocyanates is described. These transformations provide a facile and efficient construction of C2-amidated N-heterocyclic scaffolds. PMID- 26107614 TI - Conformational cooperativity between helical domains of differing geometry in oligoamide-oligourea foldamer chimeras. AB - Linking together an oligourea and an oligoamide foldamer gives rise to a conformationally well-defined structure, despite the different hydrogen-bonding patterns in the two domains, provided the oligomers are ligated amide C terminus to urea N terminus. A powerful screw-sense preference induced at the N terminus of the resulting chimeric structure provides evidence for cooperative conformational interactions within the 'block co-foldamer'. PMID- 26107615 TI - Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib. AB - Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets. PMID- 26107616 TI - A Canine Non-Weight-Bearing Model with Radial Neurectomy for Rotator Cuff Repair. AB - BACKGROUND: The major concern of using a large animal model to study rotator cuff repair is the high rate of repair retears. The purpose of this study was to test a non-weight-bearing (NWB) canine model for rotator cuff repair research. METHODS: First, in the in vitro study, 18 shoulders were randomized to 3 groups. 1) Full-width transections repaired with modified Mason-Allen sutures using 3-0 polyglactin suture, 2) Group 1 repaired using number 2 (#2) polyester braid and long-chain polyethylene suture, and 3) Partial-width transections leaving the superior 2 mm infraspinatus tendon intact without repair. In the in vivo study of 6 dogs, the infraspinatus tendon was partially transected as the same as the in vitro group 3. A radial neurectomy was performed to prevent weight bearing. The operated limb was slung in a custom-made jacket for 6 weeks. RESULTS: In the in vitro study, mean ultimate tensile load and stiffness in Group 2 were significantly higher than Group 1 and 3 (p<0.05). In the in vivo study, gross inspection and histology showed that the preserved superior 2-mm portion of the infraspinatus tendon remained intact with normal structure. CONCLUSIONS: Based on the biomechanical and histological findings, this canine NWB model may be an appropriate and useful model for studies of rotator cuff repair. PMID- 26107618 TI - A Comparison of Breast-Specific Gamma Imaging of Invasive Lobular Carcinomas and Ductal Carcinomas. PMID- 26107617 TI - The Disulfide Bond Cys255-Cys279 in the Immunoglobulin-Like Domain of Anthrax Toxin Receptor 2 Is Required for Membrane Insertion of Anthrax Protective Antigen Pore. AB - Anthrax toxin receptors act as molecular clamps or switches that control anthrax toxin entry, pH-dependent pore formation, and translocation of enzymatic moieties across the endosomal membranes. We previously reported that reduction of the disulfide bonds in the immunoglobulin-like (Ig) domain of the anthrax toxin receptor 2 (ANTXR2) inhibited the function of the protective antigen (PA) pore. In the present study, the disulfide linkage in the Ig domain was identified as Cys255-Cys279 and Cys230-Cys315. Specific disulfide bond deletion mutants were achieved by replacing Cys residues with Ala residues. Deletion of the disulfide bond C255-C279, but not C230-C315, inhibited the PA pore-induced release of the fluorescence dyes from the liposomes, suggesting that C255-C279 is essential for PA pore function. Furthermore, we found that deletion of C255-C279 did not affect PA prepore-to-pore conversion, but inhibited PA pore membrane insertion by trapping the PA membrane-inserting loops in proteinaceous hydrophobic pockets. Fluorescence spectra of Trp59, a residue adjacent to the PA-binding motif in von Willebrand factor A (VWA) domain of ANTXR2, showed that deletion of C255-C279 resulted in a significant conformational change on the receptor ectodomain. The disulfide deletion-induced conformational change on the VWA domain was further confirmed by single-particle 3D reconstruction of the negatively stained PA receptor heptameric complexes. Together, the biochemical and structural data obtained in this study provides a mechanistic insight into the role of the receptor disulfide bond C255-C279 in anthrax toxin action. Manipulation of the redox states of the receptor, specifically targeting to C255-C279, may become a novel strategy to treat anthrax. PMID- 26107619 TI - Phylogeography of the coastal mosquito Aedes togoi across climatic zones: testing an anthropogenic dispersal hypothesis. AB - The coastal mosquito Aedes togoi occurs more or less continuously from subarctic to subtropic zones along the coasts of the Japanese islands and the East Asian mainland. It occurs also in tropical Southeast Asia and the North American Pacific coast, and the populations there are thought to have been introduced from Japan by ship. To test this hypothesis, the genetic divergence among geographic populations of A. togoi was studied using one mitochondrial and three nuclear gene sequences. We detected 71 mitochondrial haplotypes forming four lineages, with high nucleotide diversity around temperate Japan and declining towards peripheral ranges. The major lineage (L1) comprised 57 haplotypes from temperate and subarctic zones in Japan and Southeast Asia including southern China and Taiwan. Two other lineages were found from subtropical islands (L3) and a subarctic area (L4) of Japan. The Canadian population showed one unique haplotype (L2) diverged from the other lineages. In the combined nuclear gene tree, individuals with mitochondrial L4 haplotypes diverged from those with the other mitochondrial haplotypes L1-L3; although individuals with L1-L3 haplotypes showed shallow divergences in the nuclear gene sequences, individuals from Southeast Asia and Canada each formed a monophyletic group. Overall, the genetic composition of the Southeast Asian populations was closely related to that of temperate Japanese populations, suggesting recent gene flow between these regions. The Canadian population might have originated from anthropogenic introduction from somewhere in Asia, but the possibility that it could have spread across the Beringian land bridge cannot be ruled out. PMID- 26107620 TI - Metabolomics Analysis Reveals that AICAR Affects Glycerolipid, Ceramide and Nucleotide Synthesis Pathways in INS-1 Cells. AB - AMPK regulates many metabolic pathways including fatty acid and glucose metabolism, both of which are closely associated with insulin secretion in pancreatic beta-cells. Insulin secretion is regulated by metabolic coupling factors such as ATP/ADP ratio and other metabolites generated by the metabolism of nutrients such as glucose, fatty acid and amino acids. However, the connection between AMPK activation and insulin secretion in beta-cells has not yet been fully elucidated at a metabolic level. To study the effect of AMPK activation on glucose stimulated insulin secretion, we applied the pharmacological activator 5 aminoimidazole-4-carboxamide ribonucleotide (AICAR) to an INS-1 (832/13) beta cell line. We measured the change in 66 metabolites in the presence or absence of AICAR using different stable isotopic labeled nutrients to probe selected pathways. AMPK activation by AICAR increased basal insulin secretion and reduced the glucose stimulation index. Although ATP/ADP ratios were not strongly affected by AICAR, several other metabolites and pathways important for insulin secretion were affected by AICAR treatment including long-chain CoAs, malonyl-CoA, 3 hydroxy-3 methylglutaryl CoA, diacylglycerol, and farnesyl pyrophosphate. Tracer studies using 13C-glucose revealed lower glucose flux in the purine and pyrimidine pathway and in the glycerolipid synthesis pathway. Untargeted metabolomics revealed reduction in ceramides caused by AICAR that may explain the beneficial role of AMPK in protecting beta-cells from lipotoxicity. Taken together, the results provide an overall picture of the metabolic changes associated with AICAR treatment and how it modulates insulin secretion and beta cell survival. PMID- 26107621 TI - Paternal Factors and Inequity Associated with Access to Maternal Health Care Service Utilization in Nepal: A Community Based Cross-Sectional Study. AB - BACKGROUND: The threat of maternal mortality can be reduced by increasing use of maternal health services. Maternal death and access to maternal health care services are inequitable in low and middle income countries.The aim of this study is to assess associated paternal factors and degree of inequity in access to maternal health care service utilization. METHODS: Analysis illustrates on a cross-sectional household survey that followed multistage-cluster sampling. Concentration curve and indices were calculated. Binary logistic regression analysis was executed to account paternal factors associated with the utilization of maternal health services. Path model with structural equation modeling (SEM) examined the predictors of antenatal care (ANC) and institutional delivery. RESULTS: The finding of this study revealed that 39.9% and 45.5% of the respondents' wives made ANC visits and utilized institutional delivery services respectively. Men with graduate and higher level of education were more likely (AOR: 5.91, 95% CI; 4.02, 8.70) to have ANC of their wives than men with no education or primary level of education. Men with higher household income (Q5) were more likely (1.99, 95% CI; 1.39, 2.86) to have ANC for their wives. Similarly, higher household income (Q5) also determined (2.74, 95% CI; 1.81, 4.15) for institutional delivery of their wives. Concentration curve and indices also favored rich than the poor. SEM revealed that ANC visit was directly associated to institutional delivery. CONCLUSIONS: Paternal factors like age, household wealth, number of children, ethnicity, education, knowledge of danger sign during pregnancy, and husband's decision making for seeking maternal and child health care are crucial factors associated to maternal health service utilization. Higher ANC coverage predicts higher utilization of the institutional delivery. Wealthier population is more concentrated to maternal health services. The inequities between the poor and the rich are necessary to be addressed through effective policy and programs. PMID- 26107622 TI - Characterization and Biological Activities of Ocellatin Peptides from the Skin Secretion of the Frog Leptodactylus pustulatus. AB - Eight new peptides were isolated from the skin secretion of the frog Leptodactylus pustulatus and their amino acid sequences determined by de novo sequencing and by cDNA cloning. Structural similarities between them and other antimicrobial peptides from the skin secretion of Leptodactylus genus frogs were found. Ocellatins-PT1 to -PT5 (25 amino acid residues) are amidated at the C terminus, while ocellatins-PT6 to -PT8 (32 amino acid residues) have free carboxylates. Antimicrobial activity, hemolytic tests, and cytotoxicity against a murine fibroblast cell line were investigated. All peptides, except for ocellatin PT2, have antimicrobial activity against at least one Gram-negative strain. Ocellatin-PT8 inhibited the growth of Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Salmonella choleraesuis strains with MICs in the 60 240 MUM range. No significant effect was observed in human erythrocytes and in a murine fibroblast cell line after exposure to the peptides at MICs. A comparison between sequences obtained by both direct HPLC-MS de novo sequencing and cDNA cloning demonstrates the secretion of mature peptides derived from a pre-pro peptide structure. PMID- 26107623 TI - Overweight as a Prognostic Factor for Triple-Negative Breast Cancers in Chinese Women. AB - PURPOSE: Obesity is associated with poorer outcomes in patients with hormone receptor-positive breast cancers, but this association is not well established for women with triple-negative breast cancers (TNBC). Here, we investigated the prognostic effects of body mass index (BMI) on clinical outcomes in patients with TNBC. METHODS: We identified 1106 patients with TNBC who met the inclusion criteria and were treated between January 2002 and June 2012. Clinical and biological features were collected to evaluate the relation between BMI and breast cancer-specific survival (BCSS) and overall survival (OS) after controlling for other clinically significant variables. RESULTS: Of 1106 patients, 656 (59.3%) were normal weight (BMI <=24) and 450 patients (40.7%) were overweight(BMI>24). Median follow-up time was 44.8 months. Breast cancer specific death was observed in 140 patients. After adjusting for clinicopathologic risk factors, overweight was associated with OS (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 1.04-2.06, P =0.028) but not BCSS (HR: 1.34, 95% CI: 0.90-2.01, P =0.15)in all the patients with TNBC. When stratified with menopausal status, overweight was associated with BCSS and OS (HR: 2.27, 95% CI: 1.11-4.63, P = 0.024 and HR: 2.16, 95% CI: 1.21-3.87, P = 0.010, respectively) in premenopausal women. BMI was not associated with BCSS or OS in postmenopausal women. CONCLUSIONS: Overweight is an independent prognostic factor of OS in all women with TNBC, and menopause status may be a mitigating factor. Among premenopausal women, overweight women are at a greater risk of poor prognosis than normal weight women. If validated, these findings should be considered in developing preventive programs. PMID- 26107624 TI - Mixing Languages during Learning? Testing the One Subject-One Language Rule. AB - In bilingual communities, mixing languages is avoided in formal schooling: even if two languages are used on a daily basis for teaching, only one language is used to teach each given academic subject. This tenet known as the one subject one language rule avoids mixing languages in formal schooling because it may hinder learning. The aim of this study was to test the scientific ground of this assumption by investigating the consequences of acquiring new concepts using a method in which two languages are mixed as compared to a purely monolingual method. Native balanced bilingual speakers of Basque and Spanish-adults (Experiment 1) and children (Experiment 2)-learnt new concepts by associating two different features to novel objects. Half of the participants completed the learning process in a multilingual context (one feature was described in Basque and the other one in Spanish); while the other half completed the learning phase in a purely monolingual context (both features were described in Spanish). Different measures of learning were taken, as well as direct and indirect indicators of concept consolidation. We found no evidence in favor of the non mixing method when comparing the results of two groups in either experiment, and thus failed to give scientific support for the educational premise of the one subject-one language rule. PMID- 26107626 TI - Analytically confirmed recreational use of Phenibut (beta-phenyl-gamma aminobutyric acid) bought over the internet. PMID- 26107625 TI - Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. AB - Although the microneutralization (MN) assay has been shown to be more sensitive than the hemagglutination inhibition (HAI) assay for the measurement of humoral immunity against influenza viruses, further evidence relating MN titres to protective efficacy against infection is needed. Serum antibodies against seasonal H1N1 and H3N2 influenza were measured in children and adolescents (n = 656) by MN and hemagglutination inhibition (HAI) assays. Compared to HAI, the MN assay is more sensitive in detecting serum antibodies and estimates of protective effectiveness against PCR-confirmed infection were higher for both subtypes. Given our findings, the MN assay warrants further consideration as a formal tool for the routine evaluation of vaccine-induced antibody responses. PMID- 26107627 TI - Acetaminophen concentrations prior to 4 hours of ingestion: impact on diagnostic decision-making and treatment. AB - BACKGROUND: Consensus recommendations for acute acetaminophen exposure include plotting an acetaminophen concentration at >= 4 h post ingestion on the Rumack Matthew nomogram to determine the need for acetylcysteine treatment. We studied the frequency of acetaminophen concentrations drawn within 4 h post ingestion and whether the Rumack-Matthew nomogram was properly used in making acetylcysteine treatment decisions. METHODS: This was a retrospective, observational case series at three regional poison centers of acute acetaminophen exposures between 1/1/13 and 12/31/13. Cases were analyzed for demographics, timing of acetaminophen concentrations, and application of the Rumack-Matthew nomogram in acetylcysteine initiation or termination. RESULTS: 1,123 cases of acute acetaminophen exposure were reviewed. Of 520 acute acetaminophen exposure cases presenting < 4 h post ingestion, 323 (62%) had a pre-4-hour acetaminophen concentration measured and 197 (38%) did not. Those with a known pre-4-hour acetaminophen concentration were less likely to have a 4-hour acetaminophen concentration (59% vs. 93%) or an acetaminophen concentration within 8 h (87% vs. 99%) and were more likely to be treated with acetylcysteine (29% vs. 17%) and less likely to be treated based on the Rumack-Matthew nomogram (72% vs. 97%). CONCLUSIONS: Patients with a known exposure time and presenting within 4 h of acetaminophen ingestion had a pre-4 hour acetaminophen concentration obtained 62% of the time. Pre-4-hour acetaminophen concentrations cannot be used to determine the need for acetylcysteine therapy and are associated with an increased likelihood of not obtaining optimally timed acetaminophen concentrations and acetylcysteine management not based on the proper application of the Rumack-Matthew nomogram. Current practice results in additional cost, unnecessary treatment, potential adverse medication effects, and the possibility of non-treatment of patients at risk of hepatotoxicity. PMID- 26107629 TI - The Functional Significance of Chiral Genitalia: Patterns of Asymmetry, Functional Morphology and Mating Success in the Praying Mantis Ciulfina baldersoni. AB - Genital asymmetry is relatively common and widespread throughout the animal kingdom. The functional significance of genital asymmetry is however, poorly understood for most species. Male praying mantids of the genus Ciulfina are remarkable in possessing complex and directionally asymmetric genital phallomeres in some species, and chirally dimorphic/antisymmetric genitalia in others. Here we explore the chiral dimorphism in male genitalia of Ciulfina baldersoni which appear to exhibit genital antisymmetry. We test whether genital orientation influences mating success, copulation duration and the attachment duration of spermatophores. Additionally we investigate genital interactions between male and females using x-ray micro-computed tomography (micro-CT) and scanning electron microscopy (SEM). Lastly we assess whether genital asymmetry is associated with non-genital morphological asymmetry of a range of traits. Our results highlight the complex functional morphology of genitalia in this praying mantis species and yet demonstrate no functional difference between dextral and sinistral morphs other than the direction of attachment with both morphs enjoying equal levels of mating success. Chiral morphs also did not strongly associate with any other forms of asymmetry. We therefore conclude that genital chirality in Ciulfina baldersoni is a likely case of antisymmetry with no functional significance to genital orientation, and is likely to be selectively neutral. PMID- 26107628 TI - Characterization and Regulation of the Amino Acid Transporter SNAT2 in the Small Intestine of Piglets. AB - The sodium-dependent neutral amino acid transporter 2 (SNAT2), which has dual transport/receptor functions, is well documented in eukaryotes and some mammalian systems, but has not yet been verified in piglets. The objective of this study was to investigate the characteristics and regulation of SNAT2 in the small intestine of piglets. The 1,521-bp porcine full cDNA sequence of SNAT2 (KC769999) from the small intestine of piglets was cloned. The open reading frame of cDNA encodes 506 deduced amino acid residues with a calculated molecular mass of 56.08 kDa and an isoelectric point (pI) of 7.16. Sequence alignment and phylogenetic analysis revealed that SNAT2 is highly evolutionarily conserved in mammals. SNAT2 mRNA can be detected in the duodenum, jejunum and ileum by real-time quantitative PCR. During the suckling period from days 1 to 21, the duodenum had the highest abundance of SNAT2 mRNA among the three segments of the small intestine. There was a significant decrease in the expression of SNAT2 mRNA in the duodenal and jejunal mucosa and in the expression of SNAT2 protein in the jejunal and ileal mucosa on day 1 after weaning (P < 0.05). Studies with enterocytes in vitro showed that amino acid starvation and supplementation with glutamate, arginine or leucine enhanced, while supplementation with glutamine reduced, SNAT2 mRNA expression (P < 0.05). These results regarding the characteristics and regulation of SNAT2 should help to provide some information to further clarify its roles in the absorption of amino acids and signal transduction in the porcine small intestine. PMID- 26107630 TI - Incidence and Risk Factors for Respiratory Syncytial Virus and Human Metapneumovirus Infections among Children in the Remote Highlands of Peru. AB - INTRODUCTION: The disease burden and risk factors for respiratory syncytial virus (RSV) and human metapneumovirus (MPV) infections among children living in remote, rural areas remain unclear. MATERIALS AND METHODS: We conducted a prospective, household-based cohort study of children aged <3 years living in remote rural highland communities in San Marcos, Cajamarca, Peru. Acute respiratory illnesses (ARI), including lower respiratory tract infection (LRTI), were monitored through weekly household visits from March 2009 through September 2011. Nasal swabs collected during ARI/LRTI were tested for RSV, MPV, and other respiratory viruses using real-time RT-PCR. Incidence rates and rate ratios were calculated using mixed effects Poisson regression. RESULTS: Among 892 enrolled children, incidence rates of RSV and MPV ARI were 30 and 17 episodes per 100 child-years, respectively. The proportions of RSV and MPV ARI that presented as LRTI were 12.5% and 8.9%, respectively. Clinic visits for ARI and hospitalizations were significantly more frequent (all p values <0.05) among children with RSV (clinic 41% and hospital 5.3%) and MPV ARI (38% and 3.5%) when compared with other viral infections (23% and 0.7%) and infections without virus detected (24% and 0.6%). In multivariable analysis, risk factors for RSV detection included younger age (RR 1.02, 95% CI: 1.00-1.03), the presence of a smoker in the house (RR 1.63, 95% CI: 1.12-2.38), residing at higher altitudes (RR 1.93, 95% CI: 1.25-3.00 for 2nd compared to 1st quartile residents; RR 1.98, 95% CI: 1.26-3.13 for 3rd compared to 1st quartile residents). Having an unemployed household head was significantly associated with MPV risk (RR 2.11, 95% CI: 1.12-4.01). CONCLUSION: In rural high altitude communities in Peru, childhood ARI due to RSV or MPV were common and associated with higher morbidity than ARI due to other viruses or with no viral detections. The risk factors identified in this study may be considered for interventional studies to control infections by these viruses among young children from developing countries. PMID- 26107631 TI - Inter-Seasonal Influenza is Characterized by Extended Virus Transmission and Persistence. AB - The factors that determine the characteristic seasonality of influenza remain enigmatic. Current models predict that occurrences of influenza outside the normal surveillance season within a temperate region largely reflect the importation of viruses from the alternate hemisphere or from equatorial regions in Asia. To help reveal the drivers of seasonality we investigated the origins and evolution of influenza viruses sampled during inter-seasonal periods in Australia. To this end we conducted an expansive phylogenetic analysis of 9912, 3804, and 3941 hemagglutinnin (HA) sequences from influenza A/H1N1pdm, A/H3N2, and B, respectively, collected globally during the period 2009-2014. Of the 1475 viruses sampled from Australia, 396 (26.8% of Australian, or 2.2% of global set) were sampled outside the monitored temperate influenza surveillance season (1 May - 31 October). Notably, rather than simply reflecting short-lived importations of virus from global localities with higher influenza prevalence, we documented a variety of more complex inter-seasonal transmission patterns including "stragglers" from the preceding season and "heralds" of the forthcoming season, and which included viruses sampled from clearly temperate regions within Australia. We also provide evidence for the persistence of influenza B virus between epidemic seasons, in which transmission of a viral lineage begins in one season and continues throughout the inter-seasonal period into the following season. Strikingly, a disproportionately high number of inter-seasonal influenza transmission events occurred in tropical and subtropical regions of Australia, providing further evidence that climate plays an important role in shaping patterns of influenza seasonality. PMID- 26107633 TI - Correction: Effect of Antihelminthic Treatment on Vaccine Immunogenicity to a Seasonal Influenza Vaccine in Primary School Children in Gabon: A Randomized Placebo-Controlled Trial. PMID- 26107632 TI - Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways. AB - The renin-angiotensin system (RAS) plays a central role in blood pressure regulation. Although clinical and experimental studies have suggested that inhibition of RAS is associated with progression of anemia, little evidence is available to support this claim. Here we report that knockout mice that lack angiotensin II, including angiotensinogen and renin knockout mice, exhibit anemia. The anemia of angiotensinogen knockout mice was rescued by angiotensin II infusion, and rescue was completely blocked by simultaneous administration of AT1 receptor blocker. To genetically determine the responsible receptor subtype, we examined AT1a, AT1b, and AT2 knockout mice, but did not observe anemia in any of them. To investigate whether pharmacological AT1 receptor inhibition recapitulates the anemic phenotype, we administered AT1 receptor antagonist in hypotensive AT1a receptor knockout mice to inhibit the remaining AT1b receptor. In these animals, hematocrit levels barely decreased, but blood pressure further decreased to the level observed in angiotensinogen knockout mice. We then generated AT1a and AT1b double-knockout mice to completely ablate the AT1 receptors; the mice finally exhibited the anemic phenotype. These results provide clear evidence that although erythropoiesis and blood pressure are negatively controlled through the AT1 receptor inhibition in vivo, the pathways involved are complex and distinct, because erythropoiesis is more resistant to AT1 receptor inhibition than blood pressure control. PMID- 26107634 TI - Emerging Object Representations in the Visual System Predict Reaction Times for Categorization. AB - Recognizing an object takes just a fraction of a second, less than the blink of an eye. Applying multivariate pattern analysis, or "brain decoding", methods to magnetoencephalography (MEG) data has allowed researchers to characterize, in high temporal resolution, the emerging representation of object categories that underlie our capacity for rapid recognition. Shortly after stimulus onset, object exemplars cluster by category in a high-dimensional activation space in the brain. In this emerging activation space, the decodability of exemplar category varies over time, reflecting the brain's transformation of visual inputs into coherent category representations. How do these emerging representations relate to categorization behavior? Recently it has been proposed that the distance of an exemplar representation from a categorical boundary in an activation space is critical for perceptual decision-making, and that reaction times should therefore correlate with distance from the boundary. The predictions of this distance hypothesis have been born out in human inferior temporal cortex (IT), an area of the brain crucial for the representation of object categories. When viewed in the context of a time varying neural signal, the optimal time to "read out" category information is when category representations in the brain are most decodable. Here, we show that the distance from a decision boundary through activation space, as measured using MEG decoding methods, correlates with reaction times for visual categorization during the period of peak decodability. Our results suggest that the brain begins to read out information about exemplar category at the optimal time for use in choice behaviour, and support the hypothesis that the structure of the representation for objects in the visual system is partially constitutive of the decision process in recognition. PMID- 26107635 TI - Orthostatic blood pressure test for risk stratification in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death (SCD) in young adults, mainly ascribed to ventricular tachycardia (VT). Assuming that VT is the major cause of (pre-) syncope in HCM patients, its occurrence is essential for SCD risk stratification and primarily preventive ICD implantation. However, evidence of VT during syncope is often missing. As the differentiation of potential lethal causes for syncope such as VT from more harmless reasons is crucial, HCM patients were screened for orthostatic dysregulation by using a simple orthostatic blood pressure test. METHODS: Over 15 months (IQR [9;20]) 100 HCM patients (55.8+/-16.2 yrs, 61% male) were evaluated for (pre-)syncope and VT (24h-ECGs, device-memories) within the last five years. Eighty patients underwent an orthostatic blood pressure test. Logistic regression models were used for statistical analysis. RESULTS: In older patients (>40 yrs) a positive orthostatic test result increased the chance of (pre-) syncope by a factor of 63 (95%-CI [8.8; 447.9], p<0.001; 93% sensitivity, 95%-CI [76; 99]; 74% specificity, 95%-CI [58; 86]). No correlation with VT was shown. A prolonged QTc interval also increased the chance of (pre-) syncope by a factor of 6.6 (95%-CI [2.0; 21.7]; p=0.002). CONCLUSIONS: The orthostatic blood pressure test is highly valuable for evaluation of syncope and presyncope especially in older HCM patients, suggesting that orthostatic syncope might be more relevant than previously assumed. Considering the high complication rates due to ICD therapies, this test may provide useful information for the evaluation of syncope in individual risk stratification and may help to prevent unnecessary device implantations, especially in older HCM patients. PMID- 26107636 TI - Joint effect of education and main lifetime occupation on late life health: a cross-sectional study of older adults in Xiamen, China. AB - BACKGROUND: The effects of education and occupation on health have been well documented individually, but little is known about their joint effect, especially their cumulative joint effect on late life health. METHODS: We enrolled 14,292 participants aged 60+ years by multistage sampling across 173 communities in Xiamen, China, in 2013. Heath status was assessed by the ability to perform six basic activities of daily life. Education was classified in four categories: 'Illiterate', 'Primary', 'Junior high school' and 'Senior high school and beyond'. Main lifetime occupation was also four categorized: 'Employed', 'Farmer', 'Jobless' and 'Others'. Odds ratios (ORs) were estimated by random intercept multilevel models regressing health status on education and main lifetime occupation with or without their interactions, adjusting by some covariates. RESULTS: Totally, 13,880 participants had complete data, of whom 12.5% suffered from disability, and 'Illiterate' and 'Farmer' took up the greatest proportion (33.01% and 42.72%, respectively). Participants who were higher educated had better health status (ORs = 0.62, 0.46, and 0.44 for the 'Primary', 'Junior high school', and 'Senior high school and beyond', respectively, in comparison with 'Illiterate'). Those who were long term jobless in early life had poorest heath (ORs = 1.88, 95% CI 1.47 to 2.40). Unexpectedly, for the farmers, the risk of poor health gradually increased in relation to higher education level (ORs = 1.26, 1.28, 1.40 and 2.24, respectively). For the 'Employed', similar ORs were obtained for the 'Junior high school' and 'Senior high school and beyond' educated (both ORs = 1.01). For the 'Farmer' and 'Jobless', participants who were 'Illiterate' and 'Primary' educated also showed similar ORs. CONCLUSIONS: Both education and main lifetime occupation were associated with late life health. Higher education was observed to be associated with better health, but such educational advantage was mediated by main lifetime occupation. PMID- 26107637 TI - Targeting Medication Non-Adherence Behavior in Selected Autoimmune Diseases: A Systematic Approach to Digital Health Program Development. AB - BACKGROUND: 29 autoimmune diseases, including Rheumatoid Arthritis, gout, Crohn's Disease, and Systematic Lupus Erythematosus affect 7.6-9.4% of the population. While effective therapy is available, many patients do not follow treatment or use medications as directed. Digital health and Web 2.0 interventions have demonstrated much promise in increasing medication and treatment adherence, but to date many Internet tools have proven disappointing. In fact, most digital interventions continue to suffer from high attrition in patient populations, are burdensome for healthcare professionals, and have relatively short life spans. OBJECTIVE: Digital health tools have traditionally centered on the transformation of existing interventions (such as diaries, trackers, stage-based or cognitive behavioral therapy programs, coupons, or symptom checklists) to electronic format. Advanced digital interventions have also incorporated attributes of Web 2.0 such as social networking, text messaging, and the use of video. Despite these efforts, there has not been little measurable impact in non-adherence for illnesses that require medical interventions, and research must look to other strategies or development methodologies. As a first step in investigating the feasibility of developing such a tool, the objective of the current study is to systematically rate factors of non-adherence that have been reported in past research studies. METHODS: Grounded Theory, recognized as a rigorous method that facilitates the emergence of new themes through systematic analysis, data collection and coding, was used to analyze quantitative, qualitative and mixed method studies addressing the following autoimmune diseases: Rheumatoid Arthritis, gout, Crohn's Disease, Systematic Lupus Erythematosus, and inflammatory bowel disease. Studies were only included if they contained primary data addressing the relationship with non-adherence. RESULTS: Out of the 27 studies, four non-modifiable and 11 modifiable risk factors were discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting): patients not understanding treatment (44%), side effects (41%), age (37%), dose regimen (33%), and perceived medication ineffectiveness (33%). An unanticipated finding that emerged was the need for risk stratification tools (81%) with patient centric approaches (67%). CONCLUSIONS: This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns. PMID- 26107638 TI - Comparison of the Equine Reference Sequence with Its Sanger Source Data and New Illumina Reads. AB - The reference assembly for the domestic horse, EquCab2, published in 2009, was built using approximately 30 million Sanger reads from a Thoroughbred mare named Twilight. Contiguity in the assembly was facilitated using nearly 315 thousand BAC end sequences from Twilight's half brother Bravo. Since then, it has served as the foundation for many genome-wide analyses that include not only the modern horse, but ancient horses and other equid species as well. As data mapped to this reference has accumulated, consistent variation between mapped datasets and the reference, in terms of regions with no read coverage, single nucleotide variants, and small insertions/deletions have become apparent. In many cases, it is not clear whether these differences are the result of true sequence variation between the research subjects' and Twilight's genome or due to errors in the reference. EquCab2 is regarded as "The Twilight Assembly." The objective of this study was to identify inconsistencies between the EquCab2 assembly and the source Twilight Sanger data used to build it. To that end, the original Sanger and BAC end reads have been mapped back to this equine reference and assessed with the addition of approximately 40X coverage of new Illumina Paired-End sequence data. The resulting mapped datasets identify those regions with low Sanger read coverage, as well as variation in genomic content that is not consistent with either the original Twilight Sanger data or the new genomic sequence data generated from Twilight on the Illumina platform. As the haploid EquCab2 reference assembly was created using Sanger reads derived largely from a single individual, the vast majority of variation detected in a mapped dataset comprised of those same Sanger reads should be heterozygous. In contrast, homozygous variations would represent either errors in the reference or contributions from Bravo's BAC end sequences. Our analysis identifies 720,843 homozygous discrepancies between new, high throughput genomic sequence data generated for Twilight and the EquCab2 reference assembly. Most of these represent errors in the assembly, while approximately 10,000 are demonstrated to be contributions from another horse. Other results are presented that include the binary alignment map file of the mapped Sanger reads, a list of variants identified as discrepancies between the source data and resulting reference, and a BED annotation file that lists the regions of the genome whose consensus was likely derived from low coverage alignments. PMID- 26107639 TI - From Abstinence to Relapse: A Preliminary Qualitative Study of Drug Users in a Compulsory Drug Rehabilitation Center in Changsha, China. AB - BACKGROUND: Relapse among abstinent drug users is normal. Several factors are related to relapse, but it remains unclear what individuals' actual life circumstances are during periods of abstinence, and how these circumstances facilitate or prevent relapse. OBJECTIVE: To illuminate drug users' experiences during abstinence periods and explore the real-life catalysts and inhibitors contributing to drug use relapse. METHOD: Qualitative in-depth interviews were conducted with 20 drug users recruited from a compulsory isolated drug rehabilitation center in Changsha. The interviews were guided by open-ended questions on individuals' experiences in drug use initiation, getting addicted, treatment history, social environment, abstinence, and relapse. Participants were also encouraged to share their own stories. Interviews were digitally recorded and fully transcribed. The data of 18 participants who reported abstinence experiences before admission were included in the analyses. The data were analyzed using a thematic analysis with inductive hand coding to derive themes. RESULTS: Most drug users were able to successfully abstain from drugs. During abstinence, their lives were congested with challenges, such as adverse socioeconomic conditions, poor family/social support, interpersonal conflicts, and stigma and discrimination, all of which kept them excluded from mainstream society. Furthermore, the police's system of ID card registration, which identifies individuals as drug users, worsened already grave situations. Relapse triggers reported by the participants focused mainly on negative feelings, interpersonal conflicts, and stressful events. Craving was experienced but not perceived as a relapse trigger by most participants. CONCLUSIONS: This study of in-depth interview with drug users found evidence of situations and environments they live during abstinence appear rather disadvantaged, making it extremely difficult for them to remain abstinent. Comprehensive programs on relapse prevention that acknowledge these disadvantages are implicated. PMID- 26107640 TI - Spatiotemporal Distribution, Sources, and Photobleaching Imprint of Dissolved Organic Matter in the Yangtze Estuary and Its Adjacent Sea Using Fluorescence and Parallel Factor Analysis. AB - To investigate the seasonal and interannual dynamics of dissolved organic matter (DOM) in the Yangtze Estuary, surface and bottom water samples in the Yangtze Estuary and its adjacent sea were collected and characterized using fluorescence excitation-emission matrices (EEMs) and parallel factor analysis (PARAFAC) in both dry and wet seasons in 2012 and 2013. Two protein-like components and three humic-like components were identified. Three humic-like components decreased linearly with increasing salinity (r>0.90, p<0.001), suggesting their distribution could primarily be controlled by physical mixing. By contrast, two protein-like components fell below the theoretical mixing line, largely due to microbial degradation and removal during mixing. Higher concentrations of humic like components found in 2012 could be attributed to higher freshwater discharge relative to 2013. There was a lack of systematic patterns for three humic-like components between seasons and years, probably due to variations of other factors such as sources and characteristics. Highest concentrations of fluorescent components, observed in estuarine turbidity maximum (ETM) region, could be attributed to sediment resuspension and subsequent release of DOM, supported by higher concentrations of fluorescent components in bottom water than in surface water at two stations where sediments probably resuspended. Meanwhile, photobleaching could be reflected from the changes in the ratios between fluorescence intensity (Fmax) of humic-like components and chromophoric DOM (CDOM) absorption coefficient (a355) along the salinity gradient. This study demonstrates the abundance and composition of DOM in estuaries are controlled not only by hydrological conditions, but also by its sources, characteristics and related estuarine biogeochemical processes. PMID- 26107642 TI - Harvesting light energy by iridium(III) complexes on a clay surface. AB - Energy transfer was investigated between two types of iridium(III) complexes, [Ir(dfppy)2(Cn-bpy)](+) (dfppyH = 2-(2',4'-difluorophenyl)pyridine; Cn-bpy = 4,4' dialkyl-2,2'-bipyridine; dialkyl = dimethyl (C1), didodecyl (C12), and dinonyldecyl (C19)) and [Ir(piq)2(Cn-bpy)](+) (piqH = 1-phenylisoquinoline) as a donor and an acceptor, respectively. The complexes were co-adsorbed by colloidally dispersed synthetic saponite. The efficiency of energy transfer (eta(ET)) was obtained from emission spectra at various donor-to-acceptor ratios (D/A) on the basis of the Forster-type energy transfer mechanism. For C1-bpy, eta(ET) was as high as 0.5 with a D/A of ca. 20. The results implied that the photon energy captured by several donor molecules was collected by a single acceptor molecule (i.e. the harvesting of light energy). Enantioselectivity was observed, which indicates the participation of a contact pair of donor and acceptor molecules. For C12-bpy and C19-bpy, eta(ET) was low and exhibited no enantioselectivity, because their long alkyl chains inhibited close contact between the donor and acceptor molecules. PMID- 26107641 TI - Prevalence and predictors of early cardiovascular events after kidney transplantation: evaluation of pre-transplant cardiovascular work-up. AB - INTRODUCTION: Cardiovascular disease is the leading cause of mortality after renal transplantation. The purpose of this study was to analyze cardiovascular risk factors at transplantation, occurrence of cardiovascular events in the first year after transplantation and evaluate pre-transplant work-up. MATERIAL AND METHOD: In total, 244 renal transplant recipients older than 50 years were included. The results of pre-transplant work-up, including clinical evaluation, electrocardiogram, echocardiography, myocardial perfusion testing and coronary angiography were analyzed. RESULTS: Patients had multiple risk factors at inclusion on renal transplantation waiting list as high blood pressure (94.7%), dyslipidemia (81.1%), smoking (45.3%), diabetes (23.6%), past history of cardiovascular disease (21.3%) and obesity (12.7%). Following transplantation, 15.5% (n = 38) of patients experienced a cardiovascular event, including 2.8% (n = 7) acute coronary syndrome, 5.8% (n = 14) isolated increase in troponin level and 5.3% (n = 13) new onset atrial fibrillation. The pre-transplant parameters associated with a cardiovascular event were a past medical history of cardiovascular disease (HR = 2.06 [1.06-4.03], p = 0.03), echocardiographic left ventricular hypertrophy (HR = 2.04 [1.04-3.98], p = 0.037) and abnormal myocardial perfusion testing (HR = 2.25 [1.09 -5.96], p = 0.03). Pre transplantation evaluation allowed the diagnosis of unknown coronary artery lesions in 8.9% of patients. PMID- 26107643 TI - Deriving Animal Behaviour from High-Frequency GPS: Tracking Cows in Open and Forested Habitat. AB - The increasing spatiotemporal accuracy of Global Navigation Satellite Systems (GNSS) tracking systems opens the possibility to infer animal behaviour from tracking data. We studied the relationship between high-frequency GNSS data and behaviour, aimed at developing an easily interpretable classification method to infer behaviour from location data. Behavioural observations were carried out during tracking of cows (Bos Taurus) fitted with high-frequency GPS (Global Positioning System) receivers. Data were obtained in an open field and forested area, and movement metrics were calculated for 1 min, 12 s and 2 s intervals. We observed four behaviour types (Foraging, Lying, Standing and Walking). We subsequently used Classification and Regression Trees to classify the simultaneously obtained GPS data as these behaviour types, based on distances and turning angles between fixes. GPS data with a 1 min interval from the open field was classified correctly for more than 70% of the samples. Data from the 12 s and 2 s interval could not be classified successfully, emphasizing that the interval should be long enough for the behaviour to be defined by its characteristic movement metrics. Data obtained in the forested area were classified with a lower accuracy (57%) than the data from the open field, due to a larger positional error of GPS locations and differences in behavioural performance influenced by the habitat type. This demonstrates the importance of understanding the relationship between behaviour and movement metrics, derived from GNSS fixes at different frequencies and in different habitats, in order to successfully infer behaviour. When spatially accurate location data can be obtained, behaviour can be inferred from high-frequency GNSS fixes by calculating simple movement metrics and using easily interpretable decision trees. This allows for the combined study of animal behaviour and habitat use based on location data, and might make it possible to detect deviations in behaviour at the individual level. PMID- 26107644 TI - Larval Environment Alters Amphibian Immune Defenses Differentially across Life Stages and Populations. AB - Recent global declines, extirpations and extinctions of wildlife caused by newly emergent diseases highlight the need to improve our knowledge of common environmental factors that affect the strength of immune defense traits. To achieve this goal, we examined the influence of acidification and shading of the larval environment on amphibian skin-associated innate immune defense traits, pre and post-metamorphosis, across two populations of American Bullfrogs (Rana catesbeiana), a species known for its wide-ranging environmental tolerance and introduced global distribution. We assessed treatment effects on 1) skin associated microbial communities and 2) post-metamorphic antimicrobial peptide (AMP) production and 3) AMP bioactivity against the fungal pathogen Batrachochytrium dendrobatidis (Bd). While habitat acidification did not affect survival, time to metamorphosis or juvenile mass, we found that a change in average pH from 7 to 6 caused a significant shift in the larval skin microbial community, an effect which disappeared after metamorphosis. Additionally, we found shifts in skin-associated microbial communities across life stages suggesting they are affected by the physiological or ecological changes associated with amphibian metamorphosis. Moreover, we found that post-metamorphic AMP production and bioactivity were significantly affected by the interactions between pH and shade treatments and interactive effects differed across populations. In contrast, there were no significant interactions between treatments on post-metamorphic microbial community structure suggesting that variation in AMPs did not affect microbial community structure within our study. Our findings indicate that commonly encountered variation in the larval environment (i.e. pond pH and degree of shading) can have both immediate and long term effects on the amphibian innate immune defense traits. Our work suggests that the susceptibility of amphibians to emerging diseases could be related to variability in the larval environment and calls for research into the relative influence of potentially less benign anthropogenic environmental changes on innate immune defense traits. PMID- 26107645 TI - Effect of CYP2B6 Gene Polymorphisms on Efavirenz Plasma Concentrations in Chinese Patients with HIV Infection. AB - OBJECTIVES: The main aim of this study was to investigate the effect of CYP2B6 gene polymorphisms on efavirenz (EFV) plasma concentrations in Han Chinese patients with human immunodeficiency virus (HIV) infection. METHODS: In total, 322 patients were recruited for study. EFV plasma concentrations at steady-state were determined using high-performance liquid chromatography. Genotyping for seven single nucleotide polymorphisms (SNPs), including 171+967C>A, 171+3212C>T, 171+4335T>C, 516G>T, 785A>G, 1295-913G>A, and *1355A>G of CYP2B6, was performed using ligase detection reaction (LDR). SPSS 18.0 and Haploview 4.2 were applied for statistical analyses. RESULTS: The average EFV concentration of patients was 2.35+/-2.09 MUg/mL. Overall, 22% patients displayed EFV concentrations out of the therapeutic range of 1-4 MUg/mL (13.1% < 1 MUg/mL, 9.3% > 4 MUg/mL). We observed significant association of 171+967C>A, 171+4335T>C, 516G>T, 785A>G and *1355A>G with high plasma EFV levels (p<.01). The predictive accuracy values of 171+4335CC, 516TT and 785GG for EFV concentrations > 4 MUg/mL were 56.7%, 56.7% and 60%, respectively. We observed strong linkage disequilibrium for 171+967C>A, 171+4335T>C, 516G>T and 785A>G, resulting in five haplotypes. The frequencies of the five haplotypes (high to low) were as follows: CCTG (0.328), ACTG (0.280), ACCT (0.189), ATTG (0.186) and ACCG (0.017). The frequency of CCTG (0.524) in patients with EFV plasma concentrations < 1 MUg/mL was significantly higher than that in other patient groups, while that of ACCT (0.733) was significantly higher in patients with EFV concentrations > 4 MUg/mL, relative to other patient groups. Average EFV concentrations of patients carrying ACTG (1.78 MUg/mL), ACCT (7.50 MUg/mL), and ATTG (1.92 MUg/mL) haplotypes were markedly higher than those of patients carrying the CCTG haplotype. The predictive accuracy of ACCT for EFV > 4 MUg/mL was 81%. CONCLUSIONS: Chinese patients administered standard doses of EFV require therapeutic drug monitoring or personalized medication management. Based on the current findings, we propose that 171+4335T>C, 516G>T, 785A>G and haplotype ACCT may be effectively used as genomic markers for EFV, which should aid in improving the efficacy of EFV-containing treatments and reduce the incidence of adverse reactions. PMID- 26107646 TI - Task uncertainty can account for mixing and switch costs in task-switching. AB - Cognitive control is required in situations that involve uncertainty or change, such as when resolving conflict, selecting responses and switching tasks. Recently, it has been suggested that cognitive control can be conceptualised as a mechanism which prioritises goal-relevant information to deal with uncertainty. This hypothesis has been supported using a paradigm that requires conflict resolution. In this study, we examine whether cognitive control during task switching is also consistent with this notion. We used information theory to quantify the level of uncertainty in different trial types during a cued task switching paradigm. We test the hypothesis that differences in uncertainty between task repeat and task switch trials can account for typical behavioural effects in task-switching. Increasing uncertainty was associated with less efficient performance (i.e., slower and less accurate), particularly on switch trials and trials that afford little opportunity for advance preparation. Interestingly, both mixing and switch costs were associated with a common episodic control process. These results support the notion that cognitive control may be conceptualised as an information processor that serves to resolve uncertainty in the environment. PMID- 26107647 TI - Identification of Prey Captures in Australian Fur Seals (Arctocephalus pusillus doriferus) Using Head-Mounted Accelerometers: Field Validation with Animal-Borne Video Cameras. AB - This study investigated prey captures in free-ranging adult female Australian fur seals (Arctocephalus pusillus doriferus) using head-mounted 3-axis accelerometers and animal-borne video cameras. Acceleration data was used to identify individual attempted prey captures (APC), and video data were used to independently verify APC and prey types. Results demonstrated that head-mounted accelerometers could detect individual APC but were unable to distinguish among prey types (fish, cephalopod, stingray) or between successful captures and unsuccessful capture attempts. Mean detection rate (true positive rate) on individual animals in the testing subset ranged from 67-100%, and mean detection on the testing subset averaged across 4 animals ranged from 82-97%. Mean False positive (FP) rate ranged from 15-67% individually in the testing subset, and 26-59% averaged across 4 animals. Surge and sway had significantly greater detection rates, but also conversely greater FP rates compared to heave. Video data also indicated that some head movements recorded by the accelerometers were unrelated to APC and that a peak in acceleration variance did not always equate to an individual prey item. The results of the present study indicate that head-mounted accelerometers provide a complementary tool for investigating foraging behaviour in pinnipeds, but that detection and FP correction factors need to be applied for reliable field application. PMID- 26107648 TI - Limitations in conduct and reporting of cochrane reviews rarely inhibit the determination of the validity of evidence for clinical decision-making. AB - OBJECTIVE: To determine how often clinical conclusions derived from Cochrane Reviews have uncertain validity due to review conduct and reporting deficiencies. METHODS: We evaluated 5142 clinical conclusions in DynaMed (an evidence-based point-of-care clinical reference) based on 4743 Cochrane Reviews. Clinical conclusions with level 2 evidence due to shortcomings in the review's conduct or reporting (rather than deficiencies in the underlying evidence) were confirmed by a DynaMed editor and two Cochrane Review authors. RESULTS: Thirty-one Cochrane Reviews (0.65%) had confirmed deficiencies in conduct and reporting as the reason for classifying 37 assessed clinical conclusions (0.72%) as level 2 evidence. In all cases, it was not feasible for the assessors to specify a clear criticism of the studies included in the reviews. The deficiencies were specific to not accounting for dropouts (2) or inadequate assessment and reporting of allocation concealment (11), other specific trial quality criteria (14), or all trial quality criteria (4). CONCLUSIONS: Cochrane Reviews provide high-quality assessment and synthesis of evidence, with fewer than 1% of Cochrane Reviews having limitations which hinder the summary of best current evidence for clinical decision-making. We expect this will further decrease following recent Cochrane quality initiatives. PMID- 26107649 TI - A New Classification of Ficus Subsection Urostigma (Moraceae) Based on Four Nuclear DNA Markers (ITS, ETS, G3pdh, and ncpGS), Morphology and Leaf Anatomy. AB - Ficus subsection Urostigma as currently circumscribed contains 27 species, distributed in Africa, Asia, Australia and the Pacific, and is of key importance to understand the origin and evolution of Ficus and the fig-wasp mutualism. The species of subsection Urostigma are very variable in morphological characters and exhibit a wide range of often partly overlapping distributions, which makes identification often difficult. The systematic classification within and between this subsection and others is problematic, e.g., it is still unclear where to classify F. amplissima and F. rumphii. To clarify the circumscription of subsection Urostigma, a phylogenetic reconstruction based on four nuclear DNA markers (ITS, ETS, G3pdh, and ncpGS) combined with morphology and leaf anatomy is conducted. The phylogenetic tree based on the combined datasets shows that F. madagascariensis, a Madagascan species, is sister to the remainder of subsect. Urostigma. Ficus amplissima and F. rumphii, formerly constituting sect. Leucogyne, appear to be imbedded in subsect. Conosycea. The result of the phylogenetic analysis necessitates nomenclatural adjustments. A new classification of Ficus subsection Urostigma is presented along with the morphological and leaf anatomical apomorphies typical for the clades. Two new species are described ? one in subsect. Urostigma, the other in Conosycea. One variety is raised to species level. PMID- 26107650 TI - Construction of an Ultrahigh Pressure Liquid Chromatography-Tandem Mass Spectral Library of Plant Natural Products and Comparative Spectral Analyses. AB - A plant natural product tandem mass spectral library has been constructed using authentic standards and purified compounds. Currently, the library contains 1734 tandem mass spectra for 289 compounds, with the majority (76%) of the compounds being plant phenolics such as flavonoids, isoflavonoids, and phenylpropanoids. Tandem mass spectra and chromatographic retention data were acquired on a triple quadrupole mass spectrometer coupled to an ultrahigh pressure liquid chromatograph using six different collision energies (CEs) (10-60 eV). Comparative analyses of the tandem mass spectral data revealed that the loss of ring substituents preceded the C-ring opening during the fragmentation of flavonoids and isoflavonoids. At lower CE (i.e., 10 and 20 eV), the flavonoids and isoflavonoid central ring structures typically remained intact, and fragmentation was characterized by the loss of the substituents (i.e., methyl and glycosyl groups). At higher CE, the flavonoid and isoflavonoid core ring systems underwent C-ring cleavage and/or rearrangement depending on the structure, particularly hydroxylation patterns. In-source electrochemical oxidation was observed for phenolics that had ortho-diphenol moieties (i.e., vicinal hydroxyl groups on the aromatic rings). The ortho-diphenols were oxidized to ortho quinones, yielding an intensive and, in most cases, a base ion peak corresponding to a [(M - 2H) - H](-) ion in their mass spectra. The library also contains reverse-phase retention times, allowing for the construction, validation, and testing of an artificial neural network retention prediction of other flavonoids and isoflavonoids not contained within the library. The library is freely available for nonprofit, academic use and it can be downloaded at http://www.noble.org/apps/Scientific/WebDownloadManager/DownloadArea.aspx. PMID- 26107651 TI - T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents. AB - OBJECTIVES: To prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus. MATERIALS AND METHODS: Healthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data. RESULTS: A significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 +/- 0.024) compared to the gadoterate meglumine group (1.000 +/- 0.033; P < 0.001) and control group (1.019 +/- 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 +/- 0.91 nmol/g) compared with the gadoterate meglumine (0.26 +/ 0.12 nmol/g; P < 0.05) and control (0.06 +/- 0.10 nmol/g; P < 0.05) groups. CONCLUSIONS: Repeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed. PMID- 26107652 TI - Commentary on T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents. PMID- 26107653 TI - Ion-precursor and ion-dose dependent anti-galvanic reduction. AB - Controlling alloy nanoparticles with atomic monodispersity is challenging, and the recently revealed anti-galvanic reduction (AGR) provides a unique solution to this challenge. Herein we demonstrate that AGR is ion-precursor and ion-dose dependent, which offers novel strategies to tune the composition, structure and properties of nanoparticles by varying the ion-precursor and ion-dose in the AGR reaction. PMID- 26107654 TI - How Many Genes Are Expressed in a Transcriptome? Estimation and Results for RNA Seq. AB - RNA-seq experiments estimate the number of genes expressed in a transcriptome as well as their relative frequencies. However, an undetermined number of genes can remain undetected due to their low expression relative to the sample size (sequence depth). Estimation of the true number of genes expressed in a transcriptome is essential in order to determine which genes are exclusively expressed in specific tissues or under particular conditions. A reliable estimate of the true number of expressed genes is also required to accurately measure transcriptome changes and to predict the sequencing depth needed to increase the proportion of detected genes. This problem is analogous to ecological sampling problems such as estimating the number of species at a given site. Here we present a non-parametric estimator for the number of undetected genes as well as for the extra sample size needed to detect a given proportion of the undetected genes. Our estimators are superior to ones already published by having smaller standard errors and biases. We applied our method to a set of 32 publicly available RNA-seq experiments, including the evaluation of 311 individually sequenced libraries. We found that in the majority of the cases more than one thousand genes are undetected, and that on average approximately 6% of the expressed genes per accession remain undetected. This figure increases to approximately 10% if individual sequencing libraries are analyzed. Our method is also applicable to metagenomic experiments. Using our method, the number of undetected genes as well as the sample size needed to detect them can be calculated, leading to more accurate and complete gene expression studies. PMID- 26107658 TI - Rice protein hydrolysates stimulate GLP-1 secretion, reduce GLP-1 degradation, and lower the glycemic response in rats. AB - Rice has historically been consumed in Asia as a major source of carbohydrates, however, little is known regarding the functional roles of rice proteins as dietary factors. In the present study, we investigated whether peptides derived from rice proteins could stimulate GLP-1 secretion, which results in reducing glycemia via the incretin effect in normal rats. Hydrolysates were prepared from the protein fraction of rice endosperm or rice bran, and the effects of these hydrolysates on GLP-1 secretion were examined in a murine enteroendocrine cell line GLUTag. Plasma was collected after oral administration of the rice protein hydrolysates, under anesthesia, or during glucose tolerance tests in rats. In anesthetized rats, plasma dipeptidyl peptidase-IV (DPP-IV) activity was measured after ileal administration of the rice protein hydrolysates. GLP-1 secretion from GLUTag cells was potently stimulated by the rice protein hydrolysates, especially by the peptic digest of rice endosperm protein (REPH) and that of rice bran protein (RBPH). Oral administration of REPH or RBPH elevated plasma GLP-1 concentrations, which resulted in the reduction of glycemia under the intraperitoneal glucose tolerance test. In addition, the plasma DPP-IV activity was attenuated after ileal administration of REPH or RBPH, which resulted in a higher ratio of intact (active) GLP-1 to total GLP-1 in the plasma. These results demonstrate that rice proteins exert potent stimulatory effects on GLP-1 secretion, which could contribute to the reduction of postprandial glycemia. The inhibitory effect of these peptides on the plasma DPP-IV activity may potentiate the incretin effect of GLP-1. PMID- 26107655 TI - Development and Validation of an Index to Measure the Quality of Facility-Based Labor and Delivery Care Processes in Sub-Saharan Africa. AB - BACKGROUND: High quality care is crucial in ensuring that women and newborns receive interventions that may prevent and treat birth-related complications. As facility deliveries increase in developing countries, there are concerns about service quality. Observation is the gold standard for clinical quality assessment, but existing observation-based measures of obstetric quality of care are lengthy and difficult to administer. There is a lack of consensus on quality indicators for routine intrapartum and immediate postpartum care, including essential newborn care. This study identified key dimensions of the quality of the process of intrapartum and immediate postpartum care (QoPIIPC) in facility deliveries and developed a quality assessment measure representing these dimensions. METHODS AND FINDINGS: Global maternal and neonatal care experts identified key dimensions of QoPIIPC through a modified Delphi process. Experts also rated indicators of these dimensions from a comprehensive delivery observation checklist used in quality surveys in sub-Saharan African countries. Potential QoPIIPC indices were developed from combinations of highly-rated indicators. Face, content, and criterion validation of these indices was conducted using data from observations of 1,145 deliveries in Kenya, Madagascar, and Tanzania (including Zanzibar). A best-performing index was selected, composed of 20 indicators of intrapartum/immediate postpartum care, including essential newborn care. This index represented most dimensions of QoPIIPC and effectively discriminated between poorly and well-performed deliveries. CONCLUSIONS: As facility deliveries increase and the global community pays greater attention to the role of care quality in achieving further maternal and newborn mortality reduction, the QoPIIPC index may be a valuable measure. This index complements and addresses gaps in currently used quality assessment tools. Further evaluation of index usability and reliability is needed. The availability of a streamlined, comprehensive, and validated index may enable ongoing and efficient observation based assessment of care quality during labor and delivery in sub-Saharan Africa, facilitating targeted quality improvement. PMID- 26107659 TI - A new application of high-efficient silver salts-based photocatalyst under natural indoor weak light for wastewater cleaning. AB - As a high-quantum-efficiency photocatalyst, the serious photo-corrosion of silver phosphate (Ag3PO4), limits the practical applications in water purification and challenges us. Herein, Ag3PO4 is found to have a high stability under natural indoor weak light irradiation, suggesting that we can employ it by adopting a new application strategy. In our studies, rhodamine B (RhB, cationic dye), methyl orange (MO, anionic dye) and RhB-MO mixture aqueous solutions are used as the probing reaction for the degradation of organic wastewater. It is found that RhB, MO and RhB-MO can be completely degraded after 28 h under natural indoor weak light irradiation, indicating that multi-component organic contaminants can be efficiently degraded by Ag3PO4 under natural indoor weak light irradiation. The density of natural indoor weak light is measured to be 72cd, which is merely one thousandth of 300 W xenon lamp (68.2 * 10(3)cd). Most importantly, Ag3PO4 shows a high stability under natural indoor weak light irradiation, demonstrated by the formation of fairly rare Ag. Furthermore, we also investigate the influence of inorganic ions on organic dyes degradation. It shows that the Cl(-) and Cr(6+) ions with high concentrations in wastewater have significantly decreased the degradation rate. From the viewpoint of energy saving and stability, this study shows us that we can utilize the Ag-containing photocatalysts under natural indoor weak light, which could be extended to indoor air cleaning process. PMID- 26107660 TI - Highly stereoselective construction of novel dispirooxindole-imidazolidines via self-1,3-dipolar cyclization of ketimines. AB - An acid-promoted self-1,3-dipolar cycloaddition of ketimines derived from isatins and benzylamines was successfully developed to assemble unprecedented dispirooxindole-imidazolidine ring systems. Generally, excellent diastereoselectivities (only a single stereoisomer formed) and good yields (up to 94%) were obtained. Consequently, this self-1,3-dipolar cycloaddition protocol offers facile access to a novel dispiroheterocyclic skeleton. PMID- 26107661 TI - Simulation as a new tool to establish benchmark outcome measures in obstetrics. AB - BACKGROUND: There are not enough clinical data from rare critical events to calculate statistics to decide if the management of actual events might be below what could reasonably be expected (i.e. was an outlier). OBJECTIVES: In this project we used simulation to describe the distribution of management times as an approach to decide if the management of a simulated obstetrical crisis scenario could be considered an outlier. DESIGN: Twelve obstetrical teams managed 4 scenarios that were previously developed. Relevant outcome variables were defined by expert consensus. The distribution of the response times from the teams who performed the respective intervention was graphically displayed and median and quartiles calculated using rank order statistics. RESULTS: Only 7 of the 12 teams performed chest compressions during the arrest following the 'cannot intubate/cannot ventilate' scenario. All other outcome measures were performed by at least 11 of the 12 teams. Calculation of medians and quartiles with 95% CI was possible for all outcomes. Confidence intervals, given the small sample size, were large. CONCLUSION: We demonstrated the use of simulation to calculate quantiles for management times of critical event. This approach could assist in deciding if a given performance could be considered normal and also point to aspects of care that seem to pose particular challenges as evidenced by a large number of teams not performing the expected maneuver. However sufficiently large sample sizes (i.e. from a national data base) will be required to calculate acceptable confidence intervals and to establish actual tolerance limits. PMID- 26107662 TI - Plasmodium simium, a Plasmodium vivax-related malaria parasite: genetic variability of Duffy binding protein II and the Duffy antigen/receptor for chemokines. AB - Plasmodium simium is a parasite from New World monkeys that is most closely related to the human malaria parasite Plasmodium vivax; it also naturally infects humans. The blood-stage infection of P. vivax depends on Duffy binding protein II (PvDBPII) and its cognate receptor on erythrocytes, the Duffy antigen receptor for chemokines (hDARC), but there is no information on the P. simium erythrocytic invasion pathway. The genes encoding P. simium DBP (PsDBPII) and simian DARC (sDARC) were sequenced from Southern brown howler monkeys (Alouatta guariba clamitans) naturally infected with P. simium because P. simium may also depend on the DBPII/DARC interaction. The sequences of DBP binding domains from P. vivax and P. simium were highly similar. However, the genetic variability of PsDBPII was lower than that of PvDBPII. Phylogenetic analyses demonstrated that these genes were strictly related and clustered in the same clade of the evolutionary tree. DARC from A. clamitans was also sequenced and contained three new non synonymous substitutions. None of these substitutions were located in the N terminal domain of DARC, which interacts directly with DBPII. The interaction between sDARC and PvDBPII was evaluated using a cytoadherence assay of COS7 cells expressing PvDBPII on their surfaces. Inhibitory binding assays in vitro demonstrated that antibodies from monkey sera blocked the interaction between COS 7 cells expressing PvDBPII and hDARC-positive erythrocytes. Taken together, phylogenetic analyses reinforced the hypothesis that the host switch from humans to monkeys may have occurred very recently in evolution, which sheds light on the evolutionary history of new world plasmodia. Further invasion studies would confirm whether P. simium depends on DBP/DARC to trigger internalization into red blood cells. PMID- 26107665 TI - The Prognostic Impact of Preoperative and Postoperative Chemoradiation in Clinical Stage II and III Esophageal Squamous Cell Carcinomas: A Population Based Study in Taiwan. AB - While preoperative chemoradiation followed by surgery (pre-OP CRT) has been widely applied in the treatment of patients with esophageal cancer, some studies have shown a survival benefit of postoperative chemoradiation (post-OP CRT). The optimal combination of multimodality therapy and the sequence of surgery and chemoradiation for esophageal cancer remain to be investigated. A total of 1385 patients with clinical stage II and III esophageal squamous cell carcinoma (ESCC) were included. On the basis of the sequence of surgery and chemoradiation, the patients were grouped as follows: preoperative chemoradiation followed by surgery (pre-OP CRT+S), surgery alone (S), and surgery followed by postoperative chemoradiation (S+post-OP CRT). Propensity score matching analysis was used to identify 78 well-balanced patients in each group for outcome comparison.In all, 753, 339, and 293 patients were in the pre-OP CRT+S, S, and S+post-OP CRT groups, respectively. Before matching, no differences were observed in the overall survival among the patients in these 3 groups (P = 0.422). After matching, both the pre-OP CRT+S and S+post-OP CRT groups were significantly associated with a better survival compared with the S group (pre-OP CRT+S vs. S: P < 0.001; S+post OP CRT vs. S: P = 0.005). In contrast, the survival was similar between the pre OP CRT+S and S+post-OP CRT groups (P = 0.544). In the subgroup analysis, patients with clinical T3/4 stage tumors or those with a tumor size greater than 5 cm were more likely to demonstrate an overall survival benefit from pre-OP CRT compared with post-OP CRT. Both pre-OP CRT and post-OP CRT demonstrated a survival benefit compared with surgery alone, which indicates the importance of trimodality therapy in patients with clinical stage II/III ESCC. However, no survival difference was observed among patients in the pre-OP CRT+S and S+post-OP CRT groups, which suggests that the sequence of surgery and chemoradiation may be irrelevant to the outcome. PMID- 26107666 TI - Techniques of Fluorescence Cholangiography During Laparoscopic Cholecystectomy for Better Delineation of the Bile Duct Anatomy. AB - To evaluate the clinical and technical factors affecting the ability of fluorescence cholangiography (FC) using indocyanine green (ICG) to delineate the bile duct anatomy during laparoscopic cholecystectomy (LC).Application of FC during LC began after laparoscopic fluorescence imaging systems became commercially available.In 108 patients undergoing LC, FC was performed by preoperative intravenous injection of ICG (2.5 mg) during dissection of Calot's triangle, and clinical factors affecting the ability of FC to delineate the extrahepatic bile ducts were evaluated. Equipment-related factors associated with bile duct detectability were also assessed among 5 laparoscopic systems and 1 open fluorescence imaging system in ex vivo studies.FC delineated the confluence between the cystic duct and common hepatic duct (CyD-CHD) before and after dissection of Calot's triangle in 80 patients (74%) and 99 patients (92%), respectively. The interval between ICG injection and FC before dissection of Calot's triangle was significantly longer in the 80 patients in whom the CyD-CHD confluence was detected by fluorescence imaging before dissection (median, 90 min; range, 15-165 min) than in the remaining 28 patients in whom the confluence was undetectable (median, 47 min; range, 21-205 min; P < 0.01). The signal contrast on the fluorescence images of the bile duct samples was significantly different among the laparoscopic imaging systems and tended to decrease more steeply than those of the open imaging system as the target-laparoscope distance increased and porcine tissues covering the samples became thicker.FC is a simple navigation tool for obtaining a biliary roadmap to reach the "critical view of safety" during LC. Key factors for better bile duct identification by FC are administration of ICG as far in advance as possible before surgery, sufficient extension of connective tissues around the bile ducts, and placement of the tip of laparoscope close and vertically to Calot's triangle. PMID- 26107664 TI - Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. AB - Oxidative stress and inflammation play a role in cognitive impairment, which is a core symptom of schizophrenia. Furthermore, a hallmark of the pathophysiology of this disease is the dysfunction of cortical inhibitory gamma-aminobutyric acid (GABA) neurons expressing parvalbumin (PV), which is also involved in cognitive impairment. Sulforaphane (SFN), an isothiocyanate derived from broccoli, is a potent activator of the transcription factor Nrf2, which plays a central role in the inducible expressions of many cytoprotective genes in response to oxidative stress. Keap1 is a cytoplasmic protein that is essential for the regulation of Nrf2 activity. Here, we found that pretreatment with SFN attenuated cognitive deficits, the increase in 8-oxo-dG-positive cells, and the decrease in PV positive cells in the medial prefrontal cortex and hippocampus after repeated administration of phencyclidine (PCP). Furthermore, PCP-induced cognitive deficits were improved by the subsequent subchronic administration of SFN. Interestingly, the dietary intake of glucoraphanin (a glucosinolate precursor of SFN) during the juvenile and adolescence prevented the onset of PCP-induced cognitive deficits as well as the increase in 8-oxo-dG-positive cells and the decrease in PV-positive cells in the brain at adulthood. Moreover, the NRF2 gene and the KEAP1 gene had an epistatic effect on cognitive impairment (e.g., working memory and processing speed) in patients with schizophrenia. These findings suggest that SFN may have prophylactic and therapeutic effects on cognitive impairment in schizophrenia. Therefore, the dietary intake of SFN-rich broccoli sprouts during the juvenile and adolescence may prevent the onset of psychosis at adulthood. PMID- 26107667 TI - Initial Metastatic Site as a Prognostic Factor in Patients With Stage IV Pancreatic Ductal Adenocarcinoma. AB - Few studies have evaluated the presence of hepatic or peritoneal metastasis as a prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the prognostic value of the initial metastatic, extrahepatic, or hepatic site in patients with metastatic PDAC. Between January 2007 and December 2013, the medical records of 343 patients with metastatic PDAC treated at Seoul National University Bundang Hospital were retrospectively reviewed. Patients were classified as having extrahepatic metastasis alone (EH), hepatic metastasis alone (LV), and both hepatic and extrahepatic metastasis (BOTH). The median age was 67 years; 207 patients were men. Patients were classified as having EH (111 patients), LV (106), and BOTH (126). Totally, 212 patients underwent chemotherapy with a FOLFIRINOX (23 patients) or gemcitabine-based regimen (189). On multivariate analysis, an ECOG score >=2 (hazard ratio [HR]: 3.2, 95% confidence interval [CI]: 2.2-4.5), albumin < 35 g/L (HR: 1.6, 95% CI: 1.1-2.3), C-reactive protein > 10 mg/L (HR: 2.3, 95% CI: 1.6-3.2), neutrophil-lymphocyte ratio > 5 (HR: 1.4, 95% CI: 1.0 2.0), no chemotherapy (HR: 2.0, 95% CI: 1.0-4.1), and metastatic site (LV, HR: 2.1, 95% CI: 1.4-3.1; BOTH, HR: 2.2, 95% CI: 1.6-3.2) were significantly associated with shorter overall survival (OS). Considering the initial metastatic site, the median OS of patients with EH, LV, and BOTH were 7.5 (95% CI: 6.3-8.8), 4.8 (95% CI: 4.1-5.5), and 2.4 (95% CI: 1.9-2.9) months, respectively. The initial metastatic site is significantly and independently associated with OS in patients with metastatic PDAC, serving as an effective prognostic factor. PMID- 26107668 TI - Rescue Radioguided Laparoscopy Surgery for Meckel's Diverticulum: Technical Notes. AB - The extirpation of Meckel's diverticulum (MD) via conventional or laparoscopic surgery is the definitive treatment. However, certain circumstances may modify or alter this situation and require the application of exceptional measures.We report a case under our observation who previously had an exploratory abdominal laparotomy for a suspected MD; however, the findings were negative. At that time, the diagnosis was established based on low-level gastrointestinal bleeding and isotopic tests that confirmed the existence of the diverticulum. Given the findings of gamma-graphic exploration and the previous negative surgical exploration, a decision was made to remove the lesion by laparoscopic radioguided surgery.The patient underwent bilateral laparoscopic radioguided surgery using a gamma radiation detection probe. The exploration of the abdominal cavity noted the existence of the diverticulum about 60 to 70 cm from the ileocecal valve. In this way, it was possible to proceed with the resection of the bowel loop and perform an intracorporeal anastomosis termino lateral. The postoperative course was uneventful, and the patient was discharged on the fifth postoperative day.We believe that the combination of radioguided surgery and single photon emission computed tomography/computed tomography could be useful for treating lesions in locations that are surgically difficult because of the characteristics of the lesion itself or the peculiarities of an individual patient. PMID- 26107669 TI - No Development of Imipenem Resistance in Pneumonia Caused by Escherichia coli. AB - BACKGROUND: Antibiotic resistance continues to rise due to the increased number of antibiotic prescriptions and is now a major threat to public health. In particular, there is an increase in antibiotic resistance to Escherichia coli according to the latest reports. TRIAL DESIGN: This article examines, retrospectively, antibiotic resistance in patients with community- and nosocomial acquired pneumonia caused by E coli. METHODS: The data of all patients with community- and nosocomial-acquired pneumonia caused by E coli were collected from the hospital charts at the HELIOS Clinic, Witten/Herdecke University, Wuppertal, Germany, within the study period 2004 to 2014. An antibiogram was performed for the study patients with pneumonia caused by E coli. Antimicrobial susceptibility testing was performed for the different antibiotics that have been consistently used in the treatment of patients with pneumonia caused by E coli. All demographic, clinical, and laboratory data of all of the patients with pneumonia caused by E coli were collected from the patients' records. RESULTS: During the study period of January 1, 2004 to August 12, 2014, 135 patients were identified with community- and nosocomial-acquired pneumonia affected by E coli. These patients had a mean age of 72.5 +/- 11.6 (92 [68.1%, 95% CI 60.2%-76.0%] males and 43 [31.9%, 95% CI 24.0%-39.8%] females). E coli had a high resistance rate to ampicillin (60.7%), piperacillin (56.3%), ampicillin-sulbactam (44.4%), and co trimoxazole (25.9%). No patients with pneumonia caused by E coli showed resistance to imipenem (P < 0.0001). CONCLUSION: E coli was resistant to many of the typically used antibiotics. No resistance was detected toward imipenem in patients with pneumonia caused by E coli. PMID- 26107670 TI - Treatment of a Simple Bone Cyst Using a Cannulated Hydroxyapatite Pin. AB - Simple bone cysts (SBCs) are benign bone tumors. However, the treatment of SBCs remains controversial because of their healing rate and the invasiveness of surgery. The purpose of the present study was to evaluate the treatment of SBCs using a cannulated hydroxyapatite (HA) pin.A total of 43 patients (35 males, 8 females; mean age 12.1 years; age range, 5-22 years) with SBCs were treated with continuous decompression by inserting ceramic HA pins between 1989 and 2014. The SBCs were located in the calcaneus in 23, the humerus in 15, the femur in 3, and the pelvis in 2 cases. In all patients, minimal fenestration of the cyst wall and curettage and multiple drilling in the cyst wall were performed, followed by insertion of the HA pin. The mean follow-up period was 26.6 months. Operating time, healing period, risk factors for recurrence, and the cure rate were evaluated.Healing was achieved without intervention in 38 patients after a mean of 6.4 months. Two patients had persistent small residual cysts, which had no changes after 1 year at the latest follow-up. There were 5 patients with recurrences (humerus 4, femur 1), who were cured by curettage and artificial bone grafting. The final healing rate by cannulation only using an HA pin was 88.2%. On Fisher exact test, age, site of SBCs, and distance from the physis were found to be significantly associated with SBC recurrence (P < 0.05).In the present study, cannulation using an HA pin for SBCs was found to be a useful technique, particularly for calcaneal cysts, because it is a minimally invasive procedure with a high cure rate. In patients <10 years, involvement of the humerus and contact with the growth plate were significant risk factors for SBC recurrence. PMID- 26107671 TI - Intravoxel Incoherent Motion MR Imaging: Comparison of Diffusion and Perfusion Characteristics for Differential Diagnosis of Soft Tissue Tumors. AB - We used intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) to explore the possibility of preoperative diagnosis of soft tissue tumors (STTs). This prospective study enrolled 23 patients. Conventional MRI and IVIM examinations were performed on a 3.0T MR imager. Eight (35%) hemangiomas, 11 (47%) benign soft tissue tumors excluding hemangiomas (BSTTEHs) and 4 soft tissue sarcomas (STSs) were assessed. The mean tumor size was about 1652.36 +/- 233.66 mm(2). Ten b values (0-800 s/mm(2)) were used to evaluate diffusion and perfusion characteristics of IVIM. IVIM parameters (ADC(standard), ADC(slow), ADC(fast), and f) of STTs were measured and evaluated for differentiating hemangiomas, BSTTEHs, and STSs. ADC(slow) and ADC(fast) value were different for hemangiomas, BSTTEHs, and STSs separately (P < 0.001, P < 0.001, and P = 0.001). ADC(slow), cut-off value smaller than 0.93 * 10(-3) mm(2)/s, was the best parameter to differ STSs (0.689 +/- 0.173 * 10 (-3)mm(2)/s) from hemangiomas (0.933 +/- 0.237 * 10 (-3)mm(2)/s) and BSTTEHs (1.156 +/- 0.120 * 10 (-3)mm(2)/s) (P = 0.001). ADC(slow) (0.93 * 10(-3) mm(2)/s =15 years with hypoglycemia as a main diagnosis for hospitalization were eligible. We estimated the annual number of hospitalizations in Japan and compared the annual admission rate by age and treatment groups. We also analyzed the association between patient characteristics and in-hospital mortality.Among 22.7 million discharge records from July 2008 and March 2013, a total of 25,071 patients were eligible. The mean age was 73.4 years, and the mean body mass index (BMI) was 22.3 kg/m(2). The estimated annual hospitalization for hypoglycemia in Japan was ~20,000. Annual admission rates for hypoglycemia per 1000 diabetic patients and 1000 diabetic patients receiving insulin or oral hypoglycemic agents were 2.1 and 4.1, respectively. Patients <40 years and >70 years old were at a higher risk of hospitalization. In-hospital mortality was 3.8%, and risk factors associated with poor survival were male sex, older age, lower bed capacity, community hospital, low BMI, coma at admission, and higher Charlson Comorbidity Index.To prevent severe hypoglycemia that leads to death and complications, individualized and careful glycemic control are important, especially in very old or young patients and in those with comorbid conditions or low BMI. PMID- 26107673 TI - Accurate Dosing of Antiretrovirals at Home Using a Foilized, Polyethylene Pouch to Prevent the Transmission of HIV From Mother to Child. AB - Mother-to-child HIV transmission rates remain elevated in countries with high home birth rates. This risk can be dramatically reduced if infants receive antiretroviral (ARV) medication within 24 hours after birth. However, many barriers prevent access to these medications immediately after delivery, for example, there is currently no suitable mechanism to preserve predosed ARVs in the home during the months before birth. In response to this, students of the Duke University developed the Pratt pouch, a foilized polyethylene packet designed to preserve predosed ARVs.This cross-sectional study presents the data from the first clinical trials of the Pratt pouch in Guayaquil, Ecuador.Fourteen HIV-positive mothers and nurses were observed using the pouch to deliver a dose of ARVs to an infant. Weight measurements, time, and notes on spillage were taken at each observation period. Successful usage was quantitatively assessed through the calculation of dosing accuracy based on the volume of liquid medication emptied from the pouch. Additionally, mothers were surveyed after a month of using the device at home to assess their perception of the accuracy, acceptability, and ease of use of the pouch. Used pouches were collected for physical analysis of tearing.Observed users delivered accurate doses (M = 101.1%, standard deviation = 8.2%) in an average time of 2.6 minutes. A total of 2869 used pouches were recovered. No seal failures or failed attempts at opening/delivering the pouches were observed or detected. Forty-three mothers were surveyed. All mothers (100%) reported that they were able to follow their physician's treatment plan, all pouches were received in good condition and the pictorial sheets provided clear instructions.We conclude that the Pratt pouch is a highly accurate and easy-to-use device for delivering liquid oral ARVs to infants and is appropriate for prepackaging ARVs for home use. PMID- 26107674 TI - A Case Report of Male Occult Breast Cancer First Manifesting as Axillary Lymph Node Metastasis With Part of Metastatic Mucinous Carcinoma. AB - Occult breast cancer (OBC) is a type of breast cancer without any symptoms in the breast (no primary cancer lesion is found in either breast on a physical examination or imaging examination such as ultrasound and mammography). The incidence of OBC is rare in females, whereas in males, there are few cases of breast cancer, and the rate of OBC is very low. This is the first time report a case of male OBC first manifested as axillary metastasis, of which the pathological results showed moderately differentiated adenocarcinoma with part of metastatic mucinous carcinoma.A 40-year-old male patient presenting palpable masses in his left axillary on physical and imaging examination revealed unremarkable despite of multiple swollen lymph nodes in the left axillary, and the resected sample showed metastatic adenocarcinoma with part of metastatic mucinous carcinoma. Based on immunohistochemical analysis, positive of estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (Her 2), it was identified as an OBC.This is the fourth case report of male OBC in the literature; 1 case was reported in China in 2008, and it was metastatic infiltrating ductal carcinoma, and 2 cases were reported in Korea in 2012, one of which was reported as metastatic carcinoma and the other was metastatic adenocarcinoma; however, our case was a moderately differentiated adenocarcinoma with part of mucinous carcinoma. Our case of male OBC could metastasize to supraclavicular region and lung in addition to axillary lymph nodes, and the prognosis was relatively poor compared to the 3 cases reported before.The aim of this case report is to introduce the imaging, pathological features, and management of a rare male OBC. PMID- 26107675 TI - A Cohort Study of Decompressive Craniectomy for Malignant Middle Cerebral Artery Infarction: A Real-World Experience in Clinical Practice. AB - Decompressive hemicraniectomy with malignant middle cerebral artery (MCA) infarction is effective but remains underutilized. The aim of this study was to observe the utilization of this intervention in mainland China.We included patients with malignant MCA infarction who admitted in West China Hospital between December 2007 to March 2011. The outcomes were death and favorable outcome (mRS < 4) at 1 month and 1 year. The multivariate logistic regression model was used to identify the independent predictors for outcomes.Ten percent (219/2174) of patients with acute ischemic stroke had malignant MCA infarction and 31.1% (68/219) patients meet the criteria that <=60 years of age and the timing to hospital <48 hours after stroke onset. Of them, 18 patients (26.5%) underwent to decompressive hemicraniectomy. In total, 31 patients (14.2%) underwent the decompressive surgery. The average age was 53 +/- 12 years; median NIHSS score was 21. The case fatality rate of patients in surgery group was significantly lower than those of in nonsurgery group at 1 month and 1 year follow-ups (32.3% and 38.7% vs. 51.1% and 61.2%, respectively, P < 0.05). Patients in surgery group had a higher proportion of good outcome at 1 year follow-up (32.2% vs. 13.3%, P = 0.006). After adjusting for confounders including age, sex, NIHSS score, and GCS score on admission, decompressive hemicraniectomy was an independent predictor of good outcome for 1 year (OR = 3.44, 95% CI, 1.27 9.31).This study shows better outcomes in the surgical group, which are consistent with findings in previous prospective randomized trials. However, this beneficial intervention remains underutilized in clinical settings. PMID- 26107676 TI - The Pivotal Role of a Novel Biomarker of Reactive Oxygen Species in Chronic Kidney Disease. AB - Risk stratification of chronic kidney disease (CKD) is clinically important because such patients are at high risk of cardiovascular events. Although reactive oxygen species (ROS) are reported to be closely associated with the pathophysiology of CKD, there are few useful ROS biomarkers known for CKD patients. Hence, our objectives in this study were to investigate whether serum derivatives of reactive oxygen metabolites (DROM), a novel biomarker of ROS, is involved in the pathophysiology of CKD (case-control study), and is a significant predictor of future cardiovascular events in CKD patients (follow-up study).Patients with suspected coronary artery disease (CAD) were enrolled and underwent coronary angiography. Patients with CKD (estimated glomerular filtration ratio <60 mL/min/1.73 m(2) and/or proteinuria, n = 324) were compared with those without CKD (non-CKD). Serum DROM was measured at stable conditions. A case-control study of the 324 CKD patients and 263 non-CKD patients was conducted after matching risk factors, and a follow-up study of the 324 CKD patients was performed. CKD patients were divided into low- and high-DROM groups using their median value (348 unit; called the Carratelli unit [U.CARR]), and followed until the occurrence of cardiovascular events.DROM levels were significantly higher in risk factors-matched CKD patients than in risk factors matched non-CKD patients (347.0 [301.8-391.8] U.CARR vs. 338.5 [299.8-384.3] U.CARR, P = 0.03). During mean 23 +/- 14 months follow-up of 324 CKD patients, 83 cardiovascular events were recorded. Kaplan-Meier analysis demonstrated a higher probability of cardiovascular events in CKD patients with high DROM than in those with low DROM (P < 0.001, log-rank test). Multivariate Cox hazard analysis including significant predictors in simple Cox hazard analysis demonstrated that high DROM was a significant and independent predictor of cardiovascular events in CKD patients (hazard ratio: 1.76, 95% confidence interval: 1.10-2.82, P = 0.02).In conclusion, serum DROM values were significant and independent predictors of cardiovascular events in CKD patients, indicating that the measurements of DROM might provide clinical benefits for risk stratification of CKD patients. PMID- 26107677 TI - A Case Report of Adrenocortical Adenoma Mimicking Congenital Adrenal Hyperplasia in a Young Girl. AB - Adrenal cortical tumors are rare in children. Secondary tumors associated with untreated congenital adrenal hyperplasia (CAH) have also been reported in pediatric population. It is difficult for pediatricians to differentiate these 2 lesions.We described a 4.5-year-old girl who presented with symptoms and signs of virilization. Bone age was 9.5 years. Genetic analysis of CYP21A2 and CYP11B1 revealed a heterozygous mutation of CYP11B1 at c.1157C>T (A386V). No germline p53 gene mutation including R337H was detected.The patient was first misdiagnosed as CAH and treated with hydrocortisone for 3 months. Diagnosis of an adrenal cortical tumor was confirmed by laboratory data and abdominal computed tomography. After resection of the tumor, serum steroids normalized and clinical signs receded. The child received no additional treatment and remains disease free after 12 months of close observation. Histological examination showed neoplasia cells with predominantly eosinophilic cytoplasm and few atypical mitotic figures. The proliferation-associated Ki-67 index was <1% detected by immunohistochemistry.Neoplasm is a rare but significant cause of precocious puberty (PP). The possibility of neoplasms should always be considered early to avoid delayed cancer diagnosis and treatment in cases of PP. PMID- 26107678 TI - Insulinoma Masquerading as Rapid Eye Movement Sleep Behavior Disorder: Case Series and Literature Review. AB - Insulinoma is a rare endocrine tumor that can cause a wide variety of symptoms, including abnormal nocturnal behavior. We report on 3 patients with insulinoma who presented with abnormal nocturnal behavior and injury during sleep, which simulated rapid eye movement (REM) sleep behavior disorder (RBD). In case 1, the fasting glucose level was 15 mg/dL, and insulin levels were elevated (15 MUU/mL). In case 3, when the patient was transferred to the hospital because of a disturbance of consciousness, hypoglycemia (29 mg/dL) was detected. In contrast, in case 2, fasting glucose sampling did not indicate hypoglycemia, but continuous glucose monitoring revealed nocturnal hypoglycemia. The time from initial symptoms to a diagnosis of insulinoma ranged from 7 months to 2 years. All 3 patients had previously received anticonvulsant drugs for suspected epilepsy, but the medications were ineffective. Polysomnography showed no evidence of REM sleep without atonia in any of the 3 patients. No patient remembered any events that occurred during sleep. When a patient manifests abnormal behavior during the night and early morning, glucose monitoring should be performed, especially during the night and early morning. Clinicians should be aware that although insulinomas are rare, they can mimic parasomnias, such as RBD. PMID- 26107679 TI - Unintentional Discontinuation of Chronic Medications for Seniors in Nursing Homes: Evaluation of a National Medication Reconciliation Accreditation Requirement Using a Population-Based Cohort Study. AB - Transitions of care leave patients vulnerable to the unintentional discontinuation of medications with proven efficacy for treating chronic diseases. Older adults residing in nursing homes may be especially susceptible to this preventable adverse event. The effect of large-scale policy changes on improving this practice is unknown.The objective of this study was to analyze the effect of a national medication reconciliation accreditation requirement for nursing homes on rates of unintentional medication discontinuation after hospital discharge.It was a population-based retrospective cohort study that used linked administrative records between 2003 and 2012 of all hospitalizations in Ontario, Canada. We identified nursing home residents aged >=66 years who had continuous use of >=1 of the 3 selected medications for chronic disease: levothyroxine, HMG CoA reductase inhibitors (statins), and proton pump inhibitors (PPIs).In 2008 medication reconciliation became a required practice for accreditation of Canadian nursing homes.The main outcome measures included the proportion of patients who restarted the medication of interest after hospital discharge at 7 days. We also performed a time series analysis to examine the impact of the accreditation requirement on rates of unintentional medication discontinuation.The study included 113,088 adults aged >=66 years who were nursing home residents, had an acute hospitalization, and were discharged alive to the same nursing home. Overall rates of discontinuation at 7-days after hospital discharge were highest in 2003-2004 for all nursing homes: 23.9% for thyroxine, 26.4% for statins, and 23.9% for PPIs. In most of the cases, these overall rates decreased annually and were lowest in 2011-2012: 4.0% for thyroxine, 10.6% for statins, and 8.3% for PPIs. The time series analysis found that nursing home accreditation did not significantly lower medication discontinuation rates for any of the 3 drug groups.From 2003 to 2012, there were marked improvements in rates of unintentional medication discontinuation among hospitalized older adults who were admitted from and discharged to nursing homes. This change was not directly associated with the new medication reconciliation accreditation requirement, but the overall improvements observed may have been reflective of multiple processes and not 1 individual intervention. PMID- 26107680 TI - Prognostic Significance of Statin Use in Colorectal Cancer: A Systematic Review and Meta-Analysis. AB - Statin intake has been reported to reduce the risk of several malignancies beyond its cholesterol-lowering effects. However, little is known regarding the survival benefit of statins for patients with colorectal cancer (CRC).We conducted a systematic literature search of multiple databases for studies published before November 2014, which investigated associations between statin intake and CRC prognosis. Meta-analysis was performed using random-effects model. The primary outcomes of interest were all-cause mortality (ACM) and cancer-specific mortality (CSM).Ten studies involving 76,851 patients were eligible for this meta-analysis, with 7 studies investigating prediagnosis statin use and 5 studies reporting postdiagnosis statin use. Prediagnosis statin use was associated with reduced ACM (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.61-0.88, P = 0.001) and CSM (HR 0.80, 95% CI 0.77-0.84, P < 0.001) for patients with CRC. This effect persisted when stratified by tumor site and in studies adjusted by nonsteroidal anti-inflammatory drug use. In addition, postdiagnosis statin use was associated with decreased CSM (HR 0.70, 95% CI 0.60-0.82, P < 0.001). However, we did not note reduced ACM for postdiagnosis statin use (HR 0.93, 95% CI 0.68-1.27, P = 0.639). There appeared to be an association between postdiagnosis statin use and increased ACM in KRAS-mutated CRC.Our findings provide evidence that prediagnosis statin therapy was associated with reduced ACM and CSM in CRC patients; postdiagnosis statin therapy indicated decreased CSM. However, findings may not apply to patients with postdiagnosis statin therapy for ACM. Further studies are warranted to determine the relation between statin dose and duration on CRC survival. PMID- 26107681 TI - Outcomes of Early Ligation of Patent Ductus Arteriosus in Preterms, Multicenter Experience. AB - Persistent ductal patency may have serious effects in preterm infants. Analysis of the results of different trials were inconclusive in determining whether medical or surgical closure of the ductus is preferable and what is the best timing for surgical intervention.The aim of this study was to evaluate the effect of timing of surgical closure of patent ductus arteriosus (PDA) on ventilatory, hemodynamic, and nutritional status of preterm infants.The authors retrospectively looked at the outcomes of surgical ligation of PDA from January 2010 to June 2014 at 2 Saudi neonatal intensive units at 2 tertiary care centers and the authors compared the results of early ligation (before 3 weeks) to the late ligation (after 3 weeks) regarding different hemodynamic, ventilatory, and nutritional parameters.A total of 120 preemies were included (75 preemies with early ligation and 45 with late ligation of PDA). The early ligation group had shorter duration of assisted ventilation of 10 (8-37) days as compared with 37 (26-90) days in the late ligation group (P < 0.05). The median fraction of inspired oxygen, needed to maintain good oxygen saturation in patients, was higher in the late ligation group [0.29 (0.21-0.70)] than in the early group [0.23 (0.21-0.55)] at 24 hours postoperatively. Full oral feeding was achieved earlier in the early ligation group than in the late group, 29 (15-73) days of life versus 53 (34-118) days of life, respectively (P < 0.05). Body weight at 36 weeks postconceptional age was higher in the early group--2100 (1350-2800) g- than in the late group-1790 (1270-2300) g--(P < 0.05).Our study demonstrated that earlier surgical ligation of the PDA in preterm infants has a more favorable nutritional and ventilatory outcome. PMID- 26107682 TI - Severity of Anemia Predicts Hospital Length of Stay but Not Readmission in Patients with Chronic Kidney Disease: A Retrospective Cohort Study. AB - The aim of this study was to examine the relationship of severe anemia to hospital readmission and length of stay (LOS) in patients with chronic kidney disease (CKD) stage 3-5. Compared with the general population, patients with moderate CKD have a higher hospital readmission rate and LOS. Anemia in patients with moderate CKD is associated with higher morbidity and mortality. The influence of anemia on hospital outcomes in patients with moderate CKD has not been characterized.We conducted a retrospective cohort study at Maine Medical Center, a 606-bed academic tertiary care hospital. Patients with CKD stages 3-5 and not on dialysis admitted during February 2013 to January 2014 were eligible. Patients with end stage renal disease on hemodialysis or peritoneal dialysis, kidney transplant, acute kidney injury, gastrointestinal bleeding, active malignancy, pregnancy, and surgery were excluded. The cohort was split into severe anemia (hemoglobin <=9 g/dL) versus a comparison group (hemoglobin >9 g /dL), and examined for differences in 30-day hospital readmission and LOS.In this study, the data of 1141 patients were included, out of which 156 (13.7%) had severe anemia (mean hemoglobin 8.1 g/dL, SD 0.8). Severe anemia was associated with increased hospital LOS (mean 6.4 (SD 6.0) days vs mean 4.5 (SD 4.0) days, P < 0.001). The difference was 1.7 day longer (95% CI 0.94, 2.45). There was no difference in readmission rate (mean 11.5% vs 10.2%, P = 0.7).Patients with moderate CKD and severe anemia are at risk for increased hospital LOS. Interventions targeting this high-risk population, including outpatient management of anemia, may benefit patient care and save costs through improved hospital outcomes. PMID- 26107683 TI - Prevalence of Common Non-Hodgkin Lymphomas and Subtypes of Hodgkin Lymphoma by Nodal Site of Involvement: A Systematic Retrospective Review of 938 Cases. AB - Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) represent a heterogeneous group of malignant lymphoid tumors, which have distinct histological and/or biological characteristics with preferential nodal involvement. However, none of the previous studies have assessed the prevalence of common NHL and HL subtypes at each nodal site of involvement. The aim of our study was to determine the prevalence of HL and NHL subtypes depending on their nodal sites of involvement.We conducted a single-center retrospective study of 938 lymphoma cases diagnosed in the Pathology Department of Toulouse Purpan Hospital in France between 2001 and 2008, taking into account the site that corresponded to the diagnostic biopsy. The most frequent sites were cervical lymph nodes (36.8% of all cases), inguinal lymph nodes (16.4%), axillary lymph nodes (11.9%), and supraclavicular lymph nodes (11%). We found an unexpected association between intraparotid nodes and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and between inguinal nodes and follicular lymphoma. The risk of having classical Hodgkin lymphoma (CHL) was 15 times greater in patients with mediastinal lymphoma compared to those with other sites of involvement. Regarding HL, nodal and extranodal mediastinal sites and supraclavicular nodes were more likely to be involved by nodular sclerosis Hodgkin lymphoma (NSCHL). In addition, intra abdominal lymph nodes were more frequently involved by lymphocyte depleted Hodgkin lymphoma compared to inguinal nodes where NLPHL predominated.Our study shows that some lymph node sites have a disproportionate prevalence of specific subtypes of lymphoma. Identifying these sites may aid to diagnose and better elucidate the pathogenesis of these tumors. PMID- 26107684 TI - The Effect of the Modified Eighth Section of Eight-Section Brocade on Osteoporosis in Postmenopausal Women: A Prospective Randomized Trial. AB - Osteoporosis and related fragility fractures represent a serious and global public health problem. To evaluate whether the modified eighth section of Eight section Brocade (MESE) exercise could improve the symptom and indexes associated with osteoporosis in postmenopausal women. Guangzhou and Liuzhou hospital of traditional Chinese medicine in China. Women (n = 198) aged 50 to 75 years were randomized into Control, Ca, MESE, and MESE + Ca. Subjects in Ca and MESE groups were separately asked to consume thrice daily Calcium Carbonate Chewable D3 tablet and to perform thrice daily MESE exercise by 7 repetitions per time for 12 months. Subjects in MESE + Ca group performed such the combined treatment project for 12 months. Body height and Hospital for Special Surgery (HSS) scores of both knees, chronic back pain visual analogue scale scores (VAS), bone mineral density (BMD) at L2 to L4 and the left femoral neck, 3-feet Up and Go Test (3') and one leg Stance (OLS). In our study, the improvement in chronic back pain of the patients in Ca, MESE, and MESE + Ca group was better than that in control group. There was 1.9% and 1.7%, 2.3%, and 2.1% net profit in left femoral neck and lumbar BMD after the treatment for 12 months in MESE and MESE + Ca groups. For the balance capacity, the subjects in MESE and MESE + Ca groups secured much better performance than those in Ca and control group after the treatment for 12 months (P < 0.001, P < 0.001). The treatment of MESE exercise is the most effective for the improvement of the symptom and indexes in postmenopausal women. Importantly, the low attrition and the high exercise compliance indicate that MESE exercise is safe, feasible, and well tolerated by postmenopausal women. PMID- 26107685 TI - Predictors and Periprocedural Myocardial Injury Rate of Small Side Branches Occlusion in Coronary Bifurcation Intervention. AB - Occlusion of small side branch (SB) may result in significant adverse clinical events. We aim to characterize the predictors of small SB occlusion and incidence of periprocedural myocardial injury (PMI) in coronary bifurcation intervention.Nine hundred twenty-five consecutive patients with 949 bifurcation lesions (SB <= 2.0 mm) treated with percutaneous coronary intervention (PCI) were studied. All clinical characteristics, coronary angiography findings, PCI procedural factors, and quantitative coronary angiographic analysis data were collected. SB occlusion after main vessel (MV) stenting was defined as no blood flow or any thrombolysis in myocardial infarction (TIMI) flow grade decrease in SB after MV stenting. Multivariate logistic regression analysis was performed to identify independent predictors of small SB occlusion. Creatine kinase-myocardial band activity was determined by using an immunoinhibition assay and confirmed by mass spectrometry. Incidence of PMI between no SB occlusion group and SB occlusion group was compared.SB occlusion occurred in 86 (9.1%) of 949 bifurcation lesions. Of SB occlusion, total occlusion occurred in 64 (74.4%) lesions and a decrease in TIMI flow occurred in 22 (25.6%) lesions. True bifurcation lesion, irregular plaque, predilation in SB, preprocedural SB TIMI flow grade, preprocedural diameter stenosis of distal MV, preprocedural diameter stenosis of bifurcation core, bifurcation angle, diameter ratio between MV and SB, diameter stenosis of SB before MV stenting, and MV lesion length were independent risk factors of SB occlusion. We observed a significantly higher incidence of PMI in each cutoff level in patients with SB occlusion compared with those without SB occlusion.True bifurcation lesion, irregular plaque, and 8 other predictors were independent predictors of SB occlusion. Patients with small SB occlusion had significant higher incidence of PMI. PMID- 26107686 TI - GLI1 Transcription Factor Affects Tumor Aggressiveness in Patients With Papillary Thyroid Cancers. AB - A significant proportion of patients with papillary thyroid cancer (PTC) present with extrathyroidal extension (ETE) and lymph node metastasis (LNM). However, the molecular mechanism of tumor invasiveness in PTC remains to be elucidated. The aim of this study is to understand the role of Hedgehog (Hh) signaling in tumor aggressiveness in patients with PTC. Subjects were patients who underwent thyroidectomy from 2012 to 2013 in a single institution. Frozen or paraffin embedded tumor tissues with contralateral-matched normal thyroid tissues were collected. Hh signaling activity was analyzed by quantitative RT-PCR (qRT-PCR) and immunohistochemical (IHC) staining. Datasets from Gene Expression Omnibus (GEO) (National Center for Biotechnology Information) were subjected to Gene Set Enrichment Analysis (GSEA). BRAFT1799A and telomerase reverse transcriptase promoter mutation C228T were analyzed by direct sequencing. Among 137 patients with PTC, glioma-associated oncogene homolog 1 (GLI1) group III (patients in whom the ratio of GLI1 messenger ribonucleic acid (mRNA) level in tumor tissue to GLI1 mRNA level in matched normal tissue was in the upper third of the subject population) had elevated risk for ETE (odds ratio [OR] 4.381, 95% confidence interval [CI] 1.414-13.569, P = 0.01) and LNM (OR 5.627, 95% CI 1.674-18.913, P = 0.005). Glioma-associated oncogene homolog 2 (GLI2) group III also had elevated risk for ETE (OR 4.152, 95% CI 1.292-13.342, P = 0.017) and LNM (OR 3.924, 95% CI 1.097-14.042, P = 0.036). GSEA suggested that higher GLI1 expression is associated with expression of the KEGG gene set related to axon guidance (P = 0.031, false discovery rate < 0.05), as verified by qRT-PCR and IHC staining in our subjects.GLI1 and GLI2 expressions were clearly related to aggressive clinicopathological features and aberrant activation of GLI1 involved in the axon guidance pathway. These results may contribute to development of new prognostic markers, as well as novel therapeutic targets. PMID- 26107688 TI - A minimal description of morphological hierarchy in two-dimensional aggregates. AB - A dimensionless parameter Lambda is proposed to describe a hierarchy of morphologies in two-dimensional (2D) aggregates formed due to varying competition between short-range attraction and long-range repulsion. Structural transitions from finite non-compact to compact to percolated structures are observed in the configurations simulated by molecular dynamics at a constant temperature and density. Configurational randomness across the transition, measured by the two body excess entropy S2, exhibits data collapse with the average potential energy [small epsilon, Greek, macron] of the systems. Independent master curves are presented among S2, the reduced second virial coefficient B2* and Lambda, justifying this minimal description. This work lays out a coherent basis for the study of 2D aggregate morphologies relevant to diverse nano- and bio-processes. PMID- 26107687 TI - Hope and Hopelessness: The Role of Hope in Buffering the Impact of Hopelessness on Suicidal Ideation. AB - OBJECTIVES: The present study investigated whether hope and hopelessness are better conceptualized as a single construct of bipolar spectrum or two distinct constructs and whether hope can moderate the relationship between hopelessness and suicidal ideation. METHODS: Hope, hopelessness, and suicidal ideation were measured in a community sample of 2106 participants through a population-based household survey. RESULTS: Confirmatory factor analyses showed that a measurement model with separate, correlated second-order factors of hope and hopelessness provided a good fit to the data and was significantly better than that of the model collapsing hope and hopelessness into a single second-order factor. Negative binomial regression showed that hope and hopelessness interacted such that the effect of hopelessness on suicidal ideation was lower in individuals with higher hope than individuals with lower hope. CONCLUSIONS: Hope and hopelessness are two distinct but correlated constructs. Hope can act as a resilience factor that buffers the impact of hopelessness on suicidal ideation. Inducing hope in people may be a promising avenue for suicide prevention. PMID- 26107689 TI - Molybdenum complexes derived from the oxydianiline [(2-NH2C6H4)2O]: synthesis, characterization and epsilon-caprolactone ROP capability. AB - The reaction of Na2MoO4 with 2,2'-oxydianiline (2-aminophenylether), (2 NH2C6H4)2O, LH4, in DME (DME = 1,2-dimethoxyethane) in the presence of Et3N and Me3SiCl afforded either the bis(imido) molybdenum(vi) complex {Mo(L)Cl2(DME)} (), where L = (2-NC6H4)2O, or the molybdenum(v) salt [Mo(L')Cl4][Et3NH] (), where L' = [(2-NH2C6H4)(2-NC6H4)O], depending on the work-up method employed. The same diamine reacted with in situ [Mo(NtBu)2Cl2(DME)] afforded a tetra-nuclear complex [Mo4Cl3(NtBu)3(OSiMe3)(MU4-O)(L)2(L')2].2MeCN (.2MeCN). The crystal structures of , and .2MeCN have been determined. The structure of the bis(imido) complex contains two unique molecules paired up via weak pi-stacking, whereas the structure of contains a chelating amine/imido ligand, and is made up of discrete units of two cations and two anions which are interacting via H-bonding. The tetra-nuclear structure contains four different types of distorted octahedral molybdenum centre, and a bent Me3SiO group thought to originate from the precursor synthesis. Complexes have been screened for their ability to ring open polymerize (ROP) epsilon-caprolactone. For and (not ), conversion rates were good (>90%) at high temperatures (100 degrees C) over 6-24 h, and the polymerization proceeded in a living manner. PMID- 26107690 TI - Finding needles in haystacks: scanning tunneling microscopy reveals the complex reactivity of Si(100) surfaces. AB - Many chemical reactions-etching, growth, and catalytic-produce highly faceted surfaces. Examples range from the atomically flat silicon surfaces produced by anisotropic etchants to the wide variety of faceted nanoparticles, including cubes, wires, plates, tetrapods, and more. This faceting is a macroscopic manifestation of highly site-specific surface reactions. In this Account, we show that these site-specific reactions literally write a record of their chemical reactivity in the morphology of the surface-a record that can be quantified with scanning tunneling microscopy. Paradoxically, the sites targeted by these highly site-specific reactions are extremely rare. This paradox can be understood from a simple kinetic argument. An etchant that produces atomically flat surfaces must rapidly etch every surface site except the terrace atoms on the perfectly flat surface. As a result, the etch morphology is dominated by the least reactive species (here, the terrace sites), not the most reactive species. In contrast, the most interesting chemical species-the site where the reaction occurs most rapidly and most selectively-is the hardest one to find. This highly reactive site, the key to the reaction, is the needle in the haystack, often occurring in densities far below 1% of a monolayer and thus invisible to surface spectroscopies. This kinetic argument is quite general and applies to a wide variety of reactions, not just etching reactions. Understanding these highly site specific reactions requires a combination of experimental and computational techniques with both exquisite defect sensitivity and high chemical sensitivity. In this Account, we present examples of highly site-specific chemistry on the technologically important face of silicon, Si(100). In one example, we show that the high reactivity of one particular surface site, a silicon dihydride bound to a silicon monohydride, or an "alpha-dihydride", provides a fundamental explanation for anisotropic silicon etching, a technology widely used in micromachining to selectively produce flat Si{111} surfaces. Fast-etching surfaces, such as Si(100) and Si(110), have geometries that support autocatalytic etching of alpha-dihydrides. In contrast, alpha-dihydrides exist only at kink sites on Si(111) surfaces. As a result, the etch rate of surfaces vicinal to Si(111) scales with the step density, approaching zero on the atomically flat surface. In a second example, we explain the chemistry that underlies pyramidal texturing of silicon wafers, a technique that is sometimes used to decrease the reflectivity of silicon solar cells. We show that a subtle change in chemical reactivity transforms a near-perfect Si(100) etchant into one that spontaneously produces nanoscale pyramids. The pyramids are not static features; they are self propagating structures that evolve in size and location as the etching proceeds. The key to this texturing is the production of a very rare defect at the apex of each pyramid, a site that also etches autocatalytically. These experiments show that simple chemical reactions can enable an exquisite degree of atomic-scale control if only we can learn to harness them. PMID- 26107691 TI - Cerebellar Liponeurocytoma, an Unusual Tumor of the Central Nervous System- Ultrastructural Examination. AB - Cerebellar liponeurocytoma is a rare tumor of the central nervous system which shows neuronal and variable astrocytic differentiation, along with foci of lipomatous differentiation. It is usually located in the cerebellum, and may be mistaken for medulloblastoma with lipidized cells or lipomatous ependymoma. Histopathological examination, supplemented by immunohistochemistry and electron microscopy, is required to distinguish between these entities. This 35-year-old male presented with vomiting and headache for three months, followed by gait imbalance. Neurological examination showed positive cerebellar signs with ataxic gait. Magnetic resonance imaging showed a lesion measuring 4.4 cm* 4.3 cm* 3.9 cm involving the cerebellum. The patient underwent midline suboccipital craniotomy to excise the tumor. Histopathological examination showed a circumscribed, cellular tumor composed of round to polygonal cells with moderate cytoplasm and minimal pleomorphism. Clear intracytoplasmic vacuoles were seen within the tumor cells. These tumor cells were immunopositive for synaptophysin, NSE, and MAP-2, confirming their neurocytic origin. On ultrastructural examination, lipid vacuoles as well as dense-core neurosecretory granules were identified within these neurocytic cells, confirming the diagnosis of liponeurocytoma. No cilia, microvilli, or gap junctions were identified in the tumor cells, ruling out the possibility of lipomatous ependymoma. The differentiation of liponeurocytoma from its morphological mimics is imperative, as their treatment differs drastically. The role of electron microscopy is extremely important in this differential diagnosis. PMID- 26107692 TI - Analysis of Interlimb Asymmetry in Patients Undergoing Simultaneous Bilateral Total Knee Arthroplasty. AB - Simultaneous bilateral TKA (SBTKA) has been a favored surgical solution due to reduced costs and patient suffering. The purpose of the present study was to investigate the risk factors of asymmetric recovery in patients who underwent SBTKA and whether that affected quality of life. A total of 187 patients undergoing SBTKA were included. During this study, patients underwent physical examination (knee swelling, active range of motion (ROM) of knee and quadriceps strength) and completed three surveys (VAS pain rating, Short Form-36 and requisite information lists in this study). Our results reveal interlimb asymmetries existed at least two years postoperatively. Between-limb differences in active ROM, quadriceps strength, and VAS pain scores were significantly detected in our study. Risk factors included being female, being older, and having high BMI and high levels of anxiety and depression; different diagnosis and different component size could be risk factors. Finally, interlimb differences in VAS pain scores and active ROM were negatively associated with SF 36 scores. However, interlimb differences in swelling and quadriceps strength were unrelated to SF-36 scores. Risk factors of asymmetric recovery should be evaluated and appreciated due to their significant impact on patients' quality of life. Before performing SBTKA, clinicians should consider possible risk factors and inform patients of asymmetric recovery between limbs, which could help decrease the unnecessary consultations and postoperative patient dissatisfaction. PMID- 26107693 TI - Cerebral Lipiodol Embolism in Hepatocellular Carcinoma Patients Treated with Transarterial Embolization/Chemoembolization. AB - BACKGROUND AND PURPOSE: Liver cancer is the third leading cause of cancer mortality worldwide. The aim of this study was to investigate the frequency and characteristics of cerebral lipiodol embolism (CLE) in patients with hepatocellular carcinoma (HCC) receiving transarterial embolization/chemoembolization (TAE/TACE). METHODS: We reviewed all HCC patients who received TAE/TACE during the period of 2007 and 2013 at a university medical center. The frequency of CLE per procedure and the clinical manifestations of CLE, including the review of previous reported cases (n = 24), were analyzed. RESULTS: During the study period, a total of 7855 TAE/TACE procedures were conducted on 3277 patients. There were 8 patients (mean age 59+/-11 years; 5 males and 3 females) who developed CLE. The frequency of TAE/TACE-related CLE was 1.02 (95% CI, 0.44-2.01) per 1000 procedures. Acute disturbance of consciousness and respiratory distress after TAE/TACE were the most common presentations of CLE. All patients had disseminated infarcts involving both the anterior and posterior cerebral circulations. For 3 patients with shunting between the tumor feeding artery and the pulmonary vein, a specific imaging pattern of coexisting scattered hyperdense spots was found. Furthermore, combined with our 8 cases, the total of 32 cases indicated that old age and female sex were the two risk factors for poor outcome after CLE. CONCLUSIONS: CLE is a rare but potentially serious complication in HCC patients receiving TAE/TACE. The clinical characteristics of CLE summarized in our study would help facilitate the ability of clinicians to provide timely diagnosis and management. PMID- 26107694 TI - Professor Giovanni Berlinguer: healthcare, nursing and ethics will all miss you! PMID- 26107695 TI - [Knowledge, attitude and practice of condom use by women of an impoverished urban area]. AB - OBJECTIVE: Assessing the adequacy of knowledge, attitude and practice of women regarding male and female condoms as STI/HIV preventive measures. METHOD: An evaluative Knowledge, Attitude and Practice (KAP) household survey with a quantitative approach, involving 300 women. Data collection took place between June and August 2013, in an informal urban settlement within the municipality of Joao Pessoa, Paraiba, Northeast Brazil. RESULTS: Regarding the male condom, most women showed inadequate knowledge and practice, and an adequate attitude. Regarding the female condom, knowledge, attitude and practice variables were unsatisfactory. Significant associations between knowledge/religious orientation and attitude/education regarding the male condom were observed. CONCLUSION: A multidisciplinary team should be committed to the development of educational practices as care promotion tools in order to improve adherence of condom use. PMID- 26107696 TI - [Accidental intoxication of the infant-juvenile population in households: profiles of emergency care]. AB - OBJECTIVE: Analyzing profiles of intoxication and accidental poisoning of infant juvenile population (0-24 years) in the household, treated at a reference facility for Emergency and Primary Care, during the year 2013. METHOD: A descriptive, cross-sectional study. Data were analyzed using Epi-Info, by way of simple and bivariate analyzes. The project was approved by the Research Ethics Committee (protocol 405.578). RESULTS: There were 45 intoxications, with a prevalence of males (60.0%), aged 1-4 years (71.1%). Among children under one, there was a higher frequency of pesticide poisoning (66.6%), between the ages of 1-4 by cleaning products (34.4%), and between 5-9 years of age by pharmacological substances (66.6%). The primary assistance was provided only at health institutions, with hospital admissions in 24.4% of the cases. CONCLUSION: The importance of prevention through legislation is evident, in order to ensure greater safety in packaging of various products, and community awareness to eliminate risks in the household environment. PMID- 26107697 TI - [Instrument for assessing the quality of mobile emergency pre-hospital care: content validation]. AB - OBJECTIVES: To validate an instrument to assess quality of mobile emergency pre hospital care. METHOD: A methodological study where 20 professionals gave their opinions on the items of the proposed instrument. The analysis was performed using Kappa test (K) and Content Validity Index (CVI), considering K> 0.80 and CVI >= 0.80. RESULTS: Three items were excluded from the instrument: Professional Compensation; Job Satisfaction and Services Performed. Items that obtained adequate K and CVI indexes and remained in the instrument were: ambulance conservation status; physical structure; comfort in the ambulance; availability of material resources; user/staff safety; continuous learning; safety demonstrated by the team; access; welcoming; humanization; response time; costumer privacy; guidelines on care; relationship between professionals and costumers; opportunity for costumers to make complaints and multiprofessional conjunction/actuation. CONCLUSION: The instrument to assess quality of care has been validated and may contribute to the evaluation of pre-hospital care in mobile emergency services. PMID- 26107698 TI - [Self-Care, Sense Of Coherence And Depression In Patients Hospitalized For Decompensated Heart Failure]. AB - OBJECTIVE: To analyze the self-care behaviors according to gender, the symptoms of depression and sense of coherence and compare the measurements of depression and sense of coherence according to gender. METHOD: A correlational, cross sectional study that investigated 132 patients with decompensated heart failure (HF). Data were collected through interviews and consultation to medical records, and analyzed using the chi-square and the Student's t tests with significance level of 0.05. Participants were 75 men and 57 women, aged 63.2 years on average (SD = 13.8). RESULTS: No differences in self-care behavior by gender were found, except for rest after physical activity (p = 0.017). Patients who practiced physical activity showed fewer symptoms of depression (p<0.001). There were no differences in sense of coherence according to self-care behavior and gender. Women had more symptoms of depression than men (p = 0.002). CONCLUSION: Special attention should be given to women with HF considering self-care and depressive symptoms. PMID- 26107699 TI - [Effectiveness Of 2% And 4% Papain Gels In The Healing Of Venous Ulcers]. AB - OBJECTIVE: To analyze the effectiveness of 2% and 4% papain gels in tissue repair of venous ulcers. METHOD: Quasi-experimental study with consecutive sample of 16 patients with 30 venous ulcers treated at the outpatient clinic of a teaching hospital, from April to November in 2011, using a form for clinical assessment of the patient and its lesion. Variables were analyzed by Wilcoxon and McNemar test (p < 0.05). RESULTS: Most participants were female; aged between 51 and 59 years; obese; with hypertension. Regarding ulcers, there was an average decrease of 7.9 cm2 (50% of its original size) in 90 days; 20% of the ulcers completely healed within 56.67 days. There was an increase in epithelialization, significant reduction in the slough and edema, improved depth, in the type and amount of exudate (p < 0.0001). CONCLUSION: 2% and 4% papain gels were effective in healing venous ulcers. PMID- 26107700 TI - [Cross-cultural adaptation of the Quality of Life Index Spinal Cord Injury - Version III]. AB - OBJECTIVE: To translate and culturally adapt to Portuguese the Ferrans and Powers Quality of Life Index Spinal Cord Injury - Version III and characterize the sample in relation to sociodemographic and clinical aspects. METHOD: A methodological study with view to cross-cultural adaptation, following the particular steps of this method: initial translation, translation synthesis, back translation (translation back to the original language), review by a committee of judges and pretest of the final version. The pretest was carried out with 30 patients with spinal cord injury. RESULTS: An index of 74 items divided into two parts (satisfaction/importance) was obtained. The criteria of semantic equivalence were evaluated as very adequate translation, higher than 87%, and vocabulary and were grammar higher than 86%. Idiomatic equivalence was higher than 74%, experimental greater than 78% and conceptual was greater than 70%. CONCLUSION: After cross-cultural adaptation, the instrument proved semantic, idiomatic, experimental and conceptual adequacy, in addition to helping the evaluation of the quality of life of people with spinal cord injury. PMID- 26107701 TI - [Mapping Nursing language terms of Parkinson's disease]. AB - OBJECTIVE: Implementing cross-mapping of Nursing language terms with the terminology of NANDA International, contained in records of patients with Parkinson's disease in rehabilitation. METHOD: Descriptive study of cross mapping, carried out in three steps. A simple random sample of 67 files of patients who participated in the rehabilitation in the period between March 2009 and April 2013. RESULTS: We identified 454 terms of Nursing language that resulted in 54 diagnoses after cross-mapping, present in 11 of the 13 taxonomy domains. The most mapped diagnosis was "Impaired urinary elimination" (59.7%), followed by "Urgent urinary incontinence" (55.2%), "Willingness to self-control improved health" (50.7%), "Constipation" (47.8%) and "Compromised physical mobility" (29.9%). Seven described terms were not mapped due to a corresponding defining characteristic being absent. CONCLUSION: It was possible to determine the profile of patients, as well as the complexity of nursing care in the rehabilitation of patients with Parkinson's disease. PMID- 26107702 TI - [Life experiences of elderly with cancer pain: the existential comprehensive approach]. AB - OBJECTIVE: Understanding the experiences of elderly with cancer pain. METHOD: Qualitative research based on Heidegger's phenomenology. 12 elderly cancer patients from a city in northwest Parana were interviewed from November 2013 to February 2014. RESULTS: Analysis performed by vague, median and interpretive understanding which resulted in two ontological themes: Cancer pain: unveiling the imprisonment and impositions experienced by the elderly, and Unveiling the anguish of living with cancer pain; it revealed not only how the elderly experience pain in their daily lives, but also how hard it is to live with its particularities. CONCLUSION: Cancer pain has biopsychosocial repercussions for the elderly, generating changes in their existence in the world, requiring holistic and authentic care. PMID- 26107703 TI - [Cross-cultural adaptation of the Caregiver Reaction Assessment for use in Brazil with informal caregivers of the elderly]. AB - This study aimed to carry out the cross-cultural adaptation of the Caregiver Reaction Assessment CRA for use in Brazil with informal caregivers of dependent elderly METHOD: A methodological study, of five steps: initial translation, synthesis of translations, retro-translation, evaluation by a judge committee and a pre-test, with 30 informal caregivers of older persons in Fortaleza, Brazil. Content validity was assessed by five experts in gerontology and geriatrics. The cross-cultural adaptation was rigorously conducted, allowing for inferring credibility. RESULTS: The Brazilian version of the CRA had a simple and fast application (ten minutes), easily understood by the target audience. It is semantically, idiomatically, experimentally and conceptually equivalent to the original version, with valid content to assess the burden of informal caregivers for the elderly (Content Validity Index = 0.883). CONCLUSION: It is necessary that other psychometric properties of validity and reliability are tested before using in care practice and research. PMID- 26107704 TI - [Educational pamphlets on health: a reception study]. AB - OBJECTIVES: Identifying the socioeconomic and cultural profile of users/readers of educational pamphlets, characterizing the context of the reading material and people involved; describing the user/reader evaluation on language and style used, as well as content range or limitations, and its characterization as an educational material in assisting users for meeting homecare demands. METHOD: A reception, cross-sectional, qualitative study. 27 respondents who had received five educational pamphlets were interviewed on Oncology signs and symptoms during primary care consultations. RESULTS: Study participants were adults, with average schooling of more than 10 years and low income. Pamphlets were assessed as appropriate for consistent language, quantity and quality of content, and especially in relation to the capacity of helping in the homecare decision making process. The importance of receiving pamphlets at the initial stage of the disease was verified. CONCLUSION: Users acceptance was positive and the study revealed aspects that should be reinforced in the creation of educational pamphlets. PMID- 26107705 TI - [Prevalence of self-reported constipation in adults from the general population]. AB - OBJECTIVE: To estimate the prevalence of self-reported constipation and associated factors in the general population of a Brazilian city. METHOD: Secondary analysis of an epidemiological study, population-based, cross-sectional study, about bowel habits of Brazilian population. A total of 2,162 individuals were interviewed using two instruments: sociodemographic data and the adapted and validated Brazilian version of the "Bowel Function in the Community" tool. RESULTS: There was a prevalence of 25.2% for the self-reported constipation, 37.2% among women and 10.2% among men. Stroke and old age were associated with constipation in the three statistical models used. CONCLUSION: The prevalence found showed to be similar to the findings in the literature, although some associated factors obtained here have never been investigated. PMID- 26107706 TI - [Massage with aromatherapy: effectiveness on anxiety of users with personality disorders in psychiatric hospitalization]. AB - OBJECTIVE: To investigate the effectiveness of aromatherapy massage using the essential oils (0.5%) of Lavandula angustifolia and Pelargonium graveolens for anxiety reduction in patients with personality disorders during psychiatric hospitalization. METHOD: Uncontrolled clinical trial with 50 subjects submitted to six massages with aromatherapy, performed on alternate days, on the cervical and the posterior thoracic regions. Vital data (heart and respiratory rate) were collected before and after each session and an anxiety scale (Trait Anxiety Inventory-State) was applied at the beginning and end of the intervention. The results were statistically analyzed with the chi square test and paired t test. RESULTS: There was a statistically significant decrease (p < 0.001) of the heart and respiratory mean rates after each intervention session, as well as in the inventory score. CONCLUSION: Aromatherapy has demonstrated effectiveness in anxiety relief, considering the decrease of heart and respiratory rates in patients diagnosed with personality disorders during psychiatric hospitalization. PMID- 26107707 TI - [Violence, Burnout and Minor Psychiatric Disorders in Hospital Work]. AB - OBJECTIVE: Identifying the violence suffered by the health team workers and their association with Burnout and minor psychiatric disorders. METHODS: Cross sectional study with 269 health team professionals of a public hospital in southern Brazil. Data were collected through the use of the Survey Questionnaire: Workplace Violence in the Health Sector, Maslach Inventory Burnout and Self Report Questionnaire. RESULTS: Workplace violence struck 63.2% of workers, prevailing mostly in women (p = 0.001), among nursing auxiliaries/technicians (p=0.014) and was associated with minor psychiatric disorders (p<0.05), as exposure to different forms of violence increased the chances of these disorders by 60% (CI 95%: 1.2-2.1). The three Burnout dimensions were also associated to violence at work (p<0.05). CONCLUSION: Health workers experience violence in the workplace and this exposure is associated with Burnout symptoms and minor psychiatric disorders. PMID- 26107708 TI - [Pleasure-suffering indicators of nursing work in a hemodialysis nursing service]. AB - OBJECTIVE: To measure the pleasure and suffering indicators at work and relate them to the socio-demographic and employment characteristics of the nursing staff in a hemodialysis center in southern Brazil. METHOD: Quantitative research, with 46 workers. We used a self-completed form with demographic and labor data and the Pleasure and Suffering Indicators at Work Scale (PSIWS). We conducted a bivariate and correlation descriptive analysis with significance levels of 5% using the Epi Info(r) and PredictiveAnalytics Software programs. RESULTS: Freedom of Speech was considered critical; other factors were evaluated as satisfactory. The results revealed a possible association between sociodemographic characteristics and work, and pleasure and suffering indicators. There was a correlation between the factors evaluated. CONCLUSION: Despite the satisfactory evaluation, suffering is present in the studied context, expressed mainly by a lack of Freedom of Speech, with the need for interventions to prevent injury to the health of workers. PMID- 26107709 TI - [Factors influencing adherence to standard precautions among nursing professionals in psychiatric hospitals]. AB - OBJECTIVE: Evaluate and correlate individual, work-related and organizational factors that influence adherence to standard precautions among nursing professionals of psychiatric hospitals in Sao Paulo. METHOD: An exploratory cross sectional study conducted with 35 nursing professionals, using the assessment tool for adherence to standard precautions through the Likert scale, ranging from 1 to 5. RESULTS: Knowledge of the precautions received a high score (4.69); adherence received (3.86) and obstacles (3.78), while intermediaries and the scales of organizational factors received low scores (2.61). There was a strong correlation between the magnitude adherence scale and the personal protective equipment availability (r = 0.643; p = 0.000). The training scale for prevention of HIV exposure (p = 0.007) was statistically different between the nurses and nursing assistants. CONCLUSION: The organizational factors negatively contributed to adherence to standard precautions, indicating that psychiatric institutions lack safe working conditions, ongoing training and management actions to control infections. PMID- 26107710 TI - [Nursing staff sizing in the emergency room of a university hospital]. AB - OBJECTIVE: To verify the adequacy of the professional nursing staff in the emergency room of a university hospital and to evaluate the association between categories of risk classification triage with the Fugulin Patient Classification System. METHOD: The classification of patients admitted into the emergency room was performed for 30 consecutive days through the methodology proposed by Gaidzinski for calculating nursing requirements. RESULTS: The calculation determines the need for three registered nurses and four non-registered nursing for each six hour shift. However, only one registered nurse and four non registered nurse were available per shift. There was no correlation between triage risk classification and classification of care by the Fugulin Patient Classification System. CONCLUSION: A deficit in professional staff was identified in the emergency room. The specificity of this unit made it difficult to measure. To find the best strategy to do so, further studies should be performed. PMID- 26107711 TI - [Direct Cost of Reprocessing Cotton-woven Surgical Drapes: a Case Study]. AB - OBJECTIVE: Identify the direct cost of reprocessing double and single cotton woven drapes of the surgical LAP package. METHOD: A quantitative, exploratory and descriptive case study, performed at a teaching hospital. The direct cost of reprocessing cotton-woven surgical drapes was calculated by multiplying the time spent by professionals involved in reprocessing the unit with the direct cost of labor, adding to the cost of materials. The Brazilian currency (R$) originally used for the calculations was converted to US currency at the rate of US$0.42/R$. RESULTS: The average total cost for surgical LAP package was US$9.72, with the predominance being in the cost of materials (US$8.70 or 89.65%). It is noteworthy that the average total cost of materials was mostly impacted by the cost of the cotton-woven drapes (US$7.99 or 91.90%). CONCLUSION: The knowledge gained will subsidize discussions about replacing reusable cotton-woven surgical drapes for disposable ones, favoring arguments regarding the advantages and disadvantages of this possibility considering human resources, materials, as well as structural, environmental and financial resources. PMID- 26107712 TI - [Reasons and meanings attributed by women who experienced induced abortion: an integrative review]. AB - OBJECTIVE: Identifying the contribution of developed research on what motivates women to induce an abortion and the meaning attributed to these experiences in their lives. METHOD: An integrative review conducted in MEDLINE/PubMed, LILACS, BDENF, CINAHL and SciELO databases, covering the periods from 2001 to 2011. RESULTS: We selected and analyzed 11 studies with selection criteria being reasons given by women for inducing abortion and/or the meaning attributed to this experience in their lives, including social, religious, ethical and moral aspects related to this practice, as well as the suffering experienced from the experience. The illegality of abortion is identified as a risk factor for unsafe abortions, reaffirming this issue as a public health and social justice problem. CONCLUSION: Results evidence aspects that can contribute to improving health quality and ratify the importance of research to support nursing practices. PMID- 26107713 TI - [Prevalence of infection in kidney transplantation from living versus deceased donor: systematic review and meta-analysis]. AB - OBJECTIVE: To verify if the type of donor is a risk factor for infection in kidney transplant recipients. METHODS: Systematic Review of Literature with Meta analysis with searches conducted in the databases MEDLINE, LILACS, Embase, Cochrane, Web of Science, SciELO and CINAHL. RESULTS: We selected 198 studies and included four observational studies describing infections among patients distinguishing the type of donor. Through meta-analysis, it was shown that in patients undergoing deceased donor transplant, the outcome infection was 2.65 higher, than those who received an organ from a living donor. CONCLUSION: The study showed that deceased kidney donor recipients are at an increased risk for developing infections and so the need for establishing and enforcing protocols from proper management of ischemic time to the prevention and control of infection in this population emerges. PMID- 26107714 TI - [Distance education in neonatal nursing scenarios: a systematic review]. AB - OBJECTIVE: Identify resources that support learning mediated by technology in the field of neonatal nursing. METHOD: Systematic review with searches conducted in MEDLINE, LILACS and SciELO. Titles and abstracts were independently evaluated by two experts. RESULTS: Of the 2,051 references, 203 full-text articles were analyzed, resulting in the inclusion of nine studies on semiotics and semiology, cardiopulmonary resuscitation, general aspects of neonatal care, diagnostic reasoning and assessment of pain. Only two articles addressed the development of educational strategies and seven papers described the assessment of these strategies by experts and/or users. CONCLUSION: Distance education is an important resource for education, and its improvement and updating, and it particularly adds advantages for neonatal nursing by approximating teaching and real-life situations and by minimizing the exposure of newborns for teaching purposes. The lack of educational initiatives mediated by technology suggests the need for the development, evaluation and dissemination of educational resources focused on nursing care of newborns and their families. PMID- 26107715 TI - The Impact of Selection with Diflubenzuron, a Chitin Synthesis Inhibitor, on the Fitness of Two Brazilian Aedes aegypti Field Populations. AB - Several Aedes aegypti field populations are resistant to neurotoxic insecticides, mainly organophoshates and pyrethroids, which are extensively used as larvicides and adulticides, respectively. Diflubenzuron (DFB), a chitin synthesis inhibitor (CSI), was recently approved for use in drinking water, and is presently employed in Brazil for Ae. aegypti control, against populations resistant to the organophosphate temephos. However, tests of DFB efficacy against field Ae. aegypti populations are lacking. In addition, information regarding the dynamics of CSI resistance, and characterization of any potential fitness effects that may arise in conjunction with resistance are essential for new Ae. aegypti control strategies. Here, the efficacy of DFB was evaluated for two Brazilian Ae. aegypti populations known to be resistant to both temephos and the pyrethroid deltamethrin. Laboratory selection for DFB resistance was then performed over six or seven generations, using a fixed dose of insecticide that inhibited 80% of adult emergence in the first generation. The selection process was stopped when adult emergence in the diflubenzuron-treated groups was equivalent to that of the control groups, kept without insecticide. Diflubenzuron was effective against the two Ae. aegypti field populations evaluated, regardless of their resistance level to neurotoxic insecticides. However, only a few generations of DFB selection were sufficient to change the susceptible status of both populations to this compound. Several aspects of mosquito biology were affected in both selected populations, indicating that diflubenzuron resistance acquisition is associated with a fitness cost. We believe that these results can significantly contribute to the design of control strategies involving the use of insect growth regulators. PMID- 26107718 TI - Are Cancer Survivors Physically Active? A Comparison by US States. AB - BACKGROUND: Cancer survivors who engage in physical activity (PA) have improved quality of life, reduced fatigue, and lower mortality rates. We compare the percentage of cancer survivors meeting PA recommendations for US states, stratified by age and gender, to identify the need for PA education and intervention among cancer survivors. METHODS: Pooled data from the 1997-2010 National Health Interview Survey were used to determine and rank age-adjusted PA by state. American Cancer Society guidelines (>=150 min/wk of PA) were used to compare prevalence by state, stratified by age group (< 65 and >=65) and gender. RESULTS: Thirty-three percent of cancer survivors met PA recommendations. The highest age-adjusted compliance to PA recommendations was in Vermont (59.9%, 95% confidence interval [CI], 40.8-76.3) and the lowest was in Louisiana (14.8%, 95% CI, 9.6-22.1) and Mississippi (15.5%, 95% CI, 10.4-22.3). The lowest percentages meeting recommendations were in Arkansas for males (8.6%, 95% CI, 7.0-10.6), Louisiana for females (12.5%, 95% CI, 6.8-21.9), Louisiana for survivors < 65 (15.6%, 95% CI, 10.5-22.6), and West Virginia for those >=65 years (12.7%, 95% CI, 7.6-20.6). CONCLUSIONS: Meeting PA recommendations by cancer survivors varies markedly by state of residence. Future efforts should target states with low percentages, tailoring interventions to the special needs of this high-risk population. The importance of PA should be incorporated within cancer survivorship care plans. PMID- 26107717 TI - Putative IL-10 Low Producer Genotypes Are Associated with a Favourable Etanercept Response in Patients with Rheumatoid Arthritis. AB - Outcome predictors of biologic therapeutic drugs like TNF inhibitors are of interest since side effects like serious infections or malignancy cannot be completely ruled out. Response rates are heterogeneous. The present study addressed the question whether in patients with rheumatoid arthritis (RA) interleukin-10 (IL-10) promoter genotypes with potential relevance for IL-10 production capacity are associated with response to long-term treatment with etanercept. Caucasian RA patients that, according to the EULAR criteria, responded well (n = 25), moderately (n = 17) or not (n = 8) to etanercept therapy (median 36 months, range 4-52), and 160 matched controls were genotyped for the IL-10 promoter SNPs -2849 G>A (rs6703630), -1082 G>A (rs1800896), -819 C>T (rs1800871) and -592 C>A (rs1800872). Haplotypes were reconstructed via mathematic model and tested for associations with disease susceptibility and therapy response. We identified the four predominant haplotypes AGCC, GATA, GGCC, and GACC in almost equal distribution. Patients that responded well carried the putative IL-10 low producer allele -2849 A or the haplotypes AGCC and GATA (RR 2.1 and 4.0, respectively; 95% CI 1.1-4.0 and 1.1-14.8), whereas an unfavourable response was associated with carriage of the putative high producer haplotype GGCC (RR 1.9, 95% CI 1.1-3.3). No significant associations of alleles or haplotypes with disease susceptibility were observed. In RA, a low IL-10 production which is genetically determined rather by haplotypes than by SNPs may favour the response to etanercept treatment. Iatrogenic blockade of TNF may reveal proinflammatory effects of its endogeneous antagonist IL-10. Further studies are needed to correlate these genetic findings to direct cytokine measurements. PMID- 26107719 TI - A role for OVATE FAMILY PROTEIN1 (OFP1) and OFP4 in a BLH6-KNAT7 multi-protein complex regulating secondary cell wall formation in Arabidopsis thaliana. AB - Formation of secondary walls is a complex process that requires the coordinated and developmentally regulated expression of secondary wall biosynthetic genes. In Arabidopsis thaliana, a transcriptional network orchestrates the biosynthesis and deposition of the main SCW components in xylem and fiber cells. It was recently reported that interacting TALE homeodomain proteins BEL-LIKE HOMEODOMAIN6 (BLH6) and KNOTTED ARABIDOPSIS THALIANA7 (KNAT7) negatively regulate secondary cell wall formation in the interfascicular fibers of Arabidopsis inflorescence stems. Members of the Arabidopsis OVATE FAMILY PROTEIN (OFP) family of transcriptional regulators have been shown to physically interact in yeast with various KNAT and BLH proteins, forming a proposed TALE-OFP protein interaction network. This study presents molecular and genetic data indicating that OFP1 and OFP4, previously reported to interact with TALE homeodomain proteins, enhance the repression activity of BLH6, supporting a role for these OFPs as components of a putative multi-protein transcription regulatory complex containing BLH6 and KNAT7. PMID- 26107716 TI - Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice. AB - Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumors, particularly in in immune-compromised individuals. Due to the stringent host tropism, rodents are resistant to infection by human gamma herpesviruses, creating a significant barrier for the in vivo study of viral genes that contribute to tumorigenesis. The closely-related murine gamma herpesvirus 68 (gammaHV68) efficiently infects laboratory mouse strains and establishes robust persistent infection without causing apparent disease. Here, we report that a recombinant gammaHV68 carrying the KSHV G protein-coupled receptor (kGPCR) in place of its murine counterpart induces angiogenic tumors in infected mice. Although viral GPCRs are conserved in all gamma herpesviruses, kGPCR potently activated downstream signaling and induced tumor formation in nude mouse, whereas gammaHV68 GPCR failed to do so. Recombinant gammaHV68 carrying kGPCR demonstrated more robust lytic replication ex vivo than wild-type gammaHV68, although both viruses underwent similar acute and latent infection in vivo. Infection of immunosuppressed mice with gammaHV68 carrying kGPCR, but not wild-type gammaHV68, induced tumors in mice that exhibited angiogenic and inflammatory features shared with human Kaposi's sarcoma. Immunohistochemistry staining identified abundant latently-infected cells and a small number of cells supporting lytic replication in tumor tissue. Thus, mouse infection with a recombinant gammaHV68 carrying kGPCR provides a useful small animal model for tumorigenesis induced by a human gamma herpesvirus gene in the setting of a natural course of infection. PMID- 26107720 TI - Ten Years of PLoS Computational Biology: A Decade of Appreciation and Innovation. PMID- 26107721 TI - Annual Reviews in Ophthalmology, a New Feature of the Asia-Pacific Journal of Ophthalmology. PMID- 26107722 TI - The Asia-Pacific Academy of Ophthalmology's Grand Rounds Around the World-An Online Educational Program Freely Accessible to All. AB - Grand rounds are excellent learning platforms for physicians and other health care professionals to keep up with important evolving areas in the management and treatment models of various diseases. However, there are hardly any freely accessible grand rounds in ophthalmology to meet the need for ophthalmic education in the Asia-Pacific region and beyond. The Asia-Pacific Academy of Ophthalmology would like to meet the need by sponsoring a new initiative "Grand Rounds Around the World" so that ophthalmologists and eye care professionals in the Asia-Pacific region and beyond can benefit from the program, leading to improved patient care and the elimination of learning barriers. PMID- 26107723 TI - Intracorneal Ring Segment Reimplantation in Keratectasia. AB - PURPOSE: The objective of this study was to evaluate the safety and potential for visual improvement of replacing INTACS with Kerarings in patients with keratectasia. DESIGN: Retrospective case series. METHODS: A review of patients undergoing intracorneal segment exchange was conducted. Ten eyes of 9 patients that underwent INTACS explantation and Keraring re-implantation were included. Visual acuity, manifest refraction, keratometry, and corneal asphericity readings were collected. Data were analyzed preoperatively, immediately before Keraring insertion, and at 3, 6, and 12 months after Keraring implantation. RESULTS: The mean age of subjects was 44.5 +/- 11.23 years. The mean time to exchange was 13.9 +/- 9.8 months. The initial indications for surgery were post- Laser-Assisted in Situ Keratomileusis ectasia (n = 6) and keratoconus (n = 4). The removal and re implantation procedure were successfully completed in all eyes without significant complications. No statistical difference was observed with respect to keratometry readings, manifest sphere, and manifest cylinder during follow-up. There was a significant improvement in mean decimal corrected distance visual acuity at 3, 6, and 12 months after Keraring insertion (P>0.05). The Q values were -0.37 +/- 0.94 after INTACS implantation and -0.18 +/- 0.62, 0.06 +/- 0.31, and 0.00 +/- 0.38 at 3, 6, and 12 months after insertion of Kerarings. CONCLUSIONS: Replacement of INTACS with Kerarings appears to be a safe procedure and may lead to an increase in corrected distance visual acuity in some eyes. This may be related to the change in corneal asphericity as experienced by our cohort. PMID- 26107724 TI - The Impact of Knowledge and Attitudes on Access to Eye-Care Services in Cambodia. AB - PURPOSE: To investigate how knowledge and attitudes influence the access to eye care services in Takeo Province, Cambodia. DESIGN: A cross-sectional survey (n=600). METHODS: 30 villages were randomly selected. Groups included: >50 years, 30-49 years, and parents with children <5 years. A newly developed Knowledge, Attitude and Practice in Eye Health (KAP-EH) questionnaire about knowledge and treatment of eye diseases, practices and attitudes to accessing services was used to interview respondents. Descriptive analysis, including Chi square and logistic regression tested for associations with sub-groups of gender, age group, education and self-reported type of disability. RESULTS: The proportion of respondents who reported having knowledge of specific eye conditions ranged from 97% for eye injury, to 8% for diabetic eye disease. While 509 (85%) people reported knowledge of cataract, 47% did not know how cataract was treated and only 19% listed surgery. The older group (66.5%) were least informed about cataract (p= 0.001) compared to other groups, and were least likely to believe that some blindness could be prevented (p < 0.001). Women (55%) were more likely than men (46%) (p=0 .003) to report that a child with blindness could attend school, as did people without a disability compared to those with a disability (58% vs 34%) (p < 0.001). CONCLUSIONS: The knowledge about cataract and refractive error and what to do to resolve the problems was low among this population and this study suggests that poor knowledge of eye diseases might contribute to the occurrence of un-operated cataract and uncorrected refractive error. PMID- 26107725 TI - Pain and Its Determinants in Photorefractive Keratectomy. AB - PURPOSE: To assess the determinants of early postoperative pain in photorefractive keratectomy. DESIGN: A prospective cross-sectional study. METHODS: One hundred and four myopic-astigmatic patients undergoing bilateral standard photorefractive keratectomy were evaluated for early postoperative pain severity. On day 1 postoperatively, the level of pain experienced was reported by the patient on a visual analog scale of 0 to 10. At the preoperative interview, data were collected on clinical, demographic, and social characteristics to find potential pain determinants. RESULTS: The median reported pain level was 3. About 20% of subjects reported a pain score of 6 or higher, and 2.9% (6 eyes of 4 patients) reported the highest pain score. The presence of external eye inflammatory signs was associated with higher levels of pain (P < 0.001). Patients with a higher body mass index reported more severe pain (P = 0.006). An inverse association was found between pain and harmful lifestyle choices (P = 0.008). Demographic characteristics, history of contact lens wear, history of major operation, past experience of severe pain, knowledge about the operation's adverse effects, preoperative insomnia, preoperative anxiety, operative factors, and refractive indices were not related to the severity of pain experienced (all P > 0.05). CONCLUSIONS: The association of pain with ocular surface inflammation suggests that inflammatory processes have a role in early postoperative pain, supporting the use of anti-inflammatory agents for pain management. Prescription of weight-adjusted dosages of analgesics is recommended on the basis of the association between severity of postoperative pain and body mass index. PMID- 26107726 TI - Outcome and Monitoring of Cataract Surgical Services at Takeo Province, Cambodia. AB - PURPOSE: To evaluate outcome and monitoring of cataract surgical services at Takeo Eye Hospital, Cambodia DESIGN: A prospective, hospital-based report using a cataract surgical record form from the International Center for Eye Health, London. METHODS: Data including preoperative and postoperative visual acuity (VA), proportion of ocular pathology, intraoperative and postoperative complications, type of surgery, and causes of poor outcome of all patients with cataract were collected. Exclusion criteria were age of patients being younger than 20 years, combined cataract-glaucoma surgeries, and having traumatic cataract. RESULTS: A total of 8211 cataract surgeries were performed from January 2007 to December 2011. Preoperatively, the presenting VA was less than 6/60 in 65.8%. At discharge, 51.8% had a presenting VA of 6/18 or better.Outcome was poor (VA < 6/60) in 10.6%. Over 5 years, the percentage of patients with poor outcome decreased from 12.6% to 8.5%. Total operative complications decreased from 18.2% in 2007 to 3.3% in 2011, with a reduction of vitreous loss from 6.5% to 1.8%. Of all surgeries, 21.2% were performed by resident physicians. At the first follow up 1 to 3 weeks postoperatively, 62.6% of the patients presented, whereas 23.9% presented for a second follow-up after 4 to 6 weeks. CONCLUSIONS: Monitoring of cataract surgical services indicated an increase in quantity and quality. Hospital-based data collection as recommended by the World Health Organization action plan for the prevention of avoidable blindness is possible, but biased data collection has to be considered in the interpretation of the data. PMID- 26107727 TI - Two-Stage Correction of Blepharophimosis Syndrome: Analysis of Surgical Outcome. AB - PURPOSE: To evaluate the outcome of surgical correction of blepharophimosis syndrome. DESIGN: A retrospective, non-randomized, interventional case series. METHODS: Ten patients undergoing surgical correction of blepharophimosis syndrome in 2 stages were reviewed. In the first stage, correction of epicanthic fold and telecanthus was done by either Y-V plasty or Roveda procedure with or without medial canthal tendon shortening. In the second stage, ptosis correction was done by bilateral frontalis sling. The preoperative and postoperative ratio of intercanthal distance (ICD) to horizontal palpebral fissure length (HPFL) was compared to assess the outcome of surgical correction of blepharophimosis. The ratio was graded as good (ratio < 1.3), suboptimal (ratio between 1.3 and 1.5), and poor (ratio > 1.5). The outcome of ptosis correction was graded as good, moderate, and poor. RESULTS: Of 10 patients, 5 (50%) underwent Y-V plasty, and 5 (50%) underwent Roveda procedure. Medial canthal tendon shortening was done in 5 patients (50%) having a preoperative ICD of 35 mm or more. After surgical correction, mean reduction in ICD was 4.8 mm (P < 0.0001), and mean improvement in HPFL was 5.45 mm (P < 0.0001). The mean ICD to HPFL ratio changed from 2.02 to 1.31 after surgery, which was statistically significant (P < 0.0001). Two patients (20%) had a ratio greater than 1.5. Nine patients (90%) had either good or moderate ptosis correction after bilateral frontalis sling with silicone rod. CONCLUSIONS: Functionally and cosmetically acceptable outcome can be achieved after surgical correction of blepharophimosis syndrome in 2 stages. PMID- 26107728 TI - Recurrent Corneal Erosion Syndrome. AB - Recurrent corneal erosion syndrome is characterized by repeated episodes of sudden onset of pain usually upon awakening or at night because of detachment of the weakly adhered corneal epithelium. Most of the cases can be attributed to trauma or superficial corneal dystrophies. Because of the variable clinical course, the disease causes much frustration to patients and to the ophthalmologists. Treatment options range from conservative management with lubricants, bandage contact lenses, and matrix metalloproteinase inhibitors to surgical interventions such as epithelial debridement, anterior stromal puncture, alcohol delamination, and excimer laser therapy. PMID- 26107729 TI - Retinal Vein Occlusions. AB - Retinal vein occlusions (RVOs) are second to diabetic retinopathy in the prevalence as retinal vascular disorder and are characterized by dilatation of the retinal veins with retinal and subretinal hemorrhages, macular edema, hard retinal exudates, retinal ischemia, and consequent atrophy of the retina and optic nerve. They are differentiated into central RVOs and branch RVOs (BRVO), into ischemic versus nonischemic RVOs, and in the case of BRVOs, into intrapapillary BRVOs and extrapapillary BRVOs. Diagnosis is based on ophthalmoscopy, fluorescein angiography, and spectral-domain optical coherence tomography. The latter can display the presence and integrity of the retinal outer limiting membrane and of the inner and outer segments of the photoreceptors as useful information for prognosis and a guide for treatment. Risk factors for RVOs are glaucoma and arterial hypertension. Ischemic RVOs can develop iris neovascularization and secondary angle-closure glaucoma. Formerly, therapy consisted of laser photocoagulation in a "grid" pattern over the leaking area, leading to a reduction of macular edema and, as adverse effect, to focal retinal destruction. Intravitreal medical therapy including steroids and vascular endothelial growth factor inhibitors shows a marked antiedematous effect leading to an at least temporary reduction in foveal edema and correspondingly improves visual function. Intravitreal medical therapy is associated with the disadvantage of a limited duration of its effect and the advantage of not damaging the retina. A preventive therapy to avoid a recurrence of RVO or the development of an RVO in the contralateral eye has not been proven yet. PMID- 26107730 TI - One Year of Glaucoma Research in Review: 2011 to 2012. AB - PURPOSE: To provide the practicing clinical ophthalmologist with an update of pertinent glaucoma literature published over the past 12 months. METHODS: The authors conducted a one year (July 1, 2011 to June 30, 2012) English language glaucoma literature search on Pubmed using the following terms: automated perimetry, optic nerve imaging, optical coherence tomography, glaucoma structure and function, intraocular pressure, central corneal thickness, medical therapy and compliance in glaucoma, glaucoma laser treatment, cataract extraction and intraocular pressure, secondary glaucoma, glaucoma surgery, pediatric glaucoma, molecular biology in glaucoma, and miscellaneous topics in glaucoma. DESIGN: Literature review. RESULTS: This review includes original and review articles that reflect novel aspects and updates in the field of glaucoma, while excluding letters to the editor, unpublished works, and abstracts. CONCLUSIONS: This review is not meant to be all-inclusive-rather, it highlights literature that is most applicable to ophthalmologists in practice. PMID- 26107731 TI - Drug Screening to Treat Early-Onset Eye Diseases: Can Zebrafish Expedite the Discovery? AB - The molecular basis of many early-onset eye diseases has been uncovered, but the number of available drug treatments for improving deteriorated vision is still scarce. Consequently, there is a high demand for new drugs to treat these diseases. This review first provides a brief synopsis of the use of zebrafish model for screening drugs with vision benefits. In particular, visual-motor response, the activity response of larvae to a change in light stimuli, is proposed to serve as a simple and efficient tool for screening drugs that may improve vision in various zebrafish visual mutants. The second part of the review discusses the identification of novel drug candidates, with particular emphasis on naturally derived chemicals including traditional Chinese medicines and nutritional therapies on retinal degenerative diseases. Many of these chemicals have been used in neuroprotection and/or have been consumed by many populations for good health and vision; thus, the screening of these chemicals with various zebrafish visual mutants would expedite the development of novel drugs for treating early-onset eye diseases. PMID- 26107732 TI - Pars Plana Vitrectomy With or Without Silicone Oil Endotamponade in Surgical Management of Endophthalmitis. PMID- 26107733 TI - Author Reply to "Letter to the Editor on the Article: Nagpal M, Jain P, Nagpal K. Pars Plana Vitrectomy With or Without Silicone Oil Endotamponade in Surgical Management of Endophthalmitis". PMID- 26107734 TI - In Response to "Epi-LASIK Discarding the Epithelial Flap Versus LASIK for Myopia and Myopic Astigmatism". PMID- 26107735 TI - Epi-LASIK Discarding the Epithelial Flap Versus LASIK for Myopia and Myopic Astigmatism: Author Reply. PMID- 26107736 TI - Correction: Correction: Proteomic Analysis of Urine Exosomes Reveals Renal Tubule Response to Leptospiral Colonization in Experimentally Infected Rats. PMID- 26107740 TI - Endogenous Price Bubbles in a Multi-Agent System of the Housing Market. AB - Economic history shows a large number of boom-bust cycles, with the U.S. real estate market as one of the latest examples. Classical economic models have not been able to provide a full explanation for this type of market dynamics. Therefore, we analyze home prices in the U.S. using an alternative approach, a multi-agent complex system. Instead of the classical assumptions of agent rationality and market efficiency, agents in the model are heterogeneous, adaptive, and boundedly rational. We estimate the multi-agent system with historical house prices for the U.S. market. The model fits the data well and a deterministic version of the model can endogenously produce boom-and-bust cycles on the basis of the estimated coefficients. This implies that trading between agents themselves can create major price swings in absence of fundamental news. PMID- 26107737 TI - Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs. AB - Blocking the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of HER2 positive breast carcinoma cells. The hypothesis is that blocking FASN, in combination with anti-HER2 signaling agents, would be an effective antitumor strategy in preclinical HER2+ breast cancer models of trastuzumab and lapatinib resistance. We developed and molecularly characterized in vitro HER2+ models of resistance to trastuzumab (SKTR), lapatinib (SKLR) and both (SKLTR). The cellular interactions of combining anti-FASN polyphenolic compounds (EGCG and the synthetic G28UCM) with anti-HER2 signaling drugs (trastuzumab plus pertuzumab and temsirolimus) were analyzed. Tumor growth inhibition after treatment with EGCG, pertuzumab, temsirolimus or the combination was evaluated in two in vivo orthoxenopatients: one derived from a HER2+ patient and another from a patient who relapsed on trastuzumab and lapatinib-based therapy. SKTR, SKLR and SKLTR showed hyperactivation of EGFR and p-ERK1/2 and PI3KCA mutations. Dual-resistant cells (SKLTR) also showed hyperactivation of HER4 and recovered levels of p-AKT compared with mono-resistant cells. mTOR, p-mTOR and FASN expression remained stable in SKTR, SKLR and SKLTR. In vitro, anti-FASN compounds plus pertuzumab showed synergistic interactions in lapatinib- and dual- resistant cells and improved the results of pertuzumab plus trastuzumab co-treatment. FASN inhibitors combined with temsirolimus displayed the strongest synergistic interactions in resistant cells. In vivo, both orthoxenopatients showed strong response to the antitumor activity of the combination of EGCG with pertuzumab or temsirolimus, without signs of toxicity. We showed that the simultaneous blockade of FASN and HER2 pathways is effective in cells and in breast cancer models refractory to anti-HER2 therapies. PMID- 26107741 TI - Rheumatoid Arthritis as a Therapeutic Challenge in a Patient with Lynch Syndrome. AB - BACKGROUND: Lynch syndrome (LS) is an inherited colorectal cancer (CRC) syndrome accounting for about 3-5% of all cases and involves significantly higher risk of subsequent malignancies, colonic as well as extra-colonic. Increased risk of malignancies, especially lymphoid malignancies, have been described in patients with autoimmune diseases like rheumatoid arthritis (RA), systemic lupus erythematosus, and Sjogren's syndrome. Epidemiological studies demonstrated that hematopoietic, lung, skin, and prostate cancers are increased in RA, while breast and colon cancers are decreased, with an overall slight increase in all cancers. CASE REPORT: Our case demonstrates the development of CRC, endometrial cancer, and breast cancer as a presentation of LS in a patient with RA and presents a therapeutic challenge for RA treatment. CONCLUSIONS: We describe a patient with LS and RA presenting a therapeutic challenge because biologic agents commonly used to treat severe RA need to be used cautiously in patients with history of malignancy. PMID- 26107738 TI - Vitamin D regulates cytokine patterns secreted by dendritic cells to promote differentiation of IL-22-producing T cells. AB - One central mechanism, by which vitamin D regulates human immune responses, is the direct modulation of dendritic cells (DCs). However, the effect of vitamin D on several key DC functions, such as the secretion of central inflammatory cytokines, remains controversial. Moreover, whether vitamin D treatment of DCs regulates their ability to promote differentiation of IL-17-/IL-22-producing T cell subsets, such as Th17 and Th22 cell, is not known. Here, we report that vitamin D treatment during differentiation of monocytes into DCs markedly enhanced their ability to secrete TNF-alpha, IL-6, IL-1beta and IL-23. Cytokines secreted by vitamin D-treated DC were significantly more potent in driving differentiation of IL-22-producing T cells, but not IL-17-producing T cells, as compared to secreted cytokines of not-vitamin D-treated DCs. Finally, we found that the differentiation of IL-22-producing T cells mediated by supernatants of vitamin D-treated DCs was dependent on TNF-alpha IL-6 and IL-23. In summary, our study suggests a novel role of vitamin D in regulating DC-mediated immune responses in humans. PMID- 26107742 TI - Effects of Synchronization during Noninvasive Intermittent Mandatory Ventilation in Preterm Infants with Respiratory Distress Syndrome Immediately after Extubation. AB - BACKGROUND: Noninvasive ventilation is increasingly used in very-low-birth-weight infants (VLBWI) to reduce complications that occur with invasive ventilation. However, the physiological effects of synchronization during noninvasive nasal intermittent mandatory ventilation (IMV) have not been tested in VLBWI immediately after extubation. OBJECTIVE: We aimed to study the short-term effects of synchronized nasal IMV (S-NIMV) compared to nonsynchronized nasal IMV (NIMV) on breathing effort as measured by phasic esophageal pressure (Pe) deflection, spontaneous respiratory rate (RR), gas exchange, cerebral tissue oxygen saturation (StO2) and intermittent episodes of bradycardia or hypoxemia in VLBWI recovering from respiratory distress syndrome (RDS). METHODS: Fourteen VLBWI recovering from RDS were studied using a randomized cross-over design during both S-NIMV and NIMV (of 2 h each) immediately after extubation. RESULTS: Phasic Pe deflection, spontaneous RR and transcutaneous PCO2 decreased significantly while transcutaneous PO2 and synchrony rate (defined as peak ventilator pressure delivered within the first half of spontaneous inspiration) increased significantly during S-NIMV compared to during NIMV. There was no difference in blood pressure, average arterial oxygen saturation (SpO2), cerebral StO2, fractional tissue oxygen extraction of the brain and severe bradycardia (defined as time with a heart rate <100 beats/min lasting >=10 s) and in hypoxemic episodes (SpO2 <80%) between the two modes. CONCLUSION: Synchronization during nasal ventilation immediately after extubation in VLBWI recovering from RDS improved gas exchange and decreased the respiratory effort, and it could therefore be considered to provide a more efficient respiratory support and synchrony. PMID- 26107743 TI - Evaluation of Immunomodulatory Effects of Mesenchymal Stem Cells Soluble Factors on miR-155 and miR-23b Expression in Mice Dendritic Cells. AB - Mesenchymal stem cells (MSCs) can modulate dendritic cells (DCs) activation and induce tolerogenic characteristics in DCs. All mechanisms involved in MSCs induced tolerogenic DCs are not fully understood. MicroRNAs (miRs) play important role in maturation and function of DCs. In this study, we investigated the effects of MSCs culture supernatant (C.S.) on expression of miR-155 and miR-23b in mice DCs. BALB/c mice spleens were used for DCs isolation. MSCs were isolated from the mice bone marrow and cultured in DMEM media. When MSCs expanded to sixth passage, C.S. was collected after 12, 24 and 48 h. Quantitative polymerase chain reaction (QPCR) was used to determine the expression of miR-155 and miR-23b in DCs treated with C.S. after 6 and 12 h. Secretion of IL-23 and TGF- beta were detected in DCs treated with C.S. by ELISA after 24 h. miR-23b expression was significantly increased in DCs treated with 12 h C.S. for 12 h compared to negative controls. miR-155 expression did not change in DCs treated with C.S. after 6 and 12 h. miR-23b expression was significantly increased in DCs treated with 12 h C.S. for 12 h, compared to those treated with C.S. for 6 h. Similarly, miR-23b expression was increased in DCs treated with 24 h C.S. for 12 h when compared to those treated for 6 h. Production of TGF-beta and IL-23 were not influenced by C.S. In conclusion, miR-23b is considered to be one of the mechanisms involved in tolerogenic DCs induction by C.S. in a time-dependent manner. PMID- 26107744 TI - Comparison of an Enzyme-Linked Immunosorbent Assay with an Immunochromatographic Assay for Detection of Lincomycin in Milk and Honey. AB - An enzyme-linked immunosorbent assay (ELISA) and an immunochromatographic assay were constructed for the detection of lincomycin (LIN) in both milk and honey samples based on the monoclonal antibody named 5F6. The half-maximum inhibition of ELISA was 0.3 ng/mL after optimizing pH and ionic strength conditions; the limit of detection was 0.07 ng/mL. The cross-reactivity with clindamycin was 0.6%. LIN recovery in spiked milk and honey samples ranged from 84.6% to 115.6% with intra-assay coefficient variations of 1.7-25.4% and inter-assay coefficient variations of 2.7-8.9%. The detection limits were estimated as 2.1 ug/L for milk and 2.1 ug/kg for honey samples. The immunochromatographic assay revealed a LIN cut-off value of 10 ng/mL in PBS, 5 ng/mL in milk, and 120 ng/g in honey, and a visual lower detection limit of 2.5 ng/mL, 1 ng/mL and 30 ng/g in PBS, milk and honey, respectively. The immunochromatographic assay is preferred for large-scale practical application for its simpler pretreatment and satisfied sensitivity compared with ELISA assay. PMID- 26107745 TI - Partial Reversal of Obesity-Induced Insulin Resistance Owing to Anti-Inflammatory Immunomodulatory Potential of Flaxseed Oil. AB - The present study was designed to assess the potential of supplementation of diet with Flaxseed (Linum usitatissimum, L.) oil (FXO), on obesity-related inflammation and reversal of obesity-induced insulin resistance. Swiss Albino mice, C57bl/6 mice and co-culture of 3T3-L1 adipocytes - RAW 264.7 macrophages to mimick obese adipose tissue environment were used for the study. Oral gavage of FXO at concentrations of 4, 8 or 16 mg/kg body weight (bwt) for 4 weeks or high fat diet (HFD, 60% energy as fat) supplemented with dietary FXO (4, 8 or 16 mg/kg bwt) was given to the mice. FXO was characterised using gas chromatography - mass spectrometry. FXO supplemented HFD-fed mice (4 mg/kg bwt exhibited reduced adiposity index, serum glucose levels and triglycerides (8 and 16 mg/kg bwt) and improvement in insulin sensitisation (4, 8 and 16 mg/kg bwt) when compared with HFD mice. The co-culture showed a dose-dependent shift in cytokines towards anti inflammatory (IL-4) state, with a decrease in pro-inflammatory TNF-alpha (p < 0.05). For immunomodulatory studies a dose-dependent increase (p < 0.05) was observed in antigen-specific levels of Th2 (IL-4) cytokine, serum anti-ova IgG1 and IgE levels. Suppression in anti-ova IgG2a, IgG2b, and IgG3 and antigen specific Th1 cytokines like TNF-alpha and IFN-gamma significantly (p < 0.05) was observed at 16 mg/kg bwt dosage. The results indicate that FXO exhibits an anti inflammatory immunomodulatory potential and may partially relieve symptoms of obesity-associated insulin resistance. PMID- 26107746 TI - Preventive Effect of a Novel Recombinant sTNFRII on Collagen-Induced Arthritis. AB - We developed a novel trimeric sTNFRII fusion protein, named sTNFRII-gAD, which exhibited a higher in vitro antagonistic efficacy for TNFalpha in comparison with sTNFRII-Fc. This study aimed to investigate the arthritic protection of sTNFRII gAD in a rat collagen-induced arthritis (CIA). The rats were injected intradermally with collagen type II at days 0 and 7. Three days after the second injection (day 10), the rats were intraperitoneally given sTNFRII-gAD or sTNFRII Fc, or PBS. Effects of treatments were examined with respect of CIA incidence, severity and pathological changes. Serum TNFalpha, IL-17A and regulatory T cell (Treg) in periphery were determined at days 10 and 16, respectively. Our results showed that sTNFRIIgAD significantly reduced CIA incidence and severity (p < 0.05); meanwhile it led to a dramatic improvement in cartilage and bone damage. Moreover, the increase in serum anti-CII and IL-17A, and the reduction in Treg population were inhibited (p < 0.05) by sTNFRII-gAD or sTNFRII-Fc. Serum TNFalpha was found to be accumulated in the groups treated with sTNFRII-gAD or sTNFRII-Fc compared with the group treated with PBS (p < 0.05). It is noteworthy that sTNFRII-gAD displayed a better efficacy than sTNFRII-Fc in CIA incidence, pathological changes in cartilage and the elevation of anti-CII antibody, indicating that sTNFRII-gAD is potentially a more efficacious anti-TNFalpha agent for rheumatoid arthritis. PMID- 26107747 TI - Protective Immune Responses Elicited by Fusion Protein Containing PsaA and PspA Fragments. AB - Streptococcus pneumoniae is an important pathogen accounting for a large number of deaths worldwide. Due to drawbacks of the current polysaccharide-based vaccine, the most promising way to generate an improved vaccine may be to utilize protection-eliciting pneumococcal proteins. Pneumococcal surface adhesin A (PsaA) and pneumococcal surface protein A (PspA) are two vaccine candidates which have been evaluated against S. pneumoniae infection in animal models or human clinical trials with encouraging results. In this study, the efficacy of the fusion protein PsaA-PspA, which includes PsaA part and PspA part, in inducing immunoprotective effects against fatal pneumococcal challenge was evaluated in an animal model. PspA part of PsaA-PspA fusion protein contains both family1 N terminal region and family 2 N-terminal clade-defining region of PspA. Immunization with the PsaA-PspA fusion protein induced high levels of antibodies against both PsaA and PspA, which could bind to intact S. pneumoniae strains bearing different PspAs. Ex vivo stimulation of splenocytes from mice immunized with PsaA-PspA induced IL-17A secretion. Mice immunized with PsaA-PspA showed reduced S. pneumoniae levels in the blood and lungs compared with the PBS group after intranasal infection. Finally, mice immunized with PsaA-PspA fusion proteins were protected against fatal challenge with pneumococcal strains expressing different PspAs regardless of the challenge route. These results support the PsaA-PspA fusion protein as a promising vaccine strategy, as demonstrated by its ability to enhance the immune response and stimulate production of high titer antibodies against S. pneumoniae strains bearing heterologous PspAs, as well as confer protection against fatal challenge with PspA family 1 and family 2 strains. PMID- 26107748 TI - Aberrant Low Expression of A20 in Tumor Necrosis Factor-alpha-stimulated SLE Monocytes Mediates Sustained NF-kappaB Inflammatory Response. AB - The aberrantly activated monocytes and nuclear factor-kappaB (NF-kappaB) pathway contribute to the pathogenesis of systemic lupus erythematosus (SLE), and the aberrantly activated NF-kappaB is associated with defects in the anti inflammatory A20 in SLE. However, whether SLE monocytes express A20 and whether the A20 expression under sustained proinflammatory stimulation is altered to contribute to the uncontrolled NF-kappaB inflammatory response are unclear. In this study, we found that the freshly isolated monocytes from SLE patients and healthy controls did not differ in expression levels of IL-1beta, IkappaBalpha and A20. After TNF-alpha stimulation for 48 h, the monocytes from both groups expressed higher levels of IL-1beta and IkappaBalpha than the monocytes without TNF-alpha treatment. Although the increased levels of NF-kappaB were observed in the nucleus of both the SLE and control monocytes after 24 h of TNF-alpha stimulation, the enhancement in SLE monocytes was significantly more robust than in the control monocytes. In addition, while the p-IkappaBalpha level in healthy monocytes was increased, the p-IkappaBalpha level in SLE monocytes was slightly decreased after TNF-alpha stimulation. Interestingly, after TNF-alpha treatment, the A20 expression in SLE monocytes was not markedly altered compared with the untreated SLE monocytes; moreover, the SLE monocytes expressed significantly lower A20 than healthy monocytes with TNF-alpha treatment at each time point. Results in this study demonstrate that TNF-alpha activates a significant NF kappaB inflammatory response in SLE monocytes, which is at least partially mediated by the aberrantly low expression of A20 upon TNF-alpha stimulation, contributing to the prolonged inflammatory response in SLE. PMID- 26107749 TI - Chemotactic and Phagocytic Activity of Blood Neutrophils in Allergic Asthma. AB - Allergic asthma is a chronic inflammatory airway disease, and has been considered a T helper-2-biased response. Studies suggest that neutrophils may be associated with exacerbation and asthma severity. We sought to evaluate the chemotactic activity and phagocytic capacity by peripheral blood neutrophils from individuals with controlled and uncontrolled allergic asthma, and compare the results with non-asthmatic controls groups. Blood neutrophils were isolated from 95 patients: 24 with controlled asthma, 24 uncontrolled asthma, 24 healthy subjects and 23 patients with IgE-mediated allergies other than asthma. The neutrophil chemotaxis, stimulated with LPS, autologous serum or homologous serum, was determined using Boyden chambers. The phagocytic capacity was assessed by ingestion of zimosan particles, and digestion phase was analyzed by NBT test. The phagocytic digestion phase and chemotaxis by neutrophils from asthmatic patients was higher than in non-asthmatic controls (p < 0.05). Autologous serum-induced neutrophil chemotaxis in patients with uncontrolled asthma was greater (p < 0.05) than in other study groups. The ingestion phase of phagocytosis showed similar values in asthmatics and non-asthmatics. We conclude that the blood neutrophil from controlled and uncontrolled asthmatic patients exhibit activation markers, particularly phagocytic digestion and chemotactic activities. PMID- 26107750 TI - The multicopper oxidase gene family in the brown planthopper, Nilaparvata lugens. AB - The multicopper oxidase (MCO) family of enzymes includes laccases, ascorbate oxidases, bilirubin oxidases and a subgroup of metal oxidases. On the basis of a bioinformatics investigation, we identified 7 genes encoding putative multicopper oxidase proteins in the genome of the brown planthopper (BPH), Nilaparvata lugens (Hemiptera: Delphacidae). MCO1 and MCO2 are conserved, while others diverse in insects. Analysis of developmental and tissue-specific expression patterns revealed the following: NlMCO2 was mainly expressed in the integument, and its expression peaked periodically during molting; NlMCO3 was an ovary-specific MCO gene with a high expression level only at the adult stage; NlMCO4 was a salivary gland-specific MCO gene that was expressed at all developmental stages; NlMCO5 only had short-term expression in the middle of the fourth instar stage and was expressed mainly in the gut; NlMCO6 had a developmental expression pattern similar to that of NlMCO2 and was expressed in most N. lugens tissues; and NlMCO1 was expressed in most N. lugens tissues except for the testis, whereas NlMCO7 was mainly expressed in the gut and the Malpighian tube. BPHs injected with double stranded RNA (dsRNA) targeting NlMCO2 failed to pigment and sclerotize, were colorless and soft-bodied and subsequently died in a short time. Lethal phenotypes were also observed in insects challenged by dsRNA targeting NlMCO6. However, no observable morphological or internal structural abnormality was obtained in the insects treated with dsRNA for NlMCO1, NlMCO3, NlMCO4, NlMCO5 or NlMCO7. PMID- 26107751 TI - Less Surgery, Improved Survival From Stage IV Colorectal Cancer? PMID- 26107753 TI - Enhanced CH4 Recovery Induced via Structural Transformation in the CH4/CO2 Replacement That Occurs in sH Hydrates. AB - The CH4/CO2 replacement that occurs in sH hydrates is investigated, with a primary focus on the enhanced CH4 recovery induced via structural transformation with a CO2 injection. In this study, neohexane (NH) is used as a liquid hydrocarbon guest in the sH hydrates. Direct thermodynamic measurements and spectroscopic identification are investigated to reveal the replacement process for recovering CH4 and simultaneously sequestering CO2 in the sH (CH4 + NH) hydrate. The hydrate phase behavior and the (13)C NMR and Raman spectroscopy results of the CH4 + CO2 + NH systems demonstrate that CO2 functions as a coguest of sH hydrates in CH4-rich conditions, and that the structural transition of sH to sI hydrates occurs in CO2-rich conditions. CO2 molecules are found to preferentially occupy the medium 4(3)5(6)6(3) cages of sH hydrates or the large 5(12)6(2) cages of sI hydrates during the replacement. Due to the favorable structural transition and resulting re-establishment of guest distributions, approximately 88% of the CH4 is recoverable from sH (CH4 + NH) hydrates with a CO2 injection. The hydrate dissociation and subsequent reformation caused by the structural transformation of sH to sI is also confirmed using a high-pressure microdifferential scanning calorimeter through the detection of the significant heat flows generated during the replacement. PMID- 26107752 TI - Long-Acting Injectable Risperidone for Relapse Prevention and Control of Breakthrough Symptoms After a Recent First Episode of Schizophrenia. A Randomized Clinical Trial. AB - IMPORTANCE: Long-acting, injectable, second-generation antipsychotic medication has tremendous potential to bring clinical stability to persons with schizophrenia. However, long-acting medications are rarely used following a first episode of schizophrenia. OBJECTIVE: To compare the clinical efficacy of the long acting injectable formulation of risperidone with the oral formulation in the early course of schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial performed at a university-based research clinic, between 2005 and 2012. Eighty-six patients with recent onset of schizophrenia were randomized to receive long-acting injectable risperidone or oral risperidone. Half of each group was simultaneously randomized to receive cognitive remediation to improve cognitive functioning or healthy-behaviors training to improve lifestyle habits and well-being. An intent-to-treat analysis was performed between October 4, 2012, and November 12, 2014. INTERVENTIONS: A 12-month trial comparing the long acting injectable vs oral risperidone and cognitive remediation vs healthy behaviors training. MAIN OUTCOMES AND MEASURES: Psychotic relapse and control of breakthrough psychotic symptoms. RESULTS: Of the 86 patients randomized, 3 refused treatment in the long-acting injectable risperidone group. The psychotic exacerbation and/or relapse rate was lower for the long-acting risperidone group compared with the oral group (5% vs 33%; chi21 = 11.1; P < .001; relative risk reduction, 84.7%). Long-acting injectable risperidone better controlled mean levels of hallucinations and delusions throughout follow-up (beta = -0.30; t68 = 2.6, P = .01). The cognitive remediation and healthy-behaviors training groups did not differ significantly regarding psychotic relapse, psychotic symptom control, or hospitalization rates, and there were no significant interactions between the 2 medications and the 2 psychosocial treatments. Discontinuations owing to inadequate clinical response were more common in the oral group than in the long-acting risperidone group (chi21 = 6.1; P = .01). Adherence to oral risperidone did not appear to differ before randomization but was better for the long-acting risperidone group compared with the oral group (t80 = 5.3; P < .001). Medication adherence was associated with prevention of exacerbation and/or relapse (chi21 =11.1; P = .003) and control of breakthrough psychotic symptoms (beta = 0.2; t79 = 2.1; P = .04). CONCLUSIONS AND RELEVANCE: The use of long acting injectable risperidone after a first episode of schizophrenia has notable advantages for clinical outcomes. The key clinical advantages are apparently owing to the more consistent administration of the long-acting injectable. Such formulations should be offered earlier in the course of illness. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00333177. PMID- 26107754 TI - Association of SNPs with the efficacy and safety of immunosuppressant therapy after heart transplantation. AB - AIM: Studying the possible influence of SNPs on efficacy and safety of calcineurin inhibitors upon heart transplantation. MATERIALS & METHODS: In 60 heart transplant patients treated with tacrolimus or cyclosporine, we studied a panel of 36 SNPs correlated with a series of clinical parameters during the first post-transplantation year. RESULTS: The presence of serious infections was correlated to ABCB1 rs1128503 (p = 0.012), CC genotype reduced the probability of infections being also associated with lower blood cyclosporine concentrations. Lower renal function levels were found in patients with rs9282564 AG (p = 0.003), related to higher blood cyclosporine blood levels. A tendency toward increased graft rejection (p = 0.05) was correlated to rs2066844 CC in NOD2/CARD15, a gene related to lymphocyte activation. CONCLUSION: Pharmacogenetics can help identify patients at increased risk of clinical complications. Original submitted 30 January 2015; revision submitted 27 March 2015. PMID- 26107755 TI - Metabolic side effects and pharmacogenetics of second-generation antipsychotics in children. AB - Second-generation antipsychotics (SGAs) are increasingly being used to treat children for a range of mental health conditions, for example, anxiety disorder, attention deficit hyperactivity disorder and bipolar disorder. SGA treatment is associated with weight gain and cardiometabolic side effects such as dyslipidemia, insulin resistance and elevated blood pressure, in some, but not all children. This review provides an overview of the potential role of pharmacogenomics in predisposing a child to unhealthy weight gain and cardiometabolic side effects with SGA treatment. Specifically, the review includes a synopsis of the evidence for cardiometabolic side effects in SGA treated children, illustrating the extent and depth of the problem; summarizes the potential long-term consequences of developing cardiometabolic risk during childhood and highlights genetic variants that may be useful in predicting cardiometabolic side effects in SGA-treated children. PMID- 26107756 TI - Corneal Transplants-the Sooner the Better? PMID- 26107757 TI - A Prospective Study of Pterygium Excision and Conjunctival Autograft With Human Fibrin Tissue Adhesive: Effects on Vision, Refraction, and Corneal Topography. AB - PURPOSE: This study aimed to investigate changes in visual acuity, corneal parameters, and topographic parameters after pterygium surgery. DESIGN: A prospective observational study was conducted. METHODS: Twenty eyes of 20 participants undergoing pterygium excision with conjunctival autograft secured using human fibrin tissue adhesive were included in the study. All the participants were assessed preoperatively and 1 and 3 months postoperatively. The parameters included subjective refraction, visual acuity, and pterygium size (pterygium horizontal corneal length [PHCL]) and corneal tomography by Pentacam rotating Scheimpflug tomographer (OCULUS Optikgerate GmbH, Wetzlar, Germany). The astigmatic changes were calculated using vector analysis. RESULTS: The mean age of participants was 49.3 +/- 12.1 years. Mean PHCL was 2.68 +/- 0.30 mm. The mean best corrected visual acuity preoperatively was 6/7.5, improving significantly to 6/6 at 1 month (P = 0.001) with this improvement remaining stable at 3 months postoperatively (P = 0.34). There was no significant change in subjective astigmatism, however, mean topographic astigmatism decreased significantly at 1 month (4.36 diopter, P < 0.01) and remained unchanged at 3 months (P < 0.01). Greater PHCL was associated with greater changes in corneal astigmatism. CONCLUSIONS: Significant improvements and early stabilization of visual acuity and topographic astigmatism confirm the optical benefits of pterygium excision. These data also suggest a significant advantage of performing pterygium before rather than simultaneously with or after cataract surgery by enabling the most accurate biometry. PMID- 26107758 TI - Endothelial Keratoplasty: A Review of Indications at a Tertiary Eye Care Centre in South India. AB - PURPOSE: The objective of this study was to review the indications for endothelial keratoplasty (EK) performed at a tertiary eye care center in South India between January 2007 and December 2011. DESIGN: This was a hospital-based, cross-sectional study. METHODS: A retrospective analysis of the indications of EK surgeries between January 2007 and December 2011 was done using the Corneal Tissue Utilization Register available with the Ramayamma International Eye Bank, L. V. Prasad Eye Institute, Hyderabad, India. Additional data such as age, sex, and socioeconomic status of the transplant recipients were obtained from the Medical Records Department, L. V. Prasad Eye Institute. RESULTS: Data were available for 1048 EK surgeries performed on 978 patients. The number of EK surgeries increased from 40 in 2007 to 232 in 2011. The median age of the patients was 58 years (range, 5 months to 92 years) with a male-female ratio of 1.5:1. The clinical indications for EK were pseudophakic corneal edema (47.9%), failed prior penetrating keratoplasty (20.0%), Fuchs endothelial corneal dystrophy (10.8%), aphakic corneal edema (6.0%), failed prior EK (4.3%), congenital hereditary endothelial dystrophy (1.8%), Descemet membrane detachment/tear (1.6%), iridocorneal endothelial syndrome (1.4%), and corneal edema due to other reasons (6.2%). CONCLUSIONS: The most common indication for EK was pseudophakic corneal edema, followed by post-penetrating keratoplasty graft failure and Fuchs endothelial corneal dystrophy. PMID- 26107759 TI - The Association of Delayed Corneal Surface and Visual Recovery After Corneal Transplantation With Longer Donor Storage Time-A Prospective Analysis. AB - PURPOSE: This study aimed to assess the influence of donor corneal storage time on endothelial cell count (ECC), corneal epithelial recovery, and visual rehabilitation after corneal transplantation in the first postoperative year. DESIGN: A collaborative prospective study involving a local eye bank and a tertiary ophthalmic unit was conducted. METHODS: Donor cornea buttons were stored in Optisol-GS (Chiron Ophthalmics Inc, Irvine, Calif) storage media for a maximum of 14 days before transplantation. Before corneal distribution, the eye bank collected information on death-to-harvesting time, death-to-surgery time, donor central corneal thickness, and donor ECC at various time points. Subjects who underwent penetrating keratoplasty and endothelial keratoplasty were recruited and monitored for 1 year. Postoperative epithelial healing, visual acuity, ECC, and hospital stay were evaluated. RESULTS: Thirty-one eyes of 31 patients completed the study. There was a significant positive correlation between donor storage time and epithelial healing (Spearman rho = 0.39, P = 0.031). Faster epithelial healing was significantly correlated with posttransplantation visual improvements at months 1, 3, and 6 and shorter hospital stay (Spearman rho = 0.74, P < 0.001). Mean ECC loss was 23.8% at 12 months posttransplantation. There was no significant correlation between storage time and ECC loss preoperatively and posttransplantation. CONCLUSIONS: The duration of graft storage in Optisol-GS storage media up to 14 days had no significant effects on long-term visual acuity and ECC postoperatively. Shorter storage time had significant correlation with earlier epithelial healing and faster visual rehabilitation. PMID- 26107760 TI - 23-Gauge Pars Plana Vitrectomy Versus Scleral Buckling Versus Combined Pars Plana Vitrectomy-Scleral Buckling for Medium-Complexity Retinal Detachment Repair. AB - PURPOSE: To compare the anatomic and visual outcomes of 23-gauge pars plana vitrectomy (PPV), scleral buckling (SB), and combined 23-gauge PPV/SB in the treatment of primary medium-complexity rhegmatogenous retinal detachment (RRD). DESIGN: A retrospective, consecutive case series. METHODS: A consecutive chart review of patients with medium-complexity RRD treated with PPV, SB, and combined PPV/SB was conducted. The primary outcome measure was retinal reattachment at 6 months' follow-up. The secondary outcome measure was Snellen best-corrected visual acuity (BCVA) of 20/40 or better at 6 months' follow-up. RESULTS: Five hundred sixty-five cases met inclusion criteria. The overall primary anatomic success rate was 83.6% (95% confidence interval, 80.3%-86.5%). Logistic regression analysis did not demonstrate a significant difference between the 3 techniques in terms of likelihood of anatomic success or likelihood of achieving a Snellen BCVA of 20/40 or better. Patients with multiple breaks in 2 or more quadrants or inferior breaks were more likely to undergo SB/PPV, whereas patients with phakic lens status with breaks confined to 1 quadrant were more likely to undergo SB. Patients with macula-off detachments and those with postoperative proliferative vitreoretinopathy were less likely to achieve a Snellen BCVA of 20/40 or better. CONCLUSIONS: Although there was not a statistically significant difference in the anatomic and visual outcomes between the repair techniques analyzed, SB/PPV was performed on the more complicated spectrum of medium complexity RRDs with the overall highest anatomic success rate and therefore may be the most effective repair technique for this patient population. PMID- 26107761 TI - Treatment Paradigm After Uncomplicated Cataract Surgery: A Prospective Evaluation. AB - PURPOSE: To compare 3 clinical variables, namely, visual recovery, anterior chamber inflammation, and macular edema, between 2 different regimens after uncomplicated cataract surgery. DESIGN: Prospective, randomized, single-blind study at a single center, private, teaching practice in Las Vegas, NV. METHODS: Patients randomized to group I (nonsteroidal anti-inflammatory drugs, n = 113) received besifloxacin ophthalmic suspension 0.6% and bromfenac 0.09%, whereas those randomized to group II (steroid, n = 109) received besifloxacin ophthalmic suspension 0.6% and prednisolone acetate 1%.Preoperative evaluation included a baseline macular optical coherence tomography. Postoperative data collected included visual acuity, direct visual anterior segment cell and flare counts, and macular optical coherence tomographies. Foveal thickness and total macular volume were used to assess the presence of cystoid macular edema. RESULTS: Visual recovery was statistically insignificant with P values at 0.7, 0.10, 0.2, and 0.7 at 1 day, 1 week, 1 month, and 2 months, respectively.The degree of anterior segment inflammation was not statistically significant (P = 0.8) between the studied populations.The foveal thickness (1 week, P = 0.8; 1 month, P = 0.2; 2 months, P = 0.2) and total macular volume (1 week, P = 0.7; 1 month, P = 0.1; 2 months, P = 0.2) were not statistically significant between the groups, and the observed power were 0.902 and 0.666, respectively. CONCLUSIONS: This study demonstrated that bromfenac was equally efficacious when compared with a potent topical steroid in restoring visual function, decreasing and resolving anterior chamber inflammation, and preventing the development of macular edema. PMID- 26107762 TI - Prognostic Value of Ocular Trauma Score in Evaluating Visual Outcome of Pediatric (4-16 Years) Open Globe Injuries. AB - PURPOSE: This study aimed to assess the prognostic value of ocular trauma score (OTS) in pediatric open globe injury. DESIGN: A prospective observational study was conducted. METHODS: A total of 210 patients aged 4 to 16 years (mean +/- SD age, 9.30 +/- 3.29 years) with open globe injury were recruited by nonrandomized purposive sampling based on the inclusion and exclusion criteria. Ocular trauma score variables, including visual acuity (VA), rupture, endophthalmitis, perforating injury, retinal detachment, and afferent pupillary defect, were determined and converted into OTS categories. The final VA in each category was compared with the prognostic outcome. RESULTS: Patients were categorized into 5 groups according to the OTS model, with 30 (14.28%) patients in category 1, 52 (24.77%) patients in category 2, 40 (19.05%) patients in category 3, 40 (19.05%) patients in category 4, and 48 (22.86%) patients in category 5.Forty-three (20.48%) patients had a final VA of 20/40 or greater, all of whom were in category 5. No patients in category 1 could achieve a VA of 20/40 or greater. Of the 35 (16.67%) patients who had no perception of light in follow-up visits, 28 were from category 1 and 7 were from category 2. CONCLUSIONS: Ocular trauma score has good prognostic significance if other interventions such as proper evaluation, early surgery, and proper follow-up can be ensured. PMID- 26107763 TI - Understanding the Neuro-ophthalmology of Head Trauma: A Review of the Current Literature. AB - Head trauma is a major medical, social, economic, national, and public health priority issue in the United States. In severe head trauma, the overwhelming clinical manifestations are so compelling that damage to the visual system is most likely to be ignored. Both the afferent and efferent visual systems are susceptible to injury after head trauma, and physicians should be aware of the visual system and perform a thorough neuro-ophthalmic evaluation in patients presenting with head trauma.Most of the data available on neuro-ophthalmic complications of head trauma including cortical blindness, Horner's syndrome, traumatic internuclear ophthalmoplegia, and ocular motor palsy, comes from case reports highlighting the need for future studies to better understand these complications.This review summarizes some of the most important neuro-ophthalmic complications of head trauma including cortical blindness, Horner's syndrome, traumatic internuclear ophthalmoplegia, and ocular motor palsy. Search of the peer-reviewed literature was conducted using MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Global Health, and MD Consult. PMID- 26107764 TI - Posterior Capsule Opacification After Phacoemulsification: Annual Review. AB - PURPOSE: The purpose of this article is to provide a clinical update on posterior capsule opacification (PCO) after phacoemulsification by reviewing the literature from the last 12 months. DESIGN: This article is a literature review. METHODS: The authors conducted a 1-year literature search in the English language on PCO using PubMed. The period used to conduct the literature search was from January 1, 2013, to January 1, 2014. The following search terms were used during the PubMed search: phacoemulsification, microcoaxial incision, posterior capsule opacification, long-term evaluation of intraocular lens (IOL) implantation, IOL edge design and material, surgical technique, anterior capsule overlap on the IOL optic, diabetes mellitus, myopia, pseudoexfoliation, retinitis pigmentosa, uveitis, and neodymium: yttrium-aluminum-garnet laser capsulotomy. RESULTS: This review incorporates original articles that provided fresh insights and updates on PCO. Particular attention was paid to observational, randomized, controlled clinical trials, as well as analyses of larger cohorts with a prospective and retrospective study design. Letters to the editor, unpublished works, experimental trials and abstracts were not considered. CONCLUSIONS: This annual review provides a brief update on PCO that might be of interest to the practicing clinical ophthalmologist. PMID- 26107765 TI - Update on Ophthalmic Oncology 2013: Retinoblastoma and Uveal Melanoma. AB - PURPOSE: The aim of this study was to discuss the clinical and translational content of the literature as well as advancement in our knowledge pertaining to retinoblastoma and uveal melanoma that were published from January to December 2013. DESIGN: This study is a literature review. METHODS: The search terms retinoblastoma and uveal melanoma were used in a MEDLINE literature search. Abstracts were studied, and the most relevant articles were selected for inclusion and further in-depth review. RESULTS: In retinoblastoma, fewer eyes are lost because of the expanded use of ophthalmic artery chemosurgery and intravitreal melphalan, and the past year marks a deepening in our understanding of these modalities. Knowledge on the genetic underpinnings of uveal melanoma has broadened to include genes associated with a favorable prognosis. This is accompanied by promising results in the treatment of metastatic uveal melanoma. CONCLUSIONS: This past year, there were important advancements in our knowledge of retinoblastoma and uveal melanoma. PMID- 26107766 TI - Virtual Screening of Natural and Synthetic Ligands Against Diabetic Retinopathy by Molecular Interaction With Angiopoietin-2. AB - PURPOSE: Diabetic retinopathy (DR) is the most common diabetic eye disease and a leading cause of blindness. The role of angiopoietin-2 a tyrosine kinase receptor is well-reported in angiogenesis during the onset of the disease. The purpose of this study is to screen out more potential herbal molecules which can evidently be used as a better, natural and safe herbal drug against this disease. DESIGN: In silico virtual screening and molecular interaction studies were performed. METHODS: The current course of work focused on molecular interactions on angiopoietin-2 protein with selected natural ligands, namely allicin, ajoene, D pinitol and salacinol, along with synthetic ones like nateglinide, biguanide, tolbutamide and tolazamide. There was an attempt to carry out the virtual comparative study between natural and synthetic ligands. Proceeding toward this approach, docking of all molecules was performed using the Autodock 4.2 program. RESULTS: Inference of this interaction study is that D-pinitol, which is the herbal extract of Glycine max, shows a very reliable docking pattern as compared with the synthetic ligand tolazamide. Although the binding energy of a synthetic ligand is lower compared to that of the natural ones, the binding energy of synthetic and natural ligands are at an approximate level. The lower the binding energy, the better the ligand molecular interaction. CONCLUSIONS: Our findings suggest that D-pinitol, the natural, safe ligand, can be used in the treatment of diabetic retinopathy with few or no side effects after estimating and calculating proper doses using in vitro approaches. PMID- 26107767 TI - Letter to the Editor Regarding Patients' Short-term Satisfaction With Cataract Surgery and Long-term Sustainability of Improved Visual-Related Quality of Life Over 3 Postoperative Years'. PMID- 26107768 TI - AUTHORS' REPLY to the Letter to the Editor Regarding "Patients' Short-term Satisfaction With Cataract Surgery and Long-term Sustainability of Improved Visual-Related Quality of Life Over 3 Postoperative Years". PMID- 26107769 TI - Preclinical Potency and Biodistribution Studies of an AAV 5 Vector Expressing Human Interferon-beta (ART-I02) for Local Treatment of Patients with Rheumatoid Arthritis. AB - INTRODUCTION: Proof of concept for local gene therapy for the treatment of arthritis with immunomodulatory cytokine interferon beta (IFN-beta) has shown promising results in animal models of rheumatoid arthritis (RA). For the treatment of RA patients, we engineered a recombinant adeno-associated serotype 5 vector (rAAV5) encoding human (h)IFN-beta under control of a nuclear factor kappaB promoter (ART-I02). METHODS: The potency of ART-I02 in vitro as well as biodistribution in vivo in arthritic animals was evaluated to characterize the vector prior to clinical application. ART-I02 expression and bioactivity after transduction was evaluated in fibroblast-like synoviocytes (FLS) from different species. Biodistribution of the vector after local injection was assessed in a rat adjuvant arthritis model through qPCR analysis of vector DNA. In vivo imaging was used to investigate transgene expression and kinetics in a mouse collagen induced arthritis model. RESULTS: Transduction of RA FLS in vitro with ART-I02 resulted in high expression levels of bioactive hIFN-beta. Transduction of FLS from rhesus monkeys, rodents and rabbits with ART-I02 showed high transgene expression, and hIFN-beta proved bioactive in FLS from rhesus monkeys. Transgene expression and bioactivity in RA FLS were unaltered in the presence of methotrexate. In vivo, vector biodistribution analysis in rats after intra articular injection of ART-I02 demonstrated that the majority of vector DNA remained in the joint (>93%). In vivo imaging in mice confirmed local expression of rAAV5 in the knee joint region and demonstrated rapid detectable and sustained expression up until 7 weeks. CONCLUSIONS: These data show that hIFN-beta produced by RA FLS transduced with ART-I02 is bioactive and that intra-articular delivery of rAAV5 drives expression of a therapeutic transgene in the joint, with only limited biodistribution of vector DNA to other tissues, supporting progress towards a phase 1 clinical trial for the local treatment of arthritis in patients with RA. PMID- 26107770 TI - Design and feasibility of "PREMATurity as predictor of children's Cardiovascular renal Health" (PREMATCH): A pilot study. AB - The microvasculature and macrovasculature undergo extensive, organ-specific perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular-renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8-13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark field imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will identify risk factors during childhood for subsequent cardiovascular-renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular-renal outcome may provide new information on perinatal risk factors. PMID- 26107773 TI - Struggling to be part of Swedish society: Strategies used by immigrants with late effects of polio. AB - OBJECTIVE: To explore and describe strategies in daily occupations among immigrants with late effects of polio. METHOD: The strategies were explored by interviews with 12 immigrants from Eastern Africa with late effects of polio. Sampling and data analysis was carried out according to grounded theory. RESULTS: The participants struggled for occupational participation and normality in an effort to participate in, and be part of, society. The study identified 14 strategies used by the immigrants in their daily occupations. The strategies can be presented in the following four categories: managing physical capacity; promoting occupational performance; strategies for gaining respect; and preparing the ground for one's existence. The participants struggled to find a balance between physical capacity and meaningful occupations, conception of their own and others' norms and values, and living conditions in Swedish society. The strategies were related to the participants' will to manage daily occupations, maintain social relationships, and be part of society. CONCLUSIONS: The strategies revealed that the participants strive to participate in occupations and society. This study reinforces the importance of occupation for immigrants with disability. The results highlight the need for adequate health care and rehabilitation but should also alert other social institutions. PMID- 26107772 TI - Changing Malaria Prevalence on the Kenyan Coast since 1974: Climate, Drugs and Vector Control. AB - BACKGROUND: Progress toward reducing the malaria burden in Africa has been measured, or modeled, using datasets with relatively short time-windows. These restricted temporal analyses may miss the wider context of longer-term cycles of malaria risk and hence may lead to incorrect inferences regarding the impact of intervention. METHODS: 1147 age-corrected Plasmodium falciparum parasite prevalence (PfPR2-10) surveys among rural communities along the Kenyan coast were assembled from 1974 to 2014. A Bayesian conditional autoregressive generalized linear mixed model was used to interpolate to 279 small areas for each of the 41 years since 1974. Best-fit polynomial splined curves of changing PfPR2-10 were compared to a sequence of plausible explanatory variables related to rainfall, drug resistance and insecticide-treated bed net (ITN) use. RESULTS: P. falciparum parasite prevalence initially rose from 1974 to 1987, dipped in 1991-92 but remained high until 1998. From 1998 onwards prevalence began to decline until 2011, then began to rise through to 2014. This major decline occurred before ITNs were widely distributed and variation in rainfall coincided with some, but not all, short-term transmission cycles. Emerging resistance to chloroquine and introduction of sulfadoxine/pyrimethamine provided plausible explanations for the rise and fall of malaria transmission along the Kenyan coast. CONCLUSIONS: Progress towards elimination might not be as predictable as we would like, where natural and extrinsic cycles of transmission confound evaluations of the effect of interventions. Deciding where a country lies on an elimination pathway requires careful empiric observation of the long-term epidemiology of malaria transmission. PMID- 26107774 TI - An efficient ratiometric fluorescent probe for tracking dynamic changes in lysosomal pH. AB - Lysosomes are acidic organelles (approximately pH 4.5-5.5) and tracking the changes in lysosomal pH is of great biological importance. To address this issue, quite a few of fluorescent probes have been developed. However, few of these probes can realize the tracking of dynamic changes in lysosomal pH. Herein, we report a new lysosome-targeted ratiometric fluorescent probe (FR-Lys) by hybridizing morpholine with a xanthane derivative and an o-hydroxy benzoxazole group. In this probe, the morpholine group serves as a targeting unit for lysosome, the xanthane derivative exhibits a pH-modulated open/close reaction of the spirocycle, while the o-hydroxy benzoxazole moiety shows a pH modulated excited-state intramolecular proton transfer (ESIPT) process. Such a design affords the probe a ratiometric fluorescence response towards pH with pH values ranging from 4.0 to 6.3. The response of the probe to pH was fast and reversible with high selectivity. Moreover, this probe possesses further advantages such as easy synthesis, high photostability and low cytotoxicity. These features are favorable for tracking dynamic pH changes in biosystems. It was then applied for dynamic imaging pH changes in lysosomes with satisfactory results. PMID- 26107771 TI - HIV Epidemic in Asia: Implications for HIV Vaccine and Other Prevention Trials. AB - An overall decrease of HIV prevalence is now observed in several key Asian countries due to effective prevention programs. The decrease in HIV prevalence and incidence may further improve with the scale-up of combination prevention interventions. The implementation of future prevention trials then faces important challenges. The opportunity to identify heterosexual populations at high risk such as female sex workers may rapidly wane. With unabating HIV epidemics among men who have sex with men (MSM) and transgender (TG) populations, an effective vaccine would likely be the only option to turn the epidemic. It is more likely that efficacy trials will occur among MSM and TG because their higher HIV incidence permits smaller and less costly trials. The constantly evolving patterns of HIV-1 diversity in the region suggest close monitoring of the molecular HIV epidemic in potential target populations for HIV vaccine efficacy trials. CRF01_AE remains predominant in southeast Asian countries and MSM populations in China. This relatively steady pattern is conducive to regional efficacy trials, and as efficacy warrants, to regional licensure. While vaccines inducing nonneutralizing antibodies have promise against HIV acquisition, vaccines designed to induce broadly neutralizing antibodies and cell-mediated immune responses of greater breadth and depth in the mucosal compartments should be considered for testing in MSM and TG. The rationale and design of efficacy trials of combination prevention modalities such as HIV vaccine and preexposure prophylaxis (PrEP) remain hypothetical, require high adherence to PrEP, are more costly, and present new regulatory challenges. The prioritization of prevention interventions should be driven by the HIV epidemic and decided by the country specific health and regulatory authorities. Modeling the impact and cost-benefit may help this decision process. PMID- 26107775 TI - Genome Calligrapher: A Web Tool for Refactoring Bacterial Genome Sequences for de Novo DNA Synthesis. AB - Recent advances in synthetic biology have resulted in an increasing demand for the de novo synthesis of large-scale DNA constructs. Any process improvement that enables fast and cost-effective streamlining of digitized genetic information into fabricable DNA sequences holds great promise to study, mine, and engineer genomes. Here, we present Genome Calligrapher, a computer-aided design web tool intended for whole genome refactoring of bacterial chromosomes for de novo DNA synthesis. By applying a neutral recoding algorithm, Genome Calligrapher optimizes GC content and removes obstructive DNA features known to interfere with the synthesis of double-stranded DNA and the higher order assembly into large DNA constructs. Subsequent bioinformatics analysis revealed that synthesis constraints are prevalent among bacterial genomes. However, a low level of codon replacement is sufficient for refactoring bacterial genomes into easy-to synthesize DNA sequences. To test the algorithm, 168 kb of synthetic DNA comprising approximately 20 percent of the synthetic essential genome of the cell cycle bacterium Caulobacter crescentus was streamlined and then ordered from a commercial supplier of low-cost de novo DNA synthesis. The successful assembly into eight 20 kb segments indicates that Genome Calligrapher algorithm can be efficiently used to refactor difficult-to-synthesize DNA. Genome Calligrapher is broadly applicable to recode biosynthetic pathways, DNA sequences, and whole bacterial genomes, thus offering new opportunities to use synthetic biology tools to explore the functionality of microbial diversity. The Genome Calligrapher web tool can be accessed at https://christenlab.ethz.ch/GenomeCalligrapher . PMID- 26107779 TI - Variation in the X-linked EFHC2 gene is associated with social cognitive abilities in males. AB - Females outperform males on many social cognitive tasks. X-linked genes may contribute to this sex difference. Males possess one X chromosome, while females possess two X chromosomes. Functional variations in X-linked genes are therefore likely to impact more on males than females. Previous studies of X-monosomic women with Turner syndrome suggest a genetic association with facial fear recognition abilities at Xp11.3, specifically at a single nucleotide polymorphism (SNP rs7055196) within the EFHC2 gene. Based on a strong hypothesis, we investigated an association between variation at SNP rs7055196 and facial fear recognition and theory of mind abilities in males. As predicted, males possessing the G allele had significantly poorer facial fear detection accuracy and theory of mind abilities than males possessing the A allele (with SNP variant accounting for up to 4.6% of variance). Variation in the X-linked EFHC2 gene at SNP rs7055196 is therefore associated with social cognitive abilities in males. PMID- 26107780 TI - Testosterone supplementation in men: a practical guide for the gynecologist and obstetrician. AB - PURPOSE OF REVIEW: Prescribing habits for the treatment of symptomatic hypogonadism have recently stirred controversy surrounding testosterone replacement therapy. As a result, the gynecologist will need to recognize this iatrogenic form of decreased sperm production in couples seeking fertility advice. We have compiled a review of the current literature on testosterone supplementation pertaining to the gynecologic practice. RECENT FINDINGS: Over the last decade, testosterone use has seen a recent increase including in men desiring to become fathers. Many physicians and hypogonadal men do not recognize that testosterone replacement therapy can have a detrimental effect on spermatogenesis. Fortunately, the cessation of treatment will yield predictable recovery of sperm production for most men. A growing body of evidence supports the use of selective estrogen receptor modulators, such as clomiphene citrate, or human chorionic gonadotropin for the treatment of hypogonadism in men who wish to maintain fertility potential. Recently, the Food and Drug Administration has recommended a labeling update on testosterone products to warn of possible increased risk of venous thromboembolism, cardiovascular events and stroke. SUMMARY: Clinicians should be familiar with current practices involving testosterone replacement therapy and the implications on male factor fertility. PMID- 26107782 TI - Latest developments and techniques in gynaecological oncology surgery. AB - PURPOSE OF REVIEW: To highlight the advances and the data published in the field of gynaecological oncology surgery in the last few years. The review includes not only newly introduced surgical techniques but also data that consolidate recent developments. RECENT FINDINGS: Ultimate data on the use of laparoscopy in the treatment of gynaecologic malignancies have proven similar survival outcomes to the traditional surgical route and confirmed the benefits in terms of faster recovery and lower morbidity. Thanks to a faster learning curve, the use of robotic surgery has contributed to the increase in the number of surgeons who moved away from open surgery. A few pioneers are expanding the indications of laparoscopy to exenterative surgery and treatment of ovarian cancer. SUMMARY: Laparoscopic surgery has become the gold standard treatment for patients with primary endometrial or cervical cancer. The advent of robotic surgery has reinforced the domain of endoscopic surgery. PMID- 26107783 TI - The role of three-dimensional high-definition laparoscopic surgery for gynaecology. AB - PURPOSE OF REVIEW: This article reviews the potential benefits and disadvantages of new three-dimensional (3D) high-definition laparoscopic surgery for gynaecology. RECENT FINDINGS: With the new-generation 3D high-definition laparoscopic vision systems (LVSs), operation time and learning period are reduced and procedural error margin is decreased. New-generation 3D high definition LVSs enable to reduce operation time both for novice and experienced surgeons. Headache, eye fatigue or nausea reported with first-generation systems are not different than two-dimensional (2D) LVSs. The system's being more expensive, having the obligation to wear glasses, big and heavy camera probe in some of the devices are accounted for negative aspects of the system that need to be improved. SUMMARY: Depth loss in tissues in 2D LVSs and associated adverse events can be eliminated with 3D high-definition LVSs. By virtue of faster learning curve, shorter operation time, reduced error margin and lack of side effects reported by surgeons with first-generation systems, 3D LVSs seem to be a strong competition to classical laparoscopic imaging systems. Thanks to technological advancements, using lighter and smaller cameras and monitors without glasses is in the near future. PMID- 26107781 TI - Endocrinology of uterine fibroids: steroid hormones, stem cells, and genetic contribution. AB - PURPOSE OF REVIEW: Uterine fibroids are extremely common, and can cause significant morbidity, yet the exact cause of these tumors remains elusive and there are currently no long-term treatments available. In this review, we aim to provide an overview of steroid hormones, genetic abnormalities, and stem cells in the pathogenesis of uterine fibroids. RECENT FINDINGS: A universal feature of fibroids is responsiveness to estrogen and progesterone, and most of the currently available therapies exploit this characteristic. Ulipristal acetate has recently shown particular promise for providing long-term relief from uterine fibroids. Additionally, fibroid stem cells were isolated and appear to be necessary for growth. The recent discovery of somatic mutations involving mediator subunit complex 12 (MED12) or high-mobility group AT-hook 2 (HMGA2) in the majority of fibroids and the links to their pathophysiology were also significant advances. SUMMARY: The recent shift in focus from hormones to fibroid stem cells and genetic aberrations should lead not only to a deeper understanding of the specific cause of fibroids, but also to the discovery of new therapeutic targets. Targeting the products of genetic mutations or fibroid stem cells has the potential to achieve both better control of current tumors and the prevention of new fibroids. PMID- 26107784 TI - Reproductive endocrinology and infertility fellowships: is the 'reproductive endocrinology' portion obsolete? AB - PURPOSE OF REVIEW: To take inventory of the past and present and project the future direction of our field to help train the next generation of providers. RECENT FINDINGS: Review the history of the subspecialty and factors contributing to its evolution. SUMMARY: Reproductive endocrinology and infertility's in-vitro fertilization future is shaping the intellectual priorities and surgical skill requirements of the next generation. PMID- 26107785 TI - The dangers of junk science in obstetrics and gynecology: lessons from the power morcellation controversy. PMID- 26107786 TI - Metabolic precursors in astrophysical ice analogs: implications for meteorites and comets. AB - We report the synthesis of complex organic compounds including nicotinic and quinolinic acid, two members involved in the nicotinamide adenine dinucleotide (NAD) biosynthetic pathway, in irradiated astrophysical ice analogs. If delivered to Earth by meteorites and comets, these compounds may have contributed to the origin and early evolution of life. PMID- 26107788 TI - An evidence-based review of commonly used dietary supplements. AB - Use of complementary and alternative medicine (CAM) is increasing in the United States. Physician assistants need to know about the efficacy of CAM therapies if they practice integrative medicine (which combines CAM and traditional therapies), recommend a CAM therapy occasionally as part of their treatment plan, refer patients to CAM providers, or have patients who self-select CAM therapies. This article describes integrative medicine and reviews the most commonly used dietary supplements. PMID- 26107789 TI - Haiti. PMID- 26107790 TI - A man with pruritic eruptions. PMID- 26107791 TI - What new therapeutic options exist for the relief of menopausal symptoms? AB - Two new products recently approved for the treatment of menopausal symptoms contain estrogen receptor agonists/antagonists, which have varying effects on bone, breast, endometrial, and vaginal tissues. Ospemifene improves symptoms of dyspareunia associated with vulvovaginal atrophy. Bazedoxifene combined with conjugated estrogens improves vasomotor symptoms and bone mineral density in postmenopausal women. Clinicians must consider the increased risk for venous and arterial thromboembolic disease posed by these drugs. Clinical trials are ongoing to fully evaluate the drugs' efficacy and safety compared with traditional estrogen-based regimens. PMID- 26107792 TI - A framework for physician assistant intervention for overweight and obesity. AB - Overweight and obesity compose a chronic disease process of epidemic proportions that presents on a continuum, likely affecting nearly two out of every three patients treated by physician assistants (PAs). However, meaningful and actionable definitions, including but not limited to anthropometric and clinical descriptors, are needed. The effective treatment of overweight and obesity requires an efficient and timely process of screening, diagnosis, evaluation of complications, staging, and clear algorithmic management. PAs are trained as primary care providers and can diagnose and treat overweight and obese patients regardless of practice setting and across the spectrum of the disease and patient's age. PMID- 26107793 TI - Managing nonteratogenic adverse reactions to isotretinoin treatment for acne vulgaris. AB - Isotretinoin is the strongest, most effective oral treatment for patients with severe acne vulgaris, with remission rates of 89% and higher. Because of its potency, isotretinoin causes many adverse reactions. This article reviews common and severe adverse reactions to isotretinoin and how providers can best manage these reactions. Because of inconclusive research on the correlation between isotretinoin and depression and irritable bowel syndrome, providers should ask patients about symptoms monthly. Prescribing micronized isotretinoin and starting at the lowest dose with gradual upward titration also can help reduce the incidence of adverse reactions. PMID- 26107794 TI - Alert fatigue in electronic health records. AB - Electronic health records (EHRs) are changing the practice of medicine. EHRs offer potential benefits but also potential problems and threats to patient safety, especially in the area of electronic prescribing. PMID- 26107795 TI - International medical graduates as physician assistants. AB - This study describes the MEDEX physician assistant (PA) program's experience with screening, educating, and graduating PA students who were international medical graduates (IMGs). METHODS: The study reviewed IMG-PA demographics including country of origin; prior primary care practice; and current practice location, specialty, and medically underserved designation. Descriptive statistics and chi square analysis or Fisher exact test summarize outcomes. RESULTS: Thirty-nine IMG PAs were graduated from 1991 through 2013. IMGs came from central and eastern Europe (48.7%), Asia (33.3%), and other regions. Most (69.2%) are women. Almost all (91.7%) practice in urban settings, 55.6% are in primary care, and 30.6% work in medically underserved areas. IMG-PAs in primary care were more likely to practice in underserved areas (P=0.009). CONCLUSION: MEDEX has graduated IMG-PAs who possess appropriate clinical and professional PA skills. PMID- 26107796 TI - Multiple myeloma. PMID- 26107797 TI - A case of dental pain. PMID- 26107798 TI - Understanding Middle East respiratory syndrome. AB - Middle East respiratory syndrome is an infection caused by a novel coronavirus. The primary source of the virus is infected camels in several countries in the Arabian peninsula. The infection is acquired by coming into contact with infected animals, animal products, or with patients who have the syndrome. Mortality for this syndrome is 30% to 40%, and treatment is supportive because no antiviral therapy exists. PMID- 26107799 TI - New medications for treatment of chronic hepatitis C. AB - Treating chronic hepatitis C is crucial to preventing long-term complications such as cirrhosis and liver cancer. New treatments may improve response rates, but the high cost of therapy is a major concern. This article reviews two of these new treatments, sofosbuvir and simeprevir. PMID- 26107801 TI - A puzzling case of arm paresthesias. PMID- 26107802 TI - Breathing space. PMID- 26107803 TI - Chemical Stability of Titania and Alumina Thin Films Formed by Atomic Layer Deposition. AB - Thin films formed by atomic layer deposition (ALD) are being examined for a variety of chemical protection and diffusion barrier applications, yet their stability in various fluid environments is not well characterized. The chemical stability of titania and alumina thin films in air, 18 MOmega water, 1 M KCl, 1 M HNO3, 1 M H2SO4, 1 M HCl, 1 M KOH, and mercury was studied. Films were deposited at 150 degrees C using trimethylaluminum-H2O and tetrakis(dimethylamido)titanium H2O chemistries for alumina and titania, respectively. A subset of samples were heated to 450 and 900 degrees C in inert atmosphere. Films were examined using spectroscopic ellipsometry, atomic force microscopy, optical microscopy, scanning electron microscopy, and X-ray diffraction. Notably, alumina samples were found to be unstable in pure water, acid, and basic environments in the as-synthesized state and after 450 degrees C thermal treatment. In pure water, a dissolution precipitation mechanism is hypothesized to cause surface roughening. The stability of alumina films was greatly enhanced after annealing at 900 degrees C in acidic and basic solutions. Titania films were found to be stable in acid after annealing at or above 450 degrees C. All films showed a composition independent increase in measured thickness when immersed in mercury. These results provide stability-processing relationships that are important for controlled etching and protective barrier layers. PMID- 26107804 TI - Selective sensing of pyrophosphate in physiological media using zinc(II)dipicolylamino-functionalised peptides. AB - A series of linear peptide based anion receptors, in which the distance between the bis[zinc(II)dipicolylamine] binding sites and the peptide backbone was varied systematically, was prepared and their anion binding ability was investigated using indicator displacement assays. Shortening the distance between the binding site and the peptide backbone was found to enhance both the receptor affinity and selectivity for pyrophosphate over other organic polyphosphate anions in Krebs buffer with the maximum selectivity and affinity observed with a spacer length of two methylene units. The suitability of these receptors for the determination of pyrophosphate concentrations in Krebs buffer and in artificial urine was examined. PMID- 26107805 TI - Daily life with depressive symptoms: Gender differences in adolescents' everyday emotional experiences. AB - Depression is a prevalent and debilitating illness facing many adolescents, especially adolescent girls, whose risk for this disorder is approximately twice that of boys. Many studies have identified mechanisms that place girls at higher risk for depression during adolescence. Few, however, have examined differences in the everyday emotional experiences of boys and girls with varying levels of depressive symptoms. Using the Experience Sampling Method, this study investigated the roles of gender and depressive symptomatology in the emotional experiences of a community sample of youth (11-18 year-olds) from the Sloan 500 Family Study. Females with higher levels of depressive symptoms were more likely than females with fewer depressive symptoms and all males to experience strong negative emotions and to attribute the cause of these emotions to other people. These results suggest that emotional reactivity in interpersonal contexts is especially important to understand gender differences in the daily experience of depressive symptoms. PMID- 26107806 TI - Dielectric Scattering Patterns for Efficient Light Trapping in Thin-Film Solar Cells. AB - We demonstrate an effective light trapping geometry for thin-film solar cells that is composed of dielectric light scattering nanocavities at the interface between the metal back contact and the semiconductor absorber layer. The geometry is based on resonant Mie scattering. It avoids the Ohmic losses found in metallic (plasmonic) nanopatterns, and the dielectric scatterers are well compatible with nearly all types of thin-film solar cells, including cells produced using high temperature processes. The external quantum efficiency of thin-film a-Si:H solar cells grown on top of a nanopatterned Al-doped ZnO, made using soft imprint lithography, is strongly enhanced in the 550-800 nm spectral band by the dielectric nanoscatterers. Numerical simulations are in good agreement with experimental data and show that resonant light scattering from both the AZO nanostructures and the embedded Si nanostructures are important. The results are generic and can be applied on nearly all thin-film solar cells. PMID- 26107807 TI - Hypoxic niche-mediated regeneration of hematopoiesis in the engraftment window is dominantly affected by oxygen tension in the milieu. AB - The bone marrow (BM) microenvironment or the hematopoietic stem cell (HSC) niche is normally hypoxic, which maintains HSC quiescence. Paradoxically, transplanted HSCs rapidly proliferate in this niche. Pretransplant myelosuppression results in a substantial rise in oxygen levels in the marrow microenvironment due to reduced cellularity and consequent low oxygen consumption. Therefore, it may be construed that the rapid proliferation of the engrafted HSCs in the BM niche is facilitated by the transiently elevated oxygen tension in this milieu during the "engraftment window." To determine whether oxygen tension dominantly affects the regeneration of hematopoiesis in the BM niche, we created an "oxygen-independent hypoxic niche" by treating BM-derived mesenchymal stromal cells (BMSCs) with a hypoxia mimetic compound, cobalt chloride (CoCl2) and cocultured them with BM-derived HSC enriched cells under normoxic conditions (HSCs; CoCl2-cocultures). Cocultures with untreated BMSCs incubated under normoxia (control- cocultures) or hypoxia (1% O2; hypoxic-cocultures) were used as comparators. Biochemical analyses showed that though, both CoCl2 and hypoxia evoked comparable signals in the BMSCs, the regeneration of hematopoiesis in their respective cocultures was radically different. The CoCl2-BMSCs supported robust hematopoiesis, while the hypoxic BMSCs exerted strong inhibition. The hematopoiesis-supportive ability of CoCl2 BMSCs was abrogated if the CoCl2-cocultures were incubated under hypoxia, demonstrating that the prevalent oxygen tension in the milieu dominantly affects the outcome of the HSC-BM niche interactions. Our data suggest that pharmacologically delaying the reestablishment of hypoxia in the BM may boost post-transplant regeneration of hematopoiesis. PMID- 26107809 TI - Live Cell Imaging of Butterfly Pupal and Larval Wings In Vivo. AB - Butterfly wing color patterns are determined during the late larval and early pupal stages. Characterization of wing epithelial cells at these stages is thus critical to understand how wing structures, including color patterns, are determined. Previously, we successfully recorded real-time in vivo images of developing butterfly wings over time at the tissue level. In this study, we employed similar in vivo fluorescent imaging techniques to visualize developing wing epithelial cells in the late larval and early pupal stages 1 hour post pupation. Both larval and pupal epithelial cells were rich in mitochondria and intracellular networks of endoplasmic reticulum, suggesting high metabolic activities, likely in preparation for cellular division, polyploidization, and differentiation. Larval epithelial cells in the wing imaginal disk were relatively large horizontally and tightly packed, whereas pupal epithelial cells were smaller and relatively loosely packed. Furthermore, larval cells were flat, whereas pupal cells were vertically elongated as deep as 130 MUm. In pupal cells, many endosome-like or autophagosome-like structures were present in the cellular periphery down to approximately 10 MUm in depth, and extensive epidermal feet or filopodia-like processes were observed a few micrometers deep from the cellular surface. Cells were clustered or bundled from approximately 50 MUm in depth to deeper levels. From 60 MUm to 80 MUm in depth, horizontal connections between these clusters were observed. The prospective eyespot and marginal focus areas were resistant to fluorescent dyes, likely because of their non-flat cone-like structures with a relatively thick cuticle. These in vivo images provide important information with which to understand processes of epithelial cell differentiation and color pattern determination in butterfly wings. PMID- 26107810 TI - Dissociable Behavioral, Physiological and Neural Effects of Acute Glucose and Fructose Ingestion: A Pilot Study. AB - Previous research has revealed that glucose and fructose ingestion differentially modulate release of satiation hormones. Recent studies have begun to elucidate brain-gut interactions with neuroimaging approaches such as magnetic resonance imaging (MRI), but the neural mechanism underlying different behavioral and physiological effects of glucose and fructose are unclear. In this paper, we have used resting state functional MRI to explore whether acute glucose and fructose ingestion also induced dissociable effects in the neural system. Using a cross over, double-blind, placebo-controlled design, we compared resting state functional connectivity (rsFC) strengths within the basal ganglia/limbic network in 12 healthy lean males. Each subject was administered fructose, glucose and placebo on three separate occasions. Subsequent correlation analysis was used to examine relations between rsFC findings and plasma concentrations of satiation hormones and subjective feelings of appetite. Glucose ingestion induced significantly greater elevations in plasma glucose, insulin, GLP-1 and GIP, while feelings of fullness increased and prospective food consumption decreased relative to fructose. Furthermore, glucose increased rsFC of the left caudatus and putamen, precuneus and lingual gyrus more than fructose, whereas within the basal ganglia/limbic network, fructose increased rsFC of the left amygdala, left hippocampus, right parahippocampus, orbitofrontal cortex and precentral gyrus more than glucose. Moreover, compared to fructose, the increased rsFC after glucose positively correlated with the glucose-induced increase in insulin. Our findings suggest that glucose and fructose induce dissociable effects on rsFC within the basal ganglia/limbic network, which are probably mediated by different insulin levels. A larger study would be recommended in order to confirm these findings. PMID- 26107811 TI - Biomedical Data Sharing and Reuse: Attitudes and Practices of Clinical and Scientific Research Staff. AB - BACKGROUND: Significant efforts are underway within the biomedical research community to encourage sharing and reuse of research data in order to enhance research reproducibility and enable scientific discovery. While some technological challenges do exist, many of the barriers to sharing and reuse are social in nature, arising from researchers' concerns about and attitudes toward sharing their data. In addition, clinical and basic science researchers face their own unique sets of challenges to sharing data within their communities. This study investigates these differences in experiences with and perceptions about sharing data, as well as barriers to sharing among clinical and basic science researchers. METHODS: Clinical and basic science researchers in the Intramural Research Program at the National Institutes of Health were surveyed about their attitudes toward and experiences with sharing and reusing research data. Of 190 respondents to the survey, the 135 respondents who identified themselves as clinical or basic science researchers were included in this analysis. Odds ratio and Fisher's exact tests were the primary methods to examine potential relationships between variables. Worst-case scenario sensitivity tests were conducted when necessary. RESULTS AND DISCUSSION: While most respondents considered data sharing and reuse important to their work, they generally rated their expertise as low. Sharing data directly with other researchers was common, but most respondents did not have experience with uploading data to a repository. A number of significant differences exist between the attitudes and practices of clinical and basic science researchers, including their motivations for sharing, their reasons for not sharing, and the amount of work required to prepare their data. CONCLUSIONS: Even within the scope of biomedical research, addressing the unique concerns of diverse research communities is important to encouraging researchers to share and reuse data. Efforts at promoting data sharing and reuse should be aimed at solving not only technological problems, but also addressing researchers' concerns about sharing their data. Given the varied practices of individual researchers and research communities, standardizing data practices like data citation and repository upload could make sharing and reuse easier. PMID- 26107812 TI - A novel poly(polyoxometalate) built by {Cu9}/{Cu5} clusters and {PW9}/{PW10}/{PW11} lacunary fragments. AB - The hydrothermal reactions of [A-alpha-PW9O34](9-) with CuCl2.2H2O in the presence of ethanediamine (en) and acetate afforded a novel poly(polyoxotungstate) containing different lacunary fragments: monolacunary {alpha-PW11O39}, dilacunary {alpha-PW10O37}, trilacunary {B-alpha-PW9O34}, etc. In addition, a cockhorse-like nona-copper {Cu9} slab is incorporated. Magnetic investigation indicates overall antiferromagnetic interactions in this compound. PMID- 26107813 TI - Cardiac surgery costs according to the preoperative risk in the Brazilian public health system. AB - BACKGROUND: Heart surgery has developed with increasing patient complexity. OBJECTIVE: To assess the use of resources and real costs stratified by risk factors of patients submitted to surgical cardiac procedures and to compare them with the values reimbursed by the Brazilian Unified Health System (SUS). METHOD: All cardiac surgery procedures performed between January and July 2013 in a tertiary referral center were analyzed. Demographic and clinical data allowed the calculation of the value reimbursed by the Brazilian SUS. Patients were stratified as low, intermediate and high-risk categories according to the EuroSCORE. Clinical outcomes, use of resources and costs (real costs versus SUS) were compared between established risk groups. RESULTS: Postoperative mortality rates of low, intermediate and high-risk EuroSCORE risk strata showed a significant linear positive correlation (EuroSCORE: 3.8%, 10%, and 25%; p < 0.0001), as well as occurrence of any postoperative complication EuroSCORE: 13.7%, 20.7%, and 30.8%, respectively; p = 0.006). Accordingly, length-of-stay increased from 20.9 days to 24.8 and 29.2 days (p < 0.001). The real cost was parallel to increased resource use according to EuroSCORE risk strata (R$ 27.116,00 +/- R$ 13.928,00 versus R$ 34.854,00 +/- R$ 27.814,00 versus R$ 43.234,00 +/- R$ 26.009,00, respectively; p < 0.001). SUS reimbursement also increased (R$ 14.306,00 +/- R$ 4.571,00 versus R$ 16.217,00 +/- R$ 7.298,00 versus R$ 19.548,00 +/- R$935,00; p < 0.001). However, as the EuroSCORE increased, there was significant difference (p < 0.0001) between the real cost increasing slope and the SUS reimbursement elevation per EuroSCORE risk strata. CONCLUSION: Higher EuroSCORE was related to higher postoperative mortality, complications, length of stay, and costs. Although SUS reimbursement increased according to risk, it was not proportional to real costs. PMID- 26107814 TI - Effects of one resistance exercise session on vascular smooth muscle of hypertensive rats. AB - BACKGROUND: Hypertension is a public health problem and increases the incidence of cardiovascular diseases. OBJECTIVE: To evaluate the effects of a resistance exercise session on the contractile and relaxing mechanisms of vascular smooth muscle in mesenteric arteries of NG-nitro L-arginine methyl ester (L-NAME) induced hypertensive rats. METHODS: Wistar rats were divided into three groups: control (C), hypertensive (H), and exercised hypertensive (EH). Hypertension was induced by administration of 20 mg/kg of L-NAME for 7 days prior to experimental protocols. The resistance exercise protocol consisted of 10 sets of 10 repetitions and intensity of 40% of one repetition maximum. The reactivity of vascular smooth muscle was evaluated by concentration-response curves to phenylephrine (PHEN), potassium chloride (KCl) and sodium nitroprusside (SNP). RESULTS: Rats treated with L-NAME showed an increase (p < 0.001) in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) compared to the initial period of induction. No difference in PHEN sensitivity was observed between groups H and EH. Acute resistance exercise reduced (p < 0.001) the contractile response induced by KCl at concentrations of 40 and 60 mM in group EH. Greater (p < 0.01) smooth muscle sensitivity to NPS was observed in group EH as compared to group H. CONCLUSION: One resistance exercise session reduces the contractile response induced by KCl in addition to increasing the sensitivity of smooth muscle to NO in mesenteric arteries of hypertensive rats. PMID- 26107815 TI - Reduced progression of cardiac allograft vasculopathy with routine use of induction therapy with basiliximab. AB - INTRODUCTION: Cardiac allograft vasculopathy (CAV) is a major limitation for long term survival of patients undergoing heart transplantation (HT). Some immunosuppressants can reduce the risk of CAV. OBJECTIVES: The primary objective was to evaluate the variation in the volumetric growth of the intimal layer measured by intracoronary ultrasound (IVUS) after 1 year in patients who received basiliximab compared with that in a control group. METHODS: Thirteen patients treated at a single center between 2007 and 2009 were analyzed retrospectively. Evaluations were performed with IVUS, measuring the volume of a coronary segment within the first 30 days and 1 year after HT. Vasculopathy was characterized by the volume of the intima of the vessel. RESULTS: Thirteen patients included (7 in the basiliximab group and 6 in the control group). On IVUS assessment, the control group was found to have greater vessel volume (120-185.43 mm3 vs. 127.77 131.32 mm3; p = 0.051). Intimal layer growth (i.e., CAV) was also higher in the control group (27.30-49.15 mm3 [?80%] vs. 20.23-26.69 mm3[?33%]; p = 0.015). Univariate regression analysis revealed that plaque volume and prior atherosclerosis of the donor were not related to intima growth (r = 0.15, p = 0.96), whereas positive remodeling was directly proportional to the volumetric growth of the intima (r = 0.85, p < 0.001). CONCLUSION: Routine induction therapy with basiliximab was associated with reduced growth of the intima of the vessel during the first year after HT. PMID- 26107816 TI - Autophagy-associated atrophy and metabolic remodeling of the mouse diaphragm after short-term intermittent hypoxia. AB - BACKGROUND: Short-term intermittent hypoxia (IH) is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm. METHODS: We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%), and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways), markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC) expression, and in vitro contractile properties. RESULTS: After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size) together with increased LC3B-II protein (2.4 fold) and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3), whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1) were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold) after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro. CONCLUSIONS: Short-term IH induces preferential atrophy in the mouse diaphragm together with increased autophagy and a rapid compensatory metabolic adaptation associated with enhanced fatigue resistance. PMID- 26107817 TI - Simultaneous inhibition of EGFR/VEGFR and cyclooxygenase-2 targets stemness related pathways in colorectal cancer cells. AB - Despite the demonstrated benefits of anti-EGFR/VEGF targeted therapies in metastatic colorectal cancer (mCRC), many patients initially respond, but then show evidence of disease progression. New therapeutic strategies are needed to make the action of available drugs more efficient. Our study aimed to explore whether simultaneous targeting of EGFR/VEGF and cyclooxygenase-2 (COX-2) may aid the treatment and management of mCRC patients. The dual tyrosine kinase inhibitor AEE788 and celecoxib were used to inhibit EGFR/VEGFR and COX-2, respectively, in colorectal cancer cells. COX-2 inhibition with celecoxib augmented the antitumoral and antiangiogenic efficacy of AEE788, as indicated by the inhibition of cell proliferation, induction of apoptosis and G1 cell cycle arrest, down regulation of VEGF production by cancer cells and reduction of cell migration. These effects were related with a blockade in the EGFR/VEGFR signaling axis. Notably, the combined AEE788/celecoxib treatment prevented beta-catenin nuclear accumulation in tumor cells. This effect was associated with a significant downregulation of FOXM1 protein levels and an impairment in the interaction of this transcription factor with beta-catenin, which is required for its nuclear localization. Furthermore, the combined treatment also reduced the expression of the stem cell markers Oct 3/4, Nanog, Sox-2 and Snail in cancer cells, and contributed to the diminution of the CSC subpopulation, as indicated by colonosphere formation assays. In conclusion, the combined treatment of AEE788 and celecoxib not only demonstrated enhanced anti-tumoral efficacy in colorectal cancer cells, but also reduced colon CSCs subpopulation by targeting stemness related pathways. Therefore, the simultaneous targeting of EGFR/VEGF and COX-2 may aid in blocking mCRC progression and improve the efficacy of existing therapies in colorectal cancer. PMID- 26107818 TI - Efficacy of Cognitive Behavioral Therapy on Opiate Use and Retention in Methadone Maintenance Treatment in China: A Randomised Trial. AB - AIMS: Methadone maintenance treatment (MMT) is widely available in China; but, high rates of illicit opiate use and dropout are problematic. The aim of this study was to test whether cognitive behavioral therapy (CBT) in conjunction with MMT can improve treatment retention and reduce opiate use. METHOD: A total of 240 opiate-dependent patients in community-based MMT clinics were randomly assigned to either weekly CBT plus standard MMT (CBT group, n=120) or standard MMT (control group, n=120) for 26 weeks. The primary outcomes were treatment retention and opiate-negative urine test results at 12 weeks and 26 weeks. The secondary outcomes were composite scores on the Addiction Severity Index (ASI) and total scores on the Perceived Stress Scale (PSS) at 12 weeks and 26 weeks. RESULTS: Compared to the control group in standard MMT, the CBT group had higher proportion of opiate-negative urine tests at both 12 weeks (59% vs. 69%, p<0.05) and 26 weeks (63% vs. 73%, p<0.05); however, the retention rates at 12 weeks (73.3% vs. 74.2%, p=0.88) and 26 weeks were not different (55.8% vs. 64.2%, p=0.19) between the two groups. At both 12 and 26 weeks, all of the ASI component scores and PSS total scores in the CBT group and control group decreased from baseline; but the CBT group exhibited more decreases in ASI employment scores at week 26 and more decrease in the PSS total score at week 12 and week 26. CONCLUSIONS: CBT counselling is effective in reducing opiate use and improving employment function and in decreasing stress level for opiate-dependent patients in MMT in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT01144390. PMID- 26107819 TI - Effect of Cadmium on Cellular Ultrastructure in Mouse Ovary. AB - This study aimed at analyzing the cytotoxicity and pathological effects of cadmium on the ovary. Our studies revealed that cadmium was deposited in the mouse ovary after 8 d cadmium injection in vivo. Also, the increase in the rate of body weight was slowed, while the gonadosomatic index was reduced in the CdCl2 group, compared with the control group. Meanwhile, cadmium affected the maturation of follicles, the degradation of corpus luteum, the arrangement of follicles and corpus luteum, and increased the number of atresia follicles. Besides, under the electron microscope, chromatin margination, karopyknosis, swelling of mature cisternae of Golgi apparatus, mitochondrial cristae disappearance, and swelling of the rough endoplasmic reticulum can be observed in the CdCl2 group mice. Collectively, our findings elucidated the morphological mechanism that the exposure of cadmium changed the ultrastructure of cells in ovary tissues. PMID- 26107820 TI - Safety and tolerability of antipsychotic-mood stabilizer co-treatment in the management of acute bipolar disorder: results from a systematic review and exploratory meta-analysis. AB - INTRODUCTION: Mood stabilizer (MS) plus antipsychotic (AP) co-treatment is common in patients with acute bipolar disorder (BD), but adverse effects (AEs) of this strategy have not been systematically reviewed. AREAS COVERED: We conducted a systematic review searching PubMed/MEDLINE and PsycINFO on April 1, 2015 for randomized trials in >= 20 adults with acute manic/mixed or depressed BD comparing MS or AP monotherapy with their combination that reported quantitative AE data. Pooled together, MS+AP versus MS monotherapy (studies = 18, n = 4419) was associated with significantly higher burden regarding 21/53 (39.6%) individual AEs, particularly weight gain-related (5/5 = 100%), extrapyramidal (5/12 = 41.7%) and glucose/lipid-related AEs (3/8 = 37.5%). AP+MS versus AP monotherapy (studies = 3, n = 397) was associated with significantly higher burden regarding 4/21 (19.0%) individual AEs (>= 1 AE, tremor, sedation/somnolence, vomiting). EXPERT OPINION: Efficacy advantages of AP+MS co treatment versus monotherapy should be balanced with its greater AE burden. AE risk is higher for adding AP to MS (17 additional AEs) than adding MS to an AP, including the particularly concerning cardiometabolic AEs. More data are needed, as only one or two studies provided data for 21/21 (100%) AEs of MS augmentation of AP, and 13/53 (24.5%) AEs of AP augmentation of MS, and as sparse data suggest clinically relevant AE differences across individual AP+MS combinations. PMID- 26107821 TI - The Government Finance Database: A Common Resource for Quantitative Research in Public Financial Analysis. AB - Quantitative public financial management research focused on local governments is limited by the absence of a common database for empirical analysis. While the U.S. Census Bureau distributes government finance data that some scholars have utilized, the arduous process of collecting, interpreting, and organizing the data has led its adoption to be prohibitive and inconsistent. In this article we offer a single, coherent resource that contains all of the government financial data from 1967-2012, uses easy to understand natural-language variable names, and will be extended when new data is available. PMID- 26107822 TI - Global Health. PMID- 26107824 TI - Cultural experiences of immigrant nurses at two hospitals in Chile. AB - OBJECTIVE: to explore the cultural experiences of nurses who immigrated to Chile. The study's theoretical framework was the Purnell Model for Cultural Competence. METHOD: Leininger's Observation-Participation-Reflection method was developed at two hospitals in the city of Santiago, and ethnographic interviews were held with 15 immigrant nurses. RESULTS: among Purnell's 12 domains, the following were identified: Overview/heritage, Communication, Workforce issues, Family roles and organization, Biocultural ecology and Health-care practices. The difficulties were related to the language and its semantic meaning, the new responsibilities and the difficult relationship with colleagues. "In search of better horizons - the decision to immigrate", "Gaining confidence and establishing a support network - employability and professional performance" and "Seeking for people's acceptance - professional adaptation in a new cultural scenario" are cultural themes that represent their experiences. CONCLUSIONS: the competence to offer cultural care demands the development of public policies and continuing education programs at health institutions, specifically focused on immigrant nurses. PMID- 26107823 TI - Global health competencies according to nursing faculty from Brazilian higher education institutions. AB - OBJECTIVES: to identify the agreement of faculty affiliated with Brazilian higher education institutions about the global health competencies needed for undergraduate nursing students' education and whether these competencies were covered in the curriculum offered at the institution where they were teaching. METHOD: exploratory-descriptive study, involving 222 faculty members who answered the Brazilian version of the "Questionnaire on Core Competencies in Global Health", made available electronically on the website Survey Monkey. RESULTS: participants predominantly held a Ph.D. (75.8%), were women (91.9%) and were between 40 and 59 years of age (69.3%). The mean and standard deviation of all competencies questioned ranged between 3.04 (0.61) and 3.88 (0.32), with scores for each competency ranging from 1 "strongly disagree" to 4 "strongly agree". The results demonstrated the respondents' satisfactory level of agreement with the global health competencies. CONCLUSIONS: the study demonstrated a high mean agreement level of the nursing faculty from Brazilian HEI with the global health competencies in the questionnaire. The curricula of the HEI where they teach partially address some of these. The competencies in the domain "Globalization of health and health care" are the least addressed. PMID- 26107825 TI - Translation and cultural adaptation for Brazil of the Developing Nurses' Thinking model. AB - OBJECTIVES: to translate and culturally adapt to Brazilian Portuguese the Developing Nurses' Thinking model, used as a strategy for teaching clinical reasoning. METHOD: the translation and cultural adaptation were undertaken through initial translation, synthesis of the translations, back-translation, evaluation by a committee of specialists and a pre-test with 33 undergraduate nursing students. RESULTS: the stages of initial translation, synthesis of the translations and back-translation were undertaken satisfactorily, small adjustments being needed. In the evaluation of the translated version by the committee of specialists, all the items obtained agreement over 80% in the first round of evaluation and in the pre-test with the students, so the model was shown to be fit for purpose. CONCLUSION: the use of the model as a complementary strategy in the teaching of diagnostic reasoning is recommended, with a view to the training of nurses who are more aware regarding the diagnostic task and the importance of patient safety. PMID- 26107826 TI - Professional Master's degree in Nursing: knowledge production and challenges. AB - OBJECTIVE: to analyze the production of knowledge resulting from the professional master's degree programs in Nursing and to reflect about their perspectives for the area. METHOD: descriptive and analytical study. Data collected from the dissertations of three educational institutions that graduated students in programs of professional master's degree in Nursing between 2006 and 2012 were included. RESULTS: most of the 127 course completion studies analyzed were developed within hospital contexts; there was a focus on the organizational and healthcare areas, in the research fields care process and management, and predominance of qualitative studies. There are various products resulting from the course completion studies: evaluation of services/healthcare programs and development of processes, care or educational protocols. CONCLUSION: the programs of professional master's degree in Nursing, which are undergoing a consolidation stage, have recent production under development and there is a gap in the creation of hard technologies and innovation. They are essential for the development of innovative professional practices that articulate the healthcare and educational areas. PMID- 26107827 TI - Predictive factors for renal failure and a control and treatment algorithm. AB - OBJECTIVES: to evaluate the renal function of patients in an intensive care unit, to identify the predisposing factors for the development of renal failure, and to develop an algorithm to help in the control of the disease. METHOD: exploratory, descriptive, prospective study with a quantitative approach. RESULTS: a total of 30 patients (75.0%) were diagnosed with kidney failure and the main factors associated with this disease were: advanced age, systemic arterial hypertension, diabetes mellitus, lung diseases, and antibiotic use. Of these, 23 patients (76.6%) showed a reduction in creatinine clearance in the first 24 hours of hospitalization. CONCLUSION: a decline in renal function was observed in a significant number of subjects, therefore, an algorithm was developed with the aim of helping in the control of renal failure in a practical and functional way. PMID- 26107828 TI - Assessment and risk classification protocol for patients in emergency units. AB - OBJECTIVE: to develop, validate the contents and verify the reliability of a risk classification protocol for an Emergency Unit. METHOD: the content validation was developed in a University Hospital in a country town located in the state of Sao Paulo and was carried out in two stages: the first with the individual assessment of specialists and the second with the meeting between the researchers and the specialists. The use of the protocol followed a specific guide. Concerning reliability, the concordance or equivalent method among observers was used. RESULTS: the protocol developed showed to have content validity and, after the suggested changes were made, there were excellent results concerning reliability. CONCLUSION: the assistance flow chart was shown to be easy to use, and facilitate the search for the complaint in each assistance priority. PMID- 26107829 TI - Experience of nurses in the process of donation of organs and tissues for transplant. AB - OBJECTIVE: to investigate the meaning of the action of nurses in the donation process to maintain the viability of organs and tissues for transplantation. METHOD: this qualitative study with a social phenomenological approach was conducted through individual interviews with ten nurses of three Organ and Tissue Procurement Services of the city of Sao Paulo. RESULTS: the experience of the nurses in the donation process was represented by the categories: obstacles experienced in the donation process, and interventions performed. The meaning of the action to maintain the viability of organs and tissues for transplantation was described by the categories: to change paradigms, to humanize the donation process, to expand the donation, and to save lives. FINAL CONSIDERATIONS: knowledge of the experience of the nurses in this process is important for healthcare professionals who work in different realities, indicating strategies to optimize the procurement of organs and tissues for transplantation. PMID- 26107830 TI - Reliability of indicators of nursing care quality: testing interexaminer agreement and reliability. AB - OBJECTIVE: this study sought to test the interexaminer agreement and reliability of 15 indicators of nursing care quality. METHODS: this was a quantitative, methodological, experimental, and applied study conducted at a large, tertiary, public teaching hospital in the state of Parana. For data analysis, the Kappa (k) statistic was applied to the categorical variables - indicators 1 to 11 and 15 - and the interclass correlation coefficient (ICC) to the continuous variables - indicators 12, 13, and 14, with the corresponding 95% confidence intervals. The categorical data were analyzed using the Lee software, elaborated by the Laboratory of Epidemiology and Statistics of Dante Pazzanese Institute of Cardiology - Brazil, and the continuous data were assessed using BioEstat 5.0. RESULTS: the k-statistic results indicated excellent agreement, which was statistically significant, and the values of the ICC denoted excellent and statistically significant reproducibility/agreement relative to the investigated indicators. CONCLUSION: the investigated indicators exhibited excellent reliability and reproducibility, thus showing that it is possible to formulate valid and reliable assessment instruments for the management of nursing care. PMID- 26107831 TI - Experiences of family members of patients with colostomies and expectations about professional intervention. AB - OBJECTIVE: the objective was to understand the experience of a group of family members of patients with colostomies, revealing their expectations regarding the intervention of health professionals. METHOD: qualitative research, with the social phenomenological approach of Alfred Schutz, conducted in Montevideo in 2012; twelve family members of patients with colostomies participated, from an ostomy service of a health institution. RESULTS: the following categories were identified: family ties, trust in the health care team, the nurse as the articulator of the process, the desire to humanize care, and adaptation to new family life. CONCLUSIONS: knowing the experience and expectations of the families of colostomy patients was achieved, emphasizing the previous family relationships to build upon them, and the trust in the health team, emphasizing the nurse as articulator of the process. Expectations focused on the desire for humanized care, enhancing adaptation of the nuclear family to the new way of life, restoring and enhancing its strengths, and collaborating in overcoming its weaknesses. PMID- 26107832 TI - Hope and spirituality among patients with chronic kidney disease undergoing hemodialysis: a correlational study. AB - OBJECTIVE: to analyze the relationship between the hope and spirituality of patients with chronic kidney disease undergoing hemodialysis. METHOD: this is a cross-sectional, correlational study. The sample was composed of 127 patients of a Renal Replacement Unit. Data were collected through individual interviews guided by the following instruments: participant characterization, Herth Hope Index (HHI), and Pinto Pais-Ribeiro Spirituality Scale (PP-RSS). RESULTS: the average HHI score was 38.06 (+/-4.32) while the average PP-RSS score was 3.67 (+/ 0.62) for "beliefs" and 3.21 (+/-0.53) for "hope/optimism". Spearman's coefficient indicated there was a moderate positive correlation between the HHI and PP-RSS dimensions of "beliefs" (r=0.430; p<0.001) and "hope/optimism" (r=0.376; p<0.001). CONCLUSION: Since a relationship between the sense of hope and spirituality of patients with chronic kidney disease was found, these constructs should be taken into account at the time health professionals deliver care to help patients coping with the disease and treatment. PMID- 26107833 TI - Nursing diagnoses of newborns with sepsis in a Neonatal Intensive Care Unit. AB - OBJECTIVES: to elaborate the Nursing Diagnoses of newborns with sepsis in a neonatal intensive care unit and characterize the profile of the neonates and their mothers. METHOD: a cross-sectional and quantitative study, with a sample of 41 neonates. A physical examination and consultation of the hospital records were undertaken, using an instrument. The elaboration of the Nursing Diagnoses followed a process of diagnostic inference and was based on the North American Nursing Diagnosis Association 2012-2014. RESULTS: the mothers were around 25 years old, had a low average number of pre-natal consultations, and various complications during the pregnancy; and the newborns were predominantly premature and with very low birth weights. Five Nursing Diagnoses predominated, and all the neonates presented Risk of Shock and Risk of fluid volume imbalance. CONCLUSION: the Nursing Diagnoses of the neonates with sepsis can guide the formulating of specific assistential plans. The study contributes to the generation of new knowledge and found various relationships between the Nursing Diagnoses and the variables selected in the characterization of the neonates, which deserve to be elucidated in greater detail based on further research on the issue. PMID- 26107834 TI - Nursing Diagnosis Risk for falls: prevalence and clinical profile of hospitalized patients. AB - OBJECTIVES: to identify the prevalence of the Nursing Diagnosis (ND) Risk for falls in the hospitalizations of adult patients in clinical and surgical units, to characterize the clinical profile and to identify the risk factors of the patients with this ND. METHOD: a cross-sectional study with 174 patients. The data was collected from the computerized nursing care prescriptions system and on line hospital records, and analyzed statistically. RESULTS: the prevalence of the ND Risk for falls was 4%. The patients' profile indicated older adults, males (57%), those hospitalized in the clinical units (63.2%), with a median length of hospitalization of 20 (10-24) days, with neurological illnesses (26%), cardio vascular illnesses (74.1%) and various co-morbidities (3+/-1.8). The prevalent risk factors were neurological alterations (43.1%), impaired mobility (35.6%) and extremes of age (10.3%). CONCLUSION: the findings contributed to evidencing the profile of the patients with a risk of falling hospitalized in clinical and surgical wards, which favors the planning of interventions for preventing this adverse event. PMID- 26107835 TI - Weaving meanings from the deliberative process of collegiate management in nursing. AB - OBJECTIVE: to understand the meanings of the collegiate deliberations attributed by its members on an undergraduate nursing course. METHOD: Grounded Theory, interviews being held with 30 participants, making up 4 sample groups, between January and June 2012, in a public higher education institution. RESULT: 5 categories emerged, indicating the phenomenon and weaving the paradigmatic model: Understanding the experience of the complex relationships and interactions in the deliberations of collegiate management in nursing: intertwining divergences, convergences, dialogs, collectivities and diversities. This deliberative process presents various meanings involving discussion, and divergent, convergent and complementary positions, through dialog, commitment and negotiation. CONCLUSION: the deliberations in the collegiate of nursing, intertwining dialogs, collectivities and diversities, mold the complex relational fabrics. PMID- 26107836 TI - Assessment of techniques of massage and pumping in the treatment of breast engorgement by thermography. AB - OBJECTIVE: to evaluate techniques of massage and pumping in the treatment of postpartum breast engorgement through thermography. METHOD: the study was conducted in the Human Milk Bank of a hospital in Curitiba, Brazil. We randomly selected 16 lactating women with engorgement with the classification lobar, ampullary and glandular, moderate and intense. We compared the differential patterns of temperature, before and after the treatment by means of massage and pumping. RESULTS: we found a negative gradient of 0.3 degrees C of temperature between the pre- and post-treatment in the experimental group. Breasts with intense engorgement were 0.7 degrees C warmer when compared with moderate engorgement. CONCLUSION: massage and electromechanical pumping were superior to manual methods when evaluated by thermography. REBEC: U1111-1136-9027. PMID- 26107837 TI - Maternal Eating and Physical Activity Strategies and their Relation with Children's Nutritional Status. AB - OBJECTIVES: to describe the maternal eating and physical activity strategies (monitoring, discipline, control, limits and reinforcement) [MEES]; to determine the relation between MEES and the child's nutritional status [body mass index (BMI) and body fat percentage (BFP)]; to verify whether the MEES differ according to the child's nutritional status. METHOD: participants were 558 mothers and children (3 to 11 years of age) who studied at public schools. The Parental Strategies for Eating and Activity Scale (PEAS) was applied and the child's weight, height and BFP were measured. For analysis purposes, descriptive statistics were obtained, using multiple linear regression and the Kruskal-Wallis test. RESULTS: the highest mean score was found for reinforcement (62.72) and the lowest for control (50.07). Discipline, control and limits explained 12% of the BMI, while discipline and control explained 6% of the BFP. Greater control is found for obese children (chi2=38.36, p=0.001) and greater reinforcement for underweight children (chi2=7.19, p<0.05). CONCLUSIONS: the mothers exert greater control (pressure to eat) over obese children and greater recognition (congratulating due to healthy eating) in underweight children. Modifications in parental strategies are recommended with a view to strengthening healthy eating and physical activity habits. PMID- 26107838 TI - Post-abortion contraception: care and practices. AB - OBJECTIVE: to analyze assistance regarding contraception methods received by women during hospitalization due to abortion, and contraceptive practices the month after this episode. METHODS: a longitudinal study of women hospitalized due to abortion in a public hospital in the city of Sao Paulo. Face-to-face interviews (n=170) followed by telephone interviews in the subsequent month (n=147) were conducted between May and December of 2011. RESULTS: a small number of women reported they received guidance on, and prescription for, contraceptive methods at hospital discharge. A trend of statistical significance was identified for prescription of contraceptive methods at discharge and its use in the following month, when adjusted for age. Most women reported sexual intercourse (69.4%) with the use of contraceptive method (82.4%), but no health professional guidance (63.1%). CONCLUSION: despite the fact that post-abortion contraception assistance was lower than the recommended guidelines by public health policies, women demonstrated willingness to use contraceptive methods. PMID- 26107840 TI - Participation of adolescents in the Family Health Strategy from the theoretical methodological structure of an enabler to participation. AB - OBJECTIVE: to evaluate the participation of adolescents in the Family Health Strategy, from the theoretical-methodological structure of an enabler to participation. METHOD: a quantitative study, conducted from December of 2010 to March of 2011, with 213 professionals in the FHS in the region of Cariri-Ceara Brazil. Data were collected through a questionnaire and organized in SPSS 18.0. RESULTS: the level of normative participation becomes manifest beginning with the adolescent search for health services, motivated by disease (77.9%). Normative participation + independence appear when they seek prenatal care and family planning. Emancipatory participation was identified by the frequency of adolescents in group activities, in the schools, and a move in the direction of the level of transformative participation was observed. CONCLUSION: in this context, it is understood that there exists a need to stimulate the participatory process of the adolescents for a change in health promotion in this group. PMID- 26107839 TI - Neutropenia: occurrence and management in women with breast cancer receiving chemotherapy. AB - OBJECTIVES: to identify the prevalence, and describe the management of, neutropenia throughout the chemotherapy treatment among women with breast cancer. METHODS: observational study, cycles of chemotherapy. 116 neutropenic events were recorded, and 63.3% of the patients presented neutropenia at some point of their treatment, 46.5% of these presenting grade II. The management used was temporary suspension between the cycles and the mean number of delays was 6 days. The study was prospective and longitudinal, where the evaluation of the hematological toxicities was undertaken at each cycle of chemotherapy, whether neoadjuvant or adjuvant. RESULTS: 79 women were included, who received 572 cycles. However, the reasons for the suspensions were the lack of a space in the chemotherapy center, followed by neutropenia. CONCLUSION: neutropenia is one of the most common and serious adverse events observed during the chemotherapy. Nursing must invest in research regarding this adverse event and in management strategies for organizing the public health system, so as to offer quality care. PMID- 26107841 TI - Evaluation of dysphagia risk, nutritional status and caloric intake in elderly patients with Alzheimer's. AB - OBJECTIVE: to evaluate the risk of dysphagia and its relationship with the stage of Alzheimer's Disease, as well as the relationship between the risk of dysphagia and nutritional status and caloric intake in elderly people with Alzheimer's disease. METHODS: the sample consisted of 30 subjects of both genders with probable Alzheimer's disease. The stage of the disease, nutritional status, energy intake, and risk of dysphagia were assessed. RESULTS: it was found that increased risk of dysphagia is associated with the advance in the stages of Alzheimer's disease and that even patients in the early stages of disease have a slight risk of developing dysphagia. No association was found between nutritional status and the risk of dysphagia. High levels of inadequate intake of micronutrients were also verified in the patients. CONCLUSION: an association between dysphagia and the development of Alzheimer's disease was found. The results indicate the need to monitor the presence of dysphagia and the micronutrient intake in patients with Alzheimer's disease. PMID- 26107842 TI - Nursing Activities Score: nursing work load in a burns Intensive Care Unit. AB - OBJECTIVE: to evaluate the nursing work load in a Burns Intensive Care Unit according to the Nursing Activities Score. METHOD: an exploratory, descriptive cross-sectional study with a quantitative approach. The Nursing Activities Score was used for data collection between October 2011 and May 2012, totalling 1,221 measurements, obtained from 50 patients' hospital records. Data for qualitative variables was described in tables; for the quantitative variables, calculations using statistical measurements were used. RESULTS: the mean score for the Nursing Activities Score was 70.4% and the median was 70.3%, corresponding to the percentage of the time spent on direct care to the patient in 24 hours. CONCLUSION: the Nursing Activities Score provided information which involves the process of caring for patients hospitalized in a Burns Intensive Care Unit, and indicated that there is a high work load for the nursing team of the sector studied. PMID- 26107843 TI - Impact of a physical activity program on the anxiety, depression, occupational stress and burnout syndrome of nursing professionals. AB - OBJECTIVE: to assess the effects of a workplace physical activity (WPA) program on levels of anxiety, depression, burnout, occupational stress and self perception of health and work-related quality of life of a nursing team in a palliative care unit. METHODS: the WPA was conducted five days per week, lasting ten minutes, during three consecutive months. Twenty-one nursing professionals were evaluated before and after the intervention, with the Hospital Anxiety and Depression Scale, the Maslch Burnout Inventory, and the Job Stress Scale. The changes in self-perceived health and work-related quality of life were measured using a semi-structured questionnaire. RESULTS: the WPA did not yield significant results on the levels of anxiety, depression, burnout or occupational stress. However, after the intervention, participants reported improved perceptions of bodily pain and feeling of fatigue at work. CONCLUSION: the WPA did not lead to beneficial effects on occupational stress and psychological variables, but it was well accepted by the nursing professionals, who reported improvement in perceptions of health and work-related quality of life. PMID- 26107845 TI - Erratum. PMID- 26107844 TI - Telephone follow-up of patients after radical prostatectomy: a systematic review. AB - OBJECTIVE: to assess and summarize the best scientific evidence from randomized controlled clinical trials about telephone follow-up of patients after radical prostatectomy, based on information about how the phone calls are made and the clinical and psychological effects for the individuals who received this intervention. METHOD: the search was undertaken in the electronic databases Medline, Web of Science, Embase, Cinahl, Lilacs and Cochrane. Among the 368 references found, five were selected. RESULTS: two studies tested interventions focused on psychological support and three tested interventions focused on the physical effects of treatment. The psychoeducative intervention to manage the uncertainty about the disease and the treatment revealed statistically significant evidences and reduced the level of uncertainty and anguish it causes. CONCLUSION: the beneficial effects of telephone follow-up could be determined, as a useful tool for the monitoring of post-prostatectomy patients. PMID- 26107847 TI - Spatial and Temporal Variation in Reproduction of a Generalist Crocodilian, Caiman crocodilus yacare, in a Seasonally Flooded Wetland. AB - We monitored the number of caiman (Caiman crocodilus yacare) nests in two ranches in the Brazilian Pantanal that cover an area of about 50.000 ha for 28 years (1987-2014). The number of nests was related to combinations of rainfall, water level, and number of days with temperature below 20 degrees C, depending on the area. Most of the variation in number of nests could not be predicted by the environmental variables, but could be represented mathematically by a sine wave. We were not able to identify any external driver and suspect that the regular fluctuations may have resulted from an intrinsic population process. Presently, ranches are used as management units under the legislation for ranching Pantanal caimans. However, although some breeding females were recaptured in the area after periods of up to 21 years, most were not recaptured near nests or in general surveys of the area, suggesting that females are not strongly philopatric and that ranches do not represent isolated demographic units. PMID- 26107846 TI - Pharmacological Cognitive Enhancement in Healthy Individuals: A Compensation for Cognitive Deficits or a Question of Personality? AB - The ongoing bioethical debate on pharmacological cognitive enhancement (PCE) in healthy individuals is often legitimated by the assumption that PCE will widely spread and become desirable for the general public in the near future. This assumption was questioned as PCE is not equally save and effective in everyone. Additionally, it was supposed that the willingness to use PCE is strongly personality-dependent likely preventing a broad PCE epidemic. Thus, we investigated whether the cognitive performance and personality of healthy individuals with regular nonmedical methylphenidate (MPH) use for PCE differ from stimulant-naive controls. Twenty-five healthy individuals using MPH for PCE were compared with 39 age-, sex-, and education-matched healthy controls regarding cognitive performance and personality assessed by a comprehensive neuropsychological test battery including social cognition, prosocial behavior, decision-making, impulsivity, and personality questionnaires. Substance use was assessed through self-report in an interview and quantitative hair and urine analyses. Recently abstinent PCE users showed no cognitive impairment but superior strategic thinking and decision-making. Furthermore, PCE users displayed higher levels of trait impulsivity, novelty seeking, and Machiavellianism combined with lower levels of social reward dependence and cognitive empathy. Finally, PCE users reported a smaller social network and exhibited less prosocial behavior in social interaction tasks. In conclusion, the assumption that PCE use will soon become epidemic is not supported by the present findings as PCE users showed a highly specific personality profile that shares a number of features with illegal stimulant users. Lastly, regular MPH use for PCE is not necessarily associated with cognitive deficits. PMID- 26107848 TI - Fracture risk and adjuvant therapies in young breast cancer patients: a population-based study. AB - BACKGROUND: Breast cancer survivors have an increased risk of bone fracture. But the risk among young patients with adjuvant therapies remains unknown. This population-based study is aimed to assess the incidence and risk of fracture among young (age of 20 to 39 years) breast cancer patients who received adjuvant therapies. METHODS: From January 2001 to December 2007, 5,146 newly diagnosed breast cancer patients were enrolled from the National Health Insurance Research Database (NHIRD) in Taiwan. Patients were observed for a maximum of 6 years to determine the incidence of newly onset fracture. Kaplan Meier and Cox regression analyses were used to evaluate the risk of fracture in young breast cancer patients who received adjuvant treatments. RESULTS: Of the total 5,146 young (age of 20 to 39 years) breast cancer patients, the Cox multivariate proportional hazards analysis showed that AIs, radiotherapy, and monoclonal antibodies were significantly associated with a high risk of fracture. Moreover, patients who received AIs for more than 180 days had a high hazard ratio (HR) of 1.77 (95% CI = 0.68-4.57), and patients who received more than four radiotherapy visits had a high HR of 2.54 (95% CI = 1.07-6.06). Under the site-specific analysis, young breast cancer patients who received AIs had the highest risk of hip fracture (HR = 8.520, 95% CI = 1.711-42.432, p < 0.04), whereas patients who received radiotherapy had the highest risk of vertebral fracture (HR = 5.512, 95% CI = 1.847-16.451, p < 0.01). CONCLUSION: Young breast cancer patients who are receiving AIs, radiotherapy or monoclonal antibody need to be more careful for preventing fracture events. Breast cancer treatment plans are suggested to incorporate fracture prevention interventions. PMID- 26107849 TI - Entropy at the right atrium as a predictor of atrial fibrillation recurrence outcome after pulmonary vein ablation. AB - Atrial fibrillation (AF) recurrence rates after successful ablation procedures are still high and difficult to predict. This work studies the capability of entropy measured from intracardiac recordings as an indicator for recurrence outcome. Intra-atrial recordings from 31 AF patients were registered previously to an ablation procedure. Four electrodes were located at the right atrium (RA) and four more at the left atrium (LA). Sample entropy measurements were applied to these signals, in order to characterize different non-linear AF dynamics at the RA and LA independently. In a 3 months follow-up, 19 of them remained in sinus rhythm, whereas the other 12 turned back to AF. Entropy values can be associated to a proarrhythmic indicator as they were higher in patients with AF recurrence (1.11+/-0.15 vs. 0.91+/-0.13), in persistent patients (1.03+/-0.19 vs. 0.96+/-0.15), and at the LA with respect to the RA (1.03+/-0.23 vs. 0.89+/-0.15 for paroxysmal AF patients). Furthermore, entropy values at the RA arose as a more reliable predictor for recurrence outcome than at the LA. Results suggest that high entropy values, especially at the RA, are associated with high risk of AF recurrence. These findings show the potential of the proposed method to predict recurrences post-ablation, providing additional insights to the understanding of arrhythmia. PMID- 26107850 TI - Subgroup-specific intrinsic disorder profiles of Arabidopsis NAC transcription factors: Identification of functional hotspots. AB - Protein intrinsic disorder (ID), referring to the lack of a fixed tertiary structure, is significant in signaling and transcription. We recently characterized ID in 6 phylogenetically representative Arabidopsis thaliana NAC transcription factors. Their transcription regulatory domains are mostly disordered but contain short, functionally important regions with structure propensities known as molecular recognition features. Here, we analyze for NAC subgroup-specific ID patterns. Some subgroups, such as the VND subgroup implicated in secondary cell wall biosynthesis, and the NAP/SHYG subgroup have highly conserved ID profiles. For the stress-associated ATAF1 subgroup and the CUC/ORE1 subgroup involved in development, only sub clades have similar ID patterns. For similar ID profiles, conserved molecular recognition features and sequence motifs represent likely functional determinants of e.g. transcriptional activation and interactions. Based on our analysis, we suggest that ID profiling of regulatory proteins in general can be used to guide identification of interaction partners of network proteins. PMID- 26107851 TI - Responsiveness to Self-Report Interview Questions by Adults With Intellectual and Developmental Disability. AB - An important line of research involves asking people with intellectual and developmental disability (IDD) to self-report their experiences and opinions. We analyzed the responsiveness of 11,391 adult users of IDD services to interview questions from Section 1 of the 2008-2009 National Core Indicators-Adult Consumer Survey (NCI-ACS). Proxy responses were not allowed for the selected questions. Overall, 62.1% of participants answered the questions and were rated by interviewers as understanding the questions and as responding consistently. Most participants responded in an all-or-none fashion, answering either all or most questions or few to none. Individuals with milder levels of IDD and with speech as their primary means of expression were more likely to answer the questions and provide a scoreable response. Interviewer ratings of interviewees' answering questions, understanding of questions, and consistent responding were each related to responsiveness. PMID- 26107852 TI - Competency-Based Training and Worker Turnover in Community Supports for People With IDD: Results From a Group Randomized Controlled Study. AB - Turnover among direct support professionals (DSPs) in community support settings for individuals with intellectual and developmental disabilities (IDD) has been regarded as a challenge since tracking of this workforce began in the 1980s. This study utilized a group randomized controlled design to test the effects of a competency-based training intervention for DSPs on site-level turnover rates over a one year period. Results suggested that, compared with the control group, sites receiving the training intervention experienced a significant decrease in annual turnover, when multiple factors were controlled. Implications, including the importance of considering quality training as a long term organizational investment and intervention to reduce turnover, are discussed. PMID- 26107853 TI - Teaching Sight Words to Elementary Students With Intellectual Disability and Autism: A Comparison of Teacher-Directed Versus Computer-Assisted Simultaneous Prompting. AB - The purpose of this study was to compare the effects of teacher-directed simultaneous prompting to computer-assisted simultaneous prompting for teaching sight words to 3 elementary school students with intellectual disability. Activities in the computer-assisted condition were designed with Intellitools Classroom Suite software whereas traditional materials (i.e., flashcards) were used in the teacher-directed condition. Treatment conditions were compared using an adapted alternating treatments design. Acquisition of sight words occurred in both conditions for all 3 participants; however, each participant either clearly responded better in the teacher-directed condition or reported a preference for the teacher-directed condition when performance was similar with computer assisted instruction being more efficient. Practical implications and directions for future research are discussed. PMID- 26107854 TI - Elite Repudiation of the R-Word and Public Opinion About Intellectual Disability. AB - Part of the motivation for encouraging elite stakeholders-like governments, professionals, and advocacy groups-to replace the language of "mental retardation" with "intellectual disability" (ID) is the belief that elite endorsement could undermine negative attitudes and influence the public to follow suit. We examine the veracity of this expectation empirically with an experiment that exposed individuals to information about endorsements of the terminology change made by the federal government, Special Olympics, or professional psychologists. We subsequently measured attitudes about persons with ID and the language used to describe ID. Results indicate that exposure to information about elite endorsement of the terminological shift either exacerbated negative attitudes or had no effect, suggesting that other factors may have primacy over "expert" opinion. PMID- 26107855 TI - Prevalence and Characteristics of Falls in Adults with Intellectual Disability Living in a Residential Facility: A Longitudinal Study [PreFallID]. AB - The objective of our study was to describe the prevalence and characteristics of falls in adults with intellectual disability living in a residential care setting and to define differences between fallers and non-fallers in younger and older resident groups. In contrast to the general population, falls are a problem for both aged and younger adults with intellectual disability living in a residential care setting. Falls of 147 residents, aged between 21-89 years with different grades of ID, were recorded prospectively over a 12 months period using a digital fall report form. For all participants, a total of 140 falls were reported and high fall rates per person-year were found in the younger (0.85) as well as in the older aged residents (1.06). PMID- 26107856 TI - Standards to Guide the Use of Clinical Judgment in the Field of Intellectual Disability. AB - The purpose of this article is to discuss 10 Clinical Judgment Standards and associated best practice indicators based on current literature and an understanding of the context of clinical judgment. Throughout the article, we stress the important role that clinical judgment plays in formulating valid and precise decisions and recommendations regarding diagnosis, classification, and planning supports. PMID- 26107859 TI - Is There One Less Hurdle for Patients Undergoing Macular Hole Surgery? PMID- 26107860 TI - Ten Chairpersons of the Ophthalmology Department at Peking Union Medical College. AB - With the full academic and financial support of the China Medical Board of the Rockefeller Foundation, Peking Union Medical College (PUMC) was officially inaugurated in 1921. Since then, PUMC has been one of the most prestigious medical schools in China and the only one that is connected to the Chinese Academy of Medical Science. From its founding, there have been 10 chairpersons at the PUMC Department of Ophthalmology. The first 4 chairpersons, Howard, Pillat, Von Sallmann, and Kronfeld, were trained in Vienna and established the program's Western system. The latter 6 chairpersons, Luo, Hu, Zhang, Li, Zhao, and Dong, who were educated mainly in China, have maintained the program's excellence and made significant contributions to ophthalmology and medicine in China and the world. Under the strong leadership still in place today, PUMC will continue to provide generations of leaders for academic modern medicine and health care in China. Accordingly, the Department of Ophthalmology, one of the oldest ophthalmology departments in China, will continue making significant contributions to the global realm of eye and vision research and health care. PMID- 26107861 TI - Combined Topical-Intracameral Anesthesia in Manual Small-Incision Cataract Surgery: A Prospective, Randomized, Double-Masked, Placebo-Controlled Trial. AB - PURPOSE: To determine whether intracameral lidocaine plus topical anesthesia could further reduce patients' pain experience during manual small-incision cataract surgery, compared with topical anesthesia alone. DESIGN: A prospective, randomized, double-masked, placebo-controlled clinical trial was conducted. METHODS: This research was approved by the institutional review board of the Eye Hospital of Wenzhou Medical College in China. All patients gave written, informed consent, and no untoward pressure or coercion was used for the written informed consent. A total of 300 patients were randomly assigned into the placebo group (topical anesthesia plus intracameral balanced salt solution) or the interventional group (combined topical plus intracameral anesthesia). The pains they experienced during the different stages of the operation were evaluated by a visual analog pain scale. At the end of the surgery, the surgeon was given a questionnaire to evaluate the cooperation of the patient. The endothelial cell count was collected preoperatively and 1 month postoperatively. RESULTS: The patient-reported pain scores were significantly lower in the interventional group at the following stages of the operation: nucleus rotation (P < 0.001), bisection of the nucleus (P < 0.001), and prolapse of the nucleus (P < 0.001). The surgeon assessment showed better patient cooperation in the lidocaine group (P = 0.04). There was no significant difference in endothelial cell loss between the 2 groups. CONCLUSIONS: Although topical anesthesia alone provides acceptable anesthesia for manual small-incision cataract surgery, combined topical and intracameral anesthesia decreased patients' discomfort and increased their cooperation during the operation. PMID- 26107862 TI - Changes in Forward and Backward Light Scatter in Keratoconus Resulting From Corneal Cross-Linking. AB - PURPOSE: To study the forward and backward light scatter in keratoconic corneas before and after cross-linking. DESIGN: An institutional, prospective, cross sectional study was conducted. METHODS: This study includes 35 eyes of 25 patients with keratoconus scheduled for either standard corneal collagen cross linking with riboflavin (CXL) or transepithelial corneal cross-linking (TE-CXL). A group of 26 healthy myopic eyes from 26 prerefractive patients was included as normal reference. Before and 6 months after cross-linking, forward light scatter was measured using the compensation comparison method, whereas backward light scatter was measured using Scheimpflug imaging. RESULTS: In keratoconic eyes, backward light scatter originating from the corneal stroma was [mean (SD)] 27.2% (8.2%) higher than in the normal eyes (P < 0.001). In the anterior stroma, this increased backscatter was significantly correlated with the maximum corneal curvature Kmax as a measure of keratoconus severity (Pearson rho = 0.582, P = 0.003). For forward light scatter, no significant difference was seen between the normal and keratoconus groups, nor was there any correlation with keratoconus severity. After CXL, the backscatter increased significantly by [mean (SD)] 33.0% (9.5%) in the entire corneal stroma (P = 0.001), whereas for TE-CXL, no significant increase was seen. Forward scatter increased significantly by [mean (SD)] 0.10 (0.10) log units (P = 0.009) and 0.09 (0.10) log units (P = 0.003) for CXL and TE-CXL, respectively, which is near the detection limit for an average patient. CONCLUSIONS: Unlike TE-CXL, CXL increases the already-elevated stromal backscatter in keratoconus. Forward scatter increases equally for both techniques. PMID- 26107863 TI - Idiopathic Macular Hole Vitrectomy Without Postoperative Face-Down Positioning Performed by Different Surgeons. AB - PURPOSE: To evaluate the efficacy of vitrectomy with internal limiting membrane peeling and sulfur hexafluoride gas tamponade without postoperative face-down positioning for macular holes (MHs) when performed by 3 surgeons at 2 centers. DESIGN: A retrospective, consecutive, observational case series. METHODS: Fifty seven eyes operated on by 1 of 3 surgeons and followed for 12 months after surgery were studied. Exclusion criteria included cases with MH duration longer than 6 months, secondary MH, and clear lenses. The surgical procedure involved cataract extraction and intraocular lens implantation in all phakic eyes before vitrectomy. Internal limiting membrane removal and 20% sulfur hexafluoride gas tamponade without postoperative face-down positioning were performed in all cases. Preoperative factors [age at surgery, sex, symptom duration, visual acuity (VA), MH size, and MH stage], initial and final hole-closure rates and VA at 1, 3, 6, and 12 months after surgery, were evaluated. RESULTS: Mean patient age was 65.3 years. Of the 57 eyes, 40 were in women, and 17 were in men. Macular hole (mean size, 0.30 disc diameter) was present for a mean of 2.37 months. Eight eyes had stage 2, 37 had stage 3, and 12 had stage 4 MH. Fifty-four holes (94.7%) initially closed. Final closure rate was 100%. Mean VA significantly improved from 0.65 to 0.41 at 1 month, 0.35 at 3 months, 0.28 at 6 months, and 0.21 at 12 months after surgery. CONCLUSIONS: Vitrectomy without face-down positioning for MHs produced favorable anatomic and functional results, regardless of which surgeon performed the procedure. PMID- 26107864 TI - Depression of Late Age-Related Macular Degeneration Patients in Korea. AB - PURPOSE: The aim of study was to investigate the relationship between depression and age-related macular degeneration (AMD) in Korea treated with intravitreal ranibizumab. METHODS: This was a cross-sectional study. This study included 107 patients diagnosed with AMD treated with intravitreal ranibizumab. All patients answered the Korean version of the Geriatric Depression Scale (GDS-K), and the prevalence of depression was evaluated. The patients from 1 center were classified into groups with and without depression according to GDS-K. Visual acuity (VA), duration, bilaterality, history of previous treatment for AMD, and comorbidities were assessed and compared between groups. The correlations between GDS-K and other variables were investigated. RESULTS: The prevalence of depression was 26.2% with AMD treated with intravitreal ranibizumab in this study. In subanalysis, the 23 depressed patients (33.3%) were older (P = 0.022) than the nondepressed. Positive correlations were observed between GDS-K and age, VA of injected eye, VA of better eye, duration of AMD, and the number of previous treatments for AMD. CONCLUSIONS: This is the first study evaluating the relationship between depression and AMD in Koreans treated with intravitreal ranibizumab. The prevalence of depression in AMD is substantial and similar to those in previous reports. Interventions to diagnose and treat depression in AMD patients are necessary. PMID- 26107865 TI - Utilization of Eye Care Services Among Staff of a Tertiary Hospital. AB - PURPOSE: To determine the level of utilization of eye care services and to identify the barriers to uptake of eye care services among the staff in a hospital. DESIGN: A cross-sectional study conducted at a university teaching hospital. METHODS: A total of 250 staff members were selected using a proportionate sampling among the segment of study population. Data were collected using semistructured questionnaires, including demographic data, awareness about eye clinic and the services rendered, facilities utilized by staff in receiving eye treatment, and reasons for not utilizing the hospital eye care services. Data analysis was done using SPSS version 15. RESULTS: The majority (66%) of the staff were younger than 40 years. Around 229 staff members (91.6%) were aware of the clinic, whereas 222 (88.8%) were aware of at least 1 of the various services rendered. They received treatment from chemists (30.7%), private hospitals (26.3%), and optical shops (16.1%). The hospital eye clinic (11.8%) was the least chosen place to receive eye treatment. The reasons for nonutilization of eye care services were lack of finance (42.1%), poor staff attitude (23.7%), fear of damage to the eye (15.3%), high cost of treatment (9.7%), and ignorance of its existence (9.2%). Visual impairment was seen in 14 of the staff (5.6%), whereas blindness was seen in 1 (0.4%). CONCLUSIONS: The level of utilization of eye care services in the hospital by the staff is poor and very low compared with other facilities, although the majority had previous history of eye complaints. PMID- 26107866 TI - Asian Age-Related Macular Degeneration: Current Concepts and Gaps in Knowledge. AB - Data on the epidemiology and treatment of age-related macular degeneration (AMD) in Asian populations have been scarce. Recently, significant advances in the current knowledge of AMD in Asia have been made, but deficiencies in important areas remain. Epidemiological data on AMD in those 80 years or older are lacking.There are also few incidence data on AMD or polypoidal choroidal vasculopathy (PCV), an important variant of AMD that seems to be more common in Asia. The risk factors for PCV have not been clearly defined to the extent that those for AMD have. No trials of nutritional supplementation for AMD prevention in Asia exist, and there is also a lack of long-term clinical trial data on combination therapy for PCV and indeed very few trial data on PCV. These represent opportunities for future research. With aging populations in Asia, increased data on the prevalence, risk factors, prevention, and treatment of AMD and PCV in Asian populations will be needed to formulate evidence-based public health and clinical guidelines. PMID- 26107867 TI - Neuro-ophthalmology Annual Review. AB - PURPOSE: To provide a clinical update of the neuro-ophthalmology literature over the last twelve months. DESIGN: This is an annual review of current literature from August 1, 2011 to August 1, 2012. METHODS: The authors conducted a one year English language neuro-ophthalmology literature search using PubMed from August 1, 2011 to August 1, 2012 using the following search terms: pupil abnormalities, eye movements, diseases of muscle and musculoskeletal junction, optic nerve disorders, optic neuritis and multiple sclerosis, chiasm and posterior primary visual pathway lesions, increased intracranial pressure and related entities, tumors (e.g., meningioma) and aneurysm affecting the visual pathways, vascular diseases, higher visual functions, advances in neuroimaging, and miscellaneous topics in neuro-ophthalmology. The authors included original articles, review articles, and case reports, which revealed the new aspects and updates in neuro ophthalmology. Letters to the editor, unpublished work, and abstracts were not included in this annual literature review. We propose to update the practicing clinical ophthalmologist on the most clinically relevant literature from the past year. However, this review is not meant to be all-inclusive and highlights only the literature most applicable to the practicing clinical ophthalmologist. RESULTS: We reviewed the literature over the past year in neuro-ophthalmology of potential interest and relevance to the comprehensive ophthalmologist. CONCLUSION: This annual review provides a brief update on a number of neuroophthalmic conditions that might be of interest to the practicing clinical ophthalmologist. PMID- 26107868 TI - Prospects of Stem Cells for Retinal Diseases. AB - Retinal diseases, including glaucoma, retinitis pigmentosa, diabetic retinopathy, and age-related macular degeneration, are the leading causes of irreversible visual impairment and blindness in developed countries. Traditional and current treatment regimens are based on surgical or medical interventions to slow down the disease progression. However, the number of retinal cells would continue to diminish, and the diseases could not be completely cured. There is an emerging role of stem cells in retinal research. The stem cell therapy on retinal diseases is based on 2 theories: cell replacement therapy and neuroprotective effect. The former hypothesizes that new retinal cells could be regenerated from stem cells to substitute the damaged cells in the diseased retina, whereas the latter believes that the paracrine effects of stem cells modulate the microenvironments of the diseased retina so as to protect the retinal neurons. This article summarizes the choice of stem cells in retinal research. Moreover, the current progress of retinal research on stem cells and the clinical applications of stem cells on retinal diseases are reviewed. In addition, potential challenges and future prospects of retinal stem cell research are discussed. PMID- 26107869 TI - Bioinformatics in Retina. AB - Bioinformatics, a word coined for the applications of computer science in biology, is now promising as a major constituent in modern biology and biomedical research. Bioinformatics plays an important role for the integration of broad disciplines of biology to understand the complex mechanisms of the cell. Bioinformatics also aids the way in which biomedical investigators use the information in their testing. Development and implementation of this novel field enable efficient access and management of different types of biological information including those at the genomic, proteomic, and metabolomic level to understand about disease mechanisms and identify new molecular targets for drug discovery. Bioinformatics has expanded its wings in exploring out different important contributions in relation with medical sciences such as neurology, parasitology, hematology, and pathology including ophthalmology. Many bioinformatics-oriented studies have contributed a lot in ophthalmology and given birth to new avenues of occuloinformatics, hence, a new coined term, occuloinformatics: a new approach of research and diagnostics related to ocular disorders with significant inputs of bioinformatics. In this current review, we tried to focus on current avenues and significant contributions of bioinformatics with special reference to retinal disorders. PMID- 26107870 TI - Letter to the Editor Regarding "Two Stage Correction of Blepharophimosis Syndrome: Analysis of Surgical Outcome". PMID- 26107871 TI - Two-Stage Correction of Blepharophimosis Syndrome: Analysis of Surgical Outcome Author Reply. PMID- 26107872 TI - In Response to "Comparison of the Surgical Outcomes of Various Methods of Endothelial Keratoplasty. APJO (Volume 1, Number 5, September/October 2012 259 64". PMID- 26107873 TI - Comparison of the Surgical Outcomes of Various Methods of Endothelial Keratoplasty- Author Reply. PMID- 26107874 TI - The influence of synaptic size on AMPA receptor activation: a Monte Carlo model. AB - Physiological and electron microscope studies have shown that synapses are functionally and morphologically heterogeneous and that variations in size of synaptic junctions are related to characteristics such as release probability and density of postsynaptic AMPA receptors. The present article focuses on how these morphological variations impact synaptic transmission. We based our study on Monte Carlo computational simulations of simplified model synapses whose morphological features have been extracted from hundreds of actual synaptic junctions reconstructed by three-dimensional electron microscopy. We have examined the effects that parameters such as synaptic size or density of AMPA receptors have on the number of receptors that open after release of a single synaptic vesicle. Our results indicate that the maximum number of receptors that will open after the release of a single synaptic vesicle may show a ten-fold variation in the whole population of synapses. When individual synapses are considered, there is also a stochastical variability that is maximal in small synapses with low numbers of receptors. The number of postsynaptic receptors and the size of the synaptic junction are the most influential parameters, while the packing density of receptors or the concentration of extrasynaptic transporters have little or no influence on the opening of AMPA receptors. PMID- 26107875 TI - Clearance of Pneumococcal Colonization in Infants Is Delayed through Altered Macrophage Trafficking. AB - Infections are a common cause of infant mortality worldwide, especially due to Streptococcus pneumoniae. Colonization is the prerequisite to invasive pneumococcal disease, and is particularly frequent and prolonged in children, though the mechanisms underlying this susceptibility are unknown. We find that infant mice exhibit prolonged pneumococcal carriage, and are delayed in recruiting macrophages, the effector cells of clearance, into the nasopharyngeal lumen. This lack of macrophage recruitment is paralleled by a failure to upregulate chemokine (C-C) motif ligand 2 (Ccl2 or Mcp-1), a macrophage chemoattractant that is required in adult mice to promote clearance. Baseline expression of Ccl2 and the related chemokine Ccl7 is higher in the infant compared to the adult upper respiratory tract, and this effect requires the infant microbiota. These results demonstrate that signals governing macrophage recruitment are altered at baseline in infant mice, which prevents the development of appropriate innate cell infiltration in response to pneumococcal colonization, delaying clearance of pneumococcal carriage. PMID- 26107876 TI - Computational Biology: Moving into the Future One Click at a Time. PMID- 26107877 TI - Correction: IRES-Containing VEEV Vaccine Protects Cynomolgus Macaques from IE Venezuelan Equine Encephalitis Virus Aerosol Challenge. PMID- 26107878 TI - The Veterans Access, Choice, and Accountability Act of 2014: Examining Graduate Medical Education Enhancement in the Department of Veterans Affairs. AB - From 2006 to 2011, the Department of Veterans Affairs (VA) introduced the Graduate Medical Education (GME) Enhancement initiative to increase residency positions at VA training sites. VA once again has an opportunity to fund new residency positions through the Veterans Access, Choice, and Accountability Act of 2014 (VACAA). Congressional requirements under VACAA give priority to positions in primary care, mental health, and other specialties that the Secretary of Veterans Affairs deems appropriate. Moreover, facilities meeting the following criteria will be awarded priority for expansion: no prior GME activities, a shortage of physicians, rural locations, areas with a "high concentration of veterans," or located in Health Professional Shortage Areas as defined by the Health Resources and Services Administration. The authors of this Commentary discuss the implications of the new legislation, reviewing the past VA GME Enhancement efforts to examine the potential impact of further expansion of VA GME positions. Understanding the intent of the legislation and its provisions will allow qualified existing and potentially new affiliates to successfully pursue new residency positions during the five-year period of VA GME expansion under VACAA. PMID- 26107879 TI - Community Engagement Studios: A Structured Approach to Obtaining Meaningful Input From Stakeholders to Inform Research. AB - PROBLEM: Engaging communities in research increases its relevance and may speed the translation of discoveries into improved health outcomes. Many researchers lack training to effectively engage stakeholders, whereas academic institutions lack infrastructure to support community engagement. APPROACH: In 2009, the Meharry-Vanderbilt Community-Engaged Research Core began testing new approaches for community engagement, which led to the development of the Community Engagement Studio (CE Studio). This structured program facilitates project specific input from community and patient stakeholders to enhance research design, implementation, and dissemination. Developers used a team approach to recruit and train stakeholders, prepare researchers to engage with stakeholders, and facilitate an in-person meeting with both. OUTCOMES: The research core has implemented 28 CE Studios that engaged 152 community stakeholders. Participating researchers, representing a broad range of faculty ranks and disciplines, reported that input from stakeholders was valuable and that the CE Studio helped determine project feasibility and enhanced research design and implementation. Stakeholders found the CE Studio to be an acceptable method of engagement and reported a better understanding of research in general. A tool kit was developed to replicate this model and to disseminate this approach. NEXT STEPS: The research core will collect data to better understand the impact of CE Studios on research proposal submissions, funding, research outcomes, patient and stakeholder engagement in projects, and dissemination of results. They will also collect data to determine whether CE Studios increase patient-centered approaches in research and whether stakeholders who participate have more trust and willingness to participate in research. PMID- 26107880 TI - Improving Documentation Timeliness: A "Brighter Future" for the Electronic Medical Record in Resident Clinics. AB - PROBLEM: Electronic medical records have many observed benefits but may cause work disruption, resulting in delayed documentation completion. The purpose of this project was to improve compliance with institutional standards of documentation of well child checks for residents and attendings without increasing stress. APPROACH: This project was completed at Children's Hospital Primary Care Clinic at Vanderbilt, which is staffed by 74 residents, supervised by 17 attendings. A longitudinal observational study using convenience sampling for the last full week of each month from October 2010-January 2012 was planned. Baseline documentation completion rates were assessed, then age-specific, structured data-entry forms were introduced beginning in March 2011. Run charts were created for completion data for all clinic visits in the sample. Physician self-report of satisfaction with and stress related to documentation was assessed through pre- and postintervention surveys. OUTCOMES: Data were derived for an average of 231 patient visits per month. The median percentage of documentation or attestations completed within the institutional standards increased from 54.7% to 78.9% for residents and from 38.2% to 83.5% for attendings. Physicians reporting high satisfaction with documentation increased from 20.5% to 85.7% (P < .01) for residents and from 11.1% to 76.9% (P < .01) for attendings. Residents reporting high stress with documentation decreased from 59.1% to 28.6% (P < .02). NEXT STEPS: Use of age-specific, structured data-entry forms achieved marked improvement in documentation timeliness, but there is still room for improvement. The authors are now teaching computer-based documentation in exam rooms and instituting accountability measures. PMID- 26107881 TI - Appraising the quality of medical education research methods: the Medical Education Research Study Quality Instrument and the Newcastle-Ottawa Scale Education. AB - PURPOSE: The Medical Education Research Study Quality Instrument (MERSQI) and the Newcastle-Ottawa Scale-Education (NOS-E) were developed to appraise methodological quality in medical education research. The study objective was to evaluate the interrater reliability, normative scores, and between-instrument correlation for these two instruments. METHOD: In 2014, the authors searched PubMed and Google for articles using the MERSQI or NOS-E. They obtained or extracted data for interrater reliability-using the intraclass correlation coefficient (ICC)-and normative scores. They calculated between-scale correlation using Spearman rho. RESULTS: Each instrument contains items concerning sampling, controlling for confounders, and integrity of outcomes. Interrater reliability for overall scores ranged from 0.68 to 0.95. Interrater reliability was "substantial" or better (ICC > 0.60) for nearly all domain-specific items on both instruments. Most instances of low interrater reliability were associated with restriction of range, and raw agreement was usually good. Across 26 studies evaluating published research, the median overall MERSQI score was 11.3 (range 8.9-15.1, of possible 18). Across six studies, the median overall NOS-E score was 3.22 (range 2.08-3.82, of possible 6). Overall MERSQI and NOS-E scores correlated reasonably well (rho 0.49-0.72). CONCLUSIONS: The MERSQI and NOS-E are useful, reliable, complementary tools for appraising methodological quality of medical education research. Interpretation and use of their scores should focus on item specific codes rather than overall scores. Normative scores should be used for relative rather than absolute judgments because different research questions require different study designs. PMID- 26107882 TI - Residents' Perspectives on Rewards and Challenges of Caring for Ambulatory Care Patients Living With Chronic Illness: Findings From Three Academic Health Centers. AB - PURPOSE: To elicit residents' perspectives on rewards and challenges of caring for ambulatory patients with chronic illness and ways to improve their education in caring for these patients. METHOD: The authors conducted a qualitative study with internal medicine residents during ambulatory medicine block rotations at three academic health centers from October 2011 through February 2012. Focus group questions covered rewards and challenges of caring for patients with chronic illness and strengths and weaknesses of residency education therein, and the Chronic Care Model provided a framework for interpretation. Qualitative analysis was used to identify themes. RESULTS: Five focus groups were conducted with 28 residents. Discussions yielded 224 comments, which were categorized into 5 domains and 36 themes. Twelve themes related to perceptions of challenges in providing care, and 3 themes related to perceptions of rewards in providing care. Eight themes focused on strategies to improve the patient experience. Strengths of the residency program were identified in 7 themes. Six themes related to ways for improving learning about caring for patients with chronic disease in the ambulatory setting. CONCLUSIONS: Residents perceived rewards, challenges, and barriers in caring for patients with chronic illness in the ambulatory setting, from providers' and patients' perspectives. They have developed strategies to provide effective patient care. Residents identified best practices in their residency for resident education and patient care and also made suggestions for improvement. Findings have significant implications for residency education and practice redesign in the 21st century for care of patients with chronic illness. PMID- 26107883 TI - Favorable alteration of tumor microenvironment by immunomodulatory cytokines for efficient T-cell therapy in solid tumors. AB - Unfavorable ratios between the number and activation status of effector and suppressor immune cells infiltrating the tumor contribute to resistance of solid tumors to T-cell based therapies. Here, we studied the capacity of FDA and EMA approved recombinant cytokines to manipulate this balance in favor of efficient anti-tumor responses in B16.OVA melanoma bearing C57BL/6 mice. Intratumoral administration of IFN-alpha2, IFN-gamma, TNF-alpha, and IL-2 significantly enhanced the anti-tumor effect of ovalbumin-specific CD8+ T-cell (OT-I) therapy, whereas GM-CSF increased tumor growth in association with an increase in immunosuppressive cell populations. None of the cytokines augmented tumor trafficking of OT-I cells significantly, but injections of IFN-alpha2, IFN-gamma and IL-2 increased intratumoral cytokine secretion and recruitment of endogenous immune cells capable of stimulating T-cells, such as natural killer and maturated CD11c+ antigen-presenting cells. Moreover, IFN-alpha2 and IL-2 increased the levels of activated tumor-infiltrating CD8+ T-cells concomitant with reduction in the CD8+ T-cell expression of anergy markers CTLA-4 and PD-1. In conclusion, intratumoral administration of IFN-alpha2, IFN-gamma and IL-2 can lead to immune sensitization of the established tumor, whereas GM-CSF may contribute to tumor associated immunosuppression. The results described here provide rationale for including local administration of immunostimulatory cytokines into T-cell therapy regimens. One appealing embodiment of this would be vectored delivery which could be advantageous over direct injection of recombinant molecules with regard to efficacy, cost, persistence and convenience. PMID- 26107886 TI - Monte Carlo Simulations of HIV Capsid Protein Homodimer. AB - Capsid protein (CA) is the building block of virus coats. To help understand how the HIV CA proteins self-organize into large assemblies of various shapes, we aim to computationally evaluate the binding affinity and interfaces in a CA homodimer. We model the N- and C-terminal domains (NTD and CTD) of the CA as rigid bodies and treat the five-residue loop between the two domains as a flexible linker. We adopt a transferrable residue-level coarse-grained energy function to describe the interactions between the protein domains. In seven extensive Monte Carlo simulations with different volumes, a large number of binding/unbinding transitions between the two CA proteins are observed, thus allowing a reliable estimation of the equilibrium probabilities for the dimeric vs monomeric forms. The obtained dissociation constant for the CA homodimer from our simulations, 20-25 MUM, is in reasonable agreement with experimental measurement. A wide range of binding interfaces, primarily between the NTDs, are identified in the simulations. Although some observed bound structures here closely resemble the major binding interfaces in the capsid assembly, they are statistically insignificant in our simulation trajectories. Our results suggest that although the general purpose energy functions adopted here could reasonably reproduce the overall binding affinity for the CA homodimer, further adjustment would be needed to accurately represent the relative strength of individual binding interfaces. PMID- 26107884 TI - High-Density Dielectrophoretic Microwell Array for Detection, Capture, and Single Cell Analysis of Rare Tumor Cells in Peripheral Blood. AB - Development of a reliable platform and workflow to detect and capture a small number of mutation-bearing circulating tumor cells (CTCs) from a blood sample is necessary for the development of noninvasive cancer diagnosis. In this preclinical study, we aimed to develop a capture system for molecular characterization of single CTCs based on high-density dielectrophoretic microwell array technology. Spike-in experiments using lung cancer cell lines were conducted. The microwell array was used to capture spiked cancer cells, and captured single cells were subjected to whole genome amplification followed by sequencing. A high detection rate (70.2%-90.0%) and excellent linear performance (R2 = 0.8189-0.9999) were noted between the observed and expected numbers of tumor cells. The detection rate was markedly higher than that obtained using the CellSearch system in a blinded manner, suggesting the superior sensitivity of our system in detecting EpCAM- tumor cells. Isolation of single captured tumor cells, followed by detection of EGFR mutations, was achieved using Sanger sequencing. Using a microwell array, we established an efficient and convenient platform for the capture and characterization of single CTCs. The results of a proof-of principle preclinical study indicated that this platform has potential for the molecular characterization of captured CTCs from patients. PMID- 26107885 TI - Serum Total Cholinesterase Activity on Admission Is Associated with Disease Severity and Outcome in Patients with Traumatic Brain Injury. AB - BACKGROUND: Traumatic brain injury (TBI) is one of the leading causes of neurological disability. In this retrospective study, serum total cholinesterase (ChE) activities were analyzed in 188 patients for diagnostic as well as predictive values for mortality. METHODS AND FINDINGS: Within 72 hours after injury, serum ChE activities including both acetylcholinesterase and butyrylcholinesterase were measured. Disease severity was evaluated with Acute Physiology and Chronic Health Evaluation (APACHE) II score, Glasgow Coma Score, length of coma, post-traumatic amnesia and injury feature. Neurocognitive and functional scores were assessed using clinical records. Of 188 patients, 146 (77.7%) survived and 42 (22.3%) died within 90 days. Lower ChE activities were noted in the non-survivors vs. survivors (5.94+/-2.19 vs. 7.04+/-2.16 kU/L, p=0.023), in septic vs. non-infected patients (5.93+/-1.89 vs. 7.31+/-2.45 kU/L, p=0.0005) and in patients with extremely severe injury vs. mild injury (6.3+/ 1.98 vs. 7.57+/-2.48 kU/L, p=0.049). The trajectories of serum ChE levels were also different between non-survivors and survivors, septic and non-infected patients, mild and severely injured patients, respectively. Admission ChE activities were closely correlated with blood cell counts, neurocognitive and functional scores both on admission and at discharge. Receiver operating characteristic analysis showed that the area under the curve for ChE was inferior to that for either APACHE II or white blood cell (WBC) count. However, at the optimal cutoff value of 5 kU/L, the sensitivity of ChE for correct prediction of 90-day mortality was 65.5% and the specificity was 86.4%. Kaplan-Meier analysis showed that lower ChE activity (<5 kU/L) was more closely correlated with poor survival than higher ChE activity (>5 kU/L) (p=0.04). After adjusting for other variables, ChE was identified as a borderline independent predictor for mortality as analyzed by Binary logistic regression (P=0.078). CONCLUSIONS: Lowered ChE activity measured on admission appears to be associated with disease severity and outcome for TBI patients. PMID- 26107887 TI - Successful use of tigecycline for treatment of culture-negative pyogenic vertebral osteomyelitis. AB - BACKGROUND: Pyogenic vertebral osteomyelitis (PVO) is a severe infection that requires prolonged antimicrobial therapy and/or surgical interventions. Limited data are available on the safety and clinical efficacy of tigecycline in PVO. The objective of this study was to describe the clinical outcomes of patients treated with tigecycline for culture-negative PVO that was unresponsive to empirical antibiotic therapy including intravenous ampicillin-sulbactam plus ciprofloxacin or ampicillin-sulbactam alone. METHODS: We retrospectively reviewed 15 patients with culture-negative PVO from 2009 through 2014. The patients received tigecycline as secondary empirical therapy, after not responding to the first empirical therapy. Clinical success was defined as recovery from symptoms and normalization of laboratory parameters at the end of therapy. Continued clinical success at 24 weeks after the end of the therapy was defined as sustained clinical success. RESULTS: Tigecycline treatment was completed in 14 patients and discontinued in 1 due to severe nausea and vomiting. The mean age of the patients was 67.7 years (range 58-77 years), and 57.1% (8/14) were women. In all, 78.6% (11/14) of patients had risk factors for probable resistant staphylococcal and gram-negative infections such as diabetes mellitus, presence of hemodialysis catheters, and prior antibiotic usage. The average duration of tigecycline treatment was 8.3 weeks (range 6-11 weeks). Sustained clinical success was obtained in all patients. CONCLUSIONS: Tigecycline should be considered as an alternative agent for the treatment of PVO in selected patients due to microbiological activity against resistant gram-positive and gram-negative bacteria. PMID- 26107888 TI - Less Surgery, Improved Survival From Stage IV Colorectal Cancer? PMID- 26107889 TI - Modeling amyotrophic lateral sclerosis in pure human iPSc-derived motor neurons isolated by a novel FACS double selection technique. AB - Amyotrophic lateral sclerosis (ALS) is a severe and incurable neurodegenerative disease. Human motor neurons generated from induced pluripotent stem cells (iPSc) offer new perspectives for disease modeling and drug testing in ALS. In standard iPSc-derived cultures, however, the two major phenotypic alterations of ALS- degeneration of motor neuron cell bodies and axons--are often obscured by cell body clustering, extensive axon criss-crossing and presence of unwanted cell types. Here, we succeeded in isolating 100% pure and standardized human motor neurons by a novel FACS double selection based on a p75(NTR) surface epitope and an HB9::RFP lentivirus reporter. The p75(NTR)/HB9::RFP motor neurons survive and grow well without forming clusters or entangled axons, are electrically excitable, contain ALS-relevant motor neuron subtypes and form functional connections with co-cultured myotubes. Importantly, they undergo rapid and massive cell death and axon degeneration in response to mutant SOD1 astrocytes. These data demonstrate the potential of FACS-isolated human iPSc-derived motor neurons for improved disease modeling and drug testing in ALS and related motor neuron diseases. PMID- 26107890 TI - [Rearrangement and inference of chromosome structures]. AB - The chromosome structure is defined as a set of chromosomes that consist of genes assigned to one of the DNA strands and represented in a circular or linear arrangement. A widely investigated problem is to define the shortest algorithmic path of chromosome rearrangements that transforms one chromosome structure into another. When equal rearrangement costs and constant gene content are considered, the solution to the problem is known. In this work, a principally novel approach was developed that presents an exact algorithm with linear time complexity for both equal and unequal costs, in which chromosome structures defined on the same set of genes were considered. In addition, to solve the problem of the inference of ancestral chromosome structures containing different sets of genes when the original structures are fixed in leaves, exact and heuristic algorithms were developed. PMID- 26107891 TI - [Bacteriophage lambda: electrostatic properties of the genome and its elements]. AB - Bacteriophage lambda is a classical model object in molecular biology, but little is still known on the physical properties of its DNA and regulatory elements. A study was made of the electrostatic properties of phage lambda DNA and regulatory elements. A global electrostatic potential distribution along the phage genome was found to be nonuniform with main regulatory elements being located in a limited region with a high potential. The RNA polymerase binding frequency on the linearized phage chromosome directly correlates with its local potential. Strong promoters of the phage and its host Escherichia coli have distinct electrostatic upstream elements, which differ in nucleotide sequence. Attachment and recombination sites of phage lambda and its host have a higher potential, which possibly facilitates their recognition by integrase. Phage lambda and host Rho independent terminators have a symmetrical M-shaped potential profile, which only slightly depends on the annotated terminator palindrome length, and occur in a region with a substantially higher potential, which may cause polymerase retention, facilitating the formation of a terminator hairpin in RNA. It was concluded that virtually all elements of phage lambda genome have potential distribution specifics, which are related to their structural properties and may play a role in their biological function. The global potential distribution along the phage genome reflects the architecture of the regulation of its transcription and integration in the host genome. PMID- 26107892 TI - [Conserved motifs in the primary and secondary ITS1 structures in bryophytes]. AB - A study of the ITS1 nucleotide sequences of 1000 moss species of 62 families, 11 liverwort species from five orders, and one hornwort Anthoceros agrestis identified five highly conserved motifs (CM1-CM5), which are presumably involved in pre-rRNA processing. Although the ITS1 sequences substantially differ in length and the extent of divergence, the conserved motifs are found in all of them. ITS1 secondary structures were constructed for 76 mosses, and main regularities at conserved motif positioning were observed. The positions of processing sites in the ITS1 secondary structure of the yeast Saccharomyces cerevisiae were found to be similar to the positions of the conserved motifs in the ITS1 secondary structures of mosses and liverworts. In addition, a potential hairpin formation in the putative secondary structure of a pre-rRNA fragment was considered for the region between ITS1 CM4-CM5 and a highly conserved region between hairpins 49 and 50 (H49 and H50) of the 18S rRNA. PMID- 26107893 TI - [Repetitive DNA sequences as an indicator of the level of genetic isolation in fish]. AB - Although the functional role is still unknown for most types of nuclear noncoding repetitive sequences, some of them proved to provide adequate phylogenetic and taxonomic markers for studying the genetic relationships of organisms at the species and within-species levels. Several markers were used in this work. First, microsatellite markers were used to examine populations varying in the extent of genetic subdivision in marine and anadromous fish, including the Chilean jack mackerel Trachurus murphyi, anadromous brown trout Salmo trutta, and isolated and anadromous char populations. Locus polymorphism was proportional to the gene flow between populations in all cases. Second, satellite DNA was used to study the phylogenetic relationships within the genera Salmo, Oncorhynchus, Salvelinus, and Coregonus. Genetic distances agreed well with the taxonomic relationships based on morphological traits and various biochemical markers and correlated with the evolutionary ages estimated for the groups by other markers. Third, RAPD PCR with a set of 20-mer primers was performed to study the genus Coregonus and anadromous and isolated populations and species of the genus Salvelinus. The resulting phylogenetic trees may help to resolve some disputable taxonomic issues for the groups. A comparison showed that several RAPD-detected sequences contain conserved fragments of coding sequences and polymorphic repeats (minisatellites) from intergenic regions or introns. The finding point to a nonrandom nature of repetitive DNA divergence and may reflect the evolution of the fish groups examined. Heterochromatic satellite repeats were assumed to contribute to generating a reproductive barrier. PMID- 26107894 TI - [Characterization of retrotransposon Bov-B LINE reverse transcriptase gene sequences in parthenogenetic lizards Darevskia unisexualis and bisexual species D. nairensis and D. valentini]. AB - Cloning and sequencing of the partial reverse transcriptase gene (750 bp) of the Bov-B LINE retrotransposon have been held in parthenogenetic lizards Darevskia unisexualis and its assumed parental bisexual species D. nairensis and D.valentini. It was shown that the percentage of transcriptionally active copies of this gene, which does not contain a stop codon, is almost the same in the three species and is about 75%. The intragenomic divergence level of these sequences is low and was found to be 2.6% in D. unisexualis, 1.9% in D. nairensis, and 1.6% in D. valentini. The phylogenetic analysis shows the distribution of copies of D. unisexualis in each of the two clusters of RT sequences characteristic of D. nairensis and D. valentini. This result supports the view of the hybrid origin of D. unisexualis and does not exclude intraspecific hybridization between D. nairensis and D. valentini. PMID- 26107895 TI - [Molecular genetic characterization of the Far Eastern trematode Skrjabino lecithum spasskii Belous, 1954 (Digenea: Haploporidae)), a parasite of mullets]. AB - Intraspecific genetic differentiation of the trematode Skrjabinolecithum spasskii and its phylogenetic relationships with other species of the family Haploporidae were studied by comparing the nucleotide sequences of a part of the 28S rRNA gene and the ITS1-5.8S-ITS2 rDNA region. Trematodes were isolated from so-iuy mullet Liza haematocheila fishes collected in rivers of Primorye and flathead grey mullet Mugil cephalus fishes collected in water bodies of Vietnam (27 fishes in total). A phylogenetic analysis showed that S. spasskii is close to species of the genus Capitimitta of the subfamily Waretrematinae. By intraspecific variation of rDNA sequences, trematodes were divided into three groups with tree different genotypes, which had fixed nucleotide substitutions. Genotype I was found in trematodes from fishes collected in Primorye. Genotype II was detected in trematodes from M. cephalus fishes collected in the Tonkin Bay, Cat Ba Island, Vietnam. Genotype III was found in five trematodes from L. haematocheila collected in the Kievka River, Primorye. The genetic distances between genotypes I and III from Primorye were 0.4 and 0.65% by 28S and ITS rDNA sequences, respectively. The lowest genetic distances were observed between genotypes II (Vietnam) and III (Primorye), 0.1 and 0.33% by 28S and ITS rDNA sequences, respectively. Possible causes of genetic differentiation of S. spasskii from different geographic locations and different definitive host species are discussed. PMID- 26107896 TI - [Regularities of the ubiquitous polyhostal microorganisms selection by the example of three taxa]. AB - The investigation of the bacterial populations' heterogeneity contributes to the control of natural foci, causative agents of nosocomial infections, to the analysis of the microbial evolution. Multilocus sequence typing (MLST) was employed for the analysis of the diversity and features of the distribution of polyhostal ubiquitous microorganisms of the genera Burkholderia, Leptospira, and Listeria, which belong to three bacterial phyla: Proteobacteria, Spirochaetes, and Firmicutes. According to the bacterial samples analysis microbial genotypes prevalent and unique to Russia were identified; their occurrence in different Federal Regions was investigated; their similarity with global spread genotypes was appreciated. Obtained results allowed identifying common regularities of the selection of the microorganisms capable to cause the diseases of human and animals. The formation of genotypes that are most pathogenic for the host was demonstrated for all groups of bacteria. Leptospira spp. and Listeria monocytogenes strains with these genotypes have been circulating for a long time, being supported by natural foci. The formation of a wide variety of genotypes with different pathogenicity was demonstrated in the local geographic areas. In Russia, the zonal difference in all three groups of bacteria is most clearly traced to the Far Eastern Federal Region. The results are thought to contribute to analyzing the factors of selection and the phylogeny of the taxa under study. PMID- 26107897 TI - [Phylogeny of genus Spermophilus and position of Alashan ground squirrel (Spermophilus alashanicus, Buchner, 1888) on phylogenetic tree of Paleartic short tailed ground squirrels]. AB - Phylogenetic relationships within a group of Paleartic short tailed ground squirrels (Spermophilus), recently defined as genus, are not sufficiently clear and need a critical revision. Interspecies hybridization, found in Eurasian Spermophilus, can affect the results of reconstruction of molecular phylogeny. Alashan ground squirrel position on the phylogenetic tree needs clarification. We analyzed eight nucleotide sequences of cytb gene of S. alashanicus and 127 sequences of other Spermophilus species form GenBank. S.alashanicus and S. dauricus close phylogenetic relationship, and their affinity to ancestral forms of the group are revealed. Monophyly of Colobotis subgenus was confirmed. Paraphyly of eastern and western forms of S. relictus was shown. PMID- 26107898 TI - [Influence of anthropogenous factors on the genetic variety of the sable (Martes zibellina L.)]. AB - The genetic variety of seven geographic populations of sable has been studied; its distribution area stretches from the Urals to the Far East. It was shown using the panel of eight nuclear microsatellite markers that the sable populations from different geographical regions retain their individual genetic characteristics, despite the influence of anthropogenous factors (overhunting and introduction). There is a significant genetic similarity between the three populations of Central Siberia (Reynolds distances are 0.170-0.200) due to the influence of natural migrations that weaken genetic differentiation, while genetic difference is maximum (0.361) between populations located at the edges of the sable' habitat. The population of the Kamchatka Peninsula is isolated and exists as an independent phylogenetic group. An analysis of the topology of the phylogenetic tree suggests that the populations of Kamchatka and the Sikhote-Alin are closest to the ancestral form. Despite the existence of interspecific hybrids of sable and marten, the level of interspecific genetic differentiation between them is maximal. PMID- 26107900 TI - [The complete mitochondrial genome of peacock sole Pardachirus pavoninus (Pleuronectiformes: Soleidae) and comparative analysis of the control region among 13 soles]. AB - The complete mitogenome of the peacock sole Pardachirus pavoninus (Lacepede, 1802) was determined. The total length is 16 536 bp, containing 13 protein-coding genes, 22 tRNA genes and two rRNA genes, as well as one control region (CR). The L-strand replication origin (OL), which is typically located in the WANCY cluster, is lost in P. pavoninus. The gene arrangement is identical to that in most teleosts. Comparison of the CR sequences among 13 soles reveals that a 211 bp fragment at the 5'-end of the CR is lost in the P. pavoninus mitogenome, responsible for its short sequence with a length of 872 bp. All typical conservative blocks (TAS, CSB-F, E, D, C, B, A, CSB-1, 2, 3) are identified. Seven out of 13 soles contain tandem repeats in the CR and the possible mechanisms of their formation are discussed. These results may provide the consensus sequences of the conserved units in the sole CR as well as molecular data for phylogenetic studies on Soleidae and Pleuronectiformes. PMID- 26107899 TI - [The amplification of CYP9 genes as a preadaptation of the black garden ant Lasius niger to urban conditions]. AB - Ants are one of the most ancient and successful groups of eusocial animals and they are spread all over the world. The nucleotide sequences of the genomes of eight ant species were determined by the year 2014. In these species, the mechanisms of ecological success, cast differentiation, and social communication were studied at genomic level. In ants, the genes of the cytochromes P450 involved in metabolism of xenobiotics and various endogenic substances are amplified. Although the substrates for several cytochrome P450 families have been identified, the functions of the ninth family, which is one of the most amplified, remain unknown. The black garden ant Lasius niger is one of the spices that have successfully adapted to urban conditions. To study the mechanisms of adaptation, we have read and annotated the nucleotide sequence of the L. niger genome; we have predicted the functions of the CYP9 genes using virtual screening. The obtained data allow us to suggest that cytochromes P450 are involved in the metabolism of various xenobiotics such as phytotoxins, mycotoxins, and insecticides. We assume that the functional divergence of the new CYP9 duplications was initially aimed at developing resistance to various mycotoxins, in particular to those produced by Fusarium fungi and, subsequently, to other xenobiotics. PMID- 26107901 TI - [Methods to study the RNA-protein interactions]. AB - RNA-binding proteins (RBPs) play an important role in regulating gene expression at the posttranscriptional level, including the steps of pre-mRNA splicing, polyadenylation, mRNA stabilization, mRNA export from the nucleus to the cytoplasm, mRNA localization, and translation. RBPs regulate these processes primarily by binding to specific sequence elements in newly synthesized or mature transcripts. While many RPBs are known to recognize certain nucleotide sequences in RNA, information is insufficient for others. In particular, RBPs often compete for RNA binding or interact with RNA cooperatively. Hence, it is of importance to study the RNA-protein interactions in vivo. Numerous methods have been developed to identify the target nucleotide sequences of RBPs. The methods include the electrophoretic mobility shift assay (EMSA), systematic evolution of ligands by exponential enrichment (SELEX), RNA pull-down assay, RNA footprinting, RNA immunoprecipitation (RIP), UV-induced crosslinking immunoprecipitation (CLIP) and its variants, and measurement of the level for newly synthesized transcripts. Each of the methods has its limitation, and several methods supplementing each other should be employed in order to detect the RNA sequence to which a protein binds. PMID- 26107902 TI - [Comparative analysis of the role of CD4(+) and CD8(+) T cells in severe asthma development]. AB - The role of CD8^(+) T cells in asthma has not been fully discussed. The mechanisms of CD4^(+) and CD8^(+) cells in severe asthma (SA) development were compared. The microarray data (GSE31773) was downloaded from the Gene Expression Omnibus (GEO) database, including 20 samples of CD4^(+) and CD8^(+) T cells, which were collected from 8 health controls (HC), 4 non-severe asthma (NSA) and 8 SA patients. DEGs of CD4^(+) and CD8^(+) T cells in the HC vs. NSA and HC vs. SA groups were identified using the limma package in R. GO and pathway enrichment analysis of the common DEGs between the two groups were analyzed using DAVID. The interactive network of DEGs and significant modules were further explored. In CD4^(+) cells, there were 168 DEGs in HC vs. NSA group and 685 DEGs in HC vs. SA group, while for CD8^(+) T cells there were 719 DEGs in the HC vs. NSA groups and 1255 DEGs in the HC vs. SA groups. Besides, 80 common DEGs from CD4^(+) samples were enriched in the MAPKKK cascade and molecular metabolism, and 385 common DEGs of CD8^(+) T cells were significantly related with cell apoptosis and transformation. Moreover, two significant modules of DEGs in CD4^(+) were found to be involved with MPO and BPI. One module of CD8^(+) T cells containing PDHA1 and MRPL42 was identified to be related with glycolysis. In conclusion, MPO and BPI in CD4^(+), and PDHA1 and MRPL42 in CD8^(+) T cells might be used as specific biomarkers of SA progression. Therapy targeting the functions of CD4^(+) and CD8^(+) T cells may provide a novel perspective for SA treatment. PMID- 26107903 TI - [Importin-beta1 plays a key role in the nucleocytoplasmic transportation process of MARVELD1]. AB - While MARVEL domain-containing protein 1 (MARVELD1) is widely expressed in normal tissue, its expression is decreased in tumor tissue. Importin-beta1 is a kind of nucleocytoplasmic transport protein, which participates in protein transportation between the nucleus and cytoplasm. It has been known that MARVELD1 binds importin beta1. To define the biological functions of the binding between MARVELD1 and importin-beta1, confocal laser scanning microscopy was applied to confirm the distribution of MARVELD1 in the cells when importin-beta1, is knocked down, and the results show that MARVELD1's concentration is decreased in the nucleus and elevated in the cytoplasm. GST-pull down and western blot were applied to test the binding affinity between the normal importin-beta1, and several truncations of MARVELD1, and the binding affinity between the normal MARVELD1 and several truncations of importin-beta1. These results show that there exist several binding points between MARVELD1 and importin-beta1. Basing on these results one can come to a conclusion that importin-beta1 mediates the non-classical nucleocytoplasmic transportation of MARVELD1. It was also found that knockdown of importin-beta1, leads to an increase in the total density of MARVELD1. Considering the abnormally reduced expression of MARVELD1 in tumor tissue, the results of this study will help gaining a better understanding of the roles of MARVELD1 in the signal network systems during tumorigenesis in cancer cells. PMID- 26107904 TI - [Joint locus of a/b-globin genes in Danio rerio is segregated into structural subdomains active at different stages of development]. AB - In the domain model of eukaryotic genome organization, the functional unit of the genome, along with the relevant regulatory elements, is considered to be a gene or a gene family. In hot-blooded vertebrate animals, the domains of a- and b globin genes are positioned at different chromosomes and are organized and regulated in different fashion. In cold-blooded animals, in particular in tropical fish Danio rerio, a- and b globin genes are located in a common gene cluster. However, the joint a/b-globin gene cluster is subdivided into two development stage-specific subdomains, the adult one and the embryonic-larval one. In an attempt to find out whether this functional segregation correlates with structural segregation of the domain we compared the DNase I sensitivity and profiles of histone modifications of adult and embryonic-larval segments of the domain in cultured D. rerio fibroblasts. We have demonstrated that, in these nonerythroid cells, adult and embryonic- larval subdomains possess different DNase I sensitivities and different profiles of H3K27me3, a histone modification introduced by PRC2 complex. These observations suggest that joint a/b globin gene domain of Danio rerio is segregated into two structural subdomain harboring adult and embryonic-larval globin genes. PMID- 26107905 TI - [Effect of mutations and modifications of amino acid residues on zinc-induced interaction of the metal-binding domain of beta-amyloid with DNA]. AB - Interaction of intranuclear beta-amyloid with DNA is considered to be a plausible mechanism of Alzheimer's disease pathogenesis. The interaction of single- and double-stranded DNA with synthetic peptides was analyzed using surface plasmon resonance. The peptides represent the metal-binding domain of beta-amyloid (amino acids 1-16) and its variants with chemical modifications and point substitutions of amino acid residues which are associated with enhanced neurotoxicity of beta amyloid in cell tests. It has been shown that the presence of zinc ions is necessary for the interaction of the peptides with DNA in solution. H6R substitution has remarkably reduced the ability of domain 1-16 to bind DNA. This is in accordance with the supposition that the coordination of a zinc ion by amino acid residues His6, Glu11, His13, and His14 of the beta-amyloid metal binding domain results in the occurrence of an anion-binding site responsible for the interaction of the domain with DNA. Zinc-induced dimerization and oligomerization of domain 1-16 associated with phosphorylation of Ser8 and the presence of unblocked amino- and carboxy-terminal groups have resulted in a decrease of peptide concentrations required for detection of the peptide-DNA interaction. The presence of multiple anion-binding sites on the dimers and oligomers is responsible for the enhancement of the peptide-DNA interaction. A substitution of the negatively charged residue Asp7 for the neutral residue Asn in close proximity to the anion-binding site of the domain 1-16 of Abeta facilitates the electrostatic interaction between this site and phosphates of a polynucleotide chain, which enhances zinc-induced binding to DNA. PMID- 26107906 TI - [Strategy of probe selection for studying mRNAs that participate in receptor mediated apoptosis signaling]. AB - Death receptors (DRs) and the participants of DR-mediated signaling are characterized by a large number of mRNA isoforms generated by alternative splicing. Due to their high labor intensity and high cost, conventional methods (RT-PCR and RT-PCR in real time) are ineffective when the simultaneous detection of a plurality of mRNA isoforms is needed. In this regard, the use of DNA biochips is has prospective applications in analyzing the expression of many genes simultaneously. In this paper, we suggest an optimal strategy of probes selection aimed at detecting the maximum number of mRNA splice variants generated by major participants of DR-signaling. The objects of the study were 185 genes that form 1134 mRNA isoforms. As a result, a biochip design was developed that enables the detection of 499 mRNA isoforms (44% of total mRNA splice variants). The proposed strategy combines a high degree of modularity, the use of modern high-performance computers, and broad opportunities for setting up the selection criteria in accordance with the objectives of the study. PMID- 26107907 TI - [An intriguing model for 5S rDNA sequences dispersion in the genome of freshwater stingray Potamotrygon motoro (Chondrichthyes: Potamotrygonidae)]. AB - 5S rDNA genes of the stingray Potamotrygon motoro were PCR replicated, purified, cloned and sequenced. Two distinct classes of segments of different sizes were obtained. The smallest, with 342 bp units, was classified as class I, and the largest, with 1900 bp units, was designated as class II. Alignment with the consensus sequences for both classes showed changes in a few bases in the 5S rDNA genes. TATA-like sequences were detected in the nontranscribed spacer (NTS) regions of class I and a microsatellite (GCT) 10 sequence was detected in the NTS region of class II. The results obtained can help to understand the molecular organization of ribosomal genes and the mechanism of gene dispersion. PMID- 26107908 TI - Metagenomic Investigation of Viral Communities in Ballast Water. AB - Ballast water is one of the most important vectors for the transport of non native species to new aquatic environments. Due to the development of new ballast water quality standards for viruses, this study aimed to determine the taxonomic diversity and composition of viral communities (viromes) in ballast and harbor waters using metagenomics approaches. Ballast waters from different sources within the North America Great Lakes and paired harbor waters were collected around the Port of Duluth-Superior. Bioinformatics analysis of over 550 million sequences showed that a majority of the viral sequences could not be assigned to any taxa associated with reference sequences, indicating the lack of knowledge on viruses in ballast and harbor waters. However, the assigned viruses were dominated by double-stranded DNA phages, and sequences associated with potentially emerging viral pathogens of fish and shrimp were detected with low amino acid similarity in both ballast and harbor waters. Annotation-independent comparisons showed that viromes were distinct among the Great Lakes, and the Great Lakes viromes were closely related to viromes of other cold natural freshwater systems but distant from viromes of marine and human designed/managed freshwater systems. These results represent the most detailed characterization to date of viruses in ballast water, demonstrating their diversity and the potential significance of the ship-mediated spread of viruses. PMID- 26107909 TI - Comparison of the effects of systemic sildenafil, tadalafil, and vardenafil treatments on skin flap survival in rats. AB - OBJECTIVE: The most important issue in flap surgery is flap viability. This study aimed to compare the effects of most commonly used phosphodiesterase type 5 (PDE5) inhibitors on flap survival. METHODS: A 3 * 9 cm flap was elevated from the dorsum of 32 Wistar albino rats. In the control group, saline was administered 2 hours before the flap elevation and continued for 2 days after the surgery. In the sildenafil, tadalafil, and vardenafil groups, the related drug was administered. Blood flow in the flaps was monitored with laser Doppler flowmetry. On postoperative day 7, flaps were photographed and biopsies were obtained. RESULTS: The ratios of flap necrosis area in the tadalafil, sildenafil, and vardenafil groups were lower than that in the control group, but without significant difference (p = 0.077). Histopathological evaluation revealed no significant difference among the groups. CONCLUSION: The ratio of flap necrosis area tended to be lower in the groups receiving oral PDE5 inhibitors than in the control group, although not statistically significant. The role of PDE5 inhibitors needs to be evaluated in larger studies before a conclusion can be made regarding their effects on flap viability. PMID- 26107910 TI - Visual Field Progressive Rate in Normal Tension Glaucoma Before and After Trabeculectomy. PMID- 26107911 TI - Visual Field Progressive Rate in Normal Tension Glaucoma Before and After Trabeculectomy: A Subfield-Based Analysis. AB - PURPOSE: To compare pretrabeculectomy and posttrabeculectomy progression rates in normal-tension glaucoma in 6 subfields of the central 30 visual field. DESIGN: A retrospective study. METHODS: Clinical records of 34 patients with normal-tension glaucoma (12 males and 22 females) with progressive visual field loss undergoing successful trabeculectomy were studied. The time course of the mean deviation (MD) and mean of total deviation in the superior/inferior arcuate, paracentral, and cecocentral subfields were analyzed using a linear mixed-effects model. RESULTS: Patients' age, intraocular pressure (IOP), MD, and pretrabeculectomy and posttrabeculectomy follow-up averaged 57.7 +/- 9.6 years, 15.7 +/- 1.7 mm Hg, 12.7 +/- 5.5 dB, and 4.6 +/- 1.5 and 5.7 +/- 1.2 years, respectively. Average IOP was lowered by 6.1 +/- 3.3 to 10.3 +/- 2.7 mm Hg (5-14 mm Hg) over the postoprerative period with MD change rate of -0.25 dB/y (P < 0.003), which was slower (P < 0.001) than the preoperative one (-0.70 dB/y). The preoperative mean of total deviation change rate (-0.31 to -1.35 dB/y) improved postoperatively in the superior and inferior paracentral subfields (P < 0.001), whereas it remained unchanged in the inferior cecocentral/arcuate subfields (P > 0.10). The postoperative rate of progression showed no significant variation in these subfields. CONCLUSIONS: The rate of progression significantly varied among the 6 subfields preoperatively. It was significantly slowed down in the superior subfields by surgical IOP reduction, but not in the inferior cecocentral/arcuate subfields. PMID- 26107912 TI - Increased Gait Speed After Cataract Surgery Confers Longer Predicted Survival. AB - PURPOSE: Cataract surgery has potential systemic health effects. Gait speed is a potential health index of predicted life expectancy and incidence of severe illness. We thus measured quality of vision and gait speed before and after cataract surgery. DESIGN: A prospective clinical study. METHODS: We followed up 30 patients for 6 months following cataract surgery by implantation of a yellow soft acrylic lens. A 4-m gait speed was determined, and patients were evaluated before and after surgery using the National Eye Institute Visual Function Questionnaire (vision-related quality of life) as well as ophthalmological and systemic examinations. Life span was estimated on the basis of standard curves derived from a literature. RESULTS: Mean preoperative gait speed was 0.81 +/- 0.23 m/s, with significant increases recorded at 2 and 6 months after surgery to 0.85 +/- 0.20 and 0.91 +/- 0.22 m/s, respectively (P < 0.01, paired t test). According to patient survival determined by gait speed, life expectancy (years) before and 6 months after surgery was approximately 83.4 and 84.9, respectively, for men (1.5-year increase) and 88.8 and 89.8, respectively, for women (1.0-year increase). The mean preoperative 25-item Visual Function Questionnaire score was 59.2 +/- 16.3, and significant improvements were observed 2 months (76.2 +/- 13.9) and 6 months (78.6 +/- 14.4) after surgery (P < 0.001, vs preoperative score). CONCLUSION: In conclusion, cataract surgery improved quality of vision and gait speed for 6 months. PMID- 26107913 TI - Diabetes and Diabetic Retinopathy Management in East Africa: Knowledge, Attitudes, and Practices of Hospital Staff in Kenya. AB - PURPOSE: Good diabetes mellitus (DM) and diabetic retinopathy (DR) management depends largely on involved medical staff, prompting us to investigate knowledge, attitudes, and practices about DM and DR at a tertiary referral center in Kenya. DESIGN: The design for this study is exploratory qualitative using semistructured interviews. METHODS: Data from eye and diabetes clinic staff were collected until thematic saturation was reached, transcribed, and iteratively analyzed for relevant themes based on the constant comparative method. RESULTS: Among 46 participants (mean age, 38 years; 54% females), most were physicians (n = 25, 54%), followed by nurses (n = 14, 30%) and clinical officers (n = 6, 13%). Diabetes mellitus and DR were seen as urgent health problems (n = 42, 91%), and regular ophthalmic screening of diabetic patients was universally recommended. Two thirds (n = 32, 70%) were unaware of DM and DR management guidelines at the hospital. Participants identified training of staff in diagnosing (n = 30, 65%), efficient detection and referral of diabetic patients (n = 24, 52%), and improved outreach services (n = 14, 30%) as most pressing areas of need. Communication among hospital departments was found to be suboptimal. Reported barriers to good DR management were lack of retinal laser treatment and costs. CONCLUSIONS: Management outcomes for DM and DR may be improved by implementing integrated service provision, direct ophthalmological involvement in diabetic clinics, endorsement and effective distribution of guidelines, an increase in screening capacity, and the introduction of ongoing medical education covering DM and DR. PMID- 26107914 TI - Factors Contributing to Discrepancy Between Visual Acuity Fractions Derived From a Snellen Chart and Letter Scores on the Early Treatment Diabetic Retinopathy Study Chart. AB - PURPOSE: To report factors influencing the relationship between visual acuity (VA) fractions measured on Snellen chart and letter scores on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. DESIGN: This was a retrospective review from a single ophthalmology outpatient clinic. METHODS: All patients had routine consecutive VA testing in the right eye using a Snellen chart (1-6 m) and the ETDRS chart (4 m and/or 1 m), by the same optometrist, using a standardized testing protocol for each chart. Both acuity fractions and letter scores were converted to their equivalent logarithm of minimum angle of resolution (logMAR) for comparison. Multiple regression analysis was performed. RESULTS: A total of 237 patients with a wide range of ocular disease and VAs were enrolled. Mean age was 63 years (range, 18-95 years). Recorded VA (logMAR) was better on Snellen chart by a mean (95% limits of agreement) of -0.07 (-0.33 to +0.18, P < 0.001). There was a trend for subjects with VA worse than 6/36 to read 3 to 6 letters more and those better than 6/36 to read 4 to 5 letters less on the ETDRS chart. Visual acuity level and amblyopia contributed to a small portion (17%-26%) of the total variance in the difference between logMAR equivalents derived from the 2 charts. CONCLUSIONS: The discrepancy in VA derived from Snellen and ETDRS charts was nonuniform across VA range. This has implications on interpretation of published studies converting Snellen fractions to logMAR for analysis and reporting of VA outcomes. PMID- 26107915 TI - The Prevalence and Determinants of Desire for and Use of Psychological Support in Patients With Low Vision. AB - PURPOSE: The objective of this study was to identify the prevalence and determinants of desire for and use of psychological support in patients with low vision. DESIGN: The study was cross-sectional, utilizing telephone-administered interviews. METHODS: Patients were recruited from Vision Australia and the Royal Victorian Eye and Ear Hospital with visual acuity of less than 6/12 in the better eye. Measures were the 9-item Patient Health Questionnaire, Stigma Scale for Receiving Psychological Help, Brief Illness Perception Questionnaire, and Impact of Vision Impairment Questionnaire. RESULTS: Of the total 161 participants (mean +/- SD, 69.94 +/- 15.76 years; 67% female), 63% desired psychological support, but only 20% reported ever receiving this. Higher levels of depressive symptoms and poorer coping in relation to vision impairment were significantly associated with desire for psychological support. Younger age, experience/s of depression, and beliefs about depression and its treatment were associated with use of professional support. CONCLUSIONS: Many patients with low vision desired psychological support but were not receiving this, suggesting barriers to receipt of care. This highlights the need for early screening of emotional difficulties, depression education, and easy access to psychological support within low vision services. PMID- 26107916 TI - Microbial Keratitis Due to Aeromonas Species at a Tertiary Eye Care Center in Southern India. AB - PURPOSE: To review the incidence, microbiological profile, antibiogram, clinical course, treatment, and outcome in patients with microbial keratitis due to Aeromonas species at a tertiary eye care center in Southern India. DESIGN: A retrospective, noncomparative study. METHODS: This study included all patients of corneal ulcer with a significant growth of Aeromonas species on culture of corneal scrapings managed at an eye institute in India between January 2005 and October 2011. The patients underwent standard diagnostic microbiological evaluation, and their treatment was guided by microbiology results and clinical response to therapy. Data were analyzed for the incidence, predisposing factors, clinical picture, microbiology, and the treatment outcome. RESULTS: Fifteen patients of microbial keratitis showed Aeromonas species to be the causative agent, constituting 0.5% of bacterial keratitis diagnosed during this period. Laboratory results showed that Aeromonas hydrophila was the predominant species isolated. Most of the isolates were susceptible to commonly used ocular antibiotics. Medical therapy resulted in resolution of infection in 9 (60%) of 15 cases. Five patients required application of cyanoacrylate tissue adhesive with bandage contact lens for corneal perforation. Two of the 5 patients needed penetrating keratoplasty for uncontrolled infection. Twelve of 15 patients had some local predisposing host factors for the infection. CONCLUSIONS: Aeromonas species are uncommon but important causal agents of microbial keratitis. The organisms most often cause infection in individuals with local predisposing factors. Aeromonas hydrophila is the predominant species associated with keratitis. Although the organisms are susceptible to most antibiotics, a third of the patients required additional surgical intervention. PMID- 26107917 TI - Ocular Pathology: Role of Emerging Viruses in the Asia-Pacific Region-A Review. AB - The role of viral infections in ocular pathology varies greatly, involving all the components of the eye. Some viruses like herpes simplex, herpes zoster, adenovirus, enterovirus 70, influenza virus, human immunodeficiency virus, and cytomegalovirus are well-known for their role in ocular pathology. In recent years, emerging and resurging viral infections represent an important public health problem. The Asia-Pacific region has witnessed a number of pandemic and epidemic outbreaks caused by these viruses during the last 2 decades. The number of ocular complications being reported in patients of these viral infections has also increased significantly during this period. Ophthalmologists and physicians should be aware of ocular manifestations of newly emerging or resurging viral diseases. We conducted a review of the literature published during the last 20 years with the objectives of finding out outbreaks of emerging and reemerging viruses in the Asia-Pacific region and finding out any ocular involvement in these viral infections. An iterative search of the MEDLINE and the Google databases was made using the search terms emerging virus, ocular manifestations, ocular complications, Chikungunya, Dengue, Japanese encephalitis, West Nile fever, Kyasanur forest disease, Rift valley fever, Hantavirus, Henipavirus, Influenza virus, Enterovirus 71, and Asia-Pacific region, separately and with reported ocular involvement in combination. This review article discusses the epidemiology and the systemic and ocular manifestations of all emerging viral infections with reported ocular involvement in the Asia-Pacific region. PMID- 26107918 TI - Technology and Intraocular Lenses to Enhance Cataract Surgery Outcomes-Annual Review (January 2013 to January 2014). AB - PURPOSE: This article is aimed to provide a clinical update on recent developments in cataract surgical techniques, with specific focus on femtosecond laser technology. The article also focuses on recent improvements in the technology used in implanting intraocular lenses (IOLs). DESIGN: Literature review. METHODS: The authors conducted a review of literature available in the last 12 months in the English language using PubMed. The period used to conduct the literature search was from January 1, 2013, to December 31, 2013. The following search terms were used during the PubMed search: phacoemulsification, femtosecond laser, toric IOLs, multifocal IOLs, multifocal toric IOLs, manual small-incision cataract surgery, outcomes, surgically induced astigmatism, rotational stability, trifocal IOLs, laser cataract surgery, safety, and efficacy. RESULTS: This review incorporates selected original articles that provide fresh insights and updates on the fields of toric and multifocal IOLs, femtosecond laser cataract surgery, and manual small-incision cataract surgery. Particular attention has been paid to observational, randomized controlled clinical trials, experimental trials, and analyses of larger cohorts with prospective and retrospective study designs. Letters to the editor, unpublished works, and abstracts do not fall under the purview of this review. CONCLUSIONS: This review is not designed to be all-inclusive. It highlights and provides insights on literature that is most useful and applicable to practicing ophthalmologists. PMID- 26107919 TI - Orbital Immunoglobulin G4-Related Disease: A Systematic Review. AB - Immunoglobulin G4-related disease (IgG4-RD) is a clinically distinct systemic condition that can involve the orbital tissue. Characterized by a triad of a mass forming lesion, infiltration by IgG4-positive plasma cells, and elevated serum IgG4 titers in many cases, IgG4-RD has clinicopathologic features that overlap with ocular adnexal lymphomas and orbital inflammatory conditions. Although most cases of orbital IgG4-RD respond well to steroids, it may become necessary to include supplemental immunosuppressant therapy in the management. PMID- 26107920 TI - Letter to the Editor Regarding "Predicted Trends in the Incidence of Retinoblastoma in the Asia-Pacific Region". PMID- 26107921 TI - Authors' Reply for "Predicted Trends in the Incidence of Retinoblastoma in the Asia-Pacific Region". PMID- 26107922 TI - Association Between Obstetric Mode of Delivery and Autism Spectrum Disorder: A Population-Based Sibling Design Study. AB - IMPORTANCE: Because the rates of cesarean section (CS) are increasing worldwide, it is becoming increasingly important to understand the long-term effects that mode of delivery may have on child development. OBJECTIVE: To investigate the association between obstetric mode of delivery and autism spectrum disorder (ASD). DESIGN, SETTING, AND PARTICIPANTS: Perinatal factors and ASD diagnoses based on the International Classification of Diseases, Ninth Revision (ICD-9),and the International Statistical Classification of Diseases, 10th Revision (ICD 10),were identified from the Swedish Medical Birth Register and the Swedish National Patient Register. We conducted stratified Cox proportional hazards regression analysis to examine the effect of mode of delivery on ASD. We then used conditional logistic regression to perform a sibling design study, which consisted of sibling pairs discordant on ASD status. Analyses were adjusted for year of birth (ie, partially adjusted) and then fully adjusted for various perinatal and sociodemographic factors. The population-based cohort study consisted of all singleton live births in Sweden from January 1, 1982, through December 31, 2010. Children were followed up until first diagnosis of ASD, death, migration, or December 31, 2011 (end of study period), whichever came first. The full cohort consisted of 2,697,315 children and 28,290 cases of ASD. Sibling control analysis consisted of 13,411 sibling pairs. EXPOSURES: Obstetric mode of delivery defined as unassisted vaginal delivery (VD), assisted VD, elective CS, and emergency CS (defined by before or after onset of labor). MAIN OUTCOMES AND MEASURES: The ASD status as defined using codes from the ICD-9 (code 299) and ICD 10 (code F84). RESULTS: In adjusted Cox proportional hazards regression analysis, elective CS (hazard ratio, 1.21; 95% CI, 1.15-1.27) and emergency CS (hazard ratio, 1.15; 95% CI, 1.10-1.20) were associated with ASD when compared with unassisted VD. In the sibling control analysis, elective CS was not associated with ASD in partially (odds ratio [OR], 0.97; 95% CI, 0.85-1.11) or fully adjusted (OR, 0.89; 95% CI, 0.76-1.04) models. Emergency CS was significantly associated with ASD in partially adjusted analysis (OR, 1.20; 95% CI, 1.06-1.36), but this effect disappeared in the fully adjusted model (OR, 0.97; 95% CI, 0.85 1.11). CONCLUSIONS AND RELEVANCE: This study confirms previous findings that children born by CS are approximately 20% more likely to be diagnosed as having ASD. However, the association did not persist when using sibling controls, implying that this association is due to familial confounding by genetic and/or environmental factors. PMID- 26107923 TI - Rhodium-Catalyzed Enantioselective Hydroamination of Alkynes with Indolines. AB - The hydroamination of internal alkynes via tandem rhodium catalysis gives branched N-allylic indolines with high regio- and enantioselectivity. An acid switch provides access to the linear isomer in preference to the branched isomer by an isomerization mechanism. Mechanistic studies suggest formation of an allene intermediate, which undergoes hydroamination to generate allylic amines instead of the enamine or imine products typically observed in alkyne hydroaminations. PMID- 26107925 TI - Scenes of fathering: The automobile as a place of occupation. AB - OBJECTIVE: While occupations are increasingly analyzed within contexts, other than the home, the ordinary places that facilitate occupations have been overlooked. The aim of this article is to explore the automobile as a place of occupation using data from an ethnographic study of fathers of children with disabilities. METHODS: Qualitative data obtained through observations and interviews with the fathers and their families were analyzed using a narrative approach. Properties that influence interactions include opportunities to communicate, the vehicle itself, and electronics. RESULTS: Driving children in the automobile fulfills fathering responsibilities and is a time for connecting. For the fathers in this study, the automobile represents a place for negotiating complex demands of fathering. CONCLUSIONS: This study demonstrates not only the importance of the automobile, but also the influence of the immediate space on the construction of occupations. PMID- 26107926 TI - A novel cascade strategy with supramolecular and chemodosimetric methods for designing a fluorescent ratiometric detector hypersensitive to trace water. AB - An intensely fluorescent zinc-salicylideneimine complex (-Zn(II)) was developed as a fluorescent ratiometric detector for the quantitative determination of trace water contents both in THF and methanol. It works based on a water-triggered cascade process: the dissociation reaction of the supramolecular ensemble and the subsequent hydrolysis reaction of its ligand. PMID- 26107924 TI - Using ClinicalTrials.gov to supplement information in ophthalmology conference abstracts about trial outcomes: a comparison study. AB - BACKGROUND: Including results from unpublished randomized controlled trials (RCTs) in a systematic review may ameliorate the effect of publication bias in systematic review results. Unpublished RCTs are sometimes described in abstracts presented at conferences, included in trials registers, or both. Trial results may not be available in a trials register and abstracts describing RCT results often lack study design information. Complementary information from a trials register record may be sufficient to allow reliable inclusion of an unpublished RCT only available as an abstract in a systematic review. METHODS: We identified 496 abstracts describing RCTs presented at the 2007 to 2009 Association for Research in Vision and Ophthalmology (ARVO) meetings; 154 RCTs were registered in ClinicalTrials.gov. Two persons extracted verbatim primary and non-primary outcomes reported in the abstract and ClinicalTrials.gov record. We compared each abstract outcome with all ClinicalTrials.gov outcomes and coded matches as complete, partial, or no match. RESULTS: We identified 800 outcomes in 152 abstracts (95 primary [51 abstracts] and 705 [141 abstracts] non-primary outcomes). No outcomes were reported in 2 abstracts. Of 95 primary outcomes, 17 (18%) agreed completely, 53 (56%) partially, and 25 (26%) had no match with a ClinicalTrials.gov primary or non-primary outcome. Among 705 non-primary outcomes, 56 (8%) agreed completely, 205 (29%) agreed partially, and 444 (63%) had no match with a ClinicalTrials.gov primary or non-primary outcome. Among the 258 outcomes partially agreeing, we found additional information on the time when the outcome was measured more often in ClinicalTrials.gov than in the abstract (141/258 (55%) versus 55/258 (21%)). We found no association between the presence of non-matching "new" outcomes and year of registration, time to registry update, industry sponsorship, or multi-center status. CONCLUSION: Conference abstracts may be a valuable source of information about results for outcomes of unpublished RCTs that have been registered in ClinicalTrials.gov. Complementary additional descriptive information may be present for outcomes reported in both sources. However, ARVO abstract authors also present outcomes not reported in ClinicalTrials.gov and these may represent analyses not originally planned. PMID- 26107928 TI - Anatomical landmarks of the lateral nasal wall: implications for endonasal lacrimal surgery. AB - PURPOSE OF REVIEW: An accurate understanding of the anatomy of the lateral nasal wall is key to achieving complete exposure of the lacrimal sac during endonasal dacryocystorhinostomy (EnDCR) and the avoidance of complications such as basal skull fracture and orbital fat prolapse. This review provides a comprehensive summary of the clinical and cadaveric anatomical studies of the lateral nasal wall to date and their application to endonasal lacrimal surgery. RECENT FINDINGS: The maxillary line and the axilla of the middle turbinate are the major landmarks commonly utilized by lacrimal surgeons to localize the lacrimal sac. Numerous clinical, cadaveric and radiologic studies have attempted to define the relationship of these and other important anatomical landmarks, closely related to the lacrimal sac and routinely encountered during endonasal surgery, such as the frontal process of the maxilla, the agger nasi air cell and the uncinate process. A greater understanding of the relevant endonasal anatomy over time has led to safer and more effective surgical techniques. SUMMARY: Greater insights into the precise anatomical relationship of the lacrimal sac to other structures on the lateral nasal wall has enabled lacrimal surgeons to perform EnDCR surgery in a more accurate, efficient and well tolerated manner, matching its success to that of the external approach. PMID- 26107927 TI - Beat Synchronization across the Lifespan: Intersection of Development and Musical Experience. AB - Rhythmic entrainment, or beat synchronization, provides an opportunity to understand how multiple systems operate together to integrate sensory-motor information. Also, synchronization is an essential component of musical performance that may be enhanced through musical training. Investigations of rhythmic entrainment have revealed a developmental trajectory across the lifespan, showing synchronization improves with age and musical experience. Here, we explore the development and maintenance of synchronization in childhood through older adulthood in a large cohort of participants (N = 145), and also ask how it may be altered by musical experience. We employed a uniform assessment of beat synchronization for all participants and compared performance developmentally and between individuals with and without musical experience. We show that the ability to consistently tap along to a beat improves with age into adulthood, yet in older adulthood tapping performance becomes more variable. Also, from childhood into young adulthood, individuals are able to tap increasingly close to the beat (i.e., asynchronies decline with age), however, this trend reverses from younger into older adulthood. There is a positive association between proportion of life spent playing music and tapping performance, which suggests a link between musical experience and auditory-motor integration. These results are broadly consistent with previous investigations into the development of beat synchronization across the lifespan, and thus complement existing studies and present new insights offered by a different, large cross-sectional sample. PMID- 26107929 TI - Catalytic chemoselective [3+3] cycloadditions of azomethine ylides with quinone monoimides leading to the construction of a dihydrobenzoxazine scaffold. AB - A chemoselective [3+3] cycloaddition of in situ generated azomethine ylides with quinone monoimides has been established, which efficiently led to the construction of dihydrobenzoxazine frameworks with biological relevance, with excellent chemoselectivities and high yields (up to >95 : 5 cr and 98% yield). PMID- 26107930 TI - Hepatitis C (chronic). AB - INTRODUCTION: About 60% to 85% of people infected with hepatitis C virus will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population. METHODS AND OUTCOMES: We conducted a systematic overview and aimed to answer the following clinical questions: What are the effects of interferon-free treatments in treatment-naive people with chronic hepatitis C infection without cirrhosis? What are the effects of interferon-free treatments in treatment-naive people with chronic hepatitis C infection with cirrhosis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this review). RESULTS: After deduplication and removal of conference abstracts, 30 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 11 studies and the further review of 19 full publications. Of the 19 full articles evaluated, two systematic reviews and one RCT were added. We performed a GRADE evaluation for two PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for 12 different intervention/comparison combinations, based on information relating to the effectiveness and safety of sofosbuvir (with or without ribavirin), sofosbuvir (with or without ribavirin) plus ledipasvir, and sofosbuvir (with or without ribavirin) plus simeprevir, all in people with and without cirrhosis. PMID- 26107931 TI - Adhesive force measurement between HOPG and zinc oxide as an indicator for interfacial bonding of carbon fiber composites. AB - Vertically aligned zinc oxide (ZnO) nanowires have recently been utilized as an interphase to increase the interfacial strength of carbon fiber composites. It was shown that the interaction between the carbon fiber and the ZnO nanowires was a critical parameter in adhesion; however, fiber based testing techniques are dominated by local defects and cannot be used to effectively study the bonding interaction directly. Here, the strength of the interface between ZnO and graphitic carbon is directly measured with atomic force microscopy (AFM) using oxygen plasma treated highly oriented pyrolytic graphite (HOPG) and an AFM tip coated with ZnO nanoparticles. X-ray photoelectron spectroscopy analysis is used to compare the surface chemistry of HOPG and carbon fiber and to quantify the presence of various oxygen functional groups. An indirect measurement of the interfacial strength is then performed through single fiber fragmentation testing (SFF) on functionalized carbon fibers coated with ZnO nanowires to validate the AFM measurements. The SFF and AFM methods showed the same correlation, demonstrating the capacity of the AFM method to study the interfacial properties in composite materials. Additionally, the chemical interactions between oxygen functional groups and the ionic structure of ZnO suggest that intermolecular forces at the interface are responsible for the strong interface. PMID- 26107932 TI - Leaving Group Effects on the Selectivity of the Silylation of Alcohols: The Reactivity-Selectivity Principle Revisited. AB - TBS protection of primary alcohol naphthalen-1-ylmethanol (4a) and secondary alcohol 1-(naphthalen-1-yl)ethanol (4b) has been studied under various reaction conditions. The primary/secondary selectivity is largest in the comparatively slow Lewis base catalyzed silylation in apolar solvents and systematically lower in DMF. Lowest selectivities (and fastest reaction rates) are found for TBS triflate 1b, where only minor effects of solvent polarity or Lewis base catalysis can be observed. PMID- 26107933 TI - Movement patterns, habitat use and site fidelity of the white croaker (Genyonemus lineatus) in the Palos Verdes Superfund Site, Los Angeles, California. AB - White croaker (Genyonemus lineatus family: Sciaenidae) are a schooling, benthic foraging fish historically associated with soft sediment and wastewater outfalls in southern California. While they are often used as an indicator species due to their high organochlorine contaminant loads, little is known of their movements in relation to contaminated habitats. A Vemco Positioning System acoustic telemetry array was used to collect fine-scale movement data and characterize the site fidelity, area use, and dispersal of 83 white croaker on the Palos Verdes Shelf Superfund Site, California over 27 months. White croaker generally demonstrated low residency and recurrence to the Palos Verdes Shelf, and were observed to be largely nomadic. However, individual behavior was highly variable. Although the entire monitored shelf was visited by tagged white croaker, habitats in 0-200 m proximity to wastewater outfalls and between 25 and 35 m depth were used most frequently. Approximately half of white croaker migrated into Los Angeles and Long Beach Harbors; areas where they may be targeted by subsistence fishers. A model framework for incorporating fish movement data into contaminant exposure estimates was developed to better understanding organochlorine contaminant exposure for planning future remediation and monitoring. PMID- 26107934 TI - Correction: EGR1 functions as a potent repressor of MEF2 transcriptional activity. PMID- 26107935 TI - Risk of premotor symptoms in patients with newly diagnosed PD: a nationwide, population-based, case-control study in Taiwan. AB - BACKGROUND: To evaluate the risk of premotor symptoms, namely rapid eye movement behavior disorder (RBD), constipation, and depression among patients with newly diagnosed Parkinson disease (PD). METHODS: A total of 705 PD patients and 2,820 control subjects were selected from the Taiwan National Health Insurance Research Database. Patients were traced back for a maximum of 14 years to determine the diagnoses of RBD, depression, and constipation. Logistic regression analysis was used to identify risk of premotor symptoms for PD. Moreover, subgroup analyses were performed by dividing the patients into a middle-age onset group (<= 64 years) and an old-age onset group (>= 65 years). The associations between these premotor symptoms and age of PD onset were further examined. RESULTS: An association was found between a history of premotor symptoms and newly diagnosed PD in which a high occurrence of premotor symptoms was identified in PD patients as compared to selected controls (4.3% vs. 1.2% for RBD, 40.4% vs. 24.0% for constipation, and 13.0% vs. 5.1% for depression). The strength of this association remained statistically significant after adjustment for potential confounders (3.69 fold risk for RBD, 2.36 for constipation, and 2.82 for depression, all p < 0.0001). The average interval between premotor symptoms and PD ranged from 4.5 to 6.2 years. RBD and depression carried higher risks for PD in the middle-age onset group than in the old-age onset group (7.20- vs. 2.24 fold risk for RBD, 6.06 vs. 1.40 for depression). CONCLUSION: The prevalence of premotor symptoms was higher among the PD patients than in the controls. Premotor symptoms appeared to be associated with a higher risk for PD in subjects with an earlier age of onset. PMID- 26107936 TI - ErmF and ereD are responsible for erythromycin resistance in Riemerella anatipestifer. AB - To investigate the genetic basis of erythromycin resistance in Riemerella anatipestifer, the MIC to erythromycin of 79 R. anatipestifer isolates from China and one typed strain, ATCC11845, were evaluated. The results showed that 43 of 80 (53.8%) of the tested R. anatipestifer strains showed resistance to erythromycin, and 30 of 43 erythromycin-resistant R. anatipestifer strains carried ermF or ermFU with an MIC in the range of 32-2048 MUg/ml, while the other 13 strains carrying the ereD gene exhibited an MIC of 4-16 MUg/ml. Of 30 ermF + R. anatipestifer strains, 27 (90.0%) carried the ermFU gene which may have been derived from the CTnDOT-like element, while three other strains carried ermF from transposon Tn4351. Moreover, sequence analysis revealed that ermF, ermFU, and ereD were located within the multiresistance region of the R. anatipestifer genome. PMID- 26107937 TI - Prognostic Significance of the Systemic Inflammatory and Immune Balance in Alcoholic Liver Disease with a Focus on Gender-Related Differences. AB - OBJECTIVES: Mechanisms of immune regulation in alcoholic liver disease (ALD) are still unclear. The aim of our study was to determine an impact of Th17 / regulatory T (Treg) cells balance and its corresponding cytokine profile on the ALD outcome. Possible gender-related differences in the alcohol-induced inflammatory response were also assessed. MATERIALS AND METHODS: 147 patients with ALD were prospectively recruited, assigned to subgroups based on their gender, severity of liver dysfunction and presence of ALD complications at admission, and followed for 90 days. Peripheral blood frequencies of Th17 and Treg cells together with IL-1beta, IL-6, IL-17A, IL-23, and TGF-beta1 levels were investigated. Flow cytometry was used to identify T cell phenotype and immunoenzymatic ELISAs for the corresponding cytokine concentrations assessment. Multivariable logistic regression was applied in order to select independent predictors of advanced liver dysfunction and the disease complications. RESULTS: IL-17A, IL-1beta, IL-6 levels were significantly increased, while TGF-beta1 decreased in ALD patients. The imbalance with significantly higher Th17 and lower Treg frequencies was observed in non-survivors. IL-6 and TGF-beta1 levels differed in relation to patient gender in ALD group. Concentrations of IL-6 were associated with the severity of liver dysfunction, development of ALD complications, and turned out to be the only independent immune predictor of 90 day survival in the study cohort. CONCLUSIONS: We conclude that IL-6 revealed the highest diagnostic and prognostic potential among studied biomarkers and was related to the fatal ALD course. Gender-related differences in immune regulation might influence the susceptibility to alcohol-associated liver injury. PMID- 26107938 TI - Early-onset atopic dermatitis in children: which are the phenotypes at risk of asthma? Results from the ORCA cohort. AB - BACKGROUND: Atopic dermatitis (AD) is known to predate asthma and other atopic disorders described under the term "atopic march". However, this classic sequence is not always present and only a few studies have addressed children at risk of developing asthma. The objective of this study is to define early-onset AD phenotypes leading to asthma. METHODS: We performed a cluster analysis with 9 variables of 214 infants with early-onset AD prospectively enrolled in the ORCA cohort and followed each year on the occurrence of asthma until the age of 6. RESULTS: We identified 3 clusters - cluster 1 (n = 94) with low to no sensitization to food (27.7%) or aeroallergens (10.6%) and moderate AD severity (SCORAD 25.29 +/- 14.6) called "AD with low sensitization"; - cluster 2 (n = 84) characterized by a higher AD severity (SCORAD 32.66+/-16.6) and frequent sensitization to food (98.9%) or aeroallergens (26.2%), most likely multiple (96.4% for food allergens), called "AD with multiple sensitizations" - cluster 3 (n = 36) with parental history, moderate AD severity (SCORAD 24.46+/-15.7), moderate rate of sensitization to food allergens (38.9%) (exclusively single) with no sensitization to aeroallergens, called "AD with familial history of asthma". Percentages of children suffering from asthma at the age of 6 were higher in clusters 2 and 3 (36.1% and 33.3% respectively versus 14.9% in cluster 1, p<0.01). CONCLUSION: Two phenotypes in infants with early-onset AD convey a higher risk of developing asthma during childhood: multiple sensitization and familial history of asthma. PMID- 26107939 TI - Foxg1-Cre Mediated Lrp2 Inactivation in the Developing Mouse Neural Retina, Ciliary and Retinal Pigment Epithelia Models Congenital High Myopia. AB - Myopia is a common ocular disorder generally due to increased axial length of the eye-globe. Its extreme form high myopia (HM) is a multifactorial disease leading to retinal and scleral damage, visual impairment or loss and is an important health issue. Mutations in the endocytic receptor LRP2 gene result in Donnai Barrow (DBS) and Stickler syndromes, both characterized by HM. To clearly establish the link between Lrp2 and congenital HM we inactivated Lrp2 in the mouse forebrain including the neural retina and the retinal and ciliary pigment epithelia. High resolution in vivo MRI imaging and ophthalmological analyses showed that the adult Lrp2-deficient eyes were 40% longer than the control ones mainly due to an excessive elongation of the vitreal chamber. They had an apparently normal intraocular pressure and developed chorioretinal atrophy and posterior scleral staphyloma features reminiscent of human myopic retinopathy. Immunomorphological and ultrastructural analyses showed that increased eye lengthening was first observed by post-natal day 5 (P5) and that it was accompanied by a rapid decrease of the bipolar, photoreceptor and retinal ganglion cells, and eventually the optic nerve axons. It was followed by scleral thinning and collagen fiber disorganization, essentially in the posterior pole. We conclude that the function of LRP2 in the ocular tissues is necessary for normal eye growth and that the Lrp2-deficient eyes provide a unique tool to further study human HM. PMID- 26107940 TI - Adaptations to Hydrothermal Vent Life in Kiwa tyleri, a New Species of Yeti Crab from the East Scotia Ridge, Antarctica. AB - Hydrothermal vents in the Southern Ocean are the physiologically most isolated chemosynthetic environments known. Here, we describe Kiwa tyleri sp. nov., the first species of yeti crab known from the Southern Ocean. Kiwa tyleri belongs to the family Kiwaidae and is the visually dominant macrofauna of two known vent sites situated on the northern and southern segments of the East Scotia Ridge (ESR). The species is known to depend on primary productivity by chemosynthetic bacteria and resides at the warm-eurythermal vent environment for most of its life; its short-range distribution away from vents (few metres) is physiologically constrained by the stable, cold waters of the surrounding Southern Ocean. Kiwa tylerihas been shown to present differential life history adaptations in response to this contrasting thermal environment. Morphological adaptations specific to life in warm-eurythermal waters, as found on - or in close proximity of - vent chimneys, are discussed in comparison with adaptations seen in the other two known members of the family (K. hirsuta, K. puravida), which show a preference for low temperature chemosynthetic environments. PMID- 26107941 TI - Chick Chorioallantoic Membrane Assay: A 3D Animal Model for Study of Human Nasopharyngeal Carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer. However, mechanistic study of the invasion and metastasis of NPC has been hampered by the lack of proper in vivo models. We established an in vivo chick embryo chorioallantoic membrane (CAM) model to study NPC tumor biology. We found 100% micro-tumor formation 3 days after inoculation with NPC cell lines (4/4) or primary tumor biopsy tissue (35/35). The transplanted NPC micro-tumors grew on CAMs with extracellular matrix interaction and induced angiogenesis. In addition, the CAM model could be used to study the growth of transplanted NPC tumors and also several important steps of metastasis, including tumor invasion by detecting the extent of basement membrane penetration, tumor angiogenesis by analyzing the area of neo-vessels, and tumor metastasis by quantifying tumor cells in distant organs. We established and described a feasible, easy-to-manipulate and reliable CAM model for in vivo study of NPC tumor biology. This model closely simulates the clinical features of NPC growth, progression and metastasis and could help elucidate the biological mechanisms of the growth pattern and invasion of NPC cells and in quantitative assessment of angiogenesis and cell intravasation. PMID- 26107942 TI - Vasopressin Infusion with Small-Volume Fluid Resuscitation during Hemorrhagic Shock Promotes Hemodynamic Stability and Survival in Swine. AB - INTRODUCTION: Current management of hemorrhagic shock (HS) in the battlefield and civilian settings favors small-volume fluid resuscitation before controlling the source of bleeding. We investigated in a swine model of HS the effects of vasopressin infusion along with small-volume fluid resuscitation; with erythropoietin (EPO) and HS severity as additional factors. METHODS: HS was induced in 24 male domestic pigs (36 to 41 kg) by blood withdrawal (BW) through a right atrial cannula modeling spontaneous bleeding by a mono-exponential decay function. The initial 12 pigs received no fluids; the last 12 pigs received normal saline (NS) half the BW volume. Pigs were randomized 2:1 to receive intraosseously vasopressin (0.04 U/kg.min-1) or vehicle control from minute 7 to minute 210. Pigs assigned to vasopressin were further randomized 1:1 to receive EPO (1,200 U/kg) or vehicle control and 1:1 to have 65% or 75% BW of their blood volume. Shed blood was reinfused at 210 minutes and the pigs recovered from anesthesia. RESULTS: Survival at 72 hours was influenced by vasopressin and NS but not by EPO or % BW. Vasopressin with NS promoted the highest survival (8/8) followed by vasopressin without NS (3/8), NS without vasopressin (1/4), and neither treatment (0/4) with overall statistical significance (log-rank test, p = 0.009) and each subset different from vasopressin with NS by Holm-Sidak test. Vasopressin increased systemic vascular resistance whereas NS increased cardiac output. CONCLUSION: Vasopressin infusion with small-volume fluid resuscitation during severe HS was highly effective enabling critical hemodynamic stabilization and improved 72 hour survival. PMID- 26107943 TI - Measurement of Shoulder Range of Motion in Patients with Adhesive Capsulitis Using a Kinect. AB - Range of motion (ROM) measurements are essential for the evaluation for and diagnosis of adhesive capsulitis of the shoulder (AC). However, taking these measurements using a goniometer is inconvenient and sometimes unreliable. The Kinect (Microsoft, Seattle, WA, USA) is gaining attention as a new motion detecting device that is nonintrusive and easy to implement. This study aimed to apply Kinect to measure shoulder ROM in AC; we evaluated its validity by calculating the agreement of the measurements obtained using Kinect with those obtained using goniometer and assessed its utility for the diagnosis of AC. Both shoulders of 15 healthy volunteers and affected shoulders of 12 patients with AC were included in the study. The passive and active ROM of each were measured with a goniometer for flexion, abduction, and external rotation. Their active shoulder motions for each direction were again captured using Kinect and the ROM values were calculated. The agreement between the two measurements was tested with the intraclass correlation coefficient (ICC). Diagnostic performance using the Kinect ROM was evaluated with Cohen's kappa value. The cutoff values of the limited ROM were determined in the following ways: the same as passive ROM values, reflecting the mean difference, and based on receiver operating characteristic curves. The ICC for flexion/abduction/external rotation between goniometric passive ROM and the Kinect ROM were 0.906/0.942/0.911, while those between active ROMs and the Kinect ROMs were 0.864/0.932/0.925. Cohen's kappa values were 0.88, 0.88, and 1.0 with the cutoff values in the order above. Measurements of the shoulder ROM using Kinect show excellent agreement with those taken using a goniometer. These results indicate that the Kinect can be used to measure shoulder ROM and to diagnose AC as an alternative to goniometer. PMID- 26107944 TI - BASiCS: Bayesian Analysis of Single-Cell Sequencing Data. AB - Single-cell mRNA sequencing can uncover novel cell-to-cell heterogeneity in gene expression levels in seemingly homogeneous populations of cells. However, these experiments are prone to high levels of unexplained technical noise, creating new challenges for identifying genes that show genuine heterogeneous expression within the population of cells under study. BASiCS (Bayesian Analysis of Single Cell Sequencing data) is an integrated Bayesian hierarchical model where: (i) cell-specific normalisation constants are estimated as part of the model parameters, (ii) technical variability is quantified based on spike-in genes that are artificially introduced to each analysed cell's lysate and (iii) the total variability of the expression counts is decomposed into technical and biological components. BASiCS also provides an intuitive detection criterion for highly (or lowly) variable genes within the population of cells under study. This is formalised by means of tail posterior probabilities associated to high (or low) biological cell-to-cell variance contributions, quantities that can be easily interpreted by users. We demonstrate our method using gene expression measurements from mouse Embryonic Stem Cells. Cross-validation and meaningful enrichment of gene ontology categories within genes classified as highly (or lowly) variable supports the efficacy of our approach. PMID- 26107945 TI - MiR-133a Is Functionally Involved in Doxorubicin-Resistance in Breast Cancer Cells MCF-7 via Its Regulation of the Expression of Uncoupling Protein 2. AB - The development of novel targeted therapies holds promise for conquering chemotherapy resistance, which is one of the major hurdles in current breast cancer treatment. Previous studies indicate that mitochondria uncoupling protein 2 (UCP-2) is involved in the development of chemotherapy resistance in colon cancer and lung cancer cells. In the present study we found that lower level of miR133a is accompanied by increased expression of UCP-2 in Doxorubicin-resistant breast cancer cell cline MCF-7/Dox as compared with its parental cell line MCF-7. We postulated that miR133a might play a functional role in the development of Doxorubicin-resistant in breast cancer cells. In this study we showed that: 1) exogenous expression of miR133a in MCF-7/Dox cells can sensitize their reaction to the treatment of Doxorubicin, which is coincided with reduced expression of UCP-2; 2) knockdown of UCP-2 in MCF-7/Dox cells can also sensitize their reaction to the treatment of Doxorubicin; 3) intratumoral delivering of miR133a can restore Doxorubicin treatment response in Doxorubicin-resistant xenografts in vivo, which is concomitant with the decreased expression of UCP-2. These findings provided direct evidences that the miR133a/UCP-2 axis might play an essential role in the development of Doxorubicin-resistance in breast cancer cells, suggesting that the miR133a/UCP-2 signaling cohort could be served as a novel therapeutic target for the treatment of chemotherapy resistant in breast cancer. PMID- 26107946 TI - Three-Dimensional Reconstruction, by TEM Tomography, of the Ultrastructural Modifications Occurring in Cucumis sativus L. Mitochondria under Fe Deficiency. AB - BACKGROUND: Mitochondria, as recently suggested, might be involved in iron sensing and signalling pathways in plant cells. For a better understanding of the role of these organelles in mediating the Fe deficiency responses in plant cells, it is crucial to provide a full overview of their modifications occurring under Fe-limited conditions. The aim of this work is to characterize the ultrastructural as well as the biochemical changes occurring in leaf mitochondria of cucumber (Cucumis sativus L.) plants grown under Fe deficiency. METHODOLOGY/RESULTS: Mitochondrial ultrastructure was investigated by transmission electron microscopy (TEM) and electron tomography techniques, which allowed a three-dimensional (3D) reconstruction of cellular structures. These analyses reveal that mitochondria isolated from cucumber leaves appear in the cristae junction model conformation and that Fe deficiency strongly alters both the number and the volume of cristae. The ultrastructural changes observed in mitochondria isolated from Fe-deficient leaves reflect a metabolic status characterized by a respiratory chain operating at a lower rate (orthodox-like conformation) with respect to mitochondria from control leaves. CONCLUSIONS: To our knowledge, this is the first report showing a 3D reconstruction of plant mitochondria. Furthermore, these results suggest that a detailed characterization of the link between changes in the ultrastructure and functionality of mitochondria during different nutritional conditions, can provide a successful approach to understand the role of these organelles in the plant response to Fe deficiency. PMID- 26107947 TI - Greater cognitive decline with aging among elders with high serum concentrations of organochlorine pesticides. AB - Although cognitive decline is very common in elders, age-related cognitive decline substantially differs among elders and the determinants of the differences in age-related cognitive decline are unclear. We investigated our hypothesis that the association between age and cognition was stronger in those with higher serum concentrations of organochlorine (OC) pesticides, common persistent and strongly lipophilic neurotoxic chemicals. Participants were 644 elders aged 60-85, participating in the National Health and Nutrition Examination Survey 1999-2002. Six OC pesticides (p,p'-dichlorodiphenyltrichloroethane (DDT), p,p'-dichlorodipenyldichloroethylene (DDE), beta-hexachlorocyclohexane, trans nonachlor, oxychlordane, and heptachlor epoxide) were evaluated. "Lower cognitive function" was defined as having a low Digit-Symbol Substitution Test (DSST) score (<25th percentile of DSST score, cutpoint 28 symbols substituted). Higher levels of beta-hexachlorocyclohexane, trans-nonachlor, oxychlordane, and heptachlor epoxide modified the associations between age and lower cognitive function (Pinteraction<0.01, 0.03, <0.01, and 0.02, respectively). Elders in the 3rd tertile of these chemicals demonstrated a greater risk of lower cognitive function with aging, compared to those in the combined 1st and 2nd tertiles. Among those with highest OC pesticides (3rd tertile), the odds ratio for the risk of lower cognitive function was about 6 to 11 for the highest quintile of age (80 85 years) vs. the first quintile of age (60-63 years), while the association between age and lower cognitive function became flatter in those with lower OC pesticides (combined 1st and 2nd tertiles). Both DDT and DDE showed no interaction, with lower DSST scores for higher age irrespective of serum concentrations of DDT or DDE. Even though DSST score measures only one aspect of cognition, several OC pesticides modified aging-related prevalence of low cognitive score, a finding which should be evaluated in prospective studies. PMID- 26107948 TI - Biogenic Mn-Oxides in Subseafloor Basalts. AB - The deep biosphere of the subseafloor basalts is recognized as a major scientific frontier in disciplines like biology, geology, and oceanography. Recently, the presence of fungi in these environments has involved a change of view regarding diversity and ecology. Here, we describe fossilized fungal communities in vugs in subseafloor basalts from a depth of 936.65 metres below seafloor at the Detroit Seamount, Pacific Ocean. These fungal communities are closely associated with botryoidal Mn oxides composed of todorokite. Analyses of the Mn oxides by Electron Paramagnetic Resonance spectroscopy (EPR) indicate a biogenic signature. We suggest, based on mineralogical, morphological and EPR data, a biological origin of the botryoidal Mn oxides. Our results show that fungi are involved in Mn cycling at great depths in the seafloor and we introduce EPR as a means to easily identify biogenic Mn oxides in these environments. PMID- 26107950 TI - Correction: individual topographic variability is inherent to cortical physiology but task-related differences may be noise. PMID- 26107949 TI - Whole Exome Sequencing Reveals Novel PHEX Splice Site Mutations in Patients with Hypophosphatemic Rickets. AB - OBJECTIVE: Hypophosphatemic rickets (HR) is a heterogeneous genetic phosphate wasting disorder. The disease is most commonly caused by mutations in the PHEX gene located on the X-chromosome or by mutations in CLCN5, DMP1, ENPP1, FGF23, and SLC34A3. The aims of this study were to perform molecular diagnostics for four patients with HR of Indian origin (two independent families) and to describe their clinical features. METHODS: We performed whole exome sequencing (WES) for the affected mother of two boys who also displayed the typical features of HR, including bone malformations and phosphate wasting. B-lymphoblast cell lines were established by EBV transformation and subsequent RT-PCR to investigate an uncommon splice site variant found by WES. An in silico analysis was done to obtain accurate nucleotide frequency occurrences of consensus splice positions other than the canonical sites of all human exons. Additionally, we applied direct Sanger sequencing for all exons and exon/intron boundaries of the PHEX gene for an affected girl from an independent second Indian family. RESULTS: WES revealed a novel PHEX splice acceptor mutation in intron 9 (c.1080-3C>A) in a family with 3 affected individuals with HR. The effect on splicing of this mutation was further investigated by RT-PCR using RNA obtained from a patient's EBV-transformed lymphoblast cell line. RT-PCR revealed an aberrant splice transcript skipping exons 10-14 which was not observed in control samples, confirming the diagnosis of X-linked dominant hypophosphatemia (XLH). The in silico analysis of all human splice sites adjacent to all 327,293 exons across 81,814 transcripts among 20,345 human genes revealed that cytosine is, with 64.3%, the most frequent nucleobase at the minus 3 splice acceptor position, followed by thymidine with 28.7%, adenine with 6.3%, and guanine with 0.8%. We generated frequency tables and pictograms for the extended donor and acceptor splice consensus regions by analyzing all human exons. Direct Sanger sequencing of all PHEX exons in a sporadic case with HR from the Indian subcontinent revealed an additional novel PHEX mutation (c.1211_1215delACAAAinsTTTACAT, p.Asp404Valfs*5, de novo) located in exon 11. CONCLUSIONS: Mutation analyses revealed two novel mutations and helped to confirm the clinical diagnoses of XLH in two families from India. WES helped to analyze all genes implicated in the underlying disease complex. Mutations at splice positions other than the canonical key sites need further functional investigation to support the assertion of pathogenicity. PMID- 26107951 TI - Use of Approximate Bayesian Computation to Assess and Fit Models of Mycobacterium leprae to Predict Outcomes of the Brazilian Control Program. AB - Hansen's disease (leprosy) elimination has proven difficult in several countries, including Brazil, and there is a need for a mathematical model that can predict control program efficacy. This study applied the Approximate Bayesian Computation algorithm to fit 6 different proposed models to each of the 5 regions of Brazil, then fitted hierarchical models based on the best-fit regional models to the entire country. The best model proposed for most regions was a simple model. Posterior checks found that the model results were more similar to the observed incidence after fitting than before, and that parameters varied slightly by region. Current control programs were predicted to require additional measures to eliminate Hansen's Disease as a public health problem in Brazil. PMID- 26107952 TI - Citizen science based monitoring of Greylag goose (Anser anser) in Bavaria (Germany): combining count data and bag data to estimate long-term trends between 1988/89 and 2010/11. AB - INTRODUCTION, MATERIAL AND METHODS: Numbers of large grazing bird (geese, swans, cranes) have increased all over Europe, but monitoring these species, e.g. for management purposes, can be time consuming and costly. In Bavaria, sedentary Greylag geese (Anser anser) are monitored during the winter by two different citizen-based monitoring schemes: the International Waterbird Census [IWC] and hunting bag statistics. We compared the results of both schemes for the seasons 1988/89 to 2010/11 by analysing annual indices calculated using the software TRends and Indices for Monitoring Data-TRIM. RESULTS AND DISCUSSION: We identified similar, highly significant rates of increase in both data sets for the entire region of Bavaria (IWC 14% [13-15%], bag 13% [12-14%]). Furthermore, in all of the seven Bavarian regions, trends in annual indices of both data sets correlated significantly. The quality of both datasets as indicators of abundances in Greylag geese populations in Bavaria was not undermined by either weaknesses typically associated with citizen based monitoring or problems generally assumed for IWC and bag data. We also show that bag data are, under the German system of collecting bag statistics, a reliable indicator of species' distribution, especially for detecting newly colonized areas. Therefore, wildlife managers may want to consider bag data from citizen science led monitoring programmes as evidence supporting the decision making processes. We also discuss requirements for any bag monitoring schemes being established to monitor trends in species' distribution and abundance. PMID- 26107953 TI - Methylome Analysis in Chickens Immunized with Infectious Laryngotracheitis Vaccine. AB - In this study we investigated the methylome of chickens immunized with Infectious laryngotracheitis (ILT) vaccine derived from chicken embryos. Methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) method was employed in the detection of the 1,155 differentially methylated regions (DMRs) across the entire genome. After validation, we ascertained the genomic DMRs distribution and annotated them regarding genes, transcription start sites (TSS) and CpG islands. We found that global DNA methylation decreased in vaccinated birds, presenting 704 hypomethylated and 451 hypermethylated DMRs, respectively. Additionally, we performed an enrichment analysis detecting gene networks, in which cancer and RNA post-transcriptional modification appeared in the first place, followed by humoral immune response, immunological disease and inflammatory disease. The top four identified canonical pathways were EIF2 signaling, regulation of EIF4 and p70S6K signaling, axonal guidance signaling and mTOR signaling, providing new insight regarding the mechanisms of ILT etiology. Lastly, the association between DNA methylation and differentially expressed genes was examined, and detected negative correlation in seventeen of the eighteen genes. PMID- 26107954 TI - Luminance, Colour, Viewpoint and Border Enhanced Disparity Energy Model. AB - The visual cortex is able to extract disparity information through the use of binocular cells. This process is reflected by the Disparity Energy Model, which describes the role and functioning of simple and complex binocular neuron populations, and how they are able to extract disparity. This model uses explicit cell parameters to mathematically determine preferred cell disparities, like spatial frequencies, orientations, binocular phases and receptive field positions. However, the brain cannot access such explicit cell parameters; it must rely on cell responses. In this article, we implemented a trained binocular neuronal population, which encodes disparity information implicitly. This allows the population to learn how to decode disparities, in a similar way to how our visual system could have developed this ability during evolution. At the same time, responses of monocular simple and complex cells can also encode line and edge information, which is useful for refining disparities at object borders. The brain should then be able, starting from a low-level disparity draft, to integrate all information, including colour and viewpoint perspective, in order to propagate better estimates to higher cortical areas. PMID- 26107955 TI - Identification of a novel p.Q1772X ANK1 mutation in a Korean family with hereditary spherocytosis. AB - Hereditary spherocytosis (HS), a common form of inherited hemolytic anemia, is a heterogeneous group of disorders with regard to clinical severity, protein defects, and mode of inheritance. Causal mutations in at least five genes have been reported so far. Because multiple genes have been associated with HS, clinical genetic testing that relies on direct sequencing will be a challenge. In this study, we used whole exome sequencing to identify a novel nonsense mutation in ANK1 (p.Q1772X, NM_020476) that resulted in a truncated protein in a Korean patient with HS. Sanger sequencing confirmed the two affected individuals in the patient's family were heterozygous for the mutation. This is the first report of a Korean family that carries an ANK1 mutation responsible for HS. Our results demonstrate that next generation sequencing is a powerful approach for rapidly determining the genetic etiology of HS. PMID- 26107956 TI - Anti-hepatitis C virus T-cell immunity in the context of multiple exposures to the virus. AB - Characterisation of Hepatitis C virus (HCV)-specific CD8+ T-cell responses in the context of multiple HCV exposures is critical to identify broadly protective immune responses necessary for an effective HCV vaccine against the different HCV genotypes. However, host and viral genetic diversity complicates vaccine development. To compensate for the observed variation in circulating autologous viruses and host molecules that restrict antigen presentation (human leucocyte antigens; HLA), this study used a reverse genomics approach that identified sites of viral adaptation to HLA-restricted T-cell immune pressure to predict genotype specific HCV CD8+ T-cell targets. Peptides representing these putative HCV CD8+ T cell targets, and their adapted form, were used in individualised IFN-gamma ELISpot assays to screen for HCV-specific T-cell responses in 133 HCV seropositive subjects with high-risk of multiple HCV exposures. The data obtained from this study i) confirmed that genetic studies of viral evolution is an effective approach to detect novel in vivo HCV T-cell targets, ii) showed that HCV-specific T-cell epitopes can be recognised in their adapted form and would not have been detected using wild-type peptides and iii) showed that HCV-specific T-cell (but not antibody) responses against alternate genotypes in chronic HCV infected subjects are readily found, implying clearance of previous alternate genotype infection. In summary, HCV adaptation to HLA Class I-restricted T-cell responses plays a central role in anti-HCV immunity and multiple HCV genotype exposure is highly prevalent in at-risk exposure populations, which are important considerations for future vaccine design. PMID- 26107957 TI - In Vivo Induction of Functionally Suppressive Induced Regulatory T Cells from CD4+CD25- T Cells Using an Hsp70 Peptide. AB - Therapeutic peptides that target antigen-specific regulatory T cells (Tregs) can suppress experimental autoimmune diseases. The heat shock protein (Hsp) 70, with its expression elevated in inflamed tissue, is a suitable candidate antigen because administration of both bacterial and mouse Hsp70 peptides has been shown to induce strong immune responses and to reduce inflammation via the activation or induction of Hsp specific Tregs. Although two subsets of Tregs exist, little is known about which subset of Tregs are activated by Hsp70 epitopes. Therefore, we set out to determine whether natural nTregs (derived from the thymus), or induced iTregs (formed in the periphery from CD4+CD25- naive T cells) were targeted after Hsp70-peptide immunization. We immunized mice with the previously identified Hsp70 T cell epitope B29 and investigated the formation of functional iTregs by using an in vitro suppression assay and adoptive transfer therapy in mice with experimental arthritis. To study the in vivo induction of Tregs after peptide immunization, we depleted CD25+ cells prior to immunization, allowing the in vivo formation of Tregs from CD4+CD25- precursors. This approach allowed us to study in vivo B29-induced Tregs and to compare these cells with Tregs from non depleted immunized mice. Our results show that using this approach, immunization induced CD4+CD25+ T cells in the periphery, and that these cells were suppressive in vitro. Additionally, adoptive transfer of B29-specific iTregs suppressed disease in a mouse model of arthritis. This study shows that immunization of mice with Hsp70 epitope B29 induces functionally suppressive iTregs from CD4+CD25- T cells. PMID- 26107958 TI - Systematic review and meta-analysis of outcomes after cardiopulmonary arrest in childhood. AB - BACKGROUND: Cardiopulmonary arrest in children is an uncommon event, and often fatal. Resuscitation is often attempted, but at what point, and under what circumstances do continued attempts to re-establish circulation become futile? The uncertainty around these questions can lead to unintended distress to the family and to the resuscitation team. OBJECTIVES: To define the likely outcomes of cardiopulmonary resuscitation in children, within different patient groups, related to clinical features. DATA SOURCES: MEDLINE, MEDLINE in-Process & Other non-Indexed Citations, EMBASE, Cochrane database of systematic reviews and Cochrane central register of trials, Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment database, along with reference lists of relevant systematic reviews and included articles. STUDY ELIGIBILITY CRITERIA: Prospective cohort studies which derive or validate a clinical prediction model of outcome following cardiopulmonary arrest. PARTICIPANTS AND INTERVENTIONS: Children or young people (aged 0 - 18 years) who had cardiopulmonary arrest and received an attempt at resuscitation, excluding resuscitation at birth. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias assessment developed the Hayden system for non-randomised studies and QUADAS2 for decision rules. Synthesis undertaken by narrative, and random effects meta-analysis with the DerSimonian Laird estimator. RESULTS: More than 18,000 episodes in 16 data sets were reported. Meta-analysis was possible for survival and one neurological outcome; others were reported too inconsistently. In-hospital patients (average survival 37.2% (95% CI 23.7 to 53.0%)) have a better chance of survival following cardiopulmonary arrest than out-of-hospital arrests (5.8% (95% CI 3.9% to 8.6%)). Better neurological outcome was also seen, but data were too scarce for meta analysis (17% to 71% 'good' outcomes, compared with 2.8% to 3.2%). LIMITATION: Lack of consistent outcome reporting and short-term neurological outcome measures limited the strength of conclusions that can be drawn from this review. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: There is a need to collaboratively, prospectively, collect potentially predictive data on these rare events to understand more clearly the predictors of survival and long-term neurological outcome. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO 2013:CRD42013005102. PMID- 26107959 TI - The identification of proteoglycans and glycosaminoglycans in archaeological human bones and teeth. AB - Bone tissue is mineralized dense connective tissue consisting mainly of a mineral component (hydroxyapatite) and an organic matrix comprised of collagens, non collagenous proteins and proteoglycans (PGs). Extracellular matrix proteins and PGs bind tightly to hydroxyapatite which would protect these molecules from the destructive effects of temperature and chemical agents after death. DNA and proteins have been successfully extracted from archaeological skeletons from which valuable information has been obtained; however, to date neither PGs nor glycosaminoglycan (GAG) chains have been studied in archaeological skeletons. PGs and GAGs play a major role in bone morphogenesis, homeostasis and degenerative bone disease. The ability to isolate and characterize PG and GAG content from archaeological skeletons would unveil valuable paleontological information. We therefore optimized methods for the extraction of both PGs and GAGs from archaeological human skeletons. PGs and GAGs were successfully extracted from both archaeological human bones and teeth, and characterized by their electrophoretic mobility in agarose gel, degradation by specific enzymes and HPLC. The GAG populations isolated were chondroitin sulfate (CS) and hyaluronic acid (HA). In addition, a CSPG was detected. The localization of CS, HA, three small leucine rich PGs (biglycan, decorin and fibromodulin) and glypican was analyzed in archaeological human bone slices. Staining patterns were different for juvenile and adult bones, whilst adolescent bones had a similar staining pattern to adult bones. The finding that significant quantities of PGs and GAGs persist in archaeological bones and teeth opens novel venues for the field of Paleontology. PMID- 26107962 TI - [Commonwealth Fund Survey 2012: Survey of Primary Care Doctors in 11 Countries: Use of Health Information Technology and Important Aspects of Care]. AB - BACKGROUND: In 2006 and 2009 the US-American Commonwealth Fund (CMWF) already conducted international surveys with primary care physicians regarding their daily work and important aspects of care. In 2012 a third survey took place in 11 countries, with an emphasis on use of information technology. METHODS: There was a written survey and a telephone survey of primary care physicians conducted in eleven industrial countries. In Germany, a random sample of 4 500 primary care physicians out of all 16 federal states were contacted by mail between April and July 2012. The data acquisition in Germany was conducted by the BQS Institute for Quality and Patient Safety and funded by the Federal Ministry of Health. The results were weighted by age, sex, region and medical specialty of the participating doctors. RESULTS: 9 776 primary care physicians participated; 909 of them in Germany. The response rate in Germany was 20%. 80% of the primary care physicians in Germany are using electronic patient records. But special IT functions, with the exception of electronic prescriptions and ordering of laboratory tests, are little used compared to other countries. Even in countries with a wide use of special IT functions within the practices, the possibility of communicating with colleagues and patients electronically is often lacking. 35% of the German primary care physicians think the quality of care has declined since the last survey in 2009. Only in France do more primary care physicians share that feeling (37%). In 2012 a lot more German primary care physicians stated to have problems with long waiting times for specialist consults (2009: 10%; 2012: 68%). PMID- 26107960 TI - The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding. AB - The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3's function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation. Our study suggests that Foxp3, even in the absence of its DNA-binding forkhead domain, acts as a bridge between DNA-binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We show that, in one such mechanism, Foxp3 recruits class I histone deacetylases to the promoters of target genes, counteracting activation-induced histone acetylation and thereby suppressing their expression. PMID- 26107963 TI - [Stepwise Diagnostics, Federal Joint Committee Directive and Actual Care in the Case of Sleep-related Breathing Disorders - An Analysis Based on Claims Data of the Techniker Krankenkasse]. AB - In 2004, the Federal Joint Committee (G-BA) published a new directive for examination and treatment methods with respect to sleep-related breathing disorders for SHI-accredited physicians. The examination procedure is classified in four steps: anamnesis, clinical assessment, cardiorespiratory polygraphy (PG) and cardiorespiratory polysomnography (PSG). Starting with the date of the first PSG we analysed 1. whether this examination was preceded by a polygraphy, 2. whether there was a gain of diagnostic information through PSG, and 3. whether a PSG was used for the first adjustment examinations and controls after prescription of a positive airway pressure device. The analysis is based on claims data from the Techniker Krankenkasse (2009-2012). Diagnostic services were identified by fee schedule codes (EBM) for outpatient services and by procedure codes (OPS) for inpatient services. Sleep disorders were operationalised by ICD 10 codes and information was completed by prescriptions of a CPAP equipment.The study is based on data from 6.6 million persons who were permanently insured from 01.01.2009 to 30.06.2012 by TK. A preceding PG 90 (180) days before PSG was found for less than 56% (73%) of the analysed insured persons. By the latter procedure, only about 60% of the cases with no clear diagnostic information (G47.39) in the preceding quarter could be specified. Prescription of a positive airway pressure device within 90 days after PSG was found for about 45% of the insured. Concerning the stepwise diagnostic procedure for sleep disorders for SHI accredited physicians, the directive was followed only partly. Against the background of an evidence-based, effective, and efficient diagnostic approach, the results show a clear need for action. PMID- 26107964 TI - [Surface Cleaning and Disinfection in the Hospital. Improvement by Objective Monitoring and Intervention]. AB - Background and Objective: An assessment of cleaning and disinfection in hospitals by the use of objective surveillance and review of mandatory corrective measures was undertaken. Methods: A prospective examination of the cleaning and disinfection of surfaces scheduled for daily cleaning in 5 general care hospitals by use of an ultraviolet fluorescence targeting method (UVM) was performed, followed by structured educational and procedural interventions. The survey was conducted in hospital wards, operating theatres and intensive care units. Cleaning performance was measured by complete removal of UVM. Training courses and reinforced self-monitoring were implemented after the first evaluation. 6 months later, we repeated the assessment for confirmation of success. Results: The average cleaning performance was 34% (31/90) at base-line with significant differences between the 5 hospitals (11-67%). The best results were achieved in intensive care units (61%) and operating theatres (58%), the worst results in hospital wards (22%). The intervention significantly improved cleaning performance up to an average of 69% (65/94; +34.7%; 95% confidence interval (CI): 21.2-48.3; p<0.05), with differences between the hospitals (20-95%). The largest increase was achieved in hospital wards (+45%; CI 29.2-60.8; p<0.05). Improvements in operating theatres (+22.9%; CI 10.9-56.7) and intensive care units (+5.6%; CI 25.8-36.9) were statistically not significant. Conclusions: The monitoring of cleaning and disinfection of surfaces by fluorescence targeting is appropriate for evaluating hygiene regulations. An intervention can lead to a significant improvement of cleaning performance. As part of a strategy to improve infection control in hospitals, fluorescence targeting enables a simple inexpensive and effective surveillance of the cleaning performance and corrective measures. PMID- 26107965 TI - [Cost-Effectiveness of the 21 Gene Assay in Patients with Node-Positive Breast Cancer]. AB - Aim: Breast cancer is the most common type of cancer for women. Most guidelines recommend patients with lymph-node positive (LN+) early stage breast cancer to undergo adjuvant chemotherapy to prevent or delay distant recurrence. This may lead to frequent, general usage of chemotherapy accompanied with high costs and side effects. The Oncotype DX, also called 21 Gene Assay, by Genomic Health is a genomic test which predicts the individual risk of breast cancer recurrence as well as the benefits of chemotherapy. Economic analyses have indicated the cost effectiveness of the 21 Gene Assay for patients with LN- breast cancer. This paper discusses recent research on the cost-effectiveness of using this assay for patients with LN+ breast cancer. Methods: A systematic literature research was undertaken using the following databases: Pubmed, Embase, Business Source Complete and EconLit. Studies found were analysed for study design, parameters, and analysis of uncertainty. The transferability of the results to Germany was examined using a list of criteria. Results: 7 relevant economic analyses were identified. Incremental cost-utility ratios ranged from cost-savings of ? 3 548 per patient to additional costs of ? 9 113 per QALY gained. The transferability of the results to Germany is limited particularly by differences in the medical cost approach, in absolute and relative prices in health-care, and by practice variation. Conclusion: There is evidence that the cost-utility of the assay when used for LN+ breast cancer is basically comparable to that for the use with the LN- type. More precise results for Germany would require valid data on the risk of recurrence as well as on the description and evaluation of health-related quality of life of patients. PMID- 26107966 TI - [Risk Factors for Disability Pensioning Caused by Mental Disorders - A Systematic Review]. AB - Background: Meanwhile, mental disorders are the main reason for receiving a disability pension. The present study aimed at providing an overview of the German literature on characteristics and factors related to ERMD and pointing out the current state in this field of research. Revealing parameters that are accompanied by an ERMD is a precondition to prospectively prevent this trend. Methods: A systematic literature review was conducted from 2001 through to 2014. All results regarding German statutory pension insurants pensioned due to mental disorders after 2001 were included. Studies were considered if they reported 2 or more relevant results. Research design was not limited, except for excluding anonymous questionnaires. Results: 20 studies were found meeting eligibility criteria. All included studies were based on secondary analyses of data derived from the German statutory pension insurance. By means of gender-specific regression analyses the level of qualification and the geographical region were unveiled to be significant predictors of the ERMD. Basically, most reported results were descriptive or explorative. Besides various single results and evidence for interactions, frequently reported results are that: (i) female insurants get pensioned more frequently due to mental disorders than male insurants, (ii) affective disorders are the most frequent diagnoses, (iii) insurants with mental disorders are younger than insurants with somatic disorders when they get pensioned and (iv) insurants with schizophrenic disorders are younger than insurants with other mental disorders when they get pensioned. The utilisation of rehabilitative services before getting pensioned is limited at 50%. Conclusion: This work demonstrates a lack of empirical evidence of how (and what) disability risks are associated with ERMD in Germany. Furthermore, our results illustrate that a major part of the insurants do not attend rehabilitative services before their retirement, even though rehabilitation of mental illness is assumed to be effective. Future studies should hence focus on identifying disability related risk factors and barriers to using rehabilitative services in order to develop starting points for preventive and individual strategies. PMID- 26107967 TI - Clinical applications of next-generation sequencing in histocompatibility and transplantation. AB - PURPOSE OF REVIEW: Next-generation sequencing (NGS) can overcome traditional methodological barriers to facilitate detailed studies of large genomes. Here, we summarize recent NGS-based developments in histocompatibility and transplantation, and highlight the dynamic range of clinical applications achievable on this platform. RECENT FINDINGS: Multiple NGS-based protocols have been established to achieve unambiguous human leukocyte antigen genotyping. These methods are presently engaged to serve the high-throughput demand of large bone marrow registries; however, the scalable nature of NGS makes it an equally attractive technology for select applications within solid organ transplantation. Recently, the exquisite sensitivity of NGS has been leveraged to perform noninvasive allograft monitoring by tracking the dynamics of donor-derived cell free DNA. Further, NGS-based T-cell receptor and immunoglobulin heavy chain repertoire profiling appear to be useful in clarifying disease-specific diagnoses in certain complex allograft pathology; detecting/quantifying minimal residual disease following allogeneic stem cell transplantation; and tracking donor reactive T cells to understand the mechanism of tolerance in kidney transplant recipients. SUMMARY: NGS is superior to classical Sanger sequencing in its throughput, sensitivity, and the ability to provide phase-defined sequence data. These unique properties allow its broad application to diverse areas in clinical transplantation. PMID- 26107968 TI - Urinary biomarkers of renal transplant outcome. AB - PURPOSE OF REVIEW: Renal allograft loss remains an important cause of morbidity and mortality. The objective of this review was to provide a rationale for noninvasive monitoring to identify patients at high risk for graft loss; discuss key steps in prognostic biomarker development from bench-to-bedside; and review promising biomarkers for late renal allograft outcomes. RECENT FINDINGS: In a multicentre prospective cohort, early 6-month urinary CCL2 was demonstrated to be associated with the development of 24-month interstitial fibrosis/tubular atrophy and inflammation (IFTA+i). These findings were extended to a single centre cohort, which showed that 6-month urinary CCL2 was a predictor of death-censored graft loss independent of donor-specific antibody and delayed graft function. In a large, multicentre prospective observational study (CTOT-01), 6-month urinary CXCL9 was significantly associated with more than 30% decline of graft function at 24 months. SUMMARY: Urinary chemokines may identify recipients who are at high risk of graft loss. The early detection of high-risk recipients may allow for more intensive posttransplant surveillance; avoidance of drug minimization/withdrawal protocols; and the identification of patients who may benefit from enrolment in novel interventional trials. Prospective trials are needed to demonstrate that urinary chemokine-guided posttransplant surveillance strategies improve long-term graft outcomes. PMID- 26107969 TI - Tolerance signatures in transplant recipients. AB - PURPOSE OF REVIEW: The intent of this review was to describe biomarkers that predict or identify individuals who exhibit tolerance to a transplanted organ. The identification of tolerance biomarkers would spare some individuals the toxicity of immunosuppressive agents, enhance the safety of studies to induce tolerance, and provide insights into mechanisms of tolerance that may aid in designing new regimens. RECENT FINDINGS: Studies of tolerant kidney transplant recipients have revealed an association with B cells. More recent studies have suggested that these B cells may be less mature than from those in nontolerant recipients, and especially suited to suppress alloimmune responses. Biomarkers in tolerant liver transplant patients appear to be distinct from those associated renal tolerance. Most reports have identified an association with natural killer and/or gammadelta T cells rather than B cells. Recent data indicate biomarkers associated with iron homeostasis within the transplanted liver more accurately predict the tolerant state than do biomarkers expressed in the blood, suggesting that the renal allograft itself, which is infrequently sampled, would be informative. SUMMARY: Given the encouraging progress in identifying tolerance biomarkers, it will be important to validate these markers in larger studies of transplant recipients undergoing prospective minimization or withdrawal of immunosuppression. PMID- 26107970 TI - Role of B cells in tolerance induction. AB - PURPOSE OF REVIEW: B cells are known to play a central role in humoral immunity and to boost cellular immunity, however, in a variety of experimental models, B cell subsets ameliorate inflammation and autoimmune disease, indicating that they can also play a regulatory role. Here, we highlight the advances in regulatory B cell (Breg) biology of the past year with an emphasis on findings pertinent to transplantation. Several recent observations highlight the relevance to clinical transplantation. Data from at least three independent groups demonstrated that spontaneously tolerant renal transplant recipients exhibit a peripheral blood B cell signature although the significance of these data remains unclear. Moreover, new data suggest that regulatory B cells may serve as a biomarker for long-term allograft outcomes. Finally, recent evidence suggesting that plasma cells may be an essential component of Bregs raises new concerns about targeting antibody producing cells. RECENT FINDINGS: We describe new information on Breg mechanisms of action to suppress the alloresponse, signals to expand Bregs in vitro, and more functional evidence of Breg involvement in operationally tolerant kidney patients and in maintaining stable allograft function. SUMMARY: Although lymphocyte depletion remains central to tolerance induction therapy, the sparing or expansion of regulatory B cells may be an additional strategy to preempt graft rejection. PMID- 26107971 TI - Innate lymphoid cells: the new kids on the block. AB - PURPOSE OF REVIEW: The purpose of this article is to review recent advances in our understanding of innate lymphoid cell function and to speculate on how these cells may become activated and influence the immune response to allogeneic tissues and cells following transplantation. RECENT FINDINGS: Innate lymphoid cells encompass several novel cell types whose wide-ranging roles in the immune system are only now being uncovered. Through cytokine production, cross-talk with both haematopoietic and nonhaematopoietic populations and antigen presentation to T cells, these cells have been shown to be key regulators in maintaining tissue integrity, as well as initiating and then sustaining immune responses. SUMMARY: It is now clear that innate lymphoid cells markedly contribute to immune responses and tissue repair in a number of disease contexts. Although experimental and clinical data on the behaviour of these cells following transplantation are scant, it is highly likely that innate lymphoid cells will perform similar functions in the alloimmune response following transplantation and therefore may be potential therapeutic targets for manipulation to prevent allograft rejection. PMID- 26107972 TI - Population Subdivision of Fusarium graminearum from Barley and Wheat in the Upper Midwestern United States at the Turn of the Century. AB - Fusarium graminearum, the causal agent of Fusarium head blight (FHB) in wheat and barley, is one of the most economically destructive pathogens of these grains worldwide. Recent population genetic studies of the pathogen obtained from wheat in North America supported population subdivision in part correlated with the spectrum of trichothecene mycotoxins (chemotype) produced by individuals within each population. In contrast, a recent study of F. graminearum obtained from diseased barley in the upper Midwestern United States concluded that only a single population was present, consisting of individuals with various chemotypes. To test whether strains derived from different hosts potentially have different population dynamics, we obtained the barley strains used in the previous study and compared them with wheat strains isolated at a similar time and geographic origin. A total of 247 F. graminearum isolates from barley were assigned firmly into two clusters using a Bayesian clustering method. Subdivision within the barley population corresponded to the previously described NA1 (correlated with the 15ADON chemotype) and NA2 (correlated with the 3ADON chemotype) populations from wheat. However, in both sampling periods the barley population exhibited a higher level of genetic differentiation between NA1 and NA2 populations, fewer admixed individuals and evidence of unidirectional gene introgression (15ADON strains with NA2 genetic backgrounds). These results suggest less recombination between NA1 and NA2 populations on barley compared with wheat. The frequency of 3ADON chemotype strains in the most recently surveyed barley population suggests a latitudinal cline from the northern (49%), central (40%) to the southern (29%) sampling area. The potential to produce a novel trichothecene, 3alpha acetoxy,7alpha,15-dihydroxy-12,13-epoxytrichothe-9-ene (NX-2), was not detected in the barley population but occurred at a low rate (2.4%) in the wheat population. PMID- 26107973 TI - Biocatalytic synthesis of starch esters by immobilized lipase on magnetic microparticles. AB - Enzymatic esterification is an efficient approach for modifying starch to functionalized biomaterials. In this study, conversion of cassava starch to fatty acid acyl esters using immobilized Thermomyces lanuginosus lipase on Fe3O4 microparticles modified with 3-aminopropyltriethoxysilane and covalently linked by 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide and N-hydroxysuccinimide (Fe3O4-AP-ED-lipase) in a solvent-free system was studied. An optimized reaction containing 5% w/v gelatinized starch, 1% v/v Triton X-100, and 1% w/v biocatalyst with 2.5% w/v of fatty acids (palmitic, oleic, or linoleic acid) resulted in esterified products with a degree of substitution (DS) of 0.12-0.14, while a slightly lower DS was observed using crude palm fatty acid distillate as the acyl donor with 42.9-59.6% recovery yield. Increasing DS led to lower glass transition temperature and higher viscosity of the esterified products. The enzyme showed high operational stability with 85% retaining in activity after recycling in three consecutive batches with simple separation by magnetization, leading to improved process economics. PMID- 26107974 TI - Retrospective Comparison of 25- and 23-Gauge Microincision Vitrectomy Surgery and 20-Gauge Vitrectomy for the Repair of Macular Hole Retinal Detachment. AB - PURPOSE: To compare the anatomical and functional outcomes of 25- and 23-gauge microincision vitrectomy surgery (25G and 23G MIVS) instrumentation with the standard 20G pars plana vitrectomy (20G PPV) system in the treatment of primary macular hole retinal detachment (MHRD). DESIGN: A retrospective comparative study. METHODS: Forty-six eyes of 45 patients with MHRD underwent pars plana vitrectomy from March 1, 2006 to April 31, 2011. Fourteen, 13, and 19 eyes underwent 20G PPV, 23G MIVS, and 25G MIVS, respectively. The analysis included characteristics of the patients, single operation reattachment rate, final reattachment rate, closure rate of the macular hole, and rate of complications. The median follow-up period was 273 days. RESULTS: Preoperative characteristics were similar in the 3 groups. The single operation success rate was 11 (79%) of 14 for 20G PPV, 10 (77%) of 13 for 23G MIVS, and 14 (74%) of 19 for 25G MIVS (P = 0.95). The closure rate of the macular hole was 9 (64%) of 14 for 20G PPV, 9 (69%) of 13 for 23G MIVS, and 11 (58%) of 19 for 25G MIVS (P = 0.78). One hundred percent of patients achieved final reattachment after multiple surgeries, excluding 2 patients who dropped out during the follow-up period. Rates of visual recovery and complications, including hypotony, were similar for all 3 procedures. CONCLUSIONS: The outcomes of 25G and 23G MIVS for the management of MHRD did not differ significantly from 20G PPV. Microincision vitrectomy surgery may be considered an alternative treatment, even for MHRD. PMID- 26107975 TI - A Cross-sectional Study of Prevalence and Etiology of Childhood Visual Impairment in Auckland, New Zealand. AB - PURPOSE: Childhood visual impairment has significant individual and socioeconomic costs with global differences in etiology and prevalence. This study aimed to determine prevalence, etiology, and avoidable causes of childhood visual impairment in New Zealand. DESIGN: Retrospective data analysis from a national referral center, the Blind and Low Vision Education Network New Zealand, Auckland. METHODS: The World Health Organization Program for Prevention of Blindness eye examination records for visually impaired children, 16 years or younger, registered with the Auckland Visual Resource Centre, were included. Data analyzed included demographics, etiology, visual acuity, visual fields, educational setting, and rehabilitation plan. RESULTS: Charts of 340 children were examined, of which 267 children (144 blind, 123 low vision) were included in the analysis, whereas the remaining 73 charts of children with no visual impairment were excluded. The calculated prevalence of blindness and low vision was 0.05% and 0.04%, respectively, in the Auckland region. Principal causes of blindness affecting 91 children (63.9%) were cerebral visual impairment in 61 children (42.4%), optic nerve atrophy in 18 children (12.5%), and retinal dystrophy in 13 children (9.0%). The main potentially avoidable causes of blindness in 27 children (19%) were neonatal trauma, asphyxia in 9 children (33%), and nonaccidental injury 6 children (22%). CONCLUSIONS: This first report of prevalence for childhood blindness and low vision in New Zealand is similar to data from Established Market Economy countries. The leading causes of blindness are also comparable to other high-income countries; however, proportions of avoidable causes differ significantly. PMID- 26107976 TI - The Malaysian Cataract Surgery Registry: Cataract Surgery Practice Pattern. AB - PURPOSE: To present the cataract surgery practice pattern among the ophthalmic surgeons in hospitals managed by the Ministry of Health (MOH) in Malaysia. DESIGN: Secondary data analysis on Malaysian Cataract Surgery Registry (CSR). METHODS: The Malaysian CSR collected data on cataract surgeries done at all the ophthalmology departments in MOH from year 2002 to 2004 (paper-based) and 2007 to 2011 (web-based). Data collected include type of admission, surgical techniques, type of anesthesia, and intraocular lens (IOL). Descriptive and inferential analysis was performed. RESULTS: Of the 185,388 cataract surgeries done over 8 years, 171,482 (91.5%) were captured in CSR. There was a steep rise in phacoemulsification cataract surgery from 39.7% in 2002 to 78.0% in 2011 with a corresponding fall in extracapsular cataract extraction from 54.0% to 17.3% in the respective years. This explained the surge in the use of foldable IOL from 26.5% in 2002 to 88.3% in 2011. The proportion of cataract surgery with IOL implantation was 97.5% in 2012 and 98.2% in 2011. The proportion of day-care cataract surgery was low, with 39.3% in 2002 to 52.3% in 2011. Vitreoretinal surgery was the commonest type of combined surgery performed. CONCLUSIONS: Although phacoemulsification was performed in two thirds of the patients who presented to MOH hospitals in Malaysia, extracapsular cataract extraction was still being performed because of a significant proportion of cataract that were brunescent and limited access to phacoemulsification machines and consumables. There is a need to increase day-care cataract surgery as it will eventually save cost. PMID- 26107977 TI - Effect of Intraocular Pressure and Anisotropy on the Optical Properties of the Cornea: A Study Using Polarization Sensitive Optical Coherence Tomography. AB - PURPOSE: We hypothesize that because of the anisotropic properties of the cornea, there should be a nonuniform change in birefringence with an increase in intraocular pressure (IOP). In this in vitro study, anisotropic properties, stress distribution within the cornea, and the effect of IOP on changes in stress level were investigated. DESIGN: Button inflation tests for deformation with polarization sensitive optical coherence tomography were used to demonstrate optical and material anisotropy on ex vivo human corneas. METHODS: Inflation tests were performed on human donor corneoscleral rims. Using a turntable and hydrostatic column, each corneoscleral rim was subjected to a hydrostatic pressure of 0, 10, 15, and 20 mm Hg. At each pressure step, 4 scans at 0, 45, 90, and 135 degrees were taken by a polarization sensitive optical coherence tomography system, and the birefringence images and normal intensity-based images were recorded; images were later compiled for analysis. RESULTS: The retardation changed with the axis of orientation (P [T <= t] 1-tailed = 0.025) and IOP (P [T <= t] 1-tailed = 0.019). Optical thickness of the cornea decreased with increasing IOP. CONCLUSIONS: The optical properties of the cornea are modified with change in IOP. This is not uniform because of distinct anisotropic properties. Anisotropic properties may unpredictably affect the optical quality of cornea during or after the surgeries. Changes in corneal birefringence can be also used as a tool for measuring the IOP of the eye. PMID- 26107978 TI - Delayed Hydrocephalus and Perianeurysmal Cyst Formation After Stent-Assisted Coil Embolization of a Large, Unruptured Basilar Apex Aneurysm: A Case Report and Literature Review. AB - PURPOSE: Endovascular aneurysm embolization possesses a unique set of infrequently seen complications distinct from those associated with microsurgical clipping, which may arise after an otherwise uncomplicated coil embolization procedure, including postembolization, hydrocephalus, and perianeurysmal cyst formation. DESIGN: The authors report an illustrative case of 2 rarely seen complications of aneurysm embolization with literature review. METHODS: We present a case of a basilar apex aneurysm that was treated with endovascular coil embolization with multiple Cerecyte (Micrus Endovascular, San Jose, Calif) coils and 2 Enterprise (Codman & Shurtleff, Inc, Raynham, Mass) stents. RESULTS: Postembolization angiography demonstrated complete aneurysm obliteration without distal branch occlusion or other complication. Twenty-two months after the embolization, however, the patient presented with progressively worsening headaches. Repeat magnetic resonance imaging revealed hydrocephalus and a perianeurysmal cyst measuring 1 * 2 cm adjacent to the previously coiled basilar apex aneurysm. After endoscopic third ventriculostomy, the patient experienced significant relief of her headaches and was discharged to rehabilitation. CONCLUSIONS: Clinicians should be aware that worsening or new neuro-ophthalmic findings may be the presenting sign of postembolization hydrocephalus or perianeurysmal cyst formation. PMID- 26107979 TI - Sturge-Weber Syndrome (Encephalotrigeminal Angiomatosis): Recent Advances and Future Challenges. AB - Sturge-Weber syndrome (SWS) is a congenital, sporadically occurring, neurocutaneous syndrome that presents classically with port-wine stain, leptomeningeal angiomas, and glaucoma. The systemic implications of SWS are vast and involve not only ophthalmic manifestations but also dermatologic, neurologic, and oral manifestations. Neuroimaging, in particular, plays an important role in the diagnosis and management of this disease. Recent discoveries have been made regarding the genetic pathogenesis of SWS. In addition, recent advances have been made in the management of the 2 most common ophthalmic manifestations of SWS: diffuse choroidal hemangioma and glaucoma. Despite these new contributions to the field, many challenges still remain. The management of diffuse choroidal hemangioma is wide ranging and includes photodynamic therapy, brachytherapy, radiotherapy, and antivascular endothelial growth factor injections, but all have had limited or varied success. Although there have been recent advances in knowledge and technique, the management of glaucoma is extremely complex, given the high surgical risks for complications and a poor response rate to medical therapy. Further studies are critical to maximize our knowledge of this difficult disease. PMID- 26107980 TI - Intravitreal Bevacizumab in Retinopathy of Prematurity: Inject or Not? AB - This article is aimed to review and summarize the indications, outcomes and safety profiles regarding the use of intravitreal bevacizumab in patients with retinopathy of prematurity (ROP) as reported in previous studies with no intention to compare the efficacy between intravitreal bevacizumab and laser photocoagulation.Literature search was conducted in databases such as PubMed, Cochrane, Ovid, and Ophthalmology Advance using the terms "ROP," "antiangiogenic," "antivascular endothelial growth factor," "intravitreal bevacizumab," and "Avastin."Eight prospective studies of 278 eyes of ROP infants and 15 retrospective studies involving 385 eyes of ROP infants treated with intravitreal bevacizumab were found. Bevacizumab was used as monotherapy, adjunctive therapy, and/or combined therapy.The varied use of intravitreal bevacizumab in treating ROP and he limited number of landmark studies contribute to the difficulties in drawing a strong conclusion in this review. Intravitreal bevacizumab was more commonly injected in: (1) type 1 ROP zone I and/or posterior zone II; (2) aggressive posterior ROP with poor retinal visualization in which laser photocoagulation would be difficult to perform; and (3) stage 4 ROP before vitrectomy. All cases demonstrated regression of neovascular activity during a varied follow-up period (from 1 week to 1 month) after injection. However, recurrence may occur. Follow-up until 80 weeks of postmenstrual age is thus recommended. Acceleration of fibrous traction is the most common ocular adverse effect after injection, whereas the systemic adverse effect remains uncertain. Landmark studies of the efficacy of intravitreal bevacizumab injection in treating ROP are warranted. PMID- 26107981 TI - A 1-Year Review of Amblyopia and Strabismus Research. AB - PURPOSE: This current review highlights some of the literature published in the past year from April 2013 to May 2014. DESIGN: Literature Review. METHODS: The present review is based on an extended search for pertinent articles on amblyopia and strabismus published during the specified period. RESULTS: Many articles are often not very comparable to one another because of a lack of randomized clinical trials with most of the studies being retrospective in nature. There is often disagreement on some terminology. Typically, the definition of binocular vision is rarely related to the tests used for evaluating it. CONCLUSIONS: The authors conclude that adult strabismus patients seem to gain benefits from corrective surgery not only for their ocular misalignment, but also for social anxiety levels that may be associated with improvements in their quality of life and disability levels. PMID- 26107983 TI - Letter to the Editor Regarding "Virtual Screening of Natural and Synthetic Ligands Against Diabetic Retinopathy by Molecular Interaction With Angiopoietin 2". PMID- 26107982 TI - Riboflavin Concentration Analysis in Rabbit Corneas Before and After Corneal Collagen Cross-Linking Using Confocal Laser Scanning Microscopy. AB - PURPOSE: The aim of this study was to evaluate riboflavin in rabbit corneas before and after corneal collagen cross-linking (CXL) using confocal laser scanning microscopy. DESIGN: A randomized controlled experimental study. METHODS: The study was divided into 3 parts. In part 1 of this study, 30 eyes from 15 rabbits were used to evaluate riboflavin in de-epithelialized corneas before standard CXL. In part 2, 12 eyes from 6 rabbits were used to compare the differences of riboflavin concentration between standard CXL and transepithelial CXL (TE-CXL). In part 3, 12 eyes from another set of 6 rabbits were used to evaluate 1-day postoperative changes of riboflavin concentration between standard CXL and TE-CXL. Riboflavin concentrations in corneas were evaluated by calculating fluorescence densities with a confocal laser scanning microscope. RESULTS: In part 1, the riboflavin concentration after a 20-minute instillation was 0.036%, and did not reach the safety threshold (0.040%) for standard CXL. In part 2, the riboflavin concentration before TE-CXL was lower than 0.010%, which was significantly lower than standard CXL (P < 0.001). In part 3, corneal fluorescence decreased by approximately 100% (fluorescence quenching) 1 day after standard CXL and approximately 60% 1 day after TE-CXL. CONCLUSIONS: Application of 0.010% riboflavin solution for 30 minutes is essential for standard CXL. TE CXL is not recommended because the epithelial layers are inadequately permeable to riboflavin during and 1 day after surgery. PMID- 26107984 TI - Solid-State (17)O NMR of Oxygen-Nitrogen Singly Bonded Compounds: Hydroxylammonium Chloride and Sodium Trioxodinitrate (Angeli's Salt). AB - We report a solid-state NMR study of (17)O-labeled hydroxylammonium chloride ([H(17)O-NH3]Cl) and sodium trioxodinitrate monohydrate (Na2[(17)ONNO2].H2O, Angeli's salt). The common feature in these two compounds is that they both contain oxygen atoms that are singly bonded to nitrogen. For this class of oxygen containing functional groups, there is very limited solid-state (17)O NMR data in the literature. In this work, we experimentally measured the (17)O chemical shift and quadrupolar coupling tensors. With the aid of plane-wave DFT computation, the (17)O NMR tensor orientations were determined in the molecular frame of reference. We found that the characteristic feature of an O-N single bond is that the (17)O nucleus exhibits a large quadrupolar coupling constant (13-15 MHz) but a rather small chemical shift anisotropy (100-250 ppm), in sharp contrast with the nitroso (O?N) functional group for which both quantities are very large (e.g., 16 MHz and 3000 ppm, respectively). PMID- 26107985 TI - Fabrication and characterization of toughness-enhanced scaffolds comprising beta TCP/POC using the freeform fabrication system with micro-droplet jetting. AB - A novel elastomeric material, poly(1,8-octanediol-co-citrate) (POC), has demonstrated tremendous versatility because of its advantageous toughness, tunable degradation properties, and efficient drug release capability. In this study, POC was used to improve the mechanical performance of beta-tricalcium phosphate (beta-Ca3(PO4)2, beta-TCP). (3D) beta-TCP/POC composite scaffolds were fabricated by a 3D printing technique based on the freeform fabrication system with micro-droplet jetting (FFS-MDJ). The physiochemical properties, compressive modulus, drug release behavior, and cell response of beta-TCP/POC composite scaffolds were systematically investigated. The results showed that beta-TCP/POC scaffolds had uniform macropores of 300-400 MUm, porosity of approximately 45%, biodegradability in phosphate-buffered saline, and high compressive modulus of 50 75 MPa. With the incorporation of POC into beta-TCP, the toughness of the composite scaffolds was improved significantly. Moreover, beta-TCP/POC scaffolds exhibited sustained drug (ibuprofen (IBU)) release capability. Additionally, beta TCP/POC scaffolds facilitated C2C12 cell attachment and proliferation. It was indicated that the 3D-printed porous beta-TCP/POC scaffolds with high compressive modulus and good drug delivery performance might be a promising candidate for bone defect repair. PMID- 26107986 TI - Community-based Adapted Tango Dancing for Individuals with Parkinson's Disease and Older Adults. AB - A correction to the author list has been made for the article Community-based Adapted Tango Dancing for Individuals with Parkinson's Disease and Older Adults. There was an error with the author, Madeleine Hackney's, name. The author's name has been updated to: Madeleine E. Hackney from: Madeleine Hackney. PMID- 26107987 TI - Imaging agents. PMID- 26107988 TI - The rapidly evolving associations among herbivore associated elicitor-induced phytohormones in Nicotiana. AB - In response to herbivore attack, plants perceive herbivore associated elicitors (HAE) and rapidly accumulate jasmonic acid (JA) and other phytohormones, which interact in complex ways, such as the crosstalk between JA and salicylic acid (SA). Although recent studies have shown that HAE-induced individual phytohormones can be highly specific among closely related species, it remains unclear how conserved and specific the relationships among HAE-induced phytohormones are. Here we analyzed the correlations among 4 different phytohormones, JA, JA-isoleucine (JA-Ile), SA, and abscisic acid (ABA) in 6 closely related Nicotiana species that were induced by 3 different HAEs. Our results showed that while no clear association between ABA and other phytohormones were found, the positive association between JA and JA-Ile is mostly conserved among closely related Nicotiana species. Interestingly, the association between JA and SA are highly variable and can be regulated by different HAEs. PMID- 26107989 TI - Less Surgery, Improved Survival From Stage IV Colorectal Cancer?-Reply. PMID- 26107990 TI - Direct photocatalytic fluorination of benzylic C-H bonds with N fluorobenzenesulfonimide. AB - The late-stage fluorination of common synthetic building blocks and drug leads is an appealing reaction for medicinal chemistry. In particular, fluorination of benzylic C-H bonds provides a means to attenuate drug metabolism at this metabolically labile position. Here we report two complimentary strategies for the direct fluorination of benzylic C-H bonds using N-fluorobenzenesulfonimide and either a decatungstate photocatalyst or AIBN-initiation. PMID- 26107992 TI - Diagnostic accuracy of heart murmur in newborns with suspected congenital heart disease. AB - BACKGROUND: The correlation between heart murmur and congenital heart disease (CHD) is complex and varies with observed population. METHODS: Ninety consecutive newborns (41 with heart murmur and 49 controls) were routinely examined with auscultation and echocardiography. Intensity and characteristics of heart murmur, presence and type of CHD were recorded. Echocardiographic findings were considered as benchmark. RESULTS: Heart murmur was related to the presence of ostium secundum [odds ratio (OR) 4.2], patent ductus arteriosus (OR 11.9), tricuspidal regurgitation (OR 9.5), muscle ventricular septal defect (VSD) (OR 12.3), membranous VSD (OR 9.7), and any CHD (OR 26.7) (P < 0.05 in all cases). Diagnostic accuracy of clinical examination with a finding of heart murmur was 83%, lower if considering single CHD (58-69%), negative predictive value 90%, and positive predictive value 76%. Patients with any CHD, tricuspidal regurgitation and muscle VSD were characterized by a more intense heart murmur. In case of concomitant multiple CHD, intensity of heart murmur correlated with the number of congenital heart anomalies. CONCLUSION: Diagnostic accuracy of heart murmur at clinical examination (83%) declines when single CHDs are considered. Higher negative predictive value and lower positive predictive value suggest an echocardiographic second-level confirmation in the case of heart murmur at clinical examination suspected for CHD, probably unnecessary in the case of negative auscultative findings. Heart murmur intensity correlates with the number of concomitant congenital heart anomalies. PMID- 26107991 TI - Olfactomedin 1 Deficiency Leads to Defective Olfaction and Impaired Female Fertility. AB - Olfactomedin 1 (OLFM1) is a glycoprotein highly expressed in the brain. Olfm1(-/ ) female mice were previously reported to have reduced fertility. Previous microarray analysis revealed Olfm1 among the most highly upregulated genes in the uterine luminal epithelium upon embryo implantation, which was confirmed by in situ hybridization. We hypothesized that Olfm1 deficiency led to defective embryo implantation and thus impaired fertility. Indeed, Olfm1(-/-) females had defective embryo implantation. However, Olfm1(-/-) females rarely mated and those that mated rarely became pregnant. Ovarian histology indicated the absence of corpora lutea in Olfm1(-/-) females, indicating defective ovulation. Superovulation using equine chorionic gonadotropin-human chorionic gonadotropin rescued mating, ovulation, and pregnancy, and equine chorionic gonadotropin alone rescued ovulation in Olfm1(-/-) females. Olfm1(-/-) females had a 13% reduction of hypothalamic GnRH neurons but comparable basal serum LH levels and GnRH induced LH levels compared with wild-type controls. These results indicated no obvious local defects in the female reproductive system and a functional hypothalamic-pituitary-gonadal axis. Olfm1(-/-) females were unresponsive to the effects of male bedding stimulation on pubertal development and estrous cycle. There were 41% fewer cFos-positive cells in the mitral cell layer of accessory olfactory bulb upon male urine stimulation for 90 minutes. OLFM1 was expressed in the main and accessory olfactory systems including main olfactory epithelium, vomeronasal organ, main olfactory bulb, and accessory olfactory bulb, with the highest expression detected in the axon bundles of olfactory sensory neurons. These data demonstrate that defective fertility in Olfm1(-/-) females is most likely a secondary effect of defective olfaction. PMID- 26107993 TI - Nanoparticle-conjugated aptamer targeting hnRNP A2/B1 can recognize multiple tumor cells and inhibit their proliferation. AB - In this study, we further investigated a previously developed aptamer targeting ROS 17/2.8 (rat osteosarcoma) cells. We found that this C6-8 aptamer specifically binds to heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 and that it specifically labeled multiple tumor-cell lines as effectively as hnRNP A2/B1 monoclonal antibodies. When conjugated with fluorescent carbon nanodots (CDots) it could freely enter multiple living tumor cell lines (HepG2, MCF-7, H1299, and HeLa), whose growth it inhibited by targeting hnRNP A2/B1. Similar inhibitory effects were observed when the GFP-HepG2 hepatocarcinoma cells treated with C6-8 conjugated CDots were implanted in nude mice. Our work provides a new aptamer for targeting/labeling multiple tumor cell types, and its nanoparticle conjugates bring further advantages that increase its potential for use in cancer diagnosis and therapy. PMID- 26107994 TI - Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy. AB - IMPORTANCE: Vitiligo is a common condition that is often emotionally devastating for patients. At present, no reliably effective treatments are available. OBSERVATIONS: Recent advances in the understanding of the pathogenesis of vitiligo suggest that Janus kinase inhibitors may be a therapeutic option. We report a case of generalized vitiligo for which treatment with tofacitinib citrate, an oral Janus kinase 1/3 inhibitor, resulted in significant repigmentation. CONCLUSIONS AND RELEVANCE: The results suggest that tofacitinib and other Janus kinase inhibitors may be effective in the treatment of vitiligo. Additional studies will be needed to confirm their efficacy and to explore their safety. PMID- 26107996 TI - Parents' perspectives on care of children with autistic spectrum disorder in South Asia - Views from Pakistan and India. AB - Autism spectrum disorder (ASD) affects about 1.4% of the population in South Asia but very few have access to any form of health care service. The objective of this study was to explore the beliefs and practices related to the care of children with ASD to inform strategies for intervention. In Pakistan, primary data were collected through in-depth interviews of parents (N = 15), while in India a narrative review of existing studies was conducted. The results show that the burden of care is almost entirely on the mother, leading to high levels of stress. Poor awareness of the condition in both family members and front-line health-providers leads to delay in recognition and appropriate management. There is considerable stigma and discrimination affecting children with autism and their families. Specialist services are rare, concentrated in urban areas, and inaccessible to the majority. Strategies for intervention should include building community and family support networks to provide respite to the main carer. In the absence of specialists, community members such as community health workers, traditional practitioners and even motivated family members could be trained in recognizing and providing evidence-based interventions. Such task-shifting strategies should be accompanied by campaigns to raise awareness so greater inclusivity can be achieved. PMID- 26107995 TI - Functionalized Multiwalled Carbon Nanotubes as Carriers of Ruthenium Complexes to Antagonize Cancer Multidrug Resistance and Radioresistance. AB - Multidrug resistance and radioresistance are major obstacles for successful cancer therapy. Due to the unique characteristics of high surface area, improved cellular uptake, and the possibility to be easily bound with therapeutics, carbon nanotubes (CNTs) have attracted increasing attention as potential nanodrug delivery systems. In this study, a CNT-based radiosensitive nanodrug delivery system was rationally designed to antagonize the multidrug resistance in hepatocellular carcinoma. The nanosystem was loaded with a potent anticancer ruthenium polypyridyl complex (RuPOP) via pi-pi interaction and formation of a hydrogen bond. The functionalized nanosystem (RuPOP@MWCNTs) enhanced the cellular uptake of RuPOP in liver cancer cells, especially drug-resistant R-HepG2 cells, through endocytosis. Consistently, the selective cellular uptake endowed the nanosystem amplified anticancer efficacy against R-HepG2 cells but not in normal cells. Interestingly, RuPOP@MWCNTs significantly enhanced the anticancer efficacy of clinically used X-ray against R-HepG2 cells through induction of apoptosis and G0/G1 cell cycle arrest, with the involvement of ROS overproduction, which activated several downstream signaling pathways, including DNA damage-mediated p53 phosphorylation, activation of p38, and inactivation of AKT and ERK. Moreover, the nanosystem also effectively reduces the toxic side effects of loaded drugs and prolongs the blood circulation in vivo. Taken together, the results demonstrate the rational design of functionalized carbon nanotubes and their application as effective nanomedicine to overcome cancer multidrug resistance. PMID- 26107997 TI - Routine outcome measurement in the Netherlands - A focus on benchmarking. AB - Routine outcome measurement (ROM) is a 'hot' topic in the Netherlands. Over recent years the Netherlands have developed a centralized monitoring system for all reimbursed mental health interventions, in an attempt to improve the quality of care. The Foundation for Benchmarking Mental Health (SBG) is an independent knowledge centre for mental health providers and insurance companies. It was founded to organize and manage the countrywide ROM initiative. A Dutch countrywide ROM initiative is appealing, and the procedures in the Netherlands are described. However, the national ROM system was oversold. Arguments are discussed. It would have been a far better strategy if insurance companies and authorities had not focused on a national system but stimulated local data collection and requested a managerial plan-do-check-act (PDCA) cycle to stimulate service improvements from year to year. Within the same service, chances are higher that the same kind of clientele is served from year to year and therefore it will be easier to interpret the data. The ROM should regain its clinical focus. Mobile ROM systems using smartphones that collect sampled experiences could be an interesting future solution. PMID- 26107998 TI - The recent arbovirus disease epidemic in Brazil. PMID- 26107999 TI - New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment. AB - Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB) is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL), its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit ratio. PMID- 26108000 TI - Influenza infection and Kawasaki disease. AB - INTRODUCTION: The objective of this study was to investigate the possible link between influenza (Flu) infection and Kawasaki disease (KD). METHODS: We examined the medical records of 1,053 KD cases and 4,669 influenza infection cases hospitalized at our institute from January 1, 2011 to December 31, 2013. Cases of KD with concomitant influenza infection formed the KD + Flu group. Each KD + Flu case was matched with 2 KD cases and 2 influenza infection cases, and these cases were assigned to the KD group and Flu group, respectively. The differences in the principal clinical manifestations, course of disease, incomplete KD rate, intravenous immunoglobulin (IVIG) resistance rate, and echocardiographic detection results between the KD + Flu group and KD group were compared. The fever durations and laboratory test results of these three groups were compared. RESULTS: 1) The seasonal variations of the KD + Flu group, KD group and Flu group were similar. 2) The morbidity rate of incomplete KD was higher in the KD + Flu group compared with the KD group. 3) Patients in the KD + Flu group exhibited a longer time to KD diagnosis compared with patients in the KD group. 4) The KD + Flu group exhibited the longest fever duration among the three groups. 5) The CRP and ESR values in the KD + Flu group were higher those in the Flu or KD groups. CONCLUSIONS: Concomitant influenza infection affects the clinical manifestations of KD and can impact the laboratory test results and the diagnosis and treatment of the disease. However, it remains unclear whether influenza contributes to KD etiology. PMID- 26108001 TI - HIV-1 epidemiology and circulating subtypes in the countryside of South Brazil. AB - INTRODUCTION: Human immunodeficiency virus type 1 (HIV-1) has spread worldwide, with several subtypes and circulating recombinant forms. Brazil has an incidence of 20.5 HIV-1/acquired immunodeficiency syndrome (AIDS) patients per 100,000 inhabitants; however, the Southernmost State of Rio Grande do Sul (RS) has more than twice the number of HIV-1-infected people (41.3/100,000 inhabitants) and a different pattern of subtype frequencies, as previously reported in studies conducted in the capital (Porto Alegre) and its metropolitan region. This study examined HIV-1/AIDS epidemiological and molecular aspects in the countryside of Rio Grande do Sul. METHODS: Socio-demographic, clinical and risk behavioral characteristics were obtained from HIV-1-positive adult patients using a structured questionnaire. HIV-1 subtypes were determined by nested-polymerase chain reaction (PCR) and sequencing of the pol and env genes. RESULTS: The study sample included 149 (55% women) patients with a mean age of 41.8 +/- 11.9 years. Most (73.8%) patients had a low education level and reported heterosexual practices as the most (91.9%) probable transmission route. HIV-1 subtypes were detected in 26 patients: 18 (69.2%) infected with subtype C, six (23.1%) infected with subtype B and two (7.7%) infected with BC recombinant forms. CONCLUSIONS: These data highlight the increasing number of HIV-1 subtype C infections in the countryside of South Brazil. PMID- 26108002 TI - Occult HBV infection status among chronic hepatitis C and hemodialysis patients in Northeastern Egypt: regional and national overview. AB - INTRODUCTION: Occult hepatitis B infection (OBI) is considered to be one of the major risks for patients suffering from end-stage renal disease (ESRD) on regular hemodialysis (HD) and patients with chronic hepatitis C virus (HCV) infection. This study compared the prevalence of OBI among these two high-risk groups in the Suez Canal region, Northeastern Egypt, to obtain a better national overview of the magnitude of OBI in this region. METHODS: Serum samples were collected from 165 HD patients and 210 chronic HCV-infected patients. Anti-HCV antibody, hepatitis B surface antigen (HBsAg), total hepatitis B core (anti-HBc) antibody, and hepatitis B surface antibody (anti-HBs) were detected by enzyme-linked immunosorbent assay (ELISA). HCV RNA was detected using a quantitative real-time RT-PCR assay, and HBV was detected using a nested PCR. RESULTS: All patients were negative for HBsAg. A total of 49.1% and 25.2% of the patients in the HD and HCV groups, respectively, were anti-HBc-positive. In addition, more anti-HBs-positive patients were detected in the HD group compared to the HCV group (52.1% and 11.4%, respectively). Three cases were positive for HBV DNA in the HD group, while eighteen positive cases were detected in the HCV group. Both study groups showed significant differences in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level as well as anti-HBc, anti-HBs and HBV-DNA positivity. CONCLUSIONS: OBI was more prevalent among chronic HCV patients than HD patients in the Suez Canal region, Egypt, with rates of 8.5% and 1.8%, respectively. However, more precise assessment of this infection requires regular patient follow-up using HBV DNA detection methods. PMID- 26108003 TI - Phlebotominae sand flies (Diptera: Psychodidae): potential vectors of American cutaneous leishmaniasis agents in the area associated with the Santo Antonio Hydroelectric System in Western Amazonian Brazil. AB - INTRODUCTION: An entomological study was conducted as part of a vector-monitoring program in the area associated with the Santo Antonio hydroelectric system in State of Rondonia, Western Amazonian Brazil. METHODS: Fourteen sampling sites were surveyed to obtain data on the potential vectors of Leishmania spp. in the area. Sand flies were collected from 2011 to 2014 during the months of January/February (rainy season), May/June (dry season), and September/October (intermediary season) using light traps arranged in three vertical strata (0.5, 1, and 20m). RESULTS: A total of 7,575 individuals belonging to 62 species/subspecies were collected. The five most frequently collected sand flies were Psychodopygus davisi (Root) (36.67%), Trichophoromyia ubiquitalis (Mangabeira) (8.51%), Nyssomyia umbratilis (Ward & Fraiha) (6.14%), Bichromomyia flaviscutellata (Mangabeira) (5.74%), and Psychodopygus complexus (Mangabeira) (5.25%). These species have been implicated in the transmission of American cutaneous leishmaniasis agents in the Brazilian Amazon region and described as potential vectors of this disease in the study area. CONCLUSIONS: Additional surveillance is needed, especially in areas where these five species of sand fly are found. PMID- 26108004 TI - Leptospirosis in animals and human contacts in Egypt: broad range surveillance. AB - INTRODUCTION: Leptospirosis is a re-emerging zoonotic disease of humans and animals worldwide. The disease is caused by pathogenic species of the genus Leptospira. These organisms are maintained in nature via chronic renal infection of carrier animals, which excrete the organisms in their urine. Humans become infected through direct or indirect exposure to infected animals and their urine or through contact with contaminated water and soil. This study was conducted to investigate Leptospira infections as a re-emerging zoonosis that has been neglected in Egypt. METHODS: Samples from 1,250 animals (270 rats, 168 dogs, 625 cows, 26 buffaloes, 99 sheep, 14 horses, 26 donkeys and 22 camels), 175 human contacts and 45 water sources were collected from different governorates in Egypt. The samples were collected from different body sites and prepared for culture, PCR and the microscopic agglutination test (MAT). RESULTS: The isolation rates of Leptospira serovars were 6.9%, 11.3% and 1.1% for rats, dogs and cows, respectively, whereas the PCR results revealed respective detection rates of 24%, 11.3% and 1.1% for rats, dogs and cows. Neither the other examined animal species nor humans yielded positive results via these two techniques. Only six Leptospira serovars (Icterohaemorrhagiae, Pomona, Canicola, Grippotyphosa, Celledoni and Pyrogenes) could be isolated from rats, dogs and cows. Moreover, the seroprevalence of leptospiral antibodies among the examined humans determined using MAT was 49.7%. CONCLUSIONS: The obtained results revealed that rats, dogs and cows were the most important animal reservoirs for leptospirosis in Egypt, and the high seroprevalence among human contacts highlights the public health implications of this neglected zoonosis. PMID- 26108005 TI - Antimicrobial resistance of Helicobacter pylori strains to five antibiotics, including levofloxacin, in Northwestern Turkey. AB - INTRODUCTION: Antibiotic resistance is the main factor that affects the efficacy of current therapeutic regimens against Helicobacter pylori. This study aimed to determine the rates of resistance to efficacy clarithromycin, amoxicillin, tetracycline, levofloxacin and metronidazole among H. pylori strains isolated from Turkish patients with dyspepsia. METHODS: H. pylori was cultured from corpus and antrum biopsies that were collected from patients with dyspeptic symptoms, and the antimicrobial susceptibility of H. pylori was determined using the E-test (clarithromycin, amoxicillin, tetracycline, metronidazole and levofloxacin) according to the EUCAST breakpoints. Point mutations in the 23S rRNA gene of clarithromycin-resistant strains were investigated using real-time PCR. RESULTS: A total of 98 H. pylori strains were isolated, all of which were susceptible to amoxicillin and tetracycline. Of these strains, 36.7% (36/98) were resistant to clarithromycin, 35.5% (34/98) were resistant to metronidazole, and 29.5% (29/98) were resistant to levofloxacin. Multiple resistance was detected in 19.3% of the isolates. The A2143G and A2144G point mutations in the 23S rRNA-encoding gene were found in all 36 (100%) of the clarithromycin-resistant strains. Additionally, the levofloxacin MIC values increased to 32 mg/L in our H. pylori strains. Finally, among the clarithromycin-resistant strains, 27.2% were resistant to levofloxacin, and 45.4% were resistant to metronidazole. CONCLUSIONS: We conclude that treatment failure after clarithromycin- or levofloxacin-based triple therapy is not surprising and that metronidazole is not a reliable agent for the eradication of H. pylori infection in Turkey. PMID- 26108006 TI - Study of the risk factors related to acquisition of urinary tract infections in patients submitted to renal transplant. AB - INTRODUCTION: Urinary tract infections (UTI) among transplant recipients are usually caused by gram-negative microorganisms and can provoke a high incidence of morbidity and mortality. The aim of this study was to evaluate the risk factors associated with the acquisition of UTIs during the first year after renal transplantation. METHODS: Here, we report a single-center retrospective cohort study of 99 renal transplant patients followed for the first year after surgery. The definition of a UTI episode was a urine culture showing bacterial growth and leucocyturia when patients presented with urinary symptoms. The absence of infection (asymptomatic bacteriuria) was defined as an absence of symptoms with negative urine culture or bacterial growth with any number of colonies. RESULTS: Ninety-nine patients were included in the study. During the study, 1,847 urine cultures were collected, and 320 (17.3%) tested positive for bacterial growth. Twenty-six (26.2%) patients developed a UTI. The most frequent microorganisms isolated from patients with UTIs were Klebsiella pneumoniae (36%), with 33% of the strains resistant to carbapenems, followed by Escherichia coli (20%). There were no deaths or graft losses associated with UTI episodes. CONCLUSIONS: Among the UTI risk factors studied, the only one that was associated with a higher incidence of infection was female sex. Moreover, the identification of drug resistant strains is worrisome, as these infections have become widespread globally and represent a challenge in the control and management of infections, especially in solid organ transplantation. PMID- 26108007 TI - Spatial analysis of visceral leishmaniasis in the municipality of Rondonopolis, in the Brazilian State of Mato Grosso, from 2003 to 2012: human, canine and vector distribution in areas of disease transmission. AB - INTRODUCTION: Visceral leishmaniasis (VL) is a zoonosis of great importance to public health and is considered a neglected disease by the World Health Organization. The disease has expanded and become more prevalent in urban areas in Brazil. METHODS: Geospatial analyses were performed and thematic maps of the triad of the disease were produced for the study period (2003-2012) in the urban area of the municipality of Rondonopolis in the midwestern State of Mato Grosso (MT), Brazil, TerraView 4.2.2 software was used for the analyses. RESULTS: A total of 87.9% of the 186 confirmed human cases of VL were cured. Children between the ages of 1 and 4 were the most affected. Registered deaths were predominant among adults aged 60 years or older. The urban area of the municipality consists of eight strata and 12 census districts include 237 neighborhoods. All sectors had confirmed cases of VL. During the study period, human cases of the disease were recorded in 90 neighborhoods. The 23 deaths from the disease were distributed in 21 neighborhoods. Sandflies carrying the parasite were captured in 192 out of 200 neighborhoods evaluated for the presence of the VL vector. The presence of dogs carrying the parasite was confirmed in, 140 out of 154 surveyed neighborhoods. CONCLUSIONS: The data demonstrated the endemic nature of VL, with a high percentage of infected children, a high distribution of canine infection, and a wide adaptation and dispersal of the vectors in the urban environment. These results, illustrate the process of urbanization of VL in the municipality of Rondonopolis, MT, Brazil. PMID- 26108008 TI - Epidemiological aspects of Toxoplasma gondii infection in riverside communities in the Southern Brazilian Amazon. AB - INTRODUCTION: Toxoplasma gondii infection is widely prevalent in humans and other animals worldwide. Information on the prevalence of T. gondii infection is scarce in some regions of Brazil, including riverside communities along the Amazon River basin. M METHODS: The prevalence of T. gondii in 231 people, aged 1-85 years, who were living in four riverside communities along the Purus River, Labrea, State of Amazonas, Brazil, was determined. Antibodies against T. gondii were assayed using a commercial enzyme-linked immunosorbent assay (ELISA) kit. The hearts and brains of 50 chickens, which were raised free-range in the communities, were pooled according to the community of origin and bioassayed in mice. The isolates were genotyped using polymorphisms at 12 nuclear markers (SAG1, 5' and 3'-SAG2, alt.SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, Apico and CS3). RESULTS: The overall seroprevalence of T. gondii was 56.7% (131/231). IgG antibodies were presented by 117 (89.3%) and IgM by 14 (10.7%) of the 131 positive individuals. No association between age group and gender with prevalence was observed (chi square test, p > 0.05); however, the comparison between localities showed that the seroprevalence of T. gondii was significantly lower among the individuals living in the Boca do Ituxi (p < 0.05) community. Five isolates of T. gondii were obtained in the mouse bioassay, and genotyping revealed two complete genotypes that had not been described previously and three mixed isolates. CONCLUSIONS: These results support previous findings that T. gondii population genetics are highly diverse in Brazil and that T. gondii infection is active in these riverside communities. PMID- 26108009 TI - Prevalence and evolution of Mycobacterium tuberculosis infection in tuberculosis case contacts. AB - INTRODUCTION: The tuberculin test is a diagnostic method for detecting latent tuberculosis (TB) infection, especially among disease contact cases. The objective of this study was to analyze the prevalence and evolution of Mycobacterium tuberculosis infection among TB contact cases. METHODS: A retrospective cohort study was performed in a reference center for TB. The study population consisted of 2,425 patients who underwent a tuberculin test from 2003 to 2010 and whose results indicated contact with individuals with TB. The data were collected from the registry book of the tuberculin tests, patient files and the Information System Records of Notification Grievance. To verify the evolution of TB, case records through September 2014 were consulted. Data were analyzed using the Statistical Package for the Social Sciences (SPSS). In all hypothesis tests, a significance level of 0.05 was used. RESULTS: From the studied sample, 435 (17.9%) contacts did not return for reading. Among the 1,990 contacts that completed the test, the prevalence of latent TB infection was 35.4%. Of these positive cases, 50.6% were referred to treatment; the dropout rate was 42.5%. Among all of the contacts, the TB prevalence was 1.8%, from which 13.2% abandoned treatment. CONCLUSIONS: The collected data indicate the need for more effective public policies to improve TB control, including administering tests that do not require a return visit for reading, enhancing contact tracing and encouraging actions that reinforce full treatment adherence. PMID- 26108010 TI - Post-splenectomy infections in chronic schistosomiasis as a consequence of bacterial translocation. AB - INTRODUCTION: Bacterial translocation is the invasion of indigenous intestinal bacteria through the gut mucosa to normally sterile tissues and internal organs. Schistosomiasis may cause alterations in the immune system and damage to the intestines, portal system and mesenteric lymph nodes. This study investigated bacterial translocation and alterations in the intestinal microbiota and mucosa in schistosomiasis and splenectomized mice. METHODS: Forty female 35-day-old Swiss Webster mice were divided into the following four groups with 10 animals each: schistosomotic (ESF), splenectomized schistosomotic (ESEF), splenectomized (EF) and control (CF). Infection was achieved by introduction of 50 Schistosoma mansoni (SLM) cercariae through the skin. At 125 days after birth, half of the parasitized and unparasitized mice were subjected to splenectomy. Body weights were recorded for one week after splenectomy; then, the mice were euthanized to study bacterial translocation, microbiota composition and intestinal morphometry. RESULTS: We observed significant reductions in the weight increases in the EF, ESF and ESEF groups. There were increases of at least 1,000 CFU of intestinal microbiota bacteria in these groups compared with the CF. The EF, ESF and ESEF mice showed decreases in the heights and areas of villi and the total villus areas (perimeter). We observed frequent co-infections with various bacterial genera. CONCLUSIONS: The ESEF mice showed a higher degree of sepsis. This finding may be associated with a reduction in the immune response associated with the absence of the spleen and a reduction in nutritional absorption strengthened by both of these factors (Schistosoma infection and splenectomy). PMID- 26108011 TI - Clinical conditions associated with intestinal strongyloidiasis in Rio de Janeiro, Brazil. AB - INTRODUCTION: Strongyloides stercoralis is a soil-transmitted helminth that produces an infection that can persist for decades. The relationships between certain clinical conditions and strongyloidiasis remains controversial. This study aims to identify the clinical conditions associated with intestinal strongyloidiasis at a reference center for infectious diseases in Rio de Janeiro, Brazil. METHODS: The clinical conditions that were assessed included HIV/AIDS, HTLV infection, cardiovascular diseases, diabetes, obstructive respiratory diseases, viral hepatitis, tuberculosis, cancer, chronic renal disease, nutritional/metabolic disorders, psychiatric conditions, rheumatic diseases and dermatologic diseases. We compared 167 S. stercoralis-positive and 133 S. stercoralis-negative patients. RESULTS: After controlling for sex (male/female OR = 2.29; 95% (CI): (1.42 - 3.70), rheumatic diseases remained significantly associated with intestinal strongyloidiasis (OR: 4.96; 95% CI: 1.34-18.37) in a multiple logistic regression model. With respect to leukocyte counts, patients with strongyloidiasis presented with significantly higher relative eosinophil (10.32% +/- 7.2 vs. 4.23% +/- 2.92) and monocyte (8.49% +/- 7.25 vs. 5.39% +/- 4.31) counts and lower segmented neutrophil (52.85% +/- 15.31 vs. 61.32% +/- 11.4) and lymphocyte counts (28.11% +/- 9.72 vs. 30.90% +/- 9.51) than S. stercoralis-negative patients. CONCLUSIONS: Strongyloidiasis should be routinely investigated in hospitalized patients with complex conditions facilitate the treatment of patients who will undergo immunosuppressive therapy. Diagnoses should be determined through the use of appropriate parasitological methods, such as the Baermann-Moraes technique. PMID- 26108012 TI - Prevalence of and risk factors for late diagnosis of HIV infection in Brazilian infants and children. AB - INTRODUCTION: Late human immunodeficiency virus (HIV) diagnosis is an important cause of HIV-related morbidity and mortality in infants and children. METHODS: This retrospective cohort study of HIV-infected children diagnosed in Sergipe, in northeastern Brazil, between 2002 and 2011 aimed to determine the prevalence of and risk factors for late HIV diagnosis. RESULTS: Of 55 infants and children with confirmed infection, 42 (76.5%) were diagnosed at >= 12 months old. No antiretroviral prophylaxis during delivery (OR 5.48, 95% CI 1.11-32.34) was associated with late diagnosis. CONCLUSIONS: More than 75% of cases were diagnosed late. Efforts are needed to improve early HIV diagnosis in infants. PMID- 26108013 TI - Serological diagnosis of Chagas disease in HIV-infected patients. AB - INTRODUCTION: This study assessed the rate of request for the serological diagnosis of Chagas disease among human immunodeficiency virus (HIV)-infected patients treated at the Specialized Care Service of Pelotas, Rio Grande do Sul, Brazil. METHODS: This cross-sectional study used secondary data obtained from the medical records of 252 patients aged between 18 and 75 years. RESULTS: The serological diagnosis of Chagas disease was requested only in 3.2% of cases. CONCLUSIONS: The results demonstrate poor adherence to protocols on the part of healthcare professionals, indicating the need to reevaluate the procedures applied to HIV-infected patients from endemic regions for both diseases. PMID- 26108014 TI - Characterization of a foodborne outbreak caused by Salmonella Enteritidis in Aracaju, State of Sergipe, Brazil. AB - INTRODUCTION: In December 2001, an outbreak of foodborne gastroenteritis infected 114 of 161 people who ate at a restaurant in Aracaju, State of Sergipe, Brazil. METHODS: The epidemiological and microbiological aspects of the outbreak were characterized. RESULTS: Potato salad made with homemade mayonnaise and stored at unsuitable temperatures was associated with increased risk of foodborne infection. Salmonella Enteritidis was isolated from the diarrheal stools of the hospitalized patients, and genotyping of the fecal samples generated identical randomly amplified polymorphic deoxyribonucleic acid (DNA) profiles. CONCLUSIONS: To the best of our knowledge, this is the first and the only record of a gastrointestinal outbreak in Sergipe. PMID- 26108015 TI - Toxoplasma gondii seropositivity and risk factors in pregnant women followed up by the Family Health Strategy. AB - INTRODUCTION: Toxoplasmosis is a zoonotic infection caused by Toxoplasma gondii. It is transmitted by the ingestion of contaminated water and foods, by soil contaminated with cat feces, especially while handling it, and congenitally via the placenta. The diagnosis of maternal infection is made by serological detection of either IgM or IgG antibodies. This study assessed the seropositivity in pregnant women followed up by the Family Health Strategy (FHS) in Lages, Santa Catarina, Brazil. METHODS: The study was performed in 19 FHS units and included 148 childbearing women. The outcomes evaluated were IgM and IgG seropositivity and behavioral variables. RESULTS: IgG yielded positive results in 16% of the pregnant women, whereas IgM was positive in only 1%. CONCLUSIONS: The 1% IgM positivity rate for T. gondii indicates congenital toxoplasmosis is not common in Lages. PMID- 26108016 TI - Quality assessment of clinical practice guidelines for Chagas disease. AB - INTRODUCTION: The development of clinical practice guidelines (CPGs) has increased; this study aimed to assess the quality of CPGs for the management of Chagas disease. METHODS: Following a systematic search of the scientific literature, two reviewers assessed the eligible guidelines using the Appraisal of Guidelines Research and Evaluation (AGREE) II instrument. RESULTS: Five CPGs were included. The AGREE domains of scope/purpose, stakeholder involvement, and clarity of presentation were rated well, and the domains of applicability and editorial independence received poor ratings. CONCLUSIONS: The quality of CPGs for Chagas disease is poor, and significant work is required to develop high quality guidelines. PMID- 26108017 TI - Report of new cases of Trypanosoma caninum in Brazil. AB - INTRODUCTION: Trypanosoma caninum is a protozoan species recently described in dogs, whose occurrence has been reported in areas of overlap with visceral leishmaniasis. METHODS: Trypanosoma sp. were isolated from nine dogs and characterized by molecular methods. RESULTS: PCR and sequencing confirmed the presence of T. caninum in all dogs, revealing two new areas of transmission: Barra Mansa and Sao Joao do Piaui. CONCLUSIONS: The nine new cases described, when added to those already published, account for 62 cases of natural infection by T. caninum and show the geographical spread of this species to new areas, where other trypanosomatids circulate. PMID- 26108018 TI - Evaluation of the cytokine mannose-binding lectin as a mediator of periportal fibrosis progression in patients with schistosomiasis. AB - INTRODUCTION: We hypothesized higher mannose-binding lectin level and classic factors (i.e., age, sex, alcohol consumption, exposure, and specific treatment) are associated with the severity of periportal fibrosis in schistosomiasis. METHODS: This cross-sectional study involved 79 patients infected with Schistosoma mansoni with severe or mild/moderate periportal fibrosis. Serum concentrations of mannose-binding lectin were obtained by enzyme-linked immunosorbent assay (ELISA). RESULTS: Higher serum level of mannose-binding lectin was significantly associated with advanced periportal fibrosis. CONCLUSIONS: Mannose-binding lectin may contribute to liver pathology in schistosomiasis and may represent a risk factor for advanced periportal fibrosis in the Brazilian population studied. PMID- 26108019 TI - Schistosomiasis in Southern Brazil 17 years after the confirmation of the first autochthonous case. AB - INTRODUCTION: Schistosomiasis, a parasitic disease, is an important public health issue in Brazil, particularly Northern Brazil. Since the first recorded occurrence of Biomphalaria glabrata in the States of Santa Catarina and Rio Grande do Sul, it has spread to South Brazil. METHODS: Using the Information System for Notifiable Diseases (SINAN), we assessed the disease spread in Southern Brazil. RESULTS: In Rio Grande do Sul, nine localities had confirmed cases (n = 95, 2001-2013). CONCLUSIONS: We confirmed disease expansion to Southern Brazil. We demonstrated the effectiveness of SINAN to monitor notifiable diseases. Our results are useful to develop preventive actions for schistosomiasis control. PMID- 26108020 TI - Successful treatment of lower urinary tract infections with oral fosfomycin: a report of three cases. AB - Infections due to multidrug-resistant organisms continue to increase, and therapeutic options remain scarce. Given this challenge, it has become necessary to use older antimicrobials for treatment of these pathogens. We report three patients with lower urinary tract infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae who were successfully treated with a seven-day course of oral fosfomycin monotherapy. PMID- 26108021 TI - Dirofilariasis involving the oral cavity: report of the first case from South America. AB - Oral dirofilariasis is very rare with non-specific clinical manifestations. Here, we report the case of a 65-year-old South American woman with a submucosal nodule on her right buccal mucosa. The nodule was slightly tender and painful. Differential diagnoses included mesenchymal (lipoma or fibrolipoma, solitary fibrous tumor, and neurofibroma) or glandular benign tumors (pleomorphic adenoma) with secondary infections. We performed excisional biopsy. A histopathological examination revealed a dense fibrous capsule and a single female filarial worm showing double uterus appearance, neural plaque, well-developed musculature and intestinal apparatus. Dirofilariasis was diagnosed, and the patient was followed up for 12 months without recurrence. PMID- 26108022 TI - Brucella pneumonia with microabscess and pleural effusion. PMID- 26108023 TI - Cholangiocarcinoma and opisthorchiasis in Northeast Thailand: raw fish intake may not be the sole cause. PMID- 26108024 TI - Polypropylene and polypropylene/polyglecaprone (Ultrapro(r)) meshes in the repair of incisional hernia in rats. AB - PURPOSE: To compare the inflammatory response of three different meshes on abdominal hernia repair in an experimental model of incisional hernia. METHODS: Median fascial incision and skin synthesis was performed on 30 Wistar rats. After 21 days, abdominal hernia developed was corrected as follows: 1) No mesh; 2) Polypropylene mesh; and, 3) Ultrapro(r) mesh. After 21 days, the mesh and surrounding tissue were submitted to macroscopic (presence of adhesions, mesh retraction), microscopic analysis to identify and quantify the inflammatory and fibrotic response using a score based on a predefined scale of 0-3 degrees, evaluating infiltration of macrophages, giant cells, neutrophils and lymphocytes. RESULTS: No significant difference was seen among groups in adherences, fibrosis, giant cells, macrophages, neutrophils or lymphocytes (p>0.05). Mesh shrinkage was observed in all groups, but also no difference was observed between polypropylene and Ultrapro mesh (7.0+/-9.9 vs. 7.4+/-10.1, respectively, p=0.967). Post operatory complications included fistula, abscess, dehiscence, serohematic collection and reherniation, but with no difference among groups (p=0.363). CONCLUSION: There is no difference between polypropylene (high-density) and Ultrapro(r) (low-density) meshes at 21 days after surgery in extraperitoneal use in rats, comparing inflammatory response, mesh shortening, adhesions or complications. PMID- 26108025 TI - Deleterious effects of prepubertal corticosterone treatment on rat prostate. AB - PURPOSE: To investigate the structural and functional changes induced by corticosterone (CORT) in the ventral prostrate (VP) of rats in order to study chronic stress effects in the prepubertal phase. METHODS: Wistar rats received daily saline or CORT injections during the pubertal period from the 5th to 25th day of postnatal life. The animals were distributed into four groups: 1 - Control (n=5); 2 - Control 99mTc-P (n=5); 3 - Treated with CORT (n=14); 4 - Treated with CORT and 99mTc-P (n=10). All rats were sacrificed at two months of age. Technical tissue uptakes of 99mTc-P were used to evaluate the functional and stereological methods for morphological analysis. RESULTS: Acini distribution in the group treated with CORT differed significantly (p<0.0001) from the control. The control group's epithelial average height (10.01+/-0.24 microns) was statistically significant (p<0.0001) from rats treated with CORT (19.27+/-0.73microns). The collagen distribution was lower in the treated group (2.79%) when compared to control (3.97%). The radioactivity percentage in the groups marked with 99mTc-P (%Ati/g) did not demonstrate a statistically significant difference (p=0.285897). CONCLUSION: Chronic administration of corticosterone in prepubertal rats causes changes in their acinar structure and their ventral prostate stroma, indicating possible deleterious effects of this hormone. PMID- 26108026 TI - Heart and systemic effects of statin pretreatment in a rat model of abdominal sepsis. Assessment by Tc99m-sestamibi biodistribition. AB - PURPOSE: To evaluate the heart and the Tc-99m-sestamibi biodistribution after statin pretreatment in a rat model of abdominal sepsis. METHODS: Twenty-four Wistar rats were randomly distributed into four groups (n=6 per group): 1) sepsis with simvastatin treatment, 2) sepsis with vehicle, 3) sham control with simvastatin and 4) sham control with vehicle. 24 hours after cecal ligation and puncture rats received 1.0MBq of Tc-99m-sestamibi i.v. 30min after, animals were euthanized for ex-vivo tissue counting and myocardium histological analysis. RESULTS: Myocardial histologic alterations were not detected 24 hours post sepsis. There was significantly increased cardiac Tc-99m-sestamibi activity in the sepsis group with simvastatin treatment (1.9+/-0.3%ID/g, p<0.001) in comparison to the sepsis group+vehicle (1.0+/-0.2%ID/g), control sham group+ simvastatin (1.2+/-0.3%ID/g) and control sham group (1.3+/-0.2%ID/g). Significant Tc-99m-sestamibi activity in liver, kidney and lungs was also detected in the sepsis group treated with simvastatinin comparison to the other groups. CONCLUSIONS: Statin treatment altered the biodistribution of Tc-99m-sestamibi with increased cardiac and solid organ activity in rats with abdominal sepsis, while no impact on controls. Increased myocardial tracer activity may be a result of a possible protection effect due to increased tissue perfusion mediated by statins. PMID- 26108027 TI - Selenium protects cerebral cells by cisplatin induced neurotoxicity. AB - PURPOSE: To evaluate the central nervous system toxicity of cisplatin and neuroprotective effect of selenium. METHODS: Twenty-one male Wistar albino rats were divided into three groups: control (C), cisplatin (CS), cisplatin and selenium (CSE, n=7 in each group). Cisplatin (12 mg/kg/day, i.p.) was administered to CS and CSE groups for three days. Furthermore, CSE group received 3mg/kg/day (twice-a-day as 1.5 mg/kg) selenium via oral gavage five days before cisplatin injection and continued for 11 consecutive days. The same volumes of saline were administered to C group intraperitoneally and orally at same time. RESULTS: Heterochromatic and vacuolated neurons and dilated capillary vessels in the brain were observed in the histochemical examinations of cisplatin treated group. Rats that were given a dose of 3mg/kg/day selenium decreased the cisplatin induced histopathological changes in the brain, indicating a protective effect. In addition, cytoplasmic staining of the cell for bcl-2, both cytoplasmic and nuclear staining for bax were determined to be positive in the all groups. Bax positive cells were increased in the CS group compared to C group, in contrast to decreased bcl-2 positivity. CONCLUSION: Selenium limited apototic activity and histological changes due to the cisplatin related central neurotoxicity. PMID- 26108028 TI - Antimicrobial activity of Melaleuca sp. oil against clinical isolates of antibiotics resistant Staphylococcus aureus. AB - PURPOSE: To extract the Melaleuca sp. oil and to assess its in vitro inhibitory effect against Staphylococcus aureus isolates obtained from lower limb wounds and resistant to several antibiotics. METHODS: A total of 14 test-tubes containing Mueller-Hinton broth were used to determine the Minimum Inhibitory Concentration (MIC). The following concentrations of the Melaleuca sp. oil were added to the first 11 tubes: 8; 4; 2; 1; 0.5; 0.2; 0.1; 0.05; 0.025; 0,0125 and 0.00625%. The 12th and 13th tubes, with and without oil, were used as the positive and negative controls, respectively. The experimental study was carried out in triplicate at 37oC for 18 hours. The Minimum Bactericidal Concentration (MBC), able of killing all the microorganisms, was also determined. Two S. aureus isolates were obtained from lower limb wounds of female patients and the identification of the microorganisms (Staphylococcus aureus) and the test for susceptibility to the antimicrobial agents were carried out by automation using the apparatus MicroScan(r). After identification, the isolates were preserved in liquid Trypticase Soy medium, and inoculated for determination of the MIC and MBC. RESULTS: The MIC was 0.2% and the MBC was 0.4%. CONCLUSION: The Melaleuca sp. oil showed antimicrobial properties in vitro against strains isolated from lower limb wounds which were resistant to multiple antibiotics. PMID- 26108029 TI - Effect of protective solutions and hydroxyethyl starch in the attenuation of the injuries of ischemia and reperfusion of splanchnic organs. AB - PURPOSE: Vogt's antioxidant solution (red blood cells, Ringer's solution, sodium bicarbonate, mannitol, allopurinol and 50% glucose) or its modification including hydroxyethyl starch (HES) were tested for the prevention of splanchnic artery occlusion shock. METHODS: Seventy rats were distributed in treatment (3), control (1), and sham (3) groups. Ischemia and reperfusion were induced by celiac, superior mesenteric and inferior mesenteric arteries occlusion for 40 min, followed by 60 min reperfusion or sham procedures. Controls received saline, both treatment and sham groups received the Vogt's solution, modified Vogt's solution (replacing Ringer's solution by HES), or HES. Mean arterial blood pressure (MABP), ileal malondialdehyde (MDA) and plasmatic MDA were determined, and a histologic grading system was used. RESULTS: At reperfusion, MABP dropped in all I/R groups. Only HES treatment was able to restore final MABP to the levels of sham groups. Plasmatic MDA did not show differences between groups. Ileum MDA was significantly higher in the control and treatment groups as compared to the sham group. Histology ranking was higher in the only in control group. CONCLUSIONS: Hydroxyethyl starch was able to prevent hemodynamic shock but not intestinal lesions. Both treatments with Vogt's solutions did not show any improvement. PMID- 26108030 TI - The antioxidant effect of dexmedetomidine on testicular ischemia-reperfusion injury. AB - PURPOSE: To investigate the protective effect of dexmedetomidine (Dex) on testicular damage induced by ischemia-reperfusion injury in rats. METHODS: Sham group underwent left scrotal exploration only (group 1). The ischemia-reperfusion only group underwent left testicular torsion and detorsion (group 2). The ischemia-reperfusion plus Dex group underwent left testicular torsion, received 50 ug/kg Dex (group 3) and 100 ug/kg Dex (group 4) intraperitoneally at minute 180 of ischemia and then underwent detorsion. We determined histopathological findings and performed specific biochemical analyses. RESULTS: Increasing doses of Dex significantly increased TAS, and significantly decreased OSI. Analyzing the antioxidant effects of increasing doses of Dex in torsion and contrlateral testicles: Dex 100 ug/kg statistically significant increased the tissue total antioxidant status (TAS) and oxidative stress index (OSI) when compared with Dex 50 ug/kg but not found significantly change on the tissue total oxidant status (TOS). However, Dex did not significantly improve these histological alterations. CONCLUSION: The antioxidant effects of dexmedetomidine on testicular ischemia reperfusion injury in ipsilateral and contrlateral testis, but in the histopathological level, there was no difference statistically according to Johnsen's scoring system between groups at both sides. PMID- 26108031 TI - Oxymatrine ameliorates renal ischemia-reperfusion injury from oxidative stress through Nrf2/HO-1 pathway. AB - PURPOSE: To investigate if oxymatrine pretreatment could ameliorate renal I/R injury induced in rats and explore the possible role of oxymatrine in Nrf2/HO-1 pathway. METHODS: Unilaterally nephrectomized rats were insulted by I/R in their left kidney. Twenty four rats were randomly divided into three groups: sham group, I/R + saline-treated group, I/R + OMT-treated group. Oxymatrine or vehicle solution was administered intraperitoneally injected 60 min before renal ischemia, respectively. Renal function, histology, makers of oxidative stress, cell apoptosis and Nrf2/HO-1 expressions were assessed. RESULTS: Oxymatrine pretreatment exhibited an improved renal functional recovery, alleviated histological injury and oxidative stress, inhibiting tubular apoptosis, and accompanied by upregulated the expression of Nrf2/HO-1 proteins. CONCLUSION: Oxymatrine may attenuate renal ischemia/reperfusion injury, and this renoprotective effect may be through activating the Nrf2/HO-1 pathway. PMID- 26108032 TI - Oil mixes omega 9, 6 and 3, enriched with seaweed, promoted reduction of thermal burned modulating NF-kB and Ki-67. AB - PURPOSE: To examine the effects of the oil mixes (omega-9, omega-6 and omega-3) in rats subjected to thermal burn. It was also aimed to assess whether the sources of omega3 would interfere with the effect of such mixes on the thermal injury. METHODS: Thirty-six rats distributed into five groups: burned + water, burned + isolipid mix, burned + oil mix 1 (ALA), burned + oil mix 2 (ALA + EPA + DHA of fish) and burned + oil mix 3 (ALA + DHA from seaweed). The thermal injury was involving total thickness of skin. After the burns animals received the oil mixes for seven days. The lesions were evaluated by immunohistochemistry. RESULTS: Animals receiving mix 3 showed a smaller extension of the thermal injury as compared to those that were supplemented with other oils mixes. Expression of Ki-67 in the receiving Mix 3 increased as compared to all the other groups. Animals supplemented with mix 3 were able to inhibit NF-kappaB in injured tissue. CONCLUSION: Rats received oil mix in which the source of omega3 (ALA+DHA of seaweed) showed inhibition of NF-kappaB, increase in cell proliferation, and reduction the extension of thermal lesion. PMID- 26108033 TI - Post-hemorrhagic shock mesenteric lymph is an important contributor to cardiac dysfunction following hemorrhagic shock. AB - PURPOSE: To evaluate whether post-hemorrhagic shock mesenteric lymph (PSML) is involved in cardiac dysfunction induced by hemorrhagic shock. METHODS: The hemorrhagic shock model (40+/-2 mmHg, 3h) was established in rats of the shock and shock+drainage groups; and PSML drainage was performed from hypotension 1-3h in the shock+drainage rats. Then, the isolated hearts were obtained from the rats for the examination of cardiac function with Langendorff system. Subsequently, the isolated hearts were obtained from normal rats and perfused with PSML or Krebs-Henseleit solution, and the changes of cardiac function were observed. RESULTS: The left ventricular systolic pressure (LVSP) and the maximal rates of LV developed pressure (LVDP) rise and fall (+/-dP/dt max) in the shock and shock+drainage groups were lower than that of the sham group; otherwise, these indices in the shock+drainage group were higher compared to the shock group. In addition, after isolated hearts obtained from normal rats perfusing with PSML, these cardiac function indices were gradual decline along with the extension of time, such as heart rate, LVSP, +/-dP/dt max, etc. CONCLUSION: Post-hemorrhagic shock mesenteric lymph is an important contributor to cardiac dysfunction following hemorrhagic shock. PMID- 26108034 TI - Identification and characterization of tumor necrosis factor receptor (TNFR) associated factor 3 from humphead snapper, Lutjanus sanguineus. AB - Tumor necrosis factor receptor (TNFR)-associated factor 3(TRAF3) is a key regulator in TNFR and Toll-like receptor (TLRs)/RIG-I-like receptors (RLRs) signal pathway. Here, a TRAF3 gene (Ls-TRAF3, GenBank Accession No: KJ789921) is cloned from humphead snapper (Lutjanus sanguineus). The Ls-TRAF3 cDNA contains an open reading frame of 1788 bp, which encodes a polypeptide of 595 amino acids. The deduced amino acid of Ls-TRAF3 possesses a RING finger, two TRAF-type zinc fingers, a coiled-coil and a MATH domain. Ls-TRAF3 protein shares high identities with other known TRAF3 proteins. In healthy fish, Ls-TRAF3 transcripts were broadly expressed in all examined tissues with highest expression levels in spleen, liver and head kidney. Quantitative real-time PCR (qRT-PCR) analysis revealed that Ls-TRAF3 could be induced by bacteria or viral PAMP poly I:C stimulation in vivo. Here, we also showed Ls-TRAF3 that, positively regulated IRF3 and Mx upon poly I:C stimuli, whereas prevented production of proinflammatory cytokine IL-6 after LPS injection. Moreover, over-expression of wide type (WT) Ls-TRAF3 and truncated forms, including DeltaZinc finger 1, DeltaZinc finger 2 and Deltacoiled-coil suppressed NF-kappaB activity significantly, whereas the inhibitory effect of NF-kappaB was partially impaired when the RING finger or MATH domain deletion, suggesting the latter was more important for downstream signal transduction. Taken together, these results implicated that Ls-TRAF3 might play regulatory roles in immune response to pathogen invasion. PMID- 26108035 TI - Effects of dietary Bacillus licheniformis on growth performance, immunological parameters, intestinal morphology and resistance of juvenile Nile tilapia (Oreochromis niloticus) to challenge infections. AB - The effects of oral administration of Bacillus licheniformis on growth performance, immunity, intestinal morphology and disease resistance of juvenile tilapia were investigated. Six experimental diets supplemented with different concentrations of B. licheniformis (0%, 0.02%, 0.04%, 0.06%, 0.08% and 0.1% of AlCare((r)), containing live germ 2 * 10(10) CFU/g) were formulated, viz. control, T1, T2, T3, T4 and T5. Each diet was randomly assigned to triplicate groups of 30 fishes (3.83 +/- 0.03 g). After 10 weeks of feeding trial, weight gain (WG), final body wet weight (FBW) and specific growth rate (SGR) increased significantly in groups T2, T3, T4 and T5 compared with control and T1 (p < 0.05). However, survival rate and feed conversion ratio (FCR) were not found to be significantly affected (P > 0.05). Compared with control, dietary B. licheniformis supplementation increased the content of complement C3 in serum significantly (P < 0.05). The lysozyme activity was observed to be highest in T2 (P < 0.05) without differences among other groups. However, SOD activity was not affected by B. licheniformis supplementation (P > 0.05). When tilapia were challenged against Streptococcus iniae, survival rate improved significantly when tilapia fed with T2, T3, T4 and T5 (P < 0.05). Although there was no significant differences in villi length and muscular layer thickness of anterior intestinal among the treatments, intestinal villi of fish fed with higher concentrations of B. licheniformis (T2, T3, T4, T5) tended to be regularly arranged and exhibited less exfoliation, twist and fusion. These results indicated that dietary supplementation of B. licheniformis not only increased the growth, immune response and disease resistance of juvenile tilapia, but also influenced anterior intestinal development and integrity. Furthermore, in our study, the optimal concentration of B. licheniformis in diets for tilapia was greater than or equal to 4.4 * 10(6) CFU/g. PMID- 26108036 TI - Comparative genomic and evolution of vertebrate NOD1 and NOD2 genes and their immune response in miiuy croaker. AB - The nucleotide-binding oligomerization domain proteins NOD1 and NOD2 are important cytoplasmic pathogen recognition receptors which sense microbial infections molecules to induce innate immune response. In this study, the sequence analysis showed that NOD1 and NOD2 genes in miiuy croaker (miichthys miiuy, mmiNOD1 and mmiNOD2) share some highly conserved motifs that crucial for recognizing the bacterial and viral components. Quantitative expression analysis revealed mmiNOD1 and mmiNOD2 had the highest level of expression in liver. Induction experiments with Vibrio anguillarum indicated the different expression levels of mmiNOD1 and mmiNOD2 in liver, spleen and kidney. The expressions of mmiNOD1 and mmiNOD2 increased more significantly after Poly(I:C) stimulation, meanwhile, we carried out the expression analysis at the transcriptome level and the regulation of microRNAs. In addition, the evolutionary analysis showed that the ancestral lineages of NOD1 in bony fish detected one positively selected site, however, both the current lineages of NOD1 and NOD2 genes in bony fish underwent purifying selection indicating that NOD1 gene in the ancestor of bony fish experienced positive selection. To further understand the evolutionary pattern of NOD1 and NOD2 in vertebrates, we were the first to conduct comparative genomic analysis by comparing the number and synteny of NOD1 and NOD2. Combining the duplication of NOD1, the lost of NOD2 and the more conserved synteny of NOD2 than NOD1, we proposed that the hypothetical evolutionary pattern is different between NOD1 and NOD2. PMID- 26108037 TI - Using reconfigurable microfluidics to study the role of HGF in autocrine and paracrine signaling of hepatocytes. AB - Cancer, developmental biology and tissue injury present multiple examples where groups of cells residing in close proximity communicate via paracrine factors. It is nearly impossible to dissect such cellular interactions in vivo and is quite challenging in vitro. The goal of this study is to utilize a reconfigurable microfluidic device in order to study paracrine signal exchange between groups of primary hepatocytes in vitro. Previously, we demonstrated that hepatocytes residing on protein spots containing collagen and hepatocyte growth factor (HGF) spots expressed epithelial (hepatic) phenotypes and also rescued them in neighboring hepatocytes on collagen spots that did not receive direct HGF stimulus. Herein, we designed a microfluidic device with parallel fluidic channels separated by retractable (reconfigurable) walls and employed this device to investigate interactions between groups of HGF-stimulated and unstimulated hepatocytes. Using a novel reconfigurable microfluidic device, we demonstrate that cultivation of HGF-containing protein spots upregulates the production of endogenous HGF in hepatocytes and that these HGF molecules diffuse over, causing phenotype enhancement in the recipient cells. We also show that selective treatment of the recipient hepatocytes with a c-met inhibitor (SU11274) diminishes the rescue effect, as gauged by the down-regulation of albumin and HGF expression. Our study is one of the first to demonstrate paracrine signaling via HGF in primary hepatocytes. More broadly, tools and methods described here may be used to study paracrine signaling in other types of cells and will have relevance for various fields of biomedical research from cancer to immunology. PMID- 26108038 TI - Normal Organ Weights in Women: Part II-The Brain, Lungs, Liver, Spleen, and Kidneys. AB - Organomegaly can be a sign of disease and pathology, although standard tables defining organomegaly have yet to be established and universally accepted. This study was designed to address the issue and to determine a normal weight for the major organs in adult human females. A prospective study was undertaken of healthy females who had sudden, traumatic deaths at age 18 to 35 years. Cases were excluded if there was a history of medical illness including illicit drug use, prolonged medical treatment was performed, there was a prolonged period between the time of injury and death, body length and weight could not be accurately assessed, or if any illness or intoxication was identified after gross and microscopic analysis including evidence of systemic disease. Individual organs were excluded if there was significant injury to the organ that could have affected the weight. A total of 102 cases met criteria for inclusion in the study during the approximately 10-year period of data collection from 2004 to 2014. The decedents had an average age of 24.4 years and ranged in length from 141 to 182 cm (56.4-72.8 inches) with an average length of 160 cm (64 inches). The weight ranged from 35.9 to 152 kg (79-334 lb) with an average weight of 65.3 kg (143 lb). The majority of the decedents (86%) died of either ballistic or blunt force (including craniocerebral) injuries. The mean brain weight was 1233 g (range, 1000-1618 g); liver mean weight, 1288 g (range, 775-2395 g); spleen mean weight, 115 g (range, 51-275 g); right lung mean weight, 340 g (range, 142-835 g); left lung mean, 299 g (range, 108-736 g); right kidney mean weight, 108 g (range, 67 261 g); and the left kidney mean weight, 116 g (range, 55-274 g). Regression analysis was performed and showed that there were insufficient associations between organ weight and body length, body weight, and body mass index to allow for predictability. The authors therefore propose establishing a reference range for organ weights in women, much like those in use for other laboratory tests. Reference ranges (95% inclusion) are proposed: brain, 1033 to 1404 g; liver, 603 to 1767 g; spleen, less than 230 g; right lung, 101 to 589 g; left lung, 105 to 515 g; right kidney, 38 to 174 g; and left kidney, 35 to 192 g. PMID- 26108039 TI - Fatal Cervical Spine Injury From Diving Accident. AB - Spinal cord injuries result after diving into shallow water, often after incautious jumps head first into water of unknown depth during recreational or sport activities. Mortality is generally due to upper cervical trauma. The authors present a case of a diving-related death in a young woman who underwent medicolegal investigations. The measured water depth at the supposed dive site was 1.40 m. Postmortem radiology and autopsy revealed fractures of the body and the posterior arch of the fifth cervical vertebra, a fracture of the right transverse process of the sixth cervical vertebra and hemorrhages involving the cervical paraspinal muscles. Neuropathology showed a posterior epidural hematoma involving the whole cervical region and a symmetric laceration of the spinal cord located at the fourth and fifth cervical vertebra level, surrounded by multiple petechial hemorrhages. Toxicology revealed the presence of ethanol in both blood and urine samples. The death was attributed to cervical spine fracture (C5-C6), spinal cord contusion, and subsequent drowning. This case highlights the usefulness of postmortem radiology, examination of the deep structures of the neck, toxicology, neuropathology, and a detailed research of signs of drowning to formulate appropriate hypotheses pertaining to the cause and mechanism of death. PMID- 26108040 TI - Is Era of Ocular Regeneration Near? PMID- 26108041 TI - Management of Distal Common Canalicular Obstruction: Internal or External Approach? PMID- 26108042 TI - Tip of the Iceberg: The Need for Diabetic Retinopathy Screening in Developing Countries. Lessons From Vietnam. AB - Noncommunicable diseases such as diabetes are emerging particularly in low-income countries. Diabetic retinopathy (DR) is a major complication that threatens vision among people with diabetes. Research has demonstrated that blindness from diabetes is preventable with early diagnosis, optimization of risk factors, and timely photocoagulation. Experiences from neighboring Southeast Asian countries such as Vietnam highlight the health system's challenges in managing DR in low resourced countries. Insight can be gained from successful interventions in India and Latin America. A systematic approach to manage DR is required to achieve Vision2020 goals. This must identify people at risk and engage with key stakeholders at all levels of the health system to ensure that systems for treatment and follow-up are available. PMID- 26108043 TI - Burden of Ocular Surface Disease in Patients With Glaucoma From Australia. AB - PURPOSE: In the Australian general population, the economic burden of ocular surface disease (OSD) severity and other dry eye-related diagnosis have been conducted; however, the glaucoma population has not been evaluated. We assessed the current OSD economic burden in Australian glaucoma patients. DESIGN: A cross sectional, case-comparison study that quantified OSD signs and symptoms was conducted. METHODS: Patients with and without glaucoma from an Australian eye hospital participated. Patient-/physician-reported OSD assessment and literature based cost-of-burden estimates were used to estimate burden of illness from the health care system (direct costs) and societal (indirect costs) perspectives. Ocular surface disease prevalence and costs were estimated. RESULTS: Significant OSD, defined as the presence of 2 or more signs plus 1 or more symptoms reported "often" or "always," was experienced by 39% of patients with glaucoma and 18% of a control group (P < 0.001); both populations had similar prevalence of mild OSD. Significant OSD cost estimates were Australian dollars (AU$) 1061.25 (direct costs) and AU$14078.40 (indirect costs); average (direct and indirect) was AU$6185.79 per patient per year. Based on 39% prevalence rate for significant OSD, estimated total cost to Australian society was AU$330.5 million per annum. CONCLUSIONS: The use of standard OSD definition across research would allow for comparisons between studies and for improved OSD prevalence estimates. In Australia, 39% of patients with glaucoma were found to have significant (moderate/severe) OSD, and the associated economic burden was AU$330.5 million per annum. Additional research evaluating quality of life and assessing actual direct/indirect OSD costs in the Australian population is warranted. PMID- 26108044 TI - Clinical and Cytologic Evidence of Limbal Stem Cell Deficiency in Eyes With Long Standing Vernal Keratoconjunctivitis. AB - PURPOSE: We aimed to study the impression cytology (IC) of the ocular surface in eyes with vernal keratoconjunctivitis (VKC) and clinical evidence of limbal stem cell deficiency (LSCD). DESIGN: This is a prospective comparative study. METHODS: This study included 78 eyes of 40 patients with VKC. Limbal stem cell deficiency was diagnosed clinically based on the presence of corneal findings such as dull irregular epithelial reflex, superficial neovascularization, conjunctivalization, and loss of limbal palisades of Vogt. The study group consisted of 28 eyes of 15 patients with clinically diagnosed LSCD and control group of 50 eyes of 25 patients without LSCD. Conjunctival and corneal IC was done in all eyes. Presence of goblet cells in the corneal samples on IC was considered confirmatory of LSCD. RESULTS: Compared with controls, patients with LSCD were older and had longer duration of disease. On IC, goblet cells were present on the cornea in 53.6% of eyes with clinically diagnosed LSCD and in none of the control eyes (P < 0.0001). Clinically diagnosed LSCD in study eyes correlated with cytologic findings of greater conjunctival squamous metaplasia, decreased conjunctival goblet cells, greater corneal cell metaplasia, and increased inflammation as compared with control eyes. CONCLUSIONS: Most of the eyes with VKC and clinical evidence of LSCD have cytologic evidence of LSCD with goblet cells on the cornea. PMID- 26108045 TI - Long-Term Success of Modified External Dacryocystorhinostomy for the Treatment of Distal Common Canalicular Block. AB - PURPOSE: Epiphora caused by common canalicular obstruction is difficult to manage. Distal common canalicular block caused by membranous obstruction near its junction with the lacrimal sac can be managed by modified dacryocystorhinostomy (DCR) consisting of internal membranectomy. We report our experience with this technique during long-term follow-up. DESIGN: A prospective interventional case series was performed at a tertiary care center including 15 patients with a diagnosis of distal common canalicular obstruction. METHODS: External DCR was performed, and after lacrimal sac opening, membranous obstruction at the distal end of the common canaliculus was identified and managed successfully in all cases. Mitomycin C was applied, and silicone intubation was done for 2 months. The main outcome measures were anatomical success (patent syringing) and functional success (complete relief of epiphora) at a minimum follow-up period of 1 year. RESULTS: Fourteen (93%) cases were completely relieved of epiphora with patent lacrimal syringing at a mean follow-up of 15.4 months (P = 0.0001, McNemar test). The postoperative complications occurred in 4 cases and included nasal bleeding, lateral displacement of silicone tube at medial canthus, complete extrusion of silicone tube (at 4 weeks), and noticeable incisional scar. CONCLUSIONS: Distal common canalicular obstruction can be successfully managed with DCR with internal membranectomy and silicone intubation with mitomycin C. It avoids excision of common canaliculus as compared with canaliculo-DCR. The procedure is safe and effective with minor complications. PMID- 26108046 TI - Characteristics and Ophthalmic Manifestations of the Classic Dengue Fever Epidemic in Singapore (2005-2006). AB - PURPOSE: The aim of this study was to report the characteristics and ophthalmic manifestations associated with dengue fever (DF) in the 2005-2006 DF epidemic in Singapore. METHODS: A retrospective case series. RESULTS: Eleven patients (7 males, 4 females) who were 14 to 40 years old (mean age, 27.3 years) with visual complaints occurring 1 to 2 weeks after the onset of DF underwent a complete ophthalmologic examination. The presenting visual acuity (VA) ranged from 6/6 to counting fingers. Five patients had bilateral eye involvement. Ophthalmic findings included retinal hemorrhages (15 eyes), cotton wool spots (15 eyes), retinal pigment epithelium alterations (5 eyes), optic disc swelling (3 eyes), foveolitis (3 eyes), and hyperemia (2 eyes). Impaired color vision was noted in 12 eyes. Visual field defects were noted in 13 eyes; 4 of these eyes were asymptomatic. Fundus fluorescein angiography was done in 9 patients; the findings include choroidal hyperfluorescence (9 eyes), blocked fluorescence (8 eyes), and capillary nonperfusion (1 eye). In 2 eyes, it was normal. Electrophysiology confirmed optic neuropathy in 3 eyes and maculopathy in 1 eye. The follow-up ranged from 12 days to 12 months. The VA at the last follow-up ranged from no light perception to 6/6. Visual field abnormalities were noted in 5 eyes despite a normal VA. CONCLUSIONS: Dengue fever is associated with a wide spectrum of ophthalmic manifestations. Rarely, ophthalmic complications in DF can result in permanent visual impairment. Further work can be done to elucidate the relationship between systemic and ocular manifestations of DF. PMID- 26108047 TI - Central Serous Chorioretinopathy: A Review of the Literature. AB - Central serous chorioretinopathy (CSCR) is an incompletely understood multifactorial disease of those who are middle aged characterized by the collection of fluid between the retinal pigment epithelium and the neurosensory retina. The exact etiology of CSCR and the reason of its predominance in middle aged males are still unknown. Many pharmacologic modalities are suggested for CSCR with no proven efficacy. So this article was written to give a review of the relevant and recent literature on CSCR and to summarize the etiology, clinical features, and diagnostic modalities for CSCR with special emphasis on the treatment options available and those that are still under trial and can be of help in the future to fasten the recovery and reduce the recurrences. PMID- 26108048 TI - Stem Cells and Ocular Tissue Regeneration. AB - PURPOSE: Millions worldwide have visual impairments caused by dysfunctional eye components, including cornea, lens, retina, and optic nerve, or the visual cortex in the brain. Insufficient cornea donation and inherent artificial lens problems demand alternative treatment strategies for cornea diseases and cataracts, whereas retinal degenerative diseases, including glaucoma, macular degeneration, and retinitis pigmentosa, still lack effective treatments. Stem cells have been investigated for their potential in various eye-specific pathologies to replace lost retinal ganglion cells and photoreceptors in retinal degenerative diseases and toward engineering transplantable patient-specific cornea or lens. DESIGN: Many stem cell types, including putative resident eye stem cells, mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells, have been investigated for their potential to generate specific cell types in the eye in culture and after transplantation and to engineer eye tissues in combination with structural scaffolds. METHOD: Cultured stem cells and in vitro differentiated eye specific cells are transplanted into different locations of the eye to test their ability to produce functional cells for supporting eye functions. In addition, stem cells have been directly tested in vitro for their capacity to engineer eye specific tissues. RESULTS: Different stem cell types have been shown to have distinct capacities to produce eye-specific cells or even the entire retina. CONCLUSIONS: Stem cells offer great hope for treating various eye pathologies. Despite recent progress, many challenges must still be overcome before the era of stem cell-based therapy in the eye truly arrives. PMID- 26108049 TI - Update on Ophthalmic Oncology 2012: Advances in Retinoblastoma and Uveal Melanoma. AB - PURPOSE: The purpose of this article was to review the major advances in both translational and clinical research in 2 diseases, retinoblastoma and uveal melanoma, from November 2011 through October 2012. DESIGN: Literature Review. METHODS: A MEDLINE search was performed using the search terms "retinoblastoma" and "uveal melanoma." All relevant articles were reviewed, and articles with the most clinical relevance were reported. RESULTS: In retinoblastoma, new clinical data are emerging every year regarding the safety and efficacy of intra-arterial chemotherapy as well as other even newer modalities such as intravitreal chemotherapy. Globe salvage rates for eyes without vitreous seeding approach 100% and are increasing to 80% for those with seeds with new methods of treatment. In uveal melanoma, our understanding of the genetic pathways underlying this disease is improving each day and leading to the initiation of clinical trials for adjuvant therapy and metastatic disease. CONCLUSIONS: Ocular oncology is a small but dynamic field in which our knowledge is increasing every day. Exciting data emerged in the fields of both retinoblastoma and uveal melanoma this year. PMID- 26108050 TI - The Pathogenesis of Nonarteritic Anterior Ischemic Optic Neuropathy. AB - Although nonarteritic anterior ischemic optic neuropathy (NAION) is known to occur as a result of ischemic insult to the anterior portion of the optic nerve, its etiology and pathogenesis remain elusive. Because NAION is a nonfatal condition, acute, postmortem histopathologic analysis has never been undertaken. Animal models of NAION have been created with the use of an iodinated derivative of fluorescein, rose bengal. When rose bengal is stimulated with the use of a frequency-doubled neodymium-Yttrium aluminium garnet (YAG) laser diode, vascular endothelial damage may be induced in a precise and focal manner, within the anterior optic nerve. Primate and nonprimate animal models of NAION differ from the human pattern of NAION in the duration of the disease course, as well as the anatomy. The rat lamina cribrosa contains a differing connective tissue structure, which may result in a differing pathogenesis of ischemic insult. Optic disk swelling resolves within 5 days in rats and 14 days in primates; in humans, it is known to persist for up to 6 weeks. Animal models have nonetheless enabled a deeper understanding of the underlying pathologic processes in NAION. PMID- 26108051 TI - Letter to the Editor Regarding "The Ten Chairmen of the Ophthalmology Department at Peking Union Medical College (PUMC)". PMID- 26108052 TI - Responses to "Letter to the Editor Regarding 'The Ten Chairmen of the Ophthalmology Department at Peking Union Medical College (PUMC)'" to APJO. PMID- 26108053 TI - In Response to The Knowledge Gaps Between Asian and Caucasian AMD. PMID- 26108054 TI - The Genetics of Age-Related Macular Degeneration. PMID- 26108056 TI - Microanatomical Location of Hyaluronic Acid Gel Following Injection of the Temporal Hollows. AB - PURPOSE: To examine the microanatomical location of hyaluronic acid gel injected within the temporal hollows of cadaver specimens. METHODS: The temporal hollows were injected subcutaneously with hyaluronic acid gel in 6 fresh frozen human cadaver hemifaces. Temporal soft tissues were dissected to a preperiosteal plane and fixated in 95% alcohol. A soft tissue section extending from skin to temporal bone was obtained for each specimen. Histologic examination was performed using hematoxylin and eosin stain. RESULTS: In 5 of 6 specimens, at least 95% of the hyaluronic acid was located within the subcutaneous fat. In 1 of 6 specimens, approximately 35% of the material was located within the subcutaneous fat and 60% was located within the superficial temporal fascia. Two specimens had 5% located within the temporalis muscle. In 1 specimen, hyaluronic acid was found to encompass a superficial muscular artery within the superficial temporal fascia. CONCLUSIONS: This study elucidates the location of hyaluronic acid gel after subcutaneous injection within the temporal hollow. Histology confirmed consistent placement of the gel within the subcutaneous tissues, but it also showed that injection in this region may produce unintended deeper location of filler, and a significant perivascular collection of the material. The proximity of dense temporal fascial and muscle arterial networks in this region may pose risk for perivascular injection and associated complications. PMID- 26108057 TI - Neuropathic Pain Following Poly-L-Lactic Acid (Sculptra) Injection. AB - Injectable fillers have become a prevalent means of facial rejuvenation and volume expansion. While typically well tolerated, serious complications have been reported. The authors present a case in which an otherwise healthy female with a history of multiple filler injections including poly-L-lactic acid, developed 3 weeks of neuropathic pain in the left temporal fossa following injection. To the best of the authors knowledge, neuropathic pain has not been reported as a complication following poly-L-lactic acid injection. The patient was treated with an injection of steroid and long-acting anesthetic with resolution of symptoms. PMID- 26108058 TI - The Association of Demodex with Chalazia: A Histopathologic Study of the Eyelid. AB - PURPOSE: To investigate the association of Demodex with chalazia and to describe the associated histopathologic changes in the eyelid tissue. METHODS: In a retrospective histopathologic case-control study, 78 ectropion/entropion repair eyelid wedge resections were examined. Serial sections were obtained on formalin fixed, paraffin-embedded tissues, stained with hematoxylin-eosin and studied by light microscopy. Thirty-eight patient specimens had evidence of chalazia and 40 did not. The main outcome measures included quantification of total eyelid hair follicles, meibomian glands, Demodex folliculorum and Demodex brevis; determining the presence of lipogranulomatous and non-lipogranulomatous inflammation, hair follicle and meibomian gland duct dilatation and hyperkeratinization, and meibomian gland acinar dilation, keratinization, and atrophy. RESULTS: There was a significantly greater mean number of D. folliculorum in biopsies with chalazia, when compared with biopsies without chalazia (5.55 vs. 2.68, p = 0.044). The presence of D. folliculorum was strongly associated with hair follicle duct dilatation and hyperkeratinization and with perifollicular nongranulomatous inflammation (p = 0.00). Hair follicle duct dilatation, hyperkeratinization, and perifollicular inflammation were also independently associated with chalazia (p = 0.040 and 0.031, respectively). D. brevis was observed only in meibomian glands with chalazia (mean = 0.342), but this finding did not reach statistical significance; p= 0.068. CONCLUSION: While the authors cannot establish causality between Demodex and chalazia, these findings suggest that D. folliculorum indirectly may be involved in the pathogenesis of chalazia via its effect on the anterior eyelid margin. PMID- 26108059 TI - Redesigning German Maternity Records: Results from a Pilot study. AB - PURPOSE: The German maternity record (GMR, "Mutterpass") is the most important document for pregnant women and their health care providers during antenatal care. While the serological and ultrasound sections have been updated regularly, the document's catalogue of pre-existing factors has remained unaltered since 1986. We investigated whether a health-focused revision of the GMR would serve the needs of pregnant women and their care providers. METHODS: A revised version of the Mutterpass was developed by a multidisciplinary panel of experts, focusing on health and salutogenesis. The new document highlights the uncomplicated pregnancy, and gives pregnant women the opportunity to make their own notes and to choose an appropriate place of birth after consultation with the doctor or midwife. These changes were developed within the requirements of the latest version of the German maternity guidelines (GMG) mandatory during the revision process. To test for user-friendliness and acceptance, 23 persons--8 consultants, 7 midwives and 8 pregnant women--were asked to evaluate the revised GMR. Comments could be entered in the GMR itself and in an electronic survey. Notes in the GMR (n=296 comments) were assigned to one of 7 categories (e. g. general comments, structural aspects) by 2 reviewers. After 6 weeks one of the reviewers repeated her evaluation. RESULTS: 20 of the 23 persons approached wrote comments in the document, 19 participated in the electronic survey. Consultants and midwives predominantly stated that they would prefer to work with the revised GMR (92%). Pregnant women appreciated the space for their own notes (83%). Most respondents (90%) had a good general impression. Inter-observer agreement was kappa=0.43, intra-observer agreement kappa=0.55. CONCLUSIONS: This health-focused version of the German maternity record is a first step towards optimising maternity records in Germany. Future investigations should consider revisions going beyond the content of the mandatory guidelines. PMID- 26108060 TI - CHILDREN'S AND ADULTS' JUDGMENTS OF FACIAL TRUSTWORTHINESS: THE RELATIONSHIP TO FACIAL ATTRACTIVENESS. AB - Existing research suggests that adults make effective trustworthiness judgments based on facial attractiveness during initial interactions. However, little is known about how children judge trustworthiness from faces. The present study examined the facial features that contributed to judgments of trustworthiness and attractiveness by three groups of Chinese children aged 8 years old (n=34; 17 boys), 10 years old (n=34; 17 boys), and 12 years old (n = 34; 17 boys) and a comparison group of 37 undergraduates (M age=20.2 yr.; 16 men). Using FaceGen Modeler 3.1, a total of 400 East Asian adult faces (200 male, 200 female) portraying neutral emotions with direct gazes were generated. The faces were represented by 61 shape features and were presented for a maximum of 3,000 msec. in the center of the computer screen in randomized order. The participants were asked to judge whether each person was trustworthy and to rate the level of trustworthiness; 1 month later, the attractiveness of the same faces was judged using a similar procedure. The children and the adults used similar facial features to judge trustworthiness (e.g., the brow ridge, nose, and chin). Some of the facial features used by the different age groups as the basis for the trustworthiness and attractiveness judgments were similar. Facial attractiveness accounted for roughly 30 to 60% of the variance in the groups' trustworthiness judgments. Thus, facial attractiveness may serve as a heuristic property that signals trustworthiness and guides adaptive social decisions. More importantly, even children as young as 8 years old use a strategy similar to that of adults to make trustworthiness judgments, although some differences in the use of specific facial features were observed among the age groups. PMID- 26108061 TI - POSTURAL CONTROL MECHANISMS IN HEALTHY ADULTS IN SITTING AND STANDING POSITIONS. AB - This study explored differences in the center of pressure in healthy people in a sitting and standing position and with eyes open and closed. With this purpose, 32 healthy participants (16 men, 16 women; M age=25.2 yr., SD=10.0, range=18-55) were measured with an extensiometric force plate. Using a two-way repeated measures multivariate analysis of variance (MANOVA), the root mean square, velocity, range, and sway, in both visual conditions, had higher values in the standing task than in the sitting task. In the frequency domain, the low frequency band had higher values during the standing task. For control mechanism variables, mean distance and time were greater when standing while mean peaks were greater when sitting. Thus, stability is worse in the standing position and more neuromuscular activity is required to maintain balance. PMID- 26108062 TI - ATTRIBUTES OF AESTHETIC QUALITY USED BY TEXTILE CONSERVATORS IN EVALUATING CONSERVATION INTERVENTIONS ON MUSEUM COSTUMES. AB - Aesthetic quality is central to textile conservators when evaluating a conservation method. However, the literature on textile conservation chiefly focuses on physical properties, and little is known about what factors determine aesthetic quality according to textile conservators. The latter was explored through two experiments. Experiment 1 explored the underlying attributes of aesthetic quality of textile conservation interventions. Experiment 2 explored the relationships between these attributes and how well they predicted aesthetic quality. Rank-order correlation analyses revealed two latent factors called Coherence and Completeness. Ordinal regression analysis revealed that Coherence was the most important predictor of aesthetic quality. This means that a successful conservation intervention is visually well-integrated with the textile item in terms of the material and method. PMID- 26108063 TI - Update on the immunobiology of Sjogren's syndrome. AB - PURPOSE OF REVIEW: The purpose of this review is to give an update on the understanding of the immune responses involved in the pathogenesis of primary Sjogren's syndrome (pSS), and to highlight recent findings on the underlying molecular and cellular mechanisms at play. RECENT FINDINGS: In recent years, genetic studies have confirmed the importance of aberrant type I interferon (IFN) and B cell responses in pSS and highlighted critical pathways involved in disease pathogenesis. In particular, the formation of ectopic lymphoid structures has emerged as an important factor in the establishment of chronic autoimmune responses in target organs. Interestingly, recent studies on viral infection in the context of pSS, as well as findings on the contribution of salivary gland epithelial cells in local immune responses, offer further clues to understand pSS etiology and its target organ specificity. Finally, new evidence brings T cells and natural killer cells under renewed attention as possible important contributors to pSS pathogenesis. SUMMARY: Progress made during the last few years on the pathogenesis of pSS has been mirrored by clinical trials directed at inhibiting cytokines, B, or T cell responses. Future efforts should focus on identifying additional pSS specific targets and developing methods to help choose optimal therapeutic strategies for the individual patient. PMID- 26108064 TI - The risk of chronic kidney disease in a metabolically healthy obese population. AB - Obesity has become an important risk factor for chronic kidney disease (CKD). The metabolically healthy obese (MHO) phenotype refers to obese individuals with a favorable metabolic profile. However, its prognostic value remains controversial and may depend on the health outcome being investigated. To assess this, we examined the risk of MHO phenotype with incident CKD in a Korean population of 41,194 people without CKD. Individuals were stratified by body mass index (cutoff value, 25.0 kg/m(2)) and metabolic health state (assessed using Adult Treatment Panel-III criteria). Incident CKD was defined as a glomerular filtration rate of <60 ml/min per 1.73 m(2) calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Over the median follow-up period of 38.7 months, 356 of the individuals developed incident CKD. Compared with the metabolically healthy nonobese (MHNO) group, the MHO group showed increased risk of incident CKD with a multivariate-adjusted hazard ratio of 1.38 (95% CI, 1.01-1.87). Nonobese but metabolically unhealthy individuals were at an increased risk of incident CKD (multivariate-adjusted hazard ratio, 1.37 (95% CI, 1.02-1.93)) than the MHNO group. Metabolically unhealthy obese individuals were at the highest risk of incident CKD. Thus, a healthy metabolic profile does not protect obese adults from incident CKD. Hence, it is important to consider metabolic health along with obesity when evaluating CKD risk. PMID- 26108065 TI - Antithrombin III/SerpinC1 insufficiency exacerbates renal ischemia/reperfusion injury. AB - Antithrombin III, encoded by SerpinC1, is a major anti-coagulation molecule in vivo and has anti-inflammatory effects. We found that patients with low antithrombin III activities presented a higher risk of developing acute kidney injury after cardiac surgery. To study this further, we generated SerpinC1 heterozygous knockout rats and followed the development of acute kidney injury in a model of modest renal ischemia/reperfusion injury. Renal injury, assessed by serum creatinine and renal tubular injury scores after 24 h of reperfusion, was significantly exacerbated in SerpinC1(+/-) rats compared to wild-type littermates. Concomitantly, renal oxidative stress, tubular apoptosis, and macrophage infiltration following this injury were significantly aggravated in SerpinC1(+/-) rats. However, significant thrombosis was not found in the kidneys of any group of rats. Antithrombin III is reported to stimulate the production of prostaglandin I2, a known regulator of renal cortical blood flow, in addition to having anti-inflammatory effects and to protect against renal failure. Prostaglandin F1alpha, an assayable metabolite of prostaglandin I2, was increased in the kidneys of the wild-type rats at 3 h after reperfusion. The increase of prostaglandin F1alpha was significantly blunted in SerpinC1(+/-) rats, which preceded increased tubular injury and oxidative stress. Thus, our study found a novel role of SerpinC1 insufficiency in increasing the severity of renal ischemia/reperfusion injury. PMID- 26108066 TI - Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats. AB - Chronic activation of the renin-angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia, and inflammation. Despite similar hypertension, an injurious response to excess angiotensin II is greater in F344 than in Lewis rats; the latter displaying renoprotection. Here we studied whether p2rx7, encoding the P2X7 receptor (P2X7R), is a candidate gene for the differential susceptibility to vascular dysfunction under high angiotensin II tone. A 14-day infusion of angiotensin II into F344 rats increased blood pressure by about 15 mm Hg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by half, and the corticomedullary oxygenation gradient disrupted. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the slope. Sodium excretion was increased sixfold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in angiotensin II-treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Thus, activation of P2X7R induces microvascular dysfunction and regional hypoxia when angiotensin II is elevated and these effects may contribute to progression of renal injury induced by chronic angiotensin II. PMID- 26108067 TI - Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation. AB - Delayed graft function (DGF) is commonly considered a risk factor for acute rejection, although this finding has not been uniformly observed across all studies. The link between DGF and acute rejection may have changed over time due to advances in immunosuppression and medical management. Here we conducted a cohort study of 645 patients over 12 years to evaluate the association of DGF and biopsy-proven acute rejection (BPAR) in a modern cohort of kidney transplant recipients. DGF was defined as the need for at least one dialysis session in the first week after kidney transplantation. The 1-, 3-, and 5-year cumulative probabilities of BPAR were 16.0, 21.8, and 22.6% in the DGF group, significantly different from the 10.1, 12.4, and 15.7% in the non-DGF group. In multivariable Cox proportional hazards model, the adjusted relative hazard for BPAR in DGF (vs. no DGF) was 1.55 (95% confidence interval (CI): 1.03, 2.32). This association was generally robust to different definitions of DGF. The relative hazard was also similarly elevated for T-cell- or antibody-mediated BPAR (1.52 (0.92, 2.51) and 1.54 (0.85, 2.77), respectively). Finally, the association was consistent across clinically relevant subgroups. Thus DGF remains an important risk factor for BPAR in a contemporary cohort of kidney transplant recipients. Interventions to reduce the risk of DGF and/or its aftereffects remain of paramount importance to improve kidney transplant outcomes. PMID- 26108069 TI - B7-H3 expression in children with asthma exacerbation. AB - BACKGROUND: Recent studies have shown that B7-H3, a recently identified B7 family member, plays a critical role in the development of asthma. OBJECTIVE: This study is to explore the expression of B7-H3 in children with asthma exacerbation. METHODS: Twenty-one Chinese children with asthma exacerbation as well as 18 nonasthmatic control Chinese children were enrolled. B7-H3 level and cytokines (interferon [IFN]-gamma, interleukin [IL]-4, and IL-10) determination were performed by enzyme-linked immunosorbent assay (ELISA) technique. Meanwhile, clinical parameters including laboratory findings, forced expiratory volume in one second (FEV(1)) and fractional exhaled nitric oxide were obtained. RESULTS: Children with asthma exacerbation had significantly higher levels of B7-H3 than controls (4.46 +/- 1.33 versus 3.42 +/- 1.48 ng/mL; p = 0.027). Plasma IL-4 level was significantly higher in asthma exacerbation subjects than controls (157.98 +/ 21.57 versus 121.92 +/- 24.37 pg/mL; p < 0.0001), and IFN-gamma level was significantly lower in asthma exacerbation subjects (292.73 +/- 152.47 versus 421.78 +/- 145.84 pg/mL; p = 0.0107). Level of B7-H3 in asthma exacerbation subjects with inhaled corticosteroid (ICS) treatment recently was significantly lower than subjects without ICS treatment (t = 2.706; p = 0.0136). Additionally, levels of B7-H3 decreased remarkably after prednisone treatment. Level of sB7-H3 in asthma exacerbation subjects was inversely correlated with level of IFN-gamma (r(p) = -0.605; p = 0.005) after adjustment. CONCLUSION: B7-H3 may play an important role in asthma exacerbation and was a useful clinical biomarker to evaluate asthma exacerbation. PMID- 26108068 TI - Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria. AB - Proteinuria is a central component of chronic kidney disease and an independent risk factor for cardiovascular disease. Kidney podocytes have an essential role as a filtration barrier against proteinuria. Kruppel-like Factor 4 (KLF4) is expressed in podocytes and decreased in glomerular diseases leading to methylation of the nephrin promoter, decreased nephrin expression and proteinuria. Treatment with an angiotensin receptor blocker (ARB) reduced methylation of the nephrin promoter in murine glomeruli of an adriamycin nephropathy model with recovery of KLF4 expression and a decrease in albuminuria. In podocyte-specific KLF4 knockout mice, the effect of ARB on albuminuria and the nephrin promoter methylation was attenuated. In cultured human podocytes, angiotensin II reduced KLF4 expression and caused methylation of the nephrin promoter with decreased nephrin expression. In patients, nephrin promoter methylation was increased in proteinuric kidney diseases with decreased KLF4 and nephrin expression. KLF4 expression in ARB-treated patients was higher in patients with than without ARB treatment. Thus, angiotensin II can modulate epigenetic regulation in podocytes and ARB inhibits these actions in part via KLF4 in proteinuric kidney diseases. This study provides a new concept that renin angiotensin system blockade can exert therapeutic effects through epigenetic modulation of the kidney gene expression. PMID- 26108070 TI - Effect of solar irradiation on serum specific immunoglobulin E to house-dust mite. AB - BACKGROUND: The relationship between sensitization to Dermatophagoides species and solar irradiation, as reflected by vitamin D, remains elusive. OBJECTIVE: We investigated the lag time and the cumulative and maximum effects of exposure to solar irradiation on sensitization to house-dust mites. METHODS: A time series study design was applied to solar irradiation (MJ/m(2)) and relative humidity (%) for specific immunoglobulin E (IgE) levels against Dermatophagoides pteronyssinus (n = 20,451) and Dermatophagoides farinae (n = 22,824). We used the distributed lag nonlinear model to assess the difference of log IgE to house-dust mites in relation to climate variables. RESULTS: Compared with specific IgE levels of those exposed to 18 MJ/m(2), the maximum increase in sensitization to D. pteronyssinus was observed at a solar irradiation of 10 MJ/m(2) at peak 0 week (difference of log IgE 0.368 [95% confidence interval (CI), 0.209-0.529], p < 0.001), and this increase continued for 3 weeks. The IgE level was significantly affected by the relative humidity of the 3rd- to 12th-lag week, and the effect reached its peak at 75% on the 8th week (difference of log IgE 0.394 [95% CI, 0.221-0.566], p < 0.001). The logistic regression analysis showed that solar irradiation was associated with a decreased risk to sensitization to D. pteronyssinus (odds ratio 0.988 per 1 MJ/m(2) [95% CI, 0.979-0.997], p < 0.013) on the testing week after controlling for humidity and temperature. CONCLUSION: This study demonstrated that low solar irradiation immediately increased the risk of sensitization to two house-dust mite species. Further research is warranted to delineate the underlying mechanism of the effect of solar irradiation on aeroallergen sensitization. PMID- 26108071 TI - The association of vitamin D, cathelicidin, and vitamin D binding protein with acute asthma attacks in children. AB - BACKGROUND: Recent evidence about the various effects of vitamin D (vit D) on innate and adaptive immunity has led to a search for the role of vit D in asthma. It is postulated that a decrease in cathelicidin, a multifunctional host defense molecule, production due to low vit D status may predispose to infectious complications in children with asthma. OBJECTIVE: The aim of this study was to determine the association of vit D, vit D-binding protein (VDBP) and cathelicidin with acute asthma attacks among children with allergic asthma. METHODS: This prospective study included 35 patients with acute asthma attack and 32 children with controlled asthma, and all were matched by sampling season, sensitization to mites, and previous severity of asthma. A comprehensive questionnaire about risk factors, blood sampling for 25-hydroxyvitamin D vit D, VDBP, and cathelicidin levels; spirometric indices were used. Factors that influence serum vit D and cathelicidin levels and the development of asthma attacks were evaluated with multivariate analysis. RESULTS: The mean serum vit D levels of the attack group was significantly lower than that of the controlled asthma group (p < 0.001). The mean cathelicidin level was significantly higher in the acute asthma group than with the controlled subjects with asthma (p = 0.002). There was no difference between the acute and controlled asthma groups in terms of markers of allergy and serum VDBP levels. Risk factors that may influence vit D levels revealed that body mass index (BMI) (p = 0.038), duration of sun exposure (p < 0.001), and amount of dietary vit D (p < 0.001) independently affected serum vit D levels. Risk factors that may result in acute asthma showed that low serum levels of vit D were significantly related to the risk of asthma attacks (p < 0.001, adjusted odds ratio 16.11). Cathelicidin levels showed a significant positive association with asthma attacks and BMI. CONCLUSIONS: Vit D deficiency showed a significant relationship to the development of asthma attacks independent of cathelicidin deficiency and other factors associated with the severity of chronic asthma. PMID- 26108072 TI - Association of urine CC16 and lung function and asthma in Chinese children. AB - BACKGROUND: Many studies have shown the relationship between serum Club cell secretory protein-16 (CC16) and respiratory diseases. However, little research has been done to study urinary CC16 in relation to respiratory diseases. Our objective was to examine the association of urinary CC16 and physician-diagnosed asthma or lung function measurements in Chinese children. METHODS: A total of 147 physician-diagnosed children with asthma, ages 9-15 years, were recruited from our cross-sectional study population in northeast China. The 390 healthy children who were not asthmatic and not smokers were selected at random from the population according to 10% proportional sampling. Lung function values, including forced expiratory volume in 1 second and forced vital capacity were measured with two portable spirometers. Urine CC16 was determined by using an enzyme-link immunoassay kit. The relationships between urine CC16 levels and asthma, lung function were assessed by multiple regression models. RESULTS: The geometric mean (95% confidence interval [CI]) creatinine-adjusted urine CC16 level was, for creatinine, 9.77 ng/mg (95% CI, 8.12-12.02 ng/mg). After adjustments for sex, age, body mass index, parental education, and smoking status, lower urine CC16 levels were found to be associated with asthma (odds ratio 0.782 [95% CI, 0.617- 0.990]). A positive association was found between urine CC16 and forced vital capacity (beta 0.064 [95% CI, 0.008-0.119]). CONCLUSION: Our study demonstrated lower levels of urine CC16 and lung function in patients with asthma than in those patients without asthma. CC16 in urine may be a useful tool or biomarker for investigating lung epithelium integrity among children with asthma or lung injury. PMID- 26108073 TI - Risk factors in pediatric shrimp allergy. AB - BACKGROUND: The prevalence of shellfish allergy is ~1.3% in the United States, with shrimp most commonly reported. Shellfish is one of the top causes of food induced anaphylactic reactions, yet there are no reported rates of pediatric shrimp anaphylaxis in the literature. In previously reported adults with shrimp allergy, the rate of anaphylaxis to shrimp was 42%. OBJECTIVE: To describe the rate of anaphylaxis among children with shrimp allergy, demographics, clinical presentation, and cross-reactive sensitization. METHODS: Retrospective chart review of children <=18 years old who presented with shrimp allergy to Texas Children's Hospital Allergy and Immunology Clinic over 11 years. RESULTS: Sixty eight patients were identified with shrimp allergy (61% male, 39% female), with a median age of diagnosis at 5.6 years (range, 0.96-16.6 years). The rate of anaphylaxis was 12%, and mucocutaneous symptoms were most common (skin symptoms, 70%; urticaria, 58%; and angioedema, 58%). No factors were positively associated with anaphylaxis, whereas patients without anaphylaxis had a significantly higher rate of eczema compared with those with anaphylaxis (p = 0.02). African Americans and Asian Americans were disproportionately affected (p < 0.001). There were low rates of cross-sensitization for other crustaceans and for mollusks (57% and 26%, respectively). CONCLUSION: The rate of anaphylaxis to shrimp was significantly lower in children with shrimp allergy than in adults, and anaphylactic reactions were negatively associated with eczema. Cross-reactivity to other crustaceans and mollusks does not uniformly occur. Prospective studies with double blinded placebo-controlled food challenges are needed to further characterize patients with shrimp allergy. PMID- 26108074 TI - The effect of prenatal exposure to phthalates on food allergy and early eczema in inner-city children. AB - BACKGROUND AND OBJECTIVE: We hypothesized that maternal prenatal and children urine metabolite concentration of phthalates would be associated with food allergy and early eczema among inner-city children. The study was based on data from the Polish Mother and Child Cohort. METHODS: Prenatal and postnatal exposure to the following phthalates: diethyl phthalate, diisobutyl phthalate, di-n-butyl phthalate, butyl-benzyl phthalate, di(2-ethylhexyl) phthalate, diisononyl phthalate, and di-n-octyl phthalate were determined by measuring phthalate metabolites in the urine collected from the mothers during the third trimester of pregnancy and from their children at age 2 years. Pre- and postnatal observations limited the response rate and final sample size; data from 147 participants were included in the analysis. Children's health status was assessed at 24 months of age by using a questionnaire administered to the mothers. We studied associations between the urine level of phthalates and the presence of food allergy and atopic dermatitis in logistic regression analysis. All associations were adjusted for independent risk factors of dependent variables. Associations with atopic dermatitis were adjusted for the effect of atopy in the family, the father's education, frequency of house cleaning, and breastfeeding; associations with food allergy were adjusted for the presence of pets at home during pregnancy and breastfeeding. RESULTS: The prevalence of the outcomes were as follows: atopic dermatitis, 12.2%, and food allergy, 48.9%. We showed that higher urine concentrations of monobenzyl phthalate in mothers during pregnancy increased the risk of food allergy in children during the first 2 years of life (odds ratio 4.17 [95% confidence interval, 1.17-17.89]). There were no associations with children's urine and allergic symptoms. CONCLUSIONS: Results of our study indicated awareness of environmental factors that may affect children's health because the phthalates were shown to be risk factors for food allergy in children. PMID- 26108075 TI - Allergic conjunctivitis: Time for a new classification. PMID- 26108076 TI - Addressing the challenges of severe asthma. PMID- 26108077 TI - Rebuttal Comments from Dr. Dunn and Dr. Wechsler. PMID- 26108078 TI - Rebuttal Comments from Dr. Iyer and Dr. Lim. PMID- 26108079 TI - Bronchial thermoplasty: Quo vadis? PMID- 26108080 TI - Reducing asthma attacks in patients with severe asthma: The role of bronchial thermoplasty. AB - Asthma remains one of the most common diseases worldwide and results in significant societal health care costs and in morbidity and mortality to those afflicted. Despite currently available medications, 5-10% of patients with asthma have severe disease with debilitating symptoms and/or life-threatening exacerbations. Bronchial thermoplasty is a device-based therapy with proven efficacy in this subgroup of patients. Thus far, bronchial thermoplasty has been shown to reduce exacerbations and to improve important measures of asthma control. The purpose of this article is to review the pathophysiology of severe asthma, including the role of airway smooth muscle cells and the procedural aspects of bronchial thermoplasty, and to review the evidence behind this important therapy. PMID- 26108081 TI - Bronchial thermoplasty: Where there is smoke, there is fire. AB - Bronchial thermoplasty (BT) is the first nonpharmacologic interventional therapy approved by the U.S. Food and Drug Administration in 2010 for severe asthma. This approval was based on randomized sham-controlled trial called Asthma Intervention Research (AIR) 2 published in 2010. BT involves the application of radiofrequency energy to airways with an aim to selectively ablate airway smooth muscle. BT is currently marketed for patients with "severe" asthma. Most practicing clinicians apply this severity category to patients with oral corticosteroid dependence, frequent exacerbations, or a significantly reduced forced expiratory volume in 1 second along with a poor quality of life. Did the patients studied in the AIR-2 trial have these clinical features? Was there a reduction in severe asthma exacerbation achieved in the intervention group? Did any of the primary or secondary end points in the AIR-2 trial show a positive signal? There continues to be controversy regarding patient selection and primary outcome. Its efficacy in the management of the patient with difficult-to-manage asthma is uncertain. This review covered pertinent aspects of BT, the design and results of the AIR-2 trial, and provides the practicing allergist with a comprehensive overview of this therapy. PMID- 26108082 TI - Asthma, stress, and depression in women. AB - The occurrence of depression with asthma is very common, especially in women, and can influence behavioral factors, such as treatment compliance, self-assessment, and management of environmental triggers, that can collectively result in poor asthma management and control. This review describes the association and major clinical implications of stress, anxiety, and depression, and the associated hormonal changes frequently seen in women with poorly controlled asthma. Several validated instruments have recently been developed for screening patients for depression that can now be used and benefit patients with asthma by earlier detection of these confounding risk factors. The review also highlights the need for further delineation and characterization of specific underlying pathophysiologic and immunologic mechanisms responsible for depression in women. PMID- 26108083 TI - Stepping down inhaled corticosteroids from scheduled to as needed in stable asthma: Systematic review and meta-analysis. AB - BACKGROUND: Many patients with asthma are potentially overtreated, which results in unnecessary cost and unnecessary exposure to drugs that may result in adverse events. Step down helps reduce overtreatment, may mitigate these harms, and is advocated by major guidelines. Unfortunately, data that support step down are sparse. OBJECTIVES: This systematic review aimed to examine the effect of stepping down from scheduled inhaled corticosteroids (ICS) to as-needed ICS in patients with stable asthma. METHODS: Several electronic databases were systematically searched in April 2014. Articles were screened independently in duplicate. Studies were required to have at least a 12-week follow-up duration and to have compared stepping down from scheduled ICS to as-needed ICS and maintenance of scheduled ICS. Patients were required to have stable asthma as evidenced by at least 4 weeks without asthma exacerbation before intervention. RESULTS: A total of 3025 abstracts were retrieved initially, 77 of which were retrieved for full-text screening. Of these, only two articles were found to be eligible for inclusion, both were randomized controlled trials. By using random effects meta-analysis, it was determined that, after a follow-up of 6-10 months, the relative risk of exacerbation of stepping down from scheduled to as-needed ICS was 1.32 (95% confidence interval [CI], 0.81-2.16; p = 0.27, I(2) = 0%). Those who did not step down had more symptom-free days (standard mean difference 0.26 [95% CI, 0.02-0.49; p = 0.03; I(2) = 22%]). CONCLUSION: There is currently insufficient evidence to associate stepping down from scheduled to as-needed ICS with a change in exacerbations, although it may lead to fewer symptom-free days. PMID- 26108085 TI - Effect of systemic corticosteroids on serum apoptotic markers and quality of life in patients with asthma. AB - Despite corticosteroids being the first line drug treatment for asthma symptom control, the mechanisms of action of corticosteroids in asthma are still poorly understood. The current study aimed to evaluate the effect of systemic corticosteroids on serum level of apoptotic markers Survivin (for inflammatory cells) and M30 apoptosense (for bronchial epithelial cells) in patients of acute exacerbation of bronchial asthma. The study involved 60 patients with acute exacerbation of bronchial asthma who were prescribed systemic corticosteroids. Patients were evaluated for their serum levels of apoptotic markers (Survivin and M30 apoptosense) and their quality of life (QOL), before and after treatment with oral prednisolone. Paired t-test was used to compare the change in the serum values. The mean baseline serum Survivin and M30 apoptosense levels were 224.10 +/- 42.76 and 123.00 +/- 18.79 U/L, respectively, which decreased significantly (p < 0.05) to 111.20 +/- 32.26 and 29.67 +/- 7.53 U/L after seven days of oral prednisolone treatment. Systemic corticosteroids also significantly improved QOL scores and peak expiratory flow rate % (PEFR%) in the asthma patients. This improvement was seen irrespective of the initial severity score. Results from the study suggest that systemic corticosteroids administration decreases the survival of inflammatory cells and increases that of bronchial epithelial cells in patients with acute exacerbation of bronchial asthma. The study has been registered with Clinical Trials Registry-India. Registry database number CTRI/2014/08/00483. PMID- 26108084 TI - Risk of corticosteroid-related adverse events in asthma patients with high oral corticosteroid use. AB - BACKGROUND: Oral corticosteroids (OCS) are a mainstay of asthma treatment. Their use increases the risk of various corticosteroid-related adverse events, but the extent of risk is poorly characterized. OBJECTIVE: To determine the incremental risk of possible corticosteroid-related adverse events (AE) in asthma among patients with high OCS use compared with patients who do not use OCS. METHODS: Patients with asthma in a commercial health care claims data base who were high OCS users (>=30 days of OCS use annually) were matched to no-OCS users by age, sex, and geographic region, and the presence or absence of chronic obstructive pulmonary disease (COPD) as a comorbidity. We examined bone-related conditions, pneumonia, opportunistic infections, diabetes mellitus, and other disorders as potential AEs by using chi(2) tests to compare potential AE prevalence between the cohorts, with and without stratification by a COPD diagnosis. We controlled for the number of inhaled steroids (ICS) canisters filled. RESULTS: A total of 3604 patients with asthma and high OCS use were matched to 3604 patients who did not use OCS (mean age, 54.4; 68.1% female; 44.9% with COPD). Patients with high OCS use had statistically significantly higher rates of any potential AE compared with patients who did not use OCS (83.5% versus 78.1%), (p < 0.001). Rates of individual potential AEs were also higher in patients who used higher doses of OCS. Patterns of AEs were similar in patients with and those without COPD, with statistically significantly higher overall AE risk and individual risks in high OCS users. The number of ICS canisters filled was not a significant predictor of AE. CONCLUSION: Patients with asthma who were treated with OCS for >=30 days per year have a greater overall risk of possible corticosteroid-related AEs compared with those patients with no OCS use, whether or not they had COPD. PMID- 26108086 TI - Changes in asthma control, work productivity, and impairment with omalizumab: 5 year EXCELS study results. AB - BACKGROUND: Asthma poses a significant disease burden worldwide. Current guidelines emphasize achieving and maintaining asthma control. OBJECTIVE: To describe longitudinal changes of asthma control and asthma-related work, school, and activity impairment for patients with moderate-to-severe asthma treated with omalizumab and those who did not receive omalizumab in a real-world setting. METHODS: This study used 5 years of data from patients ages >=12 years old with moderate-to-severe persistent allergic asthma who were enrolled in the Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma observational study. Asthma control was assessed with the Asthma Control Test for 5 years, and asthma-related work, school, and activity impairment was measured with the Work Productivity/Activity Impairment-Asthma questionnaire for the first 2 years. RESULTS: The percentage of patients treated with omalizumab (n = 4930) and with well-controlled asthma (Asthma Control Test score, >20) increased from 45% at baseline to 61% at month 60, and it was 49% (baseline) and 67% (month 60) for the non-omalizumab-treated cohort (n = 2779). For new starters to omalizumab (n = 576), the percentage with well-controlled asthma increased from 25% at baseline to 51% at month 6, and to 60% at month 60. Patients in the omalizumab-treated cohort and those in the non-omalizumab-treated cohort experienced a reduction in asthma-related work, school, and activity impairment. The amount of improvement in asthma control achieved and the reduction in asthma related work, school, and activity impairment were similar, regardless of asthma severity. CONCLUSION: On average, patients in the Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma observational study who initiated omalizumab experienced clinically significant improvement in asthma control, which was observed within 6 months and persisted for 5 years. PMID- 26108087 TI - Contrasting associations of body mass index and measles with asthma and rhinitis in young adults. AB - Asthma and allergic rhinitis often coexist and are increasing worldwide, particularly among the younger generation. Although the prevalences of adult asthma and allergic rhinitis and their risk factors have been reported, there have been few studies focusing on young adults. The aim of this study was to evaluate the prevalences of asthma and allergic rhinitis and their associated factors in Japanese young adults. A questionnaire survey of new students at Hokkaido University about the presence of current wheeze and rhinitis and a history of several viral infections during childhood was conducted in 2008 and 2010. The prevalences of wheeze and rhinitis and their associated factors were evaluated. Of 4076 nonsmoking subjects aged 18-25 years, 261 (6.4%) had current wheeze and 1373 (33.7%) had allergic rhinitis. On multivariate analyses, current wheeze was associated with high body mass index (BMI), atopic dermatitis, allergic rhinitis, food allergy, and a history of measles infection. In contrast, allergic rhinitis was associated with low BMI, current wheeze, atopic dermatitis, food allergy, and no history of measles. When subjects were classified into four groups by the presence or absence of wheeze and rhinitis, both high BMI and a history of measles were positively associated with wheeze without rhinitis but negatively associated with rhinitis without wheeze. High BMI and past measles infection showed contrasting associations with asthma and allergic rhinitis in nonsmoking young adults. It is important to not only recognize the common pathophysiological characteristics of asthma and allergic rhinitis but also to understand their differences. PMID- 26108088 TI - A comparison of fluticasone propionate nasal spray and cetirizine in ragweed fall seasonal allergic rhinitis. AB - BACKGROUND: Intranasal corticosteroids are generally considered the most effective medication class for controlling allergic rhinitis. Previous comparative studies with oral antihistamines have been only partially informative due to a variety of variables encountered during their execution. OBJECTIVE: To compare fluticasone propionate nasal spray (FPNS) with the second-generation antihistamine cetirizine (oral tablet) and with placebo in a head-to-head study in a 2-week treatment study during fall ragweed season. METHODS: A total of 978 subjects were screened for this study. Six hundred and eighty-two subjects were randomized into the study (170 subjects, FPNS 200 mcg once daily; 170, cetirizine 10 mg once daily; 171, FPNS placebo; 171, cetirizine placebo) and comprised the intent-to-treat population. A 1-week placebo run-in was followed by a 2-week active treatment period during which time a total nasal symptom score (TNSS), total ocular symptom score, and the Nocturnal Rhinoconjunctivitis Quality of Life Questionnaire were collected. RESULTS: The primary efficacy end point was the mean change from baseline over the entire treatment period in A.M. reflective TNSS. The TNSS was the sum of the four individual nasal congestion, nasal itching, rhinorrhea, and sneezing scores, in which each symptom was scored on a scale of 0 to 3. Both FPNS and cetirizine improved the primary end point when compared with placebo during the active treatment period. Although there was a trend that favored FPNS with regard to the primary and secondary end points, there was not a statistical difference between the two treatments. CONCLUSION: FPNS and cetirizine were equally effective in treating fall seasonal allergic rhinitis during a 2-week head-to-head treatment investigation. Clinical trial NCT01916226, www.clinicaltrials.gov. PMID- 26108089 TI - Plasma endothelin-1 levels during exacerbation of atopic dermatitis. AB - BACKGROUND: Endothelin (ET) -1 was found to participate in the pathogenesis of bronchial asthma. At present, there is no information regarding the role of ET-1 in the pathophysiology of atopic dermatitis (AD). OBJECTIVE: We assessed blood ET 1 levels during the exacerbation of AD and during the 4 months postexacerbation period, to assess the relationships between blood ET-1 levels and clinical severity of AD and pruritus. METHODS: Patients with AD and during exacerbation were recruited from the dermatology department at the Chita Medical Academy (Chita, Russia). Objective Severity Scoring of Atopic Dermatitis index, itch intensity, plasma concentrations of ET-1, and serum total immunoglobulin E levels were measured at study entry and after 4 months. RESULTS: Eighty-two patients with AD, 35 women (45.1%) and 47 men (54.9%), mean (SD) age of 42.2 +/- 11.5 years were included. Thirty healthy volunteers served as controls. The mean (SD) objective Severity Scoring of Atopic Dermatitis index score during AD exacerbation was 48.8 +/- 19.4 and at the 4 months postexacerbation period was 16.1 +/- 8.3 (p < 0.01). Mean (SD) itch score during AD exacerbation was 6.9 +/- 1.9 and, at 4 months postexacerbation was 2.6 +/- 0.7 (p < 0.01). Mean (SD) plasma levels of ET-1 in patients with AD (0.74 +/- 0.45 fmol/mL) were significantly higher than in healthy subjects (0.43 +/- 0.24 fmol/mL) (p < 0.001). Significant correlations were found between plasma ET-1 levels with the objective Severity Scoring of Atopic Dermatitis index (r = 0.51; p < 0.001), Itch severity (r = 0.62; p < 0.001), and with serum immunoglobulin E levels (r = 0.63; p < 0.001) at the exacerbation time point in patients with AD. CONCLUSION: During AD exacerbation, plasma ET-1 levels were elevated and were positively correlated with AD clinical severity, itch intensity, and serum IgE levels. PMID- 26108090 TI - For the Patient. PMID- 26108091 TI - Relationship Between Hospital Performance on a Patient Satisfaction Survey and Surgical Quality. AB - IMPORTANCE: The Centers for Medicare and Medicaid Services include patient experience as a core component of its Value-Based Purchasing program, which ties financial incentives to hospital performance on a range of quality measures. However, it remains unclear whether patient satisfaction is an accurate marker of high-quality surgical care. OBJECTIVE: To determine whether hospital performance on a patient satisfaction survey is associated with objective measures of surgical quality. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study of participating American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) hospitals. We used data from a linked database of Medicare inpatient claims, ACS NSQIP, the American Hospital Association annual survey, and Hospital Compare from December 2, 2004, through December 31, 2008. A total of 103 866 patients older than 65 years undergoing inpatient surgery were included. Hospitals were grouped by quartile based on their performance on the Hospital Consumer Assessment of Healthcare Providers and Systems survey. Controlling for preoperative risk factors, we created hierarchical logistic regression models to predict the occurrence of adverse postoperative outcomes based on a hospital's patient satisfaction scores. MAIN OUTCOMES AND MEASURES: Thirty-day postoperative mortality, major and minor complications, failure to rescue, and hospital readmission. RESULTS: Of the 180 hospitals, the overall mean patient satisfaction score was 68.0% (first quartile mean, 58.7%; fourth quartile mean, 76.7%). Compared with patients treated at hospitals in the lowest quartile, those at the highest quartile had significantly lower risk-adjusted odds of death (odds ratio = 0.85; 95% CI, 0.73-0.99), failure to rescue (odds ratio = 0.82; 95% CI, 0.70-0.96), and minor complication (odds ratio = 0.87; 95% CI, 0.75-0.99). This translated to relative risk reductions of 11.1% (P = .04), 12.6% (P = .02), and 11.5% (P = .04), respectively. No significant relationship was noted between patient satisfaction and either major complication or hospital readmission. CONCLUSIONS AND RELEVANCE: Using a national sample of hospitals, we demonstrated a significant association between patient satisfaction scores and several objective measures of surgical quality. Our findings suggest that payment policies that incentivize better patient experience do not require hospitals to sacrifice performance on other quality measures. PMID- 26108092 TI - Prevalence and Correlates of Indoor Tanning in Nonsalon Locations Among a National Sample of Young Women. PMID- 26108094 TI - Spinal Bone Texture Assessed by Trabecular Bone Score in Adolescent Girls With Anorexia Nervosa. AB - CONTEXT: Trabecular bone score (TBS) is a bone assessment tool that offers information beyond that afforded by dual-energy x-ray absorptiometry (DXA) bone mineral density (BMD) measurements. Adolescents with anorexia nervosa (AN) are known to exhibit compromised bone density and skeletal strength. OBJECTIVES: This study aimed to determine TBS among adolescents with AN and evaluate the correlation with anthropometric, clinical and densitometric variables. DESIGN: Areal BMD spinal measures were analyzed for TBS. Findings were compared with clinical (height, weight, body mass index [BMI], age, pubertal development, 25 hydroxyvitamin D) and self-reported data (illness duration, amenorrhea, exercise, fracture, family history of osteoporosis, and antidepressant use), and BMD measures by DXA and peripheral quantitative computed tomography (pQCT). SETTING AND PARTICIPANTS: This was an urban adolescent program consisting of 57 females with AN, age 11-18 y. INTERVENTIONS: Interventions included DXA (absolute BMD and Z-score), pQCT (volumetric BMD [vBMD] and stress-strain index [SSI]), laboratory evaluation, and questionnaire administration. MAIN OUTCOME MEASURES: Main outcome measures included TBS, areal and vBMD, SSI, fracture history, disease duration. RESULTS: The TBS of six participants (11%) showed degraded and 19 (33%) partially degraded microarchitecture. Spinal TBS was correlated (P < .05) with age, height, weight, BMI, pubertal stage, BMD, and body composition by DXA, and BMD and SSI by pQCT. TBS was not correlated with disease duration, fracture, vitamin D status, race, or ethnicity, and self-reported health data. CONCLUSIONS: TBS showed evidence of degraded microarchitecture in over 40% of this study sample, and strongly correlated with anthropometric data and measures of BMD and skeletal strength. TBS is a novel tool that captures another dimension of bone health in adolescents with AN. PMID- 26108093 TI - Endogenous Opioid Mechanisms Are Implicated in Obesity and Weight Loss in Humans. AB - CONTEXT: Successful long-term weight loss is challenging. Brain endogenous opioid systems regulate associated processes; however, their role in the maintenance of weight loss has not been adequately explored in humans. OBJECTIVE: In a preliminary study, the objective was to assess central MU-opioid receptor (MOR) system involvement in eating behaviors and their relationship to long-term maintenance of weight loss. DESIGN: This was a case-control study with follow-up of the treatment group at 1 year after intervention. SETTING: The study was conducted at a tertiary care university medical center. PARTICIPANTS: Lean healthy (n = 7) and chronically obese (n = 7) men matched for age and ethnicity participated in the study. INTERVENTIONS: MOR availability measures were acquired with positron emission tomography and [(11)C]carfentanil. Lean healthy men were scanned twice under both fasted and fed conditions. Obese men were placed on a very low-calorie diet to achieve 15% weight loss from baseline weight and underwent two positron emission tomography scans before and two after weight loss, incorporating both fasted and fed states. MAIN OUTCOME MEASURES: Brain MOR availability and activation were measured by reductions in MOR availability (nondisplaceable binding potential) from the fed compared with the fasted-state scans. RESULTS: Baseline MOR nondisplaceable binding potential was reduced in obese compared with the lean and partially recovered obese after weight loss in regions that regulate homeostatic, hedonic, and emotional responses to feeding. Reductions in negative affect and feeding-induced MOR system activation in the right temporal pole were highly correlated in leans but not in obese men. A trend for an association between MOR activation in the right temporal pole before weight loss and weight regain 1 year was found. CONCLUSIONS: Although these preliminary studies have a small sample size, these results suggest that obesity and diet-induced weight loss impact central MOR binding and endogenous opioid system function. MOR system activation in response to an acute meal may be related to the risk of weight regain. PMID- 26108095 TI - Methylmercury inhibits prolactin release in a cell line of pituitary origin. AB - Heavy metals, such as methylmercury, are key environmental pollutants that easily reach human beings by bioaccumulation through the food chain. Several reports have demonstrated that endocrine organs, and especially the pituitary gland, are potential targets for mercury accumulation; however, the effects on the regulation of hormonal release are unclear. It has been suggested that serum prolactin could represent a biomarker of heavy metal exposure. The aim of this study was to evaluate the effect of methylmercury on prolactin release and the role of the nitrergic system using prolactin secretory cells (the mammosomatotroph cell line, GH3B6). Exposure to methylmercury (0-100 MUM) was cytotoxic in a time- and concentration-dependent manner, with an LC50 higher than described for cells of neuronal origin, suggesting GH3B6 cells have a relative resistance. Methylmercury (at exposures as low as 1 MUM for 2 h) also decreased prolactin release. Interestingly, inhibition of nitric oxide synthase by N-nitro L-arginine completely prevented the decrease in prolactin release without acute neurotoxic effects of methylmercury. These data indicate that the decrease in prolactin production occurs via activation of the nitrergic system and is an early effect of methylmercury in cells of pituitary origin. PMID- 26108097 TI - Comparative efficacy and safety of the left versus right radial approach for percutaneous coronary procedures: a meta-analysis including 6870 patients. AB - The radial approach is widely used in the treatment of patients with coronary artery disease. We conducted a meta-analysis of published results on the efficacy and safety of the left and right radial approaches in patients undergoing percutaneous coronary procedures. A systematic search of reference databases was conducted, and data from 14 randomized controlled trials involving 6870 participants were analyzed. The left radial approach was associated with significant reductions in fluoroscopy time [standardized mean difference (SMD)= 0.14, 95% confidence interval (CI)=-0.19 to -0.09; P<0.00001] and contrast volume (SMD=-0.07, 95%CI=-0.12 to -0.02; P=0.009). There were no significant differences in rate of procedural failure of the left and the right radial approaches [risk ratios (RR)=0.98; 95%CI=0.77-1.25; P=0.88] or procedural time (SMD=-0.05, 95%CI=0.17-0.06; P=0.38). Tortuosity of the subclavian artery (RR=0.27, 95%CI=0.14-0.50; P<0.0001) was reported more frequently with the right radial approach. A greater number of catheters were used with the left than with the right radial approach (SMD=0.25, 95%CI=0.04-0.46; P=0.02). We conclude that the left radial approach is as safe as the right radial approach, and that the left radial approach should be recommended for use in percutaneous coronary procedures, especially in percutaneous coronary angiograms. PMID- 26108096 TI - Plasticity of neutrophils reveals modulatory capacity. AB - Neutrophils are widely known as proinflammatory cells associated with tissue damage and for their early arrival at sites of infection, where they exert their phagocytic activity, release their granule contents, and subsequently die. However, this view has been challenged by emerging evidence that neutrophils have other activities and are not so short-lived. Following activation, neutrophil effector functions include production and release of granule contents, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). Neutrophils have also been shown to produce a wide range of cytokines that have pro- or anti inflammatory activity, adding a modulatory role for this cell, previously known as a suicide effector. The presence of cytokines almost always implies intercellular modulation, potentially unmasking interactions of neutrophils with other immune cells. In fact, neutrophils have been found to help B cells and to modulate dendritic cell (DC), macrophage, and T-cell activities. In this review, we describe some ways in which neutrophils influence the inflammatory environment in infection, cancer, and autoimmunity, regulating both innate and adaptive immune responses. These cells can switch phenotypes and exert functions beyond cytotoxicity against invading pathogens, extending the view of neutrophils beyond suicide effectors to include functions as regulatory and suppressor cells. PMID- 26108098 TI - Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence. AB - Chronic ethanol consumption can produce learning and memory deficits. Brain derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory), at low and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4). Expression levels of both BDNF and TrkB were decreased in chronic alcoholism, and increased after abstinence. The CA4 region appeared to show the greatest differences. Changes in p75NTR expression were the opposite of those of BDNF and TrkB, with the greatest differences observed in the DG and CA4 regions. PMID- 26108099 TI - Changes in circulating endothelial progenitor cells predict responses of multiple myeloma patients to treatment with bortezomib and dexamethasone. AB - Four cycles of chemotherapy are required to assess responses of multiple myeloma (MM) patients. We investigated whether circulating endothelial progenitor cells (cEPCs) could be a biomarker for predicting patient response in the first cycle of chemotherapy with bortezomib and dexamethasone, so patients might avoid ineffective and costly treatments and reduce exposure to unwanted side effects. We measured cEPCs and stromal cell-derived factor-1alpha (SDF-1alpha) in 46 MM patients in the first cycle of treatment with bortezomib and dexamethasone, and investigated clinical relevance based on patient response after four 21-day cycles. The mononuclear cell fraction was analyzed for cEPC by FACS analysis, and SDF-1alpha was analyzed by ELISA. The study population was divided into 3 groups according to the response to chemotherapy: good responders (n=16), common responders (n=12), and non-responders (n=18). There were no significant differences among these groups at baseline day 1 (P>0.05). cEPC levels decreased slightly at day 21 (8.2+/-3.3 cEPCs/MUL) vs day 1 (8.4+/-2.9 cEPCs/MUL) in good responders (P>0.05). In contrast, cEPC levels increased significantly in the other two groups (P<0.05). SDF-1alpha changes were closely related to changes in cEPCs. These findings indicate that change in cEPCs at day 21 in the first cycle might be considered a noninvasive biomarker for predicting a later response, and extent of change could help decide whether to continue this costly chemotherapy. cEPCs and the SDF-1alpha/CXCR4 axis are potential therapeutic targets for improved response and outcomes in MM patients. PMID- 26108100 TI - Gender, race and socioeconomic influence on diagnosis and treatment of thyroid disorders in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - Thyroid diseases are common, and use of levothyroxine is increasing worldwide. We investigated the influence of gender, race and socioeconomic status on the diagnosis and treatment of thyroid disorders using data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a multicenter cohort study of civil servants (35-74 years of age) from six Brazilian cities. Diagnosis of thyroid dysfunction was by thyrotropin (TSH), and free thyroxine (FT4) if TSH was altered, and the use of specific medications. Multivariate logistic regression models were constructed using overt hyperthyroidism/hypothyroidism and levothyroxine use as dependent variables and sociodemographic characteristics as independent variables. The frequencies of overt hyper- and hypothyroidism were 0.7 and 7.4%, respectively. Using whites as the reference ethnicity, brown, and black race were protective for overt hypothyroidism (OR=0.76, 95%CI=0.64-0.89, and OR=0.53, 95%CI=0.43-0.67, respectively, and black race was associated with overt hyperthyroidism (OR=1.82, 95%CI=1.06-3.11). Frequency of hypothyroidism treatment was higher in women, browns, highly educated participants and those with high net family incomes. After multivariate adjustment, levothyroxine use was associated with female gender (OR=6.06, 95%CI=3.19-11.49) and high net family income (OR=3.23, 95%CI=1.02-10.23). Frequency of hyperthyroidism treatment was higher in older than in younger individuals. Sociodemographic factors strongly influenced the diagnosis and treatment of thyroid disorders, including the use of levothyroxine. PMID- 26108101 TI - Individual differences in common factors of emotional traits and executive functions predict functional connectivity of the amygdala. AB - Evidence suggests that individual differences in emotion control are associated with frontoparietal-limbic networks and linked to emotional traits and executive functions. In a first attempt to directly target the link between emotional traits and executive functions using resting-state fMRI analysis, 43 healthy adults completed a test battery including executive tasks and emotional trait self-assessments that were subjected to a principal component analysis. Of the three factors detected, two explained 40.4% of the variance and were further investigated. Both factors suggest a relation between emotional traits and executive functions. Specifically, the first factor consisted of measures related to inhibitory control and negative affect, and the second factor was related to reward and positive affect. To investigate whether this interplay between emotional traits and executive functions is reflected in neural connectivity, we used resting-state fMRI to explore the functional connectivity of the amygdala as a starting point, and progressed to other seed-based analyses based on the initial findings. We found that the first factor predicted the strength of connectivity between brain regions known to be involved in the cognitive control of emotion, including the amygdala and the dorsolateral prefrontal cortex, whereas the second factor predicted the strength of connectivity between brain regions known to be involved in reward and attention, including the amygdala, the caudate and the thalamus. These findings suggest that individual differences in the ability to inhibit negative affect are mediated by prefrontal-limbic pathways, while the ability to be positive and use rewarding information is mediated by a network that includes the amygdala and thalamostriatal regions. PMID- 26108103 TI - What's New in Uveitis and Ocular Inflammation? PMID- 26108102 TI - Applying random forest and subtractive fuzzy c-means clustering techniques for the development of a novel G protein-coupled receptor discrimination method using pseudo amino acid compositions. AB - G protein-coupled receptors (GPCRs) constitute the largest superfamily of integral membrane proteins (IMPs) and they tremendously contribute in the flow of information into cells. In this study, the random forest (RF) and the subtractive fuzzy c-means clustering (SBC) methods have been used to determine the importance of input variables and discriminate GPCRs from non-GPCRs using twenty amino acid and fifty pseudo amino acid compositions derived from GPCR sequences. The studied dataset was retrieved from the UniProt/SWISSPROT database and consists of 1000 GPCR and 1000 non-GPCR reviewed sequences. The top ranked RF-SBC-based model discriminates GPCRs and non-GPCRs successfully with the accuracy, sensitivity, specificity and Matthew's coefficient correlation (MCC) rates of 99.15%, 99.60%, 98.70% and 0.983%, respectively. These rates were obtained from averaged values of 5-fold cross validation using only twenty four out of fifty pseudo amino acid composition features. The results show that the proposed RF-SBC-based model outperforms other existing algorithms in terms of the evaluated performance criteria. The webserver for the proposed algorithm is available at http://brcinfo.shinyapps.io/GPCRIden. PMID- 26108104 TI - Eye Genetics in Post-Genome-Wide Association Studies Era. PMID- 26108105 TI - Development of the Department of Ophthalmology at Osaka University. AB - Osaka University is one of the largest national universities and the sixth oldest university in Japan. Its academic roots extend to Tekijuku and Kaitokudo in the Edo period. Osaka University has the motto, "Live Locally, Grow Globally." This means that they work for their own local community and also work worldwide at the same time.The Osaka University Graduate School of Medicine is famous for basic research in immunology, including research on interleukin 6 and innate immunity, and translational research for regenerative medicine. Osaka University Hospital has 31 clinical departments and 2159 staff members, including 834 physicians. It serves 2515 outpatients and 940 inpatients per day. Approximately 8500 surgeries are performed every year. The Department of Ophthalmology at Osaka University is one of the largest ophthalmology departments in Japan. It has 24 faculty members, 9 graduate school students, and 9 residents. It has had 9 professors throughout its history. Their department has also produced active professors in the wide field of ophthalmology.Their department is known for a large amount of high clinical activity. Their advanced clinical practice performs translational research on the regenerative medicine of the cornea, artificial retina, diagnostic instruments and tools, apoptosis of photoreceptors, and drug discovery. Many ophthalmologists and staff members have contributed to the development of the Department of Ophthalmology at Osaka University. PMID- 26108106 TI - Aged Drivers May Experience Decreased Visual Function While Driving. AB - PURPOSE: To investigate conventional visual acuity (VA) and changes therein over time in older drivers. DESIGN: A cross-sectional study. METHODS: One hundred twenty-four drivers (41 younger drivers aged 21-39 years, 40 middle-aged drivers aged 40-59 years, and 43 older drivers aged 60-77 years) who consented to undergo conventional and functional VA testing, perform the Trail Making Test B, and complete a questionnaire on visual performance while driving at an expressway rest stop in Ashigara, Japan, were studied. RESULTS: The overall proportion of the study subjects with a decimal bilateral VA less than 0.7, the Japanese threshold score for obtaining and renewing a driver's license, was 10%. The number of the subjects with decimal functional VA scores and minimum VA scores less than 0.7 was significantly higher in the older group than in the younger group (P < 0.05), although the conventional VA scores did not differ significantly between the older and younger groups (P = 0.621). The Trail Making Test B scores were significantly higher in the older group than in the younger and middle-aged groups (P < 0.05). The total score of the "visual performance during driving at night" category correlated significantly with the logMAR functional VA and logMAR minimum VA (P < 0.05) but not the logMAR VA. CONCLUSIONS: Older drivers might experience decreased functional VA and increased frequency of transient decreases in VA while driving. The functional VA test might capture visual impairment among older drivers that went undetected by the conventional VA test. PMID- 26108107 TI - Comparison of Goldmann Tonometry and Dynamic Contour Tonometry in Normal and Descemet Stripping Endothelial Keratoplasty Eyes. AB - PURPOSE: This study aimed to compare intraocular pressures (IOP) measured by dynamic contour tonometry (DCT) with Goldmann tonometry (GAT) in Descemet stripping endothelial keratoplasty (DSEK) eyes. The agreeability between the 2 established methods and their relation to central corneal thickness (CCT) was also studied. DESIGN: A comparative case series. METHODS: Forty-six eyes of DSEK were enrolled at least 3 months after the procedure. Thirty-five other eyes of the same patient cohort served as control. Intraocular pressures were measured by DCT and GAT by 2 different examiners in a randomized manner. Central corneal thickness was measured by ultrasonic pachymetry. Statistical analysis was used for the calculation of means, SD, coefficient of determination, linear regression, and Bland and Altman plot. Statistical significance was considered as P < 0.05. RESULTS: Mean CCT was 624.49 MUm and 518.41 MUm in DSEK and control eyes, respectively. Mean IOP by GAT and DCT, respectively, was 19.4 and 21.5 mm Hg in DSEK eyes and 15.12 and 17.6 mm Hg in controls. Descemet stripping endothelial keratoplasty eyes showed universally higher IOP by either method in comparison with normal controls. Dynamic contour tonometry reading was significantly higher than GAT in both (P < 0.05) groups. The correlation between IOP and CCT was not significant in DSEK eyes (P > 0.05). CONCLUSIONS: A higher baseline IOP is to be expected in DSEK eyes, which is independent of corneal thickness. Both GAT and DCT can be used as a standard method to measure IOP in DSEK eyes, but their readings cannot be used interchangeably. PMID- 26108108 TI - Scleral Buckling for Rhegmatogenous Retinal Detachment Using Vitrectomy-Based Visualization Systems and Chandelier Illumination. AB - PURPOSE: The objective of this study was to evaluate an alternative approach to scleral buckling surgery using vitrectomy-based chandelier visualization systems instead of the indirect ophthalmoscope. DESIGN: This was a prospective case series. METHODS: Ten eyes underwent scleral buckling under microscope using contact wide-angle lens with 25-gauge chandelier illumination and were followed up for 6 months. RESULTS: An encirclage was done in 8 eyes, and segmental buckle used in 2 eyes. Excellent intraoperative visualization was achieved, and all routine buckling steps were easily replicated with this approach. CONCLUSIONS: Using contact wide-angle lens along with chandelier illumination under microscope allows good visualization for scleral buckling procedure. This approach may allow excellent visibility with zooming capabilities for each step of the procedure as well as allows transmission to a monitor in the theater for teaching purposes apart from allowing better ergonomics for the surgeon. PMID- 26108109 TI - Bacterial Species and Surgical Sites Involved in Contamination During Strabismus Surgery. AB - PURPOSE: Residual bacterial colonization of the eye after strabismus surgery is common. This study aimed to identify the bacterial pathogens and contaminated sites involved during strabismus surgery. DESIGN: A prospective, case-control study of 44 patients aged 1-78 years who underwent strabismus surgery. METHODS: Before participation, we received clinical research board approval, and informed consent was obtained from each of the patients or the parents. Five percent povidone-iodine was used to sterilize the surgical site in all cases. Intraoperative swabs were taken from conjunctival incision site, plain gut suture, scleral surgery site, Vicryl suture, and lid specula. Bacteria isolates were identified by culture growth and Gram staining. Positive and negative control samples were collected. RESULTS: Samples from 13 (29.5%) of 44 cases were positive for growth of bacteria. The conjunctival incision site was involved in 9 cases (20.5%), and the lid speculum in 7 cases (15.9%). All 13 colonized plates grew the coagulase-negative Staphylococcus strain. Staphylococcus aureus was cultured in 1 case (2.3%) and was associated with the only case of postoperative infection. The S. aureus cultures came from both the conjunctival incision site and the lid speculum. CONCLUSIONS: Despite a high contamination rate of 29.5%, incidence of clinically significant infection was low. Our study suggests involvement of the eyelids and conjunctiva in harboring bacteria even after the use of povidone-iodine. Regardless of the mechanism of contamination, we should continue to focus our efforts on reducing intraoperative conjunctival bacterial load. Irregular tear film can contribute to postoperative complications. PMID- 26108110 TI - Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma. AB - The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were "drug induced ocular hypertension" and "drug induced glaucoma" used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. PMID- 26108111 TI - Developments in Ocular Genetics: Annual Review. AB - PURPOSE: The purpose of this study was to summarize major developments in ocular genetics over the past year. DESIGN: A literature review was performed for articles relating to the genetics of eye diseases and morphology. The search focused on articles published between September 15, 2011, and September 15, 2012. METHODS: PubMed and Google Scholar search tools were used to search for ocular genetics articles in the desired date range. RESULTS: Major advances have been reported in numerous areas including glaucoma, age-related macular degeneration, and keratoconus. Numerous novel associations have been identified through large genome-wide association studies. In addition, numerous disease genes have been identified through next-generation sequencing technologies. CONCLUSIONS: Ocular genetics continues to advance at a rapid pace and benefit from new technologies. Numerous discoveries in the past year point toward areas for continued research. PMID- 26108112 TI - Research in Uveitis and Ocular Inflammation, 2011 to 2012. AB - PURPOSE: This study was aimed to provide ophthalmologists with an update of recent research and developments in the areas of ocular immunology and uveitis. DESIGN: This is a literature review. METHODS: A 1-year search (July 1, 2011, to June 30, 2012) of the English language literature on PubMed was conducted using the search terms ocular immunology, ocular inflammation, uveitis, iritis, iridocyclitis, intermediate uveitis, posterior uveitis, panuveitis, pediatric uveitis, scleritis, choroiditis, retinitis, uveitic glaucoma, uveitic cataract, hypotony, immunomodulators, immunosuppressive therapy, corticosteroids, drug induced uveitis, sarcoidosis, toxoplasmosis, tuberculosis, syphilis, herpes simplex virus, herpes zoster virus, cytomegalovirus, optical coherence tomography, mucous membrane pemphigoid, experimental autoimmune uveitis, and endotoxin-induced uveitis. Approximately 10% of articles studied were included in this article. RESULTS: This review incorporates original articles encompassing new insights and updates to the field of uveitis and ocular immunology. Particular consideration was given to randomized, controlled clinical trials as well as analyses of larger cohorts; however, smaller studies and case reports involving new aspects of treatment/diagnosis or expanding the understanding of disease processes were also included. CONCLUSIONS: Review of the literature reflected an improved understanding of uveitic disease and treatments, especially in the areas of immunomodulatory therapy, uveitic cystoid macular edema, toxoplasmosis, and sarcoidosis. Results from the Systemic Immunosuppressive Therapy for Eye Diseases Study and the Multicenter Uveitis Steroid Treatment trial, especially, yielded useful information in a number of areas. By its nature, this review cannot be all inclusive but is meant to focus on the literature and results most relevant to ophthalmologists in practice. PMID- 26108114 TI - Cultural Barriers to the Uptake of Diabetic Retinopathy Treatment. PMID- 26108113 TI - Efficacy of Intravitreal Levofloxacin 0.5% Ophthalmic Solution in Treating Pseudomonas Aeruginosa Endophthalmitis on a Rabbit Model. AB - PURPOSE: To evaluate the efficacy of intravitreal levofloxacin 0.5% ophthalmic solution as treatment of Pseudomonas aeruginosa endophthalmitis in a rabbit model. DESIGN: This is a parallel randomized experimental study. METHODS: Twenty six New Zealand white rabbits were enrolled. P. aeruginosa was inoculated intravitreally on the right eyes of all rabbits, which were further categorized into 2 groups, the treatment group (Group A) receiving 0.1 mL intravitreal injection levofloxacin 0.5% 24 hours after inoculation and the control group (Group B), which had 0.1 mL intravitreal aqua destilata (placebo). Clinical observation of the eyes in each group was performed on the first until the sixth day after the inoculation using clinical grading scale. On the sixth day, the eyes were examined for microbiological and histopathologic evaluations. RESULTS: The total clinical grading scores of each group were similar 24 hours after P. aeruginosa inoculation (P > 0.05). The total clinical grading scores of Group A on the sixth day and the difference in total clinical scores on the first and the sixth day were shown to be significantly lower than that of Group B (P < 0.05). Microbiological analysis revealed that there was a lower bacterial count in Group A (mean = 1.18 +/- 0.93 logCFU/0.1 mL) compared with Group B (mean = 4.09 +/- 1.51 logCFU/0.1 mL), and the histopathologic scores of both groups were also significantly different (P < 0.05). CONCLUSIONS: Intravitreal levofloxacin 0.5% ophthalmic solution at 0.1 mL dose appeared to be effective in treating P. aeruginosa endophthalmitis in rabbits. PMID- 26108115 TI - The Need for Diabetic Retinopathy Screening in Low-Resource Settings. PMID- 26108116 TI - Letter to the Editor in Response to "An Update on the Diagnosis and Management of Central Serous Chorioretinopathy". PMID- 26108117 TI - Reply to Letter to the Editor Regarding Central Serous Chorioretinopathy. PMID- 26108118 TI - Ethical Issues Surrounding Body Integrity and Research. PMID- 26108119 TI - A Comparative Survey of Pacemaker Implantation in Trinidad and Tobago in 2005 and 2009. AB - OBJECTIVE: The indications for permanent pacemaker implantations in Trinidad have expanded from initially symptomatic bradycardia to now include complex devices. A retrospective review of the available data was conducted to better understand the evolving trends in device implantation in Trinidad and Tobago. METHODS: Data were collated from the two major implanting teams in Trinidad for the years 2005 and 2009. The two implanting centres were the Advanced Cardiovascular Institute (ACI) at Westshore Medical Centre and the Catheterization Laboratory of the Eric Williams Medical Sciences Complex (EWMSC). Data were based on retrospective collation using the implantation records. RESULTS: The implantation rate for new devices increased from 39 per million to 103 per million population. The most common indications for new device implants in 2009 were high degree atrioventricular (AV) block (53%) and sick sinus syndrome (22%) with the notable appearance of congestive cardiomyopathy (13%) which was not present in the earlier cohort. Of particular note, 23 high-end devices were implanted in 2009. These were five cardiac-resynchronization therapy (CRT-P) devices, 14 automatic implantable cardio-defibrillator (AICD) devices and four combined cardiac resynchronization therapy with defibrillator (CRT-D) devices versus none in 2005. CONCLUSIONS: In summary, over the period 2005 to 2009, a substantial increase in device implantation rates has occurred which now include high-end, complex devices. Absolute rates, however, remain far below that of developed countries, indicating that the true need remains underserved. Furthermore, adjustment for gross domestic product suggests that the relatively buoyant economy of Trinidad and Tobago is capable of servicing a greater proportion of this need than is currently met. PMID- 26108120 TI - Efficacy of Vinblastine in Primary Cutaneous Anaplastic Large Cell Lymphoma. PMID- 26108122 TI - A Population-Based Care Improvement Initiative for Patients at Risk for Delirium, Alcohol Withdrawal, and Suicide Harm. AB - BACKGROUND: In a population-based approach, a hospital-wide interprofessional care redesign at Brigham and Women's Hospital (BWH; Boston), was conducted to provide optimal evidence-informed care for patients at risk for delirium, alcohol abuse, and suicide harm (DASH). The initiative involved enhanced screening and the introduction of new care management guidelines and order sets pertaining to the DASH diagnoses. METHODS: An interprofessional group from medicine, nursing, and psychiatry jointly led a hospitalwide effort for the improvement of care and outcomes of patients presenting with a DASH diagnosis (delirium, alcohol withdrawal, and suicide harm). The care improvement process consisted of four phases: (1) development of guidelines, (2) imple mentation/rollout, (3) integration into practice, and (4) sustainability, including ongoing practice development and evaluation. RESULTS: Implementation outcomes were evaluated using eight parameters-acceptability, adoption, appropriateness, feasibility, fidelity, implementation cost, penetration, and sustainability. Internal billing data and ICD-9-CM [International Classification of Diseases, Ninth Revision, Clinical Modification] diagnostic codes were used to identify the DASH population. Patients were compared pre- and postprogram implementation for fiscal years 2010 through 2013. The average length of stay, reported as the number of midnights in the hospital, remained consistent for DASH patients-9.3-10.0 days (versus 5.3-6.0 days for BWH over all). The DASH readmission rate decreased by 9%-from 15.1% to 13.7%, approaching the overall BWH rate of 13.3%. CONCLUSION: Close nurse physician collaboration, including joint leadership and simultaneous rollout for nurses and physicians, contributed to the initiative's effective implementation. PMID- 26108123 TI - Nurse Knowledge Exchange Plus: Human-Centered Implementation for Spread and Sustainability. AB - BACKGROUND: Kaiser Permanente implemented a new model of nursing communication at shift change-in the bedside nursing report known as the Nurse Knowledge Exchange (NKE) in 2004-but noted variations in its spread and sustainability across medical centers five years later. METHODS: The six core elements of NKEplus were as follows: team rounding in the last hour before shift changes, pre-shift patient assignments that limit the number of departing nurses at shift change, unit support for uninterrupted bedside reporting, standardization for report and safety check formats, and collaboration with patients to update in-room care boards. In January 2011 Kaiser Permanente Southern California (KPSC; Pasadena) began implementing NKEplus in 125 nursing units across 14 hospitals, with the use of human-centered design principles: creating shared understanding of the need for change, minimum specifications, and customization by frontline staff. Champion teams on each nursing unit designed and pilot tested unit-specific versions of NKEplus for four to eight weeks. Implementation occurred in waves and proceeded from medical/surgical units to specialty units. Traditional performance improvement strategies of accountability, measurement, and management were also applied. RESULTS: By the end of 2012, 100% of the 64 medical/surgical units and 47 (77.0%) of the 61 specialty units in KPSC medical centers implemented NKEplus as had all but 1 of the specialty units by May 2013. The mean KPSC score on the NKEplus nursing behavior bundle improved from 65.9% in 2010 to 71.3% in the first quarter of 2014. The mean KPSC Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) score for nurse communication improved from 73.1% in 2010 to 76.4% in the first quarter of 2014 (p < . 001). CONCLUSION: Human centered implementation appeared to help spread a new model of nursing handoffs and change the culture of professional nursing practice related to shift change. PMID- 26108124 TI - Redefining Overuse to Include Costs: A Decision Analysis for Computed Tomography in Minor Head Injury. AB - BACKGROUND: A study was conducted to (1) determine the testing threshold for head computed tomography (CT) in minor head injury in the emergency department using decision analysis with and without costs included in the analysis, (2) to determine which variables have significant impact on the testing threshold, and (3) to compare this calculated testing threshold to the pretest risk estimate previously reported when the Canadian CT Head Rule (CCHR) was applied. It was hypothesized that the CCHR might not identify all patients above the testing threshold. METHODS: A decision analytic model was constructed using commercially available software and data from published literature. Outcomes were assigned values on the basis of quality-adjusted life-years (QALYs) and cost. Two testing thresholds were calculated, the first based only on the effectiveness of either strategy, the second on the overall net monetary benefit. Two-way sensitivity analyses were performed to determine which variables most affected the testing threshold. RESULTS: When only effectiveness (QALYs) was considered, the testing threshold for obtaining head CT was 0.039%. This threshold increased to 0.421% when the net monetary benefit was considered in lieu of QALYs. Age, probability of lesion on CT requiring neurosurgery, and cost of CT were the main drivers of the model. CONCLUSION: If only effectiveness is considered, current clinical decision rules might not provide a sufficient degree of certainty to ensure identification of all patients for whom the benefits of CT outweigh its risks. However, inclusion of cost in the analysis increases the testing threshold by an order of magnitude and well outside the range of uncertainty of current clinical decision rules. These results suggest that the term overuse should be redefined to include the provision of medical services with no benefits or for which harms including cost outweigh benefits. PMID- 26108125 TI - Process Performance Measures for Inpatient Glucose Management Programs. PMID- 26108126 TI - Modeling Inpatient Glucose Management Programs on Hospital Infection Control Programs: An Infrastructural Model of Excellence. PMID- 26108127 TI - Premature death in people with learning disabilities. PMID- 26108128 TI - The case for collaboration in primary care for depression. PMID- 26108129 TI - Musicians and Dystonia: Is Sleep Part of the Problem? PMID- 26108130 TI - Authors' reply. PMID- 26108131 TI - Authors' reply. PMID- 26108132 TI - Authors' reply. PMID- 26108133 TI - Validation of a questionnaire for asthma case identification in pre-schools in Latin America. AB - BACKGROUND AND OBJECTIVE: We recently developed and validated a screening questionnaire for determining which school-aged children may need further investigation to diagnose and manage asthma. In the present study we sought to extend this to pre-school aged children. METHODS: Questions from the school-aged questionnaire and literature on pre-school asthma were used to inform a focus group of parents with pre-school-aged children with asthma to develop a screening questionnaire. Parents of children attending 6 randomly selected kindergartens in Trelew, Argentina (n = 639) were invited to respond to the questionnaire. A reliability test-retest was undertaken in 187 randomly selected parents who completed the same questionnaire twice within 2-5 weeks. Clinical assessment included a standardized history and physical examination, spirometry before and after a beta-agonist inhaler, and chest X-ray. Asthma was diagnosed by the pulmonologist. RESULTS: Completed surveys were returned for 620 children, 607 of whom underwent clinical evaluation. The mean age was 4.21 years (range of 3.01 5.50) and included 82.5% white and 49.4% male children. Asthma was diagnosed in 103 (17.0%) children); 72 (69.9%) of these children did not have a previous diagnosis of asthma. The specificity, sensitivity, positive predictive value and negative predictive value of the questionnaire were 93.2%, 86.1%, 57.8% and 98.4%, respectively. CONCLUSIONS: We have demonstrated the utility of a screening questionnaire for identifying pre-school-aged children who may benefit from further assessment for asthma. PMID- 26108134 TI - Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta analysis of observational studies. AB - BACKGROUND: The reported risk of hypomagnesemia in patients with proton pump inhibitor (PPI) use is conflicting. The objective of this meta-analysis was to assess the association between the use of PPIs and the risk of hypomagnesemia. METHODS: A literature search of observational studies was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through September 2014. Studies that reported odd ratios or hazard ratios comparing the risk of hypomagnesemia in patients with PPI use were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Nine observational studies (three cohort studies, five cross-sectional studies and a case-control study) with a total of 109,798 patients were identified and included in the data analysis. The pooled RR of hypomagnesemia in patients with PPI use was 1.43 (95% CI, 1.08-1.88). The association between the use of PPIs and hypomagnesemia remained significant after the sensitivity analysis including only studies with high quality score (Newcastle-Ottawa scale score >= 8) with a pooled RR of 1.63 (95% CI, 1.14-2.23). CONCLUSIONS: Our study demonstrates a statistically significant increased risk of hypomagnesemia in patients with PPI use. The finding of this meta-analysis of observational studies suggests that PPI use is associated with hypomagnesemia and may impact clinical management of patients who are taking PPIs and at risk for hypomagnesemia related cardiovascular events. PMID- 26108135 TI - The incidence of thrombocytopenia associated with continuous renal replacement therapy in critically ill patients. AB - INTRODUCTION: Thrombocytopenia in the intensive care unit (ICU) is a commonly experienced complication; the pathology is not always easily understood. Continuous renal replacement therapy (CRRT) provides a method to dialyze unstable critically ill patients. We hypothesized that CRRT may precipitate a form of thrombocytopenia. In trials thrombocytopenia occurred at rates as high as 70%. The etiology remains unknown and results in additional diagnostic workup, as well as possible drug therapy. The extent, duration and temporal relation of thrombocytopenia remain to be determined. OBJECTIVES: Identify a pattern in platelet fluctuations after the initiation of CRRT and its impact on health care. METHODS: A retrospective study was conducted in patients receiving CRRT for >24 h with no pre-existing thrombocytopenia. Patients initiated on CRRT had daily platelet counts monitored, and CRRT attributes and therapeutic interventions were collected. Platelets were assessed for time to nadir, degree of decline and time to return to baseline after discontinuation of CRRT. RESULTS: Forty-nine patients met inclusion criteria. Thirty-seven percent of patients receiving heparinoids were tested for heparin-induced thrombocytopenia (HIT), during CRRT, with 39% of these patients having therapy changed to non-heparinoid agents due to suspected HIT; no HIT antibodies were positive. Eleven patients (22%) receiving anticoagulants, prophylactically or therapeutically had them held for a drop in platelets. There was a mean decline in platelets of 48% with a mean of 4.6 days to the nadir. An average 2.48 days were observed until rebound to >150 * 10(3)/mm(3). Statistical analysis failed to identify any patient attributes that correlated with the probability of thrombocytopenia. CONCLUSION: CRRT appears to be associated with a drop in platelets within the first 5 days of therapy with an average decline of 48%. However, platelets appear to return to >150 * 10(3)/mm(3) after cessation of CRRT. This fluctuation should be considered in the setting of patients developing thrombocytopenia after initiation of CRRT. PMID- 26108136 TI - Short-term effect of electrical nerve stimulation on spinal reciprocal inhibition during robot-assisted passive stepping in humans. AB - The purpose of this study was to investigate the effect of electrical stimulation to the common peroneal nerve (CPN) on the spinal reflex and reciprocal inhibition (RI) during robot-assisted passive ground stepping (PGS) in healthy subjects. Five interventions were applied for 30 min in healthy subjects: PGS alone; strong CPN stimulation [50% of the maximal tibialis anterior (TA) M-wave, functional electrical stimulation (FES)] alone; weak CPN stimulation [just above the MT for the TA muscle, therapeutic electrical stimulation (TES)] alone; PGS with FES; and PGS with TES. FES and TES were applied intermittently to the CPN at 25 Hz. The soleus (Sol) H-reflex and RI, which was assessed by conditioning the Sol H-reflex with CPN stimulation, were investigated before (baseline), and 5, 15 and 30 min after each intervention. The amplitudes of the Sol H-reflex were not significantly different after each intervention as compared with the baseline values. The amounts of RI were significantly decreased 5 min after PGS with FES as compared with the baseline values, whereas they were significantly increased 5 and 15 min after PGS with TES. The other interventions did not affect the amount of RI. These results suggest that interventions that combined PGS with CPN stimulation changed the spinal RI in an intensity-dependent manner. PMID- 26108137 TI - Sequelae of Cannabis as Medicine. PMID- 26108139 TI - Management of Noncardiac Comorbidities in Chronic Heart Failure. AB - Prevalence of heart failure is increasing, especially in the elderly population. Noncardiac comorbidities complicate heart failure care and are increasingly common in elderly patients with reduced or preserved ejection fraction heart failure, owing to prolongation of patient's lives by advances in chronic heart failure (CHF) management. Common comorbidities include respiratory disease, renal dysfunction, anemia, arthritis, obesity, diabetes mellitus, cognitive dysfunction, and depression. These conditions contribute to the progression of the disease and may alter the response to treatment, partly as polypharmacy is inevitable in these patients. Cardiologists and other physicians caring for patients with CHF need to be vigilant to comorbid conditions that complicate the care of these patients. There is now more guidance on management of noncardiac comorbidities in heart failure, and this article contains a comprehensive review of the most recent updates on management of noncardiac comorbidities in CHF. PMID- 26108138 TI - Acrylamide toxic effects on mouse oocyte quality and fertility in vivo. AB - Acrylamide is an industrial chemical that has attracted considerable attention due to its presumed carcinogenic, neurotoxic, and cytotoxic effects. In this study we investigated possible acrylamide reproductive toxic effects in female mice. Mice were fed an acrylamide-containing diet for 6 weeks. Our results showed the following effects of an acrylamide-containing diet. (1) Ovary weights were reduced in acrylamide-treated mice and oocyte developmental competence was also reduced, as shown by reduced GVBD and polar body extrusion rates. (2) Acrylamide feeding resulted in aberrant oocyte cytoskeletons, as shown by an increased abnormal spindle rate and confirmed by disrupted gamma-tubulin and p-MAPK localization. (3) Acrylamide feeding resulted in oxidative stress and oocyte early stage apoptosis, as shown by increased ROS levels and p-MAPK expression. (4) Fluorescence intensity analysis showed that DNA methylation levels were reduced in acrylamide-treated oocytes and histone methylation levels were also altered, as H3K9me2, H3K9me3, H3K4me2, and H3K27me3 levels were reduced after acrylamide treatment. (5) After acrylamide feeding, the litter sizes of acrylamide-treated mice were significantly smaller compared to thus of control mice. Thus, our results indicated that acrylamide might affect oocyte quality through its effects on cytoskeletal integrity, ROS generation, apoptosis induction, and epigenetic modifications. PMID- 26108140 TI - Comparison of early outcomes and quality of life after laparoscopic Heller's cardiomyotomy to peroral endoscopic myotomy for treatment of achalasia. AB - BACKGROUND AND AIM: This retrospective cohort study compared clinical outcomes and quality of life after peroral endoscopic myotomy (POEM) against laparoscopic Heller myotomy (LHM) for treatment of achalasia. METHODS: Patient demographics, operation time, intraoperative blood loss, hospital stay, time to resume diet and analgesic requirement were recorded. Clinical outcomes including recurrence of dysphagia, need for reintervention, and occurrence of gastroesophageal reflux disease (GERD) were recorded. RESULTS: From 2001 to 2014, 33 patients underwent POEM whereas 23 patients received LHM. Patients LHM had with longer mean operative time (P = 0.02), more blood loss (P = 0.001) and higher requirement for analgesics (P = 0.009) than those treated by POEM. Hospital stay and time to resume diet were similar. Both POEM and LHM achieved similar dysphagia scores at postoperative 4 weeks, 3 months and 6 months. Twenty-six percent of LHM patients and 15.2% of POEM patients sustained gastroesophageal reflux disease (GERD) after treatment (P = 0.311). Six patients required regular proton pump inhibitor three after POEM and three after LHM (P = 0.639). Thirteen percent of LHM patients sustained recurrent dysphagia and one required reintervention. There was no recurrence in the POEM group. Follow-up duration (mean [SD]) for the LHM group was significantly longer (60 [42] months vs 6 [4] months; P = 0.001). There was also no difference in all four aspects of GERD-related quality of life outcomes. CONCLUSION: Compared to LHM, POEM achieved shorter operative time, less blood loss and pain. POEM is comparable to LHM for treatment of achalasia with similar incidence of GERD after the procedure. PMID- 26108141 TI - Genetic panmixia within a narrow contact zone between chromosomally and ecologically distinct black fly sibling species (Diptera: Simuliidae). AB - Hybrid zones are windows into the speciation process, and their study can give clues into the maintenance and breakdown of species boundaries. Using both genetic and ecological tools, we investigate lineage diversification across a contact zone characterized by chromosome rearrangements. We show that black fly sibling species, Simulium arcticum sensu stricto (s.s.) and Simulium saxosum, lack genetic differentiation at both microsatellite and mtDNA loci in allopatry and sympatry, as well as exhibit high levels of gene flow and continuous chromosome variation in sympatry. Furthermore, hybrid frequencies at the contact zone are similar to those seen between races, rather than species. In contrast, S. arcticum s.s. and S. saxosum maintain ecological differences and distinct habitat associations - the contact zone situated at the margin of suitable habitat for each sibling species. Moreover, gene flow occurs only in a narrow band along an ecological transition. Except for the contact zone, S. arcticum s.s. and S. saxosum hybrids do not occur elsewhere within the sibling species' ranges. Although S. arcticum s.s. and S. saxosum maintain the potential to interbreed freely, we conclude that habitat associations and, perhaps, chromosome systems prevent expansion of ranges and assimilation of lineages. PMID- 26108142 TI - Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals. AB - The Tohoku Medical Megabank Organization constructed the reference panel (referred to as the 1KJPN panel), which contains >20 million single nucleotide polymorphisms (SNPs), from whole-genome sequence data from 1070 Japanese individuals. The 1KJPN panel contains the largest number of haplotypes of Japanese ancestry to date. Here, from the 1KJPN panel, we designed a novel custom made SNP array, named the Japonica array, which is suitable for whole-genome imputation of Japanese individuals. The array contains 659,253 SNPs, including tag SNPs for imputation, SNPs of Y chromosome and mitochondria, and SNPs related to previously reported genome-wide association studies and pharmacogenomics. The Japonica array provides better imputation performance for Japanese individuals than the existing commercially available SNP arrays with both the 1KJPN panel and the International 1000 genomes project panel. For common SNPs (minor allele frequency (MAF)>5%), the genomic coverage of the Japonica array (r(2)>0.8) was 96.9%, that is, almost all common SNPs were covered by this array. Nonetheless, the coverage of low-frequency SNPs (0.5%G and c.929T>C (p.Met310Thr)) in LIAS. To date, three homozygous mutations have been reported in LIAS. All previously reported GCE patients also show elevated level of serum glycine. Our data further supports LIAS mutations as a genetic cause for GCE. PMID- 26108147 TI - RNAi Silencing of IL-1beta and TNF-alpha in the Treatment of Post-traumatic Arthritis in Rabbits. AB - Post-traumatic arthritis is a secondary complication to severe joint trauma. With the disease progression, it may eventually lead to osteoarthritis in patients whose age is considerably younger than patients with traditional bone arthritis. The main objective of this study was to explore the feasibility of using lentiviral-mediated RNA interference silencing of IL-1beta and TNF-alpha to treat post-traumatic arthritis in rabbits. About 48 New Zealand rabbits underwent bilateral knee joint surgery to stimulate traumatic arthritis. They were then randomly divided into four groups of 12 rabbits each. The histopathology of the cartilage was observed, and the changes were assessed by Mankin scoring. ELISA was used to detect the expression of IL-1beta and TNF-alpha in the synovial fluid. (i) Compared with the control group, the transfection and co-transfected groups displayed reduced cartilage damage and speed of degeneration. The co transfected group showed the greatest alleviation of symptoms. The Mankin score was statistically different (p < 0.01). (ii) Compared with the control group, the expression of IL-1beta or TNF-alpha was reduced in the respective transfection groups (p < 0.01 in both groups) and IL-1beta and TNF-alpha were reduced in the co-transfected group (p < 0.01). The co-transfected group showed the lowest expression of the three experimental groups of both IL-1beta and TNF-alpha (p < 0.01). Lentivirus-mediated RNA interference can knock down the expression of IL 1beta and TNF-alpha in joint fluids and, in a synergistic effect when two siRNAs are co-transfected, ease cartilage degeneration. PMID- 26108148 TI - The pharmacokinetics change of cefepime after Shuanghuanglian injection administration in subjects with the renal damage. AB - Shuanghuanglian injection (SHLI) has been widely used for administration with cephalosporin in China for long time. The objective of this study was to evaluate the pharmacological properties and biochemical changes of cefepime combined with SHLI. The SD rats included were received either an intravenous (iv. 4 mL/kg) dose of normal saline, or intravenous (iv. 0.74, 0.37, 0.185 g/kg, respectively) doses of SHLI once daily for 7 days. After last administration, cefepime (0.41 g/kg) was intravenous injected to the animals. The serum and urine samples were acquired and stored at 4 degrees C. They were used for quantitative determination of urea nitrogen (BUN), creatinine (CRE), urine protein, alkaline phosphatase (ALP) and N-acetyl-B-d-glucosaminidase (NAG). At different time points, the levels of cefepime in rat plasma were estimated for pharmacokinetic measures by HPLC. Aspirin was selected as internal standard (IS). The results showed that there were positive effects by increasing the total amount of CRE, BUN, NAG and urine protein (p < 0.01 or <0.05) and decreasing the levels of ALP (especially the high dose group of SHLI with cefepime) (p < 0.01). Besides, the pharmacokinetic results indicated that cefepime was distributed as non compartment model after intravenous administration. Compared with the corresponding values for the compounds given alone, the area under the blood drug concentration time curve (AUC0-t and AUC0-infinity) was better increased in middle- and high-dose groups (pall < 0.01), the mean residence time (MRT) of cefepime was larger (pall < 0.01) and the total clearance (CL) was lower at different levels. The results mean that the duration and concentration of cefepime could be prolonged and the clearance reduced while in combination with SHLI. Furthermore, the cefepime in the three tested doses caused changes of renal tubular epithelial cells while the severity of changes mainly dependent on the specific doses. In conclusion, the results above-mentioned suggest a possible contribution of drug combination in the nephrotoxicity and biochemical alterations especially at high doses. Further, monitoring measures for the renal functions are warranted to evaluate during the combination of these two drugs. PMID- 26108149 TI - Sexually transmitted infections in pediatric renal transplant recipients: Time to take notice! AB - We sought to assess the prevalence of STIs, contraception use, and unintentional pregnancy in our pediatric renal transplant recipients. We performed a retrospective chart review. Forty-nine of 65 patients in our program are currently in the high-risk age window of 13 yr or older (34 men, 15 women; mean age 17 yr old, range 13-23 yr old). There was a disproportionate difference in sexual behavior among the men and women, such that while only 15% of the men reported being sexually active, 53% of the women were sexually active. Among high risk age-group women, 40% were on hormonal contraception. This increased to 75% in sexually active women. There were no cases of unintentional pregnancy. Thirty percent of sexually active recipients had at least one STI. This was higher among sexually active women (37.5%) compared to men (20%). STIs identified included gonococcal and chlamydial urethritis/cervicitis, Trichomonas vaginitis, HSV-2 genital sores, pelvic inflammatory disease, and HIV. In conclusion, STIs are a realistic public health concern in our pediatric renal transplant recipients. Consensus guidelines on STI screening and reproductive health counseling are needed to address this understudied problem. PMID- 26108151 TI - Sex-specific daily spawning seaward migration of striped mullet Mugil cephalus in a coastal lagoon. AB - The sex-specific daily spawning seaward migration of striped mullet Mugil cephalus was analysed in Palaiopotamos Lagoon (western Greek coast, eastern Mediterranean Sea) in an 86 day time series. The data set included the daily number of M. cephalus catches in barrier traps, as well as a time series of some weather variables. The analysis revealed an important linkage of the daily migration rate as well as a sex-specific response of the species to the lunar cycle and the short-term fluctuation of weather variables. The daily migration pattern of females was more persistent than that of males, indicating a possible female leadership role during the spawning migration. Multiregression models described quite accurately the sex-specific daily migration rates of the species, thus providing a potentially powerful tool regarding the lagoon fishery management of M. cephalus, especially in the context of climate change. PMID- 26108150 TI - The first crop plant genetically engineered to release an insect pheromone for defence. AB - Insect pheromones offer potential for managing pests of crop plants. Volatility and instability are problems for deployment in agriculture but could be solved by expressing genes for the biosynthesis of pheromones in the crop plants. This has now been achieved by genetically engineering a hexaploid variety of wheat to release (E)-beta-farnesene (Ebetaf), the alarm pheromone for many pest aphids, using a synthetic gene based on a sequence from peppermint with a plastid targeting amino acid sequence, with or without a gene for biosynthesis of the precursor farnesyl diphosphate. Pure Ebetaf was produced in stably transformed wheat lines with no other detectable phenotype but requiring targeting of the gene produced to the plastid. In laboratory behavioural assays, three species of cereal aphids were repelled and foraging was increased for a parasitic natural enemy. Although these studies show considerable potential for aphid control, field trials employing the single and double constructs showed no reduction in aphids or increase in parasitism. Insect numbers were low and climatic conditions erratic suggesting the need for further trials or a closer imitation, in the plant, of alarm pheromone release. PMID- 26108152 TI - Postmortem computed tomography (PMCT) and disaster victim identification. AB - Radiography has been used for identification since 1927, and established a role in mass fatality investigations in 1949. More recently, postmortem computed tomography (PMCT) has been used for disaster victim identification (DVI). PMCT offers several advantages compared with fluoroscopy, plain film and dental X rays, including: speed, reducing the number of on-site personnel and imaging modalities required, making it potentially more efficient. However, there are limitations that inhibit the international adoption of PMCT into routine practice. One particular problem is that due to the fact that forensic radiology is a relatively new sub-speciality, there are no internationally established standards for image acquisition, image interpretation and archiving. This is reflected by the current INTERPOL DVI form, which does not contain a PMCT section. The DVI working group of the International Society of Forensic Radiology and Imaging supports the use of imaging in mass fatality response and has published positional statements in this area. This review will discuss forensic radiology, PMCT, and its role in disaster victim identification. PMID- 26108153 TI - Errors in multidetector row computed tomography. AB - Multidetector row computed tomography (MDCT) represents the technique of choice for the majority of pathologies today and is responsible for the majority of diagnoses. However, despite the low number of studies dedicated to errors in MDCT, CT reporting seems especially prone to generating errors and errors are an inevitable part of MDCT practice. Most of these arise during image interpretation but, differently from other radiological techniques, the awareness of radiologists regarding technical CT aspects and pathologies substantially contribute in generating errors, in particular because CT technology expands rapidly and radiologists do not routinely receive specific and appropriate training for its use and because CT examinations are not the same for each patient and each pathology and the choice of the most appropriate CT examination (including the dose exposure to the patient) presumes a very large awareness from radiologists. This review is aimed at increasing awareness regarding the type of errors in MDCT and in particular to also highlight technical and procedural errors. PMID- 26108154 TI - Knowledge and attitudes towards evidence-based medicine of mentors in general practice can be influenced by using medical students as academic detailers. AB - BACKGROUND: Regular use of evidence-based medicine (EBM) among general practitioners (GP) is insufficient. OBJECTIVE: To analyse whether knowledge and attitudes about EBM can be improved among mentors in general practice by involving sixth-year medical students as academic detailers. METHODS: An interventional non-randomized before-and-after study included 98 GPs (49 in the intervention group of mentors and 49 controls) and 174 medical students attending family medicine clinical rotations. A telephone survey on knowledge and attitudes towards EBM was conducted among participating physicians before, and six months after the rotation. During the rotation, each mentor chose two cases from real life, and the students' task was to form an answerable clinical question, find the evidence-based answer and to write a brief report. The mentor reviewed the report and discussed it with the student. RESULTS: Students' EBM detailing intervention led to significant improvement in knowledge and attitudes about EBM in the intervention group of mentors in general practice compared to control GPs (relative increase in knowledge was 20 +/- 46.9% vs 6 +/- 12.1%, respectively; P = 0.042). Among participants with Ph.D. or specialization in family medicine, the observed effects of the intervention were similar as in the total sample, and statistically significant, but not in the group of participants with neither scientific degree nor specialization in family medicine. CONCLUSION: Knowledge and attitudes of GP mentors towards EBM can be improved by involving medical students as academic detailers. Further studies should explore the effectiveness of this method among GPs that are not mentors, and who do not have a specialization or research degree. PMID- 26108155 TI - Organocatalytic asymmetric reaction of indol-2-yl carbinols with enamides: synthesis of chiral 2-indole-substituted 1,1-diarylalkanes. AB - The chiral phosphoramide-catalyzed asymmetric reaction of indol-2-yl carbinols with enamides is presented. The method provided an efficient and novel way for the synthesis of chiral 2-indole-substituted 1,1-diarylalkane derivatives. PMID- 26108156 TI - Functional Capacity Evaluation Research: Report from the Second International Functional Capacity Evaluation Research Meeting. AB - INTRODUCTION: Functional capacity evaluations are an important component of many occupational rehabilitation programs and can play a role in facilitating reintegration to work thus improving health and disability outcomes. The field of functional capacity evaluation (FCE) research has continued to develop over recent years, with growing evidence on the reliability, validity and clinical utility of FCE within different patient and healthy worker groups. The second International FCE Research Conference was held in Toronto, Canada on October 2nd 2014 adjacent to the 2014 Work Disability Prevention Integration conference. This paper describes the outcomes of the conference. REPORT: Fifty-four participants from nine countries attended the conference where eleven research projects and three workshops were presented. The conference provided an opportunity to discuss FCE practice, present new research and provide a forum for discourse around the issues pertinent to FCE use. Conference presentations covered aspects of FCE use including the ICF-FCE interface, aspects of reliability and validity, consideration of specific injury populations, comparisons of FCE components and a lively debate on the merits of 'Man versus Machine' in FCE's. FUTURE DIRECTIONS: Researchers, clinicians, and other professionals in the FCE area have a common desire to improve the content and quality of FCE research and to collaborate to further develop research across systems, cultures and countries. PMID- 26108158 TI - Successful treatment of oral pemphigus vulgaris in an insulin-dependant geriatric patient. AB - OBJECTIVE: To present a clinical report of a patient treated with corticosteroids for oral pemphigus vulgaris (PV) lesions. BACKGROUND: PV is the type of pemphigus that most often affects the oral mucosa and tends not to appear in elderly people. METHODS: Two biopsies were needed for diagnosis. She was treated with oral prednisone and topically with 0.05% clobetasol propionate. CONCLUSION: An early diagnosis and treatment is needed for a good prognosis, especially in elderly patients with multiple systemic pathology. PMID- 26108157 TI - Daptomycin in the Clinical Setting: 8-Year Experience with Gram-positive Bacterial Infections from the EU-CORE(SM) Registry. AB - INTRODUCTION: The aim of this study was to evaluate the clinical outcomes and safety of daptomycin therapy in patients with serious Gram-positive infections. METHODS: Patients were enrolled in the European Cubicin((r)) Outcomes Registry and Experience (EU-CORE(SM)), a non-interventional, multicenter, observational registry. The real-world data were collected across 18 countries (Europe, Latin America, and Asia) for patients who had received at least one dose of daptomycin between January 2006 and April 2012. Two-year follow-up data were collected until 2014 for patients with endocarditis, intracardiac/intravascular device infection, osteomyelitis, or orthopedic device infection. RESULTS: A total of 6075 patients were enrolled. The most common primary infections were complicated skin and soft tissue infection (31.7%) and bacteremia (20.7%). Staphylococcus aureus was the most frequently reported pathogen (42.9%; methicillin-resistant S. aureus [MRSA], 23.2%), followed by Staphylococcus epidermidis and other coagulase-negative staphylococci (CoNS, 28.5%). The most commonly prescribed dose of daptomycin was 6 mg/kg/day (43.6%), and the median duration of therapy was 11 (range 1-300) days. Overall clinical success rate was 80.5%, and was similar whether daptomycin was used as first-line (82.9%) or second-line (79.2%) therapy. Clinical success rates were high in patients with S. aureus (83.9%; MRSA 83.0%) and CoNS (including S. epidermidis, 82.5%) infections. The majority of patients with endocarditis or intracardiac/intravascular device infection (86.7%) or osteomyelitis/orthopedic device infection (85.9%) had a sustained response during the 2-year follow-up period. There were no new or unexpected safety findings. CONCLUSION: Results from real-world clinical experience showed that daptomycin is a valuable therapeutic option in the management of various difficult-to-treat Gram-positive infections. FUNDING: This study was funded by Novartis Pharma AG. PMID- 26108159 TI - Improved gene amplification by cell-cycle engineering combined with the Cre-loxP system in Chinese hamster ovary cells. AB - The dihydrofolate reductase gene amplification system is widely used in Chinese hamster ovary (CHO) cells for the industrial production of therapeutic proteins. To enhance the efficiency of conventional gene amplification systems, we previously presented a novel method using cell-cycle checkpoint engineering. Here, we constructed high-producing and stable cells by the conditional expression of mutant cell division cycle 25 homolog B (CDC25B) using the Cre-loxP system. A bispecific antibody-producing CHO DG44-derived cell line was transfected with floxed mutant CDC25B. After inducing gene amplification in the presence of 250 nM methotrexate, mutant CDC25B sequence was removed by Cre recombinase protein expression. Overexpression of the floxed mutant CDC25B significantly enhanced the efficiency of transgene amplification and productivity. Moreover, the specific production rate of the isolated clone CHO Cre-1 and Cre-2 were approximately 11-fold and 15-fold higher than that of mock transfected clone CHO Mock-S. Chromosomal aneuploidy was increased by mutant CDC25B overexpression, but Cre-1 and Cre-2 did not show any changes in chromosome number during long-term cultivation, as is the case with CHO Mock-S. Our results suggest that high-producing and stable cells can be constructed by conditionally controlling a cell-cycle checkpoint integrated in conventional gene amplification systems. PMID- 26108160 TI - Secretory expression of a phospholipase A2 from Lactobacillus casei DSM20011 in Kluyveromyces lactis. AB - The pla2 gene encoding a phospholipase A2 (EC 3.1.1.4) of Lactobacillus casei DSM20011 was cloned and expressed in the yeast Kluyveromyces lactis GG799 successfully for the first time. The structural pla2 gene fused in frame with the K. lactis secretion signal alpha-mating factor was integrated into the LAC4 locus and expressed under the control of the LAC4 promoter. sPLA2 activity was detected in the culture supernatant during shake flask culture of K. lactis/pKLAC1-pla2. In comparison with the control strain K. lactis/pKLAC1, SDS-PAGE analysis revealed a 17-kDa recombinant protein band in K. lactis/pKLAC1-pla2, which was consistent with the predicted molecular weight of the mature protein. Real-time quantitative PCR analysis indicated that the copy number of the integrated pla2 gene ranged from 2 to 6 and positively correlated with sPLA2 activity. When the inducer galactose was used as the carbon source, the sPLA2 activity in the culture supernatant of the recombinant that harbored six pla2 gene copies reached 1.96 +/- 0.15 U/mL. The influence of the culture composition and conditions on the recombinant sPLA2 activity in shake flask culture were also studied. When the recombinant was cultured at 30 degrees C in a YPD medium culture volume of 70 mL in a 250-mL shake flask with an initial pH of 7.0, the sPLA2 activity reached 2.16 +/- 0.18 U/mL. PMID- 26108161 TI - Direct infusion ESI-IT-MSn alkaloid profile and isolation of tetrahydroharman and other alkaloids from Bocageopsis pleiosperma maas (Annonaceae). AB - INTRODUCTION: The Annonaceae family is known as a promising abundant source of secondary metabolites, especially annonaceous acetogenins, terpenoids and isoquinoline-derived alkaloids. Although widely investigated from the phytochemical viewpoint, this family still presents some largely unexplored genera, e.g. the Bocageopsis. OBJECTIVE: To investigate the alkaloid content of Bocageopsis pleiosperma Maas using direct infusion electrospray ionisation ion trap tandem mass spectrometry (ESI-IT-MS(n)) analysis. METHODOLOGY: Dichloromethane extracts of aerial parts were subjected to acid-base partitioning to yield the alkaloidal fractions. These fractions were analysed by direct infusion into a (+)ESI-IT-MS(n) system. The alkaloidal fraction from the leaves was also obtained on a large scale and subjected to chromatographic separation. RESULTS: The tentative MS(n) -based identification of alkaloids in leaves, twigs and trunk bark showed that aporphine alkaloids were restricted to the leaves and twigs, tetrahydroprotoberberine alkaloids were only found in the twigs and trunk bark while benzylisoquinoline alkaloids were found in the leaves, twigs and trunk bark. Chromatographic separation of the leaf alkaloidal fraction yielded the aporphine alkaloids nornuciferine, asimilobine and isoboldine, the beta-carboline alkaloid tetrahydroharman and some mixtures containing benzylisoquinoline and aporphine alkaloids, all described for the first time in the Bocageopsis genus. Furthermore, tetrahydroharman has not previously been reported in the Magnoliales order. CONCLUSION: Direct infusion ESI-IT-MS(n) analysis of alkaloids allowed fast recognition of alkaloidal classes previously reported in the Annonaceae family, aiding the chromatographic step and allowing a selective isolation of compounds previously not identified in the Bocageopsis genus. PMID- 26108162 TI - Rheolityc thrombectomy in acute myocardial infarction: Effect on microvascular obstruction, infarct size, and left ventricular remodeling. AB - OBJECTIVES: We sought to analyze whether rheolytic thrombectomy (RT) in comparison with manual thrombus aspiration (MTA) may reduce microvascular obstruction (MVO), infarct size (IS), and left ventricular (LV) remodeling in ST elevation myocardial infarction (STEMI). BACKGROUND: Conflicting results have been reported as to whether MTA reduces MVO and IS. METHODS AND RESULTS: Eighty STEMI reperfused by primary angioplasty and abciximab were randomly allocated (1:1) to RT or MTA. Cardiac magnetic resonance imaging (MRI) was performed in 37 patients (19 RT) and after 1 year in 19 (9 RT); baseline, 1- and 6-month 2D-echo was performed in all patients. MVO and IS were measured 8 min after gadolinium injection with late enhancement sequences and were analyzed quantitatively at a core laboratory blinded to randomization. At baseline TIMI thrombus grade were similar (RT: 4.47 +/- 0.84 vs. MTA: 4.67 +/- 0.76, P = 0.453). After thrombectomy, thrombus grade decreased to 1.11 +/- 1.04 in RT vs. 2.17 +/- 1.29 in MTA arm (P = 0.009). RT compared with MTA did not reduced significantly myocardial IS [12.2% (6.4-22.1) vs. 19.0% (7-28.5), P = 0.224] as well as the extent of MVO [0.0% (0.0-0.17) vs. 0.6% (0.0-1.4), P = 0.117], but a trend toward a lower incidence of MVO (16% vs. 44%, P = 0.056) and a less LV remodeling rate were found in RT arm (11% vs. 24%, P < 0.140). CONCLUSION: RT in comparison with MTA was more effective in thrombus removal, but it did not reduced significantly the IS and the extent of MVO. However, a trend toward a lower incidence of MVO and a better preservation of LV volumes were found in RT arm. (c) 2015 Wiley Periodicals, Inc. PMID- 26108164 TI - A systematic review of the effect of piston diameter in stapes surgery for otosclerosis on hearing results. AB - OBJECTIVE: To evaluate the effect of piston diameter in primary stapedotomy for otosclerosis patients measured by hearing outcome. DATA SOURCES: PubMed, Embase, and the Cochrane Library. REVIEW METHODS: A systematic search was conducted. Studies reporting original data on the effect of piston diameter on pure-tone audiometric results in patients undergoing primary stapedotomy for otosclerosis were included. Relevance and risk of bias of the selected articles were assessed. Studies with low relevance, high risk of bias, or both were excluded. Absolute risks and risk differences, means and mean differences, and 95% confidence intervals were extracted. RESULTS: Twelve studies with moderate to high relevance and moderate risk of bias were included for data extraction. Air-bone gap closure to 10 dB or less was assessed in six studies, the majority of which did not show a statistically significant or clinically relevant difference between two pistons with a different diameter. More importantly, the differences that were found were not consistently in favor of smaller-diameter pistons or larger-diameter pistons. Mean postoperative air-bone gap ranged from 3 dB in favor of a smaller-diameter piston to 3 dB in favor of a larger-diameter piston across four studies. Permanent sensorineural hearing loss was assessed in eight studies and occurred in only one study. In this study, no difference was found between a 0.4-mm diameter piston and a 0.6-mm-diameter piston. CONCLUSION: There is not sufficient evidence to support the superiority of the use of a larger-diameter piston compared to a smaller-diameter piston for primary stapedotomy in otosclerosis patients. PMID- 26108163 TI - IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vgamma6(+)gammadelta T cells. AB - Interleukin-17 (IL-17)-producing gammadelta T (gammadelta17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4(+) and gammadelta17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4(+) T cells direct gammadelta T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vgamma6(+) subset of CCR2(+) gammadelta T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on gammadelta T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vgamma6(+) cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner. PMID- 26108165 TI - Interleaved multishot imaging by spatiotemporal encoding: A fast, self-referenced method for high-definition diffusion and functional MRI. AB - PURPOSE: Single-shot imaging by spatiotemporal encoding (SPEN) can provide higher immunity to artifacts than its echo planar imaging-based counterparts. Further improvements in resolution and signal-to-noise ratio could be made by rescinding the sequence's single-scan nature. To explore this option, an interleaved SPEN version was developed that was capable of delivering optimized images due to its use of a referenceless correction algorithm. METHODS: A characteristic element of SPEN encoding is the absence of aliasing when its signals are undersampled along the low-bandwidth dimension. This feature was exploited in this study to segment a SPEN experiment into a number of interleaved shots whose inaccuracies were automatically compared and corrected as part of a navigator-free image reconstruction analysis. This could account for normal phase noises, as well as for object motions during the signal collection. RESULTS: The ensuing interleaved SPEN method was applied to phantoms and human volunteers and delivered high quality images even in inhomogeneous or mobile environments. Submillimeter functional MRI activation maps confined to gray matter regions as well as submillimeter diffusion coefficient maps of human brains were obtained. CONCLUSION: We have developed an interleaved SPEN approach for the acquisition of high-definition images that promises a wider range of functional and diffusion MRI applications even in challenging environments. PMID- 26108167 TI - A cultural heuristic approach to the study of Jamaican undergraduate students' achievement motivation. AB - BACKGROUND: In recent years, there have been increasing calls to develop a more contextually based sociocultural perspective of achievement motivation. AIM: This mixed-methods study examined why Jamaican undergraduate students are motivated or unmotivated and how this relates to the extant literature on achievement motivation. SAMPLE(S): This study was conducted in two phases and consisted of 175 and 189 Jamaican undergraduate students across phases one and two, respectively. METHODS: First, a qualitative investigation using open-ended questionnaires and semi-structured interviews explored Jamaican undergraduate students' conceptualization of motivation and the factors that positively or negatively impacted their motivation. The second phase consisted of using prototype theory to capture a hierarchical cognitive representation of Jamaican students' motivation using coded themes derived from phase one of the study. RESULTS AND CONCLUSIONS: The overall results indicated that personal, cognitive, contextual, and sociocultural factors are important determinants of Jamaican undergraduate students' academic motivation and that sociocultural (e.g., familial, economic, religious) factors appear to play a more critical role in impacting their motivation. PMID- 26108166 TI - Phytotoxic Mechanism of Nanoparticles: Destruction of Chloroplasts and Vascular Bundles and Alteration of Nutrient Absorption. AB - This study focused on determining the phytotoxic mechanism of CeO2 nanoparticles (NPs): destroying chloroplasts and vascular bundles and altering absorption of nutrients on conventional and Bt-transgenic cottons. Experiments were designed with three concentrations of CeO2 NPs including: 0, 100 and 500 mg.L(-1), and each treatment was three replications. Results indicate that absorbed CeO2 nanoparticles significantly reduced the Zn, Mg, Fe, and P levels in xylem sap compared with the control group and decreased indole-3-acetic acid (IAA) and abscisic acid (ABA) concentrations in the roots of conventional cotton. Transmission electron microscopy (TEM) images revealed that CeO2 NPs were absorbed into the roots and subsequently transported to the stems and leaves of both conventional and Bt-transgenic cotton plants via xylem sap. In addition, the majority of aggregated CeO2 NPs were attached to the external surface of chloroplasts, which were swollen and ruptured, especially in Bt-transgenic cotton. The vascular bundles were destroyed by CeO2 nanoparticles, and more damage was observed in transgenic cotton than conventional cotton. PMID- 26108168 TI - Illness cognitions and family adjustment: psychometric properties of the Illness Cognition Questionnaire for parents of a child with cancer. AB - PURPOSE: Illness cognitions are an important mediator between disease and psychological adjustment. This study assessed the psychometric properties of the Illness Cognition Questionnaire (ICQ), adjusted for the parents of an ill child. METHODS: Participants were recruited from two multicenter studies: sample 1 included 128 parents of a child diagnosed with acute lymphoblastic leukemia (ALL) (response rate 82 %) and sample 2 included 114 parents of a child diagnosed with cancer (response rate 74 %). Parents completed an adapted version of the ICQ (Illness Cognition Questionnaire-Parent version (ICQ-P)), together with the Profile of Mood States (POMS; sample 1) or the Hospital Anxiety and Depression Scale (HADS; sample 2). The factor structure of the ICQ-P was examined by means of principal component analysis. Cronbach's alpha for each subscale and correlations between the ICQ-P scales and the HADS and POMS were calculated. The illness cognitions of parents with and without psychological distress were compared. RESULTS: Factor analysis confirmed the hypothesized structure of the ICQ-P in our sample (n = 242). The three scales Helplessness, Acceptance, and Perceived Benefits explained 9.8, 31.4, and 17.9 % of the variance, respectively. Cronbach's alpha showed adequate internal consistency (.80-.88). Concurrent and criterion-related validity were appropriate. CONCLUSIONS: The results confirm that the ICQ-P reliably assesses the illness cognitions of the parents of a child with cancer. Psychologically distressed parents showed less acceptance and more helplessness. The availability of a short and valid illness cognition questionnaire will help clinicians gain insight into parental cognitions regarding the illness of their child, information that might be helpful for targeting interventions. PMID- 26108169 TI - Defining optimal control of chemotherapy-induced nausea and vomiting-based on patients' experience. AB - PURPOSE: A considerable challenge when comparing antiemetic trials for chemotherapy-induced nausea and vomiting (CINV) is the large number of outcome measures for nausea and vomiting. The objective of this study is to determine the optimal definition of CINV control from the patients' perspective. METHODS: Patients with early-stage breast cancer who had received anthracycline cyclophosphamide-based chemotherapy were surveyed. They were asked about their experiences of CINV and perceptions of different CINV assessment tools. RESULTS: Of 201 patients approached, 168 (83 %) completed the survey. Patients consistently ranked nausea over vomiting as the "worst side effect from chemotherapy." Despite the use of multi-agent antiemetic regimens, 71 % of patients experienced nausea and 26 % vomiting. Only 57 % of patients with any nausea or vomiting took rescue medications and only then when the symptom was severe. Most (76 %) patients believed that the primary end point of antiemetic trials should include the absence of both nausea and vomiting. Patients felt that CINV should be evaluated for the overall period post chemotherapy (i.e., days 1 5) and not simply the acute (the first 24 h) or delayed (days 2-5) periods. CONCLUSIONS: Patients strongly favored a CINV end point that includes the absence of both nausea and vomiting. Patients' experience with CINV is underestimated when nausea is not included in composite end points. "Use of rescue medication," a commonly used surrogate for emesis control, is inappropriate as it underestimates nausea. A standardized primary end point that includes nausea is essential if CINV control is to be improved. PMID- 26108170 TI - Fear of cancer recurrence in colorectal cancer survivors. AB - PURPOSE: Although long-term colorectal cancer (CRC) survivors generally report a good quality of life, fear of cancer recurrence (FCR) remains an important issue. This study investigated whether the Cancer Worry Scale (CWS) can detect high FCR, the prevalence, and characteristics of FCR in CRC survivors. METHODS: Two hundred and eleven patients who had undergone successful CRC surgery in the period 2003 2010 in the Radboud University Medical Center in the Netherlands were asked to participate. All patients were sent an information letter plus questionnaires for collecting information on demographic and medical variables, FCR, distress, and quality of life. RESULTS: Seventy-six patients (36 %; median age of 67.7 years range 41-88 years) completed the questionnaires a median of 5.1 years after surgery. A cut-off score of 14 or higher on the CWS was optimal to detect high FCR. Twenty-nine patients (38 %) experienced high levels of FCR, characterized by higher levels of distress, post-traumatic stress symptoms, and lower quality of life. These individuals particularly reacted to disease-related triggers, felt helpless, were worried, and experienced limitations in daily functioning. High FCR was not associated with demographic or medical variables. CONCLUSION: Long after successful CRC surgery, FCR is a serious problem that impairs the quality of life for a substantial proportion of patients. With the CWS, it is possible to detect high FCR and thereby assist survivors in receiving appropriate care. PMID- 26108171 TI - After initial treatment for primary breast cancer: information needs, health literacy, and the role of health care workers. AB - PURPOSE: After a short hospital stay of just some days follows long-term outpatient care for breast cancer patients. The aim of the study is to describe the information needs of breast cancer outpatients and to get in touch with aspects of health literacy, as well as contact various health care workers. METHODS: In a multicenter study, patients were asked about their information needs 10 weeks after surgery. The analysis on hand includes data about 1248 female patients. In addition to descriptive analyses identifying the most prevalent information needs, logistic regression analyses were calculated to identify factors associated with these. RESULTS: The results show that information needs of breast cancer outpatients are mainly in "follow-up after acute treatment", "coping with long-term side effects", and "heredity of breast cancer". In addition to sociodemographic patient characteristics, perceived helpful contacts with various health care workers as well as a satisfactory patient's level of health literacy reduced the probability of unmet information needs. CONCLUSIONS: Breast cancer outpatients have numerous information needs. In addition to provide information at the right time regarding a specific disease phase, it is important that health professionals' support affected breast cancer patients in coping with the new situation. PMID- 26108172 TI - Drug fever after cancer chemotherapy is most commonly observed on posttreatment days 3 and 4. AB - BACKGROUND: This study was undertaken to analyze the characteristics of fever after cancer chemotherapy in order to reduce unnecessary medical care. METHODS: Retrospectively, 1016 consecutive cycles of cancer chemotherapy were analyzed. Fever was defined as a temperature of >= 37.5 degrees C lasting for 1 h. Age, sex, tumor histology, the treatment regimen, the timing of fever onset, the number of days for which the fever persisted, the cause of the fever, the presence or absence of radiotherapy, and the use of granulocyte colony stimulating factor (G-CSF) were examined. RESULTS: The patients included 748 males and 268 females (median age = 68, range = 29-88), of whom 949, 52, and 15 were suffering from lung cancer, malignant pleural mesothelioma, and other diseases, respectively. Fever was observed in 367 cycles (36 %), including 280 cycles (37 %) involving males and 87 cycles (32 %) involving females. Fever occurred most commonly in the first cycles and was higher than later cycles (41 vs. 30 %, p < 0.001). Fever occurred most frequently on posttreatment days 4 (8 %), 3 (7 %), and 12 (7 %), and the distribution of fever episodes exhibited two peaks on posttreatment days 3 and 4 and 10-14. Fever on posttreatment days 3 and 4 was most commonly observed in patients treated with gemcitabine (20 %) or docetaxel (18 %). The causes of fever included infection (47 %; including febrile neutropenia [24 %]), adverse drug effects (24 %), unknown causes (19 %), and tumors (7 %). Radiotherapy led to a significant increase in the frequency of fever (46 vs. 34 %, p < 0.001). Thirty-three percent of patients received G-CSF, and the incidence ratios of fever in patients who received G-CSF were higher than those who did not receive G-CSF (44 vs. 31 %, p < 0.001). CONCLUSION: The febrile episodes that occurred on posttreatment days 3 and 4 were considered to represent adverse drug reactions after cancer chemotherapy. Physicians should be aware of this feature of chemotherapy-associated fever and avoid unnecessary examination and treatments including prescribing antibiotics. PMID- 26108173 TI - Effect of egg freshness on texture and baking characteristics of batter systems formulated using egg, flour and sugar. AB - BACKGROUND: The aim of this work was to evaluate the effects of egg freshness on baking properties and final qualities in batter systems. Batters were made with eggs of different freshness, and the properties of batter systems were studied through rheological analysis, rapid viscosity analysis (RVA), differential scanning calorimetry (DSC), batter density and expansion rate during the baking and cooling processes. Moreover, the qualities of final baked systems were investigated, including specific volume and texture profile analysis (TPA). RESULTS: The flow behavior of batters showed that the consistency index (K) decreased as the Haugh unit (HU) value decreased, while the flow behavior index (n) increased. Both the storage modulus (G') and loss modulus (G") determined by mechanical spectra at 20 degrees C decreased with decreasing HU. RVA and DSC determinations revealed that lower-HU samples had a lower viscosity in the baking process and a shorter time for starch gelatinization and egg protein denaturation. Observation of the batter density revealed an increasing change, which was reflected by a decrease in the specific volume of final models. TPA showed significant differences in hardness and chewiness, but no significant differences in springiness and cohesiveness were found. CONCLUSION: The egg freshness affected the properties of batter systems. PMID- 26108175 TI - Reply to comments on Farr et al.: "Clinical experience with arthroscopically assisted repair of peripheral triangular fibrocartilage complex tears in adolescents-technique and results". PMID- 26108174 TI - IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection. AB - Initial events after exposure determine HIV-1 disease progression, underscoring a critical need to understand host mechanisms that interfere with initial viral replication. Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity. Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR 29) as an antiviral factor induced by IL-21 in CD4 T cells. IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling. Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression. Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo. PMID- 26108176 TI - Analysis of the autologous chondrocyte quality of matrix-based autologous chondrocyte implantation in the knee joint. AB - PURPOSE: Matrix based autologous chondrocyte implantation is an established method for treatment of full cartilage defects in the knee joint, but little is known about the influence of the implanted autologous chondrocyte quality and its clinical value. The aim of this study is to evaluate the influence of the gene expression of the implanted autologous chondrocytes on the clinical outcomes in the follow-up period of three years. METHODS: Biological parameters of the implanted chondrocytes were analysed histologically and immunohistologically. An analysis of the gene expression of the relevant chondrogenic dedifferentiation markers was performed as well. In order to detect the rate of apoptosis, we analysed specific apoptosis markers. To evaluate the clinical outcome, the International Knee Documentation Committee (IKDC) subjective score and the visual analogue scale (VAS) were used pre-operatively and after 0.5, one, two and three years. RESULTS: Significantly improved clinical scores were observed. The subjective IKDC score increased from 50.6 +/- 20.7 points to 69.3 +/- 26.1 points at three years (p = 0.001). The implanted chondrocytes showed a typical expression of the chondrogenic markers with a high rate of collagen type II expression without dedifferentiation. The analysed differentiation, dedifferentiation and apoptosis markers showed no influence on the clinical outcome. CONCLUSIONS: The implanted autologous chondrocytes have a high chondrogenic quality with a high rate of collagen type II expression without dedifferentiation. An influence of differentiation, de-differentiation and apoptosis marker gene expression on the clinical outcomes could not be found in a follow-up period of three years. LEVEL OF EVIDENCE: Case series; Level of evidence, 3. PMID- 26108178 TI - Erratum to: Revision surgery after third generation autologous chondrocyte implantation in the knee. PMID- 26108177 TI - Minimally invasive treatment of displaced femoral shaft fractures with a rapid reductor and intramedullary nail fixation. AB - PURPOSE: Traction table-based intrameduallary (IM) nail fixation is an accepted treatment method for displaced femoral shaft fractures in adults. However, some complications have been described. To avoid complications associated with the use of a traction table, a rapid reductor was invented. This study aims to assess the outcomes of displaced femoral shaft fractures treated by a novel minimally invasive technique that employs a rapid reductor to reduce fracture and facilitate IM nail fixation. METHODS: Between November 2012 and March 2013, 22 cases of displaced femoral shaft fractures were enrolled into this study. The patients included 13 males and nine females who were between 21 and 42 years old (average, 31.3 years). All the fractures were unilateral and comprised four cases of type 32-A, 13 cases of type 32-B, and five case of type 32-C according to AO/OTA classification of fracture. During the operation, the displaced femoral shaft fractures were firstly reduced by skeletal traction with the use of a rapid reductor, and the residual antero-posterior or lateral displacement were then corrected percutaneously by using a Kirschner wire or Schantz pin with a "joy stick" technique. The fracture reduction was maintained with the rapid reductor and an IM nail was inserted to fix the fracture. The operation time, reduction time, fluoroscopy time, and intra-operative blood loss were recorded. Follow-up was conducted to assess the healing of the fractures and the functional recovery of the injured limbs. RESULTS: Anatomical or nearly anatomical fracture reduction was achieved in all 22 cases and open reduction was not required in any case. The average operative time, fracture reduction time, fluoroscopy time and blood loss were 58 minutes (range, 43-95 minutes), 9.1 min (range, 6-15 minutes), 13.2 seconds (range, 4.5-41.0 seconds) and 87 mL (range, 60-150 mL), respectively. During the operation, no incident of reductor-induced neurovascular injury or Schantz pin-induced ilium splitting occurred. Twenty-two patients were followed up for an average of 20.3 months (range, 18-22 months). All fractures healed well on an average of six months. No limb length discrepancy was noted. CONCLUSIONS: The rapid reductor can be applied to effectively achieve and maintain the reduction of displaced femoral shaft fractures in a minimally invasive fashion, which is conducive for IM nailing fixation. The patients exhibited excellent functional recovery. PMID- 26108179 TI - Morphological specializations for fetal maintenance in viviparous vertebrates: An introduction and historical retrospective. AB - In many viviparous vertebrates, pregnant females sustain their developing embryos and provide them with nutrients by means of placentas and a diversity of other types of specializations. With this article, we introduce a virtual (online) issue of the Journal of Morphology that presents 12 recent papers on fetal maintenance in viviparous vertebrates. We also outline the history of research in this area and document the central role of morphology in helping to explain the function and evolution of specializations for fetal nutrition. This virtual issue of the Journal of Morphology is an outgrowth of a symposium held under auspices of the International Congress of Vertebrate Morphology. The included papers reflect a diversity of taxa, research methods, and biological issues. To celebrate the publication of this virtual issue of the Journal of Morphology, the publisher is making freely available to readers a number of other relevant papers published in the journal over the past 128 years. PMID- 26108180 TI - PLGA Nanoparticles Loaded Cerebrolysin: Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury. AB - Cerebrolysin is a peptide mixture able to ameliorate symptomatology and delay progression of neurological disorders such as Alzheimer's disease and dementia. The administration of this drug in humans presents several criticisms due to its short half-life, poor stability, and high doses needed to achieve the effect. This paper investigates the potential of polylactic-co-glycolide (PLGA) nanoparticles (NPs) as sustained release systems for iv administration of cerebrolysin in normal and brain injured rats. NPs were prepared by water-in-oil in-water (w/o/w) double emulsion technique and characterized by light scattering for mean size and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The NPs produced by double sonication under cooling at 60 W for 45 s, 12 mL of 1 % w:v of PVA, and 1:0.6 w:w drug/PLGA ratio (C-NPs4) displayed an adequate loading of drug (24 +/- 1 mg/100 mg of NPs), zeta potential value (-13 mV), and average diameters (ranged from 250 to 330 nm) suitable to iv administration. SEM images suggested that cerebrolysin was molecularly dispersed into matricial systems and partially adhered to the NP surface. A biphasic release with an initial burst effect followed by sustained release over 24 h was observed. Long-term stability both at room and at low temperature of freeze-dried NPs was investigated. To gain deeper insight into NP stability after in vivo administration, the stability of the best NP formulation was also tested in serum. These PLGA NPs loaded with cerebrolysin were able to reduce brain pathology following traumatic brain injury. However, the size, the polydispersivity, and the surface properties of sample were significantly affected by the incubation time and the serum concentration. PMID- 26108181 TI - Cardiac Arrest Alters Regional Ubiquitin Levels in Association with the Blood Brain Barrier Breakdown and Neuronal Damages in the Porcine Brain. AB - The possibility that ubiquitin expression is altered in cardiac arrest-associated neuropathology was examined in a porcine model using immunohistochemical and biochemical methods. Our observations show that cardiac arrest induces progressive increase in ubiquitin expression in the cortex and hippocampus in a selective and specific manner as compared to corresponding control brains using enzyme-linked immunoassay technique (enzyme-linked immunosorbent assay (ELISA)). Furthermore, immunohistochemical studies showed ubiquitin expression in the neurons exhibiting immunoreaction in the cytoplasm and karyoplasm of distorted or damaged cells. Separate Nissl and ubiquitin staining showed damaged and distorted neurons and in the same cortical region ubiquitin expression indicating that ubiquitin expression after cardiac arrest represents dying neurons. The finding that methylene blue treatment markedly induced neuroprotection following identical cardiac arrest and reduced ubiquitin expression strengthens this view. Taken together, our observations are the first to show that cardiac arrest enhanced ubiquitin expression in the brain that is related to the magnitude of neuronal injury and the finding that methylene blue reduced ubiquitin expression points to its role in cell damage, not reported earlier. PMID- 26108182 TI - Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder, resulting in dopaminergic (DA) neuronal loss in the substantia nigra pars compacta (SNpc) and damage to the extranigral spinal cord neurons. Current therapies do not prevent the disease progression. Hence, developing efficacious therapeutic strategies for treatment of PD is of utmost importance. The goal of this study is to delineate the involvement of calpain-mediated inflammation and neurodegeneration in SN and spinal cord in MPTP-induced parkinsonian mice (C57BL/6 N), thereby elucidating potential therapeutic target(s). Increased calpain expression was found localized to tyrosine hydroxylase (TH(+)) neurons in SN with significantly increased TUNEL-positive neurons in SN and spinal cord neurons in MPTP mice. Inflammatory markers Cox-2, caspase-1, and NOS-2 were significantly upregulated in MPTP mouse spinal cord as compared to control. These parameters correlated with the activation of astrocytes, microglia, infiltration of CD4(+)/CD8(+) T cells, and macrophages. We found that subpopulations of CD4(+) cells (Th1 and Tregs) were differentially expanded in MPTP mice, which could be regulated by inhibition of calpain with the potent inhibitor calpeptin. Pretreatment with calpeptin (25 MUg/kg, i.p.) attenuated glial activation, T cell infiltration, nigral dopaminergic degeneration in SN, and neuronal death in spinal cord. Importantly, calpeptin ameliorated MPTP-induced altered gait parameters (e.g., reduced stride length and increased stride frequency) as demonstrated by analyses of spatiotemporal gait indices using ventral plane videography. These findings suggest that calpain plays a pivotal role in MPTP induced nigral and extranigral neurodegenerative processes and may be a valid therapeutic target in PD. PMID- 26108184 TI - NF-kappaB Upregulates Type 5 Phosphodiesterase in N9 Microglial Cells: Inhibition by Sildenafil and Yonkenafil. AB - Our previous studies showed that the phosphodiesterase-5 (PDE5) inhibitor sildenafil inhibited the microglial activation induced by lipopolysaccharide (LPS). However, whether yonkenafil, a novel PDE5 inhibitor, also inhibits microglial activation and the underlying mechanism of inhibition remain elusive. Here we found that yonkenafil significantly suppressed the production of NO, interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) and the protein expression of inducible NO synthase (iNOS) induced by LPS in microglial cells in a concentration-dependent manner. Knockdown of PDE5 inhibits NO and iNOS protein expression in LPS-stimulated N9 microglia. Moreover, we observed that the nuclear factor-kappaB (NF-kappaB) transcriptionally upregulated PDE5 expression, which was inhibited by sildenafil and yonkenafil in LPS-stimulated N9 microglia. Therefore, sildenafil and yonkenafil may exert their inhibitory effects on microglial activation by reducing the expression of PDE5. Furthermore, sildenafil and yonkenafil increased the cyclic guanosine monophosphate (cGMP) level in N9 microglia, and 8-Br-cGMP, an analogue of cGMP, downregulates extracellular signal regulated kinases 1 and 2 (ERK1/2)/the NF-kappaB pathway, suggesting that sildenafil and yonkenafil inhibit microglial activation by decreasing PDE5 expression and increasing the cGMP level. Importantly, sildenafil and yonkenafil significantly alleviated the death of SH-SY5Y neuroblastoma cells and primary cortical neurons induced by the conditioned medium from activated microglia. Together, these findings position PDE5 as a potential therapy target for the treatment of neuroinflammation accompanied by microglial activation. PMID- 26108183 TI - Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced beta-Endorphin Release. AB - Activation of cannabinoid receptor-2 (CB2) results in beta-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gbetagamma subunits from Gi/o, but not Galphas, were involved in CB2 receptor activation-induced beta endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced beta-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca(2+). Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced beta-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced beta-endorphin release through Gi/o-Gbetagamma-MAPK-Ca(2+) signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists. PMID- 26108185 TI - PPAR-gamma Ameliorates Neuronal Apoptosis and Ischemic Brain Injury via Suppressing NF-kappaB-Driven p22phox Transcription. AB - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a stress-induced transcription factor, protects neurons against ischemic stroke insult by reducing oxidative stress. NADPH oxidase (NOX) activation, a major driving force in ROS generation in the setting of reoxygenation/reperfusion, constitutes an important pathogenetic mechanism of ischemic brain damage. In the present study, both transient in vitro oxygen-glucose deprivation and in vivo middle cerebral artery (MCA) occlusion-reperfusion experimental paradigms of ischemic neuronal death were used to investigate the interaction between PPAR-gamma and NOX. With pharmacological (PPAR-gamma antagonist GW9662), loss-of-function (PPAR-gamma siRNA), and gain-of-function (Ad-PPAR-gamma) approaches, we first demonstrated that 15-deoxy-?(12,14)-PGJ2 (15d-PGJ2), via selectively attenuating p22phox expression, inhibited NOX activation and the subsequent ROS generation and neuronal death in a PPAR-gamma-dependent manner. Secondly, results of promoter analyses and subcellular localization studies further revealed that PPAR-gamma, via inhibiting hypoxia-induced NF-kappaB nuclear translocation, indirectly suppressed NF-kappaB-driven p22phox transcription. Noteworthily, postischemic p22phox siRNA treatment not only reduced infarct volumes but also improved functional outcome. In summary, we report a novel transrepression mechanism involving PPAR-gamma downregulation of p22phox expression to suppress the subsequent NOX activation, ischemic neuronal death, and brain infarct. Identification of a PPAR-gamma -> NF-kappaB -> p22phox neuroprotective signaling cascade opens a new avenue for protecting the brain against ischemic insult. PMID- 26108187 TI - Accelerated corpus callosum development in prematurity predicts improved outcome. AB - OBJECTIVES: To determine: (1) whether corpus callosum (CC) size and microstructure at 7 years of age or their change from infancy to 7 years differed between very preterm (VP) and full-term (FT) children; (2) perinatal predictors of CC size and microstructure at 7 years; and (3) associations between CC measures at 7 years or trajectories from infancy to 7 years and neurodevelopmental outcomes. EXPERIMENTAL DESIGN: One hundred and thirty-six VP (gestational age [GA] <30 weeks and/or birth weight <1,250 g) and 33 FT children had usable magnetic resonance images at 7 years of age, and of these, 76 VP and 16 FT infants had usable data at term equivalent age. The CC was traced and divided into six sub-regions. Fractional anisotropy, mean, axial, radial diffusivity and volume were measured from tractography. Perinatal data were collected, and neurodevelopmental tests administered at 7 years' corrected age. PRINCIPAL OBSERVATIONS: VP children had smaller posterior CC regions, higher diffusivity and lower fractional anisotropy compared with FT 7-year-olds. Reduction in diffusivity over time occurred faster in VP than FT children (P <= 0.002). Perinatal brain abnormality and earlier GA were associated with CC abnormalities. Microstructural abnormalities at 7 years or slower development of the CC were associated with motor dysfunction, poorer mathematics and visual perception. CONCLUSIONS: This study is the first to demonstrate an accelerated trajectory of CC white matter diffusion following VP birth, associated with improved neurodevelopmental functioning. Findings suggest there is a window of opportunity for neurorestorative intervention to improve outcomes. Hum Brain Mapp 36:3733-3748, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26108188 TI - O-GlcNAcylation of the human epidermal growth factor receptor. AB - The reversible O-linked attachment of single beta-D-N-acetylglucosamine (GlcNAc) moieties to serine/threonine residues in target proteins is a frequently occurring post-translational modification affecting the functionality of many cellular systems. In this report we present experimental evidence suggesting that the epidermal growth factor receptor (EGFR) is subjected to O-GlcNAcylation in human carcinoma epidermoid A431 cells and human lung carcinoma A549 cells. However, no signal was detected in human cervix adenocarcinoma HeLa cells or in mouse EGFR-T17 fibroblasts ectopically expressing the human EGFR. We detected a positive O-GlcNAcylation signal in the immunoprecipitated EGFR by Western blotting using two distinct specific anti-O-GlcNAc antibodies even after N deglycosylation of the receptor using peptide-N-glycosidase F (PNGase F). Conversely, the presence of EGFR was detected by Western blotting using an anti EGFR antibody in the immunocomplex of O-GlcNAcylated proteins immunoprecipitated with an anti-O-GlcNAc antibody. These signals were enhanced when the O-linked beta-N-acetylglucosaminidase (OGA) inhibitor Thiamet G was added to prevent the deglycosylation of the GlcNAc moiety(ies). Moreover, we also detected a positive signal in the immunoprecipitated and N-deglycosylated EGFR using PNGase F, and tunicamycin when the cells were metabolically labeled with azido-GlcNAc (GlcNAz), biotinylated and probed with a streptavidin-labeled peroxidase. Finally, EGFR and O-linked beta-N-acetylglucosamine transferase (OGT) co-immunoprecipitate, and incubation of the immunoprecipitated EGFR with the immunoprecipitated OGT in the presence of uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc) resulted in a significant enhancement of the EGFR O-GlcNAcylation signal as detected by Western blotting using an anti-O-GlcNAc antibody. We conclude that the human EGFR is subjected to O-GlcNAcylation in the A431 and A549 tumor cell lines. PMID- 26108186 TI - The Role of Nitric Oxide and Sympathetic Control in Cerebral Autoregulation in the Setting of Subarachnoid Hemorrhage and Traumatic Brain Injury. AB - Cerebral autoregulation is defined as the mechanism by which constant cerebral blood flow is maintained despite changes of arterial blood pressure, and arterial blood pressure represents the principle aspect of cerebral autoregulation. The impairment of cerebral autoregulation is reported to be involved in several diseases. However, the concept, mechanisms, and pathological dysfunction of cerebral autoregulation are beyond full comprehension. Nitric oxide control and sympathetic control are main contributors to cerebral autoregulation. Although impaired cerebral autoregulation after nitric oxide inhibition or sympathetic ganglia blockade is reported, managing the inhibition or blockade can have negative consequences and needs further exploration. Additionally, impaired cerebral autoregulation following subarachnoid hemorrhage and traumatic brain injury has been proven by several descriptive studies, although without corresponding explanations. As the most important mechanisms of cerebral autoregulation, the changes of nitric oxide and sympathetic stimulation play significant roles in these insults. Therefore, the in-depth researches of nitric oxide and sympathetic nerve in cerebral autoregulation may help to develop new therapeutic targets. PMID- 26108189 TI - Determining Pathways to Improvements in Fatigue in Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. AB - OBJECTIVE: There is debate as to the role of inflammatory disease activity in the etiology of rheumatoid arthritis (RA)-related fatigue. We undertook this study to determine the relationship of fatigue to disease activity by examining pathways associated with change in fatigue in subjects starting anti-tumor necrosis factor (anti-TNF) therapy for the first time. METHODS: Participants who had been recruited to the British Society for Rheumatology Biologics Register for RA provided information on fatigue (Short Form 36 [SF-36] vitality scale) and other health status variables at the start of anti-TNF therapy and 6 months later. The Disease Activity Score in 28 joints (DAS28) and inflammation (erythrocyte sedimentation rate [ESR]/C-reactive protein [CRP] level) were also reported. A path analysis model comprising changes in fatigue, pain, disease activity, disability, and mental health, along with effects of sex and a history of depression, was used to examine those with high levels of fatigue at baseline (score of <=12.5 units on the SF-36 vitality scale). The DAS28 was substituted for ESR/CRP to delineate the specific role of inflammation. RESULTS: With a total of 2,652 participants, we identified a well-fitting model (chi2 = 0.18, P = 0.98) accounting for 40% of the variance in fatigue change. There was no direct pathway from change in inflammation to change in fatigue; instead, significant pathways to change in fatigue were observed from changes in disease activity, pain, mental health, and disability, along with effects of sex and a history of depression. A total of 82% of the effect of change in disease activity was indirect, of which ~50% was mediated through a change in pain. CONCLUSION: Improvements in fatigue do not appear to be driven by inflammatory disease activity; instead, they appear to result indirectly from improvements in pain. Additional significant pathways through disability and mental health suggest potentially modifiable factors that could be targeted to improve clinically important levels of fatigue. PMID- 26108190 TI - Observational study of intravenous lacosamide in patients with convulsive versus non-convulsive status epilepticus. AB - BACKGROUND AND OBJECTIVES: Status epilepticus (SE) is an important emergency situation associated with high morbidity and mortality. The goal of pharmacological therapy-rapid seizure termination-is only achieved in just over half of patients with first-line anti-epileptic drug (AED) therapy and many patients require second and higher lines of AEDs to achieve seizure termination; therefore, there is a clear need for more effective treatment options. Lacosamide is a relatively new AED and the intravenous formulation has shown promise for treatment of SE. The aim of the current study was to compare electroencephalographic (EEG) response and seizure termination with intravenous lacosamide (+/-other AEDs) in patients with convulsive versus non-convulsive SE, in a Spanish intensive care setting. METHODS: In this prospective, observational study, patients with convulsive or non-convulsive SE who received intravenous lacosamide 400 mg/day for 8 days were compared in terms of EEG response and seizure termination. Adverse events were not specifically assessed. RESULTS: Fifty-three patients (69.8 % male; mean age 55.2 years) were treated with lacosamide (mean dose 390.6 mg) as first- (20.8 %), second- (34 %), third (22.6 %) or fourth-line (22.6 %) treatment for convulsive (n = 23, 43.4 %) or non convulsive (n = 30, 56.6 %) SE. The majority of patients (73.6 %) had a comorbid condition, predominantly hypertension (35.8 %), and most (79.2 %) received at least one concomitant AED, including midazolam (54.7 %), valproic acid (52.8 %), and levetiracetam (30.2 %). Patient characteristics and treatment received did not differ significantly between the convulsive and non-convulsive SE groups. EEG recordings following lacosamide treatment demonstrated the elimination of paroxysmal activity (disappearance and/or attenuation of epileptiform activity in >60 % of recording time) in 56.6 % of patients; 69.6 % of convulsive and 46.7 % of non-convulsive SE groups. Among all patients, 90.6 % showed some EEG improvement (disappearance of epileptiform activity in <30 % total recording time or disappearance and/or attenuation of epileptiform activity in 30-60 % total recording time); and there was no significant between-group difference for achievement of seizure termination (90.0 vs. 91.3 % for non-convulsive vs. convulsive SE). CONCLUSIONS: Intravenous lacosamide (+/-other AEDs) was similarly effective in patients with convulsive or non-convulsive SE. Further investigation into the use of lacosamide in the treatment of SE is warranted. PMID- 26108191 TI - Universal Approach to FRAP Analysis of Arbitrary Bleaching Patterns. AB - The original approach to calculating diffusion coefficients of a fluorescent probe from Fluorescence Recovery After Photobleaching (FRAP) measurements assumes bleaching with a circular laser beam of a Gaussian intensity profile. This method was used without imaging the bleached cell. An empirical equation for calculating diffusion coefficients from a rectangular bleaching geometry, created in a confocal image, was later published, however a single method allowing the calculation of diffusion coefficients for arbitrary geometry does not exist. Our simulation approach allows computation of diffusion coefficients regardless of bleaching geometry used in the FRAP experiment. It accepts a multiple-frame TIFF file, representing the experiment as input, and simulates the (pure) diffusion of the fluorescent probes (2D random walk) starting with the first post-bleach frame of the actual data. It then fits the simulated data to the real data and extracts the diffusion coefficient. We validate our approach using a well characterized diffusing molecule (DiIC18) against well-established analytical procedures. We show that the algorithm is able to calculate the absolute value of diffusion coefficients for arbitrary bleaching geometries, including exaggeratedly large ones. It is provided freely as an ImageJ plugin, and should facilitate quantitative FRAP measurements for users equipped with standard fluorescence microscopy setups. PMID- 26108192 TI - Cross-sectional study on socio-demographic and clinical correlates of depression among human immunodeficiency virus-positive patients in Surat City, Western India. AB - INTRODUCTION: Surat has the highest incidence of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) in Gujarat, the main reason being its large migrant population. Mental health in HIV/AIDS has most often been a topic of neglect all over the world. This study attempts to assess the magnitude of depression and the socio-demographic and clinical variables associated with it in HIV-positive patients. METHODS: A cross-sectional study was conducted in 270 HIV-positive patients using Beck Depression Inventory (BDI; translated and validated in Gujarati and Hindi) along with a questionnaire for eliciting information on socio-demographic and clinical variables. RESULTS: The prevalence of depression among HIV-positive patients was 30% with 12.22% having mild depression; 14.07% with moderate depression and 3.7% with severe depression. Bivariate analysis showed that physical pain, physical illness, Cluster of Differentiation 4 (CD4)<300 cells/mm3, HIV positive spouse, discrimination at hospital, discrimination in society, government setup as the first place of HIV test and broken relationship with spouse after HIV disclosure were significantly associated with depression among the patients. On multiple logistic regression, discrimination at hospital, physical pain and CD4<300 cells/mm3 were found to be the significant predictors of depression among the patients. DISCUSSION: HIV positive patients can be screened by counselors using easy-to-administer scales like BDI, which can be translated and validated into any regional language. A trained psychiatrist should be appointed at the Anti-Retroviral Therapy (ART) center to take care of the mental health issues of the patients. PMID- 26108193 TI - Distribution of toxin genes among different spa types and phage types of animal Staphylococcus aureus. AB - We analyzed distribution of toxin genes (sea-seo, eta, etb, tst, lukS/lukF-PV) among spa types and phage types of 39 Staphylococcus aureus (S. aureus) isolates from healthy and diseased animals. All isolates turned out to be mecA negative (MSSA). Nine spa types were identified: t144 and t723 (dogs), t084 (dogs and pigs), t5447 (cat), t1491 and t008 (pigs), t002, t127 and t3478 (poultry). Seven phage types were detected, enclosed within four phage groups: I (cat), II (dogs), III (pigs) and mixed group (dogs and pigs). Three poultry spa types proved to be non-typeable by phages. Toxin genes were detected in 33 out of the 39 animal isolates. Our analysis revealed that the incidence of some toxin genes in S. aureus is host specific. Canine isolates t144 of phage group II harbored exfoliative toxin gene (eta), and porcine isolates type t1491 representing phage group III showed enterotoxin A gene (sea). The enterotoxin gene cluster (egc1) and enterotoxin gene seh were found in non-typeable isolates from chicken and in one feline isolate type t5447. PMID- 26108194 TI - Rhodium(III)-catalyzed cyanation of vinylic C-H bonds: N-cyano-N-phenyl-p toluenesulfonamide as a cyanation reagent. AB - Rh(III)-catalyzed direct vinylic C-H cyanation reaction has been developed as a practical method for the synthesis of alkenyl nitriles. N-Cyano-N-phenyl-p methylbenzenesulfonamide (NCTS), a user-friendly cyanation reagent, was used in the transformation. Both acrylamides and ketoximes can be employed in the new C-H cyanation process. PMID- 26108196 TI - Oral Abstracts of the ISPD 19th International Conference on Prenatal Diagnosis and Therapy, Washington, DC, USA, 12-15 July 2015. PMID- 26108195 TI - Evaluating the bone regeneration in calvarial defect using osteoblasts differentiated from adipose-derived mesenchymal stem cells on three different scaffolds: an animal study. AB - The aim of this study was to investigate the effect of three different scaffolds on the viability and differentiation of adipose-derived mesenchymal stem cells (ADMSCs) to osteoblast for bone regeneration of calvarial defect in rabbit model. Adipose was harvested from the nape of 12 rabbits by direct surgery or hollow-tip cannula. Two standardized circular calvarial defects (case and control), 8 mm in diameter each, were created in all the animals. The animals were divided into 3 different groups. In group 1 (G1), the defect was filled with polyamide + ADMSC. In group 2, poly lactic-co-glycolic acid + ADMSC was used. In group 3, decellularized amniotic membrane + ADMSC was applied. In the control defect, the non-seeded scaffolds were applied for filling the defect. Decellularized pericardial scaffolds were used as a membrane on the scaffolds. The animals were euthanized 2, 4, and 8 weeks of operation and new bone formation was assessed by different analyses. Immunohistochemical (IHC) staining with osteopontin and osteocalcin antibodies was also performed. After 2 weeks of wound healing, minimal bone regeneration was detected in all groups. Almost complete defect closure was observed in all experimental groups after 8 weeks of operation, with the greatest defect closure in the animals treated with polyamide scaffolds as compared to biopsies obtained from control defects and other experimental groups. The maximal tensile load was higher in G1, 4 and 8 weeks postoperatively, suggesting the usefulness of polyamide + ADMSC for bone regeneration in calvarial defects. Results of the IHC staining demonstrated a significant difference between seeded and non-seeded scaffold in both short- and long-term follow-ups (P < 0.05). In addition, a significant difference was observed in enhancement of IHC staining of both markers in polyamide group (seeded or non-seeded) 4 and 8 weeks postoperatively in comparison with other scaffolds. It was concluded that bone regeneration in critical calvarial defect was more successful in seeded polyamide. PMID- 26108197 TI - Poster Abstracts of the ISPD 19th International Conference on Prenatal Diagnosis and Therapy, Washington, DC, USA, 12-15 July 2015. PMID- 26108199 TI - Novel helical assembly of a Pt(II) phenylbipyridine complex directed by metal metal interaction and aggregation-induced circularly polarized emission. AB - Pt(ii) phenylbipyridine complexes possessing bis(phenylisoxazolyl)phenylacetylene ligands self-assembled to form stacked aggregates via Pt-Pt, pi-pi stacking, and dipole-dipole interactions. The assembled structures were influenced by the solvent properties. Non-helical assemblies found in chloroform displayed metal metal-to-ligand charge transfer absorption and emission, whereas helical assemblies formed in toluene showed aggregation-induced enhancement of emission and aggregation-induced circularly polarized luminescence. The rates of the association and dissociation of the assemblies were significantly reduced in toluene, and the non-helical structures formed in chloroform were surprisingly memorized. PMID- 26108198 TI - The unsolved chapter of vocal fold scars and how tissue engineering could help us solve the problem. AB - Vocal fold scarring is a relatively small field in scar research with prerequisites found nowhere else. The deterioration of the delicate tri-layered micro-structure of the epithelium of the vocal folds leads to impaired vibration characteristics resulting in a permanent hoarse and breathy voice. Tissue engineering approaches could help to restore the pre-injury status. Despite a considerable progress in this field during the last years, routine clinical applications are not available so far. One reason might be that vocal fold fibroblasts, as the responsible cell type for fibrogenesis, have very particular properties that are only poorly characterized. Moreover, in vivo trials are costly and time consuming and a representative in vitro model does not exist so far. These particular circumstances lead to innovative in vitro strategies and concepts such as macro-molecular crowding that can also be applied in adjacent fields. PMID- 26108200 TI - c-Met identifies a population of matrix metalloproteinase 9-producing monocytes in peritumoural stroma of hepatocellular carcinoma. AB - Macrophages (Mphi) are prominent components of solid tumours and exhibit distinct phenotypes in different microenvironments. Previously, we found that tumours could alter the normal developmental process of Mphi to trigger transient activation of monocytes in the peritumoural stroma of human hepatocellular carcinoma (HCC). In the present study, we showed that a fraction of monocytes in the peritumoural stroma, but not in HCC cancer nests, expressed surface c-Met molecules. Monocytes exposed to tumours strongly expressed c-Met proteins with kinetics similar to their activation status, and significant correlations were found between c-Met levels and HLA-DR expression on tumour-infiltrating monocytes. NF-kappaB-mediated autocrine TNF-alpha stimulated the expression of c Met on activated monocytes, and by interacting with its ligand hepatocyte growth factor (HGF), c-Met increased the motility and matrix metalloproteinase (MMP) 9 producing capacity of tumour-associated monocytes. The intensity of c-Met expression on tumour-infiltrating monocytes was associated with high mortality and reduced survival of patients with HCC. Therefore, the expression of c-Met on activated monocytes/Mphi may represent a novel mechanism by which a tumour actively and precisely regulates the distribution and functions of these cells to facilitate disease progression. PMID- 26108201 TI - Impact of high (131)I-activities on quantitative (124)I-PET. AB - Peri-therapeutic (124)I-PET/CT is of interest as guidance for radioiodine therapy. Unfortunately, image quality is complicated by dead time effects and increased random coincidence rates from high (131)I-activities. A series of phantom experiments with clinically relevant (124)I/(131)I-activities were performed on a clinical PET/CT-system. Noise equivalent count rate (NECR) curves and quantitation accuracy were determined from repeated scans performed over several weeks on a decaying NEMA NU-2 1994 cylinder phantom initially filled with 25 MBq (124)I and 1250 MBq (131)I. Six spherical inserts with diameters 10-37 mm were filled with (124)I (0.45 MBq ml(-1)) and (131)I (22 MBq ml(-1)) and placed inside the background of the NEMA/IEC torso phantom. Contrast recovery, background variability and the accuracy of scatter and attenuation corrections were assessed at sphere-to-background activity ratios of 20, 10 and 5. Results were compared to pure (124)I-acquisitions. The quality of (124)I-PET images in the presence of high (131)I-activities was good and image quantification unaffected except at very high count rates. Quantitation accuracy and contrast recovery were uninfluenced at (131)I-activities below 1000 MBq, whereas image noise was slightly increased. The NECR peaked at 550 MBq of (131)I, where it was 2.8 times lower than without (131)I in the phantom. Quantitative peri-therapeutic (124)I-PET is feasible. PMID- 26108202 TI - Shining trinkets and unkempt gardens: on the materiality of care. AB - The increasing use of telecare will profoundly change nursing care. How to understand these changes is, however, far from clear. This is because (i) studies on telecare seldom consider the situation it replaces, and (ii) current concepts and methods used to study the impact of telecare may not allow us to fully grasp these changes. We suggest that an analysis of the changing materiality of care practices is a suitable way to articulate and reflect on possible concerns. It allows us to compare care practices in the same terms before and after telecare has been introduced. To demonstrate this, we study the materiality of the classical care setting, the nursing house call, to map the situation before telecare is introduced. Building on science and technology studies, we apply four categories as heuristics to analyse materiality in care: signs, dis/enablers (or scripted things), tools and practical arrangements. We leave open the question of how material arrangements could or should be matters of concern in nursing care, and instead argue for studies that give insights into the everyday tinkering with the materiality of care that both nurses and patients need to engage in. PMID- 26108203 TI - Neural Tissue Motion Impacts Cerebrospinal Fluid Dynamics at the Cervical Medullary Junction: A Patient-Specific Moving-Boundary Computational Model. AB - Central nervous system (CNS) tissue motion of the brain occurs over 30 million cardiac cycles per year due to intracranial pressure differences caused by the pulsatile blood flow and cerebrospinal fluid (CSF) motion within the intracranial space. This motion has been found to be elevated in type 1 Chiari malformation. The impact of CNS tissue motion on CSF dynamics was assessed using a moving boundary computational fluid dynamics (CFD) model of the cervical-medullary junction (CMJ). The cerebellar tonsils and spinal cord were modeled as rigid surfaces moving in the caudocranial direction over the cardiac cycle. The CFD boundary conditions were based on in vivo MR imaging of a 35-year old female Chiari malformation patient with ~150-300 um motion of the cerebellar tonsils and spinal cord, respectively. Results showed that tissue motion increased CSF pressure dissociation across the CMJ and peak velocities up to 120 and 60%, respectively. Alterations in CSF dynamics were most pronounced near the CMJ and during peak tonsillar velocity. These results show a small CNS tissue motion at the CMJ can alter CSF dynamics for a portion of the cardiac cycle and demonstrate the utility of CFD modeling coupled with MR imaging to help understand CSF dynamics. PMID- 26108204 TI - A Non-invasive Real-time Localization System for Enhanced Efficacy in Nasogastric Intubation. AB - Nasogastric (NG) intubation is one of the most commonly performed clinical procedures. Real-time localization and tracking of the NG tube passage at the larynx region into the esophagus is crucial for safety, but is lacking in current practice. In this paper, we present the design, analysis and evaluation of a non invasive real-time localization system using passive magnetic tracking techniques to improve efficacy of the clinical NG intubation process. By embedding a small permanent magnet at the insertion tip of the NG tube, a wearable system containing embedded sensors around the neck can determine the absolute position of the NG tube inside the body in real-time to assist in insertion. In order to validate the feasibility of the proposed system in detecting erroneous tube placement, typical reference intubation trajectories are first analyzed using anatomically correct models and localization accuracy of the system are evaluated using a precise robotic platform. It is found that the root-mean-squared tracking accuracy is within 5.3 mm for both the esophagus and trachea intubation pathways. Experiments were also designed and performed to demonstrate that the system is capable of tracking the NG tube accurately in biological environments even in presence of stationary ferromagnetic objects (such as clinical instruments). With minimal physical modification to the NG tube and clinical process, this system allows accurate and efficient localization and confirmation of correct NG tube placement without supplemental radiographic methods which is considered the current clinical standard. PMID- 26108205 TI - Surgical treatment of renal carcinoma with atrial tumor thrombus avoiding cardiopulmonary bypass: step-by-step description. AB - Tumor thrombus in the inferior vena cava (IVC) occurs in 4-10% of patients with renal cell carcinoma (RCC) and poses a challenge for the surgical team. Because there is no systemic therapy available to significantly reduce tumor burden, surgical intervention is the only treatment. However, the surgical approach is associated with significant morbidity and mortality. When the thrombus extends above the diaphragm, the use of cardiopulmonary bypass (CPB) and accompanying deep hypothermic circulatory arrest (DHCA) has usually been advocated. However, complications inherent to CPB and DHCA, such as coagulopathy and central nervous system complications, have led us to search for an alternative surgical approach to these tumors. The purpose of this study is to describe the surgical technique used in five patients with large RCC with tumor thrombus extending into the supradiaphragmatic IVC and Right atrium (RA), Right atrium, who underwent extensive resection without CPB and DHCA. PMID- 26108207 TI - Protocol for a randomised controlled trial of an outreach support program for family carers of older people discharged from hospital. AB - BACKGROUND: Presentations to hospital of older people receiving family care at home incur substantial costs for patients, families, and the health care system, yet there can be positive carer outcomes when systematically assessing/addressing their support needs, and reductions in older people's returns to hospital attributed to appropriate discharge planning. This study will trial the Further Enabling Care at Home program, a 2-week telephone outreach initiative for family carers of older people returning home from hospital. Hypotheses are that the program will (a) better prepare families to sustain their caregiving role and (b) reduce patients' re-presentations/readmissions to hospital, and/or their length of stay; also that reduced health system costs attributable to the program will outweigh costs of its implementation. METHODS/DESIGN: In this randomised controlled trial, family carers of older patients aged 70+ discharged from a Medical Assessment Unit in a Western Australian tertiary hospital, plus the patients themselves, will be recruited at discharge (N = 180 dyads). Carers will be randomly assigned (block allocation, assessors blinded) to receive usual care (control) or the new program (intervention). The primary outcome is the carer's self-reported preparedness for caregiving (Preparedness for Caregiving Scale administered within 4 days of discharge, 2-3 weeks post-discharge, 6 weeks post discharge). To detect a clinically meaningful change of two points with 80 % power, 126 carers need to complete the study. Patients' returns to hospital and subsequent length of stay will be ascertained for a minimum of 3 months after the index admission. Regression analyses will be used to determine differences in carer and patient outcomes over time associated with the group (intervention or control). Data will be analysed using an Intention to Treat approach. A qualitative exploration will examine patients' and their family carers' experiences of the new program (interviews) and explore the hospital staff's perceptions (focus groups). Process evaluation will identify barriers to, and facilitators of, program implementation. A comprehensive economic evaluation will determine cost consequences. DISCUSSION: This study investigates a novel approach to identifying and addressing family carers' needs following discharge from hospital of the older person receiving care. If successful, the program has potential to be incorporated into routine post-discharge support. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12614001174673 . PMID- 26108208 TI - Sampling circulating tumor cells for clinical benefits: how frequent? AB - Circulating tumor cells (CTCs) are cells shed from tumors or metastatic sites and are a potential biomarker for cancer diagnosis, management, and prognostication. The majority of current studies use single or infrequent CTC sampling points. This strategy assumes that changes in CTC number, as well as phenotypic and molecular characteristics, are gradual with time. In reality, little is known today about the actual kinetics of CTC dissemination and phenotypic and molecular changes in the blood of cancer patients. Herein, we show, using clinical case studies and hypothetical simulation models, how sub-optimal CTC sampling may result in misleading observations with clinical consequences, by missing out on significant CTC spikes that occur in between sampling times. Initial studies using highly frequent CTC sampling are necessary to understand the dynamics of CTC dissemination and phenotypic and molecular changes in the blood of cancer patients. Such an improved understanding will enable an optimal, study-specific sampling frequency to be assigned to individual research studies and clinical trials and better inform practical clinical decisions on cancer management strategies for patient benefits. PMID- 26108210 TI - Effects of rhodiola crenulata on mice hearts under severe sleep apnea. AB - BACKGROUND: The goal of this study is to determine if Rhodiola Crenulata (RC) has protective effects on mice hearts with severe sleep apnea model. METHODS: Sixty four C57BL/6 J mice 5-6 months old were distributed into 4 groups i.e. Control group (21% O2, 24 h per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60 s, 20% O2 alternating 60 s, 8 h per day, 8 weeks, n=16); Hypoxia+90RC and Hypoxia+270RC group (Hypoxia for 1st 4 weeks and hypoxia pretreated 90 mg/Kg and 270 mg/Kg Rhodiola Crenulata by oral gavage per day for 2nd 4 weeks, each n=16). Excised hearts from 4 groups of mice were analyzed for heart weight index changes using H&E staining, TUNEL-positive assays and Western Blotting protein. RESULTS: Cardiac widely dispersed TUNEL-positive apoptotic cells in mice hearts were less in Hypoxia+RC90 and Hypoxia+RC270 than those in Hypoxia. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas dependent apoptotic pathways) were decreased in Hypoxia+RC90, Hypoxia+RC270. The protein levels of Bad, Bax, t-Bid, activated caspase 9, activated caspase 3 (mitochondria dependent apoptotic pathway) were less in Hypoxia+RC90, Hypoxia+RC270 than those in hypoxia. The protein levels of Bcl2, Bcl-xL, p-Bad (Bcl2-realted anti apoptotic pathway) and VEGF, p-PI3k, p-AKT (VEGF-related pro-survival pathway) were higher in Hypoxia+RC90, Hypoxia+RC270 than those in hypoxia. CONCLUSIONS: Our findings suggest that Rhodiola Crenulata have protective effects on chronic intermittent hypoxia-induced cardiac widely dispersed apoptosis via Fas-dependent and mitochondria-dependent apoptotic and VEGF-related pro-survival pathway. PMID- 26108211 TI - Molecular analyses on host-seeking black flies (Diptera: Simuliidae) reveal a diverse assemblage of Leucocytozoon (Apicomplexa: Haemospororida) parasites in an alpine ecosystem. AB - BACKGROUND: Molecular studies have suggested that the true diversity of Leucocytozoon (Apicomplexa: Haemospororida) species well exceeds the approximately 35 currently described taxa. Further, the degree of host specificity may vary substantially among lineages. Parasite distribution can be influenced by the ability of the parasite to infect a host, vector preferences for certain avian hosts, or other factors such as microhabitat requirements that increase the probability that vertebrate hosts and vectors are in frequent contact with each other. Whereas most studies of haemosporidians have focused on passerine hosts, sampling vectors in the same habitats may allow the detection of other lineages affecting other hosts. METHODS: We sampled abundant, ornithophilic black flies (Simuliidae) across a variety of sites and habitats in the Colorado Rocky Mountains throughout the summer of 2007. Black flies were screened with PCR using Leucocytozoon-specific primers that amplify a portion of the cytochrome b gene, and the sequences were compared to the haplotypes in the MalAvi database. Infections of Leucocytozoon from birds sampled in the same area were also included. RESULTS: We recovered 33 unique haplotypes from the black flies in this study area, which represented a large phylogenetic diversity of Leucocytozoon parasites. However, there were no clear patterns of avian host species or geography for the distribution of Leucocytozoon haplotypes in the phylogeny. CONCLUSIONS: Sampling host-seeking vectors is a useful way to obtain a wide variety of avian haemosporidian haplotypes from a given area and may prove useful for understanding the global patterns of host, parasite, and vector associations of these ubiquitous and diverse parasites. PMID- 26108212 TI - Non-Dipping Pattern and Subclinical Cardiac Damage in Untreated Hypertension: A Systematic Review and Meta-Analysis of Echocardiographic Studies. AB - AIM: The association of non-dipping (ND) pattern with cardiac damage is debated. We performed a meta-analysis in order to provide comprehensive information on subclinical cardiac alterations in untreated ND hypertensives. DESIGN: A computerized search was performed using PubMed, OVID, EMBASE, and Cochrane library databases from 1 January 1990 up to 31 October 2014. Full articles published in English language providing data on subclinical cardiac damage in ND as compared to dipper (D) hypertensives, as assessed by echocardiography, were considered. RESULTS: A total of 3,591 untreated adult subjects (1,291 ND and 2,300 D hypertensives) included in 23 studies were considered. Left ventricular (LV) mass index (LVMI) was higher in ND than in D hypertensives (122+/-3.8 g/m2 vs. 111+/-3.3 g/m2, standardized mean difference, SMD: 0.40+/-0.07, confidence interval (CI): 0.26-0.53, P < 0.001); relative wall thickness (RWT) and left atrium (LA) diameter were greater (SMD: 0.14+/-0.005, CI: 0.05-0.23, P = 0.002; 0.36+/-0.10, CI: 0.16-0.56, P < 0.001, respectively), while mitral E/A ratio was lower in ND than in D counterparts (SMD: -0.23+/-0.08, CI: -0.39 to -0.08, P = 0.003). After assessing data for publication bias, the difference between groups was still significant, with the exception of E/A ratio. CONCLUSIONS: Our meta analysis supports an association between ND pattern and increased risk of LV structural alterations in untreated essential hypertensives. This observation supports the view that an effective BP control throughout the entire 24-hour cycle may have a key role in preventing or regressing subclinical cardiac damage associated to ND pattern. PMID- 26108213 TI - In Delft: a personal account. AB - The author looks back on his development in microbiology and yeast research, and on the establishment in Delft of the FEMS Central Office, FEMS Publications Office and the birth of FEMS Yeast Research. PMID- 26108214 TI - Solving the mystery of health inequality. PMID- 26108215 TI - Implications of the concept of minimal risk in research on informed choice in clinical practice. AB - The concept of a minimal risk threshold in research, beneath which exception to informed consent and ethics review processes may occur, has been codified for over 30 years in many national research regulations and by the Council for International Organizations of Medical Sciences. Although minimal risk in research constitutes one of the criteria for allowing waiver of informed consent or modification to the consent process and a large body of literature exists, discussion of a minimal risk threshold in clinical practice has not occurred. One reason for lack of discussion may be that implicit consent is accepted for a wide range of routine clinical practices. Extending the role of minimal risk in research to clinical practice might assist clinicians in identifying circumstances for which implicit consent is indeed sufficient and circumstances in which it is not. Further, concepts from minimal risk in research might assist clinicians regarding when information provision in health promotion is required. We begin by reviewing concepts in both minimal risk in research and informed choice in clinical practice. We then explore how a clinical minimal risk concept may clarify recommendations for information provision in clinical practice and support the patient's informed choice regarding therapeutic and diagnostic procedures and also health promotion. Given that clinical practice involves a broad scope of health information, professional practice guidelines on information provision based on the application of the minimal risk threshold in research could be developed to guide clinicians in what information must be provided to their patients. PMID- 26108216 TI - Does postoperative blood pressure influence development of aortic regurgitation following continuous-flow left ventricular assist device implantation??. AB - OBJECTIVES: The true impact of postoperative blood pressure (BP) control on development of aortic regurgitation (AR) following continuous-flow left ventricular assist device (CF-LVAD) implantation remains uncertain. This study examines the influence of BP in patients with de novo AR following CF-LVAD implantation. METHODS: All patients with no or =3months (n = 90) were studied. Serial echocardiograms and BP readings were obtained preoperatively, postoperatively at 1, 3 and 6 months, and then at a minimum of 4-monthly intervals. BP readings were compared between patients who developed mild AR (AR group) versus those who did not (non-AR group). Logistic regression analysis was used to define independent predictors of >=mild AR following CF-LVAD implantation. RESULTS: Median duration of CF-LVAD support was 575 days (range: 98-2433 days). Forty-eight patients (53.3%) developed mild AR over a median duration of 126 days. BP readings (median values, mmHg) between AR and non-AR groups showed statistically significant differences: at 3 months-systolic 99.5 vs 92.5 (P = 0.038), diastolic 81.5 vs 66 (P < 0.001), mean 86.5 vs 74 (P < 0.001) and at 6 months-diastolic 73 vs 62 (P = 0.044), mean 83 vs 74.5 (P = 0.049), respectively. Systolic BP at 3 months (P = 0.047, 95% CI 0.453-0.994, OR 0.671), aortic valve (AoV) closure (P = 0.01, 95% CI 0.002-0.429, OR 0.029) and duration of support (P = 0.04, 95% CI 1.000-1.009, OR 1.004) were found to be independent predictors of AR following CF-LVAD implantation. CONCLUSIONS: BP readings at 3 months and 6 months showed a statistically significant association with >=mild AR following CF-LVAD implantation, with systolic blood pressure at 3 months, aortic valve closure and longer support duration being independent predictors. Clinical implications of these data may warrant consideration of aggressive early control of BP to protect against the development/progress of AR following CF-LVAD implantation. PMID- 26108217 TI - Prescrire: France's Choosing Wisely initiative. PMID- 26108218 TI - Module-based construction of plasmids for chromosomal integration of the fission yeast Schizosaccharomyces pombe. AB - Integration of an external gene into a fission yeast chromosome is useful to investigate the effect of the gene product. An easy way to knock-in a gene construct is use of an integration plasmid, which can be targeted and inserted to a chromosome through homologous recombination. Despite the advantage of integration, construction of integration plasmids is energy- and time-consuming, because there is no systematic library of integration plasmids with various promoters, fluorescent protein tags, terminators and selection markers; therefore, researchers are often forced to make appropriate ones through multiple rounds of cloning procedures. Here, we establish materials and methods to easily construct integration plasmids. We introduce a convenient cloning system based on Golden Gate DNA shuffling, which enables the connection of multiple DNA fragments at once: any kind of promoters and terminators, the gene of interest, in combination with any fluorescent protein tag genes and any selection markers. Each of those DNA fragments, called a 'module', can be tandemly ligated in the order we desire in a single reaction, which yields a circular plasmid in a one step manner. The resulting plasmids can be integrated through standard methods for transformation. Thus, these materials and methods help easy construction of knock-in strains, and this will further increase the value of fission yeast as a model organism. PMID- 26108220 TI - Youth Preferences for Roll-Your-Own Versus Factory-Made Cigarettes: Trends and Associations in Repeated National Surveys (2006-2013) and Implications for Policy. AB - INTRODUCTION: We investigated trends in roll-your-own (RYO) and factory-made (FM) cigarette use over time among youth in New Zealand (NZ), a high RYO use country. We also explored factors associated with RYO use. METHODS: We analyzed data from an annual survey of NZ students (14-15 years old) from 2006-2013. Smokers were asked whether they usually smoked RYO or FM cigarettes, and provided details of their source of supply. We estimated prevalences and developed a binary logistic regression model to explore determinants of RYO use. RESULTS: Between 6663 (2006) and 3143 (2013) current smokers responded. Each year, around 80% reported usually smoking RYO or FM cigarettes. The proportion reporting usual RYO use was 45% (95% confidence interval [CI] +/-3%) in 2006, reducing to 40% (95% CI +/-3%) in 2013 (trend test: P < .001). By contrast, the proportions reporting usual FM use increased slightly over time from 36% (95% CI +/-3%) in 2006 to 38% (95% CI +/ 3%) in 2013 (trend test: P < .001). Usual RYO use was more common amongst regular smokers, those who initiated smoking younger, who belonged to low or medium socioeconomic status groups, and whose friends and family both smoked. CONCLUSIONS: RYO use is very high among NZ youth who smoke. Preference for RYO cigarettes amongst longer-term, regular smokers suggests RYO tobacco supports and maintains youth smoking. There was some initial evidence that a 2010 differential tax increase on RYO tobacco was associated with a shift away from usual RYO use amongst those who sourced tobacco from caregivers or friends. Additional measures such as further differential excise tax increases appear warranted. PMID- 26108219 TI - LMO2 at 25 years: a paradigm of chromosomal translocation proteins. AB - LMO2 was first discovered through proximity to frequently occurring chromosomal translocations in T cell acute lymphoblastic leukaemia (T-ALL). Subsequent studies on its role in tumours and in normal settings have highlighted LMO2 as an archetypical chromosomal translocation oncogene, activated by association with antigen receptor gene loci and a paradigm for translocation gene activation in T ALL. The normal function of LMO2 in haematopoietic cell fate and angiogenesis suggests it is a master gene regulator exerting a dysfunctional control on differentiation following chromosomal translocations. Its importance in T cell neoplasia has been further emphasized by the recurrent findings of interstitial deletions of chromosome 11 near LMO2 and of LMO2 as a target of retroviral insertion gene activation during gene therapy trials for X chromosome-linked severe combined immuno-deficiency syndrome, both types of event leading to similar T cell leukaemia. The discovery of LMO2 in some B cell neoplasias and in some epithelial cancers suggests a more ubiquitous function as an oncogenic protein, and that the current development of novel inhibitors will be of great value in future cancer treatment. Further, the role of LMO2 in angiogenesis and in haematopoietic stem cells (HSCs) bodes well for targeting LMO2 in angiogenic disorders and in generating autologous induced HSCs for application in various clinical indications. PMID- 26108221 TI - Expression and Dendritic Trafficking of BDNF-6 Splice Variant are Impaired in Knock-In Mice Carrying Human BDNF Val66Met Polymorphism. AB - BACKGROUND: The human Val66Met polymorphism in brain-derived neurotrophic factor (BDNF), a key factor in neuroplasticity, synaptic function, and cognition, has been implicated in the pathophysiology of neuropsychiatric and neurodegenerative disorders. BDNF is encoded by multiple transcripts with distinct regulation and localization, but the impact of the Val66Met polymorphism on BDNF regulation remains unclear. METHODS: In BDNF Val66Met knock-in mice, which recapitulate the phenotypic hallmarks of individuals carrying the BDNF(Met) allele, we measured expression levels, epigenetic changes at promoters, and dendritic trafficking of distinct BDNF transcripts using quantitative PCR, chromatin immunoprecipitation (ChIP), and in situ hybridization. RESULTS: BDNF-4 and BDNF-6 transcripts were reduced in BDNF(Met/Met) mice, compared with BDNF(Val/Val) mice. ChIP for acetyl histone H3, a marker of active gene transcription, and trimethyl-histone-H3-Lys27 (H3K27me3), a marker of gene repression, showed higher H3K27me3 binding to exon 5, 6, and 8 promoters in BDNF(Met/Met). The H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) is involved in epigenetic regulation of BDNF expression, because in neuroblastoma cells BDNF expression was increased both by short interference RNA for EZH2 and incubation with 3-deazaneplanocin A, an inhibitor of EZH2. In situ hybridization for BDNF-2, BDNF-4, and BDNF-6 after pilocarpine treatment showed that BDNF-6 transcript was virtually absent from distal dendrites of the CA1 and CA3 regions in BDNF(Met/Met) mice, while no changes were found for BDNF-2 and BDNF-4. CONCLUSIONS: Impaired BDNF expression and dendritic targeting in BDNF(Met/Met) mice may contribute to reduced regulated secretion of BDNF at synapses, and may be a specific correlate of pathology in individuals carrying the Met allele. PMID- 26108222 TI - Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans. AB - BACKGROUND: The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice. METHODS: We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 MUg) in 8 male and 8 female healthy subjects. RESULTS: Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean+/-SD: 4.5+/-1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6+/-0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9+/-5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. CONCLUSIONS: These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide. PMID- 26108223 TI - Structural insights into the substrate specificity of two esterases from the thermophilic Rhizomucor miehei. AB - Two hormone-sensitive lipase (HSL) family esterases (RmEstA and RmEstB) from the thermophilic fungus Rhizomucor miehei, exhibiting distinct substrate specificity, have been recently reported to show great potential in industrial applications. In this study, the crystal structures of RmEstA and RmEstB were determined at 2.15 A and 2.43 A resolutions, respectively. The structures of RmEstA and RmEstB showed two distinctive domains, a catalytic domain and a cap domain, with the classical alpha/beta-hydrolase fold. Catalytic triads consisting of residues Ser161, Asp262, and His292 in RmEstA, and Ser164, Asp261, and His291 in RmEstB were found in the respective canonical positions. Structural comparison of RmEstA and RmEstB revealed that their distinct substrate specificity might be attributed to their different substrate-binding pockets. The aromatic amino acids Phe222 and Trp92, located in the center of the substrate-binding pocket of RmEstB, blocked this pocket, thus narrowing its catalytic range for substrates (C2-C8). Two mutants (F222A and W92F in RmEstB) showing higher catalytic activity toward long chain substrates further confirmed the hypothesized interference. This is the first report of HSL family esterase structures from filamentous fungi. The information on structure-function relationships could open important avenues of exploration for further industrial applications of esterases. PMID- 26108224 TI - Site-1 protease-activated formation of lysosomal targeting motifs is independent of the lipogenic transcription control. AB - Site-1 protease (S1P) cleaves membrane-bound lipogenic sterol regulatory element binding proteins (SREBPs) and the alpha/beta-subunit precursor protein of the N acetylglucosamine-1-phosphotransferase forming mannose 6-phosphate (M6P) targeting markers on lysosomal enzymes. The translocation of SREBPs from the endoplasmic reticulum (ER) to the Golgi-resident S1P depends on the intracellular sterol content, but it is unknown whether the ER exit of the alpha/beta-subunit precursor is regulated. Here, we investigated the effect of cholesterol depletion (atorvastatin treatment) and elevation (LDL overload) on ER-Golgi transport, S1P mediated cleavage of the alpha/beta-subunit precursor, and the subsequent targeting of lysosomal enzymes along the biosynthetic and endocytic pathway to lysosomes. The data showed that the proteolytic cleavage of the alpha/beta subunit precursor into mature and enzymatically active subunits does not depend on the cholesterol content. In either treatment, lysosomal enzymes are normally decorated with M6P residues, allowing the proper sorting to lysosomes. In addition, we found that, in fibroblasts of mucolipidosis type II mice and Niemann Pick type C patients characterized by aberrant cholesterol accumulation, the proteolytic cleavage of the alpha/beta-subunit precursor was not impaired. We conclude that S1P substrate-dependent regulatory mechanisms for lipid synthesis and biogenesis of lysosomes are different. PMID- 26108226 TI - Paclitaxel-sensitization enhanced by curcumin involves down-regulation of nuclear factor-kappaB and Lin28 in Hep3B cells. AB - Although paclitaxel is an effective chemotherapeutic drug used in the treatment of many tumors, hepatoma cells, in particular, are known to be highly resistant to it. Previously, we discovered that Lin28 was closely associated with resistance to paclitaxel in Hep3B cells. The nuclear factor-kappa B (NF-kappaB) transcription factor, which plays an important role in tumor survival, directly activates Lin28 expression through a binding site on the first intron. Curcumin, a non-toxic anti-inflammatory agent, inhibits NF-kappaB activity in vitro. In this study, we reported that a combination of curcumin and paclitaxel exhibited synergistic anti-proliferative and pro-apoptosis effects on Hep3B cells, and curcumin down-regulated paclitaxel-induced enhanced expression of Lin28 and NF kappaB activation. Furthermore, our results revealed that curcumin reduced Lin28 levels via mechanisms directly mediated by inhibition of NF-kappaB activity. These mechanism-based observations evidence that curcumin enhances the sensitivity of hepatoma cells to paclitaxe, and strongly support the notion that paclitaxel in combination with curcumin may provide a superior therapeutic index for HCC chemotherapy. PMID- 26108225 TI - A compendium of expression patterns of cholesterol biosynthetic enzymes in the mouse embryo. AB - Cholesterol and its biosynthetic pathway intermediates and derivatives are required for many developmental processes including membrane biogenesis, transmembrane receptor signaling, steroid biogenesis, nuclear receptor activation, and posttranslational modification of hedgehog (Hh) proteins. To perform such multifaceted tasks depends on stringent regulation of expression of cholesterol biosynthetic enzymes (CBEs). We established for a whole organism, for the first time, the 3D expression pattern of all genes required for cholesterol biosynthesis (CBS), starting from acetyl-CoA and ending with cholesterol. This data was produced by high-throughput in situ hybridization on serial sections through the mouse fetus. The textually annotated image data were seamlessly integrated into the METscout and GenePaint public databases. This novel information helps in the understanding of why CBEs are expressed at particular locations within the fetus. For example, strong CBE expression is detected at sites of cell proliferation and also where cell growth increases membrane surface, such as in neurons sprouting axons and forming synapses. The CBE data also sheds light on the spatial relationship of cells and tissue that express sonic Hh (Shh) and produce cholesterol, respectively. We discovered that not all cells expressing Shh are capable of CBS. This finding suggests novel ways by which cholesterylation of Shh is regulated. PMID- 26108227 TI - Spontaneous lactogenesis and galactopoeisis in a virgin dairy heifer with evidence of a granulosa theca cell tumour. PMID- 26108228 TI - Systems biological approaches to the cardiac signaling network. AB - Recent systems biological studies of cardiac systems have greatly advanced our understanding of cardiac physiology with a particular focus on the excitation contraction coupling. With these advancements, there is a growing interest in systems analysis of the cardiac signaling network because its dynamical property is closely associated with cardiac diseases. In this article, we review recent attempts at computational modeling of the cardiac signaling network and provide a system-level perspective on the analysis of the large-scale cardiac signaling network. We discuss why the systems biological approach is useful and what novel insights it can provide for the development of personalized therapeutic strategies for cardiac diseases in the post-genomic era. PMID- 26108229 TI - Systematically evaluating interfaces for RNA-seq analysis from a life scientist perspective. AB - RNA-sequencing (RNA-seq) has become an established way for measuring gene expression in model organisms and humans. While methods development for refining the corresponding data processing and analysis pipeline is ongoing, protocols for typical steps have been proposed and are widely used. Several user interfaces have been developed for making such analysis steps accessible to life scientists without extensive knowledge of command line tools. We performed a systematic search and evaluation of such interfaces to investigate to what extent these can indeed facilitate RNA-seq data analysis. We found a total of 29 open source interfaces, and six of the more widely used interfaces were evaluated in detail. Central criteria for evaluation were ease of configuration, documentation, usability, computational demand and reporting. No interface scored best in all of these criteria, indicating that the final choice will depend on the specific perspective of users and the corresponding weighting of criteria. Considerable technical hurdles had to be overcome in our evaluation. For many users, this will diminish potential benefits compared with command line tools, leaving room for future improvement of interfaces. PMID- 26108230 TI - Statistical detection of differentially expressed genes based on RNA-seq: from biological to phylogenetic replicates. AB - RNA-seq has been an increasingly popular high-throughput platform to identify differentially expressed (DE) genes, which is much more reproducible and accurate than the previous microarray technology. Yet, a number of statistical issues remain to be resolved in data analysis, largely due to the high-throughput data volume and over-dispersion of read counts. These problems become more challenging for those biologists who use RNA-seq to measure genome-wide expression profiles in different combinations of sampling resources (species or genotypes) or treatments. In this paper, the author first reviews the statistical methods available for detecting DE genes, which have implemented negative binomial (NB) models and/or quasi-likelihood (QL) approaches to account for the over-dispersion problem in RNA-seq samples. The author then studies how to carry out the DE test in the context of phylogeny, i.e., RNA-seq samples are from a range of species as phylogenetic replicates. The author proposes a computational framework to solve this phylo-DE problem: While an NB model is used to account for data over dispersion within biological replicates, over-dispersion among phylogenetic replicates is taken into account by QL, plus some special treatments for phylogenetic bias. This work helps to design cost-effective RNA-seq experiments in the field of biodiversity or phenotype plasticity that may involve hundreds of species under a phylogenetic framework. PMID- 26108232 TI - The collapsed cone algorithm for (192)Ir dosimetry using phantom-size adaptive multiple-scatter point kernels. AB - The aim of this work was to investigate how dose distributions calculated with the collapsed cone (CC) algorithm depend on the size of the water phantom used in deriving the point kernel for multiple scatter. A research version of the CC algorithm equipped with a set of selectable point kernels for multiple-scatter dose that had initially been derived in water phantoms of various dimensions was used. The new point kernels were generated using EGSnrc in spherical water phantoms of radii 5 cm, 7.5 cm, 10 cm, 15 cm, 20 cm, 30 cm and 50 cm. Dose distributions derived with CC in water phantoms of different dimensions and in a CT-based clinical breast geometry were compared to Monte Carlo (MC) simulations using the Geant4-based brachytherapy specific MC code Algebra. Agreement with MC within 1% was obtained when the dimensions of the phantom used to derive the multiple-scatter kernel were similar to those of the calculation phantom. Doses are overestimated at phantom edges when kernels are derived in larger phantoms and underestimated when derived in smaller phantoms (by around 2% to 7% depending on distance from source and phantom dimensions). CC agrees well with MC in the high dose region of a breast implant and is superior to TG43 in determining skin doses for all multiple-scatter point kernel sizes. Increased agreement between CC and MC is achieved when the point kernel is comparable to breast dimensions. The investigated approximation in multiple scatter dose depends on the choice of point kernel in relation to phantom size and yields a significant fraction of the total dose only at distances of several centimeters from a source/implant which correspond to volumes of low doses. The current implementation of the CC algorithm utilizes a point kernel derived in a comparatively large (radius 20 cm) water phantom. A fixed point kernel leads to predictable behaviour of the algorithm with the worst case being a source/implant located well within a patient/phantom for which low doses at phantom edges can be overestimated by 2-5 %. It would be possible to improve the situation by using a point kernel for multiple-scatter dose adapted to the patient/phantom dimensions at hand. PMID- 26108231 TI - A roadmap to multifactor dimensionality reduction methods. AB - Complex diseases are defined to be determined by multiple genetic and environmental factors alone as well as in interactions. To analyze interactions in genetic data, many statistical methods have been suggested, with most of them relying on statistical regression models. Given the known limitations of classical methods, approaches from the machine-learning community have also become attractive. From this latter family, a fast-growing collection of methods emerged that are based on the Multifactor Dimensionality Reduction (MDR) approach. Since its first introduction, MDR has enjoyed great popularity in applications and has been extended and modified multiple times. Based on a literature search, we here provide a systematic and comprehensive overview of these suggested methods. The methods are described in detail, and the availability of implementations is listed. Most recent approaches offer to deal with large-scale data sets and rare variants, which is why we expect these methods to even gain in popularity. PMID- 26108235 TI - A bundled-stack discotic columnar liquid crystalline phase with inter-stack electronic coupling. AB - The first compound capable of forming a bundled-stack discotic columnar liquid crystalline (BSDCLC) phase was designed and synthesized. The unique perylene anhydride inter-stack interaction was found to be the key to the formation of the BSDCLC structure and inter-stack electronic coupling (ISEC). PMID- 26108234 TI - A potent and selective C-11 labeled PET tracer for imaging sphingosine-1 phosphate receptor 2 in the CNS demonstrates sexually dimorphic expression. AB - Sphingosine-1-phosphate receptor 2 (S1PR2) plays an essential role in regulating blood-brain barrier (BBB) function during demyelinating central nervous system (CNS) disease. Increased expression of S1PR2 occurs in disease-susceptible CNS regions of female versus male SJL mice and in female multiple sclerosis (MS) patients. Here we reported a novel sensitive and noninvasive method to quantitatively assess S1PR2 expression using a C-11 labeled positron emission tomography (PET) radioligand [(11)C]5a for in vivo imaging of S1PR2. Compound 5a exhibited promising binding potency with IC50 value of 9.52 +/- 0.70 nM for S1PR2 and high selectivity over S1PR1 and S1PR3 (both IC50 > 1000 nM). [(11)C]5a was synthesized in ~40 min with radiochemistry yield of 20 +/- 5% (decayed to the end of bombardment (EOB), n > 10), specific activity of 222-370 GBq MUmol(-1) (decayed to EOB). The biodistribution study in female SJL mice showed the cerebellar uptake of radioactivity at 30 min of post-injection of [(11)C]5a was increased by Cyclosporin A (CsA) pretreatment (from 0.84 +/- 0.04 ID% per g to 2.21 +/- 0.21 ID% per g, n = 4, p < 0.01). MicroPET data revealed that naive female SJL mice exhibited higher cerebellar uptake compared with males following CsA pretreatment (standardized uptake values (SUV) 0.58 +/- 0.16 vs. 0.48 +/- 0.12 at 30 min of post-injection, n = 4, p < 0.05), which was consistent with the autoradiographic results. This data suggested that [(11)C]5a had the capability in assessing the sexual dimorphism of S1PR2 expression in the cerebellum of the SJL mice. The development of radioligands for S1PR2 to identify a clinical suitable S1PR2 PET radiotracer, may greatly contribute to investigating sex differences in S1PR2 expression that contribute to MS subtype and disease progression and it will be very useful for detecting MS in early state and differentiating MS with other patients with neuroinflammatory diseases, and monitoring the efficacy of treating diseases using S1PR2 antagonism. PMID- 26108236 TI - Dosimetric verification of stereotactic body radiation therapy for lung cancer treatment plans using flattening filter-free beams. AB - AIMS: This study aimed to analyze the dose distribution using different dosimetric tools in conducting pretreatment quality assurance for lung cancer stereotactic body radiation therapy (SBRT) plans with flattening filter free (FFF) beams. METHODS: Nine patients with lung cancer treated via SBRT were randomly selected, and their treatment plans were generated using the Eclipse treatment planning system (TPS) with FFF beams. For each patient, the same plan was applied to the Delta4 phantom and MatriXX by the TPS, which calculated the dose distribution. The Delta4 and MatriXX phantoms were then used to measure the actual dose distribution at the linear accelerator, and these measured doses were compared to with the calculated doses. Gamma analysis was employed in verifying the correspondence between the dose distributions. The absolute point doses were measured by a 0.016 mL Microchamber with the RW3 phantom and Thorax phantom. RESULTS: The absolute point doses measured by the 0.016 mL Microchamber were within +/-3% of the calculated results for the central point of the RW3 and Thorax phantoms. The Delta4 and MatriXX dose distributions agreed well with the measured and calculated doses, over 98%, based on the 3% maximum dose and 3 mm gamma criteria. CONCLUSIONS: Both measured and calculated doses for the Delta4 and MatriXX phantoms agreed well for each patient with lung cancer. The absolute point dose measurements using the 0.016 mL Microchamber exhibited excellent agreement with the TPS calculated between the RW3 and Thorax phantoms. PMID- 26108237 TI - Reirradiation in head and neck recurrent or second primary tumor: efficacy, safety, and prognostic factors. AB - AIMS AND BACKGROUND: We investigated efficacy, safety, and prognostic factors of reirradiation in patients with recurrent or second primary head and neck cancer. METHODS: Records of 75 consecutive patients treated with reirradiation between August 2005 and December 2013 were reviewed. RESULTS: Median overall survival (OS) and cancer-specific survival (CSS) were 29.5 and 33.6 months. Median local control (LC) and progression-free survival (PFS) were 21.7 and 16.2 months. Univariate analysis showed that patients younger than 70 years, with a Karnofsky Performance Status (KPS) >90 or with 2 or less comorbidities at time of reirradiation, have a better OS; KPS >90 and biological equivalent dose (BED) >72 Gy positively influenced the PFS. At multivariate analysis, KPS at reirradiation was an independent predictive factor for OS, while BED was an independent predictive factor for CSS and OS. At univariate analysis, patients with planning target volume (PTV) >221 mL had worse LC and PFS rates, with results confirmed at multivariate analysis. The rate of fatal treatment-related adverse events was 6.7% (3 carotid blowout, 1 soft tissue necrosis, and 1 thromboembolic event). CONCLUSIONS: This study confirms the role and outcomes of reirradiation. A careful selection of patients could minimize acute and late side effects and influence survival: elderly patients, with significant medical comorbidities or poor KPS, are worse candidate for reirradiation. Total dose delivered with reirradiation and PTV appear to be other potential prognostic factors. Further studies of dose escalation are needed to establish the total dose that could achieve better LC rates with a safer toxicity profile. PMID- 26108238 TI - Cytology smears as diagnostic material for EGFR gene testing in non-small cell lung cancer. AB - AIMS AND BACKGROUND: Cytology smears can be effectively used for EGFR mutation testing in the qualification of NSCLC patients for EGFR tyrosine kinase inhibitor therapy. However, tissue specimens are preferred for EGFR mutation analysis. The aim of this study was to estimate the effectiveness of the real-time PCR method for EGFR testing in histology and cytology materials obtained simultaneously from NSCLC patients. METHODS: Fourteen adenocarcinoma patients with EGFR-mutation positive primary tumor tissues were included in the study. Corresponding cytological smears of metastatic lymph nodes obtained by EBUS-TBNA were examined. EGFR Mutation Analysis Kit (EntroGen, USA) and real-time PCR (m2000rt system, Abbott, USA) were used for EGFR mutation analysis in both types of material. RESULTS: In primary tumor tissues, 12 deletions in exon 19 and 2 substitutions in exon 21 (L858R mutation) of the EGFR gene were found. Except for 1 deletion in exon 19, the same EGFR gene mutations were detected in all corresponding cytology samples. The percentage of tumor cells, DNA concentration, percentage of mutated DNA as well as DeltaCt values were similar in cytology slides and histology material. In both types of materials, no significant correlations were found between the percentage of tumor cells and the percentage of mutated DNA nor between the DNA concentration and the percentage of mutated DNA. CONCLUSIONS: We demonstrated the high effectiveness of a sensitive real-time PCR method in EGFR gene mutation detection in cytology smears. PMID- 26108239 TI - Adjuvant aromatase inhibitor therapy in early breast cancer: what factors lead patients to discontinue treatment? AB - BACKGROUND: Aromatase inhibitors (AIs) are standard hormone therapy (HT) for the adjuvant treatment of postmenopausal endocrine-sensitive early breast cancer. Treatment discontinuation due to toxicity is an important issue that may help clinicians identify effective clinical interventions to allow adequate treatment duration. We reviewed the main reasons for interruption of AIs at our institution from 2006 to 2009. METHODS: 236 patients treated with adjuvant AIs were eligible for analysis. Median age was 64 years (35-89), median follow-up 53 months (6-60). Prior adjuvant chemotherapy was taxane based in 47 patients and anthracycline based in 43 patients. 118 patients had received letrozole, 101 anastrozole, and 17 exemestane. RESULTS: Twenty-four patients (10%) needed discontinuation of the first AI assigned as a result of toxicity. Grade 2/3 arthralgia was the main reason for discontinuation in 13/24 patients. No differences in the incidence of arthralgia were noted in patients who had received taxanes or anthracyclines. Headache, alopecia, itching, diffuse skin reaction, allergic reaction with hypertensive crisis, xerostomia and xerophthalmia, insomnia and somnolence were the other reasons for discontinuation. In multivariate logistic regression analysis, age (65 years) and HT were independent factors associated with the onset of arthralgia (p = 0.006 and p = 0.008, respectively; OR 2.65, 95% CI 1.32 5.31). Alternative HT (AI or tamoxifen) was offered to patients who wanted or needed to permanently interrupt the ongoing drug. CONCLUSIONS: In our analysis, 10% of patients discontinued the first AI assigned because of toxicity. Median time course of all adverse events leading to HT discontinuation was 155 days and 135 days for arthralgia. A switch to alternative HT with toxicity monitoring is a recommended option for avoiding premature and permanent interruption of an effective treatment. PMID- 26108240 TI - Bevacizumab treatment for vestibular schwannoma in a patient with neurofibromatosis type 2: hearing improvement and tumor shrinkage. AB - PURPOSE: Neurofibromatosis type 2 (NF2) is a dominantly inherited genetic condition that clinically manifests through the appearance of multiple meningiomas, ependymomas and bilateral vestibular schwannomas (acoustic neuromas) which lead to progressive hearing loss. Neovascularization is necessary for tumor growth and is driven by tumor-produced angiogenic factors such as vascular endothelial growth factor (VEGF). Bevacizumab is a humanized monoclonal antibody that neutralizes the activity of VEGF. Recent data have shown that VEGF is produced by schwannoma tumor cells. Bevacizumab treatment in patients with NF2 who were considered poor candidates for surgery and radiation therapy was found to result in clinically meaningful hearing improvement and tumor volume reduction in previous studies. METHODS: We report the case of a 40-year-old woman with sudden right-sided hearing loss. Magnetic resonance imaging (MRI) revealed multiple meningiomas and neurinomas (C2 and L5 lesions) and a right-sided acoustic neurinoma, confirming the diagnosis of NF2. Bevacizumab was given as infusion every 2 weeks at a dose of 5.0 mg/kg body weight with MRI monitoring every 6 months. RESULTS: After 6 months from the start of therapy the patient reported progressive improvement of hearing response in audiometry, word recognition and face-to-face conversation. MRI evidenced reduction of the volume of the right vestibular schwannoma and the multiple meningiomas as well as attenuation of brain stem compression. CONCLUSIONS: At the time of writing the patient is continuing treatment with bevacizumab without adverse events. She has good functional status and quality of life. PMID- 26108241 TI - Nausea and vomiting during the first 3 intercycle periods in chemo-naive cancer patients receiving moderately/highly emetogenic therapy. AB - AIMS AND BACKGROUND: There is a paucity of data regarding the incidence, intensity, and treatment of nausea and vomiting during the intercycle periods of chemotherapy (CHT). The aims of the study were to assess the incidence and intensity of intercycle nausea and vomiting, to assess the use of rescue antiemetic medications, and to define the more uncomfortable symptom between nausea and vomiting. METHODS: In a prospective study, 108 chemotherapy-naive patients treated with highly or moderately emetogenic CHT for different primary cancers were enrolled. All patients filled out the Edmonton Symptom Assessment System tool before the first cycle of CHT (T0) and on 14-16 days thereafter for the first 3 cycles of CHT (i.e., T1, T2, T3). RESULTS: Sixty-seven patients completed the study. During CHT administration, all patients received antiemetics according to international guidelines. During the intercycle periods, nausea was reported in 6.0% of patients at T0, 10.5% at T1, and 26.9% at T2 and T3, respectively. The intensity of nausea was mild for 6.0%, 21%, and 18% of patients at T1, T2, and T3, respectively; moderate for 1.5%, 3.0%, and 6.0% at T1 to T3; and severe in only 3.0% of patients at any time. Vomiting was present in 1.5% and 10.5% of patients at T2 and T3. Rescue antiemetic medication was required for 41.8% at T1, 53% at T2, and 47.8% at T3. At the end of the study, 70.1% of patients described nausea as the more uncomfortable symptom compared to vomiting. CONCLUSIONS: Nausea has a higher burden of impact over vomiting and should be assessed and treated separately throughout multiple cycles of CHT. PMID- 26108242 TI - TOKIO rationale and protocol: a phase II study to evaluate the activity and safety of third-line tyrosine kinase inhibitor after 2 tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma. AB - AIMS AND BACKGROUND: The introduction of agents targeting vascular endothelial growth factor has radically changed the approach to metastatic renal cell carcinoma (mRCC): sunitinib and pazopanib are now the standard first-line therapy in mRCC. At sunitinib failure, second-line axitinib or everolimus or sorafenib should be considered to improve the clinical outcome. No data are available for a third-line tyrosine kinase inhibitor (TKI) after 2 previous lines of therapy with TKIs. At pazopanib failure, no prospective data are available. STUDY DESIGN: The TOKIO study was designed to evaluate progression-free survival, safety, and efficacy of third-line therapy with TKI in 44 patients already treated with 2 previous lines of TKIs in 10 Italian centers, and relapsed from sunitinib axitinib (group A) or pazopanib-sorafenib (group B). Standard treatment is sorafenib in group A and sunitinib in group B, administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety, and quality of life. PMID- 26108243 TI - Proteomic analysis of a nasopharyngeal carcinoma cell line and a nasopharyngeal epithelial cell line. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy exhibiting a strong geographic preference and a close association with Epstein-Barr virus (EBV). The aim of this study was to investigate the precise mechanism of nasopharyngeal epithelial-to-NPC tumorigenesis and to identify possible biomarkers and targets for therapy. METHODS: Proteomic analysis was performed on the immortalized nasopharyngeal epithelial cell line NP69 and the NPC cell line C666. RESULTS: A comparative analysis of total lysates from the cell lines using 2-D gel electrophoresis-mass spectrometry resulted in the identification of 87 different protein spots. The different proteins were grouped into 5 main categories: (i) energy production and general metabolism, (ii) adaptation/stress tolerance, (iii) cell proliferation, (iv) cell structure and (v) epithelial mesenchymal transition. The detection of metabolism-related proteins indicated that the NPC cells relied on aerobic glycolysis, with reduced use of the citric acid cycle. Glucose uptake and lactate secretion increased in the medium of C666 compared with NP69. CONCLUSIONS: The present study revealed that glycolysis was up-regulated in the NPC cell lines compared with nasopharyngeal epithelial cells. A number of molecules involved in metabolism were identified, and further investigations will be needed to validate these potential biomarkers or targets. PMID- 26108244 TI - Patient and caregiver needs in oncology. An Italian survey. AB - AIMS AND BACKGROUND: Cancer is a disease that has far-reaching consequences for patients and their families. The present study targets unmet caregiver needs so that better support can be provided and planned for. METHODS: The first phase of the study was to conduct a survey designed to explore basic needs (medical and nursing information, psychological support, social welfare). The survey also investigated the caregiver's personal details (age, sex, degree of kinship). The survey was distributed to caregivers coming to the day hospitals of the 4 oncology departments involved in the study. RESULTS: A total of 137 relatives of cancer patients completed the survey. Among the explored needs, the most recurrent was the availability of a doctor who provides full information on the treatment choices. A further important request was for consistency between the information provided by doctors and that provided by other health-care workers, with specific reference to a patient-centered approach that can be easily and fully understood, available therapeutic options especially at home, and prognosis. CONCLUSIONS: The study showed that the need for exhaustive and simple information provided by a referral physician is still an unmet need in the Internet age. PMID- 26108245 TI - Sarcomatoid mesothelioma: future advances in diagnosis, biomolecular assessment, and therapeutic options in a poor-outcome disease. AB - Malignant pleural mesothelioma (MPM) is the most frequent pleural neoplasm, with asbestos exposure as one of the recognized carcinogen agents, causative in 80% of cases. The prognosis is poor; median survival of untreated cases is 6-9 months, with fewer than 5% of patients surviving 5 years. Sarcomatoid mesothelioma (SM) represents the subtype with the worst outcome and median survival ranging from 3.5 to 8 months. In the last few years, an accurate differentiation between the subtypes of MPM has become a crucial issue, due to differences in chemosensitivity and clinical outcome, and several studies have evaluated different immunohistochemical markers to better define the diagnosis. The different and worse outcome of patients with SM and, in general, nonepithelioid subtypes makes it intriguing to select these cases to better study the biomolecular profile in order to find factors linked to prognosis and/or predictive of therapeutic response. Considering recent studies on miRNA and genetic mapping, further investigation of this rare subtype might represent a field for basic and clinical-translational research providing for more tailored therapies. PMID- 26108246 TI - miRNA-214: expression, therapeutic and diagnostic potential in cancer. AB - MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression by binding to the 3' untranslated region of their target mRNAs. Recent work supports a role for miRNAs in the initiation and progression of human cancer. miRNA-214 not only mediates differentiation, senescence, angiogenesis, cell migration and virus replication but also acts as a tumor suppressor gene and oncogene. Increasing evidence indicates that miRNA-214 may serve as a biomarker in some cancer types. The aim of this review is to highlight and clarify the complexity of miRNA-214 activity, emphasizing its significant therapeutic and diagnostic potential. PMID- 26108247 TI - Trabectedin plus pegylated liposomal doxorubicin: retrospective analysis in heavily pretreated platinum-sensitive ovarian cancer. AB - PURPOSE: This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy. METHODS: Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%). CONCLUSIONS: The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease. PMID- 26108248 TI - Reduction of risk of dying from tobacco-related diseases after quitting smoking in Italy. AB - AIMS AND BACKGROUND: The aims of this paper are to compute the risks of dying of ischemic heart disease (IHD), lung cancer (LC), stroke, and chronic obstructive pulmonary disease (COPD) for Italian smokers by gender, age and daily number of cigarettes smoked, and to estimate the benefit of stopping smoking in terms of risk reduction. METHODS: Life tables by sex and smoking status were computed for each smoking-related disease based on Italian smoking data, and risk charts with 10-year probabilities of death were computed for never, current and former smokers. RESULTS: Men aged 45-49 years, current smokers, have a 8, 10, 3 and 1 in 1,000 chance of dying of IHD, LC, stroke and COPD, respectively, whereas women with the same characteristics have a 2, 6, 3 and 1 in 1,000 chance, respectively, for all smokers combined, i.e., independent of the smoking intensity. The risk reduction rates from quitting smoking are remarkable: a man who quits smoking at 45-49 years can reduce the risk of dying of IHD, LC, stroke and COPD in the next 10 years by 43%, 53%, 57% and 55%, respectively; a woman by 49%, 49%, 59% and 57%, respectively. CONCLUSIONS: Estimates of risk reduction by quitting smoking are useful to provide a sounder scientific basis for public health messages and clinical advice. PMID- 26108249 TI - Giant cemento-ossifying fibroma of the maxilla. AB - INTRODUCTION: Fibro-osseous lesions of the skull and facial bones are benign tumors, but they can be mistaken for malignant tumors due to their clinically aggressive behavior. Cemento-ossifying fibroma (COF) is a benign fibro-osseous lesion characterized by slow growth and fibrous and calcified tissue content. COFs are locally destructive lesions causing deformities in the bones. The recurrence risk is high if they are not completely removed. CASE REPORT: In this case report we describe a giant COF mimicking chondrosarcoma in the oral cavity of a 55-year-old woman causing significant facial deformity and feeding problems. CONCLUSIONS: Giant COF occurs rarely in the jaws and given that this lesion has similar imaging and clinical features to several other tumors, the diagnosis is always a challenge for clinicians, radiologists and pathologists. PMID- 26108250 TI - Stability of spinal bone metastases and survival analysis in renal cancer after radiotherapy. AB - PURPOSE: This retrospective analysis evaluated the outcome of patients with spinal bone metastases of renal cell cancer after radiotherapy (RT) in terms of stability and survival, using a validated scoring system for spinal stability assessment. MATERIALS AND METHODS: The survival rates of 155 patients with bone metastases of renal cancer treated from January 2000 to January 2012 were determined. The stability of irradiated osteolytic lesions of the thoracic and lumbar spine was evaluated retrospectively using the Taneichi score and analyzed for predictive factors. The effects of therapy in terms of changes in neurological signs and tumor-related pain were recorded. RESULTS: Follow-up with regular computed tomography (CT) was available for 28 patients, 14 with unstable metastases. One hundred thiry-two patients (85%) died during follow-up. RT could not improve the stability of vertebral bodies after 3 and 6 months. Consequently, none of the examined predictive factors such as age, number of bone metastases and systemic therapy showed a significant correlation with stability 6 months after RT. The median survival of all 155 patients after diagnosis of bone metastases was 12.9 months. Improvement of pain and neurological deficits occurred in 60%, and in 24% of the respective affected in all patients. CONCLUSIONS: RT was unable to improve the stability of vertebral metastases, probably due to the short overall survival, which resulted in an insufficient number of patients with evaluable follow-up. RT allowed reduction of pain and neurological deficits. A short fractionation schedule may be preferred in this situation. PMID- 26108252 TI - Identification of Missing Proteins Defined by Chromosome-Centric Proteome Project in the Cytoplasmic Detergent-Insoluble Proteins. AB - Finding protein evidence (PE) for protein coding genes is a primary task of the Phase I Chromosome-Centric Human Proteome Project (C-HPP). Currently, there are 2948 PE level 2-4 coding genes per neXtProt, which are deemed missing proteins in the human proteome. As most samples prepared and analyzed in the C-HPP framework were focusing on detergent soluble proteins, we posit that as a natural composition the cytoplasmic detergent-insoluble proteins (DIPs) represent a source of finding missing proteins. We optimized a workflow and separated cytoplasmic DIPs from three human lung and three human hepatoma cell lines via differential speed centrifugation. We verified that the detergent-soluble proteins (DSPs) could be sufficiently depleted and the cytoplasmic DIP isolation was partially reproducible with Spearman r > 0.70 according to two independent SILAC MS experiments. Through label-free MS, we identified 4524 and 4156 DIPs from lung and liver cells, respectively. Among them, a total of 23 missing proteins (22 PE2 and 1 PE4) were identified by MS, and 18 of them had translation evidence; in addition, six PE5 proteins were identified by MS, three with translation evidence. We showed that cytoplasmic DIPs were not an enrichment of transmembrane proteins and were chromosome-, cell type-, and tissue-specific. Furthermore, we demonstrated that DIPs were distinct from DSPs in terms of structural and physical-chemical features. In conclusion, we have found 23 missing proteins and 6 PE5 proteins from the cytoplasmic insoluble proteome that is biologically and physical-chemically different from the soluble proteome, suggesting that cytoplasmic DIPs carry comprehensive and valuable information for finding PE of missing proteins. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the data set identifier PXD001694. PMID- 26108251 TI - Hepatosplenic T-cell lymphoma with aberrant expression of serum beta-HCG: a case report. AB - BACKGROUND: Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of hematologic malignancies frequently presenting at advanced stage of diagnosis. METHODS: We report a case of PTCL with an uncommon and aggressive onset with disseminated intravascular coagulation (DIC). RESULTS: Laboratory findings revealed an aberrant expression of beta subunit of human chorionic gonadotropin (beta-HCG). Other than for determination of pregnancy, beta-HCG is regularly found as a tumor marker in germ cell tumors with trophoblastic differentiation and its aberrant expression has been reported in the literature in other neoplastic conditions only in the context of case reports. CONCLUSIONS: In hematologic malignancies, beta-HCG expression has been described only in sporadic cases. Awareness of this feature could avoid diagnostic delay in such an aggressive disease. PMID- 26108253 TI - PLGA-Mesoporous Silicon Microspheres for the in Vivo Controlled Temporospatial Delivery of Proteins. AB - In regenerative medicine, the temporospatially controlled delivery of growth factors (GFs) is crucial to trigger the desired healing mechanisms in the target tissues. The uncontrolled release of GFs has been demonstrated to cause severe side effects in the surrounding tissues. The aim of this study was to optimize a translational approach for the fine temporal and spatial control over the release of proteins, in vivo. Hence, we proposed a newly developed multiscale composite microsphere based on a core consisting of the nanostructured silicon multistage vector (MSV) and a poly(dl-lactide-co-glycolide) acid (PLGA) outer shell. Both of the two components of the resulting composite microspheres (PLGA-MSV) can be independently tailored to achieve multiple release kinetics contributing to the control of the release profile of a reporter protein in vitro. The influence of MSV shape (hemispherical or discoidal) and size (1, 3, or 7 MUm) on PLGA-MSV's morphology and size distribution was investigated. Second, the copolymer ratio of the PLGA used to fabricate the outer shell of PLGA-MSV was varied. The composites were fully characterized by optical microscopy, scanning electron microscopy, zeta potential, Fourier transform infrared spectroscopy, and thermogravimetric analysis-differential scanning calorimetry, and their release kinetics over 30 days. PLGA-MSV's biocompatibility was assessed in vitro with J774 macrophages. Finally, the formulation of PLGA-MSV was selected, which concurrently provided the most consistent microsphere size and allowed for a zero-order release kinetic. The selected PLGA-MSVs were injected in a subcutaneous model in mice, and the in vivo release of the reporter protein was followed over 2 weeks by intravital microscopy, to assess if the zero-order release was preserved. PLGA MSV was able to retain the payload over 2 weeks, avoiding the initial burst release typical of most drug delivery systems. Finally, histological evaluation assessed the biocompatibility of the platform in vivo. PMID- 26108254 TI - Room transfers and the risk of delirium incidence amongst hospitalized elderly medical patients: a case-control study. AB - BACKGROUND: Room transfers are suspected to promote the development of delirium in hospitalized elderly patients, but no studies have systematically examined the relationship between room transfers and delirium incidence. We used a case control study to determine if the number of room transfers per patient days is associated with an increased incidence of delirium amongst hospitalized elderly medical patients, controlling for baseline risk factors. METHODS: We included patients 70 years of age or older who were admitted to the internal medicine or geriatric medicine services at St. Michael's Hospital between October 2009 and September 2010 for more than 24 h. The cases consisted of patients who developed delirium during the first week of hospital stay. The controls consisted of patients who did not develop delirium during the first week of hospital stay. Patients with evidence of delirium at admission were excluded from the analysis. A multivariable logistic regression model was used to determine the relationship between room transfers and delirium development within the first week of hospital stay. RESULTS: 994 patients were included in the study, of which 126 developed delirium during the first week of hospital stay. Using a multivariable logistic regression model which controlled for age, gender, cognitive impairment, vision impairment, dehydration, and severe illness, room transfers per patient days were associated with delirium incidence (OR: 9.69, 95 % CI (6.20 to15.16), P < 0.0001). CONCLUSIONS: An increased number of room transfers per patient days is associated with an increased incidence of delirium amongst hospitalized elderly medical patients. This is an exploratory analysis and needs confirmation with larger studies. PMID- 26108255 TI - Comparing the Effect of Tampering on the Oral Pharmacokinetic Profiles of Two Extended-Release Oxycodone Formulations with Abuse-Deterrent Properties. AB - OBJECTIVE: Oxycodone DETERx(r) is an extended-release (ER), microsphere-in capsule abuse-deterrent-formulation designed to retain its extended-release properties following tampering or misuse (e.g., chewing, crushing). This study assessed the safety and pharmacokinetics of orally administered intact and crushed Oxycodone DETERx(r) capsules compared with intact and crushed reformulated OxyContin(r) tablets and crushed immediate-release oxycodone tablets (IR oxycodone). METHODS: This was a randomized, open-label, active-controlled, cross-over study. Healthy subjects received five oxycodone treatments (40 mg) with a standardized high-fat, high-calorie meal: Oxycodone DETERx(r) (intact or crushed), OxyContin(r) (intact or crushed), and IR oxycodone (crushed). Blood samples were collected for assessment of oxycodone plasma concentrations. RESULTS: Thirty-eight subjects completed the study. Both crushed and intact Oxycodone DETERx(r) resulted in lower peak plasma concentrations when compared with IR oxycodone. Crushed Oxycodone DETERx(r) was bioequivalent to intact Oxycodone DETERx(r) and exhibited a numerically lower Cmax . Also, median Tmax was unchanged by crushing. In contrast, mean peak plasma oxycodone concentrations for crushed OxyContin(r) were significantly higher compared with intact OxyContin(r) and were bioequivalent to IR oxycodone. Median Tmax for crushed OxyContin(r) was the same as IR oxycodone and 3.25 hours shorter than intact OxyContin(r). CONCLUSIONS: These data demonstrate that when crushed and taken orally, Oxycodone DETERx(r) maintains its EXTENDED-release profile, while crushed OxyContin(r) shows a pharmacokinetic profile similar to an immediate-release product. These results suggest that Oxycodone DETERx(r) may be less attractive to illicit drug users compared with existing abuse-deterrent-formulations, while providing a safer option for patients who may unknowingly crush their medication such as those who have difficulty swallowing. PMID- 26108256 TI - Progesterone 5beta-reductase genes of the Brassicaceae family as function associated molecular markers. AB - This study aimed to define progesterone 5beta-reductases (P5betaR, EC 1.3.99.6, enone 1,4-reductases) as function-associated molecular markers at the plant family level. Therefore cDNAs were isolated from 25 Brassicaceae species, including two species, Erysimum crepidifolium and Draba aizoides, known to produce cardiac glycosides. The sequences were used in a molecular phylogeny study. The cladogram created is congruent to the existing molecular analyses. Recombinant His-tagged forms of the P5betaR cDNAs from Aethionema grandiflorum, Draba aizoides, Nasturtium officinale, Raphanus sativus and Sisymbrium officinale were expressed in E. coli. Enone 1,4-reductase activity was demonstrated in vitro using progesterone and 2-cyclohexen-1-one as substrates. Evidence is provided that functional P5betaRs are ubiquitous in the Brassicaceae. The recombinant P5betaR enzymes showed different substrate preferences towards progesterone and 2 cyclohexen-1-one. Sequence comparison of the catalytic pocket of the P5betaR enzymes and homology modelling using Digitalis lanata P5betaR (PDB ID: 2V6G) as template highlighted the importance of the hydrophobicity of the binding pocket for substrate discrimination. It is concluded that P5betaR genes or P5betaR proteins can be used as valuable function-associated molecular markers to infer taxonomic relationship and evolutionary diversification from a metabolic/catalytic perspective. PMID- 26108257 TI - Dorsolateral striatum is critical for the expression of surprise-induced enhancements in cue associability. AB - The dorsolateral striatum (DLS) is frequently implicated in sensory-motor integration, including the performance of sensory orienting responses (ORs) and learned stimulus-response habits. Our laboratory previously identified a role for the DLS in rats' performance of conditioned ORs to Pavlovian cues for food delivery. Here, we considered whether DLS is also critical to another aspect of attention in associative learning, the surprise-induced enhancement of cue associability. A large behavioral literature shows that a cue present when an expected event is omitted enters into new associations more rapidly when that cue is subsequently paired with food. Research from our laboratory has shown that both cue associability enhancements and conditioned ORs depend on the function of a circuit that includes the amygdala central nucleus and the substantia nigra pars compacta. In three experiments, we explored the involvement of DLS in surprise-induced associability enhancements, using a three-stage serial prediction task that permitted separation of DLS function in registering surprise (prediction error) and enhancing cue associability, and in using that increased associability to learn more rapidly about that cue later. The results showed that DLS is critical to the expression, but not the establishment, of the enhanced cue associability normally produced by surprise in this task. They extend the role of DLS and the amygdalo-nigro-striatal circuit underlying learned orienting to more subtle aspects of attention in associative learning, but are consistent with the general notion that DLS is more important in the expression of previously acquired tendencies than in their acquisition. PMID- 26108258 TI - Evaluation of blood group antibodies in ABO-incompatible living-donor kidney transplantation. AB - OBJECTIVE: To assess changes in anti-blood type antibody titers and postoperative outcomes (graft survival and rejection rates) at our center with the use of the immunosuppressant, rituximab, in ABO-incompatible kidney transplants from living donors. Confirming anti-donor blood group antibodies is important for avoiding humoral rejection in ABO-incompatible kidney transplants. Splenectomy has been carried out in our hospital according to Alexandre's policy in order to suppress the production of anti-donor blood group antibodies. However, splenectomy has recently been avoided due to the administration of the immunosuppressant rituximab, which gives satisfactory outcomes. Thus, pre- and postoperative anti donor blood group antibodies were measured, and the outcomes achieved with rituximab were examined. METHODS: A total of 134 cases of ABO-incompatible kidney transplants were carried out at Toho University Omori Medical Center between March 1989 and February 2013. These cases were classified as follows: azathioprine group (n = 62 patients); mycophenolate mofetil group (n = 33 patients); rituximab group (n = 39 patients). The anti-donor blood group antibodies levels (immunoglobulin G and immunoglobulin M) were measured in all groups before antibody removal, immediately before surgery, and 1, 2, 4 weeks and 3 months after surgery, and then compared. RESULTS: Rates of antibody-mediated rejection, including hyperacute rejection, in the azathioprine, mycophenolate mofetil, and rituximab groups were 32.2%, 18.1% and 7.6%, respectively. Graft survival rates were higher in the mycophenolate mofetil and rituximab groups than in the azathioprine group, but were lower in patients with higher preoperative antibody titers (>=128-fold higher immunoglobulin G) than in those with lower titers (<128-fold higher immunoglobulin G). In addition, postoperative anti-blood type antibody titers were significantly suppressed in the rituximab group. CONCLUSIONS: Administration of rituximab results in better antibody control than previous protocols including splenectomy, even in the postoperative period during which humoral rejection often occurs. This protocol eliminates the physical invasiveness of pre-transplant splenectomy, and is expected to provide better outcomes in chronic renal failure patients who undergo kidney transplants. PMID- 26108261 TI - Refugia and connectivity sustain amphibian metapopulations afflicted by disease. AB - Metapopulation persistence in fragmented landscapes depends on habitat patches that can support resilient local populations and sufficient connectivity between patches. Yet epidemiological theory for metapopulations has largely overlooked the capacity of particular patches to act as refuges from disease, and has suggested that connectivity can undermine persistence. Here, we show that relatively warm and saline wetlands are environmental refuges from chytridiomycosis for an endangered Australian frog, and act jointly with connectivity to sustain frog metapopulations. We coupled models of microclimate and infection probability to map chytrid prevalence, and demonstrate a strong negative relationship between chytrid prevalence and the persistence of frog populations. Simulations confirm that frog metapopulations are likely to go extinct when they lack environmental refuges from disease and lose connectivity between patches. This study demonstrates that environmental heterogeneity can mediate host-pathogen interactions in fragmented landscapes, and provides evidence that connectivity principally supports host metapopulations afflicted by facultative pathogens. PMID- 26108260 TI - Synthesis, Characterization, and Anticancer Activity of Novel Lipophilic Emodin Cationic Derivatives. AB - Seventeen novel emodin derivatives were synthesized, and the structures were confirmed by IR, H NMR, MS, and elemental analysis. The cytotoxic activity of the derivatives was evaluated against A375, BGC-823, HepG2, and HELF cells by MTT assay. Compound 9a with highest potency and low toxicity was selected to further investigate its detailed molecular mechanism. The lead compound 9a induced a loss of the mitochondrial transmembrane potential (?Psim), an increase in reactive oxygen species (ROS), release of cytochrome c and activation of caspase-3 and caspase-9. In addition, the confocal study showed that emodin derivative 9a (containing asymmetric hydrocarbon tails) was mainly localized in mitochondria, demonstrating a key role of the mitochondria-mediated apoptosis pathway in cancer cells. Taken together, the results demonstrate that embodin derivative 9a preferentially regulates the ROS-mediated apoptosis in A375 cells through the induction of cytochrome c expression and activation of caspase-3 and caspase-9 proteins. PMID- 26108263 TI - Mudi-chood: an interesting dermatological entity. PMID- 26108262 TI - Magnetic resonance elastography and transient elastography as non-invasive analyses for liver fibrosis: can they obviate the need for liver biopsy in psoriasis patients treated with methotrexate? AB - The liver biopsy has been regarded as the reference standard method of monitoring hepatic fibrosis in psoriasis patients treated with methotrexate. It has also been subject to concerns over sampling error, internal and external variability, and potential for morbidity and mortality. During the past two decades, two imaging techniques, magnetic resonance elastography and transient elastography, have been developed and approved by the US Food and Drug Administration (FDA) for the assessment of hepatic fibrosis. Although high-quality, psoriasis-specific data are lacking, both methods have been shown to have outstanding efficacy in the detection of hepatic fibrosis, particularly the more advanced stages which may warrant the choice of a therapeutic alternative to methotrexate. Dermatologists should be aware of the availability of these tests and understand their limitations. Prospective studies in psoriasis and methotrexate management using these techniques are needed. PMID- 26108259 TI - Alcohol Differentially Alters Extracellular Matrix and Adhesion Molecule Expression in Skeletal Muscle and Heart. AB - BACKGROUND: The production of fibrosis in response to chronic alcohol abuse is well recognized in liver but has not been fully characterized in striated muscle and may contribute to functional impairment. Therefore, the purpose of this study was to use an unbiased discovery-based approach to determine the effect of chronic alcohol consumption on the expression profile of genes important for cell cell and cell-extracellular matrix (ECM) interactions in both skeletal and cardiac muscle. METHODS: Adult male rats were pair-fed an alcohol-containing liquid diet or control diet for 24 weeks, and skeletal muscle (gastrocnemius) and heart were collected in the freely fed state. A pathway-focused gene expression polymerase chain reaction array was performed on these tissues to assess mRNA content for 84 ECM proteins, and selected proteins were confirmed by Western blot analysis. RESULTS: In gastrocnemius, alcohol feeding up-regulated the expression of 11 genes and down-regulated the expression of 1 gene. Alcohol increased fibrosis as indicated by increased mRNA and/or protein for collagens alpha1(I), alpha2(I), alpha1(III), and alpha2(IV) as well as hydroxyproline. Alcohol also increased alpha-smooth muscle actin protein, an index of myofibroblast activation, but no concomitant change in transforming growth factor-beta was detected. The mRNA and protein content for other ECM components, such as integrin alpha5, L-selectin, PECAM, SPARC, and ADAMTS2, were also increased by alcohol. Only laminin-alpha3 mRNA was decreased in gastrocnemius from alcohol-fed rats, while 66 ECM- or cell adhesion-related mRNAs were unchanged by alcohol. For heart, expression of 16 genes was up-regulated, expression of 3 genes was down regulated, and 65 mRNAs were unchanged by alcohol; there were no common alcohol induced gene expression changes between heart and skeletal muscle. Finally, alcohol increased tumor necrosis factor-alpha and interleukin (IL)-12 mRNA in both skeletal and cardiac muscle, but IL-6 mRNA was increased and IL-10 mRNA decreased only in skeletal muscle. CONCLUSIONS: These data demonstrate a fibrotic response in striated muscle from chronic alcohol-fed rats which is tissue specific in nature, suggesting different regulatory mechanisms. PMID- 26108264 TI - Does class attendance matter? Results from a second-year medical school dermatology cohort study. AB - BACKGROUND: Little is known about the impacts of class attendance and learning preferences on academic performance in dermatology. OBJECTIVES: This study was designed to examine the effects of medical student class attendance and learning preferences on students' academic performance in an introductory dermatology course. METHODS: A total of 101 second-year medical students enrolled in a required introductory dermatology course were surveyed regarding their learning preferences. Records of class attendance and scores on the final examination were reviewed. RESULTS: The most frequently cited reason for attending classes was social expectation (96%), whereas the least cited was learning well in a classroom-type setting (65%). The top reasons cited by students for not attending classes were availability of lectures online (35%), preference for individual study outside the classroom setting (26%), and the inconvenience of traveling to class (24%). Multivariate analysis found no statistically significant relationship between class attendance and performance on the final examination (estimate -0.074, standard error 0.12; P = 0.54) after adjusting for sex, age, Medical College Admission Test (MCAT) score, having children at home, and reason for attending class. Those who prefer to learn by watching online videos scored significantly higher on the final examination (prefer online videos: 87 +/- 5.5; neutral: 86 +/- 5.9; do not prefer online videos: 82 +/- 2.6 [P = 0.049]). CONCLUSIONS: Class attendance was not associated with improved academic performance in a dermatology course. Those who preferred to learn by watching online videos demonstrated a higher level of performance than those who did not prefer to learn this way. PMID- 26108265 TI - A comparative study between the efficacy of oral cimetidine and low-dose systemic meglumine antimoniate (MA) with a standard dose of systemic MA in the treatment of cutaneous leishmaniasis. AB - Cutaneous leishmaniasis (CL) is a major world health problem, which is increasing in incidence. Pentavalent antimonials have been considered as standard treatment for leishmaniasis. Many studies are performed to find an effective and safe treatment for patients with CL. The aim of this study was to compare the effect of oral cimetidine and low-dose systemic meglumine antimoniate (MA) with standard dose of systemic MA in the treatment of CL. This study was, to our knowledge, the first to show the effect of combination therapy oral cimetidine and MA in the treatment of CL all over the world. In this randomized double-blind placebo controlled clinical trial, 120 patients with suspected CL were referred to the Aleppo University Hospital Clinic; 90 of these patients with the clinical and parasitological diagnosis of CL were recruited and were randomly divided into three treatment groups of 30 subjects each. Group A was treated with MA 60 mg/kg/d IM and oral placebo. Groups B and C received MA 30 mg/kg/d IM and oral cimetidine 1200 mg/d, MA 30 mg/kg/d IM and oral placebo, respectively. The duration of treatment was three weeks for all groups. The effectiveness of the treatment was classified in three levels as complete response, partial response, and no response. Data were analyzed by SPSS 19 using KI square, Mann-Whitney, Kaplan-Mayer, and ANOVA tests. At the end of the study (12 weeks), the rate of complete response was 91.11% in the first group, and 84.66% and 78.33% in groups B and C, respectively (P < 0.05). The highest response rate was for the group treated with a standard dose of systemic MA and placebo. Our results showed that although oral cimetidine and low-dose systemic MA had less efficacy in comparison to a standard dose of systemic MA in the treatment of CL, it still can be considered as a replacement therapy in high-risk patients (such as patients with heart, kidney, and/or liver disease) under close supervision of physicians. PMID- 26108266 TI - Prevalence of latent tuberculosis infection in patients with moderate to severe psoriasis taking biologic therapies in a dermatologic private practice in Miami, Florida. AB - BACKGROUND: The reactivation of a latent tuberculosis infection is one of the possible major events that may occur during biologic therapies for inflammatory chronic diseases such as psoriasis. Although its main screening test is regularly used in clinical practice, there are few studies about the prevalence of this silent mycobacterial infection and the rate of positive convertors during treatment. OBJECTIVE: To assess the prevalence of latent tuberculosis infection (LTBI) in patients with moderate to severe psoriasis receiving biologic therapy by using tuberculin skin test as a screening method and to evaluate the rate of conversion of tuberculin skin test (TST) during the treatment with biologics. METHODS: A total of 445 patients were included in our retrospective study, conducted from January 2006 to September 2012. Tuberculin skin test was performed in all patients prior to treatment and once a year during the follow-up. PPD was considered positive with an induration above 5 mm, following the recommendations of Centers for Disease Control and Prevention/ America Thoracic Society. Data analysis was obtained with SPSS 20.0. RESULTS: The prevalence of LTBI in our population before initiating the treatment was 4.5% by using TST screening method. During the treatment, 10 cases that were initially TST-negative became positive. Only one of the patients developed active tuberculosis infection. The other 9 TST-positive patients were detected during the regular annual screening, and no symptoms or findings on chest x-ray were seen. All the patients were treated with isoniazid (INH) for nine months, and biologic therapy was restarted after one month of treatment with INH without development of overt TB infection in any of them during the follow-up period of the study. The mean time to becoming TST positive from start date was 26.7 months (range from 8 months to 5 years). As the PPD was done annually, it is unknown exactly when the patients became TST positive. Prior to initiating treatment, 20 patients were found to be TST positive. All patients had clear chest x-rays and were treated with nine months of INH prior to initiating biologic therapy at least month later. CONCLUSIONS: The use of a screening tool for LTBI is mandatory in patients taking biologic therapies to avoid severe infectious complications. Periodic follow-up is also crucial as positive results may be seen after prolonged use of these agents. PMID- 26108267 TI - The effect of dimethyl fumarate on gene expression and the level of cytokines related to different T helper cell subsets in peripheral blood mononuclear cells of patients with psoriasis. AB - BACKGROUND: Fumaric acid esters such as dimethyl fumarate (DMF) have proven to be effective in the treatment of psoriasis. OBJECTIVES: In view of the role of Th17 in the pathogenesis of psoriasis, the present study was conducted to investigate the effects of DMF on Th1, Th2, and Th17 responses in patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from psoriasis patients and healthy individuals and were cultured in the presence or absence of phytohemagglutinin and DMF. The cell supernatants were removed to measure cytokine secretion, and the lymphocytes were used for real-time polymerase chain reaction to establish gene expression. RESULTS: An increase in gene expression of interferon-gamma (IFN-gamma), as a marker for Th1 activity, and interleukin-17 (IL-17), granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-22 representing the Th17 subset in the PBMCs of patients in comparison with those of control subjects was observed. Culture of PBMCs from psoriasis patients and controls in the presence of DMF decreased IFN-gamma and increased IL-4 gene expression in both groups. Treatment with DMF could significantly decrease IL-17, GM-CSF, and IL-22 mRNA levels in the PBMCs of patients. Decreased release of IFN gamma and GM-CSF cytokine secretion after DMF treatment was also observed in PBMC cultures of patients and controls. CONCLUSIONS: These data show the effectiveness of DMF in modulating Th17 cells in addition to Th1/Th2 cells and reflect one of the underlying mechanisms of action of DMF in psoriasis. These findings may also support the possible benefits of using fumarate in the treatment of other autoimmune diseases in the pathogeneses of which Th1 and Th17 cells play major roles. PMID- 26108268 TI - Serum levels of thymus and activation-regulated chemokine can be used in the clinical evaluation of atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by the predominant infiltration of Th2-type cells in lesional skin. Thymus and activation-regulated chemokine (TARC) is overproduced in AD patients, and its serum levels are significantly higher in individuals with AD than in those with other inflammatory skin diseases. OBJECTIVES: The purpose of this study was to examine whether serum levels of TARC can assess the severity of AD and be used in the clinical evaluation of AD. METHODS: A total of 73 AD patients, 11 patients with generalized atopic eczema (AE), and 30 healthy control subjects were enrolled. SCORAD (SCORing of Atopic Dermatitis) indices were calculated according to skin symptom scores. The Th2 chemokines TARC kit was then used to obtain serum TARC values in each group. Finally, statistical analysis was used to identify any correlations between serum TARC level and SCORAD index in AD and AE patients. RESULTS: Mean serum TARC values were 159.95 in healthy controls, 146.46 in the mild AD group, 202.71 in the moderate AD group, 1216.61 in the severe AD group and 1554.50 in the severe AE group. The serum TARC level was significantly correlated with SCORAD score in AD patients (P < 0.01). However, there was no significant correlation between SCORAD score and TARC in AE patients (P = 0.610). CONCLUSIONS: The serum TARC level can be used to assess the severity of AD and as a reference index for the fast clinical evaluation of AD. PMID- 26108269 TI - Changes in growth and maturation parameters of Pacific sardine Sardinops sagax collected off California during a period of stock recovery from 1994 to 2010. AB - Whether fluctuation in density influenced the growth and maturation variables of three aggregated cohorts (fish born during the 1986-1993, 1996-2003 and 2004-2008 periods) of Pacific sardine Sardinops sagax caeruleus collected off the Californian coast from 2004 to 2010 was investigated. Using a von Bertalanffy mixed-effects model with aggregated cohorts as covariates, estimated growth rate significantly covaried with aggregated cohorts. Growth rate (K) was modelled as a fixed effect and estimated to be 0.264 +/- 0.015 (+/-s.e). Statistical contrasts among aggregated cohorts showed that the 1996-2003 cohorts had a significantly lower growth rate than the other two aggregated cohorts. The theoretical age at length zero (t0) and the standard length at infinity (L(Sinfinity)) were modelled as random effects, and were estimated to be -2.885 +/- 0.259 (+/-s.e) and 273.13 +/- 6.533 mm (+/-s.e). The relation of ovary-free mass at length was significantly different among the three aggregated cohorts, with the allometric coefficient estimated to be 2.850 +/- 0.013 (+/-s.e) for the S. sagax population. The age-at-length trajectory of S. sagax born between 1986 and 2008 showed strong density dependence effects on somatic growth rates. In contrast to the density dependent nature of growth, the probability to be mature at-size or at-age was not significantly affected by aggregated cohort density. The size and the age-at 50% maturity were estimated to be 150.92 mm and 0.56 years, respectively. Stock migration, natural fluctuations in biomass and removal of older and larger S. sagax by fishing might have been interplaying factors controlling growth parameters during 1986-2010. PMID- 26108270 TI - Evaluation of hGM-CSF/hTNFalpha surface-modified prostate cancer therapeutic vaccine in the huPBL-SCID chimeric mouse model. AB - To validate its efficacy in the context of the human immune system, a novel therapeutic vaccine of hGM-CSF/hTNFalpha surface-modified PC-3 cells against human prostate cancer was evaluated in the human peripheral blood lymphocytes severe combined immunodeficiency (huPBL-SCID) chimeric mouse model. The hGM-CSF or/and hTNFalpha modified vaccines inhibited prostate cancer growth effectively so as to prolong the mouse survival significantly. The splenocytes from the hGM CSF/hTNFalpha vaccine-inoculated mice showed the strongest tumor-specific cytotoxicity against PC-3 cells and the highest production of IFN?. These features indicated that type 1 protective immune response was induced efficiently against human prostate cancer and further enhanced through synergetic adjuvant effects of hGM-CSF and hTNFalpha. PMID- 26108271 TI - Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study. AB - BACKGROUND: Phthalates are endocrine-disrupting chemicals that influence thyroid hormones and sex steroids, both critical for brain development. AIM: We studied phthalate concentrations in house dust in relation to the risks of developing autism spectrum disorder (ASD) or developmental delay (DD). METHODS: Participants were a subset of children from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) case-control study. ASD and DD cases were identified through the California Department of Developmental Services system or referrals; general population controls were randomly sampled from state birth files and frequency matched on age, sex, and broad geographic region to ASD cases. All children (50 ASD, 27 DD, 68 typically developing (TD)) were assessed with Mullen Scales of Early Learning, Vineland Adaptive Behavior Scales (VABS) and Aberrant Behavior Checklist. We measured 5 phthalates in dust collected in the child's home using a high volume small surface sampler. RESULTS: None of the phthalates measured in dust was associated with ASD. After adjustment, we observed greater di(2 ethylhexyl) phthalate (DEHP) and butylbenzyl phthalate (BBzP) concentrations in indoor dust from homes of DD children: Odds ratios (OR) were 2.10 (95% confidence interval (CI); 1.10; 4.09) and 1.40 (95% CI; 0.97; 2.04) for a one-unit increase in the ln-transformed DEHP and BBzP concentrations, respectively. Among TD children, VABS communication, daily living, and adaptive composite standard scores were lower, in association with increased diethyl phthalate (DEP) concentrations in dust. Participants with higher dibutyl phthalate (DBP) concentrations in house dust also trended toward reduced performance on these subscales. Among ASD and DD boys, higher indoor dust concentrations of DEP and DBP were associated with greater hyperactivity-impulsivity and inattention. DISCUSSION AND CONCLUSION: House dust levels of phthalates were not associated with ASD. The inability to distinguish past from recent exposures in house dust and the fact that house dust does not capture exposure from all sources, limit the interpretation of both positive and null findings and further work is needed. However, the associations observed for DEP and DBP with impairments in several adaptive functions and greater hyperactivity, along with evidence for increased risk of DD raise concerns that these chemicals may affect neurodevelopment in children. PMID- 26108272 TI - Infantile form of muscle phosphofructokinase deficiency in a premature neonate. AB - Muscle phosphofructokinase (PFK) deficiency is a rare autosomal recessive disease. We report the case of a preterm female infant who was diagnosed with the infantile form of phosphofructokinase deficiency due to a lack of PFK activity in her muscles, manifesting at a corrected age of 1 month as floppy infant syndrome, congenital joint contracture, cleft palate and duplication of the pelvicalyceal system. She died at a corrected age of 6 months due to respiratory failure. We further reviewed other infantile cases in the literature. Congenital hypotonia (78.6%), arthrogryposis (64.3%) and other systemic involvement including encephalopathy (35.7%) and cardiomyopathy (21.4%) are common presentations of the infantile form of PFK deficiency. The overall survival rate of the infantile form is low. The early recognition of multiple system involvement is essential to provide better clinical care for infants with the infantile form of PFK deficiency. PMID- 26108273 TI - Risk factors for loss to follow-up prior to ART initiation among patients enrolling in HIV care with CD4+ cell count >=200 cells/MUL in the multi-country MTCT-Plus Initiative. AB - BACKGROUND: In resource-limited settings, many HIV-infected patients are lost to follow-up (LTF) before starting ART; risk factors among those not eligible for ART at enrollment into care are not well described. METHODS: We examined data from 4,278 adults (3,613 women, 665 men) enrolled in HIV care through March 2007 in the MTCT-Plus Initiative with a CD4 count >=200 cells/mm(3) and WHO stage <= 2 at enrollment. Patients were considered LTF if > 12 months elapsed since their last clinic visit. Gender-specific Cox regression models were used to assess LTF risk factors. RESULTS: The proportion LTF was 8.2 % at 12 months following enrollment, and was higher among women (8.4 %) than men (7.1 %). Among women, a higher risk of LTF was associated with younger age (adjusted hazard ratio [AHR]15 19/30+: 2.8, 95 % CI:2.1-3.6; AHR20-24/30+:1.9, 95 % CI:1.7-2.2), higher baseline CD4 count (AHR350-499/200-349:1.5; 95 % CI:1.0-2.1; AHR500+/200-349:1.5; 95 % CI:1.0-2.0), and being pregnant at the last clinic visit (AHR:1.9, 95 % CI:1.4 2.5). Factors associated with a lower risk of LTF included, employment outside the home (AHR:0.73, 95 % CI:0.59-0.90), co-enrollment of a family/household member (AHR:0.40, 95 % CI:0.26-0.61), and living in a household with >=4 people (AHR:0.74, 95 % CI:0.64-0.85). Among men, younger age (AHR15-19/30+: 2.1, 95 % CI:1.2-3.5 and AHR30-34/35+:1.5, 95 % CI:1.0-2.4) had a higher risk of LTF. Electricity in the home (AHR:0.61, 95 % CI:0.41-0.91) and living in a household with >=4 people (AHR:0.58, 95 % CI:0.39-0.85) had a lower risk of LTF. CONCLUSIONS: Socio-economic status and social support may be important determinants of retention in patients not yet eligible for ART. Among women of child-bearing age, strategies around sustaining HIV care during and after pregnancy require attention. PMID- 26108274 TI - Prevalence and molecular characterization of Cryptosporidium in giant panda (Ailuropoda melanoleuca) in Sichuan province, China. AB - BACKGROUND: Cryptosporidium spp. have been extensively reported to cause significant diarrheal disease in humans and domestic animals. On the contrary, little information is available on the prevalence and characterization of Cryptosporidium in wild animals in China, especially in giant pandas. The aim of the present study was to detect Cryptosporidium infections and identify Cryptosporidium species at the molecular level in both captive and wild giant pandas in Sichuan province, China. FINDINGS: Using a PCR approach, we amplified and sequenced the 18S rRNA gene from 322 giant pandas fecal samples (122 from 122 captive individuals and 200 collected from four habitats) in Sichuan province, China. The Cryptosporidium species/genotypes were identified via a BLAST comparison against published Cryptosporidium sequences available in GenBank followed by phylogenetic analysis. The results revealed that both captive and wild giant pandas were infected with a single Cryptosporidium species, C. andersoni, at a prevalence of 15.6% (19/122) and 0.5% (1/200) in captive and wild giant pandas, respectively. CONCLUSIONS: The present study revealed the existence of C. andersoni in both captive and wild giant panda fecal samples for the first time, and also provided useful fundamental data for further research on the molecular epidemiology and control of Cryptosporidium infection in giant pandas. PMID- 26108275 TI - Ubiquitination and regulation of Smad7 in the TGF-beta1/Smad signaling of aristolochic acid nephropathy. AB - Aristolochic acid I (AAI) affects TGF-beta1/Smad signaling, which causes AA nephropathy (AAN), but the mechanisms are not fully understood. We aimed to clarify whether Arkadia and UCH37 participate in TGF-beta1/Smad signaling via Smad7, and the regulatory mechanisms of Smad7. One side, mice and cultured mouse renal tubular epithelial cells (RTECs) were treated with various AAI doses and concentrations, respectively; on the other side, RTECs were transfected with small interfering RNA (siRNA) expression vectors against Arkadia and UCH37 and then treated with 10 ug/ml AAI. And then detect the mRNA and protein levels of Smad7, UCH37, Arkadia and any other relative factors by RT-PCR and Western blotting. In kidney tissues and RTECs, the mRNA and protein levels of Smad7 decreased with increasing AAI doses concentrations by real-time PCR and Western blotting, whereas those of Arkadia, UCH37, Smad2, Smad3 and TbetaRI increased. Cells transfected with the Arkadia siRNA expression vector showed reduced mRNA and protein levels of vimentin, alpha-SMA, Smad2, Smad3 and TbetaRI after AAI treatment, while those of CK18 and Smad7 increased compared with those of untransfected RTECs. Conversely, cells transfected with the UCH37 siRNA expression vector showed the opposite effect on analyzed signaling molecules after AAI treatment. Arkadia and UCH37 participate in TGF-beta1/Smad signaling mediated renal fibrosis, and Smad7 blocks TGF-beta1 signaling by inhibiting Smad2/Smad3 phosphorylation and enhancing the degradation of TbetaRI. PMID- 26108276 TI - Evaluate the impact of neurogenic bladder in veterans with traumatic spinal cord injury. AB - OBJECTIVE: This observational study aimed to determine the prevalence of neurogenic bladder (NGB), and its impact (frequency of urinary tract infection [UTI], autonomic dysreflexia (AD) pressure ulcers, spasticity, and hospitalization rates) on veterans with traumatic spinal cord injury (SCI). BACKGROUND: NGB (detrusor muscle and urethral sphincter dysfunction with loss of bladder sensation to void), secondary to SCI, is commonly encountered in daily practice; however, its impact on veterans' overall health has been less well studied. METHOD: We retrospectively reviewed the electronic charts of veterans with SCI enrolled in our program and regularly followed in our SCI clinic. Demographic data collected included: age, sex, race/ethnicity, and age, level, severity and cause of spinal injury. Also noted was presence of NGB, episodes of UTI, presence of pressure ulcers, AD, spasticity, and hospitalization rate. Differences between those with and without NGB were evaluated using Generalized Linear Models. RESULTS: Of 161 veterans with SCI, symptoms of NGB was present in 133 (83%). Presence of NGB was associated with severe spinal cord injury. Veterans with NGB had more frequent UTI and presence of pressure ulcers (P < 0.05). They also were more likely to need hospitalization and were at an increased risk of dying. CONCLUSION: Incidence of NGB in veterans with SCI is high, is mainly associated with severe spinal cord injury, and severely impacts veterans' health by frequently causing UTIs, increasing hospitalization rate, and increases risk of death. PMID- 26108277 TI - Quantitative proton imaging from multiple physics processes: a proof of concept. AB - Proton imaging is developed in order to improve the accuracy of charged particle therapy treatment planning. It makes it possible to directly map the relative stopping powers of the materials using the information on the energy loss of the protons. In order to reach a satisfactory spatial resolution in the reconstructed images, the position and direction of each particle is recorded upstream and downstream from the patient. As a consequence of individual proton detection, information on the transmission rate and scattering of the protons is available. Image reconstruction processes are proposed to make use of this information. A proton tomographic acquisition of an anthropomorphic head phantom was simulated. The transmission rate of the particles was used to reconstruct a map of the macroscopic cross section for nuclear interactions of the materials. A two-step iterative reconstruction process was implemented to reconstruct a map of the inverse scattering length of the materials using the scattering of the protons. Results indicate that, while the reconstruction processes should be optimized, it is possible to extract quantitative information from the transmission rate and scattering of the protons. This suggests that proton imaging could provide additional knowledge on the materials that may be of use to further improve treatment planning. PMID- 26108278 TI - Long-term effects of cardiac rehabilitation in elderly individuals with stable coronary artery disease. AB - PURPOSE: To compare exercise capacity and cardiovascular response to exercise in elderly individuals with coronary artery disease (CAD) who attend ongoing community-based maintenance cardiac rehabilitation (CR) versus age- and gender matched healthy "very active" (HVA; >= 2000 kcal/week) and healthy "less active" (HLA; <2000 kcal/week) individuals. METHOD: Sixty-three participants (age: 72.3 +/- 5.1 years; 62% men; n = 21 per group) completed the following assessments: (1) symptom-limited graded exercise test with expired gas analysis and bioimpedance assessment of cardiovascular function during exercise; (2) walking tests; (3) physical function; (4) anthropometry and (5) 12-month physical activity recall. RESULTS: The CR group achieved 98% (range: 73-154%) of age- and gender-predicted peak oxygen consumption for healthy individuals. Peak oxygen consumption was lower in CR compared to HVA but not HLA group (VO2peak: CR: 19.0 +/- 4.5, HVA: 23.7 +/- 2.9, HLA: 20.7 +/- 4.7 ml .kg(-1)cmin(-1), p = 0.001 versus HVA; p = 0.390 versus HLA). Peak heart rate was lower in CR compared to both HVA and HLA. Walking test results and cardiovascular and physical function were not different between the groups. CONCLUSIONS: Elderly individuals with CAD participating in maintenance CR have similar exercise capacity and cardiorespiratory response to exercise compared to their age- and gender-matched less active healthy peers. The findings support referral of elderly patients to community-based CR. IMPLICATIONS FOR REHABILITATION: Fitness benefits of long term maintenance cardiac rehabilitation (CR) programs remain unknown. Elderly individuals with coronary artery disease participating in maintenance CR have exercise capacity and cardiorespiratory response to exercise similar to their less active healthy peers. Maintenance CR may play an important role prolonging independent living in elderly individuals. PMID- 26108279 TI - GDC 2: Compression of large collections of genomes. AB - The fall of prices of the high-throughput genome sequencing changes the landscape of modern genomics. A number of large scale projects aimed at sequencing many human genomes are in progress. Genome sequencing also becomes an important aid in the personalized medicine. One of the significant side effects of this change is a necessity of storage and transfer of huge amounts of genomic data. In this paper we deal with the problem of compression of large collections of complete genomic sequences. We propose an algorithm that is able to compress the collection of 1092 human diploid genomes about 9,500 times. This result is about 4 times better than what is offered by the other existing compressors. Moreover, our algorithm is very fast as it processes the data with speed 200 MB/s on a modern workstation. In a consequence the proposed algorithm allows storing the complete genomic collections at low cost, e.g., the examined collection of 1092 human genomes needs only about 700 MB when compressed, what can be compared to about 6.7 TB of uncompressed FASTA files. The source code is available at http://sun.aei.polsl.pl/REFRESH/index.php?page=projects&project=gdc&subpage=about PMID- 26108280 TI - Oculofaciocardiodental syndrome: novel BCOR mutations and expression in dental cells. PMID- 26108281 TI - Competition-cooperation relationship networks characterize the competition and cooperation between proteins. AB - By analyzing protein-protein interaction (PPI) networks, one can find that a protein may have multiple binding partners. However, it is difficult to determine whether the interactions with these partners occur simultaneously from binary PPIs alone. Here, we construct the yeast and human competition-cooperation relationship networks (CCRNs) based on protein structural interactomes to clearly exhibit the relationship (competition or cooperation) between two partners of the same protein. If two partners compete for the same interaction interface, they would be connected by a competitive edge; otherwise, they would be connected by a cooperative edge. The properties of three kinds of hubs (i.e., competitive, modest, and cooperative hubs) are analyzed in the CCRNs. Our results show that competitive hubs have higher clustering coefficients and form clusters in the human CCRN, but these tendencies are not observed in the yeast CCRN. We find that the human-specific proteins contribute significantly to these differences. Subsequently, we conduct a series of computational experiments to investigate the regulatory mechanisms that avoid competition between proteins. Our comprehensive analyses reveal that for most yeast and human protein competitors, transcriptional regulation plays an important role. Moreover, the human-specific proteins have a particular preference for other regulatory mechanisms, such as alternative splicing. PMID- 26108282 TI - Understanding nanocellulose chirality and structure-properties relationship at the single fibril level. AB - Nanocellulose fibrils are ubiquitous in nature and nanotechnologies but their mesoscopic structural assembly is not yet fully understood. Here we study the structural features of rod-like cellulose nanoparticles on a single particle level, by applying statistical polymer physics concepts on electron and atomic force microscopy images, and we assess their physical properties via quantitative nanomechanical mapping. We show evidence of right-handed chirality, observed on both bundles and on single fibrils. Statistical analysis of contours from microscopy images shows a non-Gaussian kink angle distribution. This is inconsistent with a structure consisting of alternating amorphous and crystalline domains along the contour and supports process-induced kink formation. The intrinsic mechanical properties of nanocellulose are extracted from nanoindentation and persistence length method for transversal and longitudinal directions, respectively. The structural analysis is pushed to the level of single cellulose polymer chains, and their smallest associated unit with a proposed 2 * 2 chain-packing arrangement. PMID- 26108283 TI - Large Seebeck effect by charge-mobility engineering. AB - The Seebeck effect describes the generation of an electric potential in a conducting solid exposed to a temperature gradient. In most cases, it is dominated by an energy-dependent electronic density of states at the Fermi level, in line with the prevalent efforts towards superior thermoelectrics through the engineering of electronic structure. Here we demonstrate an alternative source for the Seebeck effect based on charge-carrier relaxation: a charge mobility that changes rapidly with temperature can result in a sizeable addition to the Seebeck coefficient. This new Seebeck source is demonstrated explicitly for Ni-doped CoSb3, where a marked mobility change occurs due to the crossover between two different charge-relaxation regimes. Our findings unveil the origin of pronounced features in the Seebeck coefficient of many other elusive materials characterized by a significant mobility mismatch. When utilized appropriately, this effect can also provide a novel route to the design of improved thermoelectric materials. PMID- 26108285 TI - Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant. AB - Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigA(C)) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigA(C), either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigA(C) or LigA(C) coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID- 26108284 TI - Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils. AB - Despite numerous studies, a detailed description of the transthyretin (TTR) self assembly mechanism and fibril structure in TTR amyloidoses remains unresolved. Here, using a combination of primarily small -angle X-ray scattering (SAXS) and hydrogen exchange mass spectrometry (HXMS) analysis, we describe an unexpectedly dynamic TTR protofibril structure which exchanges protomers with highly unfolded monomers in solution. The protofibrils only grow to an approximate final size of 2,900 kDa and a length of 70 nm and a comparative HXMS analysis of native and aggregated samples revealed a much higher average solvent exposure of TTR upon fibrillation. With SAXS, we reveal the continuous presence of a considerably unfolded TTR monomer throughout the fibrillation process, and show that a considerable fraction of the fibrillating protein remains in solution even at a late maturation state. Together, these data reveal that the fibrillar state interchanges with the solution state. Accordingly, we suggest that TTR fibrillation proceeds via addition of considerably unfolded monomers, and the continuous presence of amyloidogenic structures near the protofibril surface offers a plausible explanation for secondary nucleation. We argue that the presence of such dynamic structural equilibria must impact future therapeutic development strategies. PMID- 26108287 TI - IP-10 Is a Sensitive Biomarker of Antigen Recognition in Whole-Blood Stimulation Assays Used for the Diagnosis of Mycobacterium bovis Infection in African Buffaloes (Syncerus caffer). AB - African buffaloes (Syncerus caffer) are maintenance hosts of Mycobacterium bovis, the causative agent of bovine tuberculosis. They act as reservoirs of this infection for a wide range of wildlife and domestic species, and the detection of infected animals is important to control the geographic spread and transmission of the disease. Interferon gamma (IFN-gamma) release assays (IGRAs) utilizing pathogen-derived peptide antigens are highly specific tests of M. bovis infection; however, the diagnostic sensitivities of these assays are suboptimal. We evaluated the diagnostic utility of measuring antigen-dependent interferon gamma-induced protein 10 (IP-10) release as an alternative to measuring IFN-gamma levels. M. bovis-exposed buffaloes were tested using the Bovigam PC-EC and Bovigam PC-HP assays and a modified QuantiFERON TB-Gold (mQFT) assay. IP-10 was measured in the harvested plasma and was produced in significantly greater abundance in response to M. bovis antigens in Bovigam-positive than in Bovigam negative animals. For each assay, using the Bovigam results as a reference, receiver operating characteristic curve analysis was done to determine diagnostically relevant cutoff values for IP-10. Thereafter, mQFT test results derived from measurement of IP-10 and IFN-gamma were compared and a larger number of Bovigam-positive animals were detected using IP-10 as a diagnostic marker. Moreover, using IP-10, agreement between the mQFT assay and the Bovigam assays was increased, while the excellent agreement between the Bovigam assays was retained. We conclude that IP-10 is a sensitive marker of antigen recognition and that measurement of this cytokine in antigen-stimulated whole blood might increase the sensitivity of conventional IGRAs in African buffaloes. PMID- 26108286 TI - International Laboratory Comparison of Influenza Microneutralization Assays for A(H1N1)pdm09, A(H3N2), and A(H5N1) Influenza Viruses by CONSISE. AB - The microneutralization assay is commonly used to detect antibodies to influenza virus, and multiple protocols are used worldwide. These protocols differ in the incubation time of the assay as well as in the order of specific steps, and even within protocols there are often further adjustments in individual laboratories. The impact these protocol variations have on influenza serology data is unclear. Thus, a laboratory comparison of the 2-day enzyme-linked immunosorbent assay (ELISA) and 3-day hemagglutination (HA) microneutralization (MN) protocols, using A(H1N1)pdm09, A(H3N2), and A(H5N1) viruses, was performed by the CONSISE Laboratory Working Group. Individual laboratories performed both assay protocols, on multiple occasions, using different serum panels. Thirteen laboratories from around the world participated. Within each laboratory, serum sample titers for the different assay protocols were compared between assays to determine the sensitivity of each assay and were compared between replicates to assess the reproducibility of each protocol for each laboratory. There was good correlation of the results obtained using the two assay protocols in most laboratories, indicating that these assays may be interchangeable for detecting antibodies to the influenza A viruses included in this study. Importantly, participating laboratories have aligned their methodologies to the CONSISE consensus 2-day ELISA and 3-day HA MN assay protocols to enable better correlation of these assays in the future. PMID- 26108289 TI - Hydrophobic zeolites coated with microporous organic polymers: adsorption behavior of ammonia under humid conditions. AB - ZSM-5 nanoparticles coated with microporous organic polymers showed 88% retention of ammonia adsorption capacity at 43% RH. PMID- 26108288 TI - Evaluation of the Immunogenicity of Mycobacterium bovis BCG Delivered by Aerosol to the Lungs of Macaques. AB - Nine million cases of tuberculosis (TB) were reported in 2013, with a further 1.5 million deaths attributed to the disease. When delivered as an intradermal (i.d.) injection, the Mycobacterium bovis BCG vaccine provides limited protection, whereas aerosol delivery has been shown to enhance efficacy in experimental models. In this study, we used the rhesus macaque model to characterize the mucosal and systemic immune response induced by aerosol-delivered BCG vaccine. Aerosol delivery of BCG induced both Th1 and Th17 cytokine responses. Polyfunctional CD4 T cells were detected in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) 8 weeks following vaccination in a dose-dependent manner. A similar trend was seen in peripheral gamma interferon (IFN-gamma) spot-forming units measured by enzyme-linked immunosorbent spot (ELISpot) assay and serum anti-purified protein derivative (PPD) IgG levels. CD8 T cells predominantly expressed cytokines individually, with pronounced tumor necrosis factor alpha (TNF-alpha) production by BAL fluid cells. T-cell memory phenotype analysis revealed that CD4 and CD8 populations isolated from BAL fluid samples were polarized toward an effector memory phenotype, whereas the frequencies of peripheral central memory T cells increased significantly and remained elevated following aerosol vaccination. Expression patterns of the alpha4beta1 integrin lung homing markers remained consistently high on CD4 and CD8 T cells isolated from BAL fluid and varied on peripheral T cells. This characterization of aerosol BCG vaccination highlights features of the resulting mycobacterium-specific immune response that may contribute to the enhanced protection previously reported in aerosol BCG vaccination studies and will inform future studies involving vaccines delivered to the mucosal surfaces of the lung. PMID- 26108291 TI - Metal and base free synthesis of primary amines via ipso amination of organoboronic acids mediated by [bis(trifluoroacetoxy)iodo]benzene (PIFA). AB - A metal and base free synthesis of primary amines has been developed at ambient temperature through ipso amination of diversely functionalized organoboronic acids, employing a combination of [bis(trifluoroacetoxy)iodo]benzene (PIFA)-N bromosuccinimide (NBS) and methoxyamine hydrochloride as the aminating reagent. The amines were primarily obtained as their trifluoroacetate salts which on subsequent aqueous alkaline work up provided the corresponding free amines. The combination of PIFA-NBS is found to be the mildest choice compared to the commonly used strong bases (e.g. n-BuLi, Cs2CO3) for activating the aminating agent. The reaction is expected to proceed via activation of the aminating reagent followed by B-N 1,2-aryl migration. PMID- 26108292 TI - Heterostructure of AuAg nanoparticles tipping on Ag2S quantum tubes. AB - We report synthesis of a novel metal-semiconductor heterostructure, in which AuAg alloy nanoparticles locate at Ag2S quantum tube tips. Ag2S quantum tubes have ultrathin walls below 1 nm thickness. The formation mechanism, UV-vis, luminescence and photoelectrochemical activity of the prepared heterostructure were further studied. PMID- 26108293 TI - Robot guidance of an ultrasound probe toward a 3D region of interest detected through X-ray mammography. AB - PURPOSE: This research is situated in the context of breast cancer detection where the standard procedure is the succession of an initial mammography (MX) examination and a supplementary ultrasound (US) scan. One major difficulty of this procedure results from the fact that breast geometry changes between both examinations due to different patient's positions. The proposed system facilitates this combined examination by keeping the breast geometry and by adding a US probe guidance robot to the mammography system. METHODS: A comanipulation system is set up where the robot and user simultaneously manipulate the probe toward the target previously localized in MX images. Calibration procedures and robot control are detailed. RESULTS: A test protocol was presented to conduct two tests that are both related to the medical application. The first tests aim at evaluating robot guidance for localizing a lesion which was previously defined in the X-ray images. The second tests aim at quantifying robot influence when scanning a target lesion. The studied task consists of a pointing/scanning exercise, where the US beam intersects a breast lesion. CONCLUSIONS: The experiments show a significant increase in examination quality when using robot guidance as compared to the nonassisted examination. PMID- 26108294 TI - Three-dimensional modeling of an individualized functional masticatory system and bite force analysis with an orthodontic bite plate. AB - PURPOSE: Orthodontic tooth movement is affected by bite forces generated from the masticatory system. This study aims to study three-dimensional (3D) modeling of the individualized functional masticatory system and explore its application in orthodontics. METHODS: An individualized masticatory system model containing the craniomaxilla, mandible, 4 pairs of primary masticatory muscles and complete dentition, including roots and precise dental crowns, was developed using 3D images from spiral computed tomography and digital casts. By registering global coordinates and using data transformation, individual movement data for mandibular opening, lateral excursion and protrusion were recorded with an Arcus Digma system and applied to this model to simulate the functional movements of the mandible. Using the finite element method, deformations and displacement of the masticatory muscles were simulated along with the mandibular movements. Under individualized muscle loading, the bite forces of the lower incisors with the orthodontic bite plate were analyzed. RESULTS: Individualized mandibular movements were simulated, and the performance of the masticatory muscles along with the mandibular movements was measured. The bite force generated on the lower incisors with different thicknesses and the orientations of the orthodontic bite plate were acquired. CONCLUSION: An individualized 3D masticatory system model was constructed using advanced 3D data processing software that integrated 3D images from different sources. Individualized mandibular movement and masticatory muscle performance were simulated using this model. The analysis of the bite force generated on the lower incisors with the orthodontic bite plate suggested that a thickness of 3 mm may be appropriate for clinical use. PMID- 26108295 TI - Dynamics of Cellular Reorientation on a Substrate under Biaxial Cyclic Stretches. AB - It is widely known that mechanical signals such as force, geometry, and substrate elasticity can be utilized by cells to regulate their structures, functions, and behaviors. However, the exact nature of the underlying mechanisms of cellular mechanosensing is unclear. Recently, extensive experiments on cellular reorientation dynamics on a substrate under biaxial cyclic stretches were performed, and the measured behaviors were found to be incompatible with existing theories. Here, we show that a theoretical model based on both tensile and shearing forces on focal adhesions (FAs) is capable of reproducing the new experimental data. This work provides important mechanistic insights into how behaviors of FAs can strongly affect cellular reorientation dynamics on a cyclically stretched substrate. PMID- 26108296 TI - Lead Iodide Thin Film Crystallization Control for High-Performance and Stable Solution-Processed Perovskite Solar Cells. AB - PbI2 thin film crystallization control is a prerequisite of high-quality perovskite thin film for sequentially solution-processed perovskite solar cells. An efficient and simple method has been developed by adding HCl to improve perovskite thin film quality, and an efficiency of 15.2% is obtained. This approach improves coverage, uniformity, and stability of pervoskite thin film. PMID- 26108297 TI - Accidents and Incidents Related to Intravenous Drug Administration: A Pre-Post Study Following Implementation of Smart Pumps in a Teaching Hospital. AB - INTRODUCTION: Smart pumps are expected to prevent and reduce medication errors. The implementation of smart pumps requires a significant effort and collaboration of physicians, nurses, pharmacists, and other stakeholders. OBJECTIVES: The main objective of this study was to evaluate the impact of new smart pumps on reported drug-related accidents and incidents (AIs). METHOD: This is a descriptive retrospective pre-post study conducted at a women's and pediatric hospital with 500 beds. A strong multidisciplinary team (nurse, pharmacist, pharmacy resident, physician, biomedical technician, information technology technician, patient safety officer, manager) was involved in the planning, implementation, and monitoring technology implementation. A total of 1045 smart pumps were implemented in 2011 in our hospital. The reported number of AIs related to intravenous drug administration (AIIV) before and after the implementation of 1045 smart pumps were collected. RESULTS: A total of 2911 AI events related to medications, devices, and equipment were self-reported by clinical staff in the pre-phase (Y0), 3523 in the post-phase (Y1), and 2788 in the post-phase (Y2). The total AIIV increased from 1432 in Y0 to 1834 in Y1 and decreased to 1389 in Y2. CONCLUSIONS: We observed no risk reduction associated with the implementation of smart pumps in a 500 bed mother-child hospital. Further studies are required to explore the details of the potential risk reduction associated with the use of smart pumps. PMID- 26108298 TI - Evaluating AE Reporting of Two Off-Patent Biologics to Inform Future Biosimilar Naming and Reporting Practices. AB - Historical studies of voluntary, spontaneous drug reports show poor attribution of adverse events to generic versions of commonly prescribed medications. As biosimilars enter the market place, it may be similarly difficult to accurately attribute adverse events to their respective reference products. At this time, lack of global consensus with regard to biosimilar naming conventions may result in drug reporting confusion, misattribution of adverse events and insufficient active monitoring of safety signals. Now, with the first biosimilar approval in the USA and many biosimilars expected to be launched globally in the near future, US Food and Drug Administration (FDA) guidance on biosimilar naming conventions will be essential. To inform the FDA and the global drug development community, the Tufts Center for the Study of Drug Development (Tufts CSDD) examined primary suspect reports sent to the FDA's Adverse Event Reporting System (FAERS) from US reporters for two biologics that have lost patent exclusivity--somatropin and human insulin--and extracted 4703 insulin reports and 6487 somatropin reports from FAERS. The results show that reporting practices are inconsistent between the two biologics that were evaluated and that manufacturer identifiability and traceability are lacking. Ways to improve biosimilar naming conventions and improve reporting practices are suggested. PMID- 26108300 TI - Emotional competencies in geriatric nursing: empirical evidence from a computer based large scale assessment calibration study. AB - The care of older people was described as involving substantial emotion-related affordances. Scholars in vocational training and nursing disagree whether emotion related skills could be conceptualized and assessed as a professional competence. Studies on emotion work and empathy regularly neglect the multidimensionality of these phenomena and their relation to the care process, and are rarely conclusive with respect to nursing behavior in practice. To test the status of emotion related skills as a facet of client-directed geriatric nursing competence, 402 final-year nursing students from 24 German schools responded to a 62-item computer-based test. 14 items were developed to represent emotion-related affordances. Multi-dimensional IRT modeling was employed to assess a potential subdomain structure. Emotion-related test items did not form a separate subdomain, and were found to be discriminating across the whole competence continuum. Tasks concerning emotion work and empathy are reliable indicators for various levels of client-directed nursing competence. Claims for a distinct emotion-related competence in geriatric nursing, however, appear excessive with a process-oriented perspective. PMID- 26108299 TI - Pharmacogenetics of Drug-Induced QT Interval Prolongation: An Update. AB - A prolonged QT interval is an important risk factor for ventricular arrhythmias and sudden cardiac death. QT prolongation can be caused by drugs. There are multiple risk factors for drug-induced QT prolongation, including genetic variation. QT prolongation is one of the most common reasons for withdrawal of drugs from the market, despite the fact that these drugs may be beneficial for certain patients and not harmful in every patient. Identifying genetic variants associated with drug-induced QT prolongation might add to tailored pharmacotherapy and prevent beneficial drugs from being withdrawn unnecessarily. In this review, our objective was to provide an overview of the genetic background of drug-induced QT prolongation, distinguishing pharmacokinetic and pharmacodynamic pathways. Pharmacokinetic-mediated genetic susceptibility is mainly characterized by variation in genes encoding drug-metabolizing cytochrome P450 enzymes or drug transporters. For instance, the P-glycoprotein drug transporter plays a role in the pharmacokinetic susceptibility of drug-induced QT prolongation. The pharmacodynamic component of genetic susceptibility is mainly characterized by genes known to be associated with QT interval duration in the general population and genes in which the causal mutations of congenital long QT syndromes are located. Ethnicity influences susceptibility to drug-induced QT interval prolongation, with Caucasians being more sensitive than other ethnicities. Research on the association between pharmacogenetic interactions and clinical endpoints such as sudden cardiac death is still limited. Future studies in this area could enable us to determine the risk of arrhythmias more adequately in clinical practice. PMID- 26108301 TI - Animacy-Based Accessibility and Competition in Relative Clause Production in Hindi and Malayalam. AB - Two studies investigated interaction of animacy-based accessibility and competition processes with language specific constraints in shaping production preferences. Relative clause elicitation tasks (Gennari et al. in Cogn Psychol 65:141-176, 2012) were performed by two groups with 40 participants in each. Significantly more passives were produced with animate question/focus and assigned subject function to them in Malayalam, while the difference was insignificant in Hindi with animacy not equating with grammatical function assignment. Both languages produced active objects with OSV order significantly more with animate question/focus. This indicates animacy effect on word order. Animacy also influenced the expression of the agent phase in both languages as a tendency was found to omit the agent by-phase or to delay its appearance, when the two animate nouns entering into the structure are highly similar. The results point to language specific constraints in relative clause production and variability in the role of animacy-based retrieval order across languages. PMID- 26108302 TI - Artificial ascites is feasible and effective for difficult-to-ablate hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments for early-stage HCC include local ablation, hepatic resection, and liver transplant. Radiofrequency ablation (RFA) is a minimally invasive treatment and can be used in patients who have an increased risk of hepatic resection, including a liver reserve of Child-Pugh B status and suboptimal general condition. However, a difficult location of HCC can interfere with the performance of RFA because of a conspicuous lesion, poor electrode path, or increased risk of thermal injury to adjacent organs. Difficult locations include tumors abutting the diaphragm or near vital organs such as the gastrointestinal tract and gallbladder. Because artificial ascites can provide an improved sonic view and protects adjacent vital organs from thermal injury, it widens the indication of RFA in the treatment of HCC. The systemic review showed that the technique of artificial ascites has a high success rate (>90 %) without the clear appearance of severe adverse events such as intraperitoneal hemorrhage or gastrointestinal perforation. The risk of intraperitoneal seeding is not increased. In addition, the therapeutic effectiveness, such as the complete ablation rate or local tumor progression rate, remains satisfactory for difficult to-ablate HCCs. In conclusion, RFA after infusion of artificial ascites is feasible and effective for difficult-to-ablate HCCs. However, because data on the local tumor progression rate, heat-sink effect, and intraperitoneal seeding are scarce, additional studies are required. PMID- 26108303 TI - IL-10 and IL-17F Promoter Single Nucleotide Polymorphism and Asthma: A Case Control Study in South India. AB - BACKGROUND: Several studies have assessed the association between IL-17F and IL 10 promoter polymorphisms and asthma, but the results were conflicting. Furthermore, few studies have evaluated the association of cytokine polymorphisms with asthma and its clinical phenotypes. OBJECTIVE: This study was conducted to evaluate the association of IL-10 (interleukin 10) and IL-17F (interleukin 17F) promoter polymorphisms (rs1800871, rs1800896 and rs1889570) with asthma and its clinical phenotypes including severity, atopic status, spirometric parameters, and response to treatment in south Indian population. A sub-study was conducted to assess cytokine levels in subjects with different gene variants. METHODS: IL 10 and IL-17F polymorphisms were genotyped in 419 asthmatic patients and 393 controls using Mass ARRAY. RESULTS: Our results showed an association between IL 10 SNPs and mild asthma. No association was found with any of three SNPs in moderate to severe asthma. Comparison of genotype distribution of IL-17F rs1887570 AA variant among atopic and non-atopic patients showed significant difference (p = 0.024). Correlation analysis of IL-10 and IL-17F SNPs to clinical variables showed a positive correlation between IL-17F rs1887570 AA and number of allergen sensitized (rs = 0.142, p = 0.004). Significant improvement in lung function was observed after 2 months of ICS (Inhaled corticosteroids) and LABA (long acting beta2 agonist) treatment in all subjects with no statistically significant difference among SNPs variants. Cytokines levels were similar in different SNP variants. CONCLUSION: We observed an association between IL-10 rs1800871 and rs1800896 SNPs and mild asthma, as well as IL-17F rs1887570 AA variant and number of allergens sensitized. PMID- 26108304 TI - A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans. AB - Empagliflozin (formerly known as BI 10773) is a potent, competitive, and selective inhibitor of the sodium glucose transporter SGLT2, which mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. Accordingly, empagliflozin treatment increased urinary glucose excretion. This has been observed across multiple species including humans and was reported under euglycemic conditions, in obesity and, most importantly, in type 2 diabetic patients and multiple animal models of type 2 diabetes and of type 1 diabetes. This led to a reduction in blood glucose, smaller blood glucose excursions during oral glucose tolerance tests, and, upon chronic treatment, a reduction in HbA1c in animal models and patients. In rodents, such effects were observed in early and late phases of experimental diabetes and were associated with preservation of pancreatic beta-cell function. Combination studies in animals demonstrated that beneficial metabolic effects of empagliflozin may also manifest when added to other types of anti-hyperglycemic treatments including linagliptin and pioglitazone. While some anti-hyperglycemic drugs lead to weight gain, empagliflozin treatment was associated with reduced body weight in normoglycemic obese and non-obese animals despite an increased food intake, largely due to a loss of adipose tissue; on the other hand, empagliflozin preserved body weight in models of type 1 diabetes. Empagliflozin improved endothelial dysfunction in diabetic rats and arterial stiffness, reduced blood pressure in diabetic patients, and attenuated early signs of nephropathy in diabetic animal models. Taken together, the SGLT2 inhibitor empagliflozin improves glucose metabolism by enhancing urinary glucose excretion; upon chronic administration, at least in animal models, the reductions in blood glucose levels are associated with beneficial effects on cardiovascular and renal complications of diabetes. PMID- 26108305 TI - How Long Do Adolescents Wait for Psychiatry Appointments? AB - Appointment wait times are a neglected dimension of children's access to psychiatry. We systematically examined how long an adolescent waits for a new patient appointment with a psychiatrist for routine medication management. From state directories, we identified 578 providers of adolescent psychiatric care in Ohio. Researchers posing as parents telephoned randomly selected offices, seeking care for a hypothetical 14-year-old patient under different scenarios. Overall, we measured 498 wait times at 140 unique offices. The median wait time was 50 days (interquartile range = 29-81 days). In adjusted models, adolescents with Medicaid waited longer than those with private insurance, especially during the spring (geometric mean = 50.9 vs. 41.9 days; p = 0.02). Wait times also varied markedly by region, with geometric means ranging from 22.4 to 75.1 days (p < 0.01). This study demonstrates that adolescents often experience lengthy wait times for routine care. This methodology represents a useful approach to real time monitoring of psychiatric services. PMID- 26108306 TI - Rapunzel syndrome presenting as jejuno-jejunal intussusception. AB - The term Rapunzel syndrome is used to describe a trichobezoar of the stomach with a long tail of hair extending into the duodenum and small intestine. It is a rare clinical entity, and it is even rarer in these cases that jejuno-jejunal intussusception and resulting intestinal obstruction is a presenting feature. We report one such case, a young female who presented in the emergency department with abdominal pain and bilious vomiting of short duration. Contrast-enhanced CT of the abdomen enabled a diagnosis of a trichobezoar in the stomach extending into the small gut, along with jejuno-jejunal intussusception. On exploration, gastrotomy was performed to remove the gastric trichobezoar, and jejuno-jejunal intussusception was found on three segments in the proximal jejunum, which was resolved upon complete removal of the tail of the bezoar. This case report is unusual, since intussusception is a rare occurrence in Rapunzel syndrome, and this is the first time that it has been diagnosed preoperatively. PMID- 26108307 TI - Testing of the Hospital Anxiety and Depression Scale in Patients With Chronic Obstructive Pulmonary Disease. AB - PURPOSE: The aim of this study was to develop the Arabic version of the Hospital Anxiety and Depression Scale (A-HADS) and test its psychometric proprieties for the assessment of anxiety and depression in patients with chronic obstructive pulmonary disease (COPD). METHOD: The A-HADS and Quality of Life Index Pulmonary version were completed by 67 Jordanian patients with COPD. RESULTS: Cronbach's alpha coefficient has been found to be 0.75 for the A-HADS anxiety subscale and 0.82 for the A-HADS depression subscale. A-HADS scores correlated significantly with the Quality of Life Index Pulmonary version and demonstrated construct validity. IMPLICATIONS: This preliminary validation study supports the A-HADS as a reliable and valid instrument for the assessment of anxiety and depression in Arabic speaking patients with COPD. PMID- 26108308 TI - Ganglion Impar Blocks for Coccydynia: A Case Series Prerequisite for Efficacy Trial. PMID- 26108309 TI - [Febrile seizures: some issues related to the diagnosis and treatment]. AB - Febrile seizures are the most common convulsive disorder and one of the most common nervous system diseases in childhood. Generally, the prognosis is good. Recent studies have revealed a greater understanding about many issues related to the diagnosis and treatment of febrile seizures, including the definition of febrile seizures, clinical diagnosis and evaluation, drug treatment, and prevention. Clinicians should note the association between febrile seizures and epilepsy syndromes. Excessive examination and treatment for patients should be avoided. Effective communication with the parents of patients and health education are also the key points of diagnosis and treatment. PMID- 26108310 TI - [Etiology and diagnosis of intellectual disability]. AB - Intellectual disability, occurring in 1%-3% of the general population, is a common disease of the nervous system in children. Since diverse genetic and environmental factors contribute to its pathogenesis, the etiological diagnosis of intellectual disability is challenging with respect to the selection of diagnostic tests. It is important to determine the etiology of intellectual disability for the assessment of prognosis, treatment and the family plan. This paper summarizes the research progress in etiology and diagnosis for intellectual disability and introduces the recommended clinical genetics diagnostic approach from the American Academy of Pediatrics. PMID- 26108311 TI - [Progress in diagnosis and treatment of intracranial hypertension and hydrocephalus in children with intracranial infections]. AB - Intracranial infections are one of the most common neurological diseases in children and are associated with high mortality and morbidity. Intracranial hypertension and hydrocephalus are the common, fatal complications of intracranial infections, so early diagnosis and timely treatment are the keys to saving patients' lives and reducing neurological sequelae. This paper introduces the progress in the etiology, diagnosis, and treatment of intracranial hypertension and hydrocephalus in children with intracranial infections. PMID- 26108312 TI - [MRI-DTI evaluation of punctate cerebral white matter damage in preterm infants]. AB - OBJECTIVE: To evaluate different degrees of punctate cerebral white matter damage (CWMD) using diffusion tensor imaging (DTI), and to investigate the value of DTI for CWMD in preterm infants. METHODS: Thirty-one preterm infants who were hospitalized in the Shengjing Hospital of China Medical University between November 2011 and April 2012 were enrolled and divided into focal CWMD (n=11), widespread CWMD (n=10), and normal groups (n=10). The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were determined in the periventricular regions of patients in three groups, and comparison of the two indices between the three groups was performed using one-way analysis of variance. The correlation between the changes in ADC and FA values was analyzed using the Pearson coefficient, and the color-encoded FA maps in the three groups were evaluated. RESULTS: The ADC values in the focal CWMD and widespread CWMD groups were both significantly higher than in the normal group, while the FA values in the focal CWMD and widespread CWMD groups were both significantly lower than in the normal group. The FA value in the widespread CWMD group was significantly lower than in the focal CWMD group. The color-encoded FA maps after post-processing indicated that the normal group had the highest FA value in the periventricular white matter regions, followed by the focal CWMD group and the widespread CWMD group. CONCLUSIONS: The DTI technique can quantitatively evaluate the degree of punctate CWMD. The FA value may be more accurate than the ADC value in the evaluation of CWMD. PMID- 26108313 TI - [Association of mammalian target of rapamycin gene polymorphisms with the risk of pediatric epilepsy]. AB - OBJECTIVE: To study the association between two single nucleotide polymorphisms (SNP), rs2295080 and rs2536, in mammalian target of rapamycin (mTOR) gene and the susceptibility to pediatric epilepsy. METHODS: A case- control study was performed on 480 children with epilepsy (116 cases of refractory epilepsy) and 503 healthy children. SNP rs2295080 and rs2536 in the mTOR gene were detected by polymerase chain reaction restriction and fragment length polymorphisms (PCR RFLP). Genotype and allele frequencies of SNP rs2295080 and rs2536 were compared between the children with epilepsy and healthy controls. RESULTS: There were no significant differences in the genotype and allele frequencies of SNP rs2295080 between the children with epilepsy and healthy controls. There were no significant differences in the genotype frequencies of SNP rs2536 between the two groups either, but the frequency of G allele of SNP rs2536 was higher in children with epilepsy than that in healthy controls (P=0.042, OR=1.344, 95%CI: 1.010 1.789). CONCLUSIONS: SNP rs2536 of mTOR gene may be associated with the risk of pediatric epilepsy. PMID- 26108314 TI - [Investigation of psychological state and its influencing factors in children with epilepsy]. AB - OBJECTIVE: To evaluate the psychological state of children with epilepsy and analyze its influencing factors. METHODS: The Mental Health Scale for Child and Adolescent was used to survey 113 children with epilepsy and 114 normal children to evaluate and compare their psychological state. Questionnaires were used to investigate the general status of all subjects and the disease condition and treatment of children with epilepsy. The possible influencing factors for the psychological state of children with epilepsy were analyzed. RESULTS: The mental health status of children with epilepsy was poorer than that of normal children in cognition, thinking, emotion, will-behavior, and personality traits (P<0.05). Multivariate logistic regression analysis showed that family education, family relations, seizure frequency, seizure duration, EEG epileptiform discharges in the last six months, and number of types of antiepileptic drugs were correlated with the psychological state of children with epilepsy. CONCLUSIONS: There is a wider range of psychological health problems in children with epilepsy than in normal children. Poor family living environment, poor seizure control, and use of many antiepileptic drugs are the risk factors affecting the psychological state of children with epilepsy. Improving family living environment, controlling seizures, and monotherapy help to improve the psychological state of children with epilepsy. PMID- 26108315 TI - [Relationship between Panayiotopoulos syndrome and Rolandic epilepsy]. PMID- 26108316 TI - [Purulent meningitis caused by group B streptococcus: report of two cases]. PMID- 26108317 TI - [Progressive motor and intellectual retardation for more than one year in a 4 year-old boy]. PMID- 26108318 TI - [Intermittent convulsions and progressive motor and intelligence regression for 4 years in a 11-year-old girl]. PMID- 26108319 TI - [Behavioral dysfunction for half a month accompanied by abnormal movements and sleep disorders for 5 days in a more than 2-year-old girl]. PMID- 26108320 TI - [Association between some factors in maternal pregnancy and childhood asthma with an onset before 3 years of age]. AB - OBJECTIVE: To study the association between some factors in maternal pregnancy and childhood asthma with an onset before 3 years of age, and to provide a basis for the prevention and treatment of childhood asthma and further research on its pathogenesis. METHODS: A retrospective clinical epidemiological study was carried out in 100 children with asthma (age of onset<3 years) and 100 children without allergic disease who were randomly selected as controls. The related information of children and mothers was investigated by questionnaire survey, including general information, medical history, personal and family allergic history, perinatal data, and mothers' health and lifestyle during their pregnancy such as diet, disease, and environmental exposure. The main survey indices were preliminarily analyzed, selected, and assigned, and then the data were subjected to univariate and multivariate logistic regression analyses. RESULTS: The univariate and multivariate logistic regression analyses showed that the fetal sex, history of atopic disease before pregnancy, history of respiratory infection in pregnancy, and the intake of fish, shrimp, crab, meat and spicy food in pregnancy were significantly associated with childhood asthma with an onset before 3 years of age, with odds ratios of 2.868, 5.051, 4.640, 3.746, 2.971, 3.075, and 2.225, respectively. CONCLUSIONS: Many factors in maternal pregnancy are associated with childhood asthma with an onset before 3 years of age, and the risk of which can be reduced by the prevention of respiratory infection and appropriate diet in pregnancy. PMID- 26108321 TI - [Quality control for maximal expiratory flow-volume curve as a pulmonary function test in school-age children]. AB - OBJECTIVE: To assess the quality control for the maximal expiratory flow-volume (MEFV) curve in school-age children. METHODS: Eight hundred and sixty-two children who had two or more MEFV manoeuvres were classified into >=6-year-old (n=379), >=8-year-old (n=210), >=10-year-old (n=64), and 12-17-year-old groups (n=109). The parameters of quality control and concordance with quality control criteria for MEFV were compared between the two groups. In addition, patients who were diagnosed with asthma were classified into two groups, one with normal pulmonary function (n=155) and the other with abnormal pulmonary function (n=62), based on the results of spirometry. Differences in the parameters of quality control for spirometry were compared between the two groups. RESULTS: Eight hundred and sixty-two children underwent 2 367 MEFV manoeuvres, 97.8% of which met the start of test criterion for backward extrapolated volume (VBE) of less than 0.15 L, with the highest concordance in the >=6-year-old group and the lowest concordance in the 12-17-year-old group. Three hundred and eighty-one children (44.2%) met the end of test criterion for forced expiratory time (FET) and the concordance in children over 10 years of age was lower than that in children under 10 years of age (P<0.05). Differences in two best forced expiratory volume in first second (FEV1) and forced vital capacity (FVC) manoeuvres were within 150 mL in 91.9% and 84.8%, respectively, of the children. The parameters of quality control for spirometry were better for asthmatic children with abnormal pulmonary function compared with asthmatic children with normal pulmonary function (P<0.05). CONCLUSIONS: Concordance with the start of test criteria and the manoeuvre repeatability criteria is high, whereas the concordance with the end of test criteria is low. It is suggested that the concordance with the FET criteria should be improved. PMID- 26108322 TI - [Epidemiological survey of Haemophilus influenzae-positive hospitalized children: a retrospective analysis]. AB - OBJECTIVE: To investigate the basic clinical characteristics and drug resistance of Haemophilus influenzae (Hi) infection in hospitalized children in the past two years. METHODS: A retrospective cross-sectional study was conducted to analyze Hi strains isolated from the sputum and pharyngeal swabs of children aged 0-17 years who were hospitalized in the Third People's Hospital of Chengdu between June 2011 and May 2013. RESULTS: A total of 117 strains were isolated from 111 hospitalized children. There were 102 cases (91.9%) of respiratory infection and 9 cases (8.1%) of other diseases. The positive rates of Hi in children with bronchopneumonia or pneumonia (50.8%, 30/59) and in children with acute laryngotracheobronchitis (50.0%, 2/4) were relatively high, followed by in children with capillary bronchitis (34.6%, 9/26), in children with acute bronchitis (24.2%, 32/132), in children with herpangina (19.0%, 4/21), in children with asthmatoid bronchitis (17.9%, 5/28), in children with acute upper respiratory tract infection (11.8%, 9/76), in children with acute tonsillitis (8.2%, 7/85), and in children with neonatal pneumonia (5.6%, 3/54). There were significant differences in the rates of resistance to amoxicillin-clavulanate (15% vs 23%; P=0.010) and chloramphenicol (25% vs 8%; P=0.015) between the two survey years. The frequencice of beta-lactamase-nonproducing-ampicillin-resistant (BLNAR) strains and beta-lactamase-producing-amoxicilli/clavulanate-resistant (BLPACR) strains increased from 12% to 21% and from 13% to 19% respectively during the two survey years (P>0.05). CONCLUSIONS: Hi plays an important role in the respiratory tract infection of children aged 0-17 years. The increasing trend of BLNAR and BLPACR rates makes it harder for antibiotic selection in clinical practice. PMID- 26108323 TI - [Clinical values and optimal cut-off points of basic vital signs in early identification of critical hand, foot, and mouth disease]. AB - OBJECTIVE: To study the clinical values of basic vital signs in early identification of critical hand-foot-mouth disease (HFMD). METHODS: The clinical data of 358 children with severe HFMD [212 cases in stage 2 (central nervous system involvement) and 146 cases in stage 3 (earlier stage of cardiopulmonary failure, critical type)] were reviewed. The diagnostic values of peak temperature and duration of fever, as well as the heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in different age groups, for critical HFMD (stage 3) were analyzed using the receiver operating characteristic (ROC) curve. RESULTS: HFMD might progress to critical type in case of HR>=148.5 beats/minutes, RR>=36.5 times/minutes, SBP>=95 mm Hg, and DBP>=59 mm Hg among children aged 0-1 year. HR>=142.5 times/minutes, RR>=31.5 times/mintes, SBP>=103 mm Hg, and DBP>=60.5 mm Hg in children aged 1-2 years had a certain diagnostic value for critical HFMD. HFMD might progress to critical type in case of HR>=139.5 times/minutes, RR>=29.5 times/minutes, and SBP>=103 mm Hg among children>=3 years of age. The sensitivity and specificity of every indicator were higher than 0.517 and 0.769, respectively. The area under the ROC curve (AUC) for peak temperature was 0.507 (P=0.816, compared with AUC=0.5). When the duration of fever was >=5.5 days, the sensitivity and specificity were 0.589 and 0.571, respectively. CONCLUSIONS: HR, RR, and BP are good indicators to identify critical HFMD (stage 3) early. The optimal cut-off points conform to the age characteristics of children. DBP in children>=3 years of age, peak temperature, and duration of fever have a low value in early identification of critical HFMD. PMID- 26108324 TI - [Relationship between heart rate variability and coronary artery lesion in children with Kawasaki disease]. AB - OBJECTIVE: To explore the correlation of heart rate variability (HRV) indices with cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT proBNP) in children with Kawasaki disease (KD) and their prognostic value. METHODS: A total of 130 children with KD were assigned into coronary artery lesion (CAL) group (n=47) and non-coronary artery lesion (NCAL) group (n=83). Meanwhile, 110 healthy children and 29 children in the recovery stage of non cardiovascular diseases were selected as control and non-KD groups, respectively. Patients in the four groups received 24-hour HRV monitoring. Levels of serum cTnI and NT-proBNP were measured in the KD and the non-KD group. RESULTS: Compared with the controls of the same sex and age, the KD patients had significantly reduced standard deviation of all normal sinus RR intervals (SDNN), mean of SDNN (SDNN index), percentage of successive normal sinus RR intervals>50 ms (pNN50), very low frequency (VLF), low frequency (LF), and high frequency (HF) but a significantly increased LF/HF ratio (P<0.05). The HRV indices including SDNN, standard deviation of all mean 5-minute RR intervals (SDANN), SDNN index, root mean squared successive difference, pNN50, VLF, LF, and HF in the CAL group all significantly decreased compared with those in the control and non-KD groups, while the LF/HF ratio was higher in the CAL group than in the control group (P<0.05). The serum levels of cTnI and NT-proBNP in the CAL and NCAL groups were significantly higher than those in the non-KD group (P<0.05). In children with KD, serum cTnI level was negatively correlated with SDNN and HF but positively correlated with the LF/HF ratio (P<0.05); serum NT-proBNP level was negatively correlated with SDNN, SDANN, and HF (P<0.05). CONCLUSIONS: HRV indices have certain clinical significance in assessing CAL of children with KD. PMID- 26108325 TI - [Clinical analysis of 52 cases of 21-hydroxylase-deficient congenital adrenal hyperplasia]. AB - OBJECTIVE: To gain more insight into congenital adrenal hyperplasia (CAH) by analyzing the clinical data of children with 21-hydroxylase-deficient CAH. METHODS: The clinical data of 52 children with 21-hydroxylase-deficient CAH were collected. Based on the disease severity and the presence of salt-losing manifestations, the children were classified into three groups: masculine type (n=15), salt-losing type (n=28), and atypical type (n=9). The clinical data of children with different types of CAH were analyzed and compared. RESULTS: The male-to-female ratio of the 52 cases was 1.6:1; the age of onset was less than 1 month after birth in 41 cases; 4 cases had a positive family history. Clitoral hypertrophy was the most common symptom in children with masculine CAH (87%). Pigmentation (89%), feeding difficulties and growth retardation (61%) were the most common symptoms in children with salt-losing CAH. Pigmentation (78%) was the most common symptom in children with atypical CAH. The three groups of children had different degrees of changes in the levels of adrenocorticotrophic hormone, cortisol, testosterone, and estradiol. Such changes were most pronounced in children with salt-losing CAH and were often accompanied by hyponatremia, hyperkalemia, and metabolic acidosis. After treatment with hydrocortisone and/or 9-alpha fluorohydrocortisone, cortical hormone levels improved in all the children, and the levels of cortisol, testosterone, estradiol, and electrolytes improved significantly after treatment in children with salt-losing CAH (P<0.05). In 22 patients who were followed up, 9 were re-hospitalized due to infection, and 8 developed sexual precocity. CONCLUSIONS: Different types of CAH have different clinical symptoms. It is important that hormone replacement should be initiated as early as possible to improve prognosis. PMID- 26108326 TI - [Clinical significance of determination of serum IgE in infants with milk allergy]. AB - OBJECTIVE: To determine the clinical significance of milk protein-specific IgE (sIgE) for infants with cow's milk protein allergy (CMPA). METHODS: Ninety-six infants with CMPA were divided into IgE+ group (n=26) and IgE- group (n=70) and clinical characteristics were compared between the two groups. Infants were denied allergy-inducing food and fed instead extensively hydrolyzed formulas or amino-acid formulas for 16 weeks before the two groups were compared. RESULTS: Twenty-seven percent of the infants were sIgE-seropositive. The first onset age of CMPA was significantly younger in the IgE+ group than in the IgE- group (P<0.05), and the family history of allergy and respiratory symptoms were significantly less common in the IgE- group than in the IgE+ group (P<0.05). Severe CMPA, gastrointestinal symptoms, underweight, growth retardation, anemia, and hypoproteinemia were significantly more common in the IgE- group than in the IgE+ group (P<0.05). Erythema, urticaria, vomiting, nasal discharge, cough, wheezing, and paroxysms of crying were major clinical symptoms of the IgE+ group, and their incidences were significantly higher in the IgE+ group than in the IgE- group (P<0.05); eczema, constipation, and diarrhea were major symptoms of the IgE group, and their incidences were significantly higher in the IgE- group than in the IgE+ group (P<0.05). The remission rate of each symptom was as high as over 80% in the two groups after 16 weeks of intervention and there was no significant difference in the remission rates between the two groups (P>0.05). CONCLUSIONS: IgE seropositive rate is not high in infants with CMPA. Atypical signs instead of allergic symptoms are more common in the IgE seronegative infants with CMPA. Avoiding allergy-inducing food and eating extensively hydrolyzed formulas or amino-acid formulas in early age benefit infants with IgE-mediated or non-IgE mediated CMPA. PMID- 26108327 TI - [Expression of leptin and its receptor in lungs of asthmatic BALB/c mice and effect of budesonide on their expression]. AB - OBJECTIVE: To determine the changes in the expression of leptin and its receptor in the lungs of mice with varying degrees of asthma before and after budesonide treatment. METHODS: Forty Balb/c mice were randomly assigned into 4 groups with 10 animals in each. One group received no treatment (control group) and the other groups were challenged with either nebulized ovalbumin (OVA) for three days (3 day group) or seven days (7-day group), or with nebulized ovalbumin followed by budesonide administration (treatment group). Changes in airway inflammation were observed using hematoxylin-eosin staining. The protein and mRNA levels of leptin and its receptor in lung tissues were determined using immunohistochemistry/Western blot and real-time PCR, respectively. RESULTS: The two asthmatic groups showed more significant pathological changes in the airway than the control and the treatment groups. Mice that were challenged by OVA for seven days showed more marked pathological changes in the airway compared with mice challenged by OVA for three days. The protein and mRNA levels of leptin in the lung tissues of the 3-day group were significantly higher than those of the control group (P<0.01), but significantly lower than those of the 7-day group (P<0.01). The protein levels of leptin receptor in the lung tissues of the 3-day group were significantly lower than those of the control group (P<0.01). The treatment group showed increased protein levels of leptin receptor compared with the 7-day group (P<0.01). No significant difference was noted between the four groups with respect to the mRNA levels of leptin receptor in the lung tissues. CONCLUSIONS: Leptin is highly expressed whereas its receptor is lowly expressed in the lung tissues of asthmatic mice. Budesonide can increase the expression of leptin receptor, but has no significant impact on the expression of leptin. PMID- 26108328 TI - [Roles of histone acetyltransferase and histone deacetylase in the pathogenesis of bronchial asthma]. AB - OBJECTIVE: To evaluate the roles of various cytokines, histone acetyltransferase (HAT) and histone deacetylase (HDAC) in the pathogenesis of bronchial asthma. METHODS: BALB/C mice were randomly assigned to control, untreated asthma, hormone treatment and TSA treatment groups. Bronchial asthma was induced by intraperitoneal injections and atomization inhalation of ovalbumin (OVA) in the asthma, hormone treatment and trichostatin (TSA) treatment groups. The mice in the hormone treatment and TSA treatment groups were administered with dexamethasone 1.0 mg/kg and TSA 1.0 mg/kg respectively by an intraperitoneal injection 30 minutes before challenge of asthma. At 24 hours after the last challenge, IL-4, IL-8 and IFN- levels in serum were measured using ELISA, and activities of HAT and HDAC in peripheral blood mononuclear cells (PBMC) were determined by the enzyme linked immunofluorescence assay. RESULTS: The serum levels of IL-4 and IL-8 in the untreated asthma group were higher than in the control, hormone treatment and TSA treatment groups (P<0.05). There was no difference in the serum levels of IL-4 and IL-8 among the control, hormone treatment and TSA treatment groups (P>0.05). The activity of HDAC in the untreated asthma group was lower than in the control, hormone treatment and TSA treatment groups (P<0.05). Hormone treatment significantly decreased the activity of HAT compared with the untreated asthma group (P<0.05). There was no difference in the activities of HAT and HDAC among the control, hormone treatment and TSA treatment groups (P>0.05). CONCLUSIONS: The decreased activity of HDAC leads to an increased secretion of inflammatory factors and thus induces asthma. PMID- 26108329 TI - [Efficacy and safety of tyrosine kinase inhibitor dasatinib plus chemotherapy in the treatment of childhood Philadelphia chromosome-positive acute lymphoblastic leukemia]. PMID- 26108330 TI - [Efficacy of continuous blood purification in the treatment of childhood fulminant myocarditis]. PMID- 26108331 TI - [Kawasaki disease complicated by ischemic cerebral stroke: a case report]. PMID- 26108332 TI - [Research advances in the role of JAK2 mutations in acute leukemia]. AB - The Janus kinase -signal transducer and activator of transcription (JAK-STAT) pathway plays pivotal roles in the regulation of cell proliferation, differentiation, migration and apoptosis, which is closely related with the development of hematopoietic cells and some hematological diseases. As an important signaling axis in JAK-STAT pathway, abnormally activated JAK2-STAT signaling is involved in the development of the hematological malignancies. JAK2V617F mutation is the important molecular pathogenesis of myeloproliferative disorders. Recent studies have demonstrated that JAK2 mutations are present in different acute leukemia subtypes and the frequency of mutations is different and that JAK2 mutations might be closely correlated with acute leukemia formation, treatment and prognosis. The pathogenic mechanism of JAK2 mutations has not been completely elucidated. JAK2 mutations might lead to JAK-STAT overactivation, resulting in the excessive proliferation, apoptosis resistance and differentiation blocking of blood cells. JAK2 inhibitors have been rapidly developed as targeted therapies for hematological disorders with JAK2 mutations. This article mainly focuses on recent studies about the role of JAK2 mutations in the pathogenesis, clinical characteristics and targeted therapies of acute leukemia. PMID- 26108333 TI - Importance of gene dosage in controlling dendritic arbor formation during development. AB - Proper dendrite morphology is crucial for normal nervous system functioning. While a number of genes have been implicated in dendrite morphogenesis in both invertebrates and mammals, it remains unclear how developing dendrites respond to changes in gene dosage and what type of patterns their responses may follow. To understand this, I review here evidence from the recent literature, focusing on the genetic studies performed in the Drosophila larval dendritic arborization class IV neuron, an excellent cell type to understand dendrite morphogenesis. I summarize how class IV arbors change morphology in response to developmental fluctuations in the expression levels of 47 genes, studied by means of genetic manipulations such as loss-of-function and gain-of-function, and for which sufficient information is available. I find that arbors can respond to changing gene dosage in several distinct ways, each characterized by a singular dose response curve. Interestingly, in 72% of cases arbors are sensitive, and thus adjust their morphology, in response to both decreases and increases in the expression of a given gene, indicating that dendrite morphogenesis is a process particularly sensitive to gene dosage. By summarizing the parallels between Drosophila and mammals, I show that many Drosophila dendrite morphogenesis genes have orthologs in mammals, and that some of these are associated with mammalian dendrite outgrowth and human neurodevelopmental disorders. One notable disease related molecule is kinase Dyrk1A, thought to be a causative factor in Down syndrome. Both increases and decreases in Dyrk1A gene dosage lead to impaired dendrite morphogenesis, which may contribute to Down syndrome pathoetiology. PMID- 26108335 TI - Editorial Comment from Dr Manning to Botulinum toxin type A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response. PMID- 26108334 TI - Evidence that Melanocortin Receptor Agonist Melanotan-II Synergistically Augments the Ability of Naltrexone to Blunt Binge-Like Ethanol Intake in Male C57BL/6J Mice. AB - BACKGROUND: The nonselective opioid receptor antagonist, naltrexone (NAL), reduces alcohol (ethanol [EtOH]) consumption in animals and humans and is an approved medication for treating alcohol abuse disorders. Proopiomelanocortin (POMC)-derived melanocortin (MC) and opioid peptides are produced in the same neurons in the brain, and recent preclinical evidence shows that MC receptor (MCR) agonists reduce excessive EtOH drinking in animal models. Interestingly, there is a growing body of literature revealing interactions between the MC and the opioid systems in the modulation of pain, drug tolerance, and food intake. METHODS: In the present report, a mouse model of binge EtOH drinking was employed to determine whether the MCR agonist, melanotan-II (MTII), would improve the effectiveness of NAL in reducing excessive binge-like EtOH drinking when these drugs were co-administered prior to EtOH access. RESULTS: Both NAL and MTII blunt binge-like EtOH drinking and associated blood EtOH levels, and when administered together, a low dose of MTII (0.26 mg/kg) produces a 7.6-fold increase in the effectiveness of NAL in reducing binge-like EtOH drinking. Using isobolographic analysis, it is demonstrated that MTII increases the effectiveness of NAL in a synergistic manner. CONCLUSIONS: The current observations suggest that activators of MC signaling may represent a new approach to treating alcohol abuse disorders and a way to potentially improve existing NAL-based therapies. PMID- 26108336 TI - Characterization of the First Fungal Glycosyl Hydrolase Family 19 Chitinase (NbchiA) from Nosema bombycis (Nb). AB - Chitinases (EC 3.2.1.14), as one kind of glycosyl hydrolase, hydrolyze the beta (1,4) linkages of chitin. According to the sequence similarity, chitinases can be divided into glycoside hydrolase family 18 and family 19. Here, a chitinase from Nosema bombycis (NbchiA) was cloned and purified by metal affinity chromatography and molecular exclusion chromatography. Sequence analysis indicated that NbchiA belongs to glycoside hydrolase family 19 class IV chitinase. The optimal pH and temperature of NbchiA are 7.0 and 40 degrees C, respectively. This purified chitinase showed high activity toward soluble substrates such as ethylene glycol chitin and soluble chitosan. The degradation of chitin oligosaccharides (GlcNAc)(2-5) detected by high-performance liquid chromatography showed that NbchiA hydrolyzed mainly the second glycosidic linkage from the reducing end of (GlcNAc)(3-5). On the basis of structure-based multiple-sequence alignment, Glu51 and Glu60 are believed to be the key catalytic residues. The site-directed mutation analysis revealed that the enzymatic activity was decreased upon mutation of Glu60, whereas mutation of Glu51 totally abolished the enzymatic activity. This is the first report of a GH19 chitinase in fungi and in Microsporidia. PMID- 26108337 TI - TIA Caused by Contrast Echocardiography in Patient with Platypnea-Orthodeoxia. AB - Platypnea-orthodeoxia syndrome (POS) is a rare clinical disorder characterized by dyspnea caused by the upright position and relieved at recumbent position. Few cases of POS and stroke were reported in literature, and the association between stroke and POS with evidence of patent foramen ovale (PFO) is rare. Stroke may occur in patients with cardiac shunt who undergo contrast echocardiography. We present a patient with POS who experienced transitory ischemic attack (TIA) most likely caused by injection of agitated saline microbubbles during screen for PFO. No case report of TIA/stroke during contrast echocardiography in patients with POS has previously been published. PMID- 26108338 TI - Leaf economics and hydraulic traits are decoupled in five species-rich tropical subtropical forests. AB - Leaf economics and hydraulic traits are critical to leaf photosynthesis, yet it is debated whether these two sets of traits vary in a fully coordinated manner or there is room for independent variation. Here, we tested the relationship between leaf economics traits, including leaf nitrogen concentration and leaf dry mass per area, and leaf hydraulic traits including stomatal density and vein density in five tropical-subtropical forests. Surprisingly, these two suites of traits were statistically decoupled. This decoupling suggests that independent trait dimensions exist within a leaf, with leaf economics dimension corresponding to light capture and tissue longevity, and the hydraulic dimension to water-use and leaf temperature maintenance. Clearly, leaf economics and hydraulic traits can vary independently, thus allowing for more possible plant trait combinations. Compared with a single trait dimension, multiple trait dimensions may better enable species adaptations to multifarious niche dimensions, promote diverse plant strategies and facilitate species coexistence. PMID- 26108339 TI - Associations among Depression Symptoms with Alcohol and Smoking Tobacco Use in Adult Patients with Congenital Heart Disease. AB - BACKGROUND: Adult congenital heart disease (ACHD) patients have high rates of untreated depression and anxiety disorders. We evaluated associations among self reported depression symptoms and alcohol/smoking tobacco use. METHODS: From 2009 to 2013, 202 ACHD patients (45% male) completed questionnaires on depressive symptoms, anxiety symptoms, and substance use as part of routine clinical care. Data were collected by retrospective chart review. RESULTS: Mean age was 31 +/- 10 years, 21% reported often feeling depressed and 33% reported feeling nervous or anxious. Sixty-one percent of patients reported some alcohol intake; 25% reported current or previous smoking tobacco use. Patients with depressive symptoms were 3* as likely to report drinking alcohol (OR 2.89; 95% CI 1.29-6.5) and 5* more likely to report smoking tobacco use (OR 5.17; 95% CI 1.49-17.87). Fourteen percent of patients were prescribed antidepressant/antianxiety medications; 43% of patients on medication reported depressive symptoms. In patients reporting symptoms, those who consumed alcohol were less likely to be on antidepressant/antianxiety medications (21%) than those who did not consume alcohol (56%). CONCLUSION: Self-reported depressive symptoms are associated with increased alcohol and smoking tobacco use by ACHD patients. Alcohol use may be a means of self-medicating for untreated depression, but further investigation is needed. Risk factors, including depressive symptoms and substance use, should be routinely assessed and addressed in ACHD patients. PMID- 26108340 TI - Antibiotic use in the care home setting: a retrospective cohort study analysing routine data. AB - BACKGROUND: Point prevalence studies in care homes show a high use of antibiotics, especially to treat urinary tract infections (UTI). There is a lack of large studies presenting annual antibiotic prescription data in care homes compared to those not in care homes. This study aimed to describe the pattern of antibiotic prescribing in those 75 years and over, with a focus on UTI. METHODS: In this retrospective longitudinal cohort study we used the Hampshire Health Record (HHR) containing routine data from general practices in Hampshire area, UK covering 1.24 million residents. Data were extracted throughout 2011 from the Hampshire Health Record on age, gender, care home status, antibiotic prescriptions, urinary catheters and comorbidity. Prescription pattern expressed as rate per 100 people. Nursing home residence defined by postcode. Logistic regression was used to assess independent risk of one or more antibiotic prescriptions in care home residents adjusting for age, sex and comorbidity, separately by catheter use. RESULTS: 102,020 of 1,244,313 residents in the Hampshire Health Record (8.2 %) were aged >=75 years of whom 7481 (7.3 %) were resident in care home settings. The annual antibiotic prescriptions increased from 53/100 inhabitants among those <75 years, to 142/100 among those >=75 years not in a care home and to 199/100 among those >=75 years in a care home. Care home residents with urinary catheters (4.4 %) had even higher use at 440/100 versus 188/100 if no catheter. UTI antibiotics showed a similar but more rapidly increasing pattern. For those in care homes without a urinary catheter, the odds ratio was 2.2 (2.1-2.3) higher for prescriptions of UTI antibiotics compared to those not in care homes after adjusting for age, gender and comorbidity. For those with a urinary catheter the odds ratio was 1.4 (1.1-1.8) for UTI antibiotics compared to those not in care homes. For all antibiotics the odds ratio was 1.2 (1.2-1.3). CONCLUSIONS: Residence in a care home setting is associated with high antibiotic consumption; this is especially evident for UTI antibiotics where the odds of prescription is doubled. PMID- 26108341 TI - Carbonic anhydrase inhibition blocks skeletogenesis and echinochrome production in Paracentrotus lividus and Heliocidaris tuberculata embryos and larvae. AB - Carbonic anhydrases (CAs) are a family of widely distributed metalloenzymes, involved in diverse physiological processes. These enzymes catalyse the reversible conversion of carbon dioxide to protons and bicarbonate. At least 19 genes encoding for CAs have been identified in the sea urchin genome, with one of these localized to the skeletogenic mesoderm (primary mesenchyme cells, PMCs). We investigated the effects of a specific inhibitor of CA, acetazolamide (AZ), on development of two sea urchin species with contrasting investment in skeleton production, Paracentrotus lividus and Heliocidaris tuberculata, to determine the role of CA on PMC differentiation, skeletogenesis and on non-skeletogenic mesodermal (NSM) cells. Embryos were cultured in the presence of AZ from the blastula stage prior to skeleton formation and development to the larval stage was monitored. At the dose of 8 mmol/L AZ, 98% and 90% of P. lividus and H. tuberculata embryos lacked skeleton, respectively. Nevertheless, an almost normal PMC differentiation was indicated by the expression of msp130, a PMC-specific marker. Strikingly, the AZ-treated embryos also lacked the echinochrome pigment produced by the pigment cells, a subpopulation of NSM cells with immune activities within the larva. Conversely, all ectoderm and endoderm derivatives and other subpopulations of mesoderm developed normally. The inhibitory effects of AZ were completely reversed after removal of the inhibitor from the medium. Our data, together with new information concerning the involvement of CA on skeleton formation, provide evidence for the first time of a possible role of the CAs in larval immune pigment cells. PMID- 26108342 TI - Characterization of progenitor cells and stem cells from the periodontal ligament tissue derived from a single person. AB - BACKGROUND: Periodontal ligament progenitor cells (PDLPs) and PDL stem cells (PDLSCs) are progenitor and stem cells that were isolated from PDL tissues using the outgrowth and single cell isolation methods respectively. The differences between PDLPs and PDLSCs characteristics could be observed from previous studies. However, these cells were obtained from different patients. This study was the first report to compare the characterization of PDLPs and PDLSCs from the same person. MATERIAL AND METHODS: The characterization of PDLPs and PDLSCs includes flow cytometry analysis, cell proliferation assay and the assessment of the colony-forming unit fibroblast. The osteogenic differentiation was evaluated by alkaline phosphatase activity, biomineralization (alizarin red staining) and gene expression of osteogenic markers. The adipogenic differentiation was examined by Oil Red O staining and adipocyte-related gene expression. RESULTS: Mesenchymal stem cell marker expression and colony-forming unit fibroblast analysis of PDLPs and PDLSCs were similar. However, PDLSCs grew faster than PDLPs on days 3 and 5 of the cell proliferation assay. Both PDLPs and PDLSCs could differentiate into osteoblast and adipocyte-like cells. However, the mineralization of PDLSCs was stronger than that of PDLPs. CONCLUSIONS: The characteristics of undifferentiated PDL cells in our study were not significantly impacted by the isolation method. We assumed that both PDLPs and PDLSCs are valuable cell sources for periodontal regeneration. However, PDLSCs have a possible advantage for the regeneration of alveolar bone. PMID- 26108343 TI - High expression of endoplasmic reticulum chaperone grp94 is a novel molecular hallmark of malignant plasma cells in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is a hematologic malignancy that is characterized by the proliferation of abnormal bone marrow plasma cells (BMPC) and overproduction of immunoglobulin or light chains with evidence of end-organ damage such as bone damage, anemia, hypercalcemia, and renal dysfunction. The pathogenesis of MM is closely linked to dysregulated unfolded protein response (UPR) in the endoplasmic reticulum (ER). Constitutive activation of UPR in mice, as demonstrated by transgenic expression of a master UPR transcription factor XBP1s (a UPR-specific splice variant of X-box binding protein 1), causes myeloma. grp94 (gp96) is a key downstream chaperone in the ER that mediates the UPR as a part of the protein quality control mechanism in the secretory pathway. Our recent study has shown that the persistence of plasma cells as well as the development of myeloma in XBP1s-transgenic mice is critically dependent on grp94. However, the role of grp94 in the initiation and progression of human MM is still unknown. METHODS: The expression level of grp94 in BMPCs was measured by flow cytometry, real-time RT-PCR, and Western blot analysis. We compared the expression levels of grp94 in BMPCs in a spectrum of patients including MM, monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), as well as non-plasma cell disorders (NPC). RESULTS: We found that grp94 was highly expressed in malignant plasma cells in patients with MM, but not in BMPCs in patients with MGUS/SMM and NPC. The expression level of grp94 correlated significantly with CD138 expression level. We also found that the grp94 expression level in BMPCs from International Staging System (ISS) stage III MM patients is higher than those in ISS stage I/II MM patients. CONCLUSIONS: grp94 is highly expressed in BMPCs in MM, which correlates with the advanced stage of this disease. Our data demonstrated that grp94 is a novel diagnostic and prognostic biomarker. It also positioned grp94 as a promising therapeutic target for MM. PMID- 26108344 TI - Prevalence of tetracycline resistance genes among multi-drug resistant bacteria from selected water distribution systems in southwestern Nigeria. AB - BACKGROUND: Antibiotic resistance genes [ARGs] in aquatic systems have drawn increasing attention they could be transferred horizontally to pathogenic bacteria. Water treatment plants (WTPs) are intended to provide quality and widely available water to the local populace they serve. However, WTPs in developing countries may not be dependable for clean water and they could serve as points of dissemination for antibiotic resistant bacteria. Only a few studies have investigated the occurrence of ARGs among these bacteria including tetracycline resistance genes in water distribution systems in Nigeria. METHODOLOGY: Multi-drug resistant (MDR) bacteria, including resistance to tetracycline, were isolated from treated and untreated water distribution systems in southwest Nigeria. MDR bacteria were resistant to >3 classes of antibiotics based on break-point assays. Isolates were characterized using partial 16S rDNA sequencing and PCR assays for six tetracycline-resistance genes. Plasmid conjugation was evaluated using E. coli strain DH5alpha as the recipient strain. RESULTS: Out of the 105 bacteria, 85 (81 %) and 20 (19 %) were Gram- negative or Gram- positive, respectively. Twenty-nine isolates carried at least one of the targeted tetracycline resistance genes including strains of Aeromonas, Alcaligenes, Bacillus, Klebsiella, Leucobacter, Morganella, Proteus and a sequence matching a previously uncultured bacteria. Tet(A) was the most prevalent (16/29) followed by tet(E) (4/29) and tet30 (2/29). Tet(O) was not detected in any of the isolates. Tet(A) was mostly found with Alcaligenes strains (9/10) and a combination of more than one resistance gene was observed only amongst Alcaligenes strains [tet(A) + tet30 (2/10), tet(A) + tet(E) (3/10), tet(E) + tet(M) (1/10), tet(E) + tet30 (1/10)]. Tet(A) was transferred by conjugation for five Alcaligenes and two E. coli isolates. CONCLUSIONS: This study found a high prevalence of plasmid-encoded tet(A) among Alcaligenes isolates, raising the possibility that this strain could shuttle resistance plasmids to pathogenic bacteria. PMID- 26108345 TI - Endovascular revascularization of a surgically ligated superficial femoral artery: A case report. AB - We present a case of a patient with left lower extremity ischemic rest pain who initially underwent surgical profundaplasty requiring ligation of his superficial femoral artery (SFA). The patient developed continued rest pain due to diffuse disease of his profunda and inadequate collaterals. Endovascular intervention was therefore performed to the oversewn SFA. Retrograde left SFA access was obtained and the origin of the SFA was recanalized with true lumen re-entry using an ultrasound guided re-entry catheter. Angioplasty was performed at the origin of the SFA and self-expanding stents were deployed in the proximal and mid left SFA. Hemostasis at the distal left SFA access site was obtained by balloon inflation at the access site and manual compression. This case illustrates the feasibility of endovascular repair of a ligated SFA. PMID- 26108346 TI - The wing and the eye: a parsimonious theory for scaling and growth control? AB - How a developing organ grows and patterns to its final shape is an important question in developmental biology. Studies of growth and patterning in the Drosophila wing imaginal disc have identified a key player, the morphogen Decapentaplegic (Dpp). These studies provided insights into our understanding of growth control and scaling: expansion of the Dpp gradient correlated with the growth of the tissue. A recent report on growth of a Drosophila organ other than the wing, the eye imaginal disc, prompts a reconsideration of our models of growth control. Despite striking differences between the two, the Dpp gradient scales with the target tissues of both organs and the growth of both the wing and the eye is controlled by Dpp. The goal of this review is to discuss whether a parsimonious model of scaling and growth control can explain the relationship between the Dpp gradient and growth in these two different developmental systems. PMID- 26108348 TI - Sinonasal outcomes in obstructive sleep apnea syndrome. AB - OBJECTIVES/HYPOTHESIS: Obstructive sleep apnea syndrome (OSAS) is a common adult and pediatric sleep disorder, which, if left untreated, is associated with severe medical consequences. Otolaryngologists are often challenged by the impact of OSAS on sinonasal symptoms, as well as by the contribution of primary nasal disorders to exacerbation of OSAS. The objectives of this study are to explore the relationship between patients with known OSAS and quality-of-life outcomes as measured by 22-iem Sino-Nasal Outcome Test (SNOT-22) questionnaire scores. STUDY DESIGN: Retrospective chart review. METHODS: Patients with a polysomnographic diagnosis of OSAS completed SNOT-22 questionnaires. SNOT-22 questionnaire items were subcategorized into rhinologic, nonrhinologic otolaryngic, sleep, and psychological symptoms. Total, individual, and subcategorized SNOT-22 scores were correlated with apnea-hypopnea index (AHI), body mass index (BMI), lowest oxygen desaturation, and sleep efficiency using Spearman rank correlation. RESULTS: A total of 30 consecutive OSAS patients were included in the analysis. BMI was positively correlated with nonrhinologic otolaryngic symptoms (P=.03), specifically ear fullness (P=.02) and facial pain/pressure (P=.04). AHI was negatively correlated with postnasal drip (P=.02). Lowest oxygen saturation was correlated with reduced productivity (P=.03). Sleep efficiency was negatively correlated with difficulty falling asleep (P=.03) and feelings of frustration (P=.01), with a trend toward significant correlation with overall sleep symptoms (P=.08). CONCLUSIONS: Several sinonasal complaints appear to be correlated with OSAS severity. As such, otolaryngologists should utilize a comprehensive approach to the care of the OSAS patient, with special attention to sinonasal factors. LEVEL OF EVIDENCE: NA. PMID- 26108349 TI - Stimulation of Cell Migration by Flagellin Through the p38 MAP Kinase Pathway in Cultured Intestinal Epithelial Cells. AB - Toll-like receptor 5 (TLR5) is a receptor for flagellin and is present on the basolateral surface of intestinal epithelial cells. However, the pathological roles of TLR5 in intestinal epithelial cells are not clear at present. In previous reports, we demonstrated that treatment of cultured alveolar epithelial cells with flagellin activated the p38 mitogen-activated protein kinase (MAPK) pathway and enhanced epithelial-mesenchymal transition induced by transforming growth factor beta 1 (TGF-beta1). In translating our findings in alveolar epithelial cells to intestinal epithelial cells, we found that both flagellin and TGF-beta1 activated p38 MAPK and its downstream protein kinase, MAPK-activated protein kinase-2 (MAPKAPK-2) in an IEC-6 intestinal epithelial cell line. The phosphorylation of HSP27, one of the substrates for MAPKAPK-2, was also increased. TGF-beta1 increased the protein level of alpha-smooth muscle actin (alphaSMA), and flagellin enhanced the effect of TGF-beta1. A wound healing assay revealed that flagellin and TGF-beta1 stimulated the migration of cells. SB203580, an inhibitor of p38 MAPK, and an inhibitor of MAPKAPK-2 inhibited flagellin-stimulated migration. These results suggested that TLR5 is involved in the migration of intestinal epithelial cells through activation of the p38 MAPK pathway. PMID- 26108347 TI - Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia. AB - Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. PMID- 26108350 TI - Differences in sedentary time and physical activity between female patients with fibromyalgia and healthy controls: the al-Andalus project. AB - OBJECTIVE: To characterize the levels of objectively measured time spent in sedentary activities (sedentary time) and physical activities in female patients with fibromyalgia and compare them with the levels in age-matched healthy control women. METHODS: The study comprised 413 female patients with fibromyalgia (mean +/- SD age 51.9 +/- 7.4 years) and 188 female control subjects (age 50.9 +/- 7.5 years). Sedentary time, the amount of time spent engaged in physical activity, and step counts were measured using triaxial accelerometry. The amounts of time (minutes/day) during which the participants were engaged in sedentary behaviors as well as in physical activity of different intensities (light, moderate, and moderate-to-vigorous) and the step counts were calculated. RESULTS: The amount of time spent in sedentary behavior was longer in patients with fibromyalgia compared with controls (estimated mean +/- SEM difference 39 +/- 8 minutes/day; P < 0.001). The patients with fibromyalgia spent less time than controls engaged in light physical activity (mean +/- SEM difference -21 +/- 7 minutes/day; P = 0.005), moderate physical activity (mean +/- SEM difference -17 +/- 3 minutes/day; P < 0.001), and moderate-to-vigorous physical activity (mean +/- SEM difference -19 +/- 3 minutes/day; P < 0.001). The patients with fibromyalgia took fewer steps/day compared with the control subjects (mean +/- SEM difference 1,881 +/- 262 steps/day; P < 0.001). Only 20.6% of the patients with fibromyalgia and 46.3% of the control subjects fulfilled the recommendation for 150 minutes/week of moderate-to-vigorous physical activity in bouts of at least 10 minutes/bout (chi(2) = 41.8, P < 0.001). Similarly, only 16.0% of the patients fulfilled the recommendation for >=10,000 steps/day compared with 44.7% of the control subjects (chi(2) = 56.8, P < 0.001). Both the patients and the control subjects were more active (physical activity of all intensities and numbers of steps) on weekdays than on weekend days (all P <= 0.001). CONCLUSION: Female patients with fibromyalgia spent more time in sedentary behaviors and were less physically active than age-matched controls. The low proportions of female patients with fibromyalgia and control subjects who met the physical activity and step count recommendations is worrisome. PMID- 26108351 TI - Regulatory perspective on minimal residual disease flow cytometry testing in multiple myeloma. AB - The FDA has co-sponsored three workshops to address minimal residual disease (MRD) detection in acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) as well as an FDA-NCI roundtable symposium on MRD detection and its use as a response biomarker in Multiple Myeloma (MM). As clinical outcomes in MM continue to improve with the introduction of new therapeutics, consideration of biomarkers and their development as validated surrogate endpoints that can be used in the place of traditional clinical trial endpoints of progression-free survival (PFS) will be fundamental to expeditious drug development. This article will describe the FDA drug approval process, the regulatory framework through which a biomarker can be used as a surrogate endpoint for drug approval, and how MRD detection in MM fits within this context. In parallel, this article will also describe the FDA current device clearance process with emphasis on the analytical development as it might apply to an in vitro diagnostic assay for the detection of MRD in MM. It is anticipated that this Special Issue may possibly represent how MRD might serve as a drug development tool in hematological malignancies. PMID- 26108352 TI - Impact of detector design on imaging performance of a long axial field-of-view, whole-body PET scanner. AB - Current generation of commercial time-of-flight (TOF) PET scanners utilize 20-25 mm thick LSO or LYSO crystals and have an axial FOV (AFOV) in the range of 16-22 mm. Longer AFOV scanners would provide increased intrinsic sensitivity and require fewer bed positions for whole-body imaging. Recent simulation work has investigated the sensitivity gains that can be achieved with these long AFOV scanners, and has motivated new areas of investigation such as imaging with a very low dose of injected activity as well as providing whole-body dynamic imaging capability in one bed position. In this simulation work we model a 72 cm long scanner and prioritize the detector design choices in terms of timing resolution, crystal size (spatial resolution), crystal thickness (detector sensitivity), and depth-of-interaction (DOI) measurement capability. The generated list data are reconstructed with a list-mode OSEM algorithm using a Gaussian TOF kernel that depends on the timing resolution and blob basis functions for regularization. We use lesion phantoms and clinically relevant metrics for lesion detectability and contrast measurement. The scan time was fixed at 10 min for imaging a 100 cm long object assuming a 50% overlap between adjacent bed positions. Results show that a 72 cm long scanner can provide a factor of ten reduction in injected activity compared to an identical 18 cm long scanner to get equivalent lesion detectability. While improved timing resolution leads to further gains, using 3 mm (as opposed to 4 mm) wide crystals does not show any significant benefits for lesion detectability. A detector providing 2 level DOI information with equal crystal thickness also does not show significant gains. Finally, a 15 mm thick crystal leads to lower lesion detectability than a 20 mm thick crystal when keeping all other detector parameters (crystal width, timing resolution, and DOI capability) the same. However, improved timing performance with 15 mm thick crystals can provide similar or better performance than that achieved by a detector using 20 mm thick crystals. PMID- 26108353 TI - "The ABCs of AD": A prospective evaluation of the efficacy of an educational intervention to increase knowledge of autonomic dysreflexia management among emergency health care professionals. AB - CONTEXT/OBJECTIVE: Despite the availability of consensus-based resources, first responders and emergency room (ER) health care professionals (HCPs) have limited knowledge regarding autonomic dysreflexia (AD) recognition and treatment. The purpose of this study was to assess the efficacy of "The ABCs of AD" educational seminar for improving HCPs' short- and long-term knowledge of AD recognition, diagnosis, and management. DESIGN: Multi-center prospective pre, post, and follow up questionnaire study. SETTING: Level I trauma centers with emergency departments in British Columbia, Manitoba, and Ontario. METHODS: ER professionals completed measures immediately before and after (n = 108), as well as 3-months following (n = 23), attendance at "The ABCs of AD" seminar. OUTCOME MEASURES: AD knowledge test; seminar feedback. RESULTS: Following the seminar, participants had higher ratings of their AD knowledge and had significantly higher AD knowledge test scores (M +/- SD pre = 11.85 +/- 3.88, M +/- SD post = 18.95 +/- 2.39, out of 22; P < 0.001, d = 2.21). Most participants believed the seminar changed their AD knowledge, and rated the seminar information as having the potential to influence and change their practice. AD knowledge test scores significantly decreased between post-seminar and 3-month follow-up (M +/- SD 3mo = 17.04 +/- 3.28; P = 0.004, d = -0.70); however, 3-month scores remained significantly higher than baseline. CONCLUSION: "The ABCs of AD" seminar improves HCPs' perceived and actual AD knowledge in the short-term. To enhance knowledge retention in both the short- and long-term, the inclusion of additional active learning strategies and follow-up activities are recommended. The seminar is being translated into an online training module to enhance the dissemination of the AD clinical practice guidelines among first responders, ER staff, and SCI practitioners. PMID- 26108354 TI - Comparison of different drying methods on the physical properties, bioactive compounds and antioxidant activity of raspberry powders. AB - BACKGROUND: Dehydration has been considered as one of the traditional but most effective techniques for perishable fruits. Raspberry powders obtained after dehydration can be added as ingredients into food formulations such as bakery and dairy products. In this study, raspberry powders obtained by hot air drying (HAD), infrared radiation drying (IRD), hot air and explosion puffing drying (HA EPD), infrared radiation and microwave vacuum drying (IR-MVD) and freeze drying (FD) were compared on physical properties, bioactive compounds and antioxidant activity. RESULTS: Drying techniques affected the physical properties, bioactive compounds and antioxidant activity of raspberry powders greatly. FD led to significantly higher (P < 0.05) values of water solubility (45.26%), soluble solid (63.46%), hygroscopicity (18.06%), color parameters and anthocyanin retention (60.70%) of raspberry powder compared with other drying methods. However, thermal drying techniques, especially combined drying methods, were superior to FD in final total polyphenol content, total flavonoid content and antioxidant activity. The combined drying methods, especially IR-MVD, showed the highest total polyphenol content (123.22 g GAE kg(-1) dw) and total flavonoid content (0.30 g CAE kg(-1) dw). Additionally, IR-MVD performed better in antioxidant activity retention. CONCLUSION: Overall, combined drying methods, especially IR-MVD, were found to result in better quality of raspberry powders among the thermal drying techniques. IR-MVD could be recommended for use in the drying industry because of its advantages in time saving and nutrient retention. PMID- 26108355 TI - AMPKalpha2 reduces renal epithelial transdifferentiation and inflammation after injury through interaction with CK2beta. AB - TGFbeta1/Smad, Wnt/beta-catenin and snail1 are preferentially activated in renal tubular epithelia after injury, leading to epithelial-mesenchymal transition (EMT). The stress response is coupled to EMT and kidney injury; however, the underlying mechanism of the stress response in EMT remains elusive. AMP-activated protein kinase (AMPK) signalling is responsive to stress and regulates cell energy balance and differentiation. We found that knockdown of AMPKalpha, especially AMPKalpha2, enhanced EMT by up-regulating beta-catenin and Smad3 in vitro. AMPKalpha2 deficiency enhanced EMT and fibrosis in a murine unilateral ureteral obstruction (UUO) model. AMPKalpha2 deficiency also increased the expression of chemokines KC and MCP-1, along with enhanced infiltration of inflammatory cells into the kidney after UUO. CK2beta interacted physically with AMPKalpha and enhanced AMPKalpha Thr172 phosphorylation and its catalytic activity. Thus, activated AMPKalpha signalling suppresses EMT and secretion of chemokines in renal tubular epithelia through interaction with CK2beta to attenuate renal injury. PMID- 26108356 TI - Novel drugs in clinical development for hepatocellular carcinoma. AB - INTRODUCTION: Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. AREAS COVERED: This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. EXPERT OPINION: In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline alpha-fetoprotein (AFP) >= 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC. PMID- 26108358 TI - Evaluating the enantioselective distribution, degradation and excretion of epoxiconazole in mice following a single oral gavage. AB - 1. The enantiomeric enrichment or degradation of epoxiconazole has been reported in grape, soil, tubifex and mealworm beetle. But, little is known about its enantioselective behaviors in mammals. 2. To further understand differences in the distribution, degradation and excretion of epoxiconazole enantiomers in vivo, male CD-1 mice were selected as the test model to investigate the enantioselective behaviors after a single oral gavage. Mice were sacrificed after 1 h, 3 h, 7 h, 12 h, 24 h, 48 h, 72 h treatment, blood, tissues and excretions were collected for epoxiconazole analysis by LC-MS/MS. 3. On the Lux-Cellulose-1 chiral column, an enrichment of the second eluting (+)-epoxiconazole was generally observed, and feces and urine showed similar EF with major tissues. 4. To elucidate the potential role of intestinal bacterial flora in stereospecific degradation of epoxiconazole, mice fecal flora were cultured in vitro and incubated with epoxiconazole for 48 h. Results showed that (-)-epoxiconazole was preferentially degraded by intestinal bacterial. 5. These results may provide useful information for risk assessment of epoxiconazole on non-target animals. PMID- 26108357 TI - Comet assay measures of DNA damage as biomarkers of irinotecan response in colorectal cancer in vitro and in vivo. AB - The use of irinotecan to treat metastatic colorectal cancer (CRC) is limited by unpredictable response and variable toxicity; however, no reliable clinical biomarkers are available. Here, we report a study to ascertain whether irinotecan induced DNA damage measures are suitable/superior biomarkers of irinotecan effect. CRC-cell lines (HCT-116 and HT-29) were treated in vitro with irinotecan and peripheral blood lymphocytes (PBL) were isolated from patients before and after receiving irinotecan-based chemotherapy. Levels of in vitro-, in vivo-, and ex vivo-induced DNA damage were measured using the Comet assay; correlations between damage levels with in vitro cell survival and follow-up clinical data were investigated. Irinotecan-induced DNA damage was detectable in both CRC cell lines in vitro, with higher levels of immediate and residual damage noted for the more sensitive HT-29 cells. DNA damage was not detected in vivo, but was measurable in PBLs upon mitogenic stimulation prior to ex vivo SN-38 treatment. Results showed that, following corrections for experimental error, those patients whose PBLs demonstrated higher levels of DNA damage following 10 h of SN-38 exposure ex vivo had significantly longer times to progression than those with lower damage levels (median 291 vs. 173 days, P = 0.014). To conclude, higher levels of irinotecan-induced initial and residual damage correlated with greater cell kill in vitro and a better clinical response. Consequently, DNA damage measures may represent superior biomarkers of irinotecan effect compared to the more often-studied genetic assays for differential drug metabolism. PMID- 26108359 TI - Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation. AB - Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFkappaB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFkappaB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring. PMID- 26108364 TI - Convergence in urban-rural prevalence of hypertension in India. AB - Hypertension has emerged as important public health problem in India. During the later half of the last century, epidemiological studies in India reported that hypertension (diagnosed by systolic blood pressure (BP) ?160 and/or diastolic BP ?95 mm Hg) increased from about 1% in 1950's to 15% in 1990's in urban (R(2)=0.47) and from 0.5 to 7% in rural (R(2)=0.21) populations. Hypertension epidemiological studies from India in the last twenty years have shown that prevalence of hypertension (diagnosed by systolic BP ?140 mm Hg and/or diastolic BP ?90 mm Hg) in urban locations has stabilized to about 25-30% (R(2)=0.08) but it has increased in rural populations from 15 to 25% (R(2)=0.04). This urban rural convergence of hypertension in India is due to rapid urbanization of rural populations with consequent changes in lifestyles (sedentariness, high dietary salt, sugar and fat intake) and increase in overweight and obesity. Hypertension prevention, screening and control, policies and programs, need to be widely implemented in India, especially in rural populations. PMID- 26108363 TI - Undiagnosed hypertension in a rural district in Bangladesh: The Bangladesh Population-based Diabetes and Eye Study (BPDES). AB - Hypertension is mainly asymptomatic and remains undiagnosed until the disease progresses. The objective of the study was to determine the prevalence of and risk factors for hypertension in rural Bangladesh. Using a population-based cluster random sampling strategy, 3096 adults aged ?30 years were recruited from a rural district in Bangladesh. Data collected included two blood pressure (BP) measurements, fasting blood glucose, socio-demographic and anthropometric measurements. Hypertension was defined as systolic BP (SBP) ?140 mm Hg or diastolic BP (DBP) ?90 mm Hg or self-reported diagnosed hypertension. Logistic regression techniques were used for data analyses. The crude prevalence of hypertension was 40% (95% confidence interval (CI) 38-42%) of which 82% were previously undiagnosed. People from lower socio-economic status (SES) had a significantly higher percentage of undiagnosed hypertension compared with people with higher SES (P<0.001). There was no significant gender difference in severity of hypertension. Males with higher education level compared with no education had a higher prevalence of hypertension (odds ratio 2.34, 95% CI 1.49-3.69). Older age and waist circumference in both genders, and diabetes, lack of physical activity in females were found to be associated with higher prevalence of hypertension. Our research suggests the prevalence of undiagnosed hypertension was higher in the rural area in Bangladesh than that reported from the rural area in neighbouring India and China. Lower SES was associated with a higher risk of undiagnosed hypertension. Public health programs at the grass-roots level must emphasise the provision of primary care and preventive services in managing this non-communicable disease. PMID- 26108365 TI - Metabolic syndrome is associated with left ventricular dilatation in primary hypertension. AB - Metabolic syndrome (MS) has been shown to predict cardiovascular events in hypertension. Recently, a new four-group left ventricular (LV) hypertrophy classification based on both LV dilatation and concentricity was proposed. This classification has been shown to provide a more accurate prediction of cardiovascular events, suggesting that the presence of LV dilatation may add prognostic information. We investigated the relationship between MS and the new classification of LV geometry in patients with primary hypertension. A total of 372 untreated hypertensive patients were studied. Four different patterns of LV hypertrophy (eccentric nondilated, eccentric dilated, concentric nondilated and concentric dilated hypertrophy) were identified by echocardiography. A modified National Cholesterol Education Program definition for MS was used, with body mass index replacing waist circumference. The overall prevalence of MS and LV hypertrophy (LVH) was 29% and 61%, respectively. Patients with MS showed a higher prevalence of LVH (P=0.0281) and dilated LV geometries, namely eccentric dilated and concentric dilated hypertrophy (P=0.0075). Moreover, patients with MS showed higher LV end-diastolic volume (P=0.0005) and prevalence of increased LV end diastolic volume (P=0.0068). The prevalence of LV chamber dilatation increased progressively with the number of components of MS (P=0.0191). Logistic regression analysis showed that the presence of MS entails a three times higher risk of having LV chamber dilatation even after adjusting for several potential confounding factors. MS is associated with LV dilatation in hypertension. These findings may, in part, explain the unfavourable prognosis observed in patients with MS. PMID- 26108366 TI - Modification over time of pulse wave velocity parallel to changes in aortic BP, as well as in 24-h ambulatory brachial BP. AB - Arterial stiffness as assessed by carotid-femoral pulse wave velocity (cfPWV) is a marker of preclinical organ damage and a predictor of cardiovascular outcomes, independently of blood pressure (BP). However, limited evidence exists on the association between long-term variation (Delta) on aortic BP (aoBP) and DeltacfPWV. We aimed to evaluate the relationship of DeltaBP with DeltacfPWV over time, as assessed by office and 24-h ambulatory peripheral BP, and aoBP. AoBP and cfPWV were evaluated in 209 hypertensive patients with either diabetes or metabolic syndrome by applanation tonometry (Sphygmocor) at baseline(b) and at 12 months of follow-up(fu). Peripheral BP was also determined by using validated oscillometric devices (office(o)-BP) and on an outpatient basis by using a validated (Spacelabs-90207) device (24-h ambulatory BP). DeltacfPWV over time was calculated as follows: DeltacfPWV=[(cfPWVfu-cfPWVb)/cfPWVb] * 100. DeltaBP over time resulted from the same formula applied to BP values obtained with the three different measurement techniques. Correlations (Spearman 'Rho') between DeltaBP and DeltacfPWV were calculated. Mean age was 62 years, 39% were female and 80% had type 2 diabetes. Baseline office brachial BP (mm Hg) was 143+/-20/82+/-12. Follow-up (12 months later) office brachial BP (mm Hg) was 136+/-20/79+/-12. DeltacfPWV correlated with DeltaoSBP (Rho=0.212; P=0.002), Delta24-h SBP (Rho=0.254; P<0.001), Deltadaytime SBP (Rho=0.232; P=0.001), Deltanighttime SBP (Rho=0.320; P<0.001) and DeltaaoSBP (Rho=0.320; P<0.001). A multiple linear regression analysis included the following independent variables: DeltaoSBP, Delta24-h SBP, Deltadaytime SBP, Deltanighttime SBP and DeltaaoSBP. DeltacfPWV was independently associated with Delta24-h SBP (beta-coefficient=0.195; P=0.012) and DeltaaoSBP (beta-coefficient= 0.185; P=0.018). We conclude that changes in both 24-h SBP and aoSBP more accurately reflect changes in arterial stiffness than do office BP measurements. PMID- 26108368 TI - The effect of land-use on the diversity and mass-abundance relationships of understory avian insectivores in Sri Lanka and southern India. AB - Understory avian insectivores are especially sensitive to deforestation, although regional differences in how these species respond to human disturbance may be linked to varying land-use histories. South Asia experienced widespread conversion of forest to agriculture in the nineteenth century, providing a comparison to tropical areas deforested more recently. In Sri Lanka and the Western Ghats of India, we compared understory insectivores to other guilds, and to insectivores with different vertical strata preferences, both inside mixed species flocks and for the whole bird community. Overall species richness did not change across the land-use gradient, although there was substantial turnover in species composition between land-use types. We found that the proportion of species represented by insectivores was ~1.14 times higher in forest compared to agriculture, and the proportion of insectivores represented by understory species was ~1.32 times higher in forests. Mass-abundance relationships were very different when analyzed on mixed-species flocks compared to the total community, perhaps indicating reduced competition in these mutualisms. We show that South Asia fits the worldwide pattern of understory insectivores declining with increased land-use intensity, and conclude that these species can be used globally as indicator and/or umbrella species for conservation across different disturbance time scales. PMID- 26108367 TI - Wild type human TDP-43 potentiates ALS-linked mutant TDP-43 driven progressive motor and cortical neuron degeneration with pathological features of ALS. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder, and cytoplasmic inclusions containing transactive response (TAR) DNA binding protein (TDP-43) are present in ~90 % of cases. Here we report detailed pathology in human TDP-43 transgenic mice that recapitulate key features of TDP-43-linked ALS. RESULTS: Expression of human wild-type TDP-43 (TDP-43(WT)) caused no clinical or pathological phenotype, while expression of Q331K mutant (TDP-43(Q331K)) resulted in a non-lethal age-dependent motor phenotype, accompanied by cytoplasmic TDP-43 aggregation, mild neuronal loss, with astroglial and microglial activation in the motor cortex and spinal cord at 24 months. However, co-expression of WT and Q331K mutant (TDP-43(WTxQ331K)) resulted in an extremely aggressive motor phenotype with tremor from 3 weeks and progressive hind-limb paralysis necessitating euthanasia by 8-10 weeks of age. Neuronal loss and reactive gliosis was observed in the spinal cord and layer V region of the cortex, with TDP-43, ubiquitin and p62 cytoplasmic inclusions and an increase in insoluble TDP-43. Nuclear clearance of TDP-43 was not observed in TDP-43(Q331K) mice but was seen in 65 % of aggregate containing spinal cord motor neurons in TDP-43(WTxQ331K) mice. CONCLUSIONS: We hypothesise that cytoplasmic TDP-43(Q331K) aggregates facilitate the recruitment of WT protein in compound animals, which dramatically accelerates neurodegeneration and disease progression. The exploration of disease mechanisms in slow and rapid disease models of TDP-43 proteinopathy will help elucidate novel drug targets and provide a more informative platform for preclinical trials. PMID- 26108370 TI - Mapping plasmonic topological states at the nanoscale. AB - We report on the first experimental observation of topological edge states in zigzag chains of plasmonic nanodisks. We demonstrate that such edge states can be selectively excited with the linear polarization of the incident light, and visualize them directly by near-field scanning optical microscopy. Our work provides experimental verification of a novel paradigm for manipulating light at the nanoscale in topologically nontrivial structures. PMID- 26108369 TI - Force-induced chemical reactions on the metal centre in a single metalloprotein molecule. AB - Metalloproteins play indispensable roles in biology owing to the versatile chemical reactivity of metal centres. However, studying their reactivity in many metalloproteins is challenging, as protein three-dimensional structure encloses labile metal centres, thus limiting their access to reactants and impeding direct measurements. Here we demonstrate the use of single-molecule atomic force microscopy to induce partial unfolding to expose metal centres in metalloproteins to aqueous solution, thus allowing for studying their chemical reactivity in aqueous solution for the first time. As a proof-of-principle, we demonstrate two chemical reactions for the FeS4 centre in rubredoxin: electrophilic protonation and nucleophilic ligand substitution. Our results show that protonation and ligand substitution result in mechanical destabilization of the FeS4 centre. Quantum chemical calculations corroborated experimental results and revealed detailed reaction mechanisms. We anticipate that this novel approach will provide insights into chemical reactivity of metal centres in metalloproteins under biologically more relevant conditions. PMID- 26108371 TI - A new mechanism for low and temperature-independent elastic modulus. AB - The first Elinvar alloy, FeNiCr, which has invariant elastic modulus over a wide temperature range, was discovered almost 100 years ago by Guillaume. The physical origin of such an anomaly has been attributed to the magnetic phase transition taking place in the system. However, the recent discovery of non-magnetic Elinvar such as multi-functional beta-type Ti alloys has imposed a new challenge to the existing theories. In this study we show that random field from stress-carrying defects could suppress the sharp first-order martensitic transformation into a continuous strain glass transition, leading to continued formation and confined growth of nano-domains of martensite in a broad temperature range. Accompanying such a unique transition, there is a gradual softening of the elastic modulus over a wide temperature range, which compensates the normal modulus hardening due to anharmonic atomic vibration, resulting in a low and temperature-independent elastic modulus. The abundance of austenite/martensite interfaces are found responsible for the low elastic modulus. PMID- 26108372 TI - Caenorhabditis elegans is a useful model for anthelmintic discovery. AB - Parasitic nematodes infect one quarter of the world's population and impact all humans through widespread infection of crops and livestock. Resistance to current anthelmintics has prompted the search for new drugs. Traditional screens that rely on parasitic worms are costly and labour intensive and target-based approaches have failed to yield novel anthelmintics. Here, we present our screen of 67,012 compounds to identify those that kill the non-parasitic nematode Caenorhabditis elegans. We then rescreen our hits in two parasitic nematode species and two vertebrate models (HEK293 cells and zebrafish), and identify 30 structurally distinct anthelmintic lead molecules. Genetic screens of 19 million C. elegans mutants reveal those nematicides for which the generation of resistance is and is not likely. We identify the target of one lead with nematode specificity and nanomolar potency as complex II of the electron transport chain. This work establishes C. elegans as an effective and cost-efficient model system for anthelmintic discovery. PMID- 26108373 TI - Prolonged patients' In-Hospital Waiting Period after discharge eligibility is associated with increased risk of infection, morbidity and mortality: a retrospective cohort analysis. AB - BACKGROUND: Prolonged, inappropriate hospital stay after patients' eligibility for discharge from internal medicine departments is a world-wide health-care systems' problem. Nevertheless, the extent to which such surplus hospital stays are associated with infectious complications, their time frame of appearance and their long-term implications was not previously addressed. METHODS: We conducted a retrospective cohort analysis of patients experiencing an In-hospital Waiting Period (IHWP) after discharge eligibility in a single, tertiary hospital. RESULTS: We screened the records of 245 patients out of which 104 patients fulfilled our inclusion criteria. The mean length of IHWP was 15.7 +/- 4.79 day during which 9(8.7 %) patients died. The study primary composite end-point, in hospital mortality or hospital acquired infection (pneumonia, UTI or sepsis) occurred in 32(31 %) patients. The most hazardous time was during the first 3 IHWP days: 63.7 % of patients experienced a complication and 44 % of the total complications occurred during this period. The occurrence of any complication during IHWP was associated, with statistical significance, with increased risk of mortality during the first year after IHWP initiation (HR = 6.02, p = 0.014). CONCLUSION: Prolongation of hospital stay after patients are deemed to be discharged from internal medicine departments is associated with increased morbidity and mortality, mainly during the first surplus days of in-hospital stay. Efforts should be made to shorten such hospital stays as much as possible. PMID- 26108375 TI - DFT studies on the directing group dependent arene-alkene cross-couplings: arene activation vs. alkene activation. AB - Due to its green-chemistry advantages, the dehydrogenative Heck reaction (DHR) has experienced enormous growth over the past few decades. In this work, two competing reaction channels were comparatively studied for the Pd(OAc)2-catalyzed DHRs of arenes with alkenes, referred to herein as the arene activation mechanism and the alkene activation mechanism, respectively, which mainly differ in the involvement of the reactants in the C-H activation step. Our calculations reveal that the commonly accepted arene activation mechanism is plausible for the desired arene-alkene cross-coupling; in contrast, the alternative alkene activation mechanism is kinetically inaccessible for the desired cross-coupling, but it is feasible for the homo-coupling of alkenes. The nature of directing groups on reactants could mainly determine the dominance of the two competing reaction routes, and therefore, influence the experimental yields. A wide range of directing groups experimentally used are examined by the density functional theory (DFT) method in this work, providing theoretical guidance for screening compatible reactants. PMID- 26108376 TI - The Missing Memristor has Not been Found. AB - In 1971, not only the theoretical and by definition already existing 'ideal memristor' concept was introduced, but a real memristor device was suggested on grounds of the already known real inductors. The latter is a scientifically significant hypothesis grounded in fundamental symmetries of basic physics, here electro-magnetism. 2008 claimed the discovery of the "missing memristor." Controversy arose: The devices were not new, and the hypothesized device needs magnetism but has no material memory, while the available devices constitute analogue memory that would work in a world without magnetism. Nevertheless, even the originator of the prediction accepted the discovery. Defenders of the 2008 claim emphasize that the devices are not merely 'memristive systems,' which is however a distinction defined in 1976, not 1971. We clarify widely confused concepts and maintain that the originally hypothesized real memristor device is missing and likely impossible. The argument is illustrated also by finding an ideal mechanical memristor element and purely mechanical memristive systems, and hypothesizing a real mechanical memristor device that requires inert mass just like the 1971 implied device requires magnetic induction. PMID- 26108377 TI - Pharmacist Substitution of Biological Products: Issues and Considerations. AB - Biosimilars are biological products that are highly similar to their biological reference products, notwithstanding minor differences in clinically inactive components. However, unlike generics of small-molecule drugs, biosimilars are not identical to their reference products, since each manufacturer uses unique cell lines and processes, and these lead to slight structural differences between products. Because these structural variations can lead to differences in clinical response, clinical studies demonstrating biosimilarity are required before and robust pharmacovigilance after approval. Although the FDA has not yet issued formal guidance on interchangeable biosimilars, higher standards of similarity will be required in order to achieve an interchangeable designation. In this commentary, we review the differences between generics and biosimilars, describe their respective regulatory approval pathways, discuss interchangeability and substitution, and review substitution of interchangeable biosimilars, focusing on key professional considerations for pharmacists. PMID- 26108374 TI - Inhibition of the endosymbiont "Candidatus Midichloria mitochondrii" during 16S rRNA gene profiling reveals potential pathogens in Ixodes ticks from Australia. AB - BACKGROUND: The Australian paralysis tick (Ixodes holocyclus) is of significant medical and veterinary importance as a cause of dermatological and neurological disease, yet there is currently limited information about the bacterial communities harboured by these ticks and the risk of infectious disease transmission to humans and domestic animals. Ongoing controversy about the presence of Borrelia burgdorferi sensu lato (the aetiological agent of Lyme disease) in Australia increases the need to accurately identify and characterise bacteria harboured by I. holocyclus ticks. METHODS: Universal PCR primers were used to amplify the V1-2 hyper-variable region of bacterial 16S rRNA genes present in DNA samples from I. holocyclus and I. ricinus ticks, collected in Australia and Germany respectively. The 16S amplicons were purified, sequenced on the Ion Torrent platform, and analysed in USEARCH, QIIME, and BLAST to assign genus and species-level taxonomy. Initial analysis of I. holocyclus and I. ricinus identified that > 95 % of the 16S sequences recovered belonged to the tick intracellular endosymbiont "Candidatus Midichloria mitochondrii" (CMM). A CMM-specific blocking primer was designed that decreased CMM sequences by approximately 96 % in both tick species and significantly increased the total detectable bacterial diversity, allowing identification of medically important bacterial pathogens that were previously masked by CMM. RESULTS: Borrelia burgdorferi sensu lato was identified in German I. ricinus, but not in Australian I. holocyclus ticks. However, bacteria of medical significance were detected in I. holocyclus ticks, including a Borrelia relapsing fever group sp., Bartonella henselae, novel "Candidatus Neoehrlichia" spp., Clostridium histolyticum, Rickettsia spp., and Leptospira inadai. CONCLUSIONS: Abundant bacterial endosymbionts, such as CMM, limit the effectiveness of next-generation 16S bacterial community profiling in arthropods by masking less abundant bacteria, including pathogens. Specific blocking primers that inhibit endosymbiont 16S amplification during PCR are an effective way of reducing this limitation. Here, this strategy provided the first evidence of a relapsing fever Borrelia sp. and of novel "Candidatus Neoehrlichia" spp. in Australia. Our results raise new questions about tick-borne pathogens in I. holocyclus ticks. PMID- 26108378 TI - Proceedings of the AMCP Partnership Forum: NCPDP Electronic Prior Authorization Standards-Building a Managed Care Implementation Plan. AB - Today's manual prior authorization (PA) process is often viewed by providers, payers, pharmacists, and patients as cumbersome, costly, and inefficient. The recent approval by the National Council for Prescription Drug Programs of a standard transaction for electronic prior authorization (e-PA) has paved the way for more rapid and efficient processing of PA requests. On April 23, 2014, the Academy of Managed Care Pharmacy (AMCP) convened a meeting of key stakeholders to explore how to support the process of implementing the new standard transactions for e-PA and to recommend activities and programs that AMCP can promote to speed the adoption of e-PA. This Partnership Forum included individuals from managed care organizations, the pharmaceutical industry, pharmacy benefit managers, electronic prescription hubs or networks, and health information technology vendors. The speakers and panelists recommended that AMCP should develop measurable goals for staged and full implementation of e-PA. To accomplish this, it was recommended that AMCP work to collaborate with organizations representing these stakeholders. Additionally, it was recommended that AMCP develop managed care e-PA implementation and e-PA criteria guides, as well as an e-PA scorecard. PMID- 26108379 TI - Financial Analysis of CYP2C19 Genotyping in Patients Receiving Dual Antiplatelet Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention. AB - BACKGROUND: Dual antiplatelet therapy is an established standard of care for patients with acute coronary syndrome (ACS) to reduce thrombotic risk. Reduced CYP2C19 activity impairs clopidogrel bio-activation and increases risk of adverse clinical outcomes. Patients with poor and intermediate CYP2C19 metabolizers treated with clopidogrel incur higher cardiovascular event rates, including myocardial infarction, stroke, and stent thrombosis, following ACS than patients with normal CYP2C19 function. Tests are available to identify the CYP2C19 genotype and can be used to support individualization of antiplatelet therapy. OBJECTIVE: To estimate the financial impact of CYP2C19 genotyping in a theoretical cohort of 1,000 patients with ACS, who received percutaneous coronary intervention and coronary stent implantation and were treated with clopidogrel, prasugrel, or ticagrelor in a managed care setting. METHODS: Differences in overall and average cost per patient were estimated based on the rate of CYP2C19 genotyping in a theoretical cohort of 1,000 patients. Sensitivity analysis was carried out for varying costs, adherence, and the percentage of patients treated according to genotyping results. All clinical event costs were reported in terms of 2012 U.S. dollars. The budget impact analysis used published event rates from primary literature to estimate costs of events analysis for 3 different scenarios: Scenario A, no CYP2C19 genotyping; Scenario B, 50% of patients received CYP2C19 genotyping with appropriate treatment based on genotype; and Scenario C, 100% of patients received CYP2C19 genotyping with appropriate treatment based on genotype. RESULTS: According to this model, there was no change in the market share for the 3 antiplatelet agents in Scenario A. Initial market share for clopidogrel, prasugrel, and ticagrelor was 93%, 5%, and 2%, respectively; however, use of CYP2C19 genotyping is expected to shift market share from clopidogrel to either prasugrel or ticagrelor. In Scenario B, where 50% of the patients received genotyping, clopidogrel market share was reduced to 83%, while prasugrel increased to 12.1% and ticagrelor increased to 4.9%. In Scenario C, where all patients received genotyping, clopidogrel market share was reduced to 73%, prasugrel increased to 19.3%, and ticagrelor increased to 7.7%. Total estimated cost differences when all possible patients were genotyped included annual savings of roughly $444,852. CONCLUSIONS: Important financial benefits may be realized through use of genotype-guided antiplatelet therapy to reserve prasugrel or ticagrelor use for patients with reduced CYP2C19 activity to avoid costs associated with adverse cardiac events. PMID- 26108380 TI - Intravenous Versus Subcutaneous Anti-TNF-Alpha Agents for Crohn's Disease: A Comparison of Effectiveness and Safety. AB - BACKGROUND: In recent years, there have been a number of pharmacological innovations for Crohn's disease (CD), a difficult-to-treat condition, including new treatment philosophies (e.g., top-down therapy) and new therapeutic options in terms of the agent and the route of administration. Three anti-tumor necrosis factor (anti-TNF-alpha) agents are available for use among CD patients in the United States: infliximab, an intravenous agent, and adalimumab and certolizumab pegol, 2 newer subcutaneous products. Infliximab is considered the "gold standard" because it has the longest clinical experience, and adalimumab and certolizumab pegol have each gained significant market share. OBJECTIVE: To examine differences in effectiveness and safety between currently available intravenous and subcutaneous anti-TNF-alpha agents used to treat patients with CD. METHODS: Data for this retrospective, administrative claims analysis were obtained from pharmacy and medical claims from major U.S. health plans geographically dispersed across 14 states during 2007-2011. Patients had at least 1 ICD-9-CM diagnosis for CD, 6 months pre-index eligibility, and initiated anti TNF-alpha therapy on the index date. Patients in each cohort were propensity score matched on pre-index demographics, clinical characteristics, and baseline health care use. During the post-index period, age-sex adjusted incidence rate ratios (IRRs) of CD-related symptoms, infections, cancers, and hepatic-related conditions were compared using Cox (PH) models. RESULTS: The matched cohorts included 515 patients in each group, with an average age of 39 years. Median follow-up was 17.5 months in the intravenous cohort and 17.7 months in the subcutaneous cohort. In terms of effectiveness outcomes, age-sex adjusted IRRs for the subcutaneous group, with the intravenous cohort as a reference, were as follows: 0.61 (95% CI = 0.32-1.18, P = 0.14) for anal fissures; 0.97 (95% CI = 0.72-1.30, P = 0.85) for abscess; 1.08 (95% CI = 0.79-1.04, P = 0.64) for fistulas; 1.12 (95% CI = 0.83-1.54, P = 0.45) for gastrointestinal hemorrhage; and 1.22 (95% CI = 0.93-1.59, P = 0.14) for a combined measure of obstruction, occlusion, stenosis, and stricture of intestine. In terms of safety outcomes, age sex adjusted IRRs for the subcutaneous group were as follows: 0.85 (95% CI = 0.62 1.16, P = 0.30) for infections; 1.16 (95% CI = 0.71-1.89, P = 0.55) for cancers; and 1.23 (95% CI = 0.79-1.92, P = 0.35) for hepatic-related conditions. CONCLUSIONS: After adjusting for baseline characteristics, effectiveness and safety outcomes appear to be comparable between intravenous and subcutaneous anti TNF-alpha agents in patients with CD. With similar outcomes, other considerations such as convenience of administration and patient preference may play a more prominent role in choice of agent. Health care providers and health payers should inform CD patients about the range of options available when selecting an anti TNF-alpha agent. PMID- 26108381 TI - Health Care Resource Utilization and Costs for Influenza-like Illness Among Midwestern Health Plan Members. AB - BACKGROUND: Each year, 6%-20% of U.S. residents are infected by influenza, and more than 200,000 people are hospitalized due to complications related to influenza. In 2003, it was estimated that the direct medical costs for the treatment of influenza were $10.4 billion in the United States. OBJECTIVES: To (a) assess the current practice associated with the diagnosis and treatment of influenza-like illnesses (ILIs) in inpatient, ambulatory/outpatient, and emergency room settings and (b) evaluate how the use of rapid influenza diagnostic tests (RIDTs) impacts patient health care utilization and cost in these clinical settings. METHODS: For this retrospective cohort study, patients with an influenza-related health care encounter were identified using claims data from a midwestern commercial health insurance plan. In order to select the claims relevant to this study, the corresponding influenza ICD-9-CM codes, GPI codes, and CPT codes for the diagnosis, prescriptions, and procedures were identified and used to detect ILI claims. For the cost analysis of these data, the allowed amount in the billing claims was utilized. Using these data, the median cost, mean cost, minimum cost, and maximum cost were determined for each episode of care. The median costs were compared, and Wilcoxon two-sample tests and Kruskal Wallis tests with a P value of 0.05 were used as the level of significance. RESULTS: Over 32% of the influenza-like illness episodes identified in this study involved empiric antiviral therapy as either treatment (15%) or prophylaxis (17.1%) without an accompanying medical visit. Of patient episodes with a medical visit, patients with an RIDT for influenza received antiviral treatment in 27.5% of the episodes compared with 55% of the episodes for patients with no RIDT. Episodes with a medical visit and an RIDT had statistically significant (P less than 0.001) lower median 30-day influenza-related health care costs ($62.46) than episodes with a medical visit but no RIDT ($192.83), as well as with empiric therapy but no accompanying medical visit ($105.64). CONCLUSIONS: The results of this analysis for ILI claims over a 2-year period suggest that utilization of RIDTs for influenza may reduce overall influenza-related health care costs and improve proper utilization of anti- influenza medications. PMID- 26108382 TI - Impact of COPD Exacerbation Frequency on Costs for a Managed Care Population. AB - BACKGROUND: There is scarce information on chronic obstructive pulmonary disease (COPD) outcomes and costs for patients with differing levels of COPD exacerbations. OBJECTIVE: To examine COPD-related and all-cause health care resource use and costs in subsequent years for frequently and infrequently exacerbating COPD patients. METHODS: Patients with a diagnosis of COPD (ICD-9-CM codes 491.xx, 492.xx, and 496.xx) were identified (1 hospitalization or 1 emergency department visit or at least 2 outpatient visits) using administrative claims data in 2007. Patients were classified in 2008 as frequent (at least 2 exacerbations/year), infrequent (1 exacerbation/year) and nonexacerbators. Outcomes were computed during a subsequent 2-year period (2009 and 2010). Average per person estimates and total sample-level estimates were calculated. A logistic regression model estimated the predictors of having 2 or more exacerbations per year during the follow-up period. RESULTS: 61,750 COPD patients met the study criteria (mean age 67 years). Of these, 6% (n = 3,852) were frequent exacerbators; 14% were infrequent exacerbators (n = 8,416); and 80% were nonexacerbators (n = 49,482). At baseline, average all-cause health care costs per patient for frequent exacerbators were highest followed by infrequent and nonexacerbators ($12,837, $10,480, and $7,756, respectively). On average, 60% of frequent and 40% of infrequent exacerbators had at least 1 exacerbation per year in follow-up. Average annual per patient COPD-related costs for frequent exacerbators ($3,565 in 2009 and $3,528 in 2010) were more than 3 times (P less than 0.05) and infrequent exacerbators ($2,264 in 2009 and $2,265 in 2010) were more than 2 times (P less than 0.05) higher compared with nonexacerbators ($1,007 in 2009 and $1,027 in 2010). On a total sample-level, infrequent exacerbators were similar if not more burdensome compared with frequent exacerbators in the proportion accounted by these cohorts for total COPD-related costs (23% vs. 18%, respectively) and total number of COPD exacerbations per year (26% vs. 26%). Compared with nonexacerbators, infrequent exacerbators were 3 times (OR = 2.8, P less than 0.001) significantly more likely to have 2 or more exacerbations per year in follow-up, and frequent exacerbators were 7 times (OR = 6.76, P less than 0.001) significantly more likely to have 2 or more exacerbations per year in follow-up. CONCLUSIONS: Infrequent exacerbators have an increased risk for future exacerbations compared with nonexacerbators and, on a total sample-level, incur greater costs compared with frequent exacerbators, demonstrating a significant economic burden. PMID- 26108383 TI - Risk Factors, Clinical Characteristics, and Treatment Differences Between Residents With and Without Nursing Home- and Non-Nursing Home-Acquired Clostridium difficile Infection. AB - BACKGROUND: The incidence of Clostridium difficile infection (CDI) in nursing home residents is believed to be high because of the prevalence of predisposing factors such as decreased immune response, multiple comorbidities, medications, increased risk of infection, close proximity of residents, and recent hospitalization. Yet, specific information on CDI in this population is scarce. OBJECTIVES: To investigate differences in clinical and demographic characteristics, treatment, and underlying comorbidities in residents who acquired CDI preadmission (non-nursing home-acquired [NNH-Acquired]) compared with those who acquired CDI after admission to a nursing home (nursing home acquired [NH-Acquired]) and matched controls. METHODS: We conducted a retrospective case-control study of CDI in nursing home residents with a cross sectional and longitudinal aspect of linked and de-identified pharmacy claims and Minimum Data Set data (MDS) 2.0 records from October 1, 2009, to September 30, 2010. The control group was frequency matched 1:1 for gender, race, and age range to residents with CDI. RESULTS: Of 195,498 residents, 5,044 (2.6%) had a diagnosis of CDI. Compared with controls, CDI patients had less severe cognitive impairment (P less than 0.01) and more severe functional impairment (P less than 0.01), incontinence (P less than 0.01), and diarrhea (P less than 0.01). They were more likely to (a) have diabetes, stroke, heart failure, cancer, renal failure, and infections; (b) be treated with antibiotics, corticosteroids, megestrol, and proton pump inhibitors; and (c) be discharged to the hospital (29.3% vs. 14.7%, P = 0.001) than controls. NNH-Acquired CDI was 3 times more prevalent than NH-Acquired CDI. Most residents with NNH-Acquired CDI (85.0%) came from acute care hospitals and were more likely to have heart disease, cancer, and infections, while those with NH-Acquired CDI tended to have more cognitive impairment, reliance on staff for activities of daily living, incontinence, and stroke. Thirty-day retreatment rates for NH-Acquired CDI and NNH-Acquired CDI with metronidazole were 72.7% and 68.4%, and with vancomycin were 83.9% and 69.3%, respectively. The facility (Medicare Part A) was the payer for 93.6% of NNH-Acquired CDI and 75% of NH-Acquired CDI treatment; Medicare Part D was the prevalent secondary payer for NNH-Aquired CDI (19.4%) and NH-Acquired CDI (37.5%). CONCLUSIONS: Residents with CDI had more comorbidities, and the NNH Acquired group bore a higher burden of illness, resulting in differing treatment patterns and outcomes than the NH-Acquired CDI group. PMID- 26108384 TI - Discontinuation/Interruption of Warfarin Therapy in Patients with Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Use of warfarin is standard of care for stroke prevention in patients with atrial fibrillation (AF). However, AF patients experience high rates of warfarin discontinuation/interruption, resulting in increased health risks and health care costs. As such, it is important to study the rates and predictors of warfarin discontinuation/interruption in this population. OBJECTIVES: To determine (a) rates of warfarin discontinuation and interruption and (b) demographic, clinical, and health care-related factors associated with discontinuation and interruption in patients with nonvalvular AF (NVAF) in the usual clinical practice settings in the United States. METHODS: This retrospective cohort study used the MarketScan Database and included patients (aged >= 18 years) with NVAF who were initiated on warfarin. The study period was January 1, 2008, to June 30, 2012. To be included, patients were required to have at least 2 claims with AF diagnosis separated by >= 30 days and <= 12 months and at least 1 outpatient claim. Warfarin initiation had to occur within 30 days of the AF diagnosis. Patients also had to have continuous enrollment in prescription drug plans from 6 months prior to warfarin use to at least 12 months after warfarin initiation. Patients were followed for 1 year after warfarin initiation. Persistence was defined as warfarin therapy without a gap >= 45 days between the end date of the former prescription and the start date of the current prescription or with international normalized ratio (INR) monitoring at least every 42 days. Interruption was defined as a gap in warfarin therapy >= 45 days and <= 90 days between the end date of the former prescription and the start date of the current prescription and without INR monitoring at least every 42 days. Discontinuation was defined as greater than 90 days without warfarin therapy between the end date of the former prescription and the start date of the current prescription and without INR monitoring at least every 42 days. Chi-square tests were used to analyze categorical variables, and independent samples t-tests were used for continuous variables. Cox proportional hazards regression model was performed to determine factors associated with warfarin discontinuation/interruption, including demographic (e.g., age, gender); clinical (e.g., comorbidities, CHADS2 score); and health care-related (e.g., hospitalizations or emergency room visits) characteristics. Sensitivity analyses were conducted by varying prescription gaps by 7, 14, and 30 days. RESULTS: A total of 58,593 patients with NVAF were included. The mean age was approximately 71 years (SD = 12.00) and mean CHADS2 score was 1.66 (SD = 1.23). The majority of patients were male (60%). During 12 months after warfarin initiation, 45% of patients were persistent with warfarin; 12% had interruption without discontinuation; and 43% had discontinuation. The risk of warfarin interruption or discontinuation was significantly greater in patients who were younger than 65 years (HR = 1.22; 95% CI = 1.19-1.25), lived in the West (HR = 1.07; 95% CI = 1.03-1.11), had history of anemia (HR = 1.10; 95% CI = 1.06-1.14), had history of bleeding (HR = 1.10; 95% CI = 1.06-1.14), or had history of hospitalization or emergency room visits (HR = 1.11; 95% CI = 1.08-1.13). The significant factors associated with interruption and discontinuation were similar. In the sensitivity analyses, the significant factors associated with discontinuation/interruption were similar across different prescription gaps. CONCLUSIONS: In the U.S. clinical practice setting, more than 50% of NVAF patients discontinued or interrupted warfarin within 1 year after initiation. Aged less than 65 years, history of anemia, and history of hospitalization/emergency room visits were associated with increased risk of discontinuation/interruption. Given the high prevalence of warfarin discontinuation/interruption, health care providers should take a more active role in understanding and addressing the reasons behind patient discontinuation/interruption. PMID- 26108386 TI - Assessment of vascular dysfunction after transradial coronary angiography. Is a single catheter better? AB - BACKGROUND: The aim of this study was to investigate the midterm effects of transradial coronary angiography (TRCAG) on the radial and brachial artery diameter, the vasodilator characteristics, as well as to assess the factors determining functional recovery. METHODS: This study included 136 consecutive patients who underwent TRCAG. The radial artery was evaluated with ultrasonography before and 1 month after the procedure. RESULTS: The basal right radial artery diameter (2.97 +/- 0.46 vs. 2.82 +/- 0.51, p < 0.001), after flow mediated dilatation (FMD; 3.18 +/- 0.45 vs. 2.99 +/- 0.54, p < 0.001) and after nitroglycerin-mediated dilatation (NMD; 3.32 +/- 0.45 vs. 3.11 +/- 0.54, p < 0.001), and the percentage change in diameter after FMD (7.50 +/- 3.62 vs. 5.89 +/- 3.04, p < 0.001) and NMD (12.42 +/- 4.96 vs. 10.54 +/- 4.47, p < 0.001) were significantly decreased 1 month after TRCAG. The mean basal diameter of the right brachial artery (4.41 +/- 0.58 vs. 4.40 +/- 0.58, p = 0.012) after FMD (4.61 +/- 0.60 vs. 4.59 +/- 0.59, p < 0.001) and the percentage change in diameter after FMD (4.53 +/- 2.29 vs. 4.33 +/- 2.56, p = 0.038) were significantly decreased 1 month after TRCAG. The number of catheters used (B = 0.372, p < 0.001, 95 % CI = 0.006-0.013), basal radial artery diameter (B = - 0.217, p = 0.001, 95 % CI = - 0.021- 0.006), presence of hypertension (B = - 0.151, p = 0.011, 95 % CI = - 0.015 - 0.002), and pain score (B = 0.493, p < 0.001, 95 % CI = 0.007 - 0.012) were independent predictors of radial artery FMD change in multivariate regression analysis. The number of catheters used (B = 0.378, p < 0.001, 95 % CI = 0.009 - 0.020), basal radial artery diameter (B = - 0.210, p = 0.010, 95 % CI = - 0.034 - 0.005), and pain score (B = 0.221, p < 0.001, 95 % CI = 0.002-0.011) were independent predictors of radial artery NMD change in multivariate regression analysis. CONCLUSION: Basal radial artery diameter, the number of catheters used during TRCAG, and the pain perceived during the procedure seem to be important predictors of vascular functional changes after TRCAG. PMID- 26108385 TI - Inducing Stem Cell Myogenesis Using NanoScript. AB - Transcription factors (TFs) are multidomain proteins that play a critical role in orchestrating stem cell differentiation, but several limitations hinder the full potential of TF-based gene regulation. Here we report a unique strategy to emulate TFs and differentiate stem cells in a nonviral approach using an artificial, nanoparticle-based transcription factor called NanoScript. The NanoScript platform consists of a gold nanoparticle functionalized with small molecules that mimic the various domains of TFs. As a result, NanoScript mimics the function and structure of TF proteins. Specifically, NanoScript was designed to regulate muscle cell differentiation by targeting myogenic regulatory factors (MRFs), which play an important role in inducing myogenesis. This NanoScript-MRF is stable in physiological environments, localizes within the nucleus, induces differentiation of adipose-derived mesenchymal stem cells into mature muscle cells in 7 days, and is naturally excreted from induced muscle cells. As such, NanoScript represents a safe and powerful tool for applications requiring gene manipulation. PMID- 26108387 TI - Antepartum surgical management of Pott's paraplegia along with maintenance of pregnancy during second trimester. AB - INTRODUCTION: The existing literature is limited and inconclusive regarding management of spinal tuberculosis with neurological deficit during advanced pregnancy. None of the previously published case series concerning this problem during the second trimester of pregnancy have explored the option of simultaneous surgical intervention for it along with maintenance of pregnancy. CASE REPORT: A 22-year-old woman with 26 weeks of pregnancy (2nd trimester) presented with upper back pain for the past 2 months, inability to move both lower limbs for the last 1 week, bladder and bowel dysfunction for the past 5 days (Frankel Grade B). Patient subsequently underwent MRI scan dorsal spine and the image findings were suggestive of spinal tuberculosis T2 level. After obstetric evaluation and opinion of the expectant mother, in view of extensive neurological deficit which progressed rapidly, decision was taken for surgical intervention along with maintenance of pregnancy. Patient was positioned in right lateral position after giving general anesthesia using double lumen endotracheal tube with lung isolation technique. Exposure was done using transthoracic third rib excision approach. Decompression was achieved by radical debridement at T2 vertebrae level followed by multiple rib strut grafts and stabilization with screw and rod construct between T1 and T3 vertebrae. Intra-operative measures including type of anesthesia, prevention of maternal hypotension, hypoxemia and hypothermia, and fetal monitoring by attending obstetrician were undertaken to maintain feto maternal safety. Postoperative ultrasonography evaluation of the fetus revealed a normal study. Post-surgery histopathological evaluation of the surgical specimen confirmed tuberculosis infection and the patient continued anti-tubercular drug therapy for 9 months. She delivered a healthy girl child at 36 weeks of gestation by cesarean section. After about 14 months of postoperative follow-up, patient has completely recovered motor power with mild persistent sensory symptoms. She is self-voiding with mild constipation requiring occasional intermittent laxative use. Radiological improvements in comparison to the previous reports were also seen at the last follow-up. CONCLUSION: Although this is only a single case but being the first to our knowledge, the good results highlight the point that both surgical management and maintenance of pregnancy during second trimester complicated by Pott's paraplegia are possible, involving a multi-disciplinary team approach for optimal maternal and fetal outcome. PMID- 26108388 TI - A longitudinal study to assess the volumetric growth rate of spinal intradural extramedullary tumour diagnosed with schwannoma by magnetic resonance imaging. AB - PURPOSE: Spinal intradural extramedullary (IDEM) schwannoma diagnosed by magnetic resonance (MR) imaging is sometimes detected incidentally. Because the natural history of spinal IDEM schwannoma has not been established well, questions remain regarding whether small and asymptomatic tumour has to be removed. We aimed to assess the natural history of spinal schwannoma diagnosed by MR imaging using an accurate and reliable method. METHODS: All patients who were diagnosed with spinal IDEM schwannoma by MR imaging and did not undergo surgical resection immediately were recruited. A number of 56 tumours were enrolled finally. Tumour volume was measured using the volume quantification method from the baseline through the final follow-up. Receiver operating characteristics plots were used to define cut-off value of discrimination. RESULTS: The probable schwannoma grew 5.45% [median value of volumetric growth rate (VGR); interquartile range 0.14 14.19] annually with a mean surveillance interval of 43.6 months. Of the 56 tumours, some tumours kept growing rapidly and the others did not. The median annual VGR of the growing and stable probable schwannomas was 13.02 and -0.09%, respectively (P<0.001). They can be roughly divided by 2.5% of the annual VGR and usually maintained each growth pattern and the cross-over rate to growth pattern was 15.6%. CONCLUSIONS: Spinal probable IDEM schwannoma grew 5.45% of the tumour volume annually and can be divided into growing and stable tumours. The tumour that grows>=2.5% of volume per year needs a careful inspection because it may be not benign schwannoma and keep growing continuously. PMID- 26108389 TI - L5-S1 disc degeneration and the anatomic parameters of the iliac crest: imaging study. AB - PURPOSE: To evaluate the relationship between height ratio of the iliac crest to L4 (HR), width ratio of the iliac crest to L4 (WR) and L5-S1 disc degeneration. METHODS: On T2-weighted sagittal images of the 50 randomly selected patients, two observers graded L5-S1 discs and some other parameters were measured. Then, relative signal intensity (RSI) of the L5-S1 nucleus pulposus was calculated. On anteroposterior and lateral radiographs of the same 50 patients' lumbar spine, the parameters such as the height of the iliac crest were measured and then HR and WR were calculated. Finally, HR, WR and the percentage of the sROM of L5-S1 in L1-S1 segments of the other 51 randomly selected patients were calculated. RESULTS: Positive correlations were found between HR, WR and RSI of the L5-S1 disc. Negative correlations were found between HR, WR and modified Pfirrmann scores of L5-S1 nucleus pulposus. A statistically significant negative correlation was found between HR and the percentage of sROM of L5-S1 in L1-S1 segments. CONCLUSIONS: Low HR and (or) WR were the risk factors for L5-S1 disc degeneration. High HR could reduce the percentage of sROM of L5-S1 in L1-S1 segments and high HR and (or) WR could reduce the incidence of L5-S1 disc degeneration. PMID- 26108390 TI - Erratum to: Trends analysis of rhBMP utilization in single-level posterior lumbar fusion (PLF) in the United States. PMID- 26108391 TI - Obsessive-Compulsive Symptoms in Medical Students: Prevalence, Severity, and Correlates. AB - OBJECTIVES: The study aims were to estimate the prevalence and correlates of symptoms suggestive of obsessive-compulsive disorder (OCD) among medical students and investigate the severity and correlates of specific obsessive-compulsive symptom (OCS) dimensions in this population. METHODS: A cross-sectional study with 471 Brazilian medical students, who were assessed using the Obsessive Compulsive Inventory-Revised (OCI-R). The main outcomes were "probable OCD" (OCI R score >27) and overall/dimensional OCI-R scores. Sociodemographic data, depressive symptoms, and several aspects of academic life were also investigated. Bivariate analyses were followed by regression models. RESULTS: Eighteen (3.8%) participants presented probable OCD, which was associated with depression. The mean OCI-R score was 8.9, and greater overall severity was independently associated with being a freshman, difficulty in adaptation, and depressive symptoms. Higher scores in the "checking" and "washing" dimensions were associated with being a freshman, in the "neutralization" and "ordering" dimensions with adaptation difficulties, and in the "hoarding" dimension with adaptation difficulties and depressive symptoms. The "obsession" dimension was associated with being a freshman, difficulty making friends, depressive symptoms, and psychological/psychiatric treatment. CONCLUSIONS: Probable OCD is more frequent in medical students than in the general population and is associated with depressive symptoms. Efforts are required to identify OCS in this population, particularly among first-year students and to provide treatment, when necessary. Institutional programs that properly receive freshmen, enhancing their integration with other colleagues and their adaptation to the city, may decrease the level of stress and, consequently, OCS severity. PMID- 26108392 TI - Meaningful Feedback in Medical Education: Challenging the "Failure to Fail" Using Narrative Methodology. PMID- 26108393 TI - Bureaucrapathologies: Galloping Regulosis, Assessment Degradosis, and Other Unintended Organizational Maladies in Post-Graduate Medical Education. AB - As decadelong observers of evolving administrative regulations governing academic medicine, the authors have identified several organizational disorders they define as "bureaucrapathologies," pathological conditions caused by dysfunctional bureaucratic processes that generate excesses of wasted time, effort, and other resources. Appearing wherever bureaucratic organizations exist, they have become particularly egregious in health care, research, and education. In past decades, graduate medical education has been beset by proliferating assessment requirements accompanied by corresponding documentation requirements imposed by academic educational regulatory agencies (specifically the Accreditation Council on Graduate Medical). Although originating from the best of intentions, these largely untested, unvalidated, and unfunded mandates generate burdensome personnel, time, and resource requirements. As they trickle down organizational levels, the intentions of the originators are inevitably degraded. As motivations and incentives of lower level administrators and faculty differ considerably from those at higher levels, we inevitably encounter debatable assessment practices yielding results of dubious reliability and validity. These processes invariably lead to proliferating reports and paperwork. All of this raises serious questions about the benefits vs. harms of these enterprises. In our view, these pathogenic processes can be recognized as diagnosable subtypes of bureaucrapathology. Here the authors briefly describe two, Galloping Regulosis and Assessment Degradosis, which reflect on their pathogenesis and offer preliminary thoughts for potential remedies. Several other recently identified bureaucrapathological syndromes awaiting future delineation are noted. PMID- 26108394 TI - Factors Modifying Burnout in Osteopathic Medical Students. AB - OBJECTIVE: The purposes of the current study are to examine factors modifying burnout and identify which of these factors place osteopathic medical students at risk for developing burnout. METHODS: The current study used a cross-sectional study design and an anonymous, web-based survey to assess burnout and depression in osteopathic medical students. The survey included Maslach Burnout Inventory, the Patient Health Questionnaire, the Stressors and their impact scale, students' sleeping and studying habits, and students' extracurricular involvement. RESULTS: In total, 1294 osteopathic medical students completed the survey. Burnout was present in 516 (39.9%) osteopathic medical students, and 1006 (77.0%) met criteria for depression. Females were 1.5 times more likely to be burned out in comparison to males. For the burnout subscales, males had lower emotional exhaustion, slightly higher depersonalization, and lower personal accomplishment. Lesbian/gay/bisexual/asexual students were 2.62 times more likely to be burned out compared with heterosexual students. Depression and academic, personal, and family stressors were all strongly linked to overall burnout. Finally, for modifiable factors, average hours of sleep, average hours spent studying, and club involvement appeared to be linked to burnout. CONCLUSIONS: The current study suggested that a variety of factors, including non-modifiable, situational, and modifiable, impact burnout in osteopathic medical students. Future research is necessary since burnout in physicians affects the quality of care provided to patients. PMID- 26108395 TI - Evaluation of a National Online Educational Program in Geriatric Psychiatry. AB - OBJECTIVE: This study provides evaluation results of an online study group (OSG) for geriatric psychiatry continuing professional development. METHODS: The OSG is an interactive, expert-facilitated, asynchronous educational experience for psychiatrists and residents in Canada. A retrospective web survey assessed self efficacy, knowledge in geriatric psychiatry, comfort with online learning, and perceived effectiveness of the instructional methods. Wilcoxon signed-rank tests and descriptive statistics were calculated. RESULTS: Twenty-nine (of 50) participants (58 %) completed the questionnaire. Although only 48 % of respondents reported improved perceived knowledge, 79 % reported improved efficacy beliefs, and 76 % reported improved comfort with online learning. Most (79 %) would consider taking OSG again, and 93 % would recommend it to others. CONCLUSIONS: The OSG was well-received, with greater benefits for self-efficacy with the material and comfort with online learning than for perceived knowledge itself. Further research is needed to ascertain actual knowledge change in the context of online learning in medical education. PMID- 26108397 TI - Reality Check: How Reality Television Can Affect Youth and How a Media Literacy Curriculum Can Help. AB - For the past decade, reality television programming has dominated the television market while inherently giving the impression that what occurs on the screen is in fact reality. Although mature audiences may be savvy about the differences between reality and reality television, for children and adolescents, these differences can be less clear. It is important to know what values youth are ascertaining from reality television, as studies have suggested that these media images may have a negative impact on adolescent values. Fortunately, media literacy education has shown promising results in counteracting the negative impact of some television programming. The goals of this paper are to show the potential benefits for the development of a media literacy curriculum for psychiatry residents, including critical media literacy skills, media history taking, and counseling concepts. Our hopes are that trained residents may learn to effectively teach these literacy skills to their patients, patients' families, educators, and other health professionals as a preventive measure against potential negative mental health effects of reality television. PMID- 26108396 TI - A Qualitative Analysis of Medical Students' Reflection on Attending an Alcoholics Anonymous Meeting: Insights for Future Addiction Curricula. AB - OBJECTIVE: This paper describes medical students' views of alcoholism and their response to attending an Alcoholics Anonymous (AA) meeting during their psychiatry clerkship. This may assist other educators in planning their addiction curricula. METHODS: Medical students were required to attend an AA meeting during their psychiatry clerkship and then to write a reflection piece on this experience. We selected a random sample of 40 pieces and performed a qualitative analysis to identify the prominent ideas and themes in this sample. RESULTS: Medical students found their experience attending an AA meeting to be educationally valuable. They reported their familiarity with AA prior to this experience was largely limited to popular media depictions. Students reported understanding alcoholism as a disease with both biological and psychosocial components. They were often concerned with the presence of religiosity and spirituality at the meetings. Following the experience, students felt more comfortable referring patients to AA and identified empathy, honesty, and openness as crucial contributors to the efficacy of AA. CONCLUSIONS: Students felt that attending an AA meeting during their psychiatry clerkship was an educationally valuable experience. Medical students' familiarity with addiction treatment is limited, and attending an AA meeting may be helpful in increasing their comfort with treating addicted patients in the future. In addition, educators may want to explicitly address the spirituality issue related to some treatment programs to increase the likelihood that future physicians feel comfortable referring their patients to recovery programs. PMID- 26108398 TI - Addiction Psychiatry in PGY-3: Use of the Intensive Outpatient Treatment Setting to Train Senior Residents. PMID- 26108399 TI - Massachusetts General Hospital Global Psychiatric Clinical Research Training Program: A New Fellowship in Global Mental Health. PMID- 26108400 TI - Accelerating Maternal and Child Health Gains in Papua New Guinea: Modelled Predictions from Closing the Equity Gap Using LiST. AB - BACKGROUND: Many priority countries in the countdown to the millennium development goals deadline are lagging in progress towards maternal and child health (MCH) targets. Papua New Guinea (PNG) is one such country beset by challenges of geographical inaccessibility, inequity and health system weakness. Several countries, however, have made progress through focused initiatives which align with the burden of disease and overcome specific inequities. This study identifies the potential impact on maternal and child mortality through increased coverage of prioritised interventions within the PNG health system. METHODS: The burden of disease and health system environment of PNG was documented to inform prioritised MCH interventions at community, outreach, and clinical levels. Potential reductions in maternal and child mortality through increased intervention coverage to close the geographical equity gap were estimated with the lives saved tool. RESULTS: A set community-level interventions, with highest feasibility, would yield significant reductions in newborn and child mortality. Adding the outreach group delivers gains for maternal mortality, particularly through family planning. The clinical services group of interventions demands greater investment but are essential to reach MCH targets. Cumulatively, the increased coverage is estimated to reduce the rates of under-five mortality by 19 %, neonatal mortality by 26 %, maternal mortality ratio by 10 % and maternal mortality by 33 %. CONCLUSIONS: Modest investments in health systems focused on disadvantaged populations can accelerate progress in maternal and child survival even in fragile health systems like PNG. The critical approach may be to target interventions and implementation appropriately to the sensitive context of lagging countries. PMID- 26108401 TI - Prevention of Nurses' Work-Related Musculoskeletal Disorders Resulting From Repositioning Patients in Bed: Comprehensive Narrative Review. AB - Repositioning patients in bed to promote comfort and prevent impairments caused by continuously lying in a prone position is a task frequently performed by nurses and nursing assistants. Repositioning is a high-risk activity, frequently causing occupational injuries. These occupational injuries are attributed to excessive physical demands on nurses due to patients' weight and awkward nurse postures. During repositioning, risk of injury can be lowered by reducing friction between the patient and the bed. Hence, certain friction-reducing devices have been developed to reduce the manual force required to move patients. Nevertheless, further research is needed to evaluate the potential effectiveness of these devices. Therefore, the aim of this review was to present current research about the risk factors, prevention strategies, and assistive devices that could reduce work-related musculoskeletal disorders caused by repositioning patients in bed. PMID- 26108403 TI - Fatigue Risk Management. AB - The occupational and environmental health nurse can be instrumental in developing a fatigue risk management system. PMID- 26108404 TI - Femoral Pseudoaneurysm as a Complication of Infective Endocarditis. PMID- 26108405 TI - Observation of Single-Protein and DNA Macromolecule Collisions on Ultramicroelectrodes. AB - Single-molecule detection is the ultimate sensitivity in analytical chemistry and has been largely unavailable in electrochemical analysis. Here, we demonstrate the feasibility of detecting electrochemically inactive single biomacromolecules, such as enzymes, antibodies, and DNA, by blocking a solution redox reaction when molecules adsorb and block electrode sites. By oxidizing a large concentration of potassium ferrocyanide on an ultramicroelectrode (UME, radius <=150 nm), time resolved, discrete adsorption events of antibodies, enzymes, DNA, and polystyrene nanospheres can be differentiated from the background by their "footprint". Further, by assuming that the mass transport of proteins to the electrode surface is controlled mainly by diffusion, a size estimate using the Stokes-Einstein relationship shows good agreement of electrochemical data with known protein sizes. PMID- 26108406 TI - Systemic chemotherapy as a main strategy for liver metastases from gastric cancer. AB - BACKGROUND: Liver metastasis is associated with poor prognosis in gastric cancer. Surgical resection and systemic chemotherapy have been reported to be effective in gastric cancer with liver metastasis (GCLM). However, the best strategy for GCLM has not been established. METHODS: From May 2009 to July 2014, a consecutive series of GCLM patients in Zhongshan Hospital of Fudan University were studied. Treatment strategies were evaluated with regard to different extents of metastases. RESULTS: A total of 163 patients were included. The overall survival was 10.1 months. Active treatment significantly prolongs the survival of GCLM patients. The overall survival time for patients with liver-limited metastases and extra-hepatic liver metastases was 11.6 mo and 8.7 mo, respectively (P = 0.012). The median survival time for liver-limited disease of H1, H2 and H3 was 14.2, 15.8, and 8.5 months, respectively (H3 vs H2, P = 0.001; H3 vs H1, P = 0.000; H1 vs H2, P = 0.900). Systemic chemotherapy was chosen as the main strategy for the 'extensive' patients with extra-hepatic metastases and H3 type liver-limited metastases. Patients' survival was benefited by multi-line chemotherapy. No differences were shown between systemic chemotherapy and curative resection or palliative resection in H1 and H2 liver-limited metastases (16.0 mo vs 12.0 mo, P = 0.711; 16.0 vs 18.8 months, P = 0.654). CONCLUSION: Systemic chemotherapy was the main treatment for gastric cancer patients with liver metastases. Curative resection could be considered for highly selected patients. PMID- 26108407 TI - Mutual interaction between BCL6 and miRNAs contributing to the pathogenesis of various cancers. AB - MicroRNA (miRNA), a class of non-protein-coding RNAs, plays a critical role in many cellular processes, such as invasion, proliferation and migration, and also function in disease pathology. The transcription factor and proto-oncogene B cell CLL/lymphoma 6 (BCL6) is aberrantly expressed in various cancers. An increasing body of evidence has demonstrated that miRNAs and BCL6 can target one another and mutually adjust their expression which are of great importance in the pathogenesis of various cancers. In this report, we summarize the mutual interaction between miRNAs and BCL6, which have been studied in cancers, highlighting their mechanisms and potential therapeutic targets in cancers. PMID- 26108408 TI - Effectiveness and toxicity of helical tomotherapy for patients with locally recurrent nasopharyngeal carcinoma. AB - PURPOSE: We assessed therapeutic outcomes of reirradiation with helical tomotherapy (HT) for locoregional recurrent nasopharyngeal carcinoma (LRNPC) patients. METHODS AND MATERIALS: Treatment outcomes were evaluated retrospectively in 17 consecutive LRNPC patients receiving HT between 2006 and 2012. Median age was 57 years and most patients (n = 13) were male. Simultaneous systemic therapy was applied in 5 patients. Initial treatment covered the gross tumor volume with a median dose of 70 Gy (60-81.6 Gy). Reirradiation was confined to the local relapse region with a median dose of 63 Gy (50-70.2 Gy), resulting in a median cumulative dose of 134 Gy (122-148.2 Gy). The median time interval between initial and subsequent treatment was 42 months (11-126). RESULTS: The median follow-up for the entire cohort was 23 and 35 months for survivors. Three patients (18 %) developed both local and distant recurrences and only one patient (6 %) suffered from isolated local recurrence. Two-year actuarial DFS and LC rates were 74 and 82 %, respectively. Two-year OS rate was 79 %. Acute and late grade 2 toxicities were observed in 8 patients (47 %). No patient experienced late grade >=3 toxicity. Late toxicity included fibrosis of skin, hypoacusia, dysphagia, and xerostomia. Patients with higher Karnofsky performance status scores associated with a lower risk of mortality (HR 0.85, p = 0.015). CONCLUSION: Reirradiation with HT in patients with LRNPC is feasible and yields encouraging results in terms of local control and overall survival with acceptable toxicity. PMID- 26108409 TI - Cancer in children and adolescents in Spain: incidence, treatment setting and provider specialty. AB - PURPOSE: To analyze cancer incidence, distribution of malignancy, treatment setting and provider specialty of cancer patients, 0-19 years old, in the Comunitat Valenciana, Spain. METHODS/PATIENTS: All incident childhood and adolescent (0-19 years) cancer cases registered in the population-based Comunitat Valenciana Childhood Cancer Registry (RTICV) from 2007 to 2010 were included. Pathological and hematological diagnoses were recoded using the International Classification of Childhood Cancer Third Edition (ICCC-3). Treatment setting and provider specialty were analyzed. RESULTS: 696 patients <20 years were diagnosed with cancer: 513 cases were children (0-14 years) and 183 were adolescents (15-19 years). Overall age-adjusted incidence for 2007-2010 was 176.0 cases per million (95 % CI 162.8-189.2), with incidence being the highest among infants (287.4), followed by 1-4 years (205.5), adolescents (179.9), 10-14 years (150.2) and 5-9 years (140.6). Among adolescents aged 14-19 years, the treatment setting differed by cancer type; 87 % of them were never seen at pediatric oncology units, while 40 % were treated in up to 20 different medical oncology departments in institutions without pediatric oncology expertise. CONCLUSIONS: This is the first population-based epidemiological study carried out in Spain on children and adolescents with cancer. Centralization of care to a small number of specialized centers and thorough pediatric and oncology team collaboration are needed to improve care and survival for adolescents with cancer in our country. We suggest the creation of specific adolescent tumor boards in main tertiary care hospitals, in which adolescents with cancer can benefit from the shared expertise of medical and pediatric specialists. PMID- 26108411 TI - Population Growth and Its Impact on the Design Capacity and Performance of the Wastewater Treatment Plants in Sedibeng and Soshanguve, South Africa. AB - This study investigated the effects of population growth on the performance of the targeted wastewater treatment plants in Sedibeng District and Soshanguve peri urban area, South Africa. The impact of population growth was assessed in terms of plant design, operational capacity (flow rate) and other treatment process constraints. Between 2001 and 2007, the number of households connected to the public sewerage service increased by 15.5, 17.2 and 37.8% in Emfuleni, Lesedi and Midvaal Local Municipalities, respectively. Soshanguve revealed a 50% increment in the number of households connected to the sewerage system between 1996 and 2001. Except for Sandspruit (-393.8%), the rate of influent flows received by Meyerton increased by 6.8 ML/day (67.8%) and 4.7 ML/day (46.8%) during the dry and wet seasons, respectively. The flow rate appeared to increase during the wet season by 6.8 ML/day (19.1%) in Leeuwkuil and during the dry season by 0.8 ML/day (3.9%) in Rietgat. Underperformance of the existing wastewater treatment plants suggests that the rapid population growth in urban and peri-urban areas (hydraulic overloading of the wastewater treatment plants) and operational constraints (overflow rate, retention time, oxygen supply capacity of the plants and chlorine contact time) resulted in the production of poor quality effluents in both selected areas. This investigation showed that the inefficiency of Meyerton Wastewater Treatment Plant was attributed to the population growth (higher volumes of wastewater generated) and operational constraints, while the cause of underperformance in the other three treatment plants was clearly technical (operational). PMID- 26108410 TI - Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. AB - The safety and efficacy of intravenous thrombolysis (IVT) in dissection-related ischemic stroke (DRIS) has not been established. We sought to determine safety and recovery rates of IVT in DRIS using prospective, international, multicenter data and by conducting a comprehensive meta-analysis of reported case series. We analyzed consecutive DRIS patients treated with IVT according to national guidelines during a 5-year period at six tertiary-care stroke centers, and also conducted a comprehensive review and meta-analysis of all available case series reporting safety outcomes in DRIS treated with IVT according to PRISMA guidelines. A total of 39 DRIS patients (mean age 60 +/- 18 years; 59% men; median NIHSS 13 points, IQR 9-17) received IVT in our multicenter study. Symptomatic intracranial hemorrhage (sICH), in-hospital mortality, complete recanalization, favorable functional outcome (FFO; mRS-score of 0-1) and functional independence (FI; mRS-score of 0-2) were 0% (adjusted Wald 95% CI 0 8%), 10% (3-24%), 55% (40-70%), 61% (45-74%) and 68% (52-81%). The pooled sICH and mortality rates in meta-analysis including 10 case series (234 IVT-DRIS patients) were 2% (0-5%) and 4% (0-8%). The pooled recanalization, FFO and FI rates were 45% (26-67%), 41% (29-54%) and 61% (48-72%), respectively. Substantial heterogeneity was only found for FFO (I(2) = 61%; p = 0.006). Subsequent meta regression analysis identified baseline NIHSS and dissection in the posterior circulation as independent predictors of FFO (p < 0.05), accounting for FFO variance across different studies. Our prospective, international data coupled with comprehensive meta-analysis results underscore IVT safety in DRIS, while further independent validation is required in larger observational registries or RCTs. PMID- 26108412 TI - Hot Spots and Hot Times: Wildlife Road Mortality in a Regional Conservation Corridor. AB - Strategies to reduce wildlife road mortality have become a significant component of many conservation efforts. However, their success depends on knowledge of the temporal and spatial patterns of mortality. We studied these patterns along the 1000 Islands Parkway in Ontario, Canada, a 37 km road that runs adjacent to the St. Lawrence River and bisects the Algonquin-to-Adirondacks international conservation corridor. Characteristics of all vertebrate road kill were recorded during 209 bicycle surveys conducted from 2008 to 2011. We estimate that over 16,700 vertebrates are killed on the road from April to October each year; most are amphibians, but high numbers of birds, mammals, and reptiles were also found, including six reptiles considered at-risk in Canada. Regression tree analysis was used to assess the importance of seasonality, weather, and traffic on road kill magnitude. All taxa except mammals exhibited distinct temporal peaks corresponding to phases in annual life cycles. Variations in weather and traffic were only important outside these peak times. Getis-Ord analysis was used to identify spatial clusters of mortality. Hot spots were found in all years for all taxa, but locations varied annually. A significant spatial association was found between multiyear hot spots and wetlands. The results underscore the notion that multi-species conservation efforts must account for differences in the seasonality of road mortality among species and that multiple years of data are necessary to identify locations where the greatest conservation good can be achieved. This information can be used to inform mitigation strategies with implications for conservation at regional scales. PMID- 26108413 TI - Carbon Sequestration in Tidal Salt Marshes of the Northeast United States. AB - Tidal salt marshes provide important ecological services, habitat, disturbance regulation, water quality improvement, and biodiversity, as well as accumulation and sequestration of carbon dioxide (CO2) in vegetation and soil organic matter. Different management practices may alter their capacity to provide these ecosystem services. We examined soil properties (bulk density, percent organic C, percent N), C and N pools, C sequestration and N accumulation at four marshes managed with open marsh water management (OMWM) and four marshes that were not at U.S. Fish and Wildlife National Wildlife Refuges (NWRs) on the East Coast of the United States. Soil properties (bulk density, percent organic C, percent N) exhibited no consistent differences among managed and non-OMWM marshes. Soil organic carbon pools (0-60-cm depth) also did not differ. Managed marshes contained 15.9 kg C/m(2) compared to 16.2 kg C/m(2) in non-OMWM marshes. Proportionately, more C (per unit volume) was stored in surface than in subsurface soils. The rate of C sequestration, based on (137)Cs and (210)Pb dating of soil cores, ranged from 41 to 152 g/m(2)/year. Because of the low emissions of CH4 from salt marshes relative to freshwater wetlands and the ability to sequester C in soil, protection and restoration of salt marshes can be a vital tool for delivering key ecosystem services, while at the same time, reducing the C footprint associated with managing these wetlands. PMID- 26108414 TI - The PROMISE of Nuclear Cardiology. PMID- 26108415 TI - CZT cameras: A technological jump for myocardial perfusion SPECT. PMID- 26108416 TI - Open surgical management of oesophageal diverticulum. AB - Epiphrenic diverticula are defined as the herniation of the mucosa and submucosa through the muscular layers of the oesophageal wall in its lower third. An increased intraluminal pressure associated with an oesophageal motility disorder is usually present in the pathophysiology of the disease. Surgical treatment is indicated mostly in symptomatic patients. The current surgical treatment consists in: (i) removing the diverticulum; (ii) relieving the functional distal obstruction with an oesophageal myotomy including the lower oesophageal sphincter; and (iii) preventing an associated reflux by the addition of a non obstructive partial fundoplication. Minimally invasive techniques have been reported, but traditional open procedures remain the treatment of choice of the disease. PMID- 26108417 TI - Pharmacological stress cardiovascular magnetic resonance: feasibility and safety in a large multicentre prospective registry. AB - AIMS: To assess the feasibility and incidence of immediate complications of stress cardiovascular magnetic resonance (CMR) and to determine associated factors. METHODS AND RESULTS: This was a large multicentre, prospective registry of pharmacologic stress CMR in a referral population. We used dipyridamole when no contraindication was present and dobutamine in the remaining patients. Stress CMR was performed at 1.5 T. We recorded the clinical and demographic data, quality of test, CMR findings, haemodynamic data, and complications. Stress CMR was performed in 11 984 patients (98.2% of requested), using dipyridamole in 95.4% and dobutamine in 4.6%. The study could not be performed due to claustrophobia in 0.2%. Quality was optimal in 93.4%, suboptimal in 6.2%, and poor in 0.4% of studies. Images were diagnostic in 97.6% of patients (98.7% with dipyridamole and 75.1% with dobutamine, P < 0.0001). No patient died or had acute myocardial infarction during the test. Ten patients (0.08%) had severe immediate complications, seven after dipyridamole and two after dobutamine (P = 0.062), and one anaphylactic shock post-gadolinium. The only factor significantly associated with higher incidence of serious complications was the detection of inducible ischaemia. Incidence of non-severe complications was low (1.5%), severe controlled chest pain being the most frequent. Minor symptoms occurred frequently (24.8%). Both were significantly more frequent when dobutamine was used. CONCLUSION: Performance of stress CMR is safe in a referral population. Inducible ischaemia was the only factor identified which was associated with serious complications. The incidence of non-severe complications and minor symptoms was greater with dobutamine. PMID- 26108418 TI - Interaction Between Gastric Carcinoma Cells and Neural Cells Promotes Perineural Invasion by a Pathway Involving VCAM1. AB - BACKGROUND: Perineural invasion (PNI) is one of the important routes for local spread of gastric carcinoma associated with poor prognosis. However, the exact cellular characteristics and molecular mechanisms of PNI are still unclear. AIM: To identify the interaction between gastric carcinoma cells and neural cells, and whether vascular cell adhesion molecule-1 (VCAM1) is involved in this process. METHODS: We adopted in vitro cell coculture assays to investigate the cellular and molecular interaction between gastric cancer cells and neural cells. RESULTS: We find upregulation of VCAM1 in clinical gastric cancer tissue samples. In in vitro tumor-neural cell coculture system, gastric cancer cells with high level of VCAM1 promote proliferation of neural progenitor cells and induce the process outgrowth and branching of neural cells. Reciprocally, neural cells enhance neurotropic migration and mobility of tumor cells. Repressing VCAM1 function through VCAM1 blocking antibody can attenuate these effects. CONCLUSIONS: Our study indicates that VCAM1 is significantly involved in tumor invasion via mediating nerve-tumor interaction, which is a mutually beneficial process. It is possible that interaction between neural cells and tumor cells might contribute to PNI of gastric carcinoma. Inhibiting the activity of VCAM1 could be a potential strategy targeting PNI in gastric carcinoma therapy. PMID- 26108420 TI - Adherence to Post-polypectomy Guidelines: Just One Piece of an Important Puzzle. PMID- 26108421 TI - Successful transplantation of kidneys from elderly circulatory death donors by using microscopic and macroscopic characteristics to guide single or dual implantation. AB - Most kidneys from potential elderly circulatory death (DCD) donors are declined. We report single center outcomes for kidneys transplanted from DCD donors over 70 years old, using preimplantation biopsy Remuzzi grading to inform implantation as single or dual transplants. Between 2009 and 2012, 43 single transplants and 12 dual transplants were performed from elderly DCD donors. Remuzzi scores were higher for dual than single implants (4.4 vs. 3.4, p < 0.001), indicating more severe baseline injury. Donor and recipient characteristics for both groups were otherwise similar. Early graft loss from renal vein thrombosis occurred in two singly implanted kidneys, and in one dual-implanted kidney; its pair continued to function satisfactorily. Death-censored graft survival at 3 years was comparable for the two groups (single 94%; dual 100%), as was 1 year eGFR. Delayed graft function occurred less frequently in the dual-implant group (25% vs. 65%, p = 0.010). Using this approach, we performed proportionally more kidney transplants from elderly DCD donors (23.4%) than the rest of the United Kingdom (7.3%, p < 0.001), with graft outcomes comparable to those achieved nationally for all deceased-donor kidney transplants. Preimplantation biopsy analysis is associated with acceptable transplant outcomes for elderly DCD kidneys and may increase transplant numbers from an underutilized donor pool. PMID- 26108419 TI - SATB1 Promotes Pancreatic Cancer Growth and Invasion Depending on MYC Activation. AB - BACKGROUND: SATB1 plays an important role in human malignant progression, inducing cancer cell proliferation and metastasis by regulating downstream gene expressions. However, little is known about the underlying mechanisms in which SATB1 promotes pancreatic cancer tumorigenesis. AIMS: To investigate SATB1 expression levels and its biological functions in promoting pancreatic cancer growth and invasion. METHODS: SATB1 expression levels were detected in seven human pancreatic cancer cell lines and 16 pairs of normal pancreatic/pancreatic cancer tissues using RT-PCR and western blot. SW1990 or Capan-1 cells stably knockdown (shRNA) or transiently knockdown (siRNA) SATB1 cells, and PANC-1 stably overexpressing SATB1 cells were investigated with MTT, EdU assay, flow cytometry, and transwell invasion assay for cell proliferation and invasion activity. The binding of SATB1 to MYC promoter region was examined using reporter assay. Expression of SATB1 in 68 pancreatic cancer samples was studied by immunohistochemical staining and scoring. RESULTS: SATB1 was overexpressed in pancreatic cancer tissues samples, showing strong correlation with pancreatic cancer invasion depth and tumor staging. SATB1 induced MYC mRNA and protein expression; promoted pancreatic cancer cell growth; increased cell population in S phase; and enhanced pancreatic cancer cell invasion in vitro. On the other hand, SATB1 knockdown showed opposite effects. Furthermore, MYC blocking in SATB1 overexpressing cells attenuated the promotion of pancreatic cancer cell growth and invasion. Our data also indicated that SATB1 bound to specific promoter region of MYC. CONCLUSIONS: SATB1 is overexpressed in pancreatic cancer, promoting cancer cell proliferation and invasion through the activation of MYC. PMID- 26108423 TI - Commentary to 'Putting the past behind us - Social stress induced urinary retention can be overcome'. PMID- 26108422 TI - Effects of Developmental Alcohol Exposure on Potentiation and Depression of Visual Cortex Responses. AB - BACKGROUND: Neuronal plasticity deficits are thought to underlie abnormal neurodevelopment in fetal alcohol spectrum disorders and in animal models of this condition. Previously, we found that alcohol exposure during a period that is similar to the last months of gestation in humans disrupts ocular dominance plasticity (ODP), as measured in superficial cortical layers. We hypothesize that exposure to alcohol can differentially affect the potentiation and depression of responses that are necessary for activity-dependent sprouting and pruning of neuronal networks. ODP is an established paradigm that allows the assessment of activity-dependent depression and potentiation of responses in vivo. METHODS: Mouse pups were exposed to 3.6 to 5 g/kg of ethanol in saline daily or every other day between postnatal days 4 and 9. Visual cortex plasticity was then assessed during the critical period for ODP using 2 techniques that separately record in layers 4 (visually evoked potentials [VEPs]) and 2/3 (optical imaging of intrinsic signals [OI]). RESULTS: We discovered a layer-specific effect of early alcohol exposure. Recording of VEPs from layer 4 showed that while the potentiation component of ODP was disrupted in animals treated with alcohol when compared with saline controls, the depression component of ODP (Dc-ODP) was unaltered. In contrast, OI from layers 2/3 showed that Dc-ODP was markedly disrupted in alcohol-treated animals when compared with controls. CONCLUSIONS: Combined with our previous work, these findings strongly suggest that developmental alcohol exposure has a distinct and layer-specific effect on the potentiation and depression of cortical responses after monocular deprivation. PMID- 26108424 TI - Laparoscopic pyeloplasty in infants: single-surgeon experience. AB - INTRODUCTION: Although laparoscopic pyeloplasty (LP) is popular in children, its role in infants is less well defined. It is presumed that infant LP is technically challenging, with a higher failure rate. OBJECTIVE: To consider the hypothesis that LP can be safely and successfully performed in infants. METHODS: The records of 111 infants that underwent LP from March 2009 to December 2013 with at least 1 year of follow-up, were retrospectively reviewed. The results of pre- and postoperative imaging studies (ultrasound (US) and diuretic renogram (DR)), operative details and complications were noted. Pre- and postoperative parameters were compared using statistical software. RESULTS: The details are given in the Table. Laparoscopic pyleoplasty was successfully completed using three ports in all children without any open conversions. There were complications in 14 children (12%); 13 did not require a second intervention and the final outcome was not affected. One child (1%) had a re-obstruction with worsening hydronephrosis (HDN) 2 months after stent removal; she underwent successful redo LP. Median follow-up was 2 years; LP was successful in relieving the obstruction in 115 kidneys (99%); all had follow-up US, while 76 children had follow-up DR. The tests showed significant reduction in HDN (mean pre-operative anteroposterior diameter (APD) of renal pelvis, 34.4 mm (SD 13.4) versus mean post-operative APD 10.6 mm (SD 5.7), p < 0.001) and improved drainage in all kidneys. In unilateral cases, there was significant improvement in mean split renal function (SRF) of the operated kidneys (pre-operative 22.1% (SD 8.6) versus post-operative 35.6% (SD 11.4), p < 0.001). DISCUSSION: Over the past 6 years, all pyeloplasties at our unit have been performed by laparoscopy, irrespective of the age or weight of the child. In this large retrospective series, it is demonstrated that infant LP is a safe and successful operation; pyeloplasty in this age group not only resulted in significant reduction of hydronephrosis, but also in significant functional improvement. The results are comparable to published series comparing open pyeloplasty to laparoscopic and robotic-assisted laparoscopic pyeloplasty, which report success rates ranging from 70 to 96%, and complication rates ranging from 0 to 24% for open pyeloplasty. PMID- 26108425 TI - A novel photocrosslinkable and cytocompatible chitosan coating for Ti6Al4V surfaces. AB - BACKGROUND: In this work, chitosan (CH) was used to produce a novel coating for Ti6Al4V, the most widely used alloy in orthopedic implants, so as to improve the biological tissue response at the metallic surface. METHODS: The Ti6Al4V surface was sandblasted with alumina particles. CH was chemically modified, via carbodiimide chemistry, using lactobionic and 4-azidebenzoic acid to make it soluble at physiological pH and photocrosslinkable, respectively. The reaction was verified by FTIR, NMR and UV/vis spectroscopy. Ti6Al4V surfaces were coated with solutions of the modified CH and exposed to UV light, causing polymer crosslinking and formation of a hydrogel on the surface. The crosslinking reaction was monitored by FTIR at different exposure times. Coating morphology was observed by SEM. The coating's cytocompatibility was determined in vitro through the culture of rat bone marrow mesenchymal stem cells, using an MTT assay, with their morphology assessed by SEM. RESULTS: The developed coating behaved as a hydrogel on the Ti6Al4V and was stable on the surface. FTIR and NMR confirmed the crosslinking mechanism, based on an arile ring expansion, and subsequent reaction with the CH amine groups. Furthermore, the coating was able to support cell proliferation and osteogenic differentiation. CONCLUSIONS: UV crosslinking of CH is easy to apply and has potential for future metallic implant surface modifications. Due to its nature as a hydrogel, the coating could be used for further studies in the encapsulation of bioactive molecules to improve osteogenic potential at the tissue-implant interface. PMID- 26108426 TI - Effects of nanofillers on mechanical properties of fiber-reinforced composites polymerized with light-curing and additional postcuring. AB - BACKGROUND: The purpose of the present study was to evaluate the effect of nanofillers on the mechanical properties of 2 sizes (diameters 0.6 and 0.9 mm) of conventional and nanofilled fiber-reinforced composites (FRCs) polymerized with conventional light-curing and additional postcuring. METHODS: The FRCs samples were divided into 8 groups (10 specimens each). Conventional FRCs with glass fibers preimpregnated with polymethyl methacrylate (groups 1, 2, 3 and 4) and FRCs with impregnating solution containing 32% nanofilled resin (groups 5, 6, 7 and 8) were tested in 2 different sections (0.6 and 0.9 mm in diameter). Two different polymerizations were analyzed: hand light-curing for 40 seconds with an halogen light, and additional postcuring for 25 minutes in a light-curing oven. Each sample was evaluated with a 3-point bending test on a universal testing machine, after 48 hours of dry storage. All of the data were statistically analyzed. RESULTS: After oven postcuring, nanofilled FRCs exhibited significantly higher load values than conventional FRCs. No significant differences were found when comparing conventional and nanofilled FRCs after hand light-curing. Moreover, 0.6-mm FRCs showed significantly lower load values than 0.9-mm FRCs, both for conventional and nanofilled FRCs. CONCLUSIONS: Nanofilled FRCs showed higher load values after additional oven postcuring. PMID- 26108427 TI - Mechanical and biocompatibility performance of bicomponent polyester/silk fibroin small-diameter arterial prostheses. AB - BACKGROUND: In this study, we fabricated prototype bicomponent polyester/silk fibroin small-diameter arterial prostheses using a specially designed narrow ribbon shuttle loom. METHODS: The 2-layered flat fabrics were then heatset on a mandrel to form tubes with a round cross section. RESULTS: The woven samples had a wall thickness between 0.23 mm and 0.29 mm and an inner diameter between 3.53 mm and 3.95 mm, depending on the yarn type and the weave structure. CONCLUSIONS: The bicomponent polyester/silk fibroin samples had superior bursting strength, circumferential strength and suture retention strength compared with a commercial small-diameter arterial prosthesis made from ePTFE. In addition, these prototype samples had greater suture retention strengths than a dog femoral artery, which indicates that they have adequate biostability for clinical use. While their amount of radial compliance was superior to that of the ePTFE commercial graft control, it did not match that of a natural artery. So there is still a need for future improvement in compliance. All of the woven prototypes had water permeability values between 26 and 180 ml/(cm(2)*min), which confirms that none of these arterial prostheses needs to be preclotted at the time of implantation. The biocompatibility of the woven prototypes was evaluated using porcine endothelial cells and an MTT assay. Their cytocompatibility was found to be superior to the ePTFE commercial control, and the level of cell attachment was observed to increase on these prototypes woven with a higher silk fibroin content. PMID- 26108428 TI - Enhanced drug delivery of antibiotic-loaded acrylic bone cements using calcium phosphate spheres. AB - BACKGROUND: Local infection near an implant may pose a serious problem for patients. Antibiotic delivery from acrylic (poly(methyl methacrylate)-based) cements is commonly used to prevent and treat infections in the proximity of, e.g., hip joint implants. However, at present, the drug release properties of PMMA cements are not optimal. An initial burst followed by very slow release means that an unnecessarily large amount of antibiotic needs to be added to the cement, increasing the risk of bacterial resistance. The main purpose of this study was to enhance drug delivery from PMMA cements without influencing the mechanical properties. METHODS: We incorporated strontium-doped calcium phosphate spheres (SCPS) into PMMA cement to enhance the antibiotic release and potentially improve the bone-cement integration. The release of strontium and vancomycin was investigated using inductively coupled plasma atomic emission spectroscopy and UV spectrophotometry, respectively. RESULTS: It was found that incorporating SCPS into PMMA could enhance the antibiotic release and deliver strontium ions to the surroundings. The incorporation of SCPS also increased the radiopacity as well as the working time of the cement. The compressive strength and Young's modulus were not affected. CONCLUSIONS: Our results showed that SCPS/PMMA antibiotic-loaded cement had enhanced antibiotic release, delivered strontium ions and maintained mechanical properties, indicating that the SCPS additive could be a good alternative for controlling the drug-delivery properties of PMMA cement. PMID- 26108429 TI - Color and structural changes of a maxillofacial elastomer: the effects of accelerated photoaging, disinfection and type of pigments. AB - PURPOSE: The aim of this study was to investigate the color and structural changes of a maxillofacial silicone colored with 2 different pigments, after photoaging and immersion in disinfectants. METHODS: Ninety-six cylindrical specimens were fabricated and divided into 3 equal groups. The specimens of the first group consisted of unpigmented silicone (Multisil Epithetik), those of the second group consisted of unpigmented silicone, colored with red functional liquid pigment (Cosmesil Reactive 0.2% wt). The specimens of the third group were fabricated using unpigmented silicone colored with red powder pigment Cosmesil Dry at 0.2% wt. Specimens of each group were divided into 4 equal subgroups (immersed in soap solution, ethanol 95 degrees or distilled water or placed in a photoaging apparatus for 174 hours). Structural changes were examined by infrared spectroscopy (ATR-FTIR) before and after aging. Color changes (DeltaEpsilon*) were measured using the CIE L*a*b* system. Two-way ANOVA and Tukey's test for post hoc comparison were used at a = 0.05. RESULTS: Infrared spectroscopy showed no structural changes after immersion in solutions and photoaging, for all the materials tested. No statistically significant differences for DeltaEpsilon* among the tested groups were found. CONCLUSIONS: It can be concluded that no structural changes of pigmented and unpigmented silicone elastomers were observed among all aging procedures. Recorded color changes for the materials tested were within the limits of clinical acceptability after all aging procedures. Immersion in distilled water presented the best color stability, whereas photoaging, the poorest, for all materials. PMID- 26108430 TI - Color match of resin composites to intact tooth structure. AB - INTRODUCTION: The optical properties of dental restorative materials have a dramatic effect on patient esthetics, which may be compromised by the poor blending effect of composites resins at the composite-tooth interface. OBJECTIVE: The objective of this study was to evaluate the color-matching ability and the blending effects of 3 different composite resins when restoring natural teeth. METHODS: Three commercially available composites and 60 central incisors were used for this experiment. Each tooth was sectioned horizontally at the level of the cementum-enamel junction, and the crown was then bisected along the long axis of the tooth. One half of each tooth was restored individually with composite resin, after matching with the corresponding tooth shade. The tooth color was evaluated preoperatively and postoperatively using an intraoral spectrophotometer and a scientific spectrophotometer. Color differences were then evaluated by the CIEDE2000 color difference formula. RESULTS: The results showed the existence of color differences between the intact and the restored sections of the teeth. However, these differences were considered acceptable, since the DeltaEpsilon value ranged below 3.3. The DeltaE, Deltaa and Deltab parameters showed no statistically significant differences between the groups (p>0.05). CONCLUSIONS: The 3 composites tested were able to mimic natural teeth and produce acceptable restorations. However, the color of the resin composites needs to be evaluated over the long term, because it is subject to alterations in the oral environment over time. PMID- 26108431 TI - Effect of increased exposure times on amount of residual monomer released from single-step self-etch adhesives. AB - BACKGROUND: The aim of this study was to evaluate the effect of increased exposure times on the amount of residual Bis-GMA, TEGDMA, HEMA and UDMA released from single-step self-etch adhesive systems. METHODS: Two adhesive systems were used. The adhesives were applied to bovine dentin surface according to the manufacturer's instructions and were polymerized using an LED curing unit for 10, 20 and 40 seconds (n = 5). After polymerization, the specimens were stored in 75% ethanol-water solution (6 mL). Residual monomers (Bis-GMA, TEGDMA, UDMA and HEMA) that were eluted from the adhesives (after 10 minutes, 1 hour, 1 day, 7 days and 30 days) were analyzed by high-performance liquid chromatography (HPLC). The data were analyzed using 1-way analysis of variance and Tukey HSD tests. RESULTS: Among the time periods, the highest amount of released residual monomers from adhesives was observed in the 10th minute. There were statistically significant differences regarding released Bis-GMA, UDMA, HEMA and TEGDMA between the adhesive systems (p<0.05). There were no significant differences among the 10, 20 and 40 second polymerization times according to their effect on residual monomer release from adhesives (p>0.05). CONCLUSIONS: Increasing the polymerization time did not have an effect on residual monomer release from single-step self-etch adhesives. PMID- 26108432 TI - The effect of dexmedetomidine on the firing properties of STN neurons in Parkinson's disease. AB - Dexmedetomidine (an alpha-2 adrenergic agonist) sedation is commonly used during subthalamic nucleus (STN) deep-brain stimulation (DBS). Its effects on the electrophysiological characteristics of human STN neurons are largely unknown. We hypothesised that dexmedetomidine modulates the firing rates and bursting of human STN neurons. We analysed microelectrode recording (MER) data from patients with Parkinson's disease who underwent STN DBS. A 'Dex bolus' group (dexmedetomidine bolus prior to MER; 27 cells from seven patients) was compared with a 'no sedation' group (29 cells from 11 patients). We also performed within patient comparisons with varying dexmedetomidine states. Cells were classified as dorsal half or ventral half based on their relative location in the STN. Neuronal burst and oscillation characteristics were analysed using the Kaneoke-Vitek methodology and local field potential (LFP) oscillatory activity was also investigated. Dexmedetomidine was associated with a slight increase in firing rate (41.1 +/- 9.9 vs. 34.5 +/- 10.6 Hz, P = 0.02) but a significant decrease in burstiness (number of bursts, P = 0.02; burst index, P < 0.001; percentage of spikes in burst, P = 0.002) of dorsal but not ventral STN neurons. This was not associated with modulation of beta oscillations in the spike-oscillations analysis(beta peak, P = 0.4; signal-to-noise ratio in the beta range for spikes and bursts, P = 0.3 and P = 0.5, respectively) and LFP analysis (Beta power, P = 0.17). As bursting pattern is often used to identify STN and guide electrode placement, we recommend that high-dose dexmedetomidine should be avoided during DBS surgery. PMID- 26108433 TI - The use of measures of obesity in childhood for predicting obesity and the development of obesity-related diseases in adulthood: a systematic review and meta-analysis. AB - BACKGROUND: It is uncertain which simple measures of childhood obesity are best for predicting future obesity-related health problems and the persistence of obesity into adolescence and adulthood. OBJECTIVES: To investigate the ability of simple measures, such as body mass index (BMI), to predict the persistence of obesity from childhood into adulthood and to predict obesity-related adult morbidities. To investigate how accurately simple measures diagnose obesity in children, and how acceptable these measures are to children, carers and health professionals. DATA SOURCES: Multiple sources including MEDLINE, EMBASE and The Cochrane Library were searched from 2008 to 2013. METHODS: Systematic reviews and a meta-analysis were carried out of large cohort studies on the association between childhood obesity and adult obesity; the association between childhood obesity and obesity-related morbidities in adulthood; and the diagnostic accuracy of simple childhood obesity measures. Study quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) and a modified version of the Quality in Prognosis Studies (QUIPS) tool. A systematic review and an elicitation exercise were conducted on the acceptability of the simple measures. RESULTS: Thirty-seven studies (22 cohorts) were included in the review of prediction of adult morbidities. Twenty-three studies (16 cohorts) were included in the tracking review. All studies included BMI. There were very few studies of other measures. There was a strong positive association between high childhood BMI and adult obesity [odds ratio 5.21, 95% confidence interval (CI) 4.50 to 6.02]. A positive association was found between high childhood BMI and adult coronary heart disease, diabetes and a range of cancers, but not stroke or breast cancer. The predictive accuracy of childhood BMI to predict any adult morbidity was very low, with most morbidities occurring in adults who were of healthy weight in childhood. Predictive accuracy of childhood obesity was moderate for predicting adult obesity, with a sensitivity of 30% and a specificity of 98%. Persistence of obesity from adolescence to adulthood was high. Thirty-four studies were included in the diagnostic accuracy review. Most of the studies used the least reliable reference standard (dual-energy X-ray absorptiometry); only 24% of studies were of high quality. The sensitivity of BMI for diagnosing obesity and overweight varied considerably; specificity was less variable. Pooled sensitivity of BMI was 74% (95% CI 64.2% to 81.8%) and pooled specificity was 95% (95% CI 92.2% to 96.4%). The acceptability to children and their carers of BMI or other common simple measures was generally good. LIMITATIONS: Little evidence was available regarding childhood measures other than BMI. No individual-level analysis could be performed. CONCLUSIONS: Childhood BMI is not a good predictor of adult obesity or adult disease; the majority of obese adults were not obese as children and most obesity-related adult morbidity occurs in adults who had a healthy childhood weight. However, obesity (as measured using BMI) was found to persist from childhood to adulthood, with most obese adolescents also being obese in adulthood. BMI was found to be reasonably good for diagnosing obesity during childhood. There is no convincing evidence suggesting that any simple measure is better than BMI for diagnosing obesity in childhood or predicting adult obesity and morbidity. Further research on obesity measures other than BMI is needed to determine which is the best tool for diagnosing childhood obesity, and new cohort studies are needed to investigate the impact of contemporary childhood obesity on adult obesity and obesity-related morbidities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005711. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26108434 TI - New study supports MHRA advice on combined oral contraceptives. PMID- 26108435 TI - Oral contraceptive study omitted several confounders. PMID- 26108436 TI - Data Resource Profile: The Human Mortality Database (HMD). PMID- 26108437 TI - Multiobjective triclustering of time-series transcriptome data reveals key genes of biological processes. AB - BACKGROUND: Exploratory analysis of multi-dimensional high-throughput datasets, such as microarray gene expression time series, may be instrumental in understanding the genetic programs underlying numerous biological processes. In such datasets, variations in the gene expression profiles are usually observed across replicates and time points. Thus mining the temporal expression patterns in such multi-dimensional datasets may not only provide insights into the key biological processes governing organs to grow and develop but also facilitate the understanding of the underlying complex gene regulatory circuits. RESULTS: In this work we have developed an evolutionary multi-objective optimization for our previously introduced triclustering algorithm delta-TRIMAX. Its aim is to make optimal use of delta-TRIMAX in extracting groups of co-expressed genes from time series gene expression data, or from any 3D gene expression dataset, by adding the powerful capabilities of an evolutionary algorithm to retrieve overlapping triclusters. We have compared the performance of our newly developed algorithm, EMOA- delta-TRIMAX, with that of other existing triclustering approaches using four artificial dataset and three real-life datasets. Moreover, we have analyzed the results of our algorithm on one of these real-life datasets monitoring the differentiation of human induced pluripotent stem cells (hiPSC) into mature cardiomyocytes. For each group of co-expressed genes belonging to one tricluster, we identified key genes by computing their membership values within the tricluster. It turned out that to a very high percentage, these key genes were significantly enriched in Gene Ontology categories or KEGG pathways that fitted very well to the biological context of cardiomyocytes differentiation. CONCLUSIONS: EMOA- delta-TRIMAX has proven instrumental in identifying groups of genes in transcriptomic data sets that represent the functional categories constituting the biological process under study. The executable file can be found at http://www.bioinf.med.uni-goettingen.de/fileadmin/download/EMOA-delta TRIMAX.tar.gz . PMID- 26108438 TI - Resistance exercise training increases lower limb speed of strength generation during stair ascent and descent in people with diabetic peripheral neuropathy. AB - AIM: To examine the effects of a 16-week resistance exercise training intervention on the speed of ankle and knee strength generation during stair ascent and descent, in people with neuropathy. METHODS: A total of 43 people: nine with diabetic peripheral neuropathy, 13 with diabetes but no neuropathy and 21 healthy control subjects ascended and descended a custom-built staircase. The speed at which ankle and knee strength were generated, and muscle activation patterns of the ankle and knee extensor muscles were analysed before and after a 16-week intervention period. RESULTS: Ankle and knee strength generation during both stair ascent and descent were significantly higher after the intervention than before the intervention in the people with diabetes who undertook the resistance exercise intervention (P < 0.05). Although muscle activations were altered by the intervention, there were no observable patterns that underpinned the observed changes. CONCLUSIONS: The increased speed of ankle and knee strength generation observed after the intervention would be expected to improve stability during the crucial weight acceptance phase of stair ascent and descent, and ultimately contribute towards reducing the risk of falling. Improvements in muscle strength as a result of the resistance exercise training intervention are likely to be the most influential factor for increasing the speed of strength generation. It is recommended that these exercises could be incorporated into a multi-faceted exercise programme to improve safety in people with diabetes and neuropathy. PMID- 26108439 TI - A validation study of a modified Bouchard activity record that extends the concept of 'uptime' to Rett syndrome. AB - AIM: The aim of this study was to investigate the validity of using a Bouchard activity record (BAR) in individuals with Rett syndrome to measure physical activity, as compared with pragmatic criterion standard measures of walking status and step counts recorded using the StepWatch activity monitor (SAM). METHOD: During the waking hours of 1 day, 43 females (mean age 21y, SD 9y) wore a SAM whilst a proxy completed a modified BAR. Responses to the BAR were compared among participants, who were grouped according to walking status, using the Mann Whitney two-sample rank-sum test. Relationships were sought between BAR responses and step counts using linear regression. RESULTS: According to the proxy-reported BAR responses, those who needed assistance with walking spent more time sitting (median [interquartile range] 9h 15min [8h 8min-10h 30min] vs 6h 15min [4h 15min 8h 30min]; p<0.001) and less time standing (1h [38min-1h 30min] vs 2h 15min [45min-3h 45min]; p=0.04) than those who could walk independently. In those who could walk independently, time classified as 'uptime' (standing and walking) using the BAR was associated with increased step count (r(2) =0.58; p<0.001). INTERPRETATION: These data support the validity of proxy-reported BAR responses. In those who could walk independently, uptime, classified using the BAR, could be used to estimate daily step count. This tool offers an inexpensive method for clinicians to gain insights into physical activity levels in individuals with Rett syndrome. PMID- 26108440 TI - Multiplex pyrosequencing assay using AdvISER-MH-PYRO algorithm: a case for rapid and cost-effective genotyping analysis of prostate cancer risk-associated SNPs. AB - BACKGROUND: Single Nucleotide Polymorphisms (SNPs) identified in Genome Wide Association Studies (GWAS) have generally moderate association with related complex diseases. Accordingly, Multilocus Genetic Risk Scores (MGRSs) have been computed in previous studies in order to assess the cumulative association of multiple SNPs. When several SNPs have to be genotyped for each patient, using successive uniplex pyrosequencing reactions increases analytical reagent expenses and Turnaround Time (TAT). While a set of several pyrosequencing primers could theoretically be used to analyze multiplex amplicons, this would generate overlapping primer-specific pyro-signals that are visually uninterpretable. METHODS: In the current study, two multiplex assays were developed consisting of a quadruplex (n=4) and a quintuplex (n=5) polymerase chain reaction (PCR) each followed by multiplex pyrosequencing analysis. The aim was to reliably but rapidly genotype a set of prostate cancer-related SNPs (n=9). The nucleotide dispensation order was selected using SENATOR software. Multiplex pyro-signals were analyzed using the new AdvISER-MH-PYRO software based on a sparse representation of the signal. Using uniplex assays as gold standard, the concordance between multiplex and uniplex assays was assessed on DNA extracted from patient blood samples (n = 10). RESULTS: All genotypes (n=90) generated with the quadruplex and the quintuplex pyroquencing assays were perfectly (100 %) concordant with uniplex pyrosequencing. Using multiplex genotyping approach for analyzing a set of 90 patients allowed reducing TAT by approximately 75 % (i.e., from 2025 to 470 min) while reducing reagent consumption and cost by approximately 70 % (i.e., from ~229 US$ /patient to ~64 US$ /patient). CONCLUSIONS: This combination of quadruplex and quintuplex pyrosequencing and PCR assays enabled to reduce the amount of DNA required for multi-SNP analysis, and to lower the global TAT and costs of SNP genotyping while providing results as reliable as uniplex analysis. Using this combined multiplex approach also substantially reduced the production of waste material. These genotyping assays appear therefore to be biologically, economically and ecologically highly relevant, being worth to be integrated in genetic-based predictive strategies for better selecting patients at risk for prostate cancer. In addition, the same approach could now equally be transposed to other clinical/research applications relying on the computation of MGRS based on multi-SNP genotyping. PMID- 26108441 TI - Salinity tolerance of crops - what is the cost? AB - Soil salinity reduces crop yield. The extent and severity of salt-affected agricultural land is predicted to worsen as a result of inadequate drainage of irrigated land, rising water tables and global warming. The growth and yield of most plant species are adversely affected by soil salinity, but varied adaptations can allow some crop cultivars to continue to grow and produce a harvestable yield under moderate soil salinity. Significant costs are associated with saline soils: the economic costs to the farming community and the energy costs of plant adaptations. We briefly consider mechanisms of adaptation and highlight recent research examples through a lens of their applicability to improving the energy efficiency of crops under saline field conditions. PMID- 26108443 TI - Practical guidance on immunogenicity to biologic agents used in the treatment of psoriasis: What can be learnt from other diseases? AB - The clinical efficacy of biologic agents for the treatment of moderate to severe psoriasis is well proven in clinical studies, but patients may lose response over time. Loss of response may be due to immunogenicity and the formation of anti drug antibodies (ADA). Although data on the immunogenicity of drugs used to treat psoriasis are now emerging, more information on the impact of factors, such as dosing regimens and concomitant immunosuppressive therapy is needed. Exploring research from other disease areas where immunogenicity has long been recognised as a significant clinical issue may help in developing future strategies for using drug level and ADA measurements to help tailor biologic therapy to meet individual needs. To this end, we analyse what is known about biologics and immunogenicity in psoriasis. In order to learn from other indications, we then address the issue of immunogenicity for three different types of biologic treatments. First, factor VIII-substitution in haemophilia, where the immune system is newly exposed to a physiologic but formerly absent protein. Second, the use of biologics in inflammatory bowel disease, where similar treatment challenges apply as observed in psoriasis. Third, immunogenicity in multiple sclerosis caused by therapeutic antibodies or interferons. Immunogenicity strategies used in other disease areas will need to be tested in psoriasis before they can be widely adopted in routine clinical practice. PMID- 26108444 TI - Clinical features of Behcet's disease: A retrospective chart review of 26 patients. AB - BACKGROUND: Behcet's disease (BD) is a multi-organ inflammatory disorder with mucocutaneous, ocular, neurological, musculoskeletal, gastrointestinal, and pulmonary manifestations. The aim of this study was to determine the clinical features of BD in a cohort of patients diagnosed at the University of California, Davis, United States. METHODS: The medical records of 59 patients with an ICD9 code of BD were retrospectively reviewed. The International Criteria for BD was used to identify patients with a point score >=5. The clinical manifestations of BD were investigated over a 10-year period in this cohort. RESULTS: Twenty-six patients (20 women, six men; female:male ratio = 3.3:1.0) had a point score >=5 based on the International Criteria. The average age of onset of BD was 29.25 +/- 14.25 years. Oral ulcers (100%), genital ulcers (84.6%), articular involvement (69.2%), ocular involvement (65.3%), and skin lesions (50.0%) were the most prevalent manifestations of BD in this cohort. CONCLUSION: Oral ulcers were the most common presenting and lifetime sign of BD. In our cohort, oral and genital ulcers were hallmarks of BD, independent of patient demographics. Thus, patients with these signs require close surveillance for other manifestations of the disease. PMID- 26108442 TI - The complex of ASYMMETRIC LEAVES (AS) proteins plays a central role in antagonistic interactions of genes for leaf polarity specification in Arabidopsis. AB - Leaf primordia are born around meristem-containing stem cells at shoot apices, grow along three axes (proximal-distal, adaxial-abaxial, medial-lateral), and develop into flat symmetric leaves with adaxial-abaxial polarity. Axis development and polarity specification of Arabidopsis leaves require a network of genes for transcription factor-like proteins and small RNAs. Here, we summarize present understandings of adaxial-specific genes, ASYMMETRIC LEAVES1 (AS1) and AS2. Their complex (AS1-AS2) functions in the regulation of the proximal-distal leaf length by directly repressing class 1 KNOX homeobox genes (BP, KNAT2) that are expressed in the meristem periphery below leaf primordia. Adaxial-abaxial polarity specification involves antagonistic interaction of adaxial and abaxial genes including AS1 and AS2 for the development of two respective domains. AS1 AS2 directly represses the abaxial gene ETTIN/AUXIN RESPONSE FACTOR3 (ETT/ARF3) and indirectly represses ETT/ARF3 and ARF4 through tasiR-ARF. Modifier mutations have been identified that abolish adaxialization and enhance the defect in the proximal-distal patterning in as1 and as2. AS1-AS2 and its modifiers synergistically repress both ARFs and class 1 KNOXs. Repression of ARFs is critical for establishing adaxial-abaxial polarity. On the other hand, abaxial factors KANADI1 (KAN1) and KAN2 directly repress AS2 expression. These data delineate a molecular framework for antagonistic gene interactions among adaxial factors, AS1, AS2, and their modifiers, and the abaxial factors ARFs as key regulators in the establishment of adaxial-abaxial polarity. Possible AS1-AS2 epigenetic repression and activities downstream of ARFs are discussed. PMID- 26108445 TI - Topical combination therapy with vitamin D3 and corticosteroid ointment for palmoplantar pustulosis: A prospective, randomized, left-right comparison study. AB - BACKGROUND: Vitamin D3 ointment and corticosteroid ointment are both used for the treatment of palmoplantar pustulosis (PPP). However, to date there is no systematic study of the efficacy of combination therapy for the treatment of PPP. OBJECTIVE: We compared the efficacy of a topical combination therapy with vitamin D3 and a topical corticosteroid with that of topical corticosteroid alone in the treatment of PPP. METHOD: We evaluated left-right comparison study of the efficacy of a combination therapy consisting of maxacalcitol ointment and betamethasone butyrate propionate ointment (BBP), and monotherapy with BBP alone in 27 patients with PPP for 8 weeks. RESULTS: The improvement in the symptom (erythema, pustules/vesicles, hyperkeratosis/scales) scores was high for the combination therapy. In particular, the improvement rate for pustules/vesicles at week 8 after the combination therapy was significantly higher than for the monotherapy (p < 0.05). CONCLUSION: This combination regimen demonstrated that not only topical corticosteroids, but also topical vitamin D3 ointment, is useful for the treatment of PPP. PMID- 26108446 TI - Schwannoma of the parotid gland. Case report. AB - Schwannoma is encapsulated benign tumors arising from nerve cell. Of which ancient schwannoma is one of five variants. Intraparotid facial nerve schwannoma is been documented sporadical throught the medical literature, althought a few ancient schwannomas have been reported in different locations in the head and neck region. In this report, a 31 year old man patient with an misunderstanding tumor of the parotid gland is described and the histopathologic exam was performed to diagnosed the schwannoma. PMID- 26108447 TI - Azoles activate Atf1-mediated transcription through MAP kinase pathway for antifungal effects in fission yeast. AB - Azole antifungals directly inhibit enzymes for ergosterol biosynthesis, and this direct action is thought to underlie antifungal actions of these drugs. Recent studies showed that azoles alter expression of genes for various cellular functions. However, transcription factors regulated by azoles and their roles in antifungal actions remain poorly characterized. Using luciferase assay, we found that miconazole increased luciferase activity under the promoter containing the cAMP response element (CRE) motif. This azole-induced activation of CRE reporter was abolished in Atf1-deficient cells, suggesting that azoles induce Atf1 activation. As Atf1 is activated by stress-activated MAP kinase Sty1 upon various stressors, we examined its involvement. Azoles increased phosphorylation of Sty1 for its activation, and Sty1 deletion impaired azole-induced CRE reporter activation. In contrast, deletion of Pyp1, a tyrosine phosphatase which negatively regulates Sty1, increased CRE reporter activation. In addition, cells deficient in Atf1 and stress-activated MAP kinase pathway showed resistance to azoles, whereas cells lacking Pyp1 increased azole susceptibility, suggesting a critical role for azole-induced activation of MAP kinase-Atf1 pathway in antifungal actions of azoles. Collectively, these results suggest that azoles activate stress-activated MAP kinase pathway, thereby facilitating Atf1-mediated transcription for antifungal effects. PMID- 26108448 TI - Nano forsterite biocomposites for medical applications: Mechanical properties and bioactivity. AB - The aim of the present study was to obtain and to investigate nano forsterite and nano forsterite biocomposites for biomedical application. New self-curing forsterite biocomposites were obtained by mixing nano forsterite powder (5, 15, 30, 50, 70 wt %) with 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy) phenyl]propane (bis-GMA) and triethyleneglycol dimethacrylate (TEGDMA) monomers. The new nano forsterite biocomposites were investigated for mechanical properties: compressive strength (CS) (143-147.12 MPa), compressive modulus (CM) (1.67-2.75 GPa), diametral tensile strength (DTS) (27.33-31.55 MPa), flexural strength (FS) (59.47-83.20 MPa) and flexural modulus (FM) (2.05-8.60 GPa). Increases of CS, DTS, FS with increasing amount of forsterite were observed up to 50 wt %. The highest CM and FM values were registered for 70 wt % and a direct correlation between the forsterite volume fraction (%) was observed. SEM micrographs revealed the morphology of surface of fractured biocomposites after CS test. XPS indicated that these biocomposites promoted the hydroxyapatite formation on their surface immersed in simulated body fluid (SBF). AFM images showed that the growth of the hydroxyapatite layer occurs with a preferred orientation on the surface of forsterite biocomposites after immersion in SBF. Incorporation of nano forsterite in the polymer matrix (bis-GMA/TEGDMA) did show osteoblast adhesion and proliferation was improved on nano forsterite biocomposites. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1290-1301, 2016. PMID- 26108449 TI - Differential associations of age with volume and microstructure of hippocampal subfields in healthy older adults. AB - Hippocampal atrophy in advanced healthy aging has frequently been reported. However, the vulnerability of different hippocampal subfields to age-related atrophy is still a source of debate. Moreover, the association of age with the microstructural integrity of subfields is largely unknown. In this study, we investigated the associations between age and volume as well as microstructural integrity of hippocampal subfields using a three-dimensional (3D) surface mapping approach. Forty-three healthy older adults spanning the age range from 60 to 85 years underwent T1-weighted and diffusion-tensor imaging. Analyses demonstrated an association of age with hippocampal volume predominantly in the most anterior part of the hippocampal head, mainly corresponding to the subiculum. In contrast, the association of age with hippocampal microstructural integrity was mainly confined to regions located in the hippocampal body and tail, corresponding to the subiculum and CA1. Results indicate that age-related volumetric and microstructural alterations within hippocampal subfields provide complementary information and reflect different age-related processes. Potential mechanisms underlying the differential associations of age with volume and microstructure of hippocampal subfields are discussed. PMID- 26108450 TI - Nephrotic-range Albuminuria as the presenting symptom of Dent-2 disease. AB - Dent disease is a rare X-linked tubulopathy with low molecular weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis and progressive renal failure. We describe the case of a 9-year-old boy who presented with nephrotic-range albuminuria at the age of 3 years. In the absence of a clear diagnosis, a renal biopsy was performed at 4 years, which revealed minimal change disease. Due to the presence of low molecular weight proteinuria, even in the absence of hypercalciuria, a diagnosis of Dent disease was considered. While there were no mutations in the CLCN5 gene, the diagnosis was confirmed by the presence of a missense mutation (p.Arg318Cys) in the OCRL gene. CONCLUSION: Given the large phenotypic variability of the disease and based on our experience, we believe that children with low molecular weight proteinuria, even without hypercalciuria, should be investigated for Dent disease. PMID- 26108451 TI - Evidence-based management of the thyroid gland during a total laryngectomy. AB - OBJECTIVES/HYPOTHESIS: To propose an original experience-based reference framework for the management of the thyroid gland during a total laryngectomy in our institution. The steps were based on 1) the incidence and patterns of thyroid gland invasion (TGI), 2) preoperative and pathologic factors associated with TGI, and 3) the relationship between TGI and oncologic efficacy endpoints after treatment. STUDY DESIGN: Retrospective cohort study. METHODS: We reviewed the records of 182 patients who had undergone a total laryngectomy with a total thyroidectomy or loboisthmectomy in our center. RESULTS: Among 23 patients (12.6%), the thyroid gland was directly invaded by disease in 22 and by metastasis in one. Subglottic primary site was the only preoperative factor associated (P =.03). TGI was associated with pathological signs of anterior extralaryngeal invasive disease (thyroid cartilage transfixion, P = .002; cricothyroid membrane invasion, P < .0001; and prelaryngeal soft tissue infiltration, P < .0001) and ipsilateral VIb lymph node metastasis (P = .004). As expected, disease-free survival was significantly lower in patients with TGI (P = .04) and peristomal control was significantly reduced in patients with TGI (P = .038). CONCLUSIONS: To our knowledge, this is the largest monocentric series of TGI specimens after a total laryngectomy for laryngeal neoplasms described to date. Focus must be placed on anteroinferior spread, which is likely to invade the cricothyroid membrane, because TGI is part of the extension of extralaryngeal cancer. We propose original experience-based management of thyroid management during a total laryngectomy to improve the level of accuracy of decision making during the surgical procedure whenever possible. LEVEL OF EVIDENCE: 4 PMID- 26108452 TI - Longitudinal cleavage of the penis in chronic spinal cord injury: two case reports. AB - CONTEXT: Penile cleavage is a rare complication of spinal cord injury (SCI) in patients with a chronic indwelling catheter. We report two cases of chronic SCI who developed penile urethral cleavage after prolonged use of an indwelling catheter for bladder management. FINDINGS: A 25-year-old wheelchair mobile male with T7 American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade A paraplegia developed a 4 * 1.5 cm ventral urethral cleavage after using an indwelling catheter for four months with inadequate care. He had an associated urinary tract infection and undiagnosed diabetes mellitus. A suprapubic catheter was inserted and surgical repair recommended after resolution of UTI and adequate control of his diabetes mellitus. After initial treatment he was lost to follow up. The second patient was a 15-year-old male with AIS grade B tetraplegia who presented with a 2.5 cm cleavage on the ventral aspect of penis for the preceding three months. He had been using an indwelling catheter for bladder management for the previous 18 months. He had modified Ashworth scale grade III spasticity in lower limbs resistant to conservative management. There was no history of trauma, infection or diabetes mellitus. The patient was advised penile urethral repair surgery but was lost to follow-up. CONCLUSION: Penile cleavage is a rare complication of neurogenic bladder in SCI patients. Patients and care givers should be trained in proper bladder management techniques during the hospital stay, counseled regarding the need for regular follow up, and be taught identification and prevention of common complications. PMID- 26108454 TI - Phospholipids in foods: prooxidants or antioxidants? AB - Lipid oxidation is one of the major causes of quality deterioration in natural and processed foods and thus a large economic concern in the food industry. Phospholipids, especially lecithins, are already widely used as natural emulsifiers and have been gaining increasing interest as natural antioxidants to control lipid oxidation. This review summarizes the fatty acid composition and content of phospholipids naturally occurring in several foods. The role of phospholipids as substrates for lipid oxidation is discussed, with a focus on meats and dairy products. Prooxidant and antioxidant mechanisms of phospholipids are also discussed to get a better understanding of the possible opportunities for using phospholipids as food antioxidants. PMID- 26108453 TI - Loss of keratin 19 favours the development of cholestatic liver disease through decreased ductular reaction. AB - Keratins (K) are cytoprotective proteins and keratin mutations predispose to the development of multiple human diseases. K19 represents the most widely used marker of biliary and hepatic progenitor cells as well as a marker of ductular reaction that constitutes the basic regenerative response to chronic liver injury. In the present study, we investigated the role of K19 in biliary and hepatic progenitor cells and its importance for ductular reaction. K19 wild-type (WT) and knockout (KO) mice were fed: (a) 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC); (b) cholic acid (CA); (c) a choline-deficient, ethionine supplemented (CDE) diet; or (d) were subjected to common bile duct ligation (CBDL). The bile composition, liver damage, bile duct proliferation, oval cell content and biliary fibrosis were analysed. In untreated animals, loss of K19 led to redistribution of the K network in biliary epithelial cells (BECs) but to no obvious biliary phenotype. After DDC feeding, K19 KO mice exhibited (compared to WTs): (a) increased cholestasis; (b) less pronounced ductular reaction with reduced ductular proliferation and fewer oval cells; (c) impaired Notch 2 signalling in BECs; (d) lower biliary fibrosis score and biliary bicarbonate concentration. An attenuated oval cell proliferation in K19 KOs was also found after feeding with the CDE diet. K19 KOs subjected to CBDL displayed lower BEC proliferation, oval cell content and less prominent Notch 2 signal. K19 deficiency did not change the extent of CA- or CBDL-induced liver injury and fibrosis. Our results demonstrate that K19 plays an important role in the ductular reaction and might be of importance in multiple chronic liver disorders that frequently display a ductular reaction. PMID- 26108455 TI - Emerging corticosteroid agonists for the treatment of asthma. AB - INTRODUCTION: Asthma is one of the most frequent chronic diseases worldwide. For decades, asthma has been treated with bronchodilators and inhaled corticosteroids (ICS). However, adverse effects of ICS and disease heterogeneity necessitate improvements in the existing treatment regimes. Recently approved ICS show improved pharmocodynamic properties. Nevertheless, emerging drugs acting on the same receptor as the ICS, glucocorticoid receptor agonists (GRAs), are under current research. These drugs exhibit selective action on the glucocorticoid receptor (GR), which may improve their adverse effect profile, compared to the currently approved ICS that act unselectively on the GR. AREAS COVERED: The present article reviews emerging GRAs for the treatment of asthma. Furthermore, the more recently approved ICS with improved safety profiles are reviewed. EXPERT OPINION: Compared with drugs acting on other pathological pathways, research in GRAs for asthma is sparse. However, a few promising agents acting selectively on the GR are currently under investigation and may reach approval for asthma treatment. These drugs exhibit improved pharmacodynamic properties due to selectivity in the mechanism of action, including promotion of transrepression and reduction of transactivation. However, competition from already approved ICS and other emerging treatment options may lead to cessation of development of the new GRAs. PMID- 26108456 TI - Errata: Identification and characterization of a novel salt-tolerant esterase from a Tibetan glacier metagenomic library. PMID- 26108457 TI - Ion channel and lipid scramblase activity associated with expression of TMEM16F/ANO6 isoforms. AB - TMEM16F is a membrane protein with possible dual function as an ion channel and a phospholipid scramblase. The properties of ion channels associated with TMEM16F and the link between ion channel and scramblase activity are a matter of debate. We studied the properties of four isoforms of TMEM16F generated by alternative splicing. Upregulation of three TMEM16F isoforms or silencing of endogenous TMEM16F increased and decreased, respectively, both scramblase and channel activities. Introduction of an activating mutation in TMEM16F sequence caused a marked increase in phosphatidylserine scrambling and in ion transport indicating direct involvement of the protein in both functions. TMEM16F, also known as ANO6, is a membrane protein that has been associated with phospholipid scramblase and ion channel activity. However, the characteristics of TMEM16F-dependent channels, particularly the ion selectivity, are a matter of debate. Furthermore, the direct involvement of TMEM16F in phospholipid scrambling has been questioned. We studied the properties of different TMEM16F variants generated by alternative splicing. Using whole-cell patch-clamp recordings, we found that V1, V2 and V5 variants generated membrane currents activated by very high (micromolar) intracellular Ca(2+) concentrations and positive membrane potentials. These variants showed different degrees of Ca(2+) sensitivity and kinetics of activation but similar ion permeability, characterized by a slight selectivity for Cl(-) over Na(+) . A fourth variant (V3) showing a unique carboxy-terminus was devoid of activity, in agreement with its intracellular localization. We also measured scramblase activity using the binding of annexin V to detect phosphatidylserine on the cell surface. V1, V2 and V5 variants were associated with calcium-dependent phosphatidylserine externalization. Interestingly, introduction of an activating mutation, D409G, produced a marked increase in the apparent Ca(2+) sensitivity of TMEM16F-dependent channels. In parallel, this mutation also enhanced the extent of phosphatidylserine externalization that occurred even under resting conditions. These results support the conclusion that TMEM16F proteins are directly involved in dual activity, as a phospholipid scramblase and as an ion channel. PMID- 26108458 TI - A new scoring system for predicting survival in patients with non-small cell lung cancer. AB - This analysis was performed to create a scoring system to estimate the survival of patients with non-small cell lung cancer (NSCLC). Data from 1274 NSCLC patients were analyzed to create and validate a scoring system. Univariate (UV) and multivariate (MV) Cox models were used to evaluate the prognostic importance of each baseline factor. Prognostic factors that were significant on both UV and MV analyses were used to develop the score. These included quality of life, age, performance status, primary tumor diameter, nodal status, distant metastases, and smoking cessation. The score for each factor was determined by dividing the 5 year survival rate (%) by 10 and summing these scores to form a total score. MV models and the score were validated using bootstrapping with 1000 iterations from the original samples. The score for each prognostic factor ranged from 1 to 7 points with higher scores reflective of better survival. Total scores (sum of the scores from each independent prognostic factor) of 32-37 correlated with a 5-year survival of 8.3% (95% CI = 0-17.1%), 38-43 correlated with a 5-year survival of 20% (95% CI = 13-27%), 44-47 correlated with a 5-year survival of 48.3% (95% CI = 41.5-55.2%), 48-49 correlated to a 5-year survival of 72.1% (95% CI = 65.6 78.6%), and 50-52 correlated to a 5-year survival of 84.7% (95% CI = 79.6-89.8%). The bootstrap method confirmed the reliability of the score. Prognostic factors significantly associated with survival on both UV and MV analyses were used to construct a valid scoring system that can be used to predict survival of NSCLC patients. Optimally, this score could be used when counseling patients, and designing future trials. PMID- 26108459 TI - Toxicity, mutagenicity and transport in Saccharomyces cerevisiae of three popular DNA intercalating fluorescent dyes. AB - We have compared the toxicity, mutagenicity and transport in Saccharomyces cerevisiae of three DNA-intercalating fluorescent dyes widely used to stain DNA in gels. Safety data about ethidium bromide (EtBr) are contradictory, and two compounds of undisclosed structure (Redsafe and Gelred) have been proposed as safe alternatives. Our results indicate that all three compounds inhibit yeast growth, with Gelred being the most inhibitory and also the only one causing cell death. EtBr and Gelred, but not Redsafe, induce massive formation of petite (non respiratory) mutants, but only EtBr induces massive loss of mitochondrial DNA. All three compounds increase reversion of a chromosomal point mutation (lys2 801(amber) ), with Gelred being the most mutagenic and Redsafe the least. These dyes are all cationic and are probably taken by cells through non-selective cation channels. We could measure the glucose-energized transport of EtBr and Gelred inside the cells, while uptake of Redsafe was below our detection limit. We conclude that although all three compounds are toxic and mutagenic in the yeast system, Redsafe is the safest for yeast, probably because of very limited uptake by these cells. PMID- 26108460 TI - Using Immune Marker Panels to Evaluate the Role of Inflammation in Cancer: Summary of an NCI-sponsored Workshop. AB - Chronic inflammation is recognized to play a role in the development of several cancers. Past investigations of inflammation and cancer have typically been small, used varied assay platforms, and included a narrow range of analytes. Multiplex technologies have now been developed to measure larger numbers of inflammatory markers using small volumes of specimens. This has created an opportunity for systematic, large-scale epidemiological studies to evaluate the role of inflammation in cancer. However, lack of consensus on the approach to these studies, the technologies/assays to be used, and the most adequate analysis/interpretation of findings have thus far hindered progress. In June of 2014, the National Cancer Institute convened a workshop involving epidemiologists, immunologists, statisticians, and laboratory biologists to share their experiences with new inflammation marker technologies and findings from association studies using such methods and technologies (http://epi.grants.cancer.gov/workshops/). Consensus and gaps in our understanding of the role of chronic inflammation in cancer were identified and recommendations made to improve future efforts in this area. These recommendations are summarized herein, along with specific suggestions for how they may be implemented. By facilitating discussions among various groups, and encouraging interdisciplinary collaborations, we anticipate that the pace of research in this field will be accelerated and duplication of efforts can be minimized. PMID- 26108461 TI - The HOXB13 G84E Mutation Is Associated with an Increased Risk for Prostate Cancer and Other Malignancies. AB - BACKGROUND: A rare nonconservative substitution (G84E) in the HOXB13 gene has been shown to be associated with risk of prostate cancer. DNA samples from male patients included in the Mayo Clinic Biobank (MCB) were genotyped to determine the frequency of the G84E mutation and its association with various cancers. METHODS: Subjects were genotyped using a custom TaqMan (Applied Biosystems) assay for G84E (rs138213197). In addition to donating a blood specimen, all MCB participants completed a baseline questionnaire to collect information on medical history and family history of cancer. RESULTS: Forty-nine of 9,012 male patients were carriers of G84E (0.5%). Thirty-one percent (n = 2,595) of participants had been diagnosed with cancer, including 51.1% of G84E carriers compared with just 30.6% of noncarriers (P = 0.004). G84E was most frequently observed among men with prostate cancer compared with men without cancer (P < 0.0001). However, the mutation was also more commonly observed in men with bladder cancer (P = 0.06) and leukemia (P = 0.01). G84E carriers were more likely to have a positive family history of prostate cancer in a first-degree relative compared to noncarriers (36.2% vs. 16.0%, P = 0.0003). CONCLUSIONS: Our study confirms the association between the HOXB13 G84E variant and prostate cancer and suggests a novel association between G84E and leukemia and a suggestive association with bladder cancer. Future investigation is warranted to confirm these associations in order to improve our understanding of the role of germline HOXB13 mutations in human cancer. IMPACT: The associations between HOXB13 and prostate, leukemia, and bladder suggest that this gene is important in carcinogenesis. PMID- 26108462 TI - microRNA Biomarker Discovery and High-Throughput DNA Sequencing Are Possible Using Long-term Archived Serum Samples. AB - BACKGROUND: The impacts of long-term storage and varying preanalytical factors on the quality and quantity of DNA and miRNA from archived serum have not been fully assessed. Preanalytical and analytical variations and degradation may introduce bias in representation of DNA and miRNA and may result in loss or corruption of quantitative data. METHODS: We have evaluated DNA and miRNA quantity, quality, and variability in samples stored up to 40 years using one of the oldest prospective serum collections in the world, the Janus Serumbank, a biorepository dedicated to cancer research. RESULTS: miRNAs are present and stable in archived serum samples frozen at -25 degrees C for at least 40 years. Long-time storage did not reduce miRNA yields; however, varying preanalytical conditions had a significant effect and should be taken into consideration during project design. Of note, 500 MUL serum yielded sufficient miRNA for qPCR and small RNA sequencing and on average 650 unique miRNAs were detected in samples from presumably healthy donors. Of note, 500 MUL serum yielded sufficient DNA for whole-genome sequencing and subsequent SNP calling, giving a uniform representation of the genomes. CONCLUSIONS: DNA and miRNA are stable during long-term storage, making large prospectively collected serum repositories an invaluable source for miRNA and DNA biomarker discovery. IMPACT: Large-scale biomarker studies with long follow-up time are possible utilizing biorepositories with archived serum and state-of-the art technology. PMID- 26108463 TI - Sox2-CreER mice are useful for fate mapping of mature, but not neonatal, cochlear supporting cells in hair cell regeneration studies. AB - Studies of hair cell regeneration in the postnatal cochlea rely on fate mapping of supporting cells. Here we characterized a Sox2-CreER knock-in mouse line with two independent reporter mouse strains at neonatal and mature ages. Regardless of induction age, reporter expression was robust, with CreER activity being readily detectable in >85% of supporting cells within the organ of Corti. When induced at postnatal day (P) 28, Sox2-CreER activity was exclusive to supporting cells demonstrating its utility for fate mapping studies beyond this age. However, when induced at P1, Sox2-CreER activity was also detected in >50% of cochlear hair cells, suggesting that Sox2-CreER may not be useful to fate map a supporting cell origin of regenerated hair cells if induced at neonatal ages. Given that this model is currently in use by several investigators for fate mapping purposes, and may be adopted by others in the future, our finding that current protocols are effective for restricting CreER activity to supporting cells at mature but not neonatal ages is both significant and timely. PMID- 26108465 TI - Expanding the Psoriasis Disease Profile: Interrogation of the Skin and Serum of Patients with Moderate-to-Severe Psoriasis. PMID- 26108464 TI - Expression of Protease-Activated Receptor-2 in SZ95 Sebocytes and its Role in Sebaceous Lipogenesis, Inflammation, and Innate Immunity. PMID- 26108468 TI - Strong piezoelectricity in single-layer graphene deposited on SiO2 grating substrates. AB - Electromechanical response of materials is a key property for various applications ranging from actuators to sophisticated nanoelectromechanical systems. Here electromechanical properties of the single-layer graphene transferred onto SiO2 calibration grating substrates is studied via piezoresponse force microscopy and confocal Raman spectroscopy. The correlation of mechanical strains in graphene layer with the substrate morphology is established via Raman mapping. Apparent vertical piezoresponse from the single-layer graphene supported by underlying SiO2 structure is observed by piezoresponse force microscopy. The calculated vertical piezocoefficient is about 1.4 nm V(-1), that is, much higher than that of the conventional piezoelectric materials such as lead zirconate titanate and comparable to that of relaxor single crystals. The observed piezoresponse and achieved strain in graphene are associated with the chemical interaction of graphene's carbon atoms with the oxygen from underlying SiO2. The results provide a basis for future applications of graphene layers for sensing, actuating and energy harvesting. PMID- 26108467 TI - Differential gene retention as an evolutionary mechanism to generate biodiversity and adaptation in yeasts. AB - The evolutionary history of the characters underlying the adaptation of microorganisms to food and biotechnological uses is poorly understood. We undertook comparative genomics to investigate evolutionary relationships of the dairy yeast Geotrichum candidum within Saccharomycotina. Surprisingly, a remarkable proportion of genes showed discordant phylogenies, clustering with the filamentous fungus subphylum (Pezizomycotina), rather than the yeast subphylum (Saccharomycotina), of the Ascomycota. These genes appear not to be the result of Horizontal Gene Transfer (HGT), but to have been specifically retained by G. candidum after the filamentous fungi-yeasts split concomitant with the yeasts' genome contraction. We refer to these genes as SRAGs (Specifically Retained Ancestral Genes), having been lost by all or nearly all other yeasts, and thus contributing to the phenotypic specificity of lineages. SRAG functions include lipases consistent with a role in cheese making and novel endoglucanases associated with degradation of plant material. Similar gene retention was observed in three other distantly related yeasts representative of this ecologically diverse subphylum. The phenomenon thus appears to be widespread in the Saccharomycotina and argues that, alongside neo-functionalization following gene duplication and HGT, specific gene retention must be recognized as an important mechanism for generation of biodiversity and adaptation in yeasts. PMID- 26108470 TI - Luminescent supramolecular soft nanostructures from amphiphilic dinuclear Re(I) complexes. AB - Luminescent metallo-surfactants based on highly emissive dinuclear Re(I) complexes have been synthesized combining the peculiar photophysical behaviour of this class of neutral hydrophobic complexes with new properties imparted by hydrophilic chains anchored on the coordinated chromophoric ligand. In solution, the resulting neutral amphiphiles tend to self-assembly in soft structures. The aggregation properties have been thoroughly investigated in dioxane-water mixtures, where all the complexes assembly in globular-like supramolecular architectures with well-defined size (hydrodynamic diameter = 200-400 nm). The morphology of these nano-objects has been completely characterized with Dynamic Light Scattering (DLS) analysis, Scanning Transmission Electron Microscopy (STEM) and cryo-TEM to determine the size, polydispersity, and stability of the nanoparticles in relationship with the structure of the metallo-surfactants. The photophysical properties of both the isolated metal complexes and their aggregates have been investigated by means of UV-Vis absorption, steady-state and time-resolved emission spectroscopy. Noteworthy, the self-assembly properties of the reported luminescent rhenium metallo-amphiphiles can be modulated by solvent polarity. Even more importantly, such aggregation process yielded a small hypsochromic shift of the emission energy accompanied by a sizeable elongation of the excited-state lifetime and an enhancement of the photoluminescence quantum yield, reaching a remarkably high value of 0.20 despite the air-equilibrated aqueous condition. The presented findings endorse novel possibilities for the efficient use of soft-nanostructures based on metallo-amphiphiles in dual (electron and optical microscopy) bio-imaging applications and theranostics where the non-covalent nature of the intermolecular interactions would offer the powerful and unique possibility to reversibly assemble and disassemble imaging agents. PMID- 26108469 TI - Molecular and neuronal homology between the olfactory systems of zebrafish and mouse. AB - Studies of the two major olfactory organs of rodents, the olfactory mucosa (OM) and the vomeronasal organ (VNO), unraveled the molecular basis of smell in vertebrates. However, some vertebrates lack a VNO. Here we generated and analyzed the olfactory transcriptome of the zebrafish and compared it to the olfactory transcriptomes of mouse to investigate the evolutionary and molecular relationship between single and dual olfactory systems. Our analyses revealed a high degree of molecular conservation, with orthologs of mouse olfactory cell specific markers and all but one of their chemosensory receptor classes expressed in the single zebrafish olfactory organ. Zebrafish chemosensory receptor genes are expressed across a large dynamic range and their RNA abundance correlates positively with the number of neurons expressing that RNA. Thus we estimate the relative proportions of neuronal sub-types expressing different chemosensory receptors. Receptor repertoire size drives the absolute abundance of different classes of neurons, but we find similar underlying patterns in both species. Finally, we identified novel marker genes that characterize rare neuronal populations in both mouse and zebrafish. In sum, we find that the molecular and cellular mechanisms underpinning olfaction in teleosts and mammals are similar despite 430 million years of evolutionary divergence. PMID- 26108472 TI - Bi- and trimetallic rare-earth-palladium complexes ligated by phosphinoamides. AB - The synthesis of the heterometallic early-late 4d/4f bi- and trinuclear phosphinoamido Ln-Pd(0) complexes [(Ph2PNHPh)Pd{MU-(Ph2PNPh)}3Ln(MU-Cl)Li(THF)3] (Ln = Y, Lu) and [Li(THF)4][{(Ph2PNHPh)Pd}2{MU-(Ph2PNPh)}4Ln] (Ln = Y, Lu) is described. The latter compounds are the first early-late trimetallic phosphinoamido complexes. Although the metal atoms are forced into close proximity by the phosphinoamido ligands, quantum chemical calculations show only weak metal-to-metal interactions. PMID- 26108471 TI - Two-dimensional isobutyl acetate production pathways to improve carbon yield. AB - For an economically competitive biological process, achieving high carbon yield of a target chemical is crucial. In biochemical production, pyruvate and acetyl CoA are primary building blocks. When sugar is used as the sole biosynthetic substrate, acetyl-CoA is commonly generated by pyruvate decarboxylation. However, pyruvate decarboxylation during acetyl-CoA formation limits the theoretical maximum carbon yield (TMCY) by releasing carbon, and in some cases also leads to redox imbalance. To avoid these problems, we describe here the construction of a metabolic pathway that simultaneously utilizes glucose and acetate. Acetate is utilized to produce acetyl-CoA without carbon loss or redox imbalance. We demonstrate the utility of this approach for isobutyl acetate (IBA) production, wherein IBA production with glucose and acetate achieves a higher carbon yield than with either sole carbon source. These results highlight the potential for this multiple carbon source approach to improve the TMCY and balance redox in biosynthetic pathways. PMID- 26108473 TI - Nanotechnology in Disease Diagnostic Techniques. AB - Currently the major research highlights of bioengineering and medical technology are directed towards development of improved diagnostic techniques to screen complex diseases. Screening requirements are for the identification of the cause of illnesses, monitoring the improvement or progression of the state of diseases such as cancer, cardiovascular or neurodegenerative diseases. Nanotechnology enables the manipulation of materials at nanoscale and has shown potential to enhance sensitivity, selectivity and lower the cost of a diagnosis. The causative biomolecules (DNA, proteins) can be detected by red-shifted absorbance of gold nanoparticles or alteration in the conductance of a nanowire or nanotubes, and deflection of a micro or nano-cantilever. Several types of nanomaterials such as metals, metal-oxides and quantum dots have shown ample advantages over traditional diagnosis, intracellular labeling and visualization of target cells/tissues. Nanotechnology has also opened several avenues which could be further developed to enable enhanced visualization of tissues, cells, DNA and proteins over a point-of-care device. Protein or gene chips created using nanomaterials could be further be integrated into a convenient nano-fluidic device for better disease diagnosis. PMID- 26108474 TI - Sensitive fluorescence-based detection of magnetic field effects in photoreactions of flavins. AB - Magnetic field effect studies have been conducted on a variety of flavin-based radical pair systems chosen to model the magnetosensitivity of the photoinduced radical pairs found in cryptochrome flavoproteins. Cryptochromes are blue-light photoreceptor proteins which are thought to mediate avian magnetoreception, an hypothesis supported by recent in vitro observations of magnetic field-dependent reaction kinetics for a light-induced radical pair in a cryptochrome from the plant Arabidopsis thaliana. Many cryptochromes are difficult to express in large quantities or high concentrations and are easily photodegraded. Magnetic field effects are typically measured by spectroscopic detection of the transient radical (pair) concentrations. Due to its low sensitivity, single-pass transient absorption spectroscopy can be of limited use in such experiments and much recent work has involved development of other methodologies offering improved sensitivity. Here we explore the use of flavin fluorescence as the magnetosensitive probe and demonstrate the exceptional sensitivity of this technique which allows the detection of magnetic field effects in flavin samples at sub-nanomolar concentrations and in cryptochromes. PMID- 26108475 TI - A platform for efficient, thiol-stable conjugation to albumin's native single accessible cysteine. AB - Herein we report the use of bromomaleimides for the construction of stable albumin conjugates via conjugation to its native, single accessible, cysteine followed by hydrolysis. Advantages over the classical maleimide approach are highlighted in terms of quantitative hydrolysis and absence of undesirable retro Michael deconjugation. PMID- 26108476 TI - Influence of carbapenem resistance on mortality of patients with Pseudomonas aeruginosa infection: a meta-analysis. AB - Treatment of infectious diseases caused by the carbapenem-resistant Pseudomonas aeruginosa (CRPA) is becoming more challenging with each passing year. We conducted a meta-analysis to assess the impact of carbapenem resistance on mortality of patients with P. aeruginosa infection. We searched PUBMED, Web of science, EMBASE, Google Scholar and the Cochrane Library up to December 25, 2014, to identify published cohort or case-control studies. 17 studies, including 6660 patients carrying P. aeruginosa, were identified. The pooling analysis indicated that patients infected with CRPA had significantly higher mortality than those infected with carbapenem-susceptible P. aeruginosa (CSPA) (crude OR = 1.64; 95%CI = 1.40, 1.93; adjusted OR = 2.38; 95%CI = 1.53, 3.69). The elevated risk of mortality in patients with CRPA infection was not lessened when stratified by study design, sites of infection, or type of carbapenem, except that the estimate effect vanished in CRPA high-incidence region, South America (crude OR = 1.12; 95%CI = 0.64, 1.99). Begg's (z = 0.95, p = 0.34) and Egger's test (t = 1.23, p = 0.24) showed no evidence of publication bias. Our results suggest that carbapenem resistance may increase the mortality of patients with P. aeruginosa infection, whether under univariate or multivariate analysis. PMID- 26108477 TI - Impact of rurality on the oral health status of 6-year-old children from central Chile: the EpiMaule study. AB - INTRODUCTION: The aim of this study was the assessment of dental caries and the gingival status of 6-year-old children living in the Maule region, Chile's most rural region, and to determine if rurality was related to a higher prevalence of oral conditions. METHODS: A representative sample of 485 children aged 6 years was examined using WHO methods. Children were chosen from schools belonging to urban and rural districts of the region. Caries status was obtained by deft (decayed, extracted, filled teeth), DMFT (decayed, missing, filled teeth) and SiC (Significant Caries) indexes. To assess gingival health status, the oral hygiene (OHI) and the gingival index (GI) were used. Urban and rural children data were compared using student's t-test at p < 0.05. RESULTS: Overall caries prevalence was 80.62%. Rural children showed higher prevalence (p < 0.0001) than urban 6 year-olds, with 88.3% and 69.9%, respectively. The deft (decayed, extracted, filled teeth) index was 4.63 for the region, with 5.74 for rural and 3.09 for urban districts (p < 0.05). The SiC index was 10.23 for rural and 7.13 for urban children (p < 0.05). Mean OHI score was 1.44, but rural children had higher OHI: 1.49 compared with 1.37 for urban 6-year-olds (p < 0.0001). The GI of the region was 1.37, but no differences were detected between rural and urban children (p < 0.05). CONCLUSIONS: Children from the Maule region in Chile have a severely deteriorated oral health, higher than Chile's mean. Rural are significantly more affected than urban children. A special focus on rural communities when designing oral health policies is strongly suggested. PMID- 26108478 TI - Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone. AB - INTRODUCTION: The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1). RESULTS: The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1. CONCLUSIONS: Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background. PMID- 26108479 TI - The discourses on induced abortion in Ugandan daily newspapers: a discourse analysis. AB - BACKGROUND: Ugandan law prohibits abortion under all circumstances except where there is a risk for the woman's life. However, it has been estimated that over 250 000 illegal abortions are being performed in the country yearly. Many of these abortions are carried out under unsafe conditions, being one of the most common reasons behind the nearly 5000 maternal deaths per year in Uganda. Little research has been conducted in relation to societal views on abortion within the Ugandan society. This study aims to analyze the discourse on abortion as expressed in the two main daily Ugandan newspapers. METHOD: The conceptual content of 59 articles on abortion between years 2006-2012, from the two main daily English-speaking newspapers in Uganda, was studied using principles from critical discourse analysis. RESULTS: A religious discourse and a human rights discourse, together with medical and legal sub discourses frame the subject of abortion in Uganda, with consequences for who is portrayed as a victim and who is to blame for abortions taking place. It shows the strong presence of the Catholic Church within the medial debate on abortion. The results also demonstrate the absence of medial statements related to abortion made by political stakeholders. CONCLUSIONS: The Catholic Church has a strong position within the Ugandan society and their stance on abortion tends to have great influence on the way other actors and their activities are presented within the media, as well as how stakeholders choose to convey their message, or choose not to publicly debate the issue in question at all. To decrease the number of maternal deaths, we highlight the need for a more inclusive and varied debate that problematizes the current situation, especially from a gender perspective. PMID- 26108480 TI - Pretreatment of Nitric Acid with Hydrogen Peroxide Reduces Total Procedural Os Blank to Femtogram Levels. AB - Determining and correcting for background contributions of Re and Os from chemical reagents is critical for accurate and precise Re-Os dating of materials with parts per billion to parts per trillion Re and Os concentrations. Here we investigate reducing Os content in nitric acid, as it is the main contributor to the Os blank. Pretreating high-purity nitric acid with hydrogen peroxide (H2O2) significantly reduces nitric acid's Os contribution to femtogram levels, greatly reducing Os blank corrections. The improvement in background Os allows analysis of samples with extremely low Os concentrations (into the low ppt level). We present experimental data identifying key factors in reducing Os blank, including nitric acid to hydrogen peroxide volume ratios, wet versus dry glassware, and dark versus lighted reaction environments. These variables affect the reaction time between the two reagents, which in turn correlates inversely with the final Os content. The volume ratio of H2O2/HNO3 is shown to be the fundamental control on reaction time and final Os content, yielding a well-defined exponential relationship; minor variations in reaction time result from wet/dry glassware and light/dark reaction environment. At a H2O2/HNO3 volume ratio of ~0.24, the total procedural Os blank is reduced from 6.5 pg (no H2O2) to 0.043 pg. The (187)Os/(188)Os of the Os blank ranges from 0.18 to 0.36, consistent with the Os blank compositions obtained by the AIRIE Program and other Re-Os laboratories worldwide, and is uncorrelated with any experimental variables. In contrast to Os, pretreatment with hydrogen peroxide did not improve the Re blank of nitric acid; Re background reduction requires conventional methods such as sub-boiling distillation. PMID- 26108481 TI - [Analysis of the internet presence of the German Society of Neuroradiology]. PMID- 26108482 TI - [Not Available]. PMID- 26108483 TI - The role of juvenile hormone and insulin/TOR signaling in the growth of Manduca sexta. AB - BACKGROUND: In many insect species, fitness trade-offs exist between maximizing body size and developmental speed. Understanding how various species evolve different life history strategies requires knowledge of the physiological mechanisms underlying the regulation of body size and developmental timing. Here the roles of juvenile hormone (JH) and insulin/target of rapamycin (TOR) signaling in the regulation of the final body size were examined in the tobacco hornworm, Manduca sexta. RESULTS: Feeding rapamycin to wild-type larvae decreased the growth rate but did not alter the peak size of the larvae. In contrast, feeding rapamycin to the JH-deficient black mutant larvae caused the larvae to significantly increase the peak size relative to the DMSO-fed control animals by lengthening the terminal growth period. Furthermore, the critical weight was unaltered by feeding rapamycin, indicating that in Manduca, the critical weight is not influenced by insulin/TOR signaling. In addition, post-critical weight starved black mutant Manduca given rapamycin underwent metamorphosis sooner than those that were fed, mimicking the "bail-out mechanism". CONCLUSIONS: Our study demonstrates that JH masks the effects of insulin/TOR signaling in the determination of the final body size and that the critical weights in Drosophila and Manduca rely on distinct mechanisms that reflect different life history strategies. Our study also suggests that TOR signaling lengthens the terminal growth period in Manduca as it does in Drosophila, and that JH levels determine the relative contributions of nutrient- and body size-sensing pathways to metamorphic timing. PMID- 26108484 TI - Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for beta cell function. AB - Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic beta cells, it has been proposed that the luminal H2O2 concentration might be very high. As the role of this H2O2 in ER stress and proinsulin processing is still unsolved, an ER targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H2O2 removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H2O2 significantly with a threefold increase of the EC50 value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with beta cell toxic cytokines (IL1beta alone or together with TNFalpha+IFNgamma) was not affected by ER Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H2O2 reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2 toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2 in the ER in spite of a reduced insulin transcription and processing. PMID- 26108485 TI - Demethylation of the MafB promoter in a compromised beta-cell model. AB - Recent studies suggest that dedifferentiation of pancreatic beta-cells is involved in compromised beta-cell function in diabetes mellitus. We have previously shown that the promoter activity of MafB, which is expressed in alpha cells of adult islets and immature beta-cells in embryonic pancreas but not in mature beta-cells in mice, is increased in compromised beta-cells of diabetic model mice. Here, we investigated a rat beta-cell line of INS1 cells with late passage numbers, which showed extremely low expression of MafA and insulin, as an in vitro model of compromised beta-cells. In these INS1 cells, the mRNA expression and the promoter activity of MafB were upregulated compared with the early-passage ('conventional') INS1 cells. Analysis of the MafB promoter in these late-passage INS1 cells revealed that specific CpG sites in the MafB promoter were partially demethylated. The reporter assay revealed that the unmethylated promoter activity of the 373 bp region containing these CpG sites was higher than the in vitro methylated promoter activity. These results suggest that the chronic culture of the rat beta-cell line resulted in partial DNA demethylation of the MafB promoter, which may have a role in MafB promoter activation and possible dedifferentiation in our compromised beta-cell model. PMID- 26108486 TI - CYP11A1 expression in bone is associated with aromatase inhibitor-related bone loss. AB - Aromatase inhibitors (AIs) used as adjuvant therapy in postmenopausal women with hormone receptor-positive breast cancer cause diverse musculoskeletal side effects that include bone loss and its associated fracture. About half of the 391 patients treated with AIs in the Barcelona-Aromatase induced bone loss in early breast cancer cohort suffered a significant bone loss at lumbar spine (LS) and/or femoral neck (FN) after 2 years on AI-treatment. In contrast, up to one-third (19.6% LS, 38.6% FN) showed no decline or even increased bone density. The present study aimed to determine the genetic basis for this variability. SNPs in candidate genes involved in vitamin D and estrogen hormone-response pathways (CYP11A1, CYP17A1, HSD3B2, HSD17B3, CYP19A1, CYP2C19, CYP2C9, ESR1, DHCR7, GC, CYP2R1, CYP27B1, VDR and CYP24A1) were genotyped for association analysis with AI related bone loss (AIBL). After multiple testing correction, 3 tag-SNPs (rs4077581, s11632698 and rs900798) located in the CYP11A1 gene were significantly associated (P<0.005) with FN AIBL at 2 years of treatment. Next, CYP11A1 expression in human fresh bone tissue and primary osteoblasts was demonstrated by RT-PCR. Both common isoforms of human cholesterol side-chain cleavage enzyme (encoded by CYP11A1 gene) were detected in osteoblasts by western blot. In conclusion, the genetic association of CYP11A1 gene with AIBL and its expression in bone tissue reveals a potential local function of this enzyme in bone metabolism regulation, offering a new vision of the steroidogenic ability of this tissue and new understanding of AI-induced bone loss. PMID- 26108487 TI - Interaction between the trout mineralocorticoid and glucocorticoid receptors in vitro. AB - The salmonid corticosteroid receptors (CRs), glucocorticoid receptors 1 and 2 (GR1 and GR2) and the mineralocorticoid receptor (MR) share a high degree of homology with regard to structure, ligand- and DNA response element-binding, and cellular co-localization. Typically, these nuclear hormone receptors homodimerize to confer transcriptional activation of target genes, but a few studies using mammalian receptors suggest some degree of heterodimerization. We observed that the trout MR confers a several fold lower transcriptional activity compared to the trout GRs. This made us question the functional relevance of the MR when this receptor is located in the same cells as the GRs and activated by cortisol. A series of co-transfection experiments using different glucocorticoid response elements (GREs) containing promoter-reporter constructs were carried out to investigate any possible interaction between the piscine CRs. Co-transfection of the GRs with the MR significantly reduced the total transcriptional activity even at low MR levels, suggesting interaction between these receptors. Co-transfection of GR1 or GR2 with the MR did not affect the subcellular localization of the GRs, and the MR-mediated inhibition seemed to be independent of specific activation or inhibition of the MR. Site-directed mutagenesis of the DNA-binding domain and dimerization interface of the MR showed that the inhibition was dependent on DNA binding but not necessarily on dimerization ability. Thus, we suggest that the interaction between MR and the GRs may regulate the cortisol response in cell types where the receptors co-localize and propose a dominant-negative role for the MR in cortisol-mediated transcriptional activity. PMID- 26108488 TI - Preoperative independent prognostic factors in patients with borderline resectable pancreatic ductal adenocarcinoma following curative resection: the neutrophil-lymphocyte and platelet-lymphocyte ratios. AB - PURPOSE: The therapeutic strategy for borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) has remained unestablished because the preoperative prognostic factors have not been determined. METHODS: One hundred eighty-four consecutive PDAC patients who underwent upfront surgery with a curative resection between January 2000 and June 2013 at Kobe University Hospital were retrospectively studied. The PDAC patients were stratified into resectable (R) PDAC (n = 147) and BR-PDAC patients (n = 37). We evaluated the independent prognostic significance of the neutrophil-lymphocyte ratio (NLR) and the platelet lymphocyte ratio (PLR) in the BR-PDAC patients. RESULTS: BR-PDAC patient survival was significantly worse than R-PDAC patient survival (median survival time: 22.1 months vs. 24.3 months; 5-year survival rate 6 vs. 21 %; P = 0.042). The median survival in BR-PDAC patients with a preoperative NLR of >3 (n = 12) was 10.2 months, while that in patients with preoperative NLR of <=3 (n = 25) was 24.9 months (P = 0.002). Moreover, the median survival in BR-PDAC patients with a preoperative PLR of >225 (n = 8) was 10.2 months, while that in patients with a preoperative PLR of <=225 (n = 29) was 24.7 months (P = 0.003). Preoperative NLR >3 (HR = 2.980, 95 % CI 1.251-6.920; P = 0.015) and PLR >225 (HR = 3.050, 95 % CI 1.169-7.468; P = 0.024) were independent prognostic factors in BR-PDAC patients. CONCLUSIONS: Higher preoperative NLR and PLR can be independent predictive risk factors in BR-PDAC patients following curative resection. PMID- 26108489 TI - Physical Mapping and Refinement of the Painted Turtle Genome (Chrysemys picta) Inform Amniote Genome Evolution and Challenge Turtle-Bird Chromosomal Conservation. AB - Comparative genomics continues illuminating amniote genome evolution, but for many lineages our understanding remains incomplete. Here, we refine the assembly (CPI 3.0.3 NCBI AHGY00000000.2) and develop a cytogenetic map of the painted turtle (Chrysemys picta-CPI) genome, the first in turtles and in vertebrates with temperature-dependent sex determination. A comparison of turtle genomes with those of chicken, selected nonavian reptiles, and human revealed shared and novel genomic features, such as numerous chromosomal rearrangements. The largest conserved syntenic blocks between birds and turtles exist in four macrochromosomes, whereas rearrangements were evident in these and other chromosomes, disproving that turtles and birds retain fully conserved macrochromosomes for greater than 300 Myr. C-banding revealed large heterochromatic blocks in the centromeric region of only few chromosomes. The nucleolar-organizing region (NOR) mapped to a single CPI microchromosome, whereas in some turtles and lizards the NOR maps to nonhomologous sex-chromosomes, thus revealing independent translocations of the NOR in various reptilian lineages. There was no evidence for recent chromosomal fusions as interstitial telomeric DNA was absent. Some repeat elements (CR1-like, Gypsy) were enriched in the centromeres of five chromosomes, whereas others were widespread in the CPI genome. Bacterial artificial chromosome (BAC) clones were hybridized to 18 of the 25 CPI chromosomes and anchored to a G-banded ideogram. Several CPI sex determining genes mapped to five chromosomes, and homology was detected between yet other CPI autosomes and the globally nonhomologous sex chromosomes of chicken, other turtles, and squamates, underscoring the independent evolution of vertebrate sex-determining mechanisms. PMID- 26108490 TI - Selfish Mitochondrial DNA Proliferates and Diversifies in Small, but not Large, Experimental Populations of Caenorhabditis briggsae. AB - Evolutionary interactions across levels of biological organization contribute to a variety of fundamental processes including genome evolution, reproductive mode transitions, species diversification, and extinction. Evolutionary theory predicts that so-called "selfish" genetic elements will proliferate when the host effective population size (Ne) is small, but direct tests of this prediction remain few. We analyzed the evolutionary dynamics of deletion-containing mitochondrial DNA (DeltamtDNA) molecules, previously characterized as selfish elements, in six different natural strains of the nematode Caenorhabditis briggsae allowed to undergo experimental evolution in a range of population sizes (N = 1, 10, 100, and 1,000) for a maximum of 50 generations. Mitochondrial DNA (mtDNA) was analyzed for replicate lineages at each five-generation time point. Ten different DeltamtDNA molecule types were observed and characterized across generations in the experimental populations. Consistent with predictions from evolutionary theory, lab lines evolved in small-population sizes (e.g., nematode N = 1) were more susceptible to accumulation of high levels of preexisting DeltamtDNA compared with those evolved in larger populations. New DeltamtDNA elements were observed to increase in frequency and persist across time points, but almost exclusively at small population sizes. In some cases, DeltamtDNA levels decreased across generations when population size was large (nematode N = 1,000). Different natural strains of C. briggsae varied in their susceptibilities to DeltamtDNA accumulation, owing in part to preexisting compensatory mtDNA alleles in some strains that prevent deletion formation. This analysis directly demonstrates that the evolutionary trajectories of DeltamtDNA elements depend upon the population-genetic environments and molecular-genetic features of their hosts. PMID- 26108491 TI - Variation in the X:Autosome Distribution of Male-Biased Genes among Drosophila melanogaster Tissues and Its Relationship with Dosage Compensation. AB - Genes that are expressed differently between males and females (sex-biased genes) often show a nonrandom distribution in their genomic location, particularly with respect to the autosomes and the X chromosome. Previous studies of Drosophila melanogaster found a general paucity of male-biased genes on the X chromosome, although this is mainly limited to comparisons of whole flies or body segments containing the reproductive organs. To better understand the chromosomal distribution of sex-biased genes in various tissues, we used a common analysis framework to analyze microarray and RNA sequence data comparing male and female gene expression in individual tissues (brain, Malpighian tubule, and gonads), composite structures (head and gonadectomized carcass), and whole flies. Although there are relatively few sex-biased genes in the brain, there is a strong and highly significant enrichment of male-biased genes on the X chromosome. A weaker enrichment of X-linked male-biased genes is seen in the head, suggesting that most of this signal comes from the brain. In all other tissues, there is either no departure from the random expectation or a significant paucity of male-biased genes on the X chromosome. The brain and head also differ from other tissues in that their male-biased genes are significantly closer to binding sites of the dosage compensation complex. We propose that the interplay of dosage compensation and sex-specific regulation can explain the observed differences between tissues and reconcile disparate results reported in previous studies. PMID- 26108492 TI - Phylogeographic Refinement and Large Scale Genotyping of Human Y Chromosome Haplogroup E Provide New Insights into the Dispersal of Early Pastoralists in the African Continent. AB - Haplogroup E, defined by mutation M40, is the most common human Y chromosome clade within Africa. To increase the level of resolution of haplogroup E, we disclosed the phylogenetic relationships among 729 mutations found in 33 haplogroup DE Y-chromosomes sequenced at high coverage in previous studies. Additionally, we dissected the E-M35 subclade by genotyping 62 informative markers in 5,222 samples from 118 worldwide populations. The phylogeny of haplogroup E showed novel features compared with the previous topology, including a new basal dichotomy. Within haplogroup E-M35, we resolved all the previously known polytomies and assigned all the E-M35* chromosomes to five new different clades, all belonging to a newly identified subhaplogroup (E-V1515), which accounts for almost half of the E-M35 chromosomes from the Horn of Africa. Moreover, using a Bayesian phylogeographic analysis and a single nucleotide polymorphism-based approach we localized and dated the origin of this new lineage in the northern part of the Horn, about 12 ka. Time frames, phylogenetic structuring, and sociogeographic distribution of E-V1515 and its subclades are consistent with a multistep demic spread of pastoralism within north-eastern Africa and its subsequent diffusion to subequatorial areas. In addition, our results increase the discriminative power of the E-M35 haplogroup for use in forensic genetics through the identification of new ancestry-informative markers. PMID- 26108494 TI - Fermentative capabilities and volatile compounds produced by Kloeckera/Hanseniaspora and Saccharomyces yeast strains in pure and mixed cultures during Agave tequilana juice fermentation. AB - The fermentative and aromatic capabilities of Kloeckera africana/Hanseniaspora vineae K1, K. apiculata/H. uvarum K2, and Saccharomyces cerevisiae S1 and S2 were studied in pure and mixed culture fermentations using Agave tequila juice as the culture medium. In pure and mixed cultures, Kloeckera/Hanseniaspora strains showed limited growth and sugar consumption, as well as low ethanol yield and productivity, compared to S. cerevisiae, which yielded more biomass, ethanol and viable cell concentrations. In pure and mixed cultures, S. cerevisiae presented a similar behaviour reaching high biomass production, completely consuming the sugar, leading to high ethanol production. Furthermore, the presence of S. cerevisiae strains in the mixed cultures promoted the production of higher alcohols, acetaldehyde and ethyl esters, whereas Kloeckera/Hanseniaspora strains stimulated the production of ethyl acetate and 2-phenyl ethyl acetate compounds. PMID- 26108493 TI - Brain microsomal fatty acid elongation is increased in abcd1-deficient mouse during active myelination phase. AB - The dysfunction of ABCD1, a peroxisomal ABC protein, leads to the perturbation of very long chain fatty acid (VLCFA) metabolism and is the cause of X-linked adrenoleukodystrophy. Abcd1-deficient mice exhibit an accumulation of saturated VLCFAs, such as C26:0, in all tissues, especially the brain. The present study sought to measure microsomal fatty acid elongation activity in the brain of wild type (WT) and abcd1-deficient mice during the course of development. The fatty acid elongation activity in the microsomal fraction was measured by the incorporation of [2-(14)C]malonyl-CoA into fatty acids in the presence of C16:0 CoA or C20:0-CoA. Cytosolic fatty acid synthesis activity was completely inhibited by the addition of N-ethylmaleimide (NEM). The microsomal fatty acid elongation activity in the brain was significantly high at 3 weeks after birth and decreased substantially at 3 months after birth. Furthermore, we detected two different types of microsomal fatty acid elongation activity by using C16:0-CoA or C20:0-CoA as the substrate and found the activity toward C20:0-CoA in abcd1 deficient mice was higher than the WT 3-week-old animals. These results suggest that during the active myelination phase the microsomal fatty acid elongation activity is stimulated in abcd1-deficient mice, which in turn perturbs the lipid composition in myelin. PMID- 26108495 TI - Photokinesis is magnetic field dependent in the multicellular magnetotactic prokaryote Candidatus Magnetoglobus multicellularis. AB - Candidatus Magnetoglobus multicellularis is a spherical, multicellular, magnetotactic prokaryote (MMP) composed of 10-40 genetically-identical, Gram negative cells. It is known that monochromatic light of low intensity influences its average swimming velocity, being higher for red light (628 nm) and lower for green light (517 nm). In this study, we determined the effect of light of different wavelengths and intensities on the swimming velocity of Ca. Magnetoglobus multicellularis under different magnetic field intensities. The swimming velocities of several organisms exposed to blue light (469 nm), green light (517 nm) and red light (628 nm) with intensities ranging from 0.36 to 3.68 Wm(-2) were recorded under magnetic field intensities ranging from 0.26 to 1.47 Oe. Our results showed that MMPs exposed to green light display consistently lower average swimming velocities compared to other wavelengths of light. We also show for the first time that photokinesis in Ca. Magnetoglobus multicellularis is dependent on the magnetic field being applied. The relationship between light wavelength and intensity and magnetic field strength and swimming velocity in this MMP is therefore complex. Although the mechanism for the observed behaviour is not completely understood, a flavin-containing chromophore may be involved. PMID- 26108496 TI - Marine Algae: a Source of Biomass for Biotechnological Applications. AB - Biomass derived from marine microalgae and macroalgae is globally recognized as a source of valuable chemical constituents with applications in the agri horticultural sector (including animal feeds and health and plant stimulants), as human food and food ingredients as well as in the nutraceutical, cosmeceutical, and pharmaceutical industries. Algal biomass supply of sufficient quality and quantity however remains a concern with increasing environmental pressures conflicting with the growing demand. Recent attempts in supplying consistent, safe and environmentally acceptable biomass through cultivation of (macro- and micro-) algal biomass have concentrated on characterizing natural variability in bioactives, and optimizing cultivated materials through strain selection and hybridization, as well as breeding and, more recently, genetic improvements of biomass. Biotechnological tools including metabolomics, transcriptomics, and genomics have recently been extended to algae but, in comparison to microbial or plant biomass, still remain underdeveloped. Current progress in algal biotechnology is driven by an increased demand for new sources of biomass due to several global challenges, new discoveries and technologies available as well as an increased global awareness of the many applications of algae. Algal diversity and complexity provides significant potential provided that shortages in suitable and safe biomass can be met, and consumer demands are matched by commercial investment in product development. PMID- 26108497 TI - Structure and Function of Macroalgal Natural Products. AB - Since the initial discovery of marine phyco-derived secondary metabolites in the 1950s there has been a rapid increase in the description of new algal natural products. These metabolites have multiple ecological roles as well as commercial value as potential drugs or lead compounds. With the emergence of resistance to our current arsenal of drugs as well as the development of new chemotherapies for currently untreatable diseases, new compounds must be sourced. As outlined in this chapter algae produce a diverse range of chemicals many of which have potential for the treatment of human afflictions.In this chapter we outline the classes of metabolites produced by this chemically rich group of organisms as well as their respective ecological roles in the environment. Algae are found in nearly every environment on earth, with many of these organisms possessing the ability to shape the ecosystem they inhabit. With current challenges to climate stability, understanding how these important organisms interact with their environment as well as one another might afford better insight into how they respond to a changing climate. PMID- 26108498 TI - Spectrophotometric Assays of Major Compounds Extracted from Algae. AB - This chapter describes spectrophotometric assays of major compounds extracted from microalgae and macroalgae, i.e., proteins, carbohydrates, pigments (chlorophylls, carotenoids, and phycobiliproteins) and phenolic compounds. In contrast to other specific analytical techniques, such as high pressure liquid chromatography (HPLC) or mass spectrometry (MS), commonly applied to purified extracts to reveal more detailed composition and structure of algal compound families, these assays serve as a first assessment of the global contents of extracts. PMID- 26108499 TI - Extraction and Enrichment of Protein from Red and Green Macroalgae. AB - Macroalgae, in particular red and green species, are gaining interest as protein rich foods for human consumption and sources of proteinaceous biofunctional peptide ingredients. During protein extraction the starting raw material, the cell disruption method utilized and the reagents employed have a major effect on the yield of protein recovered. A method is described herein for extraction and semi-purification of food-grade aqueous and alkaline soluble proteins from red and green macroalgae. Dried milled macroalgae are disrupted by osmotic shock with subsequent removal of aqueous soluble proteins by centrifugation. Alkaline soluble proteins are removed following consecutive treatment of the resultant pellet with an alkaline solution. Aqueous and alkaline soluble proteins are then enriched from the crude extracts by isoelectric precipitation. PMID- 26108500 TI - Extraction and Purification of R-phycoerythrin from Marine Red Algae. AB - This chapter focuses on the recovery of an R-Phycoerythrin (R-PE)-enriched fraction from marine algae. Since R-PE is a proteinaceous pigment, we have developed a simple and rapid two-step method devoted to the extraction and purification of R-PE from marine red algae. Here we describe a phosphate buffer extraction followed by anion exchange chromatography carried on a DEAE Sepharose Fast Flow column. To ensure the quality and quantity of R-PE recovery, we also indicate different methods to monitor each fraction obtained, such as spectrophotometric indicators, gel filtration, and SDS-PAGE analysis. PMID- 26108501 TI - Extraction and Analysis of Mycosporine-Like Amino Acids in Marine Algae. AB - Marine organisms use mycosporine-like amino acids (MAAs) as biological sunscreens for the protection from damaging ultraviolet (UV) radiation and the prevention of oxidative stress. MAAs have been discovered in many different marine and freshwater species including cyanobacteria, fungi, and algae, but also in animals like cnidarian and fishes. Here, we describe a general method for the isolation and characterization of MAA compounds from red algae and symbiotic dinoflagellates isolated from coral hosts. This method is also suitable for the extraction and analyses of MAAs from a range of other algal and marine biota. PMID- 26108502 TI - Extraction and Purification of Phlorotannins from Brown Algae. AB - The interest in the physiological roles and bioactivities of plant phenols has increased over the past decades. In seaweeds, many investigations have dealt with phenolic compounds of Phaeophyceae (phlorotannins), even though little is known so far about the ecophysiological variations of their pool or their biosynthetic pathways. We describe here a simple procedure based on the use of water-organic solvent mixtures for the extraction of phlorotannins. Crude extracts are semi purified and fractionated by separating methods based on both the polarity and the molecular size of compounds. Phenols are then quantified by the Folin Ciocalteu method and their radical-scavenging activity is characterized using the DPPH test. All along the purification process of phenolic compounds, the efficiency of separation is assessed by (1)H-NMR. PMID- 26108503 TI - Enzyme-Enhanced Extraction of Antioxidant Ingredients from Algae. AB - Marine algae are not only a rich source of dietary fibre, proteins, vitamins, and minerals, but also contain a great variety of secondary metabolites with diverse biological activities. Marine macroalgae are a rich source of various natural antioxidants such as polyphenols, especially phlorotannins (made of polyphloroglucinol units) derived from brown algae, which play an important role in preventing lipid peroxidation. In recent years, a number of potent antioxidant compounds have been isolated and identified from different types of edible seaweeds. Extraction methods commonly used for the isolation of antioxidants are based on conventional water or organic solvent extractions. However, recent advances have shown that enzymatic hydrolysis can achieve higher yield of bioactive compounds from algae. Here we describe a method based on enzymatic hydrolysis which both increases yield and decreases cost associated with organic solvents. This method achieves cell wall disruption and breakdown of internal storage components for more effective release of intracellular bioactive compounds. In addition, hydrolysis of proteins produces peptides which may have antioxidant properties, thus enhancing the bioactivity of the algal extract. The method described can be used for production of extracts from red and brown macroalgal species. PMID- 26108504 TI - Microwave-Assisted Extraction of Fucoidan from Marine Algae. AB - Microwave-assisted extraction (MAE) is a technique that can be applied to extract compounds from different natural resources. In this chapter, the use of this technique to extract fucoidan from marine algae is described. The method involves a closed MAE system, ultrapure water as extraction solvent, and suitable conditions of time, pressure, and algal biomass/water ratio. By using this procedure under the specified conditions, the penetration of the electromagnetic waves into the material structure occurs in an efficient manner, generating a distributed heat source that promotes the fucoidan extraction from the algal biomass. PMID- 26108505 TI - Extraction and Analysis of Oxylipins from Macroalgae Illustrated on the Example Gracilaria vermiculophylla. AB - Oxylipins are natural products that are derived by oxidative transformations of unsaturated fatty acids. These metabolites are found in a wide range of organisms from the animal kingdom to plants and algae. They represent an important class of signaling molecules, mediating intra- and intercellular processes such as development, inflammation, and other stress responses. In addition, these metabolites directly function as chemical defense against grazers and pathogens. In the red alga Gracilaria vermiculophylla, oxylipin production is initiated by mechanical tissue disruption and can also be induced in intact algae in response to external stress signals. The defense metabolites mostly result from the lipase and lipoxygenase-mediated conversion of phospho- and galactolipids. Oxylipins can vary greatly in their size, degree of unsaturation, oxidation state, and functional groups. But also isomers with only subtle chemical differences are found. A variety of methods have been developed for separation, detection, and identification of oxylipins. This chapter focuses on the analysis of oxylipins in macroalgae and covers all aspects from sample preparation (including protocols for the investigation of oxylipins in wounded and intact algal tissue), extraction, purification, and subsequent analysis using liquid chromatography coupled to a UV detector or a mass spectrometer. The protocols developed for G. vermiculophylla can be readily adapted to the investigation of other macroalgae. PMID- 26108506 TI - Lipids and Fatty Acids in Algae: Extraction, Fractionation into Lipid Classes, and Analysis by Gas Chromatography Coupled with Flame Ionization Detector (GC FID). AB - Despite the number of biochemical studies exploring algal lipids and fatty acid biosynthesis pathways and profiles, analytical methods used by phycologists for this purpose are often diverse and incompletely described. Potential confusion and potential variability of the results between studies can therefore occur due to change of protocols for lipid extraction and fractionation, as well as fatty acid methyl esters (FAME) preparation before gas chromatography (GC) analyses. Here, we describe a step-by-step procedure for the profiling of neutral and polar lipids using techniques such as solid-liquid extraction (SLE), thin-layer chromatography (TLC), and gas chromatography coupled with flame ionization detector (GC-FID). As an example, in this protocol chapter, analyses of neutral and polar lipids from the marine microalga Pavlova lutheri (an EPA/DHA-rich haptophyte) will be outlined to describe the distribution of fatty acid residues within its major lipid classes. This method has been proven to be a reliable technique to assess changes in lipid and fatty acid profiles in several other microalgal species and seaweeds. PMID- 26108507 TI - HRMAS NMR Analysis of Algae and Identification of Molecules of Interest via Conventional 1D and 2D NMR: Sample Preparation and Optimization of Experimental Conditions. AB - Nuclear magnetic resonance (NMR) has become an astounding tool for molecular characterization. Thanks to the development of probes and the increase of magnetic field, NMR has entered the field of biology and facilitated the identification of natural compounds. Indeed, this nondestructive NMR tool makes possible the complete characterization of less and less quantities of material via 1D and 2D sequences on many nuclei (e.g., (1)H, (13)C, (31)P, (15)N). More recently, the development of high-resolution magic-angle spinning (HRMAS) probes have permitted direct analysis of living tissue (e.g., a piece of algae) without prior extraction providing information on both the total content and the ratio of different molecules within the sample; thus HRMAS facilitates a wide range of analyses, such as species differentiation or studies of metabolomics according to various environmental or experimental conditions. This chapter describes the specific sample preparation, based on an algal sample or extract, required for all NMR analyses in order to optimize the NMR response and obtain the most valuable information. PMID- 26108508 TI - Extraction, Purification, and NMR Analysis of Terpenes from Brown Algae. AB - Algal terpenes constitute a wide and well-documented group of marine natural products with structures differing from their terrestrial plant biosynthetic analogues. Amongst macroalgae, brown seaweeds are considered as one of the richest source of biologically and ecologically relevant terpenoids. These metabolites, mostly encountered in algae of the class Phaeophyceae, are mainly diterpenes and meroditerpenes (metabolites of mixed biogenesis characterized by a toluquinol or a toluquinone nucleus linked to a diterpene moiety).In this chapter, we describe analytical processes commonly employed for the isolation and structural characterization of the main terpenoid constituents obtained from organic extracts of brown algae. The successive steps include (1) extraction of lipidic content from algal samples; (2) purification of terpenes by column chromatography and semi-preparative high-performance liquid chromatography; and (3) structure elucidation of the isolated terpenes by means of 1D and 2D nuclear magnetic resonance (NMR). More precisely, we propose a representative methodology which allows the isolation and structural determination of the monocyclic meroditerpene methoxybifurcarenone (MBFC) from the Mediterranean brown alga Cystoseira amentacea var. stricta. This methodology has a large field of applications and can then be extended to terpenes isolated from other species of the family Sargassaceae. PMID- 26108509 TI - Extraction, Isolation, and Identification of Sesquiterpenes from Laurencia Species. AB - The knowledge about the chemical structure of the secondary metabolites and their relative abundances in algae is very important to several fields of basic and applied research in biology, chemistry, and many other disciplines. The attainment of such knowledge requires special attention to the origin of the organism in question and the methodology applied. Here, we present a protocol to obtain and identify some sesquiterpenes from Laurencia species based on traditional methodologies, such as flash and thin-layer chromatographies, nuclear magnetic resonance spectroscopy, and gas chromatography mass spectrometry. Red algae of the genus Laurencia are known to produce structurally diverse terpenes; most of them are halogenated compounds with important ecological functions and significant potential for the discovery of new biotechnological applications. PMID- 26108510 TI - The Use of HPLC for the Characterization of Phytoplankton Pigments. AB - HPLC is still the technique of choice for the analysis and characterization of phytoplankton pigments. In this chapter we describe procedures for sample preparation and pigment extraction, and the use of octyl silica columns and pyridine-containing mobile phases to separate chlorophylls and carotenoids. The identification of pigments on the basis of their retention times and visible spectra, the preparation of pigment standards, and the quantitative analysis by either external or internal standard procedures are also described. PMID- 26108511 TI - Characterization of Phlorotannins from Brown Algae by LC-HRMS. AB - Phlorotannins are a class of polyphenols found in brown seaweeds that have significant potential for use as therapeutics, owing to their wide range of bioactivities. Molecular characterization of phlorotannin-enriched extracts is challenging due to the extreme sample complexity and the wide range of molecular weights observed. Herein, we describe a method for characterizing phlorotannins employing ultrahigh-pressure liquid chromatography (UHPLC) operating in hydrophilic interaction liquid chromatography (HILIC) mode combined with high resolution mass spectrometry (HRMS). PMID- 26108512 TI - Analysis of Betaines from Marine Algae Using LC-MS-MS. AB - Betaines are a class of quaternary ammonium compounds found in marine algae that can act as osmolytes and/or affect gene expression, and therefore improve plant tolerance to stresses such as temperature extremes, drought, and salinity when applied to agricultural crops. In humans, glycine betaine acts as a methyl donor and has been shown to protect internal organs, improve vascular risk factors, and enhance sport performance. Here we describe a sensitive LC-MS-MS method for the baseline separation and quantification of four betaines found in algae, namely, glycine betaine, delta-aminovaleric acid betaine, gamma-aminobutyric acid betaine, and laminine. PMID- 26108513 TI - Analysis of Marine Biotoxins Using LC-MS/MS. AB - Different clinical types of algae-related poisoning have attracted scientific and commercial attention: paralytic shellfish poisoning (PSP), diarrhetic shellfish poisoning (DSP), and amnesic shellfish poisoning (ASP). Bioassays are common methods for the determination of marine biotoxins. However, biological tests are not completely satisfactory, mainly due to the low sensitivity and the absence of specialized variations. In this context LC-MS methods replaced HPLC methods with optical detectors, allowing both effective seafood control and monitoring of phytoplankton in terms of the different groups of marine biotoxins. This chapter describes state-of-the-art LC-MS/MS methods for the detection and quantitation of different classes of phycotoxins in shellfish matrices. These classes include the highly hydrophilic paralytic shellfish poisoning (PSP) toxins. Hydrophilic interaction liquid chromatography (HILIC) has been shown to be useful in the separation of PSP toxins and is described in detail within this chapter. Another important class of phycotoxins is diarrhetic shellfish poisoning (DSP) toxins. This group traditionally comprises okadaic acid and dinophysistoxins (DTXs), pectenotoxins (PTXs), and yessotoxins (YTXs). The most recently described shellfish poisoning syndrome, azaspiracid shellfish poisoning (AZP) is caused by azaspiracids, which in turn are diarrhetic, but usually are treated separately as AZP. The last group of regulated shellfish toxins is the amnesic shellfish poisoning (ASP) toxin domoic acid, produced by species of the genus Pseudo nitzschia. PMID- 26108514 TI - Fucoidan Analysis by Tandem MALDI-TOF and ESI Mass Spectrometry. AB - The application of mass spectrometry towards the structural analysis of the most interesting sulfated biopolymers of the brown algae-fucoidans only developed relatively recently. During method development, many problems, both chemical and instrumental, have to be solved. For example, mass spectrometry has a limitation in the analysis of anionic high molecular weight (HMW) polysaccharides because of the labile nature of sulfate groups which cause the polysaccharide to desulfate rather than ionize. Thus, decomposition methods should be developed taking into account the structural features of such a complex and fragile compound. The selection of optimal instrument settings for the electrospray ionization mass spectrometry (ESIMS) and of matrix media for matrix-assisted laser desorption/ionization mass spectrometry (MALDIMS) is also required. When optimal parameters for mass spectrometric analyses are found, the application of these methods to the elucidation of structural features of fucoidans (by studying their fragments) allows researchers to rapidly obtain new and unique data, often impossible to achieve by other techniques. Herein, we describe tandem mass spectrometry of sulfated fucooligosaccharides, obtained by an autohydrolysis technique from structurally different fucoidans. PMID- 26108515 TI - Determination of Substitution Patterns of Galactans from Green Seaweeds of the Bryopsidales. AB - Sulfated and pyruvylated galactans are the major soluble polysaccharides produced by seaweeds of the Bryopsidales. Their backbones have a complex and variable pattern of substitution which, until now, has only been elucidated for a few species. Methods for determination of sulfate and pyruvic acid content, and chemical strategies to determine their position in the galactan chain are outlined here. These methods can also be applied to other sulfated and/or pyruvylated polysaccharides. PMID- 26108516 TI - Structural Characterization of a Hybrid Carrageenan-Like Sulfated Galactan from a Marine Red Alga Furcellaria lumbricalis. AB - Carrageenans are sulfated galactan isolated from marine red algae with different disaccharide forms. There are also some hybrid carrageenan-like oligomers, which are reported to possess a number of bioactivities. Here, we describe a method to study the structural characterization of a carrageenan-like sulfated galactan FB1 extracted from the red seaweed Furcellaria lumbricalis. We show the process of the general analysis of FB1, including the molecular weight, sulfate content, total sugar content, protein content, and 3,6-anhydrogalactose (3,6-AnG) content analyses. The fine structure identification methods, including desulfation and methylation, nuclear magnetic resonance (NMR), and electrospray ionization collision induced dissociation tandem mass spectrometry (ES-CID-MS/MS), are also described in detail. PMID- 26108517 TI - Characterization of Alginates by Nuclear Magnetic Resonance (NMR) and Vibrational Spectroscopy (IR, NIR, Raman) in Combination with Chemometrics. AB - This chapter describes three different spectroscopic methods for structural characterization of the commercial important hydrocolloid alginate extracted from brown seaweed. The "golden" reference method for characterization of the alginate structure is (1)H liquid-state NMR of depolymerized alginate polymers using a stepwise hydrolysis. Having implemented this method, predictive and rapid non destructive methods using vibrational spectroscopy and chemometrics can be developed. These methods can predict the M/G-ratio of the intact alginate powder with at least the same precision and accuracy as the reference method in a fraction of the time that is required to measure the alginate using the reference method. The chapter also demonstrates how solid-state (13)C CP/MAS NMR can be used to determine the M/G ratio on the intact sample by the use of multivariate chemometrics and how this method shares the characteristics of the solid-state non-destructive IR method rather than its liquid-state counterpart. PMID- 26108518 TI - Imaging and Identification of Marine Algal Bioactive Compounds by Surface Enhanced Raman Spectroscopy (SERS). AB - Surface-enhanced Raman spectroscopy (SERS) is a highly selective technique that can be used for imaging of single algae cells. In contrast to normal Raman spectroscopy, SERS utilizes light interaction with colloidal gold or silver particles working as antennas to match the sensitivity of fluorescence measurements. Furthermore, SERS enables a more profound picture of not only the analyte of interest but also the present biological matrix without the need for additional fluorescence labelling. The introduction of an internal standard in the form of a thiol self-assembled monolayer (SAM) on the colloidal gold or silver particles can be used to normalize the SERS response that otherwise would also depend on the locations of the colloid particles in the microscope image.In light of the vast amounts of data that is generated in each spectrum and the large variance in enhancement signal, multivariate analysis is necessary for accurate evaluation. This can be done by the use of transposed orthogonal projections to latent structures (T-OPLS), where the variations of properties in the reference spectra, Y table, and the variation in spectra, X table, are correlated. PMID- 26108520 TI - Disk Diffusion Assay to Assess the Antimicrobial Activity of Marine Algal Extracts. AB - Marine algae are a relatively untapped source of bioactive natural products, including those with antimicrobial activities. The ability to assess the antimicrobial activity of cell extracts derived from algal cultures is vital to identifying species that may produce useful novel antibiotics. One assay that is used widely for this purpose is the disk diffusion assay due to its simplicity, rapidity, and low cost. Moreover, this assay gives output data that are easy to interpret and can be used to screen many samples at once irrespective of the solvent used during preparation. In this chapter, a step-by-step protocol for performing a disk diffusion assay is described. The assay is particularly well suited to testing algal cell extracts and fractions resulting from separation through bioassay-guided approaches. PMID- 26108519 TI - In Vitro Protocols for Measuring the Antioxidant Capacity of Algal Extracts. AB - In the last decade a large amount of research has been directed at targeting algal resources for biologically active molecules. High-throughput in vitro antioxidant assays are routinely used to screen for biologically active compounds present in algal extracts when the requirement is to identify samples for progression to more detailed biological scrutiny. Whilst a myriad of antioxidant assays have been developed, this present chapter aims to give step-by-step practical guidance on how to carry out some of the most popular and biologically relevant assays at the bench. PMID- 26108521 TI - Screening of a Marine Algal Extract for Antifungal Activities. AB - Over the past few years algal extracts have become increasingly interesting to the scientific community due to their promising biological properties. Phlorotannin extracts are particularly attractive partly due to their reported antifungal activity against several yeast and dermatophyte strains.The micromethod used for the evaluation of the minimum inhibitory concentration (MIC) and the minimum lethal concentration (MLC) represents an effective and solvent saving procedure to evaluate the antifungal activity of algae extracts. Here we describe the micromethod for determining the MIC and the MLC of algal extracts by using the example of a purified phlorotannin extract of brown algae. PMID- 26108522 TI - Protocol for Assessing Antifouling Activities of Macroalgal Extracts. AB - The development of novel environmentally friendly antifouling (AF) solutions is a very active field in fundamental and applied research. An attractive option in producing such material resides in biomimetic studies: living organisms have evolved well-adapted structures and materials over geological times through natural selection. In this chapter, we explain the experimental procedure to be followed for the preparation of macroalgal extracts and to assess their AF efficiency towards key species. All bioassays described here have the advantage of being fast, reliable, and standardized. PMID- 26108523 TI - Traditional Chinese medical comprehensive therapy for cancer-related fatigue. AB - Cancer-related fatigue (CRF) is a common and one of the most severe symptom in the period of onset, diagnosis, treatment and rehabilitation process of cancer. But there are no confirmed measures to relieve this problem at present. Traditional Chinese medical comprehensive therapy has its advantages in dealing with this condition. Based on the research status of CRF, the following problems have been analyzed and solved: the term of CRF has been defined and recommended, and the definition has been made clear; the disease mechanism is proposed, i.e. healthy qi has been impaired in the long-term disease duration, in the process of surgery, chemotherapy, radiotherapy and biology disturbing; it is clear that the clinical manifestations are related to six Chinese medicine patterns: decreased functioning of the Pi (Spleen) and Wei (Stomach), deficiency of the Pi with dampness retention, deficiency of the Xin (Heart) and Pi, disharmony between the Gan (Liver) and Pi, deficiency of the Pi and Shen (Kidney), and deficiency of the Fei (Lung) and Shen. Based on its severity, the mild patients are advised to have non-drug psychological intervention and sleep treatment in cooperation with appropriate exercise; diet therapy are recommended to moderate patients together with sleep treatment and acupuncture, severe patients are recommended to have herbal treatment based on pattern differentiation together with physiological sleep therapy. PMID- 26108524 TI - Effect of ear-acupoint pressing and Ear Apex (HX6,7) bloodletting on haemorheology in chloasma patients with Gan depression pattern. AB - OBJECTIVE: To explore the therapeutical effect of ear-acupoint pressing combined with Ear Apex (HX6,7) bloodletting on haemorheology in chloasma patients with Gan (Liver) depression pattern. METHODS: A total of 180 chloasma patients were randomly assigned to three groups, 60 cases in each. Patients in the earacupuncture (EA) group were treated with ear-acupoint pressing combined with Ear Apex (HX6,7) bloodletting; vitamins C and E were put into practice in the Western medicine (WM) group together with 0.025% tretinoin cream for local external application; patients in the placebo group were treated with urea-cream by external use, while 30 healthy volunteers were in the control group. After a treatment course of 2 months, the changes of haemorheology, injury skin area, colour score and symptom score before and after the treatment were observed. RESULTS: There was no significant difference on whole blood reduced viscosity (high shear, medium shear, and low shear), erythrocyte aggregation index, hematocrit, plasma viscosity among the four groups (F =2.65, P>0.05). Compared with those before treatment, the whole blood viscosity (high shear) and whole blood reduced viscosity (high shear) after treatment in the EA group, the WM group and the placebo group were with no statistical significance (P>0.05). The injury skin area and colour score after treatment were significantly lower than those before treatment in the EA group and the WM group (P<0.05), while there was no significant difference in placebo group (P>0.05). Clinical symptoms of the EA group were obviously improved after the 2-month treatment, which was significantly different compared with those before treatment (P<0.05), there was significant difference compared with those of WM group and placebo group (P<0.05). CONCLUSION: There was no significant difference on haemorheology index between healthy people and chloasma patients without angionosis, cerebrovascular disease, hematopathy, metabolic disease or any other organic disease. Ear acupoint pressing combined with Ear Apex (HX6,7) bloodletting can effectively improve concurrent symptoms, lighten chloasma and lower chloasma area in patients accompanied by Gan depression. PMID- 26108525 TI - Rule-Based Prediction Models of Cytochrome P450 Inhibition. AB - Hepatotoxicity, drug-induced liver injury, and competitive Cytochrome P-450 (CYP) isozyme binding are serious problems associated with drug use. It would be favorable to avoid or to understand potential CYP inhibition at the developmental stages. However, current in silico CYP prediction models or available public prediction servers can provide only yes/no classification results for just one or a few CYP enzymes. In this study, we utilized a rule-based C5.0 algorithm with different descriptors, including PaDEL, Mold(2), and PubChem fingerprints, to construct rule-based inhibition prediction models for five major CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4-that account for 90% of drug oxidation or hydrolysis. We also developed a rational sampling algorithm for the selection of compounds in the training data set, to enhance the performance of these CYP prediction models. The optimized models include several improved features. First, the final models significantly outperformed all of the currently available models. Second, the final models can also be used for rapid virtual screening of a large set of compounds due to their ruleset-based nature. Moreover, such rule based prediction models can provide rulesets for structural features related to the five major CYP enzymes. The five most significant rules for CYP inhibition were identified for each CYP enzymes and discussed. An example was chosen for each of the five CYP enzymes to demonstrate how rule-based models can be used to gain insights into structural features that correspond with CYP inhibitions. A newer version of the freely accessible CYP prediction server, CypRules, is presented here as a result of the aforementioned improvements. PMID- 26108526 TI - Baseline haemoglobin A1c influences retinal function after long-term insulin pump therapy. AB - PURPOSE: The purpose of the study was to characterize the long-term effect of insulin pump therapy (CSII) on electroretinography and dark adaptometry and to examine the influence of baseline glycaemic control on retinal function in patients with type 1 diabetes mellitus. METHODS: This prospective observational extension study enrolled 13 patients out of 17 who completed a primary 1-year study of the effect of CSII on retinal function. Twelve patients were still on CSII at follow-up. The extension study included a single examination 3.5 years (range 3.0-4.0 years) after initiation of CSII of one study eye per patient. Procedures included full-field electroretinography (ERG), dark adaptometry, optical coherence tomography, and fundus photography. RESULTS: Mean ERG amplitudes 3.5 years after initiation of CSII were 15-43 % lower than at baseline (all p < 0.05) and 21-45 % lower than after 1 year on CSII. The mean rate of dark adaptation had returned to baseline after a transient 13 % (p = 0.0024) acceleration at the 1-year visit. Reduction of ERG amplitudes between 1 and 3.5 years was statistically associated predominantly with baseline haemoglobin A1c (HbA1c) >= 8.7 % and, to a smaller extent, with HbA1c reductions larger than 1.9 % after initiation of CSII. No significant changes in ERG amplitudes were found in patients with baseline HbA1c < 8.7 % and HbA1c reductions smaller than 1.9 %. CONCLUSIONS: Deterioration of subclinical retinal function from 1 to 3.5 years after initiation of CSII was associated predominantly with poorer metabolic control before initiation of CSII. Analyses of retinal function may supplement structural and morphological characteristics in the study of diabetic complications. PMID- 26108527 TI - Erratum to: Determinants of patient satisfaction and function related to vision following cataract surgery in eyes with no visually consequential ocular co morbidity. PMID- 26108528 TI - Primary Nasopharyngeal Hodgkin Lymphoma. PMID- 26108529 TI - Hyperscape: visualization for complex biological networks. AB - MOTIVATION: Network biology has emerged as a powerful tool to uncover the organizational properties of living systems through the application of graph theoretic approaches. However, due to limitations in underlying data models and visualization software, knowledge relating to large molecular assemblies and biologically active fragments is poorly represented. RESULTS: Here, we demonstrate a novel hypergraph implementation that better captures hierarchical structures, using components of elastic fibers and chromatin modification as models. These reveal unprecedented views of the biology of these systems, demonstrating the unique capacity of hypergraphs to resolve overlaps and uncover new insights into the subfunctionalization of variant complexes. AVAILABILITY AND IMPLEMENTATION: Hyperscape is available as a web application at http://www.compsysbio.org/hyperscape. Source code, examples and a tutorial are freely available under a GNU license. CONTACTS: john.parkinson@utoronto.ca or graham.cromar@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26108530 TI - Determinants of timing and amplitude in the plant general stress response. AB - Plants have evolved intricate signaling cascades to rapidly and effectively respond to biotic and abiotic challenges. The precise timing of these responses enables optimal resource reallocation to maintain the balance between stress adaptation and growth. Thus, an in-depth understanding of the immediate and long term mechanisms regulating resource allocation is critical in deciphering how plants withstand environmental challenges. To date however, understanding of this tradeoff has focused on the amplitude of long-term responses, rather than the timing of rapid stress responses. This review presents current knowledge on kinetics of secondary messengers involved in regulation of rapid and general stress responses, followed by rapid stress responsive transduction machinery, and finally the transcriptional response of a functional general stress responsive cis-element. Within this context we discuss the role of timing of initial peak activation and later oscillating peak responses, and explore hormonal and stress signaling crosstalk confounding greater understanding of these cascades. PMID- 26108531 TI - Elise Dennis wins ABC Best Paper Award. PMID- 26108532 TI - Studies on the metabolism and toxicological detection of the new psychoactive designer drug 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2 methoxyphenyl)methyl]ethanamine (25I-NBOMe) in human and rat urine using GC-MS, LC-MS(n), and LC-HR-MS/MS. AB - 25I-NBOMe, a new psychoactive substance, is a potent 5-HT2A receptor agonist with strong hallucinogenic potential. Recently, it was involved in several fatal and non-fatal intoxication cases. The aim of the present work was to study its phase I and II metabolism and its detectability in urine screening approaches. After application of 25I-NBOMe to male Wistar rats, urine was collected over 24 h. The phase I and II metabolites were identified by LC-HR-MS/MS in urine after suitable workup. For the detectability studies, standard urine screening approaches (SUSA) by GC-MS, LC-MS(n), and LC-HR-MS/MS were applied to rat and also to authentic human urine samples submitted for toxicological analysis. Finally, an initial CYP activity screening was performed to identify CYP isoenzymes involved in the major metabolic steps. 25I-NBOMe was mainly metabolized by O-demethylation, O,O-bis demethylation, hydroxylation, and combinations of these reactions as well as by glucuronidation and sulfation of the main phase I metabolites. All in all, 68 metabolites could be identified. Intake of 25I-NBOMe was detectable mainly via its metabolites by both LC-MS approaches, but not by the GC-MS SUSA. Initial CYP activity screening revealed the involvement of CYP1A2 and CYP3A4 in hydroxylation and CYP2C9 and CYP2C19 in O-demethylation. The presented study demonstrated that 25I-NBOMe was extensively metabolized and could be detected only by the LC-MS screening approaches. Since CYP2C9 and CYP3A4 are involved in initial metabolic steps, drug-drug interactions might occur in certain constellations. PMID- 26108533 TI - Retraction Note to: Nicorandil accelerates recovery of neuromuscular block caused by vecuronium. AB - Retraction Note to: Can J Anesth 2001; 1: 28-33, DOI 10.1007/BF03019810. To our readers: Further to the Expression of Concern (http://www.springer.com/medicine/anesthesiology/journal/12630) posted online, it is with considerable regret that the Canadian Journal of Anesthesia hereby retracts the above-cited article by Dr. Yoshitaka Fujii as a result of: 1) overwhelming evidence of fabrication relating to the fact that the distribution of many variables reported by Dr. Fujii in this study are exceedingly unlikely; and 2) the inability of Dr. Fujii's institution to attest to the integrity of the study and/ or the data conducted under its auspices, as set out in the Joint Editors-in-Chief Request for Determination of April 9, 2012. PMID- 26108534 TI - Perspectives of anesthesia residents training in Canada on fellowship training, research, and future practice location. AB - PURPOSE: We conducted this study to determine the preferences of anesthesia residents training in Canada for fellowship training, research, and future practice location and to identify the factors that influence those preferences. METHODS: Using a cross-sectional study design, a survey was sent to all anesthesia residents enrolled at an accredited Canadian anesthesiology residency program (N = 629). Data were collected on demographics and preferences for fellowship training, research, and future practice location. A multivariable logistic regression model was used to determine significant associations. RESULTS: Two hundred forty-four residents (39%) responded to the survey. Seventy percent of residents intended to pursue fellowship training. The top three fellowships they favoured were regional anesthesia, intensive care, and cardiac anesthesia. Male sex was positively associated with the decision to pursue fellowship training, whereas having an additional graduate degree was negatively associated with this choice. Among those pursuing fellowship training, the most influential factors were personal interest, enhancing employability, and an interest in an academic career. Fifty-seven percent of residents preferred to work at an academic hospital. Thirty-four percent of residents intended to incorporate research into their future practice, and personal interest, employability, and colleagues were most influential in their decision. Research activity and publishing in residency were associated with the desire to pursue future research initiatives. CONCLUSION: The majority of anesthesia residents training in Canada choose to pursue fellowship training and work at an academic hospital. Approximately one-third of residents have an interest in incorporating research into their future careers. PMID- 26108535 TI - Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting. AB - Recycling synaptic vesicles (SVs) transit through early endosomal sorting stations, which raises a fundamental question: are SVs sorted toward endolysosomal pathways? Here, we used snapin mutants as tools to assess how endolysosomal sorting and trafficking impact presynaptic activity in wild-type and snapin(-/-) neurons. Snapin acts as a dynein adaptor that mediates the retrograde transport of late endosomes (LEs) and interacts with dysbindin, a subunit of the endosomal sorting complex BLOC-1. Expressing dynein-binding defective snapin mutants induced SV accumulation at presynaptic terminals, mimicking the snapin(-/-) phenotype. Conversely, over-expressing snapin reduced SV pool size by enhancing SV trafficking to the endolysosomal pathway. Using a SV targeted Ca(2+) sensor, we demonstrate that snapin-dysbindin interaction regulates SV positional priming through BLOC-1/AP-3-dependent sorting. Our study reveals a bipartite regulation of presynaptic activity by endolysosomal trafficking and sorting: LE transport regulates SV pool size, and BLOC-1/AP-3 dependent sorting fine-tunes the Ca(2+) sensitivity of SV release. Therefore, our study provides new mechanistic insights into the maintenance and regulation of SV pool size and synchronized SV fusion through snapin-mediated LE trafficking and endosomal sorting. PMID- 26108536 TI - Characterization of linkage disequilibrium, consistency of gametic phase and admixture in Australian and Canadian goats. AB - BACKGROUND: Basic understanding of linkage disequilibrium (LD) and population structure, as well as the consistency of gametic phase across breeds is crucial for genome-wide association studies and successful implementation of genomic selection. However, it is still limited in goats. Therefore, the objectives of this research were: (i) to estimate genome-wide levels of LD in goat breeds using data generated with the Illumina Goat SNP50 BeadChip; (ii) to study the consistency of gametic phase across breeds in order to evaluate the possible use of a multi-breed training population for genomic selection and (iii) develop insights concerning the population history of goat breeds. RESULTS: Average r(2) between adjacent SNP pairs ranged from 0.28 to 0.11 for Boer and Rangeland populations. At the average distance between adjacent SNPs in the current 50 k SNP panel (~0.06 Mb), the breeds LaMancha, Nubian, Toggenburg and Boer exceeded or approached the level of linkage disequilibrium that is useful (r(2) > 0.2) for genomic predictions. In all breeds LD decayed rapidly with increasing inter marker distance. The estimated correlations for all the breed pairs, except Canadian and Australian Boer populations, were lower than 0.70 for all marker distances greater than 0.02 Mb. These results are not high enough to encourage the pooling of breeds in a single training population for genomic selection. The admixture analysis shows that some breeds have distinct genotypes based on SNP50 genotypes, such as the Boer, Cashmere and Nubian populations. The other groups share higher genome proportions with each other, indicating higher admixture and a more diverse genetic composition. CONCLUSIONS: This work presents results of a diverse collection of breeds, which are of great interest for the implementation of genomic selection in goats. The LD results indicate that, with a large enough training population, genomic selection could potentially be implemented within breed with the current 50 k panel, but some breeds might benefit from a denser panel. For multi-breed genomic evaluation, a denser SNP panel also seems to be required. PMID- 26108537 TI - Meta-analysis should not be subject to selectivity and imbalance. PMID- 26108538 TI - Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats. AB - PURPOSE: Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs. METHODS: SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses. RESULTS: Dox significantly reduced tumor volume (+/-Drz) and increased heart weight in all genders (13-30% vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts. CONCLUSIONS: Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs. PMID- 26108539 TI - miR-7 modulates chemoresistance of small cell lung cancer by repressing MRP1/ABCC1. AB - MicroRNAs (miRNAs) represent a class of small non-coding RNAs and have been shown to play important roles in various biological processes including cell growth, differentiation and apoptosis by regulating the target genes. miR-7 has been described not only as a tumour suppressor gene but also as an oncogene in human cancers. The aim of this study was to investigate the functional roles of miR-7 in chemoresistance of SCLC and its underlying mechanism. By using a bioinformatic assay, we found that MRP1/ABCC1 was a potential target gene of miR-7. Expression of miR-7 and MRP1/ABCC1 was examined in 44 SCLC samples by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry methods. Low level expression of miR-7 was associated significantly with drug responsiveness and overall survival rate of patients with SCLC, but not with gender, age and stage. There was an inverse relationship between miR-7 and MRP1/ABCC1 expression. Downregulation of MRP1/ABCC1 level was revealed after transfection with a miR-7 mimic in H69 AR cells. Transfection of a miR-7 inhibitor into H69 cells restored MRP1/ABCC1 expression. A dual-luciferase reporter assay confirmed that miR-7 targeted predicted sites in the 3'-untranslated region (3'-UTR) of the MRP1/ABCC1 gene. Our data suggested that miR-7 mediated SCLC chemoresistance by repressing MRP1/ABCC1 and may be a prognostic predictor and potential therapeutic target in human SCLC. PMID- 26108540 TI - Methionyl-Methionine Promotes alpha-s1 Casein Synthesis in Bovine Mammary Gland Explants by Enhancing Intracellular Substrate Availability and Activating JAK2 STAT5 and mTOR-Mediated Signaling Pathways. AB - BACKGROUND: Interest is increasing in the role of peptide-bound amino acids (AAs) in milk protein synthesis because studies have found that the uptake of some essential AAs by the mammary gland cannot meet the requirements for milk protein synthesis. Although the role of dipeptides in milk protein synthesis is clearly established, little is known about the underlying mechanisms. OBJECTIVE: The objective of this study was to determine whether small peptides can be taken up intact by the peptide transporters in mammary tissue explants and the underlying mechanisms of the effects of methionyl-methionine (Met-Met) supplementation on milk protein synthesis. METHODS: Mammary tissue explants were cultured in conditional medium and then treated with different concentrations of Met-Met that replaced 0%, 5%, 10%, 15%, 20%, and 25% of free Met for another 24 h. In some experiments, explants were cultured with an optimal dose of Met-Met with or without the inhibitors of peptide transporter 2 [PepT2; diethylpyrocarbonate (DEPC), 0.1 mmol/L] and aminopeptidase N (APN; bestatin, 20 MUmol/L) for 24 h. RESULTS: The substitutions of 15% free Met with Met-Met significantly promoted alpha-s1 casein (alphas1-CN) expression in the mammary explants (P < 0.05). The inhibition of the PepT2 by DEPC or APN by bestatin significantly decreased the Met-Met-stimulated increase of alphas1-CN expression (P < 0.05). Compared with the control group (0% Met-Met), absorption of Val, Met, Leu, Phe, Lys, and His was improved, and mRNA abundance of the neutral and basic AA transporter was increased in the 15% Met-Met group (P < 0.05). In addition, the mRNA abundance of the mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase 1 gene, eukaryotic initiation factor 4E binding protein 1 gene , Janus kinase 2 (JAK2), and signal transducer and activator of transcription 5 (STAT5) was increased in the 15% Met-Met-treated group (P < 0.05). CONCLUSION: Met-Met promoted alphas1-CN synthesis in cultured bovine mammary gland explants, and this stimulation may be mediated by enhanced intracellular substrate availability and by activating JAK2 STAT5 and mTOR signaling pathways. PMID- 26108542 TI - Food Insecurity Mediates the Effect of a Poverty-Alleviation Program on Psychosocial Health among the Ultra-Poor in Bangladesh. AB - BACKGROUND: Poor psychosocial health is a major global burden. A challenge to improving psychosocial health is that its associations with risk factors are complicated, inadequately understood, and difficult to modify, and/or require action outside the health sector. OBJECTIVE: We capitalized on the quasi experimental assignment of a poverty-alleviation program for the ultra-poor in Bangladesh to investigate how this program affected 2 aspects of psychosocial health; distress, (i.e., the negative cognitive appraisal of stress) and subjective well-being (i.e., satisfaction with domains of life), and the importance of food insecurity as a mediator relative to other stressors and economic status. METHODS: The study was conducted in 3 northern districts of Bangladesh where the program operated. The ultra-poor households were selected through a multistage selection process. The economically better-off households were excluded during the process and included as study controls. The program supported women by providing income-earning opportunities, strengthening sociopolitical livelihood, and building self-awareness and self-confidence. Data were collected in 2006 from 209 women on demography, psychosocial health, and stressors (i.e., domestic violence, food insecurity, economic status, perceived economy, and emotional social constraints). Data collected in 2002 from the same individuals were used to control for the baseline differences between groups. By using path analysis we showed the direct and indirect effects of the program on distress and well-being. RESULTS: The program positively affected psychosocial health by alleviating stressors. The indirect effect of the program contributed 74% in reducing distress and 30% in improving well-being. Food insecurity was by far the most important mediator, explaining 50% of indirect effect on distress and 66% of the indirect effect on well-being. CONCLUSION: Food insecurity is modifiable and an appropriate target for poverty-alleviation and agricultural programs. These findings suggest programmatic and policy attention to the social dimensions of poor psychosocial health, particularly to food insecurity as a central cause. PMID- 26108541 TI - Diet Quality and Risk of Melanoma in an Italian Population. AB - BACKGROUND: Some results from laboratory and epidemiologic studies suggest that diet may influence the risk of melanoma, but convincing evidence for a role of single nutrients or food items is lacking. Diet quality, which considers the combined effect of multiple food items, may be superior for examining this relation. OBJECTIVE: We sought to assess whether diet quality, evaluated with the use of 4 different dietary indexes, is associated with melanoma risk. METHODS: In this population-based case-control study, we analyzed the relation between 4 diet quality indexes, the Healthy Eating Index 2010 (HEI-2010), Dietary Approaches to Stop Hypertension (DASH) index, Greek Mediterranean Index (GMI), and Italian Mediterranean Index (IMI), and melanoma risk in a northern Italian community, with the use of data from 380 cases and 719 matched controls who completed a semiquantitative food frequency questionnaire. RESULTS: In the overall sample, we found an inverse association between disease risk and the HEI-2010 and DASH index, but not the Mediterranean indexes, adjusting for potential confounders (skin phototype, body mass index, energy intake, sunburn history, skin sun reaction, and education). However, in sex stratified analyses, the association appeared only in women (P-trend: 0.10 and 0.04 for the HEI-2010 and DASH index, respectively). The inverse relations were stronger in women younger than age 50 y than in older women, for whom the GMI and IMI scores also showed an inverse association with disease risk (P-trend: 0.05 and 0.02, respectively). CONCLUSIONS: These results suggest that diet quality may play a role in cutaneous melanoma etiology among women. PMID- 26108543 TI - Saturated and Unsaturated Fatty Acids Differently Modulate Colonic Goblet Cells In Vitro and in Rat Pups. AB - BACKGROUND: High-fat diets induce intestinal barrier alterations and promote intestinal diseases. Little is known about the effects of long-chain fatty acids (LCFAs) on mucin 2 (MUC2) production by goblet cells, which are crucial for intestinal protection. OBJECTIVE: We investigated the effects of LCFAs on the differentiation of colonic goblet cells, MUC2 expression, and colonic barrier function. METHODS: Upon reaching confluence, human colonic mucus-secreting HT29 MTX cells were stimulated (21 d) with a saturated LCFA (palmitic or stearic acid), a monounsaturated LCFA (oleic acid), or a polyunsaturated LCFA (linoleic, gamma-linolenic, alpha-linolenic, or eicosapentaenoic acid). In addition, rat pups underwent oral administration of oil (palm, rapeseed, or sunflower oil) or water (10 MUL/g body weight, postnatal days 10-15). Subsequently, colon goblet cells were studied by Western blotting, reverse transcriptase-quantitative polymerase chain reaction, and immunohistochemistry and colonic transmucosal electrical resistance was measured by using Ussing chambers. RESULTS: In vitro, palmitic acid enhanced MUC2 production (140% of control) and hepatocyte nuclear factor 4alpha expression, whereas oleic, linoleic, gamma-linolenic, alpha linolenic, and eicosapentaenoic acids reduced MUC2 expression (at least -50% of control). All unsaturated LCFAs decreased the expression of human atonal homolog 1, a transcription factor controlling goblet cell differentiation (at least -31% vs. control). In vivo, rats fed palm oil had higher palmitic acid concentrations (3-fold) in their colonic contents and increased mucus granule surfaces in their goblet cells (>2-fold) than did all other groups. Palm oil also increased colonic transmucosal electrical resistance (245% of control), yet had no effect on occludin and zonula occludens-1 expression. In contrast, sunflower and rapeseed oils decreased goblet cell number when compared with control (at least -10%) and palm oil (at least -14%) groups. CONCLUSIONS: Palm oil in rat pups and palmitic acid in HT29-MTX cells increase the production of MUC2 and strengthen the intestinal barrier. In contrast, unsaturated LCFAs decrease MUC2 expression. These data should be taken into account in the context of preventive or therapeutic nutritional programs. PMID- 26108544 TI - Dietary Supplementation with Raspberry Seed Oil Modulates Liver Functions, Inflammatory State, and Lipid Metabolism in Rats. AB - BACKGROUND: Although raspberry seed oil (RO) is rich in essential fatty acids, there is a lack of experiments assessing benefits of its consumption. OBJECTIVE: We investigated the effects of dietary supplementation with RO on healthy rats and rats with low-grade systemic inflammation, liver disorders, and dyslipidemia induced by a high-fat/low-fiber (HF/LF) diet. METHODS: Thirty-two rats were allocated into 4 groups of 8 rats each and fed for 8 wk a control (C; 7% lard and 5% cellulose) or HF/LF (21% lard and 2% cellulose) diet or modifications of these diets in which 7% RO replaced all (C+RO group) or a proportion of (HF/LF+RO group) the lard. Effects of diet and RO and their interaction on bacterial activity and metabolite formations in the distal intestine, liver fat and glutathione concentration, plasma lipid profile, transaminase activities, and plasma concentrations of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) were tested. RESULTS: Dietary RO decreased plasma alanine and aspartate transaminase activities (43.4 and 157 vs. 25.6 and 115 U/L, respectively; P < 0.05 and P < 0.005) and plasma TNF-alpha and triglyceride concentrations (132 pg/mL and 2.07 mmol/L vs. 86.5 pg/mL and 0.99 mmol/L, respectively; P < 0.05). In livers of the C+RO group, the fat concentration was decreased, whereas the glutathione to glutathione disulfide ratio was increased compared with the C group (30.1% and 6.20 MUmol/g vs. 23.3% and 7.25 MUmol/g, respectively; P <= 0.05); however, those differences were not observed between the HF/LF groups (P-interaction < 0.05). In the HF/LF+RO group, the plasma CRP concentration was lower than in the HF/LF group (88.1 vs. 765 pg/mL; P <= 0.05) and similar to that in the C and C+RO groups (158 and 128 pg/mL, respectively). CONCLUSION: Dietary RO improves plasma lipid profile and liver functions and reduces low-grade systemic inflammation in rats; however, the extent of these beneficial effects is partly dependent on the diet type. PMID- 26108545 TI - Zinc Absorption Is Not Related to Dietary Phytate Intake in Infants and Young Children Based on Modeling Combined Data from Multiple Studies. AB - BACKGROUND: It is widely understood that the 2 primary factors affecting dietary zinc absorption in adults are the quantities of zinc and phytate in the diet. Although a similar association of absorption to dietary zinc and phytate is presumed to exist in children, to our knowledge, no large-scale examination of the relation of zinc absorption to dietary and growth factors has been conducted. OBJECTIVE: The goal was to apply an adult absorption model and related models to data from zinc absorption studies of infants and children in order to determine the nature of the relation of zinc absorption to dietary zinc and phytate, age, body size, and zinc homeostatic variables. METHODS: Data from 236 children between 8 and 50 mo of age were obtained from stable-isotope studies of zinc absorption. Statistical and mechanistic models were fit to the data using linear and nonlinear regression analysis. RESULTS: The effect of dietary phytate on zinc absorption when controlling for dietary zinc was very small and not statistically discernable (P = 0.29). A 500-mg/d increase in dietary phytate reduced absorbed zinc by <0.04 mg/d. Absorption was observed to vary with age, weight, and height (P < 0.0001) when controlling for dietary zinc. For example, absorption from 6 mg/d of dietary zinc increased by as much as 0.2 mg/d with a 12-mo increase in age. Absorption varied with weight and exchangeable zinc pool size (0.01 < P < 0.05) when controlling for dietary zinc and age. CONCLUSIONS: The absence of a detectable phytate effect on zinc absorption raises caution about use of dietary phytate:zinc molar ratios to predict zinc bioavailability and does not support phytate reduction as a strategy to improve zinc status of young children. The effect of age on zinc absorption and the absence of a phytate effect should facilitate estimations of dietary zinc needs in young children. PMID- 26108547 TI - Corrigendum: Diverse chemotypes disrupt ion homeostasis in the malaria parasite. PMID- 26108546 TI - Reducing the price of new hepatitis C drugs in the Tuscany region of Italy. PMID- 26108548 TI - The unexplored relationship between urinary tract infections and the autonomic nervous system. AB - Urinary tract infections (UTIs), the majority of which are caused by uropathogenic E. coli (UPEC), are extremely common infections that preferentially effect women. Additional complicating factors, such as catheterization, diabetes, and spinal cord injuries can increase the frequency and severity of UTIs. The rise of antimicrobial resistant uropathogens and the ability of this disease to chronically recur make the development of alternative preventative and therapeutic modalities a priority. The major symptoms of UTIs, urgency, frequency, and dysuria, are readouts of the autonomic nervous system (ANS) and the majority of the factors that lead to complicated UTIs have been shown to impact ANS function. This review summarizes the decades' long efforts to understand the molecular mechanisms of the interactions between UPEC and the host, with a particular focus on the recent findings revealing the molecular, bacteriological, immunological and epidemiological complexity of pathogenesis. Additionally, we describe the progress that has been made in: i) generating vaccines and anti-virulence compounds that prevent and/or treat UTI by blocking bacterial adherence to urinary tract tissue and; and ii) elucidating the mechanism by which anti-inflammatories are able to alleviate symptoms and improve disease prognosis. Finally, the potential relationships between the ANS and UTI are considered throughout. While these relationships have not been experimentally explored, the known interactions between numerous UTI characteristics (symptoms, complicating factors, and inflammation) and ANS function suggest that UTIs are directly impacting ANS stimulation and that ANS (dys)function may alter UTI prognosis. PMID- 26108549 TI - Older patients with ANCA-associated vasculitis and dialysis dependent renal failure: a retrospective study. AB - BACKGROUND: ANCA-associated vasculitis (AAV) with renal involvement is not uncommon in older individuals. Unfortunately, this can be catastrophic requiring hemodialysis (HD) and may lead to end stage renal disease (ESRD). However, more than 50 % of patients with AAV who require HD initially have renal recovery and discontinue HD. The aim of this study was to describe a retrospective cohort of older patients with AAV and severe renal involvement which required hemodialysis. METHODS: Between 1995 and 2013 a total of 30 patients with histologic evidence of pauci-immune glomerulonephritis who required HD were evaluated at a single university center. The association of demographic and clinical parameters with age was assessed. Older age of disease onset was defined as age >= 60 years. The risk of developing ESRD at 3 months was examined using univariate logistic regression analysis. RESULTS: Among 30 patients with AAV who required HD, the mean age of disease onset was 59 +/- 17 years (range 22-88 years). Twelve patients were in the older age group, and 18 were in the younger group. Three months after diagnosis, 43 % of the cohort had ESRD with a statistically similar proportion of older (n = 9, 50 %) versus younger (n = 4, 33 %) patients (p = 0.367). Most patients (93 %) received immunosuppressive therapy. There was not a statistically significant association between age and ESRD. CONCLUSIONS: These data suggest that age alone does not predict renal recovery among individuals on HD due to AAV. Renal recovery is a realistic expectation and outcome, if patients are treated, even among older patients with AAV who require HD initially. PMID- 26108550 TI - Men's Sheds function and philosophy: towards a framework for future research and men's health promotion. AB - ISSUE ADDRESSED: The Men's Shed movement supports a range of men's health promotion initiatives. This paper examines whether a Men's Shed typology could inform future research and enable more efficient and targeted health promotion activities through Men's Sheds. METHODS: The International Men's Shed Survey consisted of a cross-sectional exploration of sheds, their members, and health and social activities. Survey data about shed 'function' and 'philosophy' were analysed using descriptive and inferential statistics. RESULTS: A framework of Men's Sheds based on function and philosophy demonstrated that most sheds serve a primary utility function, a secondary social function, but most importantly a primary social opportunity philosophy. Sheds with a primary health philosophy participated in fewer health promotion activities when compared with sheds without a primary health philosophy. CONCLUSIONS: In addition to the uniform health promotion resources distributed by the Men's Shed associations, specific health promotion activities, such as prostate education, are being initiated from an individual shed level. This framework can potentially be used to enable future research and health promotion activities to be more efficiently and effectively targeted. SO WHAT? Men experience poorer health and well being outcomes than women. This framework offers a novel approach to providing targeted health promotion activities to men in an environment where it is okay to talk about men's health. PMID- 26108551 TI - Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer. AB - Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions. PMID- 26108553 TI - Prevalence, awareness, treatment and control of diabetes mellitus in rural China: results from Shandong Province. AB - AIMS: To estimate the prevalence, awareness, treatment and control of diabetes in rural areas in Shandong Province, China. METHODS: The Luxemburg-WHO-Shandong Project on Rural Health Personnel Training and Chronic Disease Control, a cross sectional study, examined 16 375 rural residents aged 25 years and over using multistage cluster sampling in April 2007. An overnight fasting blood specimen was collected to measure plasma glucose and a 2-h 75-g oral glucose tolerance test was conducted among people with a fasting blood glucose of >= 6.1 mmol/l. Information on the history of diabetes and hypoglycaemic medication was obtained using a standard questionnaire. Diabetes and prediabetes were defined according to the 1999 World Health Organization diagnostic criteria. RESULTS: Overall, the prevalence rates for diabetes, prediabetes and previously diagnosed diabetes in the rural population were estimated to be 3.5%, 6.0% and 1.2%, respectively. Among those with diabetes, only 34.8% were aware of their condition, 30.6% were currently undergoing medication treatment, and 11.5% achieved glycaemic control. CONCLUSIONS: These results indicate that diabetes has become a public health problem in poor rural areas of China and the rates of awareness, treatment and control of diabetes were relatively low. There is an urgent need for strategies aimed at the prevention and treatment of diabetes in the rural population in Shandong Province, China. PMID- 26108552 TI - The great fluid debate: saline or so-called "balanced" salt solutions? AB - BACKGROUND: Intravenous fluids are commonly prescribed in childhood. 0.9 % saline is the most-used fluid in pediatrics as resuscitation or maintenance solution. Experimental studies and observations in adults suggest that 0.9 % saline is a poor candidate for fluid resuscitation. Although anesthesiologists, intensive care specialists, perioperative physicians and nephrologists have been the most active in this debate, this issue deserves some physiopathological considerations also among pediatricians. RESULTS: As compared with so-called "balanced" salt crystalloids such as lactated Ringer, administration of large volumes of 0.9 % saline has been associated with following deleterious effects: tendency to hyperchloremic metabolic acidosis (called dilution acidosis); acute kidney injury with reduced urine output and salt retention; damaged vascular permeability and stiffness, increase in proinflammatory mediators; detrimental effect on coagulation with tendency to blood loss; detrimental gastrointestinal perfusion and function; possible uneasiness at the bedside resulting in unnecessary administration of more fluids. Nevertheless, there is no firm evidence that these adverse effects are clinically relevant. CONCLUSIONS: Intravenous fluid therapy is a medicine like insulin, chemotherapy or antibiotics. Prescribing fluids should fit the child's history and condition, consider the right dose at the right rate as well as the electrolyte levels and other laboratory variables. It is unlikely that a single type of fluid will be suitable for all pediatric patients. "Balanced" salt crystalloids, although more expensive, should be preferred for volume resuscitation, maintenance and perioperatively. Lactated Ringer appears unsuitable for patients at risk for brain edema and for those with overt or latent chloride-deficiency. Finally, in pediatrics there is a need for new fluids to be developed on the basis of a better understanding of the physiology and to be tested in well-designed trials. PMID- 26108555 TI - Typical and atypical lymphatic flows in breast carcinoma. AB - AIM: The study of sentinel lymph node has greatly increased the knowledge about lymphatic drainage in breast cancer. MATERIAL OF STUDY: The experience of 181 patients operated for breast carcinoma in the last two years, of which 70 undergoing SLN biopsy, allowed us to highlight some peculiarities of lymphatic drainage of the breast and led us to physiological and pathological considerations about lymphatic flow in patients for breast carcinoma. We studied patients undergoing lymphoscintigraphic mapping with SLN biopsy who were candidates for breast cancer surgery. RESULTS: Searching for SLN's location, we found that in 88.6% cases the SLN was at level I, in 8.6% it was at level II, in no case it was at level III and in 2.8% we found lymphatic drainage to the contralateral axilla. DISCUSSION: Thanks to this dynamic study we were able to highlight a preferential subcutaneous lymphatic path from the breast parenchyma reaching the contralateral axilla, crossing anteriorly the thorax. Literature review showed CAM incidence ranges from 3.6% to 6% and can be caused by occult primary cancer of the contralateral breast, contralateral spread of breast cancer and presence of another kind of tumor. CONCLUSIONS: The presence of contralateral axillary metastasis, although known, allowed us to scintigrafically document (for the first time) the pathway of an alternative lymph flow and to suppose the possible causes. Thanks to this observation, considerations can be drawn about clinical, pathophysiological and oncological implications, with an impact on post operative follow-up. PMID- 26108554 TI - Label-free NIR-SERS discrimination and detection of foodborne bacteria by in situ synthesis of Ag colloids. AB - BACKGROUND: Rapid detection and discrimination of bacteria for biomedical and food safety applications remain a considerable challenge. We report a label-free near infrared surface-enhanced Raman scattering (NIR-SERS) method for the discrimination of pathogenic bacteria from drinking water. The approach relies on the in situ synthesis of silver nanoparticles (Ag NPs) within the bacterial cell suspensions. RESULTS: Pre-treatment of cells with Triton X-100 significantly improved the sensitivity of the assay. Using this method, we were able to discriminate several common pathogenic bacteria such as Escherichia coli, Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus (MRSA) and Listeria spp. A comparison of the SERS spectra allowed for the discrimination of two Listeria species, namely L. monocytogenes and L. innocua. We further report the application of the method to discriminate two MRSA strains from clinical isolates. The complete assay was completed in a span of 5 min. CONCLUSIONS: The proposed analytical method proves to be a rapid tool for selective and label-free identification of pathogenic bacterium. Pre-treatment of bacterial cells with Triton X-100 resulted in new features on the SERS spectra, allowing for a successful discrimination of common disease related bacteria including E. coli, P. aeruginosa, Listeria and MRSA. We also demonstrate that the spectral features obtained using in situ synthesis of nanoparticles could be could be used to differentiate two species of listeria. By using L. innocua as a model sample, we found the limit of detection of our assay to be 10(3) CFU/mL. The method can selectively discriminate different bacterial species, and has a potential to be used in the development of point-of-care diagnostics with biomedical and food safety applications. PMID- 26108556 TI - Genomics as the key to unlocking the polyploid potential of wheat. AB - Polyploidy has played a central role in plant genome evolution and in the formation of new species such as tetraploid pasta wheat and hexaploid bread wheat. Until recently, the high sequence conservation between homoeologous genes, together with the large genome size of polyploid wheat, had hindered genomic analyses in this important crop species. In the past 5 yr, however, the advent of next-generation sequencing has radically changed the wheat genomics landscape. Here, we review a series of advances in genomic resources and tools for functional genomics that are shifting the paradigm of what is possible in wheat molecular genetics and breeding. We discuss how understanding the relationship between homoeologues can inform approaches to modulate the response of quantitative traits in polyploid wheat; we also argue that functional redundancy has 'locked up' a wide range of phenotypic variation in wheat. We explore how genomics provides key tools to inform targeted manipulation of multiple homoeologues, thereby allowing researchers and plant breeders to unlock the full polyploid potential of wheat. PMID- 26108557 TI - Understanding central carbon metabolism of rapidly proliferating mammalian cells based on analysis of key enzymatic activities in GS-CHO cell lines. AB - The central carbon metabolism (glycolysis, the pentose phosphate pathway [PPP], and the tricarboxylic acid [TCA] cycle) plays an essential role in the supply of biosynthetic precursors and energy. How the central carbon metabolism changes with the varying growth rates in the in vitro cultivation of rapidly proliferating mammalian cells, such as cancer cells and continuous cell lines for recombinant protein production, remains elusive. Based on relationships between the growth rate and the activity of seven key enzymes from six cell clones, this work reports finding an important metabolic characteristic in rapidly proliferating glutamine synthetase-Chinese hamster ovary cells. The key enzymatic activity involved in the TCA cycle that is responsible for the supply of energy became elevated as the growth rate exhibited increases, while the activity of key enzymes in metabolic pathways (glycolysis and the PPP), responsible for the supply of biosynthetic precursors, tended to decrease-suggesting that rapidly proliferating cells still depended predominantly on the TCA cycle rather than on aerobic glycolysis for their energetic demands. Meanwhile, the growth-limiting resource was most likely biosynthetic substrates rather than energy provision. In addition, the multifaceted role of glucose-6-phosphate isomerase (PGI) was confirmed, based on a significant correlation between PGI activity and the percentage of G2/M-phase cells. PMID- 26108558 TI - The Antia-Buch flap revisited. PMID- 26108559 TI - Reactivity change of IgE to buckwheat protein treated with high-pressure and enzymatic hydrolysis. AB - BACKGROUND: Buckwheat is a popular food material in eastern Asian countries that can cause allergenic response. This study was conducted to evaluate the effects of hydrolysis with papain and high-pressure (HP) treatment of buckwheat protein (BWP) on reactivity of immunoglobulin E (IgE) and its secondary structure. RESULTS: Reactivity of IgE was examined by enzyme-linked immunosorbent assay (ELISA) with serum samples from 16 patients allergic to buckwheat. Reactivity of IgE to hydrolysate of BWP with papain showed a maximum decrease of 79.8%. After HP treatment at 600 MPa for 1 min, reactivity of IgE to BWP decreased by up to 55.1%. When extracted, BWP was hydrolyzed with papain overnight following HP treatment at 600 MPa which the reactivity of IgE decreased significantly by up to 87.1%. Significant changes in secondary structure of BWP were observed by circular dichroism (CD) analysis after hydrolysis with papain following HP treatment. CONCLUSION: Reduction of reactivity of IgE showed a correlation with changes in secondary structure of BWP, which may cause changes in conformational epitopes. This suggests the possibility of decreasing the reactivity of IgE to BWP using combined physical and enzymatic treatments. PMID- 26108560 TI - Long-term functional airway assessment after open airway surgery for laryngotracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to evaluate our patient reported and objective long-term outcomes of patients treated for laryngotracheal stenosis. STUDY DESIGN: Prospective cohort study. METHODS: Sixty-five patients were evaluated after a median follow-up of 7 years after surgery. Follow-up measurements consisted of pulmonary function testing, Bruce treadmill test, and Child Health Questionnaires (CHQ). RESULTS: Pulmonary function tests were available in 43 patients, and 30/43 had abnormal forced expiratory volume in 1 second/forced inspiratory volume in 1 second (FIV1), 25/43 had abnormal FIV1/maximum vital capacity, and 24/43 had abnormal peak expiratory flow. One third of patients had reduced exercise tolerance. CHQ revealed significant positive correlations with pulmonary function results and exercise tolerance. Multivariate analysis showed that glottic involvement of the stenosis and the presence of comorbidities at time of surgery are the only factors for poor long term functional outcome. CONCLUSIONS: The majority of patients show deficits in pulmonary function and exercise tolerance related to lower scores of quality of life. Glottic involvement of the stenosis and the presence of comorbidities are the only significant factors for poor functional outcome. Long-term multidisciplinary follow up is mandatory after surgery for laryngotracheal stenosis. LEVEL OF EVIDENCE: 2B. PMID- 26108561 TI - Benefits of an exercise wellness program after spinal cord injury. AB - OBJECTIVE: To describe the initial benefits of a structured group exercise program on exercise frequency and intensity, perceived health, pain, mood, and television watching habits. DESIGN: Pre-test/post-test. PARTICIPANTS/METHODS: Eighty-nine persons with SCI participated voluntarily in a no-cost, twice weekly physical therapy group exercise class over 3 months. Forty-five persons completed pre- and post-participation interviews on exercise frequency and intensity, perceived health, pain, mood, sleep, and television watching habits. RESULTS: Mean participant age of the respondents was 43.82 years. 49% had AIS C or D injuries, 24% had AIS A,B paraplegia, 9% had AIS A,B C1-C4 and 18% had AIS A,B C5 C8. 75.6% of participants were male and 84.4% had a traumatic etiology as the cause of their SCI. There was a significant improvement in days of strenuous and moderate exercise as well as health state. There was an average decrease in pain scores, depression scores, number of hours spent watching television, and days/week of mild exercise. CONCLUSION: Participation in structured, small group exercise as a component of a wellness program after SCI shows promise for improving regular exercise participation and health state, but benefits may also occur across other areas of health and function including mood, pain, and hours spent watching television. Further follow-up is needed to determine whether improvements can be maintained after program completion and across all neurological levels. PMID- 26108562 TI - The role of nitric oxide in passive leg movement-induced vasodilatation with age: insight from alterations in femoral perfusion pressure. AB - The passive leg movement (PLM) model is a novel approach to assess vascular function. Increasing femoral perfusion pressure (FPP) by moving from the supine to the upright-seated posture augments the vasodilatory response to PLM in the young, with no effect in the old, but whether this augmented vasodilatation is nitric oxide (NO) dependent is unknown. Using an intra-arterial infusion of N(G) monomethyl-L -arginine (L -NMMA) to inhibit nitric oxide synthase (NOS), the posture-induced increases in the PLM responses in the young were nearly ablated, with no effect of NOS inhibition in the old. Therefore, PLM in combination with alterations in posture can be used to determine changes in NO-mediated vasodilatation with age, and thus, may be a clinically useful tool for assessing NO bioavailability across the human lifespan. We sought to better understand the contribution of nitric oxide (NO) to passive leg movement (PLM)-induced vasodilatation with age, with and without a posture-induced increase in femoral perfusion pressure (FPP). PLM was performed in eight young (24 +/- 1 years) and eight old (74 +/- 3 years) healthy males, with and without NO synthase inhibition via intra-arterial infusion of N(G) -monomethyl-L -arginine (L -NMMA) into the common femoral artery in both the supine and upright-seated posture. Central and peripheral haemodynamic responses were determined second-by-second with finger photoplethysmography and Doppler ultrasound, respectively. PLM-induced increases in heart rate, stroke volume, cardiac output and reductions in mean arterial pressure were similar between age groups and conditions. In the young, L -NMMA attenuated the peak change in leg vascular conductance (DeltaLVCpeak ) in both the supine (control: 7.4 +/- 0.9; L -NMMA: 5.2 +/- 1.1 ml min(-1) mmHg(-1) , P < 0.05) and upright-seated (control: 12.3 +/- 2.0; L -NMMA: 6.4 +/- 1.0 ml min(-1) mmHg(-1) , P < 0.05) posture, with no significant change in the old (supine control: 4.2 +/- 1.3; supine L -NMMA: 3.4 +/- 0.8; upright-seated control: 4.5 +/ 0.8; upright-seated L -NMMA: 3.4 +/- 0.8 ml min(-1) mmHg(-1) , P > 0.05). Increased FPP augmented the DeltaLVCpeak in the young control condition only (P < 0.05). In the upright-seated posture, NOS inhibition attenuated the FPP-induced augmentation of rapid vasodilatation in the young (control: 1.25 +/- 0.23; L NMMA: 0.74 +/- 0.11 ml min(-1) mmHg(-1) s(-1) ; P < 0.05), but not the old (control: 0.37 +/- 0.07; L -NMMA: 0.25 +/- 0.07 ml ml min(-1) mmHg(-1) s(-1) ; P > 0.05). These data reveal that greater FPP increases the role of NO in PLM induced vasodilatation in the young, but not the old, due to reduced NO bioavailability with age. Therefore, PLM involving alterations in posture may be useful to determine changes in NO bioavailability with age. PMID- 26108564 TI - A comparison of iopromide and iopamidol, two acidoCEST MRI contrast media that measure tumor extracellular pH. AB - Acidosis within tumor and kidney tissues has previously been quantitatively measured using a molecular imaging technique known as acidoCEST MRI. The previous studies used iopromide and iopamidol, two iodinated contrast agents that are approved for clinical CT diagnoses and have been repurposed for acidoCEST MRI studies. We aimed to compare the performance of the two agents for measuring pH by optimizing image acquisition conditions, correlating pH with a ratio of CEST effects from an agent, and evaluating the effects of concentration, endogenous T1 relaxation time and temperature on the pH-CEST ratio correlation for each agent. These results showed that the two agents had similar performance characteristics, although iopromide produced a pH measurement with a higher dynamic range while iopamidol produced a more precise pH measurement. We then compared the performance of the two agents to measure in vivo extracellular pH (pHe) within xenograft tumor models of Raji lymphoma and MCF-7 breast cancer. Our results showed that the pHe values measured with each agent were not significantly different. Also, iopromide consistently measured a greater region of the tumor relative to iopamidol in both tumor models. Therefore, an iodinated contrast agent for acidoCEST MRI should be selected based on the measurement properties needed for a specific biomedical study and the pharmacokinetic properties of a specific tumor model. PMID- 26108565 TI - Initial recommendations for higher-tier risk assessment protocols for bumble bees, Bombus spp. (Hymenoptera: Apidae). AB - Global declines of bumble bees and other pollinator populations are of concern because of their critical role for crop production and maintenance of wild plant biodiversity. Although the consensus among scientists is that the interaction of many factors, including habitat loss, forage scarcity, diseases, parasites, and pesticides, potentially plays a role in causing these declines, pesticides have received considerable attention and scrutiny. In response, regulatory agencies have introduced more stringent pollinator testing requirements for registration and reregistration of pesticides, to ensure that the risks to pollinators are minimized. In this context, guidelines for testing bumble bees (Bombus spp.) in regulatory studies are not yet available, and a pressing need exists to develop suitable protocols for routine higher-tier studies with these non-Apis sp., social bees. To meet this need, Bayer CropScience LP, Syngenta Crop Protection LLC US, and Valent USA. Corporation organized a workshop bringing together a group of global experts on bumble bee behavior, ecology, and ecotoxicology to discuss and develop draft protocols for both semi-field (Tier II) and field (Tier III) studies. The workshop was held May 8-9, 2014, at the Bayer Bee Care Center, North Carolina, USA. The participants represented academic, consulting, and industry scientists from Europe, Canada, the United States, and Brazil. The workshop identified a clear protection goal and generated proposals for basic experimental designs, relevant measurements, and endpoints for both semifield (tunnel) and field tests. These initial recommendations are intended to form the basis of discussions to help advance the development of appropriate protocol guidelines. PMID- 26108563 TI - Pancreatic alpha-cells from female mice undergo morphofunctional changes during compensatory adaptations of the endocrine pancreas to diet-induced obesity. AB - Obesity is frequently associated with insulin resistance. To compensate for this situation and maintain normoglycaemia, pancreatic beta-cells undergo several morphofunctional adaptations, which result in insulin hypersecretion and hyperinsulinaemia. However, no information exists about pancreatic alpha-cells during this compensatory stage of obesity. Here, we studied alpha-cells in mice fed a high-fat diet (HFD) for 12 weeks. These animals exhibited hyperinsulinaemia and normoglycaemia compared with control animals in addition to hypoglucagonaemia. While the in vivo response of glucagon to hypoglycaemia was preserved in the obese mice, the suppression of glucagon secretion during hyperglycaemia was impaired. Additionally, in vitro glucagon release at low glucose levels and glucagon content in isolated islets were decreased, while alpha-cell exocytosis remained unchanged. Assessment of morphological parameters revealed that alpha-cell area was reduced in the pancreas of the obese mice in association with alpha-cell hypotrophy, increased apoptosis and decreased proliferation. HFD feeding for 24 weeks led to significant deterioration in beta cell function and glucose homeostasis. Under these conditions, the majority of alpha-cell changes were reversed and became comparable to controls. These findings indicate that pancreatic compensatory adaptations during obesity may also involve pancreatic alpha-cells. Additionally, defects in alpha-cell function during obesity may be implicated in progression to diabetes. PMID- 26108566 TI - Scattering of Sculpted Light in Intact Brain Tissue, with implications for Optogenetics. AB - Optogenetics uses light to control and observe the activity of neurons, often using a focused laser beam. As brain tissue is a scattering medium, beams are distorted and spread with propagation through neural tissue, and the beam's degradation has important implications in optogenetic experiments. To address this, we present an analysis of scattering and loss of intensity of focused laser beams at different depths within the brains of zebrafish larvae. Our experimental set-up uses a 488 nm laser and a spatial light modulator to focus a diffraction limited spot of light within the brain. We use a combination of experimental measurements of back-scattered light in live larvae and computational modelling of the scattering to determine the spatial distribution of light. Modelling is performed using the Monte Carlo method, supported by generalised Lorenz-Mie theory in the single-scattering approximation. Scattering in areas rich in cell bodies is compared to that of regions of neuropil to identify the distinct and dramatic contributions that cell nuclei make to scattering. We demonstrate the feasibility of illuminating individual neurons, even in nucleus-rich areas, at depths beyond 100 MUm using a spatial light modulator in combination with a standard laser and microscope optics. PMID- 26108568 TI - Dispelling cliches at the nanoscale: the true effect of polymer electrolytes on the performance of dye-sensitized solar cells. AB - In the field of dye-sensitized solar cells, polymer electrolytes are among the most studied materials due to their ability to ensure both high efficiency and stability, the latter being a critical point of these devices. Hundreds of polymeric matrices have been proposed over the years, and their functionalization with several groups, the variation of their molecular weight and the tuning of the crosslinking degree have been investigated. However, the true effect that polymeric matrices have on the cell parameters has often been addressed superficially, and hundreds of papers justify the obtained results with a simple bibliographic reference to other systems (sometimes completely different). This work proposes a system of nanoscale growth and crosslinking of a polymer electrolyte inside a nanostructured photoanode. Electrochemical and photovoltaic parameters are carefully monitored as a function of thickness and degree of penetration of the electrolyte. The results derived from this study refute many cliches generally accepted and taken for granted in many literature articles, and - for the first time - a compromise between the amount of polymer, cell efficiency and stability is achieved. PMID- 26108567 TI - Phosphorylation of Beet black scorch virus coat protein by PKA is required for assembly and stability of virus particles. AB - Plant virus coat proteins (CPs) play a fundamental role in protection of genomic RNAs, virion assembly, and viral movement. Although phosphorylation of several CPs during virus infection have been reported, little information is available about CP phosphorylation of the spherical RNA plant viruses. Here, we demonstrate that the CP of Beet black scorch virus (BBSV), a member of the genus Necrovirus, can be phosphorylated at threonine-41 (T41) by cAMP-dependent protein kinase (PKA)-like kinase in vivo and in vitro. Mutant viruses containing a T41A non phosphorylatable alanine substitution, and a T41E glutamic acid substitution to mimic threonine phosphorylation were able to replicate but were unable to move systemically in Nicotiana benthamiana. Interestingly, the T41A and T41E mutants generated unstable 17 nm virus-like particles that failed to package viral genomic (g) RNA, compared with wild-type BBSV with 30 nm virions during viral infection in N. benthamiana. Further analyses showed that the T41 mutations had little effect on the gRNA-binding activity of the CP. Therefore, we propose a model whereby CP phosphorylation plays an essential role in long-distance movement of BBSV that involves formation of stable virions. PMID- 26108569 TI - Correlating 3D morphology with molecular pathology: fibrotic remodelling in human lung biopsies. AB - Assessing alterations of the parenchymal architecture is essential in understanding fibrosing interstitial lung diseases. Here, we present a novel method to visualise fibrotic remodelling in human lungs and correlate morphological three-dimensional (3D) data with gene and protein expression in the very same sample. The key to our approach is a novel embedding resin that clears samples to full optical transparency and simultaneously allows 3D laser tomography and preparation of sections for histology, immunohistochemistry and RNA isolation. Correlating 3D laser tomography with molecular diagnostic techniques enables new insights into lung diseases. This approach has great potential to become an essential tool in pulmonary research. PMID- 26108570 TI - Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia. AB - BACKGROUND: Asthma exacerbations represent a significant disease burden and are commonly caused by rhinovirus (RV), which is sensed by Toll-like receptors (TLR) such as TLR7. Some asthmatics have impaired interferon (IFN) responses to RV, but the underlying mechanisms of this clinically relevant observation are poorly understood. OBJECTIVES: To investigate the importance of intact TLR7 signalling in vivo during RV exacerbation using mouse models of house dust mite (HDM) induced allergic airways disease exacerbated by a superimposed RV infection. METHODS: Wild-type and TLR7-deficient (Tlr7(-/-)) BALB/c mice were intranasally sensitised and challenged with HDM prior to infection with RV1B. In some experiments, mice were administered recombinant IFN or adoptively transferred with plasmacytoid dendritic cells (pDC). RESULTS: Allergic Tlr7(-/-) mice displayed impaired IFN release upon RV1B infection, increased virus replication and exaggerated eosinophilic inflammation and airways hyper reactivity. Treatment with exogenous IFN or adoptive transfer of TLR7-competent pDCs blocked these exaggerated inflammatory responses and boosted IFNgamma release in the absence of host TLR7 signalling. TLR7 expression in the lungs was suppressed by allergic inflammation and by interleukin (IL)-5-induced eosinophilia in the absence of allergy. Subjects with moderate-to-severe asthma and eosinophilic but not neutrophilic airways inflammation, despite inhaled steroids, showed reduced TLR7 and IFNlambda2/3 expression in endobronchial biopsies. Furthermore, TLR7 expression inversely correlated with percentage of sputum eosinophils. CONCLUSIONS: This implicates IL-5-induced airways eosinophilia as a negative regulator of TLR7 expression and antiviral responses, which provides a molecular mechanism underpinning the effect of eosinophil-targeting treatments for the prevention of asthma exacerbations. PMID- 26108571 TI - Clinical application of autologous technetium-99m-labelled eosinophils to detect focal eosinophilic inflammation in the lung. AB - The detection of focal eosinophilic inflammation by non-invasive means may aid the diagnosis and follow-up of a variety of pulmonary pathologies. All current methods of detection involve invasive sampling, which may be contraindicated or too high-risk to be performed safely. The use of injected autologous technetium 99m (Tc-99m)-labelled eosinophils coupled to single-photon emission computed tomography (SPECT) has been demonstrated to localise eosinophilic inflammation in the lungs of a patient with antineutrophil cytoplasmic antibody-positive vasculitis. Here, we report on the utility of this technique to detect active eosinophilic inflammation in a patient with focal lung inflammation where a biopsy was contraindicated. PMID- 26108572 TI - Response to: 'CT assessment for pulmonary hypertension requires systematic assessment of cardiac, vascular and parenchymal signs' by Marloes et al. PMID- 26108573 TI - Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. AB - INTRODUCTION: Cytoplasmic TDP-43 inclusions are the pathological hallmark of amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal lobar dementia (FTLD). The G4C2 repeat mutation in C9ORF72 is the most common cause of ALS and FTLD in which, in addition to TDP-43 inclusions, five different di peptide repeat (DPR) proteins have been identified. Di-peptide repeat proteins are translated in a non-canonical fashion from sense and antisense transcripts of the G4C2 repeat (GP, GA, GR, PA, PR). DPR inclusions are abundant in the cerebellum, as well as in the frontal and temporal lobes of ALS and FTLD patients and some are neurotoxic in a range of cellular and animal models, implying that DPR aggregation directly contributes to disease pathogenesis. Here we sought to quantify inclusions for each DPR and TDP-43 in ALS cases with and without the C9ORF72 mutation. We characterised the abundance of DPRs and their cellular location and compared this to cytoplasmic TDP-43 inclusions in order to explore the role of each inclusion in lower motor neuron degeneration. RESULTS: Spinal cord sections from ten cases positive for the C9ORF72 repeat expansion (ALS C9+ve) and five cases that were not were probed by double immunofluorescence staining for individual DPRs and TDP-43. Inclusions immunoreactive for each of the DPRs were present in the spinal cord but they were rare or very rare in abundance (in descending order of frequency: GA, GP, GR, PA and PR). TDP-43 cytoplasmic inclusions were 45- to 750-fold more frequent than any DPR, and fewer than 4 % of DPR inclusions colocalized with TDP-43 inclusions. In motor neurons, a single cytoplasmic DPR inclusion was detected (0.1 %) in contrast to the 34 % of motor neurons that contained cytoplasmic TDP-43 inclusions. Furthermore, the number of TDP-43 inclusions in ALS cases with and without the C9ORF72 mutation was nearly identical. CONCLUSIONS: For all other neurodegenerative diseases, the neurotoxic protein aggregates are detected in the affected population of neurons. TDP-43 cytoplasmic aggregation is the dominant feature of ALS spinal cord pathology irrespective of C9ORF72 mutation status. The near absence of DPR inclusions in spinal cord motor neurons challenges their contribution to lower motor neuron degeneration in ALS-C9+ve cases. PMID- 26108574 TI - The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development. AB - A 2-compartment in vitro eye flow model has been developed to estimate ocular drug clearance by the anterior aqueous outflow pathway. The model is designed to accelerate the development of longer-acting ophthalmic therapeutics. Dye studies show aqueous flow is necessary for a molecule injected into the vitreous cavity to clear from the model. The clearance times of proteins can be estimated by collecting the aqueous outflow, which was first conducted with bevacizumab using phosphate-buffered saline in the vitreous cavity. A simulated vitreous solution was then used and ranibizumab (0.5 mg) displayed a clearance time of 8.1 +/- 3.1 days, which is comparable to that observed in humans. The model can estimate drug release from implants or the dissolution of suspensions as a first step in their clearance mechanism, which will be the rate-limiting step for the overall resident time of a candidate dosage form in the vitreous. A suspension of triamcinolone acetonide (Kenalog(r)) (4.0 mg) displayed clearance times spanning 26-28 days. These results indicate that the model can be used to determine in vitro-in vivo correlations in preclinical studies to develop long-lasting therapeutics to treat blinding diseases at the back of the eye. PMID- 26108575 TI - Viewpoint: It is time to reconsider policy for population-based mammography screening. AB - Breast cancer in women is an important cause of morbidity and mortality. Many countries in the Western world have widely promoted early detection through mammography screening and established population-based screening programs. Over the past 15 years, there has been growing debate about the benefits and harms of universal mammography screening. This article presents findings from the latest systematic review conducted by the Cochrane Collaboration and from the Canadian National Breast Screening Study 25-year follow up. The authors of both reports conclude there is no reliable evidence that population-based mammography screening reduces mortality, but there is good evidence of harm in the form of false positive findings, over-diagnosis and unnecessary treatment, and associated psychological distress. It is time for policymakers to discontinue universal population-based mammography screening and shift to a more selective approach to early detection. PMID- 26108576 TI - A new resource for identifying and assessing the impacts of research. AB - The impact case studies submitted by UK Higher Education Institutions to the Research Excellence Framework (REF) in 2014 provide a rich resource of text describing impact beyond academia and across all disciplines. Using text mining techniques and qualitative assessment, the 6,679 non-redacted case studies submitted were analysed and the impact described was found to be multidisciplinary, multi-impactful, and multinational. By digging deeper into the data, the health gains from health research in terms of Quality Adjusted Life Years was also estimated. Similar analyses are possible using these case studies, but will require the data to be 're-purposed' from the original intention (i.e., for assessment purposes) for robust analysis. PMID- 26108577 TI - Next-generation biofuels: a new challenge for yeast. AB - Economic growth depends strongly on the availability and price of fuels. There are various reasons in different parts of the world for efforts to decrease the consumption of fossil fuels, but biofuels are one of the main solutions considered towards achieving this aim globally. As the major bioethanol producer, the yeast Saccharomyces cerevisiae has a central position among biofuel-producing organisms. However, unprecedented challenges for yeast biotechnology lie ahead, as future biofuels will have to be produced on a large scale from sustainable feedstocks that do not interfere with food production, and which are generally not the traditional carbon source for S. cerevisiae. Additionally, the current trend in the development of biofuels is to synthesize molecules that can be used as drop-in fuels for existing engines. Their properties should therefore be more similar to those of oil-derived fuels than those of ethanol. Recent developments and challenges lying ahead for cost-effective production of such designed biofuels, using S. cerevisiae-based cell factories, are presented in this review. PMID- 26108579 TI - Ab initio modelling of the anomeric and exo anomeric effects in 2 methoxytetrahydropyran and 2-methoxythiane corrected for intramolecular BSSE. AB - Accurate ab initio calculations including basis set limit (BSL) extrapolations, removal of intramolecular basis set superposition error (BSSE), solvent effect corrections, and thermal effects have been carried out to compare the structure and the anomeric and exo-anomeric effect in 2-methoxytetrahydropyran and 2 methoxythiane. The effect of intramolecular BSSE on the energetics was outlined for the first time in these types of compounds. It was found that both title compounds show comparable behaviour with respect to BSSE. The energy gap between the axial and equatorial form of 2-methoxythiane is reduced by 0.23 kcal mol(-1) due to the BSSE correction at the MP2/aug-cc-pVTZ level of theory, and in 2 methoxytetrahydropyran it is reduced by 0.21 kcal mol(-1). The intramolecular BSSE influenced also the energy differences between the gauche and trans conformers in both compounds. Energy decomposition analysis (EDA) reveals that the dominant destabilising interaction is repulsion and its primary stabilizing counterpart is the polarization interaction. PMID- 26108580 TI - Viral hepatitis in Saudi Arabia. An unfinished story. PMID- 26108578 TI - Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. AB - Mechanical stress and aging are major risk factors of cartilage degeneration. Human studies have previously reported that oxidative damage increased, while SOD2 protein was reciprocally downregulated in osteoarthritic degenerated cartilage. However, it remains unclear whether mitochondrial superoxide imbalance in chondrocytes causes cartilage degeneration. We herein demonstrate that mechanical loading promoted mitochondrial superoxide generation and selective Sod2 downregulation in chondrocytes in vivo and that mitochondrial superoxide inducer also downregulated Sod2 expression in chondrocytes in vitro. A genetically manipulated model revealed that Sod2 deficiency in chondrocytes also resulted in mitochondrial superoxide overproduction and dysfunction, thus leading to cartilage degeneration. Intra-articular injection of a permeable antioxidant effectively suppressed the mechanical loading-induced mitochondrial superoxide generation and cartilage degeneration in mice. Our findings demonstrate that mitochondrial superoxide plays a pivotal role in the development and progression of osteoarthritis, and the mitochondrial superoxide balance may therefore be a promising target for the treatment of cartilage degeneration. PMID- 26108581 TI - The role of microRNAs in regulating myocardial ischemia reperfusion injury. AB - Myocardial ischemia and reperfusion (I/R) injury is a pathological condition characterized by an initial restriction of blood supply to the heart followed by the subsequent restoration of perfusion and concomitant re-oxygenation. This condition may cause heart injury and contribute to morbidity and mortality. Although tremendous advances have been made in understanding the mechanisms of myocardial I/R injury, the translation of these findings into the clinical setting has been largely disappointing. MicroRNAs (miRNAs) are endogenous, single stranded, non-coding RNAs ranging from 18-24 nucleotides in length. They are highly conserved and ubiquitously expressed in all species, which control diverse cellular functions by either promoting degradation or inhibiting target mRNA translation. In particular, a multitude of studies demonstrated miRNAs played an important role in acute and chronic cardiovascular disease processes. In this review, we focus on miRNAs and summarize the latest insights on the role of the specific miRNAs in myocardial I/R injury. PMID- 26108582 TI - Corticotomy-assisted orthodontic treatment. A systematic review of the biological basis and clinical effectiveness. AB - OBJECTIVES: To systematically review the literature to assess the quality of evidence related to corticotomy-assisted orthodontic treatment (CAOT) as adjunctive treatment in orthodontics. METHODS: The study was conducted in the Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia between 2013 and 2014. Various electronic databases were searched and abstracts were retrieved. Defined inclusion criteria were then applied to the obtained original articles for further evaluation by 2 examiners independently. The criteria of selection included human, or animal studies, which assessed some aspects of CAOT and/or the biological principles behind it. Case reports and series were excluded. The quality of the studies was evaluated by the methodological score for clinical trials developed. RESULTS: Fourteen articles were retrieved initially, but only 12 articles were finally selected for the study. The CAOT was found to accelerate tooth movement by 2-2.5 folds when compared with conventional orthodontic tooth movement. The CAOT was found safe on periodontal health and exhibits no or little risk of root resorption. A localized turnover of alveolar spongiosa and the absence of a hyalinized zone was the acceptable biological explanation of CAOT. There is no evidence to support that CAOT enhances the movement of ankylosed teeth, closing old extraction sites, post-orthodontic stability, or transverse expansion. CONCLUSIONS: Corticotomy-assisted orthodontic treatment should be considered with caution. Long term randomized clinical trials are still needed. PMID- 26108583 TI - Prevalence of human immunodeficiency virus, hepatitis C virus, and hepatitis B virus infection among heroin injectors in the central region of Saudi Arabia. AB - OBJECTIVES: To calculate the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infections among inpatient heroin users, and to study the relationships between these infections and patient demographics. METHODS: In this retrospective study, heroin users' inpatient records from the Alamal Hospital, Riyadh, Saudi Arabia were reviewed for HIV, HBV, and HCV screening results, age, number of admissions, education, and marital and occupational status. The study took place between January 2006 and November 2012. The prevalences of HIV, HBV, and HCV and their associations to demographics were evaluated. RESULTS: A sample of 357 inpatients Saudi male heroin users (all injectors) aged 40 (+/-8.6) years with lifetime admissions averaged 5.8 (+/-5) times were studied. Screening results revealed that 20.1% of subjects were infection-free, 56.6% had a single infection, 13.2% were infected by 2 viruses, and 1.1% were infected by 3 viruses. Prevalence of HBV surface antigen was 7.7%, antibodies for HCV 77.8%, and HIV 9.8%. A significant association was found between positive HCV and positive HIV tests. Furthermore, HCV was more common among patients aged 20-29 years, those who were unemployed, and who had primary, secondary, or postsecondary education. Finally, HBV was associated in patients aged 30-39 years and those with secondary educations. CONCLUSION: Contracting serious contagious viral infections is very common among Saudi heroin injectors at rates similar to those seen among injectors in Western countries. Infection control, education, and harm reduction programs are of paramount importance. PMID- 26108584 TI - Prevalence of methicillin-resistant Staphylococcus aureus nasal colonization among medical students in Jeddah, Saudi Arabia. AB - OBJECTIVES: To identify Methicillin-resistant Staphylococcus aureus (MRSA) nasal carriage status among medical students during their clinical rotations. METHODS: This cross-sectional study detected the prevalence of MRSA among medical students at King Abdulaziz University (KAU), Jeddah, Saudi Arabia, using molecular approaches. Nasal swabs were collected from 150 internship and sixth-year medical students between September 2014 and January 2015, and compared with the control group of 32 third-year medical students who were not exposed to clinical work. Polymerase chain reaction (PCR) screening was performed to identify Staphylococcus aureus (S. aureus) nucgene, and an additional PCR was performed on S. aureus positive samples to detect the presence of mecA gene. RESULTS: Out of 150 students screened, 38 were nasal carriers of S. aureus. The prevalence of methicillin-sensitive S. aureus (MSSA) carriers was 18.7% (n=28), whereas 10 students (6.7%) were mecA-positive, representing MRSA carriers. Interns carry MRSA more than 6th year students and students who were not exposed to clinical work (p less than 0.05), while MSSA is found more in students who were not exposed to clinical work (p less than 0.01). CONCLUSION: We found MRSA carriers among medical students at KAU, which showed a possible contribution of this group to transmit infection to hospitalized patients. Medical students must receive sufficient knowledge regarding control measures to avoid spread of this infection in hospitals. PMID- 26108586 TI - Completeness of adverse drug reactions reports of the Saudi adverse event reporting system. AB - OBJECTIVES: To assess completeness of reports in the Saudi Adverse Event Reporting System (SAERS), which is a part of the Saudi Food and Drug Authority pharmacovigilance system for monitoring the safety of medications. METHODS: A cross-sectional study was conducted in Riyadh, Saudi Arabia using the reports that were received between December 2009 and June 2012 in the SAERS. The completeness was assessed by reviewing the components of the adverse drug reactions (ADRs) form, and how many fields were completed. Descriptive statistics are reported. RESULT: There were 14,783 reports during the study period. Eighty percent of these reports were spontaneous reports. Information related to the drug (99%) and adverse events (98%) of the reports were completed. While the patient's demographic data were completed only in 38% of all reports, the least completed item in the ADRs form was the reporter information (15%). The most reported drug class was tumor necrosis factor inhibitors (7%), whereas events involving the respiratory organ system were the most frequently reported (4.5%). CONCLUSION: Although the SAERS is considered new, it has a high number of reports. More efforts are needed to improve the completeness of the SAERS to be a good source to assess the signals between events and suspected drugs, especially when there is a high number of reports. PMID- 26108585 TI - Perceptions and knowledge regarding antimicrobial stewardship among clinicians in Jeddah, Saudi Arabia. AB - OBJECTIVES: To understand the perceptions, attitude, and prescribing practices of clinicians regarding antimicrobial resistance (AMR). METHODS: A multidisciplinary cross-sectional study comprising 447 clinicians of university, public, and private hospitals of Jeddah, Saudi Arabia was carried out from August to October 2014 using a self-administered questionnaire. RESULTS: Interestingly, 33% of the general physicians yielded to patient/parent's demand for the choice of antimicrobials (AMs) as compared with only 13.2% of the residents, and 4.3% of the specialists. In addition, expensive AMs are more often prescribed by the general physician (70.4%) in comparison with 26.4% residents and 30.4% of the specialists. However, no significant differences were observed between the knowledge and perceptions regarding the current scope of AM agents, as well as their use and misuse. Furthermore, dependability of specialist and residents seems to be significantly higher than general physicians on pocketbooks and smartphone for AM education sources. CONCLUSION: This study revealed that despite a clear concept of AMR, general physicians lacks consistency in prescribing aptitude and use of effective educational resources, while all respondents lacks dedication to follow the guidelines of AM use. This highlights the requirement of AM stewardship with decisive objective of reduction in AMR. PMID- 26108587 TI - Efficacy of insulin analogues in diabetic patients attending primary care centers. AB - OBJECTIVES: To measure the efficacy of new insulin analogues compared with the conventional types of insulin, and to compare their effects on patient satisfaction regarding their weight changes and the frequency of hypoglycemic episodes. METHODS: In this retrospective cohort observational study, data was collected from the medical records of 122 eligible diabetics on insulin therapy attending government primary care centers, in Jeddah, Kingdom of Saudi Arabia from June 2013 to July 2014. The data collected considered the efficacy, safety, and patient satisfaction of the types of insulin therapy used for their treatment. RESULTS: After 12 weeks, there was a reduction in mean glycosylated hemoglobin (HbA1c) of -0.88% for the analogue type versus -0.19% for the conventional type, and at 24 weeks, the mean drop in HbA1c was -2.02% for the analogue type versus -1.12% for the conventional type, but the differences were not statistically significant. More patients (87% versus 38%) on analogue compared with conventional insulin treatment were satisfied with therapy. CONCLUSION: In the primary health care setting, insulin analogues showed greater efficacy improvements than conventional insulin therapy within 6 months. However, conventional insulin therapy can still be used at primary care centers with limited resources, and when patients refuse to be converted. PMID- 26108588 TI - Review of 244 cases of ovarian cysts. AB - OBJECTIVES: To review cases of ovarian cysts managed at a University Hospital, and to identify the factors necessitating the use of laparotomy over laparoscopy. METHODS: We carried out a retrospective chart review of all cases of ovarian cysts diagnosed and managed at the Department of Obstetrics and Gynecology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia between January 2010 and August 2014. All data collected from medical record charts, patents details, clinical presentations, ovarian cysts description, and pathology type were recorded, and management by laparoscopy or laparotomy was identified. Ethical approval was obtained from ethical hospital committee. RESULTS: There were 244 cases of ovarian cysts during the study period. The age ranged from 3 months to 77 years of age. The parity from 0-6. The height range from 37-180 cm. The weight range from 3-161 kg, and calculated body mass index ranged from 12-47. Out of 244 patients diagnosed, 165 were married (67.4%). Of those, only 16 patients were pregnant (6.6%). The most common presentation was abdominal pain in 142 patients (58.2%). Only 79.9% were ovarian cysts, and 17.5% were either para-ovarian or retroperitoneal. The right ovaries were affected in 63.1%, and only 18.9% were bilateral. The types of ovarian cysts included functional cysts 33.2%, benign cyst-adenoma 19.3%, and dermoid cysts 12.3%. CONCLUSION: Factors associated with laparotomy management rather than laparoscopy included older age more than 35, single, pregnant, or patients presenting with abdominal pain, and more than one cyst. PMID- 26108589 TI - Hyperhomocysteinemia as a metabolic disorder parameter is independently associated with the severity of coronary heart disease. AB - OBJECTIVES: To study the associations between hyperhomocysteinemia (HHcy) and the severity of coronary heart disease (CHD). METHODS: We retrospectively analyzed metabolic parameters, anthropometric variables, and life style habits in 292 CHD patients of different categories, and 100 controlled non-CHD patients with chest pain symptoms who were hospitalized in the Department of Cardiovascular Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China between October 2013 and September 2014. RESULTS: The prevalence of HHcy in CHD patients was 79.1%, while only 5% of non-CHD patients had elevated serum homocysteine (Hcy) concentrations. The prevalence of HHcy significantly increased from 5% in non-CHD controls to 66% in the stable angina pectoris (SAP) group, to 81.9% in the unstable angina pectoris group, and to 93.15% in the acute myocardial infarction (AMI) group (p less than 0.001). After adjusting for confounding factors, multivariate logistic regression analysis showed that HHcy was independently associated with CHD category (AMI versus SAP, odds ratio [6.38], 95% confidence interval; 1.18-34.46). The Hcy was negatively correlated with folic acid (r=-0.67, p less than 0.001) and vitamin B12 (r=-0.56, p less than 0.001). Of the CHD patients with HHcy, 51.1% had low folic acid and 42% had low vitamin B12, 7 or 5 times higher than that of CHD patients with normal-low Hcy concentrations (p less than 0.001). CONCLUSION: Hyperhomocysteinemia is independently associated with the severity of CHD, and significantly correlated with low status of folic acid and vitamin B12 in CHD patients. PMID- 26108590 TI - Effects of cigarette smoking on morphological features of platelets in healthy men. AB - OBJECTIVES: To assess the effects of cigarette smoking on thrombocytopoiesis and some platelet morphological parameters in healthy male smokers. METHODS: In this cross-sectional study, 542 consecutive healthy men (aged 20 to 88 years), referred to the laboratory of Fatemieh Hospital, Semnan, Iran, between November 2011 and November 2012 for checking up were enrolled. The subjects were divided into 2 groups of smokers (n=258 with frequency of 10 or more cigarette per day with more than 12 months duration of smoking) and non-smokers (n=284). The blood samples were extracted to examine values of platelet indices using an ABX Micros 60 cell counter. RESULTS: Comparing platelet indices across smokers and non smokers showed that the mean platelet count was statistically significantly higher in adult smokers than in nonsmokers (264.1 +/- 81.2/ul versus 247.7 +/- 83.9/ul, p=0.021), while the mean plateletcrit value was contrarily lower in the adult smokers (18.0 +/- 12.0% versus 25.0 +/- 10.0%, p less than 0.001). Other platelet indicators were not discrepant between the smokers and non-smokers. CONCLUSION: Cigarette smoking in healthy individuals results in significant and considerable effects on platelet morphological indices. The mean platelet count is significantly increased, and plateletcrit values are reduced, compared with non-smoking status. PMID- 26108591 TI - Epidemiological review of scorpion stings in Qatar. The need for regional management guidelines in emergency departments. AB - OBJECTIVES: To review the epidemiology of scorpion sting in Qatar, to explore both the clinical significance, and the role of the emergency department (ED) in the management of such cases. METHODS: In this retrospective study, we reviewed the records of all scorpion sting cases presented to the ED of Hamad General Hospital, Doha, Qatar between October 2010 and May 2013. RESULTS: A total of 111 cases of scorpion stings were reviewed, 81 (72.9%) were males and 30 (27.1%) were females, with a mean age of 38 years. Localized pain was the most frequent presenting complaint (89 [80.2%]), whereas localized redness (44 [39.6%]) and swelling (38 [34.2%]) were the most common clinical signs. Abroug's classification was used, and all cases were found to be class I. All patients received symptomatic treatment and were sent home. CONCLUSION: Scorpion sting problem in Qatar has a low clinical significance. Data from such studies should be utilized to create more specific (local) management guidelines, which should be more efficient with more rational utilization of ED resources. PMID- 26108592 TI - Plasma and salivary total antioxidant capacity in healthy controls compared with aggressive and chronic periodontitis patients. AB - OBJECTIVES: To evaluate the plasma and salivary total antioxidant capacity (TAOC) in patients with generalized chronic periodontitis (CP), generalized aggressive periodontitis (AgP), and periodontally healthy controls. METHODS: This cross sectional study includes of 88 individuals seeking dental treatment at the Faculty of Dentistry, Istanbul University, Istanbul, Turkey between January 2011 and March 2012. Fifteen AgP patients were compared with 21 healthy controls (C1), while 36 CP patients were compared with 16 healthy controls (C2). Clinical periodontal measurements were recorded, and plasma and saliva samples were collected. The TAOC of the plasma and saliva samples were determined using a commercially available colorimetric kit. RESULTS: The plasma TAOC of both AgP and CP patients was significantly lower for C1 and C2. The salivary TAOC of CP patients was significantly lower for C2, but there was no significant difference between AgP patients and C1. CONCLUSION: Our results demonstrate that severe periodontitis may be associated with a lower plasma antioxidant capacity. The reduced antioxidant capacity in patients with severe periodontitis, especially with aggressive forms may be an important contributing factor to severe tissue destruction. PMID- 26108593 TI - Chronic renal failure in a patient with bilateral ureterocele. AB - Ureterocele is a congenital anomaly, in which there is mal-development of the caudal segments of the ureter. There is a female preponderance with most cases seen in Caucasians. Among the reported complications of this condition, chronic renal failure occurring in the setting of ureterocele has not been well documented. We report a case of a young girl with bilateral ureterocele presenting with chronic renal failure, whose management presented a diagnostic failure and inadequate treatment. PMID- 26108594 TI - Management of rhino-orbital mucormycosis. AB - Mucormycosis is an uncommon acute invasive fungal infection that affects immunocompromised patients. It progresses rapidly and has poor prognosis if diagnosed late. Early detection, control of the underlying condition with aggressive surgical debridement, administration of systemic and local antifungal therapies, hyperbaric oxygen as adjunctive treatment improves prognosis and survivability. PMID- 26108595 TI - Outcomes of a type 2 diabetes education program adapted to the cultural contexts of Saudi women. A pilot study. AB - OBJECTIVE: To explore the outcomes of a pilot intervention of a type 2 diabetes (T2D) education program, based on international standards, and adapted to the cultural and religious contexts of Saudi women. METHODS: This study is an experiment of a pilot intervention carried out between August 2011 and January 2012 at the primary health clinics in Dammam. Women at risk of or diagnosed with T2D (N=35 including dropouts) were assigned to one of 2 groups; an intervention group participated in a pilot intervention of T2D education program, based on international standards and tailored to their cultural and religious contexts; and a usual care group received the usual care for diabetes in Saudi Arabia. Outcomes included blood glucose, body composition, 6-minute walk distance, life satisfaction, quality of life, and diabetes knowledge. The intervention group participated in a focus group of their program experience. Data analysis was based on mixed methods. RESULTS: Based on 95% confidence interval comparisons, improvements were noted in blood sugar, 6-minute walk distance, quality of life, and diabetes knowledge in participants of the intervention group. They also reported improvements in lifestyle-related health behaviors after the education program. CONCLUSION: Saudi women may benefit from a T2D education program based on international standards and adapted to their cultural and religious contexts. PMID- 26108596 TI - The prevalence of thyroid cancer in patients with hyperthyroidism. AB - OBJECTIVES: To determine the prevalence of thyroid cancer in patients with hyperthyroidism. METHODS: This is a retrospective observational study using the data of 71 Omani patients with a diagnosis of hyperthyroidism due to Grave's disease, toxic multinodular goiter, and solitary toxic adenoma. These patients underwent thyroidectomy at the Royal Hospital (RH), Muscat, Oman, and were followed up at the National Diabetes and Endocrine Center (NDEC) between 2007 and 2013. The details were collected from the medical records of both the RH and the NDEC. Patients who underwent thyroidectomy for other reasons like non-toxic goiter and hypothyroidism with cancer were excluded from the study. RESULTS: Thyroid cancer was identified in 32.8% (n=23) of patients with hyperthyroidism. Half of these patients 52.1% (n=12) had papillary micro-cancer (intra-thyroidal), and 3 patients with Grave's disease (13%) had lymph nodes metastasis (loco regional infiltration. The cancer preponderance was higher in young (n=21, 91.3%) and female patients (n=18, 73.9%). Most patients with thyroid cancer had abnormal ultrasound neck findings and thyroid scintigraphy (99 mTc uptake). CONCLUSION: Many patients with hyperthyroidism in Muscat, Oman, especially those with Grave's disease, show malignancy, and hence a proper initial evaluation of these patients is required as part of long-term management. PMID- 26108597 TI - Large hepatic abscess caused by fish bone. PMID- 26108598 TI - A young male presenting with swelling on the left lower anterior aspect of the neck. PMID- 26108599 TI - Desmoid tumor (fibromatosis) of the head and neck. PMID- 26108600 TI - Atomic force microscopy and tridimensional topography analysis of human enamel after resinous infiltration and storage in water. PMID- 26108601 TI - Effects of pregnancy on sexual function. Findings from a survey of Saudi women. PMID- 26108602 TI - The comparison of ProSeal and I-gel laryngeal mask airways in anesthetized adult patients under controlled ventilation. PMID- 26108603 TI - Effect of tactile kinesthetic stimulation on preterm infants' weight and length of hospital stay in Khartoum, Sudan. PMID- 26108604 TI - Increasing trends in kidney cancer over the last 2 decades in Saudi Arabia. PMID- 26108606 TI - YY super sperm lead to all male triploids and tetraploids. AB - BACKGROUND: Androgenesis is a unique and rarely encountered reproductive mode in which the offspring only inherit the paternal nuclear genome, resulting in relatively few viable individuals. RESULTS: In this study, a super male (YY) crucian carp was obtained by androgenesis with the diploid sperm of autotetraploid crucian carp (4n = 200). Flow cytometry assay confirmed the fish was diploid. The scanning electron microscopy and flow cytometry analysis results of sperm revealed that the YY crucian carp produced unreduced diploid sperm. To prove the special reproductive characteristic and homozygosity of the YY crucian carp, three rounds of hybridization experiments were performed. First, self crossing between female androgenic progenies and YY crucian carp generated all male tetraploids. Then, hybridization of female red crucian carp (2n = 100) and female autotetraploid fish (4n = 200) with YY crucian carp produced all male triploids and all male tetraploids, respectively. CONCLUSIONS: This is the first time reported producing a viable diploid homozygous YY fish with unreduced diploid sperm of the autotetraploid fish, which were derived from distant hybridization. These results will not only help explaining the sex determination mechanism in teleost fish, but also play a significant role in genetic breeding in aquaculture. PMID- 26108607 TI - Analysis of early resistance development at the first failure timepoint in elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate-treated patients. AB - OBJECTIVES: The patterns of emergent HIV-1 drug resistance in patients failing a single-tablet regimen consisting of elvitegravir, boosted by cobicistat, plus emtricitabine and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) include mutations in HIV-1 reverse transcriptase (RT) and integrase (IN). The order of development of mutations at early virological failure has not been described. The aim of this study was to determine the first resistance mutations to emerge during virological failure on EVG/COBI/FTC/TDF. PATIENTS AND METHODS: Population sequencing was conducted at the first virological failure timepoint with HIV-1 RNA >=400 copies/mL for each of the 18 patients with emergent resistance in the EVG/COBI/FTC/TDF arms of two randomized, double-blind, Phase 3 studies of EVG/COBI/FTC/TDF through Week 144. RESULTS: At first failure compared with confirmed virological failure, 4 of the 18 patients had no detectable resistance mutation in their virus and only 51% of the RT and IN mutations were detected overall. M184V/I in RT was the first mutation to appear in many cases (n = 6) and was then followed by additional mutations in RT and IN. No case with development of resistance to the IN strand-transfer inhibitor prior to the development of M184V/I was detected. CONCLUSIONS: The analysis of first failure found fewer patients with emergent resistance and fewer resistance mutations than the standard analysis at the later confirmation of virological failure. The early detection of resistance may preserve later treatment options. PMID- 26108605 TI - Lucilia cuprina genome unlocks parasitic fly biology to underpin future interventions. AB - Lucilia cuprina is a parasitic fly of major economic importance worldwide. Larvae of this fly invade their animal host, feed on tissues and excretions and progressively cause severe skin disease (myiasis). Here we report the sequence and annotation of the 458-megabase draft genome of Lucilia cuprina. Analyses of this genome and the 14,544 predicted protein-encoding genes provide unique insights into the fly's molecular biology, interactions with the host animal and insecticide resistance. These insights have broad implications for designing new methods for the prevention and control of myiasis. PMID- 26108609 TI - Authors' reply to Lin and colleagues. PMID- 26108610 TI - Why the panic? South Korea's MERS response questioned. PMID- 26108608 TI - Validation and clinical application of a method to quantify nevirapine in dried blood spots and dried breast-milk spots. AB - OBJECTIVES: The validation and clinical application of an LC-MS/MS method for the quantification of nevirapine in dried blood spots (DBS) and dried breast-milk spots (DBMS) are presented. METHODS: DBS and DBMS were prepared from 50 and 30 MUL of nevirapine-spiked whole blood and human breast milk, respectively. Chromatographic separation was achieved on a reverse-phase C18 column with 0.1% formic acid in water/acetonitrile using a solvent gradient programme at a flow rate of 400 MUL/min, and detection was by a TSQ Quantum Access triple quadrupole mass spectrometer. The clinical application was evaluated in HIV-positive nursing mothers and their breastfed infants. RESULTS: The assay was validated over the concentration range 50-10,000 ng/mL. Accuracy ranged from 93.3% to 113.4% and precision ranged from 1.9% to 12.0%. The mean (percentage coefficient of variation) recovery of nevirapine from DBS and DBMS was >= 70.7% (<= 8.2) and the matrix effect was <= 1.04 (<= 6.1). Nevirapine was stable in DBS and DBMS for >= 15 months at room temperature and -80 degrees C. Mean (SD) AUC0-12, Cmax and Cmin in maternal plasma versus breast milk were 57,808 ng . h/mL (24,315) versus 55,817 ng . h/mL (22,368), 6140 ng/mL (2605) versus 5231 ng/mL (2215) and 4334 ng/mL (1880) versus 4342 ng/mL (2245), respectively. The milk-to-plasma concentration ratio over the dosing interval was 0.94 (0.15). Infant plasma concentrations 2 and 8 h after maternal dosing were 580.6 ng/mL (464.7-1607) and 584.1 ng/mL (381.5-1570), respectively. CONCLUSIONS: These methods further extend opportunities for conducting clinical pharmacokinetic studies in nursing mother infant pairs, especially in resource-limited settings. PMID- 26108611 TI - Organic-free synthesis of ultrathin gold nanowires as effective SERS substrates. AB - We present a novel and facile fabrication of ultrathin gold nanowires in the absence of organic reagents. Measurements of surface-enhanced Raman scattering (SERS) demonstrated that the obtained organic-free ultrathin Au nanowires can serve as simple and effective SERS substrates. PMID- 26108612 TI - Brain Network Reconfiguration and Perceptual Decoupling During an Absorptive State of Consciousness. AB - Trance is an absorptive state of consciousness characterized by narrowed awareness of external surroundings and has long been used-for example, by shamans to gain insight. Shamans across cultures often induce trance by listening to rhythmic drumming. Using functional magnetic resonance imaging (fMRI), we examined the brain-network configuration associated with trance. Experienced shamanic practitioners (n = 15) listened to rhythmic drumming, and either entered a trance state or remained in a nontrance state during 8-min scans. We analyzed changes in network connectivity. Trance was associated with higher eigenvector centrality (i.e., stronger hubs) in 3 regions: posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (dACC), and left insula/operculum. Seed-based analysis revealed increased coactivation of the PCC (a default network hub involved in internally oriented cognitive states) with the dACC and insula (control-network regions involved in maintaining relevant neural streams). This coactivation suggests that an internally oriented neural stream was amplified by the modulatory control network. Additionally, during trance, seeds within the auditory pathway were less connected, possibly indicating perceptual decoupling and suppression of the repetitive auditory stimuli. In sum, trance involved coactive default and control networks, and decoupled sensory processing. This network reconfiguration may promote an extended internal train of thought wherein integration and insight can occur. PMID- 26108613 TI - The Dorsoventral Boundary of the Germinal Zone is a Specialized Niche for the Generation of Cortical Oligodendrocytes during a Restricted Temporal Window. AB - Oligodendrocyte precursor cells (OPCs) appear in the late embryonic brain, mature to become oligodendrocytes (OLs), and form myelin in the postnatal brain. Recently, it has been proposed that early-born OPCs derived from the ventral forebrain are eradicated postnatally and that late-born OLs predominate in the cortex of the adult mouse brain. However, intrinsic and extrinsic factors that specify the ability of self-renewing multipotent neural stem cells in the embryonic brain to generate cortical OL-lineage cells remain largely unknown. Using an inducible Cre/loxP system to permanently label Nestin- and Olig2-lineage cells, we identified that cortical OL-lineage cells start differentiating from neural stem cells within a restricted temporal window just prior to E16.5 through P10. We then showed, by means of electroporation of a Cre expression plasmid into the VZ/SVZ of E15.5 reporter mouse brains, that neural precursor cells in the dorsal VZ/SVZ are inhibited by Wnt signaling from contributing to cortical OLs in the adult brain. In contrast, neural precursor cells present in the dorsoventral boundary VZ/SVZ produce a significant amount of OLs in the adult cortex. Our results suggest that neural stem cells at this boundary are uniquely specialized to produce myelin-forming OLs in the cortex. PMID- 26108614 TI - Development of Tool Representations in the Dorsal and Ventral Visual Object Processing Pathways. AB - Tools represent a special class of objects, because they are processed across both the dorsal and ventral visual object processing pathways. Three core regions are known to be involved in tool processing: the left posterior middle temporal gyrus, the medial fusiform gyrus (bilaterally), and the left inferior parietal lobule. A critical and relatively unexplored issue concerns whether, in development, tool preferences emerge at the same time and to a similar degree across all regions of the tool-processing network. To test this issue, we used functional magnetic resonance imaging to measure the neural amplitude, peak location, and the dispersion of tool-related neural responses in the youngest sample of children tested to date in this domain (ages 4-8 years). We show that children recruit overlapping regions of the adult tool-processing network and also exhibit similar patterns of co-activation across the network to adults. The amplitude and co-activation data show that the core components of the tool processing network are established by age 4. Our findings on the distributions of peak location and dispersion of activation indicate that the tool network undergoes refinement between ages 4 and 8 years. PMID- 26108615 TI - Ectopic expression of snapdragon transcription factors facilitates the identification of genes encoding enzymes of anthocyanin decoration in tomato. AB - Given the potential health benefits of polyphenolic compounds in the diet, there is a growing interest in the generation of food crops enriched with health protective flavonoids. We undertook a series of metabolite analyses of tomatoes ectopically expressing the Delila and Rosea1 transcription factor genes from snapdragon (Antirrhinum majus), paying particular attention to changes in phenylpropanoids compared to controls. These analyses revealed multiple changes, including depletion of rutin and naringenin chalcone, and enhanced levels of anthocyanins and phenylacylated flavonol derivatives. We isolated and characterized the chemical structures of the two most abundant anthocyanins, which were shown by NMR spectroscopy to be delphinidin-3-(4'''-O-trans-p coumaroyl)-rutinoside-5-O-glucoside and petunidin-3-(4'''-O-trans-p-coumaroyl) rutinoside-5-O-glucoside. By performing RNA sequencing on both purple fruit and wild-type fruit, we obtained important information concerning the relative expression of both structural and transcription factor genes. Integrative analysis of the transcript and metabolite datasets provided compelling evidence of the nature of all anthocyanin biosynthetic genes, including those encoding species-specific anthocyanin decoration enzymes. One gene, SlFdAT1 (Solyc12g088170), predicted to encode a flavonoid-3-O-rutinoside-4''' phenylacyltransferase, was characterized by assays of recombinant protein and over-expression assays in tobacco. The combined data are discussed in the context of both our current understanding of phenylpropanoid metabolism in Solanaceous species, and evolution of flavonoid decorating enzymes and their transcriptional networks in various plant species. PMID- 26108616 TI - Chimpanzees' Bystander Reactions to Infanticide: An Evolutionary Precursor of Social Norms? AB - Social norms-generalized expectations about how others should behave in a given context-implicitly guide human social life. However, their existence becomes explicit when they are violated because norm violations provoke negative reactions, even from personally uninvolved bystanders. To explore the evolutionary origin of human social norms, we presented chimpanzees with videos depicting a putative norm violation: unfamiliar conspecifics engaging in infanticidal attacks on an infant chimpanzee. The chimpanzees looked far longer at infanticide scenes than at control videos showing nut cracking, hunting a colobus monkey, or displays and aggression among adult males. Furthermore, several alternative explanations for this looking pattern could be ruled out. However, infanticide scenes did not generally elicit higher arousal. We propose that chimpanzees as uninvolved bystanders may detect norm violations but may restrict emotional reactions to such situations to in-group contexts. We discuss the implications for the evolution of human morality. PMID- 26108617 TI - Lipid-mediated muscle insulin resistance: different fat, different pathways? AB - Increased dietary fat intake and lipolysis result in excessive lipid availability, which relates to impaired insulin sensitivity. Over the last years, several mechanisms possibly underlying lipid-mediated insulin resistance evolved. Lipid intermediates such as diacylglycerols (DAG) associate with changes in insulin sensitivity in many models. DAG activate novel protein kinase C (PKC) isoforms followed by inhibitory serine phosphorylation of insulin receptor substrate 1 (IRS1). Activation of Toll-like receptor 4 (TLR4) raises another lipid class, ceramides (CER), which induce pro-inflammatory pathways and lead to inhibition of Akt phosphorylation. Inhibition of glucosylceramide and ganglioside synthesis results in improved insulin sensitivity and increased activatory tyrosine phosphorylation of IRS1 in the muscle. Incomplete fat oxidation can increase acylcarnitines (ACC), which in turn stimulate pro-inflammatory pathways. This review analyzed the effects of lipid metabolites on insulin action in skeletal muscle of humans and rodents. Despite the evidence for the association of both DAG and CER with insulin resistance, its causal relevance may differ depending on the subcellular localization and the tested cohorts, e.g., athletes. Nevertheless, recent data indicate that individual lipid species and their degree of fatty acid saturation, particularly membrane and cytosolic C18:2 DAG, specifically activate PKCtheta and induce both acute lipid-induced and chronic insulin resistance in humans. PMID- 26108618 TI - Effects of choline on health across the life course: a systematic review. AB - CONTEXT: Choline is a precursor of both betaine and acetylcholine and might, therefore, influence cardiovascular and cognitive outcomes. There has been concern, however, that it may influence blood lipid levels because it is an essential component of very-low-density lipoproteins. OBJECTIVE: The aim was to systematically review, using PRISMA guidelines, the literature pertaining to the effects of choline on body composition and on metabolic, cardiovascular, respiratory, and neurological outcomes in different life stages. DATA SOURCES: The MEDLINE, Embase, Cochrane Central, Web of Science, PubMed, and Google Scholar databases were searched up to July 2014. DATA EXTRACTION: Fifty relevant articles were identified. These comprised trials and cohort, case-control, and cross sectional studies that assessed blood levels of choline, dietary intake of choline, and supplementation with choline in a population free of diseases at baseline. DATA SYNTHESIS: There is some observational evidence that choline during pregnancy may be beneficial for the neurological health of the child. In adults, choline may have beneficial effects on cognition, but high-quality (intervention) studies are lacking. Results on the effects of choline on body composition, blood lipids, and cardiovascular health were inconsistent. CONCLUSIONS: Evidence to confirm the suggested effects of choline on health in different stages of life is scarce. Potential effects of choline need to be confirmed by intervention studies. Possible harmful effects on cardiometabolic health need careful evaluation. PMID- 26108619 TI - Unconditional and conditional standards for fetal abdominal circumference and estimated fetal weight in an ethnic Chinese population: a birth cohort study. AB - BACKGROUND: Diagnosis of intrauterine fetal growth restriction and prediction of small-for-gestation age are often based on fetal abdominal circumference or estimated fetal weight (EFW). The present study aims to create unconditional (cross-sectional) and conditional (longitudinal) standards of fetal abdominal circumference and EFW for use in an ethnic Chinese population. METHODS: In the Growing Up in Singapore Towards healthy Outcome (GUSTO) birth cohort study in Singapore, fetal biometric measurements were obtained at enrolment to antenatal care (11-12 weeks) and up to three more time points during pregnancy. Singleton pregnancies with a healthy profile defined by maternal, pregnancy and fetal characteristics and birth outcomes were selected for this analysis. The Hadlock algorithm was used to calculate EFW. Mixed effects model was used to establish unconditional and conditional standards in z-scores and percentiles for both genders pooled and for each gender separately. RESULTS: A total of 313 women were included, of whom 294 had 3 and 19 had 2 ultrasound scans other than the gestational age dating scan. Fetal abdominal circumference showed a roughly linear trajectory from 18 to 36 weeks of gestation, while EFW showed an accelerating trajectory. Gender differences were more pronounced in the 10(th) percentile than the 50(th) or 90(th) percentiles. As compared to other published charts, this population showed growth trajectories that started low but caught up at later gestations. CONCLUSIONS: Unconditional and conditional standards for monitoring fetal size and fetal growth in terms of abdominal circumference and EFW are available for this ethnic-Chinese population. Electronic spreadsheets are provided for their implementation. PMID- 26108620 TI - Mam33 promotes cytochrome c oxidase subunit I translation in Saccharomyces cerevisiae mitochondria. AB - Three mitochondrial DNA-encoded proteins, Cox1, Cox2, and Cox3, comprise the core of the cytochrome c oxidase complex. Gene-specific translational activators ensure that these respiratory chain subunits are synthesized at the correct location and in stoichiometric ratios to prevent unassembled protein products from generating free oxygen radicals. In the yeast Saccharomyces cerevisiae, the nuclear-encoded proteins Mss51 and Pet309 specifically activate mitochondrial translation of the largest subunit, Cox1. Here we report that Mam33 is a third COX1 translational activator in yeast mitochondria. Mam33 is required for cells to adapt efficiently from fermentation to respiration. In the absence of Mam33, Cox1 translation is impaired, and cells poorly adapt to respiratory conditions because they lack basal fermentative levels of Cox1. PMID- 26108621 TI - Phosphorylation and SCF-mediated degradation regulate CREB-H transcription of metabolic targets. AB - CREB-H, an endoplasmic reticulum-anchored transcription factor, plays a key role in regulating secretion and in metabolic and inflammatory pathways, but how its activity is modulated remains unclear. We examined processing of the nuclear active form and identified a motif around S87-S90 with homology to DSG-type phosphodegrons. We show that this region is subject to multiple phosphorylations, which regulate CREB-H stability by targeting it to the SCF(Fbw1a) E3 ubiquitin ligase. Data from phosphatase treatment, use of phosophospecific antibody, and substitution of serine residues demonstrate phosphorylation of candidate serines in the region, with the core S87/S90 motif representing a critical determinant promoting proteasome-mediated degradation. Candidate kinases CKII and GSK-3b phosphorylate CREB-H in vitro with specificities for different serines. Prior phosphorylation with GSK-3 at one or more of the adjacent serines substantially increases S87/S90-dependent phosphorylation by CKII. In vivo expression of a dominant-negative Cul1 enhances steady-state levels of CREB-H, an effect augmented by Fbw1a. CREB-H directly interacts with Fbw1a in a phosphorylation dependent manner. Finally, mutations within the phosphodegron, when incorporated into the full-length protein, result in increased levels of constitutively cleaved nuclear protein and increased transcription and secretion of a key endogenous target gene, apolipoprotein A IV. PMID- 26108622 TI - Nuclear-localized CTP:phosphocholine cytidylyltransferase alpha regulates phosphatidylcholine synthesis required for lipid droplet biogenesis. AB - The reversible association of CTP:phosphocholine cytidylyltransferase alpha (CCTalpha) with membranes regulates the synthesis of phosphatidylcholine (PC) by the CDP-choline (Kennedy) pathway. Based on results with insect CCT homologues, translocation of nuclear CCTalpha onto cytoplasmic lipid droplets (LDs) is proposed to stimulate the synthesis of PC that is required for LD biogenesis and triacylglycerol (TAG) storage. We examined whether this regulatory mechanism applied to LD biogenesis in mammalian cells. During 3T3-L1 and human preadipocyte differentiation, CCTalpha expression and PC synthesis was induced. In 3T3-L1 cells, CCTalpha translocated from the nucleoplasm to the nuclear envelope and cytosol but did not associate with LDs. The enzyme also remained in the nucleus during human adipocyte differentiation. RNAi silencing in 3T3-L1 cells showed that CCTalpha regulated LD size but did not affect TAG storage or adipogenesis. LD biogenesis in nonadipocyte cell lines treated with oleate also promoted CCTalpha translocation to the nuclear envelope and/or cytoplasm but not LDs. In rat intestinal epithelial cells, CCTalpha silencing increased LD size, but LD number and TAG deposition were decreased due to oleate-induced cytotoxicity. We conclude that CCTalpha increases PC synthesis for LD biogenesis by translocation to the nuclear envelope and not cytoplasmic LDs. PMID- 26108623 TI - Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status. AB - Endoplasmic reticulum (ER) stress occurs when misfolded proteins overwhelm the capacity of the ER, resulting in activation of the unfolded protein response (UPR). Ire1, an ER transmembrane nuclease and conserved transducer of the UPR, cleaves the mRNA encoding the transcription factor Xbp1 at a dual stem-loop (SL) structure, leading to Xbp1 splicing and activation. Ire1 also cleaves other mRNAs localized to the ER membrane through regulated Ire1-dependent decay (RIDD). We find that during acute ER stress in mammalian cells, Xbp1-like SLs within the target mRNAs are necessary for RIDD. Furthermore, depletion of Perk, a UPR transducer that attenuates translation during ER stress, inhibits RIDD in a substrate-specific manner. Artificially blocking translation of the SL region of target mRNAs fully restores RIDD in cells depleted of Perk, suggesting that ribosomes disrupt SL formation and/or Ire1 binding. This coordination between Perk and Ire1 may serve to spatially and temporally regulate RIDD. PMID- 26108624 TI - The disease-linked Glu-26-Lys mutant version of Coronin 1A exhibits pleiotropic and pathway-specific signaling defects. AB - Coronin 1A (Coro1A) is involved in cytoskeletal and signaling events, including the regulation of Rac1 GTPase- and myosin II-dependent pathways. Mutations that generate truncated or unstable Coro1A proteins cause immunodeficiencies in both humans and rodents. However, in the case of the peripheral T-cell-deficient (Ptcd) mouse strain, the immunodeficiency is caused by a Glu-26-Lys mutation that targets a surface-exposed residue unlikely to affect the intramolecular architecture and stability of the protein. Here we report that this mutation induces pleiotropic effects in Coro1A protein, including the exacerbation of Coro1A-dependent actin-binding and -bundling activities; the formation of large meshworks of Coro1A(E26K)-decorated filaments endowed with unusual organizational, functional, and staining properties; and the elimination of Coro1A functions associated with both Rac1 and myosin II signaling. By contrast, it does not affect the ability of Coro1A to stimulate the nuclear factor of activated T-cells (NF-AT). Coro1A(E26K) is not a dominant-negative mutant, indicating that its pathological effects are derived from the inability to rescue the complete loss of the wild-type counterpart in cells. These results indicate that Coro1A(E26K) behaves as either a recessive gain-of-function or loss-of function mutant protein, depending on signaling context and presence of the wild type counterpart in cells. PMID- 26108625 TI - Meaningful health outcomes for paediatric neurodisability: Stakeholder prioritisation and appropriateness of patient reported outcome measures. AB - BACKGROUND: Health services are increasingly focused on measuring and monitoring outcomes, particularly those that reflect patients' priorities. To be meaningful, outcomes measured should be valued by patients and carers, be consistent with what health professionals seek to achieve, and be robust in terms of measurement properties. The aim of this study was (i) to seek a shared vision between families and clinicians regarding key aspects of health as outcomes, beyond mortality and morbidity, for children with neurodisability, and (ii) to appraise which multidimensional patient reported outcome measures (PROMs) could be used to assess salient health domains. METHODS: Relevant outcomes were identified from (i) qualitative research with children and young people with neurodisability and parent carers, (ii) Delphi survey with health professionals, and (iii) systematic review of PROMs. The International Classification of Functioning Disability and Health provided a common language to code aspects of health. A subset of stakeholders participated in a prioritisation meeting incorporating a Q-sorting task to discuss and rank aspects of health. RESULTS: A total of 33 pertinent aspects of health were identified. Fifteen stakeholders from the qualitative and Delphi studies participated in the prioritisation meeting: 3 young people, 5 parent carers, and 7 health professionals. Aspects of health that emerged as more important for families and targets for health professionals were: communication, emotional wellbeing, pain, sleep, mobility, self-care, independence, mental health, community and social life, behaviour, toileting and safety. Whilst available PROMs measure many aspects of health in the ICF, no single PROM captures all the key domains prioritised as for children and young people with neurodisability. The paucity of scales for assessing communication was notable. CONCLUSIONS: We propose a core suite of key outcome domains for children with neurodisability that could be used in evaluative research, audit and as health service performance indicators. Future work could appraise domain-specific PROMs for these aspects of health; a single measure assessing the key aspects of health that could be applied across paediatric neurodisability remains to be developed. PMID- 26108627 TI - Requirements for plant coexistence through pollination niche partitioning. AB - Plant-pollinator interactions are often thought to have been a decisive factor in the diversification of flowering plants, but to be of little or no importance for the maintenance of existing plant diversity. In a recent opinion paper, Pauw (2013 Trends Ecol. Evol. 28, 30-37. (doi:10.1016/j.tree.2012.07.019)) challenged this view by proposing a mechanism of diversity maintenance based on pollination niche partitioning. In this article, I investigate under which conditions the mechanism suggested by Pauw can promote plant coexistence, using a mathematical model of plant and pollinator population dynamics. Numerical simulations show that this mechanism is most effective when the costs of searching for flowers are low, pollinator populations are strongly limited by resources other than pollen and nectar, and plant-pollinator interactions are sufficiently specialized. I review the empirical literature on these three requirements, discuss additional factors that may be important for diversity maintenance through pollination niche partitioning, and provide recommendations on how to detect this coexistence mechanism in natural plant communities. PMID- 26108626 TI - Expression change in Angiopoietin-1 underlies change in relative brain size in fish. AB - Brain size varies substantially across the animal kingdom and is often associated with cognitive ability; however, the genetic architecture underpinning natural variation in these key traits is virtually unknown. In order to identify the genetic architecture and loci underlying variation in brain size, we analysed both coding sequence and expression for all the loci expressed in the telencephalon in replicate populations of guppies (Poecilia reticulata) artificially selected for large and small relative brain size. A single gene, Angiopoietin-1 (Ang-1), a regulator of angiogenesis and suspected driver of neural development, was differentially expressed between large- and small-brain populations. Zebra fish (Danio rerio) morphants showed that mild knock down of Ang-1 produces a small-brained phenotype that could be rescued with Ang-1 mRNA. Translation inhibition of Ang-1 resulted in smaller brains in larvae and increased expression of Notch-1, which regulates differentiation of neural stem cells. In situ analysis of newborn large- and small-brained guppies revealed matching expression patterns of Ang-1 and Notch-1 to those observed in zebrafish larvae. Taken together, our results suggest that the genetic architecture affecting brain size in our population may be surprisingly simple, and Ang-1 may be a potentially important locus in the evolution of vertebrate brain size and cognitive ability. PMID- 26108628 TI - Decisions reduce sensitivity to subsequent information. AB - Behavioural studies over half a century indicate that making categorical choices alters beliefs about the state of the world. People seem biased to confirm previous choices, and to suppress contradicting information. These choice dependent biases imply a fundamental bound of human rationality. However, it remains unclear whether these effects extend to lower level decisions, and only little is known about the computational mechanisms underlying them. Building on the framework of sequential-sampling models of decision-making, we developed novel psychophysical protocols that enable us to dissect quantitatively how choices affect the way decision-makers accumulate additional noisy evidence. We find robust choice-induced biases in the accumulation of abstract numerical (experiment 1) and low-level perceptual (experiment 2) evidence. These biases deteriorate estimations of the mean value of the numerical sequence (experiment 1) and reduce the likelihood to revise decisions (experiment 2). Computational modelling reveals that choices trigger a reduction of sensitivity to subsequent evidence via multiplicative gain modulation, rather than shifting the decision variable towards the chosen alternative in an additive fashion. Our results thus show that categorical choices alter the evidence accumulation mechanism itself, rather than just its outcome, rendering the decision-maker less sensitive to new information. PMID- 26108629 TI - Ocean acidification impairs crab foraging behaviour. AB - Anthropogenic elevation of atmospheric CO2 is driving global-scale ocean acidification, which consequently influences calcification rates of many marine invertebrates and potentially alters their susceptibility to predation. Ocean acidification may also impair an organism's ability to process environmental and biological cues. These counteracting impacts make it challenging to predict how acidification will alter species interactions and community structure. To examine effects of acidification on consumptive and behavioural interactions between mud crabs (Panopeus herbstii) and oysters (Crassostrea virginica), oysters were reared with and without caged crabs for 71 days at three pCO2 levels. During subsequent predation trials, acidification reduced prey consumption, handling time and duration of unsuccessful predation attempt. These negative effects of ocean acidification on crab foraging behaviour more than offset any benefit to crabs resulting from a reduction in the net rate of oyster calcification. These findings reveal that efforts to evaluate how acidification will alter marine food webs should include quantifying impacts on both calcification rates and animal behaviour. PMID- 26108630 TI - Advanced technologies for genetically manipulating the silkworm Bombyx mori, a model Lepidopteran insect. AB - Genetic technologies based on transposon-mediated transgenesis along with several recently developed genome-editing technologies have become the preferred methods of choice for genetically manipulating many organisms. The silkworm, Bombyx mori, is a Lepidopteran insect of great economic importance because of its use in silk production and because it is a valuable model insect that has greatly enhanced our understanding of the biology of insects, including many agricultural pests. In the past 10 years, great advances have been achieved in the development of genetic technologies in B. mori, including transposon-based technologies that rely on piggyBac-mediated transgenesis and genome-editing technologies that rely on protein- or RNA-guided modification of chromosomes. The successful development and application of these technologies has not only facilitated a better understanding of B. mori and its use as a silk production system, but also provided valuable experiences that have contributed to the development of similar technologies in non-model insects. This review summarizes the technologies currently available for use in B. mori, their application to the study of gene function and their use in genetically modifying B. mori for biotechnology applications. The challenges, solutions and future prospects associated with the development and application of genetic technologies in B. mori are also discussed. PMID- 26108631 TI - Allometry of animal-microbe interactions and global census of animal-associated microbes. AB - Animals live in close association with microorganisms, mostly prokaryotes, living in or on them as commensals, mutualists or parasites, and profoundly affecting host fitness. Most animal-microbe studies focus on microbial community structure; for this project, allometry (scaling of animal attributes with animal size) was applied to animal-microbe relationships across a range of species spanning 12 orders of magnitude in animal mass, from nematodes to whales. Microbial abundances per individual animal were gleaned from published literature and also microscopically counted in three species. Abundance of prokaryotes/individual versus animal mass scales as a nearly linear power function (exponent = 1.07, R(2) = 0.94). Combining this power function with allometry of animal abundance indicates that macrofauna have an outsized share of animal-associated microorganisms. The total number of animal-associated prokaryotes in Earth's land animals was calculated to be 1.3-1.4 * 10(25) cells and the total of marine animal-associated microbes was calculated to be 8.6-9.0 * 10(24) cells. Animal associated microbes thus total 2.1-2.3 * 10(25) of the approximately 10(30) prokaryotes on the Earth. Microbes associated with humans comprise 3.3-3.5% of Earth's animal-associated microbes, and domestic animals harbour 14-20% of all animal-associated microbes, adding a new dimension to the scale of human impact on the biosphere. This novel allometric power function may reflect underlying mechanisms involving the transfer of energy and materials between microorganisms and their animal hosts. Microbial diversity indices of animal gut communities and gut microbial species richness for 60 mammals did not indicate significant scaling relationships with animal body mass; however, further research in this area is warranted. PMID- 26108632 TI - Neural correlates of individual differences in circadian behaviour. AB - Daily rhythms in mammals are controlled by the circadian system, which is a collection of biological clocks regulated by a central pacemaker within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Changes in SCN function have pronounced consequences for behaviour and physiology; however, few studies have examined whether individual differences in circadian behaviour reflect changes in SCN function. Here, PERIOD2::LUCIFERASE mice were exposed to a behavioural assay to characterize individual differences in baseline entrainment, rate of re-entrainment and free-running rhythms. SCN slices were then collected for ex vivo bioluminescence imaging to gain insight into how the properties of the SCN clock influence individual differences in behavioural rhythms. First, individual differences in the timing of locomotor activity rhythms were positively correlated with the timing of SCN rhythms. Second, slower adjustment during simulated jetlag was associated with a larger degree of phase heterogeneity among SCN neurons. Collectively, these findings highlight the role of the SCN network in determining individual differences in circadian behaviour. Furthermore, these results reveal novel ways that the network organization of the SCN influences plasticity at the behavioural level, and lend insight into potential interventions designed to modulate the rate of resynchronization during transmeridian travel and shift work. PMID- 26108633 TI - Quantitative genetic analysis of brain size variation in sticklebacks: support for the mosaic model of brain evolution. AB - The mosaic model of brain evolution postulates that different brain regions are relatively free to evolve independently from each other. Such independent evolution is possible only if genetic correlations among the different brain regions are less than unity. We estimated heritabilities, evolvabilities and genetic correlations of relative size of the brain, and its different regions in the three-spined stickleback (Gasterosteus aculeatus). We found that heritabilities were low (average h(2) = 0.24), suggesting a large plastic component to brain architecture. However, evolvabilities of different brain parts were moderate, suggesting the presence of additive genetic variance to sustain a response to selection in the long term. Genetic correlations among different brain regions were low (average rG = 0.40) and significantly less than unity. These results, along with those from analyses of phenotypic and genetic integration, indicate a high degree of independence between different brain regions, suggesting that responses to selection are unlikely to be severely constrained by genetic and phenotypic correlations. Hence, the results give strong support for the mosaic model of brain evolution. However, the genetic correlation between brain and body size was high (rG = 0.89), suggesting a constraint for independent evolution of brain and body size in sticklebacks. PMID- 26108634 TI - Treatment of textile wastewater by submerged membrane bioreactor: In vitro bioassays for the assessment of stress response elicited by raw and reclaimed wastewater. AB - The performance of a pilot-scale membrane bioreactor (MBR) system for the treatment of textile wastewater was investigated. The MBR was continuously operated for 7 months. Very high treatment efficiencies were achieved (color, 100%; chemical oxygen demand (COD), 98%; biochemical oxygen demand (BOD5), 96%; suspended solids (SS), 100%). Furthermore, the MBR treatment efficiency was analyzed from a toxicological-risk assessment point of view, via different In vitro bioassays using Caco-2 cells, a widely used cell model in toxicological studies. Results showed that MBR treatment significantly reduced the raw textile wastewater (RTWW) cytotoxicity on Caco-2 cells by 53% for a hydraulic retention time (HRT) of 2 days. Additionally, the RTWW-induced disruption in the barrier function (BF) of the Caco-2 cell monolayer was also significantly reduced after MBR treatment under a HRT of 2 days (no disruption of BF was observed). Moreover, the effect of RTWW and treated wastewater on stress response was investigated using different stress genes: AHSA1, HSPD1, HSPA1A, HSPA5 and HSPA8. The cell exposure to RTWW significantly increased the expression of all used stress genes; interestingly, the treated wastewater (HRT 2 days) did not show any significant modulation of the stress genes. PMID- 26108635 TI - Severe brittle dyskinesias following DBS battery replacement. PMID- 26108636 TI - A "turn-on" silver nanocluster based fluorescent sensor for folate receptor detection and cancer cell imaging under visual analysis. AB - A novel terminal protection based label-free and "turn-on" fluorescent sensor for detection of folate receptors (FRs) and HeLa cells is developed by fluorescence resonance energy transfer (FRET) between single-walled carbon nanotubes (SWCNTs) and silver nanoclusters (AgNCs). Multilevel visual analysis (m(2)VA) was firstly proposed and applied in optimizing the experimental parameters. PMID- 26108637 TI - Glycopeptide Nanoconjugates Based on Multilayer Self-Assembly as an Antitumor Vaccine. AB - Antitumor vaccine, which is promising for tumor therapy, has been extensively studied. Some encouraging results of chemically synthetic vaccine designs based on the tumor-associated antigen mucin 1 have been achieved. However, some shortcomings such as low efficiency and difficult purification restrict their clinical application. To overcome these difficulties, we designed a novel antitumor vaccine of glycopeptide nanoconjugates based on the multilayer self assembly through the interaction of positive and negative charges. This vaccine formed the spherical structure and effectively activated the macrophage in vitro. Besides, it also induced high titer of antibodies against mucin 1 glycopeptide. The induced antibodies could highly bind to the tumor cells and effectively kill them by activation of the complement dependent cytotoxicity complex. This novel strategy provides a new way for the development of simple and effective antitumor vaccine. PMID- 26108638 TI - Micronutrient Deficiencies in Morbidly Obese Women Prior to Bariatric Surgery. AB - BACKGROUND: Although morbid obesity is related to excess of energy and macronutrient intake, it does not rule out the presence of micronutrient deficiencies. The aim of this study was to evaluate food intake and the prevalence of micronutrient deficiencies in a group of morbidly obese women seeking bariatric surgery. METHODS: A total of 103 morbidly obese women were studied prior to bariatric surgery. Anthropometry and body composition (dual energy X-ray absorptiometry, DEXA) were performed on all subjects. Energy and nutrient intake was determined by food frequency questionnaire. Blood tests to assess micronutrients status, including plasma iron, ferritin, transferrin, zinc, copper, calcium, phosphorus, hemoglobin, hematocrit, mean corpuscular volume (MCV), and hair zinc, were performed. Folic acid, vitamin B12, vitamin D, and parathyroid hormone (PTH) were also assessed in 66 subjects. RESULTS: Mean energy intake was 2801 +/- 970 kcal/day. Carbohydrate, protein, and lipid intake represented 55 +/- 9.1, 13.9 +/- 3.3, and 32.5 +/- 8.2% of total energy intake, respectively. Iron, calcium, and vitamin D intake was below the recommended dietary allowance. The prevalence of nutritional deficiencies were as follows: plasma iron 12.6%, ferritin 8.7%, transferrin 14.6%, plasma zinc 2.9%, calcium 3.3%, phosphorus 2.3%, hemoglobin 7.7%, hematocrit 13.6%, MCV 6.8%, and hair zinc 15.7%. In the subsample, 10.6% had a vitamin B12 deficiency, 71.7% showed low concentrations of vitamin D, and 66% had high PTH levels. No folic acid or copper deficiencies were detected. CONCLUSIONS: Despite high daily energy intake and adequate macronutrient distribution, morbidly obese Chilean women seeking bariatric surgery present with deficient intake of some micronutrients and a high prevalence of micronutrient deficiencies. PMID- 26108639 TI - Superstatistical analysis and modelling of heterogeneous random walks. AB - Stochastic time series are ubiquitous in nature. In particular, random walks with time-varying statistical properties are found in many scientific disciplines. Here we present a superstatistical approach to analyse and model such heterogeneous random walks. The time-dependent statistical parameters can be extracted from measured random walk trajectories with a Bayesian method of sequential inference. The distributions and correlations of these parameters reveal subtle features of the random process that are not captured by conventional measures, such as the mean-squared displacement or the step width distribution. We apply our new approach to migration trajectories of tumour cells in two and three dimensions, and demonstrate the superior ability of the superstatistical method to discriminate cell migration strategies in different environments. Finally, we show how the resulting insights can be used to design simple and meaningful models of the underlying random processes. PMID- 26108640 TI - Dynamic multidetector CT and non-contrast-enhanced MR for right adrenal vein imaging: comparison with catheter venography in adrenal venous sampling. AB - OBJECTIVES: To evaluate visualization of the right adrenal vein (RAV) with multidetector CT and non-contrast-enhanced MR imaging in patients with primary aldosteronism. METHODS: A total of 125 patients (67 men) scheduled for adrenal venous sampling (AVS) were included. Dynamic 64-detector-row CT and balanced steady-state free precession-based non-contrast-enhanced 3-T MR imaging were performed. RAV visualization based on a four-point score was documented. Both anatomical location and variation on cross-sectional imaging were evaluated, and the findings were compared with catheter venography as the gold standard. RESULTS: The RAV was visualized in 93.2% by CT and 84.8% by MR imaging (p = 0.02). Positive predictive values of RAV visualization were 100% for CT and 95.2% for MR imaging. Imaging score was significantly higher in CT than MR imaging (p < 0.01). The RAV formed a common trunk with an accessory hepatic vein in 16% of patients. The RAV orifice level on cross-sectional imaging was concordant with catheter venography within the range of 1/3 vertebral height in >70% of subjects. Success rate of AVS was 99.2%. CONCLUSIONS: Dynamic CT is a reliable way to map the RAV prior to AVS. Non-contrast-enhanced MR imaging is an alternative when there is a risk of complication from contrast media or radiation exposure. KEY POINTS: Dynamic CT and non-contrast-enhanced MR imaging detect the right adrenal vein (RAV). Dynamic CT can visualize the RAV more than non-contrast-enhanced MR imaging. Mapping the RAV helps to achieve successful adrenal venous sampling. Sixteen per cent of RAVs share the common trunk with accessory hepatic veins. PMID- 26108641 TI - Clinical significance of three-dimensional measurement of tumour thickness on magnetic resonance imaging in patients with oral tongue squamous cell carcinoma. AB - OBJECTIVES: To identify the clinical significance of primary tumour thickness (TT) and its direction in patients with oral tongue squamous cell carcinoma (OTSCC), we measured TT in all axial/coronal/sagittal views on magnetic resonance imaging (MRI) and evaluated their meaning. METHODS: A total of 53 OTSCC patients were analysed who had undergone preoperative three-dimensional MRI and had been surgically treated. TT measured on axial (mediolateral direction), coronal (superoinferior direction), and sagittal (anteroposterior direction) views was compared to that in pathologic specimens. The association between TT on MRI and other pathologic parameters was also evaluated. RESULTS: TT on MRI in each plane showed relatively high concordance rates with the histological measurements. TT in all three planes was significantly correlated with lymph node (LN) metastasis. Occult LN metastasis was found in 15 of 39 (38.5%) patients, and the cutoff value of TT in axial/coronal/sagittal MRI predicting occult LN metastasis was 6.7 mm, 7.2 mm, and 12.3 mm, respectively. TT on MRI did not show any significant association with recurrence and survival. CONCLUSIONS: TT on MRI in all three planes showed relatively high coincidence with TT on histopathology and presented a potential cut-off value as a predictive indicator for occult LN metastasis. KEY POINTS: Three-dimensional measurement of tumour thickness (TT) is important for oral cancer treatment. Magnetic resonance imaging (MRI) is a useful diagnostic tool for oral cancer. TT on MRI has a high coincidence with TT on histopathology. TT on MRI is a predictive marker for occult lymph node metastasis. PMID- 26108643 TI - Characterizing the Quality Workforce in Private U.S. Child and Family Behavioral Health Agencies. AB - Behavioral health agencies have been encouraged to monitor performance and improve service quality. This paper characterizes the workforce charged with these tasks through a national survey of 238 behavioral health quality professionals. A latent class analysis suggests only 30 % of these workers report skills in both basic research and quality-specific skills. Respondents wanted to learn a variety of research and data analytic skills. The results call into question the quality of data collected in behavioral health agencies and the conclusions agencies are drawing from their data. Professional school and continuing education programs are needed to prepare this workforce. PMID- 26108642 TI - Post-translationally-modified structures in the autophagy machinery: an integrative perspective. AB - Autophagy is a self-cleaning process that occurs at a constitutive basal level, and is upregulated in response to stress. Macroautophagy (hereafter autophagy) is the most robust type of autophagy, where cargo (specific or nonspecific) is engulfed within a double-membrane structure termed an autophagosome. This process needs to be tightly regulated to maintain normal cellular homeostasis and prevent dysfunction; therefore, a fuller knowledge of the mechanisms of autophagy regulation is crucial for understanding the entire pathway. The autophagy-related proteins are the primary components that carry out autophagy. Many of these proteins are conserved from yeast to humans. A number of significant discoveries with regard to protein functional domains, protein-protein interactions or post translational modifications of proteins involved in autophagy have been reported in parallel with, or followed by, solving the NMR or crystal structures of autophagy proteins or their protein domains. In the present review, we summarize structural insights gathered to date on the proteins of the autophagy machinery that are modulated by a post-translational modification, specifically phosphorylation, acetylation, ubiquitination and/or SUMOylation. For each protein, we link the reported results with information on the propensity of the corresponding amino acid sequence toward order/disorder. This integrative approach yields a comprehensive overview for each post-translationally modified protein, and also reveals areas for further investigation. PMID- 26108644 TI - Healthcare costs and outcomes for pediatric inpatients with bronchiolitis: comparison of urban versus rural hospitals. PMID- 26108645 TI - Clinical Findings and Natural History in Ten Unrelated Families with Juvenile and Adult GM1 Gangliosidosis. AB - We describe 12 subjects of ten unrelated families from the region of Campinas and the southern state of Minas Gerais, Brazil, who presented with juvenile (n = 4) and adult (n = 8) GM1 gangliosidosis. Data includes clinical history, physical examination, and ancillary exam findings. Six subjects presented initially with skeletal deformities, while the remaining six had neurological manifestations at onset. Over time, all exhibited a combination of osteoarticular and neurologic degeneration with varying degrees of severity. Corneal clouding, angiokeratomas, and inguinal hernia were seen in one individual each. Other features commonly described in lysosomal storage disorders were not found in this series, such as coarse faces, gingival hypertrophy, visceromegaly, and cherry red spot. All subjects presented with short stature, dysostosis multiplex, dysarthria, and impairment of activities of daily living, 10/12 had extrapyramidal signs, 8/12 had pyramidal signs, 8/12 had oculomotor abnormalities, 4/12 had behavioral alterations, and 2/12 had ataxia. None had seizures or Parkinsonism. All female subjects developed severe hip dysplasia and underwent arthroplasty due to chronic pain. A vertebral bone bar and os odontoideum, not previously described in this condition, were found in one patient each. There was no clear genotype-phenotype correlation regarding enzyme residual activity and clinical findings, since all subjects were compound heterozygous, but the p.T500A was the most frequent allele in eight families and was associated to Morquio B phenotype. Two sets of siblings allowed intrafamilial comparison revealing consistent features among the families. Interfamilial correlation among unrelated families presenting the same mutations was less consistent. PMID- 26108646 TI - PNPO Deficiency and Cirrhosis: Expanding the Clinical Phenotype? AB - We report the case of a 4-year-old boy with pyridoxamine 5-phosphate oxidase deficiency, now the second reported case to develop hepatic cirrhosis. He presented with an encephalopathy in the first 1.5 h of life and received a first dose of PLP at 40 h of life. PNPO gene sequencing identified homozygosity for a novel variant in exon 7, c.637C>T (p.Pro213Ser). Persistent elevations in alanine transferase and aspartate transferase combined with an echogenic liver on ultrasound prompted performance of a liver biopsy which demonstrated hepatic cirrhosis. This is the second reported case of hepatic cirrhosis in PNPO deficiency. The pathogenesis is unclear but may be related to epigenetic activation of purinergic signaling in the hepatic stellate cells. PNPO deficiency may in time prove to be a suitable candidate for consideration of therapeutic orthotropic liver transplantation in select patients. PMID- 26108647 TI - The Spectrum of Krabbe Disease in Greece: Biochemical and Molecular Findings. AB - Krabbe disease is an autosomal recessive neurodegenerative lysosomal storage disease caused by the deficiency of beta-galactocerebrosidase. This deficiency results in the impaired degradation of beta-galactocerebroside, a major myelin lipid, and of galactosylsphingosine. Based on the age of onset of neurological symptoms, an infantile form (90% patients) and late-onset forms (10% patients) of the disease are recognized. Over 130 disease-causing mutations have been identified in the beta-galactocerebrosidase gene. We present the biochemical and molecular findings in 19 cases of Krabbe disease, 17 of them unrelated, diagnosed in Greece over the last 30 years. beta-Galactocerebrosidase activity assayed in leukocyte homogenates using either the tritium-labeled or the fluorescent substrate was diagnostic for all. Increased plasma chitotriosidase activity was found in 11/15 patients.Mutational analysis, carried out in 11 unrelated cases, identified seven different mutations, four previously described (p.I250T, c.1161+6532_polyA+9kbdel, p.K139del, p.D187V) and three novel mutations (p.D610A, c.583-1 G>C, p.W132X), and seven distinct genotypes. The most prevalent mutation was mutation p.I250T, first described in a patient of Greek origin. It accounted for 36.4% (8/22) of the mutant alleles. The second most frequent mutation was c.1161+6532_polyA+9kbdel that accounted for 22.7% (5/22) of the mutant alleles. The observed frequency was lower than that described in Northern European countries and closer to that described in Italian patients. PMID- 26108648 TI - Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation. AB - The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR and direct sequencing of the MT-ND1 genes from blood showed that all seven family members were homoplasmic for the m.4087A>G mutation (NC_012920.1:c.781A>G). The mutation predicts a threonine to alanine substitution at position 261 (p.T261A). The same mutation was found in muscle of all four family members available for muscle biopsy, and biochemical analyses revealed an isolated complex I defect in muscle of all family members (range 22-52% of normal). Muscle morphology showed severe myopathic changes with internal nuclei in multiple fibers of all family members. Monosymptomatic myopathy with recurrent myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA. PMID- 26108649 TI - Physical Activity, Bone Health, and Obesity in Peri-/Pre- and Postmenopausal Women: Results from the EPIC-Potsdam Study. AB - Physical activity (PA) is suggested to increase the peak bone mass and to minimize age-related bone loss, and thereby to reduce the risk of osteoporosis. However, the relation between PA and bone health considering the obesity status is unclear so far. The present study examines the association between PA levels and calcaneal broadband ultrasound attenuation (BUA), particularly under consideration of obesity. Data from a population-based sample of 6776 German women from the EPIC-Potsdam cohort were analyzed. Calibrated PA data were used. Statistical analyses were stratified by menopausal and obesity status. Multiple linear regression was used to model the relationship between PA and BUA levels after adjustment for age, body mass index (BMI), smoking status, education, alcohol and calcium intake, and hormone use. Peri-/premenopausal had higher BUA levels (112.39 +/- 10.05 dB/MHz) compared to postmenopausal women (106.44 +/- 9.95 dB/MHz). In both groups, BUA levels were higher in the fourth compared to the lowest quartile of PA (p for trend < 0.05). In women with BMI < 30, but not BMI >= 30 kg/m(2), PA remained positively associated with BUA levels (p for interaction = 0.03). However, when waist circumference higher than 88 cm or body fat percentage (BF%) measures above the median were used to define obesity, a significant positive relationship was also observed in women with BMI < 30 kg/m(2) but with higher waist circumference or BF%. In conclusion, our results strengthen the hypothesis that PA has a positive influence on BUA levels, though dependent on weight. PMID- 26108650 TI - Pregnancy and Lactation-Associated Osteoporosis: Bone Histomorphometric Analysis and Response to Treatment with Zoledronic Acid. AB - Pregnancy and lactation-associated osteoporosis (PAO) is a rare condition with little known pathophysiology. Most cases are diagnosed in the third trimester of pregnancy or in the first weeks postpartum, particularly in first pregnancies. Vertebral fractures are most commonly observed and characterised by prolonged severe pain, functional limitations and a loss of height. Measurements of bone mineral density and biochemical markers of bone remodelling are the clinical methods most commonly used for the management of these patients. However, a bone biopsy with histomorphometric analysis has been considered to be the gold standard. Few studies have evaluated the histomorphometry in patients with this clinical condition and none of them performed the procedure at the beginning of the clinical assessment. In this study, we report a case of PAO in a 31-year-old postpartum patient who had undergone a twin pregnancy. We describe the clinical, laboratory tests and imaging features. Bone histomorphometry showed a high resorption rate and excellent evolution after 1 year of treatment with intravenous zoledronic acid. Our data suggest that osteoclastogenesis plays a central role in the pathophysiological processes of this disease. PMID- 26108651 TI - Serum interleukin 8 and 12 levels predict severity and mortality in patients with alcoholic hepatitis. AB - BACKGROUND: Alcoholic hepatitis (AH) is a common life-threatening illness particularly when it is severe. Alcoholic liver disease is associated with cytokine imbalance. There is paucity of information about the relationship of interleukin (IL) levels with severity and mortality of patients with AH. Our aim was to correlate serum IL-8 and IL-12 values with disease severity (mild vs. severe) and mortality. METHODS: Fifty patients and 25 healthy subjects were included in the study. Serum IL-8 and -12 levels were analyzed and correlated with disease severity and mortality. Predictive value for 6 months mortality of IL-8, IL-12, Maddreys discriminant function (mDF), age, bilirubin, international normalized ratio, and creatinine score (ABIC) and Glasgow alcoholic hepatitis score (GAHS) was compared by the area under the receiver operating curve (AUROC). RESULTS: Mean (+/-SD) serum IL-8 levels were significantly higher in patients with severe AH as compared to mild AH [539.04 +/- 89.77 vs. 253.66 +/- 56.66 pg/mL (p < 0.001)] and controls [539.04 +/- 89.77 vs. 99.96 +/- 20.94 pg/mL (p < 0.001)]. Similarly, mean (+SD) serum IL-12 levels in severe AH were also significantly higher as compared to mild AH [344.47 +/- 93.04 vs. 101.92 +/- 16.70 pg/mL (p < 0.001)] and controls [344.47 +/- 93.04 vs. 47.84 +/- 11.22 pg/mL (p < 0.001)]. AUROCs of IL-8, IL-12, mDF, ABIC, and GAHS were 0.995, 0.998, 0.975, 0.873, and 0.883 for predicting 6 months mortality. CONCLUSION: Serum IL-8 and -12 levels were markedly elevated in AH with increasing levels as the severity increases. Serum levels of IL-8 and -12 were better predictors of short term mortality as compared to conventional prognostic scores. PMID- 26108652 TI - Serum ferritin levels predict histological severity in patients with nonalcoholic fatty liver disease in India. AB - AIM: The aims of the study were to determine the levels of serum ferritin which predict fibrosis in Indian patients with nonalcoholic fatty liver disease (NAFLD) and to establish correlation between Fibroscan values and serum ferritin levels. METHODS: The clinical, biochemical, radiologic, and histological findings of consecutive adult NAFLD patients accessed at a tertiary care center over a 3-year period were analyzed. Those with concurrent liver diseases were excluded. Fifty five of 250 NAFLD patients with fatty liver on ultrasound and raised enzymes (>40 IU/L) underwent liver biopsy. Patients were stratified into two groups based on their histological stage steatosis (with or without inflammation) but no fibrosis and nonalcoholic steatohepatitis (NASH) with fibrosis/cirrhosis. Serum ferritin levels were measured at the same time as getting liver biopsy. Fibroscan was carried out in each of these patients. These were compared with 50 age- and sex matched controls with normal ultrasound, liver enzymes, and no history of alcohol. Student's t test was used as the test for significance. RESULTS: Fifty five NAFLD patients diagnosed on ultrasound and with raised enzymes underwent biopsy. Steatosis (with or without inflammation, but no fibrosis/ballooning) was seen in 35 patients, fibrosis/ballooning in 14 patients, and cirrhosis in 6 patients. Mean ferritin levels in groups with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) were 39.4 and 72.7 ng/mL, respectively (p < 0.001). The mean ferritin levels in NAFLD and controls were 51.2 and 35.2 ng/mL, respectively (p < 0.05). The area under the curve (AUC) of serum ferritin at value 48.0 ng/mL was 0.779. The coefficient of correlation between Fibroscan and serum ferritin levels was 0.9864 while that with alanine transaminase and aspartate aminotransferase was 0.69. Serum ferritin at the cutoff of 48 ng/mL differentiated significantly patients with fibrosis and higher Fibroscan levels. CONCLUSION: Serum ferritin was low in Indian individuals, and levels even within apparently normal range indicated fibrosis and cirrhosis. A cutoff level of 48.0 IU/mL distinguished fibrosis in NAFLD. Fibroscan correlated well with serum ferritin levels. PMID- 26108653 TI - Success of endoscopic ultrasound-guided ethanol ablation of pancreatic cysts: a meta-analysis and systematic review. AB - BACKGROUND: Endoscopic ultrasound (EUS)-guided ethanol ablation has emerged as an efficacious and safe alternative management option for pancreatic cysts. We undertook a meta-analysis and systematic review to assess the overall safety and efficacy of EUS-guided ethanol ablation of pancreatic cysts. METHOD STUDY SELECTION CRITERIA: EUS-guided ethanol ablation of pancreatic cysts. DATA COLLECTION EXTRACTION: Articles were searched in Medline, Pubmed, and Ovid journals. STATISTICAL METHOD: Fixed and random effects models were used to calculate the pooled proportions. RESULTS: Initial search identified 1,319 reference articles, in which 120 relevant articles were selected and reviewed. Data was extracted from seven studies (n = 152) of EUS-guided ethanol ablation of pancreatic cysts, which met the inclusion criteria. With EUS-guided ethanol ablation, the pooled proportion of patients with complete cyst resolution was 56.20 % (95 % CI = 48.16 to 64.08) and partial cyst resolution was 23.72 % (95 % CI = 17.24 to 30.89). Postprocedural complications after ablation were significant for abdominal pain in 6.51 % (95 % CI = 3.12 to 11.04) and pancreatitis in 3.90 % (95 % CI = 1.39 to 7.60) of the pooled percentage of patients. Publication bias calculated using Harbord-Egger bias indicator gave a value of -1.09 (95 % CI = 10.21 to 8.03, p = 0.77). The Begg-Mazumdar indicator gave a Kendall's tau b value of 0.05 (p >= 0.99). CONCLUSIONS: EUS-guided ethanol ablation may be a safe alternative treatment modality for pancreatic cysts, with acceptable intraprocedural and postprocedural complications. However, due to the limited data available, prospective randomized controlled trials with a long follow up period are required in this area. PMID- 26108654 TI - The smoking population in the USA and EU is softening not hardening. AB - BACKGROUND: It has been argued that as smoking prevalence declines in countries, the smokers that remain include higher proportions of those who are unwilling or unable to quit (a process known as 'hardening'). Smokeless tobacco and e cigarettes have been promoted as a strategy to deal with such smokers. If hardening is occurring, there would be a positive association between smoking prevalence and quitting, with less quitting at lower prevalence. There would also be a neutral or negative association between prevalence and the number of cigarettes smoked. METHODS: We examined US state-level associations using the Tobacco Use Supplement (1992/1993-2010/2011) and Eurobarometer surveys for 31 European countries (2006-2009-2012) using regressions of quit attempts, quit ratios, and number of cigarettes smoked on smoking prevalence over time. RESULTS: For each 1% drop in smoking prevalence, quit attempts increase by 0.55%+/-.07 (p<0.001) in the USA and remain stable in Europe (p=0.53), US quit ratios increase by 1.13%+/-0.06 (p<0.001), and consumption drops by 0.32 cig/day+/-0.02 (p<0.001) in the USA and 0.22 cig/day+/-0.05 (p<0.001) in Europe. These associations remain stable over time (p>0.24), with significantly lower consumption at any given prevalence level as time passed in the USA (-0.15 (cig/day)/year+/-0.06, p<0.05). CONCLUSIONS: Consistent with prior research using different data and methods, these population-level results reject the hypothesis of hardening as smoking prevalence drops, instead supporting softening of the smoking population as prevalence declines. PMID- 26108655 TI - The researcher and the consultant: from testing to probability statements. AB - In the first instalment of this series, Stang and Poole provided an overview of Fisher significance testing (ST), Neyman-Pearson null hypothesis testing (NHT), and their unfortunate and unintended offspring, null hypothesis significance testing. In addition to elucidating the distinction between the first two and the evolution of the third, the authors alluded to alternative models of statistical inference; namely, Bayesian statistics. Bayesian inference has experienced a revival in recent decades, with many researchers advocating for its use as both a complement and an alternative to NHT and ST. This article will continue in the direction of the first instalment, providing practicing researchers with an introduction to Bayesian inference. Our work will draw on the examples and discussion of the previous dialogue. PMID- 26108657 TI - Evidence-based clinical practice parameter guidelines for the treatment of adults with diffuse low grade glioma: introduction and methods. PMID- 26108656 TI - Intraarterial drug delivery for glioblastoma mutiforme: Will the phoenix rise again? AB - Intraarterial (IA) drug delivery is a physiologically appealing strategy as drugs are widely distributed throughout the tumor capillary network and high regional tissue concentrations can be achieved with low total doses. IA treatment of glioblastoma multiforme (GBM) has been attempted since the 1950s but success has been elusive. Although IA treatments have been embraced for the treatment of retinoblastoma and advanced liver cancers, this has not been the case for GBM. The development of IA drug delivery for the treatment of brain cancer over the last several decades reveals a number of critical oversights. For example, very few studies took into consideration the underlying hydrodynamic factors. Therapeutic failures were often blamed on an inability to penetrate the blood brain barrier or on the streaming of drugs. Similarly, there were few methods to investigate the ultra-fast pharmacokinetics of IA drugs. Despite past failures, clinical interest in IA drugs for the treatment of GBM persists. The advent of modern imaging methods along with a better understanding of hydrodynamics factors, better appreciation of the complex morphology of GBM, improved drug selection and formulations, and development of methods to minimize treatment related neurological injury, promise to considerably advance the application of IA drugs for GBM treatment. There are several clinical trials with IA treatments in the National Trial Registry that are actively recruiting patients. This review of IA drug delivery for GBM treatment is therefore timely and is intended to assess how this method of drug delivery could be better applied to future treatments. PMID- 26108658 TI - VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is among the most highly vascularized of solid tumors, contributing to the infiltrative nature of the disease, and conferring poor outcome. Due to the critical dependency of GBM on growth of new endothelial vasculature, we evaluated the preclinical activity of a novel adenoviral gene therapy that targets the endothelium within newly formed blood vessels for apoptosis. VB-111, currently in phase II clinical trials, consists of a non replicating Adenovirus 5 (El deleted) carrying a proapoptotic human Fas-chimera (transgene) under the control of a modified murine promoter (PPE-1-3*) which specifically targets endothelial cells within the tumor vasculature. Here we report that a single intravenous dose of 2.5 * 10(11) or 1 * 10(11) VPs was sufficient to extend survival in nude rats bearing U87MG-luc2 or nude mice bearing U251-luc, respectively. Bioluminescence imaging of nude rats showed that VB-111 effectively inhibited tumor growth within four weeks of treatment. This was confirmed in a select group of animals by MRI. In our mouse model we observed that 3 of 10 nude mice treated with VB-111 completely lost U251 luciferase signal and were considered long term survivors. To assess the antiangiogenic effects of VB-111, we evaluated the tumor-associated microvaculature by CD31, a common marker of neovascularization, and found a significant decrease in the microvessel density by IHC. We further assessed the neovasculature by confocal microscopy and found that VB-111 inhibits vascular density in two separate mouse models bearing U251-RFP xenografts. Collectively, this study supports the clinical development of VB-111 as a treatment for GBM. PMID- 26108660 TI - Potassium channel KCNJ15 is required for histamine-stimulated gastric acid secretion. AB - Gastric acid secretion is mediated by the K(+)-dependent proton pump (H(+),K(+) ATPase), which requires a continuous supply of K(+) at the luminal side of the apical membrane. Several K(+) channels are implicated in gastric acid secretion. However, the identity of the K(+) channel(s) responsible for apical K(+) supply is still elusive. Our previous studies have shown the translocation of KCNJ15 from cytoplasmic vesicles to the apical membrane on stimulation, indicating its involvement in gastric acid secretion. In this study, the stimulation associated trafficking of KCNJ15 was observed in a more native context with a live cell imaging system. KCNJ15 molecules in resting live cells were scattered in cytoplasm but exhibited apical localization after stimulation. Furthermore, knocking down KCNJ15 expression with a short hairpin RNA adenoviral construct abolished histamine-stimulated acid secretion in rabbit primary parietal cells. Moreover, KCNJ15, like H(+),K(+)-ATPase, was detected in all of the parietal cells by immunofluorescence staining, whereas only about half of the parietal cells were positive for KCNQ1 under the same condition. Consistently, the endogenous protein levels of KCNJ15, analyzed by Western blotting, were higher than those of KCNQ1 in the gastric mucosa of human, mouse, and rabbit. These results provide evidence for a major role of KCNJ15 in apical K(+) supply during stimulated acid secretion. PMID- 26108659 TI - Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases. AB - Patients with limited brain metastases are often candidates for stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Among patients who receive SRS, the likelihood and timing of salvage WBRT or SRS remains unclear. We examined rates of salvage WBRT or SRS among 180 patients with 1-4 newly diagnosed brain metastases who received index SRS from 2008-2013. Competing risks multivariable analysis was used to examine factors associated with time to WBRT. Patients had non-small cell lung (53 %), melanoma (23 %), breast (10 %), renal (6 %), or other (8 %) cancers. Median age was 62 years. Patients received index SRS to 1 (60 %), 2 (21 %), 3 (13 %), or 4 (7 %) brain metastases. Median survival after SRS was 9.7 months (range, 0.3-67.6 months). No further brain-directed radiotherapy was delivered after index SRS in 55 % of patients. Twenty-seven percent of patients ever received salvage WBRT, and 30 % ever received salvage SRS; 12 % of patients received both salvage WBRT and salvage SRS. Median time to salvage WBRT or salvage SRS were 5.6 and 6.1 months, respectively. Age <=60 years (adjusted hazard ratio [AHR] = 2.80; 95 % CI 1.05-7.51; P = 0.04) and controlled/absent extracranial disease (AHR = 6.76; 95 % CI 1.60-28.7; P = 0.01) were associated with shorter time to salvage WBRT. Isolated brain progression caused death in only 11 % of decedents. In summary, most patients with 1-4 brain metastases receiving SRS never require salvage WBRT or SRS, and the remainder do not require salvage treatment for a median of 6 months. PMID- 26108661 TI - Endothelial cell tumor growth is Ape/ref-1 dependent. AB - Tumor-forming endothelial cells have highly elevated levels of Nox-4 that release H2O2 into the nucleus, which is generally not compatible with cell survival. We sought to identify compensatory mechanisms that enable tumor-forming endothelial cells to survive and proliferate under these conditions. Ape-1/ref-1 (Apex-1) is a multifunctional protein that promotes DNA binding of redox-sensitive transcription factors, such as AP-1, and repairs oxidative DNA damage. A validated mouse endothelial cell (EOMA) tumor model was used to demonstrate that Nox-4-derived H2O2 causes DNA oxidation that induces Apex-1 expression. Apex-1 functions as a chaperone to keep transcription factors in a reduced state. In EOMA cells Apex-1 enables AP-1 binding to the monocyte chemoattractant protein-1 (mcp-1) promoter and expression of that protein is required for endothelial cell tumor formation. Intraperitoneal injection of the small molecule inhibitor E3330, which specifically targets Apex-1 redox-sensitive functions, resulted in a 50% decrease in tumor volume compared with mice injected with vehicle control (n = 6 per group), indicating that endothelial cell tumor proliferation is dependent on Apex-1 expression. These are the first reported results to establish Nox-4 induction of Apex-1 as a mechanism promoting endothelial cell tumor formation. PMID- 26108662 TI - Physical and functional interactions between a glioma cation channel and integrin beta1 require alpha-actinin. AB - Major plasma membrane components of the tumor cell, ion channels, and integrins play crucial roles in metastasis. Glioma cells express an amiloride-sensitive nonselective cation channel composed of acid-sensing ion channel (ASIC)-1 and epithelial Na(+) channel (ENaC) alpha- and gamma-subunits. Inhibition of this channel is associated with reduced cell migration and proliferation. Using the ASIC-1 subunit as a reporter for the channel complex, we found a physical and functional interaction between this channel and integrin-beta1. Short hairpin RNA knockdown of integrin-beta1 attenuated the amiloride-sensitive current, which was due to loss of surface expression of ASIC-1. In contrast, upregulation of membrane expression of integrin-beta1 increased the surface expression of ASIC-1. The link between the amiloride-sensitive channel and integrin-beta1 was mediated by alpha-actinin. Downregulation of alpha-actinin-1 or -4 attenuated the amiloride-sensitive current. Mutation of the putative binding site for alpha actinin on the COOH terminus of ASIC-1 reduced the membrane localization of ASIC 1 and also resulted in attenuation of the amiloride-sensitive current. Our data suggest a novel interaction between the amiloride-sensitive glioma cation channel and integrin-beta1, mediated by alpha-actinin. This interaction may form a mechanism by which channel activity can regulate glioma cell proliferation and migration. PMID- 26108663 TI - Expression of rat Na-K-ATPase alpha2 enables ion pumping but not ouabain-induced signaling in alpha1-deficient porcine renal epithelial cells. AB - Na-K-ATPase is a fundamental component of ion transport. Four alpha isoforms of the Na-K-ATPase catalytic alpha subunit are expressed in human cells. The ubiquitous Na-K-ATPase alpha1 was recently discovered to also mediate signal transduction through Src kinase. In contrast, alpha2 expression is limited to a few cell types including myocytes, where it is coupled to the Na(+)/Ca(2+) exchanger. To test whether rat Na-K-ATPase alpha2 is capable of cellular signaling like its alpha1 counterpart in a recipient mammalian system, we used an alpha1 knockdown pig renal epithelial cell (PY-17) to create an alpha2-expressing cell line with no detectable level of alpha1 expression. These cells exhibited normal ouabain-sensitive ATPase, but failed to effectively regulate Src. In contrast to alpha1-expressing cells, ouabain did not stimulate Src kinase or downstream effectors such as ERK and Akt in alpha2 cells, although their signaling apparatus was intact as evidenced by EGF-mediated signal transduction. Additionally, alpha2 cells were unable to rescue caveolin-1. Unlike the NaKtide sequence derived from Na-K-ATPase alpha1, which downregulates basal Src activity, the corresponding alpha2 NaKtide was unable to inhibit Src in vitro. Finally, coimmunoprecipitation of cellular Src was diminished in alpha2 cells. These findings indicate that Na-K-ATPase alpha2 does not regulate Src and, therefore, may not serve the same role in signal transduction as alpha1. This further implies that the signaling mechanism of Na-K-ATPase is isoform specific, thereby supporting a model where alpha1 and alpha2 isoforms play distinct roles in mediating contraction and signaling in myocytes. PMID- 26108664 TI - Amelioration of nonalcoholic fatty liver disease by hepatic stimulator substance via preservation of carnitine palmitoyl transferase-1 activity. AB - Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease and so far is supposed to be related with mitochondrial impairment. Hepatic stimulator substance (HSS) has been defined as a liver-protective factor promoting hepatocyte DNA synthesis and hepatic proliferation after liver intoxication. We previously reported that HSS ameliorated hepatocyte death, probably because of its preservation of mitochondria. This study aims to explore whether HSS could protect carnitine palmitoyl transferase-1 (CPT-1), an essential enzyme responsible for beta-oxidation of free fatty acids in mitochondria, from lipotoxicity, thus alleviating hepatic lipid deposition. To test this, the HSS gene was delivered into C57BL/6J mice and efficiently expressed in the liver. NASH mice were prepared with high-fat diet or methionine-choline-deficient diet. The results showed that hepatic inflammation and liver functions were alleviated in the HSS-transfected mice; meanwhile, the activity of CPT-1 was obviously protected. Moreover, oleic acid (OA) treatment resulted in remarkable lipid accumulation in HepG2 cells; this deposition was improved by HSS transfection. Simultaneously, the CPT-1 activity, which was impaired by OA treatment, was profoundly rescued in the HSS-expressing cells. CPT-1 activity was more severely impaired if the OA treatment was combined with S15176, a CPT-1 inhibitor. However, this impairment was effectively reduced by the HSS transfection, and the effect was enhanced by C75, a CPT-1 activator. Interestingly, if the cells were transfected with HSS-siRNA, the preservation of CPT-1 provided by HSS was again diminished. In conclusion, HSS reduces lipotoxicity to mitochondria most likely via preservation of CPT-1. PMID- 26108666 TI - TNAP: a new player in cardiac fibrosis? Focus on "Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts". PMID- 26108665 TI - BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins. AB - The potent trypanolytic properties of human apolipoprotein L1 (APOL1) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOL1 haplotypes present uniquely in individuals of West African ancestry each encode APOL1 variants resistant to serum resistance-associated protein, and each confers substantial resistance to human African sleeping sickness. In contrast to the dominantly inherited anti-trypanosomal activity of APOL1, recessive inheritance of these two trypanoprotective APOL1 alleles predisposes to kidney disease. Proposed mechanisms of APOL1 toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOL1 in Xenopus laevis oocytes. APOL1 expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOL1-associated oocyte toxicity in the order MCL1 ~ BCLW > BCLXL ~ BCL2A1 ? BCL2. Deletion of nine nominal core BH3 domain residues abolished APOL1-associated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOL1 BH3 domain was similarly dispensable for the ability of APOL1 to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na(+) by K(+) also reduced APOL1-associated oocyte toxicity, allowing demonstration of APOL1-associated increases in Ca(2+) and Cl(-) fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOL1 toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins. PMID- 26108667 TI - Seeing is believing: NO therapy for glaucoma? Focus on "Role of nitric oxide in murine conventional outflow physiology". PMID- 26108668 TI - Biomechanical strain induces elastin and collagen production in human pluripotent stem cell-derived vascular smooth muscle cells. AB - Blood vessels are subjected to numerous biomechanical forces that work harmoniously but, when unbalanced because of vascular smooth muscle cell (vSMC) dysfunction, can trigger a wide range of ailments such as cerebrovascular, peripheral artery, and coronary artery diseases. Human pluripotent stem cells (hPSCs) serve as useful therapeutic tools that may help provide insight on the effect that such biomechanical stimuli have on vSMC function and differentiation. In this study, we aimed to examine the effect of biomechanical strain on vSMCs derived from hPSCs. The effects of two types of tensile strain on hPSC-vSMC derivatives at different stages of differentiation were examined. The derivatives included smooth muscle-like cells (SMLCs), mature SMLCs, and contractile vSMCs. All vSMC derivatives aligned perpendicularly to the direction of cyclic uniaxial strain. Serum deprivation and short-term uniaxial strain had a synergistic effect in enhancing collagen type I, fibronectin, and elastin gene expression. Furthermore, long-term uniaxial strain deterred collagen type III gene expression, whereas long-term circumferential strain upregulated both collagen type III and elastin gene expression. Finally, long-term uniaxial strain downregulated extracellular matrix (ECM) expression in more mature vSMC derivatives while upregulating elastin in less mature vSMC derivatives. Overall, our findings suggest that in vitro application of both cyclic uniaxial and circumferential tensile strain on hPSC-vSMC derivatives induces cell alignment and affects ECM gene expression. Therefore, mechanical stimulation of hPSC-vSMC derivatives using tensile strain may be important in modulating the phenotype and thus the function of vSMCs in tissue-engineered vessels. PMID- 26108670 TI - Comparative efficacy trials with no placebo group cannot determine efficacy. PMID- 26108669 TI - Structural basis for Mob1-dependent activation of the core Mst-Lats kinase cascade in Hippo signaling. AB - The Mst-Lats kinase cascade is central to the Hippo tumor-suppressive pathway that controls organ size and tissue homeostasis. The adaptor protein Mob1 promotes Lats activation by Mst, but the mechanism remains unknown. Here, we show that human Mob1 binds to autophosphorylated docking motifs in active Mst2. This binding enables Mob1 phosphorylation by Mst2. Phosphorylated Mob1 undergoes conformational activation and binds to Lats1. We determine the crystal structures of phospho-Mst2-Mob1 and phospho-Mob1-Lats1 complexes, revealing the structural basis of both phosphorylation-dependent binding events. Further biochemical and functional analyses demonstrate that Mob1 mediates Lats1 activation through dynamic scaffolding and allosteric mechanisms. Thus, Mob1 acts as a phosphorylation-regulated coupler of kinase activation by virtue of its ability to engage multiple ligands. We propose that stepwise, phosphorylation-triggered docking interactions of nonkinase elements enhance the specificity and robustness of kinase signaling cascades. PMID- 26108671 TI - Hippocampal hemispheric and long-axis differentiation of stimulus content during episodic memory encoding and retrieval: An activation likelihood estimation meta analysis. AB - While there is ample evidence that the hippocampus is functionally heterogeneous along its longitudinal axis, there is still no consensus regarding its exact organization. Whereas spatial memory tasks frequently engage the posterior hippocampus, the regions engaged during episodic memory are more varying and may depend on the specific nature of the stimuli. Here, we investigate the effect of stimulus content on the location of hippocampal recruitment during episodic memory encoding and retrieval of pictorial and verbal material with a meta analysis approach, using activation likelihood estimation and restricting the analysis to the hippocampus. Verbal material was associated with left-lateralized anterior activation, compared to pictorial material that recruited a more posterior aspect of the hippocampus, primarily within the right hemisphere. This effect held for encoding of both single items and item-item associations but was less clear during retrieval. The findings lend further support to a functional subdivision of the hippocampus along its longitudinal axis and indicate that the content of episodic memories is one factor that determines the location of hippocampal recruitment. PMID- 26108672 TI - Quantitative proteomic analysis shows differentially expressed HSPB1 in glioblastoma as a discriminating short from long survival factor and NOVA1 as a differentiation factor between low-grade astrocytoma and oligodendroglioma. AB - BACKGROUND: Gliomas account for more than 60 % of all primary central nervous system neoplasms. Low-grade gliomas display a tendency to progress to more malignant phenotypes and the most frequent and malignant gliomas are glioblastomas (GBM). Another type of glioma, oligodendroglioma originates from oligodendrocytes and glial precursor cells and represents 2-5 % of gliomas. The discrimination between these two types of glioma is actually controversial, thus, a molecular distinction is necessary for better diagnosis. METHODS: iTRAQ-based quantitative proteomic analysis was performed on non-neoplastic brain tissue, on astrocytoma grade II, glioblastoma with short and long survival and oligodendrogliomas. RESULTS: We found that expression of nucleophosmin (NPM1), glucose regulated protein 78 kDa (GRP78), nucleolin (NCL) and heat shock protein 90 kDa (HSP90B1) were increased, Raf kinase inhibitor protein (RKIP/PEBP1) was decreased in glioblastoma and they were associated with a network related to tumor progression. Expression level of heat shock protein 27 (HSPB1/HSP27) discriminated glioblastoma presenting short (6 +/- 4 months, n = 4) and long survival (43 +/- 15 months, n = 4) (p = 0.00045). Expression level of RNA binding protein nova 1 (NOVA1) differentiated low-grade oligodendroglioma and astrocytoma grade II (p = 0.0082). Validation were done by Western blot, qRT-PCR and immunohistochemistry in a larger casuistry. CONCLUSION: Taken together, our quantitative proteomic analysis detected the molecular triad, NPM1, GRP78 and RKIP participating together with NCL and HSP27/HSPB1 in a network related to tumor progression. Additionally, two new important targets were uncovered: NOVA1 useful for diagnostic refinement differentiating astrocytoma from oligodendroglioma, and HSPB1/HSP27, as a predictive factor of poor prognosis for GBM. PMID- 26108673 TI - One-year survival and resource use after critical illness: impact of organ failure and residual organ dysfunction in a cohort study in Brazil. AB - INTRODUCTION: In this study, we evaluated the impacts of organ failure and residual dysfunction on 1-year survival and health care resource use using Intensive Care Unit (ICU) discharge as the starting point. METHODS: We conducted a historical cohort study, including all adult patients discharged alive after at least 72 h of ICU stay in a tertiary teaching hospital in Brazil. The starting point of follow-up was ICU discharge. Organ failure was defined as a value of 3 or 4 in its corresponding component of the Sequential Organ Failure Assessment score, and residual organ dysfunction was defined as a score of 1 or 2. We fit a multivariate flexible Cox model to predict 1-year survival. RESULTS: We analyzed 690 patients. Mortality at 1 year after discharge was 27%. Using multivariate modeling, age, chronic obstructive pulmonary disease, cancer, organ dysfunctions and albumin at ICU discharge were the main determinants of 1-year survival. Age and organ failure were non-linearly associated with survival, and the impact of organ failure diminished over time. We conducted a subset analysis with 561 patients (81%) discharged without organ failure within the previous 24 h of discharge, and the number of residual organs in dysfunction remained strongly associated with reduced 1-year survival. The use of health care resources among hospital survivors was substantial within 1 year: 40% of the patients were rehospitalized, 52% visited the emergency department, 90% were seen at the outpatient clinic, 14% attended rehabilitation outpatient services, 11% were followed by the psychological or psychiatric service and 7% used the day hospital facility. Use of health care resources up to 30 days after hospital discharge was associated with the number of organs in dysfunction at ICU discharge. CONCLUSIONS: Organ failure was an important determinant of 1-year outcome of critically ill survivors. Nevertheless, the impact of organ failure tended to diminish over time. Resource use after critical illness was elevated among ICU survivors, and a targeted action is needed to deliver appropriate care and to reduce the late critical illness burden. PMID- 26108674 TI - Factors underlying the perception of effort during constant heart rate running above and below the critical heart rate. AB - PURPOSE: This study examined: (1) the sustainability of the critical heart rate (CHR) minus 5 b min(-1) (CHR - 5) and CHR plus 5 b min(-1) (CHR + 5); (2) the ratings of perceived exertion (RPE), velocity, [Formula: see text], minute ventilation ([Formula: see text]), breathing frequency (f b ), and electromyographic amplitude (EMG AMP) and EMG mean power frequency (MPF) responses during treadmill running at CHR - 5 and CHR + 5 to determine what factors underlie the perception of effort when heart rate (HR) is held constant; and (3) the relationships among RPE, [Formula: see text], and HR, to determine which variable(s) reflect exhaustion during exercise performed at a constant HR. METHODS: The CHR was determined in eight runners (mean +/- SD; age = 24 +/- 3 years) from a series of four exhaustive, constant velocity runs. The RPE, velocity, [Formula: see text], [Formula: see text], f b , EMG AMP, and EMG MPF responses were recorded during runs at the CHR - 5 and CHR + 5. RESULTS: At CHR - 5, RPE, f b, and EMG MPF increased, while velocity, [Formula: see text], [Formula: see text], and EMG AMP decreased. At CHR + 5, RPE and f b increased, velocity, [Formula: see text], [Formula: see text], and EMG AMP decreased, and EMG MPF remained constant. CONCLUSIONS: The close association between f b and RPE throughout the run at CHR - 5 and during the last 50 % of the run at CHR + 5 indicated that muscle afferents may have provided feedback from metabolic and mechanical stimuli that contributed to the perceptual responses. In addition, only RPE consistently indicated exhaustion and the current findings supported its use to monitor exercise performed at a constant HR. PMID- 26108675 TI - Confusion surrounds physical activity prescription for pregnant women. PMID- 26108676 TI - Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study. AB - BACKGROUND: Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations. METHODS: Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations. RESULTS: Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-beta-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3beta (DNMT3B), methionine adenosyltransferase I alpha (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS). CONCLUSIONS: Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk. PMID- 26108677 TI - Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses. AB - Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ~60%. However, supplementing gAd fully rescued insulin's microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. PMID- 26108678 TI - Alternative Routes to Induce Naive Pluripotency in Human Embryonic Stem Cells. AB - Human embryonic stem cells (hESCs) closely resemble mouse epiblast stem cells exhibiting primed pluripotency unlike mouse ESCs (mESCs), which acquire a naive pluripotent state. Efforts have been made to trigger naive pluripotency in hESCs for subsequent unbiased lineage-specific differentiation, a common conundrum faced by primed pluripotent hESCs due to heterogeneity in gene expression existing within and between hESC lines. This required either ectopic expression of naive genes such as NANOG and KLF2 or inclusion of multiple pluripotency associated factors. We report here a novel combination of small molecules and growth factors in culture medium (2i/LIF/basic fibroblast growth factor + Ascorbic Acid + Forskolin) facilitating rapid induction of transgene-free naive pluripotency in hESCs, as well as in mESCs, which has not been shown earlier. The converted naive hESCs survived long-term single-cell passaging, maintained a normal karyotype, upregulated naive pluripotency genes, and exhibited dependence on signaling pathways similar to naive mESCs. Moreover, they undergo global DNA demethylation and show a distinctive long noncoding RNA profile. We propose that in our medium, the FGF signaling pathway via PI3K/AKT/mTORC induced the conversion of primed hESCs toward naive pluripotency. Collectively, we demonstrate an alternate route to capture naive pluripotency in hESCs that is fast, reproducible, supports naive mESC derivation, and allows efficient differentiation. PMID- 26108679 TI - Health-related quality of life for medical rescuers one month after Ludian earthquake. AB - BACKGROUND: An earthquake struck Ludian in Yunnan province of China on August 3, 2014, resulting in 3143 injuries, 617 deaths, and 112 missing persons. Our study aimed at estimating the quality of life and associated determinants among medical rescuers after Ludian earthquake. METHODS: A cross-sectional survey was performed among personnel from three hospitals that assumed rescue tasks in Ludian earthquake. Descriptive statistics, t-tests, ANOVA and stepwise linear regression analysis were used for data analysis. RESULTS: The mean scores on the physical component summary (PCS) and mental component summary (MCS) were 49.86 (SD = 6.01) and 35.85(SD = 6.90), respectively. Lower PCS in the aftermath of an earthquake was associated with non-military medical rescuers, elderly age, and being trapped/in danger while lower MSC in the aftermath of an earthquake was associated with non-military medical rescuers, young age, being female, being trapped/in danger and low education degree. CONCLUSIONS: In conclusion, our study demonstrates that medical rescuers are at risk for a lower HRQoL after exposure to Ludian earthquake. The results of this study help expand our knowledge of health-related quality of life among medical rescuers after the Ludian earthquake. PMID- 26108680 TI - Quantitative Mass Spectrometry Reveals Partial Translational Regulation for Dosage Compensation in Chicken. AB - There is increasing evidence that dosage compensation is not a ubiquitous feature following sex chromosome evolution, especially not in organisms where females are the heterogametic sex, like in birds. Even when it occurs, compensation can be incomplete and limited to dosage-sensitive genes. However, previous work has mainly studied transcriptional regulation of sex-linked genes, which may not reflect expression at the protein level. Here, we used liquid chromatography tandem mass spectrometry to detect and quantify expressed levels of more than 2,400 proteins in ten different tissues of male and female chicken embryos. For comparison, transcriptome sequencing was performed in the same individuals, five of each sex. The proteomic analysis revealed that dosage compensation was incomplete, with a mean male-to-female (M:F) expression ratio of Z-linked genes of 1.32 across tissues, similar to that at the RNA level (1.29). The mean Z chromosome-to-autosome expression ratio was close to 1 in males and lower than 1 in females, consistent with partly reduced Z chromosome expression in females. Although our results exclude a general mechanism for chromosome-wide dosage compensation at translation, 30% of all proteins encoded from Z-linked genes showed a significant change in the M:F ratio compared with the corresponding ratio at the RNA level. This resulted in a pattern where some genes showed balanced expression between sexes and some close to 2-fold higher expression in males. This suggests that proteomic analyses will be necessary to reveal a more complete picture of gene regulation and sex chromosome evolution. PMID- 26108681 TI - Downregulation of RND3/RhoE in glioblastoma patients promotes tumorigenesis through augmentation of notch transcriptional complex activity. AB - Activation of Notch signaling contributes to glioblastoma multiform (GBM) tumorigenesis. However, the molecular mechanism that promotes the Notch signaling augmentation during GBM genesis remains largely unknown. Identification of new factors that regulate Notch signaling is critical for tumor treatment. The expression levels of RND3 and its clinical implication were analyzed in GBM patients. Identification of RND3 as a novel factor in GBM genesis was demonstrated in vitro by cell experiments and in vivo by a GBM xenograft model. We found that RND3 expression was significantly decreased in human glioblastoma. The levels of RND3 expression were inversely correlated with Notch activity, tumor size, and tumor cell proliferation, and positively correlated with patient survival time. We demonstrated that RND3 functioned as an endogenous repressor of the Notch transcriptional complex. RND3 physically interacted with NICD, CSL, and MAML1, the Notch transcriptional complex factors, promoted NICD ubiquitination, and facilitated the degradation of these cofactor proteins. We further revealed that RND3 facilitated the binding of NICD to FBW7, a ubiquitin ligase, and consequently enhanced NICD protein degradation. Therefore, Notch transcriptional activity was inhibited. Forced expression of RND3 repressed Notch signaling, which led to the inhibition of glioblastoma cell proliferation in vitro and tumor growth in the xenograft mice in vivo. Downregulation of RND3, however, enhanced Notch signaling activity, and subsequently promoted glioma cell proliferation. Inhibition of Notch activity abolished RND3 deficiency-mediated GBM cell proliferation. We conclude that downregulation of RND3 is responsible for the enhancement of Notch activity that promotes glioblastoma genesis. PMID- 26108682 TI - Technical tip: high-resolution isolation of nanoparticle-protein corona complexes from physiological fluids. AB - Nanoparticles (NPs) in contact with biological fluids are generally coated with environmental proteins, forming a stronger layer of proteins around the NP surface called the hard corona. Protein corona complexes provide the biological identity of the NPs and their isolation and characterization are essential to understand their in vitro and in vivo behaviour. Here we present a one-step methodology to recover NPs from complex biological media in a stable non aggregated form without affecting the structure or composition of the corona. This method allows NPs to be separated from complex fluids containing biological particulates and in a form suitable for use in further experiments. The study has been performed systematically comparing the new proposed methodology to standard approaches for a wide panel of NPs. NPs were first incubated in the biological fluid and successively recovered by sucrose gradient ultracentrifugation in order to separate the NPs and their protein corona from the loosely bound proteins. The isolated NP-protein complexes were characterized by size and protein composition through Dynamic Light Scattering, Nanoparticle Tracking Analysis, SDS-PAGE and LC MS. The protocol described is versatile and can be applied to diverse nanomaterials and complex fluids. It is shown to have higher resolution in separating the multiple protein corona complexes from a biological environment with a much lower impact on their in situ structure compared to conventional centrifugal approaches. PMID- 26108683 TI - Improving the NHS demands more than just extra money. PMID- 26108684 TI - Calebin-A inhibits adipogenesis and hepatic steatosis in high-fat diet-induced obesity via activation of AMPK signaling. AB - SCOPE: Diet-induced obesity and associated nonalcoholic fatty liver disease have increased and become a major health problem worldwide. This study was conducted to investigate the chemopreventive effects of dietary Calebin-A, a curcuminoid, on differentiation of 3T3-L1 adipocytes and high-fat diet (HFD) induced obesity and hepatic steatosis. Potential mechanisms contributing to these effects were also elucidated. METHODS AND RESULTS: Calebin-A effectively and dose dependently suppressed accumulation of lipid droplets in adipocytes through the suppression of adipogenic specific factor peroxisome proliferator-activated receptor (PPAR) gamma and fatty acid synthase and activated acetyl-CoA carboxylase. Dietary Calebin-A effectively decreased weight gain and relative perigonadal, retroperitoneal, and mesenteric fat weight in HFD-fed mice. Furthermore, Calebin A markedly reduced hepatic steatosis and the serum levels of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, total cholesterol, and triacylglycerol. These effects were associated with the downregulation of PPARgamma, sterol regulatory element-binding protein-1, and particularly the activation of AMP-activated protein kinase alpha signaling found in both adipocytes and liver tissues. CONCLUSION: Taken together, these results demonstrated for the first time that Calebin-A suppressed adipocyte differentiation, prevented HFD-induced obesity, and improved hepatic steatosis, suggesting a novel application for the prevention and treatment of obesity and associated nonalcoholic fatty liver disease. PMID- 26108685 TI - An electrochemical biosensor based on cobalt nanoparticles synthesized in iron storage protein molecules to determine ascorbic acid. AB - The electrochemical detection of ascorbic acid (AA) was investigated using a cobalt(III)-ferritin immobilized on a self-assembled monolayer modified gold electrode in phosphate buffer solution (pH 7.5). The modified electrode showed excellent electrochemical activity for oxidation of AA. The response to AA on the modified electrode was examined using cyclic and differential pulse voltammetry techniques. The resulting biosensor showed a linear response to AA in a concentration range from 6.25*10-6 to 2.31*10-5 M with sensitivity of 86,437 MUAM 1 and detection limit of 4.65 * 10-6 M based on a signal-to-noise ratio of 3. Electrochemical parameters including the charge transfer coefficient (alpha) and the apparent heterogeneous electron transfer rate constant (ks ) for AA were found to be 0.52 and 1.054 Sec-1 , respectively. It has been shown that, using this modified electrode, AA can be determined with high sensitivity, low detection limit, and high selectivity. PMID- 26108686 TI - Longitudinal trends in all healthcare-associated infections through comprehensive hospital-wide surveillance and infection control measures over the past 12 years: substantial burden of healthcare-associated infections outside of intensive care units and "other" types of infection. AB - OBJECTIVE: Targeted surveillance has focused on device-associated infections and surgical site infections (SSIs) and is often limited to healthcare-associated infections (HAIs) in high-risk areas. Longitudinal trends in all HAIs, including other types of HAIs, and HAIs outside of intensive care units (ICUs) remain unclear. We examined the incidences of all HAIs using comprehensive hospital-wide surveillance over a 12-year period (2001-2012). METHODS: This retrospective observational study was conducted at the University of North Carolina (UNC) Hospitals, a tertiary care academic facility. All HAIs, including 5 major infections with 14 specific infection sites as defined using CDC criteria, were ascertained through comprehensive hospital-wide surveillance. Generalized linear models were used to examine the incidence rate difference by infection type over time. RESULTS: A total of 16,579 HAIs included 6,397 cases in ICUs and 10,182 cases outside ICUs. The incidence of overall HAIs decreased significantly hospital-wide (-3.4 infections per 1,000 patient days), in ICUs (-8.4 infections per 1,000 patient days), and in non-ICU settings (-1.9 infections per 1,000 patient days). The incidences of bloodstream infection, urinary tract infection, and pneumonia in hospital-wide settings decreased significantly, but the incidences of SSI and lower respiratory tract infection remained unchanged. The incidence of Clostridium difficile infection (CDI) increased remarkably. The outcomes were estimated to include 700 overall HAIs prevented, 40 lives saved, and cost savings in excess of $10 million. CONCLUSIONS: We demonstrated success in reducing overall HAIs over a 12-year period. Our data underscore the necessity for surveillance and infection prevention interventions outside of the ICUs, for non-device-associated HAIs, and for CDI. PMID- 26108687 TI - Endoscopic endonasal surgery for benign fibro-osseous lesions of the pediatric skull base. AB - OBJECTIVES/HYPOTHESIS: To describe the presentation, treatment, and outcomes of benign fibro-osseous tumors involving the skull base in a pediatric population. METHODS: Retrospective chart review from January 2002 to September 2013 of pediatric patients (ages 0-18 years) who underwent endoscopic endonasal surgery (EES) for benign fibro-osseous tumors involving the skull base. RESULTS: Fourteen patients were identified with an age range of 2.7 to 17.9 years (mean, 12.5 years). Six juvenile ossifying fibromas, five benign fibro-osseous lesions, two osteomas, and one fibrous dysplasia were treated. Ocular symptoms and nasal obstruction were the most common presenting symptoms in nine (64%) and six (43%) of patients, respectively; five (36%) presented with proptosis and four (29%) with diplopia. Two (14%) patients had cranial nerve VI palsy. Transsellar and transclival approaches were used in five (36%) of patients. Orbital and optic nerve decompressions were the most common components of the approaches performed in nine (64%) of the surgeries. Gross total resection (GTR) was achieved with single-stage surgery in 10 (71%) patients; two additional patients underwent staged GTR. Two intraoperative cerebrospinal fluid (CSF) leaks occurred and were repaired endoscopically. There were no postoperative CSF leaks or infectious complications. Two patients had transient diplopia, and two had transient diabetes insipidus, all of which resolved. The mean follow-up was 13.8 months. Two patients had a recurrence, and both required additional EES achieving GTR. CONCLUSIONS: EES for benign fibro-osseous tumors of the skull base is a safe and effective treatment for excision of these lesions in the pediatric population. LEVEL OF EVIDENCE: 4. PMID- 26108688 TI - Production of farnesene and santalene by Saccharomyces cerevisiae using fed-batch cultivations with RQ-controlled feed. AB - Terpenes have various applications as fragrances, cosmetics and fuels. One of the most prominent examples is the sesquiterpene farnesene, which can be used as diesel substitute in its hydrogenated form farnesane. Recent metabolic engineering efforts have enabled efficient production of several terpenes in Saccharomyces cerevisiae and Escherichia coli. Plant terpene synthases take on an essential function for sesquiterpene production as they catalyze the specific conversion of the universal precursor farnesyl diphosphate (FPP) to the sesquiterpene of interest and thereby impose limitations on the overall productivity. Using farnesene as a case study, we chose three terpene synthases with distinct plant origins and compared their applicability for farnesene production in the yeast S. cerevisiae. Differences regarding the efficiency of these enzymes were observed in shake flask cultivation with maximal final titers of 4 mg/L using alpha-farnesene synthase from Malus domestica. By employing two existing platform strains optimized for sesquiterpene production, final titers could be raised up 170 mg/L in fed-batch fermentations with RQ-controlled exponential feeding. Based on these experiments, the difference between the selected synthases was not significant. Lastly, the same fermentation setup was used to compare these results to production of the fragrance sesquiterpene santalene, and almost equivalent titers were obtained with 163 mg/L, using the highest producing strain expressing a santalene synthase from Clausena lansium. However, a reduction of the product yield on biomass by 50% could indicate a higher catalytic efficiency of the farnesene synthase. PMID- 26108690 TI - MicroRNA-551b is highly expressed in hematopoietic stem cells and a biomarker for relapse and poor prognosis in acute myeloid leukemia. PMID- 26108689 TI - Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. AB - We recently demonstrated that acute myeloid leukemia (AML) cell lines and patient derived blasts release exosomes that carry RNA and protein; following an in vitro transfer, AML exosomes produce proangiogenic changes in bystander cells. We reasoned that paracrine exosome trafficking may have a broader role in shaping the leukemic niche. In a series of in vitro studies and murine xenografts, we demonstrate that AML exosomes downregulate critical retention factors (Scf, Cxcl12) in stromal cells, leading to hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow. Exosome trafficking also regulates HSPC directly, and we demonstrate declining clonogenicity, loss of CXCR4 and c-Kit expression, and the consistent repression of several hematopoietic transcription factors, including c-Myb, Cebp-beta and Hoxa-9. Additional experiments using a model of extramedullary AML or direct intrafemoral injection of purified exosomes reveal that the erosion of HSPC function can occur independent of direct cell cell contact with leukemia cells. Finally, using a novel multiplex proteomics technique, we identified candidate pathways involved in the direct exosome mediated modulation of HSPC function. In aggregate, this work suggests that AML exosomes participate in the suppression of residual hematopoietic function that precedes widespread leukemic invasion of the bone marrow directly and indirectly via stromal components. PMID- 26108691 TI - Characterization of the genome-wide TLX1 binding profile in T-cell acute lymphoblastic leukemia. AB - The TLX1 transcription factor is critically involved in the multi-step pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) and often cooperates with NOTCH1 activation during malignant T-cell transformation. However, the exact molecular mechanism by which these T-cell specific oncogenes cooperate during transformation remains to be established. Here, we used chromatin immunoprecipitation followed by sequencing to establish the genome-wide binding pattern of TLX1 in human T-ALL. This integrative genomics approach showed that ectopic TLX1 expression drives repression of T cell-specific enhancers and mediates an unexpected transcriptional antagonism with NOTCH1 at critical target genes, including IL7R and NOTCH3. These phenomena coordinately trigger a TLX1 driven pre-leukemic phenotype in human thymic precursor cells, reminiscent of the thymus regression observed in murine TLX1 tumor models, and create a strong genetic pressure for acquiring activating NOTCH1 mutations as a prerequisite for full leukemic transformation. In conclusion, our results uncover a functional antagonism between cooperative oncogenes during the earliest phases of tumor development and provide novel insights in the multi-step pathogenesis of TLX1 driven human leukemia. PMID- 26108693 TI - FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. AB - Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of beta-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated beta-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of beta catenin. At the molecular level, FoxO1 interacts with beta-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated beta catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues. PMID- 26108692 TI - Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent. AB - We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3beta (GSK-3beta) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3beta inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner. PMID- 26108694 TI - FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors. AB - Activating mutations in FLT3 occur in ~30% of adult acute myeloid leukemia, primarily consisting of internal tandem duplication (ITD) mutations (~25%) and point mutations in the tyrosine kinase domain (~5%), commonly at the activation loop residue D835. Secondary kinase domain mutations in FLT3-ITD, particularly at the D835 residue are frequently associated with acquired clinical resistance to effective FLT3 tyrosine kinase inhibitors (TKIs). Molecular docking studies have suggested that D835 mutations primarily confer resistance by stabilizing an active Asp-Phe-Gly in ('DFG-in') kinase conformation unfavorable to the binding of type II FLT3 TKIs, which target a 'DFG-out' inactive conformation. We profiled the activity of active type II FLT3 TKIs against D835 kinase domain mutants that have been clinically detected to date. We found that type II inhibitors (quizartinib, sorafenib, ponatinib and PLX3397) retain activity against specific D835 substitutions. Modeling studies suggest that bulky hydrophobic substitutions (D835Y/V/I/F) at this residue are particularly resistant, whereas mutations that preserve interactions between D835 and S838 are relatively sensitive (D835E/N). All mutants retain sensitivity to the type I inhibitor crenolanib. These results suggest that patients with relatively sensitive D835 mutations should be included in clinical trials of type II FLT3 TKIs. PMID- 26108697 TI - [In Process Citation]. PMID- 26108695 TI - Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib. AB - Although the therapeutic benefit of proteasome inhibition in multiple myeloma remains unchallenged, drug resistance inevitably emerges through mechanisms that remain elusive. Bortezomib provokes unwanted protein accumulation and the endoplasmic reticulum stress to activate the unfolded protein response (UPR) and autophagy as compensatory mechanisms that restore protein homeostasis. High throughput screens to detect pharmacologics that modulated autophagy to enhance the anti-myeloma effect of bortezomib revealed metformin, a widely used antidiabetic agent with proven efficacy and limited adverse effects. Metformin co treatment with bortezomib suppressed induction of the critical UPR effector glucose-regulated protein 78 (GRP78) to impair autophagosome formation and enhance apoptosis. Gene expression profiling of newly diagnosed myeloma patient tumors further correlated the hyperexpression of GRP78-encoding HSPA5 with reduced clinical response to bortezomib. The effect of bortezomib was enhanced with metformin co-treatment using myeloma patient tumor cells and the chemoresistant, stem cell-like side population that may contribute to disease recurrence. The relevance of the findings was confirmed in vivo as shown by metformin co-treatment with bortezomib that delayed the growth of myeloma xenotransplants. Taken together, our results suggest that metformin suppresses GRP78, a key driver of bortezomib-induced autophagy, and support the pharmacologic repositioning of metformin to enhance the anti-myeloma benefit of bortezomib. PMID- 26108696 TI - Impact of Substituents in Tumor Uptake and Fluorescence Imaging Ability of Near Infrared Cyanine-like Dyes. AB - This report presents a simple strategy to introduce various functionalities in a cyanine dye (bis-indole-N-butylsulfonate-polymethine bearing a fused cyclic chloro-cyclohexene ring structure), and assess the impact of these substitutions in tumor uptake, retention and imaging. The results obtained from the structural activity relationship (SAR) study demonstrate that certain structural features introduced in the cyanine dye moiety make a remarkable difference in tumor avidity. Among the compounds investigated, the symmetrical CDs containing an amino-phenyl thioether group attached to a cyclohexene ring system and the two N butyl linkers with terminal sulfonate groups in benzoindole moieties exhibited excellent tumor imaging ability in BALB/c mice bearing Colon26 tumors. Compared to indocyanine green (ICG), approved by FDA as a blood pooling agent, which has also been investigated for the use in tumor imaging, the modified CD selected on the basis of SAR study produced enhanced uptake and longer retention in tumor(s). A facile approach reported herein for introducing a variety of functionalities in tumor-avid CD provides an opportunity to create multi-imaging modality agent(s). Using a combination of mass spectrometry and absorbance techniques, the photobleaching of one of the CDs was analyzed and significant regioselective photooxidation was observed. PMID- 26108698 TI - Internal Quality Control Practices in Coagulation Laboratories: recommendations based on a patterns-of-practice survey. AB - INTRODUCTION: Internal quality control (IQC) procedures are crucial for ensuring accurate patient test results. The IQMH Centre for Proficiency Testing conducted a web-based survey to gather information on the current IQC practices in coagulation testing. METHODS: A questionnaire was distributed to 174 Ontario laboratories licensed to perform prothrombin time (PT) and activated partial thromboplastin time (APTT). RESULTS: All laboratories reported using two levels of commercial QC (CQC); 12% incorporate pooled patient plasma into their IQC program; >68% run CQC at the beginning of each shift; 56% following maintenance, with reagent changes, during a shift, or with every repeat sample; 6% only run CQC at the beginning of the day and 25% when the instruments have been idle for a defined period of time. IQC run frequency was determined by manufacturer recommendations (71%) but also influenced by the stability of test (27%), clinical impact of an incorrect test result (25%), and sample's batch number (10%). IQC was monitored using preset limits based on standard deviation (66%), precision goals (46%), or allowable performance limits (36%). 95% use multirules. Failure actions include repeating the IQC (90%) and reporting patient results; if repeat passes, 42% perform repeat analysis of all patient samples from last acceptable IQC. CONCLUSION: Variability exists in coagulation IQC practices among Ontario clinical laboratories. The recommendations presented here would be useful in encouraging standardized IQC practices. PMID- 26108699 TI - Effect of environmental factors on Internet searches related to sinusitis. AB - OBJECTIVES/HYPOTHESIS: Sinusitis significantly affects the population of the United States, exacting direct cost and lost productivity. Patients are likely to search the Internet for information related to their health before seeking care by a healthcare professional. Utilizing data generated from these searches may serve as an epidemiologic surrogate. STUDY DESIGN: A retrospective time series analysis was performed. METHODS: Google search trend data from the Dallas-Fort Worth metro region for the years 2012 and 2013 were collected from www.google.com/trends for terms related to sinusitis based on literature outlining the most important symptoms for diagnosis. Additional terms were selected based on common English language terms used to describe the disease. Twelve months of data from the same time period and location for common pollutants (nitrogen dioxide, ozone, sulfur dioxide, and particulates), pollen and mold counts, and influenza-like illness were also collected. Statistical analysis was performed using Pearson correlation coefficients, and potential search activity predictors were assessed using autoregressive integrated moving average. RESULTS: Pearson correlation was strongest between the terms congestion and influenza-like illness (r=0.615), and sinus and influenza-like illness (r=0.534) and nitrogen dioxide (r=0.487). Autoregressive integrated moving average analysis revealed ozone, influenza-like illness, and nitrogen dioxide levels to be potential predictors for sinus pressure searches, with estimates of 0.118, 0.349, and 0.438, respectively. Nitrogen dioxide was also a potential predictor for the terms congestion and sinus, with estimates of 0.191 and 0.272, respectively. CONCLUSIONS: Google search activity for related terms follow the pattern of seasonal influenza-like illness and nitrogen dioxide. These data highlight the epidemiologic potential of this novel surveillance method. LEVEL OF EVIDENCE: NA. PMID- 26108701 TI - Journal editors impasse with outcome reporting bias. AB - Several requirements and regulations have been issued to promote clinical trial transparency through prospective registration of trials, disclosure of results, access to trial reports submitted to regulatory agencies and access to anonymized patient-level data. Clinical trial results are disseminated through articles. Yet, many present outcome reporting bias. Open access to trial data will help to deter outcome reporting bias. However, this is not enough to clinicians. Access to trial protocols by journal staff has proven rather inefficacious in preventing outcome reporting bias. Two proposals have been suggested or implemented to tackle outcome reporting bias that are discussed in this article. Editors should implement quality-control processes aiming at preventing outcome reporting bias. Readers should be informed as to the efficiency of the implemented process. PMID- 26108700 TI - High metabolic tumor volume and total lesion glycolysis are associated with lateral lymph node metastasis in patients with incidentally detected thyroid carcinoma. AB - OBJECTIVE: The objective of this study was to investigate whether total lesion glycolysis (TLG) and metabolic tumor volume (MTV) measured by 18F fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) could predict the aggressiveness and lymph node metastasis (LNM) in patients with incidentally detected differentiated thyroid carcinoma. METHODS: A total 358 patients with focal FDG-avid thyroid incidentaloma during cancer evaluation were enrolled. Among 235 patients in whom fine-needle aspiration biopsy was performed, 51 patients underwent total thyroidectomy with LN dissection. We analyzed the relationship between volume-based parameters and clinicopathologic characteristics. RESULTS: The mean age and tumor size were 57.1 +/- 11.3 years and 1.15 +/- 0.81 cm, respectively. The prevalence of malignancy was 21.7 % (51/235). When SUV(max) > 5.91, MTV2.5 > 2.05 cm3, and TLG2.5 > 9.09 were used as cutoff points, sensitivity, specificity, and area under curve (AUC) for prediction of lateral LNM were 77.9, 69.1 %, 0.716 (P = 0.047), 77.8, 88.1 %, 0.839 (P < 0.001), 77.8, 85.1 %, and 0.815 (P = 0.002), respectively. However, MTV and TLG had no value in prediction of central LNM, extrathyroidal extension, and multifocality. On comparison ROC curve analysis, the MTV and TLG showed the statistical differences for the prediction of lateral LNM compared with SUV(max) (all P's < 0.05). CONCLUSIONS: This study has shown for the first time that volume-based PET functional parameters had a significant value for the prediction of lateral LNM in incidentally detected PTC. These results suggest that higher MTV and TLG can be potential new risk factors for preoperative risk stratification. The usefulness of TLG and MTV in preoperative risk stratification in patients with PTC needs to be confirmed in further large studies. PMID- 26108702 TI - A 3-year-old girl with Trisomy 18 and intussusception with Meckel's diverticulum. PMID- 26108703 TI - Bis(phenothiazine)arene diradicaloids: isolation, characterization and crystal structures. AB - A class of bis(phenothiazine)arene dications were isolated and structurally characterized by using weakly coordinating anions. Their electronic structures were investigated by various experiments in tandem with DFT calculations. They all feature singlet ground states with a considerable diradical character and may be regarded as nearly pure diradicals. Our work demonstrates the important role of orthogonal alignment of spin-carrying pi-systems in tuning the electronic structures of bis(triarylamine) dications. PMID- 26108704 TI - Beyond Gisin's Theorem and its Applications: Violation of Local Realism by Two Party Einstein-Podolsky-Rosen Steering. AB - We demonstrate here that for a given mixed multi-qubit state if there are at least two observers for whom mutual Einstein-Podolsky-Rosen steering is possible, i.e. each observer is able to steer the other qubits into two different pure states by spontaneous collapses due to von Neumann type measurements on his/her qubit, then nonexistence of local realistic models is fully equivalent to quantum entanglement (this is not so without this condition). This result leads to an enhanced version of Gisin's theorem (originally: all pure entangled states violate local realism). Local realism is violated by all mixed states with the above steering property. The new class of states allows one e.g. to perform three party secret sharing with just pairs of entangled qubits, instead of three qubit entanglements (which are currently available with low fidelity). This significantly increases the feasibility of having high performance versions of such protocols. Finally, we discuss some possible applications. PMID- 26108706 TI - Determination of the linear coefficient of thermal expansion in polymer films at the nanoscale: influence of the composition of EVA copolymers and the molecular weight of PMMA. AB - Nanothermal-expansion of poly(ethylene-co-vinylacetate), EVA, and poly(methyl methacrylate), PMMA, in the form of films was measured to finally obtain linear coefficients of thermal expansion, CTEs. The simple deflection of a cantilever in an atomic force microscope, AFM, was used to monitor thermal expansions at the nanoscale. The influences of: (a) the structure of EVA in terms of its composition (vinylacetate content) and (b) the size of PMMA chains in terms of the molecular weight were studied. To carry out this, several polymer samples were used, EVA copolymers with different weight percents of the vinylacetate comonomer (12, 18, 25 and 40%) and PMMA polymers with different weight average molecular weights (33.9, 64.8, 75.600 and 360.0 kg mol(-1)). The dependencies of the vinyl acetate weight fraction of EVA and the molecular weight of PMMA on their corresponding CTEs were analyzed to finally explain them using new, intuitive and very simple models based on the rule of mixtures. In the case of EVA copolymers a simple equation considering the weighted contributions of each comonomer was enough to estimate the final CTE above the glass transition temperature. On the other hand, when the molecular weight dependence is considered the free volume concept was used as novelty. The expansion of PMMA, at least at the nanoscale, was well and easily described by the sum of the weighted contributions of the occupied and free volumes, respectively. PMID- 26108705 TI - Photon Devil's staircase: photon long-range repulsive interaction in lattices of coupled resonators with Rydberg atoms. AB - The realization of strong coherent interactions between individual photons is a long-standing goal in science and engineering. In this report, based on recent experimental setups, we derive a strong photon long-range repulsive interaction, by controlling the van der Waals repulsive force between Cesium Rydberg atoms located inside different cavities in extended Jaynes-Cummings-Hubbard lattices. We also find novel quantum phases induced by this photon long-range repulsive interaction. For example, without photon hopping, a photon Devil's staircase, induced by the breaking of long-range translation symmetry, can emerge. If photon hopping occurs, we predict a photon-floating solid phase, due to the motion of particle- and hole-like defects. More importantly, for a large chemical potential in the resonant case, the photon hopping can be frozen even if the hopping term exists. We call this new phase the photon-frozen solid phase. In experiments, these predicted phases could be detected by measuring the number of polaritons via resonance fluorescence. PMID- 26108707 TI - Analysis of Clinical Cohort Data Using Nested Case-control and Case-cohort Sampling Designs. A Powerful and Economical Tool. AB - BACKGROUND: Sampling from a large cohort in order to derive a subsample that would be sufficient for statistical analysis is a frequently used method for handling large data sets in epidemiological studies with limited resources for exposure measurement. For clinical studies however, when interest is in the influence of a potential risk factor, cohort studies are often the first choice with all individuals entering the analysis. OBJECTIVES: Our aim is to close the gap between epidemiological and clinical studies with respect to design and power considerations. Schoenfeld's formula for the number of events required for a Cox' proportional hazards model is fundamental. Our objective is to compare the power of analyzing the full cohort and the power of a nested case-control and a case cohort design. METHODS: We compare formulas for power for sampling designs and cohort studies. In our data example we simultaneously apply a nested case-control design with a varying number of controls matched to each case, a case cohort design with varying subcohort size, a random subsample and a full cohort analysis. For each design we calculate the standard error for estimated regression coefficients and the mean number of distinct persons, for whom covariate information is required. RESULTS: The formula for the power of a nested case-control design and the power of a case-cohort design is directly connected to the power of a cohort study using the well known Schoenfeld formula. The loss in precision of parameter estimates is relatively small compared to the saving in resources. CONCLUSIONS: Nested case-control and case-cohort studies, but not random subsamples yield an attractive alternative for analyzing clinical studies in the situation of a low event rate. Power calculations can be conducted straightforwardly to quantify the loss of power compared to the savings in the num-ber of patients using a sampling design instead of analyzing the full cohort. PMID- 26108708 TI - RAD51 135G>C substitution increases breast cancer risk in an ethnic-specific manner: a meta-analysis on 21,236 cases and 19,407 controls. AB - RAD51 is a homolog of bacterial RecA protein, which plays an important role in preserving stability of the genome. RAD51 interacts with BRCA1 and BRCA2 for homologous recombination repair. A functional polymorphism (135G > C) in the RAD51 gene has been a subject of great interest, which is evidenced by at least 28 case-control studies and eight meta-analyses undertaken on this polymorphism till now. We undertook a meta-analysis on RAD51 135G > C data for 21,236 cases and 19,407 controls pooled from 28 studies on breast cancer in women. Pooled data analysis suggested a significant association of the substitution with breast cancer in the recessive model (GG + GC versus CC) and in the co-dominant models comparing GG versus CC and GC versus CC. Analysis of the results suggested that 'CC' genotype is a significant breast cancer risk factor in comparison to 'GG' and 'GC' genotypes. We also undertook pooled analyses on different ethnic groups and found that 'CC' was a strong risk factor in Caucasians, but not in East Asians and populations of mixed ethnicity. In conclusion, the RAD51 135G > C substitution in the homozygous form (CC) increases the risk of breast cancer in an ethnic-specific manner. PMID- 26108710 TI - "Hit-and-Run" leaves its mark: catalyst transcription factors and chromatin modification. AB - Understanding how transcription factor (TF) binding is related to gene regulation is a moving target. We recently uncovered genome-wide evidence for a "Hit-and Run" model of transcription. In this model, a master TF "hits" a target promoter to initiate a rapid response to a signal. As the "hit" is transient, the model invokes recruitment of partner TFs to sustain transcription over time. Following the "run", the master TF "hits" other targets to propagate the response genome wide. As such, a TF may act as a "catalyst" to mount a broad and acute response in cells that first sense the signal, while the recruited TF partners promote long-term adaptive behavior in the whole organism. This "Hit-and-Run" model likely has broad relevance, as TF perturbation studies across eukaryotes show small overlaps between TF-regulated and TF-bound genes, implicating transient TF target binding. Here, we explore this "Hit-and-Run" model to suggest molecular mechanisms and its biological relevance. PMID- 26108709 TI - A Review of the Toxicologic Implications of Obesity. AB - The increasing prevalence of obesity in developed nations has far-reaching implications for medical toxicology. The management of obese patients is complicated by comorbid illnesses, changes in cardiovascular and respiratory physiology, alterations in pharmacokinetics, and a lack of studies to identify appropriate dosing for current therapeutics and antidotes. In this review article, we examine obesity-associated physiologic and pharmacokinetic changes that may increase the vulnerability of obese patients to overdose. Further research is needed to characterize the relationship between drug toxicity and obesity. PMID- 26108711 TI - A Systematic Study on Manufacturing of Prilled Microgels into Lipids for Oral Protein Delivery. AB - The development of novel systems with oral protein delivery as ultimate goal represents an important field of pharmaceutics. Prilling of protein-loaded polymeric solutions into lipid-based hardening baths could provide here an attractive formulating technology. As the obtained microgel dispersion can be directly capsule-filled, no drying step is required and thermal drug degradation is avoided. This study aims to find excipient combinations for the novel prilling process and investigate systematically diverse material and process factors. Bovine serum albumin and mono-N-carboxymethyl chitosan were selected as model protein and prilling polymer, respectively. The prilling suitability of 880 formulations was screened with 60 ternary phase diagrams comprising two co solvents, 10 different glycerides, and three so-called complementary excipients. Preliminary capsule compatibility was tested for one month on 245 formulations in hard and soft capsules with different shell materials. Ternary phase diagrams' center points were used to evaluate morphology, encapsulation efficiency, and protein stability of the prilled microgels. As result, several formulations proved suitable for prilling and compatible for capsule filling. Statistical analysis using partial least square regression revealed significant factors regarding different quality attributes of microgel dispersions. Therefore, an improved understanding was obtained for this promising drug delivery approach. PMID- 26108712 TI - Changes in Hypoxia-Inducible Factor-1 (HIF-1) and Regulatory Prolyl Hydroxylase (PHD) Enzymes Following Hypoxic-Ischemic Injury in the Neonatal Rat. AB - Hypoxia leads to activation of many cellular adaptive processes which are regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1). HIF-1 consists of HIF-1alpha and HIF-1beta subunits and levels of HIF-1alpha protein are regulated by HIF prolyl-hydroxylase enzymes (PHD1, 2, 3). The aim of the current study was to investigate the expression of HIF-1alpha and PHDs at various time points after hypoxia-ischemia (HI), using a neonatal rat model of HI brain injury. Sprague-Dawley rat pups (postnatal day 7) were anaesthetized and underwent right carotid artery occlusion and were then exposed to 6 % oxygen for 2.5 h at 37 degrees C. HI injured animals demonstrated a significant reduction in the size of the ipsilateral hemisphere, compared to sham controls. Protein analysis using western blotting and enzyme-linked immunosorbent assay showed that 24 h after HI, there was a significant increase in PHD3 protein and an increase of HIF-1alpha compared to controls. At the 72 h time point, there was a reduction in PHD3 protein, which appeared to relate to cellular loss. There were no changes in PHD1 or PHD2 protein levels after HI when compared to age-matched controls. Further studies are necessary to establish roles for the HIF-1 regulatory enzyme PHD3 in brain injury processes. PMID- 26108714 TI - Iridium-catalyzed allyl-allyl cross-coupling of allylic carbonates with (E)-1,3 diarylpropenes. AB - An efficient Ir-catalyzed allyl-allyl cross-coupling reaction of allylic carbonates with (E)-1,3-diarylpropenes was developed to form linear allylated products, 1,5-dienes, regioselectively in excellent yields and with high turnover numbers (up to 2000 S/Ir). PMID- 26108713 TI - Maternal Oxytocin Administration Before Birth Influences the Effects of Birth Anoxia on the Neonatal Rat Brain. AB - Ineffective contractions and prolonged labor are common birth complications in primiparous women, and oxytocin is the most common agent given for induction or augmentation of labor. Clinical studies in humans suggest oxytocin might adversely affect the CNS response to hypoxia at birth. In this study, we used a rat model of global anoxia during Cesarean section birth to test if administering oxytocin to pregnant dams prior to birth affects the acute neonatal CNS response to birth anoxia. Anoxic pups born from dams pre-treated with intravenous injections or infusions of oxytocin before birth showed significantly increased brain lactate, a metabolic indicator of CNS hypoxia, compared to anoxic pups from dams pre-treated with saline. Anoxic pups born from dams given oxytocin before birth also showed decreased brain ATP compared to anoxic pups from saline dams. Direct injection of oxytocin to postnatal day 2 rat pups followed by exposure to anoxia also resulted in increased brain lactate and decreased brain ATP, compared to anoxia exposure alone. Oxytocin pre-treatment of the dam decreased brain malondialdehyde, a marker of lipid peroxidation, as well as protein kinase C activity, both in anoxic pups and controls, suggesting oxytocin may reduce aspects of oxidative stress. Finally, when dams were pretreated with indomethacin, a cyclooxygenase (COX) inhibitor, maternal oxytocin no longer potentiated effects of anoxia on neonatal brain lactate, suggesting this effect of oxytocin may be mediated via prostaglandin production or other COX-derived products. The results indicate that maternal oxytocin administration may have multiple acute effects on CNS metabolic responses to anoxia at birth. PMID- 26108715 TI - Androgen Receptor Targeted Conjugate for Bimodal Photodynamic Therapy of Prostate Cancer in Vitro. AB - Prostate cancer (PC) represents the most common type of cancer among males and is the second leading cause of cancer death in men in Western society. Current options for PC therapy remain unsatisfactory, since they often produce uncomfortable long-term side effects, such as impotence (70%) and incontinence (5 20%) even in the first stages of the disease. Light-triggered therapies, such as photodynamic therapy, have the potential to provide important advances in the treatment of localized and partially metastasized prostate cancer. We have designed a novel molecular conjugate (DR2) constituted of a photosensitizer (pheophorbide a, Pba), connected to a nonsteroidal anti-androgen molecule through a small pegylated linker. This study aims at investigating whether DR2 represents a valuable approach for PC treatment based on light-induced production of single oxygen and nitric oxide (NO) in vitro. Besides being able to efficiently bind the androgen receptor (AR), the 2-trifluoromethylnitrobenzene ring on the DR2 backbone is able to release cytotoxic NO under the exclusive control of light, thus augmenting the general photodynamic effect. Although DR2 is similarly internalized in cells expressing different levels of androgen receptor, the AR ligand prevents its efflux through the ABCG2-pump. In vitro phototoxicity experiments demonstrated the ability of DR2 to kill cancer cells more efficiently than Pba, while no dark toxicity was observed. Overall, the presented approach is very promising for further development of AR-photosensitizer conjugates in the multimodal photodynamic treatment of prostate cancer. PMID- 26108716 TI - Welcome aboard! PMID- 26108717 TI - Genetic variation links creativity to psychiatric disorders. PMID- 26108718 TI - Go with your gut: microbiota meet microglia. PMID- 26108719 TI - MIR137: big impacts from small changes. PMID- 26108720 TI - How amyloid, sleep and memory connect. PMID- 26108721 TI - Molecular mechanisms governing Ca(2+) regulation of evoked and spontaneous release. AB - The relationship between transmitter release evoked by action potentials and spontaneous release has fascinated neuroscientists for half a century, and separate biological roles for spontaneous release are emerging. Nevertheless, separate functions for spontaneous and Ca(2+)-evoked release do not necessarily indicate different origins of these two manifestations of vesicular fusion. Here we review how Ca(2+) regulates evoked and spontaneous release, emphasizing that Ca(2+) can briefly increase vesicle fusion rates one-millionfold above spontaneous rates. This high dynamic range suggests that docked and readily releasable pool (RRP) vesicles might be protected against spontaneous release while also being immediately available for ultrafast Ca(2+)-evoked release. Molecular mechanisms for such release clamping of highly fusogenic RRP vesicles are increasingly investigated. Thus, we view spontaneous release as a consequence of the highly release-competent state of a standing pool of RRP vesicles, which is molecularly fine-tuned to control spontaneous release. PMID- 26108723 TI - [Combination of a universal antidote and temporary skin substitute for chemical burns: Extended case report]. AB - In this article we describe our experiences in the treatment of chemical burns with Diphoterine((r)) solution and Suprathel((r)) as a temporary skin substitute material, a treatment which in the past was not commonly used for this pattern of injuries. In the study period from October 2012 to December 2013 we treated five patients (four male and one female including two children and three adults) with chemical burns by decontamination with Diphoterine((r)) and wound covering with Suprathel((r)). The control group included five patients with similar injury patterns who were treated with Diphoterine((r)) and occlusive wound dressings. No wound infections occurred in any of the five cases and no interactions were observed between Suprathel((r)) and the chemical substance involved. In four cases the skin areas with IIa-IIb degree damage showed good wound healing and only slight scarring in the follow-up after 3 months and one of the five patients had to be treated surgically. Suprathel((r)) can be used as a temporary skin substitute for the treatment of skin burns and is also available for the treatment of chemical burns. PMID- 26108724 TI - [P.A.R.T.Y. An initiative for more risk awareness among young road users]. AB - BACKGROUND AND OBJECTIVES: Accident prevention strategies aim to inform young people about risk-taking behavior and the consequences of trauma. The Prevent Alcohol and Risk-related Trauma in Youth (P.A.R.T.Y.) program is an accident prevention program that focuses on the prevention of road traffic accidents among young road users. Initial results of the program were evaluated to find out if the implementation of this prevention program is feasible in Germany. MATERIAL AND METHODS: During a 1-day interactive course young road users were introduced to the work carried out in an accident trauma unit and were informed about injury mechanisms and about the consequences of trauma. A systematic evaluation was made by all participants. The results were analyzed to find out whether it is possible to implement the program and the impressions gained by the participants of the program in order to be able to make further adjustments. RESULTS: A total of 219 young road users participated in the P.A.R.T.Y. program between 2011 and 2013. All participants reviewed the structure of the program with the help of school grades. Of the participants 59 % (n = 129) rated the program as "very good" and 41 % gave the rating of "good". Overall, 70 % of all participants advocated that all people of the same age should participate in the program. The structure was described as being well-balanced with respect to the theoretical and practical stations. CONCLUSION: The P.A.R.T.Y. program is a standardized and well established concept that can also contribute to accident prevention in Germany. It provides the possibility to implement an accident awareness program throughout Germany. Initial results show that the program can be implemented in German hospitals and that the program appeals to the target group of young road users. PMID- 26108722 TI - Diversity of astrocyte functions and phenotypes in neural circuits. AB - Astrocytes tile the entire CNS. They are vital for neural circuit function, but have traditionally been viewed as simple, homogenous cells that serve the same essential supportive roles everywhere. Here, we summarize breakthroughs that instead indicate that astrocytes represent a population of complex and functionally diverse cells. Physiological diversity of astrocytes is apparent between different brain circuits and microcircuits, and individual astrocytes display diverse signaling in subcellular compartments. With respect to injury and disease, astrocytes undergo diverse phenotypic changes that may be protective or causative with regard to pathology in a context-dependent manner. These new insights herald the concept that astrocytes represent a diverse population of genetically tractable cells that mediate neural circuit-specific roles in health and disease. PMID- 26108727 TI - [Gunshot and stabbing injuries: Look beyond the horizon]. PMID- 26108726 TI - [Posttraumatic arthritis of the glenohumeral joint. Joint-preserving therapy options]. AB - BACKGROUND: The management of glenohumeral osteoarthritis in younger patients with high activity levels remains a challenge to orthopedic surgeons. The clinical results of joint replacement surgery are commonly unsatisfactory in this particular cohort with the associated problem of limited longevity of the implant. OBJECTIVES: This paper reviews the indications, techniques and outcomes of joint-preserving arthroscopic surgery for the treatment of osteoarthritis of the shoulder. METHODS: A selective literature search was performed and personal surgical experiences are reported. RESULTS: Besides significant pain reduction, improved range of motion and increased patient satisfaction, arthroscopic surgery can delay the need for total shoulder arthroplasty. A comprehensive approach that addresses all concomitant pathologies of the shoulder joint is of particular importance. Recent studies have shown that a glenohumeral joint space of less than 2 mm predicts significantly poorer results with arthroscopic therapy. CONCLUSION: Arthroscopic procedures are a good option to treat young, active patients with osteoarthritis of the shoulder. Patient selection and setting a consensus for appropriate preoperative expectations are of particular relevance. PMID- 26108725 TI - [Posttraumatic nonunions and malunions of the proximal humerus. Possibilities and limitations of corrective osteotomy]. AB - BACKGROUND: According to the future demographic trends the incidence of proximal humeral fractures and subsequent posttraumatic malunions and nonunions of the proximal humerus are expected to substantially increase. OBJECTIVES: This article reviews the indications, techniques and outcomes of corrective osteotomy for the treatment of posttraumatic nounions and malunions of the proximal humerus. METHODS: A selective literature search was performed and personal surgical experiences are reported. RESULTS: Malunions of the proximal humerus can occur after both surgical and conservative management of fractures. Due to the complex anatomy of the proximal humerus, malunions have to be systematically assessed regarding epiphyseal and metaphyseal malpositioning. Furthermore, the objective anatomical disorder has to be completely correlated with the subjective patient complaints. The associated soft tissue structures, such as the glenohumeral joint capsule and ligaments, long head of the biceps tendon, rotator cuff and muscles inserting in the metaphysis, can independently cause discomfort to the patient and need to be meticulously identified as such. CONCLUSION: A variety of corrective surgical strategies are available, which are indicated depending on the location and extent of the malunion. The depicted single-cut osteotomy technique represents an elegant therapeutic option for multidimensional deformities of the proximal humerus. Nonunions of the proximal humerus can usually be successfully managed with autologous cancellous bone grafting and locking plate osteosynthesis. PMID- 26108728 TI - Autophagy protects meniscal cells from glucocorticoids-induced apoptosis via inositol trisphosphate receptor signaling. AB - Intra-articular injection of glucocorticoids (GCs) has been widely used in the management of osteoarthritis and rheumatoid arthritis. Nevertheless, several studies showed that GCs had toxic effects on chondrocytes as well as synovial cells. Previously we reported the protective role of autophagy in the degeneration of meniscal tissues. However, the effects of GCs on autophagy in the meniscal cells have not been fully elucidated. To investigate whether GCs can regulate autophagy in human meniscal cells, the meniscal cells were cultured in vitro and exposed in the presence of dexamethasone. The levels of apoptosis and autophagy were investigated via flow cytometry as well as western blotting analysis. The changes of the aggrecanases were measured using real-time PCR. The role of autophagy in dexamethasone-induced apoptosis was investigated using pharmacological agents and RNA interference technique. An agonist of inositol 1,4,5-trisphosphate receptor (IP3R) was used to investigate the mechanism of dexamethasone-induced autophagy. The results showed that dexamethasone induced autophagy as well as apoptosis in normal human meniscal cells. Using RNA interference technique and pharmacological agents, our results showed that autophagy protected the meniscal cells from dexamethasone-induced apoptosis. Our results also indicated that dexamethasone increased the mRNA levels of aggrecanases. This catabolic effect of dexamethasone was enhanced by 3-MA, the autophagy inhibitor. Furthermore, our results showed that dexamethasone induced autophagy via suppressing the phosphorylation of IP3R. In summary, our results indicated that autophagy protected meniscal cells from GCs-induced apoptosis via inositol trisphosphate receptor signaling. PMID- 26108730 TI - Disturbances in Bone Largely Predict Aortic Calcification in an Alternative Rat Model Developed to Study Both Vascular and Bone Pathology in Chronic Kidney Disease. AB - Because current rat models used to study chronic kidney disease (CKD)-related vascular calcification show consistent but excessive vascular calcification and chaotic, immeasurable, bone mineralization due to excessive bone turnover, they are not suited to study the bone-vascular axis in one and the same animal. Because vascular calcification and bone mineralization are closely related to each other, an animal model in which both pathologies can be studied concomitantly is highly needed. CKD-related vascular calcification in rats was induced by a 0.25% adenine/low vitamin K diet. To follow vascular calcification and bone pathology over time, rats were killed at weeks 4, 8, 10, 11, and 12. Both static and dynamic bone parameters were measured. Vascular calcification was quantified by histomorphometry and measurement of the arterial calcium content. Stable, severe CKD was induced along with hyperphosphatemia, hypocalcemia as well as increased serum PTH and FGF23. Calcification in the aorta and peripheral arteries was present from week 8 of CKD onward. Four and 8 weeks after CKD, static and dynamic bone parameters were measurable in all animals, thereby presenting typical features of hyperparathyroid bone disease. Multiple regression analysis showed that the eroded perimeter and mineral apposition rate in the bone were strong predictors for aortic calcification. This rat model presents a stable CKD, moderate vascular calcification, and quantifiable bone pathology after 8 weeks of CKD and is the first model that lends itself to study these main complications simultaneously in CKD in mechanistic and intervention studies. PMID- 26108729 TI - The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17. AB - The metalloproteinase ADAM17 activates ErbB signalling by releasing ligands from the cell surface, a key step underlying epithelial development, growth and tumour progression. However, mechanisms acutely controlling ADAM17 cell-surface availability to modulate the extent of ErbB ligand release are poorly understood. Here, through a functional genome-wide siRNA screen, we identify the sorting protein PACS-2 as a regulator of ADAM17 trafficking and ErbB signalling. PACS-2 loss reduces ADAM17 cell-surface levels and ADAM17-dependent ErbB ligand shedding, without apparent effects on related proteases. PACS-2 co-localizes with ADAM17 on early endosomes and PACS-2 knockdown decreases the recycling and stability of internalized ADAM17. Hence, PACS-2 sustains ADAM17 cell-surface activity by diverting ADAM17 away from degradative pathways. Interestingly, Pacs2 deficient mice display significantly reduced levels of phosphorylated EGFR and intestinal proliferation. We suggest that this mechanism controlling ADAM17 cell surface availability and EGFR signalling may play a role in intestinal homeostasis, with potential implications for cancer biology. PMID- 26108731 TI - Classification of stress urinary incontinence. AB - INTRODUCTION: The relevant terminology for stress urinary incontinence (SUI) is affected by the context, namely the clinical assessment (the symptom of SUI elicited on history taking and the sign of SUI observed during examination) or diagnostic investigations (urodynamic stress incontinence). In some cases, SUI may only be observed after the reduction in coexistent prolapse (occult SUI). Classifying SUI often relies on distinguishing between intrinsic sphincter deficiency (ISD), and urethral malposition or hypermobility, although this potentially an over-simplification. REVIEW: Classification systems have been derived based on clinical assessment and diagnostic testing, notably videourodynamics. Modern developments in imaging technology may allow other techniques such as ultrasound to offer additional basis for future developments in classification. Other urodynamic approaches include urethral pressure profilometry and Valsalva leak point pressure; these may offer indicators of thresholds below which ISD is more likely to explain SUI, but they are not generally accepted in routine practice. CONCLUSIONS: While SUI classification is potentially relevant to treatment selection, evidence for influence on management outcome is limited. Generating a high-quality evidence base for treatment selection on these criteria is problematic, particularly due to the range of confounding factors. In practice, the modern practitioner relies on various tools to form an opinion on some key aspects, using the findings to derive a treatment strategy. Accordingly, there remains a need to confirm how a classification of SUI translates into treatment selection and better outcomes. PMID- 26108733 TI - Translational value of liquid chromatography coupled with tandem mass spectrometry-based quantitative proteomics for in vitro-in vivo extrapolation of drug metabolism and transport and considerations in selecting appropriate techniques. AB - INTRODUCTION: Drug-metabolizing enzymes and transporters play an important role in drug absorption, distribution, metabolism and excretion and, consequently, they influence drug efficacy and toxicity. Quantification of drug-metabolizing enzymes and transporters in various tissues is therefore essential for comprehensive elucidation of drug absorption, distribution, metabolism and excretion. Recent advances in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) have improved the quantification of pharmacologically relevant proteins. AREAS COVERED: This report presents an overview of mass spectrometry-based methods currently used for the quantification of drug metabolizing enzymes and drug transporters, mainly focusing on applications and cost associated with various quantitative strategies based on stable isotope labeled standards (absolute quantification peptide standards, quantification concatemers, protein standards for absolute quantification) and label-free analysis. EXPERT OPINION: In mass spectrometry, there is no simple relationship between signal intensity and analyte concentration. Proteomic strategies are therefore complex and several factors need to be considered when selecting the most appropriate method for an intended application, including the number of proteins and samples. Quantitative strategies require appropriate mass spectrometry platforms, yet choice is often limited by the availability of appropriate instrumentation. Quantitative proteomics research requires specialist practical skills and there is a pressing need to dedicate more effort and investment to training personnel in this area. Large-scale multicenter collaborations are also needed to standardize quantitative strategies in order to improve physiologically based pharmacokinetic models. PMID- 26108732 TI - Prostatitis, other genitourinary infections and prostate cancer: results from a population-based case-control study. AB - PURPOSE: We relied on a population-based case-control study (PROtEuS) to examine a potential association between the presence of histologically confirmed prostate cancer (PCa) and history of genitourinary infections, e.g., prostatitis, urethritis, orchitis and epididymitis. PATIENTS AND METHODS: Cases were 1933 men with incident PCa, diagnosed across Montreal hospitals between 2005 and 2009. Population controls were 1994 men from the same residential area and age distribution. In-person interviews collected information about socio-demographic characteristics, lifestyle and medical history, e.g., self-reported history of several genitourinary infections, as well as on PCa screening. Logistic regression analyses tested overall and grade-specific associations, including subgroup analyses with frequent PSA testing. RESULTS: After multivariable adjustment, prostatitis was associated with an increased risk of any PCa (OR 1.81 [1.44-2.27]), but not urethritis (OR 1.05 [0.84-1.30]), orchitis (OR 1.28 [0.92 1.78]) or epididymitis (OR 0.98 [0.57-1.68]). The association between prostatitis and PCa was more pronounced for low-grade PCa (Gleason <= 6: OR 2.11 [1.61-2.77]; Gleason >= 7: OR 1.59 [1.22-2.07]). Adjusting for frequency of physician visits, PSA testing frequency or restricting analyses to frequently screened subjects did not affect these results. CONCLUSION: Prostatitis was associated with an increased probability for detecting PCa even after adjustment for frequency of PSA testing and physician visits, but not urethritis, orchitis or epididymitis. These considerations may be helpful in clinical risk stratification of individuals in whom the risk of PCa is pertinent. PMID- 26108735 TI - Remaining cancer cells within the fibrosis after neo-adjuvant treatment for locally advanced rectal cancer. AB - AIM: To analyse the incidence and distribution of remaining cancer cells within the fibrosis induced by preoperative chemo-radiotherapy (CRT) for locally advanced rectal cancer. METHODS: The histopathological specimens from 46 patients operated on with extensive surgery for locally advanced rectal cancer after CRT were examined. The extension of fibrosis in relation to the mesorectal fascia (MRF) and the distribution of cancer cells within the fibrosis was examined using routine haematoxylin-eosin staining. In addition, immunohistochemical staining with CK20 was done to examine if cancer cells were missed by routine pathological work up. RESULTS: All specimens showed CRT induced fibrosis. Two specimens showed complete response without viable cancer cells (ypT0). The fibrosis was limited inside the MRF in three cases, adherent to or involved the MRF in ten cases and in 33 cases the fibrosis was obvious outside as well as inside the fascia. Twenty one cases showed fibrosis on the surgical resection margin, and in 9 of these cancer cells were found on the surgical margin (R1, R2-resection). 37 patients had R0 resections and among those 24 showed fibrosis beyond the MFR and 13 had scattered cancer cells in the fibrosis along or outside the MRF. CONCLUSIONS: The rate of remaining cancer cells within the fibrosis was high in patients with locally advanced rectal cancer treated with CRT. Frequently cancer cells were detected near the border of the fibrosis. A complete resection of the fibrosis is therefore recommended to achieve an R0 resection after neo-adjuvant treatment. PMID- 26108734 TI - Healthcare professionals' preferences for surgery or primary endocrine therapy to treat older women with operable breast cancer. AB - INTRODUCTION: Primary endocrine therapy (PET) is an alternative treatment to surgery for oestrogen receptor (ER) positive operable breast cancer in older women. However, there is variable use of PET in the UK, with up to 40% of patients aged over 70 receiving PET instead of surgery in some regions. Treatment options offered to patients rely heavily on healthcare professional (HCP) assessment and opinion on which treatments are appropriate. MATERIALS AND METHODS: This was a mixed methods study combining semi-structured interviews with HCPs working in high and low PET regions in the UK, followed by a postal questionnaire survey distributed via the Association of Breast Surgery (ABS). RESULTS: Thirty-four HCPs (20 breast surgeons; 13 nurse specialists; 1 geriatrician) were interviewed from 14 sites across the UK and 252/641 questionnaires returned (39%). There was an overriding view that PET is not suitable for patients under the age of 80 unless there are significant comorbidities. Opinion was split regarding the best way to treat patients with dementia. Patient preference was generally stated to be the most important factor when considering treatment, however only around a quarter 65/244 (26.6%) felt that all patients over the age of 70 should be offered PET as an alternative treatment option. CONCLUSIONS: Opinions differ on the best way to treat women over 70 with operable breast cancer, especially if they have co-existing dementia, as well as whether they should be offered PET as a treatment option. This may be a significant cause of treatment variation in the UK. PMID- 26108736 TI - Simple criteria to predict margin involvement after chemoradiotherapy and sphincter-sparing for low rectal cancer. AB - BACKGROUND: Low rectal cancers carry a high risk of circumferential margin involvement (CRM+). The anatomy of the lower part of the rectum and a long course of chemoradiotherapy (CRT) limit the accuracy of imaging to predict the CRM+. Additional criteria are required. METHODS: Eighty six patients undergoing rectal resection with a sphincter-sparing procedure after CRT for low rectal cancer between 2000 and 2013 were retrospectively reviewed. Risk factors of CRM+ and the cut-off number of risk factors required to accurately predict the CRM+ were analyzed. RESULTS: The CRM+ rate was 9.3% and in the multivariate analysis, the significant risk factors were a tumor size exceeding 3 cm, poor response to CRT and a fixed tumor. The best cut-off to predict CRM+ was the presence of 2 risk factors. Patients with 0-1 and 2-3 risk factors had a CRM+ respectively in 1.3% and 50% of cases and a 3-year recurrence rate of 7% and 35% after a median follow up of 50 months. CONCLUSIONS: Poor response, a residual tumor greater than 3 cm and a fixed tumor are predictive of CRM+. Sphincter sparing is an oncological safety procedure for patients with 0-1 criteria but not for patients with 2-3 criteria. PMID- 26108737 TI - Contralateral lymph node recurrence in breast cancer: Regional event rather than distant metastatic disease. A systematic review of the literature. AB - AIMS: After treatment for breast cancer, some patients experience a contralateral lymph node recurrence (CLNR). Traditionally, contralateral nodes are considered a distant site. However, aberrant lymph drainage after previous surgery is common. This might indicate that CLNR is a regional event. This study aimed to review the literature to determine prognosis after CLNR. METHODS: PubMed was searched up until July 2014. Articles on CLNR with or without ipsilateral breast tumour recurrence (IBTR), and repeat sentinel node (SN) studies reporting on positive contralateral nodes were included. Exclusion criteria were synchronous contralateral breast cancer and synchronous distant events. RESULTS: 24 articles were included, describing 48 patients. Of these 48, 26 patients had an isolated CLNR, 7 IBTR and clinically detected CLNR, and 15 IBTR with a positive contralateral repeat SN. Isolated CLNR occurred earlier (45.9 months) than IBTR with CLNR (126.6 months, p < 0.001) or with a positive contralateral repeat SN (217.2, p = 0.02). Surgical treatment was described for 38 patients, and consisted of axillary lymph node dissection for 34 (89.5%). Information on adjuvant therapy was available for 27 patients, 21 (77.8%) received chemotherapy. Follow-up information after CLNR was available for 23 patients (47.9%). Mean follow-up was 50.3 months. Overall survival and disease-free survival were 82.6% [95% CI 67.1-98.1] and 65.2% [45.7-84.7] respectively at last follow-up. CONCLUSIONS: Although observed in a small population, the survival of CLNR is not comparable to distant disease. Most patients received locoregional and systemic treatment suggesting a curative approach. This indicates that CLNR should be regarded as a regional event. PMID- 26108738 TI - PDCD1 single nucleotide genes polymorphisms confer susceptibility to juvenile onset systemic lupus erythematosus. AB - Juvenile-onset systemic lupus erythematosus (JSLE) is a multisystem autoimmune disease in which both the genetic and environmental factors seem to be involved in the etiopathogenesis of the disease. The aim of this study was to evaluate the association of programmed cell death 1 (PDCD1, also called PD-1) gene polymorphisms with JSLE susceptibility in Iranian population. In this case control association study, three PDCD1 SNPs, including PD-1.1 G/A, PD-1.3 G/A and PD-1.9 C/T were genotyped in 50 Iranian patients with JSLE and 202 healthy unrelated controls, using PCR-RFLP method. The PD-1.1 A allele was found to be more frequent in the case group compared with controls (6% vs. 1.5%, p = 0.024). Moreover, the GG genotype was less frequent in cases than in controls (88% vs. 97%, p = 0.021). The other PDCD1 SNPs did not show association. At the haplotypic level, no significant differences was recognized between the two groups of case and control neither for the GAC (PD-1.1 G, PD-1.3 A, PD-1.9 C) nor for the GGC haplotype (PD-1.1 G, PD-1.3 G, PD-1.9 C). Our findings support the influence of the PD1.1 A SNP on the development of JSLE in Iranian population. PMID- 26108739 TI - Comprehensive analysis of patient and caregiver predictors for caregiver burden, anxiety and depression in Alzheimer's disease. AB - AIMS AND OBJECTIVES: The primary aim of this study was to examine the correlations between patient and caregiver characteristics with caregiver burden, anxiety and depression in Alzheimer's Disease. Secondary aim was to determine which behavioural and psychological symptoms had the greatest impact on caregiver burden, anxiety and depression in Alzheimer's Disease. BACKGROUND: Caregivers of individuals with Alzheimer's Disease experience high levels of burden, both psychologically and physically. Previous studies have examined caregiver burden, anxiety and depression separately. However, no paper has examined these three psychological conditions simultaneously. DESIGN: A cross-sectional design. METHODS: A total of 310 patients with probable Alzheimer's Disease and their primary caregivers were assessed. Cognitive impairment and neuropsychiatric symptoms were assessed with the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test and Neuropsychiatric Inventory, respectively. Caregiver burden, anxiety and depression were assessed with the ZBI, Generalised Anxiety Disorder Scale-7 and Patient Health Questionnaire-9, respectively. RESULTS: All 12 neuropsychiatric symptoms in the Neuropsychiatric Inventory were significantly correlated with caregiver burden, anxiety and depression, with the top three neuropsychiatric predictors being depression, apathy and anxiety. Furthermore, higher levels of caregiver anxiety were associated with a longer duration of being a caregiver. Within caregivers, higher levels of depression were independently associated with higher numbers of additional caregivers, lower educational background and being the spouse of the patient. Higher levels of burden were associated with a longer duration of being a caregiver and being the spouse of the patient. Caregiver burden, anxiety or depression were not significantly correlated with hours/day of caring for the patient. CONCLUSIONS: Caregiver burden, anxiety and depression were significantly correlated with different neuropsychiatric symptoms in the Neuropsychiatric Inventory. RELEVANCE TO CLINICAL PRACTICE: Practitioners are able to identify caregivers at risk for burden, anxiety and depression. Understanding which Neuropsychiatric Inventory symptom is more closely associated with distress in caregivers will help practitioners to be more specific and effective in detecting caregiver distress. PMID- 26108740 TI - Effects of ankle-foot braces on medial gastrocnemius morphometrics and gait in children with cerebral palsy. AB - PURPOSE: In children with cerebral palsy (CP), braces are used to counteract progressive joint and muscle contracture and improve function. We examined the effects of positional ankle-foot braces on contracture of the medial gastrocnemius (MG) and gait in children with CP while referencing to typically developing children. METHODS: Seventeen independently ambulant children with CP and calf muscle contracture (age 10.4 +/- 3.0y) and 17 untreated typically developing peers (age 9.5 +/- 2.6y) participated. Children with CP were analysed before and 16 +/- 4 weeks after ankle-foot bracing. MG muscle belly length and thickness, tendon and fascicle length, as well as their extensibility were captured by 2D ultrasound and 3D motion capturing during passive, manually applied stretches. In addition, 3D gait analysis was conducted. RESULTS: Prior to bracing, the MG muscle-tendon unit in children with CP was 22 % less extensible. At matched amounts of muscle-tendon unit stretch, the muscle belly and fascicles in CP were 7 % and 14 % shorter while the tendon was 11 % longer. Spastic fascicles displayed 32 % less extensibility than controls. Brace wear increased passive dorsiflexion primarily with the knees flexed. During gait, children walked faster and foot lift in swing improved. MG muscle belly and tendon length showed little change, but fascicles further shortened (-11 %) and muscle thickness (-8 %) decreased. CONCLUSIONS: Use of ankle-foot braces improves function but may lead to a loss of sarcomeres in series, which could explain the shortened fascicles. To potentially induce gastrocnemius muscle growth, braces may also need to extend the knee or complementary training may be necessary to offset the immobilizing effects of braces. PMID- 26108741 TI - A quantitative transcriptome reference map of the normal human hippocampus. AB - We performed an innovative systematic meta-analysis of 41 gene expression profiles of normal human hippocampus to provide a quantitative transcriptome reference map of it, i.e. a reference typical value of expression for each of the 30,739 known mapped and the 16,258 uncharacterized (unmapped) transcripts. For this aim, we used the software called TRAM (Transcriptome Mapper), which is able to generate transcriptome maps based on gene expression data from multiple sources. We also analyzed differential expression by comparing the hippocampus with the whole brain transcriptome map to identify a typical expression pattern of this subregion compared with the whole organ. Finally, due to the fact that the hippocampus is one of the main brain region to be severely affected in trisomy 21 (the best known genetic cause of intellectual disability), a particular attention was paid to the expression of chromosome 21 (chr21) genes. Data were downloaded from microarray databases, processed, and analyzed using TRAM software. Among the main findings, the most over-expressed loci in the hippocampus are the expressed sequence tag cluster Hs.732685 and the member of the calmodulin gene family CALM2. The tubulin folding cofactor B (TBCB) gene is the best gene at behaving like a housekeeping gene. The hippocampus vs. the whole brain differential transcriptome map shows the over-expression of LINC00114, a long non-coding RNA mapped on chr21. The hippocampus transcriptome map was validated in vitro by assaying gene expression through several magnitude orders by "Real-Time" reverse transcription polymerase chain reaction (RT-PCR). The highly significant agreement between in silico and experimental data suggested that our transcriptome map may be a useful quantitative reference benchmark for gene expression studies related to human hippocampus. Furthermore, our analysis yielded biological insights about those genes that have an intrinsic over-/under expression in the hippocampus. PMID- 26108742 TI - Erratum to: Ammonia Toxicity to the Freshwater Planarian Polycelis felina: Contrasting Effects of Continuous Versus Discontinuous Exposures. PMID- 26108743 TI - Calpeptin, not calpain, directly inhibits an ion channel of the inner mitochondrial membrane. AB - The permeability transition pore (PTP) of inner mitochondrial membranes is a large conductance pathway for ions up to 1500 Da which opening is responsible for ion equilibration and loss of membrane potential in apoptosis and thus in several neurodegenerative diseases. The PTP can be regulated by the Ca(2+)-activated mitochondrial K channel (BK). Calpains are Ca(2+)-activated cystein proteases; calpeptin is an inhibitor of calpains. We wondered whether calpain or calpeptin can modulate activity of PTP or BK. Patch clamp experiments were performed on mitoplasts of rat liver (PTP) and of an astrocytoma cell line (BK). Channel independent open probability (P(o)) was determined (PTP) and, taking into account the number of open levels, NP(o) by single channel analysis (BK). We find that PTP in the presence of Ca(2+) (200 MUM) is uninfluenced by calpain (13 nM) and shows insignificant decrease by the calpain inhibitor calpeptin (1 MUM). The NP(o) of the BK is insensitive to calpain (54 nM), too. However, it is significantly and reversibly inhibited by the calpain inhibitor calpeptin (IC50 = 42 MUM). The results agree with calpeptin-induced activation of the PTP via inhibition of the BK. Screening experiments with respirometry show calpeptin effects, fitting to inhibition of the BK by calpeptin, and strong inhibition of state 3 respiration. PMID- 26108745 TI - A new framework to evaluate ecosystem health: a case study in the Wei River basin, China. AB - Due to the rapid growth of the population and the development of economies in the Guanzhong district, central China, the river ecosystem is gradually deteriorating, which makes it important to assess the aquatic ecosystem health and take measures to restore the damaged ecosystem. An index of catchment ecosystem health has been developed to assist large-scale management of watersheds by providing an integrated measure of ecosystem health, including aquatic and terrestrial ecosystem. Most researches focus on aquatic ecosystem or terrestrial ecosystem, but little research integrates both of them to assess the catchment ecosystem health. In this paper, we combine these two aspects into catchment ecosystem health. Ecosystem indicators derived from field samples and modeling are identified to integrate into ecosystem health. These included indicators of ecological landscape pattern (based on normalized difference vegetation index (NDVI), vegetation cover, dominance index, Shannon's diversity index, Shannon's evenness index, and fragmentation index), hydrology regime (based on 33 hydrological parameters), physical form condition (based on substrate, habitat complexity, velocity/depth regimes, bank stability, channel alteration), water quality (based on electrical conductivity (Cond), dissolved oxygen (DO), NH3_N, total nitrogen (TN), total phosphorus (TP), chemical oxygen demand-permanganate (CODMn)), and biological quality (based on fish abundance). The index of ecosystem health is applied in the Guanzhong district, and the ecosystem health was fair. The ecosystem health in the upstream to Linjiacun (U L) and Linjiacun to Weijiabao (L-W) reaches was in good situation, while that in Weijiabao to Xianyang (W-X), Xianyang-Weijiabao (X-W), and Weijiabao to Tongguan (W-T) reaches was in fair situation. There is a trend that the ecosystem health in the upstream was better than that in the downstream. The ecosystem health assessment is expected to play a key role in future water and watershed management of the Wei River basin, or even the Yellow River basin. PMID- 26108744 TI - Comparative analysis of transcription factor gene families from Papaver somniferum: identification of regulatory factors involved in benzylisoquinoline alkaloid biosynthesis. AB - Opium poppy (Papaver somniferum L.), known for biosynthesis of several therapeutically important benzylisoquinoline alkaloids (BIAs), has emerged as the premier organism to study plant alkaloid metabolism. The most prominent molecules produced in opium poppy include narcotic analgesic morphine, the cough suppressant codeine, the muscle relaxant papaverine and the anti-microbial agent sanguinarine and berberine. Despite several health benefits, biosynthesis of some of these molecules is very low due to tight temporal and spatial regulation of the genes committed to their biosynthesis. Transcription factors, one of the prime regulators of secondary plant product biosynthesis, might be involved in controlled biosynthesis of BIAs in P. somniferum. In this study, identification of members of different transcription factor gene families using transcriptome datasets of 10 cultivars of P. somniferum with distinct chemoprofile has been carried out. Analysis suggests that most represented transcription factor gene family in all the poppy cultivars is WRKY. Comparative transcriptome analysis revealed differential expression pattern of the members of a set of transcription factor gene families among 10 cultivars. Through analysis, two members of WRKY and one member of C3H gene family were identified as potential candidates which might regulate thebaine and papaverine biosynthesis, respectively, in poppy. PMID- 26108746 TI - A modeling approach for agricultural water management in citrus orchards: cost effective irrigation scheduling and agrochemical transport simulation. AB - The water flow and the mass transport of agrochemicals in the unsaturated and saturated zone were simulated in the extended alluvial basin of Keritis river in Crete, Greece (a predominantly flat and most productive citrus growing area) using the hydrological model MIKE SHE. This model was set up based on information on land use, geology, soil structure, meteorological data, as well as groundwater level data from pumping wells. Additionally, field measurements of the soil moisture at six different locations from three soil depths (0.1, 0.2, and 0.3 m) were used as targets to calibrate and validate the unsaturated flow model while for saturated condition, groundwater level data from three well locations were used. Following the modeling approach, the agrochemical mass transport simulation was performed as well, based on different application doses. After the successful calibration processes, the obtained 1D modeling results of soil moisture-pressure related to soil depth at different locations were used to design a proper and cost-effective irrigation programme (irrigation timing, frequency, application rates, etc.) for citrus orchards. The results of the present simulation showed a very good correlation with the field measurements. Based on these results, a proper irrigation plan can be designed at every site of the model domain reducing the water consumption up to 38% with respect to the common irrigation practices and ensuring the citrus water productivity. In addition, the effect of the proposed irrigation scheduling on citrus yield was investigated. Regarding the agrochemical concentration in the groundwater for all dose cases was below the maximum permissible limit. The only exception was for the highest dose in areas where the water table is high. Thus, this modeling approach could be used as a tool for appropriate water management in an agricultural area estimating at each time and location the availability of soil water, contributing to a cost effective irrigation plan. PMID- 26108747 TI - Decadal changes in the land use/land cover and shoreline along the coastal districts of southern Gujarat, India. AB - The coastal zone along the districts of Surat, Navsari, and Valsad in southern Gujarat, India, is reported to be facing serious environmental challenges in the form of shoreline erosion, wetland loss, and man-made encroachments. This study assesses the decadal land use/ land cover (LULC) changes in these three districts for the years 1990, 2001, and 2014 using satellite datasets of Landsat TM, ETM, and OLI. The LULC changes are identified by using band ratios as a pre classification step, followed by implementation of hybrid classification (a combination of supervised and unsupervised classification). An accuracy assessment is carried out for each dataset, and the overall accuracy ranges from 90 to 95%. It is observed that the spatial extents of aquaculture, urban built up, and barren classes have appreciated over time, whereas the coverage of mudflats has depreciated due to rapid urbanization. The changes in the shoreline of these districts have also been analyzed for the same years, and significant changes are found in the form of shoreline erosion. The LULC maps prepared as well as the shoreline change analysis done for this study area will enable the local decision makers to adopt better land-use planning and shoreline protection measures, which will further aid in sustainable future developments in this region. PMID- 26108749 TI - [BASIC ASPECTS OF IMMUNOTHERAPY]. PMID- 26108750 TI - [ALLERGEN IMMUNOTHERAPY FOR ALLERGIC RHINITIS]. PMID- 26108748 TI - Long-term evolution of highly alkaline steel slag drainage waters. AB - The disposal of slag generated by the steel industry can have negative consequences upon the surrounding aquatic environment by the generation of high pH waters, leaching of potentially problematic trace metals, and rapid rates of calcite precipitation which smother benthic habitats. A 36-year dataset was collated from the long-term ambient monitoring of physicochemical parameters and elemental concentrations of samples from two steel slag leachate-affected watercourses in northern England. Waters were typified by elevated pH (>10), high alkalinity, and were rich in dissolved metals (e.g. calcium (Ca), aluminium (Al), and zinc (Zn)). Long-term trend analysis was performed upon pH, alkalinity, and Ca concentration which, in addition to Ca flux calculations, were used to highlight the longevity of pollution arising as a result of the dumping and subsequent leaching of steel slags. Declines in calcium and alkalinity have been modest over the monitoring period and not accompanied by significant declines in water pH. If the monotonic trends of decline in alkalinity and calcium continue in the largest of the receiving streams, it will be in the region of 50-80 years before calcite precipitation would be expected to be close to baseline levels, where ecological impacts would be negligible. PMID- 26108751 TI - [LATEX ALLERGY SAFETY-MEASURES GUIDELINE 2013]. PMID- 26108752 TI - [PATHOGENESIS AND TREATMENT OF ALLERGIC SKIN DISEASE -ATOPIC DERMATITIS]. PMID- 26108753 TI - [CLINICAL EFFICACY OF SUSTAINED HIGH-EFFICACY DAILY DIAFILTRATION USING A MEDIATOR-ADSORBING MEMBRANE AND DIRECT HEMOPERFUSION WITH A POLYMYXIN B IMMOBILIZED FIBER COLUMN IN TREATING ACUTE EXACERBATION OF IDIOPATHIC INTERSTITIAL PNEUMONIAS]. AB - OBJECTIVES: The aim of this study is to investigate the clinical outcomes of patients with steroid-resistant acute exacerbation of idiopathic interstitial pneumonias treated with blood purification therapy comprising direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX-DHP) and sustained high-efficacy daily diafiltration using a mediator-adsorbing membrane (SHEDD-fA). METHODS: The clinical outcomes and respiratory function were retrospectively compared between 6 patients who underwent blood purification therapy (blood purification group) and 15 patients (control group) who blood purification therapy. RESULTS: The patients in the blood purification group showed a higher PaO2/FiO2 ratio than those in the control group. Twenty-eight days (83%; 5/6 vs. 20%; 3/15) and ninety days (67%; 4/6 vs. 6.7%; 1/15) survival rates were also higher in the blood purification group. The blood purification group also showed a better 90-day survival curve (Hazard ratio=0.260) compared to the control group. CONCLUSIONS: In conclusion, combination blood purification therapy comprising PMX-DHP and SHEDD-fA may be used to treat acute exacerbation of idiopathic interstitial pneumonias. PMID- 26108754 TI - [RATIONALE FOR ELIMINATING CERTAIN FOODS IN CHILDREN WITH FOOD ALLERGY]. AB - BACKGROUND: Some caregivers of children with food allergy may eliminate specific foods from the diet of these children without first consulting doctors. The aim of this study was to investigate the prevalence of such practice and the sensitization of the offending foods. METHODS: All participants were patients aged one year or over who visited our outpatients unit with complaints of food allergy. Caregivers of the patients were asked to fill out a questionnaire to state the eliminated food items and the grounds for avoidance ("doctor's instructions", "family's judgment", and "not consumed in daily diet") of nine food items including chicken egg, cow's milk, wheat, soy bean, rice, buckwheat, peanut, sesame and shrimp. Data on food-specific IgE titers were extracted from the patients' electronic medical charts. RESULTS: A total of 463 subjects were included in the analyses. Prevalence of patients with specific food avoidance of each of the food item was higher in the lower age group than the higher age group. More than 83% of the patients who avoided chicken egg, cow's milk or wheat were advised by their doctors to do so, while less than 49% of patients who avoided buckwheat did so for the same reason. The percentage of the patients who showed positive sensitization to buckwheat, peanut or shrimp, and avoided it without doctor's instructions, was 46%, 48%, and 34%, respectively. CONCLUSION: While the majority of caregivers of the children who visited our outpatient unit eliminated specific foods according to doctor's instructions, a considerable proportion of them do so inappropriately without first consulting a doctor. PMID- 26108755 TI - [DEVELOPMENT OF MEDICAL EDUCATIONAL PROGRAM FOR PEDIATRICIANS TO IMPROVE THEIR BEHAVIOR IN THE MANAGEMENT OF FOOD ALLERGY]. AB - BACKGROUND: Many children are suffering from food allergy, however, not all of them are treated properly by pediatricians based on the latest practice guideline. The guideline does not recommend excessive elimination diet, but suggests initial appropriate skincare treatment before examining candidate allergens for food-allergy-patients with atopic dermatitis. We developed and evaluated a curriculum for continuing medical education for pediatrician about food allergy. METHODS: We provided a medical educational program for pediatricians at the Division of Allergy in National Center for Child Health and Development, from January 2013 to January 2014. The program was aimed to improve their behavior in the management of food allergy, if they excessively eliminated diet from the patients and did not treat atopic dermatitis appropriately. The program was constituted of SBOs and educational strategy. Participant's self evaluation of learning and that of behavior were carried out before and after the training, and their scores were analyzed for the program evaluation. RESULTS: Thirty-five participants completed the program. All the scores rating 22 items for evaluation of learning were increased. Five items out of 7 about evaluation of behavior were significantly improved. CONCLUSION: We developed a medical educational program about food allergy for pediatricians. After training based on this program, the participants' knowledge and skills were improved and their behavior was desirably modified. PMID- 26108756 TI - Exposure to concentrated ambient particulate matter induces reversible increase of heart weight in spontaneously hypertensive rats. AB - BACKGROUND: Exposure to ambient PM2.5 increases cardiovascular mortality and morbidity. To delineate the underlying biological mechanism, we investigated the time dependence of cardiovascular response to chronic exposure to concentrated ambient PM2.5 (CAP). METHODS: Spontaneously hypertensive rats (SHR) were exposed to CAP for 15 weeks, and blood pressure (BP), cardiac function and structure, and inflammations of lung, hypothalamus, and heart were measured at different time points. RESULTS: Chronic exposure to CAP significantly increased BP, and withdrawal from CAP exposure restored BP. Consistent with its BP effect, chronic exposure to CAP significantly decreased cardiac stroke volume and output in SHR, accompanied by increased heart weight and increased cardiac expression of hypertrophic markers ACTA1 and MYH7. Withdrawal from CAP exposure restored cardiac function, weight, and expression of hypertrophic markers, supporting the notion that cardiac dysfunction and hypertrophy is subsequent to hypertension. In agreement with the role of systemic inflammation in mediating the cardiovascular effects of CAP exposure, chronic exposure to CAP markedly increased expression of pro-inflammatory cytokines in lung, heart, and hypothalamus. However, withdrawal from exposure resolves inflammation in the heart and hypothalamus, but not in the lung, suggesting that CAP exposure-induced systemic inflammation may be independent of pulmonary inflammation. CONCLUSION: Chronic exposure to CAP induces reversible cardiac dysfunction and hypertrophy, which is likely to be subsequent to the elevation in BP and induction of systemic inflammation as evidenced by increased mRNA expression of pro-inflammatory cytokines in diverse tissues. PMID- 26108758 TI - [Laparoscopic surgery for colorectal cancer with liver metastasis]. AB - For the patients who have colorectal cancer with liver metastasis, synchronous resection or staged surgery for primary colorectal tumor and liver metastasis is usually needed which is associated with significant trauma. The role of laparoscopic colorectal surgery has been established and its application in colorectal cancer with liver metastasis increases gradually. Laparoscopic surgery for colorectal liver metastasis as a minimally invasive approach should also follow the oncological principles of colorectal liver metastasis, and the appropriate timing for laparoscopic surgery should be individualized. With the development of the laparoscopic surgery, more patients will benefit from minimally invasive surgery for colorectal liver metastasis. PMID- 26108757 TI - Grand mal seizure induced by low-dose fentanyl and lidocaine in a young child. AB - Surgical procedures require general anesthesia using combinations of drugs including fentanyl and/or lidocaine. Because many of these drugs have bimodal anticonvulsant/proconvulsant effects, they must be administered carefully. We herein report a case of seizure attack during anesthesia induction with low-dose fentanyl and lidocaine in a young child with no history of seizures. A 10-year old girl was scheduled to receive an elective tenectomy. After a few seconds of fentanyl and lidocaine administration for anesthesia induction, she developed generalized tonic-clonic seizures. Seizures subsided spontaneously after 3 minutes. The patient's blood sugar, serum electrolytes, and arterial blood gas analysis were normal immediately after the event. She remained hemodynamically stable; however, the surgery was postponed after communication and discussion with the surgeon. Postoperatively, there was no evidence of postictal phase, and serum electrolytes and magnetic resonance imaging of the brain were normal. The patient had an uneventful recovery. However, electroencephalogram showed that hyperventilation stimulation test induced isolated epileptiform spikes over O1, suggesting a potential paroxysmal disorder over the left occipital area. This report is on a rare complication likely caused by fentanyl or lidocaine, which suggests that these drugs should be used cautiously in children whose clinical epileptic activities have been verified or are strongly suspected. PMID- 26108759 TI - [Applied anatomy of laparoscopic-assisted right hemicolectomy for colon cancer]. AB - Laparoscopic-assisted colon surgery is an alternative to open surgery. Furthermore, complete mesocolic excision (CME) as a new concept in colon cancer surgery was first proposed by Hohenberger from Germany, which follows the oncological principle of the tumor and is based on the embryology and anatomy. Some researches about CME showed that this procedure could improve the prognosis, decrease the local recurrence of the tumor without increased complications. Although a laparoscopic approach for right colon cancer is performed frequently, identifying an adequate dissection plane is not always easy. The surgeons need to know well about local anatomy of laparoscopic-assisted radical right hemicolectomy, and to master the right surgical plane in operation process, then to reduce the incidence of conversion to laparotomy and side injury. The superior mesenteric vein (SMV) is the key landmark. The fusion fascia space is the right surgical plane, as well as a series of peripheral peritoneal attachments are important fixations in laparoscopic right hemicolectomy by medial access. Identifying the anatomical location of the SMV and performing meticulous dissection along the SMV is an essential procedure to dissect all potential lymphatic drainage during laparoscopic CME for right colon cancer. PMID- 26108760 TI - [Techniques of autonomic nerve preservation in laparoscopic radical resection for rectal cancer]. AB - Pelvic autonomic nerve is a three-dimensional structure surrounding the rectum. There are several key points related to nerve injury during laparoscopic radical resection for rectal cancer. Hypogastric nerve has close relation with the upper and middle part of the rectum. Combined with S2-S4 pelvic splanchnic nerve, hypogastric nerve forms pelvic plexus. Incorrect operation in pelvic parietal peritoneum during dissection of upper rectum will lead to nerve injury. When performing dissection of inferior mesenteric artery, bilateral nerve tracts should be pushed to posterior abdominal wall and anterior fascia of the abdominal aorta should be well protected to avoid nerve injury. Pelvic plexus fibers located lateral to the rectum of pelvic floor, as well as neurovascular bundle closed to Denonvillier's fascia, also have close relations with nerve injury. Dissection of either lateral or anterior wall of rectum should be performed behind the Denonvillier's fascia and in front of the proper fascia of rectum. Sharp dissection should be performed closed to the mesorectum to protect branches of pelvic plexus. PMID- 26108761 TI - [Prevention and management of complications after laparoscopic colorectal surgery]. AB - Laparoscopic colorectal operation is one of the most reliable procedures and widely used in the treatment of gastrointestinal tumor. Its advantages, including minimed invasiveness and rapid postoperative recovery have been widely accepted, but the complications are still chanllenging for surgeons. Intraoperative complications mainly include vascular injury, bowel injury and ureteral damage. Postoperative complications include anastomotic leak, bleeding and stenosis. Understanding of anatomy and precise operation are critical to prevent complications. Diagnosis of postoperative complications in time and proper treatment can achieve maximal improvement of outcomes. PMID- 26108762 TI - [Application of endoscopic resection for colorectal neoplasms]. AB - With the development and maturation of endoscopic management, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), submucosal tunneling endoscopic resection (STER) and laparoscopic-endoscopic cooperative surgery (LECS) show absolute advantages in minimal invasion and functional preservation in the treatment of colorectal neoplasms. More and more endoscopic managements are carried out to treat colorectal neoplasms. The aim of this article is to summarize the application of endoscopic management for colorectal neoplasms. PMID- 26108763 TI - [Application of combined laparoscopic endoscopic procedures in the treatment of colorectal neoplasms]. AB - Combined laparoscopic endoscopic procedures (CLEP) is a technical advance in minimally invasive approaches, combining the advantages of both laparoscopy and endoscopy. CLEP expands the use of minimally invasive surgery, and improves the safety, precision and efficacy in the treatment of colorectal neoplasms.Endoscopy assisted laparoscopic surgery (EALS), laparoscopy- assisted endoscopic surgery (LAES), and laparoscopy endoscopy cooperative surgery (LECS) are being used. The combined application of laparoscopy and colonoscopy or transanal endoscopic microsurgery (TEM) provides a new minimally invasive approach for the treatment of colorectal benign and malignant tumors, especially suitable for the patients undergoing single laparoscopic or endoscopic surgery with greater difficulty and higher risk, or those who would have undergone open operation in the past. CLEP enhances the safety and efficacy of minimally invasive surgery, and achieves the minimal invasiveness and maximal preservation of physiological function at the same time. To a large extent, the integrated operating room and multidisciplinary team help to promote the development of these new minimally invasive procedures. PMID- 26108764 TI - [Robotic surgery in colorectal cancer: present and future]. AB - After more than a decade of development, the role of robotic rectal cancer surgery has been established. However robotic right hemicolectomy has just commenced. For rectal cancer surgery, the Da Vinci system is more flexible, accurate, and stable than traditional laparoscopy. The robotic surgery is safe and efficient, and protects the pelvic autonomic nerve function better. At the same time, robotic surgery is easy to learn, promoting its popularization. In robotic right hemicolectomy, the surgery suitable for Da Vinci system is also improved. Da Vinci system is not perfect. High cost is a major obstacle to the wide applications. Lack of tactile feedback and limited mobility of robotic arms also should not be ignored. The next generation of robotic system may make up for these deficiencies through a number of new technologies. The combination of robotics with single port laparoscopic techniques and multi-organ resections is expected to expand the advantages of robotic surgery in colorectal cancer and promote its development. PMID- 26108765 TI - [Practice and investigation of clinical teaching mode of standardized treatment in colorectal cancer for fellows in training]. AB - A new clinical teaching mode of standardized treatment in colorectal cancer for fellows in training is reported here with good results. This one-year program included medical ethics education, humanistic management, pre job training, clinical thinking mode, surgery teaching, and computerized teaching. This new clinical teaching mode with distinct features is effective and introduced in this article. PMID- 26108766 TI - [Application of carbon nanoparticles labeled lymph node staining in curative laparoscopic resection for colorectal carcinoma]. AB - OBJECTIVE: To evaluate the clinical application of carbon nanoparticles labeled lymph node staining in curative laparoscopic resection for colorectal carcinoma. METHODS: Sixty-five patients undergoing curative laparoscopic resection for colorectal carcinoma in the Sun Yat-sen Memorial Hospital between September 2011 and June 2013 were prospectively enrolled and randomly divided into label group (with carbon nanoparticles, n=34) and control group (without carbon nanoparticles, n=31). Association between labeled lymph nodes and metastasis was analyzed. The total number of retrieved lymph nodes and lymph nodes metastatic ratio were compared between the two groups. RESULTS: Mean number of retrieved lymph node of the label group was higher as compared to the control group (22.3+/ 4.2 vs. 15.4+/-3.5, P<0.05). The total number of retrieved lymph node was 725 in the label group and 478 in the control group. Among them, lymph node < 5 mm accounted for 4.6% (33/725) in the label group, which was higher than 2.0% (10/478) (P=0.025) in the control group. The number of black stain label lymph node was 412, with black stain ratio 56.8% (412/725) in the label group. Metastatic ratio of black stain nodes was significantly higher than that of non stain nodes [28.6% (118/412) vs. 19.5% (61/313), P=0.005]. CONCLUSIONS: The technique of carbon nanoparticles labeled lymph node staining in curative laparoscopic resection for colorectal carcinoma is easy and effective, which can increase the retrieved number of lymph nodes, especially for nodes < 5 mm. The black stain lymph nodes indicate higher risk of metastasis. PMID- 26108767 TI - [Prognostic value of lymph node ratio and N stage in stage III colorectal cancer]. AB - OBJECTIVE: To compare the prognostic value of lymph node ratio and N staging in stage III colorectal cancer. METHODS: The clinicopathologic factors and follow-up data of 304 cases with stage III colorectal cancer from January 1998 to December 2011 were analyzed retrospectively. Multivariate analysis was performed using Cox proportional hazard regression model in forward stepwise regression. Patients were divided into different subgroups according to the number of lymph nodes sample. RESULTS: LNR and N stage were independent risk factors for stage III colorectal cancer, the prognostic value of LNR was better than that of N stage [Odds ratio were 1.838(95% CI:1.563~2.161) vs. 1.625 (95% CI:1.392~1.898)]. Subgroup analysis showed that, when the number of lymph nodes sample was less than 13, the prognostic value of LNR was better than that of N stage (Odds ratio were 1.836 vs. 1.639). But when the number of lymph nodes sample was more than 13, they were comparable (Odds ratio were 1.876 vs. 1.853). CONCLUSIONS: The prognostic value of LNR and N stage were comparable for stage III colorectal cancer, but when the number of lymph nodes sample was less than 13, LNR was more valuable. PMID- 26108768 TI - [Impact of macroscopic enlarged lymph node on stage II colorectal cancer prognosis and its potential mechanism]. AB - OBJECTIVE: To evaluate the impact of macroscopic enlarged lymph node on the clinicopathological characteristics of stage II colorectal cancer, and to explore the potential mechanism. METHODS: Clinicopathological data of 116 consecutive patients with stage II colorectal cancer, who underwent colorectal radical resection and were identified as stage II colorectal cancer without mesenteric metastasis by postoperative pathology, in our department between December 2001 and December 2002 were analyzed retrospectively. All the patients were examined by the surgeons with gross appearance to decide the enlarged lymph nodes as metastasis during operation. There were 43 patients with macroscopic enlarged lymph nodes and 73 without such lymph nodes. Survival rate was compared between the two groups. Impact of macroscopic enlarged lymph node on the prognosis of stage II colorectal cancer was analyzed. Structure of macroscopic enlarged lymph node was observed. CK expression in 107 macroscopic enlarged lymph nodes from 43 cases was examined by immunohistochemistry. RESULTS: The 10-year disease-free survival (DFS) of the whole group was 83.5%. The 10-year DFS of patients with macroscopic enlarged lymph nodes was 75.9%, which was significantly lower than 89.3% (P=0.038) of patients without macroscopic enlarged lymph nodes. Univariate analysis showed that macroscopical enlarged lymph node (P=0.038), perioperative blood transfusion (P=0.004), number of retrieved lymph nodes (P=0.016), concomitant disease (P=0.003), and preoperative serum carcinoembryonic antigen (CEA) level (P=0.050) were related to the prognosis of all the 116 patients. Multivariate analysis showed that macroscopical enlarged lymph node (P=0.044), number of retrieved lymph nodes (P=0.021), and perioperative blood transfusion (P=0.032) were independent prognostic factors. Haematoxylin and eosin (HE) staining indicated that enlarged lymph nodes had hyperplasia reaction. Immunohistochemistry showed that among 107 enlarged lymph nodes, 1 had macrometastases, 1 micrometastasis, 4 isolated tumor cell (ITC), and the rest 101 had no positive CK expression. CONCLUSION: Macroscopic enlarged lymph node indicates a poor prognosis in patients with stage II colorectal cancer. PMID- 26108769 TI - [Risk factor analysis on postoperative complications after laparoscopic total mesorectal excision with preventive terminal ileostomy and timing of stoma closure in rectal cancer]. AB - OBJECTIVE: To summarize the application of protective terminal ileostomy in laparoscopic total mesorectal excision for rectal cancer patients, and explore the risk factors associated with postoperative complications and timing of stoma closure. METHODS: Clinical data of 77 patients with middle or low rectal cancer undergoing laparoscopic total mesorectal excision (TME) with preventive terminal ileostomy in our department from January 2007 to December 2013 were retrospectively analyzed. Independent risk factors associated to postoperative complications of terminal ileostomy were examined by logistic regression and timing of stoma closure was investigated. RESULT: The total postoperative complication morbidity was 57.1% (44/77). Electrolyte disturbance was found in 39 cases (50.6%, 39/77), including 1 case of hypovolemic syncope. Parastomal hernia occurred in 9 cases (11.7%, 9/77). Peristomal dermatitis and subcutaneous abscess was observed in 1 case (1.3%, 1/77). The result of the single factor analysis of the water electrolyte disturbance after operation, the risk factors of P<0.2 were new adjuvant chemotherapy (P=0.094), tumor antigen (P=0.086) and TNM staging (P=0.026); Postoperative parastomal hernia of the single factor analysis results, the risk factors of P<0.2 included uses of antidiabetic drugs (P=0.172), ASA anesthesia (P=0.168) grading and TNM stage(P=0.161); But multivariate analysis revealed no risk factors associated with the above complications (all P>0.05). Sixty-five patients underwent stoma closure during follow-up, including 2 cases (3.1%) within 90 days, 20 cases (30.8%) from 90 to 180 days, and 43 cases (66.2%) more than 180 days. CONCLUSIONS: No risk factors were found to be associated with main postoperative complications of protective terminal ileostomy after laparoscopic TME for rectal cancer patients, such as electrolytes imbalance and parastomal hernia. The timing of stoma closure should be longer than 180 days. PMID- 26108770 TI - [Oncologic safety of laparoscopic surgery in radical resection for different stage rectal cancer]. AB - OBJECTIVE: To evaluate the oncologic safety and short-term outcomes of laparoscopic surgery in early and advanced rectal cancers. METHODS: Clinical and follow-up data of 186 cases with rectal cancer undergoing laparoscopic radical resection from June 2009 to December 2013 were analyzed retrospectively, including 48 early rectal cancer (stage 0-I) and 138 advanced cancer (stage II III). Thirty-seven cases with early rectal cancer and 275 with advanced cancer undergoing open radical surgery were selected as control group. Surgical safety, oncologic safety and short-term outcomes were compared between two groups. RESULTS: As for either early or advanced rectal cancer, there were no significant differences in the number of harvested lymph nodes, length of distal resection margin, complication morbidity, rate of local recurrence, distant metastasis, and 3-year survival rate between the two groups (all P>0.05). Although the operation time was longer in laparoscopic group, the laparoscopic group presented less intra-operative blood loss, faster recovery of bowel function, and shorter postoperative hospital stay (all P<0.05). As for advanced rectal cancer, laparoscopic radical surgery tended to achieve less lymph nodes dissected (mean, 13.5 vs. 15.0) and develop more anastomotic leakage (8.0% vs. 5.5%) compared to open surgery, although neither reached statistical significance (P=0.112, P=0.221). Moreover, the conversion rate in patients with advanced rectal cancer was significantly higher than that in those with early cancer (10.9% vs 2.1%, P=0.048). CONCLUSIONS: Laparoscopic surgery can obtain the same oncologic and surgical safety for early rectal cancer as compared to open surgery. However, due to higher conversion rate, potential risk of decreased number of harvested lymph nodes and increased anastomotic leakage, laparoscopic surgery for advanced rectal cancer should be carried out prudently, especially in some hospitals with less laparoscopic experience. PMID- 26108771 TI - [Application of protective appendicostomy after sphicter-preserving surgery for patients with low rectal carcinoma who are at high-risk of anastomotic leakage]. AB - OBJECTIVE: To explore the application of protective appendicostomy after sphicter preserving surgery for patients with low rectal carcinoma who are at high-risk of anastomotic leakage. METHODS: Clinical data of 74 low rectal cancer cases with high-risk anastomotic leakage undergoing laparoscope-assisted total mesorectal excision(TME) sphincter-preserving operation in our department from September 2013 to September 2014 were analyzed retrospectively. Patients were randomly divided into two groups: 36 patients received appendicostomy and catheter was removed 4 to 6 weeks after operation when sinus tract formation in abdominal wall was identified; 38 patients received traditional ileostomy and stoma closure was performed 3 to 6 months after operation. RESULTS: The operation time was (149.2+/ 9.4) min vs. (146.7+/-12.7) min, postoperative complication morbidity was 8.3%(3/36) vs. 13.2%(5/38), anastomotic leakage rate was 2.8%(1/38) vs. 2.6%(1/36), mean drainage volume of 1-week stoma was (203.2+/-76.9) ml vs. (195.8+/-76.5) ml, intestinal function recovery time was (25.5+/-5.6) h vs. (24.0+/-5.8) h in intubation colostomy group and ileostomy group respectively, and these differences were not significant (all P>0.05). While total hospital stay was shorter and cost was less in intubation colostomy group as compared to ileostomy group [(8.8+/-1.7) d vs. (18.0+/-1.7) d, (32 000+/-3000) yuan vs. (51 000+/-4000) yuan], and these differences were significant (all P<0.05). CONCLUSION: For low rectal cancer patients who are at high-risk of developing anastomotic leakage undergoing sphincter-preserving anterior resection, protective appendicostomy can decrease anastomotic leakage rate, avoid second stoma closure, shorten hospital stay and reduce hospital cost. PMID- 26108772 TI - [Laparoscopic-assisted natural orifice specimen extraction radical left colectomy]. AB - OBJECTIVE: To explore the feasibility of laparoscopic-assisted natural orifice specimen extraction radical left colectomy. METHODS: Retrospective analysis was performed on clinicopathological dada of 15 colorectal patients who were treated by laparoscopic-assisted anal specimen extraction radical left colectomy with self-developed surgical instrument Cai tube between January and September in 2014. Tumor location included descending colon (n=3), the junction of descending colon and sigmoid colon (n=2), the sigmoid colon (n=6) and upper rectum (n=4). Clinical efficacy of patients was observed. RESULTS: There were no perioperative deaths or postoperative complications, such as anastomotic bleeding or leakage. The median operation time was 257 (range 103-337) min, median blood loss was 50(range 20-200) ml, median time to first flatus was 3 (range 1-5) d and median hospital stay was 14 (range 11-21) d. All the patients had good quality of life and normal defecation function without tumor recurrence or metastasis after 1-8 months of follow-up. CONCLUSION: Laparoscopic-assisted anal specimen extraction radical left colectomy is safe and feasible. PMID- 26108773 TI - [Transanal laparoscopic radical resection with telescopic anastomosis for low rectal cancer]. AB - OBJECTIVE: To assess the safety, feasibility and clinical outcome of laparoscopic radical resection for low rectal cancer with telescopic anastomosis or with colostomy by stapler through transanal resection without abdominal incisions. METHODS: From January 2010 to September 2014, 37 patients underwent laparoscopic radical resection for low rectal cancer through transanal resection without abdominal incisions. The tumors were 4-7 cm above the anal verge. On preoperative assessment, 26 cases were T1N0M0 and 11 were T2N0M0. RESULTS: For all cases, successful surgery was performed. In telescopic anastomosis group, the mean operative time was (178+/-21) min, with average blood loss of (76+/-11) ml and (13+/-7) lymph nodes harvested. Return of bowel function was (3.0+/-1.2) d and the hospital stay was (12.0+/-4.2) d without postoperative complications. Patients were followed up for 3-45 months. Twelve months after surgery, 94.6%(35/37) patients achieved anal function Kirwan grade 1, indicating that their anal function returned to normal. CONCLUSIONS: Laparoscopic radical resection for low rectal cancer with telescopic anastomosis or colostomy by stapler through transanal resection without abdominal incisions is safe and feasible. Satisfactory clinical outcome can be achieved mini-invasively. PMID- 26108774 TI - [Clinical efficacy observation of cetuximab combined with chemotherapy in the treatment of metastatic colorectal carcinoma]. AB - OBJECTIVE: To observe the clinical efficacy of cetuximab plus chemotherapy in the treatment of metastatic colorectal carcinoma. METHODS: Clinicopathological data of 128 patients with metastatic colorectal cancer admitted in the Department of Oncology, Chinese PLA General Hospital from 2008 to June 2012 were analyzed retrospectively. Among them, 91 patients received cetuximab as the first-line therapy and 37 in the second-line or more-line therapy. The chemotherapy regimens included oxaliplatin-based therapy (FOLFOX/XELOX), irinotecan-based therapy (FOLFIRI/XELIRI) and fluorouracil-based therapy (Xeloda). The efficacy was evaluated according to RECIST 1.0 criteria. The remission rate, control rate and time to disease progression were compared among patients receiving cetuximab combined with different chemotherapy regimens in different periods. RESULTS: The disease control rate of cetuximab applied in the first-line treatment was higher than that of the second-line or more-line [85.9% (61/71) vs. 59.3% (16/27), P=0.004]. The disease control rate of the group treated with cetuximab plus oxaliplatin-based chemotherapy was much higher compared to the other two groups [91.1% (41/45) vs. 68.1% (32/47), 4/6, P=0.021]. But there were no significant differences among three regimens in the terms of overall response rate (all P>0.05). The median time to progression of groups with cetuximab plus irinotecan, oxaliplatin or capecitabine was 7.8 months, 8.5 months and 5.2 months respectively. The median time to progression of cetuximab combined with chemotherapy in the first-line treatment and the second-line or more-line was 8.2 and 7.7 months respectively. However, the differences were not statistically significant (P>0.05). CONCLUSIONS: Cetuximab in combination with oxaliplatin based chemotherapy is recommended as the first-line application in the treatment of metastatic colorectal carcinoma patients, because it is helpful to improve the rate of disease control. PMID- 26108775 TI - [Association of long-term oral low-dose aspirin and survival in colorectal cancer: a meta-analysis]. AB - OBJECTIVE: To examine the association between long-term oral low-dose aspirin and overall survival in colorectal cancer patients after diagnosis. METHODS: The literature databases, such as PubMed, Embase, Cochrane Library, Web of Science, CBM, CNKI, and Wanfang database, were extensively searched to retrieve the comparative studies about the association between low-dose aspirin use after colorectal cancer diagnosis and overall survival published before June 2014. The state 12.0 version software was used for meta-analysis. The quality of these studies was assessed using the Newcastle-Ottawa scale. RESULTS: There were eight studies meeting the inclusion criteria for meta-analysis. The total sample size of these studies included 28 103 cases and the score of all the studies was more than 6 points. Meta-analysis of the data using I(2) test showed significant heterogeneity (I(2)=78.2%, P<0.01), therefore, a random effect model was performed. Aspirin use after diagnosis was associated with longer overall survival (HR=0.732, 95% CI:0.613-0.875, P<0.01). There were seven studies with the same design or tumor stage in I-IIII period respectively for sensitivity analysis. The results of studies showed that the sensitivity was low and accurate (HR=0.687, 95% CI: 0.557-0.849, P<0.01; HR=0.682, 95% CI: 0.539-0.864, P<0.01). CONCLUSION: Meta-analysis shows that long-term oral low-dose aspirin after diagnosis of colorectal cancer is identified as a significant prognostic factor. PMID- 26108776 TI - [Impact of spasmolytic on polyp and adenoma detection during colonoscopy: a meta analysis]. AB - OBJECTIVE: To investigate the impact of intestinal spasmolytic on colon polyps and adenoma detection rate during colonoscopy. METHODS: Literatures related to the effect of intestinal spasmolytic on colon polyp or adenoma detection rate were retrieved from PubMed, Medline, EBSCO, High Wire Press, OVID, EMBASE, and the China National Knowledge Articles, etc. published before July 2014. Unified data were extracted by two researchers independently and organized using Jadad scale to evaluate the quality of the enrolled studies through Review manager 5.2 Meta-analysis software. RESULTS: Six articles were enrolled with total 47,509 cases, including 16,867 cases in the scopolamine group and 30,642 cases in the placebo group. Meta analysis showed spasmolytic could increase the detective rate of polyps (OR=1.24, 95% CI:1.19-1.30), adenoma (OR=1.25, 95% CI:1.19-1.30) and high-risk adenoma (OR=1.22, 95% CI:1.16-1.29). CONCLUSION: Using colonoscopy spasmolytic scopolamine can increase the detection rate of colonic polyp and adenoma. PMID- 26108777 TI - [Human epidermal growth factor receptor 2 expression in rectal cancer and its clinical implication]. AB - OBJECTIVE: To investigate the consistence of human epidermal growth factor receptor 2 (HER-2) expression in resection samples and biopsy samples from rectal cancer and its clinical implication. METHODS: Clinical data and tissue samples of 544 rectal cancer patients who received surgical resection at Peking University Cancer Hospital from September 2009 to March 2012 were collected and analyzed retrospectively. Immunohistochemical method was used to test HER-2 expression in both surgical resection samples and preoperative biopsy samples. Suspect positive samples with HER-2 (++) were further examined by FISH. Consistence of HER-2 expression between resection samples and biopsy samples, and between resection samples from those patients undergoing neoadjuvant radiotherapy or radiochemotherapy and biopsy samples was analyzed. Association between HER-2 expression and clinicopathological characteristics was examined as well. RESULTS: Among 544 surgical resection samples, positive HER-2 samples of 20 cases (3.7%) were identified either by immunohistochemistry (HER-2, +++) or by FISH amplification. Among 235 paired biopsy samples, positive HER-2 samples of 5 cases (2.1%) were identified. Consistence of HER-2 expression between these two samples was 99.6% (234/235). The kappa value of consistence test was 0.907 (P<0.01). Consistence between resection samples from patients receiving neoadjuvant therapy and biopsy samples was 98.6% (73/74). There was no association of HER-2 over expression or amplification with gender, age, tumor differentiation grade, lymph node metastasis, distant metastasis, TNM stage and overall survival. CONCLUSIONS: Positive rate of HER-2 expression is quite low in rectal cancer and has no relation to clinicopathological characteristics and prognosis. HER-2 status in biopsy samples of rectal cancer is highly consistent with paired surgical resection samples, which is not affected by neoadjuvant radiochemotherapy. PMID- 26108778 TI - [Mechanism of radiotherapy sensitization of curcumin on rectal cancer cells]. AB - OBJECTIVE: To elucidate the mechanism of curcumin in radiotherapy sensitization for colorectal cancer cells. METHODS: Colorectal cancer HT-29 cells were cultured and treated with radiation and curcumin. MTT method was used to detect the cell growth inhibition. Then the high-throughput microarray was used to detect the differences in gene expression levels for each test group to identify differentially expressed genes, and each differential gene was validated by Western blotting. RESULTS: Cell growth inhibition rates at 48-hour and 72-hour in curcumin combined with radiotherapy group were significantly higher than those in simple radiotherapy group (P<0.05). Expression of 95 genes associated with gene injury repair was detected by microarray. Compared to simple radiotherapy group, LIG4 and PNKP expression was down-regulated, and XRCC5 and CCNH expression was up regulated in the curcumin combined with radiotherapy group (all P<0.05). Western blotting revealed LIG4 and PNKP protein expression decreased, and XRCC5 and CCNH protein expression increased in the curcumin combined with radiotherapy group as compared to the simple radiotherapy group (all P<0.05). CONCLUSION: Radiation sensitization effect of curcumin on colorectal cancer cells HT-29 may be associated with the regulation of genes of CCNH, LIG4, XRCC5, PNKP. PMID- 26108779 TI - [Impact of lysosome-associated protein transmembrane-4 beta on proliferation and invasion of colorectal cancer]. AB - OBJECTIVE: To determine whether lysosome-associated protein transmembrane-4 beta (LAPTM4B) over-expression is associated with the proliferation and invasion in colorectal cancer (CRC). METHODS: Thirty pairs of CRC tissues, containing carcinoma and adjacent tissues, were used for the examination of LAPTM4B mRNA expression by real-time quantitative PCR (qPCR) assays. Then immunohistochemistry was performed to examine LAPTM4B protein expression in 6 pairs of CRC tissues. Over-expression LAPTM4B and low-expression LAPTM4B cell models were constructed with HCT116 CRC cell lines. CCK8 assay was used to detect the proliferation and Transwell assay was used to detect the invasion of the model cells. RESULTS: qPCR and immunohistochemistry results showed that LAPTM4B expression levels in CRC were higher compared to adjacent tissues (all P<0.01). CCK8 and Transwell assays results showed that LAPTM4B promoted proliferation and invasion of HCT116 cell lines model cells (all P<0.01). CONCLUSION: LAPTM4B promotes the proliferation and invasion in CRC patients, and may be used as an important potential marker. PMID- 26108780 TI - [Association of gankyrin protein expression in human colorectal cancer with postoperative prognosis]. AB - OBJECTIVE: To investigate the association of gankyrin protein expression in colorectal cancer (CRC) with its prognosis. METHODS: Clinical data and resection samples of 100 colorectal cancer patients identified by pathology undergoing resection in our department from June 2008 to June 2009 were collected. The gankyrin expression in CRC tissues and matched adjacent noncancerous tissues collected during the operation of 100 CRC cases was detected by immunohistochemical staining and Western blotting. The associations of gankyrin expression level with overall survival, clinicopathologic features were analyzed by Chi square test, Cox regression analysis, Kaplan-Meier analysis and log rank test. RESULTS: Immunohistochemical staining showed that the positive brown granules were mainly distributed in the cytoplasm, and nuclear immunostaining was observed in tissue samples of 29 cases, of whom 16 cases had distal metastasis [55.2% (16/29)]. The positive rate of gankyrin and the relative gray value of Western blotting in CRC tissues were 67% (67/100) and 0.69+/-0.23, respectively, which were significantly higher than those of 2 cm adjacent noncancerous tissues [6% (6/100) and 0.31+/-0.16] and 10 cm adjacent noncancerous tissues [1%(1/100) and 0.16+/-0.11] (all P<0.001). Patients with positive expression of gankyrin had worse survival than those with negative ones (41.8% vs. 72.7%, P=0.008). The gankyrin expression was associated to lymph node metastasis (P=0.005), tumor stage (P=0.001) and distal metastasis (P=0.002). Cox regression analysis showed that distal metastasis (P=0.004) and high expression of gankyrin (P=0.038) were independent risk factors for poor prognosis of patients with CRC. CONCLUSION: Up regulated expression of gankyrin is related to invasion and metastasis of human CRC, and gankyrin may be valuable in predicting prognosis. PMID- 26108781 TI - [Expression of high mobility group box-1 in colorectal cancer and its clinical significance]. AB - OBJECTIVE: To investigate the expression level of high mobility group box-1 (HMGB1) in human colorectal cancer and its relation with different clinicopathological characteristics and prognosis of colorectal cancer patients. METHODS: Immunohistochemical method was used to detect the HMGB1 expression in tissue samples of 86 colorectal cancer patients and 32 normal colorectal tissue samples. Positive rates of HMGB1 expression were compared among different clinicopathological characteristics. Relation of HMGB1 expression with survival was analyzed. RESULTS: HMGB1 expression was mainly in colorectal cancer cell nucleus, with a few appearance of co-expression in nucleus and cytoplasm. Positive rate of HMGB1 expression in normal tissues was significantly lower than that in colorectal cancers [9.4% (3/32) vs. 66.3% (57/86), P=0.000], and it was much higher in large cancers, lower differentiation, invasion to outside serosa, advanced clinical stage and lymph node metastasis (all P<0.05), but was similar in terms of age and gender (P>0.05). Survival analysis showed that 3-year survival rate of patients with positive HMGB1 expression was significantly lower as compared to those with negative HMGB1 expression (56.1% vs. 85.7%, P=0.021), meanwhile it was significantly lower in patients with co-expression in nucleus and cytoplasm as compared to those with simple nuclear expression (41.4% vs. 75.0%, P=0.013). CONCLUSIONS: HMGB1 expression in colorectal cancer is high, and its positive rate increases with the low differentiation, invasion and metastasis. HMGB1 co-expression in nucleus and cytoplasm indicates poor prognosis of colorectal cancer patients. PMID- 26108782 TI - [Research progression on preoperative mechanical bowel preparation for elective colorectal surgery]. AB - Preoperative mechanical bowel preparation (MBP) has been established as a standard procedure for elective colorectal surgery in most surgical centers since 1950s. However, the routine use of MBP for elective colorectal surgery is still in debate, as the researches on the evaluation of MBP have been carried out in recent 20 years. By searching and analyzing the existing evidence, we conclude that MBP should be routinely abandoned for elective open colorectal surgery, but should be routinely used for elective laparoscopic rectal surgery, and it still awaits large-scale RCTs for further evaluation of MBP for elective laparoscopic colonic surgery. PMID- 26108783 TI - Coniferyl alcohol hinders the growth of tobacco BY-2 cells and Nicotiana benthamiana seedlings. AB - MAIN CONCLUSION: Externally added coniferyl alcohol at high concentrations reduces the growth of Nicotiana cells and seedlings. Coniferyl alcohol is metabolized by BY-2 cells to several compounds. Coniferyl alcohol (CA) is a common monolignol and a building block of lignin. The toxicity of monolignol alcohols has been stated in the literature, but there are only few studies suggesting that this is true. We investigated the physiological effects of CA on living plant cells in more detail. Tobacco (Nicotiana tabacum) Bright yellow-2 cells (BY-2) and Nicotiana benthamiana seedlings both showed concentration dependent growth retardation in response to 0.5-5 mM CA treatment. In some cases, CA addition caused cell death in BY-2 cultures, but this response was dependent on the growth stage of the cells. Based on LC-MS/MS analysis, BY-2 cells did not accumulate the externally supplemented CA, but metabolized it to ferulic acid, ferulic acid glycoside, coniferin, and to some other phenolic compounds. In addition to growth inhibition, CA caused the formation of a lignin-like compound detected by phloroglucinol staining in N. benthamiana roots and occasionally in BY-2 cells. To prevent this, we added potassium iodide (KI, at 5 mM) to overcome the peroxidase-mediated CA polymerization to lignin. KI had, however, toxic effects on its own: in N. benthamiana seedlings, it caused reduction in growth; in BY-2 cells, reduction in growth and cell viability. Surprisingly, CA restored the growth of KI-treated BY-2 cells and N. benthamiana seedlings. Our results suggest that CA at high concentrations is toxic to plant cells. PMID- 26108784 TI - Reproductive hormones affect follicular cells and ooplasm of Stage I and II oocytes in zebrafish. AB - The basic pathway of oocyte development and its regulation is evolutionarily conserved among vertebrates; however, little is known about the role of hormones at the first stages (Stages I and II) of follicle development in fish. In the present study, zebrafish follicles at Stages I and II were exposed in vitro to the reproductive hormones 17beta-oestradiol (E2), 11-ketotestosterone (11KT), 17,20beta-dihydroxy-4-pregnen-3-one (DHP) and to the secondary messenger dibutyryl cyclic adenosine monophosphate (db-cAMP) at a concentration of 1uM for a 48-h period. Morphological alterations of the ooplasm were assessed by transmission electron microscopy and of the granulosa cell layer by quantitative stereology. Expression of mRNA was analysed for cell-cycle genes (cyclin B and E) and resident proteins of the endoplasmic reticulum (calnexin and 78-kDa glucose regulated protein (grp78/bip)). E2 and db-cAMP stimulated the presence of endoplasmic reticulum in the ooplasm and calnexin mRNA increased in the db-cAMP treatment, but also in response to 11KT and DHP. 11KT, DHP and db-cAMP inhibited the progression of the cell cycle in the granulosa-theca cell layer, indicated by a reduction of the nucleus volume-weighted size of granulosa cells and of increased cyclin E mRNA expression. Reproductive hormones had different effects on the ooplasm and the granulosa-theca cell layer of zebrafish follicles, predominantly at Stage II. PMID- 26108785 TI - Toxicity of a novel therapeutic agent targeting mitochondrial complex I. AB - R118 is an experimental compound that completed preclinical development as a potential medical therapy for the exercise limitation in peripheral artery disease. Animal studies established that R118 provided partial and reversible mitochondrial complex I inhibition with consequent increases in adenosine monophosphate (AMP) kinase activation in liver and skeletal muscle. After demonstration of improved exercise performance in a mouse model and safety in rodent and primate models, a phase I trial was performed in 24 subjects randomized to R118 vs. placebo (5:1) in escalating doses. Plasma lactic acid levels were transiently elevated in 20% of subjects at the lowest dose and in 100% of subjects using a different formulation at the highest dose, which was associated with hospitalization in all subjects and severe metabolic acidosis requiring prolonged intubation in two subjects. Thus, inhibition of mitochondrial complex I with R118 resulted in severe lactic acidosis, representing unacceptable toxicity from this mechanism of action. PMID- 26108787 TI - Baseline characteristics in stroke patients with atrial fibrillation: clinical trials versus clinical practice. AB - BACKGROUND: When applying information gathered from medical research to the clinical setting, it is imperative that the sample of the investigated patients be representative of the clinical population. Because of this fact, it is necessary to closely examine the sample's baseline characteristics in clinical trials. METHODS: We analysed baseline data of relevant trials investigating considerable proportions of patients with atrial fibrillation (AF) in the secondary stroke prevention: EAFT, SIFA, Active-W, BAFTA, RE-LY, AVERROES, ARISTOTLE and ROCKET AF. For comparing baseline data stroke patients with AF documented in a statutory stroke registry were considered. In a subgroup of patients (members of a large insurance) data on subsequent prescription for oral anticoagulants (oAK) were available. RESULTS: In the stroke registry (n = 15,886) the mean age was higher than in the selected clinical trials (mean 77.7 versus 70 72 years). Among insurance members (n = 1,828), those with a prescription for oAK (n = 827) were older than patients recruited in clinical trials (mean 75.1 versus 70-72 years). Results also showed that the male sex was overrepresented in clinical trials (59-63% versus 46%). The distribution of vascular risk factors in recent clinical trials was comparable to proportions in the registry (hypertension: 77-85% versus 80%; diabetes mellitus: 20-26% versus 27%). CONCLUSIONS: The majority of stroke patients with AF in the clinical setting are considerably older than those included in clinical trials. While the distribution of vascular risk factors in clinical trials corresponds to proportions observed in clinical practice, an overrepresentation of the male sex in clinical trials is evident. PMID- 26108786 TI - Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres. AB - Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI). In skeletal muscle, the hyperosmotic shock-induced CS is accompanied by a small membrane depolarization responsible for a release of Ca(2+) from intracellular pools. Hyperosmotic shock also induces phosphorylation of STE20/SPS1-related proline/alanine-rich kinase (SPAK). TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca(2+) response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function. We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca(2+) release from the sarcoplasmic reticulum, activation of the Na(+) -K(+) -Cl(-) cotransporter by SPAK, and the RVI response. Increased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca(2+) from intracellular pools. We observed that both hyperosmotic shock-induced Ca(2+) transients and RVI were inhibited by Gd(3+) , ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non-permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca(2+) induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock-induced membrane depolarization was impaired in TRPV2-DN fibres, suggesting that TRPV2 activation triggers the release of Ca(2+) from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and NKCC1, a Na(+) -K(+) -Cl(-) cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2-DN as well as in fibres in which Ca(2+) transients were abolished by the Ca(2+) chelator BAPTA, the level of P-SPAK(Ser373) in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca(2+) . We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P-SPAK-activated NKCC1. PMID- 26108788 TI - Insight into a Physiological Role for the EC Night-Time Repressor in the Arabidopsis Circadian Clock. AB - Life cycle adaptation to seasonal variation in photoperiod and temperature is a major determinant of ecological success of widespread domestication of Arabidopsis thaliana. The circadian clock plays a role in the underlying mechanism for adaptation. Nevertheless, the mechanism by which the circadian clock tracks seasonal changes in photoperiod and temperature is a longstanding subject of research in the field. We previously showed that a set of the target genes (i.e. GI, LNK1. PRR9 and PRR7) of the Evening Complex (EC) consisting of LUX-ELF3-ELF4 is synergistically induced in response to both warm-night and night light signals. Here, we further show that the responses occur within a wide range of growth-compatible temperatures (16-28 degrees C) in response to a small change in temperature (Delta4 degrees C). A dim light pulse (<1 umol m(-2) s(-1)) causes the enhanced effect on the transcription of EC targets. The night-light pulse antagonizes against a positive effect of the cool-night signal on the EC activity. The mechanism of double-checking external temperature and light signals through the EC nighttime repressor might enable plants to ignore (or tolerate) daily fluctuation of ambient temperature within a short time interval in their natural habitats. Taken together, the EC night-time repressor might play a physiological role in tracking seasonal variation in photoperiod and temperature by conservatively double-checking both the light and temperature conditions. Another EC target output gene PIF4 regulating plant morphologies is also regulated by both the temperature and light stimuli during the night. Hence, the EC night-time repressor is also implicated in a physiological output of the PIF4 mediated regulation of morphologies in response to seasonal variation in photoperiod and ambient temperature. PMID- 26108789 TI - Involvement of NRF2 in Perfluorooctanoic Acid-Induced Testicular Damage in Male Mice. AB - Perfluorooctane acid (PFOA) is a hazardous environmental pollutant that has been reported to exert adverse effects on animal and human health. In this study, male mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day) to evaluate the reproductive toxicity. Exposure to PFOA for 14 consecutive days obviously disrupted seminiferous tubules and reduced sperm count. The highest concentration of PFOA (10 mg/kg/day) caused growth retardation and diminished absolute testis weight. Furthermore, PFOA treatment significantly increased the generation of oxidative stress indicators malondialdehyde and hydrogen peroxide, decreased the expression of transcription factor NRF2, and inhibited the activities of antioxidant enzymes superoxide dismutase and catalase in the testis. Moreover, PFOA exposure up-regulated p-p53 and BAX expression and down-regulated BCL-2 expression in the testis. These results indicated that PFOA induced male reproductive disorders might be involved in developmental impairment and inhibition of NRF2-mediated antioxidant response in the testis of mice. PMID- 26108790 TI - Applying SWATH Mass Spectrometry to Investigate Human Cervicovaginal Fluid During the Menstrual Cycle. AB - Inherent interindividual and intraindividual variation in the length of the menstrual cycle limits the accuracy of predicting days of peak fertility. To improve detection of days of peak fertility, a more detailed understanding of longitudinal changes in cervicovaginal fluid (CVF) biomarkers during the normal menstrual cycle is needed. The aim of this study, therefore, was to characterize longitudinal changes in CVF proteins during the menstrual cycle using a quantitative, data-independent acquisition mass spectrometry approach. Six serial samples were collected from women (n = 10) during the menstrual cycle. Samples were obtained at two time points for each phase of the cycle: early and late preovulatory, ovulatory, and postovulatory. Information-dependent acquisition (IDA) of mass spectra from all individual CVF samples was initially performed and identified 278 total proteins. Samples were then pooled by time of collection (n = 6 pools) and analyzed using IDA and information-independent acquisition (Sequential Windowed Acquisition of All Theoretical Mass Spectra [SWATH]). The IDA library generated contained 176 statistically significant protein identifications (P < 0.000158). The variation in the relative abundance of CVF proteins across the menstrual cycle was established by comparison with the SWATH profile against the IDA library. Using time-series, pooled samples obtained from 10 women, quantitative data were obtained by SWATH analysis for 43 CVF proteins. Of these proteins, 28 displayed significant variation in relative abundance during the menstrual cycle (assessed by ANOVA). Statistical significant changes in the relative expression of CVF proteins during preovulatory, ovulatory, and postovulatory phases of menstrual cycle were identified. The data obtained may be of utility not only in elucidating underlying physiological mechanisms but also as clinically useful biomarkers of fertility status. PMID- 26108791 TI - CD34 and CD49f Double-Positive and Lineage Marker-Negative Cells Isolated from Human Myometrium Exhibit Stem Cell-Like Properties Involved in Pregnancy-Induced Uterine Remodeling. AB - Repeated and dramatic pregnancy-induced uterine enlargement and remodeling throughout reproductive life suggests the existence of uterine smooth muscle stem/progenitor cells. The aim of this study was to isolate and characterize stem/progenitor-like cells from human myometrium through identification of specific surface markers. We here identify CD49f and CD34 as markers to permit selection of the stem/progenitor cell-like population from human myometrium and show that human CD45(-) CD31(-) glycophorin A(-) and CD49f(+) CD34(+) myometrial cells exhibit stem cell-like properties. These include side population phenotypes, an undifferentiated status, high colony-forming ability, multilineage differentiation into smooth muscle cells, osteoblasts, adipocytes, and chondrocytes, and in vivo myometrial tissue reconstitution following xenotransplantation. Furthermore, CD45(-) CD31(-) glycophorin A(-) and CD49f(+) CD34(+) myometrial cells proliferate under hypoxic conditions in vitro and, compared with the untreated nonpregnant myometrium, show greater expansion in the estrogen-treated nonpregnant myometrium and further in the pregnant myometrium in mice upon xenotransplantation. These results suggest that the newly identified myometrial stem/progenitor-like cells influenced by hypoxia and sex steroids may participate in pregnancy-induced uterine enlargement and remodeling, providing novel insights into human myometrial physiology. PMID- 26108792 TI - Gonadal Identity in the Absence of Pro-Testis Factor SOX9 and Pro-Ovary Factor Beta-Catenin in Mice. AB - Sex-reversal cases in humans and genetic models in mice have revealed that the fate of the bipotential gonad hinges upon the balance between pro-testis SOX9 and pro-ovary beta-catenin pathways. Our central query was: if SOX9 and beta-catenin define the gonad's identity, then what do the gonads become when both factors are absent? To answer this question, we developed mouse models that lack either Sox9, beta-catenin, or both in the somatic cells of the fetal gonads and examined the morphological outcomes and transcriptome profiles. In the absence of Sox9 and beta-catenin, both XX and XY gonads progressively lean toward the testis fate, indicating that expression of certain pro-testis genes requires the repression of the beta-catenin pathway, rather than a direct activation by SOX9. We also observed that XY double knockout gonads were more masculinized than their XX counterpart. To identify the genes responsible for the initial events of masculinization and to determine how the genetic context (XX vs. XY) affects this process, we compared the transcriptomes of Sox9/beta-catenin mutant gonads and found that early molecular changes underlying the XY-specific masculinization involve the expression of Sry and 21 SRY direct target genes, such as Sox8 and Cyp26b1. These results imply that when both Sox9 and beta-catenin are absent, Sry is capable of activating other pro-testis genes and drive testis differentiation. Our findings not only provide insight into the mechanism of sex determination, but also identify candidate genes that are potentially involved in disorders of sex development. PMID- 26108794 TI - Environmental behavior and analysis of agricultural sulfur. AB - Sulfur has been widely used for centuries as a staple for pest and disease management in agriculture. Presently, it is the largest-volume pesticide in use worldwide. This review describes the sources and recovery methods for sulfur, its allotropic forms and properties and its agricultural uses, including development and potential advantages of nanosulfur as a fungicide. Chemical and microbial reactivity, interactions in soil and water and analytical methods for determination in environmental samples and foodstuffs, including inexpensive analytical methods for sulfur residues in wine, beer and other food/beverage substrates, will be reviewed. The toxicology of sulfur towards humans and agriculturally important fungi is included, with some restrictions on use to promote safety. The review concludes with areas for which more research is warranted. PMID- 26108793 TI - Nucleolar Translocation of Histone Deacetylase 2 Is Involved in Regulation of Transcriptional Silencing in the Cat Germinal Vesicle. AB - Histone deacetylase 2 (HDAC2) is a key transcriptional coregulator that is suspected to play a role during oogenesis. It is known that RNA transcription in the cat germinal vesicle (GV) stops during folliculogenesis at the late antral follicle stage and is unrelated to histone deacetylation or chromatin condensation. The objective of the present study was to determine if and how HDAC2 participates in transcription regulation in the cat GV. Spatiotemporal HDAC2 protein expression was examined by immunostaining oocytes from primary to large antral follicles. HDAC2 was detected in the majority of GVs within oocytes from early, small, and large antral follicles. At early and small antral stages, HDAC2 was found primarily in the GV's nucleoplasm. There then was a significant shift in HDAC2 localization into the nucleolus, mostly in oocytes from large antral follicles. Assessments revealed that transcription was active in oocytes that contained nucleoplasm-localized HDAC2, whereas nucleolar-bound HDAC2 was associated with loss of both global transcription and ribosomal RNA presence at all antral stages. When oocytes were exposed to the HDAC inhibitor valproic acid, results indicated that HDAC regulated transcriptional activity in the nucleoplasm, but not in the nucleolus. Collective results suggest that nucleolar translocation of HDAC2 is associated with transcriptional silencing in the GV, thereby likely contributing to an oocyte's acquisition of competence. PMID- 26108795 TI - Time-dependent evolution of the Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 heterostructure for enhanced photocatalytic activity via the interfacial hole migration. AB - Hierarchical Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 isotype heterostructures were successfully prepared via a one-pot hydrothermal route by using Bi2O3 porous nanospheres as a sacrificial template. By tuning the reaction time, the formation process of the Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 heterostructure involving Mo etching, phase transition and anisotropic growth was clearly identified. More importantly, the Bi(3.64)Mo(0.36)O(6.55)/Bi2MoO6 heterostructure displayed remarkably enhanced photocatalytic activity for dye photodegradation than pure phase bismuth molybdate due to the efficient electron-hole separation and the interfacial photogenerated hole migration from inside the Bi(3.64)Mo(0.36)O(6.55) layer to outside the Bi2MoO6 layer. The opposite hole migration from the outer layer to the inner layer was also detected in Bi2O3/Bi2WO6 heterostructures, which resulted in the decrease of photocatalytic activity, further verifying the importance of hole migration direction. This work provides a novel route to fabricate heterostructured photocatalysts, as well as gives a strategy for mediating the charge migration to improve photocatalytic performance. PMID- 26108797 TI - Erratum to: Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence. PMID- 26108796 TI - LTA + 252A > G polymorphism is associated with risk of nasal NK/T-cell lymphoma in a Chinese population: a case-control study. AB - BACKGROUND: Nasal NK/T-cell lymphoma is a rare type of lymphoma in Caucasian individuals, but is relatively common in Asian populations. Genetic variants in immune and inflammatory response genes may thus be associated with the risk of developing lymphoma. Here, we investigated the association between immuno modulatory gene polymorphisms and risk for nasal NK/T-cell lymphoma in a Chinese population. METHODS: Analysis of 12 single nucleotide polymorphisms (SNPs) in IL 10, TNF-alpha, lymphotoxin-alpha (LTA), and CTLA-4 genes was performed for 125 patients with NK/T-cell lymphoma and 300 healthy controls by PCR-ligase detection reactions. RESULTS: The LTA +252 GA + AA genotypes were associated with increased risk for NK/T-cell lymphoma (OR = 2.96, 95 % CI = 1.42-6.19, P = 0.004 for GA + AA genotype). Haplotype C-G-G-A (TNF-alpha -857, -308, -238 and LTA +252) also conferred an increased risk (OR = 1.52, 95% CI = 1.14-2.06, P = 0.005). Additionally, the LTA +252 GA + AA genotype was associated with an even higher risk in populations positive for Epstein-Barr virus (OR = 5.20, 95% CI = 1.22 23.41, P = 0.03 for the GA + AA genotype). CONCLUSIONS: Our data suggest that the LTA +252 A > G polymorphism is associated with the risk of developing NK/T-cell lymphoma, especially for Epstein-Barr virus-positive NK/T-cell lymphoma in the Chinese population. PMID- 26108798 TI - US Supreme Court throws out law that forced doctors in North Carolina to deliver antiabortion message. PMID- 26108799 TI - Sirolimus effects on cancer incidence after kidney transplantation: a meta analysis. AB - Sirolimus, an immunosuppressant option for kidney transplant recipients, may reduce cancer risk by interrupting the mammalian target of rapamycin pathway. However, studies of sirolimus and cancer incidence in kidney recipients have not been definitive, and have had limited ability to examine specific cancer types. The literature was systematically reviewed to identify randomized controlled trials (RCTs) and observational studies of kidney recipients that compared sirolimus users to sirolimus nonusers. Meta-analytic methods were used to obtain pooled estimates of the association between sirolimus use and incidence of total cancer and specific cancer types. Estimates were stratified by study type (RCT vs. observational) and use of cyclosporine (an immunosuppressant that affects DNA repair). Twenty RCTs and two observational studies were eligible for meta analysis, including 39,039 kidney recipients overall. Sirolimus use was associated with lower overall cancer incidence (incidence rate ratio [IRR] = 0.71, 95% CI = 0.56-0.90), driven by a reduction in incidence of nonmelanoma skin cancer (NMSC, IRR = 0.49, 95% CI = 0.32-0.76). The protective effect of sirolimus on NMSC risk was most notable in studies comparing sirolimus against cyclosporine (IRR = 0.19, 95% CI = 0.04-0.84). After excluding NMSCs, there was no overall association between sirolimus and incidence of other cancers (IRR = 1.06, 95% CI = 0.69-1.63). However, sirolimus use had associations with lower kidney cancer incidence (IRR = 0.40, 95% CI = 0.20-0.81), and higher prostate cancer incidence (IRR = 1.85, 95% CI = 1.17-2.91). Among kidney recipients, sirolimus users have lower NMSC risk, which may be partly due to removal of cyclosporine. Sirolimus may also reduce kidney cancer risk but did not appear protective for other cancers, and it may actually increase prostate cancer risk. PMID- 26108800 TI - Systematic Asymmetric Synthesis of All Diastereomers of (-)-Talaumidin and Their Neurotrophic Activity. AB - (-)-Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, shows significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF differentiated PC12 cells. The four stereogenic centers on the tetrahydrofuran moiety in 1 result in the presence of seven diastereomers except for their enantiomers. In order to investigate the stereochemistry-activity relationships of the stereoisomers, the systematic synthesis of all stereoisomers of 1 was accomplished by employing Evans aldol, diastereoselective hydroboration, reductive deoxygenation, and Mitsunobu reactions as key steps. The ability of all of the synthesized stereoisomers to promote neurite-outgrowth in PC12 and neuronal cells was evaluated. All stereoisomers exhibited moderate to potent neurotrophic activities in NGF-differentiated PC12 cells at 30 MUM and in primary cultured rat cortical neuronal cells at 0.01 MUM. In particular, 1e bearing all cis substituents resulted in the most potent neurite-outgrowth promotion. PMID- 26108801 TI - Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells. AB - SCOPE: The phytochemical sulforaphane (SF) has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. SF has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence SF cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following SF treatment. METHODS AND RESULTS: We conducted an investigation to assess the impact of SF on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that SF can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. CONCLUSION: These results suggest that SF does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of SF-mediated prostate cancer suppression. PMID- 26108803 TI - In-silico analysis of Sirt2 from Schistosoma mansoni: structures, conformations, and interactions with inhibitors. AB - Sirtuins are NAD+-dependent lysine deacetylases member of the class III HDAC family. These are demonstrated to be therapeutic targets in parasitic diseases like schistosomiasis. Observations suggested that sirtuin enzyme is necessary for the functionality of fe/male reproductive system, due to which SmSirt2 is treated as a potential therapeutic target. There are no structural and molecular features of SmSirt2 have been reported yet. In this study, homology modeling has been used to determine the three-dimensional features of the SmSITRT2. Further, structure validation has been performed by energy minimization and Ramachandran plot. Validated structures are further subjected to molecular docking and virtual screening to find the best lead molecules for downstream analysis. Ten lead molecules were selected while comparing virtual screening of hSirt2 and SmSirt2 both. These leads are further compared with AKG2 which is known inhibitor of hSirt2 (-8.8 kcal/mol). Out of selected 10 leads, four of them (ZINC23995485 ( 9.5 kcal/mol), ZINC53298162 (-9.4 kcal/mol), ZINC70927268 (-10.0 kcal/mol), ZINC89878705 (-11.2 kcal/mol)) have shown better interaction with SmSirt2, in which ZINC89878705 (-11.2 kcal/mol) shows a more compact packing as compared to AKG2 and rest of ligands. These molecules could be further subject to in vitro study and model of SmSirt2 has been proposed for further structure-based drug design projects concerning sirtuins from Schistosoma mansoni. PMID- 26108802 TI - Prognostic role of hormone receptors in endometrial cancer: a systematic review and meta-analysis. AB - BACKGROUND: The aim of this study was to summarize the global predicting role of hormone receptors for survival in endometrial cancer. METHODS: Eligible studies were identified and assessed for quality through multiple search strategies. Data were collected from studies comparing overall survival (OS), cancer-specific survival (CSS), or progression-free survival (PFS) in patients with elevated levels of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) with those in patients with lower levels. The combined hazard ratios of ER, PR, and HER2 for survival were calculated. RESULTS: A total of 98 studies were included for meta-analysis (44 for ER, 38 for PR, and 16 for HER2). Higher levels of either ER or PR could significantly indicate better survival. The pooled hazard ratios (HRs) of ER for OS, CSS, and PFS were 0.75 (95% CI, 0.68-0.83), 0.45 (95% CI, 0.33-0.62), and 0.66 (95% CI, 0.52-0.85), respectively. The combined HRs of PR for OS, CSS, and PFS reached 0.63 (95% CI, 0.56-0.71), 0.62 (95% CI, 0.42-0.93), and 0.45 (95% CI, 0.30-0.68), respectively. In contrast, elevated levels of HER2 could predict worse outcome with a HR of 1.98 (95% CI, 1.49-2.62) for OS, and a HR of 2.26 (95% CI, 1.57-3.25) for PFS. CONCLUSIONS: In patients with endometrial cancer, higher level of ER and PR predicted favorable survival, and increased level of HER2 was associated with poorer survival. All of the three hormone receptors had prognostic value for survival. PMID- 26108804 TI - Acute kidney injury following surgical aortic valve replacement. AB - BACKGROUND: Acute kidney injury (AKI) is a significant complication of surgical aortic valve replacement (SAVR). This study sought to describe AKI following SAVR, its risk factors, predictors and effect on long-term survival. METHODS: We retrospectively reviewed 2169 patients who underwent isolated SAVR between 2000 and 2012. The main end-points were occurrence of AKI, postoperative complications, and short- and long-term survival rates following SAVR. Patients were divided into two groups: AKI+ (n = 181) and AKI- (n = 1945). RESULTS: AKI occurred in 8.5% of patients, of which 3.9% (n = 7) needed dialysis. Predictors of AKI after SAVR were body mass index (BMI) and intraoperative packed red blood cells (PRBC) transfusion. AKI+ patients had a more complicated postoperative course and higher cumulative mortality (25% vs. 17%, p = 0.012) with a median follow-up of 4.1 years. AKI was not found to be an independent predictor of mortality. CONCLUSIONS: Predictors of AKI after SAVR are increased BMI and intraoperative PRBC transfusion. AKI conferred an increase in hospital length of stay and cumulative mortality while the need for postoperative dialysis was associated with the most complicated hospital stays and the highest in-hospital and cumulative mortalities; therefore careful recognition of patients at risk of AKI is warranted for a better preoperative renal optimization. However, incidence of AKI was lower than what is reported after both on-CPB cardiac surgeries and transcatheter aortic valve replacement, moreover AKI was not found to be an independent predictor of mortality. PMID- 26108805 TI - WNT3 and membrane-associated beta-catenin regulate trophectoderm lineage differentiation in human blastocysts. AB - WNT/beta-catenin signaling has been described as a crucial regulator of embryonic stem cells and embryogenesis. However, little is known on its role during human preimplantation embryo development, besides the RNA expression of its multiple players. In this study, we performed beta-catenin loss- and gain-of-function studies on human preimplantation embryos by adding either Cardamonin or GSK3 inhibitor, 1-Azakenpaullone, to the embryo culture medium from the cleavage until blastocyst stages (Days 3-5/6). beta-Catenin was displayed in the cortical region underneath the membrane during all stages, but it only showed nuclear localization at cleavage stages after stabilization with 1-Azakenpaullone. We did not observe any effects on the inner cell mass markers NANOG, POU5F1, SOX2 and SALL4 in these functional experiments. However, both beta-catenin degradation and stabilization caused inhibition of the trophectoderm (TE) fate, illustrated by KRT18 and GATA3 RNA, and CDX2 protein expression. Based on the TE-specific WNT3 protein expression in blastocysts, we postulated that this protein may be an upstream regulator for the observed membrane beta-catenin function. The addition of either WNT3 or 1-Azakenpaullone to the culture medium promoted EOMES expression specific for trophoblast development. In both studies, the canonical WNT pathway target gene, TCF1, was not affected. Therefore, we conclude that WNT3 and membrane-associated beta-catenin promote progenitor trophoblast development in human blastocysts. These results have important implications in assisted reproduction and stem cell biology. PMID- 26108806 TI - In response to Treatment of epilepsy by stimulation of the vagus nerve from head and-neck surgical point of view. PMID- 26108807 TI - Cardiac tachyarrhythmias and patient values and preferences for their management: the European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE). PMID- 26108809 TI - Syncope Unit: rationale and requirement--the European Heart Rhythm Association position statement endorsed by the Heart Rhythm Society. PMID- 26108808 TI - Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: clinical significance and implications for decision making-a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. PMID- 26108810 TI - Advanced process monitoring and feedback control to enhance cell culture process production and robustness. AB - It is a common practice in biotherapeutic manufacturing to define a fixed-volume feed strategy for nutrient feeds, based on historical cell demand. However, once the feed volumes are defined, they are inflexible to batch-to-batch variations in cell growth and physiology and can lead to inconsistent productivity and product quality. In an effort to control critical quality attributes and to apply process analytical technology (PAT), a fully automated cell culture feedback control system has been explored in three different applications. The first study illustrates that frequent monitoring and automatically controlling the complex feed based on a surrogate (glutamate) level improved protein production. More importantly, the resulting feed strategy was translated into a manufacturing friendly manual feed strategy without impact on product quality. The second study demonstrates the improved process robustness of an automated feed strategy based on online bio-capacitance measurements for cell growth. In the third study, glucose and lactate concentrations were measured online and were used to automatically control the glucose feed, which in turn changed lactate metabolism. These studies suggest that the auto-feedback control system has the potential to significantly increase productivity and improve robustness in manufacturing, with the goal of ensuring process performance and product quality consistency. PMID- 26108812 TI - Data overprotection. PMID- 26108813 TI - Hope from the Pope. PMID- 26108811 TI - Photodynamic Action Mechanism Mediated by Zinc(II) 2,9,16,23-Tetrakis[4-(N methylpyridyloxy)]phthalocyanine in Candida albicans Cells. AB - The photoreaction type I/type II pathways mediated by zinc(II) 2,9,16,23 tetrakis[4-(N-methylpyridyloxy)]phthalocyanine (ZnPPc(4+) ) was studied in Candida albicans cells. This photosensitizer was strongly bound to C. albicans cells at short times. After 30 min irradiation, 5 MUM ZnPPc(4+) produced ~5 log decrease in cell viability. Different probes were used to detect reactive oxygen species (ROS) in cell suspensions (~10(6) CFU mL(-1) ). Singlet molecular oxygen, O2 ((1) Deltag ), was observed by the reaction with 9,10-dimethylanthracene (DMA) and tetrasodium 2,2-(anthracene-9,10-diyl)bis(methylmalonate) (ABMM), whereas the nitro blue tetrazolium (NBT) method was used to sense superoxide anion radical (O2.-). Moreover, the effects produced by an anoxic atmosphere and cell suspensions in D2 O, as well as the addition of sodium azide and mannitol as ROS trapping were evaluated in the PDI of C. albicans. These investigation indicates that O2 ((1) Deltag ) is generated in the cells, although a minor extension other radical species can also be involved in the PDI of C. albicans mediated by ZnPPc(4+) . PMID- 26108814 TI - Life under the ice. PMID- 26108815 TI - Judge by actions, not words. PMID- 26108827 TI - Urban microbes come out of the shadows. PMID- 26108828 TI - Bacteria may help bats to fight deadly fungus. PMID- 26108829 TI - Astronomers claim first glimpse of primordial stars. PMID- 26108830 TI - Private asteroid hunt lacks cash to spy threats in orbit. PMID- 26108831 TI - Earth science wrestles with conflict-of-interest policies. PMID- 26108832 TI - Ancient American genome rekindles legal row. PMID- 26108833 TI - Correction. PMID- 26108834 TI - Europe's superlab: Sir Paul's cathedral. PMID- 26108835 TI - Neuroscience: The hard science of oxytocin. PMID- 26108836 TI - CRISPR: Science can't solve it. PMID- 26108837 TI - CRISPR: Move beyond differences. PMID- 26108841 TI - India: Assess social impact of technology. PMID- 26108842 TI - Research misconduct: Speed translation of misconduct reports. PMID- 26108843 TI - India: Multi-author papers skew ranking. PMID- 26108844 TI - Dynasty Foundation: Russian science loses to politics. PMID- 26108845 TI - North America: US sanctions alarm physicians from Iran. PMID- 26108846 TI - John Forbes Nash (1928-2015). PMID- 26108847 TI - Astrophysics: Dust-poor galaxies at early times. PMID- 26108848 TI - Climate science: The dynamics of temperature extremes. PMID- 26108850 TI - Cell metabolism: Sugar for sight. PMID- 26108852 TI - The changing form of Antarctic biodiversity. AB - Antarctic biodiversity is much more extensive, ecologically diverse and biogeographically structured than previously thought. Understanding of how this diversity is distributed in marine and terrestrial systems, the mechanisms underlying its spatial variation, and the significance of the microbiota is growing rapidly. Broadly recognizable drivers of diversity variation include energy availability and historical refugia. The impacts of local human activities and global environmental change nonetheless pose challenges to the current and future understanding of Antarctic biodiversity. Life in the Antarctic and the Southern Ocean is surprisingly rich, and as much at risk from environmental change as it is elsewhere. PMID- 26108853 TI - Galaxies at redshifts 5 to 6 with systematically low dust content and high [C II] emission. AB - The rest-frame ultraviolet properties of galaxies during the first three billion years of cosmic time (redshift z > 4) indicate a rapid evolution in the dust obscuration of such galaxies. This evolution implies a change in the average properties of the interstellar medium, but the measurements are systematically uncertain owing to untested assumptions and the inability to detect heavily obscured regions of the galaxies. Previous attempts to measure the interstellar medium directly in normal galaxies at these redshifts have failed for a number of reasons, with two notable exceptions. Here we report measurements of the forbidden C ii emission (that is, [C II]) from gas, and the far-infrared emission from dust, in nine typical star-forming galaxies about one billion years after the Big Bang (z ~ 5-6). We find that these galaxies have thermal emission that is less than 1/12 that of similar systems about two billion years later, and enhanced [C II] emission relative to the far-infrared continuum, confirming a strong evolution in the properties of the interstellar medium in the early Universe. The gas is distributed over scales of one to eight kiloparsecs, and shows diverse dynamics within the sample. These results are consistent with early galaxies having significantly less dust than typical galaxies seen at z < 3 and being comparable in dust content to local low-metallicity systems. PMID- 26108854 TI - A giant comet-like cloud of hydrogen escaping the warm Neptune-mass exoplanet GJ 436b. AB - Exoplanets orbiting close to their parent stars may lose some fraction of their atmospheres because of the extreme irradiation. Atmospheric mass loss primarily affects low-mass exoplanets, leading to the suggestion that hot rocky planets might have begun as Neptune-like, but subsequently lost all of their atmospheres; however, no confident measurements have hitherto been available. The signature of this loss could be observed in the ultraviolet spectrum, when the planet and its escaping atmosphere transit the star, giving rise to deeper and longer transit signatures than in the optical spectrum. Here we report that in the ultraviolet the Neptune-mass exoplanet GJ 436b (also known as Gliese 436b) has transit depths of 56.3 +/- 3.5% (1sigma), far beyond the 0.69% optical transit depth. The ultraviolet transits repeatedly start about two hours before, and end more than three hours after the approximately one hour optical transit, which is substantially different from one previous claim (based on an inaccurate ephemeris). We infer from this that the planet is surrounded and trailed by a large exospheric cloud composed mainly of hydrogen atoms. We estimate a mass-loss rate in the range of about 10(8)-10(9) grams per second, which is far too small to deplete the atmosphere of a Neptune-like planet in the lifetime of the parent star, but would have been much greater in the past. PMID- 26108855 TI - Linking high harmonics from gases and solids. AB - When intense light interacts with an atomic gas, recollision between an ionizing electron and its parent ion creates high-order harmonics of the fundamental laser frequency. This sub-cycle effect generates coherent soft X-rays and attosecond pulses, and provides a means to image molecular orbitals. Recently, high harmonics have been generated from bulk crystals, but what mechanism dominates the emission remains uncertain. To resolve this issue, we adapt measurement methods from gas-phase research to solid zinc oxide driven by mid-infrared laser fields of 0.25 volts per angstrom. We find that when we alter the generation process with a second-harmonic beam, the modified harmonic spectrum bears the signature of a generalized recollision between an electron and its associated hole. In addition, we find that solid-state high harmonics are perturbed by fields so weak that they are present in conventional electronic circuits, thus opening a route to integrate electronics with attosecond and high-harmonic technology. Future experiments will permit the band structure of a solid to be tomographically reconstructed. PMID- 26108856 TI - Contribution of changes in atmospheric circulation patterns to extreme temperature trends. AB - Surface weather conditions are closely governed by the large-scale circulation of the Earth's atmosphere. Recent increases in the occurrence of some extreme weather phenomena have led to multiple mechanistic hypotheses linking changes in atmospheric circulation to increasing probability of extreme events. However, observed evidence of long-term change in atmospheric circulation remains inconclusive. Here we identify statistically significant trends in the occurrence of atmospheric circulation patterns, which partially explain observed trends in surface temperature extremes over seven mid-latitude regions of the Northern Hemisphere. Using self-organizing map cluster analysis, we detect robust circulation pattern trends in a subset of these regions during both the satellite observation era (1979-2013) and the recent period of rapid Arctic sea-ice decline (1990-2013). Particularly substantial influences include the contribution of increasing trends in anticyclonic circulations to summer and autumn hot extremes over portions of Eurasia and North America, and the contribution of increasing trends in northerly flow to winter cold extremes over central Asia. Our results indicate that although a substantial portion of the observed change in extreme temperature occurrence has resulted from regional- and global-scale thermodynamic changes, the risk of extreme temperatures over some regions has also been altered by recent changes in the frequency, persistence and maximum duration of regional circulation patterns. PMID- 26108857 TI - Cell death during crisis is mediated by mitotic telomere deprotection. AB - Tumour formation is blocked by two barriers: replicative senescence and crisis. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo spontaneous mitotic arrest, resulting in death during mitosis or in the following cell cycle. This phenotype is induced by loss of p53 function, and is suppressed by telomerase overexpression. Telomere fusions triggered mitotic arrest in p53-compromised non-crisis cells, indicating that such fusions are the underlying cause of cell death. Exacerbation of mitotic telomere deprotection by partial TRF2 (also known as TERF2) knockdown increased the ratio of cells that died during mitotic arrest and sensitized cancer cells to mitotic poisons. We propose a crisis pathway wherein chromosome fusions induce mitotic arrest, resulting in mitotic telomere deprotection and cell death, thereby eliminating precancerous cells from the population. PMID- 26108859 TI - Delivery of HIV test results, post-test discussion and referral in health care settings: a review of guidance for European countries. AB - OBJECTIVES: HIV testing and counselling (HTC) guidelines support and promote best practice among service providers. Few European countries have national HTC guidelines and most rely on guidance from regional and international bodies. This study examines recommendations in current pan-European and global guidelines regarding test result delivery, post-test discussion and referral pathways in health care settings, and reviews the types of evidence upon which recommendations are based. METHODS: A systematic review and comparative content analysis of relevant guidelines identified through a literature search and review of targeted organization websites were carried out. RESULTS: One global and three pan-European guidelines were reviewed. There was general consensus that any test result should be confidential and delivered privately to a patient; positive results should be delivered in person by a health care professional; negative test results could also be delivered by telephone, text message or post. Analyses show conflicting guidance relating to the provision of post-test counselling, and inconsistencies in referral pathways to specialist treatment for positive test results. There is limited reference to published evidence in support of recommendations. Instead there is heavy reliance on expert opinion/consultation and other previous/existing guidelines when developing guidelines. Scientific evidence, where stated, is often more than ten years old, and based predominantly on US/UK research. CONCLUSIONS: While largely in agreement, current pan-European and global HTC guidelines have inconsistencies, particularly regarding post-test counselling and referral pathways to specialized services. Our findings highlight the need for an up-to-date review of more current evidence from wider European settings to support the process of expert consultation. PMID- 26108860 TI - Radiographer technique: Does it contribute to the question of clip migration? AB - INTRODUCTION: Marker clips are commonly deployed at the site of a percutaneous breast biopsy. Studies have shown that displacement of the clip from the site of deployment is not uncommon. The objective of this study was to determine how much 'migration' could be seen with fixed structures within the breast tissue across three consecutive annual screening examinations, and therefore attempt to quantify how much of the reported clip migration could be due to radiographer technique. METHODS: Large, easily identified benign calcifications were measured by two investigators across three consecutive cycles of screening mammography. The position of the calcifications on the two standard mammographic views was measured in two planes. Other variables recorded included breast size and density, compression force used, and location of the benign calcifications within the breast. RESULTS: In 38% of cases, benign breast calcifications showed a mimicked movement of >15 mm in at least one plane. This was greatest in large breasts, those where fibroglandular tissue occupied less than 50% of the breast volume, and in the upper outer quadrant of the breast where mimicked movement >10 mm was noted in up to 90% of the larger breasts. CONCLUSION: Fixed immobile objects in the breast can appear to move a distance of >15 mm in up to 30% of cases. Clinically, some of what has previously been called marker 'migration' may be spurious and accounted for by differences in radiographic positioning techniques. PMID- 26108861 TI - Chemo-port insertion: A cause of vocal cord palsy. AB - We describe extremely rare cases of vocal cord palsy following surgical insertion of a chemo port. Our cohort consisted of patients with cancer who developed hoarseness immediately after central venous line placement for the administration of chemotherapy, with vocal cord palsy confirmed with flexible laryngoscopy. Given the timing, central venous line placement appears to be the most likely cause. PMID- 26108862 TI - High velocity gunshot injuries to the extremities: management on and off the battlefield. AB - The gunshot wounds sustained on the battlefield caused by military ammunition can be different in nature to those usually encountered in the civilian setting. The main difference is that military ammunition has typically higher velocity with therefore greater kinetic energy and consequently potential to destroy tissue. The surgical priorities in the management of gunshot wounds are hemorrhage control, preventing infection, and reconstruction. The extent to which a gunshot wound needs to be surgically explored can be difficult to determine and depends on the likely amount of tissue destruction and the delay between wounding and initial surgical treatment. Factors associated with greater energy transfer, e.g., bullet fragmentation and bony fractures, are predictors of increased wound severity and therefore a requirement for more surgical exploration and likely debridement. Gunshot wounds should never be closed primarily; the full range of reconstruction from secondary intention to free tissue transfer may be required. PMID- 26108864 TI - When folic acid fails: Insights from 20 years of neural tube defect surveillance in South Carolina. AB - Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence. PMID- 26108863 TI - Monocytes of Patients with Type 1 Diabetes Harbour Enterovirus RNA. AB - BACKGROUND: Intracellular enterovirus (EV) RNA was detected in blood of patients with type 1 diabetes (T1D). The presence of EV RNA in subsets of peripheral blood mononuclear cells (PBMCs) of patients, and the in vitro infection of these cells with an EV, was investigated. MATERIALS AND METHODS: Blood was collected from 42 patients with T1D, PBMCs were isolated and monocytes were purified. Interferon alpha (IFNalpha) mRNA and EV RNA were investigated using RT-PCR. Levels of IFNalpha in plasma were measured using an immunoassay. Cells were inoculated with Coxsackievirus B4 (CBV4) in vitro, and infection was assessed by indirect immunofluorescence (IFI). RESULTS: Interferon alpha mRNA was detected in blood and in monocytes of 12 of 42 patients with T1D, but not in monocyte-depleted PBMCs of the same individuals. Significant plasma levels of IFNalpha (>= 5 IU/mL) were found in six patients. EV RNA was detected in whole blood and in monocytes of seven patients and negative-strand EV RNA was found in monocytes of 6 of them. When monocytes of patients with IFNalpha and/or EV RNA in their blood were inoculated with CVB4, the proportion of cells stained by an anti-VP1 antibody was 8.8 +/- 1%, whereas no VP1 was detected in the monocytes of IFNalpha, EV RNA negative patients. Nevertheless, when CBV4 was mixed with plasma, VP1 was detected in monocytes of all patients with T1D (staining ranging from 12 to 36%). CONCLUSIONS: Our data indicate that monocytes of patients with T1D can harbor EV RNA and IFNalpha mRNA and can be infected with an EV in vitro. PMID- 26108865 TI - Protective immune response against newly emerging goose tembusu virus infection induced by immunization with a recombinant envelope protein. AB - Flavivirus envelope protein locates at the outermost surface of viral particle and mediates virus entry and fusion infection, and plays an important role in eliciting neutralizing antibody. In this study, goose tembusu virus (GTV) E protein was expressed and purified from Escherichia coli. The immunological changes and protection efficiency of this protein serving as recombinant subunit vaccine were then tested. In ducks, recombinant E protein markedly elicited specific neutralizing antibody, stimulated the secretion of IL-2, TNF-alpha and IFN-gamma cytokines and promoted the proliferation of lymphocytes. Additionally, population of soluble CD4 and soluble CD8 molecules in sera significantly increased in response to this antigen. Moreover, virus challenge revealed that recombinant E protein contributed to protection against GTV challenge. Taken together, the data indicate that recombinant GTV E protein could induce significant humoral and cell-mediated responses and that recombinant E protein can serve as a potential subunit vaccine candidate against GTV. SIGNIFICANCE AND IMPACT OF THE STUDY: The sudden outbreak and quick spread of newly emerging goose tembusu virus (GTV) have resulted in serious economic loss. There is no effective commercial vaccine or reasonably available control measure so far. In this study, GTV E protein was expressed and purified from Escherichia coli, and it was found that recombinant E protein could induce significant humoral and cell-mediated responses. It indicated that recombinant E protein can serve as a potential subunit vaccine candidate against GTV. PMID- 26108866 TI - Gd(III)-Gd(III) EPR distance measurements--the range of accessible distances and the impact of zero field splitting. AB - Gd(III) complexes have emerged as spin labels for distance determination in biomolecules through double-electron-electron resonance (DEER) measurements at high fields. For data analysis, the standard approach developed for a pair of weakly coupled spins with S = 1/2 was applied, ignoring the actual properties of Gd(III) ions, i.e. S = 7/2 and ZFS (zero field splitting) ? 0. The present study reports on a careful investigation on the consequences of this approach, together with the range of distances accessible by DEER with Gd(III) complexes as spin labels. The experiments were performed on a series of specifically designed and synthesized Gd-rulers (Gd-PyMTA-spacer-Gd-PyMTA) covering Gd-Gd distances of 2-8 nm. These were dissolved in D2O-glycerol-d8 (0.03-0.10 mM solutions) which is the solvent used for the corresponding experiments on biomolecules. Q- and W-band DEER measurements, followed by data analysis using the standard data analysis approach, used for S = 1/2 pairs gave the distance-distribution curves, of which the absolute maxima agreed very well with the expected distances. However, in the case of the short distances of 2.1 and 2.9 nm, the distance distributions revealed additional peaks. These are a consequence of neglecting the pseudo secular term in the dipolar Hamiltonian during the data analysis, as is outlined in a theoretical treatment. At distances of 3.4 nm and above, disregarding the pseudo-secular term leads to a broadening of a maximum of 0.4 nm of the distance distribution curves at half height. Overall, the distances of up to 8.3 nm were determined, and the long evolution time of 16 MUs at 10 K indicates that a distance of up to 9.4 nm can be accessed. A large distribution of the ZFS parameter, D, as is found for most Gd(III) complexes in a frozen solution, is crucial for the application of Gd(III) complexes as spin labels for distance determination via Gd(III)-Gd(III) DEER, especially for short distances. The larger ZFS of Gd-PyMTA, in comparison to that of Gd-DOTA, makes Gd-PyMTA a better label for short distances. PMID- 26108867 TI - 2015 Wayne Fenton Award for Exceptional Clinical Care. PMID- 26108868 TI - Effort-Based Decision Making in Schizophrenia: Evaluation of Paradigms to Measure Motivational Deficits. AB - Effort-based decision making requires one to decide how much effort to expend for a certain amount of reward. As the amount of reward goes up most people are willing to exert more effort. This relationship between reward level and effort expenditure can be measured in specialized performance-based tasks that have only recently been applied to schizophrenia. Such tasks provide a way to measure objectively motivational deficits in schizophrenia, which now are only assessed with clinical interviews of negative symptoms. The articles in this theme provide reviews of the relevant animal and human literatures (first 2 articles), and then a psychometric evaluation of 5 effort-based decision making paradigms (last 2 articles). This theme section is intended to stimulate interest in this emerging area among basic scientists developing paradigms for preclinical studies, human experimentalists trying to disentangle factors that contribute to performance on effort-based tasks, and investigators looking for objective endpoints for clinical trials of negative symptoms in schizophrenia. PMID- 26108869 TI - Fuel metabolism in Canada geese: effects of glucagon on glucose kinetics. AB - During prolonged fasting, birds must rely on glucose mobilization to maintain normoglycemia. Glucagon is known to modulate avian energy metabolism during prolonged fasting, but the metabolic effects of this hormone on long-distance migrant birds have never been investigated. Our goal was to determine whether glucagon regulates the mobilization of the main lipid and carbohydrate fuels in migrant birds. Using the Canada goose (Branta canadensis) as a model species, we looked for evidence of fuel mobilization via changes in metabolite concentrations. No changes could be found for any lipid fraction, but glucagon elicited a strong increase in glucose concentration. Therefore, we aimed to quantify the effects of this hormone on glucose kinetics using continuous infusion of 6-[(3)H]-d-glucose. Glucagon was found to cause a 50% increase in glucose mobilization (from 22.2 +/- 2.4 MUmol.kg(-1).min(-1) to 33.5 +/- 3.3 MUmol.kg(-1).min(-1)) and, together with an unchanged rate of carbohydrate oxidation, led to a 90% increase in plasma glucose concentration. This hormone also led to a twofold increase in plasma lactate concentration. No changes in plasma lipid concentration or composition were observed. This study is the first to demonstrate how glucagon modulates glucose kinetics in a long-distance migrant bird and to quantify its rates of glucose mobilization. PMID- 26108870 TI - Viral transduction of renin rapidly establishes persistent hypertension in diverse murine strains. AB - Mice provide a unique platform to dissect disease pathogenesis, with the availability of recombinant inbred strains and diverse genetically modified strains. Leveraging these reagents to elucidate the mechanisms of hypertensive tissue injury has been hindered by difficulty establishing persistent hypertension in these inbred lines. ANG II infusion provides relatively short term activation of the renin-angiotensinogen system (RAS) with concomitant elevated arterial pressure. Longer-duration studies using renin transgenic mice are powerful models of chronic hypertension, yet are limited by the genetic background on which the transgene exists and the exposure throughout development. The present studies characterized hypertension produced by transduction with a renin-coding adeno-associated virus (ReninAAV). ReninAAV mice experienced elevated circulating renin with concurrent elevations in arterial pressure. Following a single injection of ReninAAV, arterial pressure increased on average +56 mmHg, an increase that persisted for at least 12 wk in three distinct and widely used strains of adult mice: 129/S6, C56BL/6, and DBA/2J. This was accomplished without surgical implantation of pumps or complex breeding and backcrossing. In addition, ReninAAV mice developed pathophysiological changes associated with chronic hypertension, including increased heart weight and albuminuria. Thus ReninAAV provides a unique tool to study the onset of and effects of persistent hypertension in diverse murine models. This model should facilitate our understanding of the pathogenesis of hypertensive injury. PMID- 26108871 TI - A high-throughput assay for quantifying appetite and digestive dynamics. AB - Food intake and digestion are vital functions, and their dysregulation is fundamental for many human diseases. Current methods do not support their dynamic quantification on large scales in unrestrained vertebrates. Here, we combine an infrared macroscope with fluorescently labeled food to quantify feeding behavior and intestinal nutrient metabolism with high temporal resolution, sensitivity, and throughput in naturally behaving zebrafish larvae. Using this method and rate based modeling, we demonstrate that zebrafish larvae match nutrient intake to their bodily demand and that larvae adjust their digestion rate, according to the ingested meal size. Such adaptive feedback mechanisms make this model system amenable to identify potential chemical modulators. As proof of concept, we demonstrate that nicotine, l-lysine, ghrelin, and insulin have analogous impact on food intake as in mammals. Consequently, the method presented here will promote large-scale translational research of food intake and digestive function in a naturally behaving vertebrate. PMID- 26108873 TI - Using an Automatic Tool to Identify Potential Readability Issues in a Large Sample of Medicinal Package Inserts. PMID- 26108872 TI - Synthesis, characterization and apoptotic activity of quinazolinone Schiff base derivatives toward MCF-7 cells via intrinsic and extrinsic apoptosis pathways. AB - The current study investigated the cytotoxic effect of 3-(5-chloro-2 hydroxybenzylideneamino)-2-(5-chloro-2-hydroxyphenyl)-2,3-dihydroquinazolin-41(H) one (A) and 3-(5-nitro-2-hydroxybenzylideneamino)-2-(5-nitro-2-hydroxyphenyl)-2,3 dihydroquinazolin-4(1H)-one (B) on MCF-7, MDA-MB-231, MCF-10A and WRL-68 cells. The mechanism involved in apoptosis was assessed to evaluate the possible pathways induced by compound A and B. MTT assay results using A and B showed significant inhibition of MCF-7 cell viability, with IC50 values of 3. 27 +/- 0.171 and 4.36 +/- 0.219 MUg/mL, respectively, after a 72 hour treatment period. Compound A and B did not demonstrate significant cytotoxic effects towards MDA-MB 231, WRL-68 and MCF-10A cells. Acute toxicity tests also revealed an absence of toxic effects on mice. Fluorescent microscopic studies confirmed distinct morphological changes (membrane blebbing and chromosome condensation) corresponding to typical apoptotic features in treated MCF-7 cells. Using Cellomics High Content Screening (HCS), we found that compound A and B could trigger the release of cytochrome c from mitochondria to the cytosol. The release of cytochrome c activated the expression of caspases-9 and then stimulated downstream executioner caspase-3/7. In addition, caspase-8 showed remarkable activity, followed by inhibition of NF-kappaB activation in A-and B-treated MCF-7 cells. The results indicated that A and B could induce apoptosis via a mechanism that involves either extrinsic or intrinsic pathways. PMID- 26108875 TI - Correction. PMID- 26108876 TI - [Genetics of dementia]. AB - Most psychiatric diseases in adulthood have a multifactorial origin. This also applies for most cases of dementia; however, rare familial forms of Alzheimer's disease and frontotemporal lobar degeneration follow an autosomal dominant (Mendelian) inheritance pattern. Alzheimer's disease that is caused by mutations in the genes for presenilin 1, presenilin 2 and amyloid precursor protein has an onset under the age of 65 years in most cases. Approximately 10 % of frontotemporal lobar degeneration cases display an autosomal dominant inheritance pattern. According to the current S3 guidelines on dementia of the German Association for Psychiatry, Psychotherapy and Psychosomatics and the German Society of Neurology, genetic counseling should be offered if an autosomal dominant disease pattern is suspected. Genetic counseling must conform to the German Genetic Diagnostics Act (Gendiagnostikgesetz). PMID- 26108877 TI - [Intensive care therapy of space-occupying large hemispheric infarction. Summary of the NCS/DGNI guidelines]. AB - Large hemispheric infarction (LHI), synonymously called malignant middle cerebral artery (MCA) infarction, is a severe neurological disease with a high mortality and morbidity. Treating physicians as well as relatives are often faced with few and low quality data when attempting to apply optimal treatment to these patients and make decisions. While current stroke treatment guidelines focus on risk factors, prevention and acute management, they include only limited recommendations concerning intensive care management of LHI. The Neurocritical Care Society (NCS) and the German Society for Neurocritical and Emergency Medicine (DGNI) organized an interdisciplinary consensus conference on intensive care management of LHI to meet this demand. European and American experts in neurology, neurocritical care, neurosurgery, neuroradiology and neuroanesthesiology were selected based on their expertise and research focus. Subgroups for several main topics elaborated a number of central clinical questions concerning this topic and evaluated the quality of the currently available data according to the grading of recommendation assessment, development and evaluation (GRADE) guideline system. Subsequently, evidence-based recommendations were compiled after weighing the advantages against the disadvantages of certain management options. This is a commented abridged version of the results of the consensus conference. PMID- 26108878 TI - Internalization, Trafficking, Intracellular Processing and Actions of Antibody Drug Conjugates. AB - PURPOSE: This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy. METHODS: this review goes over major progress in preclinical and clinical studies of ADCs, in the past 5 years. RESULTS: The pharmacokinetics and pharmacodynamics of ADCs involve multiple mechanisms, including internalization of ADCs by target cells, intracellular trafficking, release of conjugated drugs, and payload. CONCLUSION: These mechanisms actually jointly determine the efficacy of ADCs. Therefore, the optimization of ADCs should take them as necessary rationales. PMID- 26108879 TI - An Introduction to the Regulatory and Nonclinical Aspects of the Nonclinical Development of Antibody Drug Conjugates. AB - Antibody drug conjugates (ADCs) are promising therapies currently in development for oncology with unique and challenging regulatory and scientific considerations. While there are currently no regulatory guidelines specific for the nonclinical development of ADCs, there are harmonized international guidelines (e.g., ICHS6(R1), ICHM3(R2), ICHS9) that apply to ADCs and provide a framework for their complex development with issues that apply to both small and large molecules. The regulatory and scientific perspectives on ADCs are evolving due to both the advances in ADC technology and a better understanding of the safety and efficacy of ADCs in clinical development. This paper introduces the key scientific and regulatory aspects of the nonclinical development of ADCs, discusses important regulatory and scientific issues in the nonclinical to clinical dose translation of ADCs, and introduces new concepts in the areas of pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. PMID- 26108880 TI - Identification of cytokine-induced modulation of microRNA expression and secretion as measured by a novel microRNA specific qPCR assay. AB - microRNAs are an abundant class of small non-coding RNAs that control gene expression post-transcriptionally. Importantly, microRNA activity participates in the regulation of cellular processes and is a potentially valuable source of biomarkers in the diagnosis and prognosis of human diseases. Here we introduce miQPCR, an innovative method to quantify microRNAs expression by using Real-Time PCR. miQPCR exploits T4 RNA ligase activities to extend uniformly microRNAs' 3' ends by addition of a linker-adapter. The adapter is then used as 'anchor' to prime cDNA synthesis and throughout qPCR to amplify specifically target amplicons. miQPCR is an open, adaptable and cost-effective procedure, which offers the following advantages; i) universal elongation and reverse transcription of all microRNAs; ii) Tm-adjustment of microRNA-specific primers; iii) high sensitivity and specificity in discriminating among closely related sequences and; iv) suitable for the analysis of cellular and cell-free circulating microRNAs. Analysis of cellular and cell-free circulating microRNAs secreted by rat primary hepatocytes stimulated with cytokines and growth factors identifies for the first time a widespread modulation of both microRNAs expression and secretion. Altogether, our findings suggest that the pleiotropic activity of humoral factors on microRNAs may extensively affect liver function in response to injury and regeneration. PMID- 26108881 TI - Amphiphilic Residues 29-44 of DREAM N-Termini Mediate Calmodulin:DREAM Complex Formation. AB - DREAM (downstream regulatory element antagonist modulator) is a neuronal calcium sensor that has been shown to modulate gene expression as well as to be involved in numerous neuronal processes. In this report, we show that association of calcium-bound calmodulin (CaM) with DREAM is mediated by a short amphipathic amino acid sequence located between residues 29 and 44 on DREAM. The association of CaM with a peptide analogous to DREAM(29-44) or to full-length DREAM protein is calcium-dependent with a dissociation constant of 136 nM or 3.4 MUM, respectively. Thermodynamic and kinetic studies show that the observed decrease in affinity for the native protein is due to electrostatic interactions between the basic N-terminus and an electronegative surface on DREAM. These results are further supported by circular dichroism, binding studies, and molecular dynamics simulations. Additionally, fluorescence anisotropy decay measurements show a rotational correlation time of 10.8 ns for a complex of CaM with a DREAM(29-44) peptide, supporting a wraparound semispherical model with 1:1 stoichiometry. Furthermore, the interaction between an IEDANS-labeled CaM construct with DREAM is best modeled as a heterotetramer that adopts an elongated conformation with a correlation time of 45 ns in the presence of Ca(2+). We also demonstrate that association of CaM with DREAM eliminates the nonspecific interaction of DREAM with the DRE double-stranded DNA sequence of the human prodynorphin gene. This work provides molecular insight into the CaM:DREAM complex and its potential role in modulation of gene expression. PMID- 26108882 TI - The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puscas (1932-2015). AB - Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puscas used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the alpha-class and the other one to the beta-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puscas for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend. PMID- 26108883 TI - Balancing Risks in Developing a Personalised Approach to the Treatment of Early Hodgkin Lymphoma: Have We Got the Balance Right? PMID- 26108884 TI - Where Do We Look for Markers of Radiotherapy Fraction Size Sensitivity? AB - The response of human normal tissues to radiotherapy fraction size is often described in terms of cellular recovery, but the causal links between cellular and tissue responses to ionising radiation are not necessarily straightforward. This article reviews the evidence for a cellular basis to clinical fractionation sensitivity in normal tissues and discusses the significance of a long established inverse association between fractionation sensitivity and proliferative indices. Molecular mechanisms of fractionation sensitivity involving DNA damage repair and cell cycle control are proposed that will probably require modification before being applicable to human cancer. The article concludes by discussing the kind of correlative research needed to test for and validate predictive biomarkers of tumour fractionation sensitivity. PMID- 26108885 TI - An Alternative Phosphorylation Switch in Integrin beta2 (CD18) Tail for Dok1 Binding. AB - Integrins are involved in cell migration and adhesion. A large number of proteins interact with the cytoplasmic tails of integrins. Dok1 is a negative regulator of integrin activation and it binds to the phosphorylated membrane proximal NxxY motif in a number of integrin beta tails. The beta tail of the beta2 integrins contains a non-phosphorylatable NxxF motif. Hence it is unclear how Dok1 associates with the beta2 integrins. We showed in this study using NMR and cell based analyses that residues Ser745 and Ser756 in the integrin beta2 tail, which are adjacent to the NxxF motif, are required for Dok1 interaction. NMR analyses detected significant chemical shift changes and higher affinity interactions between Dok1 phospho-tyrosine binding (PTB) domain and integrin beta2 tail peptide containing pSer756 compared to pSer745. The phosphorylated beta2 peptide occupies the canonical ligand binding pocket of Dok1 based on the docked structure of the beta2 tail-Dok1 PTB complex. Taken together, our data suggest an alternate phosphorylation switch in beta2 integrins that regulates Dok1 binding. This could be important for cells of the immune system and their functions. PMID- 26108886 TI - Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model. AB - Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia. PMID- 26108887 TI - Amblyomma americanum tick saliva insulin-like growth factor binding protein related protein 1 binds insulin but not insulin-like growth factors. AB - Silencing Amblyomma americanum insulin-like growth factor binding protein-related protein 1 (AamIGFBP-rP1) mRNA prevented ticks from feeding to repletion. In this study, we used recombinant (r)AamIGFBP-rP1 in a series of assays to obtain further insight into the role(s) of this protein in tick feeding regulation. Our results suggest that AamIGFBP-1 is an antigenic protein that is apparently exclusively expressed in salivary glands. We found that both males and females secrete AamIGFBP-rP1 into the host during feeding and confirmed that female ticks secrete this protein from within 24-48 h after attachment. Our data suggest that native AamIGFBP-rP1 is a functional insulin binding protein in that both yeast- and insect cell-expressed rAamIGFBP-rP1 bound insulin, but not insulin-like growth factors. When subjected to anti-blood clotting and platelet aggregation assays, rAamIGFBP-rP1 did not have any effect. Unlike human IGFBP-rP1, which is controlled by trypsinization, rAamIGFBP-rP1 is resistant to digestion, suggesting that the tick protein may not be under mammalian host control at the tick feeding site. The majority of tick-borne pathogens are transmitted 48 h after the tick has attached. Thus, the demonstrated antigenicity and secretion into the host within 24-48 h of the tick starting to feed makes AamIGFBP-rP1 an attractive target for antitick vaccine development. PMID- 26108888 TI - Impact of neonatal intensive care bed configuration on rates of late-onset bacterial sepsis and methicillin-resistant Staphylococcus aureus colonization. AB - BACKGROUND: Infections cause morbidity and mortality in neonatal intensive care units (NICUs). The association between nursery design and nosocomial infections is unclear. OBJECTIVE: To determine whether rates of colonization by methicillin resistant Staphylococcus aureus (MRSA), late-onset sepsis, and mortality are reduced in single-patient rooms. DESIGN Retrospective cohort study. SETTING: NICU in a tertiary referral center. METHODS: Our NICU is organized into single-patient and open-unit rooms. Clinical data sets including bed location and microbiology results were examined over 29 months. Differences in outcomes between bed configurations were determined by chi2 and Cox regression. PATIENTS: All NICU patients. RESULTS: Among 1,823 patients representing 55,166 patient-days, single patient and open-unit models had similar incidences of MRSA colonization and MRSA colonization-free survival times. Average daily census was associated with MRSA colonization rates only in single-patient rooms (hazard ratio, 1.31; P=.039), whereas hand hygiene compliance on room entry and exit was associated with lower colonization rates independent of bed configuration (hazard ratios, 0.834 and 0.719 per 1% higher compliance, respectively). Late-onset sepsis rates were similar in single-patient and open-unit models as were sepsis-free survival and the combined outcome of sepsis or death. After controlling for demographic, clinical, and unit-based variables, multivariate Cox regression demonstrated that bed configuration had no effect on MRSA colonization, late-onset sepsis, or mortality. CONCLUSIONS: MRSA colonization rate was impacted by hand hygiene compliance, regardless of room configuration, whereas average daily census affected only infants in single-patient rooms. Single-patient rooms did not reduce the rates of MRSA colonization, late-onset sepsis, or death. PMID- 26108889 TI - Development and In Vitro Evaluation of Vitamin E-Enriched Nanoemulsion Vehicles Loaded with Genistein for Chemoprevention Against UVB-Induced Skin Damage. AB - There is a great need for effective protection against cutaneous pathologies arising from chronic exposure to harmful solar UVB radiations. A promising pharmaceutical strategy to improve the efficacy of chemotherapeutic/preventative natural compounds (e.g., soy isoflavone Genistein, Gen) is to enhance their dermal delivery using nanoemulsion (NE) formulations. This report investigates the development of nanoemulsified tocotrienol(T3)-rich fraction of red palm oil (Tocomin(r)), to yield an optimal NE delivery system for dermal photoprotection (z-average size <150 nm, zeta-potential ~ -30 mV, polydispersity index < 0.25). Physicochemical characterization and photostability studies indicate NE formulations utilizing surfactant mixture (Smix) of Solutol(r) HS-15 (SHS15) blended with vitamin E TPGS (TPGS) as cosurfactant was significantly superior to formulations that utilized Lutrol(r) F68 (LF68) as the cosurfactant. A ratio of 60:40 of SHS15-TPGS-NE was further identified as lead Tocomin(r) NE topical platform using in vitro pharmaceutical skin reactivity studies that assess cutaneous irritancy and cytotoxicity. Prototype Tocomin(r) NE loaded with the antiphotocarcinogenic molecule Gen (Gen-Tocomin(r) NE) showed slow-release profile in both liquid and cream forms. Gen-Tocomin(r) NE also showed excellent biocompatibility, and provided substantial UVB protection to cultured subcutaneous L929 fibroblasts, indicating the great potential of our Tocomin(r) NE warranting further prototype development as topical pharmaceutical platform for skin photoprotection applications. PMID- 26108890 TI - Nanoscale memristive radiofrequency switches. AB - Radiofrequency switches are critical components in wireless communication systems and consumer electronics. Emerging devices include switches based on microelectromechanical systems and phase-change materials. However, these devices suffer from disadvantages such as large physical dimensions and high actuation voltages. Here we propose and demonstrate a nanoscale radiofrequency switch based on a memristive device. The device can be programmed with a voltage as low as 0.4 V and has an ON/OFF conductance ratio up to 10(12) with long state retention. We measure the radiofrequency performance of the switch up to 110 GHz and demonstrate low insertion loss (0.3 dB at 40 GHz), high isolation (30 dB at 40 GHz), an average cutoff frequency of 35 THz and competitive linearity and power handling capability. Our results suggest that, in addition to their application in memory and computing, memristive devices are also a leading contender for radiofrequency switch applications. PMID- 26108891 TI - A feasibility study for using ABS plastic and a low-cost 3D printer for patient specific brachytherapy mould design. AB - This feasibility study aims to determine if a low-cost 3D printer (BitsFromBytes 3D Touch) with ABS plastic can print custom mould structures and catheter channels defined in a brachytherapy treatment planning system (Nucletron Oncentra) for patient-specific treatment. Printer accuracy was evaluated through physical measurement, and print quality was investigated by adjusting print parameters (print speed, layer thickness, percentage infill). Catheter positioning and reproducibility were measured over repeated insertions. ABS plastic water equivalency was investigated by comparing Ir-192 HDR source dose distributions, measured with radiochromic film, in ABS plastic and in water. Structures and catheter channels were printed accurately to within 0.5 mm laterally and 1 mm in the vertical print direction. Adjusting print parameters could reduce print time, albeit with reduced print quality. 3.5 mm channel diameters allowed for easy catheter insertion. Catheter positioning was reproducible to within 0.5 mm but, because of catheter flex within the channel, was on average 1 mm offset from defined TPS positions. This offset could be accounted for by repeating the treatment planning CT scan with the printed mould positioned on the patient. Dose attenuation in ABS plastic and in water was equivalent to within the measurement limitations. While clinical uses for this particular low-cost printer and ABS plastic are limited by print size restrictions and non-certification for biocompatibility, it has been demonstrated that a low-cost 3D printer set-up can accurately create custom moulds and catheter channels potentially acceptable for clinical use. PMID- 26108892 TI - Left Ventricular Non-compaction: Is It Genetic? AB - Left ventricular non-compaction (LVNC) is reported to affect 0.14 % of the pediatric population. The etiology is heterogeneous and includes a wide number of genetic causes. As an illustration, we report two patients with LVNC who were diagnosed with a genetic syndrome. We then review the literature and suggest a diagnostic algorithm to evaluate individuals with LVNC. Case 1 is a 15-month-old girl who presented with hypotonia, global developmental delay, congenital heart defect (including LVNC) and facial dysmorphism. Case 2 is a 7-month-old girl with hypotonia, seizures, laryngomalacia and LVNC. We performed chromosomal microarray for both our patients and detected chromosome 1p36 microdeletion. We reviewed the literature for other genetic causes of LVNC and formulated a diagnostic algorithm, which includes assessment for syndromic disorders, inborn error of metabolism, copy number variants and non-syndromic monogenic disorder associated with LVNC. LVNC is a relatively newly recognized entity, with heterogeneity in underlying etiology. For a systematic approach of evaluating the underlying cause to improve clinical care of these patients, a diagnostic algorithm for genetic evaluation of patients with LVNC is proposed. PMID- 26108893 TI - Osteoclast TGF-beta Receptor Signaling Induces Wnt1 Secretion and Couples Bone Resorption to Bone Formation. AB - Osteoblast-mediated bone formation is coupled to osteoclast-mediated bone resorption. These processes become uncoupled with age, leading to increased risk for debilitating fractures. Therefore, understanding how osteoblasts are recruited to sites of resorption is vital to treating age-related bone loss. Osteoclasts release and activate TGF-beta from the bone matrix. Here we show that osteoclast-specific inhibition of TGF-beta receptor signaling in mice results in osteopenia due to reduced osteoblast numbers with no significant impact on osteoclast numbers or activity. TGF-beta induced osteoclast expression of Wnt1, a protein crucial to normal bone formation, and this response was blocked by impaired TGF-beta receptor signaling. Osteoclasts in aged murine bones had lower TGF-beta signaling and Wnt1 expression in vivo. Ex vivo stimulation of osteoclasts derived from young or old mouse bone marrow macrophages showed no difference in TGF-beta-induced Wnt1 expression. However, young osteoclasts expressed reduced Wnt1 when cultured on aged mouse bone chips compared to young mouse bone chips, consistent with decreased skeletal TGF-beta availability with age. Therefore, osteoclast responses to TGF-beta are essential for coupling bone resorption to bone formation, and modulating this pathway may provide opportunities to treat age-related bone loss. PMID- 26108894 TI - Sex-Specific Disparities in Risk Factors for Coronary Heart Disease. AB - In the past two decades, focused research on women at risk for cardiovascular disease (CVD) has helped to clarify our understanding of some of the sex-specific factors that are important in the prevention and early detection of coronary atherosclerosis with a resultant 30 % decrease in the number of women dying from CVD. In spite of these advances, CVD, specifically, ischemic heart disease due to coronary atherosclerosis is the leading cause of cardiovascular death of women in the USA. The 2010 landmark Institute of Medicine (IOM) report, "Women's Health Research--Progress, Pitfalls and Promise," highlighted the fact that although major progress had been made in reducing cardiovascular mortality in women, there were disparities in disease burden among subgroups of women, particularly those women who are socially disadvantaged because of race, ethnicity, income level, and educational attainment [1]. The IOM recommended targeted research on these subpopulations of women with the highest risk and burden of disease. Causes of disparities are multifactorial and are related to differences in risk factor prevalence, access to care, use of evidence-based guidelines, and social and environmental factors. In this article, we review a few of the contributing factors to the disparities in ischemic heart disease in women with a focus on the subgroups of women of Black, Latino, and South Asian descent who are at high risk for morbidity and mortality from CVD. PMID- 26108896 TI - Development of a comprehensive clinical performance assessment system for nursing students: A programmatic approach. AB - AIM: Evaluation of achievement of learning objectives needs an accurate assessment program. Hence, nursing educators should move away from the use of individual assessment methods to apply a programmatic approach. The aim of this study was to develop a comprehensive assessment system for nursing students in their critical care rotation based on a programmatic approach. METHODS: The population of this study was nursing students in their critical care course. The learning objectives of the course were determined using an expert panel and classified into three categories. Suitable assessment methods were identified for each category according to the consensus of experts. Then, the assessment tools were designed and the content validity was established using content validity ratio (CVR) and index (CVI). The reliability was determined by Cronbach's alpha coefficient. The satisfaction of the participants was investigated using a questionnaire. RESULTS: According to the findings, all items of the assessment system had a high CVR (P < 0.05) and CVI ranged 0.93-0.97. The alpha coefficient of the whole system was more than 0.90 and for subsystems ranged 0.72-0.96. The findings showed that 87.5% of the instructors and 89.47% of students believed that the new assessment system had a positive impact on learning. In addition, the majority of them were satisfied with the new assessment system. CONCLUSION: A programmatic approach should be used for effective evaluation of clinical performance of nursing students in critical care settings because of high validity and reliability, multidimensionality, positive educational impact, and acceptability. PMID- 26108895 TI - Mechanical Properties and Failure of Biopolymers: Atomistic Reactions to Macroscale Response. AB - The behavior of chemical bonding under various mechanical loadings is an intriguing mechanochemical property of biological materials, and the property plays a critical role in determining their deformation and failure mechanisms. Because of their astonishing mechanical properties and roles in constituting the basis of a variety of physiologically relevant materials, biological protein materials have been intensively studied. Understanding the relation between chemical bond networks (structures) and their mechanical properties offers great possibilities to enable new materials design in nanotechnology and new medical treatments for human diseases. Here we focus on how the chemical bonds in biological systems affect mechanical properties and how they change during mechanical deformation and failure. Three representative cases of biomaterials related to the human diseases are discussed in case studies, including: amyloids, intermediate filaments, and collagen, each describing mechanochemical features and how they relate to the pathological conditions at multiple scales. PMID- 26108897 TI - Challenges to clinical utilization of hereditary cancer gene panel testing: perspectives from the front lines. AB - Next generation sequencing (NGS) technology is rapidly being implemented into clinical practice. Qualitative research was performed to gain an improved understanding of the landscape surrounding the use of NGS in cancer genetics. A focus group was conducted at the Wisconsin Cancer Risk Programs Network biannual meeting. Free flowing discussion with occasional open-ended questions provided insights into the use of NGS. 19 genetic counselors and medical professionals participated. Three major themes were identified with respect to NGS and its use in cancer genetics: knowledge gaps, the evolving clinician role, and uncertain utility. Several corresponding subthemes were identified. With respect to knowledge gaps, participants expressed concern regarding unexpected results and variants of unknown significance, lack of data about NGS findings, absence of standardization regarding use of NGS and guidelines for interpretation, and discomfort with new technology. Regarding the evolving clinician role, necessary changes to the roles of genetic counselors and physicians were noted, as was the resultant impact on care received by patients and their families. Finally, the clinical and economic utility of NGS was questioned. While a shift from traditional Sanger sequencing to NGS is occurring in molecular genetic testing for disease susceptibility, there are several obstacles that need to be overcome before widespread adoption of this technology can occur. Furthermore, key aspects of NGS and it utility remain unexplored. Continued investigation into these subjects is necessary before this technology will consistently be of benefit to patients and their families. PMID- 26108898 TI - A longitudinal study of interpersonal relationships among lesbian, gay, and bisexual adolescents and young adults: mediational pathways from attachment to romantic relationship quality. AB - The current study examined the potential for mental health to mediate associations between earlier attachment to parents and peers and later relationship adjustment during adolescence and young adulthood in a sample of sexual minority youth. Secondarily, the study examined associations between peer and parental attachment and relationship/dating milestones. Participants included 219 lesbian, gay, and bisexual youth who participated in six waves of data collection over 3.5 years. Parental attachment was associated with an older age of dating initiation, while peer attachment was associated with longer relationship length. Both peer and parental attachment were significantly associated with mental health in later adolescence and young adulthood. Mental health mediated the association between peer attachment and main partner relationship quality. While the total indirect effect of parental attachment on main partner relationship quality was statistically significant, specific indirect effects were not. Implications for the application of attachment theory and integration of interpersonal factors into mental health intervention with sexual minority youth are discussed. PMID- 26108899 TI - A Pilot Study on Tamoxifen Sexual Side Effects and Hand Preference in Male Breast Cancer. AB - Recent clinical and imaging studies suggest that sex hormones modulate sexuality according to a psychophysiologic process of lateralization of the brain, with androgens playing a greater role in sexual functioning of left hemibrain/right handedness and estrogens possibly for right hemibrain/left handedness. Based on this perspective, the current study attempted to specify the relationship between hand preference, estrogens, and sexual function in subjects with male breast cancer, taking into account the sexual side effects of tamoxifen as the agent for inhibiting estrogen action. Twenty-eight Romanian men-17 right-handed and 11 left handed-undergoing treatment with tamoxifen for male breast cancer participated in this study. These men were assessed both prior to and during tamoxifen treatment using the International Index of Erectile Function, a standardized instrument used for the evaluation of various aspects of sexual functioning, including erectile function (EF), orgasmic function (OF), sexual desire (SD), and overall functioning (OF). A main effect for handedness was found on EF, OF, SD, and OS scales, with right-handed men showing higher functioning than left-handed men. Regarding interaction effects, the left-handed group of men showed greater decreased sexual functioning during tamoxifen (on three subscales: OF, SD, OS) compared to right-handed men. Further research should be conducted in order to support and refine this potential lateralized process of sexual neuromodulation within the brain. PMID- 26108900 TI - Effects of Addition of Early Enteral Nutritional Support During the Postoperative Phase in Patients after Living-Donor Liver Transplantation. AB - BACKGROUND: Early initiation of enteral nutrition is recommended after some surgical procedures. This study retrospectively analyzed the effects of addition of early enteral nutrition (EEN) support during the postoperative phase in patients after living-donor liver transplantation (LDLT). MATERIAL AND METHODS: The subjects were adult patients who underwent LDLT in our department and received either total parenteral nutrition (TPN) or EEN for postoperative nutritional support. We retrospectively compared clinical parameters between the TPN group (n=50) and the EEN group (n=45). RESULTS: There were no significant differences in preoperative demographic data between the EEN and TPN groups with the exception of the follow-up period after surgery. In the EEN group, EEN was provided uneventfully; the daily amount of enteral nutrition was 996+/-465 kcal on postoperative day 7. Central venous catheters were removed significantly earlier in the EEN group than in the TPN group (postoperative day 11+/-7 vs. 28+/ 18). The postoperative C-reactive protein level and the incidence of bacterial infection were significantly lower in the EEN group than in the TPN group. The postoperative length of hospital stay was significantly shorter and 6-month survival was significantly higher in the EEN group than in the TPN group. A multivariate analysis indicated that EEN was a significant factor for both shorter hospital stay and 6-month survival. CONCLUSIONS: Our retrospective analyses suggest that introduction of EEN had a great impact on postoperative short-term outcomes of LDLT. PMID- 26108901 TI - Treatment of latent tuberculosis infection induces changes in multifunctional Mycobacterium tuberculosis-specific CD4+ T cells. AB - To ascertain whether multiparametric flow cytometry assessment of multifunctional Mycobacterium tuberculosis (Mtb)-specific CD4(+) and CD8(+) T cells can distinguish between untreated and treated patients with latent tuberculosis infection (LTBI), we enrolled 14 LTBI subjects treated with isoniazid (INH) therapy, 16 untreated LTBI patients, and 25 healthy controls. The analysis of mono-functional CD4(+) and CD8(+) T cells producing single cytokines showed significant differences only between uninfected and infected LTBI subjects (both treated and untreated). Conversely, the analysis of multifunctional CD4(+) T cells revealed a significant reduction in the frequency of two CD4(+) T cells subsets, those producing IFN-gamma, IL-2, and TNF-alpha simultaneously (triple positive; p = 0.005) and those producing IL-2 alone (p = 0.0359), as well as a shift towards T cells producing only one cytokine in treated as compared to untreated LTBI subjects. Assigning a triple-positive CD4(+) T cells a cut-off >0.082 %, 94 % of untreated LTBI patients were scored as positive, as compared to only 28 % of treated LTBI patients and none of the healthy controls. No significant differences between untreated and treated LTBI subjects in terms of Mtb-specific CD8(+) T cell cytokine profiles (p > 0.05) were identified. The significant changes in the cytokine profiles of Mtb-specific T cells after INH therapy suggest that analysis of multifunctional T cells may be a promising means for the monitoring of LTBI treatment success. PMID- 26108902 TI - [Diagnostic validity of ultrasonography in carpal tunnel syndrome]. AB - INTRODUCTION: Ultrasonography has emerged as an alternative tool for diagnosing peripheral neuropathies, such as carpal tunnel syndrome (CTS). Yet, data are still lacking as regards the diagnostic validity of the different ultrasonography measurements for detecting CTS in clinical settings. AIMS: To determine the diagnostic validity of ultrasound measurements of the cross-sectional area of the median nerve in the wrist (CSA-M) and of the ratio of the area of the median nerve between the wrist and the forearm (R-WF) in the diagnosis of CTS, using electroneuromyography (ENG) as the reference technique. PATIENTS AND METHODS: Ultrasound measurements were performed on 59 subjects (100 wrists) who were referred to have an ENG due to suspected CTS. The examiners that performed the ultrasonography scan did not know the results of the ENG. The cut-off points were later calculated by means of ROC curves for each of the measurements (CSA-M and R WF) and their diagnostic validity was analysed. RESULTS: With a cut-off point of 9.15 mm2, CSA-M measurement obtained a sensitivity of 75.81%, a specificity of 74.29%, a positive likelihood ratio of 2.95 and a negative likelihood ratio of 0.33. For the R-WF measurement and a cut-off point of 1.56, the values for sensitivity, specificity, and positive and negative likelihood ratios were 70.97%, 71.43%, 2.48 and 0.4, respectively. CONCLUSIONS: Both the CSA-M and R-WF appear to be useful measures in the diagnosis of CTS, taking the ENG as a reference test. PMID- 26108903 TI - [Etiology, clinical presentation and outcome of severe viral acute childhood encephalitis (ECOVE study)]. AB - INTRODUCTION: Viral encephalitis are rare and potentially serious conditions with different etiologist, and not always identifiable. Our aim is to describe the etiological, clinical presentation and neurological outcome of viral encephalitis admitted in Paediatrics Intensive Care Units (PICUs) in Spain. PATIENTS AND METHODS: Observational prospective multicenter study. Children with viral encephalitis admitted to 14 PICUs, for a period of 3 years (2010-2013) were included. Polymerase chain reaction for the etiological diagnosis and neurotropic virus serology in blood and cerebrospinal fluid were used. Personal history, clinical presentation, evolution and neurological status at discharge were recorded. RESULTS: 80 patients were included with a mean age of 5 years, 70% male. The most relevant clinical symptoms were decreased consciousness (86%), fever (82.4%), seizures (67%), vomiting (42%), headache (27%), agitation (25%) and dis-orientation (23%). The etiologic diagnosis was established in 35%, being more frequent herpes simplex virus and enterovirus. The outcome was discharge without sequelae in 55 patients (69%), mild to moderate sequelae in 19 (23.5%) and severe in 6 (7.5%). Two patients died. CONCLUSIONS: In the Spanish PICU etiological diagnosis was established only in a third of cases of children with suspected acute viral encephalitis. Despite the clinical severity we observed a low mortality and morbidity rate. At discharge from the PICU, most children had no neurological sequelae or were mild. PMID- 26108904 TI - [Subtypes of mild cognitive impairment in Parkinson's disease and factors predicting its becoming dementia]. AB - INTRODUCTION: Cognitive impairment may appear at the earliest stages in Parkinson's disease (PD). To assess the prevalence of mild cognitive impairment (MCI) and its different subtypes, as transitional stage, is complicated by the lack of consensus diagnostic criteria. AIM: To review MCI in PD (MCI-PD), diagnostic criteria and predictive factors of conversion to dementia. PATIENTS AND METHODS: Systematic review of articles published in Medline (PubMed) using the combination of keywords 'mild cognitive impairment' and 'Parkinson's disease'. RESULTS: MCI-PD diagnostic criteria published by the Movement Disorders Society are an interesting tool for the diagnosis, in spite they are not validated. Its implementation has the following limitations: 1) the heterogeneity of cognitive deficits described in PD; 2) a variable evolution of cognitive symptoms in PD which difficult the identification of dementia predictors; 3) selection of the more appropriate neuropsychological tests and cut-off points; 4) patient characteristics, disease stage and type of antiparkinsonian treatment. CONCLUSIONS: Neuropsychological subtypes, neuroimaging, biomarkers or limitation in some instrumental activities seem to be very sensitive for detecting patients with MCI-PD and increased risk of conversion to dementia. PMID- 26108905 TI - [Neuropsychological deficits in alternating hemiplegia of childhood: a case study]. AB - INTRODUCTION: Alternating hemiplegic of childhood is a predominantly sporadic neurodevelopmental syndrome of uncertain etiology, characterized by alternating transient attacks of hemiplegia. Additional features include tonic fits, dystonic posturing, ocular motor abnormalities and deficits in cognitive functioning. CASE REPORT: A girl of 7 years-old with alternating hemiplegic of childhood. The first symptoms debut at 17 months of age in the form of lower limb weakness, migraine, nystagmus and hemiplegic crisis alternating both hemibodies. We administrate the Wechsler Intelligence Scale for Children IV (WISC-IV), the Conners Continuous Performance Test II (CPT-II), the Conners scales for parents (CPRS-48) and teachers (CTRS-28) and the Behavior Rating Inventory Executive Function (BRIEF). CONCLUSIONS: In our study we found deficits in sustained attention, reduced speed of information processing, and difficulties in understanding, speaking and working memory. In addition, parents and teachers reported behavioral disturbances, difficulties inhibition capability, in self-control and in regulating emotions. PMID- 26108906 TI - [Association between periodontal disease and cerebrovascular disease. A review of the literature]. AB - Periodontal disease and cerebrovascular disease are two of the most prevalent processes in elderly people. Various studies have shown an association between them, although some methodological differences exist and this difficult the data interpretation. The aim of this paper is to conduct a critical review of the studies published about this association. Eleven prospective studies and 11 retrospective studies are included in this review. We analyse the different methodological outcomes (study population, periodontal diagnosis, cerebrovascular disease definition, adjusted outcomes and odds ratio/relative risk). Furthermore, we review several pathogenic mechanisms implicated in the progression and the relationship between both processes. PMID- 26108908 TI - [Ullrich congenital muscular dystrophy. The usefulness of muscular magnetic resonance imaging in its diagnosis]. PMID- 26108909 TI - [Internal carotid artery dissection following cocaine use]. PMID- 26108910 TI - [Experience with eslicarbazepine in patients with hiponatremia due to carbamazepine and oxcarbacepine]. PMID- 26108911 TI - [Colloid cyst and Bruns syndrome]. PMID- 26108912 TI - Effects of brain-derived neurotrophic factor on oocyte maturation and embryonic development in a rat model of polycystic ovary syndrome. AB - Brain-derived neurotrophic factor (BDNF) is expressed extensively in the mammalian female reproductive system and has been implicated in the development of follicles and oocytes. However, BDNF expression patterns in the ovary and its effects on oocyte maturation and embryonic development in polycystic ovary syndrome (PCOS) have not been established. In the present study, we established a PCOS model by treating the rats with insulin and human chorionic gonadotropin (hCG). Rats treated with insulin + hCG had heavier bodyweight and ovarian weight, higher circulating concentrations of luteinising hormone (LH) and testosterone (T), and greater homeostatic model assessment of insulin resistance (HOMA-IR) values compared with control rats (P<0.05). BDNF and its receptor tyrosine kinase type B (TrkB) were located in cyst walls, granulosa and theca cells, and BDNF protein levels were lower in ovaries of insulin + hCG-treated rats (P<0.05). The rate of oocyte maturation and formation of blastocysts and morulae was greatest in rats treated with 5ngmL-1 BDNF (P<0.05) compared to other BDNF groups (1 and 10ngmL-1) and the control. The control rats were also PCOS rats and were treated without BDNF. There were no significant differences in the rate of germinal vesicle breakdown (GVBD) and fertilisation among the various treatment groups (1, 5 and 10ngmL-1) and the control group (P>0.05). The results indicate that in vitro treatment with an appropriate concentration of BDNF not only promotes oocyte maturation, but also rescues embryonic development in rats treated with insulin + hCG as a model of PCOS. PMID- 26108913 TI - Oseltamivir for the treatment of H1N1 influenza during pregnancy. AB - Pregnancy heightens the risk of adverse outcomes from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Seasonal influenza vaccines are the focus of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu) is currently the recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease after exposure, treat infected individuals, as well as lessen the likelihood of complications. The physiologic adaptations of pregnancy alter the pharmacokinetics of this important drug. Evidence of these alterations, knowledge gaps, and future investigative directions to fill these knowledge gaps are highlighted. PMID- 26108916 TI - Cinnamic Acid and Cinnamaldehyde Ameliorate Cisplatin-Induced Splenotoxicity in Rats. AB - Cinnamic acid (CA) and cinnamaldehyde (CD) are major constituents of cinnamon species. They possess various pharmacological properties of which their antioxidant activity is a prime one. This study aims to investigate potential protective effects against cisplatin (CP)-induced splenotoxicity in rats. A single dose of CP (5 mg/kg) injected i.p. caused a significant decrease in hemoglobin content (18%), total leucocytic count (46%), neutrophils (78%), and catalase (CAT) splenic activity (64%) with a marked increase in lymphocytes (26%) and splenic content of malondialdehyde (68%) and TNF-alpha (69%) as compared with the control group. Contrarily, CA (50 mg/kg, p.o.) or CD (40 mg/kg, p.o.) administration for 7 days before CP ameliorated CP-induced splenotoxicity as indicated by mitigation of the biochemical parameters and histopathological changes. These results revealed the promising protective effects of CA and CD on CP-induced splenotoxicity in rats; an effect that might be attributed to antioxidant and anti-inflammatory activities. PMID- 26108917 TI - Liver transplantation in patients with end-stage liver disease requiring intensive care unit admission and intubation. PMID- 26108915 TI - Increased gravitational force reveals the mechanical, resonant nature of physiological tremor. AB - KEY POINTS: Physiological hand tremor has a clear peak between 6 and 12 Hz, which has been attributed to both neural and resonant causes. A reduction in tremor frequency produced by adding an inertial mass to the limb has usually been taken as a method to identify the resonant component. However, adding mass to a limb also inevitably increases the muscular force required to maintain the limb's position against gravity, so ambiguous results have been reported. Here we measure hand tremor at different levels of gravitational field strength using a human centrifuge, thereby increasing the required muscular force to preserve limb position without changing the limb's inertia. By comparing the effect of added mass (inertia + force) versus solely added force upon hand acceleration, we conclude that tremor frequency can be almost completely explained by a resonant mechanical system. ABSTRACT: Human physiological hand tremor has a resonant component. Proof of this is that its frequency can be modified by adding mass. However, adding mass also increases the load which must be supported. The necessary force requires muscular contraction which will change motor output and is likely to increase limb stiffness. The increased stiffness will partly offset the effect of the increased mass and this can lead to the erroneous conclusion that factors other than resonance are involved in determining tremor frequency. Using a human centrifuge to increase head-to-foot gravitational field strength, we were able to control for the increased effort by increasing force without changing mass. This revealed that the peak frequency of human hand tremor is 99% predictable on the basis of a resonant mechanism. We ask what, if anything, the peak frequency of physiological tremor can reveal about the operation of the nervous system. PMID- 26108914 TI - Clinicopathologic features of plasmablastic lymphoma: Single-center series of 8 cases from Saudi Arabia. AB - BACKGROUND: Plasmablastic lymphoma (PBL) is a rare subtype of non-Hodgkin's lymphoma. Characterized by its aggressive nature and plasmacytic differentiation, PBL remains a therapeutic and diagnostic challenge; it generally has a poor prognosis with very few long-term survivors and most patients dying within 2 years from initial presentation. PBL has been reported in several other countries; however, there have been no reported cases from Saudi Arabia. Here, we report 8 cases of PBL depicting the clinical presentation, immunocompetency, immunphenotypic characterization, diagnostic challenges and treatment outcome. METHODS: The medical records were reviewed for clinical presentation, staging, laboratory data, radiological studies, treatments, and outcomes. A broad immunohistochemical panel consisting of CD45, CD3, CD20, CD79a, Pax5, CD38, CD138, MUM1, EMA, Kappa, Lambda, CD 56, CD30, Bcl-2, Bcl-6, Alk-1, Ki-67, EBV-LMP 1, and HHV8 was performed. RESULTS: The tumors predominantly exhibited immunoblastic/plasmablastic or plasmacytic morphologic features and had a plasma cell-like immunophenotype. All cases were immunoreactive for CD38, CD138 and MUM1 confirming plasma cell differentiation of the tumor cells. CD20 was negative for all cases; whereas CD79a and Pax5 were weakly positive in 2cases. All 8 cases were EBV-LMP-1/EBER-1 negative, and 1 case was HHV8 positive. Similar to previously published studies, PBL in Saudi Arabia is characterized by male predominance (6/8), median age 51.5 years (mean age 46 years), associated with early dissemination, poor response to therapy, and limited survival (average survival time, 6.4 months, median overall survival 5.5 months). However, it does have some unique features. It occurs more commonly in immunocompetent persons (6/8, 75%), is not associated with EBV infection (0/8), and nodal involvement (either primary or secondary) is common among patients (6/8). In addition, extra oral sites are more common than oral/nasal cavities (7/8) and the c-myc gene is not common (1/8, 12.5%). CONCLUSION: It appears that PBL is heterogeneous in terms of clinical presentation and morphology. PBL is a therapeutic challenge with a clinical course that is characterized by its high rate of relapse and death. To date, treatment responses are usually partial and temporary. Therapies that are more intensive than CHOP do not seem to prolong survival. Further research is needed to understand the biology and molecular pathogenesis of PBL in order to improve therapies. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1465801416161912. PMID- 26108918 TI - A clinically based protein discovery strategy to identify potential biomarkers of response to anti-TNF-alpha treatment of psoriatic arthritis. AB - PURPOSE: Psoriatic arthritis (PsA) can be treated using biologic therapies targeting biomolecules such as tumor necrosis factor alpha, interleukins (IL)-17 and IL-23. Although 70% PsA patients respond well to therapy, 30% patients show no or limited clinical improvement. Biomarkers that predict response to therapy would help to avoid unnecessary use of expensive biologics in nonresponding patients and enable alternative treatments to be explored. EXPERIMENTAL DESIGN: Patient synovial tissue samples from two clinical studies were analysed using difference in-gel electrophoresis-based proteomics to identify protein expression differences in response to anti-TNF-alpha treatment. Subsequent multiplexed MRM measurements were used to verify potential biomarkers. RESULTS: A total of 119 proteins were differentially expressed (p<0.05) in response to anti-TNF-alpha treatment and 25 proteins were differentially expressed (p<0.05) between "good responders" and "poor responders". From these differentially expressed proteins, MRM assays were developed for four proteins to explore their potential as treatment predictive biomarkers. CONCLUSION AND CLINICAL RELEVANCE: Gel-based proteomics strategy has demonstrated differential protein expression in synovial tissue of PsA patients, in response to anti-TNF-alpha treatment. Development of multiplex MRM assays to these differentially expressed proteins has the potential to predict response to therapy and allow alternative, more effective treatments to be explored sooner. PMID- 26108919 TI - SnO2 quantum dots decorated on RGO: a superior sensitive, selective and reproducible performance for a H2 and LPG sensor. AB - We report the H2 and LPG gas sensing behavior of RGO/SnO2 QDs synthesized by a surfactant assisted hydrothermal method. The RGO/SnO2 QD based sensor shows a high response of ~89.3% to H2 and ~92.4% to LPG for 500 ppm test gas concentration at operating temperatures of 200 degrees C and 250 degrees C, respectively. Further, the RGO/SnO2 QD based sensor shows good selectivity for H2 and LPG in the presence of other interfering gases such as ammonia, chloroform, toluene, benzene, acetone, n-butylacetate, acetic acid and formic acid. We observed that the gas response to H2 is 29.8 times higher than that to acetic acid whereas the gas response to LPG is 17.8 times higher than that to formic acid. Long-term analyses have also been performed to demonstrate the reproducible nature of the RGO/SnO2 QD based sensor over passing time which shows excellent reproducibility. PMID- 26108920 TI - Prevalence of respiratory virus in symptomatic children in private physician office settings in five communities of the state of Veracruz, Mexico. AB - BACKGROUND: Acute respiratory tract infections are the leading cause of morbidity and mortality in children worldwide. Many studies have described the frequency of viruses in hospitalized patients, but studies describing the prevalence of viruses in the community setting are limited, particularly in developing countries, where most of the deaths from serious respiratory diseases occur. The aim of this study was to evaluate the diversity of respiratory viruses in the community setting using molecular diagnostic tools, as well as the clinical characteristics of respiratory viral infections in the general pediatric practice in Mexico. METHODS: Children with respiratory tract infections attending private pediatric practices during a 10-month period in five cities of the state of Veracruz were included. Nasal swabs were taken and processed by a multiplex detection kit for 15 respiratory viruses. RESULTS: 525 children were included from July 2011 to May 2012; 44% were female, mean age was 45 months. The 3 most frequent clinical diagnosis were: rhinopharyngitis 68%, pharyngitis 18%, and 3.3% influenza-like illness. 71.5% of the samples were positive for virus. The five most frequent pathogens were respiratory syncycitial virus in 18.3% of the children, rhinovirus in 17.5%, influenza A 9.1%, adenovirus 7.2%, and enterovirus 3.4%, although all 15 viruses were detected; there were viral coinfections in 14.1%, and 28.5% of the samples were negative. CONCLUSIONS: A large proportion of respiratory infections in the community setting in Mexico was associated to viruses. Although testing for common respiratory pathogens in children with acute respiratory tract infections may lead to a better understanding of the role of viral pathogens in, and eventually to improvement in the management of, individual patients, additional prospective studies are required to study the need of routinely using such tests in general pediatric practices in resource limited countries. PMID- 26108922 TI - Considering Critical Factors of Li-rich Cathode and Si Anode Materials for Practical Li-ion Cell Applications. AB - In order to keep pace with increasing energy demands for advanced electronic devices and to achieve commercialization of electric vehicles and energy-storage systems, improvements in high-energy battery technologies are required. Among the various types of batteries, lithium ion batteries (LIBs) are among the most well developed and commercialized of energy-storage systems. LIBs with Si anodes and Li-rich cathodes are one of the most promising alternative electrode materials for next-generation, high-energy batteries. Si and Li-rich materials exhibit high reversible capacities of <2000 mAh g(-1) and >240 mAh g(-1) , respectively. However, both materials have intrinsic drawbacks and practical limitations that prevent them from being utilized directly as active materials in high-energy LIBs. Examples for Li-rich materials include phase distortion during cycling and side reactions caused by the electrolyte at the surface, and for Si, large volume changes during cycling and low conductivity are observed. Recent progress and important approaches adopted for overcoming and alleviating these drawbacks are described in this article. A perspective on these matters is suggested and the requirements for each material are delineated, in addition to introducing a full cell prototype utilizing a Li-rich cathode and Si anode. PMID- 26108921 TI - Discrepancy of target sites between clinician and cytopathological reports in head neck fine needle aspiration: Did I miss the target or did the clinician mistake the organ site? AB - The diagnostic accuracy of fine needle aspiration cytology (FNAC) of head and neck lesions is relatively high, but cytologic interpretation might be confusing if the sample is lacking typical cytologic features according to labeled site by physician. These errors may have an impact on pathology search engines, healthcare costs or even adverse outcomes. The cytology archive database of multiple institutions in southern Iran and Australia covering the period 2001 2011, were searched using keywords: salivary gland, head, neck, FNAC, and cytology. All the extracted reports were reviewed. The reports which showed discordance between the clinician's impression of the organ involved and subsequent fine needle biopsy request, and the eventual cytological diagnosis were selected. The cytological diagnosis was confirmed by histology or cell block, with assistance from imaging, clinical outcome, physical examination, molecular studies, or microbiological culture. The total number of 10,200 head and neck superficial FNAC were included in the study, from which 48 cases showed discordance between the clinicians request and the actual site of pathology. Apart from the histopathology, the imaging, clinical history, physical examination, immunohistochemical study, microbiologic culture and molecular testing helped to finalize the target organ of pathology in 23, 6, 7, 8, 2, and 1 cases respectively. The commonest discrepancies were for FNAC of "salivary gland" [total: 20 with actual final pathology in: bone (7), soft tissue (5), lymph node (3), odontogenic (3) and skin (2)], "lymph node" [total: 12 with final pathology in: soft tissue (3), skin (3), bone (1) and brain (1)], "soft tissue" [total: 11 with final pathology in: bone (5), skin (2), salivary gland (1), and ocular region (1)] and "skin" [total: 5 with final pathology in: lymph node (2), bone (1), soft tissue (1) and salivary gland (1)]. The primary physician requesting FNAC of head and neck lesions are incorrect in their clinical impression of the actual site in nearly 0.5 percent of cases, due to the overlapping clinical and imaging findings or possibly due to inadequate history taking or physical examination. PMID- 26108923 TI - Vision, direction and inspiration. PMID- 26108925 TI - Adult social care in crisis as 'efficiencies' exhausted. PMID- 26108926 TI - Scanner that detects early signs of tissue damage to be trialled. PMID- 26108928 TI - Study finds home care focused on household activities. PMID- 26108929 TI - Isolation project secures funds to build more sheds for men. PMID- 26108930 TI - Initiative boosts cleanliness and safety for residents. PMID- 26108931 TI - Worldwide research finds dementia affects women more than men. PMID- 26108935 TI - Reading between the lines. PMID- 26108936 TI - Holistic solutions. PMID- 26108942 TI - Practice question. Medication management. PMID- 26108943 TI - Introduction to the transforming dementia care in hospitals series. AB - A short series of articles in Nursing Older People, starting in September, presents case study examples of the positive work achieved by trusts that participated in the RCN's development programme to improve dementia care in acute hospitals. This introductory article reports on the independent evaluation of the programme. The programme included a launch event, development days, site visits, ongoing support by the RCN lead and carer representatives and a conference to showcase service improvements. The evaluation drew on data from a survey, the site visits, trust action plans and a range of self-assessment tools for dementia care. The findings highlight substantial progress towards programme objectives and learning outcomes and suggest that the programme provided the focus, impetus and structure for trusts to make sustainable changes. It also equipped participants with the strategies and confidence to change practice. Recommendations are made for taking the programme forward. PMID- 26108944 TI - Incontinence and sexuality in later life. AB - This article explores the interrelated aspects of incontinence and sexuality in older age. It describes the physiological changes that may have an effect on sexual function and the genitourinary system as people age. The enduring importance of sexual intimacy is discussed. Treatments for incontinence and to improve sexual function are explored. The authors conclude that nurses, particularly those involved in continence management, have a role in ensuring sensitive assessment and access to treatment, which can support many older people to maintain fulfilling sexual activity. PMID- 26108945 TI - Reflection, return to practice and revalidation. AB - This article explores the use of reflection and critical thinking during a return to-practice programme, demonstrating both concepts and their value in developing insight. The aim of the article is to provide insight into a learner's reflection about nursing older people and encourage nurses to reflect and think critically about their own practice, which is a requirement of forthcoming revalidation. Lessons learned as a result of reflection must be demonstrated in order for registered nurses to revalidate. Reflection and insight gained from critical thinking can have a positive effect on individual nurses and the quality of patient care they provide. PMID- 26108946 TI - The power of art. PMID- 26108947 TI - Evaluation of potential flavonoid inhibitors of glyoxalase-I based on virtual screening and in vitro studies. AB - Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in the conversion of methylglyoxal (MG) to d-lactate in the glycolytic pathway. MG toxicity arises from its ability to form advanced glycation end products. GLO-I has been reported to be frequently overexpressed in various types of cancer cells. In this study, we performed structure-based virtual screening of focused flavonoids commercial library to identify potential and specific inhibitors of GLO-I. The compounds were ranked based on Glide extra precision docking score and five hits (curcumin, quercetin, morin, naringin and silibinin) were selected on the basis of their interaction with active site amino acid residues of GLO-I. Mixed mode QM/MM calculation was performed on the top-scoring hit to ascertain the role of zinc ion in ligand binding. In addition, the identified hits were subjected to MM/GBSA binding energy prediction, ADME prediction and similarity studies. The hits were tested in vitro for cell viability, and GLO-I inhibition. Naringin (ST072162) was found to be most potent inhibitor of GLO-I among the identified hits with highest glide XP dock score of 14.906. These findings suggest that naringin could be a new scaffold for designing inhibitors against GLO-I with potential application as anticancer agents. PMID- 26108948 TI - Assessing the impact of the U.S. Endangered Species Act recovery planning guidelines on managing threats for listed species. AB - The Endangered Species Act (ESA) of the United States was enacted in 1973 to prevent the extinction of species. Recovery plans, required by 1988 amendments to the ESA, play an important role in organizing these efforts to protect and recover species. To improve the use of science in the recovery planning process, the Society for Conservation Biology (SCB) commissioned an independent review of endangered species recovery planning in 1999. From these findings, the SCB made key recommendations for how management agencies could improve the recovery planning process, after which the U.S. Fish and Wildlife Service and the National Marine Fisheries Service redrafted their recovery planning guidelines. One important recommendation called for recovery plans to make threats a primary focus, including organizing and prioritizing recovery tasks for threat abatement. We sought to determine the extent to which results from the SCB study were incorporated into these new guidelines and whether the SCB recommendations regarding threats manifested in recovery plans written under the new guidelines. Recovery planning guidelines generally incorporated the SCB recommendations, including those for managing threats. However, although recent recovery plans have improved in their treatment of threats, many fail to adequately incorporate threat monitoring. This failure suggests that developing clear guidelines for monitoring should be an important priority in improving ESA recovery planning. PMID- 26108949 TI - Erratum: neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis. PMID- 26108950 TI - Hour-long adaptation in the awake early visual system. AB - Sensory adaptation serves to adjust awake brains to changing environments on different time scales. However, adaptation has been studied traditionally under anesthesia and for short time periods. Here, we demonstrate in awake rabbits a novel type of sensory adaptation that persists for >1 h and acts on visual thalamocortical neurons and their synapses in the input layers of the visual cortex. Following prolonged visual stimulation (10-30 min), cells in the dorsal lateral geniculate nucleus (LGN) show a severe and prolonged reduction in spontaneous firing rate. This effect is bidirectional, and prolonged visually induced response suppression is followed by a prolonged increase in spontaneous activity. The reduction in thalamic spontaneous activity following prolonged visual activation is accompanied by increases in 1) response reliability, 2) signal detectability, and 3) the ratio of visual signal/spontaneous activity. In addition, following such prolonged activation of an LGN neuron, the monosynaptic currents generated by thalamic impulses in layer 4 of the primary visual cortex are enhanced. These results demonstrate that in awake brains, prolonged sensory stimulation can have a profound, long-lasting effect on the information conveyed by thalamocortical inputs to the visual cortex. PMID- 26108951 TI - Failure to use corollary discharge to remap visual target locations is associated with psychotic symptom severity in schizophrenia. AB - Corollary discharge (CD) refers to "copies" of motor signals sent to sensory areas, allowing prediction of future sensory states. They enable the putative mechanisms supporting the distinction between self-generated and externally generated sensations. Accordingly, many authors have suggested that disturbed CD engenders psychotic symptoms of schizophrenia, which are characterized by agency distortions. CD also supports perceived visual stability across saccadic eye movements and is used to predict the postsaccadic retinal coordinates of visual stimuli, a process called remapping. We tested whether schizophrenia patients (SZP) show remapping disturbances as evidenced by systematic transsaccadic mislocalizations of visual targets. SZP and healthy controls (HC) performed a task in which a saccadic target disappeared upon saccade initiation and, after a brief delay, reappeared at a horizontally displaced position. HC judged the direction of this displacement accurately, despite spatial errors in saccade landing site, indicating that their comparison of the actual to predicted postsaccadic target location relied on accurate CD. SZP performed worse and relied more on saccade landing site as a proxy for the presaccadic target, consistent with disturbed CD. This remapping failure was strongest in patients with more severe psychotic symptoms, consistent with the theoretical link between disturbed CD and phenomenological experiences in schizophrenia. PMID- 26108952 TI - Long-lasting facilitation of respiratory rhythm by treatment with TRPA1 agonist, cinnamaldehyde. AB - The transient receptor potential (TRP) channels are widely distributed in the central nervous system (CNS) and peripheral nervous system. We examined the effects of TRP ankyrin 1 (TRPA1) agonists (cinnamaldehyde and allyl isothiocyanate) on respiratory rhythm generation in brainstem-spinal cord preparations from newborn rats [postnatal days 0-3 (P0-P3)] and in in situ perfused preparations from juvenile rats (P11-P13). Preparations were superfused with modified Krebs solution at 25-26 degrees C, and activity of inspiratory C4 ventral root (or phrenic nerve) was monitored. In the newborn rat, an in vitro preparation of cinnamaldehyde (0.5 mM) induced typically biphasic responses in C4 rate: an initial short increase and subsequent decrease, then a gradual recovery of rhythm during 15 min of bath application. After washout, the respiratory rhythm rate further increased, remaining 200% of control for >120 min, indicating long-lasting facilitation. Allyl isothiocyanate induced effects similar to those of cinnamaldehyde. The long-lasting facilitation of respiratory rhythm was partially antagonized by the TRPA1 antagonist HC-030031 (10 MUM). We obtained similar long-lasting facilitation in an in situ-perfused reparation from P11-P13 rats. On the basis of results from transection experiments of the rostral medulla and whole-cell recordings from preinspiratory neurons in the parafacial respiratory group (pFRG), we suggest that the rostral medulla, including the pFRG, is important to the induction of long-lasting facilitation. A histochemical analysis demonstrated a wide distribution of TRPA1 channel-positive cells in the reticular formation of the medulla, including the pFRG. Our findings suggest that TRPA1 channel activation could induce long-lasting facilitation of respiratory rhythm and provide grounds for future study on the roles of TRPA1 channels in the CNS. PMID- 26108953 TI - Mechanics of mouse ocular motor plant quantified by optogenetic techniques. AB - Rigorous descriptions of ocular motor mechanics are often needed for models of ocular motor circuits. The mouse has become an important tool for ocular motor studies, yet most mechanical data come from larger species. Recordings of mouse abducens neurons indicate the mouse mechanics share basic viscoelastic properties with larger species but have considerably longer time constants. Time constants can also be extracted from the rate at which the eye re-centers when released from an eccentric position. The displacement can be accomplished by electrically stimulating ocular motor nuclei, but electrical stimulation may also activate nearby ocular motor circuitry. We achieved specific activation of abducens motoneurons through photostimulation in transgenic mice expressing channelrhodopsin in cholinergic neurons. Histology confirmed strong channelrhodopsin expression in the abducens nucleus with relatively little expression in nearby ocular motor structures. Stimulation was delivered as 20- to 1,000-ms pulses and 40-Hz trains. Relaxations were modeled best by a two-element viscoelastic system. Time constants were sensitive to stimulus duration. Analysis of isometric relaxation of isolated mouse extraocular muscles suggest the dependence is attributable to noninstantaneous decay of active forces in non twitch fibers following stimulus offset. Time constants were several times longer than those obtained in primates, confirming that the mouse ocular motor mechanics are relatively sluggish. Finally, we explored the effects of 0.1- to 20-Hz sinusoidal photostimuli and demonstrated their potential usefulness in characterizing ocular motor mechanics, although this application will require further data on the temporal relationship between photostimulation and neuronal firing in extraocular motoneurons. PMID- 26108954 TI - Stimulus-dependent spiking relationships with the EEG. AB - The development and refinement of noninvasive techniques for imaging neural activity is of paramount importance for human neuroscience. Currently, the most accessible and popular technique is electroencephalography (EEG). However, nearly all of what we know about the neural events that underlie EEG signals is based on inference, because of the dearth of studies that have simultaneously paired EEG recordings with direct recordings of single neurons. From the perspective of electrophysiologists there is growing interest in understanding how spiking activity coordinates with large-scale cortical networks. Evidence from recordings at both scales highlights that sensory neurons operate in very distinct states during spontaneous and visually evoked activity, which appear to form extremes in a continuum of coordination in neural networks. We hypothesized that individual neurons have idiosyncratic relationships to large-scale network activity indexed by EEG signals, owing to the neurons' distinct computational roles within the local circuitry. We tested this by recording neuronal populations in visual area V4 of rhesus macaques while we simultaneously recorded EEG. We found substantial heterogeneity in the timing and strength of spike-EEG relationships and that these relationships became more diverse during visual stimulation compared with the spontaneous state. The visual stimulus apparently shifts V4 neurons from a state in which they are relatively uniformly embedded in large-scale network activity to a state in which their distinct roles within the local population are more prominent, suggesting that the specific way in which individual neurons relate to EEG signals may hold clues regarding their computational roles. PMID- 26108955 TI - Transspinal constant-current long-lasting stimulation: a new method to induce cortical and corticospinal plasticity. AB - Functional neuroplasticity in response to stimulation and motor training is a well-established phenomenon. Transcutaneous stimulation of the spine is used mostly to alleviate pain, but it may also induce functional neuroplasticity, because the spinal cord serves as an integration center for descending and ascending neuronal signals. In this work, we examined whether long-lasting noninvasive cathodal (c-tsCCS) and anodal (a-tsCCS) transspinal constant-current stimulation over the thoracolumbar enlargement can induce cortical, corticospinal, and spinal neuroplasticity. Twelve healthy human subjects, blind to the stimulation protocol, were randomly assigned to 40 min of c-tsCCS or a tsCCS. Before and after transspinal stimulation, we established the afferent mediated motor evoked potential (MEP) facilitation and the subthreshold transcranial magnetic stimulation (TMS)-mediated flexor reflex facilitation. Recruitment input-output curves of MEPs and transspinal evoked potentials (TEPs) and postactivation depression of the soleus H reflex and TEPs was also established. We demonstrate that both c-tsCCS and a-tsCCS decrease the afferent mediated MEP facilitation and alter the subthreshold TMS-mediated flexor reflex facilitation in a polarity-dependent manner. Both c-tsCCS and a-tsCCS increased the tibialis anterior MEPs recorded at 1.2 MEP resting threshold, intermediate, and maximal intensities and altered the recruitment input-output curve of TEPs in a muscle- and polarity-dependent manner. Soleus H-reflex postactivation depression was reduced after a-tsCCS and remained unaltered after c-tsCCS. No changes were found in the postactivation depression of TEPs after c-tsCCS or a tsCCS. Our findings reveal that c-tsCCS and a-tsCCS have distinct effects on cortical and corticospinal excitability. This method can be utilized to induce targeted neuroplasticity in humans. PMID- 26108956 TI - Degradation of extracellular chondroitin sulfate delays recovery of network activity after perturbation. AB - Chondroitin sulfate proteoglycans (CSPGs) are widely studied in vertebrate systems and are known to play a key role in development, plasticity, and regulation of cortical circuitry. The mechanistic details of this role are still elusive, but increasingly central to the investigation is the homeostatic balance between network excitation and inhibition. Studying a simpler neuronal circuit may prove advantageous for discovering the mechanistic details of the cellular effects of CSPGs. In this study we used a well-established model of homeostatic change after injury in the crab Cancer borealis to show first evidence that CSPGs are necessary for network activity homeostasis. We degraded CSPGs in the pyloric circuit of the stomatogastric ganglion with the enzyme chondroitinase ABC (chABC) and found that removal of CSPGs does not influence the ongoing rhythm of the pyloric circuit but does limit its capacity for recovery after a networkwide perturbation. Without CSPGs, the postperturbation rhythm is slower than in controls and rhythm recovery is delayed. In addition to providing a new model system for the study of CSPGs, this study suggests a wider role for CSPGs, and perhaps the extracellular matrix in general, beyond simply plastic reorganization (as observed in mammals) and into a foundational regulatory role of neural circuitry. PMID- 26108957 TI - Offline reactivation of experience-dependent neuronal firing patterns in the rat ventral tegmental area. AB - In a rest period immediately after a task, neurons in the hippocampus, neocortex, and striatum exhibit spatiotemporal correlation patterns resembling those observed during the task. This reactivation has been proposed as a neurophysiological substrate for memory consolidation. We provide new evidence that rodent ventral tegmental area (VTA) neurons are selective for different types of food stimuli and that stimulus-sensitive neurons strongly reactivate during the rest period following a task that involved those stimuli. Reactivation occurred primarily during slow wave sleep and during quiet awakeness. In these experiments, VTA reactivation patterns were uncompressed and occurred at the firing rate level, rather than on a spike-to-spike basis. Mildly aversive stimuli were reactivated more often than positive ones. The VTA is a pivotal structure involved in the perception and prediction of reward and stimulus salience and is a key neuromodulatory system involved in synaptic plasticity. These results suggest new ways in which dopaminergic signals could contribute to the biophysical mechanisms of selective, system-wide, memory consolidation, and reconsolidation during sleep. PMID- 26108958 TI - A model for attentional information routing through coherence predicts biased competition and multistable perception. AB - Selective attention allows to focus on relevant information and to ignore distracting features of a visual scene. These principles of information processing are reflected in response properties of neurons in visual area V4: if a neuron is presented with two stimuli in its receptive field, and one is attended, it responds as if the nonattended stimulus was absent (biased competition). In addition, when the luminance of the two stimuli is temporally and independently varied, local field potentials are correlated with the modulation of the attended stimulus and not, or much less, correlated with the nonattended stimulus (information routing). To explain these results in one coherent framework, we present a two-layer spiking cortical network model with distance-dependent lateral connectivity and converging feed-forward connections. With oscillations arising inherently from the network structure, our model reproduces both experimental observations. Hereby, lateral interactions and shifts of relative phases between sending and receiving layers (communication through coherence) are identified as the main mechanisms underlying both biased competition as well as selective routing. Exploring the parameter space, we show that the effects are robust and prevalent over a broad range of parameters. In addition, we identify the strength of lateral inhibition in the first model layer as crucial for determining the working regime of the system: increasing lateral inhibition allows a transition from a network configuration with mixed representations to one with bistable representations of the competing stimuli. The latter is discussed as a possible neural correlate of multistable perception phenomena such as binocular rivalry. PMID- 26108961 TI - Handgrip strength and dysphagia assessment following cardiac surgery. AB - OBJECTIVES/HYPOTHESIS: Prolonged intubation has been recognized as a risk factor for dysphagia following cardiac surgery. We conducted a study to determine whether those patients intubated longer than 12 hours following cardiac surgery exhibit low handgrip strength and if dysphagia is prevalent in those with low handgrip strength. STUDY DESIGN: Feasibility study. METHODS: Patients intubated more than 12 hours after cardiac surgery were enrolled. Handgrip strength was measured. If subjects were found to have low grip strength they underwent clinical swallowing exam by a speech-language pathologist followed by modified barium swallow (MBS) to assess for dysphagia. Severity of dysphagia was assessed with the Penetration-Aspiration Scale (PAS) and need for diet modification. RESULTS: Eighty-six percent (12/14) of patients tested had low handgrip strength. Eight patients with low grip strength completed the bedside swallowing exam and MBS. Four of the eight patients (50%) had deep laryngeal penetration (PAS scores 4-5) on MBS and three (38%) patients were found to have silent aspiration (PAS 8). The findings on MBS resulted in the recommendation of a swallowing strategy and/or modified diet for six of the eight (80%) patients. Nonoral feedings were recommended for two patients (25%) based on MBS results. CONCLUSIONS: A majority of patients intubated >12 hours after cardiac surgery exhibit low handgrip strength. Dysphagia is prevalent among those with low handgrip strength. The role of frailty measures in screening for dysphagia deserves further investigation. LEVEL OF EVIDENCE: 4. PMID- 26108960 TI - Compensatory stepping in Parkinson's disease is still a problem after deep brain stimulation randomized to STN or GPi. AB - The effects of deep brain stimulation (DBS) on balance in people with Parkinson's disease (PD) are not well established. This study examined whether DBS randomized to the subthalamic nucleus (STN; n = 11) or globus pallidus interna (GPi; n = 10) improved compensatory stepping to recover balance after a perturbation. The standing surface translated backward, forcing subjects to take compensatory steps forward. Kinematic and kinetic responses were recorded. PD-DBS subjects were tested off and on their levodopa medication before bilateral DBS surgery and retested 6 mo later off and on DBS, combined with off and on levodopa medication. Responses were compared with PD-control subjects (n = 8) tested over the same timescale and 17 healthy control subjects. Neither DBS nor levodopa improved the stepping response. Compensatory stepping in the best-treated state after surgery (DBS+DOPA) was similar to the best-treated state before surgery (DOPA) for the PD GPi group and the PD-control group. For the PD-STN group, there were more lateral weight shifts, a delayed foot-off, and a greater number of steps required to recover balance in DBS+DOPA after surgery compared with DOPA before surgery. Within the STN group five subjects who did not fall during the experiment before surgery fell at least once after surgery, whereas the number of falls in the GPi and PD-control groups were unchanged. DBS did not improve the compensatory step response needed to recover from balance perturbations in the GPi group and caused delays in the preparation phase of the step in the STN group. PMID- 26108959 TI - An arterially perfused nose-olfactory bulb preparation of the rat. AB - A main feature of the mammalian olfactory bulb network is the presence of various rhythmic activities, in particular, gamma, beta, and theta oscillations, with the latter coupled to the respiratory rhythm. Interactions between those oscillations as well as the spatial distribution of network activation are likely to determine olfactory coding. Here, we describe a novel semi-intact perfused nose-olfactory bulb-brain stem preparation in rats with both a preserved olfactory epithelium and brain stem, which could be particularly suitable for the study of oscillatory activity and spatial odor mapping within the olfactory bulb, in particular, in hitherto inaccessible locations. In the perfused olfactory bulb, we observed robust spontaneous oscillations, mostly in the theta range. Odor application resulted in an increase in oscillatory power in higher frequency ranges, stimulus locked local field potentials, and excitation or inhibition of individual bulbar neurons, similar to odor responses reported from in vivo recordings. Thus our method constitutes the first viable in situ preparation of a mammalian system that uses airborne odor stimuli and preserves these characteristic features of odor processing. This preparation will allow the use of highly invasive experimental procedures and the application of techniques such as patch-clamp recording, high-resolution imaging, and optogenetics within the entire olfactory bulb. PMID- 26108963 TI - What is the most effective treatment for severe gastro-oesophageal reflux disease? PMID- 26108964 TI - In vitro incorporation of a cell-binding protein to a lentiviral vector using an engineered split intein enables targeted delivery of genetic cargo. AB - Gene therapy represents a promising therapeutic paradigm for addressing many disorders, but the absence of a vector that can be robustly and reproducibly functionalized with cell-homing functionality to mediate the delivery of genetic cargo specifically to target cells following systemic administration has stood as a major impediment. In this study, a high-affinity protein-protein pair comprising a splicing-deficient naturally split intein was used as molecular Velcro to append a HER2/neu-binding protein (DARPin) onto the surface of a binding-deficient, fusion-competent lentivirus. HER2/neu-specific lentiviruses created using this in vitro pseudotyping approach were able to deliver their genetic reporter cargo specifically to cells that express the target receptor at high levels in a co-culture. We envision that the described technology could provide a powerful, broadly applicable platform for the incorporation of cell targeting functionality onto viral vectors. PMID- 26108965 TI - Surgical resection of massive liposarcomas at the extremities: a 10-year experience in a referral musculoskeletal sarcoma unit. AB - BACKGROUND: There is still no consensus regarding the management of patients with massive liposarcomas located in the extremities. Several discrepancies related to the aggressiveness of the surgery and the application of concomitant radiotherapy and chemotherapy treatments remain controversial. The purpose of this study was to analyse the clinicopathological characteristics, prognostic factors and outcomes of a series of patients with massive liposarcomas of the extremities who were treated at a referral hospital specializing in musculoskeletal oncology. METHODS: This was an observational, descriptive and retrospective case series covering 10 years of clinical practice. The records of 26 adults, 14 men and 12 women, with localized massive liposarcomas in the extremities were studied. The average age was 53 years. The patients were treated from January 2003 until January 2012. Wide surgical resections with limb-sparing surgeries were performed for most patients (96.2 %). RESULTS: The average tumour size was 15.1 +/- 6.8 cm in the greatest dimension. Regarding the histological subtypes, there were 11 well-differentiated or atypical lipomatous tumours (42.3 %), 10 myxoid (38.5 %) and 5 (19.2 %) round cell and pleomorphic liposarcomas. Regarding the malignancy grades, 19 cases (73 %) were classified as low grade. Among these low-grade tumours predominated the well-differentiated subtype (57.9 %). Within high-grade tumours, the round cell and pleomorphic subtype was most frequent (57.1 %; p = 0.011). Radiotherapy was additionally applied to 12 patients (46.2 %) and adjuvant chemotherapy to 5 (19.3 %). Tumour recurrence was observed in only 2 cases (7.7 %). Only 1 of these cases developed lung metastatic dissemination. CONCLUSIONS: Across the entire series, these massive tumours did not compromise the survival of the patients. The histologic subtype and the malignancy degree were closely related. Proper and early diagnosis and therapeutic management of these patients via the application of wide-margin surgical excision are essential to ensure long-term survival. PMID- 26108966 TI - Melanopsins: Localization and Phototransduction in Xenopus laevis Melanophores. AB - Xenopus laevis melanophores express two melanopsins, Opn4x and Opn4m. We identified Opn4x immunoreactivity throughout the melanophore cytoplasm and in the cell membrane. The strongest immunopositivity for Opn4m was observed in the nuclear region, and no labeling was seen in the cell membrane. This immunodistribution suggests Opn4x as the functional photopigment. In X. laevis melanophores, light triggers pigment dispersion and clock gene induction at blue wavelength, which maximally activates melanopsins. Although light stimulation activates phospholipase C and increases intracellular calcium and cGMP, this nucleotide does not participate in photo-induced melanin dispersion. Nevertheless, the guanylyl cyclase activator YC-1 stimulates Per1 expression, similar to blue light pulse, and the use of pharmacological inhibitors indicates the participation of the phosphoinositide cascade. Since cAMP levels does not change after blue light stimulation, the cAMP/PKA pathway most probably is not involved in blue light induction of Per in X. laevis melanophores. Given the localization of melanopsins and our pharmacological data, the light-induced clock gene expression seems to be mediated by Opn4x through phosphoinositide cascade and rise in cGMP, thus leading to the reset of the biological clock in our model. PMID- 26108967 TI - Lead iodide perovskite light-emitting field-effect transistor. AB - Despite the widespread use of solution-processable hybrid organic-inorganic perovskites in photovoltaic and light-emitting applications, determination of their intrinsic charge transport parameters has been elusive due to the variability of film preparation and history-dependent device performance. Here we show that screening effects associated to ionic transport can be effectively eliminated by lowering the operating temperature of methylammonium lead iodide perovskite (CH3NH3PbI3) field-effect transistors. Field-effect carrier mobility is found to increase by almost two orders of magnitude below 200 K, consistent with phonon scattering-limited transport. Under balanced ambipolar carrier injection, gate-dependent electroluminescence is also observed from the transistor channel, with spectra revealing the tetragonal to orthorhombic phase transition. This demonstration of CH3NH3PbI3 light-emitting field-effect transistors provides intrinsic transport parameters to guide materials and solar cell optimization, and will drive the development of new electro-optic device concepts, such as gated light-emitting diodes and lasers operating at room temperature. PMID- 26108968 TI - Gene expression analysis of skin grafts and cultured keratinocytes using synthetic RNA normalization reveals insights into differentiation and growth control. AB - BACKGROUND: Keratinocytes (KCs) are the most frequent cells in the epidermis, and they are often isolated and cultured in vitro to study the molecular biology of the skin. Cultured primary cells and various immortalized cells have been frequently used as skin models but their comparability to intact skin has been questioned. Moreover, when analyzing KC transcriptomes, fluctuation of polyA+ RNA content during the KCs' lifecycle has been omitted. RESULTS: We performed STRT RNA sequencing on 10 ng samples of total RNA from three different sample types: i) epidermal tissue (split-thickness skin grafts), ii) cultured primary KCs, and iii) HaCaT cell line. We observed significant variation in cellular polyA+ RNA content between tissue and cell culture samples of KCs. The use of synthetic RNAs and SAMstrt in normalization enabled comparison of gene expression levels in the highly heterogenous samples and facilitated discovery of differences between the tissue samples and cultured cells. The transcriptome analysis sensitively revealed genes involved in KC differentiation in skin grafts and cell cycle regulation related genes in cultured KCs and emphasized the fluctuation of transcription factors and non-coding RNAs associated to sample types. CONCLUSIONS: The epidermal keratinocytes derived from tissue and cell culture samples showed highly different polyA+ RNA contents. The use of SAMstrt and synthetic RNA based normalization allowed the comparison between tissue and cell culture samples and thus proved to be valuable tools for RNA-seq analysis with translational approach. Transciptomics revealed clear difference both between tissue and cell culture samples and between primary KCs and immortalized HaCaT cells. PMID- 26108969 TI - Population-based trends in prenatal screening and diagnosis for aneuploidy: a retrospective analysis of 38 years of state-wide data. AB - OBJECTIVE: To analyse population-based trends over the entire history of prenatal testing for aneuploidy. DESIGN: Retrospective analysis of state-wide data sets. SETTING: Australian state of Victoria with ~70 000 annual births. POPULATION: All pregnant women undergoing invasive prenatal testing at <25 weeks' gestation from 1976 to 2013. METHODS: Analysis of three state-wide data sets: (1) Prenatal diagnosis data set of 119 404 amniocenteses and chorionic villus samplings from 1976 to 2013; (2) central serum screening laboratory data set from 1996 to 2013; (3) government birth statistics from 1976 to 2013. MAIN OUTCOME MEASURES: Annual numbers and uptake rates of invasive prenatal tests and serum screening, indications for invasive prenatal testing, prenatal diagnoses of aneuploidy, diagnostic yield of invasive tests. RESULTS: Annual numbers of invasive prenatal tests climbed steadily from 1976, then declined from 2000. In 2013, the number of invasive prenatal tests was the lowest in 25 years, while the number of trisomy 21 diagnoses was the highest ever recorded. Annual uptake of serum screening climbed from 1.6 to 83% over 1996-2013. Results from 2013 showed a high diagnostic yield (15.8%) for a low rate of invasive testing (3.4% of births). Over four decades, the number of invasive procedures performed for each diagnosis of major chromosome abnormality declined from 100 to six. CONCLUSIONS: This study demonstrates historic reductions in the proportion of women undergoing invasive testing and dramatic improvements in diagnostic yield. Monitoring the impact of new prenatal technologies on this progress remains an important research priority. TWEETABLE ABSTRACT: Invasive prenatal testing has reached historic lows due to dramatic improvements in Down syndrome screening. PMID- 26108970 TI - Imaging evaluation of treated benign bone tumours. AB - A number of benign bone tumours can be treated with curettage and packing with either bone cement or graft. It is essential that the radiologist be familiar with both the normal and abnormal post-operative imaging appearance of these treated tumours. Through the use of numerous imaging examples, we aim to provide a pictorial review of the expected post-operative appearance of benign bone tumours treated with curettage and packing, as well as the imaging features of recurrence, the most common potential complication. PMID- 26108971 TI - Whole-exome sequencing reveals genetic variants associated with chronic kidney disease characterized by tubulointerstitial damages in North Central Region, Sri Lanka. AB - OBJECTIVES: The familial clustering observed in chronic kidney disease of uncertain etiology (CKDu) characterized by tubulointerstitial damages in the North Central Region of Sri Lanka strongly suggests the involvement of genetic factors in its pathogenesis. The objective of the present study is to use whole exome sequencing to identify the genetic variants associated with CKDu. METHODS: Whole-exome sequencing of eight CKDu cases and eight controls was performed, followed by direct sequencing of candidate loci in 301 CKDu cases and 276 controls. RESULTS: Association study revealed rs34970857 (c.658G > A/p.V220M) located in the KCNA10 gene encoding a voltage-gated K channel as the most promising SNP with the highest odds ratio of 1.74. Four rare variants were identified in gene encoding Laminin beta2 (LAMB2) which is known to cause congenital nephrotic syndrome. Three out of four variants in LAMB2 were novel variants found exclusively in cases. CONCLUSION: Genetic investigations provide strong evidence on the presence of genetic susceptibility for CKDu. Possibility of presence of several rare variants associated with CKDu in this population is also suggested. PMID- 26108972 TI - Lysosomal Sequestration Determines Intracellular Imatinib Levels. AB - The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here, we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by liquid chromatography-tandem mass spectrometry. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses, and apoptosis assays were performed to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562 and SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time-, dose-, temperature-, and energy dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Prazosin, amantadine, NH4Cl, and the vacuolar ATPase inhibitor bafilomycin A1 significantly decreased the IUR of imatinib and likely interfere with lysosomal retention and accumulation of imatinib. Costaining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. Inhibition of the lysosomal sequestration had no effect on the inhibition of c-Kit signaling and imatinib-mediated cell cycle arrest but significantly increased apoptosis in imatinib-sensitive GIST-T1 cells. We conclude that intracellular imatinib levels are primarily determined by lysosomal sequestration and do not depend on SLC22A1 expression. PMID- 26108974 TI - Biologic variability in NT-proBNP and cardiac troponin-I in healthy dogs and dogs with mitral valve degeneration. AB - BACKGROUND: The N-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and cardiac troponin-I are candidate biomarkers for cardiac disease in dogs. The degree of biologic variation in these biomarkers has not previously been reported in healthy dogs or dogs with mitral regurgitation. OBJECTIVES: The purpose of the study was to derive estimates of intrinsic biologic variability and reference change values for NT-proBNP and cardiac troponin-I in healthy dogs and dogs with mitral regurgitation grade IB and II according to the International Small Animal Cardiac Health Council (ISACHC) grading system. METHODS: Plasma and sera were collected weekly for up to 7 weeks from 12 control dogs and 9 dogs with mitral regurgitation. NT-proBNP and troponin-I (C-TnI) concentrations were determined. Indices of biologic variation such as reciprocal index of individuality (r-IoI) and reference change values (RCV) were calculated in both the groups. RESULTS: Individuality was high in control dogs and dogs with grade IB and II mitral valve regurgitation for both C-TnI (r-IoI 1.6 and 2) and NT proBNP (1.5 and 2.7), while the 2-sided RCV for NT-proBNP was significantly lower in dogs with mitral regurgitation (52.5% vs 99.4%, P<0.01.). CONCLUSIONS: High individuality of these cardiac biomarkers suggests that, following diagnosis, these assays are best interpreted by serial determination in individual canine patients rather than by comparison to a population-based reference interval. The smaller RCV values for dogs with mitral regurgitation suggest that smaller relative changes in NT-proBNP are clinically meaningful in these patients. PMID- 26108975 TI - Structures, stability and hydrogen bonding in inositol conformers. AB - Various ab initio calculations using the density-functional (DFT), the second order Moller-Plesset perturbation (MP2) and self-consistent reaction field (SCRF) theories were performed on thirteen theoretically possible inositol stereoisomers. Gas phase calculations reveal that the myo- and neo-isomers of inositol (bearing one and two axial hydroxyl groups, respectively) are marginally more stable (by 0.5 kcal mol(-1)) than the all equatorially substituted scyllo inositol. The calculations when done in different polar solvents show that the scyllo-inositol becomes the most stable inositol isomer, a fact attributed to weaker intramolecular hydrogen bonds. The individual hydrogen bond energy in all the isomers of inositol was also estimated using the molecular tailoring approach (MTA). The calculated hydrogen bond energies in these isomers are in excellent agreement with reported O-H...O hydrogen bond distances and nu(O-H) stretching frequencies. The estimated H-bond energy values suggest that the order of the intramolecular hydrogen bond strength follows: axial-axial > equatorial-axial > axial-equatorial > equatorial-equatorial hydrogen bonds. The intramolecular hydrogen bonds in the scyllo isomer are much weaker than those in other conformers, thus making this isomer more stable in polar solvents. PMID- 26108973 TI - Ursodeoxycholyl Lysophosphatidylethanolamide modifies aberrant lipid profiles in NAFLD. AB - BACKGROUND: Hepatic fat accumulation with disturbed lipid homoeostasis is a hallmark of nonalcoholic fatty liver disease (NAFLD). The bile acid phospholipid conjugate Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a novel anti inflammatory agent with hepatoprotective effects in murine high-fat-diet (HFD) induced NAFLD. The aim of this work was to study changes in the hepatic lipidome due to UDCA-LPE. MATERIALS AND METHODS: High fat diet mouse model, mass spectometry, RT-PCR. RESULTS: Hepatic lipid extracts of HFD mice were analysed by mass spectrometry. The results determined higher levels of total, saturated, mono and diunsaturated fatty acids (FA) in HFD mice, which were decreased by UDCA-LPE predominantly by the reducing the most abundant FA species palmitic acid and oleic acid. Unlike other FA species, levels of long-chain polyunsaturated fatty acids (LCPUFA), which are composed of arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were increased in HFD mice upon UDCA LPE treatment, mainly due to elevated hepatic ARA pools. Analysis of hepatic phospholipids species showed a decrease in total phosphatidylcholine (PC), especially monounsaturated PC (PUFA-PC) levels in HFD mice. Loss of total PC was reversed due to UDCA-LPE by increasing hepatic PUFA-PC pools. Gene expression analysis showed that UDCA-LPE upregulated PPARalpha, a key transcriptional regulator of fatty acid oxidation, as well as downstream target genes CPT1alpha and AOX, which are crucially involved in mitochondrial and peroxisomal fatty acid oxidation. CONCLUSION: UDCA-LPE modulates defective fatty acid metabolism during experimental NAFLD thereby restoring altered lipid profiles in addition to its pronounced anti-inflammatory effects. Thus, UDCA-LPE may be a promising drug candidate for the management of NAFLD. PMID- 26108976 TI - Tuberous sclerosis, polycystic kidney disease and mucolipidosis III gamma caused by a microdeletion unmasking a recessive mutation. PMID- 26108977 TI - Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-transgenic (3xTg)-AD mouse model of AD, compared with those in nontransgenic (non-Tg) controls, at 6, 8, and 14 mo of age. We found a more pronounced cortical Abeta accumulation (2- and 3.5-fold increase in Abeta42 in the soluble and insoluble protein fractions, respectively) in female 3xTg-AD mice than in the males. Furthermore, female 3xTg-AD mice displayed a significant deterioration in glucose tolerance (AUC, +118% vs. non-Tg mice at 14 mo). Fasting plasma insulin levels rose 2.5-fold from 6 to 14 mo of age in female 3xTg-AD mice. Glucose intolerance and cortical amyloid pathology worsened with age, and both were more pronounced in the females. Pancreatic amyloidopathy was revealed and could underlie the observed deficit in glycemic response in 3xTg-AD mice. The present results suggest that AD-like neuropathology extends to the pancreas in the 3xTg-AD mouse, leading to glucose intolerance and contributing to a pathologic self-amplifying loop between AD and T2D. PMID- 26108978 TI - Portuguese Man-of-War (Physalia physalis) in the Mediterranean: A permanent invasion or a casual appearance? AB - In 2010, the Mediterranean basin experienced Portuguese Man-of-War (Physalia physalis) swarms that had dramatic consequences, including the region's first recorded human fatality attributed to a jellyfish sting. Despite the impact of jellyfish on coastal economic activity and the importance of the tourism industry for the Mediterranean region (accounting for 15% of global tourism), no scientific consensus has been achieved regarding the causes of this episode. Here, we analyse the meteorological and oceanographic conditions of the North East Atlantic Ocean during the months previous to the appearance of P. physalis in the Mediterranean. We simulate the probable drift of Atlantic populations into the Mediterranean basin with a numerical model and compare model results with available observations. We conclude that the summer 2010 P. Physalis swarm was the result of an unusual combination of meteorological and oceanographic conditions during the previous winter and not a permanent invasion favoured by climatic changes. PMID- 26108979 TI - Memorandum "Open Metadata". Open Access to Documentation Forms and Item Catalogs in Healthcare. AB - At present, most documentation forms and item catalogs in healthcare are not accessible to the public. This applies to assessment forms of routine patient care as well as case report forms (CRFs) of clinical and epidemiological studies. On behalf of the German chairs for Medical Informatics, Biometry and Epidemiology six recommendations to developers and users of documentation forms in healthcare were developed. Open access to medical documentation forms could substantially improve information systems in healthcare and medical research networks. Therefore these forms should be made available to the scientific community, their use should not be unduly restricted, they should be published in a sustainable way using international standards and sources of documentation forms should be referenced in scientific publications. PMID- 26108980 TI - A lactam building block for efficient polymer solar cells. AB - A new lactam acceptor unit, [7,7'-bidithieno[3,2-b:2',3'-d]pyridine]-5,5'(4H,4'H) dione (BDTP), was developed. A D-A copolymer PThBDTP using BDTP as the acceptor unit and thiophene as the donor unit was synthesized. PThBDTP:PC71BM solar cells gave a decent PCE of 9.13% with a V(oc) of 0.96 V. PThBDTP is one of the few D-A copolymers with PCEs of over 9%. PMID- 26108981 TI - Relatively strong intramolecular antiferromagnetic coupling in a neutral Cr(III)2Nb(V)2 heterobimetallic molecular square. AB - A relatively large antiferromagnetic interaction between the two chromium(III) ions from the molecular square [{Cr(dmso)4}2{Nb(MU-O)2(C2O4)2}2] () (J = -12.0 cm(-1)) is mediated by the diamagnetic oxo-Nb(V)-oxo pathway, its nature and magnitude being substantiated by DFT type theoretical calculations. PMID- 26108982 TI - Recurrence of atrial tachyarrhythmia during the second month of the blanking period is associated with more extensive pulmonary vein reconnection at repeat electrophysiology study. AB - BACKGROUND: Current guidelines recommend a 3-month blanking period after pulmonary vein isolation (PVI) as early recurrence of atrial tachyarrhythmia (ERAT) may be due to transient proarrhythmic factors. However, studies have suggested that these factors resolve by 1 month. PV reconnection (PVrc) is strongly associated with postblanking AT recurrence in paroxysmal atrial fibrillation. We hypothesized that ERAT occurring beyond 4 weeks after PVI is associated with PVrc at repeat electrophysiology study. METHODS AND RESULTS: Forty patients with paroxysmal atrial fibrillation underwent mandatory repeat electrophysiology study 2 months after PVI, regardless of symptoms, to document the number of reconnected PVs. Antiarrhythmic drugs, including beta-blockers, were discontinued 4 weeks after PVI. Patients were instructed to record a 30 second ECG everyday between the 2 procedures using a portable monitor, with additional recordings for symptoms. ERAT was defined as >=30 seconds of AT. Patients recorded a total of 3293 ECGs. Four (10%) patients had ERAT in the first 4 weeks (M1) only, 2 (5%) in month 2 (M2) only, and 11 (28%) in both. PVrc of 1 PV was identified in 12 (30%) patients and of >1 PV in 13 (32%) patients. ERAT in M2 was associated with PVrc, whereas M1 was not (11/13 [85%] versus 0/4 [0%]; P=0.006). M2 ERAT was strongly associated with PVrc of >1 PV (10/13 [77%] versus 3/27 [11%] without M2 ERAT; P<0.0001). CONCLUSIONS: ERAT occurring beyond 4 weeks after PVI is associated with PVrc and particularly of PVrc of >1 PV. ERAT confined to M1 is unrelated to underlying PVrc. The relationship between ERAT beyond 4 weeks after PVI and postblanking AT recurrence merits further investigation. PMID- 26108983 TI - Adenosine accelerates the healing of diabetic ischemic ulcers by improving autophagy of endothelial progenitor cells grown on a biomaterial. AB - Endothelial progenitor cells (EPCs) seeded on biomaterials can effectively promote diabetic ischemic wound healing. However, the function of transplanted EPCs is negatively affected by a high-glucose and ischemic microenvironment. Our experiments showed that EPC autophagy was inhibited and mitochondrial membrane potential (MMP) was increased in diabetic patients, while adenosine treatment decreased the energy requirements and increased the autophagy levels of EPCs. In animal experiments, we transplanted a biomaterial seeded with EPCs onto the surface of diabetic wounds and found that adenosine-stimulated EPCs effectively promoted wound healing. Increased microvascular genesis and survival of the transplanted cells were also observed in the adenosine-stimulated groups. Interestingly, our study showed that adenosine increased the autophagy of the transplanted EPCs seeded onto the biomaterial and maintained EPC survival at 48 and 96 hours. Moreover, we observed that adenosine induced EPC differentiation through increasing the level of autophagy. In conclusion, our study indicated that adenosine-stimulated EPCs seeded onto a biomaterial significantly improved wound healing in diabetic mice; mechanistically, adenosine might maintain EPC survival and differentiation by increasing high glucose-inhibited EPC autophagy and maintaining cellular energy metabolism. PMID- 26108984 TI - Na(+) /H(+) exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury. AB - The intercellular adhesion molecule 1 (ICAM-1) is induced in mouse liver after bile duct ligation (BDL) and plays a key role in neutrophil-mediated liver injury in BDL mice. ICAM-1 has been shown to interact with cytoskeletal ezrin-radixin moesin (ERM) proteins that also interact with the PDZ protein, Na(+) /H(+) exchanger regulatory factor 1 (NHERF-1/EBP50). In NHERF-1(-/-) mice, ERM proteins are significantly reduced in brush-border membranes from kidney and small intestine. ERM knockdown reduces ICAM-1 expression in response to tumor necrosis factor alpha. Here we show that NHERF-1 assembles ERM proteins, ICAM-1 and F actin into a macromolecule complex that is increased in mouse liver after BDL. Compared to wild-type (WT) mice, both sham-operated and BDL NHERF-1(-/-) mice have lower levels of activated ERM and ICAM-1 protein in the liver accompanied by significantly reduced hepatic neutrophil accumulation, serum alanine aminotransferase, and attenuated liver injury after BDL. However, total bile acid concentrations in serum and liver of sham and BDL NHERF-1(-/-) mice were not significantly different from WT controls, although hepatic tetrahydroxylated bile acids and Cyp3a11 messenger RNA levels were higher in NHERF-1(-/-) BDL mice. CONCLUSION: NHERF-1 participates in the inflammatory response that is associated with BDL-induced liver injury. Deletion of NHERF-1 in mice leads to disruption of the formation of ICAM-1/ERM/NHERF-1 complex and reduction of hepatic ERM proteins and ICAM-1, molecules that are up-regulated and are essential for neutrophil mediated liver injury in cholestasis. Further study of the role of NHERF-1 in the inflammatory response in cholestasis and other forms of liver injury should lead to discovery of new therapeutic targets in hepatic inflammatory diseases. PMID- 26108985 TI - [Cardiac and vascular malformations]. AB - Malformations of the heart and great vessels show a high degree of variation. There are numerous variants and defects with only few clinical manifestations and are only detected by chance, such as a persistent left superior vena cava or a partial anomalous pulmonary venous connection. Other cardiovascular malformations are manifested directly after birth and need prompt mostly surgical interventions. At this point in time echocardiography is the diagnostic modality of choice for morphological and functional characterization of malformations. Additional imaging using computed tomography (CT) or magnetic resonance imaging (MRI) is only required in a minority of cases. If so, the small anatomical structures, the physiological tachycardia and tachypnea are a challenge for imaging modalities and strategies. This review article presents the most frequent vascular, cardiac and complex cardiovascular malformations independent of the first line diagnostic imaging modality. PMID- 26108986 TI - [Secreting and destroying infection of the foot]. PMID- 26108987 TI - Computational Evidence for the Catalytic Mechanism of Tyrosylprotein Sulfotransferases: A Density Functional Theory Investigation. AB - In this paper we have examined the mechanism of tyrosine O-sulfonation catalyzed by human TPST-2. Our computations, in agreement with Teramoto's hypothesis, indicate a concerted SN2-like reaction (with an activation barrier of 18.2 kcal mol(-1)) where the tyrosine oxygen is deprotonated by Glu(99) (base catalyst) and simultaneously attacks as a nucleophile the sulfuryl group. For the first time, using a quantum mechanics protocol of alanine scanning, we identified unequivocally the role of the amino acids involved in the catalysis. Arg(78) acts as a shuttle that "assists" the sulfuryl group moving from the 3' phosphoadenosine-5'-phosphosulfate molecule to threonine and stabilizes the transition state (TS) by electrostatic interactions. The residue Lys(158) keeps close the residues participating in the overall H-bond network, while Ser(285), Thr(81), and Thr(82) stabilize the TS via strong hydrogen interactions and contribute to lower the activation barrier. PMID- 26108988 TI - From standard to new genome-based therapy of gastric cancer. AB - Randomized trials and meta-analyses have established surgery, radiotherapy, chemotherapy and targeted therapy in the multidisciplinary treatment of gastric cancer. However, personalized prediction of both therapeutic resistance and recurrence or metastatic disease progression still remains a researcher's dream. In this editorial, we summarize standard treatment approaches as well as their limitations, with an effort to highlight novel, next-generation sequencing technology-based clinical approaches for gastric cancer treatment. PMID- 26108989 TI - Development of trastuzumab-resistant human gastric carcinoma cell lines and mechanisms of drug resistance. AB - Trastuzumab has been successfully employed for the treatment of Her-2-positive gastric cancer. However, there are problems with both primary and secondary resistance to trastuzumab. In this study, we employed the human gastric carcinoma cell line NCI-N87 with high Her-2 expression to create trastuzumab-resistant NCI N87/TR cells by stepwise exposure to increasing doses of trastuzumab. Western blotting and Real-time PCR were conducted to detect protein and gene levels. Compared with NCI-N87 cells, the expression of P-IGF-1R and P-AKT proteins was significantly increased in NCI-N87/TR cells (both P = 0.000), while PTEN gene and protein expression showed a significant decrease (both P = 0.000). In addition, mutations of the PTEN gene were detected at exons 5, 7, and 8. The sensitivity of NCI-N87/TR cells to trastuzumab was increased by transfection with the PTEN gene, or by incubation with a PI3K inhibitor (LY294002) or an IGF-IR inhibitor (AG1024), as well as siRNA targeting PI3K p110 or IGF-1R. Taken together, our findings showed that activation of the PI3K-AKT signaling pathway was one of the major mechanisms leading to resistance of NCI-N87/TR gastric cancer cells to trastuzumab, which was probably associated with PTEN gene down-regulation and mutation, as well as with over-activity of the IGF-1R signaling pathway. PMID- 26108990 TI - Association between all-cause and cause-specific mortality and the GOLD stages 1 4: A 30-year follow-up among Finnish adults. AB - BACKGROUND: Mortality correlates with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria of airway obstruction. Yet, little data exist concerning the long-term survival of patients presenting with different levels of obstruction. METHODS: We studied the association between all-cause and cause-specific mortality and GOLD stages 1-4 in a 30-year follow-up among 6636 Finnish men and women aged 30 or older participating in the Mini-Finland Health Study between 1978 and 1980. RESULTS: After adjusting for age, sex, and smoking history, the GOLD stage of the subject showed a strong direct relationship with all-cause mortality, mortality from cardiovascular and respiratory diseases, and cancer. The adjusted hazard ratios of death were 1.27 (95% confidence interval (CI) 1.06-1.51), 1.40 (1.21-1.63), 1.55 (1.21-1.97) and 2.85 (1.65-4.94) for GOLD stages 1-4, respectively, with FEV1/FVC >=70% as the reference. The association between GOLD stages 2-4 and mortality was strongest among subjects under 50 years of age at the baseline measurement. Cardiovascular mortality increased consistently for all GOLD stages. CONCLUSIONS: Airway obstruction indicates an increased risk for all-cause mortality according to the severity of the GOLD stage. We found that even stage 1 carries a risk for cardiovascular death independently of smoking history and other known risk factors. PMID- 26108991 TI - Short- and Long-Term Effects of a Challenge Dose of Hepatitis B Vaccine in Individuals With and Without Residual Anti-HBs. PMID- 26108992 TI - Signatures of positive selection: from selective sweeps at individual loci to subtle allele frequency changes in polygenic adaptation. AB - In the past 15 years, numerous methods have been developed to detect selective sweeps underlying adaptations. These methods are based on relatively simple population genetic models, including one or two loci at which positive directional selection occurs, and one or two marker loci at which the impact of selection on linked neutral variation is quantified. Information about the phenotype under selection is not included in these models (except for fitness). In contrast, in the quantitative genetic models of adaptation, selection acts on one or more phenotypic traits, such that a genotype-phenotype map is required to bridge the gap to population genetics theory. Here I describe the range of population genetic models from selective sweeps in a panmictic population of constant size to evolutionary traffic when simultaneous sweeps at multiple loci interfere, and I also consider the case of polygenic selection characterized by subtle allele frequency shifts at many loci. Furthermore, I present an overview of the statistical tests that have been proposed based on these population genetics models to detect evidence for positive selection in the genome. PMID- 26108993 TI - Associative memory realized by a reconfigurable memristive Hopfield neural network. AB - Although synaptic behaviours of memristors have been widely demonstrated, implementation of an even simple artificial neural network is still a great challenge. In this work, we demonstrate the associative memory on the basis of a memristive Hopfield network. Different patterns can be stored into the memristive Hopfield network by tuning the resistance of the memristors, and the pre-stored patterns can be successfully retrieved directly or through some associative intermediate states, being analogous to the associative memory behaviour. Both single-associative memory and multi-associative memories can be realized with the memristive Hopfield network. PMID- 26108994 TI - [Cancer screening in the elderly: Explorative mixed methods study]. AB - BACKGROUND: The benefits of cancer screening in the elderly are uncertain. While the risk of cancer increases with age the participation in cancer screening decreases. AIM: The study investigated the attitudes of older adults towards cancer screening as well as their motives for or against participation. MATERIAL AND METHODS: This population-based explorative mixed methods study was based on a survey of residents aged 69-89 years from the district of Western Pomerania Greifswald (northeast Germany). Criteria for exclusion were cognitive deficits and/or cancer. Attitudes towards different statements regarding cancer screening were assessed by a questionnaire using 5-point Likert scales. Semi-structured interviews were used to explore the motivations. RESULTS: Out of 630 contacted residents, 120 (19%) with an average age of 77 years (SD +/- 6 years) participated in the face-to-face survey. The majority were in favor of lifelong cancer screening, 14% stated other health problems to be more important than cancer screening and 7% assumed that they would not live long enough to benefit from screening. Motives for participation in cancer screening were habit, regularity, sense of obligation, fear and belief in benefits. Motives for discontinuing screening included a lack of interest, no assumed necessity and fear. Disadvantages were not feared. CONCLUSION: Elderly people show great trust in cancer screening. They overestimated the benefits of cancer screening and their risk to die of cancer. The elderly should be better informed about the benefits and risks of cancer screening. Shared decision-making should be based on life expectancy and personal preferences. PMID- 26108996 TI - Glucose-regulated protein 94 is a novel glioma biomarker and promotes the aggressiveness of glioma via Wnt/beta-catenin signaling pathway. AB - Malignant glioma is the most common type of primary brain tumor and represents one of the most aggressive and lethal human cancer types. Glioma recurrence is a common event; however, the relevant molecular mechanisms in this setting are not well-understood. In this study, we investigated glucose-regulated protein 94 (GRP94) expressions in human glioma and aimed to determine the roles of GRP94 expression affects cell proliferation, invasion, and regulatory signaling in human glioma U87 cells. Our results showed that GRP94 was overexpressed at both mRNA and protein levels in high-grade glioblastoma as compared with normal brain tissues. High GRP94 levels also predict shorter overall survival of glioma patients. RNAi-mediated silencing of GRP94 suppressed cellular proliferation, colony formation ability in glioma cells. Depletion of GRP94 also inhibited cell migration and invasion ability in glioma cell. Furthermore, gene microarray analysis revealed that GRP94 depletion caused the dysregulation of critical pathway, Wnt/beta-catenin signaling pathway. We next demonstrated GRP94 regulates Wnt/beta-catenin signaling pathway to promote the proliferation of glioblastoma cells. Conclusion, our findings establish GRP94 as progression markers and druggable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/beta-catenin signaling pathway. PMID- 26108995 TI - Suberoylanilide hydroxamic acid enhances chemosensitivity to 5-fluorouracil in hepatocellular carcinoma via inhibition of thymidylate synthase. AB - Hepatocellular carcinoma (HCC) is associated with a high rate of mortality worldwide. Here, we investigated the effect of combination treatment with suberoylanilide hydroxamic acid (SAHA) and 5-fluorouracil (5-FU) on HCC cells. HepG2, SMMC7721, and BEL7402 cells were treated with SAHA and/or 5-FU and subjected to cell viability, colony formation, and soft agarose assays; cell cycle, apoptosis, and reverse transcription-PCR analyses; western blotting; immunohistochemistry; and xenograft tumorigenicity assay. SAHA and 5-FU inhibited the proliferation of the three cell lines, and combination treatment with SAHA and 5-FU resulted in a combination index <1 and a dose-reduction index value >1, indicating a synergistic effect. Co-treatment with SAHA and 5-FU caused G0/G1 phase arrest and induced caspase-dependent apoptosis, inhibiting tumorigenicity in vitro and in vivo. 5-FU upregulated thymidylate synthase, whereas SAHA downregulated its expression. Our results indicate that SAHA and 5-FU act synergistically to inhibit cell growth and tumorigenicity in HCC via the induction of cell-cycle arrest and apoptosis through a mechanism involving the inhibition of thymidylate synthase, suggesting that combination treatment with 5 FU and SAHA may be beneficial for the treatment of inoperable HCC. PMID- 26108997 TI - Targeting DNA-PKcs increased anticancer drug sensitivity by suppressing DNA damage repair in osteosarcoma cell line MG63. AB - Many chemotherapy drugs exert anticancer effects through causing DNA damage, such as DNA topoisomerase inhibitor and platinum-containing drugs. DNA damage repair is an important mechanism of drug resistance which is responsible for metastasis and recurrence after chemotherapy. DNA-dependent protein kinase (DNA-PK) plays an important role in non-homology end joining (NHEJ) pathway. In this study, we aimed to determine whether DNA-PK catalytic subunit (DNA-PKcs) is expressed in osteosarcoma MG63 cell line and involved in drug resistance induced by DNA repair. We found that DNA-PKcs was expressed in osteosarcoma cell line MG63. The pDNA-PKcs(T2609) was more expressed in cells treated with cisplatin (DDP) and etoposide (VP16). Down-regulation of DNA-PKcs produced higher sensitivity of MG63 cells to DDP or VP16 through increasing apoptosis and causing cell cycle arrest in the G1 phase. Our study supported that DNA-PKcs was involved in drug-induced DNA damage repair and related to chemosensitivity of osteosarcoma MG63 cells. PMID- 26108998 TI - The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines. AB - KRAS mutations are found in 15-25 % of patients with lung adenocarcinoma, and they lead to constitutive activation of KRAS signaling pathway that results in sustained cell proliferation. Currently, there are no direct anti-KRAS therapies available. Therefore, it is rational to target the downstream molecules of KRAS signaling pathway, which are mitogen-activated protein kinase (MAPK) signaling pathway (RAF-MEK-ERK) and PI3K pathway (PI3K-AKT-mTOR). Here, we examined the inhibition of both these pathways alone and in combination and analyzed the anti proliferative and apoptotic events in KRAS mutant NSCLC cell lines, A549 and Calu 1. Cytotoxicity was determined by MTT assay after the cells were treated with LY294002 (PI3K inhibitor), U0126 (MEK inhibitor), and RAD001 (mTOR inhibitor) for 24 and 48 h. The expression levels of p-ERK, ERK, AKT, p-AKT, p53, cyclinD1, c myc, p27(kip1), BAX, BIM, and GAPDH were detected by western blot after 6 and 24 h treatment. Although PI3K/mTOR inhibition is more effective in cytotoxicity in A549 and Calu-1 cells, MEK/mTOR inhibition markedly decreases cell proliferation protein marker expressions. Our data show that combined targeting of MEK and PI3K AKT with mTOR is a better option than single agents alone for KRAS mutant NSCLC, thus opening the possibility of a beneficial treatment strategy in the future. PMID- 26108999 TI - Multifaceted roles of HSF1 in cancer. AB - Heat shock transcription factor 1 (HSF1) is the master regulator of the heat shock response. Accumulating evidence shows that HSF1 is overexpressed in a variety of human cancers, is associated with cancer aggressiveness, and could serve as an independent diagnostic or prognostic biomarker. In this review, we will provide an overview of the multifaceted roles of HSF1 in cancer, with a special focus on the four underlying molecular mechanisms involved. First, HSF1 regulates the expression of heat shock proteins (HSPs) including HSP90, HSP70, and HSP27. Second, HSF1 regulates cellular metabolism, including glycolysis and lipid metabolism. Third, HSF1 serves as a regulator of different signaling pathways, such as HuR-HIF-1, Slug, protein kinase C (PKC), nuclear factor-kappaB (NF-kappaB), PI3K-AKT-mTOR, and mitogen-activated protein kinase (MAPK) pathways. Finally, HSF1 regulates microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Overall, HSF1 plays many important roles in cancer via regulating cell proliferation, anti-apoptosis, epithelial-mesenchymal transition (EMT), migration, invasion, and metastasis and may be a potential therapeutic target for human cancers. PMID- 26109001 TI - RETRACTED ARTICLE: The value of U-NGAL expression as a potential prognostic biomarker in patients with renal cancer after neoadjuvant chemotherapy with cisplatin. PMID- 26109000 TI - Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma. AB - Hepatic annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical symptoms and plays a key role in development, metastasis, and drug resistance of lethal hepatocellular carcinoma (HCC). However, the prognostic significance of ANXA2 for HCC has not been elucidated up to now. In this study, ANXA2 was frequently found to be up-regulated in HCC tissues compared with benign liver disease (BLD) tissues, which was consistent with the results in serum samples and tissue specimens of patients with HCC. Furthermore, ANXA2 expression was significantly correlated with differentiated degree, intrahepatic metastasis, portal vein thrombus, and tumor node metastasis (TNM) staging. More importantly, increased ANXA2 level was first confirmed to be closely associated with shortened overall survival of HCC (chi (2) = 12.872, P = 0.005) and identified as an independent prognostic factor (hazard ratio 1.338, 95 % confidence interval (CI) 1.013 ~ 1.766, P = 0.040), suggesting that ANXA2 up-regulation might represent an acquired metastasis phenotype of HCC, help to screen out high-risk population for HCC, or more effectively treat a subset of postsurgical HCC patients positive for ANXA2. PMID- 26109002 TI - Quercetin 3-O-glucoside suppresses epidermal growth factor-induced migration by inhibiting EGFR signaling in pancreatic cancer cells. AB - Pancreatic cancer is one of the most dangerous cancers and is associated with a grave prognosis. Despite increased knowledge of the complex signaling networks responsible for progression of pancreatic cancer, many challenging therapies have fallen short of expectations. In this study, we examined the anti-migratory effect of quercetin 3-O-glucoside in epidermal growth factor-induced cell migration by inhibiting EGF receptor (EGFR) signaling in several human pancreatic cancer cell lines. Treatment with quercetin, quercetin 3-O-glucoside, and quercetin 7-O-glucoside differentially suppressed epidermal growth factor-induced migration activity of human pancreatic cancer cells. In particular, quercetin 3-O glucoside strongly inhibited the infiltration activity of pancreatic cancer cells in a dose-dependent manner. Furthermore, quercetin 3-O-glucoside exerted the anti migratory effect even at a relatively low dose compared with other forms of quercetin. The anti-tumor effects of quercetin 3-O-glucoside were mediated by selectively inhibiting the EGFR-mediated FAK, AKT, MEK1/2, and ERK1/2 signaling pathway. Combinatorial treatment with quercetin 3-O-glucoside plus gemcitabine showed the synergistic anti-migratory effect on epidermal growth factor-induced cell migration in human pancreatic cancer cell lines. These results suggest that quercetin 3-O-glucoside has potential for anti-metastatic therapy in human pancreatic cancer. PMID- 26109003 TI - Molecular weight-dependent degradation of D-lactate-containing polyesters by polyhydroxyalkanoate depolymerases from Variovorax sp. C34 and Alcaligenes faecalis T1. AB - Polyhydroxyalkanoate depolymerase derived from Variovorax sp. C34 (PhaZVs) was identified as the first enzyme that is capable of degrading isotactic P[67 mol% (R)-lactate(LA)-co-(R)-3-hydroxybutyrate(3HB)] [P(D-LA-co-D-3HB)]. This study aimed at analyzing the monomer sequence specificity of PhaZVs for hydrolyzing P(LA-co-3HB) in comparison with a P(3HB) depolymerase from Alcaligenes faecalis T1 (PhaZAf) that did not degrade the same copolymer. Degradation of P(LA-co-3HB) by action of PhaZVs generated dimers, 3HB-3HB, 3HB-LA, LA-3HB, and LA-LA, and the monomers, suggesting that PhaZVs cleaved the linkages between LA and 3HB units and between LA units. To provide a direct evidence for the hydrolysis of these sequences, the synthetic methyl trimers, 3HB-3HB-3HB, LA-LA-3HB, LA-3HB-LA, and 3HB-LA-LA, were treated with the PhaZs. Unexpectedly, not only PhaZVs but also PhaZAf hydrolyzed all of these substrates, namely PhaZAf also cleaved LA-LA linkage. Considering the fact that both PhaZs did not degrade P[(R)-LA] (PDLA) homopolymer, the cleavage capability of LA-LA linkage by PhaZs was supposed to depend on the length of the LA-clustering region in the polymer chain. To test this hypothesis, PDLA oligomers (6 to 40 mer) were subjected to the PhaZ assay, revealing that there was an inverse relationship between molecular weight of the substrates and their hydrolysis efficiency. Moreover, PhaZVs exhibited the degrading activity toward significantly longer PDLA oligomers compared to PhaZAf. Therefore, the cleaving capability of PhaZs used here toward the D-LA-based polymers containing the LA-clustering region was strongly associated with the substrate length, rather than the monomer sequence specificity of the enzyme. PMID- 26109004 TI - Production of phenylpyruvic acid from L-phenylalanine using an L-amino acid deaminase from Proteus mirabilis: comparison of enzymatic and whole-cell biotransformation approaches. AB - Phenylpyruvic acid (PPA) is an important organic acid that has a wide range of applications. In this study, the membrane-bound L-amino acid deaminase (L-AAD) gene from Proteus mirabilis KCTC 2566 was expressed in Escherichia coli BL21(DE3) and then the L-AAD was purified. After that, we used the purified enzyme and the recombinant E. coli whole-cell biocatalyst to produce PPA via a one-step biotransformation from L-phenylalanine. L-AAD was solubilized from the membrane and purified 52-fold with an overall yield of 13 %, which corresponded to a specific activity of 0.94 +/- 0.01 MUmol PPA min(-1).mg(-1). Then, the biotransformation conditions for the pure enzyme and the whole-cell biocatalyst were optimized. The maximal production was 2.6 +/- 0.1 g.L(-1) (specific activity of 1.02 +/- 0.02 MUmol PPA min(-1).mg(-1) protein, 86.7 +/- 5 % mass conversion rate, and 1.04 g.L(-1).h(-1) productivity) and 3.3 +/- 0.2 g L(-1) (specific activity of 0.013 +/- 0.003 MUmol PPA min(-1).mg(-1) protein, 82.5 +/- 4 % mass conversion rate, and 0.55 g.L(-1).h(-1) productivity) for the pure enzyme and whole-cell biocatalyst, respectively. Comparative studies of the enzymatic and whole-cell biotransformation were performed in terms of specific activity, production, conversion, productivity, stability, need of external cofactors, and recycling. We have developed two eco-friendly and efficient approaches for PPA production. The strategy described herein may aid the biotransformational synthesis of other alpha-keto acids from their corresponding amino acids. PMID- 26109005 TI - The lifestyle of prokaryotic organisms influences the repertoire of promiscuous enzymes. AB - The metabolism of microbial organisms and its diversity are partly the result of an adaptation process to the characteristics of the environments that they inhabit. In this work, we analyze the influence of lifestyle on the content of promiscuous enzymes in 761 nonredundant bacterial and archaeal genomes. Promiscuous enzymes were defined as those proteins whose catalytic activities are defined by two or more different Enzyme Commission (E.C.) numbers. The genomes analyzed were categorized into four lifestyles for their exhaustive comparisons: free-living, extremophiles, pathogens, and intracellular. From these analyses we found that free-living organisms have larger genomes and an enrichment of promiscuous enzymes. In contrast, intracellular organisms showed smaller genomes and the lesser proportion of promiscuous enzymes. On the basis of our data, we show that the proportion of promiscuous enzymes in an organism is mainly influenced by the lifestyle, where fluctuating environments promote its emergence. Finally, we evidenced that duplication processes occur preferentially in metabolism of free-living and extremophiles species. PMID- 26109006 TI - Protective Factors of the Gastric and Duodenal Mucosa: An Overview. AB - The structural and functional integrity of the gastric and duodenal mucosa represents equilibrium between aggressive factors and protective mechanisms. Mucus-buffers-phospholipid layer as pre-epithelial barrier, enhanced by prostaglandins and epidermal growth factor, remains a vanguard of mucosal protection. It maintains a neutral pH at the surface epithelial luminal interface, facing luminal pH dropping to 1.0, i.e., hydrogen ion concentration gradient equal 1,000,000. The surface epithelial cells, elaborating mucins, buffers, phospholipids, prostaglandins, trefoil peptides, peptide growth factor and their receptors, heat shock proteins, cathelicidins, and beta-defensins form the second line of defense. Endothelium exerts mucosal protection through production of potent vasodilators like nitric oxide and prostacyclins and through release of angiogenic growth factors, securing adequate blood flow and representing the third and an ultimate line of mucosal protection. This microcirculation is instrumental for supply of oxygen, nitric oxide, hydrogen sulfide and removal of ad hoc generated toxic substances as well as for continuous mucosal cell renewal from progenitor cells, secured by growth factors accompanied by survivin preventing early apoptosis. PMID- 26109008 TI - A peer-led teaching initiative for foundation doctors. AB - BACKGROUND: Peer teaching has been used informally throughout the history of medical education. Formal studies within the medical student and allied health care professional communities have found it to be a popular, and highly effective, method of teaching. CONTEXT: Newly qualified doctors are currently an underused resource in terms of teaching one another. INNOVATION: A committee, made up of newly qualified doctors and postgraduate education staff, was established. Using only a few resources, this committee organised regular, peer led tutorials and used educational needs assessment tools, such as questionnaires, to make improvements to early postgraduate training. IMPLICATION: A realistic and well-received intervention to improve the teaching of newly qualified doctors, which is feasible in the modern, busy health care setting. Other institutions may find this method and its resources valuable. Newly qualified doctors are currently an underused resource in terms of teaching one another. PMID- 26109007 TI - Balo's concentric sclerosis: still to be considered as a variant of multiple sclerosis? AB - Balo's concentric sclerosis (BCS) is considered a rare demyelinating disease and regarded as an aggressive variant of multiple sclerosis (MS). We describe three cases (one male and two females) with neuroimaging features suggestive of BCS and heterogeneous symptoms, with benign long-term clinical course upon treatment with natalizumab and fingolimod. Neurological examination, blood and cerebrospinal fluid analyses, brain and spinal cord magnetic resonance imaging (MRI) and brain proton magnetic resonance spectroscopy were performed. At onset, patient #1 showed predominant cognitive impairment with consciousness disturbances; patient #2 presented with left hemiparesis; patient #3 demonstrated hesitance in speech and in written word production, along with right central facial palsy. All patients showed the typical MRI changes associated with BCS, such as concentric rings or a whorled appearance on T2-weighted and contrast-enhanced T1-weighted images. They were treated with high dosage i.v. steroid with clinical improvement and followed-up for 3 years with different clinical course. Two patients fulfilled the revised McDonald criteria for MS and received preventive therapy, natalizumab and fingolimod, respectively, whereas the third patient is still stable without clinical and radiological evolution. All of them did not have new exacerbations or MRI lesions over 2-4 year follow-up. Our descriptions demonstrate the heterogeneity of clinical presentation of BCS. Moreover, these case reports suggest that BCS may neither be rapidly progressive nor fatal and may be considered part of the MS spectrum. In line with this hypothesis, current treatments for MS were effective in our patients. PMID- 26109010 TI - The Impact of Maternal-Fetal Genetic Conflict Situations on the Pathogenesis of Preeclampsia. AB - Preeclampsia leads to maternal and perinatal morbidity and mortality. The literature in English was reviewed to summarize recent advances in understanding the global gene expression changes in the pathogenesis of preeclampsia. We identified at least eight consistently enriched categories, relating to pregnancy maintenance, metabolism, oxidative stress, cell cycle regulation, implantation, decidualization, immune modulation, and vascular function. Expression profiling in preeclampsia placenta and normal placenta revealed 140 transcripts that were significantly differentially expressed, 30 (21.4%) of which were evolved for the protection of the mother, approximately three times less than the number of genes evolved for the benefit of the fetus [110 genes (78.6%)] in preeclampsia placenta versus normal placenta. The genome-wide analysis emphasizes the dysfunctional decidualization as the main mechanism involved in the development of preeclampsia. These genetic signaling events may occur from an imbalance in the maternal-fetal genetic response in the affected placenta. This is to our knowledge the first report on the pathogenesis of preeclampsia, in which preeclampsia may occur as a genetic consequence of maternal-fetal conflict situations during the early decidualization process. PMID- 26109009 TI - Dietary Aloe vera improves plasma lipid profile, antioxidant, and hepatoprotective enzyme activities in GIFT-tilapia (Oreochromis niloticus) after Streptococcus iniae challenge. AB - The current study investigated the effects of dietary Aloe vera on plasma lipid profile status, antioxidant, and hepatoprotective enzyme activities of GIFT tilapia juveniles under Streptococcus iniae challenge. Five dietary groups were designed including a control and 100 % Aloe powder incorporated into a tilapia feed at 0.5, 1, 2, and 4 %/kg feed, which were administered for 8 weeks. Fish fed dietary Aloe at 4 %/kg feed significantly reduced in total cholesterol, while triacylglycerol reduced (P < 0.05) in those fed 0.5, 2, and 4 % Aloe/kg feed compared to unsupplemented ones. High-density lipoprotein was significantly elevated in fish fed 0.5 and 1 % Aloe/kg feed compared to unsupplemented ones, and no significant changes (P > 0.05) were noted in low-density lipoprotein among test groups. Furthermore, high activities of superoxide dismutase, catalase, and glutathione peroxide in liver tissues were observed in Aloe-supplemented fish compared to unsupplemented ones, before and after S. iniae challenge (7.7 * 10(6) CFU cells/mL). Variations were also noted in malondialdehyde activity throughout the trial, but no significant difference (P > 0.05) was observed between groups. Meanwhile, Aloe-supplemented fish reduced serum aspartate and alanine aminotransferase (AST and ALT) activities before and after challenge. Based on the second-order polynomial regression analysis, dietary Aloe inclusion levels less than or equal to 1.88, 1.86, and 2.79 %/kg feed were determined to be suitable in improving plasma lipid profile status, antioxidant, and hepatoprotective enzyme activities in GIFT-tilapia in this study, respectively. Thus, A. vera extracts may be recommended as a tilapia feed supplement to enhance fish antioxidant and hepatoprotective capacities, especially during disease outbreaks. PMID- 26109011 TI - Cocaine-Induced Acute Fatal Basilar Artery Thrombosis: Report of a Case and Review of the Literature. AB - BACKGROUND: Cocaine use is a well-known contributing factor for both ischemic and hemorrhagic stroke; however, basilar artery thrombosis due to cocaine use is a rare entity with few cases reported in the literature. CASE REPORT: A 75-year-old African-American man with history of hypertension and cocaine use presented to the emergency room with coma. Neurological examination revealed asymmetrical dilated pupils and preserved oculocephalic and gag reflexes. The patient was noted to have semi-rhythmic jerking movement of the right arm and extensor posturing in response to noxious stimuli. Non-contrast computed tomography (CT) of the brain showed hyperdense basilar sign consistent with acute thrombosis. On brain magnetic resonance imaging (MRI), he was found to have bilateral pons acute ischemic stroke with early petechial hemorrhagic conversion. His laboratory work up was unremarkable except for positive cocaine in the urine toxicology screen test. CONCLUSIONS: Cocaine is a common global illicit drug that may trigger acute basilar artery thrombosis leading to a catastrophic neurological outcome. PMID- 26109012 TI - Intracranial hemorrhage and other symptoms in infants associated with human parechovirus in Vienna, Austria. AB - The human parechovirus (HPeV), mainly genotype 3, may cause severe illness in young infants and neonates, including sepsis-like illness and central nervous system (CNS) infection. We lack data concerning the impact and symptoms of HPeV infection in infants in Austria. The aim of the study is to evaluate the spectrum of symptoms and findings in infants with the parechovirus in Vienna and its environs. Patients younger than 3 months of age, with clinically suspected sepsis like illness or CNS infection and a positive polymerase chain reaction (PCR) for HPeV, were included in the study. Medical records were analyzed retrospectively. Twenty patients were included in the study from 2009 to 2013. The most frequent manifestations were fever and neurological symptoms (89 and 80 %, respectively). Fifty percent of the infants had white blood cell counts out of range. The most notable aspect was cerebral hemorrhage in three neonates, which has not been reported earlier in association with HPeV infection. CONCLUSION: In Austria, HPeV is a relevant pathogen in sepsis-like disease in infants. The clinical presentation is similar to that described in other studies; cerebral hemorrhage is a new aspect. WHAT IS KNOWN: * Parechovirus infection can cause severe illness in infants. * Symptoms have been described to involve all organs; sepsis-like signs, fever, and irritability are most frequent. WHAT IS NEW: * Also in Austria, HPeV plays an important role in severe illnesses in infants. * Severe intracranial hemorrhage is described as a new finding. PMID- 26109013 TI - Femoroacetabular impingement: what is its link with osteoarthritis? PMID- 26109014 TI - African cycling: dormant to dominant? PMID- 26109015 TI - Large lamellar corneoscleral grafts: tectonic role in initial management of severe ocular chemical injuries. AB - PURPOSE: To report the outcome of large tectonic lamellar grafts in cases of severe chemical injury associated with corneal melt/perforation and scleral ischemia, with or without retinal detachment. METHODS: This was a retrospective interventional analysis of 7 eyes of 6 patients within 3 months of injury with simultaneous/subsequent surgical procedures to salvage globe integrity. RESULTS: Of 7 included eyes, both eyes of one patient underwent phthisical changes. In one eye, the retinal detachment was inoperable; in another, the retina was reattached with silicone oil tamponade, and underwent subsequent Boston type 1 keratoprosthesis with a final best-corrected visual acuity of 20/80 at 3-year follow-up. One eye underwent Lucia type 2 keratoprosthesis, one eye the modified osteo-odonto keratoprosthesis procedure, with visual recovery of 20/120 and 20/80, respectively, and one maintained vision of 20/200 for 2 years following a penetrating keratoplasty. The final best-corrected visual acuity was better than 20/200 in 4 out of these 7 eyes (57.14%). CONCLUSIONS: In acute severe chemical injuries, corneal perforation with scleral ischemia can threaten globe integrity as well as preclude routine tectonic penetrating procedure. Presence of a concurrent retinal detachment in this setting further complicates the approach as well as the outcome. The use of a large tectonic corneoscleral lamellar graft provides a viable option in the achievement of tectonic stability in these eyes, facilitating future visual rehabilitative procedures. PMID- 26109016 TI - Endophthalmitis today: a multispecialty ophthalmology department perspective. AB - PURPOSE: To portray the current scene of endophthalmitis in a multispecialty ophthalmology department regarding etiologies and treatment guidelines. METHODS: Retrospective chart review of all patients diagnosed with endophthalmitis or suspected endophthalmitis from 2009 to 2012. RESULTS: A total of 24 eyes were diagnosed with endophthalmitis or suspected endophthalmitis during a 4-year period. The etiologies included endogenous endophthalmitis (6), blebitis (3), Ahmed valve implantation (3, 2 of them with late infection), postcataract surgery (3), intravitreal injections (4), penetrating injury (2), and other surgical procedures (3). Of the postcataract surgery cases, 1 was a congenital cataract surgery, and 2 were referrals. There were no endophthalmitis cases in 4603 adults undergoing cataract surgery in our department during this period. There were 14 positive cultures: 1 was candida and the rest bacteria. Ten of the bacteria cases were Gram-positive cocci (predominantly strep species), 3 were Gram-negative, and coagulase negative staphylococci were detected in 2 cases. CONCLUSIONS: Our study indicates a significant change in the case mix of endophthalmitis. The past leading cause, cataract surgery, was dramatically reduced, and intravitreal injections became a major cause. The change in etiologies, and possibly in the microbial flora, warrants reconsideration of the rules that guided the management of endophthalmitis since the Endophthalmitis Vitrectomy Study. PMID- 26109017 TI - DMEK lenticule preparation using an air dissection technique: central versus peripheral injection. AB - PURPOSE: To compare 2 sites of air injection to prepare donor lenticules for Descemet membrane (DM) endothelial keratoplasty. METHODS: Fifty-one human corneoscleral buttons from donors aged 4 to 57 years were used. Corneoscleral buttons were placed endothelial side up and a 27-G needle was inserted just outside Schwalbe line and advanced immediately beneath the endothelium. Air was injected centrally inside the 8-mm zone (group 1) or peripherally approximately 1 mm in front of the limbus (group 2). Air injection was continued to extend the DM detachment as far as possible into the corneal periphery. Comparisons of central versus peripheral air injection were performed for reproducibility, the rate of usable tissue, and the type and diameter of the acquired bubble. RESULTS: The mean donor age was 30.0 +/- 12.9 years. A big bubble was achieved following central or peripheral air injection in all cases. A usable donor lenticule (>= 8.0 mm) was achieved in 95.7% of cases in group 1 and 89.3% of cases in group 2 (p>0.99). Both injection sites were comparable with regard to the diameter of the achieved bubbles (9.57 +/- 2.11 mm versus 10.22 +/- 2.34 mm, respectively, p = 0.32), the chance of complete DM detachment (39.1% versus 53.6%, respectively, p = 0.25), and the risk of bubble bursting (4.4% versus 7.1%, respectively, p = 0.41). The odds of a type 2 bubble increased by 11.86 for peripheral air injections compared to central injections (p = 0.01). CONCLUSIONS: Both injection sites exhibited comparable rates of usable donor lenticules. However, peripheral air injection was more likely to yield stroma-free grafts. PMID- 26109018 TI - Quantitative evaluation of visual function 12 months after bilateral implantation of a diffractive trifocal IOL. AB - PURPOSE: To quantitatively evaluate visual function 12 months after bilateral implantation of the Physiol FineVision(r) trifocal intraocular lens (IOL) and to compare these results with those obtained in the first postoperative month. METHODS: In this prospective case series, 20 eyes of 10 consecutive patients were included. Monocular and binocular, uncorrected and corrected visual acuities (distance, near, and intermediate) were measured. Metrovision(r) was used to test contrast sensitivity under static and dynamic conditions, both in photopic and low-mesopic settings. The same software was used for pupillometry and glare evaluation. Motion, achromatic, and chromatic contrast discrimination were tested using 2 innovative psychophysical tests. A complete ophthalmologic examination was performed preoperatively and at 1, 3, 6, and 12 months postoperatively. Psychophysical tests were performed 1 month after surgery and repeated 12 months postoperatively. RESULTS: Final distance uncorrected visual acuity (VA) was 0.00 +/- 0.08 and distance corrected VA was 0.00 +/- 0.05 logMAR. Distance corrected near VA was 0.00 +/- 0.09 and distance corrected intermediate VA was 0.00 +/- 0.06 logMAR. Glare testing, pupillometry, contrast sensitivity, motion, and chromatic and achromatic contrast discrimination did not differ significantly between the first and last visit (p>0.05) or when compared to an age-matched control group (p>0.05). CONCLUSIONS: The Physiol FineVision(r) trifocal IOL provided satisfactory full range of vision and quality of vision parameters 12 months after surgery. Visual acuity and psychophysical tests did not vary significantly between the first and last visit. PMID- 26109019 TI - Modified injector for optimal insertion of standard CTRs in lax zonules. AB - PURPOSE: Capsular tension rings (CTRs) are commonly used for stabilizing the capsule in lax zonules. Blind and uncontrolled maneuvering of the ring free end may cause intraoperative incidents during CTR insertion. We improved the design of a standard CTR typical injector that eliminates the risks associated with the lack of control during its insertion. METHODS: We present a modification of a typical injector used for insertion of standard CTR as well as the insertion technique. The modification consists of a metal anchoring element attached to the free end of the tube, on which the second eyelet of a standard CTR is fixed. The device was used in the surgical treatment of 50 adult patients with cataract associated with lax zonule. RESULTS: The improved injector led to a reduced injection duration and complexity, and there were no intraoperative incidents or postoperative complications. CONCLUSIONS: The fixation of the second eyelet allows a controlled insertion of the standard CTRs, which facilitates the intraocular implantation technique, reduces surgical complications associated with the blind maneuvering of the free end of the ring inserted by traditional methods, and has a less disruptive action on the integrity of the remaining undamaged zonular fibers in the lax zonules. The accessory attached to the typical injector tube reduces the risk of surgical incidents caused by the uncontrolled progression of the ring's free end inside the capsular bag. PMID- 26109020 TI - Spectral-domain optical coherence tomography and fundus autofluorescence features in a case of typical retinocytoma. AB - PURPOSE: To report spectral-domain optical coherence tomography (OCT) and fundus autofluorescence (FAF) features observed in a case of typical retinocytoma. METHODS: Case report. RESULTS: A 17-year-old girl on routine ophthalmologic evaluation for headache had an elevated translucent lesion with peripheral pigmentation and adjacent chorioretinal atrophy close to the disc in the nasal retinal quadrant of the left eye. The lesion was confirmed to be retinocytoma on fluorescein angiography. Optical coherence tomography revealed a hyperreflective layer akin to preserved nerve fiber layer overlying the lesion in most of the scans. Symmetrical hyporeflective spaces in the underlying choroid and at places sudden disruption of choroid was also observed in the area of choroidal atrophy. Fundus autofluorescence revealed areas of hyperfluorescence, isofluorescence, and hypofluorescence in the different regions of the lesion. These features on FAF were consistent with posttreatment regressed retinoblastoma. Scleral hyperreflectivity on OCT as well as unmasked hyperfluorescence on FAF was observed in areas of chorioretinal atrophy. CONCLUSIONS: We report novel findings of superficial hyperreflective layer presumed to be preserved nerve fiber layer in a case of typical retinocytoma as well as FAF features consistent with regressed retinoblastoma. PMID- 26109021 TI - Early results of dexamethasone implant, ranibizumab, and triamcinolone in macular edema due to branch retinal vein occlusion. AB - PURPOSE: To compare the short-term results of the efficacy and safety of dexamethasone intravitreal implant (DEX), ranibizumab (RAN), and intravitreal triamcinolone acetonide (IVTA) in macular edema secondary to branch retinal vein occlusion (BRVO). METHODS: One eye each of 32 patients who were treated with intravitreal injections for macular edema secondary to BRVO was studied. This retrospective study included 3 groups. The patients received DEX in group 1 (n = 11), RAN in group 2 (n = 11), and IVTA in group 3 (n = 10). Data were collected before and after the injections at the first and third months. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) were analyzed statistically. RESULTS: The median duration of the follow-up was 3.0 months in overall groups. The BCVA increased significantly in all groups (p = 0.018, p = 0.034, p = 0.014, respectively). The CMT increased significantly in groups 1 and 3 (p = 0.02, p<0.001, respectively), but not in group 2 (p = 0.14). The IOP increased significantly in groups 1 and 3 (p = 0.05, p<0.001, respectively). Antiglaucomatous treatment was required only in group 3. Cataract developed in 2 patients (20%) in group 3 and surgery was required. CONCLUSIONS: Although RAN was the safest among the 3 agents, DEX and IVTA reduced CMT more than RAN, while significant improvement was achieved in BCVA in all groups. All 3 agents can be effectively used in the treatment of macular edema due to BRVO. PMID- 26109022 TI - Association of autosomal dominant familial exudative vitreoretinopathy and spinal muscular atrophy. AB - We present an 8-month-old boy with severe retinal detachment from familial exudative vitreoretinopathy (FZD4 exon 1 deletion). He was subsequently diagnosed with spinal muscular atrophy with SMN1 deletion. beta-catenin signaling is dysregulated in both disorders, so we hypothesize that the co-occurrence may have exacerbated the vitreoretinal phenotype. PMID- 26109023 TI - Correlation of spectral-domain optical coherence tomography with fundus fluorescein angiography in an infant with retinal hamartomas. AB - PURPOSE: To describe the correlation between the surface morphology on spectral domain optical coherence tomography (SD-OCT) and leakage pattern on fundus fluorescein angiography (FFA) in an infant with multiple retinal hamartomas. METHODS: An Asian Indian female infant was found to have 2 retinal lesions in the right eye and 1 in the left eye during Retcam (Clarity MSI, CA, USA) screening for retinopathy of prematurity at 45 weeks postmenstrual age. Spectral-domain optical coherence tomography on the hand-held OCT (Envisu 2300, Bioptigen, NC, USA) and FFA on the Retcam 3 were performed under monitoring in the office. RESULTS: Spectral-domain OCT detected all 3 lesions but only 1 lesion was detected on FFA. While this lesion had an irregular surface with overlying vitreoretinal (VR) traction on SD-OCT, the other 2 lesions not detected on FFA were smooth and had no VR traction. After a follow-up to 18 months corrected age, there was no change in the morphology of any of the lesions. CONCLUSIONS: It is possible to characterize retinal hamartomas in infants using SD-OCT and correlate them with FFA. Spectral-domain OCT examination can be used to diagnose and monitor lesions even if they are not detectable on angiography. PMID- 26109025 TI - Which biochemical assay is best for measuring diabetes prevalence? PMID- 26109026 TI - Findings from the National Birth Defects Prevention Study: Interpretation and translation for the clinician. AB - BACKGROUND: The National Birth Defects Prevention Study (NBDPS) is a large U.S. multi-site case-control study first established in 1996 to identify potentially preventable environmental causes and genetic risk factors for more than 30 selected categories of major birth defects. METHODS: Numerous reports with both positive and negative findings have been produced by the NBDPS, and many have influenced clinical practice. Many NBDPS reports have included novel findings, and in some cases these findings could only be considered hypothesis-generating. Other reports have met criteria for causality such as replication of findings in other studies, biological plausibility, and coherence. RESULTS: However, translation of even strongly supported associations, in some cases, has required clinicians to learn to communicate information to patients about small and uncertain absolute risks in the context of the potential effects of under- or poorly treated maternal conditions. CONCLUSION: The NBDPS has continued to play an important role as a rich U.S. data source that can advance the understanding of maternal conditions and their treatments in relation to birth defects. PMID- 26109029 TI - Corrigendum: Conformation-Specific Circular Dichroism Spectroscopy of Cold, Isolated Chiral Molecules. PMID- 26109033 TI - Characterization of the structural defects in CVD-grown monolayered MoS2 using near-field photoluminescence imaging. AB - Structural defects can critically influence the electrical and optical properties of monolayered molybdenum disulfide (MoS2) grown by chemical vapor deposition (CVD); thus, convenient optical methods that can visualize grain boundaries (GBs) and other structural defects are in great demand. Although photoluminescence (PL) imaging can identify the presence of relatively large defects, the limited spatial resolution of PL imaging prevents the identification of nanosized structural defects in the monolayered MoS2. Additionally, the origin of the PL signal contrast observed at certain types of structural defects, such as GBs, is not yet understood. Here, we present near-field PL images of CVD-grown monolayered MoS2, collected to identify nanosized line defects and adlayer defects in the monolayered MoS2. Our results of correlated scanning electron microscopy imaging and the inspection of near-field PL profiles of line defects and GBs suggest that decreased PL on GBs is due to the local physical damage of the MoS2 film rather than due to the presence of localized states. PMID- 26109032 TI - Alteration of the Helicobacter pylori membrane proteome in response to changes in environmental salt concentration. AB - PURPOSE: Helicobacter pylori infection and a high dietary salt intake are each risk factors for the development of gastric cancer. We hypothesize that changes in environmental salt concentrations lead to alterations in the H. pylori membrane proteome. EXPERIMENTAL DESIGN: Label-free and iTRAQ methods were used to identify H. pylori proteins that change in abundance in response to alterations in environmental salt concentrations. In addition, we biotinylated intact bacteria that were grown under high- or low-salt conditions, and thereby analyzed salt-induced changes in the abundance of surface-exposed proteins. RESULTS: Proteins with increased abundance in response to high salt conditions included CagA, the outer membrane protein HopQ, and fibronectin domain-containing protein HP0746. Proteins with increased abundance in response to low salt conditions included VacA, two VacA-like proteins (ImaA and FaaA), outer-membrane iron transporter FecA3, and several proteins involved in flagellar activity. Consistent with the proteomic data, bacteria grown in high salt conditions exhibited decreased motility compared to bacteria grown in lower salt conditions. CONCLUSION AND CLINICAL RELEVANCE: Alterations in the H. pylori membrane proteome in response to high salt conditions may contribute to the increased risk of gastric cancer associated with a high salt diet. PMID- 26109040 TI - Dispersive liquid-liquid microextraction based on amine-functionalized Fe3O4 nanoparticles for the determination of phenolic acids in vegetable oils by high performance liquid chromatography with UV detection. AB - A novel dispersive liquid-liquid microextraction method based on amine functionalized Fe3O4 magnetic nanoparticles was developed for the determination of six phenolic acids in vegetable oils by high-performance liquid chromatography. Amine-functionalized Fe3O4 was synthesized by a one-pot solvothermal reaction between Fe3O4 and 1,6-hexanediamine and characterized by transmission electron microscopy and Fourier transform infrared spectrophotometry. A trace amount of phosphate buffer solution (extractant) was adsorbed on bare Fe3O4-NH2 nanoparticles by hydrophilic interaction to form the "magnetic extractant". Rapid extraction could be achieved while the "magnetic extractant" on amine-functionalized Fe3O4 nanoparticles was dispersed in the sample solution by vortexing. After extraction, the "magnetic extractant" was collected by application of an external magnet. Some important parameters, such as pH and volume of extraction and desorption solvents, the extraction and desorption time needed were carefully investigated and optimized to achieve the best extraction efficiency. Under the optimal conditions, satisfactory extraction recoveries were obtained for the six phenolic acids in the range of 84.2-106.3%. Relative standard deviations for intra- and inter-day precisions were less than 6.3 and 10.0%, respectively. Finally, the established method was successfully applied for the determination of six phenolic acids in eight kinds of vegetable oils. PMID- 26109041 TI - Understanding unmet contraceptive needs among rural Khasi men and women in Meghalaya. AB - There is a global push for increased access to contraception to respond to unmet contraceptive needs. Meghalaya state, with a majority of Indigenous people, has one of the highest unmet contraceptive needs and the lowest contraceptive prevalence rates in India. This qualitative study explores the reasons for the low uptake of contraceptives among Khasi people in a rural district. While policy makers assume that individuals may not be practising family planning because of religion and lack of education, couples actually do use a variety of 'natural' or 'traditional' contraceptive methods to obtain their desired family composition and size. Health providers focus on the provision of hormonal contraceptives, such as the pill, and on technologies such as IUDs and tubectomies that require regular follow-ups by trained medical staff. Health concerns, distrust of contraceptive technologies, the inadequate local health system and a desire to have more than two children are important factors in the low uptake of available contraceptive technologies. Contraceptive choices in rural areas are shaped by the historically problematic political engagement of Indigenous people with the central state, with policy implementation taking place on the basis of widespread assumptions rather than on evidence from contextually relevant behavioural sciences research. PMID- 26109042 TI - Targeting and limiting surgery for patients with node-positive breast cancer. AB - The presence of axillary nodal metastases has a significant impact on locoregional and systemic treatment decisions. Historically, all node-positive patients underwent complete axillary lymph node dissection; however, this paradigm has changed over the last 10 years. The use of sentinel lymph node dissection has expanded from its initial role as a surgical staging procedure in clinically node-negative patients. Clinically node-negative patients with small volume disease found on sentinel lymph node dissection now commonly avoid more extensive axillary surgery. There is interest in expanding this role to node positive patients who receive neoadjuvant chemotherapy as a way to restage the axilla in hopes of sparing women who convert to node-negative status from the morbidity of complete nodal clearance. While sentinel lymph node dissection alone may not accomplish this goal, there are novel techniques, such as targeted axillary dissection, that may now allow for reliable nodal staging after chemotherapy. PMID- 26109043 TI - Differences in survival outcome between stage I and stage II glottic cancer: A SEER-based analysis. AB - OBJECTIVE: The purpose of this study was to investigate and compare the cause specific survival (CSS) of stage I (tumor [T]1 node [N]0 metastasis [M]0) versus stage II (T2N0M0) glottic cancer in a large population cohort. STUDY DESIGN: We analyzed data from the Surveillance, Epidemiology, and End Results 18 database from 1973 to 2009, comprising patients diagnosed with T1N0M0 or T2N0M0 squamous cell glottic cancer. Kaplan-Meier survival analysis, multivariable Cox proportional hazards regression analysis, and competing-risks survival regression were used for statistical analysis. RESULTS: There were 4,422 patients who met all inclusion criteria. The 36-month CSS was 93.9% for stage I verus 86.5% for stage II, with P < 0.0001. Stage II status conferred a 2.494 hazard ratio for increased risk of cause-specific death compared to stage I. CONCLUSIONS: Stage II glottic cancers have a significantly worse prognosis and may need a different approach to management than stage I tumors. LEVEL OF EVIDENCE: 4. PMID- 26109044 TI - Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study. AB - BACKGROUND: Chronic hepatitis C (CHC) is a global health challenge. New therapeutic agents with excellent sustained virological response (SVR) rates are available mainly in developed countries, while the majority of CHC patients live in countries with low health budget. Predictors of therapeutic response are therefore necessary. Vitamin B12 appears to be involved in hepatitis C virus replication. METHODS: We therefore studied retrospectively the relationship between baseline serum vitamin B12 levels and clinical features in 116 CHC genotype 1 infected patients. Logistic regression models with univariate and multivariate analysis were used in the statistical analysis. RESULTS: Baseline serum vitamin B12 levels were found to be positively associated with serum transaminase activities (AST, p = 0.002, ALT, p = 0.04), baseline viral load (p < 0.0001), stage of fibrosis (p = 0.0001) and favorable interferon-lambda3/4 (IFNL3/IFNL4) rs12979860 genotypes (p = 0.04), and inversely with SVR (p < 0.001) as well as with rapid virological response (p = 0.001). Patients with baseline serum vitamin B12 levels below a cut-off value of 570 ng/L achieved a SVR rate of 59% with an odds ratio (OR) of 13.4 [confidence interval (CI) 4.3-41.9, p < 0.0001] compared to patients above the cut-off value. By combining serum vitamin B12 levels and IFNL3/IFNL4 rs12979860 genotypes, patients with baseline serum vitamin B12 levels below the cut-off value of 570 ng/L and IFNL3/IFNL4 rs12979860 CC genotype achieved a SVR rate of even 80% with an OR of 54 (CI 9.9-293, p < 0.0001) compared to patients above the cut-off value and non-CC-genotypes. CONCLUSION: Our data suggest baseline serum vitamin B12 levels as useful noninvasive marker for characterizing CHC patients. They might further help to identify responders to a standard treatment. PMID- 26109024 TI - Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331,288 participants. AB - BACKGROUND: Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA1c. We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. METHODS: We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA1c (HbA1c >=6.5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG >=7.0 mmol/L or 2hOGTT >=11.1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. FINDINGS: Population prevalence of diabetes based on FPG-or 2hOGTT was correlated with prevalence based on FPG alone (r=0.98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA1c was lower than prevalence based on FPG in 42.8% of age-sex-survey groups and higher in another 41.6%; in the other 15.6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA1c-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA1c 6.5% or more had a pooled sensitivity of 52.8% (95% CI 51.3-54.3%) and a pooled specificity of 99.74% (99.71-99.78%) compared with FPG 7.0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30.5% (28.7-32.3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA1c versus FPG. INTERPRETATION: Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA1c-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test. FUNDING: Wellcome Trust, US National Institutes of Health. PMID- 26109045 TI - Antimicrobial mechanism of resveratrol-trans-dihydrodimer produced from peroxidase-catalyzed oxidation of resveratrol. AB - Plant polyphenols are known to have varying antimicrobial potencies, including direct antibacterial activity, synergism with antibiotics and suppression of bacterial virulence. We performed the in vitro oligomerization of resveratrol catalyzed by soybean peroxidase, and the two isomers (resveratrol-trans dihydrodimer and pallidol) produced were tested for antimicrobial activity. The resveratrol-trans-dihydrodimer displayed antimicrobial activity against the Gram positive bacteria Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus (minimum inhibitory concentration (MIC) = 15.0, 125, and 62.0 MUM, respectively) and against Gram-negative Escherichia coli (MIC = 123 MUM, upon addition of the efflux pump inhibitor Phe-Arg-beta-naphthylamide). In contrast, pallidol had no observable antimicrobial activity against all tested strains. Transcriptomic analysis implied downregulation of ABC transporters, genes involved in cell division and DNA binding proteins. Flow cytometric analysis of treated cells revealed a rapid collapse in membrane potential and a substantial decrease in total DNA content. The active dimer showed >90% inhibition of DNA gyrase activity, in vitro, by blocking the ATP binding site of the enzyme. We thus propose that the resveratrol-trans-dihydrodimer acts to: (1) disrupt membrane potential; and (2) inhibit DNA synthesis. In summary, we introduce the mechanisms of action and the initial evaluation of an active bactericide, and a platform for the development of polyphenolic antimicrobials. PMID- 26109047 TI - Intestinal apical polarity mediates regulation of TORC1 by glucosylceramide in C. elegans. AB - TORC1 (target of rapamycin complex 1) plays a central role in regulating growth, development, and behavior in response to nutrient cues. We previously showed that leucine-derived monomethyl branched-chain fatty acids (mmBCFAs) and derived glucosylceramide promote intestinal TORC1 activity for post-embryonic development and foraging behavior in Caenorhabditis elegans. Here we show that clathrin/adaptor protein 1 (AP-1)-dependent intestinal apical membrane polarity and polarity-dependent localization of the vacuolar-type H(+)-ATPase (V-ATPase) mediate the impact of the lipid pathway on intestinal TORC1 activation. Moreover, NPRL-3 represses mmBCFA-dependent intestinal TORC1 activity at least partly by regulating apical membrane polarity. Our results provide new insights into TORC1 regulation by lipids and membrane polarity in a specific tissue. PMID- 26109046 TI - Cancer stem cells in glioblastoma. AB - Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial. PMID- 26109048 TI - Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells. AB - Transcription factor-mediated reprograming is a powerful method to study cell fate changes. In this study, we demonstrate that the transcription factor Gata6 can initiate reprograming of multiple cell types to induced extraembryonic endoderm stem (iXEN) cells. Intriguingly, Gata6 is sufficient to drive iXEN cells from mouse pluripotent cells and differentiated neural cells. Furthermore, GATA6 induction in human embryonic stem (hES) cells also down-regulates pluripotency gene expression and up-regulates extraembryonic endoderm (ExEn) genes, revealing a conserved function in mediating this cell fate switch. Profiling transcriptional changes following Gata6 induction in mES cells reveals step-wise pluripotency factor disengagement, with initial repression of Nanog and Esrrb, then Sox2, and finally Oct4, alongside step-wise activation of ExEn genes. Chromatin immunoprecipitation and subsequent high-throughput sequencing analysis shows Gata6 enrichment near pluripotency and endoderm genes, suggesting that Gata6 functions as both a direct repressor and activator. Together, this demonstrates that Gata6 is a versatile and potent reprograming factor that can act alone to drive a cell fate switch from diverse cell types. PMID- 26109049 TI - DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination. AB - DNA methylation is essential for protecting the mammalian germline against transposons. When DNA methylation-based transposon control is defective, meiotic chromosome pairing is consistently impaired during spermatogenesis: How and why meiosis is vulnerable to transposon activity is unknown. Using two DNA methylation-deficient backgrounds, the Dnmt3L and Miwi2 mutant mice, we reveal that DNA methylation is largely dispensable for silencing transposons before meiosis onset. After this, it becomes crucial to back up to a developmentally programmed H3K9me2 loss. Massive retrotransposition does not occur following transposon derepression, but the meiotic chromatin landscape is profoundly affected. Indeed, H3K4me3 marks gained over transcriptionally active transposons correlate with formation of SPO11-dependent double-strand breaks and recruitment of the DMC1 repair enzyme in Dnmt3L(-/-) meiotic cells, whereas these features are normally exclusive to meiotic recombination hot spots. Here, we demonstrate that DNA methylation restrains transposons from adopting chromatin characteristics amenable to meiotic recombination, which we propose prevents the occurrence of erratic chromosomal events. PMID- 26109051 TI - Homeostatic control of Hippo signaling activity revealed by an endogenous activating mutation in YAP. AB - The Hippo signaling pathway converges on YAP to regulate growth, differentiation, and regeneration. Previous studies with overexpressed proteins have shown that YAP is phosphorylated by its upstream kinase, Lats1/2, on multiple sites, including an evolutionarily conserved 14-3-3-binding site whose phosphorylation is believed to inhibit YAP by excluding it from the nucleus. Indeed, nuclear localization of YAP or decreased YAP phosphorylation at this site (S168 in Drosophila, S127 in humans, and S112 in mice) is widely used in current literature as a surrogate of YAP activation even though the physiological importance of this phosphorylation event in regulating endogenous YAP activity has not been defined. Here we address this question by introducing a Yap(S112A) knock-in mutation in the endogenous Yap locus. The Yap(S112A) mice are surprisingly normal despite nuclear localization of the mutant YAP protein in vivo and profound defects in cytoplasmic translocation in vitro. Interestingly, the mutant Yap(S112A) mice show a compensatory decrease in YAP protein levels due to increased phosphorylation at a mammalian-specific phosphodegron site on YAP. These findings reveal a robust homeostatic mechanism that maintains physiological levels of YAP activity and caution against the assumptive use of YAP localization alone as a surrogate of YAP activity. PMID- 26109050 TI - A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. AB - YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation. PMID- 26109052 TI - Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol. AB - Sirtuins with an extended N-terminal domain (NTD), represented by yeast Sir2 and human SIRT1, harbor intrinsic mechanisms for regulation of their NAD-dependent deacetylase activities. Elucidation of the regulatory mechanisms is crucial for understanding the biological functions of sirtuins and development of potential therapeutics. In particular, SIRT1 has emerged as an attractive therapeutic target, and the search for SIRT1-activating compounds (STACs) has been actively pursued. However, the effectiveness of a class of reported STACs (represented by resveratrol) as direct SIRT1 activators is under debate due to the complication involving the use of fluorogenic substrates in in vitro assays. Future efforts of SIRT1-based therapeutics necessitate the dissection of the molecular mechanism of SIRT1 stimulation. We solved the structure of SIRT1 in complex with resveratrol and a 7-amino-4-methylcoumarin (AMC)-containing peptide. The structure reveals the presence of three resveratrol molecules, two of which mediate the interaction between the AMC peptide and the NTD of SIRT1. The two NTD-bound resveratrol molecules are principally responsible for promoting tighter binding between SIRT1 and the peptide and the stimulation of SIRT1 activity. The structural information provides valuable insights into regulation of SIRT1 activity and should benefit the development of authentic SIRT1 activators. PMID- 26109054 TI - Corrigendum: Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming. PMID- 26109053 TI - Structure-function studies of histone H3/H4 tetramer maintenance during transcription by chaperone Spt2. AB - Cells use specific mechanisms such as histone chaperones to abrogate the inherent barrier that the nucleosome poses to transcribing polymerases. The current model postulates that nucleosomes can be transiently disrupted to accommodate passage of RNA polymerases and that histones H3 and H4 possess their own chaperones dedicated to the recovery of nucleosomes. Here, we determined the crystal structure of the conserved C terminus of human Suppressors of Ty insertions 2 (hSpt2C) chaperone bound to an H3/H4 tetramer. The structural studies demonstrate that hSpt2C is bound to the periphery of the H3/H4 tetramer, mimicking the trajectory of nucleosomal-bound DNA. These structural studies have been complemented with in vitro binding and in vivo functional studies on mutants that disrupt key intermolecular contacts involving two acidic patches and hydrophobic residues on Spt2C. We show that contacts between both human and yeast Spt2C with the H3/H4 tetramer are required for the suppression of H3/H4 exchange as measured by H3K56ac and new H3 deposition. These interactions are also crucial for the inhibition of spurious transcription from within coding regions. Together, our data indicate that Spt2 interacts with the periphery of the H3/H4 tetramer and promotes its recycling in the wake of RNA polymerase. PMID- 26109055 TI - Obsessive-compulsive disorder is a heterogeneous disorder: evidence from diffusion tensor imaging and magnetization transfer imaging. AB - BACKGROUND: Current models of obsessive compulsive disorder (OCD) propose abnormalities of cortico-striatal circuits that involve the orbitofrontal cortex, anterior cingulate cortex, thalamus and the striatum. Nevertheless, during the last years, results of morphometric studies were contradictory. Since fully automated whole-brain voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) are used to assess structural changes in OCD patients, increased consistent evidence has been reported that brain abnormalities are not limited exclusively to the "affective" orbitofronto-striatal circuit. Moreover, several studies conducted using a symptom dimensional approach demonstrated that different symptoms are mediated by distinct neural systems. METHOD: We investigated structural brain abnormalities in 14 carefully selected adult (>=18 years), male and unmedicated patients with OCD - separately for obsession and compulsion scores (Y-BOCS) - compared to 20 healthy controls as reflected according to white matter changes by fractional anisotropy and apparent diffusion coefficient. Moreover, this is the first study in OCD patients, using magnetization transfer imaging (MTI). This method is said to be more sensitive to subtle structural brain changes than conventional volumetric imaging. RESULTS: In our study, we show a positive correlation between MTR and Y-BOCS obsession scores with an increased integrity of tissue structure in the parietal cortex, including myelination and axonal density reflected by the magnetization transfer ratio (MTR) which was used for the first time in our study. Furthermore, Y-BOCS scores for compulsions correlated negatively with ADC-maps in the left nucleus lentiformis and the cingulum. CONCLUSION: The results support the hypothesis that OCD is a heterogeneous disorder with distinct neural correlates across symptom dimensions and call for a substantial revision of such a model that takes into account the heterogeneity of the disorder. PMID- 26109057 TI - Silicon carbide-free graphene growth on silicon for lithium-ion battery with high volumetric energy density. AB - Silicon is receiving discernable attention as an active material for next generation lithium-ion battery anodes because of its unparalleled gravimetric capacity. However, the large volume change of silicon over charge-discharge cycles weakens its competitiveness in the volumetric energy density and cycle life. Here we report direct graphene growth over silicon nanoparticles without silicon carbide formation. The graphene layers anchored onto the silicon surface accommodate the volume expansion of silicon via a sliding process between adjacent graphene layers. When paired with a commercial lithium cobalt oxide cathode, the silicon carbide-free graphene coating allows the full cell to reach volumetric energy densities of 972 and 700 Wh l(-1) at first and 200th cycle, respectively, 1.8 and 1.5 times higher than those of current commercial lithium ion batteries. This observation suggests that two-dimensional layered structure of graphene and its silicon carbide-free integration with silicon can serve as a prototype in advancing silicon anodes to commercially viable technology. PMID- 26109059 TI - Peter Hindley: Warm, energetic, positive. PMID- 26109058 TI - Nuclear respiratory factor 2 induces SIRT3 expression. AB - The mitochondrial deacetylase SIRT3 regulates several important metabolic processes. SIRT3 is transcriptionally upregulated in multiple tissues during nutrient stresses such as dietary restriction and fasting, but the molecular mechanism of this induction is unclear. We conducted a bioinformatic study to identify transcription factor(s) involved in SIRT3 induction. Our analysis identified an enrichment of binding sites for nuclear respiratory factor 2 (NRF 2), a transcription factor known to play a role in the expression of mitochondrial genes, in the DNA sequences of SIRT3 and genes with closely correlated expression patterns. In vitro, knockdown or overexpression of NRF-2 modulated SIRT3 levels, and the NRF-2alpha subunit directly bound to the SIRT3 promoter. Our results suggest that NRF-2 is a regulator of SIRT3 expression and may shed light on how SIRT3 is upregulated during nutrient stress. PMID- 26109056 TI - Comparison of RNA-seq and microarray-based models for clinical endpoint prediction. AB - BACKGROUND: Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. RESULTS: We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. CONCLUSIONS: We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice. PMID- 26109060 TI - Prognostic and clinical significance of claudin-4 in gastric cancer: a meta analysis. AB - BACKGROUND: The current reports on the association of claudin-4 expression with gastric cancer outcome were inconsistent. Thus, we conducted a meta-analysis to assess the association of claudin-4 expression with the prognosis and clinical parameters more precisely. METHODS: Systematic searches on PubMed, Embase, and Cochrane Library prior to December 2014 were performed. The pooled hazard ratio (HR) with its 95 % confidence interval (95 %CI) was used to assess the prognostic value of claudin-4 expression with gastric cancer patients, and the pooled odds ratio (OR) with its 95 %CI was used to assess the association with clinical parameters. RESULTS: Nine studies with a total of 1265 gastric cancer patients were included. Overall, the pooled results showed that over-expression of claudin 4 was associated with a poor survival in gastric cancer patients (HR: 2.01, 95 % CI: 1.62-2.50). Over-expression of claudin-4 was also associated with advanced stage (OR: 1.96, 95 % CI: 1.08-3.56) and lymphoid node metastasis (OR: 1.72, 95 % CI: 1.05-2.81) of gastric cancer patients. No significant publication bias was found among the studies (P > 0.05). CONCLUSIONS: This meta-analysis shows that over-expression of claudin-4 is associated with progress of gastric cancer and poor prognosis of gastric cancer patients. PMID- 26109061 TI - The human cardiac and skeletal muscle proteomes defined by transcriptomics and antibody-based profiling. AB - BACKGROUND: To understand cardiac and skeletal muscle function, it is important to define and explore their molecular constituents and also to identify similarities and differences in the gene expression in these two different striated muscle tissues. Here, we have investigated the genes and proteins with elevated expression in cardiac and skeletal muscle in relation to all other major human tissues and organs using a global transcriptomics analysis complemented with antibody-based profiling to localize the corresponding proteins on a single cell level. RESULTS: Our study identified a comprehensive list of genes expressed in cardiac and skeletal muscle. The genes with elevated expression were further stratified according to their global expression pattern across the human body as well as their precise localization in the muscle tissues. The functions of the proteins encoded by the elevated genes are well in line with the physiological functions of cardiac and skeletal muscle, such as contraction, ion transport, regulation of membrane potential and actomyosin structure organization. A large fraction of the transcripts in both cardiac and skeletal muscle correspond to mitochondrial proteins involved in energy metabolism, which demonstrates the extreme specialization of these muscle tissues to provide energy for contraction. CONCLUSIONS: Our results provide a comprehensive list of genes and proteins elevated in striated muscles. A number of proteins not previously characterized in cardiac and skeletal muscle were identified and localized to specific cellular subcompartments. These proteins represent an interesting starting point for further functional analysis of their role in muscle biology and disease. PMID- 26109062 TI - Differentially Expressed MicroRNA-483 Confers Distinct Functions in Pancreatic beta- and alpha-Cells. AB - Insulin secreted from pancreatic beta-cells and glucagon secreted from pancreatic alpha-cells are the two major hormones working in the pancreas in an opposing manner to regulate and maintain a normal glucose homeostasis. How microRNAs (miRNAs), a population of non-coding RNAs so far demonstrated to be differentially expressed in various types of cells, regulate gene expression in pancreatic beta-cells and its closely associated alpha-cells is not completely clear. In this study, miRNA profiling was performed and compared between pancreatic beta-cells and their partner alpha-cells. One novel miRNA, miR-483, was identified for its highly differential expression in pancreatic beta-cells when compared to its expression in alpha-cells. Overexpression of miR-483 in beta cells increased insulin transcription and secretion by targeting SOCS3, a member of suppressor of cytokine signaling family. In contrast, overexpression of miR 483 decreased glucagon transcription and secretion in alpha-cells. Moreover, overexpressed miR-483 protected against proinflammatory cytokine-induced apoptosis in beta-cells. This correlates with a higher expression level of miR 483 and the expanded beta-cell mass observed in the islets of prediabetic db/db mice. Together, our data suggest that miR-483 has opposite effects in alpha- and beta-cells by targeting SOCS3, and the imbalance of miR-483 and its targets may play a crucial role in diabetes pathogenesis. PMID- 26109063 TI - Distribution and Function of Cardiac Ryanodine Receptor Clusters in Live Ventricular Myocytes. AB - The cardiac Ca(2+) release channel (ryanodine receptor, RyR2) plays an essential role in excitation-contraction coupling in cardiac muscle cells. Effective and stable excitation-contraction coupling critically depends not only on the expression of RyR2, but also on its distribution. Despite its importance, little is known about the distribution and organization of RyR2 in living cells. To study the distribution of RyR2 in living cardiomyocytes, we generated a knock-in mouse model expressing a GFP-tagged RyR2 (GFP-RyR2). Confocal imaging of live ventricular myocytes isolated from the GFP-RyR2 mouse heart revealed clusters of GFP-RyR2 organized in rows with a striated pattern. Similar organization of GFP RyR2 clusters was observed in fixed ventricular myocytes. Immunofluorescence staining with the anti-alpha-actinin antibody (a z-line marker) showed that nearly all GFP-RyR2 clusters were localized in the z-line zone. There were small regions with dislocated GFP-RyR2 clusters. Interestingly, these same regions also displayed dislocated z-lines. Staining with di-8-ANEPPS revealed that nearly all GFP-RyR2 clusters were co-localized with transverse but not longitudinal tubules, whereas staining with MitoTracker Red showed that GFP-RyR2 clusters were not co localized with mitochondria in live ventricular myocytes. We also found GFP-RyR2 clusters interspersed between z-lines only at the periphery of live ventricular myocytes. Simultaneous detection of GFP-RyR2 clusters and Ca(2+) sparks showed that Ca(2+) sparks originated exclusively from RyR2 clusters. Ca(2+) sparks from RyR2 clusters induced no detectable changes in mitochondrial Ca(2+) level. These results reveal, for the first time, the distribution of RyR2 clusters and its functional correlation in living ventricular myocytes. PMID- 26109064 TI - Identification of the Docking Site for CD3 on the T Cell Receptor beta Chain by Solution NMR. AB - The T cell receptor (TCR)-CD3 complex is composed of a genetically diverse alphabeta TCR heterodimer associated noncovalently with the invariant CD3 dimers CD3epsilongamma, CD3epsilondelta, and CD3zetazeta. The TCR mediates peptide-MHC recognition, whereas the CD3 molecules transduce activation signals to the T cell. Although much is known about downstream T cell signaling pathways, the mechanism whereby TCR engagement by peptide-MHC initiates signaling is poorly understood. A key to solving this problem is defining the spatial organization of the TCR-CD3 complex and the interactions between its subunits. We have applied solution NMR methods to identify the docking site for CD3 on the beta chain of a human autoimmune TCR. We demonstrate a low affinity but highly specific interaction between the extracellular domains of CD3 and the TCR constant beta (Cbeta) domain that requires both CD3epsilongamma and CD3epsilondelta subunits. The mainly hydrophilic docking site, comprising 9-11 solvent-accessible Cbeta residues, is relatively small (~400 A(2)), consistent with the weak interaction between TCR and CD3 extracellular domains, and devoid of glycosylation sites. The docking site is centered on the alphaA and alphaB helices of Cbeta, which are located at the base of the TCR. This positions CD3epsilongamma and CD3epsilondelta between the TCR and the T cell membrane, permitting us to distinguish among several possible models of TCR-CD3 association. We further correlate structural results from NMR with mutational data on TCR-CD3 interactions from cell-based assays. PMID- 26109065 TI - The Tubular Sheaths Encasing Methanosaeta thermophila Filaments Are Functional Amyloids. AB - Archaea are renowned for their ability to thrive in extreme environments, although they can be found in virtually all habitats. Their adaptive success is linked to their unique cell envelopes that are extremely resistant to chemical and thermal denaturation and that resist proteolysis by common proteases. Here we employ amyloid-specific conformation antibodies and biophysical techniques to show that the extracellular cell wall sheaths encasing the methanogenic archaea Methanosaeta thermophila PT are functional amyloids. Depolymerization of sheaths and subsequent MS/MS analyses revealed that the sheaths are composed of a single major sheath protein (MspA). The amyloidogenic nature of MspA was confirmed by in vitro amyloid formation of recombinant MspA under a wide range of environmental conditions. This is the first report of a functional amyloid from the archaeal domain of life. The amyloid nature explains the extreme resistance of the sheath, the elastic properties that allow diffusible substrates to penetrate through expandable hoop boundaries, and how the sheaths are able to split and elongate outside the cell. The archaeal sheath amyloids do not share homology with any of the currently known functional amyloids and clearly represent a new function of the amyloid protein fold. PMID- 26109066 TI - Role of Deacetylase Activity of N-Deacetylase/N-Sulfotransferase 1 in Forming N Sulfated Domain in Heparan Sulfate. AB - Heparan sulfate (HS) is a highly sulfated polysaccharide that plays important physiological roles. The biosynthesis of HS involves a series of enzymes, including glycosyltransferases (or HS polymerase), epimerase, and sulfotransferases. N-Deacetylase/N-Sulfotransferase isoform 1 (NDST-1) is a critical enzyme in this pathway. NDST-1, a bifunctional enzyme, displays N deacetylase and N-sulfotransferase activities to convert an N-acetylated glucosamine residue to an N-sulfo glucosamine residue. Here, we report the cooperative effects between N-deacetylase and N-sulfotransferase activities. Using baculovirus expression in insect cells, we obtained three recombinant proteins: full-length NDST-1 and the individual N-deacetylase and N sulfotransferase domains. Structurally defined oligosaccharide substrates were synthesized to test the substrate specificities of the enzymes. We discovered that N-deacetylation is the limiting step and that interplay between the N sulfotransferase and N-deacetylase accelerates the reaction. Furthermore, combining the individually expressed N-deacetylase and N-sulfotransferase domains produced different sulfation patterns when compared with that made by the NDST-1 enzyme. Our data demonstrate the essential role of domain cooperation within NDST 1 in producing HS with specific domain structures. PMID- 26109067 TI - Wnt/beta-Catenin Mediates AICAR Effect to Increase GATA3 Expression and Inhibit Adipogenesis. AB - A better understanding of the mechanism and manipulation of the tightly regulated cellular differentiation process of adipogenesis may contribute to a reduction in obesity and diabetes. Multiple transcription factors and signaling pathways are involved in the regulation of adipogenesis. Here, we report that the AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) can activate AMPK in preadipocytes and thus increase the expression of GATA3, an anti-adipogenic factor. However, AICAR-increased GATA3 is mediated by the stimulation of Wnt/beta-catenin signaling in preadipocytes. Mechanistically, AICAR-activated AMPK inhibits GSK3beta through a phosphorylation process that stabilizes beta-catenin. This stabilized beta-catenin then translocates into nucleus where it interacts with T-cell factors (TCF), leading to the increased beta-catenin/TCF transcriptional activity that induces GATA3 expression. In addition, AICAR also relieves the repressing effect of the C-terminal-binding protein (CtBP) co-repressor by diverting CtBP away from the beta-catenin.TCF complex at the GATA3 promoter. The anti-adipogenic effect of GATA3 and AICAR is consistently attenuated by the disruption of Wnt/beta-catenin signaling. Furthermore, GATA3 suppresses key adipogenic regulators by binding to the promoters of these regulators, such as the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene, and the disruption of Wnt/beta-catenin signaling reduces the GATA3 binding at the PPARgamma promoter. In differentiated adipocytes, GATA3 expression inhibition is facilitated by the down-regulation of beta-catenin levels, the reduction in beta-catenin binding, and the increase in CtBP binding at the GATA3 promoter. Our findings shed light on the molecular mechanism of adipogenesis by suggesting that different regulation pathways and adipogenic regulators collectively modulate adipocyte differentiation through cross-talk. PMID- 26109068 TI - Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis. AB - Gene-environment interactions determine the biological outcomes through mechanisms that are poorly understood. Mouse embryonic eyelid closure is a well defined model to study the genetic control of developmental programs. Using this model, we investigated how exposure to dioxin-like environmental pollutants modifies the genetic risk of developmental abnormalities. Our studies reveal that mitogen-activated protein 3 kinase 1 (MAP3K1) signaling is a focal point of gene environment cross-talk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocked eyelid closure in genetic mutants in which MAP3K1 signaling was attenuated but did not disturb this developmental program in either wild type or mutant mice with attenuated epidermal growth factor receptor or WNT signaling. Exposure also markedly inhibited c-Jun phosphorylation in Map3k1(+/-) embryonic eyelid epithelium, suggesting that dioxin-induced AHR pathways can synergize with gene mutations to inhibit MAP3K1 signaling. Our studies uncover a novel mechanism through which the dioxin-AHR axis interacts with the MAP3K1 signaling pathways during fetal development and provide strong empirical evidence that specific gene alterations can increase the risk of developmental abnormalities driven by environmental pollutant exposure. PMID- 26109069 TI - Factor B Is the Second Lipopolysaccharide-binding Protease Zymogen in the Horseshoe Crab Coagulation Cascade. AB - Factor B is a serine-protease zymogen in the horseshoe crab coagulation cascade, and it is the primary substrate for activated factor C, the LPS-responsive initiator of the cascade. Factor C is autocatalytically activated to alpha-factor C on LPS and is artificially converted to beta-factor C, another activated form, by chymotrypsin. It is not known, however, whether LPS is required for the activation of factor B. Here we found that wild-type factor B expressed in HEK293S cells is activated by alpha-factor C, but not by beta-factor C, in an LPS dependent manner and that beta-factor C loses the LPS binding activity of factor C through additional cleavage by chymotrypsin within the N-terminal LPS-binding region. Surface plasmon resonance and quartz crystal microbalance analyses revealed that wild-type factor B binds to LPS with high affinity comparable with that of factor C, demonstrating that factor B is the second LPS-binding zymogen in the cascade. An LPS-binding site of wild-type factor B was found in the N terminal clip domain, and the activation rate of a clip domain deletion mutant was considerably slower than that of wild-type factor B. Moreover, in the presence of LPS, Triton X-100 inhibited the activation of wild-type factor B by alpha-factor C. We conclude that the clip domain of factor B has an important role in localizing factor B to the surface of Gram-negative bacteria or LPS released from bacteria to initiate effective proteolytic activation by alpha factor C. PMID- 26109070 TI - Generating a Metal-responsive Transcriptional Regulator to Test What Confers Metal Sensing in Cells. AB - FrmR from Salmonella enterica serovar typhimurium (a CsoR/RcnR-like transcriptional de-repressor) is shown to repress the frmRA operator-promoter, and repression is alleviated by formaldehyde but not manganese, iron, cobalt, nickel, copper, or Zn(II) within cells. In contrast, repression by a mutant FrmRE64H (which gains an RcnR metal ligand) is alleviated by cobalt and Zn(II). Unexpectedly, FrmR was found to already bind Co(II), Zn(II), and Cu(I), and moreover metals, as well as formaldehyde, trigger an allosteric response that weakens DNA affinity. However, the sensory metal sites of the cells' endogenous metal sensors (RcnR, ZntR, Zur, and CueR) are all tighter than FrmR for their cognate metals. Furthermore, the endogenous metal sensors are shown to out compete FrmR. The metal-sensing FrmRE64H mutant has tighter metal affinities than FrmR by approximately 1 order of magnitude. Gain of cobalt sensing by FrmRE64H remains enigmatic because the cobalt affinity of FrmRE64H is substantially weaker than that of the endogenous cobalt sensor. Cobalt sensing requires glutathione, which may assist cobalt access, conferring a kinetic advantage. For Zn(II), the metal affinity of FrmRE64H approaches the metal affinities of cognate Zn(II) sensors. Counter-intuitively, the allosteric coupling free energy for Zn(II) is smaller in metal-sensing FrmRE64H compared with nonsensing FrmR. By determining the copies of FrmR and FrmRE64H tetramers per cell, then estimating promoter occupancy as a function of intracellular Zn(II) concentration, we show how a modest tightening of Zn(II) affinity, plus weakened DNA affinity of the apoprotein, conspires to make the relative properties of FrmRE64H (compared with ZntR and Zur) sufficient to sense Zn(II) inside cells. PMID- 26109071 TI - RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3. AB - Fibroblast growth factor receptors (FGFRs) are involved in proliferative and differentiation physiological responses. Deregulation of FGFR-mediated signaling involving the Ras/PI3K/Akt and the Ras/Raf/ERK MAPK pathways is causally involved in the development of several cancers. The caspase-3/p120 RasGAP module is a stress sensor switch. Under mild stress conditions, RasGAP is cleaved by caspase 3 at position 455. The resulting N-terminal fragment, called fragment N, stimulates anti-death signaling. When caspase-3 activity further increases, fragment N is cleaved at position 157. This generates a fragment, called N2, that no longer protects cells. Here, we investigated in Xenopus oocytes the impact of RasGAP and its fragments on FGF1-mediated signaling during G2/M cell cycle transition. RasGAP used its N-terminal Src homology 2 domain to bind FGFR once stimulated by FGF1, and this was necessary for the recruitment of Akt to the FGFR complex. Fragment N, which did not associate with the FGFR complex, favored FGF1 induced ERK stimulation, leading to accelerated G2/M transition. In contrast, fragment N2 bound the FGFR, and this inhibited mTORC2-dependent Akt Ser-473 phosphorylation and ERK2 phosphorylation but not phosphorylation of Akt on Thr 308. This also blocked cell cycle progression. Inhibition of Akt Ser-473 phosphorylation and entry into G2/M was relieved by PHLPP phosphatase inhibition. Hence, full-length RasGAP favors Akt activity by shielding it from deactivating phosphatases. This shielding was abrogated by fragment N2. These results highlight the role played by RasGAP in FGFR signaling and how graded stress intensities, by generating different RasGAP fragments, can positively or negatively impact this signaling. PMID- 26109073 TI - Resveratrol nanoformulation for cancer prevention and therapy. AB - Chemoprevention of human cancer(s) is a viable option for cancer control, especially when chemopreventive intervention is involved during the early stages of the carcinogenesis process. Naturally occurring bioactive food components, such as dietary polyphenols, have shown good antioxidant activity and other beneficial activities. In addition, compounds belonging to the polyphenolic chemical class may play promising roles in cancer prevention. Among them, the phytoalexin resveratrol has demonstrated antiproliferative effects, as well as the ability to inhibit initiation and promotion of induced cancer progression in a wide variety of tumor models. However, resveratrol, like other natural polyphenols, is an extremely photosensitive compound with low chemical stability and limited bioavailibility, which limit the therapeutic application of its beneficial effects. In this context, the development of innovative formulation strategies able to overcome physicochemical and pharmacokinetic limitations of this compound could be beneficial. This may be achieved via nanotechnology approaches utilizing suitable carriers that allow slow, sustained, and controlled release of the encapsulated agent. This review focuses on the recent developments of novel nanoformulations used to deliver sustained levels of resveratrol. PMID- 26109074 TI - Where does the carbon go?--Plant carbon allocation under climate change. PMID- 26109072 TI - A Vaccine Approach for the Prevention of Infections by Multidrug-resistant Enterococcus faecium. AB - The incidence of multidrug-resistant Enterococcus faecium hospital infections has been steadily increasing. With the goal of discovering new vaccine antigens, we systematically fractionated and purified four distinct surface carbohydrates from E. faecium endocarditis isolate Tx16, shown previously to be resistant to phagocytosis in the presence of human serum. The two most abundant polysaccharides consist of novel branched heteroglycan repeating units that include signature sugars altruronic acid and legionaminic acid, respectively. A minor high molecular weight polysaccharide component was recognized as the fructose homopolymer levan, and a glucosylated lipoteichoic acid (LTA) was identified in a micellar fraction. The polysaccharides were conjugated to the CRM197 carrier protein, and the resulting glycoconjugates were used to immunize rabbits. Rabbit immune sera were evaluated for their ability to kill Tx16 in opsonophagocytic assays and in a mouse passive protection infection model. Although antibodies raised against levan failed to mediate opsonophagocytic killing, the other glycoconjugates induced effective opsonic antibodies, with the altruronic acid-containing polysaccharide antisera showing the greatest opsonophagocytic assay activity. Antibodies directed against either novel heteroglycan or the LTA reduced bacterial load in mouse liver or kidney tissue. To assess antigen prevalence, we screened a diverse collection of blood isolates (n = 101) with antibodies to the polysaccharides. LTA was detected on the surface of 80% of the strains, and antigens recognized by antibodies to the two major heteroglycans were co-expressed on 63% of these clinical isolates. Collectively, these results represent the first steps toward identifying components of a glycoconjugate vaccine to prevent E. faecium infection. PMID- 26109075 TI - Molecular typing of clinical isolates of Cryptococcus neoformans/Cryptococcus gattii species complex from Northeast Mexico. AB - Cryptococcosis is caused by members of the Cryptococcus neoformans/Cryptococcus gattii species complex. Based on molecular identification, these two species have been further differentiated into molecular types. The aim of this work was to characterize clinical cryptococcal isolates recovered from six hospitals in Northeast Mexico from 1995 to 2011. One hundred and sixty-six isolates, which were characterized by biochemical tests and in vitro susceptibility to amphotericin B, fluconazole, and voriconazole, and M13 PCR fingerprinting, were included in this study. Utilizing phenotypic tests, 153 isolates (92.16 %) were identified as C. neoformans and 13 (7.83 %) as C. gattii. All isolates were susceptible to all antifungals tested. Employing M13 PCR fingerprinting, eight molecular types were detected. VNI was the most common genotype (124 cases; 74.6 %), followed by VNII (15 cases; 9 %), VNIII (8 cases; 4.8 %), VNIV (6 cases; 3.6 %), VGI (6 cases; 3.6 %), VGII (3 cases; 1.8 %), and VGIII and VGIV (2 cases, 1.2 % each). We confirm the presence of C. gattii in clinical isolates in Northeast Mexico, and a high clonal diversity in the studied strains of C. neoformans/C. gattii species complex. PMID- 26109076 TI - A proposal for scientific framework enabling specific population drug dosing recommendations. AB - Over the last 3 decades, there has been little change in the paradigm to derive dosing recommendations for specific populations (e.g., renal failure, elderly, or obese patients) despite better understanding of clearance pathways in these groups and availability of modeling and simulation tools. Dosing recommendations for specific populations are often incomplete or unavailable at the time of drug approval. Currently, there is no regulatory framework to incorporate model-based dosing recommendations for specific populations. This paper proposes a scientific framework for using modeling and simulation to support specific population dosing recommendations. This framework creates a knowledgebase of drug and population attributes where model-based approaches can be developed to inform dosing recommendations. The framework may benefit patients by having reliable dosing information at the time of drug approval. Patients with conditions where studies are difficult to perform would benefit from dosing based on state-of-the-art knowledge. Industry and regulators would benefit from a scientific and efficient approach to improve specific population prediction. A research approach to determine specific population dose prediction is discussed along with challenges and risks. We hope to initiate a dialogue to explore the role of modeling based on data for drugs with similar clearance mechanisms to predict drug dosing. PMID- 26109077 TI - Border control: Anatomical origins of the thymus medulla. AB - The thymus is an anatomically compartmentalized primary lymphoid organ that fosters the production of self-tolerant T cells. The thymic cortex provides a specialized microenvironment in which cortical thymic epithelial cells (cTECs) support the positive selection and further differentiation of self-MHC-restricted thymocytes. Following their migration into the medulla, positively selected thymocytes are further screened for self-reactivity, which involves both negative selection and Foxp3(+) regulatory T cell generation via interactions with medullary thymic epithelial cells (mTECs). Given the importance of both cortical and medullary microenvironments for T cell development, studies that address the developmental origins of cTECs and mTECs are important in understanding the processes that shape the developing T cell receptor repertoire, and reduce the frequency of self-reactive T cells that initiate autoimmune disease. In this issue of the European Journal of Immunology, Onder et al. [Eur. J. Immunol. 2015. 45: 2218-2231] identified a subset of podoplanin(+) mTECs in mice that reside at the corticomedullary junction (CMJ), show that their development is important to establish self-tolerance, and require the presence of self-reactive T cells. Collectively, their findings highlight the CMJ as a potential repository for precursors of the mTEC lineage, and provide a better understanding of thymus medulla formation. PMID- 26109078 TI - Identification of snake arenaviruses in live boas and pythons in a zoo in Germany. AB - OBJECTIVE: Recent studies have described the detection and characterisation of new, snake specific arenaviruses in boas and pythons with inclusion body disease (IBD). The objective of this study was to detect arenaviral RNA in live snakes and to determine if these were associated with IBD in all cases. Samples for arenavirus detection in live animals were compared. Detected viruses were compared in order to understand their genetic variability. MATERIALS AND METHODS: Esophageal swabs and whole blood was collected from a total of 28 boas and pythons. Samples were tested for arenaviral RNA by RT-PCR. Blood smears from all animals were examined for the presence of inclusion bodies. Internal tissues from animals that died or were euthanized during the study were examined for inclusions and via RT-PCR for arenaviral RNA. All PCR products were sequenced and the genomic sequences phylogenetically analysed. RESULTS: Nine live animals were found to be arenavirus-positive. Two additional snakes tested positive following necropsy. Five new arenaviruses were detected and identified. The detected viruses were named "Boa Arenavirus Deutschland (Boa Av DE) numbers 1-4" and one virus detected in a python (Morelia viridis) was named "Python Av DE1". Results from sequence analyses revealed considerable similarities to a portion of the glycoprotein genes of recently identified boid snake arenaviruses. CONCLUSIONS: Both oral swabs and whole blood can be used for the detection of arenaviruses in snakes. In most cases, but not in all, the presence of arenaviral RNA correlated with the presence of inclusions in the tissues of infected animals. There was evidence that some animals may be able to clear arenavirus infection without development of IBD. This is the first detection of arenaviruses in live snakes. CLINICAL RELEVANCE: The detection of arenaviruses in live snakes is of importance for both disease detection and prevention and for use in quarantine situations. The findings in this study support the theory that arenaviruses are the cause of IBD, but indicate that in some cases it may be possible for animals to clear arenavirus infections without developing IBD. PMID- 26109079 TI - A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. AB - Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously. PMID- 26109080 TI - Experimental Realization of Extreme Heat Flux Concentration with Easy-to-Make Thermal Metamaterials. AB - The ability to harvest thermal energy and manipulate heat fluxes has recently attracted a great deal of research interest because this is critical to achieve efficient solar-to-thermal energy conversion in the technology of concentrated solar thermal collectors. Thermal metamaterials with engineered thermal conduction are often utilized to control the diffusive heat flow in ways otherwise not possible with naturally occurring materials. In this work, we adopt the transformation thermodynamics approach to design an annular fan-shaped thermal metamaterial which is capable of guiding heat fluxes and concentrating thermal energy to the central region of the metamaterial device without disturbing the temperature profile outside the structure--a fascinating and unique feature impossibly achieved with homogeneous materials. In experiment, this rationally-designed metamaterial structure demonstrates extreme heat flux compression from both line-shaped and point thermal sources with measured concentration efficiency up to 83.1%, providing the first experimental realization of our recent theoretical prediction (T. Han et al., Energy Environ. Sci., 2013, 6, 3537-3541). These unprecedented results may open up new possibilities for engineering thermal materials with desired properties that can be used for dramatically enhancing the efficiency of the existing solar thermal collectors. PMID- 26109081 TI - From lime to silica and alumina: systematic modeling of cement clinkers using a general force-field. AB - Thirteen different cement-clinker crystalline phases present in the lime-silica alumina system have been systematically modeled using a simple and general force field. This constitutes a new type of approach towards the study of lime-silica alumina systems, where the simpler and more transferable Lennard-Jones potential was used instead of the more traditional Buckingham potential. The results were validated using experimental density and structural data. The elastic properties were also considered. Six amorphous phases (corresponding to calcium/silicon ratios corresponding to belite, rankinite, wollastonite and alumina-doped amorphous wollastonite with 5%, 10% and 15% alumina content) were also studied using molecular dynamics simulations. The obtained MD trajectories were used to characterize the different crystalline and amorphous phases in terms of the corresponding radial distribution functions, aggregate analyses and connectivity among silica groups. These studies allowed a direct comparison between the crystalline and amorphous phases and revealed how the structure of the silica network was modified in the amorphous materials or by the inclusion of other structural units such as alumina. The knowledge at an atomistic level of such modifications is paramount for the formulation of new cement-clinker phases. PMID- 26109082 TI - Participation in college laboratory research apprenticeships among students considering careers in medicine. AB - OBJECTIVE: We sought to determine the prevalence of college laboratory research apprenticeship (CLRA) participation among students considering medical careers and to examine the relationship between CLRA participation and medical-school acceptance among students who applied to medical school. METHODS: We used multivariate logistic regression to identify predictors of: 1) CLRA participation in a national cohort of 2001-2006 Pre-Medical College Admission Test (MCAT) Questionnaire (PMQ) respondents and 2) among those PMQ respondents who subsequently applied to medical school, medical-school acceptance by June 2013, reporting adjusted odds ratios (aOR) and 95% confidence intervals (95% CI). RESULTS: Of 213,497 PMQ respondents in the study sample (81.2% of all 262,813 PMQ respondents in 2001-2006), 72,797 (34.1%) reported CLRA participation. Each of under-represented minorities in medicine (URM) race/ethnicity (vs. white, aOR: 1.04; 95% CI: 1.01-1.06), Asian/Pacific Islander race/ethnicity (vs. white, aOR: 1.20; 95% CI: 1.17-1.22), and high school summer laboratory research apprenticeship (HSLRA) participation (aOR: 3.95; 95% CI: 3.84-4.07) predicted a greater likelihood of CLRA participation. Of the 213,497 PMQ respondents in the study sample, 144,473 (67.7%) had applied to medical school and 87,368 (60.5% of 144,473 medical-school applicants) had been accepted to medical school. Each of female gender (vs. male, aOR: 1.19; 95% CI: 1.16-1.22), URM race/ethnicity (vs. white, aOR: 3.91; 95% CI: 3.75-4.08), HSLRA participation (aOR: 1.11; 95% CI: 1.03-1.19), CLRA participation (aOR: 1.12; 95% CI: 1.09-1.15), college summer academic enrichment program participation (aOR: 1.26; 95% CI: 1.21-1.31), and higher MCAT score (per point increase, aOR: 1.31; 95% CI: 1.30-1.31) predicted a greater likelihood of medical-school acceptance. CONCLUSIONS: About one-third of all PMQ respondents had participated in CLRAs prior to taking the MCAT, and such participation was one of the several variables identified that were independently associated with medical-school acceptance. PMID- 26109084 TI - Acantholytic squamous cell carcinoma of the lung showing significant signet ring cell component. PMID- 26109083 TI - Evaluating the accuracy of the XVI dual registration tool compared with manual soft tissue matching to localise tumour volumes for post-prostatectomy patients receiving radiotherapy. AB - INTRODUCTION: Cone beam computerised tomography (CBCT) enables soft tissue visualisation to optimise matching in the post-prostatectomy setting, but is associated with inter-observer variability. This study assessed the accuracy and consistency of automated soft tissue localisation using XVI's dual registration tool (DRT). METHODS: Sixty CBCT images from ten post-prostatectomy patients were matched using: (i) the DRT and (ii) manual soft tissue registration by six radiation therapists (RTs). Shifts in the three Cartesian planes were recorded. The accuracy of the match was determined by comparing shifts to matches performed by two genitourinary radiation oncologists (ROs). A Bland-Altman method was used to assess the 95% levels of agreement (LoA). A clinical threshold of 3 mm was used to define equivalence between methods of matching. RESULTS: The 95% LoA between DRT-ROs in the superior/inferior, left/right and anterior/posterior directions were -2.21 to +3.18 mm, -0.77 to +0.84 mm, and -1.52 to +4.12 mm, respectively. The 95% LoA between RTs-ROs in the superior/inferior, left/right and anterior/posterior directions were -1.89 to +1.86 mm, -0.71 to +0.62 mm and 2.8 to +3.43 mm, respectively. Five DRT CBCT matches (8.33%) were outside the 3 mm threshold, all in the setting of bladder underfilling or rectal gas. The mean time for manual matching was 82 versus 65 s for DRT. CONCLUSIONS: XVI's DRT is comparable with RTs manually matching soft tissue on CBCT. The DRT can minimise RT inter-observer variability; however, involuntary bladder and rectal filling can influence the tools accuracy, highlighting the need for RT evaluation of the DRT match. PMID- 26109085 TI - Improving stability of elastic stable intramedullary nailing in a transverse midshaft femur fracture model: biomechanical analysis of using end caps or a third nail. AB - BACKGROUND: Elastic stable intramedullary nailing (ESIN) is accepted widely for treatment of diaphyseal femur fractures in children. However, complication rates of 10 to 50 % are described due to shortening or axial deviation, especially in older or heavier children. Biomechanical in vitro testing was performed to determine whether two modified osteosyntheses with end caps or a third nail could significantly improve the stability in comparison to classical elastic stable intramedullary nailing in a transverse femur fracture model. METHODS: We performed biomechanical testing in 24 synthetic adolescent femoral bone models (Sawbones(r)) with a transverse midshaft (diaphyseal) fracture. First, in all models, two nails were inserted in a C-shaped manner (2 * 3.5 mm steel nails, prebent), then eight osteosyntheses were modified by using end caps and another eight by adding a third nail from the antero-lateral (2.5-mm steel, not prebent). Testing was performed in four-point bending, torsion, and shifting under physiological 9 degrees compression. RESULTS: The third nail from the lateral showed a significant positive influence on the stiffness in all four-point bendings as well as in internal rotation comparing to the classical 2C configuration: mean values were significantly higher anterior-posterior (1.04 vs. 0.52 Nm/mm, p < 0.001), posterior-anterior (0.85 vs. 0.43 Nm/mm, p < 0.001), lateral-medial (1.26 vs. 0.70 Nm/mm, p < 0.001), and medial-lateral (1.16 vs. 0.76 Nm/mm, p < 0.001) and during internal rotation (0.16 vs. 0.11 Nm/ degrees , p < 0.001). The modification with end caps did not improve the stiffness in any direction. CONCLUSIONS: The configuration with a third nail provided a significantly higher stiffness than the classical 2C configuration as well as the modification with end caps in this biomechanical model. This supports the ongoing transfer of the additional third nail into clinical practice to reduce the axial deviation occurring in clinical practice. PMID- 26109086 TI - MicroRNA-150 deletion in mice protects kidney from myocardial infarction-induced acute kidney injury. AB - Despite greater understanding of acute kidney injury (AKI) in animal models, many of the preclinical studies are not translatable. Most of the data were derived from a bilateral renal pedicle clamping model with warm ischemia. However, ischemic injury of the kidney in humans is distinctly different and does not involve clamping of renal vessel. Permanent ligation of the left anterior descending coronary artery model was used to test the role of microRNA (miR)-150 in AKI. Myocardial infarction in this model causes AKI which is similar to human cardiac bypass surgery. Moreover, the time course of serum creatinine and biomarker elevation were also similar to human ischemic injury. Deletion of miR 150 suppressed AKI which was associated with suppression of inflammation and interstitial cell apoptosis. Immunofluorescence staining with endothelial marker and marker of apoptosis suggested that dying cells are mostly endothelial cells with minimal epithelial cell apoptosis in this model. Interestingly, deletion of miR-150 also suppressed interstitial fibrosis. Consistent with protection, miR 150 deletion causes induction of its target gene insulin-like growth factor-1 receptor (IGF-1R) and overexpression of miR-150 in endothelial cells downregulated IGF-1R, suggesting miR-150 may mediate its detrimental effects through suppression of IGF-1R pathways. PMID- 26109087 TI - Deficient acid handling with distal RTA in the NBCe2 knockout mouse. AB - In many circumstances, the pathogenesis of distal renal tubular acidosis (dRTA) is not understood. In the present study, we report that a mouse model lacking the electrogenic Na(+)-HCO3 (-) cotransporter [NBCe2/Slc4a5; NBCe2 knockout (KO) mice] developed dRTA after an oral acid challenge. NBCe2 expression was identified in the connecting tubule (CNT) of wild-type mice, and its expression was significantly increased after acid loading. NBCe2 KO mice did not have dRTA when on a standard mouse diet. However, after acid loading, NBCe2 KO mice exhibited complete features of dRTA, characterized by insufficient urinary acidification, hyperchloremic hypokalemic metabolic acidosis, and hypercalciuria. Additional experiments showed that NBCe2 KO mice had decreased luminal transepithelial potential in the CNT, as revealed by micropuncture. Further immunofluorescence and Western blot experiments found that NBCe2 KO mice had increased expression of H(+)-ATPase B1 in the plasma membrane. These results showed that NBCe2 KO mice with acid loading developed increased urinary K(+) and Ca(2+) wasting due to decreased luminal transepithelial potential in the CNT. NBCe2 KO mice compensated to maintain systemic pH by increasing H(+)-ATPase in the plasma membrane. Therefore, defects in NBCe2 can cause dRTA, and NBCe2 has an important role to regulate urinary acidification and the transport of K(+) and Ca(2+) in the distal nephron. PMID- 26109089 TI - Cyclophosphamide-induced vasopressin-independent activation of aquaporin-2 in the rat kidney. AB - Because cyclophosphamide-induced hyponatremia was reported to occur without changes in plasma vasopressin in a patient with central diabetes insipidus, we hypothesized that cyclophosphamide or its active metabolite, 4 hydroperoxycyclophosphamide (4-HC), may directly dysregulate the expression of water channels or sodium transporters in the kidney. To investigate whether intrarenal mechanisms for urinary concentration are activated in vivo and in vitro by treatment with cyclophosphamide and 4-HC, respectively, we used water loaded male Sprague-Dawley rats, primary cultured inner medullary collecting duct (IMCD) cells, and IMCD suspensions prepared from male Sprague-Dawley rats. In cyclophosphamide-treated rats, significant increases in renal expression of aquaporin-2 (AQP2) and Na-K-2Cl cotransporter type 2 (NKCC2) were shown by immunoblot analysis and immunohistochemistry. Apical translocation of AQP2 was also demonstrated by quantitative immunocytochemistry. In both rat kidney and primary cultured IMCD cells, significant increases in AQP2 and vasopressin receptor type 2 (V2R) mRNA expression were demonstrated by real-time quantitative PCR analysis. Confocal laser-scanning microscopy revealed that apical translocation of AQP2 was remarkably increased when primary cultured IMCD cells were treated with 4-HC in the absence of vasopressin stimulation. Moreover, AQP2 upregulation and cAMP accumulation in response to 4-HC were significantly reduced by tolvaptan cotreatment in primary cultured IMCD cells and IMCD suspensions, respectively. We demonstrated that, in the rat kidney, cyclophosphamide may activate V2R and induce upregulation of AQP2 in the absence of vasopressin stimulation, suggesting the possibility of drug-induced nephrogenic syndrome of inappropriate antidiuresis (NSIAD). PMID- 26109088 TI - Glomerulosclerosis in the diet-induced obesity model correlates with sensitivity to nitric oxide inhibition but not glomerular hyperfiltration or hypertrophy. AB - The diet-induced obesity (DIO) model is frequently used to examine the pathogenesis of obesity-related pathologies; however, only minimal glomerulosclerosis (GS) has been reported after 3 mo. We investigated if GS develops over longer periods of DIO and examined the potential role of hemodynamic mechanisms in its pathogenesis. Eight-week-old male obesity-prone (OP) and obesity-resistant (OR) rats (Charles River) were administered a moderately high-fat diet for 5 mo. Radiotelemetrically measured blood pressure, proteinuria, and GS were assessed. OP (n=10) rats developed modest hypertension (142+/-3 vs. 128+/-2 mmHg, P<0.05) and substantial levels of proteinuria (63+/-12 vs. 12+/-1 mg/day, P<0.05) and GS (7.7+/-1.4% vs. 0.4+/-0.2%) compared with OR rats (n=8). Potential hemodynamic mechanisms of renal injury were assessed in additional groups of OP and OR rats fed a moderately high-fat diet for 3 mo. Kidney weight (4.3+/-0.2 vs. 4.3+/-0.1 g), glomerular filtration rate (3.3+/-0.3 vs. 3.1+/-0.1 ml/min), and glomerular volume (1.9+/-0.1 vs. 2.0+/-0.1 MUm3*10( 6)) were similar between OP (n=6) and OR (n=9) rats. Renal blood flow autoregulation was preserved in both OP (n=7) and OR (n=7) rats. In contrast, Nomega-nitro-L-arginine methyl ester (L-NAME) administration in conscious, chronically instrumented OP (n=11) rats resulted in 15% and 39% increases in blood pressure and renal vascular resistance, respectively, and a 16% decrease in renal blood flow. Minimal effects of L-NAME were seen in OR (n=9) rats. In summary, DIO-associated GS is preceded by an increased hemodynamic sensitivity to L-NAME but not renal hypertrophy or hyperfiltration. PMID- 26109090 TI - Parameter estimation for mathematical models of a nongastric H+(Na+)-K(+)(NH4+) ATPase. AB - The role of nongastric H(+)-K(+)-ATPase (HKA) in ion homeostasis of macula densa (MD) cells is an open question. To begin to explore this issue, we developed two mathematical models that describe ion fluxes through a nongastric HKA. One model assumes a 1H(+):1K(+)-per-ATP stoichiometry; the other assumes a 2H(+):2K(+)-per ATP stoichiometry. Both models include Na+ and NH4+ competitive binding with H+ and K+, respectively, a characteristic observed in vitro and in situ. Model rate constants were obtained by minimizing the distance between model and experimental outcomes. Both 1H(+)(1Na(+)):1K(+)(1NH4 (+))-per-ATP and 2H(+)(2Na(+)):2K(+)(2NH4 (+))-per-ATP models fit the experimental data well. Using both models, we simulated ion net fluxes as a function of cytosolic or luminal ion concentrations typical for the cortical thick ascending limb and MD region. We observed that (1) K+ and NH4+ flowed in the lumen-to-cytosol direction, (2) there was competitive behavior between luminal K+ and NH4+ and between cytosolic Na+ and H+, 3) ion fluxes were highly sensitive to changes in cytosolic Na+ or H+ concentrations, and 4) the transporter does mostly Na+ / K+ exchange under physiological conditions. These results support the concept that nongastric HKA may contribute to Na+ and pH homeostasis in MD cells. Furthermore, in both models, H+ flux reversed at a luminal pH that was <5.6. Such reversal led to Na+ / H+ exchange for a luminal pH of <2 and 4 in the 1:1-per-ATP and 2:2-per-ATP models, respectively. This suggests a novel role of nongastric HKA in cell Na+ homeostasis in the more acidic regions of the renal tubules. PMID- 26109091 TI - Ketamine-induced ulcerative cystitis and bladder apoptosis involve oxidative stress mediated by mitochondria and the endoplasmic reticulum. AB - Ketamine abusers develop severe lower urinary tract symptoms. The major aims of the present study were to elucidate ketamine-induced ulcerative cystitis and bladder apoptosis in association with oxidative stress mediated by mitochondria and the endoplasmic reticulum (ER). Sprague-Dawley rats were distributed into three different groups, which received normal saline or ketamine for a period of 14 or 28 days, respectively. Double-labeled immunofluorescence experiments were performed to investigate tight junction proteins for urothelial barrier functions. A TUNEL assay was performed to evaluate the distribution of apoptotic cells. Western blot analysis was carried out to examine the expressions of urothelial tight junction proteins, ER stress markers, and apoptosis-associated proteins. Antioxidant enzymes, including SOD and catalase, were investigated by real-time PCR and immunofluorescence experiments. Ketamine-treated rats were found to display bladder hyperactivity. This bladder dysfunction was accompanied by disruptions of epithelial cadherin- and tight junction-associated proteins as well as increases in the expressions of apoptosis-associated proteins, which displayed features of mitochondria-dependent apoptotic signals and ER stress markers. Meanwhile, expressions of mitochondria respiratory subunit enzymes were significantly increased in ketamine-treated bladders. Conversely, mRNA expressions of the antioxidant enzymes Mn-SOD (SOD2), Cu/Zn-SOD (SOD1), and catalase were decreased after 28 days of ketamine treatment. These results demonstrate that ketamine enhanced the generation of oxidative stress mediated by mitochondria- and ER-dependent pathways and consequently contributed to bladder apoptosis and urothelial lining defects. Such oxidative stress-enhanced bladder cell apoptosis and urothelial barrier defects are potential factors that may play a crucial role in bladder overactivity and ulceration. PMID- 26109092 TI - A girl with incomplete Prader-Willi syndrome and negative MS-PCR, found to have mosaic maternal UPD-15 at SNP array. AB - The Prader-Willi syndrome (PWS) is caused by lack of expression of paternal allele of the 15q11.2-q13 region, due to deletions at paternal 15q11.2-q13 (<70%), maternal uniparental disomy of chromosome 15 (mat-UPD 15) (30%) or imprinting defects (1%). Hyperphagia, intellectual disabilities/behavioral disorders, neonatal hypotonia, and hypogonadism are cardinal features for PWS. Methylation sensitive PCR (MS-PCR) of the SNRPN locus, which assesses the presence of both the unmethylated (paternal) and the methylated (maternal) allele of 15q11.2-q13, is considered a sensitive reference technique for PWS diagnosis regardless of genetic subtype. We describe a 17-year-old girl with severe obesity, short stature, and intellectual disability, without hypogonadism and history of neonatal hypotonia, who was suspected to have an incomplete PWS. The MS-PCR showed a normal pattern with similar maternal and paternal electrophoretic bands. Afterwards, a SNP array showed the presence of iso-UPD 15, that is, UPD15 with two copies of the same chromosome 15, in about 50% of cells, suggesting a diagnosis of partial PWS due to mosaic maternal iso-UPD15 arisen as rescue of a post-fertilization error. A quantitative methylation analysis confirmed the presence of mosaic UPD15 in about 50% of cells. We propose that complete clinical criteria for PWS and MS-PCR should not be considered sensitive in suspecting and diagnosing partial PWS due to mosaic UPD15. In contrast, clinical suspicion based on less restrictive criteria followed by SNP array is a more powerful approach to diagnose atypical PWS due to UPD15 mosaicism. PMID- 26109093 TI - Tobacco seeds as efficient production platform for a biologically active anti HBsAg monoclonal antibody. AB - The use of plants as heterologous hosts is one of the most promising technologies for manufacturing valuable recombinant proteins. Plant seeds, in particular, constitute ideal production platforms for long-term applications requiring a steady supply of starting material, as they combine the general advantages of plants as bioreactors with the possibility of biomass storage for long periods in a relatively small volume, thus allowing manufacturers to decouple upstream and downstream processing. In the present work we have used transgenic tobacco seeds to produce large amounts of a functionally active mouse monoclonal antibody against the Hepatitis B Virus surface antigen, fused to a KDEL endoplasmic reticulum retrieval motif, under control of regulatory sequences from common bean (Phaseolus vulgaris) seed storage proteins. The antibody accumulated to levels of 6.5 mg/g of seed in the T3 generation, and was purified by Protein A affinity chromatography combined with SEC-HPLC. N-glycan analysis indicated that, despite the KDEL signal, the seed-derived plantibody bore both high-mannose and complex type sugars that indicate partial passage through the Golgi compartment, although its performance in the immunoaffinity purification of HBsAg was unaffected. An analysis discussing the industrial feasibility of replacing the currently used tobacco leaf-derived plantibody with this seed-derived variant is also presented. PMID- 26109094 TI - Fluorescence imaging preparation methods for tissue scaffolds implanted into a green fluorescent protein porcine model. AB - Green fluorescent protein (GFP) animal models have become increasingly popular due to their potential to enhance in vivo imaging and their application to many fields of study. We have developed a technique to observe host tissue integration into scaffolds using GFP expressing swine and fluorescence imaging. Current fluorescence imaging preparation methods cannot be translated to a full GFP animal model due to several challenges and limitations that are investigated here. We have implanted tissue scaffolds into GFP expressing swine and have prepared explanted scaffolds for fluorescence imaging using four different methods including formalin fixation and paraffin embedding, vapor fixation, freshly prepared paraformaldehyde fixation, and fresh frozen tissue. Explanted scaffolds and tissue were imaged using confocal microscopy with spectral separation to evaluate the GFP animal model for visualization of host tissue integration into explanted scaffolds. All methods except fresh frozen tissue induced autofluorescence of the scaffold, preventing visualization of detail between host tissue and scaffold fibers. Fresh frozen tissue preparation allowed for the most reliable visualization of fluorescent host tissue integration into non-fluorescent scaffolds. It was concluded that fresh frozen tissue preparation is the best method for fluorescence imaging preparation when using scaffolds implanted into GFP whole animal models. PMID- 26109095 TI - The effect of sulfate on selenate bioaccumulation in two freshwater primary producers: A duckweed (Lemna minor) and a green alga (Pseudokirchneriella subcapitata). AB - Predicting selenium bioaccumulation is complicated because site-specific conditions, including the ionic composition of water, affect the bioconcentration of inorganic selenium into the food web. Selenium tissue concentrations were measured in Lemna minor and Pseudokirchneriella subcapitata following exposure to selenate and sulfate. Selenium accumulation differed between species, and sulfate reduced selenium uptake in both species, indicating that ionic constituents, in particular sulfate, are important in modifying selenium uptake by primary producers. PMID- 26109096 TI - Review of select causes of drug-induced AKI. PMID- 26109097 TI - Pharmacological treatment of attention-deficit/hyperactivity disorder: assessing outcomes. AB - A substantial body of evidence has supported the efficacy and safety of pharmacological treatment available for attention deficit/hyperactivity disorder (ADHD). There is increasing agreement that the important treatment outcomes for ADHD extend beyond improvement in core symptoms and that a more generic (or global) concept of remission is the overarching goal of treatment. However, there is no consensus on the best definition of remission or on how best to conceptualize and measure broader treatment outcomes. In this article, we provide an overview of the various methods and approaches to measuring treatment outcomes for ADHD with respect to symptoms, impairment, quality of life, adverse events and safety as well as cognition. We will describe the ways that they may be used within routine clinical practice and think ahead about the kinds of studies that are required to move the field forward. PMID- 26109098 TI - Long-acting muscarinic antagonists. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting beta2-agonists, eventually in fixed dose combinations. Long-acting beta2-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients. PMID- 26109100 TI - Reply. PMID- 26109099 TI - Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models. AB - PURPOSE: Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer. EXPERIMENTAL DESIGN: Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated. RESULTS: Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. CONCLUSIONS: The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID- 26109101 TI - Developing predictive assays: the phenotypic screening "rule of 3". AB - Phenotypic drug discovery approaches can positively affect the translation of preclinical findings to patients. However, not all phenotypic assays are created equal. A critical question then follows: What are the characteristics of the optimal assays? We analyze this question and propose three specific criteria related to the disease relevance of the assay-system, stimulus, and end point-to help design the most predictive phenotypic assays. PMID- 26109102 TI - Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia. AB - T cell prolymphocytic leukemia (T-PLL) is a rare, mature T cell neoplasm with distinct features and an aggressive clinical course. Early relapse and short overall survival are commonplace. Use of the monoclonal anti-CD52 antibody alemtuzumab has improved the rate of complete remission and duration of response to more than 50% and between 6 and 12 months, respectively. Despite this advance, without an allogeneic transplant, resistant relapse is inevitable. We report seven complete and one partial remission in eight patients receiving alemtuzumab and cladribine with or without a histone deacetylase inhibitor. These data show that administration of epigenetic agents can overcome alemtuzumab resistance. We also report epigenetically induced expression of the surface receptor protein CD30 in T-PLL. Subsequent treatment with the anti-CD30 antibody-drug conjugate brentuximab vedotin overcame organ-specific (skin) resistance to alemtuzumab. Our findings demonstrate activity of combination epigenetic and immunotherapy in the incurable illness T-PLL, particularly in the setting of previous alemtuzumab therapy. PMID- 26109103 TI - Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis. AB - Various diseases have been linked to the human microbiota, but the underlying molecular mechanisms of the microbiota in disease pathogenesis are often poorly understood. Using acne as a disease model, we aimed to understand the molecular response of the skin microbiota to host metabolite signaling in disease pathogenesis. Metatranscriptomic analysis revealed that the transcriptional profiles of the skin microbiota separated acne patients from healthy individuals. The vitamin B12 biosynthesis pathway in the skin bacterium Propionibacterium acnes was significantly down-regulated in acne patients. We hypothesized that host vitamin B12 modulates the activities of the skin microbiota and contributes to acne pathogenesis. To test this hypothesis, we analyzed the skin microbiota in healthy subjects supplemented with vitamin B12. We found that the supplementation repressed the expression of vitamin B12 biosynthesis genes in P. acnes and altered the transcriptome of the skin microbiota. One of the 10 subjects studied developed acne 1 week after vitamin B12 supplementation. To further understand the molecular mechanism, we revealed that vitamin B12 supplementation in P. acnes cultures promoted the production of porphyrins, which have been shown to induce inflammation in acne. Our findings suggest a new bacterial pathogenesis pathway in acne and provide one molecular explanation for the long-standing clinical observation that vitamin B12 supplementation leads to acne development in a subset of individuals. Our study discovered that vitamin B12, an essential nutrient in humans, modulates the transcriptional activities of skin bacteria, and provided evidence that metabolite-mediated interactions between the host and the skin microbiota play essential roles in disease development. PMID- 26109105 TI - Sensitivity, Specificity, PPV, and NPV for Predictive Biomarkers. AB - Molecularly targeted cancer drugs are often developed with companion diagnostics that attempt to identify which patients will have better outcome on the new drug than the control regimen. Such predictive biomarkers are playing an increasingly important role in precision oncology. For diagnostic tests, sensitivity, specificity, positive predictive value, and negative predictive are usually used as performance measures. This paper discusses these indices for predictive biomarkers, provides methods for their calculation with survival or response endpoints, and describes assumptions involved in their use. PMID- 26109104 TI - Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. AB - To explore the potential of tumor-specific DNA as a biomarker for head and neck squamous cell carcinomas (HNSCC), we queried DNA from saliva or plasma of 93 HNSCC patients. We searched for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n = 10) and 95% (n = 37), respectively. When segregated by site, tumor DNA was detected in 100% (n = 15), 91% (n = 22), 100% (n = 7), and 100% (n = 3) of patients with tumors of the oral cavity, oropharynx, larynx, and hypopharynx, respectively. In saliva, tumor DNA was found in 100% of patients with oral cavity cancers and in 47 to 70% of patients with cancers of the other sites. In plasma, tumor DNA was found in 80% of patients with oral cavity cancers, and in 86 to 100% of patients with cancers of the other sites. Thus, saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in saliva was found postsurgically in three patients before clinical diagnosis of recurrence, but in none of the five patients without recurrence. Tumor DNA in the saliva and plasma appears to be a potentially valuable biomarker for detection of HNSCC. PMID- 26109106 TI - The Fundamental Difficulty With Evaluating the Accuracy of Biomarkers for Guiding Treatment. AB - Developing biomarkers that can predict whether patients are likely to benefit from an intervention is a pressing objective in many areas of medicine. Recent guidance documents have recommended that the accuracy of predictive biomarkers, ie, sensitivity, specificity, and positive and negative predictive values, should be assessed. We clarify the meanings of these entities for predictive markers and demonstrate that generally they cannot be estimated from data without making strong untestable assumptions. Language suggesting that predictive biomarkers can identify patients who benefit from an intervention is also widespread. We show that in general one cannot estimate the chance that a patient will benefit from treatment. We recommend instead that predictive biomarkers be evaluated with respect to their ability to predict clinical outcomes among patients treated and among patients receiving standard of care, and the population impact of treatment rules based on those predictions. Ideally these entities are estimated from a randomized trial comparing the experimental intervention with standard of care. PMID- 26109107 TI - On the quantitative assessment of predictive biomarkers. PMID- 26109108 TI - Near-normoglycaemia and development of neuropathy: a 24-year prospective study from diagnosis of type 1 diabetes. AB - OBJECTIVE: Complete prevention of diabetic neuropathies has not been previously demonstrated. We sought to determine whether long-term near-normoglycaemia maintained from the diagnosis of type 1 diabetes is associated with polyneuropathy and cardiac autonomic dysfunction. DESIGN: Prospective observational study over 24 years. SETTING: Ambulatory care. PARTICIPANTS: 32 newly diagnosed patients with type 1 diabetes aged 20.3 +/- 1.0 years, duration of diabetes 2.7 +/- 0.3 weeks. INTERVENTION: Insulin therapy according to standards of care. PRIMARY AND SECONDARY OUTCOME MEASURES: Motor and sensory nerve conduction velocity (MNCV and SNCV), heart rate variability (HRV), and confirmed clinical polyneuropathy measured at 15 time points over 24 years and quantitative sensory testing (QST) determined over 20-22 years. RESULTS: 11 patients were well controlled over 24 years with mean glycated haemoglobin (HbA1c) <7.0% (6.5 +/- 0.1%; group 1), whereas 21 patients were poorly controlled (mean HbA1c >= 7.0%: 8.3 +/- 0.2%; group 2). After 24 years, MNCV was faster in group 1 versus group 2 in the median (55.5 +/- 1.6 vs 48.9 +/- 1.6 m/s), ulnar (56.5 +/- 1.5 vs 49.3 +/- 1.7 m/s) and peroneal nerve (44.7 +/- 1.6 vs 36.8 +/- 2.5 m/s), while SNCV was faster in the median (53.6 +/- 1.6 vs 45.5 +/- 2.8 m/s), ulnar (54.7 +/- 1.8 vs 43.0 +/- 3.9 m/s), and sural nerve (44.5 +/- 1.8 vs 35.5 +/- 2.6 m/s; all p<0.05). The annual decline in peroneal MNCV and sural SNCV in group 1 was sixfold and threefold faster in group 2 than in group 1, respectively. Likewise, impairment in QST and HRV developed at faster rates in group 2. After 24 years, 64% of patients in group 2, but none in group 1, developed confirmed clinical polyneuropathy. CONCLUSIONS: Near-normoglycaemia maintained from the diagnosis of type 1 diabetes over 24 years was associated with a complete prevention of the decline in hyperglycaemia-related peripheral and autonomic nerve function, and development of confirmed clinical polyneuropathy. PMID- 26109109 TI - Traumatic episodes and mental health effects in young men and women in Rwanda, 17 years after the genocide. AB - OBJECTIVES: To investigate mental health effects associated with exposure to trauma in Rwanda during the 1994 genocide period, and over the lifetime, in Rwandan men and women aged 20-35 years. SETTING: This was a cross-sectional population-based study conducted in the southern province of Rwanda. Data was collected during December 2011 to January 2012. PARTICIPANTS: A total population of 917 individuals were included, 440 (48%) men and 477 (52%) women aged 20-35 years. Number of households for inclusion in each village was selected proportional to the total number of households in each selected village. The response rate was 99.8%. Face-to-face interviewing was done by experienced and trained clinical psychologists, following a structured questionnaire. RESULTS: Women were slightly less exposed during the genocide period (women 35.4% and men 37.5%; p=0.537), but more women than men were exposed to traumatic episodes over their lifetime (women 83.6%, n=399; men 73.4%, n=323; p<0.001). Current major depressive episodes (MDE) were twice as prevalent in women as in men. Traumatic episodes experienced in the genocide period severely affected men's current mental health status with relative risk (RR) 3.02 (95% CI 1.59 to 5.37) for MDE past and with RR 2.15 (95% CI 1.21 to 3.64) for suicidality. Women's mental health was also affected by trauma experienced in the genocide period but to an even higher extent, by similar trauma experienced in the lifetime with RR 1.91 (95% CI 1.03 to 3.22) for suicidality and RR 1.90 (95% CI 1.34 to 2.42) for generalised anxiety disorder, taking spousal physical/sexual violence into consideration. CONCLUSIONS: Depression, post-traumatic stress disorder, anxiety and suicidal attempts are prevalent in Rwanda, with rates twice as high in women compared with men. For women, exposure to physical and sexual abuse was independently associated with all these disorders. Early detection of gender based violence through homes and community interventions is important. PMID- 26109110 TI - Retention in care prior to antiretroviral treatment eligibility in sub-Saharan Africa: a systematic review of the literature. AB - OBJECTIVE: We aimed at summarising rates and factors associated with retention in HIV care prior to antiretroviral treatment (ART) eligibility in sub-Saharan Africa. DESIGN: We conducted a systematic literature review (2002-2014). We searched Medline/Pubmed, Scopus and Web of Science, as well as proceedings of conferences. We included all original research studies published in peer-reviewed journals, which used quantitative indicators of retention in care prior to ART eligibility. PARTICIPANTS: People not yet eligible for ART. PRIMARY AND SECONDARY OUTCOMES: Rate of retention in HIV care prior to ART eligibility and associated factors. RESULTS: 10 papers and 2 abstracts were included. Most studies were conducted in Southern and Eastern Africa between 2004 and 2011 and reported retention rates in pre-ART care up to the second CD4 measurement. Definition of retention in HIV care prior to ART eligibility differed substantially across studies. Retention rates ranged between 23% and 88% based on series ranging from 112 to 10,314 individuals; retention was higher in women, individuals aged >25 years, those with low CD4 count, high body mass index or co-infected with tuberculosis, and in settings with free cotrimoxazole use. CONCLUSIONS: Retention in HIV care prior to ART eligibility in sub-Saharan Africa has been insufficiently described so far leaving major research gaps, especially regarding long-term retention rates and sociodemographic, economic, clinical and programmatic logistic determinants. The prospective follow-up of newly diagnosed individuals is required to better evaluate attrition prior to ART eligibility among HIV-infected people. PMID- 26109111 TI - CAFE: a multicomponent audit and feedback intervention to improve implementation of healthy food policy in primary school canteens: protocol of a randomised controlled trial. AB - INTRODUCTION: A number of jurisdictions internationally have policies requiring schools to implement healthy canteens. However, many schools have not implemented such policies. One reason for this is that current support interventions cannot feasibly be delivered to large numbers of schools. A promising solution to support population-wide implementation of healthy canteen practices is audit and feedback. The effectiveness of this strategy has, however, not previously been assessed in school canteens. This study aims to assess the effectiveness and cost effectiveness of an audit and feedback intervention, delivered by telephone and email, in increasing the number of school canteens that have menus complying with a government healthy-canteen policy. METHODS AND ANALYSIS: Seventy-two schools, across the Hunter New England Local Health District in New South Wales Australia, will be randomised to receive the multicomponent audit and feedback implementation intervention or usual support. The intervention will consist of between two and four canteen menu audits over 12 months. Each menu audit will be followed by two modes of feedback: a written feedback report and a verbal feedback/support via telephone. Primary outcomes, assessed by dieticians blind to group status and as recommended by the Fresh Tastes @ School policy, are: (1) the proportion of schools with a canteen menu containing foods or beverages restricted for sale, and; (2) the proportion of schools that have a menu which contains more than 50% of foods classified as healthy canteen items. Secondary outcomes are: the proportion of menu items in each category ('red', 'amber' and 'green'), canteen profitability and cost-effectiveness. ETHICS AND DISSEMINATION: Ethical approval has been obtained by from the Hunter New England Human Research Ethics Committee and the University of Newcastle Human Research Ethics Committee. The findings will be disseminated in usual forums, including peer-reviewed publication and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12613000543785. PMID- 26109112 TI - Effectiveness, safety and costs of orphan drugs: an evidence-based review. AB - INTRODUCTION: Several orphan drugs have been approved by the European Medicines Agency (EMA) over the past two decades. However, the drugs are expensive, and in some instances, the evidence for effectiveness is not convincing at the time of regulatory approval. Our objective was to evaluate the clinical effectiveness of orphan drugs that have been granted marketing licenses in Europe, determine the annual costs of each drug, compare the costs of branded orphan drugs against their generic equivalents, and explore any relationships between orphan drug disease prevalence and annual costs. METHODS: We searched the EMA database to identify orphan drugs granted marketing authorisation up to April 2014. Electronic searches were also conducted in PubMed, EMBASE and Google Scholar, to assess data on effectiveness, safety and annual costs. 2 reviewers independently evaluated the levels and quality of evidence, and extracted data. RESULTS: We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of evidence. 85% showed significant clinical effects, but serious adverse events were reported in 86.5%. Their annual costs were between L726 and L378,000. There was a significant inverse relationship between disease prevalence and annual costs (p = 0.01); this was largely due to the influence of the ultra-orphan diseases. We could not determine whether the balance between effectiveness and safety influenced annual costs. For 10 drugs where generic alternatives were available, the branded drugs were 1.4 to 82,000 times more expensive. CONCLUSIONS: The available evidence suggests that there is inconsistency in the quality of evidence of approved orphan drugs, and there is no clear mechanism for determining their prices. In some cases, far cheaper generic agents appear to be available. A more robust, transparent and standard mechanism for determining annual costs is imperative. PMID- 26109113 TI - Flare frequency, healthcare resource utilisation and costs among patients with gout in a managed care setting: a retrospective medical claims-based analysis. AB - OBJECTIVES: For most gout patients, excruciatingly painful gout attacks are the major clinical burden of the disease. The goal of this study was to assess the association of frequent gout flares with healthcare burden, and to quantify how much lower gout-related costs and resource use are for those with infrequent flares compared to frequent gout flares. DESIGN: Retrospective cohort study. SETTING: Administrative claims data from a large US health plan. PARTICIPANTS: Patients aged 18 years or above, and with evidence of gout based on medical and pharmacy claims between January 2009 and April 2012 were eligible for inclusion. Patient characteristics were assessed during a 12-month baseline period. OUTCOME MEASURES: Frequency of gout flares, healthcare costs and resource utilisation were assessed in the 12 months following the first qualifying gout claim. Generalised linear models were employed to assess the impact of flare frequency on cost outcomes after adjusting for covariates. RESULTS: 102,703 patients with gout met study inclusion criteria; 89,201 had 0-1 gout flares, 9714 had 2 flares, and 3788 had 3+ flares. Average counts of gout-related inpatient stays, emergency room visits and ambulatory visits were higher among patients with 2 or 3+ flares, compared to those with 0-1 flares (all p<0.001). Adjusted annual gout-related costs were $1804, $3014 and $4363 in those with 0-1, 2 and 3+ gout flares, respectively (p<0.001 comparing 0-1 flares to 2 or 3+ flares). CONCLUSIONS: Gout related costs and resource use were lower for those with infrequent flares, suggesting significant cost benefit to a gout management plan that has a goal of reducing flare frequency. PMID- 26109114 TI - Enduring health effects of asbestos use in Belgian industries: a record-linked cohort study of cause-specific mortality (2001-2009). AB - OBJECTIVE: To investigate cause-specific mortality among asbestos workers and potentially exposed workers in Belgium and evaluate potential excess in mortality due to established and suspected asbestos-related diseases. DESIGN: This cohort study is based on an individual record linkage between the 1991 Belgian census and cause-specific mortality information for Flanders and Brussels (2001-2009). SETTING: Belgium (Flanders and Brussels region). PARTICIPANTS: The study population consists of 1,397,699 male workers (18-65,years) with 72,074 deaths between 1 October 2001 and 31 December 2009. Using a classification of high-risk industries, mortality patterns between 2056 asbestos workers, 385,046 potentially exposed workers and the working population have been compared. OUTCOME MEASURES: Standardised mortality ratios (SMRs) and 95% CIs are calculated for manual and non-manual workers. RESULTS: Our findings show clear excess in asbestos-related mortality in the asbestos industry with SMRs for mesothelioma of 4071 (CI 2327 to 6611) among manual workers and of 4489 (CI 1458 to 10,476) among non-manual workers. Excess risks in asbestos-related mortality are also found in the chemical industry, the construction industry, the electrical generation and distribution industry, the basic metals manufacturing industry, the metal products manufacturing industry, the railroad industry, and the shipping industry. Oral cancer mortality is significantly higher for asbestos workers (SMR 383; CI 124 to 894), railroad workers (SMR 192; CI 112 to 308), shipping workers (SMR 172; CI 102 to 271) and construction workers (SMR 125; CI 100 to 153), indicating a possible association with occupational asbestos exposure. Workers in all four industries have elevated mortality rates for cancer of the mouth. Only construction workers experience significantly higher pharyngeal cancer mortality (SMR 151; CI 104 to 212). CONCLUSIONS: The study identifies vulnerable groups of Belgian asbestos workers, demonstrating the current-day health repercussions of historical asbestos use. Results support the hypothesis of a possible association between the development of oral cancer and occupational asbestos exposure. PMID- 26109115 TI - Video decision aids to assist with advance care planning: a systematic review and meta-analysis. AB - OBJECTIVE: Advance care planning (ACP) can result in end-of-life care that is more congruent with patients' values and preferences. There is increasing interest in video decision aids to assist with ACP. The objective of this study was to evaluate the impact of video decision aids on patients' preferences regarding life-sustaining treatments (primary outcome). DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: MEDLINE, EMBASE, PsycInfo, CINAHL, AMED and CENTRAL, between 1980 and February 2014, and correspondence with authors. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of adult patients that compared a video decision aid to a non-video-based intervention to assist with choices about use of life sustaining treatments and reported at least one ACP-related outcome. DATA EXTRACTION: Reviewers worked independently and in pairs to screen potentially eligible articles, and to extract data regarding risk of bias, population, intervention, comparator and outcomes. Reviewers assessed quality of evidence (confidence in effect estimates) for each outcome using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: 10 trials enrolling 2220 patients were included. Low-quality evidence suggests that patients who use a video decision aid are less likely to indicate a preference for cardiopulmonary resuscitation (pooled risk ratio, 0.50 (95% CI 0.27 to 0.95); I(2)=65%). Moderate-quality evidence suggests that video decision aids result in greater knowledge related to ACP (standardised mean difference, 0.58 (95% CI 0.38 to 0.77); I(2)=0%). No study reported on the congruence of end-of-life treatments with patients' wishes. No study evaluated the effect of video decision aids when integrated into clinical care. CONCLUSIONS: Video decision aids may improve some ACP-related outcomes. Before recommending their use in clinical practice, more evidence is needed to confirm these findings and to evaluate the impact of video decision aids when integrated into patient care. PMID- 26109116 TI - Exposure to traffic and lung function in adults: a general population cohort study. AB - OBJECTIVES: To investigate the association between living near dense traffic and lung function in a cohort of adults from a single urban region. DESIGN: Cross sectional results from a cohort study. SETTING: The adult-onset asthma and exhaled nitric oxide (ADONIX) cohort, sampled during 2001-2008 in Gothenburg, Sweden. Exposure was expressed as the distance from participants' residential address to the nearest road with dense traffic (>10,000 vehicles per day) or very dense traffic (>30,000 vehicles per day). The exposure categories were: low (>500 m; reference), medium (75-500 m) or high (<75 m). PARTICIPANTS: The source population was a population-based cohort of adults (n=6153). The study population included 5441 participants of European descent with good quality spirometry and information about all outcomes and covariates. OUTCOME MEASURES: Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured at a clinical examination. The association with exposure was examined using linear regression adjusting for age, gender, body mass index, smoking status and education in all participants and stratified by sex, smoking status and respiratory health status. RESULTS: We identified a significant dose-response trend between exposure category and FEV1 (p=0.03) and borderline significant trend for FVC (p=0.06) after adjusting for covariates. High exposure was associated with lower FEV1 (-1.0%, 95% CI -2.5% to 0.5%) and lower FVC (-0.9%, 95% CI -2.2% to 0.4%). The effect appeared to be stronger in women. In highly exposed individuals with current asthma or chronic obstructive pulmonary disease, FVC was lower (-4.5%, 95% CI -8.8% to -0.1%). CONCLUSIONS: High traffic exposure at the residential address was associated with lower than predicted FEV1 and FVC lung function compared with living further away in a large general population cohort. There were particular effects on women and individuals with obstructive disease. PMID- 26109117 TI - Randomised controlled trial of topical kanuka honey for the treatment of rosacea. AB - OBJECTIVE: To investigate the efficacy of topical 90% medical-grade kanuka honey and 10% glycerine (Honevo) as a treatment for rosacea. DESIGN: Randomised controlled trial with blinded assessment of primary outcome variable. SETTING: Outpatient primary healthcare population from 5 New Zealand sites. PARTICIPANTS: 138 adults aged >= 16, with a diagnosis of rosacea, and a baseline blinded Investigator Global Assessment of Rosacea Severity Score (IGA-RSS) of >= 2. 69 participants were randomised to each treatment arm. 1 participant was excluded from the Honevo group, and 7 and 15 participants withdrew from the Honevo and control groups, respectively. INTERVENTIONS: Participants were randomly allocated 1:1 to Honevo or control cream (Cetomacrogol), applied twice daily for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of participants who had a >= 2 improvement in the 7-point IGA-RSS at week 8 compared to baseline. Secondary outcomes included change in IGA-RSS and subject-rated visual analogue score of change in severity (VAS-CS) on a 100 mm scale (0 mm 'much worse', 100 mm 'much improved') at weeks 2 and 8. RESULTS: 24/68 (34.3%) in the Honevo group and 12/69 (17.4%) in the control group had a >= 2 improvement in IGA-RSS at week 8 compared to baseline (relative risk 2.03; 95% CI 1.11 to 3.72, p=0.020). The change in IGA-RSS for Honevo compared to control at week 2 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to 0, p=0.03), and at week 8 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to 0, p=0.005). The VAS CS at week 2 was 9.1 (95% CI 3.5 to 14.7), p=0.002, and at week 8 was 12.3 (95% CI 5.7 to 18.9) p<0.001 for Honevo compared to control. CONCLUSIONS: Honevo is an effective treatment for rosacea. TRIAL REGISTRATION NUMBER: This trial was registered in the Australian and New Zealand Clinical Trials Registry ACTRN12614000004662. PMID- 26109118 TI - Comparison of methodological quality of positive versus negative comparative studies published in Indian medical journals: a systematic review. AB - OBJECTIVES: Published negative studies should have the same rigour of methodological quality as studies with positive findings. However, the methodological quality of negative versus positive studies is not known. The objective was to assess the reported methodological quality of positive versus negative studies published in Indian medical journals. DESIGN: A systematic review (SR) was performed of all comparative studies published in Indian medical journals with a clinical science focus and impact factor >1 between 2011 and 2013. The methodological quality of randomised controlled trials (RCTs) was assessed using the Cochrane risk of bias tool, and the Newcastle-Ottawa scale for observational studies. The results were considered positive if the primary outcome was statistically significant and negative otherwise. When the primary outcome was not specified, we used data on the first outcome reported in the history followed by the results section. Differences in various methodological quality domains between positive versus negative studies were assessed by Fisher's exact test. RESULTS: Seven journals with 259 comparative studies were included in this SR. 24% (63/259) were RCTs, 24% (63/259) cohort studies, and 49% (128/259) case-control studies. 53% (137/259) of studies explicitly reported the primary outcome. Five studies did not report sufficient data to enable us to determine if results were positive or negative. Statistical significance was determined by p value in 78.3% (199/254), CI in 2.8% (7/254), both p value and CI in 11.8% (30/254), and only descriptive in 6.3% (16/254) of studies. The overall methodological quality was poor and no statistically significant differences between reporting of methodological quality were detected between studies with positive versus negative findings. CONCLUSIONS: There was no difference in the reported methodological quality of positive versus negative studies. However, the uneven reporting of positive versus negative studies (72% vs 28%) indicates a publication bias in Indian medical journals with an impact factor of >1. PMID- 26109119 TI - Socioeconomic status and self-reported health among middle-aged Japanese men: results from a nationwide longitudinal study. AB - OBJECTIVE: To examine potential associations between socioeconomic factors and self-rated health among a national sample of Japanese men aged 50-59 years between 2005 and 2010, including the 2008 global financial crisis. DESIGN: Prospective cohort study. SETTING: Randomly selected 2515 census areas from a total of 1.8 million census areas in Japan. PARTICIPANTS: This study utilised data from a national, longitudinal survey conducted by the Ministry of Health, Labour and Welfare. Starting in 2005, 16,738 Japanese men aged 50-59 years were recruited and sent a questionnaire each year. We analysed data for the 6-year period (2005-2010) from participants who had worked for over 20 years in the same industry (n=9727). MAIN OUTCOME MEASURES: We focused on worsening self-rated health status by occupation, education and employment contract. RESULTS: Working in the manufacturing industry was associated with worsening self-rated health scores when compared to those working in management (HR=1.19; 95% CI 1.04 to 1.37). A relationship between education level and worsening self-rated health was also identified as follows: junior high school (HR=1.49; 95% CI 1.31 to 1.69), high school (HR=1.29; 95% CI 1.17 to 1.42), and vocational college (HR=1.25; 95% CI 1.07 to 1.46), when compared with those holding university-level qualifications. Precarious employment (HR=1.17; 95% CI 1.00 to 1.37) was also associated with worsening self-rated health status in the current study. CONCLUSIONS: This study suggests that working in manufacturing for more than 20 years and having lower education levels may have a significant impact on the self rated health of middle-aged Japanese men. This may reflect a progressive decline in Japanese working conditions following the global financial crisis and/or the impact of lower socioeconomic status. PMID- 26109120 TI - A multicentre, randomised controlled, non-inferiority trial, comparing high flow therapy with nasal continuous positive airway pressure as primary support for preterm infants with respiratory distress (the HIPSTER trial): study protocol. AB - INTRODUCTION: High flow (HF) therapy is an increasingly popular mode of non invasive respiratory support for preterm infants. While there is now evidence to support the use of HF to reduce extubation failure, there have been no appropriately designed and powered studies to assess the use of HF as primary respiratory support soon after birth. Our hypothesis is that HF is non-inferior to the standard treatment--nasal continuous positive airway pressure (NCPAP)--as primary respiratory support for preterm infants. METHODS AND ANALYSIS: The HIPSTER trial is an unblinded, international, multicentre, randomised, non inferiority trial. Eligible infants are preterm infants of 28-36(+6) weeks' gestational age (GA) who require primary non-invasive respiratory support for respiratory distress in the first 24 h of life. Infants are randomised to treatment with either HF or NCPAP. The primary outcome is treatment failure within 72 h after randomisation, as determined by objective oxygenation, blood gas, and apnoea criteria, or the need for urgent intubation and mechanical ventilation. Secondary outcomes include the incidence of intubation, pneumothorax, bronchopulmonary dysplasia, nasal trauma, costs associated with hospital care and parental stress. With a specified non-inferiority margin of 10%, using a two-sided 95% CI and 90% power, the study requires 375 infants per group (total 750 infants). ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at The Royal Women's Hospital (13/12), The Royal Children's Hospital (33144A), The Mercy Hospital for Women (R13/34), and the South-Eastern Norway Regional Health Authority (2013/1657). The trial is currently recruiting at 9 centres in Australia and Norway. The trial results will be published in peer-reviewed international journals, and presented at national and international conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ID: ACTRN12613000303741. PMID- 26109121 TI - [Diagnostic imaging of urolithiais. Current recommendations and new developments]. AB - BACKGROUND AND METHOD: Prevalence of urolithiasis is increasing in industrialized countries--in both adults and children, representing a unique diagnostic and therapeutic challenge. Risk-adapted diagnostic imaging currently means assessment with maximized sensitivity and specificity together with minimal radiation exposure. In clinical routine, imaging is performed by sonography, unenhanced computed tomography (NCCT) or intravenous urography (IVU) as well as plain kidney ureter-bladder (KUB) radiographs. AIM: The aim of the present review is a critical guideline-based and therapy-aligned presentation of diagnostic imaging procedures for optimized treatment of urolithiasis considering the specifics in children and pregnant women. PMID- 26109122 TI - [Positron-emission tomography in urooncology]. AB - The use of positron emission tomography (PET) is an established method for the diagnosis of urological malignancies. Several tracers are currently available to obtain metabolic information or directly detect molecular targets. While (18)F FDG-PET is recognized in current guidelines for the staging of seminoma, PET is not used in clinical routine in renal malignancies due to the lack of specific tracers. Despite initial promising results in bladder cancer, no relevant additional diagnostic value with PET using (18)F-FDG or choline-based tracers could be obtained in most patients and therefore should be used with caution or only within clinical trials. In prostate cancer, however, after development of new tracers that, for example, target prostate-specific membrane antigen (PSMA), a paradigm shift in imaging can be recognized. Here, (68)Ga-PSMA-PET might be included in the future as part of standard imaging work-up. PMID- 26109123 TI - Altered regional activity and inter-regional functional connectivity in psychogenic non-epileptic seizures. AB - Although various imaging studies have focused on detecting the cerebral function underlying psychogenic non-epileptic seizures (PNES), the nature of PNES remains poorly understood. In this study, we combined the resting state fMRI with fractional amplitude of low-frequency fluctuations (fALFF) and functional connectivity based on the seed voxel linear correlation approach to examine the alterations of regional and inter-regional network cerebral functions in PNES. A total of 20 healthy controls and 18 patients were enrolled. The PNES patients showed significantly increased fALFF mainly in the dorsolateral prefrontal cortex (DLPFC), parietal cortices, and motor areas, as well as decreased fALFF in the triangular inferior frontal gyrus. Thus, our results add to literature suggesting abnormalities of neural synchrony in PNES. Moreover, PNES exhibited widespread inter-regional neural network deficits, including increased (DLPFC, sensorimotor, and limbic system) and decreased (ventrolateral prefrontal cortex) connectivity, indicating that changes in the regional cerebral function are related to remote inter-regional network deficits. Correlation analysis results revealed that the connectivity between supplementary motor area and anterior cingulate cortex correlated with the PNES frequency, further suggesting the skewed integration of synchronous activity could predispose to the occurrence of PNES. Our findings provided novel evidence to investigate the pathophysiological mechanisms of PNES. PMID- 26109124 TI - High patient satisfaction in 445 patients who underwent fast-track hip or knee replacement. AB - BACKGROUND AND PURPOSE: Patient satisfaction is important in fast-track total hip and knee replacement (THR, TKR). We assessed: (1) how satisfied patients were with the treatment; (2) factors related to overall satisfaction; and (3) whether there was a difference between THR and TKR regarding length of stay (LOS) and patient satisfaction. PATIENTS AND METHODS: In this follow-up study, a consecutive series of 445 patients undergoing THR and TKR completed a questionnaire 2 weeks after discharge. LOS and short-term patient satisfaction with the fast-track management were measured. Patient satisfaction was measured using a numerical rating scale (NRS; 0-10). RESULTS: For THR, the median satisfaction score was 9-10 and for TKR it was 8.5-10 in all parameters. Older THR patients had higher overall satisfaction. No association was found between overall satisfaction following THR or TKR and sex comorbidity, or LOS. THR patients had shorter mean LOS than TKR patients, even though the median LOS was 2 days for both groups. THR patients were more satisfied than TKR patients in the first weeks after discharge. INTERPRETATION: Patient satisfaction is high following fast-track THR and TKR, with scores ranging from 8.5 to 10 on the NRS. A qualitative investigation of the first weeks after discharge is required to learn more about how to improve the experience of recovery. PMID- 26109125 TI - A plastic relationship between vinculin-mediated tension and adhesion complex area defines adhesion size and lifetime. AB - Cell-matrix adhesions are central mediators of mechanotransduction, yet the interplay between force and adhesion regulation remains unclear. Here we use live cell imaging to map time-dependent cross-correlations between vinculin-mediated tension and adhesion complex area, revealing a plastic, context-dependent relationship. Interestingly, while an expected positive cross-correlation dominated in mid-sized adhesions, small and large adhesions display negative cross-correlation. Furthermore, although large changes in adhesion complex area follow vinculin-mediated tension alterations, small increases in area precede vinculin-mediated tension dynamics. Modelling based on this mapping of the vinculin-mediated tension-adhesion complex area relationship confirms its biological validity, and indicates that this relationship explains adhesion size and lifetime limits, keeping adhesions focal and transient. We also identify a subpopulation of steady-state adhesions whose size and vinculin-mediated tension become stabilized, and whose disassembly may be selectively microtubule-mediated. In conclusion, we define a plastic relationship between vinculin-mediated tension and adhesion complex area that controls fundamental cell-matrix adhesion properties. PMID- 26109126 TI - Patient Factors that Impact upon Cognitive Behavioural Therapy for Psychosis: Therapists' Perspectives. AB - BACKGROUND: Randomized controlled trials have established that cognitive behavioural therapy (CBT) is effective in helping people with psychosis, though there is enormous variability in outcome. It is not clear what patient factors contribute to good outcomes. In fact, most studies considering client factors have excluded people with psychosis. It is clinicians who are deciding who is likely to benefit from CBT for psychosis (CBTp), though little is understood in terms of their views on who benefits from CBTp. AIMS: This study investigated clinicians' views on client characteristics that influence outcome in CBTp. METHOD: A Q-set of 61 client characteristics was developed from a literature search and interviews with clinicians experienced in working with CBT and/or psychosis. Twenty-one participants (familiar with psychosis and CBT through education, profession, practice or knowledge) rated the items based on their importance in effecting a positive outcome, on a forced normal distribution. RESULTS: 21 completed Q-sorts yielded four factors, named as: acceptance and application of the cognitive model; attending to the present; secure base; meaningful active collaboration. CONCLUSIONS: Items regarding therapeutic alliance were highly endorsed throughout all factors. Some empirically-based items were not endorsed, although overall, clinician responses were consistent with prior research. PMID- 26109127 TI - Innate immunity: New PAMP discovered. PMID- 26109131 TI - B cells: Mediators of central tolerance. PMID- 26109133 TI - Cellulose production in Pseudomonas syringae pv. syringae: a compromise between epiphytic and pathogenic lifestyles. AB - Genome sequencing and annotation have revealed a putative cellulose biosynthetic operon in the strain Pseudomonas syringae pv. syringae UMAF0158, the causal agent of bacterial apical necrosis. Bioinformatics analyses and experimental methods were used to confirm the functionality of the cellulose biosynthetic operon. In addition, the results showed the contribution of the cellulose operon to important aspects of P. syringae pv. syringae biology, such as the formation of biofilms and adhesion to the leaf surface of mango, suggesting that this operon increases epiphytic fitness. However, based on the incidence and severity of the symptoms observed in tomato leaflets, cellulose expression reduces virulence, as cellulose-deficient mutants increased the area of necrosis, whereas the cellulose overproducing strain decreased the area of necrosis compared with the wild type. In conclusion, the results of this study show that the epiphytic and pathogenic stages of the P. syringae pv. syringae UMAF0158 lifestyle are intimately affected by cellulose production. PMID- 26109132 TI - Genetic susceptibility to invasive Salmonella disease. AB - Invasive Salmonella disease, in the form of enteric fever and invasive non typhoidal Salmonella (iNTS) disease, causes substantial morbidity and mortality in children and adults in the developing world. The study of genetic variations in humans and mice that influence susceptibility of the host to Salmonella infection provides important insights into immunity to Salmonella. In this Review, we discuss data that have helped to elucidate the host genetic determinants of human enteric fever and iNTS disease, alongside data from the mouse model of Salmonella infection. Considered together, these studies provide a detailed picture of the immunobiology of human invasive Salmonella disease. PMID- 26109134 TI - Metagenomic analyses reveal no differences in genes involved in cellulose degradation under different tillage treatments. AB - Incorporation of plant litter is a frequent agricultural practice to increase nutrient availability in soil, and relies heavily on the activity of cellulose degrading microorganisms. Here we address the question of how different tillage treatments affect soil microbial communities and their cellulose-degrading potential in a long-term agricultural experiment. To identify potential differences in microbial taxonomy and functionality, we generated six soil metagenomes of conventional (CT) and reduced (RT) tillage-treated topsoil samples, which differed in their potential extracellular cellulolytic activity as well as their microbial biomass. Taxonomic analysis of metagenomic data revealed few differences between RT and CT, and a dominance of Proteobacteria and Actinobacteria, whereas eukaryotic phyla were not prevalent. Prediction of cellulolytic enzymes revealed glycoside hydrolase families 1, 3 and 94, auxiliary activity family 8 and carbohydrate-binding module 2 as the most abundant in soil. These were annotated mainly to the phyla of Proteobacteria, Actinobacteria and Bacteroidetes. These results suggest that the observed higher cellulolytic activity in RT soils can be explained by a higher microbial biomass or changed expression levels but not by shifts in the soil microbiome. Overall, this study reveals the stability of soil microbial communities and cellulolytic gene composition under the investigated tillage treatments. PMID- 26109135 TI - Distribution patterns of bacterioplankton in the oligotrophic south-eastern Mediterranean Sea. AB - The spatial variability in the composition of bacterioplankton communities from the Levantine basin off the Israeli coast (south-eastern Mediterranean Sea) was studied using water samples from nine stations down to 1880 m depth. An nMDS (non metric multidimensional scaling) ordination plot of ARISA (automated rRNA intergenic spacer analyses) fingerprints performed on 39 water samples revealed three groups of communities based on depth (epi, meso and bathypelagial waters), while the stations' geographical location did not seem to have an effect on the distribution of bacterioplankton assemblages. Interestingly, communities from the two deep pelagic zones were further grouped depending on the three prevailing water masses in the Levantine basin, and depth, salinity, temperature and silicic acid were significantly related to the variations of the bacterial community compositions. Cloning of internal transcribed spacer (ITS) sequences of dominant ARISA peaks showed that abundant bacteria in all depths were ubiquitous uncultured Alpha- and Gammaproteobacteria. The results further indicate that distinct microbial community profiles in the Levantine basin are associated with prevailing water masses that have formed due to different physico-chemical parameters and thus might act as physical barriers rather than physiological discriminators, as has been suggested in studies from other ocean regions. PMID- 26109136 TI - Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID(2) ): an evidence-based mnemonic for the treatment of systolic heart failure. AB - Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline-based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID (2) , standing for beta-blocker, angiotensin converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega-3 fatty acids, statins or anti-thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence-based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition. PMID- 26109137 TI - Interventions to prevent tenant evictions: a systematic review. AB - Tenant evictions are a significant cause of homelessness. As evictions are a traumatic experience for those being evicted and involve high costs, preventing evictions is vital and should be part of local and national policy. In order to develop and implement preventive practices and policies, it is essential to know which interventions are effective in preventing evictions. However, little is known about these interventions. Therefore, a systematic search of the international literature, providing an overview of interventions to prevent evictions published in scientific journals and reporting on their (cost )effectiveness, was conducted. Nine electronic databases and Google Scholar were searched for peer-reviewed and non-reviewed publications describing research into interventions to prevent tenant evictions published in English between January 1985 and May 2012. Two researchers reviewed titles, abstracts and full-text articles and eventually seven publications describing eight interventions to prevent tenant evictions were analysed. The eight interventions vary widely in terms of their target population, focus, type of support and duration, which makes comparison of results difficult. Only three effect studies on preventive interventions regarding tenant evictions were found; two researchers assessed their quality. One of these studies was of insufficient quality to assess the effectiveness of the intervention described. Legal assistance and debt advice are promising interventions that seem to be effective in decreasing the risk of eviction. The effectiveness of the other five interventions cannot be determined. More methodologically sound research into the prevention of tenant evictions is needed and future research will have to clarify what works for whom, in which context. PMID- 26109138 TI - Photodynamic therapy using talaporfin sodium induces concentration-dependent programmed necroptosis in human glioblastoma T98G cells. AB - Photodynamic therapy (PDT) using photosensitizer induces several types of cell death, such as apoptosis, necrosis, and autophagy, depending on the PDT procedure, photosensitizer type, and cell type. We previously demonstrated that PDT using the photosensitizer talaporfin sodium (mono-L-aspartyl chlorine e6, NPe6; NPe6-PDT) induces both mitochondrial apoptotic and necrotic cell death in human glioblastoma T98G cells. However, details regarding the mechanism of necrosis caused by NPe6-PDT are unclear. Here, we investigated whether or not necroptosis, a recently suggested form of programmed necrosis, is involved in the necrotic cell death of NPe6-PDT-treated T98G cells. Leakage of lactate dehydrogenase (LDH) from the cell layer into conditioned medium was significantly increased by NPe6 (25 and 50 MUg/ml)-PDT, indicating that NPe6-PDT induces necrosis in these cells. NPe6 (25 MUg/ml)-PDT treatment also induced conversion of microtubule-associated protein 1 light-chain 3 (LC3)-I into phosphatidylethanolamine-conjugated LC3-II accompanying autophagosome formation, indicators of autophagy; however, of note, NPe6 (50 MUg/ml)-PDT did not induce such autophagic changes. In addition, both necrostatin-1 (a necroptosis inhibitor) and knockdown of necroptotic pathway-related proteins [e.g., receptor interacting serine-threonine kinase (RIP)-1, RIP-3, and mixed lineage kinase domain-like protein (MLKL)] inhibited leakage of LDH caused by NPe6 (25 MUg/ml) PDT. Taken together, the present findings revealed that NPe6-PDT-induced necrotic cell death is mediated in part by the necroptosis pathway in glioblastoma T98G cells. PMID- 26109139 TI - The new approach to the rectal cancer: 'down-to-up' double endolaparoscopic pelvic access. Preliminary evaluation of outcomes. AB - Laparoscopic access in low anterior rectal resection is widely adopted, performing an 'up-to-down' dissection. The aim of this study is to present and analyze the outcomes of a novel surgical 'down-to-up' total mesorectal excision technique that could obviate to the well-known issues of the standard treatment. 18 suitable patients underwent double endolaparoscopic pelvic access (DEPA) 'down to-up' technique. DEPA TME was completed in all patients, with intact mesorectum. Mean operative time was 365 min (range 280-510 min). The morbidity rate was 22%, including three radiologically detected leakage (grade A) and one pelvic abscess, requiring only a conservative management. Mortality rate at 30 and 90 days was 0%. Resection margins were negative in all patients. A median of 11 nodes (range 5-19) was retrieved per specimen. Mean length of hospital stay was 9 days (range 7-19 days). Patients were followed for an average of 14 months (range 0-42 months), with no recurrence. Despite exiguous patient's sample in this pilot study, transanal endoscopic TME with laparoscopic assistance seems to be feasible and safe, and is a promising alternative to open and laparoscopic TME. However, a conspicuous functional and oncologic long-term evaluation is required, before the widespread adoption could be recommended. PMID- 26109140 TI - Oncological outcomes of laparoscopic surgery of liver metastases: a single-centre experience. AB - In the era of multimodal management of liver metastases, surgical resection remains the only curative option, with open approach still being referred to as the standard of care. Currently, the feasibility and benefits of the laparoscopic approach for liver resection have been largely demonstrated. However, its oncologic adequacy remains to be confirmed. The aim of this study is to report the oncological results of laparoscopic liver resection for metastatic disease in a single-centre experience. A single-centre database of 413 laparoscopic liver resections was reviewed and procedures for liver metastases were selected. The assessment of oncologic outcomes included analysis of minimal tumour-free margin, R1 resection rate and 3-year survival. The feasibility and safety of the procedures were also evaluated through analysis of perioperative outcomes. The study comprised 209 patients (294 procedures). Colorectal liver metastases were the commonest indication (67.9%). Fourteen patients had conversion (6.7%) and oncological concern was the commonest reason for conversion (42.8%). Median tumour-free margin was 10 mm and complete radical resections were achieved in 211 of 218 curative-intent procedures (96.7%). For patients affected by colorectal liver metastases, 1- and 3-year OS resulted 85.9 and 66.7%. For patients affected by neuroendocrine liver metastases, 1- and 3-year OS resulted 93 and 77.8%. Among the patients with metastases from other primaries, 1- and 3-year OS were 83.3 and 70.5%. The laparoscopic approach is a safe and valid option in the treatment of patients with metastatic liver disease undergoing curative resection. It does offer significant perioperative benefits without compromise of oncologic outcomes. PMID- 26109141 TI - Methylenetetrahydrofolate Reductase CpG Islands: Epigenotyping. AB - BACKGROUND: Determination of the differential DNA methylation patterns of methylenetetrahydrofolate reductase (MTHFR) that are associated with differential MTHFR activity is important to understand the pathogenesis of ischemic stroke. However, to date, no data are available on the differential DNA methylation profiles of Kelantanese Malays. Therefore, we developed a rapid and efficient serial pyrosequencing assay to determine differential DNA methylation profiles of MTHFR, which help to further our understanding of the pathogenesis of ischemic stroke. The developed assay also served as the validation platform for our previous computational epigenetic research on MTHFR. METHODS: Polymerase chain reaction primers were designed and validated to specifically amplify the cytosine that is followed by guanine residues (CpGs) A and B regions. Prior epigenotyping on 110 Kelantanese Malays, the serial pyrosequencing assays for the CpGs A and B regions were validated using five validation controls. The mean values of the DNA methylation profiles of CpGs A and B were calculated. RESULTS: The mean DNA methylation levels for CpGs A and B were 0.984 +/- 0.582 and 2.456 +/- 1.406, respectively. The CpGs 8 and 20 showed the highest (5.581 +/- 4.497) and the lowest (0.414 +/- 2.814) levels of DNA methylation at a single-base resolution. CONCLUSION: We have successfully developed and validated a pyrosequencing assay that is fast and can yield high-quality pyrograms for DNA methylation analysis and is therefore applicable to high throughput study. Using this newly developed pyrosequencing assay, the MTHFR DNA methylation profiles of 110 Kelantanese Malays were successfully determined. It also validated our computational epigenetic research on MTHFR. PMID- 26109142 TI - Choroidal metastasis from primary bone leiomyosarcoma. AB - Choroidal metastases, the most common form of intraocular malignancies, are principally caused by primary tumors from breast, lung, and gastrointestinal tract. These lesions are mostly symptomatic and rarely detected incidentally in the extension study of a previously diagnosed tumor. Leiomyosarcoma is a neoplasm of mesenchymal cells with smooth muscle differentiation and represents the most prevalent soft-tissue sarcoma. Leiomyosarcoma is a notably rare tumor in ophthalmic region. We report a case of primary bone leiomyosarcoma metastatic to the choroid that was treated with chemotherapy and surgery. Although three cases of choroidal metastasis from leiomyosarcomas have been already reported, to our knowledge this is the first case of choroidal metastasis from primary bone leiomyosarcoma. PMID- 26109143 TI - A Clinical Investigation of Contralateral Neurological Symptom after Transforaminal Lumbar Interbody Fusion (TLIF). AB - BACKGROUND: The aim of this study was to analyze treatment outcomes and morbidity of contralateral neurological symptom in patients after TLIF surgery and to explore its possible causes. MATERIAL AND METHODS: A retrospective study was conducted involving a total of 476 patients who underwent TILF from 2009 to 2012 in our hospital. These cases were divided into a symptomatic group (Group S) and a non-symptomatic group. The differences in contralateral foramen area and disc height index(DHI) before and after surgery were compared between Group S and a random sample of 40 cases of non-symptomatic group patients (group N). In addition, according to whether the patient underwent second surgery, Group S patients were further divided into a transient neurologic symptoms group (Group T) and an operations exploration group (Group O). The time of symptom appearance, duration, and symptomatic severity (JOA VAS score) were compared between Group T and O. RESULTS: Among the 476 patients, 18 had postoperative contralateral neurological symptoms; thus, the morbidity was 3.7815%. The indicators in Group S were lower than in Group N in the differences in contralateral foramen area and disc-height index(DHI) before and after surgery (p<0.05). Five patients (Group O) in Group S had second surgery because of invalid conservative treatment. The surgical exploration rate was 1.0504%. Compared with Group T, the symptoms of Group O patients appeared earlier, persisted longer, and were more serious (p<0.05). CONCLUSIONS: Contralateral neurological symptom is a potential complication after TLIF, and its causes are diverse. Surgical explorations should be conducted early for those patients with the complication who present with obvious nerve damage. PMID- 26109144 TI - Using a nano-flare probe to detect RNA in live donor cells prior to somatic cell nuclear transfer. AB - Many transgenes are silenced in mammalian cells (donor cells used for somatic cell nuclear transfer [SCNT]). Silencing correlated with a repressed chromatin structure or suppressed promoter, and it impeded the production of transgenic animals. Gene transcription studies in live cells are challenging because of the drawbacks of reverse-transcription polymerase chain reaction and fluorescence in situ hybridization. Nano-flare probes provide an effective approach to detect RNA in living cells. We used 18S RNA, a housekeeping gene, as a reference gene. This study aimed to establish a platform to detect RNA in single living donor cells using a Nano-flare probe prior to SCNT and to verify the safety and validity of the Nano-flare probe in order to provide a technical foundation for rescuing silenced transgenes in transgenic cloned embryos. We investigated cytotoxic effect of the 18S RNA-Nano-flare probe on porcine fetal fibroblasts, characterized the distribution of the 18S RNA-Nano-flare probe in living cells and investigated the effect of the 18S RNA-Nano-flare probe on the development of cloned embryos after SCNT. The cytotoxic effect of the 18S RNA-Nano-flare probe on porcine fetal fibroblasts was dose-dependent, and 18S RNA was detected using the 18S RNA-Nano-flare probe. In addition, treating donor cells with 500 pM 18S RNA-Nano-flare probe did not have adverse effects on the development of SCNT embryos at the pre-implantation stage. In conclusion, we established a preliminary platform to detect RNA in live donor cells using a Nano-flare probe prior to SCNT. PMID- 26109145 TI - Epidemiologic and Mechanistic Associations Between Smoking and Pancreatitis. AB - OPINION STATEMENT: Alcohol has long been associated with pancreatitis. Although first described more than three decades ago, smoking has been widely accepted as an important risk factor for all forms of pancreatitis only in the past few years. Empiric data has confirmed smoking as an independent and dose-dependent risk for both acute and chronic pancreatitis. Smoking also increases the risk of recurrences and progression of established chronic pancreatitis. The effects of smoking are enhanced in the presence of alcohol consumption. Indirect evidence suggests that smoking cessation may be beneficial in preventing disease progression. Smoking cessation can therefore be an important strategy for primary as well as secondary prevention of pancreatitis. Therefore, in addition to alcohol, physicians should routinely counsel patients for the benefits of smoking cessation. The mechanisms through which cigarette smoke triggers pathological cellular events, resulting in pancreatitis, are unresolved. Although cigarette smoke contains greater than 4000 compounds, principally nicotine and the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) have been broadly studied with regard to pancreatic diseases. Both nicotine and NNK have been shown to induce morphological changes in the pancreas consistent with those seen in pancreatitis. Furthermore, nicotine affects pancreatic secretion and NNK induces premature zymogen activation, two well-known features of pancreatitis. These cigarette toxins may mediate both pro- and anti-inflammatory pathways and can induce changes in pancreatic acinar cell function at the level of transcription, leading to conditions such as thiamin deficiency and mitochondrial dysfunction. Such circumstances could leave the pancreas prone to the development of pancreatitis. This review summarizes relevant research findings and focuses on the epidemiologic links between smoking and pancreatitis, and the cellular pathways that may be significant in induction and evolution of smoking-related pancreatitis. PMID- 26109146 TI - Production of conjugated linoleic acid by heterologous expression of linoleic acid isomerase in oleaginous fungus Mortierella alpina. AB - OBJECTIVE: To increase the commercial value of oleaginous fungus Mortierella alpina by incorporation of trans-10,cis-12 conjugated linoleic acid (CLA) into the polyunsaturated fatty acids (PUFAs) of M. alpina via Propionibacterium acnes isomerase (PAI) conversion. RESULTS: The PAI gene and the codon optimization version were heterologously expressed in M. alpina via Agrobacterium tumefaciens mediated transformation (ATMT). Coding usage modification significantly improved the translation of PAI transcripts and trans-10,cis-12 CLA was produced up to 1.2 mg l(-1), which corresponds to approx. 0.05% of the total fatty acid (TFA). Since PAI prefers free linoleic acid as a substrate rather than any other forms, 5 MUM long-chain acyl CoA synthetase inhibitor was added and the trans-10,cis-12 CLA content increased approx. 24-fold to 29 mg l(-1), reaching up to 1.2% (w/w) of the TFA in M. alpina. CONCLUSION: Heterologous expression of PAI in M. alpina by ATMT methods is a practicable way in biosynthesis of CLA and this system may be a feasible platform for industrial production of CLA. PMID- 26109149 TI - What do pregnant women think of student training? AB - BACKGROUND: Clinical experience is fundamental for medical and midwifery student education. Patient willingness for student participation is perceived as low in obstetrics and gynaecology. We explored the views of pregnant women on medical and midwifery student training. METHODS: Pregnant women were invited to participate in a cross-sectional survey at antenatal out-patient clinics at a maternity hospital serving a regional population during June and July 2012. RESULTS: Only 53 per cent (110/206) of women reported that they would allow a medical student to assist with the delivery of their baby, and 61 per cent (127/206) would allow a midwifery student to assist; however, 84 per cent (174/206) of women were willing to undergo an obstetric abdominal examination by a medical student, and similarly 87 per cent (180/206) agreed to an examination by a midwifery student. Primigravid women were significantly less likely to agree to student assistance at delivery compared with parous women for medical (p < 0.01) and midwifery students (p = 0.02). Women appear generally more willing to accept midwifery students compared with medical students (p < 0.01). Women who would decline student participation expressed concerns over lack of student supervision, desire for privacy, student training level, need for 'experienced' staff and concerns regarding first or previous complicated pregnancies. Patient willingness for student participation is perceived as low in obstetrics and gynaecology DISCUSSION: Negative attitudes remain towards students in the labour ward. Women have concerns over student supervision and competence. Research is needed to address women's reluctance to student participation during labour and delivery to determine if particular fears exist related to birth. The development of innovative educational tools could address specific modifiable concerns that pregnant women have with student training in the labour ward. PMID- 26109147 TI - PLCepsilon signaling in cancer. AB - PURPOSE: As one of the members of the PLC family, the phosphoinositide-specific phospholipase Cepsilon (PLCepsilon) has been shown to play pivotal roles in multiple signal pathways and control a variety of cellular functions. A number of studies have shown that aberrant regulation of PLCepsilon was involved in various types of animal and human cancer. However, the role of PLCepsilon in cancer remains elusive. In this review, we provide an overview of the PLCepsilon, especially its roles in multiple signal pathways, and summarize the recent findings that highlight the roles of PLCepsilon in carcinogenesis and cancer progression, making an avenue to provide a novel therapeutic strategy for the treatment of cancer. METHODS: A literature search mainly paying attention to the network of PLCepsilon involved in tumorigenesis and development was performed in electronic databases. RESULTS: PLCepsilon plays a key role in medicating the development and progression of human cancers with highest potency to be a target of cancer prevention and treatment. PMID- 26109150 TI - Surfactants have multi-fold effects on skin barrier function. AB - BACKGROUND: The stratum corneum (SC) is responsible for the barrier properties of the skin and the role of intercorneocyte skin lipids, particularly their structural organization, in controlling SC permeability is acknowledged. Upon contacting the skin, surfactants interact with the SC components leading to barrier damage. OBJECTIVE: To improve knowledge of the effect of several classes of surfactant on skin barrier function at three different levels. METHODS: The influence of treatments of human skin explants with six non-ionic and four ionic surfactant solutions on the physicochemical properties of skin was investigated. Skin surface wettability and polarity were assessed through contact angle measurements. Infrared spectroscopy allowed monitoring the SC lipid organization. The lipid extraction potency of surfactants was evaluated thanks to HPLC-ELSD assays. RESULTS: One anionic and one cationic surfactant increased the skin polarity by removing the sebaceous and epidermal lipids and by disturbing the organization of the lipid matrix. Another cationic surfactant displayed a detergency effect without disturbing the skin barrier. Several non-ionic surfactants disturbed the lipid matrix organization and modified the skin wettability without any extraction of the skin lipids. Finally two non-ionic surfactants did not show any effect on the investigated parameters or on the skin barrier. CONCLUSIONS: The polarity, the organization of the lipid matrix and the lipid composition of the skin allowed describing finely how surfactants can interact with the skin and disturb the skin barrier function. PMID- 26109151 TI - Do hip prosthesis related infection codes in administrative discharge registers correctly classify periprosthetic hip joint infection? AB - PURPOSE: Administrative discharge registers could be a valuable and easily accessible single-sources for research data on periprosthetic hip joint infection. The aim of this study was to estimate the positive predictive value of the International Classification of Disease 10th revision (ICD-10) periprosthetic hip joint infection diagnosis code in the Danish National Patient Register. METHODS: Patients were identified with an ICD-10 discharge diagnosis code of T84.5 ("Infection and inflammatory reaction due to internal joint prosthesis") in association with hip-joint associated surgical procedure codes in The Danish National Patient Register. Medical records of the identified patients (n = 283) were verified for the existence of a periprosthetic hip joint infection. Positive predictive values with 95% confidence intervals (95% CI) were calculated. RESULTS: A T84.5 diagnosis code irrespective of the associated surgical procedure code had a positive predictive value of 85% (95% CI: 80-89). Stratified to T84.5 in combination with an infection-specific surgical procedure code the positive predictive value increased to 86% (95% CI: 80-91), and in combination with a noninfection-specific surgical procedure code decreased to 82% (95% CI: 72-89). CONCLUSIONS: Misclassification must be expected and taken into consideration when using administrative discharge registers for epidemiological research on periprosthetic hip joint infection. We believe that the periprosthetic hip joint infection diagnosis code can be of use in future single-source register based studies, but preferably should be used in combination with alternate data sources to ensure higher validity. PMID- 26109148 TI - Loss of fatty acid synthase suppresses the malignant phenotype of colorectal cancer cells by down-regulating energy metabolism and mTOR signaling pathway. AB - PURPOSE: Altered cellular metabolism has received increased attention as an important hallmark of cancer. Activation of FASN has been found to be involved in many human tumors. Despite extensive research in FASN function on cancer, the underlying mechanism is not entirely understood yet. METHODS: Cerulenin was used to suppress the FASN expression in human colorectal cancer cell lines (HT29 and LoVo). Expression of PI3K, Akt, p-Akt, mTOR, p-mTOR, FASN, and AZGP1 was measured using western blotting and qPCR. ATP and lactic acid were assessed to investigate the activation of energy metabolism. Cell cytotoxicity assay was studied by cell counting kit-8 assay. The capacity of cell proliferation and migration was investigated by clonogenic and invasion assay. Analysis of apoptosis and the cell cycle was detected by flow cytometry. RESULTS: We found that the expression of FASN was down-regulated, while the expression of PI3K, p-Akt, p-mTOR, and AZGP1 was down-regulated in HT29 and LoVo cells treated with FASN inhibitor. Proliferation was reduced in FASN inhibitor-treated cells, which is consistent with an increased apoptosis rate. Furthermore, the migration of FASN inhibitor treated cells was decreased and the content of ATP and lactic acid was also dropped. CONCLUSION: These findings suggest that inhibited FASN suppresses the malignant phenotype of colorectal cancer cells by down-regulating energy metabolism and mTOR signaling pathway. The results have paved the way to understand the relations of FASN, mTOR signaling pathway, and energy metabolism in colorectal cancer cells. PMID- 26109152 TI - Prognostic factors for mid-term symptom relief after open surgical correction for femoroacetabular impingement. AB - BACKGROUND: We sought to identify, which patient and radiographic factors at preoperative and 1-year follow up will predict patient symptom relief at mid term. MATERIALS AND METHODS: A total of 50 hips in 47 patients with symptomatic FAI were included in this retrospective study. We stratified the hips into "success" and "failure" groups based on the change from baseline to mid-term follow up WOMAC pain score (mean follow up of 5.8 years). An attempt was made to identify factors that are predictive of mid-term outcome among preoperative radiographic measures, dGEMRIC index, range of motion and WOMAC score as well as 1-year follow-up range of motion, radiographic measures, and WOMAC pain scores. RESULTS: At 1-year follow up, the success rate was 72% (36/50) and at mid-term follow the success rate increased to 82% (41/50). There were no significant associations between mid-term pain scores and baseline factors (all p-values >=0.10). One-year pain score and hip internal rotation was associated with poor mid-term pain scores but only the 1-year pain score was associated with the mid term success/failure outcome. CONCLUSIONS: We did not identify clear preoperative predictors of mid-term results but patients with poor pain scores and limited hip internal rotation at 1-year follow-up are less likely to do well at mid-term. PMID- 26109153 TI - Predicting high blood metal ion concentrations following hip resurfacing. AB - PURPOSE: To determine whether gender, femoral head size, acetabular inclination, and time since surgery predicted high blood metal ion concentrations following Birmingham Hip Resurfacing (BHR). METHODS: BHR patients with unilateral bearings at one specialist centre with blood cobalt and chromium concentrations measured up to May 2013 were included. This comprised a mixed (at-risk) group including symptomatic patients and asymptomatic individuals with specific clinical and/or radiological findings. Blood sampling was at a mean of 7.5 years (range 1-15.4 years) postoperatively. RESULTS: Of 319 patients (mean age 49.3 years; 53% male), blood metal ions greater than 7 ug/l were observed in 9% (n = 28). Blood metal ions were significantly higher in females (p<0.001), femoral head sizes <=48 mm (p<0.01), and cup inclinations >55 degrees (p<0.001). Linear regression demonstrated femoral head size was responsible for the highest proportion of variance in blood metal ions (cobalt p<0.001, R2 = 8%; chromium p<0.001, R2 = 11%). Analysis of femoral head size and inclination together demonstrated 36% of BHRs with head sizes of 38-44 mm and inclination >55 degrees had blood metal ions >7 ug/l. BHR 10-year survival for this at-risk group was 91% (95% confidence intervals 86.0%-95.0%) with 30 hips revised. CONCLUSIONS: If blood metal ions are used to screen hip resurfacing patients for adverse reactions to metal debris it is recommended those with small femoral head sizes (38-44 mm) and high acetabular inclinations (>55 degrees ) are targeted. These findings require validation in other cohorts as they may not be applicable to all hip resurfacing devices given the differences in radial clearance, coverage arc, and metallurgy. PMID- 26109154 TI - Outcome of the Stryker(r) Trident 'All-Poly' constraint acetabular insert: a district general hospital experience. AB - INTRODUCTION: Constrained acetabular inserts are designed as revision solutions for unstable total hip arthroplasties to prevent dislocation and as a possible primary option for elderly patients at risk of recurrent dislocation. PURPOSE: Our aim was to establish clinical and radiological outcomes of an 'all-poly' constrained acetabular device and to highlight reasons for component failure. METHODS: We retrospectively reviewed our use of the Stryker(r) Trident 'all-poly' constrained acetabular insert between 2008 and 2013. All inserts were cemented directly into the acetabulum. Demographic data was collated. The indication for use of a constrained insert and postoperative complications were determined. Patients were reviewed clinically and underwent radiographic follow-up. RESULTS: A total of 56 constrained inserts were utilised during the study period. Follow up was for a minimum of 2 years (mean 4.0 years and range 2.0-6.8 years). The mean latest follow-up Oxford hip score was 34.6 (11-48). One postoperative superficial wound infection, 1 breakage of the constraining ring without clinical consequence and 1 recognised complication of liner failure at the bipolar interface were noted. CONCLUSIONS: In the short to medium term, acetabular constraint offers a useful primary or revision option in patients at risk or with recurrent dislocation. PMID- 26109155 TI - Late onset imminent femoral fatigue fracture associated with intraoperative cement extrusion as a rare cause of thigh pain after total hip replacement. AB - INTRODUCTION: Cement extrusions on the femoral side after total hip replacement can occur in approximately 0.3% of cemented primary total hip replacements. Not recognised until a postoperative x-ray is performed, the willingness to dismiss and treat these extrusions conservatively is high. METHODS: We report on 3 patients presenting with sudden onset of thigh pain associated with an inability to weight-bear after a 2 to 15 month period of uneventful healthy recovery from cemented total hip replacement. On immediate postoperative x-rays occult cement extrusion in the posterolateral circumference of the femoral component tip were present. X-rays and CT scans showed no fracture signs. Scintigraphy revealed late increased uptake at the extrusion height. With the hypothesis of imminent femoral fatigue fracture, all patients underwent revision surgery. The defect sites were surgically exposed, thoroughly cleaned of cement, filled with iliac crest bone graft and stabilised with tension band plating. RESULTS: This procedure resulted in fully recovered asymptomatic patients at 6 weeks and after a mean follow-up period of 48 months, as demonstrated by their pain level and tolerance of full weight bearing. CONCLUSIONS: These cases lead us to adopt a low threshold for immediate revision when occult cement extrusion is recognised near the tip of a cemented stem on postoperative films, and to adopt a low threshold for surgical revision when, in the presence of cement extrusion, thigh pain is a complaint. We favour tension band plating and bone grafting over more complex implant revisions since a fast recovery was achieved in these patients. PMID- 26109156 TI - Hip resurfacing: history, current status, and future. AB - Hip resurfacing arthroplasty (HRA) presents several advantages over conventional total hip arthroplasty (THA), including conservation and preservation of bone, reduced risk of dislocation, easy replication of hip biomechanics and easy revision if needed. It is a particularly appealing procedure for young patients. HRA has been performed for over 40 years following the same technological advances as THA. The bearing material used by most designs is metal-on-metal (MoM), which has the best compromise between strength and wear properties. However, MoM HRA has a specific set of possible complications. Aseptic femoral failures were initially the most prevalent cause for revision but progress in patient selection and surgical technique seem to have resolved this problem. Wear related failures (high metal ion levels and adverse local tissue reactions) are now the main concern, and are essentially associated with poor acetabular component design and orientation, to which MoM is more sensitive than other bearing materials. The concept of functional coverage is key to understanding how MoM bearings are affected by edge wear. Only a 3-D assessment of cup position (e.g., the contact patch to rim distance) provides the necessary information to determine the role of cup positioning in relationship with abnormal bearing wear.The concept of hip resurfacing is more valid today than ever as the age of the patients in need of hip arthroplasty keeps getting lower. The recent publication of several excellent long-term survivorship results suggests that selection of a well-designed resurfacing system and accuracy in the placement of the cup can achieve long-term durability. PMID- 26109157 TI - Two-stage management of the infected total hip arthroplasty. AB - There is currently no consensus on the optimal management of the infected total hip arthroplasty. Multiple management techniques have been described in contemporary literature.This paper focuses on 2-stage revision for the infected total hip arthroplasty. We discuss the rationale and examine the current evidence for the use of this technique. PMID- 26109158 TI - Effect of angular deformities of the proximal femur on impingement-free hip range of motion in a three-dimensional rigid body model. AB - INTRODUCTION: Abnormalities in hip morphology can reduce range of motion (ROM) through femoroacetabular impingement (FAI). Structural issues, such as asphericity of the head-neck junction and regional or global acetabular over coverage, have been extensively discussed in the literature. The effect of varying femoral neck-shaft angle or torsion on native hip range of motion, however, has been poorly studied. Our hypothesis was that varying neck-shaft angles or femoral torsion affect the impingement-free ROM of the hip and can be treated by femoral osteochondroplasty or acetabular rim resection. MATERIAL AND METHODS: A computer-aided design tool and a 3-D model of the hip were used to simulate incremental deformation of the proximal femur. Neck-shaft angles ranging from 90-160 degrees , and femoral torsions ranging from -15-50 degrees , were created. Femoroacetabular impingement was defined as bone-to-bone contact within physiological hip ROM, as described in the literature. RESULTS AND CONCLUSION: With decreasing neck-shaft angles (<=110 degrees ) or femoral torsion (<=10 degrees ), impingement occurred at the anterosuperior rim area. With increasing neck-shaft angles (>=135 degrees ) and femoral torsion (>=25 degrees ) posteroinferior or ischiofemoral impingement occurred. Acetabular rim trimming could compensate for neck-shaft angles >=90 degrees and femoral torsion >=-5 degrees , without creating acetabular dysplasia. Femoral impingement zones in low neck-shaft and low femoral torsion angles were found to be distal to the head neck junction at the mid-cervical region. The cross-sectional area at this neck region was the smallest, and thus osteochondroplasty at this location may prove potentially dangerous. PMID- 26109159 TI - Pelvic reference selection in patients with unilateral Crowe type IV DDH for measuring leg length inequality. AB - We identified the presence of deformities in the affected pelvis of unilateral Crowe type IV DDH patients, and if present, whether the teardrop and ischial lines were parallel with the sacral base line. We also verified whether the sacral base line provided a better pelvic landmark than the teardrop line for determining leg length inequality (LLI). After leveling the pelvis by using a block to lift the short leg, standard anterior-posterior full-length radiography was performed on 10 patients and 10 healthy volunteers as controls. The ratio of pelvic heights on each side of the pelvis, the angles formed by the sacral base line and the other 2 lines between 2 groups were measured. LLI were measured by sacral base line and teardrop line respectively. The ratio between the pelvic heights was lower in the patient group than in the control group (0.95 versus 0.99). The angles between the teardrop and ischial lines and the sacral base line in the patient group were both greater than in the control group (6.08 degrees versus 0.92 degrees and 7.13 degrees versus 0.97 degrees ). LLI measured from the sacral base line was larger than from the teardrop line in the patient group (5.55 cm versus 4.36 cm). There was pelvic asymmetry and the sacral base line was not parallel with the other 2 lines in unilateral Crowe type IV DDH. The leveled sacral base line was perpendicular to the longitudinal axis of the body, and may be a better choice for accurate LLI measurement in this situation. PMID- 26109160 TI - One-stage exchange for prosthetic joint infection of the hip. AB - Exchange arthroplasty remains the gold standard of treatment of established prosthetic joint infection. This can be achieved using a one or two stage approach. The ENDO-Klinik, in Hamburg, has pioneered the one-stage technique since 1970 utilising antibiotic loaded acrylic cement (ALAC). This editorial discusses the relevant literature and describes the indications and surgical technique employed by the ENDO-Klinik Hamburg. PMID- 26109161 TI - Erratum. PMID- 26109162 TI - Erratum. PMID- 26109164 TI - Mutagenesis of an Asn156 Residue in a Surface Region of S-Selective Hydroxynitrile Lyase from Baliospermum montanum Enhances Catalytic Efficiency and Enantioselectivity. AB - The S-selective hydroxynitrile lyase from Baliospermum montanum (BmHNL) has broad substrate specificity toward aromatic substrates as well as high temperature stability, although with low enantioselectivity and specific activity. To expand the industrial application of this enzyme, we improved its enantioselectivity and specific activity toward (S)-mandelonitrile by mutagenesis. The specific activity of the BmHNL H103C/N156G mutant for (S)-mandelonitrile production was raised to 154 U mg-1 (WT BmHNL: 52 U mg-1 ). The enantiomeric excess was increased to 93 % (WT BmHNL: 55 %). The kinetic analysis revealed Km for (R)-mandelonitrile and kcat for (S)-mandelonitrile increased by the mutation at Asn156, thus contributing to the increase in enantiomeric excess. This is the first report on an improvement in catalytic efficiency and enantiomeric excess of BmHNL for (S) mandelonitrile synthesis by random and site-directed mutagenesis. PMID- 26109165 TI - Dynamically configurable hybridization of plasmon modes in nanoring dimer arrays. AB - We present a novel strategy capable of dynamically configuring the plasmon induced transparency (PIT) effect with a polarization-dependent controllability based on a nanoring dimer array. The controllable coupling strength between the superradiant and subradiant modes is due to the polarization-dependent field distributions. It is shown that this dynamically controlled PIT is realized with a modulation depth as high as 95%, and a linear dependence of the coupling strength on polarization angle is deduced using a coupled-oscillator model. We believe that our results will inspire further exciting achievements that utilize various polarization states of the electromagnetic wave and pave a way towards applications using PIT with dynamic controllability such as slow light, optical nonlinearities and chemical/bio-sensing. PMID- 26109166 TI - Skeletal muscle interleukin-6 regulates metabolic factors in iWAT during HFD and exercise training. AB - OBJECTIVE: To investigate the role of skeletal muscle (SkM) interleukin (IL)-6 in the regulation of adipose tissue metabolism. METHODS: Muscle-specific IL-6 knockout (IL-6 MKO) and IL-6(loxP/loxP) (Floxed) mice were subjected to standard rodent diet (Chow), high-fat diet (HFD), or HFD in combination with exercise training (HFD ExTr) for 16 weeks. RESULTS: Total fat mass increased (P < 0.05) in both genotypes with HFD. However, HFD IL-6 MKO mice had lower (P < 0.05) inguinal adipose tissue (iWAT) mass than HFD Floxed mice. Accordingly, iWAT glucose transporter 4 (GLUT4) protein content, 5'AMP activated protein kinase (AMPK)(Thr172) phosphorylation, and fatty acid synthase (FAS) mRNA content were lower (P < 0.05) in IL-6 MKO than Floxed mice on Chow. In addition, iWAT AMPK(Thr172) and hormone-sensitive lipase (HSL)(Ser565) phosphorylation as well as perilipin protein content was higher (P < 0.05) in HFD IL-6 MKO than HFD Floxed mice, and pyruvate dehydrogenase E1alpha (PDH-E1alpha) protein content was higher (P < 0.05) in HFD ExTr IL-6 MKO than HFD ExTr Floxed mice. CONCLUSIONS: These findings indicate that SkM IL-6 affects iWAT mass through regulation of glucose uptake capacity as well as lipogenic and lipolytic factors. PMID- 26109167 TI - EGFP-Based Protein Nanoparticles with Cell-Penetrating Peptide for Efficient siRNA Delivery. AB - Development of an innovative nucleic acid nanocarriers still represents a challenge. In this study, we develop a protein nanoparticle (H6-TatEGFP) and examine its siRNA condensing activity. Gel retardation assay show that protein nanoparticle can condense siRNA into stable nanoparticle/siRNA complexes. UsingCy3-labelled siRNA, we also evaluate siRNA transport characteristic of protein nanoparticles in tumor cells, the results indicate that H6-TatEGFP nanoparticle may be a potential nanocarrier for siRNA in tumor cells. PMID- 26109168 TI - Self-Immolative Linkers Literally Bridge Disulfide Chemistry and the Realm of Thiol-Free Drugs. AB - The ultimate goal of controlled, intracellulardrug delivery is to get the drug to the target cell without spilling the contents in transit and then release the entire payload upon cell entry. One of the most powerful platforms to achieve this relies on the intracellular disulfide reshuffling as a trigger for drug release form the engineered prodrugs. However, utility of disulfide reshuffling for drug release is naturally applicable only to the thiol containing molecules ultimately leaving nearly all commercialized drugs beyond the scope of this platform. This is a drastic limitation. A cunning new tool of organic chemistry is fast entering the mainstream of prodrug design: the self-immolative linkers. This platform allows overcoming the natural chemical barrier and makes it possible to link virtually any drug to its carrier via a disulfide bond and engineer a specific intracellular release. It is a game-changing accomplishment of modern organic chemistry. The scope and limitations of this novel opportunity for medicinal chemistry and nanomedicine are outlined. PMID- 26109169 TI - Spatial and Orientational Structure of the Hydration Shell of Benzene in Sub- and Supercritical Water. AB - The spatial and orientational structure of the solvation shell of benzene in sub- and supercritical water are investigated by means of molecular dynamics simulations. The present study reveals different local organization of water molecules at different parts of the solute. The pi-hydrogen-bonding between benzene and water along the axial direction is found to exist even at supercritical conditions although to a reduced extent. The coordination number of benzene decreases substantially on increase of temperature and decrease of density. While the pi-hydrogen-bonded part in the axial region shows a slight expansion, the hydrophobically solvated part in the equatorial plane shows an opposite behavior as the temperature is increased from normal to the supercritical temperature. Two other distribution functions, namely the radial/angular and spatial orientational functions (SOFs) are calculated to explore the spatially resolved angular preferences of water molecules around the benzene solute. Water molecules located axial to the benzene are found to have strong inward orientation toward the solute, however an opposite behavior is found in the equatorial region. Although at supercritical conditions, the orientational distributions of water molecules are broadened, the preferential orientations in the axial and equatorial regions remain similar to that under ambient condition on average. PMID- 26109170 TI - Imagining parenthood: the possibilities and experiences of parenthood among transgender people. AB - This paper reports on a qualitative study exploring the ways in which transgender adults imagine a place for parenthood in their lives, and/or the ways they have negotiated parenthood with their transgender identity. A total of 13 transgender adults (including parents and non-parents) were interviewed with respect to their thoughts and experiences about family, relationships and parenting. The study sought to understand the possibilities for parenthood that transgender people create, despite barriers imposed by restrictive laws, medical practices and cultural attitudes. Interview data showed how normative assumptions about gender and parenthood shape the way people imagined and desired parenthood. It also showed how participants re-appropriated and resisted normative cultural scripts by either re-imagining parenthood in different terms (such as step-parenthood) or by creating different family forms, such as co-parented families. Participants reported a variety of experiences with healthcare providers when it came to conversations about fertility preservation and family building. PMID- 26109172 TI - Eosinophilic esophagitis associated with celiac disease in children. AB - BACKGROUND: Celiac disease (CD) and eosinophilic esophagitis (EoE) are distinct diseases of the gastrointestinal tract with specific clinico-pathological characteristics. Recent studies have found higher rates of EoE in patients with CD than in the general population. Our aim was to estimate the incidence of EoE among children who were diagnosed with CD over a 42-month period. METHODS: The study included patients diagnosed with CD based on endoscopy and histopathological findings between January 2010 and June 2013. Histopathology reports of esophageal biopsies were reviewed to identify all cases of EoE. The patients' presenting symptoms, laboratory evaluations, endoscopic and histopathological findings, treatments, and follow-ups were analysed. RESULTS: Fifty-six patients with CD were identified, of whom six (10.7%) were diagnosed with both CD and EoE. Four of these patients presented with abdominal pain and diarrhea, two presented with failure to thrive, and three presented with food allergies. Endoscopic and histopathological changes typical of EoE were observed in all six patients. During follow-up, two patients showed significant improvement with the gluten-free diet and a proton-pump inhibitor (PPI). Two patients improved with the elimination diet and two patients were treated with topical corticosteroid therapy. Endoscopic appearance was normal in all children on follow-up endoscopy after treatment. Biopsy samples also showed resolution of the histologic features of EoE in all of the children. CONCLUSION: The incidence of EoE in our cohort of children with CD was 10.7%, which is higher than what has been reported for the general population. In all children undergoing upper gastrointestinal endoscopy for suspected CD, coexistence of EoE should be considered. PMID- 26109171 TI - Integrated genomics has identified a new AT/RT-like yet INI1-positive brain tumor subtype among primary pediatric embryonal tumors. AB - BACKGROUND: Pediatric embryonal brain tumors (PEBTs), which encompass medulloblastoma (MB), primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (AT/RT), are the second most prevalent pediatric brain tumor type. AT/RT is highly malignant and is often misdiagnosed as MB or PNET. The distinction of AT/RT from PNET/MB is of clinical significance because the survival rate of patients with AT/RT is substantially lower. The diagnosis of AT/RT relies primarily on morphologic assessment and immunohistochemical (IHC) staining for a few known markers such as the lack of INI1 protein expression. However, in our clinical practice we have observed several AT/RT-like tumors, that fulfilled histopathological and all other biomarker criteria for a diagnosis of AT/RT, yet retained INI1 immunoreactivity. Recent studies have also reported preserved INI1 immunoreactivity among certain diagnosed AT/RTs. It is therefore necessary to re-evaluate INI1(+), AT/RT-like cases. METHOD: Sanger sequencing, array CGH and mRNA microarray analyses were performed on PEBT samples to investigate their genomic landscapes. RESULTS: Patients with AT/RT and those with INI(+) AT/RT-like tumors showed a similar survival rate, and global array CGH analysis and INI1 gene sequencing showed no differential chromosomal aberration markers between INI1(-) AT/RT and INI(+) AT/RT-like cases. We did not misdiagnose MBs or PNETs as AT/RT-like tumors because transcriptome profiling revealed that not only did AT/RT and INI(+) AT/RT-like cases express distinct mRNA and microRNA profiles, their gene expression patterns were different from those of MBs and PNETs. The most similar transcriptome profile to that of AT/RTs was the profile of embryonic stem cells. However; the transcriptome profile of INI1(+) AT/RT-like tumors was more similar to that of somatic neural stem cells, while the profile of MBs was closer to that of fetal brain tissue. Novel biomarkers were identified that can be used to distinguish INI1(-) AT/RTs, INI1(+) AT/RT-like cases and MBs. CONCLUSION: Our studies revealed a novel INI1(+) ATRT-like subtype among Taiwanese pediatric patients. New diagnostic biomarkers, as well as new therapeutic tactics, can be developed according to the transcriptome data that were unveiled in this work. PMID- 26109174 TI - Management of intermediate-risk pulmonary embolism: uncertainties and challenges. AB - Current guidelines on the treatment of acute pulmonary embolism (PE) recommend stratification of hemodynamically stable patients in 'low risk' and 'intermediate risk'. Validated risk scores, cardiac biomarkers, and imaging of the right ventricle all help in distinguishing both patient categories. The relevance of this risk stratification lies in the determination of the most optimal treatment for the individual patient. In this clinical review, we will discuss how patients with 'intermediate-risk' PE can be identified as well as recent advances in their therapeutic management. Based on a clinical case, we will highlight the indications for reperfusion therapy and the current experience with non-vitamin K dependent oral anticoagulant (NOACs) in this specific patient's category. PMID- 26109173 TI - Implementation of a stepped-wedge cluster randomized design in routine public health practice: design and application for a tuberculosis (TB) household contact study in a high burden area of Lima, Peru. AB - BACKGROUND: We designed a pragmatic stepped-wedge cluster randomized controlled trial in order to evaluate provider-initiated evaluation of household contacts (HCs) of smear positive tuberculosis (TB) cases within a routine TB program in Lima, Peru. METHODS/DESIGN: National TB program (NTP) officers of San Juan de Lurigancho District (Lima, Peru) and university-based researchers jointly designed a pragmatic stepped-wedge cluster randomized trial design in order to evaluate a planned active case finding (ACF) program for all HCs of smear positive TB cases in 34 district healthcare centres. Randomization of time to intervention initiation was stratified by health centre TB case rate. The ACF intervention included provider-initiated home visits of all new sputum smear positive TB patients in order to evaluate household contacts for active TB. Active TB was diagnosed using symptom screening, sputum screening, chest x-ray and clinical evaluation. Once initiated, ACF was provided by NTP staff and integrated into the routine DOTS TB program activities. DISCUSSION: This study protocol describes the pragmatic stepped-wedge cluster randomized trial of active household contact evaluations within an NTP. The stepped-wedge design met overlapping needs of local TB programmers and researchers to adequately evaluate the large-scale roll out of a new control program in a TB endemic setting. Multiple planning meetings were required to develop the necessary networks and in order to understand the operations, needs and goals of the NTP staff and researchers collaborating on this project. The advantages and challenges of using this study design in practice and within existing routine TB programs in a middle income country context are discussed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02174380. Registered 24 Jun 2014. PMID- 26109175 TI - Nucleated erythrocytes in blood smears of dogs undergoing chemotherapy. AB - The frequency of normoblastemia in dogs receiving chemotherapy is unknown. To provide this information, we calculated the percentage and number of nucleated erythrocytes (nRBCs) in blood of dogs treated for lymphoma (n = 284), mast cell tumour (n = 40) or carcinoma (n = 46). Relative normoblastemia (>1 or >5%) and absolute normoblastemia (>0.1 or >0.4 * 103 uL-1 ) were found after administration of vincristine (49.3, 20.5, 42.5, 19.2%, respectively), carboplatin (37.0, 2.2, 34.8, 13.0%), cyclophosphamide (30.8, 7.7, 23.1, 7.7%), doxorubicin (25.0, 8.3, 21.7, 6.7%), vinblastine and prednisone (25.0; 5.0; 22.5; 7.5%). Absolute normoblastemia was very severe (>1.0 * 103 nRBC uL-1 ) after administration of vincristine (9.6%), doxorubicin (3.3%), vinblastine and prednisone (2.5%). Absolute normoblastemia negatively correlated with RBC counts (P < 0.001) and positively (P < 0.001) with reticulocyte and WBC counts, but correlation coefficients were low (-0.19, 0.37, 0.15). Vincristine, doxorubicin or vinblastine and prednisone may induce severe normoblastemia. This may increase WBC counts and mask neutropenia associated with chemotherapy. PMID- 26109176 TI - The catheter hub disinfection cap as esophageal foreign body. AB - Disinfection caps are increasingly being used to prevent catheter-associated bloodstream infections. These devices, designed for continuous passive disinfection of catheter hubs, are typically small and often brightly colored. As such, they have the potential to become pediatric airway and esophageal foreign bodies. We report two patients who developed esophageal foreign body following ingestion of disinfection caps. Given the increasing use of these devices, it is imperative that health care providers be aware of this potential iatrogenic problem. We propose that the use of disinfection caps may not be appropriate in pediatric patients with risk factors for foreign body ingestion. PMID- 26109177 TI - Piezoelectric effect in chemical vapour deposition-grown atomic-monolayer triangular molybdenum disulfide piezotronics. AB - High-performance piezoelectricity in monolayer semiconducting transition metal dichalcogenides is highly desirable for the development of nanosensors, piezotronics and photo-piezotransistors. Here we report the experimental study of the theoretically predicted piezoelectric effect in triangle monolayer MoS2 devices under isotropic mechanical deformation. The experimental observation indicates that the conductivity of MoS2 devices can be actively modulated by the piezoelectric charge polarization-induced built-in electric field under strain variation. These polarization charges alter the Schottky barrier height on both contacts, resulting in a barrier height increase with increasing compressive strain and decrease with increasing tensile strain. The underlying mechanism of strain-induced in-plane charge polarization is proposed and discussed using energy band diagrams. In addition, a new type of MoS2 strain/force sensor built using a monolayer MoS2 triangle is also demonstrated. Our results provide evidence for strain-gating monolayer MoS2 piezotronics, a promising avenue for achieving augmented functionalities in next-generation electronic and mechanical electronic nanodevices. PMID- 26109178 TI - Coexistence of Andersen-Tawil Syndrome with Polymorphisms in hERG1 Gene (K897T) and SCN5A Gene (H558R) in One Family. AB - BACKGROUND: Andersen-Tawil Syndrome (ATS) is a channelopathy caused by mutations in KCNJ2 gene. It is characterized by symptoms of ventricular arrhythmias, periodic paralysis or muscle weakness, and dysmorphic features. ATS can present with the triad of symptoms, any combination or none of them. Risk factors for dangerous arrhythmias are unknown. The study assessed the impact of K897T polymorphism in hERG1 gene and H558R polymorphism in SCN5A gene coexisting with R218Q mutation in KCNJ2 in one family on clinical manifestation. METHODS: Family members underwent clinical assessment, ECG and genotyping. Holter monitoring was performed in mutation carriers and additionally in one family member with no mutation, but with K897T polymorphism. RESULTS: Proband with ATS mutation, K897T and H558R polymorphisms and proband's sister with ATS mutation and K897T polymorphism presented following symptoms: loss of consciousness, bidirectional and polymorphic ventricular tachycardia and about 5000 ventricular extrasystoles. Symptoms presented by the member with only the ATS mutation and by member with ATS mutation and H558R polymorphism were not as severe. U wave appeared in all examined family members regardless of the mutation presence. Studied individuals with ATS mutation had the T-peak-U-peak interval longer than 200 ms. In all ATS mutation carriers it was longer than in family members with no mutation. T-peak-T end interval was the longest (>120 ms) in members with coexisting mutation and K897T polymorphism. CONCLUSION: ATS severity possibly depends on other genes' polymorphisms. In the presented family, it could depend on the presence of K897T polymorphism in hERG1. PMID- 26109179 TI - Vitrification of human ovarian tissue: a practical and relevant alternative to slow freezing. AB - BACKGROUND: Cryopreservation of ovarian tissue can be used to preserve the fertility of patients who are about to receive treatment(s) that could compromise their future ovarian function. Here we evaluate the effectiveness of a vitrification protocol by carrying out a systematic comparison with a conventional slow-freezing method on human ovarian tissue. METHODS: Human ovarian samples (mean age 28.0 +/- 1.1 years) were processed in parallel for each cryopreservation procedure: vitrification and slow-freezing. Following warming/thawing, histological observations and a TUNEL assay in ovarian follicles were performed and compared to unfrozen control. RESULTS: Both cryopreservation protocols gave comparable histological outcomes. Percentage of intact follicles was 83.6 % following vitrification in a 1.5 M 1,2-propanediol (PrOH), 1.5 M ethylene glycol (EG) and 0.5 M raffinose solution, 80.7 % after slow-freezing in 1.5 M PrOH and 0.025 M raffinose, and 99.6 % in fresh tissue. Follicle density was unchanged by vitrification (0.6 follicles/mm2) or slow-freezing (0.5 follicles/mm2) compared to fresh tissue (0.7 follicles/mm2). Percentage of follicles with DNA fragmentation was not statistically different in vitrified (20.8 %) or slow-frozen (31.3 %) tissues compared to the unfrozen control (35.0 %). There was no difference in proportion of stroma cells with DNA fragmentation in vitrified (6.4 %) and slow-frozen (3.7 %) tissues compared to unfrozen tissue (4.2 %). CONCLUSIONS: This vitrification protocol enables good preservation of ovarian quality post-warming. The evaluation of endocrine function after vitrification need to be perform in a higher cohort to evaluate if this protocol may offer a relevant alternative to conventional slow-freezing for the cryopreservation of human ovarian tissue. PMID- 26109180 TI - The effects of resveratrol and SIRT1 activation on dystrophic cardiomyopathy. AB - The muscular dystrophies, which cause progressive weakening of the skeletal muscles, are frequently associated with cardiomyopathy. In fact, the leading cause of mortality in patients with Duchenne muscular dystrophy, the most common and most severe type of muscular dystrophy, is heart failure due to cardiomyopathy. Therefore, more effective methods for treating cardiomyopathy are expected to improve long-term outcomes for patients with Duchenne muscular dystrophy. Our recent preclinical data show that treatment with the SIRT1 activator resveratrol is beneficial for dystrophic cardiomyopathy. We examined the effects of resveratrol treatment in two different models of muscular dystrophy: dystrophin-deficient mdx mice and delta-sarcoglycan-deficient TO-2 hamsters. In both models, resveratrol suppressed cardiac hypertrophy, preserved cardiac function, and reduced tissue fibrosis in the diseased heart. Importantly, resveratrol significantly improved survival in TO-2 hamsters. Resveratrol also attenuated skeletal muscle pathology in mdx mice. These promising results indicate resveratrol's potential for clinical translation to treat cardiomyopathy in patients with muscular dystrophies. PMID- 26109182 TI - Experts disagree over necessity of hepatitis E vaccine in Nepal. PMID- 26109181 TI - Tc-MYBPA an Arabidopsis TT2-like transcription factor and functions in the regulation of proanthocyanidin synthesis in Theobroma cacao. AB - BACKGROUND: The flavan-3-ols catechin and epicatechin, and their polymerized oligomers, the proanthocyanidins (PAs, also called condensed tannins), accumulate to levels of up to 15 % of the total weight of dry seeds of Theobroma cacao L. These compounds have been associated with several health benefits in humans. They also play important roles in pest and disease defense throughout the plant. In Arabidopsis, the R2R3 type MYB transcription factor TT2 regulates the major genes leading to the synthesis of PA. RESULTS: To explore the transcriptional regulation of the PA synthesis pathway in cacao, we isolated and characterized an R2R3 type MYB transcription factor MYBPA from cacao. We examined the spatial and temporal gene expression patterns of the Tc-MYBPA gene and found it to be developmentally expressed in a manner consistent with its involvement in PAs and anthocyanin synthesis. Functional complementation of an Arabidopsis tt2 mutant with Tc-MYBPA suggested that it can functionally substitute the Arabidopsis TT2 gene. Interestingly, in addition to PA accumulation in seeds of the Tc-MYBPA expressing plants, we also observed an obvious increase of anthocyanidin accumulation in hypocotyls. We observed that overexpression of the Tc-MYBPA gene resulted in increased expression of several key genes encoding the major structural enzymes of the PA and anthocyanidin pathway, including DFR (dihydroflavanol reductase), LDOX (leucoanthocyanidin dioxygenase) and BAN (ANR, anthocyanidin reductase). CONCLUSION: We conclude that the Tc-MYBPA gene that encodes an R2R3 type MYB transcription factor is an Arabidopsis TT2 like transcription factor, and may be involved in the regulation of both anthocyanin and PA synthesis in cacao. This research may provide molecular tools for breeding of cacao varieties with improved disease resistance and enhanced flavonoid profiles for nutritional and pharmaceutical applications. PMID- 26109184 TI - The reactions of TiCl3, and of UF4 with TiCl3 in liquid ammonia: unusual coordination spheres in [Ti(NH3)8]Cl3.6NH3 and [UF(NH3)8]Cl3.3.5NH3. AB - TiCl3 and NH3 form octaammine titanium(III) chloride ammonia (1/6), [Ti(NH3)8]Cl3.6NH3, which is the first structurally characterized octaammine complex of a transition metal. An excess of TiCl3 reacts with UF4 in liquid NH3 and forms octaammine fluorido uranium(IV) chloride ammonia (1/3.5), [UF(NH3)8]Cl3.3.5NH3. It shows a distorted threefold-capped trigonal-prismatic coordination sphere around U(IV). PMID- 26109183 TI - Estrogen and n-3 polyunsaturated fatty acid supplementation have a synergistic hypotriglyceridemic effect in ovariectomized rats. AB - The n-3 polyunsaturated fatty acids (PUFAs), EPA and DHA, as well as estrogen have been shown to decrease circulating levels of triglyceride (TG), but their underlying mode of action is unclear. The purpose of this study was to determine the effects of n-3 PUFA consumption and estrogen injection on TG metabolism. Rats (n = 48) were fed a modified AIN-93G diet with 0, 1, or 2 % EPA + DHA relative to the total energy intake during 12 weeks. At 8 weeks, rats were ovariectomized (OVX), and after a 1-week recovery, rats were injected with either 17beta estradiol-3-benzoate (E2) or corn oil for the last 3 weeks. The n-3 PUFA consumption and E2 injection independently decreased the hepatic expressions of sterol regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase (FAS), and diacylglycerol acyltransferase 2 (DGAT2) (P < 0.05). There were interactions between n-3 PUFA consumption and E2 injection on hepatic expression of FAS and DGAT2. In addition, n-3 PUFA consumption and E2 injection up-regulated the expression of AMP-activated protein kinase (AMPK), phosphorylated AMPK, peroxisomal proliferator-activated receptor alpha, and carnitine palmitoyltransferase 1 in liver and skeletal muscle. E2 injection increased the expression of estrogen receptor alpha and beta in skeletal muscle and liver, but n-3 PUFA consumption increased the expression of both receptors only in skeletal muscle. The present study suggests that the hypotriglyceridemic effects of n-3 PUFA consumption and E2 injection could be due to the down regulation of hepatic TG synthesis and up-regulation of TG oxidation in liver and skeletal muscle in OVX rats. PMID- 26109185 TI - Expression of calcium-buffering proteins in rat intrinsic laryngeal muscles. AB - Intrinsic laryngeal muscles (ILM) are highly specialized muscles involved in phonation and airway protection, with unique properties that allow them to perform extremely rapid contractions and to escape from damage in muscle dystrophy. Due to that, they may differ from limb muscles in several physiological aspects. Because a better ability to handle intracellular calcium has been suggested to explain ILM unique properties, we hypothesized that the profile of the proteins that regulate calcium levels in ILM is different from that in a limb muscle. Calcium-related proteins were analyzed in the ILM, cricothyroid (CT), and tibialis anterior (TA) muscles from male Sprague-Dawley rats (8 weeks of age) using quantitative PCR and western blotting. Higher expression of key Ca(2+) regulatory proteins was detected in ILM compared to TA, such as the sarcoplasmic reticulum (SR) Ca(2+)-reuptake proteins (Sercas 1 and 2), the Na(+)/Ca(2+) exchanger, phospholamban, and the Ca(2+)-binding protein calsequestrin. Parvalbumin, calmodulin and the ATPase, Ca(2+)-transporting, and plasma membrane 1 were also expressed at higher levels in ILM compared to TA. The store-operated calcium entry channel molecule was decreased in ILM compared to the limb muscle and the voltage-dependent L-type and ryanodine receptor were expressed at similar levels in ILM and TA. These results show that ILM have a calcium regulation system profile suggestive of a better ability to handle calcium changes in comparison to limb muscles, and this may provide a mechanistic insight for their unique pathophysiological properties. PMID- 26109186 TI - Sex comparisons in muscle sympathetic nerve activity and arterial pressure oscillations during progressive central hypovolemia. AB - Increased tolerance to central hypovolemia is generally associated with greater sympathoexcitation, high-frequency oscillatory patterns of mean arterial pressure (MAP), and tachycardia. On average, women are less tolerant to central hypovolemia than men; however, the autonomic mechanisms governing these comparisons are not fully understood. We tested the hypothesis that women with relatively high tolerance (HT) to central hypovolemia would display similar physiological reserve capacity for sympathoexcitation and oscillations in MAP at presyncope compared to HT men. About 10 men and five women were exposed to progressive lower body negative pressure (LBNP) until the presence of presyncopal symptoms. Based on our previous classification system, all subjects were classified as HT because they completed at least -60 mmHg LBNP. Muscle sympathetic serve activity (MSNA) was measured directly from the peroneal nerve via microneurography and arterial pressure (AP) was measured at the finger by photoplethysmography. LBNP time to presyncope was less (P < 0.01) in women (1727 +/- 70 sec) than in men (2022 +/- 201 sec). At presyncope, average MSNA in men (50 +/- 12 bursts/min) and women (51 +/- 7 bursts/min) was similar (P = 0.87). Coincident with similar stroke volume (SV) at presyncope, women had similar MAP and heart rates. However, women had less physiological reserve capacity for SV, AP-MSNA coherence, and oscillations in the high-frequency (HF) components of arterial pressure compared to men. Contrary to our hypothesis, lower tolerance to central hypovolemia in women was not associated with sympathoexcitation, but can be explained, in part by lower physiological reserve to elicit oscillatory patterns in AP, maintenance of AP-MSNA coherence and SV when compared to men. PMID- 26109187 TI - The urothelium of a hibernator: the American black bear. AB - The American black bear undergoes a 3-5 month winter hibernation during which time bears do not eat, drink, defecate, or urinate. During hibernation renal function (GFR) is 16-50% of normal but urine is reabsorbed across the urinary bladder (UB) urothelium thus enabling metabolic recycling of all urinary constituents. To elucidate the mechanism(s) whereby urine is reabsorbed, we examined the UBs of five nonhibernating wild bears using light, electron (EM), and confocal immunofluorescent (IF) microscopy-concentrating on two components of the urothelial permeability barrier - the umbrella cell apical membranes and tight junctions (TJ). Bear UB has the same tissue layers (serosa, muscularis, lamina propria, urothelia) and its urothelia has the same cell layers (basal, intermediate, umbrella cells) as other mammalians. By EM, the bear apical membrane demonstrated a typical mammalian scalloped appearance with hinge and plaque regions - the latter containing an asymmetric trilaminar membrane and, on IF, uroplakins Ia, IIIa, and IIIb. The umbrella cell TJs appeared similar to those in other mammals and also contained TJ proteins occludin and claudin - 4, and not claudin -2. Thus, we were unable to demonstrate urothelial apical membrane or TJ differences between active black bears and other mammals. Expression and localization of UT-B, AQP-1 and -3, and Na(+), K(+)-ATPase on bear urothelial membranes was similar to that of other mammals. Similar studies of urothelia of hibernating bears, including evaluation of the apical membrane lipid bilayer and GAGs layer are warranted to elucidate the mechanism(s) whereby hibernating bears reabsorb their daily urine output and thus ensure successful hibernation. PMID- 26109188 TI - Impaired cerebral blood flow and oxygenation during exercise in type 2 diabetic patients. AB - Endothelial vascular function and capacity to increase cardiac output during exercise are impaired in patients with type 2 diabetes (T2DM). We tested the hypothesis that the increase in cerebral blood flow (CBF) during exercise is also blunted and, therefore, that cerebral oxygenation becomes affected and perceived exertion increased in T2DM patients. We quantified cerebrovascular besides systemic hemodynamic responses to incremental ergometer cycling exercise in eight male T2DM and seven control subjects. CBF was assessed from the Fick equation and by transcranial Doppler-determined middle cerebral artery blood flow velocity. Cerebral oxygenation and metabolism were evaluated from the arterial-to-venous differences for oxygen, glucose, and lactate. Blood pressure was comparable during exercise between the two groups. However, the partial pressure of arterial carbon dioxide was lower at higher workloads in T2DM patients and their work capacity and increase in cardiac output were only ~80% of that established in the control subjects. CBF and cerebral oxygenation were reduced during exercise in T2DM patients (P < 0.05), and they expressed a higher rating of perceived exertion (P < 0.05). In contrast, CBF increased ~20% during exercise in the control group while the brain uptake of lactate and glucose was similar in the two groups. In conclusion, these results suggest that impaired CBF and oxygenation responses to exercise in T2DM patients may relate to limited ability to increase cardiac output and to reduced vasodilatory capacity and could contribute to their high perceived exertion. PMID- 26109189 TI - High-threshold Ca2+ channels behind gamma band activity in the pedunculopontine nucleus (PPN). AB - The pedunculopontine nucleus (PPN) is part of the Reticular Activating System, and active during waking and REM sleep. Previous results showed that all PPN cells plateau at gamma frequencies and intrinsic membrane oscillations in PPN neurons are mediated by high-threshold N- and P/Q-type Ca(2+) channels. The present study was designed to determine whether some PPN cells have only N-, only P/Q-, or both N- and P/Q-type Ca(2+) channels. We used patch-clamp recordings in PPN cells in slices from anesthetized rat pups in the presence of synaptic receptor blockers (SB) and Tetrodotoxin (TTX), and applied ramps to induce intrinsic membrane oscillations. We found that all PPN cell types showed gamma oscillations in the presence of SB+TTX when using current ramps. In 50% of cells, the N-type Ca(2+) channel blocker omega-Conotoxin-GVIA (omega-CgTx) reduced gamma oscillation amplitude, while subsequent addition of the P/Q-type blocker omega Agatoxin-IVA (omega-Aga) blocked the remaining oscillations. Another 20% manifested gamma oscillations that were not significantly affected by the addition of omega-CgTx, however, omega-Aga blocked the remaining oscillations. In 30% of cells, omega-Aga had no effect on gamma oscillations, while omega-CgTx blocked them. These novel results confirm the segregation of populations of PPN cells as a function of the calcium channels expressed, that is, the presence of cells in the PPN that manifest gamma band oscillations through only N-type, only P/Q-type, and both N-type and P/Q-type Ca(2+) channels. PMID- 26109190 TI - Reduction of VO2 slow component by priming exercise: novel mechanistic insights from time-resolved near-infrared spectroscopy. AB - Novel time-resolved near-infrared spectroscopy (TR-NIRS), with adipose tissue thickness correction, was used to test the hypotheses that heavy priming exercise reduces the VO2 slow component (VO2SC) (1) by elevating microvascular [Hb] volume at multiple sites within the quadriceps femoris (2) rather than reducing the heterogeneity of muscle deoxygenation kinetics. Twelve subjects completed two 6 min bouts of heavy work rate exercise, separated by 6 min of unloaded cycling. Priming exercise induced faster overall VO2 kinetics consequent to a substantial reduction in the VO2SC (0.27 +/- 0.12 vs. 0.11 +/- 0.09 L.min(-1), P < 0.05) with an unchanged primary VO2 time constant. An increased baseline for the primed bout [total (Hb + Mb)] (197.5 +/- 21.6 vs. 210.7 +/- 22.5 MUmol L(-1), P < 0.01), reflecting increased microvascular [Hb] volume, correlated significantly with the VO2SC reduction. At multiple sites within the quadriceps femoris, priming exercise reduced the baseline and slowed the increase in [deoxy (Hb + Mb)]. Changes in the intersite coefficient of variation in the time delay and time constant of [deoxy (Hb + Mb)] during the second bout were not correlated with the VO2SC reduction. These results support a mechanistic link between priming exercise-induced increase in muscle [Hb] volume and the reduced VO2SC that serves to speed overall VO2 kinetics. However, reduction in the heterogeneity of muscle deoxygenation kinetics does not appear to be an obligatory feature of the priming response. PMID- 26109191 TI - Evaluating PAI-1 as a biomarker for stress in diving: human serum total PAI-1 is unaltered after 2 h dry exposures to 280 kPa hyperbaric air. AB - Plasminogen activator inhibitor (PAI-1) is induced in the vasculature and secreted into the vascular lumen in response to inflammation and oxidative stress. We have previously reported a fivefold increase in plasma PAI-1 from rats exposed to 708 kPa hyperbaric air. In the current study we assess the potential of human serum total PAI-1 as a biomarker for stress in compressed air diving. Eleven recreational divers, nine males and two females, completed four 2 h hyperbaric air exposures to 280 kPa in a pressure chamber over a period of 2 weeks. The air pressure corresponds to a diving depth of 18 m in water. Serum was collected before the study and again 3 h 30 min after completion of each hyperbaric exposure. All samples were taken in the afternoon to minimize the contribution of circadian variation. The analysis revealed no change in serum total PAI-1 after hyperbaric exposures within the group of divers (P = 0.064), but significant interindividual differences persisted throughout the study (P < 0.0005). A case of decompression sickness after the third round of hyperbaric exposure did not affect PAI-1. In conclusion, compressed air exposure to 280 kPa does not affect serum total PAI-1, and significant interindividual variation in PAI-1 levels may limit its usefulness as a biomarker. This does, however, not give a complete answer regarding PAI-1 in physiologically stressful dives. Further studies with different exposures and timing are needed for that. PMID- 26109192 TI - Effect of omega-3 polyunsaturated fatty acid supplementation on central arterial stiffness and arterial wave reflections in young and older healthy adults. AB - Increased central arterial stiffness and enhanced arterial wave reflections may contribute to increased risk of cardiovascular disease development with advancing age. Omega-3 polyunsaturated fatty acid (n-3) ingestion may reduce cardiovascular risk via favorable effects exerted on arterial structure and function. We determined the effects of n-3 supplementation (4 g/day for 12 weeks) on important measures of central arterial stiffness (carotid-femoral pulse wave velocity; PWV) and arterial wave reflection (central augmentation index) in young (n = 12; 25 +/ 1-year-old, mean +/- SE) and older (n = 12; 66 +/- 2) healthy adults. We hypothesized that n-3 supplementation would decrease carotid-femoral PWV and central augmentation index in older adults. Our results indicate that carotid femoral PWV and central augmentation index were greater in older (988 +/- 65 cm/sec and 33 +/- 2%) than in young adults (656 +/- 16 cm/sec and 3 +/- 4%: both P < 0.05 compared to older) before the intervention (Pre). N-3 supplementation decreased carotid-femoral PWV in older (?-9 +/- 2% Precompared to Post; P < 0.05), but not young adults (?2 +/- 3%). Central augmentation index was unchanged by n-3 supplementation in young (3 +/- 4 vs. 0 +/- 4% for Pre and Post, respectively) and older adults (33 +/- 2 vs. 35 +/- 3%). Arterial blood pressure at rest, although increased with age, was not altered by n-3 supplementation in young or older adults. Collectively, these data indicate that 12 weeks of daily n 3 supplementation decreases an important measure of central arterial stiffness (carotid-femoral PWV) in older, but not young healthy adults. The mechanism underlying decreased central arterial stiffness with n-3 supplementation is unknown, but appears to be independent of effects on arterial blood pressure or arterial wave reflections. PMID- 26109193 TI - Chlorine inhalation-induced myocardial depression and failure. AB - Victims of chlorine (Cl2) inhalation that die demonstrate significant cardiac pathology. However, a gap exists in the understanding of Cl2-induced cardiac dysfunction. This study was performed to characterize cardiac dysfunction occurring after Cl2 exposure in rats at concentrations mimicking accidental human exposures (in the range of 500 or 600 ppm for 30 min). Inhalation of 500 ppm Cl2 for 30 min resulted in increased lactate in the coronary sinus of the rats suggesting an increase in anaerobic metabolism by the heart. There was also an attenuation of myocardial contractile force in an ex vivo (Langendorff technique) retrograde perfused heart preparation. After 20 h of return to room air, Cl2 exposure at 500 ppm was associated with a reduction in systolic and diastolic blood pressure as well echocardiographic/Doppler evidence of significant left ventricular systolic and diastolic dysfunction. Cl2 exposure at 600 ppm (30 min) was associated with biventricular failure (observed at 2 h after exposure) and death. Cardiac mechanical dysfunction persisted despite increasing the inspired oxygen fraction concentration in Cl2-exposed rats (500 ppm) to ameliorate hypoxia that occurs after Cl2 inhalation. Similarly ex vivo cardiac mechanical dysfunction was reproduced by sole exposure to chloramine (a potential circulating Cl2 reactant product). These results suggest an independent and distinctive role of Cl2 (and its reactants) in inducing cardiac toxicity and potentially contributing to mortality. PMID- 26109195 TI - Corrigendum. PMID- 26109194 TI - Ventilatory oscillations at exercise: effects of hyperoxia, hypercapnia, and acetazolamide. AB - Periodic breathing has been found in patients with heart failure and sleep apneas, and in healthy subjects in hypoxia, during sleep and wakefulness, at rest and, recently, at exercise. To unravel the cardiorespiratory parameters liable to modulate the amplitude and period of ventilatory oscillations, 26 healthy subjects were tested under physiological (exercise) and environmental (hypoxia, hyperoxia, hyperoxic hypercapnia) stresses, and under acetazolamide (ACZ) treatment. A fast Fourier transform spectral analysis of breath-by-breath ventilation (VE) evidenced an increase in VE peak power under hypercapnia (vs. normoxia and hyperoxia, P < 0.001) and a decrease under ACZ (vs. placebo, P < 0.001), whereas it was not modified in hyperoxia. VE period was shortened by exercise in all conditions (vs. rest, P < 0.01) and by hypercapnia (vs. normoxia, P < 0.05) but remained unchanged under ACZ (vs. placebo). VE peak power was positively related to cardiac output (Qc) and VE in hyperoxia (P < 0.01), in hypercapnia (P < 0.001) and under ACZ (P < 0.001). VE period was negatively related to Qc and VE in hyperoxia (P < 0.01 and P < 0.001, respectively), in hypercapnia (P < 0.05 and P < 0.01, respectively) and under ACZ (P < 0.05 and P < 0.01, respectively). Total respiratory cycle time was the main factor responsible for changes in VE period. In conclusion, exercise, hypoxia, and hypercapnia increase ventilatory oscillations by increasing Qc and VE, whereas ACZ decreases ventilatory instability in part by a contrasting action on O2 and CO2 sensing. An intrinsic oscillator might modulate ventilation through a complex system where peripheral chemoreflex would play a key role. PMID- 26109196 TI - Two cases of successful pregnancy in patients with Gitelman's syndrome. AB - Gitelman's syndrome (GS) is a distal convoluted tubule (DCT) defect clinically characterized by hypokalemic metabolic alkalosis. Pregnancy in women with GS often results in severe hypomagnesemia and hypokalemia. We report two cases of successful pregnancies, after previous fetal loss, in patients with GS managed with aggressive oral and intravenous electrolyte repletion. These cases illustrate increased potassium and magnesium requirements over the course of the pregnancies and are notable due to the high doses of electrolytes required. They also demonstrate the possibility of successful pregnancy outcomes with frequent laboratory monitoring and aggressive titration of electrolyte replacement either orally or intravenously to maintain appropriate serum levels necessary to provide a suitable environment for fetal development. PMID- 26109197 TI - Mucinous micropapillary pattern in lung adenocarcinomas: a unique histology with genetic correlates. AB - AIMS: In lung adenocarcinoma (ADC), micropapillary carcinomas (MPCs) are associated with poor prognosis because these tumours exhibit higher metastatic potential. Despite this, there are no studies investigating the differences between mucinous and non-mucinous MPC. METHODS AND RESULTS: We evaluated the proportion of micropapillary components in lung ADCs, and compared the differences with respect to the presence or absence of associated mucin. Tumour specimens from 694 patients with consecutively resected primary lung ADC were reviewed, and 37 cases of invasive mucinous ADCs were excluded. A significant (>=5%) micropapillary component was noted in 320 (48.7%) of 657 evaluable cases. When the cases with micropapillary component were divided into 67 (20.9%) mucinous and 253 (79.1%) non-mucinous subtypes, tumours with mucinous micropapillary component exhibited significantly more aggressive pathological features, a higher proportion of HER2 mutations (P = 0.002) and ALK rearrangements (P < 0.001), and a lower proportion of EGFR mutations (P = 0.038) compared to those with a non-mucinous micropapillary component. In survival analyses, mucinous MPC tended to be more aggressive compared with non-mucinous MPC, but its prognostic value was not statistically significant (P = 0.076). CONCLUSIONS: Mucinous micropapillary pattern is an under-recognized unique growth associated significantly with HER2 mutation and ALK rearrangement. PMID- 26109198 TI - Right intra lobar pulmonary sequestration with feeding artery arising from abdominal aorta: a case report. AB - Pulmonary sequestration (PS) is a rare congenital malformation. Right intra lobar PS with a feeding artery arising from the abdominal aorta is extremely rare. This case report describes a 30-year-old man with a history of mental deficiency and repeated pneumonia who was referred to our hospital for further work-up of PS. Three-dimensional enhanced computed tomography of the chest and aorta revealed right intra lobar PS with an aberrant systemic artery from the abdominal aorta. We resected the PS using lower lobectomy by video-assisted thoracic surgery (VATS). The patient was discharged 10 days later without complications. PMID- 26109199 TI - Identification and disposition of novel mono-hydroxyl mefenamic acid and their potentially toxic 1-O-acyl-glucuronides in vivo. AB - Mefenamic acid (MEF) is a widely prescribed non-steroidal anti-inflammatory drug that has been found associated with rare but severe cases of hepatotoxicity, nephrotoxicity and gastrointestinal toxicity. The formation of protein-reactive acylating metabolites such as 1-O-acyl-MEF glucuronide (MEFG) and 3' hydroxymethyl-MEF 1-O-acyl-glucuronide is one proposed cause. In addition to the well-reported 3'-hydroxymethyl-MEF, two mono-hydroxyl-MEF (OH-MEFs) were recently identified in vitro. However, in vivo evidence is lacking and whether these OH MEFs would be further glucuronidated to the potentially reactive 1-O-acyl glucuronides (OH-MEFGs) is unknown. Utilizing UPLC-Q-TOF/MS and LC-MS/MS, the current study identified, for the first time, four OH-MEFs and their corresponding OH-MEFGs from plasma after a single oral administration of MEF (40 mg/kg) to rats, including an OH-MEF that has not been reported previously. The systemic exposure of these identified metabolites was high, with metabolic to parent AUC0 -> 24 h ratios reaching 23-52% (OH-MEFs) and 8-29% (OH-MEFGs). These metabolites also had a long systemic exposure time in both single and 5 day multiple oral MEF-treated rats, with elimination half-lives between 9 h and > 24 h. In addition to these novel metabolites, the previously reported MEFG was also identified and its systemic exposure was found to be doubled after multiple MEF administrations. These pharmacokinetic results suggest that systemic toxicities caused by the potentially reactive MEFG and OH-MEFGs could be considerable, especially after repeated MEF treatment. Nevertheless, MEFG and OH-MEFGs had negligible uptake in the brain, indicating a minimal risk of brain toxicities. Furthermore, an in situ intestinal perfusion study revealed that during MEF absorption, it was extensively metabolized to MEFG while < 5% was metabolized to OH-MEFs and OH-MEFGs. PMID- 26109201 TI - Technical and clinical accuracy of five blood glucose meters: clinical impact assessment using error grid analysis and insulin sliding scales. PMID- 26109200 TI - The chemokine receptor CXCR7 influences prognosis in human glioma in an IDH1 dependent manner. AB - AIMS: The chemokine receptor CXCR7 is found on glioma cells and glioma-associated vessels and dependent upon its localisation on tumour or endothelial cells the CXCR7 receptor can mediate glioma cell invasion and tumour angiogenesis. Its expression predicts survival in several types of cancers. METHODS: We immunohistochemically studied the expression of CXCR7 and its ligand SDF1alpha in a cohort of 354 human patients with glioma. In an in vivo glioma model, we studied the effect of selective CXCR7 inhibition on mean vascular density. RESULTS: Here we show that expression of either mutant isocitrate dehydrogenase (IDH) 1 or podoplanin (PDPN), two proteins present in basically non-overlapping glioma populations, predicts the prognostic significance of CXCR7. Specifically, expression of CXCR7 on endothelial cells in IDH1 mutant cases predicted poor outcome. Surprisingly, in PDPN expressing gliomas, one of the marker genes for the recently identified mesenchymal subgroup, expression of CXCR7 predicts diminished prognosis on tumour cells and better prognosis on endothelial cells. CONCLUSIONS: Since CXCR7 is expressed on migrating cells our data suggest that, although ubiquitously present, angiogenesis and invasion are outcome-relevant events in specific glioma subgroups, providing a potentially important tool for targeted therapy assignment. PMID- 26109202 TI - Salvage chemotherapy and autologous stem cell transplantation for transformed indolent lymphoma: a subset analysis of NCIC CTG LY12. AB - The treatment of transformed indolent lymphoma (TRIL) often includes salvage chemotherapy (SC) and autologous stem cell transplant (ASCT). NCIC CTG LY12 is a randomized phase 3 trial comparing gemcitabine, dexamethasone, and cisplatin (GDP) with dexamethasone, cytarabine, and cisplatin (DHAP) before ASCT. This analysis compares the results of SC and ASCT for TRIL with de novo diffuse large B-cell lymphoma (DLBCL). Six-hundred nineteen patients with relapsed/refractory aggressive non-Hodgkin lymphoma were randomized to GDP or DHAP; 87 patients (14%) had TRIL and 429 (69%) had DLBCL. The response rate to SC was 47% in TRIL and 45% in DL (P = .81). Transplantation rates were similar: TRIL 53% and DL 52% (P = 1.0). With a median follow-up of 53 months, 4 year overall survival was 39% for TRIL and 41% for DL (P = .78); 4 year event-free survival (EFS) was 27% for TRIL and 27% for DL (P = .83). Post-ASCT, 4-year EFS was 45% for TRIL and 46% for DL. Histology (TRIL or DL) was not a predictor of any outcome in multivariate models. Patients with relapsed or refractory TRIL and DLBCL have similar outcomes with SC and ASCT; this therapy should be considered the standard of care for patients with TRIL who have received prior systemic chemotherapy. NCIC CTG LY12 is registered at ClinicalTrials.gov as #NCT00078949. PMID- 26109203 TI - RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1. AB - Diamond-Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count. Mutations in ribosomal protein genes have been identified in approximately half of all DBA cases. Corticosteriod therapy and bone marrow transplantation are common treatment options for patients; however, significant risks and complications are associated with these treatment options. Therefore, novel therapeutic approaches are needed for treating DBA. Sotatercept (ACE-011, and its murine ortholog RAP-011) acts as an activin receptor type IIA ligand trap, increasing hemoglobin and hematocrit in pharmacologic models, in healthy volunteers, and in patients with beta-thalassemia, by expanding late stage erythroblasts through a mechanism distinct from erythropoietin. Here, we evaluated the effects of RAP-011 in zebrafish models of RPL11 ribosome deficiency. Treatment with RAP-011 dramatically restored hemoglobin levels caused by ribosome stress. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by sequestering lefty1 from erythroid cells. These findings identify lefty1 as a signaling component in the development of erythroid cells and rationalize the use of sotatercept in DBA patients. PMID- 26109204 TI - Essential role of class II PI3K-C2alpha in platelet membrane morphology. AB - The physiologic roles of the class II phosphoinositide 3-kinases (PI3Ks) and their contributions to phosphatidylinositol 3-monophosphate (PI3P) and PI(3,4)P2 production remain elusive. Here we report that mice heterozygous for a constitutively kinase-dead PI3K-C2alpha display aberrant platelet morphology with an elevated number of barbell-shaped proplatelets, a recently discovered intermediate stage in the final process of platelet production. Platelets with heterozygous PI3K-C2alpha inactivation have critical defects in alpha-granules and membrane structure that are associated with modifications in megakaryocytes. These platelets are more rigid and unable to form filopodia after stimulation. Heterozygous PI3K-C2alpha inactivation in platelets led to a significant reduction in the basal pool of PI3P and a mislocalization of several membrane skeleton proteins known to control the interactions between the plasma membrane and cytoskeleton. These alterations had repercussions on the performance of platelet responses with delay in the time of arterial occlusion in an in vivo model of thrombosis and defect in thrombus formation in an ex vivo blood flow system. These data uncover a key role for PI3K-C2alpha activity in the generation of a basal housekeeping PI3P pool and in the control of membrane remodeling, critical for megakaryocytopoiesis and normal platelet production and function. PMID- 26109205 TI - Platelets at the interface of thrombosis, inflammation, and cancer. AB - Although once primarily recognized for its roles in hemostasis and thrombosis, the platelet has been increasingly recognized as a multipurpose cell. Indeed, circulating platelets have the ability to influence a wide range of seemingly unrelated pathophysiologic events. Here, we highlight some of the notable observations that link platelets to inflammation, reinforcing the platelet's origin from a lower vertebrate cell type with both hemostatic and immunologic roles. In addition, we consider the relevance of platelets in cancer biology by focusing on the hallmarks of cancer and the ways platelets can influence multistep development of tumors. Beyond its traditional role in hemostasis and thrombosis, the platelet's involvement in the interplay between hemostasis, thrombosis, inflammation, and cancer is likely complex, yet extremely important in each disease process. The existence of animal models of platelet dysfunction and currently used antiplatelet therapies provide a framework for understanding mechanistic insights into a wide range of pathophysiologic events. Thus, the basic scientist studying platelet function can think beyond the traditional hemostasis and thrombosis paradigms, while the practicing hematologist must appreciate platelet relevance in a wide range of disease processes. PMID- 26109206 TI - Risk-adapted therapy for early-stage extranodal nasal-type NK/T-cell lymphoma: analysis from a multicenter study. AB - The optimal combination and sequence of radiotherapy (RT) and chemotherapy (CT) for extranodal nasal-type natural killer/T-cell lymphoma (NKTCL) are not well defined. The aim of this study was to create a risk-adapted therapeutic strategy for early-stage NKTCL. A total of 1273 early-stage patients from 10 institutions were reviewed. Patients received CT alone (n = 170), RT alone (n = 253), RT followed by CT (n = 209), or CT followed by RT (n = 641). A comprehensive comparative study was performed using multivariable and propensity score-matched analyses. Early-stage NKTCL was classified as low risk or high risk based on 5 independent prognostic factors (stage, age, performance status, lactate dehydrogenase, primary tumor invasion). RT alone and RT with or without CT were more effective than CT alone (5-year overall survival [OS], 69.6% and 67.7% vs 33.9%, P < .001). For low-risk patients, RT alone achieved a favorable OS (88.8%); incorporation of induction or consolidation CT did not provide additional benefit (86.9% and 86.3%). For high-risk patients, RT followed by CT resulted in superior OS (72.2%) compared with induction CT and RT (58.3%, P = .004) or RT alone (59.6%, P = .017). After adjustment, similar significant differences in OS were still observed between treatment groups. New CT regimens provided limited benefit in early-stage NKTCL. Risk-adapted therapy involving RT alone for low-risk patients and RT consolidated by CT for high-risk patients is a viable, effective strategy for early-stage NKTCL. PMID- 26109208 TI - Ultrathin Carbon with Interspersed Graphene/Fullerene-like Nanostructures: A Durable Protective Overcoat for High Density Magnetic Storage. AB - One of the key issues for future hard disk drive technology is to design and develop ultrathin (<2 nm) overcoats with excellent wear- and corrosion protection and high thermal stability. Forming carbon overcoats (COCs) having interspersed nanostructures by the filtered cathodic vacuum arc (FCVA) process can be an effective approach to achieve the desired target. In this work, by employing a novel bi-level surface modification approach using FCVA, the formation of a high sp(3) bonded ultrathin (~1.7 nm) amorphous carbon overcoat with interspersed graphene/fullerene-like nanostructures, grown on magnetic hard disk media, is reported. The in-depth spectroscopic and microscopic analyses by high resolution transmission electron microscopy, scanning tunneling microscopy, time-of-flight secondary ion mass spectrometry, and Raman spectroscopy support the observed findings. Despite a reduction of ~37% in COC thickness, the FCVA-processed thinner COC (~1.7 nm) shows promising functional performance in terms of lower coefficient of friction (~0.25), higher wear resistance, lower surface energy, excellent hydrophobicity and similar/better oxidation corrosion resistance than current commercial COCs of thickness ~2.7 nm. The surface and tribological properties of FCVA-deposited COC was further improved after deposition of lubricant layer. PMID- 26109207 TI - Mild Chronic Hyponatremia in the Ambulatory Setting: Significance and Management. AB - Mild chronic hyponatremia, as defined by a persistent (>72 hours) plasma sodium concentration between 125 and 135 mEq/L without apparent symptoms, is common in ambulatory patients and generally perceived as being inconsequential. The association between increased mortality and hyponatremia in hospitalized patients in various settings and etiologies is widely recognized. This review analyzes the significance of mild chronic hyponatremia in ambulatory subjects and its effects on mortality and morbidity. It addresses whether this disorder should even be treated and if so, which patients are likely to benefit from treatment. The available approaches to correct hyponatremia in such patients in the context of recently published panel-generated recommendations and guidelines are described. PMID- 26109209 TI - Anti-VEGF treatment in branch retinal vein occlusion: a real-world experience over 4 years. AB - PURPOSE: To determine long-term outcome of intraocular antagonism of vascular endothelial growth factor (VEGF) in macular oedema (ME) secondary to branch retinal vein occlusion (BRVO). METHODS: A total of 28 consecutive patients were treated with either intravitreal bevacizumab (IVB) or intravitreal ranibizumab (IVR) in the first series and were evaluated after a mean follow-up of 5 years for their functional and anatomical outcome. RESULTS: Time between onset of macular oedema and initial treatment was 5.2 +/- 0.4/0.1 +/- 0.1 (IVB/IVR) months. A mean of 4 intravitreal injections were given per patients in the first 6 months. In months 7-12 intravitreal injections decreased to 2 and further decreased in the second year (months 13-18: 1.14; months 19-24: 0.5) and third year (months 25-30: 0.4; months 31-36: 0.2). After the fourth year, only two of the 28 patients received further treatment. Average visual acuity (VA) increased by 16 letters after 1 year (p < 0.01) and although not statistically significantly, by a mean of 5 letters (p = 0.3) at long-term evaluation (IVB group). However, after mean of 5 years, central retinal sensitivity (CRS) improved by 3.6 dB (p = 0.01) and central retinal thickness (CRT) decreased by 161 MUm (p = 0.02). In the IVR-group, VA and CRS increased significantly (31 letters and respectively 4.4 dB, p < 0.001) and CRT decreased by 229 MUm (p < 0.001) after long-term follow-up. Final functional results were significantly better in patients with treatment initiation <3 months (79 versus 55 letters, p = 0.01). Microvascular abnormalities were detected in 88% (21 of 24 patients), hyperfluorescence in 42% (10 of 24 patients) on wide-field fluorescein angiography in both groups. CONCLUSIONS: Inhibition of VEGF provides substantial long-term benefits for patients with ME secondary to BRVO. Early treatment with anti-VEGF agents and extended therapeutic surveillance was associated with improved visual recovery. PMID- 26109210 TI - Impact of metabolic syndrome in surgical patients: should we bother? AB - Clinicians inevitably encounter patients who meet the diagnostic criteria for the metabolic syndrome (MetS); these criteria include central obesity, hypertension, atherogenic dyslipidaemia, and hyperglycaemia. Regardless of the variations in its definition, MetS may be associated with adverse outcomes in patients undergoing both cardiac and non-cardiac surgery. There is a paucity of data concerning the anaesthetic management of patients with MetS, and only a few observational (mainly retrospective) studies have investigated the association of MetS with perioperative outcomes. In this narrative review, we consider the impact of MetS on the occurrence of perioperative adverse events after cardiac and non-cardiac surgery. Metabolic syndrome has been associated with higher rates of cardiovascular, pulmonary, and renal perioperative events and wound infections compared with patients with a non-MetS profile. Metabolic syndrome has also been related to increased health service costs, prolonged hospital stay, and a greater need for posthospitalization care. Therefore, physicians should be able to recognize the MetS in the perioperative period in order to formulate management strategies that may modify any perianaesthetic and surgical risk. However, further research is needed in this field. PMID- 26109211 TI - From crystal to glass-like thermal conductivity in crystalline minerals. AB - The ability of some materials with a perfectly ordered crystal structure to mimic the heat conduction of amorphous solids is a remarkable physical property that finds applications in numerous areas of materials science, for example, in the search for more efficient thermoelectric materials that enable to directly convert heat into electricity. Here, we unveil the mechanism in which glass-like thermal conductivity emerges in tetrahedrites, a family of natural minerals extensively studied in geology and, more recently, in thermoelectricity. By investigating the lattice dynamics of two tetrahedrites of very close compositions (Cu12Sb2Te2S13 and Cu10Te4S13) but with opposite glasslike and crystal thermal transport by means of powder and single-crystal inelastic neutron scattering, we demonstrate that the former originates from the peculiar chemical environment of the copper atoms giving rise to a strongly anharmonic excess of vibrational states. PMID- 26109212 TI - [Bilateral renal sclerotherapy as a treatment option in a mixed breed male dog with idiopathic renal haematuria]. AB - A 2-year-old male castrated German Shepherd dog mix was presented with chronic macroscopic haematuria. Further diagnostics included abdominal ultrasound and urethrocystoscopy and led to a diagnosis of severe bilateral idiopathic renal haematuria (IRH). Medical treatment with Yunnan Baiyao was unsuccessful. Bilateral renal-sparing sclerotherapy was performed and, despite distal migration of both ureteral stents within 12 days, permanently resolved the macroscopic haematuria. PMID- 26109213 TI - The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis. AB - AIMS/HYPOTHESIS: Thiazolidinediones (TZDs) are associated with an increased risk of fracture but the mechanism is unclear. We sought to determine the effect of TZDs on bone mineral density (BMD) and bone turnover markers. METHODS: PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception until January 2015 for randomised controlled trials comparing TZDs with metformin, sulfonylureas or placebo, and those reporting changes in BMD and/or bone turnover markers. The primary outcome was percentage change in BMD from baseline and results were pooled with random effects meta-analyses. RESULTS: In all, 18 trials were included in the primary analyses and another two were included in the sensitivity analyses (n = 3,743, 50% women, mean age 56 years, median trial duration 48 weeks). TZDs decreased BMD at the lumbar spine (difference -1.1% [95% CI -1.6, -0.7]; p < 0.0001), total hip (-1.0% [-1.4, -0.6]; p < 0.0001) and forearm (-0.9% [-1.6, -0.3]; p = 0.007). There were statistically non-significant decreases in BMD at the femoral neck (-0.7% [-1.4, 0.0]; p = 0.06) and total body (-0.3% [-0.5, 0.0]; p = 0.08). Five trials (n = 450) showed no statistically significant difference in percentage change in BMD between the TZD group and controls up to 1 year following TZD withdrawal. In 14 trials, the effect of TZD treatment on turnover markers varied considerably between individual studies. CONCLUSIONS/INTERPRETATION: Treatment with TZDs results in modest bone loss that may not be reversed 1 year after cessation of treatment. PMID- 26109214 TI - The hitchhiker's guide to PGC-1alpha isoform structure and biological functions. AB - Proteins of the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1 (PGC-1) family of transcriptional coactivators coordinate physiological adaptations in many tissues, usually in response to demands for higher nutrient and energy supply. Of the founding members of the family, PGC 1alpha (also known as PPARGC1A) is the most highly regulated gene, using multiple promoters and alternative splicing to produce a growing number of coactivator variants. PGC-1alpha promoters are selectively active in distinct tissues in response to specific stimuli. To date, more than ten novel PGC-1alpha isoforms have been reported to be expressed from a novel promoter (PGC-1alpha-b, PGC 1alpha-c), to undergo alternative splicing (NT-PGC-1alpha) or both (PGC-1alpha2, PGC-1alpha3, PGC-1alpha4). The resulting proteins display differential regulation and tissue distribution and, most importantly, exert specific biological functions. In this review we discuss the structural and functional characteristics of the novel PGC-1alpha isoforms, aiming to provide an integrative view of this constantly expanding system of transcriptional coactivators. PMID- 26109215 TI - Variable effects of statins on glucose homeostasis parameters and their diabetogenic role. Reply to Kostapanos MS, Agouridis AP and Elisaf MS [letter]. PMID- 26109218 TI - Aryl hydrocarbon receptor-fibroblast growth factor 21 dissociation of fatty liver from insulin resistance: A timely matter? PMID- 26109216 TI - Maternal VDR variants rather than 25-hydroxyvitamin D concentration during early pregnancy are associated with type 1 diabetes in the offspring. AB - AIMS/HYPOTHESIS: We investigated whether single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D concentration in the metabolic pathway of vitamin D show different genotype distributions between Finnish families with an offspring with type 1 diabetes (cases) and families with a healthy offspring (controls). METHODS: A total of 31 SNPs in eight genes were studied in case and control mothers and family members (offspring with type 1 diabetes and healthy siblings, healthy control children and fathers) (n = 2,854). The 25 hydroxyvitamin D concentration was studied in 474 case and 348 matched control mothers during pregnancy. RESULTS: The genotype distributions of 13 SNPs (in the following genes: 7-dehydrocholesterol reductase NADSYN1/DHCR7, vitamin D receptor VDR, group-specific component GC and CYP27A1) that showed a nominal association with 25-hydroxyvitamin D concentration (p < 0.05) were compared between case and control families. SNPs in VDR had different genotype distributions between the case and control mothers (rs1544410, p = 0.007; rs731236, p = 0.003; rs4516035, p = 0.015), two SNPs (rs1544410 and rs731236) remaining significant after correction for multiple testing using a false discovery rate. The mean 25 hydroxyvitamin D concentrations during pregnancy did not differ between the case and control mothers. CONCLUSIONS/INTERPRETATION: Our preliminary results suggest that the maternal genotypes of SNPs in VDR may influence the in utero environment and thus contribute to the early programming of type 1 diabetes in the fetus. It is possible that the effects are only relevant in the presence of vitamin D insufficiency. PMID- 26109217 TI - Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome. AB - BACKGROUND: Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers. METHODS: We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for >=5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for >=5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use. CONCLUSION: Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer. PMID- 26109219 TI - Characterization of the molecular degradation mechanism of diphenyl ethers by Cupriavidus sp. WS. AB - Commonly used flame retardants, such as polybrominated diphenyl ethers, are extremely persistent in the environment, causing serious environmental risks. Certain strains of bacteria are able to degrade several low brominated congeners of PBDEs aerobically. However, the aerobic degradation pathway is not yet well understood, particularly at the genetic level. In this study, we isolated Cupriavidus sp. WS from the environment that could degrade diphenyl ether (DE), 4 bromodiphenyl ether, and 4,4'-bromodiphenyl ether. DE was completely degraded in 6 days without any detectable end-product. Using transposon mutagenesis, several DE degradation-deficient mutants were obtained. Knocking out bphA1, bphA2, and bphA3 eliminated the ability of the Cupriavidus sp. WS bacterium to degrade DE, indicating that the bph genes play a crucial role in DE degradation by this strain. The specific roles of bphA, bphB, and bphC were identified by systematically expressing these genes in Escherichia coli. The dihydrodiol product of BphA was dehydrogenated into 2,3-dihydroxydiphenyl ether by BphB. 2,3 Dihydroxydiphenyl ether was then decomposed into phenol and 2-pyrone-6-carboxylic acid by BphC. Thus, BphA, BphB, and BphC act sequentially in the aerobic degradation of DE, 4-bromodiphenyl ether, and 4,4'-dibromodiphenyl ether by the Cupriavidus sp. WS bacterium. PMID- 26109220 TI - Effect of inorganic amendments for in situ stabilization of cadmium in contaminated soils and its phyto-availability to wheat and rice under rotation. AB - Cadmium (Cd) toxicity is a widespread problem in crops grown on contaminated soils, and little information is available on the role of inorganic amendments in Cd immobilization, uptake, and tolerance in crops especially under filed conditions. The effect of three amendments, monoammonium phosphate (MAP), gypsum, and elemental sulfur (S), on Cd immobilization in soil and uptake in wheat and rice plants, under rotation, were investigated under field conditions receiving raw city effluent since >20 years and contaminated with Cd. Three levels of each treatment, 0.2, 0.4, and 0.8% by weight, were applied at the start of the experiment, and wheat was sown in the field. After wheat harvesting, rice was sown in the same field without application of amendments. Both crops were harvested at physiological maturity, and data regarding grain yield, straw biomass, Cd concentrations, and uptake in grain and straw, and bioavailable Cd in soil and soil pH were recorded. Both MAP and gypsum application increased grain yield and biomass of wheat and rice, while S application did not increase the yield of both crops. MAP and gypsum amendments decreased gain and straw Cd concentrations and uptake in both crops, while S application increased Cd concentrations in these parts which were correlated with soil bioavailable Cd. We conclude that MAP and gypsum amendments could be used to decrease Cd uptake by plants receiving raw city effluents, and gypsum might be a better amendment for in situ immobilization of Cd due to its low cost and frequent availability. PMID- 26109221 TI - Biochar increased water holding capacity but accelerated organic carbon leaching from a sloping farmland soil in China. AB - A hydrologically contained field study, to assess biochar (produced from mixed crop straws) influence upon soil hydraulic properties and dissolved organic carbon (DOC) leaching, was conducted on a loamy soil (entisol). The soil, noted for its low plant-available water and low soil organic matter, is the most important arable soil type in the upper reaches of the Yangtze River catchment, China. Pore size distribution characterization (by N2 adsorption, mercury intrusion, and water retention) showed that the biochar had a tri-modal pore size distribution. This included pores with diameters in the range of 0.1-10 MUm that can retain plant-available water. Comparison of soil water retention curves between the control (0) and the biochar plots (16 t ha(-1) on dry weight basis) demonstrated biochar amendment to increase soil water holding capacity. However, significant increases in DOC concentration of soil pore water in both the plough layer and the undisturbed subsoil layer were observed in the biochar-amended plots. An increased loss of DOC relative to the control was observed upon rainfall events. Measurements of excitation-emission matrix (EEM) fluorescence indicated the DOC increment originated primarily from the organic carbon pool in the soil that became more soluble following biochar incorporation. PMID- 26109222 TI - Study of photodegradation and photooxidation of p-arsanilic acid in water solutions at pH = 7: kinetics and by-products. AB - The paper presents the kinetics and proposed pathways photodegradation and photooxidation of p-arsanilic acid, in a neutral environment by ozone and hydrogen peroxide. The results showed that in a neutral environment, photoozonation process was characterized by the highest decomposition rate constant (k) (k = 31.8 * 10(-3) min(-1)). The rate constants decreased in the order UV/O3 > O3 > UV/H2O2 > H2O2 > UV. It was also found that under pH = 7, decomposition of p-arsanilic acid leads mainly to the formation of aniline, which undergoes secondary reactions. Intermediate products of oxidation and photooxidation by hydrogen peroxide like nitrobenzene, nitrophenol, azobenzenes, and phenylazophenol were identified depending on processes. However, in the photodegradation process, formation of nitrasone as a reaction product of p arsanilic acid with oxygen in the singlet state was observed. In the case of ozonation and photoozonation, in addition, aniline formation of carboxylic acids was observed. PMID- 26109223 TI - Extraction and application of starch-based coagulants from sago trunk for semi aerobic landfill leachate treatment. AB - Malaysia is one of the highest starch producers. In this study, sago starch was utilized as a natural coagulant aid to reduce the dosage of aluminum-based coagulant in leachate treatment. The potential of native sago trunk starch (NSTS) and commercial sago starch (CSS) was evaluated as sole coagulant and coagulant aid in the presence of polyaluminum chloride (PACl) in the removal of color, suspended solids (SS), NH3-N, turbidity, chemical oxygen demand, organic UV254, Cd, and Ni. Leachate was sampled from Pulau Burung Landfill Site, one of the semi aerobic landfills in Malaysia. The optimum dosage for PACl in the presence of NSTS or CSS as coagulant aid was reduced from 3100 to 2000 mg/L. In the presence of 2000 mg/L PACl with 6000 mg/L NSTS and 2000 mg/L PACl with 5000 mg/L CSS, the removal performance for color, SS, and turbidity are 94.7, 99.2, and 98.9%, respectively. Similar results were obtained with the use of 3100 mg/L PACl alone. Therefore, CSS and NSTS can be used as coagulant aid. PMID- 26109224 TI - Low level impurities in imported wheat are a likely source of feral transgenic oilseed rape (Brassica napus L.) in Switzerland. AB - In Switzerland, the cultivation of genetically modified (GM) oilseed rape (Brassica napus L.) and the use of its seeds for food and feed are not permitted. Nevertheless, the GM oilseed rape events GT73, MS8*RF3, MS8 and RF3 have recently been found in the Rhine port of Basel, Switzerland. The sources of GM oilseed rape seeds have been unknown. The main agricultural good being imported at the Rhine port of Basel is wheat and from 2010 to 2013, 19% of all Swiss wheat imports originated from Canada. As over 90% of all oilseed rape grown in Canada is GM, we hypothesised that imports of Canadian wheat may contain low level impurities of GM oilseed rape. Therefore, waste fraction samples gathered during the mechanical cleaning of Canadian wheat from two Swiss grain mills were analysed by separating oilseed rape seeds from waste fraction samples and testing DNA of pooled seeds for the presence of transgenes by real-time PCR. Furthermore, oilseed rape seeds from each grain mill were sown in a germination experiment, and seedling DNA was tested for the presence of transgenes by real-time PCR. GT73, MS8*RF3, MS8 and RF3 oilseed rape was detected among seed samples and seedlings of both grain mills. Based on this data, we projected a mean proportion of 0.005% of oilseed rape in wheat imported from Canada. Besides Canadian wheat, the Rhine port of Basel does not import any other significant amounts of agricultural products from GM oilseed rape producing countries. We therefore conclude that Canadian wheat is the major source of unintended introduction of GM oilseed rape seeds into Switzerland. PMID- 26109225 TI - Electrokinetic remediation of fluorine-contaminated soil and its impact on soil fertility. AB - Compared to soil pollution by heavy metals and organic pollutants, soil pollution by fluorides is usually ignored in China. Actually, fluorine-contaminated soil has an unfavorable influence on human, animals, plants, and surrounding environment. This study reports on electrokinetic remediation of fluorine contaminated soil and the effects of this remediation technology on soil fertility. Experimental results showed that electrokinetic remediation using NaOH as the anolyte was a considerable choice to eliminate fluorine in contaminated soils. Under the experimental conditions, the removal efficiency of fluorine by the electrokinetic remediation method was 70.35%. However, the electrokinetic remediation had a significant impact on the distribution and concentrations of soil native compounds. After the electrokinetic experiment, in the treated soil, the average value of available nitrogen was raised from 69.53 to 74.23 mg/kg, the average value of available phosphorus and potassium were reduced from 20.05 to 10.39 mg/kg and from 61.31 to 51.58 mg/kg, respectively. Meanwhile, the contents of soil available nitrogen and phosphorus in the anode regions were higher than those in the cathode regions, but the distribution of soil available potassium was just the opposite. In soil organic matter, there was no significant change. These experiment results suggested that some steps should be taken to offset the impacts, after electrokinetic treatment. PMID- 26109226 TI - Erratum to: Characterization of carbonaceous aerosols at Mount Lu in South China: implication for secondary organic carbon formation and long-range transport. PMID- 26109227 TI - Clonazepam in the treatment of status epilepticus. AB - Status epilepticus (SE) is a common and serious neurological disorder. The prognosis of SE may be improved by effectively treating the disorder as early as possible. Clonazepam (CZP) has rarely been included in treatment guidelines for SE; however, this drug has been widely used in the treatment of SE patients and has unique advantages. Here, we elaborate on the clinical application of CZP in the treatment of SE and provide an effective and alternative treatment method for this disorder. We review selected literature, summarize action mechanisms, pharmacokinetics and clinical applications of CZP in the treatment of SE. We found that the effects of CZP are rapid and reliable and that adverse reactions are mild and transient. We conclude that CZP may be safely used to treat SE. PMID- 26109228 TI - Prehospital stroke care: telemedicine, thrombolysis and neuroprotection. AB - Over the last 15 years, new approaches regarding neuroprotective and thrombolytic strategies in stroke management have been evaluated in the prehospital setting. These efforts have provided exciting new potentials of hyperacute stroke care. Trials have shown that the use of specialized stroke ambulances increases the proportion of patients receiving intravenous thrombolysis and shortens alarm-to treatment time by approximately half an hour compared to standard care. Intravenous thrombolysis within the ultra-early time window of the 'golden hour' has become a realistic scenario. However, direct effects of prehospital stroke care on functional outcome have yet to be shown and other approaches such as neuroprotective treatments could not demonstrate clinical benefit so far. There is a clear need for systematic research in the prehospital field to test the clinical effectiveness and cost-effectiveness of new therapeutic strategies. It will be necessary to test various components of prehospital stroke care alone and in combination. PMID- 26109229 TI - Combining TMS-EEG with transcranial direct current stimulation language treatment in aphasia. AB - Despite the fact that different studies have been performed using transcranial direct current stimulation (tDCS) in aphasia, so far, to what extent the stimulation of a cerebral region may affect the activity of anatomically connected regions remains unclear. The authors used a combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to explore brain areas' excitability modulation before and after active and sham tDCS. Six chronic aphasics underwent 3 weeks of language training coupled with tDCS over the right inferior frontal gyrus. To measure the changes induced by tDCS, TMS-EEG closed to the area stimulated with tDCS were calculated. A significant improvement after tDCS stimulation was found which was accompained by a modification of the EEG over the stimulated region. PMID- 26109230 TI - Diversity of gut microflora is required for the generation of B cell with regulatory properties in a skin graft model. AB - B cells have been reported to promote graft rejection through alloantibody production. However, there is growing evidence that B cells can contribute to the maintenance of tolerance. Here, we used a mouse model of MHC-class I mismatched skin transplantation to investigate the contribution of B cells to graft survival. We demonstrate that adoptive transfer of B cells prolongs skin graft survival but only when the B cells were isolated from mice housed in low sterility "conventional" (CV) facilities and not from mice housed in pathogen free facilities (SPF). However, prolongation of skin graft survival was lost when B cells were isolated from IL-10 deficient mice housed in CV facilities. The suppressive function of B cells isolated from mice housed in CV facilities correlated with an anti-inflammatory environment and with the presence of a different gut microflora compared to mice maintained in SPF facilities. Treatment of mice in the CV facility with antibiotics abrogated the regulatory capacity of B cells. Finally, we identified transitional B cells isolated from CV facilities as possessing the regulatory function. These findings demonstrate that B cells, and in particular transitional B cells, can promote prolongation of graft survival, a function dependent on licensing by gut microflora. PMID- 26109231 TI - Overexpression of succinyl-CoA synthase for poly (3-hydroxybutyrate-co-3 hydroxyvalerate) production in engineered Escherichia coli BL21(DE3). AB - AIM: This study aims to increase the 3-hydroxyvalerate (3HV) fraction in poly(3 hydroxybutyrate-co-3-hydroxyvalerate) [P(HB-co-HV)] using succinyl-CoA synthase. METHODS AND RESULTS: Escherichia coli YH090, a polyhydroxyalkonate (PHA) producing strain, was further engineered for overexpression of succinyl-CoA synthase genes (sucCD), and examined for P(HB-co-HV) copolymer production in the presence of various precursor molecules using mixture analysis. Glycerol, succinate and propionate were screened as important factors for controlling intracellular PHA accumulation and monomer composition. Glycerol concentrations exerted the greatest influence on the overall biomass concentration and the intracellular PHA content, while propionate concentrations in the presence of succinate influenced the 3HV content of the copolymer. Mixture analysis also demonstrated that the engineered strain has the capacity to accumulate up to 80% of its cell dry weight (CDW) as PHA with a variable fraction of 3HV monomer (maximum of 72 wt %) depending on the controlled conditions. CONCLUSIONS: Propionate is the principal precursor for 3HV monomer in P(HB-co-HV) biopolymer and its utilization requires conversion to propionyl-CoA. Engineered E. coli YHY99, overexpressing sucCD genes, leads to an increase of the succinyl-CoA pool, which enhances the conversion rate of propionate by providing a CoA supply to other acyltransferase enzymes that have a role in propionate utilization. SIGNIFICANCE AND IMPACT OF THE STUDY: Engineered E. coli YHY99 was able to utilize propionate with a 4.5-fold increase in rate, as compared to the control strain, and resulted in the synthesis of a copolymer with high 3HV monomer content. PMID- 26109232 TI - Dandy-Walker malformation, genitourinary abnormalities, and intellectual disability in two families. AB - We report on two families, each with documented consanguinity and two affected with overlapping features of Dandy-Walker malformation, genitourinary abnormalities, intellectual disability, and hearing deficit. This phenotype shares similar findings with many well-known syndromes. However, the clinical findings of this syndrome categorize this as a new syndrome as compared with the phenotype of already established syndromes. Due to parental consanguinity, occurrence in siblings of both genders and the absence of manifestations in obligate carrier parents, an autosomal recessive pattern of inheritance is more likely. The authors believe that these families suggest a novel autosomal recessive cerebello-genital syndrome. Array CGH analyses of an affected did not show pathological deletions or duplications. PMID- 26109234 TI - Method of visualisation influences accuracy of measurements in cone-beam computed tomography. AB - This study evaluated the potential impact of different visualisation methods of cone-beam computed tomography (CBCT) on the accuracy of linear measurements of calcified structures, and assessed their interchangeability. High resolution (0.125 mm voxel) CBCT scans were obtained from eight cadaveric heads. The distance between the alveolar bone ridge and the incisal edge was determined for all mandibular incisors and canines, both anatomically and with measurements based on the following five CBCT visualisation methods: isosurface, direct volume rendering, multiplanar reformatting (MPR), maximum intensity projection of the volume of interest (VOIMIP), and average intensity projection of the volume of interest (VOIAvIP). All radiological methods were tested for repeatability and compared with anatomical results for accuracy, and limits of agreement were established. Interchangeability was evaluated by reviewing disparities between the methods and disclosing deterministic differences. Fine intra- and inter observer repeatability was asserted for all visualisation methods (intraclass correlation coefficient <=0.81). Measurements were most accurate when performed on MPR images and performed most disappointingly on isosurface-based images. Direct volume rendering, VOIMIP and VOIAvIP achieved acceptable results. It can be concluded that visualisation methods influence the accuracy of CBCT measurements. The isosurface viewing method is not recommended, and multiplanar reformatted images should be favoured for linear measurements of calcified structures. PMID- 26109233 TI - Adaptive rheology and ordering of cell cytoskeleton govern matrix rigidity sensing. AB - Matrix rigidity sensing regulates a large variety of cellular processes and has important implications for tissue development and disease. However, how cells probe matrix rigidity, and hence respond to it, remains unclear. Here, we show that rigidity sensing and adaptation emerge naturally from actin cytoskeleton remodelling. Our in vitro experiments and theoretical modelling demonstrate a biphasic rheology of the actin cytoskeleton, which transitions from fluid on soft substrates to solid on stiffer ones. Furthermore, we find that increasing substrate stiffness correlates with the emergence of an orientational order in actin stress fibres, which exhibit an isotropic to nematic transition that we characterize quantitatively in the framework of active matter theory. These findings imply mechanisms mediated by a large-scale reinforcement of actin structures under stress, which could be the mechanical drivers of substrate stiffness-dependent cell shape changes and cell polarity. PMID- 26109235 TI - Role of the stromal vascular fraction from adipose tissue in association with a phosphocalcic scaffold in bone regeneration in an irradiated area. AB - BACKGROUND: Osteoradionecrosis of the jaw is a major side-effect of radiotherapy used in the treatment of squamous cell carcinomas of the upper aerodigestive tract. The standard reconstruction procedure is a free flap transfer of autogenous bone. A new approach using a tissue engineering strategy has shown that total bone marrow (TBM) associated with biphasic calcium phosphate (BCP) is the best combination for bone regeneration in an irradiated area. Recently, the stromal vascular fraction from adipose tissue (SVF) was described as an alternative to TBM for promoting new bone formation. The aim of this study was to identify the capacity of a freshly isolated SVF to induce new bone formation in an irradiated area. METHODS: Four weeks after irradiation of the hind limbs of 15 rats, bone defects were created and filled with either SVF or TBM with and without BCP. RESULTS: Three weeks after the implantations, analysis showed that the BCP-TBM mixture improved new bone formation after radiation (p < 0.05). The BCP-SVF association induced significant neoangiogenesis but failed to enhance new bone formation. CONCLUSION: The BCP-SVF mixture was insufficient to enhance new bone formation in the irradiated area, suggesting that the role of the environment might be crucial for ossification. PMID- 26109236 TI - Surgical management of cross-bites in orthognathic surgery: Surgically assisted rapid maxillary expansion (SARME) versus two-piece maxilla. AB - PURPOSE: The surgical treatment of cross-bites includes surgically-assisted maxillary expansion (SARME) or maxillary-bipartition during bimaxillary surgery. This study evaluates and compares the changes in the teeth and lower nasal passage, as well as the stability of the expansion. PATIENTS AND METHODS: The measurements were performed on the cone-beam computed tomography (CBCT) scans of 32 patients with transverse (width) deficiencies of the maxilla. To expand the maxilla, 12 patients underwent the two-piece maxilla method, while 20 patients received SARME. RESULTS: The mean distraction width for SARME was 6.8 mm (SD 3.7), while that for the two-piece maxilla was 4.1 mm (SD 1.6). The expansion with SARME was over the entire length of the maxilla, from anterior to posterior, whereas the expansion of the two-piece patient group was only in the posterior part of the maxilla. The segments of the maxilla opened nearly parallel in SARME, while they were reverse V-shaped in the two-piece maxilla, from anterior to posterior. CONCLUSION: A key point in the planning of combined orthodontic orthognathic therapy with surgical correction of a cross-bite is the precise determination of the area where the width needs to be increased, and the amount of correction needed to treat the patient using minimal surgical procedures. PMID- 26109237 TI - Nitrogen limitation as a driver of genome size evolution in a group of karst plants. AB - Genome size is of fundamental biological importance with significance in predicting structural and functional attributes of organisms. Although abundant evidence has shown that the genome size can be largely explained by differential proliferation and removal of non-coding DNA of the genome, the evolutionary and ecological basis of genome size variation remains poorly understood. Nitrogen (N) and phosphorus (P) are essential elements of DNA and protein building blocks, yet often subject to environmental limitation in natural ecosystems. Using phylogenetic comparative methods, we test this hypothesis by determining whether leaf N and P availability affects genome sizes in 99 species of Primulina (Gesneriaceae), a group of soil specialists adapted to limestone karst environment in south China. We find that genome sizes in Primulina are strongly positively correlated with plant N content, but the correlation with plant P content is not significant when phylogeny history was taken into account. This study shows for the first time that N limitation might have been a plausible driver of genome size variation in a group of plants. We propose that competition for nitrogen nutrient between DNA synthesis and cellular functions is a possible mechanism for genome size evolution in Primulina under N-limitation. PMID- 26109238 TI - Modeling the transport of organic chemicals between polyethylene passive samplers and water in finite and infinite bath conditions. AB - Understanding the transfer of chemicals between passive samplers and water is essential for their use as monitoring devices of organic contaminants in surface waters. By applying Fick's second law to diffusion through the polymer and an aqueous boundary layer, the authors derived a mathematical model for the uptake of chemicals into a passive sampler from water, in finite and infinite bath conditions. The finite bath model performed well when applied to laboratory observations of sorption into polyethylene (PE) sheets for various chemicals (polycyclic aromatic hydrocarbons, polychlorinated biphenyls [PCBs], and dichlorodiphenyltrichloroethane [DDT]) and at varying turbulence levels. The authors used the infinite bath model to infer fractional equilibration of PCB and DDT analytes in field-deployed PE, and the results were nearly identical to those obtained using the sampling rate model. However, further comparison of the model and the sampling rate model revealed that the exchange of chemicals was inconsistent with the sampling rate model for partially or fully membrane controlled transfer, which would be expected in turbulent conditions or when targeting compounds with small polymer diffusivities and small partition coefficients (e.g., phenols, some pesticides, and others). The model can be applied to other polymers besides PE as well as other chemicals and in any transfer regime (membrane, mixed, or water boundary layer-controlled). Lastly, the authors illustrate practical applications of this model such as improving passive sampler design and understanding the kinetics of passive dosing experiments. PMID- 26109239 TI - Suicide ideation among oncologic patients in a Spanish ward. AB - Oncologic patients are exposed to a higher risk of suicidal behaviors than the general population. In this study, we aim to examine the severity of suicidal ideation in a sample of oncologic patients considering different psychological and clinical features. We interviewed 202 inpatients receiving curative or palliative treatment in a medical oncology ward of a Spanish hospital during the period 2012-2014. A complete assessment of psychosocial factors, cancer diagnoses (lung, colon rectum, and genitourinary system), and suicidal behaviors were made during admission, including validated questionnaires about depression, anxiety, personality, quality of life, body image, life threatening events, hopelessness, and suicidal ideation. The characteristics of inpatients with high and low suicidal ideation were retrospectively compared. A logistic regression model was constructed to examine the relationship between the significant factors retained after the univariate analyses. One of every four patients (n = 51; 25.24%) presented high scores of suicidal ideation. Logistic regression analyses retained depression (OR = 3.55; 95% CI = 1.25-11.68; p = .016), hopelessness (OR = 8.78; 95% CI = 3.44-25.88; p <= .001), personality (OR = .44; 95% CI = .2-.96; p = .038), and advanced age (OR = 2.60; 95% CI = 1.18-5.98; p = .016) as the main risk factors for high suicidal ideation. Suicidal ideation was frequent among oncologic patients. These patients should receive closer monitoring, especially, when old, retired, or severely depressed. PMID- 26109240 TI - Implications of radiologic-pathologic correlation for gallbladder disease in children and young adults with sickle cell disease. AB - The purpose of this study is to describe gallbladder imaging findings in patients with sickle cell disease, and to determine how they correspond with occurrence of complications, need for cholecystectomy, and surgical pathology. This study is IRB approved and HIPAA compliant. Informed consent requirements were waived. We reviewed records of 77 children with sickle cell disease ages 0-18 years at the time of their first gallbladder imaging study. Demographics, hospital courses, and radiologic and pathologic reports were collected. Two pediatric radiologists independently and retrospectively reviewed the imaging studies. Statistical analysis was performed using kappa statistic, chi-squared test, and ANOVA F-test. Continuous variables were described with mean, median, variance, and range. Patients who underwent cholecystectomy (N = 25) were more likely than the patients who did not undergo cholecystectomy (N = 52) to have gallstones or sludge (100 versus 36.5 %, p = <0.0001) or other gallbladder or biliary abnormality (70.8 versus 1.9 %, p = <0.0001). Patients who did not undergo cholecystectomy more frequently had normal-appearing gallbladders and biliary tracts (63.5 versus 0 %, p = <0.0001). Ninety-two percent of patients with cholecystectomy had chronic cholecystitis on pathology, and 96 % had a complication, including chronic cholecystitis and sequelae of biliary obstruction. Young patients with sickle cell disease, cholelithiasis, and any other biliary imaging abnormality will almost certainly require cholecystectomy, and many will experience complications. The most common surgical pathologic diagnosis in this group is chronic cholecystitis, which has a variable radiologic appearance. Our findings support recommendations to perform elective cholecystectomy for children and young adults with sickle cell disease and cholelithiasis or gallbladder sludge. PMID- 26109241 TI - Epidemiology and risk factors for chronic kidney disease in Chinese patients with biopsy-proven lupus nephritis. AB - BACKGROUND: Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). It is the most common secondary glomerulonephritis leading to end-stage renal disease. AIM: The purpose of this study is to evaluate the epidemiology and risk factors of chronic kidney disease (CKD) in Chinese patients with LN. METHODS: Clinical, laboratory, renal histopathology, treatment and outcome data were collected and retrospectively analysed in LN patients with or without CKD. RESULTS: At the end of the study, 94 (45.63%) patients were identified as having CKD among 206 individuals with renal biopsy-proven LN. Renal function, represented by serum creatinine and estimated glomerular filtration rate, was significantly decreased in the CKD patients (P = 0.008 and P < 0.001, respectively) at the time of the kidney biopsy. Compared with the non-CKD group, significantly increased proportions of hypertension (P < 0.001), serositis (P = 0.042) and anti-histone antibody positivity (P = 0.004) were detected in the CKD patients. Renal pathological activity and chronicity index scores were significantly increased in the CKD group (P < 0.001 for all). Finally, hypertension (hazard ratio (HR) 2.432, 95% confidence interval (CI) 1.575-3.754, P < 0.001), anti-histone antibody (HR 2.907, 95% CI 1.837-4.600, P < 0.001), and tubular atrophy (HR 1.248, 95% CI 1.007-1.547, P = 0.043) were independent risk factors for CKD. CONCLUSIONS: Hypertension, anti-histone antibody and tubular atrophy are independent risk factors for CKD in Chinese LN patients. PMID- 26109242 TI - Reliability and concurrent validity of instrumented balance error scoring system using a portable force plate system. AB - OBJECTIVES: The Balance Error Scoring System (BESS) is a commonly used test in adolescents and young adults. Affordability and portability of newer force plates has led to instrumentation of many clinical balance tests including the BESS. Despite the higher precision of force plate measures compared with clinical scoring, it is unclear if the instrumented BESS demonstrate concurrent validity and reliability when compared with the original BESS. The purpose of this study was to examine the reliability and concurrent validity of instrumented BESS testing using a commercially available force plate system. METHODS: Thirty-six participants participated in the initial testing day (17 male/19 female, M = 15.9 years, SD = 1.5 years). The test-retest sample consisted of 26 participants who completed the same testing procedure after 1 week. For all testing sessions, participants performed the BESS while standing on a portable force plate system. Number of errors and sway velocity were obtained. Concurrent validity was established through correlation analysis examining the relationship between the original and the instrumented BESS scores. Reliability was established using Intraclass Correlation Coefficient (ICC3,1) computed for the instrumented and the original BESS. RESULTS: A significant moderate relationship exists between the total scores of the original and the instrumented BESS (rs = 0.54, p = 0.001). Despite a range of reliability scores for the different conditions in the instrumented BESS (ICC3,1 = 0.19-0.61) and the clinically scored BESS (ICC3,1 = 0.13-0.71), the reliability score for the total test score was the same for the instrumented and the clinical test (ICC3,1 = 0.74). CONCLUSION: Although the instrumented BESS may appear to demonstrate concurrent validity against the original BESS, instrumentation did not improve its reliability. Future research should examine if the instrumented BESS demonstrates validity against laboratory level force plates and if it is able to overcome the ceiling effect reported for the clinical BESS test. PMID- 26109243 TI - Data analysis and review of radiology services at Glasgow 2014 Commonwealth Games. AB - BACKGROUND: Medical services at the Glasgow 2014 Commonwealth Games (CWG) were provided though a purpose-built medical polyclinic, which had a fully equipped radiology department along with other services, set up within the main Games Village. Data analysis of radiology services offered at CWG has not been published before. SETTING: Imaging services within the polyclinic, Athletes Village, Glasgow 2014 CWG. AIM: The aim of the paper is to analyse data on radiological investigations and assess the demand and distribution of workload on imaging services at CWG 2014. METHODOLOGY: Data on radiology investigations at the CWG 2014 was retrieved from the Carestream picture archiving and communication system (PACS) and Pharmasys (CWG official centralised electronic database system) and analysed. RESULTS: Six hundred ninety-seven diagnostic and interventional procedures were performed. Of these 37.9% were magnetic resonance imaging (MRI) scans, 22% were diagnostic ultrasound (US) examinations, 33.1% were radiographs, 4.3% were computed tomography (CT) scans and 2.7% were imaging guided interventional procedures. 88% of imaging was performed on athletes and the remainder were performed on team officials and workforce. Demand on radiology services gradually picked up through the pre-competition period and peaked half way through the CWG. CONCLUSIONS: Radiology played a vital role in the successful provision of medical services at the Glasgow 2014 CWG. High demand on imaging services can be expected at major international sporting events and therefore pre event planning is vital. Having back-up facilities in case of technical failure should be given due importance when planning radiology services at future CWG events. PMID- 26109245 TI - Systemic inflammation activates satellite glial cells in the mouse nodose ganglion and alters their functions. AB - Satellite glial cell (SGCs) in trigeminal and dorsal root ganglia are altered structurally and functionally under pathological conditions associated with chronic pain. These changes include reactive gliosis, augmented coupling by gap junctions, and increased responses to ATP via purinergic P2 receptors. Similar information for nodose ganglia (NG), which receive sensory inputs from internal organs via the vagus nerves, is missing. Here, we investigated changes in SGCs in mouse NG after the intraperitoneal administration of lipopolysaccharide (LPS), which induces systemic inflammation. Using calcium imaging we found that SGCs in intact, freshly isolated NG are sensitive to ATP, acting largely via purinergic P2 receptors (mixed P2X and P2Y), with threshold at 0.1 MUM. A single systemic injection of LPS (2.5 mg/kg) induced a 6-fold increase in the responses to ATP, largely by augmenting the sensitivity of P2X receptors. Immunohistochemical analysis revealed that at 1-14 days post-LPS injection the expression of glial fibrillary acidic protein in SGCs was 2-3-fold greater than controls. The expression of pannexin 1 channels increased 2-fold at day 7 after LPS injection. Using intracellular labeling we examined dye coupling among SGCs around different neurons, and observed an over 2-fold higher incidence of dye coupling after the induction of inflammation. Incubating the ganglia with ATP increased dye coupling by acting on neuronal P2X receptors, suggesting a role for ATP in the LPS-induced changes. We conclude that inflammation induces prominent changes in SGCs of NG, which might have a role in vagal afferent functions, such as the inflammatory reflex. GLIA 2015;63:2121-2132. PMID- 26109246 TI - Eye-tracking measurements of language processing: developmental differences in children at high risk for ASD. AB - To explore how being at high risk for autism spectrum disorder (ASD), based on having an older sibling diagnosed with ASD, affects word comprehension and language processing speed, 18-, 24- and 36-month-old children, at high and low risk for ASD were tested in a cross- sectional study, on an eye gaze measure of receptive language that measured how accurately and rapidly the children looked at named target images. There were no significant differences between the high risk ASD group and the low risk control group of 18- and 24-month-olds. However, 36-month-olds in the high risk for ASD group performed significantly worse on the accuracy measure, but not on the speed measure. We propose that the language processing efficiency of the high risk group is not compromised, but other vocabulary acquisition factors might have lead to the high risk 36-month-olds to comprehend significantly fewer nouns on our measure. PMID- 26109247 TI - A Randomized Controlled Trial to Improve Social Skills in Young Adults with Autism Spectrum Disorder: The UCLA PEERS((r)) Program. AB - Research suggests that impaired social skills are often the most significant challenge for those with autism spectrum disorder (ASD), yet few evidence-based social skills interventions exist for adults on the spectrum. This replication trial tested the effectiveness of PEERS, a caregiver-assisted social skills program for high-functioning young adults with ASD. Using a randomized controlled design, 22 young adults 18-24 years of age were randomly assigned to a treatment (n = 12) or delayed treatment control (n = 10) group. Results revealed that the treatment group improved significantly in overall social skills, frequency of social engagement, and social skills knowledge, and significantly reduced ASD symptoms related to social responsiveness following PEERS. Most treatment gains were maintained at a 16-week follow-up assessment with new improvements observed. PMID- 26109248 TI - Functional regulation of the apurinic/apyrimidinic endonuclease 1 by nucleophosmin: impact on tumor biology. PMID- 26109249 TI - The Antimicrobial Activity of an Acidic Phospholipase A2 (NN-XIa-PLA2) from the Venom of Naja naja naja (Indian Cobra). AB - Microbial resistance against antibiotics is considered as a potentially serious threat to public health. Therefore, there is much interest in developing new molecules with novel modes of action. In this study, when antimicrobial potential of an acidic protein-NN-XIa-PLA2 (Naja naja venom phospholipase A2 fraction-XIa) of N. naja venom was evaluated, it demonstrated potent bactericidal action against the human pathogenic strains. It inhibited more significantly, the gram positive bacteria, when compared to gram-negative bacteria. The minimum inhibitory concentration (MIC) values ranged from 17 to 20 MUg/ml. It was interesting to observe that the NN-XIa-PLA2 showed comparable antibacterial activity to the standard antibiotics used. It was found that there was a strong correlation between phospholipase A2 (PLA2) activities, hemolytic, and antimicrobial activity. Further, it is found that in the presence of p bromophenacyl bromide (p-BPB), there is a significant decrease in enzymatic activity and associated antimicrobial activities, suggesting that a strong correlation exists between catalytic activity and antimicrobial effects, which thereby destabilize the membrane bilayer. However, other mechanisms cannot be completely ruled out. Thus, these studies encourage further in-depth study on molecular mechanisms of antibacterial properties and thereby help in development of this protein into a possible therapeutic lead molecule for treating bacterial infections. PMID- 26109250 TI - Hepcidin and its potential clinical utility. AB - A number of pathophysiological conditions are related to iron metabolism disturbances. Some of them are well known, others are newly discovered or special. Hepcidin is a newly identified iron metabolism regulating hormone, which could be a promising biomarker for many disorders. In this review, we provide background information about mammalian iron metabolism, cellular iron trafficking, and the regulation of expression of hepcidin. Beside these molecular biological processes, we summarize the methods that have been used to determine blood and urine hepcidin levels and present those pathological conditions (cancer, inflammation, neurological disorders) when hepcidin measurement may have clinical relevance. PMID- 26109251 TI - Rationale and design of the RE-LATED AF--AFNET 7 trial: REsolution of Left atrial Appendage Thrombus--Effects of Dabigatran in patients with Atrial Fibrillation. AB - BACKGROUND: Dabigatran etexilate, a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with non-valvular atrial fibrillation (AF). However, there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage (LAA) thrombi in AF patients. OBJECTIVE: The primary objective of the RE-LATED AF trial is to assess whether dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin K antagonist phenprocoumon. Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate within 6 weeks of treatment and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon. METHODS: The study is designed as a prospective, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transoesophageal echocardiography (TEE) will be randomized to receive either dabigatran (150 mg bid) or phenprocoumon (INR 2-3) for the resolution of LAA thrombus formation for at least 21 days. Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at weeks 4 and 6, if the LAA thrombus has not been resolved before. A total of 110 patients are planned to be randomized. CONCLUSION: This is the first prospective, multicentre, randomized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF. PMID- 26109252 TI - Molecular characterization and sequence diversity of genes encoding the large subunit of the ADP-glucose pyrophosphorylase in wheat (Triticum aestivum L.). AB - The large subunit of ADP glucose pyrophosphorylase (AGPase), the rate limiting enzyme in starch biosynthesis in Triticum aestivum L., is encoded by the ADP glucose pyrophosphorylase large subunit (AGP-L) gene. This was the first report on the development of three genome-specific primer sets for isolating the complete genomic sequence of all three homoeologous AGP-L genes on group 1 chromosomes. All three AGP-L genes consisted of 15 introns and 15 exons. The lengths of the structural genes from start to stop codon were 3334 bp for AGP-L A1, 3351 bp for AGP-L-B1, and 3340 bp for AGP-L-D1. The coding region was 1569 bases long in all three genomes. All three AGP-L genes encoded 522 amino acid residues including the transit peptide sequences with 62 amino acid residues and the mature protein with 460 amino acid residues. The mature protein of three AGP L genes was highly conserved. Three AGP-L genes were sequenced in 47 diverse spring and winter wheat genotypes. One and two haplotypes were found for AGP-L-D1 and AGP-L-A1, respectively. In total, 67 SNPs (single nucleotide polymorphisms) and 13 indels (insertions or deletions) forming five haplotypes were identified for AGP-L-B1. All 13 indels and 58 of the 67 SNPs among the 47 genotypes were located in the non-coding regions, while the remaining nine SNPs were synonymous substitutions in the coding region. Significant LD was found among the 45 SNPs and ten indels located from intron 2 to intron 3. Association analysis indicated that four SNPs were strongly associated with seed number per spike and thousand kernel weight. PMID- 26109253 TI - The Metacognitive Anger Processing (MAP) Scale: Preliminary Testing. AB - BACKGROUND: Few studies have explored the metacognitive components of anger, and at present there is no metacognitive framework on anger incorporating both positive and negative beliefs about anger and distinct maladaptive processing routines, such as rumination. AIMS: The aim of the present preliminary studies was to apply a metacognitive framework to anger and put forward a new anger self report scale, the Metacognitive Anger Processing (MAP) scale, intended as a supplement to existing measures of anger disposition and to enhance anger treatment targets. METHOD: The new measure was tested in a nonclinical and a clinical sample together with measures of anger and metacognition to establish factor structure, reliability, concurrent, and convergent validity. RESULTS: The MAP showed a reliable factor structure with three factors - Positive Beliefs about anger, Negative Beliefs about anger, and Rumination; good internal reliability, and test-retest reliability. The subscales showed positive correlations with anger and the pattern of correlation with the general metacognitive measure supported the idea that the MAP represents dimensions of metacognition as it relates to anger. CONCLUSIONS: The present data indicate that positive as well as negative beliefs are involved in the tendency to ruminate about angry emotions. Clinical interventions may benefit from an exploration of the patient's experience of anger, as structured by the MAP's factors and their interrelationships. The psychometric properties of the MAP should be further investigated in clinical samples using larger test batteries and objective measures of aggression. PMID- 26109254 TI - Gene transfer engineering for astrocyte-specific silencing in the CNS. AB - Cell-type-specific gene silencing is critical to understand cell functions in normal and pathological conditions, in particular in the brain where strong cellular heterogeneity exists. Molecular engineering of lentiviral vectors has been widely used to express genes of interest specifically in neurons or astrocytes. However, we show that these strategies are not suitable for astrocyte specific gene silencing due to the processing of small hairpin RNA (shRNA) in a cell. Here we develop an indirect method based on a tetracycline-regulated system to fully restrict shRNA expression to astrocytes. The combination of Mokola-G envelope pseudotyping, glutamine synthetase promoter and two distinct microRNA target sequences provides a powerful tool for efficient and cell-type-specific gene silencing in the central nervous system. We anticipate our vector will be a potent and versatile system to improve the targeting of cell populations for fundamental as well as therapeutic applications. PMID- 26109255 TI - Antimalarial and antioxidant activities of Indigofera oblongifolia on Plasmodium chabaudi-induced spleen tissue injury in mice. AB - Malaria is still one of the most common infectious diseases and leads to various public health problems worldwide. Medicinal plants are promising sources for identifying novel agents with potential antimalarial activity. This study aimed to investigate the antimalarial and the antioxidant activities of Indigofera oblongifolia on Plasmodium chabaudi-induced spleen tissue injury in mice. Mice were divided into five groups. The first group served as a vehicle control; the second, third, fourth, and fifth groups were infected with 1 * 10(6) P. chabaudi parasitized erythrocytes. Mice of the last three groups were gavaged with 100 MUl of I. oblongifolia leave extract (IOLE) at a dose of 100, 200, and 300 mg IOLE/kg, respectively, once daily for 7 days. IOLE was significantly able to lower the percentage of parasitemia. The most effective dose was the 100 mg IOLE/kg, which could reduce the parasitemia from about 38 to 12 %. The infection induced spleen injury. This was evidenced by disorganization of spleen white and red pulps, appearance of hemozoin granules and parasitized erythrocytes. These changes in spleen led to the increased histological score. Also, the infection increased the spleen oxidative damage where the levels of nitrite/nitrate, malondialdehyde, and catalase were significantly altered. All these infection induced parameters were significantly improved during IOLE treatment. In addition, the mRNA expression of inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha were upregulated after infection with P. chabaudi, whereas IOLE significantly reduced the expression of these genes. Our results indicate that I. oblongifolia leaves extract exhibits a significant antimalarial and antioxidant effects, and protects host spleen tissue from injuries induced by P. chabaudi. PMID- 26109256 TI - Detection of Dirofilaria immitis DNA in host serum by nested PCR. AB - The heartworm Dirofilaria immitis is the causative agent of dirofilariasis in dogs. Studies have shown that parasite-derived cell-free DNA (cfDNA) can be detected in host blood and may be a promising diagnostic marker for parasitic infections. Thus, our aim was to detect D. immitis-derived cfDNA in host serum by nested PCR. Sera were collected from 12 dogs with natural D. immitis infections; eight were microfilaria (mf)-positive, and the remaining four were mf-negative. Culture fluids derived from single-sex adult D. immitis worms (mf-producing females and males) were also tested for cfDNA. All mf-positive sera were positive by nested PCR, whereas no amplification products were detected in mf-negative sera. The culture fluid of mf-producing females was positive by nested PCR but that of males was negative. All products amplified by nested PCR were sequenced to confirm that the amplicons were those of D. immitis. These results indicate that D. immitis DNA circulates freely in dog serum, except in mf-negative dogs. Additionally, D. immitis cfDNA may primarily be derived from the mf, and adult worms appeared to be minor contributors of cfDNA concentrations in serum; however, the contribution of D. immitis cfDNA derived from larvae of other developmental stages is unclear. An evaluation of the kinetics of D. immitis cfDNA in host serum throughout the parasite life cycle could facilitate the development of early molecular diagnostic techniques. To the best of our knowledge, this is the first report of the detection of mitochondrial DNA from a filarial parasite in host serum. PMID- 26109257 TI - Alternative nighttime nutrition regimens in glycogen storage disease type I: a controlled crossover study. AB - BACKGROUND: Traditional approaches for nighttime glycemic control in glycogen storage disease type I (GSDI) include continuous tube feeding, or ingestion of uncooked corn starch (CS) at bedtime. A modified corn starch (MCS) has been shown to prolong euglycemia in some patients. The aim of this study was to evaluate whether stable nighttime glucose control can be achieved with other types of slowly digested carbohydrates in adult GSDI patients. METHODS: In this cross-over study, nocturnal glucose control and fasting times were assessed with three different nocturnal nutrition regimens in five patients, using continuous glucose monitoring (CGMS) in an outpatient everyday life setting. For each patient, continuous glucose profiles were measured after ingestion of (1) CS, (2) MCS or (3) a pasta meal at bedtime, during 5 to 6 consecutive nights for each regimen. RESULTS: Stable nocturnal glucose control was achieved for all patients with a pasta meal, with a mean duration of glycemia >3.5 mmol/l of 7.6 h (range 5.7 10.8), and >4 mmol/l of 7 h (5.2-9.2), similar to CS and MCS. Fasting glucose before breakfast on workdays (after 7.1 +/- 0.8 h) was not significantly different between the three interventions (CS 4.1 +/- 0.5 mmol/l, MCS 4.6 +/- 0.7 mmol/l, pasta 4.3 +/- 0.9 mmol/l). During prolonged fasting on weekends, longer duration of normoglycemia was achieved with CS or MCS than with pasta. CONCLUSION: Consumption of cooked pasta is a suitable and more palatable alternative to uncooked corn starch to achieve nighttime glucose control in adult patients with GSDI. PMID- 26109258 TI - Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate. AB - Mitochondrial trifunctional protein (MTP) deficiency caused by HADHA or HADHB gene mutations exhibits substantial molecular, biochemical, and clinical heterogeneity and ranks among the more severe fatty acid oxidation (FAO) disorders, without pharmacological treatment. Since bezafibrate has been shown to potentially correct other FAO disorders in patient cells, we analyzed its effects in 26 MTP-deficient patient fibroblasts representing 16 genotypes. Overall, the patient cell lines exhibited variable, complex, biochemical profiles and pharmacological responses. HADHA-deficient fibroblasts showed markedly reduced alpha subunit protein levels together with decreased beta-subunit abundance, exhibited a -86 to -96% defect in LCHAD activity, and produced large amounts of C14 and C16 hydroxyacylcarnitines. In control fibroblasts, exposure to bezafibrate (400 MUM for 48 h) increased the abundance of HADHA and HADHB mRNAs, immune-detectable alpha and beta subunit proteins, activities of LCHAD and LCKAT, and stimulated FAO capacities, clearly indicating that MTP is pharmacologically up-regulated by bezafibrate in human fibroblasts. In MTP-deficient patient fibroblasts, which were found markedly FAO-deficient, bezafibrate improved FAO capacities in six of 26 (23%) cases, including three cell lines heterozygous for the common c1528G > C mutation. Altogether, our results strongly suggest that, due to variable effects of HADHA and HADHB mutations on MTP abundance and residual activity, improvement of MTP deficiency in response to bezafibrate was achieved in a subset of responsive genotypes. PMID- 26109260 TI - Improving education: just-in-time splinting video. AB - BACKGROUND: Just-in-time training (JITT) is an emerging concept in medical procedural education, but with few studies to support its routine use. Providing a brief educational intervention in the form of a digital video immediately prior to patient care may be an effective method to reteach knowledge for procedural techniques learned previously. METHODS: Paediatric resident physicians were taught to perform a volar splint in a small workshop setting. Subsequently, they were asked to demonstrate their splinting proficiency by performing a splint on another doctor. Proficiency was scored on a five-point assessment tool. After 2 12 months, participants were asked to demonstrate their splinting proficiency on one of the investigators, and were divided into the control group (no further instruction) and the intervention group, which viewed a 3-minute JITT digital video demonstrating the splinting technique prior to performing the procedure. RESULTS: Thirty subjects were enrolled between August 2012 and July 2013, and 29 of 30 completed the study. The retest splinting time was not significantly different, but if the JITT group included watching the video, the total time difference was statistically significant: 3.86 minutes (control) versus 7.07 minutes (JITT) (95% confidence interval: 2.20-3.90 minutes). The average assessment score difference was 1.87 points higher for the JITT group, which was a statistically significant difference (95% confidence interval: 1.00-3.00). Just in-time training is an emerging concept in medical procedural education DISCUSSION: JITT seems to be an effective tool in medical education for reinforcing previously learned skills. JITT may offer other possibilities for enhancing medical education. PMID- 26109259 TI - Ketogenic diets in patients with inherited metabolic disorders. AB - Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, usually without catabolism. Since the mid-1990s such diets have been widely used in patients with seizures/epilepsies, mostly children. This review focuses on the use of KDs in patients with various inherited metabolic disorders (IMD). In glucose transporter type 1 deficiency syndrome (GLUT1-DS) and pyruvate dehydrogenase complex (PDHc) deficiency, KDs are deemed the therapy of choice and directly target the underlying metabolic disorder. Moreover, in other IMD, mainly of intermediary metabolism such as glycogen storage diseases and disorders of mitochondrial energy supply, KDs may ameliorate clinical symptoms and laboratory parameters. KDs have also been used successfully to treat symptoms such as seizures/epilepsy in IMD, e.g. in urea cycle disorders and non-ketotic hyperglycinemia. As a note of caution, catabolism may cause the condition of patients with IMD to deteriorate and should thus be avoided during KDs. For this reason, careful monitoring (clinical, laboratory and apparatus-supported) is warranted. In some IMDs specific macronutrient supply is critical. Therefore, in cases of PDHc deficiency the carbohydrate intake tolerated without lactate increase and in urea cycle disorders the protein tolerance should be determined. Considering this, it is particularly important in patients with IMD that the use of KDs be individualized and well documented. PMID- 26109262 TI - Analysis of Price Changes in Washington Following the 2012 Liquor Privatization. AB - AIMS: In June, 2012 the state of Washington ended a wholesale and retail monopoly on liquor sales resulting in about five times as many stores selling liquor. Three-tier restrictions were also removed on liquor, while beer and wine availability did not increase. Substantial taxes at both the wholesale and retail levels were implemented and it was expected that prices would rise. METHODS: To evaluate price changes after privatization we developed an index of about 68 brands that were popular in Washington during early 2012. Data on final liquor prices (including all taxes) in Washington were obtained through store visits and on-line sources between November 2013 and March of 2014. Primary analyses were conducted on five or six brand indexes to allow the inclusion of most stores. RESULTS: Washington liquor prices rose by an average of 15.5% for the 750 ml size and by 4.7% for the 1.75 l size, while only small changes were seen in the bordering states of Oregon and Idaho. Prices were found to vary greatly by store type. Liquor Superstores had generally the lowest prices while drugstore, grocery and especially smaller Liquor Store prices were found to be substantially higher. CONCLUSION: Our findings indicate that liquor prices in Washington increased substantially after privatization and as compared to price changes in bordering states, with a much larger increase seen for the 750 ml size and with wide variation across store types. However, persistent drinkers looking for low prices will be able to find them in certain stores. PMID- 26109261 TI - Comparing Patients' Opinions on the Hospital Discharge Process Collected With a Self-Reported Questionnaire Completed Via the Internet or Through a Telephone Survey: An Ancillary Study of the SENTIPAT Randomized Controlled Trial. AB - BACKGROUND: Hospital discharge, a critical stage in the hospital-to-home transition of patient care, is a complex process with potential dysfunctions having an impact on patients' health on their return home. No study has yet reported the feasibility and usefulness of an information system that would directly collect and transmit, via the Internet, volunteer patients' opinions on their satisfaction concerning the organization of hospital discharge. OBJECTIVE: Our primary objective was to compare patients' opinions on the discharge process collected with 2 different methods: self-questionnaire completed on a dedicated website versus a telephone interview. The secondary goal was to estimate patient satisfaction. METHODS: We created a questionnaire to examine hospital discharge according to 3 dimensions: discharge logistics organization, preplanned posthospital continuity-of-care organization, and patients' impressions at the time of discharge. A satisfaction score (between 0 and 1) for each of those dimensions and an associated total score were calculated. Taking advantage of the randomized SENTIPAT trial that questioned patients recruited at hospital discharge about the evolution of their health after returning home and randomly assigned them to complete a self-questionnaire directly online or during a telephone interview, we conducted an ancillary study comparing satisfaction with the organization of hospital discharge for these 2 patient groups. The questionnaire was proposed to 1141 patients included in the trial who were hospitalized for >=2 days, among whom 867 eligible patients had access to the Internet at home and were randomized to the Internet or telephone group. RESULTS: Of the 1141 patients included, 755 (66.17%) completed the questionnaire. The response rates for the Internet (39.1%, 168/430) and telephone groups (87.2%, 381/437) differed significantly (P<.001), but their total satisfaction scores did not (P=.08) nor did the satisfaction subscores (P=.58 for discharge logistics organization, P=.12 for preplanned posthospital continuity-of-care organization, and P=.35 for patients' impressions at the time of discharge). The total satisfaction score (median 0.83, IQR 0.72-0.92) indicated the patients' high satisfaction. CONCLUSIONS: The direct transmission of personal health data via the Internet requires patients' active participation and those planning surveys in the domain explored in this study should anticipate a lower response rate than that issued from a similar survey conducted by telephone interviews. Nevertheless, collecting patients' opinions on their hospital discharge via the Internet proved operational; study results indicate that conducting such surveys via the Internet yields similar estimates to those obtained via a telephone survey. The results support the establishment of a permanent dedicated website that could also be used to obtain users' opinions on other aspects of their hospital stay and follow-up. TRIAL REGISTRATION: Clinicaltrials.gov NCT01769261; http://clinicaltrials.gov/ct2/show/NCT01769261 (Archived by WebCite at http://www.webcitation.org/6ZDF5bdQb). PMID- 26109263 TI - Who Purchases Low-Cost Alcohol in Australia? AB - AIMS: Debates surrounding potential price-based polices aimed at reducing alcohol related harms tend to focus on the debate concerning who would be most affected harmful or low-income drinkers. This study will investigate the characteristics of people who purchase low-cost alcohol using data from the Australian arm of the International Alcohol Control study. METHODS: 1681 Australians aged 16 and over who had consumed alcohol and purchased it in off-licence premises were asked detailed questions about both practices. Low-cost alcohol was defined using cut points of 80c, $1.00 or $1.25 per Australian standard drink. RESULTS: With a $1.00 cut-off low income (OR = 2.1) and heavy drinkers (OR = 1.7) were more likely to purchase any low-cost alcohol. Harmful drinkers purchased more, and low income drinkers less, alcohol priced at less than $1.00 per drink than high income and moderate drinkers respectively. The relationship between the proportion of units purchased at low cost and both drinker category and income is less clear, with hazardous, but not harmful, drinkers purchasing a lower proportion of units at low cost than moderate drinkers. CONCLUSIONS: The impact of minimum pricing on low income and harmful drinkers will depend on whether the proportion or total quantity of all alcohol purchased at low cost is considered. Based on absolute units of alcohol, minimum unit pricing could be differentially effective for heavier drinkers compared to other drinkers, particularly for young males. PMID- 26109264 TI - Lean body mass assessment based on UV absorbance in spent dialysate and dual energy x-ray absorptiometry. AB - PURPOSE: The aim of the study was to explore the possibility of assessing lean body mass (LBM) based on UV absorbance measurements in spent dialysate. METHODS: 9 patients on chronic three-times-a-week HD (4 female, 5 male, mean age 58.8 +/- 8.6 years) were studied. Blood and spent dialysate samples were collected for 3 consecutive hemodialysis (HD) sessions from every patient. A double-beam spectrophotometer was used for the determination of UV absorbance in the collected spent dialysate samples. Dual-energy x-ray absorptiometry (DXA) scans were performed on an interdialytic day. LBM was calculated based on creatinine concentration in blood (LBMblood) and UV absorbance in spent dialysate (LBMa) and assessed by DXA (LBMDXA). Also, in vitro experiments were carried out to investigate the effect of tissue hydration on DXA measurements. RESULTS: Although LBMa was slightly lower compared to LBMblood, the estimates based on UV absorbance in spent dialysate presented greater accuracy and precision compared to LBMDXA. The significant difference between LBMblood and LBMDXA was with high probability caused by the altered tissue hydration of HD patents. CONCLUSIONS: In summary, the results show that it is possible to asses LBM based on UV absorbance in spent dialysate. PMID- 26109265 TI - Detection and role of minimal disseminated disease in children with lymphoblastic lymphoma: The AIEOP experience. AB - BACKGROUND: The use of intensive chemotherapy regimens in children with lymphoblastic lymphoma (LBL) has significantly improved outcome, but the salvage rate for these patients is still poor. The aim of this study was to evaluate the prognostic value of minimal disseminated disease (MDD), studied by multiparametric flow cytometry (MFC), in pediatric patients with T- and B-lineage LBL. PROCEDURE: We examined bone marrow (BM) and peripheral blood (PB) samples from a series of 65 children affected by T- (52) and B-lineage (13) LBL using an MFC method; 10 of them were also analyzed for clonality of T-cell receptor gene rearrangements. RESULTS: MDD was detected in 49% (32/65) of BM samples, whereas only 21% (14/65) were positive at standard morphological evaluation. Findings from MFC analyses of paired BM and PB samples were highly concordant. We analyzed the prognostic significance of MDD results detected at diagnosis in morphologically negative patients, as almost all relapsed cases (10/11) did not have any morphological involvement of BM at diagnosis. Using an MDD cut-off level of 3% by FCM (75th percentile), 5-year event-free survival (EFS) was 60% (SE +/- 22) for patients with MDD >3% LBL cells versus 83% (SE +/- 6) for the remaining patients (P = 0.04). No statistically significant difference in EFS was observed between LBL patients considering all the other clinical characteristics. CONCLUSIONS: Our data demonstrated that MDD studied at diagnosis by MFC could represent a useful prognostic tool in childhood LBL and further application for better stratification is warranted. PMID- 26109266 TI - Mechanistic Analysis of an Engineered Enzyme that Catalyzes the Formose Reaction. AB - An enzyme that catalyzes the formose reaction, termed "formolase", was recently engineered through a combination of computational protein design and directed evolution. We have investigated the kinetic role of the computationally designed residues and further characterized the enzyme's product profile. Kinetic studies illustrated that the computationally designed mutations were synergistic in their contributions towards enhancing activity. Mass spectrometry revealed that the engineered enzyme produces two products of the formose reaction-dihydroxyacetone and glycolaldehyde-with the product profile dependent on the formaldehyde concentration. We further explored the effects of this product profile on the thermodynamics and yield of the overall carbon assimilation from the formolase pathway to help guide future efforts to engineer this pathway. PMID- 26109267 TI - Visible diffraction from quasi-crystalline arrays of carbon nanotubes. AB - Large area arrays of vertically-aligned carbon nanotubes (VACNTs) are patterned in a quasi-crystalline Penrose tile arrangement through electron beam lithography definition of Ni catalyst dots and subsequent nanotube growth by plasma-enhanced chemical vapour deposition. When illuminated with a 532 nm laser beam high quality and remarkable diffraction patterns are seen. The diffraction is well matched to theoretical calculations which assume apertures to be present at the location of the VACNTs for transmitted light. The results show that VACNTs act as diffractive elements in reflection and can be used as spatially phased arrays for producing tailored diffraction patterns. PMID- 26109268 TI - Fabrication and assessment of 3D printed anatomical models of the lower limb for anatomical teaching and femoral vessel access training in medicine. AB - For centuries, cadaveric dissection has been the touchstone of anatomy education. It offers a medical student intimate access to his or her first patient. In contrast to idealized artisan anatomical models, it presents the natural variation of anatomy in fine detail. However, a new teaching construct has appeared recently in which artificial cadavers are manufactured through three dimensional (3D) printing of patient specific radiological data sets. In this article, a simple powder based printer is made more versatile to manufacture hard bones, silicone muscles and perfusable blood vessels. The approach involves blending modern approaches (3D printing) with more ancient ones (casting and lost wax techniques). These anatomically accurate models can augment the approach to anatomy teaching from dissection to synthesis of 3D-printed parts held together with embedded rare earth magnets. Vascular simulation is possible through application of pumps and artificial blood. The resulting arteries and veins can be cannulated and imaged with Doppler ultrasound. In some respects, 3D-printed anatomy is superior to older teaching methods because the parts are cheap, scalable, they can cover the entire age span, they can be both dissected and reassembled and the data files can be printed anywhere in the world and mass produced. Anatomical diversity can be collated as a digital repository and reprinted rather than waiting for the rare variant to appear in the dissection room. It is predicted that 3D printing will revolutionize anatomy when poly material printing is perfected in the early 21st century. PMID- 26109269 TI - Identification of polyamine-responsive bacterioplankton taxa in South Atlantic Bight. AB - Putrescine and spermidine are short-chained aliphatic polyamines (PAs) that are ubiquitously distributed in seawater. These compounds may be important sources of dissolved organic carbon and nitrogen for marine bacterioplankton. Here, we used pyrotag sequencing to quantify the response of bacterioplankton to putrescine and spermidine amendments in microcosms established using surface waters collected at various stations in the South Atlantic Bight in October 2011. Our analysis showed that PA-responsive bacterioplankton consisted of bacterial taxa that are typically dominant in marine systems. Rhodobacteraceae (Alphaproteobacteria) was the taxon most responsive to PA additions at the nearshore site. Gammaproteobacteria of the families Piscirickettsiaceae; Vibrionaceae; and Vibrionaceae and Pseudoalteromonadaceae, were the dominant PA-responsive taxa in samples from the river-influenced coastal station, offshore station and open ocean station, respectively. The spatial variability of PA-responsive taxa may be attributed to differences in composition of the initial bacterial community and variations of in situ physiochemical conditions among sites. Our results also provided the first empirical evidence that Gammaproteobacteria might play an important role in PA transformation in marine systems. PMID- 26109270 TI - Polymer Supported Directed Differentiation Reveals a Unique Gene Signature Predicting Stable Hepatocyte Performance. AB - In theory, pluripotent stem cells can give rise to all somatic cell types found in the human body. The ability to generate renewable sources of human cells has enormous potential to improve human health and wealth. One major obstacle to the routine deployment of stem cell-derived cells is their instability in culture. To tackle this issue a synthetic polymer surface is used. PMID- 26109271 TI - Characterization of wastewater treatment by two microbial fuel cells in continuous flow operation. AB - A two serially connected single-chamber microbial fuel cell (MFC) was applied to the treatment of diluted molasses wastewater in a continuous operation mode. In addition, the effect of series and parallel connection between the anodes and the cathode on power generation was investigated experimentally. The two serially connected MFC process achieved 79.8% of chemical oxygen demand removal and 11.6% of Coulombic efficiency when the hydraulic retention time of the whole process was 26 h. The power densities were 0.54, 0.34 and 0.40 W m(-3) when electrodes were in individual connection, serial connection and parallel connection modes, respectively. A high open circuit voltage was obtained in the serial connection. Power density decreased at low organic loading rates (OLR) due to the shortage of organic matter. Power generation efficiency tended to decrease as a result of enhancement of methane fermentation at high OLRs. Therefore, high power density and efficiency can be achieved by using a suitable OLR range. PMID- 26109272 TI - Fast food consumption in pregnancy and subsequent asthma symptoms in young children. AB - BACKGROUND: Recent cross-sectional studies suggested children's current fast food consumption to be related to frequency of asthma and allergies. Maternal prenatal diet has been suspected to contribute to children's asthma and atopic disease risks. OBJECTIVES: We hypothesized that maternal fast food intake during pregnancy increases offspring's risk for asthmatic symptoms. METHODS: We conducted a population-based study of 1201 mother/child pairs in Los Angeles, California. Detailed information about prenatal fast food intake and other dietary, lifestyle/environmental factors, and pregnancy was collected shortly after birth; further data were retrieved from birth certificates. Using the International Study of Asthma and Allergies in Childhood core questions, asthma and rhinitis symptoms were assessed, and doctor's diagnoses were recorded in offspring 3.5 years after birth. Poisson regression with robust error variance using a log link function was used to estimate relative risks (RRs). Models were adjusted using covariates or propensity scores. RESULTS: Maternal prenatal fast food consumption related to increased relative risks of their children for severe, and current asthma symptoms (wheeze last 12 months combined with doctor's diagnosis) in a dose-dependent manner: 'once a month': RR: 0.99 (95% CI: 0.36, 2.75), 'once a week': 1.26 (0.47, 3.34); '3-4 days a week': 2.17 (0.77, 6.12); and 'every day' 4.46 (1.36 14.6) compared to 'never', adjusting for potential confounders (p for trend = 0.0025). There was also suggestion of increased risks for rhinitis symptoms. CONCLUSIONS: These findings suggest that in utero exposure to frequent fast food through maternal diet may be a risk factor for asthmatic symptoms in young children. PMID- 26109273 TI - Migraine features in patients with Meniere's disease. AB - OBJECTIVES/HYPOTHESIS: To better understand the features of migraine in Meniere's disease (MD). STUDY DESIGN: Retrospective review of prospectively obtained surveys in an outpatient clinic of a tertiary medical center. METHODS: Detailed questionnaires on headaches and dizziness were given to consecutive patients presenting with dizziness. The responses were verified by the clinician with the patient. The data, in addition to the clinical history and audiogram, were used to diagnose patients with migraine headaches and MD using criteria set by the International Headache Society (IHS) and the American Academy of Otolaryngology Head and Neck Surgery, respectively. The prevalence of migraine-like symptoms in those patients with MD, who did not fit the diagnostic criteria for migraine, was evaluated. RESULTS: Thirty-seven patients with definite MD were included. There was a predominance of females (female/male:26/11). Mean age of patients was 52 +/ 14 years. Nineteen patients (51%) had migraine headaches. Fifteen patients fulfilled the criteria for definite vestibular migraine. Of those who did not fulfill the IHS migraine criteria, a majority had characteristics such as a family history of migraine, visual motion sensitivity, or lifelong motion sickness that were highly suggestive of a migraine disorder. CONCLUSIONS: A majority of patients with MD have migraine headaches as defined by the IHS. Sensitivity to visual motion, light and sound, head motion, smells, weather changes, or medication was present in 95% of all patients with definite MD and 82% of non-IHS migraine MD patients. This may suggest that MD may be an atypical variant of migraine. PMID- 26109274 TI - Antibiotic consumption among a Swedish cohort of children born in 2006. AB - AIM: It is important to measure antibiotic consumption because it contributes to antimicrobial resistance. Our objective was to follow all children born in 2006 in Sweden and to analyse antibiotic consumption during each month of life for the first two years and thereafter for every year during their third to fifth years of life. METHODS: This was a register-based, open-cohort study where we used the Swedish Prescribed Drug Register, which covers the whole population, to identify the type and date of purchase of antibiotics for the children in the cohort. RESULTS: During the first one-year follow-up period, 101 555 children up to one year of age were living in Sweden, of which 50 135 were boys and 49 420 were girls. Children consumed the largest amount of antibiotics during their second year of life. In our cohort, 51% received antibiotics at some point during the second year and 24% received multiple treatments. The consumption then dropped with every year of life during the follow-up. CONCLUSION: This study suggests that actions against overprescribing of antibiotics to children should be targeted towards the second year of life in order to have the greatest effect on consumption. PMID- 26109275 TI - Treatment of feline intermediate- to high-grade lymphoma with a modified university of Wisconsin-Madison protocol: 119 cases (2004-2012). AB - CHOP-based (cyclophosphamide, doxorubicin, vinca alkaloid, prednisolone) chemotherapy protocols are often recommended for treatment of feline lymphoma. While maintenance-free CHOP-based protocols have been published and readily used in dogs, there is limited literature regarding similar maintenance-free protocols in cats. The purpose of this study was to describe the outcome of cats with intermediate- to high-grade lymphoma that were prescribed a modified 25-week University of Wisconsin-Madison (UW-25) chemotherapy protocol. A secondary objective was examination of potential prognostic factors. One hundred and nineteen cats from five institutions treated with a UW-25-based protocol were included. The Kaplan-Meier median progression-free interval (PFI) and survival time (MST) were 56 and 97 (range 2-2019) days, respectively. Cats assessed as having a complete response (CR) to therapy had significantly longer PFI and MST than those with partial or no response (PFI 205 versus 54 versus 21 days, respectively, P < 0.0001 and MST 318 versus 85 versus 27 days, respectively, P < 0.0001). PMID- 26109277 TI - Systematic review and critical appraisal of the impact of acellular dermal matrix use on the outcomes of implant-based breast reconstruction. AB - BACKGROUND: Acellular dermal matrix (ADM) may improve outcomes in implant-based breast reconstruction (IBBR). The aim of this study was critically to appraise and evaluate the current evidence for ADM-assisted IBBR. METHODS: Comprehensive electronic searches identified complete papers published in English between January 2000 and August 2013, reporting any outcome of ADM-assisted IBBR. All systematic reviews, randomized clinical trials (RCTs) and non-randomized studies (NRSs) with more than 20 ADM recipients were included. Studies were critically appraised using AMSTAR for systematic reviews, the Cochrane risk-of-bias tool for RCTs and its adaptation for NRSs. Characteristics and results of identified studies were summarized. RESULTS: A total of 69 papers (8 systematic reviews, 1 RCT, 40 comparative studies and 20 case series) were identified, all of which were considered at high risk of bias, mostly due to patient selection and selective outcome reporting. The median ADM group sample size was 51.0 (i.q.r. 33.0-127.0). Most studies were single-centre (54), and they were often single surgeon (16). ADM was most commonly used for immediate (40) two-stage IBBR (36) using human ADM (47), with few studies evaluating ADM-assisted single-stage procedures (10). All reported clinical outcomes (for example implant loss) and more than half of the papers (33) assessed process outcomes, but few evaluated cosmesis (16) or patient-reported outcomes (10). Heterogeneity between study design and, especially, outcome measurement precluded meaningful data synthesis. CONCLUSION: Current evidence for the value of ADMs in IBBR is limited. Use in practice should therefore be considered experimental, and evaluation within registries or well designed and conducted studies, ideally RCTs, is recommended to prevent widespread adoption of a potentially inferior intervention. PMID- 26109276 TI - A random forest approach to capture genetic effects in the presence of population structure. AB - The accurate mapping of causal variants in genome-wide association studies requires the consideration of both, confounding factors (for example, population structure) and nonlinear interactions between individual genetic variants. Here, we propose a method termed 'mixed random forest' that simultaneously accounts for population structure and captures nonlinear genetic effects. We test the model in simulation experiments and show that the mixed random forest approach improves detection power compared with established approaches. In an application to data from an outbred mouse population, we find that mixed random forest identifies associations that are more consistent with prior knowledge than competing methods. Further, our approach allows predicting phenotypes from genotypes with greater accuracy than any of the other methods that we tested. Our results show that approaches that simultaneously account for both, confounding due to population structure and epistatic interactions, are important to fully explain the heritable component of complex quantitative traits. PMID- 26109278 TI - Social science and linguistic text analysis of nurses' records: a systematic review and critique. AB - The two aims of the paper were to systematically review and critique social science and linguistic text analyses of nursing records in order to inform future research in this emerging area of research. Systematic searches in reference databases and in citation indexes identified 12 articles that included analyses of the social and linguistic features of records and recording. Two reviewers extracted data using established criteria for the evaluation of qualitative research papers. A common characteristic of nursing records was the economical use of language with local meanings that conveyed little information to the uninitiated reader. Records were dominated by technocratic-medical discourse focused on patients' bodies, and they depicted only very limited aspects of nursing practice. Nurses made moral evaluations in their categorisation of patients, which reflected detailed surveillance of patients' disturbing behaviour. The text analysis methods were rarely transparent in the articles, which could suggest research quality problems. For most articles, the significance of the findings was substantiated more by theoretical readings of the institutional settings than by the analysis of textual data. More probing empirical research of nurses' records and a wider range of theoretical perspectives has the potential to expose the situated meanings of nursing work in healthcare organisations. PMID- 26109279 TI - Intrinsic properties of germinal center-derived B cells promote their enhanced class switching to IgE. AB - BACKGROUND: Research on the origins and development of human IgE-expressing (IgE(+) ) cells is required for understanding the pathogenesis of allergy and asthma. These studies have been thwarted by the rarity of IgE(+) cells in vivo and the low frequency of class switch recombination (CSR) to IgE ex vivo. To determine the main source of IgE(+) cells, we investigated the relation between the phenotypic composition of tonsil B cells and the CSR to IgE ex vivo. METHODS: Human tonsil B cells were analyzed by flow cytometry (FACS) and cultured with IL 4 and anti-CD40 to induce CSR to IgE. Naive, germinal center (GC), early GC (eGC), and memory tonsil B cells were isolated by FACS, and their capacities for IL-4 and anti-CD40 signaling, cell proliferation, and de novo class switching to IgE were analyzed by RT-PCR and FACS. RESULTS: B cells from different tonsils exhibited varying capacities for CSR to IgE ex vivo. This was correlated with the percentage of eGC B cells in the tonsil at the outset of the culture. Despite relatively poor cell viability, eGC and GC B-cell cultures produced the highest yields of IgE(+) cells compared to naive and memory B-cell cultures. The main factors accounting for this result were the strength of IL-4R and CD40 signaling and relative rates of cell proliferation. CONCLUSIONS: This study shows that the maturation state of tonsil B cells determines their capacity to undergo class switching to IgE ex vivo, with the GC-derived B cells yielding the highest percentage of IgE(+) cells. PMID- 26109282 TI - Absence of Encephalitozoon cuniculi antibodies in wild rabbits in England. PMID- 26109280 TI - Experimental models of neuromyelitis optica: current status, challenges and future directions. AB - Neuromyelitis optica (NMO) is a recurrent inflammatory disease that predominantly attacks the opticnerves and spinal cord. NMO-IgG, the specific autoantibody present in the vast majority of NMO patients, targets the astrocytic water channel protein aquaporin 4 (AQP4), and differentiates NMO from multiple sclerosis. The growing clinical and research interest in NMO makes it urgent to produce an animal model of NMO. The pathogenic effect of anti-AQP4 antibodies derived from the serum of patients paves the way to generating an experimental model based on the anti-AQP4-mediated astrocyte damage. In this review, we discuss the contribution of experimental models to the understanding of the pathogenesis of the disease and drug development. Key questions raised by the existing models are also discussed. PMID- 26109283 TI - Minimal interleukin expression in canine intracranial meningiomas. PMID- 26109284 TI - Prevalence and clinical features of exertional rhabdomyolysis in Andalusian horses. PMID- 26109285 TI - A preliminary investigation into the moral reasoning abilities of UK veterinarians. AB - Veterinary medicine is an ethically challenging profession, but the ethical reasoning abilities of practising veterinarians in the UK have never been formally assessed. This study investigated moral reasoning ability in 65 qualified veterinarians (38 practising and 27 academic) and 33 members of the public in the UK using the Defining Issues Test. Academic veterinarians had higher scores than members of the public but practising veterinarians did not. There was large variation in moral reasoning abilities among qualified veterinarians. Moral reasoning score in veterinarians did not improve with years of experience. These results show that despite having a professional degree moral reasoning skills of practising veterinarians may be insufficient to deal with the demands of their profession. This could have implications for animal welfare, client services and veterinarian wellbeing. The results highlight the need for more training in this area. PMID- 26109286 TI - Effective vaccination against rabies in puppies in rabies endemic regions. AB - In rabies endemic regions, a proportionally higher incidence of rabies is often reported in dogs younger than 12 months of age, which includes puppies less than 3 months of age; this presents a serious risk to public health. The higher incidence of rabies in young dogs may be the effect of low vaccination coverage in this age class, partly as a result of the perception that immature immune systems and maternal antibodies inhibit seroconversion to rabies vaccine in puppies less than three months of age. Therefore, to test this perception, the authors report the virus neutralising antibody titres from 27 dogs that were vaccinated with high quality, inactivated rabies vaccine aged three months of age and under as part of larger serological studies undertaken in Gauteng Province, South Africa, and the Serengeti District, Tanzania. All of these dogs seroconverted to a single dose of vaccine with no adverse reactions reported and with postvaccinal peak titres ranging from 2.0 IU/ml to 90.5 IU/ml. In light of these results, and the risk of human beings contracting rabies from close contact with puppies, the authors recommend that all dogs in rabies endemic regions, including those less than three months of age, are vaccinated with high quality, inactivated vaccine. PMID- 26109287 TI - A cross-sectional observational study of the nutritional intake of UK primary school children from deprived and non-deprived backgrounds: implications for school breakfast schemes. AB - BACKGROUND: This study examined the nutritional intake of 9-11 year old children in Wales, UK, to assess the rationale for, and potential of, school breakfast initiatives. It also examined the possible unintended consequence of over consumption. METHODS: The study employed a cross-sectional observational design within a randomized controlled trial of a free school breakfast programme. A total of 111 primary schools were randomly assigned to an intervention condition (in which a free school breakfast programme was implemented) or a control condition (in which implementation of the scheme was delayed). Sub-samples of children completed multiple-pass 24-hr dietary recall interviews at baseline (n = 581), and 12 months later (n = 582). Deprivation was assessed for each child in terms of whether or not they were entitled to free school meals. RESULTS: Prior to the introduction of the programme, rates of breakfast skipping were low and there was little evidence of widespread nutritional deficiency. However, there was a subset of children who consumed inadequate levels of a range of vitamins and minerals and 29 % of children ate very little for breakfast (less than 100 kcal). Children that ate larger breakfasts, had higher daily intakes of all nutrients that were examined. Children from deprived backgrounds consumed significantly lower levels of several vitamins and minerals at breakfast. Following the introduction of the breakfast scheme in intervention schools, there was little difference in the nutritional quality of school versus home breakfasts (n = 35 and 211 respectively). Where children ate breakfast at both school and home (n = 33), their overall energy intake was higher, but not significantly so. CONCLUSIONS: Although the overall diet of this group of children was generally good prior to the breakfast scheme, the results suggest that such schemes could be beneficial for a subset of children who are poorly nourished and for those children who consume very little for breakfast. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18336527. PMID- 26109288 TI - Identification of novel viral infections of human concern provides continued opportunity for strengthening systemic public health capacity in Southeast Asia. PMID- 26109290 TI - Mutational analysis of MED12 exon 2 in a spectrum of fibroepithelial tumours of the breast: implications for pathogenesis and histogenesis. AB - AIMS: Fibroadenomas (FAs) and phyllodes tumours (PTs) are fibroepithelial tumours. Mutations in MED12 exon 2 have been reported in FAs. This study investigated the MED12 mutations in a spectrum of fibroepithelial tumours. METHODS AND RESULTS: Using direct sequencing, we analysed MED12 exon 2 mutations on 121 samples, including PTs and FAs and variants. We found MED12 mutations in 71.4% of PTs. No significant difference in the mutation frequency was observed between benign, borderline and malignant PTs, and a general lack of correlation existed between mutations and pathological factors associated with PT grading. The mutation patterns were similar between PTs and FAs, with codon 44 being involved most frequently. MED12 mutations were identified in 47.1, 52.6 and 50.0% of complex FAs, juvenile FAs and tubular adenomas (TAs), respectively, and the frequency and mutation patterns were similar between these FA variants and usual FAs. CONCLUSIONS: The high frequency and similar patterns of MED12 mutations in FAs and various grades of PTs implies that the MED12 mutation is a common and early pathological event in these fibroepithelial tumours. The similar frequency and patterns of the MED12 mutation between FAs and variants suggests that FA variants are bona fide FAs, with identical pathogenesis involving MED12 mutations. PMID- 26109291 TI - [Pharmacological Basis for Therapeutics. Pharmacological Analysis of Summary of Product Characteristics (SPC) for Physicians]. AB - The summary of product characteristics, the SPC, is the major annex document of Marketing Authorisation (MA) dossier for a medicine. This document is the reference document for health care professionnals since it contains all necessary and opposable information for its therapeutic use. The SPC is initially submitted by the MA applicant and deeply revised in details by regulatory authorities, the national agencies for national MA, and the European Medicine Agency (EMA) for the european centralized procedures. The SPC presents with 12 sections each one being divided into several paragraphs. Sections 1-3 present the name, dosage, qualitative and quantitative composition, the pharmaceutical form of the medicine. Section 4 contains all the clinical particulars: Therapeutic indications, posology and methods of administration, contra-indications, special warnings and precautions for use, interactions, impact on fertility, contraception, pregnancy, lactation, effects on ability to drive and use machines, undesirable effects and risk associated with overdose. Section 5 describes pharmacological properties (pharmacodynamics and pharmacokinetics) and preclinical safety data. Section 6 describes the pharmaceutical particulars: excipients, incompatibilities, shelf live, nature and content of container, special precautions for disposal. Sections 7-10 are administrative ones (date of MA, MA holder), sections 11 and 12 are specific to radiopharmaceuticals (dosimetry and modalities of preparation). SPC is available free of charge on national regulatory agency websites and on EMA website. Sections of SPC finally have to be considered as the pharmacological basis of therapeutic use for each medicine. PMID- 26109289 TI - Characterization of the cork oak transcriptome dynamics during acorn development. AB - BACKGROUND: Cork oak (Quercus suber L.) has a natural distribution across western Mediterranean regions and is a keystone forest tree species in these ecosystems. The fruiting phase is especially critical for its regeneration but the molecular mechanisms underlying the biochemical and physiological changes during cork oak acorn development are poorly understood. In this study, the transcriptome of the cork oak acorn, including the seed, was characterized in five stages of development, from early development to acorn maturation, to identify the dominant processes in each stage and reveal transcripts with important functions in gene expression regulation and response to water. RESULTS: A total of 80,357 expressed sequence tags (ESTs) were de novo assembled from RNA-Seq libraries representative of the several acorn developmental stages. Approximately 7.6 % of the total number of transcripts present in Q. suber transcriptome was identified as acorn specific. The analysis of expression profiles during development returned 2,285 differentially expressed (DE) transcripts, which were clustered into six groups. The stage of development corresponding to the mature acorn exhibited an expression profile markedly different from other stages. Approximately 22 % of the DE transcripts putatively code for transcription factors (TF) or transcriptional regulators, and were found almost equally distributed among the several expression profile clusters, highlighting their major roles in controlling the whole developmental process. On the other hand, carbohydrate metabolism, the biological pathway most represented during acorn development, was especially prevalent in mid to late stages as evidenced by enrichment analysis. We further show that genes related to response to water, water deprivation and transport were mostly represented during the early (S2) and the last stage (S8) of acorn development, when tolerance to water desiccation is possibly critical for acorn viability. CONCLUSIONS: To our knowledge this work represents the first report of acorn development transcriptomics in oaks. The obtained results provide novel insights into the developmental biology of cork oak acorns, highlighting transcripts putatively involved in the regulation of the gene expression program and in specific processes likely essential for adaptation. It is expected that this knowledge can be transferred to other oak species of great ecological value. PMID- 26109292 TI - Authors' reply to: High naevus counts confer a favourable prognosis in patients with melanoma. PMID- 26109293 TI - Half of public think weekend access to GPs should be NHS priority. PMID- 26109294 TI - Relationship of ocular and systemic factors to the visibility of choroidal scleral interface using spectral domain optical coherence tomography. AB - PURPOSE: To assess the visibility of the choroidal-scleral interface (CSI) from spectral domain optical coherence tomography (SD-OCT) and evaluate the ocular and systemic factors influencing the visibility of CSI in healthy eyes from population-based Malay sample. METHODS: Participants were consecutively recruited from the population-based Singapore Malay Eye Study-2 (SiMES-2). SD-OCT images were obtained by Spectralis OCT with enhanced depth imaging (EDI) mode. Visibility of CSI was assessed by a grading system ranging from 0 to 2 scores. The reliability of choroidal thickness measurement in different grades of CSI visibility was assessed using intraclass correlation coefficient. Ordinal regression analyses were performed to evaluate a range of ocular and systemic factors influencing the visibility of CSI. RESULTS: A total of 176 healthy eyes were analysed, and 59.1% of our subjects had well-defined CSI (score 2), 8.5% had poorly defined CSI (score 0), and 32.4% had CSI between well and poorly defined (score 1). The reliability of subfoveal choroidal thickness measurement decreased with each grade of CSI visibility score. Decreased axial length (AL) (estimate of ordinal regression [OR] = 0.465, p = 0.003), thicker retinal thickness (estimate of OR = -0.030, p = 0.004), younger age (estimate of OR = 0.045, p = 0.030) and diabetes (estimate of OR = -0.746, p = 0.004) were associated with lower CSI visibility score. CONCLUSIONS: Only 60% of normal healthy eyes had well-defined CSI from SD-OCT images. Our data suggest that choroidal thickness measurements can be substantially affected by the visibility of CSI. The visibility of CSI varies with AL, retinal thickness, age and diabetes. PMID- 26109295 TI - Hierarchical Assembly of SnO2/ZnO Nanostructures for Enhanced Photocatalytic Performance. AB - SnO2/ZnO hierarchical heterostructures have been successfully synthesized by combining electrospinning technique and hydrothermal method. Various morphologies of the secondary ZnO nanostructures including nanorods (NRs) and nanosheets (NSs) can be tailored by adding surfactants. Photocatalytic performance of the heterostructures was investigated and obvious enhancement was demonstrated in degradation of the organic pollutant, compared to the primary SnO2-based nanofibers (NFs) and bare ZnO. Furthermore, it was found that the H2 evolution from water splitting was achieved by photocatalysis of heterostructured nanocomposites after sulfurization treatment. This synthetic methodology described herein promises to be an effective approach for fabricating variety of nanostructures for enhanced catalytic applications. The heterostructured nanomaterials have considerable potential to address the environmental and energy issues via degradation of pollutant and generation of clean H2 fuel. PMID- 26109296 TI - Origin of neurotoxins from defensins. AB - There are at least three conserved protein folds shared by ion channel-targeted neurotoxins and antimicrobial defensins, including cysteine-stabilized alpha helix and beta-sheet fold (CSalphabeta), inhibitor cystine knot fold (ICK) and beta-defensin fold (BDF). Based on a combined data of sequences, structures and functions, it has been proposed that these neurotoxins could originate from related ancient antimicrobial defensins by neofunctionalization. This provides an ideal system to study how a novel function emerged from a conserved structural scaffold during evolution. The elucidation of functional novelty of proteins not only has great significance in evolutionary biology but also will be helpful in guiding rational molecular design. This review describes recent progresses in origin of neurotoxins, focusing on the three conserved protein scaffolds. PMID- 26109297 TI - Shal-type (Kv4.x) potassium channel pore blockers from scorpion venoms. AB - Voltage-gated potassium channels (Kv4.1, Kv4.2 and Kv4.3) encoded by the members of the KCND/Kv4 (Shal) channel family mediate the native, fast inactivating (A type) K(+) current (IA) described both in heart and neurons. This IA current is specifically blocked by short scorpion toxins that belong to the alpha-KTx15 subfamily and which act as pore blockers, a different mode of action by comparison to spider toxins known as gating modifiers. This review summarizes our present chemical and pharmacological knowledge on the alpha-KTx15 toxins. PMID- 26109298 TI - Unique interactions between scorpion toxins and small conductance Ca(2+) activated potassium channels. AB - Small conductance Ca(2+)-activated potassium channels (SK channels) distributing in the nervous system play an important role in learning, memory and synaptic plasticity. Most pharmacological properties of them are determined by short-chain scorpion toxins. Different from most voltage-gated potassium channels and large conductance Ca(2+)-activated potassium channels, SK channels are only inhibited by a small quantity of scorpion toxins. Recently, a novel peptide screener in the extracellular pore entryway of SK channels was considered as the structural basis of toxin selective recognition. In this review, we summarized the unique interactions between scorpion toxins and SK channels, which is crucial not only in deep-researching for physiological function of SK channels, but also in developing drugs for SK channel-related diseases. PMID- 26109299 TI - Venoms, toxins and derivatives from the Brazilian fauna: valuable sources for drug discovery. AB - Animal venoms have been widely investigated throughout the world. The great number of biotechnological articles as well as patent applications in the field of drug discovery based on these compounds indicates how important the source is. This review presents a list of the most studied Brazilian venomous animal species and shows the most recent patent applications filed from 2000 to 2013, which comprise Brazilian venoms, toxins and derivatives. We analyze the data according to the species, the type of products claimed and the nationality of the inventors. Fifty-five patent applications were found, involving 8 genera. Crotalus, Lachesis, Bothrops and Loxosceles represented 78% of the patent applications. The other 22% were represented by Phoneutria, Tityus, Acanthoscurria and Phyllomedusa. Most of the inventions (42%) involved anticancer, immunomodulator or antimicrobial drugs, while 13% involved anti venoms and vaccines, 11% involved hypotensive compositions, 9% involved antinociceptive and/or anti-inflammatory compositions, and the other 25% involved methods, kits or compositions for various purposes. Brazilian inventors filed 49% of the patent applications, but other countries, mainly the United States of America, Germany, Russia and France, also filed patent applications claiming products comprising venoms, toxins and/or derivatives from the Brazilian fauna. Brazil holds an important number of patent applications which mostly belong to universities and research institutes, but the pharmaceutical industry in this field is still weak in Brazil. Although, Brazilian venomous animal species have been reported in drug discovery throughout the world, many species remain to be explored as valuable and promising tools for drug discovery and development. PMID- 26109300 TI - Lipid bilayer modification alters the gating properties and pharmacological sensitivity of voltage-gated sodium channel. AB - Voltage-gated sodium channels (VGSCs) are widely distributed in most cells and tissues, performing many physiological functions. As one kind of membrane proteins in the lipid bilayer, whether lipid composition plays a role in the gating and pharmacological sensitivity of VGSCs still remains unknown. Through the application of sphingomyelinase D (SMaseD), the gating and pharmacological sensitivity of the endogenous VGSCs in neuroblastoma ND7-23 cell line to BmK I and BmK AS, two sodium channel-specific modulators from the venom of Buthus martensi Karsch (BmK), were assessed before and after lipid modification. The results showed that, in ND7-23 cells, SMaseD did not change the gating properties of VGSCs. However, SMaseD application altered the slope factor of activation with the treatment of 30 nmol/L BmK I, but caused no significant effects at 100 and 500 nmol/L BmK I. With low concentration of BmK I (30 and 100 nmol/L) treatment, the application of SMaseD exerted hyperpolarizing effects on both slow inactivation and steady-state inactivation, and increased the recovery time constant, whereas total inactivation and recovery remained unaltered at 500 nmol/L BmK I. Meanwhile, SMaseD modulation hyperpolarized the voltage dependence of slow-inactivation at 0.1 nmol/L BmK AS and altered the slope factor of slow inactivation at 10 nmol/L BmK AS, whereas other parameters remained unchanged. These results indicated a possibility that the lipid bilayer would disturb the pharmacological sensitivity of VGSCs for the first time, which might open a new way of developing new drugs for treating sodium channelopathies. PMID- 26109301 TI - Spinal 5-HT3AR contributes to BmK I-induced inflammatory pain in rats. AB - Subcutaneous injection of BmK I could be adopted to well establish a novel pain model. Moreover, 5-hydroxytryptamine (serotonin, 5-HT) receptor is involved in regulating animal pain-related behaviors. However, the underlying mechanism of 5 HT3R on BmK I-induced pain remains unclear. Animal behavioral testing, RT-PCR and Western blotting were used to yield the following results: first, intraplantar (i.pl.) injection of BmK I (10 MUg) induced elevated mRNA and protein levels of 5 HT3AR in bilateral L4-L5 spinal cord; Second, intrathecal (i.t.) injection of ondansetron (a specific antagonist of 5-HT3AR) reduced spontaneous pain responses, attenuated unilateral thermal and bilateral mechanical hypersensitivity elicited by BmK I; Microglia could be activated by BmK I (i.pl.) in both sides of L4-L5 spinal cord, and this effect was reversed by intrathecal pre-treatment with 5-HT3AR antagonist. Meanwhile, the 5-HT3AR in L4-L5 spinal cord was almost co-localized with NeuN (a marker of nerve cell), but not co expressed with Iba-1 (a marker of microglia). Finally, the expression level of CX3CL1 and CX3CR1 was reduced by intrathecal pre-treatment with ondansetron. Our results indicate that both 5-HT3AR signaling pathway and microglia are activated in the process of induction and maintenance of BmK I-induced pain nociception. Meanwhile, our results suggest that the neuronal 5-HT3AR may communicate with microglia indirectly via CX3CL1 which is involved in regulating the BmK I-induced hyperalgesia and sensitization. PMID- 26109302 TI - Characterization of Am IT, an anti-insect beta-toxin isolated from the venom of scorpion Androctonus mauretanicus. AB - In the present study, a 'novel' toxin, called Am IT from the venom of scorpion Androctonus mauretanicus is isolated and characterized. A detailed analysis of the action of Am IT on insect axonal sodium currents is reported. Am IT was purified through gel filtration followed by C18 reversed-phase HPLC. Toxicity of Am IT in vivo was assessed on male German cockroach (Blattella germanica) larvae and C57/BL6 mice. Cross-reactivity of Am IT with two beta-toxins was evidenced using (125)I-iodinated toxin-based radioimmunoassays with synaptosomal preparations from rat brain. The complete amino acid sequence of Am IT was finally determined by Edman sequencing. Am IT was observed to compete with AaH IT4 purified from the venom of scorpion Androctonus australis in binding assays. It was recognized by an antibody raised against a beta-type toxin, which indicated some structural similarity with beta-toxins (or related toxin family). The 'novel' toxin exhibited dual activity since it competed with anti-mammal toxins in binding assays as well as showed contracting activity to insect. The toxin competed with radio-labeled beta-toxin Css IV by binding to Na(+) channels of rat brain synaptosomes. Analysis of toxin amino acid sequences showed that Am IT shares high structural identity (92%) with AaH IT4. In conclusion, Am IT not only reveals an anti-insect compound properties secreted by 'Old World' scorpions, paralyzing insect larvae by binding to Na(+) channels on larvae's nerve-cell membranes, but also exerts toxic activity in mice, which is similar to anti-mammal toxins from 'New World' scorpions (North and South Americas). Therefore, Am IT appears to be structurally and functionally similar to AaH IT4. PMID- 26109303 TI - AcMNPV-mediated expression of BmK IT promotes the apoptosis of Sf9 cells and replication of AcMNPV. AB - Chinese scorpion Buthus martensii Karsch (BmK) venom is a rich source of neurotoxins which bind to various ion channels with high affinity and specificity and thus widely used as compounds to modulate channel gating or channel currents. To promote the insecticidal effects of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV), the gene encoding an excitatory insect toxin, BmK IT, was inserted into the genome of AcMNPV to construct a recombinant baculovirus, AcMNPV-BmK IT. Spodopter frugiperda 9 (Sf9) cells were infected with AcMNPV and AcMNPV-BmK IT respectively for 24 h. Results from the MTT assay, TUNEL assay, analysis of the expression level of apoptosis-related proteins (c-Myc, cleaved-Caspase3, Bcl-2 and Bax) of Sf9 cells, the transcription level of key genes (38K, C42, P78, F) of AcMNPV, and viral propagation assay demonstrated that AcMNPV-mediated expression of BmK IT promoted the apoptosis of Sf9 cells and replication of AcMNPV. The results laid a foundation for further structural and functional analysis of BmK IT. PMID- 26109304 TI - [The expression of the sperm-specific lactate dehydrogenase gene Ldh-c in plateau pika (Ochotona curzoniae) cardiac muscle and its effect on the anaerobic glycolysis]. AB - The plateau pika (Ochotona curzoniae) has a strong adaptability to hypoxic plateau environment. We found that the sperm-specific lactate dehydrogenase (LDH C4) gene Ldh-c expressed in plateau pika cardiac muscle. In order to shed light on the effect of LDH-C4 on the anaerobic glycolysis in plateau pika cardiac muscle, 20 pikas were randomly divided into the inhibitor group and the control group, and the sample size of each group was 10. The pikas of inhibitor group were injected with 1 mL 1 mol/L N-isopropyl oxamate, a specific LDH-C4 inhibitor, in biceps femoris muscle of hind legs, each leg with 500 MUL. The pikas of control group were injected with the same volume of normal saline (0.9% NaCl). The mRNA and protein expression levels of Ldh-c gene in plateau pika cardiac muscle were determined by real-time PCR and Western blot. The activities of LDH, and the contents of lactate (LD) and ATP in cardiac muscle were compared between the inhibitor group and the control group. The results showed that 1) the expression levels of Ldh-c mRNA and protein were 0.47 +/- 0.06 and 0.68 +/- 0.08, respectively; 2) 30 min after injection of 1 mL 1 mol/L N-isopropyl oxamate in biceps femoris muscle, the concentration of N-isopropyl oxamate in blood was 0.08 mmol/L; 3) in cardiac muscle of the inhibitor group and the control group, the LDH activities were (6.18 +/- 0.48) U/mg and (9.08 +/- 0.58) U/mg, the contents of LD were (0.21 +/- 0.03) mmol/g and (0.26 +/- 0.04) mmol/g, and the contents of ATP were (4.40 +/- 0.69) nmol/mg and (6.18 +/- 0.73) nmol/mg (P < 0.01); 5) the inhibition rates of N-isopropyl oxamate to LDH, LD and ATP were 31.98%, 20.90% and 28.70%, respectively. The results suggest that Ldh-c expresses in cardiac muscle of plateau pika, and the pika cardiac muscle may get at least 28% ATP for its activities by LDH-C4 catalyzed anaerobic glycolysis, which reduces the dependence on oxygen and enhances the adaptation to the hypoxic environments. PMID- 26109305 TI - The role of the TLR4/NF-kappaB signaling pathway in Abeta accumulation in primary hippocampal neurons. AB - The present study aimed to investigate the role of the Toll-like receptor 4 (TLR4)/nuclear factor kappaB (NF-kappaB) signaling pathway in the accumulation of amyloid beta protein (Abeta) in primary hippocampal neurons of rats. The purity of these cultured neurons was determined by using immunofluorescence techniques. Lipopolysaccharide (LPS, a TLR4 ligand) or CLI-095 (a TLR4 inhibitor) was used to activate or inhibit TLR4 signaling, respectively. Pyrrolidine dithiocarbamate (PDTC), on the other hand, was used to inhibit NF-kappaB, a downstream effector of the TLR4 signaling pathway. The contents of tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and Abeta1-42 in the supernatant were assessed by enzyme-linked immunosorbent assay (ELISA). The mRNA levels of TNF alpha, IL-1beta, a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), beta-site APP cleaving enzyme 1 (BACE-1), Presenilin-1 (PS-1), and beta amyloid precursor protein (beta-APP) were examined by real-time quantitative PCR (RT-qPCR). The protein levels of ADAM10, BACE-1, PS-1 and beta-APP were examined by Western blotting. Meanwhile, the levels of TLR4 mRNA and protein in hippocampal neurons were tested by RT-qPCR and Western blotting, respectively, after stimulation with Abeta1-42 at different concentrations. We observed that the purity of cultured hippocampal neurons after being cultured for 7 days was above 95%. Compared with untreated neurons, LPS-treated neurons showed higher expression levels of TNF-alpha, IL-1beta, BACE-1, PS-1, beta-APP, and Abeta1-42, but a lower expression level of ADAM10. These effects were reversed upon pre treatment with CLI-095 or PDTC. Furthermore, TLR4 expression was upregulated in the presence of Abeta1-42. Taken together, these results provide evidence that elevation in the level of inflammatory cytokines accompanies the activation of TLR4 signaling, and that the consequent downregulation of ADAM10 and upregulation of BACE-1/PS-1 are likely responsible for the accumulation of beta-APP and Abeta, which in turn increases TLR4 level to create a positive feedback loop that may constitute the basis for the progression of Alzheimer's disease. PMID- 26109306 TI - [Isoliquiritigenin relaxes the cerebral basilar artery by enhancing BKCa current in spontaneously hypertensive rat: role of sGC/cGMP]. AB - The purpose of the present study is to investigate the effect of isoliquiritigenin (ISL) on the cerebral basilar artery in spontaneously hypertensive rats (SHR). The change of SHR systolic pressure was measured by tail artery pressure measurement instrument before and after ISL intervention. After perfusion with 1 * 10(-5) mol/L phenylephrine (PE), 1 * 10(-5) mol/L PE + 1 * 10( 4) mol/L ISL and 1 * 10(-5) mol/L PE, the diameter of the cerebral basilar artery separated from SHR was measured by pressure myograph. The current of large conductance calcium-activated potassium (BKCa) channel of SHR single vascular smooth muscle cell (VSMC) was recorded by whole-cell patch-clamp technique and the cGMP levels of basilar artery was evaluated by ELISA. The results showed that 1) after intervention with ISL for 14 days, the systolic pressure of SHR was decreased from (218.3 +/- 1.6) mmHg to (119.2 +/- 1.9) mmHg (P < 0.01), but there was no difference in systolic pressure between ISL-treated SHR and Wistar-Kyoto (WKY) rat; 2) 1 * 10(-4) mol/L ISL relaxed the SHR cerebral basilar artery (P < 0.01); 3) ISL significantly increased the outward current density of VSMC from SHR cerebral basilar artery (P < 0.01, n = 6), and the effect could be reversed by 1 * 10(-3) mol/L TEA (a BKCa channel inhibitor), but 3 * 10(-4) mol/L 4-AP (a Kv channel inhibitor) had no effect on the enhanced current density induced by ISL in VSMC; 4) 1 * 10(-5) mol/L Methylene blue (a sGC inhibitor) significantly inhibited the ISL-enhanced current density in VSMC (P < 0.05, n = 6); 5) ISL significantly increased the cGMP level of SHR basilar artery (P < 0.05, n = 6). The results suggest that the role of the ISL in relaxing the SHR cerebral basilar artery may be related to its effect in enhancing BKCa current by increasing the levels of cGMP in the VSMC. PMID- 26109307 TI - [Role of renal sympathetic nerve and oxidative stress in foot shock-induced hypertension in rats]. AB - The present study was aimed to investigate the roles of renal sympathetic nerve and oxidative stress in the development of foot shock-induced hypertension. Ninety rats were divided into 6 groups (the number of each group was 15): control group, foot shock group, denervation of renal sympathetic nerve group, denervation of renal sympathetic nerve + foot shock group, Tempol treatment + foot shock group, denervation of renal sympathetic nerve + Tempol treatment + foot shock group. Rats were received electrical foot shock for 14 days (2-4 mA, 75 V, shocks of 50-100 ms every 30 s, for 4 h each session through an electrified grid floor every day). Renal sympathetic ablation was used to remove bilateral renal sympathetic nerve in rats (rats were allowed to recover for one week before the beginning of the foot shock procedure). The antioxidant Tempol was injected intraperitoneally at 1 h before foot shock. Systolic blood pressure was measured at 1 h after foot shock on day 0, 3, 7, 10 and 14. Contents of thiobarbituric acid reactive substance (TBARS), renin, angiotensin II (AngII) and glutathione peroxidase (GSH-Px) in plasma were measured by ELISA after 14-day foot shock. The results showed that systolic blood pressure of foot shock group was significantly increased (P < 0.05) compared with that of control group from day 7 to day 14 of foot shock. Denervation of renal sympathetic nerve and/or Tempol treatment significantly reduced the increase of systolic blood pressure induced by foot shock. Levels of TBARS, renin and AngII in plasma were increased significantly in foot shock group compared with that of control group (P < 0.05). Plasma GSH-Px concentration was decreased in foot shock group rats compared with that of control group (P < 0.05). Denervation of renal sympathetic nerve and/or tempol treatment significantly reduced the increase in TBARS, renin, AngII levels induced by foot shock in comparison with that of foot shock group (P < 0.05), but had no effects on the reduction of GSH-Px concentration. The results suggest that renal sympathetic nerve may play an important role in the development of foot shock-induced hypertension, and renal sympathetic nerve may influence oxidative stress and directly or indirectly activate renin-angiotensin-aldosterone system, so the foot shock-induced high blood pressure may be maintained and hypertension may therefore be produced. PMID- 26109308 TI - [Anti-metastasis of celastrol on esophageal cancer cells and its mechanism]. AB - Celastrol is a quinone methyl terpene extracted from the traditional Chinese medicine Tripterygium wilfordii, which has anti-inflammatory, immune suppression and pharmacological activities, as well as anti-tumor activity. The effects of celastrol on adhesion, migration and invasion of esophageal cancer cells were investigated in this experiment. Human esophageal cancer cell line ECA-109 was used. The inhibition of ECA-109 cells' adhesion induced by celastrol was measured by MTT test. The inhibition of ECA-109 cells' migration induced by celastrol was measured by scratch test. The invasion inhibition of ECA-109 cells induced by celastrol was measured by Transwell experiment. Quantitative real-time PCR and Western blot were used to determine the effects of different concentrations of celastrol on integrin family and Wnt signaling pathway in ECA-109 cells. The results showed that celastrol inhibited adhesion, migration and invasion of ECA 109 cells and expressions of integrins beta1, beta4, alphav and beta-Catenin, LRP6 in Wnt signal pathway in a dose-dependent manner. Therefore the study suggests that celastrol could inhibit the cell metastasis of esophageal cancer by inhibiting the Wnt signaling pathway and the expressions of integrins. PMID- 26109309 TI - Potential Health Hazard Assessment in Terms of Some Heavy Metals Determined in Demersal Fishes Caught in Eastern Aegean Sea. AB - A heavy metal risk assessment based on estimated daily intake (EDI) and target hazard quotient was made for children and adults. Five fish species captured from the eastern Aegean Sea were analyzed for Cr, Cu, Cd, Hg and Pb by inductively coupled plasma spectroscopy in muscle tissue of red mullet (Mullus barbatus), surmullet (Mullus surmuletus), sand steenbras (Lithognathus mormyrus), common two banded seabream (Diplodus vulgaris) and common pandora (Pagellus erythinus). The ranges for mean metal concentration (mg/kg wet wt) in the five species were 0.27 0.39 Cr, 0.12-0.22 Cu, 0.09-0.10 Hg and 0.10-0.12 Pb. All means were identical for Cd at 0.03 mg/kg wet wt. The EDI values for each metal were ascertained not to exceed the tolerable daily intake amount. Fish did not contain sufficiently high levels of these metals to pose a carcinogenic risk. PMID- 26109310 TI - PAH Metabolites in Bile of European Eel (Anguilla anguilla) from Morocco. AB - Environmental pollution of fish with organic contaminants is a topic of rising attention in Morocco. Polycyclic aromatic hydrocarbons (PAH) are prominent organic contaminants which are rapidly metabolized in fish. Their metabolites are accumulated in the bile fluid and can be used to assess PAH exposure. The two PAH metabolites 1-hydroxypyrene and 1-hydroxyphenanthrene were quantified in European eels (Anguilla anguilla) from two Moroccan river systems by high-performance liquid chromatography with fluorescence detection. Mean values ranged from 52 to 210 ng/mL 1-hydroxypyrene and from 61 to 73 ng/mL 1-hydroxyphenanthrene. The overall concentrations of PAH metabolites in eel from Morocco appeared moderate compared to eel from European rivers and coastal sites. The present study provides first information on concentrations of PAH metabolites in fish from Morocco. PMID- 26109311 TI - Resection of thoracic malignancies infiltrating cardiac structures with use of cardiopulmonary bypass. AB - BACKGROUND: Only few reports exist on malignant thoracic neoplasms that require cardiopulmonary bypass during resection. We aimed to investigate the early and late clinical outcome of these patients. METHODS: Patients with thoracic malignancies that underwent surgery between 2002 and 2014 were analyzed. All patients had cardiopulomonary bypass support during resection. Clinical and perioperative data was retrospectively reviewed for outcome and overall survival. RESULTS: Fifteen patients (12 female, mean age of 55 +/- 15 years, range 24 to 80 years) were identified. Eleven (8 female) were diagnosed with primary thoracic malignomas and four with metastases. Three patients died early postoperatively. Patients diagnosed with sarcoma had a significantly worse outcome than non sarcoma patients (83.3 +/- 15.2 % after 1 year, 31.3 +/- 24.5 % after 5 years vs. 83.3 +/- 5.2 % after 1 year, 0 +/- 0 % after 5 years, p = 0.005). CONCLUSIONS: Malignancies with extension into cardiac structures or infiltration of great vessels can be resected with cardiopulmonary bypass support and tolerable risk. Carefully selected patients can undergo advanced operative procedures with an acceptable 1-year-survival, but only few patients achieved good long-term outcome. PMID- 26109312 TI - Histone deacetylase 4 promotes cholestatic liver injury in the absence of prohibitin-1. AB - Prohibitin-1 (PHB1) is an evolutionarily conserved pleiotropic protein that participates in diverse processes depending on its subcellular localization and interactome. Recent data have indicated a diverse role for PHB1 in the pathogenesis of obesity, cancer, and inflammatory bowel disease, among others. Data presented here suggest that PHB1 is also linked to cholestatic liver disease. Expression of PHB1 is markedly reduced in patients with primary biliary cirrhosis and biliary atresia or with Alagille syndrome, two major pediatric cholestatic conditions. In the experimental model of bile duct ligation, silencing of PHB1 induced liver fibrosis, reduced animal survival, and induced bile duct proliferation. Importantly, the modulatory effect of PHB1 is not dependent on its known mitochondrial function. Also, PHB1 interacts with histone deacetylase 4 (HDAC4) in the presence of bile acids. Hence, PHB1 depletion leads to increased nuclear HDAC4 content and its associated epigenetic changes. Remarkably, HDAC4 silencing and the administration of the HDAC inhibitor parthenolide during obstructive cholestasis in vivo promote genomic reprogramming, leading to regression of the fibrotic phenotype in liver-specific Phb1 knockout mice. CONCLUSION: PHB1 is an important mediator of cholestatic liver injury that regulates the activity of HDAC4, which controls specific epigenetic markers; these results identify potential novel strategies to treat liver injury and fibrosis, particularly as a consequence of chronic cholestasis. PMID- 26109313 TI - Differential effects of relaxin deficiency on vascular aging in arteries of male mice. AB - Exogenous treatment with the naturally occurring peptide relaxin increases arterial compliance and reduces vascular stiffness. In contrast, relaxin deficiency reduces the passive compliance of small renal arteries through geometric and compositional vascular remodeling. The role of endogenous relaxin on passive mechanical wall properties in other vascular beds is unknown. Importantly, no studies have investigated the effects of aging in arteries of relaxin-deficient mice. Therefore, we tested the hypothesis that mesenteric and femoral arteries stiffen with aging, and this is exacerbated with relaxin deficiency. Male wild-type (Rln (+/+)) and relaxin knockout (Rln (-/-)) mice were aged to 3, 6, 12, 18, and 23 months. Passive mechanical wall properties were assessed by pressure myography. In both genotypes, there was a significant increase in circumferential stiffening in mesenteric arteries with aging, whereas in the femoral artery, aging reduced volume compliance. This was associated with a reduced ability of the artery to lengthen with aging. The predominant phenotype observed in Rln (-/-) mice was reduced volume compliance in young mice in both mesenteric and femoral arteries. In summary, aging induces circumferential stiffening in mesenteric arteries and axial stiffening in femoral arteries. Passive mechanical wall properties of Rln (-/-) mouse arteries predominantly differ at younger ages compared with Rln (+/+) mice, suggesting that a lack of endogenous relaxin only has a minor effect on vascular aging. PMID- 26109314 TI - Why e-cigarettes are dividing the public health community. PMID- 26109315 TI - Current status and future prospects of point-of-care testing around the globe. AB - In the past half-century, routine central laboratory testing has become increasingly automated and efficient. The majority of clinical chemistry, immunochemistry and hematology testing are performed using high throughput instrumentation, with sophisticated automation. Microbiology, immunohematology and molecular diagnostic testing are also becoming increasingly automated. Recent challenges in healthcare demand new diagnostic solutions worldwide. Point-of-care testing (POCT) offers considerable advantages over central laboratory testing, such as fast and simple specimen handling, and simpler sample requirement (no additives and mostly blood from finger stick; and urine). No transportation is required, and POCT delivers short turnaround time of approximately 5-15 min. In recent years, POCT has gained ground worldwide. In advanced healthcare systems, POCT may be beneficial if health or cost-benefits can be established. In resource poor countries, POCT may be the only means of delivering advanced testing for epidemiologically important diseases, such as tuberculosis of HIV infection. PMID- 26109316 TI - Companion diagnostics: a regulatory perspective from the last 5 years of molecular companion diagnostic approvals. AB - Companion diagnostics are essential for the safe and effective use of the corresponding therapeutic products. The US FDA has approved a number of companion diagnostics used to select cancer patients for treatment with contemporaneously approved novel therapeutics. The processes of co-development and co-approval of a therapeutic product and its companion diagnostic have been a learning experience that continues to evolve. Using several companion diagnostics as examples, this article describes the challenges associated with the scientific, clinical and regulatory hurdles faced by FDA and industry alike. Taken together, this discussion is intended to assist manufacturers toward a successful companion diagnostics development plan. PMID- 26109317 TI - Evaluating the Structure of Early English Literacy Skills in Deaf and Hard-of Hearing Children. AB - Better understanding the mechanisms underlying developing literacy has promoted the development of more effective reading interventions for typically developing children. Such knowledge may facilitate effective instruction of deaf and hard-of hearing (DHH) children. Hence, the current study examined the multivariate associations among phonological awareness, alphabetic knowledge, word reading, and vocabulary skills in DHH children who have auditory access to speech. One hundred and sixty-seven DHH children (M age = 60.43 months) were assessed with a battery of early literacy measures. Forty-six percent used at least 1 cochlear implant; 54% were fitted with hearing aids. About a fourth of the sample was acquiring both spoken English and sign. Scores on standardized tests of phonological awareness and vocabulary averaged at least 1 standard deviation (SD) below the mean of the hearing norming sample. Confirmatory factor analyses showed that DHH children's early literacy skills were best characterized by a complex 3 factor model in which phonological awareness, alphabetic knowledge, and vocabulary formed 3 separate, but highly correlated constructs, with letter-sound knowledge and word reading skills relating to both phonological awareness and alphabetic knowledge. This supports the hypothesis that early reading of DHH children with functional hearing is qualitatively similar to that of hearing children. PMID- 26109318 TI - Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model. AB - Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, but its role in neuropathic pain remains unclear. In this study, we examined the ER stress and the unfolded protein response (UPR) activation in a L5 spinal nerve ligation (SNL)-induced rat neuropathic pain model. SNL-induced neuropathic pain was assessed behaviorally using the CatWalk system, and histologically with microglial activation in the dorsal spinal horn. L5 SNL induced BIP upregulation in the neuron of superficial laminae of dorsal spinal horn. It also increased the level of ATF6 and intracellular localization into the nuclei in the neurons. Moreover, spliced XBP1 was also markedly elevated in the ipsilateral spinal dorsal horn. The PERK-elF2 pathway was activated in astrocytes of the spinal dorsal horn in the SNL model. In addition, electron microscopy revealed the presence of swollen cisternae in the dorsal spinal cord after SNL. Additionally, inhibition of the ATF6 pathway by intrathecal treatment with ATF6 siRNA reduced pain behaviors and BIP expression in the dorsal horn. The results suggest that ER stress might be involved in the induction and maintenance of neuropathic pain. Furthermore, a disturbance in UPR signaling may render the spinal neurons vulnerable to peripheral nerve injury or neuropathic pain stimuli. PMID- 26109321 TI - Familial 7q11.23 duplication with variable phenotype. AB - Chromosomal microdeletions and microduplications are known to cause variable clinical features ranging from apparently normal phenotype to intellectual disability, multiple congenital anomalies, and/or other variable clinical features. 7q11.23 region deletion is the cause for Williams-Beuren syndrome and duplication of same region 7q11.23 causes distinguishable clinical phenotype. Familial inheritance is known for both microdeletion and microduplication of 7q11.23 region. Here, we report a patient of paternally inherited 7q11.23 microduplication with developmental delay, macrocephaly, and structural brain malformations. PMID- 26109320 TI - Bacteriophages and bacteriophage-derived endolysins as potential therapeutics to combat Gram-positive spore forming bacteria. AB - Since their discovery in 1915, bacteriophages have been routinely used within Eastern Europe to treat a variety of bacterial infections. Although initially ignored by the West due to the success of antibiotics, increasing levels and diversity of antibiotic resistance is driving a renaissance for bacteriophage derived therapy, which is in part due to the highly specific nature of bacteriophages as well as their relative abundance. This review focuses on the bacteriophages and derived lysins of relevant Gram-positive spore formers within the Bacillus cereus group and Clostridium genus that could have applications within the medical, food and environmental sectors. PMID- 26109319 TI - Retinoic Acid Signaling Coordinates Macrophage-Dependent Injury and Repair after AKI. AB - Retinoic acid (RA) has been used therapeutically to reduce injury and fibrosis in models of AKI, but little is known about the regulation of this pathway and what role it has in regulating injury and repair after AKI. In these studies, we show that RA signaling is activated in mouse and zebrafish models of AKI, and that these responses limit the extent of injury and promote normal repair. These effects were mediated through a novel mechanism by which RA signaling coordinated the dynamic equilibrium of inflammatory M1 spectrum versus alternatively activated M2 spectrum macrophages. Our data suggest that locally synthesized RA represses proinflammatory macrophages, thereby reducing macrophage-dependent injury post-AKI, and activates RA signaling in injured tubular epithelium, which in turn promotes alternatively activated M2 spectrum macrophages. Because RA signaling has an essential role in kidney development but is repressed in the adult, these findings provide evidence of an embryonic signaling pathway that is reactivated after AKI and involved in reducing injury and enhancing repair. PMID- 26109322 TI - Telomere dynamics in parasitic great spotted cuckoos and their magpie hosts. AB - Although little is known on the impact of environment on telomere length dynamics, it has been suggested to be affected by stress, lifestyle and/or life history strategies of animals. We here compared telomere dynamics in erythrocytes of hatchlings and fledglings of the brood parasite great spotted cuckoos (Clamator glandarius) and of magpies (Pica pica), their main host in Europe. In magpie chicks, telomere length decreased from hatching to fledging, whereas no significant change in telomere length of great spotted cuckoo chicks was found. Moreover, we found interspecific differences in the association between laying date and telomere shortening. Interspecific differences in telomere shortening were interpreted as a consequence of differences in lifestyle and life-history characteristics of magpies and great spotted cuckoos. In comparison with magpies, cuckoos experience reduced sibling competition and higher access to resources and, consequently, lower stressful environmental conditions during the nestling phase. These characteristics also explain the associations between telomere attrition and environmental conditions (i.e. laying date) for magpies and the absence of association for great spotted cuckoos. These results therefore fit expectations on telomere dynamics derived from interspecific differences in lifestyle and life history of brood parasites and their bird hosts. PMID- 26109324 TI - Coverage of supraumbilical abdominal wall defects: The tunnelled-pedicled ALT technique. AB - Abdominal wall defects are a challenge for reconstructive surgeons. Although the utility of anterolateral thigh perforator (ALT) flap has been well established for lower abdominal wall reconstruction, pedicled ALT flap is usually not considered for supraumbilical defects in the most recent algorithms. The purpose of this paper is to report the results of a tunneled pedicled ALT flap for reconstruction of supraumbilical defect from a series of patients. From July 2009 to September2014, six patients underwent delayed abdominal wall coverage using pedicled ALT flaps and reinforcement with polypropylene meshes. Defects occurred after surgical complications and abdominal trauma. Flaps were tunneled beneath the rectus femoris and sartorius muscles to increase the pedicle length. The size of the skin islands ranged from 22-29 * 10-14 cm. All flaps survived and the healing of the wounds was successful. Partial dehiscence of donor site occurred in one patient, and small wound dehiscence due to minimal distal necrosis was observed in another patient. No functional problems were reported in donor site, and no complications occurred in 6-68 months of follow-up. The tunneled pedicled ALT flap may provide a reliable alternative method for abdominal wall reconstruction, including supraumbilical defects. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:119-127, 2017. PMID- 26109323 TI - Cell migration and antigen capture are antagonistic processes coupled by myosin II in dendritic cells. AB - The immune response relies on the migration of leukocytes and on their ability to stop in precise anatomical locations to fulfil their task. How leukocyte migration and function are coordinated is unknown. Here we show that in immature dendritic cells, which patrol their environment by engulfing extracellular material, cell migration and antigen capture are antagonistic. This antagonism results from transient enrichment of myosin IIA at the cell front, which disrupts the back-to-front gradient of the motor protein, slowing down locomotion but promoting antigen capture. We further highlight that myosin IIA enrichment at the cell front requires the MHC class II-associated invariant chain (Ii). Thus, by controlling myosin IIA localization, Ii imposes on dendritic cells an intermittent antigen capture behaviour that might facilitate environment patrolling. We propose that the requirement for myosin II in both cell migration and specific cell functions may provide a general mechanism for their coordination in time and space. PMID- 26109325 TI - Demonstrating quantum contextuality of indistinguishable particles by a single family of noncontextuality inequalities. AB - Quantum theory has the intriguing feature that is inconsistent with noncontextual hidden variable models, for which the outcome of a measurement does not depend on which other compatible measurements are being performed concurrently. While various proofs of such contextual behavior of quantum systems have been established, relatively little is known concerning the possibility to demonstrate this intriguing feature for indistinguishable particles. Here, we show in a simple and systematic manner that with projective measurements alone, it is possible to demonstrate quantum contextuality for such systems of arbitrary Hilbert space dimensions, including those corresponding to a qubit. Our demonstration is applicable to a single fermion as well as multiple fermions, and thus also a composite boson formed from an even number of fermions. In addition, our approach gives a clear demonstration of the intimate connection between complementarity and contextuality, two seemingly unrelated aspects of quantum theory. PMID- 26109326 TI - Fomepizole versus ethanol in the treatment of acute methanol poisoning: Comparison of clinical effectiveness in a mass poisoning outbreak. AB - CONTEXT: Mass or cluster methanol poisonings are frequently reported from around the world. The comparative effectiveness of ethanol and fomepizole as antidotes for methanol poisoning is unknown due to the difficulty of performing a randomized controlled trial. OBJECTIVE: During an outbreak of mass poisonings in the Czech Republic in 2012-2014, we compared the effects of antidotes on the frequency of health sequelae and mortality. METHODS: The study was designed as a cross-sectional case series and quasi-case-control study. Patients with a diagnosis of methanol poisoning on admission to hospitals were identified for the study. Diagnosis was established when (i) a history of recent ingestion of illicit spirits was available and serum methanol was higher than 6.2 mmol/L (20 mg/dL), or (ii) there was a history/clinical suspicion of methanol poisoning, and serum methanol was above the limit of detection with at least two of the following: pH < 7.3, serum bicarbonate < 20 mmol/L, and anion gap or AG >= 20 mmol/L. Fomepizole was given as a bolus dose of 15 mg/kg i.v. diluted in isotonic saline, followed by 10 mg/kg every 12 h (every 4 h during hemodialysis); ethanol was administered both intravenously as a 10% solution in 5% glucose, and per os in boluses of 20% solution. Multivariate regression was applied to determine the effect of antidote on outcome. Additionally, for a retrospective quasi-case control study, a control group of patients treated with ethanol, matched carefully on severity of poisoning and other key parameters, was selected. RESULTS: Data were obtained from 100 hospitalized patients with confirmed poisoning: 25 patients treated with fomepizole were compared with 68 patients receiving ethanol (seven patients did not receive any antidote). More severely acidotic (p < 0.001) and late-presenting (>12 h; p = 0.028) patients received fomepizole more often than ethanol, as reflected in the higher number of fomepizole-treated patients being intubated (p = 0.009). No association was found between the type of antidote and the survival in either the case series (p = 0.205) or the quasi-control groups (p = 0.705) in which patients were very closely matched to minimize confounding by allocation. In the multivariate analysis, positive serum ethanol (odds ratio [OR], 10.8; 95% confidence interval [CI], 2.9-39.9) and arterial blood pH (OR, 3.7; 95% CI, 1.3-10.5) on admission were the only independent variables for the survival. The median intensive care unit length of stay was 6 (range, 2-22) days in the fomepizole group and 4 (range, 1-33) days in the ethanol group (p = 0.131). There were no differences in the use of elimination techniques between the two groups (neither in the full material (n = 100), nor the case-control groups (n = 50)). CONCLUSIONS: This study on antidotes for methanol poisoning did not show any evidence of different clinical effectiveness. Although ethanol is generally associated with a higher incidence of complications, this study suggests that both antidotes are similarly effective and that ethanol should not be avoided on grounds of effectiveness. PMID- 26109327 TI - Robotics and transanal minimal invasive surgery (TAMIS): The "sweet spot" for robotics in colorectal surgery? PMID- 26109328 TI - Admission blood glucose predicts mortality and length of stay in patients admitted through the emergency department. AB - BACKGROUND: Hyperglycaemia has been associated with adverse outcomes in several different hospital populations. AIM: The aim of this study was to investigate the relationship between admission blood glucose level (BGL) and outcomes in all patients admitted through the emergency department. METHODS: This study was a retrospective observational cohort study from an Australian tertiary referral hospital. Patients admitted in the first week of each month from April to October 2012 had demographic data, co-morbidities, BGL, intensive care unit admission, length of stay and dates of death recorded. Factors associated with outcomes were assessed by multi-level mixed-effects linear regression. RESULTS: Admission BGL was recorded for 601 admissions with no diagnosis of diabetes and for 219 admissions diagnosed with type 2 diabetes (T2DM). In patients with no diagnosis of diabetes, admission BGL was associated with in-hospital and 90-day mortality (P < 0.001). After multivariate analysis, BGL greater than 11.5 mmol/L was significantly associated with increased mortality at 90 days (P < 0.05). In patients with T2DM increased BGL on admission was not associated with in-hospital or 90-day mortality but was associated with length of hospital stay (beta: 0.22 days/mmol/L; 95% confidence interval 0.09-0.35; P < 0.001), although this association was lost on multivariable analysis. In patients with T2DM, increased coefficient of variation of BGL was also positively associated with length of hospital stay in an almost dose-dependent fashion (P < 0.001). CONCLUSION: Admission BGL was independently associated with increased mortality in patients with no diagnosis of diabetes. Glycaemic variability was associated with increased length of hospital stay in patients with T2DM. PMID- 26109329 TI - First-in-human evaluation of a hybrid modality that allows combined radio- and (near-infrared) fluorescence tracing during surgery. AB - PURPOSE: The clinical introduction of the hybrid tracer indocyanine green (ICG) (99m)Tc-nanocolloid, composed of a radioactive and a near-infrared (NIR) fluorescence component, has created the need for surgical (imaging) modalities that allow for simultaneous detection of both signals. This study describes the first-in-human use of a prototype opto-nuclear probe during sentinel node (SN) biopsy using ICG-(99m)Tc-nanocolloid. METHODS: To allow for fluorescence tracing, a derivative of the conventional gamma probe technology was generated in which two optical fibers were integrated to allow for excitation (785 nm) and emission signal collection (> 810 nm). The ability of this opto-nuclear probe to detect the fluorescence signal of the hybrid tracer ICG-(99m)Tc-nanocolloid was firstly determined ex vivo in (non)SNs samples obtained from 41 patients who underwent hybrid tracer-based SN biopsy in the head and neck or urogenital area. In an in vivo proof-of-concept study in nine of these 41 patients, SNs were localized using combined gamma and fluorescence tracing with the opto-nuclear probe. Fluorescence tracing was performed in a similar manner as gamma tracing and under ambient light conditions. RESULTS: Ex vivo, the gamma tracing option of the opto nuclear probe correctly identified the SN in all 150 evaluated (non)SN samples. Ex vivo fluorescence tracing in the low-sensitivity mode correctly identified 71.7% of the samples. This increased to 98.9% when fluorescence tracing was performed in the high-sensitivity mode. In vivo fluorescence tracing (high sensitivity mode) accurately identified the SNs in all nine patients (20 SNs evaluated; 100%). CONCLUSION: This study demonstrates the first-in-human evaluation of a hybrid modality capable of detecting both gamma and fluorescence signals during a surgical procedure. Fluorescence tracing could be performed in ambient light. PMID- 26109330 TI - Conformational and Chiral Properties of Cyclic-tri(N-methyl-meta-benzamide) Bearing Amidino Groups. AB - Cyclic triamides bearing amidino groups at the meta position of the phenyl rings were synthesized, and their conformational properties in the crystal and in solution were examined. Compound exists as a capsule-type dimer of the enantiomers with a bowl-shaped syn conformation in the crystal state. Compound exists mainly in the syn form in solution, and chiral induction was observed upon addition of a chiral acid to a solution of. PMID- 26109331 TI - Increased body mass index negatively impacts blastocyst formation rate in normal responders undergoing in vitro fertilization. AB - PURPOSE: The aim of this study is to investigate the effect of female BMI and metabolic dysfunction on blastocyst formation rate. METHODS: This was a retrospective cohort study that was performed in an academic center for reproductive medicine. Patients who were normal weight, overweight with metabolic dysfunction, or obese who had >=6 oocytes retrieved in a fresh IVF cycle were included in the study. The blastocyst formation rate was calculated from the number of >=5 cell embryos on day 3 observed in culture until day 5 or day 6. Only good quality blastocysts were included in the calculation as defined by a morphologic grade of 3BB or better. RESULTS: The blastocyst formation rate was significantly better in the normal-weight controls versus overweight/obese patients (57.2 versus 43.6 %, p < 0.007). There was no difference in blastocyst formation between the patients with a BMI 25-29.9 kg/m(2) with metabolic dysfunction and those with a BMI >=30 kg/m(2). CONCLUSION: The maternal metabolic environment has a significant impact on embryo quality as measured by blastocyst formation. A decreased blastocyst formation rate is likely a significant contributor to poorer reproductive outcomes in overweight and obese women with infertility. PMID- 26109332 TI - Does sperm origin affect embryo morphokinetic parameters? AB - PURPOSE: The purpose of our study was to use time-lapse in order to evaluate the impact of sperm origin (fresh ejaculate or surgically retrieved) on embryo morphokinetic parameters and clinical outcome in intracytoplasmic sperm injection (ICSI) cycles. METHODS: This retrospective monocentric study was conducted in 485 unselected couples undergoing 604 ICSI cycles with embryo culture in the Embryoscope(r). Among them, 445 couples underwent ICSI cycle with fresh ejaculated sperm and 40 with surgically retrieved sperm (26 with testicular sperm and 14 with epididymal sperm). Embryo morphokinetic parameters and clinical cycle outcome were compared between fresh ejaculated sperm and surgically retrieved sperm. A subgroup analysis was also conducted between testicular and epididymal sperm ICSI cycles. RESULTS: Clinical outcome was comparable between groups according to sperm origin. Although most early morphokinetic parameters were comparable between ejaculated and surgical sperm groups, a few parameters were significantly different between both groups, but with a considerable overlap in their distribution. Late cellular events occurred significantly later in the surgical sperm group than in the ejaculated sperm group. CONCLUSIONS: Morphokinetic analysis did not allow us to identify clinically relevant differences between fresh ejaculate and surgically retrieved sperm groups. Further studies are needed, especially concerning the relationship between sperm origin and late morphokinetic parameters, such as blastocyst development. PMID- 26109333 TI - Cell-Free DNA Next-Generation Sequencing in Pancreatobiliary Carcinomas. AB - Patients with pancreatic and biliary carcinomas lack personalized treatment options, in part because biopsies are often inadequate for molecular characterization. Cell-free DNA (cfDNA) sequencing may enable a precision oncology approach in this setting. We attempted to prospectively analyze 54 genes in tumor and cfDNA for 26 patients. Tumor sequencing failed in 9 patients (35%). In the remaining 17, 90.3% (95% confidence interval, 73.1%-97.5%) of mutations detected in tumor biopsies were also detected in cfDNA. The diagnostic accuracy of cfDNA sequencing was 97.7%, with 92.3% average sensitivity and 100% specificity across five informative genes. Changes in cfDNA correlated well with tumor marker dynamics in serial sampling (r = 0.93). We demonstrate that cfDNA sequencing is feasible, accurate, and sensitive in identifying tumor-derived mutations without prior knowledge of tumor genotype or the abundance of circulating tumor DNA. cfDNA sequencing should be considered in pancreatobiliary cancer trials where tissue sampling is unsafe, infeasible, or otherwise unsuccessful. SIGNIFICANCE: Precision medicine efforts in biliary and pancreatic cancers have been frustrated by difficulties in obtaining adequate tumor tissue for next-generation sequencing. cfDNA sequencing reliably and accurately detects tumor-derived mutations, paving the way for precision oncology approaches in these deadly diseases. PMID- 26109334 TI - Gender differences in brain structure and resting-state functional connectivity related to narcissistic personality. AB - Although cognitive and personality studies have observed gender differences in narcissism, the neural bases of these differences remain unknown. The current study combined the voxel-based morphometry and resting state functional connectivity (rsFC) analyses to explore the sex-specific neural basis of narcissistic personality. The VBM results showed that the relationship between narcissistic personality and regional gray matter volume (rGMV) differed between sexes. Narcissistic scores had a significant positive correlation with the rGMV of the right SPL in females, but not in males. Further analyses were conducted to investigate the sex-specific relationship between rsFC and narcissism, using right SPL/frontal eye fields (FEF) as the seed regions (key nodes of the dorsal attention network, DAN). Interestingly, decreased anticorrelations between the right SPL/FEF and areas of the precuneus and middle frontal gyrus (key nodes of the the default mode network, DMN) were associated with higher narcissistic personality scores in males, whereas females showed the opposite tendency. The findings indicate that gender differences in narcissism may be associated with differences in the intrinsic and dynamic interplay between the internally directed DMN and the externally-directed TPN. Morphometry and functional connectivity analyses can enhance our understanding of the neural basis of sex specific narcissism. PMID- 26109335 TI - Effects of a Tripeptide Iron on Iron-Deficiency Anemia in Rats. AB - This study aims to investigate the effects of a tripeptide iron (REE-Fe) on iron deficiency anemia rats. Sprague-Dawley rats were randomly divided into seven groups: a normal control group, an iron-deficiency control group, and iron deficiency groups treated with ferrous sulfate (FeSO4), ferrous glycinate (Fe Gly), or REE-Fe at low-, medium-, or high-dose groups. The rats in the iron deficiency groups were fed on an iron-deficient diet to establish iron-deficiency anemia (IDA) model. After the model established, different iron supplements were given to the rats once a day by intragastric administration for 21 days. The results showed that REE-Fe had effective restorative action returning body weight, organ coefficients, and hematological parameters in IDA rats to normal level. In addition, comparing with FeSO4 or Fe-Gly, high-dose REE-Fe was more effective on improving the levels of renal coefficient, total iron-binding capacity, and transferrin. Furthermore, the liver hepcidin messenger RNA (mRNA) expression in the high-dose group was significantly higher (p < 0.05) than that in the FeSO4 or Fe-Gly group and showed no significant difference (p > 0.05) with the normal control group. The findings suggest that REE-Fe is an effective source of iron supplement for IDA rats and might be exploited as a new iron fortifier. PMID- 26109336 TI - Erratum to: Alternative Surfactants for Improved Efficiency of In Situ Tryptic Proteolysis of Fingermarks. PMID- 26109337 TI - Solid State Reaction Mechanism and Microstructure Evolution of Ni-Al Powders during High Energy Ball Milling Revisited by TEM. AB - Microstructure evolution during the formation of B2-NiAl by high energy ball milling of equiatomic elemental mixtures was studied by X-ray diffractometer, scanning electron microscopy, and transmission electron microscopy (TEM). The crystallite size, lattice defects and ordering of the B2-NiAl were monitored via TEM as function of milling time. The diffusion reaction, Ni+Al->NiAl3 or/and Ni2Al3, occurred during high energy ball milling, and to a certain extent offered the stored energy for the explosive exothermic reaction, Ni+Al->B2-NiAl. The fine microstructure of newly formed B2-NiAl after 5 h milling involved high density defects, e.g. antiphase boundary, long range ordering domains, vacancies, and dislocations. PMID- 26109338 TI - Retracted: MicroRNA-217 overexpression induces drug resistance and invasion of breast cancer cells by targeting PTEN signaling. AB - The above article, published online on 24 June 2015 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/abs/10.1002/cbin.10506), has been retracted by agreement with the journal Editor, Sergio Schenkman, and John Wiley & Sons Ltd. The retraction has been agreed because the authors have not provided a signed Copyright Transfer Agreement. Reference Zhang, A., Lu, F., Yang, Y., Ren, X., Li, Z. and Zhang, W. (2015), MicroRNA-217 overexpression induces drug resistance and invasion of breast cancer cells by targeting PTEN signaling. Cell Biol Int. Accepted Author Manuscript. doi:10.1002/cbin.10506. PMID- 26109340 TI - Mechanisms Regulating Neuromuscular Junction Development and Function and Causes of Muscle Wasting. AB - The neuromuscular junction is the chemical synapse between motor neurons and skeletal muscle fibers. It is designed to reliably convert the action potential from the presynaptic motor neuron into the contraction of the postsynaptic muscle fiber. Diseases that affect the neuromuscular junction may cause failure of this conversion and result in loss of ambulation and respiration. The loss of motor input also causes muscle wasting as muscle mass is constantly adapted to contractile needs by the balancing of protein synthesis and protein degradation. Finally, neuromuscular activity and muscle mass have a major impact on metabolic properties of the organisms. This review discusses the mechanisms involved in the development and maintenance of the neuromuscular junction, the consequences of and the mechanisms involved in its dysfunction, and its role in maintaining muscle mass during aging. As life expectancy is increasing, loss of muscle mass during aging, called sarcopenia, has emerged as a field of high medical need. Interestingly, aging is also accompanied by structural changes at the neuromuscular junction, suggesting that the mechanisms involved in neuromuscular junction maintenance might be disturbed during aging. In addition, there is now evidence that behavioral paradigms and signaling pathways that are involved in longevity also affect neuromuscular junction stability and sarcopenia. PMID- 26109339 TI - Estrogen Effects on Cognitive and Synaptic Health Over the Lifecourse. AB - Estrogen facilitates higher cognitive functions by exerting effects on brain regions such as the prefrontal cortex and hippocampus. Estrogen induces spinogenesis and synaptogenesis in these two brain regions and also initiates a complex set of signal transduction pathways via estrogen receptors (ERs). Along with the classical genomic effects mediated by activation of ER alpha and ER beta, there are membrane-bound ER alpha, ER beta, and G protein-coupled estrogen receptor 1 (GPER1) that can mediate rapid nongenomic effects. All key ERs present throughout the body are also present in synapses of the hippocampus and prefrontal cortex. This review summarizes estrogen actions in the brain from the standpoint of their effects on synapse structure and function, noting also the synergistic role of progesterone. We first begin with a review of ER subtypes in the brain and how their abundance and distributions are altered with aging and estrogen loss (e.g., ovariectomy or menopause) in the rodent, monkey, and human brain. As there is much evidence that estrogen loss induced by menopause can exacerbate the effects of aging on cognitive functions, we then review the clinical trials of hormone replacement therapies and their effectiveness on cognitive symptoms experienced by women. Finally, we summarize studies carried out in nonhuman primate models of age- and menopause-related cognitive decline that are highly relevant for developing effective interventions for menopausal women. Together, we highlight a new understanding of how estrogen affects higher cognitive functions and synaptic health that go well beyond its effects on reproduction. PMID- 26109342 TI - Evaluation of sexual function and quality of life in Iranian women with tubal ligation: a historical cohort study. AB - Tubal ligation (TL) is an option for contraception for women who have completed their family. The existence of sexual dysfunction and impaired quality of life (QOL) following this procedure has been the subject of debate for decades. The aim of this study was to evaluate the sexual function, QOL and other factors affecting Iranian women who underwent TL. A historical cohort study was carried out on 150 women who had undergone TL and on 150 women who had used a condom (as the control group). The sexual function of participants was evaluated and compared using Female Sexual Function Index (FSFI) questionnaire. They were also asked to fill out the Short Form Health Survey (SF-12) for evaluating their QOL. Furthermore, the effects of educational level and poststerilization regret in the women of TL group were evaluated. With regard to FSFI, all mean values were found to be lower in the TL women and the differences between the two groups were statistically significant in all domains. A significant difference was found in sexual dysfunction in orgasm (P = 0.02), satisfaction (P = 0.01), pain (P = 0.006) and total FSFI scores (P = 0.006) between the women regretting vs those not regretting their sterilization. In evaluating the relationship between FSFI and educational level, with the increase of educational level all domain scores increased significantly only in the TL group. There was a significant difference between the two groups in SF-12 scores (69.18 +/- 14.05 vs 78.41 +/- 12.50; P < 0.0001). Our findings reveal the adverse effects of TL on the sexual life and QOL of women. It is recommended that the awareness and knowledge of health-care professionals regarding the sexual function and QOL in women undergoing TL should be increased. PMID- 26109343 TI - Effective inactivation of Candida albicans biofilms by using supercritical carbon dioxide. AB - Present sterilization methods for biofilms in medical devices have limitations. Therefore, an alternative sterilization method using supercritical carbon dioxide (SC-CO2) was tested on Candida albicans biofilms. The effect of varying pressure, temperature, and treatment time on the inactivation of C. albicans spores in suspensions and in biofilms was examined. The parameters such as treatment time, pressure, and temperature that led to the complete inactivation of C. albicans biofilms ranged 5-20 min, 100-200 bar, and 35-45 degrees C, respectively. Notably, treatment of SC-CO2 at either 100 bar and 40 degrees C or 200 bar and 30 degrees C induced complete inactivation of spores within 5 min. Furthermore, it was found that wet biofilms (0.4 %, w/w) had higher sensitivity to SC-CO2 than dried biofilms. Finally, spore inactivation was confirmed by confocal laser scanning microscopy. In this study, the use of a low-temperature SC-CO2 sterilization method was proven to be effective in fungal biofilm inactivation, and the moisture content of biofilms was revealed to be the key factor for biofilm inactivation. PMID- 26109345 TI - Optimizing HER2 assessment in breast cancer: application of automated image analysis. AB - In breast cancer, analysis of HER2 expression is pivotal for treatment decision. This study aimed at comparing digital, automated image analysis with manual reading using the HER2-CONNECT algorithm (Visiopharm) in order to minimize the number of equivocal 2+ scores and the need for reflex fluorescence in situ hybridization (FISH) analysis. Consecutive samples from 462 patients were included. Tissue micro arrays (TMAs) were routinely manufactured including two 2 mm cores from each patient, and each core was assessed in order to ensure the presence of invasive carcinoma. Immunohistochemical staining (IHC) was performed with Roche/Ventana's HER2 ready-to-use kit. TMAs were scanned in a Zeiss Axio Z1 scanner, and one batch analysis of the HER2-CONNECT algorithm including all core samples was run using Visiopharm's cloud-based software. The automated reading was compared to conventional manual assessment of HER2 protein expression, together with FISH analysis of HER2 gene amplification for borderline (2+) protein expression samples. Compared to FISH analysis, manual assessment of the HER2 protein expression demonstrated a sensitivity of 85.8% and a specificity of 86.0% with 14.0% equivocal samples. With HER2-CONNECT, sensitivity increased to 100 % and specificity to 95.5% with less than 4.5% equivocal. Total agreement when comparing HER2-CONNECT with manual IHC assessment supplemented by FISH for borderline (2+) cases was 93.6%. Application of automated image analysis for HER2 protein expression instead of manual assessment decreases the need for supplementary FISH testing by 68%. In the routine diagnostic setting, this would have significant impact on cost reduction and turn-around time. PMID- 26109344 TI - Race-associated biological differences among Luminal A breast tumors. AB - African-American (AA) women have higher breast cancer-specific mortality rates. A higher prevalence of the worse outcome Basal-like breast cancer subtype contributes to this, but AA women also have higher mortality even within the more favorable outcome Luminal A breast cancers. These differences may reflect treatment or health care access issues, inherent biological differences, or both. To identify potential biological differences by race among Luminal A breast cancers, gene expression data from 108 CAU and 57 AA breast tumors were analyzed. Race-associated genes were evaluated for associations with survival. Finally, expression of race- and survival-associated genes was evaluated in normal tissue of AA and CAU women. Six genes (ACOX2, MUC1, CRYBB2, PSPH, SQLE, TYMS) were differentially expressed by race among Luminal A breast cancers and were associated with survival (HR <0.8, HR >1.25). For all six genes, tumors in AA had higher expression of poor prognosis genes (CRYBB2, PSPH, SQLE, TYMS) and lower expression of good prognosis genes (ACOX2, MUC1). A score based on all six genes predicted survival in a large independent dataset (HR = 1.9 top vs. bottom quartile, 95% CI: 1.4-2.5). For four genes, normal tissue of AA and CAU women showed similar expression (ACOX2, MUC1, SQLE, TYMS); however, the poor outcome associated genes CRYBB2 and PSPH were more highly expressed in AA versus CAU women's normal tissue. This analysis identified gene expression differences that may contribute to mortality disparities and suggests that among Luminal A breast tumors there are biological differences between AA and CAU patients. Some of these differences (CRYBB2 and PSPH) may exist from the earliest stages of tumor development, or may even precede malignancy. PMID- 26109348 TI - A higher incidence rate of acute coronary syndrome following radiation therapy in patients with breast cancer and a history of coronary artery diseases. AB - This study aims to investigate whether patients with breast cancer and a history of cardiovascular diseases (CADs) are at an increased incidence of acute coronary syndrome (ACS) after receiving radiation therapy (RT). In Taiwan, 5828 patients who had a history of CAD were newly diagnosed of breast cancer and received mastectomy between 1999 and 2009. Among these patients, 1851 also received RT. The study cohort was prospectively followed to the end of 2010 for estimating the incidence of ACS in association with exposure to RT. A Cox proportional hazard model that was adjusted for covariates was used to estimate the hazard ratio (HR) of ACS. Over the study period, the incident rates of ACS for RT and control patients were estimated at 1.51 and 1.77 per 100 person-years, respectively. Covariate-adjusted regression analysis indicated that the hazard of ACS significantly increased in RT patients at an adjusted HR of 1.48 [95% confidence interval (CI) 1.18-1.87]. Both hypertension and diabetes significantly increased the hazard of ACS in this patient cohort, with adjusted HRs of 3.31 (95% CI 1.94 5.66) and 1.50 (95% CI 1.19-1.89), respectively. This 12-year follow-up study suggested excess of ACS events in association with RT exposure in patients with breast cancer who had a higher cardiovascular risk. In consideration of the benefit associated with RT, intensive cardiac care should be given to patients with breast cancer and high cardiovascular risk. PMID- 26109347 TI - Outcome after neoadjuvant chemotherapy in young breast cancer patients: a pooled analysis of individual patient data from eight prospectively randomized controlled trials. AB - Young women with breast cancer (BC) have a worse survival partly due to more aggressive tumor characteristics; however, their response to chemotherapy seems better. We investigated to what extent the prognostic factor pathological complete remission (pCR) after neoadjuvant chemotherapy is applicable to young women. 8949 patients with primary BC and follow-up from eight German neoadjuvant trials were included. A subgroup of 1453 patients <40 years was compared with women aged 40-49 and >=50 years regarding pCR (ypT0 ypN0), as well as disease free survival (DFS), local recurrence free survival (LRFS), distant disease free survival (DDFS), and overall survival (OS) overall, according to pCR status and subtypes defined by hormone-receptor (HR) status and HER2. pCR was strongly associated with age without a clear age cut-off. The pCR rate was significantly higher in the young compared with other age groups (20.9 vs. 17.7 vs. 13.7 %; p < 0.001). This difference was confined to triple-negative breast cancer (TNBC) and HR +/HER2-. DFS, DDFS, LRFS, and OS were significantly worse for young women. Age was independently prognostic for survival in HR +/HER2-, with women <40 years without pCR having a worse DFS compared to their counterparts with pCR. Young women are more likely to achieve pCR after neoadjuvant chemotherapy, especially in HR +/HER2- and TNBC. Age is not an important prognostic factor in TNBC and HR /HER2 + but is in HR +/HER2-. Young women with a luminal-like BC seem to benefit more from neoadjuvant chemotherapy than older women, which needs to be taken into account. PMID- 26109349 TI - A culinary laboratory for nutrition education. AB - BACKGROUND: Proficiency in medical nutrition requires an understanding of food related biochemistry and the application of this knowledge in the context of culinary, cultural, psychosocial and interprofessional components. CONTEXT: Our aim was to develop a teaching format where medical students could learn the biochemistry of nutrition in the context of patient narratives, interactive cooking and dialogues with nutrition professionals. INNOVATION: We designed and implemented a day-long culinary laboratory intervention (lab), which is taught to first-year medical students at the University of Rochester with the help of dietetic interns from Cornell University. Here, we present the details of the intervention, the resources used and the preliminary outcomes on student attitudes. We designed and implemented a day-long culinary lab, which is taught to first-year medical students METHODS AND RESULTS: A questionnaire with quantitative rating scales and open-ended questions was used to probe student attitudes regarding the educational approach used in the lab. Our preliminary findings suggest that the lab was well received and that the dietetic interns were viewed as effective teachers in this context. IMPLICATIONS: A culinary lab is a feasible educational environment for integrating the breadth of topics within the discipline of nutrition. The experiential, food-based format appears to stimulate questions central to current nutritional controversies, particularly challenges related to translating biochemical mechanism into practical nutrition interventions. Close involvement with basic science faculty members, clinical faculty members and allied health professions are essential for this type of endeavour. PMID- 26109346 TI - Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype specific driver genes for breast cancer. AB - A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes. PMID- 26109350 TI - MRPrimer: a MapReduce-based method for the thorough design of valid and ranked primers for PCR. AB - Primer design is a fundamental technique that is widely used for polymerase chain reaction (PCR). Although many methods have been proposed for primer design, they require a great deal of manual effort to generate feasible and valid primers, including homology tests on off-target sequences using BLAST-like tools. That approach is inconvenient for many target sequences of quantitative PCR (qPCR) due to considering the same stringent and allele-invariant constraints. To address this issue, we propose an entirely new method called MRPrimer that can design all feasible and valid primer pairs existing in a DNA database at once, while simultaneously checking a multitude of filtering constraints and validating primer specificity. Furthermore, MRPrimer suggests the best primer pair for each target sequence, based on a ranking method. Through qPCR analysis using 343 primer pairs and the corresponding sequencing and comparative analyses, we showed that the primer pairs designed by MRPrimer are very stable and effective for qPCR. In addition, MRPrimer is computationally efficient and scalable and therefore useful for quickly constructing an entire collection of feasible and valid primers for frequently updated databases like RefSeq. Furthermore, we suggest that MRPrimer can be utilized conveniently for experiments requiring primer design, especially real-time qPCR. PMID- 26109341 TI - Neuronal Reward and Decision Signals: From Theories to Data. AB - Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations. The approach and choice functions involve subjective value, which is objectively assessed by behavioral choices eliciting internal, subjective reward preferences. Utility is the formal mathematical characterization of subjective value and a prime decision variable in economic choice theory. It is coded as utility prediction error by phasic dopamine responses. Utility can incorporate various influences, including risk, delay, effort, and social interaction. Appropriate for formal decision mechanisms, rewards are coded as object value, action value, difference value, and chosen value by specific neurons. Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts. The neuronal reward signals provide guidance for behavior while constraining the free will to act. PMID- 26109351 TI - Primase-polymerases are a functionally diverse superfamily of replication and repair enzymes. AB - Until relatively recently, DNA primases were viewed simply as a class of proteins that synthesize short RNA primers requisite for the initiation of DNA replication. However, recent studies have shown that this perception of the limited activities associated with these diverse enzymes can no longer be justified. Numerous examples can now be cited demonstrating how the term 'DNA primase' only describes a very narrow subset of these nucleotidyltransferases, with the vast majority fulfilling multifunctional roles from DNA replication to damage tolerance and repair. This article focuses on the archaeo-eukaryotic primase (AEP) superfamily, drawing on recently characterized examples from all domains of life to highlight the functionally diverse pathways in which these enzymes are employed. The broad origins, functionalities and enzymatic capabilities of AEPs emphasizes their previous functional misannotation and supports the necessity for a reclassification of these enzymes under a category called primase-polymerases within the wider functional grouping of polymerases. Importantly, the repositioning of AEPs in this way better recognizes their broader roles in DNA metabolism and encourages the discovery of additional functions for these enzymes, aside from those highlighted here. PMID- 26109352 TI - High-throughput prediction of RNA, DNA and protein binding regions mediated by intrinsic disorder. AB - Intrinsically disordered proteins and regions (IDPs and IDRs) lack stable 3D structure under physiological conditions in-vitro, are common in eukaryotes, and facilitate interactions with RNA, DNA and proteins. Current methods for prediction of IDPs and IDRs do not provide insights into their functions, except for a handful of methods that address predictions of protein-binding regions. We report first-of-its-kind computational method DisoRDPbind for high-throughput prediction of RNA, DNA and protein binding residues located in IDRs from protein sequences. DisoRDPbind is implemented using a runtime-efficient multi-layered design that utilizes information extracted from physiochemical properties of amino acids, sequence complexity, putative secondary structure and disorder and sequence alignment. Empirical tests demonstrate that it provides accurate predictions that are competitive with other predictors of disorder-mediated protein binding regions and complementary to the methods that predict RNA- and DNA-binding residues annotated based on crystal structures. Application in Homo sapiens, Mus musculus, Caenorhabditis elegans and Drosophila melanogaster proteomes reveals that RNA- and DNA-binding proteins predicted by DisoRDPbind complement and overlap with the corresponding known binding proteins collected from several sources. Also, the number of the putative protein-binding regions predicted with DisoRDPbind correlates with the promiscuity of proteins in the corresponding protein-protein interaction networks. Webserver: http://biomine.ece.ualberta.ca/DisoRDPbind/. PMID- 26109353 TI - Dynamic contact network between ribosomal subunits enables rapid large-scale rotation during spontaneous translocation. AB - During ribosomal translation, the two ribosomal subunits remain associated through intersubunit bridges, despite rapid large-scale intersubunit rotation. The absence of large barriers hindering rotation is a prerequisite for rapid rotation. Here, we investigate how such a flat free-energy landscape is achieved, in particular considering the large shifts the bridges undergo at the periphery. The dynamics and energetics of the intersubunit contact network are studied using molecular dynamics simulations of the prokaryotic ribosome in intermediate states of spontaneous translocation. Based on observed occupancies of intersubunit contacts, residues were grouped into clusters. In addition to the central contact clusters, peripheral clusters were found to maintain strong steady interactions by changing contacts in the course of rotation. The peripheral B1 bridges are stabilized by a changing contact pattern of charged residues that adapts to the rotational state. In contrast, steady strong interactions of the B4 bridge are ensured by the flexible helix H34 following the movement of protein S15. The tRNAs which span the subunits contribute to the intersubunit binding enthalpy to an almost constant degree, despite their different positions in the ribosome. These mechanisms keep the intersubunit interaction strong and steady during rotation, thereby preventing dissociation and enabling rapid rotation. PMID- 26109354 TI - Evidence that avian reovirus sigmaNS is an RNA chaperone: implications for genome segment assortment. AB - Reoviruses are important human, animal and plant pathogens having 10-12 segments of double-stranded genomic RNA. The mechanisms controlling the assortment and packaging of genomic segments in these viruses, remain poorly understood. RNA protein and RNA-RNA interactions between viral genomic segment precursors have been implicated in the process. While non-structural viral RNA-binding proteins, such as avian reovirus sigmaNS, are essential for virus replication, the mechanism by which they assist packaging is unclear. Here we demonstrate that sigmaNS assembles into stable elongated hexamers in vitro, which bind single stranded nucleic acids with high affinity, but little sequence specificity. Using ensemble and single molecule fluorescence spectroscopy, we show that sigmaNS also binds to a partially double-stranded RNA, resulting in gradual helix unwinding. The hexamer can bind multiple RNA molecules and exhibits strand-annealing activity, thus mediating conversion of metastable, intramolecular stem-loops into more stable heteroduplexes. We demonstrate that the ARV sigmaNS acts as an RNA chaperone facilitating specific RNA-RNA interactions between genomic precursors during segment assortment and packaging. PMID- 26109355 TI - Endogenous Small RNA Mediates Meiotic Silencing of a Novel DNA Transposon. AB - Genome defense likely evolved to curtail the spread of transposable elements and invading viruses. A combination of effective defense mechanisms has been shown to limit colonization of the Neurospora crassa genome by transposable elements. A novel DNA transposon named Sly1-1 was discovered in the genome of the most widely used laboratory "wild-type" strain FGSC 2489 (OR74A). Meiotic silencing by unpaired DNA, also simply called meiotic silencing, prevents the expression of regions of the genome that are unpaired during karyogamy. This mechanism is posttranscriptional and is proposed to involve the production of small RNA, so called masiRNAs, by proteins homologous to those involved in RNA interference silencing pathways in animals, fungi, and plants. Here, we demonstrate production of small RNAs when Sly1-1 was unpaired in a cross between two wild-type strains. These small RNAs are dependent on SAD-1, an RNA-dependent RNA polymerase necessary for meiotic silencing. We present the first case of endogenously produced masiRNA from a novel N. crassa DNA transposable element. PMID- 26109356 TI - Gene Model Annotations for Drosophila melanogaster: The Rule-Benders. AB - In the context of the FlyBase annotated gene models in Drosophila melanogaster, we describe the many exceptional cases we have curated from the literature or identified in the course of FlyBase analysis. These range from atypical but common examples such as dicistronic and polycistronic transcripts, noncanonical splices, trans-spliced transcripts, noncanonical translation starts, and stop codon readthroughs, to single exceptional cases such as ribosomal frameshifting and HAC1-type intron processing. In FlyBase, exceptional genes and transcripts are flagged with Sequence Ontology terms and/or standardized comments. Because some of the rule-benders create problems for handlers of high-throughput data, we discuss plans for flagging these cases in bulk data downloads. PMID- 26109357 TI - Gene Model Annotations for Drosophila melanogaster: Impact of High-Throughput Data. AB - We report the current status of the FlyBase annotated gene set for Drosophila melanogaster and highlight improvements based on high-throughput data. The FlyBase annotated gene set consists entirely of manually annotated gene models, with the exception of some classes of small non-coding RNAs. All gene models have been reviewed using evidence from high-throughput datasets, primarily from the modENCODE project. These datasets include RNA-Seq coverage data, RNA-Seq junction data, transcription start site profiles, and translation stop-codon read-through predictions. New annotation guidelines were developed to take into account the use of the high-throughput data. We describe how this flood of new data was incorporated into thousands of new and revised annotations. FlyBase has adopted a philosophy of excluding low-confidence and low-frequency data from gene model annotations; we also do not attempt to represent all possible permutations for complex and modularly organized genes. This has allowed us to produce a high confidence, manageable gene annotation dataset that is available at FlyBase (http://flybase.org). Interesting aspects of new annotations include new genes (coding, non-coding, and antisense), many genes with alternative transcripts with very long 3' UTRs (up to 15-18 kb), and a stunning mismatch in the number of male specific genes (approximately 13% of all annotated gene models) vs. female specific genes (less than 1%). The number of identified pseudogenes and mutations in the sequenced strain also increased significantly. We discuss remaining challenges, for instance, identification of functional small polypeptides and detection of alternative translation starts. PMID- 26109359 TI - The effect of prolonged storage on the virulence of isolates of Bacillus anthracis obtained from environmental and animal sources in the Kars Region of Turkey. AB - The stability of the plasmid-mediated virulence factors of Bacillus anthracis, a tripartite toxin located on pXO1 and an antiphagocytic capsule encoded by genes located on pXO2, following long-term storage was investigated. A collection of 159 isolates of B. anthracis were collected from the Kars region of Turkey between 2000 and 2013 and stored at -20 degrees C in Brucella broth supplemented with 20% glycerine. A total of 142 isolates were recovered of which one failed to express a capsule upon primary culture. A further 35 isolates yielded a mixture of mucoid and non-mucoid colonies; the majority of which had lost the pXO2 plasmid as determined by PCR analysis. Results would suggest that pXO2 is more unstable than pXO1 and that this instability increases with the length of storage. It is possible that the pXO2-deficient isolates of B. anthracis described here could be developed into a vaccine to treat at risk animals in the Kars region as many animal vaccines are based upon pXO2 deficiency. PMID- 26109358 TI - Comparative Evolution of Duplicated Ddx3 Genes in Teleosts: Insights from Japanese Flounder, Paralichthys olivaceus. AB - Following the two rounds of whole-genome duplication that occurred during deuterostome evolution, a third genome duplication event occurred in the stem lineage of ray-finned fishes. This teleost-specific genome duplication is thought to be responsible for the biological diversification of ray-finned fishes. DEAD box polypeptide 3 (DDX3) belongs to the DEAD-box RNA helicase family. Although their functions in humans have been well studied, limited information is available regarding their function in teleosts. In this study, two teleost Ddx3 genes were first identified in the transcriptome of Japanese flounder (Paralichthys olivaceus). We confirmed that the two genes originated from teleost specific genome duplication through synteny and phylogenetic analysis. Additionally, comparative analysis of genome structure, molecular evolution rate, and expression pattern of the two genes in Japanese flounder revealed evidence of subfunctionalization of the duplicated Ddx3 genes in teleosts. Thus, the results of this study reveal novel insights into the evolution of the teleost Ddx3 genes and constitute important groundwork for further research on this gene family. PMID- 26109360 TI - Hydrogenotrophic culture enrichment reveals rumen Lachnospiraceae and Ruminococcaceae acetogens and hydrogen-responsive Bacteroidetes from pasture-fed cattle. AB - Molecular information suggests that there is a broad diversity of acetogens in the rumen, distinct from any currently isolated acetogens. We combined molecular analysis with enrichment culture techniques to investigate this diversity further. Methane-inhibited, hydrogenotrophic enrichment cultures produced acetate as the dominant end product. Acetyl-CoA synthase gene analysis revealed putative acetogens in the cultures affiliated with the Lachnospiraceae and Ruminococcaceae as has been found in other rumen studies. No formyltetrahydrofolate synthetase genes affiliating with acetogens or with 'homoacetogen similarity' scores >90% were identified. To further investigate the hydrogenotrophic populations in these cultures and link functional gene information with 16S rRNA gene identity, cultures were subcultured quickly, twice, through medium without exogenous hydrogen, followed by incubation without exogenous hydrogen. Comparison of cultures lacking hydrogen and their parent cultures revealed novel Lachnospiraceae and Ruminococcaceae that diminished in the absence of hydrogen, supporting the hypothesis that they were likely the predominant acetogens in the enrichments. Interestingly, a range of Bacteroidetes rrs sequences that demonstrated <86% identity to any named isolate also diminished in cultures lacking hydrogen. Acetogens or sulphate reducers from the Bacteroidetes have not been reported previously; therefore this observation requires further investigation. PMID- 26109361 TI - Cell-to-cell contact and antimicrobial peptides play a combined role in the death of Lachanchea thermotolerans during mixed-culture alcoholic fermentation with Saccharomyces cerevisiae. AB - The roles of cell-to-cell contact and antimicrobial peptides in the early death of Lachanchea thermotolerans CBS2803 during anaerobic, mixed-culture fermentations with Saccharomyces cerevisiae S101 were investigated using a commercially available, double-compartment fermentation system separated by cellulose membranes with different pore sizes, i.e. 1000 kDa for mixed- and single-culture fermentations, and 1000 and 3.5-5 kDa for compartmentalized culture fermentations. SDS-PAGE and gel filtration chromatography were used to determine an antimicrobial peptidic fraction in the fermentations. Our results showed comparable amounts of the antimicrobial peptidic fraction in the inner compartments of the mixed-culture and 1000 kDa compartmentalized-culture fermentations containing L. thermotolerans after 4 days of fermentation, but a lower death rate of L. thermotolerans in the 1000 kDa compartmentalized-culture fermentation than in the mixed-culture fermentation. Furthermore, L. thermotolerans died off even more slowly in the 3.5-5 kDa than in the 1000 kDa compartmentalized-culture fermentation, which coincided with the presence of less of the antimicrobial peptidic fraction in the inner compartment of that fermentation than of the 1000 kDa compartmentalized-culture fermentation. Taken together, these results indicate that the death of L. thermotolerans in mixed cultures with S. cerevisiae is caused by a combination of cell-to-cell contact and antimicrobial peptides. PMID- 26109362 TI - Meta-analysis of microarrays: diagnostic value of microRNA-21 as a biomarker for lung cancer. AB - BACKGROUND: MicroRNA-21 (miR-21) has previously been demonstrated as a potential biomarker in diagnosis of various human tumors. This meta-analysis was performed to evaluate the possibility of miR-21 as a biomarker for early detection of lung cancer. METHODS: Relevant lung cancer-related miRNA microarray datasets were collected from the NCBI Gene Expression Omnibus (GEO) database and EBI ArrayExpress database up to February 2014. Quality control of the output data was estimated using Limma package and ExiMiR package in R. Standardized mean difference (SMD) with 95% confidence intervals (CIs) from selected datasets was pooled. Heterogeneity was assessed using Cochran's Q test and the I2 statistic, and a p value <0.0.05 or I2 >50% was defined as significant heterogeneity. Furthermore, sensitivity analysis was conducted to evaluate the stability of the pooled results. Four miRNA datasets (GSE24704, GSE17681, GSE27486 and GSE40738) from blood samples were selected, including 153 lung cancer patients and 109 healthy people. RESULTS: The pooled results generated by random-effects model revealed that no significant difference was observed between case and control groups (SMD = 0.58; 95% CI, -0.04 to 1.19; p = 0.07) with significant heterogeneity (p = 0.0032, I2 = 78.2%; p = 0.06). Sensitivity analysis indicated that the results of the meta-analysis were stable. CONCLUSIONS: MiR-21 expression levels in whole blood and peripheral blood cells did not show significant differences between lung cancer patients and healthy controls, and it might be ineffective to measure miR-21 expression to achieve an early diagnosis of lung cancer. PMID- 26109363 TI - Circulating endothelial cells for evaluation of tumor response in non-small cell lung cancer patients receiving first-line chemotherapy. AB - BACKGROUND: Circulating endothelial cells (CECs) reflect the neovascularization in the tumor mass. We therefore investigated the potential role of CEC kinetics after first-line chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. METHODS: Peripheral blood samples were obtained from 45 healthy subjects and 51 naive patients with advanced NSCLC. Quantification of CD146+ CECs was performed using immunomagnetic separation (IMS). RESULTS: Pretreatment and posttreatment CEC levels in NSCLC patients were significantly higher than in healthy subjects (p<0.0001). An objective response was achieved after chemotherapy with partial response (PR) or stable disease (SD) in 26 patients, whereas the remaining 25 patients had progressive disease (PD). Baseline CEC levels were significantly higher in PR/SD patients than in PD patients (p = 0.039). After chemotherapy, CEC count significantly decreased in PR/SD patients (p = 0.014) and increased in patients with PD (p = 0.019). Moreover, there was a significant difference in the percentage change of CEC counts between the 2 groups (p = 0.0016). No significant difference in the median progression-free survival and overall survival (OS) was observed between patients with high baseline CEC counts and those with low baseline CEC levels. However, patients with high percentage change in CEC count had longer OS than those with low percentage change after chemotherapy (p = 0.05). CONCLUSIONS: Changes in CEC counts after chemotherapy reflect tumor response in advanced NSCLC patients. Moreover, high percentage changes in CEC counts after chemotherapy may predict longer OS in advanced NSCLC. High baseline CEC levels might be an indicator of tumor response in advanced NSCLC patients after first-line chemotherapy. PMID- 26109364 TI - HER family receptor expression and prognosis in pancreatic cancer. AB - BACKGROUND: HER family receptors play a key role in tumor progression in several malignancies, such as colorectal, lung or breast cancer. The aims of this study were to investigate expression of HER-1, HER-2 and HER-3 in pancreatic cancer (PC) samples and evaluate the association between HER-family receptor expression and patients' clinical outcomes. METHODS: Tissue samples from 91 PC patients were subjected to immunohistochemical staining to assess the expression of HER-1, HER 2 and HER-3. Semiquantitative scores of zero (no staining or staining in less than 10% of cancer cells), 1+, 2+ or 3+ were assigned to each sample based on the intensity of staining for HER receptors. Scores of 2+ or 3+ were defined as positive staining. RESULTS: HER-1 overexpression was observed in 41 out of 91 samples (45.1%), while HER-2 was not overexpressed in any of the analyzed samples. HER-3 was overexpressed in 37 samples (40.7%) and was found to be associated with advanced TNM stage. In particular, HER-3 was overexpressed in 12 out of 16 stage IV patients (75%) compared with only 33.3% of stage I-III patients (p = 0.02). Among 79 patients with available survival data, the 6 patients with strong HER-3 expression (score 3+) had a shorter survival compared with remaining patients (median overall survival 6.9 months vs. 12.3 months, respectively). CONCLUSIONS: HER-1 and HER-3 were found to be expressed in a significant proportion of PC patients. Strong HER-3 expression represents an indicator of poor prognosis in PC patients, being associated with advanced stage and shorter survival. PMID- 26109365 TI - Absolute circulating pericyte progenitor cell counts in mice by flow cytometry: comparison of 2 single-platform technologies. AB - BACKGROUND: Accumulating evidence indicates that circulating pericyte progenitor cells (CPPCs) may be angiogenic biomarkers in cancer and diabetes. Their validity as biomarkers depends on the accuracy of techniques used for enumeration. In this report, absolute CPPC counts were performed by 2 single-platform technologies. The reliability of the 2 methods, including retest reliability and intraobserver and interobserver variability, was assessed according to the intraclass correlation coefficient (ICC). The linear correlation and agreement among both methods were assessed, and the stability of CPPC numbers in blood samples was analyzed. METHODS: The blood samples were obtained from ICR mice. The samples were processed through a no-lyse, 1-wash procedure, and Syto16+CD45-CD31-CD140b+ CPPCs were analyzed by exclusion of dead cells and by fluorescence-minus-one control. CPPCs were enumerated by 2 methods: bead-based 123count eBeads count (eBioscience) and direct volume-based Accuri C6 Flow Cytometer count (BD). The cells were measured immediately and after storage of blood samples for 24 and 48 hours. RESULTS: There were excellent retest correlations and intraobserver and interobserver agreement in both methods. The 2 methods showed a high linear correlation (R2 = 0.923) and with a high level of agreement (0.986). It was demonstrated that CPPCs are unstable in blood samples. CONCLUSIONS: In this study, 2 reproducible protocols for CPPC quantification were established. These protocols should facilitate future studies to further define the role of CPPCs as cellular biomarkers. PMID- 26109366 TI - Serum cripto-1 as a clinical marker for lung cancer. AB - BACKGROUND: Cripto-1 (CR-1) plays an important role in angiogenesis related to tumor growth, in concert with vascular endothelial growth factor (VEGF), and enhanced expression of CR-1 has been reported in lung cancer tissue. METHODS: Patients with lung cancer (n = 156) and healthy volunteers (n = 60) were enrolled in the study. Serum CR-1 and VEGF concentrations were measured using enzyme linked immunosorbent assay. RESULTS: Patients with lung cancer had higher serum CR-1 (4.03 +/- 1.49 ng/mL vs. 1.13 +/- 0.43 ng/mL, p<0.05) and VEGF (503.62 +/- 112.74 pg/mL vs. 398.62 +/- 117.84 pg/mL, p<0.05) levels than the control group. With stage progression in non-small cell lung cancer (NSCLC), serum CR-1 levels increased, and patients with distant metastasis had higher levels than those without metastasis (p<0.05). In NSCLC, the low CR-1 group (<1.54 ng/mL) had a better overall survival rate compared with the high CR-1 group (>1.54 ng/mL, p<0.05). CONCLUSIONS: Our study suggests that serum CR-1 is a useful diagnostic and prognostic marker for NSCLC patients. PMID- 26109367 TI - CEA in evaluation of adnexal mass: retrospective cohort analysis and review of the literature. AB - BACKGROUND: The aim of this study was to estimate the diagnostic accuracy of serum carcinoembryonic antigen (CEA) levels in conjunction with Ca125 in the triage of adnexal masses. METHODS: This retrospective cohort study was carried out in 495 patients referred to the Gynecology Department at Carmel Medical Center due to adnexal mass, between 2005 and 2012. All patients underwent surgery with histopathologically confirmed diagnosis and preoperative measurements of serum Ca125 and CEA. For each marker, sensitivity, specificity, positive predictive value, negative predictive value and risk ratio were calculated. RESULTS: Combination of CEA with Ca125, compared with Ca125 levels alone, yielded a nonsignificant effect on sensitivity (87.4% vs. 88.9%, respectively, p = 0.64) and specificity (79.3% vs. 74.3%, p = 0.18) in differentiating malignant from benign adnexal masses. CEA levels were higher in mucinous histological types, but were not helpful in detection of borderline tumors. Significantly higher CEA (21.4 +/- 53.6 vs. 3.2 +/- 11.9 ng/mL, p = 0.0002) and lower Ca125 values (103.9 +/- 84.9 vs. 796 +/- 1,331.5 U/mL, p = 0.0338) were demonstrated in the 17 metastatic cases compared with 181 primary ovarian malignancies. CONCLUSIONS: The combination of the tumor markers CEA and Ca125 did not contribute significantly to the detection of malignant adnexal masses compared with Ca125 alone. As our results suggest that higher CEA levels could be useful in differentiating metastatic tumors from primary ovarian malignancy and in diagnosis of mucinous histology, this issue should be investigated in large, well-designed, prospective cohort trials. PMID- 26109368 TI - Successful Radiofrequency Ablation for Recurrent Pulmonary Hepatoblastoma. PMID- 26109369 TI - Using Ecological Momentary Assessment to Study Tobacco Behavior in Urban India: There's an App for That. AB - BACKGROUND: Ecological momentary assessment (EMA) uses real-time data collection to assess participants' behaviors and environments. This paper explores the strengths and limitations of using EMA to examine social and environmental exposure to tobacco in urban India among older adolescents and adults. OBJECTIVE: Objectives of this study were (1) to describe the methods used in an EMA study of tobacco use in urban India using a mobile phone app for data collection, (2) to determine the feasibility of using EMA in the chosen setting by drawing on participant completion and compliance rates with the study protocol, and (3) to provide recommendations on implementing mobile phone EMA research in India and other low- and middle-income countries. METHODS: Via mobile phones and the Internet, this study used two EMA surveys: (1) a momentary survey, sent multiple times per day at random to participants, which asked about their real-time tobacco use (smoked and smokeless) and exposure to pro- and antitobacco messaging in their location, and 2) an end-of-day survey sent at the end of each study day. Trained participants, from Hyderabad and Kolkata, India, reported on their social and environmental exposure to tobacco over 10 consecutive days. This feasibility study examined participant compliance, exploring factors related to the successful completion of surveys and the validity of EMA data. RESULTS: The sample included 205 participants, the majority of whom were male (135/205, 65.9%). Almost half smoked less than daily (56/205, 27.3%) or daily (43/205, 21.0%), and 4.4% (9/205) used smokeless tobacco products. Participants completed and returned 46.87% and 73.02% of momentary and end-of-day surveys, respectively. Significant predictors of momentary survey completion included employment and completion of end-of-day surveys. End-of-day survey completion was only significantly predicted by momentary survey completion. CONCLUSIONS: This first study of EMA in India offers promising results, although more research is needed on how to increase compliance. End-of-day survey completion, which has a lower research burden, may be the more appropriate approach to understanding behaviors such as tobacco use within vulnerable populations in challenging locations. Compliance may also be improved by increasing the number of study visits, compliance checks, or opportunities for retraining participants before and during data collection. PMID- 26109370 TI - STD-NMR-Based Protein Engineering of the Unique Arylpropionate-Racemase AMDase G74C. AB - Structure-guided protein engineering achieved a variant of the unique racemase AMDase G74C, with 40-fold increased activity in the racemisation of several arylaliphatic carboxylic acids. Substrate binding during catalysis was investigated by saturation-transfer-difference NMR (STD-NMR) spectroscopy. All atoms of the substrate showed interactions with the enzyme. STD-NMR measurements revealed distinct nuclear Overhauser effects in experiments with and without molecular conversion. The spectroscopic analysis led to the identification of several amino acid residues whose substitutions increased the activity of G74C. Single amino acid exchanges increased the activity moderately; structure-guided saturation mutagenesis yielded a quadruple mutant with a 40 times higher reaction rate. This study presents STD-NMR as versatile tool for the analysis of enzyme substrate interactions in catalytically competent systems and for the guidance of protein engineering. PMID- 26109371 TI - VARK learning preferences and mobile anatomy software application use in pre clinical chiropractic students. AB - Ubiquitous smartphone ownership and reduced face-to-face teaching time may lead to students making greater use of mobile technologies in their learning. This is the first study to report on the prevalence of mobile gross anatomy software applications (apps) usage in pre-clinical chiropractic students and to ascertain if a relationship exists between preferred learning styles as determined by the validated VARK((c)) questionnaire and use of mobile anatomy apps. The majority of the students who completed the VARK questionnaire were multimodal learners with kinesthetic and visual preferences. Sixty-seven percent (73/109) of students owned one or more mobile anatomy apps which were used by 57 students. Most of these students owned one to five apps and spent less than 30 minutes per week using them. Six of the top eight mobile anatomy apps owned and recommended by the students were developed by 3D4Medical. Visual learning preferences were not associated with time spent using mobile anatomy apps (OR = 0.40, 95% CI 0.12 1.40). Similarly, kinesthetic learning preferences (OR = 1.88, 95% CI 0.18-20.2), quadmodal preferences (OR = 0.71, 95% CI 0.06-9.25), or gender (OR = 1.51, 95% CI 0.48-4.81) did not affect the time students' spent using mobile anatomy apps. Learning preferences do not appear to influence students' time spent using mobile anatomy apps. Anat Sci Educ 9: 247-254. (c) 2015 American Association of Anatomists. PMID- 26109372 TI - Comprehensive sampling of an isolated dune system demonstrates clear patterns in soil fungal communities across a successional gradient. AB - Coastal sand dunes are extremely dynamic ecosystems, characterized by stark ecological succession gradients. Dune stabilization is mainly attributed to plant growth, but the establishment and survival of dune-inhabiting vegetation is closely linked to soil microorganisms and to the ecological functions they fulfill. Fungi are particularly important in this context, as some interact intimately with plant roots, while others are critical to soil structure and nutrient availability. Our study aimed to describe wholly fungal diversity and community composition in a secluded coastal dune ecosystem at eight different stages of succession. We comprehensively sampled a relic foredune plain, which is part of an archipelago in the Gulf of Saint Lawrence (Quebec, Canada), by collecting soils from 80 sites and measuring soil characteristics. Soil fungal communities were characterized by pyrosequencing, followed by taxonomic classification and assignment of putative roles. Even though we did not observe clear patterns in diversity, we were able to detect distinct taxonomic and community composition signatures across succession stages, which seemed to translate into variations in fungal life strategies. Our results show that a taxonomically and functionally diverse fungal community exists at each dune succession stage, even in the barren foredunes. PMID- 26109373 TI - Exclusive olive oil consumption and 10-year (2004-2014) acute coronary syndrome incidence among cardiac patients: the GREECS observational study. AB - BACKGROUND: The present study evaluated the association between long-term, exclusive olive oil consumption, in cooking preparation or as a dressing, and the 10-year (2004-2014) incidence of acute coronary syndrome (ACS) among cardiac patients. METHODS: From October 2003 to September 2004, a sample of 2172 ACS consecutive patients from six major Greek hospitals were enrolled. During 2013 2014, the 10-year follow-up was performed in 1918 patients (88% participation rate). The development of fatal or nonfatal ACS was recorded through medical records or hospital registries. Among other dietary components, added fats (i.e. olive oil, butter, margarine and seed oils) consumption at baseline examination was assessed using a semi-quantitative food frequency questionnaire. RESULTS: Non exclusive olive oil consumption on a daily basis was associated with an adverse effect on the ACS incidence after taking into account various potential confounders [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.05-1.86, P = 0.024]. However, significant interactions between olive oil consumption and body mass index (BMI) (P = 0.082) and educational level (P = 0.054) led to further stratified analysis. Using BMI as strata (i.e. <=29.9 versus >29.9 kg m( 2)), the above association remained significant only in obese patients (OR = 1.80, 95% CI = 1.03-3.12, P = 0.038), whereas, on examining the education status (i.e. <=9 versus >9 years of school), a significant association was observed only among the higher educated patients (OR = 1.83, 95% CI = 1.01-3.32, P = 0.047). CONCLUSIONS: Exclusive use of olive oil, either as a salad dressing or in cooking, should be promoted through the dietary management of ACS patients, with the aim of reducing the likelihood of recurrent cardiac episodes. PMID- 26109374 TI - Sewage-sludge-derived carbonaceous materials for catalytic wet hydrogen peroxide oxidation of m-cresol in batch and continuous reactors. AB - In this study, four sewage-sludge-derived carbonaceous materials (SWs) were evaluated for their catalytic wet hydrogen peroxide oxidation (CWPO) performance of m-cresol in batch reactor and continuous reactor, respectively. The SWs were produced by carbonization (SW); carbonization with the addition of CaO (CaO-SW); HNO3 pretreatment (HNO3-SW) and steam activation (Activated-SW). The properties of SW catalysts were assessed by thermogravimetric analysis, Brunauer-Emmett Teller, Fourier Transform Infrared Spectroscopy, X-ray Fluorescence, Scanning electron microscopy, energy dispersive X-ray analysis and zeta potential. The results showed that SW treated by HNO3 (HNO3-SW) had a high conversion of m cresol in batch reactor and continuous reactor, respectively. Under the conditions of batch reaction (Cm-cresol = 100 mg L(-1), CH2O2 = 15.7 mmol L(-1), initial pH=7.0, 0.5 g L(-1) catalyst, 80 degrees C, 180 min adsorption and 210 min oxidation), the conversion of m-cresol reached 100% and total organic carbon removal was 67.1%. It had a high catalytic activity and stability on the treatment of m-cresol in CWPO for more than 1100 h. Furthermore, a possible reaction mechanism for the oxidation of m-cresol to 2-methyl-p-benzoquinone by CWPO was proposed. PMID- 26109375 TI - Modeling Electronic Polarizability Changes in the Course of a Magnesium Ion Water Ligand Exchange Process. AB - This paper introduces explicit dependence of atomic polarizabilities on intermolecular interactions within the framework of a polarizable force field AMOEBA. Polarizable models used in biomolecular simulations often poorly describe molecular electrostatic induction in condensed phase, in part, due to neglect of a strong dependency of molecular electronic polarizability on intermolecular interactions at short distances. Our variable polarizability model parameters are derived from quantum chemical calculations of small clusters of atoms and molecules, and can be applied in simulations in condensed phase without additional scaling factors. The variable polarizability model is applied to simulate a ligand exchange reaction for a Mg(2+) ion solvated in water. Explicit dependence of water polarizability on a distance between a water oxygen and Mg(2+) is derived from in vacuum MP2 calculations of Mg(2+)-water dimer. The simulations yield a consistent description of the energetics of the Mg(2+)-water clusters of different size. Simulations also reproduce thermodynamics of ion solvation as well as kinetics of a water ligand exchange reaction. In contrast, simulations that used the additive force field or that used the constant polarizability models were not able to consistently and quantitatively describe the properties of the solvated Mg(2+) ion. PMID- 26109376 TI - Emergent Awake tracheostomy--The five-year experience at an urban tertiary care center. AB - OBJECTIVES/HYPOTHESIS: There are few studies that discuss the issues surrounding emergent awake tracheostomy. We aim to review the indications, anesthesia used, complications, and outcomes of patients undergoing urgent awake tracheostomy. STUDY DESIGN: Chart review. METHODS: Medical charts of patients who underwent an emergent awake tracheostomy at our institution-affiliated tertiary care center over a 5-year period from 2009 to 2014 were reviewed. Data were collected from inpatient, outpatient, and operative records. RESULTS: Sixty-eight patients underwent emergent awake tracheostomy. Over half presented with hoarseness (n=37, 54.4%) and/or stridor (n=37, 54.4%). Acute upper airway obstruction secondary to malignancy was the most common indication and accounted for 58 cases (85.3%). Thirty-nine (70.1%) of the 55 patients with squamous cell carcinoma presented with advanced disease (stage III or IV). Other indications included glottic or subglottic stenosis (4.4%), failure to intubate (2.9%), and other (7.4%). Local anesthesia was used alone in 35.3% of cases and in combination with conscious sedation in 64.7% of cases. Mild bleeding occurred postoperatively in five patients (7.4%). There were no other postoperative complications. Nineteen patients were lost to follow-up. The mean follow-up of 49 patients was 7.2 weeks, ranging from 2 to 261 weeks. Long-term complications occurred in three patients and included tracheitis 7.4% and suprastomal granuloma 2.9%. Eleven patients (22%) were decannulated at a mean of 11.8 months following tracheostomy. CONCLUSIONS: Emergent awake tracheostomy should be considered in patients with impeding airway obstruction and is a safe and effective method to secure an airway in these patients. LEVEL OF EVIDENCE: 4. PMID- 26109377 TI - Layered approach with autogenous bone and bone substitute for ridge augmentation on implant dehiscence defects in dogs. AB - OBJECTIVES: This study compared the efficacies of different layered approaches using autogenous bone and synthetic bone substitute for ridge augmentation on implant dehiscence defects in dogs. MATERIALS AND METHODS: Right mandibular second, third, and fourth premolars and the first molar were extracted, followed by standardized one-wall defect preparation in five dogs. After a healing period of 12 weeks, three implants (Implantium((r)) ) were installed. Each of the three implant dehiscence defects was grafted with a different material as follows: (i) synthetic bone substitute combined with collagen (SBC; SBC group), (ii) inner autogenous bone layer and outer SBC layer (IAB group), and (iii) inner SBC layer and outer autogenous bone layer (OAB group). The grafted sites were covered with a resorbable collagen membrane. Quantitative and qualitative analyses of the subsequent bone regeneration were performed at 12 weeks postoperatively. RESULTS: The dome-like augmented shape was relatively well maintained in the IAB and OAB groups, while the graft particles in the SBC group were dispersed. The bone-to implant contact values tended to be significantly higher in the OAB group (49.51%) than in the SBC (36.58%) group. The amounts of newly formed bone within an area designated as 1 * 3 mm (width * height) from the implant platform in the IAB, OAB, and SBC groups were 35.59%, 28.10%, and 16.71%, respectively. CONCLUSION: Application of the layered approach using autogenous bone and synthetic biomaterial resulted in substantial new bone formation and volume maintenance on implant dehiscence defects, irrespective of the position of the autogenous bone layer. PMID- 26109378 TI - Macrolides do not affect the incidence of moderate and severe bronchopulmonary dysplasia in symptomatic ureaplasma-positive infants. AB - AIM: The aim of this study was to compare the incidence of bronchopulmonary dysplasia (BPD) in symptomatic ureaplasma-positive treated preterm infants and asymptomatic preterm infants not tested or treated for ureaplasma. METHODS: A retrospective matched cohort study was conducted in a tertiary, neonatal unit between January 2007 and December 2012. Infants <=29 completed weeks with signs and symptoms suggesting ureaplasma pneumonia who received macrolides comprised the study group. Infants <=29 weeks without signs and symptoms not tested or treated with macrolides were the controls. Infants were mandatorily matched for gestational age +/- one week or birthweight +/- 100 grams. RESULTS: There were 31 infants in the study group and 62 in the control group. The baseline demographic data of both groups were similar on the whole. The incidence of moderate and severe BPD, defined by oxygen dependency or the need for continuous positive airway pressure at 36 weeks of postconceptual age, was 45.2% in the study group and 40.3% in the controls (p = 0.65). There was no significant difference in morbidities or mortality between the groups. CONCLUSION: A selective approach of treating symptomatic ureaplasma-positive preterm infants with macrolides did not affect the incidence of moderate and severe BPD. PMID- 26109380 TI - Risk of pancreatic fistula after enucleation of pancreatic tumours. AB - BACKGROUND: Enucleation is used increasingly for small pancreatic tumours. Data on perioperative outcome after pancreatic enucleation, especially regarding the significance and risk factors associated with postoperative pancreatic fistula (POPF), are limited. This study aimed to assess risk-dependent perioperative outcome after pancreatic enucleation, with a focus on POPF. METHODS: Patients undergoing enucleation for pancreatic lesions between October 2001 and February 2014 were identified from a prospective database. A detailed analysis of morbidity was performed. Risk factors for POPF were assessed by univariable and multivariable analyses. RESULTS: Of 166 enucleations, 94 (56.6 per cent) were performed for cystic and 72 (43.4 per cent) for solid lesions. Morbidity was observed in 91 patients (54.8 per cent). Severe complications occurred in 30 patients (18.1 per cent), and one patient (0.6 per cent) died. Reoperation was necessary in nine patients (5.4 per cent). POPF was the main determinant of outcome and occurred in 68 patients (41.0 per cent): grade A POPF, 34 (20.5 per cent); grade B, ten (6.0 per cent); and grade C, 24 (14.5 per cent). Risk factors independently associated with POPF were: cystic tumour, localization in the pancreatic tail, history of pancreatitis and cardiac co-morbidity. Only cystic morphology was independently associated with clinically relevant POPF (grade B or C), occurring after enucleation in 25 (27 per cent) of 94 patients with cystic tumours versus nine (13 per cent) of 72 patients with solid tumours. Tumour size and distance to the main duct were not associated with risk of POPF. CONCLUSION: Enucleation is a safe procedure in appropriately selected patients with a low rate of severe complications. POPF is the main determinant of outcome and is more frequent after the enucleation of cystic lesions. PMID- 26109381 TI - Adverse events in nursing: A retrospective study of reports of patient and relative experiences. AB - BACKGROUND: Patient safety is an important global issue. While it is well known that patients can suffer from adverse events in nursing care, there is a lack of knowledge as to how they experience them. AIM: To examine adverse events in nursing care as they are experienced by patients and relatives. METHODS: This was a retrospective study taking both a qualitative and a quantitative approach. It was based on data regarding 242 adverse events in nursing care, as reported by patients and relatives to Sweden's Medical Responsibility Board, content analysis was used to analyse the reports. RESULTS: Patients' and relatives' experiences were analysed into four categories of adverse events, as concerning participation, clinical judgement, nursing intervention and the essentials of care. LIMITATIONS: The reports were classified by the Medical Responsibility Board, without a standardized system. The adverse events reported were few in number and were reported by patients and relatives only. CONCLUSION: Lack of participation has negative consequences and contributes to adverse events. Adverse events occur through missed care as well as through carer errors. IMPLICATIONS ON NURSING AND HEALTH PRACTICE: Nurses need to improve their skills that support patient participation. Patient participation needs to be incorporated into nurses' duties. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Resources for patients to participate in their own care needs to be a priority underpinning policy-making in health systems. Nursing education systems need to teach students about the value and benefits of involving patients in their care. PMID- 26109379 TI - Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. AB - T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. Chemokines are credited with guiding the multistep recruitment of CD8(+) T cells across tumour vessels. However, the multiplicity of chemokines within tumours has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signalling at effector sites. Here we investigate the hierarchy of chemokine receptor requirements during T-cell trafficking to murine and human melanoma. These studies reveal a non-redundant role for Galphai-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8(+) effectors that is indispensable for therapeutic efficacy. In contrast, functional CCR2 and CCR5 on CD8(+) effectors fail to support trafficking despite the presence of intratumoral cognate chemokines. Taken together, these studies identify CXCR3-mediated trafficking at the tumour vascular interface as a critical checkpoint to effective T-cell-based cancer immunotherapy. PMID- 26109382 TI - A consistent course of events or a series of coincidences: nursing in Poland from the 19(th) to the 21(st) century. AB - The development of nursing began in Poland much later than it did elsewhere, for instance in the United Kingdom, the United States, or Germany, and it came up against difficult conditions. After a brief twenty-year period of development between 1918 and 1939, it almost stalled during the war (1939-45), only to be followed by nearly twenty years of chaos. Nursing started to come out of this difficult period at the beginning of the 1960s. The turn of the 21st century saw the emergence of extensive professional development and training opportunities for nurses. This change was brought about as much by political, social and economic issues, health care requirements, and the advancement of science, medicine, the birth of humanitarism, the growth of the feminist movement, the European Agreement on the Instruction and Education of Nurses, the WHO European Strategy for Nursing and Midwifery Education, the Bologna declaration, as well as the activities undertaken by the European Union, the International Council of Nurses, the American and Polish Red Cross, the Rockefeller Foundation, the Polish Association of Nurses, and the professional self-governing body. The transformation of nursing into an independent profession was further boosted by physicians deeply involved in the issue and female pioneers of nursing. PMID- 26109383 TI - Using non-invasive bi-level positive airway pressure ventilator via tracheostomy in children with congenital central hypoventilation syndrome: two case reports. AB - INTRODUCTION: Due to the economic downturn in Thailand, two baby girls with congenital central hypoventilation syndrome had to wait for several months to obtain definite diagnosis and long-term mechanical ventilation. Genetic investigation later revealed 20/25 polyalanine expansion of PHOX2B gene in both girls. In this report we highlight the use of non-invasive bi-level positive airway pressure ventilators via tracheostomy, overnight end-tidal carbon dioxide trend graphs and outcomes of the patients whose diagnosis and treatment were delayed. CASE PRESENTATION: Case 1: A Thai baby girl showed symptoms of apnea and cyanosis from birth and required invasive mechanical ventilation via tracheostomy during sleep. At 5 months, she unfortunately was discharged from the hospital without any ventilatory support due to financial problems. She subsequently developed cor pulmonale, respiratory failure and generalized edema and was referred to us when she was 9-months old. An overnight polysomnogram was consistent with a central hypoventilation disorder, in which the severity of oxygen desaturation and hypercapnia was worsening during non-rapid eye movement compared to rapid eye movement sleep. At 12 months she was allowed to go home with a conventional home ventilator. The ventilator was changed to bi-level positive airway pressure when she was 4-years old. After she received adequate home ventilation, she thrived with normal growth and development. Case 2: A Thai baby girl developed apnea and cyanosis from the age of 5 weeks, requiring ventilatory support (on and off) for 5 months. After being extubated, she had been put on supplemental oxygen via nasal cannula for 2 months. She was then referred to us when she was 7-months old. An overnight end-tidal carbon dioxide trend graph revealed marked hypercapnia without increase in respiratory rate. An overnight polysomnogram was consistent with a central hypoventilation disorder. Since 9 months of age she has been on home bi-level positive airway pressure via tracheostomy without any complications. Genetic testing confirmed 20/25 polyalanine expansions of PHOX2B gene in both girls. CONCLUSIONS: Bi-level positive airway pressure, originally designed as a non-invasive ventilator, was found to work effectively and safely, and may be used as an invasive ventilator via tracheostomy in young children with congenital central hypoventilation syndrome. PMID- 26109386 TI - Developing Peripheral Blood Gene Expression-Based Diagnostic Tests for Coronary Artery Disease: a Review. AB - The past 20 years has witnessed the development of technologies designed to measure changes in the expressed human genome, including the levels of RNA transcripts, proteins, and metabolites. Gene expression profiling, or the measurement of RNA transcripts, allows investigators to obtain a snapshot of a subject's current physiological state and may be used to assess disease likelihood. In this review, we provide an overview of recent work using peripheral blood gene expression to assess coronary artery disease (CAD) and discuss the best approaches for developing and validating tests utilizing such gene expression signatures. PMID- 26109384 TI - 'A bite before bed': exposure to malaria vectors outside the times of net use in the highlands of western Kenya. AB - BACKGROUND: The human population in the highlands of Nyanza Province, western Kenya, is subject to sporadic epidemics of Plasmodium falciparum. Indoor residual spraying (IRS) and long-lasting insecticide treated nets (LLINs) are used widely in this area. These interventions are most effective when Anopheles rest and feed indoors and when biting occurs at times when individuals use LLINs. It is therefore important to test the current assumption of vector feeding preferences, and late night feeding times, in order to estimate the extent to which LLINs protect the inhabitants from vector bites. METHODS: Mosquito collections were made for six consecutive nights each month between June 2011 and May 2012. CDC light-traps were set next to occupied LLINs inside and outside randomly selected houses and emptied hourly. The net usage of residents, their hours of house entry and exit and times of sleeping were recorded and the individual hourly exposure to vectors indoors and outdoors was calculated. Using these data, the true protective efficacy of nets (P*), for this population was estimated, and compared between genders, age groups and from month to month. RESULTS: Primary vector species (Anopheles funestus s.l. and Anopheles arabiensis) were more likely to feed indoors but the secondary vector Anopheles coustani demonstrated exophagic behaviour (p < 0.05). A rise in vector biting activity was recorded at 19:30 outdoors and 18:30 indoors. Individuals using LLINs experienced a moderate reduction in their overall exposure to malaria vectors from 1.3 to 0.47 bites per night. The P* for the population over the study period was calculated as 51% and varied significantly with age and season (p < 0.01). CONCLUSIONS: In the present study, LLINs offered the local population partial protection against malaria vector bites. It is likely that P* would be estimated to be greater if the overall suppression of the local vector population due to widespread community net use could be taken into account. However, the overlap of early biting habit of vectors and human activity in this region indicates that additional methods of vector control are required to limit transmission. Regular surveillance of both vector behaviour and domestic human-behaviour patterns would assist the planning of future control interventions in this region. PMID- 26109387 TI - Repetitive nerve stimulation and single-fiber electromyography in the evaluation of patients with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: Review of recent literature. AB - INTRODUCTION: Our aim in this study was to provide an updated literature review of electrodiagnostic testing in myasthenia gravis and Lambert-Eaton myasthenic syndrome. METHODS: A systematic review of the recent literature was performed using the following key words: myasthenia gravis (MG); Lambert-Eaton myasthenic syndrome (LEMS); electromyography (EMG); repetitive nerve stimulation (RNS); single-fiber electromyography (SFEMG); nerve conduction study; and normative values. RESULTS: Several articles supported testing of facial, bulbar, and respiratory muscles in the diagnosis of neuromuscular junction (NMJ) disorders, including muscle-specific kinase antibody (MuSK)-seropositive MG. Several articles supported use of concentric needle EMG as an alternative to SFEMG jitter in disorders of neuromuscular transmission. A limited number of articles addressed measurement of area (vs. amplitude) decrement in RNS and decreasing the threshold of post-exercise facilitation. CONCLUSIONS: Electrodiagnostic testing continues to be useful for diagnosis of MG and LEMS, although the quality of the evidence is not great. This literature review summarizes RNS and jitter measurement of facial and respiratory muscles and use of concentric needle EMG for SFEMG. PMID- 26109388 TI - Identification and functional characterization of a novel arginine/ornithine transporter, a member of a cationic amino acid transporter subfamily in the Trypanosoma cruzi genome. AB - BACKGROUND: Trypanosoma cruzi, the etiological agent of Chagas disease, is auxotrophic for arginine. It obtains this amino acid from the host through transporters expressed on the plasma membrane and on the membranes of intracellular compartments. A few cationic amino acid transporters have been characterized at the molecular level, such as the novel intracellular arginine/ornithine transporter, TcCAT1.1, a member of the TcCAT subfamily that is composed of four almost identical open reading frames in the T. cruzi genome. METHODS: The functional characterization of the TcCAT1.1 isoform was performed in two heterologous expression systems. TcCAT subfamily expression was evaluated by real-time PCR in polysomal RNA fractions, and the cellular localization of TcCAT1.1 fused to EGFP was performed by confocal and immunoelectron microscopy. RESULTS: In the S. cerevisiae expression system, TcCAT1.1 showed high affinity for arginine (K m = 0.085 +/- 0.04 mM) and low affinity for ornithine (K m = 1.7 +/- 0.2 mM). Xenopus laevis oocytes expressing TcCAT1.1 showed a 7-fold increase in arginine uptake when they were pre-loaded with arginine, indicating that transport is enhanced by substrates on the trans side of the membrane (trans stimulation). Oocytes that were pre-loaded with [(3)H]-arginine displayed a 16 fold higher efflux of [(3)H]-arginine compared with that of the control. Analysis of polysomal RNA fractions demonstrated that the expression of members of the arginine transporter TcCAT subfamily is upregulated under nutritional stress and that this upregulation precedes metacyclogenesis. To investigate the cellular localization of the transporter, EGFP was fused to TcCAT1.1, and fluorescence microscopy and immunocytochemistry revealed the intracellular labeling of vesicles in the anterior region, in a network of tubules and vesicles. CONCLUSIONS: TcCAT1.1 is a novel arginine/ornithine transporter, an exchanger expressed in intracellular compartments that is physiologically involved in arginine homeostasis throughout the T. cruzi life cycle. The properties and estimated kinetic parameters of TcCAT1.1 can be extended to other members of the TcCAT subfamily. PMID- 26109389 TI - The relationship between microvascular complications and vitamin D deficiency in type 2 diabetes mellitus. AB - BACKGROUND: Vitamin D deficiency is reported as a possible risk factor for the development of diabetes in several epidemiologic studies. In this study, we investigated the frequency of 25-OH vitamin D deficiency in type 2 diabetes mellitus and the relationship between 25-OH vitamin D deficiency and the prevalence of microvascular complications. METHODS: In this retrospective study, we evaluated the medical records of 557 patients with type 2 diabetes admitted to the Endocrinology Outpatient Clinic from January to March 2010 and 112 healthy controls randomly selected from individuals admitted to the hospital for a check up and who had a laboratory result for serum 25-OH vitamin D concentrations at screening. The levels of 25-OH vitamin D in patients with type 2 diabetes and the relationship between 25-OH vitamin D deficiency and microvascular complications were investigated. RESULTS: No significant difference in serum 25-OH vitamin D concentrations was observed between the diabetic and control groups. No correlation was observed between HbA1C and serum 25-OH vitamin D levels. Serum 25 OH vitamin D levels were lower in diabetic patients with nephropathy, and patients not using any medication, i.e., those treated with dietary changes alone, had a higher prevalence of nephropathy. CONCLUSION: Vitamin D deficiency is more common in diabetic patients with nephropathy. When microvascular complications were evaluated, vitamin D levels were found to be lower in patients in whom these complications were more severe. Vitamin D deficiency is therefore associated with microvascular complications in diabetic patients. PMID- 26109390 TI - Offering within-category food swaps to reduce energy density of food purchases: a study using an experimental online supermarket. AB - BACKGROUND: Swaps are often used to encourage healthier food choices, but there is little evidence of their effectiveness. The current study assessed the impact of offering swaps on groceries purchased within a bespoke online supermarket; specifically the objective was to measure the impact on energy density (ED) of food purchases following the offer of lower ED alternatives (a) at point of selection or at checkout, and (b) with or without explicit consent to receive swap prompts. METHOD: Participants were asked to complete a 12-item shopping task within an online shopping platform, developed for studying food purchasing. 1610 adults were randomly assigned to a no swap control condition or to one of four interventions: consented swaps at selection; consented swaps at checkout; imposed swaps at selection; or imposed swaps at checkout. Each swap presented two lower ED options from the same category as the participant's chosen food. Swap acceptance rate and purchased food ED were the primary outcomes. RESULTS: Of the mean 12.36 (SD 1.26) foods purchased, intervention participants were offered a mean of 4.1 (SD 1.68) swaps, with the potential to reduce the ED of purchased food (effect (95% CI): -83 kJ/100 g (-110 - -56), p = <0.0001). A median of one swap (IQR 0 to 2) was accepted, not significantly reducing the purchased food ED (effect (95% CI): -24 kJ/100 g (4 - -52), p = 0.094). More swaps were accepted when offered at selection than at checkout (OR (95% CI) = 1.224 (1.11 - 1.35), p < 0.0001), but no differences were seen with consent. Purchased food ED was unaffected by point of swap or consent, but reduced with number of swaps accepted (effect per swap (95% CI) = -24 kJ/100 g (-35 - -14), p < 0.0001). CONCLUSION: Within category swaps did not reduce the ED of food purchases reflecting the observation that the use of swaps within an on-line shopping platform offered small potential gains in ED and a minority was accepted. PMID- 26109391 TI - Allelic variation at the rpv1 locus controls partial resistance to Plum pox virus infection in Arabidopsis thaliana. AB - BACKGROUND: Sharka is caused by Plum pox virus (PPV) in stone fruit trees. In orchards, the virus is transmitted by aphids and by grafting. In Arabidopsis, PPV is transferred by mechanical inoculation, by biolistics and by agroinoculation with infectious cDNA clones. Partial resistance to PPV has been observed in the Cvi-1 and Col-0 Arabidopsis accessions and is characterized by a tendency to escape systemic infection. Indeed, only one third of the plants are infected following inoculation, in comparison with the susceptible Ler accession. RESULTS: Genetic analysis showed this partial resistance to be monogenic or digenic depending on the allelic configuration and recessive. It is detected when inoculating mechanically but is overcome when using biolistic or agroinoculation. A genome-wide association analysis was performed using multiparental lines and 147 Arabidopsis accessions. It identified a major genomic region, rpv1. Fine mapping led to the positioning of rpv1 to a 200 kb interval on the long arm of chromosome 1. A candidate gene approach identified the chloroplast phosphoglycerate kinase (cPGK2) as a potential gene underlying the resistance. A virus-induced gene silencing strategy was used to knock-down cPGK2 expression, resulting in drastically reduced PPV accumulation. CONCLUSION: These results indicate that rpv1 resistance to PPV carried by the Cvi-1 and Col-0 accessions is linked to allelic variations at the Arabidopsis cPGK2 locus, leading to incomplete, compatible interaction with the virus. PMID- 26109392 TI - Investigating rehabilitation needs of visually impaired young adults according to the International Classification of Functioning, Disability and Health. AB - PURPOSE: To gain qualitative insight into the rehabilitation needs of visually impaired young adults (18-25 years) and how these needs relate to the International Classification of Functioning, Disability and Health (ICF) and patient characteristics. METHODS: Rehabilitation needs and patient characteristics of young adults (N = 392) who applied for multidisciplinary services in 2012 and 2013 were obtained from structured and semi-structured intake records. Linking rules were used to assess how the needs related to Environmental Factors, Body Functions, Body Structures, and Activity and Participation (A&P) ICF components. The relationship between the type of rehabilitation goal and patient characteristics was assessed using multivariate logistic regression analyses. RESULTS: Most rehabilitation needs (67.6%; N = 510) were found on the A&P component of the ICF. Most prevalent needs were related to 'major life areas' (e.g. finding internship or job), followed by the chapters: 'mobility' (e.g. self-reliance in travelling), 'communication' (e.g. using communication devices and techniques), 'general tasks and demands' (e.g. psychological aspects of vision loss) and 'domestic life' (e.g. household tasks). Patients in one of the multidisciplinary rehabilitation centres (odds ratio (OR) = 7.07; 95% confidence interval (CI) [2.97-16.83]) and patients with comorbidity (OR = 3.82; 95% CI [1.62-9.02]) were more likely to report rehabilitation needs related to chapter E3 'support and relationships'. CONCLUSION: 'Major life areas' prevail in the content of rehabilitation needs, but tend to overshadow topics regarding peer interaction and social, community and civic life. A suitable survey method for young adults with visual impairments is required that contains rehabilitation domains and goals relevant to their lives and development. PMID- 26109394 TI - BMA annual meeting: BMA condemns detention of children in police cells overnight. PMID- 26109393 TI - High mobility group box 1 gene polymorphism is associated with the risk of postoperative atrial fibrillation after coronary artery bypass surgery. AB - BACKGROUND: The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary cause of postoperative atrial fibrillation (POAF). The objective of this study was to determine the relationships between rs2249825 (C/G) polymorphism in high-mobility group box protein 1 (HMGB1) and POAF in patients who underwent coronary artery bypass grafting (CABG) under CPB. METHODS: A prospective cohort study was carried out between February 2011 and January 2014. Patients who had no history of atrial fibrillation undergoing CABG with CPB were recruited in this study, and were matched based on preoperative characteristics. Blood samples were obtained before, and at 4, and 24 h after CPB. HMGB1 level was measured by enzyme immunoassay. Patients were genotyped for single nucleotide polymorphisms of HMGB1 (rs2249825). Patients were genotyped for single nucleotide polymorphisms of HMGB1 (rs2249825) using pyrosequencing method. The primary clinical end point was the incidence of POAF after surgery. RESULTS: After matching, a total of 128 patients undergoing elective CABG with CPB were eligible for analysis. Plasma HMGB1 concentrations were increased 4 h after CPB (p <0.0001) and were still increased at 24 h (p <0.0001). The frequencies of CC, CG, GG genotypes were 21 (56.8 %), 29 (37.8 %), and 2 (5.4 %) in patients with POAF and 81.3, 16.5, and 2.2 % in patients without POAF (p = 0.016). CG + GG genotype was associated with high HMGB1 levels compared with the genotype CC at 4 h (p = 0.023), and 24 h (p = 0.015) after CPB. Multivariate analysis showed that age older than 60 years (OR = 1.40; 95 % CI: 1.03 to 1.89; p = 0.021) and allele G of polymorphisms (OR = 1.61; 95 % CI: 1.08 to 2.04; p = 0.034) were independent risk factors for POAF. CONCLUSIONS: The HMGB1 rs2249825 was associated with the susceptibility to POAF after CABG with CPB in a Chinese Han population. PMID- 26109395 TI - Sense About Science charity joins fight against bid to prevent transparency of trials. PMID- 26109396 TI - The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). AB - INTRODUCTION: Despite evidence demonstrating the value of performance initiatives, marked differences remain between hospitals in the delivery of care for patients with sepsis. The aims of this study were to improve our understanding of how compliance with the 3-h and 6-h Surviving Sepsis Campaign (SSC) bundles are used in different geographic areas, and how this relates to outcome. METHODS: This was a global, prospective, observational, quality improvement study of compliance with the SSC bundles in patients with either severe sepsis or septic shock. RESULTS: A total of 1794 patients from 62 countries were enrolled in the study with either severe sepsis or septic shock. Overall compliance with all the 3-h bundle metrics was 19%. This was associated with lower hospital mortality than non-compliance (20 vs. 31%, p < 0.001). Overall compliance with all the 6-h bundle metrics was 36%. This was associated with lower hospital mortality than non-compliance (22 vs. 32%, p < 0.001). After adjusting the crude mortality differences for ICU admission, sepsis status (severe sepsis or septic shock), location of diagnosis, APACHE II score and country, compliance remained independently associated with improvements in hospital mortality for both the 3-h bundle (OR = 0.64 (95% CI 0.47-0.87), p = 0.004)) and 6-h bundle (OR = 0.71 (95% CI 0.56-0.90), p = 0.005)). DISCUSSION: Compliance with all of the evidence-based bundle metrics was not high. Patients whose care included compliance with all of these metrics had a 40% reduction in the odds of dying in hospital with the 3-h bundle and 36% for the 6-h bundle. PMID- 26109397 TI - Early goal-directed therapy versus "early", "goal-directed" therapy. PMID- 26109398 TI - Physical activity, muscle strength, and exercise capacity 3 months after severe sepsis and septic shock. AB - PURPOSE: To quantify the physical activity in daily life (PADL), muscle strength, and exercise capacity in the short and medium term in survivors of severe sepsis and septic shock. METHODS: Prospective cohort study with a follow-up from hospital admission to 3 months after hospital discharge. Seventy-two patients admitted to the ICU for severe sepsis or septic shock and a control group of healthy sedentary subjects (n = 50) were enrolled. All patients had their PADL quantified by an accelerometer during their hospital stay and 3 months after. Exercise capacity and handgrip and quadriceps muscle strength were also evaluated. RESULTS: During hospitalization, patients spent the majority of their time inactive in a lying or sitting position (90 +/- 34% of daily time). Physical inactivity was partially reduced 3 months after (58 +/- 20% of daily time). However, the time patients spent walking was only 63% of the time reported for healthy subjects. Patients also showed lower movement intensity when compared with controls (2.1 +/- 0.3 vs 2.5 +/- 0.4 m/s(2)). At hospital discharge, muscle strength and exercise capacity were approximately 54% of the predicted value, and these parameters showed significant increase in patients 3 months after (70% of predicted value). Multivariable analysis demonstrated that the use of systemic corticosteroids and hospitalization time negatively influenced quadriceps strength and exercise capacity at the time of hospital discharge. CONCLUSION: Our results suggest that survivors of sepsis admitted to the ICU have a substantial reduction in physical activity, exercise capacity, and muscle strength compared to healthy subjects that persist even 3 months after hospital discharge. PMID- 26109399 TI - Management of necrotizing soft tissue infections in the intensive care unit: results of an international survey. PMID- 26109400 TI - Extracorporeal carbon dioxide removal in patients with chronic obstructive pulmonary disease: a systematic review. AB - INTRODUCTION: Extracorporeal carbon dioxide removal (ECCO2R) has been proposed for hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD) exacerbations, to avoid intubation or reduce length of invasive ventilation. Balance of risks, efficacy, and benefits of ECCO2R in patients with COPD is unclear. METHODS: We systematically searched MEDLINE and EMBASE to identify all publications reporting use of ECCO2R in COPD. We looked at physiological and clinical efficacy. A favorable outcome was defined as prevention of intubation or successful extubation. Major and minor complications were compiled. RESULTS: We identified 3123 citations. Ten studies (87 patients), primarily case series, met inclusion criteria. ECCO2R prevented intubation in 65/70 (93%) patients and assisted in the successful extubation of 9/17 (53%) mechanically ventilated subjects. One case-control study matching to noninvasively ventilated controls reported lower intubation rates and hospital mortality with ECCO2R that trended toward significance. Physiological data comparing pre- to post-ECCO2R changes suggest improvements for pH (0.07-0.15 higher), PaCO2 (25 mmHg lower), and respiratory rate (7 breaths/min lower), but not PaO2/FiO2. Studies reported 11 major (eight bleeds requiring blood transfusion of 2 units, and three line-related complications, including one death related to retroperitoneal bleeding) and 30 minor complications (13 bleeds, five related to anticoagulation, and nine clotting-related device malfunctions resulting in two emergent intubations). CONCLUSION: The technique is still experimental and no randomized trial is available. Recognizing selection bias associated with case series, there still appears to be potential for benefit of ECCO2R in patients with COPD exacerbations. However, it is associated with frequent and potentially severe complications. Higher-quality studies are required to better elucidate this risk-benefit balance. PMID- 26109401 TI - Comments on Kagan et al.: Preemptive enteral nutrition enriched with eicosapentaenoic acid, gamma-linolenic acid and antioxidants in severe multiple trauma: a prospective, randomized, double-blind study. PMID- 26109402 TI - Early goal-directed therapy versus "early", "goal-directed" therapy: response to comments by Saleh. PMID- 26109403 TI - Cutaneous toxicities associated with vemurafenib therapy in 107 patients with BRAF V600E mutation-positive metastatic melanoma, including recognition and management of rare presentations. AB - BACKGROUND: Vemurafenib significantly improved overall survival compared with dacarbazine in patients with metastatic or unresectable BRAF V600E-positive melanoma in the BRIM-3 trial. However, vemurafenib was associated with a number of skin-related adverse events (AEs). OBJECTIVES: To investigate the incidence and management of vemurafenib-associated skin AEs. METHODS: This retrospective, observational study included adult patients with stage IIIC or IV melanoma who received vemurafenib between March 2010 and August 2013. Patients received oral vemurafenib 960 mg twice daily, with dose interruptions and reductions allowed for AE management. RESULTS: In total 107 patients were treated with vemurafenib during the study period. The most frequent clinically important skin-related AEs were rash (64%), squamoproliferative growths (41%), photosensitivity (40%) and squamous cell carcinoma (SCC) or keratoacanthoma (KA; 20%). Rare cases of granulomatous dermatitis and cutaneous T-cell lymphoma were also found. Rash was manageable with corticosteroids and dose modifications; squamoproliferative growths and SCCs/KAs were treated with cryotherapy and surgical excision, respectively. Patients were counselled regarding phototoxicity. The uncontrolled nature and retrospective design of the study, and the small patient numbers are limitations. CONCLUSIONS: Vemurafenib appears to have a predictable and manageable AE profile. Proactive management can limit the impact of AEs on patients, allowing treatment to continue despite toxicities. PMID- 26109404 TI - Squamous cell carcinoma arising on plantar verrucous lesion. PMID- 26109406 TI - Model building with wind and water: Friedrich Ahlborn's photo-optical flow analysis. AB - Around 1900, several experimenters investigated turbulences in wind tunnels or water basins by creating visualizations. One of them, the German zoologist Friedrich Ahlborn (1858-1937), was familiar with the works by his contemporaries but he struck a new path. He combined three different kinds of photographs taken at the same time and showed the same situation in his water trough-but each in a different way. With this first basic operation, Ahlborn heuristically opened up a previously non-existent space for experimentation, analysis, and recombination. He generated an astonishing diversity of information by adopting the tactics of 'inversions' in which he interpreted one part of the experimental setup, or its results, in different ways. Between the variants of the 'autographs' which he developed, he defined areas of intersection to be able to translate results from individual records into each other. To this end, Ahlborn created other sets of visual artifacts such as drawn diagrams, three-dimensional wire frame constructions, and clay reliefs. His working method can be described as a cascading array of successive modeling steps, as elaborated by Eric Winsberg (1999), or of inscriptions in Bruno Latour's words (Latour, 1986). By examining Ahlborn's procedures closely we propose conceptualizations for the experimenter's various operations. PMID- 26109407 TI - The irreducibility of value-freedom to theory assessment. AB - The current ideal of value-freedom holds non-cognitive values to be illegitimate in theory appraisal but legitimate in earlier stages of the research process, for example, when affecting the selection of topics or the generation of hypotheses. Respective decisions are often considered as part of a context of discovery and as irrelevant for the justification and assessment of theories. I will argue that this premise of an epistemic independence of theory appraisal, though often taken for granted, is false. Due to the possibility of value-laden blind spots, decisions in discovery can have an indirect impact on theory assessment that the value-free ideal cannot deal with. This argument is illustrated by a case study from women's health research, namely the assessment of hormone replacement therapy as a prevention of coronary heart diseases. In consequence, the epistemic trustworthiness of science is promoted more by a pluralism of non-cognitive values than by their exclusion; and a normative philosophy of science needs to enlarge its focus to include the context of discovery as well as the social conditions of science. PMID- 26109405 TI - iRhom1 regulates proteasome activity via PAC1/2 under ER stress. AB - Proteasome is a protein degradation complex that plays a major role in maintaining cellular homeostasis. Despite extensive efforts to identify protein substrates that are degraded through ubiquitination, the regulation of proteasome activity itself under diverse signals is poorly understood. In this study, we have isolated iRhom1 as a stimulator of proteasome activity from genome-wide functional screening using cDNA expression and an unstable GFP-degron. Downregulation of iRhom1 reduced enzymatic activity of proteasome complexes and overexpression of iRhom1 enhanced it. Native-gel and fractionation analyses revealed that knockdown of iRhom1 expression impaired the assembly of the proteasome complexes. The expression of iRhom1 was increased by endoplasmic reticulum (ER) stressors, such as thapsigargin and tunicamycin, leading to the enhancement of proteasome activity, especially in ER-containing microsomes. iRhom1 interacted with the 20S proteasome assembly chaperones PAC1 and PAC2, affecting their protein stability. Moreover, knockdown of iRhom1 expression impaired the dimerization of PAC1 and PAC2 under ER stress. In addition, iRhom1 deficiency in D. melanogaster accelerated the rough-eye phenotype of mutant Huntingtin, while transgenic flies expressing either human iRhom1 or Drosophila iRhom showed rescue of the rough-eye phenotype. Together, these results identify a novel regulator of proteasome activity, iRhom1, which functions via PAC1/2 under ER stress. PMID- 26109408 TI - On the borderline between Science and Philosophy: A debate on determinism in France around 1880. AB - In the second half of the nineteenth century, a new interest in explosive chemical reactions, sudden release of energy in living beings, physical instabilities, and bifurcations in the solutions of differential equations drew the attention of some scholars. New concepts like triggering actions and guiding principles also emerged. Mathematicians, physicists, physiologists, and philosophers were attracted by this kind of phenomena since they raised a question about the actual existence of a strict determinism in science. In 1878 the mathematical physicist Joseph Boussinesq pointed out a structural analogy among physical instabilities, some essential features of living beings, and singular solutions of differential equations. These developments revived long lasting philosophical debates on the problematic link between deterministic physical laws and free will. We find in Boussinesq an original and almost isolated attempt to merge mathematical, physical, biological, and philosophical issues into a complex intellectual framework. In the last decades, some philosophers of science rediscovered the connection between physical instabilities and determinism, both in the context of chaos theory, and in the debates on the Norton dome. I put forward a consistent historical reconstruction of the main issues and characters involved. PMID- 26109410 TI - Narrative and evidence. How can case studies from the history of science support claims in the philosophy of science? AB - A common method for warranting the historical adequacy of philosophical claims is that of relying on historical case studies. This paper addresses the question as to what evidential support historical case studies can provide to philosophical claims and doctrines. It argues that in order to assess the evidential functions of historical case studies, we first need to understand the methodology involved in producing them. To this end, an account of historical reconstruction that emphasizes the narrative character of historical accounts and the theory-laden character of historical facts is introduced. The main conclusion of this paper is that historical case studies are able to provide philosophical claims with some evidential support, but that, due to theory-ladenness, their evidential import is restricted. PMID- 26109411 TI - Model robustness as a confirmatory virtue: The case of climate science. AB - I propose a distinct type of robustness, which I suggest can support a confirmatory role in scientific reasoning, contrary to the usual philosophical claims. In model robustness, repeated production of the empirically successful model prediction or retrodiction against a background of independently-supported and varying model constructions, within a group of models containing a shared causal factor, may suggest how confident we can be in the causal factor and predictions/retrodictions, especially once supported by a variety of evidence framework. I present climate models of greenhouse gas global warming of the 20th Century as an example, and emphasize climate scientists' discussions of robust models and causal aspects. The account is intended as applicable to a broad array of sciences that use complex modeling techniques. PMID- 26109412 TI - Scientific pluralism and the Chemical Revolution. AB - In a number of papers and in his recent book, Is Water H2O? Evidence, Realism, Pluralism (2012), Hasok Chang has argued that the correct interpretation of the Chemical Revolution provides a strong case for the view that progress in science is served by maintaining several incommensurable "systems of practice" in the same discipline, and concerning the same region of nature. This paper is a critical discussion of Chang's reading of the Chemical Revolution. It seeks to establish, first, that Chang's assessment of Lavoisier's and Priestley's work and character follows the phlogistonists' "actors' sociology"; second, that Chang simplifies late-eighteenth-century chemical debates by reducing them to an alleged conflict between two systems of practice; third, that Chang's evidence for a slow transition from phlogistonist theory to oxygen theory is not strong; and fourth, that he is wrong to assume that chemists at the time did not have overwhelming good reasons to favour Lavoisier's over the phlogistonists' views. PMID- 26109413 TI - A Revolution that never happened. AB - If we define scientific revolutions as changes of scientists' ontologies, types of causal explanation, and paradigmatic types of methods and instruments, Antoine Laurent Lavoisier's contribution to chemistry did not amount to a scientific revolution. Contrary to the received view that Lavoisier initiated a "chemical revolution," which is accepted by Chang and Kusch, I argue that Lavoisier shared with the phlogistonists their "flat ontology" of chemical substance, established decades before the 1770s, their types of explaining chemical transformation, and their quantitative methods. Based on my historical reconstruction, I criticize Chang's argument that the late eighteenth-century phlogistic systems and Lavoisier's system belonged to two different theoretical traditions. As a consequence, I also question Chang's argument that the acceptance of Lavoisier's system can be explained in terms of dominance of "compositionism" over "principlism." PMID- 26109414 TI - The Chemical Revolution revisited. AB - I respond to the critical comments by Martin Kusch and Ursula Klein on my account of the Chemical Revolution. I comment along three different lines: descriptive, explanatory, and normative. (1) I agree with Klein that Lavoisier did not introduce drastic changes in chemical ontology, but maintain that there was methodological incommensurability in the Chemical Revolution; in response to Kusch's view, I maintain that Lavoisier's victory was slow and incomplete. (2) Admitting that there were many causes shaping the outcome of the Chemical Revolution, including the convenience of Lavoisier's theoretical scheme and various complicated social factors, I still think that the general rise of compositionism was an important factor. (3) I defend my normative pluralist view on the Chemical Revolution, denying Kusch's argument that chemists had overwhelmingly good reasons to trust Lavoisier and his allies over the phlogistonists. Overall, I agree with Kusch that it would be desirable to have a good descriptive-normative sociological account of the Chemical Revolution, but I also think that it should be an account that allows for divergence in individuals' and sub-communities' self-determination. PMID- 26109415 TI - Bringing tacit knowledge back to contributory and interactional expertise: A reply to Goddiksen. AB - We analyse a recent paper by Goddiksen (2014) where the author raises questions about the relationship between authorship, attribution and Collins & Evans' concept of contributory and interactional expertise. We then highlight recent empirical work in the sociology of climate change science that has made similar points in order to clarify how authorship, division of labour and contribution are handled in real scientific settings. Despite this, Goddiksen's critique of both contributory and interactional expertise is ultimately ineffective because it rests on a misguided attempt to de-socialise these concepts. We conclude by stressing the importance of collective tacit knowledge acquisition through immersion as a critical step in becoming a full-blown contributory or interactional expert. PMID- 26109416 TI - Putting a spin on circulating reference, or how to rediscover the scientific subject. AB - Bruno Latour claims to have shown that a Kantian model of knowledge, which he describes as seeking to unite a disembodied transcendental subject with an inaccessible thing-in-itself, is dramatically falsified by empirical studies of science in action. Instead, Latour puts central emphasis on scientific practice, and replaces this Kantian model with a model of "circulating reference." Unfortunately, Latour's alternative schematic leaves out the scientific subject. I repair this oversight through a simple mechanical procedure. By putting a slight spin on Latour's diagrammatic representation of his theory, I discover a new space for a post-Kantian scientific subject, a subject brilliantly described by Ludwik Fleck. The neglected subjectivities and ceaseless practices of science are thus re-united. PMID- 26109418 TI - Monozygotic twins with a de novo 0.32 Mb 16q24.3 deletion, including TUBB3 presenting with developmental delay and mild facial dysmorphism but without overt brain malformation. AB - Nervous system development is highly dependent on the function of microtubules, which are assembled from tubulin heterodimers containing several alpha- and beta tubulin isotypes encoded by separate genes. A spectrum of neurological disorders with malformations of the central nervous system has recently been associated with missense mutations in this group of genes. Here, we report two patients, monozygotic twins, carrying a de novo 0.32 Mb deletion of chromosome 16q24.3 including the TUBB3 gene. The patients presented with global developmental delay, mild facial dysmorphism, secondary microcephaly, and mild spastic diplegia. Cerebral magnetic resonance imaging of the patients did not reveal cortical malformations, malformations of the corticospinal tracts, basal ganglia, corpus callosum, or optic nerves. This observation is in contrast to the group of neurological disorders that are associated with heterozygous missense mutations in genes encoding different neuronal alpha- and beta-tubulin isotypes, termed tubulinopathies. On the background of current knowledge regarding the function and genotype-phenotype correlations of mutations in the neuronal tubulin isotypes, the clinical and diagnostic findings in these patients are discussed. To our knowledge, this is the first report of patients with a de novo deletion of the TUBB3 gene. The lack of cortical or other cerebral malformations supports the current hypothesis that TUBB3-related tubulinopathies are caused by altered protein function. PMID- 26109417 TI - Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle. AB - Contractile dysfunction and increased deposition of O-linked beta-N-acetyl-d glucosamine (O-GlcNAc) in cardiac proteins are a hallmark of the diabetic heart. However, whether and how this posttranslational alteration contributes to lower cardiac function remains unclear. Using a refined beta-elimination/Michael addition with tandem mass tags (TMT)-labeling proteomic technique, we show that CpOGA, a bacterial analog of O-GlcNAcase (OGA) that cleaves O-GlcNAc in vivo, removes site-specific O-GlcNAcylation from myofilaments, restoring Ca(2+) sensitivity in streptozotocin (STZ) diabetic cardiac muscles. We report that in control rat hearts, O-GlcNAc and O-GlcNAc transferase (OGT) are mainly localized at the Z-line, whereas OGA is at the A-band. Conversely, in diabetic hearts O GlcNAc levels are increased and OGT and OGA delocalized. Consistent changes were found in human diabetic hearts. STZ diabetic hearts display increased physical interactions of OGA with alpha-actin, tropomyosin, and myosin light chain 1, along with reduced OGT and increased OGA activities. Our study is the first to reveal that specific removal of O-GlcNAcylation restores myofilament response to Ca(2+) in diabetic hearts and that altered O-GlcNAcylation is due to the subcellular redistribution of OGT and OGA rather than to changes in their overall activities. Thus, preventing sarcomeric OGT and OGA displacement represents a new possible strategy for treating diabetic cardiomyopathy. PMID- 26109419 TI - Polymorphisms in ATP-binding cassette transporter genes and interaction with diet and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study. AB - BACKGROUND AND AIMS: The ATP-binding cassette (ABC) transporter family transports various molecules across the enterocytes in the gut protecting the intestine against potentially harmful substances. Moreover, ABC transporters are involved in mucosal immune defence through interaction with cytokines. The study aimed to assess whether polymorphisms in ABCB1, ABCC2 and ABCG2 were associated with risk of colorectal cancer (CRC) and to investigate gene-environment (dietary factors, smoking and use of non-steroidal anti-inflammatory drugs) and gene-gene interactions between previously studied polymorphisms in IL1B and IL10 and ABC transporter genes in relation to CRC risk. MATERIALS AND METHODS: We used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort. Incidence rate ratios were calculated based on Cox' proportional hazards model. RESULTS: None of the polymorphisms were associated with CRC, but ABCB1 and ABCG2 haplotypes were associated with risk of CRC. ABCB1/rs1045642 interacted with intake of cereals and fiber (p-Value for interaction (P(int)) = 0.001 and 0.01, respectively). In a three-way analysis, both ABCB1/rs1045642 and ABCG2/rs2231137 in combination with IL10/rs3024505 interacted with fiber intake in relation to risk of CRC (P(int) = 0.0007 and 0.009). CONCLUSIONS: Our results suggest that the ABC transporters P glycoprotein/multidrug resistance 1 and BRCP, in cooperation with IL-10, are involved in the biological mechanism underlying the protective effect of fiber intake in relation to CRC. These results should be replicated in other cohorts to rule out chance findings. PMID- 26109420 TI - Childhood and adolescent obesity and long-term cognitive consequences during aging. PMID- 26109421 TI - Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. PMID- 26109423 TI - Oxycodone/naloxone preparation can cause acute withdrawal symptoms when misused parenterally or taken orally. AB - CONTEXT: Oral oxycodone/naloxone preparations are designed to reduce the incidence of constipation associated with oxycodone use. The low oral bioavailability (< 2%) of naloxone makes the precipitation of the acute opioid withdrawal symptoms unlikely following oral oxycodone/naloxone exposure. The incidence of acute opioid withdrawal symptoms following both oral and intravenous administration of oxycodone/naloxone preparations has not been described. OBJECTIVE: The aim of the study was to investigate the incidence and circumstances associated with oxycodone/naloxone-induced acute opioid withdrawal. METHODS: An observational case series of acute opioid withdrawal following oxycodone/naloxone administration were selected from all calls received by the Victoria Poisons Information Centre from January 2012 to December 2014. Data collected included patient demographics, reported symptoms, type of caller, intentional or accidental exposure and advice given. RESULTS: There were 107 reported exposures to oxycodone/naloxone preparations. Route of exposure was oral in 92 (86%) and intravenous injection of crushed tablets in 14 (14%) of cases, respectively. Nine callers had a history of long-standing opioid treatment and developed withdrawal symptoms with oral oxycodone/naloxone. Temporal relationship between first dose, increased dose and chewing tablets was described. There were 14 exposures to crushed oxycodone/naloxone tablets injected intravenously; all precipitated an acute withdrawal state. DISCUSSION: The development of opioid withdrawal symptoms with intravenous injection of oxycodone/naloxone is likely a result of bypassing first-pass metabolism. Withdrawal symptoms after ingesting increased dose, first dose or chewing oxycodone/naloxone suggests that there is a systemic absorption of naloxone in opioid-dependent callers. CONCLUSION: Oxycodone with naloxone tablets can lead to acute opioid withdrawal symptoms if crushed and injected parentally. First dose, increased dose and chewing of these opioid-naloxone combination tablets in opioid-dependent people can also result in acute opioid withdrawal symptoms or diminished pain relief. PMID- 26109424 TI - Erratum: Novel structural phases and superconductivity of iridium telluride under high pressures. PMID- 26109426 TI - Selective cell targeting and lineage tracing of human induced pluripotent stem cells using recombinant avian retroviruses. AB - Human induced pluripotent stem cells (hiPSC) differentiate into multiple cell types. Selective cell targeting is often needed for analyzing gene function by overexpressing proteins in a distinct population of hiPSC-derived cell types and for monitoring cell fate in response to stimuli. However, to date, this has not been possible, as commonly used viruses enter the hiPSC via ubiquitously expressed receptors. Here, we report for the first time the application of a heterologous avian receptor, the tumor virus receptor A (TVA), to selectively transduce TVA(+) cells in a mixed cell population. Expression of the TVA surface receptor via genetic engineering renders cells susceptible for infection by avian leucosis virus (ALV). We generated hiPSC lines with this stably integrated, ectopic TVA receptor gene that expressed the receptor while retaining pluripotency. The undifferentiated hiPSC(TVA+) as well as their differentiating progeny could be infected by recombinant ALV (so-called RCAS virus) with high efficiency. Due to incomplete receptor blocking, even sequential infection of differentiating or undifferentiated TVA(+) cells was possible. In conclusion, the TVA/RCAS system provides an efficient and gentle gene transfer system for hiPSC and extends our possibilities for selective cell targeting and lineage tracing studies. PMID- 26109425 TI - Ethylene Inhibits Root Elongation during Alkaline Stress through AUXIN1 and Associated Changes in Auxin Accumulation. AB - Soil alkalinity causes major reductions in yield and quality of crops worldwide. The plant root is the first organ sensing soil alkalinity, which results in shorter primary roots. However, the mechanism underlying alkaline stress-mediated inhibition of root elongation remains to be further elucidated. Here, we report that alkaline conditions inhibit primary root elongation of Arabidopsis (Arabidopsis thaliana) seedlings by reducing cell division potential in the meristem zones and that ethylene signaling affects this process. The ethylene perception antagonist silver (Ag(+)) alleviated the inhibition of root elongation by alkaline stress. Moreover, the ethylene signaling mutants ethylene response1-3 (etr1-3), ethylene insensitive2 (ein2), and ein3-1 showed less reduction in root length under alkaline conditions, indicating a reduced sensitivity to alkalinity. Ethylene biosynthesis also was found to play a role in alkaline stress-mediated root inhibition; the ethylene overproducer1-1 mutant, which overproduces ethylene because of increased stability of 1-AMINOCYCLOPROPANE-1-CARBOXYLIC ACID SYNTHASE5, was hypersensitive to alkaline stress. In addition, the ethylene biosynthesis inhibitor cobalt (Co(2+)) suppressed alkaline stress-mediated inhibition of root elongation. We further found that alkaline stress caused an increase in auxin levels by promoting expression of auxin biosynthesis-related genes, but the increase in auxin levels was reduced in the roots of the etr1-3 and ein3-1 mutants and in Ag(+)/Co(2+)-treated wild-type plants. Additional genetic and physiological data showed that AUXIN1 (AUX1) was involved in alkaline stress-mediated inhibition of root elongation. Taken together, our results reveal that ethylene modulates alkaline stress-mediated inhibition of root growth by increasing auxin accumulation by stimulating the expression of AUX1 and auxin biosynthesis-related genes. PMID- 26109427 TI - Protease nexin-1 regulates retinal vascular development. AB - We recently identified protease nexin-1 (PN-1) or serpinE2, as a possibly underestimated player in maintaining angiogenic balance. Here, we used the well characterized postnatal vascular development of newborn mouse retina to further investigate the role and the mechanism of action of PN-1 in physiological angiogenesis. The development of retinal vasculature was analysed by endothelial cell staining with isolectin B4. PN-1-deficient (PN-1(-/-)) retina displayed increased vascularization in the postnatal period, with elevated capillary thickness and density, compared to their wild-type littermate (WT). Moreover, PN 1(-/-) retina presented more veins/arteries than WT retina. The kinetics of retinal vasculature development, retinal VEGF expression and overall retinal structure were similar in WT and PN-1(-/-) mice, but we observed a hyperproliferation of vascular cells in PN-1(-/-) retina. Expression of PN-1 was analysed by immunoblotting and X-Gal staining of retinas from mice expressing beta-galactosidase under a PN-1 promoter. PN-1 was highly expressed in the first week following birth and then progressively decreased to a low level in adult retina where it localized on the retinal arteries. PCR arrays performed on mouse retinal RNA identified two angiogenesis-related factors, midkine and Smad5, that were overexpressed in PN-1(-/-) newborn mice and this was confirmed by RT-PCR. Both the higher vascularization and the overexpression of midkine and Smad5 mRNA were also observed in gastrocnemius muscle of PN-1(-/-) mice, suggesting that PN 1 interferes with these pathways. Together, our results demonstrate that PN-1 strongly limits physiological angiogenesis and suggest that modulation of PN-1 expression could represent a new way to regulate angiogenesis. PMID- 26109428 TI - Antithrombotic treatment for acute extracranial carotid artery dissections: a meta-analysis. AB - INTRODUCTION: Carotid artery dissection is a leading cause of stroke in younger patients, with an associated prevalence of 2.6-3.0 per 100,000 population. This meta-analysis aims to determine whether in patients managed medically, treatment with anticoagulants or antiplatelet agents was associated with a better outcome with respect to mortality, ischaemic stroke, and major bleeding episodes. PATIENTS AND METHODS: A comprehensive search strategy was employed of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to March 2015), and EMBASE (January 1980 to March 2015) databases. Primary outcomes were death (all causes) or disability. Secondary outcomes were ischaemic stroke, symptomatic intracranial haemorrhage, and major extracranial haemorrhage during the reported follow-up period. RESULTS: No completed randomized trials were found. Comparing antiplatelets with anticoagulants across 38 studies (1,398 patients), there were no significant differences in the odds of death (effects size, ES, -0.007, p = .871), nor in the death and disability comparison or across any secondary outcomes. CONCLUSION: There were no randomised trials comparing either anticoagulants or antiplatelets with control, thus there is no level 1 evidence to support their routine use for the treatment of carotid artery dissection. Also, there were no randomised trials that directly compared anticoagulants with antiplatelet drugs, and the reported non-randomised studies did not show any evidence of a significant difference between the two. PMID- 26109429 TI - Genome-wide mutation profiles of colorectal tumors and associated liver metastases at the exome and transcriptome levels. AB - To characterize the mutation profiles of colorectal cancer (CRC) primary tumors (PTs) and liver metastases (CLMs), we performed both whole-exome and RNA sequencing. Ten significantly mutated genes, including BMI1, CARD11, and NRG1, were found in 34 CRCs with CLMs. We defined three mutation classes (Class 1 to 3) based on the absence or presence of mutations during liver metastasis. Most mutations were classified into Class 1 (shared between PTs and CLMs), suggesting the common clonal origin of PTs and CLMs. Class 1 was more strongly associated with the clinical characteristics of advanced cancer and was more frequently superimposed with chromosomal deletions in CLMs than Class 2 (PT-specific). The integration of exome and RNA sequencing revealed that variant-allele frequencies (VAFs) of mutations in the transcriptome tended to have stronger functional implications than those in the exome. For instance, VAFs of the TP53 and APC mutations in the transcriptome significantly correlated with the expression level of their target genes. Additionally, mutations with high functional impact were enriched with high VAFs in the CLM transcriptomes. We identified 11 mutation associated splicing events in the CRC transcriptomes. Thus, the integration of the exome and the transcriptome may elucidate the underlying molecular events responsible for CLMs. PMID- 26109430 TI - Detecting cell-in-cell structures in human tumor samples by E-cadherin/CD68/CD45 triple staining. AB - Although Cell-in-cell structures (CICs) had been documented in human tumors for decades, it is unclear what types of CICs were formed largely due to low resolution of traditional way such as H&E staining. In this work, we employed immunofluorescent method to stain a panel of human tumor samples simultaneously with antibodies against E-cadherin for Epithelium, CD68 for Macrophage and CD45 for Leukocytes, which we termed as "EML method" based on the cells detected. Detail analysis revealed four types of CICs, with tumor cells or macrophage engulfing tumor cells or leukocytes respectively. Interestingly, tumor cells seem to be dominant over macrophage (93% vs 7%) as the engulfer cells in all CICs detected, whereas the overall amount of internalized tumor cells is comparable to that of internalized CD45+ leukocytes (57% vs 43%). The CICs profiles vary from tumor to tumor, which may indicate different malignant stages and/or inflammatory conditions. Given the potential impacts different types of CICs might have on tumor growth, we therefore recommend EML analysis of tumor samples to clarify the correlation of CICs subtypes with clinical prognosis in future researches. PMID- 26109431 TI - The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis. AB - MUTYH DNA glycosylase removes mismatched adenine opposite 7, 8-dihydro-8 oxoguanine (8-oxoG), which is the major mutagenic lesion induced by oxidative stress. Biallelic mutations in MUTYH are associated with MUTYH-Associated polyposis (MAP) and increased risk in colorectal cancer (CRC). We investigated cancer susceptibility associated with MUTYH inactivation in a mouse model of inflammation-dependent carcinogenesis induced by azoxymethane (AOM) and dextran sulphate (DSS). Mutyh-/- mice were more sensitive than wild-type (WT) animals to AOM/DSS toxicity and accumulated DNA 8-oxoG in their gastrointestinal tract. AOM/DSS-induced colonic adenomas were significantly more numerous in Mutyh-/- than in WT animals, and frequently showed a tubulo-villous feature along with high-grade dysplasia and larger size lesions. This condition resulted in a greater propensity to develop adenocarcinomas. The colon of untreated Mutyh-/- mice expressed higher basal levels of pro-inflammatory cytokines GM-CSF and IFNgamma, and treatment with AOM/DSS induced an early decrease in circulating CD4+ and CD8+ T lymphocytes and an increase in myeloid-derived suppressor cells (MDSCs). Adenomas from Mutyh-/- mice had a greater infiltrate of Foxp3+ T regulatory cells, granulocytes, macrophages, MDSCs and strong expression of TGF beta-latency-associated peptide and IL6. Our findings indicate that MUTYH loss is associated with an increase in CRC risk, which involves immunosuppression and altered inflammatory response. We propose that the AOM/DSS initiation/promotion protocol in Mutyh-/- mice provides a good model for MAP. PMID- 26109432 TI - Optimal drug regimens for primary biliary cirrhosis: a systematic review and network meta-analysis. AB - OBJECTIVE: Most comprehensive treatments for PBC include UDCA, combination of methotrexate (MTX), corticosteroids (COT), colchicine (COC) or bezafibrate (BEF), cyclosporin A (CYP), D-penicillamine (DPM), methotrexate (MTX), or azathioprine (AZP). Since the optimum treatment regimen remains inconclusive, we aimed to compare these therapies in terms of patient mortality or liver transplantation (MOLT) and adverse event (AE). METHODS: We searched PubMed, Embase, Scopus and the Cochrane Library for randomized controlled trials until August 2014. We estimated HRs for MOLT and ORs for AE. The sensitivity analysis based on dose of UDCA was also performed. RESULTS: The search identified 49 studies involving 12 different treatment regimens and 4182 patients. Although no statistical significance can be found in MOLT, COT plus UDCA was ranked highest for efficacy outcome amongst all the treatment regimes. While for AEs, compared with OBS or UDCA, monotherapy with COC (OR 5.6, P < 0.001; OR 5.89, P < 0.001), CYP (OR 3.24, P < 0.001; OR 3.42, P < 0.001), DPM (OR 8.00, P < 0.001; OR 8.45, P < 0.001) and MTX (OR 5.31, P < 0.001; OR 5.61, P < 0.001) were associated with statistically significant increased risk of AEs. No significant differences were found for other combination regimes. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Consistently, in the sensitivity analysis, results closely resembled our primary analysis. CONCLUSIONS: COT plus UDCA was the most efficacious among treatment regimens both for MOLT and AEs. PMID- 26109434 TI - Impact of Education on Memory Deficits in Subclinical Depression. AB - Elevated depressive symptoms are associated with cognitive deficits, while higher education protects against cognitive decline. This study was conducted to test if education level moderates the relationship between depressive symptoms and cognitive function. Seventy-three healthy, dementia-free adults aged 18-81 completed neuropsychological tests, as well as depression and anxiety questionnaires. Controlling for age, sex, and state anxiety, we found a significant interaction of depressive symptoms and education for immediate and delayed verbal memory, such that those with a higher education level performed well regardless of depressive symptomatology, whereas those with lower education and high depressive symptoms had worse performance. No effects were found for executive functioning or processing speed. Results suggest that education protects against verbal memory deficits in individuals with elevated depressive symptoms. Further research on cognitive reserve in depression-related cognitive deficits and decline is needed to understand the mechanisms behind this phenomenon. PMID- 26109435 TI - Polymer-Polymer Forster Resonance Energy Transfer Significantly Boosts the Power Conversion Efficiency of Bulk-Heterojunction Solar Cells. AB - Optically resonant donor polymers can exploit a wider range of the solar spectrum effectively without a complicated tandem design in an organic solar cell. Ultrafast Forster resonance energy transfer (FRET) in a polymer-polymer system that significantly improves the power conversion efficiency in bulk heterojunction polymer solar cells from 6.8% to 8.9% is demonstrated, thus paving the way to achieving 15% efficient solar cells. PMID- 26109433 TI - KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models. AB - Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Because of a high rate of immunoglobulin synthesis, the endoplasmic reticulum of MM cells is subjected to elevated basal levels of stress. Consequently, proteasome inhibitors, which exacerbate this stress by inhibiting ubiquitin-proteasome mediated protein degradation, are an important new class of chemotherapeutic agents being used to combat this disease. However, MM cells still develop resistance to proteasome inhibitors such as carfilzomib. Toward this end, we have established carfilzomib-resistant derivatives of MM cell lines. We found that resistance to carfilzomib was associated with elevated levels of prosurvival autophagy, and Kruppel-like factor 4 (KLF4) was identified as a contributing factor. Expression levels as well as nuclear localization of KLF4 protein were elevated in MM cells with acquired carfilzomib resistance. Chromatin immunoprecipitations indicated that endogenous KLF4 bound to the promoter regions of the SQSTM1 gene encoding the ubiquitin-binding adaptor protein sequestosome/p62 that links the proteasomal and autophagic protein degradation pathways. Ectopic expression of KLF4 induced upregulation of SQSTM1. On the other hand, inhibitors of autophagy sensitized MM cells to carfilzomib, even in carfilzomib-resistant derivatives having increased expression of the multidrug resistance protein P-glycoprotein. Thus, we report here a novel function for KLF4, one of the Yamanaka reprogramming factors, as being a contributor to autophagy gene expression which moderates preclinical proteasome inhibitor efficacy in MM. PMID- 26109437 TI - Headache disorders are third cause of disability worldwide. PMID- 26109436 TI - Two TRPV1 receptor antagonists are effective in two different experimental models of migraine. AB - BACKGROUND: The capsaicin and heat responsive ion channel TRPV1 is expressed on trigeminal nociceptive neurons and has been implicated in the pathophysiology of migraine attacks. Here we investigate the efficacy of two TRPV1 channel antagonists in blocking trigeminal activation using two in vivo models of migraine. METHODS: Male Sprague-Dawley rats were used to study the effects of the TRPV1 antagonists JNJ-38893777 and JNJ-17203212 on trigeminal activation. Expression of the immediate early gene c-fos was measured following intracisternal application of inflammatory soup. In a second model, CGRP release into the external jugular vein was determined following injection of capsaicin into the carotid artery. RESULTS: Inflammatory up-regulation of c-fos in the trigeminal brain stem complex was dose-dependently and significantly reduced by both TRPV1 antagonists. Capsaicin-induced CGRP release was attenuated by JNJ 38893777 only in higher dosage. JNJ-17203212 was effective in all doses and fully abolished CGRP release in a time and dose-dependent manner. CONCLUSION: Our results describe two TRPV1 antagonists that are effective in two in vivo models of migraine. These results suggest that TRPV1 may play a role in the pathophysiological mechanisms, which are relevant to migraine. PMID- 26109438 TI - Keeping the band together: evidence for false boundary disruptive coloration in a butterfly. AB - There is a recent surge of evidence supporting disruptive coloration, in which patterns break up the animal's outline through false edges or boundaries, increasing survival in animals by reducing predator detection and/or preventing recognition. Although research has demonstrated that false edges are successful for reducing predation of prey, research into the role of internal false boundaries (i.e. stripes and bands) in reducing predation remains warranted. Many animals have stripes and bands that may function disruptively. Here, we test the possible disruptive function of wing band patterning in a butterfly, Anartia fatima, using artificial paper and plasticine models in Panama. We manipulated the band so that one model type had the band shifted to the wing margin (nondisruptive treatment) and another model had a discontinuous band located on the wing margin (discontinuous edge treatment). We kept the natural wing pattern to represent the false boundary treatment. Across all treatment groups, we standardized the area of colour and used avian visual models to confirm a match between manipulated and natural wing colours. False boundary models had higher survival than either the discontinuous edge model or the nondisruptive model. There was no survival difference between the discontinuous edge model and the nondisruptive model. Our results demonstrate the importance of wing bands in reducing predation on butterflies and show that markings set in from the wing margin can reduce predation more effectively than marginal bands and discontinuous marginal patterns. This study demonstrates an adaptive benefit of having stripes and bands. PMID- 26109440 TI - Acute neck pain caused by atlanto-axial instability secondary to pathologic fracture involving odontoid process and C2 vertebral body: treatment with radiofrequency thermoablation, cement augmentation and odontoid screw fixation. AB - INTRODUCTION: Cervical spine metastases are relatively rare entities. Only about 10 % of all spinal metastases can be found in this localization. Magnetic resonance imaging and computed tomography are routinely used for early detection. The initial, clinical examination and patients' complaints may not always be very prominent. Treatment of such lesions is very challenging and needs to consider patient's comorbidities, quality of life and life expectation. Surgery for these lesions should always be performed in specialized spine units. CASE PRESENTATION: We present here a clinical history of a 67-year-old male with acutely occurring neck pain and some neck discomfort for last 2 weeks. No previous neck pain history or trauma. There were no neurological symptoms, only a slight tremor in the left upper extremity. The detailed past medical history of the patient revealed chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM type II), and smoking 30-pack-year. The first cervical spine X-ray did not demonstrate any pathological findings. We performed a CT scan, which demonstrated a lytic lesion involving the vertebral body of C2 with collapse of odontoid process and subsequent C1-C2 instability. In the next step, because of no medical history of cancer, we performed CT scan of the chest and abdomen, and found a suspicious mass in the right main bronchus and liver. We suggested a bronchial biopsy of the mass but the patient refused this procedure and requested only surgery for the C2 lesion. The patient underwent the described surgical procedure through high anterior cervical approach. We collected the tissue for histology, and performed radiofrequency thermoablation, cement augmentation, and odontoid screw fixation. The patient made an uneventful recovery and 2 weeks after surgery he was able to start his palliative chemotherapy for bronchial carcinoma, which was diagnosed based on biopsy acquired during this procedure. DISCUSSION: There are no specific guidelines regarding treatment of secondary lesions of C2 with instability at C1 C2 level. We describe here an interesting approach for the management of lytic lesions of C2 which may be used also at other levels of cervical spine. We did not observe any leakage of cement into the spinal canal. This procedure allows for fast recovery of patients, with early unrestricted range of motion, and beginning of early chemotherapy. PMID- 26109439 TI - Function and evolution of Magnaporthe oryzae avirulence gene AvrPib responding to the rice blast resistance gene Pib. AB - Magnaporthe oryzae (Mo) is the causative pathogen of the damaging disease rice blast. The effector gene AvrPib, which confers avirulence to host carrying resistance gene Pib, was isolated via map-based cloning. The gene encodes a 75 residue protein, which includes a signal peptide. Phenotyping and genotyping of 60 isolates from each of five geographically distinct Mo populations revealed that the frequency of virulent isolates, as well as the sequence diversity within the AvrPib gene increased from a low level in the far northeastern region of China to a much higher one in the southern region, indicating a process of host driven selection. Resequencing of the AvrPiballele harbored by a set of 108 diverse isolates revealed that there were four pathoways, transposable element (TE) insertion (frequency 81.7%), segmental deletion (11.1%), complete absence (6.7%), and point mutation (0.6%), leading to loss of the avirulence function. The lack of any TE insertion in a sample of non-rice infecting Moisolates suggested that it occurred after the host specialization of Mo. Both the deletions and the functional point mutation were confined to the signal peptide. The reconstruction of 16 alleles confirmed seven functional nucleotide polymorphisms for the AvrPiballeles, which generated three distinct expression profiles. PMID- 26109441 TI - Evaluation of a Novel Plasma (1,3)-beta-d-Glucan Detection Assay for Diagnosis of Candidemia in Pediatric Patients. AB - We evaluated a novel plasma (1,3)-beta-d-glucan (BDG) detection assay for the diagnosis of candidemia in children. The median BDG levels were 73.4 pg/ml in patients with candidemia and <10 pg/ml in patients without candidemia (P < 0.001). Receiver operating characteristic analysis revealed a cutoff point of 14 pg/ml and an area under the curve of 0.802. At these values, the assay demonstrated 68% sensitivity, 91% specificity, 66% positive predictive value, and 91% negative predictive value. Plasma BDG levels were undetectable in 18 candidemia cases. PMID- 26109442 TI - Genomic Epidemiology of Clostridium botulinum Isolates from Temporally Related Cases of Infant Botulism in New South Wales, Australia. AB - Infant botulism is a potentially life-threatening paralytic disease that can be associated with prolonged morbidity if not rapidly diagnosed and treated. Four infants were diagnosed and treated for infant botulism in NSW, Australia, between May 2011 and August 2013. Despite the temporal relationship between the cases, there was no close geographical clustering or other epidemiological links. Clostridium botulinum isolates, three of which produced botulism neurotoxin serotype A (BoNT/A) and one BoNT serotype B (BoNT/B), were characterized using whole-genome sequencing (WGS). In silico multilocus sequence typing (MLST) found that two of the BoNT/A-producing isolates shared an identical novel sequence type, ST84. The other two isolates were single-locus variants of this sequence type (ST85 and ST86). All BoNT/A-producing isolates contained the same chromosomally integrated BoNT/A2 neurotoxin gene cluster. The BoNT/B-producing isolate carried a single plasmid-borne bont/B gene cluster, encoding BoNT subtype B6. Single nucleotide polymorphism (SNP)-based typing results corresponded well with MLST; however, the extra resolution provided by the whole-genome SNP comparisons showed that the isolates differed from each other by >3,500 SNPs. WGS analyses indicated that the four infant botulism cases were caused by genomically distinct strains of C. botulinum that were unlikely to have originated from a common environmental source. The isolates did, however, cluster together, compared with international isolates, suggesting that C. botulinum from environmental reservoirs throughout NSW have descended from a common ancestor. Analyses showed that the high resolution of WGS provided important phylogenetic information that would not be captured by standard seven-loci MLST. PMID- 26109443 TI - Comparison of Established Diagnostic Methodologies and a Novel Bacterial smpB Real-Time PCR Assay for Specific Detection of Haemophilus influenzae Isolates Associated with Respiratory Tract Infections. AB - Haemophilus influenzae is a significant causative agent of respiratory tract infections (RTI) worldwide. The development of a rapid H. influenzae diagnostic assay that would allow for the implementation of infection control measures and also improve antimicrobial stewardship for patients is required. A number of nucleic acid diagnostics approaches that detect H. influenzae in RTIs have been described in the literature; however, there are reported specificity and sensitivity limitations for these assays. In this study, a novel real-time PCR diagnostic assay targeting the smpB gene was designed to detect all serogroups of H. influenzae. The assay was validated using a panel of well-characterized Haemophilus spp. Subsequently, 44 Haemophilus clinical isolates were collected, and 36 isolates were identified as H. influenzae using a gold standard methodology that combined the results of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and a fucK diagnostic assay. Using the novel smpB diagnostic assay, 100% concordance was observed with the gold standard, demonstrating a sensitivity of 100% (95% confidence interval [CI], 90.26% to 100.00%) and a specificity of 100% (95% CI, 63.06% to 100.00%) when used on clinical isolates. To demonstrate the clinical utility of the diagnostic assay presented, a panel of lower RTI samples (n = 98) were blindly tested with the gold standard and smpB diagnostic assays. The results generated were concordant for 94/98 samples tested, demonstrating a sensitivity of 90.91% (95% CI, 78.33% to 97.47%) and a specificity of 100% (95% CI, 93.40% to 100.00%) for the novel smpB assay when used directly on respiratory specimens. PMID- 26109444 TI - Management of Microbiological Samples in a Confirmed Case of Ebola Virus Disease: Constraints and Limitations. AB - In light of the recent Ebola virus outbreak, it has to be realized that besides medical treatment, precise algorithms for the management of complicating microbial infections are mandatory for Ebola virus disease (EVD) patients. While the necessity of such diagnostics is apparent, practical details are much less clear. Our approach, established during the treatment of an EVD patient at the University Hospital in Frankfurt am Main, Germany, provides a roadmap for reliable and safe on-site microbiological testing. PMID- 26109446 TI - Prospective Two-Center Comparison of Three Chromogenic Agars for Methicillin Resistant Staphylococcus aureus Screening in Hospitalized Patients. AB - Three chromogenic media, chromID MRSA SMART (SMART), chromID MRSA first generation (chromID), and Brilliance MRSA (OX2), were evaluated for methicillin resistant Staphylococcus aureus (MRSA) screening using 1,220 samples. The sensitivity at 24 h was significantly better with the SMART agar (66.4%) than that with chromID agar (50.5%). Enrichment and incubation until 48 h are still needed for an optimal yield. PMID- 26109445 TI - First Human Case of Fungal Keratitis Caused by a Putatively Novel Species of Lophotrichus. AB - We report an aggressive fungal keratitis caused by a putatively novel species of Lophotrichus in a patient with traumatic injury to the cornea from a dog paw. The organism was isolated from the patient's necrotic cornea, which perforated despite coverage with hourly fortified broad-spectrum topical antibiotic therapy. This report represents the first case of human infection caused by this species. PMID- 26109447 TI - Novel Molecular Assay for Simultaneous Identification of Neglected Lungworms and Heartworms Affecting Cats. AB - Feline lungworms and heartworms are stimulating the interest of the scientific community due to their clinical impact and apparent geographical expansion. Diagnosis of the infections caused by these nematodes is indeed challenging. This report describes a novel multiplex PCR able to identify simultaneously three species of lungworms (Aelurostrongylus abstrusus and Troglostrongylus brevior) and heartworms (Angiostrongylus chabaudi) affecting felids. Epidemiological and clinical perspectives are discussed. PMID- 26109448 TI - Vertebral Osteomyelitis Caused by Helicobacter cinaedi. AB - Helicobacter cinaedi causes bacteremia, cellulitis, and gastroenteritis. We report the first case of vertebral osteomyelitis caused by H. cinaedi in an elderly man with low back pain and fever. The pathogen was detected in blood and lumbar disc, and the infection was successfully treated with oral doxycycline for 11 weeks. PMID- 26109449 TI - Water-soluble Moringa oleifera lectin interferes with growth, survival and cell permeability of corrosive and pathogenic bacteria. AB - AIMS: This work evaluated the antibacterial activity of a water-soluble Moringa oleifera seed lectin (WSMoL) by evaluating its effect on growth, survival and cell permeability of Bacillus sp., Bacillus cereus, Bacillus pumillus, Bacillus megaterium, Micrococcus sp., Pseudomonas sp., Pseudomonas fluorescens, Pseudomonas stutzeri and Serratia marcescens. In addition, the effect of lectin on membrane integrity of most sensitive species was also evaluated. All the tested bacteria are able to cause biocorrosion and some are also responsible for human infections. METHODS AND RESULTS: WSMoL inhibited the bacterial growth, induced agglutination and promoted the leakage of proteins from cells of all strains. Bactericidal effect was detected against Bacillus sp., B. pumillus, B. megaterium, Ps. fluorescens and Ser. marcescens. The bacteriostatic effect of lectin was evident with only 6 h of incubation. Fluorescence microscopy of Ser. marcescens showed that WSMoL caused loss of cell integrity and indicated an anti biofilm activity of the lectin. CONCLUSIONS: WSMoL was active against the bacteria by inhibiting growth and affecting cell permeability. The lectin also interfered with membrane integrity of Ser. marcescens, the most sensitive species. SIGNIFICANCE AND IMPACT OF THE STUDY: The study indicates that WSMoL was active against bacteria that cause serious problems in both industrial and health sectors. Also, the study contributes for the 'state-of-art' on antibacterial mechanisms of lectins. PMID- 26109450 TI - Assessing personal talent determinants in young racquet sport players: a systematic review. AB - Since junior performances have little predictive value for future success, other solutions are sought to assess a young player's potential. The objectives of this systematic review are (1) to provide an overview of instruments measuring personal talent determinants of young players in racquet sports, and (2) to evaluate these instruments regarding their validity for talent development. Electronic searches were conducted in PubMed, PsychINFO, Web of Knowledge, ScienceDirect and SPORTDiscus (1990 to 31 March 2014). Search terms represented tennis, table tennis, badminton and squash, the concept of talent, methods of testing and children. Thirty articles with information regarding over 100 instruments were included. Validity evaluation showed that instruments focusing on intellectual and perceptual abilities, and coordinative skills discriminate elite from non-elite players and/or are related to current performance, but their predictive validity is not confirmed. There is moderate evidence that the assessments of mental and goal management skills predict future performance. Data on instruments measuring physical characteristics prohibit a conclusion due to conflicting findings. This systematic review yielded an ambiguous end point. The lack of longitudinal studies precludes verification of the instrument's capacity to forecast future performance. Future research should focus on instruments assessing multidimensional talent determinants and their predictive value in longitudinal designs. PMID- 26109451 TI - A bibenzyl from Dendrobium ellipsophyllum inhibits migration in lung cancer cells. AB - Metastatic cancer cells have been shown to have aggressive behaviors accounting for the high incidence of chemotherapeutic failure and mortality. Because migration and invasion are crucial behaviors for cancer cell dissemination, promising compounds exhibiting potential antimigration effects are of interest for metastasis-based therapeutic approaches. This study aimed to evaluate the activity of a bibenzyl, 4,5,4'-trihydroxy-3,3'-dimethoxybibenzyl (TDB), isolated from Dendrobium ellipsophyllum Tang and Wang, in the suppression of migration in human lung cancer cells. TDB at nontoxic concentrations (1 and 5 uM) significantly inhibited the motility of lung cancer cells in scratch-wound assay. Chemotaxis-induced migration and invasion assays also revealed that the cell motility dramatically diminished in the cells treated with 1-5 uM TDB. Western blot analysis provided the underlying molecular mechanism, showing that TDB reduced such cell migration and invasion by decreasing migration-regulating proteins, including integrins alphav, alpha4, beta1, beta3 and beta5, as well as downstream signaling proteins, such as activated focal adhesion kinase (pFAK), activated Ras-related C3 botulinum toxin substrate 1 (Rac1-GTP) and cell division control protein 42 (Cdc42). As the presence of cellular protrusion, called filopodia, has been indicated as a hallmark of migrating cells, we showed that the reduction of the mentioned proteins correlated well with the disappearance of filopodia. In summary, this study demonstrates the promising activity of TDB and its mechanism in the inhibition of lung cancer cell migration, which might be useful for encouraging the development of this compound for antimetastatic approaches. PMID- 26109452 TI - 45S5 Bioglass((r))-MWCNT composite: processing and bioactivity. AB - Multi-walled carbon nanotube (MWCNT)-Bioglass (BG) matrix composite was fabricated using a facile and scalable aqueous colloidal processing method without using any surfactants followed by spark plasma sintering (SPS) consolidation. The individual MWCNTs were initially uniformly dispersed in water and then entirely immobilized on the BG particles during the colloidal processing, avoiding their common re-agglomeration during the water-removal and drying step, which guaranteed their uniform dispersion within the dense BG matrix after the consolidation process. SPS was used as a fast sintering technique to minimise any damage to the MWCNT structure during the high-temperature consolidation process. The electrical conductivity of BG increased by 8 orders of magnitude with the addition of 6.35 wt% of MWCNTs compared to pure BG. Short duration tests were used in the present study as a preliminary evaluation to understand the effect of incorporating MWCNTs on osteoblast-like cells. The analysed cell proliferation, viability and phenotype expression of MG-63 cells showed inhibition on 45S5 Bioglass((r))-MWCNT composite surfaces. PMID- 26109453 TI - Printable elastic conductors with a high conductivity for electronic textile applications. AB - The development of advanced flexible large-area electronics such as flexible displays and sensors will thrive on engineered functional ink formulations for printed electronics where the spontaneous arrangement of molecules aids the printing processes. Here we report a printable elastic conductor with a high initial conductivity of 738 S cm(-1) and a record high conductivity of 182 S cm( 1) when stretched to 215% strain. The elastic conductor ink is comprised of Ag flakes, a fluorine rubber and a fluorine surfactant. The fluorine surfactant constitutes a key component which directs the formation of surface-localized conductive networks in the printed elastic conductor, leading to a high conductivity and stretchability. We demonstrate the feasibility of our inks by fabricating a stretchable organic transistor active matrix on a rubbery stretchability-gradient substrate with unimpaired functionality when stretched to 110%, and a wearable electromyogram sensor printed onto a textile garment. PMID- 26109454 TI - Nanoscale control of phonon excitations in graphene. AB - Phonons, which are collective excitations in a lattice of atoms or molecules, play a major role in determining various physical properties of condensed matter, such as thermal and electrical conductivities. In particular, phonons in graphene interact strongly with electrons; however, unlike in usual metals, these interactions between phonons and massless Dirac fermions appear to mirror the rather complicated physics of those between light and relativistic electrons. Therefore, a fundamental understanding of the underlying physics through systematic studies of phonon interactions and excitations in graphene is crucial for realising graphene-based devices. In this study, we demonstrate that the local phonon properties of graphene can be controlled at the nanoscale by tuning the interaction strength between graphene and an underlying Pt substrate. Using scanning probe methods, we determine that the reduced interaction due to embedded Ar atoms facilitates electron-phonon excitations, further influencing phonon assisted inelastic electron tunnelling. PMID- 26109455 TI - Editorial. PMID- 26109456 TI - Does the passage of seeds through frugivore gut affect their storage: A case study on the endangered plant Euryodendron excelsum. AB - Plant-frugivore mutualism serves an important function in multiple ecological processes. Although previous studies have highlighted the effect of frugivore gut passage on fresh seed germinability, no study has investigated the effect on seed storage after frugivore gut passage. We used the endangered plant, Euryodendron excelsum, to determine the combined effects of frugivore gut passage and storage conditions on the germination percentage and rate of seeds. In particular, three treatments that included storage periods, storage methods, and seed types were designed in the experiment. We hypothesized that seeds that passed through the gut will exhibit enhanced germination capacity and rate during storage. Results showed that the final germination percentage decreased in seeds that passed through the gut, whereas the germination rate increased during seed storage. Germination decreased in most types of seeds under both dry and wet storage after 6 months compared with storage after 1 and 3 months. The results suggest that after frugivore gut passage, E. excelsum seeds cannot form persistent soil seed bank in the field, and were not suitable for species germplasm storage. These finding underscore that seeds that passed through frugivore gut have long-term impact on their viability and germination performance. PMID- 26109457 TI - Advance directives and suicide attempts-ethical considerations in light of Carter v. Canada, SCC 5. PMID- 26109458 TI - Reconstruction of post-traumatic drop foot deformity by the chimeric deep inferior epigastric artery perforator free flap associated with a composite quadriceps osteotendinous graft. AB - Dorsiflexor tendons are particularly exposed in crush injury of the foot. Anterior tibialis tendon defects may be responsible for a steppage gait and a drop foot deformity. Drop foot reconstruction is challenging because of the high risk of postoperative adhesions and functional sequelae. In this report, we present the results of the reconstruction of post-injury anterior tibialis tendon defects with chimeric deep inferior epigatric artery perforator (DIEP) free flap associated with a quadriceps osteotendinous graft in two patients. Two men (32 year-old and 19-year-old) presented drop foot deformity with defect of the anterior tibialis tendon secondary to a crush injury. The sizes of the soft tissues defects at the foot dorsum were 24 cm * 8 cm and 20 cm * 8 cm, respectively. The quadriceps osteotendinous grafts were used to reconstruct the anterior tibialis tendon in both patients. The chimeric DIEP free flaps with skin paddles (24 cm * 8 cm and 20 cm * 8 cm) and rectus abdominis fascia (24 cm * 4 cm and 20 cm * 4 cm) were used for reconstruction. The skin component based on a musculocutaneous perforator was used for soft tissue reconstruction of the foot dorsum. The fascial component based on a second perforator was used to create a sliding surface around the osteotendinous graft. Postoperative course was uneventful. Rehabilitation lasted 3 months. The range of ankle movement was measured during 12 months. The first patient recovered 10 degree of dorsiflexion. The second patient recovered 25 degree of dorsiflexion. Walk recovery was satisfying in both patients. The single-stage procedure using the chimeric DIEP free flap may be an option for post-injury drop foot reanimation. Creating a sliding surface around a composite osteotendinous quadriceps graft with a vascularized fascial component avoid postoperative peritendinous adhesions. This technique may improve foot dorsiflexion and walk recovery. (c) 2015 Wiley Periodicals, Inc. Microsurgery 36:334-338, 2016. PMID- 26109459 TI - Threat modulates neural responses to looming visual stimuli. AB - Objects on a collision course with an observer produce a specific pattern of optical expansion on the retina known as looming, which in theory exactly specifies the time-to-collision (TTC) of approaching objects. It was recently demonstrated that the affective content of looming stimuli influences perceived TTC, with threatening objects judged as approaching sooner than non-threatening objects. Here, the neural mechanisms by which perceived threat modulates spatiotemporal perception were investigated. Participants judged the TTC of threatening (snakes, spiders) or non-threatening (butterflies, rabbits) stimuli, which expanded in size at a rate indicating one of five TTCs. Visual-evoked potentials (VEPs) and oscillatory neural responses measured with electroencephalography were analysed. The arrival time of threatening stimuli was underestimated compared with non-threatening stimuli, though an interaction suggested that this underestimation was not constant across TTCs. Further, both speed of approach and threat modulated both VEPs and oscillatory responses. Speed of approach modulated the N1 parietal and oscillations in the beta band. Threat modulated several VEP components (P1, N1 frontal, N1 occipital, early posterior negativity and late positive potential) and oscillations in the alpha and high gamma band. The results for the high gamma band suggest an interaction between these two factors. Previous evidence suggests that looming stimuli activate sensorimotor areas, even in the absence of an intended action. The current results show that threat disrupts the synchronization over the sensorimotor areas that are likely activated by the presentation of a looming stimulus. PMID- 26109460 TI - Salt intake and mental distress among rural community-dwelling Japanese men. AB - BACKGROUND: Activated mineralocorticoid receptors influence the association between daily salt intake and blood pressure. A relatively low mineralocorticoid receptor function is reported to be a risk for mental distress such as depression. Since mental distress is also a known risk for hypertension and cardiovascular disease, understanding of the association between estimated daily salt intake and mental distress contributing to hypertension is important for risk estimation for cardiovascular disease. However, no single study has reported this association. METHODS: We conducted a cross-sectional study of 1014 Japanese men undergoing general health check-ups. Mental distress was diagnosed as a Kessler 6 scale score >=5. We also classified mental distress by levels of hypertension. Estimated daily salt intake was calculated from a causal urine specimen. RESULTS: Independent from classical cardiovascular risk factors and thyroid disease, we found a significant inverse association between estimated daily salt intake and mental distress. When we analyzed for mental distress and hypertension, we also found a significant association. With the reference group being the lowest tertiles of estimated daily salt intake, the multivariable odds ratios (ORs) of mental distress and mental distress with hypertension for the highest tertiles were 0.50 (0.29-0.88) and 0.46 (0.22-0.96). CONCLUSIONS: Lower estimated daily salt intake is a significant risk of mental distress for rural community-dwelling Japanese men. Since depression is reported to be associated with cardiovascular disease, risk estimation for the lower intake of salt on mental distress, especially for mental distress with hypertension, may become an important tool to prevent cardiovascular disease. PMID- 26109461 TI - Prevalence of malaria parasitaemia in school children from two districts of Ghana earmarked for indoor residual spraying: a cross-sectional study. AB - BACKGROUND: Indoor residual spraying (IRS) is considered a valuable transmission control measure against malaria but exact efficacy data are not available for many epidemiological settings. This study was conducted to determine indicators for malaria epidemiology and transmission among school children as baseline assessment before IRS implementation in Ghana. METHODS: A cross-sectional study was conducted in Adansi South District of the Ashanti Region and Wa West District of the Upper West Region of Ghana. Malarial parasitaemia and anaemia were determined in pupils between the ages of 2 and 14 years from Early Childhood Development Centres and primary schools. Plasmodium falciparum parasitaemia was detected by light microscopy. RESULTS: Out of 1,649 pupils who were enrolled at participating schools, 684 were positive for plasmodia resulting in a baseline parasitaemia prevalence of 41.5%. Parasite rate was similar in the two districts (42.0% in Adansi South and 40.7% in Wa West), but differed across the nine sentinel schools ranging from 21 to 63% (p < 0.001). The mean haemoglobin concentration was 11.3 g/dl [standard deviation (SD) +/-2.1]. Pupils who had moderate to mild anaemia (7.0-10.9 g/dl) constituted 41.7% of the study sample. CONCLUSION: The burden of parasitaemia, malaria and anaemia is a major public health problem among school children in rural Ghana with extensive heterogeneity between schools and warrants further investment in intervention measures. PMID- 26109462 TI - Patient navigation to increase colorectal cancer screening among Latino Medicare enrollees: a randomized controlled trial. AB - PURPOSE: Latino Medicare enrollees report suboptimal rates of colorectal cancer screening (CRCS) despite Medicare policies designed to improve CRCS access for older persons. Patient navigation (PN) may address many underlying barriers to CRCS, yet little is known about the effectiveness of PN to increase CRCS adherence among Latino Medicare enrollees. METHODS: Using a randomized controlled trial study design, we evaluated tailored PN delivered outside of primary care settings as an intervention to increase CRCS adherence in this population. Intervention participants (n = 135) received tailored PN services which included education, counseling, and logistical support administered in their language of choice. Comparison participants (n = 168) received mailed cancer education materials. We compared CRCS rates between interventions and used multivariable logistic regression to assess the odds of CRCS adherence for PN versus comparison groups after adjusting for covariates of interest. RESULTS: More navigated than non-navigated participants became CRCS adherent during the study period (43.7 vs. 32.1%, p = 0.04). The odds of CRCS adherence were significantly higher for PN relative to comparison participants before and after adjusting for covariates (unadjusted OR 1.64, p = 0.04; adjusted OR 1.82, p = 0.02). Higher CRCS adherence rates were observed primarily in the uptake of endoscopic screening methods. CONCLUSION: This study demonstrates that PN delivered outside of the primary care environment is modestly effective in increasing CRCS adherence among Latino Medicare enrollees. This intervention strategy should be further evaluated as a complement to primary care-based PN and other care coordination strategies to increase adherence with CRCS and other evidence-based screenings among older Latinos. PMID- 26109463 TI - Association of total cancer and lung cancer with environmental exposure to cadmium: the meta-analytical evidence. AB - BACKGROUND: Recent studies are indicative of substantial progress in understanding the dose-response relation between the incidence of total and lung cancer and environmental cadmium exposure. We conducted a meta-analysis of population studies that examined the risk of cancer in relation to lifetime exposure to cadmium. METHODS: We searched MEDLINE, Web of Science, and relevant reviews until August 2014 for studies on the association between cancer risk and cadmium exposure. Eligible studies had to include an estimate of lifetime exposure to cadmium as reflected by the urinary cadmium concentration and adjustment of the cancer risk at least for age and smoking. We pooled relative risk across the studies estimates for cancer and lung cancer using variance weighted random-effect models and expressed association sizes for a twofold increase in urinary cadmium, thereby respecting the continuous nature of the association. RESULTS: The meta-analysis included 20,459 participants from three prospective population studies. The average urinary cadmium concentration across populations ranged from 0.25 to 0.93 ug/g creatinine. The relative risk of total cancer, associated with a doubling of the urinary cadmium concentration, ranged across the different studies from 1.18 to 1.31, and the pooled relative risk was 1.22 (95% CI 1.13-1.31; p < 0.0001). For lung cancer, the relative risk ranged from 1.21 to 1.70 for a doubling of the urinary cadmium concentration, while the pooled relative risk amounted to 1.68 (1.47-1.92; p < 0.0001). Excluding one study at the time did not move the pooled estimates outside the confidence interval of the overall estimate for all studies combined. CONCLUSION: The epidemiological evidence of the last decade consistently identifies low-level environmental exposure to cadmium as a risk factor for total cancer and lung cancer. PMID- 26109464 TI - 5-alpha reductase inhibitors, benign prostatic hyperplasia, and risk of male breast cancer. AB - PURPOSE: 5-alpha reductase inhibitors (5-ARI) have been suggested to increase the risk of male breast cancer. The aim of this study was to study the risk of breast cancer in men on 5-ARI, in men with benign prostatic hyperplasia (BPH) not on 5 ARI, and in men without BPH. METHODS: We performed a population-based cohort study in Sweden with data from The Prescribed Drug Register, The Patient Register, and The Cancer Register. Men on 5-ARI, men on alpha-blockers, or men who had undergone a transurethral resection of the prostate (TUR-P) prior to or during 2006-2008 were included as exposed to BPH and a specific treatment thereof. For each exposed man, five unexposed men were selected. Risk of breast cancer was calculated in Cox proportional hazard models. RESULTS: There were 124,183 exposed men and 545,293 unexposed men, and during follow-up (median 6 years), 99 men with breast cancer were diagnosed. Compared to unexposed men, men on 5-ARI had a hazard ratio (HR) of breast cancer of 0.74 (95% confidence interval (CI) 0.27-2.03), men on alpha-blockers had HR 1.47 (95% CI 0.73-2.95), and men with a TUR-P had HR 1.99 (95% CI 1.05-3.75). CONCLUSION: No increased risk of breast cancer was observed for men on 5-ARI. However, the increased risk of breast cancer among men who had undergone a TUR-P, a strong indicator of BPH, suggests that the endocrine milieu conducive to BPH is associated with male breast cancer. PMID- 26109465 TI - Using isopropyl alcohol impregnated disinfection caps in the neonatal intensive care unit can cause isopropyl alcohol toxicity. AB - AIM: The safety of SwabCap alcohol impregnated disinfection caps was questioned in our unit because of malfunctions in luer access valves. We examined whether SwabCaps affected the integrity of two luer access valves and were associated with alcohol injected into the lines. METHODS: Our bench test study included seven circuits using SmartSite or CARESITE valves exposed to two environmental temperatures. Passive circuits consisted of a 96-hour contact system using SwabCap without other interventions. Active circuits consisted of nine sham injections during a 24-hour period, with the SwabCap replaced after each injection. The active control circuit used isopropyl alcohol impregnated pads to disinfect valves. Isopropyl alcohol was measured at the extremity of all active circuits by gas chromatography. RESULTS: The visual appearance of all SmartSite valves and 67% of the CARESITE valves was changed by SwabCap use. The mean isopropyl alcohol dosages were 52 mmol/L in the SmartSite and 8 mmol/L in the CARESITE at room temperature and 73 and 7 mmol/L, respectively, at 35 degrees C. No alcohol was found in the control circuit. CONCLUSION: The SwabCap altered the valves' appearance and allowed significant amounts of isopropyl alcohol to be injected. It should not be used for neonates without further research. PMID- 26109466 TI - Molecular classification of idiopathic pulmonary fibrosis: personalized medicine, genetics and biomarkers. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease associated with high morbidity and poor survival. Characterized by substantial disease heterogeneity, the diagnostic considerations, clinical course and treatment response in individual patients can be variable. In the past decade, with the advent of high-throughput proteomic and genomic technologies, our understanding of the pathogenesis of IPF has greatly improved and has led to the recognition of novel treatment targets and numerous putative biomarkers. Molecular biomarkers with mechanistic plausibility are highly desired in IPF, where they have the potential to accelerate drug development, facilitate early detection in susceptible individuals, improve prognostic accuracy and inform treatment recommendations. Although the search for candidate biomarkers remains in its infancy, attractive targets such as MUC5B and MPP7 have already been validated in large cohorts and have demonstrated their potential to improve clinical predictors beyond that of routine clinical practices. The discovery and implementation of future biomarkers will face many challenges, but with strong collaborative efforts among scientists, clinicians and the industry the ultimate goal of personalized medicine may be realized. PMID- 26109467 TI - Bioprotective carnitinoids: lipoic acid, butyrate, and mitochondria-targeting to treat radiation injury: mitochondrial drugs come of age. AB - Preclinical Research Given nuclear-power-plant incidents such as the 2011 Japanese Fukushima-Daiichi disaster, an urgent need for effective medicines to protect against and treat the harmful biological effects of radiation is evident. To address such a challenge, we describe potential strategies herein including mitochondrial and epigenetic-driven methods using lipoic and butyric acid ester conjugates of carnitine. The antioxidant and other therapeutically beneficial properties of this class of agents may protect against ionizing radiation and resultant mitochondrial dysfunction. Recent studies of the compounds described herein reveal the potential-although further research and development is required to prove the effectiveness of this approach-to provide field-ready radiation protective drugs. PMID- 26109468 TI - Effects of kramecyne on LPS induced chronic inflammation and gastric ulcers. AB - Preclinical Research Krameria cytisoides is used for the treatment of inflammation, stomach pain, and gastric ulcers. The active ingredient from this plant is a peroxide, kramecyne (KACY) which has anti-inflammatory effects. The aim of the present study was to evaluate the anti-inflammatory activities of KACY in lipopolysaccharide (LPS)-induced systemic chronic inflammation in mice for 60 days, using dexamethasone (DEX) as the positive control, vehicle (the LPS group) as the negative control and the control group (mice without inflammation). KACY did not affect survival, body weight or relative organ weight in mice but it: decreased nitric oxide (NO) production by 68%; prostaglandin E2 (PGE2 ) by 67%; increased release of anti-inflammatory cytokine IL-10 (2.0-fold), and reduced production of the proinflammatory cytokines, IL-6 (2.0-fold), IL-1beta (2.4 fold), and TNF-alpha (2.0-fold). Furthermore, the gastroprotective effects of KACY in mice were evaluated in an ethanol-induced gastric ulcer model. The results showed that KACY at 50 and 100 mg/kg exerted gastroprotective effects with similar activity to 50 mg/kg ranitidine. In gastric tissues, KACY decreased the level of malondialdehyde (MDA) but increased the catalase (CAT) activity. KACY have potential for the treatment of chronic inflammatory diseases due its similar activity to that of DEX. It also has gastroprotective effects. PMID- 26109469 TI - Carvedilol attenuates inflammatory biomarkers and oxidative stress in a rat model of ulcerative colitis. AB - Preclinical Research This study evaluated the effects of the carvedilol, a nonselective beta-adrenoceptor anatgonist with alpha1-adrenoceptor antagonist activity, in a rat model of experimentally induced ulcerative colitis (UC). UC was produced using acetic acid (AA) in animals previously treated with carvedilol (30 mg/kg po, qd) for seven days. Mucus content, lipid peroxidation (LPO) products, sulfhydryl groups, antioxidant enzyme activities, proinflammatory cytokines, prostaglandin E2 and nitric oxide levels were measured in colonic tissues and histopathological changes were assessed. LPO and proinflammatory biomarkers were markedly increased, while mucus content, sulfhydryl groups and enzymatic activities were inhibited in animals administered AA. Pretreatment with carvedilol attenuated LPO elevation, mucus content and sulfhydryl group inhibitions. Antioxidant enzymatic activity and proinflammatory biomarker levels were also restored in carvedilol-pretreated animals. Colonic protection associated with carvedilol pretreatment was further confirmed by histopathological assessment and found to be similar to the standard therapy of mesalazine (100 mg/kg po qd), suggesting that the effects of carvedilol action may be attributable to its anti-inflammatory and antioxidant properties. PMID- 26109470 TI - Effect of six years intensified multifactorial treatment on levels of hs-CRP and adiponectin in patients with screen detected type 2 diabetes: the ADDITION Netherlands randomized trial. AB - BACKGROUND: Levels of high-sensitivity C-reactive protein (hs-CRP) and adiponectin, reflecting chronic inflammation, are associated with cardiovascular disease in type 2 diabetes. The long-term effects of multifactorial therapy in type 2 diabetes patients on CRP and adiponectin are unknown. METHODS: The ADDITION-NL study is a randomized clinical trial among screen-detected type 2 diabetes patients, randomized to intensive treatment (HbA1c <7.0% (53 mmol/mol), blood pressure <=135/85 mmHg, total cholesterol <=3.5 mmol/L) or routine care. Hs CRP and adiponectin were measured before and 1, 2 and 6 years after inclusion. We analysed the effectiveness of the intervention on hs-CRP and adiponectin levels using a mixed effects model, taking into account practice, baseline levels and different medications. RESULTS: A total of 424 patients were included (intensive care n = 235; routine care n = 189). Both groups were well matched. Body mass index, systolic blood pressure, total cholesterol and HbA1c improved significantly more in the intensive care group compared to routine care group. Levels of hs-CRP decreased significantly in both treatment groups over time. Mean hs-CRP in the routine care group was 24% higher (p = 0.0027) than in the intensive treatment group during follow-up. After an initial increase the adiponectin values levelled off to nearly baseline values in both groups. The difference between the two groups after 6 years was 0.44 ug/mL (p = 0.27). CONCLUSIONS: Intensified multifactorial treatment in type 2 diabetes results in an enhanced decrease in hs-CRP. Whether this is clinically meaningful remains uncertain. The link to adiponectin seems to be more complex. PMID- 26109471 TI - The bone-preserving effects of exendin-4 in ovariectomized rats. AB - Exendin-4 was found to be beneficial to the skeleton in diabetic rodents. In this study, we assessed the changes of bone mineral densities (BMDs) and quality in non-diabetic ovariectomized (OVX) rats after treatment with exendin-4. The regulatory role of exendin-4 on osteoblastogenesis and adipogenesis in rat bone marrow stromal cells (BMSCs) was also explored. Three months after sham surgery or OVX, 18 5-month-old female Wistar rats were divided into three groups and received the following treatment for 8 weeks: (1) Sham + vehicle; (2) OVX + vehicle; and (3) OVX + exendin-4 20 ug/kg/day. Micro-CT and three-point bending test were used to evaluate the BMDs, bone morphometric parameters, and biomechanical properties. Real-time PCR and Western blot were performed to measure gene and protein expression after exendin-4 treatment in adipogenesis and osteoblastogenesis of rat BMSCs. Exendin-4 could improve trabecular volume, thickness, and number, increase BMD, and reduce trabecular spacing in the lumbar spine and femur of OVX rats. Exendin-4 had little impact on the mechanical resistance of femurs to fracture. When rat BMSCs were treated with exendin-4, the mRNA expression levels of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and collagen alpha1 (Coll-1) were increased, while those of peroxisome proliferators activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha) decreased. Exendin-4 treatment also resulted in increased expression levels of p38, p42/44, and beta-catenin proteins. Exendin-4 was anabolic to bone in OVX rats possibly by facilitating osteoblastogenesis while repressing adipogenesis during BMSC lineage differentiation. PMID- 26109473 TI - Is mitomycin C useful as an adjuvant therapy in endoscopic treatment of laryngotracheal stenosis? PMID- 26109472 TI - Radioiodine-remnant ablation in low-risk differentiated thyroid cancer: pros. AB - Differentiated thyroid carcinomas are typically treated with total thyroidectomy as initial therapy. Subsequent radioactive iodine (RAI) ablation destroys post surgical thyroid remnants, can additionally provide adjuvant therapy of residual and metastatic thyroid cancers, and enhances the sensitivity and specificity of further diagnostic studies. There is current controversy regarding whether a large number of patients, broadly considered to have "low-risk" disease, should be provided RAI ablation. This is consequent to over-reliance on short-term studies, under-appreciation of the value of RAI remnant ablation, and inflation of the side effects of RAI therapy. A balanced assessment of all of these issues provides justification to utilize post-surgical radioiodine ablation, even in cases that are considered low risk on the basis of surgical findings. PMID- 26109474 TI - Wild bird-associated Campylobacter jejuni isolates are a consistent source of human disease, in Oxfordshire, United Kingdom. AB - The contribution of wild birds as a source of human campylobacteriosis was investigated in Oxfordshire, United Kingdom (UK) over a 10 year period. The probable origin of human Campylobacter jejuni genotypes, as described by multilocus sequence typing, was estimated by comparison with reference populations of isolates from farm animals and five wild bird families, using the STRUCTURE algorithm. Wild bird-attributed isolates accounted for between 476 (2.1%) and 543 (3.5%) cases annually. This proportion did not vary significantly by study year (P = 0.934) but varied seasonally, with wild bird-attributed genotypes comprising a greater proportion of isolates during warmer compared with cooler months (P = 0.003). The highest proportion of wild bird-attributed illness occurred in August (P < 0.001), with a significantly lower proportion in November (P = 0.018). Among genotypes attributed to specific groups of wild birds, seasonality was most apparent for Turdidae-attributed isolates, which were absent during cooler, winter months. This study is consistent with some wild bird species representing a persistent source of campylobacteriosis, and contributing a distinctive seasonal pattern to disease burden. If Oxfordshire is representative of the UK as a whole in this respect, these data suggest that the national burden of wild bird-attributed isolates could be in the order of 10,000 annually. PMID- 26109475 TI - Treatment of EBV-associated nodular sclerosing Hodgkin lymphoma in a patient with ataxia telangiectasia with brentuximab vedotin and reduced COPP plus rituximab. AB - Patients with ataxia telangiectasia (AT) with malignancies face poor prognosis due to increased treatment-related toxicity. Here, we report a 14-year-old male with AT and Hodgkin lymphoma (HL) who received brentuximab vedotin and reduced COPP plus rituximab courses. This treatment resulted in complete remission and showed no severe toxicity. PMID- 26109477 TI - Managerial practices and factors influencing reproductive performance of dairy cows in urban/peri-urban areas of Kampala and Gulu, Uganda. AB - BACKGROUND: Urban/peri-urban dairy production and sales has evolved as an adjustment to cope with food security and economic needs for urban dwellers in low-income countries and created an opportunity to transform from subsistence rural lifestyles of dairy farming to commercial engagement in towns. However, urban/peri-urban dairy farms differ in challenges from rural dairy farms and reproduction is important and critical for assuring sustainable economic output in both environments. Here we recorded for the first time differences between two geographically and economically different cities corresponding to different settings within the same country in managerial factors influencing reproductive performance in urban/peri-urban dairy cowherds. RESULTS: The urban/peri-urban dairy farmers in the capital Kampala were more often male (P = 0.002) and commercialized (P = 0.0025), more experienced (P = 0.0001) and practiced zero grazing more often (P = 0.05) than in the regional municipality Gulu. Also, the milk production per herd and cow (P = 0.0005) and calving rate were (P = 0.0001) higher in Kampala and artificial insemination was more commonly (P = 0.002) used than in Gulu. There was no difference in abortion nor neonatal mortality rate between the two locations. Overall, calving rates were higher (P = 0.0003) in smaller (<=3 dairy cows) and open grazing (P = 0.003) herds. Abortion rates were higher among dairy herds practicing late (>=5 months) (P = 0.003) calf weaning and in herds with commercial purposes (P = 0.0001). Neonatal calf mortality was lower (P = 0.01) in small herds. CONCLUSION: The study showed significant differences between Kampala and Gulu in reproductive performance and related husbandry factors for cows in the urban/peri-urban dairy farming systems. For several reproductive performance traits we found associations with husbandry and production traits, which should be taken into account when providing advice to the urban and peri-urban dairy farmers in the tropics. PMID- 26109476 TI - Disrupted functional connectivity of cerebellar default network areas in attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is increasingly understood as a disorder of spontaneous brain-network interactions. The default mode network (DMN), implicated in ADHD-linked behaviors including mind-wandering and attentional fluctuations, has been shown to exhibit abnormal spontaneous functional connectivity (FC) within-network and with other networks (salience, dorsal attention and frontoparietal) in ADHD. Although the cerebellum has been implicated in the pathophysiology of ADHD, it remains unknown whether cerebellar areas of the DMN (CerDMN) exhibit altered FC with cortical networks in ADHD. Here, 23 adults with ADHD and 23 age-, IQ-, and sex-matched controls underwent resting state fMRI. The mean time series of CerDMN areas was extracted, and FC with the whole brain was calculated. Whole-brain between-group differences in FC were assessed. Additionally, relationships between inattention and individual differences in FC were assessed for between-group interactions. In ADHD, CerDMN areas showed positive FC (in contrast to average FC in the negative direction in controls) with widespread regions of salience, dorsal attention and sensorimotor networks. ADHD individuals also exhibited higher FC (more positive correlation) of CerDMN areas with frontoparietal and visual network regions. Within the control group, but not in ADHD, participants with higher inattention had higher FC between CerDMN and regions in the visual and dorsal attention networks. This work provides novel evidence of impaired CerDMN coupling with cortical networks in ADHD and highlights a role of cerebro-cerebellar interactions in cognitive function. These data provide support for the potential targeting of CerDMN areas for therapeutic interventions in ADHD. PMID- 26109478 TI - Safety of intravenous metoprolol use in unmonitored wards: a single-centre observational study. AB - BACKGROUND AND AIM: This study aims to examine and quantify the risks associated with the use of intravenous metoprolol on unmonitored wards. METHOD: This study was a retrospective single-centre observational study from 1 January 2009 to 31 December 2013. The study hospital was a 415-bed, private hospital in Melbourne, Victoria. The study population was all patients who received intravenous metoprolol on an unmonitored ward. The primary outcome measure was the rate of serious adverse events (SAE), defined as a complication of intravenous metoprolol resulting in transfer to a critical-care environment, a medical emergency team call or death. RESULTS: Six hundred and nine patients received a total of 8260 doses of intravenous metoprolol. Seven cases were identified with a SAE deemed possibly related to beta-blocker use and there was one death. All SAE were hypotension, giving an overall rate of hypotension of 7/609 or 1.1% (95% confidence interval (CI), 0.5 to 2.4%) with a rate per dose delivered of 0.8/1000 doses (95% CI 0.3 to 1.7). The death occurred in a 94-year-old woman with abdominal sepsis. After case file review, consensus opinion deemed this to be unrelated to intravenous metoprolol. CONCLUSION: The use of intravenous metoprolol on unmonitored wards appears to be safe. The complication rate was low, suggesting that this may be a sensible approach to the management of in hospital populations at risk of beta-blocker withdrawal. PMID- 26109479 TI - Molecular Simulation of the DPPE Lipid Bilayer Gel Phase: Coupling between Molecular Packing Order and Tail Tilt Angle. AB - The structural properties and thermal stability of dipalmitoylphosphatidylethanolamine (DPPE) in the ordered gel phase have been studied by molecular dynamics simulation using two force fields: the Berger united-atom model and the CHARMM C36 atomistic model. As is widely known, structural features are sensitive to the initial preparation of the gel phase structure, as some degrees of freedom are slow to equilibrate on the simulation time scale of hundreds of nanoseconds. In particular, we find that the degree of alignment of the lipids' glycerol backbones, which join the two hydrocarbon tails of each molecule, strongly affects the tilt angle of the tails in the resulting structures. Disorder in the backbone correlates with lower tilt angles: bilayer configurations initiated with aligned backbones produced tilt angles near 21 degrees and 29 degrees for the Berger and C36 force fields, respectively, while structures initiated with randomized backbone orientations showed average tilt angles of 7 degrees and 18 degrees , in closer agreement with the untilted structure observed experimentally. The transition temperature for the Berger force field gel bilayer has been determined by monitoring changes in width of gel phase stripe domains as a function of temperature and is 12 +/- 5 K lower than the experimental value. PMID- 26109481 TI - Site-specific Substitutions Eliminate Aggregation Properties of Hemopressin. AB - Hemopressin is a naturally occurring and therapeutically relevant peptide with applications in hypertension, pain, addiction, and obesity. We had previously demonstrated that hemopressin converts into amyloid-like fibrils under aqueous conditions. However, the amino acid residues that modulate the aggregation propensity of hemopressin were not identified. In this study, we designed and synthesized 25 different analogs of hemopressin and analyzed their aggregation properties using the principle of dynamic light scattering. As a result, we were able to identify four conservative changes in the peptide sequence (Val(2) >DVal(2), Asn(3) ->Gln(3) Leu(7) ->Npg(7) and C-OH->C-NH2) that minimize aggregation propensity of hemopressin. The results indicate that hemopressin aggregation is cooperative in nature and involves contribution from multiple amino acids within the peptide chain. The analogs and the corresponding aggregation propensity data reported in this study would be useful for researchers investigating therapeutic properties of hemopressin, which have been hampered due to the tendency of hemopressin to aggregate in aqueous solutions. PMID- 26109480 TI - Metabolic network modeling of microbial communities. AB - Genome-scale metabolic network reconstructions and constraint-based analyses are powerful methods that have the potential to make functional predictions about microbial communities. Genome-scale metabolic networks are used to characterize the metabolic functions of microbial communities via several techniques including species compartmentalization, separating species-level and community-level objectives, dynamic analysis, the 'enzyme-soup' approach, multiscale modeling, and others. There are many challenges in the field, including a need for tools that accurately assign high-level omics signals to individual community members, the need for improved automated network reconstruction methods, and novel algorithms for integrating omics data and engineering communities. As technologies and modeling frameworks improve, we expect that there will be corresponding advances in the fields of ecology, health science, and microbial community engineering. PMID- 26109482 TI - How Hong Kong helped Vietnamese refugees in 1979. PMID- 26109483 TI - Improved cognitive performance after a single dialysis session: where do we go from here? PMID- 26109484 TI - Novel lectin-independent approach to detect galactose-deficient IgA1 in IgA nephropathy. AB - BACKGROUND: Galactose-deficient IgA1 (Gd-IgA1) is a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN). Although many researchers have measured serum levels of Gd-IgA1 using snail helix aspersa agglutinin (HAA) lectin-based assay, the lectin-dependent assay has some serious problems in robustness. In this study, we aimed to establish a more robust and stable enzyme linked immunosorbent assay (ELISA) method that uses a specific monoclonal antibody to recognize a hinge region in human Gd-IgA1 (Gd-IgA1 ELISA). METHODS: Rats were immunized with human Gd-IgA1 hinge region peptide to obtain Gd-IgA1 specific monoclonal antibody KM55. Gd-IgA1 ELISA for specifically detecting serum Gd-IgA1 was consequently constructed. Serum Gd-IgA1 concentrations in human subjects were measured using KM55 ELISA assay. To further confirm specificity of the Gd-IgA1-specific antibody, KM55 was also applied for immunofluorescence staining of glomerular Gd-IgA1 in paraffin-embedded sections of renal biopsy specimens. RESULTS: Measurement of serum levels of Gd-IgA1 in human subjects by Gd-IgA1 ELISA revealed increased serum Gd-IgA1 level in patients with IgAN compared with patients with other renal diseases or non-renal diseases. Importantly, the results obtained from Gd-IgA1 ELISA positively correlated with those from the HAA lectin-based assay (R = 0.75). Immunofluorescence staining of renal biopsy specimens with KM55 detected glomerular co-localization of Gd-IgA1 and IgA. CONCLUSION: This novel lectin-independent method with KM55 for measuring serum levels of Gd-IgA1 can pave the way for more convincing diagnosis and activity assessment of IgAN, and can expedite clinical research to better understand this difficult disease. PMID- 26109485 TI - Cost of renal replacement: how to help as many as possible while keeping expenses reasonable? AB - The treatment of kidney diseases consumes a substantial amount of the health budget for a relatively small fraction of the overall population. If the nephrological community and society do not develop mechanisms to contain those costs, it will become impossible to continue assuring optimal outcomes and quality of life while treating all patients who need it. In this article, we describe several mechanisms to maintain sustainability of renal replacement therapy. These include (i) encouragement of transplantation after both living and deceased donation; (ii) stimulation of alternative dialysis strategies besides classical hospital haemodialysis, such as home haemodialysis, peritoneal dialysis or self-care and necessitating less reimbursement; (iii) promotion of educational activities guiding the patients towards therapies that are most suited for them; (iv) consideration of one or more of cost containment incentives such as bundling of reimbursement (if not affecting quality of the treatment), timely patient referral, green dialysis, start of dialysis based on clinical necessity rather than renal function parameters and/or prevention of CKD or its progression; (v) strategically planned adaptations to the expected growth of the ageing population in need of renal replacement; (vi) the necessity for support of research in the direction of helping as large as possible patient populations for acceptable costs; and (vii) the need for more patient-centred approaches. We also extend the discussion to the specific situation of kidney diseases in low- and middle-income countries. Finally, we point to the dramatic differences in accessibility and reimbursement of different modalities throughout Europe. We hope that this text will offer a framework for the nephrological community, including patients and nurses, and the concerned policy makers and caregivers on how to continue reaching all patients in need of renal replacement for affordable expenses. PMID- 26109486 TI - Prospective assessment of consensus criteria for evaluation of patients with suspected choledocholithiasis. AB - BACKGROUND AND AIM: American Society for Gastrointestinal Endoscopy (ASGE) guidelines have proposed criteria to stratify patients into low, intermediate and high risk of choledocholithiasis. The criteria include variables that are readily available in clinical practice. The objective of the present study was to prospectively assess the accuracy of these criteria. METHODS: A prospective observational cohort study was conducted at Beth Israel Deaconess Medical Center. All adult patients referred for endoscopic retrograde cholangiopancreatography (ERCP) with suspected choledocholithiasis were considered for inclusion. ASGE criteria were applied, and each patient was categorized as high, intermediate or low risk for choledocholithiasis. Presence of stone at ERCP served as criteria standard. RESULTS: During the study period, 402 patients met study inclusion criteria and 336 were reported in the final analysis. Of the 244 patients in the high risk for choledocholithiasis group, 185 were found to have stones at ERCP (75.8%, 95% CI 70.2-80.1%). Of the 92 patients in the intermediate risk for choledocholithiasis group, 45 had stones at ERCP (48.9%, 95% CI 38.8-59.1%); P value for difference between groups = 0.001. Diagnostic accuracy for choledocholithiasis in the high-risk group was 69.05%, and for the intermediate group was 39.95%. Presence of choledocholithiasis on pre-ERCP imaging (OR: 3.6; 95% CI 2.2-6.0; P < 0.01), and bilirubin >1.8 but <4 mg/dL (OR: 1.69; 95% CI 1.0 2.8; P < 0.04) were the strongest predictors of choledocholithiasis. No additional variable that improved accuracy of ASGE criteria was identified. CONCLUSION: ASGE criteria stratify patients by risk for choledocholithiasis and can be used in routine clinical practice. PMID- 26109487 TI - Portal vein embolization and its effect on tumour progression for colorectal cancer liver metastases. AB - BACKGROUND: The aim of this study was to evaluate the long-term outcomes of patients with colorectal cancer liver metastasis (CRCLM) exhibiting disease progression after portal vein embolization (PVE). METHODS: Patients with CRCLM requiring PVE before hepatectomy between 2003 and 2014 were included. Clinical variables, and liver and tumour volumes determined by three-dimensional CT volumetry were assessed before and after PVE. Overall and disease-free survival data were obtained. Univariable and multivariable logistic regression analyses were performed to identify predictors of tumour progression after PVE. RESULTS: Of 141 patients who underwent PVE, 93 (66.0 per cent) had tumour progression and 17 (12.1 per cent) developed new contralateral lesions. Significantly fewer patients had resectable disease in the group with disease progression than among those with stable disease: 43 (46 per cent) of 93 versus 36 (75 per cent) of 48 respectively (P = 0.001). Median survival was similar in patients with and without tumour growth after PVE: 22.5 versus 26.0 months for patients with unresectable tumours (P = 0.706) and 46.2 versus 52.2 months for those with resectable disease (P = 0.953). However, disease-free survival for patients with tumour progression after PVE was shorter than that for patients with stable disease (6.0 versus 20.2 months; P = 0.045). Response to neoadjuvant chemotherapy was the only significant factor associated with tumour progression in multivariable analysis. CONCLUSION: Tumour progression after PVE did not affect overall survival, but patients with resected tumours who had tumour growth after embolization experienced earlier recurrence. A borderline response to neoadjuvant chemotherapy seemed to be associated with tumour progression after PVE. PMID- 26109488 TI - Arrangement and Applying of Movement Patterns in the Cerebellum Based on Semi supervised Learning. AB - Biological control systems have long been studied as a possible inspiration for the construction of robotic controllers. The cerebellum is known to be involved in the production and learning of smooth, coordinated movements. Therefore, highly regular structure of the cerebellum has been in the core of attention in theoretical and computational modeling. However, most of these models reflect some special features of the cerebellum without regarding the whole motor command computational process. In this paper, we try to make a logical relation between the most significant models of the cerebellum and introduce a new learning strategy to arrange the movement patterns: cerebellar modular arrangement and applying of movement patterns based on semi-supervised learning (CMAPS). We assume here the cerebellum like a big archive of patterns that has an efficient organization to classify and recall them. The main idea is to achieve an optimal use of memory locations by more than just a supervised learning and classification algorithm. Surely, more experimental and physiological researches are needed to confirm our hypothesis. PMID- 26109490 TI - Effect of premedication and other factors on the occurrence of acute transfusion reactions in dogs. AB - OBJECTIVE: To evaluate the effect of premedication on transfusion reactions (TRs) within 24 hours after blood product transfusions in dogs. DESIGN: Retrospective study between 2008 and 2011. SETTING: Private veterinary referral hospital. ANIMALS: Nine hundred and thirty-five transfusion events in 558 dogs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records of dogs receiving blood product transfusions were reviewed. Information collected included signalment, weight, transfusion product type, reason for transfusion, first or subsequent transfusion, whether an acute reaction occurred, type of reaction, whether the reaction was treated, premedication prior to the transfusion and the premedication used, other medications the animal was given, whether the animal had an immune-mediated process, and whether the transfusion was administered in the perioperative period. A total of 144 (15%) acute TRs were documented in 136 dogs. The most common TRs were fever alone (77/144 [53%]) and vomiting alone (26/144 [18%]). Six dogs died due to the TR (4%). TR was not associated with age (P = 0.257), sex (P = 0.754), weight (P = 0.829), or premedication (P = 0.312). The type of blood product transfused (P < 0.001) was significantly associated with TRs, with packed RBCs most likely associated with a TR, and plasma least likely. Immune disease (P = 0.015) was significantly associated with occurrence of a TR. Significantly fewer reactions were documented following transfusions given in the perioperative period (P = 0.023). CONCLUSIONS: While most TRs were mild, there were some serious reactions observed including hemolysis, dyspnea, and 6 deaths. Immune-mediated disease was associated with development of a TR, while transfusion during the perioperative period was associated with lower likelihood of reaction. Packed RBC transfusions were associated with development of acute TRs. Overall occurrence of TR was not significantly altered with premedication; however, when evaluated alone, antihistamines decreased the incidence of acute allergic reactions. PMID- 26109491 TI - Clinical application of 3D display device in ophthalmology: measurement of metamorphopsia. AB - PURPOSE: To develop a new tool for detecting metamorphopsia. METHOD: Evaluation of diagnostic test. Novel tool for measuring metamorphopsia was developed using commercial 3D display. Fifty-eight patients diagnosed with macular disease, which included epiretinal membrane, age-related macular degeneration, central serous chorioretinopathy and macular hole, as confirmed by macular optical coherence tomography were tested with Amsler grid and novel method. The subjective perception of metamorphopsia and its effect on the lives of the participants with macular disease was also evaluated using a brief questionnaire. The sensitivity and specificity to subjective perception of metamorphopsia were compared. RESULTS: The sensitivity and specificity were 66.7% and 97.7%, respectively, using the Amsler grid test, and 100% and 90.7%, respectively, using the 3D novel metamorphopsia test developed for this study. CONCLUSIONS: The detection rate of metamorphopsia in macular disease using novel metamorphopsia test was significantly higher than that using the Amsler grid test. This novel approach to detecting for metamorphopsia can also be used at home for self-assessment. PMID- 26109492 TI - Adalimumab markedly improves enthesitis in patients with psoriatic arthritis: Evaluation with a magnetic resonance imaging scoring system. AB - Psoriatic arthritis (PsA), a seronegative arthropathy, may often result in progressive joint damage without treatment, leading to disability and impaired quality of life. Early therapeutic intervention of PsA is therefore crucial before the development of irreversible joint damage. Because psoriatic skin lesions generally precede the onset of PsA, dermatologists occupy an important position in treating patients with early PsA. This study aimed to evaluate the efficacy of adalimumab in treating joint disease in patients with PsA, using the PsA magnetic resonance imaging scoring system (PsAMRIS). Five adult Japanese male patients with active PsA were treated with adalimumab. Magnetic resonance imaging was obtained at baseline and 8-32 weeks with 2-3 time points following adalimumab treatment and assessed using PsAMRIS. Adalimumab treatment markedly improved clinical symptoms and disease activities of joint disease, which was confirmed by the reduction of PsAMRIS scores in all patients. Bone marrow edema and periarticular inflammation, reflecting the presence of enthesitis, were dramatically improved at week 8, while improvement of synovitis and flexor tenosynovitis was observed later, at week 24 or 32. However, bone erosion was not improved by adalimumab treatment during the follow-up period. These results indicate that adalimumab treatment is associated with dramatic improvement of enthesitis in patients with PsA, whereas bone erosion may be resistant to such treatment. PsAMRIS appears to be useful for the evaluation of treatment efficacy in PsA. PMID- 26109493 TI - Multidrug resistant TB is less transmissible than drug susceptible strains, study shows. PMID- 26109495 TI - Revealing patterns of local species richness along environmental gradients with a novel network tool. AB - How species richness relates to environmental gradients at large extents is commonly investigated aggregating local site data to coarser grains. However, such relationships often change with the grain of analysis, potentially hiding the local signal. Here we show that a novel network technique, the "method of reflections", could unveil the relationships between species richness and climate without such drawbacks. We introduced a new index related to potential species richness, which revealed large scale patterns by including at the local community level information about species distribution throughout the dataset (i.e., the network). The method effectively removed noise, identifying how far site richness was from potential. When applying it to study woody species richness patterns in Spain, we observed that annual precipitation and mean annual temperature explained large parts of the variance of the newly defined species richness, highlighting that, at the local scale, communities in drier and warmer areas were potentially the species richest. Our method went far beyond what geographical upscaling of the data could unfold, and the insights obtained strongly suggested that it is a powerful instrument to detect key factors underlying species richness patterns, and that it could have numerous applications in ecology and other fields. PMID- 26109489 TI - Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis. AB - OBJECTIVE: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions. METHODS: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated. RESULTS: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody-positive patients received lower median dosages of methotrexate compared with antidrug antibody-negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of >=30 kg/m(2) and poor adherence were associated with lower drug levels. CONCLUSION: Pharmacologic testing in anti-tumor necrosis factor-treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months. PMID- 26109496 TI - Oxytocin and bone status in men: analysis of the MINOS cohort. AB - Oxytocin, a neurohypophysial hormone, regulates bone metabolism in animal studies and postmenopausal women. In men, oxytocin is not associated with bone mineral density, bone turnover markers, or prevalent fractures, but weakly negatively with incident fragility fracture requiring further studies. INTRODUCTION: We previously showed that serum oxytocin (OT) level is associated with bone mineral density (BMD) and bone turnover rate in postmenopausal women. The aim of our study was to assess the relationship between circulating OT levels and bone status in men. METHODS: In 552 men aged 50 and older from the MINOS cohort, we measured serum levels of OT. We assessed the association of serum OT levels with BMD (lumbar, femoral neck, total hip), bone turnover markers (BTM) (serum N terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (bone ALP), and C-terminal telopeptide of type I collagen (CTX-I)) and fracture risk. RESULTS: In the univariate analysis, serum OT level was not associated with BMD at any site, BTM levels, or with prevalent or incident fracture. OT was significantly correlated with body mass index (BMI) (r = 0.17, p < 0.001), total or bioavalaible 17beta-estradiol (r = 0.09, p = 0.04 and r = 0.20, p < 0.001, respectively), free testosterone (r = 0.17, p < 0.001), and leptin (r = 0.16, p < 0.001). Multivariate analysis did not show significant relationship between serum OT and BMD. After adjustment for age, BMI, interaction BMI/age, history of fall in the last year, and BMD, OT and prevalent fracture were not associated. By contrast, the same analysis with additional adjustment for prevalent fracture showed a weakly significant negative association between OT and incident fracture, e.g., after adjustment for femoral neck BMD, HR = 0.73, 95 %CI 0.55-0.99, p = 0.04. CONCLUSION: In men, serum OT levels are not associated with BMD, bone turnover rate, or prevalent fractures. The weak negative relationship with fracture risk requires further studies. PMID- 26109497 TI - A far-red fluorescent probe for flow cytometry and image-based functional studies of xenobiotic sequestering macrophages. AB - Clofazimine (CFZ) is an optically active, red-colored chemotherapeutic agent that is FDA approved for the treatment of leprosy and is on the World Health Organization's list of essential medications. Interestingly, CFZ massively accumulates in macrophages where it forms crystal-like drug inclusions (CLDIs) after oral administration of the drug in animals and humans. The analysis of the fluorescence spectra of CLDIs formed by resident tissue macrophages revealed that CFZ, when accumulated as CLDIs, undergoes a red shift in fluorescence excitation (from Ex: 540-570 to 560-600 nm) and emission (Em: 560-580 to 640-700 nm) signal relative to the soluble and free-base crystal forms of CFZ. Using epifluorescence microscopy, CLDI(+) cells could be identified, relative to CLDI(-) cells, based on a >3-fold increment in mean fluorescence signal at excitation 640 nm and emission at 670 nm. Similarly, CLDI(+) cells could be identified by flow cytometry, based on a >100-fold increment in mean fluorescence signal using excitation lasers at 640 nm and emission detectors >600 nm. CLDI's fluorescence excitation and emission was orthogonal to that of cell viability dyes such as propidium iodide and 4,6-diamidino-2-phenylindole dihydrochloride (DAPI), cellular staining dyes such as Hoechst 33342 (nucleus) and FM 1-43 (plasma membrane), as well as many other fluorescently tagged antibodies used for immunophenotyping analyses. In vivo, >85% of CLDI(+) cells in the peritoneal exudate were F4/80(+) macrophages and >97% of CLDI(+) cells in the alveolar exudate were CD11c(+). Most importantly, the viability of cells was minimally affected by the presence of CLDIs. Accordingly, these results establish that CFZ fluorescence in CLDIs is suitable for quantitative flow cytometric phenotyping analysis and functional studies of xenobiotic sequestering macrophages. PMID- 26109498 TI - Heat-related illness in China, summer of 2013. AB - Extreme heat events have occurred more frequently in China in recent years, leading to serious impacts on human life and the health care system. To identify the characteristics of individuals with heat-related illnesses in China during the summer of 2013, we collected the data from the Heat-related Illness Surveillance System in Chinese Center for Disease Control and Prevention (China CDC). A total of 5758 cases were reported in the summer of 2013, mostly concentrated in urban areas around the middle and lower reaches of the Yangtze River. We found a difference in age distribution of percentage of deaths from heat-related illness between males and females. Severe cases in males mostly occurred in the age group 45-74 years but in females mostly in the age group over 75. A distributed lag non-linear model had been used to identify population vulnerabilities in Ningbo and Chongqing. The results show that there was a clear positive relationship between maximum temperature and heat-related illness, and the heat effect was nonlinear and could last for 3 days. The elderly and males in the range of 45-64 years old might be the most vulnerable people of heat-related illness in China. We also highlighted some deficiencies of the surveillance system, such that the reported data were not accurate, comprehensive, or timely enough at this stage. PMID- 26109499 TI - 20(S)-protopanaxatriol inhibits liver X receptor alpha-mediated expression of lipogenic genes in hepatocytes. AB - 20(S)-protopanaxatriol (PPT) is an aglycone of ginsenosides isolated from Panax ginseng and has several interesting activities, including anti-inflammatory and anti-oxidative stress effects. Herein, PPT was identified as an inhibitor against the ligand-dependent transactivation of liver X receptor alpha (LXRalpha) using a Gal4-TK-luciferase reporter system. LXRalpha is a transcription factor of nuclear hormone receptor family and stimulates the transcription of many metabolic genes, such as lipogenesis- or reverse cholesterol transport (RCT)-related genes. Quantitative RT-PCR analysis showed that PPT inhibited the LXRalpha-dependent transcription of lipogenic genes, such as sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase, and stearoyl CoA desaturase 1. These inhibitory effects of PPT are, at least in part, a consequence of the reduced recruitment of RNA polymerase II to the LXR response element (LXRE) of the SREBP 1c promoter. Furthermore, LXRalpha-dependent triglyceride accumulation in primary mouse hepatocytes was significantly reduced by PPT. Interestingly, PPT did not inhibit the LXRalpha-dependent transcription of ABCA1, a crucial LXRalpha target gene involved in RCT. Chromatin immunoprecipitation assays revealed that PPT repressed recruitment of the lipogenic coactivator TRAP80 to the SREBP-1c LXRE, but not the ABCA1 LXRE. Overall, these data suggest that PPT has selective inhibitory activity against LXRalpha-mediated lipogenesis, but not LXRalpha stimulated RCT. PMID- 26109500 TI - Lifetime Reduction and Enhanced Emission of Single Photon Color Centers in Nanodiamond via Surrounding Refractive Index Modification. AB - The negatively-charged nitrogen vacancy (NV(-)) center in diamond is of great interest for quantum information processing and quantum key distribution applications due to its highly desirable long coherence times at room temperature. One of the challenges for their use in these applications involves the requirement to further optimize the lifetime and emission properties of the centers. Our results demonstrate the reduction of the lifetime of NV(-) centers, and hence an increase in the emission rate, achieved by modifying the refractive index of the environment surrounding the nanodiamond (ND). By coating the NDs in a polymer film, experimental results and numerical calculations show an average of 63% reduction in the lifetime and an average enhancement in the emission rate by a factor of 1.6. This strategy is also applicable for emitters other than diamond color centers where the particle refractive index is greater than the refractive index of the surrounding media. PMID- 26109501 TI - Cardiomyocyte-Driven Actuation in Biohybrid Microcylinders. AB - Biohybrid microcylinders are fabricated using electrohydrodynamic cojetting followed by a surface chemistry approach to maximize cell-adhesive characteristics. As proper cell alignment and mechanical stiffness are important components of bioactuator design, spatial cell selectivity and stress/strain properties of microcylinders are characterized to demonstrate their capability of response to rat cardio-myocyte contraction. These microcylinders can find applications in a host of micromechanical systems. PMID- 26109502 TI - Mismatch of Sleep and Work Timing and Risk of Type 2 Diabetes. AB - OBJECTIVE: To examine whether a mismatch between chronotype (i.e., preferred sleep timing) and work schedule is associated with type 2 diabetes risk. RESEARCH DESIGN AND METHODS: In the Nurses' Health Study 2, we followed 64,615 women from 2005 to 2011. Newly developed type 2 diabetes was the outcome measure (n = 1,452). A question on diurnal preference ascertained chronotype in 2009; rotating night shift work exposure was assessed regularly since 1989. RESULTS: Compared with intermediate chronotypes, early chronotypes had a slightly decreased diabetes risk after multivariable adjustment (odds ratio 0.87 [95% CI 0.77 0.98]), whereas no significant association was observed for late chronotypes (1.04 [0.89-1.21]). Among early chronotypes, risk of type 2 diabetes was modestly reduced when working daytime schedules (0.81 [0.63-1.04]) and remained similarly reduced in women working <10 years of rotating night shifts (0.84 [0.72-0.98]). After >=10 years of shift work exposure, early chronotypes had a nonsignificant elevated diabetes risk (1.15 [0.81-1.63], Ptrend = 0.014). By contrast, among late chronotypes, the significantly increased diabetes risk observed among day workers (1.51 [1.13-2.02]) appeared largely attenuated if their work schedules included night shifts (<10 years: 0.93 [0.76-1.13]; >=10 years: 0.87 [0.56-1.34]; Ptrend = 0.14). The interaction between chronotype and shift work exposure was significant (Pinteraction = 0.0004). Analyses restricting to incident cases revealed similar patterns. CONCLUSIONS: In early chronotypes, type 2 diabetes risk increased with increasing duration of shift work exposure, whereas late types had the highest diabetes risk working daytime schedules. These data add to the growing body of evidence that workers could benefit from shift schedules minimizing interference with chronotype-dependent sleep timing. PMID- 26109503 TI - Identifying Glucokinase Monogenic Diabetes in a Multiethnic Gestational Diabetes Mellitus Cohort: New Pregnancy Screening Criteria and Utility of HbA1c. AB - OBJECTIVE: Glucokinase monogenic diabetes (GCK-maturity-onset diabetes of the young [MODY]) should be differentiated from gestational diabetes mellitus (GDM) because management differs. New pregnancy-specific screening criteria (NSC) have been proposed to identify women who warrant GCK genetic testing. We tested NSC and HbA1c in a multiethnic GDM cohort and examined projected referrals for GCK testing. RESEARCH DESIGN AND METHODS: Using a GDM database, 63 of 776 women had a postpartum oral glucose tolerance test suggestive of GCK-MODY. Of these 63 women, 31 agreed to undergo GCK testing. NSC accuracy and HbA1c were examined. Projected referrals were calculated by applying the NSC to a larger GDM database (n = 4,415). RESULTS: Four of 31 women were confirmed as having GCK-MODY (prevalence ~0.5-1/100 with GDM). The NSC identified all Anglo-Celtic women but did not identify one Indian woman. The NSC will refer 6.1% of GDM cases for GCK testing, with more Asian/Indian women referred despite lower disease prevalence. Antepartum HbA1c was not higher in those with GCK-MODY. CONCLUSIONS: The NSC performed well in Anglo-Celtic women. Ethnic-specific criteria should be explored. PMID- 26109504 TI - Apocynin Attenuates Cardiac Injury in Type 4 Cardiorenal Syndrome via Suppressing Cardiac Fibroblast Growth Factor-2 With Oxidative Stress Inhibition. AB - BACKGROUND: Type 4 cardiorenal syndrome (CRS) refers to the cardiac injury induced by chronic kidney disease. We aimed to assess oxidative stress and cardiac injury in patients with type 4 CRS, determine whether the antioxidant apocynin attenuated cardiac injury in rats with type 4 CRS, and explore potential mechanisms. METHODS AND RESULTS: A cross-sectional study was conducted among patients with type 4 CRS (n=17) and controls (n=16). Compared with controls, patients with type 4 CRS showed elevated oxidative stress, which was significantly correlated with cardiac hypertrophy and decreased ejection fraction. In vivo study, male Sprague-Dawley rats underwent 5/6 subtotal nephrectomy and sham surgery, followed with apocynin or vehicle treatment for 8 weeks. Eight weeks after surgery, the 5/6 subtotal nephrectomy rats mimicked type 4 CRS, showing increased serum creatinine, cardiac hypertrophy and fibrosis, and decreased ejection fraction compared with sham-operated animals. Cardiac malondialdehyde, NADPH oxidase activity, fibroblast growth factor-2, and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation increased significantly in the 5/6 subtotal nephrectomy rats. These changes were significantly attenuated by apocynin. In vitro study showed that apocynin reduced angiotensin II-induced NADPH oxidase-dependent oxidative stress, upregulation of fibroblast growth factor-2 and fibrosis biomarkers, and ERK1/2 phosphorylation in cardiac fibroblasts. Importantly, the ERK1/2 inhibitor U0126 reduced the upregulation of fibroblast growth factor-2 and fibrosis biomarkers in angiotensin II-treated fibroblasts. CONCLUSIONS: Oxidative stress is a candidate mediator for type 4 CRS. Apocynin attenuated cardiac injury in type 4 CRS rats via inhibiting NADPH oxidase-dependent oxidative stress-activated ERK1/2 pathway and subsequent fibroblast growth factor-2 upregulation. Our study added evidence to the beneficial effect of apocynin in type 4 CRS. PMID- 26109506 TI - Effects of fetal cardiac anomalies on ductus venosus and aortic isthmus doppler profiles. AB - PURPOSE: To demonstrate the blood flow profiles of fetuses with cardiac anomalies at the level of Ductus venosus (DV) and Aortic isthmus (AI) to evaluate the effects of fetal cardiac anomalies on these profiles, and how these profile changes contribute to cardiac anomaly screening studies as a marker. METHODS: DV and AI doppler studies were applied to 64 singleton pregnant women with fetal cardiac anomalies and 74 pregnant women with healthy fetuses. DV-PVIV (peak velocity index for veins) for DV and IFI (isthmic flow index) for AI were used. RESULTS: DV doppler studies in fetuses with cardiac anomalies and healthy fetuses did not show statistically significant difference. But the results of the AI doppler studies had statistically significant difference in the fetal cardiac anomaly group with the exception of cases with dilatation and regurgitation. When right-sided heart anomaly and the remaining cases were compared with the control groups, AI doppler results also showed lower IFI values. CONCLUSIONS: DV doppler studies in the second or third trimester may not be suitable as a screening test for congenital heart disease, but AI doppler studies might be considered as a supporting parameter. But further studies are needed for routine clinical use. PMID- 26109505 TI - High Cholesterol Awareness, Treatment, and Control Among Hispanic/Latinos: Results From the Hispanic Community Health Study/Study of Latinos. AB - BACKGROUND: We assessed high cholesterol (HC) awareness, treatment, and control rates among US Hispanic/Latino adults and describe factors associated with HC awareness and management. METHODS AND RESULTS: Baseline data (collected 2008 2011) from a multisite probability sample of Hispanic/Latino adults in the Hispanic Community Health Study/Study of Latinos (18 to 74 years old; N=16 207) were analyzed. HC was defined as low-density lipoprotein-cholesterol >=130 mg/dL and/or total cholesterol >=240 mg/dL or use of cholesterol-lowering medication. Among Hispanic/Latino adults with HC, almost half (49.3%) were not aware of their condition and only 29.5% were receiving treatment. Men had a higher HC prevalence than women (44.0% versus 40.5%) but a lower rate of treatment (28.1% versus 30.6%). Younger adults were significantly less likely to be HC aware compared to those who were older. Those with hypertension, diabetes, and high socioeconomic position were more likely to be HC aware. US-born Hispanic/Latino were more likely to be HC unaware than foreign-born Hispanics/Latinos, but longer US residency was significantly associated with being HC aware, treated, and controlled. Cholesterol control was achieved among 64.3% of those who were HC treated. However, younger adults, women, those with lower income, those uninsured, and more recent immigrants were less likely to be HC controlled. Individuals of Puerto Rican or Dominican background were most likely to be HC aware and treated, whereas those of Mexican or Central American background were least likely to be HC treated. Individuals of Cuban and South American background had the lowest rates of HC control, whereas Puerto Ricans had the highest. CONCLUSIONS: Understanding gaps in HC awareness, treatment, and control among US Hispanic/Latino adults can help inform physicians and policymakers to improve disease management and patient education programs. PMID- 26109507 TI - Single-site trinuclear copper oxygen clusters in mordenite for selective conversion of methane to methanol. AB - Copper-exchanged zeolites with mordenite structure mimic the nuclearity and reactivity of active sites in particulate methane monooxygenase, which are enzymes able to selectively oxidize methane to methanol. Here we show that the mordenite micropores provide a perfect confined environment for the highly selective stabilization of trinuclear copper-oxo clusters that exhibit a high reactivity towards activation of carbon-hydrogen bonds in methane and its subsequent transformation to methanol. The similarity with the enzymatic systems is also implied from the similarity of the reversible rearrangements of the trinuclear clusters occurring during the selective transformations of methane along the reaction path towards methanol, in both the enzyme system and copper exchanged mordenite. PMID- 26109508 TI - Efficient production of indigoidine in Escherichia coli. AB - Indigoidine is a bacterial natural product with antioxidant and antimicrobial activities. Its bright blue color resembles the industrial dye indigo, thus representing a new natural blue dye that may find uses in industry. In our previous study, an indigoidine synthetase Sc-IndC and an associated helper protein Sc-IndB were identified from Streptomyces chromofuscus ATCC 49982 and successfully expressed in Escherichia coli BAP1 to produce the blue pigment at 3.93 g/l. To further improve the production of indigoidine, in this work, the direct biosynthetic precursor L-glutamine was fed into the fermentation broth of the engineered E. coli strain harboring Sc-IndC and Sc-IndB. The highest titer of indigoidine reached 8.81 +/- 0.21 g/l at 1.46 g/l L-glutamine. Given the relatively high price of L-glutamine, a metabolic engineering technique was used to directly enhance the in situ supply of this precursor. A glutamine synthetase gene (glnA) was amplified from E. coli and co-expressed with Sc-indC and Sc-indB in E. coli BAP1, leading to the production of indigoidine at 5.75 +/- 0.09 g/l. Because a nitrogen source is required for amino acid biosynthesis, we then tested the effect of different nitrogen-containing salts on the supply of L-glutamine and subsequent indigoidine production. Among the four tested salts including (NH4)2SO4, NH4Cl, (NH4)2HPO4 and KNO3, (NH4)2HPO4 showed the best effect on improving the titer of indigoidine. Different concentrations of (NH4)2HPO4 were added to the fermentation broths of E. coli BAP1/Sc-IndC+Sc-IndB+GlnA, and the titer reached the highest (7.08 +/- 0.11 g/l) at 2.5 mM (NH4)2HPO4. This work provides two efficient methods for the production of this promising blue pigment in E. coli. PMID- 26109509 TI - Nanopore sensing of individual transcription factors bound to DNA. AB - Transcription factor (TF)-DNA interactions are the primary control point in regulation of gene expression. Characterization of these interactions is essential for understanding genetic regulation of biological systems and developing novel therapies to treat cellular malfunctions. Solid-state nanopores are a highly versatile class of single-molecule sensors that can provide rich information about local properties of long charged biopolymers using the current blockage patterns generated during analyte translocation, and provide a novel platform for characterization of TF-DNA interactions. The DNA-binding domain of the TF Early Growth Response Protein 1 (EGR1), a prototypical zinc finger protein known as zif268, is used as a model system for this study. zif268 adopts two distinct bound conformations corresponding to specific and nonspecific binding, according to the local DNA sequence. Here we implement a solid-state nanopore platform for direct, label- and tether-free single-molecule detection of zif268 bound to DNA. We demonstrate detection of single zif268 TFs bound to DNA according to current blockage sublevels and duration of translocation through the nanopore. We further show that the nanopore can detect and discriminate both specific and nonspecific binding conformations of zif268 on DNA via the distinct current blockage patterns corresponding to each of these two known binding modes. PMID- 26109510 TI - Interaction of Anthracycline 3'-azido-epirubicin with Calf Thymus DNA via Spectral and Molecular Modeling Techniques. AB - Anthracycline antibiotics are extensively applied to clinical antitumor therapy. The binding mode and mechanism of a new anthracycline 3'-azido-epirubicin (AEPI) with calf thymus deoxyribonucleic acid (ctDNA) were investigated employing multiple spectroscopy techniques in Tris-HCl buffer solution (pH 7.4). Effect of pH on the interaction was provided to determine the proper environment for whole research. Iodide quenching studies and fluorescence polarization measurement indicated that ctDNA quenched the fluorescence of AEPI significantly via intercalation binding mode. The binding constants and binding sites for the interaction were calculated. From binding constant dependence on the temperature, static quenching mechanism of AEPI by ctDNA was confirmed based on the Stern Volmer equation. Additionally, the thermodynamic parameters for the reaction revealed that the van der Waals force and hydrogen bonding were the main acting forces in the binding process. Molecular modeling result indicated that the hydrogen bonding played a major role in the binding of AEPI to ctDNA. PMID- 26109511 TI - Non-oncologic applications of diffusion-weighted imaging (DWI) in the genitourinary system. AB - Diffusion-weighted imaging (DWI) has become an increasingly used tool in abdominal and pelvic magnetic resonance imaging (MRI), primarily in the oncologic setting. DWI sequences are being added to routine MRI protocols at many institutions, and as its use has spread, more non-oncologic applications have been explored. The purpose of this article is to provide a review of DWI applications in inflammatory, infectious, autoimmune-mediated, and ischemic processes affecting the genitourinary system. PMID- 26109512 TI - Warmer temperature accelerates methane emissions from the Zoige wetland on the Tibetan Plateau without changing methanogenic community composition. AB - Zoige wetland, locating on the Tibet Plateau, accounts for 6.2% of organic carbon storage in China. However, the fate of the organic carbon storage in the Zoige wetland remains poorly understood despite the Tibetan Plateau is very sensitive to global climate change. As methane is an important greenhouse gas and methanogenesis is the terminal step in the decomposition of organic matter, understanding how methane emissions from the Zoige wetland is fundamental to elucidate the carbon cycle in alpine wetlands responding to global warming. In this study, microcosms were performed to investigate the effects of temperature and vegetation on methane emissions and microbial processes in the Zoige wetland soil. A positive correlation was observed between temperature and methane emissions. However, temperature had no effect on the main methanogenic pathway- acetotrophic methanogenesis. Moreover, methanogenic community composition was not related to temperature, but was associated with vegetation, which was also involved in methane emissions. Taken together, these results indicate temperature increases methane emissions in alpine wetlands, while vegetation contributes significantly to methanogenic community composition and is associated with methane emissions. These findings suggest that in alpine wetlands temperature and vegetation act together to affect methane emissions, which furthers a global warming feedback loop. PMID- 26109513 TI - Alternative treatment of vaginal infections - in vitro antimicrobial and toxic effects of Coriandrum sativum L. and Thymus vulgaris L. essential oils. AB - AIMS: The aims of study were to examine the antibacterial potential of two commercial essential oils (EOs) from coriander (Coriandrum sativum L.) and thyme (Thymus vulgaris L.) against vaginal clinical strains of bacteria and yeast and their chemical composition. METHODS AND RESULTS: Antimicrobial activities of commercial essential oils were determined using macro-diffusion (disc, well) and micro-dilution method in 96-well micro plates against twelve clinical strains of bacteria: Escherichia coli, Proteus mirabilis, Staphylococcus aureus and Enterococcus sp., Staph. aureus ATCC 25923, ATCC 6538 and E. coli 25922 and two clinical Candida albicans strains, including ATTC 10231. Spectrophotometric method was used for determination on C. albicans growth. An antimicrobial effect of EOs was strain specific. Bactericidal activity was higher for coriander EO (minimal inhibitory concentration (MICs) 0.4-45.4 MUl ml(-1)) against almost all tested bacteria, except multiple resistant strains of Eneterococcus sp. and Proteus sp. Thyme EO showed slightly better fungicidal activity reaching MIC at 0.11 mg ml(-1) for all C. albicans strains. The effect of EOs on biofilm-forming ability was tested for two strains of Staph. aureus and E. coli, as well as on C. albicans filamentation ability. Brine shrimp lethality bioassay revealed thymus oil total toxicity and coriander oil intoxicity (LC50 = 2.25 mg ml(-1)). The chemical composition of oils was analysed by gas chromatography mass spectrometry showing oxygenated monoterepenes as dominant constituents. CONCLUSIONS: The results provide in-vitro scientific support for the safety possible use of Coriander EO against E. coli, Staph. aureus and C. albicans vaginal infections in alternative gynaecological treatment. SIGNIFICANCE AND IMPACT OF STUDY: To examine EOs as possible constituent of naturally based antimicrobial agents in vaginaletes for safety gynaecological application. PMID- 26109514 TI - Viral activities and life cycles in deep subseafloor sediments. AB - Viruses are highly abundant in marine subsurface sediments and can even exceed the number of prokaryotes. However, their activity and quantitative impact on microbial populations are still poorly understood. Here, we use gene expression data from published continental margin subseafloor metatranscriptomes to qualitatively assess viral diversity and activity in sediments up to 159 metres below seafloor (mbsf). Mining of the metatranscriptomic data revealed 4651 representative viral homologues (RVHs), representing 2.2% of all metatranscriptome sequence reads, which have close translated homology (average 77%, range 60-97% amino acid identity) to viral proteins. Archaea-infecting RVHs are exclusively detected in the upper 30 mbsf, whereas RVHs for filamentous inoviruses predominate in the deepest sediment layers. RVHs indicative of lysogenic phage-host interactions and lytic activity, notably cell lysis, are detected at all analysed depths and suggest a dynamic virus-host association in the marine deep biosphere studied here. Ongoing lytic viral activity is further indicated by the expression of clustered, regularly interspaced, short palindromic repeat-associated cascade genes involved in cellular defence against viral attacks. The data indicate the activity of viruses in subsurface sediment of the Peruvian margin and suggest that viruses indeed cause cell mortality and may play an important role in the turnover of subseafloor microbial biomass. PMID- 26109515 TI - Impact of Lean on surgical instrument reduction: Less is more. AB - OBJECTIVES/HYPOTHESIS: To determine whether instrument sets that are frequently used by multiple surgeons can be substantially reduced in size with consensus. STUDY DESIGN: Prospective quality improvement study using Lean Six Sigma for purposeful and consensual reduction of non-value-added instruments in adenotonsillectomy instrument sets. METHODS: Value stream mapping was utilized to determine instrumentation usage and reprocessing workflow. Preintervention instrument utilization surveys allowed consensual and intelligent set reduction. Non-value-added instruments were targeted for waste elimination by placement in a supplemental set. Times for pre- and postintervention instrument assembly, Mayo setup, and surgery were collected for adenotonsillectomies. Postintervention satisfaction surveys of surgeons and staff were conducted. RESULTS: Adenotonsillectomy sets were reduced from 52 to 24 instruments. Median assembly times were significantly reduced from 8.4 to 4.7 minutes (P < .0001) with a set assembly cost reduction of 44%. Following natural log transformations, mean Mayo setup times were significantly reduced from 97.6 to 76.1 seconds (P < .0001), and mean operative times were not significantly affected (1,773 vs. 1,631 seconds, P > .05). The supplemental set was opened in only 3.6% of cases. Satisfaction was >90% regarding the intervention. Set build cost was reduced by $1,468.99 per set. CONCLUSIONS: Lean Six Sigma improves efficiency and reduces waste by empowering team members to improve their environment. Instrument set reduction is ideal for waste elimination because of tool accumulation over time and instrument obsolescence as newer technologies are adopted. Similar interventions could easily be applied to larger sinus, mastoidectomy, and spine sets. LEVEL OF EVIDENCE: NA. PMID- 26109516 TI - Reconstruction of maxillary defect with musculo-adipose rectus free flap. AB - BACKGROUND: The rectus myocutaneous free flap (RMFF) is used for medium to large maxillectomy defects. However, in patients with central obesity the inset could be difficult due to the bulk from excessive layer of adipose tissue. We describe a modification of the RMFF for patients with excessive central obesity with a flap consisting of adipose tissue with minimal rectus muscle; the musculo-adipose rectus free flap (MARF). METHODS: Five cases of MARF reconstruction were performed between 2003 and 2013, with patients' body mass indexes ranging from 29.0 to 41.2 kg/m2 . All patients had sinonasal tumor, of which three were adenoid cystic carcinoma, one squamous cell carcinoma, and one melanoma. Four patients had Codeiro IIIb defects and one had Codeiro II defect. Using the MARF technique, the maxillectomy defect was obliterated with vascularized adipose tissue overlying the rectus muscle and was trimmed to fit the maxillectomy defect. The adipose tissue was allowed to granulate and mucosalize. RESULTS: The volume of adipose tissue harvested was between 120 and 160 mL. All flaps survived with no requirement for re-exploration. Complete oro-nasal separation was achieved in all patients. The time to commencement of oral intake ranges from 5 to 15 days. One patient developed seroma and one developed wound breakdown on the donor site. The length of stay at the hospital ranges from 9 to 22 days. On follow-up ranging 7.5-32.8 months, two patients died from their malignancies. The other three patients were able to tolerate oral soft diet. CONCLUSION: The MARF may be considered as an alternative to myocutaneous rectus free flap particularly for the reconstruction of maxillary defects in patients with central obesity. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:137-141, 2017. PMID- 26109517 TI - The Role of 17beta-Estradiol in Myocardial Hypertrophy in Females in the Presence and Absence of Hypertension. AB - PURPOSE: There are gender-differences in the development of cardiac hypertrophy, which appear to be related, in part, to sex hormones. This report gives an overview of this relationship and reports on original data assessing how varying levels of plasma 17beta-estradiol determine relative heart size, in vivo function, in hypertensive versus normotensive rats. METHODS: Female spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were either surgically neutered or sham operated at 21 days of age. A subgroup of neutered females received 17beta-estradiol replacement. At 6 months, in vivo heart function was measured, the heart/body weight ratio (mg/g) was assessed as a measure of hypertrophy and correlated with plasma 17beta-estradiol. RESULTS: There was a significant positive relationship between plasma 17beta-estradiol and heart/body weight ratio in both WKY (R = 0.509, P = 0.011) and SHR females (R = 0.359, P = 0.032). Interestingly, the slope of this relationship was 2-fold steeper in the WKY females, suggesting a blunted effect in the SHR, whose hearts also had 35 % lower ERbeta content. With increasing plasma estradiol levels, WKY females showed improved LV function while SHR females showed impaired LV relaxation. CONCLUSIONS: Plasma estradiol modulates relative heart mass in both normotensive and hypertensive female rats. With any increase in plasma 17beta estradiol, hypertensive females show a blunted response compared with the normotensive females, which may be related to a reduced estrogen receptor expression in the presence of hypertension. In contrast to normotensive females, hypertensive females showed impaired function with increases in plasma 17beta estradiol. PMID- 26109518 TI - Prestimulus oscillatory alpha power and connectivity patterns predispose perceptual integration of an audio and a tactile stimulus. AB - To efficiently perceive and respond to the external environment, our brain has to perceptually integrate or segregate stimuli of different modalities. The temporal relationship between the different sensory modalities is therefore essential for the formation of different multisensory percepts. In this magnetoencephalography study, we created a paradigm where an audio and a tactile stimulus were presented by an ambiguous temporal relationship so that perception of physically identical audiotactile stimuli could vary between integrated (emanating from the same source) and segregated. This bistable paradigm allowed us to compare identical bimodal stimuli that elicited different percepts, providing a possibility to directly infer multisensory interaction effects. Local differences in alpha power over bilateral inferior parietal lobules (IPLs) and superior parietal lobules (SPLs) preceded integrated versus segregated percepts of the two stimuli (audio and tactile). Furthermore, differences in long-range cortical functional connectivity seeded in rIPL (region of maximum difference) revealed differential patterns that predisposed integrated or segregated percepts encompassing secondary areas of all different modalities and prefrontal cortex. We showed that the prestimulus brain states predispose the perception of the audiotactile stimulus both in a global and a local manner. Our findings are in line with a recent consistent body of findings on the importance of prestimulus brain states for perception of an upcoming stimulus. This new perspective on how stimuli originating from different modalities are integrated suggests a non-modality specific network predisposing multisensory perception. PMID- 26109519 TI - Classification of diabetes maculopathy images using data-adaptive neuro-fuzzy inference classifier. AB - Prolonged diabetes retinopathy leads to diabetes maculopathy, which causes gradual and irreversible loss of vision. It is important for physicians to have a decision system that detects the early symptoms of the disease. This can be achieved by building a classification model using machine learning algorithms. Fuzzy logic classifiers group data elements with a degree of membership in multiple classes by defining membership functions for each attribute. Various methods have been proposed to determine the partitioning of membership functions in a fuzzy logic inference system. A clustering method partitions the membership functions by grouping data that have high similarity into clusters, while an equalized universe method partitions data into predefined equal clusters. The distribution of each attribute determines its partitioning as fine or coarse. A simple grid partitioning partitions each attribute equally and is therefore not effective in handling varying distribution amongst the attributes. A data adaptive method uses a data frequency-driven approach to partition each attribute based on the distribution of data in that attribute. A data-adaptive neuro-fuzzy inference system creates corresponding rules for both finely distributed and coarsely distributed attributes. This method produced more useful rules and a more effective classification system. We obtained an overall accuracy of 98.55%. PMID- 26109520 TI - Quantitative measurement of Parkinsonian gait from walking in monocular image sequences using a centroid tracking algorithm. AB - Parkinson's disease (PD) is a neurodegenerative disease of the central nervous system that results from the degeneration of dopaminergic neurons in the substantia nigra. Abnormal gait begins in the early stage and becomes severe as the disease progresses; therefore, the assessment of gait becomes an important issue in evaluating the progression of PD and the effectiveness of treatment. To provide a clinically useful gait assessment in environments with budget and space limitations, such as a small clinic or home, we propose and develop a portable method utilizing the monocular image sequences of walking to track and analyze a Parkinsonian gait pattern. In addition, a centroid tracking algorithm is developed and used here to enhance the method of quantifying kinematic gait parameters of PD in different states. Twelve healthy subjects and twelve mild patients with PD participate in this study. This method requires one digital video camera and subjects with two joint markers attached on the fibula head and the lateral malleolus of the leg. All subjects walk with a natural pace in front of a video camera during the trials. Results of our study demonstrate the stride length and walking velocity significantly decrease in PD without drug compared to PD with drug in both proposed method and simultaneous gait assessment performed by GAITRite((r)) system. In gait initiation, step length and swing velocity also decrease in PD without drug compared to both PD with drug and controls. Our results showed high correlation in gait parameters between the two methods and prove the reliability of the proposed method. With the proposed method, quantitative measurement and analysis of Parkinsonian gait could be inexpensive to implement, portable within a small clinic or home, easy to administer, and simple to interpret. Although this study is assessed Parkinsonian gait, the proposed method has the potential to help clinicians and researchers assess the gait of patients with other neuromuscular diseases, such as traumatic brain injury and stroke patients. PMID- 26109521 TI - Quantitative analysis of vascular parameters for micro-CT imaging of vascular networks with multi-resolution. AB - Previous studies showed that all the vascular parameters from both the morphological and topological parameters were affected with the altering of imaging resolutions. However, neither the sensitivity analysis of the vascular parameters at multiple resolutions nor the distinguishability estimation of vascular parameters from different data groups has been discussed. In this paper, we proposed a quantitative analysis method of vascular parameters for vascular networks of multi-resolution, by analyzing the sensitivity of vascular parameters at multiple resolutions and estimating the distinguishability of vascular parameters from different data groups. Combining the sensitivity and distinguishability, we designed a hybrid formulation to estimate the integrated performance of vascular parameters in a multi-resolution framework. Among the vascular parameters, degree of anisotropy and junction degree were two insensitive parameters that were nearly irrelevant with resolution degradation; vascular area, connectivity density, vascular length, vascular junction and segment number were five parameters that could better distinguish the vascular networks from different groups and abide by the ground truth. Vascular area, connectivity density, vascular length and segment number not only were insensitive to multi-resolution but could also better distinguish vascular networks from different groups, which provided guidance for the quantification of the vascular networks in multi-resolution frameworks. PMID- 26109522 TI - Two Sources of Error in Data on Migration From Mexico to the United States in Mexican Household-Based Surveys. AB - We examine the nature and degree of two sources of error in data on migration from Mexico to the United States in Mexican household-based surveys: (1) sampling error that results when whole households migrate and no one is left behind to report their migration; and (2) reporting errors that result when migrants are not identified by survey respondents. Using data from the first two waves of the Mexican Family Life Survey, which tracked Mexican migrants to the United States from 2002 to 2005, we find that one-half of migrants from Mexico to the United States are not counted as a result of these two sources of error. Misreporting is the larger source of error, accounting for more than one-third of all migrants. Those who are not counted, especially whole-household migrants, are a unique group. Their omission results in an underestimate of female migrants, child migrants, and migrants from the Mexican border region, and an overestimate of migrants from the periphery region. PMID- 26109523 TI - Dose finding with longitudinal data: simpler models, richer outcomes. AB - Phase I oncology clinical trials are designed to identify the optimal dose that will be recommended for phase II trials. This dose is typically defined as the dose associated with a certain probability of severe toxicity at cycle 1, although toxicity is repeatedly measured over cycles on an ordinal scale. Recently, a proportional odds mixed-effect model for ordinal outcomes has been proposed to (i) identify the optimal dose accounting for repeated events and (ii) to provide some framework to explore time trend. We compare this approach to a method based on repeated binary variables and to a method based on an under parameterized model of the dose-time toxicity relationship. We show that repeated binary and ordinal outcomes both improve the accuracy of dose-finding trials in the same proportion; ordinal outcomes are, however, superior to detect time trend even in the presence of nonproportional odds models. Moreover, less parameterized models led to the best operating characteristics. These approaches are illustrated on two dose-finding phase I trials. Integration of repeated measurements is appealing in phase I dose-finding trials. PMID- 26109524 TI - Role of high-risk variants in the development of impaired glucose metabolism was modified by birth weight in Han Chinese. AB - BACKGROUND: The aim of this study was to investigate the role of common variants in the genes SLC30A8, KCNQ1, and TCF7L2 in the association between birth weight and increased risk of type 2 diabetes in Han Chinese. METHODS: Seven variants (SLC30A8-rs13266634 and rs2466293; KCNQ1-rs2237895 and rs2074196; and TCF7L2 rs11196218, rs7903146, and rs290487) were genotyped in 1181 individuals born in Peking Union Medical College Hospital from 1921 to 1954 by Taqman allelic discrimination assay. All the subjects were stratified by birth weight into groups of >=3000 g and <3000 g. Associations of genetic variants with birth weight and with risk of type 2 diabetes and impaired glucose tolerance (together as impaired glucose metabolism) were analysed. RESULTS: After adjustment for sex, gestational weeks, parity, and maternal age, the G allele of KCNQ1-rs2074196 was associated with higher birth weight (p = 0.032). KCNQ1-rs2074196, rs2234895, and TCF7L2-rs290487 were associated with increased risk of impaired glucose metabolism. However, the associations were modified by size at birth. The associations above were only found in subjects with birth weights greater than (or equal to) 3000 g. In subjects with birth weights less than 3000 g, impaired glucose metabolism was associated with variants SLC30A8-rs2466293 and TCF7L2 rs11196218. CONCLUSIONS: The role of common variants in susceptible genes in the development of impaired glucose metabolism was modified by birth weight in Han Chinese. This provides evidence that genetic variants influence birth weight and are involved in development of type 2 diabetes. PMID- 26109525 TI - Tamoxifen-Induced Cell Death of Malignant Glioma Cells Is Brought About by Oxidative-Stress-Mediated Alterations in the Expression of BCL2 Family Members and Is Enhanced on miR-21 Inhibition. AB - High-grade gliomas are refractory to the current mode of treatment primarily due to their inherent resistance to cell death. Tamoxifen has been reported to inhibit growth and induce cell death of glioma cells in vitro, in an estrogen receptor-independent manner. Delineating the molecular mechanism underlying tamoxifen-induced cell death of human glioma cells would help in identifying pathways/genes that could be targeted to induce tumor-cell-specific cell death. In the present study, tamoxifen was found to bring about autophagic cell death of human glioma cells that was accompanied by oxidative stress induction, JNK activation, downregulation of anti-autophagic BCL2 family members, viz. BCL2 and BCL-XL, and increased expression of the pro-autophagic members BCL-Xs and BAK. Oxidative stress induction appears to be primarily responsible for the tamoxifen induced cell death since the cell death, JNK activation, and the alterations in the expression levels of BCL2 family members were abrogated on pretreatment with antioxidant vitamin E. MiR-21, an oncogenic miRNA, is known to be highly upregulated in malignant glioma. Inhibition of miR-21 activity was found to enhance tamoxifen-induced cell death of U87 MG malignant glioma cells. Tamoxifen treatment coupled with miR-21 inhibition could therefore be an effective strategy for the treatment of malignant gliomas. PMID- 26109526 TI - DNA Methylation of the EphA5 Promoter Is Associated with Rat Congenital Hypothyroidism. AB - Thyroid hormones (THs) are essential for normal development of the mammalian central nervous system through regulation of TH-responsive genes. EphA5, an important TH-responsive gene encoding the tyrosine kinase receptor EphA5, regulates synaptogenesis initiation and synaptic remodeling during brain development. Abnormal EphA5 expression is involved in the development of congenital hypothyroidism (CH). To show the regulatory mechanism of EphA5 expression in CH rats, we analyzed the correlation between methylation of the EphA5 promoter and its expression in the hypothyroid hippocampus and hippocampal neurons. Demethylation treatment using 5'-azadeoxycytidine upregulated EphA5 expression and rescued the effects of hypermethylation, suggesting a novel regulatory mechanism of EphA5 expression in CH rats. Our results suggest a potentially new approach for the development of drugs to restore neurocognitive impairments associated with CH. PMID- 26109527 TI - A simple and compact fluorescence detection system for capillary electrophoresis and its application to food analysis. AB - A novel fluorescence detection system for CE was described and evaluated. Two miniature laser pointers were used as the excitation source. A Y-style optical fiber was used to transmit the excitation light and a four-branch optical fiber was used to collect the fluorescence. The optical fiber and optical filter were imported into a photomultiplier tube without any extra fixing device. A simplified PDMS detection cell was designed with guide channels through which the optical fibers were easily aligned to the detection window of separation capillary. According to different requirements, laser pointers and different filters were selected by simple switching and replacement. The fluorescence from four different directions was collected at the same detecting point. Thus, the sensitivity was enhanced without peak broadening. The fluorescence detection system was simple, compact, low-cost, and highly sensitive, with its functionality demonstrated by the separation and determination of red dyes and fluorescent whitening agents. The detection limit of rhodamine 6G was 7.7 nM (S/N = 3). The system was further applied to determine illegal food dyes. The CE system is potentially eligible for food safety analysis. PMID- 26109528 TI - Nanoparticle-motivated gene delivery for ophthalmic application. AB - Ophthalmic gene therapy is an intellectual and intentional manipulation of desired gene expression into the specific cells of an eye for the treatment of ophthalmic (ocular) genetic dystrophies and pathological conditions. Exogenous nucleic acids such as DNA, small interfering RNA, micro RNA, and so on, are used for the purpose of managing expression of the desired therapeutic proteins in ocular tissues. The delivery of unprotected nucleic acids into the cells is limited because of exogenous and endogenous degradation modalities. Nanotechnology, a promising and sophisticated cutting edge tool, works as a protective shelter for these therapeutic nucleic acids. They can be safely delivered to the required cells in order to modulate anticipated protein expression. To this end, nanotechnology is seen as a potential and promising strategy in the field of ocular gene delivery. This review focused on current nanotechnology modalities and other promising nonviral strategies being used to deliver therapeutic genes in order to treat various devastating ocular diseases. PMID- 26109529 TI - Protecting families from recurrent stillbirth. PMID- 26109531 TI - Functional annotation of high-quality SNP biomarkers of gastric cancer susceptibility: the Yin Yang of PSCA rs2294008. PMID- 26109530 TI - The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in patients with chronic HBV infection in West Africa. AB - BACKGROUND: Simple and inexpensive non-invasive fibrosis tests are highly needed but have been poorly studied in sub-Saharan Africa. METHODS: Using liver histology as a gold standard, we developed a novel index using routine laboratory tests to predict significant fibrosis in patients with chronic HBV infection in The Gambia, West Africa. We prospectively assessed the diagnostic accuracy of the novel index, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and Fib-4 in Gambian patients with CHB (training set) and also in French and Senegalese CHB cohorts (validation sets). RESULTS: Of 135 consecutive treatment naive patients with CHB who had liver biopsy, 39% had significant fibrosis (Metavir fibrosis stage >=F2) and 15% had cirrhosis (F4). In multivariable analysis, gamma-glutamyl transpeptidase (GGT) and platelet count were independent predictors of significant fibrosis. Consequently, GGT-to-platelet ratio (GPR) was developed. In The Gambia, the area under the receiver operating characteristic curve (AUROC) of the GPR was significantly higher than that of APRI and Fib-4 to predict >=F2, >=F3 and F4. In Senegal, the AUROC of GPR was significantly better than Fib-4 and APRI for >=F2 (0.73, 95% CI 0.59 to 0.86) and better than Fib-4 and Fibroscan for >=F3 (0.93, 0.87 to 0.99). In France, the AUROC of GPR to diagnose >=F2 (0.72, 95% CI 0.59 to 0.85) and F4 (0.87, 0.76 to 0.98) was equivalent to that of APRI and Fib-4. CONCLUSIONS: The GPR is a more accurate routine laboratory marker than APRI and Fib-4 to stage liver fibrosis in patients with CHB in West Africa. The GPR represents a simple and inexpensive alternative to liver biopsy and Fibroscan in sub-Saharan Africa. PMID- 26109532 TI - Brief Report: Nonsteroidal Antiinflammatory Drug-Sparing Effect of Tumor Necrosis Factor Inhibitors in Early Axial Spondyloarthritis: Results From the DESIR Cohort. AB - OBJECTIVE: To evaluate the effect of tumor necrosis factor (TNF) inhibitors on nonsteroidal antiinflammatory drug (NSAID) intake in a cohort of patients with early axial spondyloarthritis (SpA) over the first 2 years of followup. METHODS: The Devenir des Spondylarthropathies Indifferenciees Recentes (DESIR) cohort is a prospective, multicenter, observational study cohort of patients with early inflammatory back pain. The management and treatment of these patients were decided by their treating rheumatologists. Data regarding NSAID intake (yes/no) and the Assessment of SpondyloArthritis international Society NSAID score were collected at each visit over 2 years of followup. Patients receiving a TNF inhibitor were matched with those receiving usual care, based on a propensity score. The NSAID-sparing effect of TNF inhibitors was estimated by comparing the percentage of patients reaching several end points (e.g., a decrease in the NSAID score to <10 over 2 years) and by modeling NSAID intake using mixed models. RESULTS: Among the 627 patients who were followed up, 181 (28.9%) received a TNF inhibitor, and these patients were matched to 181 patients who received usual care. The baseline characteristics of the patients in the 2 groups were comparable (~40% of the patients were male, and the mean age was 34 years). Initially, 90.2% of patients receiving TNF inhibitors and 90.0% of those receiving usual care had been treated with NSAIDs during the previous 6 months. The number of patients who received an NSAID decreased over time in both groups, but the decrease was greater in the group receiving TNF inhibitors (P = 0.04). The decrease in the median NSAID score was significantly greater in the TNF inhibitor group (54.9 versus 41.9), and the percentage of patients in whom the NSAID score decreased by >50% or to <10 or in whom NSAID treatment was discontinued was greater in the TNF inhibitor group (67.6% versus 46.2%). CONCLUSION: Treatment with TNF inhibitors was associated with a decrease in the proportion of patients taking NSAIDs and with a rapid and sustained decrease in NSAID intake. This study is the first to confirm the NSAID-sparing effect of TNF inhibitors in patients with early axial SpA in a real-life clinical setting. PMID- 26109533 TI - Transumbilical retrieval of broken umbilical artery catheter in a 1000 gm premature newborn. PMID- 26109534 TI - Cephalic vein and radial artery diameter in formation of radiocephalic arteriovenous fistula: a systematic review. AB - PURPOSE: The aim of this study is to determine the optimal range of cephalic vein and radial artery diameter following preoperative duplex imaging to enhance maturation and primary patency of Brescia-Cimino radiocephalic arteriovenous fistula. METHODS: A systematic review and meta-aggregation of literature from 1966 to January 2015 in English language and adult subjects in Pubmed, OVID, CINHAL and Cochrane database was conducted. RESULTS: This search produced a total of thirty-six (n = 36) articles. Following the application of recruitment criteria, only twelve articles (n = 12) were found eligible. Their quality was assessed by Oxford Critical Appraisal skills Programme (CASP) and their recommendation for practice was examined through National Institute for Health and Care Excellence (NICE). CONCLUSIONS: The current literature suggests that the optimal range of radial artery for maximum performance (maturation and primary patency) of RCAVF is at least 2 mm (level 2, grade a). The cephalic vein diameter of at least 2 mm (non-augmented) can result in best maturation and primary patency outcomes (level 2, grade a) and threshold below 1.5 mm is not advocated (level 2, grade b). PMID- 26109535 TI - Comment on: What is the best training for vascular access surgery? PMID- 26109536 TI - Optimizing outcomes in the elderly with end-stage renal disease--live long and prosper. AB - BACKGROUND: The elderly form an expanding proportion of patients with chronic kidney disease and end-stage renal disease worldwide. The increased physiological frailty and functional morbidity associated with the aging process pose unique challenges when planning optimal management of an older patient needing renal replacement therapy (RRT). AIMS: This position paper discusses current evidence regarding the optimal management of end-stage renal disease in the elderly with an emphasis on hemodialysis since it is the most common modality used in older patients. Further research is needed to define relevant patient-reported outcome measures for end-stage renal disease including functional assessments and psychological impacts of various forms of RRT. For those older patients who have opted for dialysis treatment, it is important to study the strategies that encourage greater uptake of home-based dialysis therapies and optimal vascular access. CONCLUSIONS: The management of advanced chronic kidney disease in the elderly can be challenging but also extremely rewarding. The key issue is adopting a patient-focused and individualized approach that seeks to achieve the best outcomes based on a comprehensive holistic assessment of what is important to the patient. PMID- 26109537 TI - Spontaneous migration of a peripherally inserted central catheter into the azygos vein in esophageal cancer patients during surgery. AB - INTRODUCTION: A peripherally inserted central catheter (PICC) is widely used for long chemotherapy regimens or total parenteral nutrition. However, spontaneous migration of the catheter into the azygos vein after satisfactory initial placement has occurred in rare cases. METHODS: We discuss three such cases in esophageal cancer patients. RESULTS: In two patients, the migrated catheters were found during surgery and were repositioned without complications. However, in the third case, the migrated catheter had to be removed to avoid severe complications, as the catheter and the azygos vein were ligatured during operation without notice. CONCLUSIONS: Migrations might be related to the material properties of silicone PICCs, the short insertion length, the left-sided placement, the changes of thoracic pressure and the intraoperative traction by thoracic surgeons. In conclusion, we recommend routine checks before cutting off the azygos vein during the operations for esophageal cancer patients with left sided PICCs. PMID- 26109538 TI - Arcanobacterium pyogenes bacteremia in a man on hemodialysis with central venous catheter. PMID- 26109539 TI - Conservative management of brachial artery pseudoaneurysms as a complication of fistula needling. PMID- 26109540 TI - Focused simulation training: emergency department nurses' confidence and comfort level in performing ultrasound-guided vascular access. AB - STUDY OBJECTIVES: The objective of this study is to assess Emergency Department (ED) nurses' confidence, comfort level, and competency in performing ultrasound guided vascular access after a focused ultrasound simulation training session. METHODS: A cross-sectional study at an academic medical center. A simulation based ultrasound training module was used to train ED nurses in ultrasound-guided intravenous (IV) access. The training module consisted of didactics followed by hands-on practice on human models and Blue Phantom ultrasound training block model. All subjects completed a questionnaire after completing the training module. RESULTS: A total of 40 nurses were enrolled. All subjects successfully demonstrated competency during the training session by identifying upper extremity sonographic vascular anatomy on a human model and performing real-time ultrasound-guided IV access on Blue Phantom ultrasound training block model. On a scale of 1-10, the average confidence level in performing the ultrasound-guided vascular access was 6.9 [95% confidence interval (95% CI) 6.3-7.46], with 98% (95% CI, 92-102%) reporting no difficulty in recognizing upper limb vascular anatomy on ultrasound. Ninety-two percent (95% CI, 84-100%) agreed that focused training in ultrasound-guided IV access was adequate to learn the procedure. CONCLUSIONS: After a focused simulation training session, ED nurses had a high level of comfort using ultrasound for vascular access. Despite having a moderate degree of confidence, ED nurses were accurate in identifying vascular anatomy and performing ultrasound-guided vascular access. PMID- 26109541 TI - Vascular access for incident hemodialysis patients in Catalonia: analysis of data from the Catalan Renal Registry (2000-2011). AB - PURPOSE: Arteriovenous fistula is the best vascular access (VA) for hemodialysis. We analyzed the VA used at first session and the factors associated with the likelihood to start hemodialysis by fistula in 2000-2011. METHODS: Data of VA type were obtained in 9,956 incident hemodialysis patients from the Catalan Registry. RESULTS: Overall, 47.9% of patients initiated hemodialysis with a fistula, 1.2% with a graft, 15.9% with a tunneled catheter and 35% with an untunneled catheter. The percentage of incident patients with fistula and catheter has remained stable at around 50% over the years. The likelihood to start hemodialysis with fistula was significantly lower in females [adjusted odds ratio: 0.69, 95% confidence interval (CI): 0.61-0.75], patients aged 18-44 years (0.78, 95% CI: 0.64-0.94), patients with comorbidity (0.67, 95% CI: 0.60-0.75) and tended to be lower in patients aged over 74 years (0.89, 95% CI: 0.78-1.01). The probability to use fistula was significantly higher in patients with polycystic kidney disease (2.08, 95% CI: 1.63-2.67), predialysis nephrology care longer than 2 years (4.14, 95% CI: 3.63-4.73) and steady chronic kidney disease (CKD) progression (10.97, 95% CI: 8.41-14.32). During 1 year of follow-up, 67.2% and 59.6% of patients using untunneled and tunneled catheter changed to fistula, respectively. CONCLUSIONS: Starting hemodialysis by fistula was related with nonmodifiable patient characteristics and modifiable CKD practice processes, such as predialysis care duration. Half of the incident patients were exposed annually in Catalonia to potential catheter complications. This scenario can be improved by optimizing the processes of CKD care. PMID- 26109542 TI - Predictors of difficult pediatric intravenous access in a community Emergency Department. AB - BACKGROUND: Successful intravenous (IV) placement is important in the care of the acutely ill and injured pediatric patient. There are little data that exist regarding predicators of difficult IV access in pediatric Emergency Department (ED) patients who present to community EDs. METHODS: We retrospectively analyzed all pediatric charts for the calendar year 2012 from a single community teaching hospital. We identified all cases with patients less than 18 years of age in whom an IV or IV medications were ordered. We defined difficult IV access as those requiring more than one attempt, or those where the IV team was required to place the IV. We identified patient, provider, and procedural characteristics. Data were analyzed using descriptive statistics and univariate logistic regression to determine the odds ratio (OR) for predictors of difficult IV access. RESULTS: We identified 652 patients, 607 (93%) without difficult access and 45 with difficult access. Increasing age [OR 0.94 (0.89-0.99) p = 0.017] was associated with decreased odds of difficult IV access. IVs attempted in the hand [OR 3.02 (1.06 8.58) p = 0.039] and lower extremity [OR 7.82 (2.27-26.91) p = 0.001)]) were associated with greater odds of difficult access than the antecubital fossa. Non black/non-white race [2.37 (1.1-5.12) p = 0.028] was also associated with difficult IV access. Other factors (sex, IV catheter size, and so on) were not associated. CONCLUSIONS: In this retrospective study of pediatric patients in a community ED, decreasing age, non-black/non-white race, and IV attempt location (hand and lower extremity vs. antecubital fossa) were associated with greater odds of difficult IV access. PMID- 26109543 TI - Retained embolized fragment of totally implantable central venous catheter in right ventricle: it is really necessary to remove? AB - INTRODUCTION: Central venous catheters are often required in oncologic patients for long-term safe administration of chemotherapeutic agents, antibiotics, and parenteral nutrition. Rupture of these devices and intracardiac migration is a rare complication. METHODS: We report one spontaneous rupture and embolization of a totally implantable vascular access device (TIVAD) in an asymptomatic patient. RESULTS: A 50-year-old woman received a TIVAD silicone catheter 8 FR for adjuvant chemotherapy. After 3 years of port time in situ, during a follow-up control, a catheter malfunction was found and radiologic investigations showed a rupture and migration of the catheter to the right ventricle. The attempt to remove the fragment under fluoroscopic control using the femoral route was unsuccessful. We did not try a surgical approach because of the complete absence of symptomatology and hemodynamic impairment. CONCLUSIONS: The catheter rupture and intracardiac embolization is a rare complication associated with totally implantable or tunneled central venous catheters. When such an event happens, the patient should be managed by expert hemodynamists or interventional radiologists making an effort to remove the fragment without surgical measures. When the intravascular percutaneous route fails, the possibility to leave the fragmented catheter in heart chambers should be evaluated, being surgery questionable in asymptomatic patients. PMID- 26109544 TI - Evaluation of the correct position of peripherally inserted central catheters: anatomical landmark vs. electrocardiographic technique. AB - PURPOSE: The purpose of this study is to verify as early as possible the correct positioning of the peripherally inserted central catheter (PICC) tip in order to reduce complications due to possible malpositioning. The ECG-guided technique proved to be reliable, easy to carry out, straightforward, low-cost and allows us to recognize an incorrect or a suboptimal positioning throughout the procedure. The purpose of this study is to compare two methods used during the PICC insertion so as to prevent catheter malpositioning; the first study estimates the catheter length by the landmark method (based on cutaneous anatomical landmarks, CALs) with the addition of the postprocedural verification of tip location by chest X-Ray (CxR), whereas the second method of intraprocedural tip location is based on the observation of the morphological variations of the P wave (ECG guided technique) with the addition of the postprocedural verification by CxR. METHODS: From 2010 to 2012, 90 PICCs were positioned, 48 using the anatomical landmarks and 42 using the ECG technique. RESULTS: Twenty-five percent of the catheters positioned with the anatomical landmark technique did not reach the correct position of the tip in SVC; of these, 6.25% were placed in an aberrant position and others in a sub-optimal position.Of the 42 PICCs positioned with the ECG technique, only in three cases (equal to 7.14%), a suboptimal position of the tip was observed, whereas there was no case of aberrant positioning. CONCLUSIONS: The ECG technique represents an accurate, low-cost and safe technique to verify the correct positioning of the tip. The use of the ECG allowed a more correct positioning in terms of catheter tip-carina distance and catheter tip tracheobronchial angle, and in no patient was it necessary to place a catheter again. PMID- 26109545 TI - Thoracoscopic-guided azygos vein catheterization and port implantation in a child with end-stage central venous access. PMID- 26109546 TI - Patterns of superficial veins of the middle upper extremity in Caucasian population. AB - PURPOSE: Superficial veins of the middle upper extremity are frequently variable in existence and arrangement. The superficial veins are clinically important in many revascularization procedures, particularly reconstructive microsurgery and arterial bypass surgery as well as intravenous injection or therapy. The aim of this study was to assess the patterns of superficial veins of middle upper extremity in healthy volunteers. METHODS: We examined both arms of 169 people. A tourniquet was applied at the mid-arm and a drawing made of the pattern of veins. It took about 1-3 min for each arm. We then examined the 338 drawings looking for similar patterns. The study took place in Department of Anatomy, Faculty of Medicine in Novi Sad, Serbia. RESULTS: We found nine patterns of middle upper extremity veins. The most common was an 'M'-shaped pattern (115/338, 34%) followed by an 'N'-shaped pattern (97/338, 29%). CONCLUSIONS: There are only nine basic patterns of middle upper extremity venous anatomy. Some are more common than others. This knowledge should help those needing venous access for medical procedures (venepuncture, transfusion, infusion, cardiac catheterization, placement of dialysis access). PMID- 26109547 TI - Higher patency of transposed brachio-basilic arteriovenous fistulas compared to brachio-axillary grafts for hemodialysis patients. AB - PURPOSE: We compared outcomes of transposed brachio-basilic arteriovenous fistulas (BBAVF) with brachio-axillary prosthetic grafts (BAPG) for hemodialysis. METHODS: All consecutive patients who underwent creation of a BBAVF or a BAPG, in one of the two institutions, between January 2008 and December 2013 were retrospectively identified. We assessed functional patency and compared complication rates. Patency was also compared between one-stage and two-stage creation procedures for the BBAVF group. RESULTS: Two hundred and thirty-eight patients underwent the creation of a BBAVF (N = 136) or a BAPG (N = 102). Median follow-up was 17 months (range, 1-79). At 6, 12 and 24 months, patients in the BBAVF group had significantly higher primary patency (80%, 69%, 56% vs. 77%, 56%, 37%, respectively; p = 0.005), assisted primary patency (90%, 80%, 71% vs. 80%, 66%, 48%; p<0.0001) and secondary patency (93%, 84%, 72% vs. 94%, 87%, 62%; p = 0.006). Two-stage BBAVF had a significantly higher secondary patency (98%, 92%, 78% vs. 90%, 80%, 68%; p = 0.04) than one-stage BBAVF. The rate of infectious complications was significantly lower in the BBAVF group than in the BAPG group (0.8% vs. 6.9%; p = 0.03). CONCLUSIONS: In this large cohort, BBAVF had a higher functional patency and lower rate of infectious complications than BAPG. After exhaustion of cephalic veins, we suggest creation of a BBAVF instead of BAPG, whenever anatomically feasible. The superiority of one-stage or two-stage BBAVF creation procedure must be further investigated. PMID- 26109548 TI - IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes. AB - BACKGROUND: Lambda interferons (IFNLs) have potent antiviral activity against HCV, and polymorphisms within the IFNL gene cluster near the IFNL3 gene strongly predict spontaneous- and treatment-related HCV infection outcomes. The mechanism(s) linking IFNL polymorphisms and HCV control is currently elusive. METHODS: IFNL induction was studied in primary human hepatocytes (PHH) from 18 human donors, peripheral blood mononuclear cells (PBMCs) from 18 human donors, multiple cell lines and induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-hepatocytes) from 7 human donors. After stimulation with intracellular RNA and infectious HCV, quantitative PCR (qPCR) primers and probes were designed to distinguish and quantify closely related IFNL messenger (m)RNAs from IFNL1, IFNL2 and IFNL3. RESULTS: PHH demonstrated the most potent induction of IFNLs, although had lower pre-stimulation levels compared to PBMCs, monocytes and cell lines. PHH stimulation with cytoplasmic poly I:C induced >1,000-fold expression of IFNL1, IFNL2 and IFNL3. PHH from donors who were homozygous for the favourable IFNL3 allele (IFNL3-CC) had higher IFNL3 induction compared to PHH from IFNL3-TT donors (P=0.03). Baseline IFNL mRNA expression and induction was also tested in iPSC-hepatocytes: iPSC-hepatocytes had significantly higher baseline expression of IFNLs compared to PHH (P<0.0001), and IFNL3 induction was marginally different in iPSC-hepatocytes by IFNL genotype (P=0.07). CONCLUSIONS: Hepatocytes express IFNLs when stimulated by a synthetic viral RNA that signals the cell through the cytoplasm. IFNL induction may be greater in persons with the favourable IFNL3 allele. These data provide insight into the strong linkage between IFNL3 genetics and control of HCV infection. PMID- 26109549 TI - Cognitive deficits at age 22 years associated with prenatal exposure to methylmercury. AB - Prenatal exposure to mercury has been associated with adverse effects on child neurodevelopment. The present study aims to determine the extent to which methylmercury-associated cognitive deficits persist into adult age. In a Faroese birth cohort originally formed in 1986-1987 (N = 1,022), prenatal methylmercury exposure was assessed in terms of the mercury concentration in cord blood and maternal hair. Clinical examinations of 847 cohort members at age 22 years were carried out in 2008-2009 using a panel of neuropsychological tests that reflected major functional domains. Subjects with neurological and psychiatric diagnoses were excluded from the data analysis, thus leaving 814 subjects. Multiple regression analysis included covariates previously identified for adjustment. Deficits in Boston Naming Test (BNT) and other tests of verbal performance were significantly associated with the cord-blood mercury concentration. Deficits were also present in all other tests applied, although most were not statistically significant. Structural equation models were developed to ascertain the possible differences in vulnerability of specific functional domains and the overall association with general intelligence. In models for individual domains, all of them showed negative associations, with crystallized intelligence being highly significant. A hierarchical model for general intelligence based on all domains again showed a highly significant negative association with the exposure, with an approximate deficit that corresponds to about 2.2 IQ points at a 10-fold increased prenatal methylmercury exposure. Thus, although the cognitive deficits observed were smaller than at examinations at younger ages, maternal diets with contaminated seafood were associated with adverse effects in this birth cohort at age 22 years. The deficits affected major domains of brain functions as well as general intelligence. Thus, prenatal exposure to this marine contaminant appears to cause permanent adverse effects on cognition. PMID- 26109550 TI - Chlamydia trachomatis virulence factor CT135 is stable in vivo but highly polymorphic in vitro. AB - Chlamydia trachomatis is an important human pathogen causing both ocular and sexually transmitted disease. Recently, we identified CT135 as an important virulence determinant in a mouse infection model. Results from CEL 1 digestion assays and sequencing analyses indicated that CT135 was much more polymorphic in high in vitro passage reference serovars than it was in clinical strains that had undergone limited passaging. Herein, we used targeted next-generation sequencing of the CT134-135 locus, from reference strains and clinical isolates, enabling accurate discovery of single nucleotide polymorphisms and other population genetic variations. Our results indicate that CT134 is stable in all C. trachomatis serovars examined. In contrast, CT135 is highly polymorphic in high passaged reference ocular and non-LGV genital serovars, with the majority of the mutations resulting in gene disruption. In low-passaged ocular clinical isolates, CT135 was frequently disrupted, whereas in genital clinical isolates CT135 was intact in almost all instances. When a serovar K isolate, with an intact CT134 and CT135, was subjected to serial passage in vitro CT134 remained invariable, while numerous gene interrupting mutations rapidly accumulated in CT135. Collectively, our data indicate that, for genital serovars, CT135 is under strong positive selection in vivo, and negative selection in vitro. PMID- 26109551 TI - Risk of recurrent stillbirth: systematic review and meta-analysis. AB - OBJECTIVE: To determine the risk of recurrent stillbirth. DESIGN: Systematic review and meta-analysis of cohort and case-control studies. DATA SOURCES: Embase, Medline, Cochrane Library, PubMed, CINAHL, and Scopus searched systematically with no restrictions on date, publication, or language to identify relevant studies. Supplementary efforts included searching relevant internet resources as well as hand searching the reference lists of included studies. Where published information was unclear or inadequate, corresponding authors were contacted for more information. STUDY SELECTION: Cohort and case-control studies from high income countries were potentially eligible if they investigated the association between stillbirth in an initial pregnancy and risk of stillbirth in a subsequent pregnancy. Stillbirth was defined as fetal death occurring at more than 20 weeks' gestation or a birth weight of at least 400 g. Two reviewers independently screened titles to identify eligible studies based on inclusion and exclusion criteria agreed a priori, extracted data, and assessed the methodological quality using scoring criteria from the critical appraisal skills programme. Random effects meta-analyses were used to combine the results of the included studies. Subgroup analysis was performed on studies that examined unexplained stillbirth. RESULTS: 13 cohort studies and three case-control studies met the inclusion criteria and were included in the meta-analysis. Data were available on 3,412,079 women with pregnancies beyond 20 weeks duration, of who 3,387,538 (99.3%) had had a previous live birth and 24,541 (0.7%) a stillbirth. A total of 14,283 stillbirths occurred in subsequent pregnancies, 606/24,541 (2.5%) in women with a history of stillbirth and 13,677/3,387,538 (0.4%) among women with no such history (pooled odds ratio 4.83, 95% confidence interval 3.77 to 6.18). 12 studies specifically assessed the risk of stillbirth in second pregnancies. Compared with women who had a live birth in their first pregnancy, those who experienced a stillbirth were almost five times more likely to experience a stillbirth in their second pregnancy (odds ratio 4.77, 95% confidence interval 3.70 to 6.15). The pooled odds ratio using the adjusted effect measures from the primary studies was 3.38 (95% confidence interval 2.61 to 4.38). Four studies examined the risk of recurrent unexplained stillbirth. Methodological differences between these studies precluded pooling the results. CONCLUSIONS: The risk of stillbirth in subsequent pregnancies is higher in women who experience a stillbirth in their first pregnancy. This increased risk remained after adjusted analysis. Evidence surrounding the recurrence risk of unexplained stillbirth remains controversial. PMID- 26109552 TI - Novel approach to measure the size of plasma-membrane nanodomains in single molecule localization microscopy. AB - Many membrane proteins are not evenly distributed over the plasma membrane, but gathered in domains assumed to have a particular lipid composition. Using single molecule localization microscopy (SMLM) we have immunolocalized a glycosylphosphatidylinositol (GPI)-anchor protein that labels nanodomains in a specialized plant cell type, and compared the suitability of three methods to estimate their size. As conventional methods full width at half maximum (FWHM) and the full diameter (FWMin) of domains were used. A boundary detection method of the domain area (DA) was performed in order to take irregular shapes into account. In order to compare the influence of the chosen measurement methods, we have developed a MatLab program that allows for automated analysis of domain sizes from multiple SMLM images and provides the statistics of three key features of domains: FWHM and FWMin along their long and short axes as well as the DA, derived from the molecular density. Domains formed by the GPI-anchor protein are approximating elliptical shapes. Direct and indirect immunolabeling resulted in a statistically significant difference in apparent domain size, reflecting the fact that the secondary antibody molecules extend the uncertainty along the nanodomain border. FWMin values along the long and short axis give good estimates of regular, geometrically centred domain shapes, while the DA value matches regular as well as irregular shapes best, as derived from computer-generated, irregular point clusters. PMID- 26109553 TI - Structural and functional imaging study in dementia with Lewy bodies and Parkinson's disease dementia. AB - INTRODUCTION: Dementia with Lewy Bodies (DLB) and Parkinson's disease with Dementia (PDD) are neurodegenerative disorders with complex clinical picture (parkinsonism, cognitive decline and neuropsychiatric disturbances). The conundrum of whether DLB and PDD represent the same or different entities is still under debate. Advanced neuroimaging techniques may represent a point of view to assess brain correlates in DLB and PDD. The study aimed at evaluating whether DLB and PDD may be labelled under the same disease entity or be considered distinctive pathologies. We compared DLB and PDD patients by assessing structural and functional brain imaging and including PD patients. METHODS: Patients with diagnosis of PD, PDD, DLB and a group of healthy controls for neuroimaging comparisons were recruited and changes in structural and resting state functional MR (Regional Homogeneity, ReHo) were studied. RESULTS: No significant atrophy in VBM analysis was evident in PD. Conversely, PDD showed a significant bilateral frontal atrophy, whereas DLB was characterized by a predominant parietal, occipital atrophy; a similar involvement of subcortical regions in PDD and DLB was observed. ReHo demonstrated reduced local coherence of frontal regions in PD and in PDD, whereas DLB patients presented a reduced local connectivity in posterior regions. CONCLUSION: Different brain areas are specifically involved in PDD and DLB. In the former group, greater atrophy of frontal regions with concomitant functional connectivity impairment was evident; conversely, structural and functional damage in the posterior regions characterized DLB. Despite an overlapping clinical spectrum, DLB and PDD have different networks involved and different underlying pathogenic pathways. PMID- 26109554 TI - Detection of Epstein-Barr virus in inflammatory pseudotumour of the spleen: a case report. AB - BACKGROUND: Various types of benign and malignant splenic tumours including hemangiomas, lymphagiomas, hamartomas, hemangiosarcomas, malignant lymphomas and metastatic carcinomas share radiological characteristics making it impossible for a physician to determine the definite aetiology of splenic masses noninvasively without histopathological evaluation. It is important that physicians recognize the importance of a careful and continuous follow-up since inflammatory pseudotumours (IPT) are considered to be tumours with an intermediate malignant potential based on their behaviour when they arise in other locations. METHODS: Our patient, a 60-year-old woman was evaluated using laboratory, gastroscopy, computed tomography and surgical methods. The resected tumour was evaluated using immunohistochemical methods. RESULTS: The patient presented with weight loss, nausea and vomiting, symptoms lasting over a course of a few months. The splenic mass was found incidentally at the time of work up for gastritis and cholelithiasis. Histologically, the tumour differed from typical splenic architecture being composed of atypical spindle cells with inflammatory elements; numerous plasma cells, macrophages, eosinophils and lymphocytes. CONCLUSIONS: Although very difficult to diagnose at initial presentation, it is very important for the physician to be aware of the importance of a careful diagnosis since IPT of the spleen are rare and considered to be tumours with an intermediate malignant potential. PMID- 26109555 TI - Gender-related differences in patients with ST-elevation myocardial infarction. AB - BACKGROUND: A decade ago women with ST-elevation myocardial infarction (STEMI) were significantly older than men, with more comorbidities, less likely treated by primary percutaneous coronary intervention (PPCI) and their prognosis was worse. The progress in treatment led to increased survival after STEMI. Our aim was to evaluate the possible current differences between the genders in treatments, mortality and the changes in women over time in STEMI population. METHODS: We retrospectively evaluated 307 STEMI patients (224 men, 83 women), admitted between October 1, 2011 and December 31, 2012 and a historic group of 523 STEMI patients from 2008 to 2009 (361 men, 162 women). Reperfusion strategy was PPCI, combined with aspirin and clopidogrel or prasugrel or ticagrelor and a heparin with glycoprotein receptor IIb/IIIa antagonist or bivalirudin. Between the genders and in women over time we compared clinical data, the use and time to PPCI, in-hospital complications, 30-day and 6-month mortality. RESULTS: STEMI patients in recent years were treated by PPCI in 94.5 %. Their 30-day mortality was 10.4 % and 6-month mortality 14.7 %. Between the genders we observed mostly nonsignificant differences (age, comorbidities, treatments, in-hospital complications, 30-day and 6-month mortality). Over the last years in women mean age significantly decreased, the use of PPCI significantly increased, the incidence of heart failure and bleedings decreased significantly, but mortalities nonsignificantly. CONCLUSION: Women still account for 1/4 of STEMI population, but the gap between the genders in presentation, treatments and outcome in STEMI population is decreasing. PMID- 26109556 TI - Needle fragment embolism into the right ventricle: a rare cause of chest pain case report and literature review. AB - Chest pain in young adults is usually self-limited and of benign etiology. However, rare causes of chest pain must be considered in patients for whom initial diagnostic tests are negative, particularly if unusual risk factors are identified. The authors present a rare case describing a 27-year-old male intravenous drug user who developed transient chest pain most likely secondary to pericardial irritation caused by a needle fragment that embolized from a peripheral vein to his right ventricle. The current literature on intracardiac needles and similar foreign bodies is discussed, providing insight to the epidemiology, complications, and treatment of such patients. PMID- 26109557 TI - AGO Austria recommendations for genetic testing of patients with ovarian cancer. AB - In Austria, 700 women are diagnosed every year with ovarian carcinoma. Approximately 15% of the patients with epithelial ovarian cancer have a germline mutation in the BRCA1 or BRCA2 genes. The increased incidence of breast and/or ovarian cancer in genetically related family members has given rise to the term "hereditary breast and ovarian cancer syndrome" (HBOC). Some 25-55% of these in family diseases are attributed to germline mutations of BRCA1 or BRCA2, and approximately 5-10% to other known tumor predisposition syndromes. The remaining persons may carry mutations in as yet unidentified genes. HBOC caused by BRCA1 and BRCA2 mutations is an autosomal dominant disorder with high penetrance. BRCA1 and BRCA2 encode for so-called tumor suppressor proteins. Inherited functional mutations of these genes cause loss of function of the respective allele. Loss of function of the second allele causes complete loss of the corresponding protein and facilitates the development of a malignancy.The Association of Gynecologic Oncology recommends that testing for a germline mutation in BRCA1 or BRCA2 should be offered to all patients with epithelial ovarian cancer. When mutations in BRCA1, BRCA2, or other cancer-susceptibility genes have been identified, patients with ovarian carcinoma can be treated with new, innovative therapies. This recommendation is intended as a standard guideline for genetic testing of patients with an ovarian carcinoma. PMID- 26109558 TI - Paris Saponin VII Inhibits the Migration and Invasion in Human A549 Lung Cancer Cells. AB - Metastasis is the main cause of death in lung cancer. Targeting the process of metastasis is a strategy to lung cancer treatment. Trillium tschonoskii Maxim., a traditional Chinese medicine, has been used for treatment of many diseases, including cancer. This study aims to determine the anti-metastatic effect of paris saponin VII (PS VII) which was extracted from T. tschonoskii Maxim. by using human lung cancer cell line A549 cells. Our results showed that PS VII could significantly suppress the viability as well as cell migration and invasion abilities of A549 cells in a concentration-dependent manner. PS VII reduced the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 by elevating the expression of TIMP1/2. These data indicated that PS VII could reduce the metastatic capability of A549 cells, probably through up-regulating the expression of TIMP1/2. These findings demonstrated a new therapeutic potential for PS VII in anti-metastatic therapy of lung cancer. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26109559 TI - Keratin-17 Promotes p27KIP1 Nuclear Export and Degradation and Offers Potential Prognostic Utility. AB - Keratins that are overexpressed selectively in human carcinomas may offer diagnostic and prognostic utility. In this study, we show that high expression of keratin-17 (K17) predicts poor outcome in patients with cervical cancer, at early or late stages of disease, surpassing in accuracy either tumor staging or loss of p27(KIP1) as a negative prognostic marker in this setting. We investigated the mechanistic basis for the biologic impact of K17 through loss- and gain-of function experiments in human cervix, breast, and pancreatic cancer cells. Specifically, we determined that K17 functions as an oncoprotein by regulating the subcellular localization and degradation of p27(KIP1). We found that K17 was released from intermediate filaments and translocated into the nucleus via a nuclear localization signal (NLS), specific among keratins, where it bound p27(KIP1) during G1 phase of the cell cycle. p27(KIP1) lacks a nuclear export signal (NES) and requires an adaptor for CRM1 binding for nuclear export. In K17, we defined and validated a leucine-rich NES that mediated CRM1 binding for export. Cervical cancer cells expressing K17 mutations in its NLS or NES signals exhibited an increase in levels of nuclear p27(KIP1), whereas cells expressing wild-type K17 exhibited a depletion in total endogenous p27(KIP1). In clinical specimens of cervical cancer, we confirmed that the expressions of K17 and p27(KIP1) were inversely correlated, both across tumors and within individual tumors. Overall, our findings establish that K17 functions specially among keratins as an oncoprotein by controlling the ability of p27(KIP1) to influence cervical cancer pathogenesis. PMID- 26109560 TI - Gestational age and newborn size according to parental social mobility: an intergenerational cohort study. AB - BACKGROUND: We examined the associations between socioeconomic trajectories from birth to adulthood and gestational age and birth size in the next generation, using linked data from two population-based birth cohorts carried out in a Brazilian city. By comparing socioeconomic trajectories of mothers and fathers, we attempted to identify-specific effects of maternal and paternal socioeconomic trajectory on offspring birth weight, birth length, head circumference and gestational age at birth. METHODS: 2 population-based birth cohort studies were carried out in 1982 and 2004 in Pelotas (Brazil); 156 mothers and 110 fathers from the earlier cohort had children in 2004. Gestational age and birth length, weight and head circumference were measured. Analyses were carried out separately for mothers and fathers. Mediation analyses assessed the role of birth weight and adult body mass index (BMI). RESULTS: Among mothers, but not for fathers, childhood poverty was strongly associated with smaller size in the next generation (about 400 g in weight and 1.5 cm in height) and shorter gestations (about 2 weeks). Adult poverty did not play a role. For mothers, the associations with gestational age, birth length and weight-but not with head circumference persisted after adjusting for maternal birth weight and for the height and weight of the grandmother. Maternal birth weight did not mediate the observed associations, but high maternal BMI in adulthood was partly responsible for the association with gestational age. CONCLUSIONS: Strong effects of early poverty on gestational age and birth size in the next generation were observed among mothers, but not among fathers. These findings suggest a specific maternal effect of socioeconomic trajectory, and in particular of early poverty on offspring size and duration of pregnancy. PMID- 26109561 TI - Reconstruction of posterior compartment of lower extremity using a functional latissimus dorsi free flap: A case report. AB - We present an unusual case in an 8-year-old male that presented with a severe crushing injury to the right lower extremity with grade IIIB open tibia/fibula fracture and composite loss of the majority of the posterior muscle compartments and overlying skin and segmental loss of the tibial nerve. Composite reconstruction was performed with internal fixation, cable autografting of the tibial nerve, and a functional latissimus dorsi musculocutaneous flap. A motor branch of the tibial nerve to the soleus was used as the donor motor nerve. The patient achieved a bony union and began ambulating at 8 weeks postoperatively. At 24 months, the patient was running and jumping with plantar push-off. Recovery of plantar flexion was to the M5 level. Static and moving 2-point discrimination of the plantar foot was 8 mm and 6 mm, respectively. Functioning muscle transfer in a child with a severe lower extremity injury with composite tissue loss may provide soft tissue and motor-unit defect reconstruction with an acceptable functional restoration. PMID- 26109562 TI - Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia Relevant Isoforms. AB - Cytochrome P450 monooxygenases (P450s), which are well-known drug-metabolizing enzymes, are thought to play a signal transduction role in u opioid analgesia and may serve as high-affinity (3)H-cimetidine ((3)HCIM) binding sites in the brain. (3)HCIM binding sites may also be related to opioid or nonopioid analgesia. However, of the more than 100 murine P450 enzymes, the specific isoform(s) responsible for either function have not been identified. Presently, three lines of constitutive P450 gene cluster knockout (KO) mice with full-length deletions of 14 Cyp2c, 9 Cyp2d, and 7 Cyp3a genes were studied for deficiencies in (3)HCIM binding and for opioid analgesia. Liver and brain homogenates from all three genotypes showed normal (3)HCIM binding values, indicating that gene products of Cyp2d, Cyp3a, and Cyp2c are not (3)HCIM-binding proteins. Cyp2d KO and Cyp3a KO mice showed normal antinociceptive responses to a moderate systemic dose of morphine (20 mg/kg, s.c.), thereby excluding 16 P450 isoforms as mediators of opioid analgesia. In contrast, Cyp2c KO mice showed a 41% reduction in analgesic responses following systemically (s.c.) administered morphine. However, the significance of brain Cyp2c gene products in opioid analgesia is uncertain because little or no analgesic deficits were noted in Cyp2c KO mice following intracerebroventricular or intrathecalmorphine administration, respectively. These results show that the gene products of Cyp2d and Cyp3a do not contribute to u opioid analgesia in the central nervous system. A possible role for Cyp2c gene products in opioid analgesia requires further consideration. PMID- 26109563 TI - Prediction of Sjogren's Syndrome Years Before Diagnosis and Identification of Patients With Early Onset and Severe Disease Course by Autoantibody Profiling. AB - OBJECTIVE: Autoantibodies are highly characteristic of primary Sjogren's syndrome (SS) and represent important tools for studying its pathogenesis. Nonetheless, thus far, no systematic investigations have assessed the presence of autoantibodies before diagnosis. This study was undertaken to analyze how early and in what order autoantibodies appear, how predictive they are of primary SS, and whether they identify disease subsets. METHODS: A nested case-control design linking data from the Malmo primary SS registry and 3 Swedish healthcare biobanks was applied. In all, 175 serum samples obtained from 117 individuals before diagnosis of primary SS and 1 serum sample from each of 117 matched controls were analyzed for antinuclear antibodies (ANAs), rheumatoid factor (RF), and antibodies against Ro 60/SSA, Ro 52/SSA, and La/SSB. RESULTS: Considering all patients with primary SS who were autoantibody positive after diagnosis, at least one autoantibody specificity was detected in 81% up to 20 years (median 4.3-5.1 years) before diagnosis. Those found most often were ANAs, followed by RF, anti Ro 60/SSA, anti-Ro 52/SSA, and anti-La/SSB. Anti-Ro/SSA and anti-La/SSB antibodies were strongly associated with the risk of developing primary SS, especially early-onset disease and a severe disease course. When Bayesian prior prevalence estimates for primary SS were included in the calculation, prediagnostic anti-Ro 60/SSA and anti-Ro 52/SSA had the highest positive predictive values (25% and 100%, respectively). CONCLUSION: Our findings indicate that autoantibodies are present for up to 18-20 years before the diagnosis of primary SS, but we cannot exclude even earlier seropositivity, since for most patients, the earliest sample analyzed was positive. In families with multiple cases of autoimmune disease, autoantibody profiling, along with assessment of genetic risk, enables identification of susceptible individuals in a predisease state. PMID- 26109564 TI - Transcriptome response to infraorbital nerve transection in the gonadally intact male rat barrel cortex: RNA-seq. AB - The effects of infraorbital nerve (ION) transection on gene expression in the adult male rat barrel cortex were investigated using RNA sequencing. After a 24 hour survival duration, 98 genes were differentially regulated by ION transection. Differentially expressed genes suggest changes in neuronal activity, excitability, and morphology. The production of mRNA for neurotrophins, including brain-derived neurotrophin factor (BNDF), was decreased following ION transection. Several potassium channels showed decreased mRNA production, whereas a sodium channel (Na(V)beta4) associated with burst firing showed increased mRNA production. The results may have important implications for phantom-limb pain and complex regional pain syndrome. Future experiments should determine the extent to which changes in RNA result in changes in protein expression, in addition to utilizing laser capture microdissection techniques to differentiate between neuronal and glial cells. PMID- 26109565 TI - Controlled preparation of wet granular media reveals limits to lizard burial ability. AB - Many animals move within ground composed of granular media (GM); the resistive properties of such substrates can depend on water content and compaction, but little is known about how such parameters affect locomotion or the physics of drag and penetration. Using apparatus to control compaction of GM, our recent studies of movement in dry GM have revealed locomotion strategies of specialized dry-sand-swimming reptiles. However, these animals represent a small fraction of the diversity and presumed burial strategies of fossorial reptilian fauna. Here we develop a system to create states of wet GM of varying moisture content and compaction in quantities sufficient to study the burial and subsurface locomotion of the Ocellated skink (C. ocellatus), a generalist lizard. X-ray imaging revealed that in wet and dry GM the lizard slowly buried (~30 s) propagating a wave from head to tail, while moving in a start-stop motion. During forward movement, the head oscillated, and the forelimb on the convex side of the body propelled the animal. Although body kinematics and 'slip' were similar in both substrates, the burial depth was smaller in wet GM. Penetration and drag force experiments on smooth cylinders revealed that wet GM was ~4* more resistive than dry GM. In total, our measurements indicate that while the rheology of the dry and wet GM differ substantially, the lizard's burial motor pattern is conserved across substrates, while its burial depth is largely constrained by environmental resistance. PMID- 26109566 TI - Evidence for primary care services at A&E. PMID- 26109567 TI - Correction for Bartolome et al., Hydrological change in Southern Europe responding to increasing North Atlantic overturning during Greenland Stadial 1. PMID- 26109568 TI - Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice. AB - Cerebral cavernous malformation (CCM) is a disease of the central nervous system causing hemorrhage-prone multiple lumen vascular malformations and very severe neurological consequences. At present, the only recommended treatment of CCM is surgical. Because surgery is often not applicable, pharmacological treatment would be highly desirable. We describe here a murine model of the disease that develops after endothelial-cell-selective ablation of the CCM3 gene. We report an early, cell-autonomous, Wnt-receptor-independent stimulation of beta-catenin transcription activity in CCM3-deficient endothelial cells both in vitro and in vivo and a triggering of a beta-catenin-driven transcription program that leads to endothelial-to-mesenchymal transition. TGF-beta/BMP signaling is then required for the progression of the disease. We also found that the anti-inflammatory drugs sulindac sulfide and sulindac sulfone, which attenuate beta-catenin transcription activity, reduce vascular malformations in endothelial CCM3 deficient mice. This study opens previously unidentified perspectives for an effective pharmacological therapy of intracranial vascular cavernomas. PMID- 26109569 TI - Vimentin filament precursors exchange subunits in an ATP-dependent manner. AB - Intermediate filaments (IFs) are a component of the cytoskeleton capable of profound reorganization in response to specific physiological situations, such as differentiation, cell division, and motility. Various mechanisms were proposed to be responsible for this plasticity depending on the type of IF polymer and the biological context. For example, recent studies suggest that mature vimentin IFs (VIFs) undergo rearrangement by severing and reannealing, but direct subunit exchange within the filament plays little role in filament dynamics at steady state. Here, we studied the dynamics of subunit exchange in VIF precursors, called unit-length filaments (ULFs), formed by the lateral association of eight vimentin tetramers. To block vimentin assembly at the ULF stage, we used the Y117L vimentin mutant (vimentin(Y117L)). By tagging vimentin(Y117L) with a photoconvertible protein mEos3.2 and photoconverting ULFs in a limited area of the cytoplasm, we found that ULFs, unlike mature filaments, were highly dynamic. Subunit exchange among ULFs occurred within seconds and was limited by the diffusion of soluble subunits in the cytoplasm rather than by the association and dissociation of subunits from ULFs. Our data demonstrate that cells expressing vimentin(Y117L) contained a large pool of soluble vimentin tetramers that was in rapid equilibrium with ULFs. Furthermore, vimentin exchange in ULFs required ATP, and ATP depletion caused a dramatic reduction of the soluble tetramer pool. We believe that the dynamic exchange of subunits plays a role in the regulation of ULF assembly and the maintenance of a soluble vimentin pool during the reorganization of filament networks. PMID- 26109570 TI - Biologically recycled continental iron is a major component in banded iron formations. AB - Banded iron formations (BIFs) record a time of extensive Fe deposition in the Precambrian oceans, but the sources and pathways for metals in BIFs remain controversial. Here, we present Fe- and Nd-isotope data that indicate two sources of Fe for the large BIF units deposited 2.5 billion y ago. High-epsilonNd and delta(56)Fe signatures in some BIF samples record a hydrothermal component, but correlated decreases in epsilonNd- and delta(56)Fe values reflect contributions from a continental component. The continental Fe source is best explained by Fe mobilization on the continental margin by microbial dissimilatory iron reduction (DIR) and confirms for the first time, to our knowledge, a microbially driven Fe shuttle for the largest BIFs on Earth. Detailed sampling at various scales shows that the proportions of hydrothermal and continental Fe sources were invariant over periods of 10(0)-10(3) y, indicating that there was no seasonal control, although Fe sources varied on longer timescales of 10(5)-10(6) y, suggesting a control by marine basin circulation. These results show that Fe sources and pathways for BIFs reflect the interplay between abiologic (hydrothermal) and biologic processes, where the latter reflects DIR that operated on a basin-wide scale in the Archean. PMID- 26109571 TI - Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade. AB - Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up. PMID- 26109572 TI - Phosphorylation is an on/off switch for 5-hydroxyconiferaldehyde O methyltransferase activity in poplar monolignol biosynthesis. AB - Although phosphorylation has long been known to be an important regulatory modification of proteins, no unequivocal evidence has been presented to show functional control by phosphorylation for the plant monolignol biosynthetic pathway. Here, we present the discovery of phosphorylation-mediated on/off regulation of enzyme activity for 5-hydroxyconiferaldehyde O-methyltransferase 2 (PtrAldOMT2), an enzyme central to monolignol biosynthesis for lignification in stem-differentiating xylem (SDX) of Populus trichocarpa. Phosphorylation turned off the PtrAldOMT2 activity, as demonstrated in vitro by using purified phosphorylated and unphosphorylated recombinant PtrAldOMT2. Protein extracts of P. trichocarpa SDX, which contains endogenous kinases, also phosphorylated recombinant PtrAldOMT2 and turned off the recombinant protein activity. Similarly, ATP/Mn(2+)-activated phosphorylation of SDX protein extracts reduced the endogenous SDX PtrAldOMT2 activity by ~ 60%, and dephosphorylation fully restored the activity. Global shotgun proteomic analysis of phosphopeptide enriched P. trichocarpa SDX protein fractions identified PtrAldOMT2 monophosphorylation at Ser(123) or Ser(125) in vivo. Phosphorylation-site mutagenesis verified the PtrAldOMT2 phosphorylation at Ser(123) or Ser(125) and confirmed the functional importance of these phosphorylation sites for O methyltransferase activity. The PtrAldOMT2 Ser(123) phosphorylation site is conserved across 93% of AldOMTs from 46 diverse plant species, and 98% of the AldOMTs have either Ser(123) or Ser(125). PtrAldOMT2 is a homodimeric cytosolic enzyme expressed more abundantly in syringyl lignin-rich fiber cells than in guaiacyl lignin-rich vessel cells. The reversible phosphorylation of PtrAldOMT2 is likely to have an important role in regulating syringyl monolignol biosynthesis of P. trichocarpa. PMID- 26109574 TI - Porcine Islet-Specific Tolerance Induced by the Combination of Anti-LFA-1 and Anti-CD154 mAbs Is Dependent on PD-1. AB - We previously demonstrated that short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) induces tolerance to neonatal porcine islet (NPI) xenografts that is mediated by regulatory T cells (Tregs) in B6 mice. In this study, we examined whether the coinhibitory molecule PD-1 is required for the induction and maintenance of tolerance to NPI xenografts. We also determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or xenogeneic rat islet grafts since we previously demonstrated that tolerance to NPI xenografts could be extended to second-party NPI xenografts. Finally, we determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or second-party porcine skin grafts. Diabetic B6 mice were transplanted with 2,000 NPIs under the kidney capsule and treated with short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs. Some of these mice were also treated simultaneously with anti-PD-1 mAb at >150 days posttransplantation. Spleen cells from some of the tolerant B6 mice were used for proliferation assays or were injected into B6 rag(-/-) mice with established islet grafts from allogeneic or xenogeneic donors. All B6 mice treated with anti-LFA-1 and anti-CD154 mAbs achieved and maintained normoglycemia until the end of the study; however, some mice that were treated with anti-PD-1 mAb became diabetic. All B6 rag(-/-) mouse recipients of first- and second-party NPIs maintained normoglycemia after reconstitution with spleen cells from tolerant B6 mice, while all B6 rag(-/-) mouse recipients of allogeneic mouse or xenogeneic rat islets rejected their grafts after cell reconstitution. Tolerant B6 mice rejected their allogeneic mouse or xenogeneic second-party porcine skin grafts while remaining normoglycemic until the end of the study. These results show that porcine islet-specific tolerance is dependent on PD-1, which could not be extended to skin grafts. PMID- 26109573 TI - Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape. AB - The timescale for the microscopic dynamics of proteins during conformational transitions is set by the intrachain diffusion coefficient, D. Despite the central role of protein misfolding and aggregation in many diseases, it has proven challenging to measure D for these processes because of their heterogeneity. We used single-molecule force spectroscopy to overcome these challenges and determine D for misfolding of the prion protein PrP. Observing directly the misfolding of individual dimers into minimal aggregates, we reconstructed the energy landscape governing nonnative structure formation. Remarkably, rather than displaying multiple pathways, as typically expected for aggregation, PrP dimers were funneled into a thermodynamically stable misfolded state along a single pathway containing several intermediates, one of which blocked native folding. Using Kramers' rate theory, D was found to be 1,000-fold slower for misfolding than for native folding, reflecting local roughening of the misfolding landscape, likely due to increased internal friction. The slow diffusion also led to much longer transit times for barrier crossing, allowing transition paths to be observed directly for the first time to our knowledge. These results open a new window onto the microscopic mechanisms governing protein misfolding. PMID- 26109575 TI - The nexus between growth and defence signalling: auxin and cytokinin modulate plant immune response pathways. AB - Plants deploy a finely tuned balance between growth and defence responses for better fitness. Crosstalk between defence signalling hormones such as salicylic acid (SA) and jasmonates (JAs) as well as growth regulators plays a significant role in mediating the trade-off between growth and defence in plants. Here, we specifically discuss how the mutual antagonism between the signalling of auxin and SA impacts on plant growth and defence. Furthermore, the synergism between auxin and JA benefits a class of plant pathogens. JA signalling also poses growth cuts through auxin. We discuss how the effect of cytokinins (CKs) is multifaceted and is effective against a broad range of pathogens in mediating immunity. The synergism between CKs and SA promotes defence against biotrophs. Reciprocally, SA inhibits CK-mediated growth responses. Recent reports show that CKs promote JA responses; however, in a feedback loop, JA suppresses CK responses. We also highlight crosstalk between auxin and CKs and discuss their antagonistic effects on plant immunity. Efforts to minimize the negative effects of auxin on immunity and a reduction in SA- and JA-mediated growth losses should lead to better sustainable plant protection strategies. PMID- 26109576 TI - Factors Affecting the Understanding and Use of Psychoanalysis in Hong Kong, Mainland China, and Taiwan. AB - The majority of Western psychotherapies are known and practiced in Hong Kong, while psychoanalysis still has little resonance. A recent study finds that psychoanalysis is perceived neither as ineffective nor as necessarily in conflict with Hong Kong Chinese values. Nevertheless, Hong Kong Chinese culture influences how psychoanalysis is received and understood, when compared to Mainland China and Taiwan. It is argued that a better reception in the latter two was possible because of different social and historical backgrounds, different clinical backgrounds of those who receive training, and the more active role of Western psychoanalysts. PMID- 26109577 TI - Anatomic and functional testing for coronary artery disease in symptomatic patients yield similar cardiovascular outcomes. PMID- 26109578 TI - Dietary cholesterol and cardiovascular disease: a systematic review and meta analysis. AB - BACKGROUND: Dietary cholesterol has been suggested to increase the risk of cardiovascular disease (CVD), which has led to US recommendations to reduce cholesterol intake. OBJECTIVE: The authors examine the effects of dietary cholesterol on CVD risk in healthy adults by using systematic review and meta analysis. DESIGN: MEDLINE, Cochrane Central, and Commonwealth Agricultural Bureau Abstracts databases were searched through December 2013 for prospective studies that quantified dietary cholesterol. Investigators independently screened citations and verified extracted data on study and participant characteristics, outcomes, and quality. Random-effect models meta-analysis was used when at least 3 studies reported the same CVD outcome. RESULTS: Forty studies (17 cohorts in 19 publications with 361,923 subjects and 19 trials in 21 publications with 632 subjects) published between 1979 and 2013 were eligible for review. Dietary cholesterol was not statistically significantly associated with any coronary artery disease (4 cohorts; no summary RR), ischemic stroke (4 cohorts; summary RR: 1.13; 95% CI: 0.99, 1.28), or hemorrhagic stroke (3 cohorts; summary RR: 1.09; 95% CI: 0.79, 1.50). Dietary cholesterol statistically significantly increased both serum total cholesterol (17 trials; net change: 11.2 mg/dL; 95% CI: 6.4, 15.9) and low-density lipoprotein (LDL) cholesterol (14 trials; net change: 6.7 mg/dL; 95% CI: 1.7, 11.7 mg/dL). Increases in LDL cholesterol were no longer statistically significant when intervention doses exceeded 900 mg/d. Dietary cholesterol also statistically significantly increased serum high-density lipoprotein cholesterol (13 trials; net change: 3.2 mg/dL; 95% CI: 0.9, 9.7 mg/dL) and the LDL to high-density lipoprotein ratio (5 trials; net change: 0.2; 95% CI: 0.0, 0.3). Dietary cholesterol did not statistically significantly change serum triglycerides or very-low-density lipoprotein concentrations. CONCLUSION: Reviewed studies were heterogeneous and lacked the methodologic rigor to draw any conclusions regarding the effects of dietary cholesterol on CVD risk. Carefully adjusted and well-conducted cohort studies would be useful to identify the relative effects of dietary cholesterol on CVD risk. PMID- 26109580 TI - Harnessing the power of disgust: a randomized trial to reduce high-calorie food appeal through implicit priming. AB - BACKGROUND: In our increasingly obesogenic environment, in which high-calorie convenience foods are readily available, food choices can drastically affect weight and overall health. Learned food preferences, which are developed through repeated pairings with positively and negatively valenced stimuli, can contribute to obesity susceptibility if positive attitudes toward high-calorie foods are developed. Thus, the modification of automatic associations with food may be a viable strategy to promote healthier eating behaviors. OBJECTIVE: In this study, we investigated the ability of an implicit priming (IP) intervention to alter responses to visual food cues by using an evaluative conditioning approach. The main objective was to implicitly (i.e., below conscious perception) associate disgust with high-calorie foods with the aim of reducing liking of these foods. DESIGN: Participants were randomly assigned to active or control IP. In active IP (n = 22), high-calorie food images were implicitly primed with negatively valenced images, and low-calorie food images were implicitly primed with positively valenced images. In control IP (n = 20), all food images were primed with neutral images of fixation crosses. Food images were rated on the desire to eat immediately before and after IP. RESULTS: A significant main effect of calorie (high compared with low; P < 0.001) and a significant calorie-by-group (active compared with control) interaction (P = 0.025) were observed. Post hoc tests identified a significantly greater high-calorie rating decline after active IP than after control IP (P = 0.036). Furthermore, there was significantly greater change in high-calorie ratings than in low-calorie ratings in the active group (P = 0.001). Active IP effects extended to high-calorie foods not specifically included in the intervention, which suggested an effect generalization. Moreover, a greater change in high-calorie ratings than in low calorie ratings persisted 3-5 d after active IP (P < 0.007), which suggested lasting effects. CONCLUSION: This study provides initial evidence that IP can be used to alter high-calorie food preferences, which could promote healthier eating habits. PMID- 26109579 TI - High glycemic index diet as a risk factor for depression: analyses from the Women's Health Initiative. AB - BACKGROUND: The consumption of sweetened beverages, refined foods, and pastries has been shown to be associated with an increased risk of depression in longitudinal studies. However, any influence that refined carbohydrates has on mood could be commensurate with their proportion in the overall diet; studies are therefore needed that measure overall intakes of carbohydrate and sugar, glycemic index (GI), and glycemic load. OBJECTIVE: We hypothesized that higher dietary GI and glycemic load would be associated with greater odds of the prevalence and incidence of depression. DESIGN: This was a prospective cohort study to investigate the relations between dietary GI, glycemic load, and other carbohydrate measures (added sugars, total sugars, glucose, sucrose, lactose, fructose, starch, carbohydrate) and depression in postmenopausal women who participated in the Women's Health Initiative Observational Study at baseline between 1994 and 1998 (n = 87,618) and at the 3-y follow-up (n = 69,954). RESULTS: We found a progressively higher dietary GI to be associated with increasing odds of incident depression in fully adjusted models (OR for the fifth compared with first quintile: 1.22; 95% CI: 1.09, 1.37), with the trend being statistically significant (P = 0.0032). Progressively higher consumption of dietary added sugars was also associated with increasing odds of incident depression (OR for the fifth compared with first quintile: 1.23; 95% CI: 1.07, 1.41; P-trend = 0.0029). Higher consumption of lactose, fiber, nonjuice fruit, and vegetables was significantly associated with lower odds of incident depression, and nonwhole/refined grain consumption was associated with increased odds of depression. CONCLUSIONS: The results from this study suggest that high-GI diets could be a risk factor for depression in postmenopausal women. Randomized trials should be undertaken to examine the question of whether diets rich in low GI foods could serve as treatments and primary preventive measures for depression in postmenopausal women. PMID- 26109581 TI - Enteral delivery of proteins enhances the expression of proteins involved in the cytoskeleton and protein biosynthesis in human duodenal mucosa. AB - BACKGROUND: Amino acids are well known to be key effectors of gut protein turnover. We recently reported that enteral delivery of proteins markedly stimulated global duodenal protein synthesis in carbohydrate-fed healthy humans, but specifically affected proteins remain unknown. OBJECTIVE: We aimed to assess the influence of an enteral protein supply on the duodenal mucosal proteome in carbohydrate-fed humans. DESIGN: Six healthy volunteers received for 5 h, on 2 occasions and in random order, either an enteral infusion of maltodextrins alone (0.25 g . kg-1 . h-1) mimicking the fed state or maltodextrins with a protein powder (0.14 g proteins . kg-1 . h-1). Endoscopic duodenal biopsy specimens were then collected and frozen until analysis. A 2-dimensional polyacrylamide gel electrophoresis-based comparative proteomics analysis was then performed, and differentially expressed proteins (at least +/-1.5-fold change; Student's t test, P < 0.05) were identified by mass spectrometry. Protein expression changes were confirmed by Western blot analysis. RESULTS: Thirty-two protein spots were differentially expressed after protein delivery compared with maltodextrins alone: 28 and 4 spots were up- or downregulated, respectively. Among the 22 identified proteins, 11 upregulated proteins were involved either in the cytoskeleton (ezrin, moesin, plastin 1, lamin B1, vimentin, and beta-actin) or in protein biosynthesis (glutamyl-prolyl-transfer RNA synthetase, glutaminyl transfer RNA synthetase, elongation factor 2, elongation factor 1delta, and eukaryotic translation and initiation factor 3 subunit f). CONCLUSIONS: Enteral delivery of proteins altered the duodenal mucosal proteome and mainly stimulated the expression of proteins involved in cytoskeleton and protein biosynthesis. These results suggest that protein supply may affect intestinal morphology by stimulating actin cytoskeleton remodeling. PMID- 26109582 TI - Simultaneous identification of elastic properties, thickness, and diameter of arteries excited with ultrasound radiation force. AB - The elastic and geometric properties of arteries have been long recognized as important predictors of cardiovascular disease. This work presents a robust technique for the noninvasive characterization of anisotropic elastic properties as well as thickness and diameter in arterial vessels. In our approach, guided waves are excited along arteries using the radiation force of ultrasound. Group velocity is used as the quantity of interest to reconstruct elastic and geometric features of the vessels. One of the main contributions of this work is a systematic approach based on sparse-grid collocation interpolation to construct surrogate models of arteries. These surrogate models are in turn used with direct search optimization techniques to produce fast and accurate estimates of elastic properties, diameter, and thickness. One of the attractive features of the proposed approach is that once a surrogate model is built, it can be used for near real-time identification across many different types of arteries. We demonstrate the feasibility of the method using simulated and in vitro laboratory experiments on a silicon rubber tube and a porcine carotid artery. Our results show that using our proposed method, we can reliably identify the longitudinal modulus, thickness, and diameter of arteries. The circumferential modulus was found to have little influence in the group velocity, which renders the former quantity unidentifiable using the current experimental setting. Future work will consider the measurement of circumferential waves with the objective of improving the identifiability of the circumferential modulus. PMID- 26109583 TI - Uncoupling of myofilament Ca2+ sensitivity from troponin I phosphorylation by mutations can be reversed by epigallocatechin-3-gallate. AB - AIMS: Heart muscle contraction is regulated via the beta-adrenergic response that leads to phosphorylation of Troponin I (TnI) at Ser22/23, which changes the Ca(2+) sensitivity of the cardiac myofilament. Mutations in thin filament proteins that cause dilated cardiomyopathy (DCM) and some mutations that cause hypertrophic cardiomyopathy (HCM) abolish the relationship between TnI phosphorylation and Ca(2+) sensitivity (uncoupling). Small molecule Ca(2+) sensitizers and Ca(2+) desensitizers that act upon troponin alter the Ca(2+) sensitivity of the thin filament, but their relationship with TnI phosphorylation has never been studied before. METHODS AND RESULTS: Quantitative in vitro motility assay showed that 30 uM EMD57033 and 100 uM Bepridil increase Ca(2+) sensitivity of phosphorylated cardiac thin filaments by 3.1- and 2.8-fold, respectively. Additionally they uncoupled Ca(2+) sensitivity from TnI phosphorylation, mimicking the effect of HCM mutations. Epigallocatechin-3 gallate (EGCG) decreased Ca(2+) sensitivity of phosphorylated and unphosphorylated wild-type thin filaments equally (by 2.15 +/- 0.45- and 2.80 +/- 0.48-fold, respectively), retaining the coupling. Moreover, EGCG also reduced Ca(2+) sensitivity of phosphorylated but not unphosphorylated thin filaments containing DCM and HCM-causing mutations; thus, the dependence of Ca(2+) sensitivity upon TnI phosphorylation of uncoupled mutant thin filaments was restored in every case. In single mouse heart myofibrils, EGCG reduced Ca(2+) sensitivity of force and kACT and also preserved coupling. Myofibrils from the ACTC E361G (DCM) mouse were uncoupled; EGCG reduced Ca(2+) sensitivity more for phosphorylated than for unphosphorylated myofibrils, thus restoring coupling. CONCLUSION: We conclude that it is possible to both mimic and reverse the pathological defects in troponin caused by cardiomyopathy mutations pharmacologically. Re-coupling by EGCG may be of potential therapeutic significance for treating cardiomyopathies. PMID- 26109585 TI - Authors' reply to Zagarella. PMID- 26109584 TI - Identification and characterization of two ankyrin-B isoforms in mammalian heart. AB - AIMS: Excitation-contraction coupling in cardiomyocytes requires the proper targeting and retention of membrane proteins to unique domains by adaptor proteins like ankyrin-B. While ankyrin-B has been shown to interact with a variety of membrane and structural proteins located at different subcellular domains in cardiomyocytes, what regulates the specificity of ankyrin-B for particular interacting proteins remains elusive. METHODS AND RESULTS: Here, we report the identification of two novel ankyrin-B isoforms AnkB-188 and AnkB-212 in human, rat, and mouse hearts. Novel cDNAs for both isoforms were isolated by long-range PCR of reverse-transcribed mRNA isolated from human ventricular tissue. The isoforms can be discriminated based on their function and subcellular distribution in cardiomyocytes. Heterologous overexpression of AnkB-188 increases sodium-calcium exchanger (NCX) membrane expression and current, while selective knockdown of AnkB-188 in cardiomyocytes reduces NCX expression and localization in addition to causing irregular contraction rhythms. Using an isoform-specific antibody, we demonstrate that the expression of AnkB-212 is restricted to striated muscles and is localized to the M-line of cardiomyocytes by interacting with obscurin. Selective knockdown of AnkB-212 significantly attenuates the expression of endogenous ankyrin-B at the M-line but does not disrupt NCX expression at transverse tubules in cardiomyocytes. CONCLUSION: The identification and characterization of two functionally distinct ankyrin-B isoforms in heart provide compelling evidence that alternative splicing of the ANK2 gene regulates the fidelity of ankyrin-B interactions with proteins. PMID- 26109586 TI - Autonomic function testing: an important diagnostic test for patients with syncope. AB - Syncope is a common problem with a large differential diagnosis. The initial history and physical examination often provide initial clues; however, some cases warrant further testing to determine the underlying cause. Autonomic function testing is a safe way to evaluate patients with syncope further, and to assess their parasympathetic and sympathetic nervous systems. Autonomic testing can help to diagnose several conditions, including orthostatic hypotension, delayed orthostatic hypotension, postural tachycardia syndrome and neutrally mediated syncope. Thus, when the cause of syncope is unclear, autonomic testing can help to assess the autonomic nervous system, stratify the risk of future episodes and to guide treatment decisions. PMID- 26109587 TI - Clinical presentation and diagnosis of myocarditis. PMID- 26109588 TI - Utilization of modified diagnostic ultrasound and microbubbles to reduce myocardial infarct size. AB - OBJECTIVE: We sought to determine whether guided high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion could augment low-dose fibrinolytic therapy in treating acute myocardial infarction (ST segment elevation myocardial infarction, STEMI). METHODS: Acute thrombotic occlusions of the left anterior descending were created in 32 atherosclerotic pigs. Fourteen historical control pigs received half dose of tissue plasminogen activator alone (half tPA), while the subsequent 18 were randomised to (a) 1.0 mg/kg tPA (full-dose tPA); (b) low-dose tPA (0.5 mg/kg) and an intravenous microbubble infusion where guided transthoracic high MI impulses were applied intermittently to the risk area (guided high MI/half tPA) or (c) guided high MI impulses and microbubbles alone (guided high MI alone). Angiographic recanalisation, ST segment resolution and wall thickening (WT) at 60 min were compared between all pigs, while indexed infarct size at 48 h was compared in the 18 randomised pigs. RESULTS: Recanalisation rates improved from 36% for half dose tPA alone to 83% with the addition of guided high MI impulses, while it was 50% for full-dose tPA and guided high MI alone. WT recovery within the risk area following treatment was highest for guided high MI/half tPA (p=0.007 compared with full-dose tPA; ANOVA), and indexed infarct size was lowest (p<0.05 compared to full-dose tPA). CONCLUSIONS: Guided high MI-induced microbubble cavitation from a diagnostic transducer added to low-dose tPA can immediately improve regional function and reduce infarct size in acute STEMI. TRIAL REGISTRATION NUMBER: Clinical Trials.gov NCT02170103. PMID- 26109589 TI - Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome. AB - OBJECTIVE: In the Apixaban for Prevention of Acute Ischemic Events (APPRAISE-2) trial, the use of apixaban, when compared with placebo, in high-risk patients with a recent acute coronary syndrome (ACS) resulted in a significant increase in bleeding without a reduction in ischaemic events. The aim of this analysis was to provide further description of these bleeding events and to determine the baseline characteristics associated with bleeding in high-risk post-ACS patients. METHODS: APPRAISE-2 was a multinational clinical trial including 7392 high-risk patients with a recent ACS randomised to apixaban (5 mg twice daily) or placebo. Bleeding including Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, and any bleeding were analysed using an on-treatment analysis. Kaplan-Meier curves were plotted to describe the timing of bleeding, and a Cox proportional hazards model was used to identify predictors of ISTH major or CRNM bleeding and any bleeding. Median follow-up was 241 days. RESULTS: The proportion of patients who experienced TIMI major or minor, ISTH major or CRNM, and any bleeding was 1.5%, 2.2% and 13.3%, respectively. The incidence of bleeding was highest in the immediate post-ACS period (0.11 in the first 30 days vs 0.03 after 30 days events per 1 patient year); however, >60% of major bleeding events occurred >30 days after the end of the index hospitalisation. Gastrointestinal bleeding was the most common cause of major bleeding, accounting for 45.9% of TIMI major or minor and 39.5% of ISTH major or CRNM bleeding events. Independent predictors of ISTH major or CRNM bleeding events included older age, renal dysfunction, dual oral antiplatelet therapy, smoking history, increased white cell count and coronary revascularisation. CONCLUSIONS: When compared with placebo, the use of apixaban is associated with an important short-term and long-term risk of bleeding in high risk post-ACS patients, with gastrointestinal bleeding being the most common source of major bleeding. The baseline predictors of major bleeding appear to be consistent with those identified in lower-risk ACS populations with shorter-term follow-up. CLINICAL TRIAL NO: NCT00831441. PMID- 26109590 TI - Evaluation of Timed Up and Go Test as a tool to measure postoperative function and prediction of one year walking ability for patients with hip fracture. AB - OBJECTIVE: To evaluate if the Timed Up and Go Test is a useful tool to measure postoperative function and to predict one-year results of rehabilitation in patients operated owing to hip fracture. DESIGN: Prospective cohort study. SETTING: The department of orthopaedic surgery at five hospitals in Norway. Patients were assessed five days postoperatively and after one year. SUBJECTS: A total of 684 patients over 60 years with trochanteric or subtrochanteric hip fractures were included. A total of 171 (25%) patients died within a year and 373 (73% of patients still alive) attended follow-up one year after surgery. MAIN MEASURES: Timed Up and Go Test and walking ability. RESULTS: A total of 258 (38%) patients passed the postoperative Timed Up and Go Test. A total of 217 (56%) patients with a prefracture independent outdoor walking ability, passed the test. The average Timed Up and Go Test score was 71 seconds. A total of 171 (25%) patients could not rise from a chair without assistance; 8% of the patients with cognitive impairment, and 8% of those admitted from nursing homes, were able to pass the postoperative Timed Up and Go Test. The sensitivity and specificity of the Timed Up and Go Test in predicting walking ability one year after the operation were low. At one year follow-up, 38% of the patients not able to perform the postoperative Timed Up and Go Test, passed the test. A total of 81 (21%) patients did not use any walking-aid, 17 of them did not pass the postoperative Timed Up and Go Test. CONCLUSION: The Timed Up and Go Test performed the fifth postoperative day was not a suitable tool to assess functional mobility for the majority of the patients with hip fractures in our study. Neither was the postoperative Timed Up and Go Test a suitable tool to predict the walking ability one year after the operation. PMID- 26109591 TI - Silence of advanced nations on the refugee crisis is shameful. PMID- 26109592 TI - Cognitive therapy plus medication management is better than antidepressants alone for patients with severe depression. PMID- 26109593 TI - Efficacy of complicated grief therapy in older adults. PMID- 26109594 TI - Do traditional risk stratification models for cerebrovascular events apply in irradiated head and neck cancer patients? AB - BACKGROUND: Primary radical radiotherapy (RT) for head and neck cancer (HNC) often results in significant radiation dose to the carotid arteries. AIM: We assessed whether HNC patients are at increased risk of a cerebrovascular event primarily due to RT or other risk factors for atherosclerosis by (i) risk stratifying patients according to validated QRISK-2 and QSTROKE scores and (ii) comparing the prevalence of carotid artery stenosis (CAS) in irradiated and unirradiated carotid arteries. DESIGN: HNC patients treated with an RT dose >50 Gy to one side of the neck >=2 years previously were included. METHODS: QRISK-2 (2014) and Q-STROKE (2014) scores were calculated. We compared the prevalence of CAS in segments of the common carotid artery on the irradiated and unirradiated sides of the neck. RESULTS: Fifty patients (median age of 58 years (interquartile range (IQR) 50-62)) were included. The median QRISK-2 score was 10% (IQR 4.4-15%) and the median QSTROKE score was 3.4% (IQR 1.4-5.3%). For both scores, no patient was classified as high risk. Thirty-eight patients (76%) had CAS in one or both arteries. There was a significant difference in the number of irradiated arteries with stenosis (N = 37) compared with unirradiated arteries (N = 16) (P < 0.0001). There were more plaques on the irradiated artery compared with the unirradiated side - 64/87 (73.6%) versus 23/87 (26.4%), respectively (P < 0.001). CONCLUSIONS: Traditional vascular risk factors do not play a role in radiation induced carotid atherosclerosis. Clinicians should be aware that traditional risk prediction models may under-estimate stroke risk in these patients. PMID- 26109595 TI - Recurrent lower limb venous thrombosis associated with a congenitally absent infrarenal inferior vena cava. PMID- 26109596 TI - Excluding the bifid uvula in children with speech impairment. PMID- 26109597 TI - Pantoea: insights into a highly versatile and diverse genus within the Enterobacteriaceae. AB - The bacterial genus Pantoea comprises many versatile species that have been isolated from a multitude of environments. Pantoea was delineated as a genus approximately 25 years ago, but since then, approximately 20 species have been identified having a diversity of characteristics. Isolates from water and soil have been harnessed for industrial purposes including bioremediation, and the degradation of herbicides and other toxic products. Other isolates possess nitrogen fixation and plant growth-promoting capabilities, which are currently being explored for agricultural applications. Some isolates are antibiotic producers, and have been developed into biocontrol agents for the management of plant diseases. Pantoea is also known to form host associations with a variety of hosts, including plants, insects and humans. Although often thought of as a plant pathogen, recent evidence suggests that Pantoea is being frequently isolated from the nosocomial environment, with considerable debate as to its role in human disease. This review will explore this highly versatile group and its capabilities, its known associations, and the underlying genetic and genomic determinants that drive its diversity and adaptability. PMID- 26109599 TI - Targeted imaging of bacterial infections: advances, hurdles and hopes. AB - Bacterial infections represent an increasing problem in modern health care, in particular due to ageing populations and accumulating bacterial resistance to antibiotics. Diagnosis is rarely straightforward and consequently treatment is often delayed or indefinite. Therefore, novel tools that can be clinically implemented are urgently needed to accurately and swiftly diagnose infections. Especially, the direct imaging of infections is an attractive option. The challenge of specifically imaging bacterial infections in vivo can be met by targeting bacteria with an imaging agent. Here we review the current status of targeted imaging of bacterial infections, and we discuss advantages and disadvantages of the different approaches. Indeed, significant progress has been made in this field and the clinical implementation of targeted imaging of bacterial infections seems highly feasible. This was recently highlighted by the use of so-called smart activatable probes and a fluorescently labelled derivative of the antibiotic vancomycin. A major challenge remains the selection of the best imaging probes, and we therefore present a set of target selection criteria for clinical implementation of targeted bacterial imaging. Altogether, we conclude that the spectrum of potential applications for targeted bacterial imaging is enormous, ranging from fundamental research on infectious diseases to diagnostic and therapeutic applications. PMID- 26109604 TI - Increasing incidence of immune-mediated necrotizing myopathy: single-centre experience. AB - OBJECTIVES: Immune-mediated necrotizing myopathy (IMNM) is characterized by the predominant presence of necrotic muscle fibres in muscle biopsy and variable response to immunosuppressive treatment. The aims of this study were to analyse the temporal trend of IMNM incidence in our centre over the past 10 years and to explore the role of statins as possible causative agents. METHODS: A retrospective evaluation of muscle biopsy results, clinical and laboratory data, including antibody associations of all patients with idiopathic inflammatory myopathy newly diagnosed between 2004 and June 2014, was performed. Available sera were tested for the presence of anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) autoantibodies. RESULTS: Of 357 biopsied patients, 233 fulfilled criteria for inflammatory/immune-mediated myopathy, including 27 (11.6%) classified as IMNM. There were no patients with IMNM diagnosed between 2004 and 2007; subsequently, two to three cases of IMNM per year were seen during the period 2008-11, with a substantial increase to 18 cases (66.6% of all IMNM biopsies) in 2012-14. Thirteen of 27 patients (48%) had a history of statin use, 11 (85%) of whom had positive anti-HMGCR antibodies. There was no IMNM patient without a history of statin use who was anti-HMGCR antibody positive. CONCLUSION: Our data show an increasing incidence of IMNM, which is mainly accounted for by anti-HMGCR-positive IMNM associated with the use of statins. PMID- 26109605 TI - Complications After Popliteal Block for Foot and Ankle Surgery. AB - BACKGROUND: A popliteal nerve block is a common analgesic procedure for patients undergoing surgery on their knee, foot, or ankle. This procedure carries less risk in a surgical setting compared with other forms of anesthesia such as a spinal block. Previous reports demonstrated few to no complications with the use of this nerve block, but it is unclear whether these data are consistent with the recent increase in use of this analgesic procedure for lower extremity surgery. METHODS: Retrospectively, a busy orthopedic foot and ankle practice performed a chart review examining for postoperative neuropathic complications possibly related to the popliteal nerve block. The 1014 patients who had undergone a popliteal block for foot and/or ankle orthopedic surgery were analyzed for short and long-term neuropathic complications. The collected data consisted of tourniquet time, pressure, and location as well as the method of finding the fossa nerve, adjuncts used, and patient medical history. Data were analyzed using chi-square, Fisher's exact, and t tests for analysis with a significance value of P < .05. RESULT: Of these 1014 patients, 52 patients (5%) developed deleterious symptoms likely resulting from their popliteal block, and 7 (0.7%) of these were unresolved after their last follow-up. No immediately apparent underlying causes were determined for these complications. CONCLUSION: The frequency of a neuropathic complication following a popliteal nerve block was notably higher in the early postoperative period than indicated in the past. The proportion of patients with unresolved neuropathic symptoms at last follow-up is comparable to that previously reported in the literature. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26109606 TI - Posterior Facet Settling and Changes in Bohler's Angle in Operatively and Nonoperatively Treated Calcaneus Fractures. AB - BACKGROUND: Patients with calcaneus fractures often exhibit settling of the posterior facet with a corresponding decrease in Bohler's angle (BA) following either operative or nonoperative treatment. Both injury BA and postoperative BA have been shown to be prognostic for outcomes; however, the demographic and surgeon-specific factors that may contribute to settling have not been critically examined in the literature. The purpose of this study was to identify these causative factors. METHODS: 234 patients with intra-articular calcaneus fractures were analyzed. All patients had preoperative plain radiographs, at least 5 months of orthopedic follow-up, and computed tomography scanning performed. BA was measured on the injury radiographs for all patients. For operatively treated patients, BA was measured on the immediate postoperative radiographs and compared with the last available radiograph. For nonoperatively treated patients, BA was measured on the last available radiograph. All patients were fully weightbearing at the time of final follow-up but not on initial radiographs due to their recent injury. Demographic data including age, gender, energy of injury mechanism, tobacco use, diabetes, osteoporosis, rheumatoid arthritis, and substance/alcohol abuse were retrospectively collected. Fractures were classified using the Essex Lopresti and Sanders classifications. Time to full weightbearing was documented, as were any reports of noncompliance with weightbearing restrictions. For patients treated operatively, type of fixation (calcaneal-specific perimeter plate, nonperimeter plate, screw fixation), use of locking screws, use of bone graft or graft substitutes, and the number of screws supporting the posterior facet were documented. RESULTS: There was a statistically significant amount of settling within the operative and nonoperative groups, but there was no statistically significant difference in settling of BA between the groups. The average settling of BA for the operative and nonoperative group was 8 degrees. Age greater than 50 years, diabetes, and alcohol abuse were all statistically significant and independent predictors of BA settling irrespective of treatment. CONCLUSION: The amount of BA settling between the operative and nonoperative group was not significant and showed an average decrease of 8 degrees in each group. However, the amount of settling that we found, irrespective of treatment, increased with patient age, alcohol abuse, and diabetes. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26109607 TI - Efficacy of Bilateral Simultaneous Hallux Valgus Correction Compared to Unilateral. AB - BACKGROUND: Hallux valgus affects up to 29% of adults and can be bilateral in 84% of cases. Contemporary surgical techniques provide the possibility of simultaneous bilateral correction, but still there is no consensus on whether staged or simultaneous correction should be performed if both feet are involved. The aim of the present study was to report our experience of treatment of patients with hallux valgus and to perform comparative analysis of results obtained from unilateral and simultaneous bilateral surgical correction. METHODS: Data on 60 feet (40 patients) with hallux valgus that underwent surgery between 2010 and 2013 using scarf osteotomy and lateral soft tissue release were analyzed. Unilateral correction was performed in 30 feet (25 patients) and bilateral correction in 30 feet (15 patients). The patients from both groups were admitted to hospital for 7 days. Functional assessment (American Orthopaedic Foot & Ankle Society [AOFAS] score) and radiographic examination (intermetatarsal and hallux valgus angles) were performed preoperatively and at 6, 12, and 24 months after the procedure. Comparative analysis between groups with bilateral and unilateral correction was carried out. RESULTS: At 24 months after surgery in the bilateral and unilateral groups, the mean AOFAS score was 86 +/- 6.2 and 86 +/- 6.9 (P > .05), the mean intermetatarsal angle was 8.4 +/- 0.5 and 8.8 +/- 0.8 degrees (P > .05), and the mean metatarsophalangeal angle was 13.0 +/- 1.2 and 13.0 +/- 0.9 degrees (P > .05), respectively. CONCLUSION: According to the data obtained, simultaneous bilateral correction had the same functional and radiographic results as unilateral surgery. LEVEL OF EVIDENCE: Level III, case series. PMID- 26109608 TI - Double First Metatarsal and Akin Osteotomy for Severe Hallux Valgus. AB - BACKGROUND: The technique of double first metatarsal osteotomies was first developed in response to the high frequency of recurrence noted in the treatment of severe adolescent congruent hallux valgus deformities. The concept behind the use of this technique is that it allows the individual correction of each component of the deformity. We have modified the technique for use in adult hallux valgus where the majority of deformities are incongruent deformities and the distal chevron osteotomy is used primarily for its additional translational properties rather than purely to correct the distal metatarsal articular angle (DMAA). We report on a series of double first metatarsal osteotomies (basal opening wedge and distal chevron osteotomy) with Akin osteotomy in the treatment of moderate to severe adult hallux valgus deformity. METHODS: All patients presenting to our institution with a hallux valgus deformity and treated with this procedure between 2008 and 2013 with a minimum of 1 year of follow-up were identified. Data were obtained through review of case notes, electronic charts, and digital imaging. A total of 50 feet in 48 patients underwent double first metatarsal osteotomy with Akin osteotomy. Three patients were excluded due to loss to follow-up, leaving 47 feet in 45 patients with a mean follow-up of 45 months (range, 14-60 months). Of these 43 (96%) were female and the mean age was 56 years (range, 35-70 years). RESULTS: The mean preoperative hallux valgus angle (HVA), intermetatarsal angle (IMA), DMAA, sesamoid position, and lateral first metatarsotalar angle were 42 degrees (range, 32-52 degrees), 18 degrees (range, 6 26 degrees), 12 degrees (range, 4-26 degrees), stage 6 (range, 4-7), and 2 degrees of dorsiflexion (range, 20 degrees of dorsiflexion to 4 degrees of plantar flexion), respectively. The mean postoperative HVA, IMA, DMAA, sesamoid position, and lateral first metatarsotalar angle were 7 degrees (range, 2 to 24 degrees), 4 degrees (range, 4-14 degrees), 6 degrees (range, 10-22 degrees), stage 2 (range, 1-5) and 6 degrees of plantar flexion (range, 8 degrees of dorsiflexion to 18 degrees of plantar flexion), respectively. The osteotomies consolidated at a mean of 7 weeks (range, 5-9 weeks). There were no cases of delayed union or nonunion. Of the cohort, 45 (96%) stated that they were satisfied overall with the results of their surgery and would have it again. The mean postoperative summary index Manchester-Oxford Foot Questionnaire (MOXFQ) score was 12.9 (range, 0-60.9) out of 100 at a mean follow-up of 45 months (range, 14-60 months). For the minority of cases, 8 (17%), that had preoperative scoring, the summary index MOXFQ score was 73.7 (range, 29.7-100). CONCLUSIONS: The double first metatarsal osteotomy (basal opening wedge and distal chevron osteotomy) with Akin osteotomy provides powerful correction and facilitates correction of the individual components of the hallux valgus deformity. The individual osteotomies that make up this procedure are familiar to the majority of foot and ankle surgeons, thus limiting the associated learning curve. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26109610 TI - Performance Demands in Softball Pitching: A Comprehensive Muscle Fatigue Study. AB - BACKGROUND: Monitoring pitch count is standard practice in minor league baseball but not in softball because of the perception that fast-pitch softball pitching is a less stressful motion. PURPOSE: To examine muscle fatigue after fast-pitch softball performances to provide an assessment of performance demand. STUDY DESIGN: Descriptive laboratory study. METHODS: Bilateral strength measurements (handheld dynamometer) were made on 19 female softball pitchers (mean age [+/ SD], 15.2 +/- 1.2 years) before and after pitching a game (mean number of pitches, 99 +/- 21; mean innings pitched, 5 +/- 1). A total of 20 tests were performed on the dominant and nondominant sides: forearm (grip, wrist flexion/extension, pronation/supination, elbow flexion/extension), shoulder (flexion, abduction/adduction, external/internal rotation, empty can test), scapula (middle/lower trapezius, rhomboid), and hip (hip flexion/extension, abduction/adduction). Fatigue (percentage strength loss) was categorized based on bilateral versus unilateral presentation using paired t tests: bilateral symmetric (significant on dominant and nondominant and not different between sides), bilateral asymmetric (significant on dominant and nondominant but significantly greater on dominant), unilateral asymmetric (significant on dominant only and significantly greater than nondominant), or unilateral equivocal (significant on dominant only but not different from nondominant). RESULTS: Bilateral symmetric fatigue was evident for all hip (dominant, 19.3%; nondominant, 15.2%) and scapular tests (dominant, 19.2%; nondominant, 19.3%). In general, shoulder tests exhibited bilateral asymmetric fatigue (dominant, 16.9%; nondominant, 11.6%). Forearm tests were more variable, with bilateral symmetric fatigue in the elbow flexors (dominant, 22.5%; nondominant, 19.2%), and wrist flexors (dominant, 21.6%; nondominant, 19.0%), bilateral asymmetric fatigue in the supinators (dominant, 21.8%; nondominant, 15.5%), unilateral asymmetric fatigue in the elbow extensors (dominant, 22.1%; nondominant, 11.3%), and unilateral equivocal fatigue in the pronators (dominant, 18.8%; nondominant, 15.2%) and grip (dominant, 11.4%; nondominant, 6.6%). The mean (+/-SD) pitch velocity was 49 +/- 4 mph, with a small loss of velocity from the first to last inning pitched (3.4% +/- 5.0%, P < .01). CONCLUSION: Fast-pitch softball pitching resulted in profound bilateral fatigue in the hip and scapular muscles, with more selective fatigue in the shoulder and arm muscles. CLINICAL RELEVANCE: These findings emphasize the importance of strength in the proximal musculature to provide a stable platform for the arm to propel the ball. PMID- 26109609 TI - A Cell-Based High-Throughput Screening for Inducers of Myeloid Differentiation. AB - Recent progress of genetic studies has dramatically unveiled pathogenesis of acute myeloid leukemia (AML). However, overall survival of AML still remains unsatisfactory, and development of novel therapeutics is required. CCAAT/enhancer binding protein alpha (C/EBPalpha) is one of the crucial transcription factors that induce granulocytic differentiation, and its activity is perturbed in human myeloid leukemias. As its reexpression can induce differentiation and subsequent apoptosis of leukemic cells in vitro, we hypothesized that chemical compounds that restore C/EBPalpha expression and/or activity would lead to myeloid differentiation of leukemic cells. Using a cell-based high-throughput screening, we identified 2-[(E)-2-(3,4-dihydroxyphenyl)vinyl]-3-(2-methoxyphenyl)-4(3H) quinazolinone as a potent inducer of C/EBPalpha and myeloid differentiation. Leukemia cell lines and primary blast cells isolated from human patients with AML treated with ICCB280 demonstrated evidence of morphological and functional differentiation, as well as massive apoptosis. We performed conformational analyses of the high-throughput screening hit compounds to postulate the spatial requirements for high potency. Our results warrant a development of novel differentiation therapies and significantly affect care of patients with AML with unfavorable prognosis in the near future. PMID- 26109611 TI - Bioabsorbable Versus Titanium Screws in Anterior Cruciate Ligament Reconstruction Using Hamstring Autograft: A Prospective, Blinded, Randomized Controlled Trial With 5-Year Follow-up. AB - BACKGROUND: Longer-term results of bioabsorbable screws for anterior cruciate ligament reconstruction (ACLR) have been reported, but results are specific to the exact screw material and design. Titanium and poly-L-lactic acid with hydroxyapatite (PLLA-HA) screw outcomes have been compared only to 2 years. PURPOSE/HYPOTHESIS: The purpose of this study was to compare the clinical and radiologic outcomes of the PLLA-HA screw versus titanium screw for hamstring tendon ACLR over a 5-year follow-up period. The hypothesis was that there are no differences in clinical scores or tunnel widening between the PLLA-HA and the titanium screws and that the PLLA-HA screw as seen on magnetic resonance imaging (MRI) should show high-grade resorption and ossification response over 5 years. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 40 patients undergoing ACLR were randomized to receive either a PLLA-HA screw (PLLA-HA group) or a titanium screw (titanium group) for ACL fixation. Blinded evaluation was performed at 2 and 5 years with the International Knee Documentation Committee and Lysholm knee score, KT-1000 arthrometer, single legged hop test, and MRI to evaluate tunnel and screw volumes, periscrew ossification, graft integration, and cyst formation. RESULTS: There was no difference in any clinical outcome measure at 2- or 5-year follow-up between the 2 groups. At 2 years, the femoral tunnel in the PLLA-HA group was smaller than that in the titanium group (P = .02); at 5 years, there was no difference. At 2 years, the femoral PLLA-HA screw was a mean 76% of its original volume, and by 5 years, it was 36%. At 2 years, the tibial PLLA-HA screw mean volume was 68% of its original volume, and by 5 years, it was 46%. At 5 years in the PLLA-HA group, 88% of femoral tunnels and 56% of tibial tunnels demonstrated a significant ossification response. There was no increase in cyst formation in the PLLA-HA group and no screw breakages. CONCLUSION: There were equivalent clinical results between the PLLA-HA and titanium groups at 2- and 5-year follow-ups. The PLLA-HA screw was not associated with increased tunnel widening or cyst formation when compared with the titanium screw. The PLLA-HA screw demonstrated progressive screw resorption and gradual but incomplete ossification over 5 years. PMID- 26109612 TI - Potential Mechanisms Leading to Overuse Injuries of the Back in Alpine Ski Racing: A Descriptive Biomechanical Study. AB - BACKGROUND: Overuse injuries of the back are a common complaint among top athletes and of competitive alpine skiers in particular. However, there is limited understanding about the sport-specific causes of these injuries that is essential for their prevention. PURPOSE/HYPOTHESIS: This study was undertaken to describe the sport-specific, overall trunk kinematics and skiers' loading during giant slalom turns and to assess the plausibility of the hypothesis that a combination of frontal bending, lateral bending, and/or torsion in the loaded trunk might be a potential mechanism leading to overuse injuries of the back in alpine ski racing. STUDY DESIGN: Descriptive laboratory study. METHODS: Eight European Cup-level athletes performed giant slalom runs with 2 different pairs of skis (varying in length, width, and sidecut). They were analyzed with respect to selected kinematic variables related to spinal disc loading. The overall trunk movement components (frontal bending, lateral bending, and torsion) were measured using 2 inertial measurement units fixed on the sacrum and sternum. Total ground reaction forces were measured by pressure insoles. RESULTS: During the turn phase in which the total ground-reaction forces were the greatest (up to 2.89 times the body weight), the highest average values of frontal bending (38.7 degrees ), lateral bending (14.7 degrees ), and torsion (7.7 degrees ) in the trunk occurred. Similar magnitudes were observed when skiing on longer, giant slalom skis with less width and sidecut. CONCLUSION: The typical loading patterns of the back in alpine ski racing include a combined occurrence of frontal bending, lateral bending, and torsion in the loaded trunk. Because these factors are known to be related to high spinal disc loading, they may be considered important components of mechanisms leading to overuse injuries of the back in alpine ski racing. CLINICAL RELEVANCE: Prevention measures should aim to control and/or reduce the magnitude of frontal bending, lateral bending, and torsion in the trunk, as well as the peak loads, while skiing. PMID- 26109598 TI - Genetic instability in budding and fission yeast-sources and mechanisms. AB - Cells are constantly confronted with endogenous and exogenous factors that affect their genomes. Eons of evolution have allowed the cellular mechanisms responsible for preserving the genome to adjust for achieving contradictory objectives: to maintain the genome unchanged and to acquire mutations that allow adaptation to environmental changes. One evolutionary mechanism that has been refined for survival is genetic variation. In this review, we describe the mechanisms responsible for two biological processes: genome maintenance and mutation tolerance involved in generations of genetic variations in mitotic cells of both Saccharomyces cerevisiae and Schizosaccharomyces pombe. These processes encompass mechanisms that ensure the fidelity of replication, DNA lesion sensing and DNA damage response pathways, as well as mechanisms that ensure precision in chromosome segregation during cell division. We discuss various factors that may influence genome stability, such as cellular ploidy, the phase of the cell cycle, transcriptional activity of a particular region of DNA, the proficiency of DNA quality control systems, the metabolic stage of the cell and its respiratory potential, and finally potential exposure to endogenous or environmental stress. PMID- 26109613 TI - Sexual signalling by females: do unmated females increase their signalling effort? AB - Theory predicts that females should invest least in mate searching when young, but increase their effort with age if they remain unmated. Few studies have examined variation in female sexual signalling. Female Dawson's burrowing bees (Amegilla dawsoni) search for males by signalling their receptivity on emergence, but many leave the emergence site unmated and must attract males at feeding sites. Female bees prevented from mating on emergence had more extreme versions of cuticular hydrocarbon profiles that make them attractive to males, lending empirical evidence of adaptive shifts in female mating effort. PMID- 26109614 TI - Racehorses are getting faster. AB - Previous studies have concluded that thoroughbred racehorse speed is improving very slowly, if at all, despite heritable variation for performance and putatively intensive selective breeding. This has led to the suggestion that racehorses have reached a selection limit. However, previous studies have been limited, focusing only on the winning times of a few elite races run over middle and long distances, and failing to account for potentially confounding factors. Using a much larger dataset covering the full range of race distances and accounting for variation in factors such as ground softness, we show that improvement is, in fact, ongoing for the population as a whole, but driven largely by increasing speed in sprint races. In contrast, speed over middle and long distances, at least at the elite level, appears to be reaching an asymptote. Whether this reflects a selection limit to speed over middle and long distances or a shift in breeding practices to target sprint performances remains to be determined. PMID- 26109615 TI - Romundina and the evolutionary origin of teeth. AB - Theories on the origin of vertebrate teeth have long focused on chondrichthyans as reflecting a primitive condition-but this is better informed by the extinct placoderms, which constitute a sister clade or grade to the living gnathostomes. Here, we show that 'supragnathal' toothplates from the acanthothoracid placoderm Romundina stellina comprise multi-cuspid teeth, each composed of an enameloid cap and core of dentine. These were added sequentially, approximately circumferentially, about a pioneer tooth. Teeth are bound to a bony plate that grew with the addition of marginal teeth. Homologous toothplates in arthrodire placoderms exhibit a more ordered arrangement of teeth that lack enameloid, but their organization into a gnathal, bound by layers of cellular bone associated with the addition of each successional tooth, is the same. The presence of enameloid in the teeth of Romundina suggests that it has been lost in other placoderms. Its covariation in the teeth and dermal skeleton of placoderms suggests a lack of independence early in the evolution of jawed vertebrates. It also appears that the dentition-manifest as discrete gnathal ossifications-was developmentally discrete from the jaws during this formative episode of vertebrate evolution. PMID- 26109616 TI - Altered beta1,6-GlcNAc and bisecting GlcNAc-branched N-glycan on integrin beta1 are associated with early spontaneous miscarriage in humans. AB - STUDY QUESTION: Do N-acetylglucosaminyltransferase (GnT-V) and N acetylglucosaminyltransferase III (GnT-III) play an important role in early spontaneous miscarriage (ESM) in humans. SUMMARY ANSWER: The dynamic balance between GnT-V and GnT-III expression in chorionic villi differed between early normal pregnancy and ESM and was associated with altered beta1,6-N acetylglucosamine (beta1,6-GlcNAc) and bisecting N-acetylglucosamine (bis-GlcNAc) branched N-glycans on integrin beta1. WHAT IS KNOWN ALREADY: GnT-V contributes to metastasis, while GnT-III is recognized as a metastasis suppressor. It has been reported that GnT-V contributes to placentation in the early phase of pregnancy, possibly regulating trophoblast invasion. However, the expressions of GnT-V and GnT-III in ESM have not been reported. STUDY DESIGN, SIZE, DURATION: Villous samples from 6 to 9 weeks of gestation were collected in the First Affiliated Hospital of Chongqing Medical University from May 2013 to September 2014 from 60 normal pregnant women undergoing elective termination of pregnancy and from 40 patients with a clinical diagnosis of ESM. PARTICIPANTS, MATERIALS, SETTING, METHODS: Quantitative PCR and western blots were used to examine the GnT-V and GnT-III mRNA (Mgat5 and Mgat3) and protein expression, respectively, of chorionic villi in both the ESM group and the normal group from week 6 to week 9. We used immunofluorescence and immunohistochemistry to detect the location of GnT-V and GnT-III. Lectin fluorescence and histochemistry were used to test the location of beta1,6-GlcNAc and bis-GlcNAc branching in the normal and ESM groups. To assess the functional capacity of GnT-V and GnT-III in the chorionic villi between the two groups, we used an enzyme-linked immunosorbent assay kit to measure the activity of these enzymes. Using co-precipitated integrin alpha5beta1 followed by phytohaemagglutinin (PHA)-L and PHA-E blotting, we investigated whether GnT-V and GnT-III could modify the N-glycosylation profile in terms of the beta1,6-GlcNAc and bis-GlcNAc structures in integrin alpha5beta1 during the first trimester in both groups. MAIN RESULTS AND THE ROLE OF CHANCE: In the normal group expression and activity of GnT-V and the concentration of its product, beta1,6-GlcNAc were higher at week 9 than at weeks 6, 7 and 8 (P < 0.05). In contrast, the expression and activity of GnT-III and the concentration of its product, bis-GlcNAc were higher at week 6 than at weeks 7, 8 and 9 (P < 0.05). Compared with the normal group, the ESM group exhibited a lower expression of GnT-V and beta1,6-GlcNAc (P < 0.05) and a higher expression of GnT-III and bis-GlcNAc (P < 0.05) with consistent changes in enzymatic activity. Immunofluorescence showed that GnT-V was located mainly in the cytoplasm of syncytiotrophoblasts (STBs) and chorionic villous cytotrophoblasts (CTBs), in both the ESM group and the normal group. beta1,6-GlcNAc N-glycan was mainly located outside of the STB and CTB layer in normal villi and was expressed only rarely in the ESM villi. GnT-III was expressed primarily in the cytoplasm of STBs and expressed only very weakly in the CTBs of normal villi, whereas it was highly expressed in both the STBs and CTBs in the ESM group. bis-GlcNAc was primarily located outside of the STBs in the normal villi, whereas it was expressed much more abundantly outside of both the STBs and CTBs in the ESM group at each week of gestation. Moreover, decreased beta1,6-GlcNAc-branched N-glycans and increased bis-GlcNAc-branched N-glycans on integrin beta1 (P < 0.05) were observed in the ESM group. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide a new insight for studying the mechanism of clinical ESM in humans and it might be valuable for the clinical diagnosis and treatment of ESM. LIMITATIONS, REASONS FOR CAUTION: The study lacks experiments in vitro to disclose the precise mechanism by which GnT-V and GnT-III regulate ESM. In some cases, degradation of the tissues after the miscarriage event cannot be ruled out. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from the National Natural Science Foundation of China (31271546). The authors have no competing interests. PMID- 26109617 TI - Progesterone levels in letrozole associated controlled ovarian stimulation for fertility preservation in breast cancer patients. AB - STUDY QUESTION: Are progesterone levels after letrozole-associated controlled ovarian stimulation (COS) for fertility preservation in breast cancer patients, lower than after standard in vitro fertilization (IVF) cycles? SUMMARY ANSWER: During the luteal phase of letrozole-associated COS cycles (triggered with human chorionic gonadotrophin (hCG)) progesterone levels are similarly elevated to those obtained after standard COS without letrozole. WHAT IS KNOWN ALREADY: Current fertility preservation strategies for breast cancer patients include association of COS with the aromatase inhibitor letrozole to harvest several mature oocytes while maintaining low estradiol levels. Data on progesterone levels are however lacking despite growing evidence of the role of progesterone in breast tumorigenesis. STUDY DESIGN, SIZE, DURATION: This is a prospective observational study comparing estradiol and progesterone levels of 21 breast cancer patients undergoing letrozole-associated COS with 21 infertile patients undergoing standard COS for IVF and/or intra cytoplasmic sperm injection (ICSI). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent COS with a GnRH antagonist protocol. In the fertility preservation group, ovulation induction was started in the follicular or luteal phase depending on the chemotherapy schedule and in 10 cases a GnRH antagonist was administered during luteal phase to induce luteolysis. Final oocyte maturation was induced by hCG in all patients. Estradiol and progesterone levels were measured on the day of hCG, at oocyte retrieval, and on days 3 and 8 after oocyte retrieval. Hormone levels in fertility preservation patients were compared with those observed in infertility patients. MAIN RESULTS AND THE ROLE OF CHANCE: While estradiol levels were significantly lower in the fertility preservation group compared with the control group (P < 0.001), progesterone levels were similar at all times, including patients receiving a GnRH antagonist during the luteal phase. LIMITATIONS, REASONS FOR CAUTION: The studied populations (breast cancer and infertile patients) are different, which may induce selection bias. The small sample size limits the study's statistical power and the possibility to perform multivariate analysis. Recruitment of the study and control patients was completed at the same time; however, enrollment of controls started at a later time. WIDER IMPLICATIONS OF THE FINDINGS: While the use of letrozole in fertility preservation patients has a favorable effect on estrogen levels, no benefit is seen for progesterone levels which are high and comparable with progesterone levels after standard COS in IVF patients. As progesterone has been associated with tumor cell proliferation, caution is mandatory. Modified protocols including GnRH agonist triggering should be investigated. PMID- 26109618 TI - Fibronectin stimulates human sperm capacitation through the cyclic AMP/protein kinase A pathway. AB - STUDY QUESTION: Does fibronectin (Fn) stimulate the sperm capacitation process in humans? SUMMARY ANSWER: Fibronectin stimulates human sperm capacitation. WHAT IS KNOWN ALREADY: Capacitation is a process that occurs in the oviduct. It has been suggested that some molecules present in the oviductal fluid and cells as well as proteins present in the cumulus oophorus could be involved in the modulation of sperm function and their acquisition of fertilizing capacity. Fibronectin is a glycoprotein that is present in the fluid and the oviduct epithelium, and its receptor (alpha 5 beta 1 integrin) is present in human sperm. When alpha 5 beta 1 (alpha5beta1) integrin binds to fibronectin, intracellular signals similar to the process of sperm capacitation are activated. STUDY DESIGN, SIZE, DURATION: Human sperm were selected via a percoll gradient and were then incubated in non capacitated medium (NCM) or reconstituted capacitated medium (RCM), in the presence or absence of fibronectin for different time periods. A total of 39 donors were used during the study, which lasted 3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Freshly ejaculated sperm from healthy volunteers were obtained by masturbation. All semen samples were normal according to the World Health Organization parameters. Six approaches were used to determine the effects of fibronectin on sperm capacitation: chlortetracycline (CTC) assay, heterologous co culture of human sperm with bovine oviductal epithelial cells (BOEC), measurement of cyclic (c) AMP levels, activity of protein kinase A (PKA), phosphorylation of proteins in tyrosine (Tyr) residues, and induction of acrosome reaction with progesterone. MAIN RESULTS AND THE ROLE OF CHANCE: When sperm were incubated in RCM in the presence of Fn, we observed differences with respect to sperm incubated in RCM without Fn (control): (i) a 10% increase in the percentage of sperm with the B pattern (capacitated sperm) of CTC fluorescence from the beginning of capacitation (P < 0.001); (ii) an effect on both the concentration of cAMP (P < 0.05) and PKA activity (P < 0.05) during early capacitation; (iii) an increase in the degree of phosphorylation of proteins on tyrosine residues after 60 min of capacitation (P < 0.01); (iv) an increase in the percentage of acrosome-reacted sperm in response to progesterone (P < 0.05); and (v) a decrease in the percentage of sperm attached to BOEC (P < 0.05). Moreover, we noted that the effect of Fn was specific and mediated by alpha 5 beta 1 integrin (P < 0.001). Fn by itself had no effect on sperm capacitation. LIMITATIONS, REASONS FOR CAUTION: This study was carried out with sperm from young adult men. Men with abnormal semen samples were excluded. The results cannot be directly extrapolated to other mammalian species. WIDER IMPLICATIONS OF THE FINDINGS: Currently, male subfertility has become a huge public health problem, which makes it imperative to develop new treatments. This is a novel discovery that extends our current knowledge concerning normal and pathological sperm physiology as well as events that regulate the process of fertilization. STUDY FUNDING/COMPETING INTERESTS: This study was supported by grants from FONDECYT (1130341, E.S.D. and 1120056, P.M.) and FONCYT (PIP 2011-0496, S.P.-M). The authors have no conflicts of interest. PMID- 26109619 TI - Multiple parasitic infections in a cardiac transplant recipient. AB - Infectious complications represent an important cause of morbidity and death in patients with transplant. Parasitic infections are less frequent than viral and bacterial agents, and are often overlooked. We describe the case of a 13-year-old adolescent, born in Sao Tome Island, who was under immunosuppressive therapy after a cardiac transplant. The patient had an intermittent course of diarrhoea, abdominal pain and vomiting. She was admitted dehydrated, and Strongyloides stercoralis, Schistosoma intercalatum and Cystoisospora belli were isolated in her stools. The patient was treated with ivermectin, albendazole, praziquantel and ciprofloxacin with clinical and microbiological resolution. Her immunosuppressive therapy was reduced during hospitalisation. We believe that the parasitic infection was a result of a recrudescence of dormant infections acquired in her homeland. To the best of our knowledge, there are no reports of cystoisosporiasis or schistosomiasis in heart transplant recipients. PMID- 26109620 TI - Burst abdomen: an unusual complication of silicosis in pregnancy. AB - We present a case of silicosis in a 37-year-old pregnant woman, a second gravida with previous caesarean section. She was referred to our hospital at 42 weeks of gestation with breathlessness and oligohydramnios. She had worked in a glass and talc powder factory for 11 years and was diagnosed as having silicosis 2 years prior; she was on treatment. Following admission, she was evaluated for dyspnoea and underwent emergency Caesarean section for poor cervical dilation. She developed a burst abdomen on the third postoperative day with loops of gangrenous bowel protruding outside the abdomen. Emergency laparotomy with ileal resection and ileostomy was carried out. She was discharged on day 14 and is on follow-up. To the best of our knowledge, this is the first case of silicosis in pregnancy presenting with an unusual complication. PMID- 26109621 TI - A rapidly growing vulvar condyloma acuminatum in a young patient. AB - A young woman presented to the outpatient gynaecology clinic with a rapidly growing bulky tumour located at the external genitalia, which she first noticed 10 days prior to her visit. Examination revealed a 6 * 3 cm cauliflower-like mass located on the left genitofemoral fold. The initial biopsy had several features suggestive of a human papilloma virus (HPV) infection. A broad excision of the mass was subsequently performed. The biopsy confirmed the presence of a large condyloma acuminatum. Condyloma acuminatum is a slow-growing benign exophytic tumour that is associated with HPV infection. In cases where the tumour has aggressive features, as in our patient, the differential diagnosis has to include carcinoma or Buschke-Lowenstein tumour. The initial biopsy of the tumour in our patient, however, excluded malignancy. PMID- 26109622 TI - Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm. AB - A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral artery (PCA) aneurysm. This aneurysm was successfully treated by endovascular coil sacrifice of the affected segment of the PCA. The patient made an excellent recovery with no significant residual neurologic deficit. PMID- 26109623 TI - Transvenous sclerotherapy of a large symptomatic orbital venous varix using a microcatheter balloon and bleomycin. AB - An orbital venous varix is rare and can present with diplopia, proptosis, or hemorrhage. Treatment can be challenging, especially if the varix is in a posterior location within the orbit, since surgical exposure becomes difficult. A few case reports have been published describing transcatheter embolization of an orbital varix with coils, direct percutaneous injection of n-butyl cyanoacrylate glue, and the percutaneous injection of bleomycin. We present a case of a symptomatic orbital venous varix of the left inferior ophthalmic vein successfully treated with transvenous endovascular sclerotherapy using a microcatheter balloon and bleomycin. PMID- 26109624 TI - A 37-year-old woman with refractory coeliac disease type II disease treated by stem cell transplantation. AB - This case study describes the disease course and treatment of a rare disorder, refractory coeliac disease. This disorder is associated with a marked increase in the risk of development of enteropathy-associated T-cell lymphoma. The patient in question developed coeliac symptoms despite strict adherence to a gluten-free diet, having been symptom-free for over 7 years. She presented with marked oedema of the legs and a distended abdomen. Investigations--laboratory, radiological and enteroscopy findings--were consistent with the development of refractory coeliac disease. This case illustrates the background and course of this disease, and the treatment options. PMID- 26109625 TI - Clear cell adenocarcinoma of the bladder with intravesical cervical invasion. AB - A 26-year-old woman with a complicated urological and gynecological history with uterine didelphys with bilaterally inserting intravesical cervical oses presented with cyclical haematuria. Work up revealed a mass in the ectopic cervical os and adjacent bladder wall. Subsequent resection confirmed a clear cell adenocarcinoma of urological origin with invasion into neighbouring os. PMID- 26109626 TI - A case of lower leg skin rash and severe arthralgia. PMID- 26109627 TI - Two Blades-Up Runs Using the JetStream Navitus Atherectomy Device Achieve Optimal Tissue Debulking of Nonocclusive In-Stent Restenosis: Observations From a Porcine Stent/Balloon Injury Model. AB - PURPOSE: To determine the number of runs with blades up (BU) using the JetStream Navitus to achieving optimal debulking in a porcine model of femoropopliteal artery in-stent restenosis (ISR). METHODS: In this porcine model, 8 limbs were implanted with overlapping nitinol self-expanding stents. ISR was treated initially with 2 blades-down (BD) runs followed by 4 BU runs (BU1 to BU4). Quantitative vascular angiography (QVA) was performed at baseline, after 2 BD runs, and after each BU run. Plaque surface area and percent stenosis within the treated stented segment were measured. Intravascular ultrasound (IVUS) was used to measure minimum lumen area (MLA) and determine IVUS-derived plaque surface area. RESULTS: QVA showed that plaque surface area was significantly reduced between baseline (83.9%+/-14.8%) and 2 BD (67.7%+/-17.0%, p=0.005) and BU1 (55.4%+/-9.0%, p=0.005) runs, and between BU1 and BU2 runs (50.7%+/-9.7%, p<0.05). Percent stenosis behaved similarly with no further reduction after BU2. There were no further reductions in plaque surface area or percent stenosis with BU 3 and 4 runs (p=0.10). Similarly, IVUS (24 lesions) confirmed optimal results with BU2 runs and no additional gain in MLA or reduction in plaque surface area with BU3 and 4. IVUS confirmed no orbital cutting with JetStream Navitus. There were no stent strut discontinuities on high-resolution radiographs following atherectomy. CONCLUSION: JetStream Navitus achieved optimal tissue debulking after 2 BD and 2 BU runs with no further statistical gain in debulking after the BU2 run. Operators treating ISR with JetStream Navitus may be advised to limit their debulking to 2 BD and 2 BU runs to achieve optimal debulking. PMID- 26109628 TI - Rheolytic Pharmacomechanical Thrombectomy for the Management of Acute Limb Ischemia: Results From the PEARL Registry. AB - PURPOSE: To present the results of rheolytic pharmacomechanical thrombectomy (PMT) for the management of acute limb ischemia (ALI) as reported in the PEARL Registry (PEripheral Use of AngioJet Rheolytic Thrombectomy with a variety of catheter Lengths). METHODS: A total of 283 patients (mean age 65+/-13 years; 170 men) presenting with ALI undergoing treatment with the AngioJet System at participating institutions were enrolled in the registry. Rutherford ALI categories included 26% with viable limbs, 38% with marginally threatened limbs, 35% with immediately threatened limbs, and <1% with irreversible damage. Procedure and follow-up data were collected for the calculation of outcomes. To control for patient selection bias, propensity score matching was used to compare outcomes for patients undergoing PMT with or without catheter-directed thrombolysis (CDT). RESULTS: Procedure success was achieved in 235 (83%) of 283 patients. Half of the procedures (147, 52%) were completed without the need for adjunctive CDT. At 12-month follow-up, amputation-free survival and freedom from mortality were 81% and 91%, respectively; 12-month freedom from bleeding requiring transfusion was 91%, and freedom from renal failure was 95%. Subgroup analysis revealed significantly better outcomes in patients without infrapopliteal involvement and those who underwent PMT without CDT. In the matched cohorts, higher rates of procedure success, 12-month amputation-free survival, and 12-month freedom from amputation were observed in the PMT without CDT group (88% vs 74%, p=0.021; 87% vs 72%, p=0.028; 96% vs 81%, p=0.01, respectively). CONCLUSIONS: The results support the use of PMT as a first-line treatment for ALI, providing a rapid reperfusion to the extremity, reduced procedure time, and an acceptable risk profile without compromising limb salvage. PMID- 26109629 TI - Temporary biventricular pacing improves bypass graft flows in coronary artery bypass graft patients with permanent atrial fibrillation. AB - OBJECTIVES: We have previously demonstrated the impact of univentricular pacing modalities on bypass graft flow (BGF) in the coronary artery bypass graft (CABG) patient with permanent atrial fibrillation (AF). The aim of the present study was to determine the mechanism of this improved coronary conduit and, in addition, to explore the possible benefits with biventricular pacing in patients with and without severe left ventricular dysfunction. METHODS: In 43 CABG patients [mean age 69.5 +/- 1.3 years; ejection fraction (EF) 49 +/- 2%] with AF, we analysed coronary vascular resistances (CVRs) and the contemporary changes in the BGF obtained during right ventricular outflow tract (RVOT), right- (RV), left- (LV) and right-left ventricular pacing (biventricular pacing, BiVP) using the ultrasonic transit-time methodology. RESULTS: BiVP resulted in the highest percentage decrease of CVR in the overall study group by 17.5 +/- 3.0% (P < 0.001), followed by RVOT pacing with 13.9 +/- 3.9%. Accordingly, the highest mean BGF was achieved during BiVP, resulting in a 21.6 +/- 2.6% increase when compared with no pacing and 16 +/- 3.7% when compared with RV pacing. Analysis of patients according to their preoperative LV function (EF >=50%, n = 26; EF <50%, n = 17) showed significantly lower CVR (P < 0.037) and higher BGF during BiVP in patients with lower EF. CONCLUSIONS: Placement of an additional LV pacing wire offered a significant improvement in BGF by minimizing CVR in patients with AF and poor EF. PMID- 26109630 TI - Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S 1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05). AB - BACKGROUND: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS: Patients who had disease progression during first line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21 day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327. PMID- 26109631 TI - Cetuximab, docetaxel, and cisplatin as first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma: a multicenter, phase II GORTEC study. AB - BACKGROUND: Cetuximab in combination with platinum and 5-fluorouracil is the standard of care in the first-line treatment of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab and taxane combinations have shown promising activity. This study evaluated the efficacy and safety of four cycles of docetaxel associated with cisplatin and cetuximab (TPEx), followed by maintenance with cetuximab every 2 weeks. PATIENTS AND METHODS: Patients with a histologically confirmed HNSCC with metastasis or recurrence unsuitable for locoregional curative treatment received docetaxel and cisplatin (75 mg/m(2) both) at day 1 and weekly cetuximab 250 mg/m(2) (loading dose of 400 mg/m(2)), repeated every 21 days for four cycles, followed by maintenance cetuximab 500 mg/m(2) every 2 weeks until progression or unacceptable toxicity. Prophylactic administration of granulocyte colony-stimulating factor was done systematically after each chemotherapy cycle. Patients had a good general status (performance status <=1) and were under 71 years. Prior total doses of cisplatin exceeding 300 mg/m(2) were not allowed. The primary end point was objective response rate (ORR) after four cycles. RESULTS: Fifty-four patients were enrolled. The primary end point was met with an ORR of 44.4% (95% CI 30.9 58.6). Median overall and progression-free survivals were, respectively, 14 months (95% CI 11.3-17.3) and 6.2 months (95% CI 5.4-7.2). The most common grade 3/4 adverse events were skin rash (16.6%) and non-febrile neutropenia (20.4%). There were one pulmonary embolism and two infectious events leading to death. CONCLUSIONS: The TPEx regimen showed promising activity as first-line treatment in fit patients with recurrent/metastatic HNSCC. Further studies are needed to compare the TPEx versus EXTREME regimen in this population. CLINICALTRIALGOV: NCT01289522. PMID- 26109632 TI - The study of glioma by xenotransplantation in zebrafish early life stages. AB - Zebrafish (Danio rerio) and their transparent embryos are becoming an increasingly popular tool for studying processes involved in tumor progression and in the search for novel tumor treatment approaches. The xenotransplantation of fluorescently labeled mammalian cancer cells into zebrafish embryos is an approach enabling relatively high-throughput in vivo analyses. The small size of the embryos as well as the relative simplicity of their manipulation and maintenance allow for large numbers of embryos to be processed efficiently in a short time and at low cost. Furthermore, the possibility of fluorescence microscopic imaging of tumor progression within zebrafish embryos and larvae holds unprecedented potential for the real-time visualization of these processes in vivo. This review presents the methodologies of xenotransplantation studies on zebrafish involving research on tumor invasion, proliferation, tumor-induced angiogenesis and screening for antitumor therapeutics. We further focus on the application of these zebrafish to the study of glioma; in particular, its most common and malignant form, glioblastoma. PMID- 26109633 TI - An analytical approach to bistable biological circuit discrimination using real algebraic geometry. AB - Biomolecular circuits with two distinct and stable steady states have been identified as essential components in a wide range of biological networks, with a variety of mechanisms and topologies giving rise to their important bistable property. Understanding the differences between circuit implementations is an important question, particularly for the synthetic biologist faced with determining which bistable circuit design out of many is best for their specific application. In this work we explore the applicability of Sturm's theorem--a tool from nineteenth-century real algebraic geometry--to comparing 'functionally equivalent' bistable circuits without the need for numerical simulation. We first consider two genetic toggle variants and two different positive feedback circuits, and show how specific topological properties present in each type of circuit can serve to increase the size of the regions of parameter space in which they function as switches. We then demonstrate that a single competitive monomeric activator added to a purely monomeric (and otherwise monostable) mutual repressor circuit is sufficient for bistability. Finally, we compare our approach with the Routh-Hurwitz method and derive consistent, yet more powerful, parametric conditions. The predictive power and ease of use of Sturm's theorem demonstrated in this work suggest that algebraic geometric techniques may be underused in biomolecular circuit analysis. PMID- 26109635 TI - Adhesive interactions of geckos with wet and dry fluoropolymer substrates. AB - Fluorinated substrates like Teflon(r) (poly(tetrafluoroethylene); PTFE) are well known for their role in creating non-stick surfaces. We showed previously that even geckos, which can stick to most surfaces under a wide variety of conditions, slip on PTFE. Surprisingly, however, geckos can stick reasonably well to PTFE if it is wet. In an effort to explain this effect, we have turned our attention to the role of substrate surface energy and roughness when shear adhesion occurs in media other than air. In this study, we removed the roughness component inherent to commercially available PTFE and tested geckos on relatively smooth wet and dry fluoropolymer substrates. We found that roughness had very little effect on shear adhesion in air or in water and that the level of fluorination was most important for shear adhesion, particularly in air. Surface energy calculations of the two fluorinated substrates and one control substrate using the Tabor-Winterton approximation and the Young-Dupre equation were used to determine the interfacial energy of the substrates. Using these interfacial energies we estimated the ratio of wet and dry normal adhesion for geckos clinging to the three substrates. Consistent with the results for rough PTFE, our predictions show a qualitative trend in shear adhesion based on fluorination, and the quantitative experimental differences highlight the unusually low shear adhesion of geckos on dry smooth fluorinated substrates, which is not captured by surface energy calculations. Our work has implications for bioinspired design of synthetics that can preferentially stick in water but not in air. PMID- 26109636 TI - Giant Brunner's gland hamartoma! PMID- 26109637 TI - Reporting a novel variant of type VI dual left anterior descending artery: a rare coronary anomaly. AB - A dual left anterior descending artery (LAD) is a rare congenital coronary anomaly and is classified into six types based on the origin and course of the long LAD. In type VI dual LAD, the short LAD arises from the left main coronary artery, and the long anomalous LAD, from the proximal right coronary artery (RCA), coursing between the right ventricular outflow tract and aortic root to reach its normal course in the mid interventricular groove. We present a novel variant of type VI dual LAD where the course of the long LAD is the same but the origin is not from the RCA but, instead, separately, from the right coronary sinus. PMID- 26109634 TI - Strategies for the chemical and biological functionalization of scaffolds for cardiac tissue engineering: a review. AB - The development of biomaterials for cardiac tissue engineering (CTE) is challenging, primarily owing to the requirement of achieving a surface with favourable characteristics that enhances cell attachment and maturation. The biomaterial surface plays a crucial role as it forms the interface between the scaffold (or cardiac patch) and the cells. In the field of CTE, synthetic polymers (polyglycerol sebacate, polyethylene glycol, polyglycolic acid, poly-l lactide, polyvinyl alcohol, polycaprolactone, polyurethanes and poly(N isopropylacrylamide)) have been proven to exhibit suitable biodegradable and mechanical properties. Despite the fact that they show the required biocompatible behaviour, most synthetic polymers exhibit poor cell attachment capability. These synthetic polymers are mostly hydrophobic and lack cell recognition sites, limiting their application. Therefore, biofunctionalization of these biomaterials to enhance cell attachment and cell material interaction is being widely investigated. There are numerous approaches for functionalizing a material, which can be classified as mechanical, physical, chemical and biological. In this review, recent studies reported in the literature to functionalize scaffolds in the context of CTE, are discussed. Surface, morphological, chemical and biological modifications are introduced and the results of novel promising strategies and techniques are discussed. PMID- 26109638 TI - TGF-beta-Dependent Dendritic Cell Chemokinesis in Murine Models of Airway Disease. AB - Small airway chronic inflammation is a major pathologic feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Dendritic cells (DCs) accumulate around small airways in COPD. DCs are critical mediators of Ag surveillance and Ag presentation and amplify adaptive immune responses. How DCs accumulate around airways remains largely unknown. We use 2 photon DC imaging of living murine lung sections to directly visualize the dynamic movement of living DCs around airways in response to either soluble mediators (IL-1beta) or environmental stimuli (cigarette smoke or TLR3 ligands) implicated in COPD pathogenesis. We find that DCs accumulate around murine airways primarily by increasing velocity (chemokinesis) rather than directional migration (chemotaxis) in response to all three stimuli. DC accumulation maximally occurs in a specific zone located 26-50 MUm from small airways, which overlaps with zones of maximal DC velocity. Our data suggest that increased accumulation of DCs around airways results from increased numbers of highly chemokinetic DCs entering the lung from the circulation with balanced rates of immigration and emigration. Increases in DC accumulation and chemokinesis are partially dependent on ccr6, a crucial DC chemokine receptor, and fibroblast expression of the integrin alphavbeta8, a critical activator of TGF-beta. alphavbeta8-Mediated TGF-beta activation is known to enhance IL-1beta-dependent fibroblast expression of the only known endogenous ccr6 chemokine ligand, ccl20. Taken together, these data suggest a mechanism by which alphavbeta8, ccl20, and ccr6 interact to lead to DC accumulation around airways in response to COPD relevant stimuli. PMID- 26109639 TI - Cutting Edge: Synchronization of IRF1, JunB, and C/EBPbeta Activities during TLR3 TLR7 Cross-Talk Orchestrates Timely Cytokine Synergy in the Proinflammatory Response. AB - Multiple pathogen-associated molecular pattern-induced TLR pathway cross-talk provokes proinflammatory cytokine synergy in macrophages, which is important for pathogen resistance and immune homeostasis. However, the detailed mechanisms are unclear. In this article, we demonstrate viral RNA analog-induced transcription synergy of Il6 and Il12b via IFN regulatory factor (IRF)1 (TLR3-TIR domain containing adaptor inducing IFN-beta [TRIF] responsive), C/EBPbeta (TLR7-MyD88 responsive), and JunB (all responsive). Coactivation of the TLR3 and TLR7 pathways synchronizes the interaction of IRF1, JunB, and C/EBPbeta with the Il6 and Il12b promoters, facilitating maximal gene expression. MyD88 pathway activation suppresses TRIF-induced IRF1 in a delayed manner, controlling the magnitude and timing of cytokine expression. Our findings provide novel mechanisms of cooperation of different TLR pathways to achieve optimal immune responses, with the potential for immunomodulatory strategies. PMID- 26109640 TI - KIR3DS1-Specific D0 Domain Polymorphisms Disrupt KIR3DL1 Surface Expression and HLA Binding. AB - KIR3DL1 is a polymorphic inhibitory receptor that modulates NK cell activity through interacting with HLA-A and HLA-B alleles that carry the Bw4 epitope. Amino acid polymorphisms throughout KIR3DL1 impact receptor surface expression and affinity for HLA. KIR3DL1/S1 encodes inhibitory and activating alleles, but despite high homology with KIR3DL1, the activating receptor KIR3DS1 does not bind the same ligand. Allele KIR3DL1*009 resulted from a gene recombination event between the inhibitory receptor allele KIR3DL1*001 and the activating receptor allele KIR3DS1*013. This study analyzed the functional impact of KIR3DS1-specific polymorphisms on KIR3DL1*009 surface expression, binding to HLA, and functional capacity. Flow-cytometric analysis of primary human NK cells as well as transfected HEK293T cells shows that KIR3DL1*009 is expressed at a significantly lower surface density compared with KIR3DL1*001. Using recombinant proteins of KIR3DL1*001, KIR3DL1*009, and KIR3DS1*013 to analyze binding to HLA, we found that although KIR3DL1*009 displayed some evidence of binding to HLA compared with KIR3DS1*013, the binding was minimal compared with KIR3DL1*001 and KIR3DL1*005. Mutagenesis of polymorphic sites revealed that the surface phenotype and reduced binding of KIR3DL1*009 are caused by the combined amino acid polymorphisms at positions 58 and 92 within the D0 extracellular domain. Resulting from these effects, KIR3DL1*009(+) NK cells exhibited significantly less inhibition by HLA Bw4(+) target cells compared with KIR3DL1*001(+) NK cells. The data from this study contribute novel insight into how KIR3DS1-specific polymorphisms in the extracellular region impact KIR3DL1 surface expression, ligand binding, and inhibitory function. PMID- 26109641 TI - Cutting Edge: Regulation of Exosome Secretion by the Integral MAL Protein in T Cells. AB - Exosomes secreted by T cells play an important role in coordinating the immune response. HIV-1 Nef hijacks the route of exosome secretion of T cells to modulate the functioning of uninfected cells. Despite the importance of the process, the protein machinery involved in exosome biogenesis is yet to be identified. In this study, we show that MAL, a tetraspanning membrane protein expressed in human T cells, is present in endosomes that travel toward the plasma membrane for exosome secretion. In the absence of MAL, the release of exosome particles and markers was greatly impaired. This effect was accompanied by protein sorting defects at multivesicular endosomes that divert the exosomal marker CD63 to autophagic vacuoles. Exosome release induced by HIV-1 Nef was also dependent on MAL expression. Therefore, MAL is a critical element of the machinery for exosome secretion and may constitute a target for modulating exosome secretion by human T cells. PMID- 26109642 TI - Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular damage and fibrosis of the skin and internal organs. Because activated and oligoclonally expanded CD8(+) T cells can be detected in peripheral blood and lungs of SSc patients, effector memory CD8(+) T cells may play a critical role for organ involvement in SSc; however, the pathogenic functions of effector memory CD8(+) T cells remain incompletely understood. In this study, we performed DNA microarray analysis of the sort-purified effector memory CD8(+) T cells from SSc patients and healthy controls, and showed that the expression of genes related to immune response and cell adhesion, including CD226 (also known as DNAX accessory molecule-1 [DNAM-1]), was significantly altered. Moreover, detailed analysis of CD226 revealed that CD226(high)CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease. Furthermore, CD226(+)CD8(+) T cells produced higher amount of various cytokines than CD226(-) ones, and CD226(high)CD8(+) T cells from SSc patients showed upregulated IL-13 production and positive correlation with the cytotoxic capacity of CD8(+) T cells against HUVECs. Finally, the neutralization of CD226 in CD8(+) T cells impaired costimulation, cytokine productions, and cytolysis against HUVECs. These findings indicate that upregulated CD226 expression on CD8(+) T cells reflects disease severity and is involved in SSc pathogenesis via the production of various cytokines, including profibrotic IL-13 and endothelial cell injury, and that CD226 may be a useful target in the treatment of SSc. PMID- 26109643 TI - Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages. AB - Mycobacterium tuberculosis is an intracellular pathogen that infects lung macrophages and releases microbial factors that regulate host defense. M. tuberculosis lipoproteins and lipoglycans block phagosome maturation, inhibit class II MHC Ag presentation, and modulate TLR2-dependent cytokine production, but the mechanisms for their release during infection are poorly defined. Furthermore, these molecules are thought to be incorporated into host membranes and released from infected macrophages within exosomes, 40-150-nm extracellular vesicles that derive from multivesicular endosomes. However, our studies revealed that extracellular vesicles released from infected macrophages include two distinct, largely nonoverlapping populations: one containing host cell markers of exosomes (CD9, CD63) and the other containing M. tuberculosis molecules (lipoglycans, lipoproteins). These vesicle populations are similar in size but have distinct densities, as determined by separation on sucrose gradients. Release of lipoglycans and lipoproteins from infected macrophages was dependent on bacterial viability, implicating active bacterial mechanisms in their secretion. Consistent with recent reports of extracellular vesicle production by bacteria (including M. tuberculosis), we propose that bacterial membrane vesicles are secreted by M. tuberculosis within infected macrophages and subsequently are released into the extracellular environment. Furthermore, extracellular vesicles released from M. tuberculosis-infected cells activate TLR2 and induce cytokine responses by uninfected macrophages. We demonstrate that these activities derive from the bacterial membrane vesicles rather than exosomes. Our findings suggest that bacterial membrane vesicles are the primary means by which M. tuberculosis exports lipoglycans and lipoproteins to impair effector functions of infected macrophages and circulate bacterial components beyond the site of infection to regulate immune responses by uninfected cells. PMID- 26109644 TI - Reversing Tolerance in Isotype Switch-Competent Anti-Insulin B Lymphocytes. AB - Autoreactive B lymphocytes that escape central tolerance and mature in the periphery are a liability for developing autoimmunity. IgG insulin autoantibodies that predict type 1 diabetes and complicate insulin therapies indicate that mechanisms for tolerance to insulin are flawed. To examine peripheral tolerance in anti-insulin B cells, we generated C57BL/6 mice that harbor anti-insulin VDJH 125 site directed to the native IgH locus (VH125(SD)). Class switch-competent anti-insulin B cells fail to produce IgG Abs following T cell-dependent immunization of VH125(SD) mice with heterologous insulin, and they exhibit markedly impaired proliferation to anti-CD40 plus insulin in vitro. In contrast, costimulation with LPS plus insulin drives robust anti-insulin B cell proliferation. Furthermore, VH125(SD) mice produce both IgM and IgG2a anti insulin Abs following immunization with insulin conjugated to type 1 T cell independent Brucella abortus ring test Ag (BRT). Anti-insulin B cells undergo clonal expansion in vivo and emerge as IgM(+) and IgM(-) GL7(+)Fas(+) germinal center (GC) B cells following immunization with insulin-BRT, but not BRT alone. Analysis of Igkappa genes in VH125(SD) mice immunized with insulin-BRT reveals that anti-insulin Vkappa from the preimmune repertoire is selected into GCs. These data demonstrate that class switch-competent anti-insulin B cells remain functionally silent in T cell-dependent immune responses, yet these B cells are vulnerable to reversal of anergy following combined BCR/TLR engagement that promotes Ag-specific GC responses and Ab production. Environmental factors that lead to infection and inflammation could play a critical yet underappreciated role in driving loss of tolerance and promoting autoimmune disease. PMID- 26109646 TI - Cutting Edge: Induction of Inflammatory Disease by Adoptive Transfer of an Atypical NK Cell Subset. AB - Several mouse models of systemic lupus erythematosus, including FcgammaRIIB-KO and TLR7tg mice, develop an expansion of an atypical NK cell subset with functional similarity to cells referred as IFN-producing killer DCs or pre-mature NKs in other systems. In this study, we show that atypical NKs purified from spleens of systemic lupus erythematosus-prone mice, and identified as NK1.1(+)CD11c(+)CD122(+)MHC-II(+), induce persistent autoimmune disease in an IFN I- and CD40L-dependent manner when transferred to wild-type mice. A single transfer of 4 * 10(6) NK1.1(+) cells from TLR7tg into wild-type induces a 2-wk long wave of inflammatory cytokines in the serum; a sustained increase in T cell activation and follicular helper cells for the following months; and a progressive expansion of dendritic cells, monocytes, and granulocytes. Furthermore, IL-15 deficiency, which impedes development of NK cells, ameliorates the autoimmune pathology of TLR7tg mice. These results suggest that cells of the NK lineage can develop into cytokine-producing/APCs that affect the priming and progression of systemic autoimmune disease. PMID- 26109645 TI - IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age. AB - Regulatory T cells (Tregs), a subset of CD4(+) T cells, dramatically accumulate with age in humans and mice and contribute to age-related immune suppression. Recently, we showed that a majority of accumulating Tregs in aged mice expressed low levels of CD25, and their accrual is associated with declining levels of IL-2 in aged mice. In this study, we further investigated the origin of CD25(lo) Tregs in aged mice. First, aged Tregs had high expression of neuropilin-1 and Helios, and had a broad Vbeta repertoire. Next, we analyzed the gene expression profile of Tregs, naive T cells, and memory T cells in aged mice. We found that the gene expression profile of aged CD25(lo) Tregs were more related to young CD25(lo) Tregs than to either naive or memory T cells. Further, the gene expression profile of aged Tregs was consistent with recently described "effector" Tregs (eTregs). Additional analysis revealed that nearly all Tregs in aged mice were of an effector phenotype (CD44(hi)CD62L(lo)) and could be further characterized by high levels of ICOS and CD69. ICOS contributed to Treg maintenance in aged mice, because in vivo Ab blockade of ICOSL led to a loss of eTregs, and this loss was rescued in Bim-deficient mice. Further, serum levels of IL-6 increased with age and contributed to elevated expression of ICOS on aged Tregs. Finally, Treg accrual was significantly blunted in aged IL-6-deficient mice. Together, our data show a role for IL-6 in promoting eTreg accrual with age likely through maintenance of ICOS expression. PMID- 26109648 TI - Cutting Edge: Inflammasome Activation in Primary Human Macrophages Is Dependent on Flagellin. AB - Murine NLR family, apoptosis inhibitory protein (Naip)1, Naip2, and Naip5/6 are host sensors that detect the cytosolic presence of needle and rod proteins from bacterial type III secretion systems and flagellin, respectively. Previous studies using human-derived macrophage-like cell lines indicate that human macrophages sense the cytosolic needle protein, but not bacterial flagellin. In this study, we show that primary human macrophages readily sense cytosolic flagellin. Infection of primary human macrophages with Salmonella elicits robust cell death and IL-1beta secretion that is dependent on flagellin. We show that flagellin detection requires a full-length isoform of human Naip. This full length Naip isoform is robustly expressed in primary macrophages from healthy human donors, but it is drastically reduced in monocytic tumor cells, THP-1, and U937, rendering them insensitive to cytosolic flagellin. However, ectopic expression of full-length Naip rescues the ability of U937 cells to sense flagellin. In conclusion, human Naip functions to activate the inflammasome in response to flagellin, similar to murine Naip5/6. PMID- 26109647 TI - Ca2+ Signaling but Not Store-Operated Ca2+ Entry Is Required for the Function of Macrophages and Dendritic Cells. AB - Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is essential for immunity to infection. CRAC channels are formed by ORAI1 proteins in the plasma membrane and activated by stromal interaction molecule (STIM)1 and STIM2 in the endoplasmic reticulum. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause severe immunodeficiency with recurrent infections due to impaired T cell function. SOCE has also been observed in cells of the innate immune system such as macrophages and dendritic cells (DCs) and may provide Ca(2+) signals required for their function. The specific role of SOCE in macrophage and DC function, as well as its contribution to innate immunity, however, is not well defined. We found that nonselective inhibition of Ca(2+) signaling strongly impairs many effector functions of bone marrow-derived macrophages and bone marrow-derived DCs, including phagocytosis, inflammasome activation, and priming of T cells. Surprisingly, however, macrophages and DCs from mice with conditional deletion of Stim1 and Stim2 genes, and therefore complete inhibition of SOCE, showed no major functional defects. Their differentiation, FcR-dependent and -independent phagocytosis, phagolysosome fusion, cytokine production, NLRP3 inflammasome activation, and their ability to present Ags to activate T cells were preserved. Our findings demonstrate that STIM1, STIM2, and SOCE are dispensable for many critical effector functions of macrophages and DCs, which has important implications for CRAC channel inhibition as a therapeutic strategy to suppress pathogenic T cells while not interfering with myeloid cell functions required for innate immunity. PMID- 26109649 TI - A Prophylactic Role for Creatine in Hypoxia? PMID- 26109650 TI - Decoding Face Exemplars from fMRI Responses: What Works, What Doesn't? PMID- 26109651 TI - Hierarchical Organization of Frontotemporal Networks for the Prediction of Stimuli across Multiple Dimensions. AB - Brain function can be conceived as a hierarchy of generative models that optimizes predictions of sensory inputs and minimizes "surprise." Each level of the hierarchy makes predictions of neural events at a lower level in the hierarchy, which returns a prediction error when these expectations are violated. We tested the generalization of this hypothesis to multiple sequential deviations, and we identified the most likely organization of the network that accommodates deviations in temporal structure of stimuli. Magnetoencephalography of healthy human participants during an auditory paradigm identified prediction error responses in bilateral primary auditory cortex, superior temporal gyrus, and lateral prefrontal cortex for deviation by frequency, intensity, location, duration, and silent gap. We examined the connectivity between cortical sources using a set of 21 generative models that embedded alternate hypotheses of frontotemporal network dynamics. Bayesian model selection provided evidence for two new features of functional network organization. First, an expectancy signal provided input to the prefrontal cortex bilaterally, related to the temporal structure of stimuli. Second, there are functionally significant lateral connections between superior temporal and/or prefrontal cortex. The results support a predictive coding hypothesis but go beyond previous work in demonstrating the generalization to multiple concurrent stimulus dimensions and the evidence for a temporal expectancy input at the higher level of the frontotemporal hierarchy. We propose that this framework for studying the brain's response to unexpected events is not limited to simple sensory tasks but may also apply to the neurocognitive mechanisms of higher cognitive functions and their disorders. PMID- 26109652 TI - Complex Effects on In Vivo Visual Responses by Specific Projections from Mouse Cortical Layer 6 to Dorsal Lateral Geniculate Nucleus. AB - Understanding the role of corticothalamic projections in shaping visual response properties in the thalamus has been a longstanding challenge in visual neuroscience. Here, we take advantage of the cell-type specificity of a transgenic mouse line, the GN220-Ntsr1 Cre line, to manipulate selectively the activity of a layer 6 (L6) corticogeniculate population while recording visual responses in the dorsal lateral geniculate nucleus (dLGN). Although driving Ntsr1 projection input resulted in reliable reduction in evoked spike count of dLGN neurons, removing these same projections resulted in both increases and decreases in visually evoked spike count. Both increases and decreases are contrast dependent and the sign is consistent over the full range of contrasts. Tuning properties suggest wide convergence of Ntsr1 cells with similar spatial and temporal frequency tuning onto single dLGN cells and we did not find evidence that Ntsr1 cells sharpen spatiotemporal filtering. These nonspecific changes occur independently of changes in burst frequency, indicating that Ntsr1 corticogeniculate activity can result in both net excitation and net inhibition. PMID- 26109653 TI - An Asymmetric Increase in Inhibitory Synapse Number Underlies the Development of a Direction Selective Circuit in the Retina. AB - Neural circuits rely upon a precise wiring of their component neurons to perform meaningful computations. To compute the direction of motion in the visual scene, the direction selective circuit in the mouse retina depends on an asymmetry in the inhibitory neurotransmission from starburst amacrine cells (SACs) to direction selective ganglion cells (DSGCs). Specifically, depolarization of a SAC on the null side of a DSGC causes a threefold greater unitary inhibitory conductance than depolarization of a SAC on the preferred side. This asymmetry emerges during the second postnatal week of development, but its basis remains unknown. To determine the source of this asymmetry in inhibitory conductance, we conducted paired recordings between SACs and DSGCs at the beginning and end of the second postnatal week. We replaced calcium with strontium to promote asynchronous neurotransmitter release and produce quantal events. During the second postnatal week the quantal frequency but not the quantal amplitude of synaptic events increased more than threefold for null-side SAC-DSGC pairs but remained constant for preferred-side pairs. In addition, paired-pulse depression did not differ between SACs located on the null and preferred sides of DSGCs, indicating that all inhibitory SAC synapses onto a DSGC exhibit the same probability of release. Thus, the higher quantal frequency seen in null-side pairs results from a greater number of inhibitory synapses, revealing that an asymmetry in synapse number between SACs and DSGCs underlies the development of an essential component in the retina's direction selective circuit. PMID- 26109654 TI - Regulation of Bcl-xL-ATP Synthase Interaction by Mitochondrial Cyclin B1-Cyclin Dependent Kinase-1 Determines Neuronal Survival. AB - The survival of postmitotic neurons needs continuous degradation of cyclin B1, a mitotic protein accumulated aberrantly in the damaged brain areas of Alzheimer's disease and stroked patients. Degradation of cyclin B1 takes place in the proteasome after ubiquitylation by the anaphase-promoting complex/cyclosome (APC/C)-cadherin 1 (Cdh1), an E3 ubiquitin ligase that is highly active in neurons. However, during excitotoxic damage-a hallmark of neurological disorders APC/C-Cdh1 is inactivated, causing cyclin B1 stabilization and neuronal death through an unknown mechanism. Here, we show that an excitotoxic stimulus in rat cortical neurons in primary culture promotes cyclin B1 accumulation in the mitochondria, in which it binds to, and activates, cyclin-dependent kinase-1 (Cdk1). The cyclin B1-Cdk1 complex in the mitochondria phosphorylates the anti apoptotic protein B-cell lymphoma extra-large (Bcl-xL), leading to its dissociation from the beta subunit of F1Fo-ATP synthase. The subsequent inhibition of ATP synthase activity causes complex I oxidative damage, mitochondrial inner membrane depolarization, and apoptotic neuronal death. These results unveil a previously unrecognized role for mitochondrial cyclin B1 in the oxidative damage associated with neurological disorders. PMID- 26109655 TI - Unbalanced Peptidergic Inhibition in Superficial Neocortex Underlies Spike and Wave Seizure Activity. AB - Slow spike and wave discharges (0.5-4 Hz) are a feature of many epilepsies. They are linked to pathology of the thalamocortical axis and a thalamic mechanism has been elegantly described. Here we present evidence for a separate generator in local circuits of associational areas of neocortex manifest from a background, sleep-associated delta rhythm in rat. Loss of tonic neuromodulatory excitation, mediated by nicotinic acetylcholine or serotonin (5HT3A) receptors, of 5HT3 immunopositive interneurons caused an increase in amplitude and slowing of the delta rhythm until each period became the "wave" component of the spike and wave discharge. As with the normal delta rhythm, the wave of a spike and wave discharge originated in cortical layer 5. In contrast, the "spike" component of the spike and wave discharge originated from a relative failure of fast inhibition in layers 2/3-switching pyramidal cell action potential outputs from single, sparse spiking during delta rhythms to brief, intense burst spiking, phase-locked to the field spike. The mechanisms underlying this loss of superficial layer fast inhibition, and a concomitant increase in slow inhibition, appeared to be precipitated by a loss of neuropeptide Y (NPY)-mediated local circuit inhibition and a subsequent increase in vasoactive intestinal peptide (VIP)-mediated disinhibition. Blockade of NPY Y1 receptors was sufficient to generate spike and wave discharges, whereas blockade of VIP receptors almost completely abolished this form of epileptiform activity. These data suggest that aberrant, activity-dependent neuropeptide corelease can have catastrophic effects on neocortical dynamics. PMID- 26109657 TI - Words Jump-Start Vision: A Label Advantage in Object Recognition. AB - People use language to shape each other's behavior in highly flexible ways. Effects of language are often assumed to be "high-level" in that, whereas language clearly influences reasoning, decision making, and memory, it does not influence low-level visual processes. Here, we test the prediction that words are able to provide top-down guidance at the very earliest stages of visual processing by acting as powerful categorical cues. We investigated whether visual processing of images of familiar animals and artifacts was enhanced after hearing their name (e.g., "dog") compared with hearing an equally familiar and unambiguous nonverbal sound (e.g., a dog bark) in 14 English monolingual speakers. Because the relationship between words and their referents is categorical, we expected words to deploy more effective categorical templates, allowing for more rapid visual recognition. By recording EEGs, we were able to determine whether this label advantage stemmed from changes to early visual processing or later semantic decision processes. The results showed that hearing a word affected early visual processes and that this modulation was specific to the named category. An analysis of ERPs showed that the P1 was larger when people were cued by labels compared with equally informative nonverbal cues-an enhancement occurring within 100 ms of image onset, which also predicted behavioral responses occurring almost 500 ms later. Hearing labels modulated the P1 such that it distinguished between target and nontarget images, showing that words rapidly guide early visual processing. PMID- 26109656 TI - The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels. AB - Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP 43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full length progranulin, may contribute to disease in TDP-43 proteinopathies. PMID- 26109658 TI - Ascl1 Converts Dorsal Midbrain Astrocytes into Functional Neurons In Vivo. AB - In vivo induction of non-neuronal cells into neurons by transcription factors offers potential therapeutic approaches for neural regeneration. Although generation of induced neuronal (iN) cells in vitro and in vivo has been reported, whether iN cells can be fully integrated into existing circuits remains unclear. Here we show that expression of achaete-scute complex homolog-like 1 (Ascl1) alone is sufficient to convert dorsal midbrain astrocytes of mice into functional iN cells in vitro and in vivo. Specific expression of Ascl1 in astrocytes by infection with GFAP-adeno-associated virus (AAV) vector converts astrocytes in dorsal midbrain, striatum, and somatosensory cortex of postnatal and adult mice into functional neurons in vivo. These iN cells mature progressively, exhibiting neuronal morphology and markers, action potentials, and synaptic inputs from and output to existing neurons. Thus, a single transcription factor, Ascl1, is sufficient to convert brain astrocytes into functional neurons, and GFAP-AAV is an efficient vector for generating iN cells from astrocytes in vivo. PMID- 26109659 TI - Norepinephrine Modulates Coding of Complex Vocalizations in the Songbird Auditory Cortex Independent of Local Neuroestrogen Synthesis. AB - The catecholamine norepinephrine plays a significant role in auditory processing. Most studies to date have examined the effects of norepinephrine on the neuronal response to relatively simple stimuli, such as tones and calls. It is less clear how norepinephrine shapes the detection of complex syntactical sounds, as well as the coding properties of sensory neurons. Songbirds provide an opportunity to understand how auditory neurons encode complex, learned vocalizations, and the potential role of norepinephrine in modulating the neuronal computations for acoustic communication. Here, we infused norepinephrine into the zebra finch auditory cortex and performed extracellular recordings to study the modulation of song representations in single neurons. Consistent with its proposed role in enhancing signal detection, norepinephrine decreased spontaneous activity and firing during stimuli, yet it significantly enhanced the auditory signal-to-noise ratio. These effects were all mimicked by clonidine, an alpha-2 receptor agonist. Moreover, a pattern classifier analysis indicated that norepinephrine enhanced the ability of single neurons to accurately encode complex auditory stimuli. Because neuroestrogens are also known to enhance auditory processing in the songbird brain, we tested the hypothesis that norepinephrine actions depend on local estrogen synthesis. Neither norepinephrine nor adrenergic receptor antagonist infusion into the auditory cortex had detectable effects on local estradiol levels. Moreover, pretreatment with fadrozole, a specific aromatase inhibitor, did not block norepinephrine's neuromodulatory effects. Together, these findings indicate that norepinephrine enhances signal detection and information encoding for complex auditory stimuli by suppressing spontaneous "noise" activity and that these actions are independent of local neuroestrogen synthesis. PMID- 26109661 TI - Signal Integration in Human Visual Speed Perception. AB - Object motion in natural scenes results in visual stimuli with a rich and broad spatiotemporal frequency spectrum. While the question of how the visual system detects and senses motion energies at different spatial and temporal frequencies has been fairly well studied, it is unclear how the visual system integrates this information to form coherent percepts of object motion. We applied a combination of tailored psychophysical experiments and predictive modeling to address this question with regard to perceived motion in a given direction (i.e., stimulus speed). We tested human subjects in a discrimination experiment using stimuli that selectively targeted four distinct spatiotemporally tuned channels with center frequencies consistent with a common speed. We first characterized subjects' responses to stimuli that targeted only individual channels. Based on these measurements, we then predicted subjects' psychometric functions for stimuli that targeted multiple channels simultaneously. Specifically, we compared predictions of three Bayesian observer models that either optimally integrated the information across all spatiotemporal channels, or only used information from the most reliable channel, or formed an average percept across channels. Only the model with optimal integration was successful in accounting for the data. Furthermore, the proposed channel model provides an intuitive explanation for the previously reported spatial frequency dependence of perceived speed of coherent object motion. Finally, our findings indicate that a prior expectation for slow speeds is added to the inference process only after the sensory information is combined and integrated. PMID- 26109660 TI - Enhanced GABAA-Mediated Tonic Inhibition in Auditory Thalamus of Rats with Behavioral Evidence of Tinnitus. AB - Accumulating evidence suggests a role for inhibitory neurotransmitter dysfunction in the pathology of tinnitus. Opposing hypotheses proposed either a pathologic decrease or increase of GABAergic inhibition in medial geniculate body (MGB). In thalamus, GABA mediates fast synaptic inhibition via synaptic GABAA receptors (GABAARs) and persistent tonic inhibition via high-affinity extrasynaptic GABAARs. Given that extrasynaptic GABAARs control the firing mode of thalamocortical neurons, we examined tonic GABAAR currents in MGB neurons in vitro, using the following three groups of adult rats: unexposed control (Ctrl); sound exposed with behavioral evidence of tinnitus (Tin); and sound exposed with no behavioral evidence of tinnitus (Non-T). Tonic GABAAR currents were evoked using the selective agonist gaboxadol. Months after a tinnitus-inducing sound exposure, gaboxadol-evoked tonic GABAAR currents showed significant tinnitus related increases contralateral to the sound exposure. In situ hybridization studies found increased mRNA levels for GABAAR delta-subunits contralateral to the sound exposure. Tin rats showed significant increases in the number of spikes per burst evoked using suprathreshold-injected current steps. In summary, we found little evidence of tinnitus-related decreases in GABAergic neurotransmission. Tinnitus and chronic pain may reflect thalamocortical dysrhythmia, which results from abnormal theta-range resonant interactions between thalamus and cortex, due to neuronal hyperpolarization and the initiation of low-threshold calcium spike bursts (Walton and Llinas, 2010). In agreement with this hypothesis, we found tinnitus-related increases in tonic extrasynaptic GABAAR currents, in action potentials/evoked bursts, and in GABAAR delta-subunit gene expression. These tinnitus-related changes in GABAergic function may be markers for tinnitus pathology in the MGB. PMID- 26109662 TI - The Organization of Mitochondrial Quality Control and Life Cycle in the Nervous System In Vivo in the Absence of PINK1. AB - Maintenance of healthy mitochondria is crucial in cells, such as neurons, with high metabolic demands, and dysfunctional mitochondria are thought to be selectively degraded. Studies of chemically uncoupled cells have implicated PINK1 mitochondrial kinase, and Parkin E3 ubiquitin ligase in targeting depolarized mitochondria for degradation. However, the role of the PINK1/Parkin pathway in mitochondrial turnover is unclear in the nervous system under normal physiological conditions, and we understand little about the changes that occur in the mitochondrial life cycle when turnover is disrupted. Here, we evaluated the nature, location, and regulation of quality control in vivo using quantitative measurements of mitochondria in Drosophila nervous system, with deletion and overexpression of genes in the PINK1/Parkin pathway. We tested the hypotheses that impairment of mitochondrial quality control via suppression of PINK1 function should produce failures of turnover, accumulation of senescent mitochondria in the axon, defects in mitochondrial traffic, and a significant shift in the mitochondrial fission-fusion steady state. Although mitochondrial membrane potential was diminished by PINK1 deletion, we did not observe the predicted increases in mitochondrial density or length in axons. Loss of PINK1 also produced specific, directionally balanced defects in mitochondrial transport, without altering the balance between stationary and moving mitochondria. Somatic mitochondrial morphology was also compromised. These results strongly circumscribe the possible mechanisms of PINK1 action in the mitochondrial life cycle and also raise the possibility that mitochondrial turnover events that occur in cultured embryonic axons might be restricted to the cell body in vivo, in the intact nervous system. PMID- 26109663 TI - FXR2P Exerts a Positive Translational Control and Is Required for the Activity Dependent Increase of PSD95 Expression. AB - In brain, specific RNA-binding proteins (RBPs) associate with localized mRNAs and function as regulators of protein synthesis at synapses exerting an indirect control on neuronal activity. Thus, the Fragile X Mental Retardation protein (FMRP) regulates expression of the scaffolding postsynaptic density protein PSD95, but the mode of control appears to be different from other FMRP target mRNAs. Here, we show that the fragile X mental retardation-related protein 2 (FXR2P) cooperates with FMRP in binding to the 3'-UTR of mouse PSD95/Dlg4 mRNA. Absence of FXR2P leads to decreased translation of PSD95/Dlg4 mRNA in the hippocampus, implying a role for FXR2P as translation activator. Remarkably, mGluR-dependent increase of PSD95 synthesis is abolished in neurons lacking Fxr2. Together, these findings show a coordinated regulation of PSD95/Dlg4 mRNA by FMRP and FXR2P that ultimately affects its fine-tuning during synaptic activity. PMID- 26109665 TI - Role of Striatal Cholinergic Interneurons in Set-Shifting in the Rat. AB - The ability to change strategies in different contexts is a form of behavioral flexibility that is crucial for adaptive behavior. The striatum has been shown to contribute to certain forms of behavioral flexibility such as reversal learning. Here we report on the contribution of striatal cholinergic interneurons-a key element in the striatal neuronal circuit-to strategy set-shifting in which an attentional shift from one stimulus dimension to another is required. We made lesions of rat cholinergic interneurons in dorsomedial or ventral striatum using a specific immunotoxin and investigated the effects on set-shifting paradigms and on reversal learning. In shifting to a set that required attention to a previously irrelevant cue, lesions of dorsomedial striatum significantly increased the number of perseverative errors. In this condition, the number of never-reinforced errors was significantly decreased in both types of lesions. When shifting to a set that required attention to a novel cue, rats with ventral striatum lesions made more perseverative errors. Neither lesion impaired learning of the initial response strategy nor a subsequent switch to a new strategy when response choice was indicated by a previously relevant cue. Reversal learning was not affected. These results suggest that in set-shifting the striatal cholinergic interneurons play a fundamental role, which is dissociable between dorsomedial and ventral striatum depending on behavioral context. We propose a common mechanism in which cholinergic interneurons inhibit neurons representing the old strategy and enhance plasticity underlying exploration of a new rule. PMID- 26109666 TI - Neural Processes in the Human Temporoparietal Cortex Separated by Localized Independent Component Analysis. AB - The human temporoparietal junction (TPJ) is a topic of intense research. Imaging studies have identified TPJ activation in association with many higher-order functions such as theory-of-mind, episodic memory, and attention, causing debate about the distribution of different processes. One major challenge is the lack of consensus about the anatomical location and extent of the TPJ. Here, we address this problem using data-driven analysis to test the hypothesis that the bilateral TPJ can be parcellated into subregions. We applied independent component analysis (ICA) to task-free fMRI data within a local region around the bilateral TPJ, iterating the ICA at multiple model orders and in several datasets. The localized analysis allowed finer separation of processes and the use of multiple dimensionalities provided qualitative information about lateralization. We identified four subdivisions that were bilaterally symmetrical and one that was right biased. To test whether the independent components (ICs) reflected true subdivisions, we performed functional connectivity analysis using the IC coordinates as seeds. This confirmed that the subdivisions belonged to distinct networks. The right-biased IC was connected with a network often associated with attentional processing. One bilateral subdivision was connected to sensorimotor regions and another was connected to auditory regions. One subdivision that presented as distinct left- and right-biased ICs was connected to frontoparietal regions. Another subdivision that also had left- and right-biased ICs was connected to social or default mode networks. Our results show that the TPJ in both hemispheres hosts multiple neural processes with connectivity patterns consistent with well developed specialization and lateralization. PMID- 26109664 TI - Glial Expression of the Caenorhabditis elegans Gene swip-10 Supports Glutamate Dependent Control of Extrasynaptic Dopamine Signaling. AB - Glial cells play a critical role in shaping neuronal development, structure, and function. In a screen for Caenorhabditis elegans mutants that display dopamine (DA)-dependent, Swimming-Induced Paralysis (Swip), we identified a novel gene, swip-10, the expression of which in glia is required to support normal swimming behavior. swip-10 mutants display reduced locomotion rates on plates, consistent with our findings of elevated rates of presynaptic DA vesicle fusion using fluorescence recovery after photobleaching. In addition, swip-10 mutants exhibit elevated DA neuron excitability upon contact with food, as detected by in vivo Ca(2+) monitoring, that can be rescued by glial expression of swip-10. Mammalian glia exert powerful control of neuronal excitability via transporter-dependent buffering of extracellular glutamate (Glu). Consistent with this idea, swip-10 paralysis was blunted in mutants deficient in either vesicular Glu release or Glu receptor expression and could be phenocopied by mutations that disrupt the function of plasma membrane Glu transporters, most noticeably glt-1, the ortholog of mammalian astrocytic GLT1 (EAAT2). swip-10 encodes a protein containing a highly conserved metallo-beta-lactamase domain, within which our swip-10 mutations are located and where engineered mutations disrupt Swip rescue. Sequence alignments identify the CNS-expressed gene MBLAC1 as a putative mammalian ortholog. Together, our studies provide evidence of a novel pathway in glial cells regulated by swip-10 that limits DA neuron excitability, DA secretion, and DA-dependent behaviors through modulation of Glu signaling. PMID- 26109667 TI - Plastic Changes in Lumbar Locomotor Networks after a Partial Spinal Cord Injury in Cats. AB - After an incomplete spinal cord injury (SCI), we know that plastic reorganization occurs in supraspinal structures with residual descending tracts. However, our knowledge about spinal plasticity is rather limited. Our recent studies point to changes within the spinal cord below the lesion. After a lateral left hemisection (T10), cats recovered stepping with both hindlimbs within 3 weeks. After a complete section (T13) in these cats, bilateral stepping was seen on the next day, a skill usually acquired after several weeks of treadmill training. This indicates that durable plastic changes occurred below the lesion. However, because sensory feedback entrains the stepping rhythm, it is difficult to reveal central pattern generator (CPG) adaptation. Here, we investigated whether lumbar segments of cats with a chronic hemisection were able to generate fictive locomotion-that is, without phasic sensory feedback as monitored by five muscle nerves in each hindlimb. With a chronic left hemisection, the number of muscle nerves displaying locomotor bursts was larger on the left than on the right. In addition, transmission of cutaneous reflexes was relatively facilitated on the left. Later during the acute experiment, a complete spinalization (T13) was performed and clonidine was injected to induce rhythmic activities. There were still more muscle nerves displaying locomotor bursts on the left. The results demonstrate that spinal networks were indeed modified after a hemisection with a clear asymmetry between left and right in the capacity to generate locomotion. Plastic changes in CPG and reflex transmission below the lesion are thus involved in the stepping recovery after an incomplete SCI. PMID- 26109668 TI - Amplified Mechanically Gated Currents in Distinct Subsets of Myelinated Sensory Neurons following In Vivo Inflammation of Skin and Muscle. AB - Primary afferents are sensitized to mechanical stimuli following in vivo inflammation, but whether sensitization of mechanically gated ion channels contributes to this phenomenon is unknown. Here we identified two populations of murine A fiber-type sensory neurons that display markedly different responses to focal mechanical stimuli of the membrane based on their expression of calcitonin gene-related peptide (CGRP). Following inflammation of the hindpaw, myelinated, CGRP-positive neurons projecting to the paw skin displayed elevated mechanical currents in response to mechanical stimuli. Conversely, muscle inflammation markedly amplified mechanical currents in myelinated, CGRP-negative neurons projecting to muscle. These data show, for the first time, that mechanically gated currents are amplified following in vivo tissue inflammation, and also suggest that mechanical sensitization can occur in myelinated neurons after inflammation. PMID- 26109669 TI - The Zona Incerta Regulates Communication between the Superior Colliculus and the Posteromedial Thalamus: Implications for Thalamic Interactions with the Dorsolateral Striatum. AB - There is uncertainty concerning the circuit connections by which the superior colliculus interacts with the basal ganglia. To address this issue, anterograde and retrograde tracers were placed, respectively, into the superior colliculus and globus pallidus of Sprague-Dawley rats. In this two-tracer experiment, the projections from the superior colliculus terminated densely in the ventral zona incerta (ZIv), but did not overlap the labeled neurons observed in the subthalamic nucleus. In cases in which anterograde and retrograde tracers were placed, respectively, in sensory-responsive sites in the superior colliculus and posteromedial (POm) thalamus, the labeled projections from superior colliculus innervated the ZIv regions that contained the labeled neurons that project to POm. We also confirmed this colliculo-incertal-POm pathway by depositing a mixture of retrograde and anterograde tracers at focal sites in ZIv to reveal retrogradely labeled neurons in superior colliculus and anterogradely labeled terminals in POm. When combined with retrograde tracer injections in POm, immunohistochemical processing proved that most ZIv projections to POm are GABAergic. Consistent with these findings, direct stimulation of superior colliculus evoked neuronal excitation in ZIv and caused inhibition of spontaneous activity in POm. Collectively, these results indicate that superior colliculus can activate the inhibitory projections from ZIv to the POm. This is significant because it suggests that the superior colliculus could suppress the interactions between POm and the dorsolateral striatum, presumably to halt ongoing behaviors so that more adaptive motor actions are selected in response to unexpected sensory events. SIGNIFICANCE STATEMENT: By demonstrating that the zona incerta regulates communication between the superior colliculus and the posteromedial thalamus, we have uncovered a circuit that partly explains the behavioral changes that occur in response to unexpected sensory stimuli. Furthermore, this circuit could explain why deep brain stimulation of the zona incerta is beneficial to patients who suffer from Parkinson's disease. PMID- 26109670 TI - Slow Spatial Recruitment of Neocortex during Secondarily Generalized Seizures and Its Relation to Surgical Outcome. AB - Understanding the spatiotemporal dynamics of brain activity is crucial for inferring the underlying synaptic and nonsynaptic mechanisms of brain dysfunction. Focal seizures with secondary generalization are traditionally considered to begin in a limited spatial region and spread to connected areas, which can include both pathological and normal brain tissue. The mechanisms underlying this spread are important to our understanding of seizures and to improve therapies for surgical intervention. Here we study the properties of seizure recruitment-how electrical brain activity transitions to large voltage fluctuations characteristic of spike-and-wave seizures. We do so using invasive subdural electrode arrays from a population of 16 patients with pharmacoresistant epilepsy. We find an average delay of ~30 s for a broad area of cortex (8 * 8 cm) to be recruited into the seizure, at an estimated speed of ~4 mm/s. The spatiotemporal characteristics of recruitment reveal two categories of patients: one in which seizure recruitment of neighboring cortical regions follows a spatially organized pattern consistent from seizure to seizure, and a second group without consistent spatial organization of activity during recruitment. The consistent, organized recruitment correlates with a more regular, compared with small-world, connectivity pattern in simulation and successful surgical treatment of epilepsy. We propose that an improved understanding of how the seizure recruits brain regions into large amplitude voltage fluctuations provides novel information to improve surgical treatment of epilepsy and highlights the slow spread of massive local activity across a vast extent of cortex during seizure. PMID- 26109672 TI - PMv Neuronal Firing May Be Driven by a Movement Command Trajectory within Multidimensional Gaussian Fields. AB - The premotor cortex (PM) is known to be a site of visuo-somatosensory integration for the production of movement. We sought to better understand the ventral PM (PMv) by modeling its signal encoding in greater detail. Neuronal firing data was obtained from 110 PMv neurons in two male rhesus macaques executing four reach grasp-manipulate tasks. We found that in the large majority of neurons (~90%) the firing patterns across the four tasks could be explained by assuming that a high dimensional position/configuration trajectory-like signal evolving ~250 ms before movement was encoded within a multidimensional Gaussian field (MGF). Our findings are consistent with the possibility that PMv neurons process a visually specified reference command for the intended arm/hand position trajectory with respect to a proprioceptively or visually sensed initial configuration. The estimated MGF were (hyper) disc-like, such that each neuron's firing modulated strongly only with commands that evolved along a single direction within position/configuration space. Thus, many neurons appeared to be tuned to slices of this input signal space that as a collection appeared to well cover the space. The MGF encoding models appear to be consistent with the arm-referent, bell-shaped, visual target tuning curves and target selectivity patterns observed in PMV visual-motor neurons. These findings suggest that PMv may implement a lookup table-like mechanism that helps translate intended movement trajectory into time-varying patterns of activation in motor cortex and spinal cord. MGFs provide an improved nonlinear framework for potentially decoding visually specified, intended multijoint arm/hand trajectories well in advance of movement. PMID- 26109673 TI - Hemichannels Are Required for Amyloid beta-Peptide-Induced Degranulation and Are Activated in Brain Mast Cells of APPswe/PS1dE9 Mice. AB - Mast cells (MCs) store an array of proinflammatory mediators in secretory granules that are rapidly released upon activation by diverse conditions including amyloid beta (Abeta) peptides. In the present work, we found a rapid degranulation of cultured MCs through a pannexin1 hemichannel (Panx1 HC) dependent mechanism induced by Abeta25-35 peptide. Accordingly, Abeta25-35 peptide also increased membrane current and permeability, as well as intracellular Ca(2+) signal, mainly via Panx1 HCs because all of these responses were drastically inhibited by Panx1 HC blockers and absent in the MCs of Panx1(-/ ) mice. Moreover, in acute coronal brain slices of control mice, Abeta25-35 peptide promoted both connexin 43 (Cx43)- and Panx1 HC-dependent MC dye uptake and histamine release, responses that were only Cx43 HC dependent in Panx1(-/-) mice. Because MCs have been found close to amyloid plaques of patients with Alzheimer's disease (AD), their distribution in brain slices of APPswe/PS1dE9 mice, a murine model of AD, was also investigated. The number of MCs in hippocampal and cortical areas increased drastically even before amyloid plaque deposits became evident. Therefore, MCs might act as early sensors of amyloid peptide and recruit other cells to the neuroinflammatory response, thus playing a critical role in the onset and progression of AD. PMID- 26109671 TI - ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival. AB - Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are highly homologous yet distinct components of signal transduction pathways known to regulate cell survival and function. Recent evidence indicates an isoform-specific role for ERK2 in pain processing and peripheral sensitization. However, the function of ERK2 in primary sensory neurons has not been directly tested. To dissect the isoform-specific function of ERK2 in sensory neurons, we used mice with Cre-loxP mediated deletion of ERK2 in Nav1.8(+) sensory neurons that are predominantly nociceptors. We find that ERK2, unlike ERK1, is required for peripheral sensitization and cold sensation. We also demonstrate that ERK2, but not ERK1, is required to preserve epidermal innervation in a subset of peptidergic neurons. Additionally, deletion of both ERK isoforms in Nav1.8(+) sensory neurons leads to neuron loss not observed with deletion of either isoform alone, demonstrating functional redundancy in the maintenance of sensory neuron survival. Thus, ERK1 and ERK2 exhibit both functionally distinct and redundant roles in sensory neurons. SIGNIFICANCE STATEMENT: ERK1/2 signaling affects sensory neuron function and survival. However, it was not clear whether ERK isoform-specific roles exist in these processes postnatally. Previous work from our laboratory suggested either functional redundancy of ERK isoforms or a predominant role for ERK2 in pain; however, the tools to discriminate between these possibilities were not available at the time. In the present study, we use new genetic knock-out lines to demonstrate that ERK2 in sensory neurons is necessary for development of inflammatory pain and for postnatal maintenance of peptidergic epidermal innervation. Interestingly, postnatal loss of both ERK isoforms leads to a profound loss of sensory neurons. Therefore, ERK1 and ERK2 display both functionally distinct and redundant roles in sensory neurons. PMID- 26109674 TI - Subcutaneous immunoglobulin in CIDP and MMN: a different long-term clinical response? PMID- 26109675 TI - Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus. AB - Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7-9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines. PMID- 26109676 TI - No Benefit to Delaying Pneumococcal Polysaccharide Vaccination in HIV-Positive Adults. PMID- 26109677 TI - Prospective mapping of lymph node metastasis in Japanese patients undergoing radical cystectomy for bladder cancer: characteristics of micrometastasis. AB - OBJECTIVE: To investigate node-disease prevalence including micrometastases and its survival impact on bladder cancer patients. METHODS: A total of 60 patients participated in this study, in which extended lymph node dissection was carried out according to the prospective rule (below aortic bifurcation). Radical cystectomy and extended lymph node dissection were performed by open surgery (n = 23) or laparoscopically (n = 37). Perioperative, pathological and follow-up data were collected. Micrometastasis in lymph nodes was investigated by pan cytokeratin immunohistochemistry. Recurrence-free survival was estimated with the Kaplan-Meier method. RESULTS: The median number of lymph nodes removed was 29 (range: 10-103) and there was no significant difference between the two groups (open group: median 30, laparoscopic group: median 29). Routine pathological examination revealed that 10 patients had lymph node metastases. Immunohistochemistry revealed micrometastases in four additional patients (pNmicro+), who had been diagnosed with pN0 on routine pathological examination. After excluding the three patients with pure nonurothelial carcinoma on the final pathology (small cell carcinoma: n = 2, adenocarcinoma: n = 1), 10 out of the 57 urothelial carcinoma patients (17.5%) had node metastasis, and an additional 4 out of the 47 pN0 patients (4/47, 8.5%) had micrometastasis. The 2-year recurrence-free survival rates divided by pN stage were 82.4% for pN0, 66.7% for pNmicro+ and 12.5% for pN+ (three-sample log-rank test, P < 0.0001). Three out of the four patients with pNmicro+ were disease free at the last follow-up. CONCLUSIONS: We confirmed under extended lymph node dissection that a substantial proportion of the patients had node metastasis (pN+: n = 10 and pNmicro+: n = 4), and the pN stage influenced patient survival. Our observations of micrometastasis yielded additional evidence for the potential survival benefit of extended lymphadenectomy by eliminating microdisease. PMID- 26109678 TI - Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity. AB - The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol 5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10 dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2 expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity. PMID- 26109681 TI - The use of a biological graft for the closure of large abdominal wall defects following excision of soft tissue tumours. AB - Primary soft tissue tumours arising from the abdominal wall are uncommon and surgical excision of such tumours can result in large abdominal wall defects. There are many techniques available for abdominal wall repair following tumour excision, each having its own advantages and disadvantages. The options range from direct closure to the use of tissue flap reconstructions and/or prosthetic meshes. Currently, synthetic material such as polypropylene mesh is a common choice for closure of abdominal wall defects after tumour excision. Biological meshes are an alternative option for repair, and this report outlines two cases of abdominal wall repair using the porcine intestinal submucosa biological graft following excision of abdominal wall tumours. There was no evidence of infection, recurrence, seroma or hernias at 2-year follow-up. Following excision of soft tissue tumours of the abdominal wall, biological reconstructions can be successfully used to bridge the defect with minimal morbidity. PMID- 26109682 TI - Opponent's comments. PMID- 26109680 TI - Treatment outcomes of patients with FIGO Stage I/II uterine cervical cancer treated with definitive radiotherapy: a multi-institutional retrospective research study. AB - The purpose of this study was to analyze the patterns of care and outcomes of patients with FIGO Stage I/II cervical cancer who underwent definitive radiotherapy (RT) at multiple Japanese institutions. The Japanese Radiation Oncology Study Group (JROSG) performed a questionnaire-based survey of their cervical cancer patients who were treated with definitive RT between January 2000 and December 2005. A total of 667 patients were entered in this study. Although half of the patients were considered suitable for definitive RT based on the clinical features of the tumor, about one-third of the patients were prescribed RT instead of surgery because of poor medical status. The RT schedule most frequently utilized was whole-pelvic field irradiation (WP) of 30 Gy/15 fractions followed by WP with midline block of 20 Gy/10 fractions, and high-dose-rate intracavitary brachytherapy (HDR-ICBT) of 24 Gy/4 fractions prescribed at point A. Chemotherapy was administered to 306 patients (46%). The most frequent regimen contained cisplatin (CDDP). The median follow-up time for all patients was 65 months (range, 2-135 months). The 5-year overall survival (OS), pelvic control (PC) and disease-free survival (DFS) rates for all patients were 78%, 90% and 69%, respectively. Tumor diameter and nodal status were significant prognostic indicators for OS, PC and DFS. Chemotherapy has potential for improving the OS and DFS of patients with bulky tumors, but not for non-bulky tumors. This study found that definitive RT for patients with Stage I/II cervical cancer achieved good survival outcomes. PMID- 26109679 TI - Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis. AB - In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans' anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl(-/-) mice exhibit Jordans' anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl(-/-) mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl(-/-) mice. Mechanistically, ATGL(-/-) as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans' anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases. PMID- 26109683 TI - Opponent's comments. PMID- 26109684 TI - Bortezomib-induced acute interstitial nephritis. AB - Acute interstitial nephritis (AIN) is one of the important causes of acute kidney injury (AKI) resulting from inflammatory tubulointerstitial injury induced by medications, infections and systemic diseases. Bortezomib has been increasingly used especially in renal related indications such as multiple myeloma and monoclonal gammopathy of renal significance. Severe allergic reactions from bortezomib treatment including AIN have not been described in the literature. We report a 47-year-old white man who developed biopsy-proven allergic AIN after treatment with bortezomib for his C3 glomerulonephritis. The patient's kidney function improved after treatment with glucocorticoid therapy and discontinuation of bortezomib, but worsened with recurrent AKI episode after re-initiation of bortezomib. His renal function improved after glucocorticoid therapy and discontinuation of bortezomib. To our knowledge, this is the first report of a biopsy-proven AIN from bortezomib. PMID- 26109686 TI - Hope and mood changes throughout the primary brain tumor illness trajectory. AB - BACKGROUND: The ambiguity of defining hope impacts the level of readiness faced by health care professionals treating patients with glioma, a disease with unpredictable outcomes. This study describes the report of hope and the relationship between hope and mood in adult brain tumor patients at various points in the illness trajectory. METHODS: This was a cross-sectional study with data collection including use of the Herth Hope Index (HHI), the Profile of Mood States-Short Form (POMS-SF), and clinical information. Descriptive statistics were used to report sample characteristics. Spearman's rho and Mann-Whitney tests were used to compare and differentiate scores. RESULTS: Eighty-two patients ranging in age from 22 to 78 years (median, 44.5 y) participated in the study. Patients were primarily male (57.3%), married (76.8%), and had a high-grade glioma (35.4%). Nearly half had recurrence, and more than 20% were on active treatment. The overall HHI total score for the sample was 41.32 (range: 13-48). Patients with recurrence had a lower HHI interconnectedness (median = 14.00) score and higher total mood disturbance (median = 14.00) compared with patients without recurrence (median = 15.00 and median = 0.00, respectively; P < .05). All negative mood states on the POMS-SF were negatively correlated with HHI subscales. CONCLUSIONS: Overall, patients reporting more hope also reported less overall mood disturbance As expected, patients with tumor recurrence reported lower hope and higher mood disturbance than those who were newly diagnosed or without recurrence. Targeting interventions specifically tailored to an individual's needs for improvement in quality of life throughout the disease course may include measures to address hope in order to facilitate positive coping strategies. PMID- 26109687 TI - Randomized controlled trial of vertebroplasty versus kyphoplasty in the treatment of vertebral compression fractures. AB - BACKGROUND: We present the results of a randomized controlled trial evaluating the efficacy of vertebroplasty versus kyphoplasty in treating vertebral body compression fractures. METHODS: Patients with vertebral body compression fractures were randomly assigned to treatment with kyphoplasty or vertebroplasty. Primary endpoints were pain (0-10 scale) and disability assessed using the Roland Morris Disability Questionnaire (RMDQ). Outcomes were assessed at 3 days, 1 month, 6 months, and 1 year following the procedure. RESULTS: 115 subjects were enrolled in the trial with 59 (51.3%) randomly assigned to kyphoplasty and 56 (48.7%) assigned to vertebroplasty. Mean (SD) pain scores at baseline, 3 days, 30 days, and 1 year for kyphoplasty versus vertebroplasty were 7.4 (1.9) vs 7.9 (2.0), 4.1 (2.8) vs 3.7 (3.0), 3.4 (2.5) vs 3.6 (2.9), and 3.0 (2.8) vs 2.3 (2.6), respectively (p>0.05 at all time points). Mean (SD) RMDQ scores at baseline, 3 days, 30 days, 180 days, and 1 year were 17.3 (6.6) vs 16.3 (7.4), 11.8 (7.9) vs 10.9 (8.2), 8.6 (7.2) vs 8.8 (8.5), 7.9 (7.4) vs 7.3 (7.7), 7.5 (7.2) vs 6.7 (8.0), respectively (p>0.05 at all time points). For baseline to 12 month assessment in average pain and RMDQ scores, the standardized effect size between kyphoplasty and vertebroplasty was small at -0.36 (95% CI -1.02 to 0.31) and -0.04 (95% CI -1.68 to 1.60), respectively. CONCLUSIONS: Our study indicates that vertebroplasty and kyphoplasty appear to be equally effective in substantially reducing pain and disability in patients with vertebral body compression fractures. TRIAL REGISTRATION NUMBER: NCT00279877. PMID- 26109689 TI - Nursing: A Basic or Applied Science. PMID- 26109688 TI - Relationship between low response to clopidogrel and periprocedural ischemic events with coil embolization for intracranial aneurysms. AB - OBJECTIVES: Low response to antiplatelet drugs is one of the risk factors for ischemic events. We examined the influence of low response to clopidogrel on symptomatic ischemic events and new ischemic MRI lesions with endovascular intracranial aneurysmal coil embolization. MATERIALS AND METHODS: Between August 2010 and July 2013, 189 procedures in 181 consecutive patients who underwent endovascular coiling and received clopidogrel before treatment were investigated retrospectively. Platelet aggregation activity was examined by VerifyNow analysis. Low response to clopidogrel was defined as P2Y12 reaction units >=230 in this study. Symptomatic ischemic complications within 30 days and postoperative new ischemic lesions on MRI-diffusion weighted imaging were evaluated. RESULTS: 66 of 189 (34.9%) cases were low responders to clopidogrel. Ischemic complications occurred in 2 of 66 (3.0%) low responders compared with 6 of 123 (4.9%) responders (p=0.72). A new high intensity spot larger than 5 mm was significantly more frequent in low responders (26 of 66; 39.4%) than in responders (26 of 121; 21.2%; p=0.01). On multivariate analysis, independent risk factors for larger new ischemic lesions were low response to clopidogrel, smokers, posterior location, and aneurysms with a larger neck. CONCLUSIONS: Low response to clopidogrel had little effect on clinical outcome although it increased asymptomatic large ischemic lesions in this cohort. PMID- 26109690 TI - Awakening to Becoming. AB - This column explores the question: How do you want to be known? Three awakening stories are presented to provide a framework for discussing the humanbecoming processes of creative imagining, affirming personal becoming, and glimpsing the paradoxical. These processes are important in changing living quality and developing personal pattern preferences by which to be known. PMID- 26109691 TI - Freedom in Research: The Situation. AB - To illuminate the idea of freedom in research, the author considers the nature of being a professional, which includes the dimensions as elaborated by Flexner (1915) and Taylor (1968). The dimension of autonomy, one characteristic of being a professional, is explored by utilizing the work of Hall (1968). Then the idea of situated freedom will be presented as a means to explain the professional autonomy of nurse researchers. PMID- 26109692 TI - The Ethics of Human Freedom and Healthcare Policy: A Nursing Theoretical Perspective. AB - Global healthcare and healthcare policies are evolving with change at a swift pace. Inherent in the discussions of a person's right to choose health is the notion of freedom. The author in this column compares and contrasts bioethical views of freedom and autonomy with alternative views and possibilities by examining an ethic of freedom grounded from a different paradigm, the humanbecoming nursing theoretical perspective. PMID- 26109693 TI - The Art of Service Learning. AB - Service learning has become a buzz term in higher academic settings. However, it may be difficult to identify activities that have both a service component and a learning component that logically flows from course objectives. The authors introduce four service learning options that may be utilized by colleges and universities nationwide. They offer support for Parse's theory of humanbecoming as a natural underpinning to service learning and they discuss where specific aspects of Parse's teaching-learning model may surface within service learning activities. PMID- 26109694 TI - Hostility in Nursing. PMID- 26109695 TI - Hostility Patterns: Implications for Nursing Practice. AB - In order to present the state of the science of hostility among and across disciplines, a review of the literature was completed. The knowledge gained may influence nursing practice. Scholarly works from nursing, medical and basic sciences, psychology, sociology, education, philosophy, business, communication, and criminology were reviewed. Similar patterns in the use of the concept were discovered. The patterns revealed five themes: hostility as a health-risk factor, hostility as a factor in family relationships, hostility as a factor in perceived challenge, hostility as a factor in criminal behavior, and hostility as a factor in the workplace. Based on the knowledge gained about hostility, implications for nursing practice related to changing the hostile working environment for nurses were suggested using modeling and role-modeling nursing theory. PMID- 26109696 TI - Who Owns Nursing's Great Ideas? PMID- 26109697 TI - Intellectual Property in the Connected Age. AB - Concerns about intellectual property for nursing are becoming increasingly acute as information becomes highly accessible in the digital age. Nurse faculty members need to check policies of the agencies that they work for to evaluate explicit written policies for their protection and full understanding of the agency's rights. PMID- 26109698 TI - Neuman Systems Model as a Conceptual Framework for Nurse Resilience. AB - Due to the stressors involved in the field of nursing, resilience has been identified as an essential trait for those working in the profession. Nurses must deal with many issues that can lead to exhaustion and burnout. The Neuman Systems Model focuses on types of stressors that may cause harm to a person's health and well-being. The purposes of this article are to offer the Neuman Systems Model as a conceptual framework for exploring nurse resilience, and to describe strategies that promote resilience-building in nurses. PMID- 26109699 TI - A Globally-Conscious Nonlocal Nursing Community: From Caritas to Communitas. AB - The purpose of this article is to describe the creative process and nursing implications of the website, Holding Heartspace: A Nonphysical Ashram for the Like-hearted to Honor Story, Process, and Sacred Intentions of Caring-Healing Loving in the World. Holding Heartspace is an example of a virtual community that links the experiences of nurses from around the world to a centralized forum. This site is the culminating project of the author's participation in and graduation from the Caritas Coach Education Program (CCEP). Human caring science is a theory of nursing maintaining several relevant components and definitions that have fostered the creation of Holding Heartspace. It is within the contextual realm of caring science that facilitation from caritas (compassionate, generous love) to the more universal communitas (recognition of our collective humanity) is realized and experienced (Watson, 2008). PMID- 26109700 TI - Toward a Theory of Intuitive Decision-Making in Nursing. AB - The author in this article presents a theory of decision-making in nursing, specifically a middle-range theory of intuitive decision-making in nursing created through the synthesis of Patricia Benner's model of skill acquisition in nursing and Damasio's somatic marker hypothesis. The author proposes that Damasio's somatic state is equivalent to what Benner has identified as intuition. When a nurse is faced with a decision, intuition, if developed, is a somatic state that creates a measurable physiological biasing signal (skin conductive response) that helps in making an advantageous decision. Research, educational, clinical and theoretical implications are discussed. PMID- 26109701 TI - Being One with the Universe: Finding a Silver Lining in Dying. AB - Woody Allen once quoted, "I don't mind dying so much, I just don't want to be there when it happens" (as cited in Ingram, 2002, p. 1). Oftentimes, death is not a happy subject, a reality that most of us fear, yet something we all must face. In this paper, three articles were reviewed that explored the living-dying (Phillips, 1992) process of the terminally ill and the material was conceptualized in light of Rogers (1994) science of unitary human beings. To further understand and explore the living-dying process, creative examples (movie screenplay, novel, song and others) were cited. During the living-dying process exploration, three common themes were expressed by the subjects (dying persons), namely: valuing own perspective of quality of life; choosing personal meanings with ways of moving beyond with the possibles (Lee & Pilkington, 1999), while focusing on life's meaning rather than life's details (Dobratz, 2002); and connecting to the world-as-unknown while self-separating to the world-as-known in actively seeking the union with death (Kubler-Ross, 1981; Callanan & Kelly, 1992; Dobratz, 2002). It is important for healthcare providers to recognize and acknowledge all three themes to be able to understand dying persons, to focus on their wholeness rather than their disease, and to help families discern symbolic messages conveyed by them. Moreover, knowing these themes also enables healthcare providers to help all parties to transition and be able to accept and embrace the most difficult process-the living-dying (Phillips, 1992) process. PMID- 26109702 TI - The Financial Case for Patient-Centered Interdisciplinary Teams in the United Kingdom. AB - This column is about the financial and human benefits of effective interdisciplinary healthcare teams approach and the use of the humanbecoming school of thought in head and neck oncology in the United Kingdom. Included is a brief comparison with oncology treatment in the United States. PMID- 26109703 TI - Economic Soundness and Interdisciplinary Teamwork in the UK: Is It Financially Sound? AB - This article is chiefly concerned with the question is nursing, particularly oncology nursing, both improved and more affordable when persons are honored in the manner suggested by Rosemarie Rizzo Parse's humanbecoming school of thought and when nurses are respected members of multidisciplinary teams? The authors offer a theoretical article on the evolution of cancer multidisciplinary teams and examine current thinking on teamwork in the hospital setting. PMID- 26109704 TI - Epistemic Injustice and Nurse Moral Distress: Perspective for Policy Development. AB - The focus of this article is epistemic injustice as an underlying explanation for the lack of communication associated with moral distress in frontline nurses who provide end-of-life care. Improvements in interprofessional collaboration and communication in this challenging area of practice are needed, as supported by research on moral distress and related studies. Policy development that addresses interprofessional practice inclusive of all healthcare providers, particularly frontline nurses, in deliberations about end-of-life treatment deliberations and decisions is proposed. PMID- 26109705 TI - Thoughts About Theories and Statistics. AB - The purpose of this essay is to share my ideas about the connection between theories and statistics. The essay content reflects my concerns about some researchers' and readers' apparent lack of clarity about what constitutes appropriate statistical testing and conclusions about the empirical adequacy of theories. The reciprocal relation between theories and statistics is emphasized and the conclusion is that statistics without direction from theory is no more than a hobby. PMID- 26109709 TI - Comment: Does brain DTI MRI aid diagnosis of battlefield concussion? PMID- 26109710 TI - Ocular fundus photography of patients with focal neurologic deficits in an emergency department. AB - OBJECTIVES: We evaluated the frequency and predictive value of ocular fundus abnormalities among patients who presented to the emergency department (ED) with focal neurologic deficits to determine the utility of these findings in the evaluation of patients with suspected TIA and stroke. METHODS: In this cross sectional pilot study, ocular fundus photographs were obtained using a nonmydriatic fundus camera. Demographic, neuroimaging, and ABCD(2) score components were collected. Photographs were reviewed for retinal microvascular abnormalities. The results were analyzed using univariate statistics and logistic regression modeling. RESULTS: Two hundred fifty-seven patients presented to the ED with focal neurologic deficits, of whom 81 patients (32%) had cerebrovascular disease (CVD) and 144 (56%; 95% confidence interval: 50%-62%) had retinal microvascular abnormalities. Focal and general arteriolar narrowing increased the odds of clinically diagnosed CVD by 5.5 and 2.6 times, respectively, after controlling for the ABCD(2) score and diffusion-weighted imaging. These fundus findings also significantly differentiated TIA from non-CVD, even after controlling for the ABCD(2) score. CONCLUSIONS: Focal and general arteriolar narrowing were independent predictors of CVD overall, and TIA alone, even after controlling for the ABCD(2) score and diffusion-weighted imaging lesions. The inclusion of nonmydriatic ocular fundus photographs in the evaluation of patients presenting to the ED with focal neurologic deficits may assist in the differentiation of stroke and TIA from other causes of focal neurologic deficits. PMID- 26109711 TI - Essentially all models are wrong, but some are useful. PMID- 26109712 TI - Improving early clinical trial phase identification of promising therapeutics. AB - This review addresses decision-making underlying the frequent failure to confirm early-phase positive trial results and how to prioritize which early agents to transition to late phase. While unexpected toxicity is sometimes responsible for late-phase failures, lack of efficacy is also frequently found. In stroke as in other conditions, early trials often demonstrate imbalances in factors influencing outcome. Other issues complicate early trial analysis, including unequally distributed noise inherent in outcome measures and variations in natural history among studies. We contend that statistical approaches to correct for imbalances and noise, while likely valid for homogeneous conditions, appear unable to accommodate disease complexity and have failed to correctly identify effective agents. While blinding and randomization are important to reduce selection bias, these methods appear insufficient to insure valid conclusions. We found potential sources of analytical errors in nearly 90% of a sample of early stroke trials. To address these issues, we recommend changes in early-phase analysis and reporting: (1) restrict use of statistical correction to studies where the underlying assumptions are validated, (2) select dichotomous over continuous outcomes for small samples, (3) consider pooled samples to model natural history to detect early therapeutic signals and increase the likelihood of replication in larger samples, (4) report subgroup baseline conditions, (5) consider post hoc methods to restrict analysis to subjects with an appropriate match, and (6) increase the strength of effect threshold given these cumulative sources of noise and potential errors. More attention to these issues should lead to better decision-making regarding selection of agents to proceed to pivotal trials. PMID- 26109713 TI - Cognitive impairment 18 years before clinical diagnosis of Alzheimer disease dementia. AB - OBJECTIVE: To examine the relation of performance on brief cognitive tests to development of clinically diagnosed Alzheimer disease (AD) dementia over the following 18 years in a sample of African Americans and European Americans. METHODS: A composite cognitive test score based on tests of episodic memory, executive function, and global cognition was constructed in a prospective population-based sample of 2,125 participants (55% African American and 61% female) aged 65 years and older residing in 4 Chicago neighborhoods. Time before AD dementia diagnosis was categorized into 6 groups corresponding to data collection periods: 0.1-0.9, 1.0-3.9, 4.0-6.9, 7.0-9.9, 10.0-12.9, and 13.0-17.9 years. RESULTS: Of 2,125 participants without clinical AD dementia, 442 (21%) developed clinical AD dementia over 18 years of follow-up. Lower composite cognitive test scores were associated with the development of AD dementia over the duration of the study. The magnitude of association between composite cognitive test score and development of AD dementia increased from an odds ratio of 3.39 (95% confidence interval 1.72, 6.67; p < 0.001) at 13.0-17.9 years to 9.84 (95% confidence interval 7.41, 13.06; p < 0.001) at 0.1-0.9 years, per SD increment. These associations were consistently larger among European Americans than among African Americans. Performance on individual cognitive tests of episodic memory, executive function, and global cognition also significantly predicted the development of AD dementia, with associations exhibiting a similar trend over 18 years. CONCLUSIONS: Our findings suggest that cognitive impairment may manifest in the preclinical phase of AD dementia substantially earlier than previously established. PMID- 26109716 TI - Estrogen actions in the nervous system: Complexity and clinical implications. PMID- 26109714 TI - Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. AB - OBJECTIVE: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC). METHODS: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel. RESULTS: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all <5%]). CONCLUSIONS: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC. PMID- 26109715 TI - Clinical and imaging assessment of acute combat mild traumatic brain injury in Afghanistan. AB - OBJECTIVE: To evaluate whether diffusion tensor imaging (DTI) will noninvasively reveal white matter changes not present on conventional MRI in acute blast related mild traumatic brain injury (mTBI) and to determine correlations with clinical measures and recovery. METHODS: Prospective observational study of 95 US military service members with mTBI enrolled within 7 days from injury in Afghanistan and 101 healthy controls. Assessments included Rivermead Post Concussion Symptoms Questionnaire (RPCSQ), Post-Traumatic Stress Disorder Checklist Military (PCLM), Beck Depression Inventory (BDI), Balance Error Scoring System (BESS), Automated Neuropsychological Assessment Metrics (ANAM), conventional MRI, and DTI. RESULTS: Significantly greater impairment was observed in participants with mTBI vs controls: RPCSQ (19.7 +/- 12.9 vs 3.6 +/- 7.1, p < 0.001), PCLM (32 +/- 13.2 vs 20.9 +/- 7.1, p < 0.001), BDI (7.4 +/- 6.8 vs 2.5 +/ 4.9, p < 0.001), and BESS (18.2 +/- 8.4 vs 15.1 +/- 8.3, p = 0.01). The largest effect size in ANAM performance decline was in simple reaction time (mTBI 74.5 +/ 148.4 vs control -11 +/- 46.6 milliseconds, p < 0.001). Fractional anisotropy was significantly reduced in mTBI compared with controls in the right superior longitudinal fasciculus (0.393 +/- 0.022 vs 0.405 +/- 0.023, p < 0.001). No abnormalities were detected with conventional MRI. Time to return to duty correlated with RPCSQ (r = 0.53, p < 0.001), ANAM simple reaction time decline (r = 0.49, p < 0.0001), PCLM (r = 0.47, p < 0.0001), and BDI (r = 0.36 p = 0.0005). CONCLUSIONS: Somatic, behavioral, and cognitive symptoms and performance deficits are substantially elevated in acute blast-related mTBI. Postconcussive symptoms and performance on measures of posttraumatic stress disorder, depression, and neurocognitive performance at initial presentation correlate with return-to-duty time. Although changes in fractional anisotropy are uncommon and subtle, DTI is more sensitive than conventional MRI in imaging white matter integrity in blast related mTBI acutely. PMID- 26109717 TI - Reduced neurofilament expression in cutaneous nerve fibers of patients with CMT2E. AB - OBJECTIVE: To investigate the effects of NEFL Glu396Lys mutation on the expression and assembly of neurofilaments (NFs) in cutaneous nerve fibers of patients with Charcot-Marie-Tooth disease type 2E (CMT2E). METHODS: A large family with CMT2E underwent clinical, electrophysiologic, and skin biopsy studies. Biopsies were processed by indirect immunofluorescence (IF), electron microscopy (EM), and Western blot analysis. RESULTS: The clinical features demonstrated intrafamilial phenotypic variability, and the electrophysiologic findings revealed nerve conductions that were either slow or in the intermediate range. All patients had reduced or absent compound muscular action potential amplitudes. Skin biopsies showed axons labeled with the axonal markers protein gene product 9.5 and alpha-tubulin, but not with NFs. The results of Western blot analysis were consistent with those of IF, showing reduced or absent NFs and normal expression of alpha-tubulin. EM revealed clusters of regenerated fibers, in absence of myelin sheath abnormalities. Both IF and EM failed to show NF aggregates in dermal axons. The morphometric analysis showed a smaller axonal caliber in patients than in controls. The study of the nodal/paranodal architecture demonstrated that sodium channels and Caspr were correctly localized in patients with CMT2E. CONCLUSIONS: Decrease in NF abundance may be a pathologic marker of CMT2E. The lack of NF aggregates, consistent with prior studies, suggests that they occur proximally leading to subsequent alterations in the axonal cytoskeleton. The small axonal caliber, along with the normal molecular architecture of nodes and paranodes, explain the reduced velocities detected in patients with CMT2E. Our results also demonstrate that skin biopsy can provide evidence of pathologic and pathogenic abnormalities in patients with CMT2E. PMID- 26109718 TI - A Dual Role for the Nonreceptor Tyrosine Kinase Pyk2 during the Intracellular Trafficking of Human Papillomavirus 16. AB - The infectious process of human papillomaviruses (HPVs) has been studied considerably, and many cellular components required for viral entry and trafficking continue to be revealed. In this study, we investigated the role of the nonreceptor tyrosine kinase Pyk2 during HPV16 pseudovirion infection of human keratinocytes. We found that Pyk2 is necessary for infection and appears to be involved in the intracellular trafficking of the virus. Small interfering RNA mediated reduction of Pyk2 resulted in a significant decrease in infection but did not prevent viral entry at the plasma membrane. Pyk2 depletion resulted in altered endolysosomal trafficking of HPV16 and accelerated unfolding of the viral capsid. Furthermore, we observed retention of the HPV16 pseudogenome in the trans Golgi network (TGN) in Pyk2-depleted cells, suggesting that the kinase could be required for the viral DNA to exit the TGN. While Pyk2 has previously been shown to function during the entry of enveloped viruses at the plasma membrane, the kinase has not yet been implicated in the intracellular trafficking of a nonenveloped virus such as HPV. Additionally, these data enrich the current literature on Pyk2's function in human keratinocytes. IMPORTANCE: In this study, we investigated the role of the nonreceptor tyrosine kinase Pyk2 during human papillomavirus (HPV) infection of human skin cells. Infections with high-risk types of HPV such as HPV16 are the leading cause of cervical cancer and a major cause of genital and oropharyngeal cancer. As a nonenveloped virus, HPV enters cells by interacting with cellular receptors and established cellular trafficking routes to ensure that the viral DNA reaches the nucleus for productive infection. This study identified Pyk2 as a cellular component required for the intracellular trafficking of HPV16 during infection. Understanding the infectious pathways of HPVs is critical for developing additional preventive therapies. Furthermore, this study advances our knowledge of intracellular trafficking processes in keratinocytes. PMID- 26109719 TI - Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV. AB - Natural-host sooty mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4(+) T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4(+) T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIVsmm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4(+) T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4(+) T cell loss. IMPORTANCE: Natural hosts of SIV, such as sooty mangabeys, sustain high viral loads but do not develop disease, while nonnatural hosts, like rhesus macaques, develop AIDS. Understanding this difference may help elucidate mechanisms of pathogenesis. Natural hosts have very low levels of the SIV entry coreceptor CCR5, suggesting that restricted entry may limit infection of certain target cells, although it is unclear how the virus replicates so robustly. Here we show that in sooty mangabey lymphocytes, infection is mediated by the alternative entry coreceptor CXCR6, as well as CCR5. In rhesus macaque lymphocytes, however, infection occurs entirely through CCR5. The use of CXCR6 for entry, combined with very low CCR5 levels, may redirect the virus to different cell targets in natural hosts. It is possible that differential targeting may favor infection of nonessential cells and limit infection of critical cells in natural hosts, thus contributing to benign outcome of infection. PMID- 26109720 TI - Alfalfa Leaf Curl Virus: an Aphid-Transmitted Geminivirus. AB - The family Geminiviridae comprises seven genera differentiated by genome organization, sequence similarity, and insect vector. Capulavirus, an eighth genus, has been proposed to accommodate two newly discovered highly divergent geminiviruses that presently have no known vector. Alfalfa leaf curl virus, identified here as a third capulavirus, is shown to be transmitted by Aphis craccivora. This is the first report of an aphid-transmitted geminivirus. PMID- 26109721 TI - Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection. AB - Viruses often hijack cellular pathways to facilitate infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus etiologically associated with Kaposi's sarcoma, a vascular tumor of endothelial cells. Despite intensive studies, cellular pathways mediating KSHV infection and replication are still not well defined. Using an antibody array approach, we examined cellular proteins phosphorylated during primary KSHV infection of primary human umbilical vein endothelial cells. Enrichment analysis identified integrin/mitogen-activated protein kinase (integrin/MAPK), insulin/epidermal growth factor receptor (insulin/EGFR), and JAK/STAT as the activated networks during primary KSHV infection. The transcriptional factor CREB1 (cyclic AMP [cAMP]-responsive element-binding protein 1) had the strongest increase in phosphorylation. While knockdown of CREB1 had no effect on KSHV entry and trafficking, it drastically reduced the expression of lytic transcripts and proteins and the production of infectious virions. Chemical activation of CREB1 significantly enhanced viral lytic replication. In contrast, CREB1 neither influenced the expression of the latent gene LANA nor affected KSHV infectivity. Mechanistically, CREB1 was not activated through the classic cAMP/protein kinase A (cAMP/PKA) pathway or via the AKT, MK2, and RSK pathways. Rather, CREB1 was activated by the mitogen- and stress-activated protein kinases 1 and 2 (MSK1/2). Consequently, chemical inhibition or knockdown of MSKs significantly inhibited the KSHV lytic replication program; however, it had a minimal effect on LANA expression and KSHV infectivity. Together, these results identify the MSK1/2 CREB1 proteins as novel essential effectors of KSHV lytic replication during primary infection. The differential effect of the MSK1/2-CREB1 pathway on the expression of viral latent and lytic genes might control the robustness of viral lytic replication, and therefore the KSHV replication program, during primary infection. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. Through genome-wide kinase screening, we found that KSHV activates the MSK1/2-CREB1 pathway during primary infection and that it depends on this pathway for viral lytic replication. Inhibition of this pathway blocks KSHV lytic replication. These results illustrate a mechanism by which KSHV hijacks a cellular pathway for its replication, and they identify a potential therapeutic target. PMID- 26109722 TI - Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach. AB - Our earlier studies with pig-tailed macaques demonstrated various simian-human immunodeficiency virus (SHIV) susceptibilities during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to human immunodeficiency type 1 (HIV-1) acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine and cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute-phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, and integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins or genes might work in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCE: HIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues during the menstrual cycle were studied. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low-progesterone periods, we found more HIV inhibitory factors. This study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies. PMID- 26109723 TI - A Screen for Extracellular Signal-Regulated Kinase-Primed Glycogen Synthase Kinase 3 Substrates Identifies the p53 Inhibitor iASPP. AB - The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein is essential for the replication and maintenance of virus genomes in latently KSHV-infected cells. LANA also drives dysregulated cell growth through a multiplicity of mechanisms that include altering the activity of the cellular kinases extracellular signal regulated kinase (ERK) and glycogen synthase kinase 3 (GSK-3). To investigate the potential impact of these changes in enzyme activity, we used protein microarrays to identify cell proteins that were phosphorylated by the combination of ERK and GSK-3. The assays identified 58 potential ERK-primed GSK-3 substrates, of which 23 had evidence for in vivo phosphorylation in mass spectrometry databases. Two of these, SMAD4 and iASPP, were selected for further analysis and were confirmed as ERK-primed GSK-3 substrates. Cotransfection experiments revealed that iASPP, but not SMAD4, was targeted for degradation in the presence of GSK-3. iASPP interferes with apoptosis induced by p53 family members. To determine the importance of iASPP to KSHV-infected-cell growth, primary effusion lymphoma (PEL) cells were treated with an iASPP inhibitor in the presence or absence of the MDM2 inhibitor Nutlin-3. Drug inhibition of iASPP activity induced apoptosis in BC3 and BCBL1 PEL cells but did not induce poly(ADP-ribose) polymerase (PARP) cleavage in virus-negative BJAB cells. The effect of iASPP inhibition was additive with that of Nutlin-3. Interfering with iASPP function is therefore another mechanism that can sensitize KSHV-positive PEL cells to cell death. IMPORTANCE: KSHV is associated with several malignancies, including primary effusion lymphoma (PEL). The KSHV-encoded LANA protein is multifunctional and promotes both cell growth and resistance to cell death. LANA is known to activate ERK and limit the activity of another kinase, GSK-3. To discover ways in which LANA manipulation of these two kinases might impact PEL cell survival, we screened a human protein microarray for ERK-primed GSK-3 substrates. One of the proteins identified, iASPP, showed reduced levels in the presence of GSK-3. Further, blocking iASPP activity increased cell death, particularly in p53 wild type BC3 PEL cells. PMID- 26109725 TI - The Great (Nuclear) Escape: New Insights into the Role of the Nuclear Egress Complex of Herpesviruses. AB - Herpesviruses are unusual among enveloped viruses because they bud twice yet acquire a single envelope. They are also the only known viruses that bud into the nuclear envelope. We discovered that the herpesvirus nuclear egress complex could bud membranes without the help of other proteins by forming a coat-like hexagonal scaffold inside the budding membrane. This finding raises the possibility that a phenotypically similar nuclear export of large RNAs is cargo driven. PMID- 26109724 TI - Expected Effect of Deleterious Mutations on Within-Host Adaptation of Pathogens. AB - Adaptation is a common theme in both pathogen emergence, for example, in zoonotic cross-species transmission, and pathogen control, where adaptation might limit the effect of the immune response and antiviral treatment. When such evolution requires deleterious intermediate mutations, fitness ridges and valleys arise in the pathogen's fitness landscape. The effect of deleterious intermediate mutations on within-host pathogen adaptation is examined with deterministic calculations, appropriate for pathogens replicating in large populations with high error rates. The effect of deleterious intermediate mutations on pathogen adaptation is smaller than their name might suggest: when two mutations are required and each individual single mutation is fully deleterious, the pathogen can jump across the fitness valley by obtaining two mutations at once, leading to a proportion of adapted mutants that is 20-fold lower than that in the situation where the fitness of all mutants is neutral. The negative effects of deleterious intermediates are typically substantially smaller and outweighed by the fitness advantages of the adapted mutant. Moreover, requiring a specific mutation order has a substantially smaller effect on pathogen adaptation than the effect of all intermediates being deleterious. These results can be rationalized when the number of routes of mutation available to the pathogen is calculated, providing a simple approach to estimate the effect of deleterious mutations. The calculations discussed here are applicable when the effect of deleterious mutations on the within-host adaptation of pathogens is assessed, for example, in the context of zoonotic emergence, antigenic escape, and drug resistance. IMPORTANCE: Adaptation is critical for pathogens after zoonotic transmission into a new host species or to achieve antigenic immune escape and drug resistance. Using a deterministic approach, the effects of deleterious intermediate mutations on pathogen adaptation were calculated while avoiding commonly made simplifications that do not apply to large pathogen populations replicating with high mutation rates. Perhaps unexpectedly, pathogen adaptation does not halt when the intermediate mutations are fully deleterious. The negative effects of deleterious mutations are substantially outweighed by the fitness gains of adaptation. To gain an understanding of the effect of deleterious mutations on pathogen adaptation, a simple approach that counts the number of routes available to the pathogen with and without deleterious intermediate mutations is introduced. This methodology enables a straightforward calculation of the proportion of the pathogen population that will cross a fitness valley or traverse a fitness ridge, without reverting to more complicated mathematical models. PMID- 26109726 TI - Superoxide-Generating Nox5alpha Is Functionally Required for the Human T-Cell Leukemia Virus Type 1-Induced Cell Transformation Phenotype. AB - Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and transforms T cells in vitro. To our knowledge, the functional role of reactive oxygen species (ROS)-generating NADPH oxidase 5 (Nox5) in HTLV-1 transformation remains undefined. Here, we found that Nox5alpha expression was upregulated in 88% of 17 ATL patient samples but not in normal peripheral blood T cells. Upregulation of the Nox5alpha variant was transcriptionally sustained by the constitutive Janus family tyrosine kinase (Jak)-STAT5 signaling pathway in interleukin-2 (IL-2)-independent HTLV-1-transformed cell lines, including MT1 and MT2, whereas it was transiently induced by the IL-2-triggered Jak-STAT5 axis in uninfected T cells. A Nox inhibitor, diphenylene iodonium, and antioxidants such as N-acetyl cysteine blocked proliferation of MT1 and MT2 cells. Ablation of Nox5alpha by small interfering RNAs abrogated ROS production, inhibited cellular activities, including proliferation, migration, and survival, and suppressed tumorigenicity in immunodeficient NOG mice. The findings suggest that Nox5alpha is a key molecule for redox-signal-mediated maintenance of the HTLV-1 transformation phenotype and could be a potential molecular target for therapeutic intervention in cancer development. IMPORTANCE: HTLV-1 is the first human oncogenic retrovirus shown to be associated with ATL. Despite the extensive study over the years, the mechanism underlying HTLV-1-induced cell transformation is not fully understood. In this study, we addressed the expression and function of ROS-generating Nox family genes in HTLV-1-transformed cells. Our report provides the first evidence that the upregulated expression of Nox5alpha is associated with the pathological state of ATL peripheral blood mononuclear cells and that Nox5alpha is an integral component of the Jak-STAT5 signaling pathway in HTLV-1-transformed T cells. Nox5alpha-derived ROS are critically involved in the regulation of cellular activities, including proliferation, migration, survival, and tumorigenicity, in HTLV-1-transformed cells. These results indicate that Nox5alpha-derived ROS are functionally required for maintenance of the HTLV-1 transformation phenotype. The finding provides new insight into the redox dependent mechanism of HTLV-1 transformation and raises an intriguing possibility that Nox5alpha serves as a potential molecular target to treat HTLV-1-related leukemia. PMID- 26109727 TI - HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses. AB - HIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n = 24) (DC-HIV-1) or nonpulsed DCs (n = 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10 to 1.9 copies/10(6) CD4 T cells, P = 0.22) and did increase in controls (mean of 1.8 log10 to 2.1 copies/10(6) CD4 T cells, P = 0.02) (P = 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r [Pearson's correlation coefficient] = -0.69, P = 0.002, and r = -0.82, P < 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.) IMPORTANCE: There is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection. PMID- 26109728 TI - Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL. AB - The V3 region of HIV-1 gp120 is important for virus-coreceptor interaction and highly immunogenic. Although most anti-V3 antibodies neutralize only the sensitive tier 1 viruses, anti-V3 antibodies effective against the more resistant viruses exist, and a better understanding of these antibodies and their epitopes would be beneficial for the development of novel vaccine immunogens against HIV. The HIV-1 isolate JRFL with its cryptic V3 is resistant to most V3-specific monoclonal antibodies (MAbs). However, the V3 MAb 2424 achieves 100% neutralization against JRFL. 2424 is encoded by IGHV3-53 and IGLV2-28 genes, a pairing rarely used by the other V3 MAbs. 2424 also has distinct binding and neutralization profiles. Studies of 2424-mediated neutralization of JRFL produced with a mannosidase inhibitor further revealed that its neutralizing activity is unaffected by the glycan composition of the virus envelope. To understand the distinct activity of 2424, we determined the crystal structure of 2424 Fab in complex with a JRFL V3 peptide and showed that the 2424 epitope is located at the tip of the V3 crown ((307)IHIGPGRAFYT(319)), dominated by interactions with His(P308), Pro(P313), and Arg(P315). The binding mode of 2424 is similar to that of the well-characterized MAb 447-52D, although 2424 is more side chain dependent. The 2424 epitope is focused on the very apex of V3, away from nearby glycans, facilitating antibody access. This feature distinguishes the 2424 epitope from the other V3 crown epitopes and indicates that the tip of V3 is a potential site to target and incorporate into HIV vaccine immunogens. IMPORTANCE: HIV/AIDS vaccines are crucial for controlling the HIV epidemics that continue to afflict millions of people worldwide. However, HIV vaccine development has been hampered by significant scientific challenges, one of which is the inability of HIV vaccine candidates evaluated thus far to elicit production of potent and broadly neutralizing antibodies. The V3 loop is one of the few immunogenic targets on the virus envelope glycoprotein that can induce neutralizing antibodies, but in many viruses, parts of V3 are inaccessible for antibody recognition. This study examined a V3-specific monoclonal antibody that can completely neutralize HIV-1 JRFL, a virus isolate resistant to most V3 antibodies. Our data reveal that this antibody recognizes the most distal tip of V3, which is not as occluded as other parts of V3. Hence, the epitope of 2424 is in one of the vulnerable sites on the virus that may be exploited in designing HIV vaccine immunogens. PMID- 26109729 TI - Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific. AB - Herpes simplex virus 1 (HSV-1) and HSV-2 infect many humans and establish a latent infection in sensory ganglia. Although some infected people suffer periodic recurrences, others do not. Infected people mount both cell-mediated and humoral responses, including the production of virus-neutralizing antibodies (Abs) directed at viral entry glycoproteins. Previously, we examined IgGs from 10 HSV-seropositive individuals; all neutralized virus and were directed primarily against gD or gD+gB. Here, we expand our studies and examine 32 additional sera from HSV-infected individuals, 23 of whom had no recurrent disease. Using an Octet RED96 system, we screened all 32 serum samples directly for both glycoprotein binding and competition with known neutralizing anti-gD and -gB monoclonal Abs (MAbs). On average, the recurrent cohort exhibited higher binding to gD and gB and had higher neutralization titers. There were similar trends in the blocking of MAbs to critical gD and gB epitopes. When we depleted six sera of Abs to specific glycoproteins, we found different types of responses, but always directed primarily at gD and/or gB. Interestingly, in one dual-infected person, the neutralizing response to HSV-2 was due to gD2 and gB2, whereas HSV-1 neutralization was due to gD1 and gB1. In another case, virus neutralization was HSV-1 specific, with the Ab response directed entirely at gB1, despite this serum blocking type-common anti-gD and -gB neutralizing MAbs. These data are pertinent in the design of future HSV vaccines since they demonstrate the importance of both serotypes of gD and gB as immunogens. IMPORTANCE: We previously showed that people infected with HSV produce neutralizing Abs directed against gD or a combination of gD+gB (and in one case, gD+gB+gC, which was HSV-1 specific). In this more extensive study, we again found that gD or gD+gB can account for the virus neutralizing response and critical epitopes of one or both of these proteins are represented in sera of naturally infected humans. However, we also found that some individuals produced a strong response against gB alone. In addition, we identified type-specific contributions to HSV neutralization from both gD and gB. Contributions from the other entry glycoproteins, gC and gH/gL, were minimal and limited to HSV-1 neutralization. Knowing the variations in how humans see and mount a response to HSV will be important to vaccine development. PMID- 26109730 TI - Tetherin Sensitivity of Influenza A Viruses Is Strain Specific: Role of Hemagglutinin and Neuraminidase. AB - The expression of the antiviral host cell factor tetherin is induced by interferon and can inhibit the release of enveloped viruses from infected cells. The Vpu protein of HIV-1 antagonizes the antiviral activity of tetherin, and tetherin antagonists with Vpu-like activity have been identified in other viruses. In contrast, it is incompletely understood whether tetherin inhibits influenza A virus (FLUAV) release and whether FLUAV encodes tetherin antagonists. Here, we show that release of several laboratory-adapted FLUAV strains and a seasonal FLUAV strain is inhibited by tetherin, while pandemic FLUAV A/Hamburg/4/2009 is resistant. Studies with a virus-like particle system and analysis of reassortant viruses provided evidence that the viral hemagglutinin (HA) is an important determinant of tetherin antagonism but requires the presence of its cognate neuraminidase (NA) to inhibit tetherin. Finally, tetherin antagonism by FLUAV was dependent on the virion context, since retrovirus release from tetherin-positive cells was not rescued, and correlated with an HA- and NA dependent reduction in tetherin expression. In sum, our study identifies HA and NA proteins of certain pandemic FLUAV as tetherin antagonists, which has important implications for understanding FLUAV pathogenesis. IMPORTANCE: Influenza A virus (FLUAV) infection is responsible for substantial global morbidity and mortality, and understanding how the virus evades the immune defenses of the host may uncover novel targets for antiviral intervention. Tetherin is an antiviral effector molecule of the innate immune system which can contribute to control of viral invasion. However, it has been unclear whether FLUAV is inhibited by tetherin and whether these viruses encode tetherin antagonizing proteins. Our observation that several pandemic FLUAV strains can counteract tetherin via their HA and NA proteins identifies these proteins as novel tetherin antagonists and indicates that HA/NA-dependent inactivation of innate defenses may contribute to the efficient spread of pandemic FLUAV. PMID- 26109731 TI - HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry. AB - During HIV-1 infection of cells, the viral capsid plays critical roles in reverse transcription and nuclear entry of the virus. The capsid-targeting small molecule PF74 inhibits HIV-1 at early stages of infection. HIV-1 resistance to PF74 is complex, requiring multiple amino acid substitutions in the viral CA protein. Here we report the identification and analysis of a novel PF74-resistant mutant encoding amino acid changes in both domains of CA, three of which are near the pocket where PF74 binds. Interestingly, the mutant virus retained partial PF74 binding, and its replication was stimulated by the compound. The mutant capsid structure was not significantly perturbed by binding of PF74; rather, the mutations inhibited capsid interactions with CPSF6 and Nup153 and altered HIV-1 dependence on these host factors and on TNPO3. Moreover, the replication of the mutant virus was markedly impaired in activated primary CD4(+) T cells and macrophages. Our results suggest that HIV-1 escapes a capsid-targeting small molecule inhibitor by altering the virus's dependence on host factors normally required for entry into the nucleus. They further imply that clinical resistance to inhibitors targeting the PF74 binding pocket is likely to be strongly limited by functional constraints on HIV-1 evolution. IMPORTANCE: The HIV-1 capsid plays critical roles in early steps of infection and is an attractive target for therapy. Here we show that selection for resistance to a capsid-targeting small molecule inhibitor can result in viral dependence on the compound. The mutant virus was debilitated in primary T cells and macrophages--cellular targets of infection in vivo. The mutations also altered the virus's dependence on cellular factors that are normally required for HIV-1 entry into the nucleus. This work provides new information regarding mechanisms of HIV-1 resistance that should be useful in efforts to develop clinically useful drugs targeting the HIV-1 capsid. PMID- 26109732 TI - The Interferon-Inducible Protein Tetherin Inhibits Hepatitis B Virus Virion Secretion. AB - Interferon alpha (IFN-alpha) is an approved medication for chronic hepatitis B therapy. Besides acting as an immunomodulator, IFN-alpha elicits a pleiotropic antiviral state in hepatitis B virus (HBV)-infected hepatocytes, but whether or not IFN-alpha impedes the late steps of the HBV life cycle, such as HBV secretion, remains elusive. Here we report that IFN-alpha treatment of HepAD38 cells with established HBV replication selectively reduced HBV virion release without altering intracellular viral replication or the secretion of HBV subviral particles and nonenveloped capsids. In search of the interferon-stimulated gene(s) that is responsible for the reduction of HBV virion release, we found that tetherin, a broad-spectrum antiviral transmembrane protein that inhibits the egress of a variety of enveloped viruses, was highly induced by IFN-alpha in HepAD38 cells and in primary human hepatocytes. We further demonstrated that the expression of full-length tetherin, but not the C-terminal glycosylphosphatidylinositol (GPI) anchor-truncated form, inhibited HBV virion egress from HepAD38 cells. In addition, GPI anchor-truncated tetherin exhibited a dominant-negative effect and was incorporated into the liberated virions. We also found colocalization of tetherin and HBV L protein at the intracellular multivesicular body, where the budding of HBV virions takes place. In line with this, electron microscopy demonstrated that HBV virions were tethered in the lumen of the cisterna membrane under tetherin expression. Finally, knockdown of tetherin or overexpression of dominant negative tetherin attenuated the IFN-alpha mediated reduction of HBV virion release. Taken together, our study suggests that IFN-alpha inhibits HBV virion egress from hepatocytes through the induction of tetherin. IMPORTANCE: Tetherin is a host restriction factor that blocks the egress of a variety of enveloped viruses through tethering the budding virions on the cell surface with its membrane anchor domains. Here we report that interferon directly and selectively inhibits the secretion of HBV virions, but not subviral particles or nonenveloped capsids, through the induction of tetherin in hepatocyte-derived cells. The antiviral function of tetherin requires the carboxyl-terminal GPI anchor, while the GPI anchor deletion mutant exhibits dominant negative activity and attaches to liberated HBV virions. Consistent with the fact that HBV is an intracellular budding virus, microscopy analyses demonstrated that the tethering of HBV virions occurs in the intracellular cisterna and that tetherin colocalizes with HBV virions on the multivesicular body, which is the HBV virion budding site. Our study not only expands the antiviral spectrum of tetherin but also sheds light on the mechanisms of interferon-elicited anti-HBV responses. PMID- 26109734 TI - Impaired Epstein-Barr Virus-Specific Neutralizing Antibody Response during Acute Infectious Mononucleosis Is Coincident with Global B-Cell Dysfunction. AB - Here we present evidence for previously unappreciated B-cell immune dysregulation during acute Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). Longitudinal analyses revealed that patients with acute IM have undetectable EBV specific neutralizing antibodies and gp350-specific B-cell responses, which were associated with a significant reduction in memory B cells and no evidence of circulating antibody-secreting cells. These observations correlate with dysregulation of tumor necrosis factor family members BAFF and APRIL and increased expression of FAS on circulating B cells. PMID- 26109735 TI - Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. PMID- 26109733 TI - Serotonin Receptor Agonist 5-Nonyloxytryptamine Alters the Kinetics of Reovirus Cell Entry. AB - Mammalian orthoreoviruses (reoviruses) are nonenveloped double-stranded RNA viruses that infect most mammalian species, including humans. Reovirus binds to cell surface glycans, junctional adhesion molecule A (JAM-A), and the Nogo-1 receptor (depending on the cell type) and enters cells by receptor-mediated endocytosis. Within the endocytic compartment, reovirus undergoes stepwise disassembly, which is followed by release of the transcriptionally active viral core into the cytoplasm. In a small-molecule screen to identify host mediators of reovirus infection, we found that treatment of cells with 5-nonyloxytryptamine (5 NT), a prototype serotonin receptor agonist, diminished reovirus cytotoxicity. 5 NT also blocked reovirus infection. In contrast, treatment of cells with methiothepin mesylate, a serotonin antagonist, enhanced infection by reovirus. 5 NT did not alter cell surface expression of JAM-A or attachment of reovirus to cells. However, 5-NT altered the distribution of early endosomes with a concomitant impairment of reovirus transit to late endosomes and a delay in reovirus disassembly. Consistent with an inhibition of viral disassembly, 5-NT treatment did not alter infection by in vitro-generated infectious subvirion particles, which bind to JAM-A but bypass a requirement for proteolytic uncoating in endosomes to infect cells. We also found that treatment of cells with 5-NT decreased the infectivity of alphavirus chikungunya virus and coronavirus mouse hepatitis virus. These data suggest that serotonin receptor signaling influences cellular activities that regulate entry of diverse virus families and provides a new, potentially broad-spectrum target for antiviral drug development. IMPORTANCE: Identification of well-characterized small molecules that modulate viral infection can accelerate development of antiviral therapeutics while also providing new tools to increase our understanding of the cellular processes that underlie virus-mediated cell injury. We conducted a small-molecule screen to identify compounds capable of inhibiting cytotoxicity caused by reovirus, a prototype double-stranded RNA virus. We found that 5-nonyloxytryptamine (5-NT) impairs reovirus infection by altering viral transport during cell entry. Remarkably, 5-NT also inhibits infection by an alphavirus and a coronavirus. The antiviral properties of 5-NT suggest that serotonin receptor signaling is an important regulator of infection by diverse virus families and illuminate a potential new drug target. PMID- 26109736 TI - Recommendations for the management of autoinflammatory diseases. AB - : Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with >=80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD. PMID- 26109737 TI - ABCA1 and Inflammation: From Animal Models to Humans. PMID- 26109738 TI - Making "Waves" With a Murine Model of Aortic Insufficiency. PMID- 26109739 TI - Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins. AB - OBJECTIVE: We previously demonstrated that subjects with functional ATP-binding cassette (ABC) A1 mutations have increased atherosclerosis, which has been attributed to the role of ABCA1 in reverse cholesterol transport. More recently, a proinflammatory effect of Abca1 deficiency was shown in mice, potentially contributing to atherogenesis. In this study, we investigated whether ABCA1 deficiency was associated with proinflammatory changes in humans. APPROACH AND RESULTS: Thirty-one heterozygous, 5 homozygous ABCA1 mutation carriers, and 21 matched controls were studied. (18)Fluorodeoxyglucose positron emission tomography with computed tomographic scanning was performed in a subset of carriers and controls to assess arterial wall inflammation (target:background ratio). Heterozygous ABCA1 mutation carriers had a 20% higher target:background ratio than in controls (target:background ratio; P=0.008). In carriers using statins (n=7), target:background ratio was 21% reduced than in nonstatin users (n=7; P=0.03). We then measured plasma cytokine levels. Tumor necrosis factor alpha, monocyte chemoattractant protein-1, and interleukin-6 levels were increased in heterozygous and homozygous ABCA1 mutation carriers. We isolated monocytes from carriers and controls and measured inflammatory gene expression. Only TNFalpha mRNA was increased in monocytes from heterozygous ABCA1 mutation carriers. Additional studies in THP-1 macrophages showed that both ABCA1 deficiency and lipoprotein-deficient plasma from ABCA1 mutation carriers increased inflammatory gene expression. CONCLUSIONS: Our data suggest a proinflammatory state in ABCA1 mutation carriers as reflected by an increased positron emission tomography-MRI signal in nonstatin using subjects, and increased circulating cytokines. The increased inflammation in ABCA1 mutation carriers seems to be attenuated by statins. PMID- 26109741 TI - Correction. PMID- 26109740 TI - Platelets: Context-Dependent Vascular Protectors or Mediators of Disease. PMID- 26109743 TI - Hydrogen-Bonding Interactions Trigger a Spin-Flip in Iron(III) Porphyrin Complexes. AB - A key step in cytochrome P450 catalysis includes the spin-state crossing from low spin to high spin upon substrate binding and subsequent reduction of the heme. Clearly, a weak perturbation in P450 enzymes triggers a spin-state crossing. However, the origin of the process whereby enzymes reorganize their active site through external perturbations, such as hydrogen bonding, is still poorly understood. We have thus studied the impact of hydrogen-bonding interactions on the electronic structure of a five-coordinate iron(III) octaethyltetraarylporphyrin chloride. The spin state of the metal was found to switch reversibly between high (S=5/2) and intermediate spin (S=3/2) with hydrogen bonding. Our study highlights the possible effects and importance of hydrogen-bonding interactions in heme proteins. This is the first example of a synthetic iron(III) complex that can reversibly change its spin state between a high and an intermediate state through weak external perturbations. PMID- 26109744 TI - Tree Growth and Climate Relationship: Dynamics of Scots Pine (Pinus Sylvestris L.) Growing in the Near-Source Region of the Combined Heat and Power Plant During the Development of the Pro-Ecological Strategy in Poland. AB - Since the 1990s, the emission of pollutants was reduced in a majority of Polish and developing country factories whereas the level of energy production was similar to that prior to the 1990s. The conifer investigated in this study has grown for many years under the stress of industrial pollution. Despite this, the trees are preserved, to a large extent, sensitive to the natural climatic factors. We present a complex analysis of the climatic (sunshine, temperature, precipitation, humidity, and wind circulation) and anthropogenic factors influencing the radial increment dynamics of Scots pine (Pinus sylvestris L.) growing in the vicinity of the combined heat and power station in Laziska (Poland). We analyzed the spatiotemporal distribution of growth reductions, the depth of reduction with respect to the distance from the emitter, the relationship between tree growth and climate during the industry development period and during proecological strategy application . Samples of carbon isotopic composition in pine needles from 2012 to 2013 were additionally determined. Pines series of 3 positions indicate that they have a similar sensitivity to most climatic elements of the previous and given year, but there is also a different rhythm between the studied populations of incremental growth of pines. The causes of diversity are due to the different types of habitat (site types) and industrial pollution. The variation in carbon stable isotopic composition in pine needles was connected with an increase of CO2. PMID- 26109742 TI - Photodynamic therapy-induced angiogenic signaling: consequences and solutions to improve therapeutic response. AB - Photodynamic therapy (PDT) can be a highly effective treatment for diseases ranging from actinic keratosis to cancer. While use of this therapy shows great promise in preclinical and clinical studies, understanding the molecular consequences of PDT is critical to designing better treatment protocols. A number of publications have documented alteration in angiogenic factors and growth factor receptors following PDT, which could abrogate treatment effect by inducing angiogenesis and re-establishment of the tumor vasculature. In response to these findings, work over the past decade has examined the efficacy of combining PDT with molecular targeting drugs, such as anti-angiogenic compounds, in an effort to combat these PDT-induced molecular changes. These combinatorial approaches increase rates of apoptosis, impair pro-tumorigenic signaling, and enhance tumor response. This report will examine the current understanding of PDT-induced angiogenic signaling and address molecular-based approaches to abrogate this signaling or its consequences thereby enhancing PDT efficacy. PMID- 26109745 TI - Size and Shape Analysis of Error-Prone Shape Data. AB - We consider the problem of comparing sizes and shapes of objects when landmark data are prone to measurement error. We show that naive implementation of ordinary Procrustes analysis that ignores measurement error can compromise inference. To account for measurement error, we propose the conditional score method for matching configurations, which guarantees consistent inference under mild model assumptions. The effects of measurement error on inference from naive Procrustes analysis and the performance of the proposed method are illustrated via simulation and application in three real data examples. Supplementary materials for this article are available online. PMID- 26109746 TI - Efficient Adaptive Randomization and Stopping Rules in Multi-arm Clinical Trials for Testing a New Treatment. AB - Motivated by applications to confirmatory clinical trials for testing a new treatment against a placebo or active control when the new treatment has k possible treatment strategies (arms)-for example, k possible doses for a new drug we develop an asymptotic theory for efficient outcome-adaptive randomization schemes and optimal stopping rules. Our approach consists of developing asymptotic lower bounds for the expected sample sizes from the k treatment arms and the control arm and using generalized sequential likelihood ratio procedures to achieve these bounds. Implementation details of our design and analysis and comparative simulation studies are also provided. PMID- 26109748 TI - Circular test structure for the determination of piezoelectric constants of Sc x Al1-x N thin films applying Laser Doppler Vibrometry and FEM simulations. AB - Piezoelectric scandium aluminium nitride (Sc x Al1-x N) thin films offer a large potential for the application in micro electromechanical systems, as advantageous properties of pure AlN thin films are maintained, but combined with an increased piezoelectric actuation and sensing potential. Sc x Al1-x N thin films with x = 27% have been prepared by DC reactive magnetron sputtering to find optimized deposition parameters to maximize the piezoelectric constants d33 and d31. For the accurate and simultaneous measurement of these constants Laser Doppler Vibrometry has been applied and compared to finite element (FEM) simulations. The electrode design has been optimized to rotational symmetric structures enabling a 180 degrees phase shifted excitation, so that a straight-forward comparison of experimental displacement curves with those obtained from FEM is feasible. PMID- 26109747 TI - Biogenic nano-magnetite and nano-zero valent iron treatment of alkaline Cr(VI) leachate and chromite ore processing residue. AB - Highly reactive nano-scale biogenic magnetite (BnM), synthesized by the Fe(III) reducing bacterium Geobacter sulfurreducens, was tested for the potential to remediate alkaline Cr(VI) contaminated waters associated with chromite ore processing residue (COPR). The performance of this biomaterial, targeting aqueous Cr(VI) removal, was compared to a synthetic alternative, nano-scale zero valent iron (nZVI). Samples of highly contaminated alkaline groundwater and COPR solid waste were obtained from a contaminated site in Glasgow, UK. During batch reactivity tests, Cr(VI) removal from groundwater was inhibited by ~25% (BnM) and ~50% (nZVI) when compared to the treatment of less chemically complex model pH 12 Cr(VI) solutions. In both the model Cr(VI) solutions and contaminated groundwater experiments the surface of the nanoparticles became passivated, preventing complete coupling of their available electrons to Cr(VI) reduction. To investigate this process, the surfaces of the reacted samples were analyzed by TEM-EDX, XAS and XPS, confirming Cr(VI) reduction to the less soluble Cr(III) on the nanoparticle surface. In groundwater reacted samples the presence of Ca, Si and S was also noted on the surface of the nanoparticles, and is likely responsible for earlier onset of passivation. Treatment of the solid COPR material in contact with water, by addition of increasing weight % of the nanoparticles, resulted in a decrease in aqueous Cr(VI) concentrations to below detection limits, via the addition of ?5% w/w BnM or ?1% w/w nZVI. XANES analysis of the Cr K edge, showed that the % Cr(VI) in the COPR dropped from 26% to a minimum of 4-7% by the addition of 5% w/w BnM or 2% w/w nZVI, with higher additions unable to reduce the remaining Cr(VI). The treated materials exhibited minimal re-mobilization of soluble Cr(VI) by re-equilibration with atmospheric oxygen, with the bulk of the Cr remaining in the solid fraction. Both nanoparticles exhibited a considerable capacity for the remediation of COPR related Cr(VI) contamination, with the synthetic nZVI demonstrating greater reactivity than the BnM. However, the biosynthesized BnM was also capable of significant Cr(VI) reduction and demonstrated a greater efficiency for the coupling of its electrons towards Cr(VI) reduction than the nZVI. PMID- 26109749 TI - Impact of biotic and a-biotic parameters on structure and function of microbial communities living on sclerotia of the soil-borne pathogenic fungus Rhizoctonia solani. AB - The plant pathogen Rhizoctonia solani is very difficult to control due to its persistent, long-living sclerotial structures in soil. Sclerotia are the main source of infection for Rhizoctonia diseases, which cause high yield losses on a broad host range world-wide. Little is known about micro-organisms associated with sclerotia in soil. Therefore, microbial communities of greenhouse and field incubated Rhizoctonia sclerotia were analysed by a multiphasic approach. Using microbial fingerprints performed by PCR-SSCP, sclerotia-associated bacterial communities showed a high diversity, whereas only a few fungi could be detected. Statistical analysis of fingerprints revealed the influence of soil types, incubation conditions (greenhouse, field), and incubation time (5 and 12 weeks) on the bacterial as well as fungal community. No significant differences were found for the microbial community associated with different Rhizoctonia anastomosis sub-groups (AG 1-IB and AG 1-IC). Rhizoctonia sclerotia are an interesting bio-resource: high proportions of fungal cell-wall degrading isolates as well as those with antagonistic activity towards R. solani were found. While a fraction of 28.4% of sclerotia-associated bacteria (=40 isolates) with antagonistic properties was determined, only 4.4% (=6 isolates) of the fungal isolates were antagonistic. We identified strong antagonists of the genera Bacillus, Enterobacter, Pseudomonas, and Stenotrophomonas, which can be used as biological control agents incorporated in soil or applied to Rhizoctonia host plants. PMID- 26109750 TI - Potential of genetically modified oilseed rape for biofuels in Austria: Land use patterns and coexistence constraints could decrease domestic feedstock production. AB - Like other EU Member States, Austria will meet the substitution target of the EU European Renewable Energy Directive for transportation almost exclusively by first generation biofuels, primarily biodiesel from oilseed rape (OSR). Genetically modified (GM) plants have been promoted as a new option for biofuel production as they promise higher yield or higher quality feedstock. We tested implications of GM OSR application for biodiesel production in Austria by means of high resolution spatially explicit simulation of 140 different coexistence scenarios within six main OSR cropping regions in Austria (2400 km2). We identified structural land use characteristics such as field size, land use diversity, land holding patterns and the proportion of the target crop as the predominant factors which influence overall production of OSR in a coexistence scenario. Assuming isolation distances of 800 m and non-GM-OSR proportions of at least 10% resulted in a loss of area for cultivation of OSR in all study areas ranging from -4.5% to more than -25%, depending on the percentage of GM farmers and on the region. We could show that particularly the current primary OSR cropping regions are largely unsuitable for coexistence and would suffer from a net loss of OSR area even at isolation distances of 400 or 800 m. Coexistence constraints associated with application of GM OSR are likely to offset possible GM gains by substantially reducing farmland for OSR cultivation, thus contradicting the political aim to increase domestic OSR area to meet the combined demands of food, feed and biofuel production. PMID- 26109751 TI - 'Energy landscapes': Meeting energy demands and human aspirations. AB - Renewable energy will play a crucial role in the future society of the 21st century. The various renewable energy sources need to be balanced and their use carefully planned since they are characterized by high temporal and spatial variability that will pose challenges to maintaining a well balanced supply and to the stability of the grid. This article examines the ways that future 'energy landscapes' can be modelled in time and space. Biomass needs a great deal of space per unit of energy produced but it is an energy carrier that may be strategically useful in circumstances where other renewable energy carriers are likely to deliver less. A critical question considered in this article is whether a massive expansion in the use of biomass will allow us to construct future scenarios while repositioning the 'energy landscape' as an object of study. A second important issue is the utilization of heat from biomass energy plants. Biomass energy also has a larger spatial footprint than other carriers such as, for example, solar energy. This article seeks to provide a bridge between energy modelling and spatial planning while integrating research and techniques in energy modelling with Geographic Information Science. This encompasses GIS, remote sensing, spatial disaggregation techniques and geovisualization. Several case studies in Austria and Germany demonstrate a top-down methodology and some results while stepwise calculating potentials from theoretical to technically feasible potentials and setting the scene for the definition of economic potentials based on scenarios and assumptions. PMID- 26109752 TI - Development of an estimation model for the evaluation of the energy requirement of dilute acid pretreatments of biomass. AB - This study aims to develop a mathematical model to evaluate the energy required by pretreatment processes used in the production of second generation ethanol. A dilute acid pretreatment process reported by National Renewable Energy Laboratory (NREL) was selected as an example for the model's development. The energy demand of the pretreatment process was evaluated by considering the change of internal energy of the substances, the reaction energy, the heat lost and the work done to/by the system based on a number of simplifying assumptions. Sensitivity analyses were performed on the solid loading rate, temperature, acid concentration and water evaporation rate. The results from the sensitivity analyses established that the solids loading rate had the most significant impact on the energy demand. The model was then verified with data from the NREL benchmark process. Application of this model on other dilute acid pretreatment processes reported in the literature illustrated that although similar sugar yields were reported by several studies, the energy required by the different pretreatments varied significantly. PMID- 26109753 TI - Cytotoxic glucosphingolipid from Celtis Africana. AB - BACKGROUND: Literature survey proved the use of the powdered sun-dried bark and roots of Celtis africana for the treatment of cancer in South Africa. OBJECTIVE: The aim of this study was to do further isolation work on the ethyl acetate fraction and to investigate the cytotoxic activities of the various fractions and isolated compound. MATERIALS AND METHODS: Cytotoxicity of petroleum ether, chloroform, ethyl acetate, n-butanol fractions and compound 1 were tested on mouse lymphoma cell line L5178Y using the microculture tetrazolium assay. RESULTS: One new glucosphingolipid 1 was isolated from the aerial parts of C. africana. The structure of the new compound was determined by extensive analysis by one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy and mass spectrometry. The ethyl acetate fraction and compound 1 showed strong cytotoxic activity with an EC50 value of 8.3 MUg/mL and 7.8 MUg/mL, respectively, compared with Kahalalide F positive control (6.3 MUg/mL). CONCLUSION: This is the first report of the occurrence of a cytotoxic glucosphingolipid in family Ulmaceae. PMID- 26109754 TI - Flavonoid profile, antioxidant and cytotoxic activity of different extracts from Algerian Rhamnus alaternus L. bark. AB - BACKGROUND: Rhamnus alaternus (Rhamnaceae) L. has been traditionally used for treatment of many diseases. OBJECTIVE: In this study, we determined the antioxidant/free radical scavenger properties, the flavonoid profile and the cytotoxicity of aqueous and methanolic extracts obtained by maceration from Algerian R. alaternus bark, like also of aqueous extract prepared by decoction according to the traditional method. This to estimate the usefulness of the drug traditional preparation and compare it with those made in the laboratory. MATERIALS AND METHODS: The antioxidant activity of the extracts was evaluated using five different redox-based assays, all involving one redox reaction with the oxidant. High-performance liquid chromatography/diode array detection/electrospray ionization mass spectrometry analysis was used to identify and quantify the flavonoids content. Cytotoxicity on human monocytic leukemia cells (U937) was also carried out. RESULTS: All the extracts tested showed a good antioxidant/free radical scavenger activity and a similar flavonoid fingerprint. However, the methanolic one presented the best antioxidant activity that can be due to the highest flavonoid amount and significantly reduced the proliferation of leukemia cells. The results confirm that the extract prepared by decoction contains efficient antioxidant compounds and this justifies in part the therapeutic and preventive usefulness. Moreover, the methanolic extract exerted excellent cytotoxicity on U937 that could be attributed to kaempferol and rhamnocitrin glycosides. PMID- 26109755 TI - Inhibitory potential of some Romanian medicinal plants against enzymes linked to neurodegenerative diseases and their antioxidant activity. AB - CONTEXT: Eryngium planum, Geum urbanum and Cnicus benedictus plants are an endemic botanical from the Romanian used in folk medicine. OBJECTIVE: The extracts from three Romanian medicinal plants were investigated for their possible neuroprotective potential. MATERIALS AND METHODS: Within this study, in vitro neuroprotective activity of the extracts of E. planum, G. urbanum, and C. benedictus plants were investigated via inhibition of acetylcholinesterase (AChE) and tyrosinase (TYR). Total content of phenolics, flavonoids, and proanthocyanidins, high-performance liquid chromatography profile of the main phenolic compounds and antioxidant activity were also determined. RESULTS: Among the tested extracts, the best inhibition of AChE (88.76 +/- 5.2%) and TYR (88.5 +/- 5.2%) was caused by C. benedictus ethanol (EtOH) extract. The G. urbanum extracts exerted remarkable scavenging effect against 2, 2-diphenyl-1 picrylhydrazyl (IC50, 7.8 +/- 0.5 MUg/mL aqueous extract, and IC50, 1.3 +/- 0.1 MUg/mL EtOH extract, respectively) and reducing power, whereas the EtOH extract of C. benedictus showed high scavenging activity (IC50, 0.609 +/- 0.04 mg/mL), also. CONCLUSION: According to our knowledge, this is the first study that demonstrates in vitro neuroprotective effects of E. planum, G. urbanum and C. benedictus. PMID- 26109756 TI - Experimental treatment of breast cancer-bearing BALB/c mice by artemisinin and transferrin-loaded magnetic nanoliposomes. AB - BACKGROUND: The combination of artemisinin and transferrin exhibits versatile anticancer activities. In previous, we successfully prepared artemisinin and transferrin-loaded magnetic nanoliposomes and evaluated their anti-proliferative activity against MCF-7 and MDA-MB-231 cell lines in vitro. In this study, we investigate the in vivo anti-breast cancer activity of artemisinin and transferrin-loaded magnetic nanoliposome against breast transplanted tumors in BALB/c mice model. MATERIALS AND METHODS: Artemisinin and transferrin-loaded magnetic nanoliposomes were prepared and characterized for some physiochemical properties. Pieces of tumor tissue from the breast cancer-bearing BALB/c mice were transplanted subcutaneously to the syngeneic female BALB/c mice. In the presence of the external magnet that placed at the breast tumor site, the tissue distribution and tumor-suppressing effects of prepared nanoliposomes on tumor growth was evaluated. RESULTS: The prepared nanoliposomes have fine spherical shape, rough surface, nano-sized diameter and magnetic properties. At 2 h after treatment, the intravenous administration of artemisinin and transferrin-loaded magnetic nanoliposomes followed using the magnetic field approximately produced 10- and 5.5-fold higher levels of artemisinin and transferrin in the tumors, respectively, compared with free artemisinin and transferrin. Moreover, in the presence of an external magnetic field, the prepared nanoliposomes could significantly induce apoptosis in the mice breast cancer cells as well as could reduce tumor volume in tumorized mice at 15 days after treatment. CONCLUSION: The data suggested that the artemisinin and transferrin-loaded magnetic nanoliposomes would be a good choice for the breast tumor-targeted therapy, due to its high targeting efficiency. PMID- 26109757 TI - In silico analysis and molecular docking studies of potential angiotensin converting enzyme inhibitor using quercetin glycosides. AB - The purpose of this study was to analyze the inhibitory action of quercetin glycosides by computational docking studies. For this, natural metabolite quercetin glycosides isolated from buckwheat and onions were used as ligand for molecular interaction. The crystallographic structure of molecular target angiotensin-converting enzyme (ACE) (peptidyl-dipeptidase A) was obtained from PDB database (PDB ID: 1O86). Enalapril, a well-known brand of ACE inhibitor was taken as the standard for comparative analysis. Computational docking analysis was performed using PyRx, AutoDock Vina option based on scoring functions. The quercetin showed optimum binding affinity with a molecular target (angiotensin converting-enzyme) with the binding energy of -8.5 kcal/mol as compared to the standard (-7.0 kcal/mol). These results indicated that quercetin glycosides could be one of the potential ligands to treat hypertension, myocardial infarction, and congestive heart failure. PMID- 26109758 TI - Development and extraction optimization of baicalein and pinostrobin from Scutellaria violacea through response surface methodology. AB - OBJECTIVE: To develop a process that involves optimization of the amount of baicalein and pinostrobin from the hydro-methanolic extract of the leaves of Scutellaria violacea by response surface methodology (RSM). MATERIALS AND METHODS: The combinatorial influence of various extraction parameters on the extraction yield was investigated by adopting Box-Behnken experimental design. Preliminary experiments carried out based on the traditional one variable at a time optimization revealed four such operational parameters to play a crucial role by influencing the yield. These four process parameters at three levels were considered to obtain the Box-Behnken experimental design. RESULTS: RSM based model fitted to the resulting experimental data suggested that 52.3% methanol/water, 12.46:1 solvent-solid ratio, 285 rpm agitation and 6.07 h of extraction time are the optimal conditions which yielded a maximized amount of baicalein and pinostrobin of 2.9 and 4.05 mg/g DM. Analysis of variance revealed a high correlation coefficient (R (2) = 0.999 for baicalein and 0.994 for pinostrobin), signifying a good fit between the regression model (second order) and the experimental observations. CONCLUSION: The present study signifies that both the metabolites have been extracted from S. violacea for the first time. Further, this study developed an optimized extraction procedure to obtain maximum yield of the metabolites, which is unique and better than conventional extraction methodology. The operational parameters under optimized conditions accounts for the lowest cost in extraction process thus, providing an efficient, rapid and cost-effective method for isolation and scale up of these commercially vital flavonoids. PMID- 26109759 TI - Methanol extract of wheatgrass induces G1 cell cycle arrest in a p53-dependent manner and down regulates the expression of cyclin D1 in human laryngeal cancer cells-an in vitro and in silico approach. AB - BACKGROUND: Deregs been implicated in the malignancy of cancer. Since many years investigation on the traditional herbs has been the focus to develop novel and effective drug for cancer remedies. Wheatgrass is a medicinal plant, used in folk medicine to cure various diseases. The present study was undertaken to gain insights into antiproliferative effect of methanol extract of wheatgrass. MATERIALS METHODS: Cell viability was assessed via 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide and Lactate Dehydrogenase assays. Cell cycle was analyzed by flow cytometry. Western blot was performed to determine the p53 and cyclin D1 levels. In silico docking interaction of the 14 active components (identified by high-performance liquid chromatography/gas chromatography-mass spectroscopy) of the methanol extract was tested with cyclin D1 (Protein Data Bank ID: 2W96) and compared with the reference cyclin D1/Cdk4 inhibitor. RESULTS: Methanol extract of wheatgrass effectively reduced the cell viability. The cell cycle analysis showed that the extract treatment caused G1 arrest. The level of cyclin D1 was decreased, whereas p53 level was increased. Molecular docking studies revealed interaction of seven active compounds of the extract with the vital residues (Lys112/Glu141) of cyclin D1. CONCLUSION: These findings indicate that the methanol extract of wheatgrass inhibits human laryngeal cancer cell proliferation via cell cycle G1 arrest and p53 induction. The seven active compounds of the extract were also found to be directly involved in the inhibition of cyclin D1/Cdk4 binding, thus inhibiting the cell proliferation. PMID- 26109760 TI - The dose dependent in vitro responses of MCF-7 and MDA-MB-231 cell lines to extracts of Vatica diospyroides symington type SS fruit include effects on mode of cell death. AB - BACKGROUND: Vatica diospyroides type LS is a known source of valuable compounds for cancer treatment, however, in contrast little is known about therapeutic efficacy of type SS. OBJECTIVE: This study focused on in vitro cytotoxicity of these fruit extracts, and the cell death mode they induce in breast cancer cells. MATERIALS AND METHODS: Acetone extracts of fruit were tested for cytotoxicity against MCF-7 and MDA-MB-231 cell lines. The apoptosis and necrosis of these cells were quantified by fluorescence activated cell sorter (FACS) and western blot analyses. RESULTS: After 72 h of treatment, the 50% growth inhibition concentrations (IC50) levels were 16.21 +/- 0.13 ug/mL against MCF-7 and 30.0 +/- 4.30 ug/mL against MDA-MB-231, indicating high and moderate cytotoxicity, respectively. From the FACS results, we estimate that the cotyledon extract at half IC50 produced 11.7% dead MCF-7 cells via apoptosis, whereas another concentrations both apoptosis and necrosis modes co-existed in a dose-dependent manner. In MDA-MB-231 cell line, only the apoptosis was induced by the pericarp extract in a dose-dependent manner. With the extracts at half IC50 concentration, in both cells, the expression of p21 decreased while that of Bax increased within 12-48 h of dosing, confirming apoptosis induced by time-dependent responses. Apoptosis dependent on p53 was found in MCF-7, whereas the mutant p53 of MDA-MB 231 cells was expressed. CONCLUSION: The results indicate that fruit extracts of V. diospyroides have cytotoxic effects against MCF-7 and MDA-MB-231 cells via apoptosis pathway in a dose-dependent manner. This suggests that the extracts could provide active ingredients for the development, targeting breast cancer therapy. PMID- 26109761 TI - Cytotoxic activity of Macrosolen parasiticus (L.) Danser on the growth of breast cancer cell line (MCF-7). AB - BACKGROUND: Macrosolen parasiticus (L.) Danser belonging to Loranthaceaea (mistletoe family) is a parasitic plant that grows on different host plants such as mango, jack fruit, peepal, neem tree, etc., This study was aimed to investigate the anti-cancer activity of methanolic and aqueous extract of stem of M. parasiticus. OBJECTIVES: To investigate the in vitro cytotoxic potential of the methanolic and aqueous extracts from stems of M. parasiticus against MCF-7 breast cancer cells by brine shrimp lethality (BSL) bioassay, MTT assay and sulforhodamine B (SRB) assay. MATERIALS AND METHODS: The extracts were tested in human breast cancer cell lines in vitro for percentage cytotoxicity, apoptosis by acridine orange/ethidium bromide staining, LD50 and IC50 values after treatment with M. parasiticus extracts. RESULTS: In BSL bioassay, aqueous extract showed more significant (P < 0.01) cytotoxicity with LD50 82.79 +/- 2.67 MUg/mL as compared to methanolic extract with LD50 125 +/- 3.04 MUg/mL. The methanolic extract of M. parasiticus showed IC50 97.33 +/- 3.75 MUg/mL (MTT) (P < 0.05) and 94.58 +/- 3.84 MUg/mL (SRB) (P < 0.01) assays against MCF-7. The aqueous extract of M. parasiticus demonstrated higher activity with IC50 59.33 +/- 3.3 MUg/mL (MTT) (P < 0.01) and 51.9 +/- 1.87 MUg/mL (SRB)(P < 0.01) assays, after 48 h of exposure and thus showed significant dose-dependent cytotoxic activity. CONCLUSION: The finding demonstrated that both extracts of M. parasiticus showed significant cytotoxic activity, however aqueous extract demonstrated higher activity against MCF-7 breast cancer cells. PMID- 26109762 TI - Effects of the extract and glycoalkaloids of Solanum lycocarpum St. Hill on Giardia lamblia trophozoites. AB - BACKGROUND: Solanum lycocarpum has great importance for food and medicinal traditional use. Recently, it was also evidenced that extracts of S. lycocarpum St. Hill (Solanaceae) and its glycoalkaloids, solamargine (Sg) and solasonine (Sn), are active against flagellated protozoa. OBJECTIVE: The aim was to assess the effects of the extract of S. lycocarpum and its glycoalkaloids, Sn, and Sg, on Giardia lamblia trophozoites. MATERIALS AND METHODS: A crude extract (96%ethanol) (EB) of fruits of S. lycocarpum was prepared and fractionated by partition with 40%ethanol and n-hexane: Ethyl acetate. Glycoalkaloids, Sn, and Sg were recognized in the ethanol fraction (EF) and further isolated by column chromatography. EB, EF, the isolated Sn and Sg and a mixture (1:1) of both glycoalkaloids were tested on cultures of G. lamblia trophozoites and macrophages. RESULTS: EB, EF and glycoalkaloids of S. lycocarpum showed activity against Giardia (95.0 < Inhibitory concentration 50 [IC50] <=120.3 MUg/mL). The mixture of glycoalkaloids (1:1) was more active (IC50 = 13.23 MUg/mL) than each one individually, suggesting a synergic effect. Moreover, the mixture is nontoxic to macrophage cells. CONCLUSION: Results are optimistic concerning the anti Giardia potential of the mixture Sn + Sg. Further studies, in vitro and in vivo, will be required to consolidate the usefulness of the mixture of Sn + Sg in view of a new therapeutic strategy for giardiasis. PMID- 26109763 TI - Development of response surface methodology for optimization of extraction parameters and quantitative estimation of embelin from Embelia ribes Burm by high performance liquid chromatography. AB - BACKGROUND: Embelia ribes Burm is widely used medicinal plant for the treatment of different types of disorders in the Indian traditional systems of medicine. OBJECTIVE: The present work was aimed to optimize the extraction parameters of embelin from E. ribes fruits and also to quantify embelin content in different extracts of the plant. MATERIALS AND METHODS: Optimization of extraction parameters such as solvent: drug ratio, temperature and time were carried out by response surface methodology (RSM). Quantitative estimation of embelin in different extracts of E. ribes fruits was done through high performance liquid chromatography. RESULTS: The optimal conditions determined for extraction of embelin through RSM were; extraction time (27.50 min), extraction temperature 45 degrees C and solvent: drug ratio (8:1). Under the optimized conditions, the embelin yield (32.71%) was equitable to the expected yield (31.07%, P > 0.05). These results showed that the developed model is satisfactory and suitable for the extraction process of embelin. The analysis of variance showed a high goodness of model fit and the accomplishment of the RSM method for improving embelin extraction from the fruits of E. ribes. CONCLUSION: It is concluded that this may be a useful method for the extraction and quantitative estimation of embelin from the fruits of E. ribes. PMID- 26109764 TI - Hepatorenal protective effect of Antistax((r)) against chemically-induced toxicity. AB - BACKGROUND: Antioxidant natural products and chemoprevention are considered nowadays as an effective approach against health various disorders and diseases induced by oxidative stress or free radicals. OBJECTIVE: The aim of this study was to assess the hepato- and nephroprotective activity of a standardized red vine leaf aqueous extract AS195 (Antistax((r))). METHODS: The protective activity of AS195 (100 mg/kg) was investigated on carbon tetrachloride (CCl4)-intoxicated rats in comparison with silymarin. The flavonoid/proanthocyanidin nature of AS195 was identified by phytochemical and nuclear magnetic resonance (NMR) analyses, while its total phenol/proanthocyanidin/flavonoid content and antioxidant activity were determined by Folin-Ciocalteau, vanillin-sulfuric acid, AlCl3, and 2, 2-diphenyl-2-picrylhydrazyl radical scavenging assays, respectively. RESULTS: Relative to the control CCl4 -intoxicated group, pretreatment with AS195 could significantly suppressed the elevated serum levels of alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, triglycerides, bilirubin, creatinine, uric acid, and calcium, whereas it significantly increased the diminished serum levels of high-density lipoprotein cholesterol, albumin and total protein. Moreover, AS195 significantly decreased malondialdehyde formation in the tissues of liver and kidney, whereas it significantly elevated and nonprotein sulfhydryl groups, compared with the intoxicated control. The improvement in biochemical parameters by AS195 was obviously observed and further confirmed by restoration of normal histological features in the two organs. CONCLUSIONS: The results of the present study revealed the capacity of AS195 to enhance the recovery from xenobiotic-induced hepatorenal toxicity initiated by free radicals. PMID- 26109765 TI - Neuroprotective effects of Nigella sativa extracts during germination on central nervous system. AB - BACKGROUND: Nigella sativa Linn. which has many acclaimed medicinal properties is an indigenous herbaceous plant and belongs to the Ranunculaceae family, which grows in countries bordering the Mediterranean Sea, Pakistan and India. OBJECTIVE: This study was designed to investigate the effects of N. sativa seed extracts of different germination phases on the central nervous system (CNS) responses in experimental animals. MATERIALS AND METHODS: Anxiolytic, locomotor activity of extracts (1 g/kg of body weight) was evaluated in both stressed and unstressed animal models and antiepileptic effect was evaluated by maximal electroshock seizure model keeping diazepam (20 mg/kg) as a positive control. Antidepressant effect was evaluated by forced swim test and tail suspension test keeping imipramine (15 mg/kg) as a positive control. RESULTS: All tested extracts of N. sativa during different phases of germination (especially 5(th) day germination phase) showed significant (P < 0.001) anxiolytic effect in comparison to control. Diazepam reduced locomotor activity in control (unstressed) rats but did not show affect in stressed rats while N. sativa extracts from germination phases significantly (P < 0.001) reduced locomotor activity in unstressed as well as stressed animals. All the extracts of N. sativa from different germination phases exhibited significant (P < 0.001) reduction in various phases of epileptic seizure on comparison with the reference standard (diazepam). During antidepressant test, N. sativa extracts exhibited a slight reduction in the immobility of rats. CONCLUSION: During germination, especially in 5(th) day germination extract, N. sativa showed significant CNS depressant activity as compared to whole seeds that possibly may be due higher content of secondary metabolites produced during germination. PMID- 26109766 TI - Pharmacophore modeling, in silico screening, molecular docking and molecular dynamics approaches for potential alpha-delta bungarotoxin-4 inhibitors discovery. AB - BACKGROUND: The alpha-delta bungartoxin-4 (alpha-delta-Bgt-4) is a potent neurotoxin produced by highly venomous snake species, Bungarus caeruleus, mainly targeting neuronal acetylcholine receptors (nAchRs) and producing adverse biological malfunctions leading to respiratory paralysis and mortality. OBJECTIVE: In this study, we predicted the three-dimensional structure of alpha delta-Bgt-4 using homology modeling and investigated the conformational changes and the key residues responsible for nAchRs inhibiting activity. MATERIALS AND METHODS: From the selected plants, which are traditionally used for snake bites, the active compounds are taken and performed molecular interaction studies and also used for modern techniques like pharmacophore modeling and mapping and absorption, distribution, metabolism, elimination and toxicity analysis which may increase the possibility of success. RESULTS: Moreover, 100's of drug-like compounds were retrieved and analyzed through computational virtual screening and allowed for pharmacokinetic profiling, molecular docking and dynamics simulation. CONCLUSION: Finally the top five drug-like compounds having competing level of inhibition toward alpha-delta-Bgt-4 toxin were suggested based on their interaction with alpha-delta-Bgt-4 toxin. PMID- 26109767 TI - The potential of selected Australian medicinal plants with anti-Proteus activity for the treatment and prevention of rheumatoid arthritis. AB - BACKGROUND: A wide variety of herbal medicines are used in indigenous Australian traditional medicinal systems to treat rheumatoid arthritis (RA) and inflammation. The current study was undertaken to test the ability of a panel of Australian plants with a history of the ethnobotanical usage in the treatment of inflammation for the ability to block the microbial trigger of RA. MATERIALS AND METHODS: One hundred and six extracts from 40 plant species were investigated for the ability to inhibit the growth of the bacterial trigger of RA (Proteus mirabilis). The extracts were tested for toxicity in the Artemia nauplii bioassay. The most potent inhibitor of P. mirabilis growth was further analyzed by reversed-phase high performance liquid chromatography (RP-HPLC) coupled to high accuracy time-of-flight (TOF) mass spectroscopy. RESULTS: Sixty-five of the 106 extracts tested (61.3%) inhibited the growth of P. The Aleurites moluccanus, Datura leichardtii, Eucalyptus major, Leptospermum bracteata, L. juniperium, Macadamia integriflora nut, Melaleuca alternifolia, Melaleuca quinquenervia, Petalostigma pubescens, P. triloculorae, P. augustifolium, Scaevola spinescens, Syzygium australe, and Tasmannia lanceolata extracts were determined to be the most effective inhibitors of P. mirabilis growth, with minimum inhibitory concentration (MIC) values generally significantly below 1000 MUg/ml. T. lanceolata fruit extracts were the most effective P. mirabilis growth inhibitors, with a MIC values of 11 and 126 MUg/ml for the methanolic and aqueous extracts, respectively. Subsequent analysis of the T. lanceolata fruit extracts by RP-HPLC coupled to high-resolution TOF mass spectroscopy failed to detect resveratrol in either T. lanceolata fruit extract. However, the resveratrol glycoside piceid and 2 combretastatin stilbenes (A-1 and A-4) were detected in both T. lanceolata fruit extracts. With the exception of the Eucalyptus and Syzygium extracts, all extracts exhibiting Proteus inhibitory activity were also shown to be nontoxic, or of low toxicity in the Artemia nauplii bioassay. CONCLUSIONS: The low toxicity of these extracts and their inhibitory bioactivity against Proteus spp. indicate their potential in blocking the onset of rheumatoid arthritis. PMID- 26109768 TI - Protective role of Kalpaamruthaa in type II diabetes mellitus-induced cardiovascular disease through the modulation of protease-activated receptor-1. AB - BACKGROUND: Kalpaamruthaa (KA) is a formulatory herbal preparation has beneficial antioxidant, anti-apoptotic and anti-inflammatory properties against cardiovascular damage (CVD). OBJECTIVE: The present study was undertaken to investigate the protective role of KA in type II diabetes mellitus-induced CVD through the modulation of protease-activated receptor-1 (PAR1). MATERIALS AND METHODS: CVD was developed in 8 weeks after type II diabetes mellitus induction with high fat diet (2 weeks) and low dose of streptozotocin (2 * 35 mg/kg b.w. i.p. in 24 h interval). CVD-induced rats treated with KA (200 mg/kg b.w. in 0.5 ml of olive oil) orally for 4 weeks. RESULTS: KA increased the activities of enzymatic antioxidants and the levels of non-enzymatic antioxidants in pancreas of CVD-induced rats. KA effectively reduced the lipid peroxides and carbonyl content in the pancreas of CVD-induced rats. KA reduced cellular damage by ameliorating the activities of marker enzymes in plasma, heart and liver. The protective nature of KA was further evidenced by histological observation in pancreas. Further, KA reduced CVD by decreasing the expression of PAR1 in heart. CONCLUSION: This study exhibits the defending role of KA in type II diabetes mellitus-induced CVD through altering PAR1. PMID- 26109769 TI - Pharmacological and phytochemical evaluation of Ocimum sanctum root extracts for its antiinflammatory, analgesic and antipyretic activities. AB - BACKGROUND: Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases risk of having a range of gastrointestinal problems. Therefore, new anti-inflammatory, analgesic, antipyretic drugs having lesser side effects are being searched all overthe world as alternatives to NSAIDs. AIMS: To evaluate the anti-inflammatory, analgesic and antipyretic profile of Ocimum sanctum root extracts. MATERIALS AND METHODS: Anti-inflammatory profile of hexane (STH), chloroform (STC), ethyl acetate (STE), butanol (STB) and water (STW) extracts of OS was carried out by using carrageenan induced paw edema. STE a most active extract was further validated in dose dependent manner for anti-inflammatory, analgesic and antipyretic activity as well as oral toxicity profile in small laboratory animals. Identification of bioactives flux and chemical signature of most active fraction STE was developed by using the high-performance liquid chromatography fingerprinting. RESULTS: An ethyl acetate fraction (STE) exhibit most potent anti-inflammatory activity followed by STB, STW, STC and STH. Dose response study of STE showed anti-inflammatory, analgesic and anti-pyretic potential in dose-dependent manner without any toxic effect at dose 2000 mg/kg. Chemical fingerprint revealed the presence of flavanoids. CONCLUSIONS: The present research revealed that STE possess anti-inflammatory, analgesic and anti pyretic properties. However, future research is advocated to evaluate the pharmacological properties of isolated bioactive compounds. PMID- 26109770 TI - Phytoecdysteroids of the East Asian Caryophyllaceae. AB - BACKGROUND: Occurrence of integristerone A (1), 20-hydroxyecdysone (2), ecdysone (3), 2-deoxy-20-hydroxyecdysone (4) has been analyzed in 64 species of the East Asian Caryophyllaceae. MATERIALS AND METHODS: Ecdysteroid content was determinate by high-performance liquid chromatography (HPLC). HPLC with a high-resolution mass spectrometry was performed on Shimadzu LCMS-IT-TOF (Japan) system equipped with a LC-20A Prominence liquid chromatograph, a photodiode array detector SPD M20A and ion-trap/time-of-flight mass spectrometer. RESULTS: New sources of phytoecdysteroids: Melandrium sachalinense and Melandrium firmum have been revealed. It is the 1(st) time that two has been identified in M. sachalinense and M. firmum; 1 in the species: Lychnis fulgens, Silene repens, Silene foliosa, Silene stenophylla, Silene jenisseensis and M. sachalinense; 3 in Lychnis cognata; 4 in L. fulgens, S. stenophylla and S. jenisseensis (the tribe Lychnideae, the subfamily Caryophylloideae). Ecdysteroid-negative taxa are Spergularia rubra of the tribe Sperguleae; species of the genera Minuartia, Honckenya, Eremogone, Arenaria, Moehringia, Pseudostellaria, Fimbripetalum, Stellaria and Cerastium of the tribe Alsineae; Scleranthus annuus of the tribe Sclerantheae, as well as the East Asian representatives of the genera Gypsophila, Psammophiliela, Dianthus and Saponaria of the tribe Diantheae; Oberna and Agrostemma of the tribe Lychnideae. CONCLUSION: This investigation shows the most promising sources of ecdysteriods are species of genera Silene and Lychnis. PMID- 26109771 TI - Antimutagenic potential of harpagoside and Harpagophytum procumbens against 1 nitropyrene. AB - BACKGROUND: 1-nitropyrene (1-NPy) is one of the most abundant nitro-polycyclic aromatic hydrocarbons particularly in diesel exhausts. It is a mutagenic and carcinogenic pollutant very widespread in the environment. So the discovery of antimutagenic agents is essential. Harpagophytum procumbens (HP) is traditionally used as anti-inflammatory and analgesic particularly against painful osteoarthritis. Harpagoside (HS), its major iridoid glycoside, is considered as the main active component. OBJECTIVE: The aim of the present study was to evaluate the antimutagenic activity of HS and HP extracts against mutagenic activity of 1-NPy. MATERIALS AND METHODS: The antimutagenic activity was investigated using the in vitro cytokinesis-block micronucleus assay in cultured human lymphocytes. Cells were exposed to HS or HP extracts before (pretreatment), during (co-treatment), and after (posttreatment) treatment with 1-NPy. RESULTS: Results showed that HS significantly reduced the mutagenicity of 1-NPy in pretreatment and particularly in co-treatment, whereas all HP extracts significantly reduced the genotoxicity in the three protocols. CONCLUSION: These results suggested that HS was strongly involved in antimutagenic activity of HP extracts in co-treatment, but other components in HP extracts participated in this activity in pre- and post-treatment. PMID- 26109772 TI - Cytotoxic and apoptotic effects of Ebenus boissieri Barbey on human lung cancer cell line A549. AB - BACKGROUND: Fabaceae family members are known to possess preventive and therapeutic potentials against various types of cancers. OBJECTIVE: The aim of this study was to investigate the cytotoxic and apoptotic effects of hydroalcoholic extracts from the aerial parts and roots of an endemic Ebenus species; Ebenus boissieri Barbey in human lung cancer cell line. MATERIALS AND METHODS: After treatment with hydroalcoholic extracts cytotoxic activities of both extracts were measured by 3-(4,5-dimethylthiazolyl-2)-2,5 diphenyltetrazolium bromide assay, whereas caspase-3 activity, tumor necrosis factor-a lpha (TNF-alpha) and interferon gamma (IFN-gamma) releasewere measured by enzyme linked immunosorbent assay. RESULTS: According to in vitro assay results, the increase in all caspases activity suggested that extracts induce cells to undergo apoptosis. Especially, induction in caspase-3 activity was the most remarkable result of this study. Both aerial part and root extracts induced apoptosis by increasing caspase-3 activity, TNF-alpha and IFN-gamma release. When compared to their relative controls, the concentrations of both TNF-alpha and IFN gamma in extract-treated groups were significantly and dose dependently exalted. CONCLUSION: Taken together, our results indicate that the hydroalcoholic extracts of E. boissieri can be considered as a source of new anti-apoptotic and therefore anti-carcinogenic agent. PMID- 26109773 TI - Antiproliferative efficacy of Tabernaemontana divaricata against HEP2 cell line and Vero cell line. AB - BACKGROUND: Laryngeal cancer may also be called cancer of the larynx or laryngeal carcinoma. Conventional plants are a precious source of novel anticancer agents and are still in performance better role in health concern. The study was intended to estimation of the anticancer activity of the chloroformic extract of Tabernaemontana divaricata on the human epidermoid larynx carcinoma cell line (Hep 2). MATERIALS AND METHOD: The aerial parts (leaves, stem, and flowers) of T. divaricata were tested for its inhibitory effect in 96 microplate formats against Hep 2 cell line. The anticancer activity of samples on Hep 2 and Vero was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and various enzymatic parameters like catalase, reduced glutathione (GSH), GSH peroxidase, and superoxide anion scavenging activity. Viable cells were determined by the absorbance at 540 nm. Measurements were performed, and the concentration required for a 50% inhibition of viability (IC50) was determined graphically. The effect of the samples on the proliferation of Hep 2 and Vero cells was expressed as the % cell viability. RESULTS: The extract on Hep 2 cell line up to 7.8 MUg/ml and that IC50 value on Hep 2 cell line was 112 MUg whereas 94 MUg for Vero cell line. Hence, T. divaricata has lesser significant action on Vero cell line. CONCLUSION: Medicinal plant drug discovery continues to provide new and important leads against various pharmacological targets including cancer. Our results clearly indicate the anticancer property of the medicinal plant T. divaricata against the human laryngeal carcinoma cell lines (Hep 2 cell line). PMID- 26109774 TI - Assay method for quality control and stability studies of a new anti-diabetic and anti-dyslipidemic flavone (S002-853). AB - BACKGROUND: Flavonoid-rich extract of the plant is long known for its anti diabetic activities in traditional medicine. S002-853, a new flavone derivative synthesized by Central Drug Research Institute (CDRI) has been used for the present study. OBJECTIVES: The present study aimed at development of an assay method for quality control (QC) and stability studies of a new anti-diabetic and anti-dyslipidemic agent CDRI compound S002-853. MATERIALS AND METHODS: A validated high-performance liquid chromatography analysis method for S002-853 was developed for in process QC and stability studies. The separation was achieved on a RP-C18 (25 cm * 0.4 cm, 5 MUm, Phenomenex) at 240 nm with flow rate of 1.0 ml/min. This method was applied successfully in establishing forced degradation and drug-excipient testing protocols as per International Conference on Harmonization guidelines. RESULTS: The result of estimation and stress testing studies indicated a high degree of selectivity of this method. S002-853 was most stable at pH 7 and under photolytic conditions. The temperature degradation pattern of S002-853 was found to follow the zero order degradation. CONCLUSION: The method described is easy and simple hence can be easily reproduced. This method can be very useful for bulk manufacture QC, and drug development process. PMID- 26109775 TI - Cytotoxicity of some edible mushrooms extracts over liver hepatocellular carcinoma cells in conjunction with their antioxidant and antibacterial properties. AB - BACKGROUND: Mushrooms have been valued for their nutritive content and as traditional medicines; several important medicinal properties of mushrooms have been recognized worldwide. OBJECTIVE: The purpose of this study was to elucidate the cell growth inhibitory potential of four edible mushrooms; Coprinus comatus (O.F. Mull.) Pers. (Agaricaceae), Tricholoma fracticum (Britzelm.) Kreisel (Tricholomataceae), Rhizopogon luteolus Fr. and Nordholm (Rhizopogonaceae), Lentinus tigrinus (Bull.) Fr. (Polyporaceae) on hepatocellular carcinoma (HepG2) cells in conjunction with their antioxidant and antibacterial capacities. MATERIALS AND METHODS: Five different extracts of edible mushrooms were obtained using water, methanol, acetone, n-hexane and chloroform as solvent systems for cytotoxic, antioxidant and antibacterial properties. RESULTS: C. comatus showed substantial in vitro cytotoxic activity against HepG2 cell lines with all extracts especially with chloroform 50% inhibition (IC50 value of 0.086 mg/ml) and acetone (IC50 value of 0.420 mg/ml). Chloroform extract of C. comatus had maximum amount of beta-carotene (25.94 MUg/mg), total phenolic content (76.32 MUg/mg) and lycopene (12.00 MUg/mg), and n-hexane extract of L. tigrinus had maximum amount of flavonoid (3.67 MUg/mg). While chloroform extract of C. comatus showed the highest 2, 2-diphenyl-1-picrylhydrazyl (DPPH) capturing activity (1.579 mg/ml), the best result for metal chelating activity was obtained from methanolic extract (0.842 mg/ml). Moreover, all tested mushrooms demonstrated antibacterial activity and n-hexane extract of L. tigrinus and acetone extracts of T. fracticum were the most active against tested microorganism. CONCLUSION: These results indicate that different extracts of investigated mushroom have considerable cytotoxic, antioxidant and antibacterial properties and may be utilized as a promising source of therapeutics. PMID- 26109776 TI - Use of bergenin as an analytical marker for standardization of the polyherbal formulation containing Saxifraga ligulata. AB - BACKGROUND: Bergenin is the principle constituent of the well-known medicinal plant Saxifraga ligulata. Bergenin has anti-inflammatory, antipyretic, antiviral, immunostimulant, antihyperglycemic, and antioxidant properties. In this study, the presence of bergenin in Saxifraga ligulata and the formulations was identified using high performance thin layer chromatograpy fingerprinting technique. OBJECTIVE: To develop a novel quantitative method for the estimation of bergenin using high performance liquid chromatography. MATERIALS AND METHODS: The compound was separated, characterised and quantified using authentic reference standard. The method was validated per ICH guidelines for the parameters of accuracy, precision, linearity, limit of detection, limit of quantification and robustness. RESULTS: The method was found to be accurate, linear (r2 = 0.998) and precise (%RSD <2%). The limits of detection (0.001%) and quantification (0.002%) were found to be suitable for detection and quantification of bergenin in commercial formulations. CONCLUSION: The developed methods are suitable for the quality control applications of Saxifraga ligulata containing formulations. PMID- 26109777 TI - A novel high-performance liquid chromatography-electron spray ionization-mass spectrometry method for simultaneous determination of guggulsterones, piperine and gallic acid in Triphala guggulu. AB - "Triphalaguggulu" is an important Ayurvedic formulation comprising of Guggulu, that is, Commiphora wightii (Arn.) Bhandari as a base wherein powdered fruits of triphala, that is, Phyllanthus emblica L., Terminalia bellirica (Gaertn.) Roxb and Terminalia chebula Retz, along with powdered fruit of Piper longum L. are compounded. This polyherbal preparation has been strongly recommended in chronic inflammation, piles, and fistula. However, due to the complexity of compound formulation standardization of commercial products is challenging. In the present communication marker-based standardization of "Triphalaguggulu" preparation using gallic acid (for triphala), piperine (for P. longum L.) and guggulsterones (for guggulu) is reported. These compounds of diverse chemistry were successfully separated on a Waters HR-C18 column by isocratic elution with methanol and water (80:20 v/v) as mobile phase at the flow rate of 1.0 mL/min coupled with photodiode array detector. These optimal chromatographic conditions were used for simultaneous quantification of gallic acid, guggulsterones (E and Z) and piperine in commercial samples by high-performance liquid chromatography-electron spray ionization-mass spectrometry and method was validated as per ICH guidelines. PMID- 26109778 TI - Anti-lung cancer potential of pure esteric-glycoside condurangogenin A against nonsmall-cell lung cancer cells in vitro via p21/p53 mediated cell cycle modulation and DNA damage-induced apoptosis. AB - BACKGROUND: Marsdenia condurango (condurango) is a tropical woody vine native to South America. Our earlier study was limited to evaluation of anti-cancer potentials of crude condurango extract and its glycoside-rich components in vitro on lung cancer. OBJECTIVE: This study aims at evaluating the effect of the single isolated active ingredient condurangogenin A (ConA; C32H42O7) on A549, H522 and H460-nonsmall-cell lung cancer cells. MATERIALS AND METHODS: ConA was isolated by column chromatography and analyzed by mass spectroscopy, Fourier transform infrared spectroscopy and proton-nuclear magnetic resonance. diphenyltetrazolium bromide assays were conducted on three cell-types using 6%-alcohol as control. Critical studies on cellular morphology, cell-cycle regulation, reactive oxygen species, mitochondrial membrane potential, and DNA-damage were made, and expressions of related signaling markers studied. RESULTS: As IC50 doses of ConA proved to be too high and toxic to both A549 and H522 cells, all experimental studies were carried out on H460 cells with the IC50 dose (32 MUg/ml - 24 h). Cellular morphology revealed typical apoptotic features after ConA treatment. At early treatment hours (2 h-12 h), maximum cells were arrested at G0/G1 phase that could be correlated with reduced level of cyclin D1-CDK with p21 up-regulation. At 18 h - 24 h, sub G0/G1 cell population was increased gradually, as revealed from cytochrome-c release and caspase-3 activation, further confirming the apoptosis-inducing ability of ConA at later phases. Gradual increase of TUNEL positive cells with significant modulation of mitochondria-dependent apoptotic markers at longer time-points would establish apoptosis-induction property of ConA, indicating its potential as a strong candidate for anti-cancer drug formulation. CONCLUSION: Further studies are warranted against other types of cancer cells and animal models before its possible human use. PMID- 26109779 TI - Protective effect of young green barley leaf (Hordeum vulgare L.) on restraint stress-induced decrease in hippocampal brain-derived neurotrophic factor in mice. AB - BACKGROUND: Many health experts support the hypothesis that stressful lifestyles are the leading cause of illness, like depression. Therefore, from the standpoint of preventive medicine, it is important to reduce stress. Young green barley leaves are a good natural source of vitamins and minerals, and their juice is widely consumed as a functional food for health reasons in Japan. This study investigated the protective effect of young green barley leaves for stress control. MATERIALS AND METHODS: ICR outbred mice were exposed to 3-h sessions of restraint stress. Young green barley leaves (400 and 1,000 mg/kg) were administered orally 1 h before the sessions for 5 days. To analyze voluntary behavior, wheel-running activity was monitored during the dark period. Brain derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the whole hippocampus was measured by real-time quantitative polymerase chain reaction. RESULTS: Restraint stress resulted in a significant decrease in voluntary wheel running behavior, but this decrease was ameliorated by the administration of young green barley leaves. The leaves also enhanced the decreased levels of BDNF mRNA induced by restraint stress; in particular, a significant protective effect was shown in the exon IV variant as compared to vehicle control mice. CONCLUSION: The findings suggest that young green barley leaves have potent anti-stress properties, as evidenced by preventing decreases in the levels of voluntary wheel running activity and hippocampal BDNF mRNA in response to restraint stress. Our findings support the possibility that supplementation with young green barley leaves might be beneficial for preventing stress-related psychiatric disorders like depression. PMID- 26109780 TI - Toxicological and biochemical studies on Schinus terebinthifolius concerning its curative and hepatoprotective effects against carbon tetrachloride-induced liver injury. AB - BACKGROUND: Recently, many efforts have been made to discover new products of natural origin which can limit the xenobiotic-induced hepatic injury. Carbon tetrachloride (CCl4) is a highly toxic chemical that is widely used to study hepatotoxicity in animal models. OBJECTIVE: The present study was conducted to investigate the curative and protective effects of Schinus terbenthifolius ethanolic extract against CCl4 -induced acute hepatotoxicity in rats. MATERIALS AND METHODS: S. terbenthifolius extract was orally administered in a dose of 350 mg dried extract/kg b.wt. before and after intoxication with CCl4 for curative and protective experiments, respectively. A group of hepatotoxicity indicative enzymes, oxidant-antioxidant capacity, DNA oxidation, and apoptosis markers were measured. RESULTS: CCl4 increased liver enzyme leakage, oxidative stress, hepatic apoptosis, DNA oxidation, and inflammatory markers. Administration of S. terebinthifolius, either before or after CCl4 intoxication, significantly decreased elevated serum liver enzymes and reinstated the antioxidant capacity. Interestingly, S. terebinthifolius extract inhibited hepatocyte apoptosis as revealed by approximately 20 times down-regulation in caspase-3 expression when compared to CCl4 untreated group. On the other hand, there was neither protective nor curative effect of S. terebinthifolius against DNA damage caused by CCl4. CONCLUSION: The present study suggests that S. terebinthifolius extract could be a substantially promising hepatoprotective agent against CCl4 toxic effects and may be against other hepatotoxic chemical or drugs. PMID- 26109781 TI - Cinnamon: Mystic powers of a minute ingredient. AB - Cinnamon, due to its exotic flavor and aroma, is a key ingredient in the kitchen of every household. From the beginning of its use in 2800 BC by our ancestors for various purposes such as anointment, embalming and various ailments, it has instigated the interest of many researchers. Recently many trials have explored the beneficial effects of cinnamon in Parkinsons, diabetes, blood, and brain. After extensive research on PubMed and Google scholar, data were collected regarding its antioxidant, anti-inflammatory, antilipemic, antidiabetic, antimicrobial, and anticancer effect. This systematic review underlines the surplus health benefits of this clandestine ingredient and the scope of further research in these clinical scenarios. PMID- 26109782 TI - Antioxidant and Antiacetylcholinesterase Activity of Teucrium hyrcanicum. AB - BACKGROUND: Teucrium hyrcanicum belonging to the Lamiaceae family is a native plant in Iran; it is called Maryam nokhodi-e-jangali in Farsi. OBJECTIVE: The aim of this study is to evaluate acetylcholinesterase inhibition (AChEI), antioxidant activity and flavonoids content of T. hyrcanicum methanol extract. MATERIALS AND METHODS: The air-dried and the ground aerial parts of T. hyrcanicum were extracted by percolation method with methanol. Antioxidant activity of the extract was investigated by using 2,2'-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power assay (FRAP) methods. In addition, AChEI and flavonoid content of T. hyrcanicum methanol extract were measured. RESULTS: The results showed that total flavonoid content of T. hyrcanicum in reference to the standard curve for quercetin was 20.70 +/- 0.05 mg quercetin equivalents/g of extract. In the FRAP method, the antioxidant activity of T. hyrcanicum extract and butyl hydroxyanisole (BHA) (as a positive control) were 657.5 +/- 0.04 and 880 +/- 0.06 mmol Fe II/1 g dried extract. According to results of DPPH assay, half maximal inhibitory concentration (IC50) value for DPPH radical-scavenging activities of T. hyrcanicum methanol extract, vitamin E and BHA were 74.6, 14.12 and 7.8 MUg/mL, respectively. IC50 value for AChEI of T. hyrcanicum and donepezil as a positive control were 2.12 mg/mL and 0.013 mg/mL. CONCLUSION: The results of the present study showed T. hyrcanicum is a natural antioxidant that the flavonoid content can be responsible for extract effects. PMID- 26109783 TI - Antidermatophytic Activity of Mikania micrantha Kunth: An Invasive Weed. AB - CONTEXT: The incidence of dermatophytosis has risen dramatically in recent years. Limited availability of side-effect free drugs has led to a search for new antidermatophytic agents. OBJECTIVE: The objective was to investigate antidermatophytic activity and in vitro anti-inflammatory activity (protease inhibition assay) of whole plant (aerial parts only) of Mikania micrantha. MATERIALS AND METHODS: The dried and powdered aerial parts of M. micrantha were extracted separately with petroleum ether, ethyl acetate and methanol. Antidermatophytic activity was determined by agar tube dilution method against Epidermophyton floccosum var. nigricans, Microsporum canis, Microsporum gypseum and Trichophyton rubrum. The activities of various parts of the plant - flowers, leaves and stem were separately analyzed using their ethyl acetate extract. Fungicidal efficacy and trypsin inhibiting activity of the whole plant, flowers and leaves were also analyzed using the ethyl acetate extracts. STATISTICAL ANALYSIS USED: For trypsin inhibition assay results are expressed as mean +/- standard division. For antidermatophytic assay, the significance of the difference between control and test was analyzed statistically using Fisher's exact test. RESULTS: Ethyl acetate extract of M. micrantha exhibited excellent antidermatophytic activity, followed by petroleum ether and methanolic extracts. Ethyl acetate extracts of whole plant, flowers, leaves and stem completely inhibited the growth of dermatophytes at the tested concentration of 2 mg/mL. Furthermore, ethyl acetate extracts of whole plant, leaves and flowers were fungicidal, and the percentages of trypsin inhibition exhibited were 33.73 +/- 0.306, 39.0 +/- 0.505 and 35.53 +/- 0.503, respectively. CONCLUSIONS: Since M. micrantha possesses antidermatophytic as well as anti-inflammatory activities, the plant is an excellent candidate for the development of new medicaments against dermatophytoses in traditional as well as modern medicine. PMID- 26109784 TI - Toxicological and phytoprotective effect of Keayodendron bridelioides and Monodora myristica extracts in Wister rats. AB - OBJECTIVES: The potential toxicity of Keayodendron bridelioides (KB), Monodora myristica (MM) were examined, and phytoprotection of MM and KB stemming from their phytochemical contents against sodium arsenite (SA) induced clastogenicity in Wister's rat. MATERIALS AND METHODS: Dose range studies of KB in rats, genotoxicity of MM and KB by SOS-inductive respomse were investigated using E. coli PQ37. Male rats were exposed to varying concentrations of MM, KB over a five week period to evaluate MM and KB phytoprotectives properties were also evaluated against sodium arsenite induced micronucleated erythrocytes, hepatotoxicity and sperm quality and morphology. RESULTS: In contrast to KB, MM induced micronuclei formation in rat erythrocytes, MM and KB were however not genotoxic. MM, SA alone and in combination were hepatotoxic, characterized by elevated hepatic transaminases. Hepatoxicity were ameliorated by co-administration of KB (P < 0.05). MM and KB did not induce changes in semen morphology (P > 0.05); but decreased sperm count and motility (P < 0.05). Extracts exhibited anti clastogenic (KB > MM), hepatoprotective (KB > MM) activities and maintained semen viability against SA treatment. CONCLUSION: Finding applications as herbal medicinal and food components KB and MM may be useful in mitigating the effect of toxicants in biological systems susceptible to oxidative damage. PMID- 26109785 TI - Hematological effects of repeated graded doses of the methanol extract of Paullinia pinnata (Linn.) leaves in Wistar albino rats. AB - BACKGROUND: Paullinia pinnata is a medicinal plant used for the treatment of various diseases, including anemia in West Africa. AIM: This study was carried out to investigate the effect of increasing doses of the methanolic leaves extract of P. pinnata on hematological parameters in rats. MATERIALS AND METHODS: Thirty-six male Wistar albino rats were grouped into six groups of six animals each. Five doses; 50,100, 200, 400 and 800 mg/kg body weight of the P. pinnata extract were administered separately to five groups. The sixth group served as a control and received only the vehicle (70% physiological saline: 30% Tween 80 [v/v]). Administration was done orally daily for 28 days at 24 h interval. On day 29, the animals were made inactive, blood was then collected from the heart and various hematological parameters were evaluated. STATISTICAL ANALYSIS: Analysis of variance was employed. RESULTS: The packed cell volume and red blood cell count increased significantly (P < 0.05) in the treatment groups except at 200 mg/kg dose. The hemoglobin concentration increased in all the treatment groups. The values for the neutrophils at 50, 100, 200 and 800 mg/kg doses were higher than that of the control. The white blood cell count increased significantly (P < 0.05) at 50 and 400 mg/kg doses compared to the control and exceeded the normal physiological range. CONCLUSION: The maximum tolerable dose is 200 mg/kg body weight of the methanolic leaves extract of P. pinnata and the extract has anti anemic property with the ability to increase neutrophils count. PMID- 26109786 TI - Analgesic and anti-Inflammatory effect of UP3005, a botanical composition Containing two standardized extracts of Uncaria gambir and Morus alba. AB - BACKGROUND: Osteoarthritis (OA) is a chronic debilitating degenerative joint disease characterized by cartilage degradation and synovial inflammation exhibited by clinical symptoms such as joint swelling, synovitis, and inflammatory pain. Present day pain relief therapeutics heavily relies on the use of prescription and over the counter nonsteroidal anti-inflammatory drugs as the first line of defense where their long-term usage causes detrimental gastrointestinal and cardiovascular-related side-effects. As a result, the need for evidence based safer and efficacious alternatives from natural sources to overcome the most prominent and disabling symptoms of arthritis is a necessity. MATERIALS AND METHODS: Describe the anti-inflammatory and analgesic effect of UP3005, a composition that contains a standardized blend of two extracts from the leaf of Uncaria gambir and the root bark of Morus alba in carrageenan-induced rat paw edema, abdominal constriction (writhing's) and ear swelling assays in mouse with oral dose ranges of 100-400 mg/kg. RESULTS: In vivo, statistically significant improvement in pain resistance, and suppression of paw edema and ear thickness in animals treated with UP3005 were observed compared with vehicle treated diseased rats and mice. Ibuprofen was used a reference compound in all the studies. In vitro, enzymatic inhibition activities of UP3005 were determined with IC50 values of 12.4 MUg/ml, 39.8 MUg/ml and 13.6 MUg/ml in cyclooxygenase-2 (COX-1), COX-2 and lipoxygenase (5-LOX) enzyme activity assay, respectively. CONCLUSIONS: These data suggest that UP3005, analgesic and anti-inflammatory agent of botanical origin with balanced dual COX-LOX inhibition activity, could potentially be used for symptom management of OA. PMID- 26109787 TI - Evaluation of anxiolytic activity of aqueous extract of Coriandrum sativum Linn. in mice: A preliminary experimental study. AB - OBJECTIVES: To evaluate the anxiolytic effect of Coriandrum sativum (CS) aqueous extract in mice. To compare the antianxiety activity of CS against standard drug diazepam (3 mg/kg). MATERIALS AND METHODS: After obtaining Institutional Animal Ethics Committee approval, Swiss albino mice (18-25 g) of either sex were randomly divided into five groups of six animals each. Dried powder of CS leaves was boiled with distilled water, cooled, filtered, placed on a hotplate for complete evaporation, finally weighed and stored. The control group, test group, and standard drugs group received saline, CS extract (50, 100, and 200 mg/kg), diazepam (3 mg/kg), respectively, by oral feeding. The antianxiety effect was assessed by elevated plus maze (EPM) in mice. RESULTS: In EPM, it implied that CS 50 mg/kg (Group III), 100 mg/kg (Group IV), and 200 mg/kg (Group V) significantly (P < 0.001) increases the number of entries in open arms compared to control. The time spent in open arms also increased in all the doses of CS extract significantly. CONCLUSION: The current study demonstrates statistically significant dose-dependent antianxiety activity of CS leaves. PMID- 26109788 TI - Chemical composition analysis, antioxidant and antibacterial activity evaluation of essential oil of Atalantia monophylla Correa. AB - BACKGROUND: Atalantia monophylla Correa. a small tree belongs to the family Rutaceae. It is distributed throughout India and in Tamil Nadu the species is commonly seen in foothills of dry vegetation. OBJECTIVE: The aim was to hydrodistillate and analyze the chemical composition of essential oil from the fresh leaves of A. monophylla Correa. collected in two different seasons (December, 2013 and May, 2014) and to evaluate antioxidant and antibacterial activities of isolated essential oil. MATERIALS AND METHODS: Chemical composition of isolated essential oil was analyzed by gas chromatography, gas chromatography coupled with mass spectrometry. Antioxidant activity of oil was assessed using five different antioxidant test systems. Antibacterial activity of oil was tested against six pathogenic bacteria by broth dilution method. RESULTS: Essential oil obtained from the leaves collected during May, 2014 had shown more compounds. Antioxidant activity of oil was moderate when compared with positive control. Minimum inhibitory concentration value of oil was ranges between 139.32 +/- 0.001 and 541.11 +/- 0.003 ug/mL against all the tested bacteria. CONCLUSION: Result clearly indicates essential oil collected during May, 2014 showed more bioactive compounds. PMID- 26109789 TI - Evaluation of antioxidant, antibacterial, and antidiabetic potential of two traditional medicinal plants of India: Swertia cordata and Swertia chirayita. AB - BACKGROUND: Swertia cordata and Swertia chirayita are temperate Himalayan medicinal plants used as potent herbal drugs in Indian traditional systems of medicine (Ayurvedic, Unani and Siddha). OBJECTIVE: Assessment of Antioxidant, antibacterial, and antidiabetic potential of Swertia cordata and Swertia chirayita. MATERIALS AND METHODS: Phytochemicals of methanolic and aqueous extracts of the two Swertia species were analyzed. The antioxidant potential of all the extracts was assessed by measuring total phenolic content, total flavonoid content and free radical scavenging potential was assessed by 1,1 diphenyl-2-picrilhydrazyl (DPPH) assay, antibacterial activity was assessed against various pathogenic and nonpathogenic bacteria in vitro by Kirby-Bauer agar well diffusion method and antidiabetic activity was assessed by alpha amylase inhibition. RESULTS: Methanolic leaf extracts of both the species of Swertia contain significant antibacterial as well as anti-diabetic potential, whereas methanolic root extracts of both species were found to have potential antioxidant activity. However, Swertia chirayita showed better activities than Swertia cordata although both species have good reputation in traditional Indian medicine. CONCLUSION: Both the species are having high medicinal potential in terms of their antioxidant, antibacterial and antidiabetic activities. Studies are required to further elucidate antioxidant, anti-diabetic and antibacterial potentials using various in-vitro, in-vivo biochemical and molecular biology techniques. PMID- 26109790 TI - Induction of rat hepatic mitochondrial membrane permeability transition pore opening by leaf extract of Olax subscorpioidea. AB - BACKGROUND: The induction of the mitochondrial membrane permeability transition (MMPT) pore has been implicated in the cascade of events involved in apoptosis (programmed cell death). Olax subscorpioidea is traditionally used for the treatment of several diseases and infection. However, its role on MMPT is not yet established. This study was aimed at evaluating the effects of varying concentrations of the methanol leaf extract of O. subscorpioidea (MEOS) on MMPT pore opening, mitochondrial adenosine triphosphatase (ATPase), and mitochondrial lipid peroxidation. MATERIALS AND METHODS: Opening of the pore was spectrophotometrically assayed under succinate-energized conditions. RESULTS: In the absence of triggering agent (calcium), MEOS induced MMPT pore opening by 350, 612, 827, 845% at 36, 60, 86 and 112 MUg/ml, respectively. MEOS further induced MMPT pore opening in the presence of a triggering agent by 866, 905, 831, 840, 949% at 12, 36, 60, 86 and 112 MUg/ml, respectively. The extract significantly induced mitochondrial membrane lipid peroxidation in all the concentration used. MEOS also significantly increased mitochondrial ATP hydrolysis by mitochondrial ATPase in all concentration of the extract used. CONCLUSION: It may be deduced from this results, that MEOS contains certain bioactive components that may find use in pathological conditions that require an enhanced rate of apoptosis. PMID- 26109791 TI - Performance of chromogenic media for Candida in rapid presumptive identification of Candida species from clinical materials. AB - BACKGROUND: In perspective of the worldwide increase in a number of immunocompromised patients, the need for identification of Candida species has become a major concern. The development of chromogenic differential media, introduced recently, facilitate rapid speciation. However, it can be employed for routine mycology workup only after an exhaustive evaluation of its benefit and cost effectiveness. This study was undertaken to evaluate the benefit and cost effectiveness of chromogenic media for speciation of Candida clinical isolates. MATERIALS AND METHODS: Sputum samples of 382 patients were screened for the presence of Candida spp. by Gram stain and culture on sabouraud dextrose agar. Candida species were identified using Gram stain morphology, germ tube formation, cornmeal agar with Tween-80, sugar fermentation tests and morphology on HiCrome Candida differential agar. All the Candida isolates were inoculated on HiCrome Candida agar (HiMedia, Mumbai, India). RESULTS: The sensitivity and specificity of HiCrome agar for identification of Candida albicans were 90% and 96.42%, respectively whereas sensitivity and specificity of carbohydrate fermentation test were 86.67% and 74.07%, respectively. Sensitivity and specificity values of HiCrome agar for detection of C. albicans, Candida parapsilosis and Candida glabrata were above 90%. CONCLUSIONS: We found HiCrome agar has high sensitivity and specificity comparable to that of the conventional method. In addition, use of this differential media could significantly cut down the turnaround time as well as cost of sample processing. PMID- 26109792 TI - Quantification of total polyphenols, catechin, caffeine, L-theanine, determination of antioxidant activity and effect on antileishmanial drugs of ethiopian tea leaves extracts. AB - OBJECTIVE: In this study four tea samples Gumero black, Wushwush black and Wushwush green from Agri- Ceft Plc and East Africa black tea leaves from East African Agribusiness Plc were investigated for total polyphenols, caffeine, catechin and L-theanine content. MATERIALS AND METHODS: The aqueous extracts were investigated for their antioxidant and antileishmanial property and effect on amphotericin B, miltefocine and sodium stibogluconate, the commonly used antileishmanial drugs. Antileishmanial studies were conducted on L. aethiopica. RESULTS: Wushwush green tea had the highest content of polyphenol (19.98 +/- 1.15 mg gallic acid equivalent /100 g dry leaf weight), catechin (37.06 mg/g) and L theanine (48.54 mg/g but the lowest caffeine content). It exhibited the highest antioxidant activity. The highest antioxidant effect of Wushwush green tea may be attributed to the highest polyphenol content. East African black tea had the lowest L-theanine (20.72 mg/g) and antioxidant activity but the highest caffeine (16.60 mg/g) content. CONCLUSION: Wushwush green tea showed slight inhibitory effect on L. aethiopica while the lack tea extracts (Gumero, East Africa and Wushwush) exhibited no antileishmanial activity. Wushwush green tea did not show any synergistic or antagonistic effect on the antileishmanial drugs used in this study while Gumero, East Africa and Wushwush black tea extracts exhibited dose dependant inhibitory activity to the commonly used antileishmanial drugs included in this study. PMID- 26109793 TI - Neuropilins and liver. AB - Neuropilins (NRPs) are highly conserved transmembrane glycoproteins that possess pleiotropic functions. Neuropilin-1 (NRP1) and its homologue neuropilin-2 interact as coreceptors with both class 3 semaphorins and vascular endothelial growth factor and are involved in neuronal guidance and angiogenesis, respectively. The contribution of NRPs to tumor angiogenesis has been highlighted in previous studies, leading to the development of NRP antagonists as novel anti angiogenesis therapies. However, more recent studies have demonstrated that NRPs have a much broader spectrum of activity in the integration of different pathways in physiological and pathological conditions. A few studies investigated the role of NRPs in both malignant and non-neoplastic liver diseases. In normal liver, NRP1 is expressed in hepatic stellate cells and liver sinusoidal endothelial cells. NRP1 expression in hepatocytes has been associated with malignant transformation and may play an important role in tumor behavior. A contribution of NRPs in sinusoidal remodeling during liver regeneration has been also noted. Studies in chronic liver diseases have indicated that, besides its influence on angiogenesis, NRP1 might contribute to the progression of liver fibrosis owing to its effects on other growth factors, including transforming growth factor beta1. As a result, NRP1 has been identified as a promising therapeutic target for future antifibrotic therapies based on the simultaneous blockade of multiple growth factor signaling pathways. In this review, the structure of NRPs and their interactions with various ligands and associated cell surface receptors are described briefly. The current understanding of the roles of the NRPs in liver diseases including tumors, regeneration and fibrogenesis, are also summarized. PMID- 26109794 TI - Unsolved problems and future perspectives of hepatitis B virus vaccination. AB - Hepatitis B virus (HBV) infection is still a serious worldwide problem, and vaccination is the most effective strategy for primary prevention of the infection. Although universal vaccination may be required for total eradication, several countries, including Japan, have not yet adopted universal vaccination programs. Some individuals are non-responders to HBV vaccine and several mechanisms responsible for their poor response have been proposed. To overcome non-response, third generation vaccines with pre-S proteins have been developed. These vaccines have shown better anti-HBs responses and may also be effective in preventing infection by HBV with S mutant. Improvement of vaccine efficacy by intradermal administration, or co-administration with cytokines or adjuvants, may also be effective in non-responders. The necessity, timing and method of booster vaccination in responders with decreased anti-HBs responses, and effective vaccination against S-mutant HBV, are issues requiring resolution in the global prevention of HBV infection. PMID- 26109795 TI - Novel therapeutic approaches for hepatitis B virus covalently closed circular DNA. AB - Hepatitis B virus (HBV) infection is a major global health problem. Although current therapies, such as the use of nucleos(t)ide analogs, inhibit HBV replication efficiently, they do not eliminate covalently closed circular DNA (cccDNA), which persists in hepatocyte nuclei. As HBV cccDNA is a viral transcription template, novel therapeutic approaches to directly target HBV cccDNA are necessary to completely eradicate persistent HBV infections. HBV cccDNA levels in HBV-infected human liver cells are extremely low; thus, more reliable and simple measurement methods are needed to correctly monitor their levels during therapeutic treatment. Although reverse transcription-polymerase chain reaction or Southern blot procedures are currently used in research studies, these methods are not completely reliable and are also time-consuming and labor-intensive. Genome editing technologies, such as zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) system, which are designed to target specific DNA sequences, represent highly promising potential therapeutic tools. In particular, the CRISPR/Cas9 system is an easily customizable sequence-specific nuclease with high flexibility and may be the most feasible approach to target HBV cccDNA. Further research to develop easier, safer, and more effective protocols should be pursued. PMID- 26109797 TI - Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non celiac gluten sensitivity. AB - Cereal crops and cereal consumption have had a vital role in Mankind's history. In the recent years gluten ingestion has been linked with a range of clinical disorders. Gluten-related disorders have gradually emerged as an epidemiologically relevant phenomenon with an estimated global prevalence around 5%. Celiac disease, wheat allergy and non-celiac gluten sensitivity represent different gluten-related disorders. Similar clinical manifestations can be observed in these disorders, yet there are peculiar pathogenetic pathways involved in their development. Celiac disease and wheat allergy have been extensively studied, while non-celiac gluten sensitivity is a relatively novel clinical entity, believed to be closely related to other gastrointestinal functional syndromes. The diagnosis of celiac disease and wheat allergy is based on a combination of findings from the patient's clinical history and specific tests, including serology and duodenal biopsies in case of celiac disease, or laboratory and functional assays for wheat allergy. On the other hand, non-celiac gluten sensitivity is still mainly a diagnosis of exclusion, in the absence of clear-cut diagnostic criteria. A multimodal pragmatic approach combining findings from the clinical history, symptoms, serological and histological tests is required in order to reach an accurate diagnosis. A thorough knowledge of the differences and overlap in clinical presentation among gluten-related disorders, and between them and other gastrointestinal disorders, will help clinicians in the process of differential diagnosis. PMID- 26109796 TI - Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity. AB - Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, having a prevalence of 12%-30% in the general population. Most patients with IBS attribute their symptoms to adverse food reactions. We review the role of diet in the pathogenesis of IBS and the importance of dietary factors in the management of these patients. The MEDLINE electronic database (1966 to Jan 2015) was searched using the following keywords: "food", "diet", "food allergy", "food hypersensitivity", "food intolerance", "IBS", "epidemiology", "pathogenesis", "pathophysiology", "diagnosis", "treatment". We found 153 eligible papers; 80 were excluded because: not written in English, exclusive biochemical and experimental research, case reports, reviews, and research otherwise not relevant to our specific interest. We selected 73 papers: 43 original papers, 26 reviews and 4 letters to the editor. These papers focused on IBS pathogenesis, the association between IBS and atopy, and between IBS and food allergy, the relationship between IBS and non-celiac wheat sensitivity, the role of diet in IBS. Pending further scientific evidence, a cautious approach is advisable but the concept of food allergy should be included as a possible cause of IBS, and a dietary approach may have a place in the routine clinical management of IBS. PMID- 26109798 TI - Useful strategies to prevent severe stricture after endoscopic submucosal dissection for superficial esophageal neoplasm. AB - The minimal invasiveness of endoscopic submucosal dissection (ESD) prompted us to apply this technique to large-size early esophageal squamous cell carcinoma and Barrett's adenocarcinoma, despite the limitations in the study population and surveillance duration. A post-ESD ulceration of greater than three-fourths of esophageal circumference was advocated as an important risk factor for refractory strictures that require several sessions of dilation therapy. Most of the preoperative conditions are asymptomatic, but dilatation treatment for dysphagia associated with the stricture has potential risks of severe complications and a worsening of quality of life. Possible mechanisms of dysphasia were demonstrated based on dysmotility and pathological abnormalities at the site: (1) delayed mucosal healing; (2) severe inflammation and disorganized fibrosis with abundant extracellular matrices in the submucosa; and (3) atrophy in the muscularis proper. However, reports on the administration of anti-scarring agents, preventive dilation therapies, and regenerative medicine demonstrated limited success in stricture prevention, and there were discrepancies in the study designs and protocols of these reports. The development and consequent long-term assessments of new prophylactic technologies on the promotion of wound healing and control of the inflammatory/tumor microenvironment will require collaboration among various research fields because of the limited accuracy of preoperative staging and high-risk of local recurrence. PMID- 26109799 TI - Review of a challenging clinical issue: Intrahepatic cholestasis of pregnancy. AB - Intrahepatic cholestasis of pregnancy (ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries (9.2%-15.6% and 1.5%, respectively) than in Europe (0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue. PMID- 26109801 TI - Protective effect of bicyclol against bile duct ligation-induced hepatic fibrosis in rats. AB - AIM: To evaluate the protective effect of bicyclol against bile duct ligation (BDL)-induced hepatic fibrosis in rats. METHODS: Sprague-Dawley male rats underwent BDL and sham-operated animals were used as healthy controls. The BDL rats were divided into two groups which received sterilized PBS or bicyclol (100 mg/kg per day) orally for two consecutive weeks. Serum, urine and bile were collected for biochemical determinations. Liver tissues were collected for histological analysis and a whole genome oligonucleotide microarray assay. Reverse transcription-polymerase chain reaction and Western blotting were used to verify the expression of liver fibrosis-related genes. RESULTS: Treatment with bicyclol significantly reduced liver fibrosis and bile duct proliferation after BDL. The levels of alanine aminotransferase (127.7 +/- 72.3 vs 230.4 +/- 69.6, P < 0.05) and aspartate aminotransferase (696.8 +/- 232.6 vs 1032.6 +/- 165.8, P < 0.05) were also decreased by treatment with bicyclol in comparison to PBS. The expression changes of 45 fibrogenic genes and several fibrogenesis-related pathways were reversed by bicyclol in the microarray assay. Bicyclol significantly reduced liver mRNA and/or protein expression levels of collagen 1a1, matrix metalloproteinase 2, tumor necrosis factor, tissue inhibitors of metalloproteinases 2, transforming growth factor-beta1 and alpha-smooth muscle actin. CONCLUSION: Bicyclol significantly attenuates BDL-induced liver fibrosis by reversing fibrogenic gene expression. These findings suggest that bicyclol might be an effective anti-fibrotic drug for the treatment of cholestatic liver disease. PMID- 26109802 TI - Activated rat hepatic stellate cells influence Th1/Th2 profile in vitro. AB - AIM: To investigate the effects of activated rat hepatic stellate cells (HSCs) on rat Th1/Th2 profile in vitro. METHODS: Growth and survival of activated HSCs and CD4(+) T lymphocytes cultured alone or together was assessed after 24 or 48 h. CD4(+) T lymphocytes were then cultured with or without activated HSCs for 24 or 48 h and the proportion of Th1 [interferon (IFN)-gamma(+)] and Th2 [interleukin (IL)-4(+)] cells was assessed by flow cytometry. Th1 and Th2 cell apoptosis was assessed after 24 h of co-culture using a caspase-3 staining procedure. Differentiation rates of Th1 and Th2 cells from CD4(+) T lymphocytes that were positive for CD25 but did not express IFN-gamma or IL-4 were also assessed after 48 h of co-culture with activated HSCs. Galectin-9 expression in HSCs was determined by immunofluorescence and Western blotting. ELISA was performed to assess galectin-9 secretion from activated HSCs. RESULTS: Co-culture of CD4(+) T lymphocytes with activated rat HSCs for 48 h significantly reduced the proportion of Th1 cells compared to culture-alone conditions (-1.73% +/- 0.71%; P < 0.05), whereas the proportion of Th2 cells was not altered; the Th1/Th2 ratio was significantly decreased (-0.44 +/- 0.13; P < 0.05). In addition, the level of IFN gamma in Th1 cells was decreased (-65.71 +/- 9.67; P < 0.01), whereas the level of IL-4 in Th2 cells was increased (82.79 +/- 25.12; P < 0.05) by co-culturing, as measured by mean fluorescence intensity by flow cytometry. Apoptosis rates in Th1 (12.27% +/- 0.99%; P < 0.01) and Th2 (1.71% +/- 0.185%; P < 0.01) cells were increased 24 h after co-culturing with activated HSCs; the Th1 cell apoptosis rate was significantly higher than in Th2 cells (P < 0.01). Galectin-9 protein expression was significantly decreased in HSCs only 24 h after co-culturing (P < 0.05) but not after 48 h. Co-culture for 48 h significantly increased the differentiation of Th1 and Th2 cells; however, the increase in the proportion of Th2 cells was significantly higher than that of Th1 cells (1.85% +/- 0.48%; P < 0.05). CONCLUSION: Activated rat HSCs lower the Th1/Th2 profile, inhibiting the Th1 response and enhancing the Th2 response, and this may be a novel pathway for liver fibrogenesis. PMID- 26109800 TI - Molecular aspects of intestinal calcium absorption. AB - Intestinal Ca(2+) absorption is a crucial physiological process for maintaining bone mineralization and Ca(2+) homeostasis. It occurs through the transcellular and paracellular pathways. The first route comprises 3 steps: the entrance of Ca(2+) across the brush border membranes (BBM) of enterocytes through epithelial Ca(2+) channels TRPV6, TRPV5, and Cav1.3; Ca(2+) movement from the BBM to the basolateral membranes by binding proteins with high Ca(2+) affinity (such as CB9k); and Ca(2+) extrusion into the blood. Plasma membrane Ca(2+) ATPase (PMCA1b) and sodium calcium exchanger (NCX1) are mainly involved in the exit of Ca(2+) from enterocytes. A novel molecule, the 4.1R protein, seems to be a partner of PMCA1b, since both molecules co-localize and interact. The paracellular pathway consists of Ca(2+) transport through transmembrane proteins of tight junction structures, such as claudins 2, 12, and 15. There is evidence of crosstalk between the transcellular and paracellular pathways in intestinal Ca(2+) transport. When intestinal oxidative stress is triggered, there is a decrease in the expression of several molecules of both pathways that inhibit intestinal Ca(2+) absorption. Normalization of redox status in the intestine with drugs such as quercetin, ursodeoxycholic acid, or melatonin return intestinal Ca(2+) transport to control values. Calcitriol [1,25(OH)2D3] is the major controlling hormone of intestinal Ca(2+) transport. It increases the gene and protein expression of most of the molecules involved in both pathways. PTH, thyroid hormones, estrogens, prolactin, growth hormone, and glucocorticoids apparently also regulate Ca(2+) transport by direct action, indirect mechanism mediated by the increase of renal 1,25(OH)2D3 production, or both. Different physiological conditions, such as growth, pregnancy, lactation, and aging, adjust intestinal Ca(2+) absorption according to Ca(2+) demands. Better knowledge of the molecular details of intestinal Ca(2+) absorption could lead to the development of nutritional and medical strategies for optimizing the efficiency of intestinal Ca(2+) absorption and preventing osteoporosis and other pathologies related to Ca(2+) metabolism. PMID- 26109803 TI - Abundance and significance of neuroligin-1 and glutamate in Hirschsprung's disease. AB - AIM: To investigate the abundance and potential diagnostic significance of neuroligin-1 and glutamate (Glu) in Hirschsprung's disease (HSCR). METHODS: Ninety children with HSCR and 50 children without HSCR matched for similar nutritional status, age and basal metabolic index were studied. The expression and localization of neuroligin-1 and Glu were assessed using double-labeling immunofluorescence staining of longitudinal muscles with adherent myenteric plexus from the surgically excised colon of children with HSCR. Western blot analysis, quantitative real-time PCR (qRT-PCR) and immunohistochemistry were performed to evaluate the abundance of neuroligin-1 and Glu in different HSCR affected segments (ganglionic, transitional, and aganglionic segments). Enzyme linked immunosorbent assay (ELISA) was used to detect and compare serum Glu levels in the long-segment HSCR, short-segment HSCR and non-HSCR samples. RESULTS: Neuroligin-1 and Glu were co-expressed highest to lowest in the ganglionic, transitional and aganglionic segments based on Western blot (neuroligin-1: 0.177 +/- 0.008 vs 0.101 +/- 0.006, 0.177 +/- 0.008 vs 0.035 +/- 0.005, and 0.101 +/- 0.006 vs 0.035 +/- 0.005, P < 0.005; Glu: 0.198 +/- 0.006 vs 0.115 +/- 0.008, 0.198 +/- 0.006 vs 0.040 +/- 0.003, and 0.115 +/- 0.008 vs 0.040 +/- 0.003, P < 0.005) and qRT-PCR (neuroligin-1: 9.58 * 10(-5) +/- 9.94 * 10(-6) vs 2.49 * 10(-5) +/- 1.38 * 10(-6), 9.58 * 10(-5) +/- 9.94 * 10(-6) vs 7.17 * 10( 6 +/-) 1.12 * 10(-6), and 2.49 * 10(-5) +/- 1.38 * 10(-6) vs 7.17 * 10(-6) +/- 1.12 * 10(-6), P < 0.005). Serum Glu level was the highest to lowest in the non HSCR, short-type HSCR and long-type HSCR samples based on ELISA (in nmol/MUL, 0.93 +/- 0.31 vs 0.57 +/- 0.25, 0.93 +/- 0.31 vs 0.23 +/- 0.16, and 0.57 +/- 0.25 vs 0.23 +/- 0.16, P < 0.005). CONCLUSION: Neuroligin-1 and Glu may represent new markers of ganglion cells, whose expression may correlate with the pathogenesis, diagnosis, differential diagnosis or classification of HSCR. PMID- 26109804 TI - Effects of electroacupuncture on corticotropin-releasing hormone in rats with chronic visceral hypersensitivity. AB - AIM: To investigate the effect of electroacupuncture on corticotropin-releasing hormone (CRH) in the colon, spinal cord, and hypothalamus of rats with chronic visceral hypersensitivity. METHODS: A rat model of chronic visceral hypersensitivity was generated according to the internationally accepted method of colorectal balloon dilatation. In the 7(th) week after the procedure, rats were randomly divided into a model group (MG), electroacupuncture group (EA), and sham electroacupuncture group (S-EA). After treatment, the abdominal withdrawal reflex (AWR) score was used to assess the behavioral response of visceral hyperalgesia. Immunohistochemistry (EnVision method), ELISA, and fluorescence quantitative PCR methods were applied to detect the expression of CRH protein and mRNA in the colon, spinal cord, and hypothalamus. RESULTS: The sensitivity of the rats to the colorectal distension stimulus applied at different strengths (20-80 mmHg) increased with increasing stimulus strength, resulting in increasing AWR scores in each group. Compared with NG, the AWR score of MG was significantly increased (P < 0.01). After conducting EA, the AWR scores of the rats were decreased compared with MG rats. The relative expression of CRH mRNA in the colon, spinal cord, and hypothalamus of MG rats was significantly increased compared with NG rats (P < 0.01). CRH mRNA in the colon and spinal cord of EA and S-EA rats was decreased to varying degrees (P > 0.05) compared with normal rats (NG). However, the decrease in EA compared with MG rats was statistically significant (P < 0.01). The average optical density of CRH expression in the colon of the MG rats was significantly enhanced compared with NG (P < 0.05), while the average optical density of CRH expression in the EA and S-EA rats was significantly decreased compared with MG rats (P < 0.01, P < 0.05, respectively). Compared with MG rats, the CRH concentration in the spinal cord of EA rats was significantly reduced (P < 0.01), but there was no significant change in S-EA rats (P > 0.05). CONCLUSION: Electroacupuncture at the Shangjuxu acupoint was able to significantly reduce the visceral hypersensitivity in rats, and regulated the expression of CRH protein and mRNA in the colon, spinal cord and hypothalamus at different levels, playing a therapeutic role in this model of irritable bowel syndrome. PMID- 26109805 TI - beta-2 Adrenergic receptor gene polymorphism and response to propranolol in cirrhosis. AB - AIM: To evaluate the association of beta-2 adrenergic receptor (beta2-AR) gene polymorphism with response of variceal pressure to propranolol in cirrhosis. METHODS: Sixty-four non-related cirrhotic patients participated in this study and accepted variceal pressure measurement before and after propranolol administration. Polymorphism of the beta2-AR gene was determined by directly sequencing of the polymerase chain reaction products from the DNA samples that were prepared from the patients. RESULTS: The prevalence of Gly16-Glu/Gln27 and Arg16-Gln27 homozygotes, and compound heterozygotes was 29.7%, 10.9%, and 59.4%, respectively. Patients with cirrhosis with Gly16-Glu/Gln27 homozygotes had a greater decrease of variceal pressure after propranolol administration than those with Arg16-Gln27 homozygotes or with compound heterozygotes (22.4% +/- 2.1%, 13.1% +/- 2.7% and 12.5% +/- 3.1%, respectively, P < 0.01). CONCLUSION: The variceal pressure response to propranolol was associated with polymorphism of beta2-AR gene. Patients with the Gly(16)-Glu/Gln(27) homozygotes probably benefit from propranolol therapy. PMID- 26109806 TI - Paeoniflorin inhibits human gastric carcinoma cell proliferation through up regulation of microRNA-124 and suppression of PI3K/Akt and STAT3 signaling. AB - AIM: To examine the potential anti-tumor activity of paeoniflorin in the human gastric carcinoma cell line MGC-803. METHODS: Cell viability and cytotoxic effects in MGC-803 cells were analyzed using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and lactate dehydrogenase assay, respectively. Cell apoptosis of MGC-803 cells was measured using flow cytometry, DAPI staining assay and caspase-3 activity assay. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the expression of microRNA-124 (miR-124) in response to paeoniflorin. The expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), phospho-Akt (p-Akt) and phospho-signal transducer and activator of transcription 3 (p-STAT3) were also measured by quantitative RT-PCR and Western blot analysis in normal, miR-124 and anti-miR-124 over-expressing MGC 803 cells, treated with paeoniflorin. RESULTS: Paeoniflorin was found to inhibit MGC-803 cell viability in a dose-dependent manner. Paeoniflorin treatment was associated with the induction of apoptosis and caspase-3 activity in MGC-803 cells. Paeoniflorin treatment significantly increased miR-124 levels and inhibited the expression of PI3K, Akt, p-Akt and p-STAT3 in MGC-803 cells. Interestingly, the over-expression of miR-124 inhibits PI3K/Akt and phospho-STAT3 expressions in MGC-803 cells. PI3K agonist (IGF-1, 1 MUg/10 MUL) or over expression of STAT3 reversed the effect of paeoniflorin on the proliferation of MGC-803 cells. Over-expression of anti-miR-124 in MGC-803 cells reversed paeoniflorin-induced up-regulation. CONCLUSION: In summary, the in vitro data suggest that paeoniflorin is a potential novel therapeutic agent against gastric carcinoma, which inhibits cell viability and induces apoptosis through the up regulation of miR-124 and suppression of PI3K/Akt and STAT3 signaling. PMID- 26109807 TI - Long noncoding RNAs in hepatitis B virus-related hepatocellular carcinoma. AB - AIM: To study the expression of long noncoding RNAs (lncRNAs) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: The lncRNA profiles between HBV-related HCC tissues and corresponding normal liver tissues were generated using microarray analysis. Datasets were analyzed using multiple algorithms to depict alterations in gene expression on the basis of gene ontology (GO), pathway analysis, and lncRNA levels. RESULTS: The microarray revealed that 1772 lncRNAs and 2508 mRNAs were differently expressed. The pathway analysis demonstrated that the cell cycle, cytokine-cytokine receptor interaction, chemokine signaling pathway, and phosphoinositide 3-kinase-protein kinase B signaling pathway may play important roles in HCC. Several GO terms, such as cell cycle, DNA replication, immune response, and signal transduction, were enriched in gene lists, suggesting a potential correlation with HBV-related HCC. The upregulated large intergenic noncoding RNA ULK4P2 was physically combined with enhancer of zeste homolog 2. Therefore, the lncRNAs may participate in regulating HBV-related HCC. CONCLUSION: lncRNAs play important roles in HCC, future studies should verify whether large intergenic noncoding ULK4P2 functions by combining with enhancer of zeste homolog 2 in HCC. PMID- 26109808 TI - Impact of body mass index on complications following pancreatectomy: Ten-year experience at National Cancer Center in China. AB - AIM: To examine the impact of body mass index (BMI) on outcomes following pancreatic resection in the Chinese population. METHODS: A retrospective cohort study using prospectively collected data was conducted at the Cancer Hospital of the Chinese Academy of Medical Sciences, China National Cancer Center. Individuals who underwent pancreatic resection between January 2004 and December 2013 were identified and included in the study. Persons were classified as having a normal weight if their BMI was < 24 kg/m(2) and overweight/obese if their BMI was >= 24 kg/m(2) as defined by the International Life Sciences Institute Focal Point in China. A chi(2) test (for categorical variables) or a t test (for continuous variables) was used to examine the differences in patients' characteristics between normal weight and overweight/obese groups. Multiple logistic regression models were used to assess the associations of postoperative complications, operative difficulty, length of hospital stay, and cost with BMI, adjusting for age, sex, and type of surgery procedures. RESULTS: A total of 362 consecutive patients with data available for BMI calculation underwent pancreatic resection for benign or malignant disease from January 1, 2004 to December 31, 2013. Of the 362 patients, 156 were overweight or obese and 206 were of normal weight. One or more postoperative complications occurred in 35.4% of the patients following pancreatic resection. Among patients who were overweight or obese, 42.9% experienced one or more complications, significantly higher than normal weight (29.6%) individuals (P = 0.0086). Compared with individuals who had normal weight, those with a BMI >= 24.0 kg/m(2) had higher delayed gastric emptying (19.9% vs 5.8%, P < 0.0001) and bile leak (7.7% vs 1.9%, P = 0.0068). There were no significant differences seen in pancreatic fistula, gastrointestinal hemorrhage, reoperation, readmission, or other complications. BMI did not show a significant association with intraoperative blood loss, operative time, length of hospital stay, or cost. CONCLUSION: Higher BMI increases the risk for postoperative complications after pancreatectomy in the Chinese population. The findings require replication in future studies with larger sample sizes. PMID- 26109809 TI - Comparison of non-schistosomal rectosigmoid cancer and schistosomal rectosigmoid cancer. AB - AIM: To compare the clinicopathological features of patients with non schistosomal rectosigmoid cancer and schistosomal rectosigmoid cancer. METHODS: All the patients with rectosigmoid carcinoma who underwent laparoscopic radical surgical resection in the Shanghai Minimally Invasive Surgical Center at Ruijin Hospital affiliated to Shanghai Jiao-Tong University between October 2009 and October 2013 were included in this study. Twenty-six cases of colonic schistosomiasis diagnosed through colonoscopy and pathological examinations were collected. Symptoms, endoscopic findings and clinicopathological characteristics were evaluated retrospectively. RESULTS: There were no significant differences between patients with and without schistosomiasis in gender, age, CEA, CA19-9, preoperative biopsy findings or postoperative pathology. Patients with rectosigmoid schistosomiasis had a significantly higher CA-125 level and a larger proportion of these patients were at an early tumor stage (P = 0.003). Various morphological characteristics of schistosomiasis combined with rectosigmoid cancer could be found by colonoscopic examination: 46% were fungating mass polyps, 23% were congestive and ulcerative polyps, 23% were cauliflower-like masses, 8% were annular masses. Only 27% of the patients were diagnosed with rectal carcinoma preoperatively after the biopsy. Computed tomography (CT) scans showed thickened intestinal walls combined with linear and tram-track calcifications in 26 patients. CONCLUSION: Rectosigmoid carcinoma combined with schistosomiasis is associated with higher CA-125 values and early tumor stages. CA-125 and CT scans have a reasonable sensitivity for the accurate diagnosis. PMID- 26109810 TI - PillCam COLON 2 in Crohn's disease: A new concept of pan-enteric mucosal healing assessment. AB - AIM: To evaluate mucosal healing in patients with small bowel plus colonic Crohn's disease (CD) with a single non-invasive examination, by using PillCam COLON 2 (PCC2). METHODS: Patients with non-stricturing nonpenetrating small bowel plus colonic CD in sustained corticosteroid-free remission were included. At diagnosis, patients had undergone ileocolonoscopy to identify active CD lesions, such as ulcers and erosions, and small bowel capsule endoscopy to assess the Lewis Score (LS). After >= 1 year of follow-up, patients underwent entire gastrointestinal tract evaluation with PCC2. The primary endpoint was assessment of CD mucosal healing, defined as no active colonic CD lesions and LS < 135. RESULTS: Twelve patients were included (7 male; mean age: 32 years), and mean follow-up was 38 mo. The majority of patients (83.3%) received immunosuppressive therapy. Three patients (25%) achieved mucosal healing in both the small bowel and the colon, while disease activity was limited to either the small bowel or the colon in 5 patients (42%). It was possible to observe the entire gastrointestinal tract in 10 of the 12 patients (83%) who underwent PCC2. CONCLUSION: Only three patients in sustained corticosteroid-free clinical remission achieved mucosal healing in both the small bowel and the colon, highlighting the limitations of clinical assessment when stratifying disease activity, and the need for pan-enteric endoscopy to guide therapeutic modification. PMID- 26109811 TI - Risk factors for small bowel angioectasia: The impact of visceral fat accumulation. AB - AIM: To investigate visceral fat accumulation in association with the risk of small bowel angioectasia. METHODS: We retrospectively investigated 198 consecutive patients who underwent both capsule endoscopy and CT for investigation of obscure gastrointestinal bleeding (OGIB) from January 2009 to September 2013. The visceral fat area (VFA) and subcutaneous fat area were measured by CT, and information on comorbidities, body mass index, and medications was obtained from their medical records. Logistic regression analysis was used to evaluate associations. RESULTS: Capsule endoscopy revealed small bowel angioectasia in 18/198 (9.1%) patients with OGIB. Compared to patients without small bowel angioectasia, those with small bowel angioectasia had a significantly higher VFA (96 +/- 76.0 cm(2) vs 63.4 +/- 51.5 cm(2), P = 0.016) and a higher prevalence of liver cirrhosis (61% vs 22%, P < 0.001). The proportion of patients with chronic renal failure was higher in patients with small bowel angioectasia (22% vs 9%, P = 0.11). There were no significant differences in subcutaneous fat area or waist circumference. The prevalence of small bowel angioectasia progressively increased according to the VFA. Multivariate analysis showed that the VFA [odd ratio (OR) for each 10-cm(2) increment = 1.1; [95% confidence interval (CI): 1.02-1.19; P = 0.021] and liver cirrhosis (OR = 6.1, 95%CI: 2.2-18.5; P < 0.001) were significant risk factors for small bowel angioectasia. CONCLUSION: VFA is positively associated with the prevalence of small bowel angioectasia, for which VFA and liver cirrhosis are independent risk factors in patients with OGIB. PMID- 26109813 TI - High level of intercellular adhesion molecule-1 affects prognosis of patients with hepatocellular carcinoma. AB - AIM: To determine the cut-off value of intercellular adhesion molecule-1 (ICAM-1) and assess the correlation of ICAM-1 with clinicopathological features and the prognosis of hepatocellular carcinoma (HCC) patients who underwent surgical resection. METHODS: We prospectively collected clinicopathological data from 236 HCC patients who had undergone successful hepatectomy. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value of ICAM-1. Enzyme-linked immunosorbent assay was used to measure the concentration of ICAM-1 in 236 serum samples isolated from HCC patients and the stratified analysis was used to compare the serum level of ICAM-1 in different HCC subgroups. Immunohistochemistry was performed to test the expression level of the ICAM-1 protein in 76 cases of HCC tissues and their adjacent normal liver tissues (ANLT). The survival probability of HCC patients was estimated using Kaplan-Meier plots and differences between the groups were obtained using the log rank test. Furthermore, independent indicators of the prognosis were acquired using a stepwise Cox proportional hazard model to analyze a series of predictors that were associated with disease-free survival (DFS) and overall survival (OS) in HCC patients. RESULTS: Our findings suggested that ICAM-1 promotes HCC metastasis and high serum ICAM-1 is significantly associated with alpha fetoprotein (AFP) (P = 0.022), clinical tumor-node-metastasis stage (P < 0.001), portal vein tumor thrombus (P = 0.005), distant metastasis (P = 0.016) and recurrence (P = 0.034). We further detected the ICAM-1 protein in HCC specimens and found that 56 of 76 (73.7%) HCC tissues had ICAM-1 positive staining while only 23 of 76 (30.3%) ANLT were positively stained (P < 0.0001). Survival analysis indicated that HCC patients with increased ICAM-1 concentrations had significantly shorter DFS and OS after resection. A multivariate analysis showed that ICAM-1 > 684 ng/mL was an independent factor for DFS (HR = 1.643; 95%CI: 1.125-2.401; P = 0.010) and OS (HR = 1.692; 95%CI: 1.152-2.486; P = 0.007). CONCLUSION: ICAM-1 may be a promising serological biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection and may provide a useful reference for the prediction of intra- and extrahepatic metastasis. PMID- 26109812 TI - Living donor liver transplantation with body-weight more or less than 10 kilograms. AB - AIM: To compare the outcomes of pediatric patients weighing less than or more than 10 kg who underwent liver transplantation. METHODS: Data for 196 pediatric patients who underwent living donor liver transplantation between June 1994 and February 2011 were reviewed retrospectively. The information for each patient was anonymized and de-identified before analysis. The data included information regarding the pre-transplant conditions, intraoperative fluid replacement and outcomes for each patient. The 196 patients were divided into two groups: those with body weights of less than 10 kg were included in group 1 (G1; n = 101), while those with body weights of more than 10 kg were included in group 2 (G2; n = 95). For each group, the patients' ages, body weights, heights, pediatric end stage liver disease scores, anesthesia times, and warm and cold ischemic times were analyzed. In addition, between-group comparisons were also made. Mann Whitney U tests were used to compare all the variables except for complications and survival rates, which were analyzed using chi(2) tests and Kaplan-Meier tests, respectively. RESULTS: The general medical conditions of the G1 patients were worse than those of the G2 patients, as shown by the higher pediatric end stage liver disease scores and poorer Z-scores. In addition, the pre-operative Hb and serum albumin levels were all lower for the G1 patients than for the G2 patients. The G1 patients also had significantly more intraoperative blood loss than the G2 patients. In addition, the intraoperative fluid requirements for the G1 patients, including leukocyte poor red blood cell transfusions, 5% albumin infusions and crystalloid infusions, were significantly higher than those for the G2 patients. The risk of intraoperative portal vein thrombosis was higher for the patients in G1 than for those in G2. However, the one-year survival rates (95.9% and 96.8% for G1 and G2, respectively) and three-year survival rates (94.9% and 94.6% for G1 and G2, respectively) for both groups were similar. CONCLUSION: Patients weighing less than 10 kg typically have poorer conditions, but their survival rates are comparable to those of children weighing more than 10 kg. PMID- 26109814 TI - Autologous mobilized peripheral blood CD34(+) cell infusion in non-viral decompensated liver cirrhosis. AB - AIM: To study the effect of mobilized peripheral blood autologous CD34 positive (CD34(+)) cell infusion in patients with non-viral decompensated cirrhosis. METHODS: Cirrhotic patients of non-viral etiology were divided into 2 groups based on their willingness to be listed for deceased donor liver transplant (DDLT) (control, n = 23) or to receive autologous CD34(+) cell infusion through the hepatic artery (study group, n = 22). Patients in the study group were admitted to hospital and received granulocyte colony stimulating factor injections 520 MUg/d for 3 consecutive days to mobilize CD34(+) cells from the bone marrow. On day 4, leukapheresis was done and CD34(+) cells were isolated using CliniMAC magnetic cell sorter. The isolated CD34(+) cells were infused into the hepatic artery under radiological guidance. The patients were discharged within 48 h. The control group received standard of care treatment for liver cirrhosis and were worked up for DDLT as per protocol of the institute. Both groups were followed up every week for 4 wk and then every month for 3 mo. RESULTS: In the control and the study group, the cause of cirrhosis was cryptogenic in 18 (78.2%) and 16 (72.72%) and alcohol related in 5 (21.7%) and 6 (27.27%), respectively. The mean day 3 cell count (cells/MUL) was 27.00 +/- 20.43 with a viability of 81.84 +/- 11.99%. and purity of 80%-90%. Primary end point analysis revealed that at 4 wk, the mean serum albumin in the study group increased significantly (2.83 +/- 0.36 vs 2.43 +/- 0.42, P = 0.001) when compared with controls. This improvement in albumin was, however, not sustained at 3 mo. However, at the end of 3 mo there was a statistically significant improvement in serum creatinine in the study group (0.96 +/- 0.33 vs 1.42 +/- 0.70, P = 0.01) which translated into a significant improvement in the Model for End-Stage Liver Disease score (15.75 +/- 5.13 vs 19.94 +/- 6.68, P = 0.04). On statistical analysis of secondary end points, the transplant free survival at the end of 1 mo and 3 mo did not show any significant difference (P = 0.60) when compared to the control group. There was no improvement in aspartate transaminase, alanine transaminase, and bilirubin at any point in the study population. There was no mortality benefit in the study group. The procedure was safe with no procedural or treatment related complications. CONCLUSION: Autologous CD 34(+) cell infusion is safe and effectively improves liver function in the short term and may serve as a bridge to liver transplantation. PMID- 26109815 TI - Prevalence and predictors of hospitalization in Crohn's disease in a prospective population-based inception cohort from 2000-2012. AB - AIM: To analyze the prevalence, length and predictors of hospitalization in the biological era in the population-based inception cohort from Veszprem province. METHODS: Data of 331 incident Crohn's disease (CD) patients diagnosed between January 1, 2000 and December 31, 2010 were analyzed (median age at diagnosis: 28; IQR: 21-40 years). Both in- and outpatient records were collected and comprehensively reviewed. RESULTS: Probabilities of first CD-related hospitalization and re-hospitalization were 32.3%, 45.5%, 53.7% and 13.6%, 23.9%, 29.8%, respectively after one, three and five years of follow-up in Kaplan-Meier analysis. First-year hospitalizations were related to diagnostic procedures (37%), surgery or disease activity (27% and 21%). Non-inflammatory disease behavior at diagnosis (HR = 1.32, P = 0.001) and perianal disease (HR = 1.47, P = 0.04) were associated with time to first CD-related hospitalization, while disease behavior change (HR = 2.38, P = 0.002) and need for steroids (HR = 3.14, P = 0.003) were associated with time to first re-hospitalization in multivariate analyses. Early CD-related hospitalization (within the year of diagnosis) was independently associated with need for immunosuppressives (OR = 2.08, P = 0.001) and need for surgeries (OR = 7.25, P < 0.001) during the disease course. CONCLUSION: Hospitalization and re-hospitalization rates are still high in this cohort, especially during the first-year after the diagnosis. Non-inflammatory disease behavior at diagnosis was identified as the pivotal predictive factor of both hospitalization and re-hospitalization. PMID- 26109816 TI - Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study. AB - AIM: To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer (CRC) in Italy. METHODS: This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival (PFS). Secondary end-points included time to overall response (TOR), duration of response (DOR), time to treatment failure (TTF) and overall survival (OS). The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life (QoL) was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit. RESULTS: The intention-to-treat population included 197 patients (mean age: 62.3 +/- 9.9 years, 56.4% males). At baseline, 16/34 evaluable subjects (47.1%) harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 +/- 14.3. First-line therapy was given for 223.7 +/- 175.9 d, and after a mean follow-up of 387.7 +/- 238.8 d all patients discontinued from the study mainly for disease progression (PD, 45.4%) and AEs (25.4%). Median PFS was 9.7 mo (95%CI: 8.4-10.5) and the median values for secondary end-points were: TOR = 3.9 mo (95%CI: 2.6 4.7), DOR = 8.5 mo (95%CI: 7.3-10.3), TTF = 6.7 mo (95%CI: 6.0-7.7) and OS = 23.2 mo (95%CI: 20.1-27.2). Patients carrying at least one lesion had a lower overall response rate (66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant (P = 0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 +/- 19.1 at the last visit (signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good. CONCLUSION: The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity. PMID- 26109817 TI - Is endoscopic papillary large balloon dilatation without endoscopic sphincterotomy effective? AB - AIM: To evaluate the safety and efficacy of endoscopic papillary large balloon dilatation (EPLBD) without endoscopic sphincterotomy in a prospective study. METHODS: From July 2011 to August 2013, we performed EPLBD on 41 patients with naive papillae prospectively. For sphincteroplasty of EPLBD, endoscopic sphincterotomy (EST) was not performed, and balloon diameter selection was based on the distal common bile duct diameter. The balloon was inflated to the desired pressure. If the balloon waist did not disappear, and the desired pressure was satisfied, we judged the dilatation as complete. We used a retrieval balloon catheter or mechanical lithotripter (ML) to remove stones and assessed the rates of complete stone removal, number of sessions, use of ML and adverse events. Furthermore, we compared the presence or absence of balloon waist disappearance with clinical characteristics and endoscopic outcome. RESULTS: The mean diameters of the distal and maximum common bile duct were 13.5 +/- 2.4 mm and 16.4 +/- 3.1 mm, respectively. The mean maximum transverse-diameter of the stones was 13.4 +/- 3.4 mm, and the mean number of stones was 3.0 +/- 2.4. Complete stone removal was achieved in 97.5% (40/41) of cases, and ML was used in 12.2% (5/41) of cases. The mean number of sessions required was 1.2 +/- 0.62. Pancreatitis developed in two patients and perforation in one. The rate of balloon waist disappearance was 73.1% (30/41). No significant differences were noted in procedure time, rate of complete stone removal (100% vs 100%), number of sessions (1.1 vs 1.3, P = 0.22), application of ML (13% vs 9%, P = 0.71), or occurrence of pancreatitis (3.3% vs 9.1%, P = 0.45) between cases with and without balloon waist disappearance. CONCLUSION: EST before sphincteroplasty may be unnecessary in EPLBD. Further investigations are needed to verify the relationship between the presence or absence of balloon waist disappearance. PMID- 26109818 TI - Different roles of capsule endoscopy and double-balloon enteroscopy in obscure small intestinal diseases. AB - AIM: To compare the roles of capsule endoscopy (CE) and double-balloon enteroscopy (DBE) in the diagnosis of obscure small bowel diseases. METHODS: From June 2009 to December 2014, 88 patients were included in this study; the patients had undergone gastroscopy, colonoscopy, radiological small intestinal barium meal, abdominal computed tomography or magnetic resonance imaging scan and mesenteric angiography, but their diagnoses were still unclear. The patients with gastrointestinal obstructions, fistulas, strictures, or cardiac pacemakers, as well as pregnant women, and individuals who could not accept the capsule retention or capsule-removal surgery were excluded. Patients with heart, lung and other vital organ failure diseases were also excluded. Everyone involved in this study had undergone CE and DBE. The results were divided into: (1) the definite diagnosis (the diagnosis was confirmed at least by one of the biopsy, surgery, pathology or the drug treatment effects with follow-up for at least 3 mo); (2) the possible diagnosis (a possible diagnosis was suggested by CE or DBE, but not confirmed by the biopsy, surgery or follow-up drug treatment effects); and (3) the unclear diagnosis (no exact causes were provided by CE and DBE for the disease). The detection rate and the diagnostic yield of the two methods were compared. The difference in the etiologies between CE and DBE was estimated, and the different possible etiologies caused by the age groups were also investigated. RESULTS: CE exhibited a better trend than DBE for diagnosing scattered small ulcers (P = 0.242, Fisher's test), and small vascular malformations (chi(2) = 1.810, P = 0.179, Pearson chi(2) test), but with no significant differences, possible due to few cases. However, DBE was better than CE for larger tumors (P = 0.018, Fisher's test) and for diverticular lesions with bleeding ulcers (P = 0.005, Fisher's test). All three hemangioma cases diagnosed by DBE in this study (including sponge hemangioma, venous hemangioma, and hemangioma with hamartoma lesions) were all confirmed by biopsy. Two parasite cases were found by CE, but were negative by DBE. This study revealed no obvious differences in the detection rates (DR) of CE (60.0%, 53/88) and DBE (59.1%, 52/88). However, the etiological diagnostic yield (DY) difference was apparent. The CE diagnostic yield was 42.0% (37/88), and the DBE diagnostic yield was 51.1% (45/88). Furthermore, there were differences among the age groups (chi(2) = 22.146, P = 0.008, Kruskal Wallis Test). Small intestinal cancer (5/6 cases), vascular malformations (22/29 cases), and active bleeding (3/4 cases) appeared more commonly in the patients over 50 years old, but diverticula with bleeding ulcers were usually found in the 15-25-year group (4/7cases). The over-25-year group accounted for the stromal tumors (10/12 cases). CONCLUSION: CE and DBE each have their own advantages and disadvantages. The appropriate choice depends on the patient's age, tolerance, and clinical manifestations. Sometimes CE followed by DBE is necessary. PMID- 26109819 TI - Recombinant streptokinase vs hydrocortisone suppositories in acute hemorrhoids: A randomized controlled trial. AB - AIM: To compare the efficacy and safety of recombinant streptokinase (rSK) vs hydrocortisone acetate-based suppositories in acute hemorrhoidal disease. METHODS: A multicenter (11 sites), randomized (1:1:1), open, controlled trial with parallel groups was performed. All participating patients gave their written, informed consent. After inclusion, patients with acute symptoms of hemorrhoids were centrally randomized to receive, as outpatients, by the rectal route, suppositories of rSK 200000 IU of one unit every 8 h (first 3 units) and afterwards every 12 h until 8 administrations were completed (schedule A), one unit every 8 h until 6 units were completed (schedule B), or 25 mg hydrocortisone acetate once every 8 h up to a maximum of 24 administrations. Evaluations were performed at 3, 5, and 10 d post-inclusion. The main end-point was the 5(th)-day response (disappearance of pain and bleeding, and >= 70% reduction of the lesion size). Time to response and need for thrombectomy were secondary efficacy variables. Adverse events were also evaluated. RESULTS: Groups were homogeneous with regards to demographic and baseline characteristics. Fifth day complete response rates were 156/170 (91.8%; 95%CI: 87.3-96.2), 155/170 (91.2%; 95%CI: 86.6%-95.7%), and 46/170 (27.1%; 95%CI: 20.1%-34.0%) with rSK (schedule A and B) and hydrocortisone acetate suppositories, respectively. These 64.6% and 63.9% differences (95%CI: 56.7%-72.2% and 55.7%-72.0%) were highly significant (P < 0.001). This advantage was detected since the early 3(rd) day evaluation (68.8% and 64.1% vs 7.1% for the rSK and active control groups, respectively; P < 0.001) and was maintained even at the late 10(th) day assessment (97.1% and 93.5% vs 67.1% for rSK and hydrocortisone acetate, respectively; P < 0.001). Time to response was 3 d (95%CI: 2.9-3.1) for both rSK groups and 10 d (95%CI: 9.3-10.7) in the hydrocortisone acetate group. This difference was highly significant (P < 0.001). All subgroup stratified analyses (with or without thrombosis and hemorrhoid classification) showed a statistically significant advantage for the rSK groups. Thrombectomy was necessary in 4/251 and 14/133 patients with baseline thrombosis in the rSK and hydrocortisone acetate groups, respectively (P < 0.001). There were no adverse events attributable to the experimental treatment. CONCLUSION: rSK suppositories showed a significant advantage over a widely-used over-the-counter hydrocortisone acetate preparation for the treatment of acute hemorrhoidal illness, as well as having an adequate safety profile. PMID- 26109821 TI - How to treat an extensive form of primary intestinal lymphangiectasia? AB - We report a case of a 42-year-old man with a rare disorder known as primary intestinal lymphangiectasia, which is characterized by dilated intestinal lymphatics that lead to the development of protein-losing enteropathy. The patient presented with a grand mal seizure caused by malabsorption-derived electrolytes and a protein disorder. Signs of the disease, including chronic diarrhea and peripheral edema, manifested 10 years ago, but a diagnosis was never made. The diagnosis was suspected because of the clinical manifestations, laboratory tests, imaging and endoscopic findings. Hyperemic and edematous mucosa of the small intestine corresponded to scattered white spots with dilated intestinal lymphatics and whitish villi in the histological specimen of the biopsied jejunal mucosa. Although numerous therapeutic strategies are available, only octreotide therapy proved to be an effective means of therapeutic resolution in this patient. Although the patient had a partial remission following the use of a slow release formula of octreotide, his prognosis, clinical course, and future treatment challenges are yet to be determined. PMID- 26109820 TI - Increased risk of second malignancy in pancreatic intraductal papillary mucinous tumors: Review of the literature. AB - AIM: To analyze the available evidence about the risk of extrapancreatic malignancies and pancreatic ductal adenocarcinoma associated to pancreatic intraductal papillary mucinous tumors (IPMNs). METHODS: A systematic search of literature was undertaken using MEDLINE, EMBASE, Cochrane and Web-of-Science libraries. No limitations for year of publication were considered; preference was given to English papers. All references in selected articles were further screened for additional publications. Both clinical series and Literature reviews were selected. For all eligible studies, a standard data extraction form was filled in and the following data were extracted: study design, number of patients, prevalence of pancreatic cancer and extrapancreatic malignancies in IPMN patients and control groups, if available. RESULTS: A total of 805 abstracts were selected and read; 25 articles were considered pertinent and 17 were chosen for the present systematic review. Eleven monocentric series, 1 multicentric series, 1 case-control study, 1 population-based study and 3 case report were included. A total of 2881 patients were globally analyzed as study group, and the incidence of pancreatic cancer and/or extrapancreatic malignancies ranged from 5% to 52%, with a mean of 28.71%. When a control group was analyzed (6 papers), the same incidence was as low as 9.4%. CONCLUSION: The available Literature is unanimous in claiming IPMNs to be strongly associated with pancreatic and extrapancreatic malignancies. The consequences in IPMNs management are herein discussed. PMID- 26109822 TI - Hemorrhagic hemangioma in the liver: A case report. AB - Hemangioma is the most common type of benign tumor that arises in the liver. Although rupture and hemorrhage of hepatic hemangioma are rare complications, they can be the cause of mortality. The authors report a case of hemorrhagic hepatic hemangioma: in a 54-year-old woman who was admitted with epigastric pain. She had taken oral contraceptives several weeks prior. The results of a blood examination were normal. An abdominal computed tomography scan revealed a tumor in hepatic segment 4, and a hemorrhage inside the cystic mass was suspected. The mass was removed laparoscopically to confirm the tumor properties and control the hemorrhage. The pathologic findings of the resected mass were consistent with hepatic hemangioma with intratumoral hemorrhage. The patient was discharged 8 d after the surgery, without further complications or complaints, and the patient's condition was found to have improved during follow-up. PMID- 26109823 TI - Citrin deficiency presenting as acute liver failure in an eight-month-old infant. AB - Citrin deficiency typically presents as neonatal intrahepatic cholestasis and resolves in late infancy. Here we report a case of citrin deficiency that presented as acute liver failure in late infancy in an apparently healthy child. The full-term male infant weighed 3400 g at birth, and exhibited normal development for eight months, at which time he contracted bronchial pneumonia. The infant developed jaundice and laboratory tests indicated elevated bilirubin and ammonia levels and an abnormal coagulation profile. Plasma amino acid analysis showed elevated levels of tyrosine, methionine, citrulline, and arginine. Citrin deficiency was suspected, and genomic DNA analysis revealed a mutation (IVS16ins3kb) in SLC25A13, which encodes a mitochondrial aspartate glutamate carrier protein. The infant was immediately put on a lactose-free, medium-chain-triglyceride-enriched formula with ursodeoxycholic acid and lipid soluble vitamins. However, cholestasis and abnormal laboratory indices persisted, and the infant died at the age of 11.5 mo, two days before a scheduled liver transplantation. This case demonstrates that citrin deficiency can present in late infancy as acute liver failure triggered by infection, and may require liver transplantation. PMID- 26109825 TI - Instructions to Authors modifications. PMID- 26109824 TI - Primary combined hepatocellular-cholangiocellular sarcoma: An unusual case. AB - Primary liver carcinosarcoma is rare. Here we report an unusual case of liver carcinosarcoma containing combined hepatocellular cholangiocarcinoma. A mass in the right liver lobe of a 45-year-old man was accidentally discovered by ultrasonic inspection and computed tomography (CT) scan. Surgical resection was performed following a diagnosis of primary liver cancer. Micropathologically, both carcinomatous and sarcomatous elements were present, and diagnosis of liver carcinosarcoma was confirmed. The carcinomatous element consisted of hepatocellular carcinoma and foci of cholangiocellular carcinoma. The sarcomatous element was composed of spindle cells and bizarre cells, as well as foci of osteosarcoma and chondrosarcoma. Hepatocellular carcinoma cells diffusely expressed both hepatocyte specific markers cytokeratin (CK) 8/18 and cholangiocyte specific markers CK19, and sarcoma cells were positive for vimentin. Interestingly, both carcinomatous and sarcomatous cells expressed epithelial membrane antigen. CD117-positive ductular reactions and small undifferentiated cells were observed. A liver progenitor cell origin of the liver carcinosarcoma was proposed. PMID- 26109826 TI - The flexion-rotation test performed actively and passively: a comparison of range of motion in patients with cervicogenic headache. AB - Limitation in cervical spine range of motion (ROM) is one criterion for diagnosis of cervicogenic headaches (CHs). The flexion-rotation test, when performed passively (FRT-P), has been shown to be a useful test in diagnosis of CH. Few investigations have examined the flexion-rotation test when performed actively (FRT-A) by the individual, and no studies have examined the FRT-A in a symptomatic population. The purpose of this study was to compare ROM during the FRT-A and FRT-P in patients with CH and asymptomatic individuals and to compare ROM between sides for these two versions of the test. Twelve patients with CH and 10 asymptomatic participants were included in the study. An eight-camera Motion Analysis system was used to measure head motion relative to the trunk during the FRT-P and the FRT-A. Cervical rotation ROM was measured in a position of full cervical flexion for both tests. No significant difference was observed between right and left sides for cervical rotation ROM during the FRT-P nor the FRT-A when performed by asymptomatic participants. In patients with CH, a significant difference was observed between sides for the FRT-P (P = 0.014); however, the FRT A failed to reveal bilateral descrepancy in rotation ROM. PMID- 26109827 TI - Knowledge translation from continuing education to physiotherapy practice in classifying patients with low back pain. AB - OBJECTIVES: Physical therapists have used continuing education as a method of improving their skills in conducting clinical examination of patients with low back pain (LBP). The purpose of this study was to evaluate how well the pathoanatomical classification of patients in acute or subacute LBP can be learned and applied through a continuing education format. The patients were seen in a direct access setting. METHODS: The study was carried out in a large health care center in Finland. The analysis included a total of 57 patient evaluations generated by six physical therapists on patients with LBP. We analyzed the consistency and level of agreement of the six physiotherapists' (PTs) diagnostic decisions, who participated in a 5-day, intensive continuing education session and also compared those with the diagnostic opinions of two expert physical therapists, who were blind to the original diagnostic decisions. Evaluation of the physical therapists' clinical examination of the patients was conducted by the two experts, in order to determine the accuracy and percentage agreement of the pathoanatomical diagnoses. RESULTS: The percentage of agreement between the experts and PTs was 72-77%. The overall inter-examiner reliability (kappa coefficient) for the subgroup classification between the six PTs and two experts was 0.63 [95% confidence interval (CI): 0.47-0.77], indicating good agreement between the PTs and the two experts. The overall inter-examiner reliability between the two experts was 0.63 (0.49-0.77) indicating good level of agreement. DISCUSSION: Our results indicate that PTs' were able to apply their continuing education training to clinical reasoning and make consistently accurate pathoanatomic based diagnostic decisions for patients with LBP. This would suggest that continuing education short-courses provide a reasonable format for knowledge translation (KT) by which physical therapists can learn and apply new information related to the examination and differential diagnosis of patients in acute or subacute LBP. PMID- 26109828 TI - A preliminary study comparing the use of cervical/upper thoracic mobilization and manipulation for individuals with mechanical neck pain. AB - OBJECTIVES: Neck pain is routinely managed using manual therapy (MT) to the cervical and thoracic spines. While both mobilizations and manipulations to these areas have been shown to reduce neck pain, increase cervical range of motion, and reduce disability, the most effective option remains elusive. The purpose of this preliminary trial was to compare the pragmatic use of cervical and thoracic mobilizations vs. manipulation for mechanical neck pain. METHODS: This trial included 20 patients with mechanical neck pain. Each patient was randomized to receive either mobilization or manipulation to both the cervical and thoracic spines during their plan of care. Within-group analyses were made with Wilcoxon signed-rank tests and between-group analyses were made with Mann-Whitney U. RESULTS: There were no between-group differences for any of the dependent variables including cervical active range of motion (CAROM) (P = 0.18), deep cervical flexion (DCF) endurance (P = 0.06), numerical pain rating scale (NPRS) (P = 0.26), the neck disability index (NDI, P = 0.33), patient-specific functional scale (PSFS, P = 0.20), or the global rating of change (GROC) scale (P = 0.94). Within-group results were significant for all outcome variables (P<0.001) from initial evaluation to discharge for both groups. DISCUSSION: These findings were consistent with other trials previously conducted that applied the MT techniques in a pragmatic fashion, but varied from previous trials where the treatment was standardized. A larger experimental study is necessary to further examine the differences between mobilization and manipulation for neck pain. PMID- 26109829 TI - Risk factors associated with sacral stress fractures: a systematic review. AB - OBJECTIVES: The objective of this study was to examine and identify risk factors associated with the development of sacral stress fractures in order to improve diagnosis in clinical practice. METHODS: Electronic search strategies in PubMed, CINAHL, Scopus, and SPORTDiscus were combined with a hand search to identify articles for inclusion. Studies were considered if they described patient cases in which imaging confirmed diagnosis of a sacral stress fracture, and the diagnosis included whether the fracture was a sacral insufficiency or sacral fatigue stress fracture. RESULTS: In those that developed sacral insufficiency fractures, the risk factors that were most prevalent included osteoporosis, pelvic radiation therapy, rheumatoid arthritis, long-term corticosteroid therapy, and postmenopausal, each with a prevalence of 100%. Risk factors with 100% prevalence in those diagnosed with sacral fatigue fractures included recent increase in training intensity and deficient diet. DISCUSSION: A pattern of signs and symptoms are consistent among subjects with sacral stress fractures. Patients being unsuccessfully treated for low-back and buttock pain who fit the risk factor profiles for sacral stress fractures should be referred to a physician for further diagnostic workup. PMID- 26109830 TI - Congenital 'butterfly vertebra' associated with low back pain: a case report. AB - The butterfly vertebral defect is a rare congenital anomaly of the spine, which is generally considered benign. In this report we present the case of an active young man who presented with recurrent low back pain (LBP), and was found to have a butterfly vertebral defect at the symptomatic L4 lumbar spinal level. We describe the genesis of the butterfly vertebral defect, in the context of normal embryological development of the human vertebra and intervertebral disk. We report the clinical examination findings and therapeutic interventions undertaken prior to the radiographic discovery of the vertebral defect, and discuss the impact that the presence of a butterfly vertebral defect presented to therapeutic decision-making. PMID- 26109831 TI - Comparable effect of simulated side bending and side gliding positions on the direction and magnitude of lumbar disc hydration shift: in vivo MRI mechanistic study. AB - OBJECTIVES: To investigate the direction and magnitude of mechanical influence to the lumbar disc in side bending and side gliding positions by considering shift of disc hydration. METHODS: Twenty asymptomatic subjects completed this study. Direction of the hydration shift (theta), magnitude of the shift, and segmental lateral flexion and rotation angles from L1/L2 to L5/S1 during left side bend and side glide in lying were measured by magnetic resonance imaging (MRI) and compared using paired t-tests. RESULTS: A significant difference (P<0.001) was detected in the segmental lateral flexion angle at L1/L2 between the side bending position (mean [SD], 5.1 degrees [2.2 degrees ] left lateral flexion) and the side gliding position (mean [SD], 2.1 degrees [2.7 degrees ] left lateral flexion). However, there was neither significant difference (P>0.05) in the lateral flexion angle at other segments nor rotation angles at each segment between the two lumbar positions. There was also no significant difference (P>0.05) in the theta value and magnitude of the hydration shift between the two lumbar positions. The disc hydration generally shifted to the right in the left side bending and side gliding positions at all disc levels. DISCUSSION: This is the first study to investigate mechanical influence to each lumbar disc in the side gliding position using the shift of disc hydration on axial MRI. The comparability in the direction and magnitude of the hydration shift in the side bending and side gliding positions indicates that the maneuver of side gliding can produce comparable ipsilateral mechanical influence to each lumbar disc in comparison to side bending. PMID- 26109832 TI - Physical therapists' treatment choices for non-specific low back pain in Florida: an electronic survey. AB - OBJECTIVES: No study has described low back pain (LBP) treatment choices among physical therapists (PTs) in the United States (US) in the new millennium. Intervention for LBP in the new millennium is largely based on evidence-based practice (EBP) recommendations. The purpose of this study was twofold: (a) to describe PTs' preferences for treating acute and subacute non-specific LBP in Florida and to compare these preferences to EBP guideline recommendations and (b) to compare outpatient musculoskeletal therapist (MSPT) choices for management of acute and subacute LBP to non-outpatient musculoskeletal therapist (NMSPT) choices. METHODS: The data were collected with an electronic survey. Study participants selected treatment choices for acute and subacute LBP clinical vignettes. RESULTS: A total of 327 PTs participated in the study, of which 128 worked in outpatient musculoskeletal settings. The most common treatment choices for acute and subacute LBP were home exercise program, exercise in the clinic, back care education, joint mobilization, ice/heat, and interferential current. The EBP adherence rate for acute LBP was 30% for MSPTs and 15% for NMSPTs. Thirty seven percent (37%) of MSPTs and 30% of NMSPTs adhered to EBP guidelines for subacute LBP. DISCUSSION: The EBP adherence rate for management of acute and subacute LBP was low. Spinal manipulation was underutilized for management of acute LBP, and passive therapeutic procedures were overutilized for subacute LBP. Physical Therapy schools and professional associations should reemphasize the benefits of spinal manipulation to manage non-specific acute LBP and active interventional procedures to manage subacute LBP. PMID- 26109833 TI - In pursuit of rigour and accountability in participatory design. AB - The field of Participatory Design (PD) has greatly diversified and we see a broad spectrum of approaches and methodologies emerging. However, to foster its role in designing future interactive technologies, a discussion about accountability and rigour across this spectrum is needed. Rejecting the traditional, positivistic framework, we take inspiration from related fields such as Design Research and Action Research to develop interpretations of these concepts that are rooted in PD's own belief system. We argue that unlike in other fields, accountability and rigour are nuanced concepts that are delivered through debate, critique and reflection. A key prerequisite for having such debates is the availability of a language that allows designers, researchers and practitioners to construct solid arguments about the appropriateness of their stances, choices and judgements. To this end, we propose a "tool-to-think-with" that provides such a language by guiding designers, researchers and practitioners through a process of systematic reflection and critical analysis. The tool proposes four lenses to critically reflect on the nature of a PD effort: epistemology, values, stakeholders and outcomes. In a subsequent step, the coherence between the revealed features is analysed and shows whether they pull the project in the same direction or work against each other. Regardless of the flavour of PD, we argue that this coherence of features indicates the level of internal rigour of PD work and that the process of reflection and analysis provides the language to argue for it. We envision our tool to be useful at all stages of PD work: in the planning phase, as part of a reflective practice during the work, and as a means to construct knowledge and advance the field after the fact. We ground our theoretical discussions in a specific PD experience, the ECHOES project, to motivate the tool and to illustrate its workings. PMID- 26109835 TI - A simple program to measure and analyse tree rings using Excel, R and SigmaScan. AB - I present a new software that links a program for image analysis (SigmaScan), one for spreadsheets (Excel) and one for statistical analysis (R) for applications of tree-ring analysis. The first macro measures ring width marked by the user on scanned images, stores raw and detrended data in Excel and calculates the distance to the pith and inter-series correlations. A second macro measures darkness along a defined path to identify latewood-earlywood transition in conifers, and a third shows the potential for automatic detection of boundaries. Written in Visual Basic for Applications, the code makes use of the advantages of existing programs and is consequently very economic and relatively simple to adjust to the requirements of specific projects or to expand making use of already available code. PMID- 26109834 TI - The roles of signaling pathways in epithelial-to-mesenchymal transition of PVR. AB - Proliferative vitreoretinopathy (PVR) is the major cause of failure in patients undergoing surgery for rhegmatogenous retinal detachment (RRD). Characterized by the formation of an abnormal contractile membrane within the eye, PVR can cause tractional retinal redetachment. Epithelial-to-mesenchymal transition (EMT), in which epithelial cells morphologically and phenotypically transdifferentiate into mesenchymal cells, is the major pathological process implicated in PVR. Among the various cell types involved in the process, retinal pigment epithelium cells are primary contributors although, after decades of research, the mechanisms underlying EMT have remained elusive. Recently, signaling pathways, some involving growth factors, have been demonstrated to contribute to EMT. In this article, we review research to date about the roles of such signaling, including including transforming growth factor-beta-, hepatocyte growth factor-, platelet derived growth factor-, and Notch-, Wnt/beta-catenin-, and Hippo-signaling pathways, in the EMT of PVR. PMID- 26109836 TI - Multi-century long density chronology of living and sub-fossil trees from Lake Schwarzensee, Austria. AB - This paper presents a multi-century, maximum latewood density (MXD) chronology developed from living and sub-fossil spruce trees from the Eastern Alps. The chronology is continuous from 88AD to 2008AD. This time series has been analysed with respect to its possible use for climate reconstruction. Correlations with climatic data showed strong dependence between MXD of growth rings and temperature of April, May, June, July, August and September and a weaker, negative dependence with precipitation of May and September. For solar radiation a positive relationship was noted for April, July, August and September. Light rings were frequently observed within the analysed samples and the climate of years with light rings was examined. Mean monthly temperatures in January, June, August, September and October, averaged during light ring years, were cooler than during years without light rings. Precipitation was also significantly reduced in March during light ring years. In turn, solar radiation during light ring years has significantly lowered values in February and August. The occurrence of light rings was often positively related to strong volcanic events. PMID- 26109837 TI - Soil sand content can alter effects of different taxa of mycorrhizal fungi on plant biomass production of grassland species. AB - In this greenhouse experiment we tested whether (i) ubiquitous arbuscular mycorrhizal fungi (AMF) taxa (Glomus claroideum, Glomus geosporum, Glomus intraradices, Glomus mosseae) singly and in a mixture differently affect growth and biomass production of four co-occurring grassland species (grass: Arrhenatherum elatius, non-leguminous forbs: Plantago lanceolata, Salvia pratensis and leguminous forb Trifolium pratense), and (ii) different soil sand contents alter AMF influence. We hypothesized that AMF effects on plants will increase with an increased AMF diversity and with increasing sand content. Percent AMF colonization of roots differed between plant species and AMF taxa and was higher with higher sand content. Plant growth responses to AMF were species specific both regarding plants and AMF. Generally, biomass production of the non leguminous forbs was the most responsive, the grass species the least and the legume intermediate both for AMF treatments and sand content. Across species, AMF influence on plant biomass increased with increasing soil sand content. Plant species growing in soil containing a mix of four AMF taxa showed similar growth responses than species in soil containing only one AMF taxon. These results suggest that both interference among AMF taxa and soil sand content can trigger the influence of AMF on plant production in grassland species. PMID- 26109838 TI - Storage and shipping of tissue samples for DNA analyses: A case study on earthworms. AB - Nowadays, molecular analyses play an important role in studies of soil dwelling animals, for example in taxonomy, phylogeography or food web analyses. The quality of the DNA, used for later molecular analyses, is an important factor and depends on collection and preservation of samples prior to DNA extraction. Ideally, DNA samples are frozen immediately upon collection, but if samples are collected in the field, suitable preservation methods might be limited due to unavailability of resources or remote field sites. Moreover, shipping samples over long distances can cause loss of DNA quality e.g. by thawing or leaking of preservation liquid. In this study we use earthworms, a key organism in soil research, to compare three different DNA preservation methods - freezing at -20 degrees C, storing in 75% ethanol, and freeze drying. Samples were shipped from the United States of America to Austria. The DNA of the samples was extracted using two different extraction methods, peqGOLDTM and Chelex(r) 100. The DNA amplification success was determined by amplifying four DNA fragments of different length. The PCR amplification success is significantly influenced by preservation method and extraction method and differed significantly depending on the length of the DNA fragment. Freeze drying samples was the best preservation method when samples were extracted using the silica based extraction method peqGOLDTM. For samples that were extracted with Chelex(r) 100, storage in ethanol was the best preservation method. However, the overall amplification success was significantly lower for the extraction procedure based on Chelex(r) 100. The detection of the small DNA fragments was higher and independent from the extraction method, while the amplification success was significantly reduced for the longer DNA fragments. We recommend freeze drying of DNA samples, especially when they have to be shipped for longer distances. No special packaging or declaration is needed for freeze dried samples, and the risk of thawing is excluded. Storage of freeze dried samples also reduces costs because samples can be kept at room temperature in a desiccator. It should be noted, that the extraction methods showed significant differences in DNA amplification success. Thus, the extraction method should be taken into account when choosing the preservation method. PMID- 26109839 TI - Oribatida (Acari) in grassy arable fallows are more affected by soil properties than habitat age and plant species. AB - Oribatid mites are one of the numerically dominant arthropod groups in soils. They play an important role in soil food webs via regulating the decomposition of organic matter and propagating microorganisms within the soil. To our knowledge, the influence of different plant functional groups on oribatid mites has not been studied in abandoned farmland with undisturbed succession before. The density and assemblage structure of oribatid mites in nine grassy arable fallows relative to three habitat age classes (2-3, 6-8, 12-15 years) and three selected plant species (legume: Medicago sativa, forb: Taraxacum officinale, grass: Bromus sterilis) were investigated in soil associated with single plants. Mite density declined marginally not significant with habitat age because of high abundances of the ubiquitous species Tectocepheus velatus sarekensis and Punctoribates punctum in young and mid-aged fallows and their subsequent decline in old fallows. Oribatid mite density and species assemblage were not affected by plant species. Only P. punctum had significantly higher densities in B. sterilis samples than in T. officinale samples due to a higher amount of fine roots. Distance-based linear models revealed that 65% of the variation in mite assemblage was explained by soil properties, soil type, exposition and geographic position, while habitat age was of minor importance. Canonical correspondence analysis revealed that the mite assemblage was best explained by soil organic and microbial carbon, water content and pH. PMID- 26109840 TI - Comparison of central corneal thickness: ultrasound pachymetry versus slit-lamp optical coherence tomography, specular microscopy, and Orbscan. AB - BACKGROUND: Central corneal thickness (CCT) can be measured by using contact and non-contact methods. Ultrasound pachymetry (US pachymetry) is a contact method for measuring CCT and is perhaps the most commonly used method. However, non contact methods like scanning slit topography (Orbscan II), slit-lamp optical coherence tomography (SL-OCT), and specular microscopy are also used. Not many studies have correlated the measurement of CCT with all four modalities. The purpose of this study was to compare and correlate the CCT measurements obtained by US pachymetry with SL-OCT, specular microscopy, and Orbscan. METHOD: This is a prospective, comparative study done in an institutional setting. Thirty-two eyes of 32 subjects with no known ocular disease and best-corrected visual acuity of 20/20 were enrolled. CCT measurements were obtained using SL-OCT, specular microscopy, scanning slit topography (Orbscan), and US pachymetry. Three measurements were made with each instrument by the same operator. Mean, standard deviation, and coefficient of variation were calculated for CCT measurements acquired by the four measurement devices. Bland-Altman plot was constructed to determine the agreements between the CCT measurements obtained by different equipment. RESULTS: The mean CCT was 548.16+/-48.68 MUm by US pachymetry. In comparison, CCT averaged 546.36+/-44.17 MUm by SL-OCT, 557.61+/-49.92 MUm by specular microscopy, and 551.03+/-48.96 MUm by Orbscan for all subjects. Measurements by the various modalities were strongly correlated. Correlations (r (2)) of CCT, as measured by US pachymetry compared with other modalities, were: SL-OCT (r (2)=0.98, P<0.0001), specular microscopy (r (2)=0.98, P<0.0001), and Orbscan (r (2)=0.96, P<0.0001). All modalities had a linear correlation with US pachymetry measurements. CONCLUSION: In subjects with healthy corneas, SL-OCT, specular microscopy, and Orbscan (with correction factor) can be used interchangeably with US pachymetry in certain clinical settings. The four modalities showed significant linear correlations with one another. PMID- 26109841 TI - Anterior ischemic optic neuropathy due to biopsy-proven giant cell arteritis in Thai patients. AB - Giant cell arteritis is a systemic granulomatous vasculitis affecting medium to large arteries. An arteritic anterior ischemic optic neuropathy is the most common cause of permanent visual loss. Giant cell arteritis is very rare among Asians. We report six patients with biopsy-proven arteritic anterior ischemic optic neuropathy. Demographic data, clinical manifestations, laboratory findings, treatment, and visual outcome are described in detail and compared with Caucasian patients. We found no differences in any clinical features except for sex preference. Moreover, perioptic nerve sheath enhancement was observed in half of our patients. PMID- 26109842 TI - A case of WAGR syndrome in association with developmental glaucoma requiring bilateral Baerveldt glaucoma implants and subsequent tube repositioning. AB - Glaucoma drainage device implantation is efficacious for the treatment of pediatric glaucoma patients when multiple angle surgeries fail. However, tube touching of the corneal endothelium is one of the major postoperative complications to deal with. A 15-month-old male patient with Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome was diagnosed with bilateral developmental glaucoma. He underwent Baerveldt glaucoma implant (BGI) surgeries in both eyes after multiple failed trabeculotomies. The tube in his right eye was touching the cornea 15 months after BGI surgery. To avoid corneal endothelium damage, BGI tube repositioning with scleral fixation was performed without serious complications. The bilateral BGI surgeries achieved successful intraocular pressure reduction for over 2 years and tube repositioning with scleral fixation of BGI tube was successful for BGI tube malposition. Although careful attention to intraocular pressure and tube malposition is essential after glaucoma drainage device implantation, especially in pediatric cases, BGI surgery is effective in the management of developmental glaucoma following unsuccessful angle surgeries. PMID- 26109843 TI - Virological and epidemiological analysis of coxsackievirus A24 variant epidemic of acute hemorrhagic conjunctivitis in Okinawa, Japan, in 2011. AB - BACKGROUND: Acute hemorrhagic conjunctivitis (AHC) is a highly contagious enterovirus infection of the conjunctiva and cornea. Coxsackievirus A24 variant (CA24v) is one of its etiological agents. We report a clinical, epidemiological, and virological analysis of a large epidemic of AHC that occurred from May to September, 2011, in Okinawa, Japan. METHODS: Clinical and epidemic aspects were evaluated for 435 AHC patients (348 bilateral and 87 unilateral, 783 eyes). Virological studies were carried out on nine isolates from ten patients. Virus isolation and direct detection of the enterovirus genome by the reverse transcription polymerase chain reaction method and complete nucleotide sequencing of the VP1 gene and phylogeny-based classification using the VP4 sequences were carried out. RESULTS: The 11-15-year age group comprised the highest (62.0%) proportion of cases among all age groups. Conjunctival hyperemia was present in all patients, and subconjunctival hemorrhage, superficial punctate keratitis, and preauricular lymphadenopathy were present in 25.4%, 10.3%, and 7.8% of eyes, respectively. CA24v was isolated from the epidemic strain, and phylogenetic analysis based on a fragment of the VP1 gene showed 96%-97% identity between the current strain and the recent China/GD01/2010 strain. CONCLUSION: These findings demonstrate that the clinical and epidemiological features of AHC observed in this study were similar to those of the past epidemic in the same region. It should be noted that sequential outbreaks of AHC due to CA24v might occur in the same location after a considerable period of time, and public health precautions are necessary to control this explosive epidemic. PMID- 26109844 TI - Osteopontin promotes dendritic cell maturation and function in response to HBV antigens. AB - PURPOSE: Dendritic cells (DCs) play critical roles in promoting innate and adaptive immunity in microbial infection. Functional impairment of DCs may mediate the suppression of viral-specific T-cell immune response in chronic hepatitis B (CHB) patients. Osteopontin (OPN) is involved in several liver diseases and infectious diseases. However, whether OPN affects DC function in hepatitis B virus (HBV) infection is unknown. METHODS: Twenty CHB patients and 20 healthy volunteers were recruited. OPN secreted by DCs was compared. Peripheral blood mononuclear cells cultured with OPN antibody were examined to study the costimulatory molecular expression and interleukin (IL)-12 production of DCs after HBV antigenic stimulation. OPN-deficient mice were used to investigate the influence of OPN on DC maturation and function after HBV antigenic stimulation in vitro and in vivo. Exogenous OPN was administrated to further verify the functioning of DCs from CHB patients upon HBV antigenic stimulation. RESULTS: We found that OPN production of DCs from CHB patients was significantly lower than those from healthy volunteers. The absence of OPN impaired IL-12 production and costimulatory molecular expression of DCs upon stimulation with HBV antigens. Defective DC function led to reduced activation of Th1 response to HBV antigens. In addition, OPN deficiency in DCs reduced the HBV antigen-induced inflammatory response in the liver of mice. Importantly, OPN administration significantly promoted the maturation of DCs from CHB patients in vitro. CONCLUSION: These findings suggested that OPN could improve the maturation and functioning of DCs in the immune response to HBV antigens, which might be useful to further improve the effect of DC vaccine. PMID- 26109846 TI - Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases. AB - BACKGROUND: The use of a statistical approach to analyze cumulative adverse event (AE) reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection). Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration Adverse Event Reporting System (FAERS), and how they affect signal detection. METHODS: Two AE data sources from 2010 were examined, ie, JADER cases (JP) and Japanese cases extracted from the FAERS (FAERS-JP). Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS), were used on drug event combinations for three substances frequently recorded in both systems. RESULTS: The two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6+/-1.3 (maximum 37) in the JP and 3.3+/-3.5 (maximum 62) in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and paroxetine. Signals identified by GPS for the JP and FAERS-JP, as referenced by Japanese labeling, showed higher positive sensitivity than was expected. CONCLUSION: The FAERS-JP was different from the JADER. Signals derived from both datasets identified different results, but shared certain signals. Discrepancies in type of AEs, drugs reported, and average number of AEs per case were potential contributing factors. This study will help those concerned with pharmacovigilance better understand the use and pitfalls of using spontaneous AE data. PMID- 26109845 TI - Oleanolic acid induces mitochondrial-dependent apoptosis and G0/G1 phase arrest in gallbladder cancer cells. AB - Oleanolic acid (OA), a naturally occurring triterpenoid, exhibits potential antitumor activity in many tumor cell lines. Gallbladder carcinoma is the most common malignancy of the biliary tract, and is a highly aggressive tumor with an extremely poor prognosis. Unfortunately, the effects of OA on gallbladder carcinoma are unknown. In this study, we investigated the effects of OA on gallbladder cancer cells and the underlying mechanism. The results showed that OA inhibits proliferation of gallbladder cancer cells in a dose-dependent and time dependent manner on MTT and colony formation assay. A flow cytometry assay revealed apoptosis and G0/G1 phase arrest in GBC-SD and NOZ cells. Western blot analysis and a mitochondrial membrane potential assay demonstrated that OA functions through the mitochondrial apoptosis pathway. Moreover, this drug inhibited tumor growth in nude mice carrying subcutaneous NOZ tumor xenografts. These data suggest that OA inhibits proliferation of gallbladder cancer cells by regulating apoptosis and the cell cycle process. Thus, OA may be a promising drug for adjuvant chemotherapy in gallbladder carcinoma. PMID- 26109847 TI - Efficiency and safety of subconjunctival injection of anti-VEGF agent - bevacizumab - in treating dry eye. AB - PURPOSE: Dry eye is a chronic inflammatory ocular surface disease with high prevalence. The current therapies for dry eye remain to be unspecific and notcomprehensive. This study aims to explore safety and efficacy of a novel treatment - subconjunctival injection of bevacizumab - in dry eye patients. METHODS: Sixty-four eyes of 32 dry eye patients received subconjunctival injection of 100 MUL 25 mg/mL bevacizumab. Dry eye symptoms, signs (corrected visual acuity, intraocular pressure, conjunctival vascularity, corneal staining, tear break-up time, Marx line score, and blood pressure), and conjunctival impression cytology were evaluated 3 days before and 1 week, 1 month, and 3 months after injection. RESULTS: Significant improvements were observed in dry eye symptoms, tear break-up time, and conjunctival vascularization area at all the visits after injection compared to the baseline (P<0.05). The density of the goblet cell increased significantly at 1 month and 3 months after injection (P<0.05). There was no visual and systemic threat observed in any patient. CONCLUSION: Subconjunctival injection of 100 MUL 25 mg/mL bevacizumab is a safe and efficient treatment for ocular surface inflammation of dry eye disease. PMID- 26109848 TI - Cardioprotection against ischemia/reperfusion injury by QiShenYiQi Pill(r) via ameliorate of multiple mitochondrial dysfunctions. AB - AIM: To investigate the potential cardioprotective effects of QiShenYiQi Pill((r)) (QSYQ) on myocardial ischemia/reperfusion (I/R) injury through antioxidative stress and mitochondrial protection. METHODS AND RESULTS: Sprague Dawley rats were pretreated with QSYQ or saline for 7 days and subjected to ischemia (30 minutes occlusion of the left anterior descending coronary artery) and reperfusion (120 minutes). Cardiac functions were evaluated by echocardiogram and hemodynamics. Myocardial mitochondria were obtained to evaluate changes in mitochondrial structure and function, immediately after 120 minutes reperfusion. Pretreatment with QSYQ protected against I/R-induced myocardial structural injury and improved cardiac hemodynamics, as demonstrated by normalized serum creatine kinase and suppressed oxidative stress. Moreover, the impaired myocardial mitochondrial structure and function decreased level of ATP (accompanied by reduction of ATP5D and increase in the expression of cytochrome C). Myocardial fiber rupture, interstitial edema, and infiltrated leukocytes were all significantly ameliorated by pretreatment with QSYQ. CONCLUSION: Pretreatment of QSYQ in Sprague Dawley rats improves ventricular function and energy metabolism and reduces oxidative stress via ameliorating multiple mitochondrial dysfunctions during I/R injury. PMID- 26109849 TI - Antibiotic-modifying activity of riachin, a non-cyanogenic cyanoglycoside extracted from Bauhinia pentandra. AB - BACKGROUND: The search for new active compounds from the Brazilian flora has intensified in recent years, especially for new drugs with antibiotic potential. Accordingly, the aim of this study was to determine whether riachin has antibiotic activity in itself or is able to modulate the activity of conventional antibiotics. METHODS: A non-cyanogenic cyanoglycoside known as riachin was isolated from Bauhinia pentandra, and was tested alone and in combination with three antibiotics (clindamycin, amikacin, and gentamicin) against multiresistant bacterial strains (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). RESULTS: Riachin did not show significant antibiotic activity when tested alone against any strain (P>0.05). However, when combined with conventional antibiotics, it showed drug-modifying activity against strains of S. aureus exposed to clindamycin (P<0.001) as well as against P. aeruginosa exposed to amikacin (P<0.001). Although riachin did not show direct antibiotic activity, it had synergistic activity when combined with amikacin or clindamycin. The mechanism of action of this synergism is under investigation. CONCLUSION: The results of this work demonstrate that some substances of natural origin can enhance the effectiveness of certain antibiotics, which means a substantial reduction in the drug dose required and possibly in consequent adverse events for patients. PMID- 26109850 TI - Profile of evolocumab and its potential in the treatment of hyperlipidemia. AB - Despite the proven efficacy of statins, they often fail to achieve low-density lipoprotein (LDL) cholesterol goals, especially in high-risk patients. Moreover, a large number of subjects cannot tolerate statins or full doses of these drugs, in particular patients with familial hypercholesterolemia. Thus, there is a need for additional effective LDL cholesterol-reducing agents. Evolocumab (AMG145) is a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 that binds to the liver LDL receptor and prevents it from normal recycling by targeting it for degradation. Phase I, II, and III trials revealed that, on subcutaneous injection, either alone or in combination with statins, evolocumab is able to reduce high LDL cholesterol levels from 54% to 80%, apolipoprotein B100 from 31% to 61%, and lipoprotein(a) from 12% to 36%, in a dose-dependent manner. The incidence of side effects seems to be low and mainly limited to nasopharyngitis, injection site pain, arthralgia, and back pain. Evolocumab is an innovative powerful lipid-lowering drug, additive to statins and/or ezetimibe, with a large therapeutic range associated with a low rate of mild adverse events. If the available data are confirmed in long-term trials with strong outcome measures, evolocumab will become an essential tool in the treatment of a large number of high-risk patients, such as those affected by familial hypercholesterolemia, those who are unable to tolerate an efficacious statin dosage, and those at very high cardiovascular risk and unable to achieve their target LDL cholesterol levels with currently available lipid-lowering therapies. PMID- 26109851 TI - Inhibition of cyclooxygenase-2 prevents intra-abdominal adhesions by decreasing activity of peritoneal fibroblasts. AB - BACKGROUND: Postoperative intra-abdominal adhesions are common complications after abdominal surgery. The exact molecular mechanisms that are responsible for these complications remain unclear, and there are no effective methods for preventing adhesion formation or reformation. The aim of the study reported here was to investigate the preventive effects and underlying potential molecular mechanisms of selective cyclooxygenase-2 (COX-2) inhibitors in a rodent model of postoperative intra-abdominal adhesions. MATERIALS AND METHODS: The expression of COX-2 in postoperative intra-abdominal adhesions and normal peritoneal tissue was examined by immunohistochemistry and Western blot analysis. Assays were performed to elucidate the effect of COX-2 inhibition on hypoxia-induced fibroblast activity in vitro and on intra-abdominal adhesion formation in vivo. RESULTS: Hypoxia-induced COX-2 expression in peritoneal fibroblasts was increased in postoperative intra-abdominal adhesions. Inhibition of COX-2 attenuated the activating effect of hypoxia on normal peritoneal fibroblasts in vitro. Data indicate that selective COX-2 inhibitor prevents in vivo intra-abdominal adhesion by inhibition of basic fibroblast growth factor and transforming growth factor beta expression, but not through an antiangiogenic mechanism. Furthermore, using selective COX-2 inhibitors to prevent intra-abdominal adhesions did not adversely affect the weight, bowel motility, or healing of intestinal anastomoses in a rat model. CONCLUSION: These results show that hypoxia-induced COX-2 expression in peritoneal fibroblasts is involved in the formation of intra-abdominal adhesions. Inhibition of COX-2 prevents postoperative intra-abdominal adhesions through suppression of inflammatory cytokines. PMID- 26109852 TI - Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. Fludarabine-based regimens demonstrate higher response rates in younger patients but have a significant risk of infection and are thus poorly tolerated by older, frail patients. Anti-CD20 monoclonal antibodies have added to the efficacy of chemotherapy in CLL. Obinutuzumab is a potent Type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular toxicity and direct cell death compared with rituximab. In Phase I studies, infusion reactions and neutropenia were the predominant toxicities. Phase II studies demonstrated efficacy both as a single agent and in combination with chemotherapy in patients with CLL. The CLL11 trial was a Phase III randomized trial of chlorambucil alone or with either obinutuzumab or rituximab in elderly, unfit patients. Progression free survival (the primary end point) was 26.7 months for patients receiving obinutuzumab plus chlorambucil versus 16.3 months for those receiving rituximab plus chlorambucil and 11.1 months for those receiving chlorambucil alone (P<0.001). Overall survival was improved for patients receiving obinutuzumab plus chlorambucil versus chlorambucil alone (P=0.002). This trial led to the US Food and Drug Administration (FDA) approval of obinutuzumab in this patient population. PMID- 26109853 TI - Roflumilast, a phosphodiesterase-4 inhibitor, induces phagocytic activity in Greek COPD patients. AB - BACKGROUND: A new approach to the treatment of COPD includes controlling inflammation because of its important role in exacerbation of the disease. Recently, roflumilast has been added as a therapeutic option for COPD. Roflumilast is an oral phosphodiesterase-4 inhibitor that targets inflammatory cells involved in triggering exacerbations of COPD. The objective of the current study was to evaluate roflumilast for its contribution to phagocytic activity in COPD patients. METHODS: Twenty-one patients diagnosed with COPD received roflumilast once daily for 6 months in combination with fluticasone (an inhaled corticosteroid), salmeterol (a long-acting beta2-agonist), and tiotropium (a long acting muscarinic antagonist) or combinations of these agents. The main inclusion criterion was stable disease for at least the previous 30 days. Neutrophils and spirometric changes, ie, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), were measured in the COPD patients at indicated time points. The first sample was taken before receiving roflumilast, the second 3 months later, and the third after 6 months. Examination of defective phagocytosis was done by flow cytometry using a FagoFlowEx((r)) kit. The statistical analysis was performed using Statistica software. RESULTS: Our results indicate that phagocytic activity was increased after 3 and 6 months of treatment when compared with baseline (P<0.001). Similarly, FVC and FEV1 were also increased during the 6 month period, but only FVC differed significantly from baseline (P<0.001). CONCLUSION: Although the number of patients in this study was limited, our results indicate that roflumilast induces phagocytic activity, which improves lung function. PMID- 26109854 TI - Predicting energy requirement with pedometer-determined physical-activity level in women with chronic obstructive pulmonary disease. AB - BACKGROUND: In clinical practice, in the absence of objective measures, simple methods to predict energy requirement in patients with chronic obstructive pulmonary disease (COPD) needs to be evaluated. The aim of the present study was to evaluate predicted energy requirement in females with COPD using pedometer determined physical activity level (PAL) multiplied by resting metabolic rate (RMR) equations. METHODS: Energy requirement was predicted in 18 women with COPD using pedometer-determined PAL multiplied by six different RMR equations (Harris Benedict; Schofield; World Health Organization; Moore; Nordic Nutrition Recommendations; Nordenson). Total energy expenditure (TEE) was measured by the criterion method: doubly labeled water. The predicted energy requirement was compared with measured TEE using intraclass correlation coefficient (ICC) and Bland-Altman analyses. RESULTS: The energy requirement predicted by pedometer determined PAL multiplied by six different RMR equations was within a reasonable accuracy (+/-10%) of the measured TEE for all equations except one (Nordenson equation). The ICC values between the criterion method (TEE) and predicted energy requirement were: Harris-Benedict, ICC =0.70, 95% confidence interval (CI) 0.23 0.89; Schofield, ICC =0.71, 95% CI 0.21-0.89; World Health Organization, ICC =0.74, 95% CI 0.33-0.90; Moore, ICC =0.69, 95% CI 0.21-0.88; Nordic Nutrition Recommendations, ICC =0.70, 95% CI 0.17-0.89; and Nordenson, ICC =0.40, 95% CI 0.19 to 0.77. Bland-Altman plots revealed no systematic bias for predicted energy requirement except for Nordenson estimates. CONCLUSION: For clinical purposes, in absence of objective methods such as doubly labeled water method and motion sensors, energy requirement can be predicted using pedometer-determined PAL and common RMR equations. However, for assessment of nutritional status and for the purpose of giving nutritional treatment, a clinical judgment is important regarding when to accept a predicted energy requirement both at individual and group levels. PMID- 26109857 TI - Erratum: Cellular entry of nanoparticles via serum sensitive clathrin-mediated endocytosis, and plasma membrane permeabilization [corrigendum]. PMID- 26109856 TI - Utilization of nanotechnology to enhance percutaneous absorption of acyclovir in the treatment of herpes simplex viral infections. AB - This study aimed to formulate an optimized acyclovir (ACV) nanoemulsion hydrogel in order to provide a solution for the slow, variable, and incomplete oral drug absorption in patient suffering from herpes simplex viral infection. Solubility of ACV in different oils, surfactants, and cosurfactants was explored utilizing a cubic model mixture design to obtain a nanoemulsion with minimum globule size. Preparation of an optimized ACV nanoemulsion hydrogel using a three-factor, three level Box-Behnken statistical design was conducted. The molecular weight of chitosan (X1), percentage of chitosan (X2), and percentage of Eugenol as a skin permeation enhancer (X3) were selected to study their effects on hydrogel spreadability (Y1) and percent ACV permeated through rat skin after 2.5 hours (Y2). A pharmacokinetic study of the optimized ACV nanoemulsion hydrogel was conducted in rats. Mixtures of clove oil and castor oil (3:1 ratio), Tween 80 and Span 80 (3:1 ratio), and propylene glycol and Myo-6V (3:1 ratio) were selected as the oil, surfactant, and cosurfactant phases, respectively. Statistical analysis indicated that the molecular weight of chitosan has a significant antagonistic effect on spreadability, but has no significant effect on the percent ACV permeated. The percentage of chitosan also has a significant antagonistic effect on the spreadability and percent ACV permeated. On the other hand, the percentage of Eugenol has a significant synergistic effect on percent ACV permeated, with no effect on spreadability. The ex vivo study demonstrated that the optimized ACV nanoemulsion hydrogel showed a twofold and 1.5-fold higher permeation percentage than the control gel and marketed cream, respectively. The relative bioavailability of the optimized ACV nanoemulsion hydrogel improved to 535.2% and 244.6% with respect to the raw ACV hydrogel and marketed cream, respectively, confirming improvement of the relative bioavailability of ACV in the formulated nanoemulsion hydrogel. PMID- 26109855 TI - Multifaceted applications of bile salts in pharmacy: an emphasis on nanomedicine. AB - The human body has long provided pharmaceutical science with biomaterials of interesting applications. Bile salts (BSs) are biomaterials reminiscent of traditional surfactants with peculiar structure and self-assembled topologies. In the pharmaceutical field, BSs were employed on the basis of two different concepts. The first concept exploited BSs' metabolic and homeostatic functions in disease modulation, whereas the second one utilized BSs' potential to modify drug delivery characteristics, which recently involved nanotechnology. This review is the first to gather major pharmaceutical applications of BSs from endogenous organotropism up to integration into nanomedicine, with a greater focus on the latter domain. Endogenous applications highlighted the role of BS in modulating hypercholesterolemia and cancer therapy in view of enterohepatic circulation. In addition, recent BS-integrated nanomedicines have been surveyed, chiefly size tunable cholate nanoparticles, BS-lecithin mixed micelles, bilosomes, probilosomes, and surface-engineered bilosomes. A greater emphasis has been laid on nanosystems for vaccine and cancer therapy. The comparative advantages of BS integrated nanomedicines over conventional nanocarriers have been noted. Paradoxical effects, current pitfalls, future perspectives, and opinions have also been outlined. PMID- 26109858 TI - An exploratory study of the association between SORL1 polymorphisms and sporadic Alzheimer's disease in the Han Chinese population. AB - In previous studies, we reported that the sortilin-related receptor, L (DLR class) A repeats containing (SORL1) gene single nucleotide polymorphisms (SNPs) are associated with the risk of sporadic Alzheimer's disease (SAD) in the Han Chinese population. To further explore the relationships between SORL1 genetic variants and SAD, we conducted a two-step study. Sequencing analysis in 50 case samples identified 14 SNPs within the promoter and untranslated region of the SORL1 gene. Subsequent genotyping analysis in 106 patients with SAD and 179 healthy controls detected a significant association between the "G" allele of SNP rs1133174 in the 3' untranslated region of the SORL1 gene and SAD risk (odds ratio =1.92, 95% confidence interval [95% CI] =1.28-2.90, adjusted P=0.028). In addition, "G" allele carriers of rs1133174 (GA + GG) have a 2.15-fold increased risk of SAD compared to noncarriers (AA) (adjusted P=0.042). However, no significant positive associations were observed in the other 13 SNPs within the SORL1 gene. These preliminary findings suggest that the SORL1 SNP rs1133174 may be a potential risk locus for SAD in the Han Chinese population. PMID- 26109859 TI - Effect of music intervention on the cognitive and depression status of senior apartment residents in Taiwan. AB - OBJECTIVE: To identify the effect of music intervention on cognitive function and depression status of residents in senior citizen apartments based on the existing evidence regarding music therapy. METHODS: An experimental study was conducted from November 2008 to December 2009. Sixty healthy senior apartment residents over 65 years of age were recruited and separated into two groups. According to their opinion, 41 took part in the music intervention group and 19 in the comparison group. The music intervention involved Buddhist hymns. The short-term effects were evaluated based on the measurement of cognitive function and depression level using the Mini-Mental State Examination (MMSE) and the Geriatric Depression Scale-short form (GDS-SF) at the baseline, 1 month, and 4 months. RESULTS: The means of the initial and the 1-month MMSE and GDS-SF scores did not differ between the two groups. The 4-month MMSE score significantly declined compared with the initial level in the comparison group, whereas no significant change was observed in the experimental group. Moreover, the 4-month GDS-SF score significantly improved in both groups compared with the initial level. CONCLUSION: Music intervention may postpone cognitive decline in healthy residents preferring Buddhist hymns in the senior citizen apartments in 4 months follow-up, and intense contact with participants may improve their mood status. PMID- 26109860 TI - Focus group reflections on the current and future state of cognitive assessment tools in geriatric health care. AB - OBJECTIVE: This study provides insight into the thoughts and opinions of geriatric health-care professionals toward cognitive assessments and the use of emerging technologies, such as eye-tracking, to supplement current tools. METHODS: Two focus group sessions were conducted with nurses and physicians who routinely administer neurocognitive assessments to geriatric populations. Video recordings of the focus group sessions were transcribed and a thematic analysis was performed. RESULTS: Participants reported the need for assessment and diagnostic tools that are accessible and efficient, and that are capable of accommodating the rapid growth in the aging population. The prevalence of more complex ailments experienced by older adults has had repercussions in the quality of care that the clients receive, and has contributed to lengthy wait times and resource shortages. Health-care professionals stated that they are hampered by the disjointed structure of the health-care system and that they would benefit from a more efficient allocation of responsibilities made possible through tools that did not require extensive training or certification. Eyetracking-based cognitive assessments were thought to strongly complement this system, yet it was thought that difficulty would be faced in gaining the support and increased uptake by health-care professionals due to the nonintuitive relationship between eyetracking and cognition. CONCLUSION: The findings suggest that health-care professionals are receptive to the use of eyetracking technology to assess for cognitive health as it would conserve resources by allowing frontline staff to administer assessments with minimal training. PMID- 26109861 TI - Systematic review of the prevalence and incidence of Parkinson's disease in the People's Republic of China. AB - BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease, and obtaining accurate epidemiological data for this disease is very important for policy-making in public health. The purpose of this study was to determine the prevalence and incidence of PD in the People's Republic of China and explore possible future research directions. METHODS: We systematically retrieved studies of the prevalence and incidence of PD in the People's Republic of China, Taiwan, and Hong Kong, and standardized the data according to the world's population in 2000. RESULTS: Fifteen eligible studies were retrieved. Most were cross-sectional studies, and two thirds of the research was from the People's Republic of China. The prevalence of PD was reported in all the studies, but only two studies reported incidence data. The prevalence of PD in the People's Republic of China ranged from 16 to 440.3/100,000, and the annual incidence ranged from 1.5 to 8.7/100,000. CONCLUSION: The prevalence of PD in the People's Republic of China has been widely investigated in the studies published to date. However, due to methodological heterogeneity, the data reported by the different studies are not comparable. There is still a lack of information on the incidence of PD in the People's Republic of China. Therefore, future research is required to answer this question. PMID- 26109862 TI - Quetiapine mitigates the ethanol-induced oxidative stress in brain tissue, but not in the liver, of the rat. AB - Quetiapine, an atypical antipsychotic, has been employed to treat alcoholic patients with comorbid psychopathology. It was shown to scavenge hydroxyl radicals and to protect cultured cells from noxious effects of oxidative stress, a pathophysiological mechanism involved in the toxicity of alcohol. This study compared the redox status of the liver and the brain regions of prefrontal cortex, hippocampus, and cerebellum of rats treated with or without ethanol and quetiapine. Ethanol administration for 1 week induced oxidative stress in the liver and decreased the activity of glutathione peroxidase and total antioxidant capacity (TAC) there. Coadministration of quetiapine did not protect glutathione peroxidase and TAC in the liver against the noxious effect of ethanol, thus was unable to mitigate the ethanol-induced oxidative stress there. The ethanol induced alteration in the redox status in the prefrontal cortex is mild, whereas the hippocampus and cerebellum are more susceptible to ethanol intoxication. For all the examined brain regions, coadministration of quetiapine exerted effective protection on the antioxidants catalase and total superoxide dismutase and on the TAC, thus completely blocking the ethanol-induced oxidative stress in these brain regions. These protective effects may explain the clinical observations that quetiapine reduced psychiatric symptoms intensity and maintained a good level of tolerability in chronic alcoholism with comorbid psychopathology. PMID- 26109863 TI - Staphylococcus aureus bacteremias following liver transplantation: a clinical analysis of 20 cases. AB - BACKGROUND: To describe the incidence, clinical characteristics, and outcomes of Staphylococcus aureus bacteremia after liver transplantation and investigate the drug resistance of S. aureus to frequently used antibiotics to provide evidence for clinical prevention and therapy. MATERIALS AND METHODS: In a double-center retrospective study, blood cultures positive for S. aureus were obtained from January 1, 2001 to December 31, 2014. The BACTEC 9120 blood culture system and the Vitek-2 system were used to process blood samples and identify species, respectively. We also collected these patients' data to confirm clinical and laboratory characteristics. RESULTS: Twenty of 275 (7.3%) liver recipients developed S. aureus bacteremia during the study period. The median time to the onset of S. aureus bacteremias was 6 days after liver transplantation and all episodes of bacteremias were early onset. The lung was the most common source of primary infection, followed by the intra-abdominal/biliary tract. A total of nine (45%) liver recipients died due to S. aureus bacteremias. Of these 20 S. aureus cases, 80% were methicillin-resistant. S. aureus was highly resistant to erythromycin and penicillin (resistance rate >90%). No S. aureus resistant to glycopeptides and oxazolidone antibiotics was observed. There were seven (35%) liver recipients with an inappropriate antibiotic therapy. Between the periods of 2001-2007 and 2008-2014, the distribution of methicillin-resistant S. aureus was not significantly different (P=1.000). Pneumonia as a predominant primary source, a high body temperature, abnormal blood pressure, and decreased platelets, which occurred in the early period after liver transplantation, as well as high morbidity and mortality, were the main characteristics of S. aureus bacteremias. CONCLUSION: S. aureus led to severe bacteremias in liver recipients, with high morbidity and mortality, and the majority of them comprised methicillin-resistant S. aureus. PMID- 26109864 TI - Optimal management of digital ulcers in systemic sclerosis. AB - Raynaud's phenomenon and digital ulcerations are two common clinical features seen in patients with systemic sclerosis. They are painful and lead to significant morbidity and altered hand function within this patient population. While currently there are no US Food and Drug Administration (FDA)-approved medications for the treatment of digital ulcerations in the United States, clinical trials have supported the use of pharmacologic and nonpharmacologic modalities in facilitating healing of existing digital ulcers and preventing formation of new ulcers. This article reviews the published data on these therapeutic options. PMID- 26109866 TI - Analysis of clinical efficacy of CyberKnife((r)) treatment for locally advanced pancreatic cancer. AB - OBJECTIVE: To evaluate the efficacy and safety of CyberKnife((r)) treatment for locally-advanced pancreatic cancer (LAPC). METHODS: The efficacy of CyberKnife((r)) treatment was analyzed in 59 LAPC patients treated between October 2006 and September 2014. The median tumor volume was 27.1 mL (13.0 125.145 mL). The median prescribed dose was 45 Gy (35-50 Gy), delivered in 5 fractions (3-8 fractions). The overall survival (OS) rates and freedom from local progression (FFLP) rates were estimated using the Kaplan-Meier survival curve. RESULTS: The median follow-up for all patients was 10.9 months (3.2-48.7 months) and 15.6 months (3.9-37.6 months) among surviving patients. The median OS was 12.5 months, and the 1-year and 2-year survival rates were 53.9% and 35.1%, respectively. The 1-year FFLP rate was 90.8% based on the computed tomography (CT) evaluation. Grade 1-2 acute and late-stage gastrointestinal (GI) reactions were observed in 61% of the patients. One patient experienced grade 3 toxicity. CONCLUSION: Excellent clinical efficacy was obtained after treatment of LAPC using CyberKnife((r)), with minimal toxicity. PMID- 26109865 TI - Lipidomics in vascular health: current perspectives. AB - Identifying the mechanisms that convert a healthy vascular wall to an atherosclerotic wall is of major importance since the consequences may lead to a shortened lifespan. Classical risk factors (age, smoking, obesity, diabetes mellitus, hypertension, and dyslipidemia) may result in the progression of atherosclerotic lesions by processes including inflammation and lipid accumulation. Thus, the evaluation of blood lipids and the full lipid complement produced by cells, organisms, or tissues (lipidomics) is an issue of importance. In this review, we shall describe the recent progress in vascular health research using lipidomic advances. We will begin with an overview of vascular wall biology and lipids, followed by a short analysis of lipidomics. Finally, we shall focus on the clinical implications of lipidomics and studies that have examined lipidomic approaches and vascular health. PMID- 26109867 TI - Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials. AB - BACKGROUND: Ovarian function suppression (OFS) significantly downregulates the concentration of plasma estrogens. However, it is unclear whether it offers any survival benefits if combined with adjuvant tamoxifen treatment in premenopausal women. This meta-analysis was designed to assess data from previous studies involving adjuvant tamoxifen treatment plus OFS in premenopausal breast cancer. METHODS: Electronic literature databases (PubMed, Embase, the Web of Science, and the Cochrane Library) were searched for relevant randomized controlled trials published prior to February 1, 2015. Only randomized controlled trials that compared tamoxifen alone with tamoxifen plus OFS for premenopausal women with breast cancer were selected. The evaluated endpoints were disease-free survival and overall survival. RESULTS: Four randomized controlled trials comprising 6,279 patients (OFS combination, n=3,133; tamoxifen alone, n=3,146) were included in the meta-analysis. There was no significant improvement in disease-free survival or overall survival with addition of OFS in either the whole population or the hormone receptor-positive subgroup. The risk of distant recurrence was not reduced with the addition of OFS in the whole population. A subgroup analysis showed that addition of OFS significantly improved overall survival in patients who were administered chemotherapy. CONCLUSION: Based on the available studies, concurrent administration of OFS and adjuvant tamoxifen treatment for premenopausal women with breast cancer has no effect on prolonging disease-free survival and overall survival, excluding patients who were administered chemotherapy. It should not be widely recommended, except perhaps for women who were hormone-receptor positive and who were also administered adjuvant chemotherapy. PMID- 26109868 TI - CpG oligodeoxyribonucleotide 7909 enhances radiosensitivity via downregulating Oct-4 expression in radioresistant lung cancer cells. AB - Radiotherapy is a powerful cure for local advanced non-small cell lung cancer. However, radioresistance and tumor relapse still occur in a high proportion of patients. Octamer-4 (Oct-4), a transcription factor of the POU family, plays a key role in maintaining chemoradioresistant properties and regulating cancer progression. In this study, we demonstrated that Oct-4 expression was significantly increased in radioresistant H460 (H460R) cell line. CpG oligodeoxyribonucleotide (CpG-ODN) 7909 sensitized H460R cells when combined with irradiation treatment. The clonogenic capacity was significantly decreased, and the values of D0 and Dq were lower than those of irradiation alone group. The sensitive enhancement ratio (SER) of D0 was 1.224. This combined treatment led to a dramatic reduction in Oct-4 expression in a dose-dependent manner and also showed increased percentage of cells in the radiosensitive G2/M phase relative to either treatment alone. These results identified that Oct-4 was involved in radioresistance. CpG-ODN 7909 could enhance radiosensitivity partly through downregulating Oct-4 expression in radioresistant lung cancer cells. PMID- 26109869 TI - Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma like carcinoma. AB - BACKGROUND: Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of non-small cell lung cancer (NSCLC), and no effective treatments have been defined for advanced disease. Programmed cell death-ligand 1 (PD-L1) is expressed in a group of cancers that may be suitable targets for specific immunotherapy. METHODS: This study investigated the expression and clinical value of PD-L1 in pulmonary LELC. Seventy-nine patients with pulmonary LELC were investigated. Paraffin-embedded tumor sections were stained with PD-L1 antibody. Correlations of PD-L1 expression with clinicopathologic parameters and outcomes were analyzed. RESULTS: Fifty patients (63.3%) were PD-L1 positive. The 3-year and 5-year progression-free survival (PFS) rate was 76.0% and 68.0%, respectively, and the 3-year and 5-year overall survival (OS) rate was 88.0% and 79.0%, respectively. Kaplan-Meier analysis revealed that patients with positive PD-L1 expression had longer PFS and OS than those with negative PD-L1 expression (P=0.019 and P=0.042, respectively). In a multivariate Cox regression model including age, tumor size, stage, and PD-L1 expression status, the latter three factors were found to be independent predictors of PFS (P=0.023, P=0.000, and P=0.009, respectively), but only stage was found to be an independent factor for OS (P=0.007), and PD-L1 expression status showed a trend to be independently correlated with OS (P=0.080). CONCLUSION: Our results showed that a large proportion of patients with pulmonary LELC had positive expression of PD-L1, supporting the potential use of anti-PD-1/PD-L1-targeted therapies in this distinct type of NSCLC. PMID- 26109870 TI - Bortezomib-based vs non-bortezomib-based post-transplantation treatment in multiple myeloma patients: a systematic review and meta-analysis of Phase III randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy and safety of bortezomib-based vs non bortezomib-based post-transplantation therapy in patients with multiple myeloma. METHODS: Data of relevant randomized controlled trials assessing the effect of bortezomib as post-transplantation consolidation or maintenance therapy was obtained through a comprehensive search. The outcome measures included response rate, progression-free survival, overall survival, and adverse events (AEs). The hazard ratio (HR), Cochran-Mantel-Haenszel odds ratio (OR), and 95% confidence interval (95% CI) were applied to evaluate the effect of bortezomib in relation to the end points such as progression-free survival, overall survival, response rate, and AEs. RESULTS: Three randomized controlled trials comprising 1,518 participants were included in this study. Pooled ORs for the rates of overall response, and complete response and near complete response, were 1.85 and 1.75, respectively. Pooled HR for progression-free survival favored bortezomib-based therapy over non-bortezomib-based therapy (0.73, 95% CI: 0.67-0.81), while no statistically significant difference could be found between the two groups regarding the pooled HR for 3-year overall survival. Moreover, incidence rates of overall adverse events and grade 3 and 4 peripheral neuropathy were similar in the bortezomib-based groups and the non-bortezomib-based groups (P=0.12 and P=0.41, respectively). The corresponding cumulative meta-analyses of the rates of overall response rate, complete response and near complete response, and grades 3 and 4 peripheral neuropathy supported the superiority of bortezomib-based maintenance therapy over consolidation therapy. CONCLUSION: Bortezomib-based therapy after autologous stem cell transplantation, with tolerable AEs, could obviously improve the response as well as the outcome of multiple myeloma patients, particularly when bortezomib was administered as maintenance therapy. PMID- 26109871 TI - Prognostic role of HOTAIR in four estrogen-dependent malignant tumors: a meta analysis. AB - BACKGROUND: HOX transcript antisense intergenic RNA (HOTAIR), a long non-coding RNA transcribed from the antisense strand of the HOXC gene locus, has been shown to be overexpressed in various carcinomas and is thought to be an indicator of poor prognosis. Recently, HOTAIR was found to be an estrogen-responsive gene. We therefore conducted a meta-analysis to systematically summarize and clarify the association between HOTAIR expression and prognosis in the four main estrogen dependent tumors. METHODS: A systematic search of studies that examined the association and prognostic impact of HOTAIR in four of the main estrogen dependent tumors was conducted in PubMed and Embase. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to pool the effect size. RESULTS: A total of 1,200 patients from eight eligible studies were included. The current study found an association between HOTAIR expression and overall survival (OS) in four estrogen-dependent tumor types (HR, 1.99; 95% CI: 1.02-3.90; P Heterogeneity=0.001). Subgroup analyses indicated that high HOTAIR expression appeared to be a potential prognostic biomarker in non-breast cancer patients (HR, 2.72; 95% CI: 1.65-4.48). There was also an increased risk in Asian populations (HR, 2.55; 95% CI: 1.62-4.00) compared with Caucasian populations (HR, 1.19; 95% CI: 0.16-8.83) and in patients without preoperative treatment (HR, 2.55; 95% CI: 1.62-4.00) compared with patients with preoperative treatment (HR, 1.19; 95% CI: 0.16-8.83). In addition, the HRs of patients with high HOTAIR expression for metastasis-free survival (MFS), relapse-free survival (RFS), and disease-free survival (DFS) were 2.30 (P=0.120), 1.39 (P=0.000), and 2.53 (P=0.714), respectively, but there were insufficient data to fully confirm these associations. CONCLUSION: HOTAIR may be a predictor of poor prognosis in four of the main estrogen-dependent tumors, especially in cervical, ovarian, and endometrial cancer patients without preoperative treatment in Asian populations. It is important to note that the prognostic value of HOTAIR in MFS, RFS, and DFS should be interpreted with caution due to the limited sample size and sample heterogeneity. Well-designed and larger-scale studies are needed to validate our findings. PMID- 26109872 TI - Exploration of peptide T7 and its derivative as integrin alphavbeta3-targeted imaging agents. AB - OBJECTIVE: The aim of the present study was to develop potential candidates of integrin alphavbeta3-targeted imaging agent, which can facilitate the diagnosis and treatment of malignant solid tumors. METHODS: Peptides derived from tumstatin, named T7 and T7-6H, were derivatized to contain histidine in the C terminus of their sequence and were labeled with (99m)Tc via nitrido and carbonyl precursors. The radiochemical purity and stability of (99m)Tc-labeled T7 and T7 6H were characterized by thin-layer chromatography. The whole body biodistribution was studied in NCI-H157-bearing BALB/c nude mice. RESULTS: The (99m)Tc-labeled T7 and T7-6H showed adequate in vitro stability, with a high radiochemical purity of over 90%. The dissociation constant (Kd) value of the (99m)Tc-labeled T7 and T7-6H ranged from 68.5 nM to 140.8 nM in U251 and NCI-H157 cell lines. (99m)Tc-labeled T7 and T7-6H showed no significant difference of biodistribution in mice. Furthermore, both T7 and T7-6H exhibited a poor blood brain barrier penetration and a transient accumulation in lung; the uptake in tumor tissues was significantly higher than in muscle tissue, with a ratio of 5.8. CONCLUSION: (99m)Tc-labeled T7 and T7-6H can be regarded as promising single photon emission computed tomography probes for imaging integrin alphavbeta3, and need to be further studied for noninvasive detection of tumors. PMID- 26109873 TI - Economic value of in vitro fertilization in Ukraine, Belarus, and Kazakhstan. AB - BACKGROUND: An economic value calculation was performed to estimate the lifetime net present value of in vitro fertilization (IVF) in Ukraine, Belarus, and Kazakhstan. METHODS: Net lifetime tax revenues were used to represent governmental benefits accruing from a hypothetical cohort of an IVF population born in 2009 using the methodology of generational accounting. Governmental expenses related to this population included social benefits, education and health care, unemployment support, and pensions. Where available, country specific data referencing official sources were applied. RESULTS: The average health care cost needed to achieve one additional birth from the governmental perspective varied from $2,599 in Ukraine to $5,509 in Belarus. The net present value from the population born using IVF was positive in all countries: for Ukraine ($9,839), Belarus ($21,702), and Kazakhstan ($2,295). The break-even costs of drugs and supplies per IVF procedure is expected to be $3,870, $8,530, and $1,780, respectively. Probabilistic sensitivity analyses based on 5,000 simulations show that the average net present value per person remains positive: $1,894+/-$7,619, $27,925+/-$12,407, and $17,229+/-$24,637 in Ukraine, Belarus, and Kazakhstan, respectively. CONCLUSION: Financing IVF may represent a good investment in terms of governmental financial returns, even in lower-income countries with state-financed health care systems such as Ukraine, Belarus, and Kazakhstan. PMID- 26109874 TI - The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors. AB - INTRODUCTION: Proton pump inhibitors, which are widely used as acid-inhibitory agents for the treatment of peptic ulcers, are mainly metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). CYP2C19 has genetic polymorphisms, associated with extensive, poor, intermediate or ultra-rapid metabolism of proton pump inhibitors. Genetic polymorphisms of CYP2C19 could be of clinical concern in the treatment of peptic ulcers with proton pump inhibitors. AIM: To investigate the frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles and genotypes in Russian patients with peptic ulcers. METHODS: We retrospectively reviewed the cases of 971 patients of Caucasian origin with Russian nationality from Moscow region with endoscopically and histologically proven ulcers, 428 males (44%) and 543 females (56%). The mean age was 44.6+/-11.9 years (range: 15-88 years). DNA was extracted from ethylenediaminetetraacetic acid whole blood samples (10 mL). The polymorphisms CYP2C19 681G.A (CYP2C19*2, rs4244285), CYP2C19 636 G.A (CYP2C19*3, rs4986893) and CYP2C19 -806 C.T (CYP2C19*17, rs12248560) were evaluated using real-time polymerase chain reaction. RESULTS: Regarding CYP2C19 genotype, 317 patients (32.65%) out of 971 were CYP2C19*1/*1 carriers classified as extensive metabolizers. Three hundred and eighty-six (39.75%) with CYP2C19*1/*17 or CYP2C19*17/*17 genotype were ultra-rapid metabolizers. Two hundred and fifty-one people (25.85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. The allele frequencies were the following: CYP2C19*2 - 0.140, CYP2C19*3 - 0.006, CYP2C19*17 - 0.274. CONCLUSION: There is a high frequency of CYP2C19 genotypes associated with modified response to proton pump inhibitors in Russian patients with peptic ulcers. Genotyping for CYP2C19 polymorphisms is suggested to be a useful tool for personalized dosing of proton pump inhibitors. PMID- 26109875 TI - Treatment of refractory/relapsed adult acute lymphoblastic leukemia with bortezomib-based chemotherapy. AB - Nine pretreated patients aged >19 years with relapsed/refractory acute lymphoblastic leukemia (ALL) were treated with a combination of bortezomib plus chemotherapy before allogeneic hematopoietic stem cell transplantation (allo HSCT). Eight (88.9%) patients, including two Philadelphia chromosome-positive ALL patients, achieved a complete remission. Furthermore, the evaluable patients have benefited from allo-HSCT after response to this reinduction treatment. We conclude that bortezomib-based chemotherapy was highly effective for adults with refractory/relapsed ALL before allo-HSCT. Therefore, this regimen deserves a larger series within prospective trials to confirm these results. PMID- 26109876 TI - Clinical utility of naloxegol in the treatment of opioid-induced constipation. AB - Opioids are a class of medications frequently used for the treatment of acute and chronic pain, exerting their desired effects at central opioid receptors. Agonism at peripherally located opioid receptors, however, leads to opioid-induced constipation (OIC), one of the most frequent and debilitating side effects of prolonged opioid use. Insufficient relief of OIC with lifestyle modification and traditional laxative treatments may lead to decreased compliance with opioid regimens and undertreated pain. Peripherally acting mu-opioid receptor antagonists (PAMORAs) offer the reversal of OIC without loss of central pain relief. Until recently, PAMORAs were restricted to subcutaneous route or to narrow patient populations. Naloxegol is the first orally dosed PAMORA indicated for the treatment of OIC in noncancer patients. Studies have suggested its efficacy in patients failing traditional constipation treatments; however, insufficient evidence exists to establish its role in primary prevention of OIC at this time. PMID- 26109877 TI - A profile of enzalutamide for the treatment of advanced castration resistant prostate cancer. AB - Recent advances in understanding the mechanisms underlying the development and progression of castration resistant prostate cancer from androgen-sensitive prostate cancer have provided new avenues exploring efficacious therapies in a disease which is the second leading cause of cancer deaths among men in the western world. In the evolution of second generation anti-androgens, enzalutamide, a novel androgen-receptor signaling inhibitor, has emerged targeting multiple steps within the androgenic stimulation pathway. This review discusses what is currently known of the mechanisms surrounding castration resistant prostate cancer development and the current human clinical trials to determine whether enzalutamide presents a new hope for men with advanced prostate cancer. The issues of therapy resistance, withdrawal effects and cross-resistance are briefly touched upon. PMID- 26109879 TI - Student assistantships: bridging the gap between student and doctor. AB - In 2009, the General Medical Council UK (GMC) published its updated guidance on medical education for the UK medical schools - Tomorrow's Doctors 2009. The Council recommended that the UK medical schools introduce, for the first time, a clinical placement in which a senior medical student, "assisting a junior doctor and under supervision, undertakes most of the duties of an F1 doctor". In the UK, an F1 doctor is a postgraduation year 1 (PGY1) doctor. This new kind of placement was called a student assistantship. The recommendation was considered necessary because conventional UK clinical placements rarely provided medical students with opportunities to take responsibility for patients - even under supervision. This is in spite of good evidence that higher levels of learning, and the acquisition of essential clinical and nontechnical skills, depend on students participating in health care delivery and gradually assuming responsibility under supervision. This review discusses the gap between student and doctor, and the impact of the student assistantship policy. Early evaluation indicates substantial variation in the clarity of purpose, setting, length, and scope of existing assistantships. In particular, few models are explicit on the most critical issue: exactly how the student participates in care and how supervision is deployed to optimize learning and patient safety. Surveys indicate that these issues are central to students' perceptions of the assistantship. They know when they have experienced real responsibility and when they have not. This lack of clarity and variation has limited the impact of student assistantships. We also consider other important approaches to bridging the gap between student and doctor. These include supporting the development of the student as a whole person, commissioning and developing the right supervision, student-aligned curricula, and challenging the risk assumptions of health care providers. PMID- 26109878 TI - 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus sunitinib or bevacizumab as first-line treatment for metastatic colorectal cancer: a randomized Phase IIb study. AB - BACKGROUND: Sunitinib is an oral inhibitor of tyrosine kinase receptors implicated in tumor proliferation, angiogenesis, and metastasis. In this randomized, multicenter, open-label Phase IIb study, sunitinib plus mFOLFOX6 (oxaliplatin plus leucovorin plus 5-fluorouracil) was compared with bevacizumab plus mFOLFOX6 as first-line therapy in patients with metastatic colorectal cancer. METHODS: Patients were stratified by performance status, baseline lactate dehydrogenase level, and prior adjuvant treatment, and randomized 1:1 to receive sunitinib 37.5 mg/day for 4 weeks on and 2 weeks off plus mFOLFOX6 every 2 weeks or bevacizumab 5 mg/kg every 2 weeks plus mFOLFOX6 every 2 weeks. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate, overall survival, safety, and quality of life. RESULTS: Enrollment was closed early following accrual of 191 patients, based on an interim analysis showing an inferior trend in the primary progression-free survival efficacy endpoint for sunitinib. Ninety-six patients were randomized to sunitinib plus mFOLFOX6 and 95 to bevacizumab plus mFOLFOX6. Median progression-free survival was 9.3 months and 15.4 months, respectively, but the objective response rate was similar between the study arms. Median overall survival was 23.7 months and 34.1 months, respectively. Dose reductions and interruptions were more common with sunitinib. Hematologic toxicity was more common in the sunitinib arm. CONCLUSION: While the results of the sunitinib arm are comparable with those of previously reported FOLFOX combinations, the sunitinib-based combination was associated with more toxicity than that observed with bevacizumab and mFOLFOX6. The bevacizumab arm had an unexpectedly good outcome, and was much better than that seen in the Phase III trials. Combination therapy with sunitinib plus mFOLFOX6 is not recommended for patients with metastatic colorectal cancer. PMID- 26109880 TI - Ozone decomposition. AB - Catalytic ozone decomposition is of great significance because ozone is a toxic substance commonly found or generated in human environments (aircraft cabins, offices with photocopiers, laser printers, sterilizers). Considerable work has been done on ozone decomposition reported in the literature. This review provides a comprehensive summary of the literature, concentrating on analysis of the physico-chemical properties, synthesis and catalytic decomposition of ozone. This is supplemented by a review on kinetics and catalyst characterization which ties together the previously reported results. Noble metals and oxides of transition metals have been found to be the most active substances for ozone decomposition. The high price of precious metals stimulated the use of metal oxide catalysts and particularly the catalysts based on manganese oxide. It has been determined that the kinetics of ozone decomposition is of first order importance. A mechanism of the reaction of catalytic ozone decomposition is discussed, based on detailed spectroscopic investigations of the catalytic surface, showing the existence of peroxide and superoxide surface intermediates. PMID- 26109881 TI - Toxicity, mechanism and health effects of some heavy metals. AB - Heavy metal toxicity has proven to be a major threat and there are several health risks associated with it. The toxic effects of these metals, even though they do not have any biological role, remain present in some or the other form harmful for the human body and its proper functioning. They sometimes act as a pseudo element of the body while at certain times they may even interfere with metabolic processes. Few metals, such as aluminium, can be removed through elimination activities, while some metals get accumulated in the body and food chain, exhibiting a chronic nature. Various public health measures have been undertaken to control, prevent and treat metal toxicity occurring at various levels, such as occupational exposure, accidents and environmental factors. Metal toxicity depends upon the absorbed dose, the route of exposure and duration of exposure, i.e. acute or chronic. This can lead to various disorders and can also result in excessive damage due to oxidative stress induced by free radical formation. This review gives details about some heavy metals and their toxicity mechanisms, along with their health effects. PMID- 26109882 TI - Systems toxicology approaches enable mechanistic comparison of spontaneous and cigarette smoke-related lung tumor development in the A/J mouse model. AB - The A/J mouse is highly susceptible to lung tumor induction and has been widely used as a screening model in carcinogenicity testing and chemoprevention studies. However, the A/J mouse model has several disadvantages. Most notably, it develops lung tumors spontaneously. Moreover, there is a considerable gap in our understanding of the underlying mechanisms of pulmonary chemical carcinogenesis in the A/J mouse. Therefore, we examined the differences between spontaneous and cigarette smoke-related lung tumors in the A/J mouse model using mRNA and microRNA (miRNA) profiling. Male A/J mice were exposed whole-body to mainstream cigarette smoke (MS) for 18 months. Gene expression interaction term analysis of lung tumors and surrounding non-tumorous parenchyma samples from animals that were exposed to either 300 mg/m(3) MS or sham-exposed to fresh air indicated significant differential expression of 296 genes. Ingenuity Pathway Analysis((r)) (IPA((r))) indicated an overall suppression of the humoral immune response, which was accompanied by a disruption of sphingolipid and glycosaminoglycan metabolism and a deregulation of potentially oncogenic miRNA in tumors of MS-exposed A/J mice. Thus, we propose that MS exposure leads to severe perturbations in pathways essential for tumor recognition by the immune system, thereby potentiating the ability of tumor cells to escape from immune surveillance. Further, exposure to MS appeared to affect expression of miRNA, which have previously been implicated in carcinogenesis and are thought to contribute to tumor progression. Finally, we identified a 50-gene expression signature and show its utility in distinguishing between cigarette smoke-related and spontaneous lung tumors. PMID- 26109883 TI - Radiosensitive effect of curcumin on thyroid cancer cell death induced by radioiodine-131. AB - Curcumin is a natural product widely consumed by humans. It has many biological properties. In this study, we investigated the radiosensitive effect of curcumin on thyroid cancer cells against cellular toxicity induced by 131-I. Human thyroid cancer and human non-malignant fibroblast cells (HFFF2) were treated with 131-I and/or curcumin at different concentrations (5, 10 and 25 ug/ml) for 48 h. The cell proliferation was measured by determination of the surviving cells by using MTT assay. Our results showed that curcumin increased the killing effect of 131-I on thyroid cancer cells, while it exerted no toxicity on HFFF2 cells. This result shows a promising effect of curcumin on the enhancement of therapeutic effects of 131-I in patients. PMID- 26109884 TI - Melanogenesis inhibitory activity of Korean Undaria pinnatifida in mouse B16 melanoma cells. AB - A number of seaweed species are used as traditional foods and medicine in different parts of the world, including Asian countries. However, very few data on the anti-melanogenic effect of seaweed have been published. Undaria pinnatifida (Dolmiyeok), a brown alga, is a traditional food in Jeju Island, the southern regions of the Korea peninsula. In this study, ethylacetate extracts of U. pinnatifida (UPE) were examined for their anti-melanogenic potentials. Our results supports the finding that UPE down-regulated melanin content in a dose dependent pattern. To clarify the target of UPE action in melanogenesis, we performed Western blotting for tyrosinase and microphthalmia-associated transcription factor (MITF), which are key melanogenic enzymes. UPE inhibited tyrosinase and MITF expressions in a dose-dependent manner. These results indicate that treatment with UPE significantly inhibits the melanogenesis in B16 cells, and may be effective in the whitening agent for the skin. PMID- 26109885 TI - Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice. AB - Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1-4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2 [4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8-12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 ug/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management. PMID- 26109886 TI - Antidotal activity of Averrhoa carambola (Star fruit) on fluoride induced toxicity in rats. AB - Consumption of fluoride leads to several physiological disturbances in carbohydrate, lipid and antioxidant metabolisms. Averrhoa carambola L. fruit (Star fruit) is a commonly consumed fruit in tropical countries and is an ingredient in folklore medicines. As the fruits have high polyphenolic and antioxidant contents, the present study was undertaken to investigate the potential of star fruit as a dietary supplement in attenuating the fluoride induced hyperglycemia, hypercholesterolemia and oxidative stress in laboratory rats. A four-week exposure to fluoride caused sustained hyperglycemia, hyperlipidemia and oxidative stress and, when the diet was supplemented with star fruit powder, carbohydrate, lipid and antioxidant profiles were restored significantly. It is surmised that the antihyperglycemic, antihypercholesterolemic and antioxidant activities of star fruit in fluoride exposed rats could be due to the presence of polyphenols, flavonoids, saponins, phytosterols, ascorbic acid and fibers in the fruit, which are all well known regulators of carbohydrate, lipid and antioxidant metabolisms. These findings suggest that star fruit can be used as a dietary supplement in fluoride endemic regions to contain fluoride induced hyperglycemia, hyperlipidemia and oxidative stress. PMID- 26109887 TI - Effects of cadmium and monensin on renal and cardiac functions of mice subjected to subacute cadmium intoxication. AB - Cadmium (Cd) is a well-known nephrotoxic agent. Cd-induced renal dysfunction has been considered as one of the causes leading to the development of hypertension. The correlation between Cd concentration in blood and urine and cardiovascular diseases has been discussed in many epidemiological studies. A therapy with chelating agents is utilized for the treatment of toxic metal intoxication. Herein we present novel information indicating that monensin (applied as tetraethylammonium salt) is a promising chelating agent for the treatment of Cd induced renal and cardiac dysfunction. The study was performed using the ICR mouse model. Adult ICR male mice were divided into three groups with six animals in each group: control (received distilled water and food ad libitum for 28 days); Cd-intoxicated (treated orally with 20 mg/kg b.w. Cd(II) acetate from day 1 to day 14 of the experimental protocol), and monensin treated group (intoxicated with Cd(II) acetate as described for the Cd-intoxicated group followed by oral treatment with 16 mg/kg b.w. tetraethylammonium salt of monensic acid for 2 weeks). Cd intoxication of the animals resulted in an increase of the organ weight/body weight indexes. Cd elevated significantly creatinine and glucose level in serum. Monensin treatment improved the organ weight/body weight ratios. The therapy of the Cd-intoxicated animals with monensin ameliorated the creatinine and glucose level in serum and decreased the concentration of the toxic metal ions in the heart and kidneys by 54% and 64%, respectively. PMID- 26109888 TI - Co-morditities of environmental diseases: A common cause. AB - The global pandemic of non-vector borne environmental diseases may, in large part, be attributed to chronic exposures to ever increasing levels of exogenous lipophilic chemicals. These chemicals include persistent organic pollutants, semi volatile compounds and low molecular weight hydrocarbons. Such chemicals facilitate the sequential absorption of otherwise not absorbed more toxic hydrophilic species that attack numerous body organs and systems, leading to environmental disease. Co-morbidities of non-communicable environmental diseases are alarmingly high, with as many as half of all individuals chronically ill with two or more diseases. Co-morbidity is to be anticipated, since all of the causative chemicals identified have independently been shown to trigger the individual diseases. PMID- 26109889 TI - Younger age at onset of sporadic Parkinson's disease among subjects occupationally exposed to metals and pesticides. AB - An earlier age at onset of Parkinson's disease (PD) has been reported to be associated with occupational exposures to manganese and hydrocarbon solvents suggesting that exposure to neurotoxic chemicals may hasten the progression of idiopathic PD. In this study the role of occupational exposure to metals and pesticides in the progression of idiopathic PD was assessed by looking at age at disease onset. The effects of heritable genetic risk factors, which may also influence age at onset, was minimized by including only sporadic cases of PD with no family history of the disease (n=58). Independent samples Student t-test revealed that subjects with occupational exposure to metals and/or pesticides (n=36) were significantly (p=0.013) younger than unexposed controls (n=22). These subjects were then divided into three groups [high (n=18), low (n=18), and unexposed (n=22)] to ascertain if duration of exposure further influenced age at onset of PD. One-way ANOVA revealed that subjects in the high exposure group were significantly (p=0.0121) younger (mean age: 50.33 years) than unexposed subjects (mean age: 60.45 years). Subjects were also stratified by exposure type (metals vs. pesticides). These results suggest that chronic exposure to metals and pesticides is associated with a younger age at onset of PD among patients with no family history of the disease and that duration of exposure is a factor in the magnitude of this effect. PMID- 26109890 TI - Postponed effect of neostigmine on oxidative homeostasis. AB - Cholinesterases are enzymes able to hydrolyze the neurotransmitter acetylcholine and thus to terminate transmission. Once the enzymes are inhibited, excitotoxicity can appear in the adjacent cells. It is well known that oxidative stress is involved in the toxicity of cholinesterase inhibitors. Commonly, stress follows inhibition of cholinesterases and disappears shortly afterwards. In the present experiment, it was decided to test the impact of an inhibitor, neostigmine, on oxidative stress in BALB/c mice after a longer interval. The animals were sacrificed three days after onset of the experiment and spleens and livers were collected. Reduced glutathione (GSH), glutathione reductase (GR), glutathione S-transferase (GST), thiobarbituric acid reactive substances (TBARS), ferric reducing antioxidant power (FRAP), caspase-3 and activity of acetylcholinesterase (AChE) were assayed. The tested markers were not altered with exceptions of FRAP. The FRAP values indicate accumulation of low molecular weight antioxidants in the examined organs. The role of low molecular weight antioxidants in the toxicity of AChE inhibitors is discussed. PMID- 26109891 TI - Pd(II) complexes of acetylcholinesterase reactivator obidoxime. AB - The ability of the acetylcholinesterase reactivator obidoxime (H2L(2+)) to bind palladium(II) cations was evaluated spectrophotometrically at different reaction conditions (pH, reaction time, metal-to-ligand molar ratio). The results showed that immediately after mixing the reagents, pH 7.4, complex species of composition [PdHL](3+) existed predominantly with a value of conditional stability constant lgbeta'=6.52. The reaction was completed within 24 hours affording the formation of species [Pd2L](4+) with significantly increased stability (lgbeta'=9.34). The spectral data suggest that obidoxime coordinates metal(II) ions through the oximate functional groups. The in vitro reactivation assay of paraoxon-inhibited rat brain acetylcholinesterase revealed that the new complex species were much less active than the non-coordinated obidoxime. The lack of reactivation ability could be explained by the considerable stability of complexes in solution as well as by the deprotonation of oxime groups essential for recovery of the enzymatic activity. PMID- 26109892 TI - Salvia officinalis L. extract and its new food antioxidant formulations induce apoptosis through mitochondrial/caspase pathway in leukemia L1210 cells. AB - Salvia officinalis, L. (Lamiaceae) is one of the most widespread herbal species used in the area of human health and in the food-processing industry. Salvia and its extracts are known to be a rich source of antioxidants. As shown previously, the crude ethanolic extract of salvia (SE) exerts lower anti-oxidative properties in lard compared to the new salvia food formulations No. 1 (SF1; 32% of SE + 68% of the emulsifier Dimodan S-T) and No. 2 (SF2; 32% of SE + 68% of the emulsifier Topcithin 50). The aim of the present study was to investigate and compare the effects of the SE and its food formulations SF1 and SF2 on the toxicity and/or proliferation of L1210 leukemia cells. We found that SE and both SF1 and SF2 demonstrated different concentration- and time-dependent cytotoxic/antiproliferative cellular effects already within the first 24 h of the treatment. However, SE was nearly 10 times more effective than the new salvia food formulations SF1 and SF2. We investigated partially also the molecular mechanisms lying behind the action of SE, SF1 and SF2 induced apoptosis in our cell model. We found an apparent involvement of the mitochondrial/caspase dependent pathway in the described processes. Nevertheless, further investigation is needed before salvia extract and its new antioxidant formulations can be included among the potential food antioxidants with protective properties against cancer. PMID- 26109893 TI - Iron induced genotoxicity: attenuation by vitamin C and its optimization. AB - Vitamin C (VC) is a well-known antioxidant and strong free radical scavenger. Its antioxidant activity is useful for protection of cellular macromolecules, particularly DNA, from oxidative damage induced by different agents. This study was undertaken to evaluate the optimum level of VC in attenuating the chromosome aberrations (CAs) and DNA damage after iron sulfate (FeSO4) acute administration in Wistar rats. The results exhibited that the increase of CAs and DNA damage induced by FeSO4, 200 mg Fe/kg, could be reduced significantly by VC pretreatment at the dose of 500 mg/kg (p<0.001), but not in the 100 mg/kg group. The findings provide evidence that VC at the dose of 500 mg/kg exerted a possible protective effect against FeSO4 induced CAs and DNA damage. The possible mechanisms of VC may be attributed to its property as a free radical scavenger or to its indirect action in reducing the level of reactive oxygen species (ROS). PMID- 26109894 TI - Cardiovascular effects of high-fructose intake in rats with nitric oxide deficiency. AB - The aim of this study was to evaluate the involvement of nitric oxide (NO) system damage in the deleterious effects of high-fructose intake in rats. Fructose was administered as 10% solution in drinking water to twelve-week-old male Wistar rats for the period of 8 weeks. Blood pressure was measured by tail-cuff plethysmography. After sacrificing the rats at the end of the treatment, relative weights of heart and liver and biochemical parameters in blood plasma were determined. Reactivity of isolated conduit arteries was measured using a force displacement transducer for recording isometric tension. Fructose drinking rats had increased blood pressure and impaired acetylcholine-induced relaxation of the thoracic aorta in comparison with control rats drinking just tap water. Relative liver weight and plasma concentrations of glucose and triglycerides were also elevated after fructose administration. In a further group of Wistar rats, inhibition of NO production by administration of N(G)-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day) was performed throughout fructose intake. L-NAME treatment itself induces increase in blood pressure and relative heart weight as well as impairment in arterial relaxation and contractility. However, in these rats, fructose administration did not cause further elevation of blood pressure and other abnormalities observed in rats receiving fructose without L-NAME. Our results showed that in the state of NO deficiency (induced by L-NAME administration) fructose does not induce cardiovascular and metabolic alterations which develop in rats with a functional NO system. This indicates that impairment of the NO system may participate in many of the adverse effects induced by high fructose intake. PMID- 26109895 TI - Chronic alcoholism-mediated metabolic disorders in albino rat testes. AB - There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 (CYP3A2) mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I - control (intact animals), II - chronic alcoholism (15% ethanol self-administration during 150 days). Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (-53%) and methionine (+133%). The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure. PMID- 26109896 TI - High mortality due to accidental salinomycin intoxication in sheep. AB - In February 2012, 100% mortality was reported in a herd with 79 local sheep that were kept around of Abhar, Northwest of Iran. The ration for adult sheep was daily mixed (40 kg straw, 25 kg wheat and 2 kg Vit-C premix) and accidentally 1 500 g of salinomycin (Salinomycin 12% Premix; Aras Bazar Laboratories, Iran) had been added to the ration (22388 mg/kg = 22388 ppm) and overnight was fed to herd. At the morning, 78 sheep were founded dead and one of them showed convulsive seizures. Postmortem examination revealed pulmonary congestion and edema, hemorrhages in abomasum, large pale kidney and white streak lines in myocardium. Main histopathologic lesions were extensive subepicardial and intercardiomyofibers hemorrhages, extensive cardiomyolysis and myocarditis in heart, severe hyperemia and extensive acute tubular necrosis (ATN) in kidneys and focal necrosis and retention of bile cholangitis in the liver. In this study, on the basis of the history, observation of the ionophore remnant in the ration, clinical signs, gross and histopathological findings, acute salinomycin intoxication is definitely diagnosed. PMID- 26109897 TI - Sorption ability of the soil and its impact on environmental contamination. AB - From the physical point of view, soil is a heterogenic polydisperse system. It often becomes a place of a secondary contamination during extinguishing uncontrolled areal fires in nature. Foam extinguishing agents (FEAs), used at these events, basically contain surface active substances and perfluorinated compounds. These tend to be captured in the soil matrix due to their specific properties. Contaminants could be partly flushed out with rainwater, which causes several times dilution of contamination and lower ecotoxic activity. However in the dry season, foam solution infiltrates into the bed soil without any dilution. This study deals with the direct influence of soil the sorption complex on ecotoxicity of five selected FEAs, i.e. Expyrol F 15, Finiflam F 15, Moussol APS F 15, Pyrocool B and Sthamex F 15. The substances tested were prepared in concentration of work solution and then applied on standard soil matrix LUFA 2.3. For experimental purposes, a column infiltration apparatus was designed and compiled. Filtrates were collected and then tested using the plant organisms Sinapis alba and Allium cepa L. The study compared ecotoxicologic effects of filtrates with an original work solution. Moussol APS F 15 seems to be the least ecotoxic of the FEAs tested. A direct influence of soil sorption complex onto ecotoxicity reduction was also established. This finding demonstrates the sorption ability of soil particles and ion exchange activity of the soil matrix. It is a positive finding for biota of aquatic environment, yet at the expense of those in soil. PMID- 26109898 TI - Diquat-induced cytotoxicity on Vero and HeLa cell lines: effect of melatonin and dihydromelatonin. AB - Diquat dibromide is a moderately toxic contact herbicide belonging to the bipyridyl group of redox-active compounds that induce a strong oxidative damage. Melatonin (MEL) can protect against oxidative damage under in vivo conditions, probably through its anti-oxidative capacity and ability to induce expression of anti-oxidative enzymes. The objective of this study was to investigate effects of diquat on viability of Vero and HeLa cells and possible protective effects of MEL and its analogue 2,3-dihydromelatonin (DMEL). Cell viability was evaluated with the MTT test. First, we analyzed dose-dependent effects of diquat on cell viability using the concentration range of 0.1-100 MUM. Second, we used the diquat dose which reduced cell viability by 50% and treated cells with either MEL or DMEL (both in the concentration range of 1-100 MUM) in the presence or absence of diquat. In addition, effects of both diquat and MEL on oxidative stress in HeLa cells were measured by flow cytometry using 2',7'-dichlorofluorescin diacetate. We confirmed the expected negative effects of diquat on viability of Vero and HeLa cells. Melatonin and DMEL were able to prevent diquat reduced viability of Vero cells in rather low concentrations (1 MUM) and DMEL exerted substantially stronger protective effects than MEL. However in HeLa cells, we did not find the same effects and MEL even reduced their viability. Moreover, treatment of HeLa cells with high concentrations of MEL (100 MUM) exaggerated the pro-oxidative effects of diquat. The results suggest that in addition to the expected anti-oxidative effects, MEL exerts a pro-oxidative action which is cell type and dose dependent. PMID- 26109899 TI - Carvacrol and rosemary oil at higher concentrations induce apoptosis in human hepatoma HepG2 cells. AB - Natural essential oils are volatile herbal complex compounds which manifest cytotoxic effects on living cells depending on their type and concentration but usually they are not genotoxic. Our previous studies showed that carvacrol (CA) and rosemary essential oil (RO) induced growth inhibition of both human cell lines HepG2 and BHNF-1, with hepatoma HepG2 cells being more sensitive to either compound tested. Cytotoxic concentrations of CA and RO induced the formation of DNA strand breaks. Further ex vivo studies showed that extracts prepared from hepatocytes of CA- and RO-supplemented rats did not increase incision repair activity compared to extracts from liver cells of control animals. Therefore, the aim of this work was to determine the effect of cytotoxic concentrations of CA and RO on the cell cycle and the ability of both natural volatiles to induce DNA fragmentation and apoptotic death of human hepatoma HepG2 cells. These effects were measured after 24 h incubation of HepG2 cells with CA and RO using three independent methods - flow cytometry, internucleosomal DNA fragmentation (electrophoresis) and micronucleus assay. Evaluation of morphological changes and formation of micronuclei in HepG2 cells showed no increase in the number of micronuclei in cells treated by CA and RO compared to control cells. On the other hand, CA and RO induced morphological changes typical for apoptosis in concentration-dependent manner. The presence of necrosis was negligible. Both natural compounds caused shrinking of cytoplasmic membrane and formation of apoptotic bodies. In addition, the highest concentrations of CA and RO induced internucleosomal DNA fragmentation (formation of DNA ladder) in HepG2 cells. Cell cycle analysis revealed the accumulation of cells in the G1 phase, which was accompanied by a reduction in the number of cells in the S phase after 24 h exposure to the substances tested. The cell division was thus slowed down or stopped and this process resulted in cell death. PMID- 26109900 TI - Arbutin and decrease of potentially toxic substances generated in human blood neutrophils. AB - Neutrophils, highly motile phagocytic cells, constitute the first line of host defense and simultaneously they are considered to be central cells of chronic inflammation. In combination with standard therapeutic procedures, natural substances are gaining interest as an option for enhancing the effectiveness of treatment of inflammatory diseases. We investigated the effect of arbutin and carvedilol and of their combination on 4beta-phorbol-12beta-myristate-13alpha acetate- stimulated functions of human isolated neutrophils. Cells were preincubated with the drugs tested and subsequently stimulated. Superoxide (with or without blood platelets, in the rate close to physiological conditions [1:50]) and HOCl generation, elastase and myeloperoxidase release were determined spectrophotometrically and phospholipase D activation spectrofluorometrically. The combined effect of arbutin and carvedilol was found to be more effective than the effect of each compound alone. Our study provided evidence supporting the potential beneficial effect of arbutin alone or in combination with carvedilol in diminishing tissue damage by decreasing phospholipase D, myeloperoxidase and elastase activity and by attenuating the generation of superoxide and the subsequently derived reactive oxygen species. The presented data indicate the ability of arbutin to suppress the onset and progression of inflammation. PMID- 26109901 TI - Modulation of microglial function by the antidepressant drug venlafaxine. AB - An increasing amount of data suggests that depression is an inflammatory disease. Depressed patients have higher peripheral blood levels of inflammatory markers which have been shown to access the brain and interact with the pathophysiological domain known to be involved in depression. Furthermore, microglia activation may play an important role in the inflammatory pathophysiology of depression. In BV-2 microglia cell line, the present study investigated the potential anti-inflammatory effects of venlafaxine, along with its potential influence on injury of lipopolysaccharide (LPS)-stimulated cells. Although venlafaxine showed only marginal influence on the majority of the pro inflammatory parameters assessed (in particular NO release, phagocytosis and proliferation), it significantly suppressed superoxide production by the stimulated cells. In addition, venlafaxine exerted also a protective effect on mitochondrial membrane potential and lysosomes of the stimulated microglia. In conclusion, our results suggest that although VEN might have only a marginal effect on major pro-inflammatory parameters of microglia, its inhibitory effect on superoxide generation can contribute to the prevention of harmful effects of oxidative and nitrosative stress involved in the pathogenesis of depression. Moreover, the protective effect of VEN on viability of microglia can prevent a rapid reduction of these cells, thus avoiding limitations of several physiological processes in the brain and possibly also the progression of depression. PMID- 26109903 TI - Preparation and performance of a colorimetric biosensor using acetylcholinesterase and indoxylacetate for assay of nerve agents and drugs. AB - Different toxic compounds can target the cholinergic nervous system. Acetylcholinesterase (AChE; EC 3.1.1.7) is one of the most crucial components of the cholinergic nervous system and thus many of the toxins interact with this enzyme. As to inhibitors, nerve agents used as chemical warfare, some insecticides, and drugs influencing the cholinergic system are common examples of AChE inhibitors. Once inhibited by a neurotoxic compound, a serious cholinergic crisis can occur. On the other hand, sensitivity of AChE to the inhibition can be used for analytical purposes. In this study, a simple disposable biosensor with AChE as a recognition element was devised. AChE was immobilized onto a cellulose matrix and indoxylacetate was used as a chromogenic substrate. The enzyme reaction was assessed by the naked eye using arbitrary units and pyridostigmine, tacrine, paraoxon, carbofuran, soman and VX were assayed as selected inhibitors. A good stability of the biosensors was found, with no aging over a quarter of a year and minimal sensitivity to the interference of organic solvents. The limit of detection ranged from 10 to 100 nmol/L for the compounds tested with a sample volume of 40 uL. PMID- 26109902 TI - Protective effect of Irvingia gabonensis stem bark extract on cadmium-induced nephrotoxicity in rats. AB - Cadmium has been considered a risk factor for humans as it accumulates in body tissues, such as the liver, lungs, kidneys, bones, and reproductive organs. The aim of the present study was to evaluate the effect of Irvingia gabonensis (IG) against cadmium (Cd)-induced nephrotoxicity. The study was performed on twenty (20) male rats divided into four groups: control group, cadmium group (4 mg/kg/day, intraperitoneally), cadmium + extract (200 mg/kg body weight by oral gavage) and cadmium + extract (400 mg/kg body weight by oral gavage). Changes in the kidney biochemical markers, namely glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), aminotransferase (ALT), aspartate aminotransferase (AST) activities and levels of malondialdehyde (MDA), urea, and creatinine were determined in serum. Histological examinations were monitored. Exposure to Cd lowered the activities of kidney antioxidants, while it increased LPO levels. Levels of all disrupted parameters were alleviated by co-administration of IG extract. The malondialdehyde concentration of the rats treated with 200 and 400 mg/kg body weight of the extract significantly decreased (p<0.05) compared with the untreated cadmium rats. Yet the creatinine concentration decreased significantly (p<0.05) when the cadmium animals treated with 200 and 400 mg/kg body weight of the extract were compared with the cadmium control. Furthermore, histological alterations in the kidney were observed in cadmium untreated rats and these were ameliorated in cadmium treated rats by co-administration of IG extract. IG showed apparent protective and curative effect on Cd-induced nephrotoxicity. PMID- 26109904 TI - Hemostatic effect and distribution of new rhThrombin formulations in rats. AB - Recombinant human thrombin (rhThrombin) is a potential hemostatic alternative to bovine and human plasma-derived thrombin. Hemostatic, liver regeneration effect and plasma concentrations of rhThrombin (SCILL) tested in the form of solution and hydrogels (thermo-sensitive poloxamer gel and carbomer gel; hameln rds) were evaluated. In the bleeding model, rhThrombin was applied locally on the bleeding site. The time to hemostasis was measured. The rhThrombin in liquid form as well as the thermo-sensitive gel forming formulation significantly reduced the bleeding time in comparison to saline. In the regeneration model, a cut in the form "V" was made on the liver and rhThrombin in both formulations was applied at defined concentrations to the wound for 5 min. The rats survived 1, 3 and 5 days after the injury and treatment. Histological examination showed better results in the group treated with rh Thrombin gel in comparison to the liquid form - solution; differences were insignificant. Low [(125)I]-rhThrombin radioactivity was evaluated in plasma after topical application (solution and both hydrogels) at hemostatic effective doses to partial hepatectomy in rats. Locally applied rh Thrombin on the rat damaged liver tissue never reached pharmacologically active systemic levels. The plasmatic levels and the content of this active protein in injured liver tissue were lower after application of its hydrogels versus solution. PMID- 26109905 TI - Deriving forest fire ignition risk with biogeochemical process modelling. AB - Climate impacts the growth of trees and also affects disturbance regimes such as wildfire frequency. The European Alps have warmed considerably over the past half century, but incomplete records make it difficult to definitively link alpine wildfire to climate change. Complicating this is the influence of forest composition and fuel loading on fire ignition risk, which is not considered by purely meteorological risk indices. Biogeochemical forest growth models track several variables that may be used as proxies for fire ignition risk. This study assesses the usefulness of the ecophysiological model BIOME-BGC's 'soil water' and 'labile litter carbon' variables in predicting fire ignition. A brief application case examines historic fire occurrence trends over pre-defined regions of Austria from 1960 to 2008. Results show that summer fire ignition risk is largely a function of low soil moisture, while winter fire ignitions are linked to the mass of volatile litter and atmospheric dryness. PMID- 26109906 TI - Modeling structural change in spatial system dynamics: A Daisyworld example. AB - System dynamics (SD) is an effective approach for helping reveal the temporal behavior of complex systems. Although there have been recent developments in expanding SD to include systems' spatial dependencies, most applications have been restricted to the simulation of diffusion processes; this is especially true for models on structural change (e.g. LULC modeling). To address this shortcoming, a Python program is proposed to tightly couple SD software to a Geographic Information System (GIS). The approach provides the required capacities for handling bidirectional and synchronized interactions of operations between SD and GIS. In order to illustrate the concept and the techniques proposed for simulating structural changes, a fictitious environment called Daisyworld has been recreated in a spatial system dynamics (SSD) environment. The comparison of spatial and non-spatial simulations emphasizes the importance of considering spatio-temporal feedbacks. Finally, practical applications of structural change models in agriculture and disaster management are proposed. PMID- 26109907 TI - Extracting cluster distributions from mass spectra: IsotopeFit. AB - The availability of high resolution mass spectrometry in the study of atomic and molecular clusters opens up challenges for the interpretation of the data. In complex systems each resolved mass peak may contain contributions from multiple species because of the isotope structure of constituent elements and because a multitude of different types of clusters with different compositions are present. A computational procedure which can help to identify a specific cluster from this complex dataset and quantify its relative abundance would be extremely helpful to many who work in this field. Here some new software designed for this purpose, known as IsotopeFit, is described. PMID- 26109908 TI - Tumor-specific expression of HMG-CoA reductase in a population-based cohort of breast cancer patients. AB - BACKGROUND: The mevalonate pathway synthetizes cholesterol, steroid hormones, and non-steriod isoprenoids necessary for cell survival. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the rate-limiting enzyme of the mevalonate pathway and the target for statin treatment. HMGCR expression in breast tumors has recently been proposed to hold prognostic and treatment-predictive information. This study aimed to investigate whether HMGCR expression in breast cancer patients was associated with patient and tumor characteristics and disease free survival (DFS). METHODS: A population-based cohort of primary breast cancer patients in Lund, Sweden was assembled between October 2002 and June 2012 enrolling 1,116 patients. Tumor tissue microarrays were constructed and stained with a polyclonal HMGCR antibody (Cat. No HPA008338, Atlas Antibodies AB, Stockholm, Sweden, diluted 1:100) to assess the HMGCR expression in tumor tissue from 885 patients. HMGCR expression was analyzed in relation to patient- and tumor characteristics and disease-free survival (DFS) with last follow-up June 30(th) 2014. RESULTS: Moderate/strong HMGCR expression was associated with less axillary lymph node involvement, lower histological grade, estrogen and progesterone receptor positivity, HER2 negativity, and older patient age at diagnosis compared to weak or no HMGCR expression. Patients were followed for up to 11 years. The median follow-up time was 5.0 years for the 739 patients who were alive and still at risk at the last follow-up. HMGCR expression was not associated with DFS. CONCLUSION: In this study, HMGCR expression was associated with less aggressive tumor characteristics. However, no association between HMGCR expression and DFS was observed. Longer follow-up may be needed to evaluate HMGCR as prognostic or predictive marker in breast cancer. PMID- 26109909 TI - Mental health nurses' support to caregivers of older adults with severe mental illness: a qualitative study. AB - BACKGROUND: Literature has shown the serious impact of severe mental illness on the daily life of caregivers. We studied reported caregiver support practices by mental health nurses for use in the development of a nursing intervention. We aimed to explore current caregiver support practices by mental health nurses. METHODS: Twenty-one participants completed semi-structured interviews, and 17 participants attended two focus groups. All interviews were audio-taped, transcribed and coded for qualitative analysis. RESULTS: The diversity in caregiver support could best be described by three prototypes: the tolerator, the preventer and the concerner, representing three approaches of involvement with caregivers. At one end of the spectrum are mental health nurses (MHN) who are essentially only concerned with the wellbeing of the care recipient and see the caregiver as a potential impediment in reaching the client's goals. We call these the tolerators. At the other end of the spectrum are the MHNs who see the caregiver and the care recipient as inextricably connected with each other. In these cases the MHN directs her/his intervention towards both the informal caregiver and the care recipient. We call these the concerners. In the middle position are MHNs who realize that caregivers are important agents in the achievement of the client's goals, and therefore consider preventing them from becoming overburdened as an important goal. We call these the preventers. CONCLUSIONS: Based on the extent to which the MHNs believe that the informal caregiver plays a necessary role in the client's support system, and the degree to which they feel responsible for the caregiver's wellbeing, three MHN prototypes can be distinguished. These prototypes determine how the nurses' vision directs their understanding of their role and responsibilities and the content of their behaviour. This implies that a change in behaviour needs to be preceded by a change in vision. Therefore, promoting family support cannot be achieved by one-size-fits-all-programmes. PMID- 26109910 TI - Association between underexpression of microrna-203 and clinicopathological significance in hepatocellular carcinoma tissues. AB - BACKGROUND: Although recent studies have shown the utility of miR-203 as a cancer relevant biomarker, the validated clinical significance of miR-203 in HCC remains obscure. The aim of the present study was to evaluate the relationship between miR-203 expression and clinicopathological features in HCC patients. METHODS: MiR 203 expression in 95 formalin-fixed, paraffin embedded (FFPE) HCC tissues and their paired adjacent non-cancerous tissues was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Simultaneously, expression of miR-203 and its correlation with a variety of clinicopathological parameters and patient recurrence was analyzed. RESULTS: The relative level of miR-203 was 1.1651 +/- 0.70378 in HCC tissues, significantly lower than its expression in the corresponding adjacent non-cancerous liver tissues (2.2408 +/- 0.75351, P < 0.001). The area under curve (AUC) of low miR-203 expression to diagnose HCC was 0.85 (95 % CI: 0.796 ~ 0.904, P = 0.027) at a cut-off value 1.99 evaluated by the median expression of miR-203 in all tissues, including HCC and normal liver tissues. Expression of miR-203 was negatively correlated to metastasis (r = 0.254, P = 0.013), clinical tumor nodes metastasis (TNM) stage (r = -0.300, P = 0.003), nm23 expression (r = -0.292, P = 0.004), p21 expression (r = -0.223, P = 0.030), microvessel density (MVD)(r = -0.206, P = 0.045) and was positively correlated to cirrhosis (r = 0.487, P < 0.001). Additionally, the recurrent time of lower miR-203 expression group was 57.949 +/- 4.184 months, slightly longer than that in the high expression group (54.682 +/- 2.591 months), however, no significant difference was noted (Chi-square = 0.206, P = 0.650). CONCLUSIONS: MiR-203 plays a vital role in the carcinogenesis and progression of HCC, which makes itself as a predictor for the deterioration of HCC. Furthermore, miR-203 may become a new target for molecular therapy in HCC. PMID- 26109911 TI - Chicken chorioallantoic membrane as a reliable model to evaluate osteosarcoma-an experimental approach using SaOS2 cell line. AB - BACKGROUND: Osteosarcoma is the most common primary tumor that affects usually children. Due to its cellular complex and osteoid formation it is very difficult to understand the mechanism behind the progressiveness of osteosarcoma. Various animal models are available to study the issue but they are time consuming and costly. We aimed to understand the progressiveness and invasiveness of osteosarcoma induced by SaOS2 cells using chicken chorioallantoic membrane. CAM is a well-established model which allows in vivo studies of tumor induced angiogenesis and the testing of anti angiogenic molecules. However only a few reports showed the tumor forming ability of SaOS2 cells on CAM. METHOD: Angiogenic ability of SaOS2 cells on CAM was validated by various methods. Angiogenic ability was scored by direct visualization and scanning microscopic analysis. The sprouting ability and growth of the vessel was measured by Angioquant software under different cellular volume. The invasiveness was analyzed by histological staining. Involvement of angiogenic factors at differential stage of progressiveness was confirmed by the molecular and protein level expression analysis. RESULT: SaOS2 cells induces sprouting angiogenesis on CAM and shows its aggressiveness by rupturing the ectodermal layer of the CAM. Growth and development of osteosarcoma depends mainly on the activation of VEGF165, MMP2 and MMP9. CAM able to reproduce angiogenic response against the stimulation of SaOS2 cells exactly as in other animal models without inflammatory reactions. CONCLUSION: CAM is an excellent alternative in vivo model for studying the aggressiveness and tumor progression of osteosarcoma using various angiogenic techniques in an easily, faster and affordable way. We further provided insight about the involvement of various angiogenic growth factors on the development of osteosarcoma which will enable to find the suitable therapeutic molecule for the treatment of osteosarcoma. CAM model could provide a wide space using modern techniques like micro array or in situ hybridization to have a better understanding about the progression and invasiveness of osteosarcoma cells to develop suitable therapeutic molecules. PMID- 26109912 TI - Malnutrition and cachexia in patients with head and neck cancer treated with (chemo)radiotherapy. AB - AIM: To highlight the problems associated with nutrition that occur in patients with squamous cell carcinoma of the head and neck (SCCHN). BACKGROUND: SCCHN is associated with weight loss before, during and after radiotherapy or concurrent chemoradiotherapy. Because of serious consequences of malnutrition and cachexia on treatment outcome, mortality, morbidity, and quality of life, it is important to identify SCCHN patients with increased risk for the development of malnutrition and cachexia. MATERIALS AND METHODS: Critical review of the literature. RESULTS: This review describes pathogenesis, diagnosis and treatment of malnutrition and cancer cachexia. Treatment of malnutrition and cancer cachexia includes nutritional interventions and pharmacological therapy. Advantages and disadvantages of different nutritional interventions and their effect on the nutritional status, quality of life and specific oncological treatment are presented. CONCLUSIONS: Nutritional management is an essential part of care of these patients, including early screening, assessment of nutritional status and appropriate intervention. PMID- 26109913 TI - Uroncor consensus statement: Management of biochemical recurrence after radical radiotherapy for prostate cancer: From biochemical failure to castration resistance. AB - Management of patients who experience biochemical failure after radical radiotherapy with or without hormonal therapy is highly challenging. The clinician must not only choose the type of treatment, but also the timing and optimal sequence of treatment administration. When biochemical failure occurs, numerous treatment scenarios are possible, thus making it more difficult to select the optimal approach. Moreover, rapid and ongoing advances in treatment options require that physicians make decisions that could impact both survival and quality of life. The aim of the present consensus statement, developed by the Urological Tumour Working Group (URONCOR) of the Spanish Society of Radiation Oncology (SEOR), is to provide cancer specialists with the latest, evidence-based information needed to make the best decisions for the patient under all possible treatment scenarios. The structure of this consensus statement follows the typical development of disease progression after biochemical failure, with the most appropriate treatment recommendations given for each stage. The consensus statement is organized into three separate chapters, as follows: biochemical failure with or without local recurrence and/or metastasis; progression after salvage therapy; and treatment of castration-resistant patients. PMID- 26109914 TI - Volumetric modulated arc therapy in prostate cancer patients with metallic hip prostheses in a UK centre. AB - AIM: This study aimed to investigate whether IMRT using VMAT is a viable and safe solution in dose escalated RT in these patients. BACKGROUND: An increasing number of prostate cancer patients are elderly and have hip prostheses. These implants pose challenges in radiotherapy treatment planning. Although intensity modulated radiotherapy (IMRT) is commonly used, there is a lack of clinical studies documenting its efficacy and toxicities in this subgroup of patients. MATERIALS AND METHODS: The data from 23 patients with hip prostheses and non-metastatic prostate cancer treated with VMAT (volumetric modulated arc therapy) between 2009 and 2011, were retrospectively analyzed. Baseline characteristics, treatment details and outcome data were collected on all patients. The median follow up was 40.9 months. MRI-CT image fusion was performed and the treatment plans were created using RapidArcTM (RA) techniques utilizing 1 or 2 arcs and 10 MV photon beams. RESULTS: 96% of patients were treated with a dose of 72 Gy/32 fractions over 44 days. 21/23 plans met the PTV targets. The mean homogeneity index was 1.07. 20/23 plans met all OAR constraints (rectum, bladder). Two plans deviated from rectal constraints, four from bladder constraints; all were classed as minor deviations. One patient experienced late grade 3 genitourinary toxicity. Three other patients experienced late grade 2 or lower gastrointestinal toxicity. One patient had biochemical failure and one had a non-prostate cancer related death. CONCLUSIONS: VMAT provides an elegant solution to deliver dose escalated RT in patients with unilateral and bilateral hip replacements with minimal acute and late toxicities. PMID- 26109915 TI - Relationships between various indices of doses distribution homogeneity. AB - AIM: In this study we compared three different methods of evaluation of dose distribution. BACKGROUND: The aim of treatment planning is to prepare the treatment plan which the criteria are defined according to the international recommendations. MATERIALS AND METHODS: For three groups of patients, for lung, breast and prostate, treated radically in Brzozow with external beams the treatment plans were prepared. For each patient the metrics of dose distribution in the PTV defined according to the ICRU Reports 50, 83 and according to the Nordic Association of Clinical were calculated. Also Homogeneity Index defined by Yoon was used in this work. Additionally for similar group of patients treated in Warsaw the same calculations were performed. Correlations between the standard deviations and: (1) the differences between the maximum and minimum doses, and (2) the differences between near maximum and near minimum doses normalized to median dose and (3) to prescribed dose were calculated. RESULTS: There was a very strong correlation between the standard deviation and the difference between the near-maximum and near-minimum doses for all locations regardless the prescription. Also good correlation was observed for the standard deviation and the difference between the maximum and minimum doses for patients treated in Brzozow. CONCLUSIONS: The standard deviation may be estimated by the Homogeneity Index, however the relationship should be established for each location and each center separately. PMID- 26109916 TI - Radiotherapy for adult medulloblastoma: Long term result from a single institution. A review of prognostic factors and why we do need a multi institutional cooperative program. AB - AIM: We retrospectively analyzed our Institution experience with these patients. The endpoints of the analysis were overall survival (OS), disease-free survival (DFS), local control (LC), metastasis free survival (MFS); results were compared with the literature. BACKGROUND: Medulloblastoma in adult patients is a very rare disease; the 5 and 10-year overall survival rates range between 33-78% and 27 56%, respectively. The collection of more clinical data is strongly needed. MATERIALS AND METHODS: From September 1975 to October 2006, we treated 16 adult patients (9 males and 7 females) with a histological diagnosis of medulloblastoma. Acute and late toxicities were scored according to RTOG toxicity scale. Karnofski performance status (KPS) and neurological performance status (NPS) pre- and post-RT were reported. Median age was 27 years (range 18-53 years). All the patients received cranio-spinal irradiation, two patients were also given chemotherapy. Median follow-up period was 121.5 months. RESULTS: In January 2014, 10/16 patients were alive without evidence of disease, 6/16 died with progressive disease (1 local and spinal, 3 spinal and 2 extraneural). Ten year LC, OS, DFS, MFS were, respectively, 84%, 67%, 60% and 59%. Univariate analysis shows that gross total resection is associated with better survival. No acute or late G3-G4 toxicity was observed. CONCLUSIONS: This experience and the analysis of the literature confirm the efficacy of postoperative RT but also the need of large datasets to better define prognostic factors and the possible role of the association of chemotherapy. PMID- 26109917 TI - Effects of remedies made in patient setup process on residual setup errors and margins in head and neck cancer radiotherapy based on 2D image guidance. AB - AIM: Patient setup errors were aimed to be reduced in radiotherapy (RT) of head and-neck (H&N) cancer. Some remedies in patient setup procedure were proposed for this purpose. BACKGROUND: RT of H&N cancer has challenges due to patient rotation and flexible anatomy. Residual position errors occurring in treatment situation and required setup margins were estimated for relevant bony landmarks after the remedies made in setup process and compared with previous results. MATERIALS AND METHODS: The formation process for thermoplastic masks was improved. Also image matching was harmonized to the vertebrae in the middle of the target and a 5 mm threshold was introduced for immediate correction of systematic errors of the landmarks. After the remedies, residual position errors of bony landmarks were retrospectively determined from 748 orthogonal X-ray images of 40 H&N cancer patients. The landmarks were the vertebrae C1-2, C5-7, the occiput bone and the mandible. The errors include contributions from patient rotation, flexible anatomy and inter-observer variation in image matching. Setup margins (3D) were calculated with the Van Herk formula. RESULTS: Systematic residual errors of the landmarks were reduced maximally by 49.8% (p <= 0.05) and the margins by 3.1 mm after the remedies. With daily image guidance the setup margins of the landmarks were within 4.4 mm, but larger margins of 6.4 mm were required for the mandible. CONCLUSIONS: Remarkable decrease in the residual errors of the bony landmarks and setup margins were achieved through the remedies made in the setup process. The importance of quality assurance of the setup process was demonstrated. PMID- 26109918 TI - Smoking during radiotherapy for head and neck cancer and acute mucosal reaction. AB - AIM: We compared the incidence of RTOG/EORTC grade III and higher acute mucositis in patients with head and neck cancer who continued to smoke during radiotherapy with those who quit smoking. BACKGROUND: There are conflicting data on the relationship between smoking during radiotherapy and the severity of acute mucosal reaction. More studies dealing with this issue are needed. MATERIALS AND METHODS: Among 136 patients receiving curative radio(chemo)therapy, 37 (27%) declared that they had not quit smoking during radiotherapy. The intensity of mucositis was scored daily by a nurse and weekly by a physician using the RTOG/EORTC scale. The main end-point of the study was the highest observed RTOG/EORTC grade of mucositis. RESULTS: Patients who smoked during radiotherapy (smokers) were younger than their counterparts who quit smoking (non-smokers), p = 0.06. There were no other differences in the baseline characteristics between smokers and non-smokers. Grade III/IV acute mucositis was observed in 43.5% of all patients. The percentage of patients with grade III/IV acute mucositis was similar in smokers and non-smokers (46% vs. 42%, p = 0.71). Nine patients (smokers [13.5%]; non-smokers [4%], p = 0.05) required prolonged hospitalization to heal mucositis. CONCLUSIONS: In the whole group, smoking during radiotherapy was not related to acute mucosal toxicity evaluated as the rate of the highest observed grade of mucositis. PMID- 26109919 TI - The effect of radiotherapy and chemotherapy on osmotic fragility of red blood cells and plasma levels of malondialdehyde in patients with breast cancer. AB - BACKGROUND: Gamma radiation effects on the erythrocyte membrane from three different functional parts, lipid bilayer, cytoskeleton and protein components. When the red cell membrane is exposed to radiation, it loses its integrity and hemoglobin leaks out. In addition, irradiation leads to lipid peroxidation and the products of this process, leading to hemolysis. The aim of the present study was to measure osmotic fragility (OF) of red blood cells and malondialdehyde (MDA) levels as a marker of oxidative injury in breast cancer patients treated with radiation and chemotherapy. MATERIALS AND METHODS: The OF test was performed using different concentrations of a salt solution. The measurement of MDA was done with chemical methods.(11) The sampling was taken during three stages of treatment: first sample was taken before starting chemotherapy, the second sample was taken before radiation therapy and the third sample was taken after radiotherapy. RESULTS: No statistically significant differences between levels of MDA in these three stages of treatment were observed. However, the comparison of mean levels of MDA showed an increase after radiotherapy. The OF rate did not show significant difference (P > 0.05) during the stages of treatment. CONCLUSION: In a standard treatment program of radiotherapy and chemotherapy lipid peroxidation level and OF do not significantly increase. PMID- 26109920 TI - Hypersensitivity to chemoradiation in FANCA carrier with cervical carcinoma-A case report and review of the literature. AB - OBJECTIVE: Compared to Fanconi anemia (FA) patients with homozygous defective two alleles inheritance, there is a scarce or no evidence on one defective allele FANCA carriers, with respect to their cancer incidence, clinical and in vitro radiosensitivity and chemosensitivity. On that account, we report a case of a 30 year old FANCA mutation carrier woman with uterine cervix adenocarcinoma who was treated with chemoradiotherapy, in which unexpected acute toxicity and fatal late morbidity occured. METHODS: We also report the results of an in vitro test for radiosensitivity, immunohistochemical examination with FANCA staining and human papillomavirus genotypization, and a review of the literature for FA carrier patients with respect to cancer incidence, clinical and in vitro response to chemo/radiotherapy, options of early heterozygosity detection, and methods of in vitro prediction of hypersensitivity to oncologic treatment. CONCLUSION: Although there are no standard guidelines for management of FA carriers with malignancies and reports about chemo- or radiosensitivity in this population are scarce; patients with FA-A heterozygosity may have a high rate of complications from chemo/radiotherapy. Up to now, an optimum method for the prediction of radiosensitivity and the best parameter has not been found. Clinical radioresponsiveness is unpredictable in FA carriers and there is a pressing need of new rapid and predictive in vitro assays of radiation responses. Until then, the treatment of FA carriers with malignancies should be individualized, with respect to potential hypersensitivity to ionizing radiation or cross-linking agents. PMID- 26109921 TI - On the cutting edge of intensity modulated radiotherapy and simultaneous integrated boost (IMRT-SIB): The case of a patient with 8 brain metastases. AB - BACKGROUND: Patients with multiple brain metastases, especially those with more than 3 lesions, usually undergo to palliative whole brain (WB) radiotherapy (RT). METHODS: A breast cancer patient with 8 brain metastases was treated on the brain by a radical RT regimen. Prescription doses were according to the simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) technique with all lesions as well brain irradiated simultaneously in 20 daily fractions. Doses of 40.0 Gy (2.0 Gy/fraction) and 50.0 Gy (2.5 Gy/fraction) were prescribed to the whole brain and to eight individual metastases, respectively. RESULTS: Mean volume of the eight metastases was 8.1 cc (range: 3.8-10.1 cc). For all lesions, the volume receiving 95% of prescribed dose was 100% and dose homogeneity was within 3%. Moreover, maximum doses were less than 105% of prescribed dose, while average mean dose to lesions was 50.6 Gy (range: 49.7-51.5 Gy). Whole brain mean dose was 45.2 Gy. Maximum doses to brainstem and optic chiasma were limited to 44.5 Gy and 42.9 Gy, respectively, while maximum doses to eyes, lens and optic nerves were limited to 9.2 Gy, 4.9 Gy and 41.0 Gy, respectively. From a clinical point of view, subsequent MRI brain controls showed a complete clinical response. Forty months after treatment the patient is disease free and shows no late brain and skin toxicities. CONCLUSION: This case demonstrates the technical feasibility of a SIB-IMRT treatment in patients with more than 3 brain metastases. PMID- 26109922 TI - Osteocalcin and the Regulation of Glucose Metabolism. AB - Uncarboxylated osteocalcin enhances insulin and adiponectin release and improves glucose tolerance in mice. Data in humans do not unequivocally support a role for osteocalcin in glucose homeostasis. Changes in the amount of uncarboxylated osteocalcin induced by vitamin K or warfarin treatment are not associated with changes in glucose and insulin concentrations. Interventional studies in humans, designed to detect small changes in insulin secretion and action attributable to changes in uncarboxylated osteocalcin, will be required to reliably detect effects of osteocalcin on glucose metabolism and to better understand its interaction with adiposity and adipokines. PMID- 26109923 TI - Factors regulating excystment of Alexandrium in Puget Sound, WA, USA. AB - Factors regulating excystment of a toxic dinoflagellate in the genus Alexandrium were investigated in cysts from Puget Sound, Washington State, USA. Experiments were carried out in the laboratory using cysts collected from benthic seedbeds to determine if excystment is controlled by internal or environmental factors. The results suggest that the timing of germination is not tightly controlled by an endogenous clock, though there is a suggestion of a cyclical pattern. This was explored using cysts that had been stored under cold (4 degrees C), anoxic conditions in the dark and then incubated for 6 weeks at constant favorable environmental conditions. Excystment occurred during all months of the year, with variable excystment success ranging from 31-90%. When cysts were isolated directly from freshly collected sediments every month and incubated at the in situ bottom water temperature, a seasonal pattern in excystment was observed that was independent of temperature. This pattern may be consistent with secondary dormancy, an externally modulated pattern that prevents excystment during periods that are not favorable for sustained vegetative growth. However, observation over more annual cycles is required and the duration of the mandatory dormancy period of these cysts must be determined before the seasonality of germination can be fully characterized in Alexandrium from Puget Sound. Both temperature and light were found to be important environmental factors regulating excystment, with the highest rates of excystment observed for the warmest temperature treatment (20 degrees C) and in the light. PMID- 26109924 TI - Training needs in metabolomics. PMID- 26109925 TI - Can we trust untargeted metabolomics? Results of the metabo-ring initiative, a large-scale, multi-instrument inter-laboratory study. AB - The metabo-ring initiative brought together five nuclear magnetic resonance instruments (NMR) and 11 different mass spectrometers with the objective of assessing the reliability of untargeted metabolomics approaches in obtaining comparable metabolomics profiles. This was estimated by measuring the proportion of common spectral information extracted from the different LCMS and NMR platforms. Biological samples obtained from 2 different conditions were analysed by the partners using their own in-house protocols. Test #1 examined urine samples from adult volunteers either spiked or not spiked with 32 metabolite standards. Test #2 involved a low biological contrast situation comparing the plasma of rats fed a diet either supplemented or not with vitamin D. The spectral information from each instrument was assembled into separate statistical blocks. Correlations between blocks (e.g., instruments) were examined (RV coefficients) along with the structure of the common spectral information (common components and specific weights analysis). In addition, in Test #1, an outlier individual was blindly introduced, and its identification by the various platforms was evaluated. Despite large differences in the number of spectral features produced after post-processing and the heterogeneity of the analytical conditions and the data treatment, the spectral information both within (NMR and LCMS) and across methods (NMR vs. LCMS) was highly convergent (from 64 to 91 % on average). No effect of the LCMS instrumentation (TOF, QTOF, LTQ-Orbitrap) was noted. The outlier individual was best detected and characterised by LCMS instruments. In conclusion, untargeted metabolomics analyses report consistent information within and across instruments of various technologies, even without prior standardisation. PMID- 26109926 TI - A hypothetical astrocyte-microglia lactate shuttle derived from a 1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis. AB - Tuberculosis meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis and is particularly intense in small children; there is no universally accepted algorithm for the diagnosis and substantiation of TB infection, which can lead to delayed intervention, a high risk factor for morbidity and mortality. In this study a proton magnetic resonance (1H NMR)-based metabolomics analysis and several chemometric methods were applied to data generated from lumber cerebrospinal fluid (CSF) samples from three experimental groups: (1) South African infants and children with confirmed TBM, (2) non meningitis South African infants and children as controls, and (3) neurological controls from the Netherlands. A total of 16 NMR-derived CSF metabolites were identified, which clearly differentiated between the controls and TBM cases under investigation. The defining metabolites were the combination of perturbed glucose and highly elevated lactate, common to some other neurological disorders. The remaining 14 metabolites of the host's response to TBM were likewise mainly energy-associated indicators. We subsequently generated a hypothesis expressed as an "astrocyte-microglia lactate shuttle" (AMLS) based on the host's response, which emerged from the NMR-metabolomics information. Activation of microglia, as implied by the AMLS hypothesis, does not, however, present a uniform process and involves intricate interactions and feedback loops between the microglia, astrocytes and neurons that hamper attempts to construct basic and linear cascades of cause and effect; TBM involves a complex integration of the responses from the various cell types present within the CNS, with microglia and the astrocytes as main players. PMID- 26109928 TI - Binge Drug Use among Street-Involved Youth in a Canadian Setting. AB - BACKGROUND: Binge drug use has been associated with increased risk of HIV infection and other serious health-related harms among adult drug user populations. This study sought to determine the prevalence and correlates of binge drug use among street-involved youth in a Canadian setting. METHODS: From Sept 2005 to May 2012, data were collected from the At-Risk Youth Study (ARYS), a prospective cohort of street-involved youth aged 14 - 26 who use illicit drugs. Multivariate generalized estimating equations (GEE) was used to identify factors associated with binge drug use. RESULTS: Of the 987 participants included in this analysis, 41.5% reported binge drug use at baseline, and another 59.1% reported binge drug use at some point during the study. In multivariate GEE analysis, older age (adjusted odds ratio [AOR] = 1.11), homelessness (AOR = 1.67), drug injecting (AOR = 1.63), non-fatal overdose (AOR = 1.98), public injecting (AOR 1.42), being a victim of violence (AOR = 1.38), sex work (AOR = 2.51) and participation in drug dealing (AOR = 2.04) were independently associated with binge drug use in the previous 6 months (all p<0.05). DISCUSSION: The prevalence of reporting binge drug use among the youth was high in this setting and was independently associated with a range of high-risk activities and markers of vulnerability. Querying high-risk youth about binge drug use may help prioritize those in greatest need of addiction treatment strategies and public health interventions. PMID- 26109929 TI - Active zone stability: insights from fly neuromuscular junction. AB - The presynaptic active zone is a dynamic structure that orchestrates regulated release of neurotransmitters. Developmental and aging processes, and changes in neuronal network activity can all modulate the number, size and composition of active zone and thereby synaptic efficacy. However, very little is known about the mechanism that controls the structural stability of active zone. By studying a model synapse, the Drosophila neuromuscular junction, our recent work shed light on how two scaffolding proteins at the active zone regulate active zone stability by promoting a localized dephosphorylation event at the nerve terminal. Here we discuss the major insights from our findings and their implications for future research. PMID- 26109931 TI - Lesson from the neuromuscular junction: role of pattern and timing of nerve activity in synaptic development. PMID- 26109930 TI - Restoring nervous system structure and function using tissue engineered living scaffolds. AB - Neural tissue engineering is premised on the integration of engineered living tissue with the host nervous system to directly restore lost function or to augment regenerative capacity following nervous system injury or neurodegenerative disease. Disconnection of axon pathways - the long-distance fibers connecting specialized regions of the central nervous system or relaying peripheral signals - is a common feature of many neurological disorders and injury. However, functional axonal regeneration rarely occurs due to extreme distances to targets, absence of directed guidance, and the presence of inhibitory factors in the central nervous system, resulting in devastating effects on cognitive and sensorimotor function. To address this need, we are pursuing multiple strategies using tissue engineered "living scaffolds", which are preformed three-dimensional constructs consisting of living neural cells in a defined, often anisotropic architecture. Living scaffolds are designed to restore function by serving as a living labeled pathway for targeted axonal regeneration mimicking key developmental mechanisms- or by restoring lost neural circuitry via direct replacement of neurons and axonal tracts. We are currently utilizing preformed living scaffolds consisting of neuronal clusters spanned by long axonal tracts as regenerative bridges to facilitate long-distance axonal regeneration and for targeted neurosurgical reconstruction of local circuits in the brain. Although there are formidable challenges in preclinical and clinical advancement, these living tissue engineered constructs represent a promising strategy to facilitate nervous system repair and functional recovery. PMID- 26109927 TI - Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a review. AB - The metabolic composition of human biofluids can provide important diagnostic and prognostic information. Among the biofluids most commonly analyzed in metabolomic studies, urine appears to be particularly useful. It is abundant, readily available, easily stored and can be collected by simple, noninvasive techniques. Moreover, given its chemical complexity, urine is particularly rich in potential disease biomarkers. This makes it an ideal biofluid for detecting or monitoring disease processes. Among the metabolomic tools available for urine analysis, NMR spectroscopy has proven to be particularly well-suited, because the technique is highly reproducible and requires minimal sample handling. As it permits the identification and quantification of a wide range of compounds, independent of their chemical properties, NMR spectroscopy has been frequently used to detect or discover disease fingerprints and biomarkers in urine. Although protocols for NMR data acquisition and processing have been standardized, no consensus on protocols for urine sample selection, collection, storage and preparation in NMR-based metabolomic studies have been developed. This lack of consensus may be leading to spurious biomarkers being reported and may account for a general lack of reproducibility between laboratories. Here, we review a large number of published studies on NMR-based urine metabolic profiling with the aim of identifying key variables that may affect the results of metabolomics studies. From this survey, we identify a number of issues that require either standardization or careful accounting in experimental design and provide some recommendations for urine collection, sample preparation and data acquisition. PMID- 26109932 TI - Synthetic and nature-derived lipid nanoparticles for neural regeneration. PMID- 26109933 TI - Homeostatic regulation of brain functions by endocannabinoid signaling. PMID- 26109934 TI - Staining neurons with Golgi techniques in degenerative diseases of the brain. PMID- 26109935 TI - The brain compensatory mechanisms and Alzheimer's disease progression: a new protective strategy. PMID- 26109936 TI - The therapeutic potential of mesenchymal stem cells in Alzheimer's disease: converging mechanisms. PMID- 26109937 TI - Enhanced neuronal degradation of amyloid-beta oligomers allows synapse regeneration. PMID- 26109938 TI - Evaluating rehabilitation interventions in Parkinson's disease with functional MRI: a promising neuroprotective strategy. PMID- 26109939 TI - The innate immune system in Parkinson's disease: a novel target promoting endogenous neuroregeneration. PMID- 26109940 TI - New insights on the standardization of peripheral nerve regeneration quantitative analysis. PMID- 26109941 TI - Auditory nerve preservation and regeneration in man: relevance for cochlear implantation. PMID- 26109942 TI - Dynamic expression of ATF3 as a novel tool to study activation and migration of endogenous spinal stem cells and their role in neural repair. PMID- 26109943 TI - Aromatic L-amino acid decarboxylase cells in the spinal cord: a potential origin of monoamines. PMID- 26109944 TI - Can training extend current guidelines for cochlear implant candidacy? PMID- 26109945 TI - The p75 neurotrophin receptor: at the crossroad of neural repair and death. AB - The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regulation of neurotrophin actions. Recently, the p75 neurotrophin receptor (p75(NTR)) has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by studies demonstrating 1) regulation of neural plasticity in the mature nervous system, 2) promotion of adult neurogenesis and 3) increased expression in neurons, macrophages, microglia, astrocytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and processes that support neural function. Upregulation of the p75(NTR) under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-peptide p75(NTR) ligands can selectively modify pro survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75(NTR), studies summarized in this review highlight the immense potential for development of novel neuroprotective and neurorestorative therapies. PMID- 26109948 TI - Encephalic hemodynamic phases in subarachnoid hemorrhage: how to improve the protective effect in patient prognoses. AB - Subarachnoid hemorrhage is frequently associated with poor prognoses. Three different hemodynamic phases were identified during subarachnoid hemorrhage: oligemia, hyperemia, and vasospasm. Each phase is associated with brain metabolic changes. In this review, we correlated the hemodynamic phases with brain metabolism and potential treatment options in the hopes of improving patient prognoses. PMID- 26109949 TI - Neuroprotective effects of ginsenoside Rg1-induced neural stem cell transplantation on hypoxic-ischemic encephalopathy. AB - Ginsenoside Rg1 is the major pharmacologically active component of ginseng, and is reported to have various therapeutic actions. To determine whether it induces the differentiation of neural stem cells, and whether neural stem cell transplantation after induction has therapeutic effects on hypoxic-ischemic encephalopathy, we cultured neural stem cells in 10-80 MUM ginsenoside Rg1. Immunohistochemistry revealed that of the concentrations tested, 20 mM ginsenoside Rg1 had the greatest differentiation-inducing effect and was the concentration used for subsequent experiments. Whole-cell patch clamp showed that neural stem cells induced by 20 MUM ginsenoside Rg1 were more mature than non induced cells. We then established neonatal rat models of hypoxic-ischemic encephalopathy using the suture method, and ginsenoside Rg1-induced neural stem cells were transplanted via intracerebroventricular injection. These tests confirmed that neural stem cells induced by ginsenoside had fewer pathological lesions and had a significantly better behavioral capacity than model rats that received saline. Transplanted neural stem cells expressed neuron-specific enolase, and were mainly distributed in the hippocampus and cerebral cortex. The present data suggest that ginsenoside Rg1-induced neural stem cells can promote the partial recovery of complicated brain functions in models of hypoxic-ischemic encephalopathy. PMID- 26109947 TI - The role of exosomes in peripheral nerve regeneration. AB - Peripheral nerve injuries remain problematic to treat, with poor functional recovery commonly observed. Injuries resulting in a nerve gap create specific difficulties for axonal regeneration. Approaches to address these difficulties include autologous nerve grafts (which are currently the gold standard treatment) and synthetic conduits, with the latter option being able to be impregnated with Schwann cells or stem cells which provide an appropriate micro-environment for neuronal regeneration to occur. Transplanting stem cells, however, infers additional risk of malignant transformation as well as manufacturing difficulties and ethical concerns, and the use of autologous nerve grafts and Schwann cells requires the sacrifice of a functioning nerve. A new approach utilizing exosomes, secreted extracellular vesicles, could avoid these complications. In this review, we summarize the current literature on exosomes, and suggest how they could help to improve axonal regeneration following peripheral nerve injury. PMID- 26109946 TI - Advances in regenerative therapies for spinal cord injury: a biomaterials approach. AB - Spinal cord injury results in the permanent loss of function, causing enormous personal, social and economic problems. Even though neural regeneration has been proven to be a natural mechanism, central nervous system repair mechanisms are ineffective due to the imbalance of the inhibitory and excitatory factors implicated in neuroregeneration. Therefore, there is growing research interest on discovering a novel therapeutic strategy for effective spinal cord injury repair. To this direction, cell-based delivery strategies, biomolecule delivery strategies as well as scaffold-based therapeutic strategies have been developed with a tendency to seek for the answer to a combinatorial approach of all the above. Here we review the recent advances on regenerative/neural engineering therapies for spinal cord injury, aiming at providing an insight to the most promising repair strategies, in order to facilitate future research conduction. PMID- 26109951 TI - Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury. AB - Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 MUg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis. PMID- 26109950 TI - Changes of resting cerebral activities in subacute ischemic stroke patients. AB - This study aimed to detect the difference in resting cerebral activities between ischemic stroke patients and healthy participants, define the abnormal site, and provide new evidence for pathological mechanisms, clinical diagnosis, prognosis prediction and efficacy evaluation of ischemic stroke. At present, the majority of functional magnetic resonance imaging studies focus on the motor dysfunction and the acute stage of ischemic stroke. This study recruited 15 right-handed ischemic stroke patients at subacute stage (15 days to 11.5 weeks) and 15 age matched healthy participants. A resting-state functional magnetic resonance imaging scan was performed on each subject to detect cerebral activity. Regional homogeneity analysis was used to investigate the difference in cerebral activities between ischemic stroke patients and healthy participants. The results showed that the ischemic stroke patients had lower regional homogeneity in anterior cingulate and left cerebrum and higher regional homogeneity in cerebellum, left precuneus and left frontal lobe, compared with healthy participants. The experimental findings demonstrate that the areas in which regional homogeneity was different between ischemic stroke patients and healthy participants are in the cerebellum, left precuneus, left triangle inferior frontal gyrus, left inferior temporal gyrus and anterior cingulate. These locations, related to the motor, sensory and emotion areas, are likely potential targets for the neural regeneration of subacute ischemic stroke patients. PMID- 26109952 TI - CX3 chemokine receptor 1 deficiency leads to reduced dendritic complexity and delayed maturation of newborn neurons in the adult mouse hippocampus. AB - Previous studies have shown that microglia impact the proliferation and differentiation of neurons during hippocampal neurogenesis via the fractalkine/CX3 chemokine receptor 1 (CX3CR1) signaling pathway. However, whether microglia can influence the maturation and dendritic growth of newborn neurons during hippocampal neurogenesis remains unclear. In the present study, we found that the number of doublecortin-positive cells in the hippocampus was decreased, and the dendritic length and number of intersections in newborn neurons in the hippocampus were reduced in transgenic adult mice with CX3CR1 deficiency (CX3CR1 (GFP/GFP) ). Furthermore, after experimental seizures were induced with kainic acid in these CX3CR1-deficient mice, the expression of c-fos, a marker of neuronal activity, was reduced compared with wild-type mice. Collectively, the experimental findings indicate that the functional maturation of newborn neurons during hippocampal neurogenesis in adult mice is delayed by CX3CR1 deficiency. PMID- 26109953 TI - Effective components of Chinese herbs reduce central nervous system function decline induced by iron overload. AB - Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer's disease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer's disease patients. An APPswe /PS1DeltaE9 double transgenic mouse model of Alzheimer's disease was used. The intragastric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer's disease. These compounds reduced iron overload induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer's disease. PMID- 26109955 TI - CORRIGENDA. AB - [This corrects the article on p. 1907 in vol. 9, PMID: 25558241.][This corrects the article on p. 266 in vol. 10, PMID: 25883626.]. PMID- 26109954 TI - MicroRNA-124 slows down the progression of Huntington's disease by promoting neurogenesis in the striatum. AB - MicroRNA-124 contributes to neurogenesis through regulating its targets, but its expression both in the brain of Huntington's disease mouse models and patients is decreased. However, the effects of microRNA-124 on the progression of Huntington's disease have not been reported. Results from this study showed that microRNA-124 increased the latency to fall for each R6/2 Huntington's disease transgenic mouse in the rotarod test. 5-Bromo-2'-deoxyuridine (BrdU) staining of the striatum shows an increase in neurogenesis. In addition, brain-derived neurotrophic factor and peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein levels in the striatum were increased and SRY-related HMG box transcription factor 9 protein level was decreased. These findings suggest that microRNA-124 slows down the progression of Huntington's disease possibly through its important role in neuronal differentiation and survival. PMID- 26109956 TI - Upregulated Ras/Raf/ERK1/2 signaling pathway: a new hope in the repair of spinal cord injury. AB - An increasing number of studies report that the Ras/Raf/extracellular signal regulated kinase 1/2 (ERK1/2) signaling pathway has a death-promoting apoptotic function in neural cells. We hypothesized that the Ras/Raf/ERK1/2 signaling pathway may be abnormally regulated in rat injured spinal cord models. The weight drop method was used to establish rat spinal cord injury at T9. Western blot analysis and immunohistochemical staining revealed Ras expression was dramatically elevated, and the phosphorylations of A-Raf, B-Raf and C-Raf were all upregulated in the injured spinal cord. Both mitogen-activated protein kinase kinase 1/2 and ERK1/2, which belong to the Ras/Raf signaling kinases, were upregulated. These results indicate that Ras/Raf/ERK1/2 signaling may be upregulated in injured spinal cord and are involved in recovery after spinal cord injury. PMID- 26109957 TI - Bibliometric profile of neurogenic bladder in the literature: a 20-year bibliometric analysis. AB - Neurogenic bladder is a dysfunction of the lower urinary tract caused by nervous system disorder. We investigated the trends in publication of articles under the topic "neurogenic bladder" using bibliometric analysis. Articles on neurogenic bladder, published between 1995 and 2014, were retrieved from the ISI Web of Science citation database. We analyzed the search results for authors, countries, institutions, journals, and top-cited papers. A total of 1,904 articles were retrieved. There was a small increase in the number of articles on neurogenic bladder from 1995 (n = 43) to 2014 (n = 117). The USA was the leading country in the total number of articles (n = 598). However, the number of publications from China has rapidly increased, and China was ranked second in 2014. Emmanuel Chartier-Kastler (n = 65) was the most productive author, and University of Paris VI (Paris 6) (n = 61) was the most productive institution. The Journal of Urology published the greatest number of articles on this topic (n = 285). Articles on neurogenic bladder were often published in a professional journal under the category Urology & Nephrology, Neurosciences & Neurology, or Rehabilitation. Visualization analysis based on co-citation networks was conducted using CiteSpace III. Visualization analysis revealed that the hot spots in neurogenic bladder were botulinum toxin-A, prazosin, bethanechol, and afferent pathways. These findings provide new insight into the publication trends and hot spots in neurogenic bladder. PMID- 26109958 TI - Autologous nerve graft repair of different degrees of sciatic nerve defect: stress and displacement at the anastomosis in a three-dimensional fnite element simulation model. AB - In the repair of peripheral nerve injury using autologous or synthetic nerve grafting, the magnitude of tensile forces at the anastomosis affects its response to physiological stress and the ultimate success of the treatment. One dimensional stretching is commonly used to measure changes in tensile stress and strain; however, the accuracy of this simple method is limited. Therefore, in the present study, we established three-dimensional finite element models of sciatic nerve defects repaired by autologous nerve grafts. Using PRO E 5.0 finite element simulation software, we calculated the maximum stress and displacement of an anastomosis under a 5 N load in 10-, 20-, 30-, 40-mm long autologous nerve grafts. We found that maximum displacement increased with graft length, consistent with specimen force. These findings indicate that three-dimensional finite element simulation is a feasible method for analyzing stress and displacement at the anastomosis after autologous nerve grafting. PMID- 26109959 TI - Acupuncture and vitamin B12 injection for Bell's palsy: no high-quality evidence exists. AB - OBJECTIVE: To assess the efficacy of acupuncture combined with vitamin B12 acupoint injection versus acupuncture alone to reduce incomplete recovery in patients with Bell's palsy. DATA RETRIEVAL: A computer-based online retrieval of Medline, Web of Science, CNKI, CBM databases until April 2014 was performed for relevant trials, using the key words "Bell's palsy or idiopathic facial palsy or facial palsy" and "acupuncture or vitamin B12 or methylcobalamin". STUDY SELECTION: All randomized controlled trials that compared acupuncture with acupuncture combined with vitamin B12 in patients with Bell's palsy were included in the meta-analysis. The initial treatment lasted for at least 4 weeks. The outcomes of incomplete facial recovery were monitored. The scoring index varied and the definition of healing was consistent. The combined effect size was calculated by using relative risk (RR) with 95% confidence interval (CI) using the fixed effect model of Review Manager. MAIN OUTCOME MEASURES: Incomplete recovery rates were chosen as the primary outcome. RESULTS: Five studies involving 344 patients were included in the final analysis. Results showed that the incomplete recovery rate of Bell's palsy patients was 44.50% in the acupuncture combined with vitamin B12 group but 62.57% in the acupuncture alone group. The major acupoints were Taiyang (EX-HN5), Jiache (ST6), Dicang (ST4) and Sibai (ST2). The combined effect size showed that acupuncture combined with vitamin B12 was better than acupuncture alone for the treatment of Bell's palsy (RR = 0.71, 95%CI: 0.58-0.87; P = 0.001), this result held true when 8 patients lost to follow up in one study were included into the analyses (RR = 0.70, 95%CI: 0.58-0.86; P = 0.0005). In the subgroup analyses, the therapeutic effect in patients of the electroacupuncture subgroup was better than in the non electroacupuncture subgroup (P = 0.024). There was no significant difference in the incomplete recovery rate by subgroup analysis on drug types and treatment period. Most of the included studies were moderate or low quality, and bias existed. CONCLUSION: In patients with Bell's palsy, acupuncture combined with vitamin B12 can reduce the risk of incomplete recovery compared with acupuncture alone in our meta-analysis. Because of study bias and methodological limitations, this conclusion is uncertain and the clinical application of acupuncture combined with vitamin B12 requires further exploration. PMID- 26109960 TI - High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis. AB - Thalidomide is an effective drug for the treatment of ankylosing spondylitis but might induce peripheral neuropathy. This major adverse reaction has attracted much concern. The current study aimed to observe the incidence of thalidomide induced peripheral neuropathy among ankylosing spondylitis patients for 1 year after treatment. In this study, 207 ankylosing spondylitis cases received thalidomide treatment, while 116 ankylosing spondylitis cases received other treatments. Results showed that the incidence of thalidomide-induced peripheral neuropathy in the thalidomide group was higher than that in the non-thalidomide group. There was no significant difference in the incidence of neuropathy between the < 6 months medication and >= 6 months medication groups. There were no differences in the mean age, gender, or daily dose between the two groups. The incidence of peripheral neuropathy among patients receiving 25, 50, 75, or 100 mg thalidomide per day was 4.6%, 8.5%, 17.1%, 21.7%, respectively. The incidence was significantly different between the groups receiving 25 mg and 100 mg thalidomide. In conclusion, thalidomide can induce peripheral neuropathy within 1 year after treatment of ankylosing spondylitis; however, age and gender have no obvious impact on the incidence of peripheral neuropathy. The incidence of peripheral neuropathy is associated with increasing daily doses of thalidomide. PMID- 26109961 TI - Efficacy and safety of nerve growth factor for the treatment of neurological diseases: a meta-analysis of 64 randomized controlled trials involving 6,297 patients. AB - OBJECTIVE: China is the only country where nerve growth factor is approved for large-scale use as a clinical medicine. More than 10 years ago, in 2003, nerve growth factor injection was listed as a national drug. The goal of this article is to evaluate comprehensively the efficacy and safety of nerve growth factor for the treatment of neurological diseases. DATA RETRIEVAL: A computer-based retrieval was performed from six databases, including the Cochrane Library, PubMed, EMBASE, Sino Med, CNKI, and the VIP database, searching from the clinical establishment of nerve growth factor for treatment until December 31, 2013. The key words for the searches were "nerve growth factor, randomized controlled trials" in Chinese and in English. DATA SELECTION: INCLUSION CRITERIA: any study published in English or Chinese referring to randomized controlled trials of nerve growth factor; patients with neurological diseases such as peripheral nerve injury, central nerve injury, cranial neuropathy, and nervous system infections; patients older than 7 years; similar research methods and outcomes assessing symptoms; and measurement of nerve conduction velocities. The meta-analysis was conducted using Review Manager 5.2.3 software. MAIN OUTCOME MEASURES: The total effective rate, the incidence of adverse effects, and the nerve conduction velocity were recorded for each study. RESULTS: Sixty-four studies involving 6,297 patients with neurological diseases were included. The total effective rate in the group treated with nerve growth factor was significantly higher than that in the control group (P < 0.0001, RR: 1.35, 95%CI: 1.30-1.40). The average nerve conduction velocity in the nerve growth factor group was significantly higher than that in the control group (P < 0.00001, MD: 4.59 m/s, 95%CI: 4.12-5.06). The incidence of pain or scleroma at the injection site in the nerve growth factor group was also higher than that in the control group (P < 0.00001, RR: 6.30, 95%CI: 3.53-11.27), but such adverse effects were mild. CONCLUSION: Nerve growth factor can significantly improve nerve function in patients with nervous system disease and is safe and effective. PMID- 26109962 TI - Recovery of a degenerated corticospinal tract after injury in a patient with intracerebral hemorrhage: confirmed by diffusion tensor tractography imaging. PMID- 26109964 TI - Evaluation of the pelvic apophysis with multi-detector computed tomography for legal age estimation in living individuals. AB - BACKGROUND: Legal age estimations of living individuals are gaining increasing importance for radiologists involved in delivering expert opinions. The present study aimed to assess the correlation between chronological age and apophyseal centers distance from pelvic bone. MATERIALS AND METHODS: This was a cross sectional study carried out on 2013. Subjects were chosen from 15 to 25 years old people who had previous pelvic multi-detector computed tomography for any reason. The distance of iliac crest apophysis to iliac bone, and pubic apophysis to pubic bone were assessed. RESULTS: There was a reverse linear correlation between chronological age and distance of iliac crest apophysis (P < 0.001, r = 0.899) and pubic apophysis to pelvic bone (P < 0.001, r = 0.898). Pubic apophysis was not appeared in subjects before 16 years old and it was appeared in all of the subjects with 18 years old and more. Subjects with age of 21 had near ossification of iliac or pubic apophysis and subjects with age of 24 had full ossification of iliac or pubic apophysis. CONCLUSION: skeletalage can be estimated by assessing the apophyseal centers distance from the pelvic bone in adolescents 15-25 years old. PMID- 26109963 TI - Ligustrazine monomer against cerebral ischemia/reperfusion injury. AB - Ligustrazine (2,3,5,6-tetramethylpyrazine) is a major active ingredient of the Szechwan lovage rhizome and is extensively used in treatment of ischemic cerebrovascular disease. The mechanism of action of ligustrazine use against ischemic cerebrovascular diseases remains unclear at present. This study summarizes its protective effect, the optimum time window of administration, and the most effective mode of administration for clinical treatment of cerebral ischemia/reperfusion injury. We examine the effects of ligustrazine on suppressing excitatory amino acid release, promoting migration, differentiation and proliferation of endogenous neural stem cells. We also looked at its effects on angiogenesis and how it inhibits thrombosis, the inflammatory response, and apoptosis after cerebral ischemia. We consider that ligustrazine gives noticeable protection from cerebral ischemia/reperfusion injury. The time window of ligustrazine administration is limited. The protective effect and time window of a series of derivative monomers of ligustrazine such as 2-[(1,1 dimethylethyl)oxidoimino]methyl]-3,5,6-trimethylpyrazine, CXC137 and CXC195 after cerebral ischemia were better than ligustrazine. PMID- 26109965 TI - A noninvasive method for coronary artery diseases diagnosis using a clinically interpretable fuzzy rule-based system. AB - BACKGROUND: Coronary heart diseases/coronary artery diseases (CHDs/CAD), the most common form of cardiovascular disease (CVD), are a major cause for death and disability in developing/developed countries. CAD risk factors could be detected by physicians to prevent the CAD occurrence in the near future. Invasive coronary angiography, a current diagnosis method, is costly and associated with morbidity and mortality in CAD patients. The aim of this study was to design a computer based noninvasive CAD diagnosis system with clinically interpretable rules. MATERIALS AND METHODS: In this study, the Cleveland CAD dataset from the University of California UCI (Irvine) was used. The interval-scale variables were discretized, with cut points taken from the literature. A fuzzy rule-based system was then formulated based on a neuro-fuzzy classifier (NFC) whose learning procedure was speeded up by the scaled conjugate gradient algorithm. Two feature selection (FS) methods, multiple logistic regression (MLR) and sequential FS, were used to reduce the required attributes. The performance of the NFC (without/with FS) was then assessed in a hold-out validation framework. Further cross-validation was performed on the best classifier. RESULTS: In this dataset, 16 complete attributes along with the binary CHD diagnosis (gold standard) for 272 subjects (68% male) were analyzed. MLR + NFC showed the best performance. Its overall sensitivity, specificity, accuracy, type I error (alpha) and statistical power were 79%, 89%, 84%, 0.1 and 79%, respectively. The selected features were "age and ST/heart rate slope categories," "exercise-induced angina status," fluoroscopy, and thallium-201 stress scintigraphy results. CONCLUSION: The proposed method showed "substantial agreement" with the gold standard. This algorithm is thus, a promising tool for screening CAD patients. PMID- 26109966 TI - Diagnosed tuberculous meningitis using cerebrospinal fluid polymerase chain reaction in patients hospitalized with the diagnosis of meningitis in referral hospitals in Isfahan. AB - BACKGROUND: Tuberculosis (TB) remains one of the leading infectious diseases throughout the world. Among various forms of extrapulmonary TB, tuberculous meningitis (TBM) is the most severe form and remains a major global health problem with a high mortality rate. Our study was designed to evaluate tuberculous polymerase chain reaction (PCR) positive rate in patients who present with fairly long symptoms of meningitis. MATERIALS AND METHODS: The 162 Patients with an indolent onset of symptoms compatible with central nervous system infection were admitted. Sample of cerebrospinal fluid (CSF) was evaluated for biochemistry and tuberculous real-time PCR. Data analyzed by Student's t-test and Fisher's test. RESULTS: Patients were mostly male (69.8%), with a median age of 43.69 +/- 22.67 years. CSF real-time PCR results in 6 patients (3.7%) were positive for tuberculous DNA. Of these 6 patients, 4 of whom were men and two of whom were women. In other words, the frequency of positive tuberculous DNA was in male 5.3% and female 1.4%, respectively. CONCLUSION: Given that we live in Iran and in the vicinity of the tuberculous endemic countries, if we face a meningitis case with lasting symptoms and tendency to be chronic, TBM should be considered. PMID- 26109967 TI - Breast cancer screening: Evidence of the effect of adjunct ultrasound screening in women with unilateral mammography-negative dense breasts. AB - BACKGROUND: Patients with the previous history of breast cancer are in risk of contralateral breast cancer. On the other hand, increased breast density is a risk factor for breast cancer and the sensitivity of detecting nonpalpable cancers in screening mammography in radiographically dense breasts is low. The use of ultrasonography in dense breast remains a controversial topic. The purpose of this study was to assess the usefulness of routine ultrasonography in follow up of women with the previous history of breast cancer and negative mammography but dense breasts. MATERIALS AND METHODS: In a cross-sectional study, a total of 267 individuals with unilateral postmastectomy mammogram screened and 153 subjects assigned to study. There were 28 subjects with American College of Radiology (ACR) breast density 2 and 125 with ACR breast density 3-4, which there was no new finding in their mammogram in comparison to previous studies. We assumed subjects with ACR breast density 3-4 as mammographic Breast Imaging Reporting and Data System (BI-RADS) category 0 for malignancy. Standard two-view mammogram was performed for all participants, and breast ultrasound (US) examinations were performed by an expert radiologist in radial and anti-radial planes. The data were analyzed using SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA). RESULTS: The results showed that in subjects with ACR breast density 3-4, when there was no new density in two consecutive mammograms in comparison to previous studies, US also showed no possibility for malignancy (BI RADS 1-2). And also in subjects with ACR breast density 2, when the mammographic results were BI-RADS 1-2, the US results was the same. CONCLUSION: Our data indicate that for the detection of breast cancer, sensitivity of US was not greater than mammography in patients with postmastectomy unilateral dense breast if there is not any new density. PMID- 26109968 TI - Comparison of the effect of topical versus systemic L-arginine on wound healing in acute incisional diabetic rat model. AB - BACKGROUND: Diabetes is associated with endothelial dysfunction and impaired wound healing. The amino acid L-arginine is the only substrate for nitric oxide (NO) synthesis. The purpose of this study was to compare the topical versus systemic L-arginine treatment on total nitrite (NOx) and vascular endothelial growth factor (VEGF) concentrations in wound fluid and rate of wound healing in an acute incisional diabetic wound model. MATERIALS AND METHODS: A total of 56 Sprague-Dawley rats were used of which 32 were rendered diabetic. Animals underwent a dorsal skin incision. Dm-sys-arg group (N = 8, diabetic) and Norm-sys arg group (N = 8, normoglycemic) were gavaged with L-arginine. Dm-sys-control group (N = 8, diabetic) and Norm-sys-control group (N = 8, normoglycemic) were gavaged with water. Dm-top-arg group (N = 8, diabetic) and norm-top-arg group (N = 8, normoglycemic) received topical L-arginine gel. Dm-top-control group (N = 8, diabetic) received gel vehicle. On the day 5 the amount of NOx in wound fluid was measured by Griess reaction. VEGF/total protein in wound fluids was also measured on day 5 using enzyme-linked immunosorbent assay. All wound tissue specimens were fixed and stained to be evaluated for rate of healing. Data were analyzed using SPSS software (version 18.0, Chicago, IL, USA) through One-way analysis of variance test and Tukey's post-hoc. RESULTS: In dm-sys-arg group, the level of NOx on day 5 was significantly more than dm-top-arg group (P < 0.05). VEGF content in L-arginine treated groups were significantly more than controls (P < 0.05). Rate of diabetic wound healing in dm-sys-arg group was significantly more than dm-top-arg group. CONCLUSION: Systemic L-arginine is more efficient than topical L-arginine in wound healing. This process is mediated at least in part, by increasing VEGF and NO in the wound fluid. PMID- 26109969 TI - Rhabdomyolysis in 114 patients with acute poisonings. AB - BACKGROUND: Rhabdomyolysis is a clinical and biochemical syndrome, which is observed in some patients with acute chemical and/or pharmaceutical poisonings. We aimed to investigate rhabdomyolysis in patients with acute poisonings due to different chemicals, natural toxins or drug overdose. MATERIALS AND METHODS: Following approval of the University medical research committee and obtaining informed consents from the patients or their relatives, all patients with acute poisonings who were treated between March 2009 and February 2010 in the Toxicologic Ward of Imam Reza Hospital and had serum creatine phosphokinase (CPK) above 975 IU/L (as a definition for rhabdomyolysis) were studied. RESULTS: Of 3555 hospitalized poisoned patients, 114 patients had rhabdomyolysis with CPK of 5996 +/- 892 IU/L (mean +/- standard error). The most common intoxication to induce the rhabdomyolysis was opioid overdose (28%). Acute renal failure (ARF) was diagnosed in 11 (8.7%) patients. There was a linear correlation between CPK and creatinine (P < 0.001), which in turn had a significant correlation with death (P < 0.05). CONCLUSION: Patients with acute poisoning were at risk of rhabdomyolysis. Acute opioid poisoning was the most common cause of toxic rhabdomyolysis in the intoxicated patients, and ARF was the main complication. PMID- 26109970 TI - Developing a provisional and national renal disease registry for Iran. AB - BACKGROUND: Disease registry is a database that includes information about people suffering a special kind of disease. The aim of this study was to first identify and compare the National Renal Disease Registry (NRDR) characteristics in some countries with Iran; and second, develop a provisional and NRDR for Iran. MATERIALS AND METHODS: Retrieval of data of the NRDR was performed by scholars responsible in related agencies, including the Ministry of Health and Medical Education, Renal Disease charity, and data registries in the United States, United Kingdom, Malaysia, and Iran. This research was applied, and the study was descriptive-comparative. The study population consisted of the NRDR in selected countries in which data were collected by forms that were designed according to the study objectives. Sources of data were researchers, articles, books, journals, databases, websites, related documents, and people who are active in this regard, and related agencies, including the Ministry of Health and Medical Education, and patient support charity. The researchers collected data for each country based on the study objectives and then put them in comparative tables. Data were analyzed by descriptive, comparative, and theoretical methods. RESULTS: Most of the renal transplant teams report their own results as a single center experiences. America and Britain have a preeminent national registry of renal disease compared to other countries. CONCLUSION: Given that control, prevention, and treatment of chronic renal diseases incur high expenses and the disease is one of leading mortality factors in Iran and across the world and since national registry system for chronic renal diseases can provide better tools and strategies to manage and evaluate patients' characteristics as well as risk factors which eventually leads to making better decisions. PMID- 26109971 TI - Trends in ageing of the population and the life expectancy after retirement: A comparative country-based analysis. AB - BACKGROUND: During the 20(th) century, the share of elderly in the total population of the Earth has increased steadily. It is expected that this trend will continue in the 21(st) century. In 1950, the elderly (persons aged 60 years and older) were 8% of the world population; in 2000, is already 10%; and in 2050, according to United Nations projections, the proportion will reach 21%. This research on Kazakhstan provides demographic analysis from 1989 to 2012 and presents the main features of population' ageing through comparative analysis. MATERIALS AND METHODS: We used information-analytical, content-analysis, mathematical treatment and comparative analysis of statistical data on demographic status in Kazakhstan and some other countries of the world (UK, USA, Turkey, Russia) over the 1989-2012. RESULTS: Age dependency ratio of the Russian federation - >1.7 times, in the USA-up to 1.9 times and the UK has dependency ratio higher than 2.5 times of similar indicators in Kazakhstan in 2010. CONCLUSION: Life expectancy of the elderly population KZ after 65 years in 2010 was only 13.8 years, which is 6-9 years inferior to European and U.S. indices. Thus, increasing the retirement age is inappropriate for the current period. PMID- 26109972 TI - Diabetes research in Middle East countries; a scientometrics study from 1990 to 2012. AB - BACKGROUND: Diabetes burden is a serious warning for urgent action plan across the world. Knowledge production in this context could provide evidences for more efficient interventions. Aimed to that, we quantify the trend of diabetes research outputs of Middle East countries focusing on the scientific publication numbers, citations, and international collaboration. MATERIALS AND METHODS: This scientometrics study was performed based on the systematic analysis through three international databases; ISI, PubMed, and Scopus from 1990 to 2012. International collaboration of Middle East countries and citations was analyzed based on Scopus. Diabetes' publications in Iran specifically were assessed, and frequent used terms were mapped by VOSviewer software. RESULTS: Over 23-year period, the number of diabetes publications and related citations in Middle East countries had increasing trend. The number of articles on diabetes in ISI, PubMed, and Scopus were respectively; 13,994, 11,336, and 20,707. Turkey, Israel, Iran, Saudi Arabia, and Egypt have devoted the five top competition positions. In addition, Israel, Turkey, and Iran were leading countries in citation analysis. The most collaborative country with Middle East countries was USA and within the region, the most collaborative country was Saudi Arabia. Iran in all databases stands on third position and produced 12.7% of diabetes publications within region. Regarding diabetes researches, the frequent used terms in Iranian articles were "effect," "woman," and "metabolic syndrome." CONCLUSION: Ascending trend of diabetes research outputs in Middle East countries is appreciated but encouraging to strategic planning for maintaining this trend, and more collaboration between researchers is needed to regional health promotion. PMID- 26109973 TI - The impact of acid-suppressing drugs to the patients with chronic obstructive pulmonary disease: A nationwide, population-based, cohort study. AB - BACKGROUND: A high prevalence of gastroesophageal reflux disease symptoms has observed among chronic obstructive pulmonary disease (COPD) patients, and proton pump inhibitors (PPIs) are the main medication in clinical practices. The aim of this study is to analyze the impact of PPIs to the risk of pneumonia in the cases with COPD. MATERIALS AND METHODS: This was a nationwide, population-based, cohort study using National Health Insurance Program in Taiwan. The enrolled cases were newly-diagnosed COPD, older than 30 years, between 2001 and 2005. Patients' prescriptions with PPIs and histamine receptor 2 antagonists (HR2As), >2 months, were identified. The appearance of pneumonia and mortality of these enrolled patients was recorded. Multivariate Cox's regression was used to examine the influence of acid-suppressing drugs to pneumonia on individuals with COPD. RESULTS: A total of 17,498 patients were included, of whom 109 (0.6%) and 526 (3%) cases had used PPIs and HR2As respectively. The risk of pneumonia existed when patients had used concurrent PPIs (adjusted hazard ratio [HR] = 1.76; 95% confidence interval [CI] = 1.33-2.34) or HR2As (adjusted HR = 1.25; 95% CI = 1.07 1.47). The positive association was lost in the cases over 70 years. The ratio of mortality also increased in those with PPIs or HR2As. CONCLUSION: Acid suppressing drugs, especially PPIs, are attributed to more pneumonia happening in COPD patients compare with nonusers. The association was lost in elderly cases. Use acid-suppressing drugs should be careful about a higher possibility of pneumonia in younger individuals with COPD. PMID- 26109974 TI - Features of fatigue in patients with early-stage non-small cell lung cancer. AB - BACKGROUND: The objective of this study was to investigate the fatigue status and related factors in patients with early-stage non-small cell lung cancer (NSCLC) 1 5 years after surgery. MATERIALS AND METHODS: This cross-sectional study included 254 patients with stage IA or IB NSCLC, who had undergone surgery. They completed several surveys, including the Brief Fatigue Inventory, Karnofsky Performance Scale, Physical Activity Questionnaire, Baseline Dyspnea Index, Hospital Anxiety and Depression Scale. The association between fatigue and functional status was assessed using Chi-square analysis. Spearman rank correlation and multivariate logistic regression analysis were used to assess the correlation between fatigue and various other factors. RESULTS: The overall incidence of postoperative fatigue was 59.8%. Among patients with moderate to severe fatigue, 21.1% had obvious dysfunction, whereas only 9.6% of patients with mild or no fatigue (chi(2) = 5.369; P = 0.02) showed obvious dysfunction. Multivariate logistic regression analysis showed that functional status (odds ratio [OR]: 3.57; 95% confidence interval [CI]: 1.17-6.19), concurrent lung disease (OR: 2.34; 95% CI: 1.08-4.99), depression (OR: 6.39; 95% CI: 2.42-17.35), and anxiety (OR: 2.45; 95% CI: 1.13-4.87) were independent risk factors for fatigue, whereas physical activity (OR: 0.27; 95% CI: 0.11-0.73) could prevent fatigue. CONCLUSION: More than half of the patients with early-stage NSCLC experienced fatigue 1-5 years after surgery, and moderate to severe fatigue was often associated with obvious dysfunction. The strong association of fatigue with anxiety, depression, and lung complications suggests that fatigue and other symptoms constitute a symptom cluster. Therefore, comprehensive treatment methods may achieve better therapeutic results. PMID- 26109975 TI - Challenges of the ward round teaching based on the experiences of medical clinical teachers. AB - BACKGROUND: Holding educational sessions in a clinical environment is a major concern for faculty members because of its special difficulties and restrictions. This study attempts to recognize the challenges of the ward round teaching through investigating the experiences of clinical teachers in 2011. MATERIALS AND METHODS: This qualitative research is carried out through purposive sampling with maximum variation from among the clinical teachers of major departments in Isfahan University of Medical Sciences (9 persons). The sampling continued until data saturation. Data were collected through semi-structured interview and analyzed through Collaizzi method. Data reliability and validity was confirmed through the four aspects of Lincoln and Guba method (credibility, conformability, transferability, and dependability). RESULTS: Three major themes and their related sub-themes (minor themes) were found out including the factors related to the triad of clinical teaching (patient, learner, and clinical teacher) (concern about patient's welfare, poor preparation, lack of motivation, ethical problems), factors related to the educational environment (stressful environment, humiliating environment and poor communication) and the factors related to the educational system of the clinical environment (poor organizing and arrangement of resources, poor system's monitoring, bad planning and inadequate resource). CONCLUSION: Ward round teaching has many concerns for teachers, and this should be recognized and resolved by authorities and teachers. If these problems are not resolved, it would affect the quality of clinical teaching. PMID- 26109976 TI - Serum iron level, ferritin and total iron binding capacity level among nonpregnant women with and without melasma. AB - BACKGROUND: Melasma is a common acquired disorder characterized by symmetric, hyperpigmented patches with an irregular outline, occurring most commonly on the face. It is most prevalent among young to middle-aged women. Although iron overload affects skin pigmentation, effect of iron deficiency on skin is not clear. So, we evaluated serum iron level, ferritin and total iron binding capacity (TIBC) level among nonpregnant women with and without melasma. MATERIALS AND METHODS: A cross-sectional case study was conducted in 2012 at university dermatologic department on 33 nonpregnant women with melasma (case) and 33 nonpregnant women without melasma (control). Serum iron level, TIBC and ferritin in the two groups was measured and compared. RESULTS: Serum iron level was lower in the case group (85 +/- 11) in comparison with control group (102 +/- 9), but the difference was not significant (P: 0.9). Mean TIBC and Ferritin were higher in the case group (TIBC: 329.4 +/- 29, ferritin: 6 +/- 18) than the control group (TIBC: 329.3 +/- 29, ferritin: 33 +/- 6) without significant difference. CONCLUSION: Although the serum iron level was lower in nonpregnant women with mealsma, it was not significant compared with those without melasma. PMID- 26109977 TI - BRCA1 and BRCA2 mutations in Iranian breast cancer patients: A systematic review. AB - BACKGROUND: BRCA1/2 genes mutation prevalence varies among ethnic groups and may be influenced by founder mutations. Understanding BRCA1/2 genes mutations is important for reducing breast cancer (BC) incidence, accurate risk assessment and counseling. This systematic review of the literature was conducted to addressing BRCA1/2 mutations in Iranian BC patients. MATERIALS AND METHODS: A search for relevant articles was run on before January 2014 using MedLine, PubMed, Science Iranian Database, Google, and Web sites related to the study topic. The key words included: BC and Iran with Genes, BRCA Genes, BRCA1 and BRCA2; "Cancer Genes," and "Iran." RESULTS: Thirteen articles retrieved from this search strategy were eligible for this review. The overall BRCA1 mutation rate for Iranian female BC patients was detected 31.8% (377/1183). Although this gene mutation rate for male patients is <0.01%. Eight BRCA1 mutations (c. 4837A > G, c. 3419G > A, c. 3119G > A, c. 2612C > T, c. 3113A > G, c. 2311T > C, c. 4301T > C and c. 4308T > C in BRCA1, and one BRCA2 mutation (c. 6494G > C) were found in multiple case subjects and represent candidate founder mutations. CONCLUSION: According to these studies, there is heterogeneity in BRCA mutations in Iranian BC patients. PMID- 26109979 TI - Mercury poisoning in two 13-year-old twin sisters. AB - Mercury (Hg) is a toxic agent that evaporates in room temperature and its inhalation may cause poisoning. Due to the nonspecific symptoms, diagnosis is difficult in special circumstances with no initial history of Hg exposure. We report two such cases of Hg poisoning. The patients were two sisters, presenting with pain in extremities, itchy rashes, sweating, salivation, weakness, and mood changes. They have used a compound that contains mercury, for treatment of pedicullosis three months before admission. This compound was purchased from a herbal shop and was applied locally on the scalps for 2 days. Their urinary mercury concentrations were 50 and 70 mg/L. They were successfully treated by D penicillamine and gabapentin. In a patient with any kind of bone and joint pain, skin rash erythema and peripheral neuropathy, mercury poisoning should be considered as a differential diagnosis. PMID- 26109978 TI - Systematic review on the association of abdominal obesity in children and adolescents with cardio-metabolic risk factors. AB - BACKGROUND: The adverse health effects of abdominal obesity are well documented in adults, but such association remains to be determined in the pediatric age group. This study aims to perform a systematic review on the association between abdominal obesity and cardio-metabolic factors such as dyslipidemia, hypertension, and hyperglycemia among children and adolescents. MATERIALS AND METHODS: A systematic literature search was conducted using PubMed, Scopus and Google Scholar databases to May 2014. Two independent reviewers identified relevant papers in several steps. After studying the titles and texts of documents, repeated and irrelevant ones were excluded. The search was refined to the English language. We did not consider any time limitation. Studies with different measuring methods of abdominal obesity were included. Studies with abdominal obese patients secondary to other disease were excluded from the study. In final, the data of association of cardio-metabolic risk factors and abdominal obesity extracted from studies. RESULTS: Overall, 3966 articles were reviewed, and 61 of them were studied according to the inclusion and exclusion criteria. Waist circumference (WC), waist-to-height ratio, and waist-to-hip ratio were the most common indexes used for defining abdominal obesity. The association of high blood pressure with increasing WC was seen in several studies. The association of other cardio-metabolic risk factors was seen in some studies. CONCLUSION: Whatever the definition used for abdominal obesity and whatever the methods used for anthropometric measurements, central body fat deposition in children and adolescents increases the risk of cardio-metabolic risk factors. Therefore, more attention should be paid to abdominal obesity of children and adolescents both in clinical practice and in epidemiological studies. PMID- 26109980 TI - Interstitial pregnancy treated with a single-dose of systemic methotrexate: A successful management. AB - Interstitial pregnancy is an ectopic pregnancy at high hemorrhagic risk. It often poses a diagnostic and therapeutic challenge to the clinician, with a significant risk of morbidity and mortality. It presents a difficult management problem with no absolute standard of care; the most appropriate treatment technique for these pregnancies remains controversial. We describe a case of unruptured interstitial pregnancy successfully treated with a single-dose of systemic methotrexate with subsequent ultrasound and serum beta human chorionic gonadotropin monitoring. Medical management can be a safe and successful option in selected cases that satisfy specific criteria and in women who are able to be monitored after treatment. PMID- 26109981 TI - Etanercept plus methotrexate: An effective combination therapy for recalcitrant pemphigus vulgaris. PMID- 26109982 TI - Public health strategies to ensure optimal community participation in the Ebola outbreak in West-Africa. PMID- 26109983 TI - Absence of canalicular undescended testis during follow-up; where should be examined by ultrasound? PMID- 26109984 TI - National cerebral palsy minimum data set. PMID- 26109985 TI - Voice rehabilitation with tragal cartilage and perichondrium after vertical partial laryngectomy for glottic cancer. AB - BACKGROUND: The goal of the study is to test medialization of the neocord after oncological surgery for glottic cancer, using autologous tragal cartilage and perichondrium by the direct approach. MATERIALS AND METHODS: Sixteen patients underwent comprehensive assessment including auditory perceptual assessment, videostrobolaryngoscopy, and acoustic voice analysis. The cartilage graft was inserted into a pocket created in the tyroarytenoid - lateral cricoarytenoid muscle complex or the excavated musculomembranous part of the neocord, and fixed by placing the perichondrium by the direct approach. The patients were evaluated preoperatively, and at 14 days, 60 days, and 6 months later. RESULTS: Improvement of voice and breathiness was correlated with the increase of closed quotient and harmonic-to-noise ratio; the acoustic voice parameters studied showed significant differences between preoperative and postoperative voices, and these objective measurements of voice changes provided accurate and documentary evidence of the results of surgical treatment. CONCLUSION: This method may be considered a safe and efficient phonosurgical procedure for voice restoration. PMID- 26109986 TI - The efficacy of combination of ondansetron and aprepitant on preventing the radiotherapy-induced nausea and vomiting. AB - BACKGROUND: Depending on the site of irradiation, about 40-80% of patients undergoing radiotherapy (RT) will experience nausea and/or vomiting. The current study aimed to investigate the efficacy of ondansetronas as a single agent and with a combination to aprepitant on preventing RT-induced nausea and vomiting (RINV). MATERIALS AND METHODS: In a clinical randomized controlled trial (from September 2010 to September 2011), conducted in Radiation Oncology Department of Seyed-al-Shohada Hospital, Isfahan University of Medical Sciences, 40 abdominopelvic malignancies cancer patients were allocated into two aliquots using block randomization of size. Patients in the first group (group I) received ondansetron alone while those patients in the remaining group (group II) received ondansetron and aprepitant. Then, developing of RINV and its severity and benefit of adding aprepitant to ondansetron, in comparison with ondansetron as a single drug therapy were evaluated. RESULTS: The average age of the patients in group I was 61.15 +/- 12.27 years while in group II it was 50.1 +/- 13.27 years. No statistically significant gender differences were found between the two groups. In patients treated with ondansetron single drug therapy (group I), frequency and grade of RINV were significantly more than the group treated simultaneously by aprepitant and ondansetron (group II) (odds ratio [OR] = 21.2; P < 0.01). Compared with RT alone, the patients whom underwent RT along with chemotherapy showed lower probability of experiencing RINV (OR = 0.13; P < 0.05). CONCLUSION: The present study indicated a significant superiority of combination of ondansetron and aprepitant in management of RINV, in patients undergoing RT, compared to ondansetron as a single agent therapy. More accurate follow-up studies are needed for the evaluation of the efficacy of ondansetron with combination to aprepitant on preventing the RINV. PMID- 26109987 TI - Prevalence of overweight and obesity among Iranian preschoolers: Interrelationship with physical fitness. AB - BACKGROUND: The preschool years are a crucial time to study the determinants of childhood obesity, as it is when eating and physical activity habits are becoming established. The purpose of this study was to compare the prevalence of overweight and obesity among preschoolers living in the capital of Iran and to determine relationships between overweight and obesity and selected motor- and health-related fitness parameters. MATERIALS AND METHODS: This exploratory cross sectional study was conducted with 190 boys and 191 girls aged 5-6 years. Study children were selected from the kindergartens in Tehran, the capital of Iran. All children underwent anthropometric, motor- and health-related fitness tests. Height, body mass, body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and percentage of body fat (PBF) were measured for anthropometric assessments. Sit-and-reach, modified sit-ups, modified pull-ups, the 4 m * 9 m shuttle run, the 20 m sprint test and the 20 m multistage shuttle run test were measured for motor- and health-related fitness tests. Overweight and obesity prevalence was determined by the International Obesity Task Force, Centers for Disease Control and Prevention and World Health Organization standard criteria. RESULTS: International Obesity Task Force criteria indicate almost 12% (23/190) of boys and 22.5% (43/191) of girls were overweight or obese with 4.73% (9/190) of boys and 10.99% (21/191) of girls in the obese category. Significant correlations were found between modified pull-ups test and body mass, BMI, WC, WHR, WHtR, PBF in boys and modified pull-ups and modified sit-ups tests were significantly correlated with body mass, BMI, WC, WHR, WHtR, and PBF in girls. Compared to their counterparts, overweight and obese boys demonstrated inferior performance in modified pull-ups and predicted VO2max and overweight and obese girls demonstrated inferior performance in modified pull ups, modified sit-ups, 4 m * 9 m agility shuttle run and predicted VO2max. CONCLUSION: This study highlighted the relatively high prevalence of overweight and obesity in both genders of preschoolers and found that overweight and obesity were associated with poor fitness performances. The findings provided evidence to support the establishment of tailored physical fitness intervention programs to manage and prevent obesity in preschoolers. PMID- 26109988 TI - Usefulness of combination of grey-scale and color Doppler ultrasound findings in the diagnosis of ulnar nerve entrapment syndrome. AB - BACKGROUND: Ulnar nerve entrapment (UNE) has been diagnosed with clinical examination and electrodiagnostic studies. This study was designed to determine the value of a combination of grey-scale and color Doppler ultrasound findings in the diagnosis of patients with UNE. MATERIALS AND METHODS: During May to August 2013 41 patients with UNE (proven by electrodiagnostic studies) and 44 healthy volunteers were evaluated by ultrasound study. Three cross-sectional area (CSA) of ulnar nerve around cubital fossa was determined and measured in both groups. The maximum and minimum diameter of ulnar nerve was measured for calculating flattening ratio index (FRI). Vascularity of ulnar nerve around cubital fossa was also examined in proper color Doppler setting. RESULTS: The mean CSA of nerve at all proximal, middle and distal levels were greater in patients with UNE than in controls (P = 0.02, <0.001 and 0.34 respectively). A cut-off point of 10.5 mm(2) for CSA (in the level of the cubital fossa) yielded a sensitivity and specificity of 92.7% and 93.2%, respectively. Mean FRI was 3.1 +/- 0.6 in patients with UNE group and 1.4 +/- 0.2 in the control group with a significant difference (P < 0.001). FRI with cutoff point 2.15 has been shown as an important parameter for the detection of UNE. The vascularity in UNE has a sensitivity and specificity of 66% and 93.2%, respectively, and has a higher probability of being positive in severe UNE. CONCLUSION: Combination of grey-scale and color Doppler ultrasound may provide valuable diagnostic criteria and severity assessment of UNE. PMID- 26109989 TI - The cardiovascular implication of single nucleotide polymorphisms of chromosome 9p21 locus among Arab population. AB - BACKGROUND: Based on several reports including genome-wide association studies, genetic variability has been linked with higher (nearly half) susceptibility toward coronary artery disease (CAD). We aimed to evaluate the association of chromosome 9p21 single nucleotide polymorphisms (SNPs): rs2383207, rs10757278, and rs10757274 with the risk and severity of CAD among Arab population. MATERIALS AND METHODS: A prospective observational case-control study was conducted between 2011 and 2012, in which 236 patients with CAD were recruited from the Heart Hospital in Qatar. Patients were categorized according to their coronary angiographic findings. Also, 152 healthy volunteers were studied to determine if SNPs are associated with risk of CAD. All subjects were genotyped for SNPs (rs2383207, rs2383206, rs10757274 and rs10757278) using allele-specific real-time polymerase chain reaction. RESULTS: Patients with CAD had a mean age of 57 +/- 10; of them 77% were males, 54% diabetics, and 25% had family history of CAD. All SNPs were in Hardy-Weinberg equilibrium except rs2383206, with call rate >97%. After adjusting for age, sex and body mass index, the carriers of GG genotype for rs2383207 have increased the risk of having CAD with odds ratio (OR) of 1.52 (95% confidence interval [CI] = 1.01-2.961, P = 0.046). Also, rs2383207 contributed to CAD severity with adjusted OR 1.80 (95% CI = 1.04-3.12, P = 0.035) based on the dominant genetic model. The other SNPs (rs10757274 and rs10757278) showed no significant association with the risk of CAD or its severity. CONCLUSION: Among Arab population in Qatar, only G allele of rs2483207 SNP is significantly associated with risk of CAD and its severity. PMID- 26109990 TI - The association of personality traits and coping styles according to stress level. AB - BACKGROUND: Some personality traits and coping styles could be as risk factors in stressful situations. This study aimed to investigate the association of personality traits and coping styles according to the stress level. METERIALS AND METHODS: This cross-sectional study was performed in 2011. A total of 4628 individuals over 20 years were selected by random sampling from nonacademic employees that working in 50 different centers across Isfahan province. Data were collected using 12-item General Health Questionnaire (GHQ-12), Big Five Personality Inventory Short Form and coping strategies scale, and individuals were divided into high and low-stress groups in term of GHQ-12. To analyze the data, a binary logistic regression analysis was conducted. RESULTS: Mean age of participants was 36.3 +/- 7.91 years and 56.26% (2604) of them were female. Neuroticism with adjusting covariates of demographic characteristics and the rest of personality traits was a risk factor for stress level with odds ratios (OR) OR:1.24; but other personality traits were protective. Also, active coping styles were protective factors for OR of stress level with adjusting covariates of demographic characteristics and the rest of coping styles, and positive reinterpretation and growth was the most effective of coping style with OR:0.84. CONCLUSION: Some personality traits are associated with passive copings and cause high-stress level. So, it could be concluded that improve and strengthen effective coping strategies in individual with maladaptive traits should be considered as a crucial component of prevention and control programs of stress. PMID- 26109991 TI - A randomized clinical trial of efficacy and safety of the topical clonidine and capsaicin in the treatment of painful diabetic neuropathy. AB - BACKGROUND: Incomplete efficiency of oral medications restricts their therapeutic success in pain control of the painful form of the diabetic peripheral neuropathy (DPN). Use of topical medications because of less systemic side effects is more acceptable. This study aimed to compare the effect of clonidine gel and capsaicin cream in relieving pain associated with DPN. MATERIALS AND METHODS: This 12-week, randomized, double-blind and parallel-group trial was conducted to compare the efficacy and safety of topical clonidine and capsaicin. Totally, 139 patients with type 2 diabetes with a pain score of at least 4 as assessed by visual analog scale (VAS), were treated for up to 3 months. The endpoint of the study was the reduction in the median pain score from baseline, as assessed by the VAS at the 4 weekly follow-up visits. RESULTS: The intention-to-treat population for the efficacy analysis consists of 69 patients receiving clonidine and 70 patients receiving capsaicin. Both drugs significantly relieved pain at 12 weeks (P < 0.001 for both) but no significant difference in the efficacy between the two treatments was observed (P = 0.931). Dermatologic complications were more common in capsaicin group (P = 0.001). CONCLUSION: The results of this study showed the comparable efficacy of clonidine gel in comparison with capsaicin cream in the treatment of pain due to DPN with less adverse events. More studies are required to better evaluate the efficacy and safety of this topical compound for relieving pain in DPN. PMID- 26109992 TI - Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder. AB - BACKGROUND: One of the major causes of death in schizophrenia is a metabolic syndrome. The clozapine has the highest rate of weight gain among antipsychotics. It has been shown that metformin can promote weight loss. We aimed to investigate the effect of metformin as an adjunctive therapy with clozapine to prevent metabolic syndrome in patients with schizophrenia. MATERIALS AND METHODS: A total of 37 patients consisting metformin group (19 cases) and a group of placebo consisting of 18 cases were evaluated. A brief psychiatric rating scale score (BPRS) and metabolic profiles was determined for all patients. All of the variables were also determined at 2, 8, 16, and 20 weeks after the onset of the study. RESULTS: The mean age of the group of metformin was 47.2 +/- 10.4 compared with 45.8 +/- 10.2 for the group of placebo. The difference in mean waist circumference and serum level of triglyceride at baseline compared with the end of study showed a statistically significant difference between two groups (P = 0. 000). A statistically significant difference was also observed in a comparison of mean difference of weight and body mass index at baseline compared with end of study (P = 0. 000). There was a statistically significant difference of fasting blood sugar (P = 0.011) and serum high-density lipoprotein (P = 0.000) between two groups but this difference was not significant for mean BPRS scores, mean systolic and diastolic blood pressure, serum level of triiodothyronine, thyroxin and thyroid stimulating hormone, serum low-density lipoprotein and serum cholesterol. CONCLUSION: Metformin could be considered an adjunctive therapy with clozapine to prevent metabolic syndrome in schizophrenic patients. PMID- 26109993 TI - Effects of vitamin D on retinal nerve fiber layer in vitamin D deficient patients with optic neuritis: Preliminary findings of a randomized, placebo-controlled trial. AB - BACKGROUND: There is accumulating evidence for a possible protective role of vitamin D in the development and disease course of multiple sclerosis. Whether vitamin D is also effective in treating patients with optic neuritis (ON) is not known. The aim of this study was to evaluate the effect of oral vitamin D on the thickness of retinal nerve fiber layer (RNFL) in vitamin D deficient patients with ON by optical coherence tomography. MATERIALS AND METHODS: A Phase II placebo-controlled randomized clinical trial conducted between July 2011 and November 2012 included 52 patients with confirmed unilateral ON aged 15-38 years and low serum 25-hydroxyvitamin D levels. The main outcome measures were changes in thickness of RNFL and macula 6 months after treatment. Patients were randomly allocated to receive 6 months of treatment with adding either 50,000 IU/week vitamin D or placebo. RESULTS: In the 27 patients treated with vitamin D, the mean (standard deviation [SD]) thickness of RNFL decreased from 111.3 (18.9) MUm at baseline to 91.4 (13.3) at the end of study period (P < 0.001). Correspondingly, in the 25 patients treated with placebo, the mean (SD) thickness of RNFL decreased from 113.7 (21.5) MUm at baseline to 96.1 (12.3) at the end of study period (P < 0.01). In both groups, the mean thickness of the macula did not changed (P > 0.05). Average thickness of RNFL at the end of trial did not differ between groups. CONCLUSION: Adding vitamin D to routine disease therapy had no significant effect on the thickness of RNFL or macula in patients with ON. This trial is registered on www.clinicaltrials.gov (ID NCT01465893). PMID- 26109994 TI - Comparing efficacy of Montelukast versus doxycycline in treatment of moderate acne. AB - BACKGROUND: Treatment of acne is an important issue for reducing the cosmetic and psychological burden of disease. Regarding the inflammatory effect of LT-B4 in acne lesions and action mechanism of Montelukast, this study was performed to determine the efficacy of Montelukastin acne treatment comparison with doxycycline. MATERIALS AND METHODS: In a randomized clinical trial that was performed in Dermatology Clinic in a Training Tertiary Health Care Center in Tehran, Iran since January 2012 to May 2014, 52 patients with moderate acne were evaluated. The included patients were randomly assigned to receive doxycycline 100 mg/day plus 1% Clindamycin solution (Group 1) or Montelukast 5 mg daily plus 1% clindamycin solution (Group 2). The acne severity index was measured and compared between two groups at baseline (on admission), 1-month and 3 months later. Independent-Sample-T, Chi-Square, and Repeated-Measure ANOVA tests were used and were considered statistically significant at P < 0.05. RESULTS: The mean age was 26.8 +/- 7.1 in Group 1 and25 +/- 4.8 in Group 2 (P = 0.1). 73% women and 26.7% 4 men in Group 1 and 86.7% women, and 13.3% men in Group 2 (P = 0.01). The mean acne severity index at baseline was 18.2 +/- 6.1 and 19 +/- 4.2 in Montelukast and doxycycline group, respectively (P = 0.679). The mean acne severity index after 1-month was 10.5 +/- 6.2 and 12.9 +/- 3.3 in Montelukast and doxycycline group, respectively (P = 0). Finally, the mean acne severity index after 3 months follow-up was 8.6 +/- 4.8 and 8.2 +/- 1.2 in Montelukast and doxycycline group, respectively (P = 0.01). There was no significant difference between two groups regarding the amount of decrease in acne severity index across the study (P = 0.186). However, each groups showed a significant reduction in the acne severity index, separately (P = 0.001). CONCLUSION: It may be concluded that Montelukast is an effective and safe medication for moderate-level acne treatment. PMID- 26109995 TI - The effect of early ambulation on the incidence of neurological complication after spinal anesthesia with lidocaine. AB - BACKGROUND: Transient neurological symptoms (TNS), was described in patients recovering from spinal anesthesia with lidocaine but its etiology remains unknown this study was evaluated the influence of ambulation time on the occurrence of TNSs after spinal anesthesia with lidocaine 5%. MATERIALS AND METHODS: This randomized clinical trial was conducted on 60 patients with American Society of Anesthesiologists Grades I and II, who were candidates for lower abdominal surgery in supine or lithotomy positions. Patients were randomly divided into early ambulation group (Group A) who were asked to start walking as soon as the anesthesia was diminished or to the late ambulation group (Group B) who walked after at least 12 h bedridden. Participants were contacted 2 days after spinal anesthesia to assess any type of pain at surgical or anesthesia injection site, muscle weakness, fatigue, vertigo, nausea, vomiting, headache, and difficult urination or defecation. RESULTS: Four subjects (13.3%) in Group A and two patients (6.7%) in Group B had pain at anesthesia injection site (P = 0.019). Fourteen patients in Group A (46.7%) and six patients in Group B (20%) had post dural puncture headache (P = 0.014). Participants in Group B reported difficult urination more than Group A (P = 0.002). there were not statistically significant differences between two groups regarding frequency of fatigue, muscle weakness, vertigo, nausea, vomiting, difficult defecation, paresthesia, and the mean of visual analogue scale at the surgical site. CONCLUSION: Early ambulation after spinal anesthesia with lidocaine did not increase the risk of neurologic complication. PMID- 26109996 TI - Curriculum leadership in the postgraduate: Gap between current and optimal status. AB - BACKGROUND: Identifying the strengths and weakness points is one of the effective methods to analyze current status, and prioritizing actions based on the gap between current and optimal status is necessary for short-term and long-term planning in departments and colleges. The aim of this study was to determine the gap between current and optimal status of curriculum leadership in the postgraduate courses in two Iranian universities. MATERIALS AND METHODS: In this cross-sectional study, a sample of 212 faculty members from the two Iranian universities (one medical and one nonmedical) was randomly selected through stratified random sampling method. Data were collected by using a researcher-made questionnaire, with 55 items categorized in four areas of main dimensions in curriculum leadership. The validity of the questionnaire was determined by curriculum studies scholars, and the reliability was confirmed as the Cronbach's alpha calculated 0.969. Data were analyzed using descriptive and inferential statistics according to the variables. RESULTS: There was a gap in all dimensions and roles. The maximum gap (-1.70) with the highest frequency (98%) were related to "improving the educational atmosphere" dimension. As for items, the maximum gap (-2.41) was related to "society needs and expectations and the labor market" in "curriculum development and revision" dimension. CONCLUSION: The negative gap between all dimensions of curriculum leadership implies faculty members' dissatisfaction. Curriculum leadership at universities, colleges and departments of the study in all aspects need to be improved. Hence, it is necessary for managers to make use of the viewpoints of the faculty members to decrease the gap. PMID- 26109997 TI - Association of retinopathy and intima media thickness of common carotid artery in type 2 diabetic patients. AB - BACKGROUND: This study was carried out in order to evaluate the relationship between retinopathy and carotid intima-media thickness (CIMT). MATERIALS AND METHODS: In a cross-sectional study, 154 diabetic patients who had a history of diabetic disease were evaluated in two equal groups of 77 patients with and without retinopathy, respectively. CIMT was evaluated in all of the patients. RESULTS: Mean age of the patients was 59.65 +/- 9.37 years. Mean CIMT of all patients was 0.84 +/- 0.18. CIMT of patients with retinopathy was significantly greater than patients without retinopathy (P < 0.001). CIMT also correlated with age, duration of diabetes, systolic blood pressure, blood urea nitrogen, and serum creatinine. CONCLUSION: CIMT may be used as a simple, available and noninvasive method for screening of macro and microvascular complication of diabetic patients. PMID- 26109998 TI - Systematic review on adverse birth outcomes of climate change. AB - BACKGROUND: Climate change and global warming have significant effects on human health. This systematic review presents the effects of the climate changes on pregnancy outcomes. MATERIALS AND METHODS: The search process was conducted in electronic databases including ISI Web of Knowledge, PubMed, Scopus, and Google Scholar using key words of "environmental temperature" "pregnancy" "low birth weight (LBW)" "pregnancy outcome," "climate change," "preterm birth (PTB)," and a combination of them. We did not consider any time limitation; English-language papers were included. The related papers were selected in three phases. After quality assessment, two reviewers extracted the data while the third reviewer checked their extracted data. Finally, 15 related articles were selected and included in the current study. RESULTS: Approximately all studies have reported a significant relationship between exposure variable and intended outcomes including eclampsia, preeclampsia, cataract, LBW, PTB, hypertension, sex ratio and length of pregnancy. According to conducted studies, decrease in birth weight is more possible in cold months. Increase in temperature was followed by increase in PTB rate. According to most of the studies, eclampsia and preeclampsia were more prevalent in cold and humid seasons. Two spectrums of heat extent, different seasons of the year, sunlight intensity and season of fertilization were associated with higher rates of PTB, hypertension, eclampsia, preeclampsia, and cataract. CONCLUSION: Climate change has unfavorable effects on eclampsia, preeclampsia, PTB, and cataract. The findings of this review confirm the crucial importance of the adverse health effects of climate change especially in the perinatal period. PMID- 26109999 TI - Medicated chewing gum, a novel drug delivery system. AB - New formulations and technologies have been developed through oral drug delivery systems' researches. Such researches display significance of oral route amongst patients. We've reviewed all the features associated with medicated chewing gum as a modern drug delivery by introducing the history, advantages and disadvantages, methods of manufacturing, composition differences, evaluation tests and examples of varieties of medicated chewing gums. Acceptance of medicated chewing gum has been augmented through years. The advantages and therapeutic benefits of chewing gum support its development as we can see new formulations with new drugs contained have been produced from past and are going to find a place in market by formulation of new medicated chewing gums. Potential applications of medicated chewing gums are highly widespread as they will be recognized in future. Nowadays standards for qualifying chewing gums are the same as tablets. Patient-centered studies include medicated chewing gums as a delivery system too which creates compliance for patients. PMID- 26110000 TI - Marine-Lenhart syndrome with papillary thyroid carcinoma. AB - Graves' disease with accompanying functioning nodules is known as Marine-Lenhart syndrome. Autonomously functioning thyroid nodules (AFTNs) also within Graves' thyroid tissue are almost always bening in nature. A 45-year-old man developed hyperthyroidism due to the coexistence of Graves' disease and AFTN. Total thyroidectomy was performed. The hyperfunctioning nodule with centrally hypoactive foci detected by technetium-99m thyroid scanning was histologically diagnosed as papillary thyroid carcinoma that was 2.5 cm in diameter. We report the presence of papillary thyroid carcinoma within AFTN in patients with Marine Lenhart syndrome, which has not been reported so far. PMID- 26110001 TI - Fanconi syndrome due to prolonged use of low-dose adefovir. AB - Fanconi syndrome results from a generalized abnormality of the proximal tubules of the kidney and owing to phosphate depletion can cause hypophosphatemic osteomalacia. Adefovir dipivoxyl (ADV) effectively suppresses hepatitis B virus replication but exhibits nephrotoxicity when administered at a low dosage. We report two cases of Fanconi syndrome induced by ADV at 10 mg/day to call for regular screening for evidence of proximal tubular dysfunction and detailed bone metabolic investigations for prompt detection of ADV nephrotoxicity is critically important to ensure timely drug withdrawal before the development of irreversible tubulointerstitial injury. PMID- 26110002 TI - Geogenic thallium and lead pollution in soils and potential risk of toxicity: A report from Iran. PMID- 26110003 TI - A female with positive serum nontreponemal tests. PMID- 26110004 TI - A Review of the LARIAT Suture Delivery Device for Left Atrial Appendage Closure. AB - The prevalence of atrial fibrillation (AF) is 1-2 % in the general population, and the risk of embolic stroke in AF patients is 4-5 times higher than that in the general population. AF-related strokes are often severe, and the rate of permanent disability is much higher among individuals who have AF-related strokes than in those who have strokes unrelated to AF. In patients with AF, more than 90 % of thrombi originate from the left atrial appendage (LAA). The purpose of this paper is to review the efficacy and safety of performing the LAA closure with the LARIAT Suture Delivery Device to prevent AF-related stroke in patients with contraindications to oral anticoagulant therapy. PMID- 26110005 TI - Potential Effect of L-Carnitine on the Prevention of Myocardial Injury after Coronary Artery Bypass Graft Surgery. AB - BACKGROUND: L-carnitine has been demonstrated to confer cardiac protection against ischemia reperfusion injury in animals. This study evaluates the effects of L-carnitine administration on cardiac biomarkers after coronary artery bypass graft (CABG) surgery. METHODS: One hundred thirty-four patients undergoing elective CABG surgery, without a history of myocardial ischemia or previous L carnitine treatment, were enrolled and randomly assigned to an L-carnitine group ([n = 67], 3000 mg/d, started 2 days preoperatively and continued for 2 days after surgery) or a control group (n = 67). CK-MB (creatine kinase, muscle-brain subunits) and troponin T (TnT) levels were assessed in all the patients before surgery as baseline levels and at 8 and 24 hours postoperatively. RESULTS: Our study included 134 patients (99 [73.8%] males) at a mean +/- SD age of 59.94 +/- 8.61 years who were candidates for CABG and randomized them into control or L carnitine groups. The baseline demographic characteristics, including age (60.01 +/- 9.23 in the L-carnitine group vs. 59.88 +/- 7.98 in the control group) and sex (54 [80.6%] in the L-carnitine group vs. 45 [67.2%] in the control group) did not show any significant differences (p value=0.93 and 0.08, respectively). Patients in the L-carnitine group had lower levels of CK-MB (mean +/- SD, 25.06 +/- 20.29 in the L-carnitine group vs. 24.26 +/- 14.61 in the control group), but the difference was not significant (p value = 0.28). TnT levels also showed no significant differences between the two groups (399.50 +/- 378.91 in the L carnitine group vs. 391.48 +/- 222.02 in the control group; p value = 0.34). CONCLUSION: In this population of intermediate- to high-risk patients undergoing CABG surgery, L-carnitine did not reduce CK-MB and TnT levels. PMID- 26110006 TI - Changes in Heart Rate Variability Parameters after Elective Percutaneous Coronary Intervention. AB - BACKGROUND: Patients with chronic stable angina often have a state of sympathetic hyperactivity. It is considered associated with myocardial ischemia and disappears after ischemia elimination. The aim of this study was to investigate the changes in heart rate variability parameters, a noninvasive technique for the evaluation of the autonomic nervous system activity, after successful revascularization in these patients to evaluate this theory. METHODS: The patients were enrolled among those who underwent successful percutaneous coronary intervention. Short-term heart rate variability analyses of all the patients were obtained, and time-domain indices (standard deviation of normal-to-normal intervals [SDNN], standard deviation of differences of successive R-R intervals [SDSD], root-mean square differences of successive R-R intervals [rMSSD], percentage of R-R intervals differing > 10 ms from the preceding one [PNN10], percentage of R-R intervals differing > 20 ms from the preceding one [PNN20], percentage of R-R intervals differing > 30 ms from the preceding one [PNN30], percentage of R-R intervals differing > 40 ms from the preceding one [PNN40], percentage of R-R intervals differing > 50 ms from the preceding one [PNN50], percentage of R-R intervals differing > 60 ms from the preceding one [PNN60], and percentage of R-R intervals differing > 70 ms from the preceding one [PNN70]) were analyzed. All the measurements were made before and after percutaneous coronary intervention. RESULTS: This study included 64 patients, comprising 27 men and 37 women at a mean age of 56.8 +/- 9.1 years. There was a significant difference only between pre- and post-revascularization SDNN (27.5 +/- 19.72 vs. 41 +/- 41.4; p value = 0.013). The other parameters showed no significant differences after successful coronary intervention. Conclusion : Our data indicate that the increase in SDNN in patients with stable angina pectoris undergoing percutaneous coronary intervention seems to be prominent. PMID- 26110008 TI - Effects of Everolimus-Eluting Stents on the Left Ventricular Systolic and Diastolic Functions. AB - BACKGROUND: The drug-eluting stent (DES) decreases the rate of coronary restenosis and re-obstruction. The aim of this study was to assess prospectively the effectiveness of the new generation DES on the left ventricular (LV) systolic and diastolic functions in patients with isolated severe proximal left anterior descending (LAD) coronary artery stenosis. METHODS: A prospective study was conducted on 50 patients with isolated severe proximal LAD stenosis. Successful percutaneous coronary intervention (PCI) with Everolimus-eluting stents was performed for the whole study population. All the patients underwent transthoracic echocardiography within 24 hours before and one month after PCI, and LV systolic and diastolic parameters were compared before and after PCI using the paired samples t-test. RESULTS: The mean age of the study population was 57.68 +/- 8.82 years. Within the study population, 26 (52%) patients were male and 24 (48%) were female. There was a significant 10.6% and 5.2% increase in the early diastolic mitral annular motion (e') and the LV ejection fraction following PCI, respectively (p value = 0.005 and p value = 0.044, respectively). Before PCI, wall motion abnormality was seen in 2.21 +/- 2.91 segments, which significantly decreased to 1.49 +/- 2.58 segments (p value = 0.04) after the procedure. Also, the wall motion score index was 1.18 +/- 0.26 before PCI, which significantly decreased to 1.13 +/- 0.23 after PCI (p value < 0.001). Also, there was a trend toward a higher ratio of transmitral peak early diastolic velocity to peak late diastolic velocity after PCI (p value = 0.068). CONCLUSION: Our study showed that the use of the Everolimus-eluting stents improved the LV systolic and diastolic functions in patients with isolated severe LAD stenosis. PMID- 26110007 TI - Association between Perioperative Parameters and Cognitive Impairment in Post Cardiac Surgery Patients. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) has been an important complication of cardiac surgery over the years. Neurocognitive dysfunction can affect quality of life and lead to social, functional, emotional, and financial problems in the patient's life. To reduce POCD, we sought to identify the association between cognitive dysfunction and perioperative factors in patients undergoing cardiac surgery. METHODS: One hundred one patients aged between 45 and 75 years undergoing elective cardiac surgery were enrolled in this study. All the surgeries were performed on-pump by the same medical team. A brief Wechsler Memory Test (WMT) was administered before surgery, 3 to 5 days after the surgery, and 3 months after discharge. All related perioperative parameters were collected in order to study the effect of these parameters on the postoperative WMT scores and WMT score change. RESULTS: The study population consisted of 101 patients, comprising 14 (13.8%) females and 87 (86.2%) males aged between 45 and 75 years. In univariate analysis, the baseline WMT score, serum levels of lactate dehydrogenase and T3, cross-clamp time, and preexistence of chronic obstructive pulmonary disease showed significant effects on the postoperative WMT score (p value < 0.05), whereas only the baseline WMT score and chronic obstructive pulmonary disease showed strong effects on the postoperative WMT score in the multiple regression model. In addition, the multiple regression model demonstrated a significant association between the baseline WMT score, serum creatinine level, and nitrate administration and the WMT score change. CONCLUSION: Our study showed that preexisting chronic obstructive pulmonary disease and preoperative high serum creatinine levels negatively affected cognitive function after surgery. In addition, there was a strong relationship between the patients' basic cognition and POCD. Preoperative nitrate administration led to a significant improvement in POCD. It is also concluded that the preoperative administration of specific medicines like nitrates can reduce neurological complications after cardiac surgery. PMID- 26110009 TI - Chronic Otitis Media Resulting in Aortic Valve Replacement: A Case Report. AB - The bicuspid aortic valve is known to be the most common congenital cardiac malformation, with an approximate incidence rate of 1-2% in the general population. Most patients are unaware of the disease until the onset of infective endocarditis, which is a life-threatening complication that may affect a heart valve or other cardiac structures at the site of endothelial damage. A 22-year old man presented to our internal medicine clinic with a complaint of acute onset dyspnea and fatigue. His body temperature was 38 ( degrees )C. A diastolic murmur was detected at the right sternal border. Two-dimensional transthoracic echocardiography revealed severe aortic insufficiency, and two-dimensional transesophageal echocardiography showed that the aortic valve was bicuspid. There was also a flail lesion extending the left ventricular outflow tract, resulting in pathological coaptation and severe aortic insufficiency. The patient was referred to our cardiovascular department for surgery. We herein present this case of a bicuspid aortic valve complicated by infective endocarditis due to the underlying disease of chronic otitis media related to a rare pathogen: Alloiococcus otitidis. The patient underwent a successful aortic valve replacement surgery due to aortic insufficiency following infective endocarditis. He was discharged on the 16(th) postoperative day in good condition. PMID- 26110010 TI - Intravenous Catheter-Associated Candidemia due to Candida membranaefaciens: The First Iranian Case. AB - The incidence of candidemia due to the uncommon non-albicans Candida species appears to be increasing, and certain species such as Candida (C.) membranaefaciens have been reported in some clinical researches. Vascular catheters are considered the likely culprit for the sudden emergence of hospital acquired candidemia. The identification of C. membranaefaciens can be problematic in clinical practice owing to its phenotypic resemblance to C. guilliermondii. We report the first case of C. membranaefaciens in Iran, which occurred in a 70-year old woman, who had coronary artery bypass grafting (CABG). We isolated germ-tube negative yeast from both blood culture and central venous catheter (CVC) tip culture on brain-heart infusion agar, Sabouraud dextrose agar plates, and biphasic brain-heart infusion media bottle; it developed smooth, pink colonies on CHROMagar Candida. By using the polymerase chain reaction and sequencing of theinternal transcribed spacer region of rDNA, we identified C. membranaefaciens. After the removal of the CVC and initiation of Fluconazole treatment, the patient's condition gradually improved and she was discharged from the hospital. The early detection of organisms in the catheter, removal of the catheter, and treatment with anti-fungal antibiotics have an important role in controlling disease and preventing septicemia after CABG. As C. membranaefaciens is an opportunistic Candida species, both clinicians and microbiologists should be aware of the factors that confer fast diagnosis and appropriate treatment. PMID- 26110011 TI - Late Development of a Bronchocutaneous Fistula due to an Epicardial Cardioverter Defibrillator Lead. AB - Cutaneous complications caused by a pacemaker or defibrillator are widely documented, but the development of a bronchocutaneous fistula has never been described before. We report the case of a 79-year-old man who was admitted to our hospital because of a seemingly superficial cutaneous infection, externalized defibrillator leads, and hemoptysis. Bronchoscopical investigation proved the existence of the fistula, which connected the epicardium, the left main bronchus, and the aforementioned site of skin infection. The patient refused an operation for the complete removal of the epicardial defibrillator and was treated conservatively. This case demonstrated that the long-term presence of foreign bodies in the epicardium may cause serious complications. PMID- 26110012 TI - Acute Left Atrial Thrombus Formation on Resected Residual Cribriform Septum after Atrial Septal Defect Surgery. AB - Acute left atrial thrombosis at the site of the resection of the primary cribriform septum is an exceedingly rare and important complication after atrial septal defect (ASD) closure with a pericardial or synthetic patch. This case report presents a mobile thrombus noted on the left atrium at the raw surface site of a resected cribriform primary septum that was not caught in the suture line with the pericardial patch for the closure of the ASD in a 30-year-old woman with an uncomplicated ASD surgery. The patient had no symptoms in the postoperative period, and routine postoperative transesophageal echocardiography revealed a large pedunculated and mobile mass (thrombosis) at the left atrial side of the interatrial septum at the level of the implanted pericardial patch. The thrombus was successfully treated with surgery. The patient had an uneventful recovery in the postoperative period and was discharged from the hospital 15 days after admission. One-year follow-up showed no evidence of clot recurrence in the left or right atrium. PMID- 26110013 TI - Anomalous Origin of the Left Atrial Branch from the Left Main Trunk. PMID- 26110014 TI - Pulmonary Alveolar Proteinosis: A Very Rare Disease and the Role of the Cardiac Surgeon in its Treatment. PMID- 26110015 TI - Chemical Antagonists of Plasminogen Activator Inhibitor-1: Mechanisms of Action and Therapeutic Potential in Vascular Disease. PMID- 26110016 TI - Associations of physical activity with depressiveness and coping in subjects with high-grade obesity aiming at bariatric surgery: a cross-sectional study. AB - BACKGROUND: Reduced physical activity is supposed to be associated with depressiveness and more passive coping patterns. For further evaluation of this assumed relation we studied energy expenditure due to physical activity - usually referred to as activity thermogenesis (AT) - together with depressiveness (clinical diagnosis, depression module of the Patient Health Questionnaire), and coping behaviours (Brief COPE Inventory) in 50 patients with high-grade obesity (42 +/- 12 years; 9 with II degrees and 41 with III degrees obesity) aiming at bariatric surgery. METHODS: AT was assessed with a portable armband device (SenseWearTM armband). Depressiveness and coping were assessed using validated questionnaires. RESULTS: Weight-adjusted non-exercise AT and intensity of physical activity (metabolic equivalent) correlated inversely with body mass index (non-exercise AT: r = -0.32, P < 0.05; mean metabolic equivalent: r = 0.37, P < 0.01) but not with depressiveness. The coping strategies "support coping" and "active coping" showed significant inverse correlations to a) weight adjusted non-exercise AT ("support coping": r = -0.34, P < 0.05; "active coping": r = -0.36, P < 0.05), b) weight-adjusted exercise-related AT ("support coping": r = -0.36, P < 0.05; "active coping": r = -0.38, P < 0.01) and c) intensity of physical activity (for mean metabolic equivalent: "support coping": r = -0.38, P < 0.01; "active coping": r = -0.40, P < 0.01; for duration of exercise-related AT: "support coping": r = -0.36, P < 0.05; "active coping": r = -0.38, P < 0.01). CONCLUSIONS: AT was not associated with depressiveness. Furthermore, supposed adaptive coping strategies of individuals aiming at bariatric surgery were negatively associated with AT. PMID- 26110017 TI - Chemical lysis of cyanobacteria. AB - We have developed a mixture of enzymes and chemicals that completely lyse cyanobacteria. Since the treatment involves only readily-available chemicals and simple proteins that degrade the components of the cyanobacterial cell wall, it can easily be used in high-throughput applications requiring lysis for subsequent intracellular measurements. Our lysis technique consistently enables complete lysis of several different cyanobacterial strains, and we demonstrated that DNA, mRNA, and proteins are preserved in the lysates. Chemical lysis can be superior to existing techniques because of its convenience, reliability, and amenability to a variety of downstream applications. PMID- 26110018 TI - Rapid estimation of sugar release from winter wheat straw during bioethanol production using FTIR-photoacoustic spectroscopy. AB - BACKGROUND: Complexity and high cost are the main limitations for high-throughput screening methods for the estimation of the sugar release from plant materials during bioethanol production. In addition, it is important that we improve our understanding of the mechanisms by which different chemical components are affecting the degradability of plant material. In this study, Fourier transform infrared photoacoustic spectroscopy (FTIR-PAS) was combined with advanced chemometrics to develop calibration models predicting the amount of sugars released after pretreatment and enzymatic hydrolysis of wheat straw during bioethanol production, and the spectra were analysed to identify components associated with recalcitrance. RESULTS: A total of 1122 wheat straw samples from nine different locations in Denmark and one location in the United Kingdom, spanning a large variation in genetic material and environmental conditions during growth, were analysed. The FTIR-PAS spectra of non-pretreated wheat straw were correlated with the measured sugar release, determined by a high-throughput pretreatment and enzymatic hydrolysis (HTPH) assay. A partial least square regression (PLSR) calibration model predicting the glucose and xylose release was developed. The interpretation of the regression coefficients revealed a positive correlation between the released glucose and xylose with easily hydrolysable compounds, such as amorphous cellulose and hemicellulose. Additionally, a negative correlation with crystalline cellulose and lignin, which inhibits cellulose and hemicellulose hydrolysis, was observed. CONCLUSIONS: FTIR-PAS was used as a reliable method for the rapid estimation of sugar release during bioethanol production. The spectra revealed that lignin inhibited the hydrolysis of polysaccharides into monomers, while the crystallinity of cellulose retarded its hydrolysis into glucose. Amorphous cellulose and xylans were found to contribute significantly to the released amounts of glucose and xylose, respectively. PMID- 26110019 TI - Metabolic pathway engineering for production of 1,2-propanediol and 1-propanol by Corynebacterium glutamicum. AB - BACKGROUND: Production of the versatile bulk chemical 1,2-propanediol and the potential biofuel 1-propanol is still dependent on petroleum, but some approaches to establish bio-based production from renewable feed stocks and to avoid toxic intermediates have been described. The biotechnological workhorse Corynebacterium glutamicum has also been shown to be able to overproduce 1,2-propanediol by metabolic engineering. Additionally, C. glutamicum has previously been engineered for production of the biofuels ethanol and isobutanol but not for 1-propanol. RESULTS: In this study, the improved production of 1,2-propanediol by C. glutamicum is presented. The product yield of a C. glutamicum strain expressing the heterologous genes gldA and mgsA from Escherichia coli that encode methylglyoxal synthase gene and glycerol dehydrogenase, respectively, was improved by additional expression of alcohol dehydrogenase gene yqhD from E. coli leading to a yield of 0.131 mol/mol glucose. Deletion of the endogenous genes hdpA and ldh encoding dihydroxyacetone phosphate phosphatase and lactate dehydrogenase, respectively, prevented formation of glycerol and lactate as by products and improved the yield to 0.343 mol/mol glucose. To construct a 1 propanol producer, the operon ppdABC from Klebsiella oxytoca encoding diol dehydratase was expressed in the improved 1,2-propanediol producing strain ending up with 12 mM 1-propanol and up to 60 mM unconverted 1,2-propanediol. Thus, B12 dependent diol dehydratase activity may be limiting 1-propanol production. CONCLUSIONS: Production of 1,2-propanediol by C. glutamicum was improved by metabolic engineering targeting endogenous enzymes. Furthermore, to the best of our knowledge, production of 1-propanol by recombinant C. glutamicum was demonstrated for the first time. PMID- 26110020 TI - Partial tetrasomy of the proximal long arm of chromosome 15 in two patients: the significance of the gene dosage in terms of phenotype. AB - BACKGROUND: Large amounts of low copy number repeats in the 15q11.2q13.3 chromosomal region increase the possibility of misalignments and unequal crossover during meiosis in this region, leading to deletions, duplications, triplications and supernumerary chromosomes. Most of the reported cases with epilepsy, autism and Prader-Willi/Angelman syndrome are in association with rearrangements of the proximal long arm of chromosome 15. RESULTS: Here we report the first two unrelated Hungarian patients with the same epileptic and dysmorphic features, who were investigated by array comparative genomic hybridization (array CGH). By G-banded karyotype followed by FISH and array CGH we could detect partial tetrasomy of the 15q11.2q13.3 chromosomal region, supporting proximal 15q duplication syndrome. Findings of the array CGH gave fully explanation of the phenotypic features of these patients, including epileptic seizures, delayed development, hyperactivity and craniofacial dysmorphic signs. Besides the described features of isodicentric (15) (idic(15)) syndrome Patient 1. suffered from bigeminic extrasystoles and had postnatal growth retardation, which had been published only in a few articles. CONCLUSIONS: Dosage effect of some genes in the concerned genomic region is known, but several genes have no evidence to have dosage dependence. Our results expanded the previous literature data. We assume dosage dependence in the case of CHRNA7 and OTUD7A, which might be involved in growth regulation. On the other hand increased dosage of the KLF13 gene seems to have no direct causal relationship with heart morphology. The genomic environment of the affected genes may be responsible for the observed phenotype. PMID- 26110021 TI - 6q16.3q23.3 duplication associated with Prader-Willi-like syndrome. AB - BACKGROUND: Prader-Willi syndrome (PWS) is characterized by hypotonia, delayed neuropsychomotor development, overeating, obesity and mental deficiency. This phenotype is encountered in other conditions, defining Prader-Willi-like syndrome (PWLS). CASE PRESENTATION: We report a 14-year-old boy with a complex small supernumerary marker chromosome (sSMC) associated with PWLS. The propositus presents clinical features commonly found in patients with PWLS, including growth hormone deficit. Banding karyotype analysis and fluorescence in situ hybridization (FISH) revealed a marker derived from chromosome 6 and a neocentromere as suspected, but array-CGH enabled us to characterize this marker as a der(10)t(6;10)(6qter -> 6q23.3::10p11.1 -> 10p11.21)dn. As far as we know, this is the first diagnosed case of PWLS associated with a complex sSMC, involving a 30.9 Mb gain in the 6q16.3q23.3 region and a 3.5 Mb gain in the 10p11.21p11.1 region. Several genes have been mapped to the 6q region including the TCBA1 gene, which is associated with developmental delay and recurrent infections, the ENPP1 gene, associated with insulin resistance and susceptibility to obesity and the BMIQ3 gene, associated with body mass index (BMI). No OMIM gene was found in the smallest 10p11.21p11.1 region. CONCLUSIONS: We suggest that the duplicated chromosome segment 6q16.3q23.3 may be responsible for the phenotype of our case and may also be a candidate locus of PWLS. PMID- 26110022 TI - DNA microarray integromics analysis platform. AB - BACKGROUND: The study of interactions between molecules belonging to different biochemical families (such as lipids and nucleic acids) requires specialized data analysis methods. This article describes the DNA Microarray Integromics Analysis Platform, a unique web application that focuses on computational integration and analysis of "multi-omics" data. Our tool supports a range of complex analyses, including - among others - low- and high-level analyses of DNA microarray data, integrated analysis of transcriptomics and lipidomics data and the ability to infer miRNA-mRNA interactions. RESULTS: We demonstrate the characteristics and benefits of the DNA Microarray Integromics Analysis Platform using two different test cases. The first test case involves the analysis of the nutrimouse dataset, which contains measurements of the expression of genes involved in nutritional problems and the concentrations of hepatic fatty acids. The second test case involves the analysis of miRNA-mRNA interactions in polysaccharide-stimulated human dermal fibroblasts infected with porcine endogenous retroviruses. CONCLUSIONS: The DNA Microarray Integromics Analysis Platform is a web-based graphical user interface for "multi-omics" data management and analysis. Its intuitive nature and wide range of available workflows make it an effective tool for molecular biology research. The platform is hosted at https://lifescience.plgrid.pl/. PMID- 26110024 TI - WikiHyperGlossary (WHG): an information literacy technology for chemistry documents. AB - BACKGROUND: The WikiHyperGlossary is an information literacy technology that was created to enhance reading comprehension of documents by connecting them to socially generated multimedia definitions as well as semantically relevant data. The WikiHyperGlossary enhances reading comprehension by using the lexicon of a discipline to generate dynamic links in a document to external resources that can provide implicit information the document did not explicitly provide. Currently, the most common method to acquire additional information when reading a document is to access a search engine and browse the web. This may lead to skimming of multiple documents with the novice actually never returning to the original document of interest. The WikiHyperGlossary automatically brings information to the user within the current document they are reading, enhancing the potential for deeper document understanding. RESULTS: The WikiHyperGlossary allows users to submit a web URL or text to be processed against a chosen lexicon, returning the document with tagged terms. The selection of a tagged term results in the appearance of the WikiHyperGlossary Portlet containing a definition, and depending on the type of word, tabs to additional information and resources. Current types of content include multimedia enhanced definitions, ChemSpider query results, 3D molecular structures, and 2D editable structures connected to ChemSpider queries. Existing glossaries can be bulk uploaded, locked for editing and associated with multiple social generated definitions. CONCLUSION: The WikiHyperGlossary leverages both social and semantic web technologies to bring relevant information to a document. This can not only aid reading comprehension, but increases the users' ability to obtain additional information within the document. We have demonstrated a molecular editor enabled knowledge framework that can result in a semantic web inductive reasoning process, and integration of the WikiHyperGlossary into other software technologies, like the Jikitou Biomedical Question and Answer system. Although this work was developed in the chemical sciences and took advantage of open science resources and initiatives, the technology is extensible to other knowledge domains. Through the DeepLit (Deeper Literacy: Connecting Documents to Data and Discourse) startup, we seek to extend WikiHyperGlossary technologies to other knowledge domains, and integrate them into other knowledge acquisition workflows. PMID- 26110023 TI - Expression quantitative trait locus analysis for translational medicine. AB - Expression quantitative trait locus analysis has emerged as an important component of efforts to understand how genetic polymorphisms influence disease risk and is poised to make contributions to translational medicine. Here we review how expression quantitative trait locus analysis is aiding the identification of which gene(s) within regions of association are causal for a disease or phenotypic trait; the narrowing down of the cell types or regulators involved in the etiology of disease; the characterization of drivers and modifiers of cancer; and our understanding of how different environments and cellular contexts can modify gene expression. We also introduce the concept of transcriptional risk scores as a means of refining estimates of individual liability to disease based on targeted profiling of the transcripts that are regulated by polymorphisms jointly associated with disease and gene expression. PMID- 26110025 TI - QSAR DataBank repository: open and linked qualitative and quantitative structure activity relationship models. AB - BACKGROUND: Structure-activity relationship models have been used to gain insight into chemical and physical processes in biomedicine, toxicology, biotechnology, etc. for almost a century. They have been recognized as valuable tools in decision support workflows for qualitative and quantitative predictions. The main obstacle preventing broader adoption of quantitative structure-activity relationships [(Q)SARs] is that published models are still relatively difficult to discover, retrieve and redeploy in a modern computer-oriented environment. This publication describes a digital repository that makes in silico (Q)SAR-type descriptive and predictive models archivable, citable and usable in a novel way for most common research and applied science purposes. DESCRIPTION: The QSAR DataBank (QsarDB) repository aims to make the processes and outcomes of in silico modelling work transparent, reproducible and accessible. Briefly, the models are represented in the QsarDB data format and stored in a content-aware repository (a.k.a. smart repository). Content awareness has two dimensions. First, models are organized into collections and then into collection hierarchies based on their metadata. Second, the repository is not only an environment for browsing and downloading models (the QDB archive) but also offers integrated services, such as model analysis and visualization and prediction making. CONCLUSIONS: The QsarDB repository unlocks the potential of descriptive and predictive in silico (Q)SAR-type models by allowing new and different types of collaboration between model developers and model users. The key enabling factor is the representation of (Q)SAR models in the QsarDB data format, which makes it easy to preserve and share all relevant data, information and knowledge. Model developers can become more productive by effectively reusing prior art. Model users can make more confident decisions by relying on supporting information that is larger and more diverse than before. Furthermore, the smart repository automates most of the mundane work (e.g., collecting, systematizing, and reporting data), thereby reducing the time to decision. PMID- 26110026 TI - Insulin mediated improvement in glycemic control in elderly with type 2 diabetes mellitus can improve depressive symptoms and does not seem to impair health related quality of life. AB - BACKGROUND AND OBJECTIVES: Type 2 diabetes (T2D) is very prevalent among the elderly. Insulin therapy is often required for glycemic control. The association of starting this therapy with depressive symptoms as well the health-related quality of life (HRQoL) is unknown among the elderly patients. AIMS: Evaluate the association of starting insulin therapy depressive symptoms as well with HRQoL of elderly people with T2D. METHODS: 36 T2D participants (67.9 % females, age 66.5 years +/- 5.1) were recruited, 26 of whom completed the follow-up. Generic (Short Form 36 Health Survey - SF-36) and specific (Problem Areas in Diabetes - PAID) HRQoL questionnaires, Beck Depression Inventory (BDI), clinical, laboratorial and socio-demographic data were recorded on baseline and 6 months after the beginning of insulin treatment. RESULTS: There was a reduction in the BDI score after the use of insulin, which means an improvement in depressive symptoms (Before/After: median - 10.5 / 7; p = 0008). There were no statistically significant differences in HRQoL scores between the two time periods There was also a reduction in HbA1c (Before/After: median - 8.7/7.9). Otherwise, there were no statistically significant differences in: BMI (28.1/28.3); Abdominal circumference:(100.5/99.5) and chronic complications status. CONCLUSION: Insulin therapy in elderly people with type 2 diabetes can lead to an improvement of depressive symptoms and does not seem to affect negatively HRQoL of the participants. PMID- 26110027 TI - Understanding Bland Altman analysis. AB - In a contemporary clinical laboratory it is very common to have to assess the agreement between two quantitative methods of measurement. The correct statistical approach to assess this degree of agreement is not obvious. Correlation and regression studies are frequently proposed. However, correlation studies the relationship between one variable and another, not the differences, and it is not recommended as a method for assessing the comparability between methods.? In 1983 Altman and Bland (B&A) proposed an alternative analysis, based on the quantification of the agreement between two quantitative measurements by studying the mean difference and constructing limits of agreement.? The B&A plot analysis is a simple way to evaluate a bias between the mean differences, and to estimate an agreement interval, within which 95% of the differences of the second method, compared to the first one, fall. Data can be analyzed both as unit differences plot and as percentage differences plot.? The B&A plot method only defines the intervals of agreements, it does not say whether those limits are acceptable or not. Acceptable limits must be defined a priori, based on clinical necessity, biological considerations or other goals.? The aim of this article is to provide guidance on the use and interpretation of Bland Altman analysis in method comparison studies. PMID- 26110028 TI - Altmetrics - a complement to conventional metrics. AB - Emerging metrics based on article-level does not exclude traditional metrics based on citations to the journal, but complements them. Both can be employed in conjunction to offer a richer picture of an article use from immediate to long terms. Article-level metrics (ALM) is the result of the aggregation of different data sources and the collection of content from multiple social network services. Sources used for the aggregation can be broken down into five categories: usage, captures, mentions, social media and citations. Data sources depend on the tool, but they include classic metrics indicators based on citations, academic social networks (Mendeley, CiteULike, Delicious) and social media (Facebook, Twitter, blogs, or Youtube, among others). Altmetrics is not synonymous with alternative metrics. Altmetrics are normally early available and allow to assess the social impact of scholarly outputs, almost at the real time. This paper overviews briefly the meaning of altmetrics and describes some of the existing tools used to apply this new metrics: Public Library of Science--Article-Level Metrics, Altmetric, Impactstory and Plum. PMID- 26110029 TI - Aberrant methylation patterns in cancer: a clinical view. AB - Epigenetic mechanisms, such as DNA methylation, DNA hydroxymethylation, post translational modifications (PTMs) of histone proteins affecting nucleosome remodelling, and regulation by small and large non-coding RNAs (ncRNAs) work in concert with cis and trans acting elements to drive appropriate gene expression. Advances in detection methods and development of dedicated platforms and methylation arrays resulted in an explosion of information on aberrantly methylated sequences linking deviations in epigenetic landscape with the initiation and progression of complex diseases. Here, we consider how DNA methylation changes in malignancies, such as breast, pancreatic, colorectal, and gastric cancer could be exploited for the purpose of developing specific diagnostic tools. DNA methylation changes can be applicable as biomarkers for detection of malignant disease in easily accessible tissues. Methylation signatures are already proving to be an important marker for determination of drug sensitivity. Even more, promoter methylation patterns of some genes, such as MGMT, SHOX2, and SEPT9, have already been translated into commercial clinical assays aiding in patient assessment as adjunct diagnostic tools. In conclusion, the changes in DNA methylation patterns in tumour cells are slowly gaining entrance into routine diagnostic tests as promising biomarkers and as potential therapeutic targets. PMID- 26110030 TI - Clinical and diagnostic utility of saliva as a non-invasive diagnostic fluid: ?a systematic review. AB - This systematic review presents the latest trends in salivary research and its applications in health and disease. Among the large number of analytes present in saliva, many are affected by diverse physiological and pathological conditions. Further, the non-invasive, easy and cost-effective collection methods prompt an interest in evaluating its diagnostic or prognostic utility. Accumulating data over the past two decades indicates towards the possible utility of saliva to monitor overall health, diagnose and treat various oral or systemic disorders and drug monitoring. Advances in saliva based systems biology has also contributed towards identification of several biomarkers, development of diverse salivary diagnostic kits and other sensitive analytical techniques. However, its utilization should be carefully evaluated in relation to standardization of pre analytical and analytical variables, such as collection and storage methods, analyte circadian variation, sample recovery, prevention of sample contamination and analytical procedures. In spite of all these challenges, there is an escalating evolution of knowledge with the use of this biological matrix. PMID- 26110031 TI - Croatian survey on critical results reporting. AB - INTRODUCTION: Poor harmonization of critical results management is present in various laboratories and countries, including Croatia. We aimed to investigate procedures used in critical results reporting in Croatian medical biochemistry laboratories (MBLs). MATERIALS AND METHODS: An anonymous questionnaire, consisting of 24 questions/statements, related to critical results reporting procedures, was send to managers of MBLs in Croatia. Participants were asked to declare the frequency of performing procedures and degree of agreement with statements about critical values reporting using a Likert scale. Total score and mean scores for corresponding separate statements divided according to health care setting were calculated and compared. RESULTS: Responses from 111 Croatian laboratories (48%) were analyzed. General practice laboratories (GPLs) more often re-analyzed the sample before reporting the critical result in comparison with the hospital laboratories (HLs) (score: 4.86 (4.75-4.96) vs. 4.49 (4.25-4.72); P=0.001) and more often reported the critical value exclusively to the responsible physician compared to HLs (4.46 (4.29-4.64) vs. 3.76 (3.48-4.03), P<0.001). High total score (4.69 (4.56-4.82)) was observed for selection of the critical results list issued by the Croatian Chamber of Medical Biochemistry (CCMB) indicating a high harmonization level for this aspect of critical result management. Low total scores were observed for the statements regarding data recording and documentation of critical result notification. CONCLUSIONS: Differences in practices about critical results reporting between HLs and GPLs were found. The homogeneity of least favorable responses detected for data recording and documentation of critical results notification reflects the lack of specific national recommendations. PMID- 26110032 TI - Method evaluation study of a new generation of vitamin D assays. AB - INTRODUCTION: Recently several diagnostic manufacturers have launched new 25 hydroxy-vitamin D (25[OH]D) assays, which are aligned to the National Institute of Standards and Technology (NIST) Standard Reference Materials (SRM) (NIST, Gaithersburg, Maryland). The aim of this study was to compare the performance of one liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, one enzyme linked immunosorbent assay (ELISA), and one recalibrated and previous version of a chemiluminescence immunoassay (CLIA). MATERIAL AND METHODS: Serum-aliquots of 198 patient samples from routine 25(OH)D analysis were measured by the ClinMass(r) LC-MS/MS Complete Kit (RECIPE Chemicals+Instruments GmbH, Munich, Germany), the ORGENTEC 25(OH)D3/D2 ELISA (ORGENTEC Diagnostika GmbH, Mainz, Germany), the recalibrated Immunodiagnostic Systems (IDS)-iSYS 25(OH)DS and the previous used IDS-iSYS 25(OH)D CLIA (Immunodiagnostic Systems Ltd, Boldon, United Kingdom). Bland-Altman and Deming regression analyses were calculated for methods comparison of all tested 25(OH)D assays. The LC-MS/MS method was defined as the reference method. Within-run and between-run precision measurements were performed for all methods with three different concentration levels. RESULTS: Compared to the LC-MS/MS method, the new IDS-iSYS 25(OH)DS and ORGENTEC 25(OH)D3/D2 assay demonstrated mean relative biases of 16.3% and 17.8%. The IDS iSYS 25(OH)D assay showed the lowest mean bias of 1.5%. Deming regression analyses of the recalibrated IDS-iSYS 25(OH)DS and the ORGENTEC 25(OH)D3/D2 assay showed proportional differences, when compared to the reference method. All assays showed a within-run and between-run imprecision of <=20% at each of the evaluated concentration levels. CONCLUSIONS: The evaluated standardized immunoassays and LC-MS/MS are useful methods for measuring 25(OH)D serum-levels in clinical laboratories. PMID- 26110033 TI - National survey on intra-laboratory turnaround time for some most common routine and stat laboratory analyses in 479 laboratories in China. AB - INTRODUCTION: To investigate the state of the art of intra-laboratory turnaround time (intra-TAT), provide suggestions and find out whether laboratories accredited by International Organization for Standardization (ISO) 15189 or College of American Pathologists (CAP) will show better performance on intra-TAT than non-accredited ones. MATERIALS AND METHODS: 479 Chinese clinical laboratories participating in the external quality assessment programs of chemistry, blood gas, and haematology tests organized by the National Centre for Clinical Laboratories in China were included in our study. General information and the median of intra-TAT of routine and stat tests in last one week were asked in the questionnaires. RESULTS: The response rate of clinical biochemistry, blood gas, and haematology testing were 36% (479/1307), 38% (228/598), and 36% (449/1250), respectively. More than 50% of laboratories indicated that they had set up intra-TAT median goals and almost 60% of laboratories declared they had monitored intra-TAT generally for every analyte they performed. Among all analytes we investigated, the intra-TAT of haematology analytes was shorter than biochemistry while the intra-TAT of blood gas analytes was the shortest. There were significant differences between median intra-TAT on different days of the week for routine tests. However, there were no significant differences in median intra-TAT reported by accredited laboratories and non-accredited laboratories. CONCLUSIONS: Many laboratories in China are aware of intra-TAT control and are making effort to reach the target. There is still space for improvement. Accredited laboratories have better status on intra-TAT monitoring and target setting than the non-accredited, but there are no significant differences in median intra-TAT reported by them. PMID- 26110034 TI - Plasma centrifugation does not influence thrombin-antithrombin and plasmin antiplasmin levels but determines platelet microparticles count. AB - INTRODUCTION: Centrifugation is an essential step for plasma preparation to remove residual elements in plasma, especially platelets and platelet-derived microparticles (PMPs). Our working hypothesis was that centrifugation as a preanalytical step may influence some coagulation parameters. MATERIALS AND METHODS: Healthy young men were recruited (N=17). For centrifugation, two protocols were applied: (A) the first centrifugation at 2500xg for 15 min and (B) at 2500xg for 20 min at room temperature with a light brake. In protocol (A), the second centrifugation was carried out at 2500xg for 15 min, whereas in protocol (B), the second centrifugation involved a 10 min spin at 13,000 x g. Thrombin antithrombin (TAT) and plasmin-antiplasmin (PAP) complexes concentrations were determined by enzyme-linked immunosorbent assays. PMPs were stained with CD41 antibody and annexin V, and analyzed by flow cytometry method. Procoagulant activity was assayed by the Calibrated Automated Thrombogram method as a slope of thrombin formation (CAT velocity). RESULTS: Median TAT and PAP concentrations did not differ between the centrifugation protocols. The high speed centrifugation reduced the median (IQR) PMP count in plasma from 1291 (841-1975) to 573 (391 1010) PMP/uL (P=0.001), and CAT velocity from 2.01 (1.31-2.88) to 0.97 (0.82 1.73) nM/min (P=0.049). Spearman's rank correlation analysis showed correlation between TAT and PMPs in the protocol A plasma which was (rho=0.52, P<0.050) and between PMPs and CAT for protocol A (rho=0.74, P<0.050) and protocol B (rho=0.78, P<0.050). CONCLUSION: Centrifugation protocols do not influence the markers of plasminogen (PAP) and thrombin (TAT) generation but they do affect the PMP count and procoagulant activity. PMID- 26110035 TI - How well are pregnant women in Croatia informed about the oral glucose tolerance test? AB - INTRODUCTION: Preanalytical errors still constitute the largest source of errors in laboratory work. Proper patient preparation and patient's knowledge about a particular procedure affects its accuracy and reliability. We hypothesized that most of pregnant women are not well enough informed about the proper procedure for the OGTT. The aims of this study were to investigate: (i) how well pregnant women are informed about the OGTT; (ii) the most common way to inform pregnant women about OGTT and (iii) whether pregnant women's level of knowledge about the OGTT differ regarding source of information. MATERIALS AND METHODS: The anonymous questionnaire was conducted across the country in 23 Croatian primary and secondary healthcare centres. The questionnaire contained 9 questions on certain demographic data and familiarity with OGTT procedure. All 343 participants filled the questionnaire before the first blood draw. RESULTS: 42% of the participants demonstrated high and 38% adequate level of knowledge about the OGTT procedure. Majority of participants were informed about the procedure by gynaecologist (56%). The level of knowledge differed among participants with different sources of information (P=0.030). Further analysis showed that the level of knowledge was lower in pregnant women having received information from their gynaecologist compared to pregnant women who received information from the laboratory staff. CONCLUSIONS: In general, pregnant women are familiar with OGTT procedure, main source of information about the OGTT procedure is their gynaecologist, but the level of knowledge was higher in women who received information about the OGTT procedure from the laboratory staff. PMID- 26110036 TI - Education and communication is the key for the successful management of vitamin D test requesting. AB - INTRODUCTION: Pre-preanalytical and post-postanalytical phases are steps where the laboratory professional may play a crucial role. Measuring the serum circulating 25 hydroxyvitamin D level (25(OH)D) is recommended to evaluate vitamin D status in patients at risk for vitamin D deficiency while 1,25 hydroxyvitamin D (1,25(OH)2D) is only recommended to monitor several particular conditions (chronic kidney disease, hereditary phosphate-losing disorders, and some other) clearly defined by the current clinical guidelines of Endocrine Society.? Our research hypothesis was that through education and communication through comments in the Laboratory Information System (LIS), we could improve appropriateness in the request vitamin D tests. MATERIALS AND METHODS: A retrospective observational cross-sectional study was conducted from January 2005 to December 2014. Each 1,25(OH)2D request was reviewed individually by a member of the laboratory staff. Starting in November 2011, each inappropriate 1,25(OH)2D request was registered in LIS and 25(OH)D was measured instead of 1,25(OH)2D. We counted the overall number of 1,25(OH)2D requests and the number of inappropriate requests which then were marked with a comment. RESULTS: The request of 25(OH)D increased along years. However, 1,25(OH)2D requests increased until 2012 when demand began to diminish. CONCLUSIONS: Education and communication through comments in the LIS, corrected the inappropriate request of 1,25(OH)2D and promoted the use of 25(OH)D to study vitamin D deficiency. PMID- 26110037 TI - Circulating resistin protein and mRNA concentrations and clinical severity of coronary artery disease. AB - INTRODUCTION: Previous studies have implicated a strong link between circulating plasma resistin and coronary artery disease (CAD). The aim of this study was to evaluate the differences in peripheral blood mononuclear cells (PBMC) resistin mRNA and its plasma protein concentrations between the patients with CAD of different clinical severity. MATERIAL AND METHODS: This study included 33 healthy subjects as the control group (CG) and 77 patients requiring coronary angiography. Of the latter 30 was CAD negative whereas 47 were CAD positive [18 with stable angina pectoris (SAP) and 29 with acute coronary syndrome (ACS)]. Circulating resistin was measured by ELISA; PBMC resistin mRNA was determined by real-time PCR. RESULTS: Resistin protein was significantly higher in the ACS group compared to the CG (P=0.001) and the CAD negative group (P=0.018). Resistin mRNA expression did not vary across the study groups, despite the positive correlation seen with plasma resistin (rho=0.305, P=0.008). In patients, plasma resistin and PBMC resistin mRNA negatively correlated with HDL-C (rho=-0.404, P<0.001 and rho=-0.257, P=0.032, respectively). Furthermore, the highest plasma resistin tertile showed the lowest HDL-C (P=0.006). Plasma resistin was positively associated with serum creatinine (rho=0.353, P=0.002). CONCLUSION: Significant increase of plasma resistin in patients with ACS compared to CG and CAD negative patients was observed. Despite no change in PBMC resistin mRNA in different disease conditions a positive association between resistin mRNA and resistin plasma protein was evident. Both plasma resistin and PBMC resistin mRNA were negatively associated with plasma HDL-C, and plasma resistin positively with serum creatinine. PMID- 26110038 TI - Liver transplantation reverses hypergammaglobulinemia in patients with chronic hepatic failure. AB - INTRODUCTION: Sparse data are available about the effect of therapy methods on antibody levels in patients with liver failure. The aim of this study was to determine serum immunoglobulin concentrations in patients with chronic hepatic failure (CHF), acute- (ALF), or acute-on-chronic liver failure (ACLF) and to evaluate the impact of MARS treatment or liver transplantation (LT) on antibody levels. MATERIALS AND METHODS: We followed ten patients with ALF, twelve with ACLF and 18 with CHF. Eight patients with ALF and seven with ACLF underwent MARS therapy, whereas the rest received LT. 13 healthy volunteers served as controls. Serum antibody concentrations were measured using ELISA-technique. RESULTS: Median serum levels of IgA, IgG and IgM were significantly increased in patients with CHF compared to ALF or controls (P<0.02, P<0.01, and P<0.01). IgM and IgG concentrations were also significantly elevated in patients with CHF compared to ACLF (IgM, 3.7 vs. 1 g/L, P<0.001; IgG, 8.7 vs. 3.1 g/L, P=0.004). Immediately after LT a significant decrease of IgA (6.9 vs. 3.1 g/L, P=0.004), IgG (8.7 vs. 5.1 g/L, P=0.02) and IgM (3.7 vs. 1.8 g/L, P=0.001) was detected in patients with CHF and antibody levels further decreased the days after LT reaching levels comparable to healthy individuals. MARS treatment had no apparent effect on the immunoglobulin profile in patients with ALF or ACLF. CONCLUSION: We provide evidence that LT reverses hypergammaglobulinemia in patients suffering from CHF within one day, which could be explained to a reconstituted hepatic antibody clearance, whereas MARS treatment has no immediate effect on immunoglobulin levels. PMID- 26110039 TI - Cost-effectiveness analysis of acute kidney injury biomarkers in pediatric cardiac surgery. AB - INTRODUCTION: Acute kidney injury (AKI) is significant problem in children with congenital heart disease (CHD) who undergo cardiac surgery. The economic impact of a biomarker-based diagnostic strategy for AKI in pediatric populations undergoing CHD surgery is unknown. The aim of this study was to perform the cost effectiveness analysis of using serum cystatin C (sCysC), urine neutrophil gelatinase-associated lipocalin (uNGAL) and urine liver fatty acid-binding protein (uL-FABP) for the diagnosis of AKI in children after cardiac surgery compared with current diagnostic method (monitoring of serum creatinine (sCr) level). MATERIALS AND METHODS: We developed a decision analytical model to estimate incremental cost-effectiveness of different biomarker-based diagnostic strategies compared to current diagnostic strategy. The Markov model was created to compare the lifetime cost associated with using of sCysC, uNGAL, uL-FABP with monitoring of sCr level for the diagnosis of AKI. The utility measurement included in the analysis was quality-adjusted life years (QALY). The results of the analysis are presented as the incremental cost-effectiveness ratio (ICER). RESULTS: Analysed biomarker-based diagnostic strategies for AKI were cost effective compared to current diagnostic method. However, uNGAL and sCys C strategies yielded higher costs and lower effectiveness compared to uL-FABP strategy. uL-FABP added 1.43 QALY compared to current diagnostic method at an additional cost of $8521.87 per patient. Therefore, ICER for uL-FABP compared to sCr was $5959.35/QALY. CONCLUSIONS: Our results suggest that the use of uL-FABP would represent cost effective strategy for early diagnosis of AKI in children after cardiac surgery. PMID- 26110040 TI - In vitro diagnostic company recalls and medical laboratory practices: an Italian case. AB - INTRODUCTION: In vitro human diagnostic (IVD) company recalls are a common practice aimed to either minimize a potential error or eliminate an existing failure. In this case report, we aim to provide a critical analysis of a recent IVD recall and to provide a practical framework about what to do when an IVD company recalls product(s) based on the International Organization for Standardization--ISO 15189:2012 standard. CASE REPORT: In 2014, Abbott Laboratories(r) (Green Oaks, IL) published an urgent field safety notice regarding a product recall (Architect Intact parathyroid hormone (PTH) Assay List Number 8K25) with immediate action required. The IVD company explained the reasons for the recall as follows: i) Abbott has confirmed that a performance shift in the Architect Intact PTH assay has the potential to generate falsely elevated results on patient samples; ii) results generated with impacted lots may demonstrate a positive shift relative to those generated with previous reagent and/or calibrator lots. This issue may also impact established Architect Intact PTH reference ranges; iii) the magnitude of shift averages approximately 13% to 45%; iv) Abbott Architect Intact PTH controls do not detect the shift; and v) all current reagent, calibrator, and control inventory are impacted. The recall could have resulted in ~40,000 inaccurate laboratory tests reported by 18 laboratories from Italy (Lombardy region). CONCLUSION: IVD company recalls have a serious impact on the patient safety and require a thorough investigation and responsible approach to minimize the possible damage. Medical laboratories accredited according to the ISO 15189 standard have procedures in place to manage such situations and ensure that patient safety is maintained when such recalls are issued. PMID- 26110041 TI - A case report of short-chain acyl-CoA dehydrogenase deficiency (SCADD). AB - BACKGROUND: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare inherited mitochondrial fatty acid oxidation disorder associated with variations in the ACADS (Acyl-CoA dehydrogenase, C-2 to C-3 short chain) gene. SCADD has highly variable biochemical, genetic and clinical characteristics. Phenotypes vary from fatal metabolic decompensation to asymptomatic individuals. SUBJECT AND METHODS: A Romani boy presented at 3 days after birth with hypoglycaemia, hypotonia and respiratory pauses with brief generalized seizures. Afterwards the failure to thrive and developmental delay were present. Organic acids analysis with gas chromatography-mass spectrometry (GS/MS) in urine and acylcarnitines analysis with liquid chromatography-tandem mass spectrometry (LC-MS/MS) in dried blood spot were measured. Deoxyribonucleic acid (DNA) was isolated from blood and polymerase chain reactions (PCRs) were performed for all exons. Sequence analysis of all exons and flanking intron sequences of ACADS gene was performed. RESULTS: Organic acids analysis revealed increased concentration of ethylmalonic acid. Acylcarnitines analysis showed increase of butyrylcarnitine, C4-carnitine. C4 carnitine was 3.5 times above the reference range (<0.68 umol/L). Confirmation analysis for organic acids and acylcarnitine profile was performed on the second independent sample and showed the same pattern of increased metabolites. Sequence analysis revealed 3-bp deletion at position 310-312 in homozygous state (c.310_312delGAG). Mutation was previously described as pathogenic in heterozygous state, while it is in homozygous state in our patient. CONCLUSIONS: In our case clinical features of a patient, biochemical parameters and genetic data were consistent and showed definitely SCAD deficiency. PMID- 26110042 TI - Platelet satellitism in infectious disease? AB - BACKGROUND: Platelet satellitism is a phenomenon of unknown etiology of aggregating platelets around polymorphonuclear neutrophils and other blood cells which causes pseudothrombocytopenia, visible by microscopic examination of blood smears. It has been observed so far in about a hundred cases in the world. CASE SUBJECT AND METHODS: Our case involves a 73-year-old female patient with a urinary infection. Biochemical serum analysis (CRP, glucose, AST, ALT, ALP, GGT, bilirubin, sodium, potassium, chloride, urea, creatinine) and blood cell count were performed with standard methods on autoanalyzers. Serum protein fractions were examined by electrophoresis and urinalysis with standard methods on autoanalyzer together with microscopic examination of urine sediment. Erythrocyte sedimentation rate, blood culture and urine culture tests were performed with standard methods. RESULTS: Due to typical pathological values for bacterial urinary infection, the patient was admitted to the hospital. Blood smear examination revealed phenomenon, which has persisted for three weeks after the disease has been cured. Blood smears with EDTA as an anticoagulant had platelet satellitism whereas the phenomenon was not observed in tubes with different anticoagulants (Na, Li-heparin) and capillary blood. DISCUSSION: We hypothesize that satellitism was induced by some immunological mechanism through formation of antibodies which have mediated platelets binding to neutrophil membranes and vice versa. Unfortunately we were unable to determine the putative trigger for this phenomenon. To our knowledge this is the second case of platelet satellitism ever described in Croatia. PMID- 26110043 TI - Insulin resistance is associated with epigenetic and genetic regulation of mitochondrial DNA in obese humans. AB - BACKGROUND: Mitochondrial alterations have been observed in subjects with metabolic disorders such as obesity and diabetes. Studies on animal models and cell cultures suggest aberrant glucose and lipid levels, and impaired insulin signaling might lead to mitochondrial changes. However, the molecular mechanism underlying mitochondrial aberrance remains largely unexplored in human subjects. RESULTS: Here we show that the mitochondrial DNA copy number (mtDNAn) was significantly reduced (6.9-fold lower, p < 0.001) in the leukocytes from obese humans (BMI >30). The reduction of mtDNAn was strongly associated with insulin resistance (HOMA-IR: -0.703, p < 0.05; fasting insulin level: -0.015, p < 0.05); by contrast, the correlation between fasting glucose or lipid levels and mtDNAn was not significant. Epigenetic study of the displacement loop (D-loop) region of mitochondrial genome, which controls the replication and transcription of the mitochondrial DNA as well as organization of the mitochondrial nucleoid, revealed a dramatic increase of DNA methylation in obese (5.2-fold higher vs. lean subjects, p < 0.05) and insulin-resistant (4.6-fold higher vs. insulin-sensitive subjects, p < 0.05) individuals. CONCLUSIONS: The reduction of mtDNAn in obese human subjects is associated with insulin resistance and may arise from increased D-loop methylation, suggesting an insulin signaling-epigenetic-genetic axis in mitochondrial regulation. PMID- 26110045 TI - The Relationships Between Common Measurements of Taste Function. AB - BACKGROUND: There are five common, independent measures used to characterize taste function in humans: detection and recognition thresholds (DT and RT), suprathreshold intensity ratings of prototypical tastants, propylthiouracil (PROP) bitterness intensity, and fungiform papillae (FP) number. METHODS: We employed all five methods to assess taste function of 65 women (21.5 +/- 4 years, BMI 22.3 +/- 2.8 kg/m2). Pearson correlation coefficients were calculated between the different measures. RESULTS: The DT and RT were positively correlated for sweet, bitter, sour, and umami (p < 0.05), but not for salt. The DT or RT did not correlate with suprathreshold intensity ratings, except for umami (suprathreshold intensity and RT: r = -0.32, p = 0.009). FP number did not correlate with any measurement of taste function. PROP bitterness intensity ratings did not correlate with any measurement of taste function, except for suprathreshold ratings for saltiness (r = 0.26, p = 0.033). CONCLUSION: As most of the individual measures of taste function did not correlate with each other, with exception of the two threshold measures, we conclude that there are multiple perceptual phases of taste, with no single measure able to represent the sense of taste globally. PMID- 26110044 TI - The role of beneficial bacteria wall elasticity in regulating innate immune response. AB - BACKGROUND: Probiotics have great potential to contribute to development of healthy dietary regimes, preventive care, and an integrated approach to immunity related disease management. The bacterial wall is a dynamic entity, depending on many components and playing an essential role in modulating immune response. The impact of cell wall elasticity on the beneficial effects of probiotic strains has not been sufficiently studied. The aim was to investigate the effect of lactic acid bacteria (LAB) and bifidobacteria strains on phagocytic system cells (macrophages) as related to bacterial wall elasticity, estimated using atomic force microscopy (AFM). METHODS: We conducted studies on Balb/c line mice 18-20 g in weight using lyophilized strains of LAB-Lactobacillus acidophilus IMV B-7279, Lactobacillus casei IMV B-7280, Lactobacillus delbrueckii subsp. bulgaricus IMV B 7281, and bifidobacteria-Bifidobacterium animalis VKL and Bifidobacterium animalis VKB. We cultivated the macrophages obtained from the peritoneal cavity of mice individually with the strains of LAB and bifidobacteria and evaluated their effect on macrophages, oxygen-dependent bactericidal activity, nitric oxide production, and immunoregulatory cytokines. We used AFM scanning to estimate bacterial cell wall elasticity. RESULTS: All strains had a stimulating effect on the functional activity of macrophages and ability to produce NO/NO2 in vitro. Lactobacilli strains increased the production of IL-12 and IFN-gamma in vitro. The AFM demonstrated different cell wall elasticity levels in various strains of LAB and bifidobacteria. The rigidity of the cell walls among lactobacilli was distributed as follows: Lactobacillus acidophilus IMV B-7279 > Lactobacillus casei IMV B-7280 > Lactobacillus delbrueckii subsp. bulgaricus IMV B-7281; among the strains of bifidobacteria: B. animalis VKB > B. animalis VKL. Probiotic strain survival in the macrophages depended on the bacterial cell wall elasticity and on the time of their joint cultivation. CONCLUSION: LAB and bifidobacteria strains stimulate immune-modulatory cytokines and active oxygen and nitrogen oxide compound production in macrophages. Strains with a more elastic cell wall according to AFM data demonstrated higher resistance to intracellular digestion in macrophages and higher level of their activation. AFM might be considered as a fast and accurate method to assess parameters of probiotic strain cell wall to predict their immune-modulatory properties. PMID- 26110046 TI - Reaching for the Unreachable: Reorganization of Reaching with Walking. AB - Previous research suggests that reaching and walking behaviors may be linked developmentally as reaching changes at the onset of walking. Here we report new evidence on an apparent loss of the distinction between the reachable and nonreachable distances as children start walking. The experiment compared nonwalkers, walkers with help, and independent walkers in a reaching task to targets at varying distances. Reaching attempts, contact, leaning, and communication behaviors were recorded. Most of the children reached for the unreachable objects the first time it was presented. Nonwalkers, however, reached less on the subsequent trials showing clear adjustment of their reaching decisions with the failures. On the contrary, walkers consistently attempted reaches to targets at unreachable distances. We suggest that these reaching errors may result from inappropriate integration of reaching and locomotor actions, attention control and near/far visual space. We propose a reward mediated model implemented on a NAO humanoid robot that replicates the main results from our study showing an increase in reaching attempts to nonreachable distances after the onset of walking. PMID- 26110047 TI - Apoptotic cell-linked immunoregulation: implications for promoting immune tolerance in transplantation. AB - The induction of alloantigen-specific immune tolerance is the "Holy-Grail" in transplantation. Although it had been previously demonstrated that transient depletion of T cells through apoptosis could lead to long-term immune tolerance, the underlying mechanism responsible for this tolerance induction and maintenance was unknown. In this short article, a novel mechanism for long-term immune tolerance via transient T cell apoptosis will be discussed, based on our recent findings in a CD3-specific antibody treatment-induced immune tolerance mouse model. Transforming growth factor-beta, which is produced by immature dendritic cells whilst they phagocytose apoptotic T cells and by macrophages, plays an important role in initiating long-term immune tolerance. A possible model of how allospecific-immune tolerance can be induced in order to prevent allograft rejection in transplantation will be also proposed. PMID- 26110051 TI - EUGHS NEWS. PMID- 26110052 TI - Causes of accidental childhood deaths in China in 2010: A systematic review and analysis. AB - BACKGROUND: Infectious causes of childhood deaths in the world have decreased substantially in the 21st century. This trend has exposed accidental deaths as an increasingly important future challenge. Presently, little is known about the cause structure of accidental childhood deaths in low- and middle-income country (LMIC) settings. In this paper, we aim to establish cause structure for accidental deaths in children aged 0-4 years in China in the year 2010. METHODS: In this paper, we explored the database of 208 multi-cause child mortality studies in Chinese that formed a basis for the first published estimate of the causes of child deaths in China (for the year 2008). Only five of those studies identified specific causes of accidental deaths. Because of this, we searched the Chinese medical literature databases CNKI and WanFang for single-cause mortality studies that were focused on accidental deaths. We identified 71 further studies that provided specific causes for accidental deaths. We used epidemiological modeling to estimate the number of accidental child deaths in China in 2010 and to assign those deaths to specific causes. RESULTS: In 2010, we estimated 314 581 deaths in children 0-4 years in China, of which 31 633 (10.1%) were accidental. Accidental deaths contributed 7240 (4.0%) of all deaths in neonatal period, 8838 (10.5%) among all post-neonatal infant deaths, and 15 554 (31.7%) among children with 1-4 years of age. Among four tested models, the most predictive was used to establish the likely cause structure of accidental deaths in China. We estimated that asphyxia caused 9490 (95% confidence interval (CI) 8224-11 072), drowning 5694 (95% CI 5061-6327), traffic accidents 3796 (95% CI 3163-4745), poisoning 3163 (95% CI 2531-3796) and falls 2531 (95% CI 2214-3163) deaths. Based on medians from a few rare studies, we also predict 633 (95% CI 316-1265) deaths to be due to burns and 316 (95% CI 0-633) due to falling objects. Together, these 7 causes explain more than 80% of all accidental deaths when modeling is primarily used, and more than 95% when the analysis is based purely on medians from the 76 available studies. CONCLUSIONS: Reduction in global child mortality is a leading political priority and accidental deaths will soon emerge as one of the main challenges. In this paper we provided a detailed breakdown of causes of these deaths in a large middle-income country. We noted that, wherever the share of accidental deaths among all child deaths is increased, drowning is more likely to be the leading cause; asphyxia seems to be equally important in all contexts, while traffic accidents, poisoning and falls are relatively more important in contexts where the overall share of accidents to all child deaths is low. PMID- 26110053 TI - Deriving causes of child mortality by re-analyzing national verbal autopsy data applying a standardized computer algorithm in Uganda, Rwanda and Ghana. AB - BACKGROUND: To accelerate progress toward the Millennium Development Goal 4, reliable information on causes of child mortality is critical. With more national verbal autopsy (VA) studies becoming available, how to improve consistency of national VA derived child causes of death should be considered for the purpose of global comparison. We aimed to adapt a standardized computer algorithm to re analyze national child VA studies conducted in Uganda, Rwanda and Ghana recently, and compare our results with those derived from physician review to explore issues surrounding the application of the standardized algorithm in place of physician review. METHODS AND FINDINGS: We adapted the standardized computer algorithm considering the disease profile in Uganda, Rwanda and Ghana. We then derived cause-specific mortality fractions applying the adapted algorithm and compared the results with those ascertained by physician review by examining the individual- and population-level agreement. Our results showed that the leading causes of child mortality in Uganda, Rwanda and Ghana were pneumonia (16.5-21.1%) and malaria (16.8-25.6%) among children below five years and intrapartum-related complications (6.4-10.7%) and preterm birth complications (4.5-6.3%) among neonates. The individual level agreement was poor to substantial across causes (kappa statistics: -0.03 to 0.83), with moderate to substantial agreement observed for injury, congenital malformation, preterm birth complications, malaria and measles. At the population level, despite fairly different cause specific mortality fractions, the ranking of the leading causes was largely similar. CONCLUSIONS: The standardized computer algorithm produced internally consistent distribution of causes of child mortality. The results were also qualitatively comparable to those based on physician review from the perspective of public health policy. The standardized computer algorithm has the advantage of requiring minimal resources from the health care system and represents a promising way to re-analyze national or sub-national VA studies in place of physician review for the purpose of global comparison. PMID- 26110054 TI - Reproduction and beyond, kisspeptin in ruminants. AB - Kisspeptin (Kp) is synthesized in the arcuate nucleus and preoptic area of the hypothalamus and is a regulator of gonadotropin releasing hormone in the hypothalamus. In addition, Kp may regulate additional functions such as increased neuropeptide Y gene expression and reduced proopiomelanocortin (POMC) gene expression in sheep. Other studies have found a role for Kp to release growth hormone (GH), prolactin and luteinizing hormone (LH) from cattle, rat and monkey pituitary cells. Intravenous injection of Kp stimulated release LH, GH, prolactin and follicle stimulating hormone in some experiments in cattle and sheep, but other studies have failed to find an effect of peripheral injection of Kp on GH release. Recent studies indicate that Kp can stimulate GH release after intracerebroventricular injection in sheep at doses that do not release GH after intravenous injection. These studies suggest that Kp may have a role in regulation of both reproduction and metabolism in sheep. Since GH plays a role in luteal development, it is tempting to speculate that the ability of Kp to release GH and LH is related to normal control of reproduction. PMID- 26110055 TI - Challenges in enriching milk fat with polyunsaturated fatty acids. AB - Milk fatty acid composition is determined by several factors including diet. The milk fatty acid profile of dairy cows is low in polyunsaturated fatty acids, especially those of the n-3 series. Efforts to change and influence fatty acid profile with longer chain polyunsaturated fatty acids have proven challenging. Several barriers prevent easy transfer of dietary polyunsaturated fatty acids to milk fat including rumen biohydrogenation and fatty acid esterification. The potential for cellular uptake and differences in fatty acid incorporation into milk fat might also have an effect, though this has received less research effort. Given physiological impediments to enriching milk fat with polyunsaturated fatty acids, manipulating the genome of the cow might provide a greater increase than diet alone, but this too may be challenged by the physiology of the cow. PMID- 26110056 TI - Effects of Laminaria japonica polysaccharides on airway inflammation of lungs in an asthma mouse model. AB - BACKGROUND: Asthma is a serious chronic inflammatory disease affecting 300 million people worldwide. This aim of this study to investigate the anti inflammatory and anti-asthmatic effects of Laminaria japonica extract in the ovalbumin (OVA)-induced mouse asthma model. METHODS: A mouse asthma model was established in SPF Kunming mice by OVA-sensitization followed by inhalation of aerosol allergen for two weeks. Laminaria japonica polysaccharides (LJPS) were given by gavage feeding at 50 mg/kg/day during OVA inhalation challenge period, and their effect on asthma was compared with the standard treatment of Budesonide inhalation. The total inflammatory cells and eosinophils in bronchoalveolar lavage fluid (BALF) were determined. Histopathological changes in lung tissue were studied and scored to determine the degree of inflammation. Levels of IL-12, IL-13, and TGF-beta1 in BALF as well as serum levels of IgE were measured. Expressions of IL-12, IL-13, and TGF-beta1 in lung tissues were assessed. RESULTS: Highly inflammatory lungs infiltrated with significant increased eosinophils were observed in OVA-induced asthmatic mice. The OVA treated mice presented with a lower level of IL-12 and higher levels of IL-13 and TGF-beta1 in BALF and lung tissues, as well as an increased level of the serum IgE. Treatment with LJPS (Group B) significantly decreased the numbers of eosinophils in the BALF (P < 0.05) and alleviated lung inflammation compared to the untreated asthma mice (Group A). It also reduced the serum IgE levels, increased expression of IL 12, and decreased the expression of IL-13 and TGF-beta1 in BALF and lung (Both P < 0.05) compared with the group A. CONCLUSIONS: LJPS can significantly inhibit airway inflammation of asthmatic mice, adjust the balance of cytokines, and improve the pulmonary histopathological condition. Our data suggested that LJPS might be a potential therapeutic reagent for allergic asthma. PMID- 26110058 TI - JITC launches a new section: commentary and editorials. PMID- 26110057 TI - Characterization of cognitive deficits in spontaneously hypertensive rats, accompanied by brain insulin receptor dysfunction. AB - BACKGROUND: The spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal's sex and age as well as strains used for comparison (Wistar and Wistar Kyoto/WKY). METHODS: Three and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) beta-subunit and glycogen synthase kinase-3beta (GSK3beta) and their phosphorylated forms were obtained via ELISA. RESULTS: SHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRbeta-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3beta ratio, as compared to WKYs. CONCLUSION: Results indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia. PMID- 26110059 TI - Effects of prehospital epinephrine administration on neurological outcomes in patients with out-of-hospital cardiac arrest. AB - BACKGROUND: To determine if the effects of epinephrine administration on the outcome of out-of-hospital cardiac arrest (OHCA), patients are associated with the duration of cardiopulmonary resuscitation (CPR) performed by Emergency Medical Service (EMS) personnel. METHODS: This retrospective, nonrandomized, observational analysis used the All-Japan Utstein Registry, a prospective, nationwide population-based registry of all OHCA patients transported to the hospital by EMS staff as the data source. We stratified all OHCA patients for quartile of EMSs' CPR duration. Group 1 consisted of patients who fell under the 25th percentile of EMSs' CPR duration (under 15 min); group 2, patients who fell into the 25th to 50th percentile (between 15 and 19 min); group 3, patients who fell into the 50th to 75th percentile (between 20 and 26 min); and group 4, patients who fell at or above the 75th percentile (over 26 min). The primary endpoint was a favorable neurological outcome 1 month after cardiac arrest. The secondary endpoints were ROSC before arrival at the hospital and 1-month survival. RESULTS: A total of 383,811 patients aged over 18 years who had experienced OHCA between 2006 and 2010 in Japan, when stratified for quartile of EMSs' CPR duration, the epinephrine administration increased the rate of return of spontaneous circulation (ROSC) approximately tenfold in all groups. However, the beneficial effects of epinephrine administration on 1-month survival disappeared in patients on whom EMSs' CPR had been performed for more than 26 min, and the beneficial effects of epinephrine administration on neurological outcomes were observed only in patients on whom EMSs' CPR had been performed between 15 and 19 min (odds ratio, 1.327, 95 % confidence intervals, 1.017-1.733 P = 0.037). CONCLUSIONS: Epinephrine administration is associated with an increase of ROSC and with improvement in the neurological outcome on which EMSs' CPR duration is performed between 15 and 19 min. PMID- 26110060 TI - Changing trends in the epidemiology of vertebral osteomyelitis in Marseille, France. AB - The incidence and significant morbidity of vertebral osteomyelitis are increasing despite the progress of diagnosis competences. Among the 50 cases of vertebral osteomyelitis managed in our centers over the past 5 years, 84% of the cases were in men. The mean age was 55 years. Sixty-two percent of patients had comorbidities and risk factors: diabetes mellitus (24%), malignancy (16%), intravenous drug use (10%) and alcoholism (4%). A source of infection was identified in 66% of cases, including postvertebral surgery infection (18%) and hematogenous infection (48%). The mean time to diagnosis was 36 days. Back pain were occurred in 90% of cases, fever (70%), neurologic deficits (40%), epidural abscesses (32%), completed vertebral bone destruction (26%) and psoas abscess (12%). A single organism was isolated in 92% of cases. Gram-positive bacteria were identified in 76% of cases, while Gram-negative bacilli (GNB) were found in 18% of cases. The presence of GNB was significantly associated with malignancy (p 0.041). The mean duration of antibiotic therapy was 123 days. Surgical treatment was performed in 41 cases: spinal stabilization (26%), drainage of abscesses (32%) and relief of compression (40%). Residual pain was found in 24% of cases, and neurologic sequelae in 22%. Cervical or thoracic localization was a risk factor for neurologic compromise (p 0.042). The epidemiology of vertebral osteomyelitis has changed; an increase in malignancy that was significantly associated with vertebral osteomyelitis due to GNB has been observed. Our study shows that the rate of neurologic complications remains high despite improved diagnostic capabilities and optimal treatment. PMID- 26110061 TI - Prevalence of Smqnr and plasmid-mediated quinolone resistance determinants in clinical isolates of Stenotrophomonas maltophilia from Japan: novel variants of Smqnr. AB - Stenotrophomonas maltophilia is an important pathogen in healthcare-associated infections. S. maltophilia may contain Smqnr, a quinolone resistance gene encoding the pentapeptide repeat protein, which confers low-level quinolone resistance upon expression in a heterologous host. We investigated the prevalence of Smqnr and plasmid-mediated quinolone resistance (PMQR) determinants in S. maltophilia isolates from Japan. A total of 181 consecutive and nonduplicate clinical isolates of S. maltophilia were collected from four areas of Japan. The antimicrobial susceptibility profiles for these strains were determined. PCR was conducted for Smqnr and PMQR genes, including qnrA, qnrB, qnrC, qnrS, aac(6')-Ib and qepA. PCR products for Smqnr and aac(6')-Ib were sequenced. For the S. maltophilia isolates containing Smqnr, pulsed-field gel electrophoresis (PFGE) was performed using XbaI. Resistance rates to ceftazidime, levofloxacin, trimethoprim-sulfamethoxazole, chloramphenicol and minocycline were 67.4%, 6.1%, 17.7%, 8.8% and 0%, respectively. The minimum inhibitory concentration required to inhibit the growth of 50% and 90% of organisms were 0.5 and 2 mg/L for moxifloxacin but 1 and 4 mg/L for levofloxacin, respectively. Smqnr was detected in 104 of the 181 S. maltophilia isolates (57.5%), and the most frequent was Smqnr6, followed by Smqnr8 and Smqnr11. Eleven novel variants from Smqnr48 to Smqnr58 were detected. The 24 Smqnr-containing S. maltophilia isolates were typed by PFGE and divided into 21 unique types. Nine S. maltophilia isolates (5.0%) carried aac(6')-Ib-cr. No qnr or qepA genes were detected. This study describes a high prevalence of Smqnr and novel variants of Smqnr among S. maltophilia from Japan. Continuous antimicrobial surveillance and further molecular epidemiological studies on quinolone resistance in S. maltophilia are needed. PMID- 26110062 TI - Epidemiology of Staphylococcus aureus in Bangalore, India: emergence of the ST217 clone and high rate of resistance to erythromycin and ciprofloxacin in the community. AB - This study aimed to determine the antibiotic susceptibility pattern of Staphylococcus aureus (SA) and the circulating clones in Bangalore, India. Susceptibility testing was performed for all cases of SA infections in a tertiary care hospital. Panton-Valentine leucocidin (PVL) encoding genes were detected, and sequence type and spa type were determined. Out of the 92 collected strains, 52.2% were methicillin-resistant SA (MRSA), isolated from community-acquired (CA) infections in 60.4% and hospital-acquired (HA) infections in 39.6%. S. aureus isolates were also highly resistant to erythromycin (54.3%) and ciprofloxacin (70.6%) in methicillin-susceptible SA (MSSA) and MRSA, as well as in CA and HA infections. MRSA were found to be significantly more resistant to gentamicin (p <0.001), cotrimoxazole (p <0.001) and ciprofloxacin (p 0.001) than MSSA, but no significant difference was observed between CA- and HA-SA. ST217 appeared as a new emerging and prevalent clone, but ST772 remained the predominant clone, all being PVL-positive isolates. Our study points out the high prevalence of MRSA, even in the community, and the worrying increase of resistance to ciprofloxacin and erythromycin among CA-MSSA. Emergence of clone ST217 is reported for the first time in India. PMID- 26110063 TI - First report of Actinomyces europaeus bacteraemia result from a breast abscess in a 53-year-old man. AB - This is the first report of Actinomyces europaeus bacteraemia in a 53-year-old man. The bacteraemia was the result of a breast abscess. Identification was established by matrix-assisted desorption ionization-time of flight mass spectrometry and confirmed by 16S rRNA gene sequencing. The patient was treated with surgical drainage and penicillin for 4 weeks; the patient did not experience any relapse during 6 months of follow-up. PMID- 26110064 TI - Proteomic analysis of colon and rectal carcinoma using standard and customized databases. AB - Understanding proteomic differences underlying the different phenotypic classes of colon and rectal carcinoma is important and may eventually lead to a better assessment of clinical behavior of these cancers. We here present a comprehensive description of the proteomic data obtained from 90 colon and rectal carcinomas previously subjected to genomic analysis by The Cancer Genome Atlas (TCGA). Here, the primary instrument files and derived secondary data files are compiled and presented in forms that will allow further analyses of the biology of colon and rectal carcinoma. We also discuss new challenges in processing these large proteomic datasets for relevant proteins and protein variants. PMID- 26110065 TI - A TEX86 surface sediment database and extended Bayesian calibration. AB - Quantitative estimates of past temperature changes are a cornerstone of paleoclimatology. For a number of marine sediment-based proxies, the accuracy and precision of past temperature reconstructions depends on a spatial calibration of modern surface sediment measurements to overlying water temperatures. Here, we present a database of 1095 surface sediment measurements of TEX86, a temperature proxy based on the relative cyclization of marine archaeal glycerol dialkyl glycerol tetraether (GDGT) lipids. The dataset is archived in a machine-readable format with geospatial information, fractional abundances of lipids (if available), and metadata. We use this new database to update surface and subsurface temperature calibration models for TEX86 and demonstrate the applicability of the TEX86 proxy to past temperature prediction. The TEX86 database confirms that surface sediment GDGT distribution has a strong relationship to temperature, which accounts for over 70% of the variance in the data. Future efforts, made possible by the data presented here, will seek to identify variables with secondary relationships to GDGT distributions, such as archaeal community composition. PMID- 26110066 TI - Comparative, transcriptome analysis of self-organizing optic tissues. AB - Embryonic stem (ES) cells have a remarkable capacity to self-organize complex, multi-layered optic cups in vitro via a culture technique called SFEBq. During both SFEBq and in vivo optic cup development, Rax (Rx) expressing neural retina epithelial (NRE) tissues utilize Fgf and Wnt/beta-catenin signalling pathways to differentiate into neural retina (NR) and retinal-pigmented epithelial (RPE) tissues, respectively. How these signaling pathways affect gene expression during optic tissue formation has remained largely unknown, especially at the transcriptome scale. Here, we address this question using RNA-Seq. We generated Rx+ optic tissue using SFEBq, exposed these tissues to either Fgf or Wnt/beta catenin stimulation, and assayed their gene expression across multiple time points using RNA-Seq. This comparative dataset will help elucidate how Fgf and Wnt/beta-catenin signaling affect gene expression during optic tissue differentiation and will help inform future efforts to optimize in vitro optic tissue culture technology. PMID- 26110067 TI - The wow factor as a determinant of funding for disorders of the skin. AB - As people live beyond 100 years, there is an extended period of impaired quality of life for the increasing numbers of individuals with skin disorders. There is also a growing work force of fit elderly individuals who are able to provide low technology skin care and who can teach self-help if well instructed. The International Society of Dermatology's sub-committee Skin Care for All: Community Dermatology seeks to bring together those who care for skin diseases and those who manage wounds, burns, lymphoedema and neglected tropical diseases affecting the skin for the purpose of skin care. Their focus is the repair of four functions: barrier, thermoregulation, sensory perception and communication. The curriculum includes low cost self-help and the restoration of absent skin. The care expectation is one of technical proficiency integrated with kindness and altruism. The concept is attracting wide attention but needs to develop compelling and persuasive arguments ("wow factors") regarding why it should be funded. There is probably no greater wow factor than tracing the path of a severely injured patient from the battlefield through the course of immediate first aid by paramedics to the surgeon in the frontline tent who can almost guarantee survival. Seeing these disfigured persons winning trophies at the Olympic Games has garnered the admiration of millions of viewers. PMID- 26110068 TI - Transparency in Medicare Reimbursement: Help or Hindrance? AB - Welcome to the latest edition of JADPRO! It is my pleasure and honor to serve as an associate editor for this elite and unique journal. As one of the co-chairs of the meeting, I would like to invite you to attend the second JADPRO Live symposium to be held in sunny Orlando, Florida, this October 30 through November 2. The faculty lineup is superb, the content offerings are first rate, and you can earn up to 15 CE credits/contact hours. I am hoping to network with our entire readership there! You can find more information and learn how to register at www.apsho.org/jadprolive. PMID- 26110069 TI - Targeted Therapies in Breast Cancer: Implications for Advanced Oncology Practice. AB - The systemic therapeutic management of breast cancer has undergone significant transformation in the past decade. Without targeted therapies, conventional treatment with cytotoxic agents has reached the limit of its potential in terms of patient survival for most types of cancer. Enhanced understanding of the pathogenesis of tumor cell growth and metastasis has led to the identification of signaling growth pathways as targets for these directed therapies. Novel therapies targeted to HER2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), poly(ADP ribose) polymerase (PARP), mammalian target of rapamycin (mTOR), histone deacetylase (HDAC), the heat shock protein, and cyclin-dependent kinase (CDK) inhibitors have been developed and have demonstrated some efficacy in breast cancer. Recognition and management of the toxicities associated with targeted therapies is imperative. This review will describe the clinical development and utilization of targeted therapies currently in use or in clinical trials, with a focus on considerations for the oncology advanced practitioner. PMID- 26110070 TI - The History and Physical in Cancer Care: A Primer for the Oncology Advanced Practitioner. AB - Advanced practitioners (APs) specializing in cancer care will most likely need to perform or participate in obtaining the history and physical (H & P) of a new patient. The core infrastructure of the history-taking and physical examination process remains the same across all patients regardless of diagnosis. There are, however, important distinctions in the H & P of the patient with cancer. These distinctions can be challenging for the student or novice oncology AP, leading to frustration and potentially poor patient satisfaction and outcomes. In each component of the patient history, certain considerations related to the cancer and its diagnosis and/or treatment to date must be included; these elements are different from those in the general medical H & P. This article focuses mainly on the structure and elements of the history of the present illness phase of the H & P. The similarities and differences between taking a cancer-focused H & P vs. a traditional medical one are discussed as well. PMID- 26110071 TI - Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies. AB - Lenalidomide is an oral immunomodulatory agent approved in relapsed multiple myeloma with dexamethasone, for transfusion-dependent anemia in myelodysplastic syndrome associated with deletion 5q, and in relapsed/progressive mantle cell lymphoma following bortezomib. In recent clinical trials, lenalidomide has shown promising activity in hematologic malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Starting doses and dosing schedules vary by malignancy, with lenalidomide started at a lower dose for CLL than for NHL or multiple myeloma. Certain adverse events (AEs) are common across tumor types (e.g., neutropenia, thrombocytopenia, fatigue), whereas others are more often associated with CLL patients (e.g., tumor lysis syndrome and tumor flare reaction). Effective management requires awareness of these differences as well as appropriate prophylaxis, monitoring, and treatment of AEs. This article reviews the efficacy and safety of lenalidomide in CLL and NHL, focusing on approaches for the advanced practitioner to improve patient quality of life through optimal management of side effects. With these steps, lenalidomide can be administered safely, at the best starting doses and with minimal dose interruptions or reductions across hematologic malignancies. PMID- 26110072 TI - Management of Malignant Pericardial Effusion. PMID- 26110073 TI - The Case for Early Palliative Care in the Treatment of Ovarian Cancer. PMID- 26110074 TI - Vismodegib: First-in-Class Hedgehog Pathway Inhibitor for Metastatic or Locally Advanced Basal Cell Carcinoma. PMID- 26110075 TI - Healthy Weight Loss for the Cancer Survivor. PMID- 26110076 TI - Lessons Learned in Cancer Care Communication. PMID- 26110077 TI - Diagnostic Snapshot: Aggressive Malignancy or Benign Lesion? PMID- 26110078 TI - Outcome of cerebral arteriovenous malformations after linear accelerator reirradiation. AB - BACKGROUND: The aim of this study was to evaluate the clinical outcome of patients undergoing single-dose reirradiation using the Linear Accelerator (LINAC) for brain arteriovenous malformations (AVM). METHODS: A retrospective study of 37 patients with brain AVM undergoing LINAC reirradiation between April 2003 and November 2011 was carried out. Patient characteristics, for example, gender, age, use of medications, and comorbidities; disease characteristics, for example, Spetzler-Martin grading system, location, volume, modified Pollock Flickinger score; and treatment characteristics, for example, embolization, prescription dose, radiation dose-volume curves, and conformity index were analyzed. During the follow-up period, imaging studies were performed to evaluate changes after treatment and AVM cure. Complications, such as edema, rupture of the blood-brain barrier, and radionecrosis were classified as symptomatic and asymptomatic. RESULTS: Twenty-seven patients underwent angiogram after reirradiation and the percentage of angiographic occlusion was 55.5%. In three patients without obliteration, AVM shrinkage made it possible to perform surgical resection with a 2/3 cure rate. A reduction in AVM nidus volume greater than 50% after the first procedure was shown to be the most important predictor of obliteration. Another factor associated with AVM cure was a prescription dose higher than 15.5 Gy in the first radiosurgery. Two patients had permanent neurologic deficits. Factors correlated with complications were the prescription dose and maximum dose in the first procedure. CONCLUSION: This study suggests that single-dose reirradiation is safe and feasible in partially occluded AVM. Reirradiation may not benefit candidates whose prescribed dose was lower than 15.5 Gy in the first procedure and initial AVM nidus volume did not decrease by more than 50% before reirradiation. PMID- 26110079 TI - A case of angiographically occult, distal small anterior inferior cerebellar artery aneurysm. AB - BACKGROUND: A small aneurysm at an unusual location, such as a distal anterior inferior cerebellar artery (AICA) aneurysm, may conceal as a computed tomography angiography (CTA) and digital subtraction angiography (DSA)-occult aneurysm. CASE DESCRIPTION: We herein present the case of a patient suffering from a subarachnoid hemorrhage (SAH) with two aneurysms in which the AICA aneurysm was negative by CTA and DSA. CTA demonstrated a right anterior choroidal artery aneurysm, which was revealed to be an unruptured aneurysm after surgical exploration. A small distal AICA aneurysm was detected by 3D rotational angiography (3DRA). The patient fully recovered except for left-side hearing loss four months after the second operation. CONCLUSION: We recommend a meticulous diagnosis by 3DRA in patients with SAH in which the distribution is not coincident with a typical aneurysmal location. PMID- 26110080 TI - Neurosurgery Concepts: Key perspectives on Traumatic Brain Injury, New Treatments for Glioblastoma, Hemicraniectomy for Extensive Middle-Cerebral-Artery Stroke, Minimally Invasive Spine Surgery and Lumbar Epidural Injections for Radiculopathy. PMID- 26110081 TI - Minimal access microsurgical ligation of spinal dural arteriovenous fistula with tubular retractor. AB - BACKGROUND: Open surgical ligation is an effective treatment of spinal dural arteriovenous fistula (SDAVF). Until recently, the procedure would require an open laminectomy, which may potentially cause significant postoperative pain, spinal deformity, and instability due to disruptions of the spinal mechanics. Development in minimal access spine surgery provides an alternative approach that can minimize bone and soft tissue trauma. CASE DESCRIPTION: We report two patients who presented with progressive paraparesis secondary to thoracolumbar SDAVF. Minimal access microsurgical ligation was successfully performed through a tubular retractor using a paramedian muscle-splitting approach. CONCLUSION: With accurate localization of the fistulous point in each patient, only a hemilaminectomy and a small dura opening were required using the tube-assisted technique. This allows direct visualization and ligation of the fistulous point while minimizing postoperative morbidities. PMID- 26110082 TI - Microsurgical clipping for the true posterior communicating artery aneurysm in the distal portion of the posterior communicating artery. AB - BACKGROUND: Aneurysms arising from the posterior communicating artery (PCoA) itself are rare in which aneurysms usually located in the proximal portion of the PCoA. The authors report a case of the true PCoA ruptured aneurysm in the distal portion of the PCoA. CASE DESCRIPTION: The patient was an 83-year-old man who suffered subarachnoid hemorrhage. Cerebral angiography revealed a saccular aneurysm arising on the fetal type right PCoA itself in the distal portion of the PCoA. 2 days after the onset of symptoms, the patient underwent right interfascial pterional craniotomy, with anterior temporal approach. The aneurysm was successfully clipped with the preservation of both the PCoA and the thalamoperforating artery. CONCLUSION: We speculated that blood flow into the PCoA gradually increased after occlusion of the left vertebral artery, which induced tortuosity of the PCoA. As a result, hemodynamic stress might increase near the curvature and cause aneurysm formation. PMID- 26110083 TI - Surgical treatment of the intracranial pial arteriovenous fistula. AB - BACKGROUND: Pial arteriovenous fistula (PAVF) is a rare vascular condition comprising of one or more arterial vessels that are in direct communication with the draining veins. The condition is also characterized by the absence of a nidus. Due to high blood flows, varicose systems adjacent to the fistula appear. The key characteristic of the arteriovenous direct transition is that it offers a treatment option in which interruption of the blood flow can occur without removing the entire lesion. This study presents two cases of PAVF. CASE DESCRIPTION: The first case is of a 59-year-old male with lesions in the frontal region, fed by a branch of the right anterior cerebral artery and drained by the frontal basal vein to the sphenoparietal sinus. The second case is of a 3-year old child with a lesion in the right anterior frontal lobe, fed by a branch of the right middle cerebral artery, which drains into the Trolard vein and was associated with large a venous varix. CONCLUSION: PAVF is a disease characterized by its rarity, and knowledge of PAVF's clinical presentation is of vital importance in early diagnosis. The treatment of the condition consists of an occlusion of the supply vessel, which can be done by endovascular, microsurgical, or both procedures. Both the cases were successfully treated by microsurgical procedure. PMID- 26110084 TI - Ethical considerations regarding head transplantation. PMID- 26110085 TI - Religious morality (and secular humanism) in Western civilization as precursors to medical ethics: A historic perspective. PMID- 26110086 TI - Spontaneous cerebrospinal fluid leakage through fistulas at the clivus repaired with endoscopic endonasal approach. PMID- 26110087 TI - Rapid on-site evaluation with dynamic telecytopathology for ultrasound-guided fine-needle aspiration of head and neck nonthyroid lesions. AB - BACKGROUND: Rapid on-site evaluation (ROSE) at the time of ultrasound-guided fine needle aspiration (USGFNA) of head and neck lesion is essential for obtaining adequate samples and providing the preliminary diagnosis. We summarize our experience with ROSE of USGFNA on head and neck nonthyroid lesions using telecytopathology. MATERIALS AND METHODS: Real-time images of Diff-Quik stained cytology smears were obtained at ultrasound suite with an Olympus DP-70 digital camera attached to an Olympus CX41 microscope, and transmitted via ethernet by a cytotechnologist to a cytopathologist in cytopathology laboratory who rendered a preliminary diagnosis. Live communication was conducted with Vocera voice communication system. The ultrasound suite was located on different floor from the cytopathology laboratory. Accuracy of ROSE via telecytopathology was compared with an equal number of cases that received ROSE, prior to introduction of telecytopathology, via conventional microscopy. RESULTS: Rapid on-site evaluation was performed on a total of 116 USGFNA of head and neck nonthyroid lesions. The telecytopathology system and conventional microscopy was used to evaluate equal number of cases (58 each). Preliminary diagnoses of benign, atypical/suspicious for malignancy, and positive for malignancy were 72.4%, 17.2% and 10.3% for telecytopathology, and 69.0%, 10.3% and 20.7% for conventional microscopy. None of the cases were deemed unsatisfactory. The overall concordance between the preliminary and final diagnoses was 94.8% for telecytopathology and 98.3% for conventional microscopy and was not statistically significant (P = 0.309). The causes of discordant preliminary and final diagnoses were mainly attributed to availability of cell block and Papanicolaou-stained slides for review or flow cytometry results for lymphoma cases at the time of final sign out. CONCLUSIONS: Telecytopathology is comparable with conventional microscopy in ROSE of USGFNA of head and neck nonthyroid lesions. PMID- 26110088 TI - Automated morphometry provides accurate and reproducible virtual staging of liver fibrosis in chronic hepatitis C. AB - BACKGROUND: Liver fibrosis staging provides prognostic value, although hampered by observer variability. We used digital analysis to develop diagnostic morphometric scores for significant fibrosis, cirrhosis and fibrosis staging in chronic hepatitis C. MATERIALS AND METHODS: We automated the measurement of 44 classical and new morphometric descriptors. The reference was histological METAVIR fibrosis (F) staging (F0 to F4) on liver biopsies. The derivation population included 416 patients and liver biopsies >=20 mm-length. Two validation population included 438 patients. RESULTS: In the derivation population, the area under the receiver operating characteristic (AUROC) for clinically significant fibrosis (F stage >=2) of a logistic score combining 5 new descriptors (stellar fibrosis area, edge linearity, bridge thickness, bridge number, nodularity) was 0.957. The AUROC for cirrhosis of 6 new descriptors (edge linearity, nodularity, portal stellar fibrosis area, portal distance, granularity, fragmentation) was 0.994. Predicted METAVIR F staging combining 8 morphometric descriptors agreed well with METAVIR F staging by pathologists: kappa = 0.868. Morphometric score of clinically significant fibrosis had a higher correlation with porto-septal fibrosis area (r s = 0.835) than METAVIR F staging (r s = 0.756, P < 0.001) and the same correlations with fibrosis biomarkers, e.g., serum hyaluronate: r s = 0.484 versus r s = 0.476 for METAVIR F (P = 0.862). In the validation population, the AUROCs of clinically significant fibrosis and cirrhosis scores were, respectively: 0.893 and 0.993 in 153 patients (biopsy < 20 mm); 0.955 and 0.994 in 285 patients (biopsy >= 20 mm). The three morphometric diagnoses agreed with consensus expert reference as well as or better than diagnoses by first-line pathologists in 285 patients, respectively: significant fibrosis: 0.733 versus 0.733 (kappa), cirrhosis: 0.900 versus 0.827, METAVIR F: 0.881 versus 0.865. CONCLUSION: The new automated morphometric scores provide reproducible and accurate diagnoses of fibrosis stages via "virtual expert pathologist." PMID- 26110089 TI - Prospector: A web-based tool for rapid acquisition of gold standard data for pathology research and image analysis. AB - BACKGROUND: Obtaining ground truth for pathological images is essential for various experiments, especially for training and testing image analysis algorithms. However, obtaining pathologist input is often difficult, time consuming and expensive. This leads to algorithms being over-fitted to small datasets, and inappropriate validation, which causes poor performance on real world data. There is a great need to gather data from pathologists in a simple and efficient manner, in order to maximise the amount of data obtained. METHODS: We present a lightweight, web-based HTML5 system for administering and participating in data collection experiments. The system is designed for rapid input with minimal effort, and can be accessed from anywhere in the world with a reliable internet connection. RESULTS: We present two case studies that use the system to assess how limitations on fields of view affect pathologist agreement, and to what extent poorly stained slides affect judgement. In both cases, the system collects pathologist scores at a rate of less than two seconds per image. CONCLUSIONS: The system has multiple potential applications in pathology and other domains. PMID- 26110090 TI - Whole slide imaging for human epidermal growth factor receptor 2 immunohistochemistry interpretation: Accuracy, Precision, and reproducibility studies for digital manual and paired glass slide manual interpretation. AB - BACKGROUND: The use of digital whole slide imaging for human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) could create improvements in workflow and performance, allowing for central archiving of specimens, distributed and remote interpretation, and the potential for additional computerized automation. PROCEDURES: The accuracy, precision, and reproducibility of manual digital interpretation for HER2 IHC were determined by comparison to manual glass slide interpretation. Inter- and intra-pathologist reproducibility and precision between the glass slide and digital interpretations of HER2 IHC were determined in 5 studies using DAKO HercepTest-stained breast cancer slides with the Philips Digital Pathology System. In 2 inter-method studies, 3 pathologists interpreted glass and digital slides in sequence or in random order with a minimum of 7 days as a washout period. These studies also measured inter observer reproducibility and precision. Another two studies measured intra pathologist reproducibility on cases read 10 times by glass and digital methods. One additional study evaluated the effects of adding IHC control slides with each run, using 1 pathologist interpreting glass and digital slides randomized from the sets above along with appropriate controls for each slide in the set. RESULTS: The overall results show that there is no statistical difference between the variance of performance when comparing glass and digital HER2 interpretations; and there were no effects noted when control tissues were evaluated in conjunction with the test slides. CONCLUSIONS: The results show that there is an equivalence of result when interpreting HER2 IHC slides in breast cancer by either glass slides or digital images. Digital interpretation can therefore be safely and effectively used for this purpose. PMID- 26110091 TI - A review of the current state of digital plate reading of cultures in clinical microbiology. AB - Digital plate reading (DPR) is increasingly being adopted as a means to facilitate the analysis and improve the quality and efficiency within the clinical microbiology laboratory. This review discusses the role of DPR in the context of total laboratory automation and explores some of the platforms currently available or in development for digital image capturing of microbial growth on media. The review focuses on the advantages and challenges of DPR. Peer reviewed studies describing the utility and quality of these novel DPR systems are largely lacking, and professional guidelines for DPR implementation and quality management are needed. Further development and more widespread adoption of DPR is anticipated. PMID- 26110092 TI - Reimagining the microscope in the 21(st) century using the scalable adaptive graphics environment. AB - BACKGROUND: Whole-slide imaging (WSI), while technologically mature, remains in the early adopter phase of the technology adoption lifecycle. One reason for this current situation is that current methods of visualizing and using WSI closely follow long-existing workflows for glass slides. We set out to "reimagine" the digital microscope in the era of cloud computing by combining WSI with the rich collaborative environment of the Scalable Adaptive Graphics Environment (SAGE). SAGE is a cross-platform, open-source visualization and collaboration tool that enables users to access, display and share a variety of data-intensive information, in a variety of resolutions and formats, from multiple sources, on display walls of arbitrary size. METHODS: A prototype of a WSI viewer app in the SAGE environment was created. While not full featured, it enabled the testing of our hypothesis that these technologies could be blended together to change the essential nature of how microscopic images are utilized for patient care, medical education, and research. RESULTS: Using the newly created WSI viewer app, demonstration scenarios were created in the patient care and medical education scenarios. This included a live demonstration of a pathology consultation at the International Academy of Digital Pathology meeting in Boston in November 2014. CONCLUSIONS: SAGE is well suited to display, manipulate and collaborate using WSIs, along with other images and data, for a variety of purposes. It goes beyond how glass slides and current WSI viewers are being used today, changing the nature of digital pathology in the process. A fully developed WSI viewer app within SAGE has the potential to encourage the wider adoption of WSI throughout pathology. PMID- 26110093 TI - Enhancing automatic classification of hepatocellular carcinoma images through image masking, tissue changes and trabecular features. AB - BACKGROUND: Recent breakthroughs in computer vision and digital microscopy have prompted the application of such technologies in cancer diagnosis, especially in histopathological image analysis. Earlier, an attempt to classify hepatocellular carcinoma images based on nuclear and structural features has been carried out on a set of surgical resected samples. Here, we proposed methods to enhance the process and improve the classification performance. METHODS: First, we segmented the histological components of the liver tissues and generated several masked images. By utilizing the masked images, some set of new features were introduced, producing three sets of features consisting nuclei, trabecular and tissue changes features. Furthermore, we extended the classification process by using biopsy resected samples in addition to the surgical samples. RESULTS: Experiments by using support vector machine (SVM) classifier with combinations of features and sample types showed that the proposed methods improve the classification rate in HCC detection for about 1-3%. Moreover, detection rate of low-grades cancer increased when the new features were appended in the classification process, although the rate was worsen in the case of undifferentiated tumors. CONCLUSIONS: The masking process increased the reliability of extracted nuclei features. The additional of new features improved the system especially for early HCC detection. Likewise, the combination of surgical and biopsy samples as training data could also improve the classification rates. Therefore, the methods will extend the support for pathologists in the HCC diagnosis. PMID- 26110094 TI - Understanding the three-dimensional world from two-dimensional immunofluorescent adjacent sections. AB - Visualizing tissue structures in three-dimensions (3D) is crucial to understanding normal and pathological phenomena. However, staining and imaging of thick sections and whole mount samples can be challenging. For decades, researchers have serially sectioned large tissues and painstakingly reconstructed the 3D volume. Advances in automation, from sectioning to alignment, now greatly accelerate the process. In addition, immunofluorescent staining methods allow multiple antigens to be simultaneously detected and analyzed volumetrically. The objective was to incorporate multi-channel immunofluorescent staining and automation in 3D reconstruction of serial sections for volumetric analysis. Paraffin-embedded samples were sectioned manually but were processed, stained, imaged and aligned in an automated fashion. Reconstructed stacks were quantitatively analyzed in 3D. By combining automated immunofluorescent staining and tried-and-true methods of reconstructing adjacent sections, we were able to visualize, in detail, not only the geometric structures of the sample but also the presence and interactions of multiple proteins and molecules of interest within their 3D environment. Advances in technology and software algorithms have significantly expedited the 3D reconstruction of serial sections. Automated, multi-antigen immunofluorescent staining will significantly broaden the range and complexity of scientific questions that can be answered with this methodology. PMID- 26110095 TI - Exploring viewing behavior data from whole slide images to predict correctness of students' answers during practical exams in oral pathology. AB - The way of viewing whole slide images (WSI) can be tracked and analyzed. In particular, it can be useful to learn how medical students view WSIs during exams and how their viewing behavior is correlated with correctness of the answers they give. We used software-based view path tracking method that enabled gathering data about viewing behavior of multiple simultaneous WSI users. This approach was implemented and applied during two practical exams in oral pathology in 2012 (88 students) and 2013 (91 students), which were based on questions with attached WSIs. Gathered data were visualized and analyzed in multiple ways. As a part of extended analysis, we tried to use machine learning approaches to predict correctness of students' answers based on how they viewed WSIs. We compared the results of analyses for years 2012 and 2013 - done for a single question, for student groups, and for a set of questions. The overall patterns were generally consistent across these 3 years. Moreover, viewing behavior data appeared to have certain potential for predicting answers' correctness and some outcomes of machine learning approaches were in the right direction. However, general prediction results were not satisfactory in terms of precision and recall. Our work confirmed that the view path tracking method is useful for discovering viewing behavior of students analyzing WSIs. It provided multiple useful insights in this area, and general results of our analyses were consistent across two exams. On the other hand, predicting answers' correctness appeared to be a difficult task - students' answers seem to be often unpredictable. PMID- 26110096 TI - A perspective on digital and computational pathology. AB - The digitization of images has not only led to increasingly sophisticated methods of quantitating information from those images themselves, but also to the development of new physics-based techniques for extracting information from the original specimen and presenting this as visual data in both two and three dimensional (3D) forms. This evolution of an image-based discipline has reached maturity in Radiology, but it is only just beginning in Pathology. An historical perspective is provided both on the current state of computational imaging in pathology and of the factors that are impeding further progress in the development and application of these approaches. Emphasis is placed on barriers to the dissemination of information in this area. The value of computational imaging in basic and translational research is clear. However, while there are many examples of "virtual diagnostics" in Radiology, there are only relatively few in Pathology. Nevertheless, we can do cellular level analysis of lesions accessible by endoscopic or catheterization procedures, and a number of steps have been taken toward real-time imaging as adjuncts to traditional biopsies. Progress in computational imaging will greatly expand the role of pathologists in clinical medicine as well as research. PMID- 26110097 TI - The use of virtual microscopy and a wiki in pathology education: Tracking student use, involvement, and response. AB - BACKGROUND: The pathology laboratory course at the New York College of Podiatric Medicine involves the use of Virtual Microscopy. The students can scan the whole slide, section by section, and zoom in or out. METHODS: Using the advantages of digital pathology, the students can, in addition, access the slide collections from other medical schools and put up normal histology (control) slides side-by side with the pathology. They can cut and paste and preserve the region of interest that they find. They can edit and annotate their slides. A wiki was created (http://pathlab2014.wikifoundry.com)for the Class of 2014. The students saved, edited and uploaded their slides. In the wiki format, other students could comment, further edit, and even delete the slides. RESULTS: The students studied Basic Mechanisms and System Pathology. During this time, they saved, edited, shared, and uploaded their slides to the wiki. These were available in one full presentation and were also grouped into 16 albums. They were available to all. Student access was followed by Google analytics. At the end of the course, a questionnaire was distributed, assessing their impression of the wiki format and soliciting strengths and weaknesses. CONCLUSIONS: The use of a wiki has a number of important advantages in pathology education. It trains the students in the more sophisticated skills that they will use as professional pathologists or as clinicians: (1) Telepathology-it enables them to share slides and discuss observations. (2) Archiving and retrieval - It models the challenge faced by hospitals, diagnostic labs and physicians in maintaining a collection of slides in a form that is easily accessible. (3) Image analysis-familiarity with the wiki format allows them to jump easily to capturing and storing images found in the literature or in a pathologist's report. Experience with the use of a wiki in pathology education has been quite satisfactory from both the faculty and the student's point of view. PMID- 26110098 TI - Comparative study between quantitative digital image analysis and fluorescence in situ hybridization of breast cancer equivocal human epidermal growth factor receptors 2 score 2(+) cases. AB - BACKGROUND: Optimization of workflow for breast cancer samples with equivocal human epidermal growth factor receptors 2 (HER2)/neu score 2(+) results in routine practice, remains to be a central focus of the on-going efforts to assess HER2 status. According to the College of American Pathologists/American Society of Clinical Oncology guidelines equivocal HER2/neu score 2(+) cases are subject for further testing, usually by fluorescence in situ hybridization (FISH) investigations. It still remains on open question, whether quantitative digital image analysis of HER2 immunohistochemistry (IHC) stained slides can assist in further refining the HER2 score 2(+). AIM OF THIS WORK: To assess utility of quantitative digital analysis of IHC stained slides and compare its performance to FISH in cases of breast cancer with equivocal HER2 score 2(+). MATERIALS AND METHODS: Fifteen specimens (previously diagnosed as breast cancer and was evaluated as HER 2(-) score 2(+)) represented the study population. Contemporary new cuts were prepared for re-evaluation of HER2 immunohistochemical studies and FISH examination. All the cases were digitally scanned by iScan (Produced by BioImagene [Now Roche-Ventana]). The IHC signals of HER2 were measured using an automated image analyzing system (MECES, www.Diagnomx.eu/meces). Finally, a comparative study was done between the results of the FISH and the quantitative analysis of the virtual slides. RESULTS: Three out of the 15 cases with equivocal HER2 score 2(+), turned out to be positive (3(+)) by quantitative digital analysis, and 12 were found to be negative in FISH too. Two of these three positive cases proved to be positive with FISH, and only one was negative. CONCLUSIONS: Quantitative digital analysis is highly sensitive and relatively specific when compared to FISH in detecting HER2/neu overexpression. Therefore, it represents a potential reliable substitute for FISH in breast cancer cases, which desire further refinement of equivocal IHC results. PMID- 26110099 TI - Gender Differences in Real-Home Sleep of Young and Older Couples. AB - STUDY OBJECTIVES: To understand gender differences in sleep quality, architecture and duration of young healthy couples in comparison to older couples in their natural sleep environment. DESIGN: Sleep was monitored in a naturalistic setting using a headband sleep monitoring device over a period of two weeks for young couples and home polysomnography for the older couples. PARTICIPANTS: Ten heterosexual young couples (male mean age: 28.2+/-1.0[SD] years/female mean age: 26.8+/-0.9 years) and 14 older couples (male mean age: 59.3+/-9.6 years/female mean age: 58.8+/-9.1 years). MEASUREMENTS AND RESULTS: In the young couples, total sleep time (395+/-66 vs. 367+/-54 min., p<0.05), sleep efficiency (97.0+/ 3.0 vs. 91.1+/-7.9, p<0.001), and % REM (31.1+/-4.8 vs. 23.6+/-5.5, p<0.001) in males was higher than in females. In contrast, % light sleep (51.7+/-7.1 vs. 59.7+/-6.7, p<0.001) and number of arousals (2.9+/-1.9 vs. 5.3+/-1.9, p<0.001) were lower. These differences persisted after controlling for evening mood and various evening pre-sleep activities. In the older couples, there were no differences between genders. In addition, children in the household adversely impacted sleep. CONCLUSIONS: In couples recorded in the home, young males slept longer and had better sleep quality than young females. This difference appears to dissipate with age. In-home assessment of couples can aid in understanding of gender differences in sleep and how they are affected by age and social environment. PMID- 26110100 TI - Methotrexate utilization in Rheumatoid arthritis. A register-based cohort-study of treatment re-starts after gabs of at least 90 days. AB - OBJECTIVE: To examine restart of MTX treatment among patients with rheumatoid arthritis (RA) who discontinues treatment, and investigate predictors of restart. METHODS: A cohort study was conducted based on data from medical databases. MTX drug discontinuation was defined as a gap >= 90 days from the expiration of one MTX prescription to the redemption of a new one. Kaplan Meier estimates were used to compute the cumulative probability of restarting MTX treatment and Cox proportional hazard to estimate the hazard of return to treatment. A case crossover analysis compared the frequency of events that could potentially have a transient effect on MTX restart. RESULTS: Among 788 patients, who started MTX, 299 patients experienced a gap >= 90 days. Within 1.4 years 50 % of these patients returned to treatment, and a total of 66 % restarted treatment during follow-up. Concurrent treatment with corticosteroid and disease-modifying antirheumatic drugs (DMARDs) tended to be negatively associated with MTX restart (OR: 0.7(95 % CI: 0.5-1.2) and (OR: 0.7 (95 % CI: 0.4-1.0)). Older patients were less inclined to restart treatment than middle-aged patients (Adjustet HR 0.7 (0.4-1.2)). Patients with a CRP > 300 nmol/L less often restarted MTX than patients with a CRP < 75 nmol/L (adjHR: 0.6 (95 % CI 0.3-1.2)), and men were more inclined to MTX restart than women (adjHR 1.30 (95 % CI 0.9-2.0)). CONCLUSION: It is important to support patients in remaining continuous users of MTX. A large proportion of RA patients who discontinued MTX later restarted treatment, but especially patients with high disease activity, old age or co-morbidity were less inclined to restart treatment. PMID- 26110101 TI - Focus group discussions on the coverage of the southern separatist movement crisis in Yemeni newspapers. AB - A qualitative method using focus group discussions (FGDs) was applied in this study to identify people's perceptions on newspaper reporting pertaining to the Southern Separatist Movement (SSM) by different Yemeni newspapers. This paper also looked into the attitudes towards the movement and the popularity of the issue of Yemeni unification. Five FGD groups with a total of 30 participants discussed the subject and some other aspects related to it. The findings of the focu19 groups showed that the southern crisis and SSM had shaken the people's trust on the current form of the unity. The discussion with the groups revealed that media in general and the selected four papers from various political persuasions have no credibility and objectivity, but these papers are trying to instill democratic values which is consistent with their ideology, which have a serious impact on the value of liberal democracy. The participants assured that reporting on the southern cause and the SSM indicated the absence of professional journalism in the media and the political discourse in general. PMID- 26110102 TI - Comparative study of abdominal and thoracic aortic aneurysms: their pathogenesis and a gingival fibroblasts-based ex vivo treatment. AB - Aortic aneurysms (AAs) consist of slow proteolysis and loss of both collagen and elastin matrix in the aorta wall, leading to wall dilation, weakening and rupture in well-advanced lesions. This can occur in both abdominal aorta (Abdominal Aortic Aneurysm: AAA) and thoracic aorta (Thoracic Aortic Aneurysm: TAA). To date, no non-surgical therapy has been proposed to slow or stop AA progression. Previously published preclinical studies from our team using an aneurysm rabbit model showed a promising concept for treatment of AAs with gingival fibroblast (GFs) which are readily available cells. In this study, we investigated the possible tissue repair of human AAAs and TAAs using ex vivo models co-cultured with GFs. Histological analysis showed that TAA and AAA are two distinct pathologies. Both lesions presented destruction of the aorta wall, highly evidenced in AAA samples. The results have confirmed the presence of the bacterial Porphyromonas gingivalis (Pg) protein in all AAA samples, but not in TAA samples, indicating the possible role of an infectious factor in the developing and progression of AAA lesions compared to TAA. The co-culture of GFs with AA lesions shows increased expression of TIMP-1, the inhibitor of the aneurysm severity marker MMP-9. Our study indicates that GFs might ameliorate aorta wall reestablishment in both AA types by their regenerative and immunomodulatory capacities. It also demonstrates the possible infectious cause of AAA compared with TAA that may explain their different behavior. PMID- 26110103 TI - Characterization of proteins regulated by interleukin-4 in 3T3-L1 adipocytes. AB - Obesity is closely associated with metabolic syndrome, type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Our previous reports uncover the significant associations between interleukin-4 (IL-4)/IL-4 receptor genotypes and T2DM, as well as IL-4 genotypes and high density lipoprotein-cholesterol. Theses observations suggest that IL-4 harbors the capacity to regulate lipid metabolism. The present study is aimed at further elucidating regulatory roles of IL-4 to lipid metabolism by identifying putative proteins in 3T3-L1 adipocytes which are differentially expressed under IL-4 treatment. Proteins in mature 3T3-L1 adipocytes with altered expression levels under IL-4 treatment were identified by proteomic strategy. Our results revealed that IL-4 up-regulated levels of ATP synthase delta chain, Cytochrome c reductase, Pyrophsphatase and Vimentin, whereas, Alpha-enolase, Gelsolin, Vinculin and Valosin were down-regulated. These observations suggest that IL-4 promotes energy metabolism and inhibit lipid deposits in adipocytes by up-regulating proteins accelerating ATP synthesis. Our results suggest that IL-4 facilitates adipocytes metabolism to catabolism with a favorable condition for lipolysis. These catabolized lipids in adipocytes triggered by IL-4 might either be released into periphery or metabolized intracellularlly, and modulate systemic energy metabolism. PMID- 26110104 TI - Computed tomography findings in acute decompensated heart failure: periportal collar sign and lymphedema in the hepatoduodenal ligament and retroperitoneal space. AB - We report two cases that were diagnosed with either acute exacerbation of chronic heart failure or acute decompensated heart failure due to acute myocardial infarction; both cases exhibited computed tomography (CT) findings of the periportal collar sign in the liver and lymphedema in the hepatoduodenal ligament and retroperitoneal space. Both of these signs, particularly lymphedema in the hepatoduodenal ligament and anterior pararenal space, are considered very important CT findings when diagnosing acute decompensated heart failure. PMID- 26110106 TI - Reallocation of resources between generations and genders in the market and non market economy. The case of Italy. AB - In this article the National Transfer Accounts (NTA) method is used to develop a comprehensive account of resource reallocations between population members in Italy, encompassing the age and the gender perspective, the public and the familial institutional sectors as well as the market and non-market dimensions of the economy. The inclusion of the non-market economy, referring to household and care time, allows for an insight into the gender division of labour and the strength of intergenerational obligations in the Italian familistic welfare regime. Results highlight the existence of large flows of resources within the family both between genders and toward young generations, with men and women giving rise to considerable monetary and time transfers, respectively. PMID- 26110105 TI - Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells. AB - Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-kappaB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases. PMID- 26110107 TI - Production activities and economic dependency by age and gender in Europe: A cross-country comparison. AB - We compare selected European countries using an economic dependency ratio which emphasizes the role of age-specific levels of production and consumption. Our analysis reveals large differences in the age- and gender-specific level and type of production activities across selected European countries and identifies possible strategies to adjust age-specific economic behaviour to an ageing population. The cross-country differences in economic dependency of children and elderly persons are largely determined by the age at which people enter, respectively exit, the labour market. The ability of the working age population to support children and elderly persons in turn is strongly influenced by the participation of women in paid work. We also provide a measure for the age specific production and consumption in form of unpaid household work. The inclusion of unpaid household work leads to a decrease of the gender differences in production activities and indicates that the working age population supports children and elderly persons not only through monetary transfers but also through services produced by unpaid work (e.g. childcare, cooking, cleaning...). Given the available data, we cannot distinguish the age profile of consumption by gender and have to assume - in case of unpaid work - that each member of the household consumes the same. Hence, our results have to be regarded as a first approximation only. Our paper aims to argue that a reform of the welfare system needs to take into account not only public transfers but also private transfers, in particular the transfers in form of goods and services produced through unpaid household work. PMID- 26110108 TI - Cortical thickness estimation in longitudinal stroke studies: A comparison of 3 measurement methods. AB - There is considerable controversy about the causes of cognitive decline after stroke, with evidence for both the absence and coexistence of Alzheimer pathology. A reduction in cortical thickness has been shown to be an important biomarker for the progression of many neurodegenerative diseases, including Alzheimer's disease (AD). However, brain volume changes following stroke are not well described. Cortical thickness estimation presents an ideal way to detect regional and global post-stroke brain atrophy. In this study, we imaged a group of patients in the first month after stroke and at 3 months. We compared three methods of estimating cortical thickness on unmasked images: one surface-based (FreeSurfer) and two voxel-based methods (a Laplacian method and a registration method, DiRecT). We used three benchmarks for our analyses: accuracy of segmentation (especially peri-lesional performance), reproducibility, and biological validity. We found important differences between these methods in cortical thickness values and performance in high curvature areas and peri lesional regions, but similar reproducibility metrics. FreeSurfer had less reliance on manual boundary correction than the other two methods, while reproducibility was highest in the Laplacian method. A discussion of the caveats for each method and recommendations for use in a stroke population is included. We conclude that both surface- and voxel-based methods are valid for estimating cortical thickness in stroke populations. PMID- 26110110 TI - Hippocampal volume correlates with attenuated negative psychotic symptoms irrespective of antidepressant medication. AB - BACKGROUND: Individuals with at-risk mental state for psychosis (ARMS) often suffer from depressive and anxiety symptoms, which are clinically similar to the negative symptomatology described for psychosis. Thus, many ARMS individuals are already being treated with antidepressant medication. OBJECTIVES: To investigate clinical and structural differences between psychosis high-risk individuals with or without antidepressants. METHODS: We compared ARMS individuals currently receiving antidepressants (ARMS-AD; n = 18), ARMS individuals not receiving antidepressants (ARMS-nonAD; n = 31) and healthy subjects (HC; n = 24), in terms of brain structure abnormalities, using voxel-based morphometry. We also performed region of interest analysis for the hippocampus, anterior cingulate cortex, amygdala and precuneus. RESULTS: The ARMS-AD had higher 'depression' and lower 'motor hyperactivity' scores than the ARMS-nonAD. Compared to HC, there was significantly less GMV in the middle frontal gyrus in the whole ARMS cohort and in the superior frontal gyrus in the ARMS-AD subgroup. Compared to ARMS-nonAD, the ARMS-AD group showed more gray matter volume (GMV) in the left superior parietal lobe, but less GMV in the left hippocampus and the right precuneus. We found a significant negative correlation between attenuated negative symptoms and hippocampal volume in the whole ARMS cohort. CONCLUSION: Reduced GMV in the hippocampus and precuneus is associated with short-term antidepressant medication and more severe depressive symptoms. Hippocampal volume is further negatively correlated with attenuated negative psychotic symptoms. Longitudinal studies are needed to distinguish whether hippocampal volume deficits in the ARMS are related to attenuated negative psychotic symptoms or to antidepressant action. PMID- 26110111 TI - Increased segregation of brain networks in focal epilepsy: An fMRI graph theory finding. AB - Focal epilepsy is conceived of as activating local areas of the brain as well as engaging regional brain networks. Graph theory represents a powerful quantitative framework for investigation of brain networks. Here we investigate whether functional network changes are present in extratemporal focal epilepsy. Task-free functional magnetic resonance imaging data from 15 subjects with extratemporal epilepsy and 26 age and gender matched healthy controls were used for analysis. Local network properties were calculated using local efficiency, clustering coefficient and modularity metrics. Global network properties were assessed with global efficiency and betweenness centrality metrics. Cost-efficiency of the networks at both local and global levels was evaluated by estimating the physical distance between functionally connected nodes, in addition to the overall numbers of connections in the network. Clustering coefficient, local efficiency and modularity were significantly higher in individuals with focal epilepsy than healthy control subjects, while global efficiency and betweenness centrality were not significantly different between the two groups. Local network properties were also highly efficient, at low cost, in focal epilepsy subjects compared to healthy controls. Our results show that functional networks in focal epilepsy are altered in a way that the nodes of the network are more isolated. We postulate that network regularity, or segregation of the nodes of the networks, may be an adaptation that inhibits the conversion of the interictal state to seizures. It remains possible that this may be part of the epileptogenic process or an effect of medications. PMID- 26110113 TI - Wild chimpanzees are infected by Trypanosoma brucei. AB - Although wild chimpanzees and other African great apes live in regions endemic for African sleeping sickness, very little is known about their trypanosome infections, mainly due to major difficulties in obtaining their blood samples. In present work, we established a diagnostic ITS1-based PCR assay that allows detection of the DNA of all four Trypanosoma brucei subspecies (Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, and Trypanosoma brucei evansi) in feces of experimentally infected mice. Next, using this assay we revealed the presence of trypanosomes in the fecal samples of wild chimpanzees and this finding was further supported by results obtained using a set of primate tissue samples. Phylogenetic analysis of the ITS1 region showed that the majority of obtained sequences fell into the robust T. brucei group, providing strong evidence that these infections were caused by T. b. rhodesiense and/or T. b. gambiense. The optimized technique of trypanosome detection in feces will improve our knowledge about the epidemiology of trypanosomes in primates and possibly also other endangered mammals, from which blood and tissue samples cannot be obtained. Finally, we demonstrated that the mandrill serum was able to efficiently lyse T. b. brucei and T. b. rhodesiense, and to some extent T. b. gambiense, while the chimpanzee serum failed to lyse any of these subspecies. PMID- 26110112 TI - Disruption of caudate working memory activation in chronic blast-related traumatic brain injury. AB - Mild to moderate traumatic brain injury (TBI) due to blast exposure is frequently diagnosed in veterans returning from the wars in Iraq and Afghanistan. However, it is unclear whether neural damage resulting from blast TBI differs from that found in TBI due to blunt-force trauma (e.g., falls and motor vehicle crashes). Little is also known about the effects of blast TBI on neural networks, particularly over the long term. Because impairment in working memory has been linked to blunt-force TBI, the present functional magnetic resonance imaging (fMRI) study sought to investigate whether brain activation in response to a working memory task would discriminate blunt-force from blast TBI. Twenty-five veterans (mean age = 29.8 years, standard deviation = 6.01 years, 1 female) who incurred TBI due to blast an average of 4.2 years prior to enrollment and 25 civilians (mean age = 27.4 years, standard deviation = 6.68 years, 4 females) with TBI due to blunt-force trauma performed the Sternberg Item Recognition Task while undergoing fMRI. The task involved encoding 1, 3, or 5 items in working memory. A group of 25 veterans (mean age = 29.9 years, standard deviation = 5.53 years, 0 females) and a group of 25 civilians (mean age = 27.3 years, standard deviation = 5.81 years, 0 females) without history of TBI underwent identical imaging procedures and served as controls. Results indicated that the civilian TBI group and both control groups demonstrated a monotonic relationship between working memory set size and activation in the right caudate during encoding, whereas the blast TBI group did not (p < 0.05, corrected for multiple comparisons using False Discovery Rate). Blast TBI was also associated with worse performance on the Sternberg Item Recognition Task relative to the other groups, although no other group differences were found on neuropsychological measures of episodic memory, inhibition, and general processing speed. These results could not be attributed to caudate atrophy or the presence of PTSD symptoms. Our results point to a specific vulnerability of the caudate to blast injury. Changes in activation during the Sternberg Item Recognition Task, and potentially other tasks that recruit the caudate, may serve as biomarkers for blast TBI. PMID- 26110114 TI - Unilateral periventricular heterotopia and epilepsy in a girl with Ehlers-Danlos syndrome. AB - PURPOSE: Ehlers-Danlos syndrome (EDS), comprising a variety of inherited connective tissue disorders, has already been described in association with various neurological features, particularly with epilepsy and periventricular heterotopia (PH). Until now, there are reports of only bilateral periventricular heterotopia associated with Ehlers-Danlos syndrome. METHODS AND RESULTS: Here we describe a 1-year, 4-month-old female who came under our care in the Pediatric Emergency Room because of prolonged afebrile generalized seizures, whose clinical picture allowed us to suspect a diagnosis of Ehlers-Danlos syndrome. Neuroradiological investigations showed unilateral periventricular heterotopias, and genetic analyses confirmed the hypothesized diagnosis, identifying in particular a mutation in the COL5A1 gene. After starting anticonvulsant therapy, her seizures showed a good response with seizure control and she had a favorable long-term course. CONCLUSION: To our knowledge, this is the first report of unilateral periventricular heterotopia associated with Ehlers-Danlos syndrome. We first hypothesized a mosaicism as the cause of both, a unilateral localization of the heterotopias and a favorable long-term course with good response to anticonvulsant therapy; however, intriguingly, we could not demonstrate a mosaicism as the genetic condition in our patient and the neuroradiological findings and the favorable clinical outcome still remain unexplained. PMID- 26110116 TI - Genetic diversity analysis among male and female Jojoba genotypes employing gene targeted molecular markers, start codon targeted (SCoT) polymorphism and CAAT box derived polymorphism (CBDP) markers. AB - To detect genetic variations among different Simmondsia chinensis genotypes, two gene targeted markers, start codon targeted (SCoT) polymorphism and CAAT box derived polymorphism (CBDP) were employed in terms of their informativeness and efficiency in analyzing genetic relationships among different genotypes. A total of 15 SCoT and 17 CBDP primers detected genetic polymorphism among 39 Jojoba genotypes (22 females and 17 males). Comparatively, CBDP markers proved to be more effective than SCoT markers in terms of percentage polymorphism as the former detecting an average of 53.4% and the latter as 49.4%. The Polymorphic information content (PIC) value and marker index (MI) of CBPD were 0.43 and 1.10, respectively which were higher than those of SCoT where the respective values of PIC and MI were 0.38 and 1.09. While comparing male and female genotype populations, the former showed higher variation in respect of polymorphic percentage and PIC, MI and Rp values over female populations. Nei's diversity (h) and Shannon index (I) were calculated for each genotype and found that the genotype "MS F" (in both markers) was highly diverse and genotypes "Q104 F" (SCoT) and "82-18 F" (CBDP) were least diverse among the female genotype populations. Among male genotypes, "32 M" (CBDP) and "MS M" (SCoT) revealed highest h and I values while "58-5 M" (both markers) was the least diverse. Jaccard's similarity co-efficient of SCoT markers ranged from 0.733 to 0.922 in female genotypes and 0.941 to 0.746 in male genotype population. Likewise, CBDP data analysis also revealed similarity ranging from 0.751 to 0.958 within female genotypes and 0.754 to 0.976 within male genotype populations thereby, indicating genetically diverse Jojoba population. Employing the NTSYS (Numerical taxonomy and multivariate analysis system) Version 2.1 software, both the markers generated dendrograms which revealed that all the Jojoba genotypes were clustered into two major groups, one group consisting of all female genotypes and another group comprising of all male genotypes. During the present investigation, CBDP markers proved more informative in studying genetic diversity among Jojoba. Such genetically diverse genotypes would thus be of great significance for breeding, management and conservation of elite (high yielding) Jojoba germplasm. PMID- 26110115 TI - Metagenomics: A new horizon in cancer research. AB - Metagenomics has broadened the scope of targeting microbes responsible for inducing various types of cancers. About 16.1% of cancers are associated with microbial infection. Metagenomics is an equitable way of identifying and studying micro-organisms within their habitat. In cancer research, this approach has revolutionized the way of identifying, analyzing and targeting the microbial diversity present in the tissue specimens of cancer patients. The genomic analyses of these micro-organisms through next generation sequencing techniques invariably facilitate in recognizing the microbial population in biopsies and their evolutionary relationships with each other. In this review an attempt has been made to generate current metagenomic view on cancer microbiota. Different types of micro-organisms have been found to be linked to various types of cancers, thus, contributing significantly in understanding the disease at molecular level. PMID- 26110117 TI - So if we like the idea of peer workers, why aren't we seeing more? AB - The employment of peer support workers is widely encouraged in recovery-oriented mental health systems and services, providing a tangible example of how to translate recovery values and principles into actions. In Scotland, despite a long-term policy commitment to recovery approaches, the creation of peer worker roles has been slow and patchy. This paper describes findings from a study on the levers and barriers to the development of peer worker roles in two Scottish health board areas. Findings suggest that new evidence on effective implementation and cost effectiveness should be prioritised to support potentially complex role development in times of reduced resources. We argue that additional evidence on effectiveness is unlikely, by itself, to lead to country wide employment of peer workers. We therefore suggest that a policy commitment to peer working would be reinforced by not only a strengthened evidence base but also strengthened accountability mechanisms. In the absence of such accountability, decision-makers and planners might reasonably continue to ask "why bother"? PMID- 26110109 TI - Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity. AB - Functional, molecular and genetic neuroimaging has highlighted the existence of brain anomalies and neural vulnerability factors related to obesity and eating disorders such as binge eating or anorexia nervosa. In particular, decreased basal metabolism in the prefrontal cortex and striatum as well as dopaminergic alterations have been described in obese subjects, in parallel with increased activation of reward brain areas in response to palatable food cues. Elevated reward region responsivity may trigger food craving and predict future weight gain. This opens the way to prevention studies using functional and molecular neuroimaging to perform early diagnostics and to phenotype subjects at risk by exploring different neurobehavioral dimensions of the food choices and motivation processes. In the first part of this review, advantages and limitations of neuroimaging techniques, such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single photon emission computed tomography (SPECT), pharmacogenetic fMRI and functional near-infrared spectroscopy (fNIRS) will be discussed in the context of recent work dealing with eating behavior, with a particular focus on obesity. In the second part of the review, non invasive strategies to modulate food-related brain processes and functions will be presented. At the leading edge of non-invasive brain-based technologies is real-time fMRI (rtfMRI) neurofeedback, which is a powerful tool to better understand the complexity of human brain-behavior relationships. rtfMRI, alone or when combined with other techniques and tools such as EEG and cognitive therapy, could be used to alter neural plasticity and learned behavior to optimize and/or restore healthy cognition and eating behavior. Other promising non-invasive neuromodulation approaches being explored are repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS). Converging evidence points at the value of these non-invasive neuromodulation strategies to study basic mechanisms underlying eating behavior and to treat its disorders. Both of these approaches will be compared in light of recent work in this field, while addressing technical and practical questions. The third part of this review will be dedicated to invasive neuromodulation strategies, such as vagus nerve stimulation (VNS) and deep brain stimulation (DBS). In combination with neuroimaging approaches, these techniques are promising experimental tools to unravel the intricate relationships between homeostatic and hedonic brain circuits. Their potential as additional therapeutic tools to combat pharmacorefractory morbid obesity or acute eating disorders will be discussed, in terms of technical challenges, applicability and ethics. In a general discussion, we will put the brain at the core of fundamental research, prevention and therapy in the context of obesity and eating disorders. First, we will discuss the possibility to identify new biological markers of brain functions. Second, we will highlight the potential of neuroimaging and neuromodulation in individualized medicine. Third, we will introduce the ethical questions that are concomitant to the emergence of new neuromodulation therapies. PMID- 26110118 TI - What is schizophrenia? 25 years of research into schizophrenia - the Age Beginning Course Study. AB - We studied a population-based sample of 232 first-onset cases of schizophrenia aged 12 to 59 years at first admission retrospectively back to illness onset and prospectively up to 11.2 years later. We compared them with psychiatrically healthy age- and sex-matched population controls and equally matched first admission patients diagnosed with major depression. At schizophrenia onset women are several years older than men. The social factors tested did not explain the finding. Women's higher level of social development at onset is associated with a better medium-term functional and social outcome. Prodromal schizophrenia and depression are equal in length and diagnostically distinguishable only after the onset of positive symptoms. The sex difference in age at onset, invariable across cultures and ethnicities, is explained by a protective effect of oestrogen, which down-regulates D2 receptors. A higher genetic load antagonizes this effect. Long term symptom-related illness course exhibits a plateau after three years, the positive symptom dimension after two years, the depressive and the negative dimensions do so after three to five years. The most prevalent symptom is depressive mood. Male first episodes are more frequent and more severe in the first half of life, female ones in the second half. Aetiological conclusions will be drawn. PMID- 26110119 TI - Transcranial magnetic stimulation for geriatric depression: Promises and pitfalls. AB - As the global population gets older, depression in the elderly is emerging as an important health issue. A major challenge in treating geriatric depression is the lack of robust efficacy for many treatments that are of significant benefit to depressed working age adults. Repetitive transcranial magnetic stimulation (rTMS) is a novel physical treatment approach used mostly in working age adults with depression. Many TMS trials and clinics continue to exclude the elderly from treatment citing lack of evidence in this age group. In this review, we appraise the evidence regarding the safety and efficacy of rTMS in the elderly. A consistent observation supporting a high degree of tolerability and safety among the elderly patients emerged across the Randomised Controlled Trials and the uncontrolled trials. Further, there is no reliable evidence negating the utility of rTMS in the elderly with depression. We also identified several factors other than age that moderate the observed variations in the efficacy of rTMS in the elderly. These factors include but not limited to: (1) brain atrophy; (2) intensity and number of pulses (dose-response relationship); and (3) clinical profile of patients. On the basis of the current evidence, the practice of excluding elderly patients from TMS clinics and trials cannot be supported. PMID- 26110120 TI - Electroconvulsive therapy in catatonic patients: Efficacy and predictors of response. AB - Recent evidence favors the view of catatonia as an autonomous syndrome, frequently associated with mood disorders, but also observed in neurological, neurodevelopmental, physical and toxic conditions. From our systematic literature review, electroconvulsive therapy (ECT) results effective in all forms of catatonia, even after pharmacotherapy with benzodiazepines has failed. Response rate ranges from 80% to 100% and results superior to those of any other therapy in psychiatry. ECT should be considered first-line treatment in patients with malignant catatonia, neuroleptic malignant syndrome, delirious mania or severe catatonic excitement, and in general in all catatonic patients that are refractory or partially responsive to benzodiazepines. Early intervention with ECT is encouraged to avoid undue deterioration of the patient's medical condition. Little is known about the long-term treatment outcomes following administration of ECT for catatonia. The presence of a concomitant chronic neurologic disease or extrapyramidal deficit seems to be related to ECT non response. On the contrary, the presence of acute, severe and psychotic mood disorder is associated with good response. Severe psychotic features in responders may be related with a prominent GABAergic mediated deficit in orbitofrontal cortex, whereas non-responders may be characterized by a prevalent dopaminergic mediated extrapyramidal deficit. These observations are consistent with the hypothesis that ECT is more effective in "top-down" variant of catatonia, in which the psychomotor syndrome may be sustained by a dysregulation of the orbitofrontal cortex, than in "bottom-up" variant, in which an extrapyramidal dysregulation may be prevalent. Future research should focus on ECT response in different subtype of catatonia and on efficacy of maintenance ECT in long-term prevention of recurrent catatonia. Further research on mechanism of action of ECT in catatonia may also contribute to the development of other brain stimulation techniques. PMID- 26110121 TI - Auditory hallucinations: A review of the ERC "VOICE" project. AB - In this invited review I provide a selective overview of recent research on brain mechanisms and cognitive processes involved in auditory hallucinations. The review is focused on research carried out in the "VOICE" ERC Advanced Grant Project, funded by the European Research Council, but I also review and discuss the literature in general. Auditory hallucinations are suggested to be perceptual phenomena, with a neuronal origin in the speech perception areas in the temporal lobe. The phenomenology of auditory hallucinations is conceptualized along three domains, or dimensions; a perceptual dimension, experienced as someone speaking to the patient; a cognitive dimension, experienced as an inability to inhibit, or ignore the voices, and an emotional dimension, experienced as the "voices" having primarily a negative, or sinister, emotional tone. I will review cognitive, imaging, and neurochemistry data related to these dimensions, primarily the first two. The reviewed data are summarized in a model that sees auditory hallucinations as initiated from temporal lobe neuronal hyper-activation that draws attentional focus inward, and which is not inhibited due to frontal lobe hypo-activation. It is further suggested that this is maintained through abnormal glutamate and possibly gamma-amino-butyric-acid transmitter mediation, which could point towards new pathways for pharmacological treatment. A final section discusses new methods of acquiring quantitative data on the phenomenology and subjective experience of auditory hallucination that goes beyond standard interview questionnaires, by suggesting an iPhone/iPod app. PMID- 26110122 TI - Olfactory function in psychotic disorders: Insights from neuroimaging studies. AB - Olfactory deficits on measures of identification, familiarity, and memory are consistently noted in patients with psychotic disorders relative to age-matched controls. Olfactory intensity ratings, however, appear to remain intact while the data on hedonics and detection threshold are inconsistent. Despite the behavioral abnormalities noted, no specific regional brain hypoactivity has been identified in psychosis patients, for any of the olfactory domains. However, an intriguing finding emerged from this review in that the amygdala and pirifom cortices were not noted to be abnormal in hedonic processing (nor was the amygdala identified abnormal in any study) in psychotic disorders. This finding is in contrast to the literature in healthy individuals, in that this brain region is strongly implicated in olfactory processing (particularly for unpleasant odorants). Secondary olfactory cortex (orbitofrontal cortices, thalamus, and insula) was abnormally activated in the studies examined, particularly for hedonic processing. Further research, using consistent methodology, is required for better understanding the neurobiology of olfactory deficits. The authors suggest taking age and sex differences into consideration and further contrasting olfactory subgroups (impaired vs intact) to better our understanding of the heterogeneity of psychotic disorders. PMID- 26110123 TI - Inter-relationships between isotretinoin treatment and psychiatric disorders: Depression, bipolar disorder, anxiety, psychosis and suicide risks. AB - Isotretinoin (Accutane) is a treatment for severe acne that is resistant to other forms of treatment, including antibiotics and topical treatments. The prescription of this drug has been controversial ever since its initial marketing in 1982. It is the only non-psychotropic drug in the Food and Drug Administration top 10 drugs found to be associated with depression. Recently, Bremner et al published an extensive review (until 2010) of the evidence for the association of retinoic acid (RA) with depression and suicide. Some patients who are admitted in psychiatric hospitals report a history of present or past treatment with isotretinoin. Then, the imputability of the molecule in the occurrence of disorders represents necessarily an important question for both professionals and their patients. This paper aims to specify the links between the drug and specific psychiatric disorders. A review of the literature related to isotretinoin, RA, vitamin A, depression, suicide, anxiety, bipolar disorder, psychosis, schizophrenia was performed. Many studies demonstrated an increased risk of depression, attempted suicide and suicide following isotretinoin treatment. However, isotretinoin may have an antidepressant impact, according to some dermatological papers. They consider treating acne with this efficient treatment could improve self-image and make the patient feel better. Several studies showed that patients with bipolar disorder had an increased risk for a clinical exacerbation of symptoms undergoing treatment with isotretinoin. A few studies also seem to suggest a possible link between isotretinoin and psychosis. Nonetheless, studies point out a link between retinoid dysregulation and schizophrenia through modulation of dopamine receptors. From this review, we propose guidelines for isotretinoin prescription to healthcare professionals. PMID- 26110124 TI - Outpatient competence restoration: A model and outcomes. AB - AIM: To describe a model outpatient competence restoration program (OCRP) and provide data on time to restoration of adjudicative competence. METHODS: The authors tracked the process by which individuals are referred for outpatient competence restoration (OCR) by courts in the United States capital, describing the unique requirements of American law, and the avenues available for compelling adherence. Competence to stand trial is a critical gate-keeping function of the judicial and forensic communities and assures that defendants understand courtroom procedures. OCR is therefore an effort to assure fairness and protection of important legal rights. Multi-media efforts are described that educate patients and restore competence to stand trial. These include resources such as group training, use of licensed clinicians, visual aids, structured instruments, and cinema. Aggregate data from the OCRP's previous 4 years of OCR efforts were reviewed for demographic characteristics, restoration rate, and time to restoration. Poisson regression modeling identified the differences in restoration between sequential 45-d periods after entrance into the program. RESULTS: In the past 4 years, the DC OCRP has been successful in restoring 55 of 170 participants (32%), with an average referral rate of 35 persons per year. 76% are restored after the initial 45 d in the program. Demographics of the group indicate a predominance of African-American men with a mean age of 42. Thought disorders predominate and individuals in care face misdemeanor charges 78% of the time. Poisson regression modeling of the number attaining competence during four successive 45-d periods showed a substantial difference among the time periods for the rate of attaining competence (P = 0.0011). The three time periods after 45 d each showed a significant decrease in the restoration rate when compared to the initial 0 to 45 d period - their relative rates were only 22% to 33% as high as the rate for 0-45 d (all P-values, compared to the 0-45 d rate, were 0.013 or smaller). However, the three periods from day 45 to day 135 showed no difference among themselves (P = 0.87). CONCLUSION: The majority of restored participants were restored after 45 d, suggesting a model that may identify an optimal length of time to restoration. PMID- 26110125 TI - Audit study of the new hospitalization for assessment scheme for forensic mental health in Japan. AB - AIM: To clarify the components of hospitalization for assessment (HfA) and the management changes from the beginning of the scheme to the present. METHODS: This study is composed of two surveys. In 2013 survey, we created two paper questionnaires (facility and case questionnaires) for psychiatrists working in psychiatric hospitals accepting HfA patients. Questionnaires were sent to 205 hospitals that were identified as accepting the HfA cases, and responses were requested via mail. The facility questionnaire was designed to clarify the following specifications and characteristics of each facility: the facility organizer (public sector or private hospital), and the number of beds, psychiatrists, psychiatric nurses, occupational therapists, psychiatric social workers, psychotherapists, public health nurses, and patients treated through HfA during the survey period. The case questionnaire was then used to collect data of the patients under HfA based on the Medical Treatment and Supervision (MTS) Act who were discharged between July 1, 2012 and June 30, 2013. Gathered information included: legal information of each case, demographic data, past history of the offenders, issued offense and the relationship to the victim, information regarding past psychiatric testimonies, psychiatric diagnoses, contents of the treatment during HfA, information regarding seclusion and restraint during the HfA, the verdict of the District Court panel, and so forth. Next, we compared those results with relevant data obtained in 2007. The 2007 survey comprised data of HfA patients from July 15, 2005 (the date the MTS Act was enforced) to January 15, 2007. RESULTS: We obtained 171 cases, approximately a half of whole contemporary cases of HfA, from 134 facilities, of which 46 were national, prefectural, or semi-official hospitals, and 88 were private hospitals, in 2013 survey. The majority of subjects were male, schizophrenic, and experienced previous psychiatric treatment. The most frequent type of the offense was injury, followed by arson. Most of the subjects were medicated, and a few cases took psychotropic injection during the HfA. The frequency of injection was decreased in 2013 (chi (2) = 7.54, df = 1, P = 0.006) than in 2007. Psychiatric testimony was more likely to be conducted in 2013 (chi (2) = 8.56, df = 1, P = 0.004). The examiner psychiatrist was more likely to belong to the HfA facility to which the patient was hospitalized (chi (2) = 5.32, df = 1, P = 0.02). Hospitalization orders were more frequently selected in 2013 (chi (2) = 19.76, df = 3, P < 0.001), although the characteristics of the subjects had not changed. CONCLUSION: Although the management of HfA has improved in recent years, structural problems remain. PMID- 26110126 TI - Systematic review of suicide in economic recession. AB - AIM: To provide a systematic update of the evidence concerning the relationship between economic recession and suicide. METHODS: A keyword search of Ovid Medline, Embase, Embase Classic, PsycINFO and PsycARTICLES was performed to identify studies that had investigated the association between economic recession and suicide. RESULTS: Thirty-eight studies met predetermined selection criteria and 31 of them found a positive association between economic recession and increased suicide rates. Two studies reported a negative association, two articles failed to find such an association, and three studies were inconclusive. CONCLUSION: Economic recession periods appear to increase overall suicide rates, although further research is warranted in this area, particularly in low income countries. PMID- 26110127 TI - Intraductal Papillary Mucinous Neoplasm of Pancreas. AB - Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are neoplasms that are characterized by ductal dilation, intraductal papillary growth, and thick mucus secretion. This relatively recently defined pathology is evolving in terms of its etiopathogenesis, clinical features, diagnosis, management, and treatment guidelines. A PubMed database search was performed. All the relevant abstracts in English language were reviewed and the articles in which cases of IPMN could be identified were further scrutinized. Information of IPMN was derived, and duplication of information in several articles and those with areas of persisting uncertainties were excluded. The recent consensus guidelines were examined. The reported incidence of malignancy varies from 57% to 92% in the main duct-IPMN (MD-IPMN) and from 6% to 46% in the branch duct-IPMN (BD-IPMN). The features of high-risk malignant lesions that raise concern include obstructive jaundice in a patient with a cystic lesion in the pancreatic head, the findings on radiological imaging of a mass lesion of >30 mm, enhanced solid component, and the main pancreatic duct (MPD) of size >=10 mm; while duct size 5-9 mm and cyst size <3 mm are considered as "worrisome features." Magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) are primary investigations in diagnosing and following up on these patients. The role of pancreatoscopy and the analysis of aspirated cystic fluid for cytology and DNA analysis is still to be established. In general, resection is recommended for most MD-IPMN, mixed variant, and symptomatic BD-IPMN. The 5-year survival of patients after surgical resection for noninvasive IPMN is reported to be at 77-100%, while for those with invasive carcinoma, it is significantly lower at 27-60%. The follow-up of these patients could vary from 6 months to 1 year and would depend on the risk stratification for invasive malignancy and the pathology of the resected specimen. The understanding of IPMN has evolved over the years. The recent guidelines have played a role in this regard. PMID- 26110128 TI - Tumor-suppressor Genes, Cell Cycle Regulatory Checkpoints, and the Skin. AB - The cell cycle (or cell-division cycle) is a series of events that take place in a cell, leading to its division and duplication. Cell division requires cell cycle checkpoints (CPs) that are used by the cell to both monitor and regulate the progress of the cell cycle. Tumor-suppressor genes (TSGs) or antioncogenes are genes that protect the cell from a single event or multiple events leading to cancer. When these genes mutate, the cell can progress to a cancerous state. We aimed to perform a narrative review, based on evaluation of the manuscripts published in MEDLINE-indexed journals using the Medical Subject Headings (MeSH) terms "tumor suppressor's genes," "skin," and "cell cycle regulatory checkpoints." We aimed to review the current concepts regarding TSGs, CPs, and their association with selected cutaneous diseases. It is important to take into account that in some cell cycle disorders, multiple genetic abnormalities may occur simultaneously. These abnormalities may include intrachromosomal insertions, unbalanced division products, recombinations, reciprocal deletions, and/or duplication of the inserted segments or genes; thus, these presentations usually involve several genes. Due to their complexity, these disorders require specialized expertise for proper diagnosis, counseling, personal and family support, and genetic studies. Alterations in the TSGs or CP regulators may occur in many benign skin proliferative disorders, neoplastic processes, and genodermatoses. PMID- 26110129 TI - Gastroesophageal Reflux Symptoms After Laparoscopic Sleeve Gastrectomy for Morbid Obesity. The Importance of Preoperative Evaluation and Selection. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is prevalent in morbidly obese patients, and its severity appears to correlate with body mass index (BMI). AIM: The aim of this study is to investigate the status of GERD after laparoscopic sleeve gastrectomy (LSG). MATERIALS AND METHODS: A prospectively maintained database of all the patients who underwent LSG from February 2008 to May 2011 was reviewed. RESULTS: A total of 131 patients were included. The mean age and the BMI of the patients were 49.4 years and 48.9 kg/m(2), respectively. Prior to LSG, subjective reflux symptoms were reported in 67 (51%) patients. Anatomical presence of hiatal hernia was endoscopically confirmed in 35 (52%) patients who reported reflux symptoms prior to LSG. All these patients underwent simultaneous hiatal hernia repair during their LSG. The overall mean operative time was 106 min (range: 48-212 min). There were no intra- and 30-day postoperative complications. Out of the 67 preoperative reflux patients, 32 (47.7%) reported resolution of their symptoms after the operation, 20 (29.9%) reported clinical improvement, and 12 (22.2%) reported unchanged or persistent symptoms. Three patients developed new-onset reflux symptoms, which were easily controlled with proton pump inhibitors. No patient required conversion to gastric bypass or duodenal switch because of the severe reflux symptoms. At 18 months, the follow up data were available in 60% of the total patients. CONCLUSION: LSG results in resolution or improvement of the reflux symptoms in a large number of patients. Proper patient selection, complete preoperative evaluation to identify the presence of hiatal hernia, and good surgical techniques are the keys to achieve optimal outcomes. PMID- 26110130 TI - Status of Superoxide Dismutase in Transfusion Dependent Thalassaemia. AB - BACKGROUND: Thalassemia is a collection of genetic impairments in beta and alpha genes causing various states of anemia. Severe types of the disease need lifelong transfusions, leading to oxidant-antioxidant disturbance due to massive iron deposits. AIMS: The aim of this study was to assess the antioxidant enzyme Superoxide Dismutase (SOD) and ferritin levels of thalassemia major patients in a peripheral health facility. MATERIALS AND METHODS: Two hundred and nine probands were recruited and performed laboratory experiments for SOD and Ferritin levels. Chelation administration and clinical score were taken from interviewing the family and from medical report data. RESULTS: The study showed that SOD intensity was lower (162.41 u/ml) compared to the normal cutoff point (P = 0.001), while the mean of Ferritin levels was ten times over the normal value (4226,67 ng/dl). Observations also reported that chelation medicine was not administrated properly. CONCLUSIONS: The data indicates that thalassemic patients have oxidant antioxidant uproar due to oxidative stress. Monitored chelating administration, selective antioxidant, and a well-balanced diet may prevent oxidative injury. PMID- 26110131 TI - Telephonic Consultation and follow-up in Diabetics: Impact on Metabolic Profile, Quality of Life, and Patient Compliance. AB - BACKGROUND: Diabetes mellitus (DM), being a long-term condition, requires consistent blood glucose monitoring and adjustment of doses of the antidiabetic drugs and insulin. Telehealth is an emerging field that can have a positive impact on the management of this disease. AIM: The aim was to study the impact of the frequency of consultation and follow-up on telephone of diagnosed follow-up patients of DM on glycemic and metabolic profiles, the patients' compliance, and their quality of life (QoL), and to compare the effectiveness of different modes of follow-up. MATERIALS AND METHODS: One hundred twenty patients were enrolled from the outpatient department (OPD) including both type 1 and type 2 DM patients who had already been diagnosed and were on treatment. They were randomly assigned to one of three groups, each consisting of 40 subjects, according to the mode of follow-up: A (rare, i.e., less frequent outpatient visits), B (moderate, i.e., more frequent outpatient visits), and C (frequent, i.e., more frequent outpatient visits with weekly telephonic consultation). Metabolic profiles and the QoL were monitored. The patients' compliance with and adherence to the treatment, and dietary and exercise advice were assessed. RESULTS: The patients' compliance with and adherence to the treatment was higher in group C, followed by groups B and A. There was a net decrease in adverse events, with an increase in the frequency of follow-up. Changes in glycated hemoglobin (HbA1c) suggested a positive impact of weekly telephonic consultation. The lipid profile was also positively affected, with maximum improvement being in high-density lipoproteins (HDLs) and triglycerides. There was an improvement in the QoL domains pertaining to physical health and endurance in patients with higher frequency of follow-ups. There was no effect on emotional or mental health. There was an overall deterioration of the financial domain, being most marked in group B. The treatment satisfaction questionnaire showed better results in the telephone intervention group. CONCLUSION: Telephonic consultation can be a useful measure to improve the follow up and management of patients with DM. PMID- 26110132 TI - Long-term Results of Transcatheter Closure of Patent Ductus Arteriosus in Adolescents and Adults with Amplatzer Duct Occluder. AB - BACKGROUND: Transcatheter closure of patent ductus arteriosus (PDA) with the Amplatzer ductal occluder (ADO) has become a standard procedure in most pediatric patients. However, experience in adults and adolescents is limited. Our experience of transcatheter closure of PDA with ADO in adolescents and adults is presented in this study. AIMS: The aim of this study was to investigate long-term outcomes of transcatheter closure of PDA in adolescents and adults with ADO. MATERIALS AND METHODS: In this study, 69 patients (52 females and 17 males) with PDA underwent transcatheter closure between May 2004 and October 2012. The procedure was performed under fluoroscopic guidance. Chest radiograph, electrocardiogram, transthoracic echocardiography (TTE), and clinical assessment of the patients were conducted before the procedure. Clinical and echocardiographic follow-ups were performed on day 1 of the 1st month, 6(th) month, and 12(th) month and then yearly after the procedure. RESULTS: The mean and standard deviation age of the patients was 18.08 +/- 7.25 years (ranging 10 38 years). The mean and standard deviation angiographic diameter of PDA was 7.78 +/- 2.78 mm. The mean and standard deviation size of the implanted device was 9.3 +/- 2.9. The mean and standard deviation average pulmonary artery pressure was 32.1 +/- 14.2 mmHg. The mean pulmonary flow/systemic flow ratio was 2.2 +/- 0.61. The devices were successfully implanted in all patients (100%). Immediately after device implantation, 47 patients had residual shunts. The residual shunts disappeared in all the patients, except for one that lingered until 24 h after the procedure. No severe complication occurred at the immediate and long-term follow-ups. CONCLUSIONS: The long-term results suggested that transcatheter closure of PDA with ADO is a safe and effective treatment for adolescents and adults with PDA. Low complication rates and short hospital stays make this procedure the treatment of choice in most cardiovascular centers worldwide. PMID- 26110133 TI - Adrenal Mass in Patients who Underwent Abdominal Computed Tomography Examination. AB - BACKGROUND: Adrenal masses are usually discovered incidentally (IAM) during abdominal computed tomography (CT). AIMS: We aimed to describe the prevalence, management, and outcome of incidentally discovered adrenal mass on radiological investigation. MATERIALS AND METHODS: A retrospective analysis was conducted to look for IAM identified by abdominal CT performed for other reasons between 2004 and 2008 and were followed for 4 years. IAM patients with known malignancy or clinically evident adrenal disease or overt disease originally missed due to insufficient clinical examination were excluded. RESULTS: A total of 13,115 patients underwent abdominal CT, of which 136 were identified with adrenal mass (69 males and 67 females). Overall, 84 patients had benign IAM and six had primary adrenal carcinoma (all had tumor size >=4 cm and five were males). Hormonal evaluation was performed in 80 cases, which revealed hypersecretion in 10 cases (six had Conn's syndrome and four had pheochromocytoma). Males had higher frequency of right-sided IAMs; whereas, left-sided IAM swere more common among females (P = 0.02). Seven patients underwent surgery and all were males (one Conn's syndrome, one pheochromocytoma, three primary adrenal adenocarcinoma, one benign nonfunctional adenoma, and one metastatic tumor). Only one patient died due to brain metastasis. CONCLUSION: The overall prevalence of adrenal incidentaloma is 1% in Qatar. Unfortunately, hormonal evaluation, surgical referral, and follow-up are not appropriate in this study. Moreover, screening of IAM warrants more attention to rule out malignancy. This work could be of value as a local auditing for the current management. PMID- 26110134 TI - Cognitive Function and Control of Type 2 Diabetes Mellitus in Young Adults. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) has been associated with impairment of cognitive function. Studies show a strong negative correlation between the levels of glycosylated hemoglobin and cognitive function in adult patients above the mean age of 60 years. In healthy adults, age-related cognitive impairment is mostly reported after the age of 60 years, hence the decline in cognitive function can be a part of normal aging without diabetes. Since the majority of patients with diabetes are between the ages of 40 and 59 years, it is crucial to ascertain whether the levels of glycosylated hemoglobin negatively correlate with the levels of cognitive function scores in adult patients of age 60 years or younger, similar to the way it correlates in patients older than 60 years of age, or not. AIMS: We observed the relationship between the levels of glycosylated hemoglobin and the levels of cognitive function in patients of age 60 years or younger with T2DM. MATERIALS AND METHODS: Eighty-two patients with T2DM underwent cognitive assessment testing by using a Modified Mini-Mental State Examination (3MS), and their cognitive function scores were correlated with their glycosylated hemoglobin levels, durations of diabetes, and levels of education. RESULTS: Cognitive impairment was observed in 19.5% of the studied patients. We found a weakly negative relationship between the glycosylated hemoglobin level and cognitive function score (r = -0.292), a moderately negative relationship between the duration of diabetes and cognitive function score (r = -0.303), and a weakly positive relationship between the level of education and cognitive function score (r = 0.277). CONCLUSION: Cognitive impairment affects one-fifth of the patients of age 60 years or younger with T2DM. It is weakly negatively related to the glycosylated hemoglobin level, moderately negatively related to the duration of diabetes, and weakly positively related to the level of education. PMID- 26110135 TI - Down with the Flu: Hyponatremia in a patient with influenza. AB - CONTEXT: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a common cause of hyponatremia. Although it has been associated with different pulmonary infections, there have been only few case reports describing the association of SIADH with influenza. CASE REPORT: We report a case of SIADH in a patient with influenza who was successfully treated with fluid restriction. CONCLUSION: It is essential for clinicians to be aware of the association between influenza and SIADH. PMID- 26110136 TI - Computed Tomography in Diagnosis of Admantinoma. AB - CONTEXT: Admantinoma is second most common benign odontogenic tumor which clinically appears as an aggressive odontogenic tumor, often asymptomatic and slow growing, associated with symptoms such as swelling, dental malocclusion, pain, and paresthesia of the affected area. The radiographic appearance may vary from unilocular to multilocular radiolucencies, imparting a characteristic honey comb, soap bubble appearance or may resemble a caricature of spider. CASE REPORT: This report highlights the importance of conventional and advanced imaging in the diagnosis of large and invasive lesions. Patient reported with complaint of swelling in jaw, which progressively increased; and was found to be bony hard, both intra- and extraorally. Radiographs revealed large multilocular radiolucency on left body and ramus of mandible with soap bubble pattern and knife edged root resorption. Computed tomographic examination evaluated the extent of the lesion, internal structure, and relation to adjacent structures; further a reconstructed image was obtained to evaluate extent of destruction in three dimensions. CONCLUSION: Computed tomography has an important role in the diagnosis and treatment planning is imperative as it is superior in revealing the cortical destruction and extension into the neighboring soft tissues than conventional radiography. PMID- 26110137 TI - Pulmonary Tuberculosis in a Patient with Cystic Fibrosis. AB - CONTEXT: Mycobacterium tuberculosis (MTB) infection is rarely seen in cystic fibrosis (CF) patients. CASE REPORT: We report a 24-year-old CF patient with fever, cough, hemoptysis, and weight loss of 1week duration prior to admission. Past sputum cultures grew methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The patient was treated with broad spectrum antibiotics based on previous culture data, but failed to improve. Chest radiograph and computed tomography (CT) chest revealed chronic collapse of the anterior subsegment of right upper lobe and multiple bilateral cavitary lesions which were worse compared to prior films. MTB was suspected and was confirmed by positive acid-fast bacilli (AFB) smears and cultures. After receiving first-line antituberculous drugs, the patient's condition markedly improved. CONCLUSION: MTB is an infrequent finding, but considered a potential pathogen in CF patients, and may lead to serious pulmonary complications if there is a delay in diagnosis and treatment. PMID- 26110138 TI - Infection Control in a Far Far Away Galaxy: New and Alternative Learning Tool from Popular Culture to Improve the Antimicrobial Stewardship. PMID- 26110139 TI - Burmese Community's Beliefs on Inconsolable Crying. PMID- 26110140 TI - Metallothionein Lower Under-Expression in Benign Tumors than That in Malignant Tumors: Systematic Review Article and Meta-Analysis. AB - Metallothionein (MT) manifests varying expression levels in carcinomas, and they may be considered as valuable cell cancerization biomarkers for diagnosis of patients with cancers. A meta-analysis was conducted to evaluate comprehensively the MT expression difference in various benign tumors and malignant tumors, which compared the high with low MT expression levels in patients of the available studies. Finally, a total of 13 studies dealing with various tumors were involved for this meta-analysis. The results indicated that lower expression of MT in various benign tumors tissue than that in corresponding malignant tumors with the pooled OR of 0.52 (95 % CI 0.18-1.47, P < 0.001). In conclusion, MT expression difference is associated with tumor various stages in tumor patients and could be a useful clinical criteria of distinguishing benign tumors and malignant tumors for those patients. PMID- 26110141 TI - Prevalence of Hepatitis B Co-Infection among HIV Positive Patients: Narrative Review Article. AB - Hepatitis B virus (HBV) is the most prevalent viral infection and is among the leading causes of human liver diseases. Nearly 360 millions of people are world widely infected with prolonged forms of hepatitis B including active and inactive chronic forms. Chronic hepatitis B (CHB) is associated with cirrhosis and hepatocellular carcinoma (HCC) in patients suffering from congenital and/or acquired immunodeficiency and also following immunosuppressive therapy. The target cell of human acquired immunodeficiency virus (HIV) is CD4 positive T cells. These cells play central role(s) in both cellular and humoral immunity so that the HIV attack of CD4 positive T cells causes suppression of both cell mediated and humoral immune responses. One of the frequent complications in HIV positive patients is HBV co-infection and as a result, the co-transmission of these viral diseases is common. Due to the paramount importance of the co infection of HBV and HIV, it is noteworthy to investigate the prevalence of hepatitis B in these patients for planning of an effective therapeutic strategy. Based on these considerations, the main aim of this review article was to collect and analyze the recent and relevant studies regarding the prevalence rate of hepatitis B co-infection among HIV positive patients world widely. PMID- 26110142 TI - Developing a Clinical Diabetes Guideline in Diabetes Research Network in Iran. AB - Development of evidence-based clinical guidelines to raising standards of medical care in diabetes is a core element of coping with the global diabetes epidemic. The purpose of this study was to develop a systematic clinical diabetes guideline from the latest scientific evidences and also to localize its recommendations according to regional and cultural needs of our society. Searches were conducted using NICE, SIGN, WDPCP, IDF, JDC, ADA, AACE, ICSI, CDA, AMDA, IDC, NyDoH guidelines which were examined and criticized and scored using Agree method. Guidelines which got higher score in some important areas of Agree scale including: rigor of development, clarity and comprehensiveness of the recommendations and applicability, especially in the climatic conditions of our country were selected. The existing recommendations were extracted by committee members and supporting evidences of each recommendation were determined based on the sources listed in the clinical guideline. Recommendations grading were classified from grade A to D based on the quality of their supporting evidences (BEL1-5). This guideline covered all areas related to diabetes including screening and diagnosis, lifestyle modification and patient education, management, complications and hypoglycemia. Regarding capacities of this guideline and lack of comprehensive and updated guidelines in our country and region, it is suggested that designing a pilot study to implement this Learner centered guideline and finding its weaknesses can lead to patient care improvement and also propel us towards our goal to design a comprehensive guideline in compliance with regional and national needs in Middle East. PMID- 26110143 TI - Reducing Visit-To-Visit Variability in Systolic Blood Pressure for Improving the Progression of Carotid Atherosclerosis and Endothelial Dysfunction in Patients with Hypertension Management. AB - BACKGROUND: Visit-to-visit variability (VVV) in blood pressure (BP) creates challenges to hypertension control and was independent associated with increased all-cause mortality in hypertensive patients. The major goal of the present study was to investigate the association of VVV in systolic (S)BP with progression of carotid atherosclerosis and en-dothelial dysfunction in on-treated hypertensive patients. METHODS: Overall, 356 hypertensive patients were enrolled and completed the trial. Clinic BP was measured at baseline and at 3 monthly thereafter. Carotid artery ultrasound and endothelial function were evaluated at baseline and annually follow-up visit. VVV in BP was assessed by standard deviation (SD) and coefficient of variation (CV) of serial follow-up BP measurements. The patients were divided into low, middle, and high group by tertile of SD in SBP. RESULTS: Decrease percentage of maximum intima-media thickness (IMT) and stiffness index beta and increase percentage of brachial flow-mediated dilation (FMD) and nitric oxide (NO) in lower groups were significant greater than in higher groups (P < 0.05). Change percentage of stiffness index beta and endothelin-1 positively, and change percentage of FMD and NO negatively correlated with SD, CV, maximum, and delta of SBP (P < 0.05). SD and CV of SBP were risk factors for change percentage of IMT, stiffness index beta, FMD, NO, and endothelin-1 independently of other influential factors, such as age, and mean SBP. CONCLUSION: Excessive VVV in SBP maybe increase carotid atherosclerosis and impair endothelial function in on treated hypertensive patients. Reducing VVV in SBP is benefit for patients with hypertension management. PMID- 26110144 TI - Socioeconomic Inequalities in Non-Communicable Diseases and Self Assessed Health in Turkey. AB - BACKGROUND: Inequities in health need to be monitored and necessary actions should be taken to reduce them. This study aimed to determine the socioeconomic distribution of self-reported chronic diseases and self-assessed health (SAH) in Turkey and try to evaluate the determinants of such inequalities in terms of their contributions. METHODS: Cross-sectional data from the Turkish Health Survey conducted during year 2008, covering 14,655 adults aged 15 or older were analyzed for the first time to assess socioeconomic inequalities in chronic disease and suboptimal SAH prevalence by calculating concentration index (CI), which ranges from -1 to +1 (concentration of disease among lower and higher socioeconomic groups) and the relative index of inequality (RII), reflecting the prevalence ratio between the two extremes of wealth. RESULTS: Several diseases and sub optimal SAH were more concentrated among those with lower incomes. The concentration indices of chronic obstructive pulmonary disease (COPD), arthritis, chronic bronchitis, migraine and poor SAH were -0.180 (95% CI = -0.241,-0.111), 0.126 (95% CI = -0.148,-0.105),-0.118 (95%CI = -0.149,-0.079), -0.248(95%CI = ( 0.278,-0.219) respectively. Of all chronic diseases, COPD demonstrated the highest relative inequality with a RII value of 2.51 (95%CI: 1.57-4.01). Income was the major contributor to inequality in occurrence of COPD (88.2%), migraine (80.4%) and arthritis (77.7%). CONCLUSION: The findings indicate that majority of chronic diseases were more concentrated among less wealthy individuals in Turkey. Wealth and education had the largest contributions to observed inequalities. These inequalities need to be explicitly addressed and vulnerable subgroups should be targeted to reduce these socioeconomic disparities. PMID- 26110145 TI - Gene-Gene Interactions among Pparalpha/delta/gamma Polymorphisms for Apolipoprotein (Apo) A-I/Apob Ratio in Chinese Han Population. AB - BACKGROUND: The peroxisome proliferator-activated receptors (PPARs) -alpha, delta/beta and -gamma are the ligand-activated transcription factors involved in the regulation of fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation and atherosclerosis, etc. We investigated the associations of 10 single-nucleotide polymorphisms (SNPs) in PPARs with apolipoprotein (apo) A-I/apoB ratio in Chinese Han population. METHODS: Overall, 630 subjects (212 males, 418 females) were randomly selected from the Prevention of Metabolic Syndrome and Multiple Metabolic Disorders in Jiangsu Province of China Study Cohort. Population analyzed was as the general population which involved healthy people and individuals with disorders of apoA-I or apoB. 10 SNPs (rs1800206, rs135539, rs4253778, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were genotyped. Mean difference (Difference) and 95% confident interval (95%CI) were calculated. RESULTS: After covariates adjustment, rs1800206-V allele (LV+VV) and rs3856806-T allele (CT+TT) were significantly associated with a decreased apoA-I/apoB ratio than those wild type carriers, Difference (95%CI) were -1.29 (-1.96-0.62) and -0.8 (-1.42~-0.17), respectively. Rs4253778-C allele was significantly associated with an increased apoA-I/apoB ratio compared to the wild type carriers (GG), Difference (95%CI) was 0.76 (0.04-1.48). Generalized multifactor dimensionality reduction analysis showed that three-to-eight-locus models were significant with apoA-I/apoB ratio (P<0.05). We chose the seven-locus model (P=0.0010) as the best GMDR model (cross validation consistency was 7/10 and testing accuracy was 62.97%). CONCLUSION: Our data provided the evidence that PPARs polymorphisms might be involved in regulation of apoA-I/apoB ratio in independently and/or in an interactive manner. PMID- 26110146 TI - The Characteristics of Road Traffic Fatalities in Kazakhstan's Semey Region, 2006 2010: A Descriptive Retrospective Study. AB - BACKGROUND: Kazakhstan, a developing middle-income country, has the highest road traffic collision (RTC) mortality in the European Region. The aims of this study were to determine main characteristics of road traffic fatalities in Semey region, Kazakhstan and to compare findings with National data and middle-income European countries. METHODS: This descriptive surveillance study assesses RTC mortality rates and epidemiology in the Semey Region of East Kazakhstan Oblast. Data of all 318 road traffic fatalities form the Semey Regional Center for Forensic Medicine were analyzed for the 5-year period of January 1, 2006 through December 31, 2010. RESULTS: Over the study period, the average road traffic mortality in the Semey Region was 12.1 per 100,000 population with downward trend by 35.1% (p=0.002). The victims mean age was 37.1 (SD=17) years. Males predominated at 74.5%. Vehicle fatality was the most common mode of fatality at 61.3%. The majority of collisions, 53.1%, occurred on highways. Most victims, 67.3%, have died at the scene of collision; in 67.3% of fatalities, autopsies identified multiple injuries as cause of death. The high number of fatal collisions took place in "no snow" season (P<0.001), with an overall 5-years downward dynamic. CONCLUSION: High proportion of males, pedestrians and car occupants among road traffic fatalities; high proportion of death on scene in case of highway collisions are specifics for Semey region, Kazakhstan. These findings can be used to formulate preventive strategies to reduce fatalities and to improve the medical care system for road traffic fatalities. PMID- 26110147 TI - Utilization of Rural Primary Care Physicians' Visit Services for Diabetes Management of Public Health in Southwestern China: A Cross-Sectional Study from Patients' View. AB - BACKGROUND: Primary care physicians' visit services for diabetes management are now widely delivered in China's rural public health care. Current studies mainly focus on supply but risk factors from patients' view have not been previously explored. This study aims to present the utilization of rural primary care physicians' visit services for diabetes management in the last 12 months in southwestern China, and to explore risk factors from patients' view. METHODS: This cross sectional study selected six towns at random and all 385 diabetics managed by primary care physicians were potential participants. Basing on the inclusion and exclusion criteria, 374 diabetics were taken as valid subjects and their survey responses formed the data resource of analyses. Descriptive indicators, chi2 contingency table analyses and Logistic regression were used. RESULTS: 54.8% respondents reported the utilization of visit services. According to the multivariate analysis, the positive factors mainly associated with utilization of visit services include disease duration (OR=1.654), use of diabetic drugs (OR=1.869), consulting diabetes care knowledge (OR=1.602), recognition of diabetic complications (OR=1.662), needs of visit services (OR=2.338). CONCLUSION: The utilization of rural primary care physicians' visit services still remains unsatisfactory. Mass rural health policy awareness, support, and emphasis are in urgent need and possible risk factors including disease duration, use of diabetic drugs, consulting diabetes care knowledge, recognition of diabetic complications and needs of visit services should be taken into account when making rural health policy of visit services for diabetes management in China and many other low- and middle-income countries. PMID- 26110148 TI - The 10-year Trend of TB Rate in West Azerbaijan Province, Iran from 2001 to 2010. AB - BACKGROUND: The present study aimed to explore some risk factors affected the mean of the number of tuberculosis (TB) in West Azerbaijan Province, Iran between 2001 and 2010. METHODS: Our time series study analyzed the data of 2,560 TB patients as registered with TB Patients Care System in West Azerbaijan Province from early 2001 to 2010. A checklist was prepared for collecting the data and they were then analyzed in SPSS V.16 software. RESULTS: The percentage of male and percentage of female were close to each other (52.2% against 47.8%, respectively). A significant increasing trend of TB rate was found over the years of 2001and 2010 with a pick at 2008 (P<0.001). A Poisson log-linear analysis showed that the most important risk factor of the trend of rate was the level of education so that people with primary level or with illiterate level had a statistically significant TB rate of 5.21 (4.66-5.81), adjusted for years. The next risk factor was type of TB and place of residency, i.e., pulmonary TB cases had higher rate than External pulmonary TB cases (RR=1.67; (1.54-1.80). The last factor with the lowest risk was BCG with RR=1.29 (1.20-1.40) for people who received BCG compared to the people who had not received it. CONCLUSION: Although the co morbidity of AIDS and TB was not a major problem, it is necessary that special attention be paid to the way of implementing the TB control program based on the demographic risk factors of the study population. PMID- 26110149 TI - Rate of Pressure Ulcers in Intensive Units and General Wards of Iranian Hospitals and Methods for Their Detection. AB - BACKGROUND: This study aimed to estimate the rate of pressure ulcers in intensive care units (ICUs) and medical and surgical wards of Iranian hospitals and compare the performance of methods of medical record review as well as direct observation for their detection. METHODS: The research team visited 308 patients in medical and surgical wards of hospitals affiliated with Tehran University of Medical Sciences and a further 90 patients in their ICUs between March 2009 and April 2010. In addition 310 patient records were randomly selected from patients discharged from the ICUs between March 2009 and April 2010. And a further 600 patient records were randomly selected from the patients that were discharged from medical and surgical wards between March 2010 and April 2011. These 910 selected records were retrospectively reviewed to identify pressure ulcers. Data were collected by a structured checklist. RESULTS: In ICUs 24 of 90 patients (26.7%, 95% CI: 17.56 to 35.84) that were directly observed and 59 of 310 patients (19.0%, 95% CI: 14.63 to 23.37) that were studied by retrospective review of medical records had pressure ulcers. In medical and surgical wards, 5 of 308 patients (1.6%, 95% CI: 0.20 to 3.00) that were directly observed had pressure ulcers, but no pressure ulcer was detected by review of 600 medical records. CONCLUSION: Pressure ulcers are significantly more frequent in ICUs than in medical and surgical wards and a significant proportion of pressure ulcers are not reported. PMID- 26110150 TI - Occupational Exposure to Mercury: Air Exposure Assessment and Biological Monitoring based on Dispersive Ionic Liquid-Liquid Microextraction. AB - BACKGROUND: Exposure to mercury (Hg) as a heavy metal can cause health effects. The objective of this study was to assess occupational exposure to Hg in a chlor alkali petrochemical industry in Iran by determining of Hg concentrations in air, blood and urine samples. METHODS: The study was performed on 50 exposed subjects and 50 unexposed controls. Air samples were collected in the breathing zone of exposed subjects, using hopcalite sorbents. Analysis was performed using a cold vapor atomic absorption spectrophotometer (CV-AAS) according to NIOSH analytical method 6009. For all participants, blood and urine samples were collected and then transferred into sterile glass tubes. After micro-extraction with ionic liquid and back extraction with nitric acid, Hg concentrations in blood and urine samples were determined by CV-AAS. RESULTS: The mean concentration of air Hg was 0.042+/- 0.003 mg/m(3). The mean concentrations of Hg in blood and urine samples of exposed subjects were significantly higher than unexposed controls (22.41+/- 12.58 versus 1.19+/- 0.95 MUg/l and 30.61+/- 10.86 versus 1.99+/- 1.34 MUg/g creatinine, respectively). Correlation of air Hg with blood Hg, urine Hg and blood Hg-urine Hg ratio were significant statistically (P< 0.05). CONCLUSIONS: The values of Hg in blood and urine samples of chlor-alkali workers were considerably high. Correlation coefficients showed that blood Hg and blood Hg urine Hg ratio are better indicators than urine Hg for assessing occupationally exposed workers in terms of current exposure assessment. PMID- 26110151 TI - Factors Affecting the Survival of Patients with Gastric Cancer Undergone Surgery at Iran Cancer Institute: Univariate and Multivariate Analyses. AB - BACKGROUND: Gastric cancer is the most prevalent cancer among men and the third most prevalent cancer among women in Iran. Its most important reason for death is its belated diagnosis at the advanced stages of the disease. Various factors can be effective on the survival of these patients after surgery, which are the major concern in this study. METHODS: Data from 330 patients with Gastric cancer who had undergone surgery at Iran Cancer Institute from 1995 to 1999 were analyzed. The Survival Time of patients was determined after surgery and the effect of individual and demographic; clinical and diagnostic; and treatment and post surgical factors on patients' survival was studied. For data analysis, Kaplan- Meier, Log-Rank test and Proportional Hazards Model were used. RESULTS: The median of survival time was 16.33 months. The one-year, three-year, and five-year survival rates were, 0.66, 0.31, and 0.21. Based on univariate analysis results of age(P<0.001), metastases(P=0.012), disease stage(P=0.016), and number of renewed treatments(P<0.001), as well as multivariate analysis which was used to investigate the simultaneous effect of influencing variables on patients' survival showed that age(61-70:HR=1.40,>70:HR=2.08), marital status(HR=0.39), number of renewed treatments(1:HR=0.54, 2:HR=0.30, 3:HR=0.22), relapse(HR=1.51), type of gastrectomy (Subtotal: HR=1.12, Distal:HR=0.49, Partial:HR=0.94, Proximal:HR=0.52), liver metastases (HR=1.79), distance metastases(HR=1.84), and disease stage(II:HR=1.28, III:HR=2.12, IV:HR=1.90) variables had a significant effect on patients' survival. CONCLUSION: Patients who call on doctors in early stages of disease will have a higher survival rate due to early diagnosis whereas disease progression will increase the risk and will decrease the survival. Identifying factors affecting patients' survival and improving diagnostic methods can prevent disease progression and increase survival rate. PMID- 26110152 TI - Electronic Health in Perspective of Healthcare Managers: A Qualitative Study in South of Iran. AB - BACKGROUND: The important role of electronic health as well as importance of health care systems awareness and readiness may lead to develop the essential infrastructures for electronic health especially in developing countries. This study aims to investigate goals, gains, applications, challenges and other important issues related to success performance of electronic health. METHOD: This research proposed a grounded theory in a qualitative design and a purposive sampling was used to select participants which consisted of 28 hospital managers and staff field managers working in deputy of health and curative affairs of Medical Science Universities in south of Iran. Semi structured interviews were conducted using a topic guide and intended themes derived from the results using Max QDA software during five steps. RESULTS: Nine themes through interviewees" viewpoints were made up as followed: Electronic health definition, necessity and importance of electronic health, electronic health advantages, relationship between electronic health and internet, physicians" opposition to electronic health, prerequisites for electronic health, solutions for applying electronic health plan, factors affecting electronic health acceptance in society and electronic health system challenges. CONCLUSION: It seems that there are good circumstances in the south medical universities about settlement and implementations of electronic health and their managers are aware of its advantages, importance and necessities. The present findings implicate that these organizations should consider the user friendly and probable resistances of the present clients, in this regard it is suggested that the used technology must be accepted by users, having standard base, inexpensive and simple enough while less vulnerable in response to changes. PMID- 26110153 TI - Analysis of MTHFR Gene C.677C>T and C.1298A>C Polymorphisms in Iranian Patients with Non-Syndromic Cleft Lip and Palate. AB - BACKGROUND: Non-syndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital abnormalities of the orofacial region with a multifactorial etiology. The present study aimed to investigate the association of two common polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene (c.677C>T and c.1298A>C) with the occurrence of nsCL/P in an Iranian population. METHODS: Forty-five nsCL/P patients, 43 mothers of patients, and 101 unrelated controls participated in the present study. Analysis of c.677C>T and c.1298A>C polymorphisms in MTHFR gene was conducted using polymerase chain reaction and restriction enzyme digestions. RESULTS: There was no statistical difference in genotype and allele frequencies for c.677C>T variants between patients or their mothers and the control group. However, differences in the frequencies of alleles and genotypes of c.1298A>C polymorphism were statistically significant between patients and control group (P=0.01 for alleles and P=0.005 for genotypes). The odds ratios (OR) for the CC versus AA homozygotes were 6.1 (95% CI 1.8-20.5) and 4.2 (95% CI 1.1-15.4), in patients and mothers, respectively. CONCLUSIONS: We found no association between genetic polymorphism of MTHFR c.677C>T and the risk of nsCL/P in the population studied. Yet the results suggested that c.1298A>C polymorphism of MTHFR gene may be a risk factor for the occurrence of nsCL/P in the Iranian population. PMID- 26110154 TI - Towards a Holistic Approach to Healthy Diet: Evidence from Iranian Health Perception Study. AB - BACKGROUND: The aim of present study was to investigate the relation between the perception of population on healthy diet and lifestyle related behaviors. METHODS: As part of national study on Iranian Health Perception, a cross sectional study was carried out in Iran, 2010. A multistage sampling approach was applied to include a representative sample of population aged between 18 and 65 in the study. To collect data a designed questionnaire was administered. RESULTS: In all 27,883 individuals (50.4% women, 48.8% men) were included in the study. The mean age of participants was 34.6 years (SD = 12.8) and most were married (61%). The findings indicated that Iranian population often pay attention to healthy diet (39.5%), never smoke (74.9%), sometimes were doing exercise (29.5%), felt happy to some extent (39.5%), often care about themselves (47.1%) and rated their health as good (54.5%). Further analysis of the data showed that increased paying attention to healthy diet was associated with reduced smoking, more exercise, more self-care and happiness, and a better self-rated health status. CONCLUSION: The findings suggest that a healthy diet and other determinants of lifestyle are very integrated into each other. The efforts for changing any components of lifestyle can potentially change all individual related lifestyle behaviors. Indeed, one of effective strategies in fostering healthy diet is fostering other healthy lifestyles. This holistic approach might help decision makers to design appropriate interventions in order to influence diet behaviors of people. PMID- 26110155 TI - Genetic Diversity among Yersinia enterocolitica Isolated from Chicken and Fish in and around Coimbatore City, India. AB - BACKGROUND: Yersinia enterocolitica is rapidly emerging worldwide as an enteric pathogen and has become a major cause of diarrhea even in developed countries. The aim of this study was to characterize and genetic diversity analysis among Y. enterocolitica strains isolated from fish and chicken sources. METHODS: From 44 strains, 55% (24 strains) found to be positive for Y. enterocolitica by colony morphology, biochemical tests and 16S rRNA. We investigate the diversity of Y. enterocolitica by hemolytic activity, antimicrobial resistance, RAPD, ERIC and REP-PCRs PCR, profiling of outermembrane proteins and lipopolysaccarides. RESULTS: Forty one percent of the strains were found to be the producers of haemolysin at 37 degrees C but not at 28 degrees C. All the isolates were exhibiting multi-drug resistance and found sensitive to chloramphenicol, and resistant to ciprofloxacin and amoxicillin. Eight, eleven and twelve different genotypic patterns were observed in RAPD, ERIC and REP-PCRs respectively. Five isolates have produced high molecular weight protein (HMWP) with a molecular weight of 150 - 220 kDa. Mostly LPS produce identical profiles, 22 strains have produced smooth LPS, while 2 strains have produced the rough LPS pattern. CONCLUSION: Genotyping tools strongly confirm the co-existence wide genetic diversity among the strains tested. By using any or the combination of these molecular tools, epidemiological investigation on Y. enterocolitica could be elucidated effectively. These results showed that the REP-PCR is more informative and discriminative than other for analysis of Y. enterocolitica diversity. PMID- 26110156 TI - Unusual Occurrence of Pregnancy Tumor on the Tongue. PMID- 26110157 TI - Icariin Induced B16 Melanoma Tumor Cells Apoptosis, Suppressed Tumor Growth and Metastasis. PMID- 26110158 TI - Health-Related Quality of Life in Adolescents with Congenital Heart Disease: Importance of Parental Hope. PMID- 26110159 TI - Probable Etiology of Hypertension According To the Iranian Traditional Medicine. PMID- 26110160 TI - Near Misses and Their Importance for Improving Patient Safety. PMID- 26110161 TI - Agnosia in Canon: a Historical Issue. PMID- 26110162 TI - Only a Touch of the Flu? The Simultaneous Manifestation of Acute Necrotizing Encephalopathy in Two Consanguineous Patients. AB - This case report describes the simultaneous manifestation of acute necrotizing encephalopathy in 2 consanguineous patients after infection with influenza B based on the autosomal dominant missense mutation of the RANBP2-gene. Differential diagnosis of acute encephalopathy, clinical and radiological clues, and treatment strategies are outlined. PMID- 26110163 TI - Measles in Canada Between 2002 and 2013. AB - Background. In 1994, Canada committed to eliminate measles by the year 2000. This report presents the epidemiology of measles in Canada between 2002 and 2013 and its implications in sustaining measles elimination. Methods. Cases included individuals reported to the Canadian Measles and Rubella Surveillance System with confirmed measles. Results. In Canada, 1171 cases of measles were reported between 2002 and 2013 (incidence 0.29 cases per 100 000 population). The annual number of cases ranged from 6 to 752. The majority of cases were unvaccinated (63%) or had an unknown vaccination status (19%). The median age of cases was 14.4 years (range, <1 to 63 years) globally and 14 years when excluding the 2011 outbreak in Quebec where 68% of the 678 cases were 10 to 19 years old. With the exclusion of this outbreak, the incidence was highest in infants (1.0 per 100 000), lower but fairly similar between 1 and 19 years of age (0.2 to 0.4 per 100 000), and there was a substantial decline between 20 and 39 years of age (0.1 per 100 000). There was a significant trend towards a greater annual number of importations over the period. Although importations resulted in no transmission sustained for >=12 months, 5 chains of transmission had >30 cases. The effective reproductive number between 2002 and 2013 was estimated at 0.86 (95% confidence interval, .81-.92). Conclusions. Canada has maintained elimination between 2002 and 2013, but additional efforts are needed to reduce the proportion of unimmunized individuals and respond to importation events. PMID- 26110164 TI - Metabolic Signature Profiling as a Diagnostic and Prognostic Tool in Pediatric Plasmodium falciparum Malaria. AB - Background. Accuracy in malaria diagnosis and staging is vital to reduce mortality and post infectious sequelae. In this study, we present a metabolomics approach to diagnostic staging of malaria infection, specifically Plasmodium falciparum infection in children. Methods. A group of 421 patients between 6 months and 6 years of age with mild and severe states of malaria with age-matched controls were included in the study, 107, 192, and 122, individuals, respectively. A multivariate design was used as basis for representative selection of 20 patients in each category. Patient plasma was subjected to gas chromatography-mass spectrometry analysis, and a full metabolite profile was produced from each patient. In addition, a proof-of-concept model was tested in a Plasmodium berghei in vivo model where metabolic profiles were discernible over time of infection. Results. A 2-component principal component analysis revealed that the patients could be separated into disease categories according to metabolite profiles, independently of any clinical information. Furthermore, 2 subgroups could be identified in the mild malaria cohort who we believe represent patients with divergent prognoses. Conclusions. Metabolite signature profiling could be used both for decision support in disease staging and prognostication. PMID- 26110165 TI - Increased Regulatory T-Cell Percentage Contributes to Poor CD4(+) Lymphocytes Recovery: A 2-Year Prospective Study After Introduction of Antiretroviral Therapy. AB - Background. The primary aim of this study was to determine the impact of regulatory T cells (Tregs) percentage on immune recovery in human immunodeficiency virus (HIV)-infected patients after antiretroviral therapy introduction. Methods. A 2-year prospective study was conducted in HIV-1 chronically infected naive patients with CD4 count <500 cells/mm(3). Regulatory T cells were identified as CD4(+)CD25(high)CD127(low) cells among CD4(+) lymphocytes. Effect of Treg percentage at inclusion on CD4 evolution overtime was analyzed using a mixed-effect Poisson regression for count data. Results. Fifty eight patients were included (median CD4 = 293/mm(3), median Treg percentage = 6.1%). Percentage of Treg at baseline and CD4 nadir were independently related to the evolution of CD4 absolute value according to time: (1) at any given nadir CD4 count, 1% increase of initial Treg was associated with a 1.9% lower CD4 absolute value at month 24; (2) at any given Treg percentage at baseline, 10 cell/mm(3) increase of CD4 nadir was associated with a 2.4% increase of CD4 at month 24; and (3) both effects did not attenuate with time. The effect of Treg at baseline on CD4 evolution was as low as the CD4 nadir was high. Conclusions. Regulatory T cell percentage at baseline is a strong independent prognostic factor of immune recovery, particularly among patients with low CD4 nadir. PMID- 26110166 TI - An Infectious Diseases Physician-Led Antimicrobial Stewardship Program at a Small Community Hospital Associated With Improved Susceptibility Patterns and Cost Savings After the First Year. AB - The importance of antimicrobial stewardship is increasingly recognized, yet data from community hospitals are limited. Despite an initially low acceptance rate, an Infectious Diseases physician-led program at a 70-bed rural hospital was associated with a 42% decrease in anti-infective expenditures and susceptibility improvement in Pseudomonas aeruginosa over 3 years. PMID- 26110167 TI - Antiretroviral Effects on Host Lipoproteins Are Associated With Changes in Hepatitis C Virus (HCV) RNA Levels in Human Immunodeficiency Virus/HCV Coinfected Individuals. AB - We evaluated the impact of antiretroviral-induced dyslipidemia on hepatitis C virus (HCV) biogenesis in human immunodeficiency virus (HIV)/HCV coinfected patients. This study used serum samples from antiretroviral-naive HIV/HCV patients initiating their first regimen as part of AIDS Clinical Trials Group study protocols (A5142, A5202). Initiation of antiretrovirals increased most lipoproteins and apolipoproteins. In the multivariable model, changes in apolipoproteins were associated with changes in log10 HCV RNA from baseline to week-24 of therapy. Off-target lipogenic changes need to be considered in the context of liver and other metabolic disease in HIV/HCV patients. PMID- 26110168 TI - Limitation of the Benefit of Amphotericin-Flucytosine Combination Therapy in Patients With Lower Conscious Level: An Ecological Fallacy? PMID- 26110169 TI - Prevalence, Incidence, and Clearance of Anogenital Warts in Kenyan Men Reporting High-Risk Sexual Behavior, Including Men Who Have Sex With Men. AB - Background. Human papillomavirus (HPV) causes a spectrum of disease, ranging from warts to cancer. Prevalence, incidence, and factors associated with anogenital warts in East African men are unknown. Methods. Kenyan men reporting high-risk sexual behavior were inspected for anogenital warts at enrollment and follow-up visits. Logistic regression was performed to identify associations with anogenital warts at baseline. Cox regression was performed to analyze predictors of incident anogenital warts, and Kaplan-Meier curves were used to estimate clearance. Results. Baseline anogenital wart prevalence in 1137 men was 2.9% (95% confidence interval [CI], 2.0%-4.0%) overall, 2.0% in human immunodeficiency virus (HIV)-uninfected men, and 9.4% in HIV-1-infected men (adjusted odds ratio, 5.43; 95% CI, 2.03-11.29). Over a median of 1.4 years, anogenital wart incidence among 1104 men was 5.3 (95% CI, 4.3-6.5) per 100 person-years. Having HIV-1 infection at baseline (adjusted hazard ratio [aHR], 1.66; 95% CI, 1.01-2.72) or a genital syndrome during follow-up (aHR, 4.78; 95% CI, 3.03-7.56) was associated with increased wart incidence. Wart clearance was lower in HIV-1-infected men (log-rank P<.001). Conclusions. Anogenital wart prevalence and incidence were increased in HIV-1-infected men, and anogenital warts co-occurred with other genital syndromes. Quadrivalent HPV vaccination should be recommended for young men in settings with high HIV-1 prevalence. PMID- 26110170 TI - "Ceramic" Databases Improve the Retrospective Studies in Orthopedic Surgery. PMID- 26110172 TI - Two-Stage Nerve Graft in Severe Scar: A Time-Course Study in a Rat Model. AB - BACKGROUND: Peripheral nerve repair outcomes are suboptimal in the presence of severe soft tissue injury and excessive scarring paralleling the process in tendon reconstruction of the hand. Inspired by the advantages of the two-stage technique in tendon grafting and with encouraging preliminary results, we aimed to investigate the two-stage nerve grafting technique as an alternative method of secondary nerve repair. METHODS: Thirty female rats (~200 g) were randomly distributed into two groups (n=15). A 15 mm gap was created in the sciatic nerve of the animals and an excessive extraneural scar was induced using the "mincing" method. In this method, a thin strip of muscle was removed, minced in a petri dish and returned to the peripheral nerve. In the two-stage nerve graft group, a silicone tube was interposed in the first stage. After 4 weeks, in the second stage, the silicone tube was removed and a median nerve autograft was interposed through the newly formed vascularized sheath. In the conventional graft group, two nerve ends were protected with silicone caps in the first stage. After 4 weeks the caps were removed and the median graft was interposed. Behavioral assessments were performed at week 15 after surgery with the withdrawal reflex latency (WRL) and extensor postural thrust (EPT) and at the 3, 6 and 15-week time points with the TOA (toe out angle). Masson Trichrome staining method was used for histological assessments at week 15. RESULTS: According to the EPT and WRL, the two-stage nerve graft showed significant improvement (P=0.020 and P=0.017 respectively). The TOA showed no significant difference between the two groups. The total vascular index was significantly higher in the two-stage nerve graft group (P<0.001). CONCLUSIONS: Two-stage nerve graft using a silicone tube enhances vascularity of the graft and improves functional recovery. PMID- 26110171 TI - Prevention of Periprosthetic Joint Infection. AB - Prosthetic joint infection (PJI) is a calamitous complication with high morbidity and substantial cost. The reported incidence is low but it is probably underestimated due to the difficulty in diagnosis. PJI has challenged the orthopaedic community for several years and despite all the advances in this field, it is still a real concern with immense impact on patients, and the healthcare system. Eradication of infection can be very difficult. Therefore, prevention remains the ultimate goal. The medical community has executed many practices with the intention to prevent infection and treat it effectively when it encounters. Numerous factors can predispose patients to PJI. Identifying the host risk factors, patients' health modification, proper wound care, and optimizing operative room environment remain some of the core fundamental steps that can help minimizing the overall incidence of infection. In this review we have summarized the effective prevention strategies along with the recommendations of a recent International Consensus Meeting on Surgical Site and Periprosthetic Joint Infection. PMID- 26110173 TI - Radial Head Prosthesis Removal: a Retrospective Case Series of 14 Patients. AB - BACKGROUND: The purpose of this study was to report the preoperative complaints and postoperative outcome of patients after removal of the radial head prosthesis. METHODS: This is a retrospective review of 14 adult patients (6 females and 8 males) from 2007 to 2011, who underwent radial head prosthesis removal by three surgeons. The average time between implantation and removal was 23 months (range from 2 weeks to 12 years, median 12 months). RESULTS: The leading reported complaints before removal were restricted mobility of the elbow (active range of motion of less than 100 degrees) in 6, pain in 3, and pain together with restricted mobility in 4 patients. The objective findings before removal were restricted mobility of the elbow in 10 (71%), capitellar cartilage wear, loose implants, and heterotopic ossification each in 8 (57%), subluxation of the radio-capitellar joint or malpositioning of the stem in 5 (36%), and chronic infection in 2 (14%) patients. All patients with pain had wear of the capitellar cartilage on radiographs. The ulnar nerve was decompressed in four patients at the time of removal. Four patients underwent a subsequent operation for postoperative ulnar nerve symptoms 5 to 21 months after removal. Four patients were still complaining about persistent pain at the last follow-up visit. Except two patients, the total range of motion improved with a mean of 34 degrees (range 5 to 70) after a mean follow-up of 11 months. CONCLUSIONS: Removal of radial head prosthesis improved function and lessened pain in our case series. The reoperation rate was yet nearly 30% due to ulnar neuritis. Selective ulnar nerve decompression at the time of removal must be evaluated, especially in patients with expected large gain in range of motion after removal. PMID- 26110174 TI - Sternocostoclavicular Joint Swelling; Diagnosis of a Neglected Entity. AB - BACKGROUND: Sternocostoclavicular joint (SCCJ) swelling is an underdiagnosed, albeit important entity in clinical practice. The present study was conducted in order to identify the incidence and common causes of this entity. METHODS: Patients presenting to the Orthopaedic Clinic with a swelling of the sternocostoclavicular joint, during the study period of two years were included, and detailed history was obtained from the patient. Baseline investigations (total and differential leukocyte count, ESR, CRP, X-ray and CT) wereperformed. Magnetic resonance imaging,FNAC or joint aspiration was performed whenever clinically or radiologically indicated. RESULTS: A total of 21 patients were enrolled into the study for a duration of 2 years. Patients mainly presented with both pain and swelling of the SCCJ with predominant right sided involvement. Osteoarthritis was the most frequent diagnosis followed by infections, primary bone/cartilage tumor, and metastasis. CONCLUSIONS: Although most of the patients with SCCJ swelling have a benign etiology, it is not wise to dismiss thisswelling as degenerative changes. Serious conditions like septic arthritis or neoplasia, may masquerade with similar presentations such as osteoarthritis. It would be therefore imperative to rule out all of these potentially life threatening conditions using thorough clinic-radiological workups. PMID- 26110175 TI - Is There Any Correlation Between Patient Height and Patellar Tendon Length? AB - BACKGROUND: A potential specific problem of patellar tendon graft in ACL reconstruction is the possibility of graft-tunnel mismatch which could be more problematic with anatomic ACL reconstruction where the femoral tunnel is placed low on the lateral wall of the lateral femoral condyle. The occasional occurrence of this mismatch raises the question that whether a correlation exists between patient height and patellar tendon length. The purpose of the present study was to measure patellar tendon length as an anthropometric finding and to evaluate whether a correlation exists between patient height and patellar tendon length. METHODS: Intra-operative measurement of patellar tendon length was carried out in 267 consecutive patients during bone-patellar tendon-bone (BTB) graft ACL reconstruction. Patient age, gender, height were recorded. The patellar tendon measurements were done independently by two surgeons and the possible inter observer errors were checked. The data were analyzed using the Pearson correlation. RESULTS: The mean length of the patellar tendon was 46.4 +/- 4.8 mm (Mean +/- SD) with a range of 32-61 mm. The mean patient height was 177 +/- 7 cm (Mean +/- SD) with a range of 159-197 cm. A weak positive correlations were found between patient height and patellar tendon length (Pearson r = 0.24, P< 0.001). The linear regression equation for patellar tendon length (y, in millimeters) as a function of patient height (x, in centimeters) can be expressed as y=16.54 + 0.17x. CONCLUSIONS: Our study showed a weak correlation between patellar tendon length and patient height. This finding is in contrast to the usual measurements in human anthropometry in which taller individuals have normally longer tendons and ligaments. The graft-tunnel mismatch may be the result of this variation. PMID- 26110176 TI - Arthroscopic Meniscal Repair: "Modified Outside-In Technique". AB - BACKGROUND: Despite the introduction of different techniques for meniscal repair, no single procedure is superior in all situations. The new method for meniscal repair named "modified outside-in technique" aims to achieve higher primary fixation strength by an alternative suture technique as well as avoid disadvantages of outside-in, inside-out, and all-inside suture procedures. Additionally, the mid-term results of surgically treated patients with meniscal injuries by our new technique were evaluated. METHODS: The current prospective study included 66 patients who underwent meniscal repair by the modified outside in technique. The International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form was completed pre- and post-operatively. At final follow-up, Lysholm score was completed and patients were questioned about their return to previous sport activities. Clinical success was defined as lack of swelling and joint line tenderness, absence of locking, negative McMurray test and no need for meniscectomy. Patients' satisfaction was evaluated using the visual analogue scale (VAS). Patients were followed for 26+/-1.7 months. RESULTS: Clinical success was achieved in 61 patients (92.4%) and 5 candidates required meniscectomy (7.6%). IKDC Subjective Knee Evaluation Form score increased significantly from 54.2+/-12.7 preoperatively to 90.8+/-15.6 postoperatively (P<0.001). Lysholm score was excellent and good in 49 (80.3%) patients and fair in 12 (19.7%). Patients' satisfaction averaged at 8.35+/-1 (6-10). Neurovascular injury, synovitis and other knot-related complications were not reported. CONCLUSIONS: The modified outside-in technique has satisfactory functional and clinical outcomes. We believe that this procedure is associated with better clinical and biomechanical results; however, complementary studies should be performed to draw a firm conclusion in this regard. PMID- 26110177 TI - Evaluation of Patient Outcome and Satisfaction after Surgical Treatment of Adolescent Idiopathic Scoliosis Using Scoliosis Research Society-30. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) may lead to physical and mental problems. It also can adversely affect patient satisfaction and the quality of life. In this study, we assessed the outcomes and satisfaction rate after surgical treatment of AIS using scoliosis research society-30 questionnaire (SRS 30). METHODS: We enrolled 135 patients with AIS undergoing corrective surgery. Patients were followed for at least 2 years. We compared pre- and post-operative x-rays in terms of Cobb's angles and coronal balance. At the last visit, patients completed the SRS-30 questionnaire. We then assessed the correlation between radiographic measures, SRS-30 total score, and patient satisfaction. RESULTS: Cobb's angle and coronal balance improved significantly after surgery (P<0.001). The scores of functional activity, pain, self-image/cosmesis, mental health, and satisfaction were 27+/-4.3, 26+/-2.5, 33+/-5.2, 23+/-3.5, and 13+/-1.8, respectively. The total SRS-30 score was 127+/-13. Radiographic measures showed significant positive correlation with satisfaction and SRS-30 total scores. There was also a positive correlation between satisfaction and self-image/cosmesis domain scores. CONCLUSIONS: The greater the radiographic angles were corrected the higher the SRS-30 total score and patient satisfaction were. It is intuitive that the appearance and cosmesis is of most important factor associated with patient satisfaction. PMID- 26110179 TI - Outcome of Distal Both Bone Leg Fractures Fixed by Intramedulary Nail for Fibula & MIPPO in Tibia. AB - BACKGROUND: Fractures of the distal third of the tibia are mostly associated with a fibular fracture that often requires fixation. The preferred treatment of distal tibial fracture is the minimally invasive percutaneous plate osteosynthesis (MIPPO) procedure. However, there are no clear cut guidelines on fixation of the fibular fracture and currently most orthopedic surgeons use a plate osteosynthesis for the fibula as well. A common complication associated with dual plating is an increased chance of soft tissue necrosis, infection, and in some cases resulting in an exposed implant. We conducted a prospective study to analyze the results of fractures of the distal in both leg bones managed by the MIPPO procedure for tibial fractures and a rush nail for fibular fractures. METHODS: The study was conducted in a tertiary care hospital from November 2012 to May 2014, a total of 30 fractures in 30 patients (18 males, 12 females) with a mean age of 42.4 years (26-60 years) were treated in our institution in the aforesaid time period with MIPPO for tibia and rush nail for fibular fractures. All the cases were operated on by a single surgeon in emergency within 24 hours. The patients with skin blistering and compound fractures were excluded from this study. Rehabilitative measures were proceeded as per patient's pain profile, isometric and isotonic exercises were started on the first post-operative day, with full weight bearing at 10-12 weeks after assessing clinical and radiological union. Regular follow up of patients was done, radiographs were taken at the immediate post-operative period and at 3, 6, 12 and 24 weeks. RESULTS: All the patients were available for regular follow up. Radiological and clinical union proceeded normally in all the patients, no patients had signs of any deep infection, delayed union or nonunion, three patients had a superficial infection of the tibial incision that healed with a change in antibiotic. CONCLUSIONS: The use of dual plating for fixation of the lower tibia and fibula fractures is often associated with soft tissue complications, exposed implant, and increased risk of infection. We conclude that in fractures of the distal tibia and fibula it is better to use a rush nail for the fibula with a concurrent MIPPO for the tibia for the reasons cited above. Moreover, with the use of rush nail the cost of implant is also reduced, which is a very important factor in developing countries. PMID- 26110178 TI - A Survey of Severity and Distribution of Musculoskeletal Pain in Multiple Sclerosis Patients; a Cross-Sectional Study. AB - BACKGROUND: Pain, a common phenomenon in multiple sclerosis (MS) patients, is associated with many symptoms and problems. AIM: To investigation severity and distribution of musculoskeletal pain in MS patients. METHODS: In this cross sectional study, 115 members of the Mazandaran MS Association with confirmed MS were randomly selected to participate in the study. The patients were asked to fill out Numerical Rating Score and Nodric questionnaires, respectively. The data was analyzed by SPSS ver. 16 software. RESULTS: The mean age of the participants was 30.43+/-5.86 years and 88 cases (76.5%) were female. The mean disease duration was 26.34+/-24.32 months and 87.8% of the cases were experiencing pain at the time of study. The mean pain severity was 3.75+/-2.25 and worst pain experienced was 5.73+/-2.12. The most common pain sites were: the knees (55.7%), wrist (43.5%), and neck (41.7%). Women experience higher prevalence of shoulder, upper back, and ankle pain (P<0.05). In 62 cases (53.91%) MS interfered with daily functioning at least for a time. The prevalence of upper back and neck pain was higher in cases with a shorter disease duration (P<0.05). CONCLUSIONS: Pain was very common in patients with MS and not relevant to sex or age. In the majority of the cases more than 1 limb was involved and the prevalence of pain in the lower limbs was higher, especially in the knees. In females, the prevalence of pain in the shoulders, upper back, and ankle was higher compared to males. Also, neck and upper-back pain were found in the early stages of the disease. PMID- 26110181 TI - A Pitfall in Fixation of Distal Humeral Fractures with Pre-Contoured Locking Compression Plate. AB - Anatomically precontoured locking plates are intended to facilitate the fixation of articular fractures and particularly those associated with osteoporosis. Fractures of the distal humerus are relatively uncommon injuries where operative intervention can be exceptionally challenging. The distal humeral trochlea provides a very narrow anatomical window through which to pass a fixed-angle locking screw, which must also avoid the olecranon, coronoid, and radial fossae. We describe 3 patients (ages 27, 49, and 73 years) with a bicolumnar fracture of the distal humerus where very short distal locking screws were used. Intra articular screw placement was avoided but loss of fixation occurred in two patients and a third was treated with a prolonged period of immobilization. We postulate that fixed-angle screw trajectories may make it difficult for the surgeon to place screws of adequate length in this anatomically confined region, and may lead to insufficient distal fixation. Surgical tactics should include placement of as many screws as possible into the distal fragment, as long as possible and that each screw passes through a plate without necessarily locking in. PMID- 26110180 TI - Adult Degenerative Scoliosis with Spinal Stenosis Treated with Stand-Alone Cage via an Extreme Lateral Transpsoas Approach; a Case Report and Literature Review. AB - We report the case of a 73-year-old female with severe degenerative scoliosis and back and leg pain that was successfully treated with stand- alone cages via an extreme lateral transpsoas approach. This patient had declined open surgery and instrumentation due to her advanced age concerns about potential side effects. PMID- 26110182 TI - An Unusual Case of a Large Hematorrachis Associated with Multi-Level Osteoporotic Vertebral Compression Fractures; a Case Report. AB - Spinal epidural haemorrhage may present as back pain associated with radicular symptoms and can be a catastrophic clinical scenario with progression to paraplegia or even sudden death. Being a rare entity, it needs a high index of clinical suspicion to diagnose it. Fractures have been documented as a cause of hematorrachis but such hematomas only extend to one or two vertebral segments. Large epidural hematomas are usually associated with conditions like bleeding diathesis, arterio-venous malformations, plasma cell myeloma, and non-Hodgkin's lymphoma. Surgical management with immediate evacuation of the hematoma is the usual line of management in patients with neurological deficits. Though rare, monitored and careful conservative management can lead to recovery of neurological symptoms and resolution of the hematoma. We report a case of a very large post traumatic epidural hematorrchis extending to 11 vertebral segments from D3 to L1 vertebral bodies, who had a gradual spontaneous recovery. PMID- 26110183 TI - Femoral Condyle Fracture during Revision of Anterior Cruciate Ligament Reconstruction: Case Report and a Review of Literature. AB - A rare and devastating complication following anterior cruciate ligament (ACL) revision reconstruction is femoral fracture. A 35-year old male soccer player with a history of ACL tear from one year ago, who underwent arthroscopic ACL reconstruction and functioned well until another similar injury caused ACL re rupture. Revision of ACL reconstruction was performed and after failure of graft tension during the pumping, a fluoroscopic assessment showed a femoral condyle fracture. The patient referred to our knee clinic and was operated on in two stages first fixation of the fracture and then ACL re-revision after fracture healing was complete. Not inserting multiple guide pins, keeping a safe distance from the posterior cortex and giving more attention during graft tensioning, especially in revision surgeries, are all small points that can reduce the risk of fracture during the revision of ACL reconstruction. PMID- 26110184 TI - Childhood Facial Osteo Sarcoma: a Case Report. AB - Osteosarcoma (OS) is the eighth common cancer of childhood and its incidence is 4 cases in one million in children younger than 14. Facial OS incidence is estimated between 8 and 10% of OS cases. The main etiology of OS is unknown, but various predisposing factors are proposed such as radiation, radiotherapy, some benign bone diseases like Paget's disease or fibrous dysplasia. There is a 5-year survival rate of 68% and it decreases with the increase of age. Positive history of radiotherapy is the main predisposing factor for childhood OS. There is some evidence about the X-ray induced mutation in genomic DNA that leads to osteosarcoma. In the present paper we present a 19-month old girl with a mass located in the inferior margin of the left cheek and orbit. Our case is unique with regard to her young age and sex. Moreover, the tumor was located in an uncommon site and her disease was progressive and resistant. PMID- 26110185 TI - Elbow Stiffness Secondary to Elbow Joint Osteoid Osteoma, a Diagnostic Dilemma. AB - We present a 23-year-old man with distal humerus osteoid osteoma referring to our hospital with pain and progressive stiffness. The patient has been suffering from the disease for two years without a certain diagnosis. The radiographies of elbow did not reveal the pathology but further CT scan and MRI studies demonstrated the tumor. The en block resection of the tumor resolved the pain immediately but range of motion remained restricted. PMID- 26110186 TI - Feasibility of a hybrid elastographic-microfluidic device to rapidly process and assess pancreatic cancer biopsies for pathologists. AB - In this study, our collaborative research group explored the possibility of incorporating ultrasound elastography technology with a microfluidic device that is designed to prepare fine needle core biopsies (CBs; L=0.5-2.0 cm, D=0.4-1.2 mm) for pancreatic cancer diagnosis. For the first time, elastographic techniques were employed to measure shear wave velocity in fresh (3.7 m/s) and formalin fixed (14.7 m/s) pancreatic CBs. Shear wave velocity did not vary whether fixed specimens were free on a microscope slide, or constrained within glass microfluidic channels: 11.5+/-1.9 v. 11.8+/-2.1 m/s. 4% agarose inclusions were also embedded within 1% agarose hydrogels to simulate cysts, neoplastic, or necrotic tissue within CBs. Inclusions were successfully visualized and measured using optical coherence elastography. These preliminary experiments demonstrate in a rudimentary fashion that elastographic measurements of pancreatic CBs may be incorporated with our microfluidic device. The rapid mapping of CB stiffness may provide qualitative spatial information for pathologists to determine a more accurate diagnosis for patients. PMID- 26110187 TI - Duchenne muscular dystrophy: High-resolution melting curve analysis as an affordable diagnostic mutation scanning tool in a South African cohort. AB - BACKGROUND: Duchenne/Becker muscular dystrophy (D/BMD) is an X-linked recessive muscle disorder affecting 1/3 500 live male births worldwide. Up to 70% of all D/BMD cases are caused by exonic deletions or duplications routinely identified in diagnostic laboratories worldwide.The remaining patients harbour other sequence alterations for which testing availability is limited owing to the expense of interrogating the large DMD gene. Genetic screening for D/BMD in South Africa currently includes multiple ligase-dependent probe amplification (MLPA) for exonic deletions and duplications and linkage analysis. No genetic testing for small mutations in the DMD gene is offered, leaving a third of D/BMD families without genetic closure. The advent of potential mutation-specific therapies for DMD necessitates comprehensive testing protocols. OBJECTIVE: To investigate the effectiveness and affordability of high-resolution melting curve analysis (hrMCA) for detection of small/point mutations in the DMD gene, for possible inclusion into the local public health-funded diagnostic service. METHODS: DNA from 24 patients who had previously tested deletion-negative with multiplex polymerase chain reaction (mPCR) was analysed by MLPA and hrMCA. RESULTS: MLPA revealed eight previously undetected exonic rearrangements: five deletions and three duplications. HrMCA of the remaining samples revealed three nonsense, four frameshifts, one splice-site, one missense and one single-base substitution in the Dp427promoter/exon1 of the DMD gene. In addition, 41 polymorphisms and three changes of uncertain significance were detected. CONCLUSION: These findings identify hrMCA as an affordable and effective mutation scanning tool for incorporation into the local diagnostic setting, allowing for better genetic counselling of more DMD families and selection of potential candidates for future therapies. PMID- 26110199 TI - Subclinical Hypothyroidism is not a Risk Factor for Female Sexual Dysfunction in Korean Middle-Aged Women. AB - BACKGROUND: Previous studies have suggested that subclinical hypothyroidism is associated with the risk of anxiety or depression and can affect quality of life. However, there is a paucity of information regarding the relationship between subclinical hypothyroidism and female sexual dysfunction. METHODS: The study population consisted of sexually active middle-aged women (>=40 years old) who visited the center for health promotion and optimal aging at Seoul National University Hospital for a health check-up between 2010 and 2011. Sexual function was evaluated by the female sexual function index (FSFI) questionnaire, and female sexual dysfunction was defined as a FSFI score of <=26.55. FSFI scores and female sexual dysfunction frequencies were compared between cases with subclinical hypothyroidism and healthy controls. Nonparametric methods were used for statistical analysis. RESULTS: A total of 1086 women were included, and the frequency of subclinical hypothyroidism and female sexual dysfunction was 138 (12.7%) and 741 (68.2%), respectively. The total FSFI score and the scores in each domain were not different between the two groups (median total FSFI score (interquartile range): 23.8 (20.2-27.5) for normal thyroid status vs. 24.4 (20.6 27.6) for subclinical hypothyroidism, p=n.s.). The frequency of female sexual dysfunction was not different between the two groups, either (68.4% for normal thyroid status vs. 67.4% for subclinical hypothyroidism, p=n.s.). These findings were consistent even after adjustment for confounding variables. CONCLUSIONS: Subclinical hypothyroidism is not a risk factor for sexual dysfunction in middle aged women. PMID- 26110200 TI - Discovery and Optimization of a Porcupine Inhibitor. AB - Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and function. The inhibition of PORCN could serve as a therapeutic approach for the treatment of a number of Wnt-dependent cancers. Herein, we describe the identification of a Wnt secretion inhibitor from cellular high throughput screening. Classical SAR based cellular optimization provided us with a PORCN inhibitor with nanomolar activity and excellent bioavailability that demonstrated efficacy in a Wnt-driven murine tumor model. Finally, we also discovered that enantiomeric PORCN inhibitors show very different activity in our reporter assay, suggesting that such compounds may be useful for mode of action studies on the PORCN O-acyltransferase. PMID- 26110201 TI - Metal artefact reduction in CT imaging of hip prostheses-an evaluation of commercial techniques provided by four vendors. AB - OBJECTIVE: The aim of this study was to evaluate commercial metal artefact reduction (MAR) techniques in X-ray CT imaging of hip prostheses. METHODS: Monoenergetic reconstructions of dual-energy CT (DECT) data and several different MAR algorithms, combined with single-energy CT or DECT, were evaluated by imaging a bilateral hip prosthesis phantom. The MAR images were compared with uncorrected images based on CT number accuracy and noise in different regions of interest. RESULTS: The three MAR algorithms studied implied a general noise reduction (up to 67%, 74% and 77%) and an improvement in CT number accuracy, both in regions close to the prostheses and between the two prostheses. The application of monoenergetic reconstruction, without any MAR algorithm, did not decrease the noise in the regions close to the prostheses to the same extent as did the MAR algorithms and even increased the noise in the region between the prostheses. CONCLUSION: The MAR algorithms evaluated generally improved CT number accuracy and substantially reduced the noise in the hip prostheses phantom images, both close to the prostheses and between the two prostheses. The study showed that the monoenergetic reconstructions evaluated did not sufficiently reduce the severe metal artefact caused by large orthopaedic implants. ADVANCES IN KNOWLEDGE: This study evaluates several commercially available MAR techniques in CT imaging of large orthopaedic implants. PMID- 26110202 TI - Relative percentage signal intensity recovery of perfusion metrics-an efficient tool for differentiating grades of glioma. AB - OBJECTIVE: Glioma classification and characterization may be facilitated by a multiparametric approach of perfusion metrics, which could not be achieved by conventional MRI alone. Our aim is to explore the potential of relative percentage signal intensity recovery (rPSR) values, in addition to relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) of first pass T2* dynamic susceptibility contrast (DSC) perfusion MRI, in differentiating high- and low-grade glioma. METHODS: This prospective study included 39 patients with low-grade and 25 patients with high-grade glioma. rPSR, rCBV and rCBF were calculated from the first-pass T2* DSC perfusion MRI. rPSR was calculated using standard software and validated with dedicated perfusion metrics analysis software. The statistical analysis was performed using analysis of variance and receiver operating characteristic (ROC) curves. RESULTS: Variation in rPSR, rCBV and rCBF values between low- and high-grade gliomas were statistically significant (p < 0.005). The ROC curve analysis for each of them yielded 96% sensitivity and 71.8% specificity; 88% sensitivity and 69.2% specificity; and 72% sensitivity and 66.7% specificity. The area under the curve (AUC) from the ROC curve analysis yielded 0.893, 0.852 and 0.702 for rPSR, rCBV and rCBF, respectively. The rPSR calculation with the validation software yielded 92.3% sensitivity and 72% specificity with an AUC of 0.864. CONCLUSION: rPSR inversely correlates while rCBV and rCBF values directly correlate with the tumour grade. Furthermore, the overall diagnostic performance of rPSR is better than rCBV and rCBF values. ADVANCES IN KNOWLEDGE: rPSR of T2* DSC perfusion is an indicator of blood-brain barrier status and lesion leakiness, which has not been explored yet compared with the usual haemodynamic parameters, rCBV and rCBF. PMID- 26110203 TI - What is the minimum amount of simulated breast movement required for visual detection of blurring? An exploratory investigation. AB - OBJECTIVE: Image blurring in mammography can cause significant image degradation and interpretational problems. A potential source is due to paddle movement during image formation. Paddle movement has been shown to be as much as 1.5 mm. No study has yet been performed to determine how much motion would be noticeable visually. The aim of this study is to determine the minimum amount of simulated breast movement at which blurring can be detected visually. METHODS: 25 artefact free mammogram images were selected. Mathematical simulation software was created to mimic the effect of blurring produced by breast movement during exposure. Motion simulation was imposed to 15 levels, from 0.1 to 1.5 mm stepping through 0.1 mm increments. 15 degraded images and 1 without blurring were de-identified, randomized and assessed on a blinded basis by two clinical experts to determine the presence or absence of blurring. Statistical testing was carried out to determine the consistency between the two observers. RESULTS: The probability of simulated blurred image detection is the highest for the gaussian method and the lowest for soft-edged mask estimation. CONCLUSION: The amount of simulated breast movement at which blurring can be detected visually for gaussian blur, hard-edge mask estimation and soft-edge mask estimation is 0.4, 0.8 and 0.7 mm, respectively. Cohen's kappa for all the levels of simulated blurring is 0.689 (p < 0.05). ADVANCES IN KNOWLEDGE: This research establishes the concept of using probability to represent visual detection of blurring rather than defining a hard cut-off level. PMID- 26110204 TI - Evaluation of lymph node status after neoadjuvant chemotherapy in breast cancer patients: comparison of diagnostic performance of ultrasound, MRI and 18F-FDG PET/CT. AB - OBJECTIVE: To evaluate the diagnostic performance of ultrasound, MRI and fluorine 18 fludeoxyglucose positron emission tomography (18F-FDG PET)/CT for the diagnosis of metastatic axillary lymph node (ALN) after neoadjuvant chemotherapy (NAC) and to find out histopathological factors affecting the diagnostic performance of these imaging modalities. METHODS: From January 2012 to November 2014, 191 consecutive patients with breast cancer who underwent NAC before surgery were retrospectively reviewed. We included 139 patients with ALN metastasis that was confirmed on fine needle aspiration or core needle biopsy at initial diagnosis. RESULTS: After NAC, 39 (28%) patients showed negative conversion of ALN on surgical specimens of sentinel lymph node (LN) or ALN. The sensitivity of ultrasound, MRI and PET/CT was 50% (48/96), 72% (70/97) and 22% (16/73), respectively. The specificity of ultrasound, MRI and PET/CT was 77% (30/39), 54% (21/39) and 85% (22/26), respectively. The Az value of combination of ultrasound and PET/CT was the highest (0.634) followed by ultrasound (0.626) and combination of ultrasound, MRI and PET/CT (0.617). The size of tumour deposit in LN and oestrogen receptor was significantly associated with the diagnostic performance of ultrasound (p < 0.001 and p = 0.009, respectively) and MRI (p = 0.045 and p = 0.036, respectively). The percentage diameter decrease, size of tumour deposit in LN, progesterone receptor, HER2 and histological grade were significantly associated with the diagnostic performance of PET/CT (p = 0.023, p = 0.002, p = 0.036, p = 0.044 and p = 0.008, respectively). On multivariate logistic regression analysis, size of tumour deposit within LN was identified as being independently associated with diagnostic performance of ultrasound [odds ratio, 13.07; 95% confidence interval (CI), 2.95-57.96] and PET/CT (odds ratio, 6.47; 95% CI, 1.407-29.737). CONCLUSION: Combination of three imaging modalities showed the highest sensitivity, and PET/CT showed the highest specificity for the evaluation of ALN metastasis after NAC. Ultrasound alone or combination of ultrasound and PET/CT showed the highest positive-predictive value. The size of tumour deposit within ALN was significantly associated with diagnostic performance of ultrasound and PET/CT. ADVANCES IN KNOWLEDGE: This study is about the diagnostic performance of ultrasound, MRI, PET/CT and combination of each imaging modality for the evaluation of metastatic ALN after NAC. Of many histopathological factors, only the size of tumour deposit within ALN was an independent factor associated with the diagnostic performance of ultrasound and PET/CT. PMID- 26110205 TI - Diffusion-weighted MRI in the follow-up of chronic periaortitis. AB - OBJECTIVE: To evaluate the usefulness of diffusion-weighted MRI (DWI) for the assessment of the intraindividual follow-up in patients with chronic periaortitis (CP) under medication. METHODS: MRI data of 21 consecutive patients with newly diagnosed untreated disease were retrospectively examined before and after medical therapy, with a median follow-up of 16 weeks. DWI parameters [b800 signal, apparent diffusion coefficient (ADC) values] of the CP and psoas muscle were analysed together with the extent and contrast enhancement. Pre- and post treatment laboratory inflammation markers were acquired parallel to each MR examination. RESULTS: Statistically significant lower b800 signal intensities (p <= 0.0001) and higher ADC values (p <= 0.0001) were observed after medical treatment within the fibrous periaortic tissue. Extent and contrast enhancement of the CP showed also a statistically significant decrease (p <= 0.0001) in the follow-up examinations, while the control parameters within the psoas muscle showed no differences. CONCLUSION: DWI seems to be a useful method for the evaluation of response to treatment without contrast agents. The technique may be helpful in the assessment of disease activity to guide further therapeutic strategies. ADVANCES IN KNOWLEDGE: DWI detects significant differences in the intraindividual follow-up of CP under medical therapy. PMID- 26110206 TI - Ubiquitin in regulation of spindle apparatus and its positioning: implications in development and disease. AB - Emerging data implicates ubiquitination, a post-translational modification, in regulating essential cellular events, one of them being mitosis. In this review we discuss how various E3 ligases modulate the cortical proteins such as dynein, LGN, NuMa, Galpha, along with polymerization, stability, and integrity of spindles. These are responsible for regulating symmetric cell division. Some of the ubiquitin ligases regulating these proteins include PARK2, BRCA1/BARD1, MGRN1, SMURF2, and SIAH1; these play a pivotal role in the correct positioning of the spindle apparatus. A direct connection between developmental or various pathological disorders and the ubiquitination mediated cortical regulation is rather speculative, though deletions or mutations in them lead to developmental disorders and disease conditions. PMID- 26110208 TI - Percutaneous Removal of Filter-Induced Iliocaval Thrombus Using the AngioVac Device. AB - Most percutaneous mechanical thrombectomy devices entail thrombolysis and/or thrombus fragmentation followed by subsequent aspiration, with the associated risks of bleeding and embolization. We describe the use of the AngioVac system (Angiodynamics, Latham, NY USA) for extraction of extensive iliocaval thrombus associated with an inferior vena cava filter followed by percutaneous inferior vena cava filter extraction in a patient with an absolute contraindication to thrombolysis. The AngioVac may be considered in this scenario as it does not require thrombolytics and can remove whole thrombus, thus overcoming some of the limitations of percutaneous mechanical thrombectomy devices in the setting of subacute and early chronic thrombus. PMID- 26110207 TI - Stabilization of an alpha/beta-Hydrolase by Introducing Proline Residues: Salicylic Acid Binding Protein 2 from Tobacco. AB - alpha/beta-Hydrolases are important enzymes for biocatalysis, but their stability often limits their application. We investigated a plant esterase, salicylic acid binding protein 2 (SABP2), as a model alpha/beta-hydrolase. SABP2 shows typical stability to urea (unfolding free energy 6.9 +/- 1.5 kcal/mol) and to heat inactivation (T1/2 15min 49.2 +/- 0.5 degrees C). Denaturation in urea occurs in two steps, but heat inactivation occurs in a single step. The first unfolding step in urea eliminates catalytic activity. Surprisingly, we found that the first unfolding likely corresponds to the unfolding of the larger catalytic domain. Replacing selected amino acid residues with proline stabilized SABP2. Proline restricts the flexibility of the unfolded protein, thereby shifting the equilibrium toward the folded conformation. Seven locations for proline substitution were chosen either by amino acid sequence alignment with a more stable homologue or by targeting flexible regions in SABP2. Introducing proline in the catalytic domain stabilized SABP2 to the first unfolding in urea for three of five cases: L46P (+0.2 M urea), S70P (+0.1), and E215P (+0.9). Introducing proline in the cap domain did not stabilize SABP2 (two of two cases), supporting the assignment that the first unfolding corresponds to the catalytic domain. Proline substitutions in both domains stabilized SABP2 to heat inactivation: L46P (DeltaT1/2 15min = +6.4 degrees C), S70P (+5.4), S115P (+1.8), S141P (+4.9), and E215P (+4.2). Combining substitutions did not further increase the stability to urea denaturation, but dramatically increased resistance to heat inactivation: L46P-S70P DeltaT1/2 15min = +25.7 degrees C. This straightforward proline substitution approach may also stabilize other alpha/beta-hydrolases. PMID- 26110209 TI - Porous Carbon Nanofibers from Electrospun Biomass Tar/Polyacrylonitrile/Silver Hybrids as Antimicrobial Materials. AB - A novel route to fabricate low-cost porous carbon nanofibers (CNFs) using biomass tar, polyacrylonitrile (PAN), and silver nanoparticles has been demonstrated through electrospinning and subsequent stabilization and carbonization processes. The continuous electrospun nanofibers had average diameters ranging from 392 to 903 nm. The addition of biomass tar resulted in increased fiber diameters, reduced thermal stabilities, and slowed cyclization reactions of PAN in the as spun nanofibers. After stabilization and carbonization, the resultant CNFs showed more uniformly sized and reduced average diameters (226-507 nm) compared to as spun nanofibers. The CNFs exhibited high specific surface area (>400 m(2)/g) and microporosity, attributed to the combined effects of phase separations of the tar and PAN and thermal decompositions of tar components. These pore characteristics increased the exposures and contacts of silver nanoparticles to the bacteria including Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli, leading to excellent antimicrobial performances of as-spun nanofibers and CNFs. A new strategy is thus provided for utilizing biomass tar as a low-cost precursor to prepare functional CNFs and reduce environmental pollutions associated with direct disposal of tar as an industrial waste. PMID- 26110210 TI - Distinct Features in Koreans with Involutional Blepharoptosis. PMID- 26110211 TI - Reply: Tissue-Engineered Breast Reconstruction with Brava-Assisted Fat Grafting: A 7-Year, 488-Patient, Multicenter Experience. PMID- 26110212 TI - Tissue-Engineered Breast Reconstruction with Brava-Assisted Fat Grafting: A 7 Year, 488-Patient, Multicenter Experience. PMID- 26110213 TI - Reply: Distinct Features in Koreans with Involutional Blepharoptosis. PMID- 26110214 TI - Reply: Facial Feminization Surgery: The Forehead. Surgical Techniques and Analysis of Results. PMID- 26110215 TI - Quantitative Assessment of Parametric Uncertainty in Northern Hemisphere PAH Concentrations. AB - We quantitatively examine the relative importance of uncertainty in emissions and physicochemical properties (including reaction rate constants) to Northern Hemisphere (NH) and Arctic polycyclic aromatic hydrocarbon (PAH) concentrations, using a computationally efficient numerical uncertainty technique applied to the global-scale chemical transport model GEOS-Chem. Using polynomial chaos (PC) methods, we propagate uncertainties in physicochemical properties and emissions for the PAHs benzo[a]pyrene, pyrene and phenanthrene to simulated spatially resolved concentration uncertainties. We find that the leading contributors to parametric uncertainty in simulated concentrations are the black carbon-air partition coefficient and oxidation rate constant for benzo[a]pyrene, and the oxidation rate constants for phenanthrene and pyrene. NH geometric average concentrations are more sensitive to uncertainty in the atmospheric lifetime than to emissions rate. We use the PC expansions and measurement data to constrain parameter uncertainty distributions to observations. This narrows a priori parameter uncertainty distributions for phenanthrene and pyrene, and leads to higher values for OH oxidation rate constants and lower values for European PHE emission rates. PMID- 26110216 TI - Glenohumeral dislocation with a proximal humerus physeal fracture. PMID- 26110217 TI - Arch of the foot and postural balance in young judokas and peers. AB - Twenty-nine male judocas and nontraining peers participated in this study. The arch of the foot (as Clarke's angular values) was measured under non-weight bearing conditions in two-leg and one-leg stands. Postural balance was assessed by the Flamingo balance test. Judocas presented better static balance and higher arches of the foot. Significant differences in Clarke's angular values in a sitting and standing on two-leg position were found in both groups. After transition to a one-leg stand, the height of the arches of the foot in nontraining participants was still significantly decreased. Weight bearing did not affect Clarke's angular values in judokas. A correlation was found between the Flamingo test and Clarke's angle. Better balance was observed in adolescents with higher arch of the foot. PMID- 26110218 TI - Acute, unstable slipped capital femoral epiphysis with associated congenital coxa vara. AB - Slipped capital femoral epiphysis in patients younger than 10 years is rare and is often associated with some identifiable metabolic or endocrinologic abnormality. We present a case of a 5-year-old girl with an acute, unstable, severe slipped capital femoral epiphysis associated with congenital coxa vara and its surgical management. This association has not been described in previous literature. Surgical treatment is proposed and described. PMID- 26110219 TI - Variation in practice habits in the treatment of pediatric distal radius fractures. AB - Distal radius fractures are widespread in the pediatric population. Standardized treatment protocols have not been well defined. We sought to examine the diversity of current practice patterns in the treatment of these fractures by surveying hand, pediatric, and general orthopedic surgeons. Hand, pediatric, and general orthopedic surgeons were surveyed using an internet-based questionnaire on the management of pediatric distal radius fractures. Each surgeon was asked to select a criterion from among choices of 'acceptable' alignment criteria at the onset of the survey. Ten cases were then provided to represent a broad spectrum of injuries from minimally angulated torus fractures to complete, displaced fractures. In addition to the variation in injury pattern, the patients in the survey differed in age at the time of injury (3-15 years of age). For each case, surgeons were asked to select a preferred treatment, first on the basis of injury films, and then again after reviewing 1-week follow-up radiographs. A total of 781 surgeons completed the survey. In patients younger than 9 years of age, a residual sagittal angulation of 20 degrees or less, coronal angulation of 10 degrees or less, and 1 cm or less of bayonet apposition was deemed 'acceptable' by 88, 90, and 69% of respondents, respectively. In older patients, these percentages were 58, 64, and 29%, respectively. When specific cases were reviewed, 20.3% of surgeons recommended treatment different from their own theoretical 'acceptable' criteria. When subspecialty training was analyzed, hand surgeons and general orthopedic surgeons were 2.9 and 1.6 times more likely to recommend surgery, respectively, as compared with pediatric surgeons after viewing the initial radiograph. Private practice surgeons were 1.5 times more likely to recommend surgery compared with academic surgeons based on the initial injury radiographs. Our survey highlights the discordance between theoretical acceptable criteria of surgeons and their practice habits, as well as the substantial disparities in treatment recommendations based on subspecialty training. Further study is warranted to determine whether these variations in treatment affect patient outcomes. This survey is a level IV observational study. PMID- 26110221 TI - Methadone Medical Maintenance: An Early 21st-Century Perspective. AB - Methadone medical maintenance is the treatment of stable methadone-maintained patients in primary care physicians' offices under an exemption from federal methadone regulations. Reports from seven such programs in six states show high retention and low frequencies of illicit drug use. Patients and physicians indicate high levels of satisfaction. Although methadone maintenance has a long history of safety and efficacy, most methadone medical maintenance programs are no longer operating or accepting new patients. Federal regulations for standard methadone clinics allow some features of methadone medical maintenance, and advocacy for state approval of these changes is strongly recommended. PMID- 26110220 TI - Practical review of immunizations in adult patients with cancer. AB - Compared with the general population, patients with cancer in general are more susceptible to vaccine-preventable infections, either by an increased risk due to the malignancy itself or immunosuppressive treatment. The goal of immunizations in these patients is therefore to provide protection against these infections, and to decrease the number of vulnerable patients who can disseminate these organisms. The proper timing of immunization with cancer treatment is key to achieving better vaccine protection. As the oncology field continues to advance, leading to better quality of life and longer survival, immunization and other aspects of preventive medicine ought to move to the frontline in the care of these patients. Herein, we review the vaccines most clinically relevant to patients with cancer, as well as special cases including vaccines after splenectomy, travel immunization and recommendations for family members. PMID- 26110222 TI - Hyperactivity and lack of social discrimination in the adolescent Fmr1 knockout mouse. AB - The aims of this study were to investigate behaviour relevant to human autism spectrum disorder (ASD) and the fragile X syndrome in adolescent Fmr1 knockout (KO) mice and to evaluate the tissue levels of striatal monoamines. Fmr1 KO mice were evaluated in the open field, marble burying and three-chamber test for the presence of hyperactivity, anxiety, repetitive behaviour, sociability and observation of social novelty compared with wild-type (WT) mice. The Fmr1 KO mice expressed anxiety and hyperactivity in the open field compared with WT mice. This increased level of hyperactivity was confirmed in the three-chamber test. Fmr1 KO mice spent more time with stranger mice compared with the WT. However, after a correction for hyperactivity, their apparent increase in sociability became identical to that of the WT. Furthermore, the Fmr1 KO mice could not differentiate between a familiar or a novel mouse. Monoamines were measured by HPLC: Fmr1 KO mice showed an increase in the striatal dopamine level. We conclude that the fragile X syndrome model seems to be useful for understanding certain aspects of ASD and may have translational interest for studies of social behaviour when hyperactivity coexists in ASD patients. PMID- 26110223 TI - Neuroanatomical dichotomy of sexual behaviors in rodents: a special emphasis on brain serotonin. AB - Much of the social behavior in which rodents engage is related to reproduction, such as maintaining a breeding territory, seeking mates, mating, and caring for their young. Rodents belong to the internally fertilizing species that require sexual behavior for reproduction. The dyadic, heterosexual patterns of most mammalian species are sexually dimorphic, but they also share mutual components in both sexes: sexual attraction is reciprocal, sexual initiative is assumed, appetitive behavior is engaged in, and mating involves consummatory and postconsummatory phases in females as well as in males. Serotonin, a phylogenetically ancient molecule, is the most widely distributed neurotransmitter in the brain and its signaling pathways are essential for numerous functions including sexual behavior. Since the late 1960s, brain serotonergic neurotransmission has been considered to exert an inhibitory influence on the neural mechanisms mediating sexual behavior. This contention was based mainly on the observations that a decrease in central serotonergic activity facilitated the elicitation of sexual behavior, whereas an increase in central serotonergic activity attenuated it. However, the discovery of over 14 types of serotonin receptors has added numerous layers of complexity to the study of serotonin and sexual behavior. Evidence shows that, upon activation, certain receptor subtypes facilitate, whereas some others suppress, sexual behavior, as well as sexual arousal and motivation. Furthermore, the role of these receptors has been shown to be different in the male and female sexes. The use of serotonergic pharmacological interventions, mouse strains with genetic polymorphisms causing alterations in the levels of brain serotonin, and animal models with genetic manipulations of various serotonin effectors has helped delineate the fundamental role of this neurotransmitter in the regulation of sexual behavior. This review aims to examine the basics of the components of female and male sexual behavior and the participation of the serotonin system in the modulation of these behaviors, with emphasis on rodents. PMID- 26110225 TI - Effects of long-term agomelatine treatment on the cognitive performance and hippocampal plasticity of adult rats. AB - Agomelatine is an antidepressant with a distinct pharmacological mechanism of action as an MT1 and MT2 receptor agonist and as a 5-HT2C receptor antagonist. We evaluated the chronic effects of agomelatine administration (40 mg/kg, 20 weeks) on the cognitive performance of rats in the Morris water maze task. We applied unbiased stereological quantification methods to estimate the total numbers of granular and pyramidal neurons located in the dorsal hippocampus. We also analyzed the dendritic spines of pyramidal neurons in the CA1 region using the Golgi-Cox impregnation method. The agomelatine-treated group found the hidden platform more quickly than did the control group and spent significantly more time in the target quadrant. Agomelatine administration caused significant volumetric and numerical enhancements in granular and pyramidal neurons in the dentate gyrus and CA1-3 subregions, respectively. Increased densities of the mushroom and stubby types of spines, with no alteration in the thin-shaped spines, were observed in the agomelatine-treated group. These results showed that long-term agomelatine administration induced a nootropic effect supported by structural changes. Enhancement of the more stable types of dendritic spines might indicate improved adaptive capacity in hippocampal neurons. Future studies will provide a better understanding of the effect of this drug on synaptic plasticity. PMID- 26110226 TI - Delay discounting, self-control, and substance use among adult drug court participants. AB - The current study examined the relationship between two measures of impulsiveness and the odds of substance use among a sample of participants on an Australian drug court (n=80). Participants completed a computer-based delay discounting task, a paper-based delay discounting task, and a questionnaire-based measure of self-control. The delay discounting tasks measured individual differences in the value attributed to distal outcomes, which is one aspect of impulsive behavior that has been found to be over-represented among illicit drug users. The relationship between the measures of impulsiveness and the odds of substance use was assessed by fitting longitudinal panel regression models with adjustment for informative treatment dropout. Consistent with previous research, drug court participants were found to have higher discount rates (i.e. were more impulsive) than a noncriminal population of university students (n=101). Drug court participants also discounted delayed gains more than delayed losses. Delay discounting was not significantly associated with the odds of substance use on the drug court program. There was a positive relationship between the survey based measure of impulsivity and the mean substance use frequency. The authors conclude that impulsivity is correlated with substance use among drug court participants but not when measuring impulsivity using a delay discounting paradigm. PMID- 26110224 TI - Effects of acute and chronic social defeat stress are differentially mediated by the dynorphin/kappa-opioid receptor system. AB - Accumulating evidence indicates that kappa-opioid receptors (KORs) and their endogenous ligand, dynorphin (DYN), can play important roles in regulating the effects of stress. Here, we examined the role of KOR systems in the molecular and behavioral effects of acute (1-day) and chronic (10-day) social defeat stress (SDS) in mice. We found that acute SDS increased DYN mRNA levels within the nucleus accumbens, a key element of brain dopamine (DA) systems. In contrast, chronic SDS produced long-lasting decreases in DYN mRNA levels. We then examined whether disruption of KOR function would affect development of SDS-induced depressive-like behaviors, as measured in the intracranial self-stimulation and social interaction tests. Ablation of KORs from DA transporter-expressing neurons delayed the development of SDS-induced anhedonia in the intracranial self stimulation test, suggesting increased stress resilience. However, administration of the long-lasting KOR antagonist JDTic (30 mg/kg, intraperitoneally) before the SDS regimen did not affect anhedonia, suggesting that disruption of KOR function outside DA systems can oppose stress resilience. Social avoidance behavior measured after the 10-day SDS regimen was not altered by ablation of KORs in DA transporter-expressing neurons or by JDTic administration before testing. Our findings indicate that KORs expressed in DA systems regulate the effects of acute, but not chronic, social stress. PMID- 26110227 TI - Serum Inflammatory Cytokine Markers of Invasive Fungal Infection in Previously Immunocompetent Battle Casualties. AB - BACKGROUND: Invasive fungal infection (IFI) is described increasingly in individuals experiencing high-energy military trauma. Hallmarks of successful treatment involve aggressive surgical debridement and early initiation of systemic antimicrobial therapy. Currently, intravenous anti-fungal therapy commences based on appearance of wounds and patient's clinical course. Whereas some clinical protocols exist to predict which critically injured patients should receive anti-fungal therapies, there are no established serum markers associated with IFI. Our hypothesis is that serum inflammatory cytokines exist that can assist in identifying individuals at risk for IFI. METHODS: This is a retrospective case control study at a single institution. Nine patients with IFI (Saksenaea vasiformis, Fusarium sp., Graphium sp., Scedosporium sp., Aspergillus sp., Mucor sp., and Alternaria sp.) after battlefield trauma were matched to nine individuals with similar injury patterns whose laboratory results were negative for IFI. The combination of serum inflammatory cytokines from the first and second debridements was examined with multiplex platform proteomic analysis. We defined statistical significance as a two-tailed alpha<0.05 after adjusting for multiple comparisons using the false discovery rate method. This model was refined further with correlation-based filter selection and the area under the curve of the receiver operating characteristics (AUROC) was tested. RESULTS: Both groups had similar Injury Severity Scores (ISS) (mean+/-standard deviation [SD]) (26.8+/-15.5 vs. 29.2+/-16.8, p=0.766). Elevated RANTES (regulated on activation, normal T cell expressed and secreted) alone (10,492.8+/-4,450.1 vs. 5,333.3+/ 4,162.2, p=0.006) correlated with IFI. Also, the combination of persistent elevations in RANTES, interleukin (IL)-2R, and IL-15 was a robust model for predicting IFI with the AUROC being 0.9. CONCLUSIONS: Elevation in serum cytokines, particularly RANTES, correlated with IFI in this small group of patients. This demonstrates the potential of future rapid serum testing for early initiation and guidance of anti-fungal therapies. PMID- 26110230 TI - Treadmill Training or Progressive Strength Training to Improve Walking in People with Multiple Sclerosis? A Randomized Parallel Group Trial. AB - BACKGROUND AND PURPOSE: The most effective treatment approach to improve walking in people with multiple sclerosis (MS) is not known. The aim of this trial was to assess the efficacy of treadmill training and progressive strength training on walking in people with MS. METHODS: A single blinded randomized parallel group trial was carried out. Eligible participants were adults with MS with Expanded Disability Status Scale score <=6. A total of 29 participants were randomized and 28 received the allocated exercise intervention, treadmill (n = 13) or strength training (n = 15). Both groups exercised 30 minutes, three times a week for 8 weeks. Primary outcome was The Functional Ambulation Profile evaluated by the GAITRite walkway. Secondary outcomes were walking work economy and balance control during walking, measured by a small lightweight accelerometer connected to the lower back. Testing was performed at baseline and the subsequent week after completion of training. RESULTS: Two participants were lost to follow-up, and 11 (treadmill) and 15 (strength training) were left for analysis. The treadmill group increased their Functional Ambulation Profile score significantly compared with the strength training group (p = .037). A significant improvement in walking work economy (p = .024) and a reduction of root mean square of vertical acceleration (p = .047) also favoured the treadmill group. DISCUSSION: The results indicate that task-specific training by treadmill walking is a favourable approach compared with strength training to improve walking in persons with mild and moderate MS. Implications for Physiotherapy practice, this study adds knowledge for the decision of optimal treatment approaches in people with MS. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26110231 TI - Best friends and better coping: Facilitating psychological resilience through boys' and girls' closest friendships. AB - This is a novel investigation of whether, and how, a single close supportive friendship may facilitate psychological resilience in socio-economically vulnerable British adolescents. A total of 409 adolescents (160 boys, 245 girls, four unknown), aged between 11 and 19 years, completed self-report measures of close friendship quality, psychological resilience, social support, and other resources. Findings revealed a significant positive association between perceived friendship quality and resilience. This relationship was facilitated through inter-related mechanisms of developing a constructive coping style (comprised of support-seeking and active coping), effort, a supportive friendship network, and reduced disengaged and externalising coping. While protective processes were encouragingly significantly present across genders, boys were more vulnerable to the deleterious effects of disengaged and externalizing coping than girls. We suggest that individual close friendships are an important potential protective mechanism accessible to most adolescents. We discuss implications of the resulting Adolescent Friendship and Resilience Model for resilience theories and integration into practice. PMID- 26110232 TI - The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers. AB - PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409. PMID- 26110233 TI - Health-care professionals' responsibility to patients' relatives in genetic medicine: a systematic review and synthesis of empirical research. AB - PURPOSE: The extent of the responsibility of health-care professionals (HCPs) to ensure that patients' relatives are told of their risk is unclear. Current international guidelines take confidentiality to the individual patient as the default position, but some suggest that disclosure could be default and genetic information could be conceptualized as familial. METHODS: Our systematic review and synthesis of 17 studies explored the attitudes of HCPs, patients, and the public regarding the extent of HCPs' responsibility to relatives with respect to disclosure. RESULTS: Health-care professionals generally felt a responsibility to patients' relatives but perceived a variety of reasons why it would be difficult to act on this responsibility. Public/patient views were more wide-ranging. Participants identified several competing and overlapping arguments for and against HCP disclosure: guidelines do not permit/mandate it, privacy, medical benefit, impact on family dynamics, quality of communication, and respecting autonomy. CONCLUSION: We argue that HCPs can sometimes share genetic information without breaching confidentiality and that they could factor into their considerations the potential harm to family dynamics of nondisclosure. However, we need more nuanced research about their responsibilities to relatives, particularly as genomic tests are used more frequently in clinical practice.Genet Med 18 4, 290-301. PMID- 26110234 TI - High-Internal-Phase Emulsion Tailoring Polymer Amphiphilicity towards an Efficient NIR-Sensitive Bacteria Filter. AB - Emulsions having a high internal-phase volume fraction-termed as HIPEs for high internal phase emulsions-are in high demand as templates for functional macroporous materials. Designing molecular surfactants with appropriate amphiphilicity plays a critical role in the HIPE preparation. In this study, successful tailoring of the amphiphilicity of the originally hydrophobic block co polymer of polystyrene-b-polyvinylpyridine (PS-b-P4VP) is reported. In combination with trifluoroacetic acid, less than 5 wt% of the polymer-CF3COOH system is feasible as a surfactant for HIPE preparation; this is lower than the amounts typically needed for commonly used commercial surfactants. Using the HIPEs as templates, well-defined closed- and open-cell macroporous triacrylate based monoliths are fabricated simply through the adjustment of the ratio of the water phase to oil phase. After coating the resulting macroporous material with polypyrrole nanoparticles, the system can be exploited as an NIR-sensitive filter for bacteria; it not only excludes oversized bacteria, but it also kills the bacteria with the help of NIR-induced heat. PMID- 26110235 TI - Association of claudin2 and PRSS1-PRSS2 polymorphisms with idiopathic recurrent acute and chronic pancreatitis: A case-control study from India. AB - BACKGROUND: Gene polymorphisms, including those recently described in the claudin2 gene, have been implicated in recurrent acute (RAP) and chronic pancreatitis (CP). In India, RAP and CP have been associated with SPINK1 polymorphism. In this study, we evaluated the association of claudin2 and PRSS1 PRSS2 polymorphisms with idiopathic RAP and CP. METHODS: We included 101 prospectively followed patients with documented idiopathic RAP (IRAP) and 96 patients who presented with idiopathic chronic pancreatitis (ICP) without previous history of AP. Controls were 156 unrelated individuals undergoing master health check or with non-specific symptoms. All the samples were genotyped for the SNPs rs7057398 in the claudin2 (CLDN2) gene and rs10273639 in the PRSS1 gene on Realtime polymerase chain reaction platform. Clinical data pertaining to patient and disease characteristics were recorded. RESULTS: Claudin2 and PRSS1 polymorphisms were seen in a significantly higher proportion of female patients (P = 0.01 and 0.039, respectively). Thirty-three (32.7%) patients with IRAP developed features of early CP during follow-up (mean [95% confidence interval, CI] duration of 11.3 [8.9-13.7] months). Female patients with claudin2 (rs7057398) CC genotype were at significantly higher risk for IRAP (odds ratio [OR] [95% CI] 6.75 [1.82-23.67]; P = 0.004) and progression from IRAP to CP (OR [95% CI] 7.05 [1.51-33.01]; P = 0.007). CT genotype of PRSS1 (rs10273639) was associated IRAP (OR [95% CI] 2.59 [1.1-6.13]; P = 0.030), and both CT and CC genotypes with ICP in women (OR [95% CI] 2.86 [1.12-7.31]; P = 0.033 and 3.73 [1.03-13.59]; P = 0.048, respectively). CONCLUSION: In this study, we have demonstrated the association of claudin2 (rs7057398) polymorphism with IRAP and progression of IRAP to CP, and PRSS1 (rs10273639) polymorphism with IRAP and ICP. PMID- 26110237 TI - Stoichiometric and catalytic inter- and intramolecular hydroamination of terminal alkynes by frustrated Lewis pairs. AB - Frustrated Lewis pairs (FLPs) based on sterically encumbered anilines and the Lewis acid B(C6 F5 )3 were found to react with terminal alkynes effecting intermolecular hydroamination affording iminium alkynylborate species of the form [RPhN?C(R')Me][R'CCB(C6 F5 )3 ]. In these cases, the reagent ratio of borane, aniline, and alkyne is 1:1:2. These reactions could also be performed in an intramolecular fashion by using anilines with alkynyl substituents effecting cyclization reactions. The use of 10 mol % B(C6 F5 )3 under a H2 atmosphere provides a one-pot synthesis of the pyrrolidine 12, the piperidines 13-15, the azepane 16, the isoindoline 17, and the benzoxazine 18. PMID- 26110236 TI - Characteristics of Extended-Spectrum beta-Lactamase-Producing Escherichia coli in Retail Meats and Shrimp at a Local Market in Vietnam. AB - BACKGROUND: Contamination of food with multiantibiotic-resistant bacteria, particularly extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, is considered a potential source for the wide dissemination of ESBL-producing bacteria in communities. However, little is known about the extent of contamination of food with ESBL-producing bacteria in Vietnam. OBJECTIVE: This study was conducted to assess the characteristics of ESBL producing Escherichia coli isolated from retail meats and shrimp in Nha Trang, Vietnam. MATERIALS AND METHODS: A total of 350 food samples (poultry [n=143], pork [n=147], and shrimp [n=60]) were purchased in July and November 2013 from a local market. ESBL-producing E. coli were isolated, and ESBL genotypes, phylogenetic groups, and antibiotic resistance profiles were determined. RESULTS: The prevalence of ESBL-producing E. coli in retail foods was 40.6%. beta Lactamase-encoding genes of the CTX-M-1 (50.7%), CTX-M-9 (41.5%), TEM (59.9%), and SHV (2.8%) groups were detected singly or in combination. The percentages of single ESBL isolates harboring CTX-M-1 or -9 plus TEM groups were 35.2% and 16.2%, respectively. B1 was the most prevalent phylogroup in ESBL isolates from pork (44.7%), poultry (55.9%), and shrimp (72.7%). B2 was the least prevalent (4.2% and 4.8% for pork and poultry isolates, respectively). The prevalence of multidrug resistance (MDR; resistance to >= 3 antimicrobial groups) in ESBL producing E. coli isolated from food was 85.9%. DISCUSSION AND CONCLUSIONS: This is the first report of the characteristics of ESBL-producing E. coli in retail foods in a local city in Vietnam. Our findings indicate that retail foods are contaminated with ESBL-producing E. coli, of which many were MDR. Further monitoring and public health efforts targeting food administration are needed to control the spread of ESBL-producing bacteria in communities. PMID- 26110239 TI - Discontinuation of Inhaled Corticosteroids in COPD and the Risk Reduction of Pneumonia. AB - BACKGROUND: The widespread use of inhaled corticosteroids (ICSs) for COPD treatment has been questioned. Recent studies of weaning some patients with COPD off ICSs found little or no adverse consequences compared with long-acting bronchodilators. It is unclear, however, whether discontinuation of ICSs reduces the elevated risk of pneumonia associated with these drugs. METHODS: Using the Quebec health insurance databases, we formed a new-user cohort of patients with COPD treated with ICSs during 1990 to 2005 and followed through 2007 or until a serious pneumonia event, defined as a first hospitalization for or death from pneumonia. A nested case-control analysis of the cohort was used to estimate the rate ratio of serious pneumonia associated with discontinuation of ICS use compared with continued use, adjusted for age, sex, respiratory disease severity, and comorbidity. RESULTS: The cohort included 103,386 users of ICSs, of whom 14,020 had a serious pneumonia event during 4.9 years of follow-up (incidence rate, 2.8/100/y). Discontinuation of ICSs was associated with a 37% decrease in the rate of serious pneumonia (rate ratio [RR], 0.63; 95% CI, 0.60-0.66). The risk reduction was rapidly evident, going from 20% in the first month to 50% by the fourth month after discontinuation. The risk reduction was particularly marked with fluticasone (RR, 0.58; 95% CI, 0.54-0.61) but less so with budesonide (RR, 0.87; 95% CI, 0.78-0.97). CONCLUSIONS: Discontinuation of ICS use in COPD is associated with a reduction in the elevated risk of serious pneumonia, particularly so with fluticasone. PMID- 26110238 TI - Increased excitability of medium-sized dorsal root ganglion neurons by prolonged interleukin-1beta exposure is K(+) channel dependent and reversible. AB - KEY POINTS: Neuropathic pain resulting from peripheral nerve injury is initiated and maintained by persistent ectopic activity in primary afferent neurons. Sciatic nerve injury increases the excitability of medium-sized dorsal root ganglion (DRG) neurons. Levels of the inflammatory cytokine interleukin 1beta (IL 1beta) increase and peak after 7 days. Five to six days of exposure of medium sized DRG neurons to 100 pm IL-1beta promotes persistent increases in excitability which abate within 3-4 days of cytokine removal. This is associated with a profound attenuation of K(+) channel currents but only modest increases in function of cyclic nucleotide-sensitive hyperpolarization-activated channels (HCNs) and of voltage-gated Na(+) and Ca(2+) channel currents. It is unlikely, therefore, that direct interaction of IL-1beta with DRG neurons is capable of initiating an enduring phenotypic shift in their electrophysiological properties that follows sciatic nerve injury. The findings also underline the importance of K(+) channel modulation in the actions of inflammatory mediators on peripheral neurons. ABSTRACT: Chronic constriction injury of rat sciatic nerve promotes signs of neuropathic pain. This is associated with an increase in the level of interleukin 1beta (IL-1beta) in primary afferents that peaks at 7 days. This initial cytokine exposure has been proposed to trigger an enduring alteration in neuronal phenotype that underlies chronic hyper-excitability in sensory nerves, which initiates and maintains chronic neuropathic pain. We have shown previously that 5-6 days of exposure of rat dorsal root ganglia (DRGs) to 100 pm IL-1beta increases the excitability of medium-sized neurons. We have now found using whole cell recording that this increased excitability reverts to control levels within 3-4 days of cytokine removal. The effects of IL-1beta were dominated by changes in K(+) currents. Thus, the amplitudes of A-current, delayed rectifier and Ca(2+) -sensitive K(+) currents were reduced by ~68%, ~64% and ~36%, respectively. Effects of IL-1beta on other cation currents were modest by comparison. There was thus a slight decrease in availability of high voltage-activated Ca(2+) channel current, a small increase in rates of activation of hyperpolarization-activated cyclic nucleotide-gated channel current (IH ), and a shift in the voltage dependence of activation of tetrodotoxin-sensitive sodium current (TTX-S INa ) to more negative potentials. It is unlikely, therefore, that direct interaction of IL-1beta with DRG neurons initiates an enduring phenotypic shift in their electrophysiological properties following sciatic nerve injury. Persistent increases in primary afferent excitability following nerve injury may instead depend on altered K(+) channel function and on the continued presence of slightly elevated levels IL-1beta and other cytokines. PMID- 26110240 TI - [The Primary Health Care Situation in Saxony-Anhalt. Perception, Description and Evaluation of Local Health Care Problems by Mayors]. AB - Background: The combination of ageing general practitioners and a shortage of young doctors is having a negative effect on primary health care in almost all municipalities in the German state of Saxony-Anhalt. The communities are finding it progressively more difficult to safeguard the provision of primary health care. To solve these problems, they have neither the appropriate skills nor sufficient funding. The aim of this study was to ask mayors in Saxony-Anhalt to describe and evaluate local primary health-care systems from their perspective. Method: In June of 2013, all 124 full-time mayors in Saxony-Anhalt were asked by e-mail to participate in a web-based survey. The questionnaire was broken down into the categories: "socio-demographics", "health-care system in the communities", "causes and measures taken to deal with health-care problems", "development of the primary health-care system" and "cooperation". The data were descriptively analysed using IBM Statistics SPSS. Results: The response rate was 51.6% (n=64). For 87.5% of the respondents the primary health-care system is an important location factor in their community. 45.3% consider it their duty to ensure the provision of local health care. However, 42.6% of the polled mayors believe the infrastructure in their community to be too unattractive to convince young general practitioners to settle down there. In the next 10 years, 75.0% of the respondents expect the provision of primary health care to deteriorate further. Conclusions: In view of local deficits, the polled municipalities are very interested in safeguarding the continued existence of primary health care. As local experts, communities should get more involved in planning and decision making processes. PMID- 26110241 TI - [Current Status of Medical Care for Nursing Home Residents in Germany - Results of an Empirical Study]. AB - Following recent studies revealing deficits in general and specialised medical care of nursing home residents in Germany, the discussion on the quality of medical care of residents in residential care facilities has intensified in the past years. As a result, political efforts have been undertaken to facilitate improvements in this context. We collected data on the health status and medical care of 778 residents from 8 nursing homes in order to investigate the current situation regarding medical care for nursing home residents in Germany. Most of them were multimorbid, taking several prescribed medications. Our results showed that about 91% of the residents had personal contact to general practitioners or internists quarterly and only 1.3% had no such contacts within a year. The frequency of contacts to other medical specialists was comparably low. For example, within a year, only 18.9% of the residents had contact to urologists; only 16.7% had contact to ophthalmologists; only 39.6% had contact to dentists and only 10.6% of the female residents had contact to gynaecologists. Despite the fact that many of the residents showed specific medical care needs, these rates were below the utilisation rates of older population groups not living in long term care homes. This leads to the conclusion that previous efforts to optimise medical care in nursing homes were only partially successful. Well known deficits are still remaining. Considering potential consequences for residents, further and consequent actions are required to improve the general and specialised medical care in institutionalised long-term care. PMID- 26110242 TI - [Appraisal of Educational Programmes and Qualifications of Health Occupations/Professions: A European Comparison - Main Results and Conclusions]. AB - INTRODUCTION: This is about some results of a study called "Appraisal of the educational programmes and qualifications of health professions: a European Comparison" (in short: GesinE). It was carried out in the years 2009-2013, commissioned by the BMBF and supported by the BIBB. It is focussed on Germany, France, Great Britain, the Netherlands and Austria. The objectives have been (i) an inventory and comparative international synoptic presentation of education programmes of 16 health professions, (ii) a comparative international qualification analysis for the professions of radiographer, physiotherapist and nurse and (iii) the exposure of key aspects of the health-care and education systems in the compared countries. METHODS: This is a comparative multi-sectional study for which a mixed methods approach with qualitative and quantitative elements was used. RESULTS: According to the results of this study it is necessary that current qualification paths and competence profiles of the health professions are developed continuously in Germany. In this process the German education and the secondary education sector should not be underrated. At the same time the results suggest that there are advantages in some aspects in the academic education (which is the norm for most of the analysed professions in the surveyed countries) compared to the existing education programmes in the secondary sector. This in particular applies to the competence for finding and transferring scientific knowledge into practice and for implementing reflected processes for decision making. CONCLUSIONS: The results improve the basis of the current debate in Germany about the development and reorganisation of the profiles of health professions and their qualification in a European context. PMID- 26110243 TI - [Patients' Priorities in the Treatment of Neuroendocrine Tumours: An Analytical Hierarchy Process]. AB - Background: Neuroendocrine tumours (NET) are relatively rare, usually slow growing malignant tumours. So far there are no data on the patient preferences/priorities regarding the therapy for NET. This empirical study aimed at the elicitation of patient priorities in the drug treatment of NET. Method: Qualitative patient interviews (N=9) were conducted. To elicit the patient's perspective regarding various treatment aspects of NET a self-administered questionnaire using the Analytical Hierarchy Process (AHP) was developed. The data collection was carried out using paper questionnaires supported by an item response system in a group discussion. To evaluate the patient-relevant outcomes, the eigenvector method was applied. Results: N=24 patients, experts and relatives participated in the AHP survey. In the AHP all respondents had clear priorities for all considered attributes. The attribute "overall survival" was the most significant feature of a drug therapy for all respondents. As in the qualitative interviews, "efficacy attributes" dominated the side effects in the AHP as well. The evaluation of all participants thus showed the attributes "overall survival" (Wglobal:0.418), "progression-free survival" (Wglobal:0.172) and "response to treatment" (Wglobal:0.161) to be most relevant. "Occurrence of abdominal pain" (Wglobal:0.051) was ranked sixth, with "tiredness/fatigue" and "risk of a hypoglycaemia" (Wglobal:0.034) in a shared seventh place. Conclusion: The results thus provide evidence about how much influence a treatment capacity has on therapeutic decisions. Using the AHP major aspects of drug therapy from the perspective of those affected were captured, and positive and negative therapeutic properties could be related against each other. Based on the assessment of the patient's perspective further investigation must elicit patient preferences for NET drug therapy. In the context of a discrete choice experiment or another choice-based method of preference measurement, the results obtained here can be validated and the therapeutic features weighted according to their preferability. PMID- 26110244 TI - [Newborn Hearing Screening - Results of a Parental Survey in Saxony-Anhalt]. AB - Background: In recent years quality assurance has become an essential part of today's health-care system in the wake of the modern patient-oriented quality management. With the statutory introduction of newborn hearing screening (NHS) in 2009, a quality assurance of these early detection methods has become necessary. The aim of the study was to determine patient satisfaction in relation to the NHS in Saxony-Anhalt. Patients/Methods: During the period from November 2013 to April 2014, 394 parents were retrospectively interviewed about their experiences and expectations in relation to the NHS, using a standardised questionnaire. In total, 21 child care centres and 6 paediatric primary care centres from all over Saxony-Anhalt were involved. Results: It turns out that the majority of parents are satisfied with the NHS and 97.7% are in favour of the offer of an NHS. Of the surveyed parents, 69.3% felt the information as sufficient. However, only 66.2% of parents took a closer look at the leaflet issued by the G-BA. In addition, 17.7% of respondents are dissatisfied with the professional competence of the examining staff. Conclusion: The study shows that the general attitude among parents towards newborn hearing screening was very positive. They felt reassured by it although there are some aspects still open to criticism. PMID- 26110245 TI - [Development, Application and Evaluation of a Concept for Safe Patient Identification in Hospital - How can Knowledge Transfer Succeed?] AB - Aim of the Study: In order to minimise the risk of patient misidentification in clinical settings, the German Coalition for Patient Safety published recommendations for safety patient identification in 2008. The aim of this study was to develop, implement and evaluate a theoretical framework of knowledge transfer. The purpose of the framework was to enhance hospital staff's ability to apply the recommendations for safe patient identification in the daily routine of patient care. Method: A data bank-based research and literature review have been conducted. Research topics were: knowledge transfer, change management and implementation science. Within the application of the concept group interviews were held with hospital staff and the interview material was evaluated using content analysis. On this basis a tailored multifaceted implementation strategy has been developed and applied in 8 hospital wards of 4 hospitals belonging to a communal hospital concern. The evaluation of the developed knowledge transfer concept was conducted 4 weeks after the concept application with a written questionnaire. Results: The developed framework concept of knowledge translation consisted of 4 phases built on top of each other: initiation phase; analysis phase; implementation phase; evaluation phase. The multifaceted implementation strategy included 3 interventions: a poster, a computer-based training and a guideline for team meetings. The survey yielded responses from 56 individuals: 96% declared that they know about the existence of the recommendations for safe patient identification; 86% said that they know about the content of the recommendations; 91% have striven to apply the recommendations in the daily routine of patient care; 71% stated that the recommendations for safe patient identification have become integral part in the daily routine of patient care. To become aware of the recommendations and its content the respondents have used on average 2.3 interventions, however the effect of the CBS was relatively small. Conclusion: The developed theoretical framework concept for knowledge transfer provides a way to integrate the recommendations for safe patient identification in the daily routine of patient care and to counteract risk factors promoting misidentification. Therefore a multifaceted implementation strategy is promising. PMID- 26110246 TI - [Mortality Related to Alcohol and Tobacco Consumption - A Benchmarking of Regional Trends and Levels]. AB - STUDY AIM: Regional characteristics are being increasingly taken into account in studies on the determinants of health and health-care. A systematic observation and inclusion of regional particularities has, however, been absent from strategic planning and financing decisions to date. Furthermore, regional-level changes over time have, for the most part, not been considered in the existing studies. Accordingly, this article seeks to depict both the levels and trends in potentially avoidable mortality on the district level and to establish a benchmark that shows the theoretical goals for the reduction in avoidable deaths in each district. METHOD: Gender-specific and age-standardised potentially avoidable deaths were determined for each of the 413 German districts in the period from 2000 to 2008 on the basis of cause of death statistics provided by statistical agencies of the German federal states. Deaths due to lung cancer and alcohol-related diseases were taken into account as these are considered to be avoidable through primary prevention. The district-specific benchmark values were ascertained using 2 linear hierarchic nested models and tested for significance using an F-test. RESULTS: Overall, the lung cancer mortality was found to have declined amongst men and gradually increased amongst women during the time period under consideration. The benchmark for deaths from lung cancer in women shows that the increase in mortality is principally observed in West German and urban districts. In relation to the alcohol-related deaths we also see an east-west divide, with higher rates in eastern Germany. Shrinking districts in eastern Germany were able, however, to record a big reduction in rates in recent years. An unfortunate development in the trend of alcohol-related mortality in women was notably observed in regional areas of Bavaria. CONCLUSION: The analysis offers decision makers the possibility of pinpointing regions with high intervention need. Increasing lung cancer mortality rates in women living in cities points to, for example, a heightened need for anti-smoking campaigns in urban areas. In relation to alcohol-related diseases, a heightened need for target group-specific prevention was identified in East German districts as well as some districts in Bavaria. PMID- 26110248 TI - Modelling the mobility of positive ion clusters in normal liquid helium over large pressure ranges. AB - Positively charged helium clusters, also called 'snowballs', have been investigated within normal liquid helium. Thermodynamic state equations for ionic helium clusters in liquid helium have been developed, allowing us to discern the 'hydrodynamic' radius for a wide range of hydrostatic pressures and temperatures. The mobilities derived from the cluster sizes using stokes law match experimental data with unsurpassed accuracy. For low pressures the compressibility of the cluster ions was found to be distinctly larger than the compressibility of solid helium suggesting that in this pressure range clusters are fully or partially liquid. PMID- 26110247 TI - Strong inhibition of betanodavirus replication by ribavirin targeting RNA dependent RNA polymerase. PMID- 26110249 TI - Could we do better? Behavioural tracking on recommended consumer health websites. AB - OBJECTIVE: This study examines behavioural tracking practices on consumer health websites, contrasting tracking on sites recommended by information professionals with tracking on sites returned by Google. METHODS: Two lists of consumer health websites were constructed: sites recommended by information professionals and sites returned by Google searches. Sites were divided into three groups according to source (Recommended-Only, Google-Only or both) and type (Government, Not-for Profit or Commercial). Behavioural tracking practices on each website were documented using a protocol that detected cookies, Web beacons and Flash cookies. The presence and the number of trackers that collect personal information were contrasted across source and type of site; a second set of analyses specifically examined Advertising trackers. RESULTS: Recommended-Only sites show lower levels of tracking - especially tracking by advertisers - than do Google-Only sites or sites found through both sources. Government and Not-for-Profit sites have fewer trackers, particularly from advertisers, than do Commercial sites. CONCLUSIONS: Recommended sites, especially those from Government or Not-for-Profit organisations, present a lower privacy threat than sites returned by Google searches. Nonetheless, most recommended websites include some trackers, and half include at least one Advertising tracker. IMPLICATIONS: To protect patron privacy, information professionals should examine the tracking practices of the websites they recommend. PMID- 26110250 TI - SDF-1 liposomes promote sustained cell proliferation in mouse diabetic wounds. AB - Chronic skin wounds are a common complication of diabetes. When standard wound care fails to heal such wounds, a promising approach consists of using decellularized matrices and other porous scaffold materials to promote the restoration of skin. Proper revascularization is critical for the efficacy of such materials in regenerative medicine. Stromal cell-derived factor-1 (SDF-1) is a chemokine known to play a key role for angiogenesis in ischemic tissues. Herein we developed nanosized SDF-1 liposomes, which were then incorporated into decellularized dermis scaffolds used for skin wound healing applications. SDF-1 peptide associated with liposomes with an efficiency of 80%, and liposomes were easily dispersed throughout the acellular dermis. Acellular dermis spiked with SDF-1 liposomes exhibited more persistent cell proliferation in the dermis, especially in CD31(+) areas, compared to acellular dermis spiked with free SDF-1, which resulted in increased improved wound closure at day 21, and increased granulation tissue thickness at day 28. SDF-1 liposomes may increase the performance of a variety of decellularized matrices used in tissue engineering. PMID- 26110251 TI - Prescription patterns of inhaled corticosteroids for preschool children--A Norwegian register study. AB - BACKGROUND: Although guidelines for treatment of wheeze and asthma in preschool children are available, symptoms are overlapping and it may be difficult to decide which children should be given inhaled corticosteroids (ICS). Previous studies suggest an inappropriate prescription pattern of ICS in this age group. We studied time trends of ICS use in preschool children in Norway during 2004 2013 by age, gender and physician specialty, and the persistence of ICS use during preschool years. METHODS: Data were drawn from the Norwegian Prescription Database. The study population consisted of children <=5 years who were prescribed ICS (alone or in combination) during 2004-2013. RESULTS: The one-year prevalence of ICS use was generally high, and increased from 2004 to 2010, but decreased thereafter. The prevalence was highest in 2-year-olds (boys 12.9% and girls 9.3% in 2010) and declined by age, and higher among boys in all ages. 40 50% of ICS users received only one prescription per year. The share of children with persistent use of ICS over several preschool years was low, irrespective of the age at the first prescription. The majority of prescriptions were given by general practitioners, increasing during the study period. CONCLUSIONS: The prevalence of ICS prescription for preschool children was high, but with low persistence, suggesting that ICS are frequently given for intermittent asthma like symptoms. Asthma guidelines suggest a restrictive use of ICS during the first years of life, and the results may call for actions to better implement these guidelines. PMID- 26110252 TI - A Moderate Low-Carbohydrate Low-Calorie Diet Improves Lipid Profile, Insulin Sensitivity and Adiponectin Expression in Rats. AB - Calorie restriction (CR) via manipulating dietary carbohydrates has attracted increasing interest in the prevention and treatment of metabolic syndrome. There is little consensus about the extent of carbohydrate restriction to elicit optimal results in controlling metabolic parameters. Our study will identify a better carbohydrate-restricted diet using rat models. Rats were fed with one of the following diets for 12 weeks: Control diet, 80% energy (34% carbohydrate reduced) and 60% energy (68% carbohydrate-reduced) of the control diet. Changes in metabolic parameters and expressions of adiponectin and peroxisome proliferator activator receptor gamma (PPARgamma) were identified. Compared to the control diet, 68% carbohydrate-reduced diet led to a decrease in serum triglyceride and increases inlow density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C) and total cholesterol; a 34% carbohydrate reduced diet resulted in a decrease in triglycerides and an increase in HDL cholesterol, no changes however, were shown in LDL-cholesterol and total cholesterol; reductions in HOMA-IR were observed in both CR groups. Gene expressions of adiponectin and PPARgamma in adipose tissues were found proportionally elevated with an increased degree of energy restriction. Our study for the first time ever identified that a moderate-carbohydrate restricted diet is not only effective in raising gene expressions of adiponectin and PPARgamma which potentially lead to better metabolic conditions but is better at improving lipid profiles than a low-carbohydrate diet in rats. PMID- 26110253 TI - A Novel Approach to Improving Fat Delivery in Neonatal Enteral Feeding. AB - Continuous infusion systems used for enteral nutrition support in the neonatal intensive care unit deliver as little as 60% of the fat in human milk to the neonate. This study determined the effect of mixing common feedings for preterm infants in the feeding bag and tubing on fat losses during enteral feeding. Laboratory models were developed to assess the contribution of various mixing techniques to delivered fat content. Fat content was measured periodically during feeding and compared to baseline measurements. A multistage approach incorporating a feeding bag inverter and a tubing circulation loop delivered >90% of milk fat when used in conjunction with a commercial continuous infusion system. With unfortified human milk, this approach delivered 91.9% +/- 1.5% of fat content over a one hour feed, significantly greater (p < 0.01) than 77.5% +/- 2.2% delivered by continuous infusion controls (Mean +/- SEM). With fortified human milk, this approach delivered 92.1% +/- 2.4% of fat content, significantly greater (p < 0.01) than 79.4% +/- 1.0% delivered by a non-adapted infusion system (Mean +/- SEM). Mixing human milk during continuous infusion improves fat delivery, which may improve nutrition and growth outcomes in low birth weight neonates. PMID- 26110254 TI - Association of pretreatment with antifungal medication and fungal resistance in the mycotic ulcer treatment trial I. PMID- 26110256 TI - Acceleration of Full-thickness Wound Healing in Porcine Model by Autologous Platelet Gel. AB - Controversy over efficacy of many wound treatments, particularly autologous platelet gel (APG), is common. The objective of this study was to determine if autologous platelet gel would accelerate the healing process of full-thickness cutaneous wounds in a porcine model. Autologous platelet gel with a ratio of 10:4 was created using 10 cc platelet-rich plasma and 4 cc autologous thrombin rich plasma. A punch was used to create 24 full-thickness, cutaneous round wounds on each flank of a neutered pig and were treated with APG on 1 side versus 0.9% saline (control) on the other side. The wounds were then covered with transparent vapor permeable film dressing. On Day 14 and Day 28 post-injury, all 24 wounds were photographed and digital imaging system tracings determined the area of each wound. Biopsy specimens from each wound were obtained. On Day 14, the specimens were taken from 9- and 3 o'clock positions at the edge of the round wounds, and on Day 28 the specimens were taken from 12- and 6 o'clock positions of the round wounds. This was done to reduce bias from variations in thickness of the pig skin. Sections were stained with hematoxylin and eosin for histological study, which included microscopic review and dermal thickness measurement. The mean size of wounds treated with APG was consistently smaller than contralateral wounds treated with saline alone. On Days 14 and 28 post-injury, APG-treated wounds were 23% and 25% smaller in area than the control wounds (P < 0.001), respectively. Histological study revealed thicker dermis on APG-treated wounds and more normal anatomic skin structures on the APG side. Higher magnification revealed leukocytes consistently more prevalent in granulation tissue on the control side, indicating a delayed healing process. PMID- 26110255 TI - Sexual Dimorphism and Population Differences in Structural Properties of Barn Swallow (Hirundo rustica) Wing and Tail Feathers. AB - Sexual selection and aerodynamic forces affecting structural properties of the flight feathers of birds are poorly understood. Here, we compared the structural features of the innermost primary wing feather (P1) and the sexually dimorphic outermost (Ta6) and monomorphic second outermost (Ta5) tail feathers of barn swallows (Hirundo rustica) from a Romanian population to investigate how sexual selection and resistance to aerodynamic forces affect structural differences among these feathers. Furthermore, we compared structural properties of Ta6 of barn swallows from six European populations. Finally, we determined the relationship between feather growth bars width (GBW) and the structural properties of tail feathers. The structure of P1 indicates strong resistance against aerodynamic forces, while the narrow rachis, low vane density and low bending stiffness of tail feathers suggest reduced resistance against airflow. The highly elongated Ta6 is characterized by structural modifications such as large rachis width and increased barbule density in relation to the less elongated Ta5, which can be explained by increased length and/or high aerodynamic forces acting at the leading tail edge. However, these changes in Ta6 structure do not allow for full compensation of elongation, as reflected by the reduced bending stiffness of Ta6. Ta6 elongation in males resulted in feathers with reduced resistance, as shown by the low barb density and reduced bending stiffness compared to females. The inconsistency in sexual dimorphism and in change in quality traits of Ta6 among six European populations shows that multiple factors may contribute to shaping population differences. In general, the difference in quality traits between tail feathers cannot be explained by the GBW of feathers. Our results show that the material and structural properties of wing and tail feathers of barn swallows change as a result of aerodynamic forces and sexual selection, although the result of these changes can be contrasting. PMID- 26110257 TI - The Biological Mechanisms Behind Injury and Inflammation: How They Can Affect Treatment Strategy, Product Performance, and Healing. AB - The processes behind tissue response to injury and innate immunity are integral parts of the acute wound response and the initiation of repair. In addition, inflammation is a key factor influencing both positive and negative aspects of healing in chronic wounds. Biological data on the signaling mechanisms behind these basic processes has increased dramatically over the last 10 years, yet the products and practice of wound healing have not benefited to the fullest extent from this new knowledge. An in-depth analysis of the biological mechanisms underpinning the processes that impact healing was undertaken to discover ways this information might be used to improve the treatment of chronic wounds. A synopsis of findings is presented regarding the biological mechanisms at work in injury and inflammation. It examines the early stages of wound healing from a mechanistic, biological perspective to gain insight into how this information might translate to the better use and development of wound healing products. These biological processes can impact the effectiveness of treatment from wound bed preparation to potentially regenerative products like growth factors and bioengineered skin constructs. The authors conclude that approaching wound healing from the perspective of biological mechanism can improve how effectively wounds are treated today. As importantly, viewing the development of wound care and wound healing products from the perspective of biological mechanism can lead to new ways of treating wounds that achieve greater clinical significance. PMID- 26110258 TI - Vacuum-assisted Closure Therapy Attenuates the Inflammatory Response in a Porcine Acute Wound Healing Model. AB - Porcine full-thickness wounds were treated with V.A.C.(r) Therapy (KCI, San Antonio, Tex) or moist wound dressing without negative pressure. V.A.C. Therapy related systemic effects included postwound reduction in the number of peripheral blood monocytes and neutrophils during the inflammatory phase of wound healing, as well as reduced serum levels of the pro-inflammatory cytokines IFN-gamma and IL-6. Local effects included reduced concentrations of IL-8, TGF-beta1, and TNF alpha in wound fluid following V.A.C. THERAPY: Collectively, these responses suggest that V.A.C. Therapy may attenuate the pro-inflammatory response following cutaneous wounding. PMID- 26110260 TI - Evidence Corner: April 2007. PMID- 26110259 TI - Treatment of Postherniorrhaphy Inguinal Abscess by Hydrofiber: A Possible Option of Leaving Mesh In situ? AB - The authors present a case of inguinal abscess occurring after inguinal hernia repair that was treated with a silver-containing wound care product without removing the prosthesis. A 75-year-old woman presented with inguinal abscess and acute renal failure initially underwent hemodialysis and then surgical drainage. The mesh was not removed, the wound was left open for secondary healing, and daily wound care was conducted using Aquacel Ag Hydrofiber(r) (ConvaTec, Skillman, NJ). She was discharged 15 days after admission and her wound healed 2 months after admission. PMID- 26110261 TI - Editorial Message: Effectively Managing the Patient Not Just the Problem. PMID- 26110263 TI - Post-Heading Heat Stress in Rice of South China during 1981-2010. AB - Frequent extreme heat events are the serious threat to rice production, but the historical trend of heat stress associated with phenology shift and its impact on rice yield over a long period are poorly known. Based on the analysis of observed climate and phenology data from 228 stations in South China during 1981-2010, the spatio-temporal variation of post-heading heat stress was investigated among two single-season rice sub-regions in the northern Middle and Lower Reaches of Yangtze River (S-NMLYtz) and Southwest Plateau (S-SWP), and two double-season early rice sub-regions in the southern Middle and Lower Reaches of Yangtze River (DE-SMLYtz) and Southern China (DE-SC). Post-heading heat stress was more severe in DE-SMLYtz, west S-NMLYtz and east S-SWP than elsewhere, because of rice exposure to the hot season during post-heading stage. The spatial variation of post-heading heat stress was greater in single-season rice region than in double season early rice region due to the greater spatial variation of heading and maturity dates. Post-heading heat stress increased from 1981 to 2010 in most areas, with significant increases in the east of double-season early rice region and west S-SWP. Phenology shift during 1981-2010 mitigated the increasing trends of heat stress in most areas, but not in west S-SWP. Post-heading heat stress played a dominated role in the reduction of rice yield in South China. Grain yield was more sensitive to post-heading heat stress in double-season early rice region than that in single-season rice region. Rice yield decreased by 1.5%, 6.2%, 9.7% and 4.6% in S-NMLYtz, S-SWP, DE-SMLYtz and DE-SC, respectively, because of post-heading heat stress during 1981-2010, although there were some uncertainties. Given the current level and potential increase of post-heading heat stress in South China, the specific adaptation or mitigation strategies are necessary for different sub-regions to stabilize rice production under heat stress. PMID- 26110264 TI - Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors. AB - Cationic cell-penetrating peptides have been widely used to enhance the intracellular delivery of various types of cargoes, such as drugs and proteins. These reagents are chemically similar to the multi-basic peptides that are known to be potent proprotein convertase inhibitors. Here, we report that both HIV-1 TAT47-57 peptide and the Chariot reagent are micromolar inhibitors of furin activity in vitro. In agreement, HIV-1 TAT47-57 reduced HT1080 cell migration, thought to be mediated by proprotein convertases, by 25%. In addition, cyclic polyarginine peptides containing hydrophobic moieties which have been previously used as transfection reagents also exhibited potent furin inhibition in vitro and also inhibited intracellular convertases. Our finding that cationic cell penetrating peptides exert potent effects on cellular convertase activity should be taken into account when biological effects are assessed. PMID- 26110265 TI - Copper(II)-Mediated Self-Assembly of Hairpin Peptides and Templated Synthesis of CuS Nanowires. AB - The self-assembly of peptides and proteins under well-controlled conditions underlies important nanostructuring processes that could be harnessed in practical applications. Herein, the synthesis of a new hairpin peptide containing four histidine residues is reported and the self-assembly process mediated by metal ions is explored. The work involves the combined use of circular dichroism, NMR spectroscopy, UV/Vis spectroscopy, AFM, and TEM to follow the structural and morphological details of the metal-coordination-mediated folding and self assembly of the peptide. The results indicate that by forming a tetragonal coordination geometry with four histidine residues, copper(II) ions selectively trigger the peptide to fold and then self-assemble into nanofibrils. Furthermore, the copper(II)-bound nanofibrils template the synthesis of CuS nanowires, which display a near-infrared laser-induced thermal effect. PMID- 26110266 TI - Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance. AB - High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used--mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists. PMID- 26110268 TI - Refinement of Strut-and-Tie Model for Reinforced Concrete Deep Beams. AB - Deep beams are commonly used in tall buildings, offshore structures, and foundations. According to many codes and standards, strut-and-tie model (STM) is recommended as a rational approach for deep beam analyses. This research focuses on the STM recommended by ACI 318-11 and AASHTO LRFD and uses experimental results to modify the strut effectiveness factor in STM for reinforced concrete (RC) deep beams. This study aims to refine STM through the strut effectiveness factor and increase result accuracy. Six RC deep beams with different shear span to effective-depth ratios (a/d) of 0.75, 1.00, 1.25, 1.50, 1.75, and 2.00 were experimentally tested under a four-point bending set-up. The ultimate shear strength of deep beams obtained from non-linear finite element modeling and STM recommended by ACI 318-11 as well as AASHTO LRFD (2012) were compared with the experimental results. An empirical equation was proposed to modify the principal tensile strain value in the bottle-shaped strut of deep beams. The equation of the strut effectiveness factor from AASHTTO LRFD was then modified through the aforementioned empirical equation. An investigation on the failure mode and crack propagation in RC deep beams subjected to load was also conducted. PMID- 26110267 TI - Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition. AB - Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z+ T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1+ or 19z1-CD80+ T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z+ T cells had 10 fold reduced tumor progression compared to those treated with 19z1+ or 19z1-CD80+ T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80+ T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z+ T cells. Our results establish that CTLA-4 down regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function. PMID- 26110269 TI - Pulmonary arterial wall thickness in Eisenmenger Syndrome: Prospective, cross sectional, controlled clinical trial. AB - BACKGROUND: The aim of current study is to investigate echocardiographic pulmonary artery wall thickness (PAWT) association with angiocardiography, echocardiography, and biochemical findings and to demonstrate its predictive role in morbidity of disease. METHOD: Nineteen patients with Eisenmenger Syndrome (ES) (13 females; a mean age of 12.0 +/- 4.1 [min-max 4-17] years) and 24 (16 females; a mean age of 12.1 +/- 4.3 [min-max 3-18 years]) healthy subjects as a control group were included in this prospective, cross-sectional, controlled clinical study between December, 2012 and December, 2013. PAWT were measured at the end of systole at the distal site of pulmonary valves at the parasternal short-axis. PAWT was compared with morbidity criteria of the disease such as functional class, pulmonary vascular resistance. RESULTS: PAWT was higher in the patient group (P = 0.005) together with pulmonary arterial diameter (Z-score, P < 0.001), vena cava inferior diameter (P = 0.002), and right ventricular wall thickness (RVWT), while TAPSE was significantly lower (P = 0.002). PAWT was strongly positively correlated to RVWT (r = 0.893, P < 0.001) and moderate negatively correlated to TAPSE (r = 0.597; P < 0.011). CONCLUSION: PAWT can be used as an additional parameter with other echocardiographic parameters in the follow-up of Eisenmenger Syndrome in children. PMID- 26110270 TI - A Systematic Review of the Mortality from Untreated Leptospirosis. AB - BACKGROUND: Leptospirosis occurs worldwide, but the global incidence of human disease and its mortality are not well understood. Many patients are undiagnosed and untreated due to its non-specific symptoms and a lack of access to diagnostics. This study systematically reviews the literature to clarify the mortality from untreated leptospirosis. Results will help quantify the global burden of disease and guide health policies. METHODOLOGY/PRINCIPAL FINDINGS: A comprehensive literature search was performed to identify untreated patient series. Included patients were symptomatic, but asymptomatic patients and those who had received antibiotics, dialysis or who were treated on Intensive Care Units were excluded. Included patients had a confirmed laboratory diagnosis by culture, PCR, or serological tests. Data was extracted and individual patient series were assessed for bias. Thirty-five studies, comprising 41 patient series and 3,390 patients, were included in the study. A high degree of bias within studies was shown due to limitations in study design, diagnostic tests and missing data. Median series mortality was 2.2% (Range 0.0-39.7%), but mortality was high in jaundiced patients (19.1%) (Range 0.0-39.7%), those with renal failure 12.1% (Range 0-25.0%) and in patients aged over 60 (60%) (Range 33.3 60%), but low in anicteric patients (0%) (Range 0-1.7%). CONCLUSIONS: This systematic review contributes to our understanding of the mortality of untreated leptospirosis and provides data for the estimation of DALYs attributable to this disease. We show that mortality is significantly higher in older patients with icteric disease or renal failure but is lower in younger, anicteric patients. Increased surveillance and accurate point-of-care diagnostics are required to better understand the incidence and improve diagnosis of disease. Empirical treatment strategies should prioritize early treatment to improve outcomes from leptospirosis. PMID- 26110272 TI - Exploring Host-Pathogen Interactions through Biological Control. PMID- 26110271 TI - Emotion processing in Parkinson's disease: a three-level study on recognition, representation, and regulation. AB - BACKGROUND: Parkinson's disease (PD) is characterised by well-known motor symptoms, whereas the presence of cognitive non-motor symptoms, such as emotional disturbances, is still underestimated. One of the major problems in studying emotion deficits in PD is an atomising approach that does not take into account different levels of emotion elaboration. Our study addressed the question of whether people with PD exhibit difficulties in one or more specific dimensions of emotion processing, investigating three different levels of analyses, that is, recognition, representation, and regulation. METHODOLOGY: Thirty-two consecutive medicated patients with PD and 25 healthy controls were enrolled in the study. Participants performed a three-level analysis assessment of emotional processing using quantitative standardised emotional tasks: the Ekman 60-Faces for emotion recognition, the full 36-item version of the Reading the Mind in the Eyes (RME) for emotion representation, and the 20-item Toronto Alexithymia Scale (TAS-20) for emotion regulation. PRINCIPAL FINDINGS: Regarding emotion recognition, patients obtained significantly worse scores than controls in the total score of Ekman 60-Faces but not in any other basic emotions. For emotion representation, patients obtained significantly worse scores than controls in the RME experimental score but no in the RME gender control task. Finally, on emotion regulation, PD and controls did not perform differently at TAS-20 and no specific differences were found on TAS-20 subscales. The PD impairments on emotion recognition and representation do not correlate with dopamine therapy, disease severity, or with the duration of illness. These results are independent from other cognitive processes, such as global cognitive status and executive function, or from psychiatric status, such as depression, anxiety or apathy. CONCLUSIONS: These results may contribute to better understanding of the emotional problems that are often seen in patients with PD and the measures used to test these problems, in particular on the use of different versions of the RME task. PMID- 26110273 TI - The Multi-Drug Resistant Tuberculosis Diagnosis and Treatment Cascade in Bangladesh. AB - OBJECTIVES: To determine, in areas supported by BRAC, Bangladesh i) the pre diagnosis and pre-treatment attrition among presumptive and confirmed Multi-Drug Resistant Tuberculosis (MDR-TB) patients and ii) factors associated with attrition. METHODS: This was a retrospective cohort study involving record review. Presumptive MDR-TB patients from peripheral microscopy centres serving 60% of the total population of Bangladesh were included in the study. Attrition and turnaround time for MDR-TB diagnosis by Xpert MTB/RIF and treatment initiation were calculated between July 2012 and June 2014. RESULTS: Of 836 presumptive MDR-TB patients referred from 398 peripheral microscopy centres, 161 MDR-TB patients were diagnosed. The number of diagnosed MDR-TB patients was less than country estimates of MDR-TB patients (2000 cases) during the study period. Among those referred, pre-diagnosis and pre-treatment attrition was 17% and 21% respectively. Median turnaround time for MDR-TB testing, result receipt and treatment initiation was four, zero and five days respectively. Farmers (RR=2.3, p=0.01) and daily wage laborers (RR=2.1, p=0.04) had twice the risk of having pre diagnosis attrition. Poor record-keeping and unreliable upkeep of presumptive MDR TB patient databases were identified as challenges at the peripheral microscopy centres. CONCLUSION: There was a low proportion of pre-diagnosis and pre treatment attrition in patients with presumptive and confirmed MDR-TB under programmatic conditions. However, the recording and reporting system did not detect all presumptive MDR-TB patients, highlighting the need to improve the system in order to prevent morbidity, mortality and transmission of MDR-TB in the community. PMID- 26110274 TI - Proprioceptive body illusions modulate the visual perception of reaching distance. AB - The neurobiology of reaching has been extensively studied in human and non-human primates. However, the mechanisms that allow a subject to decide-without engaging in explicit action-whether an object is reachable are not fully understood. Some studies conclude that decisions near the reach limit depend on motor simulations of the reaching movement. Others have shown that the body schema plays a role in explicit and implicit distance estimation, especially after motor practice with a tool. In this study we evaluate the causal role of multisensory body representations in the perception of reachable space. We reasoned that if body schema is used to estimate reach, an illusion of the finger size induced by proprioceptive stimulation should propagate to the perception of reaching distances. To test this hypothesis we induced a proprioceptive illusion of extension or shrinkage of the right index finger while participants judged a series of LEDs as reachable or non-reachable without actual movement. Our results show that reach distance estimation depends on the illusory perceived size of the finger: illusory elongation produced a shift of reaching distance away from the body whereas illusory shrinkage produced the opposite effect. Combining these results with previous findings, we suggest that deciding if a target is reachable requires an integration of body inputs in high order multisensory parietal areas that engage in movement simulations through connections with frontal premotor areas. PMID- 26110275 TI - Psychological Distress in the Hospital Setting: A Comparison between Native Dutch and Immigrant Patients. AB - BACKGROUND: Prevalence of psychological distress (i.e. depressive and anxiety symptoms) in medically ill patients is high. Research in the general population shows a higher prevalence of psychological distress among immigrants compared to natives. Our aim was to examine the prevalence of psychological distress in the hospital setting comparing immigrant and native Dutch patients and first and second generation immigrant patients. METHODS: Prevalence of psychological distress was assessed using the extended Kessler-10 (EK-10) in 904 patients in a Dutch general teaching hospital. Logistic regression was used to calculate odds ratios to determine differences between native and immigrant patients and first and second generation immigrants in the prevalence of psychological distress. We adjusted for demographic and social variables, socio-economic status, physical quality of life, history of psychiatric disease and health care use. RESULTS: Of 904 patients, 585 were native Dutch patients and 319 were immigrant patients. The prevalence of psychological distress in native compared to immigrant patients was 54% and 66% respectively, with especially high prevalences among Turkish and Moroccan immigrant patients. The crude OR for prevalence of psychological distress for immigrant patients versus native patients was 1.7 (95% CI 1.2-2.2) and for first versus second generation immigrant patients 2.1 (95% CI 1.2-3.5). After full adjustment ORs were 1.7 (95% CI 1.2-2.3) and 2.2 (95% CI 1.2-4.1) respectively. CONCLUSION: Immigrant patients and first generation immigrant patients were more likely to have psychological distress compared to native patients and second generation immigrant patients respectively. We found a particularly high prevalence of psychological distress in Turkish and Moroccan immigrants. PMID- 26110276 TI - BGD: a database of bat genomes. AB - Bats account for ~20% of mammalian species, and are the only mammals with true powered flight. For the sake of their specialized phenotypic traits, many researches have been devoted to examine the evolution of bats. Until now, some whole genome sequences of bats have been assembled and annotated, however, a uniform resource for the annotated bat genomes is still unavailable. To make the extensive data associated with the bat genomes accessible to the general biological communities, we established a Bat Genome Database (BGD). BGD is an open-access, web-available portal that integrates available data of bat genomes and genes. It hosts data from six bat species, including two megabats and four microbats. Users can query the gene annotations using efficient searching engine, and it offers browsable tracks of bat genomes. Furthermore, an easy-to-use phylogenetic analysis tool was also provided to facilitate online phylogeny study of genes. To the best of our knowledge, BGD is the first database of bat genomes. It will extend our understanding of the bat evolution and be advantageous to the bat sequences analysis. BGD is freely available at: http://donglab.ecnu.edu.cn/databases/BatGenome/. PMID- 26110277 TI - Do bells affect behaviour and heart rate variability in grazing dairy cows? AB - In alpine regions cows are often equipped with bells. The present study investigated the impact of wearing a bell on behaviour and heart rate variability in dairy cows. Nineteen non-lactating Brown-Swiss cows with bell experience were assigned to three different treatments. For 3 days each, cows were equipped with no bell (control), with a bell with inactivated clapper (silent bell) or with a functional bell (functional bell). The bells weighed 5.5 kg and had frequencies between 532 Hz and 2.8 kHz and amplitudes between 90 and 113 dB at a distance of 20 cm. Data were collected on either the first and third or on all 3 days of each treatment. Whereas duration of rumination was reduced with a functional bell and a silent bell compared with no bell, feeding duration was reduced with a silent bell and was intermediate with a functional bell. Head movements were reduced when wearing a silent bell compared with no bell and tended to be reduced when wearing a functional compared to no bell. With a functional bell, lying duration was reduced by almost 4 hours on the third day of treatment compared with the first day with a functional bell and compared with no bell or a silent bell. All additional behavioural measures are consistent with the hypothesis of a restriction in the behaviour of the cows wearing bells, although this pattern did not reach significance. There was no treatment effect on heart rate variability, suggesting that the bells did not affect vago-sympathetic balance. An effect of experimental day was found for only 1 out of 10 behavioural parameters, as shown by a decrease in lying with a functional bell on day 3. The results indicate behavioural changes in the cows wearing a bell over 3 days, without indication of habituation to the bell. Altogether, the behavioural changes suggest that the behaviour of the cows was disturbed by wearing a bell. If long-lasting, these effects may have implications for animal welfare. PMID- 26110278 TI - Correction: quantitative analysis of respiration-related movement for abdominal artery in multiphase hepatic CT. PMID- 26110279 TI - Association of Climatic Variability, Vector Population and Malarial Disease in District of Visakhapatnam, India: A Modeling and Prediction Analysis. AB - BACKGROUND: Malarial incidence, severity, dynamics and distribution of malaria are strongly determined by climatic factors, i.e., temperature, precipitation, and relative humidity. The objectives of the current study were to analyse and model the relationships among climate, vector and malaria disease in district of Visakhapatnam, India to understand malaria transmission mechanism (MTM). METHODOLOGY: Epidemiological, vector and climate data were analysed for the years 2005 to 2011 in Visakhapatnam to understand the magnitude, trends and seasonal patterns of the malarial disease. Statistical software MINITAB ver. 14 was used for performing correlation, linear and multiple regression analysis. RESULTS/FINDINGS: Perennial malaria disease incidence and mosquito population was observed in the district of Visakhapatnam with peaks in seasons. All the climatic variables have a significant influence on disease incidence as well as on mosquito populations. Correlation coefficient analysis, seasonal index and seasonal analysis demonstrated significant relationships among climatic factors, mosquito population and malaria disease incidence in the district of Visakhapatnam, India. Multiple regression and ARIMA (I) models are best suited models for modeling and prediction of disease incidences and mosquito population. Predicted values of average temperature, mosquito population and malarial cases increased along with the year. Developed MTM algorithm observed a major MTM cycle following the June to August rains and occurring between June to September and minor MTM cycles following March to April rains and occurring between March to April in the district of Visakhapatnam. Fluctuations in climatic factors favored an increase in mosquito populations and thereby increasing the number of malarial cases. Rainfall, temperatures (20 degrees C to 33 degrees C) and humidity (66% to 81%) maintained a warmer, wetter climate for mosquito growth, parasite development and malaria transmission. CONCLUSIONS/SIGNIFICANCE: Changes in climatic factors influence malaria directly by modifying the behaviour and geographical distribution of vectors and by changing the length of the life cycle of the parasite. PMID- 26110280 TI - An insulator element located at the cyclin B1 interacting protein 1 gene locus is highly conserved among mammalian species. AB - Insulators are cis-elements that control the direction of enhancer and silencer activities (enhancer-blocking) and protect genes from silencing by heterochromatinization (barrier activity). Understanding insulators is critical to elucidate gene regulatory mechanisms at chromosomal domain levels. Here, we focused on a genomic region upstream of the mouse Ccnb1ip1 (cyclin B1 interacting protein 1) gene that was methylated in E9.5 embryos of the C57BL/6 strain, but unmethylated in those of the 129X1/SvJ and JF1/Ms strains. We hypothesized the existence of an insulator-type element that prevents the spread of DNA methylation within the 1.8 kbp segment, and actually identified a 242-bp and a 185-bp fragments that were located adjacent to each other and showed insulator and enhancer activities, respectively, in reporter assays. We designated these genomic regions as the Ccnb1ip1 insulator and the Ccnb1ip1 enhancer. The Ccnb1ip1 insulator showed enhancer-blocking activity in the luciferase assays and barrier activity in the colony formation assays. Further examination of the Ccnb1ip1 locus in other mammalian species revealed that the insulator and enhancer are highly conserved among a wide variety of species, and are located immediately upstream of the transcriptional start site of Ccnb1ip1. These newly identified cis-elements may be involved in transcriptional regulation of Ccnb1ip1, which is important in meiotic crossing-over and G2/M transition of the mitotic cell cycle. PMID- 26110281 TI - VarI-SIG 2014--From SNPs to variants: interpreting different types of genetic variants. PMID- 26110282 TI - Computational Modelling of NF-kappaB Activation by IL-1RI and Its Co-Receptor TILRR, Predicts a Role for Cytoskeletal Sequestration of IkappaBalpha in Inflammatory Signalling. AB - The transcription factor NF-kappaB (nuclear factor kappa B) is activated by Toll like receptors and controlled by mechanotransduction and changes in the cytoskeleton. In this study we combine 3-D predictive protein modelling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NF-kappaB. Simulations used a comprehensive agent based model of the NF-kappaB pathway, which includes the type 1 IL-1 receptor (IL 1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent based modelling relies on in silico reproductions of systems through the interactions of its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex formation and translocation of regulatory components. We show that our model faithfully reproduces the multiple steps comprising the NF-kappaB pathway, and provides a framework from which we can explore novel aspects of the system. The analysis, using 3-D predictive protein modelling and in vitro assays, demonstrated that the NF-kappaB inhibitor, IkappaBalpha is sequestered to the actin/spectrin complex within the cytoskeleton of the resting cell, and released during IL-1 stimulation, through a process controlled by the IL-1RI co-receptor TILRR (Toll-like and IL-1 receptor regulator). In silico simulations using the agent-based model predict that the cytoskeletal pool of IkappaBalpha is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for signal calibration and enables efficient, activation-sensitive regulation of NF-kappaB and inflammatory responses. PMID- 26110283 TI - Reply to Treatment decisions and outcome in very elderly patients with diffuse large B-cell lymphoma. PMID- 26110284 TI - Inhibition of Interferon Regulatory Factor 4 Suppresses Th1 and Th17 Cell Differentiation and Ameliorates Experimental Autoimmune Encephalomyelitis. AB - Multiple sclerosis (MS) is an autoimmune disease that is characterized by recurrent episodes of T-cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. Interferon regulatory factor 4 (IRF4) is expressed predominantly in the immune system and plays an important role in its development and function. Recent study demonstrated that IRF4 was critical for the generation of IL-17-producing Th17 cells. However, the effect of IRF4 on experimental autoimmune encephalomyelitis (EAE), an animal model of MS, needs to be further investigated. In our current study, inhibition of IRF4 with IRF4 siRNA (SiIRF4) decreases EAE scores and infiltration of Th1 and Th17 cells, but increases Treg infiltration. SiIRF4 inhibits Th1 and Th17 cell differentiation in vivo and in vitro. In our DC-T-cell coculture system, SiIRF4-treated DCs resulted in significantly less IFN-gamma and IL-17 production from T cells. Next, we adoptively transfer CD11c(+) DCs from SiIRF4-treated mice into recipient mice and found that these CD11c(+) DCs ameliorated EAE. Furthermore, CD11c(+) DCs from SiIRF4-treated naive mice exhibited significantly reduced expression of pro-inflammatory cytokines TNF alpha, IL-1beta, IL-6 and IL-12/IL-23 (p40), and a corresponding increase in anti inflammatory IL-10 expression. In conclusion, inhibition of IRF4 suppresses Th1 and Th17 cell differentiation and ameliorates EAE, via a direct regulation of DCs. PMID- 26110285 TI - The Effect of Solvation on Electron Attachment to Pure and Hydrated Pyrimidine Clusters. AB - The interaction of low-energy electrons with biomolecules plays an important role in the radiation-induced alteration of biological tissue at the molecular level. At electron energies below 15 eV, dissociative electron attachment is one of the most important processes in terms of the chemical transformation of molecules. So far, a common approach to study processes at the molecular level has been to carry out investigations with single biomolecular building blocks like pyrimidine as model molecules. Electron attachment to single pyrimidine, as well as to pure clusters and hydrated clusters, was investigated in this study. In striking contrast to the situation with isolated molecules and hydrated clusters, where no anionic monomer is detectable, we were able to observe the molecular anion for the pure clusters. Furthermore, there is evidence that solvation effectively prevents the ring fragmentation of pyrimidine after electron capture. PMID- 26110286 TI - Human Fetal Progenitor Tenocytes for Regenerative Medicine. AB - Tendon injuries are very frequent and affect a wide and heterogeneous population. Unfortunately, the healing process is long with outcomes that are not often satisfactory due to fibrotic tissue appearance, which leads to scar and adhesion development. Tissue engineering and cell therapies emerge as interesting alternatives to classical treatments. In this study, we evaluated human fetal progenitor tenocytes (hFPTs) as a potential cell source for treatment of tendon afflictions, as fetal cells are known to promote healing in a scarless regenerative process. hFPTs presented a rapid and stable growth up to passage 9, allowing to create a large cell bank for off-the-shelf availability. hFPTs showed a strong tenogenic phenotype with an excellent stability, even when placed in conditions normally inducing cells to differentiate. The karyotype also indicated a good stability up to passage 12, which is far beyond that necessary for clinical application (passage 6). When placed in coculture, hFPTs had the capacity to stimulate human adult tenocytes (hATs), which are responsible for the deposition of a new extracellular matrix during tendon healing. Finally, it was possible to distribute cells in porous or gel scaffolds with an excellent survival, thus permitting a large variety of applications (from simple injections to grafts acting as filling material). All of these results are encouraging in the development of an off-the-shelf cell source capable of stimulating tendon regeneration for the treatment of tendon injuries. PMID- 26110287 TI - [Is There Really Agreement between Rebound and Goldmann Applanation Tonometry Methods? Results of a Systematic Review of the Period 01/2005 to 08/2014]. AB - BACKGROUND: After its introduction in 2003 the iCare(r) rebound tonometry has gained wide acceptance, mostly as a result of immediate method comparison trials showing high concordance with the Goldmann applanation tonometry (GAT) as a reference method. The objective of this systemic review was the synopsis of the current literature as a rationale of a concordance evaluation between the iCare(r) rebound and the Goldmann applanation tonometry methods. METHODS: The PubMed database was searched for Anglo-American and German publications comparing intraindividually the two tonometry methods and having been published during the period 01/2005 to 08/2014. The primary endpoint of the review was the reported IOD deviation [mmHg] between the two devices; for each trial, this primary endpoint was parameterised in terms of the "mean deviation" as well as the "relative frequency [%] of measurements with an intraindividual deviation of >= +/- 3 mmHg". A total of 33 published method comparison studies concerning the iCare TA01i device were included, 17 of them being published between 01/2009 and 08/2014. The number of analysed eyes ranged between 28 and 445; 17 of the 33 studies reported more than 100 examined eyes. 7 of the 33 studies included only healthy eyes. RESULTS: Only 10 out of the 33 studies reported a mean deviation of more than +/- 1.5 mmHg, 7 of these were published between 01/2009 and 08/2014. Only 12 of the 33 studies reported the relative frequency of intraindividual deviations >= +/- 3 mmHg, 7 of them reporting a frequency > 20 % (with a maximum of 51 %), with higher frequencies being derived from samples showing higher IOD levels according to the GAT reference. CONCLUSION: As concluded from the current literature the iCare(r) rebound and the Goldmann applanation tonometry methods cannot be considered exchangable. PMID- 26110288 TI - Oropharyngeal Candidiasis in HIV Infection: Analysis of Impaired Mucosal Immune Response to Candida albicans in Mice Expressing the HIV-1 Transgene. AB - IL-17-producing Th17 cells are of critical importance in host defense against oropharyngeal candidiasis (OPC). Speculation about defective Th17 responses to oral C. albicans infection in the context of HIV infection prompted an investigation of innate and adaptive immune responses to Candida albicans in transgenic mice expressing the genome of HIV-1 in immune cells and displaying an AIDS-like disease. Defective IL-17 and IL-22-dependent mucosal responses to C. albicans were found to determine susceptibility to OPC in these transgenic mice. Innate phagocytes were quantitatively and functionally intact, and individually dispensable for control of OPC and to prevent systemic dissemination of Candida to deep organs. CD8+ T-cells recruited to the oral mucosa of the transgenic mice limited the proliferation of C. albicans in these conditions of CD4+ T-cell deficiency. Therefore, the immunopathogenesis of OPC in the context of HIV infection involves defective T-cell-mediated immunity, failure of crosstalk with innate mucosal immune effector mechanisms, and compensatory cell responses, which limit Candida infection to the oral mucosa and prevent systemic dissemination. PMID- 26110289 TI - Methicillin-resistant Staphylococcus aureus infections: role of daptomycin/beta lactams combination. AB - Methicillin-resistant Staphylococcus aureus (MRSA) associated infection has become a worrisome issue worldwide. Glycopeptides are the backbone antibiotics for the treatment of MRSA infections. However, several reports have highlighted the limitations of vancomycin. Daptomycin is successfully used for the treatment of serious MRSA infections, however selection of resistant strains has been reported during daptomycin-monotherapy. This review will briefly discuss the available data on daptomycin/beta-lactam combination therapies for the treatment of MRSA infections. PMID- 26110290 TI - Candidemia, and infections by Clostridium difficile and carbapenemase-producing Enterobacteriaceae: new enteropathogenetic opportunistic syndromes? AB - In this paper we analyze three enteropathogenetic opportunistic infections represented by Candida spp., C. difficile and carbapenemase-producing K. pneumoniae. The common pathogenetic pathway is based on an alteration of the intestinal flora, now mainly referred as the human microbiome, with secondary opportunism for infections caused by Candida, C. difficile and carbapenemase producing Enterobacteriaceae ("CCC"). We highlight the epidemiology, risk factors, clinical syndromes associated with the pathogens and we propose some new issues related to the epidemiology and diagnosis of candidemia, also using hierarchical cluster analysis, definitions of levels of interventions in patients colonized or infected by carbapenemase-producing bacteria. The "enteropathogenetic" opportunistic syndromes are best prevented with antimicrobial stewardship programs aiming at increasing diagnostic specificity of infectious syndromes to reduce the antimicrobial use and costs. Appropriate guidelines for infection control should also be implemented to reduce the nosocomial spread of enteropathogenetic microbes. PMID- 26110291 TI - Medical care related laboratory-confirmed bloodstream infections in paediatrics. AB - The aim of this survey was to describe the incidence, epidemiology, microbiology, risk factors and outcome of medical care related laboratory-confirmed bloodstream infections (LCBIs) observed during a twelve-month prospective study in a Paediatric Teaching Hospital in Turin, Italy. Inclusion criteria were clinical signs of sepsis and positivity of one or more of the following tests: blood culture, polymerase chain reaction for bacterial and fungal DNA on blood, and culture on intravascular device tips. In all, 140 episodes of sepsis were documented in 131 children: 37 (26.4%) were healthcare outpatient-associated, 91 (65.0%) healthcare-associated and 12 (8.6%) community-acquired. The overall incidence of healthcare-associated LCBIs was 13.6/1,000 hospitalized patients and incidence density 1.4/1,000 inpatient days. The overall mortality was 3.9%. Forty seven (36.7%) episodes involved newborns and 107 (83.6%) episodes were observed in children with an indwelling central venous catheter. Coagulase-negative staphylococci (26.8%), Staphylococcus aureus (15.2%), Escherichia coli (8.7%) and Candida spp. (7.2%) were responsible for the majority of cases. 9.5% of S. aureus isolates were methicillin-resistant and 6.5% of Gram negatives were extended spectrum beta-lactamase-producing. Incidence and epidemiology of medical care related LCBIs were similar to the existing literature data. LCBIs caused by antibiotic-resistant microorganisms were fewer and mortality rate was lower. Most of the LCBIs recorded involved newborns and oncological children. PMID- 26110292 TI - Experience of influenza A H1N1 in a paediatric emergency unit. AB - This study was carried out to evaluate symptoms, clinical findings, treatment options and complications of H1N1 influenza infection in patients who applied to our emergency unit during the influenza season in 2009. The clinical and laboratory findings of children with influenza A (H1N1) during the influenza season in 2009 were evaluated retrospectively. Influenza A was diagnosed by polymerase chain reaction and/or rapid antigen test. Clinical and laboratory findings of the patients with H1N1 (group I) and without H1N1 (group II) were compared. Fever and myalgia were noted to be higher in group I (p <0.05). The mean body temperature in group I was 39.0?, which was statistically different from group II (p <0.001). Myalgia was observed only in group I (15.4%), but not in group II (p <0.05). There were three patients with diarrhoea, two of whom were in group I, and they had no significant respiratory symptoms. Lymphopenia was seen in 18 patients (81.8%) in group I and in four patients (23.5%) in group II (p <0.05). Oseltamivir treatment was applied to 28 patients, where 24 had severe symptoms, nine had comorbid factors and two did not have any of these. The fever was higher in group I and myalgia was present only in group I. In group I, the lymphocyte count was significantly lower than in group II. The fever was higher in patients of H1N1 (average of 39 degrees C) and myalgia was present only in patients with H1N1. The lymphocyte count was significantly lower in patients with H1N1 than those without H1N1. While none of the patients required intensive care, three patients requiring hospitalization were discharged after referral and completion of their treatment. PMID- 26110293 TI - Role of ITPA and IL28B variants in the management of chronic hepatitis C treatment. AB - The inosine triphosphatase (ITPA) gene and interleukin 28B (IL28-B) gene variants have been associated to protection of anemia and sustained virological response, respectively, in patients with chronic hepatitis C (CHC) during antiviral therapy. Aim of this study was to evaluate the single and combined role of both polymorphisms in the management of peg-interferon-ribavirin treatment in CHC patients. We studied 79 Italian patients with histology proven CHC treated with pegylated interferon plus ribavirin for 6-12 months on the base of HCV genotype. Patients were carefully followed-up for anemia development which was classified as mild, moderate or severe in relation to levels of haemoglobin decreasing; ribavirin dosage reduction and/or epoietin administration were carried out, where needed. Sustained virological response (SVR) was considered for HCV-RNA clearance after 6 months of treatment stop. Decay of haemoglobin at month 1 of treatment significantly correlated with ITPA activity (p 0.0004) and at multivariate analysis ITPA activity was the only parameter associate with anemia (R - 0.4; p 0.0004). SVR was obtained in 47% of patients. IL28B CC variant was associated with SVR (p 0.01), but IL28B polymorphisms had no influence on the ITPA polymorphism. This study confirms the role of ITPA variants in the prediction of development of severe anemia during antiviral treatment for CHC and demonstrates the absence of influence of IL28B variant on ITPA polymorphisms. These two polymorphisms can be useful in the management of patients that need antiviral therapy for HCV chronic infection. PMID- 26110294 TI - [Diagnosis in patients with a painful arthroplasty]. AB - The differential diagnosis between asepting loosening or prosthetic joint infection is not always easy. Tc-99m-labelled leucocyte scans, frozen section and histology can help recognise doubtful cases. We report the experience of the Unit for Infectious Diseases and Septic Orthopaedics of the ASL-2 Liguria, Italy, with a Tc-99m-labelled leucocyte scan and intraoperative frozen section to choose the best therapeutic approach: one-stage or two-stage exchange or arthrodesis arthroplastica. All cases underwent histology and intraoperative cultures to confirm the diagnosis, and the effectiveness of the approach was evaluated at follow up after 18 months. From January 2011 to December 2012, 36 patients were evaluated (21 hip and 15 knee arthroprosthesis). The Tc-99m-labelled leukocyte scan was positive in 31 and negative in 5 patients. Frozen section was negative in 7 patients. Five of them were patients with a negative Tc-99m-labelled leucocyte scan and were treated successfully with one-stage exchange, even if, in one of them, Enterococcus faecalis was isolated at replacement and suppressive antibiotic treatment was needed. The other 31 patients were treated with arthrodesis arthroplasty (3 patients) or a two-stage exchange. In this group the Tc-99m-labelled leucocyte scan was positive in all patients and the frozen section was positive in 29/31 cases with 6% false negative. Histology was positive in 27/31 with 13% of false negative. The sensitivity and specificity value was respectively 90% and 100% in the frozen section, 84% and 100% in histology. Cultures were positive in 23/31 cases. Patients subjected to two-stage exchange were evaluated again during prosthesis replacement but the results of the Tc-99m-labelled leucocyte scan and histology showed unclear results more frequently: the Tc-99m-labelled leucocyte scan was positive in two cases, the frozen section in three and histology in seven in spite of positive culture in three cases and one relapse in a patient with a frozen section and histology positive but negative culture. In the second step sensitivity and specificity were respectively 67% and 96% in the frozen section, 75% and 88% in histology. Finally, our experience suggests the utility of nuclear and histological tests during diagnostic work-up for differential diagnosis of aseptic loosening or prosthetic joint infection. The same tests produce more uncertain data when performed in two-stage exchange during the second step. PMID- 26110295 TI - [Antiretroviral therapy in inmates: between guidelines and reality of Italian correctional facilities]. AB - In HIV-positive patients detention often represents a unique opportunity for health care. HIV-positive inmates enjoy the same rights as non-restricted people, as established under national and international legislation, declarations and guidelines. Antiretroviral therapy in restricted men shows some peculiarities such as the voluntary non-taking of drugs to worsen the health status or obtain legal benefits and the high frequency of concomitant psychiatric treatment. On the other hand, patient compliance may be considerably improved by adopting DOT strategy. Aiming to define the choices of first and subsequent lines of therapy with respect to the patient's epidemiological characteristics and other ongoing treatments in two major correctional facilities in Milan (Opera and San Vittore, harbouring about 2500 inmates), we collected punctual data (March 6, 2014) drawn from the single patient forms of therapy. Our results show the same prevalence of HIV infection in both facilities (3%), AIDS and viral hepatitis coinfection cases being more frequent in Opera. Both in Opera and San Vittore we found a high adherence to antiretroviral therapy (high CD4 count average and high percentage of HIV-RNA suppressed). The first and subsequent choice of main lines was TDF+FTC+RTV+ATV. The choice of efavirenz (EFV) as the third drug was often excluded due to its neuropsychiatric implications. The most common cause of drug change was toxicity followed by simplification and then by virological failure. Finally we showed a high frequency of concomitant psychiatric therapy (77% in Opera, 67% in San Vittore), noting the hypothetical interactions with antiretroviral drugs. PMID- 26110296 TI - Effectiveness and tolerability of short course co-trimoxazole, norfloxacin and levofloxacin in bacteriological cure of uncomplicated urinary tract infection in outpatient setting. An open label, parallel group, randomized controlled trial. AB - To compare the bacteriological cure rate of short-course (3-day) treatment of uncomplicated urinary tract infection (UTI) using co-trimoxazole, norfloxacin and levofloxacin, patients with uncomplicated UTI were randomized to receive either co-trimoxazole (960 mg) twice a day or norfloxacin (400 mg) twice a day or levofloxacin (250 mg) once a day for three days. Urine culture was done at the end of treatment and evaluated for bacteriological cure rate in each group. Among a total of 175 patients, Escherichia coli (74.29%) was the most common organism isolated followed by Klebsiella (11.43%), Streptococcus (6.29%), Staphylococcus saphrophyticus (5.14%), and Pseudomonas (2.86%). At the end of three days' treatment, bacteriological cure rates were 86.2%, 87.7% and 83.3% for co trimoxazole, norfloxacin and levofloxacin, respectively (p>0.05). Therefore short course treatment with co-trimoxazole 960 mg twice a day, norfloxacin 400 mg twice a day and levofloxacin 250 mg once a day are almost equally effective for treatment of uncomplicated UTI. PMID- 26110297 TI - Geotrichum capitatum septicaemia in a haematological patient after acute myeloid leukaemia relapse: identification using MALDI-TOF mass spectrometry and review of the literature. AB - Emerging fungal pathogens, such as Geotrichum capitatum, are often associated with poor prognosis and represent a new challenge in modern medicine. Invasive Geotrichum capitatum infection is rare and has been reported exclusively in patients who showed signs of severe immunodeficiency, particularly those affected by haematological malignancies. The optimal therapy against systemic geotricosis has not yet been identified due to limited data about its antifungal susceptibility. The use of several therapeutic strategies and the low number of cases treated does not allow identification of specific therapeutic protocols. Furthermore, in spite of antifungal therapy, mortality rates reach very high levels. We report a case of systemic Geotrichum capitatum infection in a 78-year old male treated with salvage therapy after acute myeloid leukaemia (AML) relapse. Geotrichum capitatum was isolated from his blood culture and identified by using Vitek 2 and Maldi time-of-flight system (MALDI-TOF). The infection was unsuccessfully treated, despite in vitro susceptibility, with micafungin and liposomal amphotericin B. PMID- 26110298 TI - Renal embolism as a primary manifestation of Streptococcus dysgalactiae subspecies equisimilis endocarditis in a patient with chronic aortic dissection. AB - We report a case of renal embolism as an initial manifestation of Streptococcus dysgalactiae subspecies equisimilis (SDSE) endocarditis in a patient with chronic aortic dissection. A 37-year-old man who underwent total aortic arch replacement owing to aortic dissection, presented with a 3-h history of fever, chills, and acute right-sided flank pain. The endocarditis affected the native aortic valve and was complicated by a renal embolism. Blood culture results were positive for SDSE. Intravenous penicillin resulted in satisfactory clinical and echocardiographic recovery. PMID- 26110299 TI - Salmonella paratyphi B mycotic aneurysm of the abdominal aorta in an HIV-infected patient: a case report. AB - An HIV-infected 49-year-old man was admitted with polyuria, fever, chills and a dull left lumbar pain. Laboratory tests showed increased C-reactive protein while urine analysis and abdomen ultrasound scan were negative. Blood cultures revealed a Salmonella paratyphi B, identified through MALDI-TOF mass spectrometry. Targeted antibiotic therapy with intravenous piperacillin/tazobactam was started and a multi-phase contrast-enhanced abdomen CT-scan was performed at 24 hours from admission showing a saccular aneurysm of the abdominal aorta with a 1 cm penetrating aortic ulcer on posterior wall. The patient underwent emergency vascular surgery at 34 hours from admission for debridement and homo-graft placement of sub-renal aorta, and surgical samples were sent for microbiological analysis. Unfortunately, the patient died on post-surgical day 7 after haemorrhagic shock due to laceration of his graft. Salmonella paratyphi infection can be responsible for sepsis in severely immunosuppressed patients with poorly controlled HIV, requiring careful work-up for cardiovascular involvement. PMID- 26110300 TI - A case of brucellosis presenting with acute hepatitis and bicytopenia. AB - Although liver involvement is frequently seen in brucellosis, acute hepatitis is a rare clinical entity. In its progress, haematological findings are non-specific and vary in respect to severity. In this paper, we present a case of brucellosis with acute hepatitis and bicytopenia without anaemia. A 19-year-old man presented with a 2-week history of fever, sweating, low back and leg pain, lassitude, loss appetite, nausea and vomiting. He gave a history of raw milk ingestion and animal contact. Physical examination showed signs of icteric skin and sclera, tenderness in the right hypochondriac region and hepatosplenomegaly. On admission to hospital, laboratory tests showed WBC 3500/mmc (polymorphs 63% and lymphocytes 33%), haemoglobin 13.8 g/dL, platelet 89000/mmc, erythrocyte sedimentation rate 19 mm/h, and C-reactive protein 21.7 mg/dL (N<0.8 mg/dL). Biochemical tests were as follows: AST 771 U/L, ALT 471 U/L, ALP 355 U/L, GGT 432 U/L, total bilirubin 2.61 mg/dL, direct bilirubin 1.45 mg/dL and albumin 3.7 g/dL. Viral hepatitis markers were found to be negative (HBsAg, anti-HBc total, anti-HBc IgM, anti-HAV IgM, and anti-HCV). Blood culture grew Brucella melitensis. Leukopenia and thrombocytopenia returned to normal levels at the 7th and 14th day of his admission, respectively. Liver function tests improved at the 28th day. Treatment of the brucellosis was performed with antibiotics (tetracycline 500 mg orally four times daily for 6 weeks and streptomycin 1 g IM once daily for 21 days). Finally, a case of brucellosis with acute hepatitis and bicytopenia was treated with a successful outcome. In conclusion, we suggest that due consideration be taken of bicytopenia/pancytopenia and acute hepatitis in brucellosis cases in Turkey, an endemic region. PMID- 26110301 TI - Necrotizing soft tissue infection of the right anterolateral abdominal wall caused by a ruptured gangrenous appendix in an elderly diabetic patient. AB - Necrotizing soft tissue infections (NSTIs) of the abdominal wall usually occur when either a common superficial soft tissue infection progresses down to, or an injury (e.g. knife stab) penetrates, the investing muscle fascia, or an intra abdominal infection spreads directly to the muscle layers of the abdominal wall. These infections are severe and associated with significant morbidity and mortality. We present an 83-year-old female diabetic patient who was admitted to the surgical emergency department complaining of right abdominal pain after a fall to the floor. She had previously received oral antibiotics for a minor superficial skin infection attributed to her subcutaneous use of insulin. On admission she exhibited signs of agitation and dyspnoea with hypotension and tachycardia (systolic arterial pressure 90mmHg, heart rate >110 bpm, oxygen saturation 88%). Furthermore, she had a tender right abdomen but without any demonstrable pathology on her skin or crepitus. Arterial blood gases revealed metabolic acidosis and hypoxaemia. An abdominal computed tomography (CT) scan demonstrated signs of infection of the entire right anterior abdominal wall and the LRINEC score was calculated to be 13. Subsequent operative aggressive necrosectomy of all the involved layers of the right anterolateral abdominal wall sparing the peritoneum was undertaken. Unfortunately, the patient died the next day due to multiple organ failure. PMID- 26110302 TI - Spinal lesions by infectious spondylodiscitis and hepatocellular carcinoma presenting as spinal metastasis in an HIV-HCV co-infected patient. AB - Back pain and spine tenderness over the involved spine segment are common clinical findings of a number of relative benign conditions. However, back pain may be the presenting symptom of vertebral metastases in patients with systemic cancer, including hepatocellular carcinoma, a not uncommon complication in HCV HIV infected patients. We describe a case of a 51-year-old intravenous drug user with HIV and HCV co-infection who developed dorsal spondylodiscitis due to Pseudomonas aeruginosa, which improved following antibiotic therapy. Three months after the end of therapy, the patient referred recurrence of back pain. The MRI showed different vertebral lesions of the dorsal spine and costal arch which turned out to be hepatocellular carcinoma metastasis at the histological examination. The patient had never been treated with the interferon-ribavirine combination therapy because of a major depressive syndrome. Interferon-free regimens are urgently required for HIV-HCV coinfected patients, especially when interferon-based regimens are contraindicated. PMID- 26110303 TI - Arthrographis kalrae arthritis: a new case report. AB - To date, only 11 cases of infection by Arthrographis kalrae have been described. According to the literature, we report a second case of arthritis caused by this mycete after a penetrating wound successfully treated with voriconazole before arthroscopic knee washout for six weeks. PMID- 26110304 TI - [Epidemics on the sea: migrants journeys in the nineteenth century]. AB - In the nineteenth century travelling by ship became faster due to the introduction of the steam engine. Population growth, economic crises and food shortages forced millions of Italians to consider migration towards the Americas as a real opportunity. Travel conditions on ships and steamers were particularly difficult. People were crammed into dormitories where ventilation was poor, food was insufficient, hygiene was appalling and promiscuity was rife. Under such conditions, epidemics of cholera, typhus and measles were all too likely to develop, but mycobacterium tuberculosis also proliferated. The health authorities attempted to block the spread of epidemics by means of either health licenses - papers certifying good health of the crew and passengers, which had to be exhibited on arrival - or quarantine, involving the ship and all its contents, if infectious diseases were detected or suspicious deaths occurred during the ship's voyage. In this article the particularly unfortunate stories of Italian immigrants, who boarded ships and steamers, are reported. In the second half of the nineteenth century, but also in the first decades of the twentieth, millions of Italians whose aim was to reach the Americas paid a very high price. Italy did not provide acceptable living conditions for millions of farmers and town dwellers, and migration in search of work was in many cases the only solution. Although many during their sea voyages became ill or died of starvation or infectious diseases, migration, supported by hope, continued. PMID- 26110306 TI - Combined Treatment Modalities of Hyperbaric Oxygen Therapy, Bilayer Matrix Wound Dressing, and Negative Pressure Therapy in Patients with Failed Temporoparietal Fascia Flaps. AB - Temporoparietal fascia flaps are reported to have a 94% success rate in auricular reconstruction. Bilayer matrix (IntegraTM, Integra LifeSciences, Plainsboro, NJ) dermal graft alone has an average success rate of 76.6%. When combined with fibrin glue and negative pressure therapy (V.A.C.A(r) FreedomA(r), KCI, San Antonio, Tex) the flaps have a success rate of up to 98% in patients with a variety of wound types and sites. Two patients are presented with failed temporoparietal fascia flaps. In addition, one also had prior failure of a split thickness skin graft; the second also had failure of prior Integra split thickness skin graft, and hyperbaric oxygen therapy. All 3 treatment modalities of bilayer dermal graft, negative pressure therapy, and hyperbaric oxygen used simultaneously allowed both flaps to heal. PMID- 26110305 TI - Assessment of the Effect of an Aliamide-containing Topical Gel by Evaluation of the Reduction of Wound Volume Measured by High R. AB - This study evaluated the use of an aliamide-containing gel in the treatment of skin wounds by employing noninvasive wound volume measurements acquired from wound images of high resolution ultrasonography (HRU). The dorsal thoracolumbar areas of 10 Beagle dogs were clipped and 2 rows of 6 full-thickness 5-mm punch biopsy samples were taken from either side of the midline under general anaesthesia. Wounds were allowed to heal by secondary intention, while treatment gel or base was applied 3 times daily to randomly selected treatment and control groups. Concentric 8-mm punch biopsy samples of the healing wounds were taken on Days 1, 2, 4, 8, and 14 for histopathological assessment. Wounds were imaged with 20 MHz HRU daily over a period of 28 days. Wound volume was calculated using scanner software based on the disk summation method. The wound volume was calculated in longitudinal and transverse ultrasound images and the average of the 2 values was used as the final wound volume. Repeated measures analysis of variance (ANOVA) was used to assess whether wound volume differed significantly over time, and between control and treated animals. Mean wound volume decreased significantly during the 28-day experimental period, and there was a significant time-treatment interaction indicating that the treatment effect varied at different stages during the healing process. Overall, application of the aliamide containing gel appears to improve wound healing over time. PMID- 26110307 TI - Painful Leg Ulcers: A Misdiagnosed Case Report With Literature Review. AB - A 56-year-old man presented with painful leg ulcers located on the left malleolus, tibia, the dorsal aspect of the feet and calves. He was initially treated with wound dressings, antibiotics, and other surgical debridement-'but these treatments were not effective. The results from laboratory and image examinations did not support the diagnosis of vascular and diabetic ulcerations or any specific infectious diseases. Subsequently, the patient confessed that he has been on medication with hydroxyurea for his granulocytic leukemia. The leg ulcers were fully cured after discontinuation of hydroxyurea. This case suggests that any medication the patient might be taking is always considered when evaluating a chronic ulcer. PMID- 26110308 TI - An Analysis of the Effectiveness of Skin Grafting to Treat Chronic Venous Leg Ulcers. AB - AIM: This study assessed the effectiveness of skin autografting at 6 months post treatment. MATERIALS AND METHODS: A prospective analysis of the disease course and treatment of 2 groups of patients (group S contained patients who have been treated by performing the surgery of skin autografting, group C contained patients who have been treated only by nonoperative means of treatment) after 6 months who were treated from January 2001 to June 2005 at the Department of Plastic Surgery and Burns and at the Clinic of Skin and Venereal Diseases of Kaunas Medical University Hospital was performed. The analysis evaluated the influence on the speed of epithelization (healing) of ulcers by performing surgical skin autografting and conservative treatment. The speed of epithelization (the decrement of an area of an ulcer within 6 months) for the treatment of large chronic leg ulcers after the first 6-month period was also analyzed. RESULTS: Seventy-one patients (group S, n = 40; group C, n = 31) participated in the 6-month study period. Ulcers did not heal completely in any patients in group C (100%)-ulcer size increased in 17 patients and decreased in 14 patients. The average area of ulcers for group C was 171.12 cm2 (range = 8 cm2 720 cm2). Compared to the area before treatment (m = 182.29 cm2), the reduction in average area was not significant (P > 0.5). The contamination of ulcers did not change much in either group over the course of the study. Staphylococcus aureus and Pseudomonas aeruginosa were the most commonly found pathogens. In group S, the skin epithelized completely in 27 cases (67.5%) and did not epithelize in 13 cases (32.5%). The average ulcer area was 16 cm2 (range = 6 cm2 52 cm2). In comparison with the previous area (m = 279 cm2), the current area was rather small and did not (or was insignificant) influence patient quality of life. CONCLUSION: According to the data from all factors that were analyzed, age was the only influence on the origination of large chronic venous leg ulcers (CVLUs, P < 0.05). Large CVLUs (> 50 cm2) of 67.5% of elderly patients (> 60 years) were healed within 2-3 weeks by skin grafting compared to the conservatively treated group and maintained closure up to 6 months (ie, if the subjects were studied up to 6 months). PMID- 26110310 TI - Editorial Message: 'Wound Care' Reading Is Fundamental. PMID- 26110309 TI - Odor Absorbing Hydrocolloid Dressings for Direct Wound Contact. AB - Patients in institutional settings, such as hospitals and nursing homes, often have or acquire chronic wounds such as those resulting from venous insufficiency and pressure ulcers-these wounds can possess a very offensive odor. 1 The most direct way of avoiding or eliminating wound odor is to prevent or eradicate the infection responsible for it.Topical antibiotics, such as metronidazole gel (0.8 w/v) have proved to be quite effective, but can generate resistant organisms. Further, the action of metronidazole can be sluggish; often several days are needed for any infection to be resolved, and meanwhile the odor is still being generated.Thus, in practice, other methods such as charcoal-based dressings are often used with or with-out concomitant antibiotic therapy. Odor absorbing dressings have been marketed in one form or other for many years. During the past decades a number of charcoal based dressings have been introduced into the market. Some of the more current products are Actisorb (r) Silver (Johnson & Johnson Medical Ltd, Gargrave, UK), CarboFlex (r) (ConvaTec, Princeton, NJ), Carbonet (r) (Smith and Nephew Abstract: Charcoal based odor-absorbing dressings for management of odoriferous chronic wounds have been marketed for many years. However, the presence of wound serum deactivates the charcoal and inhibits the adsorption of odor molecules. Charcoal dressings also gen-erally need adjunct fixation to hold them in place. A new series of hydrocolloid adhesives based on cyclodextrins has been developed to provide an alternative technology for the adsorption of chronic wound odors. Dressings incorporating this technology are suitable for direct wound contact. In presence of serum, superior odor absorption with these new materials in comparison with charcoal dressings has been demonstrated in vitro. These new dressings have significant fluid absorption potential, are self-adhesive, and require no additional fixa-tion. Some of the factors affecting performance of these new materi-als in vitro are presented. Comparisons of fluid handling and odor pre-vention abilities of 3 hydrocolloid dressings, Exuderm OdorShield (r) (Medline, Mundelein, Ill) a hydrocolloid dressing containing cyclodex-trins, coded MED 9150H, TegaSorb (r) (3M Health Care, St. Paul, Minn), and DuoDerm Extra Thin (r) (ConvaTec, Deeside, UK) are made. Preliminary results of the in-vivo performance of the MED9150H product on chronic wounds are also given. PMID- 26110311 TI - Long-Term Observations in an Affected Family with Neurogenic Scapuloperoneal Syndrome Caused by Mutation R269C in the TRPV4 Gene. AB - Mutations in the TRPV4 gene, encoding a polymodal Ca(2+) permeable channel, are causative for several human diseases, affecting the skeletal and the peripheral nervous system with highly variable phenotypes. We report on a family with two affected individuals. The father clinically suffered from a classical scapuloperoneal syndrome, while the son presented with a severe neonatal onset with congenital respiratory distress, feeding problems and arthrogryposis multiplex. Multi-Gene Panel sequencing by next generation sequencing revealed the heterozygous mutation c.805C>T (p.R269C) in the TRPV4 gene. Long-term observation over two decades showed no relevant disease progression in the father and, after a dramatic neonatal period, a significant improvement in the son who became ambulant with orthoses at the age of 5 years, suggesting a reasonably good prognosis even in cases with severe neonatal onset. Long-term findings in muscle ultrasound correlated with the clinical course, showing stable or even slightly improved findings. Neurography revealed a late-onset sensory neuropathy in the father, which was so far not described in TRPV4 neuropathies. PMID- 26110312 TI - SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG. AB - BACKGROUND: SYNGAP1, which encodes a RAS-GTPase-activating protein, is located on the short arm of chromosome 6. Heterozygous SYNGAP1 gene mutations have been associated with autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. Here, we report a patient with a new SYNGAP1 stop mutation, and compare the phenotype with published cases with SYNGAP1 mutations and epilepsy. PATIENT: This 15-year-old nondysmorphic girl with intellectual disability developed drop attacks at the age of 2 years, later clonic and clonic-tonic as well as myoclonic seizures predominantly during sleep. The epilepsy was well-controlled by valproic acid (VPA) and later on with levetiracetam. Electroencephalogram (EEG) showed a complete EEG-normalization with eye opening as well as photosensitivity. Magnetic resonance imaging was normal. Genetic analysis revealed a de novo heterozygous stop mutation (c.348C>A, p.Y116*) in exon 4 of the SYNGAP1 gene. DISCUSSION: The main clinical features of our patient (i.e., intellectual disability and idiopathic epilepsy) are compatible with previous reports on patients with SYNGAP1 mutations. The unusual feature of complete EEG normalization with eye opening has not been reported yet for this genetic abnormality. Furthermore, our case provides further support for efficacy of VPA in patients with SYNGAP1 mutation-related epilepsy. PMID- 26110313 TI - JAG: A Computational Tool to Evaluate the Role of Gene-Sets in Complex Traits. AB - Gene-set analysis has been proposed as a powerful tool to deal with the highly polygenic architecture of complex traits, as well as with the small effect sizes typically found in GWAS studies for complex traits. We developed a tool, Joint Association of Genetic variants (JAG), which can be applied to Genome Wide Association (GWA) data and tests for the joint effect of all single nucleotide polymorphisms (SNPs) located in a user-specified set of genes or biological pathway. JAG assigns SNPs to genes and incorporates self-contained and/or competitive tests for gene-set analysis. JAG uses permutation to evaluate gene set significance, which implicitly controls for linkage disequilibrium, sample size, gene size, the number of SNPs per gene and the number of genes in the gene set. We conducted a power analysis using the Wellcome Trust Case Control Consortium (WTCCC) Crohn's disease data set and show that JAG correctly identifies validated gene-sets for Crohn's disease and has more power than currently available tools for gene-set analysis. JAG is a powerful, novel tool for gene-set analysis, and can be freely downloaded from the CTG Lab website. PMID- 26110314 TI - The Fork in the Road: Histone Partitioning During DNA Replication. AB - In the following discussion the distribution of histones at the replication fork is examined, with specific attention paid to the question of H3/H4 tetramer "splitting." After a presentation of early experiments surrounding this topic, more recent contributions are detailed. The implications of these findings with respect to the transmission of histone modifications and epigenetic models are also addressed. PMID- 26110316 TI - Alternative Okazaki Fragment Ligation Pathway by DNA Ligase III. AB - Higher eukaryotes have three types of DNA ligases: DNA ligase 1 (Lig1), DNA ligase 3 (Lig3) and DNA ligase 4 (Lig4). While Lig1 and Lig4 are present in all eukaryotes from yeast to human, Lig3 appears sporadically in evolution and is uniformly present only in vertebrates. In the classical, textbook view, Lig1 catalyzes Okazaki-fragment ligation at the DNA replication fork and the ligation steps of long-patch base-excision repair (BER), homologous recombination repair (HRR) and nucleotide excision repair (NER). Lig4 is responsible for DNA ligation at DNA double strand breaks (DSBs) by the classical, DNA-PKcs-dependent pathway of non-homologous end joining (C-NHEJ). Lig3 is implicated in a short-patch base excision repair (BER) pathway, in single strand break repair in the nucleus, and in all ligation requirements of the DNA metabolism in mitochondria. In this scenario, Lig1 and Lig4 feature as the major DNA ligases serving the most essential ligation needs of the cell, while Lig3 serves in the cell nucleus only minor repair roles. Notably, recent systematic studies in the chicken B cell line, DT40, involving constitutive and conditional knockouts of all three DNA ligases individually, as well as of combinations thereof, demonstrate that the current view must be revised. Results demonstrate that Lig1 deficient cells proliferate efficiently. Even Lig1/Lig4 double knockout cells show long-term viability and proliferate actively, demonstrating that, at least in DT40, Lig3 can perform all ligation reactions of the cellular DNA metabolism as sole DNA ligase. Indeed, in the absence of Lig1, Lig3 can efficiently support semi conservative DNA replication via an alternative Okazaki-fragment ligation pathway. In addition, Lig3 can back up NHEJ in the absence of Lig4, and can support NER and HRR in the absence of Lig1. Supporting observations are available in less elaborate genetic models in mouse cells. Collectively, these observations raise Lig3 from a niche-ligase to a universal DNA ligase, which can potentially substitute or backup the repair and replication functions of all other DNA ligases in the cell nucleus. Thus, the old model of functionally dedicated DNA ligases is now replaced by one in which only Lig4 remains dedicated to C-NHEJ, with Lig1 and Lig3 showing an astounding functional flexibility and interchangeability for practically all nuclear ligation functions. The underlying mechanisms of Lig3 versus Lig1 utilization in DNA repair and replication are expected to be partly different and remain to be elucidated. PMID- 26110315 TI - Genetics of Type 2 Diabetes and Clinical Utility. AB - A large proportion of heritability of type 2 diabetes (T2D) has been attributed to inherent genetics. Recent genetic studies, especially genome-wide association studies (GWAS), have identified a multitude of variants associated with T2D. It is thus reasonable to question if these findings may be utilized in a clinical setting. Here we briefly review the identification of risk loci for T2D and discuss recent efforts and propose future work to utilize these loci in clinical setting-for the identification of individuals who are at particularly high risks of developing T2D and for the stratification of specific health-care approaches for those who would benefit most from such interventions. PMID- 26110317 TI - MicroRNA-224 is Readily Detectable in Urine of Individuals with Diabetes Mellitus and is a Potential Indicator of Beta-Cell Demise. AB - MicroRNA (miRNA) are a class of non-coding, 19-25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic form of diabetes; HNF1A-MODY. miR-224 is a novel miRNA in the field of diabetes. We sought to explore the role of miR-224 as a potential biomarker in diabetes, and whether such diabetes-associated-miRNA can also be detected in the urine of patients. Absolute levels of miR-224 and miR-103 were determined in the urine of n = 144 individuals including carriers of a HNF1A mutation, participants with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and normal controls. Expression levels were correlated with clinical and biochemical parameters. miR 224 was significantly elevated in the urine of carriers of a HNF1A mutation and participants with T1DM. miR-103 was highly expressed in urine across all diabetes cohorts when compared to controls. For both miR-224 and-103, we found a significant correlation between serum and urine levels (p < 0.01). We demonstrate that miRNA can be readily detected in the urine independent of clinical indices of renal dysfunction. We surmise that the differential expression levels of miR 224 in both HNF1A-MODY mutation carriers and T1DM may be an attempt to compensate for beta-cell demise. PMID- 26110319 TI - Arrest of Viral Proliferation by Ectopic Copies of Its Cognate Replication Origin. AB - The initiation step of DNA replication is the crucial determinant of proliferation in all organisms. This step depends on the specific interaction of DNA sequences present at origins of DNA replication and their cognate activators. We wished to explore the hypothesis that the presence of ectopic origin copies may interfere with proper genome duplication. Bacteriophage lambda was used as a model system. To this end, the outcome of an infection of an E. coli strain harboring ectopic copies of the lambda origin region was analyzed. By measuring the effect on the host growth, viral production, and electro-microscopic visualization of the resulting lambda replicative intermediates, we concluded that the ectopic copies had prevented the normal initiation step of lambda DNA replication. These results suggest that DNA decoys encoding viral origins could constitute effective tools to specifically arrest viral proliferation. PMID- 26110318 TI - Hedgehog Signaling during Appendage Development and Regeneration. AB - Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system. Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs. Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms. These signaling pathways have been shown to modulate multiple processes including cellular origin, positional identity and cellular maturation. The present review will focus on the cellular and molecular regulation of the hedgehog (HH) signaling pathway and its interaction with other signaling factors during appendage development and regeneration. PMID- 26110320 TI - Design and Synthesis of Novel N-Arylsulfonyl-3-(2-yl-ethanone)-6-methylindole Derivatives as Inhibitors of HIV-1 Replication. AB - Seven novel N-arylsulfonyl-3-(2-yl-ethanone)-6-methylindole derivatives 4a-f and 6 were readily synthesized and have been identified as inhibitors of human immunodeficiency virus type-1 (HIV-1) replication. Initial biological studies indicated that among these derivatives, N-(p-ethyl)phenylsulfonyl-3-[2 morpholinoethanone]-6-methylindole (4f) and N-(p-ethyl)phenylsulfonyl-3-[2-(5 phenyl-1,3,4-oxadiazole-2-yl-thio)ethanone]-6-methylindole (6) showed the most promising activity against HIV-1 replication. The effective concentration (EC50) and therapeutic index (TI) values of 4f and 6 were 9.42/4.62 MUM, and >49.77/66.95, respectively. The cytotoxicity of these compounds has also been assessed. No significant cytotoxicities were found for any of these compounds. PMID- 26110322 TI - Pharmaceuticals Best Paper Award 2015. AB - It is always a difficult task for a jury to classify articles from a selection of outstanding manuscripts. [...]. PMID- 26110323 TI - Extracellular Wound Matrices: Novel Stabilization and Sterilization Method for Collagen-based Biologic Wound Dressings. AB - Biologic extracellular matrix (ECM)-based wound dressings offer promise in the treatment of chronic wounds. A variety of animal and human tissue derived dressings are currently available. These products are processed and/or sterilized by a range of chemical and mechanical processes, which will impact the final quality of the matrices--ultimately affecting the overall wound healing process. A novel method is described to prepare a sterile and biocompatible biological wound dressing. The advantages and the clinical implications of this wound dressing preparation are also discussed. PMID- 26110321 TI - Seatbelts in CAR therapy: How Safe Are CARS? AB - T-cells genetically redirected with a chimeric antigen receptor (CAR) to recognize tumor antigens and kill tumor cells have been infused in several phase 1 clinical trials with success. Due to safety concerns related to on-target/off tumor effects or cytokine release syndrome, however, strategies to prevent or abate serious adverse events are required. Pharmacologic therapies; suicide genes; or novel strategies to limit the cytotoxic effect only to malignant cells are under active investigations. In this review, we summarize results and toxicities of investigations employing CAR redirected T-cells, with a focus on published strategies to grant safety of this promising cellular application. PMID- 26110324 TI - Small Intestinal Submucosa Wound Matrix for Chronic Wound Healing. AB - Chronic wounds represent a state where healing has stagnated. Venous, diabetic, and pressure ulcers are typically difficult to heal and are at high risk of becoming chronic. In an attempt to restart the healing of chronic wounds, many biologically important molecules, such as collagen, hyaluronic acid, and growth factors have been used to treat these wounds with varying degrees of success. Until recently, the idea of replacing the failing extracellular matrix (ECM) with an intact and biologically complex substitute was unknown. Small Intestinal Submucosa Wound Matrix (SISWM) is both a biologically complex and intact ECM, and an effective therapy for treating chronic wounds. A "drop in' replacement for the ECM of difficult to heal or chronic wounds helps to stimulate tissue ingrowth, deposition of new matrix, and rapid epithelialization-potentially leading to improved quality of life for patients. PMID- 26110325 TI - Extracellular Wound Matrices:A Novel Regenerative Tissue Matrix (RTM) Technology for Connective Tissue Reconstruction. AB - The restoration of structure, function, and physiology to damaged or missing tissue through the use of a regenerative tissue matrix (RTM) leads to regenerative healing rather than reparative scarring. While many processes exist to transform biologic materials into an extracellular matrix (ECM), only those that maintain the required structural and biochemical properties necessary to capture the intrinsic regenerative abilities of the body are suitable to produce an RTM. Histological examination using differential staining with hematoxylin and eosin stain or Verhoeff von Geisen stain of human biopsies of RTM obtained from 2 different abdominal surgery patients taken at 8- and 12 months were consistent with RTM remodeling into fascia-like tissue. A synopsis of recent studies on the use of the RTM GraftJacket(r) (Wright Medical Technologies, Memphis, Tenn) in successful closure of diabetic foot wounds is presented. Collectively, these reports indicate that LifeCell produced ECMs exemplified by GraftJacket exhibit the required clinical outcomes associated with an RTM. PMID- 26110326 TI - An Institutional Analysis of Risk Factors in Pectoralis Advancement Flap Reconstruction. AB - BACKGROUND: Between 1996 and 2004, 21 patients at the Birmingham Veterans Affairs Medical Center (BVA) underwent bilateral pectoralis flap reconstruction for treatment of post sternotomy sternal wound infection. METHODS: Data from the University of Alabama Birmingham (UAB) Medical Center were used to create a cohort group of 29 patients similar to the BVA group with respect to cardiac procedure, reconstruction type, demographics, and preoperative risk factors, such as diabetes, renal function, and nutritional status. The same surgeons performed the cardiac and reconstructive procedures at both institutions. RESULTS: Numerical comparison shows higher mortality in the BVA group (19.0% versus 6.9% at UAB, P = 0.22). It was also noted that the BVA group had a longer post-cardiac operation length of stay ([LOS], 21.8 versus 8.9 days, P = 0.03) and a longer post-reconstruction LOS (17.2 versus 9.5 days, P = 0.01). There were 3 patients in the BVA group who died of sepsis, while there were no sepsis-related deaths in the UAB group. CONCLUSION: The outcome differences between these 2 groups suggest that BVA patients presented with later more advanced sternal wound infections. Possible explanations include differences in patient populations, critical care, and referral networks. These findings further emphasize the importance of early diagnosis and treatment in sternal wound management. PMID- 26110327 TI - Evidence Corner:Pressure Ulcer Risk Scales. PMID- 26110328 TI - Editorial Message: Honor Your Wound Care Heroes. PMID- 26110329 TI - The Elimination Rate after Clozapine Overdose in Chinese Schizophrenia Patients: A Population Pharmacokinetics Model Study. PMID- 26110330 TI - Waterpipe Smoking and Regulation in the United States: A Comprehensive Review of the Literature. AB - BACKGROUND: Researchers in tobacco control are concerned about the increasing prevalence of waterpipe smoking in the United States, which may pose similar risks as cigarette smoking. This review explores the prevalence of waterpipe smoking in the United States as well as the shortcomings of current U.S. policy for waterpipe control and regulation. METHODS: Researchers conducted a literature review for waterpipe articles dated between 2004 and 2015 using five online databases: MEDLINE, CINHAHL, ScienceDirect, PMC, and Cochrane Library. RESULTS: To date, few studies have explored the marketing and regulation of waterpipe smoking in the U.S., which has increased in the last ten years, especially among women, adolescents, and young adults. Data indicate that the majority of waterpipe smokers are unaware of the potential risks of use. In addition, current tobacco control policies do not address waterpipe smoking, enabling tobacco companies to readily market and sell waterpipe products to young adults, who are at risk for becoming lifelong smokers. CONCLUSION: Policy makers in the area of public health need to update existing tobacco regulations to include waterpipe smoking. Similarly, public health researchers should develop public health campaigns and interventions to address the increasing rates of waterpipe smoking in the United States. PMID- 26110333 TI - Polyhexamethylene Biguanide (PHMB): An Addendum to Current Topical Antimicrobials. AB - Antimicrobials are routinely used in the treatment of chronic and problematic wounds. Despite the on-going increase in numbers and types of products, well designed clinical trials that support their efficacy are limited. Antimicrobial products are applied with understanding of their mechanisms of action and role in wound repair. This manuscript reviews the major categories of products on the market, providing the clinician with information on the different types of products and their purported effect on wounds. A new product containing polyhexamethylene biguanide is described in greater detail with relevant case presentations and cost data. This new product does not appear to have any known cytotoxicity in the dressing configuration and may be applied to a wide range of wounds. PMID- 26110331 TI - Physiological and Psychological Effects of Viewing a Kiwifruit (Actinidia deliciosa 'Hayward') Orchard Landscape in Summer in Japan. AB - The physiological and psychological relaxation effects of viewing a kiwifruit (Actinidia deliciosa 'Hayward') orchard landscape were investigated. Seventeen Japanese adult females (46.1 +/- 8.2 years) viewed a kiwifruit orchard landscape or a building site (control) for 10 min. The heart rate variability and heart rate were determined. The modified semantic differential method and the short form Profile of Mood States were used to assess the psychological effects. Compared with viewing the building site, viewing the kiwifruit orchard landscape resulted in a significant increase in the parasympathetic activity, a marginally significant decrease in the heart rate, a significant increase in "comfortable", "relaxed" and "natural" feelings and a significant improvement in mood states. PMID- 26110332 TI - Application Study of Comprehensive Forecasting Model Based on Entropy Weighting Method on Trend of PM2.5 Concentration in Guangzhou, China. AB - For the issue of haze-fog, PM2.5 is the main influence factor of haze-fog pollution in China. The trend of PM2.5 concentration was analyzed from a qualitative point of view based on mathematical models and simulation in this study. The comprehensive forecasting model (CFM) was developed based on the combination forecasting ideas. Autoregressive Integrated Moving Average Model (ARIMA), Artificial Neural Networks (ANNs) model and Exponential Smoothing Method (ESM) were used to predict the time series data of PM2.5 concentration. The results of the comprehensive forecasting model were obtained by combining the results of three methods based on the weights from the Entropy Weighting Method. The trend of PM2.5 concentration in Guangzhou China was quantitatively forecasted based on the comprehensive forecasting model. The results were compared with those of three single models, and PM2.5 concentration values in the next ten days were predicted. The comprehensive forecasting model balanced the deviation of each single prediction method, and had better applicability. It broadens a new prediction method for the air quality forecasting field. PMID- 26110334 TI - Quantitation of the Postoperative Vascular Response in Four Dorsal Bipedicle Flaps in the Rat. AB - The rodent bipedicle flap has been used in numerous permutations as a model of ischemia and to generate a compromised tissue bed. In this study 24 rats were used to investigate skin perfusion over time along the length of 4 distinct bipedicle flap designs-2 oriented cranial-caudally and 2 transverse. Traditional rectangular flaps were evaluated as well as unique elliptical geometries designed to maximize the area of the resulting ischemic bed. Perfusion was assessed by scanning laser Doppler and intravascular dye penetration. In all models, an initially ischemic bed as measured by Doppler reestablished basal perfusion rates within 2-4 days and went on to produce a hyperemic bed with perfusion levels well above baseline. Reduced perfusion areas visualized by fluorescein dye penetration completely resolved in 55% of flaps within 2 days, and 68% within 4 days. This study underscores the difficulty in developing a representative model of chronic ischemia in young healthy rats as well as their remarkable ability to recover from acute surgical insults. PMID- 26110335 TI - Wound Debridement by Continuous Streaming of Proteolytic Enzyme Solutions: Effects on Experimental Chronic Wound Model in Porcin. AB - Wound debridement for the removal of necrotic tissue is a crucial step in wound management. Enzymatic wound debridement is one example of a method currently used that removes necrotic tissue with proteases and offers selectivity without affecting healthy adjacent tissue. Proteolytic enzymes for wound debndement are commercially available as ointments. The authors previously proposed and demon- strated feasibility on small lab animals-an alternative mode of deliv- ery of proteolytic enzymes for wound debridement with continuous streaming of protease solutions. The present study describes the impact of streaming of papain solut ions, fort ified by the incorporation of hypertonic agents, onto an experimental larger chronic wound model in pigs. Debridement of approximately half of the necrotic tis- sue mass was achieved within 6 to 11 h of streaming of papain solu- tions onto these experimental wounds. No adverse effects or notice- able morphological changes to the wound surface or its immediate surroundings were noted, indicating enzyme selectivity and preference for attacking necrotic tissue. The mechanism of enzymatic attack on the necrotic tissue is also discussed. In the control group, streaming of the basic solution formula (devoid of papain) was performed-no debridement of necrotic tissue was noticed in this case. The results indicate that the streaming delivery mode for enzymatic debridement is a highly effective tool designed to be completed in a few sessions. thus paving the way for extension of its application in clinical trials on humans. PMID- 26110336 TI - The Burden of Pressure Ulcers in Spain. AB - Pressure ulcers are a serious and debilitating condition treated in all care settings and have a significant impact on both patients and healthcare resources. The objective of this study was to estimate overall treatment costs to the Spanish healthcare system by using a bottom-up costing approach. This study demonstrates that the cost to heal a pressure ulcer increases substantially with the severity of the ulcer, ranging from ?24 ([$32.16], Grade I) to ?6802 ([$9115], Grade IV) for patients treated in hospitals. Ulcer severity increases overall costs because the time to heal is longer and the incidence of complications is higher in more severe cases. The total cost of pressure ulcer treatment in Spain is approximately ?461 million ([$618 million], roughly 5% of total annual healthcare expenditure). Of this, 15% represents the cost of dressings and other materials, while 19% represents the cost of nursing time, and 45% represents the cost of ulcer-related hospital stays. PMID- 26110338 TI - Erratum for: A Sensitive and Specific Indirect Competitive Enzyme-Linked Immunosorbent Assay for Detection of Paeoniflorin and Its Application in Pharmacokinetic Interactions between Paeoniflorin and Glycyrrhizinic Acid. PMID- 26110337 TI - Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis. AB - MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in Mycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5'-O-[N-(Salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from suboptimal drug disposition properties resulting in a short half-life (t(1/2)), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pK(a) of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in t(1/2) and AUC. Increasing the pK(a) of the acyl-sulfonyl linker yielded incremental enhancements, while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters. PMID- 26110339 TI - Exploring the nature of atheroma and cardiovascular inflammation in vivo using positron emission tomography (PET). AB - Positron emission tomography (PET) has become widely established in oncology. Subsequently, a whole new "toolbox" of tracers have become available to look at different aspects of cancer cell function and dysfunction, including cell protein production, DNA synthesis, hypoxia and angiogenesis. In the past 5 years, these tools have been used increasingly to look at the other great killer of the developed world: cardiovascular disease. For example, inflammation of the unstable plaque can be imaged with 18-fludeoxyglucose (18F-FDG), and this uptake can be quantified to show the effect that statins have in reducing inflammation and explains how these drugs can reduce the risk of stroke. 18F-FDG has also become established in diagnosing and monitoring large-vessel vasculitis and has now entered routine practice. Other agents such as gallium-68 (68Ga) octreotide have been shown to identify vascular inflammation possibly more specifically than 18FFDG.Hypoxia within the plaque can be imaged with 18F-fluoromisonidazole and resulting angiogenesis with 18F-RGD peptides. Active calcification such as that found in unstable atheromatous plaques can be imaged with 18F-NaF. PET imaging enables us to understand the mechanisms by which cardiovascular disease, including atheroma, leads tomorbidity and death and thus increases the chance of finding new and effective treatments. PMID- 26110340 TI - Is the Relationship Between Breastfeeding and Childhood Risk of Asthma and Obesity Mediated by Infant Antibiotic Treatment? AB - BACKGROUND: Studies of the protective effect of breastfeeding on asthma have not brought unequivocal results, and thus this issue remains controversial. Antibiotic use, known to increase asthma risk, may be involved in this relationship. The objective of this study was to assess the influence of breastfeeding duration on obesity and asthma risk in childhood and to test a mediating role of antibiotic use in infancy. SUBJECTS AND METHODS: A cross sectional anthropometric and questionnaire study was conducted on 1,277 schoolchildren 8 years of age. Data on weight status, asthma, breastfeeding duration, antibiotic administration in infancy, socioeconomic status, and lifestyle were analyzed. Multivariate standard and logistic regression and mediation analyses, controlling for confounders, were applied. RESULTS: Total duration of breastfeeding was negatively related to the child's body mass index (p=0.038), fat percentage (p=0.030), and obesity risk (p=0.032). Dropping the variable of antibiotic use from the model made the breastfeeding duration a significant predictor of low asthma risk (p=0.027). Antibiotic treatment mediated the relationship between breastfeeding duration and asthma risk (Sobel's z=-2.61, p=0.009). CONCLUSIONS: Our findings support protective effects of longer duration of breastfeeding against obesity and asthma. We propose a new mechanism for a relationship between breastfeeding and asthma: shorter breastfeeding compromises infant health and thereby leads to antibiotic treatment, which in turn increases the risk of asthma. PMID- 26110341 TI - The Met allele of BDNF Val66Met polymorphism is associated with increased BDNF levels in generalized anxiety disorder. AB - BACKGROUND: Generalized anxiety disorder (GAD) is a common psychiatric disorder characterized by long-term worry, tension, nervousness, fidgeting, and symptoms of autonomic system hyperactivity. The neurobiology of this disorder is still unclear, although it has been shown consistently that the environment and the genetic profile could increase its risk. We examined whether a polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which plays a role in neuroplasticity and memory, could increase the vulnerability to this disorder. PARTICIPANTS AND METHODS: In our study, 816 participants from a population-based study were genotyped by qPCR for the BDNF functional variant rs6265 (Val66Met) and the BDNF serum levels were measured by ELISA. RESULTS: Our results showed a significant association between the Met allele and risk for GAD (P=0.014), but no differences were observed in the serum levels of BDNF according to diagnosis (P=0.531) or genotype distribution (P=0.197). However, after stratification according to the GAD diagnosis, the Met allele was associated significantly with an increase in serum BDNF levels compared with the Val/Val genotype in GAD participants (F=3.93; P=0.048). The logistic regression analysis confirmed the independent association of Met allele as a risk factor for development of GAD after adjusting for confounder variables (beta=0.528; 95% confidence interval: 0.320-0.871; P=0.012). CONCLUSION: These results suggest that BDNF could be involved in the neurobiology of GAD and might represent a useful marker associated with the disease. PMID- 26110342 TI - Serotonin transporter gene promoter polymorphism predicts relationship between years of cocaine use and impulsivity. PMID- 26110343 TI - Genetic association of the oxytocin receptor genes with panic, major depressive disorder, and social anxiety disorder. PMID- 26110344 TI - Validity and Test-Retest Reliability of the TIVRE-Basket Test for the Determination of Aerobic Power in Elite Male Basketball Players. AB - The aims of this study were to (a) determine the relationship between performance on the court-based TIVRE-Basket test and peak aerobic power determined from a criterion laboratory-based incremental treadmill test and (b) to examine the test retest reliability of the TIVRE-Basket test in elite male basketball players. To address aim 1, 36 elite male basketball players (age: 25.2 +/- 4.7 years, weight: 94.1 +/- 11.4 kg, height: 195.83 +/- 9.6 cm) completed a graded treadmill exercise test and the TIVRE-Basket within 72 hours. The mean distance recorded during the TIVRE-Basket test was 4001.8 +/- 176.4 m, and mean VO2 peak was 54.7 +/- 2.8 ml . kg(-1) . min(-1), and the correlation between the 2 parameters was r = 0.824 (p <= 0.001). Linear regression analysis identified TIVRE-Basket distance (in meters) as the only unique predictor of VO2 peak in a single variable plus constant model: VO2 peak = 2.595 + (0.13 * TIVRE-Basket distance [in meters]). Performance on the TIVRE-Basket test accounted for 67.8% of the variance in VO2 peak (t = 8.466, p <= 0.001, 95% confidence interval: 0.01-0.016, SEE: 1.61). To address aim 2, 20 male basketball players (age: 26.7 +/- 4.2 years, height: 1.94 +/- 0.92 cm, weight: 94.0 +/- 9.1 kg) performed the TIVRE-Basket test on 2 occasions. There was no significant difference in total distance covered between trial 1 (4138.8 +/- 677.3 m) and trial 2 (4188.0 +/- 648.8 m; t = 0.5798, p = 0.5688). Mean difference between trials was 49.2 +/- 399.5 m, with an intraclass correlation coefficient of 0.85 suggesting a moderate level of reliability. Standardized typical error of measurement was 0.88%, representing a moderate degree of trial-to-trial error, and the Coefficient of Variation (CV) was 6.3%. The TIVRE-Basket test therefore represents a valid and moderately reliable court based sport-specific test of aerobic power for use with individuals and teams of elite-level male basketball players. Future research is required to ascertain its validity and reliability in other basketball populations, for example, across age groups, at different levels of competition, in females and in different forms of the game, for example, wheelchair basketball. PMID- 26110345 TI - Time Course of Resistance Training-Induced Muscle Hypertrophy in the Elderly. AB - Extended periods of resistance training (RT) induce muscle hypertrophy. Nevertheless, to date, no study has investigated the time window necessary to observe significant changes in muscle cross-sectional area (CSA) in older adults. Therefore, this study investigated the time course of muscle hypertrophy after 10 weeks (20 sessions) of RT in the elderly. Fourteen healthy older subjects were randomly allocated in either the RT (n: 6) or control group (n: 8). The RT was composed of 4 sets * 10 repetitions (70-80% 1 repetition maximum [1RM]) in a leg press machine. The time course of vastus lateralis muscle hypertrophy (CSA) was assessed on a weekly basis by mode-B ultrasonography. Leg press muscle strength was assessed by dynamic 1RM test. Our results demonstrated that the RT group increased leg press 1RM by 42% (p <= 0.05) after 10 weeks of training. Significant increases in vastus lateralis muscle CSA were observed only after 18 sessions of training (9 weeks; p <= 0.05; 7.1%). In conclusion, our training protocol promoted muscle mass accrual in older subjects, and this was only observable after 18 sessions of RT (9 weeks). PMID- 26110346 TI - The Power Output-Drop Height Relationship to Determine the Optimal Dropping Intensity and to Monitor the Training Intervention. AB - The literature currently lacks in methodological approaches to quantify the drop jump intensity and to control the training intervention. This study aimed to determine the average power output-drop height relationship and to quantify the reliability of this relationship across 2 different training interventions (each 8 weeks in length). The relationships were determined for 52 volunteer sports science students who took part in this study (25 male/27 female participants). The drop jumps from 20 to 60 cm were performed on a resistive platform. The reliability of the power output-drop height relationships was quantified for 29 subjects who were selected from the sample and were assigned to a drop jump, vibration, or control groups. The average power output during the drop jump statistically depends on the gender (F(1,250) = 18.844; p = 0.0001) and drop height (F(4,250) = 7.195; p = 0.0001), whereas the interaction between gender and height did not affect the power output (F(4,250) = 0.458; p = 0.767). Both the drop jump and the vibration groups showed a significant main effect over time (F(3,200) = 40.059, p = 0.0001; and F(3,160) = 11.422, p = 0.0001, respectively). The intrasession and interday reliability ranged from "high" (intraclass correlation coefficient [ICC] > 0.80) to "excellent" (ICC > 0.90) among the various drop heights. This study suggests that an individual drop height that maximizes the power output during a drop jump exists and that the test to select this optimal drop height is repeatable over time. Consequently, the test can monitor the improvement in the power output following different training regimens. PMID- 26110347 TI - Hip External Rotator Strength Is Associated With Better Dynamic Control of the Lower Extremity During Landing Tasks. AB - The purpose of this study was to determine the association between hip strength and lower extremity kinematics and kinetics during unanticipated single-leg landing and cutting tasks in collegiate female soccer players. Twenty-three National Collegiate Athletic Association division I female soccer players were recruited for strength testing and biomechanical analysis. Maximal isometric hip abduction and external rotation strength were measured using a hand-held dynamometer and expressed as muscle torque (force * femoral length) and normalized to body weight. Three-dimensional lower extremity kinematics and kinetics were assessed with motion analysis and force plates, and an inverse dynamics approach was used to calculate net internal joint moments that were normalized to body weight. Greater hip external rotator strength was significantly associated with greater peak hip external rotation moments (r = 0.47; p = 0.021), greater peak knee internal rotation moments (r = 0.41; p = 0.048), greater hip frontal plane excursion (r = 0.49; p = 0.017), and less knee transverse plane excursion (r = -0.56; p = 0.004) during unanticipated single-leg landing and cutting tasks. In addition, a statistical trend was detected between hip external rotator strength and peak hip frontal plane moments (r = 0.39; p = 0.06). The results suggest that females with greater hip external rotator strength demonstrate better dynamic control of the lower extremity during unanticipated single-leg landing and cutting tasks and provide further support for the link between hip strength and lower extremity landing mechanics. PMID- 26110348 TI - Strength and Power Qualities Are Highly Associated With Punching Impact in Elite Amateur Boxers. AB - This study investigated the relationship between punching impact and selected strength and power variables in 15 amateur boxers from the Brazilian National Team (9 men and 6 women). Punching impact was assessed in the following conditions: 3 jabs starting from the standardized position, 3 crosses starting from the standardized position, 3 jabs starting from a self-selected position, and 3 crosses starting from a self-selected position. For punching tests, a force platform (1.02 * 0.76 m) covered by a body shield was mounted on the wall at a height of 1 m, perpendicular to the floor. The selected strength and power variables were vertical jump height (in squat jump and countermovement jump), mean propulsive power in the jump squat, bench press (BP), and bench throw, maximum isometric force in squat and BP, and rate of force development in the squat and BP. Sex and position main effects were observed, with higher impact for males compared with females (p <= 0.05) and the self-selected distance resulting in higher impact in the jab technique compared with the fixed distance (p <= 0.05). Finally, the correlations between strength/power variables and punching impact indices ranged between 0.67 and 0.85. Because of the strong associations between punching impact and strength/power variables (e.g., lower limb muscle power), this study provides important information for coaches to specifically design better training strategies to improve punching impact. PMID- 26110349 TI - Effects of 28-Day Beta-Alanine Supplementation on Isokinetic Exercise Performance and Body Composition in Female Masters Athletes. AB - Beta-alanine (BA) supplementation increases exercise performance due to increases in the intramuscular lactate buffer, carnosine. Females are more sensitive to these increases and results are further pronounced in trained individuals. Baseline intramuscular carnosine levels also naturally decrease with age; therefore, trained older females may experience augmented benefits from BA supplementation. However, the ability of BA to increase lower-body isokinetic strength (ISO) in female masters athletes (MA) is unknown. The purpose of this study was to examine the longitudinal effects of BA supplementation on ISO, handgrip strength (HG), and body composition in female MA cyclists. Twenty-two subjects participated in this double-blind randomized study. Subjects were randomized into 2 groups (placebo [PLA] = 8 g dextrose; BA = 800 mg + 8 g dextrose) and supplemented 4 times per day for 28 days. ISO, HG, and body composition were evaluated at baseline and at the same day/time each week over the 28-day intervention. No differences existed between groups at baseline or at the 7, 14, and 21 days time points for any variables (p > 0.05). When evaluating ISO (isokinetic) after 28 days, total work performed during the final third of the assessment (24.0 vs. -16.8% change) in flexion and average peak torque (5.4 vs. 2.9% change) in extension were significantly increased from baseline in BA compared with PLA (p <= 0.05). No differences existed for HG or body composition after supplementation. Twenty-eight days of BA supplementation increased peak torque and work completed, indicating BA improves lower-body exercise performance in female MA. PMID- 26110350 TI - Thermographic Assessment of Eccentric Overload Training Within Three Days of a Running Session. AB - The aim of this study was to analyze the changes in patellar and Achilles tendons between a group trained using eccentric overload and an untrained group within 3 days of a running session. To this end, infrared thermography (IRT) will be used. Twenty healthy male subjects were divided into 2 groups. One group performed a 6 week squat training in the flywheel before the running session. During the running intervention, both groups ran in 3 different days, for 1 hour each, at 80% maximal heart rate. Before, just after, and after 10 minutes of the running intervention, participants were assessed using IRT. Eccentrically trained groups showed a statistically significant difference (analysis of variance, p = 0.0049) expressed as a smaller bilateral increase in temperature in the patellar tendon just before the first running day (right side, 0.11 degrees C; left side, 0.29 degrees C). On the other days of running and in the Achilles tendon groups, similar changes were observed: an increase in the temperature after running and no significant difference between contralateral limbs. Our results point at eccentric overload training providing a better adaptation for the first day of running. IRT is an easy-to-apply noninvasive tool to analyze and compare the effects of performance on tendon tissues. PMID- 26110351 TI - Apps for immunization: Leveraging mobile devices to place the individual at the center of care. AB - Mobile technology and applications (apps) have disrupted several industries including healthcare. The advantage of apps, being personally focused and permitting bidirectional communication, make them well suited to address many immunization challenges. As of April 25, 2015 searching the Android app store with the words 'immunize app' and 'immunization app' in Canada yielded 225 apps. On the Apple App Store a similar search produced 98 results. These include apps that provide immunization related information, permit vaccine tracking both for individuals and for animals, assist with the creation of customized schedules and identification of vaccine clinics and serve as sources of education. The diverse functionality of mobile apps creates the potential for transformation of immunization practice both at a personal level and a system level. For individuals, mobile apps offer the opportunity for better record keeping, assistance with the logistics of vaccination, and novel ways of communicating with and receiving information from public health officials. For the system, mobile apps offer the potential to improve the quality of information residing in immunization information systems and program evaluation, facilitate harmonization of immunization information between individuals, health care providers and public health as well as reduce vaccine hesitancy. As mobile technology continues to rapidly evolve there will emerge new ways in which apps can enhance immunization practice. PMID- 26110352 TI - Piano-Stool Lutetium Amido and Imido Compounds Supported by a Constrained Bis(oxazoline)cyclopentadienyl Ligand. AB - {Bo(M)Cp(tet)}Lu(CH2Ph)2 (1; Bo(M)Cp(tet) = MeC(Ox(Me2))2C5Me4; Ox(Me2) = 4,4 dimethyl-2-oxazoline) was prepared in 95% yield from the reaction of Bo(M)Cp(tet)H and Lu(CH2Ph)3THF3. Compound 1 reacts with 1 or 2 equiv of H2NCH2R (R = C6H5, 1-C10H7) to give the corresponding imido complexes [{Bo(M)Cp(tet)}LuNCH2R]2 (R = C6H5 (2a), 1-C10H7 (2b)) or amido complexes {Bo(M)Cp(tet)}Lu(NHCH2R)2 (R = C6H5 (3a), 1-C10H7 (3b)). Once isolated, the imido species are insoluble in nonprotic organic solvents. Crystallographic characterization reveals dimeric [{Bo(M)Cp(tet)}LuNCH2(1-C10H7)]2 in the solid state. The reaction of 1 and NH3B(C6F5)3 affords crystallographically characterized {Bo(M)Cp(tet)}Lu{NHB(C6F5)2}C6F5. This species is proposed to form via a transient lutetium imido, which undergoes C6F5 migration to the lutetium center. PMID- 26110353 TI - Effect of AIE substituents on the fluorescence of tetraphenylethene-containing BODIPY derivatives. AB - A series of BODIPY derivatives with tetraphenylethene (TPE) moieties were designed and synthesized. The effect of positions and numbers of substitution groups on the fluorescence of the BODIPYs was investigated. Theoretical calculation and single crystal structures proved that the TPE substitution groups on the 8-position of BODIPY contributed little to the conjugation, but benefited the aggregated state emission. On the other hand, the substitutions on the 3- or 5-position of BODIPY through vinyl bridges increased the conjugation length, and generated big coplanar pi-conjugated structures with poor aggregated state emission. The compound with bright aggregated state emission has been further fabricated into biocompatible fluorescent nanoparticles and used as effective fluorescent contrast agents for intracellular imaging. PMID- 26110354 TI - Gas-Phase Rearrangement in Lysine Phosphorylated Peptides During Electron Transfer Dissociation Tandem Mass Spectrometry. AB - Tandem mass spectrometry (MS/MS) strategies coupled with collision-induced dissociation (CID) or radical-driven fragmentation techniques such as electron capture dissociation (ECD) or electron-transfer dissociation (ETD) have been successfully used for comprehensive phosphoproteome analysis. However, the unambiguous characterization of the phosphorylation site remains a significant challenge due to phosphate-related neutral losses and gas-phase rearrangements, which have been observed during CID. In particular, for the analysis of labile N phosphorylated peptides, ECD and ETD are emerging as a complementary method. In contrast to CID, the phosphorylation site of histidine, arginine, and lysine phosphorylated peptides can be characterized by ETD. Here, we present a study on the application of ETD for analysis of phospholysine (pLys) peptides. We show that, depending on the charge state of the precursor ion as well as the presence of basic amino acid side chains, phosphate transfer reactions during the ETD process can be observed leading to ambiguous fragment ion spectra. Basically, pLys is stable under ETD conditions allowing an unambiguous assignment of the site of phosphorylation, but some factors/parameters have to be considered to avoid gas-phase rearrangement which would lead to false positive results in phosphoproteomic studies. PMID- 26110356 TI - Photochemically Induced Dynamic Nuclear Polarization Observed by Solid-State NMR in a Uniformly (13)C-Isotope-Labeled Photosynthetic Reaction Center. AB - A sample of solubilized and quinone-depleted reaction centers from the purple bacterium Rhodobacter (R.) sphaeroides wild type has been prepared entirely (13)C and (15)N isotope labeled at all positions of the protein as well as of the cofactors. In this sample, the occurrence of the solid-state photo-CIDNP (photochemically induced dynamic nuclear polarization) effect has been probed by (13)C solid-state magic-angle spinning NMR under illumination. Under continuous illumination, signal intensities are modified by the three-spin mixing (TSM) mechanism. Time-resolved illumination experiments reveal the occurrence of light induced nuclear polarization on the time scale of hundreds of microseconds, initially dominated by the transient polarization of the singlet branch of the radical-pair mechanism. A first kinetic analysis shows that the lifetime of the polarization from the singlet branch, indicated by the enhanced absorptive intensities of the signals from aliphatic carbons, is significantly extended. Upon arrival of the polarization from the triplet decay branch, emissive polarization caused by the TSM mechanism is observed. Also, this arrival is significantly delayed. The decay of TSM polarization occurs in two steps, assigned to intra- and intermolecular spin diffusion. PMID- 26110355 TI - Ocular Tuberculosis--A Clinical Conundrum. PMID- 26110357 TI - Challenges and Opportunities for the Use of Medications to Treat Opioid Addiction in the United States and Other Nations of the World. AB - There has been a well documented increase in the use and abuse of prescription opioids and heroin in the United States and other parts of the world. There has also been an increasing focus to increase access to the use of medications (methadone, buprenorphine, Naltrexone/Vivitrol) for opioid addicted individuals under legal supervision. As policymakers engage in strategic initiatives to better prevent and effectively treat chronic opioid addiction, both in the United States and other countries, there are a number of unintended consequences, complicating how best to increase access to effective treatment. PMID- 26110358 TI - Yet Another Flawed "Placebo Controlled" Study in Crohn's Disease? PMID- 26110361 TI - Impact of Sepsis on Surgical Outcomes. AB - BACKGROUND: Sepsis is among the leading causes of death in the United States, and patients undergoing surgical procedures are at greater risk for infectious complications. The incidence of sepsis and its association with outcomes among patients undergoing surgical procedures in various specialties were investigated. Additionally, the infectious sources and associated primary procedures were reported for sepsis-related deaths. METHODS: Patients undergoing procedures performed by surgical services at our academic medical center between January 2010 and June 2013 were reviewed. Sepsis was identified by the assignment of related ICD-9-CM billing codes. Patient outcomes included hospital length of stay, intensive care unit (ICU) admission, ICU length of stay, and death. A subset of sepsis-related deaths was reviewed further for infectious sources and primary procedure codes. RESULTS: A total of 25,522 patients underwent a procedure by a surgical service, and sepsis developed in 863 patients (3.38%) during their hospital stays. Overall, patients with sepsis had significantly longer hospital and ICU stays, greater likelihood of ICU admission, and a higher mortality rate. The incidence of sepsis was highest in patients with procedures performed by cardiothoracic surgery (8.39%), trauma/acute care surgery (7.55%), and plastic/reconstructive surgery (5.35%). Sepsis was associated with a significant increase in the mortality rate among vascular surgery, trauma/acute care surgery, and cardiothoracic surgery patients. The most common infectious sources in sepsis-related deaths were pulmonary infections (39.5%), blood stream infections (35.1%), and gastrointestinal infections (31.6%). The procedures associated with the greatest number of sepsis-related deaths were extracorporeal membrane oxygenation, small bowel resection, and insertion of implantable heart assist systems. CONCLUSIONS: Sepsis is not an uncommon condition and is associated with longer hospital and ICU stays, greater likelihood of ICU admission, and a higher mortality rate. Accurate benchmarking of sepsis is essential for the development and monitoring of sepsis-reduction quality improvement initiatives. PMID- 26110364 TI - The Mechanism of Cell Interaction and Response on Decellularized Human Amniotic Membrane: Implications in Wound Healing. AB - ACELAGRAFTTM (Celgene Cellular Therapeutics, Cedar Knolls, NJ) was developed as a decellularized and dehydrated human amniotic membrane product (DDHAM). The product has demonstrated potential as a wound healing product with several ongoing preclinical and clinical studies in the area of acute and chronic ulcers. Although the mechanism of action of such a decellularized product has not been examined, a detailed study of the ability of fibroblasts to interact with DDHAM and subsequent cellular responses are presented. These studies indicate that the composition of DDHAM is that of an extracellular matrix (ECM)-like material with high collagen content, retaining key bioactive molecules, such as fibronectin, laminin, glycosaminoglycans (GAGs), and elastin. No cytokines or growth factors were identified as one might expect in a nondecellularized amniotic membrane product. Cell assays show that fibroblasts can recognize fibronectin in DDHAM and bind to it via typical integrin-fibronectin interactions. Fibroblasts secrete fibronectin and can actively assemble the soluble fibronectin into a complex extracellular matrix on DDHAM. Fibroblasts are also stimulated by DDHAM to secrete key proinflammatory(IL-1 and IL-6) and chemotactic cytokines or chemokines (proand IL-8) involved in regulating and enhancing wound repair processes. Microarray gene expression studies on fibroblasts bound to DDHAM show increased expression of key wound healing cytokines. Together, these studies provide insight into the mechanisms by which DDHAM may augment the wound healing process. PMID- 26110363 TI - Two Distinct Uveal Melanomas in the Same Eye. PMID- 26110365 TI - Fungal Agents as a Cause of Surgical Wound Infections: An Overview of Host Factors. AB - Microbial virulence and host resistance are the determinants of the surgical infections. Bacteria are responsible for the majority of cases, but fungi are rare. The aim of this study was to evaluate the fungi causing surgical infections and discuss host factors predisposing the infection. METHODS: A total of 824 surgical wound specimens had been evaluated. The specimens were cultured using 5% sheep blood, Sabouraud Dextrose, and Eosin methylene blue agars and the isolates were identified by classical methods and API identification system. RESULTS: Growth was obtained in 455 (55.2%) out of 824 specimens. Nine (2%) of the agents of surgical infections were yeasts: Candida albicans was isolated in 5 (55.6%), C tropicalis in 3 (33.3%), and C glabrata in 1 (11.1%) specimen(s). Examining the characteristics of the patients, fungal infection could be explained with the presence of at least 1 predisposing factor. Immunosuppression was closely related with fungal growth. CONCLUSION: Predisposing factors impairing the immune system were detected in most of the patients showing the possibility of onset of fungal, predominantly Candidal infections. It is important for clinicians to be aware of fungal infections that may develop in this group under risk, particularly after surgery and all Candida species isolated from high-risk patients should be identified to species level, as nonalbicans strains are often associated with resistance to antifungal agents. PMID- 26110366 TI - Necrotizing Fasciitis and Myonecrosis Due to Aeromonas hydrophila. AB - Aeromonas hydrophila infection has been described as the cause of necrotizing fasciitis in patients with suppressed immune systems, burns, and trauma in an aquatic setting. The following presents a case in which severe necrotizing fasciitis and myonecrosis of the lower extremity, as well as toxic shock, developed as a result of wound infection from direct contact with brackish water. Mixed aerobic and anaerobic bacteria, including Aeromonas hydrophila, were isolated from the wound culture. This case illustrates that an infection with Aeromonas hydrophila can cause severe necrotizing fasciitis and myonecrosis. Early and aggressive surgical intervention should be implemented immediately after necrotizing fasciitis is diagnosed. PMID- 26110367 TI - A Non-healing Sinus of the Lower Leg 5 Years After Vacuum-assisted Closure Therapy Due To a Gossypiboma. AB - Since its introduction, vacuum-assisted closure (V.A.C.(r) TherapyTM, KCI, San Antonio,Tex) therapy has proven to be an adequate and noninvasive method in the treatment of complicated wounds. Vacuumassisted closure can be used in the treatment of many types of chronic wounds, such as venous stasis ulcers, pressure ulcers, dehisced surgical wounds, arterial and diabetic ulcers, and a wide variety of miscellaneous, long-existing wounds. Although complications related to its use are rare; localized superficial skin irritation is the most common complication reported in the literature. Further complications involve pain, infection, bleeding, and fluid depletion. Although rare, severe complications, such as toxic shock syndrome, anaerobic sepsis, or thrombosis have been reported. This case report presents an unusual complication of vacuum-assisted closure therapy, which to the authors' knowledge has only once been reported in the literature. PMID- 26110368 TI - Treating the Complicated Neuropathic Charcot Foot. PMID- 26110369 TI - Clinical practice of ambulatory versus home blood pressure monitoring in hypertensive patients. AB - OBJECTIVES: This study aimed to analyze whether blood pressure (BP) measurement is concordant between ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM), and determine whether the decision on treatment changes is similar on the basis of information provided by both methods. METHODS: Treated hypertensive patients were studied with ABPM and HBPM to evaluate therapeutic efficacy and/or diagnose resistant hypertension (HTN). Modification of pharmacological treatment was decided on the basis of pre-established criteria; therefore, the number of therapeutic changes between both techniques was compared. RESULTS: A total of 200 patients were included. The average daytime ABPM systolic blood pressure (SBP) was 136+/-16 compared with 136+/-15 (P=1) with HBPM; the average diurnal diastolic blood pressure (DBP) was 83+/-12 and 81+/-9, respectively (P=0.06). The concordance between both methods was very good for SBP [r=0.85; Bland-Altman 0.2 (95% confidence interval 0.9-1.4 mmHg)], and good for the DBP [r=0.77; Bland-Altman 1.8 (95% confidence interval 0.8-2.8 mmHg)]. Both methods were in agreement that HTN was controlled in 68 patients and that it was not controlled in 90 patients, that is, they were concordant in 158 patients (79%, kappa=0.6). More patients required changes with ABPM than HBPM (149 vs. 99 patients, P<0.0001) CONCLUSION: There were no significant differences in the measurement of diurnal SBP and DBP between both methods. The concordance to determine proper control of HTN was 79%. There was a significant difference in the decision to modify the treatment in favor of the ABPM. PMID- 26110370 TI - The impact of arm circumference on noninvasive oscillometric blood pressure referenced with intra-aortic blood pressure. AB - OBJECTIVE: To investigate the influence of arm circumference (AC) on the brachial blood pressure (BP) measured with an adult cuff. PARTICIPANTS AND METHODS: This study included 208 patients (150 men, 61.0+/-8.0 years) for coronary angiography. Intra-aortic BP and noninvasive right brachial oscillometric BP (noninvasive BP) were measured simultaneously before coronary angiography. The noninvasive BP was measured using an electronic oscillometric device with an adult cuff (12*22 cm). The mid-ACs were measured. Thus, proper cuff-arm (<=26 cm) and small cuff (>26 cm) groups were created. The difference in intra-aortic and noninvasive BP was calculated as BPi-n. RESULTS: The correlation coefficients (r) between noninvasive and invasive systolic blood pressure (SBP), mean artery pressure, and diastolic blood pressure (DBP) were 0.88, 0.76, and 0.58, respectively. The SBPi n was higher (7.9+/-1.6 vs. 5.2+/-1.1 mmHg), but the DBPi-n (3.9+/-1.4 vs. 6.1+/ 1.0 mmHg, P<0.05) was lower in the group <=26 cm than in the group >26 cm. Among the four subgroups divided by 20-23, 24-26, 27-30, and 31-37 cm of AC, as the AC increased, the SBPi-n increased, but DBP decreased, resulting in noninvasive SBP 4.6 mmHg higher and noninvasive DBP 4.6 mmHg lower in the 31-37 cm group in comparison with the 20-23 cm group. CONCLUSION: When an adult cuff was used, the noninvasive oscillometric SBP was overestimated, but DBP was underestimated in the individuals with large arms against the intra-aortic BP. PMID- 26110372 TI - Catalytic conversion of isophorone to jet-fuel range aromatic hydrocarbons over a MoO(x)/SiO2 catalyst. AB - For the first time, jet fuel range C8-C9 aromatic hydrocarbons were synthesized in high carbon yield (~80%) by the catalytic conversion of isophorone over MoO(x)/SiO2 at atmospheric pressure. A possible reaction pathway was proposed according to the control experiments and the intermediates generated during the reaction. PMID- 26110373 TI - POINT: Is N2 Disease a Contraindication for Surgical Resection for Superior Sulcus Tumors? Yes. PMID- 26110374 TI - Severity of rhinitis and wheezing is strongly associated in preschoolers: A population-based study. AB - BACKGROUND: In preschool children, no study assessed the relation between wheezing and rhinitis severity. Our aims were to estimate the prevalence of current wheezing (CW) in preschoolers and to study the association between CW and current rhinitis (CR), considering its severity/persistency. METHODS: This is a cross-sectional, nationwide, population-based study including a representative sample of 5003 Portuguese children aged 3-5 years. Data were collected by a face to-face interview with caregivers using an adapted ISAAC questionnaire. CW was defined as presence of >=1 wheezing episode in the previous 12 months. Rhinitis severity/persistency was classified according to Allergic Rhinitis and its Impact on Asthma. RESULTS: Current wheezing prevalence was 24.5% [95% CI 23.3-25.7]; 9.4% of the participants had >=4 wheezing episodes in the previous year. Children with CR had an odds ratio (OR) of 4.0 [95% CI 3.4-4.5] for CW; it was highest for children with moderate-severe persistent rhinitis (11.5 [95% CI 8.1-16.3]), even after adjusting for possible confounders. Wheezers with CR reported more wheezing treatment use (p = 0.024) than those without CR. There was a trend for a higher number of wheezing episodes with more persistent and severe nasal disease - 48.4% of children with moderate-severe persistent rhinitis had >4 wheezing episodes vs. 28.9% in moderate-severe intermittent, 20.0% in mild persistent, 10.8% in mild intermittent, and 3.6% in those without CR; p < 0.001. CONCLUSIONS: Current wheezing was present in almost 25% of preschool children and was strongly associated with rhinitis, especially moderate-severe persistent disease. Preschoolers with both CW and rhinitis seem to have a more severe phenotype, emphasizing the need for concurrent evaluation of nasal and bronchial symptoms even in small children. PMID- 26110375 TI - New Formulation of Sustained Release Naloxone Can Reverse Opioid Induced Constipation Without Compromising the Desired Opioid Effects. AB - An international double-blind randomized placebo controlled study evaluated the safety and efficacy of four doses of a new sustained release naloxone capsule to treat Opioid Induced Constipation (OIC). METHODS: Forty patients taking opioids for noncancer related pain, and experiencing OIC, were randomized into 4 cohorts of 10 patients. A multiple ascending dose design was used to evaluate the safety and efficacy of 2.5 mg, 5 mg, 10 mg, and 20 mg naloxone sustained release (NSR) capsules vs placebo. Drug was given once-daily for 3 weeks followed by twice daily (bid) dosing between weeks 4 and 6. RESULTS: The incidence of treatment emergent adverse events was highest in the placebo group. The incidence of adverse events among the four active treatment groups were similar. There were no serious adverse events. The number of severe events was low overall but highest in the placebo group. Significant improvements were seen in Spontaneous Bowel Movements with 5 mg, 10 mg, and 20 mg NSR capsules. Mean change in SBMs from baseline of 2.21 (P = 0.052), 2.37 (P = 0.032); 4.11 (P = 0.0005); 5.19 (<0.0001) was noted with NSR 2.5 mg, 5 mg, 10 mg, and 20 mg, respectively, when taken once daily, compared with 1.38 (P = 0.2) for patients on placebo therapy. No changes in subjective or objective measures of opioid withdrawal as measured by the Subjective Opioid Withdrawal Scale or Clinical Opioid Withdrawal Scale were observed. There was no increase in patient reported pain as measured daily using a visual analogue scale. CONCLUSIONS: This Phase II study has shown that using a new sustained release formulation to deliver oral naloxone to the colon allows successful treatment of OIC without comprising the desired opioid effects. PMID- 26110376 TI - Skin Cancer Risk Factors and Preventative Behaviors among United States Military Veterans Deployed to Iraq and Afghanistan. PMID- 26110377 TI - Mutational analysis of Greek patients with suspected hereditary neuropathy with liability to pressure palsies (HNPP): a 15-year experience. AB - There has been limited information from population studies regarding the overall frequency of the common 1.5-Mb 17p11.2 deletion and even scarcer data regarding the overall frequency of PMP22 micromutations in patients with a clinical suspicion of hereditary neuropathy with liability to pressure palsies (HNPP). We have analysed 100 consecutive Greek patients referred for HNPP genetic testing over a 15-year period to our Neurogenetics Unit in Athens, a reference centre for all regions of Greece. All patients were screened for the 1.5-Mb deletion and a selected subgroup of deletion-negative patients for PMP22 micromutations. Mutation-positive and mutation-negative patients were compared for various clinical parameters. In total, 54 mutation-positive patients were identified. In index cases, the deletion frequency was 47.8%, and the PMP22 micromutation frequency was 2.2%. Within mutation-positive patients, the common deletion represented 95.7% and PMP22 micromutations 4.3% of cases. Two previously reported PMP22 micromutations (c.364_365delCC and c.79-2A>G) were detected. HNPP index cases had a 2.8-1 male-to-female ratio, similar to mutation-negative patients. A typical phenotype (recurrent or isolated palsies) was present in 82.4% of symptomatic HNPP cases, significantly higher than mutation-negative patients. Sensitivity of proposed electrophysiological diagnostic criteria for HNPP was calculated at 95.7% and specificity at 80.5%. In conclusion, the common HNPP deletion accounts for ~50% and PMP22 micromutations for ~2% of cases in a large consecutive cohort of patients with suspected HNPP. The mutational and phenotypic spectrum of HNPP is similar in the Greek population compared with other populations. Proposed electrophysiological diagnostic criteria perform satisfactorily in everyday clinical practice. PMID- 26110378 TI - Psychiatric Symptom Clusters as Risk Factors for Alcohol Use Disorders in Adolescence: A National Study. AB - BACKGROUND: Few epidemiologic studies have examined a full range of adolescent psychiatric disorders in the general population. The association between psychiatric symptom clusters (PSCs) and DSM-IV alcohol use disorders (AUDs) among adolescents is not well understood. METHODS: This study draws upon the public-use data from the 2000 National Household Survey on Drug Abuse, including a study sample of 19,430 respondents aged 12 to 17. Logistic regression and exploratory structural equation modeling assess the associations between PSCs and DSM-IV AUDs by gender. The PSCs are based on brief screening scales devised from the Diagnostic Interview Schedule for Children Predictive Scales. RESULTS: Several PSCs were found to be significantly associated with DSM-IV AUDs, including separation anxiety, generalized anxiety, depression, oppositional defiant disorder, and conduct disorder among both genders, and panic disorder and obsessive/ compulsive disorder among females. Consistent with the literature, the analysis of PSCs yields 3 factors identical for both genders-2 internalizing factors (fear and anxiety-misery) and 1 externalizing factor. Adolescents who scored higher on the externalizing factor tended to have higher levels of the AUD factor. Female adolescents who scored higher on the internalizing misery factor and lower on the internalizing fear factor also tended to have higher levels of the AUD factor. CONCLUSIONS: The associations that we found between PSCs and AUDs among adolescents in this study are consistent with those found among adults in other studies, although gender may moderate associations between internalizing PSCs and AUDs. Our findings lend support to previous findings on the developmentally stable associations between disruptive behaviors and AUDs among adolescents as well as adults in the general population. PMID- 26110379 TI - Circulating Long Noncoding RNA as a Potential Target for Prostate Cancer. AB - Prostate cancer is considered the second most common visceral malignancy in men in Western countries. Its emergence is largely due to the coordination of a malignant network, and long noncoding RNA has been recently demonstrated to play a critical role in prostate carcinogenesis. The aberrant expression of long noncoding RNA in prostate cancer patients is strongly associated with diagnosis, risk stratification and carcinogenesis, information that provides new insight into the complicated intracellular milieu of prostate cancer. This review focuses mainly on literature evidence for the role of long noncoding RNA in prostate cancer, which may suggest novel strategies for its prognosis, diagnosis and clinical treatment. PMID- 26110380 TI - Phylogeography of Thlaspi arvense (Brassicaceae) in China Inferred from Chloroplast and Nuclear DNA Sequences and Ecological Niche Modeling. AB - Thlaspi arvense is a well-known annual farmland weed with worldwide distribution, which can be found from sea level to above 4000 m high on the Qinghai-Tibetan Plateau (QTP). In this paper, a phylogeographic history of T. arvense including 19 populations from China was inferred by using three chloroplast (cp) DNA segments (trnL-trnF, rpl32-trnL and rps16) and one nuclear (n) DNA segment (Fe regulated transporter-like protein, ZIP). A total of 11 chloroplast haplotypes and six nuclear alleles were identified, and haplotypes unique to the QTP were recognized (C4, C5, C7 and N4). On the basis of molecular dating, haplotypes C4, C5 and C7 have separated from others around 1.58 Ma for cpDNA, which corresponds to the QTP uplift. In addition, this article suggests that the T. arvense populations in China are a mixture of diverged subpopulations as inferred by hT/vT test (hT <= vT, cpDNA) and positive Tajima's D values (1.87, 0.05 < p < 0.10 for cpDNA and 3.37, p < 0.01 for nDNA). Multimodality mismatch distribution curves and a relatively large shared area of suitable environmental conditions between the Last Glacial Maximum (LGM) as well as the present time recognized by MaxEnt software reject the sudden expansion population model. PMID- 26110382 TI - Supramolecular Approaches to Nanoscale Morphological Control in Organic Solar Cells. AB - Having recently surpassed 10% efficiency, solar cells based on organic molecules are poised to become a viable low-cost clean energy source with the added advantages of mechanical flexibility and light weight. The best-performing organic solar cells rely on a nanostructured active layer morphology consisting of a complex organization of electron donating and electron accepting molecules. Although much progress has been made in designing new donor and acceptor molecules, rational control over active layer morphology remains a central challenge. Long-term device stability is another important consideration that needs to be addressed. This review highlights supramolecular strategies for generating highly stable nanostructured organic photovoltaic active materials by design. PMID- 26110381 TI - Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells. AB - Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial autophagy (mitophagy), mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER) and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1), as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT) and the IP3-receptors (IP3Rs) as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU) primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis. PMID- 26110383 TI - Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors. AB - The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies and disorders. FGFRs have proved to be attractive targets for therapeutic intervention in cancer, and it is of high interest to find FGFR inhibitors with novel scaffolds. In this study, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed based on previously reported FGFR1 inhibitors with diverse structural skeletons. This model was evaluated for its prediction performance on a diverse test set containing 232 FGFR inhibitors, and it yielded a SD value of 0.75 pIC50 units from measured inhibition affinities and a Pearson's correlation coefficient R2 of 0.53. This result suggests that the combinatorial 3D-QSAR model could be used to search for new FGFR1 hit structures and predict their potential activity. To further evaluate the performance of the model, a decoy set validation was used to measure the efficiency of the model by calculating EF (enrichment factor). Based on the combinatorial pharmacophore model, a virtual screening against SPECS database was performed. Nineteen novel active compounds were successfully identified, which provide new chemical starting points for further structural optimization of FGFR1 inhibitors. PMID- 26110384 TI - Identification of Site-Specific Stroke Biomarker Candidates by Laser Capture Microdissection and Labeled Reference Peptide. AB - The search to date for accurate protein biomarkers in acute ischemic stroke has taken into consideration the stage and/or the size of infarction, but has not accounted for the site of stroke. In the present study, multiple reaction monitoring using labeled reference peptide (LRP) following laser capture microdissection (LCM) is used to identify site-specific protein biomarker candidates. In middle cerebral artery occlusion (MCAO) rat models, both intact and infarcted brain tissue was collected by LCM, followed by on-film digestion and semi-quantification using triple-quadrupole mass spectrometry. Thirty-four unique peptides were detected for the verification of 12 proteins in both tissue homogenates and LCM-captured samples. Six insoluble proteins, including neurofilament light polypeptide (NEFL), alpha-internexin (INA), microtubule associated protein 2 (MAP2), myelin basic protein (MBP), myelin proteolipid protein (PLP) and 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP), were found to be site-specific. Soluble proteins, such as neuron-specific enolase (NSE) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), and some insoluble proteins, including neurofilament heavy polypeptide (NEFH), glial fibrillary acidic protein (GFAP), microtubule-associated protein tau (MAPT) and tubulin beta 3 chain (TUBB3), were found to be evenly distributed in the brain. Therefore, we conclude that some insoluble protein biomarkers for stroke are site-specific, and would make excellent candidates for the design and analysis of relevant clinical studies in the future. PMID- 26110385 TI - Inflammatory and Other Biomarkers: Role in Pathophysiology and Prediction of Gestational Diabetes Mellitus. AB - Understanding pathophysiology and identifying mothers at risk of major pregnancy complications is vital to effective prevention and optimal management. However, in current antenatal care, understanding of pathophysiology of complications is limited. In gestational diabetes mellitus (GDM), risk prediction is mostly based on maternal history and clinical risk factors and may not optimally identify high risk pregnancies. Hence, universal screening is widely recommended. Here, we will explore the literature on GDM and biomarkers including inflammatory markers, adipokines, endothelial function and lipids to advance understanding of pathophysiology and explore risk prediction, with a goal to guide prevention and treatment of GDM. PMID- 26110386 TI - Local Controlled Release of Polyphenol Conjugated with Gelatin Facilitates Bone Formation. AB - Catechins are extensively used in health care treatments. Nevertheless, there is scarce information about the feasibility of local administration with polyphenols for bone regeneration therapy, possibly due to lack of effective delivery systems. Here we demonstrated that the epigallocatechin-3-gallate-conjugated gelatin (EGCG/Gel) prepared by an aqueous chemical synthesis using 4-(4,6 dimethoxy-1,3,5-triazin-2-yl)-4-morpholinium chloride (DMT-MM) gradually disintegrated with time and facilitated bone formation in a critical size defect of a mouse calvaria. Conjugation of EGCG with the Gel generated cross-linking between the two molecules, thereby leading to a retardation of the degradation of the EGCG/Gel and to a delayed release of EGCG. The prepared EGCG/Gels represented significant osteogenic capability compared with that of the uncross-linked Gel and the cross-linked Gel with uncombined-EGCG. In vitro experiments disclosed that the EGCG/Gel induced osteoblastogenesis of a mouse mesenchymal stem cell line (D1 cells) within 14 days. Using fluorescently-labeled EGCG/Gel, we found that the fraction of EGCG/Gel adsorbed onto the cell membrane of the D1 cells possibly via a Gel-cell interaction. The interaction might confer the long-term effects of EGCG on the cells, resulting in a potent osteogenic capability of the EGCG/Gel in vivo. These results should provide insight into local controlled release of polyphenols for bone therapy. PMID- 26110387 TI - A Plasmacytoid Dendritic Cells-Type I Interferon Axis Is Critically Implicated in the Pathogenesis of Systemic Lupus Erythematosus. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that is characterized by the generation of immune responses to various nuclear components. Impaired clearance of apoptotic cells and loss of tolerance to self antigens are involved both in the initiation and in the propagation of the disease. Dendritic cells (DCs) are key factors in the balance between autoimmunity and tolerance and play a role linking innate and adaptive immunity. DCs, particularly plasmacytoid DCs (pDCs), are the main source of type I interferon (IFN) cytokines, which contribute to the immunopathogenesis of SLE. There is accumulating evidence that pDCs and type I IFN cytokines take the leading part in the development of SLE. In this review, we discuss recent data regarding the role of pDCs and type I IFN cytokines in the pathogenesis of SLE and the potential for employing therapies targeting against aberrant regulation of the pDC-type I IFN axis for treating SLE. PMID- 26110388 TI - Memantine Attenuates Delayed Vasospasm after Experimental Subarachnoid Hemorrhage via Modulating Endothelial Nitric Oxide Synthase. AB - Delayed cerebral vasospasm is an important pathological feature of subarachnoid hemorrhage (SAH). The cause of vasospasm is multifactorial. Impairs nitric oxide availability and endothelial nitric oxide synthase (eNOS) dysfunction has been reported to underlie vasospasm. Memantine, a low-affinity uncompetitive N-methyl d-aspartate (NMDA) blocker has been proven to reduce early brain injury after SAH. This study investigated the effect of memantine on attenuation of vasospasm and restoring eNOS functionality. Male Sprague-Dawley rats weighing 350-450 g were randomly divided into three weight-matched groups, sham surgery, SAH + vehicle, and SAH + memantine groups. The effects of memantine on SAH were evaluated by assessing the severity of vasospasm and the expression of eNOS. Memantine effectively ameliorated cerebral vasospasm by restoring eNOS functionality. Memantine can prevent vasospasm in experimental SAH. Treatment strategies may help combat SAH-induced vasospasm in the future. PMID- 26110389 TI - Molecular Mechanisms Underlying Hull-Caryopsis Adhesion/Separation Revealed by Comparative Transcriptomic Analysis of Covered/Naked Barley (Hordeum vulgare L.). AB - The covered/naked caryopsis trait of barley is an important agronomic trait because it is directly linked to dietary use. The formation of covered/naked caryopsis is controlled by an NUD transcription factor, which is involved in pericarp cuticle development. However, the molecular mechanism underlying this trait remains so far largely unknown. In this study, comparative transcriptomes of grains three weeks after anthesis of Tibetan Hulless barley landrace Dulihuang and covered barley Morex were analyzed using RNA-seq technique. A total of 4031 differentially expressed genes (DEGs) were identified. The Nud gene was overexpressed in Morex, with trace expression in Dulihuang. Among seventeen cuticle related DEGs, sixteen were down regulated and one up regulated in Morex. These results suggest that the Nud gene in covered caryopsis might down regulate cuticle related genes, which may cause a permeable cuticle over pericarp, leading to a hull-caryopsis organ fusion. A functional cuticle covering the pericarp of naked caryopsis might be the result of deletion or low expression level of the Nud gene. The functional cuticle defines a perfect boundary to separate the caryopsis from the hull in naked barley. PMID- 26110390 TI - Bioactive Phytochemicals from Wild Arbutus unedo L. Berries from Different Locations in Portugal: Quantification of Lipophilic Components. AB - The lipophilic composition of wild Arbutus unedo L. berries, collected from six locations in Penacova (center of Portugal), as well as some general chemical parameters, namely total soluble solids, pH, titratable acidity, total phenolic content and antioxidant activity was studied in detail to better understand its potential as a source of bioactive compounds. The chemical composition of the lipophilic extracts, focused on the fatty acids, triterpenoids, sterols, long chain aliphatic alcohols and tocopherols, was investigated by gas chromatography mass spectrometry (GC-MS) analysis of the dichloromethane extracts. The lipophilic extractives of the ripe A. unedo berries ranged from 0.72% to 1.66% (w/w of dry weight), and consisted mainly of triterpenoids, fatty acids and sterols. Minor amounts of long chain aliphatic alcohols and tocopherols were also identified. Forty-one compounds were identified and among these, ursolic acid, lupeol, alpha-amyrin, linoleic and alpha-linolenic acids, and beta-sitosterol were highlighted as the major components. To the best of our knowledge the current research study provides the most detailed phytochemical repository for the lipophilic composition of A. unedo, and offers valuable information for future valuation and exploitation of these berries. PMID- 26110392 TI - Biomineral/Agarose Composite Gels Enhance Proliferation of Mesenchymal Stem Cells with Osteogenic Capability. AB - Hydroxyapatite (HA) or calcium carbonate (CaCO3) formed on an organic polymer of agarose gel is a biomaterial that can be used for bone tissue regeneration. However, in critical bone defects, the regeneration capability of these materials is limited. Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into bone forming osteoblasts. In this study, we loaded MSCs on HA- or CaCO3-formed agarose gel and cultured them with dexamethasone, which triggers the osteogenic differentiation of MSCs. High alkaline phosphatase activity was detected on both the HA- and CaCO3-formed agarose gels; however, basal activity was only detected on bare agarose gel. Bone-specific osteocalcin content was detected on CaCO3-formed agarose gel on Day 14 of culture, and levels subsequently increased over time. Similar osteocalcin content was detected on HA formed agarose on Day 21 and levels increased on Day 28. In contrast, only small amounts of osteocalcin were found on bare agarose gel. Consequently, osteogenic capability of MSCs was enhanced on CaCO3-formed agarose at an early stage, and both HA- and CaCO3-formed agarose gels well supported the capability at a later stage. Therefore, MSCs loaded on either HA- or CaCO3-formed agarose could potentially be employed for the repair of critical bone defects. PMID- 26110393 TI - Effect of Dose and Administration Period of Seed Cake of Genetically Modified and Non-Modified Flax on Selected Antioxidative Activities in Rats. AB - Flaxseed cake containing antioxidants is a valuable dietary component. Its nutritional effect may be diminished by the presence of anti-nutrients. The work was aimed at determining the effect of different contents of flaxseed cake in diets and their administration period on the development of rats and selected parameters of their health status. Diets with 15% and 30% addition of genetically modified (GM) flax seed cake with enhanced synthesis of polyphenols, as well as Linola non-GM flax were administered in short-term (33 days) and long-term (90 days) experiments. The 30% addition of flaxseed cake reduced digestibility of dietary nutrients, GM flaxseed cake lowered body weight gains. The relative weight of selected organs, hematological blood markers and serum activities of aspartate and alanine aminotransferases (AST, ALT) were not affected. Flaxseed cake consumption reduced serum concentration of albumins and increased globulins. Administration of 30% flaxseed cake improved plasma total antioxidant status and 30% GM flaxseed cake lowered liver thiobarbituric acid reactive substances. The activities of superoxide dismutase in erythrocytes, glutathione peroxidase in plasma and the liver concentration of 8-oxo-2'-deoxyguanosine were not changed. Most morphometric parameters of the small intestine did not differ between feeding groups. The administration of diets with 30% addition of flaxseed cake for 90 days improved the antioxidant status in rats. PMID- 26110394 TI - Biomarkers for Refractory Lupus Nephritis: A Microarray Study of Kidney Tissue. AB - The prognosis of severe lupus nephritis (LN) is very different among individual patients. None of the current biomarkers can be used to predict the development of refractory LN. Because kidney histology is the gold standard for diagnosing LN, the authors hypothesize that molecular signatures detected in kidney biopsy tissue may have predictive value in determining the therapeutic response. Sixty seven patients with biopsy-proven severely active LN by International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification III/IV were recruited. Twenty-three kidney tissue samples were used for RNA microarray analysis, while the remaining 44 samples were used for validation by real-time polymerase chain reaction (PCR) gene expression analysis. From hundreds of differential gene expressions in refractory LN, 12 candidates were selected for validation based on gene expression levels as well as relevant functions. The candidate biomarkers were members of the innate immune response molecules, adhesion molecules, calcium-binding receptors, and paracellular tight junction proteins. S100A8, ANXA13, CLDN19 and FAM46B were identified as the best kidney biomarkers for refractory LN, and COL8A1 was identified as the best marker for early loss of kidney function. These new molecular markers can be used to predict refractory LN and may eventually lead to novel molecular targets for therapy. PMID- 26110396 TI - Rapidly differentiating grape seeds from different sources based on characteristic fingerprints using direct analysis in real time coupled with time of-flight mass spectrometry combined with chemometrics. AB - The seeds of grapevine (Vitis vinifera) are a byproduct of wine production. To examine the potential value of grape seeds, grape seeds from seven sources were subjected to fingerprinting using direct analysis in real time coupled with time of-flight mass spectrometry combined with chemometrics. Firstly, we listed all reported components (56 components) from grape seeds and calculated the precise m/z values of the deprotonated ions [M-H](-) . Secondly, the experimental conditions were systematically optimized based on the peak areas of total ion chromatograms of the samples. Thirdly, the seven grape seed samples were examined using the optimized method. Information about 20 grape seed components was utilized to represent characteristic fingerprints. Finally, hierarchical clustering analysis and principal component analysis were performed to analyze the data. Grape seeds from seven different sources were classified into two clusters; hierarchical clustering analysis and principal component analysis yielded similar results. The results of this study lay the foundation for appropriate utilization and exploitation of grape seed samples. Due to the absence of complicated sample preparation methods and chromatographic separation, the method developed in this study represents one of the simplest and least time consuming methods for grape seed fingerprinting. PMID- 26110397 TI - Temperament and Interparental Conflict: The Role of Negative Emotionality in Predicting Child Behavioral Problems. AB - This study examined temperamental irritability and fearful distress as moderators of the association between interparental conflict and child behavior problems in a disadvantaged sample of two hundred and one 2-year-old children and their mothers. Using a multimethod, prospective design, findings revealed that the relation between interparental conflict and changes in child behavior problems over a 1-year period were moderated by temperamental irritability. Consistent with differential susceptibility theory, children high in irritable temperament not only exhibited poorer outcomes in contexts of high interparental conflict but also better adjustment in contexts of low levels of interparental conflict. Mediated moderation analyses revealed that fearful reactivity partly accounted for the greater susceptibility of irritable children, particularly in explaining why they fared better when interparental conflict was low. PMID- 26110391 TI - Transcriptional Factors Mediating Retinoic Acid Signals in the Control of Energy Metabolism. AB - Retinoic acid (RA), an active metabolite of vitamin A (VA), is important for many physiological processes including energy metabolism. This is mainly achieved through RA-regulated gene expression in metabolically active cells. RA regulates gene expression mainly through the activation of two subfamilies in the nuclear receptor superfamily, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RAR/RXR heterodimers or RXR/RXR homodimers bind to RA response element in the promoters of RA target genes and regulate their expressions upon ligand binding. The development of metabolic diseases such as obesity and type 2 diabetes is often associated with profound changes in the expressions of genes involved in glucose and lipid metabolism in metabolically active cells. RA regulates some of these gene expressions. Recently, in vivo and in vitro studies have demonstrated that status and metabolism of VA regulate macronutrient metabolism. Some studies have shown that, in addition to RARs and RXRs, hepatocyte nuclear factor 4alpha, chicken ovalbumin upstream promoter transcription factor II, and peroxisome proliferator activated receptor beta/delta may function as transcriptional factors mediating RA response. Herein, we summarize current progresses regarding the VA metabolism and the role of nuclear receptors in mediating RA signals, with an emphasis on their implication in energy metabolism. PMID- 26110399 TI - Relative cost-effectiveness of home visits and telephone contacts in preventing early childhood caries. AB - OBJECTIVES: To evaluate the cost-effectiveness of a home-visit intervention conducted by oral health therapists relative to a telephone-based alternative and no intervention. METHODS: A Markov model was built to combine data on dental caries incidence, dental treatments, quality of life and costs for a cohort of children from age 6 months to 6 years. The probabilities of developing caries and subsequent treatments were derived primarily from the key intervention study. The outcome measures were costs (US dollars), quality-adjusted life years (QALYs) and the number of carious teeth prevented. One-way and probabilistic sensitivity analyses were used to test the stability of the model. RESULTS: For every group of 100 children, the model predicted that having the home-visit intervention would save $167 032 and telephone contacts $144 709 over 51/2 years relative to no intervention (usual care). The home visits and telephone intervention would prevent 113 and 100 carious teeth (per 100 children) relative to no intervention in a period of 51/2 years. Sensitivity analysis showed that a lower rate of caries reduced the intervention's cost-effectiveness primarily through reducing general anaesthesia costs. The home visits and telephone interventions resulted in 7 and 6 QALYs, respectively, gained over the usual care group for the 100 children over 51/2 years. Both interventions were 'dominant,' as they saved costs and produced health benefits over usual care. CONCLUSIONS: Both the home visits and telephone-based community interventions conducted by oral health therapists were highly cost-effective than no intervention in preventing early childhood caries. PMID- 26110398 TI - Transparent, Ultrahigh-Gas-Barrier Films with a Brick-Mortar-Sand Structure. AB - Transparent and flexible gas-barrier materials have shown broad applications in electronics, food, and pharmaceutical preservation. Herein, we report ultrahigh gas-barrier films with a brick-mortar-sand structure fabricated by layer-by-layer (LBL) assembly of XAl-layered double hydroxide (LDH, X=Mg, Ni, Zn, Co) nanoplatelets and polyacrylic acid (PAA) followed by CO2 infilling, denoted as (XAl-LDH/PAA)n-CO2. The near-perfectly parallel orientation of the LDH "brick" creates a long diffusion length to hinder the transmission of gas molecules in the PAA "mortar". Most significantly, both the experimental studies and theoretical simulations reveal that the chemically adsorbed CO2 acts like "sand" to fill the free volume at the organic-inorganic interface, which further depresses the diffusion of permeating gas. The strategy presented here provides a new insight into the perception of barrier mechanism, and the (XAl-LDH/PAA)n-CO2 film is among the best gas barrier films ever reported. PMID- 26110395 TI - Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan. AB - BACKGROUND AND AIMS: The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. METHODS: Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. RESULTS: Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. CONCLUSIONS: The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients. PMID- 26110400 TI - Piezoelectric Sensor to Measure Soft and Hard Stiffness with High Sensitivity for Ultrasonic Transducers. AB - During dental sinus lift surgery, it is important to monitor the thickness of the remaining maxilla to avoid perforating the sinus membrane. Therefore, a sensor should be integrated into ultrasonic dental tools to prevent undesirable damage. This paper presents a piezoelectric (PZT) sensor installed in an ultrasonic transducer to measure the stiffness of high and low materials. Four design types using three PZT ring materials and a split PZT for actuator and sensor ring materials were studied. Three sensor locations were also examined. The voltage signals of the sensor and the displacement of the actuator were analyzed to distinguish the low and high stiffness. Using sensor type T1 made of the PZT-1 material and the front location A1 provided a high sensitivity of 2.47 Vm/kN. The experimental results demonstrated that our design can measure soft and hard stiffness. PMID- 26110402 TI - Socially Aware Heterogeneous Wireless Networks. AB - The development of smart cities has been the epicentre of many researchers' efforts during the past decade. One of the key requirements for smart city networks is mobility and this is the reason stable, reliable and high-quality wireless communications are needed in order to connect people and devices. Most research efforts so far, have used different kinds of wireless and sensor networks, making interoperability rather difficult to accomplish in smart cities. One common solution proposed in the recent literature is the use of software defined networks (SDNs), in order to enhance interoperability among the various heterogeneous wireless networks. In addition, SDNs can take advantage of the data retrieved from available sensors and use them as part of the intelligent decision making process contacted during the resource allocation procedure. In this paper, we propose an architecture combining heterogeneous wireless networks with social networks using SDNs. Specifically, we exploit the information retrieved from location based social networks regarding users' locations and we attempt to predict areas that will be crowded by using specially-designed machine learning techniques. By recognizing possible crowded areas, we can provide mobile operators with recommendations about areas requiring datacell activation or deactivation. PMID- 26110401 TI - Modulated Raman Spectroscopy for Enhanced Cancer Diagnosis at the Cellular Level. AB - Raman spectroscopy is emerging as a promising and novel biophotonics tool for non invasive, real-time diagnosis of tissue and cell abnormalities. However, the presence of a strong fluorescence background is a key issue that can detract from the use of Raman spectroscopy in routine clinical care. The review summarizes the state-of-the-art methods to remove the fluorescence background and explores recent achievements to address this issue obtained with modulated Raman spectroscopy. This innovative approach can be used to extract the Raman spectral component from the fluorescence background and improve the quality of the Raman signal. We describe the potential of modulated Raman spectroscopy as a rapid, inexpensive and accurate clinical tool to detect the presence of bladder cancer cells. Finally, in a broader context, we show how this approach can greatly enhance the sensitivity of integrated Raman spectroscopy and microfluidic systems, opening new prospects for portable higher throughput Raman cell sorting. PMID- 26110403 TI - A Cross Structured Light Sensor and Stripe Segmentation Method for Visual Tracking of a Wall Climbing Robot. AB - In non-destructive testing (NDT) of metal welds, weld line tracking is usually performed outdoors, where the structured light sources are always disturbed by various noises, such as sunlight, shadows, and reflections from the weld line surface. In this paper, we design a cross structured light (CSL) to detect the weld line and propose a robust laser stripe segmentation algorithm to overcome the noises in structured light images. An adaptive monochromatic space is applied to preprocess the image with ambient noises. In the monochromatic image, the laser stripe obtained is recovered as a multichannel signal by minimum entropy deconvolution. Lastly, the stripe centre points are extracted from the image. In experiments, the CSL sensor and the proposed algorithm are applied to guide a wall climbing robot inspecting the weld line of a wind power tower. The experimental results show that the CSL sensor can capture the 3D information of the welds with high accuracy, and the proposed algorithm contributes to the weld line inspection and the robot navigation. PMID- 26110404 TI - Photography by Cameras Integrated in Smartphones as a Tool for Analytical Chemistry Represented by an Butyrylcholinesterase Activity Assay. AB - Smartphones are popular devices frequently equipped with sensitive sensors and great computational ability. Despite the widespread availability of smartphones, practical uses in analytical chemistry are limited, though some papers have proposed promising applications. In the present paper, a smartphone is used as a tool for the determination of cholinesterasemia i.e., the determination of a biochemical marker butyrylcholinesterase (BChE). The work should demonstrate suitability of a smartphone-integrated camera for analytical purposes. Paper strips soaked with indoxylacetate were used for the determination of BChE activity, while the standard Ellman's assay was used as a reference measurement. In the smartphone-based assay, BChE converted indoxylacetate to indigo blue and coloration was photographed using the phone's integrated camera. A RGB color model was analyzed and color values for the individual color channels were determined. The assay was verified using plasma samples and samples containing pure BChE, and validated using Ellmans's assay. The smartphone assay was proved to be reliable and applicable for routine diagnoses where BChE serves as a marker (liver function tests; some poisonings, etc.). It can be concluded that the assay is expected to be of practical applicability because of the results' relevance. PMID- 26110405 TI - Classification of Potential Water Bodies Using Landsat 8 OLI and a Combination of Two Boosted Random Forest Classifiers. AB - This study proposes a new water body classification method using top-of atmosphere (TOA) reflectance and water indices (WIs) of the Landsat 8 Operational Land Imager (OLI) sensor and its corresponding random forest classifiers. In this study, multispectral images from the OLI sensor are represented as TOA reflectance and WI values because a classification result using two measures is better than raw spectral images. Two types of boosted random forest (BRF) classifiers are learned using TOA reflectance and WI values, respectively, instead of the heuristic threshold or unsupervised methods. The final probability is summed linearly using the probabilities of two different BRFs to classify image pixels to water class. This study first demonstrates that the Landsat 8 OLI sensor has higher classification rate because it provides improved signal-to ratio radiometric by using 12-bit quantization of the data instead of 8-bit as available from other sensors. In addition, we prove that the performance of the proposed combination of two BRF classifiers shows robust water body classification results, regardless of topology, river properties, and background environment. PMID- 26110406 TI - Solving Energy-Aware Real-Time Tasks Scheduling Problem with Shuffled Frog Leaping Algorithm on Heterogeneous Platforms. AB - Reducing energy consumption is becoming very important in order to keep battery life and lower overall operational costs for heterogeneous real-time multiprocessor systems. In this paper, we first formulate this as a combinatorial optimization problem. Then, a successful meta-heuristic, called Shuffled Frog Leaping Algorithm (SFLA) is proposed to reduce the energy consumption. Precocity remission and local optimal avoidance techniques are proposed to avoid the precocity and improve the solution quality. Convergence acceleration significantly reduces the search time. Experimental results show that the SFLA based energy-aware meta-heuristic uses 30% less energy than the Ant Colony Optimization (ACO) algorithm, and 60% less energy than the Genetic Algorithm (GA) algorithm. Remarkably, the running time of the SFLA-based meta-heuristic is 20 and 200 times less than ACO and GA, respectively, for finding the optimal solution. PMID- 26110407 TI - Interference Mitigation Schemes for Wireless Body Area Sensor Networks: A Comparative Survey. AB - A wireless body area sensor network (WBASN) consists of a coordinator and multiple sensors to monitor the biological signals and functions of the human body. This exciting area has motivated new research and standardization processes, especially in the area of WBASN performance and reliability. In scenarios of mobility or overlapped WBASNs, system performance will be significantly degraded because of unstable signal integrity. Hence, it is necessary to consider interference mitigation in the design. This survey presents a comparative review of interference mitigation schemes in WBASNs. Further, we show that current solutions are limited in reaching satisfactory performance, and thus, more advanced solutions should be developed in the future. PMID- 26110409 TI - Electrothermally-Actuated Micromirrors with Bimorph Actuators--Bending-Type and Torsion-Type. AB - Three different electrothermally-actuated MEMS micromirrors with Cr/Au-Si bimorph actuators are proposed. The devices are fabricated with the SOIMUMPs process developed by MEMSCAP, Inc. (Durham, NC, USA). A silicon-on-insulator MEMS process has been employed for the fabrication of these micromirrors. Electrothermal actuation has achieved a large angular movement in the micromirrors. Application of an external electric current 0.04 A to the bending-type, restricted-torsion type, and free-torsion-type mirrors achieved rotation angles of 1.69 degrees , 3.28 degrees , and 3.64 degrees , respectively. PMID- 26110408 TI - A Microfluidic Love-Wave Biosensing Device for PSA Detection Based on an Aptamer Beacon Probe. AB - A label-free and selective aptamer beacon-based Love-wave biosensing device was developed for prostate specific antigen (PSA) detection. The device consists of the following parts: LiTaO3 substrate with SiO2 film as wave guide layer, two set of inter-digital transducers (IDT), gold film for immobilization of the biorecongniton layer and a polydimethylsiloxane (PDMS) microfluidic channels. DNA aptamer, or "artificial antibody", was used as the specific biorecognition probe for PSA capture. Some nucleotides were added to the 3'-end of the aptamer to form a duplex with the 3'-end, turning the aptamer into an aptamer-beacon. Taking advantage of the selective target-induced assembly changes arising from the "aptamer beacon", highly selective and specific detection of PSA was achieved. Furthermore, PDMS microfluidic channels were designed and fabricated to realize automated quantitative sample injection. After optimization of the experimental conditions, the established device showed good performance for PSA detection between 10 ng/mL to 1 MUg/mL, with a detection limit of 10 ng/mL. The proposed sensor might be a promising alternative for point of care diagnostics. PMID- 26110410 TI - First-Principles Studies of Hydrogen Adsorption at Pd-SiO2 Interfaces. AB - The interaction of hydrogen with Pd-SiO2 interfaces has been investigated for the first time using first-principles calculations based on density functional theory. The hydrogen-induced polarization at the Pd-SiO2 interfaces was evaluated using Pd-SiO2 interface supercells. As a result, the potential change induced by interfacial hydrogen atoms was not observed even for hydrogen concentration of ~1.3 * 10(15) cm(-2) at the Pd-SiO2 interface. This result implies that hydrogen does not create an electric double layer at the Pd-SiO2 interface but change the property of the SiO2 region, resulting in the hydrogen sensitivity of the devices. PMID- 26110412 TI - Design of a Thermoacoustic Sensor for Low Intensity Ultrasound Measurements Based on an Artificial Neural Network. AB - In therapeutic ultrasound applications, accurate ultrasound output intensities are crucial because the physiological effects of therapeutic ultrasound are very sensitive to the intensity and duration of these applications. Although radiation force balance is a benchmark technique for measuring ultrasound intensity and power, it is costly, difficult to operate, and compromised by noise vibration. To overcome these limitations, the development of a low-cost, easy to operate, and vibration-resistant alternative device is necessary for rapid ultrasound intensity measurement. Therefore, we proposed and validated a novel two-layer thermoacoustic sensor using an artificial neural network technique to accurately measure low ultrasound intensities between 30 and 120 mW/cm2. The first layer of the sensor design is a cylindrical absorber made of plexiglass, followed by a second layer composed of polyurethane rubber with a high attenuation coefficient to absorb extra ultrasound energy. The sensor determined ultrasound intensities according to a temperature elevation induced by heat converted from incident acoustic energy. Compared with our previous one-layer sensor design, the new two layer sensor enhanced the ultrasound absorption efficiency to provide more rapid and reliable measurements. Using a three-dimensional model in the K-wave toolbox, our simulation of the ultrasound propagation process demonstrated that the two layer design is more efficient than the single layer design. We also integrated an artificial neural network algorithm to compensate for the large measurement offset. After obtaining multiple parameters of the sensor characteristics through calibration, the artificial neural network is built to correct temperature drifts and increase the reliability of our thermoacoustic measurements through iterative training about ten seconds. The performance of the artificial neural network method was validated through a series of experiments. Compared to our previous design, the new design reduced sensing time from 20 s to 12 s, and the sensor's average error from 3.97 mW/cm2 to 1.31 mW/cm2 respectively. PMID- 26110411 TI - Biosensing with Forster Resonance Energy Transfer Coupling between Fluorophores and Nanocarbon Allotropes. AB - Nanocarbon allotropes (NCAs), including zero-dimensional carbon dots (CDs), one dimensional carbon nanotubes (CNTs) and two-dimensional graphene, exhibit exceptional material properties, such as unique electrical/thermal conductivity, biocompatibility and high quenching efficiency, that make them well suited for both electrical/electrochemical and optical sensors/biosensors alike. In particular, these material properties have been exploited to significantly enhance the transduction of biorecognition events in fluorescence-based biosensing involving Forster resonant energy transfer (FRET). This review analyzes current advances in sensors and biosensors that utilize graphene, CNTs or CDs as the platform in optical sensors and biosensors. Widely utilized synthesis/fabrication techniques, intrinsic material properties and current research examples of such nanocarbon, FRET-based sensors/biosensors are illustrated. The future outlook and challenges for the research field are also detailed. PMID- 26110413 TI - A Low Complexity System Based on Multiple Weighted Decision Trees for Indoor Localization. AB - Indoor position estimation has become an attractive research topic due to growing interest in location-aware services. Nevertheless, satisfying solutions have not been found with the considerations of both accuracy and system complexity. From the perspective of lightweight mobile devices, they are extremely important characteristics, because both the processor power and energy availability are limited. Hence, an indoor localization system with high computational complexity can cause complete battery drain within a few hours. In our research, we use a data mining technique named boosting to develop a localization system based on multiple weighted decision trees to predict the device location, since it has high accuracy and low computational complexity. The localization system is built using a dataset from sensor fusion, which combines the strength of radio signals from different wireless local area network access points and device orientation information from a digital compass built-in mobile device, so that extra sensors are unnecessary. Experimental results indicate that the proposed system leads to substantial improvements on computational complexity over the widely-used traditional fingerprinting methods, and it has a better accuracy than they have. PMID- 26110414 TI - The Precise Synthesis of Phenylene-Extended Cyclic Hexa-peri-hexabenzocoronenes from Polyarylated [n]Cycloparaphenylenes by the Scholl Reaction. AB - The longitudinal extension of cycloparaphenylenes (CPP) towards ultrashort carbon nanotubes (CNTs) is essential for the solution based bottom-up synthesis of CNTs. Herein, the longitudinal extension of the CPP skeleton by the introduction of hexaphenylbenzene units towards polyarylated [n]CPPs is described. Further, the applicability of the Scholl reaction to selectively form graphenic sidewalls is demonstrated. The ring size and substitution patterns of the polyarylated [n]CPPs were varied to overcome strain-induced side reactions during the oxidative cyclodehydrogenation and cyclic para-hexa-peri-hexabenzocoronene trimers ([3]CHBCs) were selectively obtained. This concept is envisioned as an access to ultrashort carbon nanotubes subject to the condition that further benzene rings with the right connectivity will be inserted. PMID- 26110415 TI - Local infusion of ascorbate augments NO-dependent cutaneous vasodilatation during intense exercise in the heat. AB - Recent work demonstrates that nitric oxide (NO) contributes to cutaneous vasodilatation during moderate (400 W of metabolic heat production) but not high (700 W of metabolic heat production) intensity exercise bouts performed in the heat (35 degrees C). The present study evaluated whether the impairment in NO dependent cutaneous vasodilatation was the result of a greater accumulation of reactive oxygen species during high (700 W of metabolic heat production) relative to moderate (500 W of metabolic heat production) intensity exercise. It was shown that local infusion of ascorbate (an anti-oxidant) improves NO-dependent forearm cutaneous vasodilatation during high intensity exercise in the heat. These findings provide novel insight into the physiological mechanisms governing cutaneous blood flow during exercise-induced heat stress and provide direction for future research exploring whether oxidative stress underlies the impairments in heat dissipation that may occur in older adults, as well as in individuals with pathophysiological conditions such as type 2 diabetes. Nitric oxide (NO) dependent cutaneous vasodilatation is reportedly diminished during exercise performed at a high (700 W) relative to moderate (400 W) rate of metabolic heat production. The present study evaluated whether this impairment results from increased oxidative stress associated with an accumulation of reactive oxygen species (ROS) during high intensity exercise. On two separate days, 11 young (mean +/- SD, 24 +/- 4 years) males cycled in the heat (35 degrees C) at a moderate (500 W) or high (700 W) rate of metabolic heat production. Each session included two 30 min exercise bouts followed by 20 and 40 min of recovery, respectively. Cutaneous vascular conductance (CVC) was monitored at four forearm skin sites continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control); (2) 10 mm ascorbate (Ascorbate); (3) 10 mm l-NAME; or (4) 10 mm ascorbate + 10 mm l-NAME (Ascorbate + l-NAME). At the end of each 500 W exercise bout, CVC was attenuated with l-NAME (~35% CVCmax ) and Ascorbate + l NAME (~43% CVCmax ) compared to Control (~60% CVCmax ; all P < 0.04); however, Ascorbate did not modulate CVC during exercise (~60% CVCmax ; both P > 0.87). Conversely, CVC was elevated with Ascorbate (~72% CVCmax ; both P < 0.03) but remained similar to Control (~59% CVCmax ) with l-NAME (~50% CVCmax ) and Ascorbate + l-NAME (~47% CVCmax ; all P > 0.05) at the end of both 700 W exercise bouts. We conclude that oxidative stress associated with an accumulation of ascorbate-sensitive ROS impairs NO-dependent cutaneous vasodilatation during intense exercise. PMID- 26110416 TI - Experimental African Trypanosome Infection by Needle Passage or Natural Tsetse Fly Challenge Thwarts the Development of Collagen-Induced Arthritis in DBA/1 Prone Mice via an Impairment of Antigen Specific B Cell Autoantibody Titers. AB - Collagen-induced arthritis is a B cell-mediated autoimmune disease. Recently published studies have demonstrated that in some rare cases pathogens can confer protection from autoimmunity. Trypanosoma brucei parasites are tsetse fly transmitted extracellular protozoans causing sleeping sickness disease in humans and Nagana in livestock in sub-Saharan endemic areas. In the past, we demonstrated that trypanosome infections impair B cell homeostasis and abolish vaccine-induced protection against unrelated antigens. Hence, here we hypothesized that trypanosome infection can affect the onset of CIA by specifically dampening specific B-cell responses and type II collagen antibody titers in DBA/1 prone mice. We observed a substantial delay in the onset of collagen-induced arthritis in T. brucei-infected DBA/1 mice that correlates with a drastic decrease of type II collagen titers of the different IgG isotypes in the serum. Treatment of infected mice with Berenil, a trypanocidal drug, restored the development of CIA-associated clinical symptoms. Interestingly, these data were confirmed by the challenge of immunized DBA/1 prone mice with T. brucei infected tsetse flies. Together, these results demonstrate that T. brucei infection is impairing the maintenance of the antigen specific plasma B cell pool driving the development of CIA in DBA/1 prone mice. PMID- 26110417 TI - Salivary Thromboxane A2-Binding Proteins from Triatomine Vectors of Chagas Disease Inhibit Platelet-Mediated Neutrophil Extracellular Traps (NETs) Formation and Arterial Thrombosis. AB - BACKGROUND: The saliva of blood-feeding arthropods contains a notable diversity of molecules that target the hemostatic and immune systems of the host. Dipetalodipin and triplatin are triatomine salivary proteins that exhibit high affinity binding to prostanoids, such as TXA2, thus resulting in potent inhibitory effect on platelet aggregation in vitro. It was recently demonstrated that platelet-derived TXA2 mediates the formation of neutrophil extracellular traps (NETs), a newly recognized link between inflammation and thrombosis that promote thrombus growth and stability. METHODOLOGY/PRINCIPAL FINDINGS: This study evaluated the ability of dipetalodipin and triplatin to block NETs formation in vitro. We also investigated the in vivo antithrombotic activity of TXA2 binding proteins by employing two murine models of experimental thrombosis. Remarkably, we observed that both inhibitors abolished the platelet-mediated formation of NETs in vitro. Dipetalodipin and triplatin significantly increased carotid artery occlusion time in a FeCl3-induced injury model. Treatment with TXA2-binding proteins also protected mice from lethal pulmonary thromboembolism evoked by the intravenous injection of collagen and epinephrine. Effective antithrombotic doses of dipetalodipin and triplatin did not increase blood loss, which was estimated using the tail transection method. CONCLUSIONS/SIGNIFICANCE: Salivary TXA2 binding proteins, dipetalodipin and triplatin, are capable to prevent platelet mediated NETs formation in vitro. This ability may contribute to the antithrombotic effects in vivo. Notably, both molecules inhibit arterial thrombosis without promoting excessive bleeding. Our results provide new insight into the antihemostatic effects of TXA2-binding proteins and may have important significance in elucidating the mechanisms of saliva to avoid host's hemostatic responses and innate immune system. PMID- 26110418 TI - Synonymous codon usage bias in plant mitochondrial genes is associated with intron number and mirrors species evolution. AB - Synonymous codon usage bias (SCUB) is a common event that a non-uniform usage of codons often occurs in nearly all organisms. We previously found that SCUB is correlated with both intron number and exon position in the plant nuclear genome but not in the plastid genome; SCUB in both nuclear and plastid genome can mirror the evolutionary specialization. However, how about the rules in the mitochondrial genome has not been addressed. Here, we present an analysis of SCUB in the mitochondrial genome, based on 24 plant species ranging from algae to land plants. The frequencies of NNA and NNT (A- and T-ending codons) are higher than those of NNG and NNC, with the strongest preference in bryophytes and the weakest in land plants, suggesting an association between SCUB and plant evolution. The preference for NNA and NNT is more evident in genes harboring a greater number of introns in land plants, but the bias to NNA and NNT exhibits even among exons. The pattern of SCUB in the mitochondrial genome differs in some respects to that present in both the nuclear and plastid genomes. PMID- 26110419 TI - Metabolic Profiles in Ovine Carotid Arteries with Developmental Maturation and Long-Term Hypoxia. AB - BACKGROUND: Long-term hypoxia (LTH) is an important stressor related to health and disease during development. At different time points from fetus to adult, we are exposed to hypoxic stress because of placental insufficiency, high-altitude residence, smoking, chronic anemia, pulmonary, and heart disorders, as well as cancers. Intrauterine hypoxia can lead to fetal growth restriction and long-term sequelae such as cognitive impairments, hypertension, cardiovascular disorders, diabetes, and schizophrenia. Similarly, prolonged hypoxic exposure during adult life can lead to acute mountain sickness, chronic fatigue, chronic headache, cognitive impairment, acute cerebral and/or pulmonary edema, and death. AIM: LTH also can lead to alteration in metabolites such as fumarate, 2-oxoglutarate, malate, and lactate, which are linked to epigenetic regulation of gene expression. Importantly, during the intrauterine life, a fetus is under a relative hypoxic environment, as compared to newborn or adult. Thus, the changes in gene expression with development from fetus to newborn to adult may be as a consequence of underlying changes in the metabolic profile because of the hypoxic environment along with developmental maturation. To examine this possibility, we examined the metabolic profile in carotid arteries from near-term fetus, newborn, and adult sheep in both normoxic and long-term hypoxic acclimatized groups. RESULTS: Our results demonstrate that LTH differentially regulated glucose metabolism, mitochondrial metabolism, nicotinamide cofactor metabolism, oxidative stress and antioxidants, membrane lipid hydrolysis, and free fatty acid metabolism, each of which may play a role in genetic-epigenetic regulation. PMID- 26110420 TI - Intrinsic functional plasticity of the sensorimotor network in relapsing remitting multiple sclerosis: evidence from a centrality analysis. AB - BACKGROUND AND PURPOSE: Advanced MRI studies have revealed regional alterations in the sensorimotor cortex of patients with relapsing-remitting multiple sclerosis (RRMS). However, the organizational features underlying the relapsing phase and the subsequent remitting phase have not been directly shown at the functional network or the connectome level. Therefore, this study aimed to characterize MS-related centrality disturbances of the sensorimotor network (SMN) and to assess network integrity and connectedness. METHODS: Thirty-four patients with clinically definite RRMS and well-matched healthy controls participated in the study. Twenty-three patients in the remitting phase underwent one resting state functional MRI, and 11 patients in the relapsing-remitting phase underwent two different MRIs. We measured voxel-wise centrality metrics to determine direct (degree centrality, DC) and global (eigenvector centrality, EC) functional relationships across the entire SMN. RESULTS: In the relapsing phase, DC was significantly decreased in the bilateral primary motor and somatosensory cortex (M1/S1), left dorsal premotor (PMd), and operculum-integrated regions. However, DC was increased in the peripheral SMN areas. The decrease in DC in the bilateral M1/S1 was associated with the expanded disability status scale (EDSS) and total white matter lesion loads (TWMLLs), suggesting that this adaptive response is related to the extent of brain damage in the rapid-onset attack stage. During the remission process, these alterations in centrality were restored in the bilateral M1/S1 and peripheral SMN areas. In the remitting phase, DC was reduced in the premotor, supplementary motor, and operculum-integrated regions, reflecting an adaptive response due to brain atrophy. However, DC was enhanced in the right M1 and left parietal-integrated regions, indicating chronic reorganization. In both the relapsing and remitting phases, the changes in EC and DC were similar. CONCLUSIONS: The alterations in centrality within the SMN indicate rapid plasticity and chronic reorganization with a biased impairment of specific functional areas in RRMS patients. PMID- 26110421 TI - Visual vs Fully Automatic Histogram-Based Assessment of Idiopathic Pulmonary Fibrosis (IPF) Progression Using Sequential Multidetector Computed Tomography (MDCT). AB - OBJECTIVES: To describe changes over time in extent of idiopathic pulmonary fibrosis (IPF) at multidetector computed tomography (MDCT) assessed by semi quantitative visual scores (VSs) and fully automatic histogram-based quantitative evaluation and to test the relationship between these two methods of quantification. METHODS: Forty IPF patients (median age: 70 y, interquartile: 62 75 years; M:F, 33:7) that underwent 2 MDCT at different time points with a median interval of 13 months (interquartile: 10-17 months) were retrospectively evaluated. In-house software YACTA quantified automatically lung density histogram (10th-90th percentile in 5th percentile steps). Longitudinal changes in VSs and in the percentiles of attenuation histogram were obtained in 20 untreated patients and 20 patients treated with pirfenidone. Pearson correlation analysis was used to test the relationship between VSs and selected percentiles. RESULTS: In follow-up MDCT, visual overall extent of parenchymal abnormalities (OE) increased in median by 5%/year (interquartile: 0%/y; +11%/y). Substantial difference was found between treated and untreated patients in HU changes of the 40th and of the 80th percentiles of density histogram. Correlation analysis between VSs and selected percentiles showed higher correlation between the changes (Delta) in OE and Delta 40th percentile (r=0.69; p<0.001) as compared to Delta 80th percentile (r=0.58; p<0.001); closer correlation was found between Delta ground-glass extent and Delta 40th percentile (r=0.66, p<0.001) as compared to Delta 80th percentile (r=0.47, p=0.002), while the Delta reticulations correlated better with the Delta 80th percentile (r=0.56, p<0.001) in comparison to Delta 40th percentile (r=0.43, p=0.003). CONCLUSIONS: There is a relevant and fully automatically measurable difference at MDCT in VSs and in histogram analysis at one year follow-up of IPF patients, whether treated or untreated: Delta 40th percentile might reflect the change in overall extent of lung abnormalities, notably of ground-glass pattern; furthermore Delta 80th percentile might reveal the course of reticular opacities. PMID- 26110422 TI - Treatment decisions and outcome in very elderly patients with diffuse large B cell lymphoma. PMID- 26110423 TI - Association of Agronomic Traits with SNP Markers in Durum Wheat (Triticum turgidum L. durum (Desf.)). AB - Association mapping is a powerful approach to detect associations between traits of interest and genetic markers based on linkage disequilibrium (LD) in molecular plant breeding. In this study, 150 accessions of worldwide originated durum wheat germplasm (Triticum turgidum spp. durum) were genotyped using 1,366 SNP markers. The extent of LD on each chromosome was evaluated. Association of single nucleotide polymorphisms (SNP) markers with ten agronomic traits measured in four consecutive years was analyzed under a mix linear model (MLM). Two hundred and one significant association pairs were detected in the four years. Several markers were associated with one trait, and also some markers were associated with multiple traits. Some of the associated markers were in agreement with previous quantitative trait loci (QTL) analyses. The function and homology analyses of the corresponding ESTs of some SNP markers could explain many of the associations for plant height, length of main spike, number of spikelets on main spike, grain number per plant, and 1000-grain weight, etc. The SNP associations for the observed traits are generally clustered in specific chromosome regions of the wheat genome, mainly in 2A, 5A, 6A, 7A, 1B, and 6B chromosomes. This study demonstrates that association mapping can complement and enhance previous QTL analyses and provide additional information for marker-assisted selection. PMID- 26110425 TI - Identification of CREB3L1 as a Biomarker Predicting Doxorubicin Treatment Outcome. AB - BACKGROUND: Doxorubicin has been shown to inhibit proliferation of cancer cells through proteolytic activation of CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor. Upon doxorubicin treatment, CREB3L1 is cleaved so that the N-terminal domain of the protein can reach the nucleus where it activates transcription of genes that inhibit cell proliferation. These results suggest that the level of CREB3L1 in cancer cells may determine their sensitivity to doxorubicin. METHODS: Mice transplanted with 6 lines of renal cell carcinoma (RCC) were injected with doxorubicin to observe the effect of the chemotherapy on tumor growth. Immunohistochemistry and bioinformatics analyses were performed to compare CREB3L1 levels in types of cancer known to respond to doxorubicin versus those resistant to doxorubicin. RESULTS: Higher levels of CREB3L1 protein are correlated with increased doxorubicin sensitivity of xenograft RCC tumors (p = 0.017 by Pearson analysis). From patient tumor biopsies we analyzed, CREB3L1 was expressed in 19% of RCC, which is generally resistant to doxorubicin, but in 70% of diffuse large B-cell lymphoma that is sensitive to doxorubicin. Doxorubicin is used as the standard treatment for cancers that express the highest levels of CREB3L1 such as osteosarcoma and malignant fibrous histiocytoma but is not generally used to treat those that express the lowest levels of CREB3L1 such as RCC. CONCLUSION: Identification of CREB3L1 as the biomarker for doxorubicin sensitivity may markedly improve the doxorubicin response rate by applying doxorubicin only to patients with cancers expressing CREB3L1. PMID- 26110424 TI - Mitochondrial DNA copy number in peripheral blood and melanoma risk. AB - Mitochondrial DNA (mtDNA) copy number in peripheral blood has been suggested as risk modifier in various types of cancer. However, its influence on melanoma risk is unclear. We evaluated the association between mtDNA copy number in peripheral blood and melanoma risk in 500 melanoma cases and 500 healthy controls from an ongoing melanoma study. The mtDNA copy number was measured using real-time polymerase chain reaction. Overall, mean mtDNA copy number was significantly higher in cases than in controls (1.15 vs 0.99, P<0.001). Increased mtDNA copy number was associated with a 1.45-fold increased risk of melanoma (95% confidence interval: 1.12-1.97). Significant joint effects between mtDNA copy number and variables related to pigmentation and history of sunlight exposure were observed. This study supports an association between increased mtDNA copy number and melanoma risk that is independent on the known melanoma risk factors (pigmentation and history of sunlight exposure). PMID- 26110426 TI - Transfemoral aortic valve implantation in pure native aortic valve insufficiency using the repositionable and retrievable lotus valve. AB - Transfemoral aortic valve implantation (TAVI) for the treatment of pure native aortic insufficiency is not routine clinical practice. Absent cusp calcification, missing landmarks in combination with no perfect valve control during release with first-generation TAVI devices resulted in a high rate for need of a second valve or relevant residual aortic insufficiency. We report the first case with a native pure aortic valve insufficiency at high surgical risk successfully treated by implantation of the repositionable and completely retrievable Lotus valve, resulting in a well-controlled and safe procedure with no residual aortic insufficiency. PMID- 26110427 TI - Susceptibility-weighted imaging provides insight into white matter damage in amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder, characterised by widespread white matter damage. There is growing evidence that disturbances in iron metabolism contribute to white matter alterations. MATERIALS & METHODS: We analysed the data of susceptibility-weighted imaging (SWI) of white matter in a cohort of 27 patients with ALS and 30 healthy age-matched controls. RESULTS: Signal alterations were found on SWI in the corpus callosum; along the corticospinal tract (subcortical motor cortex, posterior limb of the internal capsule and brainstem levels) and in the subgyral regions of frontal, parietal, temporal, occipital and limbic lobes. Alterations of white matter in the corpus callosum correlated with disease severity as assessed by the revised ALS functional rating scale. CONCLUSION: SWI is capable of indicating iron and myelin disturbances in white matter of ALS patients. The SWI patterns observed in this study suggest that widespread alterations due to iron disturbances occur in patients with ALS and correlate with disease severity. PMID- 26110428 TI - Temperature-stress resistance and tolerance along a latitudinal cline in North American Arabidopsis lyrata. AB - The study of latitudinal gradients can yield important insights into adaptation to temperature stress. Two strategies are available: resistance by limiting damage, or tolerance by reducing the fitness consequences of damage. Here we studied latitudinal variation in resistance and tolerance to frost and heat and tested the prediction of a trade-off between the two strategies and their costliness. We raised plants of replicate maternal seed families from eight populations of North American Arabidopsis lyrata collected along a latitudinal gradient in climate chambers and exposed them repeatedly to either frost or heat stress, while a set of control plants grew under standard conditions. When control plants reached maximum rosette size, leaf samples were exposed to frost and heat stress, and electrolyte leakage (PEL) was measured and treated as an estimate of resistance. Difference in maximum rosette size between stressed and control plants was used as an estimate of tolerance. Northern populations were more frost resistant, and less heat resistant and less heat tolerant, but unexpectedly-they were also less frost tolerant. Negative genetic correlations between resistance and tolerance to the same and different thermal stress were generally not significant, indicating only weak trade-offs. However, tolerance to frost was consistently accompanied by small size under control conditions, which may explain the non-adaptive latitudinal pattern for frost tolerance. Our results suggest that adaptation to frost and heat is not constrained by trade-offs between them. But the cost of frost tolerance in terms of plant size reduction may be important for the limits of species distributions and climate niches. PMID- 26110429 TI - Dissociating Two Stages of Preparation in the Stop Signal Task Using fMRI. AB - Often we must balance being prepared to act quickly with being prepared to suddenly stop. The stop signal task (SST) is widely used to study inhibitory control, and provides a measure of the speed of the stop process that is robust to changes in subjects' response strategy. Previous studies have shown that preparation affects inhibition. We used fMRI to separate activity that occurs after a brief (500 ms) warning stimulus (warning-phase) from activity that occurs during responses that follow (response-phase). Both of these phases could contribute to the preparedness to stop because they both precede stop signals. Warning stimuli activated posterior networks that signal the need for top-down control, whereas response phases engaged prefrontal and subcortical networks that implement top-down control. Regression analyses revealed that both of these phases affect inhibitory control in different ways. Warning-phase activity in the cerebellum and posterior cingulate predicted stop latency and accuracy, respectively. By contrast, response-phase activity in fronto-temporal areas and left striatum predicted go speed and stop accuracy, in pre-supplementary motor area affected stop accuracy, and in right striatum predicted stop latency and accuracy. The ability to separate hidden contributions to inhibitory control during warning-phases from those during response-phases can aid in the study of models of preparation and inhibitory control, and of disorders marked by poor top down control. PMID- 26110432 TI - Estimating the Effects of Obesity and Weight Change on Mortality Using a Dynamic Causal Model. AB - BACKGROUND: A well-known challenge in estimating the mortality risks of obesity is reverse causality attributable to illness-associated and smoking-associated weight loss. Given that the likelihood of chronic and acute illnesses rises with age, reverse causality is most threatening to estimates derived from elderly populations. METHODS: I analyzed data from 12,523 respondents over 50 years old from a nationally representative longitudinal dataset, the Health and Retirement Study (HRS). The effects of both baseline body weight and time-varying weight change on mortality are estimated, adjusting for demographic and socio-economic variables, as well as time-varying confounders including illness and smoking. Body weight is measured by body mass index (BMI). In survival models for mortality, illness and smoking were lagged to minimize bias from reverse causality in estimates of the effect of weight change. Furthermore, because illness both causes and is caused by changes in BMI, I used a marginal structural model (MSM) rather than standard adjustment to control confounding by this and other time-dependent factors. RESULTS: Overall, relative to normal weight, underweight and Class II/III at baseline are associated with hazard ratios that are 2.07 (95% confidence interval (CI): 1.28-3.37) and 1.82 (1.54-2.16) respectively, whereas overweight and Class I obesity do not significantly lower or raise the mortality risks. Furthermore, relative to stable weight change, all types of weight change lead to significantly increased risk of mortality. Specifically, large weight loss results in a mortality risk that is nearly 3.86 (3.26-4.58) times of staying in the stable weight range and small weight loss is about 1.81 (1.55-2.11 ) times riskier. In contrast, large weight gain and small weight gain are associated with hazard ratios that are 1.98 (1.67-2.35) and 1.20 (1.02-1.41) respectively. CONCLUSIONS: Being underweight or severe obese at baseline is associated with excess mortality risk, and weight change tend to raise mortality risk. Both the confounding by illness and by smoking lead to overestimates of the effects of being underweight at baseline and of weight loss, but underestimates the effect of being obese at baseline. PMID- 26110430 TI - A Novel Feedback Loop That Controls Bimodal Expression of Genetic Competence. AB - Gene expression can be highly heterogeneous in isogenic cell populations. An extreme type of heterogeneity is the so-called bistable or bimodal expression, whereby a cell can differentiate into two alternative expression states. Stochastic fluctuations of protein levels, also referred to as noise, provide the necessary source of heterogeneity that must be amplified by specific genetic circuits in order to obtain a bimodal response. A classical model of bimodal differentiation is the activation of genetic competence in Bacillus subtilis. The competence transcription factor ComK activates transcription of its own gene, and an intricate regulatory network controls the switch to competence and ensures its reversibility. However, it is noise in ComK expression that determines which cells activate the ComK autostimulatory loop and become competent for genetic transformation. Despite its important role in bimodal gene expression, noise remains difficult to investigate due to its inherent stochastic nature. We adapted an artificial autostimulatory loop that bypasses all known ComK regulators to screen for possible factors that affect noise. This led to the identification of a novel protein Kre (YkyB) that controls the bimodal regulation of ComK. Interestingly, Kre appears to modulate the induction of ComK by affecting the stability of comK mRNA. The protein influences the expression of many genes, however, Kre is only found in bacteria that contain a ComK homologue and, importantly, kre expression itself is downregulated by ComK. The evolutionary significance of this new feedback loop for the reduction of transcriptional noise in comK expression is discussed. Our findings show the importance of mRNA stability in bimodal regulation, a factor that requires more attention when studying and modelling this non-deterministic developmental mechanism. PMID- 26110433 TI - Detectability in Audio-Visual Surveys of Tropical Rainforest Birds: The Influence of Species, Weather and Habitat Characteristics. AB - Indices of relative abundance do not control for variation in detectability, which can bias density estimates such that ecological processes are difficult to infer. Distance sampling methods can be used to correct for detectability, but in rainforest, where dense vegetation and diverse assemblages complicate sampling, information is lacking about factors affecting their application. Rare species present an additional challenge, as data may be too sparse to fit detection functions. We present analyses of distance sampling data collected for a diverse tropical rainforest bird assemblage across broad elevational and latitudinal gradients in North Queensland, Australia. Using audio and visual detections, we assessed the influence of various factors on Effective Strip Width (ESW), an intuitively useful parameter, since it can be used to calculate an estimate of density from count data. Body size and species exerted the most important influence on ESW, with larger species detectable over greater distances than smaller species. Secondarily, wet weather and high shrub density decreased ESW for most species. ESW for several species also differed between summer and winter, possibly due to seasonal differences in calling behavior. Distance sampling proved logistically intensive in these environments, but large differences in ESW between species confirmed the need to correct for detection probability to obtain accurate density estimates. Our results suggest an evidence based approach to controlling for factors influencing detectability, and avenues for further work including modeling detectability as a function of species characteristics such as body size and call characteristics. Such models may be useful in developing a calibration for non-distance sampling data and for estimating detectability of rare species. PMID- 26110431 TI - Loss of resting-state posterior cingulate flexibility is associated with memory disturbance in left temporal lobe epilepsy. AB - The association between cognition and resting-state fMRI (rs-fMRI) has been the focus of many recent studies, most of which use stationary connectivity. The dynamics or flexibility of connectivity, however, may be seminal for understanding cognitive functioning. In temporal lobe epilepsy (TLE), stationary connectomic correlates of impaired memory have been reported mainly for the hippocampus and posterior cingulate cortex (PCC). We therefore investigate resting-state and task-based hippocampal and PCC flexibility in addition to stationary connectivity in left TLE (LTLE) patients. Sixteen LTLE patients were analyzed with respect to rs-fMRI and task-based fMRI (t-fMRI), and underwent clinical neuropsychological testing. Flexibility of connectivity was calculated using a sliding-window approach by determining the standard deviation of Fisher transformed Pearson correlation coefficients over all windows. Stationary connectivity was also calculated. Disturbed memory was operationalized as having at least one memory subtest score equal to or below the 5th percentile compared to normative data. Lower PCC flexibility, particularly in the contralateral (i.e. right) hemisphere, was found in memory-disturbed LTLE patients, who had up to 22% less flexible connectivity. No significant group differences were found with respect to hippocampal flexibility, stationary connectivity during both rs-fMRI and t-fMRI, or flexibility during t-fMRI. Contralateral resting-state PCC flexibility was able to classify all but one patient with respect to their memory status (94% accuracy). Flexibility of the PCC during rest relates to memory functioning in LTLE patients. Loss of flexible connectivity to the rest of the brain originating from the PCC, particularly contralateral to the seizure focus, is able to discern memory disturbed patients from their preserved counterparts. This study indicates that the dynamics of resting-state connectivity are associated with cognitive status of LTLE patients, rather than stationary connectivity. PMID- 26110434 TI - Host Delivery of Favorite Meals for Intracellular Pathogens. PMID- 26110435 TI - Unnatural deaths in Shanghai from 2000 to 2009: a retrospective study of forensic autopsy cases at the Shanghai Public Security Bureau. AB - Shanghai is the most developed city in China and has a soaring population. This study uses forensic epidemiology to determine the relationship between unnatural deaths and the development in Shanghai, based on recently released forensic autopsy cases from the 2000s at the Shanghai Public Security Bureau (SPSB). There were 5425 accidental deaths, 2696 homicides, 429 suicides, 186 natural deaths, and 1399 deaths of undetermined cause. There was a male-to-female ratio of 2.02:1, and the average age was 40.9+/-18.7 years. Traffic accidents (84.2%) were the number one cause of accidental deaths, which decreased during the study period. Sharp force injury (50.6%) was the leading cause of homicides, different from Western countries, where firearms are the leading cause. Hanging (24.5%) was the leading cause of suicides, whereas drug and chemical intoxication was the leading cause in the previous decade; pesticide ingestion decreased in the 2000s. In addition to traffic accidents, manual strangulation was the leading cause of death in childhood fatalities. Children under age 2 were vulnerable to homicides. In the 2000s, there were a large number of drug overdoses, and illegal medical practices and subway-related deaths first appeared in Shanghai. A new type of terrorist attack that involved injecting people with syringes in public places was reflected in the SPSB archives. The forensic epidemiology and changes in unnatural deaths in this decade reflected their relationship with the law, policy and changes in Shanghai. Illegal medical practices, subway-related deaths and terrorist attacks were closely related to the development in Shanghai. Identifying the risks of unnatural deaths will improve public health. PMID- 26110436 TI - One Step Preparation of Reduced Graphene Oxide/Pd-Fe3 O4 @Polypyrrole Composites and Their Application in Catalysis. AB - The simple preparation of catalysts with superior catalytic activity and good reusability is highly desirable. Herein, we report a novel strategy to construct reduced graphene oxide (rGO)/Pd-Fe3 O4 @polypyrrole (PPy) catalysts with Pd and Fe3 O4 nanoparticles anchored on a rGO nanosheet surface and wrapped in a PPy shell. The synthesis and assembly of both the Pd and Fe3 O4 nanoparticles, the preparation of the PPy layer, and the reduction of graphene oxide nanosheets were finished in one step. In the system, the PPy layer not only prevented aggregation of Pd and Fe3 O4 nanoparticles, but also generated a synergistic effect with precursor Pd(2+) ions, which led to a high dispersity of as-prepared Pd nanoparticles. Although the procedure was simplified to one step, the catalytic activity and reusability were not sacrificed. In the reduction of 4-nitrophenol, their catalytic performance was better than that in recent reports. Moreover, the catalysts showed good reusability owing to their magnetic properties. PMID- 26110437 TI - Acute flavanol consumption improves the cerebral vasodilatory capacity in college aged African Americans. AB - NEW FINDINGS: What is the central question of this study? The purpose was to determine whether acute flavanol consumption improves cerebral vasodilatory capacity during rebreathing-induced hypercapnia in African Americans. What is the main finding and its importance? The reduced cerebral vasodilatory response to hypercapnia in young healthy African Americans was improved acutely following consumption of a flavanol-rich beverage. This may have important clinical implications regarding racial differences in cerebrovascular disease risk and possible interventional approaches to offset this risk. African Americans (AAs) have increased risk for cardiovascular and cerebrovascular disease. African Americans have attenuated cerebral vasodilator capacity during hypercapnia relative to Caucasian Americans (CAs). This study tested the hypothesis, using a placebo-controlled crossover design, that acute flavanol consumption improves the range of change in cerebral vascular conductance [CVCI, (a)] and the maximal CVCI (y0) achieved during rebreathing-induced increases in end-tidal carbon dioxide tension. Fourteen college-aged AAs and 14 CAs participated. Both a and y0 were lower in AAs prior to flavanols (for a, AAs, 46 +/- 16 versus CAs, 74 +/- 18% CVCI, P < 0.001; and for y0, AAs, 151 +/- 18 versus CAs, 176 +/- 20% CVCI, P = 0.002); however, these variables were increased after flavanols such that there were no differences between groups (for a, AAs, 64 +/- 19 versus CAs, 72 +/- 22% CVCI, P = 0.35; and for y0, AAs, 166 +/- 22 versus CAs, 176 +/- 22% CVCI, P = 0.26). Both a and y0 were also lower in AAs prior to placebo (for a, AAs, 52 +/- 19 versus CAs, 76 +/- 15% CVCI, P = 0.002; and for y0, AAs, 156 +/- 20 versus CAs, 177 +/- 21% CVCI, P = 0.015), and these differences remained following placebo (for a, AAs, 52 +/- 17 versus CAs, 80 +/- 20% CVCI, P < 0.001; and for y0, AAs, 152 +/- 18 versus CAs, 181 +/- 25% CVCI, P = 0.003). These data suggest that acute flavanol consumption improves cerebral vasodilatory capacity during hypercapnia in AAs. PMID- 26110438 TI - Better prediction of functional effects for sequence variants. AB - Elucidating the effects of naturally occurring genetic variation is one of the major challenges for personalized health and personalized medicine. Here, we introduce SNAP2, a novel neural network based classifier that improves over the state-of-the-art in distinguishing between effect and neutral variants. Our method's improved performance results from screening many potentially relevant protein features and from refining our development data sets. Cross-validated on >100k experimentally annotated variants, SNAP2 significantly outperformed other methods, attaining a two-state accuracy (effect/neutral) of 83%. SNAP2 also outperformed combinations of other methods. Performance increased for human variants but much more so for other organisms. Our method's carefully calibrated reliability index informs selection of variants for experimental follow up, with the most strongly predicted half of all effect variants predicted at over 96% accuracy. As expected, the evolutionary information from automatically generated multiple sequence alignments gave the strongest signal for the prediction. However, we also optimized our new method to perform surprisingly well even without alignments. This feature reduces prediction runtime by over two orders of magnitude, enables cross-genome comparisons, and renders our new method as the best solution for the 10-20% of sequence orphans. SNAP2 is available at: https://rostlab.org/services/snap2web. PMID- 26110440 TI - Neurologic Evaluation and Management of Perioperative Nerve Injury. AB - Neurologic injury after regional anesthesia or pain medicine procedures is rare. Postprocedural neurologic deficits may create high levels of anxiety for the patient and practitioner, although most deficits are limited in severity and can be expected to fully resolve with time. Postoperative anesthesia-related neuraxial and peripheral nerve injuries are reviewed to define an efficient, structured approach to these complications. Emphasis is placed on acutely stratifying the urgency and scope of diagnostic testing or consultation necessity, initiating appropriate definitive treatments, and defining appropriate out-of-hospital follow-up and symptom management. WHAT'S NEW: Studies pertinent to the recognition, evaluation, and treatment of neurologic assessment of perioperative nerve injury and published since the last advisory on the topic are reviewed and a new structured algorithmic approach is proposed. The evolving literature on postoperative inflammatory neuropathies is reviewed to help define the clinical criteria and to identify patients who would benefit from early neurological evaluation. New sections review potential acute interventions to improve neurologic outcome and long-term management of neuropathic pain resulting from perioperative nerve injury. PMID- 26110439 TI - Goals for Human Milk Feeding in Mothers of Very Low Birth Weight Infants: How Do Goals Change and Are They Achieved During the NICU Hospitalization? AB - BACKGROUND: Little is known about human milk (HM) feeding goals for mothers of very low birth weight (VLBW) (<1,500 g birth weight) infants, especially for black mothers, for whom rates of VLBW birth are higher and lactation rates lower. This study examined the establishment, modification, and achievement of HM feeding goals during neonatal intensive care unit (NICU) hospitalization for mothers of VLBW infants and the influence of maternal race and income. MATERIALS AND METHODS: A prospective cohort study measured maternal HM feeding goals (exclusive [EHM], partial, none) predelivery and during three time intervals: day of life (DOL) 1-14, 15-28, and 29-72. Goal achievement compared the goal for the time interval with the proportion of HM feedings received by the infant. Goal establishment, modification, and achievement were examined using chi-squared and contingency tables. RESULTS: Three hundred fifty-two mother-infant dyads (53% black; 70% low-income; mean birth weight, 1,048 g) were studied. Predelivery, 55% of mothers planned to provide EHM; fewer black and low-income mothers chose EHM. During DOL 1-14, 63% of mothers chose EHM, and predelivery racial differences disappeared. Only 10% of mothers chose exclusive at-breast EHM feedings. EHM feeding goals decreased during NICU hospitalization, especially for black mothers. Whereas most mothers met their HM feeding goals initially, achievement rates declined during hospitalization. Mothers' EHM goal achievement was not influenced by race or income. CONCLUSIONS: Mothers changed their predelivery HM feeding goals after birth of a VLBW infant. Longitudinally, HM feeding goals and achievement reflected less HM use, highlighting the need to target lactation maintenance in this population. PMID- 26110441 TI - A Comparison of 2 Ultrasound-Guided Approaches to the Saphenous Nerve Block: Adductor Canal Versus Distal Transsartorial: A Prospective, Randomized, Blinded, Noninferiority Trial. AB - BACKGROUND AND OBJECTIVES: Saphenous nerve blocks can be technically challenging. Recently described ultrasound techniques have improved the success rate of saphenous nerve blocks, but randomized controlled trials comparing these ultrasound-guided techniques are lacking. We compared 2 common ultrasound-guided approaches for saphenous nerve block: saphenous nerve block at the adductor canal (ACSNB) versus block by the distal transsartorial (DTSNB) approach. METHODS: Patients received either ACSNB or DTSNB in this prospective, randomized, blinded, noninferiority clinical trial. The primary objective was to show the noninferiority of ACSNB to DTSNB in terms of block success. Secondary outcome measures were time required to perform the block, time to onset of successful block, and the visibility of the nerve using ultrasound. RESULTS: One hundred twenty patients were randomized to receive DTSNB (n = 62) or ACSNB (n = 58). There were 9 failures in the DTSNB group (85% success) and no failures in the ACSNB group (100% success), 90% confidence interval of difference in success rates (DTSNB - ACSNB) was -0.195 to -0.031. Given that the upper confidence bound (-3.1%) was less than 10%, the success rate of ACSNB was noninferior to DTSNB. After satisfying noninferiority and observing a greater success rate of ACSNB compared with DTSNB, we also determined that ACSNB was superior to DTSNB (P = 0.003). The median time to success was significantly less for the ACSNB group: 9 minutes versus 3 minutes (P < 0.001). The grade of the ultrasound image, as judged by the provider, was significantly better in the ACSNB group (P = 0.001). CONCLUSIONS: Ultrasound-guided block of the saphenous nerve at the adductor canal is not only noninferior but also superior to block at the distal transsartorial level in terms of success rate, with additional advantages of faster block onset time and better nerve visibility under ultrasound. PMID- 26110442 TI - Percutaneous Rupture of a Symptomatic Facet Joint Synovial Cyst Using 2-Needle Distention. AB - OBJECTIVE: This case report calls attention to an alternative approach for management of a symptomatic facet joint synovial cyst. We describe a patient with a symptomatic facet joint synovial cyst who failed an attempted percutaneous rupture using a single-needle technique. This patient was subsequently successfully managed with percutaneous rupture using a 2-needle technique. CASE REPORT: A 60-year-old woman presented with low back pain, right lower extremity pain, and paresthesias. Magnetic resonance imaging revealed a right L5-S1 facet joint cyst, which compressed the right L5 nerve root. Before presentation, the patient failed an attempted single-needle percutaneous rupture. The decision was made to proceed with percutaneous rupture using a 2-needle technique. A 22-gauge needle was inserted into the right L5-S1 facet joint, and a Tuohy needle was inserted directly into the cyst through an interlaminar approach. A solution of methylprednisolone and hyaluronidase was simultaneously injected through both needles, and the cyst was continuously distended until rupture was achieved. Rupture was confirmed by injecting contrast into the facet joint and visualizing a normal epidurogram. The patient reported significant pain relief immediately after the procedure. At 4-month follow-up, the patient reported continued pain relief and denied any radicular symptoms. CONCLUSIONS: Percutaneous rupture of a symptomatic facet joint synovial cyst using a single-needle technique has been validated as an efficacious form of management. In a select group of patients who fail single-needle percutaneous rupture, a 2-needle approach for percutaneous facet cyst rupture may be considered as an option for management. PMID- 26110443 TI - Bioactive Sesquiterpenes and Lignans from the Fruits of Xanthium sibiricum. AB - Seven new sesquiterpenes (1, 3-8), a new sesquiterpene natural product (2), and two new lignans (9 and 10), together with 15 known compounds, were isolated from the fruits of Xanthium sibiricum. The structures of the new compounds were established by NMR spectroscopic analysis, ECD calculations, and Mo2(OAc)4 induced circular dichroism, with the structures of 1 and 4 confirmed by single crystal X-ray diffraction. Compound 1 is the first example of a 3/5/6/5 tetracyclic eudesmane sesquiterpene lactone formed at C-6 and C-7. In turn, compound 4 is the first example of a natural xanthane tetranorsesquiterpene, while compounds 5-8 are the first xanthane trinorsesquiterpenes found to date. Compounds 8, 11-15, 17, and 24 exhibited indirect anti-inflammatory activity by suppressing the lipopolysaccharide-induced proinflammatory factors in BV2 microglial cells, with IC50 values between 1.6 and 8.5 MUM. Furthermore, compounds 13 and 17 exhibited anti-inflammatory activity against ear edema in mice produced by croton oil, with inhibition rates of 46.9% and 37.7%, respectively. Compounds 8, 11, 12, 23, and 24 exhibited potent activity against influenza A virus (A/FM/1/47, H1N1) with IC50 values between 3.7 and 8.4 MUM. PMID- 26110444 TI - Nanometer-scale separation of d(10) Zn(2+)-layers and twin-shift competition in Ba8ZnNb6O24-based 8-layered hexagonal perovskites. AB - The 8-layered shifted hexagonal perovskite compound Ba8ZnNb6O24 was isolated via controlling the ZnO volatilization, which features long-range B-cation ordering with nanometer-scale separation by ~1.9 nm of octahedral d(10) cationic (Zn(2+)) layers within the purely corner-sharing octahedral d(0) cationic (Nb(5+)) host. The long-range ordering of the B-site vacancy and out-of-center distortion of the highly-charged d(0) Nb(5+) that is assisted by the second-order Jahn-Teller effect contribute to this unusual B-cation ordering in Ba8ZnNb6O24. A small amount (~15%) of d(10) Sb(5+) substitution for Nb(5+) in Ba8ZnNb6-xSbxO24 dramatically transformed the shifted structure to a twinned structure, in contrast with the Ba8ZnNb6-xTaxO24 case requiring 50% d(0) Ta(5+) substitution for Nb(5+) for such a shift-to-twin transformation. Multiple factors including B cationic sizes, electrostatic repulsion forces, long-range ordering of B-site vacancies, and bonding preferences arising from a covalent contribution to the B O bonding that includes out-of-center octahedral distortion and the B-O-B bonding angle could subtly contribute to the twin-shift phase competition of B-site deficient 8-layered hexagonal perovskites Ba8B7O24. The ceramics of new shifted Ba8ZnNb6O24 and twinned Ba8ZnNb5.1Sb0.9O24 compounds exhibited good microwave dielectric properties (epsilonr ~ 35, Qf ~ 36 200-43 400 GHz and tauf ~ 38-44 ppm/ degrees C). PMID- 26110445 TI - Duration of Antiretroviral Therapy Adherence Interruption Is Associated With Risk of Virologic Rebound as Determined by Real-Time Adherence Monitoring in Rural Uganda. AB - BACKGROUND: Antiretroviral therapy (ART) adherence interruptions have been associated with viral rebound; however, the true risk is unknown because HIV RNA has never been measured during ongoing interruptions. METHODS: The Uganda AIDS Rural Treatment Outcomes Study is an observational longitudinal cohort of adults initiating ART. We monitored adherence with the device that wirelessly transmits records of device openings, and routinely assessed HIV RNA quarterly. When lapses of 48+ hours between device openings were detected, we made unannounced visits to participants to investigate the cause and assess HIV RNA. Generalized estimating equation logistic regressions were used to assess factors associated with viral rebound. RESULTS: We followed 479 participants (median: 25 months per participant). Most were women (72%), median age was 36 years, median pre-ART CD4 count was 198 cells per microliter, median pre-ART HIV RNA level was 5.0 log10 copies per milliliter, and median duration of prior viral suppression was 13 months. A total of 587 adherence interruptions followed confirmed prior viral suppression, of which 13 (2%) had detectable viral rebound. Viral rebound was associated with duration of adherence interruption (odds ratio: 1.25 for each day beyond 48 hours; P = 0.007) and 30-day adherence before the interruption (odds ratio: 0.73; P = 0.02). DISCUSSION: This article is the first demonstration of HIV RNA rebound during adherence interruptions objectively measured in real time. Odds of viral rebound increased by 25% with each day beyond 48 hours. Real-time adherence monitoring was feasible in a sub-Saharan African setting. Further research should assess the potential for real-time adherence interventions to sustain adherence to affordable first-line regimens. PMID- 26110446 TI - Retinal and Choroidal Thickness in Children with Familial Mediterranean Fever. PMID- 26110447 TI - Industrial odor sources and air pollutant concentrations in Globeville, a Denver, Colorado neighborhood. AB - An odor of unknown origin described as a "tar" or "asphalt" smell has become unbearable for many of Globeville, CO, residents over the past few years. Residents report during odor events burning eyes and throat, headaches, skin irritation, and problems sleeping. This study was undertaken to identify the potential sources of the odor and the concentrations of air pollutants making up the odor by conducting meteorological correlations and sampling for a panel of volatile organic compounds (VOCs), sulfur gases, and polycyclic aromatic hydrocarbons (PAHs) in the neighborhood and near suspected sources. Wind speed and direction data collected every 1 min in the neighborhood indicate that when the odor is noticed, the community is directly downwind of a wood preservation facility and an asphalt roofing facility. Air samples collected during high intensity odor events have shown concentrations of methylene chloride, hexane, toluene, naphthalene, dibenz[a,h]anthracene, benzo[g,h,i]perylene, and indeno[1,2,3-cd]pyrene, each at least two times higher than background concentrations. Naphthalene and the other PAHs are known pollutants emitted from wood treatment processes, and are known to have a coal tar odor. Naphthalene was present in a sample collected directly adjacent to the Koppers facility and was not present in any background samples. Single-compound odor and health thresholds, however, were never surpassed. Given the technical and regulatory challenges of sampling odors and controlling emissions, it is recommended that Globeville residents and neighboring industry pursue a "good neighbor policy" to solve the odor issue. Specific offending industrial processes could be identified for which there exist cost-effective control technologies that would reduce exposure to odors and air toxics in Globeville. IMPLICATIONS: Meteorological correlations and samples of volatile organic compounds (VOCs), sulfur gases, and polycyclic aromatic hydrocarbons (PAHs) in the Globeville, CO, neighborhood and near suspected sources during odor events indicate potential industrial sources of a transient and noxious odor. Legislative approaches have proven unfruitful and no health or odor thresholds were typically violated. New approaches are warranted to address odor mixture effects in neighborhoods near industrial facilities. PMID- 26110448 TI - EPS Mid-Career Award 2014. The control of attention in visual search: Cognitive and neural mechanisms. AB - In visual search, observers try to find known target objects among distractors in visual scenes where the location of the targets is uncertain. This review article discusses the attentional processes that are active during search and their neural basis. Four successive phases of visual search are described. During the initial preparatory phase, a representation of the current search goal is activated. Once visual input has arrived, information about the presence of target-matching features is accumulated in parallel across the visual field (guidance). This information is then used to allocate spatial attention to particular objects (selection), before representations of selected objects are activated in visual working memory (recognition). These four phases of attentional control in visual search are characterized both at the cognitive level and at the neural implementation level. It will become clear that search is a continuous process that unfolds in real time. Selective attention in visual search is described as the gradual emergence of spatially specific and temporally sustained biases for representations of task-relevant visual objects in cortical maps. PMID- 26110449 TI - Maternal Cultural Orientation and Child Growth in New Zealand Pacific Families. AB - BACKGROUND: In New Zealand (NZ), children of Pacific heritage are generally born heavier and gain weight more quickly than non-Pacific children. Immigrants' health is commonly expected to converge with the host population through acculturation. The aim of this analysis was to examine whether mothers' acculturation is associated with less-rapid weight gain in NZ Pacific children, and whether this differs by mothers' nativity. METHODS: In a birth cohort of 1249 children followed 2000-2011, birth weight and weight and standing height, measured at years 2, 4, 6, 9, and 11, were quantified as sex- and age-specific weight (weight-for-age; WFA) and BMI z-scores. Maternal acculturation (range, 11 54) was assessed at baseline and years 4, 6, and 11. RESULTS: In adjusted models using generalized estimating equations to account for repeated measures, maternal acculturation was not significantly associated with children's WFA or BMI z scores overall. In stratified analyses, change in maternal acculturation score was inversely associated with WFA z-score change among children of NZ-born, but not immigrant, mothers (beta=-0.021; 95% confidence interval, -0.036 to -0.007; p=0.006; interaction, p=0.005). CONCLUSIONS: Our study provides the first evidence in a longitudinal sample that changes in maternal acculturation can influence children's growth, suggesting the importance of lifestyle or behavioral factors related to a mother's cultural orientation. Given the high risk of obesity and its related conditions in the NZ Pacific population, critical next steps are to identify mediating factors, as well as to understand the processes influencing growth among children of immigrant mothers. PMID- 26110450 TI - Biofilm Lysine Decarboxylase, a New Therapeutic Target for Periodontal Inflammation. AB - BACKGROUND: Lysine, a nutritionally essential amino acid, enters the oral cavity in gingival crevicular fluid (GCF). During oral hygiene restriction (OHR), lysine decarboxylase (LDC) in dento-gingival biofilms converts lysine to cadaverine. Lysine depletion impairs the dental epithelial barrier to bacterial proinflammatory products. Antibodies to LDC from Eikenella corrodens (Ecor-LDC) inhibit LDC activity and retard gingival inflammation in beagle dogs. Whether E. corrodens is the major source of LDC in dental biofilms and whether the lysine analog tranexamic acid (TA) inhibits LDC activity, biofilm accumulation, and GCF exudation in a human gingivitis model were examined. METHODS: Antibodies raised in goats to LDC-rich extracts from E. corrodens cell surfaces were used to inhibit Ecor-LDC and detect it in biofilm extracts using Western blots. Ecor-LDC activity was measured at pH 4.0 to 11.0 and its TA dissociation constant (Ki) at pH 7.0. Young adults used a 5% or 10% TA mouthwash three times daily during OHR for 1 week. RESULTS: Ecor-LDC antibodies and TA inhibited biofilm LDC. Ki of TA for Ecor-LDC was 940 MUM. TA reduced plaque index (PI) by downshifting the PI correlation with biofilm lysine content after OHR without TA. GCF was correspondingly suppressed. However, greater TA retention in saliva partially relieved GCF suppression but not biofilm lysine depletion. CONCLUSIONS: TA slightly inhibits LDC but strongly reduces biofilm by inhibiting bacterial lysine uptake. Unfortunately, TA may impair dental epithelial attachments by also inhibiting lysine transporter uptake. Ecor-LDC inhibitors other than lysine analogs may maintain sufficient lysine levels and attachment integrity to prevent periodontal inflammation. PMID- 26110452 TI - Periodontal Biotype: Gingival Thickness as It Relates to Probe Visibility and Buccal Plate Thickness. AB - BACKGROUND: Probe visibility is the clinical gold standard to discriminate thick from thin biotype but is prone to subjective interpretation. The primary objective of this study is to determine at what objective gingival thickness the probe becomes invisible through the tissue. A secondary objective is to compare mean buccal plate thickness between thick and thin biotypes as determined by probe visibility. METHODS: Maxillary anterior teeth (n = 306) were studied in 56 human patients. Biotype was determined by probe visibility through the tissue. Gingival thickness was measured via transgingival sounding. Buccal plate thickness was measured (n = 66 teeth) by cone beam computed tomography. For the primary objective, the gingival thickness that best corresponded with probe invisibility was selected using the receiver operating characteristic and area under the curve (AUC) with the highest combination of sensitivity and specificity. For the secondary objective, mean buccal plate thickness was compared between sites in which the probe was visible and when it was not (Student t test, alpha= 0.05). RESULTS: The gingival thickness that most closely corresponded with probe invisibility was >0.8 mm (0.666 AUC, 67.7% sensitivity, 65.4% specificity). When the probe was visible, mean gingival thickness was 0.17 mm less (P <0.001) compared to the "thick" counterparts. When the probe was visible, mean buccal plate thickness tended to be smaller by 0.212 mm (P = 0.08), but the difference was not statistically significant. CONCLUSIONS: The study failed to identify a gingival thickness threshold that can discriminate reliably between sites in which the probe was visible (i.e., thin biotype) and those in which it was not (i.e., thick biotype). Probe visibility was associated with thinner measurements of gingival thickness and showed a tendency to be associated with a thinner buccal plate. PMID- 26110451 TI - Association Between Periodontal Disease and Kidney Function Decline in African Americans: The Jackson Heart Study. AB - BACKGROUND: Chronic kidney disease (CKD) remains a prevalent public health problem that disproportionately affects African Americans, despite intense efforts targeting traditional risk factors. Periodontal disease, a chronic bacterial infection of the oral cavity, is both common and modifiable and has been implicated as a novel potential CKD risk factor. The authors seek to examine to what extent periodontal disease is associated with kidney function decline. METHODS: This retrospective cohort study examines 699 African American participants with preserved kidney function (defined by estimated glomerular filtration rate (eGFR) >60 mL/minute/1.73 m(2) at baseline) who underwent complete dental examinations as part of the Dental-Atherosclerosis Risk in Communities study (1996 to 1998) and subsequently enrolled in the Jackson Heart Study (2000 to 2004). Using multivariable Poisson regression, the authors examined the association of periodontal disease (severe versus non-severe) with incident CKD, defined as incident eGFR <60 mL/minute/1.73 m(2) and rapid (5% annualized) eGFR decline at follow-up among those with preserved eGFR at baseline. RESULTS: Mean (+/- SD) age at baseline was 65.4 (+/- 5.2) years, and 16.3% (n = 114) had severe periodontal disease. There were 21 cases (3.0%) of incident CKD after a mean follow-up of 4.8 (+/- 0.6) years. Compared with participants with non-severe periodontal disease, those with severe periodontal disease had a four-fold greater rate of incident CKD (adjusted incidence rate ratio 4.18 [95% confidence interval 1.68 to 10.39], P = 0.002). CONCLUSIONS: Severe periodontal disease is prevalent among a population at high risk for CKD and is associated with clinically significant kidney function decline. Further research is needed to determine if periodontal disease treatment alters the trajectory of renal deterioration. PMID- 26110453 TI - Long-Term Effect of Four Surgical Periodontal Therapies and One Non-Surgical Therapy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The aim of this systematic review is to evaluate the long term (>= 2 years) effect of four surgical and non-surgical therapies in treating periodontal disease. METHODS: An electronic search of four databases and a hand search of peer-reviewed journals for relevant articles were conducted. Prospective human controlled clinical trials were included that compared surgical therapy to non surgical therapy in >= 10 patients diagnosed with chronic periodontitis with a follow-up period of >= 2 years and that reported change in probing depth (PD) and clinical attachment level (CAL) after the therapy. Random effect meta-analysis was performed to compare the outcome of surgical and non-surgical therapy in shallow, moderate, and deep PD. RESULTS: Eight human prospective clinical trials were included. In 1- to 3-mm PD, scaling and root planing (SRP), modified Widman flap (MWF), and osseous surgery (OS) resulted in 23.2%, 39.4%, and 61.39% CAL loss, respectively; SRP, MWF, and OS resulted in increased mean PD of 2.5%, 3.3%, and 6.3%, respectively. In 4- to 6-mm PD, SRP, MWF, and OS resulted in 8.4%, 6.5%, and 5.22% CAL gain, respectively; SRP, MWF, and OS resulted in 18.7%, 25.4%, and 30.8% PD reduction, respectively. In PD >= 7 mm, SRP, MWF, and OS resulted in 9.8%, 14.2%, and 9.38% CAL gain, respectively; SRP, MWF, and OS resulted in mean PD reduction of 21.6%, 33.1%, and 42.8%, respectively. CONCLUSIONS: Surgical therapy had significantly more CAL loss than non-surgical therapy in shallow PD. In moderate PD, MWF had significantly more PD reduction than SRP, and there was significantly less CAL gain with surgical therapy. In deep PD, OS had significantly higher PD reduction than SRP. PMID- 26110455 TI - [Discussing Fertility and the Desire to have a Child in Hemato-Oncology--A Qualitative Survey]. AB - OBJECTIVES: Adolescent and young adult patients in hemato-oncology have often not fulfilled their desire to have a child, which is threatened by the malignancy and it's treatment. The oncologists have to inform their patients about possible infertility and fertility preservation. METHODS: 25 oncologists were interviewed to discuss the desire to have a child and fertility issues with the patients. Afterwards the semi-structured interviews were transcribed and analyzed according to the qualitative content analysis of Mayring. RESULTS: The following issues could be identified in the interviews: current desire to have a child; possible threat of fertility; fertility preservation and their implementation; contact to a reproduction facility; sexuality and contraception during therapy. Most of the oncologists (n=19) stated to discuss the fertility aspects in the first session. 14 oncologists stated that they have enough knowledge about fertility preservation. To improve the conditions for a discussion the oncologists wished to have more information (n=10) or patient leaflets (n=11) about fertility preservation. DISCUSSION: Addressing the desire to have a child and fertility aspects of adolescent and young adult patients in hemato-oncology have already a high priority. Further studies should analyze the discussion from patient perspective and determine patient needs in this regard. PMID- 26110454 TI - Community awareness, use and preference for pandemic influenza vaccines in Pune, India. AB - Vaccination is a cornerstone of influenza prevention, but limited vaccine uptake was a problem worldwide during the 2009-2010 pandemic. Community acceptance of a vaccine is a critical determinant of its effectiveness, but studies have been confined to high-income countries. We conducted a cross-sectional, mixed-method study in urban and rural Pune, India in 2012-2013. Semi-structured explanatory model interviews were administered to community residents (n = 436) to study awareness, experience and preference between available vaccines for pandemic influenza. Focus group discussions and in-depth interviews complemented the survey. Awareness of pandemic influenza vaccines was low (25%). Some respondents did not consider vaccines relevant for adults, but nearly all (94.7%), when asked, believed that a vaccine would prevent swine flu. Reported vaccine uptake however was 8.3%. Main themes identified as reasons for uptake were having heard of a death from swine flu, health care provider recommendation or affiliation with the health system, influence of peers and information from media. Reasons for non-use were low perceived personal risk, problems with access and cost, inadequate information and a perceived lack of a government mandate endorsing influenza vaccines. A majority indicated a preference for injectable over nasal vaccines, especially in remote rural areas. Hesitancy from a lack of confidence in pandemic influenza vaccines appears to have been less of an issue than access, complacency and other sociocultural considerations. Recent influenza outbreaks in 2015 highlight a need to reconsider policy for routine influenza vaccination while paying attention to sociocultural factors and community preferences for effective vaccine action. PMID- 26110456 TI - [What do Interpreters Understand as their Role in a Medical Consultation and How do they Carry it out in Reality?]. AB - OBJECTIVES: In the literature the role of an interpreter in the clinical setting is not yet clearly defined. The aim of the study is to explore, which role the interpreters assign to themselves and which role they actually take in the clinical setting. METHODS: In the quantitative part of the study, the interpreters evaluated their role in the clinical encounter through a questionnaire, whereas in the qualitative part the interpreters' role was assessed by analysing videotapes of the clinical encounters. RESULTS: 373 questionnaires and 19 videotapes were collated and analysed. According to the results of the questionnaire interpreters seem to prefer a neutral role in the clinical encounter. This was in contrast to what was observed in practice, as seen in the videotapes. In reality, they take in an active role while interpreting. CONCLUSIONS: It is important that medical professionals and interpreters discuss their roles and expectations before every clinical consultation. PMID- 26110457 TI - [Specific Self-Efficacy for Modifying Sexual Interest in Children (SSIC): Construction and Validation of a Measuring Instrument]. AB - The current study aimed the construction and validation of an instrument for assessing the specific self-efficacy for modifying sexual interest in children (SSIC). The construction process included 2 expert reviews resulting in a 6-item self-report questionnaire (SSIC-Scale). Regarding validation, the SSIC-Scale and additional psychometric instruments were assessed within a sample of 56 men having a sexual interest in children. Results demonstrated a good internal consistency (reliability) of the instrument with Cronbach's alpha=0.87. The good construct validity was primarily shown by expected positive correlations of the SSIC-Scale with other aspects of sexuality such as sexual self-efficacy (r=0.54, p<0.01) and by the expected negative correlation with external locus of control (r=-0.25, p<0.10). Correlations with other variables such as general self efficacy (r=0.15, p=0.29) or depression (r=-0.18, p=0.19) presented the expected direction, but did not reach statistical significance. The results indicate the existence of a construct that may be described as the specific self-efficacy for modifying sexual interest in children. Research implications especially concern the question whether the SSIC is influenceable due to specific interventions. PMID- 26110458 TI - [Relationship between Stress and Resources in Patients Waiting for Organ Transplantation: Comparison of Patients with Renal and Liver Insufficiency]. AB - INTRODUCTION: Patients on the waiting list for organ transplantation are exposed to different stress factors and use individual resources for coping. The present study examines these factors in the context of health-related quality of life in different patient groups (patients with renal vs. liver insufficiency) and attachment pattern. MATERIAL & METHODS: The following variables were measured by questionnaire in a clinical sample of 103 patients waiting for a liver or kidney transplant in Thuringia: Physical complaints (GBB), Depression and Anxiety (HADS D), Coping (EFK), Self-efficacy expectations (SWE), Resilience (RS-13), Social support (F-SozU-K-14), Health-related quality of life (SF-8) and Attachment style (BFPE). RESULTS: Patients with liver insufficiency have a higher level of anxiety and show more often an insecure attachment style as renal failure patients. Differences between secure and insecure attached patients waiting for a kidney transplant are found in physical complaints, depression, depressive coping and self-efficacy, resilience, social support, active coping and mental health, in favor of secure attachment. Insecure attachment in patients with liver insufficiency leads to a less frequent usage of active coping strategies. Furthermore, the variables anxiety, depression, resilience, social support and dysfunctional coping mediate the relationship between attachment and mental health completely. DISCUSSION: RESULTS suggest that psychological interventions should specifically consider the variables anxiety, depression, resilience, self efficacy, social support, coping and attachment. CONCLUSION: The gained insights of this study make it possible to derive implications for interventions to reduce risk factors for the development of co-morbid mental disorders and to strengthen protective factors and thus improve the well-being and quality of life of patients. PMID- 26110459 TI - [Media Exposure and Posttraumatic Stress Disorder: Review and Implications for Psychotherapy]. AB - The posttraumatic stress disorder (PTSD) is conceptualised as a psychological reaction upon traumatic events of distinct threat. Especially after the terrorists' attacks of September 11th 2001, the scientific evaluation of the impact of media coverage of war and terrorism on mental functions of healthy individuals and the question whether the exposure of previously traumatised individuals to media coverage of war and disasters may act as a trigger for a trauma re-activation has begun in the US. There are positive associations between media exposure and the presence of PTSD symptoms. The amount (length) of media consumption appears to be a crucial variable to consider. Psychotherapists are asked to broach the issue of a careful and self-protecting handling of media coverage during therapy. PMID- 26110461 TI - Tailored Magnetic and Magnetoelectric Responses of Polymer-Based Composites. AB - The manipulation of electric ordering with applied magnetic fields has been realized on magnetoelectric (ME) materials; however, their ME switching is often accompanied by significant hysteresis and coercivity that represents for some applications a severe weakness. To overcome this obstacle, this work focuses on the development of a new type of ME polymer nanocomposites that exhibits a tailored ME response at room temperature. The multiferroic nanocomposites are based on three different ferrite nanoparticles, Zn0.2Mn0.8Fe2O4 (ZMFO), CoFe2O4 (CFO) and Fe3O4 (FO), dispersed in a piezoelectric copolymer poly(vinylindene fluoride-trifluoroethylene) (P(VDF-TrFE)) matrix. No substantial differences were detected in the time-stable piezoelectric response of the composites (~-28 pC.N(1 )) with distinct ferrite fillers and for the same ferrite content of 10 wt %. Magnetic hysteresis loops from pure ferrite nanopowders showed different magnetic responses. ME results of the nanocomposite films with 10 wt % ferrite content revealed that the ME induced voltage increases with increasing dc magnetic field until a maximum of 6.5 mV.cm(-1).Oe(1-), at an optimum magnetic field of 0.26 T, and 0.8 mV.cm(-1).Oe(1-), at an optimum magnetic field of 0.15 T, for the CFO/P(VDF-TrFE) and FO/P(VDF-TrFE) composites, respectively. In contrast, the ME response of ZMFO/P(VDF-TrFE) exposed no hysteresis and high dependence on the ZMFO filler content. Possible innovative applications such as memories and information storage, signal processing, and ME sensors and oscillators have been addressed for such ferrite/PVDF nanocomposites. PMID- 26110460 TI - Subcutaneous administration of bovine superoxide dismutase protects lungs from radiation-induced lung injury. AB - BACKGROUND: The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation therapy (RT) mitigates development of pulmonary toxicity in rats. METHODS: Female F344 rats (n = 60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT + 5 mg/kg bSOD; (3) RT + 15 mg/kg bSOD; (4) No RT; (5) sham RT + 5 mg/kg bSOD; and (6) sham RT + 15 mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 h post-radiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency, and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG(+), NOX4(+), nitrotyrosine(+), and 4HNE(+) cells), macrophage activation (ED1(+)), and expression of profibrotic transforming growth factor beta or TGF-beta in irradiated tissue. RESULTS: Radiation led to an increase in all the evaluated parameters. Treatment with 15 mg/kg bSOD significantly decreased levels of all the evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance. CONCLUSIONS: The single application of bSOD (15 mg/kg) ameliorates radiation-induced lung injury through suppression of reactive oxygen species/reactive nitrogen species or ROS/RNS-dependent tissue damage. PMID- 26110463 TI - Usefulness and validity of the modified Addiction Severity Index: A focus on alcohol, drugs, tobacco, and gambling. AB - BACKGROUND: Individuals who seek treatment for an addictive disorder often exhibit comorbid substance use disorders and/or gambling disorder. The lack of a unique severity assessment instrument might be an obstacle for individuals to access integrated and comprehensive treatment. This paper aimed to examine the usefulness and validity of a modified version of the Addiction Severity Index (mASI) to assess all substance use disorders (including tobacco) and gambling. METHODS: Participants (N = 833) were interviewed with the mASI and completed a validity battery questionnaire. The validity and the reliability of the mASI were examined. RESULTS: The mASI was reliable, and its 9 assessed domains showed a relative independence, supporting its multidimensionality. CONCLUSIONS: The standardized properties of the mASI permit a comprehensive and systematic assessment of all addictive disorders independent of individuals' perceived problems and treatment settings, hence facilitating personalized treatment planning. PMID- 26110464 TI - The Impact of Bile Duct Cultures on Surgical Site Infections in Pancreatic Surgery. AB - INTRODUCTION: In pancreatic surgery pre-operative biliary drainage (PBD) is associated with bacteribilia, which increases the risk for surgical site infections (SSIs). METHODS: This study is a retrospective observational cohort design that compared micro-organisms of intra-operative bile duct cultures with micro-organisms of SSIs after pancreaticoduodenectomy. RESULTS: From January 2004 until December 2010, 887 patients underwent pancreaticoduodenectomy or hepaticojejunostomy for benign and malignant peri-ampullary lesions. Surgical site infections occurred in 10% (87/887). Cultures of SSIs with corresponding intra-operative bile duct cultures were available for 59 patients. Sixty-four percent (38/59) had undergone PBD. Pre-operative biliary drainage was associated with positive intra-operative bile duct cultures in 95% (36/38), versus 48% (10/21; p<=0.001). The correlation of SSIs with intra-operative bile duct cultures was 59% (35/59). There was a significant association between the micro organisms cultured from SSIs and the corresponding bile duct cultures for Enterococcus spp., Escherichia coli, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Enterobacteriaceae with extended spectrum beta lactamase (ESBL), and Candida spp. CONCLUSION: After pancreaticoduodenectomy, SSIs are often caused by the same micro-organisms that are present on intra operative bile duct cultures, especially after PBD. Therefore, intra-operative bile duct cultures should be performed routinely to adjust the antibiotic prophylaxis according to the local hospital surveillance data. PMID- 26110465 TI - Gas-Phase FRET Efficiency Measurements To Probe the Conformation of Mass-Selected Proteins. AB - Electrospray ionization and mass spectrometry have revolutionized the chemical analysis of biological molecules, including proteins. However, the correspondence between a protein's native structure and its structure in the mass spectrometer (where it is gaseous) remains unclear. Here, we show that fluorescence (Forster) resonance energy transfer (FRET) measurements combined with mass spectrometry provides intramolecular distance constraints in gaseous, ionized proteins. Using an experimental setup which combines trapping mass spectrometry and laser-induced fluorescence spectroscopy, the structure of a fluorescently labeled mutant variant of the protein GB1 was probed as a function of charge state. Steady-state fluorescence emission spectra and time-resolved donor fluorescence measurements of mass-selected GB1 show a marked decrease in the FRET efficiency with increasing number of charges on the gaseous protein, which suggests a Coulombically driven unfolding and expansion of its structure. This lies in stark contrast to the pH stability of GB1 in solution. Comparison with solution-phase single-molecule FRET measurements show lower FRET efficiency for all charge states of the gaseous protein examined, indicating that the ensemble of conformations present in the gas phase is, on average, more expanded than the native form. These results represent the first FRET measurements on a mass selected protein and illustrate the utility of FRET for obtaining a new kind of structural information for large, desolvated biomolecules. PMID- 26110466 TI - FRET Nanoflares for Intracellular mRNA Detection: Avoiding False Positive Signals and Minimizing Effects of System Fluctuations. AB - A new class of intracellular nanoprobe, termed fluorescence resonance energy transfer (FRET) nanoflares, was developed to sense mRNA in living cells. It consists of a gold nanoparticle (AuNP), recognition sequences, and flares. Briefly, the AuNP functionalized with recognition sequences hybridized to flares, which are designed as hairpin structures and fluorescently labeled donors and acceptors at two ends, respectively. In the absence of targets, the flares are captured by binding with the recognition sequences, separating of the donor and acceptor, and inducing low FRET efficiency. However, in the presence of targets, the flares are gradually displaced from the recognition sequences by the targets, subsequently forming hairpin structures that bring the donor and acceptor into close proximity and result in high FRET efficiency. Compared to the conventional single-dye nanoflares, the upgraded FRET nanoflares can avoid false positive signals by chemical interferences (such as nuclease and GSH) and thermodynamic fluctuations. Moreover, the signal generation in FRET nanoflares can be easily made with ratiometric measurement, minimizing the effect of system fluctuations. PMID- 26110467 TI - Determination of Free and Total Carnitine and Choline in Infant Formulas and Adult Nutritional Products by UPLC/MS/MS: Single-Laboratory Validation, First Action 2014.04. AB - A single-laboratory validation (SLV) has been performed for a method that simultaneously determines choline and carnitine in nutritional products by ultra performance LC (UPLC)/MS/MS. All 11 matrixes from the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) were tested. Depending on the sample preparation, either the added (free, with a water dilution and filtering) or total (after microwave digestion at 120 degrees C in nitric acid and subsequent neutralization with ammonia) species can be detected. For nonmilk containing products, the total carnitine is almost always equal to the free carnitine. A substantial difference was noted between free and total choline in all products. All Standard Method Performance Requirements for carnitine and choline have been met. This report summarizes the material sent to the AOAC Expert Review Panel for SPIFAN nutrient methods for the review of this method, as well as some additional data from an internal validation. The method was granted AOAC First Action status for carnitine in 2014 (2014.04), but the choline data are also being presented. A comparison of choline results to those from other AOAC methods is given. PMID- 26110468 TI - Safety and Efficacy of Expanded Polytetrafluoroethylene Implants in the Surgical Management of Traumatic Nasal Deformity. AB - IMPORTANCE: The ideal alloplastic implant for correction of traumatic nasal deformity has not been adequately examined. OBJECTIVE: To evaluate the safety profile and postoperative results of expanded polytetrafluoroethylene (ePTFE) implants used in functional nasal surgery (FNS) in the setting of traumatic nasal deformity. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 13-year retrospective medical chart review for patients treated at a tertiary academic facial plastic and reconstructive surgery practice between July 1999 and July 2012. A total of 404 FNS procedures were performed by a single surgeon during this period, 255 to repair traumatic deformities, 35 of these involving ePTFE implants. Patient demographics, medical comorbidities, operative and technical considerations, functional and aesthetic results, complications, and postoperative course findings were collected from patient records. In addition, preoperative and postoperative photographic documents were examined. EXPOSURES: Functional nasal surgery. MAIN OUTCOMES AND MEASURES: Postoperative complications or presentations necessitating revision. RESULTS: A total of 404 patients (197 male, 207 female) underwent FNS. Of those, 255 procedures were to treat traumatic deformities. Forty patients altogether required the use of an ePTFE implant, 35 of those 40 deformities being associated with a traumatic injury. One of the 35 patients in the ePTFE-repaired traumatic deformities group experienced postoperative infection. This patient ultimately developed exposure after the infection failed to resolve with oral antibiotics, and the implant was removed. An additional patient in the ePTFE group required revision of the implant owing to contour irregularity and aesthetic concerns. No infections or other complications occurred among the 220 patients with traumatic deformity treated with autologous grafts. Analysis of other variables including sex, tobacco use, diabetes, immunosuppression, implant thickness, suture material, and prior septorhinoplasty were not associated with increased rate of infection (P > .05 for all). CONCLUSIONS AND RELEVANCE: In the setting of traumatic nasal deformities requiring FNS, ePTFE implants can be used at the level of the nasal dorsum, where soft tissue coverage is often adequate, with a low risk of complications. PMID- 26110470 TI - A red-emitting ratiometric fluorescent probe based on a benzophosphole P-oxide scaffold for the detection of intracellular sodium ions. AB - We disclose the development of a ratiometric fluorescent probe based on a benzophosphole P-oxide and its application for the detection of intracellular Na(+) ions. Excitation by visible light induced red emission from this probe in water, which was subjected to a hypsochromic shift upon complexation with Na(+). Based on this change, a ratiometric analysis enabled us to visualise changes in the Na(+) concentration in living mammalian cells. PMID- 26110471 TI - Nanoparticle interaction with the immune system. AB - When nanoparticles enter the body, their interactions with cells are almost unavoidable. Unintended nanoparticle interaction with immune cells may elicit a molecular response that can have toxic effects and lead to greater susceptibility to infectious diseases, autoimmune disorders, and cancer development. As evidenced by several studies, nanoparticle interactions with biological systems can stimulate inflammatory or allergic reactions and activate the complement system. Nanoparticles can also stimulate immune response by acting as adjuvants or as haptens. Immunosuppressive effects have also been reported. This article gives a brief review of in vitro and in vivo research evidencing stimulatory or suppressive effects of nanoparticles on the immune system of mammals. In order to ensure safe use of nanosized particles, future research should focus on how their physical and chemical properties influence their behaviour in the biological environment, as they not only greatly affect nanoparticle-immune system interactions but can also interfere with experimental assays. PMID- 26110472 TI - Polymorphisms in DNA repair genes: link with biomarkers of the CBMN cytome assay in hospital workers chronically exposed to low doses of ionising radiation. AB - Individual sensitivity to ionising radiation (IR) is the result of interaction between exposure, DNA damage, and its repair, which is why polymorphisms in DNA repair genes could play an important role. We examined the association between DNA damage, expressed as micronuclei (MNi), nuclear buds (NBs), and nucleoplasmic bridges (NPBs) and single nucleotide polymorphisms in selected DNA repair genes (APE1, hOGG1, XRCC1, XRCC3, XPD, PARP1, MGMT genes; representative of the different DNA repair pathways operating in mammals) in 77 hospital workers chronically exposed to low doses of IR, and 70 matched controls. A significantly higher MNi frequency was found in the exposed group (16.2+/-10.4 vs. 11.5+/-9.4; P=0.003) and the effect appeared to be independent from the principal confounding factor. Exposed individuals with hOGG1, XRCC1, PARP1, and MGMT wild-type alleles or APEX1, as well as XPD (rs13181) heterozygous showed a significantly higher MNi frequency than controls with the same genotypes. Genetic polymorphism analysis and cytogenetic dosimetry have proven to be a powerful tool complementary to physical dosimetry in regular health surveillance programmes. PMID- 26110473 TI - ADHD-like behaviour in the offspring of female rats exposed to low chlorpyrifos doses before pregnancy. AB - The aim of this study was to investigate how chronic low-dose chlorpyrifos exposure of female Wistar rats before and during pregnancy affects behavioural parameters in their offspring. Four months before pregnancy, we exposed three groups of rats to chlorpyrifos doses of 5, 10, and 15 mg kg-1 body weight every day for 30 days, whereas one group received a single 30 mg kg-1 dose on gestational day 6. When the offspring of the exposed rats grew up, we studied their anxiety rate, motor activity, and cognitive abilities using the respective behavioural tests: open field test, dark/light box, and the extrapolation escape test. The offspring of rats exposed before pregnancy had significantly higher activity rate than controls, and even showed motor agitation and hyperactivity signs. The offspring of rats exposed to the single dose had difficulties solving the extrapolation escape test and showed poorer short- and long-term memory performance. This confirmed that even pre-pregnancy chlorpyrifos exposure can cause neurobehavioral consequences in offspring. Even though the mechanisms of the observed changes remain unclear and need further investigation, these data seem alarming and may serve as an important argument for revising the terms of safe pesticide use. PMID- 26110474 TI - Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning. AB - The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD50) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD50=21.4 mg kg-1) to mice, while monoxime K027 was the least toxic (LD50=672.8 mg kg-1). With the exception of K033, all of the tested K oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication. PMID- 26110475 TI - The effects of CaCl2 and CaBr2 on the reproduction of Daphnia magna Straus. AB - Concentrated CaCl2 and CaBr2 salt solutions of densities up to 2.3 kg L-1 are regularly used to control hydrostatic pressure in oil wells during special operations in the exploration and production of natural gas and crude oil. Various concentrations of high density salts are frequently left in mud pits near the drilling site as waste, polluting fresh and ground waters by spillage and drainage. The toxic effects of these salts have already been observed. This study investigated the effects of CaCl2 and CaBr2 on water flea Daphnia magna Straus in a 21-day reproduction test. The three tested concentrations of CaCl2 (240, 481, and 1925 mg L-1) caused a significant dose-response decrease of reproduction (p<0.001). With CaBr2 (533 and 1066 mg L-1), only aborted eggs were produced, demonstrating the embryotoxicity of the substance. The results suggest that high concentrations of the tested chemicals are harmful to Daphnia's reproduction and could reduce its abundance. PMID- 26110476 TI - Growth and photosynthetic responses of Lemna minor L. exposed to cadmium in combination with zinc or copper. AB - Metals have a variety of negative outcomes on plants, essential components of any ecosystem. The effects of CdCl2 (5 MUmol L-1), ZnCl2 (25 or 50 MUmol L-1), and CuCl2 (2.5 or 5 MUmol L-1) and combinations of CdCl2 with either ZnCl2 or CuCl2 on the growth, photosynthetic pigments, and photosystem II (PSII) efficiency of duckweed (Lemna minor L.) were investigated. All of the treatments caused growth inhibition and remarkable metal accumulation in plant tissue after 4 and 7 days. In the combined treatments, the accumulation of each metal applied was lesser in comparison to treatments with single metals. After 4 days, all of the treatments generally diminished chlorophyll a content and decreased the maximum quantum yield (Fv/Fm) and effective quantum yield (DeltaF/F'm) of PSII. However, after 7 days of exposure to a combination of Cd and Zn, pigment content and PSII activity recovered to control levels. A higher concentration of Cu (5 MUmol L-1) as well as Cd in combination with Cu had a prolonged inhibitory effect on photosynthetic features. Our results suggest that growth inhibition was due to the toxic effect of absolute metal quantity in plant tissue. Zn counteracted Cd uptake, as seen from the recovery of pigment content and PSII efficiency in plants exposed for 7 days to the Cd and Zn combination. Cu-induced oxidative stress led to a prolonged inhibitory effect in plants treated both with a higher concentration of Cu (5 MUmol L-1) and simultaneously with Cd and Cu. Our findings could contribute to general knowledge on anthropogenic and environmental contaminants that endanger plant communities and significantly disrupt the sensitive balance of an ecosystem by influencing photosynthetic mechanisms. PMID- 26110477 TI - Genotoxic effects of diazinon on human peripheral blood lymphocytes. AB - The aim of this study was to evaluate the genetic damage in human peripheral blood lymphocytes following 24 and 48- hour exposure to a commercial diazinon formulation Basudin 60EM(r) at concentrations between 0.01 and 40 MUg mL-1. For this purpose we used the micronucleus (MN), fluorescence in situ hybridization (FISH), and alkaline single cell gel electrophoresis (comet) assay. Diazinon significantly increased the frequency of micronucleated cells compared to control. Forty-eight-hour exposure increased this frequency even at lower concentrations (0.01-10 MUg mL-1). The FISH results revealed aneugenic effects at 10 MUg mL-1. The comet assay also confirmed DNA damage at concentrations between 10 and 40 MUg mL-1. Our findings have confirmed the genotoxic potential of diazinon and its cytotoxic effect on human lymphocytes. The increased DNA damage in our study raises concern about the current assessment of the health risk posed by this pesticide and calls for a high level of caution in agricultural and household use. PMID- 26110478 TI - The role of wastewater treatment in reducing pollution of surface waters with zearalenone. AB - Zearalenone (ZEA) is a mycotoxin produced by some Fusarium species in food and feed. The toxicity of ZEA and its metabolites is related to the chemical structure of the mycotoxin, which is similar to naturally occurring oestrogens. Currently, there is increasing awareness of the presence of fungi and their toxic metabolites in the aquatic environment. One of the sources of these compounds are the effluents from wastewater treatment plants. The average annual efficiency of zearalenone reduction in the Leczyca plant in our three-year study was in the range from 51.35 to 69.70 %. The threeway analysis of variance (year, month, and kind of wastewater) shows that the main effects of all factors and all interactions between them were significant for zearalenone and dissolved organic carbon content. Our findings suggest that wastewater is not the main source of surface water pollution with zearalenone. Future research should investigate the means to reduce ZEA and its migration from the fields through prevention strategies such as breeding for crops, plant debris management (crop rotation, tillage), and/or chemical and biological control. PMID- 26110479 TI - Modelling of copper(II) binding to pentapeptides related to atrial natriuretic factor using the 3chiv connectivity index. AB - Using molecular graph theory we studied the binding of NSFRY-NH2 and 12 related pentapeptide amides to Cu(II) as a model system for atrial natriuretic factor (ANF) peptide interactions with copper. Linear regression models based on the valence connectivity index of the 3rd order (3chiv) reproduced experimental stability constants (log beta) for 1N, 2N, 3N, and 4N coordinated complexes with the standard error of 0.30-0.39 log beta units. We developed separate models for seven tyrosinic (N=28) and five non-tyrosinic peptides (N=20), and a common model for both kinds of peptides (N=48) with an indicator (dummy) variable. The results indicate additional aromatic stabilisation in 4N complexes due to metal cation-pi interactions with tyrosine but not with the phenylalanine residue. We have also amended the log K and log K* values to correct miscalculations published by Janicka-Klos et al. in 2013. PMID- 26110480 TI - Real-time dissemination of air quality information using data streams and Web technologies: linking air quality to health risks in urban areas. AB - This article presents a new, original application of modern information and communication technology to provide effective real-time dissemination of air quality information and related health risks to the general public. Our on-line subsystem for urban real-time air quality monitoring is a crucial component of a more comprehensive integrated information system, which has been developed by the Institute for Medical Research and Occupational Health. It relies on a StreamInsight data stream management system and service-oriented architecture to process data streamed from seven monitoring stations across Zagreb. Parameters that are monitored include gases (NO, NO2, CO, O3, H2S, SO2, benzene, NH3), particulate matter (PM10 and PM2.5), and meteorological data (wind speed and direction, temperature and pressure). Streamed data are processed in real-time using complex continuous queries. They first go through automated validation, then hourly air quality index is calculated for every station, and a report sent to the Croatian Environment Agency. If the parameter values exceed the corresponding regulation limits for three consecutive hours, the web service generates an alert for population groups at risk. Coupled with the Common Air Quality Index model, our web application brings air pollution information closer to the general population and raises awareness about environmental and health issues. Soon we intend to expand the service to a mobile application that is being developed. PMID- 26110481 TI - Recognition of amyotrophic lateral sclerosis disease using factorial hidden Markov model. AB - Amyotrophic lateral sclerosis (ALS) is a common disease among neurological disorders that can change the pattern of gait in human. One of the effective methods for recognition and analysis of gait patterns in ALS patients is utilizing stride interval time series. With proper preprocessing for removing unwanted artifacts from the raw stride interval times and then extracting meaningful features from these data, the factorial hidden Markov model (FHMM) was used to distinguish ALS patients from healthy subjects. The results of classification accuracy evaluated using the leave-one-out (LOO) cross-validation algorithm showed that the FHMM method provides better recognition of ALS and healthy subjects compared to standard HMM. Moreover, comparing our method with a state-of-the art method named least square support vector machine (LS-SVM) showed the efficiency of the FHMM in distinguishing ALS subjects from healthy ones. PMID- 26110482 TI - Fungal biotransformation of crude glycerol into malic acid. AB - Malic acid production from the biodiesel coproduct crude glycerol by Aspergillus niger ATCC 9142, ATCC 10577 and ATCC 12846 was observed to occur with the highest malic acid level acid being produced by A. niger ATCC 12846. Fungal biomass production from crude glycerol was similar, but ATCC 10577 produced the highest biomass. Fungal biotransformation of crude glycerol into the commercially valuable organic acid malic acid appeared feasible. PMID- 26110483 TI - The effect of the bioactive sphingolipids S1P and C1P on multipotent stromal cells--new opportunities in regenerative medicine. AB - Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) belong to a family of bioactive sphingolipids that act as important extracellular signaling molecules and chemoattractants. This study investigated the influence of S1P and C1P on the morphology, proliferation activity and osteogenic properties of rat multipotent stromal cells derived from bone marrow (BMSCs) and subcutaneous adipose tissue (ASCs). We show that S1P and C1P can influence mesenchymal stem cells (MSCs), each in a different manner. S1P stimulation promoted the formation of cellular aggregates of BMSCs and ASCs, while C1P had an effect on the regular growth pattern and expanded intercellular connections, thereby increasing the proliferative activity. Although osteogenic differentiation of MSCs was enhanced by the addition of S1P, the effectiveness of osteoblast differentiation was more evident in BMSCs, particularly when biochemical and molecular marker levels were considered. The results of the functional osteogenic differentiation assay, which includes an evaluation of the efficiency of extracellular matrix mineralization (SEM-EDX), revealed the formation of numerous mineral aggregates in BMSC cultures stimulated with S1P. Our data demonstrated that in an appropriate combination, the bioactive sphingolipids S1P and C1P may find wide application in regenerative medicine, particularly in bone regeneration with the use of MSCs. PMID- 26110484 TI - Use of Depth Measure for Multivariate Functional Data in Disease Prediction: An Application to Electrocardiograph Signals. AB - In this paper we develop statistical methods to compare two independent samples of multivariate functional data that differ in terms of covariance operators. In particular we generalize the concept of depth measure to this kind of data, exploiting the role of the covariance operators in weighting the components that define the depth. Two simulation studies are carried out to validate the robustness of the proposed methods and to test their effectiveness in some settings of interest. We present an application to Electrocardiographic (ECG) signals aimed at comparing physiological subjects and patients affected by Left Bundle Branch Block. The proposed depth measures computed on data are then used to perform a nonparametric comparison test among these two populations. They are also introduced into a generalized regression model aimed at classifying the ECG signals. PMID- 26110485 TI - Remote transmission of live endoscopy over the Internet: Report from the 87th Congress of the Japan Gastroenterological Endoscopy Society. AB - Live demonstration of endoscopy is one of the most attractive and useful methods for education and is often organized locally in hospitals. However, problems have been apparent in terms of cost, preparation, and potential risks to patients. Our aim was to evaluate a new approach to live endoscopy whereby remote hospitals are connected by the Internet for live endoscopic demonstrations. Live endoscopy was transmitted to the Congress of the Japan Gastroenterological Endoscopic Society by 13 domestic and international hospitals. Patients with upper and lower gastrointestinal diseases and with pancreatobiliary disorders were the subjects of a live demonstration. Questionnaires were distributed to the audience and were sent to the demonstrators. Questions concerned the quality of transmitted images and sound, cost, preparations, programs, preference of style, and adverse events. Of the audience, 91.2% (249/273) answered favorably regarding the transmitted image quality and 93.8% (259/276) regarding the sound quality. All demonstrators answered favorably regarding image quality and 93% (13/14) regarding sound quality. Preparations were completed without any outsourcing at 11 sites (79%) and were evaluated as 'very easy' or 'easy' at all but one site (92.3%). Preparation cost was judged as 'very cheap' or 'cheap' at 12 sites (86%). Live endoscopy connecting multiple international centers was satisfactory in image and sound quality for both audience and demonstrators, with easy and inexpensive preparation. The remote transmission of live endoscopy from demonstrators' own hospitals was preferred to the conventional style of locally organized live endoscopy. PMID- 26110486 TI - Takayasu Arteritis of the Coronary Arteries Presenting as Sudden Death in a White Teenager. AB - Takayasu arteritis is a rare disease that expresses chronic, large vessel inflammation. The etiology remains unclear and its presentation depends on the affected arteries. With coronary artery involvement, manifestations range from chest pain and shortness of breath to sudden death. We report a case of a 15-year old white girl who presented with syncope immediately before passing. On autopsy, all 3 major coronary arteries grossly contained multiple proximal lesions that were consistent with Takayasu arteritis, microscopically. Takayasu arteritis solely affecting multiple coronary arteries is exceedingly rare. This report discusses the significance of coronary involvement in Takayasu arteritis at autopsy and sudden death. PMID- 26110487 TI - COUNTERPOINT: Is N2 Disease a Contraindication for Surgical Resection for Superior Sulcus Tumors? No. PMID- 26110489 TI - Hypothermic Total Liquid Ventilation Is Highly Protective Through Cerebral Hemodynamic Preservation and Sepsis-Like Mitigation After Asphyxial Cardiac Arrest. AB - OBJECTIVES: Total liquid ventilation provides ultrafast and potently neuro- and cardioprotective cooling after shockable cardiac arrest and myocardial infarction in animals. Our goal was to decipher the effect of hypothermic total liquid ventilation on the systemic and cerebral response to asphyxial cardiac arrest using an original pressure- and volume-controlled ventilation strategy in rabbits. DESIGN: Randomized animal study. SETTING: Academic research laboratory. SUBJECTS: New Zealand Rabbits. INTERVENTIONS: Thirty-six rabbits were submitted to 13 minutes of asphyxia, leading to cardiac arrest. After resumption of spontaneous circulation, they underwent either normothermic life support (control group, n = 12) or hypothermia induced by either 30 minutes of total liquid ventilation (total liquid ventilation group, n = 12) or IV cold saline (conventional cooling group, n = 12). MEASUREMENTS AND MAIN RESULTS: Ultrafast cooling with total liquid ventilation (32 degrees C within 5 min in the esophagus) dramatically attenuated the post-cardiac arrest syndrome regarding survival, neurologic dysfunction, and histologic lesions (brain, heart, kidneys, liver, and lungs). Final survival rate achieved 58% versus 0% and 8% in total liquid ventilation, control, and conventional cooling groups (p < 0.05), respectively. This was accompanied by an early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys after cardiac arrest. Later on, total liquid ventilation also mitigated the systemic inflammatory response through alteration of monocyte chemoattractant protein-1, interleukin-1beta, and interleukin-8 transcripts levels compared with control. In the conventional cooling group, cooling was achieved more slowly (32 degrees C within 90-120 min in the esophagus), providing none of the above-mentioned systemic or organ protection. CONCLUSIONS: Ultrafast cooling by total liquid ventilation limits the post-cardiac arrest syndrome after asphyxial cardiac arrest in rabbits. This protection involves an early limitation in reactive oxidative species production, blood-brain barrier disruption, and delayed preservation against the systemic inflammatory response. PMID- 26110491 TI - The Pattern of Brain Microhemorrhages After Severe Lung Failure Resembles the One Seen in High-Altitude Cerebral Edema. AB - OBJECTIVES: After suffering from severe acute respiratory distress syndrome, several patients show generalized brain alterations and atrophy. A distinctive morphologic pattern of cerebral injury, however, has not been found so far. DATA SOURCES: We present the history of three patients who survived severe acute respiratory distress syndrome. In these patients, MRI of the brain showed multiple microhemorrhages predominantly in the splenium of the corpus callosum. An identical pattern of microhemorrhages has previously been described in mountaineers who suffered from high-altitude cerebral edema. CONCLUSIONS: This report demonstrates that patients after treatment for acute respiratory distress syndrome and high-altitude cerebral edema show congruent cerebral injuries. Further investigation into the similarities of the causative conditions and neurologic consequences might reveal underlying pathophysiologic mechanisms and clinical implications of this observation. PMID- 26110490 TI - Community-, Healthcare-, and Hospital-Acquired Severe Sepsis Hospitalizations in the University HealthSystem Consortium. AB - OBJECTIVES: Severe sepsis poses a major burden on the U.S. healthcare system. Previous epidemiologic studies have not differentiated community-acquired severe sepsis from healthcare-associated severe sepsis or hospital-acquired severe sepsis hospitalizations. We sought to compare and contrast community-acquired severe sepsis, healthcare-associated severe sepsis, and hospital-acquired severe sepsis hospitalizations in a national hospital sample. DESIGN: Retrospective analysis of severe sepsis discharges from University HealthSystem Consortium hospitals in 2012. SETTING: United States. PATIENTS: We used the criteria from Angus et al (discharge diagnoses for both a serious infection and organ dysfunction) to identify severe sepsis hospitalizations. We defined healthcare associated severe sepsis as severe sepsis hospitalizations with an infection present at admission, where the patient was a nursing home resident, was on hemodialysis, or was readmitted within 30 days of a prior hospitalization. We defined community-acquired severe sepsis as all other severe sepsis patients with an infection present at admission. We defined hospital-acquired severe sepsis as severe sepsis patients where the documented infection was not present at admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Prevalence of community-acquired severe sepsis, healthcare-associated severe sepsis, and hospital-acquired severe sepsis, adjusted hospital mortality, length of hospitalization, length of stay in an ICU, and hospital costs. Among 3,355,753 hospital discharges, there were 307,491 with severe sepsis, including 193,081 (62.8%) community-acquired severe sepsis, 79,581 (25.9%) healthcare-associated severe sepsis, and 34,829 (11.3%) hospital-acquired severe sepsis. Hospital acquired severe sepsis and healthcare-associated severe sepsis exhibited higher in-hospital mortality than community-acquired severe sepsis (hospital acquired [19.2%] vs healthcare associated [12.8%] vs community acquired [8.6%]). Hospital acquired severe sepsis had greater resource utilization than both healthcare associated severe sepsis and community-acquired severe sepsis, with higher median length of hospital stay (hospital acquired [17 d] vs healthcare associated [7 d] vs community acquired [6 d]), median length of ICU stay (hospital acquired [8 d] vs healthcare associated [3 d] vs community acquired [3 d]), and median hospital costs (hospital acquired [$38,369] vs healthcare associated [$8,796] vs community acquired [$7,024]). CONCLUSIONS: In this series, severe sepsis hospitalizations included community-acquired severe sepsis (62.8%), healthcare-associated severe sepsis (25.9%), and hospital-acquired severe sepsis (11.3%) cases. Hospital acquired severe sepsis was associated with both higher mortality and resource utilization than community-acquired severe sepsis and healthcare-associated severe sepsis. PMID- 26110492 TI - Previous Ingestion of Lactococcus lactis by Ethanol-Treated Mice Preserves Antigen Presentation Hierarchy in the Gut and Oral Tolerance Susceptibility. AB - BACKGROUND: Ethanol (EtOH) consumption is able to disturb the ovalbumin (OVA) oral tolerance induction by interfering on the function of antigen presenting cells (APC), down-regulating dendritic cells (DCs) and macrophages and up regulating B-lymphocytes and their function, which results in an overall allergic type immune status. In this study, the potential of a priori administration of Lactococcus lactis (LL) in avoiding loss of oral tolerance in EtOH-treated mice was investigated. METHODS: Female C57BL/6 mice received, by oral route, ad libitum wild-type (WT) LL or heat-shock protein producer (Hsp65) LL for 4 consecutive days. Seven days later, mice were submitted to short-term high-dose EtOH treatment. After 24 hours, stomach, intestine, spleen, mesenteric lymph nodes (mLN) specimens were collected for biomarkers analysis. Following EtOH treatment protocol, a group of animals underwent single-gavage OVA-tolerance protocol and sera samples collected for antibody analysis. RESULTS: The ingestion of WT LL or Hsp65 LL is able to restore oral tolerance to OVA in EtOH-treated mice, by reducing local and systemic allergic outcomes such as gastric mast cells and gut-interleukin-4, as well as serum IgE. WT LL treatment prevents the decrease of mLN regulatory T cells induced by the EtOH treatment. Moreover, LL treatment preserves APC hierarchy and antigen presentation commitment in EtOH treated mice, with conserved DC and macrophage activity over B lymphocytes in mLN and preserved macrophage activity over DC and B-cell subsets in the spleen. CONCLUSIONS: The present findings suggest that a priori ingestion of LL preserves essential mechanisms associated with oral tolerance induction that are disturbed by EtOH ingestion. Maintenance of mucosal homeostasis by preserving APC hierarchy and antigen presentation commitment could be associated with T-regulatory subset activities in the gastrointestinal tract. PMID- 26110488 TI - Protocols and Hospital Mortality in Critically Ill Patients: The United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. AB - OBJECTIVE: Clinical protocols may decrease unnecessary variation in care and improve compliance with desirable therapies. We evaluated whether highly protocolized ICUs have superior patient outcomes compared with less highly protocolized ICUs. DESIGN: Observational study in which participating ICUs completed a general assessment and enrolled new patients 1 day each week. PATIENTS: A total of 6,179 critically ill patients. SETTING: Fifty-nine ICUs in the United States Critical Illness and Injury Trials Group Critical Illness Outcomes Study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was the number of ICU protocols; the primary outcome was hospital mortality. A total of 5,809 participants were followed prospectively, and 5,454 patients in 57 ICUs had complete outcome data. The median number of protocols per ICU was 19 (interquartile range, 15-21.5). In single-variable analyses, there were no differences in ICU and hospital mortality, length of stay, use of mechanical ventilation, vasopressors, or continuous sedation among individuals in ICUs with a high versus low number of protocols. The lack of association was confirmed in adjusted multivariable analysis (p = 0.70). Protocol compliance with two ventilator management protocols was moderate and did not differ between ICUs with high versus low numbers of protocols for lung protective ventilation in acute respiratory distress syndrome (47% vs 52%; p = 0.28) and for spontaneous breathing trials (55% vs 51%; p = 0.27). CONCLUSIONS: Clinical protocols are highly prevalent in U.S. ICUs. The presence of a greater number of protocols was not associated with protocol compliance or patient mortality. PMID- 26110494 TI - Modeling Permanent Deformations of Superelastic and Shape Memory Materials. AB - In this paper we propose a modification of the polycrystalline shape memory alloy constitutive model originally proposed by Souza. By introducing a transformation strain energy with two different hardening coefficients, we are able to take into account the effect of the martensitic transformation of unfavorably oriented grains occurring after the main plateau. By choosing a proper second hardening coefficient, it is possible to reproduce the correct stress strain behavior of the material after the plateau without the need of introducing a much smaller Young modulus for martensite. The proposed modification is introduced in the model comprising permanent deformation effects. Model results for uniaxial stress tests are compared to experimental results showing good agreement. PMID- 26110493 TI - Comparing the NIS vs. MRC and INCAT sensory scale through Rasch analyses. AB - We performed a comparison between Neuropathy Impairment Scale-sensory (NISs) vs. the modified Inflammatory Neuropathy Cause and Treatment sensory scale (mISS), and NIS-motor vs. the Medical Research Council sum score in patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and IgM monoclonal gammopathy of undetermined significance-related polyneuropathy (MGUSP). The ordinal data were subjected to Rasch analyses, creating Rasch-transformed (RT)-intervals for all measures. Comparison between measures was based on validity/reliability with an emphasis on responsiveness (using the patient's level of change related to the individually obtained varying SE for minimum clinically important difference). Eighty stable patients (GBS: 30, CIDP: 30, and MGUSP: 20) were assessed twice (entry: two observers; 2-4 weeks later: one observer), and 137 newly diagnosed or relapsing patients (GBS: 55, CIDP: 59, and IgM-MGUSP: 23) were serially examined with 12 months follow-up. Data modifications were needed to improve model fit for all measures. The sensory and motor scales demonstrated approximately equal and acceptable validity and reliability scores. Responsiveness scores were poor but slightly higher in RT-mISS compared to RT-NISs. Responsiveness was equal for the RT-motor scales, but higher in GBS compared to CIDP; responsiveness was poor in patients with MGUSP, suggesting a longer duration of follow-up in the latter group of patients. PMID- 26110495 TI - Response to thyrotropin-releasing hormone stimulation tests in preterm infants with transient hypothyroxinemia of prematurity. AB - OBJECTIVE: Whether hormone supplementation is necessary for infants with transient hypothyroxinemia of prematurity (THOP) remains controversial, and further analysis of the hypothalamus-pituitary-thyroid axis of infants with THOP is necessary. STUDY DESIGN: Thyrotropin-releasing hormone (TRH) stimulation tests were performed at 2 weeks of age in 50 infants with a gestational age of 30 weeks or less, and the data were analyzed retrospectively. RESULT: Subjects were divided into three groups; group A consisted of euthyroid infants, group B consisted of infants with THOP and group C consisted of hypothyroid infants. The basal and peak thyroid-stimulating hormone level of group C in response to TRH stimulation tests was significantly higher than the others, but no differences were observed between groups A and B. CONCLUSION: The response of infants with THOP to the TRH stimulation test was not different from that of euthyroid infants, which suggested that their hypothalamic-pituitary-thyroid axis was appropriately regulated in infants with THOP. PMID- 26110496 TI - Cervical ripening with the balloon catheter and the risk of subsequent preterm birth. AB - OBJECTIVE: To examine the risk of subsequent preterm birth after cervical ripening using a balloon catheter. STUDY DESIGN: A retrospective study was held at a university teaching hospital between January 2007 and June 2013. The study group included women who underwent cervical ripening using a balloon (single or double) catheter in the previous pregnancy followed by a subsequent singleton delivery (balloon catheter group). Two control groups were included. The first was similar to the study group except that ripening was achieved in the previous pregnancy with vaginal prostaglandin E2 (PGE2 group). The second control group had a previous pregnancy that resulted in spontaneous onset of labor at term (unexposed group). The primary outcome was the incidence of spontaneous preterm birth (before 37 weeks) in the index pregnancy. RESULT: Overall, 558 women were included; each group consisted of 186 women. The incidence of spontaneous preterm birth in the index pregnancy did not differ between the groups (0.5, 1.6 and 2.7% in the balloon catheter, PGE2 and in the unexposed groups, respectively, P=0.31). Among the balloon catheter group, 58 (31.2%) women had the ripening performed with a single-balloon catheter and 128 (68.8%) women with a double-balloon catheter. The rate of the spontaneous preterm birth in the index pregnancy did not differ between the two groups (P=1.0). CONCLUSION: Cervical ripening with a balloon catheter does not increase the rate of subsequent spontaneous preterm birth. PMID- 26110497 TI - Transcutaneous bilirubin levels in newborns <35 weeks' gestation. AB - OBJECTIVE: In infants <35 weeks' gestation, we sought to define the transcutaneous bilirubin (TcB) levels at which a total serum bilirubin (TSB) level suggesting the need for phototherapy is unlikely to occur and a TSB measurement can, therefore, be avoided. STUDY DESIGN: Nursing staff performed 896 TcB measurements within 1 h of a TSB on 225 neonates 26 0/7-34 6/7 weeks' postmenstrual age (PMA). Generalized linear models were fit with generalized estimating equations (GEEs) to model the probability of having a TSB level at or above the phototherapy initiation cutpoint as a function of the TcB; these methods allow for multiple tests per infant. RESULTS: The mean difference between TcB and TSB measurements was <1 mg dl(-1) for each PMA category. When the TcB was at least 3 mg dl(-1) below the TSB cutpoint for phototherapy, there was a ?98% probability that the TSB was not at, or above, the recommended phototherapy level. The single exception to this was a phototherapy level of 6 mg dl(-1) for infants of 28 0/7-29 6/7 weeks' PMA, where a TcB of 4 mg dl(-1) below the phototherapy level (ie a TcB ?2 mg dl(-1)) was necessary to achieve ?98% probability. CONCLUSION: Our data support the use of routine TcB screening for infants 28-34 6/7 weeks' gestation. TcB screening in the neonatal intensive care unit can identify infants who require a TSB to confirm or exclude the need for phototherapy. PMID- 26110498 TI - Ethics and professionalism education during neonatal-perinatal fellowship training in the United States. AB - OBJECTIVE: The objectives of this study were to determine the perceived adequacy of ethics and professionalism education for neonatal-perinatal fellows in the United States, and to measure confidence of fellows and recent graduates when navigating ethical issues. STUDY DESIGN: Neonatal-Perinatal Fellowship Directors, fellows and recent graduates were surveyed regarding the quality and type of such education during training, and perceived confidence of fellows/graduates in confronting ethical dilemmas. RESULT: Forty-six of 97 Directors (47%) and 82 of 444 fellows/graduates (18%) completed the surveys. Over 97% of respondents agreed that ethics training is 'important/very important'. Only 63% of Directors and 37% of fellows/graduates rated ethics education as 'excellent/very good' (P=0.004). While 96% of Directors reported teaching of ethics, only 70% of fellows/graduates reported such teaching (P<0.001). Teaching methods and their perceived effectiveness varied widely. CONCLUSION: Training in ethics and professionalism for fellows is important, yet currently insufficient; a more standardized curriculum may be beneficial to ensure that trainees achieve competency. PMID- 26110499 TI - Genetic association of AKAP10 gene polymorphism with reduced risk of preterm birth. AB - OBJECTIVE: Preterm birth (PTB) is a multifactorial complication in which genetic and environmental factors contribute to the phenotype. The AKAP10 protein encoded by AKAP10 gene has a vital role in the maintenance of myometrial quiescence and pregnancy. This study aimed to investigate whether polymorphisms in the AKAP10 gene are associated with the risk of PTB. STUDY DESIGN: A total of 664 women (132 preterm and 532 term) with spontaneous singleton deliveries were genotyped for AKAP10 polymorphisms (rs119672, rs203462 and rs169412) using Sequenom MassARRAY platform. RESULT: A significant association was observed between the CC and AC genotypes of AKAP10 rs169412 with reduced risk of PTB (CC: adjusted odds ratio (OR) 2.95, 95% confidence interval (CI): 1.23-7.09, P=0.016. AC: adjusted OR 3.46, 95% CI: 1.38-8.68, P=0.008), respectively. Following stratification by ethnicity, a significant association was observed between the AC and CC genotypes of rs169412 and term birth in the Malay ethnic subgroup. (CC: OR 2.9, 95% CI: 1.01-8.59, P=0.041. AC: OR 3.14, 95% CI: 1.04-9.54, P=0.043). A significant association was also observed between the CT genotypes of AKAP10 rs119672 with reduced risk of PTB deliveries (CT: OR 3.2, 95% CI: 1.06-9.76 P=0.007, TT: OR 2.8, 0.98-8.34, P =.0.015) Alternatively, there was no association between AKAP10 rs169412 and rs119672 polymorphisms with PTB in the Indians and Chinese ethnic groups. CONCLUSION: This study indicates a significant association between the AKAP10 polymorphisms and reduced risk of PTB in the Malays. This demonstrates the potential role of AKAP10 polymorphisms in preterm complications. PMID- 26110500 TI - Episodic Future Thinking Is Related to Impulsive Decision Making in Healthy Adolescents. AB - Delay discounting is a stable trait measure of impulsivity. Engaging in episodic future thinking (EFT) can reduce discounting, but whether individual differences in discounting are associated with differences in future thinking remains unclear. Here, this association was tested in healthy adolescents (n = 49, age range = 12-16 years, fluent German speakers, from a large German city). Data collection was between December 2011 and December 2012. Vividness of EFT (assessed via the Autobiographical Memory Interview) was negatively correlated with discounting (r = -.41, 95% CI [-.63, -.13], r(2) = .17). Regression analyses confirmed that this association was stable when controlling for additional variables, including hormonal measures of pubertal maturation and intelligence. EFT may attenuate impulsivity in young people at risk of engaging in problematic behavior. PMID- 26110501 TI - Development of a method using high-performance liquid chromatographic fingerprint and multi-ingredients quantitative analysis for the quality control of Yangxinshi Pian. AB - A simple and reliable method of high-performance liquid chromatography with diode array detection method was developed for fingerprint analysis and simultaneous determination of six compounds including puerarin, salvianolic acid B, berberine hydrochloride, palmatine chloride, dehydrocorydaline, and icariin in the Chinese medicine preparation Yangxinshi Pian. The separation was performed on an Agilent Eclipse XDB-C18 reserved-phase column (250 mm * 4.6mm I.D., 5 MUm) using gradient elution with 50 mmol/L monopotassium phosphate aqueous solution and methanol as mobile phase at a flow rate of 1.0 mL/min. The column operating temperature was set at 30 degrees C, and the detection wavelength was 280 nm. The method was validated by linearity, precision, accuracy, stability, and recovery. For fingerprint analysis, 25 peaks were selected as the common peaks, and four kinds of similarities including cosine similarity (S), ratio of similarity (S'), projection content similarity (C), and content similarity (P) were applied to evaluate the quality consistency of different batches of Yangxinshi Pian. The results showed that the developed method was an efficient tool for quality evaluation of Yangxinshi Pian. PMID- 26110502 TI - Addendum: Urusov, A.E.; Zherdev, A.V.; Petrakova, A.V.; Sadykhov, E.G.; Koroleva, O.V.; Dzantiev, B.B. Rapid Multiple Immunoenzyme Assay of Mycotoxins. Toxins, 2015, 7, 238-254. PMID- 26110503 TI - Application of Microwave Irradiation and Heat to Improve Gliadin Detection and Ricin ELISA Throughput with Food Samples. AB - The utility of microwave irradiation to accelerate the onset of equilibrium and improve ELISA performance was examined using ELISAs for the detection of the plant toxin ricin and gliadin. The ricin ELISA normally requires several one hour incubations at 37 degrees C, a total assay time of approximately five hours, and employs a complex buffer containing PBS, Tween-20(r), and non-fat milk. Different energy levels and pulse designs were compared to the use of abbreviated incubation times at 37 degrees C for the detection of ricin in food. The use of microwave irradiation had no significant advantage over the application of heat using an oven incubator and performed worse with some foods. In contrast, a gliadin ELISA that relied on 30 min incubation steps at room temperature and a salt-based buffer performed better upon irradiation but also displayed improvement upon incubating the microtiter plate at 37 degrees C. Whether microwave irradiation was advantageous compared to incubation in an oven was inconclusive. However, by abbreviating the incubation time of the ricin ELISA, it was possible to cut the assay time to less than 2 hours and still display LOD values < 10 ppb and recoveries of 78%-98%. PMID- 26110504 TI - Prevention of Aflatoxin B1-Induced DNA Breaks by beta-D-Glucan. AB - Aflatoxins are a group of naturally-occurring carcinogens that are known to contaminate different human and animal foodstuffs. Aflatoxin B1 (AFB1) is the most genotoxic hepatocarcinogenic compound of all of the aflatoxins. In this report, we explore the capacity of beta-D-glucan (Glu) to reduce the DNA damage induced by AFB1 in mouse hepatocytes. For this purpose, we applied the comet assay to groups of animals that were first administered Glu in three doses (100, 400 and 700 mg/kg bw, respectively) and, 20 min later, 1.0 mg/kg of AFB1. Liver cells were obtained at 4, 10 and 16 h after the chemical administration and examined. The results showed no protection of the damage induced by AFB1 with the low dose of the polysaccharide, but they did reveal antigenotoxic activity exerted by the two high doses. In addition, we induced a co-crystallization between both compounds, determined their fusion points and analyzed the molecules by UV spectroscopy. The data suggested the formation of a supramolecular complex between AFB1 and beta-D-glucan. PMID- 26110506 TI - Fusariotoxins in Avian Species: Toxicokinetics, Metabolism and Persistence in Tissues. AB - Fusariotoxins are mycotoxins produced by different species of the genus Fusarium whose occurrence and toxicity vary considerably. Despite the fact avian species are highly exposed to fusariotoxins, the avian species are considered as resistant to their toxic effects, partly because of low absorption and rapid elimination, thereby reducing the risk of persistence of residues in tissues destined for human consumption. This review focuses on the main fusariotoxins deoxynivalenol, T-2 and HT-2 toxins, zearalenone and fumonisin B1 and B2. The key parameters used in the toxicokinetic studies are presented along with the factors responsible for their variations. Then, each toxin is analyzed separately. Results of studies conducted with radiolabelled toxins are compared with the more recent data obtained with HPLC/MS-MS detection. The metabolic pathways of deoxynivalenol, T-2 toxin, and zearalenone are described, with attention paid to the differences among the avian species. Although no metabolite of fumonisins has been reported in avian species, some differences in toxicokinetics have been observed. All the data reviewed suggest that the toxicokinetics of fusariotoxins in avian species differs from those in mammals, and that variations among the avian species themselves should be assessed. PMID- 26110507 TI - Reduced Toxicity of Shiga Toxin (Stx) Type 2c in Mice Compared to Stx2d Is Associated with Instability of Stx2c Holotoxin. AB - Shiga toxin (Stx) is an AB5 ribotoxin made by Stx-producing Escherichia coli (STEC). These organisms cause diarrhea, hemorrhagic colitis and the hemolytic uremic syndrome. STEC make two types of Stxs, Stx1 and/or Stx2. Stx2 has one prototype (a) and six subtypes (b-g), but only STEC that make Stx2a, and/or Stx2c, or Stx2d are associated with severe disease. However, Stx2c is about 10 fold less toxic than Stx2d in vivo despite only two amino acid differences in the A subunit at positions 291 and 297. We made mutations at these two sites to create intermediate toxins between Stx2c and Stx2d, and determined the 50% cytotoxic dose on Vero cells before and after heat treatment, and the 50% lethal dose in mice of the toxins. We found that serine 291 was associated with increased toxicity in vivo and that either amino acid change from that in Stx2c to that in Stx2d increased heat stability. We also assessed the secondary structure of Stx2c and Stx2d by circular dichroism (CD) spectroscopy. The CD studies suggest that Stx2c has a less-ordered secondary structure than Stx2d. We conclude that both amino acids at positions 291 and 297 in Stx2c contribute to its decreased stability and in vivo toxicity compared to Stx2d. PMID- 26110509 TI - YAlC: A Bonding Chameleon with Heteropolyacetylene Features. AB - YAlC was prepared by a flux method. It crystallizes as a partially filled-up TlI structure, showing remarkable structural aspects at the border between Zintl phases and intermetallics. This novel ternary aluminide-carbide exhibits a unique one-dimensional multi-center bond and a polyacetylene-related aluminum carbide substructure. The different functionalities of aluminum and of yttrium are quite remarkable. While the latter behaves more like a trivalent ion, aluminum contributes considerably to covalent bonding with carbon. Still yttrium d states contribute, but hardly in a directed manner. PMID- 26110505 TI - Bioinformatics-Aided Venomics. AB - Venomics is a modern approach that combines transcriptomics and proteomics to explore the toxin content of venoms. This review will give an overview of computational approaches that have been created to classify and consolidate venomics data, as well as algorithms that have helped discovery and analysis of toxin nucleic acid and protein sequences, toxin three-dimensional structures and toxin functions. Bioinformatics is used to tackle specific challenges associated with the identification and annotations of toxins. Recognizing toxin transcript sequences among second generation sequencing data cannot rely only on basic sequence similarity because toxins are highly divergent. Mass spectrometry sequencing of mature toxins is challenging because toxins can display a large number of post-translational modifications. Identifying the mature toxin region in toxin precursor sequences requires the prediction of the cleavage sites of proprotein convertases, most of which are unknown or not well characterized. Tracing the evolutionary relationships between toxins should consider specific mechanisms of rapid evolution as well as interactions between predatory animals and prey. Rapidly determining the activity of toxins is the main bottleneck in venomics discovery, but some recent bioinformatics and molecular modeling approaches give hope that accurate predictions of toxin specificity could be made in the near future. PMID- 26110510 TI - Are we missing an opportunity for cancer prevention? Human papillomavirus vaccination for survivors of pediatric and young adult cancers. AB - Survivors of pediatric and young adult cancers remain at risk for subsequent diseases, including those related to human papillomavirus (HPV) infection. Prevention of HPV acquisition through vaccination has become possible over the last decade. HPV vaccines have been shown to be safe and effective, yet rates of vaccination among childhood cancer survivors have remained low. Multiple factors, including stronger advocacy for this intervention from providers, could potentially increase vaccination and lead to lower HPV disease burdens for childhood cancer survivors. Health care providers for survivors of pediatric and adolescent cancers should prioritize counseling for HPV vaccination at follow-up visits. Cancer 2015;121:3435-43. (c) 2015 American Cancer Society. PMID- 26110508 TI - Pain Relief in Cervical Dystonia with Botulinum Toxin Treatment. AB - Dystonia is a neurological disorder characterized by intermittent or sustained muscle contractions that cause abnormal, usually repetitive, movements and postures. Dystonic movements can be tremulous and twisting and often follow a pattern. They are frequently associated with overflow muscle activation and may be triggered or worsened by voluntary action. Most voluntary muscles can be affected and, in the case of the neck muscles, the condition is referred to as cervical dystonia (CD), the most common form of dystonia. The high incidence of pain distinguishes CD from other focal dystonias and contributes significantly to patient disability and low quality of life. Different degrees of pain in the cervical region are reported by more than 60% of patients, and pain intensity is directly related to disease severity. Botulinum toxin (BoNT) is currently considered the treatment of choice for CD and can lead to an improvement in pain and dystonic symptoms in up to 90% of patients. The results for BoNT/A and BoNT/B are similar. The complex relationship between pain and dystonia has resulted in a large number of studies and more comprehensive assessments of dystonic patients. When planning the application of BoNT, pain should be a key factor in the choice of muscles and doses. In conclusion, BoNT is highly effective in controlling pain, and its analgesic effect is sustained for a long time in most CD patients. PMID- 26110511 TI - Indolizino[5,6-b]quinoxaline Derivatives: Intramolecular Charge Transfer Characters and NIR Fluorescence. AB - Indolizino[5,6-b]quinoxaline derivatives (1 a and 1 b) with a push-pull structure were prepared to show intramolecular charge-transfer properties. Compounds 1 a and 1 b are strongly fluorescent in aprotic solvents while symmetrical derivatives (2 a and 2 b) were non-fluorescent. The pi-expanded alpha-alpha linked dimer (10) of indolizino[5,6-b]quinoxaline 1 b was serendipitously obtained to show NIR absorption over 800 nm and the fluorescence edge reached to 1400 nm. PMID- 26110514 TI - Potassium permanganate-glutaraldehyde chemiluminescence system catalyzed by gold nanoprisms toward selective determination of fluoride. AB - Gold and silver nanoparticles (NPs) are shown to exert a positive effect on the chemiluminescence (CL) reaction of permanganate aldehydes. Interestingly, between various shapes examined, Au nanoprisms have the highest beneficial effect. This effect is even more notable in the presence of sodium dodecyl sulfate (SDS) surfactant. UV-vis spectra and transmission electron microscopy were used to characterize the NP shapes and sizes. Furthermore, it was observed that iron(III) ions can slightly increase CL emission of this system. This intensification is very effective in the presence of fluoride ions (F(-)). These observations form the basis of the method for the high sensitive determination of F(-) in the 6 1200 nmol L(-1) concentration range, with a detection limit of 2.1 nmol L(-1). The proposed method has good precision and was satisfactorily used in the selective determination of low concentrations of fluoride ion in real samples. PMID- 26110513 TI - Identifying in vivo DCE MRI markers associated with microvessel architecture and gleason grades of prostate cancer. AB - BACKGROUND: To identify computer extracted in vivo dynamic contrast enhanced (DCE) MRI markers associated with quantitative histomorphometric (QH) characteristics of microvessels and Gleason scores (GS) in prostate cancer. METHODS: This study considered retrospective data from 23 biopsy confirmed prostate cancer patients who underwent 3 Tesla multiparametric MRI before radical prostatectomy (RP). Representative slices from RP specimens were stained with vascular marker CD31. Tumor extent was mapped from RP sections onto DCE MRI using nonlinear registration methods. Seventy-seven microvessel QH features and 18 DCE MRI kinetic features were extracted and evaluated for their ability to distinguish low from intermediate and high GS. The effect of temporal sampling on kinetic features was assessed and correlations between those robust to temporal resolution and microvessel features discriminative of GS were examined. RESULTS: A total of 12 microvessel architectural features were discriminative of low and intermediate/high grade tumors with area under the receiver operating characteristic curve (AUC) > 0.7. These features were most highly correlated with mean washout gradient (WG) (max rho = -0.62). Independent analysis revealed WG to be moderately robust to temporal resolution (intraclass correlation coefficient [ICC] = 0.63) and WG variance, which was poorly correlated with microvessel features, to be predictive of low grade tumors (AUC = 0.77). Enhancement ratio was the most robust (ICC = 0.96) and discriminative (AUC = 0.78) kinetic feature but was moderately correlated with microvessel features (max rho = -0.52). CONCLUSION: Computer extracted features of prostate DCE MRI appear to be correlated with microvessel architecture and may be discriminative of low versus intermediate and high GS. PMID- 26110512 TI - Hypoxia, AMPK activation and uterine artery vasoreactivity. AB - Genes near adenosine monophosphate-activated protein kinase-alpha1 (PRKAA1) have been implicated in the greater uterine artery (UtA) blood flow and relative protection from fetal growth restriction seen in altitude-adapted Andean populations. Adenosine monophosphate-activated protein kinase (AMPK) activation vasodilates multiple vessels but whether AMPK is present in UtA or placental tissue and influences UtA vasoreactivity during normal or hypoxic pregnancy remains unknown. We studied isolated UtA and placenta from near-term C57BL/6J mice housed in normoxia (n = 8) or hypoxia (10% oxygen, n = 7-9) from day 14 to day 19, and placentas from non-labouring sea level (n = 3) or 3100 m (n = 3) women. Hypoxia increased AMPK immunostaining in near-term murine UtA and placental tissue. RT-PCR products for AMPK-alpha1 and -alpha2 isoforms and liver kinase B1 (LKB1; the upstream kinase activating AMPK) were present in murine and human placenta, and hypoxia increased LKB1 and AMPK-alpha1 and -alpha2 expression in the high- compared with low-altitude human placentas. Pharmacological AMPK activation by A769662 caused phenylephrine pre-constricted UtA from normoxic or hypoxic pregnant mice to dilate and this dilatation was partially reversed by the NOS inhibitor l-NAME. Hypoxic pregnancy sufficient to restrict fetal growth markedly augmented the UtA vasodilator effect of AMPK activation in opposition to PE constriction as the result of both NO-dependent and NO-independent mechanisms. We conclude that AMPK is activated during hypoxic pregnancy and that AMPK activation vasodilates the UtA, especially in hypoxic pregnancy. AMPK activation may be playing an adaptive role by limiting cellular energy depletion and helping to maintain utero-placental blood flow in hypoxic pregnancy. PMID- 26110515 TI - Comparison of GENCODE and RefSeq gene annotation and the impact of reference geneset on variant effect prediction. AB - BACKGROUND: A vast amount of DNA variation is being identified by increasingly large-scale exome and genome sequencing projects. To be useful, variants require accurate functional annotation and a wide range of tools are available to this end. McCarthy et al recently demonstrated the large differences in prediction of loss-of-function (LoF) variation when RefSeq and Ensembl transcripts are used for annotation, highlighting the importance of the reference transcripts on which variant functional annotation is based. RESULTS: We describe a detailed analysis of the similarities and differences between the gene and transcript annotation in the GENCODE and RefSeq genesets. We demonstrate that the GENCODE Comprehensive set is richer in alternative splicing, novel CDSs, novel exons and has higher genomic coverage than RefSeq, while the GENCODE Basic set is very similar to RefSeq. Using RNAseq data we show that exons and introns unique to one geneset are expressed at a similar level to those common to both. We present evidence that the differences in gene annotation lead to large differences in variant annotation where GENCODE and RefSeq are used as reference transcripts, although this is predominantly confined to non-coding transcripts and UTR sequence, with at most ~30% of LoF variants annotated discordantly. We also describe an investigation of dominant transcript expression, showing that it both supports the utility of the GENCODE Basic set in providing a smaller set of more highly expressed transcripts and provides a useful, biologically-relevant filter for further reducing the complexity of the transcriptome. CONCLUSIONS: The reference transcripts selected for variant functional annotation do have a large effect on the outcome. The GENCODE Comprehensive transcripts contain more exons, have greater genomic coverage and capture many more variants than RefSeq in both genome and exome datasets, while the GENCODE Basic set shows a higher degree of concordance with RefSeq and has fewer unique features. We propose that the GENCODE Comprehensive set has great utility for the discovery of new variants with functional potential, while the GENCODE Basic set is more suitable for applications demanding less complex interpretation of functional variants. PMID- 26110517 TI - Anaphylactic Shock Due to Cow's Milk Allergy in the Neonatal Period. PMID- 26110516 TI - Reward-Induced Phasic Dopamine Release in the Monkey Ventral Striatum and Putamen. AB - In-vivo voltammetry has successfully been used to detect dopamine release in rodent brains, but its application to monkeys has been limited. We have previously detected dopamine release in the caudate of behaving Japanese monkeys using diamond microelectrodes (Yoshimi 2011); however it is not known whether the release pattern is the same in various areas of the forebrain. Recent studies have suggested variations in the dopaminergic projections to forebrain areas. In the present study, we attempted simultaneous recording at two locations in the striatum, using fast-scan cyclic voltammetry (FSCV) on carbon fibers, which has been widely used in rodents. Responses to unpredicted food and liquid rewards were detected repeatedly. The response to the liquid reward after conditioned stimuli was enhanced after switching the prediction cue. These characteristics were generally similar between the ventral striatum and the putamen. Overall, the technical application of FSCV recording in multiple locations was successful in behaving primates, and further voltammetric recordings in multiple locations will expand our knowledge of dopamine reward responses. PMID- 26110518 TI - Soil-Transmitted Helminths in Southwestern China: A Cross-Sectional Study of Links to Cognitive Ability, Nutrition, and School Performance among Children. AB - BACKGROUND: Empirical evidence suggests that the prevalence of soil-transmitted helminth (STH) infections in remote and poor rural areas is still high among children, the most vulnerable to infection. There is concern that STH infections may detrimentally affect children's healthy development, including their cognitive ability, nutritional status, and school performance. Medical studies have not yet identified the exact nature of the impact STH infections have on children. The objective of this study is to examine the relationship between STH infections and developmental outcomes among a primary school-aged population in rural China. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a large-scale survey in Guizhou province in southwest China in May 2013. A total of 2,179 children aged 9 11 years living in seven nationally-designated poverty counties in rural China served as our study sample. Overall, 42 percent of the sample's elementary school aged children were infected with one or more of the three types of STH--Ascaris lumbricoides (ascaris), Trichuris trichuria (whipworm) and the hookworms Ancylostoma duodenale or Necator americanus. After controlling for socioeconomic status, we observed that infection with one or more STHs is associated with worse cognitive ability, worse nutritional status, and worse school performance than no infection. This study also presents evidence that children with Trichuris infection, either infection with Trichuris only or co-infected with Trichuris and Ascaris, experience worse cognitive, nutritional and schooling outcomes than their uninfected peers or children infected with only Ascaris. CONCLUSIONS/SIGNIFICANCE: We find that STH infection still poses a significant health challenge among children living in poor, rural, ethnic areas of southwest China. Given the important linkages we find between STH infection and a number of important child health and educational outcomes, we believe that our results will contribute positively to the debate surrounding the recent Cochrane report. PMID- 26110519 TI - Bioactive Diterpenoids from the Leaves of Callicarpa macrophylla. AB - A phytochemical investigation of the leaves of Callicarpa macrophylla led to the isolation of five new diterpenoids (1-5), macrophypenes A-E, and nine known analogues (6-14). The structures of 1-5 were established on the basis of extensive analysis of NMR spectroscopic data, X-ray diffraction data, and experimental and calculated electronic circular dichroism spectra. Compound 1 is a spiroditerpenoid with a novel skeleton, and compound 5 is a rare ent-abietane diterpenoid possessing a peroxide bridge. Compounds 1, 5-7, and 11-14 stimulate nerve growth factor mediated neurite outgrowth from PC12 cells. PMID- 26110520 TI - SEQUENTIAL CENTRAL RETINAL VEIN AND OPHTHALMIC ARTERY OCCLUSIONS IN A PEDIATRIC CASE OF PRIMARY ANTIPHOSPHOLIPID SYNDROME. AB - PURPOSE: To report a case of sequential central retinal vein occlusion and ophthalmic artery occlusion in a patient with primary antiphospholipid syndrome. METHODS: Observational case report. Color fundus photography, fluorescein angiography, and optical coherence tomography were used to document the progression of a central retinal vein occlusion and sequential development of an ophthalmic artery occlusion within a 1-week period in a patient with primary antiphospholipid syndrome. RESULTS: A 15-year-old boy presented with unilateral blurry vision due to a central retinal vein occlusion along with other systemic symptoms. Within a 1-week period, he developed an ophthalmic artery occlusion in the same eye, with resulting bare light perception vision. Extensive evaluation by the pediatrics and rheumatology services led to a diagnosis of primary antiphospholipid syndrome as the etiology for the occlusions. CONCLUSION: This case report illustrates the rapid sequential venous and arterial ocular thrombosis in a patient with primary antiphospholipid syndrome. PMID- 26110521 TI - OUTER RETINAL ATROPHY ON SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY AFTER RESOLUTION OF GLAUCOMA SURGERY-ASSOCIATED HYPOTONY MACULOPATHY. AB - PURPOSE: To report two cases of persistent central vision loss after resolution of filtration surgery-associated hypotony, corresponding with foveal outer retinal atrophy on spectral domain optical coherence tomography. METHODS: Retrospective observational case series. A retrospective chart review was conducted of two patients with persistent vision loss after normalization of intraocular pressure and resolution of glaucoma surgery-associated hypotony maculopathy. RESULTS: Several months after glaucoma surgery and resolution of hypotony, both patients suffered persistent vision loss and new foveal photoreceptor loss on spectral domain optical coherence tomography. CONCLUSION: This is the first case series demonstrating foveal outer retinal atrophy on spectral domain optical coherence tomography after resolution of glaucoma surgery associated hypotony maculopathy. Both patients had previous uveitis that was controlled at the time of hypotony. Eyes with previous hypotony and compromised ciliary body function may be at greater risk of photoreceptor damage. PMID- 26110522 TI - SHEDDING LIGHT ON FUNDUS DRUSEN ASSOCIATED WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS: BREAKING STEREOTYPES OF TYPES I, II, AND III. AB - PURPOSE: Membranoproliferative glomerulonephritis (MPGN) classification has been changed from purely anatomic to molecular. This report describes two cases of MPGN with associated drusen that exemplify the importance of this change and the need for ophthalmologists to understand it. METHODS: The medical and pathologic records of two patients with MPGN and drusen were examined. RESULTS: Two patients with MPGN and risk-associated alleles of complement factor H were found to have drusen. In one case, the process led to severe visual impairment. Based on anatomic classification, one patient had MPGN Type I and the other had MPGN Type III. However, both patients had renal biopsy findings classic for C3 glomerulonephritis and the same genetic abnormality (risk-associated alleles of complement factor H). CONCLUSION: The association of MPGN and drusen needs to be reevaluated. Previously only recognized in association with Type II MPGN, drusen have been demonstrated in 2 patients with C3 glomerulonephritis in this report. These drusen are likely the result of complement pathway abnormalities. The authors propose a new nomenclature in the ophthalmic literature to classify pathology as immune complex-mediated or complement-mediated rather than solely by the electron microscopy findings. This nomenclature will better characterize the underlying genetic abnormalities and pathophysiology of these disease processes. PMID- 26110523 TI - SUBMILLIMETER CHOROIDAL MELANOMA DETECTION BY ENHANCED DEPTH IMAGING OPTICAL COHERENCE TOMOGRAPHY IN A PATIENT WITH OCULODERMAL MELANOCYTOSIS. AB - PURPOSE: To describe a tiny subclinical choroidal melanoma visualized only with enhanced depth imaging optical coherence tomography in a newly symptomatic patient with known oculodermal melanocytosis. METHODS: Case report. RESULTS: A 52 year-old white man with heterochromia and known oculodermal melanocytosis of the right eye, followed for 2 years without change, developed blurred vision and was referred for possible central serous chorioretinopathy. On examination, visual acuity was 20/20 in each eye. There was oculodermal melanocytosis in the right eye involving the periocular skin, episclera, iris, and choroid. On ophthalmoscopy and ocular ultrasonography, there was no appreciable mass, but subtle subfoveal fluid and perifoveal orange pigment were detected, as well as equatorial drusen. Enhanced depth imaging optical coherence tomography demonstrated a subtle optically dense focal choroidal mass measuring 4.5 mm in basal dimension and 0.7 mm in enhanced depth imaging optical coherence tomography thickness. There was choroidal vascular compression, obliteration of choroidal details, and related overlying subretinal fluid with shaggy photoreceptors, consistent with early choroidal melanoma in an eye with oculodermal melanocytosis. The patient elected early treatment considering the risk factors for growth and the risk for metastasis associated with melanoma in the setting of oculodermal melanocytosis. Plaque radiotherapy was performed with complete tumor regression clinically and by enhanced depth imaging optical coherence tomography. At 2-year follow-up, visual acuity remains 20/20, with regressed tumor and no systemic metastasis. CONCLUSION: Enhanced depth imaging optical coherence tomography is a useful tool in the evaluation of eyes with oculodermal melanocytosis, permitting high-resolution visualization of the choroid and detection of submillimeter early melanoma that might not be apparent with indirect ophthalmoscopy or ultrasonography. PMID- 26110524 TI - Isolation, Characterization and Biological Properties of Membrane Vesicles Produced by the Swine Pathogen Streptococcus suis. AB - Streptococcus suis, more particularly serotype 2, is a major swine pathogen and an emerging zoonotic agent worldwide that mainly causes meningitis, septicemia, endocarditis, and pneumonia. Although several potential virulence factors produced by S. suis have been identified in the last decade, the pathogenesis of S. suis infections is still not fully understood. In the present study, we showed that S. suis produces membrane vesicles (MVs) that range in diameter from 13 to 130 nm and that appear to be coated by capsular material. A proteomic analysis of the MVs revealed that they contain 46 proteins, 9 of which are considered as proven or suspected virulence factors. Biological assays confirmed that S. suis MVs possess active subtilisin-like protease (SspA) and DNase (SsnA). S. suis MVs degraded neutrophil extracellular traps, a property that may contribute to the ability of the bacterium to escape the host defense response. MVs also activated the nuclear factor-kappa B (NF-kappaB) signaling pathway in both monocytes and macrophages, inducing the secretion of pro-inflammatory cytokines, which may in turn contribute to increase the permeability of the blood brain barrier. The present study brought evidence that S. suis MVs may play a role as a virulence factor in the pathogenesis of S. suis infections, and given their composition be an excellent candidate for vaccine development. PMID- 26110525 TI - Physiological outperformance at the morphologically-transformed edge of the cyanobacteriosponge Terpios hoshinota (Suberitidae: Hadromerida) when confronting opponent corals. AB - Terpios hoshinota, an encrusting cyanosponge, is known as a strong substrate competitor of reef-building corals that kills encountered coral by overgrowth. Terpios outbreaks cause significant declines in living coral cover in Indo Pacific coral reefs, with the damage usually lasting for decades. Recent studies show that there are morphological transformations at a sponge's growth front when confronting corals. Whether these morphological transformations at coral contacts are involved with physiological outperformance (e.g., higher metabolic activity or nutritional status) over other portions of Terpios remains equivocal. In this study, we compared the indicators of photosynthetic capability and nitrogen status of a sponge-cyanobacteria association at proximal, middle, and distal portions of opponent corals. Terpios tissues in contact with corals displayed significant increases in photosynthetic oxygen production (ca. 61%), the delta13C value (ca. 4%), free proteinogenic amino acid content (ca. 85%), and Gln/Glu ratio (ca. 115%) compared to middle and distal parts of the sponge. In contrast, the maximum quantum yield (Fv/Fm), which is the indicator usually used to represent the integrity of photosystem II, of cyanobacteria photosynthesis was low (0.256~0.319) and showed an inverse trend of higher values in the distal portion of the sponge that might be due to high and variable levels of cyanobacterial phycocyanin. The inconsistent results between photosynthetic oxygen production and Fv/Fm values indicated that maximum quantum yields might not be a suitable indicator to represent the photosynthetic function of the Terpios-cyanobacteria association. Our data conclusively suggest that Terpios hoshinota competes with opponent corals not only by the morphological transformation of the sponge-cyanobacteria association but also by physiological outperformance in accumulating resources for the battle. PMID- 26110526 TI - QTL Mapping for Fiber and Yield Traits in Upland Cotton under Multiple Environments. AB - A population of 178 recombinant inbred lines (RILs) was developed using a single seed descendant from a cross between G. hirsutum. acc DH962 and G. hirsutum. cv Jimian5, was used to construct a genetic map and to map QTL for fiber and yield traits. A total of 644 polymorphic loci were used to construct a final genetic map, containing 616 loci and spanning 2016.44 cM, with an average of 3.27 cM between adjacent markers. Statistical analysis revealed that segregation distortion in the intraspecific population was more serious than that in the interspecific population. The RIL population and the two parents were phenotyped under 8 environments (two locations, six years), revealing a total of 134 QTL, including 64 for fiber qualities and 70 for yield components, independently detected in seven environments, explaining 4.40-15.28% of phenotypic variation (PV). Among the 134 QTL, 9 common QTL were detected in more than one environment, and 22 QTL and 19 new QTL were detected in combined analysis (E9). A total of 26 QTL hotspot regions were observed on 13 chromosomes and 2 larger linkage groups, and some QTL clusters related to fiber qualities or yield components were also observed. The results obtained in the present study suggested that to map accurate QTL in crops with larger plant types, such as cotton, phenotyping under multiple environments is necessary to effectively apply the obtained results in molecular marker-assisted selection breeding and QTL cloning. PMID- 26110527 TI - Openness to experience as a predictor and outcome of upward job changes into managerial and professional positions. AB - In industrial and organizational psychology, there is a long tradition of studying personality as an antecedent of work outcomes. Recently, however, scholars have suggested that personality characteristics may not only predict, but also change due to certain work experiences, a notion that is depicted in the dynamic developmental model (DDM) of personality and work. Upward job changes are an important part of employees' careers and career success in particular, and we argue that these career transitions can shape personality over time. In this study, we investigate the Big Five personality characteristics as both predictors and outcomes of upward job changes into managerial and professional positions. We tested our hypotheses by applying event history analyses and propensity score matching to a longitudinal dataset collected over five years from employees in Australia. Results indicated that participants' openness to experience not only predicted, but that changes in openness to experience also followed from upward job changes into managerial and professional positions. Our findings thus provide support for a dynamic perspective on personality characteristics in the context of work and careers. PMID- 26110529 TI - Inexpensive and Highly Reproducible Cloud-Based Variant Calling of 2,535 Human Genomes. AB - Population scale sequencing of whole human genomes is becoming economically feasible; however, data management and analysis remains a formidable challenge for many research groups. Large sequencing studies, like the 1000 Genomes Project, have improved our understanding of human demography and the effect of rare genetic variation in disease. Variant calling on datasets of hundreds or thousands of genomes is time-consuming, expensive, and not easily reproducible given the myriad components of a variant calling pipeline. Here, we describe a cloud-based pipeline for joint variant calling in large samples using the Real Time Genomics population caller. We deployed the population caller on the Amazon cloud with the DNAnexus platform in order to achieve low-cost variant calling. Using our pipeline, we were able to identify 68.3 million variants in 2,535 samples from Phase 3 of the 1000 Genomes Project. By performing the variant calling in a parallel manner, the data was processed within 5 days at a compute cost of $7.33 per sample (a total cost of $18,590 for completed jobs and $21,805 for all jobs). Analysis of cost dependence and running time on the data size suggests that, given near linear scalability, cloud computing can be a cheap and efficient platform for analyzing even larger sequencing studies in the future. PMID- 26110530 TI - Correction: activation of GPR55 receptors exacerbates oxLDL-induced lipid accumulation and inflammatory responses, while reducing cholesterol efflux from human macrophages. PMID- 26110528 TI - AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance. AB - Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively suggest that AKTIP/Ft1 works in concert with TRF1 to facilitate telomeric DNA replication. PMID- 26110531 TI - Oncocalyxone A functions as an anti-glycation agent in vitro. AB - Advanced glycation endproducts (AGE) are the result of post-translational changes to proteins, which ultimately compromise their structure and/or function. The identification of methods to prevent the formation of these compounds holds great promise in the development of alternative therapies for diseases such as diabetes. Plants used in traditional medicine are often rich sources of anti glycation agents. Therefore, in this study, we investigated the anti-glycation activity of one such compound, Oncocalyxone A (Onco A). Using spectrofluorimetric techniques, we determined that Onco A inhibits AGE formation in a concentration dependent manner. Its IC50 value (87.88 +/- 3.08 MUM) was almost two times lower than the standard anti-glycation compound aminoguanidine (184.68 +/- 4.85 MUM). The excellent anti-glycation activity of Onco A makes it an exciting candidate for the treatment of diseases associated with excessive accumulation of AGE. However, additional studies are necessary to identify its mechanism of action, as well as the in vivo response in suitable model organisms. PMID- 26110532 TI - Correction: a nonlinear mixed effects approach for modeling the cell-to-cell variability of Mig1 dynamics in yeast. PMID- 26110533 TI - Munroa argentina, a Grass of the South American Transition Zone, Survived the Andean Uplift, Aridification and Glaciations of the Quaternary. AB - The South American Transition Zone (SATZ) is a biogeographic area in which not only orogeny (Andes uplift) and climate events (aridification) since the mid Miocene, but also Quaternary glaciation cycles had an important impact on the evolutionary history of the local flora. To study this effect, we selected Munroa argentina, an annual grass distributed in the biogeographic provinces of Puna, Prepuna and Monte. We collected 152 individuals from 20 localities throughout the species' range, ran genetic and demographic analyses, and applied ecological niche modeling. Phylogenetic and population genetic analyses based on cpDNA and AFLP data identified three phylogroups that correspond to the previously identified subregions within the SATZ. Molecular dating suggests that M. argentina has inhabited the SATZ since approximately 3.4 (4.2-1.2) Ma and paleomodels predict suitable climate in these areas during the Interglacial period and the Last Glacial Maximum. We conclude that the current distribution of M. argentina resulted from the fragmentation of its once continuous range and that climate oscillations promoted ecological differences that favored isolation by creating habitat discontinuity. PMID- 26110534 TI - Performance of three prognostic models in patients with cancer in need of intensive care in a medical center in China. AB - OBJECTIVE: The aim of this study was to evaluate the performance of Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score 3 (SAPS 3), and Acute Physiology and Chronic Health Evaluation IV (APACHE IV) in patients with cancer admitted to intensive care unit (ICU) in a single medical center in China. MATERIALS AND METHODS: This is a retrospective observational cohort study including nine hundred and eighty one consecutive patients over a 2-year period. RESULTS: The hospital mortality rate was 4.5%. When all 981 patients were evaluated, the area under the receiver operating characteristic curve (AUROC, 95% Confidential Intervals) of the three models in predicting hospital mortality were 0.948 (0.914-0.982), 0.863 (0.804-0.923), and 0.873 (0.813-0.934) for SAPS 3, APACHE II and APACHE IV respectively. The p values of Hosmer-Lemeshow statistics for the models were 0.759, 0.900 and 0.878 for SAPS 3, APACHE II and APACHE IV respectively. However, SAPS 3 and APACHE IV underestimated the in-hospital mortality with standardized mortality ratio (SMR) of 1.5 and 1.17 respectively, while APACHE II overestimated the in-hospital mortality with SMR of 0.72. Further analysis showed that discrimination power was better with SAPS 3 than with APACHE II and APACHE IV whether for emergency surgical and medical patients (AUROC of 0.912 vs 0.866 and 0.857) or for scheduled surgical patients (AUROC of 0.945 vs 0.834 and 0.851). Calibration was good for all models (all p > 0.05) whether for scheduled surgical patients or emergency surgical and medical patients. However, in terms of SMR, SAPS 3 was both accurate in predicting the in-hospital mortality for emergency surgical and medical patients and for scheduled surgical patients, while APACHE IV and APACHE II were not. CONCLUSION: In this cohort, we found that APACHE II, APACHE IV and SAPS 3 models had good discrimination and calibration ability in predicting in hospital mortality of critically ill patients with cancer in need of intensive care. Of these three severity scores, SAPS 3 was superior to APACHE II and APACHE IV, whether in terms of discrimination and calibration power, or standardized mortality ratios. PMID- 26110535 TI - Waterborne Viruses: A Barrier to Safe Drinking Water. PMID- 26110536 TI - Solubilisation of Phosphate and Micronutrients by Trichoderma harzianum and Its Relationship with the Promotion of Tomato Plant Growth. AB - Trichoderma harzianum strain SQR-T037 is a biocontrol agent that has been shown to enhance the uptake of nutrients (macro- and microelements) by plants in fields. The objective of this study was to investigate the contribution of SQR T037 to P and microelement (Fe, Mn, Cu and Zn) nutrition in tomato plants grown in soil and in hydroponic conditions. Inoculation with SQR-T037 significantly improved the biomass and nutrient uptake of tomato seedlings grown in a nutrient limiting soil. So we investigated the capability of SQR-T037 to solubilise sparingly soluble minerals in vitro via four known mechanisms: acidification by organic acids, chelation by siderophores, redox by ferric reductase and hydrolysis by phytase. SQR-T037 was able to solubilise phytate, Fe2O3, CuO, and metallic Zn but not Ca3(PO4)2 or MnO2. Organic acids, including lactic acid, citric acid, tartaric acid and succinic acid, were detected by HPLC and LC/MS in two Trichoderma cultures. Additionally, we inoculated tomato seedlings with SQR T037 using a hydroponic system with specific nutrient deficiencies (i.e., nutrient solutions deficient in P, Fe, Cu or Zn and supplemented with their corresponding solid minerals) to better study the effects of Trichoderma inoculation on plant growth and nutrition. Inoculated seedlings grown in Cu deficient hydroponic conditions exhibited increases in dry plant biomass (92%) and Cu uptake (42%) relative to control plants. However, we did not observe a significant effect on seedling biomass in plants grown in the Fe- and Zn deficient hydroponic conditions; by contrast, the biomass decreased by 82% in the P-deficient hydroponic condition. Thus, we demonstrated that Trichoderma SQR-T037 competed for P (phytate) and Zn with tomato seedlings by suppressing root development, releasing phytase and/or chelating minerals. The results of this study suggest that the induction of increased or suppressed plant growth occurs through the direct effect of T. harzianum on root development, in combination with indirect mechanisms, such as mineral solubilisation (including solubilisation via acidification, redox, chelation and hydrolysis). PMID- 26110537 TI - Orientation of DNA Minicircles Balances Density and Topological Complexity in Kinetoplast DNA. AB - Kinetoplast DNA (kDNA), a unique mitochondrial structure common to trypanosomatid parasites, contains thousands of DNA minicircles that are densely packed and can be topologically linked into a chain mail-like network. Experimental data indicate that every minicircle in the network is, on average, singly linked to three other minicircles (i.e., has mean valence 3) before replication and to six minicircles in the late stages of replication. The biophysical factors that determine the topology of the network and its changes during the cell cycle remain unknown. Using a mathematical modeling approach, we previously showed that volume confinement alone can drive the formation of the network and that it induces a linear relationship between mean valence and minicircle density. Our modeling also predicted a minicircle valence two orders of magnitude greater than that observed in kDNA. To determine the factors that contribute to this discrepancy we systematically analyzed the relationship between the topological properties of the network (i.e., minicircle density and mean valence) and its biophysical properties such as DNA bending, electrostatic repulsion, and minicircle relative position and orientation. Significantly, our results showed that most of the discrepancy between the theoretical and experimental observations can be accounted for by the orientation of the minicircles with volume exclusion due to electrostatic interactions and DNA bending playing smaller roles. Our results are in agreement with the three dimensional kDNA organization model, initially proposed by Delain and Riou, in which minicircles are oriented almost perpendicular to the horizontal plane of the kDNA disk. We suggest that while minicircle confinement drives the formation of kDNA networks, it is minicircle orientation that regulates the topological complexity of the network. PMID- 26110538 TI - Demographic and Spatiotemporal Patterns of Avian Influenza Infection at the Continental Scale, and in Relation to Annual Life Cycle of a Migratory Host. AB - Since the spread of highly pathogenic avian influenza (HPAI) H5N1 in the eastern hemisphere, numerous surveillance programs and studies have been undertaken to detect the occurrence, distribution, or spread of avian influenza viruses (AIV) in wild bird populations worldwide. To identify demographic determinants and spatiotemporal patterns of AIV infection in long distance migratory waterfowl in North America, we fitted generalized linear models with binominal distribution to analyze results from 13,574 blue-winged teal (Anas discors, BWTE) sampled in 2007 to 2010 year round during AIV surveillance programs in Canada and the United States. Our analyses revealed that during late summer staging (July-August) and fall migration (September-October), hatch year (HY) birds were more likely to be infected than after hatch year (AHY) birds, however there was no difference between age categories for the remainder of the year (winter, spring migration, and breeding period), likely due to maturing immune systems and newly acquired immunity of HY birds. Probability of infection increased non-linearly with latitude, and was highest in late summer prior to fall migration when densities of birds and the proportion of susceptible HY birds in the population are highest. Birds in the Central and Mississippi flyways were more likely to be infected compared to those in the Atlantic flyway. Seasonal cycles and spatial variation of AIV infection were largely driven by the dynamics of AIV infection in HY birds, which had more prominent cycles and spatial variation in infection compared to AHY birds. Our results demonstrate demographic as well as seasonal, latitudinal and flyway trends across Canada and the US, while illustrating the importance of migratory host life cycle and age in driving cyclical patterns of prevalence. PMID- 26110539 TI - Evaluation of Appropriate Reference Genes for Gene Expression Normalization during Watermelon Fruit Development. AB - Gene expression analysis in watermelon (Citrullus lanatus) fruit has drawn considerable attention with the availability of genome sequences to understand the regulatory mechanism of fruit development and to improve its quality. Real time quantitative reverse-transcription PCR (qRT-PCR) is a routine technique for gene expression analysis. However, appropriate reference genes for transcript normalization in watermelon fruits have not been well characterized. The aim of this study was to evaluate the appropriateness of 12 genes for their potential use as reference genes in watermelon fruits. Expression variations of these genes were measured in 48 samples obtained from 12 successive developmental stages of parthenocarpic and fertilized fruits of two watermelon genotypes by using qRT-PCR analysis. Considering the effects of genotype, fruit setting method, and developmental stage, geNorm determined clathrin adaptor complex subunit (ClCAC), beta-actin (ClACT), and alpha tubulin 5 (ClTUA5) as the multiple reference genes in watermelon fruit. Furthermore, ClCAC alone or together with SAND family protein (ClSAND) was ranked as the single or two best reference genes by NormFinder. By using the top-ranked reference genes to normalize the transcript abundance of phytoene synthase (ClPSY1), a good correlation between lycopene accumulation and ClPSY1 expression pattern was observed in ripening watermelon fruit. These validated reference genes will facilitate the accurate measurement of gene expression in the studies on watermelon fruit biology. PMID- 26110540 TI - The investigation of solid slag obtained by neutralization of sewage sludge. AB - The purpose of this research is to investigate the feasibility of utilizing the slag collected after gasification of organic fuel combined with sewage sludge. The residue left after gasification process is likely usable as raw material for production of supercondensers. The sewage sludge neutralization system consists of a dosing system (fuel tank), gasifier, plasma reactor, electrostatic filter, and heat exchangers. For the gasification process, dried solid sewage is supplied in proportion of 70% to biomass 30% by weight. The slag is collected in a specially designed chamber beneath the gasifier. A scanning electron microscope (SEM) was used to evaluate surface morphology of the samples. Elemental analysis of the sewage sludge slag was performed using the energy-dispersive spectroscopy (EDS) method, which showed different solid-state elements contained in the porous structure of the solid phase: carbon 29%, aluminum 26%, potassium 20%, chlorine 1%, and others. The specific surface area of the sewage sludge slag is 6.15 m(2)/g as the BET analysis shows. In order to use the slag as a secondary raw material, detailed analysis of the structure and properties is necessary for a decision on whether the slag left after gasification of sewage sludge is suitable for any further usages. Initial results indicate that the slag may be used for production of electrodes for supercapacitors. IMPLICATIONS: Every year thousands of tons of sewage sludge are formed in Lithuania. Sewage sludge consists of organic and inorganic compounds. Partial combustion, plasma decomposition, and other methods are used to neutralize the sewage sludge. The incineration of sewage sludge results in generation of solid-phase slag. In this paper the material structure and composition of a solid slag (formed during neutralization of sewage sludge) is considered. Also, the impact the ambient temperature on structure and composition of solid slag is analyzed. PMID- 26110541 TI - Synthesis and optical power limiting properties of heteroleptic Mo3S7 clusters. AB - Substitution of the halide ligands in (Bu4N)2[Mo3S7X6] (X = Cl, Br) by diimine ligands, such as 4,4'-dimethyl-2,2'-bipyridine (dmbpy), 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen), affords the neutral heteroleptic clusters Mo3S7Cl4(dmbpy) (), Mo3S7Br4(dmbpy) (), Mo3S7Br4(bpy) (), and Mo3S7Br4(phen) (). Further substitution of the halide ligands in Mo3S7Br4(diimine) clusters by dmit (1,3-dithiole-2-thione-4,5-dithiolate) allows the preparation of the mixed diimine-dithiolene neutral cluster complexes Mo3S7(dnbpy)(dmit)2 (, dnbpy = 4,4' dinonyl-2,2'-bipyridine), Mo3S7(dcmbpy)(dmit)2 (, dcmbpy = 4,4'-dimethoxycarbonyl 2,2'-bipyridine), and Mo3S7(dcbpy)(dmit)2 (, dcbpy = 2,2'-bipyridine-4,4' dicarboxylic acid). The optical limiting properties of complexes have been assessed by the open-aperture Z-scan technique at 570 nm, employing a nanosecond optical parametric oscillator. In order to investigate the effect of increasing the pi-system, complexes , with the general formula Mo3S7X4(diimine), (X = Cl, Br), were compared to clusters , containing the dmit ligand. The influence of the metal content on the optical power limiting properties was also investigated by comparing the trinuclear series of complexes prepared herein with the bis(dithiolene) dinuclear cluster (Et4N)2[Mo2O2S2(BPyDTS2)2], which has been recently prepared by our group. All trinuclear clusters are efficient optical limiters (sigmaeff > sigma0) with the threshold limiting fluence F15% decreasing on proceeding from dinuclear to trinuclear clusters and, generally, on extending the pi-system. PMID- 26110542 TI - Illness Perceptions and Health Behaviors of Black Women. AB - The Common Sense Model of Illness Representations proposes that representations or perceptions of illness drive health behaviors. The purpose of this study was to explore the relationships between hypertension representations, exercise, and dietary behaviors in hypertensive black women (N = 204, aged 18-65 years). Regression results revealed that perceiving hypertension as chronic and perceiving it a result of environmental causes were inversely related to moderate intensity physical activity (beta = -.15 [P = .05] and beta = -.25 [P = .05], respectively). Having more emotional responses to hypertension (beta = .23, P = .05) was related to moderate-intensity physical activity and more fruit and vegetable consumption (beta = .28, P = .05). These findings suggest that hypertension representations can interfere with recommended lifestyle changes among black women. Assessing hypertension representations and implementing measures to clarify misperceptions of hypertension among black women may lead to better blood pressure control and health outcomes. PMID- 26110543 TI - Patients' Decision Making About Undergoing Transcatheter Aortic Valve Implantation for Severe Aortic Stenosis. AB - BACKGROUND: Aortic stenosis is the most common valve disease in Western countries, and its prevalence is increasing because of the aging population. Some patients, denied surgery because of high risk, can be offered transcatheter aortic valve implantation (TAVI). These patients are old and have comorbidities, and it is not always easy for them to make the decision about accepting TAVI. OBJECTIVE: The aim of this study was to describe the decision-making process about undergoing TAVI treatment among people with severe aortic stenosis who are denied surgery. METHODS: The Swedish participants (n = 24) with a mean age of 80 years who had been offered TAVI all agreed to participate in a presurgical interview. The interviews were recorded, transcribed verbatim, and analyzed using qualitative content analysis. RESULTS: Three patterns in the decision-making process about TAVI treatment-ambivalent, obedient, and reconciled-were identified. The ambivalent patient is unsure of the value of treatment and aware of the risks; the obedient patient is unsure of the value of one's own decision and wants to leave the decision to others; the reconciled patient has reached a point where there is no choice anymore and is always sure that the decision to undergo TAVI is right. CONCLUSIONS: People with aortic stenosis who are offered TAVI need to discuss the risks and benefits in order to participate in decision making about the treatment. They have different patterns in decision making and would benefit from healthcare professionals being observant of them to support them in this process in a manner consistent with their values. PMID- 26110544 TI - Association of Disease Activity with Serum and Tear IL-2 Levels in Behcet Disease. AB - PURPOSE: To investigate the association of Behcet disease activity with serum and tear interleukin-2 levels. METHODS: The study was designed as a prospective case control study. The study population consisted of 45 patients with Behcet disease and 24 age and sex-matched healthy participants. Behcet disease patients were classified as active (24 patients) or inactive (21 patients) according to disease activity. Serum and tear interleukin-2 levels were determined using the enzyme linked immunosorbent assay method. RESULTS: The mean serum and tear interleukin-2 levels of the active disease, inactive disease, and control groups were 17.04 +/- 5.02 and 32.61 +/- 16.53 pg/mL; 15.20 +/- 4.68 and 29.61 +/- 8.30 pg/mL; and 14.22 +/- 4.18 and 28.89 +/- 8.73 pg/mL, respectively. There was no statistically significant difference between the groups with respect to all measured data. CONCLUSIONS: There was no significant difference in serum or tear IL-2 levels between Behcet patients and controls; there was no association of disease activity with serum and tear IL-2 levels. PMID- 26110545 TI - Pupillometry reveals increased pupil size during indirect request comprehension. AB - Fluctuations in pupil size have been shown to reflect variations in processing demands during lexical and syntactic processing in language comprehension. An issue that has not received attention is whether pupil size also varies due to pragmatic manipulations. In two pupillometry experiments, we investigated whether pupil diameter was sensitive to increased processing demands as a result of comprehending an indirect request versus a direct statement. Adult participants were presented with 120 picture-sentence combinations that could be interpreted either as an indirect request (a picture of a window with the sentence "it's very hot here") or as a statement (a picture of a window with the sentence "it's very nice here"). Based on the hypothesis that understanding indirect utterances requires additional inferences to be made on the part of the listener, we predicted a larger pupil diameter for indirect requests than statements. The results of both experiments are consistent with this expectation. We suggest that the increase in pupil size reflects additional processing demands for the comprehension of indirect requests as compared to statements. This research demonstrates the usefulness of pupillometry as a tool for experimental research in pragmatics. PMID- 26110546 TI - Lumbar Traction for Managing Low Back Pain: A Survey of Physical Therapists in the United States. AB - STUDY DESIGN: Cross-sectional survey. OBJECTIVES: To examine how many physical therapists use traction, the patients for whom traction is used, the preferred delivery modes/parameters of traction, the supplemental interventions used with traction, and whether professional characteristics influence traction usage. BACKGROUND: Several systematic reviews and clinical guidelines have questioned the effectiveness of traction for managing low back pain, yet some patients may benefit from lumbar traction. While traction usage among physical therapists in other countries has been described, usage among physical therapists in the United States has not been examined. METHODS: We surveyed a random sample of 4000 Orthopaedic Section members of the American Physical Therapy Association. Associations among respondents' professional characteristics and survey responses were explored with chi-square analyses (alpha = .05). RESULTS: The response rate was 25.5% (n = 1001), and 76.6% (n = 767) of respondents reported using traction. Most (58.4%) of the respondents used traction for patients with signs of nerve root compression, though many (31.4%) did not. Common delivery modes included manual methods (68.3%) and mechanical tables (44.9%), most often supplemental to other interventions (eg, stabilization exercises, postural education). Levels of professional preparation (doctoral/masters level versus bachelors/certificate level) were associated with many variables, as was attainment of an orthopaedic specialist certification. CONCLUSION: Most of the orthopaedic physical therapists in the United States who responded to our survey reported that they used lumbar traction, though not necessarily consistent with proposed criteria that identify patients most likely to benefit from traction. They used various traction delivery modes/parameters and used traction within comprehensive plans of care incorporating multiple interventions. Professional characteristics (education levels and clinical specialist credentialing) were associated with traction usage. PMID- 26110547 TI - Atrophy of the Quadriceps Is Not Isolated to the Vastus Medialis Oblique in Individuals With Patellofemoral Pain. AB - STUDY DESIGN: Cross-sectional. Objectives To determine if quadriceps atrophy was present in people with patellofemoral pain (PFP), and whether the vastus medialis oblique (VMO) was selectively involved. BACKGROUND: Despite the lack of research investigating individual quadriceps muscle size in individuals with PFP, it has been suggested that selective atrophy of the VMO relative to the vastus lateralis could be associated with PFP. METHODS: The quadriceps muscle sizes of 35 participants with PFP (22 with unilateral and 13 with bilateral symptoms) and 35 asymptomatic control participants matched for age and sex were measured using real-time ultrasound. The thicknesses of the VMO, vastus lateralis, vastus medialis, rectus femoris, and vastus intermedius were measured. Paired-samples t tests were used to compare muscle thickness between limbs in those with unilateral PFP, and independent t tests were used to compare muscle thickness between groups with and without PFP. Results In those with unilateral PFP, the thickness of all portions of the quadriceps muscle was statistically smaller in the symptomatic compared to the asymptomatic limb: VMO (P = .038), vastus medialis (P<.001), vastus lateralis (P = .005), vastus intermedius (P = .013), and rectus femoris (P = .045). No difference was found in thickness of any of the portions of the quadriceps on the affected side of people with PFP compared to asymptomatic controls: VMO (P = .148), vastus medialis (P = .474), vastus lateralis (P = .122), vastus intermedius (P = .466), and rectus femoris (P = .508). CONCLUSION: Atrophy of all portions of the quadriceps muscles is present in the affected limb of people with unilateral PFP. There was no atrophy of the quadriceps in individuals with PFP compared to those without pathology. Selective atrophy of the VMO relative to the vastus lateralis was not identified in people with PFP. PMID- 26110548 TI - Responsiveness and Minimal Clinically Important Change: A Comparison Between 2 Shoulder Outcome Measures. AB - Study Design A prospective cohort study nested in a randomized controlled trial. Objectives To determine and compare responsiveness and minimal clinically important change of the modified Constant score (CS) and the Oxford Shoulder Score (OSS). Background The OSS and the CS are commonly used to assess shoulder outcomes. However, few studies have evaluated the measurement properties of the OSS and CS in terms of responsiveness and minimal clinically important change. Methods The study included 126 patients who reported having difficulty returning to usual activities 8 to 12 weeks after arthroscopic decompression surgery for subacromial impingement syndrome. The assessment at baseline and at 3 months included the OSS, the CS, and the European Quality of Life-5 Dimensions-3 Level (EQ-5D-3L) index. Responsiveness was assessed as follows: by correlation analysis between the change scores of the OSS, CS, and EQ-5D-3L index, and the Patient Global Impression of Change (PGIC) scale; by receiver-operating-characteristic (ROC) curve analysis using the PGIC scale as an external anchor; and by effect size statistics. Results At 3 months, a follow-up assessment of 112 patients (89%) was conducted. The change scores of the CS and the OSS were more strongly correlated with the external anchor (PGIC scale) than the change score of the EQ 5D-3L index. The areas under the ROC curves exceeded 0.80 for both shoulder scores, with no significant differences between them, and comparable effect-size estimates were observed for the CS and the OSS. Minimal clinically important change ROC values were 6 points for the OSS and 11 points for the CS, with upper 95% cutoff limits of 12 and 22 points, respectively. Conclusion The CS and the OSS were both suitable for assessing improvement after decompression surgery. PMID- 26110549 TI - Baseline Examination Factors Associated With Clinical Improvement After Dry Needling in Individuals With Low Back Pain. AB - STUDY DESIGN: Quasi-experimental. OBJECTIVES: To explore for associations between demographic, patient history, and physical examination variables and short-term improvement in self-reported disability following dry needling therapy performed on individuals with low back pain (LBP). BACKGROUND: Dry needling is an intervention used with increasing frequency in patients with LBP; however, the characteristics of patients who are most likely to respond are not known. METHODS: Seventy-two volunteers with mechanical LBP participated in the study. Potential prognostic factors were collected from baseline questionnaires, patient history, and physical examination tests. Treatment consisted of dry needling to the lumbar multifidus muscles bilaterally, administered during a single treatment session. Improvement was based on percent change on the Oswestry Disability Index at 1 week. The univariate and multivariate associations between 33 potential prognostic factors and improved disability were assessed with correlation coefficients and multivariate linear regression. RESULTS: Increased LBP with the multifidus lift test (rpb = 0.31, P = .01) or during passive hip flexion performed with the patient supine (rpb = 0.23, P = .06), as well as positive beliefs about acupuncture/dry needling (rho = 0.22, P = .07), demonstrated univariate associations with Oswestry Disability Index improvement. Aggravation of LBP with standing (rpb = -0.27, P = .03), presence of leg pain (rpb = -0.29, P = .02), and any perception of hypermobility in the lumbar spine (rpb = -0.21, P = .09) were associated with less improvement. The multivariate model identified 2 predictors of improved disability with dry needling: pain with the multifidus lift test and no aggravation with standing (R(2) = 0.16, P = .01). CONCLUSION: Increased LBP with the multifidus lift test was the strongest predictor of improved disability after dry needling, suggesting that the finding of pain during muscle contraction should be studied in future dry needling studies. LEVEL OF EVIDENCE: Prognosis, level 1b. PMID- 26110550 TI - Small molecule drugs with immunomodulatory effects in cancer. AB - Immunotherapy shows promise for positively changing the landscape of the management of many advanced solid tumors, including gastrointestinal (GI) malignancies. Many of these developments have been focused on vaccine-based, monoclonal antibody therapies and more recently, checkpoint inhibitors, although many small molecule inhibitors can function as immunomodulators. Small molecule compounds have several advantages over conventional immunotherapeutic agents including: ease of production and the potential for oral administration. There is a potential niche for small molecule immunomodulators to enhance the efficacy of existing immunotherapeutic and cytotoxic agents. This article focuses on two categories of small molecule compounds with immunomodulatory effects: IDO and MEK inhibitors. Indoleamine -2, 3- dioxygenase (IDO) is known for its effects in tumor immunity. IDO inhibitors are generally well-tolerated and have the potential to enhance anti-tumor responses when combined with checkpoint inhibitors. MEK inhibitors affect signal transduction of the RAS-RAF-MEK pathway and numerous MEK inhibitors are currently being investigated in solid tumors. Small molecule immunomodulators are currently being investigated for their potential role in augmenting the effects of conventional immunotherapeutic agents although further research is required to identify those patients most likely to respond to combination therapy. PMID- 26110551 TI - Cognitive bias modification as a strategy to reduce children's fears and concerns about the secondary school transition. AB - BACKGROUND AND OBJECTIVES: Cognitive Bias Modification of Interpretations (CBM-I) has emerged as an anxiety-reducing tool for children and adolescents, targeting maladaptive interpretations of everyday situations. This literature falls short of addressing whether the effects of CBM-I extend to worries about a real-life stressor, such as a school transition. DESIGN: The study comprised a between groups design comparing the effects of CBM-I to an active control (AC) intervention in children. METHOD: We recruited 38 children within two months of their primary-secondary school transition and investigated the capacity for multi session, parent-administered CBM-I, compared to an AC condition, to modify cognitive style and reduce anxiety symptoms and school concerns. RESULTS: While benign interpretations increased significantly and negative interpretations tended to decrease following CBM-I, both interventions significantly reduced anxiety symptoms and school concerns. CONCLUSIONS: These findings indicate that anxiety-reducing effects of CBM-I in children extend to a real life stressful event, but that equivalent anxiety reduction may be achieved through exposure to potentially worrying situations and parent-child interaction in the absence of bias modification. PMID- 26110553 TI - Micelles Based on Acid Degradable Poly(acetal urethane): Preparation, pH Sensitivity, and Triggered Intracellular Drug Release. AB - Polyurethanes are a unique class of biomaterials that are widely used in medical devices. In spite of their easy synthesis and excellent biocompatibility, polyurethanes are less explored for controlled drug delivery due to their slow or lack of degradation. In this paper, we report the design and development of novel acid degradable poly(acetal urethane) (PAU) and corresponding triblock copolymer micelles for pH-triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX). PAU with Mn ranging from 4.3 to 12.3 kg/mol was conveniently prepared from polycondensation reaction of lysine diisocyanate (LDI) and a novel diacetal-containing diol, terephthalilidene-bis(trimethylolethane) (TPABTME) using dibutyltin dilaurate (DBTDL) as a catalyst in N,N dimethylformamide (DMF). The thiol-ene click reaction of Allyl-PAU-Allyl with thiolated PEG (Mn = 5.0 kg/mol) afforded PEG-PAU-PEG triblock copolymers that readily formed micelles with average sizes of about 90-120 nm in water. The dynamic light scattering (DLS) measurements revealed fast swelling and disruption of micelles under acidic pH. UV/vis spectroscopy corroborated that acetal degradation was accelerated at pH 4.0 and 5.0. The in vitro release studies showed that doxorubicin (DOX) was released in a controlled and pH-dependent manner, in which ca. 96%, 73%, and 30% of drug was released within 48 h at pH 4.0, 5.0, and 7.4, respectively. Notably, MTT assays displayed that DOX-loaded PEG-PAU-PEG micelles had a high in vitro antitumor activity in both RAW 264.7 and drug-resistant MCF-7/ADR cells. The confocal microscopy and flow cytometry experiments demonstrated that PEG-PAU-PEG micelles mediated efficient cytoplasmic delivery of DOX. Importantly, blank PEG-PAU-PEG micelles were shown to be nontoxic to RAW 264.7 and MCF-7/ADR cells even at a high concentration of 1.5 mg/mL. Hence, micelles based on poly(acetal urethane) have appeared as a new class of biocompatible and acid-degradable nanocarriers for efficient intracellular drug delivery. PMID- 26110554 TI - Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance. AB - Many genetic alterations, including predisposing or somatic mutations, may contribute toward the development of melanoma. Although CDKN2A and CDK4 are high penetrance genes for melanoma, MC1R is a low-penetrance gene that has been associated most consistently with the disease. Moreover, BRAF is the most frequently somatically altered oncogene and is a validated therapeutic target in melanoma. This paper reports a case of multiple primary melanoma with germline CDK4 mutation, MC1R variant, and somatic BRAF mutation in nine out of 10 melanomas, indicating that a common pathogenesis, because of a predisposing genetic background, may be shared among distinct subsequent melanomas of probable clonal origin. After 3 months of targeted therapy with BRAF inhibitor, our patient developed resistance with rapid progression of the disease leading to death. This is the first case in which early resistance to BRAF inhibitor has been reported in a patient with CDK4 germline mutation. PMID- 26110555 TI - Repeated isolated limb perfusion in melanoma patients with recurrent in-transit metastases. AB - In-transit metastases of melanoma occur in 5-8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor-alpha and melphalan based isolated limb perfusion (TM-ILP) had proven to yield excellent local control. Here, we report on repeat TM-ILP for locoregional recurrence after isolated limb perfusion. Between 1991 and 2013, 37 consecutive repeat TM-ILPs were analyzed in 32 different patients. Three patients underwent a third TM-ILP. During a median follow-up of 20 months after repeat TM-ILP, the overall response rate was 86%. Complete response (CR) was recorded after 24 TM-ILPs (65%). CR after first TM-ILP was a strong predictor for successful repeat TM-ILP in terms of clinical response and local recurrence. Local toxicity was mild (70% Wieberdink I-II). The local recurrence rate was 59%. Five-year overall survival was 35%. Repeat TM-ILP is a safe treatment modality in melanoma patients with recurrent in-transit metastases of melanoma. Those with a CR after first TM-ILP benefit the most from repeat TM-ILP. PMID- 26110556 TI - Mechanism of Inactivation of GABA Aminotransferase by (E)- and (Z)-(1S,3S)-3 Amino-4-fluoromethylenyl-1-cyclopentanoic Acid. AB - When gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, falls below a threshold level, seizures occur. One approach to raise GABA concentrations is to inhibit GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate-dependent enzyme that degrades GABA. We have previously developed (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115), which is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved inactivator of GABA-AT. We also developed (E)- and (Z)-(1S,3S)-3-amino-4-fluoromethylenyl-1-cyclopentanoic acid (1 and 2, respectively), monofluorinated analogs of CPP-115, which are comparable to vigabatrin in inactivating GABA-AT. Here, we report the mechanism of inactivation of GABA-AT by 1 and 2. Both produce a metabolite that induces disruption of the Glu270-Arg445 salt bridge to accommodate interaction between the metabolite formyl group and Arg445. This is the second time that Arg445 has interacted with a ligand and is involved in GABA-AT inactivation, thereby confirming the importance of Arg445 in future inactivator design. PMID- 26110557 TI - The Natural Surfactant Glycerol Monolaurate Significantly Reduces Development of Staphylococcus aureus and Enterococcus faecalis Biofilms. AB - BACKGROUND: Bacterial biofilms are involved in a large proportion of clinical infections, including device-related infections. Unfortunately, biofilm associated bacteria are typically less susceptible to antibiotics, and infected devices must often be removed. On the basis of a recent observation that lipid rich biofilm matrix material is present in early biofilm formation and may protect a population of bacteria from interacting with ordinarily diffusible small molecules, we hypothesized that surfactants may be useful in preventing biofilm development. METHODS: Experimental Staphylococcus aureus or Enterococcus faecalis biofilms were cultivated on surgical suture suspended in a growth medium supplemented with the natural surfactant glycerol monolaurate (GML) or with a component molecule, lauric acid. After 16 h incubation, the numbers of viable biofilm-associated bacteria were measured by standard microbiologic techniques and biofilm biomass was measured using the colorimetric crystal violet assay. RESULTS: Both GML and lauric acid were effective in inhibiting biofilm development as measured by decreased numbers of viable biofilm-associated bacteria as well as decreased biofilm biomass. Compared with lauric acid on a molar basis, GML represented a more effective inhibitor of biofilms formed by either S. aureus or E. faecalis. CONCLUSIONS: Because the natural surfactant GML inhibited biofilm development, resulting data were consistent with the hypothesis that lipids may play an important role in biofilm growth, implying that interfering with lipid formation may help control development of clinically relevant biofilms. PMID- 26110558 TI - Correlating droplet size with temperature changes in electrospray source by optical methods. AB - We investigated how the temperature and size of charged droplets are affected by the electrospray ionization (ESI) process, using in situ measurements involving laser-induced fluorescence and Mie scattering on a thermal gradient focusing ESI source. Rhodamine dyes were employed as temperature indicators using ratiometric intensity-based fluorescence techniques. The results were compared to lifetime based techniques using tris(2,2'-bipyridyl)dichlororuthenium(II) hexahydrate, [Ru(bpy)3](2+). Both methods gave similar profiles. Nevertheless, the precision and sensitivity were higher for lifetime-based techniques in comparison to intensity-based techniques. Global warming (with DeltaT ~10 K) of the ESI plume is reported while the size of the droplet decreases along the plume. The global warming indicates that the conductive thermal transfer (between the superheated sheath gas and the solvent) is predominant and stronger than the cooling effect due to the evaporation of the droplets, and this outcome is effectively reproduced by a diffusion-controlled evaporation model. Thermal gradient focusing ESI sources therefore appear to be efficient sources for evaporating large amounts of solvent, along with an increase in temperature. PMID- 26110560 TI - Oligodendroglial markers in the cuprizone model of CNS de- and remyelination. AB - Oligodendrocytes are the myelinating cells of the central nervous system. Since many studies of demyelinating diseases focus their research on this cell type, there is growing interest for obtaining reliable markers that can specifically recognize oligodendroglia. Established markers are the myelin-associated neurite outgrowth inhibitor (NogoA), the transcription factor Olig2, and the antibody CC 1, the latter being directed against the protein adenomatous polyposis coli (APC). Unfortunately, it has been discussed whether APC and Olig2 could recognize astrocytes under pathological conditions as well. Hence, we performed immunohistochemical studies using the oligodendroglial markers NogoA, APC, and Olig2 in a murine model of cuprizone induced demyelination. We have found that APC co-localizes with NogoA and does not co-localize with the astrocytic marker GFAP. Olig2 shows co-localization with APC but there is also a small population of Olig2/GFAP double positive cells. Some Olig2/GFAP double positive cells are found in the corpus callosum in a narrow time window in which oligodendrocyte precursor cells proliferate in this model. In other brain regions including the cerebral cortex and hippocampus and in all regions in untreated control mice double positive Olig2/GFAP cells do not occur. In conclusion, our results underline that APC and NogoA are reliable markers for detection of mature oligodendrocytes. Olig2 is a suitable marker to stain cells of oligodendroglial origin but could be combined with GFAP to exclude the GFAP positive population of cells from the quantification of oligodendroglia. PMID- 26110559 TI - Unfolding Kinetics of the Human Telomere i-Motif Under a 10 pN Force Imposed by the alpha-Hemolysin Nanopore Identify Transient Folded-State Lifetimes at Physiological pH. AB - Cytosine (C)-rich DNA can adopt i-motif folds under acidic conditions, with the human telomere i-motif providing a well-studied example. The dimensions of this i motif are appropriate for capture in the nanocavity of the alpha-hemolysin (alpha HL) protein pore under an electrophoretic force. Interrogation of the current vs time (i-t) traces when the i-motif interacts with alpha-HL identified characteristic signals that were pH dependent. These features were evaluated from pH 5.0 to 7.2, a region surrounding the transition pH of the i-motif (6.1). When the i-motif without polynucleotide tails was studied at pH 5.0, the folded structure entered the nanocavity of alpha-HL from either the top or bottom face to yield characteristic current patterns. Addition of a 5' 25-mer poly-2' deoxyadensosine tail allowed capture of the i-motif from the unfolded terminus, and this was used to analyze the pH dependency of unfolding. At pH values below the transition point, only folded strands were observed, and when the pH was increased above the transition pH, the number of folded events decreased, while the unfolded events increased. At pH 6.8 and 7.2 4% and 2% of the strands were still folded, respectively. The lifetimes for the folded states at pH 6.8 and 7.2 were 21 and 9 ms, respectively, at 160 mV electrophoretic force. These lifetimes are sufficiently long to affect enzymes operating on DNA. Furthermore, these transient lifetimes are readily obtained using the alpha-HL nanopore, a feature that is not easily achievable by other methods. PMID- 26110561 TI - Association Between Obstructive Sleep Apnea and Spontaneous Cerebrospinal Fluid Leaks: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Spontaneous cerebrospinal fluid (CSF) leaks are a morbid condition associated with operative intervention for treatment. Understanding associations are key to diagnosis, treatment, and possible early detection. OBJECTIVE: To determine the clinical association and odds of having obstructive sleep apnea (OSA) and spontaneous CSF leaks. DATA SOURCES: A comprehensive search of the literature was conducted using PubMed (MEDLINE), Cochrane Library, and relevant article bibliographies. STUDY SELECTION: Systematic review and meta-analysis of studies from 2005 to 2015 investigating spontaneous CSF leaks in patients with OSA. The CSF leaks were considered spontaneous when they occurred in the absence of trauma, surgery, infection, and neoplasm. Included studies provided the number of patients diagnosed as having OSA and spontaneous CSF leaks. DATA EXTRACTION AND SYNTHESIS: Two independent investigators reviewed all studies for inclusion. The numbers of patients with OSA were systematically extracted from each study. Studies that compared the prevalence of OSA with spontaneous CSF leaks against their control cohort were pooled in the meta-analysis using a random-effects model. MAIN OUTCOME AND MEASURE: To determine whether there was increased incidence of OSA in patients with spontaneous CSF leaks. This hypothesis was formulated prior to data collection. RESULTS: The search criteria yielded 384 abstracts, and 6 clinical studies involving OSA and CSF leaks met the inclusion and exclusion criteria. They were all retrospective in nature and included 3 comparative (case-control) studies, 2 case series, and 1 case report. The cumulative reported prevalence of having OSA and spontaneous CSF leaks is 16.9% (232 of 1376 patients). Three of the studies were eligible for the meta-analysis. The odds of having OSA with a spontaneous CSF leak were 4.73 times more likely than in control cohorts (95% CI, 1.56-14.31; P = .006; I2 = 35%). In a subgroup analysis of studies including nonspontaneous CSF leaks as their control cohort, the odds of having OSA with a spontaneous CSF leak were 2.85 times more likely than OSA with a nonspontaneous CSF leak (95% CI, 1.22-6.63; P = .02; I2 = 0%). There was a notable difference in the age, BMI, or patients with hypertension in the comparative studies. CONCLUSIONS AND RELEVANCE: The association between OSA and spontaneous CSF leaks as demonstrated by retrospective studies is confounded by heterogeneous patient characteristics. Large prospective controlled studies using polysomnography and elevated intracranial pressure measurements are required to further evaluate the relationship between OSA and spontaneous CSF leaks. PMID- 26110563 TI - Increased Incidence of Spinal Abscess and Substance Abuse after Implementation of State Mandated Prescription Drug Legislation. AB - OBJECTIVES: To investigate the incidence of spinal abscess and substance abuse in a tertiary care hospital after state legislation titled "House Bill 1" (HB1) mandated stricter regulation of prescription drugs of abuse in Kentucky in 2012. DESIGN: A retrospective case series study design was used to review the incidence of spinal abscess and drug abuse diagnoses admissions from 2010 to 2014. Variances in the incidence of spinal abscess and substance abuse were plotted across this time frame. RESULTS: The incidence of intraspinal abscess increased 1.56-fold in 2011 (n = 26) and 2012 (n = 25) relative to 2010 (n = 16). However, in 2013, the year following implementation of HB1 legislation, the incidence of intraspinal abscess increased 2.38-fold (n = 38) and then 4.19-fold (n = 67) in 2014. The incidence of intraspinal abscess in subjects with drug abuse diagnosis remained constant between 2010 (n = 3) and 2012 (n = 3). However, it increased twofold (n = 7) in 2013 and then ninefold (n = 27) in 2014. A correlation coefficient (rSAD ) of 0.775 revealed a strong association between the increase incidence of intraspinal abscess and diagnosis of drug abuse. CONCLUSIONS: The results of this retrospective study demonstrate an increased incidence of intraspinal abscess associated with drug abuse after passage of HB1 legislation regulating prescriptions of controlled medications in Kentucky. This increased incidence may be related to individuals relying on nonprescription drugs of abuse due to more highly regulated access to controlled prescription medications. However, additional factors unrelated to HB1 legislation must be taken into account. PMID- 26110564 TI - Under-water unidirectional air penetration via a Janus mesh. AB - Under-water and unidirectional air penetration, viz. air "diode", was effectively achieved on the basis of a composite mesh with Janus wettability. In the aqueous solution, the air bubbles can only pass through the mesh from the hydrophilic side to the superhydrophobic side, whereas they will be blocked from the opposite direction. PMID- 26110565 TI - Rebuttal From Drs Tanner and Silvestri. PMID- 26110566 TI - AGPAT9 suppresses cell growth, invasion and metastasis by counteracting acidic tumor microenvironment through KLF4/LASS2/V-ATPase signaling pathway in breast cancer. AB - Human 1-acylglycerol-3-phosphate O-acyltransferase 9 (AGPAT9) is the gene identified from adipose tissue in 2007. We found AGPAT9 expression was significantly higher in poorly invasive MCF7 human breast cancer cells than the highly invasive MDA-MB-231 cells. AGPAT9 significantly inhibited the proliferation of breast cancer cells in vitro and in vivo. Live-cell imaging and transwell assays showed that AGPAT9 could significantly inhibit the migration and invasive capacities of breast cancer cells. The inhibitory effect of AGPAT9 on metastasis was also observed in vivo in lung metastasis model. AGPAT9 inhibited breast cancer cell proliferation, migration and invasion through, at least in part, suppressing the V-ATPase activity. In addition, increased AGPAT9 expression in MCF-7/ADR cells could increase the chemosensitivity to doxorubicin (Dox). Our findings suggest that increasing AGPAT9 expression may be a new approach that can be used for breast cancer treatment. PMID- 26110567 TI - By inhibiting snail signaling and miR-23a-3p, osthole suppresses the EMT-mediated metastatic ability in prostate cancer. AB - Here we showed that Osthole, 7-methoxy-8-(3-methyl-2-butenyl) coumarin, a bioactive coumarin derivative extracted from medicinal plants, inhibited migration, invasion, epithelial to mesenchymal transition (EMT) in androgen independent prostate cancer (AIPC) cells in vitro and metastasis of AIPC in vivo. In patients, high Snail levels were correlated with a higher histological Gleason sum and poor survival rates. Osthole inhibited the TGF-beta/Akt/MAPK pathways, reduced Snail-DNA-binding activity and induced E-cadherin. We found that osthole decreased miR-23a-3p. Ectopic miR-23a-3p suppressed E-cadherin 3' untranslated region reporter activity and E-cadherin expression, and relieved the motility suppression caused by osthole treatment. PMID- 26110568 TI - Bcl-2high mantle cell lymphoma cells are sensitized to acadesine with ABT-199. AB - Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl 2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2high MCL cells to acadesine. This effect was validated in vivo, where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients. PMID- 26110569 TI - Overexpressed tryptophanyl-tRNA synthetase, an angiostatic protein, enhances oral cancer cell invasiveness. AB - Oral squamous cell carcinoma (OSCC) is one of the most common neoplasms worldwide. Previously, we identified the angiostatic agent tryptophanyl-tRNA synthetase (TrpRS) as a dysregulated protein in OSCC based on a proteomics approach. Herein, we show that TrpRS is overexpressed in OSCC tissues (139/146, 95.2%) compared with adjacent normal tissues and that TrpRS expression positively correlates with tumor stage, overall TNM stage, perineural invasion and tumor depth. Importantly, the TrpRS levels were significantly higher in tumor cells from metastatic lymph nodes than in corresponding primary tumor cells. TrpRS knockdown or treatment with conditioned media obtained from TrpRS-knockdown cells significantly reduced oral cancer cell viability and invasiveness. TrpRS overexpression promoted cell migration and invasion. In addition, the extracellular addition of TrpRS rescued the invasion ability of TrpRS-knockdown cells. Subcellular fractionation and immunofluorescence staining further revealed that TrpRS was distributed on the cell surface, suggesting that secreted TrpRS promotes OSCC progression via an extrinsic pathway. Collectively, our results demonstrated the clinical significance and a novel role of TrpRS in OSCC. PMID- 26110570 TI - Predominant Rab-GTPase amplicons contributing to oral squamous cell carcinoma progression to metastasis. AB - Metastatic oral squamous cell carcinoma (OSCC) is frequently associated with recurrent gene abnormalities at specific chromosomal loci. Here, we utilized array comparative genomic hybridization and genome-wide screening of metastatic and non-metastatic tongue tumors to investigate genes potentially contributing to OSCC progression to metastasis. We identified predominant amplifications of chromosomal regions that encompass the RAB5, RAB7 and RAB11 genes (3p24-p22, 3q21.3 and 8p11-12, respectively) in metastatic OSCC. The expression of these Rab GTPases was confirmed by immunohistochemistry in OSCC tissues from a cohort of patients with a follow-up of 10 years. A significant overexpression of Rab5, Rab7 and Rab11 was observed in advanced OSCC cases and co-overexpression of these Rabs was predictive of poor survival (log-rank test, P = 0.006). We generated a Rab interaction network and identified central Rab interactions of relevance to metastasis signaling, including focal adhesion proteins. In preclinical models, mRNA and protein expression levels of these Rab members were elevated in a panel of invasive OSCC cell lines, and their down-regulation prevented cell invasion at least in part via inhibition of focal adhesion disassembly. In summary, our results provide insights into the cooperative role of Rab gene amplifications in OSCC progression and support their potential utility as prognostic markers and therapeutic approach for advanced OSCC. PMID- 26110571 TI - Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD L1. AB - The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD L1 (>=2+/>=5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses. PMID- 26110573 TI - The Microbiome and Cancer: Implications for Oncology Nursing Science. AB - BACKGROUND: Approximately 1.6 million Americans were diagnosed with cancer in 2014. To combat their disease, many individuals received either curative or palliative treatments that produced undesired symptoms. These symptoms, which often cause significant distress for individuals coping with cancer, may share biologic underpinnings such as epigenetic changes and immune dysregulation. Alterations in the normal flora of the gut may also influence cancer symptoms. OBJECTIVE: The aim of this review is to describe the emerging role for the gut microbiome in cancer research, especially the potential relationship between the gut microbiome and cancer symptoms. METHODS: Extant literature was reviewed and synthesized. RESULTS: The majority of studies linking the gut microbiota and cancer are animal models and focus on the relationship between dysbiosis and colorectal cancer. Emerging evidence supports that the "gut-brain" connection is a plausible mechanism for "psychoneurological" cancer symptoms such as depression, pain, and fatigue. CONCLUSIONS: There is compelling evidence that the gut microbiota affects cancer via several mechanisms, including microbial diversity and number, metabolism, and/or immune initiation. However, more research is necessary to elucidate these mechanisms, particularly among a variety of cancers and cancer-related symptoms. IMPLICATIONS FOR PRACTICE: A better understanding of the role of the gut microbiota in cancer symptoms may lead to the development of targeted individualized interventions affecting the gut microbiota that prevent or ameliorate dysbiosis, thereby reducing symptoms. These interventions may emphasize self-care management strategies essential for wellness, such as diet, nutrition, and stress reduction. PMID- 26110572 TI - Gene expression profiling signatures for the diagnosis and prevention of oral cavity carcinogenesis-genome-wide analysis using RNA-seq technology. AB - We compared the changes in global gene expression between an early stage (the termination of the carcinogen treatment and prior to the appearance of frank tumors) and a late stage (frank squamous cell carcinoma (SCC)) of tongue carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide (4-NQO) in a mouse model of human oral cavity and esophageal squamous cell carcinoma. Gene ontology and pathway analyses show that increases in "cell cycle progression" and "degradation of basement membrane and ECM pathways" are early events during SCC carcinogenesis and that changes in these pathways are even greater in the actual tumors. Myc, NFkappaB complex (NFKB1/RELA), and FOS transcription networks are the major transcriptional networks induced in early stage tongue carcinogenesis. Decreases in metabolism pathways, such as in "tricarboxylic acid cycle" and "oxidative phosphorylation", occurred only in the squamous cell carcinomas and not in the early stages of carcinogenesis. We detected increases in ALDH1A3, PTGS2, and KRT1 transcripts in both the early and late stages of carcinogenesis. The identification of the transcripts and pathways that change at an early stage of carcinogenesis provides potentially useful information for early diagnosis and for prevention strategies for human tongue squamous cell carcinomas. PMID- 26110574 TI - Womb Outsourcing: Commercial Surrogacy in India. AB - Infertility affects more than 7 million American couples. As traditional treatments fail and the costs of hiring a surrogate increase in the United States, transnational commercial surrogacy becomes a feasible alternative for many couples. Infertile couples may opt for this choice after reading enticing Internet advertisements of global medical tourism offering "special deals" on commercial surrogacy. This is particularly true in India where couples from the United States can purchase transnational surrogacy for less than one-half or even one-third of the costs in the United States, including the cost of travel. The majority of surrogate mothers in India come from impoverished, poorly educated rural areas of India. Commercial surrogacy offers the lure of earning the equivalent of 5 years of family income. This multidisciplinary review of the literature suggests that the issue of commercial surrogacy is complex and influenced by a number of factors including expensive infertility costs, ease of global travel, and the financial vulnerability of Indian commercial surrogate mothers and their families. Questions are being raised about decision making by the surrogate mother particularly as influenced by gender inequities, power differentials, and inadequate legal protection for the surrogate mother. More research is needed to understand commercial surrogacy, especially research inclusive of the viewpoints of the Indian mothers and their families involved in these transactions. PMID- 26110575 TI - Measles: Still a Significant Health Threat. AB - Measles (Rubeola), although considered eradicated in the United States, still causes periodic outbreaks. Vaccine refusal leads to vulnerable pockets of individuals who may become infected once the virus is imported from countries where it is endemic. In turn, these individuals may spread the virus to young infants and to other vulnerable individuals. Many healthcare providers are not familiar with this disease or with the factors that contribute to the risk of spread. Measles causes a serious febrile illness that may lead to pneumonia, blindness, deafness, neurological disorders, and even death. Patients with measles need supportive care and administration of oral vitamin A. The measles vaccine is highly effective and considered extremely safe, but misinformation about the safety of this and other vaccines has decreased immunization coverage in some areas of the country. Mandatory immunization laws exist in every state and have been upheld by courts including the United States Supreme Court, but laws and exemptions vary among states. Nurses can play a strong role in care of patients with measles, case identification, and prevention of transmission. Most importantly, because nurses hold positions of trust in their communities, they should be tireless frontline advocates for immunization. The purpose of this article is to provide information on measles, its transmission, signs and symptoms, treatment, prevention, and relevant laws and regulations. PMID- 26110576 TI - Assessment of the Effects of 6 Standard Rodent Diets on Binge-Like and Voluntary Ethanol Consumption in Male C57BL/6J Mice. AB - BACKGROUND: In recent years, much attention has been given to the lack of reproducibility in biomedical research, particularly in preclinical animal studies. This is a problem that also plagues the alcohol research field, particularly in consistent consumption in animal models of alcohol use disorders. One often overlooked factor that could affect reproducibility is the maintenance diet used in preclinical studies. METHODS: Herein, 2 well-established models of alcohol consumption, the "drinking in the dark" (DID) procedure and the continuous 2-bottle choice (C2BC) paradigm, were employed to determine the effects of diet on ethanol (EtOH) consumption. Male C57BL/6J mice were given 1 of 6 standard rodent chow diets obtained from Purina LabDiet((r)) , Inc. (Prolab((r)) RMH 3000) or Harlan((r)) Laboratories, Inc. (Teklad Diets T.2916, T.2918, T.2920X, T.7912, or T.8940). A separate group of animals were used to test dietary effects on EtOH pharmacokinetics and behavioral measures following intraperitoneal (IP) injections of various doses of EtOH. RESULTS: Mice eating Harlan diets T.2916 (H2916) and T.2920X (H2920) consumed significantly less EtOH and exhibited lower blood EtOH concentrations (BECs) during DID; however, during C2BC, animals maintained on Harlan T.7912 (H7912) consumed more EtOH and had a higher EtOH preference than the other diet groups. EtOH consumption levels did not stem from changes in alcohol pharmacokinetics, as a separate group of animals administered EtOH IP showed no difference in BECs. However, animals on Harlan diet T.2920X (H2920) were more sensitive to alcohol-induced locomotor activity in an open-field task. No diet-dependent differences were seen in alcohol-induced sedation as measured with loss of righting reflex. CONCLUSIONS: Although these data do not identify a specific mechanism, together, they clearly show that the maintenance diet impacts EtOH consumption. It is incumbent upon the research community to consider the importance of describing nutritional information in methods, which may help decrease interlaboratory reproducibility issues. PMID- 26110577 TI - The Selective Cross-Coupling of Secondary Alkyl Zinc Reagents to Five-Membered Ring Heterocycles Using Pd-PEPPSI-IHept(Cl). AB - The ability to cross-couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to beta hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non-rearranged) cross-coupled product with aryl or heteroaryl oxidative-addition partners, none have shown reliable selectivity with five-membered-ring heterocycles. In this report, a new, rationally designed catalyst, Pd-PEPPSI-IHept(Cl), is demonstrated to be effective in selective cross coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo-fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time. PMID- 26110578 TI - Phenotype-Driven Plasma Biobanking Strategies and Methods. AB - Biobank development and integration with clinical data from electronic medical record (EMR) databases have enabled recent strides in genomic research and personalized medicine. BioVU, Vanderbilt's DNA biorepository linked to de identified clinical EMRs, has proven fruitful in its capacity to extensively appeal to numerous areas of biomedical and clinical research, supporting the discovery of genotype-phenotype interactions. Expanding on experiences in BioVU creation and development, we have recently embarked on a parallel effort to collect plasma in addition to DNA from blood specimens leftover after routine clinical testing at Vanderbilt. This initiative offers expanded utility of BioVU by combining proteomic and metabolomic approaches with genomics and/or clinical outcomes, widening the breadth for potential research and subsequent future impact on clinical care. Here, we describe the considerations and components involved in implementing a plasma biobank program from a feasibility assessment through pilot sample collection. PMID- 26110579 TI - Bilateral Trochlear Nerve Palsy as a Consequence of Cerebellar Medulloblastoma: Clinical and Pathological Findings in a Calf. PMID- 26110580 TI - Seinajoki Adult Asthma Study (SAAS): a protocol for a 12-year real-life follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialised care. PMID- 26110581 TI - Self-plagiarism: the perspective of a convicted plagiarist! PMID- 26110582 TI - Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma. AB - Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNbeta-F0) or an IFN antagonistic protein (rNDV-NS1-F0), as well as rNDV with increased virulence (rNDV-F3aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F3aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNbeta -F0, while inoculation with rNDV NS1-F0 resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F3aa caused markedly more cytotoxicity compared to rNDV-F0, while inoculation with rNDVbeta hIFN -F0 and rNDV-NS1-F0 induced cytotoxic effects comparable to those induced by the parental rNDV-F0. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV F3aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy. PMID- 26110584 TI - The Effect of Oral Administration of dsRNA on Viral Replication and Mortality in Bombus terrestris. AB - Israeli acute paralysis virus (IAPV), a single-stranded RNA virus, has a worldwide distribution and affects honeybees as well as other important pollinators. IAPV infection in honeybees has been successfully repressed by exploiting the RNA interference (RNAi) pathway of the insect's innate immune response with virus-specific double stranded RNA (dsRNA). Here we investigated the effect of IAPV infection in the bumblebee Bombus terrestris and its tissue tropism. B. terrestris is a common pollinator of wild flowers in Europe and is used for biological pollination in agriculture. Infection experiments demonstrated a similar pathology and tissue tropism in bumblebees as reported for honeybees. The effect of oral administration of virus-specific dsRNA was examined and resulted in an effective silencing of the virus, irrespective of the length. Interestingly, we observed that non-specific dsRNA was also efficient against IAPV. However further study is needed to clarify the precise mechanism behind this effect. Finally we believe that our data are indicative of the possibility to use dsRNA for a broad range viral protection in bumblebees. PMID- 26110583 TI - APOBEC3 Interference during Replication of Viral Genomes. AB - Co-evolution of viruses and their hosts has reached a fragile and dynamic equilibrium that allows viral persistence, replication and transmission. In response, infected hosts have developed strategies of defense that counteract the deleterious effects of viral infections. In particular, single-strand DNA editing by Apolipoprotein B Editing Catalytic subunits proteins 3 (APOBEC3s) is a well conserved mechanism of mammalian innate immunity that mutates and inactivates viral genomes. In this review, we describe the mechanisms of APOBEC3 editing during viral replication, the viral strategies that prevent APOBEC3 activity and the consequences of APOBEC3 modulation on viral fitness and host genome integrity. Understanding the mechanisms involved reveals new prospects for therapeutic intervention. PMID- 26110586 TI - Honey Bee Infecting Lake Sinai Viruses. AB - Honey bees are critical pollinators of important agricultural crops. Recently, high annual losses of honey bee colonies have prompted further investigation of honey bee infecting viruses. To better characterize the recently discovered and very prevalent Lake Sinai virus (LSV) group, we sequenced currently circulating LSVs, performed phylogenetic analysis, and obtained images of LSV2. Sequence analysis resulted in extension of the LSV1 and LSV2 genomes, the first detection of LSV4 in the US, and the discovery of LSV6 and LSV7. We detected LSV1 and LSV2 in the Varroa destructor mite, and determined that a large proportion of LSV2 is found in the honey bee gut, suggesting that vector-mediated, food-associated, and/or fecal-oral routes may be important for LSV dissemination. Pathogen specific quantitative PCR data, obtained from samples collected during a small scale monitoring project, revealed that LSV2, LSV1, Black queen cell virus (BQCV), and Nosema ceranae were more abundant in weak colonies than strong colonies within this sample cohort. Together, these results enhance our current understanding of LSVs and illustrate the importance of future studies aimed at investigating the role of LSVs and other pathogens on honey bee health at both the individual and colony levels. PMID- 26110585 TI - Viral Membrane Channels: Role and Function in the Virus Life Cycle. AB - Viroporins are small, hydrophobic trans-membrane viral proteins that oligomerize to form hydrophilic pores in the host cell membranes. These proteins are crucial for the pathogenicity and replication of viruses as they aid in various stages of the viral life cycle, from genome uncoating to viral release. In addition, the ion channel activity of viroporin causes disruption in the cellular ion homeostasis, in particular the calcium ion. Fluctuation in the calcium level triggers the activation of the host defensive programmed cell death pathways as well as the inflammasome, which in turn are being subverted for the viruses' replication benefits. This review article summarizes recent developments in the functional investigation of viroporins from various viruses and their contributions to viral replication and virulence. PMID- 26110588 TI - Characterisation of Structural Proteins from Chronic Bee Paralysis Virus (CBPV) Using Mass Spectrometry. AB - Chronic bee paralysis virus (CBPV) is the etiological agent of chronic paralysis, an infectious and contagious disease in adult honeybees. CBPV is a positive single-stranded RNA virus which contains two major viral RNA fragments. RNA 1 (3674 nt) and RNA 2 (2305 nt) encode three and four putative open reading frames (ORFs), respectively. RNA 1 is thought to encode the viral RNA-dependent RNA polymerase (RdRp) since the amino acid sequence derived from ORF 3 shares similarities with the RdRP of families Nodaviridae and Tombusviridae. The genomic organization of CBPV and in silico analyses have suggested that RNA 1 encodes non structural proteins, while RNA 2 encodes structural proteins, which are probably encoded by ORFs 2 and 3. In this study, purified CBPV particles were used to characterize virion proteins by mass spectrometry. Several polypeptides corresponding to proteins encoded by ORF 2 and 3 on RNA 2 were detected. Their role in the formation of the viral capsid is discussed. PMID- 26110589 TI - Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis. AB - The composition of atherosclerotic (AS) plaques is crucial concerning rupture, thrombosis and clinical events. Two plaque types are distinguished: stable and vulnerable plaques. Vulnerable plaques are rich in inflammatory cells, mostly only M1 macrophages, and are highly susceptible to rupture. These plaques represent a high risk particularly with the standard invasive diagnosis by coronary angiography. So far there are no non-invasive low-risk clinical approaches available to detect and distinguish AS plaque types in vivo. The perspective review introduces a whole work-flow for a novel approach for non invasive detection and classification of AS plaques using the diffusion reflection method with gold nanoparticle loaded macrophages in combination with flow and image cytometric analysis for quality assurance. Classical biophotonic methods for AS diagnosis are summarized. Phenotyping of monocytes and macrophages are discussed for specific subset labelling by nanomaterials, as well as existing studies and first experimental proofs of concept for the novel approach are shown. In vitro and in vivo detection of NP loaded macrophages (MPhi). Different ways of MPhi labelling include (1) in vitro labelling in suspension (whole blood or buffy coat) or (2) labelling of short-term MPhi cultures with re-injection of MPhi-NP into the animal to detect migration of the cells in the plaques and (3) in vivo injection of NP into the organism. PMID- 26110587 TI - Phylodynamics of H5N1 Highly Pathogenic Avian Influenza in Europe, 2005-2010: Potential for Molecular Surveillance of New Outbreaks. AB - Previous Bayesian phylogeographic studies of H5N1 highly pathogenic avian influenza viruses (HPAIVs) explored the origin and spread of the epidemic from China into Russia, indicating that HPAIV circulated in Russia prior to its detection there in 2005. In this study, we extend this research to explore the evolution and spread of HPAIV within Europe during the 2005-2010 epidemic, using all available sequences of the hemagglutinin (HA) and neuraminidase (NA) gene regions that were collected in Europe and Russia during the outbreak. We use discrete-trait phylodynamic models within a Bayesian statistical framework to explore the evolution of HPAIV. Our results indicate that the genetic diversity and effective population size of HPAIV peaked between mid-2005 and early 2006, followed by drastic decline in 2007, which coincides with the end of the epidemic in Europe. Our results also suggest that domestic birds were the most likely source of the spread of the virus from Russia into Europe. Additionally, estimates of viral dispersal routes indicate that Russia, Romania, and Germany were key epicenters of these outbreaks. Our study quantifies the dynamics of a major European HPAIV pandemic and substantiates the ability of phylodynamic models to improve molecular surveillance of novel AIVs. PMID- 26110590 TI - Asymmetric Donor-pi-Acceptor-Type Benzo-Fused Aza-BODIPYs: Facile Synthesis and Colorimetric Properties. AB - Novel aza-diisoindolylmethene and their BF2 -chelating complexes (benzo-fused aza BODIPYs) were synthesized on a large scale and in a facile manner from phthalonitrile in tBuOK-DMF solution. The unique asymmetric donor-pi-acceptor structure facilitates B-N bond detachment in the presence of trifluoroacetic acid (TFA) in dichloromethane, resulting in sharp color change from red to colorless, with over 250 nm hypsochromic shift in the absorption maximum. This colorimetric process can be reversed by adding a very small amount of proton-accepting solvents or compounds. A (1) H and (11) B NMR spectroscopy study and also density functional theory (DFT) calculations suggest that TFA-induced B-N bond cleavage may disrupt the whole pi-conjugation of the BODIPY molecule, resulting in significant colorimetric behavior. PMID- 26110591 TI - The moderating effect of perceived partner empathy on body image and depression among breast cancer survivors. AB - PURPOSE: The aims of the study were the following: (1) to understand the relationship between women's perceptions of empathy from their partners and their depressive symptoms and body image and (2) to examine the moderating effects of women's perceptions of empathy from their partners on the relationship between body image and depressive symptoms. METHODS: A cross-sectional and correlational design was used, in which a convenience sample of 151 women who completed surgery and the necessary chemotherapy/radiotherapy were recruited from southern Taiwan. A structured questionnaire including the Other Dyadic Perspective-Taking Scale, the Body Image Scale, and the Center for Epidemiologic Studies Depression scale were administered. Hierarchical regression was used to examine the moderating effects of empathy from partners between the women's body image and their level of depressive symptoms. RESULTS: The results showed significant relationships between empathy from a partner and depressive symptoms (p < 0.001). However, there was no significant relationship between empathy from a partner and body image (p > 0.05). The moderating effect of empathy from a partner on the relationship between body image and depressive symptoms was also significant (p < 0.01). CONCLUSION: The more empathy women perceived from partners, the fewer depressive symptoms women reported. Empathy from a partner could moderate the impact of body image changes on depressive symptoms. Women's depressive symptoms, resulting from a change in body image after breast cancer surgery, might be minimized if they perceived greater empathy from their partners. PMID- 26110592 TI - Does one size fit all? The updated ovarian cancer staging: Still a work in progress. PMID- 26110593 TI - Disease-associated variants in different categories of disease located in distinct regulatory elements. AB - BACKGROUND: The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression. RESULTS: In this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects. We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively. CONCLUSIONS: Disease-associated variants in different disease categories are preferentially located in particular regulatory elements. These results will be useful for an overall understanding about the differences among the pathogenic mechanisms of various disease-associated variants. PMID- 26110594 TI - Maternal and Hospital Factors Associated with First-Time Mothers' Breastfeeding Practice: A Prospective Study. AB - Continuity of breastfeeding is infrequent and indeterminate. Evidence is lacking regarding factors associated with breastfeeding at different postpartum time points. This prospective study investigated the change in, and correlates of, breastfeeding practices after delivery at a hospital and at 1, 3, and 6 months postpartum among first-time mothers. We followed a cohort of 300 primiparous mothers of Taiwan who gave birth at two hospitals during 2010-2011. Logistic and Cox regression analyses were performed to determine factors that were correlated with breastfeeding practices. In the study sample, the rate of exclusive breastfeeding during the hospital stay was 66%; it declined to 37.5% at 1 month and 30.2% at 3 months postpartum. Only 17.1% of women reported continuing breastfeeding at 6 months. Early initiation of breastfeeding, rooming-in practice, and self-efficacy were significantly related to exclusive breastfeeding during the hospital stay. After discharge, health literacy, knowledge, intention, and self-efficacy were positively and significantly associated with breastfeeding exclusivity. Later initiation (hazard ratio=1.53; 95% confidence interval, 1.05, 1.97), shorter intention (hazard ratio=1.42; 95% confidence interval, 1.13, 1.68), and self-efficacy (hazard ratio=0.98; 95% confidence interval, 0.96, 0.99) were important predictors of breastfeeding cessation within 6 months of delivery. Continuous breastfeeding practice for 6 months is challenging and difficult for new mothers. Results showed that factors related to breastfeeding varied over time after delivery. Interventions seeking to sustain breastfeeding should consider new mothers' needs and barriers at different times. PMID- 26110595 TI - Infant Cancer in Taiwan: Incidence and Trends (1995-2009). AB - BACKGROUND: Current information about cancer incidence patterns among infants in East Asia is rare. The objective of this study was to report the first population based cancer surveillance of infants in Taiwan. METHODS: Cancer frequencies and incidence rates among subjects aged <1 year for the period 1995-2009 were obtained from the Taiwan Cancer Registry. Types of cancers were grouped according to the International Classification of Childhood Cancer. Rates and trends were analyzed by sex and disease groups and further compared with that of other countries. RESULTS: A total of 900 infants were diagnosed with cancers, giving an incidence rate of 250.7 per million person-years from 1995 to 2009. The male-to female incidence rate ratio was 1.22. Overall, leukemias (56.3 per million) were the most common cancer, followed by germ cell neoplasms (43.2) and neuroblastomas (41.8). The incidence increased by 2.5% annually during the 15-year study period and was predominantly contributed by male infants (3.5%). Compared with other countries, the rate of hepatoblastoma in Taiwan was second to that from Beijing (China) and 2 to 5 times greater compared with the US, France, the North of England and Osaka (Japan). The rates of germ cell neoplasms were 2 to 4 times greater in Taiwan. CONCLUSIONS: The current data suggests that cancer incidence rate among male infants was rising in Taiwan. The factors associated with higher rates of hepatoblastoma and germ cell neoplasms warrant further investigation on similar ethnic groups of different areas to elucidate the potential environmental impacts while controlling for race. PMID- 26110596 TI - INFLUENCE OF VITREOMACULAR INTERFACE ON ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY USING TREAT AND EXTEND TREATMENT PROTOCOL FOR AGE-RELATED MACULAR DEGENERATION (VINTREX). AB - PURPOSE: To determine the influence of vitreomacular adhesion (VMA) on treatment outcomes in patients with neovascular age-related macular degeneration who were treated with anti-vascular endothelial growth factor agents using a treat and extend treatment regimen. METHODS: A retrospective consecutive case series of 204 eyes from 181 patients with a minimum of 1 year of follow-up at Wills Eye Hospital Retina Service. Vitreomacular interface characteristics were determined by spectral domain optical coherence tomography. One hundred and fifty-three eyes (75%) had no signs of VMA (non-VMA), and 51 (25%) had VMA. RESULTS: Baseline mean visual acuity was 20/133 with a mean central retinal thickness of 350.5 MUm in the non-VMA group and was 20/145 with 371.8 MUm in the VMA group. Mean visual acuity in the non-VMA group was 20/83 and 20/64 at Years 1 and 2, respectively (P < 0.01 to baseline). Mean visual acuity in the VMA group was 20/81 and 20/85 at Years 1 and 2, respectively (P < 0.01 to baseline). The central retinal thickness was 289.71 MUm and 267 MUm at Years 1 and 2, respectively (P < 0.01 to baseline) in the non-VMA group and was 305.3 MUm and 289.24 MUm (P < 0.01 to baseline) in the VMA group. The mean total number of injections at Year 1 for non-VMA was 7.4 compared with 8.4 in VMA (P = 0.001) and 5.5 versus 6.7 for the 2 groups in Year 2 (P = 0.027). The mean longest extension at Year 1 was 11.8 weeks compared with 10.1 week (P = 0.005) and for Year 2 was 14.1 weeks compared with 12 weeks (P = 0.041). CONCLUSION: The vitreomacular interface seems to have a significant influence on anti-vascular endothelial growth factor treatment intervals but not visual acuity or exudative control outcomes. Eyes with VMA on spectral domain optical coherence tomography at baseline may require more intensive treatment with decreased ability to extend treatment intervals. PMID- 26110597 TI - OUTCOMES OF TREATMENT OF CHOROIDAL NEOVASCULARIZATION ASSOCIATED WITH CENTRAL SEROUS CHORIORETINOPATHY WITH INTRAVITREAL ANTIANGIOGENIC AGENTS. AB - PURPOSE: To report clinical characteristics and treatment outcomes from the largest case series of choroidal neovascularization secondary to central serous chorioretinopathy. METHODS: Retrospective analysis of 46 eyes of 43 consecutive subjects. Collected data included demographic details, history of presenting illness, clinical examination details including visual acuity at presentation and follow-up with imaging and treatment details. Main outcome measures were the proportion of eyes that had improved (3 or more lines), stable (within +/-1 line), or decreased (3 or more lines) vision at the final visit as compared with baseline examination. Secondary efficacy outcomes included change in visual acuity at final follow-up, number of injections, treatment-free interval, and adverse events. RESULTS: Mean age was 57.56 years (range 29-79 years). Mean follow-up duration was 38.3 months +/- 58.9 months. More than 3 lines of improvement in 12 eyes (26%), vision was stable (within +/-1 line) in 19 eyes (41.3%), and >3 lines of loss was noted in 6 eyes (13%). Mean change in the number of lines was 1.16 +/- 3.74. Mean number of anti-vascular endothelial growth factor injections during the follow-up was 4.45 +/- 4.1. The longest treatment-free interval was 8.9 months +/- 7.5 months. There were no adverse events noted. CONCLUSION: Anti-vascular endothelial growth factor therapy as a primary therapy for choroidal neovascularization secondary to central serous chorioretinopathy is safe and efficacious, without any serious adverse events. PMID- 26110598 TI - HIGH-RESOLUTION MULTIMODAL IMAGING AFTER IDIOPATHIC EPIRETINAL MEMBRANE SURGERY. AB - PURPOSE: To investigate the changes of the vitreomacular interface during a 1 year follow-up after idiopathic epiretinal membrane (iERM) surgery. METHODS: Six patients affected by fovea-attached iERM were recruited in this pilot study. Pars plana vitrectomy associated with epiretinal membrane peeling was performed uneventfully in all cases. In four cases, the inner limiting membrane was removed using Brilliant blue G. En face high-resolution adaptive optics and cross sectional spectral domain optical coherence tomography retinal imaging were performed before and at 1, 3, 6, and 12 months after surgery. The microstructures of vitreomacular interface in high-resolution adaptive optics images were correlated to the cross-sectional spectral domain optical coherence tomography data. RESULTS: Preoperatively, adaptive optics images showed multiple abnormalities of the vitreomacular interface, such as macrofolds, microfolds, and hyperreflective microstructures. We identified two subtypes of iERM according to the distribution of microfolds over the foveal area, which included the radial type and the grid-type iERM. After surgery, the morphology of the vitreomacular interface changed compared with the preoperative state. The number of both macrofolds and microfolds was reduced in all cases. The hyperreflective structures were still resolvable in all cases, however presenting different shape and morphology than preoperatively. In addition, they showed marked differences between eyes that had internal limiting membrane removal and eyes that did not. CONCLUSION: Adaptive optics imaging gives new insight into the changes of vitreomacular interface after iERM surgery. Enhanced multimodal imaging of the vitreomacular interface and retinal structures can be valuable to monitor treatment outcome of iERM. PMID- 26110599 TI - INSIGHTS INTO AUTOSOMAL DOMINANT STARGARDT-LIKE MACULAR DYSTROPHY THROUGH MULTIMODALITY DIAGNOSTIC IMAGING. AB - PURPOSE: Autosomal dominant Stargardt-like macular dystrophy is a rare juvenile macular dystrophy most commonly because of mutations in ELOVL4 and PROM1 genes. In this study, we review a series of cases of Stargardt-like macular dystrophy and use advanced imaging techniques to describe pathophysiologic manifestations. METHODS: A retrospective medical record review was performed for five patients from two families with ELOVL4 mutation and one patient with PROM1 mutation including reviewing diagnostic imaging, such as fundus photography, spectral domain optical coherence tomography, fundus autofluorescence, and adaptive optics flood-illuminated photography. RESULTS: All patients had reduced central visual acuity with varying degree of foveal atrophy. In the ELOVL4 group, best-corrected visual acuity ranged from 20/25 to 20/200. Early pathologic changes included thickening of the external limiting membrane and outer nuclear atrophy followed by retinal pigment epithelium loss in later stages. Adaptive optics imaging revealed photoreceptor loss even in early stages with good visual acuity. The PROM1 patient also had similar central vision loss with significant outer nuclear atrophy. In contrast to ELOVL4 mutation, there was more diffuse and patchy retinal pigment epithelium loss throughout the macula. CONCLUSION: Both ELOVL4- and PROM1-related maculopathies are characterized by progressive photoreceptor atrophy and central vision loss. Using advanced diagnostic imaging, early disease changes and disease progression can be characterized. PMID- 26110600 TI - Computation-Assisted Structural Elucidation of Epoxyroussoeone and Epoxyroussoedione Isolated from Roussoella japanensis KT1651. AB - The structures of epoxyroussoenone (1) and epoxyroussoedione (3) isolated from a culture broth of Roussoella japanensis KT1651 were determined. Although NMR spectra provided insufficient structural information, computation of the theoretical chemical shifts with DFT EDF2/6-31G* enabled us to elucidate not only the planar structure, but also the relative configuration. Their ECD (electric circular dichroism) spectra suggested the absolute configurations, which were confirmed with time-dependent DFT calculations employing BHandHLYP/TZVP. The ECD calculations for other stereoisomers yielded obviously different spectral profiles, thus confirming the relative structures of 1 and 3. PMID- 26110601 TI - A Spiritual Journey: Influence of Hannelore. AB - Little do we know as we go along our ordinary daily living that an invitation to listen could so profoundly affect another person's life. The gift of true listening can bring about connections and relationships that last for a lifetime. This reflective article reminds educators to take time to encourage, question, support, and challenge eager neophytes in their classes. PMID- 26110602 TI - Dual mode signaling responses of a rhodamine based probe and its immobilization onto a silica gel surface for specific mercury ion detection. AB - A 3-aminomethyl-(2-amino-1-pyridyl) coupled amino-ethyl-rhodamine-B based probe (2) exhibited simultaneous chromogenic and fluorogenic dual mode signaling responses in the presence of Hg(II) ions only among all the metal ions investigated in an organic aqueous medium. The spiro-cyclic rhodamine signaling subunit undergoes complexation induced structural transformation to result in absorption and fluorescence modulation. Its complexation induced signaling exhibited reversibility with various contrasting reagents having higher affinity towards Hg(II) ions, such as anions (AcO(-)) and competing chelating agents (En). It also exhibited Hg(II)-specific photophysical signaling responses when immobilized onto a silica gel surface attached through its amino-ethyl-receptor end, owing to its structure-conformational advantages for effective coordination. The surface modified silica appended with 2 (SiR-1), as evaluated through the FTIR spectral pattern, thermogravimetric analysis, FESEM images, elemental analysis, X-ray diffraction, surface area determination and particle size analysis, also exhibited reversible Hg(II)-specific signaling in its suspension state in an aqueous medium, enhancing the probe's utility for practical applications such as the detection, isolation and extraction of Hg(II) ions in the presence of other competitive metal ions. PMID- 26110603 TI - A Peptide Mimetic of 5-Acetylneuraminic Acid-Galactose Binds with High Avidity to Siglecs and NKG2D. AB - We previously identified several peptide sequences that mimicked the terminal sugars of complex glycans. Using plant lectins as analogs of lectin-type cell surface receptors, a tetravalent form of a peptide with the sequence NPSHPLSG, designated svH1C, bound with high avidity to lectins specific for glycans with terminal 5-acetylneuraminic acid (Neu5Ac)-galactose (Gal)/N-acetylgalactosamine (GalNAc) sequences. In this report, we show by circular dichroism and NMR spectra that svH1C lacks an ordered structure and thus interacts with binding sites from a flexible conformation. The peptide binds with high avidity to several recombinant human siglec receptors that bind preferentially to Neu5Ac(alpha2,3)Gal, Neu5Ac(alpha2,6)GalNAc or Neu5Ac(alpha2,8)Neu5Ac ligands. In addition, the peptide bound the receptor NKG2D, which contains a lectin-like domain that binds Neu5Ac(alpha2,3)Gal. The peptide bound to these receptors with a KD in the range of 0.6 to 1 MUM. Binding to these receptors was inhibited by the glycoprotein fetuin, which contains multiple glycans that terminate in Neu5Ac(alpha2,3)Gal or Neu5Ac(alpha2,6)Gal, and by sialyllactose. Binding of svH1C was not detected with CLEC9a, CLEC10a or DC-SIGN, which are lectin-type receptors specific for other sugars. Incubation of neuraminidase-treated human peripheral blood mononuclear cells with svH1C resulted in binding of the peptide to a subset of the CD14+ monocyte population. Tyrosine phosphorylation of siglecs decreased dramatically when peripheral blood mononuclear cells were treated with 100 nM svH1C. Subcutaneous, alternate-day injections of svH1C into mice induced several-fold increases in populations of several types of immune cells in the peritoneal cavity. These results support the conclusion that svH1C mimics Neu5Ac containing sequences and interacts with cell-surface receptors with avidities sufficient to induce biological responses at low concentrations. The attenuation of inhibitory receptors suggests that svH1C has characteristics of a checkpoint inhibitor. PMID- 26110604 TI - Diagnostic Accuracy of Recombinant Immunoglobulin-like Protein A-Based IgM ELISA for the Early Diagnosis of Leptospirosis in the Philippines. AB - BACKGROUND: Leptospirosis is an important but largely under-recognized public health problem in the tropics. Establishment of highly sensitive and specific laboratory diagnosis is essential to reveal the magnitude of problem and to improve treatment. This study aimed to evaluate the diagnostic accuracy of a recombinant LigA protein based IgM ELISA during outbreaks in the clinical-setting of a highly endemic country. METHODOLOGY/PRINCIPAL FINDINGS: A prospective study was conducted from October 2011 to September 2013 at a national referral hospital for infectious diseases in Manila, Philippines. Patients who were hospitalized with clinically suspected leptospirosis were enrolled. Plasma and urine were collected on admission and/or at discharge and tested using the LigA-IgM ELISA and a whole cell-based IgM ELISA. Sensitivity and specificity of these tests were evaluated with cases diagnosed by microscopic agglutination test (MAT), culture and LAMP as the composite reference standard and blood bank donors as healthy controls: the mean+3 standard deviation optical density value of healthy controls was used as the cut-off limit (0.062 for the LigA-IgM ELISA and 0.691 for the whole cell-based IgM ELISA). Of 304 patients enrolled in the study, 270 (89.1%) were male and the median age was 30.5 years; 167 (54.9%) were laboratory confirmed. The sensitivity and ROC curve AUC for the LigA-IgM ELISA was significantly greater than the whole cell-based IgM ELISA (69.5% vs. 54.3%, p<0.01; 0.90 vs. 0.82, p<0.01) on admission, but not at discharge. The specificity of LigA-IgM ELISA and whole cell-based IgM ELISA were not significantly different (98% vs. 97%). Among 158 MAT negative patients, 53 and 28 were positive by LigA- and whole cell-based IgM ELISA, respectively; if the laboratory confirmation was re-defined by LigA-IgM ELISA and LAMP, the clinical findings were more characteristic of leptospirosis than the diagnosis based on MAT/culture/LAMP. CONCLUSIONS/SIGNIFICANCE: The newly developed LigA-IgM ELISA is more sensitive than the whole cell-based IgM based ELISA. Although the final diagnosis must be validated by more specific tests, LigA-IgM ELISA could be a useful diagnostic test in a real clinical-setting, where diagnosis is needed in the early phase of infection. PMID- 26110605 TI - Relationship between the decomposition process of coarse woody debris and fungal community structure as detected by high-throughput sequencing in a deciduous broad-leaved forest in Japan. AB - We examined the relationship between the community structure of wood-decaying fungi, detected by high-throughput sequencing, and the decomposition rate using 13 years of data from a forest dynamics plot. For molecular analysis and wood density measurements, drill dust samples were collected from logs and stumps of Fagus and Quercus in the plot. Regression using a negative exponential model between wood density and time since death revealed that the decomposition rate of Fagus was greater than that of Quercus. The residual between the expected value obtained from the regression curve and the observed wood density was used as a decomposition rate index. Principal component analysis showed that the fungal community compositions of both Fagus and Quercus changed with time since death. Principal component analysis axis scores were used as an index of fungal community composition. A structural equation model for each wood genus was used to assess the effect of fungal community structure traits on the decomposition rate and how the fungal community structure was determined by the traits of coarse woody debris. Results of the structural equation model suggested that the decomposition rate of Fagus was affected by two fungal community composition components: one that was affected by time since death and another that was not affected by the traits of coarse woody debris. In contrast, the decomposition rate of Quercus was not affected by coarse woody debris traits or fungal community structure. These findings suggest that, in the case of Fagus coarse woody debris, the fungal community structure is related to the decomposition process of its host substrate. Because fungal community structure is affected partly by the decay stage and wood density of its substrate, these factors influence each other. Further research on interactive effects is needed to improve our understanding of the relationship between fungal community structure and the woody debris decomposition process. PMID- 26110606 TI - The relationship between childhood sexual/physical abuse and sexual dysfunction in patients with social anxiety disorder. AB - BACKGROUND: Childhood traumatic events are known as developmental factors for various psychiatric disorders. OBJECTIVE: The aim of this study was to investigate the effects of childhood sexual and physical abuse (CSA/CPA), and co morbid depression on sexual functions in patients with social anxiety disorder (SAD). METHOD: Data obtained from 113 SAD patients was analysed. Childhood traumatic experiences were evaluated using the Childhood Trauma Questionnaire, and the Arizona Sexual Experience Scale was used for the evaluation of the sexual functions. The data from interviews performed with SCID-I were used for determination of Axis I diagnosis. The Beck Anxiety Scale, Beck Depression Scale and Liebowitz Social Anxiety Scale were administered to each patient. RESULTS: History of childhood physical abuse (CPA) was present in 45.1% of the SAD patients, and 14.2% had a history of childhood sexual abuse (CSA). Depression co diagnosis was present in 30.1% of SAD patients and 36.3% had sexual dysfunction. History of CSA and depression co-diagnosis were determined as two strong predictors in SAD patients (odds ratio (OR) for CSA, 7.83; 95% CI, 1.97-31.11; p = 0.003 and OR for depression, 3.66; 95% CI, 1.47-9.13; p = 0.005). CONCLUSIONS: CSA and depression should be considered and questioned as an important factor for SAD patients who suffer from sexual dysfunction. PMID- 26110607 TI - Minor Cause--Major Effect: A Novel Mode of Control of Bistable Gene Expression. PMID- 26110608 TI - Targeting prion protein interactions in cancer. AB - In recent years, prion protein (PrP(C)) has been considered as a promising target molecule for cancer therapies, due its direct or indirect participation in tumor growth, metastasis, and resistance to cell death induced by chemotherapy. PrP(C) functions as a scaffold protein, forming multiprotein complexes on the plasma membrane, which elicits distinct signaling pathways involved in diverse biological phenomena and could be modulated depending on the cell type, complex composition, and organization. In addition, PrP(C) and its partners participate in self-renewal of embryonic, tissue-specific stem cells and cancer stem cells, which are suggested to be responsible for the origin, maintenance, relapse, and dissemination of tumors. Interference with protein-protein interaction has been recognized as an important therapeutic strategy in cancer; indeed, the possible interference in PrP(C) engagement with specific partners is a novel strategy. Recently, our group successfully used that approach to interfere with the interaction between PrP(C) and HSP-90/70 organizing protein (HOP, also known as stress-inducible protein 1 - STI1) to control the growth of human glioblastoma in animal models. Thus, PrP(C)-organized multicomplexes have emerged as feasible candidates for anti-tumor therapy, warranting further exploration. PMID- 26110609 TI - Yeast prions are useful for studying protein chaperones and protein quality control. AB - Protein chaperones help proteins adopt and maintain native conformations and play vital roles in cellular processes where proteins are partially folded. They comprise a major part of the cellular protein quality control system that protects the integrity of the proteome. Many disorders are caused when proteins misfold despite this protection. Yeast prions are fibrous amyloid aggregates of misfolded proteins. The normal action of chaperones on yeast prions breaks the fibers into pieces, which results in prion replication. Because this process is necessary for propagation of yeast prions, even small differences in activity of many chaperones noticeably affect prion phenotypes. Several other factors involved in protein processing also influence formation, propagation or elimination of prions in yeast. Thus, in much the same way that the dependency of viruses on cellular functions has allowed us to learn much about cell biology, the dependency of yeast prions on chaperones presents a unique and sensitive way to monitor the functions and interactions of many components of the cell's protein quality control system. Our recent work illustrates the utility of this system for identifying and defining chaperone machinery interactions. PMID- 26110610 TI - As a toxin dies a prion comes to life: A tentative natural history of the [Het-s] prion. AB - A variety of signaling pathways, in particular with roles in cell fate and host defense, operate by a prion-like mechanism consisting in the formation of open ended oligomeric signaling complexes termed signalosomes. This mechanism emerges as a novel paradigm in signal transduction. Among the proteins forming such signaling complexes are the Nod-like receptors (NLR), involved in innate immunity. It now appears that the [Het-s] fungal prion derives from such a cell fate defining signaling system controlled by a fungal NLR. What was once considered as an isolated oddity turns out to be related to a conserved and widespread signaling mechanism. Herein, we recall the relation of the [Het-s] prion to the signal transduction pathway controlled by the NWD2 Nod-like receptor, leading to activation of the HET-S pore-forming cell death execution protein. We explicit an evolutionary scenario in which formation of the [Het-s] prion is the result of an exaptation process or how a loss-of-function mutation in a pore-forming cell death execution protein (HET-S) has given birth to a functional prion ([Het-s]). PMID- 26110611 TI - cir-ITCH plays an inhibitory role in colorectal cancer by regulating the Wnt/beta catenin pathway. AB - Noncoding RNAs (ncRNAs) are the dominant product of eukaryotic transcription. These products range from short microRNAs (miRNAs) to long intergenic noncoding RNAs (lincRNAs). Circular RNAs composed of exonic sequences represent an understudied form of ncRNA that was discovered more than 20 years ago. Using a TaqMan-based reverse transcriptase polymerase chain reaction assay, we analyzed the relationship between cir-ITCH expression and colorectal cancer (CRC) in a total of 45 CRCs and paired adjacent non-tumor tissue samples. We found that cir ITCH expression was typically down-regulated in CRC compared to the peritumoral tissue. This result, as well as several follow-up experiments, showed that cir ITCH could increase the level of ITCH, which is involved in the inhibition of the Wnt/beta-catenin pathway. Therefore, our results showed that cir-ITCH plays a role in CRC by regulating the Wnt/beta-catenin pathway. PMID- 26110612 TI - The Importance of Exosite Interactions for Substrate Cleavage by Human Thrombin. AB - Thrombin is a serine protease of the chymotrypsin family that acts both as a procoagulant and as an anticoagulant by cleaving either factor VIII, factor V and fibrinogen or protein C, respectively. Numerous previous studies have shown that electropositive regions at a distance from the active site, so called exosites, are of major importance for the cleavage by human thrombin. Upstream of all the known major cleavage sites for thrombin in factor VIII, factor V and fibrinogen are clusters of negatively charged amino acids. To study the importance of these sites for the interaction with the exosites and thereby the cleavage by thrombin, we have developed a new type of recombinant substrate. We have compared the cleavage rate of the minimal cleavage site, involving only 8-9 amino acids (typically the P4-P4' positions) surrounding the cleavage site, with the substrates also containing the negatively charged regions upstream of the cleavage sites. The results showed that addition of these regions enhanced the cleavage rate by more than fifty fold. However, the enhancement was highly dependent on the sequence of the actual cleavage site. A minimal site that showed poor activity by itself could be cleaved as efficiently as an optimal cleavage site when presented together with these negatively charged regions. Whereas sites conforming closely to the optimal site were only minimally enhanced by the addition of these regions. The possibility to mimic this interaction for the sites in factor V and factor VIII by recombinant substrates, which do not have the same folding as the full size target, indicates that the enhancement was primarily dependent on a relatively simple electrostatic interaction. However, the situation was very different for fibrinogen and protein C where other factors than only charge is of major importance. PMID- 26110613 TI - Serum cell death biomarkers for prediction of liver fibrosis and poor prognosis in primary biliary cirrhosis. AB - The development of simple, noninvasive markers of liver fibrosis is urgently needed for primary biliary cirrhosis (PBC). This study examined the ability of several serum biomarkers of cell death to estimate fibrosis and prognosis in PBC. A cohort of 130 patients with biopsy-proven PBC and 90 healthy subjects were enrolled. We assessed the utility of the M30 ELISA, which detects caspase-cleaved cytokeratin-18 (CK-18) fragments and is representative of apoptotic cell death, as well as the M65 and newly developed M65 Epideath (M65ED) ELISAs, which detect total CK-18 as indicators of overall cell death, in predicting clinically relevant fibrosis stage. All 3 cell death biomarkers were significantly higher in patients with PBC than in healthy controls and were significantly correlated with fibrosis stage. The areas under the receiver operating characteristic curve for the M65 and M65ED assays for differentiation among significant fibrosis, severe fibrosis, and cirrhosis were 0.66 and 0.76, 0.66 and 0.73, and 0.74 and 0.82, respectively. In multivariate analysis, high M65ED (hazard ratio 6.13; 95% confidence interval 1.18-31.69; P = 0.031) and severe fibrosis (hazard ratio 7.45; 95% confidence interval 1.82-30.51; P = 0.005) were independently associated with liver-related death, transplantation, or decompensation. High serum M65ED was also significantly associated with poor outcome in PBC (log-rank test; P = 0.001). Noninvasive cell death biomarkers appear to be clinically useful in predicting fibrosis in PBC. Moreover, the M65ED assay may represent a new surrogate marker of adverse disease outcome. PMID- 26110614 TI - The relationship between impulsivity and suicide among rural youths aged 15-35 years: a case-control psychological autopsy study. AB - In China, the gender ratio of suicide rates did not match the Western patterns, which was higher for females than males. However, the rural men were at relatively high risk of suicide in Liaoning province. Impulsivity was an important factor of suicide behaviors, but there was a lack of studies in China. This research aimed to study the relationship between impulsive personality traits and suicidal behavior among Chinese rural youths. Suicides were consecutively sampled from six randomly selected counties in Liaoning Province in China. Between 2005 and 2007, a total of 162 suicide victims were enrolled in the study along with 162 community controls matched for age, gender, and location. The psychological autopsy method was used to collect data from informants knowledgeable about the selected suicide victims and controls. The results showed the suicide victims in the study were more likely to demonstrate dysfunctional impulsivity and less likely to demonstrate functional impulsivity compared with the controls. Mental disorders, acute negative life events, and dysfunctional impulsivity contributed to the risk of suicide; educational and functional impulsivity were protective factors. Suicide prevention efforts in rural China may address impulsivity. PMID- 26110615 TI - Coordination-resolved electron spectrometrics. PMID- 26110617 TI - Correction: impact of open data policies on consent to participate in human subjects research: discrepancies between participant action and reported concerns. PMID- 26110618 TI - Toward Clinically Compatible Phase-Contrast Mammography. AB - Phase-contrast mammography using laboratory X-ray sources is a promising approach to overcome the relatively low sensitivity and specificity of clinical, absorption-based screening. Current research is mostly centered on identifying potential diagnostic benefits arising from phase-contrast and dark-field mammography and benchmarking the latter with conventional state-of-the-art imaging methods. So far, little effort has been made to adjust this novel imaging technique to clinical needs. In this article, we address the key points for a successful implementation to a clinical routine in the near future and present the very first dose-compatible and rapid scan-time phase-contrast mammograms of both a freshly dissected, cancer-bearing mastectomy specimen and a mammographic accreditation phantom. PMID- 26110616 TI - Deep sequencing analysis of HBV genotype shift and correlation with antiviral efficiency during adefovir dipivoxil therapy. AB - BACKGROUND: Viral genotype shift in chronic hepatitis B (CHB) patients during antiviral therapy has been reported, but the underlying mechanism remains elusive. METHODS: 38 CHB patients treated with ADV for one year were selected for studying genotype shift by both deep sequencing and Sanger sequencing method. RESULTS: Sanger sequencing method found that 7.9% patients showed mixed genotype before ADV therapy. In contrast, all 38 patients showed mixed genotype before ADV treatment by deep sequencing. 95.5% mixed genotype rate was also obtained from additional 200 treatment-naive CHB patients. Of the 13 patients with genotype shift, the fraction of the minor genotype in 5 patients (38%) increased gradually during the course of ADV treatment. Furthermore, responses to ADV and HBeAg seroconversion were associated with the high rate of genotype shift, suggesting drug and immune pressure may be key factors to induce genotype shift. Interestingly, patients with genotype C had a significantly higher rate of genotype shift than genotype B. In genotype shift group, ADV treatment induced a marked enhancement of genotype B ratio accompanied by a reduction of genotype C ratio, suggesting genotype C may be more sensitive to ADV than genotype B. Moreover, patients with dominant genotype C may have a better therapeutic effect. Finally, genotype shifts was correlated with clinical improvement in terms of ALT. CONCLUSIONS: Our findings provided a rational explanation for genotype shift among ADV-treated CHB patients. The genotype and genotype shift might be associated with antiviral efficiency. PMID- 26110619 TI - Prenatal Alcohol Exposure and Congenital Heart Defects: A Meta-Analysis. AB - BACKGROUND: There are still inconsistent conclusions about the association of prenatal alcohol drinking with congenital heart defects (CHDs). We conducted this meta-analysis to investigate the association between prenatal alcohol exposure and the risk of overall CHDs and the CHDs subtypes. METHODS: Case-control and cohort studies published before March 2015 were searched through PubMed and Embase. Two authors independently extracted data and scored the study quality according to the Newcastle-0ttawa Scale. The pooled ORs and 95%CI were estimated using the random-effects model and heterogeneity was assessed by the Q test and I2 statistic. RESULTS: A total of 20 studies were finally included. The results provided no evidence of the association between prenatal alcohol exposure and the risk of overall CHDs (OR = 1.06, 95%CI = 0.93-1.22), ventricular septal defects (VSDs) (OR = 1.04, 95%CI = 0.86-1.25), or atrial septal defects (ASDs) (OR = 1.40, 95%CI = 0.88-2.23). However, prenatal alcohol drinking was marginally significantly associated with conotruncal defects (CTDs) (OR = 1.24, 95%CI = 0.97 1.59) and statistically significantly associated with d-Transposition of the Great Arteries (dTGA) (OR = 1.64, 95%CI = 1.17-2.30). Moreover, both prenatal heavy drinking and binge drinking have a strong association with overall CHDs (heavy drinking: OR = 3.76, 95%CI = 1.00-14.10; binge drinking: OR = 2.49, 95%CI = 1.04-5.97), and prenatal moderate drinking has a modest association with CTDs (OR = 1.35, 95%CI = 1.05-1.75) and dTGA (OR = 1.86, 95%CI = 1.09-3.20). CONCLUSIONS: In conclusion, the results suggested that prenatal alcohol exposure was not associated with overall CHDs or some subtypes, whereas marginally significant association was found for CTDs and statistically significant association was found for dTGA. Further prospective studies with large population and better designs are needed to explore the association of prenatal alcohol exposure with CHDs including the subtypes in specific groups. PMID- 26110620 TI - BMI1 is expressed in canine osteosarcoma and contributes to cell growth and chemotherapy resistance. AB - BMI1, a stem cell factor and member of the polycomb group of genes, has been shown to contribute to growth and chemoresistance of several human malignancies including primary osteosarcoma (OSA). Naturally occurring OSA in the dog represents a large animal model of human OSA, however the potential role of BMI1 in canine primary and metastatic OSA has not been examined. Immunohistochemical staining of canine primary and metastatic OSA tumors revealed strong nuclear expression of BMI1. An identical staining pattern was found in both primary and metastatic human OSA tissues. Canine OSA cell lines (Abrams, Moresco, and D17) expressed high levels of BMI1 compared with canine osteoblasts and knockdown or inhibition of BMI1 by siRNA or by small molecule BMI1-inhibitor PTC-209 demonstrated a role for BMI1 in canine OSA cell growth and resistance to carboplatin and doxorubicin chemotherapy. These findings suggest that inhibition of BMI1 in primary or metastatic OSA may improve response to chemotherapy and that the dog may serve as a large animal model to evaluate such therapy. PMID- 26110621 TI - Saturated, Monounsaturated and Polyunsaturated Fatty Acids Intake and Risk of Pancreatic Cancer: Evidence from Observational Studies. AB - BACKGROUND: Although the relationship between dietary monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and saturated fatty acids (SFAs) intake and pancreatic cancer risk has been reported by several studies, the evidence is controversial. We firstly conducted this comprehensive meta-analysis to summarize the aforementioned evidence from observational studies. METHODS: The MEDLINE (PubMed), Embase, and ISI Web of Science databases were used to search for epidemiological studies of dietary SFA, MUFA, and PUFA and pancreatic cancer risk that were published until the end of June 2014. Random- or fixed-effects models were used to estimate the relative risks (RRs) and 95% confidence intervals (CIs). We also carried out subgroup, sensitivity, and publication bias analyses. RESULTS: We identified 13 case-control studies and 7 prospective studies which including 6270 pancreatic cancer cases in the meta-analysis of SFA, MUFA, and PUFA and risk of pancreatic cancer. The summary RR was 1.13 (95%CI = 0.94-1.35, I2 = 70.7%) for SFA, 1.00 (95%CI = 0.87-1.14, I2 = 43.4%) for MUFA, and 0.87 (95%CI = 0.75-1.00, I2 = 55.3%) for PUFA for high versus low intake categories. We found no evidence of publication bias. CONCLUSION: In summary, findings of this study supports an inverse association between diets high in PUFA and pancreatic cancer risk. Further large prospective studies are warranted to report the results stratified by the subtypes of MUFA and PUFA and adjust for other potential risk factors to eliminate residual confounding. PMID- 26110622 TI - L-Amino Acids Elicit Diverse Response Patterns in Taste Sensory Cells: A Role for Multiple Receptors. AB - Umami, the fifth basic taste, is elicited by the L-amino acid, glutamate. A unique characteristic of umami taste is the response potentiation by 5' ribonucleotide monophosphates, which are also capable of eliciting an umami taste. Initial reports using human embryonic kidney (HEK) cells suggested that there is one broadly tuned receptor heterodimer, T1r1+T1r3, which detects L glutamate and all other L-amino acids. However, there is growing evidence that multiple receptors detect glutamate in the oral cavity. While much is understood about glutamate transduction, the mechanisms for detecting the tastes of other L amino acids are less well understood. We used calcium imaging of isolated taste sensory cells and taste cell clusters from the circumvallate and foliate papillae of C57BL/6J and T1r3 knockout mice to determine if other receptors might also be involved in detection of L-amino acids. Ratiometric imaging with Fura-2 was used to study calcium responses to monopotassium L-glutamate, L-serine, L-arginine, and L-glutamine, with and without inosine 5' monophosphate (IMP). The results of these experiments showed that the response patterns elicited by L-amino acids varied significantly across taste sensory cells. L-amino acids other than glutamate also elicited synergistic responses in a subset of taste sensory cells. Along with its role in synergism, IMP alone elicited a response in a large number of taste sensory cells. Our data indicate that synergistic and non-synergistic responses to L-amino acids and IMP are mediated by multiple receptors or possibly a receptor complex. PMID- 26110624 TI - Predictors of Enrollment in Cardiac Rehabilitation Programs in Spain. AB - PURPOSE: Cardiac rehabilitation (CR) is very effective for secondary prevention of cardiovascular disorders. The objective of this study was to analyze population factors associated with nonenrollment of cardiac patients in these programs. METHODS: Retrospective study of 756 patients referred to the cardiac rehabilitation program (CRP) of a tertiary referral hospital with a service area population of more than 640 000 from January 2009 to June 2012. We assessed the relationship between population characteristics of these patients and nonenrollment by logistic regression analysis. RESULTS: There were 2386 hospital admissions for an acute coronary syndrome during the study period. Out of the 2355 patients who were alive at discharge, 756 (632 men and 124 women) were referred for CR (32.1% vs 3% state average and vs 51% European average). Of these patients, 20.9% did not enroll. The referral rate was lower among women than among men (P < .001). The characteristics associated with a lower rate of enrollment in the program were age (OR: 1.05; 95% CI: 1.02-1.09), living alone (OR: 4.54; 95% CI: 2.53-8.16), living further than 50 km from the CR unit (OR: 2.90; 95% CI: 1.29-6.41) and, in women, having a history of cardiovascular disease (recurrent myocardial infarction) (OR: 6.35; 95% CI: 2.53-11.81). CONCLUSIONS: The rate of referral for CR in our setting is well above the national average but still could be improved. We identified older age, living alone, travel distance to the cardiac rehabilitation unit, and, in women, a history of a previous myocardial infarction as barriers to enrollment in CRPs. PMID- 26110623 TI - Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. AB - African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs. PMID- 26110625 TI - Balance Training in Pulmonary Rehabilitation: EFFECTS ON PSYCHOSOCIAL OUTCOMES. AB - PURPOSE: Balance impairment in chronic obstructive pulmonary disease (COPD) is associated with a worsening of quality of life (QOL) as related with fatigue perception, depression, and anxiety. The aim of this study was to examine the effect of balance training included in pulmonary rehabilitation (PR) on QOL, fatigue perception, depression, and anxiety in patients with COPD. METHODS: Patients were assigned randomly to an intervention or PR-only group. The intervention group underwent balance training 3 times a week for 6 months concurrently with PR. The PR-only group received 6 months of the standard PR program. Quality of life was assessed at the beginning and at the end of the program using the St. George's Respiratory Questionnaire, fatigue using the Multidimensional Fatigue Inventory, and anxiety and depression using the Hospital Anxiety and Depression Scale. Exercise tolerance was determined from the 6-minute walk test. RESULTS: After the 6 months of the intervention or PR-only, both the intervention (n = 32) and PR-only (n = 30) groups improved their QOL (activity, impact, and total) with a significant intergroup difference (P < .05) after PR. General fatigue, physical fatigue, and reduced activity decreased in both groups with an intergroup difference (P < .05). Anxiety decreased significantly in both groups with a greater change in the intervention group (P < .01). Only the intervention group had an improved depression score at the end of 6 months. CONCLUSIONS: Balance training added to PR improved health-related QOL, fatigue, and mental health in patients with COPD. PMID- 26110628 TI - Prominent vessel sign on susceptibility-weighted imaging in acute stroke: prediction of infarct growth and clinical outcome. AB - BACKGROUND AND PURPOSE: Predicting the risk of further infarct growth in stroke patients is critical to therapeutic decision making. We aimed to predict early infarct growth and clinical outcome from prominent vessel sign (PVS) identified on the first susceptibility-weighted image (SWI) after acute stroke. MATERIALS AND METHODS: Twenty-two patients with middle cerebral artery (MCA) infarction had diffusion-weighted imaging, SWI, MR angiography, and clinical evaluation using the National Institutes of Health Stroke Scale at 7-60 hours and 5-14 days after stroke onset. Late-stage clinical evaluation at 1 and 3 months used the modified Rankin Scale. The infarct area and growth were scored from 10 (none) to 0 (infarct or growth in all 10 zones) using the Alberta Stroke Program Early CT Score (ASPECTS) system. RESULTS: Infarct growth on the second MRI occurred in 13 of 15 patients with PVS on the first MRI and not in any patient without PVS (n=7; r=0.86, P<0.001). The extent of PVS was significantly correlated with infarct growth (r=0.82, P<0.001) and early-stage outcome (P=0.02). No between-group difference in late-stage clinical outcome was found. CONCLUSION: PVS on the first SWI after acute MCA territory stroke is a useful predictor of early infarct growth. Extensive PVS within the large MCA territory is related to poor early stage outcome and could be useful for clinical assessment of stroke. PMID- 26110629 TI - Sauna, sweat and science - quantifying the proportion of condensation water versus sweat using a stable water isotope ((2)H/(1)H and (18)O/(16)O) tracer experiment. AB - Most visitors of a sauna appreciate the heat pulse that is perceived when water is poured on the stones of a sauna stove. However, probably only few bathers are aware that this pleasant heat pulse is caused by latent heat being released onto our skin due to condensation of water vapour. In order to quantify the proportion of condensation water versus sweat to dripping water of test persons we conducted sauna experiments using isotopically labelled (delta(18)O and delta(2)H) thrown water as tracer. This allows differentiating between 'pure sweat' and 'condensation water'. Two ways of isotope mass balance calculations were applied and yielded similar results for both water isotopes. Accordingly, condensation contributed considerably to dripping water with mean proportions of 52 +/- 12 and 54 +/- 7% in a sauna experiment in winter semester 2011/12 and 30 +/- 13 and 33 +/- 6% in a sauna experiment in winter semester 2012/13, respectively, depending on the way of calculating the isotope mass balance. It can be concluded from the results of our dual isotope labelling sauna experiment that it is not all about sweat in the sauna. PMID- 26110630 TI - Direct and Indirect Influence of Non-Native Neighbours on Pollination and Fruit Production of a Native Plant. AB - BACKGROUND: Entomophilous non-native plants can directly affect the pollination and reproductive success of native plant species and also indirectly, by altering the composition and abundance of floral resources in the invaded community. Separating direct from indirect effects is critical for understanding the mechanisms underlying the impacts of non-native species on recipient communities. OBJECTIVES: Our aims are: (a) to explore both the direct effect of the non-native Hedysarum coronarium and its indirect effect, mediated by the alteration of floral diversity, on the pollinator visitation rate and fructification of the native Leopoldia comosa and (b) to distinguish whether the effects of the non native species were due to its floral display or to its vegetative interactions. METHODS: We conducted field observations within a flower removal experimental setup (i.e. non-native species present, absent and with its inflorescences removed) at the neighbourhood scale. RESULTS: Our study illustrates the complexity of mechanisms involved in the impacts of non-native species on native species. Overall, Hedysarum increased pollinator visitation rates to Leopoldia target plants as a result of direct and indirect effects acting in the same direction. Due to its floral display, Hedysarum exerted a direct magnet effect attracting visits to native target plants, especially those made by the honeybee. Indirectly, Hedysarum also increased the visitation rate of native target plants. Due to the competition for resources mediated by its vegetative parts, it decreased floral diversity in the neighbourhoods, which was negatively related to the visitation rate to native target plants. Hedysarum overall also increased the fructification of Leopoldia target plants, even though such an increase was the result of other indirect effects compensating for the observed negative indirect effect mediated by the decrease of floral diversity. PMID- 26110631 TI - Instrument Psychometrics: Parental Satisfaction and Quality Indicators of Perinatal Palliative Care. AB - BACKGROUND: Despite a life-limiting fetal diagnosis, prenatal attachment often occurs in varying degrees resulting in role identification by an individual as a parent. Parents recognize quality care and report their satisfaction when interfacing with health care providers. OBJECTIVE: The aim was to test an instrument measuring parental satisfaction and quality indicators with parents electing to continue a pregnancy after learning of a life-limiting fetal diagnosis. METHODS: A cross sectional survey design gathered data using a computer-mediated platform. Subjects were parents (n=405) who opted to continue a pregnancy affected by a life-limiting diagnosis. Factor analysis using principal component analysis with Varimax rotation was used to validate the instrument, evaluate components, and summarize the explained variance achieved among quality indicator items. The Prenatal Scale was reduced to 37 items with a three component solution explaining 66.19% of the variance and internal consistency reliability of 0.98. The Intrapartum Scale included 37 items with a four component solution explaining 66.93% of the variance and a Cronbach alpha of 0.977. The Postnatal Scale was reduced to 44 items with a six-component solution explaining 67.48% of the variance. Internal consistency reliability was 0.975. RESULTS: The Parental Satisfaction and Quality Indicators of Perinatal Palliative Care Instrument is a valid and reliable measure for parent-reported quality care and satisfaction. CONCLUSION: Use of this instrument will enable clinicians and researchers to measure quality indicators and parental satisfaction. The instrument is useful for assessing, analyzing, and reporting data on quality for care delivered during the prenatal, intrapartum, and postnatal periods. PMID- 26110632 TI - Peripapillary Retinal Nerve Fiber Layer and Ganglion Cell-Inner Plexiform Layers Thickness in Ankylosing Spondylitis. PMID- 26110633 TI - Predictors of Monomicrobial Necrotizing Soft Tissue Infections. AB - BACKGROUND: Broad-spectrum antibiotic therapy is critical in the management of necrotizing soft tissue infections (NSTI) in the emergency setting. Clindamycin often is included empirically to cover monomicrobial gram-positive pathogens but probably is of little value for polymicrobial infections and is associated with significant side effects, including the induction of Clostridium difficile colitis. However, there have been no studies predicting monomicrobial infections prior to obtaining cultures. The purpose of this study was to identify independent predictors of monomicrobial NSTI where the use of clindamycin would be most beneficial. We hypothesized that monomicrobial infections are characterized by involvement of the upper extremities and fewer co-morbid diseases. METHODS: We reviewed all cases of potential NSTI occurring between 1996 and 2013 in a single tertiary-care center. The infection was diagnosed by the finding of rapidly progressing necrotic fascia during debridement with positive cultures of tissue. Univariable analysis was performed using the Student t-, Wilcoxon rank sum, chi2, and Fisher exact tests as appropriate. Multivariable logistic regression was used to identify independent variables associated with outcomes. RESULTS: A group of 151 patients with confirmed NSTI with complete data was used. Of the monomicrobial infections, 61.8% were caused by Group A streptococci, 20.1% by Staphylococcus aureus, and 12.7% by Escherichia coli. Of the polymicrobial infections, E. coli was involved 13.7% of the time, followed by Candida spp. at 12.9%, and Bacteroides fragilis at 11.3%. On univariable analysis, immunosuppression, upper extremity infection, and elevated serum sodium concentration were associated with monomicrobial infection, whereas morbid obesity and a perineal infection site were associated with polymicrobial infection. On multivariable analysis, the strongest predictor of monomicrobial infection was immunosuppression (odds ratio [OR] 7.0; 95% confidence interval [CI] 2.2-22.3) followed by initial serum sodium concentration (OR 1.1; 95% CI 1.0 1.2). Morbid obesity (OR 0.1; 95% CI 0.0-0.5) and perineal infection (OR 0.3; 95% CI 0.1-0.8) were independently associated with polymicrobial infection. CONCLUSION: We identified independent risk factors that may be helpful in differentiating monomicrobial from polymicrobial NSTI. We suggest empiric clindamycin coverage be limited to patients who are immunosuppressed, have an elevated serum sodium concentration, or have upper extremity involvement and be avoided in obese patients or those with perineal disease. PMID- 26110635 TI - Investigation of Neuropathogenesis in HIV-1 Clade B and C Infection Associated with IL-33 and ST2 Regulation. AB - In present research work, for the first time, we demonstrate that neuropathogenesis in HIV-1 clade B and C infection is associated with IL-33 and ST2 dysregulation, that is, implication toward neuropathogenesis. It is known that neuropathogenesis of HIV infected individuals is clade dependent. Proinflammatory cytokines and related receptors play a significant role in the complex regulatory mechanisms of neuropathogenesis in HIV-1 infection. Among them, IL-33 is an inflammatory cytokine expressed in the central nervous system (CNS) and activates microglia cells and may affect neuroimmune inflammatory processes involved in HIV neuropathogenesis. Beside this, IL-33 receptor (ST2) plays a role in neuroinflammatory processes through the modulation of the biological action of IL-33. quantitative real time PCR (qRT-PCR), ELISA, Western blot (WB), and flow cytometry experiments were performed to elucidate the role of IL-33/ST2 in HIV neuropathogenesis in CNS cells. Apoptosis and mechanisms of IL 33 in neuronal cells were studied using caspase-3 assay and RT-PCR. Results of the studies suggest that the infection in CNS cells with HIV-1 clade B resulted in higher levels of IL-33/ST2L expression compared to HIV-1 clade C infection. Furthermore, higher concentrations of IL-33 were associated with a decrease in myocyte enhancer factor 2C (MEF2C) expression, a transcription factor that regulates synaptic function, and an increase in apoptosis, NOD2, and SLC11A1 in clade B infection. This led to neuroinflammation which dysregulates synaptic function and apoptosis. These parameters are common in neuroAIDS provoked by HIV infection. PMID- 26110637 TI - Correction: a systems biology approach identifies a regulatory network in parotid acinar cell terminal differentiation. PMID- 26110636 TI - Alpha-Amylase Activity in Blood Increases after Pharmacological, But Not Psychological, Activation of the Adrenergic System. AB - BACKGROUND & AIM: Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha amylase in blood in two separate studies. METHODS: In study 1, healthy subjects were examined in a placebo-controlled, double-blind paradigm using yohimbine, an alpha2-adrenergic antagonist. In study 2, subjects were examined in a standardized rest-controlled psychosocial stress protocol. Alpha-amylase activity in blood was repeatedly measured in both studies. RESULTS: Results of study 1 showed that alpha-amylase in blood is subject to stronger increases after injection of yohimbine compared to placebo. In study 2, results showed that there was no significant effect of psychological stress compared to rest. CONCLUSIONS: Alpha-amylase in blood increases after pharmacological activation of the adrenergic pathways suggesting that sympathetic receptors are responsible for these changes. Psychological stress, however, does not seem to have an impact on alpha-amylase in blood. Our findings provide insight into the mechanisms underlying activity changes in alpha-amylase in blood in healthy individuals. PMID- 26110638 TI - The Analysis of Pendolino (peo) Mutants Reveals Differences in the Fusigenic Potential among Drosophila Telomeres. AB - Drosophila telomeres are sequence-independent structures that are maintained by transposition to chromosome ends of three specialized retroelements (HeT-A, TART and TAHRE; collectively designated as HTT) rather than telomerase activity. Fly telomeres are protected by the terminin complex (HOAP-HipHop-Moi-Ver) that localizes and functions exclusively at telomeres and by non-terminin proteins that do not serve telomere-specific functions. Although all Drosophila telomeres terminate with HTT arrays and are capped by terminin, they differ in the type of subtelomeric chromatin; the Y, XR, and 4L HTT are juxtaposed to constitutive heterochromatin, while the XL, 2L, 2R, 3L and 3R HTT are linked to the TAS repetitive sequences; the 4R HTT is associated with a chromatin that has features common to both euchromatin and heterochromatin. Here we show that mutations in pendolino (peo) cause telomeric fusions (TFs). The analysis of several peo mutant combinations showed that these TFs preferentially involve the Y, XR and 4th chromosome telomeres, a TF pattern never observed in the other 10 telomere capping mutants so far characterized. peo encodes a non-terminin protein homologous to the E2 variant ubiquitin-conjugating enzymes. The Peo protein directly interacts with the terminin components, but peo mutations do not affect telomeric localization of HOAP, Moi, Ver and HP1a, suggesting that the peo dependent telomere fusion phenotype is not due to loss of terminin from chromosome ends. peo mutants are also defective in DNA replication and PCNA recruitment. However, our results suggest that general defects in DNA replication are unable to induce TFs in Drosophila cells. We thus hypothesize that DNA replication in Peo-depleted cells results in specific fusigenic lesions concentrated in heterochromatin-associated telomeres. Alternatively, it is possible that Peo plays a dual function being independently required for DNA replication and telomere capping. PMID- 26110639 TI - Micro-economic impact of congenital heart surgery: results of a prospective study from a limited-resource setting. AB - INTRODUCTION: The microeconomic impact of surgery for congenital heart disease is unexplored, particularly in resource limited environments. We sought to understand the direct and indirect costs related to congenital heart surgery and its impact on Indian households from a family perspective. METHODS: Baseline and first follow-up data of 644 consecutive children admitted for surgery for congenital heart disease (March 2013 - July 2014) in a tertiary referral hospital in Central Kerala, South India was collected prospectivelyfrom parents through questionnaires using a semi-structured interview schedule. RESULTS: The median age was 8.2 months (IQR: 3.0- 36.0 months). Most families belonged to upper middle (43.0%) and lower middle (35.7%) socioeconomic class. Only 3.9% of families had some form of health insurance. The median expense for the admission and surgery was INR 201898 (IQR: 163287-266139) [I$ 11989 (IQR: 9696-15804)], which was 0.93 (IQR: 0.52-1.49) times the annual family income of affected patients. Median loss of man-days was 35 (IQR: 24-50) and job-days was 15 (IQR: 11-24). Surgical risk category and hospital stay duration significantly predicted higher costs. One in two families reported overwhelming to high financial stress during admission period for surgery. Approximately half of the families borrowed money during the follow up period after surgery. CONCLUSION: Surgery for congenital heart disease results in significant financial burden for majority of families studied. Efforts should be directed at further reductions in treatment costs without compromising the quality of care together with generating financial support for affected families. PMID- 26110640 TI - The effect of Nrf2 pathway activation on human pancreatic islet cells. AB - BACKGROUND: Pancreatic islets are known to contain low level of antioxidants that renders them vulnerable to oxidative stress. Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Activation of Nrf2 pathway induces up-regulation of numerous genes encoding antioxidant and phase II detoxifying enzymes and related proteins. However, little is known regarding the role of this pathway in human islet cells. The aim was to investigate the effect of Nrf2 activator (dh404, CDDO-9,11-dihydro trifluoroethyl amide) on human islet cells. METHODS: Human islets were obtained from cadaveric donors. After dh404 treatment, Nrf2 translocation, mRNA expression, and protein abundance of its key target gene products were examined. The proportion of dh404-treated or non-treated viable islet beta cells was analyzed using flowcytemetry. The cytoprotective effects against oxidative stress and production of inflammatory mediators, and in vivo islet function after transplantation were determined. RESULTS: Nrf2 nuclear translocation was confirmed by con-focal microscope within 2 hours after treatment, which was associated with a dose-dependent increase in mRNA expression of anti-oxidants, including NQO1, HO-1, and GCLC. Enhanced HO-1 expression in dh404 treated islets was confirmed by Western Blot assay. Islet function after transplantation (2000 IEQ/mouse) to diabetic nude mice was not affected with or without dh404 treatment. After induction of oxidative stress with hydrogen peroxide (200 MUM) the proportion of dh404-treated viable islet cells was significantly higher in the dh404-treated than untreated islets (74% vs.57%; P<0.05). Dh404 significantly decreased production of cytokines/chemokines including IL-1beta, IL-6, IFN-gamma and MCP-1. CONCLUSION: Treatment of human pancreatic islets with the potent synthetic Nrf2 activator, dh404, significantly increased expression of the key anti-oxidants enzymes, decreased inflammatory mediators in islets and conferred protection against oxidative stress in beta cells. PMID- 26110641 TI - Patience, persistence and pragmatism: experiences and lessons learnt from the implementation of clinically integrated teaching and learning of evidence-based health care - a qualitative study. AB - BACKGROUND: Clinically integrated teaching and learning are regarded as the best options for improving evidence-based healthcare (EBHC) knowledge, skills and attitudes. To inform implementation of such strategies, we assessed experiences and opinions on lessons learnt of those involved in such programmes. METHODS AND FINDINGS: We conducted semi-structured interviews with 24 EBHC programme coordinators from around the world, selected through purposive sampling. Following data transcription, a multidisciplinary group of investigators carried out analysis and data interpretation, using thematic content analysis. Successful implementation of clinically integrated teaching and learning of EBHC takes much time. Student learning needs to start in pre-clinical years with consolidation, application and assessment following in clinical years. Learning is supported through partnerships between various types of staff including the core EBHC team, clinical lecturers and clinicians working in the clinical setting. While full integration of EBHC learning into all clinical rotations is considered necessary, this was not always achieved. Critical success factors were pragmatism and readiness to use opportunities for engagement and including EBHC learning in the curriculum; patience; and a critical mass of the right teachers who have EBHC knowledge and skills and are confident in facilitating learning. Role modelling of EBHC within the clinical setting emerged as an important facilitator. The institutional context exerts an important influence; with faculty buy-in, endorsement by institutional leaders, and an EBHC-friendly culture, together with a supportive community of practice, all acting as key enablers. The most common challenges identified were lack of teaching time within the clinical curriculum, misconceptions about EBHC, resistance of staff, lack of confidence of tutors, lack of time, and negative role modelling. CONCLUSIONS: Implementing clinically integrated EBHC curricula requires institutional support, a critical mass of the right teachers and role models in the clinical setting combined with patience, persistence and pragmatism on the part of teachers. PMID- 26110642 TI - Let-7 miRNAs Modulate the Activation of NF-kappaB by Targeting TNFAIP3 and Are Involved in the Pathogenesis of Lupus Nephritis. AB - TNFAIP3 is a ubiquitin-editing enzyme that negatively regulates multiple NF kappaB signaling pathways and dysregulation of TNFAIP3 is related to systemic lupus erythematosus (SLE). Although there exists evidence indicating that microRNAs (miRNAs) modulate the expression of TNFAIP3, whether and how miRNAs regulate TNFAIP3 and contribute to lupus nephritis (LN) is still not well understood. In this study, we screened eleven selected miRNAs that potentially regulated TNFAIP3 expression by dual luciferase assay and found that Let-7 miRNAs repressed TNFAIP3 expression by targeting the 3'UTR of TNFAIP3 mRNA. Overexpression of Let-7 miRNAs led to increased phosphorylation and sustained degradation of IkappaBalpha and enhanced phosphorylation of p65 following TNFalpha stimulation and promoted SeV-induced production of cytokines in HEK293T cells. In addition, the expression of Let-7 miRNAs was significantly up regulated, and TNFAIP3 level was remarkably down-regulated in samples from LN patients compared control samples. Our findings have uncovered Let-7-TNFAIP3-NF kappaB pathway that is involved in LN and thus provided a potential target for therapeutic intervention. PMID- 26110644 TI - Time-resolved cell culture assay analyser (TReCCA Analyser) for the analysis of on-line data: data integration--sensor correction--time-resolved IC50 determination. AB - Time-resolved cell culture assays circumvent the need to set arbitrary end-points and reveal the dynamics of quality controlled experiments. However, they lead to the generation of large data sets, which can represent a complexity barrier to their use. We therefore developed the Time-Resolved Cell Culture Assay (TReCCA) Analyser program to perform standard cell assay analyses efficiently and make sophisticated in-depth analyses easily available. The functions of the program include data normalising and averaging, as well as smoothing and slope calculation, pin-pointing exact change time points. A time-resolved IC50/EC50 calculation provides a better understanding of drug toxicity over time and a more accurate drug to drug comparison. Finally the logarithmic sensor recalibration function, for sensors with an exponential calibration curve, homogenises the sensor output and enables the detection of low-scale changes. To illustrate the capabilities of the TReCCA Analyser, we performed on-line monitoring of dissolved oxygen in the culture media of the breast cancer cell line MCF-7 treated with different concentrations of the anti-cancer drug Cisplatin. The TReCCA Analyser is freely available at www.uni heidelberg.de/fakultaeten/biowissenschaften/ipmb/biologie/woelfl/Research.html. By introducing the program, we hope to encourage more systematic use of time resolved assays and lead researchers to fully exploit their data. PMID- 26110645 TI - The Curious Road from Basic Pathogen Research to Clinical Translation. PMID- 26110643 TI - Protein-Trap Insertional Mutagenesis Uncovers New Genes Involved in Zebrafish Skin Development, Including a Neuregulin 2a-Based ErbB Signaling Pathway Required during Median Fin Fold Morphogenesis. AB - Skin disorders are widespread, but available treatments are limited. A more comprehensive understanding of skin development mechanisms will drive identification of new treatment targets and modalities. Here we report the Zebrafish Integument Project (ZIP), an expression-driven platform for identifying new skin genes and phenotypes in the vertebrate model Danio rerio (zebrafish). In vivo selection for skin-specific expression of gene-break transposon (GBT) mutant lines identified eleven new, revertible GBT alleles of genes involved in skin development. Eight genes--fras1, grip1, hmcn1, msxc, col4a4, ahnak, capn12, and nrg2a--had been described in an integumentary context to varying degrees, while arhgef25b, fkbp10b, and megf6a emerged as novel skin genes. Embryos homozygous for a GBT insertion within neuregulin 2a (nrg2a) revealed a novel requirement for a Neuregulin 2a (Nrg2a)-ErbB2/3-AKT signaling pathway governing the apicobasal organization of a subset of epidermal cells during median fin fold (MFF) morphogenesis. In nrg2a mutant larvae, the basal keratinocytes within the apical MFF, known as ridge cells, displayed reduced pAKT levels as well as reduced apical domains and exaggerated basolateral domains. Those defects compromised proper ridge cell elongation into a flattened epithelial morphology, resulting in thickened MFF edges. Pharmacological inhibition verified that Nrg2a signals through the ErbB receptor tyrosine kinase network. Moreover, knockdown of the epithelial polarity regulator and tumor suppressor lgl2 ameliorated the nrg2a mutant phenotype. Identifying Lgl2 as an antagonist of Nrg2a-ErbB signaling revealed a significantly earlier role for Lgl2 during epidermal morphogenesis than has been described to date. Furthermore, our findings demonstrated that successive, coordinated ridge cell shape changes drive apical MFF development, making MFF ridge cells a valuable model for investigating how the coordinated regulation of cell polarity and cell shape changes serves as a crucial mechanism of epithelial morphogenesis. PMID- 26110646 TI - Cardiac engraftment of genetically-selected parthenogenetic stem cell-derived cardiomyocytes. AB - Parthenogenetic stem cells (PSCs) are a promising candidate donor for cell therapy applications. Similar to embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), PSCs exhibit self-renewing capacity and clonogenic proliferation in vitro. PSCs exhibit largely haploidentical genotype, and as such may constitute an attractive population for allogenic applications. In this study, PSCs isolated from transgenic mice carrying a cardiomyocyte restricted reporter transgene to permit tracking of donor cells were genetically modified to carry a cardiomyocyte-restricted aminoglycoside phosphotransferase expression cassette (MHC-neor/pGK-hygror) to permit the generation of highly enriched cardiomyocyte cultures from spontaneously differentiating PSCs by simple selection with the neomycin analogue G148. Following engraftment into isogenic recipient hearts, the selected cardiomyocytes formed a functional syncytium with the host myocardium as evidenced by the presence of entrained intracellular calcium transients. These cells thus constitute a potential source of therapeutic donor cells. PMID- 26110648 TI - The Patterns of Coevolution in Clade B HIV Envelope's N-Glycosylation Sites. AB - The co-evolution of the potential N-glycosylation sites of HIV Clade B gp120 was mapped onto the coevolution network of the protein structure using mean field direct coupling analysis (mfDCA). This was possible for 327 positions with suitable entropy and gap content. Indications of pressure to preserve the evolving glycan shield are seen as well as strong dependencies between the majority of the potential N-glycosylation sites and the rest of the structure. These findings indicate that although mainly an adaptation against antibody neutralization, the evolving glycan shield is structurally related to the core polypeptide, which, thus, is also under pressure to reflect the changes in the N glycosylation. The map we propose fills the gap in previous attempts to tease out sequon evolution by providing a more general molecular context. Thus, it will help design strategies guiding HIV gp120 evolution in a rational way. PMID- 26110647 TI - TRPM4 Is a Novel Component of the Adhesome Required for Focal Adhesion Disassembly, Migration and Contractility. AB - Cellular migration and contractility are fundamental processes that are regulated by a variety of concerted mechanisms such as cytoskeleton rearrangements, focal adhesion turnover, and Ca2+ oscillations. TRPM4 is a Ca2+-activated non-selective cationic channel (Ca2+-NSCC) that conducts monovalent but not divalent cations. Here, we used a mass spectrometry-based proteomics approach to identify putative TRPM4-associated proteins. Interestingly, the largest group of these proteins has actin cytoskeleton-related functions, and among these nine are specifically annotated as focal adhesion-related proteins. Consistent with these results, we found that TRPM4 localizes to focal adhesions in cells from different cellular lineages. We show that suppression of TRPM4 in MEFs impacts turnover of focal adhesions, serum-induced Ca2+ influx, focal adhesion kinase (FAK) and Rac activities, and results in reduced cellular spreading, migration and contractile behavior. Finally, we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. Together, these findings provide the first evidence, to our knowledge, for a TRP channel specifically localized to focal adhesions, where it performs a central role in modulating cellular migration and contractility. PMID- 26110649 TI - Genome Analysis of the First Extensively Drug-Resistant (XDR) Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance. AB - The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at 4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia. PMID- 26110650 TI - Quality of Co-Prescribing NSAID and Gastroprotective Medications for Elders in The Netherlands and Its Association with the Electronic Medical Record. AB - OBJECTIVE: To assess guideline adherence of co-prescribing NSAID and gastroprotective medications for elders in general practice over time, and investigate its potential association with the electronic medical record (EMR) system brand used. METHODS: We included patients 65 years and older who received NSAIDs between 2005 and 2010. Prescription data were extracted from EMR systems of GP practices participating in the Dutch NIVEL Primary Care Database. We calculated the proportion of NSAID prescriptions with co-prescription of gastroprotective medication for each GP practice at intervals of three months. Association between proportion of gastroprotection, brand of electronic medical record (EMR), and type of GP practice were explored. Temporal trends in proportion of gastroprotection between electronic medical records systems were analyzed using a random effects linear regression model. RESULTS: We included 91,521 patient visits with NSAID prescriptions from 77 general practices between 2005 and 2010. Overall proportion of NSAID prescriptions to the elderly with co prescription of gastroprotective medication was 43%. Mean proportion of gastroprotection increased from 27% (CI 25-29%) in the first quarter of 2005 with a rate of 1.2% every 3 months to 55%(CI 52-58%) at the end of 2010. Brand of EMR and type of GP practice were independently associated with co-prescription of gastroprotection. CONCLUSION: Although prescription of gastroprotective medications to elderly patients who receive NSAIDs increased in The Netherlands, they are not co-prescribed in about half of the indicated cases. Brand of EMR system is associated with differences in prescription of gastroprotective medication. Optimal design and utilization of EMRs is a potential area of intervention to improve quality of prescription. PMID- 26110652 TI - Cancer survivors in the first year after treatment: the prevalence and correlates of unmet needs in different domains. AB - OBJECTIVE: To explore cancer survivors' unmet needs in the first year after primary treatment, and to investigate the relationship between demographic, disease-related, and psychosocial characteristics and the number of unmet needs in different domains. METHODS: Cancer survivors were recruited through eight Dutch hospitals (November 2012-January 2013). In a cross-sectional survey, 255 survivors were asked about unmet needs across several domains (CaSUN) and demographic, disease-related, and psychosocial characteristics, comprising quality of life (EORTC QLQ-C30), psychological distress (HADS), mental adjustment (MAC), and problem solving (SPSI-R:S). RESULTS: Sixty-three percent of survivors reported one or more unmet needs (M = 5.13, SD = 6.98, range = 0-34). Common unmet needs concerned emotional support (31.3%), smoking cessation (26.7% of smokers), managing side effects/complications (25.9%), fear of recurrence (23.0%), cancer care (22.0%), social support (22.0%), up-to-date information (19.8%), and carrying out work (19.6%). Regression analysis showed that age, higher education, participation in support programs, anxiety, depression, and negative adjustment style correlated positively, while being female, time since last treatment, and quality of life correlated negatively with the number of unmet needs. Lower number of unmet needs also accounted for other types of cancer (except colon cancer) than breast cancer. These relationships differed per need domain. CONCLUSIONS: The heterogeneity in unmet needs complicates the provision of adequate support for survivors. PMID- 26110651 TI - Enrichment of the Cancer Stem Phenotype in Sphere Cultures of Prostate Cancer Cell Lines Occurs through Activation of Developmental Pathways Mediated by the Transcriptional Regulator DeltaNp63alpha. AB - BACKGROUND: Cancer stem cells (CSC) drive prostate cancer tumor survival and metastasis. Nevertheless, the development of specific therapies against CSCs is hindered by the scarcity of these cells in prostate tissues. Suspension culture systems have been reported to enrich CSCs in primary cultures and cell lines. However, the molecular mechanisms underlying this phenomenon have not been fully explored. METHODOLOGY/PRINCIPAL FINDINGS: We describe a prostasphere assay for the enrichment of CD133+ CSCs in four commercial PCa cell lines: 22Rv1, DU145, LNCaP, and PC3. Overexpression of CD133, as determined by flow cytometric analysis, correlated with an increased clonogenic, chemoresistant, and invasive potential in vitro. This phenotype is concordant to that of CSCs in vivo. Gene expression profiling was then carried out using the Cancer Reference panel and the nCounter system from NanoString Technologies. This analysis revealed several upregulated transcripts that can be further explored as potential diagnostic markers or therapeutic targets. Furthermore, functional annotation analysis suggests that DeltaNp63alpha modulates the activation of developmental pathways responsible for the increased stem identity of cells growing in suspension cultures. CONCLUSIONS/SIGNIFICANCE: We conclude that profiling the genetic mechanisms involved in CSC enrichment will help us to better understand the molecular pathways that underlie CSC pathophysiology. This platform can be readily adapted to enrich and assay actual patient samples, in order to design patient-specific therapies that are aimed particularly against CSCs. PMID- 26110653 TI - Sequential Anion and Cation Exchange Reactions for Complete Material Transformations of Nanoparticles with Morphological Retention. AB - Ion exchange reactions of colloidal nanocrystals provide access to complex products that are synthetically challenging using traditional hot-injection methods. However, such reactions typically achieve only partial material transformations by employing either cation or anion exchange processes. It is now shown that anion and cation exchange reactions can be coupled together and applied sequentially in one integrated pathway that leads to complete material transformations of nanocrystal templates. Although the product nanocrystals do not contain any of the original constituent elements, the original morphology is retained, thereby fully decoupling morphology and composition control. The sequential anion/cation exchange process was applied to pseudo-spherical CdO nanocrystals and ZnO tetrapods, producing fully transformed and shape-controlled nanocrystals of copper and silver sulfides and selenides. Furthermore, hollow core-shell tetrapod ZnS@CdS heterostructures were readily accessible. PMID- 26110654 TI - Extracts of Feijoa Inhibit Toll-Like Receptor 2 Signaling and Activate Autophagy Implicating a Role in Dietary Control of IBD. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a heterogeneous chronic inflammatory disease affecting the gut with limited treatment success for its sufferers. This suggests the need for better understanding of the different subtypes of the disease as well as nutritional interventions to compliment current treatments. In this study we assess the ability of a hydrophilic feijoa fraction (F3) to modulate autophagy a process known to regulate inflammation, via TLR2 using IBD cell lines. METHOD: Mouse embryonic fibroblasts (MEF) deleted for ATG5, and two intestinal epithelial cells HCT15 and HCT116, were used to test the anti-inflammatory effect of F3 after stimulating the cells with a TLR2 specific ligand PAM3CSK4. RESULTS: F3 was able to reduce TLR2 specific inflammation and stimulate autophagy in MEFs and HCT15 cells but not in HCT116 cells. The anti inflammatory effect was reduced in the MEF cells deleted for ATG5. In addition, the activation of autophagy by F3 was enhanced by PAM3CSK4. CONCLUSION: F3 of feijoa can interact with cells via a TLR2 specific mechanism and reduce Nuclear factor kappa B (NF-kappaB) activation in part due to stimulation of autophagy. These results suggest that there is potential benefit in using feijoa extracts as part of dietary interventions to manage IBD in patients. PMID- 26110655 TI - Modelling the mechanoreceptor's dynamic behaviour. AB - All sensory receptors adapt, i.e. they constantly adjust their sensitivity to external stimuli to match the current demands of the natural environment. Electrophysiological responses of sensory receptors from widely different modalities seem to exhibit common features related to adaptation, and these features can be used to examine the underlying sensory transduction mechanisms. Among the principal senses, mechanosensation remains the least understood at the cellular level. To gain greater insights into mechanosensory signalling, we investigated if mechanosensation displayed adaptive dynamics that could be explained by similar biophysical mechanisms in other sensory modalities. To do this, we adapted a fly photoreceptor model to describe the primary transduction process for a stretch-sensitive mechanoreceptor, taking into account the viscoelastic properties of the accessory muscle fibres and the biophysical properties of known mechanosensitive channels (MSCs). The model's output is in remarkable agreement with the electrical properties of a primary ending in an isolated decapsulated spindle; ramp-and-hold stretch evokes a characteristic pattern of potential change, consisting of a large dynamic depolarization during the ramp phase and a smaller static depolarization during the hold phase. The initial dynamic component is likely to be caused by a combination of the mechanical properties of the muscle fibres and a refractory state in the MSCs. Consistent with the literature, the current model predicts that the dynamic component is due to a rapid stress increase during the ramp. More novel predictions from the model are the mechanisms to explain the initial peak in the dynamic component. At the onset of the ramp, all MSCs are sensitive to external stimuli, but as they become refractory (inactivated), fewer MSCs are able to respond to the continuous stretch, causing a sharp decrease after the peak response. The same mechanism could contribute a faster component in the 'sensory habituation' of mechanoreceptors, in which a receptor responds more strongly to the first stimulus episode during repetitive stimulation. PMID- 26110656 TI - DMSO/I2 mediated C-C bond cleavage of alpha-ketoaldehydes followed by C-O bond formation: a metal-free approach for one-pot esterification. AB - A novel and efficient I2/DMSO mediated metal-free strategy is presented for the direct C-C bond cleavage of aryl-/heteroaryl- or aliphatic alpha-ketoaldehydes by C2-decarbonylation and C1-carbonyl oxidation to give the corresponding carboxylic acids followed by esterification in one pot, offering excellent yields in both the steps. Here, DMSO acts as the oxygen source/oxidant and this reaction works very well under both conventional heating and microwave irradiation. This is a very simple and convenient protocol. PMID- 26110657 TI - Correction: Tyrosine Hydroxylase Is Short-Term Regulated by the Ubiquitin Proteasome System in PC12 Cells and Hypothalamic and Brainstem Neurons from Spontaneously Hypertensive Rats: Possible Implications in Hypertension. PMID- 26110658 TI - Diagnosis and Treatment of Autoimmune Pancreatitis in China: A Systematic Review. AB - AIMS: To provide comprehensive data on the diagnosis and treatment of autoimmune pancreatitis (AIP) patients in China. DESIGN: A systematic review. METHODS: All clinical studies concerning AIP from China published between January 2006 and June 2014 were retrospectively reviewed and analyzed. RESULTS: A total of 26 original articles involving 706 AIP patients were included with an estimated proportion of type 2 AIP as 4.7%. In the 706 AIP patients, the range of mean/median age was 48.6-67.0 years old and the male to female ratio was 4.47:1. The common presentations included obstructive jaundice (pooled rate: 63.4%, 95%CI: 55.4%-71.0%) and abdominal symptoms (pooled rate: 62.3%, 95%CI: 52.4% 71.7%). Biliary involvement was the most common extrapancreatic manifestations, especially the lower part of the common bile duct (pooled rate: 62.3%, 95%CI: 49.9%-73.9%). According to the imaging examinations, 53.8% and 41.6% patients were classified into focal-type and diffuse-type, respectively. Notably, upstream pancreatic duct dilatation was found in parts of patients (pooled rate: 13.8%, 95%CI: 6.6%-23.1%). The levels of serum IgG4 were elevated in most patients (pooled rate: 86.0%, 95%CI: 74.2%-94.6%). Nearly three tenths AIP patients received surgery (pooled rate: 29.7%, 95%CI: 18.1%-42.8%) due to mimicked malignancy. Steroid treatment was given to 78.4% patients (95%CI: 65.3%-89.1%) with a pooled remission rate of 96.2% (95%CI: 94.0%-97.9%). The pooled relapse rate was 13.8% (95%CI: 7.2%-22.0%) with the mean follow-up time ranging from 12 to 45 months. CONCLUSION: Type 1 is the predominant type of Chinese AIP patients and the clinical features, diagnostic modalities and therapeutic regimen were similar with those in other countries. Knowledge of AIP should be more widespread to avoid unnecessary surgery. PMID- 26110659 TI - Epigenetic Aging Signatures Are Coherently Modified in Cancer. AB - Aging is associated with highly reproducible DNA methylation (DNAm) changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA). Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a non-stochastic manner, particularly at CpGs that become hypermethylated upon aging in non-malignant tissues. This coordinated regulation in epigenetic aging signatures can therefore be used for aberrant epigenetic age predictions, which facilitate disease stratification. For example, in acute myeloid leukemia (AML) higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age predictions. Furthermore, epigenetic aging signatures correlate with overall survival in several types of cancer (such as lower grade glioma, glioblastoma multiforme, esophageal carcinoma, chromophobe renal cell carcinoma, cutaneous melanoma, lung squamous cell carcinoma, and neuroendocrine neoplasms). In conclusion, age-associated DNAm patterns in cancer are not related to chronological age of the patient, but they are coordinately regulated, particularly at CpGs that become hypermethylated in normal aging. Furthermore, the apparent epigenetic age-predictions correlate with clinical parameters and overall survival in several types of cancer, indicating that regulation of DNAm patterns in age-associated CpGs is relevant for cancer development. PMID- 26110661 TI - Surgical Treatment of Congenital Scoliosis Associated With Tethered Cord by Thoracic Spine-shortening Osteotomy Without Cord Detethering. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To investigate the safety and efficacy of spine-shortening osteotomy for congenital scoliosis with tethered cord. SUMMARY OF BACKGROUND DATA: Conventional surgery for congenital scoliosis associated with tethered cord risks the complications of detethering. Spine shortening osteotomy holds the potential to correct scoliosis and decrease spinal cord tension simultaneously without an extra detethering procedure, but no data on this issue is available. METHODS: 21 patients (14 females and 7 males, average age 15.4 yr) underwent spine-shortening osteotomy without detethering. All of the patients had tethered cord. Patients with main curve more than 90 degrees underwent vertebral column resection (VCR), whereas the others had pedicle subtraction osteotomy (PSO) performed. The average postoperative follow-up period was 45.2 months. RESULTS: The mean operation time was 544.5 min with average blood loss of 2769.1 ml. The deformity correction was 61.3% in the coronal plane and 43.9 degrees in the sagittal plane. 10 patients had neurological deficits preoperatively. At the final follow-up, the deficits in 8 (80%) patients were significantly improved, whereas 2 (20%) remained unchanged. At final follow-up, 71.4% (5/7) patients reported improvement in motor function, 100% (3/3) had improved pain scores, and 75% (3/4) reported better sensory function after the spine-shortening osteotomy. Urinary dysfunction and bowel incontinence present preoperatively in 3 patients all recovered by final follow-up. 5 (23.8%) patients incurred complications including temporary neurological deterioration in 1 patient, urinary tract infection in 2 patients, cerebrospinal fluid leakage in 1 patient, and blood loss more than 5000 ml in 1 patient. CONCLUSION: Spine shortening osteotomy is a safe and effective procedure for congenital scoliosis associated with tethered cord. Spine-shortening osteotomy at the thoracic apical vertebrae level not only corrects the spine deformity but also simultaneously releases the tension of the tethered cord, resulting in improved neurologic function. PMID- 26110660 TI - Characterization of Carbapenem-Resistant Enterobacteriaceae with High Rate of Autochthonous Transmission in the Arabian Peninsula. AB - To establish the role of local transmission versus possible pathogen import due to previous foreign exposure in infections caused by carbapenem non-susceptible Enterobacteriaceae in the Arabian Peninsula, 200 independent isolates collected in 16 hospitals of Saudi Arabia, Kuwait, Oman and the United Arab Emirates were studied. All strains were multidrug resistant; 42.5% of them also qualified as extremely drug resistant. The frequency of various carbapenemases varied according to the participating countries, but in the collection, as a whole, blaNDM-1 was the most frequently encountered carbapenemase gene (46.5%) followed by blaOXA-48-like gene (32.5%). A comparatively high rate (8.9%) of multi-clonal strains carrying both blaNDM and blaOXA-48-like genes in the United Arab Emirates, representing the most resistant subgroup, was encountered. No KPC expressing isolates were detected. Three major clones of blaNDM-1 carrying Klebsiella pneumoniae of ST152 (n = 22, Saudi Arabia), ST14 (n = 7, United Arab Emirates) and ST147 types (n = 9, Oman) were identified, the latter two clones carrying similar, but not identical HI1b incompatibility type plasmids of >170 kb. While from 78.6% of the cases with documented foreign hospitalization blaNDM positive strains were isolated, these strains formed only 25.6% of all the isolates expressing this enzyme. In fact, 56.8% of the NDM, 75.7% of OXA-48-like and 90.9% of VIM positive strains were recovered from patients without documented foreign exposure, neither in the form of travel or prior hospitalization abroad, suggesting a high rate of autochthonous infections. This, considering the extensive links of these countries to the rest of the world, predicts that trends in the local epidemiology of carbapenem resistant strains may increasingly affect the spread of these pathogens on the global scale. These results call for improved surveillance of carbapenem resistant Enterobacteriaceae in the countries of the Arabian Peninsula. PMID- 26110662 TI - A replication study for association of 53 single nucleotide polymorphisms in ScoliScore test with adolescent idiopathic scoliosis in French-Canadian population by Tang et al. PMID- 26110663 TI - Responsiveness and Interpretability of the Portuguese Version of the Neck Disability Index in Patients With Chronic Neck Pain Undergoing Physiotherapy. AB - STUDY DESIGN: A prospective cohort study with a 7-week follow-up of 113 patients with chronic neck pain undergoing physiotherapy. OBJECTIVE: To examine the responsiveness of the Portuguese Version of the Neck Disability Index (NDI-PT), and to determine the minimal clinically important difference (MCID), minimal detectable change (MDC), and floor/ceiling effects. SUMMARY OF BACKGROUND DATA: Studies that determine MDC and MCID are needed to provide more accurate outcome evaluation and critically assess potential relevant sources for differences in the minimal important change values for the NDI. METHODS: The NDI-PT was administered twice: at the baseline and after 7 weeks of physiotherapy treatment. A Global Transition Scale was used as an external criterion measure to distinguish between improved and nonimproved patients' scores between baseline and follow-up. The responsiveness of the NDI-PT was assessed through anchor-based methods (correlation coefficient and receiver operating characteristics curves ROC curves). The MCID was estimated by the ROC curve method, and the MDC through the standard Error of Measurement (SEM). RESULTS: The NDI-PT revealed moderate responsiveness when applied to patients with chronic neck pain undergoing physiotherapy (rho = 0.328 and area under the curve of 0.595, 95% confidence interval: 0.484-0.706). The MDC achieved 12 points, whereas the MCID was found to be 5.5 points. A complementary ROC analysis based on percentage differences in NDI-PT scores from baseline revealed an optimal cutoff point of 27%. The optimal cutoff point was found to be dependent of disability baseline scores. CONCLUSION: The NDI-PT demonstrated moderate levels of responsiveness. The amount of change in questionnaire scores perceived by the patient to be meaningful is smaller than the amount of change required to be statistically 95% confident that score change is not just measurement error. LEVEL OF EVIDENCE: N/A. PMID- 26110664 TI - Overall Similar Infection Rates Reported in the Physician-reported Scoliosis Research Society Database and the Chart-abstracted American College of Surgeons National Surgical Quality Improvement Program Database. AB - STUDY DESIGN: This is a retrospective cohort study. OBJECTIVE: To compare the infection rates in the Scoliosis Research Society (SRS) morbidity and mortality database to those in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. SUMMARY OF BACKGROUND DATA: Surgical databases have demonstrated value in orthopaedic surgery. However, few studies in the literature have used the SRS database relative to other available databases. To validate the surgeon-reported data of the SRS database, we compared the rate of postoperative infection in this database to that in the chart-abstracted ACS NSQIP database. METHODS: International Classification of Disease, ninth revision (ICD-9) codes were used to group patients from the 2012 and 2013 ACS-NSQIP database into groups corresponding to spinal deformity diagnoses delineated by SRS. Postoperative infection rates after surgical correction of these deformities compared with those reported in the 2012 and 2013 SRS database using chi tests. RESULTS: The overall rate of acute postoperative infection was slightly lower in the SRS database than in the ACS-NSQIP database (1.21% compared to 2.05% in ACS NSQIP, a difference of only 0.84%, statistically significant, P < 0.001).The infection rates of most diagnoses did not differ; these included scoliosis (idiopathic <10 yr of age/congenital/neuromuscular/other scoliosis), spondylolisthesis (isthmic/dysplastic), and kyphosis (congenital and other). The only differences noted were in Scheuermann kyphosis (difference of 5.49%, P = 0.003), degenerative spondylolithesis (difference of 0.69%, P = 0.003), and idiopathic scoliosis in the age 10 to18 yr and adult age ranges (differences of 1.10% and 1.28%, P < 0.001 for both). CONCLUSION: Although some statistical differences were found in infection rates between the surgeon-reported SRS database and the chart-abstracted ACS-NSQIP database, these small differences likely reflect differences in surgical cases and data collection methods. This finding supports the validity of the surgeon-reported SRS morbidity and morality database. LEVEL OF EVIDENCE: 3. PMID- 26110665 TI - Thoracic Hemangioma From Rib Presenting as Compressive Paraparesis in a Young Adult: A Treatment Dilemma. AB - STUDY DESIGN: A case report. OBJECTIVE: To describe the presentation of compressive paraparesis as a result of thoracic rib hemangioma in a young adult and its nonsurgical management. SUMMARY OF BACKGROUND DATA: Hemangiomas are rare bone tumors and those arising from rib are rarer. Only about 50 such cases have been reported in literature so far. METHODS: A 21-year-old male student, presented to us with a 6-week history of progressive weakness in both lower limbs and loss of bowel bladder control. Patient gave history of being operated for left periscapular tumor treated with wide excision and proven with biopsy to be a hemangioendothelioma (benign but locally aggressive hemangioma variant) a year ago. RESULTS: New radiograph of the chest showed an expansile lesion of left fifth rib and magnetic resonance image showed a tumor of left dorsal thoracic wall with AV malformation causing compressive thoracic myelopathy at T5 level vertebrae. We planned for immediate decompression surgery for spine along with excision of tumor with the help of a thoracic surgeon. However, on preoperative digital subtraction angiography, the tumor was found to be highly vascular with high risk of intraoperative bleeding and morbidity. So, the plan was revised and the patient underwent digital subtraction angiography, followed by embolization by an expert interventional neurosurgeon. The patient showed signs of recovery within a week. Lower limb power improved from grade 2 to 3/5 to grade 4 to 4+/5. The patient became ambulatory with single stick at 3-month follow-up; he was a nonwalker to start with. At 2 years plus follow-up, the patient fully recovered and walks without stick. CONCLUSION: This unique case brings to light the dilemma a spine surgeon sometimes faces. A case that warranted immediate surgical intervention based on clinical findings was treated with interventional fibrin glue embolizations with excellent results. LEVEL OF EVIDENCE: N/A. PMID- 26110666 TI - Determining Organ Doses from CT with Direct Measurements in Postmortem Subjects: Part 2--Correlations with Patient-specific Parameters. AB - PURPOSE: To generate empirical sets of equations that can be used to calculate patient-specific organ doses resulting from a group of computed tomographic (CT) studies by using data from direct dose measurements performed within a human body. MATERIALS AND METHODS: Organ dose measurements were obtained in eight postmortem female subjects. A chest-abdomen-pelvis protocol was used for this study. The relationships among measured organ doses, body mass index, effective diameter (D(eff)), and volume CT dose index (CTDI(vol)) were investigated. Organ dose equations were developed by means of linear regression from organ dose data, with CTDI(vol) and D(eff) as variables, by using Pearson correlation coefficients and P values to determine correlation strength of fit. Measured organ doses were compared with corresponding size-specific dose estimates (SSDEs). RESULTS: The central-section D(eff) presented similar correlations with organ doses to those from D(eff) measured at specific organ locations. The strongest correlations were observed between the central-section D(eff) and CTDI(vol)-normalized organ doses (R(2): 0.478-0.941). The average of measured organ doses for each subject resulted in an average difference of only 5% from SSDE-calculated doses; however, individual organ doses differed from +31% to -61% from the calculated SSDE. CONCLUSION: The organ dose equations developed represent a method for organ dose estimation from direct organ dose measurements that can estimate organ doses more accurately than the calculated SSDE, which provides a less-specific patient dose estimate. PMID- 26110667 TI - MR Imaging as an Additional Screening Modality for the Detection of Breast Cancer in Women Aged 50-75 Years with Extremely Dense Breasts: The DENSE Trial Study Design. AB - Women with extremely dense breasts have an increased risk of breast cancer and lower mammographic tumor detectability. Nevertheless, in most countries, these women are currently screened with mammography only. Magnetic resonance (MR) imaging has the potential to improve breast cancer detection at an early stage because of its higher sensitivity. However, MR imaging is more expensive and is expected to be accompanied by an increase in the number of false-positive results and, possibly, an increase in overdiagnosis. To study the additional value of MR imaging, a randomized controlled trial (RCT) design is needed in which one group undergoes mammography and the other group undergoes mammography and MR imaging. With this design, it is possible to determine the proportion of interval cancers within each study arm. For this to be an effective screening strategy, the additional cancers detected at MR imaging screening must be accompanied by a subsequent reduction in interval cancers. The Dense Tissue and Early Breast Neoplasm Screening, or DENSE, trial is a multicenter RCT performed in the Dutch biennial population-based screening program (subject age range, 50-75 years). The study was approved by the Dutch Minister of Health, Welfare and Sport. In this study, mammographic density is measured by using a fully automated volumetric method. Participants with extremely dense breasts (American College of Radiology breast density category 4) and a negative result at mammography (Breast Imaging Recording and Data System category 1 or 2) are randomly assigned to undergo additional MR imaging (n = 7237) or to be treated according to current practice (n = 28 948). Participants provide written informed consent before the MR imaging examination, which consists of dynamic breast MR imaging with gadolinium-based contrast medium and is intended to be performed for three consecutive screening rounds. The primary outcome is the difference in the proportions of interval cancers between the study arms. Secondary outcomes are the number of MR imaging screening-detected cancers, proportions of false-positive results, diagnostic yield of MR imaging, tumor characteristics, quality of life, and cost effectiveness. PMID- 26110669 TI - Changes in Epithelium, Stroma, and Lumen Space Correlate More Strongly with Gleason Pattern and Are Stronger Predictors of Prostate ADC Changes than Cellularity Metrics. AB - PURPOSE: To investigate the hypothesis that the clinically observed decrease in apparent diffusion coefficient (ADC) at diffusion-weighted magnetic resonance imaging with increasing prostate cancer Gleason grade can be attributed to an increasing volume of low-diffusivity epithelial cells and corresponding decreasing volumes of higher-diffusivity stroma and lumen space rather than to increased cell density. MATERIALS AND METHODS: Tissue samples were acquired after institutional ethics review committee approval and informed consent from patients were obtained. Nuclear count, nuclear area, and gland component volumes (epithelium, stroma, lumen space) were measured in tissue from 14 patients. Gland component volumes and cellularity metrics were correlated with Gleason pattern (Spearman rank correlation coefficient) and measured ADC (Pearson correlation coefficient) in six prostates ex vivo. Differences between metrics for cancerous tissue and those for normal tissue were assessed by using a two-tailed two-sample t test. Linear mixed models with a post hoc Fisher least significant difference test were used to assess differences between gland component volumes and cellularity metrics for multiple groups. To adjust for a clustering effect due to repeated measures, the organ mean value of the measured metric for each tissue type was used in the analysis. RESULTS: There were significant differences between Gleason patterns for gland component volumes (P < .05) but not nuclear count (P = .100) or area (P = .141). There was a stronger correlation of Gleason pattern with gland component volumes (n = 553) of epithelium (Spearman rho = 0.898, P < .001), stroma (rho = -0.651, P < .001), and lumen space (rho = -0.912, P = .007) than with the cellularity metrics (n = 288) nuclear area (rho = 0.422, P = .133) or nuclear count (rho = 0.082, P = .780). There was a stronger correlation between measured ADC and lumen volume (r = 0.688, P < .001) and epithelium volume (r = -0.647, P < .001) than between ADC and nuclear count (r = 0.598, P < .001) or nuclear area (r = -0.569, P < .001) (n = 57). CONCLUSION: Differences in the gland compartment volumes of prostate tissue having distinct diffusivities, rather than changes in the conventionally cited "cellularity" metrics, are likely to be the major contributor to clinically observed variations of ADC in prostate tissue. PMID- 26110668 TI - Oxygen-weighted Hyperpolarized (3)He MR Imaging: A Short-term Reproducibility Study in Human Subjects. AB - PURPOSE: To determine whether hyperpolarized helium 3 magnetic resonance (MR) imaging to measure alveolar partial pressure of oxygen (Pao2) shows sufficient test-retest repeatability and between-cohort differences to be used as a reliable technique for detection of alterations in gas exchange in asymptomatic smokers. MATERIALS AND METHODS: The protocol was approved by the local institutional review board and was HIPAA compliant. Informed consent was obtained from all subjects. Two sets of MR images were obtained 10 minutes apart in 25 subjects: 10 nonsmokers (five men, five women; mean +/- standard deviation age, 50 years +/- 6) and 15 smokers (seven women, eight men; mean age, 50 years +/- 8). A mixed effects model was developed to identify the regional repeatability of Pao2 measurements as an intraclass correlation coefficient. Ten smokers were matched with the 10 nonsmokers on the basis of signal-to-noise ratio (SNR). Three separate models were generated: one for nonsmokers, one for the SNR-matched smokers, and one for the five remaining smokers, who were imaged with a significantly higher SNR. RESULTS: Short-term back-to-back regional reproducibility was assessed by using intraclass correlation coefficients, which were 0.67 and 0.65 for SNR case-matched nonsmokers and smokers, respectively. Repeatability was a strong function of SNR; a 50% increase in SNR in the remaining smokers improved the intraclass correlation coefficient to 0.82. Although repeatability was not significantly different between the SNR-matched cohorts (P = .44), the smoker group showed higher spatial and temporal variability in Pao2. CONCLUSION: The short-term test-retest repeatability of hyperpolarized gas MR imaging of regional Pao2 was good. Asymptomatic smokers exhibited greater spatial and temporal variability in Pao2 than did the nonsmokers, which suggests that this parameter allows detection of small functional alterations associated with smoking. PMID- 26110670 TI - System Accuracy Evaluation of Different Blood Glucose Monitoring Systems Following ISO 15197:2013 by Using Two Different Comparison Methods. AB - BACKGROUND: Adherence to established standards (e.g., International Organization for Standardization [ISO] 15197) is important to ensure comparable and sufficient accuracy of systems for self-monitoring of blood glucose (SMBG). Accuracy evaluation was performed for different SMBG systems available in Europe with three reagent lots each. MATERIALS AND METHODS: Test procedures followed the recently published revision ISO 15197:2013. Comparison measurements were performed with a glucose oxidase (YSI 2300 STAT PlusTM glucose analyzer; YSI Inc., Yellow Springs, OH) and a hexokinase (cobas Integra((r)) 400 Plus analyzer; Roche Instrument Center, Rotkreuz, Switzerland) method. Compliance with ISO 15197:2013 accuracy criteria was determined by calculating the percentage of results within +/-15% or within +/-0.83 mmol/L of the comparison measurement results for glucose concentrations at and above or below 5.55 mmol/L, respectively, and by calculating the percentage of results within consensus error grid Zones A and B. RESULTS: Seven systems showed with all three tested lots that 95-100% of the results were within the accuracy limits of ISO 15197:2013 and that 100% of results were within consensus error grid Zones A and B, irrespective of the comparison method used. Regarding results of individual lots, slight differences between the glucose oxidase method and the hexokinase method were found. Accuracy criteria of ISO 15197:2003 (+/-20% for concentrations >=4.2 mmol/L and+/-0.83 mmol/L for concentrations <4.2 mmol/L) were fulfilled by eight systems with all three lots and by one system with two lots. CONCLUSIONS: In this study, seven systems complied with the accuracy criteria of ISO 15197:2013. The results also indicate that the comparison measurement method/system is important, as it may have a considerable impact on accuracy data obtained for a system. PMID- 26110671 TI - Effectiveness of Atomoxetine in the Treatment of Children With Encopresis. PMID- 26110672 TI - Correction: A RNA-Seq Analysis of the Rat Supraoptic Nucleus Transcriptome: Effects of Salt Loading on Gene Expression. PMID- 26110673 TI - Voice Outcomes Following Posterior Cordotomy With Medial Arytenoidectomy in Patients With Bilateral Vocal Fold Immobility. AB - IMPORTANCE: Voice quality-of-life (VQOL) and perceptual voice outcomes are presumed to worsen following posterior cordotomy with medial arytenoidectomy for bilateral vocal fold immobility (BVFI); however, subjective and objective voice outcomes are not well studied in this postsurgical patient population. OBJECTIVE: To evaluate VQOL and perceptual voice outcomes following posterior cordotomy with medial arytenoidectomy for BVFI. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of 15 patients with BVFI who underwent posterior cordotomy with medial arytenoidectomy at a tertiary care academic hospital from 2009 to 2012. INTERVENTIONS: Suspension microlaryngoscopy was performed to expose the posterior glottis. A posterior cordotomy and medial arytenoidectomy was performed anterior to the vocal process of the vocal fold in a medial to lateral fashion. MAIN OUTCOMES AND MEASURES: Data included age, sex, tracheostomy status, number of cordotomies, and voice outcomes. Voice-Related Quality of Life (VRQOL) and Consensus Auditory Perceptual Evaluation of Voice (CAPE-V) data were collected preoperatively and postoperatively surrounding a single procedure. Comparisons within a single group were performed with a paired t test. Statistical significance was determined at P <= .05. RESULTS: Eight patients (53%) were male, and 7 (47%) were female. Six patients (40%) required a tracheotomy at some point during treatment, 4 were successfully decannulated. For all 15 patients, the mean VRQOL scores improved 12 points from 47.33 to 59.33 after posterior cordotomy (P = .12). Mean CAPE-V overall severity scores in 13 patients increased 26 points after posterior cordotomy with medial arytenoidectomy from 38.12 to 62.77 (P = .01), indicating further deviance from normal. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first study to compare VQOL with perceptual voice outcomes following posterior cordotomy with medial arytenoidectomy in a series of patients with BVFI. Patients who underwent posterior cordotomy in this study had significantly reduced perceptual voice outcomes with unchanged VQOL. While postcordotomy patients have a dysphonia that is noticeable to voice professionals, most patients in this study subjectively felt as though their voice improved after surgery. Surgeons should be aware of these factors when counseling patients considering cordotomy for BVFI. PMID- 26110674 TI - Moderate Alcohol Consumption and Colorectal Cancer Risk. AB - BACKGROUND: Heavy alcohol drinking is a risk factor for colorectal cancer (CRC); previous studies have shown a linear dose-dependent association between alcohol intake and CRC. However, some studies suggest that moderate alcohol consumption may have a protective effect, similar to that seen in cardiovascular disease. Other factors may interact with alcohol and contribute additional risk for CRC. We aimed to determine the association between moderate alcohol consumption, limited to 30 g of alcohol per day, by beverage type on CRC risk and to assess the effects of other factors that interact with alcohol to influence CRC risk. METHODS: The PubMed database was used to find articles published between 2008 and 2014 related to alcohol and CRC. Twenty-one relevant articles were evaluated and summarized, including 11 articles reporting on CRC risk associated with moderate intake and 10 articles focusing on genetic interactions associated with alcohol and CRC risk. RESULTS: The association between alcohol and increased risk for CRC was found when intakes exceeded 30 g/d alcohol. Nonsignificant results were consistently reported for intakes <30 g/d. Additional risks for CRC were found to be related to obesity and folate status for regular alcohol consumers. Some significant results suggest that the development of CRC is dependent on the interaction of gene and environment. CONCLUSIONS: The association between the amount of alcohol consumed and the incidence of CRC was not significant at moderate intake levels. Moderate alcohol consumption was associated with a reduced CRC risk in study populations with greater adherence to a Mediterranean diet, where wine contributed substantially to the alcoholic beverage consumed. Other factors such as obesity, folate deficiency, and genetic susceptibility may contribute additional CRC risk for those consuming alcohol. To minimize CRC risk, appropriate recommendations should encourage intakes below 30 g of alcohol each day. PMID- 26110675 TI - Drug hypersensitivity reactions: more basic and clinical research is needed. PMID- 26110676 TI - Drug metabolism and hypersensitivity reactions to drugs. AB - PURPOSE OF REVIEW: The aim of the present review was to discuss recent advances supporting a role of drug metabolism, and particularly of the generation of reactive metabolites, in hypersensitivity reactions to drugs. RECENT FINDINGS: The development of novel mass-spectrometry procedures has allowed the identification of reactive metabolites from drugs known to be involved in hypersensitivity reactions, including amoxicillin and nonsteroidal antiinflammatory drugs such as aspirin, diclofenac or metamizole. Recent studies demonstrated that reactive metabolites may efficiently bind plasma proteins, thus suggesting that drug metabolites, rather than - or in addition to - parent drugs, may elicit an immune response. As drug metabolic profiles are often determined by variability in the genes coding for drug-metabolizing enzymes, it is conceivable that an altered drug metabolism may predispose to the generation of reactive drug metabolites and hence to hypersensitivity reactions. These findings support the potential for the use of pharmacogenomics tests in hypersensitivity (type B) adverse reactions, in addition to the well known utility of these tests in type A adverse reactions. SUMMARY: Growing evidence supports a link between genetically determined drug metabolism, altered metabolic profiles, generation of highly reactive metabolites and haptenization. Additional research is required to developing robust biomarkers for drug-induced hypersensitivity reactions. PMID- 26110677 TI - Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs. AB - PURPOSE OF REVIEW: NSAIDs are the main triggers of hypersensitivity reactions to drugs. However, the full genetic and molecular basis of these reactions has yet to be uncovered. In this article, we have summarized research from recent years into the effects of genetic variants on the different clinical entities induced by NSAID hypersensitivity, focusing on prostaglandin and leukotriene-related genes as well as others beyond the arachidonic acid pathway. RECENT FINDINGS: We introduce recent contributions of high-throughput approaches including genome wide association studies as well as available information from epigenetics and next-generation sequencing. Finally, we give our thoughts on future directions in this field, including the scope for bioinformatics and systems biology and the need for clear patient phenotyping. SUMMARY: The full genetic and molecular basis of clinical entities induced by NSAIDs hypersensitivity has yet to be uncovered, and despite commendable efforts over recent years, no clinically proven genetic markers currently exist for these disorders. It is clear that we will continue to find more about these reactions in the coming years, concurrently with improvements in technology and experimental techniques, and a precise definition of different phenotypes. PMID- 26110678 TI - Monitoring the acute response in severe hypersensitivity reactions to drugs. AB - PURPOSE OF REVIEW: Severe adverse drug reactions (ADRs) including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are acute life-threatening conditions. There is the urgent need for reliable, noninvasive and standardized laboratory tests for identifying patients at higher risk of developing severe ADRs. RECENT FINDINGS: Although previous studies demonstrated the pathogenic role of TNF-alpha, IFN-gamma, IL-10, perforin/granzyme B, Fas L and granulysin in the development of severe ADRs, there have been no biomarkers predicting progression to severe ADRs. We, therefore, measured serum levels of cytokines/chemokines as well as other biological markers in patients who presented with clinical symptoms suggestive of ADRs at their initial presentation. The results show that sFas L represents a useful early biomarker that can predict the subsequent progression to TEN, but not SJS, particularly when combined with the increase in IL-6 and IP-10. The increased levels of IL-6 and IP-10 are reliable biomarkers predictive of the progression to severe ADRs, such as SJS/TEN and DiHS/DRESS. SUMMARY: The use of a combination of several early biomarkers, although not sufficiently sensitive or specific on its own when used alone, could increase the diagnostic and prognostic utility for the prediction of severe ADRs. PMID- 26110679 TI - Cutaneous adverse drug reactions in the elderly. AB - PURPOSE OF REVIEW: Population ageing is a worldwide phenomenon. The presence of multiple comorbidities, polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics, as well as skin changes in the elderly contribute to a unique diagnostic and management problem. This article reviews the epidemiology of cutaneous adverse drug reactions in the elderly and elaborates on a few specific types of reactions which are more relevant to the elderly. RECENT FINDINGS: Chronic dermatoses, for example, eczema, have been reported to be associated with the use of long-term medications such as calcium channel blockers and hydrochlorothiazide. Elderly patients receiving treatment for cancers may develop chemotherapy-related cutaneous side effects, including those associated with newer 'targeted' molecular therapies. Elderly patients who develop severe cutaneous adverse drug reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have worse prognosis in terms of mortality. SUMMARY: Persons of advanced age often have multiple comorbidities and are on multiple medications. This can result in higher probability of an elderly person developing drug eruptions. It is important for the clinician to be aware of the range of drug-related eruptions and their implications. PMID- 26110680 TI - Penicillin allergy: optimizing diagnostic protocols, public health implications, and future research needs. AB - PURPOSE OF REVIEW: Unverified penicillin allergy is being increasingly recognized as a public health concern. The ideal protocol for verifying true clinically significant IgE-mediated penicillin allergy needs to use only commercially available materials, be well tolerated and easy to perform in both the inpatient and outpatient settings, and minimize false-positive determinations. This review concentrates on articles published in 2013 and 2014 that present new data relating to the diagnosis and management of penicillin allergy. RECENT FINDINGS: Penicillin allergy can be safely evaluated at this time, in patients with an appropriate clinical history of penicillin allergy, using only penicilloyl-poly lysine and native penicillin G as skin test reagents, if an oral challenge with amoxicillin 250 mg, followed by 1 h of observation, is given to all skin test negative individuals. SUMMARY: Millions of individuals falsely labeled with penicillin allergy need to be evaluated to safely allow them to use penicillin class antibiotics and avoid morbidity associated with penicillin avoidance. Further research is needed to determine optimal protocol(s). There will still be a 1-2% rate of adverse reactions reported with all future therapeutic penicillin class antibiotic use, even with optimal methods used to determine acute penicillin tolerance. Only a small minority of these new reactions will be IgE mediated. PMID- 26110681 TI - Aspirin desensitization for cardiovascular disease. AB - PURPOSE OF REVIEW: The use of aspirin in coronary artery disease and address the unmet need of aspirin therapy in patients with history of hypersensitivity reactions to aspirin (acetylsalicylic acid; ASA) or other nonsteroidal inflammatory drugs (NSAIDs). RECENT FINDINGS: Aspirin hypersensitivity is reported in 1.5% of patients with cardiovascular disease. However, many of those labeled as allergic to aspirin had experienced side-effects and could be safely treated with aspirin. Those with true hypersensitivity reactions were often not placed on appropriate antiplatelet therapy. A number of protocols of varying complexity exist in the literature for aspirin desensitization. The focus of this review is to identify the types of aspirin reactions that can occur and provide a rational approach to oral aspirin challenge and desensitization. SUMMARY: In summary, with rare exceptions, patients with a history of 'aspirin/NSAID allergy' who need ASA for cardiovascular issues will be able to safely take aspirin either after a graded challenge or desensitization providing a central role of the allergist in the management of these patients. PMID- 26110682 TI - Epinephrine in anaphylaxis: doubt no more. AB - PURPOSE OF REVIEW: The purpose of this manuscript is to review the literature in support of epinephrine (adrenaline) as first line of therapy of anaphylaxis, not H-1 antihistamines or corticosteroids. RECENT FINDINGS: The purpose of this review is to assess that epinephrine has a quick onset of activity and rapidly antagonizes multiple mediators that are active in anaphylaxis. Epinephrine has maximal pharmacodynamic effect within 10 min of intramuscular administration into the thigh. As epinephrine has a narrow therapeutic window, prefilled epinephrine auto-injectors are available. There are weight-appropriate doses of epinephrine available with auto-injectors that are prefilled with 0.15, 0.30 and 0.50 mg. In addition, needle lengths vary from 1.17 to 2.50 cm. Different doses and needle lengths are available for paediatric and adult patients, especially obese patients to ensure intramuscular delivery in the thigh. SUMMARY: Failure to administer epinephrine promptly has resulted in fatalities. Education about anaphylaxis and prompt treatment are critical for patients and their caregivers. PMID- 26110683 TI - Biomarkers of anaphylaxis, beyond tryptase. AB - PURPOSE OF REVIEW: The purpose of this study is to describe the current knowledge regarding mediators involved in anaphylactic reactions, with a special focus on key effector cells and mechanisms. RECENT FINDINGS: New insight into the potential relevance of pathways other than mast cell degranulation has been unravelled, such as the role of cytokines, platelet activation factor, lipid mediators and their metabolism or the activation of the contact system. SUMMARY: Gaining knowledge into these pathophysiologic mechanisms will allow researchers to pursue the identification of risk factors and new preventive and therapeutic strategies in anaphylaxis. PMID- 26110684 TI - Hidden allergens and oral mite anaphylaxis: the pancake syndrome revisited. AB - PURPOSE OF REVIEW: To present currently available information on oral mite anaphylaxis. RECENT FINDINGS: Oral mite anaphylaxis (pancake syndrome) is a new syndrome characterized by severe symptoms triggered by the intake of foods containing mites and their allergens. Breathlessness, face and/or laryngeal angioedema, wheezing, rhinorrhea, cough, dysphagia, and wheals are the most frequent clinical manifestations. SUMMARY: Pancake syndrome can occur in individuals at any age and in any geographical location. Foods made with wheat and corn flour, especially pancakes, are the most common inducers of the clinical picture. Both, domestic and storage mites have been incriminated. Increased physician awareness is required for early diagnosis and treatment, and for the prevention of future episodes in predisposed individuals. PMID- 26110685 TI - Anaphylaxis in adolescents: a potential tripartite management framework. AB - PURPOSE OF REVIEW: The incidence of anaphylaxis is increasing across all ages, but the risk of morbidity and fatality is disproportionately high in adolescents. This may, at least in part, be a consequence of a constellation of potentially modifiable psychosocial factors that tend to manifest during adolescence. This study highlights the shortcomings in and the barriers to effective management of anaphylaxis in adolescents, and proposes an integrated tripartite framework that may help promote successful management. RECENT FINDINGS: Existing mainstay anaphylaxis self-management approaches - comprising careful avoidance of triggers, recognition of early features indicative of anaphylaxis and prompt self administration of intra-muscular adrenaline (epinephrine) - often fail in adolescents. Key barriers to successful management centre on the impact of the psychosocial environment during adolescents' developmental transition. As a result, risk-taking, poor judgement of actions during reactions and non compliance to management instructions are common. SUMMARY: To be successful, anaphylaxis management strategies require more multidimensional approaches among adolescents. We propose a tripartite management framework that emphasizes integration of the following components: better understanding of adolescence; incorporation of the constituents of adolescents' social networks; and adolescent tailored healthcare perspectives. This theoretical framework now requires translation into an intervention, feasibility and pilot testing, and formal evaluation through randomized controlled trials. PMID- 26110686 TI - Sunlight, vitamin D and food allergy. AB - PURPOSE OF REVIEW: The role of vitamin D in the development of food allergy is unclear. We summarize recent data on the epidemiologic link between sunlight (UVB) and food allergy, and evidence for and against a specific role for vitamin D status. RECENT FINDINGS: Since 2007, most epidemiologic studies have supported low sunlight (as measured by season of birth and latitude) as a risk factor for food allergy. Investigators have also looked directly at vitamin D status (as measured by serum 25OHD level) and its potential role. Although conflicting, the vitamin D studies suggest a more complicated association than a linear dose response in all individuals, with some studies indicating different associations based on host characteristics (e.g. concominant eczema, genetic polymorphisms, country of birth). Most studies have not fully examined the myriad effects of sunlight but have instead focused on a single maternal, neonatal or childhood 25OHD level. SUMMARY: Many studies have linked sunlight with the development of food allergy but whether this is directly related to vitamin D status or a myriad of other sunlight-derived, seasonal and/or geographic factors remains uncertain. More studies are needed to investigate the role of sunlight and vitamin D status in food allergy because of their potential for primary prevention and disease modification. PMID- 26110687 TI - A 'difficult' insect allergy patient: reliable history of a sting, but all testing negative. AB - PURPOSE OF REVIEW: Few conditions are as treatable as allergy to stinging insects, with venom immunotherapy (VIT) providing up to 98% protection to subsequent stings. The challenge with VIT is not in the treatment, but in the diagnosis. To offer VIT, one must determine a history of a systemic reaction to a stinging insect in conjunction with the presence venom-specific IgE. Current diagnostic methods, although sensitive and specific, are imperfect, and some newer testing options are not widely available. A conundrum occasionally faced is the patient with a reliable and compelling history of a systemic allergic reaction yet negative venom-specific testing. This diagnostic dilemma presents an opportunity to consider possible causes for this diagnostic challenge. RECENT FINDINGS: Our evolving understanding of the role of occult mast cell disease may begin to help us understand this situation and develop appropriate management strategies. Venom-specific skin testing has long been the cornerstone of the evaluation of venom sensitivity and is often combined with in-vitro assays to add clarity, but even these occasionally may fall short. Exploring novel venom diagnostic testing methods may help to fill in some of the diagnostic gaps. Do currently available venom vaccines contain all the key venom species? Are there enough differences between insect species that we may simply be missing the relevant allergens? What is the significance of the antigenicity of carbohydrate moieties in venoms? What is the role of recombinant venom extracts? SUMMARY: VIT is the definitive treatment for insect allergic individuals. To utilize VIT, identification of the relevant Hymenoptera is necessary. Unfortunately, this cannot always be accomplished. This deficiency can have several causes: a potential comorbid condition such as occult mast cell disease, limitations of currently available diagnostic resources, or testing vaccines with an insufficient coverage of relevant venom allergens. Exploring these potential causes may help to provide important insight into this important diagnostic conundrum. The use of a case report may help clarify this challenge. PMID- 26110688 TI - Allergy to honeybee ... not only stings. AB - PURPOSE OF REVIEW: The purpose of this review is to provide a brief overview of the risks of consumption of bee products in honeybee venom allergic patients and compositae allergic patients, the potential allergens involved in these reactions, the advancement in solving diagnostic difficulties, and management of allergic reactions to bee products. RECENT FINDINGS: Allergic patients to bee venom and compositae allergic patients may be allergic to bee products. Several bee products allergens have been identified in bee venom. SUMMARY: Anaphylaxis to bee products is rare. Some studies show a clear association between some aeroallergens such as compositae with allergic reactions to bee products. Additionally, allergic reactions to bee products are associated with severe outcomes in atopic and patients with lung disorders and are a common occupational disease in beekeepers. Possible cross-reactivities have been suggested between bee components and bee venom. Furthermore some studies found patients with concomitant allergy to honey or to propolis and bee venom. Nevertheless a direct relationship between allergy to bee products and bee venom has not been shown. However, cross-reactivites between bee products and bee venom might be relevant in some cases. PMID- 26110690 TI - Mepolizumab-based therapy in asthma: an update. AB - PURPOSE OF REVIEW: There is considerable evidence that implicates eosinophils as important effector cells in the inflammation characteristic of eosinophilic asthma. IL-5 is central to eosinophil maturation and release from the bone marrow, their subsequent accumulation, activation and persistence in the tissues. IL-5 therefore represents an attractive target to prevent or blunt eosinophil mediated inflammation resulting in the development of humanized anti-IL-5 monoclonal antibody such as mepolizumab. This review is an update of the evidence demonstrating the effectiveness of mepolizumab treatment of patients with asthma. RECENT FINDINGS: Although early clinical trials with mepolizumab in patients with asthma gave disappointing clinical outcomes, it is becoming apparent that significant clinical effects with this biologic are more likely in carefully selected patient populations that take the eosinophilic asthma phenotype into account. A number of recent studies have reported significant effects by mepolizumab on reductions in exacerbations together with a significant glucocorticoid-sparing effect. SUMMARY: Mepolizumab is a potentially important and well tolerated therapy in carefully selected populations of patients with asthma. PMID- 26110689 TI - Diet and asthma: an update. AB - PURPOSE OF REVIEW: Our objective was to provide an overview and discussion of recent experimental studies, epidemiologic studies, and clinical trials of diet and asthma. We focus on dietary sources and vitamins with antioxidant properties [vitamins (A, C, and E), folate, and omega-3 and omega-6 polyunsaturated fatty acids (n-3 and n-6 PUFAs)]. RECENT FINDINGS: Current evidence does not support the use of vitamin A, vitamin C, vitamin E, or PUFAs for the prevention or treatment of asthma or allergies. Current guidelines for prenatal use of folate to prevent neural tube defects should be followed, as there is no evidence of major effects of this practice on asthma or allergies. Consumption of a balanced diet that is rich in sources of antioxidants (e.g. fruits and vegetables) may be beneficial in the primary prevention of asthma. SUMMARY: None of the vitamins or nutrients examined is consistently associated with asthma or allergies. In some cases, further studies of the effects of a vitamin or nutrient on specific asthma phenotypes (e.g. vitamin C to prevent viral-induced exacerbations) are warranted. Clinical trials of 'whole diet' interventions to prevent asthma are advisable on the basis of existing evidence. PMID- 26110691 TI - Racial differences in breast cancer survival in a large urban integrated health system. AB - BACKGROUND: African American (AA) women are known to have poorer breast cancer survival than whites, and the differences may be related to underlying disparities in their clinical presentation or access to care. This study evaluated the relationship between demographic, treatment, and socioeconomic factors and breast cancer survival among women in southeast Michigan. METHODS: The population included 2387 women (34% AA) with American Joint Committee on Cancer stage I to III breast cancer who were treated at the Henry Ford Health System (HFHS) from 1996 through 2005. Linked data sets from the HFHS, the Metropolitan Detroit Cancer Surveillance System, and the US Census Bureau were used to obtain demographic and clinical information. Comorbidities were classified with the modified Charlson comorbidity index (CCI). Economic deprivation was categorized with a census tract-based deprivation index (DI), which was stratified into 5 quintiles of increasing socioeconomic disadvantage. RESULTS: Compared with whites, AA women were significantly more likely to have larger, hormone receptor-negative tumors and more comorbidities and to reside in an economically deprived area. In an unadjusted analysis, AAs had a significantly higher risk of death (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.16 1.59); however, after adjustments for clinical (age, stage, hormone receptor, and CCI) and societal factors (DI), the effect of race was not significant (HR, 1.13 [95% CI, 0.96-1.34] , and HR, 0.97 [0.80-1.19] respectively). CONCLUSIONS: Racial differences in breast cancer survival can be explained by clinical and socioeconomic factors. Nonetheless, AA women with breast cancer remain disproportionately affected by unfavorable tumor characteristics and economic deprivation, which likely contribute to their increased overall mortality. PMID- 26110692 TI - Hepatitis C cure with antiviral therapy--benefits beyond the liver. AB - Liver disease is the major complication of chronic HCV infection. However, extrahepatic complications are common (50-75%), including mixed cryoglobulinaemia and B-cell lymphomas. Given that chronic hepatitis C has become curable using expensive oral direct-acting antivirals (DAAs), it seems worth revisiting the whole spectrum and burden of disease in HCV carriers.Herein, we update the most clinically significant medical complications associated with chronic hepatitis C and the evidence of benefits that would derive from a wide use of curative DAA therapies.Chronic HCV infection is associated with a broad spectrum of clinical conditions, including distinct rheumatic disorders (polyarthritis, sicca syndrome), lymphoproliferative conditions (mixed cryoglobulinaemia, monoclonal gammapathies and B-cell lymphomas) and damage at other organs due to persistent systemic inflammation, leading to renal, bone, neurological and/or cardiovascular disease. Eradication of HCV with DAAs is associated with amelioration and/or resolution of most liver-related and extrahepatic complications. Ultimately, gains in quality of life and survival favour treating everyone with hepatitis C regardless of liver fibrosis stage. PMID- 26110693 TI - Effects of Electrostimulation with Blood Flow Restriction on Muscle Size and Strength. AB - PURPOSE: Low-load voluntary exercise can induce muscle hypertrophy and strength gain in working muscles when combined with blood flow restriction (BFR). However, it is unknown whether such hypertrophy and strength gain can be induced by involuntary muscle contractions triggered via low-intensity neuromuscular electrical stimulation (NMES) combined with BFR. The purpose of this article was to investigate whether low-intensity NMES combined with BFR (NMES-BFR) could elicit muscle hypertrophy and strength gain in the quadriceps. METHODS: Eight untrained young male participants (mean +/- SE; age, 26.2 +/- 0.7 yr; height, 1.74 +/- 0.02 m; body weight, 71.4 +/- 4.8 kg) were subjected to 23 min of unilateral low-intensity (5%-10% of maximal voluntary contraction) NMES twice per day (5 d.wk-1) for 2 wk: one leg received NMES-BFR and the other leg received NMES alone. Quadriceps muscle thickness and isometric and isokinetic strength were measured before and every week throughout the training and detraining periods. RESULTS: In NMES-BFR legs, muscle thickness increased after 2 wk of training (+3.9%) and decreased after 2 wk of detraining (-3.0%). NMES-BFR training also increased maximal knee extension strength in isometric (+14.2%) and isokinetic (+7.0% at 90 degrees .s-1 and +8.3% at 180 degrees .s-1) voluntary contractions. In addition, maximal isometric strength decreased (-6.8%), whereas no large fall (-1.9% at 90 degrees .s-1 and -0.6% at 180 degrees .s-1) in isokinetic maximal strength was evident after 2 wk of detraining. In legs that received NMES alone, no prominent change was observed; there was a negligible effect on isometric strength. CONCLUSION: Low-intensity NMES-BFR induces muscle hypertrophy and strength gain in untrained young male participants. PMID- 26110694 TI - Affective Responses to Repeated Sessions of High-Intensity Interval Training. AB - PURPOSE: Vigorous exercise feels unpleasant, and negative emotions may discourage adherence to regular exercise. We quantified the subjective affective responses to short-term high-intensity interval training (HIT) in comparison with moderate intensity continuous training (MIT). METHODS: Twenty-six healthy middle-age (mean age, 47 +/- 5 yr; mean VO2peak, 34.2 +/- 4.1 mL.kg-1.min-1) sedentary men were randomized into HIT (n = 13, 4-6 * 30 s of all-out cycling efforts at approximately 180% of peak workload with 4-min recovery) or MIT (n = 13, 40- to 60-min continuous cycling at 60% of peak workload) groups, performing six sessions within two weeks. Perceived exertion, stress, and affective state were recorded before, during, and after each session. RESULTS: Perceived exertion and arousal were higher, and affective state, more negative during the HIT than that during MIT sessions (P < 0.001). HIT versus MIT exercise acutely increased the experience of stress, tension, and irritation and decreased positive affect (P < 0.05). In addition, satisfaction was lower and pain and negative affect were higher in the HIT than those in the MIT group (P < 0.05). However, perceived exertion and displeasure experienced during exercise alleviated similarly in response to HIT and MIT over the 6 d of training. Peak oxygen consumption increased (P < 0.001) after intervention (HIT, 34.7 +/- 3.9 vs 36.7 +/- 4.5; MIT, 33.9 +/- 4.6 vs 35.0 +/- 4.6) and was not different between HIT and MIT (P = 0.28 for group * training). CONCLUSIONS: Short-term HIT and MIT are equally effective in improving aerobic fitness, but HIT increases experience of negative emotions and exertion in sedentary middle-age men. This may limit the adherence to this time-effective training mode, even though displeasure lessens over time and suggests similar mental adaptations to both MIT and HIT. PMID- 26110695 TI - Mechanical Energy and Propulsion in Ergometer Double Poling by Cross-country Skiers. AB - PURPOSE: This study aims to investigate fluctuations in total mechanical energy of the body (Ebody) in relation to external ergometer work (Werg) during the poling and recovery phases of simulated double-poling cross-country skiing. METHODS: Nine male cross-country skiers (mean +/- SD age, 24 +/- 5 yr; mean +/- SD body mass, 81.7 +/- 6.5 kg) performed 4-min submaximal tests at low-intensity, moderate-intensity, and high-intensity levels and a 3-min all-out test on a ski ergometer. Motion capture analysis and load cell recordings were used to measure body kinematics and dynamics. From these, Werg, Ebody (sum of the translational, rotational, and gravitational potential energies of all segments), and their time differentials (power P) were calculated. Ptot--the rate of energy absorption or generation by muscles-tendons--was defined as the sum of Pbody and Perg. RESULTS: Ebody showed large fluctuations over the movement cycle, decreasing during poling and increasing during the recovery phase. The fluctuation in Pbody was almost perfectly out of phase with Perg. Some muscle-tendon energy absorption was observed at the onset of poling. For the rest of poling and throughout the recovery phase, muscles-tendons generated energy to do Werg and to increase Ebody. Approximately 50% of cycle Ptot occurred during recovery for all intensity levels. CONCLUSIONS: In double poling, the extensive contribution of the lower extremities and trunk to whole-body muscle-tendon work during recovery facilitates a "direct" transfer of Ebody to Werg during the poling phase. This observation reveals that double poling involves a unique movement pattern different from most other forms of legged terrestrial locomotion, which are characterized primarily by inverted pendulum or spring-mass types of movement. PMID- 26110696 TI - Neural Correlates of Clinical Scores in Patients with Anterior Shoulder Apprehension. AB - INTRODUCTION: Anterior shoulder apprehension is a commonly reported complaint in anterior shoulder instability, which may lead to patient morbidity and impede shoulder function. It is the result of a cognitively complex mechanism, which includes anxiety, salience, fear, and anticipation. PURPOSE: The aim of this prospective case-control study was to correlate five clinically established scores using functional magnetic resonance imaging to assess brain activation patterns in patients with apprehension related to anterior shoulder instability. METHODS: This study includes 28 consecutive male right-handed patients (mean +/- SEM, 26.8 +/- 1.2 yr) with positive shoulder apprehension test and 10 healthy matched control participants without apprehension or a history of instability. Task-related and functional connectivity functional magnetic resonance imaging activation patterns occurring during apprehension video cue stimulation were correlated with five clinical tests and scores: Visual Analog Scale (VAS), Rowe score for instability, Simple Shoulder Test, Subjective Shoulder Value (SSV), and Western Ontario Shoulder Instability (WOSI). RESULTS: Rowe, pain VAS, and WOSI scores correlated with prefrontal cortex, dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, somatosensory area, and parieto-occipital and temporal areas (default mode network). Rowe score additionally correlated with frontal pole, anterior midcingulate cortex, and visual areas. Moreover, SSV correlated with task-related brain activity in the bilateral precentral gyrus, bilateral postcentral gyrus, and bilateral superior parietal lobe. CONCLUSIONS: Overall, Rowe score provides the strongest link between shoulder apprehension and brain level alterations as it correlates with the highest number of independent components involving areas responsible for both motor and cognitive functions, whereas pain VAS and WOSI occupy an intermediately strong link recruiting less brain networks. Finally, Simple Shoulder Test and SSV have the weakest link at the brain level. PMID- 26110697 TI - Visual Inspection for Determining Days When Accelerometer Is Worn: Is This Valid? AB - PURPOSE: Logs have been traditionally used for ascertaining accelerometer wear days in mail study designs, but not all participants complete logs. Visual inspection of accelerometer output may supplement missing logs; however, no data on the validity of this method are available. METHODS: We compared visual inspection with participant logs in 197 women (mean age, 71.0 yr). Women were mailed an accelerometer to be worn during waking hours for 7 d, marking each wear day on a log before returning the accelerometer by mail. For every participant, we created a series of graphs of accelerometer counts by time of day (one chart for each day with accelerometer output, including mail days). Two raters, masked to log wear status, independently inspected these graphs and scored each day as "worn" or "not worn." RESULTS: The median (interquartile range) number of valid wear days using either visual inspection or log was 7 (7-7). For rater 1, the sensitivity and specificity of visual inspection was 99.7% (95% confidence interval, 99.2%-99.9%) and 97.2% (95.2%-98.6%), respectively; for rater 2, the sensitivity and specificity of visual inspection was 99.7% (99.2%-99.9%) and 97.0% (94.9%-98.4%), respectively. Interrater agreement was 99.5%. CONCLUSIONS: Visual inspection of accelerometer data is a valid alternative to missing participant wear logs when determining wear days in mail study designs. PMID- 26110698 TI - CO2 Clamping, Peripheral and Central Fatigue during Hypoxic Knee Extensions in Men. AB - INTRODUCTION: The central nervous system can play a critical role in limiting exercise performance during hypoxic conditions. Hypocapnia, which is associated with hypoxia-induced hyperventilation, may affect cerebral perfusion. We hypothesized that CO2 clamping during hypoxic isometric knee extensions would improve cerebral oxygenation and reduce central fatigue. METHODS: Fifteen healthy men (mean +/- SD: age, 25 +/- 8 yr; body mass, 72 +/- 11 kg; height, 179 +/- 7 cm) performed intermittent isometric knee extensions at ~50% of maximal voluntary contraction to task failure in normoxia, hypoxia with CO2 clamping (arterial O2 saturation, 80% +/- 2%; end-tidal CO2 partial pressure, 40 +/- 2 mm Hg), and hypoxia without CO2 clamping (arterial O2 saturation, 80% +/- 3%). Transcranial magnetic stimulation and femoral nerve electrical stimulation were used to assess central and peripheral determinants of fatigue. Prefrontal cortex and quadriceps femoris oxygenation were monitored by multichannel near-infrared spectroscopy. RESULTS: Exercise duration was reduced to a similar extent in hypoxia with CO2 clamping (997 +/- 460 s) or hypoxia without CO2 clamping (929 +/- 412 s) compared to normoxia (1473 +/- 876 s; P < 0.001). Prefrontal cortex and quadriceps oxygenation were increased (+5.3 +/- 8.6 and +2.6 +/- 3.0 MUmol.cm at task failure, respectively; P < 0.01) during hypoxia with CO2 clamping compared to hypoxia without CO2 clamping. Transcranial magnetic stimulation maximal voluntary activation decreased to a greater extent at task failure in hypoxia without CO2 clamping (-18% +/- 8%) compared to hypoxia with CO2 clamping (-9% +/- 9%; P < 0.01) and normoxia (-10% +/- 7%; P < 0.05). Conversely, exercise-induced peripheral fatigue was larger in hypoxia with CO2 clamping than in hypoxia without CO2 clamping (e.g., Db10-to-Db100 ratio of 0.54 +/- 0.12 and 0.63 +/- 0.11 at task failure, respectively; P < 0.05). CONCLUSION: The results demonstrate that CO2 clamping can alter central and peripheral mechanisms that contribute to neuromuscular fatigue during hypoxic isometric knee extensions in men. Hypocapnia impairs cerebral oxygenation and central drive but exerts a protective effect against fatigability in muscles. PMID- 26110701 TI - Empyema Thoracis after Blunt Traumatic Esophageal Perforation. PMID- 26110702 TI - Improved detectability of microcirculatory dynamics by laser speckle flowmetry. AB - Mechanisms of renal autoregulation generate oscillations in arterial blood flow at several characteristic frequencies. Full-field laser speckle flowmetry provides a real-time imaging of superficial blood microcirculation. The possibility to detect changes in oscillatory dynamics is an important issue in biomedical applications. In this paper we show how laser power density affects quality of the recorded signal and improves detectability of temporal changes in microvascular perfusion. PMID- 26110703 TI - Stability assessment in ligand-binding assays: a critical parameter for data integrity. PMID- 26110704 TI - Biotransformation and stability of antibody-drug conjugates: payload metabolism and linker cleavage delineation. PMID- 26110700 TI - Proton-Coupled Electron Transfer: Moving Together and Charging Forward. AB - Proton-coupled electron transfer (PCET) is ubiquitous throughout chemistry and biology. This Perspective discusses recent advances and current challenges in the field of PCET, with an emphasis on the role of theory and computation. The fundamental theoretical concepts are summarized, and expressions for rate constants and kinetic isotope effects are provided. Computational methods for calculating reduction potentials and pKa's for molecular electrocatalysts, as well as insights into linear correlations and non-innocent ligands, are also described. In addition, computational methods for simulating the nonadiabatic dynamics of photoexcited PCET are discussed. Representative applications to PCET in solution, proteins, electrochemistry, and photoinduced processes are presented, highlighting the interplay between theoretical and experimental studies. The current challenges and suggested future directions are outlined for each type of application, concluding with an overall view to the future. PMID- 26110705 TI - Effects of blood processing and sample storage on the stability of biotherapeutics and anti-drug antibodies. AB - BACKGROUND: Pre-analytical factors such as sample processing, handling or storage could affect the stability of biotherapeutics and anti-drug antibodies in clinical samples, potentially impacting the pharmacokinetic and immunogenicity assessments. METHODS: We used sarilumab, a fully human IgG1 monoclonal antibody, and evaluated the stability of sarilumab (both functional and bound forms) and anti-sarilumab antibodies in blood samples during serum collection and the impact of various processing conditions on the analyte stability in serum for long-term storage. We also assessed the incurred sample stability of these analytes in samples from clinical studies. CONCLUSION: Assessment of analyte stability can provide relevant information about sample stability under different pre analytical conditions and improve the confidence in the validity of bioanalytical data generated. PMID- 26110706 TI - Sponsor relationships, analyte stability in ligand-binding assays and critical reagent management: a bioanalytical CRO perspective. AB - This perspective article discusses key points to address in the establishment of sound partnerships between sponsors and bioanalytical CROs to assure the timeliness, quality and consistency of bioanalysis throughout biological therapeutic development. The performance of ligand-binding assays can be greatly impacted by low-grade reagents, lot-to-lot variability and lack of stability of the analyte in matrix, impacting both timelines and cost. Thorough characterization of the biologic of interest and its assay-enabling critical reagents will lend itself well to conservation of materials and continuity of assay performance. When unplanned events occur, such as performance declines or premature depletion of material, structured procedures are paramount to supplement the current loosely defined regulatory guidance on critical reagent characterization and method bridging. PMID- 26110707 TI - Incurred sample reproducibility and stability assessment in a cell-based drug concentration assay. AB - Joleen White is Principal Scientist in Translational Sciences at Biogen Idec. Throughout her career, she has applied her background in biophysical protein chemistry to pharmaceutical development in therapeutic indications with significant unmet medical need. In her current role, she supports method development and regulated bioanalysis of biomarkers, biopharmaceuticals, and immunogenicity in biological samples from nonclinical and clinical studies. Her experience with measuring macromolecules includes enzymes, monoclonal antibodies, Fc fusions, oligonucleotides, PEGylated proteins, and other novel protein constructs. She has supported studies from discovery through all phases of development including GLP nonclinical, clinical, and post-marketing commitments. Incurred samplereproducibility is one aspect of in-study validation, with white papers outlining expectations for chromatographic assays and immunoassays. This manuscript outlines an approach for performing incurred sample reproducibility for a bioequivalence study using a cell-based assay, with the complication of time elapsed between original and repeat assays. The incurred sample reproducibility passed the pre-established acceptance criteria of 45% for at least 2/3 of the samples: 174/216 samples (80.6%). Data trends between the two crossover arms were qualitatively similar. The passed incurred sample reproducibility and stability further supports the validity of the original study conclusion that the two manufacturing processes were bioequivalent. This illustrates one approach to extrapolating industry and regulatory recommendations for situations outside current guidance. PMID- 26110708 TI - When close is not close enough: a comparison of endogenous and recombinant biomarker stability samples. AB - Dr Stephanie Fraser is an Associate Research Fellow in the Pharmocokinetics, Dynamics and Metabolism department at Pfizer, Groton, Connecticut. Since 2010 she has led a small but ambitious group of scientists that provide ligand-binding and immunoassay-based support to clinical biomarker programs across multiple therapeutic areas. Prior to joining Pfizer, Stephanie spent 5 years in preclinical toxicology at Charles River Laboratories where she managed a flow cytometry laboratory. She received her PhD in cellular and molecular biology from the University of Nevada, Reno in 1999 and has since focused on biomarker development and fit-for-purpose bioanalytical assays. Stability for biomarkerassays should be established during method validation using actual samples. Due to contradictory reference papers and a near absence of biomarker guidance documents actual samples are commonly replaced with spiked validation samples. This practice often fails to identify the stability of the endogenous biomarker. Spiked QC and endogenous biomarker sample data were collected for two immunoassays, TGF- beta1 and IL-13. Following one freeze/thaw cycle purified TGF beta1 recovery ranged between 87-110% whereas endogenous TGF-beta1 was 5-96%. Spiked recombinant IL-13 validation samples were stable for 4 months, whereas placebo samples were stable for 15 months. In these two cases stability established with purified and recombinant protein did not reflect the endogenous protein stability. PMID- 26110709 TI - Serum sample stability in ligand-binding assays: challenges in assessments of long-term, bench-top and multiple freeze-thaw. AB - Chris Macaraeg has been a lead scientist for method development, validation, and study support intended for regulated pre-clinical/clinical studies within the Pharmacokinetics and Drug Metabolism department at Amgen Inc, Thousand Oaks, CA. He joined Amgen in 2006. His expertise also includes automation and method transfer to CROs. Chris received his BS degree in Physiological Science and Neuroscience from the University of California, Los Angeles, CA and MS in Forensic Science from Pace University, New York, NY. Stability of therapeutic proteins in biological matrix is an important parameter to evaluate in bioanalytical support of regulated nonclinical or clinical studies. Despite industry guidance publications, many questions still arise as to how these practices are implemented to establish therapeutic protein stability in bioanalytical method validations. This article presents findings from long-term, bench-top and freeze-thaw stability assessments for three therapeutic monoclonal antibodies using either ELISA or electrochemiluminescent technology. Studies illustrate the principles and challenges in stability tests which represent scenarios that samples will likely encounter during sample analysis. Thoughtful consideration of each study requirements and a fit-for-purpose approach is essential in successful establishment of the sample stability parameters in method validation. PMID- 26110710 TI - Current industrial practices and regulatory requirements to assess analyte and reagent stability using ligand-binding assays. AB - Specific guidelines on bioanalytical method validation for drug development support are recommended by regulatory agencies. Regarding stability assessment, US FDA states that 'Stability procedures should evaluate the stability of the analytes during sample collection and handling, after long-term (frozen at the intended storage temperature) and short-term (bench-top, room temperature) storage, and after going through freeze and thaw cycles and the analytical process'. Additional regulatory considerations are discussed including topics such as analyte and reagent stability. This article reviews the regulatory requirements as issued by the USA (FDA), Europe (EMA) and Japan (MHLW), for stability studies where bioanalytical methods are used to support drug development programs and summarizes the current industry standard for conducting stability studies when utilizing ligand-binding assays. PMID- 26110711 TI - Chip-based capillary electrophoresis platforms: toward point-of-care applications. PMID- 26110712 TI - Bioanalytical method validation considerations for LC-MS/MS assays of therapeutic proteins. AB - This paper highlights the recommendations of a group of industry scientists in validating regulated bioanalytical LC-MS/MS methods for protein therapeutics in a 2015 AAPSJ White Paper. This group recommends that most of the same precision and accuracy validation criteria used for ligand-binding assays (LBAs) be applied to LC-MS/MS-based assays where proteins are quantified using the LC-MS/MS signal from a surrogate peptide after proteolytic digestion (PrD-LCMS methods). PrD-LCMS methods are generally more complex than small molecule LC-MS/MS assays and may often include LBA procedures, leading to the recommendation for a combination of chromatographic and LBA validation strategies and appropriate acceptance criteria. Several key aspects of this bioanalytical approach that are discussed in the White Paper are treated here in additional detail. These topics include selectivity/specificity, matrix effect, digestion efficiency, stability and critical reagent considerations. PMID- 26110713 TI - Integration of microfluidic LC with HRMS for the analysis of analytes in biofluids: past, present and future. AB - Capillary LC (cLC) coupled to MS has the potential to improve detection limits, address limited sample volumes and allow multiple analyses from one sample. This is particularly attractive in areas where ultrahigh assay sensitivity, low limits of detection and small sample volumes are becoming commonplace. However, implementation of cLC-MS in the bioanalytical-drug metabolism area had been hampered by the lack of commercial instrumentation and the need for experts to operate the system. Recent advances in microfabricated devices such as chip-cube and ion-key technologies offer the potential for true implementation of cLC in the modern laboratory including the benefits of the combination of this type of separation with high-resolution MS. PMID- 26110714 TI - Analysis of resistance and tolerance to virus infection in Drosophila. AB - Host defense to virus infection involves both resistance mechanisms that reduce viral burden and tolerance mechanisms that limit detrimental effects of infection. The fruit fly, Drosophila melanogaster, has emerged as a model for identifying and characterizing the genetic basis of resistance and tolerance. This protocol describes how to analyze host responses to virus infection in Drosophila, and it covers the preparation of virus stocks, experimental inoculation of flies and assessment of host survival and virus production, which are indicative of resistance or tolerance. It also provides guidance on how to account for recently identified confounding factors, including natural genetic variation in the pastrel locus and contamination of fly stocks with persistent viruses and the symbiotic bacterium Wolbachia. Our protocol aims to be accessible to newcomers to the field and, although optimized for virus research using Drosophila, some of the techniques could be adapted to other host organisms and/or other microbial pathogens. Preparation of fly stocks requires ~1 month, virus stock preparation requires 17-20 d, virus injection and survival assays require 10-15 d and virus titration requires 14 d. PMID- 26110715 TI - Guidelines for the automated evaluation of Elispot assays. AB - The presented protocol for Elispot plate evaluation summarizes how to implement the recommendations developed following the establishment of a large-scale international Elispot plate-reading panel and subsequent multistep consensus finding process. The panel involved >100 scientists from various immunological backgrounds. The protocol includes the description and justification of steps for setting reading parameters to obtain accurate, reliable and precise automated analysis results of Elispot plates. Further, necessary adjustments for out-of specification situations are described and examples are provided. The plate analysis, including parameter adjustments, auditing of results and necessary annotations, should be achievable within a time range of 10-30 min per plate. Adoption of these guidelines should enable a further reduction in assay variability and an increase in the reliability and comparability of results obtained by Elispot. These guidelines conclude the ongoing harmonization efforts for the enzymatic Elispot assay. PMID- 26110716 TI - Intravital imaging of hair follicle regeneration in the mouse. AB - Hair follicles are mammalian skin organs that periodically and stereotypically regenerate from a small pool of stem cells. Hence, hair follicles are a widely studied model for stem cell biology and regeneration. This protocol describes the use of two-photon laser-scanning microscopy (TPLSM) to study hair regeneration within a living, uninjured mouse. TPLSM provides advantages over conventional approaches, including enabling time-resolved imaging of single hair follicle stem cells. Thus, it is possible to capture behaviors including apoptosis, proliferation and migration, and to revisit the same cells for in vivo lineage tracing. In addition, a wide range of fluorescent reporter mouse lines facilitates TPLSM in the skin. This protocol also describes TPLSM laser ablation, which can spatiotemporally manipulate specific cellular populations of the hair follicle or microenvironment to test their regenerative contributions. The preparation time is variable depending on the goals of the experiment, but it generally takes 30-60 min. Imaging time is dependent on the goals of the experiment. Together, these components of TPLSM can be used to develop a comprehensive understanding of hair regeneration during homeostasis and injury. PMID- 26110718 TI - Covalent-Allosteric Kinase Inhibitors. AB - Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation-dependent signaling of protein kinases. Herein the structure-based design, synthesis, and evaluation of pleckstrin homology (PH) domain-dependent covalent-allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chemical biology and medicinal chemistry research. PMID- 26110719 TI - Rebuttal From Dr Li et al. PMID- 26110720 TI - [Dermatology -- the most progressive discipline in medicine]. PMID- 26110722 TI - Severe drug-induced skin reactions: clinical features, diagnosis, etiology, and therapy. AB - Drugs can induce severe skin reactions that differ in clinical presentation, prognosis, and therapy. The spectrum of these reactions not only includes bullous reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and generalized bullous fixed drug eruption (GBFDE) but also acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). If AGEP or DRESS is suspected, the diagnosis should be confirmed by thorough clinical examination, a skin biopsy, and specific laboratory tests. Crucial for the patient's prognosis, the causative agent should be rapidly identified and discontinued. It is therefore important to know the most frequent triggers of severe drug reactions, some of which may induce various reaction patterns. Depending on the clinical diagnosis, symptomatic and adequate supportive therapy, as well as systemic immunomodulatory treatments are used. The prognosis in SJS/TEN is often poor and depends on the patient's age and underlying conditions as well as the extent of skin detachment. The prognosis of GBFDE is somewhat better, but recurrences may lead to more severe disease manifestations. In DRESS, protracted and recurrent courses have been described, whereas AGEP usually resolves without problems. PMID- 26110724 TI - Methods of analyzing regional dermatological care as exemplified by the city of Hamburg. AB - BACKGROUND: The rural-urban divide is often linked to regional inequalities in healthcare. However, studies have also shown regional healthcare disparities within urban areas. To evaluate these studies, further parameters such as accessibility must be added to the standard criteria. The objective of this study was to present methodic tools for evaluating dermatological healthcare provision in Hamburg, primarily focusing on accessibility. METHODS: Analyzing data from 97 districts, the geographical distribution of 101 dermatologists and the physician patient ratio were determined. In a second step, network analysis regarding accessibility was performed. RESULTS: There are regional inequalities in Hamburg with respect to dermatological care. Depending on the district, the physician patient ratio ranges from 44.9 % (undersupply) to > 500 % (oversupply). Similar differences exist regarding accessibility. Although 94.5 % of the population of Hamburg is able to reach the nearest dermatologist within ten minutes (by car), it may take more than 30 minutes depending on district and mode of transportation. CONCLUSIONS: Analysis of the physician-patient ratio reveals differences regarding dermatological care in Hamburg. However, results of the network analysis show that these differences do not significantly affect access to dermatological care. Therefore, network analysis should be used as an additional tool to evaluate regional healthcare provision. PMID- 26110728 TI - [Comment on Eberle FC, Kanyildiz M, Maria Schnabl S et al. Three dimensional (3D) histology in daily routine: practical implementation and its evaluation]. PMID- 26110729 TI - S2k guideline for the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid. PMID- 26110737 TI - Relation of Serum and Vitreous Concentrations of Fetuin-A with Diabetic Retinopathy. AB - BACKGROUND: Fetuin-A, a liver-derived glycoprotein, is correlated with diabetes. The aim of the present investigation was to evaluate serum and vitreous concentrations of fetuin-A in patients with diabetic retinopathy (DR). MATERIAL AND METHODS: We randomly selected 224 diabetic patients and 68 control subjects for this study. RESULTS :There were markedly higher serum and vitreous fetuin-A concentrations in proliferative diabetic retinopathy (PDR) patients than in the other three groups. NPDR patients exhibited elevated vitreous fetuin-A concentrations compared with patients without DR. However, no significant differences in serum fetuin-A concentrations were observed between NPDR patients and patients without DR. In addition, there were significantly lower concentrations of serum and vitreous fetuin-A in control subjects compared with the other three groups. CONCLUSIONS: The occurrence and severity of DR is correlated with serum and vitreous fetuin-A concentrations. PMID- 26110738 TI - An anion induced multisignaling probe for Hg(2+) and its application for fish kidney and liver tissue imaging studies. AB - 3',6'-Bis(diethylamino)-2-(pyridin-2-ylmethyl)spiro[isoindoline-1,9'-xanthen]-3 one () was synthesized for the selective fluorescence and colorimetric recognition of Hg(2+) at pH 6.0. In addition, was useful for imaging Hg(2+) in fish kidney and liver tissues using a fluorescence microscope. Spirolactam ring opening of for Hg(2+) recognition is strongly influenced by the nature of the mercury salt and found to be NO3(-)-induced. Other mercury salts such as HgCl2, Hg(CH3COO)2 and Hg(ClO4)2 failed to induce fluorescence and colorimetric response of under the same experimental conditions. For instance, the former salt does not exhibit spirolactam ring opening but forms a new ionic compound (H3L)2[Hg6Cl18].2H2O (), whose structure has been elucidated by single crystal X ray diffraction. This might be explained by (1) the higher covalent nature of Hg(2+) and, hence, the lower acidity of the metal center and its inability to induce the ring opening reaction, and (2) the bulky anion, in the case of Hg(ClO4)2, which is also ionic, faces steric hindrance to accommodate within the N(Et)2 group upon spirolactam ring opening. PMID- 26110739 TI - Insights from GWAS: emerging landscape of mechanisms underlying complex trait disease. AB - BACKGROUND: There are now over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease. At each of these loci, there must be some molecular level mechanism relevant to the disease. What are these mechanisms and how do they contribute to disease? RESULTS: Here we consider the roles of three primary mechanism classes: changes that directly alter protein function (missense SNPs), changes that alter transcript abundance as a consequence of variants close-by in sequence, and changes that affect splicing. Missense SNPs are divided into those predicted to have a high impact on in vivo protein function, and those with a low impact. Splicing is divided into SNPs with a direct impact on splice sites, and those with a predicted effect on auxiliary splicing signals. The analysis was based on associations found for seven complex trait diseases in the classic Wellcome Trust Case Control Consortium (WTCCC1) GWA study and subsequent studies and meta-analyses, collected from the GWAS catalog. Linkage disequilibrium information was used to identify possible candidate SNPs for involvement in disease mechanism in each of the 356 loci associated with these seven diseases. With the parameters used, we find that 76% of loci have at least of these mechanisms. Overall, except for the low incidence of direct impact on splice sites, the mechanisms are found at similar frequencies, with changes in transcript abundance the most common. But the distribution of mechanisms over diseases varies markedly, as does the fraction of loci with assigned mechanisms. Many of the implicated proteins have previously been suggested as relevant, but the specific mechanism assignments are new. In addition, a number of new disease relevant proteins are proposed. CONCLUSIONS: The high fraction of GWAS loci with proposed mechanisms suggests that these classes of mechanism play a major role. Other mechanism types, such as variants affecting expression of genes remote in the DNA sequence, will contribute in other loci. Each of the identified putative mechanisms provides a hypothesis for further investigation. PMID- 26110740 TI - State-of-the-Science: The Evolution of Occupational Exposure Limit Derivation and Application. PMID- 26110741 TI - Biocompatible organic charge transfer complex nanoparticles based on a semi crystalline cellulose template. AB - Using a bio-inspired cellulose template, new charge transfer (CT) nanoparticles (NPs) with unique and intriguing emission properties are reported. Pyrene modified 2,3-di-O-methyl cellulose formed CT complexes with small molecule acceptors, e.g. 7,7,8,8-tetracyanoquinodimethane (TCNQ), and exhibited aggregation-induced emission (AIE) in aqueous medium upon nanoparticle formation. The TCNQ-CT NPs showed multicolor fluorescence emissions at 370-400 nm, 602 nm and 777 nm, when excited at 330 nm, 485 nm and 620 nm respectively. The cellulose TCNQ NPs are biocompatible and demonstrate an advance in the use of the CT mechanism for biomedical imaging applications both in vitro and in vivo. PMID- 26110742 TI - Study of Phospholipids in Single Cells Using an Integrated Microfluidic Device Combined with Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. AB - Single-cell trapping and high-throughput mass spectrometry analysis remain challenging now. Current technologies for single-cell analysis have several limitations, such as throughput, space resolution, and multicomponent analysis. In this study, we demonstrate, for the first time, the combination of microfluidic chip and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) for high-throughput and automatic single-cell phospholipids analysis. A microwell-array-based microfluidic chip was designed and fabricated for cell array formation on an indium tin oxide (ITO)-coated glass slide. Mass spectrometry imaging measurement with 25 MUm pixel size was performed with a MALDI ion source. Eight phospholipids in a single A549 cell were detected, and their structures were further identified by MS/MS spectra. Selected ion images were generated with a bin width of Deltam/z +/- 0.005. The selected ion images and optical images of the cell array showed excellent correlation, and mass spectrometry information on phospholipids from 1-3 cells was extracted automatically by selecting pixels with the same fixed interval between microwells on the chip. The measurement and data extraction could be processed in several minutes to achieve a high-throughput analysis. Through the optimization of different microwell sizes and different matrices, this method showed potential for the analysis of other metabolites or metabolic changes at the single-cell level. PMID- 26110743 TI - Rho GTPases at the crossroad of signaling networks in mammals. PMID- 26110744 TI - High-Frequency Ultrasound in the Evaluation of Psoriatic Arthritis: A Clinical Study. AB - BACKGROUND: This study aimed to compare high-frequency ultrasound (HFU) findings in the fingers with psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and to explore the potential use of HFU in the early diagnosis of PsA. METHODS: Forty four PsA patients with 123 fingers with symptoms, 39 RA patients with 122 fingers with symptoms and 20 healthy patients were recruited as controls. The ultrasound imaging manifestation and blood flow of fingers were recorded and compared. The results were analyzed by the chi test. RESULTS: Abnormal ultrasound findings in the fingers of RA and PsA patients were identified and compared. Among RA patients, 82 (67.21%) were diagnosed with joint effusion, 78 (63.93%) were synovial thickening and 59 (48.36%) were bone erosion, while no tenosynovitis, soft tissue inflammation or enthesitis was found. However, among the patients with PsA, 75 (60.97%) were diagnosed with joint effusion, 68 (55.28%) were synovial thickening, 71 (57.72%) were bone erosion, 71 (57.72%) were tenosynovitis, 44 (35.77%) were soft tissue inflammation and 39 (31.70%) were enthesitis. CONCLUSIONS: HFU proved valuable in detecting soft tissue inflammation and enthesitis in the fingers of PsA patients. HFU may be an easy, safe and effective examination in the early diagnosis of PsA and observation of pathological changes of PsA. PMID- 26110745 TI - Toxoplasma gondii Pneumonia in an Immunocompetent Individual. PMID- 26110746 TI - Bovine Bioprosthetic Valve Endocarditis in a Cattle Rancher. PMID- 26110747 TI - Xanthinuria type I with a novel mutation of xanthine dehydrogenase. PMID- 26110752 TI - Estrogen and Cardiovascular Disease: Is Timing Everything? PMID- 26110754 TI - Joint Plenary Symposium Introduction: "From Childhood to Adulthood: Perspectives on Cardiovascular Disease in Females". PMID- 26110756 TI - Determination of Labeled Fatty Acids Content in Milk Products, Infant Formula and Adult/Pediatric Nutritional Formula by Capillary Gas Chromatography: First Action 2012.13. AB - The method described below is intended for the quantification of all fatty acids, including commercially important groups of fatty acids used for labeling reasons (i.e., TFA, SFA, MUFA, PUFA, omega-3, omega-6, omega-9) and/or individual fatty acids (i.e., LA, ALA, ARA, EPA, DHA) in milk products, infant formula and adult/pediatric nutritional formula. These products often contain milk fat and/or vegetable oils, and are supplemented or not supplemented with oils rich in long chain polyunsaturated fatty acids (LC-PUFA). The determination is performed by direct transesterification of ready-to-feed liquid concentrate or powder products, without prior fat extraction. The single laboratory validation (SLV) data was submitted to the Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) Expert Review Panel (ERP) for review at the AOAC INTERNATIONAL annual meeting held September 30 to October 3, 2012 in Las Vegas, Nevada. The ERP determined that the data reviewed met the Standard Method Performance Requirements (SMPR 2012.11) set by SPIFAN and was approved as an AOAC Official First Action. The analytical range for SPIFAN samples was between 0.001 7.94 g/100 g reconstituted product, or ready-to-feed liquid. The quantitation limit was estimated as 0.001 g/100 g, while repeatability and intermediate precision were both less than 1.8 % RSD above 0.05 g/100 g, and <3.5% RSD at 0.00 5g/100 g, respectively. Recovery values based on spiking experiments at two different levels of linoleic and linolenic acids ranged from 100.0% to 102.9% for 3 different SPIFAN products. All the parameters evaluated during the SLV were well within the values defined in SMPR 2012.011 (September 2012). PMID- 26110755 TI - (1)H NMR-Based Metabolomics and Neurotoxicity Study of Cerebrum and Cerebellum in Rats Treated with Cinnabar, a Traditional Chinese Medicine. AB - Cinnabar, an important traditional Chinese mineral medicine, has been widely used as a Chinese patent medicine ingredient for sedative therapy. Nevertheless, the neurotoxic effects of cinnabar have also been noted. In this study, (1)H NMR based metabolomics, combined with multivariate pattern recognition, were applied to investigate the neurotoxic effects of cinnabar after intragastrical administration (dosed at 2 and 5 g/kg body weight) on male Wistar rats. The metabolite variations induced by cinnabar were characterized by increased levels of glutamate, glutamine, myo-inositol, and choline, as well as decreased levels of GABA, taurine, NAA, and NAAG in tissue extracts of the cerebellum and cerebrum. These findings suggested that cinnabar induced glutamate excitotoxicity, neuronal cell loss, osmotic state changes, membrane fluidity disruption, and oxidative injury in the brain. We also show here that there is a dose- and time-dependent neurotoxicity of cinnabar, and that cerebellum was more sensitive to cinnabar induction than cerebrum. This work illustrates the utility and reliability of (1)H NMR-based metabolomics approach for examining the potential neurotoxic effects of cinnabar and other traditional Chinese medicines. PMID- 26110753 TI - Hypertension and Health Behaviors in Females Across the Lifespan. PMID- 26110757 TI - The effects of high perioperative inspiratory oxygen fraction for adult surgical patients. AB - BACKGROUND: Available evidence on the effects of a high fraction of inspired oxygen (FIO2) of 60% to 90% compared with a routine fraction of inspired oxygen of 30% to 40%, during anaesthesia and surgery, on mortality and surgical site infection has been inconclusive. Previous trials and meta-analyses have led to different conclusions on whether a high fraction of supplemental inspired oxygen during anaesthesia may decrease or increase mortality and surgical site infections in surgical patients. OBJECTIVES: To assess the benefits and harms of an FIO2 equal to or greater than 60% compared with a control FIO2 at or below 40% in the perioperative setting in terms of mortality, surgical site infection, respiratory insufficiency, serious adverse events and length of stay during the index admission for adult surgical patients.We looked at various outcomes, conducted subgroup and sensitivity analyses, examined the role of bias and applied trial sequential analysis (TSA) to examine the level of evidence supporting or refuting a high FIO2 during surgery, anaesthesia and recovery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, BIOSIS, International Web of Science, the Latin American and Caribbean Health Science Information Database (LILACS), advanced Google and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) up to February 2014. We checked the references of included trials and reviews for unidentified relevant trials and reran the searches in March 2015. We will consider two studies of interest when we update the review. SELECTION CRITERIA: We included randomized clinical trials that compared a high fraction of inspired oxygen with a routine fraction of inspired oxygen during anaesthesia, surgery and recovery in individuals 18 years of age or older. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. We conducted random-effects and fixed-effect meta-analyses, and for dichotomous outcomes, we calculated risk ratios (RRs). We used published data and data obtained by contacting trial authors.To minimize the risk of systematic error, we assessed the risk of bias of the included trials. To reduce the risk of random errors caused by sparse data and repetitive updating of cumulative meta-analyses, we applied trial sequential analyses. We used Grades of Recommendation, Assessment, Development and Evaluation (GRADE) to assess the quality of the evidence. MAIN RESULTS: We included 28 randomized clinical trials (9330 participants); in the 21 trials reporting relevant outcomes for this review, 7597 participants were randomly assigned to a high fraction of inspired oxygen versus a routine fraction of inspired oxygen.In trials with an overall low risk of bias, a high fraction of inspired oxygen compared with a routine fraction of inspired oxygen was not associated with all-cause mortality (random-effects model: RR 1.12, 95% confidence interval (CI) 0.93 to 1.36; GRADE: low quality) within the longest follow-up and within 30 days of follow-up (Peto odds ratio (OR) 0.99, 95% CI 0.61 to 1.60; GRADE: low quality). In a trial sequential analysis, the required information size was not reached and the analysis could not refute a 20% increase in mortality. Similarly, when all trials were included, a high fraction of inspired oxygen was not associated with all-cause mortality to the longest follow up (RR 1.07, 95% CI 0.87 to 1.33) or within 30 days of follow-up (Peto OR 0.83, 95% CI 0.54 to 1.29), both of very low quality according to GRADE. Neither was a high fraction of inspired oxygen associated with the risk of surgical site infection in trials with low risk of bias (RR 0.86, 95% CI 0.63 to 1.17; GRADE: low quality) or in all trials (RR 0.87, 95% CI 0.71 to 1.07; GRADE: low quality). A high fraction of inspired oxygen was not associated with respiratory insufficiency (RR 1.25, 95% CI 0.79 to 1.99), serious adverse events (RR 0.96, 95% CI 0.65 to 1.43) or length of stay (mean difference -0.06 days, 95% CI -0.44 to 0.32 days).In subgroup analyses of nine trials using preoperative antibiotics, a high fraction of inspired oxygen was associated with a decrease in surgical site infections (RR 0.76, 95% CI 0.60 to 0.97; GRADE: very low quality); a similar effect was noted in the five trials adequately blinded for the outcome assessment (RR 0.79, 95% CI 0.66 to 0.96; GRADE: very low quality). We did not observe an effect of a high fraction of inspired oxygen on surgical site infections in any other subgroup analyses. AUTHORS' CONCLUSIONS: As the risk of adverse events, including mortality, may be increased by a fraction of inspired oxygen of 60% or higher, and as robust evidence is lacking for a beneficial effect of a fraction of inspired oxygen of 60% or higher on surgical site infection, our overall results suggest that evidence is insufficient to support the routine use of a high fraction of inspired oxygen during anaesthesia and surgery. Given the risk of attrition and outcome reporting bias, as well as other weaknesses in the available evidence, further randomized clinical trials with low risk of bias in all bias domains, including a large sample size and long-term follow-up, are warranted. PMID- 26110758 TI - Augmenting LTP-Like Plasticity in Human Motor Cortex by Spaced Paired Associative Stimulation. AB - Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30 min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60 min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10 min, PAS2 prolonged the PAS1-induced LTP like plasticity. At 30 min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60 min and 180 min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30 min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60 min and 180 min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30 min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases. PMID- 26110759 TI - Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains. AB - Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (DeltaN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The DeltaN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. DeltaN-HtrA3 with the PDZ removed (DeltaN-HtrA3-DeltaPDZ) and an N-terminally truncated HtrA3S (DeltaN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, DeltaN-HtrA3 formed stable trimers while both DeltaN-HtrA3-DeltaPDZ and DeltaN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of DeltaN HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of DeltaN-HtrA3. Results reported in this paper provide new insights into the structure and function of DeltaN-HtrA3, which seems to have a unique combination of features among human HtrA proteases. PMID- 26110760 TI - Talin Is Required Continuously for Cardiomyocyte Remodeling during Heart Growth in Drosophila. AB - Mechanotransduction of tension can govern the remodeling of cardiomyocytes during growth or cardiomyopathy. Tension is signaled through the integrin adhesion complexes found at muscle insertions and costameres but the relative importance of signalling during cardiomyocyte growth versus remodelling has not been assessed. Employing the Drosophila cardiomyocyte as a genetically amenable model, we depleted the levels of Talin, a central component of the integrin adhesion complex, at different stages of heart growth and remodeling. We demonstrate a continuous requirement for Talin during heart growth to maintain the one-to-one apposition of myofibril ends between cardiomyocytes. Retracted myofibrils cannot regenerate appositions to adjacent cells after restoration of normal Talin expression, and the resulting deficit reduces heart contraction and lifespan. Reduction of Talin during heart remodeling after hatching or during metamorphosis results in pervasive degeneration of cell contacts, myofibril length and number, for which restored Talin expression is insufficient for regeneration. Resultant dilated cardiomyopathy results in a fibrillating heart with poor rhythmicity. Cardiomyocytes have poor capacity to regenerate deficits in myofibril orientation and insertion, despite an ongoing capacity to remodel integrin based adhesions. PMID- 26110761 TI - Quantitative Assessment of Intra-Patient Variation in CD4+ T Cell Counts in Stable, Virologically-Suppressed, HIV-Infected Subjects. AB - OBJECTIVES: Counts of absolute CD4+ T lymphocytes (CD4+ T cells) are known to be highly variable in untreated HIV-infected individuals, but there are no data in virologically-suppressed individuals. We investigated CD4+ T cell variability in stable, virologically-suppressed, HIV-1 infected adults on combination antiretroviral therapy (cART). METHODS: From a large hospital database we selected patients with stable virological suppression on cART for >3 years with >10 CD4+ T cell measurements performed over a further >2 years; and a control group of 95 patients not on cART. RESULTS: We identified 161 HIV-infected patients on cART without active HCV or HBV infection, with stable virological suppression for a median of 6.4 years. Over the study period 88 patients had reached a plateau in their absolute CD4+ T cell counts, while 65 patients had increasing and 8 patients had decreasing absolute CD4+ T cell counts. In patients with plateaued CD4+ T cell counts, variability in absolute CD4+ T cell counts was greater than in percent CD4+ T cells (median coefficient of variation (CV) 16.6% [IQR 13.8-20.1%] and CV 9.6% [IQR 7.4-13.0%], respectively). Patients with increasing CD4+ T cell counts had greater variability in absolute CD4+ T cell counts than those with plateaued CD4 T cell counts (CV 19.5% [IQR 16.1-23.8%], p<0.001) while there was no difference in percent CD4+ T cell variability between the two groups. As previously reported, untreated patients had CVs significantly higher than patients on cART (CVs of 21.1% [IQR 17.2-32.0%], p<0.001 and 15.2% (IQR 10.7-20.0%), p<0.001, respectively). Age or sex did not affect the degree of CD4+ variation. CONCLUSIONS: Adults with stable, virologically-suppressed HIV infection continue to have significant variations in individual absolute CD4+ T cell and percent CD4+ T cell counts; this variation can be of clinical relevance especially around CD4+ thresholds. However, the variation seen in individuals on cART is substantially less than in untreated subjects. PMID- 26110762 TI - Ambiguity in Social Network Data for Presence, Sensitive-Attribute, Degree and Relationship Privacy Protection. AB - Maintaining privacy in network data publishing is a major challenge. This is because known characteristics of individuals can be used to extract new information about them. Recently, researchers have developed privacy methods based on k-anonymity and l-diversity to prevent re-identification or sensitive label disclosure through certain structural information. However, most of these studies have considered only structural information and have been developed for undirected networks. Furthermore, most existing approaches rely on generalization and node clustering so may entail significant information loss as all properties of all members of each group are generalized to the same value. In this paper, we introduce a framework for protecting sensitive attribute, degree (the number of connected entities), and relationships, as well as the presence of individuals in directed social network data whose nodes contain attributes. First, we define a privacy model that specifies privacy requirements for the above private information. Then, we introduce the technique of Ambiguity in Social Network data (ASN) based on anatomy, which specifies how to publish social network data. To employ ASN, individuals are partitioned into groups. Then, ASN publishes exact values of properties of individuals of each group with common group ID in several tables. The lossy join of those tables based on group ID injects uncertainty to reconstruct the original network. We also show how to measure different privacy requirements in ASN. Simulation results on real and synthetic datasets demonstrate that our framework, which protects from four types of private information disclosure, preserves data utility in tabular, topological and spectrum aspects of networks at a satisfactory level. PMID- 26110763 TI - From Cell and Organismal Biology to Drugs. PMID- 26110764 TI - Characterization of SMAD3 Gene Variants for Possible Roles in Ventricular Septal Defects and Other Congenital Heart Diseases. AB - BACKGROUND: Nodal/TGF signaling pathway has an important effect at early stages of differentiation of human embryonic stem cells in directing them to develop into different embryonic lineages. SMAD3 is a key intracellular messenger regulating factor in the Nodal/TGF signaling pathway, playing important roles in embryonic and, particularly, cardiovascular system development. The aim of this work was to find evidence on whether SMAD3 variations might be associated with ventricular septal defects (VSD) or other congenital heart diseases (CHD). METHODS: We sequenced the SMAD3 gene for 372 Chinese Han CHD patients including 176 VSD patients and evaluated SNP rs2289263, which is located before the 5'UTR sequence of the gene. The statistical analyses were conducted using Chi-Square Tests as implemented in SPSS (version 13.0). The Hardy-Weinberg equilibrium test of the population was carried out using the online software OEGE. RESULTS: Three heterozygous variants in SMAD3 gene, rs2289263, rs35874463 and rs17228212, were identified. Statistical analyses showed that the rs2289263 variant located before the 5'UTR sequence of SMAD3 gene was associated with the risk of VSD (P value=0.013 <0.05). CONCLUSIONS: The SNP rs2289263 in the SMAD3 gene is associated with VSD in Chinese Han populations. PMID- 26110766 TI - Light- and Humidity-Induced Motion of an Acidochromic Film. AB - A smart acidochromic agarose-based film with 1,4-bis(para-hydroxystyryl)benzene as the pH-responsive fluorophore was prepared. This film can simultaneously harness the chemical potential of light and aerial humidity gradients to convert them into mechanical work. The strong reversible hygroscopicity of the agarose matrix induces swift locomotion by mechanical deformation owing to exchange of water with the surroundings. Driven by humidity, a 20 mg composite film coupled to a piezoelectric bending transducer sensor generates a peak output of approximately 80 mV, which corresponds to a power density of 25 MUW kg(-1). Excitation with UV light triggers isomerization of the chromophore, which appears as reshaping by spiraling, bending, or twisting of the film. The material also responds to changes in the pH value by reversible protonation of the fluorophore with rapid changes in color and fluorescence. The threefold sensing capability of this smart material could be utilized for the fabrication of multiresponsive actuating dynamic elements in biomedicine and soft robotics. PMID- 26110765 TI - On the interaction between the imidazolium cation and aromatic amino acids. A computational study. AB - Complexes formed by the imidazolium cation and the aromatic amino acids, phenylalanine, tyrosine, tryptophan, and histidine have been studied by using computational methods. Complexation energies estimated at the MP2.X level amount to -123.3, -124.6, -131.5 and -145.5 kJ mol(-1) for Phe, Tyr, Trp and His, respectively. The results obtained for Phe, Tyr and Trp complexes are similar, with the most stable minima corresponding to structures with the imidazolium cation stacked over the rings. The cation forms hydrogen bonds with the amino acid while establishing cationpi contacts with the aromatic rings. Extended structures with the amino acids in zwitterionic form are almost equally stable, though. The interaction is controlled by electrostatics and induction, though the preference for the stacked minima is due to larger contributions from induction and dispersion despite the energy cost of folding the amino acid. His complexes exhibit a totally different behaviour, and no structures displaying cationpi interactions are found among the most stable minima. Most favourable complexes of His show the cation hydrogen bonded to the amino acid in extended zwitterionic form. Overall, Phe, Tyr and Trp complexes can show parallel structures in competition with similarly stable zwitterionic ones, while His only shows zwitterionic minima, with a stability even larger than any of the other aromatic amino acids, though lacking participation of the pi cloud in the interaction. PMID- 26110767 TI - EGF-Induced Acetylation of Heterogeneous Nuclear Ribonucleoproteins Is Dependent on KRAS Mutational Status in Colorectal Cancer Cells. AB - KRAS mutational status is considered a negative predictive marker of the response to anti-EGFR therapies in colorectal cancer (CRC) patients. However, conflicting data exist regarding the variable response to EGFR-targeted therapy. The effects of oncogenic KRAS on downstream targets were studied in cell lines with different KRAS mutations. Cells harboring a single KRASG13D allele showed the most tumorigenic profile, with constitutive activation of the downstream pathway, rendering them EGF-unresponsive. Conversely, KRASA146T cells showed a full EGF response in terms of signal transduction pathways, cell proliferation, migration or adhesion. Moreover, the global acetylome of CRC cells was also dependent on KRAS mutational status. Several hnRNP family members were identified within the 36 acetylated-proteins. Acetylation status is known to be involved in the modulation of EGF-response. In agreement with results presented herein, hnRNPA1 and L acetylation was induced in response to EGF in KRASA146T cells, whereas acetyl-hnRNPA1 and L levels remained unchanged after growth factor treatment in KRASG13D unresponsive cells. Our results showed that hnRNPs induced-acetylation is dependent on KRAS mutational status. Nevertheless hnRNPs acetylation might also be the point where different oncogenic pathways converge. PMID- 26110768 TI - Clinicians' Tendencies to Under-Rate Parkinsonian Tremors in the Less Affected Hand. AB - The standard assessment method for tremor severity in Parkinson's disease is visual observation by neurologists using clinical rating scales. This is, therefore, a subjective rating that is dependent on clinical expertise. The objective of this study was to report clinicians' tendencies to under-rate Parkinsonian tremors in the less affected hand. This was observed through objective tremor measurement with accelerometers. Tremor amplitudes were measured objectively using tri-axis-accelerometers for both hands simultaneously in 53 patients with Parkinson's disease during resting and postural tremors. The videotaped tremor was rated by neurologists using clinical rating scales. The tremor measured by accelerometer was compared with clinical ratings. Neurologists tended to under-rate the less affected hand in resting tremor when the contralateral hand had severe tremor in Session I. The participating neurologists corrected this tendency in Session II after being informed of it. The under rating tendency was then repeated by other uninformed neurologists in Session III. Kappa statistics showed high inter-rater agreements and high agreements between estimated scores derived from the accelerometer signals and the mean Clinical Tremor Rating Scale evaluated in every session. Therefore, clinicians need to be aware of this under-rating tendency in visual inspection of the less affected hand in order to make accurate tremor severity assessments. PMID- 26110769 TI - Validation of the new Lucerne ICF based Multidisciplinary Observation Scale (LIMOS) for stroke patients. AB - BACKGROUND: Valid and multidisciplinary assessment of a stroke patient's ability to perform activities of daily living is very important to define individual goals and to plan targeted rehabilitation. Until today, there is no observation scale that relies on International Classification of Functioning, Disability and Health (ICF). The aim of the present study was to develop and evaluate the reliability and validity of a new multidisciplinary observation scale for stroke patients, shortly called LIMOS, which is based on ICF. METHODS: In a first phase, LIMOS was defined, using a Delphi approach, by an expert panel and a pilot testing was conducted in a small group of stroke patients (n =10) to investigate feasibility and practicability. In a second phase, LIMOS was assessed for its reliability (internal consistency and test-retest reliability) and validity in a large cohort of stroke patients (n = 102). For convergent validity, the correlation between total scores of the LIMOS and the Functional Independence Measure (FIM) was assessed. RESULTS: LIMOS consisted of seven ICF chapters incorporating 45 domains. A high internal consistency (=0.98) of LIMOS was found. Furthermore, good test-retest reliability at item and subscale level was found. Principal component analysis revealed that among the seven ICF chapters, four components could be found: (1) interpersonal activities, mobility and self-care, (2) communication, (3) knowledge and general tasks, and (4) domestic life. Significant associations were found between LIMOS and the FIM indicating good convergent validity. CONCLUSIONS: The new LIMOS is a reliable and valid observation scale for stroke patients based on ICF, which can be used by a multidisciplinary team working in a neurorehabilitation setting. PMID- 26110770 TI - In vivo high angular resolution diffusion-weighted imaging of mouse brain at 16.4 Tesla. AB - Magnetic Resonance Imaging (MRI) of the rodent brain at ultra-high magnetic fields (> 9.4 Tesla) offers a higher signal-to-noise ratio that can be exploited to reduce image acquisition time or provide higher spatial resolution. However, significant challenges are presented due to a combination of longer T1 and shorter T2/T2* relaxation times and increased sensitivity to magnetic susceptibility resulting in severe local-field inhomogeneity artefacts from air pockets and bone/brain interfaces. The Stejskal-Tanner spin echo diffusion weighted imaging (DWI) sequence is often used in high-field rodent brain MRI due to its immunity to these artefacts. To accurately determine diffusion-tensor or fibre-orientation distribution, high angular resolution diffusion imaging (HARDI) with strong diffusion weighting (b >3000 s/mm2) and at least 30 diffusion encoding directions are required. However, this results in long image acquisition times unsuitable for live animal imaging. In this study, we describe the optimization of HARDI acquisition parameters at 16.4T using a Stejskal-Tanner sequence with echo-planar imaging (EPI) readout. EPI segmentation and partial Fourier encoding acceleration were applied to reduce the echo time (TE), thereby minimizing signal decay and distortion artefacts while maintaining a reasonably short acquisition time. The final HARDI acquisition protocol was achieved with the following parameters: 4 shot EPI, b = 3000 s/mm2, 64 diffusion-encoding directions, 125*150 MUm2 in-plane resolution, 0.6 mm slice thickness, and 2h acquisition time. This protocol was used to image a cohort of adult C57BL/6 male mice, whereby the quality of the acquired data was assessed and diffusion tensor imaging (DTI) derived parameters were measured. High-quality images with high spatial and angular resolution, low distortion and low variability in DTI-derived parameters were obtained, indicating that EPI-DWI is feasible at 16.4T to study animal models of white matter (WM) diseases. PMID- 26110771 TI - Primary Hyperventilation in the Emergency Department: A First Overview. AB - BACKGROUND: Primary hyperventilation is defined as a state of alveolar ventilation in excess of metabolic requirements, leading to decreased arterial partial pressure of carbon dioxide. The primary aim of this study was to characterise patients diagnosed with primary hyperventilation in the ED. METHODS: Our retrospective cohort study comprised adult (>=16 years) patients admitted to our ED between 1 January 2006 and 31 December 2012 with the primary diagnosis of primary (=psychogenic) hyperventilation. RESULTS: A total of 616 patients were eligible for study. Participants were predominantely female (341 [55.4%] female versus 275 [44.6%] male respectively, p <0.01). The mean age was 36.5 years (SD 15.52, range 16-85). Patients in their twenties were the most common age group (181, 29.4%), followed by patients in their thirties (121, 19.6%). Most patients presented at out-of-office hours (331 [53.7%]. The most common symptom was fear (586, 95.1%), followed by paraesthesia (379, 61.5%) and dizziness (306, 49.7%). Almost a third (187, 30.4%) of our patients had previously experienced an episode of hyperventilation and half (311, 50.5%) of patients had a psychiatric co morbidity. CONCLUSION: Hyperventilation is a diagnostic chimera with a wide spectrum of symptoms. Patients predominantly are of young age, female sex and often have psychiatric comorbidities. The severity of symptoms accompanied with primary hyperventilation most often needs further work-up to rule out other diagnosis in a mostly young population. In the future, further prospective multicentre studies are needed to evaluate and establish clear diagnostic criteria for primary hyperventilation and possible screening instruments. PMID- 26110772 TI - Virus Excretion from Foot-And-Mouth Disease Virus Carrier Cattle and Their Potential Role in Causing New Outbreaks. AB - The role of foot-and-mouth disease virus (FMDV) carrier cattle in causing new outbreaks is still a matter of debate and it is important to find out these carrier animals by post-outbreak serosurveillance to declare freedom from FMDV infection. In this study we explore the differences in viral shedding between carrier and non-carrier animals, quantify the transmission rate of FMDV infection from carriers to susceptible animals and identify potential viral determinants of viral persistence. We collected nasal and saliva samples from 32 vaccinated and 7 unvaccinated FMDV carrier cattle and 48 vaccinated and 13 unvaccinated non carrier cattle (total n=100) during the acute phase of infection (up to 28 days post-challenge) and then from limited number of animals up to a maximum 168 days post-challenge. We demonstrate that unvaccinated cattle excrete significantly higher levels of virus for longer periods compared with vaccinated cattle and this is independent of whether or not they subsequently become carriers. By introducing naive cattle in to the FMDV carrier population we show the risk of new outbreaks is clearly very low in controlled conditions, although there could still be a potential threat of these carrier animals causing new outbreaks in the field situation. Finally, we compared the complete genome sequences of viruses from carrier cattle with the challenge virus and found no evidence for viral determinants of the carrier state. PMID- 26110773 TI - Enhancing the conservation of crop wild relatives in England. AB - Humans require resilient, rapidly renewable and sustainable supplies of food and many other plant-derived supplies. However, the combined effects of climate change and population growth compromise the provision of these supplies particularly in respect to global food security. Crop wild relatives (CWR) contain higher genetic diversity than crops and harbour traits that can improve crop resilience and yield through plant breeding. However, in common with most countries, CWR are poorly conserved in England. There is currently no provision for long-term CWR conservation in situ, and comprehensive ex situ collection and storage of CWR is also lacking. However, there is a commitment to achieve their conservation in England's Biodiversity Strategy and the UK has international commitments to do so as part of the Global Plant Conservation Strategy. Here, we identify a series of measures that could enhance the conservation of English CWR, thereby supporting the achievement of these national and international objectives. We provide an inventory of 148 priority English CWR, highlight hotspots of CWR diversity in sites including The Lizard Peninsula, the Dorset coast and Cambridgeshire and suggest appropriate sites for the establishment of a complementary network of genetic reserves. We also identify individual in situ and ex situ priorities for each English CWR. Based on these analyses, we make recommendations whose implementation could provide effective, long-term conservation of English CWR whilst facilitating their use in crop improvement. PMID- 26110774 TI - Trends in cancer incidence in Maputo, Mozambique, 1991-2008. AB - BACKGROUND: Very limited information is available regarding the incidence of cancer in sub-Saharan Africa. We analyzed changes in cancer patterns from 1991 to 2008 in Maputo (Mozambique). METHODS: We calculated the rates of incidence of different cancer sites by sex in the 5-year age-group of the population of Maputo city as well as age-standardized rates (ASRs) and average annual percentage changes (AAPC). RESULTS: Over the 18-year study period a total of 12,674 cases of cancer (56.9% females) were registered with an overall increase in the risk of cancer in both sexes. In males, the most common cancers were those of the prostate, Kaposi sarcoma (KS) and the liver. Prostate cancer showed the most dramatic increase over the whole study period (AAPC +11.3%; 95% CI: 9.7-13.0), with an ASR of 61.7 per 105 in 2003-2008. In females, the most frequent cancers were of the uterine cervix, the breast and KS, with the former increasing along the whole study period (AAPC + 4.7%; 95% CI: 3.4-6) with an ASR of 62.0 per 105 in 2003-2008 as well as breast cancer (AAPC +6.5%; 95%CI: 4.3-8.7). CONCLUSIONS: Overall, the risk of cancer rose in both sexes during the study period, particularly among cancers associated with westernization of lifestyles (prostate, breast), combined with increasingly rising incidences or limited changes in cancers associated with infection and poverty (uterine cervix, liver). Moreover, the burden of AIDS-associated cancers has shown a marked increase. PMID- 26110776 TI - Correction: CleavPredict: A Platform for Reasoning about Matrix Metalloproteinases Proteolytic Events. PMID- 26110775 TI - Diagnostic Accuracy of CT-Guided Transthoracic Needle Biopsy for Solitary Pulmonary Nodules. AB - To evaluate the diagnostic accuracy of computed tomography (CT)-guided percutaneous lung biopsy for solitary pulmonary nodules. Three hundred and eleven patients (211 males and 100 females), with a mean age of 59.6 years (range, 19-87 years), who were diagnosed with solitary pulmonary nodules and underwent CT guided percutaneous transthoracic needle biopsy between January 2008 and January 2014 were reviewed. All patients were confirmed by surgery or the clinical course. The overall diagnostic accuracy and incidence of complications were calculated, and the factors influencing these were statistically evaluated and compared. Specimens were successfully obtained from all 311 patients. A total of 217 and 94 cases were found to be malignant and benign lesions, respectively, by biopsy. Two hundred and twenty-five (72.3%) carcinomas, 78 (25.1%) benign lesions, and 8 (2.6%) inconclusive lesions were confirmed by surgery and the clinical course. The diagnostic accuracy, sensitivity, and specificity of CT guided percutaneous transthoracic needle biopsy were 92.9%, 95.3%, and 95.7%, respectively. The incidences of pneumothorax and self-limiting bleeding were 17.7% and 11.6%, respectively. Taking account of all evidence, CT-guided percutaneous lung biopsy for solitary pulmonary nodules is an efficient, and safe diagnostic method associated with few complications. PMID- 26110777 TI - Peer mentorship to promote physical activity among cancer survivors: effects on quality of life. AB - OBJECTIVE: Physical activity (PA) adoption can improve quality of life (QOL) and related outcomes among breast cancer survivors. To disseminate a telephone-based PA intervention to cancer survivors, we partnered with the American Cancer Society's Reach To Recovery program (RTR) whose volunteers (breast cancer survivors) provide information and emotional support to breast cancer survivors. METHOD: This randomized controlled trial compared the effects of PA telephone counseling delivered by RTR volunteers (PA Plus RTR) versus a contact control condition (RTR Control) in six New England states. RTR volunteers (n = 18; mean age = 54.9 years, mean years since breast cancer diagnosis = 7.0) delivered a 12 week PA program to help participants adopt 30 min of moderate-intensity activity >=5 days/week. Breast cancer survivors (n = 76; mean age = 55.62 years, mean years since diagnosis = 1.11, Stage 0 = 6.58%, Stage 1 = 38.16%, Stage 2 = 44.74%, Stage 3 = 10.53%) were randomized to a study group. RESULTS: Using a series of generalized linear models, we assessed intervention effects on physical health, physical functioning, mental health, fatigue, and QOL at 12 and 24 weeks, and examined whether these effects were moderated by age, marital status, chemotherapy use, and baseline values of the outcomes. There were no significant intervention effects on the outcomes but there were significant moderator effects of age, chemotherapy use, and baseline physical functioning, physical health, and breast cancer-specific symptoms (all p's < .05). CONCLUSIONS: Specific demographic and treatment variables and baseline psychosocial health moderate the impact of PA interventions on QOL. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26110778 TI - Neglected Tropical Diseases in the Ebola-Affected Countries of West Africa. PMID- 26110779 TI - Multifunctional Janus hematite-silica nanoparticles: mimicking peroxidase-like activity and sensitive colorimetric detection of glucose. AB - The design and engineering of multifunctional nanostructures with multiple components and synergistic properties are in urgent demand for variety of acceptable biosensing platforms, enabling users to fulfill multiple tasks in a single nanosystem. Herein, we report using an asymmetric hematite-silica hybrid of Janus gamma-Fe2O3/SiO2 nanoparticles (JFSNs) as a multifunctional biosensing platform for sensitive colorimetric detection of H2O2 and glucose. It was demonstrated that JFSNs exhibit an intrinsic peroxidase-like catalytic activity. Compared with natural enzyme, JFSNs nanoenzymes could be used over a wider range of pH and temperatures and were more stable over time. Importantly, besides its excellent catalytic activity, the asymmetric properties of the Janus nanoparticle enable it to form the multiple functional utilities for various biosensing applications, including the ease of surface modification without deactivation of catalytic activity and recoverable use by magnetic separation. Thus, we utilized JFSNs with glucose oxidase (GOx) immobilization for glucose-sensitive colorimetric detection, which exhibited both catalytic activity of glucose oxidase and peroxidase with high selectivity and acceptable reproducibility. By combining these two analysis systems into Janus particles, an all-in-one and reusable sensor for blood glucose was formed and has the capability for determination of glucose in complex samples such as serum. These results suggest that such Janus nanosystems have the potential to construct robust nanoarchitecture with multiple functionalities for various biosensing applications. PMID- 26110780 TI - Abridged republication of FIGO's staging classification for cancer of the ovary, fallopian tube, and peritoneum. AB - Ovarian, fallopian tube, and peritoneal cancers have a similar clinical presentation and are treated similarly, and current evidence supports staging all 3 cancers in a single system. The primary site (i.e. ovary, fallopian tube, or peritoneum) should be designated where possible. The histologic type should be recorded. Intraoperative rupture ("surgical spill") is IC1; capsule ruptured before surgery or tumor on ovarian or fallopian tube surface is IC2; and positive peritoneal cytology with or without rupture is IC3. The new staging includes a revision of stage III patients; assignment to stage IIIA1 is based on spread to the retroperitoneal lymph nodes without intraperitoneal dissemination. Extension of tumor from omentum to spleen or liver (stage IIIC) should be differentiated from isolated parenchymal metastases (stage IVB). PMID- 26110781 TI - Examining women's agency in managing intimate partner violence and the related risk of homelessness: The role of harm minimisation. AB - Intimate partner violence (IPV) has a detrimental impact on women and children's emotional, physical and social well-being and has been identified as one of the most common contributors to women's experiences of housing instabilities and homelessness. Women affected by IPV often experience a great level of uncertainty around housing solutions when trying to leave an abusive partner. This study explores women's responses to IPV and the related risk of homelessness through women's narratives (n = 22) in Queensland, Australia. Of particular interest are women's decisions and actions to minimise the impact of IPV as well as homelessness on their and their children's safety and well-being. Findings reveal that women's agency in relation to harm minimisation can take various forms, including the decision to stay with, leave or return to an abusive partner. The data offer insights into women's strategic attempts to manage IPV and the related risk of homeless while trying to minimise the harm associated with one and the other. Implications for understanding women's agency in managing IPV and the related risk of homelessness and providing adequate support mechanisms to improve women and children's social, emotional and physical well-being are discussed. PMID- 26110784 TI - Quantitative laryngeal electromyography assessment of cricothyroid function in patients with unilateral vocal fold paralysis. AB - OBJECTIVES/HYPOTHESIS: Determination of superior laryngeal nerve (SLN) involvement in addition to recurrent laryngeal nerve (RLN) paralysis in patients with unilateral vocal fold paralysis (UVFP) relies on traditional, qualitative laryngeal electromyography (LEMG) examination. It is necessary to develop a quantitative measurement that reflects the degree of denervation of the cricothyroid (CT) muscle. The present study aimed to establish a standard quantitative assessment of CT function in patients with UVFP by measuring the turn frequency. STUDY DESIGN: Case series study performed in an otolaryngology outpatient clinic. METHODS: Twenty healthy subjects and 103 patients with UVFP were recruited. The main outcome measures for the patients included acoustic analysis using traditional LEMG examination, quantitative LEMG analysis, and acoustic analysis based on fundamental frequency contours. RESULTS: Acoustic reliability was examined in the healthy subjects, and the peak fundamental frequency in an upward glissando showed good test-retest reliability, especially for the offset fundamental frequency. LEMG indicated that 33 patients had RLN and SLN lesions (RLN+SLN group) and 70 had only RLN lesions (RLN group). When patients produced a standard upward glissando sound, the peak turn frequency reflecting the recruitment of the CT muscle was significantly lower in the RLN+SLN group compared with the RLN group (406+/-256 vs. 778+/-238 Hz; P<.001). CONCLUSIONS: We conclude that quantitative measurement of the interference pattern when voicing a standard upward glissando sound may provide a feasible reflection of the degree of a SLN injury. LEVEL OF EVIDENCE: 4. PMID- 26110785 TI - Selection and Characterization of DNA Aptamers Targeting All Four Serotypes of Dengue Viruses. AB - Dengue viruses (DENVs) are members of Flaviviridae family, which are associated with human disease. The envelope (E) protein plays an important role in viral infection. However, there is no effective antibody for clinical treatment due to antibody dependent enhancement of infection. In this study, using Systematic Evolution of Ligands by Exponential Enrichment (SELEX), we demonstrated the first aptamer (S15) that can bind to DENV-2 envelop protein domain III (ED3) with a high binding affinity. S15 was found to form a parallel quadruplex based on Quadfinder prediction, gel mobility assay and circular dichroism studies. Both the quadruplex structure and the sequence on 5'-end were necessary for the binding activity of S15. NMR titration experiments indicated that S15 bound to a highly conserved loop between betaA and betaB strands of ED3. Moreover, S15 can neutralize the infections by all four serotypes of DENVs. Our result provides a new opportunity in the development of DNA aptamers against DENVs in the future. PMID- 26110788 TI - Sparsity-promoting orthogonal dictionary updating for image reconstruction from highly undersampled magnetic resonance data. AB - Image reconstruction from undersampled k-space data accelerates magnetic resonance imaging (MRI) by exploiting image sparseness in certain transform domains. Employing image patch representation over a learned dictionary has the advantage of being adaptive to local image structures and thus can better sparsify images than using fixed transforms (e.g. wavelets and total variations). Dictionary learning methods have recently been introduced to MRI reconstruction, and these methods demonstrate significantly reduced reconstruction errors compared to sparse MRI reconstruction using fixed transforms. However, the synthesis sparse coding problem in dictionary learning is NP-hard and computationally expensive. In this paper, we present a novel sparsity-promoting orthogonal dictionary updating method for efficient image reconstruction from highly undersampled MRI data. The orthogonality imposed on the learned dictionary enables the minimization problem in the reconstruction to be solved by an efficient optimization algorithm which alternately updates representation coefficients, orthogonal dictionary, and missing k-space data. Moreover, both sparsity level and sparse representation contribution using updated dictionaries gradually increase during iterations to recover more details, assuming the progressively improved quality of the dictionary. Simulation and real data experimental results both demonstrate that the proposed method is approximately 10 to 100 times faster than the K-SVD-based dictionary learning MRI method and simultaneously improves reconstruction accuracy. PMID- 26110787 TI - Gamma-smooth muscle actin expression is associated with epithelial-mesenchymal transition and stem-like properties in hepatocellular carcinoma. AB - BACKGROUND AND AIMS: The prognosis of hepatocellular carcinoma (HCC) is hampered by frequent tumour recurrence and metastases. Epithelial-Mesenchymal Transition (EMT) is now recognized as a key process in tumour invasion, metastasis and the generation of cancer initiating cells. The morphological identification of EMT in tumour samples from the expression of novel mesenchymal markers could provide relevant prognostic information and aid in understanding the metastatic process. METHODS: The expression of Smooth Muscle Actins was studied using immunofluorescence and immunohistochemistry assays in cultured liver cells during an induced EMT process and in liver specimens from adult and paediatric HCC series. RESULTS: We report here that in HCC cell lines treated with TGF-beta and in HCC specimens, the expression of alphaSMA, a known mesenchymal marker of EMT, could never be detected. In addition, our in vitro studies identified the enteric form of SMA, gammaSMA, as being a marker of EMT. Moreover, this SMA isoform was expressed in 46% of 58 tumours from 42 adult HCC patients and in 90% of 16 tumours from 12 paediatric HCC patients. Interestingly, this expression was significantly correlated with poor tumour differentiation and progenitor cell features characterized by the expression of EpCAM and K19. CONCLUSION: Taken together, our results support the conclusion that gammaSMA expression in HCC is strongly correlated with the EMT process, HCC aggressiveness and the identification of cancer stem cells. This correlation suggests that gammaSMA represents a novel and powerful marker to predict HCC progression. PMID- 26110789 TI - Development of a Bioluminescent Nitroreductase Probe for Preclinical Imaging. AB - Bacterial nitroreductases (NTRs) have been widely utilized in the development of novel antibiotics, degradation of pollutants, and gene-directed enzyme prodrug therapy (GDEPT) of cancer that reached clinical trials. In case of GDEPT, since NTR is not naturally present in mammalian cells, the prodrug is activated selectively in NTR-transformed cancer cells, allowing high efficiency treatment of tumors. Currently, no bioluminescent probes exist for sensitive, non-invasive imaging of NTR expression. We therefore developed a "NTR caged luciferin" (NCL) probe that is selectively reduced by NTR, producing light proportional to the NTR activity. Here we report successful application of this probe for imaging of NTR in vitro, in bacteria and cancer cells, as well as in vivo in mouse models of bacterial infection and NTR-expressing tumor xenografts. This novel tool should significantly accelerate the development of cancer therapy approaches based on GDEPT and other fields where NTR expression is important. PMID- 26110790 TI - Seasonal variation in the skin transcriptome of common bottlenose dolphins (Tursiops truncatus) from the northern Gulf of Mexico. AB - As long-lived predators that integrate exposures across multiple trophic levels, cetaceans are recognized as sentinels for the health of marine ecosystems. Their utility as sentinels requires the establishment of baseline health parameters. Because cetaceans are protected, measurements obtained with minimal disruption to free ranging animals are highly desirable. In this study we investigated the utility of skin gene expression profiling to monitor health and contaminant exposure in common bottlenose dolphins (Tursiops truncatus). Remote integument biopsies were collected in the northern Gulf of Mexico prior to the Deepwater Horizon oil spill (May 2010) and during summer and winter for two years following oil contamination (2010-2011). A bottlenose dolphin microarray was used to characterize the skin transcriptomes of 94 individuals from three populations: Barataria Bay, Louisiana, Chandeleur Sound, Louisiana, and Mississippi Sound, Mississippi/Alabama. Skin transcriptomes did not differ significantly between populations. In contrast, season had a profound effect on gene expression, with nearly one-third of all genes on the array differing in expression between winter and the warmer seasons (moderated T-test; p<0.01, fold-change>=1.5). Persistent organic pollutants (POPs) in blubber changed concurrently, reaching >two-fold higher concentrations in summer compared to winter, due to a seasonal decrease in blubber thickness and loss of stored lipid. However, global gene expression did not correlate strongly with seasonally changing contaminant concentrations, most likely because the refractory, lipid-stored metabolites are not substrates for phase I or II xenobiotic detoxification pathways. Rather, processes related to cell proliferation, motility, and differentiation dominated the differences in expression in winter and the warmer seasons. More subtle differences were seen between spring and summer (1.5% of genes differentially expressed). However, two presumed oil-exposed animals from spring presented gene expression profiles more similar to the summer animals (presumed exposed) than to other spring animals. Seasonal effects have not previously been considered in studies assessing gene expression in cetaceans, but clearly must be taken into account when applying transcriptomic analyses to investigate their contaminant exposure or health status. PMID- 26110791 TI - C:N:P Molar Ratios, Sources and 14C Dating of Surficial Sediments from the NW Slope of Cuba. AB - The surficial sediments recovered from 12 sites located near the channel axis of the Florida Straits and the lower slope off NW Cuba were analyzed for total organic carbon (TOC), nitrogen (TN), phosphorus (TP), elemental C:N:P ratios, C and N isotopic values, and 14C dating. The depth profiles of TOC, TN, and TP (0 18 cm) displayed a downcore trend and a significant variation. The TOC values were low (0.15 to 0.62%; 66 to 516 umol g(-1)). Sites near the island's lower slope had lower TOC average concentrations (158-333 umol g(-1)) than those closer to the channel axis (averaging 341-516 umol g(-1); p <0.05). The TN concentrations near the lower slope attained 0.11% (80 umol g(-1)), whereas, towards the channel axis, they decreased to 0.07% (55 umol g(-1); p<0.05). The C:N ratios ranged from 1.9 to 10.2. The mean molar C:N ratio (5.4) indicated a marine hemipelagic deposition. The TP was lower at sites near the lower slope (38.4 to 50.0 umol gv; 0.12% to 0.16%) than those near the channel axis (50.0 to 66 umol g(-1); 0.15 to 0.21%). C:P fluctuated from 7.7 to 14.1 in the surficial sediment layer. The bulk organic delta13Corg and delta15N values confirmed pelagic organic sources, and the 14C dating revealed that the sediments were deposited during the Holocene (1000-5000 yr BP). We suggest that the hydrodynamic conditions in the Straits influence vertical and advective fluxes of particulate organic material trapped in the mixed-layer, which reduces the particulate matter flux to the seabed. PMID- 26110792 TI - Scale Adjustments to Facilitate Two-Dimensional Measurements in OCT Images. AB - PURPOSE: To address the problem of unequal scales for the measurement of two dimensional structures in OCT images, and demonstrate the use of intra!ocular objects of known dimensions in the murine eye for the equal calibration of axes. METHODS: The first part of this work describes the mathematical foundation of major distortion effects introduced by X-Y scaling differences. Illustrations were generated with CorelGraph X3 software. The second part bases on image data obtained with a HRA2 Spectralis (Heidelberg Engineering) in SV129 wild-type mice. Subretinally and intravitreally implanted microbeads, alginate capsules with a diameter of 154+/-5 MUm containing GFP-marked mesenchymal stem cells (CellBeads), were used as intraocular objects for calibration. RESULTS: The problems encountered with two-dimensional measurements in cases of unequal scales are demonstrated and an estimation of the resulting errors is provided. Commonly, the Y axis is reliably calibrated using outside standards like histology or manufacturer data. We show here that intraocular objects like dimensionally stable spherical alginate capsules allow for a two-dimensional calibration of the acquired OCT raw images by establishing a relation between X and Y axis data. For our setup, a correction factor of about 3.3 was determined using both epiretinally and subretinally positioned beads (3.350 +/- 0.104 and 3.324 +/- 0.083, respectively). CONCLUSIONS: In this work, we highlight the distortion related problems in OCT image analysis induced by unequal X and Y scales. As an exemplary case, we provide data for a two-dimensional in vivo OCT image calibration in mice using intraocular alginate capsules. Our results demonstrate the need for a proper two-dimensional calibration of OCT data, and we believe that equal scaling will certainly improve the efficiency of OCT image analysis. PMID- 26110794 TI - 'Disaster day': global health simulation teaching. AB - BACKGROUND: As society diversifies and globalisation quickens, the importance of teaching global health to medical undergraduates increases. For undergraduates, the majority of exposure to 'hands-on' teaching on global health occurs during optional elective periods. This article describes an innovative student-led initiative, 'Disaster Day', which used simulation to teach global health to undergraduates. METHODS: The teaching day began with an introduction outlining the work of Medecins Sans Frontieres and the basic principles of resuscitation. Students then undertook four interactive simulation scenarios: Infectious Diseases in a Refugee Camp, Natural Disaster and Crush Injury, Obstetric Emergency in a Low-Income Country, and Warzone Gunshot Wound. Sessions were facilitated by experienced doctors and fourth-year students who had been trained in the delivery of the scenarios. Students completed pre- and post-session evaluation forms that included the self-rating of confidence in eight learning domains (using a five-point Likert scale). RESULTS: Twenty-seven students voluntarily attended the session, and all provided written feedback. Analysis of the pre- and post-session evaluations demonstrated statistically significant improvements in confidence across all but one domains (Wilcoxon signed rank test). Free-text feedback was overwhelmingly positive, with students appreciating the practical aspect of the scenarios. For undergraduates, the majority of exposure to 'hands-on' teaching on global health occurs during optional elective periods DISCUSSION: Simulation-based teaching can provide students with 'hands on' exposure to global health in a controlled, reproducible fashion and appears to help develop their confidence in a variety of learning domains. The more widespread use of such teaching methods is encouraged: helping tomorrow's doctors develop insight into global health challenges may produce more rounded clinicians capable of caring for more culturally diverse populations. PMID- 26110793 TI - Guanidinoacetate is more effective than creatine at enhancing tissue creatine stores while consequently limiting methionine availability in Yucatan miniature pigs. AB - Creatine (Cr) is an important high-energy phosphate buffer in tissues with a high energy demand such as muscle and brain and is consequently a highly consumed nutritional supplement. Creatine is synthesized via the S-adenosylmethionine (SAM) dependent methylation of guanidinoacetate (GAA) which is not regulated by a feedback mechanism. The first objective of this study was to determine the effectiveness of GAA at increasing tissue Cr stores. Because SAM is required for other methylation reactions, we also wanted to determine whether an increased creatine synthesis would lead to a lower availability of methyl groups for other methylated products. Three month-old pigs (n = 18) were fed control, GAA- or Cr supplemented diets twice daily. On day 18 or 19, anesthesia was induced 1-3 hours post feeding and a bolus of [methyl-3H]methionine was intravenously infused. After 30 minutes, the liver was analyzed for methyl-3H incorporation into protein, Cr, phosphatidylcholine (PC) and DNA. Although both Cr and GAA led to higher hepatic Cr concentration, only supplementation with GAA led to higher levels of muscle Cr (P < 0.05). Only GAA supplementation resulted in lower methyl 3H incorporation into PC and protein as well as lower hepatic SAM concentration compared to the controls, suggesting that Cr synthesis resulted in a limited methyl supply for PC and protein synthesis (P < 0.05). Although GAA is more effective than Cr at supporting muscle Cr accretion, further research should be conducted into the long term consequences of a limited methyl supply and its effects on protein and PC homeostasis. PMID- 26110795 TI - Imaging pathological tau in atypical parkinsonian disorders. AB - PURPOSE OF REVIEW: This review examines the current literature on tau imaging in atypical parkinsonian disorders and other tauopathies. RECENT FINDINGS: There are a number of tau PET radiotracers that have demonstrated promising preliminary results in atypical parkinsonian disorders, such as progressive supranuclear palsy and corticobasal degeneration. These radiotracers were capable of selectively labeling tau in vitro and in vivo, with high affinity. Other radiotracers tested more extensively in patients with Alzheimer's disease have also been able to successfully image tau deposition. SUMMARY: The development of tau radioligands for PET has led to the current testing of these tracers in clinical studies, many of which concentrate on patients with Alzheimer's disease. Atypical parkinsonian disorders such as progressive supranuclear palsy and corticobasal degeneration are now being investigated as well. These disorders can be very difficult to diagnose, because of their clinical overlap with other parkinsonian disorders. Imaging tau using PET could serve as a diagnostic biomarker for these tauopathies and provide a means of assessing treatment that targets tau burden. PMID- 26110796 TI - Neuroimaging signature of neuropsychiatric disorders. AB - PURPOSE OF REVIEW: This review focuses on new findings related to structural and functional changes in large-scale brain networks (i.e., pathoconnectomics) that occur in neuropsychiatric disorders, particularly Parkinson's disease, Alzheimer's disease and Gilles de la Tourette syndrome. RECENT FINDINGS: Many neuropsychiatric disorders involve dysfunction in neuronal regions that are defined as hubs; these regions are pivotal regions of information transfer in large-scale brain networks. In neuropsychiatric disorders with neurodevelopmental mechanisms, the common connectivity profiles remain unclear as both hyper- and hypoconnectivity profiles have been reported. Neurodegenerative neuropsychiatric disorders are commonly characterized by a diminished local and global efficiency of large-scale brain networks. SUMMARY: The connectome, which is largely underpinned by the network science and graph theoretical approaches, is relevant to the field of neuropsychiatry and could be successfully used for the differential diagnosis for neuropsychiatric disorders and for predicting the progression of such disorders. The analysis of large-scale brain network dynamics generates new insights into the mechanisms of action of invasive and noninvasive brain stimulation and guides further investigations of new therapeutic targets. PMID- 26110797 TI - Subtypes of Parkinson's disease: state of the field and future directions. AB - PURPOSE OF REVIEW: Previously, outstanding questions have been identified including the relationship of proposed subtypes to etiology, underlying biology, and prognosis. This situation presents an opportunity for major developments in the field. The review summarizes the progress made over the past 1-2 years. RECENT FINDINGS: The etiologic, physiological, and clinical differences between tremor dominant, postural instability gait disorder, and indeterminate phenotypes have been further explored, finding genetic influences, functional imaging and clinical differences. New cluster analyses suggest that nonmotor features are important aspects of Parkinson's disease subtypes, but there was little association found between tremor-dominant /postural instability gait disorder phenotype and nonmotor symptoms. In the cognitive realm, empirically derived subtypes of PD-MCI did not map well onto cognitive subtypes derived using a data driven approach. In data-driven subtype research, important survival differences between subtypes were identified within the PROPARK database. SUMMARY: It will be important to revisit PD-MCI classification to consider subtyping based upon data that relate cognitive phenotype to prognosis. Given the traction that traditional motor subtyping has had in the field it would be of value to consider how nonmotor symptom clusters can be used with or alongside the motor subtypes. Finally, incorporating subtypes into clinical trials remains a significant gap in Parkinson's disease research. PMID- 26110798 TI - Tracking trauma-induced structural and functional changes above the level of spinal cord injury. AB - PURPOSE OF REVIEW: This review will highlight the latest findings from neuroimaging studies that track structural and functional changes within the central nervous system at both the brain and spinal cord levels following acute human spinal cord injury (SCI). The putative, underlying biological mechanisms of structural change (e.g. degradation of neural tissue) rostral to the lesion site will be discussed in relation to animal models of SCI and their potential value in clinical studies of human SCI. RECENT FINDINGS: Recent prospective studies in human acute SCI have begun to reveal the time-course, spatial distribution and extent of structural changes following an acute SCI and their relation to functional outcome. Adaptive changes in sensory and motor pathways above the level of the lesion have prognostic value and complement clinical readouts. SUMMARY: The introduction of sensitive neuroimaging biomarkers will be an essential step forward in the implementation of interventional trials in which proof-of-concept is currently limited to clinical readouts, but more responsive measures are required to improve the sensitivity of clinical trials. PMID- 26110800 TI - Tremor entities and their classification: an update. AB - PURPOSE OF REVIEW: This review focuses on important new findings in the field of tremor and illustrates the consequences for the current definition and classification of tremor. RECENT FINDINGS: Since 1998 when the consensus criteria for tremor were proposed, new variants of tremors and new diagnostic methods were discovered that have changed particularly the concepts of essential tremor and dystonic tremor. Accumulating evidence exists that essential tremor is not a single entity rather different conditions that share the common symptom action tremor without other major abnormalities. Tremor is a common feature in patients with adult-onset focal dystonia and may involve several different body parts and forms of tremor. Recent advances, in particular, in the field of genetics, suggest that dystonic tremor may even be present without overt dystonia. Monosymptomatic asymmetric rest and postural tremor has been further delineated, and apart from tremor-dominant Parkinson's disease, there are several rare conditions including rest and action tremor with normal dopamine transporter imaging (scans without evidence of dopaminergic deficit) and essential tremor with tremor at rest. SUMMARY: Increasing knowledge in the last decades changed the view on tremors and highlights several caveats in the current tremor classification. Given the ambiguous assignment between tremor phenomenology and tremor etiology, a more cautious definition of tremors on the basis of clinical assessment data is needed. PMID- 26110799 TI - Recent developments in dystonia. AB - PURPOSE OF REVIEW: The dystonias are a family of related disorders with many different clinical manifestations and causes. This review summarizes recent developments regarding these disorders, focusing mainly on advances with direct clinical relevance from the past 2 years. RECENT FINDINGS: The dystonias are generally defined by their clinical characteristics, rather than by their underlying genetic or neuropathological defects. The many varied clinical manifestations and causes contribute to the fact that they are one of the most poorly recognized of all movement disorders. A series of recent publications has addressed these issues, offering a revised definition and more logical means for classifying the many subtypes. Our understanding of the genetic and neurobiological mechanisms responsible for different types of dystonias also has grown rapidly, creating new opportunities and challenges for diagnosis, and identifying increasing numbers of rare subtypes for which specific treatments are available. SUMMARY: Recent advances in describing the clinical phenotypes and determining associated causes have pointed to the need for new strategies for diagnosis, classification, and treatment of the dystonias. PMID- 26110801 TI - Apathy and noradrenaline: silent partners to mild cognitive impairment in Parkinson's disease? AB - PURPOSE OF REVIEW: Mild cognitive impairment (MCI) is a comorbid factor in Parkinson's disease. The aim of this review is to examine the recent neuroimaging findings in the search for Parkinson's disease MCI (PD-MCI) biomarkers to gain insight on whether MCI and specific cognitive deficits in Parkinson's disease implicate striatal dopamine or another system. RECENT FINDINGS: The evidence implicates a diffuse pathophysiology in PD-MCI rather than acute dopaminergic involvement. On the one hand, performance in specific cognitive domains, notably in set-shifting and learning, appears to vary with dopaminergic status. On the other hand, motivational states in Parkinson's disease along with their behavioral and physiological indices suggest a noradrenergic contribution to cognitive deficits in Parkinson's disease. Finally, Parkinson's disease's pattern of neurodegeneration offers an avenue for continued research in nigrostriatal dopamine's role in distinct behaviors, as well as the specification of dorsal and ventral striatal functions. SUMMARY: The search for PD-MCI biomarkers has employed an array of neuroimaging techniques, but still yields divergent findings. This may be due in part to MCI's broad definition, encompassing heterogeneous cognitive domains, only some of which are affected in Parkinson's disease. Most domains falling under the MCI umbrella include fronto-dependent executive functions, whereas others, notably learning, rely on the basal ganglia. Given the deterioration of the nigrostriatal dopaminergic system in Parkinson's disease, it has been the prime target of PD-MCI investigation. By testing well defined cognitive deficits in Parkinson's disease, distinct functions can be attributed to specific neural systems, overcoming conflicting results on PD-MCI. Apart from dopamine, other systems such as the neurovascular or noradrenergic systems are affected in Parkinson's disease. These factors may be at the basis of specific facets of PD-MCI for which dopaminergic involvement has not been conclusive. Finally, the impact of both dopaminergic and noradrenergic deficiency on motivational states in Parkinson's disease is examined in light of a plausible link between apathy and cognitive deficits. PMID- 26110802 TI - Movement disorders emergencies. AB - PURPOSE OF REVIEW: Although movement disorders are traditionally viewed as chronic diseases that are followed electively, a growing number of these patients present with acute, severe syndromes or complications of their underlying neurological problem. Identifying and managing movement disorders emergencies is challenging, even for the specialist. This review summarizes evidence outlining the clinical presentation of acute, life-threatening movement disorders. RECENT FINDINGS: We review the most significant aspects in the most common movement disorders emergencies, including acute complications related to Parkinson's disease and parkinsonism, serotonergic, and neuroleptic malignant syndromes, chorea, ballismus, dystonia, myoclonus, and tics. SUMMARY: The increasing amount of information delineating the descriptions of movement disorders emergencies provides means for more effective prevention, identification, and management for the nonspecialist. Although the commonest of these syndromes eventually have a good outcome, serious conditions such as neuroleptic malignant syndrome and status dystonicus may induce substantial rates of morbidity and mortality. This review re-emphasizes the need for their prompt identification and management. PMID- 26110803 TI - Developments in impulse control behaviours of Parkinson's disease. AB - PURPOSE OF REVIEW: Impulse control behaviours (ICBs) are a frequent comorbidity for patients with Parkinson's disease. They consist of impulse control disorders, dopamine dysregulation syndrome, and punding. The field continues to evolve in the understanding of impulsivity and assessment of risk factors in the development of these behaviours and their appropriate management in patients with Parkinson's disease. RECENT FINDINGS: Impulsivity is a multifaceted concept that is surprisingly common in untreated patients with Parkinson's disease. The incidence of ICBs increases with demographic, clinical, and biochemical risk factors. Treatments rely on reduction of dopamine agonists with exception of cognitive behavioural therapy and possibly repetitive transcranial magnetic stimulation. SUMMARY: Reduction of dopamine agonist dose is the mainstay of treatment of ICBs. Other forms of dopaminergic treatment such as deep brain stimulation or jejunal infusion are alternative treatments but may be complicated by dopamine agonist withdrawal syndrome. Other therapies show promise but data are insufficient to suggest their regular use. PMID- 26110804 TI - A field guide to current advances in paediatric movement disorders. AB - PURPOSE OF REVIEW: Recent advances in neurogenetics, neuroimmunology and nonpharmacological treatments have reshaped the field of paediatric movement disorders. In this review, we put recent findings into context providing a framework to enable navigation of the expanding literature in this field. RECENT FINDINGS: Anti-NMDA receptor encephalitis has proven to be a significant cause of treatable movement disorder in children and to present a multifaceted link with herpes simplex encephalitis. The growing use of next-generation sequencing in both research and clinical practice has unravelled an expanding number of genes related to paediatric movement disorders as well as expanding spectrums of variable expressivity and phenotypic pleiotropy for various genes. Behavioural therapies have been proven efficacious in Tourette's syndrome and are likely to be helpful in complex motor stereotypies. Management of dystonia remains a clinical priority and challenge. SUMMARY: The rapid advance of translational medicine has had major impacts on the field of paediatric movement disorders including diagnosis and treatment of these conditions. PMID- 26110805 TI - Functional brain networks in epilepsy: recent advances in noninvasive mapping. AB - PURPOSE OF REVIEW: Epilepsy is one of the most frequent chronic neurological disorders. Recent evidences strongly suggest that epilepsy is due to a dysfunction within an epileptic network, rather than due to the pathological activity of single sources. The aim of this article is to review the recent advances on functional connectivity revealed by noninvasive neuroimaging techniques. RECENT FINDINGS: Functional connectivity detected through hemodynamic [functional MRI (fMRI)] and electro-magnetic techniques (EEG/MEG) in patients with epilepsy gives an insight into the physiopathogenesis of epileptic network underlying focal epilepsies and specific epileptic syndromes. An increasing number of studies suggest a relevance for surgical cases, both for localizing the focus and for predicting postsurgical cognitive impairment, based on the interactions between pathological and physiological networks. SUMMARY: fMRI and EEG/MEG functional connectivity are complementary techniques and help in identifying the interactions between epileptic activity and physiological networks at different scales. Neuropsychological and neuropsychiatric impairment can be explained by such interactions. fMRI and EEG/MEG functional connectivity help in localizing important drivers of epileptic activity and can also help in predicting postsurgical outcome. Given the large number of methods applied, strict validation, mostly obtained in surgical series, is of utmost importance to understand the benefits and limitations of each technique. PMID- 26110806 TI - Using functional imaging to understand therapeutic effects in poststroke aphasia. AB - PURPOSE OF REVIEW: The evidence base for the treatment of poststroke aphasia continues to grow, so too does interest in the neural mechanisms that underlie these therapy-driven improvements. Although the majority of patients respond to therapy, not all of those who do improve do so in a predictable way. Here, we review 17 of the most recent articles that have attempted to deal with this important question, dividing them into those that target speech perception and production. RECENT FINDINGS: There are many methodological differences between the studies, but some neuroimaging patterns have emerged: whether the in-scanner language task is speech perception or production, left hemisphere fronto-temporal cortex is often activated/correlated with language improvement and; right inferior frontal gyrus is frequently identified although what this represents is still hotly contested. We are concerned that many studies are not well controlled making it difficult to ascribe neuroimaging changes directly to the therapeutic intervention. SUMMARY: Encouragingly, there are many more functional imaging studies in this challenging area of research. Behaviour, either alone or paired with structural imaging data, only goes part way in explaining aphasic patients' responses to therapy. An important emerging theme is exploring the role that nonlanguage cognitive processes play in aphasia recovery. PMID- 26110807 TI - alpha-Synuclein and Lewy pathology in Parkinson's disease. AB - PURPOSE OF REVIEW: The role of protein aggregates, such as Lewy body inclusions, in the molecular pathogenesis of Parkinson's disease has remained controversial and elusive. The protein alpha-synuclein is a major component of these inclusions but it can exist in many alternate conformations. Here we review advances in our understanding of the roles of Lewy pathology and alpha-synuclein in Parkinson's disease. RECENT FINDINGS: Recent work has demonstrated that certain alpha synuclein conformations are directly toxic to neurons and may also propagate Lewy pathology within the nervous system. Investigation into clinicopathological correlates in rare genetic forms of Parkinson's disease has revealed that Lewy pathology is associated with nonmotor features but may not contribute to motor symptoms in Parkinson's disease. SUMMARY: These recent findings open up new avenues of investigation into the molecular pathogenesis of Parkinson's disease. Future work will need to identify the most toxic conformations of alpha-synuclein and define their relationship to Lewy pathology. This work will be necessary to be able to develop novel therapeutic strategies that target specific pathogenic forms of alpha-synuclein for disease modification in Parkinson's disease. PMID- 26110808 TI - Deep brain stimulation for movement disorders: 2015 and beyond. AB - PURPOSE OF REVIEW: The purpose of this review was to review the recent and future developments of deep brain stimulation (DBS) for movement disorders. RECENT FINDINGS: In the last 2 years, we have gained a better understanding of established indications, particularly with respect to the debate on whether subthalamus or globus pallidus pars interna should be the target of choice for Parkinson's disease. In addition, the role of DBS for dystonia has been further defined in terms of patients' selection and outcome of surgery. Other established (e.g. essential tremor) and novel indications (e.g. Tourette syndrome) have been addressed. Along with the evolving knowledge of the clinical aspects of DBS, technological advances are also shaping the present and the future of DBS. New implantable pulse generators (e.g. allowing storage of electrophysiological data and eventual adaptive stimulation) as well as new electrode configurations are now available. Furthermore, high-resolution structural imaging, including high field MRI and diffusion tensor tractography, will facilitate both the planning of DBS procedures, and the optimization of postoperative outcomes by aiding stimulation programming. SUMMARY: The recent successes of DBS along the clinical and technological directions are changing the current practice of neuromodulation and, more importantly, will also drive future developments of this fascinating treatment. PMID- 26110809 TI - Identification and Characterization of CXCR4-Positive Gastric Cancer Stem Cells. AB - Diffuse-type solid tumors are often composed of a high proportion of rarely proliferating (i.e., dormant) cancer cells, strongly indicating the involvement of cancer stem cells (CSCs) Although diffuse-type gastric cancer (GC) patients have a poor prognosis due to high-frequent development of peritoneal dissemination (PD), it is limited knowledge that the PD-associated CSCs and efficacy of CSC-targeting therapy in diffuse-type GC. In this study, we established highly metastatic GC cell lines by in vivo selection designed for the enrichment of PD-associated GC cells. By microarray analysis, we found C-X-C chemokine receptor type 4 (CXCR4) can be a novel marker for highly metastatic CSCs, since CXCR4-positive cells can grow anchorage-independently, initiate tumors in mice, be resistant to cytotoxic drug, and produce differentiated daughter cells. In clinical samples, these CXCR4-positive cells were found from not only late metastasis stage (accumulated ascites) but also earlier stage (peritoneal washings). Moreover, treatment with transforming growth factor-beta enhanced the anti-cancer effect of docetaxel via induction of cell differentiation/asymmetric cell division of the CXCR4-positive gastric CSCs even in a dormant state. Therefore, differentiation inducers hold promise for obtaining the maximum therapeutic outcome from currently available anti-cancer drugs through re-cycling of CSCs. PMID- 26110810 TI - Use of Ethanol in the Trans-Arterial Lipiodol Embolization (TAELE) of Intermediated-Stage HCC: Is This Safer than Conventional Trans-Arterial Chemo Embolization (c-TACE)? AB - PURPOSE: To evaluate safety and efficacy of Trans-Arterial Ethanol-Lipiodol Embolization (TAELE) compared with conventional Trans-Arterial Chemo-Embolization (cTACE) in the treatment of small intermediate-HCC (BCLC-Stage B). MATERIALS AND METHODS: A random sample of 87 patients (37.93% male; 62.07% female; age range, 36-86 years) with documented small intermediate-HCC and treated with TAELE (mixture 1:1 of Ethanol and Lipiodol) or cTACE (mixture of 50mg-Epirubicin and 5cc-Lipiodol) were retrospectively studied in an institutional review board approved protocol. The two procedures were compared with chi2-test, chi2-test with Yates correction, McNemar's exact test, ANOVA test and log-rank test. RESULTS: TAELE and cTACE therapies were performed in 45 and 42 patients, respectively. Thirty days after the procedure, a Multi-Detector Computed Tomography (MDCT) showed no significant difference in the number of patients with partial and complete response between the two groups (p-value = 0.958), according to mRECIST. Contrary, significant differences were found in tumor devascularization, lesion-reduction and post-embolization syndrome occurrence (p value = 0.0004, p-value = 0.0003 and p-value = 0.009, respectively). Similar survival was observed during 36-month follow-up (p-value = 0.884). CONCLUSION: Compared to cTACE, TAELE showed a better toxicity profile with similar 36-month survival and similar one-month anti-tumor effects, which makes it better tolerated by patients, especially in case of more than one treatment. PMID- 26110811 TI - PINK1 Is Dispensable for Mitochondrial Recruitment of Parkin and Activation of Mitophagy in Cardiac Myocytes. AB - Myocyte function and survival relies on the maintenance of a healthy population of mitochondria. The PINK1/Parkin pathway plays an important role in clearing defective mitochondria via autophagy in cells. However, how the PINK1/Parkin pathway regulates mitochondrial quality control and whether it coordinates with other mitophagy pathways are still unclear. Therefore, the objective of this study was to investigate the effect of PINK1-deficiency on mitochondrial quality control in myocytes. Using PINK1-deficient (PINK1-/-) mice, we found that Parkin is recruited to damaged cardiac mitochondria in hearts after treatment with the mitochondrial uncoupler FCCP or after a myocardial infarction even in the absence of PINK1. Parkin recruitment to depolarized mitochondria correlates with increased ubiquitination of mitochondrial proteins and activation of mitophagy in PINK1-/- myocytes. In addition, induction of mitophagy by the atypical BH3-only protein BNIP3 is unaffected by lack of PINK1. Overall, these data suggest that Parkin recruitment to depolarized cardiac mitochondria and subsequent activation of mitophagy is independent of PINK1. Moreover, alternative mechanisms of Parkin activation and pathways of mitophagy remain functional in PINK1-/- myocytes and could compensate for the PINK1 deficiency. PMID- 26110813 TI - Relationships among indoor, outdoor, and personal airborne Japanese cedar pollen counts. AB - Japanese cedar pollinosis (JCP) is an important illness caused by the inhalation of airborne allergenic cedar pollens, which are dispersed in the early spring throughout the Japanese islands. However, associations between pollen exposures and the prevalence or severity of allergic symptoms are largely unknown, due to a lack of understanding regarding personal pollen exposures in relation to indoor and outdoor concentrations. This study aims to examine the relationships among indoor, outdoor, and personal airborne Japanese cedar pollen counts. We conducted a 4-year monitoring campaign to quantify indoor, outdoor, and personal airborne cedar pollen counts, where the personal passive settling sampler that has been previously validated against a volumetric sampler was used to count airborne pollen grains. A total of 256 sets of indoor, outdoor, and personal samples (768 samples) were collected from 9 subjects. Medians of the seasonally-integrated indoor-to-outdoor, personal-to-outdoor, and personal-to-indoor ratios of airborne pollen counts measured for 9 subjects were 0.08, 0.10, and 1.19, respectively. A greater correlation was observed between the personal and indoor counts (r = 0.89) than between the personal and outdoor counts (r = 0.71), suggesting a potential inaccuracy in the use of outdoor counts as a basis for estimating personal exposures. The personal pollen counts differed substantially among the human subjects (49% geometric coefficient of variation), in part due to the variability in the indoor counts that have been found as major determinants of the personal pollen counts. The findings of this study highlight the need for pollen monitoring in proximity to human subjects to better understand the relationships between pollen exposures and the prevalence or severity of pollen allergy. PMID- 26110812 TI - Highly Stereoselective Intermolecular Haloetherification and Haloesterification of Allyl Amides. AB - An organocatalytic and highly regio-, diastereo-, and enantioselective intermolecular haloetherification and haloesterification reaction of allyl amides is reported. A variety of alkene substituents and substitution patterns are compatible with this chemistry. Notably, electronically unbiased alkene substrates exhibit exquisite regio- and diastereoselectivity for the title transformation. We also demonstrate that the same catalytic system can be used in both chlorination and bromination reactions of allyl amides with a variety of nucleophiles with little or no modification. PMID- 26110814 TI - Treatment for Alexia With Agraphia Following Left Ventral Occipito-Temporal Damage: Strengthening Orthographic Representations Common to Reading and Spelling. AB - PURPOSE: Damage to left ventral occipito-temporal cortex can give rise to written language impairment characterized by pure alexia/letter-by-letter (LBL) reading, as well as surface alexia and agraphia. The purpose of this study was to examine the therapeutic effects of a combined treatment approach to address concurrent LBL reading with surface alexia/agraphia. METHOD: Simultaneous treatment to address slow reading and errorful spelling was administered to 3 individuals with reading and spelling impairments after left ventral occipito-temporal damage due to posterior cerebral artery stroke. Single-word reading/spelling accuracy, reading latencies, and text reading were monitored as outcome measures for the combined effects of multiple oral re-reading treatment and interactive spelling treatment. RESULTS: After treatment, participants demonstrated faster and more accurate single-word reading and improved text-reading rates. Spelling accuracy also improved, particularly for untrained irregular words, demonstrating generalization of the trained interactive spelling strategy. CONCLUSION: This case series characterizes concomitant LBL with surface alexia/agraphia and demonstrates a successful treatment approach to address both the reading and spelling impairment. PMID- 26110815 TI - The Utility of Commonly Used Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice. AB - BACKGROUND: This current study was undertaken to carefully assess the accuracy of routinely used laboratory tests in detecting excessive/recent alcohol use. We also determined the kinetics of these markers in subjects who underwent an intensive alcohol rehabilitation program. METHODS: The study cohort consisted of 210 nonexcessive drinkers, 272 excessive drinkers, and 76 with alcoholic cirrhosis. To determine the kinetics of these markers during alcohol abstinence, we followed 45 subjects with history of excessive alcohol use for 12 weeks during the intensive alcohol treatment program. RESULTS: Percentage of carbohydrate deficient transferrin (%CDT) provided the highest diagnostic performance (area under the curve [AUC] 0.77) followed by gamma-glutamyl transferase (GGT) (AUC 0.68) to detect excessive drinkers. The percentage of excessive drinkers with aspartate aminotransferase:alanine aminotransferase (AST:ALT) > 2 was only 2%, whereas 51% of subjects with alcoholic cirrhosis had AST:ALT > 2. In the multivariate analysis, the levels of GGT and %CDT were associated with the level of alcohol consumed during the past 30 days. The levels of GGT, mean corpuscular volume (MCV), and %CDT were significantly lower compared to those at baseline before alcohol rehabilitation, whereas the AST, ALT, and AST:ALT ratio were unchanged. The percent reduction was ~2.7% (for MCV), 19% (for GGT), and 43% (for %CDT) at the end of the 12-week follow-up compared to the baseline. CONCLUSIONS: %CDT are useful markers to screen for excessive alcohol use and for follow-up of abstinence. Most subjects with excessive alcohol use do not have a high AST:ALT ratio. Rather, the AST:ALT > 2 is suggestive of alcoholic cirrhosis. The performance of the %CDT to screen for heavy alcohol use is still not ideal. Further research to identify the noninvasive marker(s) (i.e., using proteomic or metabolomics approach) should be considered. PMID- 26110816 TI - Targeting the CaMKII/ERK Interaction in the Heart Prevents Cardiac Hypertrophy. AB - AIMS: Activation of Ca2+/Calmodulin protein kinase II (CaMKII) is an important step in signaling of cardiac hypertrophy. The molecular mechanisms by which CaMKII integrates with other pathways in the heart are incompletely understood. We hypothesize that CaMKII association with extracellular regulated kinase (ERK), promotes cardiac hypertrophy through ERK nuclear localization. METHODS AND RESULTS: In H9C2 cardiomyoblasts, the selective CaMKII peptide inhibitor AntCaNtide, its penetratin conjugated minimal inhibitory sequence analog tat CN17beta, and the MEK/ERK inhibitor UO126 all reduce phenylephrine (PE)-mediated ERK and CaMKII activation and their interaction. Moreover, AntCaNtide or tat CN17beta pretreatment prevented PE induced CaMKII and ERK nuclear accumulation in H9C2s and reduced the hypertrophy responses. To determine the role of CaMKII in cardiac hypertrophy in vivo, spontaneously hypertensive rats were subjected to intramyocardial injections of AntCaNtide or tat-CN17beta. Left ventricular hypertrophy was evaluated weekly for 3 weeks by cardiac ultrasounds. We observed that the treatment with CaMKII inhibitors induced similar but significant reduction of cardiac size, left ventricular mass, and thickness of cardiac wall. The treatment with CaMKII inhibitors caused a significant reduction of CaMKII and ERK phosphorylation levels and their nuclear localization in the heart. CONCLUSION: These results indicate that CaMKII and ERK interact to promote activation in hypertrophy; the inhibition of CaMKII-ERK interaction offers a novel therapeutic approach to limit cardiac hypertrophy. PMID- 26110817 TI - Detection of peramivir and laninamivir, new anti-influenza drugs, in sewage effluent and river waters in Japan. AB - This is the first report of the detection of two new anti-influenza drugs, peramivir (PER) and laninamivir (LAN), in Japanese sewage effluent and river waters. Over about 1 year from October 2013 to July 2014, including the influenza prevalence season in January and February 2014, we monitored for five anti influenza drugs-oseltamivir (OS), oseltamivir carboxylate (OC), zanamivir (ZAN), PER, and LAN-in river waters and in sewage effluent flowing into urban rivers of the Yodo River system in Japan. The dynamic profiles of these anti-influenza drugs were synchronized well with that of the numbers of influenza patients treated with the drugs. The highest levels in sewage effluents and river waters were, respectively, 82 and 41 ng/L (OS), 347 and 125 ng/L (OC), 110 and 35 ng/L (ZAN), 64 and 11 ng/L (PER), and 21 and 9 ng/L (LAN). However, application of ozone treatment before discharge from sewage treatment plants was effective in reducing the levels of these anti-influenza drugs in effluent. The effectiveness of the ozone treatment and the drug dependent difference in susceptibility against ozone were further evidenced by ozonation of a STP effluent in a batch reactor. These findings should help to promote further environmental risk assessment of the generation of drug-resistant influenza viruses in aquatic environments. PMID- 26110818 TI - High Subarachnoid Hemorrhage Patient Volume Associated With Lower Mortality and Better Outcomes. AB - BACKGROUND: High-volume centers have better outcomes than low-volume centers when managing complex conditions including subarachnoid hemorrhage (SAH). OBJECTIVE: To quantify SAH volume-outcome association and determine the extent to which this association is influenced by aggressiveness of care. METHODS: A serial cross sectional retrospective study using the Nationwide Inpatient Sample for 2002 to 2010 was performed. Included were all adult (older than 18 years of age) discharged patients with a primary diagnosis of SAH admitted from the emergency department or transferred to a discharging hospital; cases of trauma or arteriovenous malformation were excluded. Survey-weighted descriptive statistics estimated temporal trends. Multilevel logistic regression estimated volume outcome associations for inpatient mortality and discharge home. Models were adjusted for demographic characteristics, year, transfer status, insurance status, all individual Charlson comorbidities, intubation, and all patient refined, diagnosis-related group mortality. Analyses were repeated, excluding cases in which aggressive care was not pursued. RESULTS: A total of 32,336 discharges were included; 13,398 patients underwent clipping (59.1%) or coiling (40.9%). The inpatient mortality rate decreased from 32.2% in 2002 to 22.2% in 2010; discharge home increased from 28.5% to 40.8% during the same period. As SAH volume decreased from 100/year, the mortality rate increased from 18.7% to 19.8% at 80/year, 21.7% at 60/year, 24.5% at 40/year, and 28.4% at 20/year. As SAH patient volume decreased, the probability of discharge home decreased from 40.3% at 100/year to 38.7% at 60/year, and 35.3% at 20/year. Better outcomes persisted in patients receiving aggressive care and in those not receiving aggressive care. CONCLUSION: Short-term SAH outcomes have improved. High-volume hospitals have more favorable outcomes than low-volume hospitals. This effect is substantial, even for hospitals conventionally classified as high volume. PMID- 26110819 TI - Establishment and Characterization of PCL12, a Novel CD5+ Chronic Lymphocytic Leukaemia Cell Line. AB - Immortalized cell lines representative of chronic lymphocytic leukemia (CLL) can assist in understanding disease pathogenesis and testing new therapeutic agents. At present, very few representative cell lines are available. We here describe the characterization of a new cell line (PCL12) that grew spontaneously from the peripheral blood (PB) of a CLL patient with progressive disease and EBV infection. The CLL cell origin of PCL12 was confirmed after the alignment of its IGH sequence against the "original" clonotypic sequence. The IGH gene rearrangement was truly unmutated and no CLL-related cytogenetic or genetic lesions were detected. PCL12 cells express CD19, CD20, CD5, CD23, low levels of IgM and IgD and the poor-outcome-associated prognostic markers CD38, ZAP70 and TCL1. In accordance with its aggressive phenotype the cell line is inactive in terms of LYN and HS1 phosphorylation. BcR signalling pathway is constitutively active and anergic in terms of p-ERK and Calcium flux response to alpha-IgM stimulation. PCL12 cells strongly migrate in vitro in response to SDF-1 and form clusters. Finally, they grow rapidly and localize in all lymphoid organs when xenotrasplanted in Rag2-/-gammac-/- mice. PCL12 represents a suitable preclinical model for testing pharmacological agents. PMID- 26110820 TI - Breast Tissue Composition and Immunophenotype and Its Relationship with Mammographic Density in Women at High Risk of Breast Cancer. AB - AIM: To investigate the cellular and immunophenotypic basis of mammographic density in women at high risk of breast cancer. METHODS: Mammograms and targeted breast biopsies were accrued from 24 women at high risk of breast cancer. Mammographic density was classified into Wolfe categories and ranked by increasing density. The histological composition and immunophenotypic profile were quantified from digitized haematoxylin and eosin-stained and immunohistochemically-stained (ERalpha, ERbeta, PgR, HER2, Ki-67, and CD31) slides and correlated to mammographic density. RESULTS: Increasing mammographic density was significantly correlated with increased fibrous stroma proportion (rs (22) = 0.5226, p = 0.0088) and significantly inversely associated with adipose tissue proportion (rs (22) = -0.5409, p = 0.0064). Contrary to previous reports, stromal expression of ERalpha was common (19/20 cases, 95%). There was significantly higher stromal PgR expression in mammographically-dense breasts (p=0.026). CONCLUSIONS: The proportion of stroma and fat underlies mammographic density in women at high risk of breast cancer. Increased expression of PgR in the stroma of mammographically dense breasts and frequent and unexpected presence of stromal ERalpha expression raises the possibility that hormone receptor expression in breast stroma may have a role in mediating the effects of exogenous hormonal therapy on mammographic density. PMID- 26110821 TI - Minimizing the Risk of Disease Transmission in Emergency Settings: Novel In Situ Physico-Chemical Disinfection of Pathogen-Laden Hospital Wastewaters. AB - The operation of a health care facility, such as a cholera or Ebola treatment center in an emergency setting, results in the production of pathogen-laden wastewaters that may potentially lead to onward transmission of the disease. The research presented here evaluated the design and operation of a novel treatment system, successfully used by Medecins Sans Frontieres in Haiti to disinfect CTC wastewaters in situ, eliminating the need for road haulage and disposal of the waste to a poorly-managed hazardous waste facility, thereby providing an effective barrier to disease transmission through a novel but simple sanitary intervention. The physico-chemical protocols eventually successfully treated over 600 m3 of wastewater, achieving coagulation/flocculation and disinfection by exposure to high pH (Protocol A) and low pH (Protocol B) environments, using thermotolerant coliforms as a disinfection efficacy index. In Protocol A, the addition of hydrated lime resulted in wastewater disinfection and coagulation/flocculation of suspended solids. In Protocol B, disinfection was achieved by the addition of hydrochloric acid, followed by pH neutralization and coagulation/flocculation of suspended solids using aluminum sulfate. Removal rates achieved were: COD >99%; suspended solids >90%; turbidity >90% and thermotolerant coliforms >99.9%. The proposed approach is the first known successful attempt to disinfect wastewater in a disease outbreak setting without resorting to the alternative, untested, approach of 'super chlorination' which, it has been suggested, may not consistently achieve adequate disinfection. A basic analysis of costs demonstrated a significant saving in reagent costs compared with the less reliable approach of super-chlorination. The proposed approach to in situ sanitation in cholera treatment centers and other disease outbreak settings represents a timely response to a UN call for onsite disinfection of wastewaters generated in such emergencies, and the 'Coalition for Cholera Prevention and Control' recently highlighted the research as meriting serious consideration and further study. Further applications of the method to other emergency settings are being actively explored by the authors through discussion with the World Health Organization with regards to the ongoing Ebola outbreak in West Africa, and with the UK-based NGO Oxfam with regards to excreta borne disease management in the Philippines and Myanmar, as a component of post disaster incremental improvements to local sanitation chains. PMID- 26110822 TI - Cold Regime interannual variability of primary and secondary producer community composition in the southeastern Bering Sea. AB - Variability of hydrographic conditions and primary and secondary productivity between cold and warm climatic regimes in the Bering Sea has been the subject of much study in recent years, while interannual variability within a single regime and across multiple trophic levels has been less well-documented. Measurements from an instrumented mooring on the southeastern shelf of the Bering Sea were analyzed for the spring-to-summer transitions within the cold regime years of 2009-2012 to investigate the interannual variability of hydrographic conditions, primary producer biomass, and acoustically-derived secondary producer and consumer abundance and community structure. Hydrographic conditions in 2012 were significantly different than in 2009, 2010, and 2011, driven largely by increased ice extent and thickness, later ice retreat, and earlier stratification of the water column. Primary producer biomass was more tightly coupled to hydrographic conditions in 2012 than in 2009 or 2011, and shallow and mid-column phytoplankton blooms tended to occur independent of one another. There was a high degree of variability in the relationships between different classes of secondary producers and hydrographic conditions, evidence of significant intra-consumer interactions, and trade-offs between different consumer size classes in each year. Phytoplankton blooms stimulated different populations of secondary producers in each year, and summer consumer populations appeared to determine dominant populations in the subsequent spring. Overall, primary producers and secondary producers were more tightly coupled to each other and to hydrographic conditions in the coldest year compared to the warmer years. The highly variable nature of the interactions between the atmospherically-driven hydrographic environment, primary and secondary producers, and within food webs underscores the need to revisit how climatic regimes within the Bering Sea are defined and predicted to function given changing climate scenarios. PMID- 26110823 TI - Identifying Differences and Similarities in Static and Dynamic Contact Angles between Nanoscale and Microscale Textured Surfaces Using Molecular Dynamics Simulations. AB - We quantify some of the effects of patterned nanoscale surface texture on static contact angles, dynamic contact angles, and dynamic contact angle hysteresis using molecular dynamics simulations of a moving Lennard-Jones droplet in contact with a solid surface. We observe static contact angles that change with the introduction of surface texture in a manner consistent with theoretical and experimental expectations. However, we find that the introduction of nanoscale surface texture at the length scale of 5-10 times the fluid particle size does not affect dynamic contact angle hysteresis even though it changes both the advancing and receding contact angles significantly. This result differs significantly from microscale experimental results where dynamic contact angle hysteresis decreases with the addition of surface texture due to an increase in the receding contact angle. Instead, we find that molecular-kinetic theory, previously applied only to nonpatterned surfaces, accurately describes dynamic contact angle and dynamic contact angle hysteresis behavior as a function of terminal fluid velocity. Therefore, at length scales of tens of nanometers, the kinetic phenomena such as contact line pinning observed at larger scales become insignificant in comparison to the effects of molecular fluctuations for moving droplets, even though the static properties are essentially scale-invariant. These findings may have implications for the design of highly hierarchical structures with particular wetting properties. We also find that quantitatively determining the trends observed in this article requires the careful selection of system and analysis parameters in order to achieve sufficient accuracy and precision in calculated contact angles. Therefore, we provide a detailed description of our two-surface, circular-fit approach to calculating static and dynamic contact angles on surfaces with nanoscale texturing. PMID- 26110824 TI - Correction: climatic effects on planning behavior. PMID- 26110825 TI - Pd(II)-Catalyzed Direct Sulfonylation of Unactivated C(sp(3))-H Bonds with Sodium Sulfinates. AB - A Pd(II)-catalyzed sulfonylation of unactivated C(sp(3))-H bonds with sodium arylsulfinates using an 8-aminoquinoline auxiliary is described. This reaction demonstrates excellent functional group tolerance with respect to both the caboxamide starting material and the sodium arylsulfinate coupling partner, affording a broad range of aryl alkyl sulfones. Moreover, the late-stage modification of complex molecules was achieved via this sulfonylation protocol. PMID- 26110826 TI - An Analysis of Predator Selection to Affect Aposematic Coloration in a Poison Frog Species. AB - Natural selection is widely noted to drive divergence of phenotypic traits. Predation pressure can facilitate morphological divergence, for example the evolution of both cryptic and conspicuous coloration in animals. In this context Dendrobatid frogs have been used to study evolutionary forces inducing diversity in protective coloration. The polytypic strawberry poison frog (Oophaga pumilio) shows strong divergence in aposematic coloration among populations. To investigate whether predation pressure is important for color divergence among populations of O. pumilio we selected four mainland populations and two island populations from Costa Rica and Panama. Spectrometric measurements of body coloration were used to calculate color and brightness contrasts of frogs as an indicator of conspicuousness for the visual systems of several potential predators (avian, crab and snake) and a conspecific observer. Additionally, we conducted experiments using clay model frogs of different coloration to investigate whether the local coloration of frogs is better protected than non local color morphs, and if predator communities vary among populations. Overall predation risk differed strongly among populations and interestingly was higher on the two island populations. Imprints on clay models indicated that birds are the main predators while attacks of other predators were rare. Furthermore, clay models of local coloration were equally likely to be attacked as those of non local coloration. Overall conspicuousness (and brightness contrast) of local frogs was positively correlated with attack rates by birds across populations. Together with results from earlier studies we conclude that conspicuousness honestly indicates toxicity to avian predators. The different coloration patterns among populations of strawberry poison frogs in combination with behavior and toxicity might integrate into equally efficient anti-predator strategies depending on local predation and other ecological factors. PMID- 26110828 TI - Segregating the Effects of Seed Traits and Common Ancestry of Hardwood Trees on Eastern Gray Squirrel Foraging Decisions. AB - The evolution of specific seed traits in scatter-hoarded tree species often has been attributed to granivore foraging behavior. However, the degree to which foraging investments and seed traits correlate with phylogenetic relationships among trees remains unexplored. We presented seeds of 23 different hardwood tree species (families Betulaceae, Fagaceae, Juglandaceae) to eastern gray squirrels (Sciurus carolinensis), and measured the time and distance travelled by squirrels that consumed or cached each seed. We estimated 11 physical and chemical seed traits for each species, and the phylogenetic relationships between the 23 hardwood trees. Variance partitioning revealed that considerable variation in foraging investment was attributable to seed traits alone (27-73%), and combined effects of seed traits and phylogeny of hardwood trees (5-55%). A phylogenetic PCA (pPCA) on seed traits and tree phylogeny resulted in 2 "global" axes of traits that were phylogenetically autocorrelated at the family and genus level and a third "local" axis in which traits were not phylogenetically autocorrelated. Collectively, these axes explained 30-76% of the variation in squirrel foraging investments. The first global pPCA axis, which produced large scores for seed species with thin shells, low lipid and high carbohydrate content, was negatively related to time to consume and cache seeds and travel distance to cache. The second global pPCA axis, which produced large scores for seeds with high protein, low tannin and low dormancy levels, was an important predictor of consumption time only. The local pPCA axis primarily reflected kernel mass. Although it explained only 12% of the variation in trait space and was not autocorrelated among phylogenetic clades, the local axis was related to all four squirrel foraging investments. Squirrel foraging behaviors are influenced by a combination of phylogenetically conserved and more evolutionarily labile seed traits that is consistent with a weak or more diffuse coevolutionary relationship between rodents and hardwood trees rather than a direct coevolutionary relationship. PMID- 26110827 TI - ABC transporters and the proteasome complex are implicated in susceptibility to Stevens-Johnson syndrome and toxic epidermal necrolysis across multiple drugs. AB - Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent rare but serious adverse drug reactions (ADRs). Both are characterized by distinctive blistering lesions and significant mortality rates. While there is evidence for strong drug-specific genetic predisposition related to HLA alleles, recent genome wide association studies (GWAS) on European and Asian populations have failed to identify genetic susceptibility alleles that are common across multiple drugs. We hypothesize that this is a consequence of the low to moderate effect size of individual genetic risk factors. To test this hypothesis we developed Pointer, a new algorithm that assesses the aggregate effect of multiple low risk variants on a pathway using a gene set enrichment approach. A key advantage of our method is the capability to associate SNPs with genes by exploiting physical proximity as well as by using expression quantitative trait loci (eQTLs) that capture information about both cis- and trans-acting regulatory effects. We control for known bias-inducing aspects of enrichment based analyses, such as: 1) gene length, 2) gene set size, 3) presence of biologically related genes within the same linkage disequilibrium (LD) region, and, 4) genes shared among multiple gene sets. We applied this approach to publicly available SJS/TEN genome-wide genotype data and identified the ABC transporter and Proteasome pathways as potentially implicated in the genetic susceptibility of non-drug specific SJS/TEN. We demonstrated that the innovative SNP-to-gene mapping phase of the method was essential in detecting the significant enrichment for those pathways. Analysis of an independent gene expression dataset provides supportive functional evidence for the involvement of Proteasome pathways in SJS/TEN cutaneous lesions. These results suggest that Pointer provides a useful framework for the integrative analysis of pharmacogenetic GWAS data, by increasing the power to detect aggregate effects of multiple low risk variants. The software is available for download at https://sourceforge.net/projects/pointergsa/. PMID- 26110829 TI - A reproducible and versatile system for the dynamic expansion of human pluripotent stem cells in suspension. AB - Reprogramming of patient cells to human induced pluripotent stem cells (hiPSC) has facilitated in vitro disease modeling studies aiming at deciphering the molecular and cellular mechanisms that contribute to disease pathogenesis and progression. To fully exploit the potential of hiPSC for biomedical applications, technologies that enable the standardized generation and expansion of hiPSC from large numbers of donors are required. Paralleled automated processes for the expansion of hiPSC could provide an opportunity to maximize the generation of hiPSC collections from patient cohorts while minimizing hands-on time and costs. In order to develop a simple method for the parallel expansion of human pluripotent stem cells (hPSC) we established a protocol for their cultivation as undifferentiated aggregates in a bench-top bioreactor system (BioLevitatorTM). We show that long-term expansion (10 passages) of hPSCs either in mTeSR or E8 medium preserved a normal karyotype, three-germ-layer differentiation potential and high expression of pluripotency-associated markers. The system enables the expansion from low inoculation densities (0.3 * 10(5) cells/mL) and provides a simplified, cost-efficient and time-saving method for the provision of hiPSC at midi-scale. Implementation of this protocol in cell production schemes has the potential to advance cell manufacturing in many areas of hiPSC-based medical research. PMID- 26110830 TI - Leukemia diagnosis: today and tomorrow. AB - The European LeukemiaNet (ELN) is composed of several work packages, four of them being directly involved in the various aspects of diagnosis. On the occasion of the annual ELN meeting of 2015 in Mannheim, these four work packages collectively examined the current situation and future prospects of cytomorphology, flow cytometry, cytogenetics, next-generation sequencing, and minimal residual disease detection in the context of leukemia diagnosis and follow-up. This document summarizes the outcome of this compendium. PMID- 26110831 TI - The stage-classified matrix models project a significant increase in biomass carbon stocks in China's forests between 2005 and 2050. AB - China's forests are characterized by young age, low carbon (C) density and a large plantation area, implying a high potential for increasing C sinks in the future. Using data of provincial forest area and biomass C density from China's forest inventories between 1994 and 2008 and the planned forest coverage of the country by 2050, we developed a stage-classified matrix model to predict biomass C stocks of China's forests from 2005 to 2050. The results showed that total forest biomass C stock would increase from 6.43 Pg C (1 Pg = 10(15) g) in 2005 to 9.97 Pg C (95% confidence interval: 8.98 ~ 11.07 Pg C) in 2050, with an overall net C gain of 78.8 Tg C yr(-1) (56.7 ~ 103.3 Tg C yr(-1); 1 Tg = 10(12) g). Our findings suggest that China's forests will be a large and persistent biomass C sink through 2050. PMID- 26110832 TI - Geographic analysis of urologist density and prostate cancer mortality in the United States. AB - CONTEXT: Financial and demographic pressures in US require an understanding of the most efficient distribution of physicians to maximize population-level health benefits. Prior work has assumed a constant negative relationship between physician supply and mortality outcomes throughout the US and has not addressed regional variation. METHODS: In this ecological analysis, geographically weighted regression was used to identify spatially varying relationships between local urologist density and prostate cancer mortality at the county level. Data from 1,492 counties in 30 eastern and southern states from 2006-2010 were analyzed. FINDINGS: The ordinary least squares (OLS) regression found that, on average, increasing urologist density by 1 urologist per 100,000 people resulted in an expected decrease in prostate cancer mortality of -0.499 deaths per 100,000 men (95% CI -0.709 to -0.289, p-value < 0.001), or a 1.5% decrease. Geographic weighted regression demonstrated that the addition of one urologist per 100,000 people in counties in the southern Mississippi River states of Arkansas, Mississippi, and Louisiana, as well as parts of Illinois, Indiana, and Wisconsin is associated with decrease of 0.411 to 0.916 in prostate cancer mortality per 100,000 men (1.6-3.6%). In contrast, the urologist density was not significantly associated with the prostate state mortality in the new England region. CONCLUSIONS: The strength of association between urologist density and prostate cancer mortality varied regionally. Those areas with the highest potential for effects could be targeted for increasing the supply of urologists, as it associated with the largest predicted improvement in prostate cancer mortality. PMID- 26110833 TI - Mapping Soil Properties of Africa at 250 m Resolution: Random Forests Significantly Improve Current Predictions. AB - 80% of arable land in Africa has low soil fertility and suffers from physical soil problems. Additionally, significant amounts of nutrients are lost every year due to unsustainable soil management practices. This is partially the result of insufficient use of soil management knowledge. To help bridge the soil information gap in Africa, the Africa Soil Information Service (AfSIS) project was established in 2008. Over the period 2008-2014, the AfSIS project compiled two point data sets: the Africa Soil Profiles (legacy) database and the AfSIS Sentinel Site database. These data sets contain over 28 thousand sampling locations and represent the most comprehensive soil sample data sets of the African continent to date. Utilizing these point data sets in combination with a large number of covariates, we have generated a series of spatial predictions of soil properties relevant to the agricultural management--organic carbon, pH, sand, silt and clay fractions, bulk density, cation-exchange capacity, total nitrogen, exchangeable acidity, Al content and exchangeable bases (Ca, K, Mg, Na). We specifically investigate differences between two predictive approaches: random forests and linear regression. Results of 5-fold cross-validation demonstrate that the random forests algorithm consistently outperforms the linear regression algorithm, with average decreases of 15-75% in Root Mean Squared Error (RMSE) across soil properties and depths. Fitting and running random forests models takes an order of magnitude more time and the modelling success is sensitive to artifacts in the input data, but as long as quality-controlled point data are provided, an increase in soil mapping accuracy can be expected. Results also indicate that globally predicted soil classes (USDA Soil Taxonomy, especially Alfisols and Mollisols) help improve continental scale soil property mapping, and are among the most important predictors. This indicates a promising potential for transferring pedological knowledge from data rich countries to countries with limited soil data. PMID- 26110834 TI - Induction of the superoxide anion radical scavenging capacity of dried 'funori'Gloiopeltis furcata by Lactobacillus plantarum S-SU1 fermentation. AB - To understand the beneficial properties of edible algae obtained from the north eastern (Sanriku) Satoumi region of Japan, the antioxidant properties of hot aqueous extract solutions (AES) obtained from 18 dried algal products were determined. The samples included 4 Ceratophyllum demersum (matsumo), 5 Undaria pinnatifida (wakame), 5 Laminaria japonica (kombu), and 2 each of Gloiopeltis furcate (funori) and G. tenax (funori). Of these products, the total phenolic content and Fe-reducing power were highest in matsumo. On the other hand, the polysaccharide content, viscosity, and superoxide anion radical (O2(-)) scavenging capacity were highest in funori. Lactobacillus plantarum S-SU3, isolated from the intestine of Japanese surfperch, and Lb. plantarum S-SU1, isolated from salted squid, could ferment the AES of matsumo and funori, respectively. Although the Fe-reducing power of the matsumo solution was reduced due to fermentation, the O2(-)-scavenging capacity of the funori solution was increased by fermentation. Furthermore, the fermented funori suspension protected Saccharomyces cerevisiae, a live cell model, against H2O2 toxicity. These results suggest that the fermented funori is a promising functional food material that is capable of protecting against reactive oxygen species. PMID- 26110835 TI - Prevalence of Diagnosed and Undiagnosed HIV Infection--United States, 2008-2012. AB - Persons unaware of their human immunodeficiency virus (HIV) infection contribute nearly one third of ongoing transmission in the United States. Among the estimated 1.2 million persons living with HIV in the United States in 2011, 14% had undiagnosed infections. To accelerate progress toward reducing undiagnosed HIV infection, CDC and its partners have pursued an approach that includes expanding HIV testing in communities with high HIV infection rates. To measure the prevalence of diagnosed and undiagnosed HIV infection for the 50 states and the District of Columbia (DC), CDC analyzed data from the National HIV Surveillance System. In 42 jurisdictions with numerically stable estimates, HIV prevalence in 2012 ranged from 110 per 100,000 persons (Iowa) to 3,936 per 100,000 (DC). The percentage of persons living with diagnosed HIV ranged from 77% in Louisiana to >=90% in Colorado, Connecticut, Delaware, Hawaii, and New York. In 39 jurisdictions with numerically stable estimates, the percentage of HIV cases with diagnosed infection among men who have sex with men (MSM) ranged from 75% in Louisiana to >=90% in Hawaii and New York. These data demonstrate the need for interventions and public health strategies to reduce the prevalence of undiagnosed HIV infection. Because the percentage of persons with undiagnosed HIV varies by geographic area, efforts tailored to each area's unique circumstances might be needed to increase the percentage of persons aware of their infection. PMID- 26110836 TI - Identifying New Positives and Linkage to HIV Medical Care--23 Testing Site Types, United States, 2013. AB - Among the estimated 1.2 million persons living with human immunodeficiency virus (HIV) infection in the United States, approximately 14% have not had their HIV diagnosed. Certain populations, such as African Americans/blacks (in this report referred to as blacks), men who have sex with men (MSM), and Hispanics/Latinos (in this report referred to as Hispanics), are disproportionately affected by HIV. In areas where HIV prevalence is >=0.1%, CDC recommends routine HIV screening in health care settings for persons aged 13-64 years. Implementation of HIV screening as part of routine care can increase the number of HIV diagnoses, destigmatize HIV testing, and improve access to care for persons with new HIV infections. Additionally, targeted testing in non-health care settings might facilitate access to persons in at-risk populations (e.g., MSM, blacks, and Hispanics) who are unaware of their status and do not routinely seek care. CDC analyzed data for 23 testing site types submitted by 61 health departments and 151 CDC-funded community-based organizations to determine 1) the number of HIV tests conducted, 2) the percentage of persons with new diagnoses of HIV infection (in this report referred to as new positives), and 3) the percentage of persons who were linked to HIV medical care within 90 days after receiving diagnoses at specific site types within health care and non-health care settings. The results indicated that, in health care settings, primary care and sexually transmitted disease (STD) clinics accounted for substantially more HIV tests than did other sites, and STD clinics identified more new positives. In non-health care settings, HIV counseling and testing sites accounted for the most tests and identified the highest number of new positives. Examining program data by site type shows which sites performed better in diagnosing new positives and informs decisions about program planning and allocation of CDC HIV testing resources among and within settings. PMID- 26110837 TI - Outbreaks of Illness Associated with Recreational Water--United States, 2011 2012. AB - Outbreaks of illness associated with recreational water use result from exposure to chemicals or infectious pathogens in recreational water venues that are treated (e.g., pools and hot tubs or spas) or untreated (e.g., lakes and oceans). For 2011-2012, the most recent years for which finalized data were available, public health officials from 32 states and Puerto Rico reported 90 recreational water-associated outbreaks to CDC's Waterborne Disease and Outbreak Surveillance System (WBDOSS) via the National Outbreak Reporting System (NORS). The 90 outbreaks resulted in at least 1,788 cases, 95 hospitalizations, and one death. Among 69 (77%) outbreaks associated with treated recreational water, 36 (52%) were caused by Cryptosporidium. Among 21 (23%) outbreaks associated with untreated recreational water, seven (33%) were caused by Escherichia coli (E. coli O157:H7 or E. coli O111). Guidance, such as the Model Aquatic Health Code (MAHC), for preventing and controlling recreational water-associated outbreaks can be optimized when informed by national outbreak and laboratory (e.g., molecular typing of Cryptosporidium) data. PMID- 26110838 TI - State Tobacco Control Program Spending--United States, 2011. AB - Evidence-based, statewide tobacco control programs that are comprehensive, sustained, and accountable reduce smoking rates and tobacco-related diseases and deaths. States that made larger investments in tobacco prevention and control have seen larger declines in cigarettes sales than the United States as a whole, and the prevalence of smoking has declined faster as spending for tobacco control programs has increased. CDC's Best Practices for Comprehensive Tobacco Control Programs (Best Practices) outlines the elements of an evidence-based state tobacco control program and provides recommended state funding levels to substantially reduce tobacco-related disease, disability, and death. To analyze states' spending in relation to program components outlined within Best Practices, CDC assessed state tobacco control programs' expenditures for fiscal year 2011. In 2011, states spent approximately $658 million on tobacco control and prevention, which accounts for less than 3% of the states' revenues from the sale of tobacco products and only 17.8% of the level recommended by CDC. Evidence suggests that funding tobacco prevention and control efforts at the levels recommended in Best Practices could achieve larger and more rapid reductions in tobacco use and associated morbidity and mortality. PMID- 26110839 TI - Notes from the Field: Measles Transmission in an International Airport at a Domestic Terminal Gate--April-May 2014. AB - On April 22, 2014, the Minnesota Department of Health notified CDC of a case of measles in a child aged 19 months who had documentation of receiving 1 dose of measles, mumps, and rubella vaccine at age 12 months. The child's illness was clinically compatible with measles, which was confirmed by polymerase chain reaction and immunoglobulin M serology at the Minnesota Department of Health Public Health Laboratory. The child was febrile and developed a rash on April 17 while on an international flight from India to the United States before taking a connecting flight from Chicago to Minneapolis. Persons with measles are infectious from 4 days before to 4 days after rash onset. Therefore, travelers were exposed on both the international and domestic flights. CDC's Division of Global Migration and Quarantine was contacted and provided information on potentially exposed persons to relevant health departments for follow-up. No documented transmission was reported as a result of the two flight exposures. PMID- 26110840 TI - Influence of phthalates on in vitro innate and adaptive immune responses. AB - Phthalates are a group of endocrine disrupting chemicals, suspected to influence the immune system. The aim of this study was to investigate the influence of phthalates on cytokine secretion from human peripheral blood mononuclear cells. Escherichia coli lipopolysaccharide and phytohemagglutinin-P were used for stimulation of monocytes/macrophages and T cells, respectively. Cells were exposed for 20 to 22 hours to either di-ethyl, di-n-butyl or mono-n-butyl phthalate at two different concentrations. Both diesters were metabolised to their respective monoester and influenced cytokine secretion from both monocytes/macrophages and T cells in a similar pattern: the secretion of interleukin (IL)-6, IL-10 and the chemokine CXCL8 by monocytes/macrophages was enhanced, while tumour necrosis factor (TNF)-alpha secretion by monocytes/macrophages was impaired, as was the secretion of IL-2 and IL-4, TNF alpha and interferon-gamma by T cells. The investigated phthalate monoester also influenced cytokine secretion from monocytes/macrophages similar to that of the diesters. In T cells, however, the effect of the monoester was different compared to the diesters. The influence of the phthalates on the cytokine secretion did not seem to be a result of cell death. Thus, results indicate that both human innate and adaptive immunity is influenced in vitro by phthalates, and that phthalates therefore may affect cell differentiation and regenerative and inflammatory processes in vivo. PMID- 26110841 TI - Endocytic Adaptor Protein Tollip Inhibits Canonical Wnt Signaling. AB - Many adaptor proteins involved in endocytic cargo transport exhibit additional functions in other cellular processes which may be either related to or independent from their trafficking roles. The endosomal adaptor protein Tollip is an example of such a multitasking regulator, as it participates in trafficking and endosomal sorting of receptors, but also in interleukin/Toll/NF-kappaB signaling, bacterial entry, autophagic clearance of protein aggregates and regulation of sumoylation. Here we describe another role of Tollip in intracellular signaling. By performing a targeted RNAi screen of soluble endocytic proteins for their additional functions in canonical Wnt signaling, we identified Tollip as a potential negative regulator of this pathway in human cells. Depletion of Tollip potentiates the activity of beta-catenin/TCF-dependent transcriptional reporter, while its overproduction inhibits the reporter activity and expression of Wnt target genes. These effects are independent of dynamin mediated endocytosis, but require the ubiquitin-binding CUE domain of Tollip. In Wnt-stimulated cells, Tollip counteracts the activation of beta-catenin and its nuclear accumulation, without affecting its total levels. Additionally, under conditions of ligand-independent signaling, Tollip inhibits the pathway after the stage of beta-catenin stabilization, as observed in human cancer cell lines, characterized by constitutive beta-catenin activity. Finally, the regulation of Wnt signaling by Tollip occurs also during early embryonic development of zebrafish. In summary, our data identify a novel function of Tollip in regulating the canonical Wnt pathway which is evolutionarily conserved between fish and humans. Tollip-mediated inhibition of Wnt signaling may contribute not only to embryonic development, but also to carcinogenesis. Mechanistically, Tollip can potentially coordinate multiple cellular pathways of trafficking and signaling, possibly by exploiting its ability to interact with ubiquitin and the sumoylation machinery. PMID- 26110842 TI - Social network analysis for program implementation. AB - This paper introduces the use of social network analysis theory and tools for implementation research. The social network perspective is useful for understanding, monitoring, influencing, or evaluating the implementation process when programs, policies, practices, or principles are designed and scaled up or adapted to different settings. We briefly describe common barriers to implementation success and relate them to the social networks of implementation stakeholders. We introduce a few simple measures commonly used in social network analysis and discuss how these measures can be used in program implementation. Using the four stage model of program implementation (exploration, adoption, implementation, and sustainment) proposed by Aarons and colleagues [1] and our experience in developing multi-sector partnerships involving community leaders, organizations, practitioners, and researchers, we show how network measures can be used at each stage to monitor, intervene, and improve the implementation process. Examples are provided to illustrate these concepts. We conclude with expected benefits and challenges associated with this approach. PMID- 26110843 TI - Bioinformatics analysis of thousands of TCGA tumors to determine the involvement of epigenetic regulators in human cancer. AB - BACKGROUND: Many cancer cells show distorted epigenetic landscapes. The Cancer Genome Atlas (TCGA) project profiles thousands of tumors, allowing the discovery of somatic alterations in the epigenetic machinery and the identification of potential cancer drivers among members of epigenetic protein families. METHODS: We integrated mutation, expression, and copy number data from 5943 tumors from 13 cancer types to train a classification model that predicts the likelihood of being an oncogene (OG), tumor suppressor (TSG) or neutral gene (NG). We applied this predictor to epigenetic regulator genes (ERGs), and used differential expression and correlation network analysis to identify dysregulated ERGs along with co-expressed cancer genes. Furthermore, we quantified global proteomic changes by mass spectrometry after EZH2 inhibition. RESULTS: Mutation-based classifiers uncovered the OG-like profile of DNMT3A and TSG-like profiles for several ERGs. Differential gene expression and correlation network analyses revealed that EZH2 is the most significantly over-expressed ERG in cancer and is co-regulated with a cell cycle network. Proteomic analysis showed that EZH2 inhibition induced down-regulation of cell cycle regulators in lymphoma cells. CONCLUSIONS: Using classical driver genes to train an OG/TSG predictor, we determined the most predictive features at the gene level. Our predictor uncovered one OG and several TSGs among ERGs. Expression analyses elucidated multiple dysregulated ERGs including EZH2 as member of a co-expressed cell cycle network. PMID- 26110844 TI - Two Species with an Unusual Combination of Traits Dominate Responses of British Grasshoppers and Crickets to Environmental Change. AB - There are large variations in the responses of species to the environmental changes of recent decades, heightening interest in whether their traits may explain inter-specific differences in range expansions and contractions. Using a long-term distributional dataset, we calculated range changes of grasshoppers and crickets in Britain between the 1980s and the 2000s and assessed whether their traits (resource use, life history, dispersal ability, geographic location) explain relative performance of different species. Our analysis showed large changes in the distributions of some species, and we found a positive relationship between three traits and range change: ranges tended to increase for habitat generalists, species that oviposit in the vegetation above ground, and for those with a southerly distribution. These findings accord well with the nature of environmental changes over this period (climatic warming; reductions in the diversity and increases in the height of vegetation). However, the trait effects applied mainly to just two species, Conocephalus discolor and Metrioptera roeselii, which had shown the greatest range increases. Once they were omitted from the analysis, trait effects were no longer statistically significant. Previous studies on these two species emphasised wing-length dimorphism as the key to their success, resulting in a high phenotypic plasticity of dispersal and evolutionary-ecological feedback at their expanding range margins. This, combined with our results, suggests that an unusual combination of traits have enabled these two species to undertake extremely rapid responses to recent environmental changes. The fact that our results are dominated by two species only became apparent through cautious testing of the results' robustness, not through standard statistical checks. We conclude that trait-based analyses may contribute to the assessment of species responses to environmental change and provide insights into underlying mechanisms, but results need to be interpreted with caution and may have limited predictive power. PMID- 26110845 TI - Control of Dog Mediated Human Rabies in Haiti: No Time to Spare. AB - The American region has pledged to eliminate dog-mediated human rabies by 2015. As part of these efforts, we describe the findings of a desk and field mission review of Haiti's rabies situation by the end of 2013. While government officials recognize the importance of dog-mediated rabies control, and the national rabies plan adequately contemplates the basic capacities to that effect, regular and sufficient implementation, for example, of dog vaccination, is hampered by limited funding. Compounding insufficient funding and human resources, official surveillance figures do not accurately reflect the risk to the population, as evidenced by the large number of rabid dogs detected by focalized and enhanced surveillance activities conducted by the Ministry of Agriculture, Natural Resources and Rural Development (MARNDR) and the Health and Population Ministry (MSPP) with the technical assistance of the United States Centers for Disease Control and Prevention. Although international support is common, either in the form of on-the-ground technical support or donations of immunobiologicals, it is not comprehensive. In addition, there is limited coordination with MARNDR/MSPP and with other actors at the strategic or operational level due to human resources limitations. Given these findings, the 2015 elimination goal in the region is compromised by the situation in Haiti where control of the disease is not yet in sight despite the best efforts of the resolute national officials. More importantly, dog-mediated rabies is still a threat to the Haitian population. PMID- 26110846 TI - Correction: PSMC5, a 19S proteasomal ATPase, regulates cocaine action in the nucleus accumbens. PMID- 26110847 TI - Shank Muscle Strength Training Changes Foot Behaviour during a Sudden Ankle Supination. AB - BACKGROUND: The peroneal muscles are the most effective lateral stabilisers whose tension braces the ankle joint complex against excessive supination. The purpose of this study was to identify the morphological and biomechanical effects of two machine-based shank muscle training methods. METHODS: Twenty-two healthy male recreationally active sports students performed ten weeks of single-set high resistance strength training with 3 training sessions per week. The subjects conducted subtalar pronator/supinator muscle training (ST) with the right leg by using a custom-made apparatus; the left foot muscles were exercised with machine based talocrural plantar and dorsiflexor training (TT). Muscle strength (MVIC), muscle volume and foot biomechanics (rearfoot motion, ground reaction forces, muscle reaction times) during a sudden ankle supination were recorded before and after the intervention. RESULTS: Compared to TT, ST resulted in significantly higher pronator (14% vs. 8%, P<0.01) and supinator MVIC (25% vs. 12%, P<0.01). During sudden foot inversions, both ST and TT resulted in reduced supination velocity (-12%; P<0.01). The muscle reaction onset time was faster after the training in peroneus longus (PL) (P<0.01). Muscle volume of PL (P<0.01) and TA (P<0.01) increased significantly after both ST and TT. CONCLUSION: After both ST and TT, the ankle joint complex is mechanically more stabilised against sudden supinations due to the muscle volume increase of PL and TA. As the reduced supination velocities indicate, the strength training effects are already present during free-fall. According to a sudden ankle supination in standing position, both machine-based dorsiflexor and pronator strength training is recommended for enhancing the mechanical stability of the ankle. PMID- 26110848 TI - Physical Features of Intracellular Proteins that Moonlight on the Cell Surface. AB - Moonlighting proteins comprise a subset of multifunctional proteins that perform two or more biochemical functions that are not due to gene fusions, multiple splice variants, proteolytic fragments, or promiscuous enzyme activities. The project described herein focuses on a sub-set of moonlighting proteins that have a canonical biochemical function inside the cell and perform a second biochemical function on the cell surface in at least one species. The goal of this project is to consider the biophysical features of these moonlighting proteins to determine whether they have shared characteristics or defining features that might suggest why these particular proteins were adopted for a second function on the cell surface, or if these proteins resemble typical intracellular proteins. The latter might suggest that many other normally intracellular proteins found on the cell surface might also be moonlighting in this fashion. We have identified 30 types of proteins that have different functions inside the cell and on the cell surface. Some of these proteins are found to moonlight on the surface of multiple species, sometimes with different extracellular functions in different species, so there are a total of 98 proteins in the study set. Although a variety of intracellular proteins (enzymes, chaperones, etc.) are observed to be re-used on the cell surface, for the most part, these proteins were found to have physical characteristics typical of intracellular proteins. Many other intracellular proteins have also been found on the surface of bacterial pathogens and other organisms in proteomics experiments. It is quite possible that many of those proteins also have a moonlighting function on the cell surface. The increasing number and variety of known moonlighting proteins suggest that there may be more moonlighting proteins than previously thought, and moonlighting might be a common feature of many more proteins. PMID- 26110849 TI - TNFalpha signaling regulates cystic epithelial cell proliferation through Akt/mTOR and ERK/MAPK/Cdk2 mediated Id2 signaling. AB - Tumor necrosis factor alpha (TNFalpha) is present in cyst fluid and promotes cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, the cross-talk between TNFalpha and PKD associated signaling pathways remains elusive. In this study, we found that stimulation of renal epithelial cells with TNFalpha or RANKL (receptor activator of NF-kappaB ligand), a member of the TNFalpha cytokine family, activated either the PI3K pathway, leading to AKT and mTOR mediated the increase of Id2 protein, or MAPK and Cdk2 to induce Id2 nuclear translocation. The effects of TNFalpha/RANKL on increasing Id2 protein and its nuclear translocation caused significantly decreased mRNA and protein levels of the Cdk inhibitor p21, allowing increased cell proliferation. TNFalpha levels increase in cystic kidneys in response to macrophage infiltration and thus might contribute to cyst growth and enlargement during the progression of disease. As such, this study elucidates a novel mechanism for TNFalpha signaling in regulating cystic renal epithelial cell proliferation in ADPKD. PMID- 26110851 TI - What about our nurses' pain? PMID- 26110850 TI - Correction: differential CARM1 isoform expression in subcellular compartments and among malignant and benign breast tumors. PMID- 26110852 TI - Personal health budgets: enabling greater choice. PMID- 26110853 TI - Oral and enteral nutrition in dementia: an overview. AB - The number of people currently living with dementia in the UK is estimated to be 850 000 and this is expected to rise to over 1 million by the year 2025. Dementia is a progressive terminal disease and the rate of decline is unique to each person; however, cognitive deterioration can be accelerated by undernutrition. This article discusses evidence-based approaches in the use of oral and enteral nutrition interventions for people living with dementia and ways to support their caregivers. The discussion of interventions to improve oral nutrition includes changes to the environment, support with feeding difficulties, nutritional supplements and education and training for caregivers. PMID- 26110854 TI - Nurses' attitudes to assisted suicide: sociodemographic factors. AB - This literature review seeks to explore the factors that influence nurses' attitudes towards assisted suicide. A poll conducted by the Royal College of Nursing (RCN) showed that 49% of nurses supported assisted suicide while 40% were opposed to it. A literature review resulted in 16 articles being identified for data synthesis using a recognised critiquing framework. The articles revealed four key themes: nursing specialty, level of education, geographical location and religion. It was concluded that these four themes are key to understanding a nurse's attitude towards assisted suicide. Nursing staff need to be aware of their own influences on this topic, since they will inevitably be involved in the process in some way or another, in countries where assisted suicide has been legalised. PMID- 26110855 TI - Influencing organisational culture: a leadership challenge. AB - In the wake of the Francis report, the need for NHS trusts and hospitals to adopt a culture of learning, safety and transparency has been highlighted. This article considers different aspects of culture in health care, and hones in on the link between culture and safety for patients in putting the patient first, embedding the 6Cs and considering the options to measure and influence organisational culture. The article reflects more deeply on how leadership across all levels can influence and inspire change in organisational culture, ensuring that the patient remains the focus of any changes in care delivery. PMID- 26110856 TI - Experiences of sexual intimacy among older people. PMID- 26110857 TI - Reaccreditation of non-medical prescribers: maintaining competence. AB - There is no systematic and robust method to assess the competence of non-medical prescribers (NMPs) locally or nationally. NMPs have a responsibility to remain up to date with the knowledge and skills to enable them to prescribe competently and safely within their field of expertise. In 2012, the National Prescribing Centre developed a single competency framework for prescribers defining a set of nine dimensions within three domains that can be used to underpin personal responsibility for prescribing. The authors identified validated assessment tools using a literature search, and selected those suitable for mapping against the nine dimensions. It was hoped that trust NMPs could provide evidence of competence covering all three of the framework domains using the chosen tools. Five NMPs used the tools to create a portfolio and audited them for suitability in establishing a robust and credible evidence-led system to evaluate and accredit ongoing competence. Feedback on their ease of use and applicability was sought. Trust NMPs were then invited to a workshop where the evidence was presented and they were asked to comment on, and contribute to, finalising the tools before they were embedded within trust policy. PMID- 26110858 TI - Consumer views on A&E and inpatient care. AB - John Tingle discusses the Care Quality Commission national survey results for hospital inpatient care along with results from the Patients Association and Royal College of Emergency Medicine patient survey report on A&E care. PMID- 26110859 TI - Pledging the health of the nation's children. AB - Emeritus professor Alan Glasper, of the University of Southampton and Angela Horsley, Senior Nurse for Children and Young People at NHS England, discuss a recently published report, which outlines the progress made to achieve the government's pledge for children and young people. PMID- 26110860 TI - Raising concerns: the vulnerability of students. PMID- 26110861 TI - Coping with aspects of patient and domestic violence in nursing. AB - In this monthly column, Aysha Mendes discusses how nurses, in collaboration with healthcare organisations, can protect themselves against violence from patients, and how to care for patients who have experienced domestic abuse. PMID- 26110862 TI - Relationships: from staff nurse to nurse consultant. Part 8: mental health problems. PMID- 26110863 TI - Mindfulness: it's not just about the lotus position! PMID- 26110864 TI - Retropupillary Fixation of Iris-Claw Intraocular Lens for Aphakic Eyes in Children. AB - PURPOSE: To report outcome, complications and safety of retropupillary fixated iris-claw intraocular lenses in a pediatric population. DESIGN: Retrospective study. PATIENTS AND METHODS: Ten consecutive pediatric patients (15 eyes) underwent placement of retropupillary fixated iris-claw intraocular lenses between October 2007 and July 2013 at the Department of Ophthalmology, Medical University Graz and General Hospital Klagenfurt, Austria. Postoperative visual acuity and complications were analyzed. RESULTS: Median final best-corrected visual acuity improved by 0.12 logMAR from preoperative baseline. Mean postoperative spherical equivalent was -0.05 +/- 1.76 D. No serious complications were observed intra- or postoperatively during the entire follow-up period of up to 40 months. One patient experienced a haptic disenclavation with IOL subluxation immediately after a car accident. CONCLUSION: Our study demonstrates that iris-claw intraocular lens implantation behind the iris is safe in children with lack of capsular support and yields excellent visual outcome with low complication rate. PMID- 26110865 TI - Can Handheld Thermal Imaging Technology Improve Detection of Poachers in African Bushveldt? AB - Illegal hunting (poaching) is a global threat to wildlife. Anti-poaching initiatives are making increasing use of technology, such as infrared thermography (IRT), to support traditional foot and vehicle patrols. To date, the effectiveness of IRT for poacher location has not been tested under field conditions, where thermal signatures are often complex. Here, we test the hypothesis that IRT will increase the distance over which a poacher hiding in African scrub bushveldt can be detected relative to a conventional flashlight. We also test whether any increase in effectiveness is related to the cost and complexity of the equipment by comparing comparatively expensive (22,000 USD) and relatively inexpensive (2000 USD) IRT devices. To test these hypotheses we employ a controlled, fully randomised, double-blind procedure to find a poacher in nocturnal field conditions in African bushveldt. Each of our 27 volunteer observers walked three times along a pathway using one detection technology on each pass in randomised order. They searched a prescribed search area of bushveldt within which the target was hiding. Hiding locations were pre determined, randomised, and changed with each pass. Distances of first detection and positive detection were noted. All technologies could be used to detect the target. Average first detection distance for flashlight was 37.3 m, improving by 19.8 m to 57.1 m using LIRT and by a further 11.2m to 68.3m using HIRT. Although detection distances were significantly greater for both IRTs compared to flashlight, there was no significant difference between LIRT and HIRT. False detection rates were low and there was no significant association between technology and accuracy of detection. Although IRT technology should ideally be tested in the specific environment intended before significant investment is made, we conclude that IRT technology is promising for anti-poaching patrols and that for this purpose low cost IRT units are as effective as units ten times more expensive. PMID- 26110866 TI - Matched-Case Comparisons in a Single Institution to Determine Critical Points for Inexperienced Surgeons' Successful Performances of Laparoscopic Radical Hysterectomy versus Abdominal Radical Hysterectomy in Stage IA2-IIA Cervical Cancer. AB - This is a retrospective study which aims to identify major determinants of successful laparoscopic radical hysterectomy (LRH) versus abdominal radical hysterectomy (ARH) performed by inexperienced surgeons for stage IA2-IIA cervical cancer. A total of 161 consecutive patients with stage IA2-IIA cervical cancer who underwent RH were grouped into 2 groups according to the surgeons' experience with LRH: experienced surgeon versus inexperienced surgeon. After matching for age and risk factors, surgical and survival outcomes were compared. Experienced surgeon selected patients with earlier-stage and fewer risk factors for LRH than ARH, but inexperience surgeons did not. After matching, the vaginal tumor-free margin of LRH was shorter than that of ARH in experienced surgeon group (1.3 versus 1.7 cm, p=0.007); however, the vaginal tumor-free margin was longer than that of ARH in the inexperienced surgeon group (1.8 versus 1.3 cm, p=0.035). The postoperative hospital stay of LRH was shorter than that of ARH in experienced surgeon group (5.5 versus 7.7 days, p<0.001), but not different from that of ARH in the inexperienced surgeon group. Vaginal tumor-free margin >1.8 cm (OR 7.33, 95% CI 1.22-40.42), stage >IB1 (OR 8.83, 95% CI 1.51-51.73), and estimated blood loss >575 mL (OR 33.95, 95% CI 4.87-236.79) were independent risk factors for longer postoperative hospital stay in the inexperienced surgeon group. There was no difference of 5-year-profression-free survival of LRH patients between experienced surgeon and inexperienced surgeon groups after matching (55.1 versus 33.3%, p=0.391). Selection of earlier-stage disease and moderate vaginal tumor free margin might be important for an inexperienced surgeon to successfully perform LRH with minimal complications in stage IA2-IIA cervical cancer. PMID- 26110867 TI - Religion and Completed Suicide: a Meta-Analysis. AB - INTRODUCTION: Suicide is a major public health concern and a leading cause of death around the world. How religion influences the risk of completed suicide in different settings across the world requires clarification in order to best inform suicide prevention strategies. METHODS: A meta-analysis using search results from Pubmed and Web of Science databases was conducted following PRISMA protocol and using the keywords "religion" or "religious" or "religiosity" or "spiritual" or "spirituality" plus "suicide" or "suicidality" or "suicide attempt". Random and fixed effects models were used to generate pooled ORs and I2 values. Sub-analyses were conducted among the following categories: young age (<45 yo), older age (>=45 yo), western culture, eastern culture, and religious homogeneity. RESULTS: Nine studies that altogether evaluated 2339 suicide cases and 5252 comparison participants met all selection criteria and were included in the meta-analysis. The meta-analysis suggested an overall protective effect of religiosity from completed suicide with a pooled OR of 0.38 (95% CI: 0.21-0.71) and I2 of 91%. Sub-analyses similarly revealed significant protective effects for studies performed in western cultures (OR = 0.29, 95% CI: 0.18-0.46), areas with religious homogeneity (OR = 0.18, 95% CI: 0.13-0.26), and among older populations (OR = 0.42, 95% CI: 0.21-0.84). High heterogeneity of our meta-analysis was attributed to three studies in which the methods varied from the other six. CONCLUSION: Religion plays a protective role against suicide in a majority of settings where suicide research is conducted. However, this effect varies based on the cultural and religious context. Therefore, public health professionals need to strongly consider the current social and religious atmosphere of a given population when designing suicide prevention strategies. PMID- 26110869 TI - Estimation of Potential Availability of Essential Oil in Some Brands of Herbal Teas and Herbal Dietary Supplements. AB - INTRODUCTION: The aim of the study was to estimate potential availability of essential oil in some brands of herbal products. METHODS: A comparison was performed on the basis of the essential oil yield in the unprocessed raw materials such as leaves of peppermint and lemon balm and inflorescence of chamomile as well as herbal tea bags and in dietary supplements. The yield of essential oil was determined by distillation. Essential oil was analyzed by GC FID and GC-MS. RESULTS: It was found that the average potential availability of essential oils in the products such as dietary supplements for the doses recommended by the producers is lower than in the corresponding tea infusions: for peppermint formulations approximately 6-fold lower, for the formulations with lemon balm about 4-fold lower, and for the chamomile preparations about 3-fold lower. It was found that essential oils extracted from herbal teas have a similar chemical profile with characteristic deviations in the amount of individual components, which arise from the origin of the raw material. DISCUSSION: In contrast to homogenous pharmaceutical herbal mixtures consistent with, the Pharmacopoeia requirements, herbal teas (available in grocery stores) and dietary supplements are often out of control in terms of the yield and composition of the essential oil, which is primarily responsible for the health benefits and aromatic qualities of these products. Analysis of the composition of the dietary supplements showed that they contain on average significantly lower amounts of plant material compared to the herbal teas. PMID- 26110868 TI - Exercise Improves Host Response to Influenza Viral Infection in Obese and Non Obese Mice through Different Mechanisms. AB - Obesity has been associated with greater severity of influenza virus infection and impaired host defense. Exercise may confer health benefits even when weight loss is not achieved, but it has not been determined if regular exercise improves immune defense against influenza A virus (IAV) in the obese condition. In this study, diet-induced obese mice and lean control mice exercised for eight weeks followed by influenza viral infection. Exercise reduced disease severity in both obese and non-obese mice, but the mechanisms differed. Exercise reversed the obesity-associated delay in bronchoalveolar-lavage (BAL) cell infiltration, restored BAL cytokine and chemokine production, and increased ciliary beat frequency and IFNalpha-related gene expression. In non-obese mice, exercise treatment reduced lung viral load, increased Type-I-IFN-related gene expression early during infection, but reduced BAL inflammatory cytokines and chemokines. In both obese and non-obese mice, exercise increased serum anti-influenza virus specific IgG2c antibody, increased CD8+ T cell percentage in BAL, and reduced TNFalpha by influenza viral NP-peptide-responding CD8+ T cells. Overall, the results suggest that exercise "restores" the immune response of obese mice to a phenotype similar to non-obese mice by improving the delay in immune activation. In contrast, in non-obese mice exercise treatment results in an early reduction in lung viral load and limited inflammatory response. PMID- 26110870 TI - Relationship between Distinct African Cholera Epidemics Revealed via MLVA Haplotyping of 337 Vibrio cholerae Isolates. AB - BACKGROUND: Since cholera appeared in Africa during the 1970s, cases have been reported on the continent every year. In Sub-Saharan Africa, cholera outbreaks primarily cluster at certain hotspots including the African Great Lakes Region and West Africa. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we applied MLVA (Multi-Locus Variable Number Tandem Repeat Analysis) typing of 337 Vibrio cholerae isolates from recent cholera epidemics in the Democratic Republic of the Congo (DRC), Zambia, Guinea and Togo. We aimed to assess the relationship between outbreaks. Applying this method, we identified 89 unique MLVA haplotypes across our isolate collection. MLVA typing revealed the short-term divergence and microevolution of these Vibrio cholerae populations to provide insight into the dynamics of cholera outbreaks in each country. Our analyses also revealed strong geographical clustering. Isolates from the African Great Lakes Region (DRC and Zambia) formed a closely related group, while West African isolates (Togo and Guinea) constituted a separate cluster. At a country-level scale our analyses revealed several distinct MLVA groups, most notably DRC 2011/2012, DRC 2009, Zambia 2012 and Guinea 2012. We also found that certain MLVA types collected in the DRC persisted in the country for several years, occasionally giving rise to expansive epidemics. Finally, we found that the six environmental isolates in our panel were unrelated to the epidemic isolates. CONCLUSIONS/SIGNIFICANCE: To effectively combat the disease, it is critical to understand the mechanisms of cholera emergence and diffusion in a region-specific manner. Overall, these findings demonstrate the relationship between distinct epidemics in West Africa and the African Great Lakes Region. This study also highlights the importance of monitoring and analyzing Vibrio cholerae isolates. PMID- 26110871 TI - Neural Tuning Functions Underlie Both Generalization and Interference. AB - In sports, the role of backswing is considered critical for generating a good shot, even though it plays no direct role in hitting the ball. We recently demonstrated the scientific basis of this phenomenon by showing that immediate past movement affects the learning and recall of motor memories. This effect occurred regardless of whether the past contextual movement was performed actively, passively, or shown visually. In force field studies, it has been shown that motor memories generalize locally and that the level of compensation decays as a function of movement angle away from the trained movement. Here we examine if the contextual effect of past movement exhibits similar patterns of generalization and whether it can explain behavior seen in interference studies. Using a single force-field learning task, the directional tuning curves of both the prior contextual movement and the subsequent force field adaptive movements were measured. The adaptation movement direction showed strong directional tuning, decaying to zero by 90 degrees relative to the training direction. The contextual movement direction exhibited a similar directional tuning, although the effect was always above 60%. We then investigated the directional tuning of the passive contextual movement using interference tasks, where the contextual movements that uniquely specified the force field direction were separated by +/ 15 degrees or +/-45 degrees . Both groups showed a pronounced tuning effect, which could be well explained by the directional tuning functions for single force fields. Our results show that contextual effect of past movement influences predictive force compensation, even when adaptation does not require contextual information. However, when such past movement contextual information is crucial to the task, such as in an interference study, it plays a strong role in motor memory learning and recall. This work demonstrates that similar tuning responses underlie both generalization of movement direction during dynamic learning and contextual movements in both single force field and interference tasks. PMID- 26110873 TI - Convective Flow of Sisko Fluid over a Bidirectional Stretching Surface. AB - The present investigation focuses the flow and heat transfer characteristics of the steady three-dimensional Sisko fluid driven by a bidirectional stretching sheet. The modeled partial differential equations are reduced to coupled ordinary differential equations by a suitable transformation. The resulting equations are solved numerically by the shooting method using adaptive Runge Kutta algorithm in combination with Newton's method in the domain [0,infinity). The numerical results for the velocity and temperature fields are graphically presented and effects of the relevant parameters are discussed in detail. Moreover, the skin friction coefficient and local Nusselt number for different values of the power law index and stretching ratio parameter are presented through tabulated data. The numerical results are also verified with the results obtained analytically by the homotopy analysis method (HAM). Additionally, the results are validated with previously published pertinent literature as a limiting case of the problem. PMID- 26110872 TI - The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells. AB - Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12-15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects. Two WHO grade IV human GBM cells lines (U87MG and U118MG) and primary human dermal fibroblasts (HDFs) were repeatedly exposed to PROG and TMZ either alone or in combination for 3 and 6 days. Cell death was measured by MTT reduction assay. PROG and TMZ individually induced tumor cell death in a dose-dependent manner. PROG at high doses produced more cell death than TMZ alone. When combined, PROG enhanced the cell death-inducing effect of TMZ. In HDFs, PROG did not reduce viability even at the same high cytotoxic doses, but TMZ did so in a dose-dependent manner. In combination, PROG reduced TMZ toxicity in HDFs. PROG alone and in combination with TMZ suppressed the EGFR/PI3K/Akt/mTOR signaling pathway and MGMT expression in U87MG cells, thus suppressing cell proliferation. PROG and TMZ individually reduced cell migration in U87MG cells but did so more effectively in combination. PROG enhances the cytotoxic effects of TMZ in GBM cells and reduces its toxic side effects in healthy primary cells. PMID- 26110875 TI - International Classification of Diseases, Tenth Revision, Clinical Modification for the Pulmonary, Critical Care, and Sleep Physician. AB - After a patient encounter, the physician uses two coding systems to bill for the service rendered to the patient. The Current Procedural Terminology (CPT) code is used to describe the encounter or procedure. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code is used to describe the diagnosis(es) of the patient. On October 1, 2015, ICD-9-CM coding will end, and all physicians will be required to use a new diagnostic coding system, the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). This article describes the new diagnostic coding system and how it differs from the old system. There are resources and costs involved for physicians and physician practices to prepare properly for ICD-10-CM. Similar to other important events, the more thorough the preparation, the more likely a positive outcome will occur. Resource use is very important in preparation for the transition from ICD-9-CM to ICD-10-CM. Greater familiarity with ICD-10-CM plus a thorough, effective preparation will lead to reduced costs and a smooth transition. Coding descriptor changes and additional codes occur in ICD-10-CM for chronic bronchitis and emphysema, asthma, and respiratory failure. These changes will affect the coding of these diseases and disorders by physicians. Because the number of codes will increase more than fivefold, the complexity of documentation to support ICD-10-CM will increase substantially. The documentation in the patient's chart to support the ICD-10-CM codes used will need to be enhanced. The requirement for accurate and comprehensive documentation cannot be emphasized enough. All of the coding and documentation changes will be a challenge to pulmonary, critical care, and sleep physicians. They must be prepared fully when ICD-10-CM coding begins and ICD-9-CM coding stops abruptly on October 1, 2015. PMID- 26110874 TI - Corticotropin-Releasing Hormone (CRH) Promotes Macrophage Foam Cell Formation via Reduced Expression of ATP Binding Cassette Transporter-1 (ABCA1). AB - Atherosclerosis, the major pathology of cardiovascular disease, is caused by multiple factors involving psychological stress. Corticotropin-releasing hormone (CRH), which is released by neurosecretory cells in the hypothalamus, peripheral nerve terminals and epithelial cells, regulates various stress-related responses. Our current study aimed to verify the role of CRH in macrophage foam cell formation, the initial critical stage of atherosclerosis. Our quantitative real time reverse transcriptase PCR (qRT-PCR), semi-quantitative reverse transcriptase PCR, and Western blot results indicate that CRH down-regulates ATP-binding cassette transporter-1 (ABCA1) and liver X receptor (LXR)-alpha, a transcription factor for ABCA1, in murine peritoneal macrophages and human monocyte-derived macrophages. Oil-red O (ORO) staining and intracellular cholesterol measurement of macrophages treated with or without oxidized LDL (oxLDL) and with or without CRH (10 nM) in the presence of apolipoprotein A1 (apoA1) revealed that CRH treatment promotes macrophage foam cell formation. The boron-dipyrromethene (BODIPY)-conjugated cholesterol efflux assay showed that CRH treatment reduces macrophage cholesterol efflux. Western blot analysis showed that CRH-induced down regulation of ABCA1 is dependent on phosphorylation of Akt (Ser473) induced by interaction between CRH and CRH receptor 1(CRHR1). We conclude that activation of this pathway by CRH accelerates macrophage foam cell formation and may promote stress-related atherosclerosis. PMID- 26110876 TI - Association between DRD2/ANKK1 TaqIA Polymorphism and Susceptibility with Tourette Syndrome: A Meta-Analysis. AB - BACKGROUND: Genetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS. METHODS: Literature was searched in multiple databases including PUBMED, COCHRANE and WEB OF SCIENCE up to July 2014. The number of the genotypes for DRD2/ANKK1 TaqIA in the TS and control subjects was extracted and statistical analysis was performed using Review Manager 5.0.16 and Stata 12.0 software. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were utilized to calculate the risk of TS with DRD2/ANKK1 TaqIA. Stratified analysis based on ethnicity was also conducted. RESULTS: 523 patients with TS, 564 controls and 87 probands plus 152 relatives from five published studies were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the DRD2/ANKK1 TaqIA A1 allele were 1.69 (95%CIs = 1.42-2.00) in the fixed-effect model and 1.66 (95%CIs = 1.33-2.08) in the random-effects model. Stratification by ethnicity indicated the TaqIA A1 allele was significantly associated with TS in Caucasians (fixed-effect model: OR=1.75, 95%CI = 1.43-2.16; random-effect model: OR=1.69, 95%CI = 1.25-2.28) and in Asians (OR=1.54, 95%CI = 1.12-2.10). Meta-analysis of the A1A1 vs. A2A2 (homozygous model), A1A2 vs. A2A2 (heterozygous model) and A1A1+A1A2 vs. A2A2 (dominant model) of this polymorphism revealed a significant association with TS in overall populations and Caucasians. CONCLUSIONS: This meta-analysis suggested that the DRD2/ANKK1 TaqIA polymorphism might contribute to TS susceptibility, especially in Caucasian population. However, further investigation with a larger number of worldwide studies should be conducted to verify the association. PMID- 26110877 TI - Overcoming inactivation of the lung surfactant by serum proteins: a potential role for fluorocarbons? AB - In many pulmonary conditions serum proteins interfere with the normal adsorption of components of the lung surfactant to the surface of the alveoli, resulting in lung surfactant inactivation, with potentially serious untoward consequences. Here, we review the strategies that have recently been designed in order to counteract the biophysical mechanisms of inactivation of the surfactant. One approach includes protein analogues or peptides that mimic the native proteins responsible for innate resistance to inactivation. Another perspective uses water soluble additives, such as electrolytes and hydrophilic polymers that are prone to enhance adsorption of phospholipids. An alternative, more recent approach consists of using fluorocarbons, that is, highly hydrophobic inert compounds that were investigated for partial liquid ventilation, that modify interfacial properties and can act as carriers of exogenous lung surfactant. The latter approach that allows fluidisation of phospholipid monolayers while maintaining capacity to reach near-zero surface tension definitely warrants further investigation. PMID- 26110879 TI - Correction: MAVS Protein Is Attenuated by Rotavirus Nonstructural Protein 1. PMID- 26110878 TI - Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Beyond the joints, TNFi (tumour necrosis factor inhibitor) therapy may confer systemic benefits in rheumatoid arthritis (RA). Several studies have investigated the role of TNFi on insulin resistance/sensitivity (IR/IS). This question is of general interest given the emerging evidence linking inflammation and insulin resistance. The main aim of this review was to summarise the published data and to determine the effects of TNFi on IR/IS. METHODS: We searched the PubMed and ISI Web of Knowledge databases for studies which examined the effects of TNFi on IR/IS. The studies were assessed independently by two reviewers according to a pre-specified protocol. The data on Homeostatic Model Assessment for Insulin resistance (HOMA) and Quantitative Insulin Sensitivity Check Index (QUICKI) were pooled and reported as standard difference in means (SDM) with 95% confidence interval (CI) using a random-effects model. RESULTS: A total of eight studies with 260 subjects met the selection criteria. The duration of the studies was from 8 weeks to 12 months. There was statistically significant reduction in HOMA index in six out of eight studies and four reported significant increment in QUICKI. The pooled analysis revealed significant reduction in HOMA [SDM-0.148, 95%CI[-0.278 to -0.017], p=0.026] and increment in QUICKI [SDM 0.312, 95%CI[0.019 to 0.606], p=0.037] with TNFi. CONCLUSION: There is emerging evidence to support that TNFi therapy improves IS and reduces IR in RA. Further, well conducted trials are needed to determine if such effects translate to lower incidence of diabetes in RA or other autoimmune conditions on biologic therapy. PMID- 26110880 TI - Acute promyelocytic leukemia during pregnancy: a systematic analysis of outcome. AB - The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71 patients with new-onset APL during pregnancy. Induction therapy included various regimens of all-trans retinoic acid (ATRA), cytarabine, and anthracycline and resulted in a complete remission rate of 93%. Obstetric and fetal complications included pre-term deliveries (46%), spontaneous/therapeutic abortion/intrauterine death (33.3%) and other neonatal complications (25.9%). Mothers diagnosed in the first trimester were more likely to experience obstetric (p < 0.01) and fetal (p < 0.01) complications. To our knowledge, this is the largest systematic review of APL in pregnancy. The vast majority of APL patients in pregnancy may achieve remission with initial induction therapy. APL or its therapy in pregnancy, however, is associated with a high risk of fetal and obstetrical complications. The results of our study may help in patient counseling and informed decision-making. PMID- 26110881 TI - Methotrexate-associated EBV-positive CD20-negative diffuse large B-cell lymphoma localized to skin presenting as multiple chronic lower leg ulcers. PMID- 26110882 TI - Early-stage nodular lymphocyte-predominant Hodgkin lymphoma: the impact of radiotherapy on overall survival. AB - The purpose of this study was to use the National Cancer Database to examine the association between radiation therapy (RT) and overall survival (OS) in early stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) using standard and propensity score (PS)-adjusted Cox proportional hazards models. From 1998-2011, 1915 patients with stage I/II NLPHL were studied, with a median follow-up of 6.6 years (median age = 44). Of the cohort, 1224(64%) received RT (alone or with chemotherapy) to a median dose of 30.6 Gy. Patients were more likely to receive RT if male, younger age, lower stage, no "B"-symptoms, favorably insured, and treatment at comprehensive centers (all p < 0.05). Patients administered RT had an improved 5-year OS (HR = 0.62; 95%CI, 0.43-0.89, p = 0.01). After PS-matching (n = 868) based on all known co-variates, RT use trended towards improved OS (HR = 0.49; 95%CI, 0.23-1.05, p = 0.06). This study represents one of the largest prospective datasets examining the role of RT for stage I/II NLPHL and inclusion of RT may be considered. PMID- 26110883 TI - Marked regression of myelofibrosis during reduced-dose dasatinib treatment in chronic myelogenous leukemia in accelerated phase. PMID- 26110884 TI - Statin Treatment and Mortality in Community-Dwelling Frail Older Patients with Diabetes Mellitus: A Retrospective Observational Study. AB - BACKGROUND: Older adults are often excluded from clinical trials. Decision making for administration of statins to older patients with diabetes mellitus (DM) is under debate, particularly in frail older patients with comorbidity and high mortality risk. We tested the hypothesis that statin treatment in older patients with DM was differentially effective across strata of mortality risk assessed by the Multidimensional Prognostic Index (MPI), based on information collected with the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA). METHODS: In this retrospective observational study, we estimated the mortality risk in 1712 community-dwelling subjects with DM >= 65 years who underwent a SVaMA evaluation to establish accessibility to homecare services/nursing home admission from 2005 to 2013 in the Padova Health District, Italy. Mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) risk of mortality at baseline and propensity score-adjusted hazard ratios (HR) of three year mortality were calculated according to statin treatment. RESULTS: Higher MPI SVaMA scores were associated with lower rates of statin treatment (MPI-SVaMA-1 = 39% vs MPI-SVaMA-2 = 36% vs MPI-SVaMA-3 = 24.9%. p<0.001) and higher three-year mortality (MPI-SVaMA-1 = 12.9% vs MPI-SVaMA-2 = 24% vs MPI-SVaMA-3 = 34.4%, p<0.001). After adjustment for propensity score quintiles, statin treatment was significantly associated with lower three-year mortality irrespective of MPI SVaMA group (interaction test p = 0.303). HRs [95% confidence interval (CI)] were 0.19 (0.14-0.27), 0.28 (0.21-0.36), and 0.26 (0.20-0.34) in the MPI-SVaMA-1, MPI SVaMA-2, and MPI-SVaMA-3 groups, respectively. Subgroup analyses showed that statin treatment was also beneficial irrespective of age. HRs (95% CI) were 0.21 (0.15-0.31), 0.26 (0.20-0.33), and 0.26 (0.20-0.35) among patients aged 65-74, 75 84, and >= 85 years, respectively (interaction test p=0.812). CONCLUSIONS: Statin treatment was significantly associated with reduced three-year mortality independently of age and multidimensional impairment in community-dwelling frail older patients with DM. PMID- 26110885 TI - MED30 Regulates the Proliferation and Motility of Gastric Cancer Cells. AB - MED30 is an essential member of the mediator complex that forms a hub between transcriptional activators and RNA polymerase II. However, the expressions and roles of MED30 have been poorly characterized in cancer. In this study, we examined the functional roles of MED30 during gastric cancer progression. It was found that MED30 was overexpressed in gastric cancer tissues and cell lines. Moreover, MED30 overexpression increased the proliferation, migration, and invasion of gastric cancer cells, whereas MED30 knockdown inhibited these effects. Furthermore the knockdown significantly inhibited tumorigenicity in SCID mice. MED30 also promoted the expressions of genes related to epithelial mesenchymal transition and induced a fibroblast-like morphology. This study shows MED30 has pathophysiological roles in the proliferation, migration, and invasion of gastric cancer cells and suggests that MED30 should be viewed as a potent therapeutic target for malignant gastric carcinoma. PMID- 26110886 TI - Community Phylogenetics: Assessing Tree Reconstruction Methods and the Utility of DNA Barcodes. AB - Studies examining phylogenetic community structure have become increasingly prevalent, yet little attention has been given to the influence of the input phylogeny on metrics that describe phylogenetic patterns of co-occurrence. Here, we examine the influence of branch length, tree reconstruction method, and amount of sequence data on measures of phylogenetic community structure, as well as the phylogenetic signal (Pagel's lambda) in morphological traits, using Trichoptera larval communities from Churchill, Manitoba, Canada. We find that model-based tree reconstruction methods and the use of a backbone family-level phylogeny improve estimations of phylogenetic community structure. In addition, trees built using the barcode region of cytochrome c oxidase subunit I (COI) alone accurately predict metrics of phylogenetic community structure obtained from a multi-gene phylogeny. Input tree did not alter overall conclusions drawn for phylogenetic signal, as significant phylogenetic structure was detected in two body size traits across input trees. As the discipline of community phylogenetics continues to expand, it is important to investigate the best approaches to accurately estimate patterns. Our results suggest that emerging large datasets of DNA barcode sequences provide a vast resource for studying the structure of biological communities. PMID- 26110887 TI - The Role of Genetic Risk Score in Predicting the Risk of Hypertension in the Korean population: Korean Genome and Epidemiology Study. AB - Hypertension is regarded as a multifactorial disease with a modest contribution of genetic factors and strongly affected by environmental factors. Recent genome wide association studies have identified specific loci associated with high blood pressure (BP) and hypertension. This study aimed to examine the association between the genetic risk score (GRS), a linear function of multiple single nucleotide polymorphisms (SNPs) associated with hypertension, and high BP and prevalent hypertension at baseline examination and to evaluate the efficacy of the GRS for predicting incident hypertension with longitudinal data in Korean subjects. Data for 8,556 participants, aged 40 to 69, in a community-based cohort study were analyzed. Unweighted GRS (cGRS) and weighted GRS (wGRS) were constructed from 4 SNPs related to high BP or hypertension in previous genome wide association and its replication studies for the Korean middle-aged population. Cross-sectional analysis (n=8,556) revealed that cGRS was significantly associated with prevalent hypertension (odds ratio=1.15 per risk allele; 95%CI, 1.09-1.20). Additionally, the odds ratios (ORs) of prevalent hypertension for those who in medium and the highest tertile compared with those who in the lowest tertile of wGRS were 1.31 (95% CI, 1.15-1.50) and 1.59 (95%CI, 1.38-1.82), respectively. In a longitudinal analysis (n=5,632), participants in the highest tertile of wGRS had a 1.22-fold (OR=1.22, 95%CI, 1.02-1.46) greater risk of incident hypertension relative to those in the lowest tertile, after adjusting for a number of confounding factors. However, wGRS topped with traditional risk factors had no significant effect on discrimination ability (c statistics with and without wGRS were 0.811 and 0.810, P=0.1057). But, reclassification analysis showed that the addition of GRS to the model with conventional risk factors led to about 9% significant increment in category-free net reclassification improvement. GRSs based on 4 SNPs were independently associated with hypertension and may provide a statistically significant improvement over the existing model for prediction of incident hypertension. PMID- 26110888 TI - Rescuing Those Left Behind: Recovering and Characterizing Underdigested Membrane and Hydrophobic Proteins To Enhance Proteome Measurement Depth. AB - The marine archaeon Nanoarchaeum equitans is dependent on direct physical contact with its host, the hyperthermophile Ignicoccus hospitalis. As this interaction is thought to be membrane-associated, involving a myriad of membrane-anchored proteins, proteomic efforts to better characterize this difficult to analyze interface are paramount to uncovering the mechanism of their association. By extending multienzyme digestion strategies that use sample filtration to recover underdigested proteins for reprocessing/consecutive proteolytic digestion, we applied chymotrypsin to redigest the proteinaceous material left over after initial proteolysis with trypsin of sodium dodecyl sulfate (SDS)-extracted I. hospitalis-N. equitans proteins. Using this method, we show that proteins with increased hydrophobic character, including membrane proteins with multiple transmembrane helices, are enriched and recovered in the underdigested fraction. Chymotryptic reprocessing provided significant sequence coverage gains in both soluble and hydrophobic proteins alike, with the latter benefiting more so in terms of membrane protein representation. These gains were despite a large proportion of high-quality peptide spectra remaining unassigned in the underdigested fraction suggesting high levels of protein modification on these often surface-exposed proteins. Importantly, these gains were achieved without applying extensive fractionation strategies usually required for thorough characterization of membrane-associated proteins and were facilitated by the generation of a distinct, complementary set of peptides that aid in both the identification and quantitation of this important, under-represented class of proteins. PMID- 26110889 TI - Dietary fatty acids: Friends or foes? PMID- 26110891 TI - The aperitif effect: Alcohol's effects on the brain's response to food aromas in women. AB - OBJECTIVE: Consuming alcohol prior to a meal (an aperitif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre load increased food consumption and potentiated differences between food and non food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the aperitif phenomenon. PMID- 26110893 TI - Body fat and the cognitive pattern: A population-based study. AB - OBJECTIVE: The relationship between body fatness and cognitive pattern at a population level was investigated. METHODS: Among 500 unselected subjects from the general population, the role of body mass index (BMI) and body fat mass (BFM) on a mini-mental state examination (MMSE) and on a battery of paper and pencil neuropsychological tests was analyzed. Multiple linear regressions, accounting for potential confounders, were used. RESULTS: In fully adjusted models, MMSE (coefficient +0.027, 95% confidence intervals, 0.017-0.177), the clock drawing test (+0.141, 0.053-0.226), and the trail making test A (+1.542, 0.478-2.607) were positively associated with BMI. Adding BFM to the models, no associations were observed. The tests were also positively associated with BFM (+0.056, 0.021 0.091; +0.063, 0.025-0.101; +0.592, 0.107-1.077; respectively). At analysis of covariance, the same tests were significantly better performed over 29.4 kg m(-2) of BMI. After adding BFM as further confounder, all differences in performance across BMI were no longer significant. The three tests were better performed over 34.6 kg of BFM. CONCLUSIONS: Higher BMI and particularly higher BFM are positively associated with better performance at the cognitive tasks exploring selective attention and executive functions. PMID- 26110894 TI - Extraction, Isolation, Structural Characterization and Anti-Tumor Properties of an Apigalacturonan-Rich Polysaccharide from the Sea Grass Zostera caespitosa Miki. AB - An apigalacturonan (AGA)-rich polysaccharide, ZCMP, was isolated from the sea grass Zostera caespitosa Miki. The depolymerized fragments derived from ZCMP were obtained by either acidic degradation or pectinase degradation, and their structures were characterized by electrospray ionization collision-induced dissociation mass spectrometry (ESI-CID-MS2) and nuclear magnetic resonance (NMR) spectroscopy. The average molecular weight of ZCMP was 77.2 kD and it consisted of galacturonic acid (GalA), apiosefuranose (Api), galactose (Gal), rhamnose (Rha), arabinose (Ara), xylose (Xyl), and mannose (Man), at a molar ratio of 51.4?15.5?6.0?11.8?4.2?4.4?4.2. There were two regions of AGA (70%) and rhamnogalacturonan-I (RG-Iota, 30%) in ZCMP. AGA was composed of an alpha-1,4-D galactopyranosyluronan backbone mainly substituted at the O-3 position by single Api residues. RG-Iota possessed a backbone of repeating disaccharide units of >4GalAalpha1,2Rhaalpha1->, with a few alpha-L-arabinose and beta-D-galactose residues as side chains. The anti-angiogenesis assay showed that ZCMP inhibited the migratory activity of human umbilical vein endothelial cell (HUVECs), with no influence on endothelial cells growth. ZCMP also promoted macrophage phagocytosis. These findings of the present study demonstrated the potential anti tumor activity of ZCMP through anti-angiogenic and immunoregulatory pathways. PMID- 26110892 TI - Epigenome-wide study identifies novel methylation loci associated with body mass index and waist circumference. AB - OBJECTIVE: To conduct an epigenome-wide analysis of DNA methylation and obesity traits. METHODS: DNA methylation was quantified in CD4+ T-cells using the Illumina Infinium HumanMethylation450 array in 991 participants of the Genetics of Lipid Lowering Drugs and Diet Network. Methylation at individual cytosine phosphate-guanine (CpG) sites as a function of body mass index (BMI) and waist circumference (WC), adjusting for age, gender, study site, T-cell purity, smoking, and family structure, was modeled. RESULTS: Epigenome-wide significant associations between eight CpG sites and BMI and five CpG sites and WC, successfully replicating the top hits in whole blood samples from the Framingham Heart Study (n = 2,377) and the Atherosclerosis Risk in Communities study (n = 2,097), were found. Top findings were in CPT1A (meta-analysis P = 2.7 * 10(-43) for BMI and 9.9 * 10(-23) for WC), PHGDH (meta-analysis P = 2.0 * 10(-15) for BMI and 4.0 * 10(-9) for WC), CD38 (meta-analysis P = 6.3 * 10(-11) for BMI and 1.6 * 10(-12) for WC), and long intergenic non-coding RNA 00263 (meta-analysis P = 2.2 * 10(-16) for BMI and 8.9 * 10(-14) for WC), regions with biologically plausible relationships to adiposity. CONCLUSIONS: This large-scale epigenome-wide study discovered and replicated robust associations between DNA methylation at CpG loci and obesity indices, laying the groundwork for future diagnostic and/or therapeutic applications. PMID- 26110895 TI - Use of Natural Antimicrobial Peptides and Bacterial Biopolymers for Cultured Pearl Production. AB - Cultured pearls are the product of grafting and rearing of Pinctada margaritifera pearl oysters in their natural environment. Nucleus rejections and oyster mortality appear to result from bacterial infections or from an inappropriate grafting practice. To reduce the impact of bacterial infections, synthetic antibiotics have been applied during the grafting practice. However, the use of such antibiotics presents a number of problems associated with their incomplete biodegradability, limited efficacy in some cases, and an increased risk of selecting for antimicrobial resistant bacteria. We investigated the application of a marine antimicrobial peptide, tachyplesin, which is present in the Japanese horseshoe crab Tachypleus tridentatus, in combination with two marine bacterial exopolymers as alternative treatment agents. In field studies, the combination treatment resulted in a significant reduction in graft failures vs. untreated controls. The combination of tachyplesin (73 mg/L) with two bacterial exopolysaccharides (0.5% w/w) acting as filming agents, reduces graft-associated bacterial contamination. The survival data were similar to that reported for antibiotic treatments. These data suggest that non-antibiotic treatments of pearl oysters may provide an effective means of improving oyster survival following grafting procedures. PMID- 26110896 TI - Valorization of Sargassum muticum Biomass According to the Biorefinery Concept. AB - The biorefinery concept integrates processes and technologies for an efficient biomass conversion using all components of a feedstock. Sargassum muticum is an invasive brown algae which could be regarded as a renewable resource susceptible of individual valorization of the constituent fractions into high added-value compounds. Microwave drying technology can be proposed before conventional ethanol extraction of algal biomass, and supercritical fluid extraction with CO2 was useful to extract fucoxanthin and for the fractionation of crude ethanol extracts. Hydrothermal processing is proposed to fractionate the algal biomass and to solubilize the fucoidan and phlorotannin fractions. Membrane technology was proposed to concentrate these fractions and obtain salt- and arsenic-free saccharidic fractions. Based on these technologies, this study presents a multipurpose process to obtain six different products with potential applications for nutraceutical, cosmetic and pharmaceutical industries. PMID- 26110890 TI - Weight change in the first 2 months of a lifestyle intervention predicts weight changes 8 years later. AB - OBJECTIVE: Examine the relationship between 1- and 2-month weight loss (WL) and 8 year WL among participants enrolled in a lifestyle intervention. METHODS: 2,290 Look AHEAD participants (BMI: 35.65 +/- 5.93 kg/m(2) ) with type 2 diabetes received an intensive behavioral WL intervention. RESULTS: 1- and 2-month WL were associated with yearly WL through Year 8 (P's < 0.0001). At Month 1, participants losing 2-4% and >4% had 1.62 (95% CI: 1.32, 1.98) and 2.79 (95% CI: 2.21, 3.52) times higher odds of achieving >=5% WL at Year 4 and 1.28 (95% CI: 1.05,1.58) and 1.77 (95% CI: 1.40, 2.24) times higher odds of achieving >=5% WL at Year 8, compared to those losing <2% initially. At Month 2, 3-6% WL resulted in greater odds of achieving >=5% WL at Year 4 (OR = 1.85; CI: 1.48, 2.32), and >6% WL resulted in the greatest odds of achieving >=5% WL at Year 4 (OR = 3.85; CI: 3.05, 4.88) and Year 8 (OR = 2.28; CI: 1.81, 2.89), compared to those losing <3%. Differences in adherence between WL categories were observed as early as Month 2. CONCLUSIONS: 1- and 2-month WL was associated with 8-year WL. Future studies should examine whether alternative treatment strategies can be employed to improve treatment outcomes among those with low initial WL. PMID- 26110897 TI - Sulfated Galactan from Palisada flagellifera Inhibits Toxic Effects of Lachesis muta Snake Venom. AB - In Brazil, snakebites are a public health problem and accidents caused by Lachesis muta have the highest mortality index. Envenomation by L. muta is characterized by systemic (hypotension, bleeding and renal failure) and local effects (necrosis, pain and edema). The treatment to reverse the evolution of all the toxic effects is performed by injection of antivenom. However, such therapy does not effectively neutralize tissue damage or any other local effect, since in most cases victims delay seeking appropriate medical care. In this way, alternative therapies are in demand, and molecules from natural sources have been exhaustively tested. In this paper, we analyzed the inhibitory effect of a sulfated galactan obtained from the red seaweed Palisada flagellifera against some toxic activities of L. muta venom. Incubation of sulfated galactan with venom resulted in inhibition of hemolysis, coagulation, proteolysis, edema and hemorrhage. Neutralization of hemorrhage was also observed when the galactan was administered after or before the venom injection; thus mimicking a real in vivo situation. Moreover, the galactan blocked the edema caused by a phospholipase A2 isolated from the same venom. Therefore, the galactan from P. flagellifera may represent a promising tool to treat envenomation by L. muta as a coadjuvant for the conventional antivenom. PMID- 26110899 TI - Correction: MiR-34a/c-Dependent PDGFR-alpha/beta Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer. PMID- 26110898 TI - Opposite Expression of SPARC between the Liver and Pancreas in Streptozotocin Induced Diabetic Rats. AB - Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ)-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPbeta) and its targets (TNFalpha, Il6, CRP, and Fn1) as well as myeloperoxidase (Mpo) and C-X-C chemokine receptor type 2 (Cxcr2). Diabetic liver showed significant up regulation of Tgfb1 as well as moderately less up-regulated TNFalpha and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95 mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels. PMID- 26110900 TI - Genotoxic and Antigenotoxic Assessment of Chios Mastic Oil by the In Vitro Micronucleus Test on Human Lymphocytes and the In Vivo Wing Somatic Test on Drosophila. AB - Chios mastic oil (CMO), the essential oil derived from Pistacia lentiscus (L.) var. chia (Duham), has generated considerable interest because of its antimicrobial, anticancer, antioxidant and other beneficial properties. In the present study, the potential genotoxic activity of CMO as well as its antigenotoxic properties against the mutagenic agent mitomycin-C (MMC) were evaluated by employing the in vitro Cytokinesis Block MicroNucleus (CBMN) assay and the in vivo Somatic Mutation And Recombination Test (SMART). In the in vitro experiments, lymphocytes were treated with 0.01, 0.05 and 0.10% (v/v) of CMO with or without 0.05 MUg/ml MMC, while in the in vivo assay Drosophila larvae were fed with 0.05, 0.10, 0.50 and 1.00% (v/v) of CMO with or without 2.50 MUg/ml MMC. CMO did not significantly increase the frequency of micronuclei (MN) or total wing spots, indicating lack of mutagenic or recombinogenic activity. However, the in vitro analysis suggested cytotoxic activity of CMO. The simultaneous administration of MMC with CMO did not alter considerably the frequencies of MMC induced MN and wing spots showing that CMO doesn't exert antigenotoxic or antirecombinogenic action. Therefore, CMO could be considered as a safe product in terms of genotoxic potential. Even though it could not afford any protection against DNA damage, at least under our experimental conditions, its cytotoxic potential could be of interest. PMID- 26110903 TI - The Effects of Gastroesophageal Reflux Disease on Forensic Breath Alcohol Testing. AB - Fifteen test subjects, 10 of whom were diagnosed with gastroesophageal reflux disease (GERD), were dosed with alcohol to BACs above 0.150 g/dL. Blood and breath assays taken at 20-min intervals for 8 h after dosing demonstrated close agreement between postabsorptive BAC and BrAC values. Three subjects exhibited elevated breath alcohol concentrations up to 0.105 g/dL during the absorptive phase that were apparently due to the passage of gastric alcohol through the lower esophageal sphincter not attributable to eruction or regurgitation. The effect of gastric alcohol was not consistently proportional to the amount of unabsorbed gastric alcohol. Absorption of alcohol in the esophagus explains the nonproportionality. Breath samples contaminated by GERD-related alcohol leakage from the stomach into a breath sample were found only when there was a high concentration of alcohol in the stomach. When contaminated breath samples were encountered, they were irreproducible in magnitude. PMID- 26110901 TI - The Value of Intraoperative Near-Infrared Fluorescence Imaging Based on Enhanced Permeability and Retention of Indocyanine Green: Feasibility and False-Positives in Ovarian Cancer. AB - OBJECTIVE: In ovarian cancer, two of the most important prognostic factors for survival are completeness of staging and completeness of cytoreductive surgery. Therefore, intra-operative visualization of tumor lesions is of great importance. Preclinical data already demonstrated tumor visualization in a mouse-model using near-infrared (NIR) fluorescence imaging and indocyanine green (ICG) as a result of enhanced permeability and retention (EPR). The aim of this study was to determine feasibility of intraoperative ovarian cancer metastases imaging using NIR fluorescence imaging and ICG in a clinical setting. METHODS: Ten patients suspected of ovarian cancer scheduled for staging or cytoreductive surgery were included. Patients received 20 mg ICG intravenously after opening the abdominal cavity. The mini-FLARE NIR fluorescence imaging system was used to detect NIR fluorescent lesions. RESULTS: 6 out of 10 patients had malignant disease of the ovary or fallopian tube, of which 2 had metastatic disease outside the pelvis. Eight metastatic lesions were detected in these 2 patients, which were all NIR fluorescent. However, 13 non-malignant lesions were also NIR fluorescent, resulting in a false-positive rate of 62%. There was no significant difference in tumor-to-background ratio between malignant and benign lesions (2.0 vs 2.0; P=0.99). CONCLUSIONS: This is the first clinical trial demonstrating intraoperative detection of ovarian cancer metastases using NIR fluorescence imaging and ICG. Despite detection of all malignant lesions, a high false positive rate was observed. Therefore, NIR fluorescence imaging using ICG based on the EPR effect is not satisfactory for the detection of ovarian cancer metastases. The need for tumor-specific intraoperative agents remains. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16945066. PMID- 26110904 TI - Double CO2 activation by 14-electron eta(8)-permethylpentalene titanium dialkyl complexes. AB - The novel 14 electron species eta(8)-Pn*TiR2 (Pn* = C8Me6; R = Me, CH2Ph) have been synthesised and spectroscopically and structurally characterised. Subsequent reaction with CO2 leads to the activation and double insertion of CO2 into both Ti-alkyl bonds to form the electronically saturated eta(8)-Pn*Ti(kappa(2)-O2CR)2 (R = Me, CH2Ph) complexes. PMID- 26110902 TI - Genotypic Diversity Is Associated with Clinical Outcome and Phenotype in Cryptococcal Meningitis across Southern Africa. AB - Cryptococcal meningitis is a major cause of mortality throughout the developing world, yet little is known about the genetic markers underlying Cryptococcal virulence and patient outcome. We studied a cohort of 230 Cryptococcus neoformans (Cn) isolates from HIV-positive South African clinical trial patients with detailed clinical follow-up using multi-locus sequence typing and in vitro phenotypic virulence assays, correlating these data with clinical and fungal markers of disease in the patient. South African Cn displayed high levels of genetic diversity and locus variability compared to globally distributed types, and we identified 50 sequence types grouped within the main molecular types VNI, VNII and VNB, with 72% of isolates typed into one of seven 'high frequency' sequence types. Spatial analysis of patients' cryptococcal genotype was not shown to be clustered geographically, which might argue against recent local acquisition and in favour of reactivation of latent infection. Through comparison of MLST genotyping data with clinical parameters, we found a relationship between genetic lineage and clinical outcome, with patients infected with the VNB lineage having significantly worse survival (n=8, HR 3.35, CI 1.51-7.20, p=0.003), and this was maintained even after adjustment for known prognostic indicators and treatment regimen. Comparison of fungal genotype with in vitro phenotype (phagocytosis, laccase activity and CSF survival) performed on a subset of 89 isolates revealed evidence of lineage-associated virulence phenotype, with the VNII lineage displaying increased laccase activity (p=0.001) and ex vivo CSF survival (p=0.0001). These findings show that Cryptococcus neoformans is a phenotypically heterogeneous pathogen, and that lineage plays an important role in cryptococcal virulence during human infection. Furthermore, a detailed understanding of the genetic diversity in Southern Africa will support further investigation into how genetic diversity is structured across African environments, allowing assessment of the risks different ecotypes pose to infection. PMID- 26110905 TI - A Simple Retroelement Based Knock-Down System in Dictyostelium: Further Insights into RNA Interference Mechanisms. AB - CHARACTERISTICS OF DIRS-1 MEDIATED KNOCK-DOWNS: We have previously shown that the most abundant Dictyostelium discoideum retroelement DIRS-1 is suppressed by RNAi mechanisms. Here we provide evidence that both inverted terminal repeats have strong promoter activity and that bidirectional expression apparently generates a substrate for Dicer. A cassette containing the inverted terminal repeats and a fragment of a gene of interest was sufficient to activate the RNAi response, resulting in the generation of ~21 nt siRNAs, a reduction of mRNA and protein expression of the respective endogene. Surprisingly, no transitivity was observed on the endogene. This was in contrast to previous observations, where endogenous siRNAs caused spreading on an artificial transgene. Knock-down was successful on seven target genes that we examined. In three cases a phenotypic analysis proved the efficiency of the approach. One of the target genes was apparently essential because no knock-out could be obtained; the RNAi mediated knock-down, however, resulted in a very slow growing culture indicating a still viable reduction of gene expression. ADVANTAGES OF THE DIRS-1-RNAI SYSTEM: The knock-down system required a short DNA fragment (~400 bp) of the target gene as an initial trigger. Further siRNAs were generated by RdRPs since we have shown some siRNAs with a 5' triphosphate group. Extrachromosomal vectors facilitate the procedure and allowed for molecular and phenotypic analysis within one week. The system provides an efficient and rapid method to reduce protein levels including those of essential genes. PMID- 26110907 TI - Validating the Behavior Rating Inventory of Executive Functioning for Children With ADHD and Their Typically Developing Peers. AB - The Behavior Rating Inventory of Executive Functioning (BRIEF) has been widely used both clinically and in research for measuring executive functioning (EF) in children with attention-deficit hyperactivity disorder (ADHD). This study examined the concurrent validity of the BRIEF (both parent and teacher ratings) compared to performance-based measures of EF in children with ADHD compared to typically developing (TD) children. The authors assessed 20 children with ADHD and 20 TD controls on 4 EF domains-working memory, planning, inhibition, and set shifting-using the BRIEF and performance-based measures of EF. Children (aged 8 12 years old) with ADHD demonstrated more EF impairment than their TD peers on both questionnaire- and performance-based measures. Ratings on questionnaire- and performance-based measures did not uniquely correlate with each other. Questionnaire-based measures were better at discriminating between children with ADHD and TD children, specifically BRIEF parent ratings, and discrimination depended mostly on the Working Memory, Plan/Organize, and Inhibit subscales. The BRIEF has clinical utility for discriminating between children with ADHD and their TD peers; however, some limitations exist for interpretation of the BRIEF, and it should be used with caution in the assessment and diagnosis of ADHD. PMID- 26110906 TI - The BMP Pathway Participates in Human Naive CD4+ T Cell Activation and Homeostasis. AB - Bone Morphogenetic Proteins (BMPs) form a group of secreted factors that belongs to the TGF-beta superfamily. Among different roles in a number of immune cell types, BMPs are known to regulate T cell development within the thymus, although the role of BMP signaling in human mature T cells remains elusive. In this study, we demonstrate that canonical BMP signaling is necessary during two critical events that regulate the size and function of human naive CD4+ T cell population: activation and homeostasis. Upon stimulation via TCR, naive CD4+ T cells upregulate the expression of BMP ligands triggering canonical BMP signaling in CD25+ cells. Blockade of BMP signaling severely impairs CD4+ T cell proliferation after activation mainly through regulation of IL-2, since the addition of this cytokine recuperates normal T cell expansion after inhibition of BMP signaling. Similarly, activation of canonical BMP pathway is required for both the maintenance of cell survival and the homeostatic proliferation induced by IL-7, a key factor for T cell homeostasis. Moreover, upregulation of two critical receptors for T cell homeostasis, CXCR4 and CCR9, triggered by IL-7 is also abrogated in the absence of BMP signaling. Collectively, we describe important roles of the canonical BMP signaling in human naive CD4+ T cell activation and homeostasis that could be valuable for clinical application. PMID- 26110908 TI - Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants. AB - OBJECTIVE: Late onset sepsis (LOS) contributes to mortality and morbidity in preterm infants. We tested the hypotheses that microbes causing LOS originate from the gut, and that distortions in the gut microbial community increases subsequent risk of LOS. STUDY DESIGN: We examined the gut microbial community in prospectively collected stool samples from preterm infants with LOS and an equal number of age-matched controls at two sites (Cincinnati, OH and Birmingham, AL), by sequencing the bacterial 16S rDNA. We confirmed our findings in a subset of infants by whole genome shotgun sequencing, and analyzed the data using R and LEfSe. RESULTS: Infants with LOS in Cincinnati, as compared to controls, had less abundant Actinobacteria in the first samples after birth (median 18 days before sepsis onset), and less abundant Pseudomonadales in the last samples collected prior to LOS (median 8 days before sepsis onset). Infants with LOS in Birmingham, as compared to controls, had no differences identified in the first sample microbial communities, but Lactobacillales was less abundant in the last samples prior to LOS (median 4 days before sepsis onset). Sequencing identified detectable levels of the sepsis-causative organism in stool samples prior to disease onset for 82% of LOS cases. CONCLUSIONS: Translocation of gut microbes may account for the majority of LOS cases. Distortions in the fecal microbiota occur prior to LOS, but the form of distortion depends on timing and site. The microbial composition of fecal samples does not predict LOS onset in a generalizable fashion. PMID- 26110911 TI - Correction: Patterns of Mass Mortality among Rocky Shore Invertebrates across 100 km of Northeastern Pacific Coastline. PMID- 26110909 TI - Frequency domain ultrasound waveform tomography: breast imaging using a ring transducer. AB - Application of the frequency domain acoustic wave equation on data acquired from ultrasound tomography scans is shown to yield high resolution sound speed images on the order of the wavelength of the highest reconstructed frequency. Using a signal bandwidth of 0.4-1 MHz and an average sound speed of 1500 m s(-1), the resolution is approximately 1.5 mm. The quantitative sound speed values and morphology provided by these images have the potential to inform diagnosis and classification of breast disease. In this study, we present the formalism, practical application, and in vivo results of waveform tomography applied to breast data gathered by two different ultrasound tomography scanners that utilize ring transducers. The formalism includes a review of frequency domain modeling of the wave equation using finite difference operators as well as a review of the gradient descent method for the iterative reconstruction scheme. It is shown that the practical application of waveform tomography requires an accurate starting model, careful data processing, and a method to gradually incorporate higher frequency information into the sound speed reconstruction. Following these steps resulted in high resolution quantitative sound speed images of the breast. These images show marked improvement relative to commonly used ray tomography reconstruction methods. The robustness of the method is demonstrated by obtaining similar results from two different ultrasound tomography devices. We also compare our method to MRI to demonstrate concordant findings. The clinical data used in this work was obtained from a HIPAA compliant clinical study (IRB 040912M1F). PMID- 26110912 TI - Coupling of metals and biominerals: characterizing the interface between ferromagnetic shape-memory alloys and hydroxyapatite. AB - Durable, mechanically robust osseointegration of metal implants poses one of the largest challenges in contemporary orthopedics. The application of biomimetic hydroxyapatite (HAp) coatings as mediators for enhanced mechanical coupling to natural bone constitutes a promising approach. Motivated by recent advances in the field of smart metals that might open the venue for alternate therapeutic concepts, we explore their mechanical coupling to sputter-deposited HAp layers in a combined experimental-theoretical study. While experimental delamination tests and comprehensive structural characterization, including high-resolution transmission electron microscopy, are utilized to establish structure-property relationships, density functional theory based total energy calculations unravel the underlying physics and chemistry of bonding and confirm the experimental findings. Experiments and modeling indicate that sputter-deposited HAp coatings are strongly adherent to the exemplary ferromagnetic shape-memory alloys, Ni-Mn Ga and Fe-Pd, with delamination stresses and interface bonding strength exceeding the physiological scales by orders of magnitude. PMID- 26110913 TI - Evaluation of Hybridization Capture Versus Amplicon-Based Methods for Whole-Exome Sequencing. AB - Next-generation sequencing has aided characterization of genomic variation. While whole-genome sequencing may capture all possible mutations, whole-exome sequencing remains cost-effective and captures most phenotype-altering mutations. Initial strategies for exome enrichment utilized a hybridization-based capture approach. Recently, amplicon-based methods were designed to simplify preparation and utilize smaller DNA inputs. We evaluated two hybridization capture-based and two amplicon-based whole-exome sequencing approaches, utilizing both Illumina and Ion Torrent sequencers, comparing on-target alignment, uniformity, and variant calling. While the amplicon methods had higher on-target rates, the hybridization capture-based approaches demonstrated better uniformity. All methods identified many of the same single-nucleotide variants, but each amplicon-based method missed variants detected by the other three methods and reported additional variants discordant with all three other technologies. Many of these potential false positives or negatives appear to result from limited coverage, low variant frequency, vicinity to read starts/ends, or the need for platform-specific variant calling algorithms. All methods demonstrated effective copy-number variant calling when evaluated against a single-nucleotide polymorphism array. This study illustrates some differences between whole-exome sequencing approaches, highlights the need for selecting appropriate variant calling based on capture method, and will aid laboratories in selecting their preferred approach. PMID- 26110914 TI - Paracetamol (acetaminophen) for prevention or treatment of pain in newborns. AB - BACKGROUND: Newborn infants have the ability to experience pain. Newborns treated in neonatal intensive care units are exposed to numerous painful procedures. Healthy newborns are exposed to pain if the birth process consists of assisted vaginal birth by vacuum extraction or by forceps and during blood sampling for newborn screening tests. OBJECTIVES: Primary objectiveTo determine the efficacy and safety of paracetamol for the prevention or treatment of procedural/postoperative pain or pain associated with clinical conditions in neonates. Secondary objectiveTo review the effects of various doses and routes of administration (enteral, intravenous or rectal) of paracetamol for the prevention or treatment of pain in neonates. We designed the main comparisons according to intention of use, that is, paracetamol for prevention or treatment of pain. We included separate comparisons based on the painful intervention/procedure/condition (heel lance, insertion of nasogastric tube, insertion of intravenous catheter, lumbar puncture, assisted vaginal birth, postoperative pain, birth trauma, congenital anomalies such as myelomeningocoele and open cutaneous lesions) and the mode of administration of paracetamol. Within these comparisons, we planned to assess in subgroups (when possible) effects based on postmenstrual age (PMA) at the birth of randomly assigned infants (< 28 weeks, 28 weeks to 31 + 6 weeks, 32 weeks to 36 + 6 weeks and >= 37 weeks) or based on birth weight (or current weight) categories (<= 1000 grams, 1001 to 1500 grams, 1501 to 2500 grams and >= 2501 grams) SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (October 2014), MEDLINE (1966 to October 2014), EMBASE (1980 to October 2014) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to October 2014). We applied no language restrictions.We conducted electronic searches of abstracts from meetings of the Pediatric Academic Societies (2000 to 2014) and the Perinatal Society of Australia and New Zealand (2010 to 2014).We searched clinical trial registries for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google Scholar(TM) to identify grey literature. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials of paracetamol for the prevention or treatment of pain in neonates (<= 30 days of age). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the full-text articles using a specifically designed form. We used this form to decide trial inclusion/exclusion, to extract data from eligible trials and to request additional published information from authors of the original reports. We entered and cross-checked data using RevMan 5.3.3 software. When noted, we resolved differences by mutual discussion and consensus. MAIN RESULTS: We included eight trials with low risk of bias, which assessed paracetamol use for the treatment of pain in 614 infants. Painful interventions studied included heel lance, assisted vaginal birth, eye examination for ascertainment of retinopathy of prematurity (ROP) and postoperative care following major surgery. Results of individual studies could not be combined in meta-analyses as the painful conditions, the use of paracetamol and comparison interventions and the outcome measures differed. Paracetamol compared with water, cherry elixir or EMLA cream did not significantly reduce pain following heel lance. The Premature Infant Pain Profile score (PIPP) within three minutes following lancing was higher in the paracetamol group than in the oral glucose group (mean difference (MD) 2.21, 95% confidence interval (CI) 0.72 to 3.70; one study, 38 infants). Paracetamol did not reduce "modified facies scores" after assisted vaginal birth (one study, 119 infants). In another study (n = 123), the Echelle de Douleur et d'Inconfort du Nouveau-Ne score at two hours of age was significantly higher in the group that received paracetamol suppositories than in the placebo suppositories group (MD 1.00, 95% CI 0.60 to 1.40). In that study, when infants were subjected to a heel lance at two to three days of age, Bernese Pain Scale for Neonates scores were higher in the paracetamol group than in the placebo group, and infants spent a longer time crying (MD 19 seconds, 95% CI 14 to 24). For eye examinations, no significant reduction in PIPP scores in the first or last 45 seconds of eye examination was reported, nor at five minutes after the eye examination. In one study (n = 81), the PIPP score was significantly higher in the paracetamol group than in the 24% sucrose group (MD 3.90, 95% CI 2.92 to 4.88). For postoperative care following major thoracic or abdominal surgery, the total amount of morphine (ug/kg) administered over 48 hours was significantly less among infants randomly assigned to the paracetamol group than in those randomly assigned to the morphine group (MD -157 ug/kg, 95% CI -27 to -288). No adverse events were noted in any study. AUTHORS' CONCLUSIONS: Paracetamol does not significantly reduce pain associated with heel lance or eye examinations. Paracetamol given after assisted vaginal birth may increase the response to later painful exposures. Paracetamol should not be used for painful procedures given its lack of efficacy and its potential for adverse effects. Paracetamol may reduce the total need for morphine following major surgery, and for this aspect of paracetamol use, further research is needed. PMID- 26110915 TI - Characterization of a feruloyl esterase B from Talaromyces cellulolyticus. AB - A feruloyl esterase catalyzes the hydrolysis of the 4-hydroxy-3-methoxycinnamoyl (feruloyl) group from esterified sugars in plant cell walls. Talaromyces cellulolyticus is a high cellulolytic-enzyme producing fungus. However, there is no report for feruloyl esterase activity of T. cellulolyticus. Analysis of the genome database of T. cellulolyticus identified a gene encoding a putative feruloyl esterase B. The recombinant enzyme was prepared using a T. cellulolyticus homologous expression system and characterized. The purified enzyme exhibited hydrolytic activity toward p-nitrophenyl acetate, p-nitrophenyl trans-ferulate, methyl ferulate, rice husk, and bagasse. HPLC assays showed that the enzyme released ferulic acid and p-coumaric acid from hydrothermal-treated rice husk and bagasse. Trichoderma sp. is well-known high cellulolytic-enzyme producing fungus useful for the lignocellulosic biomass saccharification. Interestingly, no feruloyl esterase has been reported from Trichoderma sp. The results show that this enzyme is expected to be industrially useful for biomass saccharification. PMID- 26110916 TI - GH-Releasing Hormone Promotes Survival and Prevents TNF-alpha-Induced Apoptosis and Atrophy in C2C12 Myotubes. AB - Skeletal muscle atrophy is a consequence of different chronic diseases, including cancer, heart failure, and diabetes, and also occurs in aging and genetic myopathies. It results from an imbalance between anabolic and catabolic processes, and inflammatory cytokines, such as TNF-alpha, have been found elevated in muscle atrophy and implicated in its pathogenesis. GHRH, in addition to stimulating GH secretion from the pituitary, exerts survival and antiapoptotic effects in different cell types. Moreover, we and others have recently shown that GHRH displays antiapoptotic effects in isolated cardiac myocytes and protects the isolated heart from ischemia/reperfusion injury and myocardial infarction in vivo. On these bases, we investigated the effects of GHRH on survival and apoptosis of TNF-alpha-treated C2C12 myotubes along with the underlying mechanisms. GHRH increased myotube survival and prevented TNF-alpha-induced apoptosis through GHRH receptor-mediated mechanisms. These effects involved activation of phosphoinositide 3-kinase/Akt pathway and inactivation of glycogen synthase kinase-3beta, whereas mammalian target of rapamycin was unaffected. GHRH also increased the expression of myosin heavy chain and the myogenic transcription factor myogenin, which were both reduced by the cytokine. Furthermore, GHRH inhibited TNF-alpha-induced expression of nuclear factor kappaB, calpain, and muscle ring finger1, which are all involved in muscle protein degradation. In summary, these results indicate that GHRH exerts survival and antiapoptotic effects in skeletal muscle cells through the activation of anabolic pathways and the inhibition of proteolytic routes. Overall, our findings suggest a novel therapeutic role for GHRH in the treatment of muscle atrophy associated diseases. PMID- 26110917 TI - Synthesis of Previously Inaccessible Borylated Heterocycle Motifs Using Novel Boron-Containing Amphoteric Molecules. AB - The photoredox-organocatalyzed alpha-alkylation of the alpha-MIDA boryl aldehyde with a range of alpha-bromoketones resulted in the first examples of boron containing 1,4-dicarbonyl compounds. These novel trifunctional amphoteric molecules, which bear an additional, strategically placed electrophilic site compared to the starting amphoteric alpha-boryl aldehyde, were subjected to double-condensation reactions in the presence of various nucleophiles. As a result, a variety of synthetically challenging 3-borylated pyrroles and furans and 4-borylated pyridazines were generated. The borylated regioisomers accessible with this condensation-based strategy are distinctly different from those arising from the well-known lithiation and C-H activation processes. PMID- 26110918 TI - Hypoxia Enhances the Toxicity of Corexit EC9500A and Chemically Dispersed Southern Louisiana Sweet Crude Oil (MC-242) to Sheepshead Minnow (Cyprinodon variegatus) Larvae. AB - Oil exploration and production activities are common in the northern Gulf of Mexico as well as many other coastal and near coastal areas worldwide. Seasonal hypoxia is also a common feature in the Northern Gulf, and many other coastal areas, which is likely to increase in severity and extent with continuing anthropogenic nutrient inputs. Hypoxia has well established physiological effects on many organisms, and it has been shown to enhance the toxicity of polycyclic aromatic hydrocarbons (persistent components of petroleum) in fish. The goal of this study was to examine the combined effects of hypoxia and exposure to contaminants associated with oil spills. We evaluated the effects of short term (48 hr) exposures to Corexit EC9500A, water accommodated fractions (WAF), and chemically enhanced water accommodated fractions (CEWAF) prepared from Southern Louisiana Sweet Crude Oil (MC 242) on survival of sheepshead minnow (Cyprinodon variegatus) larvae held under normoxic (ambient air) or hypoxic (2 mg/L O2) conditions. Results demonstrated that hypoxia significantly enhances mortality observed in response to Corexit or CEWAF solutions. In the latter case, significant interactions between the two stressors were also observed. Our data supports the need to further evaluate the combined stresses imparted by hypoxia and exposure to petroleum hydrocarbons and dispersants. PMID- 26110919 TI - Resolution of Acute Suicidality After a Single Right Unilateral Electroconvulsive Therapy. PMID- 26110922 TI - Disease burden of chronic hepatitis C among immigrants in Canada. AB - Immigrants with chronic hepatitis C (CHC) in Canada have doubled risk of hepatocellular carcinoma. To measure the burden of CHC among immigrants in Canada. A decision analytic model was developed to compare immigrants with CHC and age-matched immigrants without CHC for survival years, quality-adjusted life years (QALYs) and medical costs per life year. Hepatitis C epidemiology among immigrants was based on hepatitis C prevalence in their home countries. A cohort of immigrant patients was retrospectively followed up to estimate fibrosis stage distribution, treatment patterns and prognosis of compensated cirrhosis. Other model variables were based on published sources. Base case analysis, one-way sensitivity analysis and probabilistic sensitivity analysis were performed to measure the burden of CHC and assess the impact of uncertainty associated with model variables on the burden of CHC. CHC could reduce survival by 9.6 years [95% credible interval (CI): 8.0-10.9 years], reduce QALYs by 9.5 years (95% CI: 6.0 13.8 years) and increase medical costs per life year by $1950 (95% CI: $1518 to $2486, 2006 Canadian dollars). Because nearly half of immigrants with CHC were not diagnosed until the development of cirrhosis, the burden of CHC was highly sensitive to the risks of liver-related complications and mortality but insensitive to pegylated interferon plus ribavirin. The burden of CHC among immigrants in Canada is substantial mainly due to liver-related complications and mortality. The delay in diagnosis was another important contributor to the burden of CHC among immigrants. PMID- 26110921 TI - Tetraarsenictetrasulfide and Arsenic Trioxide Exert Synergistic Effects on Induction of Apoptosis and Differentiation in Acute Promyelocytic Leukemia Cells. AB - Since arsenic trioxide (As3+) has been successfully used in the treatment of acute promyelocytic leukemia (APL), its adverse effects on patients have been problematic and required a solution. Considering the good therapeutic potency and low toxicity of tetraarsenictetrasulfide (As4S4) in the treatment of APL, we investigated the effects of combining As4S4 and As3+ on the apoptosis and differentiation of NB4 and primary APL cells. As4S4, acting similarly to As3+, arrested the G1/S transition, induced the accumulation of cellular reactive oxygen species, and promoted apoptosis. Additionally, low concentrations of As4S4 (0.1-0.4 MUM) induced differentiation of NB4 and primary APL cells. Compared with the As4S4- or As3+-treated groups, the combination of As4S4 and As3+ obviously promoted apoptosis and differentiation of NB4 and primary APL cells. Mechanistic studies suggested that As4S4 acted synergistically with As3+ to down-regulate Bcl 2 and nuclear factor-kappaB expression, up-regulate Bax and p53 expression, and induce activation of caspase-12 and caspase-3. Moreover, the combination of low concentrations of As4S4 and As3+ enhanced degradation of the promyelocytic leukemia-retinoic acid receptor alpha oncoprotein. In summary, As4S4 and As3+ synergistically induce the apoptosis and differentiation of NB4 and primary APL cells. PMID- 26110920 TI - Chloride Accumulators NKCC1 and AE2 in Mouse GnRH Neurons: Implications for GABAA Mediated Excitation. AB - A developmental "switch" in chloride transporters occurs in most neurons resulting in GABAA mediated hyperpolarization in the adult. However, several neuronal cell subtypes maintain primarily depolarizing responses to GABAA receptor activation. Among this group are gonadotropin-releasing hormone-1 (GnRH) neurons, which control puberty and reproduction. NKCC1 is the primary chloride accumulator in neurons, expressed at high levels early in development and contributes to depolarization after GABAA receptor activation. In contrast, KCC2 is the primary chloride extruder in neurons, expressed at high levels in the adult and contributes to hyperpolarization after GABAA receptor activation. Anion exchangers (AEs) are also potential modulators of responses to GABAA activation since they accumulate chloride and extrude bicarbonate. To evaluate the mechanism(s) underlying GABAA mediated depolarization, GnRH neurons were analyzed for 1) expression of chloride transporters and AEs in embryonic, pre-pubertal, and adult mice 2) responses to GABAA receptor activation in NKCC1-/- mice and 3) function of AEs in these responses. At all ages, GnRH neurons were immunopositive for NKCC1 and AE2 but not KCC2 or AE3. Using explants, calcium imaging and gramicidin perforated patch clamp techniques we found that GnRH neurons from NKCC1-/- mice retained relatively normal responses to the GABAA agonist muscimol. However, acute pharmacological inhibition of NKCC1 with bumetanide eliminated the depolarization/calcium response to muscimol in 40% of GnRH neurons from WT mice. In the remaining GnRH neurons, HCO3- mediated mechanisms accounted for the remaining calcium responses to muscimol. Collectively these data reveal mechanisms responsible for maintaining depolarizing GABAA mediated transmission in GnRH neurons. PMID- 26110924 TI - Editorial: IDS - here we go ... PMID- 26110923 TI - Lack of Rybp in Mouse Embryonic Stem Cells Impairs Cardiac Differentiation. AB - Ring1 and Yy1 binding protein (Rybp) has been implicated in transcriptional regulation, apoptotic signaling and as a member of the polycomb repressive complex 1, it has an important function in regulating pluripotency and differentiation of embryonic stem cells (ESCs). Earlier, we had proved that Rybp plays an essential role in mouse embryonic and central nervous system development. This work identifies Rybp, as a critical regulator of heart development. Rybp is readily detectable in the developing mouse heart from day 8.5 of embryonic development. Prominent Rybp expression persists during all embryonic stages, and Rybp marks differentiated cell types of the heart. By utilizing rybp null ESCs in an in vitro cardiac differentiation assay, we found that rybp null ESCs do not form rhythmically beating cardiomyocytes (CMCs). Gene expression profiles revealed a downregulation of cardiac terminal and upregulation of germline-specific markers in the rybp null CMCs. Furthermore, transcriptome analysis uncovered a number of novel candidate target genes regulated by Rybp. Among these are several that are important in cardiac development and contractility such as Plagl1, Isl1, and Tnnt2. Importantly, forced expression of rybp in rybp-deficient ESCs by a lentiviral vector was able to rescue the mutant phenotype. Our data provide evidence for a previously unrecognized function of Rybp in heart development and point out the importance of germ cell lineage gene silencing during somatic differentiation. PMID- 26110925 TI - Intraoral scanning systems - a current overview. AB - There is no doubt today about the possibilities and potential of digital impression-taking with the aid of intraoral optical impression systems, and the past few years have seen a considerable increase in the range of optical intraoral scanners available on the market. On the strength of numerous innovations and a wider range of indications in orthodontics and implantology, intraoral scanning systems appear to be a highly promising development for the future. Digital impression-taking with intraoral scanners has already shown itself in some respects to be clearly superior to conventional impression- taking. Particularly worthy of mention is the versatile integration of digital impressions into diagnostic and treatment concepts to provide a customizable healthcare solution for the patient. It remains exciting to look forward to future developments that will allow us to observe digital impression-taking--as with other digital applications already established in everyday life--becoming firmly established in the routine of dentistry and dental technology. This article presents an overview of the benefits and limitations of digital impression-taking using intraoral scanning systems, and includes a summary of all the relevant intraoral scanners available on the market at present. PMID- 26110926 TI - Tooth-colored CAD/CAM monolithic restorations. AB - A monolithic restoration (also known as a full contour restoration) is one that is manufactured from a single material for the fully anatomic replacement of lost tooth structure. Additional staining (followed by glaze firing if ceramic materials are used) may be performed to enhance the appearance of the restoration. For decades, monolithic restoration has been the standard for inlay and partial crown restorations manufactured by both pressing and computer-aided design and manufacturing (CAD/CAM) techniques. A limited selection of monolithic materials is now available for dental crown and bridge restorations. The IDS (2015) provided an opportunity to learn about and evaluate current trends in this field. In addition to new developments, established materials are also mentioned in this article to complete the picture. In line with the strategic focus of the IJCD, the focus here is naturally on CAD/CAM materials. PMID- 26110927 TI - Clinical performance of chairside CAD/CAM feldspathic ceramic posterior shoulder crowns and endocrowns up to 12 years. AB - In 55 patients, 25 endocrowns (test) and 40 shoulder crowns (control) were produced chairside in a private practice using the Cerec 3 (CAD/CAM) method and Vita Mark II feldspathic ceramic. The crowns were examined at baseline and after up to 12 years using modified USPHS criteria. The survival estimate was assessed by Kaplan-Meier analysis. The 12 years survival estimate of the shoulder crowns was 95% on molars and 94.7% on premolars. Endocrowns showed 90.5% survival on molars and 75% on premolars. Statistically, the differences between the survival estimates were not significant (P > 0.05). The longevity of Vita Mark II Cerec 3 shoulder crowns on molars and premolars, as well as of endocrowns on molars, proved to be--for private practice--a very acceptable result, while the premolar endocrowns tended to show a higher risk for failure. PMID- 26110928 TI - Clinical application of fully digital Cerec surgical guides made in-house. AB - It is now possible to produce full-digital drilling templates with Cerec Guide 2 (Sirona) in the dental practice relatively quickly, efficiently, and economically. Here, a patient case example is used to present an exemplary description of the procedure and method to do this. The solution described herein shows the advantageous efficiency, compared with other systems presently on the market, of a procedure that does not require the external production of the drilling template in the laboratory or a manufacturing center. PMID- 26110929 TI - Hybrid materials offer new perspectives. AB - Dental materials, especially in restorative dentistry, must not only be cost effective, they must also meet many other requirements: biocompatibility, durability, excellent shade and light effects, abrasion resistance, hardness, mechanical strength under pressure, chemical resistance, surface density, ease of manufacture, and easy intraoral maintenance. PMID- 26110931 TI - Willful Blindness. PMID- 26110930 TI - Indoleamine 2,3 Dioxygenase (IDO) Expression and Activity in Relapsing-Remitting Multiple Sclerosis. AB - BACKGROUND: Interferon gamma (IFN-gamma) production induces the transcription of indoleamine 2,3 dioxygenase (IDO) resulting in the reduction of T-cell activation and proliferation through the depletion of tryptophan and the elicitation of Treg lymphocytes. IDO was shown to be involved in the pathogenesis of autoimmune diseases; we investigated whether changes in IDO gene expression and activity could be indicative of onset of relapse in multiple sclerosis (MS) patients. METHODS: IDO and interferon-gamma (IFN-gamma) gene expression, serum IDO activity (Kynurenine/Tryptophan ratio) and serum neopterin concentration--a protein released by macrophages upon IFN-gamma stimulation--were measured in 51 individuals: 36 relapsing remitting (RR)-MS patients (21 in acute phase--AMS, 15 in stable phase--SMS) and 15 healthy controls (HC). PBMCs samples in AMS patients were collected before (BT-AMS) and during glucocorticoids-based therapy (DT-AMS). RESULTS: IDO expression was increased and IFN-gamma was decreased (p<0.001) in BT AMS compared to SMS patients. Glucocorticoids-induced disease remission resulted in a significant reduction of IDO and IFN-gamma gene expression, IDO catalytic activity (p<0.001). Serum neopterin concentration followed the same trend as IDO expression and activity. CONCLUSIONS: Measurement of IDO gene expression and activity in blood could be a useful marker to monitor the clinical course of RR MS. Therapeutic interventions modulating IDO activity may be beneficial in MS. PMID- 26110932 TI - Informed Consent and the Use of Biospecimens in Research. PMID- 26110933 TI - DNP vs. CNS. PMID- 26110934 TI - Moral Conflict. PMID- 26110935 TI - Collaboration. PMID- 26110936 TI - 'Get Trained'. PMID- 26110937 TI - Legislation Claiming to Protect Workers Would Hurt RNs. PMID- 26110938 TI - Unable to Go-But Is It an Emergency? PMID- 26110941 TI - Rethinking Sinusitis Treatment. PMID- 26110943 TI - Precautions Guidelines for Hospital Visitors. PMID- 26110944 TI - Infectious Diseases Update Shigella and Enterovirus D68. PMID- 26110945 TI - Behavioral Health Screening in Children. PMID- 26110946 TI - Haloperidol vs. Low-Potency Antipsychotic Drugs for Schizophrenia. PMID- 26110955 TI - Bringing It Home Explores Nursing Beyond the Hospital. PMID- 26110956 TI - Effective Collaboration Among Magnet Hospitals: A Win-Win for Nurses and Institutions. PMID- 26110958 TI - Conflict Engagement: A Relational Approach. AB - This article is one in a series on conflict. It is part of an ongoing series on leadership coordinated by the American Organization of Nurse Executives (AONE; www.aone.org), highlighting topics of interest to nurse managers and emerging nurse leaders. The AONE provides leadership, professional development, advocacy, and research to advance nursing practice and patient care, promote nursing leadership excellence, and shape public policy for health care. PMID- 26110959 TI - Teaching in the Middle East. PMID- 26110965 TI - Why? PMID- 26110964 TI - The Forefront of Diabetes Care. PMID- 26110966 TI - Enhanced Solvation of Peptides Attached to "Solid-Phase" Resins: Straightforward Syntheses of the Elastin Sequence Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Val. AB - The solubility-enhancing power of covalent attachment to solvent-swollen cross linked resin supports was illustrated by syntheses of the highly aggregating elastin-derived 10-residue peptide sequence Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly Val using standard protocols for both Boc and Fmoc chemistry SPPS. PMID- 26110967 TI - A Dimetalloxycarbene Bonding Mode and Reductive Coupling Mechanism for Oxalate Formation from CO2. AB - We describe the stable and isolable dimetalloxycarbene [(TiX3 )2 (MU2 -CO2 kappa(2) C,O:kappaO')] 5, where X=N-(tert-butyl)-3,5-dimethylanilide, which is stabilized by fluctuating MU2 -kappa(2) C,O:kappa(1) O' coordination of the carbene carbon to both titanium centers of the dinuclear complex 5, as shown by variable-temperature NMR studies. Quantum chemical calculations on the unmodified molecule indicated a higher energy of only +10.5 kJ mol(-1) for the MU2 -kappa(1) O:kappa(1) O' bonding mode of the free dimetalloxycarbene compared to the MU2 kappa(2) C,O:kappa(1) O' bonding mode of the masked dimetalloxycarbene. The parent cationic bridging formate complex [(TiX3 )2 (MU2 -OCHO kappaO:kappaO')][B(C6 F5)4], 4[B(C6 F5)4], was simply deprotonated with the strong base K(N(SiMe3 )2 ) to give 5. Complex 5 reacts smoothly with CO2 to generate the bridging oxalate complex [(TiX3 )2 (MU2 -C2 O4 -kappaO:kappaO'')], 6, in a C-C bond formation reaction commonly anticipated for oxalate formation by reductive coupling of CO2 on low-valent transition-metal complexes. PMID- 26110968 TI - Rethinking the gold standard for recurrent DNA mutations detection in acute myeloid leukemia. PMID- 26110969 TI - Determination of antibiotic EC50 using a zero-flow microfluidic chip based growth phenotype assay. AB - Current existing assay systems for evaluating antimicrobial activity suffer from several limitations including excess reagent consumption and inaccurate concentration gradient preparation. Recently, microfluidic systems have been developed to provide miniaturized platforms for antimicrobial susceptibility assays. However, some of current microfluidic based assays require continuous flows of reagents or elaborate preparation steps during concentration preparation. In this study, we introduce a novel microfluidic chip based growth phenotype assay that automatically generates a logarithmic concentration gradient and allows observing the growth of pathogenic bacteria under different concentrations of antibiotics in nanoliter batch culture reactors. We chose pathogen bacterium Pseudomonas aeruginosa as a model strain and evaluated the inhibitory effects of gentamicin and ciprofloxacin. We determined the EC50 values and confirmed the validity of the present system by comparing the EC50 values obtained through conventional test tube method. We demonstrated that the EC50 values acquired from present assay are comparable to those obtained from conventional test tube cultures. The potential application of present assay system for investigating combinatorial effects of antibiotics on multidrug resistant pathogenic bacteria is discussed and it can be further used for systematic evaluation of antifungal or antiviral agents. PMID- 26110970 TI - Parallels Between Action-Object Mapping and Word-Object Mapping in Young Children. AB - Across a series of four experiments with 3- to 4-year-olds we demonstrate how cognitive mechanisms supporting noun learning extend to the mapping of actions to objects. In Experiment 1 (n = 61) the demonstration of a novel action led children to select a novel, rather than a familiar object. In Experiment 2 (n = 78) children exhibited long-term retention of novel action-object mappings and extended these actions to other category members. In Experiment 3 (n = 60) we showed that children formed an accurate sensorimotor record of the novel action. In Experiment 4 (n = 54) we demonstrate limits on the types of actions mapped to novel objects. Overall these data suggest that certain aspects of noun mapping share common processing with action mapping and support a domain-general account of word learning. PMID- 26110971 TI - NET-GE: a novel NETwork-based Gene Enrichment for detecting biological processes associated to Mendelian diseases. AB - BACKGROUND: Enrichment analysis is a widely applied procedure for shedding light on the molecular mechanisms and functions at the basis of phenotypes, for enlarging the dataset of possibly related genes/proteins and for helping interpretation and prioritization of newly determined variations. Several standard and Network-based enrichment methods are available. Both approaches rely on the annotations that characterize the genes/proteins included in the input set; network based ones also include in different ways physical and functional relationships among different genes or proteins that can be extracted from the available biological networks of interactions. RESULTS: Here we describe a novel procedure based on the extraction from the STRING interactome of sub-networks connecting proteins that share the same Gene Ontology(GO) terms for Biological Process (BP). Enrichment analysis is performed by mapping the protein set to be analyzed on the sub-networks, and then by collecting the corresponding annotations. We test the ability of our enrichment method in finding annotation terms disregarded by other enrichment methods available. We benchmarked 244 sets of proteins associated to different Mendelian diseases, according to the OMIM web resource. In 143 cases (58%), the network-based procedure extracts GO terms neglected by the standard method, and in 86 cases (35%), some of the newly enriched GO terms are not included in the set of annotations characterizing the input proteins. We present in detail six cases where our network-based enrichment provides an insight into the biological basis of the diseases, outperforming other freely available network-based methods. CONCLUSIONS: Considering a set of proteins in the context of their interaction network can help in better defining their functions. Our novel method exploits the information contained in the STRING database for building the minimal connecting network containing all the proteins annotated with the same GO term. The enrichment procedure is performed considering the GO-specific network modules and, when tested on the OMIM-derived benchmark sets, it is able to extract enrichment terms neglected by other methods. Our procedure is effective even when the size of the input protein set is small, requiring at least two input proteins. PMID- 26110973 TI - Likely effect of adding flexible sigmoidoscopy to the English NHS Bowel Cancer Screening Programme: impact on colorectal cancer cases and deaths. AB - BACKGROUND: From 2013, once-only flexible sigmoidoscopy (FS) at age 55 is being phased into the England National Health Service Bowel Cancer Screening Programme (NHSBCSP), augmenting biennial guaiac faecal occult blood testing (gFOBT) at ages 60-74. Here, we project the impact of this change on colorectal cancer (CRC) cases and deaths prevented in England by mid-2030. METHODS: We simulated the life course of English residents reaching age 55 from 2013 onwards. Model inputs included population numbers, invitation rates and CRC incidence and mortality rates. The impact of gFOBT and FS alone on CRC incidence and mortality were derived from published trials, assuming an uptake of 50% for FS and 57% for gFOBT. For FS plus gFOBT, we assumed the gFOBT effect to be 75% of the gFOBT alone impact. RESULTS: By mid-2030, 8.5 million individuals will have been invited for once-only FS screening. Adding FS to gFOBT screening is estimated to prevent an extra 9627 (-10%) cases and 2207 (-12%) deaths by mid-2030. If FS uptake is 38% or 71%, respectively, an extra 7379 (-8%) or 13 689 (-15%) cases and 1691 (-9%) or 3154 (-17%) deaths will be prevented by mid-2030. CONCLUSIONS: Adding once-only FS at age 55 to the NHSBCSP will prevent ~10,000 CRC cases and ~2000 CRC deaths by mid-2030 if FS uptake is 50%. In 2030, one cancer was estimated to be prevented per 150 FS screening episodes, and one death prevented per 900 FS screening episodes. The actual reductions will depend on the FS invitation schedule and uptake rates. PMID- 26110972 TI - Systematic review and meta-analysis of immunohistochemical prognostic biomarkers in resected oesophageal adenocarcinoma. AB - BACKGROUND: Oesophageal adenocarcinoma (OAC) is one of the fastest rising malignancies with continued poor prognosis. Many studies have proposed novel biomarkers but, to date, no immunohistochemical markers of survival after oesophageal resection have entered clinical practice. Here, we systematically review and meta-analyse the published literature, to identify potential biomarkers. METHODS: Relevant articles were identified via Ovid medline 1946 2013. For inclusion, studies had to conform to REporting recommendations for tumor MARKer (REMARK) prognostic study criteria. The primary end-point was a pooled hazard ratio (HR) and variance, summarising the effect of marker expression on prognosis. RESULTS: A total of 3059 articles were identified. After exclusion of irrelevant titles and abstracts, 214 articles were reviewed in full. Nine molecules had been examined in more than one study (CD3, CD8, COX-2, EGFR, HER2, Ki67, LgR5, p53 and VEGF) and were meta-analysed. Markers with largest survival effects were COX-2 (HR=2.47, confidence interval (CI)=1.15-3.79), CD3 (HR=0.51, 95% CI=0.32-0.70), CD8 (HR=0.55, CI=0.31-0.80) and EGFR (HR=1.65, 95% CI=1.14-2.16). DISCUSSION: Current methods have not delivered clinically useful molecular prognostic biomarkers in OAC. We have highlighted the paucity of good quality robust studies in this field. A genome-to-protein approach would be better suited for the development and subsequent validation of biomarkers. Large collaborative projects with standardised methodology will be required to generate clinically useful biomarkers. PMID- 26110974 TI - Stem vs non-stem cell origin of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common cancers in the western world and is characterised by deregulation of the Wnt signalling pathway. Mutation of the adenomatous polyposis coli (APC) tumour suppressor gene, which encodes a protein that negatively regulates this pathway, occurs in almost 80% of CRC cases. The progression of this cancer from an early adenoma to carcinoma is accompanied by a well-characterised set of mutations including KRAS, SMAD4 and TP53. Using elegant genetic models the current paradigm is that the intestinal stem cell is the origin of CRC. However, human histology and recent studies, showing marked plasticity within the intestinal epithelium, may point to other cells of origin. Here we will review these latest studies and place these in context to provide an up-to-date view of the cell of origin of CRC. PMID- 26110976 TI - Take the shot: Message from the president. PMID- 26110975 TI - Macrophage polarisation changes within the time between diagnostic biopsy and tumour resection in oral squamous cell carcinomas--an immunohistochemical study. AB - BACKGROUND: The prognosis of solid malignancies has been shown to depend on immunological parameters, such as macrophage polarisation (M1/M2). Recently, it was reported that preoperative oral surgery leads to a worsening of oral squamous cell carcinomas (OSCC) prognosis. Diagnostic incision biopsies are oral surgery procedures that might lead to healing-associated M2 macrophage polarisation with a potential negative influence on tumour biology. No studies have compared macrophage polarisation in OSCC biopsies and tumour specimens. METHODS: Preoperative diagnostic incision biopsies (n=25) and tumour resection specimens (n=34) of T1/T2 OSCC were processed for immunohistochemistry to detect CD68-, CD11c-, CD163- and MRC1-positive cells. Samples were digitised using whole-slide imaging, and the expression of macrophage markers was quantitatively analysed. RESULTS: Carcinoma tissues obtained during OSCC tumour resections showed a significantly (P<0.05) increased CD163 cell count (M2 macrophages) compared with tissues obtained during preoperative incision biopsies. Additionally, the CD163/CD68 ratio (an indicator of M2 polarisation) was significantly (P<0.05) higher in tumour resection specimens than in biopsies. CONCLUSIONS: This study revealed for the first time an increase in M2 polarisation in samples obtained during OSCC tumour resection surgery compared with preoperative incision biopsies. The biopsy-induced tissue trauma might explain the observed shift in macrophage polarisation towards the tumour-promoting M2 type and could lead to accelerated tumour progression. PMID- 26110977 TI - A Comprehensive Model of Electric-Field-Enhanced Jumping-Droplet Condensation on Superhydrophobic Surfaces. AB - Superhydrophobic micro/nanostructured surfaces for dropwise condensation have recently received significant attention due to their potential to enhance heat transfer performance by shedding positively charged water droplets via coalescence-induced droplet jumping at length scales below the capillary length and allowing the use of external electric fields to enhance droplet removal and heat transfer, in what has been termed electric-field-enhanced (EFE) jumping droplet condensation. However, achieving optimal EFE conditions for enhanced heat transfer requires capturing the details of transport processes that is currently lacking. While a comprehensive model has been developed for condensation on micro/nanostructured surfaces, it cannot be applied for EFE condensation due to the dynamic droplet-vapor-electric field interactions. In this work, we developed a comprehensive physical model for EFE condensation on superhydrophobic surfaces by incorporating individual droplet motion, electrode geometry, jumping frequency, field strength, and condensate vapor-flow dynamics. As a first step toward our model, we simulated jumping droplet motion with no external electric field and validated our theoretical droplet trajectories to experimentally obtained trajectories, showing excellent temporal and spatial agreement. We then incorporated the external electric field into our model and considered the effects of jumping droplet size, electrode size and geometry, condensation heat flux, and droplet jumping direction. Our model suggests that smaller jumping droplet sizes and condensation heat fluxes require less work input to be removed by the external fields. Furthermore, the results suggest that EFE electrodes can be optimized such that the work input is minimized depending on the condensation heat flux. To analyze overall efficiency, we defined an incremental coefficient of performance and showed that it is very high (~10(6)) for EFE condensation. We finally proposed mechanisms for condensate collection which would ensure continuous operation of the EFE system and which can scalably be applied to industrial condensers. This work provides a comprehensive physical model of the EFE condensation process and offers guidelines for the design of EFE systems to maximize heat transfer. PMID- 26110978 TI - Narrow Networks and the Affordable Care Act. PMID- 26110979 TI - Individual Differences in Newborn Visual Attention Associate with Temperament and Behavioral Difficulties in Later Childhood. AB - Recently it was shown that individual differences in attention style in infants are associated with childhood effortful control, surgency, and hyperactivity inattention. Here we investigated whether effortful control, surgency and behavioral problems in childhood can be predicted even earlier, from individual differences in newborns' average duration of gaze to stimuli. Eighty newborns participated in visual preference and habituation studies. Parents completed questionnaires at follow up (mean age = 7.5 years, SD = 1.0 year). Newborns' average dwell time was negatively associated with childhood surgency (beta = .25, R(2) = .04, p = .02) and total behavioral difficulties (beta = -.28, R(2) = .05, p = .04) but not with effortful control (beta = .03, R(2) = .001, p = .76). Individual differences in newborn visual attention significantly associated with individual variation in childhood surgency and behavioral problems, showing that some of the factors responsible for this variation are present at birth. PMID- 26110980 TI - Microbial synthesis of chalcogenide semiconductor nanoparticles: a review. AB - Chalcogenide semiconductor quantum dots are emerging as promising nanomaterials due to their size tunable optoelectronic properties. The commercial synthesis and their subsequent integration for practical uses have, however, been contorted largely due to the toxicity and cost issues associated with the present chemical synthesis protocols. Accordingly, there is an immediate need to develop alternative environment-friendly synthesis procedures. Microbial factories hold immense potential to achieve this objective. Over the past few years, bacteria, fungi and yeasts have been experimented with as eco-friendly and cost-effective tools for the biosynthesis of semiconductor quantum dots. This review provides a detailed overview about the production of chalcogen-based semiconductor quantum particles using the inherent microbial machinery. PMID- 26110982 TI - The Effectiveness of Two Grammar Treatment Procedures for Children With SLI: A Randomized Clinical Trial. AB - PURPOSE: This study compared the effectiveness of two grammar treatment procedures for children with specific language impairment. METHOD: A double-blind superiority trial with cluster randomization was used to compare a cueing procedure, designed to elicit a correct production following an initial error, to a recasting procedure, which required no further production. Thirty-one 5-year old children with specific language impairment participated in 8 small group, classroom-based treatment sessions. Fourteen children received the cueing approach and 17 received the recasting approach. RESULTS: The cueing group made significantly more progress over the 8-week treatment period than the recasting group. There was a medium-large treatment effect in the cueing group and a negligible effect size in the recasting group. The groups did not differ in maintenance of treatment effects 8 weeks after treatment. In single-subject analyses, 50% of children in the cueing group and 12% in the recasting group showed a significant treatment effect. Half of these children maintained the treatment effect 8 weeks later. CONCLUSION: Treatment that used a structured cueing hierarchy designed to elicit a correct production following a child's error resulted in significantly greater improvement in expressive grammar than treatment that provided a recast following an error. PMID- 26110981 TI - Alcohol Dependence Genetics: Lessons Learned From Genome-Wide Association Studies (GWAS) and Post-GWAS Analyses. AB - BACKGROUND: Alcohol dependence (AD) is a complex psychiatric disorder and a significant public health problem. Twin and family-based studies have consistently estimated its heritability to be approximately 50%, and many studies have sought to identify specific genetic variants associated with susceptibility to AD. These studies have been primarily linkage or candidate gene based and have been mostly unsuccessful in identifying replicable risk loci. Genome-wide association studies (GWAS) have improved the detection of specific loci associated with complex traits, including AD. However, findings from GWAS explain only a small proportion of phenotypic variance, and alternative methods have been proposed to investigate the associations that do not meet strict genome-wide significance criteria. METHODS: This review summarizes all published AD GWAS and post-GWAS analyses that have sought to exploit GWAS data to identify AD associated loci. RESULTS: Findings from AD GWAS have been largely inconsistent, with the exception of variants encoding the alcohol-metabolizing enzymes. Analyses of GWAS data that go beyond standard association testing have demonstrated the polygenic nature of AD and the large contribution of common variants to risk, nominating novel genes and pathways for AD susceptibility. CONCLUSIONS: Findings from AD GWAS and post-GWAS analyses have greatly increased our understanding of the genetic etiology of AD. However, it is clear that larger samples will be necessary to detect loci in addition to those that encode alcohol metabolizing enzymes, which may only be possible through consortium-based efforts. Post-GWAS approaches to studying the genetic influences on AD are increasingly common and could greatly increase our knowledge of both the genetic architecture of AD and the specific genes and pathways that influence risk. PMID- 26110983 TI - Professional lead nurse tissue viability. PMID- 26110984 TI - 150 patient experiences with a soft silicone foam dressing. AB - Pain, malodour and exudate from acute and chronic wounds can be catastrophic to the patient. Excessive exudate results in significant tissue damage to the wound bed and surrounding skin, reduces quality of life, and often requires costly specialist service input. Effective wound assessment and management including appropriate dressing choice is, therefore, paramount to ensure wound healing can take place in a timely manner. This observational evaluation explores 150 ward based patients who presented with acute and chronic exuding wounds; it examines and evaluates the proposed benefits of the Cutimed((r)) Siltec foam dressing range over a 4-month period in an acute hospital setting. The outcomes of the evaluation were exudate management, maceration reduction, atraumatic application and removal, non-adherence and patient experience. The evaluation highlights not only an overall positive improvement in exudate management and maceration reduction, non-adherence, atraumatic application and removal but also emphasises the importance of a positive patient experience in the wound-care journey. PMID- 26110985 TI - Topical haemoglobin spray for diabetic foot ulceration. AB - The development and subsequent deterioration of diabetic foot ulceration (DFU) is a common occurrence across all healthcare divides, concerning all patient groups, age, gender and social environments. It increases demand on clinical resources and creates unnecessary hardship for patients. Chronic DFU is challenging to prevent and notoriously difficult to manage owing to the complex nature of the patient and the disease itself. The improvement of oxygenation to many chronic wound groups is gaining momentum across wound care; particularly in those wounds such as DFU that present with circulatory, oxygen-deficient scenarios. METHOD: A descriptive evaluation was undertaken in an acute clinical setting where a spray solution containing purified haemoglobin was used in a cohort of 20 patients who presented with chronic (>12 weeks) DFU. Standard wound care was undertaken by 18 health professionals with no changes to products, devices or practice before evaluation. All wounds received the addition of the product on eight set occasions over a 4-week period and the resulting data correlated in regards to the set outcomes of wound surface area reduction, ease of use, adverse events and patient acceptability. RESULTS: At 4 weeks all wounds had demonstrated positive wound reduction, there were no adverse events, all patients and clinicians found the product acceptable and easy to use. Interestingly, although not a set outcome, all wounds commenced the evaluation with wound-bed slough present and at 4 weeks 100% were deemed slough free. At a further 4-week review no patients wounds had regressed. CONCLUSION: The incorporation of a haemoglobin spray solution within this cohort of DFU resulted in a positive improvement in wound healing and slough elimination. Further work in this area is recommended to increase the evidence. PMID- 26110986 TI - Ensuring competence. PMID- 26110987 TI - Chronic wound bed preparation using a cleansing solution. AB - Chronic wound management remains challenging in clinical practice, especially in the presence of bacterial bioburden and slough. To resolve these clinical challenges, it is essential clinicians implement the TIME framework (tissue, inflammation/infection, moisture, edge of wound) as a model of effective wound bed preparation. As a result of advances in technology and wound care therapies, on the market today are products that can help reduce the wound bed clinical challenges recommended by the TIME framework. This article looks at a wound cleansing solution that reduces the wound bed bioburden by breaking down biofilms and debriding slough. PMID- 26110988 TI - Mechanical debridement: a brief overview. PMID- 26110989 TI - A programme to reduce acquired pressure ulcers in care homes. AB - Prevention of pressure ulcers is a major health concern, especially for older people. Much of the literature related to prevention of pressure ulcers focuses on hospital-acquired pressure ulcers. There is less literature related to prevention of pressure ulcers in care homes. This article presents a review of the literature related to prevention of pressure ulcers in care homes and an ambitious project undertaken by one care home provider to raise awareness of pressure ulcers, provide training in prevention and monitor and evaluate pressure ulcers in over 200 care home across the UK. Known as MI SKIN, the project involves ongoing training to all levels of care staff, a robust system of monitoring pressure ulcers and a mechanism to investigate and learn from any incident of pressure ulcer using root cause analysis. PMID- 26110990 TI - Evaluating an alternating mattress on an elderly rehabilitation ward. AB - Pressure ulcer prevention is a primary requirement for the NHS. Robust nursing procedures and the provision of pressure-relieving equipment is vital in meeting this requirement. However, the Department of Health also regards making considerable financial savings as a fundamental requirement. There is a firm clinical consensus among national and international bodies that patients at a high risk of developing pressure ulcers, or with existing tissue damage, should be cared for on an alternating (pressure-relieving) mattress system. This evaluation process looks at the performance of the lower cost Air-Flo((r)) 8 Acute alternating (pressure-relieving) mattress system to see if it is effective in meeting the needs of patients. The outcomes suggest that when combined with a pressure ulcer management plan and turning schedule the Air-Flo((r)) 8 Acute performed well, giving an option to continue to care for high-risk patients with an empirically proven effective therapy, while making considerable financial savings. PMID- 26110991 TI - The prehospital intravenous access assessment: a prospective study on intravenous access failure and access delay in prehospital emergency medicine. AB - OBJECTIVES: Intravenous access in prehospital emergency care allows for early administration of medication and extended measures such as anaesthesia. Cannulation may, however, be difficult, and failure and resulting delay in treatment and transport may have negative effects on the patient. Therefore, our study aims to perform a concise assessment of the difficulties of prehospital venous cannulation. METHODS: We analysed 23 candidate predictor variables on peripheral venous cannulations in terms of cannulation failure and exceedance of a 2 min time threshold. Multivariate logistic regression models were fitted for variables of predictive value (P<0.25) and evaluated by the area under the curve (AUC>0.6) of their respective receiver operating characteristic curve. RESULTS: A total of 762 intravenous cannulations were enroled. In all, 22% of punctures failed on the first attempt and 13% of punctures exceeded 2 min. Model selection yielded a three-factor model (vein visibility without tourniquet, vein palpability with tourniquet and insufficient ambient lighting) of fair accuracy for the prediction of puncture failure (AUC=0.76) and a structurally congruent model of four factors (failure model factors plus vein visibility with tourniquet) for the exceedance of the 2 min threshold (AUC=0.80). CONCLUSION: Our study offers a simple assessment to identify cases of difficult intravenous access in prehospital emergency care. Of the numerous factors subjectively perceived as possibly exerting influences on cannulation, only the universal - not exclusive to emergency care - factors of lighting, vein visibility and palpability proved to be valid predictors of cannulation failure and exceedance of a 2 min threshold. PMID- 26110992 TI - Determination of Histidine pKa Values in the Propeptides of Furin and Proprotein Convertase 1/3 Using Histidine Hydrogen-Deuterium Exchange Mass Spectrometry. AB - Propeptides of proprotein convertases regulate activation of their protease domains by sensing the organellar pH within the secretory pathway. Earlier experimental work highlighted the importance of a conserved histidine residue within the propeptide of a widely studied member, furin. A subsequent evolutionary analysis found an increase in histidine content within propeptides of secreted eukaryotic proteases compared with their prokaryotic orthologs. However, furin activates in the trans-golgi network at a pH of 6.5 while a paralog, proprotein convertase 1/3, activates in secretory vesicles at a pH of 5.5. It is unclear how a conserved histidine can mediate activation at two different pH values. In this manuscript, we measured the pKa values of histidines within the propeptides of furin and proprotein convertase 1/3 using a histidine hydrogen-deuterium exchange mass spectrometry approach. The high density of histidine residues combined with an abundance of basic residues provided challenges for generation of peptide ions with unique histidine residues, which were overcome by employing ETD fragmentation. During this analysis, we found slow hydrogen-deuterium exchange in residues other than histidine at basic pH. Finally, we demonstrate that the pKa of the conserved histidine in proprotein convertase 1/3 is acid-shifted compared with furin and is consistent with its lower pH of activation. PMID- 26110993 TI - Psychosocial Factors Associated With Risk Perceptions for Chronic Diseases in Younger and Middle-Aged Women. AB - Perceptions of disease risk play an important role in motivating people to adopt healthy behaviors. However, little is known about psychosocial factors that influence women's perceived risk for developing disease. The present study investigated the extent to which individual traits, social influences, objective risk factors, and demographic characteristics were associated with women's risk perceptions for cardiovascular disease, breast cancer, and lung cancer. Using structural equation modeling, we examined hypothesized associations among 452 younger (ages 18-25 years) and 167 middle-aged (ages 40-64 years) women. A greater number and variety of factors were associated with middle-aged women's risk perceptions compared to younger women. For both groups, some objective risk factors were associated with risk perceptions; yet, associations also existed between multiple psychosocial variables (optimism, health locus of control, social exposure to disease, perceived stigma) and risk perceptions. Results suggested that women may base their risk estimates on factors beyond those considered important by healthcare providers. PMID- 26110994 TI - The Additive Inflammatory In Vivo and In Vitro Effects of IL-7 and TSLP in Arthritis Underscore the Therapeutic Rationale for Dual Blockade. AB - INTRODUCTION: The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied. METHODS: Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed. RESULTS: Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/ mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors. CONCLUSION: TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA. PMID- 26110995 TI - Laparoscopic Right Posterior Sectionectomy for Malignant Lesions: An Anatomic Approach. AB - BACKGROUND: Good indications for laparoscopic hepatectomy are still considered to be tumors located over anterolateral segments of the liver. Tumors located over the right posterior section are considered to be difficult for laparoscopic resection. In this case series, we present our experience on laparoscopic right posterior sectionectomy. PATIENTS AND METHODS: All patient data were prospectively collected. Data on patient demographics, tumor characteristics, operative data, and postoperative outcome were collected and analyzed. RESULTS: During the period of May 2010-May 2014, we performed 13 laparoscopic right posterior sectionectomies. The diagnoses were hepatocellular carcinoma in 11 patients, of which 2 were cases of colorectal liver metastasis. Median operative time was 381 minutes, and median blood loss was 1500 mL. Significant bleeding occurred in the first 5 patients. The median size of the tumor resected was 3.7 cm, and the median resection margin was 8.7 mm. Four of the 13 patients (30.8%) were cirrhotic on histological examination. There was no postoperative mortality. Median hospital stay was 7 days. CONCLUSIONS: Laparoscopic right posterior sectionectomy is technically demanding. A proper inflow and outflow control is mandatory for proper anatomical resection. This surgical principle should not be compromised in the era of laparoscopic hepatectomy. PMID- 26110996 TI - Longitudinal evaluation of 100% fruit juice consumption on BMI status in 2-5-year old children. AB - BACKGROUND: Obesity in childhood is related to multiple lifestyle factors. Our objective was to evaluate the relationship between consumption of 100% fruit juice and weight status over time among pre-school children. METHODS: We used linear and logistic multivariable regression to evaluate body mass index (BMI) z score and overweight/obese status as a function of 100% fruit juice intake for 8950 children examined at ages 2, 4 and 5 years as part of the Early Childhood Longitudinal Study-Birth Cohort, a representative sample of the United States. RESULTS: Cross-sectional analysis at ages 4 and 5 years showed no difference in the prevalence of overweight and obesity between consistent juice drinkers and inconsistent/non-drinkers. Longitudinal analysis found that children who drank 100% juice consistently at age 2 years had greater increases in BMI z-score by age 4 years than infrequent/non-drinkers (P < 0.0001), a difference driven by lesser increases in height z-score (P = 0.0003) and slightly greater increases in weight z-score (P = 0.0550) among consistent juice drinkers over the 2 to 4 year time period. Additionally, consistent juice drinkers at age 2 had higher odds of becoming overweight by age 4 (adjusted odds ratio 1.30; CI 1.06-1.60). These differences in growth parameters were not noted between ages 4 and 5 years. CONCLUSIONS: Drinking 100% fruit juice regularly at age 2 is associated with higher odds of becoming overweight between 2 and 4 years. Paediatricians and parents can discourage excessive fruit juice consumption as part of a larger effort to avoid unhealthy gain in BMI in young children. PMID- 26110997 TI - Brain Herniation After Endoscopic Transnasal Resection of Anterior Skull Base Malignancies. AB - BACKGROUND: Endoscopic endonasal approaches, when appropriate, allow a less invasive method to remove anterior skull base cancer than traditional external transfacial/craniofacial approaches. The resultant skull base defect can be significantly large, potentially extending from the posterior table of the frontal sinus to the tuberculum sellae in the sagittal plane, and from one lamina papyracea to the other in the coronal plane. However, frontal lobe herniation after such expanded endoscopic resection has been considered more of a theoretical than a practical occurrence. OBJECTIVE: To report the occurrence of frontal lobe herniation into the sinonasal cavity after expanded endonasal approaches, and to analyze causes and pathogenetic mechanisms of this unusual complication, proposing how it could have been prevented. METHODS: Two cases have been observed in 2 different skull base referral centers in the United States and Italy. Surgical and perioperative complications, postoperative course, and need for revisions were analyzed. RESULTS: Available data support the hypothesis that this complication is not attributable to the size of the anterior skull base defect, to the surgical technique, or to the materials used for the reconstruction. We found that 1 possible contributing factor may be the presence of increased intracranial pressure associated with obesity and obstructive sleep apnea, observed in both patients. CONCLUSION: Frontal lobe herniation must be considered as a possible, albeit rare, complication of expanded endoscopic anterior skull base resection. Preoperative investigations concerning the presence of obstructive sleep symptoms as well as proper identification of neuroimaging signs of intracranial hypertension are recommended for such cases. PMID- 26110998 TI - Surgical Management of a Patient With Thoracic Spinal Cord Herniation: Case Report. AB - BACKGROUND AND IMPORTANCE: Thoracic spinal cord herniation (TSCH) is rare and likely underdiagnosed. It is characterized by ventral herniation of the spinal cord through a dural defect, effacement of the anterior subarachnoid space, and increased posterior subarachnoid space. We present here a case of TSCH diagnosed and surgically treated at Barrow Neurological Institute, along with supplemental intraoperative video. CLINICAL PRESENTATION: A 61-year-old man with a history of progressive myelopathy causing left lower-extremity weakness with associated numbness, impaired gait, foot drop, incontinence, and sexual impotence was referred without any previous treatment. Computed tomographic myelography and magnetic resonance imaging of the thoracic spine showed ventral spinal cord herniation at T3-T4. Neurological monitoring was recorded preoperatively and intraoperatively. The patient underwent left-sided posterolateral exploration via T3-T4 laminectomies and costotransversectomy for intradural cord release/detethering of the spinal cord with additional superior and inferior extension and repair of the dural defect. Arthrodesis was not considered necessary. After cord release, motor evoked potentials showed immediate improvement from baseline. Dural duplication was considered the cause of TSCH in this case. Total reduction of herniation was evident in postoperative images. The postoperative course was uneventful, and at the last follow-up, the patient had regained ambulation and sphincter control. CONCLUSION: Anterior displacement of the thoracic spinal cord should elicit consideration of herniation to prevent misdiagnosis and inadequate surgery. Surgical cord release and enlargement of the dural defect are safe and associated with good clinical outcomes. PMID- 26110999 TI - Intrathecal Pressure After Spinal Cord Injury. PMID- 26111000 TI - In Reply: Intrathecal Pressure After Spinal Cord Injury. PMID- 26111001 TI - Basal Autophagy and Feedback Activation of Akt Are Associated with Resistance to Metformin-Induced Inhibition of Hepatic Tumor Cell Growth. AB - While accumulating evidence has shown that the use of the diabetic drug metformin may be beneficial against various tumors in some epidemiological studies, a few studies failed to show the same beneficial effects. The molecular and cellular mechanisms for these conflicting observations are not clear. In this study, we compared the inhibitory effects of cell growth by metformin on several hepatic tumor cell lines: SMMC-7721, HCC-97L, HCC-LM3 and HepG2. While metformin inhibited cell growth in all these cells, we found that SMMC-7721, HCC-97L and HCC-LM3 cells were more resistant than HepG2 cells. Mechanistically, we found that metformin inhibited mTOR in all these hepatic tumor cells. However, SMMC 7721 cells had higher levels of basal autophagy and mTORC2-mediated feedback activation of Akt than HepG2 cells, which may render SMMC-7721 cells to be more resistant to metformin-induced inhibition of cell growth. Similarly, HCC-97L and HCC-LM3 cells also had higher feedback activation of AKT than HepG2 cells, which may also account for their resistance to metformin-induced inhibition of cell growth. Therefore, the various basal autophagy and mTOR activity in different cancer cells may contribute to the controversial findings on the use of metformin in inhibition of cancers in humans. PMID- 26111003 TI - The loss of scents: do defects in olfactory sensory neuron development underlie human disease? AB - The olfactory system is a fascinating and beguiling sensory system: olfactory sensory neurons detect odors underlying behaviors essential for mate choice, food selection, and escape from predators, among others. These sensory neurons are unique in that they have dendrites contacting the outside world, yet their first synapse lies in the central nervous system. The information entering the central nervous system is used to create odor memories that play a profound role in recognition of individuals, places, and appropriate foods. Here, the structure of the olfactory epithelium is given as an overview to discuss the origin of the olfactory placode, the plasticity of the olfactory sensory neurons, and finally the origins of the gonadotropin-releasing hormone neuroendocrine cells. For the purposes of this review, the development of the peripheral sensory system will be analyzed, incorporating recently published studies highlighting the potential novelties in development mechanisms. Specifically, an emerging model where the olfactory epithelium and olfactory bulb develop simultaneously from a continuous neurectoderm patterned at the end of gastrulation, and the multiple origins of the gonadotropin-releasing hormone neuroendocrine cells associated with the olfactory sensory system development will be presented. Advances in the understanding of the basic mechanisms underlying olfactory sensory system development allows for a more thorough understanding of the potential causes of human disease. PMID- 26111002 TI - Drug Trafficking into Macrophages via the Endocytotic Receptor CD163. AB - In inflammatory diseases, macrophages are a main producer of a range of cytokines regulating the inflammatory state. This also includes inflammation induced by tumor growth, which recruits so-called tumor-associated macrophages supporting tumor growth. Macrophages are therefore relevant targets for cytotoxic or phenotype-modulating drugs in the treatment of inflammatory and cancerous diseases. Such targeting of macrophages has been tried using the natural propensity of macrophages to non-specifically phagocytose circulating foreign particulate material. In addition, the specific targeting of macrophage-expressed receptors has been used in order to obtain a selective uptake in macrophages and reduce adverse effects of off-target delivery of drugs. CD163 is a highly expressed macrophage-specific endocytic receptor that has been studied for intracellular delivery of small molecule drugs to macrophages using targeted liposomes or antibody drug conjugates. This review will focus on the biology of CD163 and its potential role as a target for selective macrophage targeting compared with other macrophage targeting approaches. PMID- 26111004 TI - Changes in Neurofilament and Microtubule Distribution following Focal Axon Compression. AB - Although a number of cytoskeletal derangements have been described in the setting of traumatic axonal injury (TAI), little is known of early structural changes that may serve to initiate a cascade of further axonal degeneration. Recent work by the authors has examined conformational changes in cytoskeletal constituents of neuronal axons undergoing traumatic axonal injury (TAI) following focal compression through confocal imaging data taken in vitro and in situ. The present study uses electron microscopy to understand and quantify in vitro alterations in the ultrastructural composition of microtubules and neurofilaments within neuronal axons of rats following focal compression. Standard transmission electron microscopy processing methods are used to identify microtubules, while neurofilament identification is performed using antibody labeling through gold nanoparticles. The number, density, and spacing of microtubules and neurofilaments are quantified for specimens in sham Control and Crushed groups with fixation at <1 min following load. Our results indicate that the axon caliber dependency known to exist for microtubule and neurofilament metrics extends to axons undergoing TAI, with the exception of neurofilament spacing, which appears to remain constant across all Crushed axon diameters. Confidence interval comparisons between Control and Crushed cytoskeletal measures suggests early changes in the neurofilament spatial distributions within axons undergoing TAI may precede microtubule changes in response to applied loads. This may serve as a trigger for further secondary damage to the axon, representing a key insight into the temporal aspects of cytoskeletal degeneration at the component level, and suggests the rapid removal of neurofilament sidearms as one possible mechanism. PMID- 26111005 TI - Two showy traits, scent emission and pigmentation, are finely coregulated by the MYB transcription factor PH4 in petunia flowers. AB - The mechanism underlying the emission of phenylpropanoid volatiles is poorly understood. Here, we reveal the involvement of PH4, a petunia MYB-R2R3 transcription factor previously studied for its role in vacuolar acidification, in floral volatile emission. We used the virus-induced gene silencing (VIGS) approach to knock down PH4 expression in petunia, measured volatile emission and internal pool sizes by GC-MS, and analyzed transcript abundances of scent-related phenylpropanoid genes in flowers. Silencing of PH4 resulted in a marked decrease in floral phenylpropanoid volatile emission, with a concurrent increase in internal pool levels. Expression of scent-related phenylpropanoid genes was not affected. To identify putative scent-related targets of PH4, we silenced PH5, a tonoplast-localized H(+) -ATPase that maintains vacuolar pH homeostasis. Suppression of PH5 did not yield the reduced-emission phenotype, suggesting that PH4 does not operate in the context of floral scent through regulation of vacuolar pH. We conclude that PH4 is a key floral regulator that integrates volatile production and emission processes and interconnects two essential floral traits - color and scent. PMID- 26111006 TI - Revision Rhinoplasty for Short Noses in the Asian Population. AB - IMPORTANCE: Short nose, especially postoperative short nose in Asian patients, remains a challenging problem for plastic surgeons. OBJECTIVE: To determine the outcomes of revision rhinoplasty of postoperative short noses in Asian patients. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective medical record review of 41 Asian patients with postoperative short nose who underwent revision rhinoplasty in a tertiary care referral center in South Korea from October 1, 2006, through August 31, 2014. MAIN OUTCOMES AND MEASURES: Patient demographic, surgical technique, graft use, anthropometric measurement, complication, and aesthetic outcome assessment data were retrieved. RESULTS: The 41 enrolled patients were a mean (SD) of 36.5 (12.6) years old. There were 16 men and 25 women. The most commonly used dorsal graft in the previous rhinoplasty was silicone, followed by fascia with or without cartilage. Various surgical techniques were applied, including septal reconstruction, cartilage flap technique, tip surgery, lateral compartment correction, and dorsal augmentation. Autologous costal cartilage was the most commonly used septal reconstruction material. Eleven patients (27%) developed postoperative complications, including infection, nostril asymmetry, and pollybeak deformity. Revision rhinoplasty yielded statistically significant improvements in nasal length (increase of 12.0%, P < .001), nasal tip projection (increase of 13.4%, P < .001), nasofrontal angle (decrease of 2.39 degrees , P = .04), nasolabial angle (decrease of 7.62 degrees , P < .001), and columella-lobular angle (increase of 3.25 degrees , P < .001). More than 90% (37) of the patients were judged to have good or excellent aesthetic results. CONCLUSIONS AND RELEVANCE: Correction of postoperative short nose in Asian patients requires complicated surgery that usually involves more than one kind of surgical technique. Complications are not uncommon, and patients should be informed of this before surgery. LEVEL OF EVIDENCE: 4. PMID- 26111007 TI - Glycosylation enhances the aqueous sensitivity and lowers the cytotoxicity of a naphthalimide zinc ion fluorescence probe. AB - With this research we demonstrate that glycosylation of a naphthalimide zinc ion probe, using click chemistry, leads to an improvement of the aqueous sensitivity, working pH range and targeting ability for specific cells, together with significantly reduced cytotoxicity. PMID- 26111008 TI - Ultrasonic Nanobubbles Carrying Anti-PSMA Nanobody: Construction and Application in Prostate Cancer-Targeted Imaging. AB - To facilitate prostate cancer imaging using targeted molecules, we constructed ultrasonic nanobubbles coupled with specific anti-PSMA (prostate specific membrane antigen) nanobodies, and evaluated their in vitro binding capacity and in vivo imaging efficacy. The "targeted" nanobubbles, which were constructed via a biotin-streptavidin system, had an average diameter of 487.60 +/- 33.55 nm and carried the anti-PSMA nanobody as demonstrated by immunofluorescence. Microscopy revealed targeted binding of nanobubbles in vitro to PSMA-positive cells. Additionally, ultrasonography indicators of nanobubble imaging (including arrival time, peak time, peak intensity and enhanced duration) were evaluated for the ultrasound imaging in three kinds of animal xenografts (LNCaP, C4-2 and MKN45), and showed that these four indicators of targeted nanobubbles exhibited significant differences from blank nanobubbles. Therefore, this study not only presents a novel approach to target prostate cancer ultrasonography, but also provides the basis and methods for constructing small-sized and high-efficient targeted ultrasound nanobubbles. PMID- 26111009 TI - Auxin influx importers modulate serration along the leaf margin. AB - Leaf shape in Arabidopsis is modulated by patterning events in the margin that utilize a PIN-based auxin exporter/CUC2 transcription factor system to define regions of promotion and retardation of growth, leading to morphogenesis. In addition to auxin exporters, leaves also express auxin importers, notably members of the AUX1/LAX family. In contrast to their established roles in embryogenesis, lateral root and leaf initiation, the function of these transporters in leaf development is poorly understood. We report that three of these genes (AUX1, LAX1 and LAX2) show specific and dynamic patterns of expression during early leaf development in Arabidopsis, and that loss of expression of all three genes is required for observation of a phenotype in which morphogenesis (serration) is decreased. We used these expression patterns and mutant phenotypes to develop a margin-patterning model that incorporates an AUX1/LAX1/LAX2 auxin import module that influences the extent of leaf serration. Testing of this model by margin localized expression of axr3-1 (AXR17) provides further insight into the role of auxin in leaf morphogenesis. PMID- 26111011 TI - Verbal Fluency: Language or Executive Function Measure? AB - Measures of phonemic and semantic verbal fluency, such as FAS and Animal Fluency (Benton, Hamsher, & Sivan, 1989), are often thought to be measures of executive functioning (EF). However, some studies (Henry & Crawford, 2004a , 2004b , 2004c ) have noted there is also a language component to these tasks. The current exploratory factor-analytic study examined the underlying cognitive structure of verbal fluency. Participants were administered language and EF measures, including the Controlled Oral Word Association Test (FAS version), Animal Fluency, Boston Naming Test (BNT), Vocabulary (Wechsler Adult Intelligence Scale III), Wisconsin Card-Sorting Test (WCST, perseverative responses), and Trail Making Test-Part B (TMT-B). A 2-factor solution was found with the 1st factor, language, having significant loadings for BNT and Vocabulary, while the second factor was labeled EF because of significant loading from the WCST and TMT-B. Surprisingly, FAS and Animal Fluency loaded exclusively on to the language factor and not EF. The current results do not exclude EF as a determinant of verbal fluency, but they do suggest that language processing is the critical component for this task, even without significant aphasic symptoms. Thus, the results indicated that both letter (phonemic) and category (semantic) fluency are related to language, but the relationship to EF is not supported by the results. PMID- 26111013 TI - Automatic delineation of tumor volumes by co-segmentation of combined PET/MR data. AB - Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only. PMID- 26111010 TI - Emergency Department Presentations following Tropical Cyclone Yasi. AB - INTRODUCTION: Emergency departments see an increase in cases during cyclones. The aim of this study is to describe patient presentations to the Emergency Department (ED) of a tertiary level hospital (Townsville) following a tropical cyclone (Yasi). Specific areas of focus include changes in: patient demographics (age and gender), triage categories, and classification of diseases. METHODS: Data were extracted from the Townsville Hospitals ED information system (EDIS) for three periods in 2009, 2010 and 2011 to coincide with formation of Cyclone Yasi (31 January 2011) to six days after Yasi crossed the coast line (8 February 2012). The analysis explored the changes in ICD10-AM 4-character classification and presented at the Chapter level. RESULTS: There was a marked increase in the number of patients attending the ED during Yasi, particularly those aged over 65 years with a maximum daily attendance of 372 patients on 4 Feb 2011. The most marked increases were in: Triage categories--4 and 5; and ICD categories- diseases of the skin and subcutaneous tissue (L00-L99), and factors influencing health care status (Z00-Z99). The most common diagnostic presentation across all years was injury (S00-T98). DISCUSSION: There was an increase in presentations to the ED of TTH, which peaked in the first 24-48 hours following the cyclone and returned to normal over a five-day period. The changes in presentations were mostly an amplification of normal attendance patterns with some altered areas of activity. Injury patterns are similar to overseas experience. PMID- 26111014 TI - Correction: FK-16 Derived from the Anticancer Peptide LL-37 Induces Caspase Independent Apoptosis and Autophagic Cell Death in Colon Cancer Cells. PMID- 26111015 TI - N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption. AB - Although several strategies have been applied for oral insulin delivery to improve insulin bioavailability, little success has been achieved. To overcome multiple barriers to oral insulin absorption simultaneously, insulin-loaded N trimethyl chitosan chloride (TMC)-coated polylactide-co-glycoside (PLGA) nanoparticles (Ins TMC-PLGA NPs) were formulated in our study. The Ins TMC-PLGA NPs were prepared using the double-emulsion solvent evaporation method and were characterized to determine their size (247.6 +/- 7.2 nm), zeta-potential (45.2 +/ 4.6 mV), insulin-loading capacity (7.8 +/- 0.5%) and encapsulation efficiency (47.0 +/- 2.9%). The stability and insulin release of the nanoparticles in enzyme containing simulated gastrointestinal fluids suggested that the TMC-PLGA NPs could partially protect insulin from enzymatic degradation. Compared with unmodified PLGA NPs, the positively charged TMC-PLGA NPs could improve the mucus penetration of insulin in mucus-secreting HT29-MTX cells, the cellular uptake of insulin via clathrin- or adsorption-mediated endocytosis in Caco-2 cells and the permeation of insulin across a Caco-2 cell monolayer through tight junction opening. After oral administration in mice, the TMC-PLGA NPs moved more slowly through the gastrointestinal tract compared with unmodified PLGA NPs, indicating the mucoadhesive property of the nanoparticles after TMC coating. Additionally, in pharmacological studies in diabetic rats, orally administered Ins TMC-PLGA NPs produced a stronger hypoglycemic effect, with 2-fold higher relative pharmacological availability compared with unmodified NPs. In conclusion, oral insulin absorption is improved by TMC-PLGA NPs with the multiple absorption barriers overcome simultaneously. TMC-PLGA NPs may be a promising drug delivery system for oral administration of macromolecular therapeutics. PMID- 26111017 TI - TAFFYS: An Integrated Tool for Comprehensive Analysis of Genomic Aberrations in Tumor Samples. AB - BACKGROUND: Tumor single nucleotide polymorphism (SNP) array is a common platform for investigating the cancer genomic aberration and the functionally important altered genes. Original SNP array signals are usually corrupted by noise, and need to be de-convoluted into absolute copy number profile by analytical methods. Unfortunately, in contrast with the popularity of tumor Affymetrix SNP array, the methods that are specifically designed for this platform are still limited. The complicated characteristics of noise in signals is one of the difficulties for dissecting tumor Affymetrix SNP array data, as they inevitably blur the distinction between aberrations and create an obstacle for the copy number aberration (CNA) identification. RESULTS: We propose a tool named TAFFYS for comprehensive analysis of tumor Affymetrix SNP array data. TAFFYS introduce a wavelet-based de-noising approach and copy number-specific signal variance model for suppressing and modelling the noise in signals. Then a hidden Markov model is employed for copy number inference. Finally, by using the absolute copy number profile, statistical significance of each aberration region is calculated in term of different aberration types, including amplification, deletion and loss of heterozygosity (LOH). The result shows that copy number specific-variance model and wavelet de-noising algorithm fits well with the Affymetrix SNP array signals, leading to more accurate estimation for diluted tumor sample (even with only 30% of cancer cells) than other existed methods. Results of examinations also demonstrate a good compatibility and extensibility for different Affymetrix SNP array platforms. Application on the 35 breast tumor samples shows that TAFFYS can automatically dissect the tumor samples and reveal statistically significant aberration regions where cancer-related genes locate. CONCLUSIONS: TAFFYS provide an efficient and convenient tool for identifying the copy number alteration and allelic imbalance and assessing the recurrent aberrations for the tumor Affymetrix SNP array data. PMID- 26111016 TI - A de novo Assembly of the Common Frog (Rana temporaria) Transcriptome and Comparison of Transcription Following Exposure to Ranavirus and Batrachochytrium dendrobatidis. AB - Amphibians are experiencing global declines and extinctions, with infectious diseases representing a major factor. In this study we examined the transcriptional response of metamorphic hosts (common frog, Rana temporaria) to the two most important amphibian pathogens: Batrachochytrium dendrobatidis (Bd) and Ranavirus. We found strong up-regulation of a gene involved in the adaptive immune response (AP4S1) at four days post-exposure to both pathogens. We detected a significant transcriptional response to Bd, covering the immune response (innate and adaptive immunity, complement activation, and general inflammatory responses), but relatively little transcriptional response to Ranavirus. This may reflect the higher mortality rates found in wild common frogs infected with Ranavirus as opposed to Bd. These data provide a valuable genomic resource for the amphibians, contribute insight into gene expression changes after pathogen exposure, and suggest potential candidate genes for future host-pathogen research. PMID- 26111019 TI - Will a warmer and wetter future cause extinction of native Hawaiian forest birds? AB - Isolation of the Hawaiian archipelago produced a highly endemic and unique avifauna. Avian malaria (Plasmodium relictum), an introduced mosquito-borne pathogen, is a primary cause of extinctions and declines of these endemic honeycreepers. Our research assesses how global climate change will affect future malaria risk and native bird populations. We used an epidemiological model to evaluate future bird-mosquito-malaria dynamics in response to alternative climate projections from the Coupled Model Intercomparison Project. Climate changes during the second half of the century accelerate malaria transmission and cause a dramatic decline in bird abundance. Different temperature and precipitation patterns produce divergent trajectories where native birds persist with low malaria infection under a warmer and dryer projection (RCP4.5), but suffer high malaria infection and severe reductions under hot and dry (RCP8.5) or warm and wet (A1B) futures. We conclude that future global climate change will cause significant decreases in the abundance and diversity of remaining Hawaiian bird communities. Because these effects appear unlikely before mid-century, natural resource managers have time to implement conservation strategies to protect this unique avifauna from further decimation. Similar climatic drivers for avian and human malaria suggest that mitigation strategies for Hawai'i have broad application to human health. PMID- 26111018 TI - Canine Antibodies against Salivary Recombinant Proteins of Phlebotomus perniciosus: A Longitudinal Study in an Endemic Focus of Canine Leishmaniasis. AB - BACKGROUND: Phlebotomine sand flies are vectors of Leishmania parasites. During blood feeding, sand flies deposit into the host skin immunogenic salivary proteins which elicit specific antibody responses. These anti-saliva antibodies enable an estimate of the host exposure to sand flies and, in leishmaniasis endemic areas, also the risk for Leishmania infections. However, the use of whole salivary gland homogenates as antigen has several limitations, and therefore, recombinant salivary proteins have been tested to replace them in antibody detection assays. In this study, we have used for the first time sand fly salivary recombinant proteins in a longitudinal field study on dogs. METHODOLOGY/PRINCIPAL FINDINGS: Sera from dogs naturally exposed to P. perniciosus bites over two consecutive transmission seasons in a site endemic for canine leishmaniasis (CanL) were tested at different time points by ELISA for the antibodies recognizing whole saliva, single salivary 43 kDa yellow-related recombinant protein (rSP03B), and a combination of two salivary recombinant proteins, 43 kDa yellow-related protein and 35.5 kDa apyrase (rSP01). Dogs were also tested for Leishmania infantum positivity by serology, culture, and PCR and the infection status was evaluated prospectively. We found a significant association between active CanL infection and the amount of anti-P. perniciosus saliva antibodies. Importantly, we detected a high correlation between IgG antibodies recognizing rSP03B protein and the whole salivary antigen. The kinetics of antibody response showed for both a whole saliva and rSP03B a similar pattern that was clearly related to the seasonal abundance of P. perniciosus. CONCLUSIONS: These results suggest that P. perniciosus rSP03B protein is a valid alternative to whole saliva and could be used in large-scale serological studies. This novel method could be a practical and economically-sound tool to detect the host exposure to sand fly bites in CanL endemic areas. PMID- 26111020 TI - Geographical Barriers Impeded the Spread of a Parasitic Chromosome. AB - Parasitic supernumerary (B) chromosomes show high capability to spread across populations. But the existence of abrupt discontinuities in their distribution demands an explanation. The grasshopper Eyprepocnemis plorans plorans harbour supernumerary chromosomes in all natural populations hitherto analyzed from the Circum-Mediterranean region, with the single exception of the headwaters of the Iberian Segura River and several of its tributaries. To ascertain the causes of this distribution pattern, we analyze here the genetic structure of five natural populations collected in this zone (two +B and three -B), by means of ISSR markers. We found significant population structure, with two kinds of populations coinciding with +B and -B ones, separated by strong barriers to gene flow. This gives strong support to the hypothesis that the non-B populations precede B origin, and that B-carrying individuals from coastal zones have been able to colonize upstream areas, until geographical barriers (usually narrow canyons and arid areas surrounding them) impeded their advance. PMID- 26111021 TI - Propofol versus thiopental sodium for the treatment of refractory status epilepticus. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 8, 2012.Failure to respond to antiepileptic drugs in patients with uncontrolled seizure activity such as refractory status epilepticus (RSE) has led to the use of anaesthetic drugs. Coma is induced with anaesthetic drugs to achieve complete control of seizure activity. Thiopental sodium and propofol are popularly used for this purpose. Both agents have been found to be effective. However, there is a substantial lack of evidence as to which of the two drugs is better in terms of clinical outcome. OBJECTIVES: To compare the efficacy, adverse effects, and short- and long-term outcomes of RSE treated with one of the two anaesthetic agents, thiopental sodium or propofol. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (26 March 2015), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 2, February 2015) and MEDLINE (1946 to 26 March 2015). We also searched ClinicalTrials.gov (26 March 2015), the South Asian Database of Controlled Clinical Trials and IndMED (a bibliographic database of Indian Medical Journals). SELECTION CRITERIA: All randomised or quasi-randomised controlled studies (regardless of blinding) of control of RSE using either thiopental sodium or propofol in patients of any age and gender. DATA COLLECTION AND ANALYSIS: Two review authors screened the search results and reviewed the abstracts of relevant and eligible trials before retrieving the full-text publications. MAIN RESULTS: One study with a total of 24 participants was available for review. This study was a small, single-blind, multicentre trial studying adults with RSE receiving either propofol or thiopental sodium for the control of seizure activity. This study cannot be considered of high methodological quality. This study was terminated early due to recruitment problems. This study showed a wide confidence interval suggesting that the drugs may differ in efficacy up to more than two fold. Days of mechanical ventilation were more in patients receiving thiopental sodium when compared with propofol. At three months there was no evidence of a difference between the drugs with respect to outcome measures such as control of seizure activity and functional outcome. Adverse events reported in this study were infection, hypotension and intestinal ischaemia. AUTHORS' CONCLUSIONS: Since the last version of this review we have found no new studies.There is a lack of robust, randomised, controlled evidence that can clarify the efficacy of propofol and thiopental sodium compared to each other in the treatment of RSE. There is a need for large randomised controlled trials for this serious condition. PMID- 26111022 TI - Clinicopathological Analysis of Ocular Adnexal Extranodal Marginal Zone B-Cell Lymphoma with IgG4-Positive Cells. AB - This study aims to analyze clinical and pathological characteristics of ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL) accompanying IgG4 positive cells. Fifty patients with a diagnosis of primary non-conjunctival ocular adnexal EMZL were enrolled in this study. The number of IgG4-positive cells and the ratio of IgG/IgG4 were evaluated by immunohistochemistry in the biopsy specimens. The patients were divided into two groups based on the absolute number and the ratio of IgG4-positive cells (IgG4-posivite vs IgG4-negative groups). The demographic data, clinical staging at diagnosis, histopathological characteristics, and response to initial treatment were comparatively analyzed between the 2 groups. Five (10%) of 50 patients were defined as IgG4-positive group, and all the cases showed characteristic histological features such as extensive plasma cell infiltration and dense fibrosis. Most of these patients (4 of 5 patients) had lymphoma of the lacrimal gland. The patients from the IgG4 positive group showed a lower response rate to initial treatment (87.5 vs 33%, p = 0.03) than IgG4-negative group with a median follow-up period of 38 months. A part of the ocular adnexal EMZLs were accompanied with IgG4-positive cells. Significantly, most IgG4-positive ocular adnexal EMZLs occurred in the lacrimal gland, and can be related with a more frequent treatment failure. PMID- 26111023 TI - Discovery of a latent calcineurin inhibitory peptide from its autoinhibitory domain by docking, dynamic simulation, and in vitro methods. AB - Autoinhibitory domain (AID) of calcineurin (CN) was discovered two decades ago. Fewer investigations are reported to find out shortest possible peptide from the AID for CN inhibition. Hence, this study has focused on screening of nearly 150 peptide fragments derived from the AID using in silico method. Therefore, we have employed docking studies, aiming to analyze the best pose of AID-derived peptides on CN active site. We also analyzed binding free energy (DeltaG) of docked complex using molecular mechanics/generalized Born surface area (MM/GBSA). MM/GBSA predicts two short peptides P1 and P2 found to be lowest binding free energy. Two peptides exhibit better binding affinity with CN, suggests that the possible candidates for potential CN inhibition. Further, the stability of the docked complex was analyzed using molecular dynamic (MD) simulation. MD study shows that CNA:P2 is the most stable complex than CN A:P1 and CN A:AID. Besides, we have synthesized and purified P1 and P2 peptides over high performance liquid chromatography (HPLC) found to be 90.31% and 98.93% of purity, respectively. In addition, AID peptides were characterized over mass spectral analysis. Peptides were subjected to CN inhibitory assay using malachite green method. Where, P1 and P2 exhibit CN inhibition better than AID. In particular, shortest peptide P2 shows highest inhibitory activity than AID. Enzyme assay reveals CN inhibitory activity of P2 peptide is consistent within silico results. In silico and in vitro, results corroborated each other to confirm short peptide P2 can be used as a potential CN inhibitor. PMID- 26111024 TI - Toward integrative annotation of cell type-specific epigenomes to better understand human biology and disease. PMID- 26111025 TI - Breaking TADs: insights into hierarchical genome organization. PMID- 26111026 TI - The regulatory mechanisms of intragenic DNA methylation. PMID- 26111027 TI - DNMT3A moderates cognitive decline in subjects with mild cognitive impairment: replicated evidence from two mild cognitive impairment cohorts. AB - Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment. PMID- 26111028 TI - DNA methylation profiling of synovial fluid FLS in rheumatoid arthritis reveals changes common with tissue-derived FLS. AB - AIM: Alterations in DNA methylation contribute to the abnormal phenotype of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). We profiled genome-wide DNA methylation in these cells from synovial fluid, a more readily accessible source of disease-associated cells. PATIENTS & METHODS: Genome-wide DNA methylation was interrogated in fluid-derived FLS from five RA and six osteoarthritis patients using Human Methylation 450 Bead Chip and bisulfite pyrosequencing. RESULTS: Array analysis identified 328 CpGs, representing 195 genes, that were differentially methylated between RA and osteoarthritis fluid-derived FLS. Comparison with the genes identified in two independent studies of tissue-derived FLS revealed 73 genes in common (~40%), of which 22 shared identity with both studies. Pyrosequencing confirmed altered methylation of these genes. CONCLUSION: Synovial fluid-derived RA FLS show methylation changes common with tissue-derived FLS, supporting the use of fluid derived FLS for future investigations. PMID- 26111029 TI - Introducing enteral feeding induces intestinal subclinical inflammation and respective chromatin changes in preterm pigs. AB - AIM: To analyze how enteral food introduction affects intestinal gene regulation and chromatin structure in preterm pigs. MATERIALS & METHODS: Preterm pigs were fed parenteral nutrition plus/minus slowly increasing volumes of enteral nutrition. Intestinal gene-expression and chromatin structure were analyzed 5 days after birth. RESULTS: Enteral feeding led to differential upregulation of inflammatory and pattern recognition receptor genes, including IL8 (median: 5.8, 95% CI: 3.9-7.8 for formula; median: 2.2, 95% CI: 1.3-3.3 for colostrum) and TLR4 (median: 3.7, 95% CI: 2.6-4.8 for formula; no significant differences for colostrum) with corresponding decondensed chromatin configurations. On histology this correlated with mild mucosal lesions, particularly in formula-fed pigs. In CaCo-2 cells, histone hyperacetylation led to a marked increase in TLR4 mRNA and increased IL8 expression upon stimulation with lipopolysaccharide (median: 7.0; interquartile range: 5.63-8.85) compared with naive cells (median 4.2; interquartile range: 2.45-6.33; p = 0.03). CONCLUSION: Enteral feeding, particular with formula, induces subclinical inflammation in the premature intestine and more open chromatin structure in key inflammatory genes. This may increase the susceptibility for necrotizing enterocolitis. PMID- 26111031 TI - Traumatic stress and human DNA methylation: a critical review. AB - Animal studies have identified persistent and functional effects of traumatic stress on the epigenome. This review discusses the clinical evidence for trauma induced changes in DNA methylation across the life span in humans. Studies are reviewed based on reports of trauma exposure during the prenatal period (13 studies), early life (20 studies), and adulthood (ten studies). Even though it is apparent that traumatic stress influences the human epigenome, there are significant drawbacks in the existing human literature. These include a lack of longitudinal studies, methodological heterogeneity, selection of tissue type, and the influence of developmental stage and trauma type on methylation outcomes. These issues are discussed in order to present a way in which future studies can gain more insight into the functional relevance of trauma-related DNA methylation changes. Epigenetic studies investigating the detrimental effects of traumatic stress have great potential for an improved detection and treatment of trauma related psychiatric disorders. PMID- 26111032 TI - KDM1 histone lysine demethylases as targets for treatments of oncological and neurodegenerative disease. AB - Histone methylation and demethylation are important processes associated with the regulation of gene transcription, and alterations in histone methylation status have been linked to a large number of human diseases. Initially thought to be an irreversible process, histone methylation is now known to be reversed by two families of proteins containing over 30 members that act to remove methyl groups from specific lysine residues present in the tails of histone H3 and histone H4. A rapidly growing number of reports have implicated the FAD-dependent lysine specific demethylase (KDM1) family in cancer, and several small-molecule inhibitors are in development for the treatment of cancer. An additional role has emerged for KDM1 in brain function, offering additional opportunities for the development of novel therapeutic strategies in neurodegenerative disease. A decade after the identification of KDM1A as a histone demethylase, the first selective inhibitors have now reached the clinic. PMID- 26111033 TI - Epigenetics and the burden of noncommunicable disease: a paucity of research in Africa. AB - Epidemiological evidence suggests that an adverse in utero environment is associated with an increased risk for developing adult onset diseases. The molecular mechanisms for susceptibility to chronic noncommunicable diseases are not fully understood, although recent research has proposed that epigenetic modifications play an important role in fetal programming. Genetic and environmental factors contribute to interindividual and spatiotemporal tissue specific methylation patterns. Although the diverse environments and high genetic diversity of African populations provide unparalleled potential to investigate the effects of environmental change on the epigenetic profile in humans, only a small percentage of genomic and epigenetic studies have focused on populations from this continent. This emphasizes the need to build capacity in Africa for research that leads to an understanding of the association between genetic, epigenetic and environmental risk factors for noncommunicable diseases on the continent. PMID- 26111030 TI - Gadd45b and N-methyl-D-aspartate induced DNA demethylation in postmitotic neurons. AB - AIM: In nondividing neurons examine the role of Gadd45b in active 5 methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) removal at a gene promoter highly implicated in mental illnesses and cognition, Bdnf. MATERIALS & METHODS: Mouse primary cortical neuronal cultures with and without Gadd45b siRNA transfection were treated with N-methyl-d-aspartate (NMDA). Expression changes of genes reportedly involved in DNA demethylation, Bdnf mRNA and protein and 5MC and 5HMC at Bdnf promoters were measured. RESULTS: Gadd45b siRNA transfection in neurons abolishes the NMDA-induced increase in Bdnf IXa mRNA and reductions in 5MC and 5HMC at the Bdnf IXa promoter. CONCLUSION: These results contribute to our understanding of DNA demethylation mechanisms in neurons, and its role in regulating NMDA responsive genes implicated in mental illnesses. PMID- 26111034 TI - Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy. AB - Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, in cancer therapy. HDAC inhibitors have been approved as single agents for cutaneous and peripheral T-cell lymphoma and have shown promising activity in reversing therapy resistance in other tumor types. The effects of HDAC inhibitors on immune modulation have created a recent interest in their potential role in immunotherapy. This review describes the current understanding on integrating HDAC inhibitors into various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors. Furthermore, it summarizes promising treatment strategies in epigenetic immune priming from clinical trials that are currently underway. PMID- 26111035 TI - Circulating miRNAs as intercellular messengers, potential biomarkers and therapeutic targets for Type 2 diabetes. AB - miRNAs have emerged as key epigenetic regulators of metabolism. Their deregulation contributes to metabolic abnormalities, proposing their potential role as therapeutic targets for Type 2 diabetes. The exciting finding that miRNAs exist in the bloodstream suggests that circulating miRNAs may act in a hormone like fashion. Despite the fact that significant progress has been made in understanding circulating miRNAs, this topic is full of complexities and many questions remain unanswered. The goal of this review is to bring together up-to date knowledge about circulating miRNAs and their role as intercellular communicators as well as potential biomarkers and therapeutic targets in metabolic diseases, providing examples of possible clinical applications for circulating miRNAs in diabetes and cardiovascular complications. PMID- 26111036 TI - The role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: experimental evidence for therapeutic intervention. AB - The contribution of epigenetic mechanisms in diabetes mellitus (DM), beta-cell reprogramming and its complications is an emerging concept. Recent evidence suggests that there is a link between DM and histone deacetylases (HDACs), because HDAC inhibitors promote beta-cell differentiation, proliferation, function and improve insulin resistance. Moreover, gut microbes and diet-derived products can alter the host epigenome. Furthermore, butyrate and butyrate producing microbes are decreased in DM. Butyrate is a short-chain fatty acid produced from the fermentation of dietary fibers by microbiota and has been proven as an HDAC inhibitor. The present review provides a pragmatic interpretation of chromatin-dependent and independent complex signaling/mechanisms of butyrate for the treatment of Type 1 and Type 2 DM, with an emphasis on the promising strategies for its drugability and therapeutic implication. PMID- 26111037 TI - Correlates of Recent Declines of Rodents in Northern and Southern Australia: Habitat Structure Is Critical. AB - Australia has experienced dramatic declines and extinctions of its native rodent species over the last 200 years, particularly in southern Australia. In the tropical savanna of northern Australia significant declines have occurred only in recent decades. The later onset of these declines suggests that the causes may differ from earlier declines in the south. We examine potential regional effects (northern versus southern Australia) on biological and ecological correlates of range decline in Australian rodents. We demonstrate that rodent declines have been greater in the south than in the tropical north, are strongly influenced by phylogeny, and are consistently greater for species inhabiting relatively open or sparsely vegetated habitat. Unlike in marsupials, where some species have much larger body size than rodents, body mass was not an important predictor of decline in rodents. All Australian rodent species are within the prey-size range of cats (throughout the continent) and red foxes (in the south). Contrary to the hypothesis that mammal declines are related directly to ecosystem productivity (annual rainfall), our results are consistent with the hypothesis that disturbances such as fire and grazing, which occur in non-rainforest habitats and remove cover used by rodents for shelter, nesting and foraging, increase predation risk. We agree with calls to introduce conservation management that limits the size and intensity of fires, increases fire patchiness and reduces grazing impacts at ecological scales appropriate for rodents. Controlling feral predators, even creating predator-free reserves in relatively sparsely-vegetated habitats, is urgently required to ensure the survival of rodent species, particularly in northern Australia where declines are not yet as severe as those in the south. PMID- 26111038 TI - Hybridization Gap and Dresselhaus Spin Splitting in EuIr4In2Ge4. AB - EuIr4In2Ge4 is a new intermetallic semiconductor that adopts a non centrosymmetric structure in the tetragonal I42m space group with unit cell parameters a=6.9016(5) A and c=8.7153(9) A. The compound features an indirect optical band gap E(g)=0.26(2) eV, and electronic-structure calculations show that the energy gap originates primarily from hybridization of the Ir 5d orbitals, with small contributions from the Ge 4p and In 5p orbitals. The strong spin-orbit coupling arising from the Ir atoms, and the lack of inversion symmetry leads to significant spin splitting, which is described by the Dresselhaus term, at both the conduction- and valence-band edges. The magnetic Eu(2+) ions present in the structure, which do not play a role in gap formation, order antiferromagnetically at 2.5 K. PMID- 26111039 TI - Correction: Combined Use of Hyperbaric and Hypobaric Ropivacaine Significantly Improves Hemodynamic Characteristics in Spinal Anesthesia for Caesarean Section: A Prospective, Double-Blind, Randomized, Controlled Study. PMID- 26111041 TI - Lesions of the Neovagina--A Review. AB - Creation of a neovagina is uncommon, but it may be performed for congenital absence or anomaly, after exenterative cancer surgery, or in male-to-female transsexuals. A variety of tissues may be used to create the neovagina. Lesions of the neovagina are uncommon and probably not well known to most practitioners. A review of these lesions will be helpful if such a patient presents. PMID- 26111042 TI - Primary Adenocarcinoma of Intestinal Type Arising From a Vaginal Mass: A Case Report. AB - A patient with a history of a severe vaginal laceration during vaginal birth, unknown degree, presented with recurrent vaginal discharge and was found to have a vaginal mass. Pathologic analysis showed squamous mucosa transitioning into colonic type of mucosa with adenocarcinoma developed from colonic type of mucosa, reminiscent of anorectal junction. PMID- 26111040 TI - History of Abuse in Women With Vulvar Pruritus, Vulvodynia, and Asymptomatic Controls. AB - OBJECTIVE: Chronic vulvar pruritus and vulvodynia are common vulvar diseases. The aim of this study was to compare gynecologic and sexual and physical abuse histories from patients with these diagnoses and from healthy controls. MATERIALS AND METHODS: Questionnaires were self-completed by patients diagnosed with vulvar itch-scratch (n = 93), patients diagnosed with vulvodynia (n = 232), and patients presenting for annual gynecologic examinations (n = 104) at the University of Michigan Hospitals, Ann Arbor, MI. RESULTS: Patients who came for annual examinations were less likely to report past gynecologic infections (p < .05) and indicated higher interest in and more frequent sexual activity than the other 2 groups (p = .003). Vulvodynia patients had the highest scores on the McGill Pain Questionnaire (p < .001). Subjects with either vulvar disorder were more likely to self-report a history of gynecologic infections than annual examination controls. Rates of sexual (p = .78) and physical abuse (p = .12) were similar for all 3 groups. CONCLUSIONS: Patients with vulvar pruritus and vulvodynia report similar rates of sexual and physical abuse. PMID- 26111043 TI - Efficacy and Tolerability of Mometasone Furoate in Lichen Sclerosus: Further Confirming Evidence. PMID- 26111044 TI - Enhancing primary care for persons with spinal cord injury: More than improving physical accessibility. AB - In Ontario, Canada, legislation exists that mandates that all medical practices be fully accessible by 2025, in an effort to improve access to primary care for persons with physical disabilities. The simple removal of physical barriers may not guarantee improved access to appropriate care. In this clinical note, members of an interprofessional primary care-based Mobility Clinic reflect on opportunities to improve primary care beyond just better physical accessibility for persons with spinal cord injury (SCI). The importance of collaborations between funders, researchers, and clinicians are examined. Using a participatory action research model, the unique perspective of consumers and consumer networks are incorporated into the Mobility Clinic's clinical and research efforts to improve primary care for persons with SCI. PMID- 26111045 TI - Why do men suffering from LUTS seek primary medical care? A qualitative study. AB - RATIONALE, AIMS AND OBJECTIVES: Lower urinary tract symptoms (LUTS) are common problems among men, but only a small proportion actually visit their general practitioner (GP). This study aims to gain insight into the reasons why men visit a doctor, and their expectations. METHODS: We opted to perform a qualitative study with semi-structured interviews among men aged over 50 years who consulted their GP because of suffering from LUTS. All interviews were fully transcribed and coded and analysed by two researchers using ATLAS.ti. RESULTS: We interviewed 18 men between the ages of 52 and 80. Frequently mentioned reasons for seeking help can be grouped under three main themes: a wish for reassurance about not having prostate cancer, the nuisance of symptoms such as nycturia and being triggered by public information about LUTS. Most participants lacked an understanding of the cause and prognosis of their symptoms. CONCLUSION: The main reasons to seek primary medical care are the need for reassurance and the nuisance of symptoms, especially nycturia. Overall, the patients show remarkably poor knowledge about their symptoms. PMID- 26111046 TI - Region-Based Association Test for Familial Data under Functional Linear Models. AB - Region-based association analysis is a more powerful tool for gene mapping than testing of individual genetic variants, particularly for rare genetic variants. The most powerful methods for regional mapping are based on the functional data analysis approach, which assumes that the regional genome of an individual may be considered as a continuous stochastic function that contains information about both linkage and linkage disequilibrium. Here, we extend this powerful approach, earlier applied only to independent samples, to the samples of related individuals. To this end, we additionally include a random polygene effects in functional linear model used for testing association between quantitative traits and multiple genetic variants in the region. We compare the statistical power of different methods using Genetic Analysis Workshop 17 mini-exome family data and a wide range of simulation scenarios. Our method increases the power of regional association analysis of quantitative traits compared with burden-based and kernel based methods for the majority of the scenarios. In addition, we estimate the statistical power of our method using regions with small number of genetic variants, and show that our method retains its advantage over burden-based and kernel-based methods in this case as well. The new method is implemented as the R function 'famFLM' using two types of basis functions: the B-spline and Fourier bases. We compare the properties of the new method using models that differ from each other in the type of their function basis. The models based on the Fourier basis functions have an advantage in terms of speed and power over the models that use the B-spline basis functions and those that combine B-spline and Fourier basis functions. The 'famFLM' function is distributed under GPLv3 license and is freely available at http://mga.bionet.nsc.ru/soft/famFLM/. PMID- 26111047 TI - Detecting and Quantifying Forest Change: The Potential of Existing C- and X-Band Radar Datasets. AB - This paper evaluates the opportunity provided by global interferometric radar datasets for monitoring deforestation, degradation and forest regrowth in tropical and semi-arid environments. The paper describes an easy to implement method for detecting forest spatial changes and estimating their magnitude. The datasets were acquired within space-borne high spatial resolutions radar missions at near-global scales thus being significant for monitoring systems developed under the United Framework Convention on Climate Change (UNFCCC). The approach presented in this paper was tested in two areas located in Indonesia and Australia. Forest change estimation was based on differences between a reference dataset acquired in February 2000 by the Shuttle Radar Topography Mission (SRTM) and TanDEM-X mission (TDM) datasets acquired in 2011 and 2013. The synergy between SRTM and TDM datasets allowed not only identifying changes in forest extent but also estimating their magnitude with respect to the reference through variations in forest height. PMID- 26111048 TI - Flow Cytometric Immunobead Assay for Detection of BCR-ABL1 Fusion Proteins in Chronic Myleoid Leukemia: Comparison with FISH and PCR Techniques. AB - Chronic Myeloid Leukemia (CML) is characterized by a balanced translocation juxtaposing the Abelson (ABL) and breakpoint cluster region (BCR) genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR) defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i) CML can be properly diagnosed at onset, (ii) follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%>1) when BCR-ABL1IS transcripts are between 1-10%, and (iii) rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients. PMID- 26111050 TI - Safety of a second-generation tyrosine kinase inhibitor and novel targeted therapy for the treatment of a patient with chronic myeloid leukemia and multiple myeloma. AB - The prevalence of chronic myeloid leukemia and multiple myeloma has increased in recent years partly because of an improved therapeutic armamentarium for both conditions. Likewise, understanding the complexity inherent in designing combination treatment strategies will become increasingly prescient in the coming years. We describe, to the best of our knowledge, the first reported patient to be treated with second-generation tyrosine kinase inhibitor therapy while on novel therapy for myeloma. The combination was well tolerated and effective for the treatment of chronic myeloid leukemia and concurrent myeloma. PMID- 26111049 TI - Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and fluorouracil-based treatment in Taiwan colorectal cancer. AB - This study aimed to investigate the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and the prognosis of colorectal cancer (CRC) patients undergoing 5-fluorouracil (5-FU)-based chemotherapy in Taiwan. We investigated 126 CRC cases. The most common polymorphisms C677T (rs1801133) and A1298C (rs1801131) in MTHFR were genotyped using PCR-restriction fragment length polymorphism. The frequencies of C677T and A1298C were further compared with those in the HapMap database for Whites and Asians. In this study, we found that TT-homozygosity at MTHFR C677T was significantly associated with survival in CRC patients [P<0.001; 95% confidence interval (CI)=0.068-0.212]. In CRC patients receiving 5-FU-based chemotherapy, the TT genotype at C677T was also significantly associated with survival (P=0.001; 95% CI=0.113-0.400) and recurrence after surgery (P<0.001; 95% CI=0.295-0.609). The A1298C genotypes had a significant impact on survival (chi=7.103; P=0.029). The MTHFR A1298C CC genotype may increase the risk of death in Taiwanese CRC patients. The MTHFR C677T TT genotype was present at a lower frequency in our CRC patients than in the HapMap Asian population, but the frequency was similar to that in Whites in the HapMap database. The distribution of MTHFR A1298C genotypes was similar in our CRC and in the HapMap Asian population, but was different from that in the White population. This study suggested that MTHFR C677T and A1298C are associated with prognosis in CRC patients undergoing 5-FU-based chemotherapy. PMID- 26111051 TI - Synthesis of N-Hydroxy Isopeptide Containing Proteins. AB - Chemical synthesis of a peptide-ubiquitin conjugate linked by an N-hydroxy isopeptide bond to determine what effect the N-hydroxy group has on the enzymatic hydrolysis of the isopeptide linkage by deubiquitinases is reported. This conjugate was subjected to proteolysis by UCH-L3 in the presence and absence of various metal ions, and no substantive difference in hydrolysis was seen compared to a control lacking the N-hydroxy group. The accessibility of N-hydroxy ubiquitinated substrates may find uses to study other deubiquitinases in particular those which use a zinc ion as a part of their catalytic mechanism. PMID- 26111052 TI - Highly Enantioselective Nucleophilic Dearomatization of Pyridines by Anion Binding Catalysis. AB - The asymmetric dearomatization of N-heterocycles is an important synthetic method to gain bioactive and synthetically valuable chiral heterocycles. However, the catalytic enantio- and regioselective dearomatization of the simplest six membered-ring N-heteroarenes, the pyridines, is still very challenging. The first anion-binding-catalyzed, highly enantioselective nucleophilic dearomatization of pyridines with triazole-based H-bond donor catalysts is presented. Contrary to other more common NH-based H-bond donors, this type of organocatalyst shows a prominent higher C2-regioselectivity and is able to promote high enantioinductions via formation of a close chiral anion-pair complex with a preformed N-acyl pyridinium ionic intermediate. This method offers a straightforward and useful synthetic approach to chiral N-heterocycles from abundant and readily available pyridines. PMID- 26111053 TI - Flow cytometric measurement of platelet-associated immunoglobulin in children with newly diagnosed Immune Thrombocytopenia. AB - OBJECTIVE: To explore the clinical utility of measuring platelet-associated immunoglobulin (PAIG) at the time of diagnosis in children with immune thrombocytopenia (ITP). METHODS: PAIG was measured by flow cytometry using fluorescent murine anti-IgG and anti-IgM. In a cohort of 88 children with ITP, the assay was performed within 15 days of diagnosis and before any treatment in 68 cases. We reviewed the results and examined the relation of isotype profile and degree of elevation to clinical manifestations and course of disease. RESULTS: PAIG was elevated in 74%, with raised IgM being more frequent than IgG (63% vs. 44%, P = 0.04) and with isotype profile depending on symptom onset. Platelet counts at presentation were similar in all subgroups, but mucosal bleeding was less frequent in PAIG-negative patients compared to the positive groups (5.5% vs. 34%, P = 0.03). Duration of thrombocytopenia was similar in negative and positive cases, but during follow-up, significant bleeding events occurred less frequently in PAIG-negative patients (0% vs. 14%, P = 0.18). CONCLUSION: Approximately one-quarter of children are PAIG-negative, and these children have milder bleeding tendency at diagnosis and lower morbidity during follow-up. Raised PAIG possibly may cause some degree of platelet dysfunction. PMID- 26111054 TI - Nonrigid Registration Regularized by Shape Information: Application to Atlas Construction of Cardiac CT Images. AB - Cardiac atlases play an important role in the computer-aided diagnosis of cardiovascular diseases, in particular they need to deal with large and highly variable image datasets. In this paper, we propose a new nonrigid registration algorithm incorporating shape information, to produce comprehensive atlases. For one thing, the multiscale gradient orientation features of images are combined to form the construction of multifeature mutual information. Additionally, the shape information of multiple-objects in images is incorporated into the cost function for registration. We demonstrate the merits of the new registration algorithm on the 3D data sets of 15 patients. The experimental results show that the new registration algorithm can outperform the conventional intensity-based registration method. The obtained atlas can represent the cardiac structures more accurately. PMID- 26111055 TI - Case of psoriasis vulgaris developing ulcerative colitis during adalimumab treatment. PMID- 26111056 TI - Computational methods and resources for the interpretation of genomic variants in cancer. AB - The recent improvement of the high-throughput sequencing technologies is having a strong impact on the detection of genetic variations associated with cancer. Several institutions worldwide have been sequencing the whole exomes and or genomes of cancer patients in the thousands, thereby providing an invaluable collection of new somatic mutations in different cancer types. These initiatives promoted the development of methods and tools for the analysis of cancer genomes that are aimed at studying the relationship between genotype and phenotype in cancer. In this article we review the online resources and computational tools for the analysis of cancer genome. First, we describe the available repositories of cancer genome data. Next, we provide an overview of the methods for the detection of genetic variation and computational tools for the prioritization of cancer related genes and causative somatic variations. Finally, we discuss the future perspectives in cancer genomics focusing on the impact of computational methods and quantitative approaches for defining personalized strategies to improve the diagnosis and treatment of cancer. PMID- 26111057 TI - Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3beta-Snail pathway. AB - Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3beta-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling. PMID- 26111059 TI - Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer. PMID- 26111060 TI - RIPK1 promotes death receptor-independent caspase-8-mediated apoptosis under unresolved ER stress conditions. PMID- 26111058 TI - Glycation of vitronectin inhibits VEGF-induced angiogenesis by uncoupling VEGF receptor-2-alphavbeta3 integrin cross-talk. AB - Glycation of vessel wall proteins is thought to have an important role in the pathogenesis of vascular complications in diabetes mellitus. However, no previous study has implicated glycated vitronectin (VN) in the control of vascular endothelial growth factor (VEGF) signaling. To explore whether the glycation of VN affects angiogenic signaling and to understand the molecular mechanisms involved, we synthesized glycated VN by incubating VN with methylglyoxal (MGO) in vitro and identified the formation of glycated VN by an LC-ESI-MS/MS-based method. We tested the hypothesis that glycation of VN downregulates VEGF receptor 2 (VEGFR-2) activation by uncoupling the interaction between VEGFR-2 and alphavbeta3. Unmodified and MGO-glycated VN were used as substrates for human umbilical vein endothelial cells (HUVECs). The effects of glycated VN on VEGF signaling in HUVECs were investigated. The glycation of VN inhibited VEGF-induced phosphorylation of VEGFR-2 and the intracellular signaling pathway downstream of VEGFR-2. Glycated VN inhibited the binding of VEGFR-2 to beta3 integrin and inhibited the phosphorylation of beta3 integrin. Furthermore, glycation of VN significantly decreased VEGF-induced migration of HUVECs in vitro and vessel outgrowth in an ex vivo angiogenesis model. Collectively, these data indicate that the glycation of VN inhibits VEGF-induced VEGFR-2 activation by uncoupling VEGFR-2-alphavbeta3 integrin cross-talk. The glycation of VN causes a reduction in the migration of endothelial cells and vessel outgrowth. This may provide a mechanism for the failure of collateral sprouting in diabetic microangiopathy. PMID- 26111061 TI - Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain. PMID- 26111062 TI - Cellular IAP proteins and LUBAC differentially regulate necrosome-associated RIP1 ubiquitination. AB - Necroptosis is a caspase-independent regulated type of cell death that relies on receptor-interacting protein kinases RIP1 (receptor-interacting protein kinases 1) and RIP3. Tumor necrosis factor-alpha (TNFalpha)-stimulated assembly of the TNFR1 (TNF receptor 1)-associated signaling complex leads to the recruitment of RIP1, whose ubiquitination is mediated by the cellular inhibitors of apoptosis (c IAPs). Translocation of RIP1 to the cytoplasm and association of RIP1 with the necrosome is believed to correlate with deubiquitination of RIP1. However, we found that RIP1 is ubiquitinated with K63 and linear polyubiquitin chains during TNFalpha, IAP antagonist BV6 and caspase inhibitor zVAD-fmk-induced necroptotic signaling. Furthermore, ubiquitinated RIP1 is associated with the necrosome, and RIP1 ubiquitination in the necrosome coincides with RIP3 phosphorylation. Both cellular IAPs and LUBAC (linear ubiquitin chain assembly complex) modulate RIP1 ubiquitination in IAP antagonist-treated necrotic cells, but they use different mechanisms. c-IAP1 regulates RIP1 recruitment to the necrosome without directly affecting RIP1 ubiquitination, whereas HOIP and HOIL1 mediate linear ubiquitination of RIP1 in the necrosome, but are not essential for necrosome formation. Knockdown of the E3 ligase c-IAP1 decreased RIP1 ubiquitination, necrosome assembly and necroptosis induced by TNFalpha, BV6 and zVAD-fmk. c-IAP1 deficiency likely decreases necroptotic cell death through the activation of the noncanonical NF-kappaB pathway and consequent c-IAP2 upregulation. The ability to upregulate c-IAP2 could determine whether c-IAP1 absence will have a positive or negative impact on TNFalpha-induced necroptotic cell death and necrosome formation. Collectively, these results reveal unexpected complexity of the roles of IAP proteins, IAP antagonists and LUBAC in the regulation of necrosome assembly. PMID- 26111064 TI - Performance of Seven Commercial Phytases in an in Vitro Simulation of Poultry Digestive Tract. AB - The aim of this study was to compare the biochemical properties of seven commercially available phytase products as well as their catalytic performance in an in vitro simulation of the digestive tract of poultry. Their enzymatic properties relevant with respect to phytate dephosphorylation in the digestive tract of birds were determined under identical assay conditions. All phytase products included in the study showed an acid pH optimum of activity and were capable of releasing the organically bound phosphate from phytate during the in vitro simulation. However, their overall biochemical properties and relative catalytic performances were remarkably different. The in vitro degradation system was considered as a simple and useful tool to evaluate the suitability of a phytase to be used as a feed supplement. Although relevant factors such as dietary P levels, intestinal phytase, and P absorption are not implemented in the system, this approach might help to reduce the number of feeding trials necessary in the search for a better suited phytase for animal feeding application. PMID- 26111063 TI - Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. PMID- 26111065 TI - Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles. AB - A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl2 and a stoichiometric amount of N-halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reactions can be performed working solely with stoichiometric CuCl2 and CuBr2, respectively. PMID- 26111066 TI - Effectiveness of Trauma-Focused Cognitive Behavioral Therapy Among Trauma Affected Children in Lusaka, Zambia: A Randomized Clinical Trial. AB - IMPORTANCE: Orphans and vulnerable children (OVC) are at high risk for experiencing trauma and related psychosocial problems. Despite this, no randomized clinical trials have studied evidence-based treatments for OVC in low resource settings. OBJECTIVE: To evaluate the effectiveness of lay counselor provided trauma-focused cognitive behavioral therapy (TF-CBT) to address trauma and stress-related symptoms among OVC in Lusaka, Zambia. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial compared TF-CBT and treatment as usual (TAU) (varying by site) for children recruited from August 1, 2012, through July 31, 2013, and treated until December 31, 2013, for trauma-related symptoms from 5 community sites within Lusaka, Zambia. Children were aged 5 through 18 years and had experienced at least one traumatic event and reported significant trauma-related symptoms. Analysis was with intent to treat. INTERVENTIONS: The intervention group received 10 to 16 sessions of TF-CBT (n = 131). The TAU group (n = 126) received usual community services offered to OVC. MAIN OUTCOMES AND MEASURES: The primary outcome was mean item change in trauma and stress-related symptoms using a locally validated version of the UCLA Posttraumatic Stress Disorder Reaction Index (range, 0-4) and functional impairment using a locally developed measure (range, 0-4). Outcomes were measured at baseline and within 1 month after treatment completion or after a waiting period of approximately 4.5 months after baseline for TAU. RESULTS: At follow-up, the mean item change in trauma symptom score was -1.54 (95% CI, -1.81 to -1.27), a reduction of 81.9%, for the TF-CBT group and -0.37 (95% CI, -0.57 to -0.17), a reduction of 21.1%, for the TAU group. The mean item change for functioning was -0.76 (95% CI, -0.98 to -0.54), a reduction of 89.4%, and -0.54 (95% CI, -0.80 to -0.29), a reduction of 68.3%, for the TF-CBT and TAU groups, respectively. The difference in change between groups was statistically significant for both outcomes (P < .001). The effect size (Cohen d) was 2.39 for trauma symptoms and 0.34 for functioning. Lay counselors participated in supervision and assessed whether the intervention was provided with fidelity in all 5 community settings. CONCLUSIONS AND RELEVANCE: The TF-CBT adapted for Zambia substantially decreased trauma and stress-related symptoms and produced a smaller improvement in functional impairment among OVC having experienced high levels of trauma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01624298. PMID- 26111067 TI - Unique human orbital morphology compared with that of apes. AB - Humans' and apes' convergent (front-facing) orbits allow a large overlap of monocular visual fields but are considered to limit the lateral visual field extent. However, humans can greatly expand their lateral visual fields using eye motion. This study aimed to assess whether the human orbital morphology was unique compared with that of apes in avoiding lateral visual field obstruction. The orbits of 100 human skulls and 120 ape skulls (30 gibbons; 30 orangutans; 30 gorillas; 30 chimpanzees and bonobos) were analyzed. The orbital width/height ratio was calculated. Two orbital angles representing orbital convergence and rearward position of the orbital margin respectively were recorded using a protractor and laser levels. Humans have the largest orbital width/height ratio (1.19; p < 0.001). Humans and gibbons have orbits which are significantly less convergent than those of chimpanzees/bonobos, gorillas and orangutans (p < 0.001). These elements suggest a morphology favoring lateral vision in humans. More specifically, the human orbit has a uniquely rearward temporal orbital margin (107.1 degrees ; p < 0.001), suitable for avoiding visual obstruction and promoting lateral visual field expansion through eye motion. Such an orbital morphology may have evolved mainly as an adaptation to open-country habitat and bipedal locomotion. PMID- 26111068 TI - SmartArc-based volumetric modulated arc therapy can improve the middle ear, vestibule and cochlea sparing for locoregionally advanced nasopharyngeal carcinoma: a dosimetric comparison with step-and-shoot intensity-modulated radiotherapy. AB - OBJECTIVE: Radiation-induced sensorineural hearing loss is a common complication after radiotherapy in patients with nasopharyngeal carcinoma (NPC) that significantly affects their quality of life. The goal of this study was to compare SmartArc-based volumetric modulated arc therapy (VMAT-S) with step-and shoot intensity-modulated radiation therapy (IMRT) for patients with locoregionally advanced NPC with regard to the sparing effect on middle ear, vestibule and cochlea. METHODS: 20 patients with non-metastatic Stage III or IV NPC were selected to have planning with VMAT-S and IMRT [using Philips Pinnacle Planning System (Philips, Fitchburg, WI) for Varian accelerator] for dosimetric comparison. Mean middle ears, vestibule and cochlea doses for the two planning techniques were compared using a paired t-test. Target coverage and dose homogeneity were evaluated by calculating conformity index (CI) and homogeneity index (HI) values. RESULTS: VMAT-S had significantly improved homogeneity and conformity compared with IMRT. Mean HI of planning target volume of gross tumour volume (PGTV) was better with VMAT-S (1.05 +/- 0.02) than IMRT (1.09 +/- 0.03) (p < 0.001). Mean CI of PGTV is also better with VMAT-S (0.59 +/- 0.12) than IMRT (0.54 +/- 0.12) (p < 0.001). Mean doses to the left cochleas were 43.8 +/- 3.6 and 47.8 +/- 4.0 (p < 0.001) for VMAT-S and IMRT plans, respectively. Mean doses to the right cochleas were 42.7 +/- 4.7 and 47.6 +/- 5.4 (p < 0.001) for VMAT-S and IMRT plans, respectively. VMAT-S also significantly reduced the mean doses to middle ears (p < 0.001 for both) and vestibule (p < 0.001 for both). CONCLUSION: Our results indicate that VMAT-S provides better sparing of hearing apparatus in locoregionally advanced NPC. ADVANCES IN KNOWLEDGE: VMAT-S can improve the middle ear, vestibule and cochlea sparing in patients with locoregionally advanced NPC. PMID- 26111069 TI - MDCT and clinicopathological features of small bowel gastrointestinal stromal tumours in 102 patients: a single institute experience. AB - OBJECTIVE: Small bowel (SB) is the second most common site of gastrointestinal stromal tumours (GISTs). We evaluated clinical presentation, pathology, imaging features and metastatic pattern of SB GIST. METHODS: Imaging and clinicopathological data of 102 patients with jejunal/ileal GIST treated at Dana Farber Cancer Institute and Brigham and Women's Hospital (Boston, MA) between 2002 and 2013 were evaluated. Imaging of treatment-naive primary tumour (41 patients) and follow-up imaging in all patients was reviewed. RESULTS: 90/102 patients were symptomatic at presentation, abdominal pain and lower gastrointestinal blood loss being the most common symptoms. On pathology, 21 GISTs were low risk, 17 were intermediate and 64 were high risk. The mean tumour size was 8.5 cm. On baseline CT (n = 41), tumours were predominantly well circumscribed, exophytic and smooth/mildly lobulated in contour. Of 41 tumours, 16 (39%) were homogeneous, whereas 25 (61%) were heterogeneous. Of the 41 tumours, cystic/necrotic areas (Hounsfield units < 20) were seen in 16 (39%) and calcifications in 9 (22%). CT demonstrated complications in 13/41 (32%) patients in the form of tumour-bowel fistula (TBF) (7/41), bowel obstruction (4/41) and intraperitoneal rupture (2/41). Amongst 102 total patients, metastases developed in 51 (50%) patients (27 at presentation), predominantly involving peritoneum (40/102) and liver (32/102). 7/8 (87%) patients having intraperitoneal rupture at presentation developed metastases. Metastases elsewhere were always associated with hepatic/peritoneal metastases. At last follow-up, 28 patients were deceased (median survival, 65 months). CONCLUSION: SB GISTs were predominantly large, well circumscribed, exophytic tumours with or without cystic/necrotic areas. Complications such as TBF, bowel obstruction and intraperitoneal perforation were visualized at presentation, with patients with perforation demonstrating a high risk of metastatic disease. Exophytic eccentric bowel wall involvement and lack of associated adenopathy are useful indicators to help differentiate GISTs from other SB neoplasms. ADVANCES IN KNOWLEDGE: SB GISTs are predominantly large, well circumscribed, exophytic tumours, and may present with complications. They often are symptomatic at presentation, are high risk on pathology and metastasize to the peritoneum more commonly than the liver. PMID- 26111072 TI - MELD-Na as a prognostic indicator of 30- and 90-day mortality in patients with end-stage liver disease after creation of transjugular intrahepatic portosystemic shunt. AB - Previous studies have shown that the Model for End-Stage Liver Disease (MELD) score is superior to other liver disease scoring systems to establish optimal candidates for transjugular intrahepatic portosystemic shunt (TIPS) procedure and liver transplantation. Our aim was to compare MELD-Na score with MELD score as a predictor of 30-day as well as 90-day mortality for individuals with end-stage liver disease (ESLD) after creation of TIPS. We performed a chart review on cirrhotic patients who underwent TIPS procedure and documented presence and severity of ascites and hepatic encephalopathy, patient laboratory values, and results from TIPS procedures. We compared continuous variables by Student's t test for independent samples and categorical variables by chi-test(s). In non normal distributions, a nonparametric test was used. We performed a logistic regression to determine the effects of several variables and analyzed variable predictors of likelihood of death within 30 and 90 days of TIPS procedure. Of the six predictor variables, only MELD-Na score was a statistically significant predictor of 30- and 90-day mortality following TIPS procedure for ESLD (P=0.028). For each one point increase in MELD-Na score, the odds of death increased by 1.15 times [95% confidence interval (1.02-1.30), P=0.28]. Since hyponatremia may be associated with poor prognostic features of overall health, its incorporation into the MELD scoring system to predict mortality in ESLD after creation of TIPS serves a useful purpose. Our single-center experience suggests that the MELD-Na score is the most effective predictor of survival after TIPS creation. PMID- 26111071 TI - The Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet): diagnostic and adjudication processes. AB - BACKGROUND: The National Heart, Lung, and Blood Institute-sponsored IPF Clinical Research Network (IPFnet) studies enrolled subjects with idiopathic pulmonary fibrosis (IPF) to evaluate drug therapies in treatment trials. An adjudication committee (AC) provided a structured review of cases in which there was uncertainty or disagreement regarding diagnosis or clinical event classification. This article describes the diagnosis and adjudication processes. METHODS: The diagnostic process was based on review of clinical data and high-resolution CT scans with central review of lung biopsies when available. The AC worked closely with the data coordinating center to obtain clinical, radiologic, and histologic data and to communicate with the clinical centers. The AC used a multidisciplinary discussion model with four clinicians, one radiologist, and one pathologist to adjudicate diagnosis and outcome measures. RESULTS: The IPFnet trials screened 1,015 subjects; of these, 23 cases required review by the AC to establish eligibility. The most common diagnosis for exclusion was suspected chronic hypersensitivity pneumonitis. The AC reviewed 88 suspected acute exacerbations (AExs), 93 nonelective hospitalizations, and 16 cases of bleeding. Determination of AEx presented practical challenges to adjudicators, as necessary clinical data were often not collected, particularly when subjects were evaluated outside of the primary study site. CONCLUSIONS: The IPFnet diagnostic process was generally efficient, but a multidisciplinary adjudication committee was critical to assure correct phenotype for study enrollment. The AC was key in adjudicating all adverse outcomes in two IPFnet studies terminated early because of safety issues. Future clinical trials in IPF should consider logistical and cost issues as they incorporate AExs and hospitalizations as outcome measures. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00517933, NCT00650091, NCT00957242; URL: www.clinicaltrials.gov. PMID- 26111070 TI - Lower limb complications of diabetes mellitus: a comprehensive review with clinicopathological insights from a dedicated high-risk diabetic foot multidisciplinary team. AB - Diabetic complications in the lower extremity are associated with significant morbidity and mortality, and impact heavily upon the public health system. Early and accurate recognition of these abnormalities is crucial, enabling the early initiation of treatments and thus avoiding or minimizing deformity, dysfunction and amputation. Following careful clinical assessment, radiological imaging is central to the diagnostic and follow-up process. We aim to provide a comprehensive review of diabetic lower limb complications designed to assist radiologists and to contribute to better outcomes for these patients. PMID- 26111073 TI - Electronic Nose for Recognition of Volatile Vapor Mixtures Using a Nanopore Enhanced Opto-Calorimetric Spectroscopy. AB - An electronic nose (e-nose) for identification and quantification of volatile organic compounds (VOCs) vapor mixtures was developed using nanopore-enhanced opto-calorimetric spectroscopy. Opto-calorimetric spectroscopy based on specific molecular vibrational transitions in the mid infrared (IR) "molecular fingerprint" regime allows highly selective detection of VOCs vapor mixtures. Nanoporous anodic aluminum oxide (AAO) microcantilevers, fabricated using a two step anodization and simple photolithography process, were utilized as highly sensitive thermomechanical sensors for opto-calorimetric signal transduction. The AAO microcantilevers were optimized by fine-tuning AAO nanopore diameter in order to enhance their thermomechanical sensitivity as well as their surface area. The thermomechanical sensitivity of a bilayer AAO microcantilever with a 60 nm pore diameter was approximately 1 MUm/K, which is far superior to that of a bilayer plain silicon (Si) microcantilever. The adsorbed molecules of VOCs mixtures on the AAO microcantilever were fully recognized and quantified by variations of peak positions and amplitudes in the opto-calorimetric IR spectra as well as by shifts in the resonance frequency of the AAO microcantilever with the adsorbed molecules. Furthermore, identification of complex organic compounds with a real industrial sample was demonstrated by this e-nose system. PMID- 26111074 TI - Adjusting for undercoverage of access-points in creel surveys with fewer overflights. AB - Creel surveys are used in recreational fisheries to estimate angling effort, catch, and harvest. Aerial-access creel surveys rely on two components: (1) a ground component in which fishing parties returning from their trips are interviewed at some access-points of the fishery; (2) an aerial component in which the number of fishing parties is counted. A common practice is to sample fewer aerial survey days than ground survey days. This is thought by practitioners to reduce the cost of the survey, but there is a lack of sound statistical methodology for this case. In this article, we propose various estimation methods to handle this situation and evaluate their asymptotic properties from a design-based perspective. We also propose formulas for the optimal allocation of the effort between the ground and the aerial portion of the survey, for given costs and budget. A simulation study investigates the performance of the estimators. Finally, we apply our methods to data from an annual Kootenay Lake survey (Canada). PMID- 26111075 TI - Development and Application of a Sensitive, Second Antibody Format Enzymeimmunoassay (EIA) for Estimation of Plasma FSH in Mithun (Bos frontalis). AB - Mithun (Bos frontalis) is a semi-wild rare ruminant species. A simple sensitive enzymeimmunoassay suitable for assaying FSH in the blood plasma of mithun is not available which thereby limits our ability to understand this species reproductive processes. Therefore, the aim of this article was to develop a simple and sensitive enzymeimmunoassay (EIA) for estimation of FSH in mithun plasma and apply the assay to understand the estrous cycle and superovulatory process in this species. To accomplish this goal, biotinylated FSH was bridged between streptavidin-peroxidase and immobilized antiserum in a competitive assay. Forty microlitre mithun plasma was used directly in the EIA. The FSH standards were prepared in hormone free plasma and ranged from 5-1280 pg/well/40 MUL. The sensitivity of EIA was 5 pg/well FSH, which corresponds to 0.125 ng/mL plasma and the 50% relative binding sensitivity was 90 pg/well/40 MUL. Although the shape of the standard curve was not influenced by different plasma volumes viz. 40 and 80 MUL, a slight drop in the OD450 was observed with the increasing volume of plasma. Parallelism tests conducted between the endogenous mithun FSH and bovine FSH standards showed good homology between them. Plasma FSH estimated using the developed EIA and commercially available FSH EIA kit in the same samples were correlated (r = 0.98) and showed linearity. Both the Intra- and inter-assay CV were below 6%. Recovery of known concentrations of added FSH showed linearity (r = 0.99). The developed EIA was further validated biologically by estimating FSH in cyclic cows for the entire estrous cycle, in mithun heifers administered with GnRH analogues and in mithun cows during superovulatory treatment with FSH. In conclusion, the EIA developed for FSH determination in mithun blood plasma is simple and highly sensitive for estimation of mithun FSH in all physiological conditions. PMID- 26111076 TI - Assessment of the Clinical Utility of Cervical and Ocular Vestibular Evoked Myogenic Potential Testing in Elderly Patients. AB - OBJECTIVES: To assess whether patient age or sex was predictive of a bilaterally absent cervical or ocular vestibular evoked myogenic potential (cVEMP or oVEMP). STUDY DESIGN: Retrospective case review. SETTING: Tertiary center. PATIENTS: Patients presenting with normal vestibular tests (i.e. normal caloric and rotational chair) who underwent cVEMP and/or oVEMP testing. Patients with conductive hearing loss were excluded as were those with unilaterally abnormal VEMP results because they presented with evidence of a possible unilateral vestibular impairment. A total of 895 patients met criteria for cVEMPs and 297 for oVEMPs. MAIN OUTCOME MEASURES: The presence or absence of cVEMP and oVEMP responses elicited with a 500-Hz 125-dB pSPL air conduction stimulus. RESULTS: A logistic regression was performed including odd ratios and confidence intervals. Compared with adults in their 20s, the odds of bilaterally absent cVEMP responses are 6 times greater for patients in their 50s and 60s and over 22 times greater for patients in their 70s and 80s. A bilaterally absent oVEMP response is 6 times more likely for patients in their 40s, 50s, and 60 and 13 times greater for patients in their 70s. CONCLUSIONS: VEMPs in response to air conduction stimuli are bilaterally absent in a large percentage of older patients complaining of dizziness who otherwise have normal vestibular and auditory testing for their age. In combination with other abnormal vestibular findings, an absence of VEMP responses may be of value. However, the functional consequence of an isolated bilaterally absent VEMP is not known and may provide minimal information to an older patient's diagnostic picture. In cases where the response is bilaterally absent, a more intense AC stimulus should be used or bone conducted vibration should be considered. PMID- 26111077 TI - Functional Results and Subjective Benefit of a Transcutaneous Bone Conduction Device in Patients With Single-Sided Deafness. AB - OBJECTIVE: To analyze speech discrimination scores and subjective benefit of a transcutaneous bone conduction device (tBCD) in adults with single-sided deafness (SSD). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Nine adults with SSD for more than 1 year and normal hearing on the contralateral side (PTA <30 dB HL) were implanted with a tBCD. INTERVENTIONS: Transmastoidal implantation of a Bonebridge (BB, MED-EL) tBCD. MAIN OUTCOME MEASURES: Aided and unaided speech discrimination scores in three different spatial settings were measured using the Oldenburg sentence test (OLSA). Quality of life was assessed by two questionnaires, the Bern Benefit in Single Sided Deafness Questionnaire (BBSS) and the Speech, Spatial and Qualities of Hearing scale for benefit questionnaire (SSQ-B). RESULTS: Speech discrimination scores measured by OLSA showed a mean signal-to-noise ratio improvement of 1.7 dB SPL for the aided condition compared with the unaided condition in the setting where the sound signal is presented on the side of the implanted ear and the noise is coming from the front (p < 0.05). In the other two settings (signal and noise from front; signal from normal hearing ear and noise from front), the signal-to noise ratio did not change significantly. This benefit became manifest after 6 months. Good satisfaction was indicated by positive results on the questionnaires. CONCLUSION: Speech discrimination in noise for patients implanted with the BB is comparable with patients with other bone conduction hearing aids. A learning curve is clearly detectable. The subjective benefit was rated positively by the patients. With the advantage of intact skin conditions after implantation, the BB is an adequate option for patients with SSD. PMID- 26111078 TI - Virtual Endoscopy to Plan Transtympanic Approach to Labyrinthine Windows. AB - OBJECTIVE: The aim of this study was to evaluate the position and the accessibility of labyrinthine windows through the external auditory canal (EAC) by virtual endoscopy based on computed tomographic scan images. STUDY DESIGN: Prospective cross-sectional study. SETTING: Tertiary referral center. PATIENTS: Sixty-three high-resolution temporal bone computed tomographic scans were obtained from 34 adult patients undergoing various otologic procedures. INTERVENTION: Images were analyzed by the virtual endoscopy function included in Osirix (www.osirix-viewer.com). The endoscope was constrained in the EAC. The visible surfaces of target anatomic structures were assessed on multiplanar reconstruction views. RESULTS: The optimal angles of the virtual endoscope position showed a relatively high interindividual variability in the axial plane (64 +/- 2.4 degrees for the oval window [OW] and 60 +/- 2.5 degrees for the round window [RW]) position, but a low interindividual variation was noted in the coronal plane (107 +/- 1.5 degrees for the OW and 112 +/- 1.7 degrees for the RW). The RW was accessible in 87% of cases. The OW accessibility could be staged as follows: 1, invisible stapedial superstructure (10% of cases); 2, stapedial posterior crus partly visible (33%); 3, entire posterior crus and pyramid visible (44%); 4, posterior and anterior crus visible (13%). CONCLUSION: Virtual endoscopy through the EAC can evaluate the accessibility of the OW or RW via a transcanal route. This technique seems to be helpful in preplanning minimally invasive procedures by this approach such as cochlear implantation. PMID- 26111079 TI - Transition-metal-free visible-light photoredox catalysis at room-temperature for decarboxylative fluorination of aliphatic carboxylic acids by organic dyes. AB - We report herein an efficient, general and green method for decarboxylative fluorination of aliphatic carboxylic acids. By using a transition-metal-free, organocatalytic photoredox system, the reaction of various aliphatic carboxylic acids with the Selectfluor reagent afforded the corresponding alkyl fluorides in satisfactory yields under visible light irradiation at room temperature. PMID- 26111080 TI - Expanding the SPECC1L mutation phenotypic spectrum to include Teebi hypertelorism syndrome. AB - Teebi hypertelorism syndrome is a rare autosomal dominant disorder that has eluded a molecular etiology since first described in 1987. Here we report on two unrelated families with a Teebi hypertelorism-like syndrome and Teebi hypertelorism phenotype who have missense mutations in Sperm Antigen With Calponin Homology And Coiled-Coil Domains (SPECC1L), previously associated with oblique facial clefting and Opitz G/BBB syndrome. The first patient and his affected mother were previously-reported by Hoffman et al. in this journal as a new syndrome resembling Teebi hypertelorism and Aarskog syndromes in 2007. This patient had hypertelorism, sagittal and coronal craniosynostosis, ptosis, natal teeth, unusual umbilicus, shawl scrotum, small hands, and feet, with grossly normal development. Our second patient had classic Teebi hypertelorism syndrome with hypertelorism and a giant umbilical hernia. Patient one and his affected mother had a c.1260G>C:p.E420D variant and patient two had a de novo c.1198_1203delATACAC:p.I400_H401del variant in SPECC1L. We review the phenotypic findings in the previously-published Teebi hypertelorism syndrome patients, and the Opitz G/BBB patients with SPECC1L mutations. In addition we emphasize the findings of aortic root dilation and craniosynostosis in these patients, which should be considered in their management. PMID- 26111081 TI - The Predictive Impact of Biological and Sociocultural Factors on Executive Processing: The Role of Age, Education, and Frequency of Reading and Writing Habits. AB - Although the impact of education and age on executive functions (EF) has been widely studied, the influence of daily cognitive stimulation on EF has not been sufficiently investigated. Therefore, the aim of the present study was to evaluate whether the age, education, and frequency of reading and writing habits (FRWH) of healthy adults could predict their performance on measures of inhibition and cognitive flexibility. Inhibition speed, inhibitory control, and set shifting were assessed using speed, accuracy, and discrepancy scores on the Trail-Making Test (TMT) and Hayling Test. Demographic characteristics and the FRWH were assessed using specialized questionnaires. Regression analyses showed that age and the FRWH predicted speed and accuracy on the TMT. The FRWH predicted both speed and accuracy on the Hayling Test, for which speed and accuracy scores were also partly explained by age and education, respectively. Surprisingly, only the FRWH was associated with Hayling Test discrepancy scores, considered one of the purest EF measures. This highlights the importance of regular cognitive stimulation over the number of years of formal education on EF tasks. Further studies are required to investigate the role of the FRWH so as to better comprehend its relationship with EF and general cognition. PMID- 26111082 TI - Determination of Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products - Inductively Coupled Plasma-Mass Spectrometry: Collaborative Study, Final Action 2011.19. AB - AOAC First Action Method 2011.19: Chromium, Selenium, and Molybdenum in Infant Formula and Adult Nutritional Products, was collaboratively studied. This method employs microwave digestion of samples with nitric acid, hydrogen peroxide, and internal standard followed by simultaneous detection of the elements by an inductively coupled plasma mass spectrometer (ICP-MS) instrument equipped with a collision/reaction cell. During this collaborative study, nine laboratories from four different countries, using seven different models of ICP-MS instruments, analyzed blind duplicates of seven infant, pediatric, and adult nutritional formulas. One laboratory's set of data was rejected in its entirety. The method demonstrated acceptable repeatability and reproducibility and met The Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) standard method performance requirements (SMPR) for almost all of the matrices analyzed. The Cr, Mo, and Se SPIFAN requirement for repeatability was ?5% RSD. The SMPR called for a reproducibility of ??15% RSD in products for ultratrace element concentrations above the targeted limit of quantitation of 20 MUg/kg Cr/Mo and 10 MUg/kg Se (as ready-to-feed). During this collaborative study, repeatability relative standard deviation ranged from 1.0%-7.0% and reproducibility relative standard deviation ranged from 2.5-13.4% across all three ultratrace elements. PMID- 26111083 TI - Polymorphisms in adiponectin receptor genes are associated with lipodystrophy related phenotypes in HIV-infected patients receiving antiretroviral therapy. AB - OBJECTIVES: Adiponectin is a circulating peptide secreted by mature adipocytes that may act as a regulator of glucose and lipid metabolism. This study aimed to investigate the association between genetic variability in the adiponectin receptor genes ADIPOR1 (adiponectin receptor 1) and ADIPOR2 and lipodystrophy and its related anthropometric and metabolic phenotypes in HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: We studied six single nucleotide polymorphisms (SNPs) in the adiponectin receptor genes ADIPOR1 (rs1342387 and rs10920533) and ADIPOR2 (rs11061925, rs10773983, rs929434 and rs767870) and their association with adiponectin plasma levels, lipodystrophy subtypes and other parameters linked to glucose and lipid metabolism involved in the lipodystrophic syndrome. The genotypes of 407 HIV-infected patients receiving HAART were investigated using real-time polymerase chain reaction. Mean biochemical and anthropometrical parameters were compared between the different genotypes using analysis of variance. RESULTS: Two ADIPOR2 SNPs (rs11061925 and rs929434) were associated with fasting plasma triglyceride concentrations in the entire sample. Stronger significant associations were found between these SNPs and biochemical parameters (levels of triglycerides, total cholesterol, adiponectin and glucose) in men. We did not find any significant associations with ADIPOR1 gene variants. CONCLUSIONS: SNPs in the ADIPOR2 gene appear to be involved in the metabolic alterations in HIV-infected men receiving HAART. PMID- 26111084 TI - The "Chef's Knife" in Oblique Split Technique for Rhinoplasty. PMID- 26111085 TI - Embodied neural responses to others' suffering. AB - To investigate whether and how facial mimicry in observers affects their empathic neural responses to others' pain expressions, we recorded event-related potentials (ERPs) from Chinese adults while viewing pain and neutral expressions of Asian and Caucasian faces. Facial mimicry was manipulated by allowing participants to freely move their facial muscles (the relaxed condition) or asking them to hold a pen horizontally using both teeth and lips to prevent facial muscle movement and facial mimicry (the blocked condition). We found that the frontal N1 at 100-120 ms was enlarged by pain vs. neutral expressions. The N1 modulation by facial expressions was significantly reduced in the blocked compared to relaxed conditions and this effect was observed for Asian but not Caucasian faces. The findings suggest that facial mimicry plays a causal role in the early empathic neural response and the embodied empathic neural responses are constrained by the racial intergroup relationship. PMID- 26111087 TI - Effects of oxymorphone hydrochloride or hydromorphone hydrochloride on minimal alveolar concentration of desflurane in sheep. AB - OBJECTIVE: To establish the minimum alveolar concentration (MAC) of desflurane and evaluate the effects of 2 opioids on MAC in sheep. ANIMALS: 8 adult nulliparous mixed-breed sheep. PROCEDURES: A randomized crossover design was used. Each sheep was evaluated individually on 2 occasions (to allow assessment of the effects of each of 2 opioids), separated by a minimum of 10 days. On each occasion, sheep were anesthetized with desflurane in 100% oxygen, MAC of desflurane was determined, oxymorphone (0.05 mg/kg) or hydromorphone (0.10 mg/kg) was administered IV, and MAC was redetermined. Physiologic variables and arterial blood gas and electrolyte concentrations were measured at baseline (before MAC determination, with end-tidal desflurane concentration maintained at 10%) and each time MAC was determined. Timing of various stages of anesthesia was recorded for both occasions. RESULTS: Mean +/- SEM MAC of desflurane was 8.6 +/- 0.2%. Oxymorphone or hydromorphone administration resulted in significantly lower MAC (7.6 +/- 0.4% and 7.9 +/- 0.2%, respectively). Cardiac output at MAC determination for desflurane alone and for desflurane with opioid administration was higher than that at baseline. No difference was identified among hematologic values at any point. Effects of oxymorphone and hydromorphone on durations of various stages of anesthesia did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE: MAC of desflurane in nulliparous adult sheep was established. Intravenous administration of oxymorphone or hydromorphone led to a decrease in MAC; however, the clinical importance of that decrease was minor relative to the effect in other species. PMID- 26111088 TI - Cardiovascular effects of equipotent doses of isoflurane alone and isoflurane plus fentanyl in New Zealand White rabbits (Oryctolagus cuniculus). AB - OBJECTIVE To determine effects of equipotent concentrations of fentanyl and isoflurane, compared with isoflurane alone, on cardiovascular variables in New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS 6 adult female New Zealand White rabbits. PROCEDURES Rabbits were anesthetized with isoflurane, and lungs were mechanically ventilated. The minimum alveolar concentration (MAC) of isoflurane alone (baseline) and with fentanyl administered IV to achieve 3 targeted plasma concentrations was determined for each rabbit by means of an electrical stimulus. Cardiovascular variables were measured in a separate experiment at 1.3X isoflurane MAC and equipotent doses of isoflurane plus fentanyl at the same 3 targeted plasma concentrations. Blood samples were collected for measurement of blood gas variables and plasma fentanyl concentrations. Treatment effects were evaluated by repeated-measures ANOVA followed by 2-tailed paired t tests with sequentially rejective Bonferroni correction. RESULTS Mean +/- SD MAC of isoflurane was 1.95 +/- 0.27%. Mean measured plasma fentanyl concentrations of 4.97, 8.93, and 17.19 ng/mL reduced isoflurane MAC by 17%, 37%, and 56%, respectively. Mean measured plasma fentanyl concentrations during cardiovascular measurements were 5.49, 10.26, and 18.40 ng/mL. Compared with baseline measurements, heart rate was significantly lower at all 3 plasma fentanyl concentrations, mean arterial blood pressure and systemic vascular resistance were significantly higher at mean fentanyl concentrations of 10.26 and 18.40 ng/mL, and cardiac output was significantly higher at 18.40 ng of fentanyl/mL. CONCLUSIONS AND CLINICAL RELEVANCE Administration of fentanyl in isoflurane-anesthetized rabbits resulted in improved mean arterial blood pressure and cardiac output, compared with isoflurane alone. This balanced anesthesia technique may prove useful in the management of clinical cases in this species. PMID- 26111089 TI - Changes in synovial fluid biomarker concentrations following arthroscopic surgery in horses with osteochondritis dissecans of the distal intermediate ridge of the tibia. AB - OBJECTIVE: To quantify concentrations of cartilage oligomeric matrix protein (COMP) and fibromodulin in synovial fluid from the tarsocrural joints (TCJs) of horses with osteochondritis dissecans (OCD) of the distal intermediate ridge of the tibia and determine whether concentrations would change following arthroscopic removal of osteochondral fragments. ANIMALS: 115 client-owned horses with OCD of the TCJ and 29 control horses euthanized for unrelated reasons. PROCEDURES: COMP and fibromodulin concentrations were measured in synovial fluid from the TCJs of the affected horses before and after osteochondral fragments were removed arthroscopically and in synovial fluid from the TCJs of the control horses after euthanasia. Synovial biopsy specimens from the TCJs of affected and control horses were examined histologically for evidence of inflammation. RESULTS: Synovial fluid COMP and fibromodulin concentrations prior to surgery in horses with OCD were not significantly different from concentrations in control horses. Fibromodulin, but not COMP, concentration in horses with OCD was significantly decreased after surgery, compared with the concentration before surgery. Fibromodulin concentration was significantly correlated with joint effusion score but not with lameness score or results of a flexion test and was correlated with histologic score for number of synoviocytes on the surface of the synovium but not with score for degree of infiltration of inflammatory cells in the synovium. Synovial fluid COMP concentration was not significantly correlated with clinical or histologic findings. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that fibromodulin, but not COMP, could potentially be a biomarker of joint inflammation in horses with OCD of the TCJ. PMID- 26111090 TI - Development of a clonal equine myoblast cell line capable of terminal differentiation into mature myotubes in vitro. AB - OBJECTIVE: To produce a clonal equine myoblast cell line that retains the ability to divide for multiple passages and differentiate into multinucleated myotubes during specific conditions. SAMPLE: Cultured primary equine skeletal muscle derived cells from a healthy Thoroughbred. PROCEDURES: Cell cultures were transfected by electroporation with a plasmid (pNIT) that expresses the temperature-sensitive simian vacuolating virus 40 large T antigen (TAg), which can be controlled by a doxycycline-responsive promoter. Cells that stably integrated the TAg were selected and expanded to passage 25. For each passage, differentiation and fusion properties of the cells were determined and immunocytochemical analyses were performed to evaluate expression of TAg and other muscle-specific proteins. Optimum conditions that led to cell differentiation into myotubes were also determined. RESULTS: Compared with nontransfected control cells, myogenic, desmin-positive cells expressed the TAg when incubated at 33 degrees C and could be maintained in culture for numerous passages. Reduced expression of TAg was identified in cells incubated at 37 degrees C or when incubated with doxycycline at 33 degrees C. Expression of TAg was not detected when cells were incubated with doxycycline at 37 degrees C, and when serum was withdrawn from the culture medium, those clones differentiated into a pure population of multinucleated myotubes. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that production of an immortalized clonal equine skeletal muscle cell line was possible. A clonal equine skeletal muscle cell line will be a valuable in vitro tool for use in equine physiology and disease research. PMID- 26111091 TI - Effects of nitric oxide on blood-brain barrier permeability in common carp (Cyprinus carpio L.). AB - OBJECTIVE: To determine in vivo effects of nitric oxide (NO) on blood-brain barrier (BBB) permeability in common carp (Cyprinus carpio L.). ANIMALS: 148 carp. PROCEDURES Carp received glyceryl trinitrate (1 mg/kg) as an NO donor or received no treatment (control group). Nitrite and nitrate concentrations in carp sera were determined 0.25, 1, 3, 6, 8, 12, and 24 hours after treatment. In control and treatment groups, BBB permeability was analyzed by assessment of leakage of Evans blue dye into various brain areas at 6, 12, and 24 hours after glyceryl trinitrate treatment. Brain edema was determined by means of the wet-dry weight method and assessed with light microscopy on H&E-stained preparations of tissues obtained 6 and 24 hours after glyceryl trinitrate treatment. RESULTS: Treatment with glyceryl trinitrate induced endogenous synthesis of NO, which was upregulated 6 and 8 hours after treatment. Increased NO synthesis was associated with increased permeability of the BBB, which developed 6 hours after treatment with the NO donor. Although the BBB became impermeable again by 12 hours after glycerol trinitrate treatment, brain edema still persisted 24 hours after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, treatment with an NO donor caused reversible opening of the BBB and brain edema in common carp. An intact BBB is important to prevent influx of potentially harmful substances into the brain. This investigation highlighted the possibility of BBB disarrangement caused by NO, a substance found in the CNS of all vertebrates evaluated. PMID- 26111092 TI - Comparison of two- and three-times-daily topical ophthalmic application of 0.005% latanoprost solution in clinically normal dogs. AB - OBJECTIVE: To determine whether 2- or 3-times-daily application of topical ophthalmic 0.005% latanoprost solution is more effective at lowering intraocular pressure (IOP) in clinically normal dogs. ANIMALS: 9 clinically normal dogs. PROCEDURES: For each dog, I drop of latanoprost 0.005% solution was applied to 1 eye every 8 or 12 hours each day for 5 days; the contralateral eye received topical ophthalmic treatment with 1 drop of saline (0.9% NaCl) solution at the times of latanoprost application. Ocular examinations of both eyes were performed every 6 hours starting 48 hours prior to and ending 42 hours after the treatment period. Following a 5-week washout interval, the procedures were repeated but the previously latanoprost-treated eye of each dog received latanoprost application at the alternate frequency. RESULTS: Mean +/- SD IOP reduction in the latanoprost treated eyes was 31 +/- 6.9% with 2-times-daily application and 33 +/- 8.2% with 3-times-daily application. A 2-way repeated-measures ANOVA revealed significant differences in IOP with contributions by treatment (2 or 3 times daily), time of day (diurnal variation), and individual dog. The maximum mean daily IOP reduction in latanoprost-treated eyes was detected on day 3 of latanoprost treatment in each group. Eyes treated 3 times daily had significantly smaller pupil diameter and greater conjunctival hyperemia than eyes treated 2 times daily. CONCLUSIONS AND CLINICAL RELEVANCE: The clinical importance of the ocular hypotensive effects of 3-times-daily topical ophthalmic application of 0.005% latanoprost solution in dogs with glaucoma warrants investigation. PMID- 26111093 TI - Comparison of axillary and rectal temperatures for healthy Beagles in a temperature- and humidity-controlled environment. AB - OBJECTIVE: To compare axillary and rectal temperature measurements obtained with a digital thermometer for Beagles in a temperature- and humidity-controlled environment. ANIMALS: 26 healthy Beagles (17 sexually intact males and 9 sexually intact females). PROCEDURES: Dogs were maintained in a temperature- and humidity controlled environment for 56 days before rectal and axillary temperatures were measured. Axillary and rectal temperatures were obtained in triplicate for each dog by use of a single commercially available manufacturer-calibrated digital thermometer. RESULTS: Mean rectal and axillary temperatures of Beagles maintained in a temperature- and humidity-controlled environment were significantly different, with a median +/- SD difference of 1.4 degrees +/- 0.15 degrees C (range, 0.7 degrees to 2.1 degrees C). Mean rectal and axillary temperatures were 38.7 degrees C (range, 37.6 degrees to 39.5 degrees C) and 37.2 degrees C (range, 36.6 degrees to 38.3 degrees C), respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated that the historical reference of a 0.55 degrees C gradient between rectal and axillary temperatures that has been clinically used for veterinary patients was inaccurate for healthy Beagles in a temperature- and humidity-controlled environment. Rectal and axillary temperatures can be measured in veterinary patients. Reliable interpretation of axillary temperatures may accommodate patient comfort and reduce patient anxiety when serial measurement of temperatures is necessary. Further clinical studies will be needed. PMID- 26111094 TI - Effect of exercise on serum markers of muscle inflammation in Spanish Greyhounds. AB - OBJECTIVE: To investigate effects of exercise on hematologic and biochemical values (especially markers of inflammation and muscle damage) in Spanish Greyhounds used for hunting without previous training. ANIMALS: 32 Spanish Greyhounds and 31 dogs of other breeds. PROCEDURES: Hematologic variables and concentrations of C-reactive protein (CRP) and other biochemical markers were compared in samples obtained from Spanish Greyhounds 24 hours after exercise (eg, a hunting race) and 2 months after exercise (ie, at rest) and from non-Spanish Greyhounds at rest. All dogs were healthy. Hematologic and biochemical analyses were performed within 24 hours after samples were obtained, and results were compared by means of a Student t test. RESULTS: CRP concentration and muscle enzyme (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase) activities were significantly higher and serum iron concentration was significantly lower for Spanish Greyhounds after exercise than at rest. The WBC and neutrophil counts were significantly higher after exercise then at rest. Plasma alanine transaminase activity and total protein, calcium, and phosphorus concentrations were significantly higher after exercise than at rest. Spanish Greyhounds at rest had higher RBC counts, PCVs, and hemoglobin concentrations and lower WBC, neutrophil, and lymphocyte counts, compared with values for non Spanish Greyhounds at rest. CONCLUSIONS AND CLINICAL RELEVANCE: Exercise of Spanish Greyhounds without prior training activated an acute-phase response represented by an increase in serum CRP concentration and decrease in serum albumin and iron concentrations. These changes, along with leukocytosis and neutrophilia, were indicative of a subclinical inflammatory state in Spanish Greyhounds. PMID- 26111095 TI - In vitro comparison of leakage pressure and leakage location for various staple line offset configurations in functional end-to-end stapled small intestinal anastomoses of canine tissues. AB - OBJECTIVE: To compare intraluminal pressure at initial leakage (leakage pressure), leakage location, and maximum intraluminal pressure (MIP) for various staple line offset configurations of functional end-to-end stapled anastomosis (FEESA). SAMPLE: Grossly normal jejunal segments from 4 canine cadavers. PROCEDURES: 52 jejunal segments (4 control and 24 anastomosis constructs [2 segments/standard FEESA construct]) were prepared for testing. Segments were assigned to three 8-segment gastrointestinal anastomosis staple line offset groups: complete offset (CSO group), partial gastrointestinal anastomosis offset (PSO group), and no gastrointestinal anastomosis offset (NSO group). Results for leakage pressure, leakage location, and MIP were compared. RESULTS: Mean +/- SD leakage pressure differed significantly among all groups and was highest for the PSO group (34.4 +/- 3.7 mm Hg), followed by the CSO group (25.9 +/- 4.1 mm Hg) and the NSO group (18.8 +/- 1.5 mm Hg). Leakage location did not differ significantly among groups but was most commonly associated with the thoracoabdominal staple line. The MIP did not differ significantly among groups (PSO, 83.1 +/- 9.4 mm Hg; CSO, 81.7 +/- 6.7 mm Hg; and NSO, 58.5 +/- 7.7 mm Hg). CONCLUSIONS AND CLINICAL RELEVANCE: In this study, partial staple line offset leaked at a significantly higher pressure, which represented the greatest leakage protection of tested constructs. The thoracoabdominal staple line was more susceptible to leakage than was the gastrointestinal anastomosis staple line. Results suggested that surgeons should avoid FEESA with no staple line offset, strive for partial offset of the gastrointestinal anastomosis staples, and provide precise placement of the thoracoabdominal staple line. PMID- 26111096 TI - Effects of azathioprine, 6-mercaptopurine, and 6-thioguanine on canine primary hepatocytes. AB - OBJECTIVE: To investigate the cytotoxic effects of azathioprine, 6 mercaptopurine, and 6-thioguanine on canine hepatocytes. SAMPLE: Commercially available cryopreserved canine primary hepatocytes. PROCEDURES: The study consisted of 2 trials. In trial 1, hepatocytes were incubated with azathioprine, 6-mercaptopurine, or 6-thioguanine at 1 of 6 concentrations (0.468, 0.937, 1.875, 3.750, 7.500, or 15.000 MUmol/L) for 24, 48, or 72 hours. At each time, cell viability and lactate dehydrogenase (LDH) activity were determined for each thiopurine-concentration combination, and alanine aminotransferase (ALT) activity was determined for cells incubated with each thiopurine at a concentration of 15 MUmol/L. In trial 2, hepatocytes were incubated with azathioprine, 6 mercaptopurine, or 6-thioguanine at 1 of 3 concentrations (18.75, 37.50, or 75.00 MUmol/L) for 24 hours, after which the free glutathione concentration was determined for each thiopurine-concentration combination and compared with that for hepatocytes incubated without a thiopurine (control). RESULTS: Incubation of hepatocytes with each of the 3 thiopurines adversely affected cell viability in a time- and concentration-dependent manner; however, this decrease in cell viability was not accompanied by a concurrent increase in LDH or ALT activity. Likewise, free glutathione concentration for hepatocytes incubated for 24 hours with supratherapeutic thiopurine concentrations (> 18.75 MUmol/L) did not differ significantly from that of control cells. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that thiopurines adversely affected the viability of canine hepatocytes in a time- and concentration-dependent manner but had a nonsignificant effect on the LDH and ALT activities and free glutathione depletion of those hepatocytes. PMID- 26111097 TI - Constructing a High-Efficiency MoO3/Polyimide Hybrid Photocatalyst Based on Strong Interfacial Interaction. AB - A novel two-dimensional hybrid polymer photocatalyst black-MoO3/polyimide was synthesized by one-pot thermopolymerization of monomers, ammonium molybdate, and thiourea at mild temperatures. Thiourea and ammonium molybdate as fluxing agents promote the formation of black molybdenum oxide (BMO) on polyimide (PI) and enhance the crystallinity of PI. It is confirmed by X-ray photoelectron spectroscopy, electron paramagnetic resonance, and Fourier transform infrared that the strong interaction between BMO and PI leads to the formation of a Mo-N coordination bond through the coordination of N atoms of heptazine units to the unsaturated Mo atoms of BMO and results in a large number of Mo5+ cations in BMO/PI. UV-vis and photoluminescence reveal that the visible light absorption of BMO/PI was increased and the separation efficiency of photogenerated electron/hole obviously was significantly enhanced, which facilitates the improvement of the photocatalytic activity of BMO/PI. This work provides a new approach to synthesizing efficient inorganic-organic hybrid semiconductor photocatalysts. PMID- 26111098 TI - The lived experience of adults with ulcerative colitis. AB - AIMS AND OBJECTIVES: The purpose of this study was to explore the experiences of adults living with ulcerative colitis. BACKGROUND: Research to date has focused on the impact of inflammatory bowel disease, by analysing the responses of persons with ulcerative colitis and Crohn's disease collectively. This article addresses the dearth in literature by exploring the experiences of adults living with ulcerative colitis. DESIGN: An exploratory qualitative phenomenological design was used. METHOD: Semi-structured interviews were conducted with a purposive sample of 10 adults with ulcerative colitis. Verbatim transcripts were analysed using Interpretative Phenomenological Analysis. RESULTS: Three super ordinate themes emerged from the analysis: 'living with physical discomfort', 'emotional turmoil in living the experience' and 'social interactions'. CONCLUSION: The participants described a fundamental change in their lifestyle, as a result of physical discomfort and emotional turmoil. Misconceptions held regarding the causes of their disease, further compounded their negative emotional experience. RELEVANCE TO CLINICAL PRACTICE: It is of importance that health care professionals understand and explore the unique perspectives of individuals with ulcerative colitis. These perspectives relate to both physical and psychosocial issues. The needs and concerns of persons with ulcerative colitis can then guide the formulation and development of an individualised care plan. PMID- 26111099 TI - Experimental validation of the dual parameter beam quality specifier for reference dosimetry in flattening-filter-free (FFF) photon beams. AB - Removal of the flattening filter alters the energy spectrum of the photon beam such that current beam quality specifiers may not correctly account for this change when predicting the Spencer-Attix restricted water-to-air mass collision stopping-power ratio, (L/rho)(water)(air). Johnsson et al (2000 Phys. Med. Biol. 45 2733-45) proposed a beam quality specifier, known as the dual parameter beam quality specifier, which was calculated via Monte Carlo (MC) simulations using transmission data of primary kerma through two differing thicknesses of water material. Ceberg et al (2010 Med. Phys. 37 1164-8) extended this MC study to include relevant flattening filter free (FFF) beam data. Experimental investigations of this dual parameter beam quality specifier have not previously been published, therefore the purpose of this work was to validate that the dual parameter beam quality specifier could be measured experimentally for clinical beams (both with a flattening filter (WFF) and without (FFF)). Transmission measurements of primary kerma were performed by employing the setup outlined in Johnsson et al (1999 Phys. Med. Biol. 44 2445-50). Varying absorber thicknesses, in 5 cm increments from 5 to 40 cm, were placed at isocentre with the chamber positioned at an extended source to chamber distance of 300 cm. Experimental setup for TPR20,10 and %dd(10)x followed the methodology outlined in IAEA TRS398 (2004) and TG-51 (1999) with AAPM Addendum to TG-51 (2014) respectively. The maximum difference of (L/rho)(water)(air) determined using the different beam quality specifiers was found to be 0.35%. Analysis of the absorber thickness combination found that small thicknesses (<10 cm) for the first absorber and absorbers similar in thickness (<10 cm) should be avoided. Stopping-power ratios of the beams investigated were determined using three different beam quality specifiers. The results demonstrated successful experimental determination of the dual parameter beam quality specifier, indicating its potential as an alternate beam quality specifier for FFF beams. PMID- 26111101 TI - Climatic and biotic extreme events moderate long-term responses of above- and belowground sub-Arctic heathland communities to climate change. AB - Climate change impacts are not uniform across the Arctic region because interacting factors causes large variations in local ecosystem change. Extreme climatic events and population cycles of herbivores occur simultaneously against a background of gradual climate warming trends and can redirect ecosystem change along routes that are difficult to predict. Here, we present the results from sub Arctic heath vegetation and its belowground micro-arthropod community in response to the two main drivers of vegetation damage in this region: extreme winter warming events and subsequent outbreaks of the defoliating autumnal moth caterpillar (Epirrita autumnata). Evergreen dwarf shrub biomass decreased (30%) following extreme winter warming events and again by moth caterpillar grazing. Deciduous shrubs that were previously exposed to an extreme winter warming event were not affected by the moth caterpillar grazing, while those that were not exposed to warming events (control plots) showed reduced (23%) biomass from grazing. Cryptogam cover increased irrespective of grazing or winter warming events. Micro-arthropods declined (46%) following winter warming but did not respond to changes in plant community. Extreme winter warming and caterpillar grazing suppressed the CO2 fluxes of the ecosystem. Evergreen dwarf shrubs are disadvantaged in a future sub-Arctic with more stochastic climatic and biotic events. Given that summer warming may further benefit deciduous over evergreen shrubs, event and trend climate change may both act against evergreen shrubs and the ecosystem functions they provide. This is of particular concern given that Arctic heath vegetation is typically dominated by evergreen shrubs. Other components of the vegetation showed variable responses to abiotic and biotic events, and their interaction indicates that sub-Arctic vegetation response to multiple pressures is not easy to predict from single-factor responses. Therefore, while biotic and climatic events may have clear impacts, more work is needed to understand their net effect on Arctic ecosystems. PMID- 26111100 TI - AtRTD - a comprehensive reference transcript dataset resource for accurate quantification of transcript-specific expression in Arabidopsis thaliana. AB - RNA-sequencing (RNA-seq) allows global gene expression analysis at the individual transcript level. Accurate quantification of transcript variants generated by alternative splicing (AS) remains a challenge. We have developed a comprehensive, nonredundant Arabidopsis reference transcript dataset (AtRTD) containing over 74 000 transcripts for use with algorithms to quantify AS transcript isoforms in RNA seq. The AtRTD was formed by merging transcripts from TAIR10 and novel transcripts identified in an AS discovery project. We have estimated transcript abundance in RNA-seq data using the transcriptome-based alignment-free programmes Sailfish and Salmon and have validated quantification of splicing ratios from RNA seq by high resolution reverse transcription polymerase chain reaction (HR RT PCR). Good correlations between splicing ratios from RNA-seq and HR RT-PCR were obtained demonstrating the accuracy of abundances calculated for individual transcripts in RNA-seq. The AtRTD is a resource that will have immediate utility in analysing Arabidopsis RNA-seq data to quantify differential transcript abundance and expression. PMID- 26111102 TI - Clinical development of rivaroxaban: emerging new clinical evidences? AB - Rivaroxaban has proven efficacious in a variety of conditions. In fact, rivaroxaban has been approved for the prevention of venous thromboembolism after elective hip or knee replacement surgery, for the prevention and treatment of deep vein thrombosis and pulmonary embolism, for the prevention of stroke in patients with nonvalvular atrial fibrillation and for the prevention of atherothrombotic events after acute coronary syndrome with elevated cardiac biomarkers. However, clinical development of rivaroxaban is ongoing. Considering published and on-going randomized clinical trials, noninterventional studies and registries, over 275,000 patients are being analyzed. The aim of this review was to update the clinical development of rivaroxaban, including completed and ongoing studies not only randomized clinical trials, but also clinical practice studies. PMID- 26111103 TI - VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock. AB - BACKGROUND: Prospective studies on the incidence of VTE during severe sepsis and septic shock remain absent, hindering efficacy assessments regarding VTE prevention strategies in sepsis. METHODS: We prospectively studied 113 consecutively enrolled patients in the ICU with severe sepsis and septic shock at three hospitals. All patients provided informed consent. VTE thromboprophylaxis was recorded for all patients. Patients underwent ultrasonography and were followed for VTE prior to ICU discharge. All-cause 28-day mortality was recorded. Variables from univariate analyses that were associated with VTE (including central venous catheter [CVC] insertion, age, length of stay, and mechanical ventilation) were included in a multivariable logistic regression analysis using backward stepwise elimination to determine VTE predictors. RESULTS: Mean APACHE (Acute Physiology and Chronic Health Evaluation) II score was 18.2 +/- 7.0, and age was 50 +/- 18 years. Despite all patients receiving guideline-recommended thromboprophylaxis, the incidence of VTE was 37.2% (95% CI, 28.3-46.8). Most VTE events were clinically significant (defined as pulmonary embolism, proximal DVT, and/or symptomatic distal DVT) and associated with an increased length of stay (18.2 +/- 9.9 days vs 13.4 +/- 11.5 days, P < .05). Mortality was higher in patients with acute VTE but did not reach statistical significance. Insertion of a CVC and longer mechanical ventilation duration were significant VTE risk factors. VTE incidence did not differ by thromboprophylaxis type. CONCLUSIONS: To our knowledge this is the first multicenter prospective study to identify a high incidence of VTE in patients with severe sepsis and septic shock, despite the use of universal, guideline-recommended thromboprophylaxis. Our findings suggest that the systemic inflammatory milieu of sepsis may uniquely predispose patients with sepsis to VTE. More effective VTE prevention strategies are necessary in patients with sepsis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02353910; URL: www.clinicaltrials.gov. PMID- 26111105 TI - Plasma-derived C1-INH for managing hereditary angioedema in pediatric patients: A systematic review. AB - Presently, medications approved for children with Hereditary Angioedema (HAE) are extremely limited. This is especially the case for children under 12 years of age. For this reason we reviewed and summarized the data on treatment of children with HAE. Available data indicate that plasma derived C1-inhibitor is a safe, effective treatment option for HAE in pediatric patients, including those below 12 years of age. Other therapies are also appear safe for the under 12 year of age, but less data are available. Importantly, home-based treatment of HAE in this age group appears to be safe and effective and can improve quality of life. These findings support current HAE consensus guidelines which strongly recommend the use of plasma derived C1-inhibitor as a first-line treatment in children and encourage home and self-treatment. PMID- 26111106 TI - Images in Anesthesiology: Broncholithiasis: Images and Insight. PMID- 26111104 TI - A randomized phase 2 study comparing EC or CMF versus nab-paclitaxel plus capecitabine as adjuvant chemotherapy for nonfrail elderly patients with moderate to high-risk early breast cancer (ICE II-GBG 52). AB - BACKGROUND: Although greater than 40% of breast cancers occur in patients aged >=65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients. METHODS: Patients aged >=65 years with a Charlson comorbidity index <=2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m(2) and cyclophosphamide at a dose of 600 mg/m(2) intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m(2), methotrexate at a dose of 40 mg/m(2), and 5-fluorouracil at a dose of 600 mg/m(2) iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m(2) iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m(2) orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events. RESULTS: Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P<.001) with 1 and 5 deaths observed during treatment, respectively. Grade 3 to 5 adverse events were more frequent among patients treated with EC/CMF (90.9%) than among those treated with nPX (64.8%) (P<.001), with hematological toxicities being more frequent with EC/CMF (88.4% vs 22.3%; P<.001), but nonhematological toxicities (hand-foot syndrome, diarrhea, mucositis, fatigue, sensory neuropathy, thromboembolisms, and metabolic disorders) being more frequent with nPX (58.5% vs 18.7%; P<.001). None of the geriatric scores (Charlson comorbidity index, Vulnerable Elders Survey [VES-13], Instrumental Activities of Daily Living [IADL], and G8) independently predicted grade 3 to 5 toxic events or treatment discontinuations. No differences in survival between the treatment groups were observed after 22.8 months. CONCLUSIONS: Compared with EC/CMF, treatment with nPX led to more treatment discontinuations and nonhematological toxicities in elderly patients with moderate or high-risk breast cancer. PMID- 26111108 TI - Tagging Glycoproteins with Fluorescently Labeled GDP-Fucoses by Using alpha1,3 Fucosyltransferases. AB - Fucose-containing glycans mediate a variety of biological processes, but there is little information on reaction processes and mechanisms mediated by fucosyltransferases. We recently reported on fluorescently labeled GDP-beta-L fucose-ATTO 550, which enabled monitoring of alpha1,3-fucosyltransferase activity. Here we present an extension to the previously described results, based on the synthesis of a fluorescein-isothiocyanate (FITC)-labeled and two carboxyfluorescein-labeled (FAM-labeled) NDP-beta-L-fucose derivatives, and applied all four compounds in labeling of different glycoproteins with the aid of four different fucosyltransferases. The labeling processes were analyzed by in gel fluorescence and fluorescence polarization measurements. Comparison with the ATTO-labeled sugar revealed that the FITC-labeled fucose was the best of these substrates, and that the bacterial enzyme HP-FucT tolerated the fluorescent substrates better than human fucosyltransferases. PMID- 26111109 TI - Direct and Scalable Deposition of Atomically Thin Low-Noise MoS2 Membranes on Apertures. AB - Molybdenum disulfide (MoS2) flakes can grow beyond the edge of an underlying substrate into a planar freestanding crystal. When the substrate edge is in the form of an aperture, reagent-limited nucleation followed by edge growth facilitate direct and selective growth of freestanding MoS2 membranes. We have found conditions under which MoS2 grows preferentially across micrometer-scale prefabricated solid-state apertures in silicon nitride membranes, resulting in sealed membranes that are one to a few atomic layers thick. We have investigated the structure and purity of our membranes by a combination of atomic-resolution transmission electron microscopy, elemental analysis, Raman spectroscopy, photoluminescence spectroscopy, and low-noise ion-current recordings through nanopores fabricated in such membranes. Finally, we demonstrate the utility of fabricated ultrathin nanopores in such membranes for single-stranded DNA translocation detection. PMID- 26111110 TI - Conditional entropy in variation-adjusted windows detects selection signatures associated with expression quantitative trait loci (eQTLs). AB - BACKGROUND: Over the past 50,000 years, shifts in human-environmental or human human interactions shaped genetic differences within and among human populations, including variants under positive selection. Shaped by environmental factors, such variants influence the genetics of modern health, disease, and treatment outcome. Because evolutionary processes tend to act on gene regulation, we test whether regulatory variants are under positive selection. We introduce a new approach to enhance detection of genetic markers undergoing positive selection, using conditional entropy to capture recent local selection signals. RESULTS: We use conditional logistic regression to compare our Adjusted Haplotype Conditional Entropy (H|H) measure of positive selection to existing positive selection measures. H|H and existing measures were applied to published regulatory variants acting in cis (cis-eQTLs), with conditional logistic regression testing whether regulatory variants undergo stronger positive selection than the surrounding gene. These cis-eQTLs were drawn from six independent studies of genotype and RNA expression. The conditional logistic regression shows that, overall, H|H is substantially more powerful than existing positive-selection methods in identifying cis-eQTLs against other Single Nucleotide Polymorphisms (SNPs) in the same genes. When broken down by Gene Ontology, H|H predictions are particularly strong in some biological process categories, where regulatory variants are under strong positive selection compared to the bulk of the gene, distinct from those GO categories under overall positive selection. . However, cis-eQTLs in a second group of genes lack positive selection signatures detectable by H|H, consistent with ancient short haplotypes compared to the surrounding gene (for example, in innate immunity GO:0042742); under such other modes of selection, H|H would not be expected to be a strong predictor.. These conditional logistic regression models are adjusted for Minor allele frequency(MAF); otherwise, ascertainment bias is a huge factor in all eQTL data sets. Relationships between Gene Ontology categories, positive selection and eQTL specificity were replicated with H|H in a single larger data set. Our measure, Adjusted Haplotype Conditional Entropy (H|H), was essential in generating all of the results above because it: 1) is a stronger overall predictor for eQTLs than comparable existing approaches, and 2) shows low sequential auto-correlation, overcoming problems with convergence of these conditional regression statistical models. CONCLUSIONS: Our new method, H|H, provides a consistently more robust signal associated with cis-eQTLs compared to existing methods. We interpret this to indicate that some cis-eQTLs are under positive selection compared to their surrounding genes. Conditional entropy indicative of a selective sweep is an especially strong predictor of eQTLs for genes in several biological processes of medical interest. Where conditional entropy is a weak or negative predictor of eQTLs, such as innate immune genes, this would be consistent with balancing selection acting on such eQTLs over long time periods. Different measures of selection may be needed for variant prioritization under other modes of evolutionary selection. PMID- 26111111 TI - ESEM Detection of Foreign Metallic Particles inside Ameloblastomatous Cells. AB - Ameloblastoma is a borderline tumor of odontogenic origin, with a high recurrence rate and possible local aggressiveness. The etiopathogenetic factors involved in its occurrence are not still defined and our study has been precisely aimed to search for novel factors associated with its development. Sections cut from paraffin blocks, containing the representative specimens of 18 different ameloblastomas, collected in a 15-year period (1999-2014), have been observed by an environmental scanning electron microscope, in order to search micro- and nano sized particles and to identify their composition. In all the neoplastic cases, micro- and nano-sized metallic debris, differing in size and composition, have been detected inside the ameloblastomatous cells. On the contrary, the total absence of metallic particles in the healthy control cases has been emerged. Our results reveal a relationship between ameloblastoma and metallic particulate. The cigarette smoke and the routine dental practice appear the most probable source for the presence of these biopersistant inorganic particles inside the neoplastic cells. PMID- 26111112 TI - Diagnostic performance of diffusion-weighted MRI for detection of pelvic metastatic lymph nodes in patients with cervical cancer: a systematic review and meta-analysis. AB - In recent years, diffusion-weighted (DW) MRI has emerged as a new technique for detecting the pelvic lymph metastases in patients with cervical cancer. The aim of this meta-analysis was to assess the diagnostic value of DW imaging (DWI) for benign/malignant discrimination of pelvic lymph nodes (LNs). Studies about DWI for the detection of metastatic LNs were searched in the PubMed, EMBASE, Web of Science, EBSCO, the Cochrane Library and three Chinese databases. Based on the extracted data, we determined pooled sensitivities, specificities and diagnostic odds ratios (DORs) across studies, calculated positive and negative likelihood ratios (LRs) and constructed summary receiver operating characteristic curves with area under the curve (AUC) and Q* obtained. We also analysed the heterogeneity between studies based on subgroup analysis, threshold effect and publication bias. In total, 15 studies involving 1021 patients met the inclusion criteria. The pooled sensitivity, specificity and DOR of DWI were 0.86 [95% confidence interval (CI), 0.84-0.89], 0.84 (95% CI, 0.83-0.86) and 47.21 (95% CI, 25.67-86.81), respectively. LR syntheses yielded overall positive LR of 6.55 (95% CI, 4.77-9.01) and negative LR of 0.17 (95% CI, 0.12-0.23). The AUC and Q* index were 0.9384 and 0.8754, respectively. The heterogeneity was relatively high between studies; however, there was no evidence for threshold effect and publication bias. DWI is beneficial in the pelvic nodal assessment in patients with cervical cancer. Large-scale, high-quality trials with standard protocols are required to evaluate its clinical value for discrimination of metastatic from non-metastatic pelvic LNs in patients with cervical cancer. Advances in knowledge include providing evidence to assess the role of DWI in nodal staging of cervical cancer. PMID- 26111113 TI - The Extended Oxygen Window Concept for Programming Saturation Decompressions Using Air and Nitrox. AB - Saturation decompression is a physiological process of transition from one steady state, full saturation with inert gas at pressure, to another one: standard conditions at surface. It is defined by the borderline condition for time spent at a particular depth (pressure) and inert gas in the breathing mixture (nitrogen, helium). It is a delicate and long lasting process during which single milliliters of inert gas are eliminated every minute, and any disturbance can lead to the creation of gas bubbles leading to decompression sickness (DCS). Most operational procedures rely on experimentally found parameters describing a continuous slow decompression rate. In Poland, the system for programming of continuous decompression after saturation with compressed air and nitrox has been developed as based on the concept of the Extended Oxygen Window (EOW). EOW mainly depends on the physiology of the metabolic oxygen window--also called inherent unsaturation or partial pressure vacancy--but also on metabolism of carbon dioxide, the existence of water vapor, as well as tissue tension. Initially, ambient pressure can be reduced at a higher rate allowing the elimination of inert gas from faster compartments using the EOW concept, and maximum outflow of nitrogen. Then, keeping a driving force for long decompression not exceeding the EOW allows optimal elimination of nitrogen from the limiting compartment with half-time of 360 min. The model has been theoretically verified through its application for estimation of risk of decompression sickness in published systems of air and nitrox saturation decompressions, where DCS cases were observed. Clear dose-reaction relation exists, and this confirms that any supersaturation over the EOW creates a risk for DCS. Using the concept of the EOW, 76 man decompressions were conducted after air and nitrox saturations in depth range between 18 and 45 meters with no single case of DCS. In summary, the EOW concept describes physiology of decompression after saturation with nitrogen-based breathing mixtures. PMID- 26111114 TI - Intracorneal Inlays for the Correction of Ametropias. AB - Various materials have been placed in the corneal stroma to modify a spherical refractive error (usually hyperopic). As the surgical procedures evolved to simplify the insertion process so has the quality and biocompatibility of the implanted materials. Failures have been due to excessive inlay dimensions, bioincompatibility of the materials used, poor choice of test model, or combinations of the above. We present a thorough analysis of the history of the intracorneal inlay and the materials and techniques used up to and including the current materials and techniques available for the correction of spherical refractive errors. PMID- 26111115 TI - Sulfated and Glucuronated trans-Resveratrol Metabolites Regulate Chemokines and Sirtuin-1 Expression in U-937 Macrophages. AB - The natural anti-inflammatory compound resveratrol (RES) is metabolized upon ingestion. After dietary-scale doses, plasma concentrations of sulfated and glucuronated metabolites in humans exceed those of RES. The aim of this in vitro study was to assess the effect of physiological concentrations (1 MUM) of the most abundant RES metabolites (RES-3-O-sulfate, R3S; RES-disulfates, RdS; RES-3-O glucuronide, R3G; RES-4'-O-glucuronide, R4G) on genes and proteins involved in immune cell chemotaxis and inflammation (IL-8, MIP-1b, MCP-1, CCR1, CCR2, CXCR2, SIRT1) in a cell model of lipopolysaccharide (LPS)-activated U-937 macrophages. Levels of MCP-1 mRNA were comparably decreased after 3 h of treatment with R3S and RdS by -24.7 +/- 5.51 and -28.7 +/- 19.2%, respectively. LPS-induced MCP-1 protein release was reduced after 3 h of treatment by R3S (-20.8 +/- 13.9%) and RdS (-25.7 +/- 8.29%). After a 9 h treatment, RdS also inhibited IL-8 and MIP-1b protein release by -22.9 +/- 3.57 and -20.1 +/- 7.00%, respectively. Glucuronides showed differential effects after 6 h of treatment, with R4G up-regulating mRNA of MIP-1b (24.5 +/- 14.8%) and R3G and R4G down-regulating CXCR2 surface protein compared to cells treated with LPS alone, by -5.33 +/- 4.18 and -15.2 +/- 5.99%, respectively. On the contrary, R3G and R4G up-regulated SIRT1 mRNA by 22.7 +/- 17.9 and 22.8 +/- 16.9%, respectively, in LPS-stimulated U-937 macrophages, showing anti-inflammatory properties. In conclusion, sulfated RES metabolites show an interesting beneficial potential for attenuating inflammatory immune processes. PMID- 26111116 TI - CALCIUM-INDUCED LIPID PEROXIDATION IS MEDIATED BY RHODNIUS HEME-BINDING PROTEIN (RHBP) AND PREVENTED BY VITELLIN. AB - Lipid peroxidation is promoted by the quasi-lipoxygenase (QL) activity of heme proteins and enhanced by the presence of free calcium. Unlike mammalian plasma, the hemolymph of Rhodnius prolixus, a vector of Chagas disease, contains both a free heme-binding protein (RHBP) and circulating lipoproteins. RHBP binds and prevents the heme groups of the proteins from participating in lipid peroxidation reactions. Herein, we show that despite being bound to RHBP, heme groups promote lipid peroxidation through a calcium-dependent QL reaction. This reaction is readily inhibited by the presence of ethylene glycol tetraacetic acid (EGTA), the antioxidant butylated hydroxytoluene or micromolar levels of the main yolk phosphoprotein vitellin (Vt). The inhibition of lipid peroxidation is eliminated by the in vitro dephosphorylation of Vt, indicating that this reaction depends on the interaction of free calcium ions with negatively charged phosphoamino acids. Our results demonstrate that calcium chelation mediated by phosphoproteins occurs via an antioxidant mechanism that protects living organisms from lipid peroxidation. PMID- 26111117 TI - Prospective study of articular manifestations in Behcet's disease: five-year report. AB - AIM: To evaluate different aspects of articular involvements (prevalence, types, relation to extra-articular manifestations, etc.) in Iranian patients with Behcet's disease (BD). METHODS: In a prospective study, all patients with BD attending an outpatient BD clinic were enrolled. The type of articular involvements (peripheral or axial), involved joints, duration of attacks and their relation to extra-articular manifestations, human leukocyte antigen (HLA) B5 and HLA-B27 were evaluated. Data analysis was done by using descriptive statistical indices such as mean and confidence interval. The comparisons were done by chi-square test. RESULTS: In a 5-year period, 2312 patients were recruited. Musculoskeletal manifestations were recorded in 430 patients (190 without previous history of these involvements). The remaining 1882 patients showed no musculoskeletal involvements, of which 753 had past histories of musculoskeletal manifestations. The 5-year incidence rate was 18.6%, and the prevalence rate was 51.2%. History of previous musculoskeletal involvements has no effect in its new development (P = 0.2). Arthritis was the most common type of involvement (289/430, 67%). The most frequent pattern was monoarthritis (191/289, 66%), and the most frequent involved joints were knees (147/289, 50.9%). The arthritic attacks were unilateral in 82.4% of cases. Ankylosing spondylitis was seen in 44/430 (10.2%). There was no association between HLA-B5 or HLA-B27 and any type of musculoskeletal involvements (P > 0.5). Pseudofolliculitis was the only extra-articular manifestation related to arthritic attacks (P = 0.046). CONCLUSION: Musculoskeletal involvement is a common manifestation of BD seen in more than half of patients. Acute knee monoarthritis was the most common pattern of articular involvement in BD. PMID- 26111119 TI - Highly Rigid Labdane-Type Diterpenoids from a Chinese Liverwort and Light-Driven Structure Diversification. AB - Two unprecedented labdane-type diterpenoids haplomintrins A (1) and B (2) with six rings system were isolated from a Chinese liverwort Haplomitrium mnioides. Light-driven reaction of homologous haplomitrenonolides C (6), A (4), and D (3) afforded haplomintrins A-C (1, 2, and 7), respectively, while 4 was converted to more complex congeners haplomintrins D-G (8-11) through intramolecular cyclization. Formation of 1 and 2 from compounds 6 and 4, respectively, helps us to postulate that a photochemical reaction is involved in the biosynthetic pathway. These structure features can be used as molecular markers of H. mnioides, and their allelopathic effects are also preliminarily tested. PMID- 26111118 TI - Assessing the Impact of Capture on Wild Animals: The Case Study of Chemical Immobilisation on Alpine Ibex. AB - The importance of capturing wild animals for research and conservation projects is widely shared. As this activity continues to become more common, the need to assess its negative effects increases so as to ensure ethical standards and the validity of research results. Increasing evidence has revealed that indirect (physiological and behavioural) effects of capture are as important as direct risks (death or injury) and that different capture methodologies can cause heterogeneous effects. We investigated the influence of chemical immobilisation on Alpine ibex (Capra ibex): during the days following the capture we collected data on spatial behaviour, activity levels of both males and females, and male hormone levels. Moreover, we recorded the reproductive status of each marked female during the breeding seasons of 15 years. Then, by several a priori models we investigated the effects of the capture taking into account biological factors and changes in environmental conditions. Our results showed that chemical immobilisation did not affect either spatial behaviour (for both males and females) or male hormone levels, though both sexes showed reduced activity levels up to two days after the capture. The capture did not significantly affect the likelihood for a female to give birth in the following summer. Our findings highlighted the scarce impact of chemical immobilisation on ibex biology, as we detected alteration of activity levels only immediately after the capture if compared to the following days (i.e., baseline situation). Hence, the comparison of our findings with previous research showed that our methodology is one of the less invasive procedures to capture large mammals. Nonetheless, in areas characterised by high predator density, we suggest that animals released be carefully monitored for some hours after the capture. Moreover, researchers should avoid considering data collected during the first days after the manipulation in order to avoid biased information. PMID- 26111120 TI - Seeing and Holding Baby: Systematic Review of Clinical Management and Parental Outcomes After Stillbirth. AB - BACKGROUND: In 2009 there were an estimated 2.6 million stillbirths worldwide. In the United States, a 2007 systematic review found little consensus about professional behaviors perceived by parents to be most helpful or most distressing. In the United Kingdom, a bereaved parents' organization has highlighted discordance between parental views and clinical guidelines that recommend clinicians do not encourage parents to see and hold their baby. The objective of this review was to identify and synthesize available research reporting parental outcomes relating to seeing and holding. METHODS: We undertook a systematic review. We included studies of any design, reporting parental experiences and outcomes. Electronic searches (PubMed and PsychINFO) were conducted in January 2014. Three authors independently screened and assessed the quality of the studies before abstracting data and undertaking thematic analysis. RESULTS: We reviewed 741 records and included 23 studies (10 quantitative, 12 qualitative, and 1 mixed-method). Twenty-one studies suggested positive outcomes for parents who saw or held their baby. Increased psychological morbidity was associated with current pregnancy, choice not to see their baby, lack of time with their baby and/or insufficient mementos. Three themes were formulated "positive effects of contact within a traumatic life event," "importance of role of health professionals," and "impact on mothers and fathers: similarities and differences." CONCLUSIONS: Stillbirth is a risk factor for increased psychological morbidity. Parents seeing and holding their stillborn baby can be beneficial to their future well-being. Since 2007, there has been a proliferation of studies that challenge clinical guidelines recommending that clinicians do not encourage parental contact. PMID- 26111121 TI - Spontaneous corynebacterium spondylodiskitis in an immunocompetent patient: A case report and literature review. AB - BACKGROUND: Spontaneous Corynebacterium spondylodiskitis is an unusual diagnosis of spondylodiskitis, especially in healthy patients without any significant past medical history. MATERIALS AND METHODS: We describe the case of a 78-year-old man with progressive low back pain for 3 months, irradiating down the lower limbs through L5 and S1 root pathways, associated with distal muscle weakness in both lower limbs. He had no history of trauma or medical problems. Laboratory investigation revealed elevated serum C-reactive protein (CRP) and erythrocyte sedimentation rate, without leukocytosis. The magnetic resonance findings demonstrated an extensive L5-S1 spondylodiskitis and L4-L5 anterolisthesis. Prior to spinopelvic fixation and posterolateral fusion, a substantial debridement was performed. The obtained tissue samples were submitted to pathological and microbiological studies, which identified Corynebacterium infection. RESULTS: One month after surgery, the pain diminished dramatically and the CRP titer diminished significantly. CONCLUSION: Although cases are very rare, spontaneous Corynebacterium spondylodiskitis, with substantial invasion of the spine, may develop in patients lacking any history of medical or surgical problems. PMID- 26111122 TI - Detection of tick-borne Anaplasma bovis, Anaplasma phagocytophilum and Anaplasma centrale in Spain. AB - The genus Anaplasma (Rickettsiales: Anaplasmataceae) includes species of medical and veterinary importance. The presence of Anaplasma spp. in ticks from birds, as well as in Haemaphysalis punctata (Ixodida: Ixodidae) specimens collected from cattle and vegetation in northern Spain was investigated. A total of 336 ticks from birds [174 Ixodes frontalis (Ixodida: Ixodidae), 108 H. punctata, 34 Hyalomma marginatum (Ixodida: Ixodidae), 17 Ixodes ricinus (Ixodida: Ixodidae) and three Ixodes spp.], and 181 H. punctata specimens collected from cattle (n = 71) and vegetation (n = 110) were analysed. Anaplasma bovis was detected in five H. punctata, including two from birds (1.9%) and three from vegetation (2.7%). Four I. frontalis (2.3%) (one co-infected with 'Candidatus Midichloria mitochondrii') and one I. ricinus (5.9%) removed from birds, as well as four H. punctata (5.6%) collected from cattle showed Anaplasma phagocytophilum infection. In addition, Anaplasma centrale was found in two H. punctata, one from a cow (1.4%) and the other from vegetation (0.9%). This study represents the first evidence of the presence of A. bovis in European ticks, and reports the first detection of A. bovis and A. centrale in H. punctata, and the first finding of A. phagocytophilum and 'Ca. Midichloria mitochondrii' in I. frontalis. PMID- 26111124 TI - Clostridium difficile Infection. PMID- 26111123 TI - Exonuclease III-Assisted Target Recycling Amplification Coupled with Liposome Assisted Amplification: One-Step and Dual-Amplification Strategy for Highly Sensitive Fluorescence Detection of DNA. AB - Detection of ultralow concentration of specific DNA sequence is a central challenge in the early diagnosis of gene-related disease and biodefense application. Herein, we report a dual-amplification strategy for highly sensitive fluorescence detection of DNA. In this proposed strategy, a dumbbell-shaped DNA probe is designed to integrate target binding, magnetic separation, and signal response. In the presence of specific DNA target, the multifunctional dumbbell probe can initiate exonuclease III (Exo III)-aided target recycling amplification, and, in the meantime, generate a large number of fluorescein (FAM) encapsulated liposomes. The developed method offers very high sensitivity due to primary amplification via numerous FAM from a liposome and secondary amplification via target recycling amplification. The detection limit of the proposed method can reach 4 aM, which is much lower than that of the Exo III aided target recycling technique applied for DNA quantification without FAM encapsulated liposomes amplification. Moreover, the dual-signal amplification process can be completed one-step in this system. Therefore, this method provides a simple, isothermal, and low-cost approach for sensitive detection of DNA and holds a great potential for early diagnosis in gene-related diseases. PMID- 26111125 TI - Effect of Teduglutide, a Glucagon-like Peptide 2 Analog, on Citrulline Levels in Patients With Short Bowel Syndrome in Two Phase III Randomized Trials. AB - OBJECTIVES: In clinical trials, treatment with the glucagon-like peptide 2 analog teduglutide was associated with improved fluid and nutrient absorption and increased intestinal villus height and crypt depth in patients with short bowel syndrome (SBS). Plasma citrulline, an amino acid produced by enterocytes, is considered a measure of enterocyte mass. This analysis assessed changes in plasma citrulline levels in patients with SBS in 2 phase III clinical studies of teduglutide. METHODS: Both teduglutide studies (0.05 or 0.10 mg/kg/day in CL0600 004 and 0.05 mg/kg/day in CL0600-020) were phase III, 24-week, double-blind, and placebo controlled. Plasma citrulline levels were analyzed and validated by liquid chromatography coupled to tandem mass spectrometry. RESULTS: In both the CL0600-004 and CL0600-020 studies, change in mean plasma citrulline concentrations at Week 24 vs. baseline was significantly greater with teduglutide compared with placebo (10.9 (0.05-mg/kg/day dose) and 15.7 (0.10-mg/kg/day dose) vs. 2.0 MUmol/L and 20.6 vs. 0.7 MUmol/L, respectively, for each study (P<=0.0001 for each comparison with placebo)). Teduglutide treatment was associated with reductions from baseline in PS (parenteral support) volume requirements; however, a significant correlation between PS reduction and increase in plasma citrulline at Week 24 was observed in only one out of the three teduglutide treatment groups. CONCLUSIONS: In 2 phase III studies, patients receiving teduglutide had significant increases in plasma citrulline at Week 24 compared with patients receiving placebo. Increases in plasma citrulline concentrations likely reflect enterocyte mass expansion, but no clear correlation was detected between change in plasma citrulline and change in weekly PS volume. PMID- 26111126 TI - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Rising TAK 438 (Vonoprazan) Doses in Healthy Male Japanese/non-Japanese Subjects. AB - OBJECTIVES: To evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-438 (vonoprazan, a potassium-competitive acid blocker) in healthy male subjects. METHODS: In two phase I, randomized, double-blind, placebo controlled, single rising-dose studies, healthy male subjects (Japan N=84; UK N=63) received a single TAK-438 dose (1-120 mg in Japan and 1-40 mg in the UK). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (intragastric pH). RESULTS: Plasma concentration-time profiles of TAK-438 at all dose levels showed rapid absorption (median Tmax up to 2 h). Estimated mean elimination half-life was up to 9 h. Exposure was slightly greater than dose proportional. No clear difference in TAK-438 pharmacokinetics was observed between Japanese and non-Japanese subjects. Acid suppression was dose dependent and similar in both studies. The 24-h intragastric pH >=4 holding time ratio with 40 mg TAK-438 was 92% in Japan and 87% in the UK. TAK-438 was well tolerated, with no adverse events reported in Japanese subjects; 10 of 63 UK subjects experienced 12 treatment-emergent adverse events (non-serious). Increases in serum gastrin and pepsinogen I and II concentrations were observed at doses >=10 mg, but there were no changes in alanine aminotransferase concentrations. CONCLUSIONS: Single oral doses of TAK-438 20-120 mg caused rapid, profound, and 24-h suppression of gastric acid secretion in healthy male subjects, regardless of geographical region, and TAK-438 was well tolerated at all doses studied, making it a potential alternative to proton pump inhibitors for the treatment of acid-related disorders. PMID- 26111129 TI - Osteopathic Manipulative Therapy in Women With Postpartum Low Back Pain and Disability: A Pragmatic Randomized Controlled Trial. AB - CONTEXT: Persistent low back pain (LBP) is a common complaint among women during and after pregnancy, and its effects on quality of life can be disabling. OBJECTIVE: To evaluate the effectiveness of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) in women with persistent LBP and functional disability after childbirth. METHODS: A pragmatic randomized controlled trial was conducted among a sample of women with a history of pregnancy-related LBP for at least 3 months after delivery. Participants were identified from the general population in Germany. By means of external randomization, women were allocated to an OMTh group and a waitlist control group. Osteopathic manipulative therapy was provided 4 times at intervals of 2 weeks, with a follow-up after 12 weeks. The OMTh was tailored to each participant and based on osteopathic principles. The participants allocated to the control group did not receive OMTh during the 8-week study; rather, they were put on a waiting list to receive OMTh on completion of the study. Further, they were not allowed to receive any additional treatment (ie, medication, physical therapy, or other sources of pain relief) during the study period. The main outcome measures were pain intensity as measured by a visual analog scale and the effect of LBP on daily activities as assessed by the Oswestry Disability Index (ODI). RESULTS: A total of 80 women aged between 23 and 42 years (mean [SD], 33.6 [4.5] years) were included in the study, with 40 in the OMTh group and 40 in the control group. Pain intensity decreased in the OMTh group from 7.3 to 2.0 (95% CI, 4.8-5.9; P<.001) and in the control group from 7.0 to 6.5 (95% CI, -0.2 to -0.9; P=.005). The between-group comparison of changes revealed a statistically significant improvement in pain intensity in the OMTh group (between-group difference of means, 4.8; 95% CI, 4.1-5.4; P<.001) and level of disability (between-group difference of means, 10.6; 95% CI, 9.9-13.2; P<.005). The follow-up assessment in the OMTh group (n=38) showed further improvement. CONCLUSION: During 8 weeks, OMTh applied 4 times led to clinically relevant positive changes in pain intensity and functional disability in women with postpartum LBP. Further studies that include prolonged follow-up periods are warranted. (German Clinical Trials Register: DRKS00006280.). PMID- 26111130 TI - Diabetes Mellitus Coding Training for Family Practice Residents. AB - CONTEXT: Although physicians regularly use numeric coding systems such as the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) to describe patient encounters, coding errors are common. One of the most complicated diagnoses to code is diabetes mellitus. The ICD-9-CM currently has 39 separate codes for diabetes mellitus; this number will be expanded to more than 50 with the introduction of ICD-10-CM in October 2015. OBJECTIVE: To assess the effect of a 1-hour focused presentation on ICD-9-CM codes on diabetes mellitus coding. METHODS: A 1-hour focused lecture on the correct use of diabetes mellitus codes for patient visits was presented to family practice residents at Doctors Hospital Family Practice in Columbus, Ohio. To assess resident knowledge of the topic, a pretest and posttest were given to residents before and after the lecture, respectively. Medical records of all patients with diabetes mellitus who were cared for at the hospital 6 weeks before and 6 weeks after the lecture were reviewed and compared for the use of diabetes mellitus ICD-9 codes. RESULTS: Eighteen residents attended the lecture and completed the pretest and posttest. The mean (SD) percentage of correct answers was 72.8% (17.1%) for the pretest and 84.4% (14.6%) for the posttest, for an improvement of 11.6 percentage points (P<=.035). The percentage of total available codes used did not substantially change from before to after the lecture, but the use of the generic ICD-9-CM code for diabetes mellitus type II controlled (250.00) declined (58 of 176 [33%] to 102 of 393 [26%]) and the use of other codes increased, indicating a greater variety in codes used after the focused lecture. CONCLUSION: After a focused lecture on diabetes mellitus coding, resident coding knowledge improved. Review of medical record data did not reveal an overall change in the number of diabetic codes used after the lecture but did reveal a greater variety in the codes used. PMID- 26111131 TI - Heart Failure With Preserved Ejection Fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is a complex clinical condition. Initially called diastolic heart failure, it soon became clear that this condition is more than the opposite side of systolic heart failure. It is increasingly prevalent and lethal. Currently, HFpEF represents more than 50% of heart failure cases and shares a 90-day mortality and readmission rate similar to heart failure with reduced ejection fraction. Heart failure with preserved ejection fraction is best considered to be a systemic disease. From a cardiovascular standpoint, it is not just a stiff ventricle. A stiff ventricle combined with a stiff arterial and venous system account for the clinical manifestations of flash pulmonary edema and the marked changes in renal function or systemic blood pressure with minor changes in fluid volume status. No effective pharmacologic treatments are available for patients with HFpEF, but an approach to the musculoskeletal system has merit: the functional limitations and exercise intolerance that patients experience are largely due to abnormalities of peripheral vascular function and skeletal muscle dysfunction. Regular exercise training has strong objective evidence to support its use to improve quality of life and functional capacity for patients with HFpEF. This clinical review summarizes the current evidence on the pathophysiologic aspects, diagnosis, and management of HFpEF. PMID- 26111132 TI - Improving Resident Performance Through a Simulated Rapid Response Team: A Pilot Study. AB - BACKGROUND: The Joint Commission requires hospitals to develop systems in which a team of clinicians can rapidly recognize and respond to changes in a patient's condition. The rapid response team (RRT) concept has been widely adopted as the solution to this mandate. The role of house staff in RRTs and the impact on resident education has been controversial. At Christiana Care Health System, eligible residents in their second through final years lead the RRTs. OBJECTIVE: To evaluate the use of a team-based, interdisciplinary RRT training program for educating and training first-year residents in an effort to improve global RRT performance before residents start their second year. METHODS: This pilot study was administered in 3 phases. Phase 1 provided residents with classroom-based didactic sessions using case-based RRT scenarios. Multiple choice examinations were administered, as well as a confidence survey based on a Likert scale before and after phase 1 of the program. Phase 2 involved experiential training in which residents engaged as mentored participants in actual RRT calls. A qualitative survey was used to measure perceived program effectiveness after phase 2. In phase 3, led by senior residents, simulated RRTs using medical mannequins were conducted. Participants were divided into 5 teams, in which each resident would rotate in the roles of leader, nurse, and respiratory therapist. This phase measured resident performance with regard to medical decision making, data gathering, and team behaviors during the simulated RRT scenarios. Performance was scored by an attending and a senior resident. RESULTS: A total of 18 residents were eligible (N=18) for participation. The average multiple choice test score improved by 20% after didactic training. The average confidence survey score before training was 3.44 out of 5 (69%) and after training was 4.13 (83%), indicating a 14% improvement. High-quality team behaviors correlated with medical decision making (0.92) more closely than did high-quality data gathering (0.11). This difference narrowed during high-pressure scenarios (0.84 and 0.72, respectively). CONCLUSION: Our data suggest that resident training using a team based, interdisciplinary RRT training program may improve resident education, interdisciplinary team-based dynamics, and global RRT performance. In turn, data gathering and medical decision making may be enhanced, which may result in better patient outcomes during RRT scenarios. PMID- 26111133 TI - Effects of Osteopathic Manipulative Treatment on Diabetic Gastroparesis. AB - As the number of diagnoses of diabetes mellitis continues to increase, so does the incidence of diabetic complications, such as gastroparesis. The current case report examines the effect of osteopathic manipulative treatment (OMT) on the symptoms of diabetic gastroparesis in a patient with type 1 diabetes mellitus. After a prescribed regimen of OMT, the patient's Gastroparesis Cardinal Symptom Index score improved from 13 to 8, and his hospitalization stays decreased from once every 6 to 8 weeks to once in 6 months. After 6 sessions of OMT, the patient experienced a reduction in and subsequent relief of diabetic gastroparesis symptoms and improved quality of life. The role of OMT needs to be further investigated as a cost-effective adjunctive treatment for patients with diabetic gastroparesis. PMID- 26111140 TI - Chorea, Hyperglycemia, Basal Ganglia Syndrome. PMID- 26111141 TI - The Act of Listening: Perspective of a Hard-of-Hearing Medical Student. PMID- 26111142 TI - Pheochromocytoma Diagnosis After an Abnormal Stress Test: Case Report and Review of the Literature. AB - Pheochromocytoma is a rare adrenal gland tumor that is often difficult for physicians to diagnose because of its general, nonspecific complaints. Diagnosis is particularly difficult in patients with neurofibromatosis 1, because pheochromocytoma in these patients will mimic other cardiovascular abnormalities. The authors report the case of a 60-year-old woman with an extensive history of hyperlipidemia, malignant hypertension, coronary artery disease, and neurofibromatosis 1 who was referred for an elective cardiac catheterization as a result of an abnormal stress test. The patient returned to the hospital 3 days after the procedure complaining of increased angina and palpitations. While hospitalized, she developed severe episodic hypertension. A computed tomographic scan revealed bilateral adrenal masses. Findings of biochemical and imaging evaluation confirmed the diagnosis of bilateral pheochromocytoma. Early screening of pheochromocytomas in high-risk populations is essential for prompt diagnosis and successful management. PMID- 26111143 TI - Health Behavior Theory for Pressure Ulcer Prevention: Root-Cause Analysis Project in Critical Care Nursing. AB - The purpose of this project was to use a behavioral theory to examine pressure ulcer prevention by nurses in a critical care setting. A root-cause analysis approach was used, including an integrative literature review, operationalization of behavioral constructs into a survey, and root-cause analysis application in a cardiovascular intensive care unit. This article highlights an innovative approach to quality improvement in critical care. PMID- 26111144 TI - Are Lipases Still Important Biocatalysts? A Study of Scientific Publications and Patents for Technological Forecasting. AB - The great potential of lipases is known since 1930 when the work of J. B. S. Haldane was published. After eighty-five years of studies and developments, are lipases still important biocatalysts? For answering this question the present work investigated the technological development of four important industrial sectors where lipases are applied: production of detergent formulations; organic synthesis, focusing on kinetic resolution, production of biodiesel, and production of food and feed products. The analysis was made based on research publications and patent applications, working as scientific and technological indicators, respectively. Their evolution, interaction, the major players of each sector and the main subject matters disclosed in patent documents were discussed. Applying the concept of technology life cycle, S-curves were built by plotting cumulative patent data over time to monitor the attractiveness of each technology for investment. The results lead to a conclusion that the use of lipases as biocatalysts is still a relevant topic for the industrial sector, but developments are still needed for lipase biocatalysis to reach its full potential, which are expected to be achieved within the third, and present, wave of biocatalysis. PMID- 26111145 TI - Treatment decisions based on scalar and functional baseline covariates. AB - The amount and complexity of patient-level data being collected in randomized controlled trials offer both opportunities and challenges for developing personalized rules for assigning treatment for a given disease or ailment. For example, trials examining treatments for major depressive disorder are not only collecting typical baseline data such as age, gender, or scores on various tests, but also data that measure the structure and function of the brain such as images from magnetic resonance imaging (MRI), functional MRI (fMRI), or electroencephalography (EEG). These latter types of data have an inherent structure and may be considered as functional data. We propose an approach that uses baseline covariates, both scalars and functions, to aid in the selection of an optimal treatment. In addition to providing information on which treatment should be selected for a new patient, the estimated regime has the potential to provide insight into the relationship between treatment response and the set of baseline covariates. Our approach can be viewed as an extension of "advantage learning" to include both scalar and functional covariates. We describe our method and how to implement it using existing software. Empirical performance of our method is evaluated with simulated data in a variety of settings and also applied to data arising from a study of patients with major depressive disorder from whom baseline scalar covariates as well as functional data from EEG are available. PMID- 26111146 TI - Identification of Genetic Loci Associated with Quality Traits in Almond via Association Mapping. AB - To design an appropriate association study, we need to understand population structure and the structure of linkage disequilibrium within and among populations as well as in different regions of the genome in an organism. In this study, we have used a total of 98 almond accessions, from five continents located and maintained at the Centro de Investigacion y Tecnologia Agroalimentaria de Aragon (CITA; Spain), and 40 microsatellite markers. Population structure analysis performed in 'Structure' grouped the accessions into two principal groups; the Mediterranean (Western-Europe) and the non-Mediterranean, with K = 3, being the best fit for our data. There was a strong subpopulation structure with linkage disequilibrium decaying with increasing genetic distance resulting in lower levels of linkage disequilibrium between more distant markers. A significant impact of population structure on linkage disequilibrium in the almond cultivar groups was observed. The mean r2 value for all intra-chromosomal loci pairs was 0.040, whereas, the r2 for the inter-chromosomal loci pairs was 0.036. For analysis of association between the markers and phenotypic traits, five models comprising both general linear models and mixed linear models were selected to test the marker trait associations. The mixed linear model (MLM) approach using co-ancestry values from population structure and kinship estimates (K model) as covariates identified a maximum of 16 significant associations for chemical traits and 12 for physical traits. This study reports for the first time the use of association mapping for determining marker-locus trait associations in a world-wide almond germplasm collection. It is likely that association mapping will have the most immediate and largest impact on the tier of crops such as almond with the greatest economic value. PMID- 26111147 TI - Decreased Expression of CoREST1 and CoREST2 Together with LSD1 and HDAC1/2 during Neuronal Differentiation. AB - CoREST (CoREST1, rcor1) transcriptional corepressor together with the histone demethylase LSD1 (KDM1A) and the histone deacetylases HDAC1/2 form LSD1-CoREST HDAC (LCH) transcriptional complexes to regulate gene expression. CoREST1 belong to a family that also comprises CoREST2 (rcor2) and CoREST3 (rcor3). CoREST1 represses the expression of neuronal genes during neuronal differentiation. However, the role of paralogs CoREST2 and CoREST3 in this process is just starting to emerge. Here, we report the expression of all CoRESTs and partners LSD1 and HDAC1/2 in two models of neuronal differentiation: Nerve-Growth-Factor (NGF)-induced neuronal phenotype of PC12 cells, and in vitro maturation of embryonic rat cortical neurons. In both models, a concomitant and gradual decrease of LSD1, HDAC1, HDAC2, CoREST1, and CoREST2, but not CoREST3 was observed. As required by the study, full-length rat rcor1 gene was identified using in silico analysis of available rat genome. The work was also complemented by the analysis of rat RNA-seq databases. The analysis showed that all CoRESTs, including the identified four splicing variants of rat CoREST3, display a wide expression in adult tissues. Moreover, the analysis of RNA-seq databases showed that CoREST2 displays a higher expression than CoREST1 and CoREST3 in the mature brain. Immunofluorescent assays and immunoblots of adult rat brain showed that all CoRESTs are present in both glia and neurons. Regarding functional partnership, CoREST2 and CoREST3 interact with all LSD1 splicing variants. In conclusion, neuronal differentiation is accompanied by decreased expression of all core components of LCH complexes, but not CoREST3. The combination of the differential transcriptional repressor capacity of LCH complexes and variable protein levels of its different components should result in a finely tuned gene expression during neuronal differentiation and in the adult brain. PMID- 26111149 TI - Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. MATERIALS AND METHODS: To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. RESULTS: Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). CONCLUSIONS: Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs. PMID- 26111148 TI - Computer-Aided Prediction of Long-Term Prognosis of Patients with Ulcerative Colitis after Cytoapheresis Therapy. AB - Cytoapheresis (CAP) therapy is widely used in ulcerative colitis (UC) patients with moderate to severe activity in Japan. The aim of this study is to predict the need of operation after CAP therapy of UC patients on an individual level using an artificial neural network system (ANN). Ninety UC patients with moderate to severe activity were treated with CAP. Data on the patients' demographics, medication, clinical activity index (CAI) and efficacy of CAP were collected. Clinical data were divided into training data group and validation data group and analyzed using ANN to predict individual outcomes. The sensitivity and specificity of predictive expression by ANN were 0.96 and 0.97, respectively. Events of admission, operation, and use of immunomodulator, and efficacy of CAP were significantly correlated to the outcome. Requirement of operation after CAP therapy was successfully predicted by using ANN. This newly established ANN strategy would be used as powerful support of physicians in the clinical practice. PMID- 26111150 TI - Association of the ADRB2 (rs2053044) polymorphism and angiotensin-converting enzyme-inhibitor blood pressure response in the African American Study of Kidney Disease and Hypertension. AB - AIM/OBJECTIVES/BACKGROUND: Hypertension is a risk factor for cardiovascular and kidney disease and is most prevalent in African-American adults. The renin angiotensin-aldosterone system is integral in blood pressure regulation; angiotensin-converting enzyme inhibitors such as ramipril are first-line treatment options. As decreases in angiotensin result in catecholamine release, beta-adrenergic receptor (ADRB) polymorphisms may influence blood pressure response to ramipril. METHODS: Associations between ADRB polymorphisms and blood pressure response to ramipril were analyzed in the African American Study of Kidney Disease and Hypertension, a randomized clinical trial. A total of 336 participants were included in this analysis. Six polymorphisms were analyzed here: (a) ADRB1 rs1801252 (Ser49Gly) and rs1801253 (Gly389Arg); and (b) ADRB2 rs2053044, rs1042711, rs1042713 (Arg16Gly), and rs1042714 (Gln27Glu). Time to reach a mean arterial pressure (MAP) of 107 mmHg within the first 60 days after randomization was studied using Kaplan-Meier and Cox proportional hazards modeling for univariate and adjusted analyses. RESULTS: Genotypes at rs2053044, upstream from the ADRB2 5' untranslated region, were associated with time to reach target MAP among those randomized to the usual treatment group. Participants with the GG genotype achieved target MAP on average 12.2 days (38.1%) later than in comparison with those with the A allele (P=0.01). After adjusting for covariates, those with the AA/AG genotype had 2.09 greater odds of reaching MAP of 107 mmHg or less within 60 days of treatment in comparison with those with a GG genotype (hazard ratio=2.09, 95% confidence interval=1.21-3.60). CONCLUSION: Results suggest that ADRB2 rs2053044 genotypes may be a determinant of blood pressure response to ramipril. Additional studies are needed to clarify the effect of rs2053044 and other 5' untranslated region polymorphisms on gene expression and blood pressure response to angiotensin-converting enzyme inhibitors. PMID- 26111152 TI - Genetic determinants of metamizole metabolism modify the risk of developing anaphylaxis. AB - Metamizole is a NSAID that has been banned in several countries because of its toxicity. It is often involved in selective hypersensitivity reactions and most hypersensitivity patients develop anaphylaxis. Metamizole is rapidly metabolized, and metabolic profiles are related to genetic factors. We analyzed whether genetic determinants of metamizole metabolism influence the risk of developing hypersensitivity in 265 patients diagnosed with hypersensitivity to metamizole and 362 healthy individuals who tolerated metamizole. Slow acetylation is associated with an increased risk of developing selective hypersensitivity to metamizole [odds ratio for slow alleles=2.17 (95% confidence interval=1.44-3.27); P=0.00016], and particularly anaphylaxis [odds ratio=4.77 (95% confidence interval=2.28-9.98); P=0.000006], with a significant gene-dose effect. The association was not identified in patients with cross-hypersensitivity. Cytochrome P450 2C9 (CYP2C9) and cytochrome P450 2C19 (CYP2C19) genotypes did not influence risk association. Our findings raise the hypothesis of genetically determined metabolic variability as a risk factor for developing anaphylaxis with metamizole. PMID- 26111151 TI - PharmGKB summary: peginterferon-alpha pathway. PMID- 26111153 TI - Polybacterial Periodontal Pathogens Alter Vascular and Gut BH4/nNOS/NRF2-Phase II Enzyme Expression. AB - Periodontal disease is a highly prevalent chronic inflammatory disease and is associated with complex microbial infection in the subgingival cavity. Recently, American Heart Association supported a century old association between periodontal disease and atherosclerotic vascular disease. We have recently shown that polybacterial periodontal infection led to aortic atherosclerosis and modulation of lipid profiles; however the underlying mechanism(s) has not been yet demonstrated. Altered nitric oxide (NO) synthesis and tetrahydrobiopterin (BH4), a cofactor for nitric oxide synthases (NOS) has long been shown to be associated with vascular dysfunction and gastrointestinal motility disorders. We sought to examine the mechanism of periodontal infection leading to altered vascular and gastrointestinal smooth muscle relaxation, focusing on the BH4/nNOS pathways. In addition, we also have investigated how the antioxidant system (NRF2 Phase II enzyme expression) in vascular and GI specimens is altered by oral infection. Eight week old male ApoEnull mice were either sham-infected or infected orally for 16 weeks with a mixture of major periodontal bacteria Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia to induce experimental periodontitis. Serum, vascular (mesenteric), stomach, and colon specimens were collected at the end of periodontal pathogen infection. Bacterial infection induced significant (p<0.05) reductions in the levels of BH4,in ratio of BH4:BH2+B and also in nitric oxide levels compared to sham-infected controls. In addition, we identified a significant (p<0.05) reduction in eNOS dimerization, nNOS dimerization and protein expression of BH4 biosynthesis enzymes; GCH-1, DHFR and NRF2 & Phase II enzymes in infected mice versus controls in both mesenteric artery and colon tissues. However, we found no differences in nNOS/BH4 protein expression in stomach tissues of infected and sham-infected mice. This suggests that a polybacterial infection can cause significant changes in the vascular and colonic BH4/nNOS/NRF2 pathways which might lead to impaired vascular relaxation and colonic motility. PMID- 26111154 TI - Exome sequencing expands the mechanism of SOX5-associated intellectual disability: A case presentation with review of sox-related disorders. AB - The SOX5 haploinsufficiency syndrome is characterized by global developmental delay, intellectual disability, language and motor impairment, and distinct facial features. The smallest deletion encompassed only one gene, SOX5 (OMIM 604975), indicating that haploinsufficiency of SOX5 contributes to neuro developmental delay. Although multiple deletions of the SOX5 gene have been reported in patients, none are strictly intragenic point mutations. Here, we report the identification of a de novo loss of function variant in SOX5 identified through whole exome sequencing. The proband presented with moderate developmental delay, bilateral optic atrophy, mildly dysmorphic features, and scoliosis, which correlates with the previously-described SOX5-associated phenotype. These results broaden the diagnostic spectrum of SOX5-related intellectual disability. Furthermore it highlights the utility of exome sequencing in establishing an etiological basis in clinically and genetically heterogeneous conditions such as intellectual disability. PMID- 26111155 TI - Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets. AB - The fatty acid amide hydrolase (FAAH) regulates the endocannabinoid system cleaving primarily the lipid messenger anandamide. FAAH has been well characterized over the years and, importantly, it represents a promising drug target to treat several diseases, including inflammatory-related diseases and cancer. But its enzymatic mechanism for lipid selection to specifically hydrolyze anandamide, rather than similar bioactive lipids, remains elusive. Here, we clarify this mechanism in FAAH, examining the role of the dynamic paddle, which is formed by the gating residues Phe432 and Trp531 at the boundary between two cavities that form the FAAH catalytic site (the "membrane-access" and the "acyl chain-binding" pockets). We integrate microsecond-long MD simulations of wild type and double mutant model systems (Phe432Ala and Trp531Ala) of FAAH, embedded in a realistic membrane/water environment, with mutagenesis and kinetic experiments. We comparatively analyze three fatty acid substrates with different hydrolysis rates (anandamide > oleamide > palmitoylethanolamide). Our findings identify FAAH's mechanism to selectively accommodate anandamide into a multi pocket binding site, and to properly orient the substrate in pre-reactive conformations for efficient hydrolysis that is interceded by the dynamic paddle. Our findings therefore endorse a structural framework for a lipid selection mechanism mediated by structural flexibility and gating residues between multiple binding cavities, as found in FAAH. Based on the available structural data, this exquisite catalytic strategy for substrate specificity seems to be shared by other lipid-degrading enzymes with similar enzymatic architecture. The mechanistic insights for lipid selection might assist de-novo enzyme design or drug discovery efforts. PMID- 26111156 TI - Promoting Evidence-Based Decision Making in a Local Health Department, Pueblo City-County, Colorado. AB - BACKGROUND: Evidence-based decision making (EBDM) is an effective strategy for addressing population health needs. Assessing and reducing barriers to using EBDM in local health departments may improve practice and provide insight into disseminating EBDM principles among public health practitioners. COMMUNITY CONTEXT: Administrative leaders at the Pueblo City-County Health Department, Pueblo, Colorado, used a systematic approach for implementing EBDM. Research partners engaged staff to understand factors that increase or deter its use. METHODS: A survey was distributed to staff members at baseline to identify gaps in administrative and individual practice of EBDM. In-depth interviews were also conducted with 11 randomly selected staff members. Results were shared with staff and administration, after which activities were implemented to improve application of EBDM. A follow up survey was administered 1 year after the initial assessment. OUTCOME: Survey data showed evidence of progress in engaging and educating staff members, and data showed improved attitudes toward EBDM (ie, several items showed significant improvement from baseline to follow-up). For example, staff members reported having the necessary skills to develop evidence based interventions (73.9%), the ability to effectively communicate information on evidence-based strategies to policy makers (63.0%), access to current information on improving EBDM processes (65.2%), and a belief that evidence-based interventions are designed to be self-sustaining (43.5%). INTERPRETATION: Within a local health department in which leaders have made EBDM a priority, addressing the culture and climate of the department may build EBDM. Future research may provide insight into tailoring EBDM within and across local health departments. PMID- 26111157 TI - How Do You Know Which Health Care Effectiveness Research You Can Trust? A Guide to Study Design for the Perplexed. PMID- 26111158 TI - Smoke-Free Policies in Multiunit Housing: Smoking Behavior and Reactions to Messaging Strategies in Support or in Opposition. AB - INTRODUCTION: Given the high proportion of US adults living in multiunit housing (MUH) and the related risks of secondhand smoke, we examined correlates of having smoke-free MUH policies, level of support for such policies, and reactions to related messaging among a quota-based nonprobability sample of US adults. METHODS: In 2013, 752 adult MUH residents were recruited through an online survey panel to complete a cross-sectional survey assessing tobacco use, personal smoke free policies in homes and cars, smoke-free MUH policies, and reactions to messaging on smoke-free MUH policies. We sought sufficient representation of smokers, racial/ethnic minorities, and residents of the Southeast. RESULTS: Overall, 56.3% had no smoke-free MUH policies and 16.2% had complete policies; 62.8% favored living in smoke-free MUH, and 28.9% said they would move if their building became smoke-free. Multivariate regression indicated that correlates of living in MUH with partial or no policies included younger age, less education, lower income, and current smoking (P's <= .01); more restrictive smoke-free MUH policies were associated with lower cigarette consumption and recent quit attempts among current smokers (P's < .05); and correlates of support for MUH policies included greater education, nonsmoker status, and having complete MUH policies (P's < .05). Of 9 messages opposing smoke-free MUH policies, the most persuasive was "People have the right to smoke in their own homes"; the most persuasive message of 11 in support was "You have the right to breathe clean air in your home." CONCLUSION: Smoke-free MUH policies may reduce smoking. Messaging in favor of smoke-free MUH policies was more persuasive than messaging opposing such policies, indicating the potential for using these approaches. PMID- 26111160 TI - A Cu4S model for the nitrous oxide reductase active sites supported only by nitrogen ligands. AB - To model the (His)7Cu4Sn (n = 1 or 2) active sites of nitrous oxide reductase, the first Cu4(MU4-S) cluster supported only by nitrogen donors has been prepared using amidinate supporting ligands. Structural, magnetic, spectroscopic, and computational characterization is reported. Electrochemical data indicates that the 2-hole model complex can be reduced reversibly to the 1-hole state and irreversibly to the fully reduced state. PMID- 26111159 TI - A National Asian-Language Smokers' Quitline--United States, 2012-2014. AB - INTRODUCTION: Until recently, in-language telephone quitline services for smokers who speak Asian languages were available only in California. In 2012, the Centers for Disease Control and Prevention (CDC) funded the national Asian Smokers' Quitline (ASQ) to expand this service to all states. The objective of this study was to examine characteristics of ASQ callers, how they heard about the quitline, and their use of the service. METHODS: Characteristics of callers from August 2012 through July 2014 were examined by using descriptive statistics. We examined demographics, cigarette smoking status, time to first cigarette, how callers heard about the quitline, and service use (receipt of counseling and medication) by using ASQ intake and administrative data. We analyzed these data by language and state. RESULTS: In 2 years, 5,771 callers from 48 states completed intake; 31% were Chinese (Cantonese or Mandarin), 38% were Korean, and 31% were Vietnamese. More than 95% of all callers who used tobacco were current daily cigarette smokers at intake. About 87% of ASQ callers were male, 57% were aged 45 to 64 years, 48% were uninsured, and educational attainment varied. Most callers (54%) were referred by newspapers or magazines. Nearly all eligible callers (99%) received nicotine patches. About 85% of smokers enrolled in counseling; counseled smokers completed an average of 4 sessions. CONCLUSION: ASQ reached Chinese, Korean, and Vietnamese speakers nationwide. Callers were referred by the promotional avenues employed by ASQ, and most received services (medication, counseling, or both). State quitlines and local organizations should consider transferring callers and promoting ASQ to increase access to cessation services. PMID- 26111161 TI - Structure-Function Analysis of the Non-Muscle Myosin Light Chain Kinase (nmMLCK) Isoform by NMR Spectroscopy and Molecular Modeling: Influence of MYLK Variants. AB - The MYLK gene encodes the multifunctional enzyme, myosin light chain kinase (MLCK), involved in isoform-specific non-muscle and smooth muscle contraction and regulation of vascular permeability during inflammation. Three MYLK SNPs (P21H, S147P, V261A) alter the N-terminal amino acid sequence of the non-muscle isoform of MLCK (nmMLCK) and are highly associated with susceptibility to acute lung injury (ALI) and asthma, especially in individuals of African descent. To understand the functional effects of SNP associations, we examined the N-terminal segments of nmMLCK by 1H-15N heteronuclear single quantum correlation (HSQC) spectroscopy, a 2-D NMR technique, and by in silico molecular modeling. Both NMR analysis and molecular modeling indicated SNP localization to loops that connect the immunoglobulin-like domains of nmMLCK, consistent with minimal structural changes evoked by these SNPs. Molecular modeling analysis identified protein protein interaction motifs adversely affected by these MYLK SNPs including binding by the scaffold protein 14-3-3, results confirmed by immunoprecipitation and western blot studies. These structure-function studies suggest novel mechanisms for nmMLCK regulation, which may confirm MYLK as a candidate gene in inflammatory lung disease and advance knowledge of the genetic underpinning of lung-related health disparities. PMID- 26111162 TI - Degradation of Bunker C Fuel Oil by White-Rot Fungi in Sawdust Cultures Suggests Potential Applications in Bioremediation. AB - Fungal lignocellulolytic enzymes are promising agents for oxidizing pollutants. This study investigated degradation of Number 6 "Bunker C" fuel oil compounds by the white-rot fungi Irpex lacteus, Trichaptum biforme, Phlebia radiata, Trametes versicolor, and Pleurotus ostreatus (Basidiomycota, Agaricomycetes). Averaging across all studied species, 98.1%, 48.6%, and 76.4% of the initial Bunker C C10 alkane, C14 alkane, and phenanthrene, respectively were degraded after 180 days of fungal growth on pine media. This study also investigated whether Bunker C oil induces changes in gene expression in the white-rot fungus Punctularia strigosozonata, for which a complete reference genome is available. After 20 days of growth, a monokaryon P. strigosozonata strain degraded 99% of the initial C10 alkane in both pine and aspen media but did not affect the amounts of the C14 alkane or phenanthrene. Differential gene expression analysis identified 119 genes with >= log2(2-fold) greater expression in one or more treatment comparisons. Six genes were significantly upregulated in media containing oil; these genes included three enzymes with potential roles in xenobiotic biotransformation. Carbohydrate metabolism genes showing differential expression significantly accumulated transcripts on aspen vs. pine substrates, perhaps reflecting white-rot adaptations to growth on hardwood substrates. The mechanisms by which P. strigosozonata may degrade complex oil compounds remain obscure, but degradation results of the 180-day cultures suggest that diverse white-rot fungi have promise for bioremediation of petroleum fuels. PMID- 26111163 TI - Does a Simple Intervention Enhance Memory and Adherence for Neuropsychological Recommendations? AB - The variables that influence the extent to which patients and their families remember and follow neuropsychological recommendations after their appointments are unclear. There has been limited research on this topic. The current study was designed to address this knowledge gap. Patients (n = 79) and caregivers (n = 36) were randomized into 1 of 2 groups, letter or no-letter, to investigate whether providing a supplemental written reminder of the recommendations given (in addition to routine feedback procedures in our clinic) would improve memory for and adherence to recommendations. We found that recall of recommendations was better in the letter condition, although this effect was observed in the caregivers and not in the patients. Adherence to recommendations did not differ significantly between the letter and no-letter conditions. These findings show that a simple intervention can improve caregiver memory for recommendations. Future research could help determine how to translate improvements in memory into greater adherence. PMID- 26111164 TI - Self-Organizing Feature Maps Identify Proteins Critical to Learning in a Mouse Model of Down Syndrome. AB - Down syndrome (DS) is a chromosomal abnormality (trisomy of human chromosome 21) associated with intellectual disability and affecting approximately one in 1000 live births worldwide. The overexpression of genes encoded by the extra copy of a normal chromosome in DS is believed to be sufficient to perturb normal pathways and normal responses to stimulation, causing learning and memory deficits. In this work, we have designed a strategy based on the unsupervised clustering method, Self Organizing Maps (SOM), to identify biologically important differences in protein levels in mice exposed to context fear conditioning (CFC). We analyzed expression levels of 77 proteins obtained from normal genotype control mice and from their trisomic littermates (Ts65Dn) both with and without treatment with the drug memantine. Control mice learn successfully while the trisomic mice fail, unless they are first treated with the drug, which rescues their learning ability. The SOM approach identified reduced subsets of proteins predicted to make the most critical contributions to normal learning, to failed learning and rescued learning, and provides a visual representation of the data that allows the user to extract patterns that may underlie novel biological responses to the different kinds of learning and the response to memantine. Results suggest that the application of SOM to new experimental data sets of complex protein profiles can be used to identify common critical protein responses, which in turn may aid in identifying potentially more effective drug targets. PMID- 26111165 TI - Effects of a 12-Week Hatha Yoga Intervention on Metabolic Risk and Quality of Life in Hong Kong Chinese Adults with and without Metabolic Syndrome. AB - OBJECTIVE: To determine the efficacy of a 12-week Hatha yoga intervention to improve metabolic risk profiles and health-related quality of life (HRQoL) in Chinese adults with and without metabolic syndrome (MetS). METHODS: We conducted a controlled trial within an university-affiliated hospital. 173 Chinese men and women aged 18 or above were assigned to either the yoga intervention group (n = 87) or the control group (n = 86). Primary outcomes included 12-week change in metabolic risk factors and MetS z score. Secondary outcome was HRQoL (Medical Outcomes Short Form Survey at 12 weeks). RESULTS: The mean age of participants was 52.0 (SD 7.4, range 31-71) years. Analysis involving the entire study population revealed that the yoga group achieved greater decline in waist circumference (p<0.001), fasting glucose (p<0.01), triglycerides (p<0.05), and MetS z score (p<0.01). Yoga training also improved general health perceptions (p<0.01), physical component score (p<0.01), and social functioning (p<0.01) domains score of HRQoL. However, no significant differences between groups were observed in the mean change of systolic/diastolic blood pressures or high-density lipid protein cholesterol (all p>0.05). There were no significant differences in the intervention effects on waist circumference and MetS z score between the MetS subgroups (both p>0.05). CONCLUSION: A 12-week Hatha yoga intervention improves metabolic risk profiles and HRQoL in Chinese adults with and without MetS. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000816752. PMID- 26111166 TI - Oxidation of Disulfides to Thiolsulfinates with Hydrogen Peroxide and a Cyclic Seleninate Ester Catalyst. AB - Cyclic seleninate esters function as mimetics of the antioxidant selenoenzyme glutathione peroxidase. They catalyze the reduction of harmful peroxides with thiols, which are converted to disulfides in the process. The possibility that the seleninate esters could also catalyze the further oxidation of disulfides to thiolsulfinates and other overoxidation products under these conditions was investigated. This has ramifications in potential medicinal applications of seleninate esters because of the possibility of catalyzing the unwanted oxidation of disulfide-containing spectator peptides and proteins. A variety of aryl and alkyl disulfides underwent facile oxidation with hydrogen peroxide in the presence of catalytic benzo-1,2-oxaselenolane Se-oxide affording the corresponding thiolsulfinates as the principal products. Unsymmetrical disulfides typically afforded mixtures of regioisomers. Lipoic acid and N,N' dibenzoylcystine dimethyl ester were oxidized readily under similar conditions. Although isolated yields of the product thiolsulfinates were generally modest, these experiments demonstrate that the method nevertheless has preparative value because of its mild conditions. The results also confirm the possibility that cyclic seleninate esters could catalyze the further undesired oxidation of disulfides in vivo. PMID- 26111167 TI - Coarse-Grained Modeling of Peptide Docking Associated with Large Conformation Transitions of the Binding Protein: Troponin I Fragment-Troponin C System. AB - Most of the current docking procedures are focused on fine conformational adjustments of assembled complexes and fail to reproduce large-scale protein motion. In this paper, we test a new modeling approach developed to address this problem. CABS-dock is a versatile and efficient tool for modeling the structure, dynamics and interactions of protein complexes. The docking protocol employs a coarse-grained representation of proteins, a simplified model of interactions and advanced protocols for conformational sampling. CABS-dock is one of the very few tools that allow unrestrained docking with large conformational freedom of the receptor. In an example application we modeled the process of complex assembly between two proteins: Troponin C (TnC) and the N-terminal helix of Troponin I (TnI N-helix), which occurs in vivo during muscle contraction. Docking simulations illustrated how the TnC molecule undergoes significant conformational transition on complex formation, a phenomenon that can be modeled only when protein flexibility is properly accounted for. This way our procedure opens up a new possibility for studying mechanisms of protein complex assembly, which may be a supporting tool for rational drug design. PMID- 26111168 TI - Carbocations and the Complex Flavor and Bouquet of Wine: Mechanistic Aspects of Terpene Biosynthesis in Wine Grapes. AB - Computational chemistry approaches for studying the formation of terpenes/terpenoids in wines are presented, using five particular terpenes/terpenoids (1,8-cineole, alpha-ylangene, botrydial, rotundone, and the wine lactone), volatile compounds (or their precursors) found in wine and/or wine grapes, as representative examples. Through these examples, we show how modern computational quantum chemistry can be employed as an effective tool for assessing the validity of proposed mechanisms for terpene/terpenoid formation. PMID- 26111169 TI - Metabolites Produced by the Endophytic Fungus Aspergillus fumigatus from the Stem of Erythrophloeum fordii Oliv. AB - A new diketopiperazine alkaloid named spirotryprostatin K (1), and five known alkaloids, spiro[5H,10H-dipyrrolo[1,2-a:1',2'-d]pyrazine-2(3H),2'-[2H]-indole] 3',5,10(1'H) trione (2), 6-methoxyspirotryprostatin B (3), pseurotin A (4), N beta-acetyltryptamine (5), and lumichrome (6) were isolated from the endophytic fungus Aspergillus fumigatus. The structure and the absolute configuration of spirotryprostatin K were established by extensive spectroscopic analyses, acid hydrolysis and ECD calculations. Pseurotin A exhibited indirect anti-inflammatory activity by suppressing the lipopolysaccharide-induced proinflammatory factors in BV2 microglial cells, with an IC50 of 5.20 uM. PMID- 26111170 TI - Progress in Studies on Rutaecarpine. II.--Synthesis and Structure-Biological Activity Relationships. AB - Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on rutaecarpine have included isolation from new natural sources, development of new synthetic methods for its total synthesis, the discovery of new biological activities, metabolism, toxicology, and establishment of analytical methods for determining rutaecarpine content. The present review focuses on the synthesis, biological activities, and structure-activity relationships of rutaecarpine derivatives, with respect to their antiplatelet, vasodilatory, cytotoxic, and anticholinesterase activities. PMID- 26111171 TI - Comparative Evaluation of Different Extraction Techniques and Solvents for the Assay of Phytochemicals and Antioxidant Activity of Hashemi Rice Bran. AB - Secondary metabolite contents (total phenolic, flavonoid, tocopherol, and tocotrienol) and antioxidant activities of Hashemi rice bran extracts obtained by ultrasound-assisted and traditional solvent (ethanol and 50:50 (v/v) ethanol water) extraction techniques were compared. Phenolic and, flavonoid compounds were identified using ultra-high performance liquid chromatography and method validation was performed. Significant differences (p < 0.05) were observed among the different extraction techniques upon comparison of phytochemical contents and antioxidant activities. The extracts obtained using the ethanol-water (50:50 v/v) ultrasonic technique showed the highest amounts of total phenolics (288.40 mg/100 g dry material (DM)), total flavonoids (156.20 mg/100 g DM), and total tocotrienols (56.23 mg/100 g DM), and the highest antioxidant activity (84.21% 1,1-diphenyl-2-picrylhydrazyl (DPPH), 65.27% beta-carotene-linoleic bleaching and 82.20% nitric oxide scavenging activity). Secondary metabolite contents and antioxidant activities of the rice bran extracts varied depending of the extraction method used, and according to their effectiveness, these were organized in a decreasing order as follows: ethanol-water (50:50 v/v) ultrasonic, ethanol-water (50:50 v/v) maceration, ethanol ultrasonic and ethanol maceration methods. Ferulic, gallic and chlorogenic acids were the most abundant phenolic compounds in rice bran extracts. The phytochemical constituents of Hashemi rice bran and its antioxidant properties provides insights into its potential application to promote health. PMID- 26111172 TI - A Halogen-Containing Stilbene Derivative from the Leaves of Cajanus cajan that Induces Osteogenic Differentiation of Human Mesenchymal Stem Cells. AB - A new natural halogen-containing stilbene derivative was isolated from the leaves of Cajanus cajan (L.) Millsp. and identified as 3-O-(3-chloro-2-hydroxyl propanyl)-longistylin A by comprehensive spectroscopic and chemical analysis, and named cajanstilbene H (1). It is the first halogen-containing stilbene derivative found from plants. In human mesenchymal stem cells (hMSC) from bone marrow, 1 did not promote cell proliferation, but distinctly enhanced osteogenic differentiation of hMSC in time- and dose-dependent manners. In six human cancer cell lines, 1 showed a moderate inhibitory effect on cell proliferation, with IC50 values of 21.42-25.85 MUmol.L(-1). PMID- 26111173 TI - Development of a Large Set of Microsatellite Markers in Zapote Mamey (Pouteria sapota (Jacq.) H.E. Moore & Stearn) and Their Potential Use in the Study of the Species. AB - Pouteria sapota is known for its edible fruits that contain unique carotenoids, as well as for its fungitoxic, anti-inflammatory and anti-oxidant activity. However, its genetics is mostly unknown, including aspects about its genetic diversity and domestication process. We did high-throughput sequencing of microsatellite-enriched libraries of P. sapota, generated 5223 contig DNA sequences, 1.8 Mbp, developed 368 microsatellites markers and tested them on 29 individuals from 10 populations (seven wild, three cultivated) from Mexico, its putative domestication center. Gene ontology BLAST analysis of the DNA sequences containing microsatellites showed potential association to physiological functions. Genetic diversity was slightly higher in cultivated than in the wild gene pool (HE = 0.41 and HE = 0.35, respectively), although modified Garza Williamson Index and Bottleneck software showed evidence for a reduction in genetic diversity for the cultivated one. Neighbor Joining, 3D Principal Coordinates Analysis and assignment tests grouped most individuals according to their geographic origin but no clear separation was observed between wild or cultivated gene pools due to, perhaps, the existence of several admixed populations. The developed microsatellites have a great potential in genetic population and domestication studies of P. sapota but additional sampling will be necessary to better understand how the domestication process has impacted the genetic diversity of this fruit crop. PMID- 26111174 TI - Synthesis of (E)-2-Styrylchromones and Flavones by Base-Catalyzed Cyclodehydration of the Appropriate beta-Diketones Using Water as Solvent. AB - A low cost, safe, clean and environmentally benign base-catalyzed cyclodehydration of appropriate beta-diketones affording (E)-2-styrylchromones and flavones in good yields is disclosed. Water was used as solvent and the reactions were heated using classical and microwave heating methods, under open and closed vessel conditions. beta-Diketones having electron-donating and withdrawing substituents were used to evaluate the reaction scope. The reaction products were isolated in high purity by simple filtration and recrystallization from ethanol, when using 800 mg of the starting diketone under classical reflux heating conditions. PMID- 26111175 TI - Characterization of Volatile Compounds of Eleven Achillea Species from Turkey and Biological Activities of Essential Oil and Methanol Extract of A. hamzaoglui Arabaci & Budak. AB - According to distribution of genus Achillea, two main centers of diversity occur in S.E. Europe and S.W. Asia. Diversified essential oil compositions from Balkan Peninsula have been numerously reported. However, report on essential oils of Achillea species growing in Turkey, which is one of the main centers of diversity, is very limited. This paper represents the chemical compositions of the essential oils obtained by hydrodistillation from the aerial parts of eleven Achillea species, identified simultaneously by gas chromatography and gas chromatography-mass spectrometry. The main components were found to be 1,8 cineole, p-cymene, viridiflorol, nonacosane, alpha-bisabolol, caryophyllene oxide, alpha-bisabolon oxide A, beta-eudesmol, 15-hexadecanolide and camphor. The chemical principal component analysis based on thirty compounds identified three species groups and a subgroup, where each group constituted a chemotype. This is the first report on the chemical composition of A. hamzaoglui essential oil; as well as the antioxidant and antimicrobial evaluation of its essential oil and methanolic extract. PMID- 26111176 TI - Plasmodium falciparum Thioredoxin Reductase (PfTrxR) and Its Role as a Target for New Antimalarial Discovery. AB - The growing resistance to current antimalarial drugs is a major concern for global public health. The pressing need for new antimalarials has led to an increase in research focused on the Plasmodium parasites that cause human malaria. Thioredoxin reductase (TrxR), an enzyme needed to maintain redox equilibrium in Plasmodium species, is a promising target for new antimalarials. This review paper provides an overview of the structure and function of TrxR, discusses similarities and differences between the thioredoxin reductases (TrxRs) of different Plasmodium species and the human forms of the enzyme, gives an overview of modeling Plasmodium infections in animals, and suggests the role of Trx functions in antimalarial drug resistance. TrxR of Plasmodium falciparum is a central focus of this paper since it is the only Plasmodium TrxR that has been crystallized and P. falciparum is the species that causes most malaria cases. It is anticipated that the information summarized here will give insight and stimulate new directions in which research might be most beneficial. PMID- 26111177 TI - Natural Plant Alkaloid (Emetine) Inhibits HIV-1 Replication by Interfering with Reverse Transcriptase Activity. AB - Ipecac alkaloids are secondary metabolites produced in the medicinal plant Psychotria ipecacuanha. Emetine is the main alkaloid of ipecac and one of the active compounds in syrup of Ipecac with emetic property. Here we evaluated emetine's potential as an antiviral agent against Human Immunodeficiency Virus. We performed in vitro Reverse Transcriptase (RT) Assay and Natural Endogenous Reverse Transcriptase Activity Assay (NERT) to evaluate HIV RT inhibition. Emetine molecular docking on HIV-1 RT was also analyzed. Phenotypic assays were performed in non-lymphocytic and in Peripheral Blood Mononuclear Cells (PBMC) with HIV-1 wild-type and HIV-harboring RT-resistant mutation to Nucleoside Reverse Transcriptase Inhibitors (M184V). Our results showed that HIV-1 RT was blocked in the presence of emetine in both models: in vitro reactions with isolated HIV-1 RT and intravirion, measured by NERT. Emetine revealed a strong potential of inhibiting HIV-1 replication in both cellular models, reaching 80% of reduction in HIV-1 infection, with low cytotoxic effect. Emetine also blocked HIV-1 infection of RT M184V mutant. These results suggest that emetine is able to penetrate in intact HIV particles, and bind and block reverse transcription reaction, suggesting that it can be used as anti-HIV microbicide. Taken together, our findings provide additional pharmacological information on the potential therapeutic effects of emetine. PMID- 26111178 TI - Antioxidant Capacities and Analysis of Phenolic Compounds in Three Endemic Nolana Species by HPLC-PDA-ESI-MS. AB - The antioxidant features, polyphenolic composition and chromatographic fingerprints of the aerial parts from three Chilean endemic plants from the Paposo Valley located on the cost of the Atacama Desert were investigated for the first time using high pressure liquid chromatography coupled with photodiode array detector and electrospray ionization mass analysis (HPLC-PDA-ESI-MS) and spectroscopic methods. The phenolic fingerprints obtained for the plants were compared and correlated with the antioxidant capacities measured by the bleaching of the DPPH radical, the ferric reducing antioxidant power (FRAP) and quantification of the total content of phenolics and flavonoids measured by spectroscopic methods. Thirty phenolics were identified for the first time for these species, mostly phenolic acids, flavanones, flavonols and some of their glycoside derivatives, together with three saturated fatty acids (stearic, palmitic and arachidic acids). Nolana ramosissima showed the highest antioxidant activity (26.35 +/- 1.02 MUg/mL, 116.07 +/- 3.42 MUM Trolox equivalents/g dry weight and 81.23% +/- 3.77% of inhibition in the DPPH, FRAP and scavenging activity (SA) assays, respectively), followed by N. aplocaryoides (85.19 +/- 1.64 MUg/mL, 65.87 +/- 2.33 MUM TE/g DW and 53.27% +/- 3.07%) and N. leptophylla (124.71 +/- 3.01, 44.23 +/- 5.18 MUM TE/g DW and 38.63% +/- 1.85%). PMID- 26111179 TI - Ethanolic Extracts of Pluchea indica Induce Apoptosis and Antiproliferation Effects in Human Nasopharyngeal Carcinoma Cells. AB - Pluchea indica is used in traditional medicine for the treatment of lumbago, ulcer, tuberculosis and inflammation. The anti-cancer activities and the underlying molecular mechanisms of the ethanolic extracts of P. indica root (PIRE) were characterized in the present study. PIRE strongly inhibited the viability of the human nasopharyngeal carcinoma cells (NPC-TW 01 and NPC-TW 04) in a time- and dose-dependent manner. Migration of cancer cells was also suppressed by PIRE. In addition, PIRE significantly increased the occurrence of the cells in sub-G1 phase and the extent of DNA fragmentation in a dose-dependent manner, which indicates that PIRE significantly increased apoptosis in NPC cells. The apoptotic process triggered by PIRE involved up-regulation of pro-apoptotic Bax protein and down-regulation of anti-apoptotic Bcl-2 protein, consequently increasing the ratios of Bax/Bcl-2 protein levels. Moreover, the p53 protein was up-regulated by PIRE in a concentration-dependent manner. Therefore, PIRE could induce the apoptosis-signaling pathway in NPC cells by activation of p53 and by regulation of apoptosis-related proteins. PMID- 26111180 TI - Combinational Treatment of Curcumin and Quercetin against Gastric Cancer MGC-803 Cells in Vitro. AB - Gastric cancer remains a major health problem worldwide. Natural products, with stronger antitumor activity and fewer side effects, are potential candidates for pharmaceutical development as anticancer agents. In this study, quercetin and curcumin were chosen for testing and were applied separately and in combination to human gastric cancer MGC-803 cells. The MTT assay was used to evaluate cell growth inhibition. Annexin V-FITC/PI was carried out to measure apoptosis rate. Flow cytometry was performed to analyze mitochondrial membrane potential levels. Western blots were applied to detect expression of cytochrome c, total and phosphorylated ERK and AKT. Combined treatment with curcumin and quercetin resulted in significant inhibition of cell proliferation, accompanied by loss of mitochondrial membrane potential (DeltaPsim), release of cytochrome c and decreased phosphorylation of AKT and ERK. These results indicate that the combination of curcumin and quercetin induces apoptosis through the mitochondrial pathway. Notably, effect of combined treatment with curcumin and quercetin on gastric cancer MGC-803 cells is stronger than that of individual treatment, indicating that curcumin and quercetin combinations have potential as anti gastric cancer drugs for further development. PMID- 26111181 TI - Uses of 3-(2-Bromoacetyl)-2H-chromen-2-one in the Synthesis of Heterocyclic Compounds Incorporating Coumarin: Synthesis, Characterization and Cytotoxicity. AB - In this work, 3-bromoacetylcoumarin was used as the key starting material for the synthesis of pyran, pyridine, thiophene, thiazole and pyrazole derivatives through its reaction with different reagents. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All of the synthesized compounds were screened for their in vitro anticancer activity against six human cancer cell lines, namely: human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), nasopharyngeal carcinoma (HONE1), human breast cancer (MCF) and normal fibroblast cells (WI38). The IC50 values (the sample concentration that produces 50% reduction in cell growth) in nanomolars (nM)) showed most of the compounds exhibited significant cytotoxic effect. Among these derivatives, compound 6d showed almost equipotent cytotoxic activity against NUGC (IC50 = 29 nM) compared to the standard CHS 828 (IC50 = 25 nM). PMID- 26111182 TI - Trypanocidal Activity of Long Chain Diamines and Aminoalcohols. AB - Thirteen aminoalcohols and eight diamines were obtained and tested against Trypanosoma cruzi epimastigotes strains MG, JEM and CL-B5 clone. Some of them were equal or more potent (1.0-6.6 times) than the reference compound nifurtimox. From them, three aminoalcohols and two diamines were selected for amastigotes assays. Compound 5 was as potent as the reference drug nifurtimox against amastigotes of the CL-B5 strain (IC50 = 0.6 uM), with a selectivity index of 54. PMID- 26111183 TI - Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors. AB - Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers. PMID- 26111184 TI - Protective Effects of Korean Red Ginseng against Alcohol-Induced Fatty Liver in Rats. AB - The present study tested the hypothesis that Korean red ginseng (KRG) provides a protective effect against alcoholic fatty liver. Male Sprague-Dawley rats were divided into four groups and fed a modified Lieber-DeCarli diet containing 5% (w/v) alcohol or an isocaloric amount of dextrin-maltose for the controls for 6 weeks: normal control (CON), alcohol control (ET), and ET treated with 125 or 250 mg/kg body weight/day of KRG (RGL or RGH, respectively). Compared with the CON group, the ET group exhibited a significant increase in triglycerides, total cholesterol and the presence of lipid droplets in the liver, and a decrease in fat mass, which were all attenuated by KRG supplementation in adose-dependent manner. The mitigation was accompanied by AMP-activated protein kinase (AMPK) signaling pathways in the liver and adipose tissue. In addition, suppression in the alcohol-induced changes of adipose adipokine mRNA expression was also observed in KRG supplementation group. These findings suggest that KRG may have the potential to ameliorate alcoholic fatty liver by suppressing inappropriate lysis of adipose tissue and preventing unnecessary de novo lipogenesis in the liver, which are mediated by AMPK signaling pathways. A mechanism for an interplay between the two organs is still needed to be examined with further assays. PMID- 26111185 TI - Microwave-Assisted Condensation Reactions of Acetophenone Derivatives and Activated Methylene Compounds with Aldehydes Catalyzed by Boric Acid under Solvent-Free Conditions. AB - We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large variety of known or novel compounds have thus been prepared, including with substrates bearing acid or base-sensitive functional groups. PMID- 26111187 TI - The effect of initiation of antiretroviral therapy on monocyte, endothelial and platelet function in HIV-1 infection. AB - OBJECTIVES: Monocyte activation, endothelial dysfunction and platelet activation all potentially contribute to the increased risk of cardiovascular disease (CVD) reported in those with HIV-1 infection. To date, no study has examined how initiation of antiretroviral therapy (ART) affects markers of all three processes. We aimed to compare markers of monocyte, endothelial and platelet function between untreated HIV-positive subjects and HIV-negative controls and to examine the early effects of ART initiation on these markers. METHODS: We measured monocyte [soluble CD14 (sCD14) and sCD163], endothelial [von Willebrand factor (vWF), intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1)] and platelet [soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L) and soluble glycoprotein VI (sGPVI)] biomarkers before and at weeks 4 and 12 post ART initiation in HIV-positive and well-matched HIV-negative controls. RESULTS: We examined 40 subjects, 25 HIV-positive subjects and 15 controls, with a median age of 34 years [interquartile range (IQR) 31, 40 years], of whom 60% were male and 47.5% Caucasian. Pre-ART, all biomarkers (monocyte, endothelial and platelet) were significantly higher in HIV-positive patients versus controls (all P < 0.05) and decreased with ART initiation, except for sCD14, which remained unchanged [median 1680 (IQR 1489, 1946) ng/mL at week 12 versus 1570 (IQR 1287, 2102) ng/mL at week 0; P = 0.7]. Although platelet activation markers reduced to levels comparable to those in controls, endothelial dysfunction markers remained elevated, as did sCD163 [at week 12, median 1005 (IQR 791, 1577) ng/mL in HIV-positive patients versus 621 (IQR 406, 700) ng/mL in controls; P < 0.0001]. CONCLUSIONS: ART initiation resulted in reductions in levels of CVD-associated biomarkers; however, although they improved, markers of endothelial dysfunction and monocyte activation remained elevated. How these persistent abnormalities affect CVD risk in HIV infection remains to be determined. PMID- 26111186 TI - Instrumental Role of Helicobacter pylori gamma-Glutamyl Transpeptidase in VacA Dependent Vacuolation in Gastric Epithelial Cells. AB - Helicobacter pylori causes cellular vacuolation in host cells, a cytotoxic event attributed to vacuolating cytotoxin (VacA) and the presence of permeant weak bases such as ammonia. We report here the role of gamma-glutamyl transpeptidase (GGT), a constitutively expressed secretory enzyme of H. pylori, in potentiating VacA-dependent vacuolation formation in H. pylori-infected AGS and primary gastric cells. The enhancement is brought about by GGT hydrolysing glutamine present in the extracellular medium, thereby releasing ammonia which accentuates the VacA-induced vacuolation. The events of vacuolation in H. pylori wild type (WT)- and Deltaggt-infected AGS cells were first captured and visualized by real time phase-contrast microscopy where WT was observed to induce more vacuoles than Deltaggt. By using semi-quantitative neutral red uptake assay, we next showed that Deltaggt induced significantly less vacuolation in AGS and primary gastric epithelial cells as compared to the parental strain (P<0.05) indicating that GGT potentiates the vacuolating effect of VacA. Notably, vacuolation induced by WT was significantly reduced in the absence of GGT substrate, glutamine (P<0.05) or in the presence of a competitive GGT inhibitor, serine-borate complex. Furthermore, the vacuolating ability of Deltaggt was markedly restored when co incubated with purified recombinant GGT (rGGT), although rGGT itself did not induce vacuolation independently. Similarly, the addition of exogenous ammonium chloride as a source of ammonia also rescued the ability of Deltaggt to induce vacuolation. Additionally, we also show that monoclonal antibodies against GGT effectively inhibited GGT activity and successfully suppressed H. pylori-induced vacuolation. Collectively, our results clearly demonstrate that generation of ammonia by GGT through glutamine hydrolysis is responsible for enhancing VacA dependent vacuolation. Our findings provide a new perspective on GGT as an important virulence factor and a promising target in the management of H. pylori associated gastric diseases. PMID- 26111188 TI - Long-term results of pediatric cataract surgery and primary intraocular lens implantation from 7 to 22 months of life. AB - IMPORTANCE: Pediatric primary posterior intraocular lens (IOL) implantation in children older than 24 months has become the standard of care. Results of the Infantile Aphakia Treatment Study have concluded that primary IOL implantation before age 7 months has no advantages over aphakia. The current evidence does not address our understanding of the risks and benefits of primary IOL implantation for children aged 7 to 24 months. OBSERVATIONS: Final optotype acuity, adverse events, refractive growth, strabismus, binocular function, and need for additional surgery were retrospectively reviewed for 14 eyes of 10 patients from November 2001 to June 2012. The records were reviewed for children aged 6 to 24 months; included patients were aged 7 to 22 months. The mean (SD) visual acuity was 0.29 (0.30) logMAR (Snellen equivalent 20/40). The mean follow-up was 5 years. The rate of adverse events was 3 in 14 eyes (21%). Adverse events included lens reproliferation (2 eyes) and lens dislocation (1 eye). The rate of strabismus correction was 4 in 10 patients (40%). The mean (SD) rate of refractive growth at 3 times the age at surgery was -5.80 (3.09) diopters. CONCLUSIONS AND RELEVANCE: The data suggest that primary IOL implantation in this age group has a lower rate of adverse events than reported in the Infantile Aphakia Treatment Study. Additionally, favorable visual outcome was found, similar to that in children undergoing primary IOL implantation when older than 2 years. Primary IOL implantation should be considered in children who require cataract surgery after age 7 months. PMID- 26111189 TI - Possible Genetic Origin of Limb-Body Wall Complex. AB - Limb body wall complex (LBWC) is characterized by multiple severe congenital malformations including an abdominal and/or thoracic wall defect covered by amnion, a short or absent umbilical cord with the placenta almost attached to the anterior fetal wall, intestinal malrotation, scoliosis, and lower extremity anomalies. There is no consensus about the etiology of LBWC and many cases with abnormal facial cleft do not meet the requirements for the true complex. We describe a series of four patients with LBWC and other malformations in an attempt to explain their etiology. There are several reports of fetuses with LBWC and absent gallbladder and one of our patients also had polysplenia. Absent gallbladder and polysplenia are associated with laterality genes including HOX, bFGF, transforming growth factor beta/activins/BMP4, WNT 1-8, and SHH. We postulate that this severe malformation may be due to abnormal genes involved in laterality and caudal development. PMID- 26111190 TI - Factors influencing patient-reported quality of life in pretreatment orthognathic surgery patients. AB - OBJECTIVE: To investigate the relationship between condition-specific quality of life (QoL) and occlusal/skeletal traits of pretreatment orthognathic surgery patients. MATERIALS AND METHODS: Patients referred for orthognathic surgery during the 2012-2014 period were asked to complete the Orthognathic Quality of Life Questionnaire (OQLQ) at consultation. Patient demographics, indices of treatment need, occlusal traits, and cephalometric variables were also recorded. Bivariate analyses were carried out between the OQLQ scores and the clinical measurements. Significant variables were added to a multivariate regression model to determine the effect of these predictive factors on OQLQ. RESULTS: One hundred and two patients were recruited. Initial analyses showed that gender and overjet were significantly associated with the overall OQLQ score. Being female increased the overall OQLQ score by 15.6 points when compared to males (95% confidence interval [CI], 7.4-23.8). Females also had significant associations in the social and awareness domains of the OQLQ. The magnitude of overjet away from normal values was associated with poorer overall QoL, with significant relationships in the esthetic and functional domains. The Index of Orthognathic Functional Treatment Need was significantly associated with the functional domain of OQLQ, with patients in category 5 scoring a mean of 10.0 points more than patients in category 4 (95% CI, 2.1-17.8). The Index of Complexity, Outcome and Need and other cephalometric variables were not associated with the OQLQ. CONCLUSIONS: Females are more aware of their facial deformity and report a greater social detriment when compared to males. Patients with a higher orthognathic treatment need report greater functional disadvantage. PMID- 26111191 TI - In vitro and in vivo biofilm adhesion to esthetic coated arch wires and its correlation with surface roughness. AB - OBJECTIVE: To evaluate the in vitro ability of esthetic coated rectangular arch wires to retain oral biofilms and in vivo biofilm formation on these wires after 4 and 8 weeks of clinical use and to correlate the findings with the surface roughness of these wires. MATERIALS AND METHODS: Three brands of esthetic coated nickel-titanium (NiTi) arch wires were selected. Arch wires retrieved after 4 and 8 weeks of intraoral use were obtained from 30 orthodontic patients. Surface roughness (SR) was assessed with an atomic force microscope. In vitro adhesion assays were performed using Streptococcus mutans (MS), Staphylococcus aureus, and Candida albicans. The amount of bacterial adhesion was quantified using the colony-count method. Paired t-test, analysis of variance, post hoc Tukey's test, and Pearson's correlation coefficient test were used for statistical analysis at the .05 level of significance. RESULTS: In vitro bacterial adhesion showed significant differences between wires in terms of MS adhesion (P = .01). All wires showed significant increases in SR (P = .001 after 4 weeks and .007 after 8 weeks) and biofilm adhesion (P = .0001 after 4 weeks and .045 after 8 weeks) after intraoral exposure. A significant positive correlation (P = .001 after 4 weeks and .05 after 8 weeks) was observed between these two variables in vivo, but the correlation was not significant for in vitro bacterial adhesion. CONCLUSIONS: SR and biofilm adhesion increased after intraoral use at all time intervals. There was a positive correlation between SR and biofilm adhesion in vivo only. PMID- 26111192 TI - Ultrathin MoSe2 Nanosheets Decorated on Carbon Fiber Cloth as Binder-Free and High-Performance Electrocatalyst for Hydrogen Evolution. AB - MoSe2 nanosheets with ultrathin thickness and rich defects were grown on the surface of carbon fiber cloth by a facile solvent-thermal method. The active area and conductivity of the MoSe2 catalyst were increased simultaneously because of the NH4F etching effect and its incorporation with carbon fiber cloth. As a result, the MoSe2-based catalysts exhibited excellent HER activity including small onset potential, large exchange current density and small Tafel slope, which is superior to most of MoSe2-based catalysts reported previously. PMID- 26111195 TI - A Microplate Growth Inhibition Assay for Screening Bacteriocins against Listeria monocytogenes to Differentiate Their Mode-of-Action. AB - Lactic acid bacteria (LAB) have historically been used in food fermentations to preserve foods and are generally-recognized-as-safe (GRAS) by the FDA for use as food ingredients. In addition to lactic acid; some strains also produce bacteriocins that have been proposed for use as food preservatives. In this study we examined the inhibition of Listeria monocytogenes 39-2 by neutralized and non neutralized bacteriocin preparations (Bac+ preps) produced by Lactobacillus curvatus FS47; Lb. curvatus Beef3; Pediococcus acidilactici Bac3; Lactococcus lactis FLS1; Enterococcus faecium FS56-1; and Enterococcus thailandicus FS92. Activity differences between non-neutralized and neutralized Bac+ preps in agar spot assays could not readily be attributed to acid because a bacteriocin negative control strain was not inhibitory to Listeria in these assays. When neutralized and non-neutralized Bac+ preps were used in microplate growth inhibition assays against L. monocytogenes 39-2 we observed some differences attributed to acid inhibition. A microplate growth inhibition assay was used to compare inhibitory reactions of wild-type and bacteriocin-resistant variants of L. monocytogenes to differentiate bacteriocins with different modes-of-action (MOA) whereby curvaticins FS47 and Beef3, and pediocin Bac3 were categorized to be in MOA1; enterocins FS92 and FS56-1 in MOA2; and lacticin FLS1 in MOA3. The microplate bacteriocin MOA assay establishes a platform to evaluate the best combination of bacteriocin preparations for use in food applications as biopreservatives against L. monocytogenes. PMID- 26111196 TI - Interclonal proteomic responses to predator exposure in Daphnia magna may depend on predator composition of habitats. AB - Phenotypic plasticity, the ability of one genotype to express different phenotypes in response to changing environmental conditions, is one of the most common phenomena characterizing the living world and is not only relevant for the ecology but also for the evolution of species. Daphnia, the water flea, is a textbook example for predator-induced phenotypic plastic defences; however, the analysis of molecular mechanisms underlying these inducible defences is still in its early stages. We exposed Daphnia magna to chemical cues of the predator Triops cancriformis to identify key processes underlying plastic defensive trait formation. To get a more comprehensive idea of this phenomenon, we studied four genotypes with five biological replicates each, originating from habitats characterized by different predator composition, ranging from predator-free habitats to habitats containing T. cancriformis. We analysed the morphologies as well as proteomes of predator-exposed and control animals. Three genotypes showed morphological changes when the predator was present. Using a high-throughput proteomics approach, we found 294 proteins which were significantly altered in their abundance after predator exposure in a general or genotype-dependent manner. Proteins connected to genotype-dependent responses were related to the cuticle, protein synthesis and calcium binding, whereas the yolk protein vitellogenin increased in abundance in all genotypes, indicating their involvement in a more general response. Furthermore, genotype-dependent responses at the proteome level were most distinct for the only genotype that shares its habitat with Triops. Altogether, our study provides new insights concerning genotype-dependent and general molecular processes involved in predator-induced phenotypic plasticity in D. magna. PMID- 26111197 TI - High night temperatures during grain number determination reduce wheat and barley grain yield: a field study. AB - Warm nights are a widespread predicted feature of climate change. This study investigated the impact of high night temperatures during the critical period for grain yield determination in wheat and barley crops under field conditions, assessing the effects on development, growth and partitioning crop-level processes driving grain number per unit area (GN). Experiments combined: (i) two contrasting radiation and temperature environments: late sowing in 2011 and early sowing in 2013, (ii) two well-adapted crops with similar phenology: bread wheat and two-row malting barley and (iii) two temperature regimes: ambient and high night temperatures. The night temperature increase (ca. 3.9 degrees C in both crops and growing seasons) was achieved using purpose-built heating chambers placed on the crop at 19:000 hours and removed at 7:00 hours every day from the third detectable stem node to 10 days post-flowering. Across growing seasons and crops, the average minimum temperature during the critical period ranged from 11.2 to 17.2 degrees C. Wheat and barley grain yield were similarly reduced under warm nights (ca. 7% degrees C(-1) ), due to GN reductions (ca. 6% degrees C(-1) ) linked to a lower number of spikes per m(2) . An accelerated development under high night temperatures led to a shorter critical period duration, reducing solar radiation capture with negative consequences for biomass production, GN and therefore, grain yield. The information generated could be used as a starting point to design management and/or breeding strategies to improve crop adaptation facing climate change. PMID- 26111198 TI - Corrigendum. PMID- 26111199 TI - Effective Bronchoscopic Lung Volume Reduction Accelerates Exercise Oxygen Uptake Kinetics in Emphysema. AB - BACKGROUND: The impact of bronchoscopic lung volume reduction (BLVR) on physiologic responses to exercise in patients with advanced emphysema remains incompletely understood. We hypothesized that effective BLVR (e-BLVR), defined as a reduction in residual volume > 350 mL, would improve cardiovascular responses to exercise and accelerate oxygen uptake (Vo2) kinetics. METHODS: Thirty-one patients (FEV1, 36% +/- 9% predicted; residual volume, 219% +/- 57% predicted) underwent a constant intensity exercise test at 70% peak work rate to the limit of tolerance before and after treatment bronchoscopy (n = 24) or sham bronchoscopy (n = 7). Physiologic responses in patients who had e-BLVR (n = 16) were compared with control subjects (ineffective BLVR or sham bronchoscopy; n = 15). RESULTS: e-BLVR reduced residual volume (-1.1 +/- 0.5 L, P = .001), improved lung diffusing capacity by 12% +/- 13% (P = .001), and increased exercise tolerance by 181 +/- 214 s (P = .004). Vo2 kinetics were accelerated in the e BLVR group but remained unchanged in control subjects (Delta mean response time, 20% +/- 29% vs 1% +/- 25%, P = .04). Acceleration of Vo2 kinetics was associated with reductions in heart rate and oxygen pulse response half-times by 8% (84 +/- 14 to 76 +/- 15 s, P = .04) and 20% (49 +/- 16 to 34 +/- 16 s, P = .01), respectively. There were also increases in heart rate and oxygen pulse amplitudes during the cardiodynamic phase post e-BLVR. Faster Vo2 kinetics in the e-BLVR group were significantly correlated with reductions in residual volume (r = 0.66, P = .005) and improvements in inspiratory reserve volume (r = 0.56, P = .024) and exercise tolerance (r = 0.63, P = .008). CONCLUSIONS: Lung deflation induced by e BLVR accelerated exercise Vo2 kinetics in patients with emphysema. This beneficial effect appears to be related mechanistically to an enhanced cardiovascular response to exercise, which may contribute to improved functional capacity. PMID- 26111200 TI - Exhaled breath temperature in elite swimmers: The effects of a training session in adolescents with or without asthma. AB - BACKGROUND: Cooling of the airways and inflammation have been pointed as possible mechanisms for exercise-induced asthma (EIA). We aimed to investigate the effect of training and asthma on exhaled breath temperature (EBT) of elite swimmers. METHODS: Elite swimmers annually screened (skin prick tests, spirometry before and after salbutamol inhalation, induced sputum cell counts, and methacholine bronchial challenge) at our department (n = 27) were invited to this prospective study. Swimmers who agreed to participate in the present study (n = 22, 10 with asthma) had axillary temperature and EBT measured (X-halo((r)) ) before and after a swimming training session (aerobic/non-aerobic). Linear regression models were used to assess the effect of asthma and other possible explanatory variables (demographics, PD20 , baseline EBT, training intensity, axillary temperature, and the number of hours trained in that week) on EBT change. RESULTS: EBT significantly increased after training independently of lung function, airway responsiveness, and inflammation in all swimmers (mean +/- SD: 0.32 +/- 0.57; p = 0.016). No differences were observed between asthmatic swimmers and others. A significant correlation was observed between baseline and post-exercise EBTs (r = 0.827, p < 0.001). Asthma was not a predictor of DeltaEBT after adjusting for confounders; baseline EBT was the variable most strongly associated with DeltaEBT, explaining by itself alone 46% of the outcome (r(2) = 0.464). CONCLUSION: Although these are preliminary data, a relationship between airway's inflammation and respiratory heat loss during exercise could not be confirmed, suggesting that the increase in exhaled breath temperature is a physiologic rather than a pathological response to exercise. PMID- 26111202 TI - Temperature Distribution within a Cold Cap during Nuclear Waste Vitrification. AB - The kinetics of the feed-to-glass conversion affects the waste vitrification rate in an electric glass melter. The primary area of interest in this conversion process is the cold cap, a layer of reacting feed on top of the molten glass. The work presented here provides an experimental determination of the temperature distribution within the cold cap. Because direct measurement of the temperature field within the cold cap is impracticable, an indirect method was developed in which the textural features in a laboratory-made cold cap with a simulated high level waste feed were mapped as a function of position using optical microscopy, scanning electron microscopy, energy dispersive spectroscopy, and X-ray diffraction. The temperature distribution within the cold cap was established by correlating microstructures of cold-cap regions with heat-treated feed samples of nearly identical structures at known temperatures. This temperature profile was compared with a mathematically simulated profile generated by a cold-cap model that has been developed to assess the rate of glass production in a melter. PMID- 26111201 TI - Micro(mi) RNA-34a targets protein phosphatase (PP)1gamma to regulate DNA damage tolerance. AB - The DNA damage response (DDR) triggers widespread changes in gene expression, mediated partly by alterations in micro(mi) RNA levels, whose nature and significance remain uncertain. Here, we report that miR-34a, which is upregulated during the DDR, modulates the expression of protein phosphatase 1gamma (PP1gamma) to regulate cellular tolerance to DNA damage. Multiple bio-informatic algorithms predict that miR-34a targets the PP1CCC gene encoding PP1gamma protein. Ionising radiation (IR) decreases cellular expression of PP1gamma in a dose-dependent manner. An miR-34a-mimic reduces cellular PP1gamma protein. Conversely, an miR 34a inhibitor antagonizes IR-induced decreases in PP1gamma protein expression. A wild-type (but not mutant) miR-34a seed match sequence from the 3' untranslated region (UTR) of PP1CCC when transplanted to a luciferase reporter gene makes it responsive to an miR-34a-mimic. Thus, miR-34a upregulation during the DDR targets the 3' UTR of PP1CCC to decrease PP1gamma protein expression. PP1gamma is known to antagonize DDR signaling via the ataxia-telangiectasia-mutated (ATM) kinase. Interestingly, we find that cells exposed to DNA damage become more sensitive - in an miR-34a-dependent manner - to a second challenge with damage. Increased sensitivity to the second challenge is marked by enhanced phosphorylation of ATM and p53, increased gammaH2AX formation, and increased cell death. Increased sensitivity can be partly recapitulated by a miR-34a-mimic, or antagonized by an miR-34a-inhibitor. Thus, our findings suggest a model in which damage-induced miR 34a induction reduces PP1gamma expression and enhances ATM signaling to decrease tolerance to repeated genotoxic challenges. This mechanism has implications for tumor suppression and the response of cancers to therapeutic radiation. PMID- 26111204 TI - Black Gold: Plasmonic Colloidosomes with Broadband Absorption Self-Assembled from Monodispersed Gold Nanospheres by Using a Reverse Emulsion System. AB - A facile approach for the fabrication of novel black plasmonic colloidosomes assembled from Au nanospheres is developed by an emulsion-templating strategy. This self-assembly process is based on a new reverse water-in-1-butanol emulsion system, in which the water emulsion droplets can dissolve into 1-butanol (oil) phase at an appropriate rate. These Au colloidosomes possess hexagonal close packed multilayer shells and show a low reflectivity and intense broadband absorption owing to the strong interparticle plasmonic coupling, which is further investigated by a finite-difference time-domain method. This method is universal and is suitable for self-assembly of different noble-metal nanoparticles into different colloidosomes. These colloidosomes have important applications in photothermal therapy, biosensors, and drug delivery. PMID- 26111203 TI - The Impact of Elective Colon Resection on Rates of Emergency Surgery for Diverticulitis. AB - OBJECTIVE: To determine the impact of elective colectomy on emergency diverticulitis surgery at the population level. BACKGROUND: Current recommendations suggest avoiding elective colon resection for uncomplicated diverticulitis because of uncertain effectiveness at reducing recurrence and emergency surgery. The influence of these recommendations on use of elective colectomy or rates of emergency surgery remains undetermined. METHODS: A retrospective cohort study using a statewide hospital discharge database identified all patients admitted for diverticulitis in Washington State (1987 2012). Sex- and age-adjusted rates (standardized to the 2000 state census) of admissions, elective and emergency/urgent surgical and percutaneous interventions for diverticulitis were calculated and temporal changes assessed. RESULTS: A total of 84,313 patients (mean age 63.3 years and 58.9% female) were hospitalized for diverticulitis (72.2% emergent/urgent). Elective colectomy increased from 7.9 to 17.2 per 100,000 people (P < 0.001), rising fastest since 2000. Emergency/urgent colectomy increased from 7.1 to 10.2 per 100,000 (P < 0.001), nonelective percutaneous interventions increased from 0.1 to 3.7 per 100,000 (P = 0.04) and the frequency of emergency/urgent admissions (with or without a resection) increased from 34.0 to 85.0 per 100,000 (P < 0.001). In 2012, 47.5% of elective resections were performed laparoscopically compared to 17.5% in 2008 (when the code was introduced). CONCLUSIONS: The elective colectomy rate for diverticulitis more than doubled, without a decrease in emergency surgery, percutaneous interventions, or admissions for diverticulitis. This may reflect changes in thresholds for elective surgery and/or an increase in the frequency or severity of the disease. These trends do not support the practice of elective colectomy to prevent emergency surgery. PMID- 26111205 TI - Nitrite accumulation performance of aerobic MBBR treating Lurgi coal gasification waste water by adjusting pollutant load and DO concentration. AB - An aerobic moving bed biofilm reactor (MBBR) was adopted to treat Lurgi coal gasification waste water (LCGW) in about 10 months. The pollutant load and dissolve oxygen (DO) concentration were adjusted by trying to maximize the accumulation of [Formula: see text] in the MBBR for LCGW treatment. The highest [Formula: see text] accumulation proportion [Formula: see text] was 73.9%, but was not stable with influent chemical oxygen demand (COD) and DO concentrations of around 1000 and 1.5 mg/L, respectively. Around 1500 mg/L of influent COD concentration and 1.5 mg/L of DO concentration were proper operation conditions for the aerobic MBBR to achieve relatively stable [Formula: see text] accumulation, with [Formula: see text] ratio at 53% and [Formula: see text] ratio at just 4.3% in the effluent. More specifically, free ammonia concentration and DO concentration affected [Formula: see text] accumulation much more obvious than phenols concentration. The activity and quantity of nitrifying bacteria growth in suspended sludge and biofilm of the MBBR were monitored simultaneously to explain the variations of [Formula: see text] accumulation performance under different operation conditions. An aerobic moving bed biofilm reactor (MBBR) was adopted to treat Lurgi coal gasification waste water (LCGW)in about 10 months. The pollutant load and dissolve oxygen (DO) concentration were adjusted by trying to maximize the accumulation of NO(-)(2)-N in the MBBR for LCGW treatment. The highest NO( )(2)-N accumulation proportion(NO(-)(2)-Neffluent/TN effluent) was 73.9%, but was not stable with influent chemical oxygen demand (COD) and DO concentrations of around 1000 and 1.5 mg/L, respectively. Around 1500 mg/L of influent COD concentration and 1.5 mg/L of DO concentration were proper operation conditions for the aerobic MBBR to achieve relatively stable NO(-)(2)-N accumulation,with NO(-)(2)-N/TN ratio at 53% and NO(-)(3)-N/TN ratio at just 4.3% in the effluent. More specifically, free ammonia concentration and DO concentration affected NO(2)(-)N accumulation much more obvious than phenols concentration. The activity and quantity of nitrifying bacteria growth in suspended sludge and biofilm of the MBBR were monitored simultaneously toexplain the variations of NO(-)(2)-N accumulation performance under different operation conditions. PMID- 26111206 TI - Differential Evolution approach to detect recent admixture. AB - The genetic structure of human populations is extraordinarily complex and of fundamental importance to studies of anthropology, evolution, and medicine. As increasingly many individuals are of mixed origin, there is an unmet need for tools that can infer multiple origins. Misclassification of such individuals can lead to incorrect and costly misinterpretations of genomic data, primarily in disease studies and drug trials. We present an advanced tool to infer ancestry that can identify the biogeographic origins of highly mixed individuals. reAdmix can incorporate individual's knowledge of ancestors (e.g. having some ancestors from Turkey or a Scottish grandmother). reAdmix is an online tool available at http://chcb.saban-chla.usc.edu/reAdmix/. PMID- 26111207 TI - Three-Dimensional Electron Microscopy Reconstruction of Degenerative Dopaminergic Neurons Surrounded by Activated Microglia in Substantia Nigra. AB - There is an urgent need to investigate the reason for the pathogenic mechanism of intractable central neurological diseases such as Parkinson's disease. It has been reported that the activation of microglial cells is involved in the pathology of these diseases. However, due to technical difficulties, the relationship between degenerative neurons and activated microglial cells remains unclear. Therefore, we tried the improved analysis technique to clarify the spatial relationship between these cell types. We were able to establish an analysis technique that consists of a three-dimensional reconstruction method using serial immunoelectron micrographs after having identified both degenerative neurons and activated microglial cells under optical microscope. Using this technique, we have relatively easily been able to clarify the spatial relationship between degenerative neurons and activated microglial cells. Furthermore, using this technique it is possible to determine the neuronal degeneration process in detail, because it is able to identify structures implicated in degeneration, such as accumulation of lipofuscin in degenerated neuronal somata and phagocytotic structures of microglial cells. In future, this technical approach may be applied to elucidate the relationship between degenerative neurons and activated glial cells in human diseases. PMID- 26111208 TI - Multimodality imaging of primary extrahepatic portal vein obstruction (EHPVO): what every radiologist should know. AB - Portal vein thrombosis (PVT) is a frequent complication of liver cirrhosis, but it can also occur as a primary vascular disorder amid absent liver disease. Extrahepatic portal vein obstruction (EHPVO) refers to the obstruction of the extrahepatic portal vein with or without involvement of the intrahepatic portal vein branches, splenic and/or superior mesenteric vein. It is a distinct disorder that excludes PVT occurring in concurrence with liver cirrhosis or hepatocellular carcinoma. The term "EHPVO" implies chronicity and is principally reserved for a long-standing condition characterized by cavernous transformation of the portal vein. The most characteristic imaging manifestation is the formation of portoportal collaterals (via the venous plexi of Petren and Saint) that allow hepatopetal flow. However, this collateral circulation is insufficient resulting in clinically significant pre-hepatic portal hypertension, wherein the liver function and structure remain preserved until late. Although the long-term (more than 10 years) survival with controlled variceal bleeding is up to 100%, affected individuals have an impaired quality of life owing to portal cavernoma cholangiopathy, hypersplenism, neurocognitive dysfunction and growth retardation. Imaging diagnosis is not always straightforward as the collaterals can also present as a tumour-like solid mass that can be inadvertently biopsied. Moreover, EHPVO has its implications for the biliary tree, arterial circulation, liver/splenic volumes and stiffness, which merit proper understanding but have not been so well described in literature. In this review, we present the complete spectrum of the vascular, biliary and visceral changes with a particular emphasis on what our medical/surgical hepatology colleagues need to know from us in the pre-operative and post-operative settings. PMID- 26111209 TI - How to Explain the Dramatic Increase Around 2000 but Recent Leveling Off of Inflammatory Bowel Disease in Korea? PMID- 26111210 TI - Immunoregulatory Pathways Involved in Inflammatory Bowel Disease. AB - Inflammatory bowel diseases (IBD) include ulcerative colitis and Crohn's disease. The immune response in ulcerative colitis is different from the Crohn's disease. Accumulating evidence suggests that IBD results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Several immunoregulatory abnormalities have been reported in patients with IBD, including the ratio of proinflammatory (tumor necrosis factor alpha, IL-6, IL-1 beta) to immunoregulatory cytokines (IL-10, TGF-beta, IL-35) and selective activation of T-helper (Th) lymphocyte subsets (Th1, Th2, Th9, Th17, and regulatory T cells). The purpose of this review is to show the immunoregulatory pathways (regulatory cells and cytokines) involved in IBD published in recent years. PMID- 26111211 TI - Comments on Measures of Obesity and Risk of Crohn's Disease and Ulcerative Colitis. PMID- 26111212 TI - Increased Incidence of Inflammatory Bowel Disease in Korea May Not Be Explained by Food Additives. PMID- 26111213 TI - Reply to Comments on Measures of Obesity and Risk of Crohn's Disease and Ulcerative Colitis. PMID- 26111214 TI - Reply to Methodological Approach to Mesalazine Treatment in Patients with Mild-to moderate Ulcerative Colitis. PMID- 26111216 TI - Ansa-bridged bis(benzene) titanium complexes. AB - Taking advantage of an improved synthesis of [Ti(eta(6) -C6 H6 )2 ], we report here the first examples of ansa-bridged bis(benzene) titanium complexes. Deprotonation of [Ti(eta(6) -C6 H6 )2 ] with nBuLi in the presence of N,N,N',N'',N''-pentamethyldiethylenetriamine (pmdta) leads to the corresponding 1,1'-dilithio salt [Ti(eta(6) -C6 H5 Li)2 ]?pmdta that enables the preparation of the first one- and two-atom-bridged complexes by simple salt metathesis. The ansa complexes were fully characterized (NMR spectroscopy, UV/Vis spectroscopy, elemental analysis, and X-ray crystallography) and further studied electrochemically and computationally. Moreover, [Ti(eta(6) -C6 H6 )2 ] is found to react with the Lewis base 1,3-dimethylimidazole-2-ylidene (IMe) to give the bent sandwich complex [Ti(eta(6) -C6 H6 )2 (IMe)]. PMID- 26111215 TI - Potential implications of dose and diet for the effects of cocoa flavanols on cardiometabolic function. AB - The metabolic syndrome is a pathological state whereby cardiovascular and metabolic dysfunction coexist and typically progress in a mutual feed-forward manner to further dysfunction and ultimately disease. The health and function of the vascular endothelium is integral in this phenomenon and thus represents a logical target for intervention. Consumption of foods high in cocoa flavanols has demonstrated a capacity to markedly improve endothelial function and key markers of the metabolic syndrome including blood pressure and insulin sensitivity. The typically high energy content of foods containing sufficient doses of cocoa flavanols has caused some reservations around its therapeutic use, but this is dependent upon the particulars of the food matrix used. Further to this, the food matrix appears to influence the dose response curve of cocoa flavanols, particularly on blood pressure, with dark chocolate appearing to be 8 times more effective in systolic blood pressure reduction than a cocoa powder drink for the equivalent dose of flavanol. Cocoa flavanol consumption conclusively demonstrates a positive impact on cardiometabolic function; however, more research is needed to understand how best to consume it to maximize the benefit while avoiding excessive fat and sugar consumption. PMID- 26111217 TI - Mechanical and Chemical Characterization of a TiC/C System Synthesized Using a Focus Plasma Arc. AB - Titanium carbide-graphite (TiC/C) composite was successfully synthesized from Ti and C starting elemental powders using self-propagating high-temperature synthesis technique in an ultra-high plasma inert medium in a single stage. The TiC was exposed to a high-temperature inert medium to allow recrystallization. The product was then characterized using field emission scanning electron microscopy (FESEM) coupled with energy dispersive X-ray analysis (EDX), X-ray diffraction (XRD), Rietveld refinement, nanoindentation, and micro-hardness to determine the product's properties. The recorded micro-hardness of the product was 3660 HV, which is a 14% enhancement and makes is comparable to TiC materials. PMID- 26111222 TI - Reversible myoclonus, asterixis, and tremor associated with high dose trimethoprim-sulfamethoxazole: a case report. AB - CASE DIAGNOSIS: Reversible myoclonus, tremor, and asterixis induced by high dose trimethoprim-sulfamethoxazole. CASE DESCRIPTION: The patient was a 66-year-old male with T9 AIS(1) C quadriplegia secondary to spinal cord compression by a tumor due to large B cell lymphoma. Subsequent to tumor resection and chemotherapy, the patient was discovered to have Pneumocystis jiroveci pneumonia (PJP). Once started on high dose trimethoprim-sulfamethoxazole (TMP-SMX) therapy (15.6 mg/kg/day of trimethoprim) for the treatment of PJP, he displayed bilateral upper extremity myoclonic jerks at rest, asterixis, and postural tremor. Symptoms resolved once TMP-SMX therapy was discontinued. DISCUSSION: Myoclonus, asterixis, and tremor have been linked to high dose TMP-SMX therapy as a toxic side effect. Our patient's symptoms did improve with levetiracetam therapy, but did not fully resolve until TMP-SMX was discontinued. CONCLUSIONS: This is thought to be the first reported case of reversible myoclonus, tremor, and asterixis induced by high dose TMP-SMX in the spinal cord injury population. Early recognition of TMP SMX induced complications were of key importance as they negatively impacted the rehabilitation process. We also recommend consideration of symptomatic treatment with levetiracetam for the duration of required TMP-SMX therapy as it appeared to mitigate the severity of our patient's movement disorders. PMID- 26111221 TI - Complementary and Alternative Medicine Use Among Women During Pregnancy and Childbearing Years. AB - OBJECTIVES: Little is known regarding complementary and alternative medicine (CAM) use during pregnancy and the preconception period. Since half of all pregnancies in the United States are unintended, understanding the patterns of CAM use among women of childbearing age has implications for fetal and maternal health. METHODS: Descriptive statistics were generated from the 2012 National Health Interview Study (NHIS) to estimate weighted prevalence and patterns of CAM use by women of childbearing age. Comparisons were made between pregnant and nonpregnant respondents. RESULTS: In this sample of 10,002 women, 7 percent (n = 727) were recently pregnant. Over one-third of all the women used CAM during the previous year (34/38%, pregnant/nonpregnant, respectively) and only half disclosed CAM use to conventional providers (50/49%). In the adjusted model, taking multivitamins (OR 2.52 [CI 2.22-2.86]) and moderate to heavy alcohol use (OR 1.92 [CI 1.53-2.41]) were more likely associated with CAM use. The two most commonly used modalities were herbs (14/17%) and yoga (13/16%). The top reasons for CAM use were to improve general wellness or to prevent disease (33/35%) and to treat back pain (16/18%). When examining all pregnancy-related symptoms treated with CAM, no difference was found in the rates of CAM use between pregnant and nonpregnant users. CONCLUSIONS: CAM use by women of childbearing age in the United States is common, with over a third of the population using one or more therapies. However, only half disclosed their use to conventional providers despite limited evidence on safety and effectiveness. This study highlights the important need for further research in this area. PMID- 26111223 TI - Development of an obstetrics triage tool for clinical pharmacists. AB - WHAT IS KNOWN AND OBJECTIVES: Obstetrics services are a high-throughput and high risk environment poised for pharmacist involvement, but determining how to ideally allocate services is difficult. There is recent interest in the development of tools for service prioritization, but none are specifically targeted to obstetrics. Therefore, the aim of this study was (i) to conduct a practice audit surveying the demographics of patients attending obstetrics wards at a high-capacity maternity hospital; and (ii) to evaluate a triage tool developed to prioritize pharmacy services. METHODS: A retrospective case review of women discharged after birth admissions was undertaken at a hospital in National Health Service (NHS) Scotland during June 2014. Demographic and admission data were collected, as well as pharmacist interventions and missed opportunities in patient care on post-natal wards. A pharmacy triage tool was developed and retrospectively applied to each case to ascertain a risk category that would trigger and target pharmacist review. Interventions/opportunities were classified as either clinical (medication related) or administrative (potential for error development). RESULTS AND DISCUSSION: One hundred and seventy-five cases were reviewed with a median age of 29 years old. Eighty-six patients (49.1%) were retrospectively classified with elevated risk using the triage tool. A total of 117 charts (66.9%) were identified with missed opportunities for pharmacist intervention, which was significantly greater among patients classified as higher risk (75.6 vs. 58.4%, P = 0.017). Compared to low-risk patients, patients with a higher-risk classification had lower rates of administrative missed opportunities (55.4 vs. 80.8%, P = 0.015), but numerically higher rates of clinical (26.2 vs. 9.6%, p=NS) and mixed clinical/administrative (18.5 vs. 9.6%, p=NS) missed opportunities, although this failed to reach statistical significance. WHAT IS NEW AND CONCLUSION: Evaluation of a triage tool for obstetric services demonstrated potential for prioritizing higher-risk patients for pharmacist review and addressing opportunities for clinical improvements. PMID- 26111224 TI - Multivalent 3D Display of Glycopolymer Chains for Enhanced Lectin Interaction. AB - Synthetic glycoprotein conjugates were synthesized through the polymerization of glycomonomers (mannose and/or galactose acrylate) directly from a protein macroinitiator. This design combines the multivalency of polymer structures with 3D display of saccharides randomly arranged around a central protein structure. The conjugates were tested for their interaction with mannose binding lectin (MBL), a key protein of immune complement. Increasing mannose number (controlled through polymer chain length) and density (controlled through comonomer feed ratio of mannose versus galactose) result in greater interaction with MBL. Most significantly, mannose glycopolymers displayed in a multivalent and 3D configuration from the protein exhibit dramatically enhanced interaction with MBL compared to linear glycopolymer chains with similar total valency but lacking 3D display. These findings demonstrate the importance of the 3D presentation of ligand structures for designing biomimetic materials. PMID- 26111225 TI - Cross-cultural adaptation and validation of the Danish consensus version of the 10-item Perceived Stress Scale. AB - OBJECTIVES: The aims of the present study were to (i) cross-culturally adapt a Danish consensus version of the 10-item Perceived Stress Scale (PSS-10) and (ii) evaluate its psychometric properties in terms of agreement, reliability, validity, responsiveness, and interpretability among patients with work-related stress complaints. METHODS: A consensus-building process was performed involving the authors of the three previous Danish translations and the consensus version was back-translated into English and pilot-tested. Psychometric properties of the final version were examined in a sample of 64 patients with work-related stress complaints. RESULTS: The face validity, reliability, and internal consistency of the Danish consensus version of the PSS-10 were satisfactory, and convergent construct validity was confirmed. Receiver operating characteristic (ROC) curves of the change scores showed that the ability of the PSS-10 to correctly classify patients as improved or unchanged according to the patients' own judgment was acceptable. The estimates of minimal clinically important change were 11 points and 28% for absolute and relative change scores, respectively. CONCLUSION: The Danish consensus version of the PSS-10 appears to be feasible for use in clinical research settings and has good psychometric properties in terms of agreement, reliability, validity, responsiveness, and interpretability. PMID- 26111226 TI - Active Drumming Experience Increases Infants' Sensitivity to Audiovisual Synchrony during Observed Drumming Actions. AB - In the current study, we examined the role of active experience on sensitivity to multisensory synchrony in six-month-old infants in a musical context. In the first of two experiments, we trained infants to produce a novel multimodal effect (i.e., a drum beat) and assessed the effects of this training, relative to no training, on their later perception of the synchrony between audio and visual presentation of the drumming action. In a second experiment, we then contrasted this active experience with the observation of drumming in order to test whether observation of the audiovisual effect was as effective for sensitivity to multimodal synchrony as active experience. Our results indicated that active experience provided a unique benefit above and beyond observational experience, providing insights on the embodied roots of (early) music perception and cognition. PMID- 26111228 TI - Authors' Response. PMID- 26111227 TI - Transcutaneous Electrical Nerve Stimulation Increases Rectal Activity in Children. AB - OBJECTIVES: Neurostimulation is increasingly used in treating bladder and bowel dysfunction, but its effect on rectal motility is obscure. The aim of the study was to evaluate the acute effect of transcutaneous electrical nerve stimulation (TENS) on rectal motility in children with overactive bladder (OAB). METHODS: In this double-blind placebo-controlled study in 20 children with OAB (mean age 8.6 +/- 1.8 years; 7 girls), 48-hour urodynamic monitoring including rectal manometry was performed. After 24-hours of baseline investigation without stimulation the children were randomised to either active TENS (n = 10) or placebo (n = 10). Surface electrodes were placed over the sacral bone. The exterior of active and placebo stimulators was identical. Starting in the morning, the children received either continuous TENS stimulation or placebo until bedtime. Rectal contractions were defined as pressure runs exceeding 5 cm H2O and lasting >=3 minutes. RESULTS: At baseline there was no significant difference in proportion of time with rectal contractions in the 2 groups (TENS group median 31% [range 12%-66%] vs placebo group median 31% [range 10%-66%]; P = 0.75); however, on the day of stimulation there was more time with rectal contractions in the group receiving TENS (median 51% [range 25%-78%]) compared with placebo (median 32% [range 4% 68%]; P = 0.02). Also, there was an increase in time with rectal contractions in the TENS group (P = 0.007) but not in the placebo group (P = 0.39). The night after the TENS was disabled, rectal activity in both groups returned to baseline level. CONCLUSIONS: TENS acutely increases time with rectal contractions in children undergoing urodynamic investigation. The effect disappears when the stimulator is turned off. PMID- 26111230 TI - State-of-the-Art in the Computational Analysis of Cytometry Data. PMID- 26111229 TI - Drug survival for methotrexate in a daily practice cohort of adult patients with severe atopic dermatitis. PMID- 26111235 TI - Imported case of MERS-CoV infection identified in China, May 2015: detection and lesson learned. AB - At the end of May 2015, an imported case of Middle East respiratory syndrome coronavirus (MERS-CoV) infection was confirmed in China. The patient is in a stable condition and is still undergoing treatment. In this report, we summarise the preliminary findings for this imported case and the results of contact tracing. We identified 78 close contacts and after 14 days of monitoring and isolation, none of the contacts presented symptoms and all tested negative for MERS-CoV. PMID- 26111236 TI - Emergence of a new GII.17 norovirus variant in patients with acute gastroenteritis in Jiangsu, China, September 2014 to March 2015. AB - From September 2014 to March 2015, 23 outbreaks of norovirus (NoV) acute gastroenteritis occurred in Jiangsu, China. Partial sequencing of the NoV capsid gene suggested that 16 of the 23 outbreaks were related to a new GII.17 variant. This variant was first detected in sporadic specimens in October 2014, and became predominant in February 2015. Analysis of the RNA-dependent RNA polymerase (RdRp), and complete capsid including the protruding domain P2 sequences confirmed this GII.17 variant as distinct from previously identified GII variants. PMID- 26111237 TI - Detection of livestock-associated meticillin-resistant Staphylococcus aureus CC398 in retail pork, United Kingdom, February 2015. AB - Livestock-associated meticillin-resistant Staphylococcus aureus belonging to clonal complex 398 (LA-MRSA CC398) is an important cause of zoonotic infections in many countries. Here, we describe the isolation of LA-MRSA CC398 from retail meat samples of United Kingdom (UK) farm origin. Our findings indicate that this lineage is probably established in UK pig farms and demonstrate a potential pathway for the transmission of LA-MRSA CC398 from livestock to humans in the UK. PMID- 26111238 TI - Systematic review of fever, febrile convulsions and serious adverse events following administration of inactivated trivalent influenza vaccines in children. AB - In 2010, increased febrile convulsions (FC) occurred after administration of inactivated trivalent influenza vaccine (TIV) in Australia. We systematically reviewed the rates of fever, FC and serious adverse events (SAEs) after TIV, focussing on published and unpublished clinical trial data from 2005 to 2012, and performed meta-analysis of fever rates. From 4,372 records in electronic databases, 18 randomised controlled trials (RCTs), 14 non-randomised clinical trials, six observational studies and 12 registered trials (five RCTs and seven non-randomised) were identified. In published RCTs, fever >= 38 degrees C rates after first dose of non-adjuvanted TIV were 6.7% and 6.9% for children aged 6-35 months and >= 3 years, respectively. Analysis of RCTs by vaccine manufacturer showed pooled fever estimates up to 5.1% with Sanofi or GlaxoSmithKline vaccines; bioCSL vaccines were used in two non-randomised clinical trials and one unpublished RCT and were associated with fever in 22.5-37.1% for children aged 6 35 months. In RCTs, FCs occurred at a rate of 1.1 per 1,000 vaccinated children. While most TIVs induced acceptably low fever rates, bioCSL influenza vaccines were associated with much higher rates of fever in young children. Future standardised study methodology and access to individual level data would be illuminating. PMID- 26111239 TI - Waterborne outbreaks in the Nordic countries, 1998 to 2012. AB - A total of 175 waterborne outbreaks affecting 85,995 individuals were notified to the national outbreak surveillance systems in Denmark, Finland and Norway from 1998 to 2012, and in Sweden from 1998 to 2011. Between 4 and 18 outbreaks were reported each year during this period. Outbreaks occurred throughout the countries in all seasons, but were most common (n = 75/169, 44%) between June and August. Viruses belonging to the Caliciviridae family and Campylobacter were the pathogens most frequently involved, comprising n = 51 (41%) and n = 36 (29%) of all 123 outbreaks with known aetiology respectively. Although only a few outbreaks were caused by parasites (Giardia and/or Cryptosporidium), they accounted for the largest outbreaks reported during the study period, affecting up to 53,000 persons. Most outbreaks, 124 (76%) of those with a known water source (n = 163) were linked to groundwater. A large proportion of the outbreaks (n = 130/170, 76%) affected a small number of people (less than 100 per outbreak) and were linked to single-household water supplies. However, in 11 (6%) of the outbreaks, more than 1,000 people became ill. Although outbreaks of this size are rare, they highlight the need for increased awareness, particularly of parasites, correct water treatment regimens, and vigilant management and maintenance of the water supply and distribution systems. PMID- 26111240 TI - Outbreak of psittacosis in a group of women exposed to Chlamydia psittaci infected chickens. AB - Eight cases of psittacosis due to Chlamydia psittaci were identified in May 2013 among 15 individuals involved in chicken gutting activities on a mixed poultry farm in France. All cases were women between 42 and 67 years-old. Cases were diagnosed by serology and PCR of respiratory samples. Appropriate treatment was immediately administered to the eight hospitalised individuals after exposure to birds had been discovered. In the chicken flocks, mainly C. gallinacea was detected, a new member of the family Chlamydiaceae, whereas the ducks were found to harbour predominantly C. psittaci, the classical agent of psittacosis. In addition, C. psittaci was found in the same flock as the chickens that the patients had slaughtered. Both human and C. psittaci-positive avian samples carried the same ompA genotype E/B of C. psittaci, which is widespread among French duck flocks. Repeated grassland rotations between duck and chicken flocks on the farm may explain the presence of C. psittaci in the chickens. Inspection by the veterinary service led to temporary closure of the farm. All birds had to be euthanised on site as no slaughterhouses accepted processing them. Farm buildings and grasslands were cleaned and/or disinfected before the introduction of new poultry birds. PMID- 26111241 TI - Erratum for Euro Surveill. 2015;20(12). PMID- 26111243 TI - Reliability of an Adapted Version of the Modified Six Elements Test as a Measure of Executive Function. AB - The Modified Six Elements Test (MSET) is used to examine executive deficits-more specifically, planning deficits. This study investigates the reliability of an adapted version of the MSET and proposes a novel scoring method. Two parallel versions of the adapted MSET were administered in 60 healthy participants in a counterbalanced order. Test-retest and parallel-form reliability were examined using intraclass correlation coefficients, Bland-Altman analyses, standard errors of measurement, and smallest real differences, representing clinically relevant changes over time. Moreover, the ecological validity of the adapted MSET was evaluated using the Executive Function Index, a self-rating questionnaire measuring everyday executive performance. No systematic differences between the test occasions were present, and the adapted MSET including the proposed scoring method was capable of detecting real clinical changes. Intraclass correlations for the test-retest and parallel-form reliability were modest, and the variability between the test scores was high. The nonsignificant correlations with the Executive Function Index did not confirm the previously established ecological validity of the MSET. We show that both parallel versions of the test are clinically equivalent and can be used to measure executive function over the course of time without task-specific learning effects. PMID- 26111242 TI - Plasma HIV-2 RNA According to CD4 Count Strata among HIV-2-Infected Adults in the IeDEA West Africa Collaboration. AB - BACKGROUND: Plasma HIV-1 RNA monitoring is one of the standard tests for the management of HIV-1 infection. While HIV-1 RNA can be quantified using several commercial tests, no test has been commercialized for HIV-2 RNA quantification. We studied the relationship between plasma HIV-2 viral load (VL) and CD4 count in West African patients who were either receiving antiretroviral therapy (ART) or treatment-naive. METHOD: A cross sectional survey was conducted among HIV-2 infected individuals followed in three countries in West Africa from March to December 2012. All HIV-2 infected-patients who attended one of the participating clinics were proposed a plasma HIV-2 viral load measurement. HIV-2 RNA was quantified using the new ultrasensitive in-house real-time PCR assay with a detection threshold of 10 copies/ mL (cps/mL). RESULTS: A total of 351 HIV-2 infected individuals participated in this study, of whom 131 (37.3%) were treatment naive and 220 (62.7%) had initiated ART. Among treatment-naive patients, 60 (46.5%) had undetectable plasma HIV-2 viral load (<10 cps/mL), it was detectable between 10-100 cps/mL in 35.8%, between 100-1000 cps/mL in 11.7% and >1000 cps/mL in 6.0% of the patients. Most of the treatment-naive patients (70.2%) had CD4-T cell count >=500 cells/mm3 and 43 (46.7%) of these patients had a detectable VL (>=10 cps/mL). Among the 220 patients receiving ART, the median CD4-T cell count rose from 231 to 393 cells/mm3 (IQR [259-561]) after a median follow-up duration of 38 months and 145 (66.0%) patients had CD4-T cell count <= 500 cells/mm3 with a median viral load of 10 cps/mL (IQR [10-33]). Seventy five (34.0%) patients had CD4-T cell count >= 500 cells/mm3, among them 14 (18.7%) had a VL between 10-100 cps/mL and 2 (2.6%) had VL >100 cps/mL. CONCLUSION: This study suggests that the combination of CD4-T cell count and ultrasensitive HIV-2 viral load quantification with a threshold of 10 cps/mL, could improve ART initiation among treatment naive HIV-2-infected patients and the monitoring of ART response among patients receiving treatment. PMID- 26111244 TI - The Decay of Motor Memories Is Independent of Context Change Detection. AB - When the error signals that guide human motor learning are withheld following training, recently-learned motor memories systematically regress toward untrained performance. It has previously been hypothesized that this regression results from an intrinsic volatility in these memories, resulting in an inevitable decay in the absence of ongoing error signals. However, a recently-proposed alternative posits that even recently-acquired motor memories are intrinsically stable, decaying only if a change in context is detected. This new theory, the context dependent decay hypothesis, makes two key predictions: (1) after error signals are withheld, decay onset should be systematically delayed until the context change is detected; and (2) manipulations that impair detection by masking context changes should result in prolonged delays in decay onset and reduced decay amplitude at any given time. Here we examine the decay of motor adaptation following the learning of novel environmental dynamics in order to carefully evaluate this hypothesis. To account for potential issues in previous work that supported the context-dependent decay hypothesis, we measured decay using a balanced and baseline-referenced experimental design that allowed for direct comparisons between analogous masked and unmasked context changes. Using both an unbiased variant of the previous decay onset analysis and a novel highly-powered group-level version of this analysis, we found no evidence for systematically delayed decay onset nor for the masked context change affecting decay amplitude or its onset time. We further show how previous estimates of decay onset latency can be substantially biased in the presence of noise, and even more so with correlated noise, explaining the discrepancy between the previous results and our findings. Our results suggest that the decay of motor memories is an intrinsic feature of error-based learning that does not depend on context change detection. PMID- 26111246 TI - The clinical application of plasma Kaposi sarcoma herpesvirus viral load as a tumour biomarker: results from 704 patients. AB - OBJECTIVES: The aim of the study was to evaluate the role of plasma Kaposi sarcoma herpesvirus (KSHV) as a diagnostic and prognostic biomarker in people living with HIV (PLWH) and diagnosed with KSHV-associated diseases. METHODS: Using quantitative nested polymerase chain reaction (PCR) targeting the open reading frame-26 gene of KSHV, plasma levels of KSHV were measured in consecutive PLWH with KSHV-associated diseases or as part of the investigation of lymphadenopathy. RESULTS: Plasma KSHV assays were performed on samples from 684 PLWH and 20 HIV-seronegative people with KSHV-associated malignancies. In PLWH, plasma KSHV was detected in 39% of those with KS, 99% of those with multicentric Castleman disease (MCD), 9% of those with non-Hodgkin lymphoma (NHL), 2% of those with non-AIDS-defining malignancies and 0% of those with nonmalignant lymphadenopathy. There was no significant difference in plasma KSHV viral load among those with KS, MCD and KSHV-associated NHL. The 5-year overall survival rate from KS diagnosis of 335 PLWH was 95.2% (95% confidence interval 92.6 97.8%). Plasma KSHV viraemia did not predict overall survival in those with KS (P = 0.73), nor when those with T0 stage KS (P = 0.52) or T1 stage KS (P = 0.62) were analysed separately. CONCLUSIONS: Measuring the plasma levels of KSHV as a biomarker in KSHV-associated disease has a very limited value in either diagnosis or prognostication. The only potential role of clinical value is the suggestion that an undetectable plasma KSHV excludes a diagnosis of MCD in PLWH. PMID- 26111245 TI - Doxycycline Induces Apoptosis and Inhibits Proliferation and Invasion of Human Cervical Carcinoma Stem Cells. AB - BACKGROUND: Cancer stem cells (CSCs) are proposed to be responsible for high recurrence rate in cervical carcinoma. Reagents that can suppress the proliferation and differentiation of CSCs would provide new opportunities to fight against tumor recurrence. Doxycycline has been reported as a potential anti cancer compound. However, few studies investigated its inhibitory effect against cervical cancer stem cells. METHODS: HeLa cells were cultured in cancer stem cell conditional media in a poly-hema-treated dish. In this non-adhesive culture system, HeLa cells were treated with cisplatin until some cells survived and formed spheroids, which were then collected and injected into the immunodeficient mice. Cisplatin was administered every three days for five times. The tumor xenografts with CSC enrichment were cultured in cancer stem cell specific medium again to form tumorsphere, which we called HeLa-CSCs. Expression of cancer stem cell markers in HeLa-CSCs was measured by flow cytometry and qPCR. HeLa-CSCs were then treated with doxycycline. Proliferation and differentiation rates were determined by the size of spheres formed in vitro and tumor formed in vivo. RESULTS: We developed a new strategy to selectively enrich CSCs from human cervical carcinoma cell line HeLa, and these HeLa-CSCs are CD133+/CD49f+ cell populations with significantly enhanced expression of stem cell markers. When these HeLa-CSCs were treated with doxycycline, the colony formation, proliferation, migration and invasion, and differentiation were all suppressed. Meanwhile, stem cell markers SOX-2, OCT-4, NANOG, NOTCH and BMI-1 decreased in doxycycline treated cells, so as the surface markers CD133 and CD49f. Furthermore, proliferation markers Ki67 and PCNA were also decreased by doxycycline treatment in the in vivo xenograft mouse model. CONCLUSIONS: Cancer stem cells are enriched from sphere-forming and chemoresistant HeLa-derived tumor xenografts in immunodeficient mice. Doxycycline inhibits proliferation, invasion, and differentiation, and also induces apoptosis of these HeLa-CSCs in vitro and in vivo. PMID- 26111247 TI - Association of rivaroxaban anticoagulation and spontaneous vitreous hemorrhage. AB - IMPORTANCE: Rivaroxaban is an anticoagulant prescribed for the management of atrial fibrillation. We describe a correlation between rivaroxaban and spontaneous vitreous hemorrhage. OBSERVATIONS: Three patients developed spontaneous vitreous hemorrhage after initiating rivaroxaban anticoagulation. All 3 patients were taking an additional anticoagulant at the time of hemorrhage. CONCLUSIONS AND RELEVANCE: Rivaroxaban is increasingly prescribed as a replacement for warfarin sodium in the management of atrial fibrillation. Rivaroxaban anticoagulation may be associated with spontaneous vitreous hemorrhage. The risk of hemorrhage may be particularly elevated during the transition period when patients are switched from baseline anticoagulant to rivaroxaban therapy and are taking both anticoagulants simultaneously. PMID- 26111248 TI - Emotional Processing, Interaction Process, and Outcome in Clarification-Oriented Psychotherapy for Personality Disorders: A Process-Outcome Analysis. AB - It is important to understand the change processes involved in psychotherapies for patients with personality disorders (PDs). One patient process that promises to be useful in relation to the outcome of psychotherapy is emotional processing. In the present process-outcome analysis, we examine this question by using a sequential model of emotional processing and by additionally taking into account a therapist's appropriate responsiveness to a patient's presentation in clarification-oriented psychotherapy (COP), a humanistic-experiential form of therapy. The present study involved 39 patients with a range of PDs undergoing COP. Session 25 was assessed as part of the working phase of each therapy by external raters in terms of emotional processing using the Classification of Affective-Meaning States (CAMS) and in terms of the overall quality of therapist patient interaction using the Process-Content-Relationship Scale (BIBS). Treatment outcome was assessed pre- and post-therapy using the Global Severity Index (GSI) of the SCL-90-R and the BDI. Results indicate that the good outcome cases showed more self-compassion, more rejecting anger, and a higher quality of therapist-patient interaction compared to poorer outcome cases. For good outcome cases, emotional processing predicted 18% of symptom change at the end of treatment, which was not found for poor outcome cases. These results are discussed within the framework of an integrative understanding of emotional processing as an underlying mechanism of change in COP, and perhaps in other effective therapy approaches for PDs. PMID- 26111250 TI - Disappointed Love and Suicide: A Randomized Controlled Trial of "Abandonment Psychotherapy" Among Borderline Patients. AB - To determine whether ambulatory psychotherapy targeted to abandonment experiences and fears can reduce suicidality and improve outcome in borderline patients referred to the emergency room with major depressive disorder and self destructive behavior severe enough to require medical/surgical treatment and a brief psychiatric hospitalization. A total of 170 subjects were randomized at hospital discharge into three treatment groups: treatment as usual (TAU), abandonment psychotherapy delivered by certified psychotherapists, and abandonment psychotherapy delivered by nurses. Assessments were performed before randomization and at 3-month follow-up. Continued suicidality and other outcome measures were significantly worse in the treatment-as-usual as compared to both abandonment psychotherapy groups, but there were no differences between the two psychotherapy groups. These results suggest the efficacy of manualized psychotherapy that specifically targets the abandonment fears and experiences that are so common as precipitants to suicidal and self-destructive acts in borderline patients. It does not appear that formal psychotherapy training is associated with better outcomes. PMID- 26111249 TI - The Effect of Attending Good Psychiatric Management (GPM) Workshops on Attitudes Toward Patients With Borderline Personality Disorder. AB - The effect that attending a 1-day workshop on Good Psychiatric Management (GPM) had on attitudes about borderline personality disorder (BPD) was assessed among 297 clinicians. Change was recorded by comparing before and after scores on a 9 item survey previously developed to assess the effects of workshops on Systems Training for Emotional Predictability and Problem Solving (STEPPS). Participants reported decreased inclination to avoid borderline patients, dislike of borderline patients, and belief that BPD's prognosis is hopeless, as well as increased feeling of competence, belief that borderline patients have low self esteem, feeling of being able to make a positive difference, and belief that effective psychotherapies exist. Less clinical experience was related to an increased feeling of competence and belief that borderline patients have low self esteem. These findings were compared to those from the STEPPS workshop. This assessment demonstrates GPM's potential for training clinicians to meet population-wide needs related to borderline personality disorder. PMID- 26111251 TI - Documenting Differences between Early Stone Age Flake Production Systems: An Experimental Model and Archaeological Verification. AB - This study investigates morphological differences between flakes produced via "core and flake" technologies and those resulting from bifacial shaping strategies. We investigate systematic variation between two technological groups of flakes using experimentally produced assemblages, and then apply the experimental model to the Cutting 10 Mid -Pleistocene archaeological collection from Elandsfontein, South Africa. We argue that a specific set of independent variables--and their interactions--including external platform angle, platform depth, measures of thickness variance and flake curvature should distinguish between these two technological groups. The role of these variables in technological group separation was further investigated using the Generalized Linear Model as well as Linear Discriminant Analysis. The Discriminant model was used to classify archaeological flakes from the Cutting 10 locality in terms of their probability of association, within either experimentally developed technological group. The results indicate that the selected independent variables play a central role in separating core and flake from bifacial technologies. Thickness evenness and curvature had the greatest effect sizes in both the Generalized Linear and Discriminant models. Interestingly the interaction between thickness evenness and platform depth was significant and played an important role in influencing technological group membership. The identified interaction emphasizes the complexity in attempting to distinguish flake production strategies based on flake morphological attributes. The results of the discriminant function analysis demonstrate that the majority of flakes at the Cutting 10 locality were not associated with the production of the numerous Large Cutting Tools found at the site, which corresponds with previous suggestions regarding technological behaviors reflected in this assemblage. PMID- 26111253 TI - Effects of graphene modification on the bioactivation of polyethylene terephthalate-based artificial ligaments. AB - The objective of this study was to investigate whether surface coating with graphene could enhance the surface bioactivation of PET-based artificial ligaments to accelerate graft-to-bone healing after anterior cruciate ligament reconstruction. In an in vitro study, the proliferation of MC3T3-E1 cells and their differentiation on the scaffolds were quantified via 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide and real-time polymerase chain reaction assays. The significantly higher optical-density values and transcription levels of osteoblast-specific genes indicated that graphene modification could promote the proliferation of MC3T3-E1 cells and accelerate their specific differentiation into osteogenic lineages on scaffolds. In an in vivo test, rabbits were used to establish an extra-articular graft-to-bone healing model. At 4, 8, and 12 weeks after surgery, biomechanical tests, microcomputed tomography analysis, and histological observations were performed. The final results demonstrated that the microstructural parameters, the average mineral apposition rate of the bone, and the biomechanical properties of the graphene-coated polyethylene terephthalate (PET)-based artificial ligament (G-PET-AL) group were significantly higher than those of the PET-AL graft group (P < 0.05). The results of Van Gieson staining indicated that in the G-PET-AL group, there was more newly formed bone than there was in the group in which nongraphene-coated PET-ALs were used. In conclusion, graphene exhibits considerable potential for enhancing the surface bioactivation of materials. PMID- 26111254 TI - Blood donation in China: sustaining efforts and challenges in achieving safety and availability. AB - China has entered a new phase in blood safety and availability through persistent efforts in the past decades. Based on national data from 2008 to 2012, we present a comprehensive review on the blood services ranging from policy and organization, supply, donors, screening and processing, and clinical use to government response in contemporary China. Current evidence suggests that the Chinese blood industries, after continual efforts in reforms on the legal framework and national management system, have been in a relatively steady but bottleneck stage. Although the blood industries have had an impressive track record on management and resolving problems, such as low availability, limited donors, deficient laboratory tests, shortage of blood products, and unnecessary clinical usage of blood still exist nationwide. While medical technology and services have seen a rapid increase in progress in recent years, they have not coordinated with the development of the national health care system. This article presents an analysis with detailed data, rich contents, and recent response from the Chinese government, allowing readers to appreciate how China, a country with more than 19.13% of the world's population, has long endeavored to improve safety and availability of blood. Meantime, the article sincerely welcomes the guidance on policymaking and technical assistance from the international community. Data in this article do not include those of Hong Kong, Macao, or Taiwan. PMID- 26111255 TI - Photosynthesis and isoprene emission from trees along an urban-rural gradient in Texas. AB - Isoprene emission is an important mechanism for improving the thermotolerance of plant photosystems as temperatures increase. In this study, we measured photosynthesis and isoprene emission in trees along an urban-rural gradient that serves as a proxy for climate change, to understand daily and seasonal responses to changes in temperature and other environmental variables. Leaf-level gas exchange and basal isoprene emission of post oak (Quercus stellata) and sweet gum (Liquidambar styraciflua) were recorded at regular intervals over an entire growing season at urban, suburban, and rural sites in eastern Texas. In addition, the temperature and atmospheric carbon dioxide concentration experienced by leaves were experimentally manipulated in spring, early summer, and late summer. We found that trees experienced lower stomatal conductance and photosynthesis and higher isoprene emission, at the urban and suburban sites compared to the rural site. Path analysis indicated a daily positive effect of isoprene emission on photosynthesis, but unexpectedly, higher isoprene emission from urban trees was not associated with improved photosynthesis as temperatures increased during the growing season. Furthermore, urban trees experienced relatively higher isoprene emission at high CO2 concentrations, while isoprene emission was suppressed at the other sites. These results suggest that isoprene emission may be less beneficial in urban, and potentially future, environmental conditions, particularly if higher temperatures override the suppressive effects of high CO2 on isoprene emission. These are important considerations for modeling future biosphere-atmosphere interactions and for understanding tree physiological responses to climate change. PMID- 26111256 TI - Potential Impact of Food Safety Vaccines on Health Care Costs. AB - Foodborne pathogens continue to cause several outbreaks every year in many parts of the world. Among the bacterial pathogens involved, Shiga toxin-producing Escherichia coli, Campylobacter jejuni, and nontyphoidal Salmonella species cause a significant number of human infections worldwide, resulting in a huge annual economic burden that amounts to millions of dollars in health care costs. Human infections are primarily caused by the consumption of contaminated food. Vaccination of food-producing animals is an attractive, cost-effective strategy to lower the levels of these pathogens that will ultimately result in a safer food supply and fewer human infections. However, producers are often reluctant to routinely vaccinate animals against these pathogens since they do not cause any detectable clinical symptoms. This review highlights recent approaches used to develop effective food safety vaccines and the potential impact these vaccines might have on health care costs. PMID- 26111257 TI - Short-term Exposure to Ambient Fine Particulate Matter Increases Hospitalizations and Mortality in COPD: A Systematic Review and Meta-analysis. AB - BACKGROUND: Many epidemiologic studies have documented variable relationships between ambient particulate matter (PM) and COPD hospitalizations and mortality in cities worldwide. METHODS: Comprehensive and systematic searches were performed in the electronic reference databases (PubMed, EMBASE, Google Scholar, Ovid, and Web of Science) with specific search terms and selection criteria for relevant studies. Summary ORs and 95% CIs were calculated to evaluate the relationship between short-term exposure to PM with aerodynamic diameters <= 2.5 MUm (PM2.5) and COPD hospitalizations and mortality. The sources of heterogeneity and the effect of potential confounders were explored using subgroup analyses. Study findings were analyzed using a random effects model and a fixed effects model in COPD hospitalizations and mortality, respectively. RESULTS: The search yielded 12 studies suitable for meta-analysis of hospitalizations and six studies suitable for the mortality meta-analysis until April 15, 2015. A 10-MUg/m(3) increase in daily PM2.5 (lag days 0-7) was associated with a 3.1% (95% CI, 1.6% 4.6%) increase in COPD hospitalizations and a 2.5% (95% CI, 1.5%-3.5%) increase in COPD mortality. Significant publication bias was not found in studies focusing on the relationship between short-term PM2.5 exposure and COPD hospitalizations and mortality. CONCLUSIONS: Our combined analysis indicated that short-term exposure to a 10-MUg/m(3) increment of ambient PM2.5 is associated with increased COPD hospitalizations and mortality. Further study is needed to elucidate to what extent this relationship is causal, together with other factors, and to elucidate the mechanism by which PM2.5 induces activation of cellular processes promoting COPD exacerbations. PMID- 26111258 TI - Hydrogel Antimicrobial Capture Coatings for Endotracheal Tubes: A Pharmaceutical Strategy Designed to Prevent Ventilator-Associated Pneumonia. AB - This paper presents a novel strategy for the prevention of ventilator-associated pneumonia that involves coating poly(vinyl chloride, PVC) endotracheal tubes (ET) with hydrogels that may be subsequently used to entrap nebulized antimicrobial solutions. Candidate hydrogels were prepared containing a range of ratios of hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA) from 100:0 to 70:30 using free radical polymerization and, when required, simultaneous attachment to PVC was performed. The mechanical properties, glass transition temperatures, swelling kinetics, uptake of gentamicin from an aqueous medium, and gentamicin release were characterized. Increasing the MAA content of the hydrogels significantly decreased the ultimate tensile strength, % elongation at break, Young's modulus, and increased the glass transition temperature, the swelling ratio, and gentamicin uptake. Microbial (Staphylococcus aureus and Pseudomonas aeruginosa) adherence to control (drug-free) hydrogels was observed; however, while adherence to gentamicin-containing p(HEMA) occurred, no adherence occurred to gentamicin-containing HEMA:MAA copolymers. Antimicrobial persistence of gentamicin-containing hydrogels was examined by determining the zone of inhibition against each microorganism on successive days. Hydrogel composition affected the observed antimicrobial persistence, with the hydrogel composed of 70:30 HEMA:MAA exhibiting >20 days persistence against S. aureus and P. aeruginosa, respectively. To simulate clinical use, the hydrogels (coated onto PVC) were first exposed to a nebulized solution of gentamicin (4 mL, 80 mg for 20 min), and then to nebulized bacteria (4 mL ca. 1*10(9) colony forming units mL( 1), 30 min). Viable bacteria were not observed on the gentamicin-treated p(HEMA: MAA) copolymers, whereas growth was observed on gentamicin-treated p(HEMA). In light of the excellent antimicrobial activity and physicochemical properties, p(HEMA: MAA) copolymers composed of ratios of 80:20 or 70:30 HEMA: MAA were identified as potentially useful coatings of endotracheal tubes to be used in conjunction with the clinical nebulization of gentamicin and designed for the prevention of ventilator-associated pneumonia. PMID- 26111259 TI - Can Nitriles Be Stronger Bases Than Proton Sponges in the Gas Phase? A Computational Analysis. AB - DFT calculations have been performed for a series of push-pull nitriles [(R2N)n(X?Y)iC=N, where i = 0, 1, or 2, n = 1, 2, or 3, R2N = H2N, Me2N, or C4H8N, X = CH, N, or P, Y = CH or N]. The possible protonation N-sites (N-cyano, N-imino, and N-amino) have been examined and their proton affinities (PA) estimated. For all compounds in the series, even for those containing the guanidino, phosphazeno, and diphosphazeno pushing groups, the N-cyano atom is the favored site of protonation. The n-pi conjugation strongly decreases the PA value of the pushing amino group in favor of the pulling cyano one. Nitriles with the phosphazeno groups [(R2N)3P?N-P(R2N)2?N and (R2N)3P?N] exhibit the strongest basicity in the series. Some of them (with PA > 1000 kJ mol(-1)) are stronger bases than DMAN, the so-called "proton sponge". Nitriles bearing the guanidino group [(R2N)2C?N] are less basic than those with the phosphazeno group [(R2N)3P?N] but more basic than those with the formamidino group (R2N-CH?N) containing the same substituent R. The N-imino atoms, present in the transmitter group (X?N, X = CH, N, or P), display PA values lower than those of the N-cyano site by more than 30 kJ mol(-1). When proceeding from the unsubstituted derivatives (R = H) to the methylated ones (R = Me), the Me groups at the N-amino atom increase the PA value of the N-cyano site for Me2N-X?Y-C=N (X, Y = CH or N) by ca. 30-60 kJ mol(-1). For the guanidino and phosphazeno derivatives containing two and three amino groups, respectively, this effect is not additive. The four Me groups for (Me2N)2C?N-C=N and the six Me groups for (Me2N)3P?N-C=N increase the PA(N-cyano) values by only 30-50 kJ mol(-1). The C=N bond lengths of the neutral forms are well correlated with the PA(N-cyano) values. PMID- 26111260 TI - Fussy eating and feeding difficulties in infants and toddlers consuming a cows' milk exclusion diet. AB - BACKGROUND: Cows' milk allergy (CMA) is the most common infant food allergy in the United Kingdom, requiring a strict exclusion diet. Feeding difficulties and fussy eating are also very common problems in young children and can negatively influence feeding and dietary intake in an infant with CMA. The aim of this study was to compare the levels of fussy eating and feeding difficulties in two groups of young children: a group consuming an exclusion diet for CMA and a control group of children consuming an unrestricted diet. METHOD: Participants were recruited from allergy and health visitor clinics on the Isle of Wight. Parents completed a number of questionnaires about their child's feeding behaviour. RESULTS: One hundred and twenty-six participants (mean age 13 months) were recruited. Participants consuming an exclusion diet for CMA had significantly higher scores for both fussy eating and feeding difficulties (p < 0.05), although overall both groups were within the normal range. A number of symptoms were found to be positively moderately correlated with higher feeding difficulty score (p < 0.05). A higher consumption of milk/milk substitute consumed per day was positively correlated to both feeding difficulties and fussy eating (p < 0.05). CONCLUSION: Participants consuming an exclusion diet for CMA have higher scores for feeding difficulties and fussy eating than those consuming an unrestricted diet; however, the majority of participants' scores were within the normal range and did not affect the growth. PMID- 26111261 TI - Stable Carbon Isotope Fractionation During 1,2-Dichloropropane-to-Propene Transformation by an Enrichment Culture Containing Dehalogenimonas Strains and a dcpA Gene. AB - A stable enrichment culture derived from Besos river estuary sediments stoichiometrically dechlorinated 1,2-dichloropropane (1,2-DCP) to propene. Sequential transfers in defined anaerobic medium with the inhibitor bromoethanesulfonate produced a sediment-free culture dechlorinating 1,2-DCP in the absence of methanogenesis. Application of previously published genus-specific primers targeting 16S rRNA gene sequences revealed the presence of a Dehalogenimonas strain, and no amplification was obtained with Dehalococcoides specific primers. The partial sequence of the 16S rRNA amplicon was 100% identical with Dehalogenimonas alkenigignens strain IP3-3. Also, dcpA, a gene described to encode a corrinoid-containing 1,2-DCP reductive dehalogenase was detected. Resistance of the dehalogenating activity to vancomycin, exclusive conversion of vicinally chlorinated alkanes, and tolerance to short-term oxygen exposure is consistent with the hypothesis that a Dehalogenimonas strain is responsible for 1,2-DCP conversion in the culture. Quantitative PCR showed a positive correlation between the number of Dehalogenimonas 16S rRNA genes copies in the culture and consumption of 1,2-DCP. Compound specific isotope analysis revealed that the Dehalogenimonas-catalyzed carbon isotopic fractionation (epsilonC(bulk)) of the 1,2-DCP-to-propene reaction was -15.0 +/- 0.70/00 under both methanogenic and nonmethanogenic conditions. This study demonstrates that carbon isotope fractionation is a valuable approach for monitoring in situ 1,2 DCP reductive dechlorination by Dehalogenimonas strains. PMID- 26111262 TI - First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043: A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers. AB - BACKGROUND: AZD3043 is a positive allosteric modulator of the gamma-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile. METHODS: Our primary objective in this phase 1, single-center, open label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index. RESULTS: Fifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone. CONCLUSIONS: AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation. PMID- 26111263 TI - Perioperative Complications in Obstructive Sleep Apnea Patients Undergoing Surgery: A Review of the Legal Literature. AB - BACKGROUND: Obstructive sleep apnea (OSA) is common in patients undergoing surgery. OSA, known or suspected, has been associated with significant perioperative adverse events, including severe neurologic injury and death. This study was undertaken to assess the legal consequences associated with poor outcomes related to OSA in the perioperative setting. METHODS: A retrospective review of the legal literature was performed by searching 3 primary legal databases between the years 1991 and 2010 for cases involving adults with known or suspected OSA who underwent a surgical procedure associated with an adverse perioperative outcome. OSA had to be directly implicated in the outcome, and surgical mishaps (i.e., uncontrolled bleeding) were excluded. The adverse perioperative outcome had to result in a lawsuit that was then adjudicated in a court of law with a final decision rendered. Data were abstracted from each case regarding patient demographics, type of surgery, type and location of adverse event, associated anesthetic and opioid use, and legal outcome. RESULTS: Twenty four cases met the inclusion criteria. The majority (83%) occurred in or after 2007. Patients were young (average age, 41.7 years), male (63%), and had a known diagnosis of OSA (96%). Ninety-two percent of cases were elective with 33.3% considered general procedures, 37.5% were ears, nose and throat procedures for the treatment of OSA, and 29.1% were considered miscellaneous interventions. Complications occurred intraoperatively (21%), in the postanesthesia care unit (33%), and on the surgical floors (46%). The most common complications were respiratory arrest in an unmonitored setting and difficulty in airway management. Immediate adverse outcomes included death (45.6%), anoxic brain injury (45.6%), and upper airway complications (8%). Overall, 71% of the patients died, with 6 of the 11 who suffered anoxic brain injury dying at an average of 113 days later. The use of opioids and general anesthetics was believed to play a role in 38% and 58% of cases, respectively. Verdicts favored the plaintiffs in 58% of cases and the defendants in 42%. In cases favoring the plaintiff, the average financial penalty was $2.5 million (+/-$2.3 million; range, $650,000--$7.7 million). CONCLUSIONS: Perioperative complications related to OSA are increasingly being reported as the central contention of malpractice suits. These cases can be associated with severe financial penalties. These data likely underestimate the actual medicolegal burden, given that most such cases are settled out of court and are not accounted for in the legal literature. PMID- 26111264 TI - Conventional Versus Video Laryngoscopy for Tracheal Tube Exchange: Glottic Visualization, Success Rates, Complications, and Rescue Alternatives in the High Risk Difficult Airway Patient. AB - BACKGROUND: Tracheal tube exchange is a simple concept but not a simple procedure because hypoxemia, esophageal intubation, and loss of airway may occur with life threatening ramifications. Combining laryngoscopy with an airway exchange catheter (AEC) may lessen the exchange risk. Laryngoscopy is useful for a pre exchange examination and to open a pathway for endotracheal tube (ETT) passage. Direct laryngoscopy (DL) is hampered by a restricted "line of sight"; thus, airway assessment and exchange may proceed blindly and contribute to difficulty and complications. We hypothesized that video laryngoscopy (VL), when compared with DL, will improve glottic viewing for airway assessment, and the VL-AEC method of ETT exchange will result in a reduction in airway and hemodynamic complications in high-risk patients when compared with a historical group of patients who underwent DL + AEC-assisted exchange. METHODS: Critically ill patients requiring an ETT exchange underwent DL-assisted pre-exchange airway assessment. If the DL-assisted pre-exchange assessment rendered a "poor view," these patients underwent a VL-based airway assessment followed by a VL-assisted ETT exchange procedure. The DL and VL pre-exchange assessments were compared. The attempts, complications, and rescue devices required for ETT exchange were analyzed. These exchange results were then compared with a historical control group of patients who (1) were classified as a poor view on DL-assisted pre exchange airway assessment; and (2) underwent a DL + AEC-assisted exchange. The airway assessment and ETT exchange were performed by a board-certified anesthesiologist from the Department of Anesthesiology alone or with anesthesia resident assistance. RESULTS: Three hundred twenty-eight patients with a poor view on initial DL examination underwent a subsequent VL with comparison of views with the 337 patients in the historical control group (DL + AEC). A majority (88%) had a "full or near-full view" on VL examination. The first-pass success rate for ETT exchange was greater in the VL group (91.5% vs 67.7% with DL; P = 0.0001) and the number of patients requiring 3+ attempts was lower (1.2% vs 6.8% with DL; P = 0.0003). A commensurate difference in the incidence of mild and severe hypoxemia, esophageal intubation, bradycardia, and the need for rescue airway device intervention was also observed with VL exchange procedures when compared with the historical DL + AEC group. CONCLUSIONS: These findings support the hypothesis that VL may result in better glottic viewing for airway assessment and may permit the ETT exchange procedure to be performed with fewer airway and hemodynamic complications. Execution of the ETT exchange over an AEC was augmented by improved glottic visualization to allow more efficient and timely ETT passage. Multiple attempts to resecure the airway increased the number of exchange complications. VL + AEC exchange led to fewer attempts and is consistent with the recommendation of the American Society of Anesthesiologists Difficult Airway Task Force to limit laryngoscopic attempts and, as a consequence, decrease complications. A VL-based pre-exchange airway assessment may be a valuable procedure for both planning the exchange and uncovering unrecognized airway maladies, for example, partial or complete self-extubation. PMID- 26111265 TI - Atomic-Layer-Confined Doping for Atomic-Level Insights into Visible-Light Water Splitting. AB - A model of doping confined in atomic layers is proposed for atomic-level insights into the effect of doping on photocatalysis. Co doping confined in three atomic layers of In2S3 was implemented with a lamellar hybrid intermediate strategy. Density functional calculations reveal that the introduction of Co ions brings about several new energy levels and increased density of states at the conduction band minimum, leading to sharply increased visible-light absorption and three times higher carrier concentration. Ultrafast transient absorption spectroscopy reveals that the electron transfer time of about 1.6 ps from the valence band to newly formed localized states is due to Co doping. The 25-fold increase in average recovery lifetime is believed to be responsible for the increased of electron-hole separation. The synthesized Co-doped In2S3 (three atomic layers) yield a photocurrent of 1.17 mA cm(-2) at 1.5 V vs. RHE, nearly 10 and 17 times higher than that of the perfect In2S3 (three atomic layers) and the bulk counterpart, respectively. PMID- 26111266 TI - Detection of aflatoxin M1 in milk, cheese and sour cream samples from Costa Rica using enzyme-assisted extraction and HPLC. AB - Aflatoxins are toxic fungal metabolites, which can be found in feed. Aflatoxin M1 (AFM1) is excreted into milk when ruminants ingest aflatoxin B1 contaminated feedstuffs. Due to its carcinogenic potential, contamination of milk and dairy products with AFM1 may pose a risk for consumers. Hence, it is considered a public health concern. In this survey, the level of AFM1 contamination of dairy products marketed in Costa Rica was determined by enzyme-assisted extraction, immunoaffinity clean-up and high-performance liquid chromatography coupled with a fluorescent detector (HPLC-FLD) in fluid milk (n = 70), fresh cheese (n = 70) and sour cream (n = 70) collected at local convenience stores and supermarkets. AFM1 concentrations in milk and fresh cheese ranged from 19 to 629 ng/L and from 31 to 276 ng/L, with mean values of 136 ng/L and 74 ng/L, respectively, whereas none of the sour cream samples analysed tested positive for this aflatoxin. In 30 milk samples, and 10 cheese samples, AFM1 concentrations surpassed threshold concentrations as established by the European Commission. Thus, sour cream and - to a lesser extent - cheese manufacturing seems to reduce the amount of AFM1 present in milk, possibly due to fraction redistribution or microbiological degradation. The survey results reveal improper quality control procedures in the Costa Rican dairy industry. Therefore, a surveillance programme for dairy products in our country is recommended. PMID- 26111267 TI - Targeted Temperature Management (TTM 2014). PMID- 26111268 TI - Megamitochondria in Cardiomyocytes of a Knockout (Klf15-/-) Mouse. AB - The Kruppel-like factors (KLF) family of zinc-finger transcriptional regulators control many aspects of cardiomyocyte structure and function. Deletion of Klf15 from the nuclear genome in mice affects cardiac mitochondria. Some become grossly enlarged, extending many sarcomeres in length. These display many sites of incipient pinching, but there is little attenuation of the megamitochondria at these sites; there are no examples of organelles that clearly have reached the point where further membrane encroachment will cause separation into smaller daughter mitochondria. It is clear that deletion of Klf15 interferes with nuclear control of mitochondrial fission, whereas fusion appears to be unaffected. PMID- 26111269 TI - Hysterosalpingographic features of cervical abnormalities: acquired structural anomalies. AB - Cervical abnormalities may be congenital or acquired. Congenital cervical structural anomalies are relatively uncommon, whereas acquired cervical abnormalities are commonly seen in gynaecology clinics. Acquired abnormalities of the cervix can cause cervical factor infertility and recurrent spontaneous abortion. Various imaging tools have been used for evaluation of the uterine cavity and fallopian tubes. Hysterosalpingography (HSG) is a quick and minimally invasive tool for evaluation of infertility that facilitates visualization of the inner surfaces of the uterine cavity and fallopian tubes, as well as the cervical canal and isthmus. The lesions of the uterine cervix show various imaging manifestations on HSG such as narrowing, dilatation, filling defects, irregularities and diverticular projections. This pictorial review describes and illustrates the hysterosalpingographic appearances of normal variants and acquired structural abnormalities of the cervix. Accurate diagnosis of such cases is considered essential for optimal treatment. The pathological findings and radiopathological correlation will be briefly discussed. PMID- 26111270 TI - Use of (99m)Tc-doxorubicin scintigraphy in females with breast cancer: a pilot study. AB - OBJECTIVE: Doxorubicin (Eurofarma, Sao Paulo, Brazil) is an antitumour agent widely used in the treatment of breast cancer and can be used for tumour tracking when labelled with a radionuclide. Here, we present the results obtained with technetium-99m ((99m)Tc)-doxorubicin, using the direct method, to evaluate its uptake in breast cancer. METHODS: Four females with confirmed breast carcinoma diagnosis and breast image reporting and data system Category 5 on mammography underwent whole-body and thorax single-photon emission CT/CT imaging 1 and 3 h after (99m)Tc-doxorubicin administration. RESULTS: We observed increased uptake in breast carcinoma lesions and elimination via renal and hepatic pathways. CONCLUSION: These preliminary results suggest that (99m)Tc-doxorubicin may be a promising radiopharmaceutical for the evaluation of patients with breast cancer. Further studies are ongoing. ADVANCES IN KNOWLEDGE: To our knowledge, this is the first study to evaluate the use of a directly labelled doxorubicin tracer in humans. (99m)Tc-doxorubicin could provide information on the response of tumours to doxorubicin. PMID- 26111271 TI - Aurora kinase inhibition: a new light in the sky? AB - The quest for potent and selective small molecule inhibitors of the Aurora kinases has been long and resource intensive with multiple agents progressed to the clinic. To definitively explore the potential for clinical efficacy at well tolerated dosing schedules requires a well-characterized, selective inhibitor with pharmacokinetic properties, flexible dosing regimen, and suite of target engagement biomarkers suitable for clinical use. AMG900 is a promising opportunity to definitively test the clinical benefit of dual Aurora kinase A and B inhibition. PMID- 26111272 TI - Intratumoral CD8+ Lymphocyte Infiltration as a Prognostic Factor and Its Relationship With Cyclooxygenase 2 Expression and Microsatellite Instability in Endometrial Cancer. AB - OBJECTIVE: Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer. METHODS: The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor infiltrating CD8 T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses. RESULTS: The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2-high group showed significantly fewer TILs than did the COX-2-low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression. CONCLUSIONS: The number of TILs, which was increased by MSI and decreased by COX 2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment. PMID- 26111273 TI - Laparoscopic Debulking Surgery in the Management of Advanced Ovarian Cancer After Neoadjuvant Chemotherapy. AB - OBJECTIVE: The purpose of this study was to evaluate the feasibility and morbidity of total laparoscopic debulking surgery in the treatment of advanced ovarian cancer after neoadjuvant chemotherapy. METHODS/MATERIALS: We performed a retrospective review of laparoscopic approach in patients with histologically confirmed epithelial ovarian cancer (International Federation of GynaecologyObstetrics stages IIIC-IV) who received 3 courses of neoadjuvant chemotherapy, from January 2010 to December 2014, at the Gynaecologic Oncologic Unit, "Regina Elena" National Cancer Institute, Rome, Italy. RESULTS: A total of 30 patients were included. The median age was 50 years (range, 26-73 years), median body mass index was 24.5 kg/m (range, 19-39 kg/m). All patients had good clinical response to 3 cycles of neoadjuvant chemotherapy. All women underwent a complete debulking surgery with no residual disease. The median operating time was 152 minutes (range, 70-335 minutes), the median blood loss was 70 mL (range, 50-200 mL). The median number of removed pelvic lymph nodes was 15 (range, 13 25). There was 1 (3.3%) intraoperative complication and 2 (6.6%) postoperative short-term complications. The median length of hospital stay was 4 days (range, 3 13 days). The median follow-up was 15 months (range, 2-54 months). Twenty-six patients are free from recurrence at the time of this report. CONCLUSIONS: Laparoscopic cytoreduction in patients with advanced ovarian cancer after neoadjuvant chemotherapy, when performed by skilled surgeons, seems feasible and may decrease the impact of aggressive surgery on high-morbidity patients, such as on women after chemotherapy. PMID- 26111274 TI - Analyze Association of BRCA2 Arg372His Polymorphism With Ovarian Cancer Risk. AB - OBJECTIVE: Studies investigating the association between BRCA2 Arg372His polymorphism and ovarian cancer risks have yielded conflicting results. METHODS: We carried out a meta-analysis of 8488 ovarian cancer cases and 14,510 controls from 7 case-control studies in 5 articles published. The association between BRCA2 Arg372His polymorphism and ovarian cancer susceptibility was calculated using pooled odds ratios (ORs) appropriately derived from fixed effects models. RESULTS: There were no significant associations between BRCA2 Arg372His polymorphisms and ovarian cancer risk in overall comparisons in all genetic models (HH vs NN: OR, 1.06; 95% confidence interval [95% CI], 0.96-1.18; P = 0.25; NH vs NN: OR, 1.02; 95% CI, 0.96-1.07; P = 0.6; NH + HH vs NN: OR, 1.01; 95% CI, 0.98-1.04; P = 0.42; HH vs NN + NH: OR, 1.06; 95% CI, 0.95-1.17; P = 0.29). CONCLUSIONS: This meta-analysis indicates that the BRCA2 Arg372His polymorphism is not associated with ovarian cancer risk for whites. Asian and African populations should be further studied. PMID- 26111275 TI - Highly cytotoxic bioconjugated gold(I) complexes with cysteine-containing dipeptides. AB - Several gold(I) complexes with cysteine-containing dipeptides have been prepared starting from cystine by coupling different amino acids and using several orthogonal protections. The first step is the reaction of cystine, where the sulfur centre is protected as disulfide, with Boc2 O in order to protect the amino group, followed by coupling of an amino acid ester; finally the disulfide bridge is broken with mercaptoethanol to afford the dipeptide derivative. Further reaction with [AuCl(PPh3 )] gives the gold-dipeptide-phosphine species. Starting from these formally gold(I) thiolate-dipeptide phosphine complexes with the general formula [Au(SR)(PR3 )] different structural modifications, such as change in the type of the amino protecting group, the type of phosphine, the number of gold(I) atoms per molecule, or the use of a non-proteinogenic conformationally restricted amino acid ester, were introduced in order to evaluate their influence in the biological activity of the final complexes. The cytotoxic activity, in vitro, of these complexes was evaluated against different tumour human cell lines (A549, MiaPaca2 and Jurkat). The complexes show an outstanding cytotoxic activity with IC50 values in the very low micromolar range. Structure-activity relationship studies from the complexes open the possibility of designing more potent and promising gold(I) anticancer agents. PMID- 26111276 TI - 3D nitrogen-doped graphene/beta-cyclodextrin: host-guest interactions for electrochemical sensing. AB - Host-guest interactions, especially those between cyclodextrins (CDs, including alpha-, beta- and gamma-CD) and various guest molecules, exhibit a very high supramolecular recognition ability. Thus, they have received considerable attention in different fields. These specific interactions between host and guest molecules are promising for biosensing and clinical detection. However, there is a lack of an ideal electrode substrate for CDs to increase their performance in electrochemical sensing. Herein, we propose a new 3D nitrogen-doped graphene (3D NG) based electrochemical sensor, taking advantage of the superior sensitivity of host-guest interactions. Our 3D-NG was fabricated by a template-directed chemical vapour deposition (CVD) method, and it showed a large specific surface area, a high capacity for biomolecules and a high electron transfer efficiency. Thus, for the first time, we took 3D-NG as an electrode substrate for beta-CD to establish a new type of biosensor. Using dopamine (DA) and acetaminophen (APAP) as representative guest molecules, our 3D-NG/beta-CD biosensor shows extremely high sensitivities (5468.6 MUA mM(-1) cm(-2) and 2419.2 MUA mM(-1) cm(-2), respectively), which are significantly higher than those reported in most previous studies. The stable adsorption of beta-CD on 3D-NG indicates potential applications in clinical detection and medical testing. PMID- 26111281 TI - Routine Echo Follow-Up of the Patient after Transcatheter Aortic Valve Replacement. PMID- 26111280 TI - A label-free electrochemical impedance aptasensor for cylindrospermopsin detection based on thionine-graphene nanocomposites. AB - It is important to develop methods to determine cylindrospermopsin (CYN) at trace levels since CYN is a kind of widespread cyanobacterial toxin in water sources. In this study, a label-free impedimetric aptasensor has been fabricated for detecting CYN. In this case, the amino-substituted aptamer of CYN was covalently grafted onto the surface of the thionine-graphene (TH-G) nanocomposite through the cross-linker glutaraldehyde (GA). The reaction of the aptamer with CYN was monitored by electrochemical impedance spectroscopy because the CYN induced conformation change of the aptamer can cause a remarkable decrease of the electron transfer resistance. Under optimum conditions, the aptasensor exhibits high sensitivity and a low detection limit for CYN determination. The CYN can be quantified in a wide range of 0.39 to 78 ng mL(-1) with a good linearity (R(2) = 0.9968) and a low detection limit of 0.117 ng mL(-1). In addition, the proposed aptasensor displays excellent stability, reusability and reproducibility. PMID- 26111282 TI - Developing quality of care indicators for patients with traumatic and non traumatic spinal cord injury (SCI): A feasibility study using administrative health data. AB - OBJECTIVES: (1) to inform the development of health system quality indicators for traumatic and non-traumatic spinal cord injury from acute care admission to community care discharge using administrative data, and (2) to examine characteristics and differences in care among type of care facility, and type of pathology using administrative data. DESIGN: Retrospective cohort study using administrative health data. SETTING: Ontario, Canada. PARTICIPANTS: Using administrative health data, we used International Classification codes 10(th) version Canadian Edition to identify incident cases of SCI from April 1, 2006 to March 31, 2012. RESULTS: We identified 7,693 cases in our cohort, of whom 1,537 (20.0%) were categorized as traumatic spinal cord (TSCI) and 6,156 (80.0%) as non traumatic (NTSCI). Of those identified with NTSCI, more than half (54.0%) were diagnosed with either Guillain Barre syndrome and Multiple Sclerosis (n = 3,326). More individuals admitted to a trauma/spine center were seen by an orthopedic surgeon or a neurosurgeon (20.3% compared to 5.6% for NTSCI; 77.7% compared to 24.9% for TSCI). Only 25.7% (n = 724) of the NTSCI cohort were admitted to a rehabilitation facility from a trauma/spine center, compared to 58.9% (n = 754) of those with TSCI. CONCLUSIONS: Important challenges in data completeness and utility were identified. Province wide processes to flag incomplete data and provision of incentives for comprehensive data are urgently needed to develop quality indicators across the care continuum. Consensus on the coding for NTSCI for the purposes of developing health system indicators is required. PMID- 26111283 TI - [First Episode Psychosis: Relationship of Symptoms, Initial Treatment and Clinical Response]. AB - OBJECTIVE: It was aimed to explore the relationship of clinical psychopathology and treatment response with "duration of untreated psychosis" (DUP) and "duration of untreated illness"(DUI) in 15-20 years old (mean age: 17,34 +/- 1.69) inpatients in Turkey. METHOD: Mood disorders with psyhotic features were grouped as affective psychoses (18 patients, mean age: 17,28 +/- 1,75); schizophrenia, schiozophreniform disorder and other psychotic disorders were grouped as non affective psychoses (25 patients, mean age: 17,38 +/- 1,68). 43 patiens (11 females, 32 males) were evaluated for acute treatment response with Positive and Negative Scale-PANSS and Clinical Global Impressions Scale-CGI. RESULTS: Mean DUP was determined as 6,5 +/- 12,4 weeks, mean DUI was determined as 37,8 +/- 49,8 weeks. For the affective psychosis (AP) group; mean DUP was 1,9 +/- 1,2 weeks, mean DUI was 24,6 +/- 37,1 weeks, for the non-affective psychosis (NAP) group; mean DUP was 9,8 +/- 15,5 weeks, mean DUI was 47,3 +/- 55,9 weeks. Treatment response was better for the non-affective psychosis group and for the patients who had earlier access to treatment. Shorter DUP and DUI was related with better PANSS negative symptom severity at the time of the discharge. CONCLUSION: Better treatment response related with shorter DUP and DUI reveals the significance of early treatment for the disease prognosis. PMID- 26111284 TI - [Relationship between the Psychiatric Symptoms in Expecting Parents and Postpartum Depression and Infantile Colic: A Multicenter Follow up Study]. AB - OBJECTIVE: The aim of this study is to evaluate the relationship between postpartum depression (PPD), infantile colic (IC) and different psychosocial variables, psychiatric symptoms, attachment style and perceived social support in expecting parents. METHOD: Two hundred forty five expecting mothers and 150 expecting fathers were first interviewed between the 22-34 weeks of pregnancy. Sociodemografic data form, Adult Attachment Style Scale (AASS), State Anxiety Inventory (SAI), Edinburgh Postnatal Depression Scale (EPDS), Multidimensional Scale of Perceived Social Support (MSPSS) and Brief Symptom Inventory (BSI) were filled out by each expecting parent. Second interview was conducted between the postpartum 4-24 weeks. Data form consisting health, nutrition, sleep and crying problems of the infant and EPDS and SAI were filled out by mothers and SAI by fathers. RESULTS: One in every four mothers had PPD symptoms above the threshold on EPDS. Maternal and paternal insecure attachment style, maternal psychiatric symptoms and postpartum anxiety level were found to be the predictors of PPD. One in every five infants had IC and maternal education level, hostility score and PPD symptoms along with paternal insecure attachment style and psychiatric symptoms were the main predictors of IC. CONCLUSION: Results about PPD and IC regarding maternal variables are consistent with the literature. In addition, paternal insecure attachment style is found to be an important risk factor for both PPD and IC. Fathers should also be included in further studies exploring PPD or IC. PMID- 26111285 TI - [The Relationship of Suicide Attempts with Affective Temperament and Relevant Clinical Features in Patients with Mood Disorders]. AB - OBJECTIVE: In this study, patients with affective disorders with or without suicide attempts were examined according to whether their disorder was unipolar or bipolar. An analysis was made of their socio-demographic variables, comorbid psychiatric symptoms, and affective temperament dimensions in order to understand the effects of these variables on suicide risk. METHOD: The study populations consisted of 246 inpatients with affective disorders who had been admitted to the Erenkoy Research and Training Hospital for Mental and Neurological Disorders (93 patients with unipolar disorders, 153 with bipolar disorders). The TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto questionnaire), the Beck Hopelessness Scale (BHS) and the Symptom Checklist-90 Revised (SCL-90-R) psychological symptom screening tests were applied to all patients. In order to determine the affective disorder diagnosis and to identify suicide attempts, a Mini International Neuropsychiatric Interview (MINI) was performed during the first 48 hours of hospitalization. RESULTS: The cyclothymic and anxious temperament dimensions measured using TEMPS-A, somatic symptoms obtained from a symptom checklist, and psychiatric disorders in the family were found to be good indicators of suicide attempts in patients with unipolar disorders in this study. An investigation of predictors of suicide attempts in bipolar patients showed that cyclothymic temperament pattern, paranoid symptoms, evaluated through symptom screening test and having a psychiatric disorder in the family are good predictors of a suicide attempt. CONCLUSION: The findings are expected to guadiance to preventing suicide in patients with affective disorders. The inclusion in this study of patients with different index episodes of illness, including manic, depressive and mixed periods, can be accepted as a significant limitation of this study. PMID- 26111286 TI - [The Role of Worry and Rumination in the Symptoms of Anxiety and Depression]. AB - AIM: The aim of this study is to examine the unique and interactive role of worry and rumination in anxiety and depression symptoms. METHOD: A total of 328 university students responded to questionnaires assessing worry (Penn State Worry Questionnaire), rumination (Ruminative Response Styles Questionnaire-Short Form), anxiety (Beck Anxiety Inventory and Trait Anxiety Inventory), and depression (Beck Depression Inventory). RESULTS: The results of regression analyses demonstrated that the relationship between worry and depressive symptoms is significant only if individuals engage in high levels of brooding type rumination. The main effect of worry was a significant predictor of trait anxiety, but it did not make a significant contribution to somatic anxiety. Brooding was found to be associated not only with depressive symptoms but also with both types of anxiety. Finally, the reflection type of rumination did not significantly predict depressive symptoms, somatic anxiety, or trait anxiety. CONCLUSION: Findings indicated that worry and rumination are related to both anxiety and depression. Clinical implications of these results were discussed in the light of the current literature. PMID- 26111287 TI - [Dimensions of Agitation Based on the Cohen-Mansfield Agitation Inventory in Patients with Dementia]. AB - OBJECTIVE: The aim of this study was to investigate the dimensions of agitation in dementia patients using the Turkish version of the Cohen-Mansfield Agitation Inventory (CMAI-T). MATERIALS AND METHODS: The study included 100 patients diagnosed as dementia, according to the DSM-IV-TR. The CMAI-T was administered to the patients' caregivers via face-to-face interviews. The Standardized Mini Mental State Examination (SMMSE) was used to assess cognitive functions. The severity of depression and the functional state of the patients were assessed using the Cornell Scale for Depression in Dementia (CSDD) and the Functional Activities Questionnaire (FAQ). Principal component analysis and varimax rotation were used to determine the factor structure of the CMAI-T. RESULTS: Factor analysis of the CMAI-T indicated a 3-factor structure: physically aggressive agitation, verbal agitation, and physically non-aggressive agitation. In 92% of the patients there was >=1 agitation behavior during the previous 2 weeks. The CMAI-T total and factor scores were negatively correlated with the SMMSE scores, and positively correlated with the CSDD and the FAQ scores. CONCLUSIONS: The CMAI T yielded 3 factors (physically aggressive agitation, verbal agitation, and physically non-aggressive agitation), which indicated the scale had construct validity. Agitation behaviors were associated with cognitive dysfunction, symptoms of depression and general level of functioning. Additional research is necessary to identify the predictors of these dimensions in different dementia samples, and to determine the efficacy of therapeutic interventions. PMID- 26111288 TI - [Assessment of Perceived Parenting Attitudes in Childhood: Turkish Form of the S EMBU for Children]. AB - OBJECTIVE: Among the instruments aiming to assess perceived parenting attitudes during the childhood period, EMBU (Egna Minnen Barndoms Uppfostran; My memories of upbringing) is one of the frequently used scales. It is a self-report instrument in which adult participants are asked to report their perceptions of the attitudes of their parents during their childhood on the dimensions of emotional warmth, overprotection and rejection, separately for each parent. The aim of the present study was to examine the reliability and the validity of the Turkish version of the EMBU, following a previous pilot study which supported its psychometric properties and supported its cross-cultural validity. METHOD: s-EMBU C The Parental Bonding Instrument, Brief Symptom Inventory, Eysenck Personality Questionnaire-Revised Abbreviated and and General Self Efficacy Scale were administered to 271 adults living in Bursa. In order to evaluate psychometric properties of s-EMBU-C Explanatory Factor analysis, Pearson's Product Moment Correlation test, and Multivariate Analysis of Variance (MANOVA) were conducted. RESULTS: The analyses supported the reliability, concurrent, convergent and criterion validities of the Turkish version of the EMBU. CONCLUSION: It may be reported that the Turkish version of the EMBU is a reliable and valid instrument which can be used in research studies aiming to assess perceptions of parental attitudes on different psychological constructs and in clinical practice. PMID- 26111289 TI - [Schizoaffective Disorder: Evolution and Current Status of the Concept]. AB - Schizoaffective disorder as a diagnostic entity is of particular present-day relevance; however, the concept of schizoaffective disorder, and its management and prognosis remain contentious. Descriptions of the disorder have varied over time. In this literature review, after tracking the evolution of the concept and nosology of schizoaffective disorder, research findings are summarized. This review takes a broad overview of the epidemiology, neurobiology, clinical presentation, diagnostic validity and stability, treatment, course, and outcome of schizoaffective disorder. Importance is given to the distinctness of schizoaffective disorder, and the overlap with schizophrenia and mood disorders, and problems associated with the construct are examined. Possible ways to treat the construct in the future in the best interest of patients, clinicians, and researchers are discussed. PMID- 26111290 TI - [Phenomenological and Diagnostic Implications of Paraschemazia: A Case Report]. AB - Paraschemazia is characterized by distortions of body image, and has been observed in neurological disorders (epilepsies, migraine, and non-dominant cortical lesions), retinal damage, and hallucinogenic drug use. This complex symptom cluster of subjective and objective perceptual abnormalities forms an essential feature of Todd's Alice in Wonderland syndrome. This neuropsychiatric manifestation must be phenomenologically differentiated from hallucinations, illusions, and agnosias. Herein we report a patient with paraschemazia that occurred during the ictal phase of temporal lobe epilepsy; the patient was referred to the department of psychiatry due to symptoms of transient intense fear and abnormal perceptions. We also discuss the diagnostic difficulty and phenomenological implications associated with this rare phenomenon. A 45-year-old female presented with brief episodes (30-45 s) of sensory distortion, during which the faces and limbs of other people and her own appeared distorted (e.g. protruding eyes, elongated nose, and oval or square head). The episodes of sensory distortion were associated with intense fear and were followed by loss of consciousness for 5 min. She had been experiencing these episodes since the age of 12 years and responded poorly to several antiepileptic medications. 3-Tesla MRI performed using a complex partial seizure protocol showed altered signal intensity and volume loss in the right hippocampus, suggestive of right mesial temporal sclerosis. Neuropsychological assessment showed impaired sustained attention, working memory, and verbal and visual learning and memory, suggestive of bilateral dorsolateral prefrontal and temporal lobe deficits. She improved in response to a combination of levetiracetam and clobazam, and was seizure free at the 2-year follow-up. PMID- 26111291 TI - [Psychotic Disorder and Sheehan's Syndrome: Etiology or Comorbidity?: A Case Report]. AB - Sheehan's Syndrome -also called postpartum hypopituitarism- is a syndrome which characterized by lots of bleeding during or after delivery and necrosis of pituitary gland due to hypovolemic shock. It appears with not only agalactorrhea, amenorrhea, hypoythyroidism and hypoglycemia but also psychiatric disorders like psychosis. In this study, we reported a case presented with psychotic disorder and diagnosed as Sheehan's Syndrome at the same time. 44 year-old, female patient, married. She was admitted for withdrawal, irritability, insomnia, hearing voices -especially insult her- thoughts about that her husband was cheating on her and people would do evil. She was diagnosed as psychotic disorder and she was treated with olanzapine 20 mg/day. She had hypopituitarism symptoms so hormone tests and cranial MRI are done. Sheehan's syndrome was also diagnosed and prednisolone and tyroxine were added to the treatment. Her symptoms were disappeared one months later Olanzapine was stopped after 4 months and her treatment continued with prednisolone and tyroxine. Studies about etiology of psychotic symptoms refer to endocrine and autoimmune systems. In this study, we discussed a case that diagnosed as psychotic disorder and Sheehan's Syndrome diagnosed 24 years later and etiological aspect with the follow-up period and treatment. PMID- 26111292 TI - [Editorial]. PMID- 26111293 TI - Disability in Children and Adolescents With Irritable Bowel Syndrome and/or Fibromyalgia. AB - To compare disability and emotional health in individuals with irritable bowel syndrome (IBS), fibromyalgia, or both, patients completed the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III, childhood Functional Disability Inventory (FDI), and the Behavior Assessment System for Children, Second Edition. Patients' (age range 8-18 years, 19 IBS, 12 fibromyalgia, and 12 both) FDI scores showed greater disability than scores from historically healthy patients. Fibromyalgia (FDI 22.5 +/- 12.7, P = 0.018) and patients with both (FDI 26.2 +/- 13.8, P = 0.001) averaged greater disability than those with IBS (FDI 10.6 +/- 7.9). Disability was correlated with anxiety and depression symptoms. Disability and psychological symptoms are important when evaluating individuals with fibromyalgia and IBS. PMID- 26111296 TI - Emergency Department Visits and Hospitalizations in Children With Chronic Pancreatitis in the United States. AB - We analyzed 2 national databases to assess the use of health care resources by children with chronic pancreatitis (CP). In 2012, the hospital discharge rate for pediatric CP was 2.73/100,000 children. Patients with CP were sicker with a greater burden of illness than age- and sex-matched counterparts. Acute pancreatitis occurred frequently in hospitalized children with CP. Abdominal pain and nausea, and vomiting were the most common gastrointestinal symptoms associated with emergency department visits in children with CP. A significant proportion of these visits resulted in a hospitalization. These findings add to our understanding of the epidemiology of CP in the United States. PMID- 26111294 TI - Presenting Pattern of Pediatric Celiac Disease. AB - OBJECTIVES: Celiac disease (CD) is an autoimmune disease that can be complicated by impaired nutrition and growth. With the development of sensitive serologic tests, safe endoscopy, and efforts to educate primary care physicians, more children are diagnosed as having CD. The aim of this study is to evaluate the pattern of the presentation of pediatric CD in western New York. METHODS: Chart review of pediatric patients with CD was undertaken. Patients' demographics, presenting features, disaccharidase assay (DA), celiac serology, and Marsh score were reviewed from patients seen at the Digestive Diseases and Nutrition Center, State University of New York at Buffalo from January 2003 through March 2013. RESULTS: A total of 165 patients with CD were evaluated. Mean age was 10.7 +/- 4.3 years, 76 male patients. The presenting features were abdominal pain (n = 87, 52.7%), constipation (n = 65, 38.9%), diarrhea (n = 52, 31.1%), family history of first-degree relative (n = 47, 28.1%), diabetes mellitus type 1 (n = 37, 22.2%), failure to thrive (n = 36, 21.8%), reflux (n = 25, 15.1%), vomiting (n = 24, 14.5%), fatigue (n = 15, 9%), short stature (n = 9, 5.4%), thyroid disease (n = 9, 5.4%), Down syndrome (n = 8, 4.8%). We found no correlation between Marsh score and serum tissue transglutaminase (tTG) immunoglobulin (Ig) A level at diagnosis and no correlation between DA and serum tTG IgA level, presenting feature and tTG IgA level, presenting feature and Marsh score, tTG IgA and DA, or between the age and the presenting feature. CONCLUSIONS: Children newly diagnosed as having CD in western New York presented most frequently with abdominal pain and constipation and were older at the time of diagnosis than those described in the classical presentation of CD. We speculate that our patients may have a different long-term natural history and risk factors than originally described for patients with CD. PMID- 26111297 TI - Interaction of Giardia intestinalis and Systemic Oxidation in Preschool Children in the Western Highlands of Guatemala. AB - BACKGROUND: Guatemala is a country with the highest prevalence of stunting in under-5 children in the Americas, with a national average of 49.8%. Asymptomatic intestinal colonization with Giardia intestinalis is common in Guatemalan preschoolers and has been implicated as a factor in linear growth retardation. The potential mechanisms of any giardiasis-growth interaction have not been exhaustively explored. OBJECTIVES: The aim of the present study was to describe urine oxidative stress biomarkers and erythrocyte antioxidant enzyme activity, and to explore any association with prevalence or intensity of G intestinalis infection in preschoolers attending 3 government-subsidized day care centers in the Guatemalan Western Highlands. METHODS: Samples of feces, urine, and red blood cell (RBC) hemolysate were collected in a total of 74 preschoolers enrolled in 3 day care centers. Giardia prevalence and a proxy index for intensity were assessed by enzyme-linked immunosorbent assay (ELISA). Urinary biomarkers of oxidative damage to DNA (8-hydroxydeoxyguanosine [8-OHdG]) and to lipid (F2t 15 Isoprostane [F2-Iso]) were measured by ELISA. The erythrocyte activity of catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GSR), and glutathione peroxidase (GPX) were measured by respective spectroscopic substrate based reaction assays. RESULTS: Median values of RBC CAT activity (P = 0.016) and urine F2-Iso (P = 0.023) differed between children who were positive (n = 39) and negative (n = 35) for Giardia. Similarly, G intestinalis intensity was significantly and positively associated with urinary F2-Iso (r = 0.446, P < 0.001), RBC SOD (r = 283, P = 0.014), and RBC CAT (r = 0.260, P = 0.025). CONCLUSION: The optical density reading of the fecal ELISA assay for G intestinalis has potential as a proxy for the intensity of infestation. In this respect, there exists an association of this intensity with indicators of the systemic oxidation. PMID- 26111298 TI - Infliximab More Effective in Therapy-Naive Than in Therapy-Refractory Patients. PMID- 26111299 TI - Author's Response. PMID- 26111300 TI - Portopulmonary Hypertension: Opportunities for Precision Pediatrics. PMID- 26111303 TI - Challenges in Reducing Readmissions: Lessons from Leadership and Frontline Personnel at Eight Minority-Serving Hospitals. AB - BACKGROUND: Hospitals that serve minority patients have higher readmission rates than other hospitals and, as a result, receive higher penalties under the federal government's Hospital Readmissions Reduction Program. A study was conducted to determine how minority-serving hospitals are responding to federal readmissions policy and whether they face specific challenges as they work to reduce readmissions. METHODS: In-depth case studies were created for eight minority serving hospitals, selected to reflect a range of geographies and sizes. Semistructured interviews with hospital leaders and frontline personnel focused on knowledge of readmission rates and prioritization of readmission reduction, strategies to reduce readmissions, barriers to reducing readmissions, and opinions about federal readmissions policy. RESULTS: Each hospital had only a general awareness of its performance on readmissions metrics but placed a high priority on reducing readmissions, largely spurred by federal readmissions policy. Respondents reported that socioeconomics, rather than race alone, was a key factor in readmissions reduction. The hospitals followed a similar progression in strategies to reduce readmissions-moving from working on the discharge process to creating customized approaches to transitional care to, finally, focusing more on building community supports and resources. Salient barriers to reducing readmission rates included scarce resources, the variety of patient needs, limited ability to influence care in the community, and a misalignment of financial incentives. CONCLUSIONS: Among eight hospitals serving a high proportion of minority patients, the findings uncovered the importance of addressing issues specific to the patient population and community and reaching outside the walls of the hospital to implement programs that improve outpatient access and management. PMID- 26111301 TI - Fish-collagen allergy: a pitfall of the prick-to-prick test with raw fish. PMID- 26111304 TI - E-Autopsy: Using Structured Hybrid Manual/Electronic Mortality Reviews to Identify Quality Improvement Opportunities. AB - BACKGROUND: Mortality reviews are a foundation of inpatient quality improvement (QI), but low levels of harm among a random or sequential sample may not yield actionable improvement opportunities. To increase the efficiency of mortality reviews at identifying QI opportunities, Kaiser Permanente Southern California (KPSC) developed a condition-specific hybrid electronic/manual chart review called the "e-autopsy." METHODS: KPSC hospital deaths are filtered electronically by predetermined criteria. Teams consisting of a registered nurse and physician trained in QI at each hospital then manually review selected charts using a structured data-extraction tool to identify gaps in provision of evidence-based care. Results are aggregated and studied to identify improvement opportunities. RESULTS: E-autopsy has identified opportunities amenable to system improvements. The first e-autopsy of all KPSC members who died with a ruptured abdominal aortic aneurysm (AAA) in a KPSC hospital indicated that many patients meeting criteria had not been screened for AAA. This study showed KPSC leaders the value of point of-care electronic decision support to increase evidence-based AAA screening and of a tracking system for patients with positive results. Screening among high risk patients in 2012 increased by more than 8,000 individuals, compared with the annual average during the previous four years. E-autopsies have also been conducted of patients who died with aspiration pneumonia; after unplanned transfers to the ICU; and after diagnosis of colon cancer. CONCLUSION: E-autopsy reveals actionable opportunities to improve care systems, complementing other QI activities. This hybrid electronic/manual process can be applied to a wide variety of patient conditions and settings. PMID- 26111305 TI - Meaningful Use Status and Participation in Health Information Exchange Among New York State Hospitals: A Longitudinal Assessment. AB - BACKGROUND: Billions of dollars is being utilized to promote electronic health record (EHR) adoption and electronic health information exchange (HIE). Monitoring trends over time is critical to understanding the success of policies initiatives. New York State is a leader in state-based initiatives promoting health information technology (HIT), and its experiences can provide valuable lessons to inform ongoing state and federal efforts. METHODS: All hospitals in New York State were previously surveyed in 2009 to determine rates of EHR adoption, preparedness to meet meaningful use criteria, and participation in HIE. A follow-up survey was conducted from November 2012 through February 2013 to evaluate progress over time. RESULTS: Responses were received from 129 of 210 hospitals (61% response rate). Some 98% of responding hospitals (n = 126) had implemented or begun implementing an EHR-greater than a fourfold increase in three years. Nearly three-quarters had already attested to Stage 1 meaningful use for Medicaid (74.8%, n = 86) and Medicare (70.8%, n = 85), although only 10.7% (n = 13) anticipated it would be easy to achieve Stage 2 meaningful use. Seventy nine percent of respondents (n = 92) reported exchanging electronic patient-level clinical data with other partners, and 89.9% (n = 116) reported participation in regional arrangements to share data. Lack of architecture and cost remain major barriers to achieving robust HIE. DISCUSSION: Although much progress has been made since 2009, careful attention must be paid to helping hospitals meet the stricter Stage 2 meaningful use requirements and to supporting robust HIE to help fulfill HIT's promise of achieving higher-quality, lower-cost health care. PMID- 26111306 TI - A Qualitative Analysis of Physician Perspectives on Missed and Delayed Outpatient Diagnosis: The Focus on System-Related Factors. AB - BACKGROUND: Delayed and missed diagnoses lead to significant patient harm. Because physician actions are fundamental to the outpatient diagnostic process, a study was conducted to explore physician perspectives on diagnosis. METHODS: As part of a quality improvement initiative, an integrated health system conducted six physician focus groups in 2004 and 2005. The focus groups included questions about the process of diagnosis, specific factors contributing to missed diagnosis, use of guidelines, atypical vs. typical presentations of disease, diagnostic tools, and follow-up, all with regard to delays in the diagnostic process. The interviews were analyzed (1) deductively, with application of the Systems Engineering Initiative for Patient Safety (SEIPS) model, which addresses systems design, quality management, job design, and technology implementations that affect safety-related patient and organizational and/or staff outcomes, and (2) inductively, with identification of novel themes using content analysis. RESULTS: A total of 25 physicians participated in the six focus groups, which yielded 12 hours of discussion. Providers identified multiple barriers to timely and accurate diagnosis, including organizational culture, information availability, and communication factors. CONCLUSIONS: Multiple themes relating to each of the participants in the diagnostic process-health system, provider, and patient-emerged. Concerns about health system structure and providers' interactions with one another and with patients far exceeded discussion of the cognitive factors that might affect the diagnostic process. The results suggest that, at least in physicians' views, improving the diagnostic process requires attention to the organization of the health system in addition to the cognitive aspects of diagnosis. PMID- 26111307 TI - Medication Safety in the Operating Room: A Survey of Preparation Methods and Drug Concentration Consistencies in Children's Hospitals in the United States. AB - BACKGROUND: Medication errors in the perioperative environment are an important source of iatrogenic harm to patients. In 2010 the Anesthesia Patient Safety Foundation (APSF) initiated an effort to reduce medication errors in the operating room environment. One of the components of this effort was designed to minimize error opportunities for the anesthesia provider by having the hospital pharmacy supply premixed solutions from in-house pharmacies or outside pharmaceutical companies. METHODS: In a convenience sample of representatives of 34 children's hospitals across all geographic regions of the United States, the current state of the APSF medication safety paradigm was assessed. A telephone questionnaire study was conducted from June 2012 through August 2012 to determine each center's practices in providing, packaging, and administering standard anesthesia-related medications. RESULTS: All 34 institutions required at least one anesthetic drug to be prepared by the anesthesia provider in the operating room. Vasopressors were the most common class of drugs to be supplied as prefilled syringes by a hospital pharmacy or pharmaceutical company. For example, 27 of the 34 hospitals surveyed supply epinephrine in a prefilled syringe at a concentration of 0.1 mg/mL (1:10,000 solution), commonly used in cardiac arrest scenarios. Several different anesthetic medications were supplied in different concentrations both between institutions and often within the same institution. None of the surveyed children's hospitals were using bar-code medication administration technology. CONCLUSIONS: Some children's hospitals use standardized medication concentrations, and pharmacy-prepared syringes of anesthetic medications; however, the majority of anesthetic medications were still prepared by the anesthesia provider at the anesthetizing location. PMID- 26111308 TI - The Safe Day Call: Reducing Silos in Health Care Through Frontline Risk Assessment. PMID- 26111309 TI - Emerging Trends in Abdominal Wall Reinforcement: Bringing Bio-Functionality to Meshes. AB - Abdominal wall hernia is a recurrent issue world-wide and requires the implantation of over 1 million meshes per year. Because permanent meshes such as polypropylene and polyester are not free of complications after implantation, many mesh modifications and new functionalities have been investigated over the last decade. Indeed, mesh optimization is the focus of intense development and the biomaterials utilized are now envisioned as being bioactive substrates that trigger various physiological processes in order to prevent complications and to promote tissue integration. In this context, it is of paramount interest to review the most relevant bio-functionalities being brought to new meshes and to open new avenues for the innovative development of the next generation of meshes with enhanced properties for functional abdominal wall hernia repair. PMID- 26111310 TI - Critical Evaluation of Risk Factors and Early Complications in 564 Consecutive Two-Stage Implant-Based Breast Reconstructions Using Acellular Dermal Matrix at a Single Center. AB - BACKGROUND: Acellular dermal matrix for implant-based breast reconstruction appears to cause higher early complication rates, but long-term outcomes are perceived to be superior. This dichotomy is the subject of considerable debate. The authors hypothesized that patient characteristics and operative variables would have a greater impact on complications than the type of acellular dermal matrix used. METHODS: A retrospective cohort study was performed of consecutive patients who underwent two-stage, implant-based breast reconstruction with human cadaveric or bovine acellular dermal matrix from 2006 to 2012 at a single institution. Patient characteristics and operative variables were analyzed using logistic regression analyses to identify risk factors for complications. RESULTS: The authors included 564 reconstructions in the study. Radiation therapy and obesity increased the odds of all complications. Every 100-ml increase in preoperative breast volume increased the odds of any complication by 1 percent, the odds of infection by 27 percent, and the risk of explantation by 16 percent. The odds of seroma increased linearly with increasing surface area of acellular dermal matrix. Odds of infection were higher with an intraoperative expander fill volume greater than 50 percent of the total volume. Risk of explantation was twice as high when intraoperative expander fill volume was greater than 300 ml. CONCLUSIONS: Radiation therapy, obesity, larger breasts, higher intraoperative fill volumes, and larger acellular dermal matrices are all independent risk factors for early complications. Maximizing the initial mastectomy skin envelope fill must be balanced with the understanding that higher complication rates may result from a larger intraoperative breast mound. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 26111311 TI - Vertical Scar Reduction Mammaplasty. AB - Since 1989, the authors have performed vertical scar reduction mammaplasty on over 3000 patients. In 2006, the authors described their technique. Since then, the authors have made several modifications that they believe have improved both the reliability of the procedure and the outcomes that they are able to achieve. Key modifications are described in this article and the accompanying video. PMID- 26111312 TI - A Retrospective Review of Patients Undergoing Lateral Canthoplasty Techniques to Manage Existing or Potential Lower Eyelid Malposition: Identification of Seven Key Preoperative Findings. AB - BACKGROUND: Lateral canthal procedures are often indicated to correct or prevent lower eyelid malposition. When determining an appropriate lateral canthal procedure, planning is essential and includes proper analysis and identification of any contributory anatomical factors. METHODS: A 12-month retrospective review was performed on patients undergoing lateral canthal procedures. Important components of the preoperative examination were studied to relate patient anatomy and results. Outcomes were followed for a minimum of 5 years. RESULTS: Of 288 consecutive lower eyelid canthal procedures, a total of 146 met the inclusion criteria. Common designated abnormal preoperative findings included a negative vector (62 percent), lid margin eversion (12 percent), scleral show (21 percent), neutral or negative canthal tilt (49 percent and 18 percent, respectively), and lateral canthus -to -orbital rim distance of more than 1 cm (11 percent). The distribution of lateral canthal procedures performed in our study population included inferior retinacular lateral canthopexy (n = 36), inferior retinacular lateral canthoplasty (n = 88), tarsal strip lateral canthoplasty (n = 15), and dermal-orbicular pennant lateral canthoplasty (n = 7). Successful outcomes were noted to be 86 percent and 91 percent according to surgeons and patients, respectively. CONCLUSIONS: Specific findings on the preoperative physical examination identify when simple or more complex lateral canthal procedures should be performed. The authors report seven key physical findings that should be documented to effectively determine a lateral canthal procedure that is appropriate for prevention and management of lower eyelid malposition. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26111313 TI - Stereoscopic Analysis of Silicone Breast Implant Shells Damaged by Surgical Instruments. AB - BACKGROUND: Iatrogenic shell injury during the implantation and explantation of silicone gel breast implants may lead to eventual device failure. Identification of the patterns of injury caused by surgical instruments is important when attempting to characterize the cause of shell rupture. Understanding the true causes of device failure may help with its prevention. The purpose of this study was to microscopically characterize patterns of shell injury induced by various surgical instruments. METHODS: Textured and smooth silicone gel implants were intentionally damaged with a variety of surgical instruments. Various scalpels and surgical scissors ranging in fineness were used to create full-thickness injuries in the implant shell. Optical microscopy and scanning electron microscopy were then used to image the injured area to determine patterns of injury. RESULTS: Full-thickness striations across the thickness of the shell could be seen with damage caused by scissors. The density of these striations correlated directly with the fineness of scissors used. No striations were seen with injuries caused by scalpels. CONCLUSIONS: Striations were only observed in injuries caused by scissors and suture needles. Striation density correlated with the coarseness of the cutting edge. No such striations were seen in shells damaged by a scalpel even when the angle of approach was changed. This difference can be of assistance in distinguishing between scissors versus scalpel injury of an implant shell. PMID- 26111314 TI - Deaths Caused by Gluteal Lipoinjection: What Are We Doing Wrong? AB - BACKGROUND: Intramuscular gluteal lipoinjection has become one of the most commonly used surgical procedures for achieving improvement in the gluteal contour; however, there are few studies that report and analyze the causes of secondary death from this surgical procedure. METHODS: An analysis of secondary deaths from gluteal lipoinjection procedures was performed in Mexico and Colombia over periods of 10 and 15 years, respectively. In Mexico, the study was performed through a survey of all members of the Mexican Association of Reconstructive, Plastic and Aesthetic Surgery. In Colombia, the study was performed through an analysis of deaths and autopsies documented by the National Institute of Legal Medicine and Forensic Sciences Regional Bogota. RESULTS: A total of 413 Mexican plastic surgeons reported 64 deaths related to liposuction, with 13 deaths caused by gluteal lipoinjection. In Colombia, nine deaths were documented. Of the 13 deaths in Mexico, eight (61.6 percent) occurred during lipoinjection, whereas the remaining five (38.4 percent) occurred within the first 24 hours. In Colombia, six deaths (77.7 percent) occurred during surgery and three occurred (22.2 percent) immediately after surgery. In the Colombian autopsy results, seven cases of macroscopic fat embolism and two cases with a microscopic embolism were reported, with abundant fatty tissue in the infiltrated gluteal muscles. CONCLUSIONS: In this study, the authors found that intramuscular gluteal lipoinjection is associated with mortality caused by gluteal blood vessel damage allowing macroscopic and microscopic fat embolism; therefore, buttocks lipoinjection should be performed very carefully, avoiding injections into deep muscle planes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 26111315 TI - Human Adipose-Derived Mesenchymal Stromal Cells May Promote Breast Cancer Progression and Metastatic Spread. AB - BACKGROUND: Stem cell-enriched fat grafting has been proposed as a potential therapy for reconstructive, restorative, or enhancement-related procedures of the breast. Its role in postoncologic breast reconstruction is still emerging, with concerns about safety. The authors investigated the dose-dependent interaction between human adipose-derived mesenchymal stromal cells (AD-MSCs) and human breast cancer cell (BCC) lines [MDA-MB-231 (MDA) and MCF-7 (MCF)] focusing on tumor microenvironment, tumor growth, and metastatic spread. METHODS: Adipose derived mesenchymal stromal cell influence on viability and factor expression [regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor-alpha, and eotaxin) of breast cancer cells was studied in vitro using direct and indirect co-culture systems. Groups were formed according to adipose-derived mesenchymal stromal cell-to-cancer cell number ratio [MDA/MCF only, AD-MSC/(MDA/MCF), and AD-MSC/(MDA/MCF)]. A humanized orthotopic murine cancer model was used to evaluate breast cancer progression and metastasis (n = 10/group). Cells were injected into the mammary pad in different ratios and animals were monitored over 42 days. Microdialysis was performed to analyze RANTES levels in the tumor microenvironment (days 21 and 42). Primary and metastatic tumors were weighed and analyzed for oncogene, growth factor, and metastatic marker expression. RESULTS: MDA cell viability increased from 45.5 percent to 95.5 percent in presence of adipose-derived mesenchymal stromal cells in vitro. In vivo, animals with AD-MSC showed increased mean tumor weight (MDA, p < 0.01; MCF versus controls, p < 0.05) and metastatic occurrence (40 percent in MDA; 30 percent in MCF versus 0 percent in controls). Cytokine analysis revealed switching of MCF tumor phenotype to a more malignant type in the presence of adipose-derived mesenchymal stromal cells. CONCLUSION: Human adipose-derived mesenchymal stromal cells may promote progression and metastatic spread in breast cancer through a switch to a more malignant phenotype with worse prognosis. PMID- 26111317 TI - Laparoscopic Free Omental Lymphatic Flap for the Treatment of Lymphedema. AB - Advances in microsurgery have displayed promising results for the treatment of lymphedema. The use of vascularized lymph node transfers has increased in popularity but incurs the potential risk for donor-site lymphedema. The omentum has been previously described for the treatment of lymphedema but has been overlooked because of presumed high morbidity, including the need for celiotomy and pedicled complications. The authors present a novel technique and early results of the laparoscopic free omental lymphatic flap for the management of lymphedema. The minimally invasive harvest successfully avoids both the previously associated morbidity of this flap and the risk of iatrogenic lymphedema to the donor site. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 26111316 TI - A Systematic Review of Outcomes after Revision Amputation for Treatment of Traumatic Finger Amputation. AB - BACKGROUND: Revision amputation is often the treatment for traumatic finger amputation injuries. However, patient outcomes are inadequately reported, and their impact is poorly understood. The authors performed a systematic review to evaluate outcomes of revision amputation and amputation wound coverage techniques. METHODS: The authors searched all available English literature in the PubMed and Embase databases for articles reporting outcomes of nonreplantation treatments for traumatic finger amputation injuries, including revision amputation, local digital flaps, skin grafting, and conservative treatment. Data extracted were study characteristics, patient demographic data, sensory and functional outcomes, patient-reported outcomes, and complications. RESULTS: A total of 1659 articles were screened, yielding 43 studies for review. Mean static two-point discrimination was 5.0 +/- 1.5 mm (n = 23 studies) overall, 6.1 +/- 2.4 mm after local flap procedures, and 3.8 +/- 0.4 mm after revision amputation. Mean total active motion was 93 +/- 8 percent of normal (n = 6 studies) overall. It was 90 +/- 9 percent of normal after local flap procedures and 95 percent of normal after revision amputation. Seventy-seven percent of patients reported cold intolerance after revision amputation. Ninety-one percent of patients (217 of 238) reported "satisfactory" or "good/excellent" ratings regardless of treatment. CONCLUSIONS: Revision amputation and conservative treatments result in better static two-point discrimination outcomes compared with local flaps. All techniques preserve total active motion, although arc of motion is slightly better with revision amputation. Revision amputation procedures are frequently associated with cold intolerance. Patients report "satisfactory," "good," or "excellent" ratings in appearance and quality of life with all nonreplantation techniques. PMID- 26111318 TI - Progressive Tightening of the Levator Veli Palatini Muscle Improves Velopharyngeal Dysfunction in Early Outcomes of Primary Palatoplasty. AB - BACKGROUND: Management of the levator veli palatini with intravelar veloplasty has been shown to improve speech resonance. The senior author has introduced a more aggressive procedure where the levator is separately dissected, overlapped, and tightened. This study compares resonance results from four levator management protocols: non-intravelar veloplasty, Kriens intravelar veloplasty, radical intravelar veloplasty, and overlapping intravelar veloplasty. METHODS: Retrospective chart review was conducted on 252 patients who underwent primary palatoplasty with speech follow-up at 3 years of age. Velopharyngeal function was evaluated with perceptual speech examinations, and subjects were scored on a four point scale (0 = normal resonance; 1 = occasional hypernasality/nasal emission/turbulence/grimacing, no further assessment warranted; 2 = mild hypernasality/intermittent nasal turbulence/grimacing, velopharyngeal imaging suggested; and 3 = severe hypernasality, surgical intervention recommended). Fisher's exact test was used to compare outcomes. RESULTS: A single surgeon performed all the non-intravelar veloplasty (n = 92), Kriens intravelar veloplasty (n = 103), and radical intravelar veloplasty (n = 31), whereas the senior author performed the overlapping intravelar veloplasty (n = 26). Cleft severity proportions were equivalent across the four methods (p = 0.28). Patients who underwent overlapping intravelar veloplasty demonstrated significantly better velopharyngeal function, and none required further imaging or secondary surgery compared with the other three procedures (p < 0.001). CONCLUSIONS: Speech resonance outcomes at 3 years of age are improved and need for secondary velopharyngeal dysfunction management is reduced with more aggressive levator dissection and reconstruction during primary one-stage palatoplasty. Results were best when the muscle was overlapped. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26111319 TI - Discussion: Progressive Tightening of the Levator Veli Palatini Muscle Improves Velopharyngeal Dysfunction in Early Outcomes of Primary Palatoplasty. PMID- 26111320 TI - Trans-Sutural Distraction Osteogenesis for Midfacial Hypoplasia in Growing Patients with Cleft Lip and Palate: Clinical Outcomes and Analysis of Skeletal Changes. AB - BACKGROUND: Although maxillary distraction osteogenesis has been used for early treatment of midfacial hypoplasia, the inevitable osteotomies are still a complicated and invasive procedure for growing patients. Based on the bone-borne trans-sutural distraction osteogenesis, novel improvements to the approach were made to treat midfacial hypoplasia, and the clinical outcomes and skeletal changes were analyzed. METHODS: Seventy consecutive growing cleft lip and palate patients with midfacial hypoplasia were treated with trans-sutural distraction osteogenesis. The distraction system consists of a rigid external distractor, nickel-titanium shape memory alloy spring, and bone-borne traction hooks. The whole distraction process was recorded in detail clinically. Lateral cephalographs and computed tomographic scans were taken and analyzed by cephalometric measurement and color-map analysis to assess the skeletal changes. RESULTS: All of the patients except one achieved satisfactory appearance and occlusal relationship. The unilateral maximum traction force presented an increased trend with age, but this relationship was not absolute. The whole trans sutural distraction osteogenesis process was divided into three clinical stages: the startup period, the rapid movement period, and the consolidation period. Cephalometric analysis showed a great increase in SNA, ANB and horizontal movement of the maxillae after distraction, but with marginal relapse at 6 to 18 months postoperatively. Visualized changes of the midfacial skeleton were observed by three-dimensional color mapping. The results showed an unequal advancement in different regions. CONCLUSION: Trans-sutural distraction osteogenesis process with adaptations offers an alternative method for the early treatment of midfacial hypoplasia in growing patients with cleft lip and palate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26111321 TI - What Makes a Plastic Surgery Residency Program Attractive? An Applicant's Perspective. AB - BACKGROUND: Plastic surgery is among the most competitive specialties in medicine, but little is known about the attributes of programs that are most attractive to successful applicants. This study aimed to understand and provide insights regarding program characteristics that are most influential to students when ranking plastic surgery programs. METHODS: An anonymous online survey was conducted with newly matched plastic surgery residents for the integrated and combined Match in 2012 and 2013. Subjects were queried regarding their demographics, qualifications, application experiences, and motivations for residency program selection. RESULTS: A total of 92 of 245 matched plastic surgery residents (38 percent) responded to the survey. The perception of resident happiness was the most positive factor influencing program ranking, followed by high operative volume, faculty mentorship, and strong research infrastructure. Perception of a program as "malignant" was the most negative attribute. Applicants with Step 1 scores greater than 245 received significantly more interviews (p =0.001) and considered resident benefits less important (p < 0.05), but geographic location more important (p =0.005). Applicants who published more than two articles also received more interviews (p =0.001) and ranked a strong research infrastructure and program reputation as significantly more important (p < 0.05). Forty-two percent of applicants completed an away rotation at the program with which they matched, and these applicants were more likely to match at their number one ranked program (p = 0.001). CONCLUSIONS: Plastic surgery applicants have differing preferences regarding the ideal training program, but some attributes resonate. These trends can guide programs for improvement in attracting the best applicants. PMID- 26111322 TI - Discussion: What Makes a Plastic Surgery Residency Program Attractive? An Applicant's Perspective. PMID- 26111323 TI - The Development of a Wireless Implantable Blood Flow Monitor. AB - Microvascular anastomotic failure remains an uncommon but devastating problem. Although the implantable Doppler probe is helpful in flap monitoring, the devices are cumbersome, easily dislodged, and plagued by false-positive results. The authors have developed an implantable wireless Doppler monitor prototype from off the-shelf components and tested it in a swine model. The wireless probe successfully distinguished between femoral vein flow, occlusion, and reflow, and wirelessly reported the different signals reliably. This is the first description of a wireless implantable blood flow sensor for flap monitoring. Future iterations will incorporate an integrated microchip-based Doppler system that will decrease the size to 1 mm, small enough to fit onto an anastomotic coupler. PMID- 26111325 TI - Patterns and Trends in Immediate Postmastectomy Reconstruction in California: Complications and Unscheduled Readmissions. AB - BACKGROUND: Immediate reconstruction rates after mastectomy are increasing but remain low. Little is known about hospital readmissions after these procedures. The authors studied unscheduled readmissions after immediate reconstruction. METHODS: Using the Healthcare Cost and Utilization Project California State database, the authors identified patients undergoing mastectomy only or with immediate reconstruction for ductal carcinoma in situ and invasive breast cancer from 2005 to 2009. Immediate reconstruction included tissue expander/implant and autologous tissue reconstructions. The authors evaluated temporal trends in immediate reconstruction and factors associated with 30-day unscheduled readmissions after reconstruction. RESULTS: The cohort contained 48,414 patients (mastectomy only, 35,648; immediate reconstruction, 12,766; tissue expander/implant, 10,437; autologous tissue, 2329). Readmission rates were not significantly different between mastectomy only and immediate reconstruction (3.55 percent versus 3.39 percent; p = 0.39); however, autologous tissue reconstruction was associated with a significantly higher readmission rate compared with tissue expander/implant reconstruction (4.08 percent versus 3.24 percent; p = 0.04). CONCLUSIONS: Immediate reconstruction does not result in higher readmission rates compared with mastectomy only. All women undergoing mastectomy should be offered consultation for reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 26111326 TI - The Direction of Optimal Skin Incisions Derived from Striae Distensae. PMID- 26111327 TI - Reply: The Direction of Optimal Skin Incisions Derived from Striae Distensae. PMID- 26111328 TI - Nipple-Sparing Mastectomy and Ptosis: Perforator Flap Breast Reconstruction Allows Full Secondary Mastopexy with Complete Nipple Areolar Repositioning. AB - BACKGROUND: Patients with moderate to severe ptosis are often considered poor candidates for nipple-sparing mastectomy. This results from the perceived risk of nipple necrosis and/or the inability of the reconstructive surgeon to reliably and effectively reposition the nipple-areola complex on the breast mound after mastectomy. METHODS: A retrospective review identified patients with grade II/III ptosis who underwent nipple-sparing mastectomy with immediate perforator flap reconstruction and subsequently underwent a mastopexy procedure. The mastopexies included complete, full-thickness periareolar incisions with peripheral undermining around the nipple-areola complex to allow for full transposition of the nipple-areola complex relative to the surrounding skin envelope. RESULTS: Seventy patients with 116 nipple-sparing mastectomies met inclusion criteria. The most common complications were minor incisional dehiscence (7.7 percent) and variable degrees of necrosis in the preserved breast skin (3.4 percent) after the initial mastectomy. There were no cases of nipple-areola complex necrosis following the secondary mastopexy. CONCLUSIONS: The authors demonstrate that full mastopexy, including a complete full-thickness periareolar incision and nipple areola complex repositioning on the breast mound, can be safely performed after nipple-sparing mastectomy and perforator flap breast reconstruction. The underlying flap provides adequate vascular ingrowth to support the perfusion of the nipple-areola complex despite complete incisional interruption of the surrounding cutaneous blood supply. These findings may allow for inclusion of women with moderate to severe ptosis in the candidate pool for nipple-sparing mastectomy if oncologic criteria are otherwise met. These findings also represent a significant potential advantage of autogenous reconstruction over implant reconstruction in women with breast ptosis who desire nipple-sparing mastectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26111329 TI - Current Trends in Facial Rejuvenation: An Assessment of ASPS Members' Use of Fat Grafting during Face Lifting. AB - BACKGROUND: Fat grafting can be used to improve the results of face lifting. The extent to which plastic surgeons use fat grafting in their face-lift practices is unknown. The goals of this study were to understand the current use of fat grafting during facial rejuvenation surgery and identify the most common techniques used. METHODS: A 28-item questionnaire was formulated for distribution to a randomized cohort of American Society of Plastic Surgeons members. Data were collected and statistically analyzed using Pearson chi-square and Fisher's exact tests. RESULTS: A total of 309 questionnaires were collected. The questionnaire revealed that 85.2 percent of respondents use fat grafting during face lifts. Currently, the most common techniques used include abdominal harvest, centrifuge processing, blunt cannula injection without pretunneling, and placing less than 0.1 cc per pass. The deep central malar, lower lid cheek junction, and nasolabial folds are the most commonly injected areas. CONCLUSIONS: Combining surgical repositioning of fat with fat grafting offers surgeons a greater degree of aesthetic control for correcting contour in the aging face. Although there is controversy regarding the best method to surgically reposition fat, there is a growing consensus that volume augmentation is preferred by most face-lift surgeons. PMID- 26111330 TI - Comparison of Limited and Full Dissection Abdominoplasty Using Laser Fluorescence Imaging to Evaluate Perfusion of the Abdominal Skin. AB - BACKGROUND: In an effort to reduce risk, some surgeons promote a limited dissection abdominoplasty technique. They believe that preserving musculocutaneous perforators improves blood supply to the overlying abdominal tissue and that improved vascularity avoids seromas and reduces wound healing problems. Laser fluorescence imaging is a new method that allows quantitative measurements of perfusion. METHODS: Twenty-two consecutive women undergoing abdominoplasty agreed to participate in this prospective study. The inclusion rate was 100 percent. The SPY Elite Intraoperative Perfusion Assessment System was used to quantitate flap perfusion. Patients served as their own controls to avoid confounders. All patients received superwet infusions followed by liposuction of the abdomen and flanks. First, a limited dissection was performed, preserving medial musculocutaneous perforating blood vessels and the Scarpa fascia on the lower abdomen. The rectus fascia was repaired in all cases. A temporary superficial fascial wound closure was performed. The patient was imaged after injection of the contrast agent. The dissection was then extended to a full abdominoplasty and the Scarpa fascia was removed from the lower abdomen. The patient was reimaged. Wound tension was also measured. RESULTS: Complications included one distal deep venous thrombosis, one infection, and one seroma. There were no cases of marginal necrosis or dehiscence. There was no significant difference (p < 0.05) in perfusion measurements comparing the limited and full dissections. Wound tensions were significantly less (p < 0.001) in the full dissection group. CONCLUSION: The limited dissection abdominoplasty does not provide a significant improvement in perfusion compared with a full dissection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 26111331 TI - Heat Shock Protein 90 Inhibitor (17-AAG) Induces Apoptosis and Decreases Cell Migration/Motility of Keloid Fibroblasts. AB - BACKGROUND: The regulation of apoptosis, proliferation, and migration of fibroblasts is altered in keloids. The 90-kDa heat shock protein (heat shock protein 90) is known to play a key role in such regulation. Therefore, the authors investigated whether the inhibition of heat shock protein 90 in keloid fibroblasts could induce apoptosis and attenuate keloid fibroblast proliferation and migration. METHODS: The authors evaluated heat shock protein 90 expression in keloid tissues with immunohistochemistry. The authors used cell viability [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assays and annexin V/propidium iodide staining for apoptosis, a wound healing model and cell tracking system to assess cell migration, and Akt Western blotting analysis in keloid fibroblasts after inhibition of heat shock protein 90 with 17 allylaminodemethoxygeldanamycin (17-AAG). RESULTS: The expression of heat shock protein 90 in keloid tissues was significantly increased compared with normal tissues. The 17-AAG-treated keloid fibroblasts showed significantly decreased proliferation, promotion of apoptosis, and decreased expression of Akt. Furthermore, a dose-dependent decrease in cell migration was noted after 17-AAG treatment of keloid fibroblasts. The 17-AAG-treated keloid fibroblasts had less directionality to the wound center and migrated a shorter distance. CONCLUSIONS: The authors confirmed that the inhibition of heat shock protein 90 in keloid fibroblasts could promote apoptosis and attenuate proliferation and migration of keloid fibroblasts. Therefore, the authors think that the inhibition of heat shock protein 90 is a key factor in the regulation of biological processes in keloids. With further preclinical study, the authors will be able to apply these results clinically for keloid treatment. PMID- 26111332 TI - Factors in Free Fasciocutaneous Flap Complications: A Logistic Regression Analysis. AB - BACKGROUND: Free tissue transfer using fasciocutaneous flaps has increased in frequency over the past decade. Predictive analyses are lacking for fasciocutaneous free flaps in terms of complication rates for reconstruction. This study therefore was designed to identify key variables that drive complications in fasciocutaneous free flap surgery. METHODS: A retroactive chart review of 91 patients undergoing 91 fasciocutaneous flaps was performed. Twelve variables were identified and tracked through clinic and hospital charts (i.e., surgeon experience, hospital, age, flap type, traumatic wound, smoking, large fasciocutaneous flap, type of anastomosis, recipient vessel choice, sex, anatomical region of wound, and flap debulking). A logistic regression model was used to determine the presence of complications associated with the prescribed predictors. RESULTS: The model revealed that smoking, age, anatomical area of wound, flap size, flap type, and presence of a traumatic wound impacted complications. The model was found to be a good fit (Hosmer-Lemeshow, p = 0.135). Factors impacting complications with fasciocutaneous flaps included anatomical area (62.3 percent increase in complications; p = 0.047), surgeon experience (27 percent reduction in complications; p = 0.007), and reconstruction of a trauma activation patient (80 percent reduction in complications; p = 0.025). CONCLUSION: The implications of these findings can be used to contain cost and minimize poor outcomes within the health care system. PMID- 26111333 TI - Role of Postoperative Antimicrobials in Cleft Palate Surgery: Prospective, Double Blind, Randomized, Placebo-Controlled Clinical Study in India. AB - BACKGROUND: The purpose of this study was to determine whether administration of postoperative antibiotics affects the incidence of complications after primary cleft palate repair in a developing area. METHODS: This study was a prospective, double-blind, randomized, placebo-controlled trial composed of 518 consecutive patients who underwent primary cleft palate repair at a single institution. Patients were aged 1 to 43 years at the time of surgery (median, 9 years). The patients were divided randomly into two groups. One group received a 5-day regimen of oral amoxicillin (50 mg/kg/day) postoperatively and the other group received placebo medication. Both groups received a single dose of cefuroxime (30 mg/kg) before incision. Patients and providers were blinded to the randomization. Patients were followed postoperatively for early complications (infection and wound breakdown) and for late complications (palatal fistulas). RESULTS: The incidence of early complications was 13.8 percent among the patients in the placebo group and 8.7 percent among the patients in the antibiotic group (p = 0.175). Fistulas were noted in 17.1 percent in the placebo group and in 10.7 percent in the antibiotic group (p = 0.085). Logistic regression analysis identified visiting surgeons as the only covariate related to early complications (OR, 3.71; p < 0.001). However, the use of placebo (OR, 2.09; p = 0.037), female sex (OR, 2.04; p = 0.047), and Veau III and IV (OR, 3.31; p = 0.004) were observed as factors associated with the incidence of fistulas. CONCLUSION: The authors' results indicate that postoperative antibiotic prophylaxis can reduce the incidence of fistulas after primary cleft palate repair in a developing area. PMID- 26111334 TI - Effectiveness of Surgical Treatment for Neglected Congenital Muscular Torticollis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Findings on the effectiveness of surgical release for neglected congenital muscular torticollis have been conflicting. This systematic review aims to examine the literature describing the effectiveness of surgery for neglected congenital muscular torticollis. METHODS: The authors conducted a systematic review to examine the effectiveness of surgical treatment for neglected congenital muscular torticollis by means of meta-analysis. The authors searched MEDLINE, EMBASE, the Cochrane library, and KoreaMed for all articles published before May of 2014. Studies with quantitative data describing the effectiveness of surgery for congenital muscular torticollis were included. The primary outcomes after surgery were (1) clinical outcome measured by scoring systems; (2) change in range of motion of the neck; and (3) change in skeletal deformities, measured by Cobb angle and the cervicomandibular angle. Effect estimates were pooled using a random-effects meta-analysis. RESULTS: Twelve studies were included in the review (published between 1976 and 2014), including a total of 220 patients with neglected congenital muscular torticollis. All studies used an interrupted time-series design. Surgical treatment was successful in 81 percent of cases, based on the scoring systems for surgical outcome. Outcomes of surgery performed in patients older than 15 years did not differ significantly from those of surgery performed in patients aged 15 years or younger. The range of motion of the neck and skeletal deformities showed significant improvement after surgery. CONCLUSIONS: Surgical treatment for neglected congenital muscular torticollis produced satisfactorily successful results, with improvement in both the range of motion of the neck and secondary skeletal deformities. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26111335 TI - Abnormality of Auricular Muscles in Congenital Auricular Deformities. AB - BACKGROUND: It has been suggested that there is a close association of abnormality in auricular muscles with various congenital auricular deformities. However, there has been no investigation to determine what muscles are involved and how they affect the deformity. The authors examined abnormalities of auricular muscles for patients with various auricular deformities. METHODS: The authors examined 77 auricles of 62 patients with congenital auricular deformities, including cryptotia, Stahl's ear, prominent ear, lop ear, and others. The superior and posterior auricular muscles from the extrinsic auricular muscle group and the auricular oblique and transverse muscles from the auricular intrinsic muscle group were investigated. RESULTS: The authors found characteristic features of the abnormality of the muscle for each auricular deformity. In nearly all cases of cryptotia, abnormality was found in the superior auricular, auricular oblique, and auricular transverse muscles. Abnormal insertion was found mainly in the superior auricular muscle and was the main cause of cryptotia. In Stahl's ear, the major abnormality was abnormal insertion of the auricular transverse muscle, which creates an abnormal cartilaginous prominence in the scapha. The abnormality in cases of prominent ear was clearly limited mostly to the auricular transverse muscle and, in some cases, to the posterior auricular muscle. In lop ear, abnormality was mostly found in the auricular transverse muscle, with elongation, and in the superior auricular or auricular oblique muscle in some cases. CONCLUSIONS: There is a tendency for a specific muscle abnormality to be found in each deformity. It is important to identify the abnormal muscle and correct the abnormality during the operation. PMID- 26111336 TI - Outpatient Surgery. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Determine those patients appropriate for outpatient surgery. 2. Choose appropriate anesthetics. 3. Manage patients with cardiac disease. 4. Limit complications occurring intraoperatively. SUMMARY: This article provides continuing medical education information regarding the current state of practice concerning outpatient surgery. A thorough preoperative evaluation is necessary to identify comorbid conditions and patients at risk for pulmonary compromise. Guidelines are provided on the use of sedatives, analgesics, and reversal agents. The management of patients with coronary artery stents and/or cardiac rhythm management devices is discussed. Effective surgical team communication is crucial to ensure that everyone is aware of conditions that may require adjustments from the usual healthy patients. Lastly, suggestions are provided to avoid intraoperative problems such as drug reactions and pressure ulcers. As our aging population presents for an increasing number of procedures, plastic surgeons must ensure that patient safety is a priority. PMID- 26111337 TI - Employment Satisfaction in Plastic and Reconstructive Surgery and Its Influence on Graduating Residents in an Evolving Health Care Climate. AB - BACKGROUND: The current state of employment satisfaction in plastic surgery has not been defined. Similarly, the factors influencing residents as they search for employment and the role of attending surgeons as mentors in this process have not been elicited. The authors aim to elucidate these measures through a survey of attending surgeons and senior residents. METHODS: A survey was created assessing employment satisfaction and was distributed to members of the American Society of Plastic Surgeons with available contact information. Responses were analyzed, with values of p < 0.05 deemed significant. RESULTS: A total of 616 plastic surgeons and senior plastic surgery residents responded. Compared with attending surgeons in private practice, those in academic practice were more satisfied with their case mix (p = 0.0005; OR, not significant) and less satisfied with their incentive structure (p = 0.0001; OR, 0.3155) and payor mix (p = 0.0005; OR, 0.6156). Employment change occurred in 225 surgeons (39.2 percent) since beginning practice. Surgeons that changed employment ranked base salary (p = 0.0031), earning potential (p = 0.0001), and incentive structure (p = 0.0001) as most important. Those that did not change employment ranked lifestyle (p = 0.0048), location (p = 0.0001), and desire to teach (p = 0.0002) as more important. Residents ranked location (p = 0.0030), desired case mix (p = 0.0131), and desire or lack of desire to teach residents (p = 0.0329) as more important than attending surgeons felt they should be, and guaranteed salary (p = 0.0178) and incentive structure (p = 0.0069) as less important. CONCLUSIONS: In an evolving health care environment, plastic surgeons' employment satisfaction is significantly dependent on a myriad of factors. Residents and their attending mentors differ significantly in perceived importance of these factors. PMID- 26111338 TI - Comparison of sequential drug release in vitro and in vivo. AB - Development of drug-delivery devices typically involves characterizing in vitro release performance with the inherent assumption that this will closely approximate in vivo performance. Yet, as delivery devices become more complex, for instance with a sequential drug release pattern, it is important to confirm that in vivo properties correlate with the expected "programming" achieved in vitro. In this work, a systematic comparison between in vitro and in vivo biomaterial erosion and sequential release was performed for a multilayered association polymer system comprising cellulose acetate phthalate and Pluronic F 127. After assessing the materials during incubation in phosphate-buffered saline, devices were implanted supracalvarially in rats. Devices with two different doses and with different erosion rates were harvested at increasing times post-implantation, and the in vivo thickness loss, mass loss, and the drug release profiles were compared with their in vitro counterparts. The sequential release of four different drugs observed in vitro was successfully translated to in vivo conditions. Results suggest, however, that the total erosion time of the devices was longer and that release rates of the four drugs were different, with drugs initially released more quickly and then more slowly in vivo. Many comparative studies of in vitro and in vivo drug release from biodegradable polymers involved a single drug, whereas this research demonstrated that sequential release of four drugs can be maintained following implantation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1302 1310, 2016. PMID- 26111339 TI - Dynamics of preventive vs post-diagnostic cancer control using low-impact measures. AB - Cancer poses danger because of its unregulated growth, development of resistance, and metastatic spread to vital organs. We currently lack quantitative theory for how preventive measures and post-diagnostic interventions are predicted to affect risks of a life threatening cancer. Here we evaluate how continuous measures, such as life style changes and traditional treatments, affect both neoplastic growth and the frequency of resistant clones. We then compare and contrast preventive and post-diagnostic interventions assuming that only a single lesion progresses to invasive carcinoma during the life of an individual, and resection either leaves residual cells or metastases are undetected. Whereas prevention generally results in more positive therapeutic outcomes than post-diagnostic interventions, this advantage is substantially lowered should prevention initially fail to arrest tumour growth. We discuss these results and other important mitigating factors that should be taken into consideration in a comparative understanding of preventive and post-diagnostic interventions. PMID- 26111341 TI - Visible light absorption and photoelectrochemical activity of colorless molecular 1,3-bis(dicyanomethylidene)indane (BDMI) by surface complexation on TiO2. AB - Adsorption of the colorless 1,3-bis(dicyanomethylidene)indane (BDMI) onto a nanocrystalline TiO2 surface unusually turned the BDMI a deep blue color. Upon contact of the BDMI-adsorbed TiO2 (BDMI-TiO2) with an iodide-based redox electrolyte, a photocurrent density as high as 14.9 mA cm(-2) was generated with a photovoltage of 0.42 V, leading to a power conversion efficiency of 3.63%. This unprecedented photovoltaic performance was simultaneously investigated by spectroscopic studies of BDMI-TiO2 films and density functional theory (DFT)/time dependent DFT (TD-DFT) computational approaches for [BDMI](-)[Ti(OH)3.H2O](+) (1) as a simple model compound to inspect the light to current conversion abilities. All these results established that the color change from colorless to deep blue and the highly efficient photocurrent generation through binding on the TiO2 surface originates from interfacial charge transfer transitions from anionic BDMI to TiO2. PMID- 26111342 TI - Functional relations and cognitive psychology: Lessons from human performance and animal research. AB - We consider requirements for effective interdisciplinary communication and explore alternative interpretations of "building bridges between functional and cognitive psychology." If the bridges are intended to connect radical behaviourism and cognitive psychology, or functional contextualism and cognitive psychology, the efforts are unlikely to be successful. But if the bridges are intended to connect functional relationships and cognitive theory, no construction is needed because the bridges already exist within cognitive psychology. We use human performance and animal research to illustrate the latter point and to counter the claim that the functional approach is unique in offering a close relationship between science and practice. Effective communication will be enhanced and, indeed, may only occur if the goal of functional contextualism extends beyond just "the advancement of functional contextual cognitive and behavioral science and practice" to "the advancement of cognitive and behavioral science and practice" without restriction. PMID- 26111340 TI - ATF4 licenses C/EBPbeta activity in human mesenchymal stem cells primed for adipogenesis. AB - A well-established cascade of transcription factor (TF) activity orchestrates adipogenesis in response to chemical cues, yet how cell-intrinsic determinants of differentiation such as cell shape and/or seeding density inform this transcriptional program remain enigmatic. Here, we uncover a novel mechanism licensing transcription in human mesenchymal stem cells (hMSCs) adipogenically primed by confluence. Prior to adipogenesis, confluency promotes heterodimer recruitment of the bZip TFs C/EBPbeta and ATF4 to a non-canonical C/EBP DNA sequence. ATF4 depletion decreases both cell-density-dependent transcription and adipocyte differentiation. Global profiling in hMSCs and a novel cell-free assay reveals that ATF4 requires C/EBPbeta for genomic binding at a motif distinct from that bound by the C/EBPbeta homodimer. Our observations demonstrate that C/EBPbeta bridges the transcriptional programs in naive, confluent cells and early differentiating pre-adipocytes. Moreover, they suggest that homo- and heterodimer formation poise C/EBPbeta to execute diverse and stage-specific transcriptional programs by exploiting an expanded motif repertoire. PMID- 26111343 TI - Relations Between Actual Group Norms, Perceived Peer Behavior, and Bystander Children's Intervention to Bullying. AB - The goals of the study were (a) to predict children's intervention in bullying situations from class-level norms for intervention, as well as child-level perceptions of the number of peers who would intervene, and (b) to determine whether these predictions held when accounting for children's levels of empathy, prosocial behavior, and callous-unemotional traits. Participants were 751 racially and ethnically diverse fourth- and fifth-grade students (53.8% female) in 43 classes. Participants completed peer nominations about which classmates they perceived would intervene during bullying situations. Empathy and callous unemotional traits were assessed via self report, whereas prosocial behavior was measured through peer report. Using multilevel modeling, each child's intervention in bullying was positively predicted from class-level norms for intervention (class means for the percentage of children who nominated each child as intervening) but negatively predicted from child-level perceptions of the number of peers who would intervene, after accounting for the 3 child traits. Class-level findings support past research on group norms which suggest that children are more likely to display a behavior if their peers display the same behavior. Child-level findings support the presence of the "bystander effect" in children's bullying episodes, in which children are less likely to intervene if they believe that more peers will do so. Thus, although children were more likely to intervene in classrooms with cultures that made intervention more normative, within the context of each class's culture, children were more likely to intervene if they perceived that fewer peers would do so. PMID- 26111344 TI - Sequential Optical Coherence Tomographic Angiography for Diagnosis and Treatment of Choroidal Neovascularization in Multifocal Choroiditis. PMID- 26111345 TI - Calcitriol increases Dicer expression and modifies the microRNAs signature in SiHa cervical cancer cells. AB - MicroRNAs play important roles in cancer biology. Calcitriol, the hormonal form of vitamin D3, regulates microRNAs expression in tumor cells. In the present study we asked if calcitriol would modify some of the components of the microRNA processing machinery, namely, Drosha and Dicer, in calcitriol-responsive cervical cancer cells. We found that calcitriol treatment did not affect Drosha mRNA; however, it significantly increased Dicer mRNA and protein expression in VDR positive SiHa and HeLa cells. In VDR-negative C33-A cells, calcitriol had no effect on Dicer mRNA. We also found a vitamin D response element in Dicer promoter that interacts in vitro to vitamin D and retinoid X receptors. To explore the biological plausibility of these results, we asked if calcitriol alters the microRNA expression profile in SiHa cells. Our results revealed that calcitriol regulates the expression of a subset of microRNAs with potential regulatory functions in cancer pathways, such as miR-22, miR-296-3p, and miR-498, which exert tumor-suppressive effects. In summary, the data indicate that in SiHa cells, calcitriol stimulates the expression of Dicer possibly through the vitamin D response element located in its promoter. This may explain the calcitriol dependent modulation of microRNAs whose target mRNAs are related to anticancer pathways, further adding to the various anticancer mechanisms of calcitriol. PMID- 26111346 TI - A Computational, Tissue-Realistic Model of Pressure Ulcer Formation in Individuals with Spinal Cord Injury. AB - People with spinal cord injury (SCI) are predisposed to pressure ulcers (PU). PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions. An agent-based model (ABM) of ischemia/reperfusion-induced inflammation and PU (the PUABM) was created, calibrated to serial images of post-SCI PU, and used to investigate potential treatments in silico. Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI. These morphological features, along with simulated cell counts and mediator concentrations, suggested that the influence of inflammatory dynamics caused simulations to be committed to "better" vs. "worse" outcomes by 4 days of simulated time and prior to ulcer formation. Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence. Using the PUABM, in silico trials of anti-inflammatory treatments such as corticosteroids and a neutralizing antibody targeted at Damage-Associated Molecular Pattern molecules (DAMPs) suggested that, at best, early application at a sufficiently high dose could attenuate local inflammation and reduce pressure-associated tissue damage, but could not reduce PU incidence. The PUABM thus shows promise as an adjunct for mechanistic understanding, diagnosis, and design of therapies in the setting of PU. PMID- 26111348 TI - The Effectiveness of Vestibular Rehabilitation Interventions in Treating Unilateral Peripheral Vestibular Disorders: A Systematic Review. AB - BACKGROUND AND PURPOSE: Various types of vestibular rehabilitation therapy are routinely used in clinical practice to treat unilateral peripheral vestibular hypofunction. The purpose of this systematic review was to compare the effectiveness of vestibular rehabilitation interventions (adaptation, substitution and habituation) in people with unilateral peripheral vestibular hypofunction, exclusionary of benign paroxysmal positional vertigo and Meniere's disease. METHODS: A search of the literature was conducted using PubMed, CINAHL and Scopus. Studies were eligible for inclusion if they were 1) a randomized controlled trial or randomized clinical trial; 2) written in English; 3) of participants with a unilateral, peripheral vestibular hypofunction; 4) of a conservative treatment approach only; and 5) with human subjects. Quality was assessed by two authors using the Physiotherapy Evidence Database scale. Effect size was calculated to determine the effect of treatment within each study group. RESULTS: Seven papers were selected for inclusion. Physiotherapy Evidence Database scores ranged from 2/10 to 7/10. Interventions within the selected studies included combinations of adaptation, habituation, substitution or substitution by itself. Calculated effect sizes, or significance values, revealed that all interventions demonstrated effectiveness. Two studies reported improvements on the dynamic gait index, and a large difference was seen between intervention groups of the two studies. DISCUSSION: Results suggest that vestibular therapy for unilateral peripheral vestibular hypofunction is effective. When considering all seven studies included in the review, it is difficult to determine the superiority of one intervention over another in treating unilateral peripheral vestibular hypofunction except when patient outcomes are captured by the dynamic gait index or dizziness handicap inventory. Many studies in this review demonstrate notable biases, suggesting that results should be used with caution. Future research should aim to use a common set of measures to capture outcomes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26111347 TI - Predictors of All-Cause Mortality in Patients With Severe COPD and Major Depression Admitted to a Rehabilitation Hospital. AB - BACKGROUND: COPD is a major cause of all-cause mortality. We examined predictors of 1-year mortality in patients with severe COPD and major depression after inpatient treatment in a rehabilitation hospital. METHODS: We screened 898 consecutively admitted patients. Of these, 138 patients received the diagnoses of COPD according to American Thoracic Society Guidelines and major depression by Diagnostic and Statistical Manual of Mental Disorders, 4th edition and signed consent; 67 were randomized to a treatment adherence enhancement intervention and 71 to usual care. We assessed history of falls, dyspnea-related disability, severity of depression, medical burden, and cognitive functioning. Following discharge from inpatient rehabilitation, participants were prospectively followed, and mortality was ascertained over 52 weeks from hospital notes and reports of primary care physicians and relatives. RESULTS: One-year, all-cause mortality was 22% (31 of 138). Multivariate Cox regression analysis showed that history of falls in the 6 months preceding hospital admission was the strongest predictor of mortality (OR, 3.05; 95% CI, 1.40-6.66; P < .005). Dyspnea during activities (Pulmonary Functional Status and Dyspnea Questionnaire-Modified domain) was also associated with mortality (OR, 1.05; 95% CI, 1.02-1.08; P < .002). Depression severity, medical burden, and cognitive impairment were not predictors of mortality. CONCLUSIONS: Recent falls and dyspnea during activities identify subgroups of depressed patients with COPD at increased risk for all cause mortality. These subgroups are in need of clinical attention and follow-up and can serve as targets for prevention research aiming to inform clinical strategies and public health planning. PMID- 26111349 TI - Amyloid-like renal lesions in a roughtail stingray Dasyatis centroura (Mitchill 1815). PMID- 26111350 TI - Enhancement of Sodium Ion Battery Performance Enabled by Oxygen Vacancies. AB - The utilization of oxygen vacancies (OVs) in sodium ion batteries (SIBs) is expected to enhance performance, but as yet it has rarely been reported. Taking the MoO(3-x) nanosheet anode as an example, for the first time we demonstrate the benefits of OVs on SIB performance. Moreover, the benefits at deep-discharge conditions can be further promoted by an ultrathin Al2O3 coating. A series of measurements show that the OVs increase the electric conductivity and Na-ion diffusion coefficient, and the promotion from ultrathin coating lies in the effective reduction of cycling-induced solid-electrolyte interphase. The coated nanosheets exhibited high reversible capacity and great rate capability with the capacities of 283.9 (50 mA g(-1)) and 179.3 mAh g(-1) (1 A g(-1)) after 100 cycles. This work may not only arouse future attention on OVs for sodium energy storage, but also open up new possibilities for designing strategies to utilize defects in other energy storage systems. PMID- 26111351 TI - Randomized phase II trial of docetaxel with or without PSA-TRICOM vaccine in patients with castrate-resistant metastatic prostate cancer: A trial of the ECOG ACRIN cancer research group (E1809). AB - Anti-tumor vaccines have demonstrated efficacy in patients with castration resistant metastatic prostate cancer. One vaccine, Prostvac-VF(r), using a heterologous prime-boost strategy with vaccinia and fowlpox viral vectors encoding PSA, is currently being evaluated in a registration phase III multinational clinical trial. The current trial was planned to assess the clinical efficacy of this vaccine in patients with castration-resistant metastatic prostate cancer receiving subsequent docetaxel chemotherapy. 10 patients with metastatic castration-resistant prostate cancer, with a predicted survival of at least 18 months, were enrolled out of a planned 144 patients. Eight of 10 patients were treated and were randomized to receive docetaxel chemotherapy alone (Arm B, n = 2) versus treatment with Prostvac-VF (days 1, 15, 29, 43, 57) followed by docetaxel (Arm A, n = 6) chemotherapy beginning at month 3. The primary endpoint of the trial was overall survival, and secondary endpoints included time to radiographic progression and immunological response. The trial was opened within the Eastern Cooperative Oncology Group, but due to slow accrual was closed by CTEP after only 10 patients were enrolled within 13 months. RESULTS: Presented here are the safety, clinical, and immunological results from 8 eligible patients who underwent treatment. Two of 6 patients treated on Arm A, with vaccine followed by docetaxel, had a >50% PSA response, with one of these patients experiencing a PSA decline during treatment with vaccine. Significant PSA-specific CD4+ and CD8+ T-cell responses and IgG antibody responses specific for PSA were not detected. The primary endpoint of overall survival cannot be assessed due to limited accrual. The lack of T-cell responses, even in this small cohort, suggests that further validation and development of immune biomarkers will be important for future studies. Other trials remain ongoing to evaluate the role of anti-tumor vaccination in sequence with other traditional anti-tumor therapies. PMID- 26111352 TI - Obesity, asthma prevalence and IL-4: Roles of inflammatory cytokines, adiponectin and neuropeptide Y. AB - BACKGROUND: Obesity is associated with asthma risk and severity, but the underlying biological mechanisms are poorly understood. We hypothesized that cytokine markers of systemic inflammation, and adiponectin and neuropeptide Y (NPY) markers of immuno-modulating and neurohormonal regulation are involved in the obesity-asthma association. METHODS: We explored the relationships between body mass index (BMI), C-reactive protein (CRP), IL-6, TNF-alpha, adiponectin and NPY with asthma prevalence and IL-4 levels in 70 youth with asthma and 69 age- and gender-matched healthy controls using cross-sectional and longitudinal data. RESULTS: Mean BMI level was higher among patients with asthma than healthy controls (p < 0.001). In logistic regression models controlling for potential confounders, independent associations with asthma prevalence were found for obesity (p = 0.001), increasing tertiles of CRP (linear trend p < 0.001), IL-6 (linear trend p < 0.001) and lowest and highest tertiles of TNF-alpha (quadratic trend p < 0.05), increasing adiponectin (linear p = 0.022) and decreasing tertiles of NPY (linear trend p = 0.001). Among patients with asthma, NPY level was positively correlated with adiponectin (p < 0.05) and TNF-alpha (p < 0.05), and levels of NPY and IL-6 were significantly associated with IL-4 level at baseline and 1-year follow-up. CONCLUSIONS: The obesity-asthma association was not explained by systemic inflammation. Specifically, CRP, TNF-a, IL-6, NPY and adiponectin were independently associated with asthma prevalence. NPY and IL-6 were associated with IL-4 marker of allergic airway inflammation in asthma and should be further investigated as prognostic markers of asthma outcomes. PMID- 26111354 TI - Reaction Time Is Slower When Walking at a Slow Pace in Young Adults. AB - Limited research has examined attentional requirements of walking at various speeds. Twenty young adults were asked to walk 10 m at their preferred pace, 30% faster or 30% slower while verbally responding "top" as fast as possible to random auditory stimuli. Slow walking demonstrated significantly longer reaction time (RT; 457 +/- 91 ms) than preferred (423 +/- 80 ms) and fast (396 +/- 73 ms) walking speeds, F(2, 38) = 13.4, p < .001; eta(2)p = .414. Walking at a preferred pace also led to longer RT than walking at a fast pace (p < .05). Slower RT during slow walking may be attributed to increased task complexity, energy requirements and equilibrium demands. Faster RTs during fast walking could be due to familiarity of the task, higher arousal levels, and similar task instructions compared to slower speeds. PMID- 26111353 TI - Gaseous Emissions from Light-Duty Vehicles: Moving from NEDC to the New WLTP Test Procedure. AB - The Worldwide Harmonized Light Duty Test Procedure (WLTP), recently issued as GTR15 by UNECE-WP29, is designed to check the pollutant emission compliance of Light Duty Vehicles (LDVs) around the world and to establish the reference vehicle fuel consumption and CO2 performance. In the course of the development of WLTP, the Joint Research Center (JRC) of the European Commission has tested gaseous emissions of twenty-one Euro 4-6 gasoline and diesel vehicles, on both the current European type approval test procedure (NEDC) and the progressive versions of the WLTP. The results, which should be regarded just as an initial and qualitative indication of the trends, demonstrated minimal average differences between CO2 emissions over the NEDC and WLTP. On the other hand, CO2 emissions measured at JRC on the NEDC were on average 9% higher than the respective type approval values, therefore suggesting that for the tested vehicles, CO2 emissions over WLTP were almost 10% higher than the respective NEDC type approval values. That difference is likely to increase with application of the full WLTP test procedure. Measured THC emissions from most vehicles stayed below the legal emission limits and in general were lower under the WLTP compared to NEDC. Moving from NEDC to WLTP did not have much impact on NOx from gasoline vehicles and CO from diesel vehicles. On the contrary, NOx from diesel vehicles and CO from low-powered gasoline vehicles were significantly higher over the more dynamic WLTP and in several cases exceeded the emission limits. Results from this study can be considered indicative of emission patterns of modern technology vehicles and useful to both policy makers and vehicle manufacturers in developing future emission policy/technology strategies. PMID- 26111355 TI - Discovery and Modification of in Vivo Active Nrf2 Activators with 1,2,4 Oxadiazole Core: Hits Identification and Structure-Activity Relationship Study. AB - Induction of phase II antioxidant enzymes by activation of Nrf2/ARE pathway has been recognized as a promising strategy for the regulation of oxidative stress related diseases. Herein we report our effort on the discovery and optimization of Nrf2 activators with 1,2,4-oxadiazole core. Screening of an in-house collection containing 7500 compounds by ARE-luciferase reporter assay revealed a moderate Nrf2 activator, 1. Aimed at obtaining more derivatives efficiently, molecular similarity search by the combination of 2D fingerprint-based and 3D shape-based search was applied to virtually screening the Chemdiv collection. Three derivatives with the same core were identified to have better inductivity of Nrf2 than 1. The best hit 4 was selected as starting point for structurally optimization, leading to a much more potent derivative 32. It in vitro upregulated gene and protein level of Nrf2 as well as its downstream markers such as NQO1, GCLM, and HO-1. It remarkably suppressed inflammation in the in vivo LPS challenged mouse model. Our results provide a new chemotype as Nrf2-ARE activators which deserve further optimization with the aim to obtain active anti inflammatory agents through Nrf2-ARE pathway. PMID- 26111356 TI - Pregabalin for the treatment of patients with generalized anxiety disorder with inadequate treatment response to antidepressants and severe depressive symptoms. AB - To evaluate the effectiveness of pregabalin in patients with resistant generalized anxiety disorder (GAD) and severe depressive symptoms, we carried out a post-hoc analysis of a multicenter, prospective, and observational 6-month study. We included patients who were at least 18 years old, fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for GAD, showed inadequate responses to previous courses of antidepressant treatment, had Montgomery-Asberg Rating Scale scores of at least 35, had not received pregabalin previously, and were prescribed pregabalin upon entry into this study. We included 1815 patients fulfilling the DSM-IV criteria for GAD, and 133 (7.3%) fulfilled the selection criteria for these analyses. Ninety-seven percent of the patients received pregabalin (mean dose: 222 mg/day) in combination with other psychotropics. The Hamilton Anxiety Scale total score was reduced by a mean of 20.3 points (95% confidence interval, 22.1-18.4) (57.2% reduction) at month 6. Pregabalin also ameliorated comorbid depressive symptoms, with a reduction in the mean score of the Montgomery-Asberg Rating Scale of 22.3 points (95% confidence interval, 24.2-20.4) (56.6% reduction). Our results suggest that pregabalin, as part of a combination regimen with antidepressants and/or benzodiazepines, might be effective for the treatment of patients with GAD who have shown inadequate response to previous antidepressants and have severe depressive symptoms. PMID- 26111357 TI - Metal-Organic Frameworks Incorporating Various Alkoxy Pendant Groups: Hollow Tubular Morphologies, X-ray Single-Crystal Structures, and Selective Carbon Dioxide Adsorption Properties. AB - Eight porous metal-organic frameworks (MOFs) incorporating various alkoxy pendant groups (-OC(n)H(2n+1); n=1-8) in the channels have been synthesized. All MOFs have macrosized, hollow, single-crystal morphologies independent of the type of alkoxy pendant groups. The X-ray single-crystal structures indicate that the MOFs have doubly interpenetrated 3D frameworks that generate clover-shaped 1D channels, the window sizes of which reduce as the length of the alkoxy pendant groups increases from -OCH3 to -OC8H17. The hollow axes of the tubular crystals are parallel to the 1D channels of the MOFs, which suggests that the hollow crystal is grown by the unidirectional addition of pillar ligands to the 2D network. Among the activated MOFs, only the MOFs with methoxy and ethoxy pendant groups show selective CO2 adsorption over N2 and CH4, whereas those with longer alkoxy pendant groups barely adsorb CO2 at room temperature, which implies that the pendant doors of the MOFs should have an appropriate length for selective CO2 capture. PMID- 26111358 TI - Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease in Western societies. Despite its significance, there are no well-proven pharmacological treatments. Two novel classes of potential pharmacotherapies are the glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4I), collectively known as incretin based therapies. These have several metabolic and anti-inflammatory actions that may be of benefit in NAFLD. The aim of this meta-analysis was to evaluate their efficacy via a structured retrieval and pooled analysis of relevant studies. METHODS: Studies were sourced from electronic databases and meeting abstracts. Main inclusion criteria were original studies investigating treatment of adults with NAFLD using GLP-1 RA/DPP-4I. Key outcomes were a change in serum alanine transaminase (ALT), as a marker of liver inflammation, and improvement in disease status measured by imaging or histology. RESULTS: Initial searching retrieved 1357 peer-reviewed articles and abstracts. Four studies met all inclusion and exclusion criteria. There were a total of 136 participants with NAFLD and concomitant type 2 diabetes mellitus (T2DM). Meta-analysis (random-effects model) revealed a significant decrease in serum ALT following treatment (mean reduction 14.1 IU/L, 95% confidence intervals [CI] 8.3-19.8, P < 0.0001). In two studies with imaging and tissue data, treatment was found to significantly reduce steatosis, inflammation, and fibrosis. CONCLUSION: The significant decrease in a key biochemical marker of hepatic inflammation following treatment with incretin based therapies, as well as improvements in imaging and histology, suggests these agents may be effective options for managing NAFLD with comorbid T2DM. PMID- 26111360 TI - Evaluation of bipolar radiofrequency ablation for occluded self-expandable metal stents in the bile duct: in vivo and in vitro study. AB - BACKGROUND AND AIMS: Endobiliary radiofrequency ablation (RFA) has been used to treat occluded self-expandable metal stents (SEMSs). The aim of this study was to determine the characteristics of bipolar RFA in occluded SEMSs using both in vivo and in vitro models. METHODS: For the in vivo study, uncovered SEMSs were deployed in the bile ducts of three pigs; another pig was used as the control. RFA was performed at 10 W for 90 seconds. The bile duct was examined for histological changes. For the in vitro simulation of tissue ingrowth in SEMSs, RFA at 10 W for 30 seconds was performed on SEMS-occlusion polyacrylamide-gel phantoms. RESULTS: The ablation depth was markedly reduced in the stented porcine bile duct. RFA of uncovered SEMS-occlusion gel phantoms resulted in early termination of RFA when the coagulated area contacted the SEMS. This phenomenon was not observed in RFA of the covered SEMS-occlusion gel phantoms. CONCLUSIONS: The presence of SEMSs attenuated the effect of bipolar endobiliary RFA. Tumorous tissue outside the SEMS is unlikely to be affected. PMID- 26111361 TI - Endoscopic treatment of fistula after sleeve gastrectomy: results of a multicenter retrospective study. AB - BACKGROUND AND STUDY AIMS: Fistula is the main complication of laparoscopic sleeve gastrectomy (LSG), for which healing is difficult to achieve. The aims of the study were to evaluate the efficacy of interventional endoscopy for post-LSG fistula treatment, to evaluate various endoscopic techniques used and identify their complications, and to identify predictive factors of healing following endoscopic treatment. PATIENTS AND METHODS: This retrospective multicenter study included patients with post-LSG fistula. Therapeutic procedures were evaluated, taking into account complications and healing times. Endoscopic procedures were considered to have promoted healing if no other surgical procedure was performed. Predictive factors of healing were identified by univariate and multivariate analysis. RESULTS: A total of 110 patients were included, of whom 6 (5.5 %) healed spontaneously, 81 (73.6 %) healed following endoscopic treatment, and 19 (17.3 %) healed following surgery. Healing rates following endoscopic treatment were 84.4 % in the first 6 months of treatment (65/77), 52.4 % for treatment lasting 6 - 12 months (11/21), and 41.7 % after 12 months of treatment (5/12). A drainage procedure (surgical, endoscopic, or percutaneous) was performed in 92 patients (83.6 %). A total of 177 esogastric stents were placed in 88 patients (80.0 %). Surgical debridement, clip placement, glue sealing, and plug placement were also performed. Multivariate analysis identified four predictive factors of healing following endoscopic treatment: interval < 21 days between fistula diagnosis and first endoscopy (P = 0.003), small fistula (P = 0.01), interval between LSG and fistula <= 3 days (P = 0.01), no history of gastric banding (P = 0.04). CONCLUSION: Endoscopic treatment facilitated healing of post-LSG fistula in 74 % of patients. Early endoscopic treatment increased the likelihood of success, and was most effective during the first 6 months of management. After this point, surgical treatment should be considered. PMID- 26111362 TI - Surveillance strategy based on the incidence and patterns of recurrence after curative endoscopic submucosal dissection for early gastric cancer. AB - BACKGROUND AND STUDY AIMS: To suggest an appropriate surveillance strategy after curative endoscopic submucosal dissection (ESD) for early gastric cancers, based on incidence and patterns of local, metachronous, and extragastric recurrence. PATIENTS AND METHODS: Between 2003 and 2011, 1497 consecutive patients with 1539 differentiated-type early gastric cancers meeting absolute or expanded indication criteria underwent curative ESD. They were followed up with esophagogastroduodenoscopy (EGD) and abdominal computed tomography (CT) under a standardized surveillance protocol. Long-term outcomes were analyzed for 1306 patients with at least 1 year's follow-up. RESULTS: Incidences of residual and synchronous lesions detected within 1 year were 0.13 % and 0.87 %, respectively. During median 47 months of follow-up, there was 1 local recurrence (0.08 %; early gastric cancer) and 47 cases of metachronous recurrence (3.6 %; 44 early gastric cancers, 3 pT2 advanced gastric cancers); all were curatively treated. During a 5 year surveillance, the cumulative incidence curve of metachronous recurrence increased linearly. Median time from ESD to metachronous recurrence was 30 months. There were 2 extragastric recurrences (0.15 %) in lymph nodes, at 5 and 4 years, respectively, after curative ESD for absolute and expanded indications. The patient with the expanded indications underwent a palliative operation and died of gastric cancer progression. CONCLUSIONS: There was a constant incidence rate of metachronous recurrence during a 5-year surveillance period and there was extragastric recurrence at least 4 years after ESD of early gastric cancer even for absolute indications. Therefore, annual or biannual surveillance EGD and abdominal CT might be necessary for at least 5 years after curative ESD for early gastric cancers, with absolute as well as expanded indications. PMID- 26111359 TI - Targets for Ibrutinib Beyond B Cell Malignancies. AB - Ibrutinib (ImbruvicaTM) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long-term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell-derived malignancies could be beneficial and result in new indications for clinical applications. PMID- 26111365 TI - Eight Urgent Care Center Best Practices for Safe Care Transitions. PMID- 26111366 TI - Creating a Patient Complaint Capture and Resolution Process to Incorporate Best Practices for Patient-Centered Representation. AB - BACKGROUND: A growing body of evidence suggests that patient (including family) feedback can provide compelling opportunities for developing risk management and quality improvement strategies, as well as improving customer satisfaction. The Patient Representative Department (PRD) at Stanford Health Care (SHC) (Stanford, California) created a streamlined patient complaint capture and resolution process to improve the capture of patient complaints and grievances from multiple parts of the organization and manage them in a centralized database. METHODS: In March 2008 the PRD rolled out a data management system for tracking patient complaints and generating reports to SHC leadership, and SHC needed to modify and address its data input procedures. A reevaluation of the overall work flow showed it to be complex, with over-lapping and redundant steps, and to lack standard processes and actions. Best-practice changes were implemented: (1) leadership engagement, (2) increased capture of complaints, (3) centralized data and reporting, (4) improved average response times to patient grievances and complaints, and (5) improved service recovery. Standard work flows were created for each category of complaint linked to specific actions. RESULTS: Complaints captured increased from 20 to 270 per month. Links to a specific physician rose from 16%-36% to more than 80%. In addition, 68% of high-complaint physicians improved. With improved work flows, responses to patients expressing concerns met a requirement of less than seven days. CONCLUSIONS: Standardized work flows for managing complaints and grievances, centralized data management and clear leadership accountability can improve responsiveness to patients, capture incidents more consistently, and meet regulatory and accreditation requirements. PMID- 26111367 TI - Implementing Best Evidence in Smoking Cessation Treatment for Hospitalized Veterans: Results from the VA-BEST Trial. AB - BACKGROUND: Although the US Department of Veterans Affairs (VA) has promoted adherence to smoking cessation guidelines since 1997, hospitalized smokers do not consistently receive assistance in quitting. METHODS: In a pre-post guideline implementation trial on the inpatient medicine units of four VA hospitals, the effectiveness of a multimodal intervention (enhanced academic detailing, modification of the nursing admission template, patient education materials and quitline referral, practice facilitation and staff feedback) changing practice behavior was evaluated. Peridischarge interviews were conducted with 824 patients to assess receipt of nurses' and physicians' delivery of the 5A's (Ask, Advise, Assess, Assist, Arrange) in hospitalized smokers. RESULTS: Subjects were significantly more likely to have received each of the 5A's from a nurse during the postimplementation period (except for "advise to quit"). More patients were assisted in quitting (75% versus 56%, adjusted odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.6, 3.1) and had follow-up arranged (23% versus 18%, adjusted OR = 1.5, 95% CI = 1.0, 2.2) by a nurse during the postimplementation period. However, unadjusted results showed no improvement in seven-day point prevalence abstinence at six-month follow-up (13.5% versus 13.9%). Nurses' self efficacy in cessation counseling, as measured in a survey of 166 unit nurses, improved following guideline implementation. DISCUSSION: A multifaceted intervention including enhanced academic detailing is an effective strategy for improving the delivery of smoking cessation services in medical inpatients. To promote long-term cessation, more intensive interventions are needed to ensure that motivated smokers receive guideline-recommended treatment (including pharmacotherapy and referral to outpatient cessation counseling). PMID- 26111363 TI - Transforming growth factor-beta 1 in humidifier disinfectant-associated children's interstitial lung disease. AB - BACKGROUND: Humidifier disinfectant-associated children's interstitial lung disease has an unpredictable clinical course with a high morbidity and mortality. OBJECTIVES: To evaluate the differences in clinical findings between survivors and non-survivors of humidifier disinfectant-associated children's interstitial lung disease. To evaluate dynamic changes in serum cytokines related to inflammation and fibrosis in lung injury, and to determine whether these changes are predictive of survival in this disease. METHODS: We evaluated 17 children with humidifier disinfectant-associated children's interstitial lung disease, from whom serum samples were obtained weekly during hospitalization. The severity of chest tomographic and lung pathologic findings was scored. Levels of several cytokines were measured in the serial serum samples. RESULTS: Seven of the 17 children were survivors. Compared to survivors, non-survivors had greater ground glass attenuation on follow-up chest tomography, higher admission neutrophil counts, and more macrophages on pathologic findings. Transforming growth factor beta 1 persisted at an elevated level (1,000-1,500 pg/ml) in survivors, whereas it decreased abruptly in non-survivors. At the time of this decrease, non survivors had clinical worsening of their respiratory failure. Transforming growth factor-beta 1 was positively correlated with PaO2 /FiO2 (r = 0.481, P < 0.0001). CONCLUSIONS: Non-survivors exhibited more inflammatory clinical findings than survivors. Transforming growth factor-beta 1 remained elevated in survivors, suggesting that it affected the clinical course of humidifier disinfectant associated children's interstitial lung disease. The prognosis of this lung disease may depend more on controlling excessive inflammation and repairing damaged lung than on fibrosis, and transforming growth factor-beta 1 may play a key role in this process. PMID- 26111368 TI - Barriers and Strategies for Effective Patient Rescue: A Qualitative Study of Outliers. AB - BACKGROUND: Organizational factors influencing failure-to-rescue (FTR)-or death after postoperative complications-are poorly understood. Case studies were conducted to generate hypotheses that could inform future FTR research and improvement strategies. METHODS: Publicly reported 2009-2011 data were used to identify 144 outlier hospitals with statistically better or worse FTR performance than the national average. Of these 144 hospitals, 7 were selected for case studies in a purposive sample. Outliers enabled a focus on the organizational factors and processes at the extremes of performance. Semi-structured interviews were conducted in 2013 with key informants at each hospital, and transcripts were analyzed using the constant comparative method to identify emergent organizational behavioral themes. RESULTS: The 7 hospitals-4 high- and 3 low performing-yielded 106 interviews. Critical barriers to effective rescue were ineffective communication, lack of psychological safety, staffing discontinuity, imbalance of shared ownership and individual responsibility, lack of appropriate training and education, and difficulty using current metrics. Participants also identified strategies to overcome these barriers-rapid response teams, flattening the hierarchy, escalation strategies, health information technology, structured communication tools, constant team structures, standardized care pathways, and organizational learning. CONCLUSION: FTR is a complex process that is viewed, defined, and acted on differently across and within organizations. Early recognition of patients deviating from normal recovery was enhanced in high performing hospitals through the use of standardized postoperative recovery pathways and automated escalation protocols. Current FTR measures may be less actionable for the purposes of quality improvement. PMID- 26111369 TI - Lost In Translation? Addressing Barriers in the Application of Industrial Process Improvement Methodologies to Health Care. PMID- 26111370 TI - The Language Services Documentation Tool: Documenting How Patient Language Needs Were Met During Clinical Encounters. PMID- 26111371 TI - Dynamically Tuning Particle Interactions and Assemblies at Soft Interfaces: Reversible Order-Disorder Transitions in 2D Particle Monolayers. AB - Particles trapped at fluid interfaces experience long-range interactions that determine their assembly behavior. Because particle interactions at fluid interfaces tend to be unusually strong, once particles organize themselves into a 2D assembly, it is challenging to induce changes in their microstructure. In this report, a new approach is presented to induce reversible order-disorder transitions (ODTs) in the 2D monolayer of colloidal particles trapped at a soft gel-fluid interface. Particles at the soft interface, consisting of a nonpolar superphase and a weakly gelled subphase, initially form a monolayer with a highly ordered structure. The structure of this monolayer can be dynamically varied by the addition or removal of the oil phase. Upon removing the oil via evaporation, the initially ordered particle monolayer undergoes ODT, driven by capillary attractions. The ordered monolayer can be recovered through disorder-to-order transition by simply adding oil atop the particle-laden soft interface. The possibility to dynamically tune the interparticle interactions using soft interfaces can potentially enable control of the transport and mechanical properties of particle-laden interfaces and provide model systems to study particle-laden soft interfaces that are relevant to biological tissues or organs. PMID- 26111372 TI - Adsorption of bovine serum albumin on silver surfaces enhances the release of silver at pH neutral conditions. AB - Metallic biomaterials are widely used to replace and/or restore the function of damaged bodily parts. The use of silver as antibacterial coatings onto implants has recently gained large interest in medical applications. The extent of silver that can be released into different biological fluids from such coatings is, except for the surface characteristics of the coating, governed by parameters such as protein characteristics, adsorbed layer properties, formation of silver protein complexes as well as concentrations of proteins in the solution. This study aims to relate the structure of adsorbed net negatively charged bovine serum albumin (BSA), which is the most abundant protein in serum, to the release of silver from metallic silver surfaces in order to elucidate if the net charge of the protein has any effect of the silver release. Simultaneous adsorption measurements were performed in real time on the very same surface using combined ellipsometry and quartz crystal microbalance with dissipation monitoring (QCM-D) measurements to provide a more comprehensive understanding on adsorption kinetics and layer structures. The amount of released silver into solution was measured by means of graphite furnace atomic absorption spectroscopy (GF-AAS). The structure of the adsorbed BSA layer largely influenced the amount of released silver, an enhancement that increased with BSA concentration. These observations are in complete contrast to the effect of net positively charged lysozyme (LSZ) adsorbed on silver, previously studied by the authors, for which a complete surface coverage suppressed the possibility for silver release. The underlying mechanisms behind the enhanced release of silver in the presence of BSA were mainly attributed to surface complexation between BSA and silver followed by an enhanced exchange rate of these surface complexes with BSA molecules in the solution, which in turn increase the amount of released silver in solution. PMID- 26111373 TI - Wound repair during arm regeneration in the red starfish Echinaster sepositus. AB - Starfish can regenerate entire arms following their loss by both autotomic and traumatic amputation. Although the overall regenerative process has been studied several times in different asteroid species, there is still a considerable gap of knowledge as far as the detailed aspects of the repair phase at tissue and cellular level are concerned, particularly in post-traumatic regeneration. The present work is focused on the arm regeneration model in the Mediterranean red starfish Echinaster sepositus; to describe the early cellular mechanisms of arm regeneration following traumatic amputation, different microscopy techniques were employed. In E. sepositus, the repair phase was characterized by prompt wound healing by a syncytial network of phagocytes and re-epithelialisation followed by a localized subepidermal oedematous area formation. Scattered and apparently undifferentiated cells, intermixed with numerous phagocytes, were frequently found in the wound area during these first stages of regeneration and extensive dedifferentiation phenomena were seen at the level of the stump, particularly in the muscle bundles. A true localized blastema did not form. Our results confirm that regeneration in asteroids mainly relies on morphallactic processes, consisting in extensive rearrangement of the existing tissues which contribute to the new tissues through cell dedifferentiation, redifferentiation, and/or migration. PMID- 26111375 TI - An Innovative Design of a Clay-Zeolite Medium for the Adsorption of Total Phosphorus from Wastewater. AB - Phosphorus significantly influences the eutrophication process, modifying the quality of waterways and habitat, especially in stagnant waterbodies exposed to septic tank effluent at high nutrient levels. This research explores the development of a cost-effective, efficient, and affordable on-site wastewater treatment system targeted as total phosphorus (TP) removal technology. The research objective is to demonstrate the TP removal efficiency of an optimized clay-zeolite medium by chemical adsorption. The study observes the effects of pellet medium design and modifications, influent concentrations, and contact time. Following various stages of optimization, the preliminary testing achieves a 45 +/- 1.8% removal after 45 minutes of contact time. The optimized pellets are contained within a five-layer bench-scale model, achieving equilibrium TP removal of 72 +/- 2.9% after 3 hours. Theoretical extrapolation to 12 contact hours indicates an achievement of 88% removal is possible. The results show a positive correlation with the linearized Langmuir and Freundlich adsorption isotherms. PMID- 26111374 TI - Time-Course Gene Set Analysis for Longitudinal Gene Expression Data. AB - Gene set analysis methods, which consider predefined groups of genes in the analysis of genomic data, have been successfully applied for analyzing gene expression data in cross-sectional studies. The time-course gene set analysis (TcGSA) introduced here is an extension of gene set analysis to longitudinal data. The proposed method relies on random effects modeling with maximum likelihood estimates. It allows to use all available repeated measurements while dealing with unbalanced data due to missing at random (MAR) measurements. TcGSA is a hypothesis driven method that identifies a priori defined gene sets with significant expression variations over time, taking into account the potential heterogeneity of expression within gene sets. When biological conditions are compared, the method indicates if the time patterns of gene sets significantly differ according to these conditions. The interest of the method is illustrated by its application to two real life datasets: an HIV therapeutic vaccine trial (DALIA-1 trial), and data from a recent study on influenza and pneumococcal vaccines. In the DALIA-1 trial TcGSA revealed a significant change in gene expression over time within 69 gene sets during vaccination, while a standard univariate individual gene analysis corrected for multiple testing as well as a standard a Gene Set Enrichment Analysis (GSEA) for time series both failed to detect any significant pattern change over time. When applied to the second illustrative data set, TcGSA allowed the identification of 4 gene sets finally found to be linked with the influenza vaccine too although they were found to be associated to the pneumococcal vaccine only in previous analyses. In our simulation study TcGSA exhibits good statistical properties, and an increased power compared to other approaches for analyzing time-course expression patterns of gene sets. The method is made available for the community through an R package. PMID- 26111377 TI - Editorial: Moving Patients from Consultants to Partners in Health Care System Redesign: Achieving Meaningful Engagement. PMID- 26111378 TI - Engaging Patients at the Front Lines of Primary Care Redesign: Operational Lessons for an Effective Program. AB - Article-at-a-Glance Background: The lack of patient engagement in quality improvement is concerning. As part of an enterprisewide initiative to redesign primary care at UW Health, interdisciplinary primary care teams received training in patient engagement. METHODS: Organizational stakeholders held a structured discussion and used nominal group technique to identify the key components critical to fostering a culture of patient engagement and critical lessons learned. These findings were augmented and illustrated by review of transcripts of two focus groups held with clinic managers and 69 interviews with individual microsystem team members. RESULTS: From late 2009 to 2014, 47 (81%) of 58 teams have engaged patients in various stages of practice improvement projects. Organizational components identified as critical to fostering a culture of patient engagement were alignment of the organization's vision that guided the redesign with national priorities, readily available external experts, involvement of all care team members in patient engagement, integration within an existing continuous improvement team development program, and an intervention deliberately matched to organizational readiness. Critical lessons learned were the need to embed patient engagement into current improvement activities, designate a neutral point person(s) or group to navigate organizational complexities, commit resources to support patient engagement activities, and plan for sustained team-patient interactions. CONCLUSIONS: Current national health care policy and local market pressures are compelling partnering with patients in efforts to improve the value of the health care delivery system. The UW Health experience may be useful for organizations seeking to introduce or strengthen the patient role in designing delivery system improvements. PMID- 26111379 TI - Strategies for Aligning Physicians to System Redesign Goals at Eight Safety-Net Systems. AB - BACKGROUND: Facing recent economic and regulatory pressures, safety-net systems (SNSs) are redesigning their organizations to improve care delivery, remain financially viable, and maintain competitive positions. Aligning physicians with redesign goals is a priority, particularly as many SNSs shift toward patient centered, population health-focused models. No previous work has examined efforts to align physicians to safety net redesign efforts. METHODS: This qualitative study, conducted at eight SNSs, examined challenges faced in a changing health care environment, as well as strategies and resources to address them. RESULTS: Strategies clustered in two categories: physician role definition and organizational infrastructure. Physician role definition strategies were (1) changing payment and employment arrangements, (2) changing clinical roles, (3) increasing physician involvement in quality improvement, and (4) strengthening physician leadership in clinical and quality roles. Organizational infrastructure strategies were (1) ensuring medical center leadership support and integration, (2) utilizing data to drive physician behavior, and (3) addressing competing allegiances with academia. All sites reported multifaceted approaches but differed in specific strategies employed, facilitators noted, and challenges encountered. DISCUSSION: The findings highlight the need to implement multiple strategies to align physicians in redesign efforts. They suggest that all health systems, whether SNSs or not, can capitalize on qualities of physicians and existing infrastructural and leadership elements to achieve physician alignment. However, they must contend with and address challenges of competing allegiance (for example, academic, physician organization, hospital), as well as resistance to changing clinical roles and payment structures. PMID- 26111380 TI - Excellence in Transitional Care of Older Adults and Pay-for-Performance: Perspectives of Health Care Professionals. AB - Article-at-a-Glance Background: Care transitions across health care settings are common and can result in adverse outcomes for older adults. Few studies have examined health care professionals' perspectives on important process measures or pay-for-performance (P4P) strategies related to transitional care. A study was conducted to characterize health care professionals' perspectives on (1) successful transitional care of older adults (age 65 years and older), (2) suggestions for improvement, and (3) P4P strategies related to transitional care. METHODS: In a qualitative study, one-hour semistructured in-depth interviews were conducted in an acute care hospital, a skilled nursing facility, two community based primary care practices, and one home health care agency with 20 health care professionals (18 physicians and 2 home health care administrators) with direct experience in care transitions of older adults and who were likely to be affected by P4P strategies. RESULTS: Findings were organized into three thematic domains: (1) components and markers of effective transitional care, (2) difficulties in design and implementation of P4P strategies, and (3) health care professionals' concerns and unmet needs related to delivering optimal care during transitions. A conceptual framework was developed on the basis of the findings to guide design and implementation of P4P strategies for improving transitional care. CONCLUSION: In characterizing health care professionals' perspectives, specific care processes to target, challenges to address in the design of P4P strategies, and unmet needs to consider regarding education and feedback for health care professionals were described. Future investigations could evaluate whether performance targets, educational interventions, and implementation strategies based on this conceptual framework improve quality of transitional care. PMID- 26111382 TI - An Assessment of Critical Care Interventions and Resource Utilization During Medical Emergency Team Activations in Nonhospitalized Patients. PMID- 26111381 TI - Reducing Central Line-Associated Bloodstream Infections in Three ICUs at a Tertiary Care Hospital in the United Arab Emirates. AB - BACKGROUND: Central line-associated bloodstream infection (CLABSI) is associated with significant morbidity and mortality. A quality improvement project was conducted to decrease CLABSI rates by 50% across all ICUs in a tertiary care hospital (Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates). METHODS: A multifaceted interventional program was implemented in a drive to reduce CLABSI rates. Stage 1 of the intervention entailed implementation of a central line insertion bundle, an insertion checklist, dedicated central line trolleys, education of all staff involved in insertion and maintenance of central lines, and empowerment of nurses. Stage 2 entailed implementation of a maintenance bundle and a CLABSI prevention policy and inclusion of central line assessment in the daily goals. Stage 3 was implemented in the form of CLABSI champions, spot checks on maintenance techniques, and review of every CLABSI. Stage 4 entailed the implementation of a Comprehensive Unit-based Safety Program (CUSP). Stage 5 consisted of a "back to basics" campaign, which included refocusing on basic evidence-based care bundles, introduction of bundle-compliance verification, and educational sessions and awareness programs. RESULTS: Overall CLABSI rates significantly decreased (p < .0001) from a mean of 2.99 (standard deviation [SD], 1.69) in the preimplementation period (January 2008-June 2011) to 1.47 (SD, 1.01) in the postimplementation period (July 2011-August 2014) across all ICUs. Overall, there were significantly more months with CLABSI-free days in the post implementation than in the preimplementation period. CONCLUSION: The combination of evidence-based interventions, standardization of procedures, teamwork, and front-line staff involvement in the decision-making process contributed to decreases in CLABSI rates across three ICUs. PMID- 26111385 TI - Discrete Wavelet Transform-Based Whole-Spectral and Subspectral Analysis for Improved Brain Tumor Clustering Using Single Voxel MR Spectroscopy. AB - Many approaches have been considered for automatic grading of brain tumors by means of pattern recognition with magnetic resonance spectroscopy (MRS). Providing an improved technique which can assist clinicians in accurately identifying brain tumor grades is our main objective. The proposed technique, which is based on the discrete wavelet transform (DWT) of whole-spectral or subspectral information of key metabolites, combined with unsupervised learning, inspects the separability of the extracted wavelet features from the MRS signal to aid the clustering. In total, we included 134 short echo time single voxel MRS spectra (SV MRS) in our study that cover normal controls, low grade and high grade tumors. The combination of DWT-based whole-spectral or subspectral analysis and unsupervised clustering achieved an overall clustering accuracy of 94.8% and a balanced error rate of 7.8%. To the best of our knowledge, it is the first study using DWT combined with unsupervised learning to cluster brain SV MRS. Instead of dimensionality reduction on SV MRS or feature selection using model fitting, our study provides an alternative method of extracting features to obtain promising clustering results. PMID- 26111384 TI - Registered report: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. AB - The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by replicating selected results from a substantial number of high-profile papers in the field of cancer biology published between 2010 and 2012. This Registered report describes the proposed replication plan of key experiments from 'BET bromodomain inhibition as a therapeutic strategy to target c-Myc' by Delmore and colleagues, published in Cell in 2011 (Delmore et al., 2011). The key experiments that will be replicated are those reported in Figures 3B and 7C-E. Delmore and colleagues demonstrated that treatment with JQ1, a small molecular inhibitor targeting BET bromodomains, resulted in the transcriptional down-regulation of the c-Myc oncogene in vitro (Figure 3B; Delmore et al., 2011). To assess the therapeutic efficacy of JQ1 in vivo, mice bearing multiple myeloma (MM) lesions were treated with JQ1 before evaluation for tumor burden and overall survival. JQ1 treatment significantly reduced disease burden and increased survival time (Figure 7C-E; Delmore et al., 2011). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife. PMID- 26111386 TI - Depth Sensing for Improved Control of Lower Limb Prostheses. AB - Powered lower limb prostheses have potential to improve the quality of life of individuals with amputations by enabling all daily activities. However, seamless ambulation mode recognition is necessary to achieve this goal and is not yet a clinical reality. Current intent recognition systems use mechanical and EMG sensors to estimate prosthesis and user status. We propose to complement these systems by integrating information about the environment obtained through the depth sensing. This paper presents the design, characterization, and the early validation of a novel stair segmentation system based on Microsoft Kinect. Static and dynamic tests were performed. A first experiment showed how the resolution of the depth camera affects the speed and the accuracy of segmentation. A second test proved the robustness of the algorithm to different staircases. Finally, we performed an online walking test with the stair segmentation and related measures recorded online at >5 frames/s. Experimental results show that the proposed algorithm allows for an accurate estimate of distance, angle of intersection, number of steps, stair height, and stair depth for a set of stairs in the environment. The online test produced an estimate of whether the individual was approaching stairs in real time with approximately 98.8% accuracy. PMID- 26111387 TI - Current Density Imaging During Transcranial Direct Current Stimulation Using DT MRI and MREIT: Algorithm Development and Numerical Simulations. AB - OBJECTIVE: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique for neuropsychiatric diseases and neurological disorders. In the tDCS treatment, dc current is injected into the head through a pair of electrodes attached on the scalp over a target region. A current density imaging method is needed to quantitatively visualize the internal current density distribution during the tDCS treatment. METHODS: We developed a novel current density image reconstruction algorithm using 1) a subject specific segmented 3-D head model, 2) diffusion tensor data, and 3) magnetic flux density data induced by the tDCS current. We acquired T1 weighted and diffusion tensor images of the head using the MRI scanner before the treatment. During the treatment, we can measure the induced magnetic flux density data using a magnetic resonance electrical impedance tomography (MREIT) pulse sequence. In this paper, the magnetic flux density data were numerically generated. RESULTS: Numerical simulation results show that the proposed method successfully recovers the current density distribution including the effects of the anisotropic, as well as isotropic conductivity values of different tissues in the head. CONCLUSION: The proposed current density imaging method using DT-MRI and MREIT can reliably recover cross sectional images of the current density distribution during the tDCS treatment. SIGNIFICANCE: Success of the tDCS treatment depends on a precise determination of the induced current density distribution within different anatomical structures of the brain. Quantitative visualization of the current density distribution in the brain will play an important role in understanding the effects of the electrical stimulation. PMID- 26111388 TI - Improving Cardiac Phase Extraction in IVUS Studies by Integration of Gating Methods. AB - GOAL: Coronary intravascular ultrasound (IVUS) is a fundamental imaging technique for atherosclerotic plaque assessment. However, volume-based data retrieved from IVUS studies can be misleading due to the artifacts generated by the cardiac motion, hindering diagnostic, and visualization of the vessel condition. Then, we propose an image-based gating method that improves the performance of the preexisting methods, delivering a gating in an appropriate time for clinical practice. METHODS: We propose a fully automatic method to synergically integrate motion signals from different gating methods to improve the cardiac phase estimation. Additionally, we present a local extrema identification method that provides a more accurate extraction of a cardiac phase and, also, a scheme for multiple phase extraction mandatory for elastography-type studies. RESULTS: A comparison with three state-of-the-art methods is performed over 61 in-vivo IVUS studies including a wide range of physiological situations. The results show that the proposed strategy offers: 1) a more accurate cardiac phase extraction; 2) a lower frame oversampling and/or omission in the extracted phase data (error of 1.492 +/-0.977 heartbeats per study, mean +/- SD); 3) a more accurate and robust heartbeat period detection with a Bland-Altman coefficient of reproducibility (RPC) of 0.23 s, while the second closest method presents an RPC of 0.36 s. SIGNIFICANCE: The integration of motion signals performed by our method shown an improvement of the gating accuracy and reliability. PMID- 26111389 TI - Design and Evaluation of a Novel Fixation Mechanism for a Transcatheter Pacemaker. AB - GOAL: The purpose of this paper was to evaluate a nitinol tine fixation design for a transcatheter pacemaker in order to determine if the tines could be easily deployed and safely removed from the myocardium, enable low, stable pacing thresholds, and minimize the potential for dislodgment. METHODS: The penetration properties of 13 human hearts were compared to the deployment and fixation energy of the tines to determine if the tines could be easily deployed and removed from the myocardium. The safety factor for dislodgement was calculated by comparing the kinetic energy of the device to the fixation energy of the tines. The fixation stability was tested in 113 chronic implants across 89 animals via pacing threshold measurements or evidence of dislodgement at necropsy. RESULTS: Based on the tine fixation and tissue energy analysis, the tines can easily penetrate the heart. The tines can be safely removed from the myocardium based on the increased tine surface area during retraction. There were no dislodgements observed in the animals and the mean pacing threshold at implant was 0.59 +/- 0.21 V and at termination was 0.65 +/- 0.36 V. The safety factor for dislodgement was determined to be 15X during simulated exercise conditions. CONCLUSION: The nitinol tine fixation design enabled the implant of a self-contained pacemaker within the right ventricle and was effective in meeting the design requirements. SIGNIFICANCE: This fixation technology provides a novel solution to enable the attachment of a transcatheter pacemaker directly within the heart. PMID- 26111390 TI - Low-Rank Atlas Image Analyses in the Presence of Pathologies. AB - We present a common framework, for registering images to an atlas and for forming an unbiased atlas, that tolerates the presence of pathologies such as tumors and traumatic brain injury lesions. This common framework is particularly useful when a sufficient number of protocol-matched scans from healthy subjects cannot be easily acquired for atlas formation and when the pathologies in a patient cause large appearance changes. Our framework combines a low-rank-plus-sparse image decomposition technique with an iterative, diffeomorphic, group-wise image registration method. At each iteration of image registration, the decomposition technique estimates a "healthy" version of each image as its low-rank component and estimates the pathologies in each image as its sparse component. The healthy version of each image is used for the next iteration of image registration. The low-rank and sparse estimates are refined as the image registrations iteratively improve. For unbiased atlas formation, at each iteration, the average of the low rank images from the patients is used as the atlas image for the next iteration, until convergence. Since each iteration's atlas is comprised of low-rank components, it provides a population-consistent, pathology-free appearance. Evaluations of the proposed methodology are presented using synthetic data as well as simulated and clinical tumor MRI images from the brain tumor segmentation (BRATS) challenge from MICCAI 2012. PMID- 26111391 TI - Color Image Denoising via Discriminatively Learned Iterative Shrinkage. AB - In this paper, we propose a novel model, a discriminatively learned iterative shrinkage (DLIS) model, for color image denoising. The DLIS is a generalization of wavelet shrinkage by iteratively performing shrinkage over patch groups and whole image aggregation. We discriminatively learn the shrinkage functions and basis from the training pairs of noisy/noise-free images, which can adaptively handle different noise characteristics in luminance/chrominance channels, and the unknown structured noise in real-captured color images. Furthermore, to remove the splotchy real color noises, we design a Laplacian pyramid-based denoising framework to progressively recover the clean image from the coarsest scale to the finest scale by the DLIS model learned from the real color noises. Experiments show that our proposed approach can achieve the state-of-the-art denoising results on both synthetic denoising benchmark and real-captured color images. PMID- 26111392 TI - Enhancing Color Images of Extremely Low Light Scenes Based on RGB/NIR Images Acquisition With Different Exposure Times. AB - We propose a novel method to synthesize a noise- and blur-free color image sequence using near-infrared (NIR) images captured in extremely low light conditions. In extremely low light scenes, heavy noise and motion blur are simultaneously produced in the captured images. Our goal is to enhance the color image sequence of an extremely low light scene. In this paper, we augment the imaging system as well as enhancing the image synthesis scheme. We propose a novel imaging system that can simultaneously capture the red, green, blue (RGB) and the NIR images with different exposure times. An RGB image is taken with a long exposure time to acquire sufficient color information and mitigates the effects of heavy noise. By contrast, the NIR images are captured with a short exposure time to measure the structure of the scenes. Our imaging system using different exposure times allows us to ensure sufficient information to reconstruct a clear color image sequence. Using the captured image pairs, we reconstruct a latent color image sequence using an adaptive smoothness condition based on gradient and color correlations. Our experiments using both synthetic images and real image sequences show that our method outperforms other state-of the-art methods. PMID- 26111393 TI - Theoretical Bounds of Direct Binary Search Halftoning. AB - Direct binary search (DBS) produces the images of the best quality among half toning algorithms. The reason is that it minimizes the total squared perceived error instead of using heuristic approaches. The search for the optimal solution involves two operations: (1) toggle and (2) swap. Both operations try to find the binary states for each pixel to minimize the total squared perceived error. This error energy minimization leads to a conjecture that the absolute value of the filtered error after DBS converges is bounded by half of the peak value of the autocorrelation filter. However, a proof of the bound's existence has not yet been found. In this paper, we present a proof that shows the bound existed as conjectured under the condition that at least one swap occurs after toggle converges. The theoretical analysis also indicates that a swap with a pixel further away from the center of the autocorrelation filter results in a tighter bound. Therefore, we propose a new DBS algorithm which considers toggle and swap separately, and the swap operations are considered in the order from the edge to the center of the filter. Experimental results show that the new algorithm is more efficient than the previous algorithm and can produce half-toned images of the same quality as the previous algorithm. PMID- 26111394 TI - Unsupervised Texture Flow Estimation Using Appearance-Space Clustering and Correspondence. AB - This paper presents a texture flow estimation method that uses an appearance space clustering and a correspondence search in the space of deformed exemplars. To estimate the underlying texture flow, such as scale, orientation, and texture label, most existing approaches require a certain amount of user interactions. Strict assumptions on a geometric model further limit the flow estimation to such a near-regular texture as a gradient-like pattern. We address these problems by extracting distinct texture exemplars in an unsupervised way and using an efficient search strategy on a deformation parameter space. This enables estimating a coherent flow in a fully automatic manner, even when an input image contains multiple textures of different categories. A set of texture exemplars that describes the input texture image is first extracted via a medoid-based clustering in appearance space. The texture exemplars are then matched with the input image to infer deformation parameters. In particular, we define a distance function for measuring a similarity between the texture exemplar and a deformed target patch centered at each pixel from the input image, and then propose to use a randomized search strategy to estimate these parameters efficiently. The deformation flow field is further refined by adaptively smoothing the flow field under guidance of a matching confidence score. We show that a local visual similarity, directly measured from appearance space, explains local behaviors of the flow very well, and the flow field can be estimated very efficiently when the matching criterion meets the randomized search strategy. Experimental results on synthetic and natural images show that the proposed method outperforms existing methods. PMID- 26111395 TI - High-Order Topology Modeling of Visual Words for Image Classification. AB - Modeling relationship between visual words in feature encoding is important in image classification. Recent methods consider this relationship in either image or feature space, and most of them incorporate only pairwise relationship (between visual words). However, in situations involving large variability in images, one cannot capture intrinsic invariance of intra-class images using low order pairwise relationship. The result is not robust to larger variations in images. In addition, as the number of potential pairings grows exponentially with the number of visual words, the task of learning becomes computationally expensive. To overcome these two limitations, we propose an efficient classification framework that exploits high-order topology of visual words in the feature space, as follows. First, we propose a search algorithm that seeks dependence between the visual words. This dependence is used to construct higher order topology in the feature space. Then, the local features are encoded according to this higher order topology to improve the image classification. Experiments involving four common data sets, namely PASCAL VOC 2007, 15 Scenes, Caltech 101, and UIUC Sport Event, demonstrate that the dependence search significantly improves the efficiency of higher order topological construction, and consequently increases the image classification in all these data sets. PMID- 26111396 TI - Multiscale Superpixels and Supervoxels Based on Hierarchical Edge-Weighted Centroidal Voronoi Tessellation. AB - Superpixels and supervoxels play an important role in many computer vision applications, such as image segmentation, object recognition, and video analysis. In this paper, we propose a new hierarchical edge-weighted centroidal Voronoi tessellation (HEWCVT) method for generating superpixels/supervoxels in multiple scales. In this method, we model the problem as a multilevel clustering process: superpixels/supervoxels in one level are clustered to obtain larger size superpixels/supervoxels in the next level. In the finest scale, the initial clustering is directly conducted on pixels/voxels. The clustering energy involves both color similarities and boundary smoothness of superpixels/supervoxels. The resulting superpixels/supervoxels can be easily represented by a hierarchical tree which describes the nesting relation of superpixels/supervoxels across different scales. We first investigate the performance of obtained superpixels/supervoxels under different parameter settings, then we evaluate and compare the proposed method with several state-of-the-art superpixel/supervoxel methods on standard image and video data sets. Both quantitative and qualitative results show that the proposed HEWCVT method achieves superior or comparable performances with other methods. PMID- 26111397 TI - Efficient Large-Scale Structure From Motion by Fusing Auxiliary Imaging Information. AB - One of the potentially effective means for large-scale 3D scene reconstruction is to reconstruct the scene in a global manner, rather than incrementally, by fully exploiting available auxiliary information on the imaging condition, such as camera location by Global Positioning System (GPS), orientation by inertial measurement unit (or compass), focal length from EXIF, and so on. However, such auxiliary information, though informative and valuable, is usually too noisy to be directly usable. In this paper, we present an approach by taking advantage of such noisy auxiliary information to improve structure from motion solving. More specifically, we introduce two effective iterative global optimization algorithms initiated with such noisy auxiliary information. One is a robust rotation averaging algorithm to deal with contaminated epipolar graph, the other is a robust scene reconstruction algorithm to deal with noisy GPS data for camera centers initialization. We found that by exclusively focusing on the estimated inliers at the current iteration, the optimization process initialized by such noisy auxiliary information could converge well and efficiently. Our proposed method is evaluated on real images captured by unmanned aerial vehicle, StreetView car, and conventional digital cameras. Extensive experimental results show that our method performs similarly or better than many of the state-of-art reconstruction approaches, in terms of reconstruction accuracy and completeness, but is more efficient and scalable for large-scale image data sets. PMID- 26111398 TI - Robust Point Sets Matching by Fusing Feature and Spatial Information Using Nonuniform Gaussian Mixture Models. AB - Most of the traditional methods that handle the point sets matching between two images are based on local feature descriptors and the succedent mismatch eliminating strategies, which usually suffers from the sparsity of the initial match set because some correct ambiguous associations are easily filtered out by the ratio test of SIFT matching due to their second ranking in feature similarity. In this paper, we propose a nonuniform Gaussian mixture model (NGMM) for point sets matching between a pair of images which combines feature with position information of the local feature points extracted from the image pair to achieve point sets matching in a GMM framework. The proposed point set matching using an NGMM is able to change the correspondence assignments throughout the matching process and has the potential to match up even ambiguous matches correctly. The proposed NGMM framework can be either used to directly find matches between two point sets obtained from two images or applied to remove outliers in a match set. When finding matches, NGMM tries to learn a nonrigid transformation between the two point sets and provide a probability for every found match to measure the reliability of the match. Then, a probability threshold can be used to get the final robust match set. When removing outliers, NGMM requires that the vector field formed by the correct matches to be coherent and the matches contradicting the coherent vector field will be regarded as mismatches to be removed. A number of comparison and evaluation experiments reveal the good performance of the proposed NGMM framework in both finding matches and discarding mismatches. PMID- 26111399 TI - Improving the Performance Against Force Variation of EMG Controlled Multifunctional Upper-Limb Prostheses for Transradial Amputees. AB - We investigate the problem of achieving robust control of hand prostheses by the electromyogram (EMG) of transradial amputees in the presence of variable force levels, as these variations can have a substantial impact on the robustness of the control of the prostheses. We also propose a novel set of features that aim at reducing the impact of force level variations on the prosthesis controlled by amputees. These features characterize the EMG activity by means of the orientation between a set of spectral moments descriptors extracted from the EMG signal and a nonlinearly mapped version of it. At the same time, our feature extraction method processes the EMG signals directly from the time-domain to reduce computational cost. The performance of the proposed features is tested on EMG data collected from nine transradial amputees performing six classes of movements each with three force levels. Our results indicate that the proposed features can achieve significant reductions in classification error rates in comparison to other well-known feature extraction methods, achieving improvements of ~ 6% to 8% in the average classification performance across all subjects and force levels, when training with all forces. PMID- 26111400 TI - Optimal control of nonlinear continuous-time systems in strict-feedback form. AB - This paper proposes a novel optimal tracking control scheme for nonlinear continuous-time systems in strict-feedback form with uncertain dynamics. The optimal tracking problem is transformed into an equivalent optimal regulation problem through a feedforward adaptive control input that is generated by modifying the standard backstepping technique. Subsequently, a neural network based optimal control scheme is introduced to estimate the cost, or value function, over an infinite horizon for the resulting nonlinear continuous-time systems in affine form when the internal dynamics are unknown. The estimated cost function is then used to obtain the optimal feedback control input; therefore, the overall optimal control input for the nonlinear continuous-time system in strict-feedback form includes the feedforward plus the optimal feedback terms. It is shown that the estimated cost function minimizes the Hamilton-Jacobi-Bellman estimation error in a forward-in-time manner without using any value or policy iterations. Finally, optimal output feedback control is introduced through the design of a suitable observer. Lyapunov theory is utilized to show the overall stability of the proposed schemes without requiring an initial admissible controller. Simulation examples are provided to validate the theoretical results. PMID- 26111401 TI - H infinity tracking control of completely unknown continuous-time systems via off policy reinforcement learning. AB - This paper deals with the design of an H infinity tracking controller for nonlinear continuous-time systems with completely unknown dynamics. A general bounded L2 -gain tracking problem with a discounted performance function is introduced for the H infinity tracking. A tracking Hamilton-Jacobi-Isaac (HJI) equation is then developed that gives a Nash equilibrium solution to the associated min-max optimization problem. A rigorous analysis of bounded L2 -gain and stability of the control solution obtained by solving the tracking HJI equation is provided. An upper-bound is found for the discount factor to assure local asymptotic stability of the tracking error dynamics. An off-policy reinforcement learning algorithm is used to learn the solution to the tracking HJI equation online without requiring any knowledge of the system dynamics. Convergence of the proposed algorithm to the solution to the tracking HJI equation is shown. Simulation examples are provided to verify the effectiveness of the proposed method. PMID- 26111402 TI - Parallel Online Temporal Difference Learning for Motor Control. AB - Temporal difference (TD) learning, a key concept in reinforcement learning, is a popular method for solving simulated control problems. However, in real systems, this method is often avoided in favor of policy search methods because of its long learning time. But policy search suffers from its own drawbacks, such as the necessity of informed policy parameterization and initialization. In this paper, we show that TD learning can work effectively in real robotic systems as well, using parallel model learning and planning. Using locally weighted linear regression and trajectory sampled planning with 14 concurrent threads, we can achieve a speedup of almost two orders of magnitude over regular TD control on simulated control benchmarks. For a real-world pendulum swing-up task and a two link manipulator movement task, we report a speedup of 20* to 60* , with a real time learning speed of less than half a minute. The results are competitive with state-of-the-art policy search. PMID- 26111403 TI - Alternative Multiview Maximum Entropy Discrimination. AB - Maximum entropy discrimination (MED) is a general framework for discriminative estimation based on maximum entropy and maximum margin principles, and can produce hard-margin support vector machines under some assumptions. Recently, the multiview version of MED multiview MED (MVMED) was proposed. In this paper, we try to explore a more natural MVMED framework by assuming two separate distributions p1( Theta1) over the first-view classifier parameter Theta1 and p2( Theta2) over the second-view classifier parameter Theta2 . We name the new MVMED framework as alternative MVMED (AMVMED), which enforces the posteriors of two view margins to be equal. The proposed AMVMED is more flexible than the existing MVMED, because compared with MVMED, which optimizes one relative entropy, AMVMED assigns one relative entropy term to each of the two views, thus incorporating a tradeoff between the two views. We give the detailed solving procedure, which can be divided into two steps. The first step is solving our optimization problem without considering the equal margin posteriors from two views, and then, in the second step, we consider the equal posteriors. Experimental results on multiple real-world data sets verify the effectiveness of the AMVMED, and comparisons with MVMED are also reported. PMID- 26111404 TI - Cascaded Network Body Channel Model for Intrabody Communication. AB - Intrabody communication has been of great research interest in recent years. This paper proposes a novel, compact but accurate body transmission channel model based on RC distribution networks and transmission line theory. The comparison between simulation and measurement results indicates that the proposed approach accurately models the body channel characteristics. In addition, the impedance matching networks at the transmitter output and the receiver input further maximize the power transferred to the receiver, relax the receiver complexity, and increase the transmission performance. Based on the simulation results, the power gain can be increased by up to 16 dB after matching. A binary phase-shift keying modulation scheme is also used to evaluate the bit-error-rate improvement. PMID- 26111406 TI - Transmission of Therapeutic Ultrasound by Wound Dressings. AB - Ultrasound has been used for the treatment of a variety of cutaneous wounds, particularly venous ulcers. Many of the published studies involved application of ultrasound to the surrounding tissue rather than directly over the wound. Insonating the wound itself may enhance the healing process, but the lack of data regarding the transmission characteristics of dressings has limited the use of this option. This study aimed to measure the ultrasound transmissivity of dressings commonly employed for wound management. Forty-eight different dressings and wound care products were tested in vitro using a radiation force balance. Transmissivity was found to vary significantly between dressings, from excellent to zero. These findings may be useful to clinicians in deciding whether to apply ultrasound through a particular dressing. They could also inform future studies of the efficacy of ultrasound in wound management by application directly to wounds rather than to their periphery. PMID- 26111405 TI - Very high-pressure dilatation for undilatable coronary lesions: indications and results with a new dedicated balloon. AB - AIMS: Calcific coronary lesions impose a rigid obstacle to optimal balloon and stent expansion and the 20 to 30 atm limit that non-compliant (NC) balloons reach can be insufficient. The aim of our study was to evaluate the safety and efficacy of a new dedicated super high-pressure NC balloon (OPN NC(r); SIS Medical AG, Winterthur, Switzerland). METHODS AND RESULTS: We retrospectively evaluated a consecutive series of 91 lesions in which conventional NC balloons at maximal pressure failed to achieve an adequate post-dilatation luminal gain and were therefore treated with an OPN NC balloon up to 40 atm. Angiographic success was defined as residual angiographic diameter stenosis <30%. MLD and %DS were measured at baseline, after NC balloon, OPN NC balloon and stent implantation. Angiographic success was achieved in 84 lesions (92.3%). All of the remaining lesions received rotational atherectomy with the exception of two cases in which rotational atherectomy was not attempted because of small vessel size and excessive tortuosity. MLD and acute gain were significantly greater and %DS was significantly lower post OPN NC balloon compared with conventional NC balloon inflation (p<0.001). No coronary perforations occurred. No acute or 30-day follow up MACE was reported. CONCLUSIONS: When conventional NC balloons fail, the new OPN NC dedicated high-pressure balloon provides an effective and safe alternative strategy for the dilatation of resistant coronary lesions. PMID- 26111407 TI - Evaluation of Pressure Ulcers in 202 Patients with Cancer. AB - Countermeasures for pressure ulcers, which have been promoted as a national policy in Japan since 2002, have reduced the development of new pressure ulcers due to insufficient observation or treatment. On the other hand, it has become clear that pressure ulcers continue to develop in patients with cancer. The authors evaluated 419 patients (202 of whom had cancer) who had newly developed pressure ulcers. The following results were obtained: 1) among patients with terminal illnesses, cancer patients outnumbered noncancer patients; 2) there was no difference between the cancer patient group and the noncancer patient group regarding time required to heal ulcers; 3) there was no difference between the groups in the time from the development of pressure ulcer until the patients died; 4) patients with cancer were more likely to develop pressure ulcers compared to patients without cancer, even though their risk scores analysis were not high. In addition to providing enough anodynes, sedatives, and extra-soft mattresses, it is necessary to modify risk assessment measures because cancer is a risk factor for pressure ulcer development. PMID- 26111408 TI - Risk Factors for Pressure Ulcers in Hospitalized Elderly without Significant Cognitive Impairment. AB - PURPOSE: To evaluate risk factors for pressure ulcers (PU) in hospitalized elderly without significant cognitive impairment. METHODS: From July 2005 to February 2006, 40 hospitalized elderly patients without cognitive deficit were evaluated in a university hospital in Pouso Alegre, Brazil. Twenty patients with a PU formed the study group and 20 without a PU formed the control group. The Mini Mental State Examination (MMSE) was used to assess cognitive status. Pressure ulcers were classified using the National Pressure Ulcer Advisory Panel (NPUAP) guidelines, followed by evaluation of risk factors for PU using the Braden scale. The chi-squared test was applied and for the Braden scale the Mann Whitney test was used. RESULTS: In the study group, 14 (70%) of the subjects were women and 6 (30%) were men. The average age was 71.5 years. The average score for the MMSE was 19.7. The average time of hospitalization was 23.1 days for the study group and 13 days for the control. In the Braden scale, the risk factors such as humidity, activity, mobility, friction, and shear force were significant (P < 0.05). CONCLUSION: The data from the present study demonstrate that hospitalized elderly patients have an increased risk for the development of PU. Humidity, activity, mobility, friction, and shear are important risk factors during the hospitalization period. PMID- 26111409 TI - Blastomycosis Dermatitidis. PMID- 26111410 TI - Editorial Message: January 2007. PMID- 26111411 TI - Diagnostic Validity of Semiquantitative Swab Cultures. AB - Swab cultures of wounds are noninvasive and most laboratories are capable of semiquantitatively processing these specimens. This study examined the diagnostic validity of semiquantitative swab cultures obtained using Levine's technique and compared semiquantitative and quantitative swab cultures. Two swab specimens were obtained from a sample of 44 chronic wounds using Levine's technique. One was processed using quantitative laboratory procedures and the other using semiquantitative laboratory procedures. The diagnostic validity of the findings from each swab culture process was determined by associating the culture findings of each with quantitative tissue cultures (reference standard) using receiver operating characteristic (ROC) curves and by evaluating concordance. The area under the curve (AUC) of the semiquantitative swab culture was 0.639, which was not significantly higher than the .50 diagonal chance (P = 0.0501), suggesting a non-informative test. The AUC for quantitative swab cultures was 0.821. The AUC of the quantitative swab culture was significantly higher than the diagonal chance line of 0.5 and was significantly higher than the AUC of the semiquantitative swab culture (P = 0.0128). The mean concordance of semiquantitative cultures in recovering all organisms was 57%. The mean concordance of quantitative swab cultures in recovering all organisms was 72%. The findings of this study suggest that swab specimens processed using semiquantitative processes do not provide culture findings that correlate well with culture findings from tissue specimens. More meaningful information can be obtained from swab specimens if they are quantitatively processed in the laboratory. PMID- 26111412 TI - Silver Ion-releasing Dressing (CONTREET) Does Not Disturb Angiogenesis and Microvascularization In Vivo. AB - This study examined the effects of silver-releasing wound dressing on angiogenesis and microvascularization in vivo. Implants from silver-releasing and silver-free dressings were placed into dorsal skinfold chambers of BALB/c mice. A total of 30 animals (10 implants per group) were observed. Group 1 was treated with Contreet(r) (Coloplast, Holtedam, Denmark). Group 2 and Group 3 were primed with BiatainTM (Coloplast, Holtedam, Denmark) and SeaSorb Soft(r) (Coloplast, Holtedam, Denmark). Visualization of angiogenesis and quantification of functional vessel density (FVD) was performed using intravital fluorescence microscopy (IFM). Functional vessel density served as the parameter for vascularization. Functional vessel density was measured on Day 3, 7, and 12 after implantation. Intravital fluorescence microscopy revealed constant development of a sufficient network of perfused microvessels surrounding the silver-based implants. Group 1 showed a stronger morphological alteration of microvessel network at the border zone at Day 3 and even more so at Day 7, compared to the silver-free groups. Reinforced dilatation, elongation, and torsion of capillaries with progressive growth of perfused preliminary stages of new blood vessels were observed for silver-based implants. Border zone FVD of silver-based implants at Day 3 (257.1 +/- 33.9 mm/mm2) was significantly increased compared to Group 2 (230.9 +/- 31.3) and Group 3 (210.2 +/- 35.7). At Day 7, the FVD in Group 1 was still significantly higher as measured in Group 3 (265.9 +/- 30.7 versus 219.7 +/ 42.6). However, no significant difference between Groups 1 and 2 at Day 7 (265.9 +/- 30.7 versus 269.4 +/- 31.9) and at Day 12 (258.7 +/- 38.1 versus 268.3 +/- 39.0) remained. In conclusion, the silver-based implants did not show any anti angiogenic effects when compared to the silver-free implants. PMID- 26111414 TI - Evidence Corner: February 2007. PMID- 26111413 TI - Cross-leg Pedicled Free Scapular Flap for the Repair of Extensive Soft Tissue Defect with Tibial Bone Exposure. AB - Free scapular flaps are suitable for many lower extremity applications and often provide excellent contour reproduction and appearance. However, when the soft tissue defect of the lower leg is extensive and complicated there may not be vessels in the recipient site suitable to be anastomosed. A cross-leg pedicled free flap technique can be applied in this situation. This study extends the indications and reports a successful experience using cross-leg pedicled free scapular flap to cover an extensive soft tissue defect with tibial bone exposure of the lower leg. This study involved 24 patients between May 2000 and October 2005. Wounds were caused by accident (6 patients), burn (2 patients), electrical injury (3 patients), and fall (2 patients). The defects ranged in size from 8 cm x 15 cm to 15 cm x 30 cm. All patients were treated with free scapular flaps to cover the defects and the vessels of the free scapular flaps were anastomosed with the dorsalis pedis vessels of contralateral leg in order to provide temporary blood supply. Both legs were fixed in a cross-leg position by plaster cast. The pedicle was divided after 4 to 5 weeks and the donor site of dorsum pedis was re-sutured. Blood supply was re-established in all 13 patients. All free scapular flaps survived and the defects were covered completely. The defective lower extremities regained function with no deformities in donor sites of the contralateral lower leg. The authors believe that use of the cross-leg pedicled free scapular flap in patients with a difficult lower extremity wound with extensive tissue defect and tibial bone exposure is a worthwhile procedure and should be attempted if possible. The scapular flap has several advantages applicable to the cross-leg pedicled free flap technique. Although the operation is divided into 2 stages, it solves the problem and can offer temporary blood supply when there is no vessel for anastomosis in the recipient site, which decreases the risk of microanastomosis and produces good results. PMID- 26111415 TI - Editorial Message: February 2007. PMID- 26111416 TI - Chronic Wounds: Factors Influencing Healing Within 3 Months and Nonhealing After 5-6 Months of Care. AB - Chronic wounds affect approximately 2.5 million to 4.5 million people in the US and are particularly a problem for the elderly. Nonhealing or slow healing wounds represent a major health burden and drain on resources, contributing to substantial disability, morbidity, and costs. This study was conducted to identify factors that influence the healing of chronic wounds within 3 months of starting treatment, compared to factors influencing nonhealing wounds after 5 or 6 months of treatment. A retrospective review of medical records of subjects with chronic pressure, diabetic, or venous ulcers using a structured data collection form and protocol was conducted at 4 sites located in disperse geographic areas. The sample consisted of 400 subjects with at least 3 months of data. Demographic, case mix, wound characteristics, and treatment characteristics were analyzed. Consistent with the literature, wounds that were larger, deeper, infected, draining larger amounts of exudate, and/or covered with slough or eschar were significantly less likely to heal within 3 months and more likely not to heal after 5-6 months of treatment. Medicaid insurance coverage and being non-white were also associated with poorer healing. A lower percentage of antimicrobial dressings was associated with faster healing, while a lower percentage of moisture-management dressings was associated with nonhealing after 5-6 months. The analysis also showed that inappropriate management of wound exudate and necrotic tissue was associated with poorer healing outcomes. While the influence of insurance coverage and race on healing needs further exploration, healing rates could improve in certain centers through better adherence to evidence-based wound management recommendations. PMID- 26111418 TI - A Technique To Avoid a Dog-ear Deformity On the Buttock Using a "Pigeon Head" Modification of the Rotation Flap. AB - Gluteal fasciocutaneous (FC) rotation flaps can still be used to close sacral pressure ulcers but tend to develop a large dog-ear on the buttock. This study presents a new method of avoiding a dog-ear deformity (Burow's triangle) while achieving adequate repair of pressure ulcers on the buttock by using a modification of the bilobed rotation flap. This "pigeon head" modification of the rotation flap successfully covered all 7 sacral ulcers. In all cases, Burow's triangles were unobtrusive immediately after surgery. This technique is simple, can be performed quickly, has minimal associated morbidity, and yields a good outcome. PMID- 26111417 TI - Percutaneous Flexor Tenotomy-Office Procedure for Diabetic Toe Ulcerations. AB - Lesser toe deformities include, but are not limited to, hammertoes, mallet toes, and claw toes. In people with diabetes, these conditions can create pressure points and lead to callous and ulcer formation. Conservative treatment methods such as extra-depth toe box shoes, pads, inserts, and splints provide mixed results with inevitable recurrent ulcerations. Closed or percutaneous flexor tenotomy is a definitive corrective procedure for severe lesser toe deformities often complicated by ulceration in the insensate patient with diabetes. The authors illustrate this simple, office-based procedure in a step-by-step approach to correct these deformities and thereby offload pressures. The technique provides rapid healing and may prevent potential toe and lower extremity amputations. PMID- 26111419 TI - Maggot Debridement Therapy in Necrotizing Fasciitis Reduces the Number of Surgical Debridements. AB - Necrotizing fasciitis is a rare but potentially lethal bacterial infection of the fascial and subcutaneous tissues. Mortality rates of this condition remain high, ranging from 6%-76%. Bacterial cultures may show a wide variety of organisms, but Group A Streptococcus (Streptococcus pyogenes) is the causative agent in up to 71% of all human cases. The treatment consists of urgent radical surgical debridement in combination with broad-spectrum antibiotic therapy. Maggot debridement therapy (MDT) has been proven to be very effective in the treatment of gram-positive bacterial infections. The present study reports on the results of 15 patients with necrotizing fasciitis treated with surgical debridement and antibiotic therapy in combination with MDT from November 2001 to November 2005. A detailed case report of 1 patient is presented. PMID- 26111420 TI - Editorial Message: Wound Care and Wound Clinic Operations in Ecuador. PMID- 26111421 TI - [Obesity psychological treatment: beyond cognitive and behavioral therapy]. AB - The psychological assessment of the patient with obesity aims to identify the factors of maintenance of excess weight, such as eating disorders or anxio depressive disorders. Psychotherapy helps a better weight management. Cognitive behavioral therapy has shown its effectiveness in the treatment of obesity. New psychotherapeutic approaches are explored. The hypnosis and mindfulness are proposed for the management of emotions and stress. A targeted approach on the body image disorder decreases body dissatisfaction. When post-traumatic stress syndrome is involved, EMDR (Eye Movement Desensitization & Reprocessing) is better than other types of therapies. Family therapy is indicated when the entourage is impacted. Psychological difficulties should be the subject of specific care. PMID- 26111422 TI - Total Corneal Astigmatism and Posterior Corneal Surface. PMID- 26111423 TI - Findings of research misconduct. PMID- 26111424 TI - A new key character in males of the family Goodeidae (cyprinodontiformes). PMID- 26111425 TI - Update on vaccine-derived polioviruses worldwide, January 201-March 2015. PMID- 26111426 TI - Lipocalin-2 in the Inflammatory Activation of Brain Astrocytes. AB - Lipocalin-2 (LCN2), a secretory protein, regulates diverse cellular processes such as cell death/survival, cell migration/invasion, cell differentiation, iron delivery, inflammation, insulin resistance, and tissue regeneration. Recently, we reported that LCN2 is secreted by brain astrocytes under inflammatory conditions and that it promotes apoptosis, morphological changes, and migration in astrocytes both in vitro and in vivo. Activated astrocytes release LCN2 not only to induce the morphological transformation associated with reactive astrocytosis, but also to promote their own death. Under inflammatory conditions, activated astrocytes also show functional dichotomy similar to the M1/M2 phenotypes of microglia and macrophages. LCN2 is thought to be a chemokine inducer and an autocrine promoter of the classical proinflammatory activation of astrocytes. This article summarizes the current knowledge regarding the role of astrocyte derived LCN2 as a proinflammatory mediator in the central nervous system and discusses LCN2's role in neuroinflammatory disorders. PMID- 26111427 TI - Pregnancy outcome in women with gestational diabetes mellitus according to the Carpenter-Coustan criteria in Thailand. AB - AIM: To compare the pregnancy outcome of patients diagnosed with gestational diabetes mellitus (GDM) using the Carpenter-Coustan (CC) criteria with that of non-GDM pregnant women at Siriraj Hospital, Bangkok. METHODS: A retrospective study was carried out by reviewing medical records of pregnant women who underwent 100-g oral glucose tolerance test (OGTT) for diagnosing GDM between January 2009 and December 2012 at Siriraj Hospital. Pregnant women were divided into three groups according to the 100-g OGTT result: group 1, pregnant women with normal OGTT on both CC and National Diabetes Data Group (NDDG) criteria; group 2, pregnant women with normal OGTT on NDDG criteria but GDM on CC criteria; and group 3, pregnant women with GDM on CC criteria after December 2012 and enrolled in glycemic control program. Maternal and perinatal outcomes were compared between the groups. RESULTS: During the study period, the incidence of GDM increased 32.76% using the CC criteria. These women (group 2) had a higher risk of neonatal hypoglycemia (6.7% vs 0.6%; OR, 12.3; P < 0.0001), neonatal hyperbilirubinemia (13.7% vs 7.8%; OR, 1.9; P = 0.013) compared with group 1. Pregnant women in group 3 had a lower incidence of immediate post-partum hemorrhage from vaginal delivery than group 2 (0 vs 2.9%; P = 0.04) as well as lower rates of neonatal hypoglycemia and neonatal hyperbilirubinemia. CONCLUSION: Use of CC criteria increases the prevalence of GDM, but managing these women according to the program for GDM can improve the adverse neonatal outcome. PMID- 26111428 TI - Perampanel for epilepsy with partial-onset seizures: a pharmacokinetic and pharmacodynamic evaluation. AB - INTRODUCTION: Epilepsies are among the most common diseases of the CNS. As available antiepileptic drugs do not successfully control seizures in one-third of these patients, the development of drugs with new mechanisms of action is an urgent requirement. AREAS COVERED: Preclinical and clinical data of the recently released antiepileptic drug perampanel are reviewed based on search in medical databases with special reference to its mechanism of action and to its pharmacokinetic properties relevant for clinical treatment. Pharmacodynamically, perampanel is a noncompetitive AMPA-receptor antagonist exerting its antiepileptic properties by modulating glutamatergic synaptic excitation. Pharmacokinetically, perampanel is characterized by a short Tmax but slow hepatic metabolism and a mean plasma half-life of 105 h, allowing for once-daily dosing. Perampanel has shown antiepileptic properties in several animal models of seizures and epilepsy, and in clinical studies significantly reducing partial onset seizures in a dose range from 4 to 12 mg/day both in blinded short-term and in open-label long-term extension trials even in highly pharmacoresistant patients. Aside from adverse effects of dizziness and somnolence, neuropsychiatric disturbances have been reported in patient subgroups, making careful clinical monitoring during uptitration recommendable. EXPERT OPINION: The use of perampanel focusing on control of abnormal synaptic excitation profits from favorable pharmacokinetics and from proven efficacy and overall good tolerability also in patient populations nonresponsive to treatment with previously available antiepileptic drugs. PMID- 26111430 TI - Hemifacial spasm: The past, present and future. AB - Hemifacial spasm is characterised by unilateral contractions of the facial muscles. Though considered to be benign by many people, it can lead to functional blindness and a poor quality of life due to social embarrassment for the suffering individual. Botulinum toxin therapy is an excellent noninvasive tool to treat this condition. However, surgical decompression of the aberrant vessel is also an upcoming approach to therapy for this condition. PMID- 26111429 TI - 'I'm a sick person, not a bad person': patient experiences of treatments for alcohol use disorders. AB - BACKGROUND: Emerging research indicates that standard treatments for alcohol use disorders may not fully meet the needs of patients with co-occurring severe mental health symptoms. Investigating health quality indicators may provide insight into how current treatment might be improved. OBJECTIVE: To better understand the experiences of patients receiving treatment for alcohol use disorders and compare the experiences of patients with and without co-occurring severe mental health symptoms. DESIGN: Cross-sectional qualitative research design using semi-structured interviews methods and framework analysis approach. SETTING: Inpatient hospital, outpatient service, inpatient detoxification clinic and a residential/ therapeutic community. PARTICIPANT'S: Thirty-four patients receiving treatment for an alcohol use disorder. MAIN VARIABLES STUDIED: Themes relating to patients' experiences of continuity of care, treatment need and satisfaction with treatment were studied. The qualitative data were divided into two groups: patients with (n = 15) and without (n = 19) severe mental health symptoms. RESULTS: Five themes relating to patient satisfaction with treatment were identified, including: perceived effectiveness of treatment, supportive relationships, specialized but holistic care, patient autonomy and continuity of care. A diverse range of patient treatment needs, staff and service continuity and stigma were also identified as major themes. Five basic themes were identified as more critical to the experiences of patients with severe mental health symptoms. DISCUSSION AND CONCLUSIONS: Findings suggest that patients look for supportive relationships with others, to be involved in treatment decisions, effective specialized and holistic approaches to care and a non-judgemental treatment environment. PMID- 26111432 TI - Critical period for first language: the crucial role of language input during the first year of life. AB - The critical period for language acquisition is often explored in the context of second language acquisition. We focus on a crucially different notion of critical period for language, with a crucially different time scale: that of a critical period for first language acquisition. We approach this question by examining the language outcomes of children who missed their critical period for acquiring a first language: children who did not receive the required language input because they grew in isolation or due to hearing impairment and children whose brain has not developed normally because of thiamine deficiency. We find that the acquisition of syntax in a first language has a critical period that ends during the first year of life, and children who missed this window of opportunity later show severe syntactic impairments. PMID- 26111431 TI - Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation. AB - Cerebral stroke induces massive Th1-shifted inflammation both in the brain and the periphery, contributing to the outcome of stroke. A Th1-type response is neurotoxic whereas a Th2-type response is accompanied by secretion of anti inflammatory cytokines, such as interleukin-4 (IL-4). Interleukin-33 (IL-33) is a cytokine known to induce a shift towards the Th2-type immune response, polarize macrophages/microglia towards the M2-type, and induce production of anti inflammatory cytokines. We found that the plasma levels of the inhibitory IL-33 receptor, sST2, are increased in human stroke and correlate with a worsened stroke outcome, suggesting an insufficient IL-33-driven Th2-type response. In mouse, peripheral administration of IL-33 reduced stroke-induced cell death and improved the sensitivity of the contralateral front paw at 5days post injury. The IL-33-treated mice had increased levels of IL-4 in the spleen and in the peri ischemic area of the cortex. Neutralization of IL-4 by administration of an IL-4 antibody partially prevented the IL-33-mediated protection. IL-33 treatment also reduced astrocytic activation in the peri-ischemic area and increased the number of Arginase-1 immunopositive microglia/macrophages at the lesion site. In human T cells, IL-33 treatment induced IL-4 secretion, and the conditioned media from IL 33-exposed T-cells reduced astrocytic activation. This study demonstrates that IL 33 is protective against ischemic insult by induction of IL-4 secretion and may represent a novel therapeutic approach for the treatment of stroke. PMID- 26111433 TI - Methods of classification for women undergoing induction of labour: a systematic review and novel classification system. AB - BACKGROUND: A lack of reproducible methods for classifying women having an induction of labour (IOL) has led to controversies regarding IOL and related maternal and perinatal health outcomes. OBJECTIVES: To evaluate articles that classify IOL and to develop a novel IOL classification system. SEARCH STRATEGY: Electronic searches using CINAHL, EMBASE, WEB of KNOWLEDGE, and reference lists. SELECTION CRITERIA: Two reviewers independently assessed studies that classified women having an IOL. DATA COLLECTION AND ANALYSIS: For the systematic review, data were extracted on study characteristics, quality, and results. Pre-specified criteria were used for evaluation. A multidisciplinary collaboration developed a new classification system using a clinically logical model and stakeholder feedback, demonstrating applicability in a population cohort of 909 702 maternities in New South Wales, Australia, over the period 2002-2011. MAIN RESULTS: All seven studies included in the systematic review categorised women according to the presence or absence of varying medical indications for IOL. Evaluation identified uncertainties or deficiencies across all studies, related to the criteria of total inclusivity, reproducibility, clinical utility, implementability, and data availability. A classification system of ten groups was developed based on parity, previous caesarean, gestational age, number, and presentation of the fetus. Nulliparous and parous women at full term were the largest groups (21.2 and 24.5%, respectively), and accounted for the highest proportion of all IOL (20.7 and 21.5%, respectively). AUTHOR'S CONCLUSIONS: Current methods of classifying women undertaking IOL based on medical indications are inadequate. We propose a classification system that has the attributes of simplicity and clarity, uses information that is readily and reliably collected, and enables the standard characterisation of populations of women having an IOL across and within jurisdictions. PMID- 26111435 TI - Action to protect human health from climate change: an African perspective. PMID- 26111434 TI - Reproducibility of transcranial magnetic stimulation metrics in the study of proximal upper limb muscles. AB - OBJECTIVE: Reproducibility of transcranial magnetic stimulation (TMS) metrics is essential in accurately tracking recovery and disease. However, majority of evidence pertains to reproducibility of metrics for distal upper limb muscles. We investigate for the first time, reliability of corticospinal physiology for a large proximal muscle - the biceps brachii and relate how varying statistical analyses can influence interpretations. METHODS: 14 young right-handed healthy participants completed two sessions assessing resting motor threshold (RMT), motor evoked potentials (MEPs), motor map and intra-cortical inhibition (ICI) from the left biceps brachii. Analyses included paired t-tests, Pearson's, intra class (ICC) and concordance correlation coefficients (CCC) and Bland-Altman plots. RESULTS: Unlike paired t-tests, ICC, CCC and Pearson's were >0.6 indicating good reliability for RMTs, MEP intensities and locations of map; however values were <0.3 for MEP responses and ICI. CONCLUSIONS: Corticospinal physiology, defining excitability and output in terms of intensity of the TMS device, and spatial loci are the most reliable metrics for the biceps. MEPs and variables based on MEPs are less reliable since biceps receives fewer cortico motor-neuronal projections. Statistical tests of agreement and associations are more powerful reliability indices than inferential tests. SIGNIFICANCE: Reliable metrics of proximal muscles when translated to a larger number of participants would serve to sensitively track and prognosticate function in neurological disorders such as stroke where proximal recovery precedes distal. PMID- 26111436 TI - Achieving a cleaner, more sustainable, and healthier future. PMID- 26111437 TI - Peng Gong: remote sensing of near climate change. PMID- 26111438 TI - Tackling climate change: the greatest opportunity for global health. PMID- 26111439 TI - Health and climate change: policy responses to protect public health. PMID- 26111440 TI - Reduce short-lived climate pollutants for multiple benefits. PMID- 26111441 TI - Does perthionitrite (SSNO(-)) account for sustained bioactivity of NO? A (bio)chemical characterization. AB - Hydrogen sulfide (H2S) and nitric oxide (NO) are important signaling molecules that regulate several physiological functions. Understanding the chemistry behind their interplay is important for explaining these functions. The reaction of H2S with S-nitrosothiols to form the smallest S-nitrosothiol, thionitrous acid (HSNO), is one example of physiologically relevant cross-talk between H2S and nitrogen species. Perthionitrite (SSNO(-)) has recently been considered as an important biological source of NO that is far more stable and longer living than HSNO. In order to experimentally address this issue here, we prepared SSNO(-) by two different approaches, which lead to two distinct species: SSNO(-) and dithionitric acid [HON(S)S/HSN(O)S]. (H)S2NO species and their reactivity were studied by (15)N NMR, IR, electron paramagnetic resonance and high-resolution electrospray ionization time-of-flight mass spectrometry, as well as by X-ray structure analysis and cyclic voltammetry. The obtained results pointed toward the inherent instability of SSNO(-) in water solutions. SSNO(-) decomposed readily in the presence of light, water, or acid, with concomitant formation of elemental sulfur and HNO. Furthermore, SSNO(-) reacted with H2S to generate HSNO. Computational studies on (H)SSNO provided additional explanations for its instability. Thus, on the basis of our data, it seems to be less probable that SSNO(-) can serve as a signaling molecule and biological source of NO. SSNO(-) salts could, however, be used as fast generators of HNO in water solutions. PMID- 26111442 TI - Changes in Caesarean Delivery Rates in Western Australia from 1995 to 2010 by Gestational Age at Birth. AB - BACKGROUND: The caesarean delivery rate in the developed world has been increasing. It is not well understood how caesarean delivery rates have changed by gestational age at birth in Western Australia, particularly in relation to the introduction of the early-term delivery guidelines in Australia in 2006. METHODS: Data from the Western Australian Midwives Notification System were used to identify 193,136 singletons born to primiparous women at 34-42 weeks' gestation during 1995-2010. Caesarean delivery rates were calculated by gestational age group (34-36 weeks, 37-38 weeks, and 39-42 weeks) and stratified into pre-labour and in-labour caesarean delivery. The average annual percent change (AAPC) for the caesarean delivery rates was calculated using joinpoint regression. Log binomial regression was used to estimate the risk of having a caesarean delivery while adjusting for maternal and antenatal factors. RESULTS: Caesarean delivery rates rose steadily from 1995 to 2005 (AAPC = 5.9%, [95% confidence interval (CI) 4.9, 6.9]), but stabilised since then (AAPC = 0.9%, [95% CI -1.9, 3.8]). The rate of in-labour caesarean deliveries rose consistently from 1995 to 2010 across all gestational age groups. The pre-labour caesarean delivery rate rise was most dominant at 37-38 weeks' gestation from 1995 to 2005 (AAPC = 6.8%, [95% CI 5.4, 8.2]), but declined during 2006-10 (AAPC = -4.5, [95% CI -6.7, -2.3]), while at the same time the rate at 39-42 weeks rose slightly. CONCLUSIONS: The rise in pre labour caesarean deliveries during 1995-2005 occurred predominantly at 37-38 weeks' gestation, but declined again from 2006 to 2010. This suggests that the recently developed Australian early-term delivery guidelines may have had some success in reducing early-term deliveries in Western Australia. PMID- 26111443 TI - Newborn Adipokines and Birth Outcomes. AB - BACKGROUND: Adipokines can serve as a measure of adipose tissue activity. Although birthweight correlates with neonatal adiposity, findings for cord blood levels of adipokines and birth outcomes have been conflicted. Therefore, we determined the cross-sectional associations between adipokines measured in newborn dried blood spots (DBS) and birth outcomes. METHODS: The Upstate KIDS study enrolled mothers and infants from 2008 to 2010. Among infants whose parents consented to the use of residual DBS from newborn screening, 2397 singletons and 1240 twins had adipokine measurements from the Human Obesity Panel (R&D Systems) by Luminex. Odds ratios were estimated by multivariable logistic regression for risk of birth outcomes of preterm delivery (<37 weeks for singletons, <32 for twins) and small-for-gestational age (SGA <10th for singletons and <3rd for twins age- and sex-specific percentiles) by adipokine quintiles. Generalised estimating equations were applied to account for correlations between twins. RESULTS: Singletons in the lowest compared with the highest quintile of adiponectin were more likely preterm (adjusted odds ratio 3.26; 95% confidence interval [CI] 1.99, 5.34) and SGA (1.81; [95% CI 1.18, 2.77]). Similar associations were observed among twins. Resistin was associated with preterm birth (Q1 vs. Q5: 2.08; [95% CI 1.20, 3.62]) only among singletons. Adipsin had inconsistent associations after adjustment. CONCLUSIONS: This large population-based study demonstrates that newborn DBS-measured adipokines are associated with birth outcomes, particularly preterm birth and SGA among those with lower adiponectin levels regardless of plurality. PMID- 26111444 TI - The Association of Infant Growth Patterns with Adiposity in Adolescence: Prospective Observations from Hong Kong's 'Children of 1997' Birth Cohort. AB - BACKGROUND: The role of infant growth in adiposity remains unclear. METHODS: We used multivariable linear regression, with inverse probability weighting and multiple imputation to account for loss to follow-up, in a population representative Chinese birth cohort, 'Children of 1997' in Hong Kong, to examine, in terms births, the adjusted association of infant (birth to 12 months) weight growth trajectories with body mass index (BMI) (n = 6861, 88% follow-up), waist to-height ratio (WHtR), and waist-to-hip ratio (WHR) (n = 5398, 69% follow-up) at ~ 14 years. RESULTS: Infant weight growth trajectories had graded associations with adolescent BMI and WHtR but not with WHR, such that compared with adolescents born light with slow infant growth, adolescents born heavy with fast infant growth had higher BMI z-score [0.60, 95% confidence interval (CI) 0.49, 0.70], higher WHtR z-score (0.17, 95% CI 0.08, 0.26) but similar WHR z-score ( 0.02, 95% CI -0.11, 0.08), adjusted for sex, gestational age, parental education, parental BMI, parental height, and parental place of birth. CONCLUSIONS: Varying associations of infant growth with different adiposity measures suggest a complex role of infant growth in long-term health, perhaps because infant growth, or its underlying drivers, influences build and body composition as well as adiposity. PMID- 26111445 TI - Design and Conduct of an Internet-Based Preconception Cohort Study in North America: Pregnancy Study Online. AB - BACKGROUND: We launched the Boston University Pregnancy Study Online (PRESTO) to assess the feasibility of carrying out an Internet-based preconception cohort study in the US and Canada. METHODS: We recruited female participants age 21-45 and their male partners through Internet advertisements, word of mouth, and flyers. Female participants were randomised with 50% probability to receive a subscription to FertilityFriend.com (FF), a web-based programme that collects real-time data on menstrual characteristics. We compared recruitment methods within PRESTO, assessed the cost-efficiency of PRESTO relative to its Danish counterpart (Snart-Gravid), and validated retrospectively reported date of last menstrual period (LMP) against the FF data. RESULTS: After 99 weeks of recruitment (2013-15), 2421 women enrolled; 1384 (57%) invited their male partners to participate, of whom 693 (50%) enrolled. Baseline characteristics were balanced across randomisation groups. Cohort retention was similar among those randomised vs. not randomised to FF (84% vs. 81%). At study enrollment, 56%, 22%, and 22% couples had been trying to conceive for < 3, 3-5, and >= 6 months, respectively. The cost per subject enrolled was $146 (2013 US$), which was similar to our companion Danish study and half that of a traditional cohort study. Among FF users who conceived, > 97% reported their LMP on the PRESTO questionnaire within 1 day of the LMP recorded via FF. CONCLUSIONS: Use of the Internet as a method of recruitment and follow-up in a North American preconception cohort study was feasible and cost-effective. PMID- 26111446 TI - A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures. AB - Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a-/- kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. PMID- 26111447 TI - Thymosin alpha1 promotes the activation of myeloid-derived suppressor cells in a Lewis lung cancer model by upregulating Arginase 1. AB - Thymosin alpha1 (Talpha1) has been tested for cancer therapy for several years, in most cases, the anti-tumor effect of Talpha1 was limited, especially when Talpha1 was used as a single agent. The role of Talpha1 in cancer treatment and the regulatory mechanisms by which Ta1 takes effects are not yet completely understood. Using a Lewis lung caner model, here we report that Talpha1 used alone elevated CD8(+) T cells, but failed to inhibit tumor growth. Furthermore, immunosuppressive myeloid-derived suppressor cells (MDSCs) showed heightened Arginase 1 production in response to Talpha1 treatment, which led to stronger suppression of anti-tumor immunity. In addition, the upregulation of ARG1 was dependent on TLRs/MyD88 signaling, blocking MyD88 signaling abrogated the enhanced ARG1 expression and restored the anti-tumor efficacy of Talpha1. This study provides the first demonstration that Talpha1 treatment activates but not expands MDSCs via MyD88 signaling, which indicates better immunotherapeutic strategy of Talpha1 against cancer. PMID- 26111448 TI - Ablation of C/EBP homologous protein increases the acute phase mortality and doesn't attenuate cardiac remodeling in mice with myocardial infarction. AB - Endoplasmic reticulum stress is a proapoptotic and profibrotic stimulus. Ablation of C/EBP homologous protein (CHOP) is reported to reverse cardiac dysfunction by attenuating cardiac endoplasmic reticulum stress in mice with pressure overload or ischemia/reperfusion, but it is unclear whether loss of CHOP also inhibits cardiac remodeling induced by permanent-infarction. In mice with permanent ligation of left coronary artery, we found that ablation of CHOP increased the acute phase mortality. For the mice survived to 4 weeks, left ventricular anterior (LV) wall thickness was larger in CHOP knockout mice than in the wildtype littermates, while no difference was noted on posterior wall thickness, LV dimensions, LV fractional shortening and ejection fraction. Similarly, invasive assessment of LV hemodynamics, morphological analysis of heart and lung weight indexes, myocardial fibrosis and TUNEL-assessed apoptosis showed no significant differences between CHOP knockout mice and their wildtype ones, while in mice with ischemia for 45 min and reperfusion for 1 week, myocardial fibrosis and apoptosis in the infarct area were significantly attenuated in CHOP knockout mice. These findings indicate that ablation of CHOP doesn't ameliorate cardiac remodeling induced by permanent-myocardial infarction, which implicates that early reperfusion is a prerequisite for ischemic myocardium to benefit from CHOP inhibition. PMID- 26111449 TI - A new kinetochore component CENP-W interacts with the polycomb-group protein EZH2 to promote gene silencing. AB - Polycomb recessive complex 2 (PRC2) plays a central roles in chromatin compaction and remodeling. EZH2, the catalytic subunit of PRC2, is frequently overexpressed in many human tumors. Together with another essential core component, SUZ12, EZH2 trimethylates histone H3 on lysine 27 (H3K27me3). CENP-W was originally identified as a putative oncogene overexpressed in various human tumors, and later characterized as an essential factor for the formation of functional kinetochore during mitosis. In this study, we found that CENP-W associates with EZH2 to subsequently enhance the protein stability of EZH2. Chromatin immunoprecipitation revealed that ectopically expressed CENP-W bound the promoter of EZH2 target genes to enhance EZH2-mediated transcriptional repression, possibly by facilitating the recruitment of EZH2 to its target genes. Collectively, this study suggests CENP-W is a novel kinetochore component that may be involved in the EZH2-mediated silencing machinery. PMID- 26111450 TI - Identification, characterization and structure analysis of a type I ribosome inactivating protein from Sapium sebiferum (Euphorbiaceae). AB - Ribosome-inactivating proteins (RIPs) are N-glycosidases (EC3.2.2.22) that universally inactivate the ribosome, thereby inhibiting protein biosynthesis. In this study, a novel type I RIPs named SEBIN was identified in Sapium sebiferum. Nuclear acid depurine experiment showed that SEBIN had rRNA N-Glycosidase activity. Further experiment indicated that SEBIN significantly inhibited Caenorhabditis elegans development as well as resulted in worm cell apoptosis. This is the first report to evaluate RIPs toxicity using C. elegans. We proposed that SEBIN may impaire C. elegans reproduction in a DNA-damage manner besides traditional protein synthesis inhibition approach. The predicted 3D structure was modeled using threading and ab initio modeling, and the r-RNA binding residue of SEBIN was identified through the protein-ligand docking approach. It showed the amino acid residues, Glu195, Asn81, Ala82, Tyr83, Glu164, Ser163, Ile159 and Arg167, played critical roles in catalytic process. Our results provided the theoretical foundation of structure-function relationships between enzymatic properties, toxicity and structural characterization of SEBIN. PMID- 26111451 TI - Historic recollections: From polymers and proteins to autoimmunity and cancer. PMID- 26111452 TI - Role of an arginine-lysine rich motif in maturation and trafficking of CD19. AB - Normal expression of CD19 on the surface of B cells requires the presence of the tetraspanin molecule CD81. Previous studies have shown that surface expression of CD19 is highly reduced in CD81-deficient mouse B cells and that it is completely absent in an antibody deficient human patient with a mutation in the CD81 gene. The current study explored the contribution of an arginine-lysine rich motif, present in the membrane-proximal cytoplasmic domain of CD19, for the maturation and trafficking of this molecule. We demonstrate that this motif plays a role in the maturation and recycling of CD19 but in a CD81-independent manner. PMID- 26111453 TI - Cost of Treating Venous Thromboembolism With Heparin and Warfarin Versus Home Treatment With Rivaroxaban. AB - BACKGROUND: Target-specific anticoagulants such as rivaroxaban facilitate immediate discharge of low-risk venous thromboembolism (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) allowing treatment at home instead of hospitalization. OBJECTIVES: The objective was to compare costs accrued over 6 months by patients diagnosed with low-risk VTE and treated at home with rivaroxaban versus usual care with heparin-warfarin. METHODS: This case-control study calculated costs using the established charge-to-cost ratio from UB-04 billing claims of patients diagnosed at two metropolitan hospitals. Patients were defined as low risk by the Hestia criteria. All patients were anticoagulated for 6 months. Control patients were treated with usual care using low-molecular weight heparin (LMWH) and then warfarin. Case patients were treated with an initial dose of rivaroxaban in the ED followed by same-day discharge home with rivaroxaban. Medians were compared by Mann-Whitney U-test. RESULTS: Fifty cases and 47 controls were identified. Groups were well matched according to mean age, Charlson comorbidity score, and proportions by sex and location of thrombus. For all VTEs, median hospital charges for 6 months after diagnosis were $11,128 (interquartile range [IQR] = $8,110 to $23,390) for controls, compared with $4,787 (IQR = $3,042 to $7,596) for cases (Mann-Whitney U-test p < 0.001). Subgroup analyses of the first week of therapy, PE, DVT, and inpatient pharmacy costs retained significance, with costs for rivaroxaban-treated PE patients 57% lower than control PE patients (p < 0.001) and 56% lower for DVT patients (p = 0.003). CONCLUSIONS: Cost of medical care was lower for low-risk VTE patients discharged immediately from the ED with rivaroxaban therapy compared with patients treated with LMWH-warfarin. PMID- 26111454 TI - Mobility and safety issues in drivers with dementia. AB - Although automobiles remain the mobility method of choice for older adults, late life cognitive impairment and progressive dementia will eventually impair the ability to meet transport needs of many. There is, however, no commonly utilized method of assessing dementia severity in relation to driving, no consensus on the specific types of assessments that should be applied to older drivers with cognitive impairment, and no gold standard for determining driving fitness or approaching loss of mobility and subsequent counseling. Yet, clinicians are often called upon by patients, their families, health professionals, and driver licensing authorities to assess their patients' fitness-to-drive and to make recommendations about driving privileges. We summarize the literature on dementia and driving, discuss evidenced-based assessments of fitness-to-drive, and outline the important ethical and legal concerns. We address the role of physician assessment, referral to neuropsychology, functional screens, dementia severity tools, driving evaluation clinics, and driver licensing authority referrals that may assist clinicians with an evaluation. Finally, we discuss mobility counseling (e.g. exploration of transportation alternatives) since health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance our patients' social connectedness and quality of life, while meeting their psychological and medical needs and maintaining personal and public safety. PMID- 26111455 TI - Growth in neurofibromatosis 1 microdeletion patients. AB - Microdeletions of the entire NF1 gene and surrounding genomic region occur in about 5% of patients with neurofibromatosis 1 (NF1). NF1 microdeletion patients usually have more cutaneous and plexiform neurofibromas and a higher risk of developing malignant peripheral nerve sheath tumors than other people with NF1. Somatic overgrowth has also been observed in NF1 microdeletion patients, an observation that is remarkable because most NF1 patients are smaller than average for age and sex. We studied longitudinal measurements of height, weight, and head circumference in 56 patients with NF1 microdeletions and 226 NF1 patients with other kinds of mutations. Although children with NF1 microdeletions were much taller than non-deletion NF1 patients at all ages after 2 years, the lengths of deletion and nondeletion NF1 patients were similar in early infancy. NF1 microdeletion patients tended to be heavier than other NF1 patients, but height or weight more than 3 standard deviations above the mean for age and sex was infrequent in children with NF1 microdeletions. Head circumference and age of puberty were similar in deletion and non-deletion NF1 patients. The pattern of growth differs substantially in deletion and non-deletion NF1 patients, but the pathogenic basis for this difference is unknown. PMID- 26111456 TI - Ion transport through electrolyte/polyelectrolyte multi-layers. AB - Ion transport of multi-ionic solutions through layered electrolyte and polyelectrolyte structures are relevant in a large variety of technical systems such as micro and nanofluidic devices, sensors, batteries and large desalination process systems. We report a new direct numerical simulation model coined EnPEn: it allows to solve a set of first principle equations to predict for multiple ions their concentration and electrical potential profiles in electro-chemically complex architectures of n layered electrolytes E and n polyelectrolytes PE. EnPEn can robustly capture ion transport in sub-millimeter architectures with submicron polyelectrolyte layers. We proof the strength of EnPEn for three yet unsolved architectures: (a) selective Na over Ca transport in surface modified ion selective membranes, (b) ion transport and water splitting in bipolar membranes and (c) transport of weak electrolytes. PMID- 26111457 TI - In honour of the 65th birthday of Reinhard Miller. PMID- 26111458 TI - In-bore prostate transperineal interventions with an MRI-guided parallel manipulator: system development and preliminary evaluation. AB - BACKGROUND: Robot-assisted minimally-invasive surgery is well recognized as a feasible solution for diagnosis and treatment of prostate cancer in humans. METHODS: This paper discusses the kinematics of a parallel 4 Degrees-of-Freedom (DOF) surgical manipulator designed for minimally invasive in-bore prostate percutaneous interventions through the patient's perineum. The proposed manipulator takes advantage of four sliders actuated by MRI-compatible piezoelectric motors and incremental rotary encoders. Errors, mostly originating from the design and manufacturing process, need to be identified and reduced before the robot is deployed in clinical trials. RESULTS: The manipulator has undergone several experiments to evaluate the repeatability and accuracy (about 1 mm in air (in x or y direction) at the needle's reference point) of needle placement, which is an essential concern in percutaneous prostate interventions. CONCLUSION: The acquired results endorse the sustainability, precision and reliability of the manipulator. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26111459 TI - Associations of coeliac disease with coronary heart disease and cerebrovascular disease: A systematic review and meta-analysis. AB - AIMS: Clinical experience suggests that atherosclerotic disease is common in individuals with coeliac disease, but epidemiological studies have had contradicting findings. To summarise the currently available evidence, we systematically reviewed and analysed observational studies of the association of coeliac disease or dermatitis herpetiformis with coronary heart disease (CHD) or stroke. DATA SYNTHESIS: We searched for studies comparing CHD or stroke outcomes with individuals with and without coeliac disease or dermatitis herpetiformis. Three investigators independently searched electronic databases, identified relevant studies and extracted data. Study-specific results were combined in random-effects meta-analyses, and heterogeneity was quantified using the I(2) statistic and meta-regression. Twenty-one studies were included in our systematic review and 18 in the meta-analyses. For CHD, the pooled hazard ratio for incident disease was 1.05 (95% confidence interval (CI): 0.93, 1.19) and the overall standardised mortality ratio was 1.21 (0.99, 1.49). For stroke and brain haemorrhage, the corresponding estimates were 1.10 (95% CI: 1.00, 1.21) and 1.43 (0.97, 2.10), respectively. There was moderate to considerable heterogeneity among the study-specific estimates. In addition, many estimates were based on small numbers of outcomes and they had limitations in terms of adjustment for potential confounders. CONCLUSION: Our meta-analyses lend some support to an association between coeliac disease and CHD or cerebrovascular disease, but the evidence base was heterogeneous and had limitations. Our systematic review highlighted a need in this area for adequately powered prospective studies with appropriate adjustment for potentially confounding factors. PMID- 26111460 TI - Human pharmaceuticals in the marine environment: Focus on exposure and biological effects in animal species. AB - Marine waters have been poorly investigated for the occurrence of pharmaceutical contamination. Recent data confirm that pharmaceuticals occur widely in marine and coastal environments; therefore, assessment of potential risk to marine species needs further efforts. The present study represents the first extensive review of pharmaceutical contamination in marine environments addressing the effects on the marine biota analyzed at the molecular, cellular, and individual levels. Because pharmaceuticals differ from conventional pollutants, being designed to interact with specific physiological pathways at low doses, the most recent evidence on modes of action and physiological alterations on marine animal species are discussed. Data on spatial distributions of pharmaceuticals in waters and sediments, as well as bioaccumulation rates, are also presented. The present review also seeks to expand knowledge of how the quality of coastal and marine environments could be efficiently monitored to anticipate possible health and environmental risks. PMID- 26111461 TI - Acute Myeloid Leukemia: Introduction. PMID- 26111463 TI - Biochemical, Epigenetic, and Metabolic Approaches to Target IDH Mutations in Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a lethal hematologic malignancy associated with poor clinical outcomes. In recent years, mutations in the IDH1 and IDH2 genes have been discovered across a range of malignancies, including AML, raising hope for effective targeted therapies. An intriguing aspect of IDH1/2-mutant malignancies is the aberrant production of the oncometabolite 2-hydroxyglutarate (2-HG), which likely play a pivotal oncogenic role. We recently reported that 2 HG is dramatically elevated in the sera, marrow and urine of IDH1/2-mutant AML patients, and that levels of this oncometabolite directly correlate with disease burden and therapeutic response. The discovery of IDH1/2 mutations and their impact on important proteomic and metabolic pathways has triggered intensive efforts to develop novel and targeted therapies. IDH1/2 inhibitors are currently under early phase clinical investigation, with promising suggestion of efficacy. Other therapeutic approaches under preclinical and clinical investigation in this population include DNA methyltransferase inhibitors and agents that target glutamine metabolism through inhibition of glutaminase or depletion of serum glutamine by asparaginase products. PMID- 26111462 TI - Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells. AB - Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes. An important step towards this goal is the identification of common immunophenotypic surface markers and biological properties that distinguish LSCs from normal hematopoietic stem and progenitor cells (HSPCs) across AML patients. This work has resulted in the development of a large number of potential LSC-selective therapies that target cell surface molecules, intracellular signaling pathways, and the bone marrow microenvironment. Here, we will review the basic biology, immunophenotypic detection, and clinical relevance of LSCs, as well as emerging biological and small-molecule strategies that either directly target LSCs or indirectly target these cells through modulation of their microenvironment. PMID- 26111464 TI - Epigenetic Therapy in Acute Myeloid Leukemia: Current and Future Directions. AB - Epigenetic modifications affect gene expression without changes in the actual DNA sequence. Two of the most important mechanisms include DNA methylation and histone tail modifications (especially acetylation and methylation). Epigenetic modulation is a part of normal physiologic development; its dysregulation is an important mechanism of pathogenesis of some cancers, including acute myeloid leukemia (AML). Despite significant progress in understanding the pathogenesis of AML, therapeutic options remain quite limited. Technological advances have facilitated understanding of aberrant DNA methylation and histone methylation/acetylation as key elements in the development of AML and uncovered several recurrent mutations in genes important for epigenetic regulation. However, much remains to be learned about how to exploit this knowledge for epigenetic therapeutic targeting. Currently, no epigenetic therapy is approved for the treatment of AML, although two DNA methyltransferase inhibitors (azacitidine and decitabine) are commonly used in clinical practice. Among the other epigenetic modifiers undergoing research in AML, the histone deacetylase inhibitors are the most studied. Other promising drugs, such as inhibitors of histone methylation (eg, EZH2 and DOT1L inhibitors), inhibitors of histone demethylases (eg, LSD1 inhibitors), inhibitors of bromodomain-containing epigenetic "reader" BET proteins, and inhibitors of mutant isocitrate dehydrogenases, are at early stages of clinical evaluation. PMID- 26111466 TI - FLT3 Tyrosine Kinase Inhibition as a Paradigm for Targeted Drug Development in Acute Myeloid Leukemia. AB - Therapy targeting specific somatic mutations has become an increasingly important part of cancer therapy over the past 20 years. In particular, tyrosine kinase inhibitors (TKIs) have become a critical component of treatment for both solid tumors and hematologic malignancies. Since mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are relatively common in acute myeloid leukemia (AML), activating mutations in FLT3 represent an appealing target for drug development. Efforts are well underway to develop FLT3 inhibitors and to incorporate these agents into AML therapy. As the genetic landscape of AML has been mapped, other attractive targets for therapy have been discovered, including C-KIT, IDH1 and IDH2, NPM1, and MEK. Some lessons from the ongoing endeavor to develop FLT3 inhibitors may be applicable to the development of other targeted agents for AML. PMID- 26111465 TI - Advancing the Minimal Residual Disease Concept in Acute Myeloid Leukemia. AB - The criteria to evaluate response to treatment in acute myeloid leukemia (AML) have changed little in the past 60 years. It is now possible to use higher sensitivity tools to measure residual disease burden in AML. Such minimal or measurable residual disease (MRD) measurements provide a deeper understanding of current patient status and allow stratification for risk of subsequent clinical relapse. Despite these obvious advantages, and after over a decade of laboratory investigation and preclinical validation, MRD measurements are not currently routinely used for clinical decision-making or drug development in non-acute promyelocytic leukemia (non-APL) AML. We review here some potential constraints that may have delayed adoption, including a natural hesitancy of end users, economic impact concerns, misperceptions regarding the meaning of and need for assay sensitivity, the lack of one single MRD solution for all AML patients, and finally the need to involve patients in decision-making based on such correlates. It is our opinion that none of these issues represent insurmountable barriers and our hope is that by providing potential solutions we can help map a path forward to a future where our patients will be offered personalized treatment plans based on the amount of AML they have left remaining to treat. PMID- 26111467 TI - Acute Myelogenous Leukemia and its Microenvironment: A Molecular Conversation. AB - Survival of patients with acute myelogenous leukemia (AML) depends on our ability to prevent relapse in patients that achieved complete remission after intensive chemotherapy. While studies focusing on the malignant clone brought many advances in understanding AML biology and chemoresistance, little improvement has been made in eliminating the last bastion of malignant cells, the minimal residual disease (MRD). Inspired by Sir Paget's "soil and seed" hypothesis, it is becoming more clear that there is constant feedback between the malignant clone and the leukemic microenvironment. This "molecular conversation" dictates AML behavior and holds the key to eliminating MRD. Here we review recent advances in our understanding of how leukemia cells modify their microenvironment and how these changes reinforce AML homeostasis. In addition, we outline current clinical and preclinical efforts to disrupt these interactions and to therapeutically target MRD. PMID- 26111468 TI - Immunotherapy for Acute Myeloid Leukemia. AB - Despite longstanding efforts in basic research and clinical studies, the prognosis for patients with acute myeloid leukemia (AML) remains poor. About half of the patients are not medically fit for intensive induction therapy to induce a complete remission and are treated with palliative treatment concepts. The patients medically fit for intensive induction therapy have a high complete remission rate but the majority suffers from relapse due to chemo-refractory leukemic cells. Allogeneic stem cell transplantation as post-remission therapy can significantly reduce the likelihood of relapse, but it is associated with a high rate of morbidity and mortality. Novel therapeutic concepts are therefore urgently sought after. During recent years, the focus has shifted towards the development of novel immunotherapeutic strategies. Some of the most promising are drug-conjugated monoclonal antibodies, T-cell engaging antibody constructs, adoptive transfer with chimeric antigen receptor (CAR) T cells, and dendritic cell vaccination. Here, we review recent progress in these four fields and speculate about the optimal time points during the course of AML treatment for their application. PMID- 26111469 TI - Core Binding Factor Acute Myeloid Leukemia: New Prognostic Categories and Therapeutic Opportunities. AB - Core binding factor (CBF) is a heterodimeric protein complex involved in the transcriptional regulation of normal hematopoiesis. Mutations in CBF-encoding genes result in leukemogenic proliferative advantages and impaired differentiation of the hematopoietic progenitors. CBF molecular aberrations are responsible for approximately 20% of all adult acute myeloid leukemia (AML). Although CBF-AMLs are considered to have relatively good prognosis compared to other leukemia subtypes, they are a heterogeneous group of disorders and modern therapy frequently leads to relapse and the associated morbidity and mortality. Improvements in risk stratification and development of targeted therapies are needed for better outcomes. In this review we provide a brief overview of the molecular basis, prognostic categories and the advanced treatment strategies for CBF leukemias. PMID- 26111470 TI - Which Acute Myeloid Leukemia Patients Should Be Offered Transplantation? AB - Acute myeloid leukemia (AML) is a heterogeneous disease characterized by multiple genetic and epigenetic alterations. The major causes of treatment failure remain disease relapse and treatment toxicity. However, major advances in biological determinants of disease relapse, development of targeted molecules, improvement in allogeneic stem cell transplantation regimens, and better evaluation of non relapse mortality risk by comorbidity scores lead to the need to constantly revise the indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Promising post-allo-HSCT strategies will be pivotal for improving allo-HSCT outcome. This review focus on recent studies reporting new disease specific prognostic markers, in addition to allo-HSCT-related risk factors, which can be assessed at specific time points during treatment. PMID- 26111472 TI - Why Is Progress in Acute Myeloid Leukemia So Slow? AB - Therapeutic progress in acute myeloid leukemia (AML) is generally acknowledged to have been slower than that in the other commonly occurring types of leukemia. To a very large extent this reflects a relative lack of understanding of AML "biology" and in particular an inability to identify genetic and/or molecular aberrations not found in normal myeloid precursors ("targets"). Here, however, I also point out that the pace of development/acceptance of new therapies may be retarded by continued adherence to past practices, although these may lack empirical support. Among these practices are reliance on preclinical models that do not accurately represent clinical AML, delay in combining targeted therapies with each other or with "chemotherapy," and limitation of eligibility for clinical trials to patients with relapsed/refractory AML or unfit patients with newly diagnosed disease, and the stereotyped use of single-arm phase II trials followed by very large randomized phase III trials. Finally, I question whether improvement in survival should be the sole or even principal criterion for approval of new drugs in AML. PMID- 26111471 TI - Alternative Donor Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia. AB - Allogeneic hematopoietic cell transplantation (alloHCT) provides a potentially curative therapy for patients with high-risk or chemorefractory acute myeloid leukemia (AML). Historically, the applicability of alloHCT has been limited as only 30%-35% of patients have human leukocyte antigen (HLA)-matched siblings and outcomes using other donor types have been markedly inferior due to excess toxicity, graft failure, graft-versus-host disease (GVHD), and consequently non relapse mortality. Advances in HLA typing, GVHD prophylactic approaches, and other transplantation techniques have successfully addressed these historical challenges. Herein, we review recent alloHCT studies using volunteer unrelated donors, umbilical cord blood units, or HLA-haploidentical donors, specifically focusing on studies that compared outcomes between donor sources. Although none are randomized and most are retrospective, these analyses suggest that current outcomes for AML patients using most alternative donor types are comparable to those seen using HLA-matched siblings. PMID- 26111473 TI - Mitigating Fear and Loathing in Managing Acute Myeloid Leukemia. AB - The contemporary care of patients with acute myeloid leukemia (AML) is made complex by potentially toxic treatments, continuously advancing science, aging patients, and individual treatment goals. By taking a survey of present-day approaches, we aim to dispel some of the trepidation surrounding that care of patients with AML. At the beginning is the initial presentation, and we will discuss whether or not AML should be considered a medical emergency. We will explore the complex realm of patient decision-making about initial therapy, including the intricate straits of patient-doctor communication, and available options for initial treatment. We will then address post-remission approaches and the controversies that lie therein, and survivorship issues. Finally, we will investigate the current role molecular assessments are playing in therapy recommendations. PMID- 26111474 TI - EPIMAG: International Cross-Sectional Epidemiological Psoriasis Study in the Maghreb. AB - BACKGROUND: Psoriasis is a common skin disorder that is characterized by red plaques covered with silvery scales and is associated with considerable psychosocial impact. It has been described in several studies worldwide, but specific data from the Maghreb (Algeria, Morocco and Tunisia) are unavailable. OBJECTIVES: To characterize the frequency of new psoriasis cases and to describe the epidemiological and clinical profile of psoriasis in the Maghreb. METHODS: A psoriasis working group for the Maghreb initiated the EPIMAG international multicentre cross-sectional observational epidemiological study coupled with a 2 week psoriasis screening study via medical consultation. Data were collected via questionnaires. RESULTS: The total analysis population included 373 pre-existing and 326 new psoriasis cases, described by 261 participating investigators. The frequency of new psoriasis cases was 10.26/1,000 in Algeria, 15.04/1,000 in Morocco and 13.26/1,000 in Tunisia, and thus 12.08/1,000 in the Maghreb. In all 699 psoriasis subjects, the mean age was 46 years, the mean BMI was 26.6, and 55.7% of subjects were men. Two thirds of the subjects had never smoked, and 85.0% had never consumed alcohol. Half had brown skin, and 28.6% had a family history of psoriasis. Three quarters had localized psoriasis, 85.8% had plaque psoriasis, coupled with pruritus in over 70.0% of cases. Flares or outbreaks were most often triggered by stress (79.4%) and change of season (43.1%). The majority of subjects used topical therapy, and the investigators considered overall treatment efficacy to be partial in over half of the cases. Among patients with pre-existing psoriasis, secondary analyses showed that 73.2% had severe psoriasis, and that quality of life was severely affected in 40.1% of cases. The mean number of missing school or work days over 6 months was 3.2 (+/-12.1) days. CONCLUSIONS: Our study provides novel information relative to psoriasis epidemiology and characterization in the Maghreb and highlights the need to improve psoriasis screening and management in the region. The data will help optimize psoriasis management, to ensure appropriate national health care policies. PMID- 26111476 TI - Electronic and magnetism properties of two-dimensional stacked nickel hydroxides and nitrides. AB - Two-dimensional (2D) layered materials receive a lot of attention because of their outstanding intrinsic properties and wide applications. In this work, the structural, electronic and magnetic properties of nickel hydroxides (Ni(OH)2) and nitrides XN (X = B, Al, and Ga) heterostructures are studied by first-principles calculations. The results show that the pristine monolayer Ni(OH)2 owns no macro magnetism with antiferromagnetic (AFM) coupling between two nearest Ni atoms, the electronic structure can be modulated through the heterostructures. The Ni(OH)2 GaN and Ni(OH)2-AlN heterostructures retain the AFM coupling, while Ni(OH)2-BN heterostructure have a larger magnetic moment with ferromagnetic (FM) coupling. The complete electron-hole separation is found in the Ni(OH)2-GaN heterostructure. The tunable electronic and magnetic properties of the Ni(OH)2-XN heterostructures open a new door to design the spintronic devices in the 2D stacked nanostructures. PMID- 26111475 TI - Upregulation of Death Receptor 5 and Production of Reactive Oxygen Species Mediate Sensitization of PC-3 Prostate Cancer Cells to TRAIL Induced Apoptosis by Vitisin A. AB - BACKGROUND/AIMS: Although Vitisin A, derived from wine grapes, is known to have cytotoxic, anti-adipogenic, anti-inflammatory and antioxidant effects, the underlying antitumor mechanism has not been investigated in prostate cancer cells to date. In the present study, the apoptotic mechanism of Vitisin A plus TNF related apoptosis-inducing ligand (TRAIL) in prostate cancer cells was elucidated. METHODS: The cytotoxicity of Vitisin A and/or TRAIL against PC-3, DU145 and LNCaP prostate cancer cells was measured by MTT colorimetric assay. Annexin V-FITC Apoptosis Detection kit was used to detect apoptotic cells by flow cytometry. Intracellular levels of ROS were measured by flow cytometry using 2070 diacetyl dichlorofluorescein (DCFDA). RESULTS: Combined treatment with Vitisin A and TRAIL enhanced cytotoxicity and also increased sub-G1 population in PC-3 cells better than DU145 or LNCap prostate cancer cells. Similarly, Annexin V and PI staining revealed that combination increased early and late apoptosis in PC-3 cells compared to untreated control. Consistently, combination attenuated the expression of pro-caspases 7/8, DcR1, Bcl-XL or Bcl-2 and activated caspase 3, FADD, DR5 and DR4 in PC-3 cells. Also, combination increased DR5 promoter activity compared to untreated control. Furthermore, combination increased the production of reactive oxygen species (ROS) and DR5 cell surface expression. The ROS inhibitor NAC and silencing of DR5 by siRNA transfection inhibited the ability of combination to induce PARP cleavage and generate ROS. CONCLUSION: These findings provide evidence that Vitisin A can be used in conjunction with TRAIL as a potent TRAIL sensitizer for synergistic apoptosis induction via upregulation of DR5 and production of ROS in prostate cancer cells. PMID- 26111477 TI - Fusion Peptides CPU1 and CPU2 Inhibit Matrix Metalloproteinases and Protect Mice from Endotoxin Shock Within a Strict Time Window. AB - Endotoxin shock induction in mice is a commonly used animal model to evaluate the protective effect of biologically active reagents. After an lipopolysaccharides (LPS) stimulus, matrix metalloproteinase-8 (MMP-8) and matrix metalloproteinase-9 (MMP-9) are rapidly degranulated and released by neutrophils, aside other enzymes and effector molecules. MMPs cleave extracellular matrix components and cytokines, and such processes contribute to shock syndrome development. CPU1 and CPU2 are two peptide MMP inhibitors with different in vitro IC50 values to several key enzymes, including MMP-8 and MMP-9. In vivo work confirmed that CPU1 and CPU2 protected mice from endotoxin shock after intravenous and intraperitoneal injections. Furthermore, their minimal effective dose after an intravenous injection and the maximum time interval between intraperitoneal peptide injection (150 mg/kg) and intravenous LPS injection were determined. With the use of an indirect competitive ELISA, plasma CPU1 and CPU2 concentrations in different experimental settings were measured. In addition, the acuteness of MMP 9 release in the mouse circulation after an intravenous LPS injection was confirmed with the zymography technique. Our findings reinforce previous work with other inhibitors about a strict time window within which effective MMP inhibition is needed to obtain significant survival rate improvements and also show that, with strict pharmacokinetic monitoring, potent protease inhibitors may in the future become life-savers in shock conditions. PMID- 26111478 TI - Phospholipid Incorporation of Non-Methylene-Interrupted Fatty Acids (NMIFA) in Murine Microglial BV-2 Cells Reduces Pro-Inflammatory Mediator Production. AB - Sciadonic acid (SCA), pinolenic acid (PNA), and Delta7-eicosatrienoic acid (Delta7-ETrA) are three non-methylene-interrupted fatty acids (NMIFA). Using murine microglial BV-2 cells, this study determined how NMIFA incorporation modulated phospholipid fatty acid composition and the production of pro inflammatory mediators. Each NMIFA was rapidly taken up and incorporated in BV-2 cells, resulting in the differential redistribution of total lipids. The cellular phospholipid fatty acid compositions were altered, and a significant decrease in the proportions of total monounsaturated fatty acids (MUFA) was observed while the proportions of NMIFA and its metabolites accounted for 38% of the fatty acid total. Incubation of microglial cells with NMIFA suppressed production of LPS stimulated pro-inflammatory mediators, including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha), as well as the over-expression of inducible nitric oxide synthase (iNOS) and type 2 cyclooxygenase (COX-2). These inhibitory effects could be accounted for, in part, by the inactivation of mitogen-activated protein kinases (MAPK) signaling. In conclusion, Delta7-ETrA, PNA, and SCA are anti-inflammatory NMIFA that may be useful in suppressing in vitro immune responses involved in neural inflammation. PMID- 26111479 TI - Compromised immune response in infants at risk for type 1 diabetes born by Caesarean Section. AB - Children born by Caesarean Section have a higher risk for type 1 diabetes. We aimed to investigate whether Caesarean Section leads to alterations of the immune response in children with familial risk for type 1 diabetes. We examined measures of innate and adaptive immune responses in 94 prospectively followed children, including 40 born by Caesarean Section. Proinflammatory serum cytokine concentrations were determined at age 6 months. As a measure of vaccine response, IgG1, IgG2, and IgG4 tetanus antibody titers and CD4(+) T cell proliferation against tetanus toxoid were quantified. Compared to infants born by vaginal delivery, infants born by Caesarean Section had lower concentrations of the cytokines IFN-gamma (p=0.014) and IL-8 (p=0.005), and weaker CD4(+) T cell responses to tetanus measured in the first (p=0.007) and second year (p=0.047) of life. Overall, our findings provide evidence that the mode of delivery influences the immune status and responsiveness during childhood. PMID- 26111480 TI - Statistical considerations when analyzing biomarker data. AB - Biomarkers have become, and will continue to become, increasingly important to clinical immunology research. Yet, biomarkers often present new problems and raise new statistical and study design issues to scientists working in clinical immunology. In this paper I discuss statistical considerations related to the important biomarker problems of: 1) The design and analysis of clinical studies which seek to determine whether changes from baseline in a biomarker are associated with changes in a metabolic outcome; 2) The conditions that are required for a biomarker to be considered a "surrogate"; 3) Considerations that arise when analyzing whether or not a predictive biomarker could act as a surrogate endpoint; 4) Biomarker timing relative to the clinical endpoint; 5) The problem of analyzing studies that measure many biomarkers from few subjects; and, 6) The use of statistical models when analyzing biomarker data arising from count data. PMID- 26111482 TI - Sensitive, reliable and easy-performed laboratory monitoring of eculizumab therapy in atypical hemolytic uremic syndrome. AB - Complement C5 inhibitor eculizumab treatment in atypical hemolytic uremic syndrome is effective, but associated with high costs. Complement inhibition monitoring in these patients has not been standardized. In this study we evaluated novel functional assays for application in routine follow-up. We documented that the Wieslab(r) complement screen assay showed a sensitivity of 1 2% of C5 activity by adding purified C5 or normal human serum to a C5 deficient serum. All the patient samples obtained during the treatment course, were completely blocked for terminal complement pathway activity for up to four weeks after the eculizumab infusion. Levels of complexes between eculizumab and C5 were inversely correlated to the complement activity (p=0.01). Moreover, titrating serum from eculizumab-treated patients into normal serum revealed that eculizumab was present in excess up to four weeks after infusion. Thus, we demonstrate sensitive, reliable and easy-performed assays which can be used to design individual eculizumab dosage regimens. PMID- 26111481 TI - Preliminary evidence that the novel host-derived immunostimulant EP67 can act as a mucosal adjuvant. AB - EP67 is a complement component 5a (C5a)-derived peptide agonist of the C5a receptor (CD88) that selectively activates DCs over neutrophils. Systemic administration of EP67 covalently attached to peptides, proteins, or attenuated pathogens generates TH1-biased immunogen-specific humoral and cellular immune responses with little inflammation. Furthermore, intranasal administration of EP67 alone increases the proportion of activated APCs in the airways. As such, we hypothesized that EP67 can act as a mucosal adjuvant. Intranasal immunization with an EP67-conjugated CTL peptide vaccine against protective MCMV epitopes M84 and pp89 increased protection of naive female BALB/c mice against primary respiratory infection with salivary gland-derived MCMV and generated higher proportions of epitope responsive and long-lived memory precursor effector cells (MPEC) in the lungs and spleen compared to an inactive, scrambled EP67-conjugated CTL peptide vaccine and vehicle alone. Thus, EP67 may be an effective adjuvant for mucosal vaccines and warrants further study. PMID- 26111483 TI - Galectin-3 Expression in Primary Cutaneous CD30-Positive Lymphoproliferative Disorders and Transformed Mycosis Fungoides. AB - BACKGROUND: In nodal anaplastic large cell lymphoma, strong expression of galectin-3 (Gal-3) has been found, but only very few cases of primary cutaneous lymphoma have so far been examined. OBJECTIVES: To investigate 11 primary cutaneous anaplastic large cell lymphomas (PCALCL), 47 lymphomatoid papuloses (LYP) and 14 cases of transformed mycosis fungoides with CD30 expression (MF-T) for Gal-3 expression. METHODS: A Gal-3 score was applied using a photo-based morphometric evaluation program. Double staining for CD30 and Gal-3 was performed. Furthermore, we recorded the cellular and extracellular sublocalization of the signal. RESULTS: The Gal-3 expression in CD30+ tumor cells was significantly lower in MF-T in contrast to CD30+ lymphoproliferative disorders (CD30 LPD; p < 0.001), but we found no differences between PCALCL and LYP (p = 0.42). In PCALCL Gal-3 was more often localized in the cytoplasm in contrast to LYP, in which an equal distribution in the cytoplasm and the nucleus was more common (p = 0.9). CONCLUSIONS: The lower Gal-3 expression in MF-T in comparison to CD30 LPD might be an additional criterion to differentiate both entities. The different sublocalization of the Gal-3 signal might reflect a different biological function and behavior. PMID- 26111484 TI - Acinetobacter baumannii clonal lineages I and II harboring different carbapenem hydrolyzing-beta-lactamase genes are widespread among hospitalized burn patients in Tehran. AB - The aim of this study was to analyze antimicrobial resistance patterns and their encoding genes and genotypic diversity of Acinetobacter baumannii isolated from burn patients in Tehran, Iran. The presence of extended-spectrum beta-lactamase- and blaOXA-encoding genes among 37 multidrug resistant (MDR) A. baumannii strains isolated from patients hospitalized in a teaching hospital in Tehran was evaluated. Susceptibility to 7 antibiotics was tested by disk agar diffusion and to polymyxin B and colistin was tested by E-test, according to CLSI guidelines. All isolates were then analyzed by PCR for the presence of blaIMP, blaVIM, blaSIMblaOXA-23, blaOXA-24, and blaOXA-58-like carbapenemase genes, and blaOXA-51 like, blaTEM, blaSHV, blaPER, blaVEB, and blaGIM genes. Genotyping of A. baumannii strains was performed by repetitive sequence-based (REP)-PCR and cluster analysis of REP-PCR profiles. A. baumannii isolates were assigned to international clones by multiplex PCR sequence group analysis. Twenty-five A. baumannii isolates were classified as MDR, and 12 were classified as extensively drug resistant. All isolates were susceptible to colistin and polymyxin B. Eighty one percent of the isolates was resistant to imipenem or meropenem and harbored at least one or both of the blaOXA-23-like or blaOXA-24-like carbapenemase genes. Co-existence of different resistance genes was found among carbapenem-resistant isolates. Multiplex PCR sequence group analysis most commonly assigned A. baumannii isolates to international clones I (18/37; 48.6%) and II (18/37; 48.6%). An alarming increase in resistance to carbapenems and the spread of blaOXA-23-like and/or blaOXA-24-like carbapenemase genes was observed among A. baumannii strains belonging to clonal lineages I and II, isolated from burn patients in Tehran. PMID- 26111485 TI - Cortical sources of resting state electroencephalographic rhythms differ in relapsing-remitting and secondary progressive multiple sclerosis. AB - OBJECTIVE: Resting state electroencephalographic (EEG) rhythms are abnormal in multiple sclerosis (MS) patients, but it is unclear if they can reflect different neurophysiologic abnormalities in MS sub-types (phenotypes) such as relapsing remitting (RR) and secondary progressive (SP). METHODS: We tested whether cortical sources of resting state EEG rhythms are abnormal in MS patients and differ between MS phenotypes. Resting state eyes-closed EEG activity was recorded in 36 RR, 23 SP, and 41 matched healthy subjects. EEG bands of interest were individually identified based on Transition frequency (TF), Individual alpha frequency (IAF), and Individual beta frequency (IBF). LORETA freeware estimated cortical EEG sources. RESULTS: Widespread TF -4Hz (delta) and IAF (alpha) cortical sources were abnormal in the MS sub-groups compared to the control group. Furthermore, TF -4Hz sources in central, parietal, and limbic regions were higher in amplitude in the SP compared to the RR sub-group. CONCLUSION: Cortical sources of resting state EEG rhythms are abnormal in MS patients at group level and differ between RR and SP sub-groups. SIGNIFICANCE: Future studies should test the utility of these EEG markers in the diagnosis and management of MS clinical phenotypes and in the therapy evaluation. PMID- 26111486 TI - Electrophysiology of facilitation priming in obsessive-compulsive and panic disorders. AB - OBJECTIVE: Repeated experience with stimuli often primes faster, more efficient neuronal and behavioural responses. Exaggerated repetition priming effects have previously been reported in obsessive-compulsive disorder (OCD), however little is known of their underlying neurobiology or disorder-specificity, hence we investigated these factors. METHODS: We examined event-related potentials (ERPs) and behaviour while participants with OCD, panic disorder and healthy controls (20 per group) performed a Go/NoGo task which manipulated target repetition sequences. RESULTS: Both clinical groups showed stronger reaction time (RT) priming than HCs, which in OCD was greater in a checking, than washing, subgroup. Both clinical groups had similar RT deficits and ERP anomalies across several components, which correlated with psychopathology and RT priming. In OCD alone, N1 latency tended to increase to repeated stimuli, correlated with O-C symptoms, whereas it decreased in other groups. OCD-checkers had smaller target P2 amplitude than all other groups. CONCLUSIONS: Enhanced neural priming is not unique to OCD and may contribute to salient sensory-cognitive experiences in anxiety generally. These effects are related to symptom severity and occur to neutral stimuli and in the context of overall RT impairment, suggesting they may be clinically relevant and pervasive. The results indicate overlapping information-processing and neurobiological factors across disorders, with indications of OCD-specific trends and subgroup differences. SIGNIFICANCE: This first electrophysiological investigation of OCD priming in OCD to include anxious controls and OCD subgroups allows for differentiation between overlapping and OCD specific phenomena, to advance neurobiological models of OCD. PMID- 26111488 TI - EEG oscillations reflect the complexity of social interactions in a non-verbal social cognition task using animated triangles. AB - The ability to attribute independent mental states (e.g. opinions, perceptions, beliefs) to oneself and others is termed Theory of Mind (ToM). Previous studies investigating ToM usually employed verbal paradigms and functional neuroimaging methods. Here, we studied oscillatory responses in the electroencephalogram (EEG) in a non-verbal social cognition task. The aim of this study was twofold: First, we wanted to investigate differences in oscillatory responses to animations differing with regard to the complexity of social "interactions". Secondly, we intended to evaluate the basic cognitive processes underlying social cognition. To this end, we analyzed theta, alpha, beta and gamma task-related de /synchronization (TRD/TRS) during presentation of six non-verbal videos differing in the complexity of (social) "interactions" between two geometric shapes. Videos were adopted from Castelli et al. (2000)and belonged to three conditions: Videos designed to evoke attributions of mental states (ToM), interaction descriptions (goal-directed, GD) and videos in which the shapes moved randomly (R). Analyses revealed that only theta activity consistently varied as a function of social "interaction" complexity. Results suggest that ToM/GD videos attract more attention and working-memory resources and may have activated related memory contents. Alpha and beta results were less consistent. While alpha effects suggest that observation of social "interactions" may benefit from inhibition of self-centered processing, oscillatory responses in the beta range could be related to action observation. In summary, the results provide insight into basic cognitive processes involved in social cognition and render the paradigm attractive for the investigation of social cognitive processes in non-verbal populations. PMID- 26111489 TI - Sex-related functional asymmetry of the ventromedial prefrontal cortex in regard to decision-making under risk and ambiguity. AB - Previous work has provided preliminary indication of sex-related functional asymmetry of the ventromedial prefrontal cortex (vmPFC) in social and emotional functions and complex decision-making. Findings have been inconsistent, and based on small numbers of patients. Given the rarity of these neurological cases, replicable results across studies are important to build evidence for sex-related functional asymmetry of the vmPFC. Here we used a sample of sixteen neurological patients with unilateral damage to the left or right vmPFC and examined differences between men and women on a task that probed decision-making under risk or decision-making under ambiguity. We found that men with right-hemisphere vmPFC damage and women with left-hemisphere vmPFC damage demonstrated significantly reduced aversion to risk and ambiguity. Men with damage to the left vmPFC and women with damage to the right vmPFC showed aversion to risk and ambiguity comparable to participants with left or right-sided brain damage outside the vmPFC, and to comparison participants without brain damage. Our results add to previous findings of sex-related functional asymmetry of the vmPFC in decision-making. Our study also replicates findings of no observable behavioral differences between men and women without neurological damage on tests of decision-making. This pattern of neurobiological divergence but behavioral convergence between men and women may reflect a complex interplay of neuroendocrine, developmental, and psychosocial factors. PMID- 26111487 TI - A shift in perspective: Decentering through mindful attention to imagined stressful events. AB - Ruminative thoughts about a stressful event can seem subjectively real, as if the imagined event were happening in the moment. One possibility is that this subjective realism results from simulating the self as engaged in the stressful event (immersion). If so, then the process of decentering--disengaging the self from the event--should reduce the subjective realism associated with immersion, and therefore perceived stressfulness. To assess this account of decentering, we taught non-meditators a strategy for disengaging from imagined events, simply viewing these events as transient mental states (mindful attention). In a subsequent neuroimaging session, participants imagined stressful and non stressful events, while either immersing themselves or adopting mindful attention. In conjunction analyses, mindful attention down-regulated the processing of stressful events relative to baseline, whereas immersion up regulated their processing. In direct contrasts between mindful attention and immersion, mindful attention showed greater activity in brain areas associated with perspective shifting and effortful attention, whereas immersion showed greater activity in areas associated with self-processing and visceral states. These results suggest that mindful attention produces decentering by disengaging embodied senses of self from imagined situations so that affect does not develop. PMID- 26111490 TI - From blood to brain through BBB and astrocytic signaling. AB - In this Festschrift, I discuss the career and guiding principles to which Abba J. Kastin has adhered during the last 20 years we worked together. I briefly describe the history of our joint laboratory group, the context of studies of peptide permeation across the blood-brain barrier (BBB), and newer developments in the BBB Group as Abba steps down after serving 35 years as the founding Editor in-Chief for Peptides. Abba's BBB studies on peptides have contributed to concepts in the neuroendocrinology of feeding and developed information on molecular trafficking across BBB cells. The astroglial leptin signaling studies and the interactions of sleep and BBB are two major directions, whereas the long term MIF-1 project demarcates a tortuous road on translational research. PMID- 26111491 TI - Pain on administration of non-alkalinised lidocaine for carpal tunnel decompression: A comparison between the Gale and the "advancing wheal" techniques. AB - METHODS: This study compares two methods of administration of non-alkalinised lidocaine for carpal tunnel decompression in volunteers as well as in patients undergoing carpal tunnel release: The Gale subcutaneous injection technique and another subcutaneous injection technique known as the "advancing wheal" technique. The comparison was done in nine male volunteers and in 20 patients. In the volunteer part of the study, both hands were injected and, hence, each volunteer acted as his own control. In the clinical part of the study, the 20 patients were randomised, with 10 patients receiving the Gale technique and the other 10 receiving the wheal technique. RESULTS: In volunteers, the advancing wheal technique was associated with less pain; but with a longer duration of injection and a higher number of needle pricks when compared with the Gale technique. Eight volunteers preferred the advancing wheal technique because the overall pain experience was less. One volunteer preferred the Gale technique because it took less time to complete the injection procedure. Clinically, the wheal technique also had a significantly lower mean pain score than the Gale technique. CONCLUSION: It was concluded that the advancing wheal technique is associated with less pain than the Gale technique. PMID- 26111492 TI - On the Origins of Pituitary Apoplexy. AB - This paper sketches the early history of pituitary apoplexy, a disorder later fully described in 1950 by Brougham, Heusner and Adams. Haemorrhage or necrosis in an adenoma causes a characteristic sudden drowsiness, stupor or coma, headache and stiff neck, ocular palsy, and impaired acuity with visual field loss owing to optic nerve or chiasmal compression. The associated endocrinopathy and management are described. PMID- 26111493 TI - Heart donation and transplantation after circulatory death: ethical issues after Europe's first case. PMID- 26111494 TI - Intensive perioperative simvastatin treatment protects from chronic kidney allograft injury. AB - BACKGROUND/AIMS: Ischemia-reperfusion injury (IRI) and innate immune response augment adaptive immunity and may also trigger repair processes that lead to uncontrolled fibrosis and atherosclerosis as seen in chronic allograft injury. Simvastatin has been shown to protect from renal IRI in several experimental studies. The aim of this study was to examine the effect of donor simvastatin pretreatment and early initiation of recipient simvastatin treatment on chronic kidney allograft injury. METHODS: A rat renal transplantation model was used. Simvastatin was administered perorally for donor (5 mg/kg) and/or for recipient (2 mg/kg) 2 hours before transplantation and/or as daily treatment starting on the first postoperative day (2 mg/kg/day). The study included 5 groups: (1) no simvastatin, (2) donor pretreatment, (3) daily recipient treatment, (4) donor pretreatment + daily recipient treatment and (5) donor pretreatment + recipient pretreatment + daily recipient treatment. The grafts were recovered at day 90 for histopathological and immunohistochemical analysis. Kidney function was followed weekly with serum creatinine, and 24-hour urine protein was measured 60 and 90 days after transplantation. RESULTS: We found that donor and recipient simvastatin pretreatment combined with daily recipient treatment reduced graft inflammation and chronic allograft injury. Treatment using only statins started after transplantation reduced inflammation to some extent, but did not affect chronic kidney allograft injury. Pretreatment using only donor statins impaired graft function and increased proteinuria. CONCLUSION: Our data suggest that perioperative recipient statin treatment reduces inflammation and may protect the graft in the long term. PMID- 26111496 TI - Erosive Effect of Different Soft Drinks on Enamel Surface in vitro: Application of Stylus Profilometry. AB - OBJECTIVE: To assess the erosive potential of various soft drinks by measuring initial pH and titratable acidity (TA) and to evaluate enamel surface roughness using different exposure times. MATERIALS AND METHODS: The initial pH of the soft drinks (group 1: Coca-Cola; group 2: orange juice; group 3: Cedevita; group 4: Guarana, and group 5: strawberry yoghurt) was measured using a pH meter, and TA was measured by titration with NaOH. Enamel samples (n = 96), cut from unerupted human third molars, were randomly assigned to 6 groups: experimental (groups 1-5) and control (filtered saliva). The samples were exposed to 50 ml of soft drinks for 15, 30 and 60 min, 3 times daily, during 10 days. Between immersions, the samples were kept in filtered saliva. Enamel surface roughness was measured by diamond stylus profilometer using the following roughness parameters: Ra, Rq, Rz, and Ry. Data were analyzed by one-way ANOVA, Tukey's post hoc and Student-Newman Keuls post hoc tests. RESULTS: The pH values of the soft drinks ranged from 2.52 (Guarana) to 4.21 (strawberry yoghurt). Orange juice had the highest TA, requiring 5.70 ml of NaOH to reach pH 7.0, whereas Coca-Cola required only 1.87 ml. Roughness parameters indicated that Coca-Cola had the strongest erosion potential during the 15 min of exposure, while Coca-Cola and orange juice were similar during 30- and 60-min exposures. There were no significant differences related to all exposure times between Guarana and Cedevita. Strawberry yoghurt did not erode the enamel surface regardless of the exposure time. CONCLUSION: All of the tested soft drinks except yoghurt were erosive. Erosion of the enamel surfaces exposed to Coca-Cola, orange juice, Cedevita, and Guarana was directly proportional to the exposure time. PMID- 26111495 TI - Histochemical analysis of testis specific gene 13 in human normal and malignant tissues. AB - Testis-specific gene 13 (TSGA13) is abundantly expressed in testis. As previous studies of TSGA13 expression pattern have all been based on mRNA analysis, it is imperative to investigate its actual protein expression. Here, we first examined TSGA13 gene tree and protein homology among species, and found that TSGA13 is relatively well conserved. Next, we detected its protein expression in normal human tissues as well as in a limited number of malignant tumors by immunohistochemistry (IHC). It was demonstrated that, in addition to testis, high expression of TSGA13 could also be observed in multiple normal tissues, including stomach, larynx, spleen, bladder, tonsil, liver and thyroid. Notably, most types of human carcinoma tissues displayed reduced expression of TSGA13 rather than their adjacent normal tissues except glioblastoma and lung cancer. Hence, the data from the current study strongly suggest the association between TSGA13 and tumor malignancy. PMID- 26111498 TI - HBsAg spontaneous seroclearance in a cohort of HBeAg-seronegative patients with chronic hepatitis B virus infection. AB - Loss of hepatitis B surface antigen (HBsAg) is considered to reflect the resolution of a hepatitis B virus (HBV) infection. Patient characteristics and various seromarkers were evaluated to characterize factors predicting spontaneous HBsAg loss in a cohort of HBeAg-seronegative patients with presumed chronic HBV infection. Relationships between seromarkers and HBsAg loss were assessed annually and after 6 years using binary logistic regression. Among the 634 participants, 117 (18.45%) cleared HBsAg after 6 years, with a 3.08% annual seroclearance rate. Baseline HBsAg levels and platelet (PLT) counts were predictors of HBsAg seroclearance. The HBsAg level predicted HBsAg seroclearance better than the PLT count (area under the receiver operating characteristic curve (AUROC): HBsAg, 0.965 (95%CI, 0.947-0.980) versus PLT count, 0.617 (95%CI, 0.561 0.669); P < 0.001). A cutoff HBsAg level of 10 IU/ml at baseline predicted spontaneous HBsAg seroclearance at 6 years with a diagnostic accuracy of 93.4%, a sensitivity of 87.2%, a specificity of 94.8%, a positive predictive value of 79.1%, and a negative predictive value of 97.0%. HBsAg seroclearance may occur more commonly than expected. A serum HBsAg level <10 IU/ml and PLT count were accurate predictors of clearance. PMID- 26111497 TI - A major allergen in rainbow trout (Oncorhynchus mykiss): complete sequences of parvalbumin by MALDI tandem mass spectrometry. AB - Fish parvalbumin (PRVB) is an abundant and stable protein in fish meat. The variation in cross-reactivity among individuals is well known and explained by a broad repertoire of molecular forms and differences between IgE-binding epitopes in fish species. PVRB has "sequential" epitopes, which retain their IgE-binding capacity and allergenicity also after heating and digestion using proteolytic enzymes. From the allergonomics perspective, PRVB is still a challenging target due to its multiple isoforms present at different degrees of distribution. Little information is available in the databases about PVRBs from Oncorhynchus mykiss. At present, only two validated, incomplete isoforms of this species are included in the protein databases: parvalbumin beta 1 (P86431) and parvalbumin beta 2 (P86432). A simple and rapid protocol has been developed for selective solubilization of PRVB from the muscle of farmed rainbow trout (Oncorhynchus mykiss), followed by calcium depletion, proteolytic digestion, MALDI MS, and MS/MS analysis. With this strategy thermal allergen release was assessed and PRVB1 (P86431), PRVB1.1, PRVB2 (P86432) and PRVB2.1 variants from the rainbow trout were sequenced. The correct ordering of peptide sequences was aided by mapping the overlapping enzymatic digests. The deduced peptide sequences were arranged and the theoretical molecular masses (Mr) of the resulting sequences were calculated. Experimental masses (Mr) of each PRVB variant were measured by linear MALDI-TOF. PMID- 26111499 TI - Post-closure biosphere assessment modelling: comparison of complex and more stylised approaches. AB - Geological disposal facilities are the preferred option for high-level radioactive waste, due to their potential to provide isolation from the surface environment (biosphere) on very long timescales. Assessments need to strike a balance between stylised models and more complex approaches that draw more extensively on site-specific information. This paper explores the relative merits of complex versus more stylised biosphere models in the context of a site specific assessment. The more complex biosphere modelling approach was developed by the Swedish Nuclear Fuel and Waste Management Co (SKB) for the Formark candidate site for a spent nuclear fuel repository in Sweden. SKB's approach is built on a landscape development model, whereby radionuclide releases to distinct hydrological basins/sub-catchments (termed 'objects') are represented as they evolve through land rise and climate change. Each of seventeen of these objects is represented with more than 80 site specific parameters, with about 22 that are time-dependent and result in over 5000 input values per object. The more stylised biosphere models developed for this study represent releases to individual ecosystems without environmental change and include the most plausible transport processes. In the context of regulatory review of the landscape modelling approach adopted in the SR-Site assessment in Sweden, the more stylised representation has helped to build understanding in the more complex modelling approaches by providing bounding results, checking the reasonableness of the more complex modelling, highlighting uncertainties introduced through conceptual assumptions and helping to quantify the conservatisms involved. The more stylised biosphere models are also shown capable of reproducing the results of more complex approaches. A major recommendation is that biosphere assessments need to justify the degree of complexity in modelling approaches as well as simplifying and conservative assumptions. In light of the uncertainties concerning the biosphere on very long timescales, stylised biosphere models are shown to provide a useful point of reference in themselves and remain a valuable tool for nuclear waste disposal licencing procedures. PMID- 26111500 TI - What do measures of patient satisfaction with the doctor tell us? AB - OBJECTIVE: To gain an understanding of how patient satisfaction (PS) with the doctor (PSD) is conceptualized through an empirical review of how it is currently being measured. The content of PS questionnaire items was examined to (a) determine the primary domains underlying PSD, and (b) summarize the specific doctor-related characteristics and behaviors, and patient-related perceptions, composing each domain. METHODS: A scoping review of empirical articles that assessed PSD published from 2000 to November 2013. MEDLINE and PsycINFO databases were searched. RESULTS: The literature search yielded 1726 articles, 316 of which fulfilled study inclusion criteria. PSD was realized in one of four health contexts, with questions being embedded in a larger questionnaire that assessed PS with either: (1) overall healthcare, (2) a specific medical encounter, or (3) the healthcare team. In the fourth context, PSD was the questionnaire's sole focus. Five broad domains underlying PSD were revealed: (1) Communication Attributes; (2) Relational Conduct; (3) Technical Skill/Knowledge; (4) Personal Qualities; and (5) Availability/Accessibility. CONCLUSIONS: Careful consideration of measurement goals and purposes is necessary when selecting a PSD measure. PRACTICE IMPLICATIONS: The five emergent domains underlying PSD point to potential key areas of physician training and foci for quality assessment. PMID- 26111501 TI - Do multimorbidity and deprivation influence patients' emotional expressions and doctors' responses in primary care consultations?--An exploratory study using multilevel analysis. AB - OBJECTIVE: To explore whether and how patient multimorbidity and socioeconomic deprivation might influence patients' emotional expression and doctors' responses in the general practice (GP) consultations. METHODS: Video recordings of 107 consultations (eight GPs) were coded with the Verona Coding Definitions of Emotional Sequences (VR-CoDES). Multilevel logistic regressions modelled the probability of GP providing space response, considering patient multimorbidity, deprivation conditions and other contextual factors. Further multinomial regressions explored the possible impact of multimorbidity and deprivation on expression of and specific responses to patients' emotional distress. RESULTS: It was less likely for GPs to provide space as the consultation proceeded, controlling for multimorbidity and deprivation variables. Patients with multimorbidity were less likely to express emotional distress in an explicit form. GPs were more likely to provide acknowledgement to emotions expressed by patients from more deprived areas. CONCLUSION: Multimorbidity and deprivation may influence the dynamics of the GP consultations in specific ways. Rigorous methodologies using larger samples are required to explore further how these two variables relate to each other and influence cue expression, provider response and subsequent patient outcomes. PRACTICE IMPLICATIONS: Understanding how multimorbidity and deprivation impact on GP consultations may help inform future service improvement programmes. PMID- 26111502 TI - Decisions, choice and shared decision making in antenatal clinics: An observational study. AB - OBJECTIVE: The UK Government has prioritised shared decision making (SDM) and choice in maternity services, but no studies have explored the breadth of antenatal decisions or the feasibility of this aspiration. This study aimed to describe the decisions made, investigate the factors associated with choice and explore SDM practice. METHODS: Cross-sectional audio-recording of consultations in a UK district general hospital. Multi-level regression models were used to investigate associations between choice and doctor, patient, consultation and decision variables. RESULTS: 585 decisions were documented with a mean of 3.0 (SD 1.5) per consultation. No choice was offered in 75% of decisions. Choice was associated with the decision topic, consultation length, Royal College membership status and presence on the specialist register. CONCLUSIONS: Without a choice, it will be challenging for a patient and their healthcare profession to truly share decisions. PRACTICE IMPLICATIONS: If universal SDM is the aim, then further work is required to understand the factors impacting choice availability and SDM, while engaging and supporting healthcare professionals to offer options and share decisions with patients. PMID- 26111503 TI - L1CAM in human cancer. AB - L1 cell adhesion molecule (L1CAM) is one of the first neural adhesion molecules described with important functions in the development of the nervous system. Subsequent work discovered that L1CAM is expressed in many human cancers and is often associated with bad prognosis. This is most likely due to the motility and invasion promoting function of L1CAM. Here, we describe the path L1CAM has taken from a neural adhesion molecule to a recognized tumor antigen. We summarize the literature on L1CAM expression in cancers and pre-cancerous lesions. We focus on the genetic elements required for its re-expression and highlight preclinical studies for targeted therapy. The data suggest that L1CAM is a valuable diagnostic/prognostic marker and an attractive target for the therapy of several human cancers. PMID- 26111504 TI - Iron-catalyzed amination of alcohols assisted by Lewis acid. AB - An efficient Lewis acid-assisted, iron-catalyzed amination of alcohols using borrowing hydrogen methodology was developed. In particular, silver fluoride was identified to be a highly effective additive to overcome the low efficiency in the amination of secondary alcohols catalyzed by Knolker's complex. PMID- 26111506 TI - No impact without data access. PMID- 26111505 TI - Lidocaine-Associated Cardiac Events in Newborns with Seizures: Incidence, Symptoms and Contributing Factors. AB - BACKGROUND: Lidocaine is an effective therapy for neonatal seizures; however, it is not widely used, presumably due to the risk of cardiac events. OBJECTIVE: To investigate the incidence of cardiac events in full-term and preterm infants receiving lidocaine for seizures. METHODS: Full-term (n = 368) and preterm (n = 153) infants, admitted to a level 3 neonatal intensive care unit from 1992 to 2012, who received lidocaine for seizures were retrospectively studied. The causal relation between reported cardiac events and lidocaine administration was evaluated based on expected plasma concentrations, symptoms and relevant interactions during cardiac events. RESULTS: Cardiac events were reported in 11/521 infants (2.1%; 9 full-term, 2 preterm). In 7/11 infants the causal relation was considered plausible, in 3/11 questionable and in 1/11 implausible. The incidence was calculated to be 1.3-1.9% (n = 7-10/521), but was only 0.4% (n = 1/246, p = 0.02) when using reduced-dose regimens. Important risk factors for cardiac events were unstable potassium, (congenital) cardiac dysfunction and concurrent phenytoin use. CONCLUSIONS: Lidocaine-associated cardiac events were rare in our cohort, especially since the introduction of new reduced-dose regimens. This indicates that lidocaine is safe to use as an antiepileptic drug in full-term and preterm infants. PMID- 26111507 TI - The European Genome-phenome Archive of human data consented for biomedical research. PMID- 26111508 TI - Double trouble in human aneuploidy. AB - Crossing over, or reciprocal recombination, is essential for accurate segregation of homologous chromosomes at the first meiotic division, resulting in gametes containing the correct chromosome number. A new study in human oocytes analyzes the genome-wide recombination and segregation patterns in all the products of female meiosis, providing experimental support for existing theories about the origin of human aneuploidies and highlighting a novel reverse segregation mechanism of chromosome segregation during meiosis. PMID- 26111509 TI - Sweet size control in tomato. AB - All cells of an adult plant are ultimately derived from divisions that occur in small groups of cells distributed throughout the plant, termed meristems. A new study shows that carbohydrate post-translational modification of a peptide signal influences meristem and, as a consequence, fruit size in tomato. PMID- 26111510 TI - Lipid transport and human brain development. AB - How the human brain rapidly builds up its lipid content during brain growth and maintains its lipids in adulthood has remained elusive. Two new studies show that inactivating mutations in MFSD2A, known to be expressed specifically at the blood brain barrier, lead to microcephaly, thereby offering a simple and surprising solution to an old enigma. PMID- 26111511 TI - Corrigendum: Induction, suppression and requirement of RNA silencing pathways in virulent Agrobacterium tumefaciens infections. PMID- 26111512 TI - Sarcomatoid Carcinoma of the lung: A rare case of three small intestinal intussusceptions and literature review. AB - INTRODUCTION: Sarcomatoid carcinoma is an extremely rare, biphasic tumor characterized by a combination of malignant epithelial and mesenchymal cells. Limited data showed that most cases occurred with advanced local disease and metastasis. PRESENTATION OF CASE: We present a rare case of a 60-year-old man with three small intestinal intussusceptions due to metastatic pulmonary carcinosarcoma. He was explored for chest pain and hemoptysis in Emergency room. Due to his chest symptoms he had a computed tomography (CT) scan of the chest which showed a lesion about 60mm in diameter in the inferior lobe of the left lung. After 2 weeks physical examination demonstrated a distended abdomen and auscultation was indicated by hyperactive bowel sounds. Further imaging studies with abdominal computed tomography (CT) scan, showed multiple protruding small bowel tumors with entero enteric intussusceptions at three sites requiring a massive bowel resection at surgery. The pathology showed that it was positive for cytokeratin, vimentin, CD-34, and LIS; CK7 was focally positive; and CD117, CD20, and desmine were negative. The final diagnosis was metastatic small bowel carcinosarcoma with a lung primary. DISCUSSION: Lung carcinosarcoma is a high grade biphase neoplasm. The survival rate at 6 months is only around 27%. CONCLUSION: There are rare reports of small intestinal intussusceptions caused by metastatic lung carcinosarcoma, this presentation shows the third case in literature. Physicians should be more alert to symptoms or signs indicating GI metastais in patients with a history of lung cancer. PMID- 26111513 TI - Morphology of the foramen magnum in syndromic and non-syndromic brachycephaly authors' reply. PMID- 26111514 TI - Long-term outcome of accessory nerve to suprascapular nerve transfer in obstetric brachial plexus lesion: functional, morphological, and electrophysiological results. AB - PURPOSE: An accessory to suprascapular nerve (XIN-SSN) transfer is considered in patients with obstetric brachial plexus lesion who fail to recover active shoulder external rotation. The aim of this study was to evaluate the quality of extraplexal suprascapular nerve neurotization and to perform a detailed analysis of the infraspinatus muscle (IM) and shoulder external rotation. METHODS: A XIN SSN transfer was performed in 14 patients between 2000 and 2007. Patients had been operated at the age of 3.7 +/- 2.8 years. Follow-up examinations were conducted up to 8.5 +/- 2.5 years. Magnetic resonance imaging was performed to investigate muscle trophism. Fatty muscle degeneration of the IM was classified according to the Goutallier classification. We conducted nerve conduction velocity studies of the suprascapular nerve and needle electromyography of the IM to assess pathologic spontaneous activity and interference patterns. Active glenohumeral shoulder external rotation and global shoulder function were evaluated using the Mallet score. RESULTS: Postoperatively, growth of the IM increased equally on the affected and unaffected sides, although significant differences of muscle thickness persisted over time. There was only grade 1 or 2 fatty degeneration pre- and postoperatively. Electromyography of the IM revealed a full interference pattern in all except one patient, and there was no pathological spontaneous activity. Glenohumeral external rotation as well as global shoulder function increased significantly. CONCLUSION: Our results indicate that the anastomosis after XIN-SSN transfer is functional and that successful reinnervation of the infraspinatus muscle may enable true glenohumeral active external rotation. PMID- 26111515 TI - ATP-enhanced peroxidase-like activity of gold nanoparticles. AB - Gold nanoparticles (AuNPs) are known to possess intrinsic biological peroxidase like activity that has applications in development of numerous biosensors. The reactivity of the Au atoms at the surface of AuNPs is critical to the performance of such biosensors, yet little is known about the effect of biomolecules and ions on the peroxidase-like activity. In this work, the effect of ATP and other biologically relevant molecules and ions over peroxidase-like activity of AuNPs are described. Contrary to the expectation that nanoparticles exposed to biomolecules may lose the catalytic property, ATP and ADP addition enhanced the peroxidase-like activity of AuNPs. The catalytic activity was unaltered by the addition of free phosphate, sulphate and carbonate anions however, addition of ascorbic acid to the reaction mixture diminished the intrinsic peroxidase-like activity of AuNPs, even in the presence of ATP and ADP. In contrast to AuNPs, ATP did not synergize and improve the peroxidase activity of the natural peroxidase enzyme, horseradish peroxidase. PMID- 26111516 TI - Manganese Dioxide nanosheet suspension: A novel absorbent for Cadmium(II) contamination in waterbody. AB - A MnO2 nanosheet (MnO2-NS) suspension was prepared from tetramethylammonium hydroxide (TMA?OH), H2O2, and MnCl2?4H2O, and its efficiency for Cd(II) removal from aqueous solutions was investigated. The maximum adsorption capacity of the MnO2-NS for Cd(II) was evaluated to be about 348 mg/g, which is thus far the highest value reported for MnO2 at pH 6.0. This high adsorption capacity is attributed to efficient ion exchange. X-ray photoelectron spectroscopy (XPS) revealed that Cd(II) was adsorbed on MnO2 as CdO and Cd(OH)2. After Cd(II) adsorption, the suspended MnO2-NS aggregated and precipitated within 5.0 min from solution. Therefore, dispersive MnO2-NS can be used to remove Cd(II) from wastewater rapidly and with high efficiency. PMID- 26111517 TI - Order of Magnitude Signal Gain in Magnetic Sector Mass Spectrometry Via Aperture Coding. AB - Miniaturizing instruments for spectroscopic applications requires the designer to confront a tradeoff between instrument resolution and instrument throughput [and associated signal-to-background-ratio (SBR)]. This work demonstrates a solution to this tradeoff in sector mass spectrometry by the first application of one dimensional (1D) spatially coded apertures, similar to those previously demonstrated in optics. This was accomplished by replacing the input slit of a simple 90 degrees magnetic sector mass spectrometer with a specifically designed coded aperture, deriving the corresponding forward mathematical model and spectral reconstruction algorithm, and then utilizing the resulting system to measure and reconstruct the mass spectra of argon, acetone, and ethanol. We expect the application of coded apertures to sector instrument designs will lead to miniature mass spectrometers that maintain the high performance of larger instruments, enabling field detection of trace chemicals and point-of-use mass spectrometry. PMID- 26111518 TI - A calibration routine for efficient ETD in large-scale proteomics. AB - Electron transfer dissociation (ETD) has been broadly adopted and is now available on a variety of commercial mass spectrometers. Unlike collisional activation techniques, optimal performance of ETD requires considerable user knowledge and input. ETD reaction duration is one key parameter that can greatly influence spectral quality and overall experiment outcome. We describe a calibration routine that determines the correct number of reagent anions necessary to reach a defined ETD reaction rate. Implementation of this automated calibration routine on two hybrid Orbitrap platforms illustrate considerable advantages, namely, increased product ion yield with concomitant reduction in scan rates netting up to 75% more unique peptide identifications in a shotgun experiment. Graphical Abstract ?. PMID- 26111519 TI - Top-down-assisted bottom-up method for homologous protein sequencing: hemoglobin from 33 bird species. AB - Ticks are vectors for disease transmission because they are indiscriminant in their feeding on multiple vertebrate hosts, transmitting pathogens between their hosts. Identifying the hosts on which ticks have fed is important for disease prevention and intervention. We have previously shown that hemoglobin (Hb) remnants from a host on which a tick fed can be used to reveal the host's identity. For the present research, blood was collected from 33 bird species that are common in the U.S. as hosts for ticks but that have unknown Hb sequences. A top-down-assisted bottom-up mass spectrometry approach with a customized searching database, based on variability in known bird hemoglobin sequences, has been devised to facilitate fast and complete sequencing of hemoglobin from birds with unknown sequences. These hemoglobin sequences will be added to a hemoglobin database and used for tick host identification. The general approach has the potential to sequence any set of homologous proteins completely in a rapid manner. Graphical Abstract ?. PMID- 26111520 TI - Structure of Protonated Threonine Dimers in the Gas Phase: Salt-Bridged or Charge Solvated? AB - For homodimers of amino acids, their salt-bridged structures are gradually stabilized as the proton affinity of the component amino acid increases. Threonine has a proton affinity value located in the middle of the list of 20 natural amino acids. Thus, identifying whether the most stable isomer of protonated threonine dimer (Thr(2)H(+)) has a charge-solvated or salt-bridged structure is important and helpful for understanding the structures of other homodimers. By combining infrared photodissociation (IRPD) spectroscopy and theoretical calculations, the structures of Thr(2)H(+) were investigated. Based on calculations at the M062X/6-311++G(d,p)//M062X/6-311++G(d,p) level, the most stable isomer of Thr(2)H(+) was computed to be a charge-solvated structure, with an energy 3.87 kcal/mol lower than the most stable salt-bridged isomer. The predicted infrared spectrum is in good agreement with the experimental spectrum. To evaluate the temperature effect on the distribution of different isomers, the relative concentrations of the six isomers of Thr(2)H(+) were calculated at different temperatures, according to their partition functions and enthalpies. The results show that the isomers are dominated by charge-solvated structures at a temperature of 300 K. PMID- 26111521 TI - Boosting BCG-primed mice with chimeric DNA vaccine HG856A induces potent multifunctional T cell responses and enhanced protection against Mycobacterium tuberculosis. AB - The tuberculosis pandemic continues to rampage despite widespread use of the current Bacillus Calmette-Guerin (BCG) vaccine. Because DNA vaccines can elicit effective antigen-specific immune responses, including potent T cell-mediated immunity, they are promising vehicles for antigen delivery. In a prime-boost approach, they can supplement the inadequate anti-TB immunological memory induced by BCG. Based on this, a chimeric DNA vaccine HG856A encoding Mycobacterium tuberculosis (M. tuberculosis) immunodominant antigen Ag85A plus two copies of ESAT-6 was constructed. Potent humoral immune responses, as well as therapeutic effects induced by this DNA vaccine, were observed previously in M. tuberculosis infected mice. In this study, we further evaluated the antigen-specific T cell immune responses and showed that repeated immunization with HG856A gave modest protection against M. tuberculosis challenge infection and significantly boosted the immune protection primed by BCG vaccination. Enhanced protection was accompanied by increased multifunctional Th1 CD4(+) T cell responses, most notably by an elevated frequency of M. tuberculosis antigen-specific IL-2 producing CD4(+) T cells post-vaccination. These data confirm the potential of chimeric DNA vaccine HG856A as an anti-TB vaccine candidate. PMID- 26111522 TI - Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4+ effector memory T cells. AB - CD4(+) memory T cells play an important role in induction of autoimmunity and chronic inflammatory responses; however, regulatory mechanisms of CD4(+) memory T cell-mediated inflammatory responses are poorly understood. Here we show that apoptotic cell-treated dendritic cells inhibit development and differentiation of CD4(+) effector memory T cells in vitro and in vivo. Simultaneously, intravenous transfer of apoptotic T cell-induced tolerogenic dendritic cells can block development of experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system in C57 BL/6J mouse. Our results imply that it is effector memory CD4(+) T cells, not central memory CD4(+) T cells, which play a major role in chronic inflammatory responses in mice with EAE. Intravenous transfer of tolerogenic dendritic cells induced by apoptotic T cells leads to immune tolerance by specifically blocking development of CD4(+) effector memory T cells compared with results of EAE control mice. These results reveal a new mechanism of apoptotic cell-treated dendritic cell-mediated immune tolerance in vivo. PMID- 26111523 TI - Effects of sex hormones on survival of peritoneal mesothelioma. AB - BACKGROUND: Previous studies have suggested the presence of steroid receptors as a favourable prognostic factor in peritoneal mesothelioma (PM). This study aims to investigate possible hormonal effects on survival of PM. METHODS: This is a retrospective study of prospectively collected data of 52 consecutive patients with PM who underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) by the same surgical team at St George Hospital in Sydney, Australia, between April 1996 and April 2013. Females were arbitrarily divided into assumed premenopausal (< 51 years old; n = 15) and assumed postmenopausal (>= 51 years old, n = 9). In each gender group, patients were furthered divided into three age groups (< 40, 40-60, > 60). A significant statistical difference was defined as p < 0.05. RESULTS: Females with epithelial mesothelioma had a significantly higher survival than males (p = 0.023). They also had a better overall median survival (> 60 months) than males (43 months), although this difference was not statistically significant (p = 0.098). Survival of postmenopausal females became similar to males after excluding benign cystic mesothelioma. CONCLUSIONS: The better survival in premenopausal females could probably be explained by higher levels of oestradiol and progesterone. Also, our data suggests that higher rates of benign cystic mesothelioma in females was not the key reason for the better survival in female patients, further supporting the hypothesis of hormonal links with survival of PM. Therapeutic effects of sex steroid hormones on PM may be a valuable area to explore. PMID- 26111524 TI - Sepsis caused by Listeria monocytogenes during chemotherapy for small cell carcinoma of the thymus. AB - BACKGROUND: Listeria monocytogenes is a facultative intracellular parasitic bacterium that is Gram positive, catalase positive, oxidase negative, and a facultative anaerobe. It is known to infect humans through food. It is a bacillus with low virulence, but can cause meningitis and sepsis in infants and immunocompromised patients. CASE PRESENTATION: A case of 75-year-old Japanese female with small cell carcinoma of the thymus and pleural dissemination is described. She was treated with carboplatin and etoposide and showed a partial response. However, the tumor recurred 6 months later. Therefore, we again administered carboplatin and etoposide. Though peritoneal dissemination was suspected based on abdominal computed tomography findings after two courses, the assessment was stable disease. She was occasionally treated for constipation. She developed chills, rigor, and diarrhea, necessitating admission on the 7th day of the third course of chemotherapy. We suspected intestinal infection, and cefepime was thus administered. However, her blood pressure dropped and neutropenia manifested on the 4th day of admission. We therefore switched the antibiotic from cefepime to meropenem and also administered granulocyte-colony stimulating factor. Listeria monocytogenes was detected by two blood cultures, and the antimicrobial medication was thus switched to ampicillin, in consideration of sensitivity. Her general condition improved and she was able to leave the hospital on the 19th day after admission. CONCLUSIONS: During chemotherapy, factors such as impaired bowel movements, malnutrition, and myeloablation can contribute to the development of severe infections. It is necessary to comprehensively assess a patient's state and treat all aspects of illness. PMID- 26111526 TI - Bilateral vocal fold immobility: a 13 year review of etiologies, management and the utility of the Empey index. AB - BACKGROUND: Bilateral vocal fold immobility (BVFI) is a rare diagnosis causing dyspnea, dysphonia and dysphagia. Management depends on respiratory performance, airway patency, vocal ability, and quality-of-life priorities. The authors review the presentation, management and outcome in patients diagnosed with BVFI. The utility and efficacy of the Empey index (EI) and the Expiratory Disproportion Index (EDI) are evaluated as an objective monitoring tools for BVFI patients. METHODS: A 13-year retrospective review was performed of BVFI patients at St. Michael's Hospital, University of Toronto, a tertiary referral centre for laryngology. RESULTS: Forty-eight patients were included; 46 presented with airway obstruction symptoms. Tracheotomy was required for airway management in 40% of patients throughout the course of their treatment, which was reduced to 19% at the end of the study period. Twenty-one patients underwent endoscopic arytenoidectomy/cordotomy. Non-operative management included continuous positive airway pressure devices. Pulmonary function testing was carried out in 29 patients. Only a portion of the BVFI patients met the defined upper airway obstruction criteria (45% EI and 52% EDI). Seven patients had complete pre- and post-operative PFTs for comparison and all seven had ratios that significantly improved post-operatively which correlated clinically. CONCLUSION: The EI and EDI have limited use in evaluating patients with who have variable upper airway obstruction, but may be helpful in monitoring within subject airway function changes. PMID- 26111525 TI - Demographic, psychosocial, and genetic risk associated with smokeless tobacco use among Mexican heritage youth. AB - BACKGROUND: Despite well-established negative health consequences of smokeless tobacco use (STU), the number and variety of alternative non-combustible tobacco products on the market have increased tremendously over the last 10 years, as has the market share of these products relative to cigarettes. While STU among non Hispanic white youth has decreased over the last 10 years, the prevalence has remained constant among Hispanic youth. Here we examine demographic, psychosocial, and genetic risk associated with STU among Mexican heritage youth. METHODS: Participants (50.5 % girls) reported on psychosocial risk factors in 2008-09 (n = 1,087, mean age = 14.3 years), and smokeless tobacco use in 2010-11 (mean age = 16.7 years). Participants provided a saliva sample that was genotyped for genes in the dopamine, serotonin and opioid pathways. RESULTS: Overall 62 (5.7 %) participants reported lifetime STU. We identified five single nucleotide polymorphisms that increased the risk for lifetime use. Specifically, rs2023902 on SERGEF (OR = 1.93; 95 % CI: 1.05-3.53), rs16941667 on ALDH2 (OR = 3.14; 95 % CI: 1.65-5.94), and rs17721739 on TPH1 (OR = 1.71; 95 % CI: 1.00-2.91) in the dopamine pathway, rs514912 on TRH-DE (OR = 1.84; 95 % CI: 1.25-2.71) in the serotonin pathway, and rs42451417 on the serotonin transporter gene, SLC6A4 (OR = 3.53; 95 % CI: 1.56-7.97). After controlling for genetic risk, being male (OR = 1.86; 95 % CI: 1.02-3.41), obesity status (OR = 2.22; 95 % CI: 1.21-4.09), and both higher levels of anxiety (OR = 1.04; 95 % CI: 1.01-1.08) and social disinhibition (OR = 1.26; 95 % CI: 1.07-1.48) were associated with increased use. High subjective social status (OR = 0.78; 95 % CI: 0.64-0.93) was protective against use, while higher parental education (OR = 2.01; 95 % CI: 1.03-3.93) was associated with increased use. CONCLUSIONS: These data suggest that use of genetic risk, along with psychosocial, demographic, and behavioral risk factors may increase our ability to identify youth at increased risk for STU, which in turn may improve our ability to effectively target prevention messages to Mexican heritage youth. PMID- 26111527 TI - Evolution of substrate recognition sites (SRSs) in cytochromes P450 from Apiaceae exemplified by the CYP71AJ subfamily. AB - BACKGROUND: Large proliferations of cytochrome P450 encoding genes resulting from gene duplications can be termed as 'blooms', providing genetic material for the genesis and evolution of biosynthetic pathways. Furanocoumarins are allelochemicals produced by many of the species in Apiaceaous plants belonging to the Apioideae subfamily of Apiaceae and have been described as being involved in the defence reaction against phytophageous insects. RESULTS: A bloom in the cytochromes P450 CYP71AJ subfamily has been identified, showing at least 2 clades and 6 subclades within the CYP71AJ subfamily. Two of the subclades were functionally assigned to the biosynthesis of furanocoumarins. Six substrate recognition sites (SRS1-6) important for the enzymatic conversion were investigated in the described cytochromes P450 and display significant variability within the CYP71AJ subfamily. Homology models underline a significant modification of the accession to the iron atom, which might explain the difference of the substrate specificity between the cytochromes P450 restricted to furanocoumarins as substrates and the orphan CYP71AJ. CONCLUSION: Two subclades functionally assigned to the biosynthesis of furanocoumarins and four other subclades were identified and shown to be part of two distinct clades within the CYP71AJ subfamily. The subclades show significant variability within their substrate recognition sites between the clades, suggesting different biochemical functions and providing insights into the evolution of cytochrome P450 'blooms' in response to environmental pressures. PMID- 26111528 TI - Maternal and child health nurse screening and care for mothers experiencing domestic violence (MOVE): a cluster randomised trial. AB - BACKGROUND: Mothers are at risk of domestic violence (DV) and its harmful consequences postpartum. There is no evidence to date for sustainability of DV screening in primary care settings. We aimed to test whether a theory-informed, maternal and child health (MCH) nurse-designed model increased and sustained DV screening, disclosure, safety planning and referrals compared with usual care. METHODS: Cluster randomised controlled trial of 12 month MCH DV screening and care intervention with 24 month follow-up. The study was set in community-based MCH nurse teams (91 centres, 163 nurses) in north-west Melbourne, Australia. Eight eligible teams were recruited. Team randomisation occurred at a public meeting using opaque envelopes. Teams were unable to be blinded. The intervention was informed by Normalisation Process Theory, the nurse-designed good practice model incorporated nurse mentors, strengthened relationships with DV services, nurse safety, a self-completion maternal health screening checklist at three or four month consultations and DV clinical guidelines. Usual care involved government mandated face-to-face DV screening at four weeks postpartum and follow up as required. Primary outcomes were MCH team screening, disclosure, safety planning and referral rates from routine government data and a postal survey sent to 10,472 women with babies <= 12 months in study areas. Secondary outcomes included DV prevalence (Composite Abuse Scale, CAS) and harm measures (postal survey). RESULTS: No significant differences were found in routine screening at four months (IG 2,330/6,381 consultations (36.5 %) versus CG 1,792/7,638 consultations (23.5 %), RR = 1.56 CI 0.96-2.52) but data from maternal health checklists (n = 2,771) at three month IG consultations showed average screening rates of 63.1 %. Two years post-intervention, IG safety planning rates had increased from three (RR 2.95, CI 1.11-7.82) to four times those of CG (RR 4.22 CI 1.64-10.9). Referrals remained low in both intervention groups (IGs) and comparison groups (CGs) (<1 %). 2,621/10,472 mothers (25 %) returned surveys. No difference was found between arms in preference or comfort with being asked about DV or feelings about self. CONCLUSION: A nurse-designed screening and care model did not increase routine screening or referrals, but achieved significantly increased safety planning over 36 months among postpartum women. Self-completion DV screening was welcomed by nurses and women and contributed to sustainability. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12609000424202, 10/03/2009. PMID- 26111531 TI - Analysis of physiological responses associated with emotional changes induced by viewing video images of dental treatments. AB - Since the understanding of emotional changes induced by dental treatments is important for dentists to provide a safe and comfortable dental treatment, we analyzed physiological responses during watching video images of dental treatments to search for the appropriate objective indices reflecting emotional changes. Fifteen healthy young adult subjects voluntarily participated in the present study. Electrocardiogram (ECG), electroencephalogram (EEG) and corrugator muscle electromyogram (EMG) were recorded and changes of them by viewing videos of dental treatments were analyzed. The subjective discomfort level was acquired by Visual Analog Scale method. Analyses of autonomic nervous activities from ECG and four emotional factors (anger/stress, joy/satisfaction, sadness/depression and relaxation) from EEG demonstrated that increases in sympathetic nervous activity reflecting stress increase and decreases in relaxation level were induced by the videos of infiltration anesthesia and cavity excavation, but not intraoral examination. The corrugator muscle activity was increased by all three images regardless of video contents. The subjective discomfort during watching infiltration anesthesia and cavity excavation was higher than intraoral examination, showing that sympathetic activities and relaxation factor of emotion changed in a manner consistent with subjective emotional changes. These results suggest that measurement of autonomic nervous activities estimated from ECG and emotional factors analyzed from EEG is useful for objective evaluation of subjective emotion. PMID- 26111529 TI - Persistently elevated osteopontin serum levels predict mortality in critically ill patients. AB - INTRODUCTION: Inflammatory, autoimmune and metabolic disorders have been associated with alterations in osteopontin (OPN) serum levels. Furthermore, elevated serum levels of OPN were reported from a small cohort of patients with sepsis. We therefore analyzed OPN serum concentrations in a large cohort of critically ill medical patients. METHODS: A total of 159 patients (114 with sepsis, 45 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) as well as after 3 days of ICU treatment and compared to 50 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately 1 year. RESULTS: We found significantly elevated serum levels of OPN at admission to the ICU and after 3 days of treatment in critically ill patients compared to healthy controls. OPN concentrations were related to disease severity and significantly correlated with established prognosis scores and classical as well as experimental markers of inflammation and multi-organ failure. In the total cohort, OPN levels decreased from admission to day 3 of ICU treatment. However, persistently elevated OPN levels at day 3 of ICU treatment were a strong independent predictor for an unfavorable prognosis, with similar or better diagnostic accuracy than routinely used markers of organ failure or prognostic scoring systems such as SAPS2 or APACHE II score. CONCLUSIONS: Persistently elevated OPN serum concentrations are associated with an unfavourable outcome in patients with critical illness, independent of the presence of sepsis. Besides a possible pathogenic role of OPN in critical illness, our study indicates a potential value for OPN as a prognostic biomarker in critically ill patients during the early course of ICU treatment. PMID- 26111530 TI - L-Asparaginase monotherapy for EBV-positive T/NK lymphoproliferative diseases: A pilot Study. AB - We investigated the effects of L-asparaginase (L-asp) on Epstein-Barr virus (EBV) positive T/NK lymphoproliferative diseases (EBV-T/ NK-LPDs). Seven doses of L-asp (6,000 U/m2) were administered intravenously, with one dose administered on every alternate day. Five consecutive patients were enrolled. Three patients completed the treatment. The clinical symptoms resolved in 1 patient who started the administration 8 months after the onset, being the earliest among the 5 patients. Her EBV-DNA level in whole blood markedly decreased to 0.08 times of that before treatment, and the level in plasma became undetectable. In the other 2 patients whose administration was started 3 and 3.5 years after the onset, however, a remarkable improvement was not detected. Treatment was discontinued in 2 patients because of disease progression or idiopathic dystonia. The mRNA levels of asparagine synthetase in EBV-infected cells were examined. The level from the patient who responded to L-asp treatment was low, but it did not correlate with the effects in the other patients. Liver dysfunction (grades 2 and 3) was observed in 2 patients and neutropenia (grade 3) was noted in 1 patient. In conclusion, the effect of L-asp as monotherapy in EBV-T/NK-LPDs is limited, and early treatment initiation might be effective. PMID- 26111532 TI - Risk factors for cervical lymph node metastasis in superficial head and neck squamous cell carcinoma. AB - INTRODUCTION: The necessity of transoral surgery for head and neck carcinoma is increasing, but its indications for the treatment of superficial head and neck carcinomas have not yet been established. This study was intended to help establish the standard indications for transoral surgery and additional therapy in patients with superficial head and neck carcinoma. METHODS: Sixty-two patients with 83 superficial head and neck carcinoma underwent transoral tumor resection at the Cancer Institute Hospital between June 2006 and September 2011. We measured the tumor size and thickness, examined the gross appearance, permeation of vessels, and droplet infiltration, and analyzed the correlations between each parameter. RESULTS: Sessile type of tumor on gross appearance showed a significantly higher incidence of thickness>=1000 um than the other types. Tumor thickness>=1000 um was associated with higher incidences of permeation of vessels, droplet infiltration, and cervical lymph node metastasis. CONCLUSIONS: In superficial head and neck carcinoma, if the endoscopic gross appearance is the sessile type, tumor thickness is likely to be >=1000 um and risk of cervical lymph node metastasis is increased. PMID- 26111533 TI - Cochrane Column. PMID- 26111534 TI - Loss-of-Function SCN5A Mutations Associated With Sinus Node Dysfunction, Atrial Arrhythmias, and Poor Pacemaker Capture. AB - BACKGROUND: Cardiac device implantation can be complicated by inability to adequately place leads because of significant lead capture issues. This study sought to determine whether there are genetic bases that underlie poor lead capture. METHODS AND RESULTS: Retrospective review of all patients with structurally normal hearts who underwent new device implantation at Texas Children's Hospital between 2009 and 2014 was performed. Patients with inability to capture at 10 V or a final capture threshold >=3 V at 0.4 ms during implant were analyzed. Among a total of 136 patients (median age, 13 years; range, 3 days to 46 years), 11 patients (8.1%) who underwent dual chamber device implantation had elevated thresholds in the atria (4), ventricle (3), or both chambers (4; atrial-lead threshold, 4.7+/-4.3 versus 0.7+/-0.3 V; ventricular-lead, 3.0+/-3.3 versus 0.7+/-0.3 V). All 11 patients presented with sinus node dysfunction and 10 had atrial arrhythmias. At implant, inability to find atrial capture was seen in 4 patients. Three demonstrated intermittent complete loss of ventricular capture after implantation: 1 has recurrent syncope, 2 eventually died. Genetic testing performed in 10 demonstrated 7 patients with 6 distinct SCN5A mutations, all predicted to be severe loss-of-function mutations by bioinformatic analyses. In the remaining patients, although putative pathogenic mutations were not found, multiple SCN5A polymorphisms were identified in 2 and a desmin mutation in 1. CONCLUSIONS: This study suggests that significant capture issues at implant may be because of loss-of-function SCN5A mutations, providing new insights into SCN5A function. Recognition of this association may be critical for planning device implantation strategies and patient follow-up. PMID- 26111535 TI - Characterisation and materials flow management for waste electrical and electronic equipment plastics from German dismantling centres. AB - Waste electrical and electronic equipment is a complex waste stream and treatment options that work for one waste category or product may not be appropriate for others. A comprehensive case study has been performed for plastic-rich fractions that are treated in German dismantling centres. Plastics from TVs, monitors and printers and small household appliances have been characterised extensively. Based on the characterisation results, state-of-the-art treatment technologies have been combined to design an optimised recycling and upgrade process for each input fraction. High-impact polystyrene from TV casings that complies with the European directive on the restriction of hazardous substances (RoHS) was produced by applying continuous density separation with yields of about 60%. Valuable acrylonitrile butadiene styrene/polycarbonate can be extracted from monitor and printer casings by near-infrared-based sorting. Polyolefins and/or a halogen-free fraction of mixed styrenics can be sorted out by density separation from monitors and printers and small household appliances. Emerging separation technologies are discussed to improve recycling results. PMID- 26111536 TI - BMA annual meeting: BMA issues warning over dangerous working patterns. PMID- 26111537 TI - The experiences and needs of female adults with high-functioning autism spectrum disorder. AB - There is limited large-scale research into the lived experiences of female adults who have an autism spectrum disorder with no co-occurring intellectual disability. Drawing on the findings of an Australia-wide survey, this report presents self-report data from n = 82 women with high-functioning autism spectrum disorder in the areas of health, education, employment, social and community activities. Where relevant, comparisons are provided with the male subset of the same study population; however, in the majority of analyses, no discernible gender differences emerged. The findings highlight the diverse and complex challenges faced by women with high-functioning autism spectrum disorder, including high levels of mental health disorder, unmet support needs in education settings and the workplace, and social exclusion and isolation. PMID- 26111538 TI - MWCNTs Induce ROS Generation, ERK Phosphorylation, and SOD-2 Expression in Human Mesothelial Cells. AB - Biological oxidative responses are involved in the toxicity of multiwall carbon nanotubes (MWCNTs), which may cause asbestos-like pathogenicity. Superoxide dismutase 2 (SOD-2) has been proposed as a biomarker of early responses to mesothelioma-inducing fibers. This study was conducted to investigate the alteration of SOD-2 expression in the human mesothelial cell lines Met-5A after exposure to nontoxic doses of MWCNTs and the potential signaling pathway. The parameters measured included the viability, morphological change, superoxide formation, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and messenger RNA (mRNA)/protein levels of SOD-2. Our results showed that MWCNTs upregulated SOD-2 expression at both mRNA and protein level. Coincidently, both superoxide formation and ERK1/2 phosphorylation were observed in Met-5A cells exposed to MWCNTs and were diminished by pretreatment with the reactive oxidative species (ROS) scavenger, N-acetyl-l-(+)-cysteine (NAC). To further investigate the role of ROS/ERK1/2 in MWCNTs-induced SOD-2 overexpression, prior to MWCNTs exposure, cells were pretreated with the Mitogen-activated protein kinase kinase 1/2 (MEK 1/2) inhibitor (U0126) or with NAC. Both pretreatments decreased the MWCNTs-induced overexpression of SOD-2. These results suggest that upregulation of SOD-2 in Met-5A cells exposed to MWCNTs is mediated by ROS formation and ERK1/2 activation. PMID- 26111539 TI - A 9-Month Toxicity and Toxicokinetic Assessment of Subcutaneous Pegylated Human C peptide (CBX129801) in Cynomolgus Monkeys. AB - C-peptide is formed in the biosynthesis of insulin and is therefore deficient in patients with type 1 diabetes mellitus. A pegylated form of human synthetic C peptide (CBX129801) has been developed to extend the half-life of the native peptide and is undergoing clinical investigation as replacement therapy to treat diabetic peripheral neuropathy. This monkey study was conducted to evaluate the toxicity of CBX129801 with weekly subcutaneous dosing for 39 weeks at dose levels of 0 (vehicle), 0.4, 1.33, and 4.0 mg/kg/wk. No systemic adverse effects were observed at any dose with maximal CBX129801 plasma concentrations of 735 to 1050 nmol/L during the dosing period (physiological range is 1-3 nmol/L). CBX129801 related effects were limited to minimal macrophagic vacuolization at the injection sites and in the associated draining (axillary) lymph nodes; these local effects largely resolved by the end of a 7-week recovery period. No systemic macrophagic vacuolization was observed. Additionally, there was no histological evidence for plaque formation in the major arteries of these nondiabetic animals. PMID- 26111540 TI - An Animal Model of Trichloroethylene-Induced Skin Sensitization in BALB/c Mice. AB - Trichloroethylene (TCE) is a major occupational hazard and environmental contaminant that can cause multisystem disorders in the form of occupational medicamentosa-like dermatitis. Development of dermatitis involves several proinflammatory cytokines, but their role in TCE-mediated dermatitis has not been examined in a well-defined experimental model. In addition, few animal models of TCE sensitization are available, and the current guinea pig model has apparent limitations. This study aimed to establish a model of TCE-induced skin sensitization in BALB/c mice and to examine the role of several key inflammatory cytokines on TCE sensitization. The sensitization rate of dorsal painted group was 38.3%. Skin edema and erythema occurred in TCE-sensitized groups, as seen in 2,4-dinitrochlorobenzene (DNCB) positive control. Trichloroethylene sensitization positive (dermatitis [+]) group exhibited increased thickness of epidermis, inflammatory cell infiltration, swelling, and necrosis in dermis and around hair follicle, but ear painted group did not show these histological changes. The concentrations of serum proinflammatory cytokines including tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-2 were significantly increased in 24, 48, and 72 hours dermatitis [+] groups treated with TCE and peaked at 72 hours. Deposition of TNF-alpha, IFN-gamma, and IL-2 into the skin tissue was also revealed by immunohistochemistry. We have established a new animal model of skin sensitization induced by repeated TCE stimulations, and we provide the first evidence that key proinflammatory cytokines including TNF alpha, IFN-gamma, and IL-2 play an important role in the process of TCE sensitization. PMID- 26111541 TI - Integrating Image-Based Phenomics and Association Analysis to Dissect the Genetic Architecture of Temporal Salinity Responses in Rice. AB - Salinity affects a significant portion of arable land and is particularly detrimental for irrigated agriculture, which provides one-third of the global food supply. Rice (Oryza sativa), the most important food crop, is salt sensitive. The genetic resources for salt tolerance in rice germplasm exist but are underutilized due to the difficulty in capturing the dynamic nature of physiological responses to salt stress. The genetic basis of these physiological responses is predicted to be polygenic. In an effort to address this challenge, we generated temporal imaging data from 378 diverse rice genotypes across 14 d of 90 mm NaCl stress and developed a statistical model to assess the genetic architecture of dynamic salinity-induced growth responses in rice germplasm. A genomic region on chromosome 3 was strongly associated with the early growth response and was captured using visible range imaging. Fluorescence imaging identified four genomic regions linked to salinity-induced fluorescence responses. A region on chromosome 1 regulates both the fluorescence shift indicative of the longer term ionic stress and the early growth rate decline during salinity stress. We present, to our knowledge, a new approach to capture the dynamic plant responses to its environment and elucidate the genetic basis of these responses using a longitudinal genome-wide association model. PMID- 26111542 TI - Photosynthetic Genes and Genes Associated with the C4 Trait in Maize Are Characterized by a Unique Class of Highly Regulated Histone Acetylation Peaks on Upstream Promoters. AB - Histone modifications contribute to gene regulation in eukaryotes. We analyzed genome-wide histone H3 Lysine (Lys) 4 trimethylation and histone H3 Lys 9 acetylation (two modifications typically associated with active genes) in meristematic cells at the base and expanded cells in the blade of the maize (Zea mays) leaf. These data were compared with transcript levels of associated genes. For individual genes, regulations (fold changes) of histone modifications and transcript levels were much better correlated than absolute intensities. When focusing on regulated histone modification sites, we identified highly regulated secondary H3 Lys 9 acetylation peaks on upstream promoters (regulated secondary upstream peaks [R-SUPs]) on 10% of all genes. R-SUPs were more often found on genes that were up-regulated toward the blade than on down-regulated genes and specifically, photosynthetic genes. Among those genes, we identified six genes encoding enzymes of the C4 cycle and a significant enrichment of genes associated with the C4 trait derived from transcriptomic studies. On the DNA level, R-SUPs are frequently associated with ethylene-responsive elements. Based on these data, we suggest coevolution of epigenetic promoter elements during the establishment of C4 photosynthesis. PMID- 26111543 TI - Strigolactone Inhibition of Branching Independent of Polar Auxin Transport. AB - The outgrowth of axillary buds into branches is regulated systemically via plant hormones and the demand of growing shoot tips for sugars. The plant hormone auxin is thought to act via two mechanisms. One mechanism involves auxin regulation of systemic signals, cytokinins and strigolactones, which can move into axillary buds. The other involves suppression of auxin transport/canalization from axillary buds into the main stem and is enhanced by a low sink for auxin in the stem. In this theory, the relative ability of the buds and stem to transport auxin controls bud outgrowth. Here, we evaluate whether auxin transport is required or regulated during bud outgrowth in pea (Pisum sativum). The profound, systemic, and long-term effects of the auxin transport inhibitor N-1 naphthylphthalamic acid had very little inhibitory effect on bud outgrowth in strigolactone-deficient mutants. Strigolactones can also inhibit bud outgrowth in N-1-naphthylphthalamic acid-treated shoots that have greatly diminished auxin transport. Moreover, strigolactones can inhibit bud outgrowth despite a much diminished auxin supply in in vitro or decapitated plants. These findings demonstrate that auxin sink strength in the stem is not important for bud outgrowth in pea. Consistent with alternative mechanisms of auxin regulation of systemic signals, enhanced auxin biosynthesis in Arabidopsis (Arabidopsis thaliana) can suppress branching in yucca1D plants compared with wild-type plants, but has no effect on bud outgrowth in a strigolactone-deficient mutant background. PMID- 26111544 TI - A multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of single-entity, once-daily hydrocodone tablets in patients with uncontrolled moderate to severe chronic low back pain. AB - OBJECTIVES: This multicenter, randomized, double-blind, placebo-controlled study with an enriched enrollment, randomized withdrawal design was conducted to evaluate the analgesic efficacy and safety of single-entity, once-daily hydrocodone 20 to 120 mg tablets (HYD) in opioid-naive and opioid-experienced patients with uncontrolled moderate to severe chronic low back pain (CLBP). RESEARCH DESIGN AND METHODS: The primary endpoint was week 12 pain intensity scores (11-point scale, 0 = no pain) using a mixed effect model with repeated measures incorporating a pattern mixture model framework. Responder analysis was a secondary endpoint. Safety was assessed. RESULTS: Out of 905 patients who were treated with HYD during the open-label titration period, 588 (65%) were randomized to continue to receive HYD (n = 296, 20 - 120 mg taken once daily, average daily dose 57 mg) or a matching placebo (n = 292). HYD demonstrated superior pain reduction (p = 0.0016); this result was supported by sensitivity analyses using different approaches to handling missing data. Proportions of patients achieving >= 30 and >= 50% improvement in pain from screening to week 12 also favored HYD (p = 0.0033 and 0.0225, respectively). HYD was generally well tolerated. CONCLUSIONS: HYD was shown to be an efficacious treatment for CLBP in this study. There were no new or unexpected safety concerns detected. PMID- 26111545 TI - Diagnostic Accuracy of Ultrasonography in Retained Soft Tissue Foreign Bodies: A Systematic Review and Meta-analysis. AB - OBJECTIVES: Open wounds with the potential for retained foreign bodies are frequently seen in the emergency department (ED). Common foreign bodies, such as wood or glass, are often missed on physical examination and conventional radiography. The increased use of ultrasonography (US) in the ED presents an opportunity to better identify retained soft tissue foreign bodies, and understanding of its test characteristics is desirable. The authors set out to determine the test characteristics of US for detection of soft tissue foreign bodies by performing a systematic review and meta-analysis of the existing literature. METHODS: This was a thorough, systematic review of OVID Medline, SCOPUS, and Cochrane databases and a limited review of Directory of Open Access Journals, Google Scholar, and ClinicalTrials.gov to identify clinical studies examining the diagnostic accuracy of US in the identification of retained soft tissue foreign bodies. Studies were selected for full-text review by two independent reviewers to determine if they met inclusion criteria. Results were pooled for test characteristics using STATA and assessed for risk of bias and applicability using the QUADAS-2 tool. RESULTS: This systematic search strategy identified 5,059 unique articles, and 17 articles met inclusion criteria. Pooled sensitivity and specificity were, respectively, 72% (95% confidence interval [CI] = 57% to 83%) and 92% (95% CI = 88% to 95%). Overall quality of the studies was low and interstudy heterogeneity was high (I(2) = 90%, 95% CI = 80% to 100%). CONCLUSIONS: Ultrasonography is highly specific and moderately sensitive in the identification of retained soft tissue foreign bodies; however, studies to date have a high degree of heterogeneity and a high risk of bias. PMID- 26111546 TI - Fine Structure and Molecular Phylogeny of Parametopidium circumlabens (Ciliophora: Armophorea), Endocommensal of Sea Urchins. AB - Metopid armophoreans are ciliates commonly found in anaerobic environments worldwide; however, very little is known of their fine structure. In this study, the metopid Parametopidium circumlabens (Biggar and Wenrich 1932) Aescht, 1980, a common endocommensal of sea urchins, is investigated for the first time with emphasis on transmission electron microscopy, revealing several previously unknown elements of its morphology. Somatic dikinetids of P. circumlabens have a typical ribbon of transverse microtubules, an isolated microtubule near triplets 4 and 5 of the anterior kinetosome, plus two other microtubules between anterior and posterior kinetosomes, a short kinetodesmal striated fiber and long postciliary microtubules. In the dikinetids of the perizonal stripe, the kinetodesmal fiber is very pronounced, and there is a conspicuous microfibrillar network system associated with the kinetosomes. A new structure, shaped as a dense, roughly cylindrical mass surrounded by microtubules, is found associated with the posterior kinetosome of perizonal dikinetids. The paroral membrane is diplostichomonad and the adoral membranelles are of the "paramembranelle" type. Bayesian inference and maximum-likelihood analysis of the 18S-rDNA gene unambiguously placed P. circumlabens as sister group of the cluster formed by ((Atopospira galeata, Atopospira violacea) Metopus laminarius) + Clevelandellida, corroborating its classification within the Metopida. PMID- 26111547 TI - New diagnostic criteria and operative strategy for cesarean scar syndrome: Endoscopic repair for secondary infertility caused by cesarean scar defect. AB - AIM: The aim of the present study was to assess the efficacy of endoscopic repair for secondary infertility caused by post-cesarean scar defect (PCSD). Our investigation focused on the validity of new diagnostic criteria and selection methods. MATERIAL AND METHODS: The subjects were 22 women with secondary infertility due to PCSD with retention of bloody fluid in the uterine cavity. Women with a residual myometrial thickness of >= 2.5 mm and an anteflexed or straight uterus underwent hysteroscopic surgery, while all others underwent laparoscopic repair. Hysteroscopic surgery involved resection and coagulation of scarred areas, whereas laparoscopic surgery involved removal of scarred areas combined with hysteroscopy, followed by resuturing. RESULTS: Fourteen of the 22 women (63.6%) who were followed up for >= 1 year after surgery achieved pregnancy. Pregnancies occurred in all four women (100%) who underwent hysteroscopic surgery and in 10 of the 18 women (55.6%) who underwent laparoscopic surgery. Three out of four women who underwent hysteroscopic surgery had term deliveries. Among the women who underwent laparoscopic surgery, five had term deliveries. No cases of uterine rupture were experienced, and the delivery method was cesarean section in all cases. CONCLUSION: We propose that infertility associated with PCSD, cesarean scar syndrome, is caused by the retention of bloody fluid in the uterine cavity and scarring. Endoscopic treatment, such as hysteroscopy or laparoscopy, was effective for cesarean scar syndrome. PMID- 26111548 TI - Thinking Concretely Increases the Perceived Likelihood of Risks: The Effect of Construal Level on Risk Estimation. AB - Recent findings on construal level theory (CLT) suggest that abstract thinking leads to a lower estimated probability of an event occurring compared to concrete thinking. We applied this idea to the risk context and explored the influence of construal level (CL) on the overestimation of small and underestimation of large probabilities for risk estimates concerning a vague target person (Study 1 and Study 3) and personal risk estimates (Study 2). We were specifically interested in whether the often-found overestimation of small probabilities could be reduced with abstract thinking, and the often-found underestimation of large probabilities was reduced with concrete thinking. The results showed that CL influenced risk estimates. In particular, a concrete mindset led to higher risk estimates compared to an abstract mindset for several adverse events, including events with small and large probabilities. This suggests that CL manipulation can indeed be used for improving the accuracy of lay people's estimates of small and large probabilities. Moreover, the results suggest that professional risk managers' risk estimates of common events (thus with a relatively high probability) could be improved by adopting a concrete mindset. However, the abstract manipulation did not lead managers to estimate extremely unlikely events more accurately. Potential reasons for different CL manipulation effects on risk estimates' accuracy between lay people and risk managers are discussed. PMID- 26111550 TI - The population cost-effectiveness of a parenting intervention designed to prevent anxiety disorders in children. AB - BACKGROUND: Prevention and early intervention for anxiety disorders has lagged behind many other forms of mental disorder. Recent research has demonstrated the efficacy of a parent-focussed psycho-educational programme. The programme is directed at parents of inhibited preschool children and has been shown to reduce anxiety disorders at 1 and 3 years following intervention. The current study assesses the cost-effectiveness of this intervention to determine whether it could provide value-for-money across a population. METHOD: A cost-utility economic framework, using Disability-Adjusted-Life-Years (DALYs) as the outcome, was adopted. Economic modelling techniques were used to assess the incremental cost-effectiveness ratio (ICER) of the intervention within the Australian population context, which was modelled as add-on to current practice. The perspective was the health sector. Uncertainty was measured using multivariate probabilistic testing and key assumptions were tested using univariate sensitivity analysis. RESULTS: The median ICER for the intervention was AUD$8,000 per DALY averted with 99.8% of the uncertainty iterations falling below the threshold value-for-money criterion of AUD$50,000 per DALY averted. The results were robust to sensitivity testing. CONCLUSIONS: Screening young children in a preschool setting for an inhibited temperament and providing a brief intervention to the parents of children with high levels of inhibition appears to provide very good value-for-money and worth considering in any package of preventive care. Further evaluation of this intervention under routine health service conditions will strengthen conclusions. Acceptability issues associated with this intervention, particularly to preschool staff and parents, need to be considered before wide-scale adoption is undertaken. PMID- 26111549 TI - Synthesis and evaluation of 1,4-naphthoquinone ether derivatives as SmTGR inhibitors and new anti-schistosomal drugs. AB - Investigations regarding the chemistry and mechanism of action of 2-methyl-1,4 naphthoquinone (or menadione) derivatives revealed 3-phenoxymethyl menadiones as a novel anti-schistosomal chemical series. These newly synthesized compounds (1 7) and their difluoromethylmenadione counterparts (8, 9) were found to be potent and specific inhibitors of Schistosoma mansoni thioredoxin-glutathione reductase (SmTGR), which has been identified as a potential target for anti-schistosomal drugs. The compounds were also tested in enzymic assays using both human flavoenzymes, i.e. glutathione reductase (hGR) and selenium-dependent human thioredoxin reductase (hTrxR), to evaluate the specificity of the inhibition. Structure-activity relationships as well as physico- and electro-chemical studies showed a high potential for the 3-phenoxymethyl menadiones to inhibit SmTGR selectively compared to hGR and hTrxR enzymes, in particular those bearing an alpha-fluorophenol methyl ether moiety, which improves anti-schistosomal action. Furthermore, the (substituted phenoxy)methyl menadione derivative (7) displayed time-dependent SmTGR inactivation, correlating with unproductive NADPH-dependent redox cycling of SmTGR, and potent anti-schistosomal action in worms cultured ex vivo. In contrast, the difluoromethylmenadione analog 9, which inactivates SmTGR through an irreversible non-consuming NADPH-dependent process, has little killing effect in worms cultured ex vivo. Despite ex vivo activity, none of the compounds tested was active in vivo, suggesting that the limited bioavailability may compromise compound activity. Therefore, future studies will be directed toward improving pharmacokinetic properties and bioavailability. PMID- 26111551 TI - To induce or not to induce: what is the right question? PMID- 26111552 TI - Measurement challenges in shared decision making: putting the 'patient' in patient-reported measures. AB - Measuring clinicians' shared decision-making (SDM) performance is a key requirement given the intensity of policy interest in many developed countries - yet it remains one of the most difficult methodological challenges, which is a concern for many stakeholders. In this Viewpoint Article, we investigate the development of existing patient-reported measures (PRMs) of SDM identified in a recent review. We find that patients were involved in the development of only four of the 13 measures. This lack of patient involvement in PRM development is associated with two major threats to content validity, common to all 13 PRMs of SDM: (i) an assumption of patient awareness of 'decision points' and (ii) an assumption that there is only one decision point in each healthcare consultation. We provide detailed examples of these threats and their impact on accurate assessment of SDM processes and outcomes, which may hamper efforts to introduce incentives for SDM implementation. We propose cognitive interviewing as a recommended method of involving patients in the design of PRMs in the field of SDM and provide a practical example of this approach. PMID- 26111554 TI - Thrombolysis for acute ischemic stroke: does it work?-the con position - ERRATUM. PMID- 26111553 TI - Fabrication and characterization of polyacrylamide/silk fibroin hydrogels for peripheral nerve regeneration. AB - Various hydrogels have been used for repairing peripheral nerve injury; however, the silk fibroin (SF)-based hydrogels in peripheral nerve regeneration are still rarely reported. In this study, the SF/pAM hydrogels with different SF concentrations and ethanol treatment time were developed by solution blending and in situ radical polymerization. The physiochemical properties of composite hydrogels were measured, the cytotoxicity of hydrogels was evaluated by L929 fibroblasts, and the effect on peripheral nerve regeneration was evaluated via Schwann cells culture in vitro. The results showed that the physiochemical properties of SF/pAM hydrogels could be changed by varying SF concentration and ethanol treatment time, and the mechanical property was enhanced with increasing SF concentration, while the presence of SF in pAM hydrogels and ethanol treatment does not affect hydrogels structure in per se. All the composite hydrogels displayed no obvious cytotoxicity, while the SF/pAM composite hydrogels with 10% SF and 60-min ethanol treatment could obviously accelerate the attachment and proliferation of Schwann cells. Therefore, the SF/pAM composite hydrogels possessed the beneficial properties required for in situ cell scaffolding and may have potential application in peripheral nerve regeneration. PMID- 26111555 TI - Locomotor Ecology of Propithecus verreauxi in Kirindy Mitea National Park. AB - The locomotor behaviour of 2 groups of Propithecus verreauxi (Verreaux's sifaka) was studied over an 8-month period in Kirindy Mitea National Park (KMNP), Madagascar. This paper assesses the major characteristics of their locomotion, focusing on the extent that seasonal variation in climate and habitat, and local variation in habitat, is reflected in changes in locomotor behaviour. P. verreauxi is a committed leaper with a strong preference for vertical and angled supports. We found clear between-group differences in support orientation and diameter suggesting local variation in habitat. During the dry season, P. verreauxi utilizes smaller-diameter supports than in the rainy season. While this difference cannot yet be ascribed to any single cause, we discuss the factors which may contribute to this result. PMID- 26111556 TI - Brodifacoum induces early hemoglobinuria and late hematuria in rats: novel rapid biomarkers of poisoning. AB - INTRODUCTION: Brodifacoum (BDF) is a superwarfarin that is used primarily as a rodenticide. There have been increasing numbers of reports of human cases of accidental or intentional BDF ingestion with high mortality rate. Its broad availability and high lethality suggest that BDF should be considered a potential chemical threat. Currently, there is no biomarker for early detection of BDF ingestion in humans; patients typically present with severe coagulopathy. Since we demonstrated earlier that warfarin can induce acute kidney injury with hematuria, we tested whether BDF would also lead to change in urinary biomarkers. MATERIAL AND METHODS: BDF was administered to Sprague Dawley rats via oral gavage. N-acetylcysteine (NAC) was given per os in drinking water 24 h prior to BDF. Urinalysis was performed at different times after BDF administration. Anticoagulation and serum creatinine levels were analyzed in the blood. RESULTS: We observed that within a few hours the animals developed BDF-dose-dependent transient hemoglobinuria, which ceased within 24 h. This was accompanied by a transient decrease in hematocrit, gross hemolysis and an increase in free hemoglobin in the serum. At later times, animals developed true hematuria with red blood cells in the urine, which was associated with BDF anticoagulation. NAC prevented early hemoglobinuria, but not late hematuria associated with BDF. CONCLUSIONS: We propose that transient early hemoglobinuria (associated with oxidative stress) with consecutive late hematuria (associated with anticoagulation) are novel biomarkers of BDF poisoning, and they can be used in clinical setting or in mass casualty with BDF to identify poisoned patients. PMID- 26111557 TI - Fracture Resistance of Roots Restored with Four Different Fiber-Reinforced Composite Posts. AB - OBJECTIVE: The aim of this study was to compare the resistance to vertical root fracture of root-filled teeth restored with four different fiber-reinforced composite (FRC) post systems and two types of dual-cured resin luting agents. MATERIALS AND METHODS: Ninety extracted human maxillary central incisors were selected and decoronated to obtain a standardized root length of 14 mm. After root canal obturation, post spaces were prepared to a depth of 10 mm with a No. 3 post drill. The specimens (n = 80) were divided into two groups (n = 40) according to the resin luting agents used: group 1, Variolink II + ExciTE DSC; group 2, RelyX Unicem. These groups were subdivided into four subgroups (n = 10) and restored with one of the following post systems: (a) DT Light, (b) DT Light SL, (c) FRC Postec and (d) Everstick, while the remaining 10 teeth served as controls. The roots were subjected to axial compressive loading using a 2.2-mm diameter metal sphere in a universal testing machine (0.5 mm/min). A factorial experiment with a single control group (analysis of variance) was used to test the resistance of the specimens. RESULTS: Groups 2a (DT Light + RelyX Unicem; 398.5 N) and 1b (DT Light SL + Variolink II + ExciTE DSC; 431.1 N) had significantly higher resistance to fracture than the control group (334.1 N; p < 0.05). DT Light SL and FRC Postec Plus were more resistant to fracture when Variolink II was used as the luting cement. DT Light and Everstick had higher fracture resistance when they were luted with RelyX Unicem (p < 0.05). CONCLUSION: The results of this study indicate that the use of quartz fiber posts (DT Light and DT Light SL) with an adhesive luting cement in root-filled teeth may reinforce the root to some extent. PMID- 26111558 TI - Global Prevalence of Small for Gestational Age Births. AB - Fetal growth restriction is found both in babies who are preterm or full-term, and in either case has important adverse effects on subsequent survival, health, growth and development. Fetal growth restriction is usually assessed by comparing the weight of the newborn with the expected weight for the child's gestational age using less than the 10th centile of a reference population for fetal growth as the threshold for being called small for gestational age (SGA). We estimate that in 2010 32.4 million babies were born SGA in low- and middle-income countries, constituting 27% of all live births. The estimated prevalence of SGA is highest in South Asia and in Sahelian countries of Africa. India has the world's largest number of SGA births, 12.8 million in 2010, due to the large number of births and the high proportion, 46.9%, of births that are SGA. The prevalence of SGA births is approximately double the prevalence of low birthweight births (using the common indicator of <2,500 g birthweight) globally and in the world's regions. Thus, given the adverse effects of being born SGA, even weighing 2,500 g or more, it is important that maternal, neonatal and child health programs seek and use information on gestational age as well as birthweight to appropriately assess the newborn's risks and direct care. PMID- 26111559 TI - Global Incidence of Preterm Birth. AB - Estimating the incidence of preterm birth depends on accurate assessment of gestational age and pregnancy outcomes. In many countries, such data are not routinely collected, making global estimates difficult. A recent systematic approach to this problem has estimated a worldwide incidence of 11.1 per 100 live births in 2010. Significant variation in rates by country and region of the world was noted, but this variation is smaller than observed for a number of other important reproductive outcomes. Rates range from approximately 5% in some northern European countries to over 15% in some countries in sub-Saharan Africa and Asia. Time trends suggest that preterm birth incidence is increasing, but much of this change may reflect changes in medically induced early delivery practices as improvements in survival of preterm infants has improved. Whether there have been major changes in spontaneous preterm birth is unknown. New approaches to classifying etiologic heterogeneity have been proposed and offer the promise of developing specific interventions to address the range of underlying causes of this important health problem. PMID- 26111561 TI - Mortality Risk among Term and Preterm Small for Gestational Age Infants. AB - Globally, 15% of infants are low birthweight (LBW; <2,500 g) each year. Most LBW infants are either preterm (<37 weeks gestation) and/or growth restricted in utero. These etiologies of LBW have different prevalence, risk factors, health and survival consequences, and are attenuated by different interventions. Birthweight has generally been easier to measure than gestational age in low resource settings. This is now changing rapidly with access to antenatal care and ultrasound and allows providers, researchers and public health practitioners the opportunity to identify infants born too soon or too small, and to better target interventions to reduce mortality and morbidity associated with these conditions. Understanding the mortality patterns and burden of preterm or small for gestational age (SGA) is important for designing programs to prevent these outcomes and improve survival of these infants. We present here estimates of the increased mortality risk, timing of mortality, and attributable mortality burden associated with these conditions. Such data provide estimates of the potential for proven maternal interventions to reduce SGA burden and its associated mortality, as well as identify infants who would most benefit from clinical and public health interventions to improve their survival and health. PMID- 26111560 TI - Nutritional and Reproductive Risk Factors for Small for Gestational Age and Preterm Births. AB - Approximately 32.4 million small for gestational age (SGA) babies and 13.7 million preterm babies are born annually in low- and middle-income countries (LMICs), of whom 2.8 million are both SGA and preterm. These newborns who are born too small and/or too soon not only experience heightened risk of neonatal and infant mortality, but also of long-term morbidities, like adulthood chronic disease. In order to reduce these burdens worldwide, it is critical to identify and understand the epidemiology of the risk factors that contribute to SGA and preterm births. As part of the Child Health Epidemiology Reference Group, we explored nutritional and reproductive health-related maternal risk factors associated with SGA and preterm outcomes in LMICs, including short maternal stature, young/advanced maternal age, low/high parity, and short birth interval. In this chapter, we highlight our findings and relevant existing literature, and also summarize literature on how low/high BMI and low weight gain during pregnancy, respectively, are associated with SGA and/or preterm outcomes. PMID- 26111562 TI - Prevention of Intrauterine Growth Restriction and Preterm Birth with Presumptive Antibiotic Treatment of Pregnant Women: A Literature Review. AB - Intrauterine growth restriction and preterm birth (PTB) account for a large share of global child mortality, morbidity and developmental loss. Of the numerous risk factors for these conditions, maternal infections have been most consistently identified. Our aim was to study if presumptive antibiotic treatment of pregnant women before any signs of the onset of labor would promote fetal growth and reduce the incidence of PTB or low birthweight (LBW). In a systematic literature search, we identified 14 clinical trials of sufficient quality. Eight trials concluded that there was a positive effect on one or both of the conditions, and others found no such association. The trials reporting an effect were typically conducted in Sub-Saharan Africa (6 trials) and with broadest spectrum antibiotics, whereas data from India (2) suggested no intervention effect and trials in the US (5) or Europe (1) yielded both positive and negative findings. We conclude that appropriately chosen presumptive antimicrobial treatment of pregnant women, targeting infections in the reproductive tract but also other maternal infections such as malaria, other parasitic diseases, skin infections, and periodontitis, can in selected contexts promote fetal growth and reduce the incidence of PTB and LBW. PMID- 26111563 TI - Should We Promote Catch-Up Growth or Growth Acceleration in Low-Birthweight Infants? AB - The idea that catch-up growth or growth acceleration has adverse effects on long term health has generated much debate. This pattern of growth is most commonly seen after birth in infants of low birthweight; a global problem affecting over 20 million newborns a year. Faster postnatal growth may have short-term benefits but increases the long-term risk of aging, obesity and metabolic disease. Consequently, the optimal pattern of postnatal growth is unclear and is likely to differ in different populations. In infants born prematurely, faster postnatal growth improves long-term cognitive function but is associated with later risk factors for cardiovascular disease. So, on balance, the current policy is to promote faster growth by increasing nutrient intake (e.g. using higher-nutrient preterm formulas). Whether the same policy should apply to larger preterm infants is not known. Similarly, in infants from impoverished environments, the short term benefits of faster postnatal growth may outweigh long-term disadvantages. However, whether similar considerations apply to infants from countries in transition is uncertain. For term infants from developed countries, promoting catch-up growth by nutritional supplementation has few advantages for short- or long-term health. Overall therefore, a 'one size fits all' solution for the optimal pattern of postnatal growth is unlikely. PMID- 26111564 TI - Catch-Up Growth and Metabolic and Cognitive Outcomes in Adolescents Born Preterm. AB - The worldwide rate of premature birth is increasing. Survival has also improved, even for very preterm infants, meaning greater numbers of preterm infants surviving into later life. This has led to greater attention being focused on long-term outcomes. Recent interest in the Developmental Origins of Health and Disease has highlighted the importance of early life growth and nutritional exposures for chronic diseases such as cardiovascular disease, osteoporosis and type 2 diabetes. There is evidence linking preterm birth and poor growth in utero with worse long-term cognitive outcome, but also evidence to link more rapid growth in certain epochs of early life with adverse metabolic outcomes. The current data suggest that a diverse range of metabolic outcomes are affected by preterm birth, and that adult survivors may be more likely to develop certain chronic diseases. There are data to show that catch-up growth during the neonatal period and in infancy may affect these later outcomes, but studies are inconsistent in their findings. In addition, it is clear that lifestyle factors during childhood and adolescence have a major impact on metabolic disease that may be greater in magnitude to the effects of early growth and nutritional exposures. PMID- 26111565 TI - Role of Specific Nutrients in Low-Birthweight Infants. AB - Low birthweight (LBW) is defined by the World Health Organization (WHO) as body weight less than 2,500 g at birth based on epidemiological observations that infants with a birthweight less than 2,500 g are 20 times more likely to die than 'heavier' babies [1]. Moreover, according to the WHO, a birthweight below 2,500 g contributes to poor health outcomes. Worldwide, the incidence of LBW is estimated to be 15.5% with a range from 7 to 18.6% based on more developed, less developed and least developed countries. In addition to discussing causes and consequences of LBW, this chapter will discuss specific nutrients that need particular attention in this cohort of infants: calcium, phosphorus, magnesium, vitamin D, iron, copper, zinc and issues related to feeding these infants including the use of human milk. Since LBW is an important public health indicator of long-term maternal malnutrition, maternal health, poor prenatal care and, in addition, poses significant challenges in feeding and growth, this large population, globally, deserves particular attention. PMID- 26111567 TI - Stunting Persists despite Optimal Feeding: Are Toilets Part of the Solution? AB - Children in developing countries have an average length-for-age that is already below the World Health Organization standard at birth and show a further decline in linear growth over the first 24 months of life; however, complementary feeding interventions have only a modest impact on growth. Children living in conditions of poor sanitation and hygiene are frequently exposed to pathogenic microbes through feco-oral transmission. Acute diarrhea represents only the tip of the 'enteric disease iceberg', with a substantial underlying burden of chronic, subclinical enteropathy. Environmental enteric dysfunction (EED) is characterized by disturbance in small intestinal structure and impaired gut barrier function, enabling microbial translocation and chronic systemic inflammation, which may impair growth. Gut damage appears to arise early in infancy and markers of intestinal inflammation, intestinal permeability and systemic immune activation are inversely associated with linear growth. Reducing feco-oral microbial transmission by improving water, sanitation and hygiene (WASH) may theoretically prevent or ameliorate EED and improve linear growth; ongoing trials are exploring this hypothesis. Given the complex interplay of factors leading to stunting, multisectoral interventions are likely required. Improving WASH in addition to infant feeding may be one approach to improve the growth and developmental potential of infants in developing countries. PMID- 26111566 TI - Catch-Up Growth: Basic Mechanisms. AB - The neuroendocrine model of catch-up growth has been well studied in a number of animal models. During nutritional inadequacy, which invariably precedes catch-up growth, growth hormone (GH) levels increase under the influence of the oxygenic 'hunger signal' ghrelin. This increase in GH would usually be accompanied by an increase in IGF-1. However, malnutrition also induces the nutritionally responsive proteins sirtuin 1 (SIRT1) and fibroblast growth factor 21 (FGF21) that block GH signal transduction in the liver by blocking the JAK/STAT pathway, limiting IGF-1 production. The result is that GH's action is shifted from hepatic effects to effects in other tissues (for example muscle and adipose) and shifted away from IGF-1-mediated effects and towards GH-mediated effects. Once nutrients become more available, SIRT1 and FGF21 levels, and hepatic GH sensitivity return to normal, and production of IGF-1 resumes. This shifts GH signaling away from GH mediated effects, and towards IGF-1-mediated effects both in the liver and in other tissues. It presumably leads to greatly increased IGF-1 signaling that would have been expected without the prior episode of nutritional inadequacy. Although much work remains to be done, it does appear that ghrelin is increased in in utero and postnatal malnutrition, that elevations in ghrelin may be prolonged after malnutrition resolves, and that higher ghrelin levels are associated with increased rates of catch-up growth. Prolonged increases in circulating ghrelin and GH, combined with a rapid return in hepatic GH sensitivity would provide an elegant mechanism to drive catch-up growth after periods of nutritional insufficiency. PMID- 26111568 TI - Human Milk Fortification. AB - Human milk is the feed of choice for preterm infants. However, human milk does not provide enough nutrition, especially protein, for preterm infants to achieve target growth rates similar to those in utero (15-20 g/kg per day). Fortifiers for human milk, manufactured from bovine milk, are commercially available and routinely used for patients born <32 weeks' gestation prior to discharge home. Recent recommended dietary intakes (RDI) have been revised. Up to 4.2 g of protein and 135 kcal/kg per day is recommended for infants born very preterm. Additional supplements are needed to current commercial fortifiers to achieve these RDI and reduce the incidence of ex-uterine growth failure. A human milk fortifier that is manufactured from donor human milk is available in some developed countries and may confer some clinical benefits, including a reduction in necrotizing enterocolitis. Fortification can be added in a standardized protocol as per manufacturers' instructions. Human milk composition can be analyzed and fortification individualized to take into account the large variation from mother to mother. Alternatively, fortification can be increased in a stepwise manner based on assumed composition while monitoring blood urea levels for safety. The current aim is to prevent preterm infants dropping percentiles and falling below the 10th percentile at 36 weeks' corrected gestational age or discharge home. More data are required on how best to fortify human milk for preterm infants to achieve optimal growth, development and health outcomes in the long term. There is an urgent need for well-designed and informed randomized clinical trials in this vulnerable preterm population. PMID- 26111569 TI - Feeding the Larger Low-Birthweight Infant in a Resource-Poor Environment. AB - The high low birthweight prevalence in resource-poor countries (16.5%) places a burden on overstretched resources. Labor ward must have written guidelines to triage these infants for optimal nutritional support to the special care nursery (SCN; 1,500-1,800 g and <34 weeks) and postnatal ward (PW; >1,800 g and >= 34 weeks). Separation of mother and infant should be prevented. Initiating breastfeeding and kangaroo mother care (KMC) in labor ward by skilled nurses in the latter group is a priority and continues in the PW. SCN infants receive an intravenous 10% glucose-electrolyte solution and, if stable, commence with expressed colostrum and breast milk (EBM) feeding and intermittent KMC which progresses to continuous KMC and breastfeeding. Enteral feeding is advanced more slowly in unstable infants. Parenteral nutrition is only administered to infants with bowel obstruction or feeding intolerance. EBM of HIV+ mothers in the SCN is pasteurized. The decision to discharge a mother-infant dyad should be individualized. Infants in the SCN are discharged at 34 weeks, a weight of 1,600 1,800 g and are gaining adequate weight. Discharge from the PW usually takes place after 48 h, often before the infant has regained his birthweight but breastfeeding must be established. Multivitamin- and iron-containing syrup is continued for at least 12 months. The clinics in the community must provide postdischarge nutritional support. PMID- 26111570 TI - Nutrient Needs for Catch-Up Growth in Low-Birthweight Infants. AB - Growth restriction among low-birthweight (LBW) infants occurs prenatally as well as postnatally. Regardless of when and how the growth restriction occurs, growth restricted infants have the potential for catch-up growth. Catch-up growth has decidedly beneficial effects on later cognition. It also may have adverse effects on cardiovascular and metabolic health. Although the benefits for later cognition are well documented in a number of studies, growth-restricted LBW infants often do not experience catch-up growth and therefore do not enjoy its benefits. One reason is that for catch-up growth to occur, extraordinarily high protein intakes are required. Nutrient intakes have been estimated with the use of the factorial method based on the assumption that catch-up growth comprises essentially a restoration of lean body mass, with restoration of fat mass optional. The basic (no catch-up) nutritional needs of growth-restricted LBW infants are altered to a modest degree, with energy needs increased and protein needs decreased. With catch-up, however, protein needs are increased sharply. Since energy needs are only modestly increased, the protein/energy ratio of requirements is appreciably increased. The high protein needs are difficult to meet with the usual feedings for LBW infants unless special measures are taken to increase protein intakes and to increase the protein/energy ratio. Without the necessary protein intake, catch up growth is not possible or will be delayed, which may compromise the realization of the long-term benefits on cognition. PMID- 26111571 TI - Human Milk Fortification in India. AB - Human milk fortification in preterm babies has become a standard of care in developed countries. Use of human milk fortifier (HMF) in very-low-birthweight infants is not a routine practice in India. There are concerns about high osmolality, feed intolerance, necrotizing enterocolitis, risk of contamination and added cost associated with use of HMF. There are limited data from India which address the issue of safety and short-term benefits of human milk fortification. This chapter highlights the issues related to human milk fortification in our country. PMID- 26111572 TI - Probiotic Supplementation for Preterm Neonates--What Lies Ahead? AB - Systematic reviews of randomized controlled trials indicate that probiotic supplementation significantly reduces the risk of necrotizing enterocolitis (NEC) without adverse effects in preterm very-low-birthweight neonates. A change in practice in favor of probiotic supplementation is justified considering the health burden of NEC in this population. The reduction in the risk of NEC seems to occur even when the baseline incidence of the illness is as low as 5%. Facilitation of feed tolerance is a significant benefit of probiotics considering that optimizing enteral nutrition is a priority in extremely preterm neonates, including those with intrauterine growth restriction, who are at a higher risk for feed intolerance and NEC. The increasing number of reports on routine use of probiotics indicates that difficulty in accessing clinically proven and safe probiotic products is not a significant barrier towards a change in practice. Strategies to address important gaps in knowledge and the impact of routine use of probiotic supplementation are reviewed to prepare for what lies ahead in this field. PMID- 26111573 TI - Concluding Remarks. PMID- 26111574 TI - Dermoscopic Features of Onychomatricoma: A Study of 34 Cases. AB - BACKGROUND: Onychomatricoma is a benign tumor of the nail matrix with a precise histopathological definition but many different clinical features and differential diagnoses. OBJECTIVES: The diagnosis of onychomatricoma is based on the pathological examination of a surgical specimen. The objective of this study was to define preoperative diagnostic criteria using noninvasive investigations: observation and dermoscopy. METHODS: A total of 34 cases of onychomatricoma were studied. In detail, 6 observers evaluated 12 clinical and 12 dermoscopical criteria as present or absent. RESULTS: For clinical criteria, the highest mean values were leuconychia (3.21), splinter hemorrhages (3.45), and thickening of the plate (3.0). Dermoscopical criteria were more often found present, such as longitudinal parallel white lines (4.33), parallel lesion edges (4.61), splinter hemorrhages (4.48), dark dots (3.96), free-edge nail pitting (4.5), and thickening of the free edge (5.27). CONCLUSION: Dermoscopical criteria for onychomatricoma are more frequently present and less subject to divergent interpretation. This offers new and original preoperative reliable diagnostic criteria and should be used in the evaluation of nail tumors. PMID- 26111575 TI - Intravitreal Ranibizumab in Daily Clinical Practice for Age-Related Macular Degeneration: Treatment of Exudative Age-Related Macular Degeneration in Real Life. AB - PURPOSE: To describe the anatomical and functional outcomes in patients with exudative age-related macular degeneration (AMD) undergoing ranibizumab therapy in real-life practice. METHODS: This is a retrospective analysis of patients with exudative AMD treated with ranibizumab. Visual acuity (VA) and optic coherence tomography characteristics at baseline and at the end of the follow-up, clinical forms of the disease, delay between diagnosis and treatment as well as the number of follow-up visits and of intravitreal injections were collected. RESULTS: One hundred and seventy-nine patients (220 eyes) were followed up during a mean of 24 months. The mean delay between diagnosis and treatment was 20.3 days (SD +/ 16.8). VA stabilization was observed in 46.4% of eyes, 21.7% of eyes gained >=15 ETDRS (Early Treatment Diabetic Retinopathy Study) letters and 31.9% lost >=15 ETDRS letters. The mean central retinal thickness decreased from 380.6 MUm at baseline to 295.6 um at the final examination. A lower baseline VA score was associated with a greater gain of letters (OR 1.04, 95% CI 1.02-1.06; p < 0.001). CONCLUSION: Shortening the delays in diagnosis appears to be a key point in real life situations. PMID- 26111576 TI - Autophagy is Required for the Maintenance of Liver Progenitor Cell Functionality. AB - BACKGROUND: Liver progenitor cells (LPCs) are bipotent stem cells existing in the adult liver, which could be activated upon massive liver injury and contribute to liver regeneration. However, mechanisms of maintenance of LPC functionality remain poorly understood. Previous studies found that autophagy was required for the self-renewal and differentiation of several tissue stem cells. METHODS: The study compared the level of autophagic activity in LPCs and differentiated hepatocytes. Then, autophagic activity was inhibited in LPCs by lentivirus mediated autophagy-related gene 5 or Beclin 1 knockdown. Clonogenic assay, cell viability assays, hepatic differentiation assay, and senescence analysis were conducted to assess the role of autophagy in regulating self-renewal, hepatic differentiation and senescence of LPCs. RESULTS: We observed high autophagic activity in LPCs compared with differentiated hepatocytes. We found that inhibition of autophagy impaired the self-renewal, proliferation, and hepatic differentiation capability of LPCs under normal cultural condition, but had little impact on cell viability. Interestingly, while wild-type LPCs remained rarely affected by the toxin, etoposide, inhibition of autophagy induced the senescent phenotype of LPCs. Overexpression of Beclin 1 in Beclin 1-knockdown LPCs restored the functionality of stem cells. CONCLUSION: Our findings indicate that autophagy may function as a critical regulator of LPC functionality under both physiological and pathological condition. PMID- 26111577 TI - Lurasidone in the treatment of schizophrenia: a critical evaluation. AB - INTRODUCTION: Antipsychotic medications are the foundation of the pharmacological treatment of schizophrenia and lurasidone is the most recent of the 65 agents around the world to become available. In order to use it optimally, it is important to understand its pharmacological and clinical nature and its comparative effectiveness to other antipsychotic agents in the treatment of schizophrenia. AREAS COVERED: Following a comprehensive review of the literature, this article summarizes current information about the pharmacology of lurasidone, data about its short- and long-term efficacy and safety/tolerability in the treatment of schizophrenia, its comparative effectiveness to other antipsychotic agents, and guidance about its optimal use in the treatment of individuals with schizophrenia. EXPERT OPINION: Lurasidone is a benzoisothiazole with potent dopamine D2 and serotonin 5HT2A antagonist and serotonin 5HT1A partial agonist properties (like other second-generation antipsychotic agents) with additional potent 5HT7 and alpha2C noradrenergic antagonism. It has little or no activity at the alpha1 and alpha2A noradrenergic, 5HT2C serotonergic, histaminergic and cholinergic receptors. Available only in an oral formulation, it is effective in once-daily dosing (40 - 160 mg/day) and its absorption is affected by food. There is an extensive clinical trial database with short-term and long-term placebo- and antipsychotic-controlled clinical trials evaluating the efficacy and safety/tolerability of lurasidone in the treatment of schizophrenia. It has been found to be efficacious with comparable efficacy to other agents in the treatment of acute psychosis and prevention of relapse in individuals with schizophrenia. The greater antidepressant and cognitive benefits suggested by its receptor profile need substantiation in robust clinical trials. It is less likely to cause metabolic and cardiac adverse effects than most other second-generation agents and is associated with a modest risk of extrapyramidal side-effects, akathisia, and prolactin elevation. PMID- 26111580 TI - From cutting edge to guideline: A first step in harmonization of the zebrafish embryotoxicity test (ZET) by describing the most optimal test conditions and morphology scoring system. AB - In the last couple of years, the interest in the zebrafish embryotoxicity test (ZET) for use in developmental toxicity assessment has been growing exponentially. This is also evident from the recent proposal for updating the ICHS5 guideline. The methodology of the ZET used by the different groups varies greatly. To further evaluate its successfulness and to take the ZET to the next level, harmonization of procedures is crucial. In the present study, based on literature and empirical data, the most optimal study design regarding temperature, test chamber, exposure period, presence of chorion, solvent use, exposure method, choice of concentrations, and teratogenic classification is proposed. Furthermore, our morphology scoring system is reported in detail as protocol to further enhance study design harmonization. PMID- 26111579 TI - alpha2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) are the primary binding sites for nicotine within the brain. Using alpha(alpha)2 nAChR subunit-null mutant mice, the current study evaluates whether the absence of this gene product during mecamylamine-precipitated nicotine withdrawal eliminates neuronal activity within selective midbrain and limbic brain regions, as determined by the expression of the immediate early gene, cfos. Our results demonstrate that nicotine withdrawal enhances neuronal activity within the interpeduncular nucleus and dorsal hippocampus, which is absent in mice null for alpha2-containing nAChRs. In contrast, we observe that alpha2-null mutant mice exhibit a suppression of neuronal activity in the dentate gyrus in mice undergoing nicotine withdrawal. Interestingly, alpha2-null mutant mice display potentiated neuronal activity specifically within the stratum lacunosum moleculare layer of the hippocampus, independent of nicotine withdrawal. Overall, our findings demonstrate that alpha2 null mutant mice have altered cfos expression in distinct populations of neurons within selective midbrain and limbic brain structures that mediate baseline and nicotine withdrawal-induced neuronal activity. PMID- 26111581 TI - Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension. AB - The Pregnancy Prevention Program (PPP) is in place to prevent drug-induced developmental malformations. Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERA's: ambrisentan, bosentan and macitentan), which are approved for the treatment of Pulmonary Arterial Hypertension (PAH). This review describes the effects of ERA's in PAH pathobiology and cardiopulmonary fetal development. While ERA's hamper pathological remodeling of the pulmonary vasculature and as such exert beneficial effects in PAH, they disturb fetal development of cardiopulmonary tissues. By blocking ET-1-mediated positive inotropic effects and myocardial fetal gene induction, ERA's may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the fetus and the adult PAH patient. PMID- 26111582 TI - Interchange of entire communities: microbial community coalescence. AB - Microbial communities are enigmatically diverse. We propose a novel view of processes likely affecting microbial assemblages, which could be viewed as the Great American Interchange en miniature: the wholesale exchange among microbial communities resulting from moving pieces of the environment containing entire assemblages. Incidental evidence for such 'community coalescence' is accumulating, but such processes are rarely studied, likely because of the absence of suitable terminology or a conceptual framework. We provide the nucleus for such a conceptual foundation for the study of community coalescence, examining factors shaping these events, links to bodies of ecological theory, and we suggest modeling approaches for understanding coalescent communities. We argue for the systematic study of community coalescence because of important functional and applied consequences. PMID- 26111583 TI - Symbiotic options for the conquest of land. AB - The domination of the landmasses of Earth by plants starting during the Ordovician Period drastically altered the development of the biosphere and the composition of the atmosphere, with far-reaching consequences for all life ever since. It is widely thought that symbiotic soil fungi facilitated the colonization of the terrestrial environment by plants. However, recent discoveries in molecular ecology, physiology, cytology, and paleontology have brought into question the hitherto-assumed identity and biology of the fungi engaged in symbiosis with the earliest-diverging lineages of extant land plants. Here, we reconsider the existing paradigm and show that the symbiotic options available to the first plants emerging onto the land were more varied than previously thought. PMID- 26111584 TI - It is time to develop ecological thresholds of toxicological concern to assist environmental hazard assessment. AB - The threshold of toxicological concern (TTC) concept is well established for assessing human safety of food-contact substances and has been reapplied for a variety of endpoints, including carcinogenicity, teratogenicity, and reproductive toxicity. The TTC establishes an exposure level for chemicals below which no appreciable risk to human health or the environment is expected, based on a de minimis value for toxicity identified for many chemicals. Threshold of toxicological concern approaches have benefits for screening-level risk assessments, including the potential for rapid decision-making, fully utilizing existing knowledge, reasonable conservativeness for chemicals used in lower volumes (low production volume chemicals (e.g., < 1 t/yr), and reduction or elimination of unnecessary animal tests. Higher production volume chemicals (>1 t/yr) would in principle always require specific information because of the presumed higher exposure potential. The TTC approach has found particular favor in the assessment of chemicals used in cosmetics and personal care products, as well as other chemicals traditionally used in low volumes. Use of the TTC in environmental safety is just beginning, and initial attempts are being published. Key questions focus on hazard extrapolation of diverse taxa across trophic levels, importance of mode of action, and whether safe concentrations for ecosystems estimated from acute or chronic toxicity data are equally useful and in what contexts. The present study provides an overview of the theoretical basis for developing an ecological (eco)-TTC, with an initial exploration of chemical assessment and boundary conditions for use. An international collaboration under the International Life Sciences Institute Health and Environmental Sciences Institute has been established to address challenges related to developing and applying useful eco-TTC concepts. PMID- 26111585 TI - Bean Common Mosaic Virus and Bean Common Mosaic Necrosis Virus: Relationships, Biology, and Prospects for Control. AB - The closely related potyviruses Bean common mosaic virus (BCMV) and Bean common mosaic necrosis virus (BCMNV) are major constraints on common bean (Phaseolus vulgaris) production. Crop losses caused by BCMV and BCMNV impact severely not only on commercial scale cultivation of this high-value crop but also on production by smallholder farmers in the developing world, where bean serves as a key source of dietary protein and mineral nutrition. In many parts of the world, progress has been made in combating BCMV through breeding bean varieties possessing the I gene, a dominant gene conferring resistance to most BCMV strains. However, in Africa, and in particular in Central and East Africa, BCMNV is endemic and this presents a serious problem for deployment of the I gene because this virus triggers systemic necrosis (black root disease) in plants possessing this resistance gene. Information on these two important viruses is scattered throughout the literature from 1917 onward, and although reviews on resistance to BCMV and BCMNV exist, there is currently no comprehensive review on the biology and taxonomy of BCMV and BCMNV. In this chapter, we discuss the current state of our knowledge of these two potyviruses including fundamental aspects of classification and phylogeny, molecular biology, host interactions, transmission through seed and by aphid vectors, geographic distribution, as well as current and future prospects for the control of these important viruses. PMID- 26111586 TI - The Molecular Biology of Pestiviruses. AB - Pestiviruses are among the economically most important pathogens of livestock. The biology of these viruses is characterized by unique and interesting features that are both crucial for their success as pathogens and challenging from a scientific point of view. Elucidation of these features at the molecular level has made striking progress during recent years. The analyses revealed that major aspects of pestivirus biology show significant similarity to the biology of human hepatitis C virus (HCV). The detailed molecular analyses conducted for pestiviruses and HCV supported and complemented each other during the last three decades resulting in elucidation of the functions of viral proteins and RNA elements in replication and virus-host interaction. For pestiviruses, the analyses also helped to shed light on the molecular basis of persistent infection, a special strategy these viruses have evolved to be maintained within their host population. The results of these investigations are summarized in this chapter. PMID- 26111587 TI - Cyprinid Herpesvirus 3: An Archetype of Fish Alloherpesviruses. AB - The order Herpesvirales encompasses viruses that share structural, genetic, and biological properties. However, members of this order infect hosts ranging from molluscs to humans. It is currently divided into three phylogenetically related families. The Alloherpesviridae family contains viruses infecting fish and amphibians. There are 12 alloherpesviruses described to date, 10 of which infect fish. Over the last decade, cyprinid herpesvirus 3 (CyHV-3) infecting common and koi carp has emerged as the archetype of fish alloherpesviruses. Since its first description in the late 1990s, this virus has induced important economic losses in common and koi carp worldwide. It has also had negative environmental implications by affecting wild carp populations. These negative impacts and the importance of the host species have stimulated studies aimed at developing diagnostic and prophylactic tools. Unexpectedly, the data generated by these applied studies have stimulated interest in CyHV-3 as a model for fundamental research. This review intends to provide a complete overview of the knowledge currently available on CyHV-3. PMID- 26111588 TI - Human Immunodeficiency Virus Type 1 Cellular Entry and Exit in the T Lymphocytic and Monocytic Compartments: Mechanisms and Target Opportunities During Viral Disease. AB - During the course of human immunodeficiency virus type 1 infection, a number of cell types throughout the body are infected, with the majority of cells representing CD4+ T cells and cells of the monocyte-macrophage lineage. Both types of cells express, to varying levels, the primary receptor molecule, CD4, as well as one or both of the coreceptors, CXCR4 and CCR5. Viral tropism is determined by both the coreceptor utilized for entry and the cell type infected. Although a single virus may have the capacity to infect both a CD4+ T cell and a cell of the monocyte-macrophage lineage, the mechanisms involved in both the entry of the virus into the cell and the viral egress from the cell during budding and viral release differ depending on the cell type. These host-virus interactions and processes can result in the differential targeting of different cell types by selected viral quasispecies and the overall amount of infectious virus released into the extracellular environment or by direct cell-to-cell spread of viral infectivity. This review covers the major steps of virus entry and egress with emphasis on the parts of the replication process that lead to differences in how the virus enters, replicates, and buds from different cellular compartments, such as CD4+ T cells and cells of the monocyte-macrophage lineage. PMID- 26111590 TI - Random serum progesterone threshold to confirm ovulation. AB - BACKGROUND: Serum progesterone (P) rises after ovulation in the luteinisation process. OBJECTIVE: To identify an accurate progesterone threshold to confirm ovulation in the assessment of a woman's fertility. METHODS: In a secondary analysis of an observational European multicentre study, this study included 107 women over 326 menstrual cycles and tracked daily first morning urine (FMU), changes in observed cervical mucus discharge, serum progesterone, and ultrasonography to identify the day of ovulation. A serum progesterone level was available for 102 women over a total 260 cycles with one or two P levels per cycle. RESULTS: It was found that a single serum P?5ng/ml is highly specific with a specificity of 98.4 (95% CI 96.0-99.5), with a sensitivity of 89.6 (95% CI 85.2 92.9). CONCLUSION: A random serum progesterone level ?5ng/ml confirms ovulation. This may be of use for clinicians wanting to confirm that ovulation has occurred. PMID- 26111589 TI - Maternal characteristics and mid-pregnancy serum biomarkers as risk factors for subtypes of preterm birth. AB - OBJECTIVE: To examine the relationship between maternal characteristics, serum biomarkers and preterm birth (PTB) by spontaneous and medically indicated subtypes. DESIGN: Population-based cohort. SETTING: California, United States of America. POPULATION: From a total population of 1 004 039 live singleton births in 2009 and 2010, 841 665 pregnancies with linked birth certificate and hospital discharge records were included. METHODS: Characteristics were compared for term and preterm deliveries by PTB subtype using logistic regression and odds ratios adjusted for maternal characteristics and obstetric factors present in final stepwise models and 95% confidence intervals. First-trimester and second trimester serum marker levels were analysed in a subset of 125 202 pregnancies with available first-trimester and second-trimester serum biomarker results. MAIN OUTCOME MEASURE: PTB by subtype. RESULTS: In fully adjusted models, ten characteristics and three serum biomarkers were associated with increased risk in each PTB subtype (Black race/ethnicity, pre-existing hypertension with and without pre-eclampsia, gestational hypertension with pre-eclampsia, pre-existing diabetes, anaemia, previous PTB, one or two or more previous caesarean section(s), interpregnancy interval >= 60 months, low first-trimester pregnancy associated plasma protein A, high second-trimester alpha-fetoprotein, and high second-trimester dimeric inhibin A). These risks occurred in 51.6-86.2% of all pregnancies ending in PTB depending on subtype. The highest risk observed was for medically indicated PTB <32 weeks in women with pre-existing hypertension and pre eclampsia (adjusted odds ratio 89.7, 95% CI 27.3-111.2). CONCLUSIONS: Our findings suggest a shared aetiology across PTB subtypes. These commonalities point to targets for further study and exploration of risk reduction strategies. TWEETABLE ABSTRACT: Findings suggest a shared aetiology across preterm birth subtypes. Patterns may inform risk reduction efforts. PMID- 26111591 TI - Marine steroids as potential anticancer drug candidates: In silico investigation in search of inhibitors of Bcl-2 and CDK-4/Cyclin D1. AB - Star fishes (Asteroidea) are rich in polar steroids with diverse structural characteristics. The structural modifications of star fish steroids occur at 3beta, 4beta, 5alpha, 6alpha (or beta), 7alpha (or beta), 8, 15alpha (or beta) and 16beta positions of the steroidal nucleus and in the side chain. Widely found polar steroids in starfishes include polyhydroxysteroids, steroidal sulfates, glycosides, steroid oligoglycosides etc. Bioactivity of these steroids is less studied; only a few reports like antibacterial, cytotoxic activity etc. are available. In continuation of our search for bioactive molecules from natural sources, we undertook in silico screening of steroids from star fishes against Bcl-2 and CDK-4/Cyclin D1 - two important targets of progression and proliferation of cancer cells. We have screened 182 natural steroids from star fishes occurring in different parts of the world and their 282 soft-derivatives by in silico methods. Their physico-chemical properties, drug-likeliness, binding potential with the selected targets, ADMET (absorption, distribution, metabolism, toxicity) were predicted. Further, the results were compared with those of existing steroidal and non steroidal drugs and inhibitors of Bcl-2 and CDK 4/Cyclin D1. The results are promising and unveil that some of these steroids can be potent leads for cancer treatments. PMID- 26111592 TI - Cognitive cues are more compelling than facial cues in determining adults' reactions towards young children. AB - Previous research has demonstrated the significant influence that both children's facial features (Lorenz, 1943) and children's cognitive expressions (Bjorklund, Hernandez Blasi, and Periss, 2010) have on adults' perception of young children. However, until now, these two types of cues have been studied independently. The present study contrasted these two types of cues simultaneously in a group of college students. To this purpose, we designed five experimental conditions (Consistent, Inconsistent, Mature-Face, Immature-Face, and Faces-Only) in which we varied the presentation of a series of mature and immature vignettes (including two previously studied types of thinking: natural thinking and supernatural thinking) associated with a series of more mature and less mature children's faces. Performance in these conditions was contrasted with data from a Vignettes-Only condition taken from Bjorklund et al. (2010). Results indicated that cognitive cues were more powerful than facial cues in determining adults' perceptions of young children. From an evolutionary developmental perspective, we suggest that facial cues are more relevant to adults during infancy than during the preschool period, when, with the development of spoken language, the verbalized expressions of children's thoughts become the principal cues influencing adults' perceptions, with facial cues playing a more secondary role. PMID- 26111593 TI - Diversity of endophytic fungi in Glycine max. AB - Endophytic fungi are microorganisms that live within plant tissues without causing disease during part of their life cycle. With the isolation and identification of these fungi, new species are being discovered, and ecological relationships with their hosts have also been studied. In Glycine max, limited studies have investigated the isolation and distribution of endophytic fungi throughout leaves and roots. The distribution of these fungi in various plant organs differs in diversity and abundance, even when analyzed using molecular techniques that can evaluate fungal communities in different parts of the plants, such as denaturing gradient gel electrophoresis (DGGE). Our results show there is greater species richness of culturable endophytic filamentous fungi in the leaves G. max as compared to roots. Additionally, the leaves had high values for diversity indices, i.e. Simpsons, Shannon and Equitability. Conversely, dominance index was higher in roots as compared to leaves. The fungi Ampelomyces sp., Cladosporium cladosporioides, Colletotrichum gloeosporioides, Diaporthe helianthi, Guignardia mangiferae and Phoma sp. were more frequently isolated from the leaves, whereas the fungi Fusarium oxysporum, Fusarium solani and Fusarium sp. were prevalent in the roots. However, by evaluating the two communities by DGGE, we concluded that the species richness was higher in the roots than in the leaves. UPGMA analysis showed consistent clustering of isolates; however, the fungus Leptospora rubella, which belongs to the order Dothideales, was grouped among species of the order Pleosporales. The presence of endophytic Fusarium species in G. max roots is unsurprising, since Fusarium spp. isolates have been previously described as endophyte in other reports. However, it remains to be determined whether the G. max Fusarium endophytes are latent pathogens or non pathogenic forms that benefit the plant. This study provides a broader knowledge of the distribution of the fungal community in G. max leaves and roots, and identifies the genetic relationships among the isolated species. PMID- 26111594 TI - Opening-Wedge High Tibial Osteotomy: Review of 100 Consecutive Cases. AB - PURPOSE: We report intermediate-term outcomes of a large consecutive series of medial opening-wedge tibial osteotomies. METHODS: One hundred consecutive patients who underwent medial high tibial osteotomy from 2004-2013 were retrospectively reviewed. Charts were reviewed for patient age and gender, knee pain and range of motion, smoking status, and body mass index. Operative reports were reviewed for bone graft type, degree of correction, and osteotomy fixation method. Radiographs were evaluated for lateral cortical or intra-articular fracture, osteotomy healing, and preoperative and postoperative tibiofemoral angles. RESULTS: Eighty-nine osteotomies (89%) in 83 patients were included in the study. Most procedures were performed for medial knee arthritis. The mean age at surgery was 48.1 years, and the mean follow-up period was 4.0 years. The mean tibiofemoral alignment was 3.2 degrees of varus preoperatively and 6.4 degrees of valgus postoperatively. Plate and screw fixation was used in all cases. Bone grafting methods included autograft, allograft, iliac crest aspirate, platelet rich plasma, and demineralized bone matrix. Of the osteotomies, 83 (93%) healed uneventfully. Five nonunions and 1 delayed union occurred. Allograft combined with demineralized bone matrix and/or platelet-rich plasma was associated with nonunion (P = .02). Lateral cortical fracture was associated with repeat surgery for nonunion or alignment loss (P = .02). Pain was minimal or mild in 65% of patients, moderate in 16%, and severe in 19%. Osteotomy fixation with a small 4 screw plate was associated with increased postoperative pain (P = .01). Seven patients underwent arthroplasty an average of 5 years after osteotomy. The need for arthroplasty was associated with longer follow-up (P = .02) and use of a smaller plate (P = .04). CONCLUSIONS: Uncomplicated osteotomy union occurred in 93% of medial opening-wedge high tibial osteotomies. Allograft mixed with demineralized bone matrix and/or platelet-rich plasma was associated with nonunion. At intermediate follow-up, 65% of patients had minimal or mild pain. Seven patients had undergone arthroplasty. Fixation with a smaller plate was associated with increased postoperative pain and the need for subsequent arthroplasty. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26111595 TI - Health-related quality of life in mechanical circulatory support: Development of a new conceptual model and items for self-administration. AB - BACKGROUND: Generic and heart failure (HF)-specific health-related quality of life (HRQOL) instruments do not address unique burdens of mechanical circulatory support (MCS). This report describes (1) a conceptual model of adjustment to MCS and HRQOL, (2) the development of a new set of items to assess adjustment and HRQOL, and (3) establishes content validity of the new model and items. METHODS: We interviewed 15 expert clinicians, 16 patients with advanced HF, and 48 MCS patients. A grounded theory approach was used to systemically examine qualitative data. We developed a coding dictionary, with codes organized under concepts. A conceptual model of adjustment to MCS and HRQOL was developed. A set of relevant items was generated from the codes, concepts, and conceptual model. After items were refined, MCS patients participated in cognitive interviews to provide feedback on their relevance and acceptability. RESULTS: Patients described how having HF and MCS affected their daily lives. Three concepts regarding adjustment to MCS and its relationship to HRQOL emerged: (1) effect of disease and treatment (satisfaction with treatment, symptoms, and self-efficacy regarding self-care), (2) resources, and (3) implant strategy. From our codes, concepts, and model, we developed a set of 652 items that were categorized by concept. The item set was reduced from 652 items to 236 (36%), and 120 of these 236 items (51%) underwent cognitive debriefing. Our final set includes 239 items with evidence of content validity. CONCLUSIONS: Our newly developed model on adjustment to MCS and HRQOL and items will undergo further testing in the future. PMID- 26111596 TI - Improved intervention of atherosclerosis and cardiac hypertrophy through biodegradable polymer-encapsulated delivery of glycosphingolipid inhibitor. AB - D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), a glycosphingolipid synthesis inhibitor, holds promise for the treatment of atherosclerosis and cardiac hypertrophy but rapid in vivo clearance has severely hindered translation to the clinic. To overcome this impediment, we used a materials-based delivery strategy wherein D-PDMP was encapsulated within a biodegradable polymer composed of poly ethylene glycol (PEG) and sebacic acid (SA). PEG-SA was formulated into nanoparticles that were doped with (125)I labeled PEG to allow in vivo bio-distribution and release kinetics of D-PDMP to be determined by using gamma-scintigraphy and subsequently, by mass spectrometry. Polymer-encapsulation increased the residence time of D-PDMP in the body of a treated mouse from less than one hour to at least four hours (and up to 48 h or longer). This substantially increased in vivo longevity provided by polymer encapsulation resulted in an order of magnitude gain in efficacy for interfering with atherosclerosis and cardiac hypertrophy in apoE-/- mice fed a high fat and high cholesterol (HFHC) diet. These results establish that D-PDMP encapsulated in a biodegradable polymer provides a superior mode of delivery compared to unconjugated D-PDMP by way of increased gastrointestinal absorption and increased residence time thus providing this otherwise rapidly cleared compound with therapeutic relevance in interfering with atherosclerosis, cardiac hypertrophy, and probably other diseases associated with the deleterious effects of abnormally high glycosphingolipid biosynthesis or deficient catabolism. PMID- 26111598 TI - Intraosseous lipoma of sacrum. PMID- 26111597 TI - Decision analytic modeling in spinal surgery: a methodologic overview with review of current published literature. AB - BACKGROUND CONTEXT: In recent years, there has been an increase in the number of decision analysis studies in the spine literature. Although there are several published reviews on the different types of decision analysis (cost effectiveness, cost-benefit, cost-utility), there is limited information in the spine literature regarding the mathematical models used in these studies (decision tree, Markov modeling, Monte Carlo simulation). PURPOSE: The purpose of this review was to provide an overview of the types of decision analytic models used in spine surgery. A secondary aim was to provide a systematic overview of the most cited studies in the spine literature. STUDY DESIGN/SETTING: This is a systematic review of the available information from all sources regarding decision analytics and economic modeling in spine surgery. METHODS: A systematic search of PubMed, Embase, and Cochrane review was performed to identify the most relevant peer-reviewed literature of decision analysis/cost-effectiveness analysis (CEA) models including decisions trees, Markov models, and Monte Carlo simulations. Additionally, CEA models based on investigational drug exemption studies were reviewed in particular detail, as these studies are prime candidates for economic modeling. RESULTS: The initial review of the literature resulted in 712 abstracts. After two reviewer-assessment of abstract relevance and methodologic quality, 19 studies were selected: 12 with decision tree constructs and 7 with Markov models. Each study was assessed for methodologic quality and a review of the overall results of the model. A generalized overview of the mathematical construction and methodology of each type of model was also performed. Limitations, strengths, and potential applications to spine research were further explored. CONCLUSIONS: Decision analytic modeling represents a powerful tool both in the assessment of competing treatment options and potentially in the formulation of policy and reimbursement. Our review provides a generalized overview and a conceptual framework to help spine physicians with the construction of these models. PMID- 26111599 TI - Evaluation of bacterial communities by bacteriome analysis targeting 16S rRNA genes and quantitative analysis of ammonia monooxygenase gene in different types of compost. AB - Biofiltration technology based on microbial degradation and assimilation is used for the removal of malodorous compounds, such as ammonia. Microbes that degrade malodorous and/or organic substances are involved in composting and are retained after composting; therefore, mature composts can serve as an ideal candidate for a biofilter medium. In this study, we focused on different types of raw compost materials, as these are important factors determining the bacterial community profile and the chemical component of the compost. Therefore, bacterial community profiles, the abundance of the bacterial ammonia monooxygenase gene (amoA), and the quantities of chemical components were analyzed in composts produced from either food waste or cattle manure. The community profiles with the lowest beta diversity were obtained from single type of cattle manure compost. However, cattle manure composts showed greater alpha diversity, contained higher amounts of various rRNA gene fragments than those of food waste composts and contained the amoA gene by relative quantification, and Proteobacteria were abundantly found and nitrifying bacteria were detected in it. Nitrifying bacteria are responsible for ammonia oxidation and mainly belong to the Proteobacteria or Nitrospira phyla. The quantities of chemical components, such as salt, phosphorus, and nitrogen, differed between the cattle manure and food waste composts, indicating that the raw materials provided different fermentation environments that were crucial for the formation of different community profiles. The results also suggest that cattle manure might be a more suitable raw material for the production of composts to be used in the biofiltration of ammonia. PMID- 26111600 TI - Biogas production from chicken manure at different organic loading rates in a mesophilic-thermopilic two stage anaerobic system. AB - This study investigates the biogas production from chicken manure at different organic loading rates (OLRs), in a mesophilic-thermophilic two stage anaerobic system. The system was operated on semi continuous mode under different OLRs [1.9 g volatile solids (VS)/L.d - 4.7 g VS/L.d] and total solid (TS) contents (3.0 8.25%). It was observed that the anaerobic bacteria acclimatized to high total ammonia nitrogen concentration (>3000 mg/L) originated as a result of the degradation of chicken manure. High volatile fatty acid concentrations were tolerated by the system due to high pH in the reactors. The maximum average biogas production rate was found as 554 mL/g VSfeed while feeding 2.2 g VS/L-d (2.3% VS - 3.8% TS) to the system. Average methane content of produced biogas was 74% during the study. PMID- 26111601 TI - In vitro probiotic profile based selection of indigenous actinobacterial probiont Streptomyces sp. JD9 for enhanced broiler production. AB - The present study was undertaken to select exclusive indigenous actinobacterial probiont for broiler health improvement based on in vitro probiotic potentials. In total, 18 actinobacterial cultures isolated from chicken were screened for survivability (resistance to low pH, pepsin, bile and pancreatin), colonization (auto-aggregation, hydrophobicity and co-aggregation) and safety (antibiotic susceptibility and non-haemolytic activity). Ten cultures showed excellent viability at pH 2 and most of the acid-tolerant isolates exhibited resistance to pepsin (3 mg/mL), bile (0.3%) and pancreatin (1 mg/mL). Besides, the examined isolates displayed efficient adhesion properties. All the isolates were susceptible to 9 different antibiotics and none of them exhibited beta-haemolytic activity. Moreover, the culture JD9 revealed remarkable probiotic features compared to the other isolates, which was identified as Streptomyces sp. JD9 (KF878075). Taken together, the present study suggests that the probiont Streptomyces sp. JD9 could potentially be used in broiler practices as a feed additive to facilitate enhanced broiler production. PMID- 26111602 TI - Direct recovery of cyclodextringlycosyltransferase from Bacillus cereus using aqueous two-phase flotation. AB - Purification of cyclodextrin glycosyl transferase (CGTase) from Bacillus cereus using polyethylene glycol (PEG)-potassium phosphates aqueous two-phase flotation (ATPF) system was studied in this paper. The effects of varying PEG molecular weight, tie-line length (TLL) value, volume ratio (VR), pH value, crude concentration and gas nitrogen flotation time were investigated. The optimal condition for purification of CGTase was attained at 18.0% (w/w) PEG 8000, 7.0% (w/w) potassium phosphates, VR of 3.0, 20% (w/w) crude load at pH 7, and 80 min nitrogen flotation time at a flow rate of 5 L/min. With this optimal condition, purification factor (PFT) of 21.8 and a yield (YT) of 97.1% were attained. CGTase was successfully purified in a single downstream processing step using the ATPF. PMID- 26111603 TI - Sarcocystis rommeli, n. sp. (Apicomplexa: Sarcocystidae) from Cattle (Bos taurus) and its Differentiation from Sarcocystis hominis. AB - Cattle (Bos taurus) are intermediate hosts for three named species of Sarcocystis, S. cruzi, S. hirsuta, and S. hominis. Recently, a fourth species was identified and named S. sinensis. However, S. sinensis originally named a species of Sarcocystis in water buffalo (Bubalus bubalis) in China. Based on unverifiable evidence, it was suggested that the same parasite infects cattle. In addition, S. sinensis was recently declared as nomen nudum because its naming violated the rules of International Code of Zoological Nomenclature. Thus, the fourth species using cattle as an intermediate host does not have a valid name. Here, we propose a new name, Sarcocystis rommeli for the S. sinensis-like parasite from cattle in Argentina, and differentiate it ultrastructurally from S. hominis sarcocysts from experimentally infected cattle. Sarcocystis rommeli sarcocysts were microscopic with a 5-MUm-thick wall with slender villar protrusions (Vp); the Vp were up to 5 MUm long, up to 0.5 MUm wide, and of uneven thickness, often bent at an angle. The ground substance layer (Gs) was up to 0.8 MUm thick and smooth. Vesicular structures were seen at the base of the Vp. The bradyzoites were 10-12 MUm long. Sarcocystis hominis sarcocysts had Vp that were often upright, up to 7.5 MUm long, and up to 1.8 MUm wide; the Gs was up to 2 MUm thick and without vesicles. Its sarcocyst wall was up to 5.6 MUm thick, the vp were bent at an angle, up to 5.8 MUm long, the Gs was up to 2 MUm thick, but without vesicles seen in S. rommeli. Beef containing sarcocysts of S. rommeli was not orally infectious for two human volunteers and a red fox (Vulpes vulpes). The Sarcocystis described here is molecularly different from S. cruzi, S. hirsuta, and S. hominis based on 18S rRNA and cox1 gene sequences. PMID- 26111604 TI - Incorporation of capillary microsampling into whole body plethysmography and modified Irwin safety pharmacology studies in rats. AB - Limited toxicokinetic data is generated during modified Irwin screen and whole body plethysmography safety pharmacology studies, due to disturbance of primary endpoints by standard blood sampling methods. We evaluated if incorporation of microsampling would impact on data quality, as providing toxicokinetic data from main test animals could reduce the need for satellite animals. METHODS: A modified Irwin screen was performed, testing oral clonidine (0, 0.03, 0.1, or 0.3 mg/kg). One cohort of rats per dose level underwent standard blood sampling (post 4 h Irwin assessment), and another cohort underwent microsampling after the 0.5, 1, 2, 4 and 24 h Irwin assessments. The respiratory effects of oral theophylline (0 or 10 mg/kg) and oral baclofen (0 or 5 mg/kg), were tested using whole body plethysmography. Groups of animals underwent standard blood sampling (at end of recording at 4 h post-dose) or microsampling at either 0.5 h or 1 h intervals (4 or 8 microsamples, respectively). RESULTS: Microsampling did not impact on the quality of the data generated. The expected effects of clonidine on behavioural parameters, and of theophylline and baclofen on changes in ventilatory parameters were observed at a similar magnitude and duration independent of sampling method. DISCUSSION: The incorporation of multiple capillary microsamples into the modified Irwin or respiratory study did not adversely affect the primary endpoints. The capillary microsampling method is a refinement in blood sampling technique which can easily be adapted into safety pharmacology studies to generate pharmacokinetic profiles within the same animal as the primary data, thus enhancing scientific robustness and reducing the satellite animals required. PMID- 26111605 TI - Comparison of physiologic and pharmacologic parameters in Asian and mauritius cynomolgus macaques. AB - This comparative study was conducted to assess background physiologic and pharmacologic parameters of cynomolgus macaques (Macaca fascicularis) from Cambodia, from a mixed Asian source (Cambodia, Vietnam and Indonesia), and from Mauritius. This evaluation provides a comprehensive assessment of several of these parameters in a single study. Ten male and 10 female captive-bred, age matched macaques from each source were evaluated. Criteria for evaluation included weight gain, assessment of drug metabolizing enzyme activity, metabolomic analysis, immunologic assessments (lymphocyte subsets, TDAR, and serum Ig isotyping), clinical pathology evaluations, physical (respiratory, neurologic, cardiovascular, and ophthalmologic) examinations, pathogen screening, organ weights, and gross and microscopic pathology analyses. The results of this evaluation indicate that, compared to macaques of Asian origin, macaques from Mauritius had the lowest incidence and/or severity of spontaneous pathologic findings in several organs and tissues (lymphoid organs, stomach, kidney, urothelium, heart, arteries and lung) and better testicular maturity at a given age with minimal variability in organ weights. Although slight differences were observed in other parameters, none were considered detrimental to the use of macaques of Asian or Mauritius origin in pharmaceutical candidate safety studies with the use of a consistent source, concomitant controls, and appropriate background knowledge and screening. PMID- 26111606 TI - Differences in tissue distribution of iron from various clinically used intravenous iron complexes in fetal avian heart and liver. AB - Nanomedicines are more complex than most pharmacologically active substances or medicines and have been considered as non-biological complex drugs. For nanomedicines pivotal pharmacokinetic properties cannot be assessed by plasma concentration data from standard bioequivalence studies. Using intravenous iron complexes (IICs) as model we show that fetal avian tissues can be used to study time dependent tissue concentrations in heart and liver. Clear differences were found between equimolar doses of sucrose, gluconate or carboxymaltose coated iron particles. The range in tissue iron concentrations observed with these clinically widely used IICs provides an orientation as to what should be acceptable for any new IICs. Moreover, sensitivity of the experimental model was high enough to detect a 20% difference in tissue iron concentration. For the authorization of generic products under Article 10 (1) of Directive 2001/83/EC a plasma concentration of an active substance in the range of 80%-125% versus the reference product is usually considered acceptable. Based on its high discriminatory sensitivity this method was used to support a positive marketing authorization decision for a generic nanomedicine product. PMID- 26111607 TI - Toxicology of decamethylcyclopentasiloxane (D5). AB - Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the formulation of consumer products as well as an industrial intermediate. A summary of the previous studies on the toxicology of D5 is provided. Toxicokinetic studies with D5 after dermal administration demonstrate a very low uptake of due to rapid evaporation. Following inhalation exposure, exhalation of unchanged D5 and excretion of metabolites with urine are major pathways for clearance in mammals. Due to this rapid clearance by exhalation, the potential for bioaccumulation of D5 is considered unlikely. The available toxicity data on D5 adequately cover the relevant endpoints regarding potential human health hazards. D5 was not DNA reactive or mutagenic in standard in vitro and in vivo test systems. D5 also did not induce developmental and reproductive toxicity in appropriately performed studies. In repeated studies in rats with subacute, subchronic and chronic inhalation exposure, mild effects on the respiratory tract typically seen after inhalation of irritating materials, increases in liver weight (28- and 90-day inhalation studies), and a small increase in the incidence of uterine adenocarcinoma (uterine tumor) in female rats (two-year inhalation chronic bioassay) were observed. The liver effects induced by D5 were consistent with D5 as a weak "phenobarbital-like" inducer of xenobiotic metabolizing enzymes and these effects are considered to be an adaptive response. Mechanistic studies to elucidate the mode-of-action for uterine tumor induction suggest an interaction of D5 with dopamine signal transduction pathways altering the pituitary control of the estrus cycle. The resulting estrogen imbalance may cause the small increase in uterine tumor incidence at the highest D5-exposure concentration over that seen in control rats. A genotoxic mechanism or a direct endocrine activity of D5 is not supported as a mode-of-action to account for the induction of uterine tumors by the available data. PMID- 26111608 TI - Comparative assessment of nanomaterial definitions and safety evaluation considerations. AB - Nanomaterials continue to bring promising advances to science and technology. In concert have come calls for increased regulatory oversight to ensure their appropriate identification and evaluation, which has led to extensive discussions about nanomaterial definitions. Numerous nanomaterial definitions have been proposed by government, industry, and standards organizations. We conducted a comprehensive comparative assessment of existing nanomaterial definitions put forward by governments to highlight their similarities and differences. We found that the size limits used in different definitions were inconsistent, as were considerations of other elements, including agglomerates and aggregates, distributional thresholds, novel properties, and solubility. Other important differences included consideration of number size distributions versus weight distributions and natural versus intentionally-manufactured materials. Overall, the definitions we compared were not in alignment, which may lead to inconsistent identification and evaluation of nanomaterials and could have adverse impacts on commerce and public perceptions of nanotechnology. We recommend a set of considerations that future discussions of nanomaterial definitions should consider for describing materials and assessing their potential for health and environmental impacts using risk-based approaches within existing assessment frameworks. Our intent is to initiate a dialogue aimed at achieving greater clarity in identifying those nanomaterials that may require additional evaluation, not to propose a formal definition. PMID- 26111609 TI - Randomized controlled trial of enoxaparin versus intermittent pneumatic compression for venous thromboembolism prevention in Japanese surgical patients with gynecologic malignancy. AB - AIM: The aim of this study was to compare the efficacy and safety of enoxaparin and intermittent pneumatic compression (IPC) for venous thromboembolism (VTE) prevention in Japanese surgical patients with gynecologic malignancy. MATERIAL AND METHODS: Patients >= 40 years old undergoing major surgery for gynecologic malignancy without preoperative VTE were included. Written informed consent was obtained. Enrolled patients received IPC immediately before surgery. After surgery, they were randomly assigned to either an enoxaparin group or an IPC alone group. The enoxaparin group received enoxaparin injection (20 mg, subcutaneous, every 12 h) from postoperative day 2 to 8. IPC was discontinued after the first injection. In the IPC-alone group, IPC was continued until full ambulation. The primary end-point was incidence of VTE, including pulmonary embolism and deep vein thrombosis, regardless of symptoms. An interim analysis was to be conducted when the first 30 patients had completed the study protocol. A Data and Safety Monitoring Board was established for making recommendation on the continuation or termination of the study based on the interim results. RESULTS: At the time of the interim analysis, six cases of VTE were found: five in the IPC-alone group and one in the enoxaparin group (Fisher's exact test, P = 0.08). Three patients in the IPC-alone group developed pulmonary embolism, but none in the enoxaparin group did so (Fisher's exact test, P = 0.10). The study was terminated following the Data and Safety Monitoring Board's recommendation. CONCLUSION: Enoxaparin might have lowered the risk of VTE among surgical patients with gynecologic malignancy. Further studies are necessary to confirm this. PMID- 26111610 TI - BDNF signaling in the rat cerebello-vestibular pathway during vestibular compensation: BDNF signaling in vestibular compensation. AB - Vestibular compensation, which is the behavioral recovery from lesions to the peripheral vestibular system, is attributed to plasticity of the central vestibular system. It has been reported that brain-derived neurotrophic factor (BDNF) is expressed and released in an activity-dependent manner. Upon binding to the tyrosine receptor kinase B (TrkB), BDNF can acutely modulate synaptic transmission and plasticity in the central nervous system. To assess the possible contribution of BDNF to this recovery process, we studied the expression of BDNF, TrkB.FL, TrkB.T1 and KCC2 (K(+) -Cl(-) cotransporter isoform 2) in the bilateral medial vestibular nucleus (MVN) and the flocculus of rats at 4 h, 8 h, 1, 3 and 7 days following unilateral labyrinthectomy (UL) using immunohistochemistry, quantitative real-time PCR and western blotting. Our results have shown that, compared with the sham controls and the contra-lesional side, (a) the expression of BDNF and TrkB.FL increased at 4 h in the ipsi-lesional flocculus after UL; (b) the expression of TrkB.T1 decreased at 4 h and KCC2 decreased at 8 h and 1 day in the ipsi-lesional flocculus after UL; and (c) BDNF and TrkB.FL expression was enhanced and KCC2 expression was reduced in the ipsi-lesional MVN at 8 h after UL. Our data supported the hypothesis that BDNF upregulation may reduce the inhibitory effects of the flocculus and commissural inhibition system by regulating inhibitory GABAergic synaptic transmission in floccular Purkinje cells and Purkinje cell terminals in the MVN. Additionally, KCC2 may be a switch in this process. PMID- 26111611 TI - Default mode network maturation and psychopathology in children and adolescents. AB - BACKGROUND: The human default mode (DMN) is involved in a wide array of mental disorders. Current knowledge suggests that mental health disorders may reflect deviant trajectories of brain maturation. METHOD: We studied 654 children using functional magnetic resonance imaging (fMRI) scans under a resting-state protocol. A machine-learning method was used to obtain age predictions of children based on the average coefficient of fractional amplitude of low frequency fluctuations (fALFFs) of the DMN, a measure of spontaneous local activity. The chronological ages of the children and fALFF measures from regions of this network, the response and predictor variables were considered respectively in a Gaussian Process Regression. Subsequently, we computed a network maturation status index for each subject (actual age minus predicted). We then evaluated the association between this maturation index and psychopathology scores on the Child Behavior Checklist (CBCL). RESULTS: Our hypothesis was that the maturation status of the DMN would be negatively associated with psychopathology. Consistent with previous studies, fALFF significantly predicted the age of participants (p < .001). Furthermore, as expected, we found an association between the DMN maturation status (precocious vs. delayed) and general psychopathology scores (p = .011). CONCLUSIONS: Our findings suggest that child psychopathology seems to be associated with delayed maturation of the DMN. This delay in the neurodevelopmental trajectory may offer interesting insights into the pathophysiology of mental health disorders. PMID- 26111612 TI - Binding, internalization and fate of Huntingtin Exon1 fibrillar assemblies in mitotic and nonmitotic neuroblastoma cells. AB - AIMS: The aggregation of Huntingtin (HTT) protein and of its moiety encoded by its Exon1 (HTTExon1) into fibrillar structures inside neurons is the molecular hallmark of Huntington's disease. Prion-like transmission of these aggregates between cells has been demonstrated. The cell-to-cell transmission mechanisms of these protein aggregates and the susceptibility of different kinds of neuronal cells to these toxic assemblies still need assessment. METHODS: Here, we documented the binding to and internalization by differentiated and undifferentiated neuroblastoma cells of exogenous fibrillar HTTExon1 and polyglutamine (polyQ) polypeptides containing the same number of glutamines. We assessed the contribution of endocytosis to fibrillar HTTExon1 uptake, their intracellular localization and fate. RESULTS: We observed that undifferentiated neuroblastoma cells were more susceptible to fibrillar HTTExon1 and polyQ than their differentiated counterparts. Furthermore, we demonstrated that exogenous HTTExon1 aggregates are mainly taken up by endocytosis and directed to lysosomal compartments in both mitotic and quiescent cells. CONCLUSIONS: These data suggest that the rates of endocytic processes that differ in mitotic and quiescent cells strongly impact the uptake of exogenous HTTExon1 and polyQ fibrils. This may be either the consequence of distinct metabolisms or distributions of specific protein partners for amyloid-like assemblies at the surface of highly dividing versus quiescent cells. Our results highlight the importance of endocytic processes in the internalization of exogenous HTTExon1 fibrils and suggest that a proportion of those assemblies reach the cytosol where they can amplify by recruiting the endogenous protein after escaping, by yet an unknown process, from the endo-lysosomal compartments. PMID- 26111613 TI - D-Galacturonic Acid: A Highly Reactive Compound in Nonenzymatic Browning. 2. Formation of Amino-Specific Degradation Products. AB - Thermal treatment of aqueous solutions of D-galacturonic acid and L-alanine at pH 3, 5, and 8 led to rapid and more intensive nonenzymatic browning reactions compared to similar solutions of other uronic acids and to Maillard reactions of reducing sugars. The hemiacetal ring structures of uronic acids had a high impact on browning behavior and reaction pathways. Besides reductic acid (1,2-dihydroxy 2-cyclopenten-1-one), 4,5-dihydroxy-2-cyclopenten-1-one (DHCP), furan-2 carboxaldehyde, and norfuraneol (4-hydroxy-5-methyl-3-(2H)-furanone) could be detected as typical products of nonenzymatic uronic acid browning reactions. 2-(2 Formyl-1H-pyrrole-1-yl)propanoic acid (FPA) and 1-(1-carboxyethyl)-3 hydroxypyridin-1-ium (HPA) were identified as specific reaction products of uronic acids with amine participation like l-alanine. In contrast, the structurally related D-galacturonic acid methyl ester showed less browning activity and degradation under equal reaction conditions. Pectin-specific degradation products such as 5-formyl-2-furanoic acid and 2-furanoic acid were found but could not be verified for d-galacturonic acid monomers alone. PMID- 26111614 TI - Suboptimal survival for adolescent solid organ transplant recipients: A call to action? PMID- 26111615 TI - Further refinements on splitting livers for transplantation. PMID- 26111616 TI - Circulation of stem cells and the biological meaning of this phenomenon. PMID- 26111617 TI - Assessment in transition: Options, challenges, and future directions. PMID- 26111618 TI - Predicting non-adherence: Striking the right balance. PMID- 26111619 TI - Idiopathic Dilated Cardiomyopathy Treated With Intracoronary Infusion of Autologous Bone Marrow Cells: Long-term Follow-up. PMID- 26111620 TI - Optimization of process parameters for pilot-scale liquid-state bioconversion of sewage sludge by mixed fungal inoculation. AB - Liquid-state bioconversion (LSB) technique has great potential for application in bioremediation of sewage sludge. The purpose of this study is to determine the optimum level of LSB process of sewage sludge treatment by mixed fungal (Aspergillus niger and Penicillium corylophilum) inoculation in a pilot-scale bioreactor. The optimization of process factors was investigated using response surface methodology based on Box-Behnken design considering hydraulic retention time (HRT) and substrate influent concentration (S0) on nine responses for optimizing and fitted to the regression model. The optimum region was successfully depicted by optimized conditions, which was identified as the best fit for convenient multiple responses. The results from process verification were in close agreement with those obtained through predictions. Considering five runs of different conditions of HRT (low, medium and high 3.62, 6.13 and 8.27 days, respectively) with the range of S0 value (the highest 12.56 and the lowest 7.85 g L(-1)), it was monitored as the lower HRT was considered as the best option because it required minimum days of treatment than the others with influent concentration around 10 g L(-1). Therefore, optimum process factors of 3.62 days for HRT and 10.12 g L(-1) for S0 were identified as the best fit for LSB process and its performance was deviated by less than 5% in most of the cases compared to the predicted values. The recorded optimized results address a dynamic development in commercial-scale biological treatment of wastewater for safe and environment-friendly disposal in near future. PMID- 26111621 TI - Heritability of gestational weight gain--a Swedish register-based twin study. AB - Gestational weight gain (GWG) is a complex trait involving intrauterine environmental, maternal environmental, and genetic factors. However, the extent to which these factors contribute to the total variation in GWG is unclear. We therefore examined the genetic and environmental influences on the variation in GWG in the first and second pregnancy in monozygotic (MZ) and dizygotic (DZ) twin mother-pairs. Further, we explored if any co-variance existed between factors influencing the variation in GWG of the mothers' first and second pregnancies. By using Swedish nationwide record-linkage data, we identified 694 twin mother-pairs with complete data on their first pregnancy and 465 twin mother-pairs with complete data on their second pregnancy during 1982-2010. For a subanalysis, 143 twin mother-pairs had complete data on two consecutive pregnancies during the study period. We used structural equation modeling (SEM) to assess the contribution of genetic, shared, and unique environmental factors to the variation in GWG. A bivariate Cholesky decomposition model was used for the subanalysis. We found that genetic factors explained 43% (95% CI: 36-51%) of the variation in GWG in the first pregnancy and 26% (95% CI: 16-36%) in the second pregnancy. The remaining variance was explained by unique environmental factors. Both overlapping and distinct genetic and unique environmental factors influenced GWG in the first and the second pregnancy. This study showed that GWG has a moderate heritability, suggesting that a large part of the variation in the trait can be explained by unique environmental factors. PMID- 26111622 TI - gamma-Glutamyltransferase and cancer risk: The Korean cancer prevention study. AB - Elevated serum gamma-glutamyltransferase (GGT) is a marker of hepatic injury and is associated with risk of chronic disease. However, the value of GGT as a biomarker for cancer risk remains unclear. Therefore, we evaluated the association of serum GGT with cancer incidence among more than 1.6 million Koreans. We included 1,662,087 Koreans (1,108,121 men and 553,966 women aged 20 95 years) who received health insurance from the National Health Insurance Service and had a biennial medical evaluation between 1995 and 1998. Follow-up was through December 2012. Using Cox proportional hazards models, we adjusted for age, smoking status, alcohol consumption, exercise and body mass index after exclusion of early cases (cancer diagnosis or death within 5 years of starting follow-up) and estimated hazard ratios (HRs) of overall and organ-specific cancer incidence by GGT quintiles. During the 17-year follow-up, 129,087 new cancer cases occurred among the participants. Across levels of GGT, there was a positive gradient of HR and the highest quintile of GGT (>= 60 IU/L) had the highest HR for all cancers in both men and women. By cancer site, the association was strongest for liver cancer, comparing the highest and lowest strata in men [HR, 6.67; 95% confidence interval (95%CI), 5.88-7.57] and in women (HR, 7.57; 95%CI, 6.41-8.94). Significant associations were also observed for cancers of the esophagus, larynx, stomach, colorectal, bile duct and lung in men and of the bile duct in women. Increased serum GGT level is independently associated with risk of cancer. PMID- 26111623 TI - Amid the possible causes of a very famous foxing: molecular and microscopic insight into Leonardo da Vinci's self-portrait. AB - Leonardo da Vinci's self-portrait is affected by foxing spots. The portrait has no fungal or bacterial infections in place, but is contaminated with airborne spores and fungal material that could play a role in its disfigurement. The knowledge of the nature of the stains is of great concern because future conservation treatments should be derived from scientific investigations. The lack of reliable scientific data, due to the non-culturability of the microorganisms inhabiting the portrait, prompted the investigation of the drawing using non-invasive and micro-invasive sampling, in combination with scanning electron microscope (SEM) imaging and molecular techniques. The fungus Eurotium halophilicum was found in foxing spots using SEM analyses. Oxalates of fungal origin were also documented. Both findings are consistent with the hypothesis that tonophilic fungi germinate on paper metabolizing organic acids, oligosaccharides and proteic compounds, which react chemically with the material at a low water activity, forming brown products and oxidative reactions resulting in foxing spots. Additionally, molecular techniques enabled a screening of the fungi inhabiting the portrait and showed differences when different sampling techniques were employed. Swabs samples showed a high abundance of lichenized Ascomycota, while the membrane filters showed a dominance of Acremonium sp. colonizing the drawing. PMID- 26111624 TI - Bringing smiles to faces: Evidence-based guidelines for facioscapulohumeral dystrophy. PMID- 26111625 TI - Meta-analysis of Liver Resection Versus Nonsurgical Treatments for Pancreatic Neuroendocrine Tumors with Liver Metastases. AB - PURPOSE: Studies have reported limited evidence of the benefits and harms of various regimens, such as liver resection and medical therapy, for the treatment of pancreatic neuroendocrine tumors (pNETs) with liver metastases. This meta analysis aimed to evaluate the efficacy of liver resection versus nonsurgical treatments in patients with pNET. METHODS: Relevant studies published in English were retrieved from the computerized databases Medline, Embase, and Cochrane. A meta-analysis was performed to investigate the differences in the efficacy of liver resection and nonsurgical treatments based on the evaluation of 30-day mortality, symptom relief rate, median survival time, and 2-, 3-, or 5-year survival using a random-effects model. Studies were independently reviewed by two investigators. Data from eligible studies were extracted, and the meta-analysis was performed using the comprehensive meta-analysis program version 2. RESULTS: A total of seven studies were included in the analysis. The results demonstrated that liver resection was significantly associated with a higher rate of symptom relief, longer median survival time, higher 2- or 3-year survival rates, as well as a higher 5-year survival rate. There was no significant difference in 30-day mortality among patients with pNETs who were treated by liver resection and nonsurgical therapy or survival between functional and nonfunctional pNETs. No publication bias was detected. CONCLUSIONS: Liver resection has a favorable prognostic outcome in terms of higher postoperative symptom relief rates and longer survival rates. Further randomized, controlled trials with longer follow up periods are required to confirm the advantages of liver resection for pNETs. PMID- 26111627 TI - Insulin Receptor Substrate-1 Activation Mediated p53 Downregulation Protects Against Hypoxic-Ischemia in the Neonatal Brain. AB - This study determined if dietary restriction (DR) protects against hypoxic ischemia (HI) in the neonatal brain via insulin receptor substrate-1 (IRS-1)/Akt pathway-mediated downregulation of p53 in the neurovascular unit. On postnatal (P) day 7, HI was induced in rat pups grouped from P1 into normal litter size (NL, 12 pups/dam) and increased litter size (DR, 18 pups/dam). In vivo IRS-1 anti sense oligonucleotide and IRS-1 overexpressed recombinant adenovirus were given, and neurovascular damage was assessed. In vitro models of oxygen-glucose deprivation (OGD) examined the inhibition and overexpression of IRS-1 on p53 and cell death in neurons and endothelial cells. Compared to NL pups, DR pups had significantly higher IRS-1, p-IRS-1, and pAkt levels, decreased p53, more tight junction proteins, reduced blood-brain barrier (BBB) damage after HI, and less infarct volumes at P21. Immunofluorescence revealed that IRS-1 was upregulated in the endothelial cells and neurons of DR pups. IRS-1 downregulation in DR pups reduced p-Akt, increased p53, worsened BBB damage, and increased brain injury, whereas IRS-1 overexpression in NL pups upregulated p-Akt, decreased p53, attenuated BBB damage, and decreased brain injury. In vitro, IRS-1 downregulation aggravated cell death in neurons and endothelial cells and is associated with decreased p-Akt and increased p53. In contrast, IRS-1 overexpression reduced cell death in endothelial cells with increased p-Akt and decreased p53. In conclusion, DR reduces neurovascular damage after HI in the neonatal brain through an IRS 1/Akt-mediated p53 downregulation, suggesting that IRS-1 signaling is a therapeutic target for hypoxic brain injury in neonates. PMID- 26111629 TI - Anaerobic ammonium-oxidizing bacteria gain antibiotic resistance during long-term acclimatization. AB - Three broad-spectrum antibiotics, amoxicillin (AMX), florfenicol (FF) and sulfamethazine (SMZ), that inhibit bacteria via different target sites, were selected to evaluate the acute toxicity and long-term effects on anaerobic ammonium oxidation (anammox) granules. The specific anammox activity (SAA) levels reduced by approximately half within the first 3 days in the presence of antibiotics but no nitrite accumulation was observed in continuous-flow experiments. However, the SAA levels and heme c content gradually recovered as the antibiotic concentrations increased. Extracellular polymeric substances (EPS) analysis suggested that anaerobic ammonium-oxidizing bacteria gradually developed a better survival strategy during long-term acclimatization, which reduced the antibiotic stress via increased EPS secretion that provided a protective 'cocoon.' In terms of nitrogen removal efficiency, anammox granules could resist 60 mg-AMX L(-1), 10 mg-FF L(-1) and 100 mg-SMZ L(-1). This study supported the feasibility of using anammox granules to treat antibiotic-containing wastewater. PMID- 26111628 TI - Hydrogen Sulfide Ameliorates Early Brain Injury Following Subarachnoid Hemorrhage in Rats. AB - Increasing studies have demonstrated the neuroprotective effect of hydrogen sulfide (H2S) in central nervous system (CNS) diseases. However, the potential application value of H2S in the therapy of subarachnoid hemorrhage (SAH) is still not well known. This study was to investigate the potential effect of H2S on early brain injury (EBI) induced by SAH and explore the underlying mechanisms. The role of sodium hydrosulfide (NaHS), a donor of H2S, in SAH-induced EBI, was investigated in both in vivo and in vitro. A prechiasmatic cistern single injection model was used to produce experimental SAH in vivo. In vitro, cultured primary rat cortical neurons and human umbilical vein endothelial cells (HUVECs) were exposed to OxyHb at concentration of 10 MUM to mimic SAH. Endogenous production of H2S in the brain was significantly inhibited by SAH. The protein levels of the predominant H2S-generating enzymes in the brain, including cystathionineb-synthase (CBS) and 3-mercaptopyruvate sulfur transferase (3MST), were also correspondingly reduced by SAH, while treatment with NaHS restored H2S production and the expressions of CBS and 3MST. More importantly, NaHS treatment could significantly attenuate EBI (including brain edema, blood-brain barrier disruption, brain cell apoptosis, inflammatory response, and cerebral vasospasm) after SAH. In vitro, H2S protects neurons and endothelial function by functioning as an antioxidant and antiapoptotic mediator. Our results suggest that NaSH as an exogenous H2S donor could significantly reduce EBI induced by SAH. PMID- 26111626 TI - Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments: Neuroprotective Effects of an Antioxidant Compound H-290/51. AB - In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H 290/51 (Astra-Zeneca, Molndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 degrees C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 degrees C, 120-180 % larger at 34 degrees C, and almost absent at 4 degrees C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 degrees C, a four- to sixfold increase at 34 degrees C, and three- to fourfold increase at 4 degrees C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 degrees C. In NPs treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects. PMID- 26111630 TI - Anaerobic ammonium oxidation (anammox) under realistic seasonal temperature variations: Characteristics of biogranules and process performance. AB - In this study, the effects of realistic seasonal temperatures on the nitrogen removal performance of anaerobic ammonium oxidation (anammox) and the properties of the anammox granules were comparatively investigated for 330 days. The results demonstrated that the nitrogen removal efficiency (NRE), nitrogen loading rate (NLR) and nitrogen removal rate (NRR) were decreased dramatically, as the temperature decreased from 31.2 to 2.5 degrees C. However, the nitrogen removal performance recovered andante as the temperature increased gradually. After low temperature exposure, the settleability tended to worsen, and granules appeared to be more irregular with a smaller average granule diameter, and the extracellular polymeric substances (EPS) content increased slightly, while the specific anammox activity (SAA) decreased obviously. This realistic seasonal temperatures based research was an illation of the actual operation, and could be potentially implemented to maintain stability for the application of anammox technology. PMID- 26111631 TI - Effect of different organic matters on flocculation of Chlorella sorokiniana and optimization of flocculation conditions in swine manure wastewater. AB - In this study, flocculation of Chlorella sorokiniana cultivated in swine manure wastewater, BG-11 medium and BG-11 medium supplemented with different organic matters (glucose, urea and tryptone) was investigated. The results demonstrated that the minimum amount of Al(3+) required for complete flocculation in wastewater would increase substantially, and flocculation efficiency became highly sensitive to pH. Tryptone could cause similar extent of inhibition on flocculation as in wastewater. Meanwhile, glucose could increase concentrations of Algogenic Organic Matter (AOM), inhibiting flocculation strongly at higher pH, including flocculation induced by Al(3+) and autoflocculation. However, urea had little effect on flocculation of C. sorokiniana. Moreover, the major factors: dilution times, pH and flocculants dosage, which had significant impact on flocculation efficiency of C. sorokiniana in piggery wastewater, were optimized using response surface methodology (RSM). The optimal flocculation efficiency (100%) was achieved at pH 8.5, 7-folds of dilution and 52.14 mg L(-1) of Al(3+). PMID- 26111632 TI - The Effects of Smoking on the Osmotic Pressure of Human Dental Pulp Tissue. AB - OBJECTIVE: We aimed to investigate the effect of smoking on the osmotic pressure (OP) of human dental pulp tissue. MATERIALS AND METHODS: Sixty male dental patients (smokers and nonsmokers) scheduled for root canal treatment for prosthodontics were included in the study. Fifteen patients (1 premolar tooth/patient) were allocated to each of the following groups according to their smoking habits, i.e. group 1: <=10 cigarettes/day, group 2: 11-20 cigarettes/day, group 3: >20 cigarettes/day and group 4: nonsmoking controls. Apical pulp tissues were removed via coronal access. Pulp tissue supernatants were obtained to measure the pulpal OP by means of a semimicro digital osmometer. One-way analysis of variance and the post hoc Duncan test were used to analyze the differences in OP between groups. Regression analysis was used to determine the relationship between the number of cigarettes smoked daily and the pulpal OP. RESULTS: The mean (+/- SD) OP value decreased as cigarette consumption increased: group 4 (268.00 +/- 10.09 mosm/kg) > group 1 (259.20 +/- 7.16 mosm/kg) > group 2 (248.90 +/- 2.23 mosm/kg) > group 3 (239.90 +/- 7.40 mosm/kg). The OP differed significantly between groups (p < 0.01), and a significant negative correlation was found between cigarette consumption and pulpal OP (r = -0.809, p < 0.01). CONCLUSION: In this study, the OP decreased as the number of cigarettes smoked increased. In clinical examination, there may be misdiagnosis of pulpal conditions in smokers (even in healthy pulp tissue) due to the effect of altered OP on pulpal tissue reactions. PMID- 26111633 TI - Improvement of biohydrogen production using a reduced pressure fermentation. AB - This study investigated the effect of reduced pressure on biohydrogen production in an upflow anaerobic sludge blanket (UASB) reactor from whey permeate. The results showed that the reduced pressure fermentation was more effective in enhancing biohydrogen production than dark fermentative hydrogen production at atmospheric pressure. Mesophilic fermentative biohydrogen production was investigated at a constant hydraulic retention time (HRT) of 24 h and increasing organic loading rates (OLRs) of 20, 25, 30, 35 kg COD/m(3) day. The reduced pressure fermentation was successfully operated at all OLRs tested. The maximum proportion of hydrogen in biogas of 47.7 %, volumetric hydrogen production rate (VHPR) of 7.10 L H2/day and hydrogen yield of 4.55 mol H2/kg COD removed occurred at the highest OLR. Increase in OLR affected the hydrogen production in UASB reactor exploited at atmospheric pressure. The reduced pressure process was able to remarkably improve the biohydrogen performance at high OLRs. PMID- 26111634 TI - Molecular Pharmacology of the Incretin Receptors. AB - The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are important regulators of insulin and glucagon secretion as well as lipid metabolism and appetite. These biological functions make their respective receptors (GIPR and GLP-1R) attractive targets in the treatment of both type 2 diabetes mellitus (T2DM) and obesity. The use of these native peptides in the treatment of these conditions is limited by their short half-lives. However, long-acting GLP-1R agonists and inhibitors of the enzyme that rapidly inactivates GIP and GLP-1 (dipeptidyl peptidase IV) are in clinical use. Although there is a loss of response to both hormones in T2DM, this effect appears to be more pronounced for GIP. This has made targeting GIPR less successful than GLP-1R. Furthermore, results demonstrating that GIPR knockout mice were resistant to diet-induced obesity suggested that GIPR antagonists may prove to be useful therapeutics. More recently, molecules that activate both receptors have shown promise in terms of glycemic and body weight control. This review focused on recent advances in the understanding of the signaling mechanisms and regulation of these two clinically important receptors. PMID- 26111635 TI - Low anterior resection combined with a covering stoma in the treatment of rectal cancer reduces the risk of permanent anastomotic failure. AB - PURPOSE: The adoption of the total mesorectum excision technique and circular stapler devices has enabled the performance of ultralow colorectal anastomosis in rectal cancer surgery. However, rupture of the anastomosis still usually leads to a permanent stoma. The aim of this study was to analyze the cumulative failure rate and risk factors associated with reversal of colorectal or coloanal anastomosis after sphincter-saving surgery for rectal cancer, using standardized surgical regimen with the routine use of covering stoma. Our secondary interest was the feasibilities of redo surgery after failure. METHODS: This was a retrospective study with 579 consecutive rectal cancer patients operated on at Helsinki University Hospital, Helsinki, Finland during 2005-2011. Data were collected from patient records. After exclusions, 273 consecutive patients treated with a low anterior resection with a protective stoma were included. RESULTS: In total, 23 out of 271 (8.5 %) of the colorectal/coloanal anastomoses were converted to a permanent stoma. In five patients (1.8 %), the covering stoma was not closed. The permanent stoma rate was thus 28 out of 271 (10.3 %). The risk factors associated with failure were the tumor distance from the anal verge (p = 0.03), coloanal anastomosis (p = 0.003), early anastomotic complication (p < 0.001), anastomotic fistula (p < 0.001), anal incontinence (p = 0.05), and local recurrence (p < 0.001). CONCLUSIONS: Our standardized surgical regimen with a covering stoma in low anterior resection for rectal cancer resulted in a minor anastomosis failure rate and a low risk of permanent stoma. PMID- 26111636 TI - Evaluation of the heterogeneity of studies estimating the association between risk factors and the use of potentially inappropriate drug therapy for the elderly: a systematic review with meta-analysis. AB - PURPOSE: This study was conducted to evaluate the heterogeneity of studies estimating the association between risk factors (age, gender, and polypharmacy) and the use of potentially inappropriate drug therapy for the elderly (PIDT). METHODOLOGY: This study is a systematic review with meta-analysis of observational studies. LILACS, PubMed, Scopus, and the Web of Science databases were reviewed. The following data were extracted from the included studies: country, type of study, characteristics of the sample, practice scenarios, instruments to evaluate potentially inappropriate drug therapy for the older adults, and patient-related variables. RESULTS: Twenty-nine articles (17 cross sectional and 12 cohort) were included. The majority of the studies were conducted in Europe. Regarding the study durations, 3 to 18 months was necessary to perform the research. As for the sample characteristics, all the studies analyzed involved the older adults and included anywhere from 96 patients to 33,830,599 outpatient consultations. Of the variables analyzed, only polypharmacy presented a positive association with the use of PIDT. All meta-analysis studies showed high heterogeneity, indicating the lack of a methodological standardization of the studies included, among other factors. PMID- 26111637 TI - One Year's Observational Study of Acute Kidney Injury Incidence in Primary Care; Frequency of Follow-Up Serum Creatinine and Mortality Risk. AB - BACKGROUND/AIMS: Publications on acute kidney injury (AKI) have concentrated on the inpatient population. We wanted to determine the extent of AKI in the community, its follow-up and patient impact. METHOD: Primary Care creatinine results for May 2012-April 2013 from Cornwall, United Kingdom, were screened for AKI. RESULTS: Over 12 months, 991 AKI episodes were identified (0.4% of all Primary Care creatinine requests); 51% were AKI1, 29% AKI2 and 10% AKI3. Of these, 51% AKI1s, 72% AKI2s and 77% AKI3s had a repeat creatinine requested within 14 days as per National Institute for Health and Care Excellence (NICE) guidelines. Admissions (May 2012-July 2013) were identified on 46% AKI1s, 58% AKI2s and 65% AKI3s (p < 0.05). The median time from AKI identification to hospital admission was 33 days for AKI1, 12 days for AKI2 and 1 day for AKI3 (p < 0.05); with a median length of stay of 2, 4 and 7 days, respectively (p < 0.05). The 90-day mortality from AKI identification for the admitted patients was 12% AKI1s, 20% AKI2s and 27% AKI3s (p < 0.05) vs. 11, 21 and 65% (p < 0.05) for those that were not admitted. There was no significant difference in mortality for admitted patients vs. non-admitted patients, except for the AKI3s. CONCLUSION: AKI is associated with increased admission and mortality rates; although a large proportion of patients had repeat creatinine testing within 14 days, there was still a significant number with delayed follow-up. Education within Primary Care is required on how to prevent, identify, follow-up and manage AKI. PMID- 26111638 TI - Cerebral Palsy in Children as a Risk Factor for Malnutrition. AB - AIM: The main aim of this study was to determine some malnutrition risk factors among children with cerebral palsy (CP). Children with CP often require the assistance of physical therapy centers. Experience suggests that, apart from physical disabilities, this group often suffers from malnutrition. METHODS: Data were gathered in the hospital among 128 children aged 3-18 years who were suffering from CP. The children were admitted from 2011 to 2013 to the Center for Neurological Physical Therapy for children in the Regional Hospital No. 2. St. Queen Jadwiga in Rzeszow (RORE). Statistical analyses were conducted for data on gender, age, type of CP, motor function level according to Gross Motor Function Classification Scale (GMFCS), body mass index (BMI) and hemoglobin levels in blood. RESULTS: The risk of anemia differs based on gender--the risk is 6 times greater among boys than among girls (p = 0.0398). Risk of malnutrition is 3.5 times higher in children with tetraplegia than in children with diplegia or hemiplegia (p = 0.0043). Higher GMFCS scores are connected to greater proportions of malnourished children (for BMI z-score <-1.64, p = 0.0010). CONCLUSIONS: Among children with CP, malnourishment risk factors are male gender for anemia and tetraplegia and high GMFCS values. PMID- 26111640 TI - Fixation not required: characterizing oculomotor attention capture for looming stimuli. AB - A stimulus moving toward us, such as a ball being thrown in our direction or a vehicle braking suddenly in front of ours, often represents a stimulus that requires a rapid response. Using a visual search task in which target and distractor items were systematically associated with a looming object, we explored whether this sort of looming motion captures attention, the nature of such capture using eye movement measures (overt/covert), and the extent to which such capture effects are more closely tied to motion onset or the motion itself. We replicated previous findings indicating that looming motion induces response time benefits and costs during visual search Lin, Franconeri, & Enns(Psychological Science 19(7): 686-693, 2008). These differences in response times were independent of fixation, indicating that these capture effects did not necessitate overt attentional shifts to a looming object for search benefits or costs to occur. Interestingly, we found no differences in capture benefits and costs associated with differences in looming motion type. Combined, our results suggest that capture effects associated with looming motion are more likely subserved by covert attentional mechanisms rather than overt mechanisms, and attention capture for looming motion is likely related to motion itself rather than the onset of motion. PMID- 26111639 TI - Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain. AB - We reported that 2-(3,4-difluorophenylethynyl)-N (6)-3-chlorobenzyl (N) methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A3 adenosine receptors (A3ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A3AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from D-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 MUM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of <=200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed t 1/2 of 1.09 h and plasma Cmax of 204 nM at 1 h with an AUC of 213 ng * h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain. PMID- 26111641 TI - Adam17, a Target of Mir-326, Promotes Emt-Induced Cells Invasion in Lung Adenocarcinoma. AB - BACKGROUND/AIMS: A disintegrin and metalloprotease (ADAM) 17 has been reported to be implicated in cancer cells invasion. Nevertheless, its potential role in lung adenocarcinoma has not been addressed clearly. METHODS: RT-PCR and Western blot were used to detect the expression of miR-326 and ADAM17 in lung adenocarcinoma samples (n=73). miR-326 mimics and inhibitor were tansfected in human A549 and SPCA1 cell lines. The transwell assay was used to detect the cell invasive ability. The regulation mechanism was evaluated by luciferase reporter assay. The markers of (epithelial-to-mesenchymal transition) EMT were detected by using Western blot assay. RESULTS: We found increased expression of ADAM17 in lung adenocarcinoma and cell lines. In vitro, up-regulation of ADAM17 promoted cells invasion, while silencing of ADAM17 inhibited cells invasion. Meanwhile, ADAM17 could affect the markers of EMT. Furthermore, we confirmed that ADAM17 is a target of miR-326, which is involved in EMT and cells invasion. CONCLUSIONS: These findings revealed that ADAM17, a target of miR-326, promoted EMT-induced cells invasion in lung adenocarcinoma. PMID- 26111642 TI - An academic, clinical and industrial update on electrospun, additive manufactured and imprinted medical devices. AB - Electrospinning, additive manufacturing and imprint lithography scaffold fabrication technologies have attracted great attention in biomedicine, as they allow production of two- and three- dimensional constructs with tuneable topographical and geometrical features. In vitro data demonstrate that electrospun and imprinted substrates offer control over permanently differentiated and stem cell function. Advancements in functionalisation strategies have further enhanced the bioactivity and reparative capacity of electrospun and additive manufactured devices, as has been evidenced in several preclinical models. Despite this overwhelming success in academic setting, only a few technologies have reached the clinic and only a fraction of them have become commercially available products. PMID- 26111643 TI - Realizing Tunable Inverse and Normal Doppler Shifts in Reconfigurable RF Metamaterials. AB - The Doppler effect has well-established applications in astronomy, medicine, radar and metrology. Recently, a number of experimental demonstrations of the inverse Doppler effect have begun to appear. However, the inverse Doppler effect has never been observed on an electronically reconfigurable system with an external electromagnetic wave source at radio frequencies (RF) in experiment. Here we demonstrate an experimental observation of the inverse Doppler shift on an electronically reconfigurable RF metamaterial structure, which can exhibit anomalous dispersion, normal dispersion or a stop band, depending on an applied bias voltage. Either inverse or normal Doppler shift is realized by injecting an external RF signal into the electronically reconfigurable metamaterial, on which an electronically controllable moving reflective boundary is formed. The effective velocity of this boundary and the resulting frequency shift can be tuned over a wide range by a digital switching circuit. This work is expected to open up possibilities in applying the inverse Doppler effect in wireless communications, radar and satellite navigation. PMID- 26111644 TI - Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. AB - Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1 beta (IL 1beta), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections. PMID- 26111645 TI - Ketogenic diet does not impair spatial ability controlled by the hippocampus in male rats. AB - A ketogenic diet was recently shown to reduce glutamate accumulation in synaptic vesicles, decreasing glutamate transmission. We questioned whether a ketogenic diet affects hippocampal function, as glutamate transmission is critically involved in visuospatial ability. In the present study, male Wistar rats were maintained on a ketogenic diet containing 10% protein and 90% fat with complements for 3 weeks to change their energy expenditure from glucose-dependent to fat-dependent. Control rats were fed a diet containing 10% protein, 10% fat, and 80% carbohydrates. The fat-dependent energy expenditure induced by the ketogenic diet led to decreased body weight and increased blood ketone production, though the rats in the two groups consumed the same number of calories. The ketogenic diet did not alter food preferences for the control or high-fat diet containing 10% protein, 45% fat, and 45% carbohydrates. Anxiety in the open field was not altered by ingestion the ketogenic diet. However, rats fed the ketogenic diet performed better in the Y-maze test than rats fed the control diet. No difference was observed between the two groups in the Morris water maze test. Finally, Western blot revealed that the hippocampal expression of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunit 1 (GluR1) was significantly increased in mice fed a ketogenic diet. These results suggest that hippocampal function is not impaired by a ketogenic diet and we speculate that the fat-dependent energy expenditure does not impair visuospatial ability. PMID- 26111646 TI - Early use of oleanolic acid provides protection against 6-hydroxydopamine induced dopamine neurodegeneration. AB - Oleanolic acid is a triterpenoid that has been shown to possess antioxidant properties. In this study we investigated the effects of oleanolic acid in a parkinsonian rat model. Unilateral 6-hydroxydopamine (6-OHDA) lesions were carried out on postnatal day (PND) 60 in 4 groups viz. (1) Rats that started oleanolic acid treatment 7 days prior to lesion. (2) Rats not treated with oleanolic acid. (3) Rats that started oleanolic acid treatment 1 day post-lesion. (4) Rats treated with oleanolic acid 7 days post-lesion. The degree of forelimb impairment was assessed using limb use asymmetry and forelimb akinesia tests. Neurochemical changes were assessed using a Dopamine ELISA kit and mitochondrial apoptosis was measured using a mitochondrial apoptosis detection kit. In this study, animals injected with 6-OHDA displayed forelimb use asymmetry that was ameliorated by treatment with oleanolic acid 7 days pre- and 1 day post-lesion. In the cylinder test, rats injected with 6-OHDA favored using the forelimb ipsilateral (unimpaired) to the lesioned hemisphere while rats treated with oleanolic acid used the forelimb contralateral (impaired) to the lesioned hemisphere significantly more. Rats treated with oleanolic acid 7 days pre- and 1 day post-lesion had more dopamine in the striatum than the non-treated or the 7 days after lesion rats. Similarly, 6-OHDA-induced membrane depolarization was decreased in rats that received oleanolic acid treatment pre- or immediately post lesion. This suggests that early treatment with oleanolic acid protects dopamine neurons from the toxic effects of 6-OHDA. PMID- 26111647 TI - Pyruvate and cilostazol protect cultured rat cortical pericytes against tissue plasminogen activator (tPA)-induced cell death. AB - Since even a brief ischemia can cause permanent brain damage, rapid restoration of blood flow is critical to limiting damage. Although intravenous tPA during the acute stage is the treatment of choice for achieving reperfusion, this treatment is sometimes associated with brain hemorrhage. Agents that reduce tPA-related bleeding risk may help expand its therapeutic window. This study assessed whether zinc dyshomeostasis underlies the toxic effect of tPA on brain vascular pericytes; whether pyruvate, an inhibitor of zinc toxicity, protects pericytes against tPA-induced cell death; and whether cilostazol, which protects pericytes against tPA-induced cell death, affects zinc dyshomeostasis associated with tPA toxicity. Cultured pericytes from newborn rat brains were treated with 10-200 MUg/ml tPA for 24 h, inducing cell death in a concentration-dependent manner. tPA induced cell death was preceded by increases in intracellular free zinc levels, and was substantially attenuated by plasminogen activator inhibitor-1 (PAI-1) or TPEN. Pyruvate completely blocked direct zinc toxicity and tPA-induced pericyte cell death. Both cAMP and cilostazol, a PDE3 inhibitor that attenuates tPA induced pericyte cell death in vitro and tPA-induced brain hemorrhage in vivo, reduced zinc- and tPA-induced pericyte cell death, suggesting that zinc dyshomeostasis may be targeted by cilostazol in tPA toxicity. These findings show that tPA-induced pericyte cell death may involve zinc dyshomeostasis, and that pyruvate and cilostazol attenuate tPA-induced cell death by reducing the toxic cascade triggered by zinc dyshomeostasis. Since pyruvate is an endogenous metabolite and cilostazol is an FDA-approved drug, in vivo testing of both as protectors against tPA-induced brain hemorrhage may be warranted. This article is part of a Special Issue entitled SI: Neuroprotection. PMID- 26111648 TI - Cav3.1 T-type calcium channel modulates the epileptogenicity of hippocampal seizures in the kainic acid-induced temporal lobe epilepsy model. AB - The molecular mechanism of temporal lobe epilepsy has not been clearly identified. T-type calcium channels play a role in burst firing in neurons and have been implicated in several seizure models. In this study, the role of Cav3.1 T-type (alpha1G) calcium channel has been investigated in the kainic acid (KA) induced temporal lobe epilepsy model (TLE) by using conventional alpha1G knock out (ko) mice. After intraperitoneal (i.p.) administration or intrahippocampal injection of KA, depth hippocampal and cortical electroencephalogram (EEG) and behavioral monitoring were recorded, and timm and Nissl staining of brain sections were made later. Seizure was mainly identified by EEG signals, rather than behaviorally, with analytic criteria. During the acute status epilepticus (SE) period, both the duration and the frequency of hippocampal seizures were significantly reduced and increased, respectively, in alphalG ko mice compared to those of wild type mice. Epileptogenicity, the total period of seizures (hr(-1)), was also significantly reduced in alpha1G ko mice. However, the latency of seizure occurrence was not significantly different between wild type and ko mice. These differential effects were not observed in cortical seizures. Furthermore, the injection of KA caused a strong increase in delta rhythm power spectrum density (PSD) of EEG in alphalG ko mice compared to that in wild type mice. The results with conventional ko mice indicate that alpha1G T-type calcium channel plays a modulatory role in the duration and frequency of hippocampal seizures as well as the epileptogenicity of KA-induced TLE in mice, mostly during acute periods. PMID- 26111650 TI - Fetal imaging prompts maternal diagnosis: autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder. Ultrasound (US) findings can include enlarged echogenic kidneys in utero and cysts in multiple organs in adults. Though a highly penetrant disease, due to varied clinical expression and the typical late onset of symptoms, reproductive-aged women may not know their carrier status. We present two cases in which fetal US findings suggested ADPKD and additional evaluation identified likely maternal ADPKD as well. PMID- 26111649 TI - Emotion Regulatory Brain Function and SSRI Treatment in PTSD: Neural Correlates and Predictors of Change. AB - Posttraumatic stress disorder (PTSD)-a chronic, debilitating condition, broadly characterized by emotion dysregulation-is prevalent among US military personnel who have returned from Operations Enduring Freedom (OEF) and Iraqi Freedom (OIF). Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for PTSD, but treatment mechanisms are unknown and patient response varies. SSRIs may exert their effects by remediating emotion regulatory brain activity and individual differences in patient response might be explained, in part, by pre treatment differences in neural systems supporting the downregulation of negative affect. Thirty-four OEF/OIF veterans, 17 with PTSD and 17 without PTSD underwent 2 functional magnetic resonance imaging scans 12 weeks apart. At each scan, they performed an emotion regulation task; in the interim, veterans with PTSD were treated with the SSRI, paroxetine. SSRI treatment increased activation in both the left dorsolateral prefrontal cortex (PFC) and supplementary motor area (SMA) during emotion regulation, although only change in the SMA over time occurred in veterans with PTSD and not those without PTSD. Less activation of the right ventrolateral PFC/inferior frontal gyrus during pre-treatment emotion regulation was associated with greater reduction in PTSD symptoms with SSRI treatment, irrespective of pre-treatment severity. Patients with the least recruitment of prefrontal emotion regulatory brain regions may benefit most from treatment with SSRIs, which appear to augment activity in these regions. PMID- 26111651 TI - An avian model for ascertaining the mechanisms of organophosphate neuroteratogenicity and its therapy with mesenchymal stem cell transplantation. AB - INTRODUCTION: A fast and simple model which uses animals lower on the evolutionary scale is beneficial for progress in neuroteratological research. Here, we established this novel model and applied it in the study of the detrimental effects of pre-hatch exposure to chlorpyrifos on neurogenesis and several neurotransmitter systems in the chick and their reversal, using mesenchymal stem cell (MSC) transplantation. METHODS: Chicken eggs were injected with the organophosphate chlorpyrifos, 10mg/kg eggs - a dose below the threshold for dysmorphology - on incubation days (ID) 0 and 5 and subsequently the embryos were subjected to intravenous transplantation of MSC on ID 13. RESULTS: After hatching (day 1) the expression of the neurogenesis-related genes DCX (also confirmed by immunohistochemistry), BDNF, MAP 2, FGF 2, SOX 2 and VEGF in the lateral striatum area was decreased in the exposed group (p<0.005). Among the studied neurotransmitter systems (serotonergic, dopaminergic and cholinergic), increased gene expression was demonstrated for tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) with a corresponding decrease in serotonin receptor 1A (5HTR1A) (p<0.05); no changes in gene expression of choline transporter, PKC beta and D2 were found following chlorpyrifos exposure. CONCLUSION: Transplantation of MSC reversed all the neurogenic and serotonergic alterations (p<0.01). The study of chick embryo exposure to insults with subsequent MSC therapy provides a fast and simple model for elucidating the mechanisms of both the neuroteratogenicity and the therapy, steps that are critical for progress toward therapeutic applications. PMID- 26111652 TI - Characterizing the parent and oxygenated polycyclic aromatic hydrocarbons in mangrove sediments of Hong Kong. AB - Parent and oxygenated polycyclic aromatic hydrocarbons (PAHs) were investigated in mangrove sediments of Hong Kong. Most of the analytes were detected, and the dominant carbonylic and hydroxylated PAHs in mangrove sediments were 9-fluorenone and 2-hydroxy fluorene, respectively. The concentration of 9-fluorenone and 9,10 anthraquinone was higher than their parent PAHs. Moreover, the concentration of total organic matter (TOM) related with those of the parent PAHs and carbonylic PAHs, except for hydroxylated PAHs, which indicated that TOM was not the only factor regulating the distribution of oxygenated PAHs. Nevertheless, the parent PAHs in mangrove sediments was correlated positively with carbonylic PAHs which demostrated not only the similar source but also the fate of these two compound class. However, hydroxylated PAHs had different source by comparing with parent PAHs and carbonylic PAHs, they were probably originated from biodegradation and accumulated in mangrove sediments. PMID- 26111653 TI - Release of heavy metals from sediment bed under wave-induced liquefaction. AB - Sediments in lakes and coasts can release metals into water via static diffusion and especially resuspension. The resuspension under sediment liquefaction may severely affect the concentrations of metals in water. In this study, flume experiments were carried out twice to study the release of two metal combinations (Zn and Pb; Zn and Cu), respectively. Each experiment included three phases: consolidation; non-liquefaction and liquefaction. Results showed that total Zn concentration at liquefaction phase increased by a maximum rate of 26 compared with the consolidation phase. The concentration of particulate Zn at liquefaction phase increased by a maximum rate of 8.30 compared with the non-liquefaction phase. The average concentration of dissolved Zn at the liquefaction phase increased up to 0.24 times from the consolidation phase. Total Zn concentration at the non-liquefaction phase increased by several times compared with the consolidation phase. Metals were homogeneously distributed in the liquefaction layer through wave actions. PMID- 26111654 TI - Applying sediment quality guidelines on soft sediments of the Gulf of Finland, Baltic Sea. AB - The Gulf of Finland is known to have been rather largely contaminated by heavy metals during the last half of the 20th century, but indications of recovery have been reported. In order to investigate the recent levels of heavy metals and arsenic in the uppermost soft sediments of the off-shore Gulf of Finland coring of altogether 23 sites were performed. The subsamples of the cores are 605 in total and thus give a good picture of heavy metal levels in the surface sediments during the first decade of this century. In order to evaluate methods and predict sediment toxicity the sediment concentrations are compared to American SQG:s. Majority of the subsamples exceeded the threshold levels of both used SQG:s, but some exceeded also the midrange effects quality guidelines. As, Cd, Hg, and Zn concentrations still occur at unacceptably high levels in sediments of the off shore Gulf of Finland. PMID- 26111655 TI - Heavy metals in surface sediments of the intertidal Laizhou Bay, Bohai Sea, China: Distributions, sources and contamination assessment. AB - Surface sediments from the intertidal zone of the southwestern Laizhou Bay were analyzed for heavy metals to seek their concentrations, distributions, pollution status, potential ecological risks and possible sources. The concentrations of As, Cd, Cr, Cu, Hg, Ni, Pb and Zn were in the ranges of 4.65-9.65, 0.11-0.28, 25.85-42.75, 7.57-21.29, 0.022-0.054, 12.85-25.35, 9.65-17.65 and 38.22 73.81MUgg(-1) dry sediment weight, respectively. Cd and Hg presented a status of no pollution to moderate pollution and moderate to considerable potential ecological risks; they were enriched to some extent at some sampling stations, while the other studied metals were not. The combined effects of the studied metals in the sediments made them have a 21% probability of being toxic to biota. The results indicated that As, Cr, Cu, Zn, Ni and Pb were mainly from natural contribution, while a significant portion of Cd and Hg was likely from anthropogenic discharges in addition to natural inputs. PMID- 26111656 TI - A comprehensive biosensor integrated with a ZnO nanorod FET array for selective detection of glucose, cholesterol and urea. AB - We report a novel straightforward approach for simultaneous and highly-selective detection of multi-analytes (i.e. glucose, cholesterol and urea) using an integrated field-effect transistor (i-FET) array biosensor without any interference in each sensor response. Compared to analytically-measured data, performance of the ZnO nanorod based i-FET array biosensor is found to be highly reliable for rapid detection of multi-analytes in mice blood, and serum and blood samples of diabetic dogs. PMID- 26111657 TI - Patterns and correlates of alcohol use amongst heroin users: 11-year follow-up of the Australian Treatment Outcome Study cohort. AB - INTRODUCTION: The study aimed to determine long-term alcohol use patterns and correlates amongst heroin users. METHODS: Longitudinal cohort. 11-year post baseline follow-up of the Australian Treatment Outcome Study cohort. RESULTS: At 11-year follow-up, 431 (70%) participants were interviewed. Alcohol was used in the preceding month by 56%, with 27% reporting daily use and 11% heavy daily drinking. Alcohol use patterns showed remarkable consistency across waves, with the proportion who drank in the preceding month ranging between 49 and 56%, with no significant trend across time. Daily drinking ranged between 20 and 27%, and heavy daily drinking between 7 and 12%. Both declined slightly from baseline to 3 year follow-up, but by 11 years were at levels similar to baseline. Compared to female referents, males were more likely to drink (OR 1.6, CI 1.3-2.1, p < .05), to drink daily (OR 1.8, CI 1.4-2.4, p < .05) and to drink heavily (OR 1.7, 1.1 2.5, p < .05). Compared to those not in enrolled in a drug treatment programme, those enrolled were significantly less likely to drink (OR 0.7, CI 0.5-0.8, p < .05) and to drink daily (OR 0.6, 0.5-0.8, p < .05). Compared to those who did not drink heavily, heavy drinking was associated with a higher likelihood of recent overdose (OR 1.6, CI 1.0-2.4, p < .05), of criminality (OR 1.9, 1.3-2.7, p < .001), and with lower SF12 physical (mean difference -3.0, CI -4.7 to -1.4, p < .001) and mental (-2.4, CI -4.3 to -0.5, p < .001) health scores. CONCLUSIONS: There were consistently high levels of both abstinence and regular drinking, with drinking patterns staying relatively stable across the decade. From the clinical perspective, the high rates of heavy drinking are of particular relevance, given the observed associations with a poorer clinical profile. PMID- 26111658 TI - Association of second-hand smoke exposure at home with psychological distress in the Spanish adult population. AB - INTRODUCTION: Second-hand smoke (SHS) exposure has been associated with increased risks of respiratory and heart diseases. However, little is known about the potential effects of SHS on psychological distress. The aim of this study is to examine the association of SHS exposure at home with psychological distress in Spain. METHODS: A cross-sectional survey about SHS exposure, socio-demographic and health related variables, and psychological distress, measured with the 12 item version of the General Health Questionnaire (GHQ-12) with a cut-off score >= 3, was conducted from 2011-2012 among a representative sample of the adult population (aged >= 15 years) of Spain. From the total sample (n = 21,007), we used the subsample of never-smokers (n = 11,214). We computed the odds ratios (OR) and their 95% confidence intervals (95% CI) for scoring >= 3 on the GHQ by means of unconditional multiple logistic regression models adjusted for sex and age. RESULTS: In the subsample, 9.7% (n = 1,090) responded that they were exposed to SHS at home. The prevalence of subjects scoring >= 3 on the GHQ was higher for the sample exposed to SHS (22.7%) than for the non-exposed sample (18.9%; OR: 1.39; CI: 1.19-1.62). This association was also present when stratified for sex, age, marital status, socio-economic status, perceived general health, presence of any chronic disease, and alcohol intake. CONCLUSIONS: Exposure to SHS at home is associated with psychological distress. Further investigation is necessary to determine if this association is causal. Avoiding SHS exposure at home could have beneficial effects on psychological distress. PMID- 26111659 TI - A new impedance based approach to test the activity of recombinant protein- Semaphorins as a test case. AB - The biological activity of a recombinant protein is routinely measured using a bioassay such as an enzyme assay. However, many proteins have no enzymatic activity and in many cases it is difficult to devise a simple and reliable approach to test their activity. Semaphorins, Ephrins, Slits, Netrins or amylin assisted proteins have numerous activities affecting many systems and cell types in the human body. Most of them are also able to induce rapid cytoskeleton changes at least in some cell types. We assumed therefore, that such proteins might be tested based on their ability to modulate the cytoskeleton. Here we tested a number of semaphorins in an impedance based label-free platform that allows for dynamic monitoring of subtle morphological and adhesive changes. This system has proved to be a very fast, sensitive and effective way to monitor and determine the activity of such proteins. Furthermore we showed that it is possible to customize a cell-protein system by transfecting the cells with specific receptors and test the cell response following the addition of the recombinant ligand protein. Since other protein families such as Ephrins and Netrins can also influence the cytoskeleton of some cells, this approach may be applicable to a large number of proteins. PMID- 26111660 TI - Properties and functions of TRPM1 channels in the dendritic tips of retinal ON bipolar cells. AB - An increase in light intensity induces a depolarization in retinal ON-bipolar cells via a reduced glutamate release from presynaptic photoreceptor cells. The underlying transduction cascade in the dendritic tips of ON-bipolar cells involves mGluR6 glutamate receptors signaling to TRPM1 proteins that are an indispensable part of the transduction channel. Several other proteins are recognized to participate in the transduction machinery. Deficiency in many of these leads to congenital stationary night blindness, because rod bipolar cells, a subgroup of ON-bipolar cells, constitute the main route for sensory information under scotopic conditions. Here, we review the current knowledge about TRPM1 ion channels and how their activity is regulated within the postsynaptic compartment of ON-bipolar cells. The functional properties of TRPM1 channels in the dendritic compartment are not well understood as they differ substantially from those of recombinant TRPM1 channels. Critical evaluation of possible explanations of these discrepancies indicates that some key components of this transduction pathway might still not be known. The continued exploration of this pathway will yield further clinically useful insights. PMID- 26111661 TI - Two-dimensional boron-nitrogen-carbon monolayers with tunable direct band gaps. AB - The search for new candidate semiconductors with direct band gaps of ~1.4 eV has attracted significant attention, especially among the two-dimensional (2D) materials, which have become potential candidates for next-generation optoelectronics. Herein, we systematically studied 2D B(x)/2N(x/2)C(1-x) (0 < x < 1) compounds in particular focus on the four stoichiometric B(x)/2N(x/2)C(1-x) (x = 2/3, 1/2, 2/5 and 1/3) using a recently developed global optimization method (CALYPSO) in conjunction with density functional theory. Furthermore, we examine more stoichiometries by the cluster expansion technique based on a hexagonal lattice. The results reveal that all monolayer B(x)/2N(x/2)C(1-x) stoichiometries adopt a planar honeycomb character and are dynamically stable. Remarkably, electronic structural calculations show that most of B(x)/2N(x/2)C(1-x) phases possess direct band gaps within the optical range, thereby they can potentially be used in high-efficiency conversion of solar energy to electric power, as well as in p-n junction photovoltaic modules. The present results also show that the band gaps of B(x)/2N(x/2)C(1-x) can be widely tuned within the optical range by changing the concentration of carbon, thus allowing the fast development of band gap engineered materials in optoelectronics. These new findings may enable new approaches to the design of microelectronic devices. PMID- 26111664 TI - Subcutaneous abscess at epidural catheter insertion site in a patient with intestinal tuberculosis. PMID- 26111662 TI - Opposite effects of two estrogen receptors on tau phosphorylation through disparate effects on the miR-218/PTPA pathway. AB - The two estrogen receptors (ERs), ERalpha and ERbeta, mediate the diverse biological functions of estradiol. Opposite effects of ERalpha and ERbeta have been found in estrogen-induced cancer cell proliferation and differentiation as well as in memory-related tasks. However, whether these opposite effects are implicated in the pathogenesis of Alzheimer's disease (AD) remains unclear. Here, we find that ERalpha and ERbeta play contrasting roles in regulating tau phosphorylation, which is a pathological hallmark of AD. ERalpha increases the expression of miR-218 to suppress the protein levels of its specific target, protein tyrosine phosphatase alpha (PTPalpha). The downregulation of PTPalpha results in the abnormal tyrosine hyperphosphorylation of glycogen synthase kinase 3beta (resulting in activation) and protein phosphatase 2A (resulting in inactivation), the major tau kinase and phosphatase. Suppressing the increased expression of miR-218 inhibits the ERalpha-induced tau hyperphosphorylation as well as the PTPalpha decline. In contrast, ERbeta inhibits tau phosphorylation by limiting miR-218 levels and restoring the miR-218 levels antagonized the attenuation of tau phosphorylation by ERbeta. These data reveal for the first time opposing roles for ERalpha and ERbeta in AD pathogenesis and suggest potential therapeutic targets for AD. PMID- 26111663 TI - Estrogen modulation of the ethanol-evoked myocardial oxidative stress and dysfunction via DAPK3/Akt/ERK activation in male rats. AB - Evidence suggests that male rats are protected against the hypotensive and myocardial depressant effects of ethanol compared with females. We investigated whether E2 modifies the myocardial and oxidative effects of ethanol in male rats. Conscious male rats received ethanol (0.5, 1 or 1.5g/kg i.v.) 30-min after E2 (1MUg/kg i.v.) or its vehicle (saline), and hearts were collected at the conclusion of hemodynamic measurements for ex vivo molecular studies. Ethanol had no effect in vehicle-treated rats, but it caused dose-related reductions in LV developed pressure (LVDP), end-diastolic pressure (LVEDP), rate of rise in LV pressure (dP/dtmax) and systolic (SBP) and diastolic (DBP) blood pressures in E2 pretreated rats. These effects were associated with elevated (i) indices of reactive oxygen species (ROS), (ii) malondialdehyde (MDA) protein adducts, and (iii) phosphorylated death-associated protein kinase-3 (DAPK3), Akt, and extracellular signal-regulated kinases (ERK1/2). Enhanced myocardial anti-oxidant enzymes (heme oxygenase-1, catalase and aldehyde dehydrogenase 2) activities were also demonstrated. In conclusion, E2 promotes ethanol-evoked myocardial oxidative stress and dysfunction in male rats. The present findings highlight the risk of developing myocardial dysfunction in men who consume alcohol while receiving E2 for specific medical conditions. PMID- 26111666 TI - Persistent cauda equina syndrome after cesarean section under combined spinal epidural anesthesia: a case report. AB - A 29-year-old pregnant woman was delivered by cesarean section under a combined spinal-epidural anesthesia. Thirty hours after an uneventful surgery, she complained of weakness in her lower extremities and developed fecal and urinary incontinence. Lumbosacral magnetic resonance imaging showed thickening and clumping of cauda equina nerve roots at L2-3 level, consistent with the diagnosis of arachnoiditis. The patient was included in an intense rehabilitation program with a diagnosis of cauda equina syndrome. Most of the symptoms resolved within a few days, but right side foot drop persisted for 2 years after the procedure. Because there was no other etiologies being noticed, we hypothesized that the hyperbaric bupivacaine neurotoxicity was likely to be the cause for this neurologic deficit. PMID- 26111665 TI - Comparison of McGRATH MAC and Macintosh laryngoscopes for double-lumen endotracheal tube intubation by anesthesia residents: a prospective randomized clinical trial. AB - STUDY OBJECTIVE: This study aimed to compare the utility of McGRATH MAC (McG) and Macintosh (McL) laryngoscopes for double-lumen endotracheal tube intubation in patients undergoing elective surgery. DESIGN: Randomized clinical trial. SETTING: Operating room. PATIENTS: Fifty adult patients scheduled for elective surgery under 1-lung ventilation with American Society of Anesthesiologists physical status 1 to 3. INTERVENTIONS: Double-lumen endotracheal tube intubation was performed with the McG (McG group; 25 patients) or conventional McL (McL group; 25 patients) laryngoscope by anesthesia residents. MEASUREMENTS: The number of attempts to successful intubation, intubation time, percentage of glottis opening score, and subjective difficulty of laryngoscopy and tube passage through the glottis were assessed. MAIN RESULTS: The total numbers of intubation attempts were 1 (McG group, 24 patients; McL group, 16 patients), 2 (McG group, 1 patient; McL group, 8 patients), and 3 (McG group, 0 patient; McL group, 1 patient), with significant differences between the two groups (P = .018). Intubation time was significantly shorter in the McG group compared with the McL group (McG: 17.1 +/- 4.6 seconds vs McL: 20.8 +/- 5.9 seconds, P = .026). The percentage of glottis opening score was significantly higher in the McG group compared with the McL group (McG: 88.4% +/- 13.7% vs McL: 71.4% +/- 20.4%, P = .004). CONCLUSIONS: The McG demonstrated a better intubation profile compared with the McL, possibly due to its ease of use for double-lumen endotracheal tube intubation. Clinical Trial registry number: UMIN000014636. PMID- 26111667 TI - Plasma Uric Acid as a Prognostic Marker in Patients With Hypertrophic Cardiomyopathy. AB - BACKGROUND: Uric acid (UA) has been shown to be an independent risk factor for various cardiovascular diseases. However, its significance in hypertrophic cardiomyopathy (HCM) has not yet been evaluated. The objective of the present study was to evaluate clinical implications of plasma UA levels on the prognosis of patients with HCM. METHODS: A total of 588 adult patients with HCM were enrolled at FuWai Hospital from 1999-2011 and followed until 2014. The plasma levels of UA were measured at enrollment. RESULTS: During the follow-up of 5.2 +/ 2.4 years, 44 (7.5%) patients had cardiovascular-related deaths, and 100 (17.0%) patients had cardiac events. Compared with the first tertile of UA concentration (< 284.6 MUmol/L), patients in the highest tertile (> 358.7 MUmol/L) had a higher risk for the development of adverse events: cardiovascular death (adjusted hazard ratio [HR], 3.10; 95% confidence interval [CI], 1.37-7.04; P = 0.007), all-cause mortality (adjusted HR, 2.33; 95% CI, 1.11-4.89; P = 0.025), cardiac events (adjusted HR, 4.20, 95% CI, 2.38-7.42; P < 0.001), heart failure events (adjusted HR, 3.46; 95% CI, 1.86-6.45; P < 0.001), and arrhythmic events (adjusted HR, 9.19; 95% CI, 2.40-35.25; P = 0.001). Similarly, the continuous variable of UA (for every 1 mg/dL higher concentration) was also an independent predictor for adverse outcomes: cardiovascular death (adjusted HR, 1.29; 95% CI, 1.11-1.49; P = 0.001), all-cause mortality (adjusted HR, 1.23; 95% CI, 1.07-1.41; P = 0.004), cardiac events (adjusted HR, 1.27; 95% CI, 1.15-1.41; P < 0.001), heart failure events (adjusted HR, 1.19; 95% CI, 1.06-1.33; P = 0.003), and arrhythmic events (adjusted HR, 1.60; 95% CI, 1.30-1.98; P < 0.001). CONCLUSIONS: Our results indicate that UA is an independent predictor of adverse outcomes in patients with HCM. PMID- 26111668 TI - Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-kappaB Pathway. AB - BACKGROUND: Viral myocarditis, which is mostly caused by coxsackievirus infection, is characterized by myocardial inflammation. Abnormal endoplasmic reticulum (ER) stress participates in many heart diseases, but its role in viral myocarditis remains unsolved. METHODS: We investigated the influence of ER stress in coxsackievirus B3 (CVB3)-induced viral myocarditis by dynamically detecting its activation in CVB3-infected hearts, analyzing its association with myocarditis severity, and exploring its impact on disease development by modulating the strength of ER stress with the chemical activator tunicamycin (Tm) or the inhibitor tauroursodeoxycholic acid (TUDCA). The underlying signal pathway of ER stress in CVB3-induced myocarditis was also deciphered. RESULTS: We found that myocardial expression of Grp78 and Grp94, 2 ER stress markers, was significantly increased after CVB3 infection and positively correlated with myocarditis severity. Consistently, Tm-augmented ER stress obviously aggravated myocarditis, as shown by more severe myocardial inflammation, reduced cardiac function, and a lower survival rate, whereas TUDCA decreased ER stress and obviously alleviated myocarditis. This pathologic effect of ER stress could be attributed to increased levels of proinflammatory cytokine (interleukin [IL]-6, IL-12, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1) production through the IRE1-associated nuclear factor-kappaB (NF-kB) pathway. CONCLUSIONS: ER stress accentuated CVB3-induced myocardial inflammation through the IRE1-associated NF-kappaB pathway. This study may help us understand the role of ER stress in viral myocarditis and promote the development of corresponding therapeutic strategies based on manipulating ER stress. PMID- 26111669 TI - Warfarin Monotherapy in Atrial Fibrillation Patients With Stable Coronary Disease One Year After Myocardial Infarction/Stent: Two Birds With One Stone? AB - Patients with atrial fibrillation and stable coronary artery disease remain a therapeutic challenge because of the different antithrombotic therapies for the 2 conditions and the increase in bleeding with concomitant antiplatelet and anticoagulant medications. Current guidelines extrapolated data from studies of antithrombotic regimens of each condition separately but there is limited evidence for the optimal regimen in patients with atrial fibrillation and stable coronary artery disease beyond the first year after an acute coronary syndrome or stent implantation. In this review we suggest that warfarin monotherapy is sufficient for this patient population beyond 1 year. PMID- 26111670 TI - [Detection and analysis of copy number variation from 1000 Genomes trio data]. AB - OBJECTIVE: Copy number variation (CNV) is an important type of genomic structural variation and plays a crucial role in genomic disorders imposed by diseases. Most of the current bioinformatic researches focus on developing algorithms and tools for detecting CNVs from single or paired datasets, but the analysis of such CNVs is not sufficient from a family-based genetic point of view. We performed a trio sample family based parents-offspring CNV analysis using the 1000G data. We found a number of CNVs that the offsprings inherited from their parents and inferred through hierarchical analysis how they were generated. In addition, we also discovered several de novo CNV candidates. PMID- 26111671 TI - [Observation of radiobiological characteristics in a HepG2 cell line with mitochondrial DNA deletion]. AB - OBJECTIVE: To study the radiobiological characteristics of a HepG2 cell line with mitochondrial DNA (mtDNA) deletion. METHODS: HepG2 cells were cultured in a medium containing ethidium bromide, acetylformic acid and uracil. The HepG2 cell line with mtDNA deletion (rho(0)HepG2 cells) were acquired after 30 subcultures by limited dilution cloning. The cell survival was then observed in the absence of acetylformic acid and uracil, and the total mtDNA deletion in the cells was confirmed by PCR. The radiosensitivity of HepG2 and rho(0)HepG2 cells was evaluated by exposure to gradient doses of 6 MV X ray irradiation. The cell apoptosis was assessed following a 2 Gy X-ray exposure with Hochest33342 staining, and the invasiveness of rho(0)HepG2 cells was measured by Transwell assay. RESULTS: HepG2 cells could survive 30 subcultures in the presence of ethidium bromide, and massive cell death occurred after removal of acetylformic acid and uracil from the medium. PCR confirmed total mtDNA deletion from rho(0)HepG2 cells, whose alpha/beta value was significantly lower than that of HepG2 cells. rho(0)Hep-G2 cells showed an obviously lowered cell apoptosis rate following X-ray exposure with enhanced cell invasiveness. CONCLUSION: HepG2 cells can be induced by ethidium bromide into rho(0)HepG2 cells with an increased radiation resistance, anti-apoptosis ability and cell invasiveness. PMID- 26111672 TI - [3-O-beta-chacotriosyl benzyl ursolate inhibits entry of H5N1 influenza virus into target cells]. AB - OBJECTIVE: To study the inhibitory activities of 3-O-beta-chacotriosyl benzyl ursolate and its derivatives as potential new anti-influenza virus agents against the entry of H5N1 influenza viruses into the target cells. METHODS: Four target compounds were designed and synthesized, which were structurally related to the lead compound 3-O-beta-chacotriosyl methyl ursolate (1). The inhibitory activities of these compounds were tested at a cellular level psuedovirus system targeting H5N1 influenza viruse entry. RESULTS AND CONCLUSION: The compounds 1b, 1c and 1d showed potent inhibitory activities against the entry of A/Thailand/Kan353/2004 pseudovirus into the target cells, and among them compound 1d showed the strongest inhibitory activity with an IC50 value of 0.96 +/- 0.10 umol/L. The structure-activity relationship analysis of these compounds indicated that when 17-COOH of ursolic acid was esterified, introduction of Me groups rather than aryl groups more strongly enhanced the inhibitory activity. Changing 17-COOH of ursolic acid into amide could increase the antiviral activity and decrease the cytotoxicity of the compounds in MDCK cells. PMID- 26111673 TI - [Effect of suppressing apoptosis signal regulating kinase 1 on GFAP and vimentin expression and hindlimb mobility in rats after spinal cord injury]. AB - OBJECTIVE: To investigate the effect of suppressing apoptosis signal regulating kinase 1 (ASK1) on glial fibrillary acidic protein (GFAP) and vimentin expressions at the injury site and on hindlimb mobility in rats after spinal cord injury (SCI). METHODS: The rat models of SCI were established by extradural compression of the spinal cord using an aneurysm clip. The injured rats were treated with normal saline (model group), ASK1 specific inhibitor thioredoxin (Trx group), or ASK1 monoclonal antibody (Anti-ASK1 group), and the rats receiving a sham operation underwent laminectomy without SCI. The expression of GFAP and vimentin were detected by Western blotting and immunofluorescence assay at 1, 7, 14 and 28 days after SCI. The motion function of the hindlimbs of the injured rats was assessed with Basso Beattie Bresnahan (BBB) scores, and somatosensory-evoked potentials (SEP) and motor-evoked potentials (MEP) were determined to examine the electrophysiological changes. RESULTS: At 1 day after SCI, the expressions of GFAP and vimentin showed no significant differences among the groups; at 7, 14 and 28 days after SCI, GFAP and vimentin expressions significantly increased in Trx and Anti-ASK1 groups compared with those in the model group (P<0.01). The BBB scores showed no significant differences among the groups at 1, 7 and 14 days after SCI, while at 28 days, the BBB scores in Trx and Anti-ASK1 groups were significantly higher than those in the model group (P<0.01). At 28 days after SCI, the latent period of SEP and MEP decreased and the amplitude increased significantly in Trx and Anti-ASK1 groups compared with that in the model group (P<0.01). CONCLUSION: Blocking ASK1 can inhibit the expression of GFAP and vimentin in glial scars and improve the outcomes of hindlimb mobility in rats after SCI. PMID- 26111674 TI - [Expression and functional assessment of solute carrier 26A transporter family in HEK-293 cells]. AB - OBJECTIVE: To express solute carrier 26A proteins in HEK-293 cells and explore their functions. METHODS: SLC26A-eGFP plasmids were transiently transfected into HEK-293 cells, and the nonlinear capacitance of the cells expressing SLC26A proteins was measured by whole-cell patch recording. RESULTS: All the SLC26A transporters were expressed on the membrane of HEK-293 cells. Each member of the SLC26A transporter family showed robust nonlinear capacitance, which represented their binding capability with anions. CONCLUSION: The SLC26A transporters expressed on HEK cells show similar functions as expected in tissue environment. The plasmids we constructed facilitate structural and functional study of SLC26A transporters. PMID- 26111675 TI - [Treatment options in HBeAg-positive chronic hepatitis B patients with a poor response to 24-week interferon monotherapy]. AB - OBJECTIVE: To evaluate the efficacy and safety of 4 treatment options for HBeAg positive chronic hepatitis B (CHB) patients following a suboptimal response to 24 week interferon monotherapy. METHODS: The data of 193 HBeAg-positive CHB patients with suboptimal response to 24-week interferon monotherapy were collected from Nanfang Hospital between September, 2010 and January, 2013. According to the subsequent treatments, the patients were divided into group A with additional entecavir or adefovir, group B with further interferon monotherapy, group C with conversion to NAs therapy, and group D with direct therapy withdrawal, and the biochemical and virological results at weeks 24, 48 and 72 were analyzed in the 4 groups. RESULTS: At week 48, the HBV DNA negative rates and serum alanine aminotransferase (ALT) normalization rates were both significantly higher in group A and C than in group B (P<0.05); in group A, ETV therapy subgroup had a significantly higher HBV DNA negative rate than ADV therapy subgroup at week 48 (90.3% vs 59.5%, Chi=8.255, P=0.004). At week 72, 39.7%(27/68) of the patients in group A achieved HBeAg seroconversion, a rate significantly higher than those in groups B (Chi=4.238, P=0.040) and C (Chi=7.681, P=0.006); the HBV DNA negative rate and ALT normalization rate in group A were 85.3%(58/68) and 86.8%(59/68), respectively, both significantly higher than those in group B (Chi=23.018, P<0.001; Chi=5.987, P=0.014) but comparable to those in group C (P>0.05). In the two subgroups in group A, the HBV DNA negative rate and HBeAg seroconversion rate were both significantly higher in ETV subgroup (Chi=9.823, P=0.002; Chi=5.450, P=0.020). In group D, all the patients remained HBeAg-positive with abnormal ALT levels and high level of HBV DNA. CONCLUSION: For HBeAg-positive CHB patients with suboptimal response to 24-week interferon monotherapy, combined treatment with NAs (especially ETV) and extension of the treatment course can significantly improve the HBeAg seroconversion rates, HBV DNA negative rates, and ALT normalization rates. PMID- 26111676 TI - [Effect of exercise load on apparent diffusion coefficient and fractional anisotropy of normal lumbar intervertebral discs in diffusion tensor imaging]. AB - OBJECTIVE: To investigate the effect of exercise load on apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of normal lumbar intervertebral discs in magnetic resonance (MR) diffusion tensor imaging (DTI). METHODS: Thirty healthy volunteers (24 males and 6 females, aged 19 to 25 years) underwent examinations with MR T2WI and DTI of the lumbar intervertebral discs before and after exercise load. Pfirrmann grading was evaluated with T2WI, and the B0 map, ADC map and FA map were reconstructed based on the DTI data to investigate the changes in ADC and FA after exercise. RESULTS: Of the 30 volunteers (150 intervertebral discs) receiving the examination, 27 with discs of Pfirrminn grade II were included for analysis. In these 27 volunteers, the average ADC and FA before exercise were (1.99 +/- 0.18)*10-3 mm2/s and 0.155?0.059, respectively. After exercise, ADC was lowered significantly to (1.93 +/- 0.17)*10-3 mm2/s (P<0.05) and FA increased slightly to 0.1623 +/- 0.017 (P>0.05). CONCLUSION: DTI allows quantitatively analysis of the changes in water molecular diffusion and anisotropy of the lumbar intervertebral discs after exercise load, which can cause a decreased ADC and a increased FA value, and the change of ADC is more sensitive to exercise load. PMID- 26111677 TI - [Expression of BATF, a member of the activator protein-1 family, in renal tissues of MRL/lpr mice]. AB - OBJECTIVE: To investigate the expression of BATF, a member of the activator protein-1 family, in the renal tissues of mice with lupus nephritis. METHODS: The renal tissues from 24-week-old female MRL/lpr mice and age- and sex-matched C57BL/6 mice were examined for BATF protein expressions using Western blotting and for expressions of BATF, RORgammat and IL-17A mRNA using quantitative real time PCR. The results of laboratory examinations were analyzed in relation with the histopathology of the mice. RESULTS: The urinary protein and ds-DNA levels were significantly higher in MRL/lpr mice than in the control mice (P<0.05). Compared to normal control mice, MRL/lpr mice showed obvious glomerular fibrosis and inflammatory cell infiltrating with significantly increased BATF protein and mRNA expressions (P<0.05) and RORgammat and IL-17 mRNA expressions in the renal tissues (P<0.05). In MRL/lpr mice, the expression of BATF mRNA was positively correlated with the RORgammat and IL-17A mRNA expressions in the renal tissues. CONCLUSION: The renal expressions of BATF protein and mRNA is increased in MRL/lpr mice. BATF may participate in the immunopathogenesis of lupus nephritis by enhancing Thl7 cell response. PMID- 26111678 TI - [Iohexol tracing of hyaluronic acid distribution in the knee joint cavity of rabbits]. AB - OBJECTIVE: To investigate the distribution of hyaluronic acid (HA) with iohexol tracing in the knee joint cavity of rabbits using CT plain scan, three dimensional reconstruction and Chi-ray and observe how different injection sites affect HA distribution. METHODS: Mixtures of HA and iohexol (tracer) were prepared that contained final iohexol concentrations of 2.5%, 5%, 10%, 20%, or 40%. The HA-iohexol mixtures (0.5 ml) were injected into rabbit knee joints, and the optimal iohexol concentration that allowed clear differentiation of the injected agents from the surrounding tissues was determined using dual-source CT plain scan and three-dimensional reconstruction technique. The HA-iohexol mixture (0.5 ml) containing the optimal concentration of iohexol was then injected into the knees of the rabbits either through the patella medial approach or the medial joint line approach, and HA distribution in the knee joint cavity was observed using CT scan and Chi-ray. RESULTS: The CT value of HA-iohexol mixture increased progressively with the tracer concentration. After injection of the mixture containing 2.5%, 5%, 10%, 20%, and 40% iohexol, the CT value ratios of the soft tissue, HA-iohexol mixture and bone cortex were 2:7:46, 2:14:44, 2:28:44, 2:60:46, and 2:98:45, respectively, and a iohexol concentration of 5% was determined as optimal for differntiating the injected agents from the surrounding tissues. The HA-iohexol mixutre containing 5% iohexol injected through the medial patellar approach was distributed mainly over the patello-femoral joint, and that injected through the joint line approach was found mainly over the tibio-femoral joint. CONCLUSION: HA-iohexol mixture containing 5% iohexol allows clear differentiation of bone cortex and soft tissues in rabit knee joint from the injected agents on CT scan and Chi-ray, and the injection approach can influence HA distribution in the knee joint cavity. PMID- 26111680 TI - [Construction a lentiviral vector for RNA interference of glutathione peroxidase 2 gene and its effect on HepG2 cell apoptosis]. AB - OBJECTIVE: To construct a RNA interference lentiviral vector for human glutathione peroxidase 2 (GPX2) gene and observe the effect of GPX2 knockdown on cell apoptosis. METHODS: The sequence of the small interfering RNA (siRNA) for GPX2 interference was inserted into the pSicoR vector. HepG2 cells were infected by the packaged si-GPX2 lentivirus and the expression of GPX2 in the infected cells was detected by both RT-PCR and Western blotting. Changes of cell apoptosis following the infection were analyzed by flow cytometry. RESULTS: The lentiviral particles pSicoR-GPX2 were successfully packaged. The expression of GPX2 in the infected cells was obviously down-regulated at both RNA and protein levels. GPX2 knockdown caused increased apoptosis rate, increased Bax expression and lowered Bcl-2 expression in HepG2 cells. CONCLUSION: We have successfully constructed the lentiviral vector for RNA interference of human GPX2 gene. PMID- 26111679 TI - [Expression profiling and immunofluorescence localization of the major egg antigen p40 of Schistosoma japonicum in the liver of infected New Zealand white rabbits]. AB - OBJECTIVE: To examine the expression profile and immunofluorescence localization of the major egg antigen p40 of Schistosoma japonicum (Sjp40) during granuloma formation in the liver of infected New Zealand white rabbits. METHODS: New Zealand white rabbits were infected with S. japonicum cercariae, and the livers were harvested at 29 and 45 days post-infection (dpi). The total RNA of the liver tissues was extracted for expression profiling of Sjp40 by quantitative reverse transcription-PCR (qRT-PCR) with GAPDH of S. japonicum as the endogenous reference gene. The expression of Sjp40 in the liver were detected by Western blotting using anti-Sjp40 monoclonal antibody (mAb) 9G7 or anti-Toxoplasma gondii tSAG1 mAb Y3A8 (control) as the primary antibody. Paraffin sections of the liver were prepared for observing egg granuloma formation using HE staining and for indirect immunofluorescence assay of Sjp40 location in the trapped eggs and egg granulomas. RESULTS: The level of Sjp40 mRNA in the eggs trapped in rabbit livers was significantly higher at 45 dpi than that at 29 dpi (P<0.05), and Western blotting confirmed the presence of Sjp40 protein in the rabbit livers at both 29 and 45 dpi. Immunofluorescence assay demonstrated localized expression of Sjp40 in the immature eggs in the rabbit liver at 29 dpi, but at 45 dpi fluorescence was detected in clusters of mature eggs containing miracidium and in the surrounding egg granulomas. CONCLUSIONS: The transcriptional levels of Sjp40 significantly increased with the maturation of eggs trapped in the rabbit livers. Sjp40 protein spread from the eggs to the surrounding egg granuloma at 45 dpi when acute liver granulomatous lesions occur, suggesting that Sjp40 plays a key role in egg granulomas formation in the livers of infected New Zealand white rabbits. PMID- 26111681 TI - [Successful pregnancy in women with infertility following surgeries for gynecological malignancies: report of 3 cases and literature review]. AB - OBJECTIVE: We report 3 cases of successful pregnancies in women with a history of surgeries for gynecological malignancies and postoperative infertility, achieved by in vitro fertilization-embryo transfer (IVF-ET) with controlled ovarian hyperstimulation. All the 3 patients had clinical pregnancies without cancer recurrence. In such cancer survivors with infertility, the ovarian reserve is severely impaired by cancer therapies and assisted reproductive techniques should be the primary option. PMID- 26111682 TI - [Inhibitory effect of 17-AAG combined with paclitaxel on proliferation of esophageal squamous cell carcinoma Eca-109 cells in vitro]. AB - OBJECTIVE: To investigate the effect of 17-AAG combined with paclitaxel (PTX) on the proliferation and apoptosis of esophageal squamous cell carcinoma cell line Eca-109 in vitro. METHODS: Eca-109 cells were treated with 17-AAG and PTX either alone or in combination. The proliferation of Eca-109 cells was detected by MTT assay, and the cell cycle changes and cell apoptosis were determined by flow cytometry. RESULTS: Compared with the control group, both 17-AAG and PTX significantly inhibited the proliferation of Eca-109 cells. A combined treatment of the cells with 0.5 umol/L PTX and 0.625 umol/L 17-AAG produced an obviously stronger inhibitory effect on the cell proliferation than either of the agents used alone (P<0.01). Flow cytometry showed that, 17-AAG and PTX used alone caused Eca-109 cell cycle arrest in G2/M phase and S phase, respectively, and their combined use caused cell cycle arrest in both G2/M and S phases. The cell apoptosis rates of Eca-109 cells treated with 17-AAG, PTX and their combination were 4.52%, 10.91%, and 29.88%, respectively, all significantly higher than that in the control group (1.32%); the combined treatment resulted in a distinct apoptotic peak that was significantly higher than that caused by either of the agents alone. CONCLUSION: 17-AAG and PTX can inhibit cell proliferation and promote apoptosis of Eca-109 cells, and their combination produces stronger effects in inhibiting cell proliferation and increasing cell apoptosis. PMID- 26111683 TI - [Expression of progesterone-induced blocking factor in severe preeclampsia and its association with immune tolerance imbalance]. AB - OBJECTIVE: To explore progesterone-induced blocking factor (PIBF) expression in the placenta and blood of patients with severe preeclampsia and its relationship with immune tolerance imbalance. METHODS: Forty-seven patients admitted between January and December, 2012 were enrolled in this study, including 25 patients with early-onset severe preeclampsia (EOPE) and 22 with late-onset severe preeclampsia (LOPE), with 25 women with normal pregnancy serving as control group. The antenatal blood and postpartum placenta were collected for immunohistochemical staining to detect PIBF expression in the placenta and for testing serum PIBF level using ELISA. Flow cytometry was used to detect the percentage of circulating Th1 and Th2 cells and the Th1/Th2 ratio was calculated. RESULTS: PIBF was expressed in decidual cells, syncytiotrophoblasts and partial cytotrophablasts. The serum PIBF levels were 213.58 +/- 44.93 ng/ml in EOPE group, 243.00?61.19 ng/ml in LOPE group and 273.91 +/- 48.57 ng/ml in control group. There were significant differences in serum PIBF, blood Th1/Th2 and placenta PIBF-IOD among the 3 groups (P<0.05). EOPE group had significantly lower serum PIBF, lower llacental PIBF quantity (PIBF-IOD) and higher blood Th1/Th2 than the control group (P<0.05). Serum PIBF in women with severe preeclampsia was positively correlated with placenta PIBF-IOD and negatively with blood Th1/Th2 ratio (P<0.05), but a negative correlation between serum PIBF and 24-hour urinary protein was found only in EOPE group (P<0.05). CONCLUSION: The immune tolerance imbalance mediated by PIBF may participate in the pathogenesis of severe preeclampsia. PIBF, the immune suppressor secreted by lymphocytes of pregnancy women, is also a protective factor against severe preeclampsia, which is expected to be a new target in therapy. PMID- 26111684 TI - [Effects of propofol on pulmonary metastasis of intravenously injected MADB106 tumor cells and expression of E-cadherin and beta-catenin in rats]. AB - OBJECTIVE: To investigate the effects of different doses of propofol on pulmonary metastasis of intravenous injected MADB106 tumor cells and the expression of E cadherin and beta-catenin in the metastatic tumor tissue in rats. METHODS: Forty Fischer 344 male rats were randomly divided into 4 groups (n=10) for intravenous administration of normal saline, intralipid, or propofol at 30 or 50 mg/kg via the femoral vein. One hour after the infusion, MADB106 tumor cells (2*10(5)) were injected intravenously in the rats. Three weeks later, pulmonary metastasis tumor foci and metastatic inhibitory rate were observed and the expression of E cadherin and beta-catenin in the metastatic tumor tissue were detected by immunohistochemistry. RESULTS: Compared with the normal saline group, intralipid group showed no significant differences in the number of metastatic tumor foci in the lungs or E-cadherin and beta-catenin expressions (P>0.05), which were all significantly lowered in the two propofol groups (P<0.05 or 0.01). The dose of propofol was inversely correlated with the number of metastasis tumor foci (r= 0.879) and expressions of E-cadherin (r=-0.755) and beta-catenin (r=-0.693) (P<0.01). CONCLUSION: Propofol can dose-dependently suppress pulmonary metastasis of intravenous injected MADB106 tumor cells by inhibiting the Wnt/beta-catenin pathway and down-regulating E-cadherin and beta-catenin expressions in the metastatic tumor tissue. PMID- 26111686 TI - [Three-dimensional isotropic magnetic resonance imaging of the ankle joint]. AB - OBJECTIVE: To compare the image quality of isotropic 3-dimensional fast spin echo (3D-FSE), 3D fast field echo (3D-FFE), and 2D fast spin echo (2D-FSE) sequences in magnetic resonance imaging (MRI) of the anatomical structure of the ankle joint. METHODS: The ankle joints of 10 healthy volunteers were examined with isotropic 3D-FSE, 3D-FFE and 2D-FSE sequences using a 1.5T MR scanner and 3D reconstruction. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the tissues were measured. Two radiologists evaluated the image quality of the 3 sequences using a 5-point Likert scale in a double-blinded manner. RESULTS: The 3D-FSE sequences resulted in the highest SNRs for all the tissues and the highest CNRs for differentiation between cartilage and marrow, between muscle and tendon, and between tendon and fluid. In the estimation of image quality for cartilages, 3D-FFE had the highest score followed by 3D-FSE, and the latter had the highest score among the 3 sequences in displaying the tendon. CONCLUSION: 3D-FSE sequence has a high performance in displaying the anatomical structures of complex joints especially for cartilage, ligament, and tendon tissues. PMID- 26111685 TI - [Mitochondrial injury in enterovirus 71-infected Vero cells and its mechanism]. AB - OBJECTIVE: To investigate the mitochondrial injury in enterovirus 71 (EV71) infected Vero cells and explore the possible mechanism. METHODS: A clinical isolate of EV71 was inoculated to Vero cells and the EV71 antigen was detected by immunofluorescence assay. The morphological changes of Vero cells were observed using optical microscopy and transmission electron microscopy. The diameter and area density of the viral particles and the ratio and area density of vacuolated mitochondria in the cells were measured on the ultrastructural images. RESULTS: EV71-infected Vero cells underwent obvious changes and to a spherical morphology followed by cell death EV71 particles were detected in the cytoplasm by immunofluorescence. Ultrastructurally, the infected cells contained a large number of viral particles in the cytoplasm, with a clustered distribution and lattice-like arrangement. The diameter of the particles were 16.3 nm and the mean area density was 38.3%. Most of the mitochondria presented with swelling, vacuoles and degeneration. The ratio of the vacuolated mitochondria was 90.9% with a mean area density of 89.2%. Viral particles were also found in some mitochondria. CONCLUSION: EV71 proliferates in the cytoplasm and invades the mitochondria of infected Vero cells leading to mitochondrial injury and cell death, suggesting that mitochondria are the targets for EV71 infection. PMID- 26111687 TI - [Early intervention with aspirin for preventing preeclampsia in high-risk women: a meta-analysis]. AB - OBJECTIVE: To estimate the effect of early intervention with aspirin for prevention of preeclampsia in high-risk women. METHODS: A systematic review and meta-analysis were performed based on the principles and methods of Cochrane systematic reviews. Electronic databases were searched for randomized trials comparing aspirin with either placebo or no aspirin. Studies were included when meeting the inclusion criteria that the participants were pregnant women at a high risk of preeclampsia and started aspirin therapy at 16 gestational weeks or earlier, which were assessed by two independent reviewers. Meta-analysis was conducted using Review Manger 5.3 software. RESULTS: A total of 5 studies involving 860 participants were included in the final analysis. In the high-risk women, early use of aspirin showed an OR of 0.35 (95% CI 0.17-0.75) for preventing pregnancy-induced hypertension (PIH), 0.75 (95% CI 0.47-0.98) for preeclampsia, 0.53 (95% CI 0.29-0.98) for intrauterine growth retardation, and 0.20 (95% CI 0.08-0.48) for preterm birth; the average birth weight in aspirin intervention group was 107.15 g (95% CI 76.13-138.18, P<0.001) more than that in the control group. CONCLUSION: In high-risk pregnancies, early aspirin intervention starting before 16 weeks of gestation can prevent PIH, preeclampsia, IUGR, and preterm birth and help to increase the birth weight. PMID- 26111688 TI - [Feasibility of integrating tumor therapy with therapeutic effect evaluation using siRNA-loaded microbubbles]. AB - OBJECTIVE: To evaluate the feasibility of integrating cancer gene therapy with therapeutic effect evaluation using siRNA-loaded nano-scale microbubbles (siRNA NBs). METHODS: siRNA-NBs were prepared by hetero-assembly of polymeric siRNA micelles and liposomal microbubbles, and the particle sizes and surface potentials were examined with dynamic light scattering. The distributions of cy3 labled siRNA in the tumor tissues were evaluated using confocal laser scanning microscopy. A siRNA targeting the anti-apoptosis gene SIRT2 was designed and its gene silencing effects was tested in vivo using siRNA-NBs with ultrasound exposure. The therapeutic effect of the loaded siRNA-NBs was evaluated by contrast-enhanced ultrasonography. RESULTS: The siRNA-NBs had a mean diameter of 400.7 +/- 30.5 nm with a weak positive charge of +8.8 +/- 0.8 mV. With ultrasound exposure, siRNA-NBs effectively delivered cy3-siRNA into the cytoplasm of cancer cells and caused SIRT2 suppression and cell apoptosis in tumor tissues, resulting in significantly suppressed tumor growth. In addition, contrast-enhanced ultrasonography of siRNA-NBs provided good imaging quality to allow real-time observation of blood supply during gene therapy. CONCLUSIONS: As a novel ultrasound contrast agent, siRNA-NBs make possible the integration of tumor gene therapy and therapeutic effect evaluation for cancer. PMID- 26111689 TI - [Preparation and performance of pravastatin sodium-loaded chitosan microspheres]. AB - OBJECTIVE: To prepare pravastatin sodium-loaded chitosan microspheres to allow sustained drug release. METHODS: The drug-loaded chitosan microspheres were prepared by using genipin as the cross-linker. The influences of molecular weight of chitosan, volume ratio of oil and water, reaction temperature, and stirring speed on the formation of chitosan microspheres were investigated. The morphology of the microspheres was observed using scanning electron microscopy. The encapsulation efficiency, swelling ratio under different pH conditions, and in vitro drug release were measured. RESULTS: The in vitro release of pravastatin sodium could last for at least 31 days. The drug release rate varied with the reaction condition. The drug entrapment efficiency of the microsphere was 54.7%. The optimal processing conditions were as follows: chitosan viscosity of 200-400 mPa.s, oil-water proportion of 10:1, stirring speed of 850 r/min, and reaction temperature at 40 degrees celsius;. CONCLUSION: The pravastatin sodium-loaded microspheres show good sustained drug release property, and the drug release rate can be modified by controlling the cross-linking time. PMID- 26111690 TI - [Lonidamine induces apoptosis via endoplasmic reticulum stress response and down regulating cIAP expression in human breast carcinoma MCF-7 cells]. AB - OBJECTIVE: To investigate the effect of lonidamine on apoptosis of human breast carcinoma cells MCF-7 and the possible mechanisms. METHODS: MTT assay and colony forming assay were used to evaluate the growth inhibition induced by lonidamine in breast cancer MCF-7 cells. PI/Annexin-V staining was used to detect the apoptotic cells. The ATP levels in the cells were detected using an ATP assay kit. The expression of glucose regulated protein 78 (GRP78), inhibitor of apoptosis protein (cIAP1) and caspase-8 were analyzed with Western blotting. RESULTS: MTT assay and colony-forming assay showed that 50-250 mmol/L lonidamine caused a time- and concentration-dependent inhibition of MCF-7 cell proliferation. Exposure to increased concentrations of lonidamine resulted in significantly increased apoptosis rate in MCF-7 cells. In MCF-7 cells treated with 50, 150 and 250 mmol/L lonidamine for 5 h, the intracellular ATP levels were lowered to 80.67%, 62.78% and 30.73% of the control level, respectively. Western blotting showed that lonidamine up-regulated the expression of GRP78, down regulated the expression of cIAP1 and promoted caspase-8 activation as the treatment time extended. CONCLUSION: Lonidamine can inhibit the proliferation and induce apoptosis in MCF-7 cells, and these effects are probably mediated by reducing ATP level, inducing endoplasmic reticulum stress response, down regulating cIAP1, and promoting caspase-8 activation in the cells. PMID- 26111691 TI - [Plasma levels of mannan-binding lectin-associated serine protease 2 in children with upper respiratory tract infection]. AB - OBJECTIVE: To explore the significance of plasma levels of mannan-binding lectin (MBL)-associated serine protease 2 (MASP2) in children with upper respiratory tract infection (URTI). METHODS: A total of 103 children with URTI and 35 healthy children were examined for plasma levels of MASP2 and C-reactive protein (CRP). According to CRP levels, white blood cell count (WBC), stage of infection, and administration of treatments, the children with URTI were divided into the elevated CRP group (n=48) and the normal CRP group (n=54), elevated WBC group (n=61) and normal WBC group (n=40), the early stage of infection without treatment group (n=68) and mid-late stage of infection with treatment group (n=35). RESULTS: Plasma MASP2 levels was significantly higher in URTI group than in the healthy control group (P<0.001) and showed a close correlation with age (r=0.302, P<0.01). Plasma MASP2 level was significantly correlated with CRP level in elevated CRP group (r=0.310, P<0.05) but not in normal CRP group (P>0.05), correlated with WBC in elevated WBC group (r=0.392, P<0.01) but not in normal WBC group (P>0.05), and was significantly higher in early stage infection without treatment group than in mid-late stage of infection with treatment group (P<0.01). MASP2, MBL2 and CRP genes had a common binding site for the transcription factor HNF-4alpha. CONCLUSIONS: MASP2 may be an acute-phase protein, and its plasma level might serve as a new reference index in the diagnosis of URTI in children. PMID- 26111692 TI - [Quantitative detection of plasma level of human telomerase reverse transcriptase mRNA in patients with nasopharyngeal carcinoma]. AB - OBJECTIVE: To quantitatively measure plasma level of human telomerase reverse transcriptase (hTERT) mRNA in patients with nasopharyngeal carcinoma (NPC) and explore its implications for NPC diagnosis and treatment. METHODS: With 24 healthy volunteers serving as controls, the plasma level of hTERT mRNA was detected in 33 NPC patients by real-time PCR before and after treatments with chemotherapy or radiotherapy, and its association with the clinicopathological parameters of the patients were analyzed. RESULTS: The NPC patients showed a significantly higher mean plasma level of hTERT mRNA than the healthy volunteers (10.75 +/- 4.29 vs 0.95 +/- 0.37, P<0.05). The plasma hTERT mRNA level in the NPC patients was significantly correlated with clinical staging, tumor size, and degree of nodal metastasis (P<0.05) but with gender or age (P>0.05). In patients with stage I and II NPC, the plasma hTERT mRNA level decreased significantly after radiotherapy (5.60 +/- 2.33 vs 3.43 +/- 1.42); in patients in advanced stages (III and IV), plasma hTERT mRNA level decreased significantly from 12.68 +/- 3.08 to 10.68 +/- 2.48 (P<0.05) after chemotherapy and to 3.13 +/- 1.69 (P<0.05) after radiotherapy. CONCLUSION: Radiotherapy and chemotherapy can effectively suppress elevated plasma hTERT mRNA levels in NPC patients. Plasma hTERT mRNA level is closely related to the clinicopathological factors and provides important information for early diagnosis and therapeutic effect evaluation of NPC. PMID- 26111693 TI - [Effects of metformin on apoptosis induced by advanced glycation end-products and expressions of caspase-3, Bax and Bcl-2 in human dermal fibroblasts in vitro]. AB - OBJECTIVE: To investigate the effect of metformin in protecting against advanced glycation end products (AGEs)-induced apoptosis in human primary dermal fibroblasts. METHODS: Fibroblasts were exposed to 100, 200, or 300 ug/mL AGEs, 300 ug/mL bovine serum albumin (BSA), or 300 ug/mL AGEs and 1 mmol/L metformin for 24, 48, or 72 h. The exposed cells were examined for cell apoptosis using a cell counting kit. The expressions of caspase-3, Bax and Bcl-2 protein in the fibroblasts treated for 72 h were detected with Western blotting. RESULTS: AGEs exposures caused significant dose- and time-dependent apoptosis in the fibroblasts. A 72-h exposure to 300 ug/mL AGEs resulted in obviously increased apoptosis of the fibroblasts compared to the control group (0.72 +/- 0.02 vs 1 +/ 0.04, P<0.05), and metformin significantly decreased AGEs-induced apoptosis (0.98 +/- 0.02 vs 0.72 +/- 0.02, P<0.05). The expressions of caspase-3 and Bax protein were significantly increased (P<0.05) and Bcl-2 protein expression was decreased (P<0.05) with a lowered Bcl-2/Bax ratio in AGEs-treated fibroblasts (P<0.05), and such changes were significantly reversed by metformin treatment (P<0.05). CONCLUSION: Metformin can antagonize AGEs-induced apoptosis in human dermal fibroblasts by regulating the expressions of caspase-3, Bax and Bcl-2. PMID- 26111694 TI - [Effect of RNA interference of CD59 gene on proliferation of non-small cell lung cancer cell line GLC-P in vitro]. AB - OBJECTIVE: To investigate the effect of CD59 gene inhibition mediated by RNA interference on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) GLC-P cells in vitro. METHODS: Recombinant plasmids for RNA interference of CD59 gene were constructed and transfected into GLC-P cells via lipofectamine 2000. The stably transfected cells were examined with real-time RT-PCR, MTT assay and enzyme-linked immunosorbent assay to investigate the changes in cell proliferation and apoptosis. RESULTS: Compared with the control cells, the cells transfected with CD59-siRNA showed significantly decreased expression levels of CD59 mRNA (P<0.05) and significantly inhibited cell proliferation. CONCLUSION: CD59 gene is highly expressed in NSCLC and RNA interference-mediated CD59 silencing can strongly inhibit the proliferation and induce apoptosis in GLC-P cells, which shed light on a potentially new target for targeted gene therapy of NSCLC. PMID- 26111695 TI - [Construction of a online database for functional dyspepsia]. AB - OBJECTIVE: To establish a clinical database of functional dyspepsia for epidemiological researches and standardizing clinical diagnosis and treatment. METHODS: The functional dyspepsia database was designed to incorporate the data from in-patients and out-patients with functional dyspepsia treated since July, 2013 and was constructed using Visual Studio. The patient data were collected using a customized case report form designed according to the Roman criteria III and the etiology, symptoms, and treatments of the patients. All the cases deemed ineligible were excluded. The database was displayed on a website and allowed online data entry, case searches and statistical analysis of the clinical parameters. RESULTS AND CONCLUSION: The established online database for functional dyspepsia contained data of the general information, clinical symptoms, psychological status, living habits, dietary habits, medical history, examination results, clinical diagnosis, treatment methods and courses, outcomes and data statistics. The database was fully functional and provided complete and standardized data of functional dyspepsia for clinical studies. PMID- 26111696 TI - [Ovarian response and pregnancy outcome in hyper-responders during repeated in vitro fertilization and embryo transfer]. AB - OBJECTIVE: To evaluate the ovarian response and pregnancy outcomes in patients with excessive ovarian response receiving long-protocol pituitary down-regulation during repeated in vitro fertilization and embryo transfer (IVF-ET). METHODS: Sixty IVF-ET cycles from January 2008 to December 2011 were analyzed retrospectively. The clinical characteristics were compared between the various treatment cycles. RESULTS: Compared with those with the first treatment cycle, the patients receiving repeated cycles had a significantly older age (P<0.001), reduced initial doses of Gn (P=0.049), and moderately lowered estrogen level on the day of hCG administration (E2) (P=0.027) and the number of oocytes retrieved (P=0.030). The high-quality embryo formation rate (P<0.001) and clinical pregnancy rate (P=0.009) were both significantly higher in patients with repeated cycles. The dose for down-regulation, total Gn dose, duration of Gn stimulation, number of two pronuclei (PN), number of fertilized oocyte, and the cancellation rate for a high risk of ovarian hyperstimulation syndrome (OHSS) were all comparable between the two groups (P>0.05). The recurrence rate of ovarian excessive respond was 40% (12/30). CONCLUSIONS: For patients receiving repeated IVF treatment cycle with a high ovarian response, a smaller initial dose of Gn should be used to minimize the risk of hyper-response and improve the outcome of assisted reproductive treatment. PMID- 26111697 TI - [Effect of Radix euphorbiae pekinensis extract on bioavailability of paclitaxel after their oral co-administration]. AB - OBJECTIVE: To evaluate the effect of Radix euphorbiae pekinensis extract on the permeability and bioavailability of paclitaxel co-administered orally. METHODS: Based on Ussing Chamber and in vivo experiment, the permeability and bioavailability of paclitaxel were evaluated after oral co-administration with radix euphorbiae pekinensis in rats. The contents of paclitaxel in the permeates and the blood samples were determined using HPLC and LC-MS/MS method, respectively. RESULTS: In Radix euphorbiae pekinensis co-administration group, the Papp of the mucosal-to-serosal (M-S) transport or serosal-to-mucosal transport (S-M) of paclitaxel in the jejunum or ileum segment differed significantly from those in verapamil co-administration group and blank control group (P<0.05), but the Papp of S-M transport in the colon showed no significant difference from that in the blank control group. In the blank group, the average absolute bioavailability (AB%) of orally administered paclitaxel was only 2.81%, compared to that of 7.63% in radix euphorbiae pekinensis group. The average AB% in verapamil group was about 1.5 times that of the blank group. CONCLUSION: Co administration of Radix euphorbiae pekinensis extract can increase the bioavailability of orally administered paclitaxel. PMID- 26111698 TI - [Effects of obstructive sleep apnea-hypopnea syndrome and age on sleep architecture]. AB - OBJECTIVE: To investigate the effects of obstructive sleep apnea-hypopnea syndrome (OSAHS) and age on sleep architecture and the therapeutic effects of continuous positive airway pressure (CPAP). METHODS: We retrospectively analyzed 222 subjects undergoing polysomnography (PSG) for snoring, who received CPAP under PSG on the next day following the initial PSG. The sleep architecture of the subjects in different age groups and in groups with different severities of OSAHS was analyzed before and after adjustment for apnea-hypopnea index (AHI) or age. The sleep architecture and ventilation function of the patients with OSAHS were also analyzed after CPAP. RESULTS: N3 sleep showed the strongest correlation with AHI (r=-0.361), and REM sleep and wake after sleep onset (WASO) were the most strongly correlated with age (r=-0.211 and 0.216, respectively). The 4 age groups showed significant differences in sleep efficiency (P<0.001), N1 (P=0.015), N2 (P=0.013) and REM (P=0.030) sleeps, and WASO (P=0.001) but not in AHI (P=0.185). REM sleep decreased and WASO increased with an increasing age. The sleep efficiency and architecture were still significant different after adjustment for AHI. In 4 groups with different severity of OSAHS, N1, N2 and N3 sleeps were significant different after adjustment for age (P=0.011, 0.017, 0.001). In patients with moderate or severe OSAHS, N3 sleep increased with the increase of AHI. After CPAP for OSAHS, N1 and N2 sleeps significantly decreased, and N3 and REM sleeps increased (P<0.001). CONCLUSION: Between OSAHS and age, REM sleep and WTSO are more importantly affected by age, while OSAHS more strongly affects N3 sleep. CPAP can improve the sleep quality of patients with OSAHS. PMID- 26111699 TI - [Muscle tissue lymphoma presenting only with fever of unknown origin: a case report and literature review]. AB - OBJECTIVE: Extra-nodal malignant lymphoma is often characterized by a lack of typical symptoms and positive results of auxiliary examinations, which make diagnosis difficult. In some cases, fever can be the only clinical manifestation. For the lymphoma patients presenting with persistent fever with a duration over 3 weeks, characteristics of fever including time of fever attack, fever type and effects of drugs may have significant value in the diagnosis, especially in the early stage of the disease or in rare cases. PMID- 26111700 TI - COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): a multicentre randomised controlled trial protocol. AB - BACKGROUND: The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. METHODS/DESIGN: The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants' views of the intervention and factors that acted as facilitators and barriers to participation. DISCUSSION: This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT02325544. PMID- 26111701 TI - Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies. AB - BACKGROUND: The clinical efficacy of the Angiotensin II (AngII) receptor AT2R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT2R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation. We have immunostained AngII, AT2R and the capsaicin receptor TRPV1 in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons. AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT2R agonist C21, and Nerve growth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 and p42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calcium imaging. RESULTS: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control (n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised with AT2R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference between control (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves (4.09 +/- 0.36 pmol/g, n = 31), injured nerves (3.99 +/- 0.79 pmol/g, n = 7), and painful neuromas (3.43 +/- 0.73 pmol/g, n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths were significantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGF significantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitization of capsaicin responses was not observed in the presence of MAP kinase inhibitor PD98059, and the kinase inhibitor staurosporine. CONCLUSION: The major AT2R ligand in human peripheral nerves is AngII, and its levels are maintained in injured nerves. EMA401 may act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in AngII/NGF/TRPV1-convergent pathways. PMID- 26111702 TI - Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16 Leiden germline mutation carriers; a case-control study. AB - BACKGROUND: The p16-Leiden founder mutation in the CDKN2A gene is the most common cause of Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome in the Netherlands. Individuals with this mutation are at increased risk for developing melanoma of the skin, as well as pancreatic cancer. However, there is a notable interfamilial variability in the occurrence of pancreatic cancer among p16-Leiden families. We aimed to test whether previously identified genetic risk factors for pancreatic cancer modify the risk for pancreatic cancer in p16-Leiden germline mutation carriers. METHODS: Seven pancreatic cancer-associated SNPs were selected from the literature and were genotyped in a cohort of 185 p16-Leiden germline mutation carriers from 88 families, including 50 cases (median age 55 years) with pancreatic cancer and 135 controls (median age 64 years) without pancreatic cancer. Allelic odds ratios per SNP were calculated. RESULTS: No significant association with pancreatic cancer was found for any of the seven SNPs. CONCLUSIONS: Since genetic modifiers for developing melanoma have already been identified in CDKN2A mutation carriers, this study does not exclude that genetic modifiers do not play a role in the individual pancreatic cancer risk in this cohort of p16-Leiden germline mutation carriers. The search for these modifiers should therefore continue, because they can potentially facilitate more targeted pancreatic surveillance programs. PMID- 26111703 TI - Chronic heart failure alters orexin and melanin concentrating hormone but not corticotrophin releasing hormone-related gene expression in the brain of male Lewis rats. AB - OBJECTIVE: The aim of this study was to investigate the effect of chronic heart failure (HF; 16 weeks post left coronary artery ligation) on the brain's orexin (ORX) and related neuropeptide systems. METHODS: Indicators of cardiac function, including the percent fractional shortening (%FS) left ventricular posterior wall shortening velocity (LVPWSV) were assessed via echocardiography at 16 weeks post myocardial infarction or sham treatment in male Lewis rats (n=5/group). Changes in gene expression in HF versus control (CON) groups were quantified by real-time PCR in the hypothalamus, amygdala and dorsal pons. RESULTS: HF significantly reduced both the %FS and LVPWSV when compared to CON animals (P<0.02). In the hypothalamus ORX gene expression was significantly reduced in HF and correlated with changes in cardiac function when compared to CON (P<0.02). No significant changes in hypothalamic ORX receptor (type 1 or type 2) gene expression were identified. Alternatively hypothalamic melanin concentrating hormone (MCH) gene expression was significantly upregulated in HF animals and negatively correlated with LVPWSV (P<0.006). In both the amygdala and dorsal pons ORX type 2 receptor expression was significantly down-regulated in HF compared to CON. ORX receptor type 1, CRH and CRH type 1 and type 2 receptor expressions were unchanged by HF in all brain regions analyzed. CONCLUSION: These observations support previous work demonstrating that cardiovascular disease modulates the ORX system and identify that in the case of chronic HF the ORX system is altered in parallel with changes in MCH expression but independent of any significant changes in the central CRH system. This raises the new possibility that ORX and MCH systems may play an important role in the pathophysiology of HF. PMID- 26111704 TI - Cord blood adipokines, neonatal anthropometrics and postnatal growth in offspring of Hispanic and Native American women with diabetes mellitus. AB - BACKGROUND: Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women. METHODS: We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates. RESULTS: DM-O were heavier at birth than Con-O (3.7 +/- 0.6 vs. 3.4 +/- 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1 month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 +/- 14.9 vs. 9.5 +/- 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort. CONCLUSIONS: Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth. PMID- 26111705 TI - Nuclear Myocardial Perfusion Imaging Versus Stress Echocardiography in the Preoperative Evaluation of Patients for Kidney Transplantation. AB - The goal of this study was to evaluate the diagnostic accuracy, cost effectiveness, and appropriate use of SPECT myocardial perfusion imaging (SMPI) versus stress echocardiography in the preoperative evaluation of patients for kidney transplantation. METHODS: A single-institution, retrospective study was performed. SMPI was performed with regadenoson and stress echocardiography predominantly with dobutamine. Findings on subsequent coronary angiography were correlated. A cost analysis for SMPI versus stress echocardiography was modeled using reimbursements from the Center for Medicare Services. RESULTS: One hundred thirteen patients underwent imaging (53 SMPI and 60 stress echocardiography). One hundred percent of SMPI studies were diagnostic, compared with only 80% (48/60) in the stress echocardiography group, and this result was statistically significant (chi(2) = 7.96, P < 0.01). The most common reason for a nondiagnostic test was not reaching the target heart rate. In the SMPI group, 15% (8/53) of patients had ischemia on imaging and all underwent subsequent coronary angiography, which confirmed obstructive coronary lesions. One patient with a negative SMPI result underwent a subsequent angiogram that was negative. In the stress echocardiography group, 5% (3/60) of patients had ischemia on imaging and 2 underwent subsequent angiography, which was negative. Three of 12 patients with nondiagnostic examinations underwent further testing. One patient underwent a follow-up positive SMPI scan but no subsequent coronary angiography. The other 2 patients underwent coronary angiography, which was negative. Of the 45 negative stress echocardiography patients, 6 (13%) underwent angiography, with a positive result for obstructive coronary artery disease in 3 of 6. For the modeling of cost analysis, rates of $1,173 and $1,521 (Center for Medicare Services) were used for SMPI and stress echocardiography, respectively. The model assumed that all nondiagnostic imaging would be referred for further stress testing (i.e., nondiagnostic stress echocardiography would be referred for SMPI). This model estimated that initial noninvasive testing with stress echocardiography versus SMPI resulted in a 50% greater cost. CONCLUSION: For the preoperative evaluation of kidney transplantation, SMPI is more often diagnostic than stress echocardiography. A cost model estimates that initial noninvasive diagnostic testing with stress echocardiography would result in an approximately 50% greater cost than SMPI. Our data also suggest that SMPI has greater diagnostic accuracy than stress echocardiography. Therefore, this single-institution experience supports SMPI as the more appropriate test. PMID- 26111706 TI - Histamine Receptor 1 and 2 Antagonists Alter Biodistribution of Radioiodine. AB - Nuclear medicine technology assumes responsibility for examination-specific patient preparation procedures. This requires a clear understanding of the possible effects of medications on the outcome of examinations. There is evidence that common over-the-counter drugs, histamine 1 (H1) and histamine 2 (H2) receptor blockers and proton pump inhibitors, may directly or indirectly affect thyroid function. The objective was to determine whether short-term use of these drugs alters biodistribution of radioiodine in a rat model. METHODS: Rats received no drug (controls) or daily subcutaneous injections of H1 blocker (promethazine), H2 blocker (famotidine), or proton pump inhibitor (esomeprazole) commencing 1 d before a single intraperitoneal injection of 0.037 MBq (1 MUCi) of (131)I (NaI) and continuing daily until euthanasia at either 1 d or 8 d after (131)I. Organ uptake of (131)I by control and drug-treated rats was compared by gamma-well counting. RESULTS: Promethazine significantly increased uptake of (131)I by the thyroid (drug-treated-to-control ratios) both at 1 d (1.32) and 8 d (1.52) after (131)I. Both famotidine and promethazine (respectively) significantly increased salivary gland uptake of (131)I (drug-treated-to-control ratios) at 1 d (1.37, 1.40) and 8 d (4.52, 5.57) after (131)I. Promethazine significantly increased gastric (131)I uptake (drug-treated-to-control ratios) at 1 d (1.47) and 8 d (1.46) after (131)I. Famotidine and promethazine (respectively) significantly decreased uptake of (131)I by the liver (drug treated-to-control ratios) at 1 d (0.60, 0.71) after (131)I but resulted in a marked increase over control levels (11.21, 9.28) at 8 d. Blood levels of (131)I were not altered by drug treatment. Esomeprazole did not affect radioiodine distribution. CONCLUSION: H1 and H2 blockers alter the biodistribution of radioiodine in the rat. Although the findings remain to be confirmed in humans, these drugs could increase radiation exposure to nontarget tissues, particularly the stomach and salivary tissue, during (131)I therapy and consideration should be given toward avoiding the elective use of these drugs during radioiodine therapy. PMID- 26111708 TI - Prostate Cancer Metastases to Inguinal Lymph Nodes Detected by Attenuation Corrected 11C-Acetate PET/CT. AB - The inguinal lymph nodes are an unusual site of metastases for prostate adenocarcinoma. We present a case in which a 61-y-old man with biochemically recurrent prostate cancer underwent attenuation-corrected (11)C-acetate PET/CT, which demonstrated multiple foci of increased activity in the left inguinal, left iliac chain, and right inguinal regions. The attenuation-corrected CT portion of the scan also showed anterior wall thickening of the rectum. The imaging findings were suggestive of metastatic involvement of the rectum below the dentate line with subsequent spread to the inguinal lymph nodes. PMID- 26111707 TI - Comparison of Cystatin C and beta-Trace Protein Versus 99mTc-DTPA Plasma Sampling in Determining Glomerular Filtration Rate in Chronic Renal Disease. AB - Glomerular filtration rate (GFR) is the best indicator of renal function. The gold standard for GFR measurement is inulin clearance. However, its measurement is inconvenient, time-consuming, and costly. Thus, in both scientific studies and routine clinical practice nuclear medicine methods ((99m)Tc diethylenetriaminepentaacetic acid [(99m)Tc-DTPA] and (51)Cr ethylenediaminetetraacetic acid [(51)Cr-EDTA]) are preferred, and they correlate strongly with inulin clearance. In addition, cystatin C and beta-trace protein have also recently been used for this purpose. In the literature, however, data are limited about the clinical value of cystatin C and beta-trace protein in GFR measurement in chronic renal disease (CRD), and the results have been inconclusive. In this study, we aimed to determine the efficiency of cystatin C and beta-trace protein in the determination of GFR in CRD patients. METHODS: Eighty-four patients with CRD were included in the study (59 men and 25 women; age range, 21-88 y; mean age, 61 y). GFR was calculated using the gold-standard (99m)Tc-DTPA 2-sample plasma sampling method (TPSM) and 2 alternative methods: a formula using cystatin C and a formula using beta-trace protein. The correlation between TPSM and the cystatin C and beta-trace protein methods was assessed, and Bland-Altman analysis was used to graph scatterplots of the differences at a confidence interval of 95% (mean difference +/- 1.96 SDs). RESULTS: GFRs calculated using both alternative methods correlated strongly with those calculated using the gold standard. However, the correlation was stronger for the cystatin C method than for the beta-trace protein method, and neither method produced reliably consistent GFRs. CONCLUSION: This study demonstrated that cystatin C and beta-trace protein do not reflect GFR with sufficient accuracy. PMID- 26111709 TI - Incidental Diagnosis of an Asymptomatic Hydatid Cyst Through Low-Grade 18F-FDG Uptake in the Peripheral Rim. AB - Here we present a case of an untreated, asymptomatic, pulmonary hydatid cyst incidentally diagnosed on the basis of atypically low-grade (18)F-FDG uptake in the peripheral rim and a minimal increase in uptake on dual-point (18)F-FDG PET/CT. The patient underwent (18)F-FDG PET/CT for characterization of a solitary lung lesion found on chest radiography and inconclusive findings on contrast enhanced CT. Although the diagnosis was confirmed by a serum indirect hemagglutination assay positive for Echinococcus granulosus, the low-grade (18)F FDG uptake in the context of the asymptomatic presentation was noteworthy, as it could be related to minimal active inflammation. Our case, together with similar previously published findings, leads to the hypothesis that inflammatory (18)F FDG uptake may be an additional determinant of the cause of symptoms in these patients. PMID- 26111710 TI - Evaluation of the Left Ventricular Ejection Fraction with Gated IQ-SPECT Myocardial Perfusion Imaging. AB - The aim of this study was to evaluate the assessment of the left ventricular ejection fraction (LVEF) in patients by gated IQ-SPECT. METHODS: Twenty-eight patients were examined using gated (99m)Tc-sestamibi IQ-SPECT. Two different reconstruction datasets were created using the same projection data. The number of iterations, subsets, and gaussian filtering were based on 2 different recommendations from the manufacturer. For each dataset, end diastolic volume, end systolic volume, and LVEF were calculated using 4DMSPECT. A multigated planar equilibrium radionuclide ventriculography (MUGA) study with (99m)Tc-labeled red blood cells was used as a reference for the LVEF. RESULTS: The values of the different datasets were tested using the Bland-Altman analysis method. The calculated mean and 95% limits of agreement for the LVEF when dataset 1 and 2 were compared were -1.1% and +/-15% points; when dataset 1 was compared with MUGA, the mean was calculated to -3.1% points and +/-17% points for the 95% limits of agreement. When dataset 2 and MUGA were compared, the mean was -4.2% and 95% limits of agreement of +/-18% points. CONCLUSION: Neither of the gated reconstructed datasets analyzed with 4DMSPECT was comparable to LVEF estimated by MUGA, with a tendency to overestimate LVEF. However, large random variations of the end diastolic volume, end systolic volume, and LVEF between the 2 gated reconstructed datasets were found. The reconstructed datasets were not interchangeable. Thus, these values should only be used with great caution when evaluating the functional state of the heart. PMID- 26111711 TI - Gallbladder Fossa Abscess Masquerading as Cholecystitis After Cholecystectomy. AB - We present a case of a 59-y-old woman who had undergone cholecystectomy and was subsequently found to have an abscess within the gallbladder fossa. A hepatobiliary scan using (99m)Tc-diisopropyliminodiacetic acid demonstrated the characteristic rim sign, a photopenic defect surrounded by a rim of mildly increased activity immediately adjacent to the gallbladder fossa. The rim sign was thought to be the result of reactive inflammation in the hepatic tissue adjacent to a postoperative abscess within the gallbladder fossa. PMID- 26111712 TI - Incidental Liver Findings in 99mTc-Sestamibi Myocardial Perfusion SPECT. AB - In cardiac nuclear imaging, the liver is mostly remembered as a source of artifact in the left ventricular inferior wall. However, the liver may eventually display unexpected findings, which draw attention to significant noncardiac disease. In a patient referred for myocardial perfusion SPECT to investigate atypical chest pain, focal areas of increased tracer uptake revealed intrahepatic biliary dilatation. PMID- 26111713 TI - Precise Localization of a Bile Leak with Hepatobiliary Scintigraphy. AB - Hepatobiliary scintigraphy (HBS) is a widely used modality to diagnose biliary injury. In patients with a history of trauma or surgery, the common presentations of bile leaks on HBS are a progressive collection of radiotracer outside the biliary system. However, the precise localization of a bile leak is usually not conveyed by noninvasive techniques including CT or ultrasound or even HBS. This case study of a patient with liver trauma demonstrates a direct bile leak sign leading to recognition of an exact bile leakage site from the left intrahepatic duct. This diagnosis helped clinicians perform less-invasive management. PMID- 26111714 TI - Bone Scintigraphy SPECT/CT Evaluation of Mandibular Condylar Hyperplasia. AB - Mandibular condylar hyperplasia (CH) is a complex developmental deformity resulting in asymmetries of the hyperplastic condyle. Bone scan SPECT is a sensitive and accurate method of detecting the growth activity of this disorder. This method can be used to quantitate the radionuclide uptake differences between the left and right condyles. Uptake differences of 10% or more between the left and right condyles, with increased uptake ipsilateral to the CH, are considered to be evidence of active growing CH. Quantitative assessment of CH is important to select an appropriate treatment course. Degenerative arthropathies of the temporomandibular joints may result in altered uptake, but this is mostly associated with the side contralateral to the CH. The CT portion of SPECT/CT is useful to assess the condylar dimensions and underlying bony changes. PMID- 26111715 TI - Persistence and dispersal in a Southern Hemisphere glaciated landscape: the phylogeography of the spotted snow skink (Niveoscincus ocellatus) in Tasmania. AB - BACKGROUND: The aim of this research was to identify the effects of Pleistocene climate change on the distribution of fauna in Tasmania, and contrast this with biotic responses in other temperate regions in the Northern and Southern Hemisphere that experienced glacial activity during this epoch. This was achieved by examining the phylogeographic patterns in a widely distributed Tasmanian endemic reptile, Niveoscincus ocellatus. 204 individuals from 29 populations across the distributional range of N. ocellatus were surveyed for variation at two mitochondrial genes (ND2, ND4), and two nuclear genes (beta-globin, RPS8). Phylogenetic relationships were reconstructed using a range of methods (maximum parsimony, Bayesian inference and haplotype networks), and the demographic histories of populations were assessed (AMOVA, Tajima's D, Fu's Fs, mismatch distributions, extended Bayesian skyline plots, and relaxed random walk analyses). RESULTS: There was a high degree of mitochondrial haplotype diversity (96 unique haplotypes) and phylogeographic structure, where spatially distinct groups were associated with Tasmania's Northeast and a large area covering Southeast and Central Tasmania. Phylogeographic structure was also present within each major group, but the degree varied regionally, being highest in the Northeast. Only the Southeastern group had a signature of demographic expansion, occurring during the Pleistocene but post-dating the Last Glacial Maximum. In contrast, nuclear DNA had low levels of variation and a lack of phylogeographic structure, and further loci should be surveyed to corroborate the mitochondrial inferences. CONCLUSIONS: The phylogeographic patterns of N. ocellatus indicate Pleistocene range and demographic expansion in N. ocellatus, particularly in the Southeast and Central areas of Tasmania. Expansion in Central and Southeastern areas appears to have been more recent in both demographic and spatial contexts, than in Northeast Tasmania, which is consistent with inferences for other taxa of greater stability and persistence in Northeast Tasmania during the Last Glacial Maximum. These phylogeographic patterns indicate contrasting demographic histories of populations in close proximity to areas directly affected by glaciers in the Southern Hemisphere during the LGM. PMID- 26111716 TI - Placental autotaxin expression is diminished in women with pre-eclampsia. AB - AIM: Lysophosphatidic acid (LPA) is a member of a new class of lipid mediators and exerts varied physiological and pathological functions. The secreted protein, autotaxin (ATX), is a key enzymatic determinant of local LPA production. The primary aim of this study was to investigate the potential involvement of the placental ATX-LPA system in pre-eclampsia (PE). MATERIAL AND METHODS: We compared human placental ATX mRNA expression in pregnancies complicated by severe PE with that in healthy placentas using real-time polymerase chain reaction. We further assessed whether these expression levels were associated with disease-onset patterns. RESULTS: Placental transcription of ATX increased progressively during normal pregnancy. In the analysis for pre-eclamptic placentas, the placental ATX expression in the early-onset group, but not in late-onset group, was significantly lower compared to normal controls. Multiple regression analysis revealed that occurrence of early-onset PE, but not late-onset PE, was a variable that was significantly associated with the placental ATX expression level. CONCLUSION: These findings support our previous work showing reduced ATX antigen levels in the peripheral blood of pre-eclamptic women. A disturbance in placental ATX production may be linked to poor placental development and systemic maternal symptoms in early-onset PE. PMID- 26111717 TI - Protection of coronary endothelial cells from cigarette smoke-induced oxidative stress by a new Mn(II)-containing polyamine-polycarboxilate scavenger of superoxide anion. AB - Oxidative stress plays a major role in cardiovascular injury and dysfunction induced by cigarette smoke. Smoke-borne pro-oxidants impair endothelial function and predispose to thrombosis, inflammation and atherosclerosis. This in vitro study evaluates whether Mn(II)(4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7 diacetate).2H2O (Mn(II)(Me2DO2A)), a polyamine-polycarboxilate, Mn(II)-containing O2(-) scavenger, has a direct protective action on guinea pig coronary endothelial (GPCE) cells exposed to cigarette smoke extracts (CSE). Mn(II)(Me2DO2A) (1-10MUmol/l) was added to the culture medium together with CSE and maintained for 4h. In parallel experiments, the inactive congener Zn(II)(Me2DO2A), in which Zn(II) replaced the functional Mn(II) center in the same organic scaffold, was used as negative control. Mn(II)(Me2DO2A), mostly at the higher doses (5 and 10MUmol/l), significantly increased GPCE cell viability (trypan blue assay), improved mitochondrial activity (MTT test, mitochondrial membrane potential Deltapsi), reduced cellular apoptosis (mPTP, caspase-3 activity, TUNEL assay), decreased intracellular ROS levels (H2DCFDA), lipoperoxidation (BODIPY 581/591) and decreased protein nitrosylation. Of note, Zn(II)(Me2DO2A) did not preserve cell viability. These findings suggest that Mn(II)(Me2DO2A) is a promising O2(-) scavenging compound able to protect from cigarette smoke-induced oxidative cell injury. In perspective, should its efficacy be confirmed in future in vivo studies, this molecule might represent a therapeutic or preventive drug to counteract cigarette smoke toxicity. PMID- 26111718 TI - Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective. AB - Observational studies consistently reported an association between plasma total homocysteine concentrations and the risk of vascular events. In contrast, data from randomized trials largely support the hypothesis that mild elevations in homocysteine level have a modest effect on cardiovascular risk. A substantial body of evidence suggests that platelet activation is, at least in part, a transducer of the effects of high homocysteine in promoting atherothrombosis. The larger treatment effect recorded in several supplementation trials by subjects not on antiplatelet agents may support this hypothesis and justify, at least in part, the success of folate therapy in primary prevention. Circulating folate and homocysteine levels as well as MTHFR genotype, while emerging as major predictors of the risk of vascular events and of the efficacy of folic acid therapy, have also proved to be determinants of an interindividual variability in the degree of lipid peroxidation and platelet activation, and of the extent of their downregulation by folic acid. This may justify a variability in folate requirements, to be further characterized with dose-finding studies using biochemical endpoints. The combination of low-dose aspirin and low-dose folate would appear to be ideally suited for the primary prevention of both coronary and cerebrovascular events, and additional clinical trials should assess the efficacy and safety of these agents. PMID- 26111719 TI - Wound healing and all-cause mortality in 958 wound patients treated in home care. AB - Skin wounds are associated with significant morbidity and mortality. Data are, however, not readily available for benchmarking, to allow prognostic evaluation, and to suggest when involvement of wound-healing experts is indicated. We, therefore, conducted an observational cohort study to investigate wound healing and all-cause mortality associated with different types of skin wounds. Consecutive skin wound patients who received wound care by home-care nurses from January 2010 to December 2011 in a district in Eastern Denmark were included in this study. Patients were followed until wound healing, death, or the end of follow-up on December 2012. In total, 958 consecutive patients received wound care by home-care nurses, corresponding to a 1-year prevalence of 1.2% of the total population in the district. During the study, wound healing was achieved in 511 (53.3%), whereas 90 (9.4%) died. During the first 3 weeks of therapy, healing was most likely to occur in surgical wounds (surgical vs. other wounds: adjusted hazard ratio [AHR] 2.21, 95% confidence interval 1.50-3.23), while from 3 weeks to 3 months of therapy, cancer wounds, and pressure ulcers were least likely to heal (cancer vs. other wounds: AHR 0.12, 0.03-0.50; pressure vs. other wounds: AHR 0.44, 0.27-0.74). Cancer wounds and pressure ulcers were further associated with a three times increased probability of mortality compared with other wounds (cancer vs. other wounds: AHR 3.19, 1.35-7.50; pressure vs. other wounds: AHR 2.91, 1.56-5.42). In summary, the wound type was found to be a significant predictor of healing and mortality with cancer wounds and pressure ulcers being associated with poor prognosis. PMID- 26111720 TI - The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. AB - Cytokines are pleiotropic molecules with important roles in inflammatory responses. Pro-inflammatory cytokines and neuroinflammation are important not only in inflammatory responses but also in neurogenesis and neuroprotection. Sustained stress and the subsequent release of pro-inflammatory cytokines lead to chronic neuroinflammation, which contributes to depression. Hippocampal glucocorticoid receptors (GRs) and the associated hypothalamus-pituitary-adrenal (HPA) axis have close interactions with pro-inflammatory cytokines and neuroinflammation. Elevated pro-inflammatory cytokine levels and GR functional resistance are among the most widely investigated factors in the pathophysiology of depression. These two major components create a vicious cycle. In brief, chronic neuroinflammation inhibits GR function, which in turn exacerbates pro inflammatory cytokine activity and aggravates chronic neuroinflammation. On the other hand, neuroinflammation causes an imbalance between oxidative stress and the anti-oxidant system, which is also associated with depression. Although current evidence strongly suggests that cytokines and GRs have important roles in depression, they are essential components of a whole system of inflammatory and endocrine interactions, rather than playing independent parts. Despite the evidence that a dysfunctional immune and endocrine system contributes to the pathophysiology of depression, much research remains to be undertaken to clarify the cause and effect relationship between depression and neuroinflammation. PMID- 26111721 TI - The influence of sport club participation on physical activity, fitness and body fat during childhood and adolescence: The LOOK Longitudinal Study. AB - OBJECTIVES: To investigate the longitudinal effect of sport participation in physical activity, fitness and body fat changes during childhood and adolescence. DESIGN: Longitudinal study (134 boys, 155 girls) of Australian youth aged 8-16 years. METHODS: Physical activity was assessed by pedometers and accelerometers, fitness by the 20m shuttle-run, body fat by DEXA and club sport participation by questionnaire. Linear mixed models were used to determine the effects of sport participation and gender differences. RESULTS: Sports club participants were more physically active at all age groups than non-participants; boys took an extra 1800 steps (p<0.001) and girls 590 steps per day (p<0.01) and boys engaged in an extra 9min and girls 6min more moderate to vigorous PA per day (both p<0.05). Fitness was higher among sports participants (boys 27% and girls 20% higher, both p<0.001) and sport participant girls had 2.9% less body fat (p<0.05). Higher fitness scores were maintained over time by sports participants but their greater PA diminished during adolescence, this being more evident among girls. Only 20% of sports club participants met the recommended daily average of 60min MVPA. CONCLUSIONS: Sport participants were more active, fitter and had less body fat (girls only) than non-sports participants. However, the associated benefits of sport with PA diminished during adolescence and the majority of sports participants did not meet recommended levels of PA. Strategies aiming to maximise the benefits of sports participation may be enhanced by providing special attention to the early adolescent period particularly among girls. PMID- 26111722 TI - The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding. AB - The literature on inducers in epilepsy and bipolar disorder is seriously contaminated by false negative findings. Part II of this comprehensive review on antiepileptic drug (AED) inducers provides clinicians with further educational material about the complexity of interpreting AED drug-drug interactions. The basic pharmacology of induction is reviewed including the cytochrome P450 (CYP) isoenzymes, the Uridine Diphosphate Glucuronosyltransferases (UGTs), and P glycoprotein (P-gp). CYP2B6 and CYP3A4 are very sensitive to induction. CYP1A2 is moderately sensitive while CYP2C9 and CYP2C19 are only mildly sensitive. CYP2D6 cannot be induced by medications. Induction of UGT and P-gp are poorly understood. The induction of metabolic enzymes such as CYPs and UGTs, and transporters such as P-gp, implies that the amount of these proteins increases when they are induced; this is almost always explained by increasing synthesis mediated by the so-called nuclear receptors (constitutive androstane, estrogen, glucocorticoid receptors and pregnaneX receptors). Although parti provides correction factors for AEDs, extrapolation from an average to an individual patient may be influenced by administration route, absence of metabolic enzyme for genetic reasons, and presence of inhibitors or other inducers. AED pharmacodynamic DDIs may also be important. Six patients with extreme sensitivity to AED inductive effects are described. PMID- 26111723 TI - Researchers' focus on drugs over other treatments ignores doctors' and patients' views. PMID- 26111724 TI - Open Trial of an Acceptance-Based Behavior Therapy Intervention to Engage Newly Diagnosed HIV Patients in Care: Rationale and Evidence of Feasibility and Acceptability. AB - Successful linkage and retention in care of newly diagnosed individuals in the United States remains a significant gap in the HIV care continuum. This study assessed the acceptability and feasibility of an acceptance-based behavior therapy (ABBT) intervention to engage patients newly diagnosed with HIV in medical care. Nine patients were recruited over 4 months for this brief ABBT intervention, which consisted of two brief sessions, each lasting less than 20 min. The intervention was developed to promote psychological acceptance of the HIV diagnosis, thereby increasing patients' willingness to make informed disclosure of their status. Eight patients completed a 1-month follow-up assessment, and all approved of the intervention and its components. Over the 1 month period, participants showed increased acceptance, reduced perceptions of HIV stigmatization, and increased disclosure of HIV status to social supports. This pilot study provided support for the continued investigation of ABBT as an adjunctive intervention for newly diagnosed HIV patients who are at high-risk of dropping out of HIV care. PMID- 26111726 TI - Drug-Related Inadvertent Deaths in a University Hospital--A Declining Trend. AB - We studied the incidence of fatal adverse drug reactions (ADRs) in a tertiary hospital to find out which drugs were involved. The secondary objective was to compare the data from the same hospital published 12 years earlier. All 1708 death cases in the Helsinki University Central Hospital during the year 2012 were retrospectively evaluated. All suspected drug-related deaths, excluding suicides, were scrutinized by an expert panel using the WHO ADR probability classification. Of all cases, 52 (3.0%) were classified as certainly or probably drug related and 24 (1.4%) as possibly drug related. Together, these corresponded to 0.02% of all hospital admissions. The most commonly involved drugs in certain or probable cases were cytostatics (18 cases, 1.1% of all cases) and antithrombotics (17, 1.0%). Twelve years earlier, these caused 27 (1.8%) and 22 (1.5%) cases, respectively. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids caused less (2 and 0 cases) fatal ADRs than earlier (12 and 4 cases, p = 0.048 and p = 0.005, respectively). Most of the ADRs leading to death were present already in admission and affected seriously ill or elderly patients. Hospital born fatal ADRs occurred in 0.003% of patients. In conclusion, cytostatics and antithrombotics are still the leading causes of fatal ADRs, but NSAIDs and glucocorticoids seem to cause fatal ADRs less often than previously. The incidence of fatal ADRs in 2012 was 3.0% of all deaths, suggesting a decline compared to the 2000 value (5.0%). Improved awareness, prevention and treatment of ADRs and safer medicines may explain these declining trends. PMID- 26111725 TI - Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment. AB - The chronic MPTP+probenecid treatment paradigm has been used to successfully model the neurochemical, neuropathological, and behavioral effects associated with Parkinson's disease. Here, adult male C57Bl/6 mice were injected ip with 25 mg/kg MPTP and 250 mg/kg probenecid (MPTPp) or saline twice weekly for a total of 10 injections. Behavioral assessments included motor coordination, grip strength, spatial learning/memory, locomotor activity, and anhedonia. Those assessments were repeated up to 8 weeks post-treatment. In a subsequent experiment, adult male mice were treated with saline or MPTPp as described above. One-half of each group was allowed access to 1% trehalose in the water bottle. Trehalose intake averaged 1.90-2.34 g/kg. Behavioral assessments included locomotor activity, olfaction, motor coordination, grip strength, and exploratory behavior. Those assessments were repeated 4 weeks post-treatment. The strongest MPTPp effect was hyperactivity as exhibited in the open field. This increased activity was apparent in both experiments and occurred at all time points post-treatment. Assessments of grip strength, water maze performance, olfaction, and exploratory behavior did not indicate MPTPp-related alterations. When the specifications for the motor coordination test were made somewhat easier in the second experiment, there were deficits exhibited by the MPTPp group, the MPTPp+trehalose group and the trehalose group. The addition of trehalose did not alleviate any of the MPTPp induced behavioral alterations; however, trehalose treatment significantly attenuated the striatal decreases in DA, DOPAC, HVA and 5-HIAA. These results provide a more comprehensive description of the behavioral alterations resulting from the chronic MPTPp treatment regimen and suggest that trehalose at this concentration does not act as a complete neuroprotectant. PMID- 26111728 TI - First evidence of natural reproduction of the Allis shad Alosa alosa in the River Rhine following re-introduction measures. AB - After stocking with larvae from the Gironde-Garonne-Dordogne population, in 2013, three young-of-the-year Allis shad Alosa alosa, probably originating from natural reproduction, were documented for the first time in a period of nearly 100 years in the River Rhine. In 2014, a further increase was observed when 57 juveniles and eight adults were caught; seven of these eight adults were derived from stocking, indicating the success of stocking measures within the framework of the EU-LIFE project. PMID- 26111730 TI - Effects of changing housing conditions on mangabey behavior (Cercocebus atys): Spatial density, housing quality, and novelty effects. AB - The separate influences of spatial density and housing quality on the behavior of captive animals are difficult to measure because the two factors are often intrinsically linked. Here, we recorded affiliative and agonistic behavior in adult sooty mangabeys in various housing situations, testing spatial density and housing quality changes separately (N = 26 experienced spatial density changes; N = 12 experienced housing quality changes). We varied spatial density by 50% while holding housing quality constant and we varied housing quality while holding spatial density constant (achieved by comparing two types of run-housing that varied in the amount of visual privacy and outdoor access). Each housing condition was one month in duration. Prior to collecting data in each housing condition, we evaluated the subjects' initial responses to the change in housing environment during 2-week novelty periods. Affiliative behavior did not change during the novelty periods. Agonistic behavior initially increased slightly when spatial density increased and it decreased significantly when spatial density decreased; it also decreased when subjects moved to housing that offered more visual privacy and outdoor space, indicating that the mangabeys were sensitive to these housing changes. After the novelty periods, affiliative behavior increased under higher spatial density, but remained unchanged across housing quality conditions; agonistic behavior remained unchanged across all conditions. Results suggest that a prolonged increase in spatial density led the mangabeys to adopt a tension-reduction coping strategy, in which the increase in affiliative behavior alleviates a presumed increase in social tension. Reducing visual privacy and choice did not affect the mangabeys' behavior, post-novelty period. Thus, like many other primates, the mangabeys managed tension by flexibly adapting to changes in their housing environment in ways that reduce the risk of severe aggression. This study highlights the importance of controlled behavioral studies in facilitating data-driven management decisions that promote animal welfare. Am. J. Primatol. 77:1001-1014, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26111727 TI - Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. AB - AIMS: Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behaviour and have poor prognosis. Although constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-kappaB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL. METHODS: We conducted the systematic sequencing of 21 genes relevant to the NF-kappaB signalling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation. RESULTS: The results showed that 68 out of 71 PCNSLs had mutations in the NF-kappaB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumour in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265. CONCLUSIONS: The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signalling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy. PMID- 26111731 TI - Integrating Multiple Correlated Phenotypes for Genetic Association Analysis by Maximizing Heritability. AB - Many correlated disease variables are analyzed jointly in genetic studies in the hope of increasing power to detect causal genetic variants. One approach involves assessing the relationship between each phenotype and each SNP individually and using a Bonferroni correction for the effective number of tests conducted. Alternatively, one can apply a multivariate regression or a dimension reduction technique, such as principal component analysis, and test for the association with the principal components of the phenotypes rather than the individual phenotypes. Inspired by the previous approaches of combining phenotypes to maximize heritability at individual SNPs, in this paper, we propose to construct a maximally heritable (MaxH) phenotype by taking advantage of the estimated total heritability and co-heritability. The heritability and co-heritability only need to be estimated once; therefore, our method is applicable to genome-wide scans. The MaxH phenotype is a linear combination of the individual phenotypes with increased heritability and power over the phenotypes being combined. Simulations show that the heritability and power achieved agree well with the theory for large samples and two phenotypes. We compare our approach with commonly used methods and assess both the heritability and the power of the MaxH phenotype. Moreover, we provide suggestions for how to choose the phenotypes for combination. An application of our approach to a GWAS on chronic obstructive pulmonary disease shows its practical relevance. PMID- 26111733 TI - The gill microbiota of invasive and indigenous Spondylus oysters from the Mediterranean Sea and northern Red Sea. AB - The gill tissue of bivalve mollusks hosts rich symbiotic microbial communities that may contribute to the animal's metabolism. Spondylus spinosus is an invasive oyster that has become highly abundant along the eastern Mediterranean Sea (EMS) coastline, but is scarce in the northern Red Sea (NRS), its indigenous region. The composition and seasonal dynamics of the gill microbial communities of S. spinosus were examined in both regions, using 16S rRNA gene amplicon sequencing. Additionally, two Red Sea Spondylus species, S. avramsingeri and S. pickeringae, were investigated using the same approach. Significant differences were found between microbial communities of the EMS S. spinosus and the three NRS species. Bacteria from the family Hahellaceae dominated the communities of the EMS S. spinosus and the NRS S. avramsingeri, oysters that are dominant in their habitat, yet were rare in the NRS S. spinosus and S. pickeringae, which are only seldom encountered. Bacterial communities of EMS S. spinosus were more similar to those of NRS S. spinosus than to those of other NRS Spondylus species, indicating that either part of the microbiota had co-invaded with their host into the Mediterranean Sea, or that there are species-specific selective constraints on microbial composition. PMID- 26111732 TI - Structural Determinants of Client Perpetrated Violence Among Female Sex Workers in Two Mexico-U.S. Border Cities. AB - Female sex workers (FSWs) are disproportionately affected by both HIV and gender based violence, such as that perpetrated by clients (CPV). We used a structural determinants framework to assess correlates of physical or sexual CPV in the past 6 months among FSWs in the Mexico/U.S. border cities of Ciudad Juarez and Tijuana. Bivariate and multivariate logistic regression analysis identified individual, client, interpersonal, work environment and macrostructural factors associated with recent CPV. Among 496 FSWs, 5 % experienced recent CPV. Witnessing violence towards other FSWs in one's neighborhood (aOR 5.6, 95 % CI 1.8-17.2), having a majority of foreign (aOR 3.5, 95 % CI 1.4-8.4) or substance using (aOR 4.0, 95 % CI 1.5-10.4) clients, and being a street worker (aOR 3.0, 95 % CI 1.1-7.7) were independently associated with recent CPV. Our findings underscore the vulnerability of FSWs and the need to design policies and interventions addressing macro-level influences on CPV rather than exclusively targeting individual behaviors. PMID- 26111734 TI - Organo-arsenic molecular layers on silicon for high-density doping. AB - This article describes for the first time the controlled monolayer doping (MLD) of bulk and nanostructured crystalline silicon with As at concentrations approaching 2 * 10(20) atoms cm(-3). Characterization of doped structures after the MLD process confirmed that they remained defect- and damage-free, with no indication of increased roughness or a change in morphology. Electrical characterization of the doped substrates and nanowire test structures allowed determination of resistivity, sheet resistance, and active doping levels. Extremely high As-doped Si substrates and nanowire devices could be obtained and controlled using specific capping and annealing steps. Significantly, the As doped nanowires exhibited resistances several orders of magnitude lower than the predoped materials. PMID- 26111736 TI - Type 2 diabetes mellitus and risk of gallbladder cancer: a systematic review and meta-analysis of observational studies. AB - AIMS: Increasing evidence suggests that a history of type 2 diabetes mellitus (type 2 DM) may be involved in the development of various sites of cancer. However, the association with risk of gallbladder cancer remains unclear. METHODS: We identified studies by a literature search of MEDLINE and EMBASE through 31 August 2014 and by searching the reference lists of pertinent articles. All data were independently extracted by two investigators using a standardized data abstraction tool. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were calculated with a random effects model. RESULTS: A total of 20 studies (eight case-control studies and 12 cohort studies) were included in this meta-analysis. Analysis of these 20 studies found that compared with non-diabetic individuals, diabetic individuals had an increased risk of gallbladder cancer (SRR = 1.56, 95% CI: 1.36-1.79). There was evidence of moderate heterogeneity among these studies (p = 0.010 and I(2) = 43.5%). This increased risk relationship is independent of smoking, body mass index and a history of gallstones. However, whether or not controlled for, alcohol use may be one of the potential confounders that significantly affect the association between type 2 DM and the risk of gallbladder cancer. Diabetic women and men had a similarly increased risk of gallbladder cancer associated with type 2 DM. CONCLUSIONS: These findings of this systematic review indicate that compared with non-diabetic individuals, both men and women with type 2 DM had an increased risk of gallbladder cancer. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26111735 TI - Deep brush-based cytology in tonsils resected for benign diseases. AB - A fraction of oropharyngeal cancer (OPC), especially in the tonsil, is caused by human papillomavirus (HPV), mainly HPV16. Noninvasive diagnostic methods to detect precancerous lesions in the tonsil would be useful, e.g., liquid-based cytology (LBC). However, ill-characterized precancerous lesions may be hidden in the depth of the tonsillar crypts. We therefore conducted a study on HPV and tonsillar precancerous lesions to evaluate, among other things, the utility of LBC obtained by deep brushing of the resected tonsils. Two hundred non-paediatric patients (mean age: 30.3 years) who underwent tonsillectomy for infection-related conditions (69%) or other conditions (mainly obstructive sleep apnoea, 31%) were included. An ultra-sensitive Luminex bead-based platform was used to test for the DNA of 21 mucosal HPV types; 56% of slides were unsatisfactory due to low number of squamous epithelial cells or the masking effect of a large number of lymphocytes. Three patients (1.5%; 95% CI: 0.5-4.3) showed suspicious cytological findings (atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion, ASC-H) while 3 others were HPV-positive (2 for HPV16 and 1 for HPV39). None of the ASC-H patients and HPV-positive patients showed dysplasia at histological examination. The rarity of HPV infection in the tonsil conflicts with the relatively frequent detection of the virus in the mouth. In conclusion, aggressive deep brushing of tonsils, while hardly applicable in vivo, is unlikely to be a reliable method to detect precancerous lesions. The absence of OPC screening modalities places the priority on multi-purpose primary prevention strategies, i.e., HPV vaccination and reduction of smoking and drinking. PMID- 26111737 TI - Semantic Borders and Incomplete Understanding. AB - In this article, we explore a fundamental issue of Cultural Psychology, that is our "capacity to make meaning", by investigating a thesis from contemporary philosophical semantics, namely, that there is a decisive relationship between language and rationality. Many philosophers think that for a person to be described as a rational agent he must understand the semantic content and meaning of the words he uses to express his intentional mental states, e.g., his beliefs and thoughts. Our argument seeks to investigate the thesis developed by Tyler Burge, according to which our mastery or understanding of the semantic content of the terms which form our beliefs and thoughts is an "incomplete understanding". To do this, we discuss, on the one hand, the general lines of anti-individualism or semantic externalism and, on the other, criticisms of the Burgean notion of incomplete understanding - one radical and the other moderate. We defend our understanding that the content of our beliefs must be described in the light of the limits and natural contingencies of our cognitive capacities and the normative nature of our rationality. At heart, anti-individualism leads us to think about the fact that we are social creatures, living in contingent situations, with important, but limited, cognitive capacities, and that we receive the main, and most important, portion of our knowledge simply from what others tell us. Finally, we conclude that this discussion may contribute to the current debate about the notion of borders. PMID- 26111738 TI - Pitch Processing in Tonal-Language-Speaking Children with Autism: An Event Related Potential Study. AB - The present study investigated pitch processing in Mandarin-speaking children with autism using event-related potential measures. Two experiments were designed to test how acoustic, phonetic and semantic properties of the stimuli contributed to the neural responses for pitch change detection and involuntary attentional orienting. In comparison with age-matched (6-12 years) typically developing controls (16 participants in Experiment 1, 18 in Experiment 2), children with autism (18 participants in Experiment 1, 16 in Experiment 2) showed enhanced neural discriminatory sensitivity in the nonspeech conditions but not for speech stimuli. The results indicate domain specificity of enhanced pitch processing in autism, which may interfere with lexical tone acquisition and language development for children who speak a tonal language. PMID- 26111739 TI - Does Gender Moderate Core Deficits in ASD? An Investigation into Restricted and Repetitive Behaviors in Girls and Boys with ASD. AB - Due to the uneven gender ratio of autism spectrum disorders (ASD), girls are rarely studied independently from boys. Research focusing on restricted and repetitive behaviors (RRBs) indicates that above the age of six girls have fewer and/or different RRBs than boys with ASD. In this study we investigated whether girls and boys with ASD demonstrated similar rates and types of RRBs in early childhood, using discrete observational coding from a video-taped play interaction. Twenty-nine girls with ASD were matched to 29 boys based on ASD severity. While boys in our sample demonstrated a greater frequency of RRBs, this was not significant and our findings indicate that girls and boys under five are more similar than dissimilar on this core deficit. However our data also revealed a trend toward gender-differential growth trajectories--a finding worthy of further investigation in larger samples. PMID- 26111740 TI - Referral of Ovarian Cancer Patients for Genetic Counselling by Oncologists: Need for Improvement. AB - BACKGROUND/AIMS: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino--IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. METHODS: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. RESULTS: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counselling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). CONCLUSIONS: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice. PMID- 26111742 TI - Horizontal Tonic Conjugate Gaze Deviation and Arachnoid Cyst. PMID- 26111741 TI - The Role of the Modified Barium Swallow Study and Esophagram in Patients with Globus Sensation. AB - Globus sensation (GS) is a common benign finding that is often associated with frequent throat clearing and is commonly a result of laryngopharyngeal reflux. The primary objective of this investigation was to examine the role of the modified barium swallow study (MBSS) with esophagram in the diagnosis and management patients who present with chief complaints of a GS. We hypothesize that these radiographic swallow studies do not add clinically significant information in the investigation of this common complaint. Retrospective chart review of patients with chief complaints of GS between 2000 and 2009 who underwent both MBSS and esophagram was conducted. Of the 380 patients who underwent MBSS, only 68 patients were eligible for this study. Over 70 % of patients were on reflux medicines, 81 % of the MBSS studies were normal, 62 % of the esophagram results were normal, 18 % of patients had a hiatal hernia, and 10 % exhibited signs of reflux. Esophagoscopy was performed in 45 % of patients, of which 35 % were normal. One patient initially had a normal esophagogastroduodenoscopy and then was subsequently diagnosed with gastric CA. Fifty-nine percent of patients underwent CT Neck with IV contrast, of which 67 % had minor findings. Positive findings are often benign and can be treated with reflux medications. Esophagoscopy was often normal and most sensitive only for hiatal hernia. No hypopharyngeal cancer was noted. Therefore, MBSS and esophagram for patients with GS are most often negative and fail to add significant diagnostic information. PMID- 26111743 TI - Modulating spin relaxation in nanowires with infrared light at room temperature. AB - Spintronic devices usually rely on long spin relaxation times and/or long spin relaxation lengths for optimum performance. Therefore, the ability to modulate these quantities with an external agent offers unique possibilities. The dominant spin relaxation mechanism in most technologically important semiconductors is the D'yakonov-Perel' (DP) mechanism which may vanish if the spin carriers (electrons) are confined to a single conduction subband in a quantum wire. Here, we report modulating the DP spin relaxation rate (and hence the spin relaxation length) in self assembled 50 nm diameter InSb nanowires with infrared (IR) light at room temperature. In the dark, almost all the electrons in the nanowires are in the lowest conduction subband, resulting in near-complete absence of DP relaxation. This allows observation of spin-sensitive effects in the magnetoresistance. Under IR illumination, higher subbands get populated and the DP spin relaxation mechanism is revived, leading to a three-fold decrease in the spin relaxation length. Consequently, the spin sensitive effects disappear under illumination. This phenomenon may have applications in spintronic room-temperature IR photodetection. PMID- 26111744 TI - [Analysis of vaccination data of patients aged 60 years and older from Bavaria and Thuringia]. AB - BACKGROUND: Despite annual updates of vaccination recommendations by the German Standing Committee on Vaccination (STIKO) at the Robert Koch Institute, diseases preventable by vaccination still cause a relevant burden of disease in the elderly. OBJECTIVES: A comparison of the vaccination status of the elderly in Bavaria and Thuringia was carried out. MATERIAL AND METHODS: Medical settlement data from the first quarter of 2007 to the second quarter of 2008 from the association of panel doctors in Bavaria and Thuringia for insured persons aged 60 years and above were analyzed concerning vaccinations, age, gender and multimorbidity. The vaccination rates for influenza were calculated. RESULTS: The use of all recommended vaccinations in this age group was greater in Thuringia (eastern federal state) than in Bavaria (western federal state). In both states the administration rates of tetanus and diphtheria vaccines were lower in individuals with higher comorbidity and age. Protection rates against diphtheria were incomplete as a result of inadequate use of combination vaccines. In both states the administration of pneumococcal vaccine was higher in subjects with more comorbidities. In Bavaria administration rates increased with age. Influenza vaccination rates increased in association with age and comorbidity in both states. In elderly individuals influenza vaccination was used more often in the third quarter of 2007. CONCLUSION: Old age and multimorbidity are often insufficiently taken into consideration in studies on vaccination rates. The data from this study confirmed the relevant findings from other studies and emphasize the deficient implementation of standard vaccinations in primary prevention. In this study very old patients were differentiated and considered according to age groups for the first time. PMID- 26111745 TI - Influence of Lentiviral beta-Synuclein Overexpression in the Hippocampus of a Transgenic Mouse Model of Alzheimer's Disease on Amyloid Precursor Protein Metabolism and Pathology. AB - BACKGROUND: beta-Synuclein (beta-Syn) is a member of the highly homologous synuclein protein family. The most prominent family member, alpha-synuclein (alpha-Syn), abnormally accumulates in so-called Lewy bodies, one of the major pathological hallmarks of alpha-synucleinopathies. Notably, parts of the peptide backbone, called the nonamyloid component, are also found in amyloid plaques. However, beta-Syn seems to have beneficial effects by reducing alpha-Syn aggregation, and amyloid antiaggregatory activity has been described. OBJECTIVE: The aim of the study was to analyze if wild-type beta-Syn can counteract functional and pathological changes in a murine Alzheimer model over different time periods. METHODS: At the onset of pathology, lentiviral particles expressing human beta-Syn were injected into the hippocampus of transgenic mice overexpressing human amyloid precursor protein with Swedish and London mutations (APPSL). An empty vector served as the control. Behavioral analyses were performed 1, 3 and 6 months after injection followed by biochemical and histological examinations of brain samples. RESULTS: beta-Syn expression was locally concentrated and rather modest, but nevertheless changed its effect on APP expression and plaque load in a time- and concentration-dependent manner. Interestingly, the phosphorylation of glycogen synthase kinase 3 beta was enhanced in APPSL mice expressing human beta-Syn, but an inverse trend was observed in wild-type animals. CONCLUSION: The initially reported beneficial effects of beta-Syn could be partially reproduced, but locally elevated levels of beta-Syn might also cause neurodegeneration. To enlighten the controversial pathological mechanism of beta-Syn, further examinations considering the relationship between concentration and exposure time of beta-Syn are needed. PMID- 26111746 TI - Surgical Management of Vascular Stents in Pediatric Cardiac Surgery: Clues for a Staged Partnership. AB - Complex cases undergo step surgical and percutaneous procedures, including stent deployment. Concerns arise on stent removal at latest surgery. Our initial experience is presented. Forty-six stents in 35 patients were partially or totally removed at surgery. Univentricular heart was diagnosed in 20 patients. Stents were previously deployed in: ductus (6), right ventricle outflow tract (12), atrial septal defect (4), right pulmonary artery (4), left pulmonary artery (16), inferior vena cava (2), superior vena cava (1) and ascending aorta (1). Surgical procedures performed: 9 transplants, 6 Fontan, 4 Glenn, 1 comprehensive repair (Norwood + Glenn), 1 Glenn takedown, 8 conduit replacement, 2 Fallot, 2 Rastelli, 1 ventricular septal defect closure and 1 iatrogenic aortopulmonary window. Five ductal stents were clipped. Eleven stents in right ventricle, four ones in atrial septal defect, two in right pulmonary artery, seven in the left pulmonary artery and two in inferior vena cava were completely removed. Two stents in right pulmonary artery, one in superior vena cava, one in ascending aorta and nine in the left pulmonary artery were partially retrieved. Handling the stents in ductus, right ventricle and atrial septal defect was straightforward. On the contrary, stent removal in the ductus (comprehensive case), pulmonary branches, both vena cavae or aorta required short periods of deep hypothermia with circulatory arrest. Surgery over stents is increasing in complex, step procedures. Univentricular hearts are most prevalent. Congenital transplant surgery faces new challenges. Stent removal at the time of surgery may require deep hypothermic circulatory arrest. PMID- 26111747 TI - Closure of Isolated Congenital Coronary Artery Fistula: Long-Term Outcomes and Rate of Re-intervention. AB - Long-term outcome after closure of isolated congenital coronary artery fistula (ICCAF) is poorly documented. To assess late outcome after ICCAF closure, a 1983 2013 retrospective study included all patients who attempted an ICCAF closure and whose follow-up was >=1 year. ICCAF was diagnosed in 23 patients [median age 6.9 years (0.1-70.5 years), 13 children]. ICCAF was symptomatic in 12 patients (52.2 %). First intervention was either a transcatheter embolization (n = 19 patients, 82.6 %) or a surgical ligation (n = 4 patients, 17.4 %). After a follow-up of 9.0 years (2.8-33.5), neither death nor late ischemic event occurred but one patient was transplanted, because of postoperative myocardial infarction. Late ICCAF recanalization occurred in eight patients, leading to successful embolization of the shunt in all patients after a delay of 9.8 years (5.7-13.8 years) from the first intervention. Re-intervention occurred later in children (p = 0.0027), with a 50 and 37.5 % freedom from re-intervention in adults compared to a 100 and 89.0 % in children, respectively, at 1 and 6 years of follow-up. At last follow-up, coronary artery diameter had decreased from a mean z score of 12.0 +/- 7.7 to a mean z score of 6.0 +/- 6.0 (p = 0.002). Long-term outcome after ICCAF closure is excellent, with neither death nor late ischemic event, and a significant decrease in coronary artery diameter with time. Late follow-up is of paramount importance, as one-third of patients will require a re-intervention for late shunt recanalization. PMID- 26111748 TI - Histopathology of the human inner ear in Alstrom's syndrome. AB - Alstrom's syndrome is an autosomal recessive syndromic genetic disorder caused by mutations in the ALMS1 gene. Sensorineural hearing loss occurs in greater than 85% of patients. Histopathology of the inner ear abnormalities in the human has not previously been fully described. Histopathology of the inner ear in Alstrom's syndrome is presented in 2 genetically confirmed cases. The predominant histopathologic correlates of the sensorineural loss were degeneration of the organ of Corti, both inner and outer hair cells, degeneration of spiral ganglion cells, and atrophy of the stria vascularis and spiral ligament. PMID- 26111749 TI - Effect of excessive doses of oxytetracycline on stress-related biomarker expression in coho salmon. AB - Fish are exposed to a wide variety of environmental stressors, such as chemicals and acute changes in temperature. Oxytetracycline (OTC) has been used as an antibiotic for many kinds of bacterial diseases in cultured fish, but excessive doses of OTC are known to cause side effects in fish and can have negative effects on their environment. In the present study, we examined stress-related biomarker expression in response to excessive doses of dietary OTC in coho salmon (Oncorhynchus kisutch). Fish received OTC (100 mg/kg body weight/day) orally for 2 weeks. The percentage of liver to body weight (hepatosomatic index; HSI) and plasma biochemical parameter, alanine aminotransferase (ALT) activity, of the group fed a diet containing OTC were observed to be significantly higher than those of the control group. The total glutathione (tGSH) levels in the liver of OTC-fed fish were four fold higher than those in control fish and double the control levels in muscle and stomach. Plasma tGSH levels in OTC-fed fish were also higher than those in control fish. Expression levels of heat shock protein 70 in the liver, muscle, and stomach decreased by OTC administration. Accordingly, OTC-induced stress might increase the metabolic turnover of GSH due to consumption by scavenging oxidants generated by stress. These results concerning the changing patterns of stress-related biomarkers indicate that excessive doses of OTC fed to coho salmon induce oxidative stress, which might enhance oxidation in the body and result in damage to tissues, especially in the liver. The present results also suggest that tissue-specific damage caused by OTC might already exist in fish. PMID- 26111750 TI - Identifying the regional-scale groundwater-surface water interaction on the Sanjiang Plain, Northeast China. AB - Assessment on the interaction between groundwater and surface water (GW-SW) can generate information that is critical to regional water resource management, especially for regions that are highly dependent on groundwater resources for irrigation. This study investigated such interaction on China's Sanjiang Plain (10.9 * 10(4) km(2)) and produced results to assist sustainable regional water management for intensive agricultural activities. Methods of hierarchical cluster analysis (HCA), principal component analysis (PCA), and statistical analysis were used in this study. One hundred two water samplings (60 from shallow groundwater, 7 from deep groundwater, and 35 from surface water) were collected and grouped into three clusters and seven sub-clusters during the analyses. The PCA analysis identified four principal components of the interaction, which explained 85.9% variance of total database, attributed to the dissolution and evolution of gypsum, feldspar, and other natural minerals in the region that was affected by anthropic and geological (sedimentary rock mineral) activities. The analyses showed that surface water in the upper region of the Sanjiang Plain gained water from local shallow groundwater, indicating that the surface water in the upper region was relatively more resilient to withdrawal for usage, whereas in the middle region, there was only a weak interaction between shallow groundwater and surface water. In the lower region of the Sanjiang Plain, surface water lost water to shallow groundwater, indicating that the groundwater was vulnerable to pollution by pesticides and fertilizers from terrestrial sources. PMID- 26111751 TI - Blood cholinesterase activity levels of farmers in winter and hot season of Mae Taeng District, Chiang Mai Province, Thailand. AB - Organophosphate and carbamate pesticides have been widely used by farmers for crop protection and pest control. Inhibition of acetylcholinesterase (AChE) in erythrocyte and butyrylcholinesterase (BChE) in plasma is the predominant toxic effect of organophosphate and carbamate pesticides. Mae Taeng District, Chiang Mai Province, is one of the large areas of growing vegetables and fruits. Due to their regular exposure to these pesticides, the farmers are affected by this toxicity. The objective of the study was to examine the AChE and the BChE activity levels in the blood of 102 farmers for comparison of exposure in two cropping seasons, winter and hot. Blood samples were collected in December 2013 (winter) and April-June 2014 (hot). A total of 102 farmers joined the study, represented by 76 males (74.5 %) and 26 females (25.5 %). The age of most of the farmers was 53.4 +/- 8.7 years. Out of 102, 21 farmers used carbamate pesticides. The results showed that the AChE and the BChE activity levels of all the farmers were 3.27 +/- 0.84 Unit/mL and 2.15 +/- 0.58 Unit/mL, respectively. The AChE and the BChE activity levels in males were 3.31 +/- 0.88 Unit/mL and 1.97 +/- 0.60 U/mL, respectively, during winter and 3.27 +/- 0.82 Unit/mL and 2.15 +/- 0.58 U/mL, respectively, during the hot season, and AChE and the BChE activity levels in females were 3.27 +/- 0.82 U/mL and 2.44 +/- 0.56 U/mL, respectively, during the hot season. The cholinesterase activity levels, both AChE and BChE, in the male farmers' blood had significant difference between the two seasons, while in the case of the female farmers, there was significant difference in the BChE activity levels, at p < 0.05. The BChE activity level was found to significantly correlate with self-spray (p < 0.05), which implies that the BChE activity decreased when they sprayed by themselves. The cholinesterase activity levels of the present study were lower than those of the other studies, which may be an indication of some chronic effect of exposure to anticholinesterase pesticides. Thus, it is recommended that the use of pesticides be decreased, together with increase in the awareness of the impact of pesticides on health; also recommended is regular monitoring of blood cholinesterase. PMID- 26111752 TI - Are urinary polyaromatic hydrocarbons associated with adult hypertension, heart attack, and cancer? USA NHANES, 2011-2012. AB - Links between environmental chemicals and human health have emerged over the last few decades, but the effects from polyaromatic hydrocarbons were less studied, compared to other commonly known environmental chemicals such as heavy metals, phthalates, arsenic, phenols and pesticides. Therefore, it was aimed to study the relationships of urinary polyaromatic hydrocarbons and adult cardiovascular disease and cancer using human sample in a national and population-based study in recent years. Data was retrieved from US National Health and Nutrition Examination Surveys, 2011-2012, including demographics, self-reported health conditions and urinary polyaromatic hydrocarbons. Statistical analyses included chi-square test, t test, survey-weighted logistic regression modeling and population attributable risk (PAR) estimation. Of 5560 American adults aged 20-80 and included in the statistical analysis, urinary polyaromatic hydrocarbons (representatively in one-third sample) were observed to be higher in people with cardiovascular disease and total cancer. In particular, urinary 4 hydroxyphenanthrene was associated with hypertension (odds ratio (OR) 1.33, 95% confidence interval (CI) 1.00-1.76, P = 0.048, PAR 5.1%), urinary 1-hydroxypyrene was significantly associated with heart attack (OR 1.47, 95%CI 1.05-2.06, P = 0.027, PAR 1.7%), and urinary 2-hydroxynapthalene (2-naphthol) was associated with cancer (OR 1.46, 95%CI 1.12-1.90, P = 0.008, PAR 3.9%). Urinary polyaromatic hydrocarbons were associated with adult hypertension, heart attack and cancer, although the causality cannot be established. From the research perspective, future studies with a longitudinal or experimental approach would be suggested. From the law and public health perspectives, regulation on minimizing exposure to polyaromatic hydrocarbons might need to be considered in future health and environmental policies and intervention programs. PMID- 26111753 TI - The Mar Piccolo of Taranto: an interesting marine ecosystem for the environmental problems studies. AB - The National Project RITMARE (la Ricerca ITaliana per il MARE-Italian Research for the sea) started from 1 January 2012. It is one of the national research programs funded by the Italian Ministry of University and Research. RITMARE is coordinated by the National Research Council (CNR) and involves an integrated effort of most of the scientific community working on marine and maritime issues. Within the project, different marine study areas of strategic importance for the Mediterranean have been identified: Among these, the coastal area of Taranto (Ionian Sea, Southern Italy) was chosen for its different industry settlements and the relative impact on the marine environment. In particular, the research has been concentrated on the Mar Piccolo of Taranto, a complex marine ecosystem model important in terms of ecological, social, and economic activities for the presence also of extensive mussel farms. The site has been selected also because the Mar Piccolo area is a characteristic "on field" laboratory suitable to investigate release and diffusion mechanisms of contaminants, evaluate chemical ecological risks towards the marine ecosystem and human health, and suggest and test potential remediation strategies for contaminated sediments. In this context, within the project RITMARE, a task force of researchers has contributed to elaboration a functioning conceptual model with a multidisciplinary approach useful to identify anthropogenic forcings, its impacts, and solutions of environmental remediation. This paper describes in brief some of the environmental issues related to the Mar Piccolo basin. PMID- 26111754 TI - Cd isotopic signatures: a potential source tracer of metal pollution in the environment. PMID- 26111756 TI - Bufalin Inhibits the Differentiation and Proliferation of Cancer Stem Cells Derived from Primary Osteosarcoma Cells through Mir-148a. AB - BACKGROUND/AIMS: Osteosarcoma (OS) is the second leading cause of cancer-related death in children and young adults. Chemoresistance is the most important cause of treatment failure in OS, largely resulting from presence of cancer stem cells (CSCs). However, CSCs isolated from cancer cell lines do not necessarily represent those from primary human tumors due to accumulation of genetic aberrations that increase with passage number. Therefore, studies on CSCs from primary OS may be more important for understanding the mechanisms driving the chemoresistance of CSCs in OS. METHODS: We established a primary culture of OS cells, known as C1OS, from freshly resected tumor tissue. We further isolated CSCs from C1OS cells (C1OS-CSCs). We analyzed the effects of bufalin, a traditional Chinese medicine, on the stemness of C1OS-CSCs. We also analyzed the microRNA (miR) targets of bufalin on the stemness of C1OS-CSCs. Moreover, we examined these findings in the OS specimen. RESULTS: Bufalin inhibited the stemness of C1OS-CSCs. Moreover, we found that miR-148a appeared to be a target of bufalin, and miR-148a further regulated DNMT1 and p27 to control the stemness of OS cells. This mechanism was further confirmed in OS specimen. CONCLUSION: Our data suggest that bufalin may be a promising treatment for OS, and its function may be conducted through regulation of miR-148a. PMID- 26111755 TI - (No) time for control: Frontal theta dynamics reveal the cost of temporally guided conflict anticipation. AB - During situations of response conflict, cognitive control is characterized by prefrontal theta-band (3- to 8-Hz) activity. It has been shown that cognitive control can be triggered proactively by contextual cues that predict conflict. Here, we investigated whether a pretrial preparation interval could serve as such a cue. This would show that the temporal contingencies embedded in the task can be used to anticipate upcoming conflict. To this end, we recorded electroencephalography (EEG) from 30 human subjects while they performed a version of a Simon task in which the duration of a fixation cross between trials predicted whether the next trial would contain response conflict. Both their behavior and EEG activity showed a consistent but unexpected pattern of results: The conflict effect (increased reaction times and decreased accuracy on conflict as compared to nonconflict trials) was stronger when conflict was cued, and this was associated with stronger conflict-related midfrontal theta activity and functional connectivity. Interestingly, intervals that predicted conflict did show a pretarget increase in midfrontal theta power. These findings suggest that temporally guided expectations of conflict do heighten conflict anticipation, but also lead to less efficiently applied reactive control. We further explored this post-hoc interpretation by means of three behavioral follow-up experiments, in which we used nontemporal cues, semantically informative cues, and neutral cues. Together, this body of results suggests that the counterintuitive cost of conflict cueing may not be uniquely related to the temporal domain, but may instead be related to the implicitness and validity of the cue. PMID- 26111757 TI - Molecular and diagnostic features of apocrine breast lesions. AB - Apocrine morphology in breast is observed in a wide variety of lesions ranging from simple cysts and atypical hyperplasia to invasive metastatic stages of disease. The accurate diagnosis of breast apocrine carcinoma remains controversial, mainly due to the subjectivity of histopathological criteria and the lack of sensitive and specific biomarkers for reliable categorization of this subtype of breast carcinoma. Thus, many efforts are currently being made to identify novel molecular marker signature(s) that can define apocrine carcinoma with high levels of accuracy and reliability, and determine with certainty the true clinical significance of these lesions. The purpose of this article is to review the data on apocrine lesions, with an emphasis on borderline apocrine differentiation. In particular, we address relevant issues in the context of the current state of research on benign and malignant apocrine lesions of the breast, with a focus on parameters for diagnosis and potential-targeted therapeutic options. PMID- 26111758 TI - Precise Control of the Number of Layers of Graphene by Picosecond Laser Thinning. AB - The properties of graphene can vary as a function of the number of layers (NOL). Controlling the NOL in large area graphene is still challenging. In this work, we demonstrate a picosecond (ps) laser thinning removal of graphene layers from multi-layered graphene to obtain desired NOL when appropriate pulse threshold energy is adopted. The thinning process is conducted in atmosphere without any coating and it is applicable for graphene films on arbitrary substrates. This method provides many advantages such as one-step process, non-contact operation, substrate and environment-friendly, and patternable, which will enable its potential applications in the manufacturing of graphene-based electronic devices. PMID- 26111760 TI - Calcium phosphate nanoparticles are associated with inorganic phosphate-induced osteogenic differentiation of rat bone marrow stromal cells. AB - In the present study, we demonstrated that calcium phosphate (CaP) nanoparticles formed in cell culture media were implicated in the process of high inorganic phosphate (Pi) mediated osteogenic differentiation of rat bone marrow stromal cells (BMSCs). Exposure of BMSCs in vitro to high Pi-containing media reduced alkaline phosphatase (ALP) activity and the expressions of osteoblast-specific genes. The sediments of CaP nanoparticles were observed at the cell surface and some of them were concomitantly found inside cells at high Pi concentration. In addition, treatment the cells with pyrophosphate (PPi), an inhibitor of calcium crystal formation, abrogated the ALP activity induced by high Pi, suggesting the contribution of CaP nanoparticles. Moreover, for isolated CaP nanoparticles, there was a trend of conversion from amorphous calcium phosphate to hydroxyapatite with elevated Pi. The particle size of CaP increased and the surface morphology changed from spherical to irregular due to increased concentrations of serum proteins incorporated into CaP nanoparticles. The study demonstrated that those physicochemical properties of CaP nanoparticles played an important role in modulating BMSCs differentiation. Furthermore, the addition of Pi in the osteogenic media resulted in a dose-dependent increase in matrix mineralization, while treatment of the cells with PPi suppressed Pi-induced calcium deposition. The findings indicated that calcium deposition in the matrix partly came from the spontaneous precipitation of CaP nanoparticles. PMID- 26111759 TI - Quantitative analysis of the human T cell palmitome. AB - Palmitoylation is a reversible post-translational modification used to inducibly compartmentalize proteins in cellular membranes, affecting the function of receptors and intracellular signaling proteins. The identification of protein "palmitomes" in several cell lines raises the question to what extent this modification is conserved in primary cells. Here we use primary T cells with acyl biotin exchange and quantitative mass spectrometry to identify a pool of proteins previously unreported as palmitoylated in vivo. PMID- 26111761 TI - The antioxidative potential of farrerol occurs via the activation of Nrf2 mediated HO-1 signaling in RAW 264.7 cells. AB - Farrerol, (S)-2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-6,8-dimethyl-4 benzopyrone, isolated from rhododendron, has been shown to have antioxidative potential, but the molecular mechanism underlying this activity remains unclear. The inducible expression of heme oxygenase-1 (HO-1), a potent antioxidative and cytoprotective enzyme, is known to play an important role in cytoprotection in a variety of pathological models. In this study, we evaluated the antioxidative potential of farrerol against oxidative damage and investigated its antioxidative mechanism in RAW 264.7 cells. The molecular mechanism underlying the cytoprotective function of farrerol was determined by analyzing intracellular signaling pathways, transcriptional activation and the inhibitory effect of HO-1 on ROS production. Farrerol induced antioxidant enzymes mRNA expression, HO-1 protein expression and nuclear translocation of NF-E2-related factor 2 in RAW 264.7 macrophage cells. Farrerol down-regulated the expression of the Keap1 protein and the thiol reducing agents attenuated farrerol-induced HO-1 expression. Further investigation utilizing Western blotting and specific inhibitors of Akt, p38, JNK and ERK demonstrated that Akt, p38, and ERK axis of signaling pathway mediates HO-1 expression. Moreover, tert-butyl hydroperoxide (t BHP)-induced oxidative damage was ameliorated by farrerol treatment in a dose dependent manner, which was abolished by Akt, p38, ERK and HO-1 inhibitors (Snpp). It is hence likely that farrerol inactivated KEAP-1 or activated the Akt, p38 and ERK to facilitate the release of Nrf2 from Keap1 and subsequent reduced the intracellular production of reactive oxygen species via the induction of HO-1 expression. These results support the central role of HO-1 in the cytoprotective effect of farrerol. PMID- 26111762 TI - Superoxide anion radical (O2(-)) degrades methylmercury to inorganic mercury in human astrocytoma cell line (CCF-STTG1). AB - Methylmercury (MeHg) is a global pollutant that is affecting the health of millions of people worldwide. However, the mechanism of MeHg toxicity still remains somewhat elusive and there is no treatment. It has been known for some time that MeHg can be progressively converted to inorganic mercury (iHg) in various tissues including the brain. Recent work has suggested that cleavage of the carbon-metal bond in MeHg in a biological environment is facilitated by reactive oxygen species (ROS). However, the oxyradical species that actually mediates this process has not been identified. Here, we provide evidence that superoxide anion radical (O2(-)) can convert MeHg to iHg. The calculated second order rate constant for the degradation of 1MUM MeHg by O2(-) generated by xanthine/xanthine oxidase was calculated to be 2*10(5)M(-1)s(-1). We were also able to show that this bioconversion can proceed in intact CCF-STTG1 human astrocytoma cells exposed to paraquat (PQ), a O2(-) generating viologen. Notably, exposure of cells to increasing amounts of PQ led to a dose dependent increase in both MeHg and iHg. Indeed, a 24h exposure to 500MUM PQ induced a ~13-fold and ~18 fold increase in intracellular MeHg and iHg respectively. These effects were inhibited by superoxide dismutase mimetic MnTBAP. In addition, we also observed that a 24h exposure to a biologically relevant concentration of MeHg (1MUM) did not induce cell death, oxidative stress, or even changes in cellular O2(-) and H2O2. However, co-exposure to PQ enhanced MeHg toxicity which was associated with a robust increase in cell death and oxidative stress. Collectively our results show that O2(-) can bioconvert MeHg to iHg in vitro and in intact cells exposed to conditions that simulate high intracellular O2(-) production. In addition, we show for the first time that O2(-) mediated degradation of MeHg to iHg enhances the toxicity of MeHg by facilitating an accumulation of both MeHg and iHg in the intracellular environment. PMID- 26111763 TI - Ginsenoside Rd attenuates Abeta25-35-induced oxidative stress and apoptosis in primary cultured hippocampal neurons. AB - One of the most common pathological changes in Alzheimer's disease (AD) brain is the large number of amyloid beta (Abeta) peptides accumulating in lesion areas. Ginsenosides are the most active components extracted from ginseng. Ginsenoside Rd (GRd) is a newly discovered saponin that has a stronger pharmacological activity than other ginsenosides, especially in neuroprotection. Here we examined the neuroprotective effects of GRd against neuronal insults induced by Abeta25-35 in primary cultured hippocampal neurons. A 10MUM GRd treatment significantly prevented the loss of hippocampal neurons induced by Abeta25-35. In addition, GRd significantly ameliorated Abeta25-35-induced oxidative stress by decreasing the reactive oxygen species (ROS) production and malondialdehyde (MDA) level, and increasing the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px); which is similar in treatments with 10MUM of probucol (PB) and 100MUM of edaravone (EDA). Moreover, our present study demonstrated that GRd significantly enhanced the expression of Bcl-2 mRNA, and decreased the expressions of Bax mRNA and Cyt c mRNA. GRd also downregulated the protein level of cleaved Caspase-3 compared to controls. These results highlighted the neuroprotective effects of GRd against Abeta25-35-induced oxidative stress and neuronal apoptosis, suggesting that this may be a promising therapeutics against AD. PMID- 26111764 TI - A systems toxicology approach on the mechanism of uptake and toxicity of MWCNT in Caenorhabditis elegans. AB - The increased volumes of carbon nanotubes (CNTs) being utilized in industrial and biomedical processes carries with it an increased risk of unintentional release into the environment, requiring a thorough hazard and risk assessment. In this study, the toxicity of pristine and hydroxylated (OH-) multiwall CNTs (MWCNTs) was investigated in the nematode Caenorhabditis elegans using an integrated systems toxicology approach. To gain an insight into the toxic mechanism of MWCNTs, microarray and proteomics were conducted for C. elegans followed by pathway analyses. The results of pathway analyses suggested endocytosis, phagocytosis, oxidative stress and endoplasmic reticulum (ER) stress, as potential mechanisms of uptake and toxicity, which were subsequently investigated using loss-of-function mutants of genes of those pathways. The expression of phagocytosis related genes (i.e. ced-10 and rab-7) were significantly increased upon exposure to OH-MWCNT, concomitantly with the rescued toxicity by loss-of function mutants of those genes, such as ced-10(n3246) and rab-7(ok511). An increased sensitivity of the hsp-4(gk514) mutant by OH-MWCNT, along with a decreased expression of hsp-4 at both gene and protein level suggests that MWCNTs may affect ER stress response in C. elegans. Collectively, the results implied phagocytosis to be a potential mechanism of uptake of MWCNTs, and ER and oxidative stress as potential mechanisms of toxicity. The integrated systems toxicology approach applied in this study provided a comprehensive insight into the toxic mechanism of MWCNTs in C. elegans, which may eventually be used to develop an "Adverse Outcome Pathway (AOP)", a recently introduced concept as a conceptual framework to link molecular level responses to higher level effects. PMID- 26111765 TI - Angiotensin II modification by decomposition products of linoleic acid-derived lipid hydroperoxide. AB - Polyunsaturated fatty acids are highly susceptible to oxidation induced by reactive oxygen species and enzymes, leading to the formation of lipid hydroperoxides. The linoleic acid (LA)-derived hydroperoxide, 13 hydroperoxyoctadecadienoic acid (HPODE) undergoes homolytic decomposition to reactive aldehydes, 4-oxo-2(E)-nonenal (ONE), 4-hydroxy-2(E)-nonenal, trans-4,5 epoxy-2(E)-decenal (EDE), and 4-hydroperoxy-2(E)-nonenal (HPNE), which can covalently modify peptides and proteins. ONE and HNE have been shown to react with angiotensin (Ang) II (DRVYIHPF) and modify the N-terminus, Arg(2), and His(6). ONE-derived pyruvamide-Ang II (Ang P) alters the biological activities of Ang II considerably. The present study revealed that EDE and HPNE preferentially modified the N-terminus and His(6) of Ang II. In addition to the N-substituted pyrrole of [N-C4H2]-Ang II and Michael addition products of [His(6)(EDE)]-Ang II, hydrated forms were detected as major products, suggesting considerable involvement of the vicinal dihydrodiol (formed by epoxide hydration) in EDE derived protein modification in vivo. Substantial amounts of [N-(EDE-H2O)]-Ang II isomers were also formed and their synthetic pathway might involve the tautomerization of a carbinolamine intermediate, followed by intramolecular cyclization and dehydration. The main HPNE-derived products were [His(6)(HPNE)] Ang II and [N-(HPNE-H2O)]-Ang II. However, ONE, HNE, and malondialdehyde-derived modifications were dominant, because HPNE is a precursor of these aldehydes. A mixture of 13-HPODE and [(13)C18]-13-HPODE (1:1) was then used to determine the major modifications derived from LA peroxidation. The characteristic doublet (1:1) observed in the mass spectrum and the mass difference of the [M+H](+) doublet aided the identification of Ang P (N-terminal alpha-ketoamide), [N-ONE] Ang II (4-ketoamide), [Arg(2)(ONE-H2O)]-Ang II, [His(6)(HNE)]-Ang II (Michael addition product), [N-C4H2]-Ang II (EDE-derived N-substituted pyrrole), [His(6)(HPNE)]-Ang II, [N-(9,12-dioxo-10(E)-dodecenoic acid)]-Ang II, and [His(6)(9-hydroxy-12-oxo-10(E)-decenoic acid)]-Ang II as the predominant LA derived modifications. These modifications could represent the majority of lipid derived modifications to peptides and proteins in biological systems. PMID- 26111768 TI - The Mini-OAKHQOL for knee and hip osteoarthritis quality of life was obtained following recent shortening guidelines. AB - OBJECTIVES: To develop a short form of the knee and hip osteoarthritis quality of life questionnaire, the Mini-OAKHQOL, preserving the conceptual model and, as far as possible, the content and the psychometric properties of the original instrument. STUDY DESIGN AND SETTING: A two-step shortening procedure was used: (1) a consensus Delphi method, with a panel of patients and another of professionals independently asked to select items and (2) a nominal group, where patients, professionals, and methodologists reached consensus on the final selection of items, using information from the panels and from modern measurement and classical test theory analyses. The psychometric properties of the Mini OAKHQOL were assessed in an independent population-based sample of 581 subjects with knee or hip osteoarthritis. RESULTS: The two-step shortening procedure resulted in a 20-item questionnaire. Confirmatory factor analysis showed preservation of the original five-dimensional structure. Rasch analyses showed the unidimensionality and invariance by sex, age, and joint of the main dimensions. Convergent validity, reproducibility, and internal consistency were similar to or better than those of the original OAKHQOL. CONCLUSIONS: The 20-item Mini-OAKHQOL has good psychometric properties and can be used for the measurement of quality of life in subjects with osteoarthritis of the lower limbs. PMID- 26111769 TI - Creating a synergistic interplay between tubular MoS2 and particulate Fe3O4 for improved lithium storage. AB - A novel three-dimensional MoS2@Fe3O4 nanohybrid, composed of tubular MoS2 uniformly and densely decorated with particulate Fe3O4, is constructed, which exhibits significantly improved lithium storage performances through an impressive synergistic interplay between the two active materials. PMID- 26111770 TI - Comparison of obesity among Chinese and U.S. Special Olympic athletes with intellectual disabilities. AB - BACKGROUND/OBJECTIVES: Obesity is a health problem in China, but there are no reports on the obesity status of Chinese citizens with intellectual disabilities (ID). Research has shown that adults with ID have higher body mass index (BMI) than adults without ID, but this information is primarily based on populations residing in North American and European countries. The purpose of this study was to compare BMI and obesity status of Chinese and U.S. Special Olympic athletes with ID. SUBJECTS/METHODS: Height, weight, BMI and self-reported physical activity (SRPA) data from the Special Olympics 2006 U.S. National Games and 2007 Shanghai World Games databases were analyzed. Linear and logistic analyses were conducted for continuous data and dichotomous variables, respectively. Predictor variables were age, gender, country, SRPA, and obesity status according to country specific criteria. Significance was set at p < 0.05. RESULTS: The U.S. group had significantly higher BMI values than their Chinese counterparts. Age (p = 0.001) and country (p = <0.001) were the main predictors of BMI and obesity status, even when country-specific standards of obesity classifications were used. Holding all other factors constant, each unit increase of age was associated with increased odds for obesity by a factor of 1.04 and the odds of obesity occurring in U.S. athletes was 2.47 times greater than in Chinese athletes. CONCLUSION: Obesity is an emerging health problem for Chinese adults with ID. Participation in Special Olympics does not offset obesity in people with ID and other methods of intervention are needed to address obesity in this population segment. This is a global health concern that requires immediate attention. PMID- 26111771 TI - The influence of the learning effect on automated perimetry in a Turkish population. AB - PURPOSE: To evaluate the influence of learning effect on the outcome of automated perimetry and to assess the factors associated with the learning effect in a Turkish population. METHODS: The Swedish Interactive Threshold Algorithm (SITA) standard 30-2 test was performed on a Humphrey Visual Field Analyzer in 102 normal Turkish subjects who had not previously undertaken any form of perimetry. Each subject completed three testing sessions, each separated by at least one day. The SITA standard 30-2 testing sessions included both eyes. The right eye was always tested before left eye. The reliability parameters, test duration and visual field (VF) global indices (mean deviation [MD] and pattern standard deviation [PSD]) obtained from right eyes in the first and third sessions were compared to assess the learning effect. Change in these parameters between the first and third sessions was calculated, and the effect of gender, age and educational level on this change was evaluated. RESULTS: The reliability parameters, test duration and VF global indices each improved between the first and third sessions (P <= 0.001). The change in the parameters was greater in subjects over 50 years of age and with an educational level less than high school (P <= 0.01). No correlation was found between learning effect and gender. CONCLUSION: In normal Turkish subjects, a significant learning effect was observed during VF testing with the SITA standard 30-2. The learning effect was correlated with age and educational level. PMID- 26111766 TI - SLC transporters as therapeutic targets: emerging opportunities. AB - Solute carrier (SLC) transporters - a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes - have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets. PMID- 26111773 TI - Validation of circulating BNP level >1000 pg/ml in all-cause mortality: A retrospective study. AB - AIM: To determine the primary diseases and prognoses of patients with highly elevated levels of B-type natriuretic peptide (BNP; >1000 pg/ml), with or without heart failure. METHODS: Medical records and echocardiograms of patients with BNP levels that fell within one of three predetermined categories (>1000 pg/ml, 200 1000 pg/ml and <200 pg/ml) were retrospectively reviewed. RESULTS: There were no significant between-group differences in duration of hospitalization. Patients with BNP levels >1000 pg/ml (n = 103) or 200-1000 pg/ml (n = 100) had significantly worse 3-year survival than those with BNP levels <200 pg/ml (n = 100). The majority of patients (64/103) in the BNP >1000 pg/ml group had heart failure. The main cause of death in patients with other causes of BNP levels >1000 pg/ml (39/103) was community acquired pneumonia. CONCLUSION: A BNP level >1000 pg/ml has clinical importance in primary care medicine and hospital settings. PMID- 26111772 TI - PTH(1-84) Administration in Hypoparathyroidism Transiently Reduces Bone Matrix Mineralization. AB - Patients with hypoparathyroidism have low circulating parathyroid (PTH) levels and higher cancellous bone volume and trabecular thickness. Treatment with PTH(1 84) was shown to increase abnormally low bone remodeling dynamics. In this work, we studied the effect of 1-year or 2-year PTH(1-84) treatment on cancellous and cortical bone mineralization density distribution (Cn.BMDD and Ct.BMDD) based on quantitative backscattered electron imaging (qBEI) in paired transiliac bone biopsy samples. The study cohort comprised 30 adult hypoparathyroid patients (14 treated for 1 year; 16 treated for 2 years). At baseline, Cn.BMDD was shifted to higher mineralization densities in both treatment groups (average degree of mineralization Cn.CaMean +3.9% and +2.7%, p < 0.001) compared to reference BMDD. After 1-year PTH(1-84), Cn.CaMean was significantly lower than that at baseline ( 6.3%, p < 0.001), whereas in the 2-year PTH(1-84) group Cn.CaMean did not differ from baseline. Significant changes of Ct.BMDD were observed in the 1-year treatment group only. The change in histomorphometric bone formation (mineralizing surface) was predictive for Cn.BMDD outcomes in the 1-year PTH(1 84) group, but not in the 2-year PTH(1-84) group. Our findings suggest higher baseline bone matrix mineralization consistent with the decreased bone turnover in hypoparathyroidism. PTH(1-84) treatment caused differential effects dependent on treatment duration that were consistent with the histomorphometric bone formation outcomes. The greater increase in bone formation during the first year of treatment was associated with a decrease in bone matrix mineralization, suggesting that PTH(1-84) exposure to the hypoparathyroid skeleton has the greatest effects on BMDD early in treatment. PMID- 26111774 TI - Does pectoralis major flap harvesting induce upper extremity dysfunction? AB - OBJECTIVE: To evaluate the effect of pectoralis major myocutaneous (PMM) flap reconstruction on upper extremity dysfunction. METHODS: Patients undergoing PMM flap reconstruction following head and neck cancer resection were enrolled. The control group comprised age-, sex- and clinical characteristic-matched patients undergoing non-PMM flap reconstruction. All patients completed the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire preoperatively and >1 year postoperatively. RESULTS: There was no significant difference between pre- and postoperative DASH scores in the control group (n = 46; 2.38 +/- 3.33 and 2.99 +/ 4.21, respectively). In the PMM flap group (n = 46), the postoperative DASH score was significantly higher than the preoperative score (7.00 +/- 9.13 and 2.44 +/- 3.50, respectively). In the PMM flap group, flap size was significantly associated with postoperative DASH score. CONCLUSION: PMM flap reconstruction has a small but significant negative effect on upper extremity dysfunction. PMID- 26111776 TI - Tunable mid IR plasmon in GZO nanocrystals. AB - Degenerate metal oxide nanoparticles are promising systems to expand the significant achievements of plasmonics into the infrared (IR) range. Among the possible candidates, Ga-doped ZnO nanocrystals are particularly suited for mid IR, considering their wide range of possible doping levels and thus of plasmon tuning. In the present work, we report on the tunable mid IR plasmon induced in degenerate Ga-doped ZnO nanocrystals. The nanocrystals are produced by a plasma expansion and exhibit unprotected surfaces. Tuning the Ga concentration allows tuning the localized surface plasmon resonance. Moreover, the plasmon resonance is characterized by a large damping. By comparing the plasmon of nanocrystal assemblies to that of nanoparticles dispersed in an alumina matrix, we investigate the possible origins of such damping. We demonstrate that it partially results from the self-organization of the naked particles and also from intrinsic inhomogeneity of dopants. PMID- 26111775 TI - Expression of delta-like 4 (Drosophila) and vascular endothelial growth factor A in colon cancer and association with tumour angiogenesis. AB - OBJECTIVE: Angiogenesis depends on interaction between a variety of promoting and inhibiting factors, and is known to involve vascular endothelial growth factor (VEGF) A and the Notch signaling pathway. The present study investigated the expression of Notch ligand delta-like (DLL) 4 (Drosophila), and VEGFA in colon cancer and colorectal adenoma tissue, and the association with tumour angiogenesis. METHODS: Protein level DLL4, VEGFA and CD34 molecule (CD34) expression was detected immunohistochemically in tissue sections from patients with colon cancer and colorectal adenoma. RESULTS: Out of 80 cases (35 with colon cancer, 45 with colorectal adenoma) DLL4 and VEGFA expression was closely related to tumour diameter, clinical stage, histological grade and lymph node metastasis. DLL4 expression was significantly higher in colon cancer tissue than colorectal adenoma tissue. CONCLUSION: High levels of DLL4 expression were closely related to metastasis and prognosis in patients with colon cancer. The results of the present study support the conclusion that prognosis of colon cancer is significantly correlated with angiogenesis. PMID- 26111778 TI - A Quarter Century's Progress in the Treatment of Open-Angle Glaucoma. PMID- 26111777 TI - Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. AB - Female reproductive capacity declines dramatically in the fourth decade of life as a result of an age-related decrease in oocyte quality and quantity. The primary causes of reproductive aging and the molecular factors responsible for decreased oocyte quality remain elusive. Here, we show that aging of the female germ line is accompanied by mitochondrial dysfunction associated with decreased oxidative phosphorylation and reduced Adenosine tri-phosphate (ATP) level. Diminished expression of the enzymes responsible for CoQ production, Pdss2 and Coq6, was observed in oocytes of older females in both mouse and human. The age related decline in oocyte quality and quantity could be reversed by the administration of CoQ10. Oocyte-specific disruption of Pdss2 recapitulated many of the mitochondrial and reproductive phenotypes observed in the old females including reduced ATP production and increased meiotic spindle abnormalities, resulting in infertility. Ovarian reserve in the oocyte-specific Pdss2-deficient animals was diminished, leading to premature ovarian failure which could be prevented by maternal dietary administration of CoQ10. We conclude that impaired mitochondrial performance created by suboptimal CoQ10 availability can drive age associated oocyte deficits causing infertility. PMID- 26111779 TI - Improving Medication Adherence to Reduce Vision Loss in Patients with Glaucoma: Low Hanging Fruit? PMID- 26111780 TI - Re: Staurenghi et al.: Proposed lexicon for anatomic landmarks in normal posterior segment spectral-domain optical coherence tomography: the IN*OCT consensus (Ophthalmology 2014;121:1572-8). PMID- 26111781 TI - Author reply: To PMID 24755005. PMID- 26111782 TI - Re: Tham et al.: Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis (Ophthalmology 2014;121:2081 90). PMID- 26111783 TI - Author reply: To PMID 24974815. PMID- 26111784 TI - Re: Farias et al.: Choroidal thickness in patients with diabetes and microalbuminuria (Ophthalmology 2014;121:2071-3). PMID- 26111785 TI - Author reply: To PMID 24908206. PMID- 26111786 TI - Re: Kim et al.: Diagnostic classification of macular ganglion cell and retinal nerve fiber layer analysis: differentiation of false-positives from glaucoma (Ophthalmology 2015;122:502-10). PMID- 26111787 TI - Author reply: To PMID 25444638. PMID- 26111788 TI - Phase I study of intravenous (IV) docetaxel and intraperitoneal (IP) oxaliplatin in recurrent ovarian and fallopian tube cancer. AB - OBJECTIVE: The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of IV docetaxel and IP oxaliplatin in women with recurrent ovarian (OV), fallopian tube (FT) or peritoneal (PP) cancer. Secondary objectives included response rate, time to progression, pharmacokinetics (PK) and quality of life (QoL). METHODS: Patients received docetaxel 75mg/m(2) IV day (d) 1 and oxaliplatin escalating from 50mg/m(2) IP d2 every 3weeks using a 3+3 design. Treatment continued until disease progression, remission, or intolerable toxicity. Plasma and IP samples were taken to determine drug concentrations. MD Anderson Symptom Inventory and symptom interference scale were completed weekly. RESULTS: Thirteen patients were included. Median number of cycles was 6 (range 1 10). Ten patients had measureable disease. Best response was partial response (PR 2), stable disease (SD-7), and progressive disease (PD-1). Twenty-one Grades 3-4 toxicities were noted, commonly hematologic. Two patients had DLTs: prolonged neutropenia (1) and abdominal pain (1). MTD was d1 docetaxel 75mg/m(2) IV and d2 oxaliplatin 50mg/m(2) IP. Symptom burden peaked week one and returned to baseline by week two of each cycle on dose level 1. Dose level 2 had persistently high symptom burden and interference. At IP oxaliplatin doses of 50mg/m(2), total unbound drug exposure (AUC) averaged 8 times larger and Cmax reached concentrations 50-fold greater in IP fluid compared to plasma. CONCLUSIONS: Docetaxel 75mg/m(2) IV d1 and oxaliplatin 50mg/m(2) IP d2 is the MTD. Most patients had PR or SD. Patient-reported outcomes demonstrate temporary but tolerable decrements in QoL. IP oxaliplatin provides PK advantages over IV administration. PMID- 26111789 TI - Simple measurement popularizes sarcopenia evaluation in patients with heart failure. PMID- 26111791 TI - The Impact of Risk Reduction Initiatives on Readmission: THA and TKA Readmission Rates. AB - We assessed whether sequential incorporation of initiatives to decrease postoperative surgical complications were similarly effective in reducing 30-day readmission rates following total knee arthroplasty (TKA) and total hip arthroplasty (THA). Readmission rates following TKA decreased substantially (5.6% vs. 3.0%, P<0.001), but readmissions following THA (4.0% vs. 3.4%, P=0.41) were not significantly reduced. The greatest impact of the multimodal treatment approach was a reduction of surgically related TKA complications. Advanced medical disease, facility discharge status, and Medicare or Medicaid coverage contributed to the highest risk for 30-day readmission after THA. Risk models defining expected readmission rates should account for these factors to avoid penalizing hospitals that provide higher proportional care to Centers for Medicaid and Medicare Services (CMS) beneficiaries. PMID- 26111790 TI - Mapping Power Law Distributions in Digital Health Social Networks: Methods, Interpretations, and Practical Implications. AB - BACKGROUND: Social networks are common in digital health. A new stream of research is beginning to investigate the mechanisms of digital health social networks (DHSNs), how they are structured, how they function, and how their growth can be nurtured and managed. DHSNs increase in value when additional content is added, and the structure of networks may resemble the characteristics of power laws. Power laws are contrary to traditional Gaussian averages in that they demonstrate correlated phenomena. OBJECTIVES: The objective of this study is to investigate whether the distribution frequency in four DHSNs can be characterized as following a power law. A second objective is to describe the method used to determine the comparison. METHODS: Data from four DHSNs-Alcohol Help Center (AHC), Depression Center (DC), Panic Center (PC), and Stop Smoking Center (SSC)-were compared to power law distributions. To assist future researchers and managers, the 5-step methodology used to analyze and compare datasets is described. RESULTS: All four DHSNs were found to have right-skewed distributions, indicating the data were not normally distributed. When power trend lines were added to each frequency distribution, R(2) values indicated that, to a very high degree, the variance in post frequencies can be explained by actor rank (AHC .962, DC .975, PC .969, SSC .95). Spearman correlations provided further indication of the strength and statistical significance of the relationship (AHC .987. DC .967, PC .983, SSC .993, P<.001). CONCLUSIONS: This is the first study to investigate power distributions across multiple DHSNs, each addressing a unique condition. Results indicate that despite vast differences in theme, content, and length of existence, DHSNs follow properties of power laws. The structure of DHSNs is important as it gives insight to researchers and managers into the nature and mechanisms of network functionality. The 5-step process undertaken to compare actor contribution patterns can be replicated in networks that are managed by other organizations, and we conjecture that patterns observed in this study could be found in other DHSNs. Future research should analyze network growth over time and examine the characteristics and survival rates of superusers. PMID- 26111792 TI - Perioperative Complications in Patients with Inflammatory Arthropathy Undergoing Total Knee Arthroplasty. AB - Little data exists comparing acute post-operative outcomes in patients with different types of inflammatory arthritis (IA) after undergoing a total knee arthroplasty (TKA). Our objectives were to compare perioperative complications and determine the most common complications between the different IA subtypes compared with patients with osteoarthritis undergoing primary TKA. We found significant differences when comparing complications within the different subtypes of IA. RA patients, despite having a greater number of comorbidities had a reduced rate of medical complications postoperatively compared to the OA cohort. All of the inflammatory subtypes had a higher rate of orthopedic complications postoperatively compared to the OA group except for patients with AS. However, ankylosing spondylitis had the highest mortality rate as well as medical complication rate among the subtypes. PMID- 26111793 TI - Correction to Supporting Information for Sullivan et al., Spatially robust estimates of biological nitrogen (N) fixation imply substantial human alteration of the tropical N cycle. PMID- 26111794 TI - Correction for Thompson et al., Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye. PMID- 26111796 TI - Engineering Escherichia coli coculture systems for the production of biochemical products. AB - Engineering microbial consortia to express complex biosynthetic pathways efficiently for the production of valuable compounds is a promising approach for metabolic engineering and synthetic biology. Here, we report the design, optimization, and scale-up of an Escherichia coli-E. coli coculture that successfully overcomes fundamental microbial production limitations, such as high level intermediate secretion and low-efficiency sugar mixture utilization. For the production of the important chemical cis,cis-muconic acid, we show that the coculture approach achieves a production yield of 0.35 g/g from a glucose/xylose mixture, which is significantly higher than reported in previous reports. By efficiently producing another compound, 4-hydroxybenzoic acid, we also demonstrate that the approach is generally applicable for biosynthesis of other important industrial products. PMID- 26111795 TI - The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. AB - Bromodomain and extraterminal (BET) domain proteins have emerged as promising therapeutic targets in glioblastoma and many other cancers. Small molecule inhibitors of BET bromodomain proteins reduce expression of several oncogenes required for Glioblastoma Multiforme (GBM) progression. However, the mechanism through which BET protein inhibition reduces GBM growth is not completely understood. Long noncoding RNAs (lncRNAs) are important epigenetic regulators with critical roles in cancer initiation and malignant progression, but mechanistic insight into their expression and regulation by BET bromodomain inhibitors remains elusive. In this study, we used Helicos single molecule sequencing to comprehensively profile lncRNAs differentially expressed in GBM, and we identified a subset of GBM-specific lncRNAs whose expression is regulated by BET proteins. Treatment of GBM cells with the BET bromdomain inhibitor I BET151 reduced levels of the tumor-promoting lncRNA HOX transcript antisense RNA (HOTAIR) and restored the expression of several other GBM down-regulated lncRNAs. Conversely, overexpression of HOTAIR in conjunction with I-BET151 treatment abrogates the antiproliferative activity of the BET bromodomain inhibitor. Moreover, chromatin immunoprecipitation analysis demonstrated binding of Bromodomain Containing 4 (BRD4) to the HOTAIR promoter, suggesting that BET proteins can directly regulate lncRNA expression. Our data unravel a previously unappreciated mechanism through which BET proteins control tumor growth of glioblastoma cells and suggest that modulation of lncRNA networks may, in part, mediate the antiproliferative effects of many epigenetic inhibitors currently in clinical trials for cancer and other diseases. PMID- 26111797 TI - High MN1 expression increases the in vitro clonogenic activity of primary mouse B cells. AB - The MN1 (Meningioma 1) gene is overexpressed in certain subtypes of acute myeloid leukemia (AML) and high levels of MN1 expression in mouse bone marrow cells results in myeloid leukemia. We showed that compared with control bone marrow (BM) MN1 expression was increased (2-fold or more) in 29 out of 73 (40%) pediatric B-cell acute lymphoblastic leukemia (B-ALL) patient BM. Additional analysis of MN1 expression in sub-groups within our cohort carrying different chromosome translocations showed that carriers of the good prognostic marker t(12;21)(TEL-AML1) (n=27) expressed significantly more MN1 than both healthy controls (n=9) (P=0.02) and the group carrying the t(9;22)(BCR-ABL) (n=9) (P=0.001). In addition, AML1 expression was also upregulated in 31 out of 45 (68%) B-ALL patient BM compared with control and there was a significant correlation between MN1 and AML1 expression (r=0.3552, P=0.0167). Retroviral MN1 overexpression increased the colony forming activity of mouse Pro-B/Pre-B cells in vitro. Our results suggest that deregulated MN1 expression contributes to the pathogenesis of pediatric B-ALL. Further investigation into the clinical and biological significance of elevated MN1 expression in TEL-AML1(positive) leukemia might provide insight into additional molecular mechanisms contributing to B-ALL and may lead to improved treatment options for patients. PMID- 26111799 TI - Primary vaginal sarcoma: Experience of a regional cancer center in China. AB - AIM: To evaluate the clinical characteristics of primary vaginal sarcoma, which is a rare malignancy METHODS: We retrospectively reviewed the clinical records of eight patients with primary vaginal sarcoma treated at Sun Yat-Sen University Cancer Centre from 1997 to 2012. RESULTS: Eight patients aged >= 17 years were identified (four had leiomyosarcoma, two had endometrial stromal sarcoma, one had undifferentiated sarcoma, and one had adenosarcoma). Four patients had stage I disease, one had stage II, and three had stage IV. Five patients with stage I or II tumor received surgery of mainly local wide excision. One of the five patients received postoperative radiation plus chemotherapy and two had postoperative chemotherapy only. Three of the four stage I patients who had low-grade tumors and received wide local excision were alive without disease at 21, 53, and 81 months, respectively. One stage I patient with a high-grade tumor received simple tumor excision only and died of the disease at 20 months. The patient with stage II disease was lost to follow up. The three stage IV patients received radiotherapy and/or chemotherapy and all died within 2 years. CONCLUSIONS: Surgery is the main treatment for primary vaginal sarcoma. Prognosis may be associated with tumor grade and stage. PMID- 26111798 TI - Robust disruptions in electroencephalogram cortical oscillations and large-scale functional networks in autism. AB - BACKGROUND: Autism spectrum disorders (ASD) are increasingly prevalent and have a significant impact on the lives of patients and their families. Currently, the diagnosis is determined by clinical judgment and no definitive physiological biomarker for ASD exists. Quantitative biomarkers obtainable from clinical neuroimaging data - such as the scalp electroencephalogram (EEG) - would provide an important aid to clinicians in the diagnosis of ASD. The interpretation of prior studies in this area has been limited by mixed results and the lack of validation procedures. Here we use retrospective clinical data from a well characterized population of children with ASD to evaluate the rhythms and coupling patterns present in the EEG to develop and validate an electrophysiological biomarker of ASD. METHODS: EEG data were acquired from a population of ASD (n = 27) and control (n = 55) children 4-8 years old. Data were divided into training (n = 13 ASD, n = 24 control) and validation (n = 14 ASD, n = 31 control) groups. Evaluation of spectral and functional network properties in the first group of patients motivated three biomarkers that were computed in the second group of age-matched patients for validation. RESULTS: Three biomarkers of ASD were identified in the first patient group: (1) reduced posterior/anterior power ratio in the alpha frequency range (8-14 Hz), which we label the "peak alpha ratio", (2) reduced global density in functional networks, and (3) a reduction in the mean connectivity strength of a subset of functional network edges. Of these three biomarkers, the first and third were validated in a second group of patients. Using the two validated biomarkers, we were able to classify ASD subjects with 83 % sensitivity and 68 % specificity in a post-hoc analysis. CONCLUSIONS: This study demonstrates that clinical EEG can provide quantitative biomarkers to assist diagnosis of autism. These results corroborate the general finding that ASD subjects have decreased alpha power gradients and network connectivities compared to control subjects. In addition, this study demonstrates the necessity of using statistical techniques to validate EEG biomarkers identified using exploratory methods. PMID- 26111800 TI - Function and postnatal changes of dural afferent fibers expressing TRPM8 channels. AB - BACKGROUND: Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-expressing dural afferent fibers as well as the function of dural TRPM8 channels in mice. RESULTS: First, we quantified the density and the number of axonal branches of TRPM8 expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from one TRPM8 allele between postnatal day 2 (P2) to adulthood. The number of axonal branches on individual dural EGFP-positive fibers was decreased by 30% between P2 and P11. The density of dural EGFP-positive fibers was subsequently reduced by 50% between P16 and P21. Conversely, the density and the number of branches of axons expressing calcitonin gene-related peptide remained stable in postnatal mouse dura. The density of TRPM8-expressing fibers innervating the mouse cornea epithelium was significantly increased from P2 to adulthood. Next, we tested the function of dural TRPM8 channels in adult mice and found that TRPM8 agonist menthol effectively inhibited the nocifensive behavior evoked by dural application of inflammatory mediators. CONCLUSIONS: Our results indicate that the TRPM8-expressing dural afferent fibers undergo cell- and target tissue-specific axonal pruning during postnatal development. Activation of dural TRPM8 channels decreases meningeal irritation-evoked nocifensive behavior in adult mice. This provides a framework to further explore the role of postnatal changes of TRPM8-expressing dural afferents in the pathophysiology of pediatric and adult migraine. PMID- 26111801 TI - Temporal distribution of arrhythmic events in chronic kidney disease: Highest incidence in the long interdialytic period. AB - BACKGROUND: Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) have a high risk of sudden cardiac death (SCD). A unique risk factor may be a longer interval between HD sessions (interdialytic period). Inherent in conventional HD (thrice-weekly) are two 48-hour short breaks (SIDP) and one 72 hour long break (LIDP) between HD sessions. OBJECTIVE: We used an implantable cardiac monitor (ICM) to define the incidence and timing of significant arrhythmias in an HD population. METHODS: Fifty CKD patients undergoing HD with left ventricular ejection fraction >35% had an ICM inserted, with intensive follow-up to record SCD events and predefined bradyarrhythmias and tachyarrhythmias. RESULTS: Mean age of the patients was 67 +/- 11 years; 72% were male, and the mean follow-up was 18 +/- 4 months. There were 8 unexpected SCDs (16%), all during the LIDP. The terminal event was severe bradycardia with asystole in each recorded case. No episodes of polymorphic ventricular tachycardia (VT) occurred. A total of 7686 arrhythmia events were recorded in 43 patients (86%), including bradycardia in 15 patients (30%), sinus arrest in 14 (28%), second-degree atrioventricular block in 4 (8%), nonsustained VT in 10 (20%), and new-onset paroxysmal atrial fibrillation in 14 (28%). The LIDP was the highest-risk period for all arrhythmias (P < .001). The arrhythmia event rate per hour was greatest during the first pre-HD period of the week compared with any other peri-HD period (P < .001). CONCLUSION: Risk of SCD and significant arrhythmias is greatest during the LIDP. SCD was attributable to severe bradycardia and asystole. Interventions to prevent this type of SCD or shorten the LIDP deserve further evaluation. CLINICAL TRIAL REGISTRATION INFORMATION: URL: https://www.anzctr.org.au (Unique identifier: ACTRN12613001326785). PMID- 26111802 TI - To the Editor--Are esophageal lesions caused by the use of esophageal probess or conductive heat after atrial fibrillation ablation? PMID- 26111803 TI - To the Editor--Higher incidence of esophageal lesions after atrial fibrillation ablation related to the use of esophageal temperature probes. PMID- 26111804 TI - Reply to the Editor--Higher incidence of esophageal lesions after atrial fibrillation ablation related to the use of esophageal temperature probes. PMID- 26111805 TI - Comparison of cardiac MRI and 18F-FDG positron emission tomography manifestations and regional response to corticosteroid therapy in newly diagnosed cardiac sarcoidosis with complet heart block. AB - BACKGROUND: Complete heart block (CHB) caused by myocardial inflammation is a serious consequence of cardiac sarcoidosis (CS) that requires early diagnosis for effective anti-inflammatory treatment. OBJECTIVE: This study aimed to clarify the cardiac magnetic resonance imaging (MRI) and (18)F-fluoro-2-deoxyglucose positron emission tomography ((18)F-FDG PET) manifestations of newly diagnosed CS with CHB and to assess whether certain imaging features could predict responders to corticosteroid therapy. METHODS: Fifteen newly diagnosed CS patients with CHB and 17 without CHB were examined. We defined abnormal (18)F-FDG uptake on (18)F-FDG PET and increased T2-weighted signal on cardiac MRI as signs of myocardial inflammation and delayed enhancement (DE) on cardiac MRI as a sign of myocardial fibrosis. Ten CHB+ patients were then treated with corticosteroids. RESULTS: The CHB+ group showed higher (18)F-FDG uptake and increased T2-weighted signal in the interventricular septum, which involves the electrical pathway of atrioventricular conduction, than the CHB- group (P = .001 and P < .0001, respectively), whereas there was no group difference in DE (P = .232). Six corticosteroid-treated patients recovered from CHB; all had exhibited increased T2-weighted signal, (18)F-FDG uptake, and DE in the interventricular septum before therapy. In contrast, among the 4 patients without recovery, 2 showed no abnormal (18)F-FDG uptake and 3 had no increased T2-weighted signal in the interventricular septum, but all showed DE. The 2 patients without recovery with abnormal (18)F-FDG uptake showed wall thinning in the interventricular septum. CONCLUSION: Focal inflammation in the interventricular septum was associated with CHB and might predict recovery from CHB after corticosteroids if it coexists with preserved wall thickness. PMID- 26111806 TI - Re-growth, morphogenesis, and differentiation during starfish arm regeneration. AB - The red starfish Echinaster sepositus is an excellent model for studying arm regeneration processes following traumatic amputation. The initial repair phase was described in a previous paper in terms of the early cicatrisation phenomena, and tissue and cell involvement. In this work, we attempt to provide a further comprehensive description of the later regenerative stages in this species. Here, we present the results of a detailed microscopic and submicroscopic investigation of the long regenerative phase, which can be subdivided into two subphases: early and advanced regenerative phases. The early regenerative phase (1-6 weeks p.a.) is characterized by tissue rearrangement, morphogenetic processes and initial differentiation events (mainly neurogenesis and skeletogenesis). The advanced regenerative phase (after 6 weeks p.a.) is characterized by further differentiation processes (early myogenesis), and obvious morphogenesis and re growth of the regenerate. As in other starfish, the regenerative process in E. sepositus is relatively slow in comparison with that of crinoids and many ophiuroids, which is usually interpreted as resulting mainly from size-related aspects and of the more conspicuous involvement of morphallactic processes. Light and electron microscopy analyses suggest that some of the amputated structures, such as muscles, are not able to replace their missing parts by directly re growing them from the remaining tissues, whereas others tissues, such as the skeleton and the radial nerve cord, appear to undergo direct re-growth. The overall process is in agreement with the distalization-intercalation model proposed by Agata and co-workers. Further experiments are needed to confirm this hypothesis. PMID- 26111807 TI - Agreement with evidence for tissue Plasminogen Activator use among emergency physicians: a cross-sectional survey. AB - BACKGROUND: Emergency department staff play a crucial role in the triage of stroke patients and therefore the capacity to deliver time-dependent treatments such as tissue Plasminogen Activator. This study aimed to identify among emergency physicians, (1) rates of agreement with evidence supporting tissue Plasminogen Activator use in acute stroke care; and (2) individual and hospital factors associated with high agreement with evidence supporting tissue Plasminogen Activator use. METHODS: Australian fellows and trainees of the Australasian College for Emergency Medicine were invited to complete an online cross-sectional survey assessing perceptions of tissue Plasminogen Activator use in acute stroke. Demographic and hospital characteristics were also collected. RESULTS: 429 Australasian College for Emergency Medicine members responded (13% response rate). Almost half (47.2%) did not agree with any statements regarding the benefits of tissue Plasminogen Activator use for acute stroke. Perceived routine administration of tissue Plasminogen Activator by the head of respondents' emergency department was significantly associated with high agreement with the evidence supporting tissue Plasminogen Activator use in acute stroke. CONCLUSIONS: Agreement with evidence supporting tissue Plasminogen Activator use in acute stroke is not high among responding Australian emergency physicians. In order for tissue Plasminogen Activator treatment to become widely accepted and adopted in emergency settings, beliefs and attitudes towards treatment need to be in accordance with clinical practice guidelines. PMID- 26111808 TI - Hepatotoxic effect of ochratoxin A and citrinin, alone and in combination, and protective effect of vitamin E: In vitro study in HepG2 cell. AB - Ochratoxin A (OTA) and citrinin (CTN) are the most commonly co-occurring mycotoxins in a wide variety of food and feed commodities. The major target organ of these toxins is kidney but liver could also be a target organ. The combined toxicity of these two toxins in kidney cells has been studied but not in liver cell. In this study HepG2 cells were exposed to OTA and CTN, alone and in combination, with a view to compare the molecular and cellular mechanisms underlying OTA, CTN and OTA + CTN hepatotoxicity. OTA and CTN alone as well as in combination affected the viability of HepG2 cells in a dose-dependent manner. OTA + CTN, at a dose of 20% of IC50 of each, produced effect almost similar to that produced by either of the toxins at its IC50 concentration, indicating that the two toxins in combination act synergistically. The cytotoxicity of OTA + CTN on hepatocytes is mediated by increased level of intracellular ROS followed/accompanied by DNA strand breaks and mitochondria-mediated intrinsic apoptosis. Co-treatment of vitamin E (Vit E) with OTA, CTN and OTA + CTN reduced the levels of ROS and the cytotoxicity. But the genotoxic effect of OTA and OTA + CTN was not completely alleviated by Vit E treatment whereas the DNA damage as caused by CTN when treated alone was obviated, indicating that OTA induces DNA damage directly whereas CTN induces ROS-mediated DNA damage and OTA + CTN combination induces DNA damage not exclusively relying on but influenced by ROS generation. Taken together, these findings indicate that OTA and CTN in combination affect hepatocytes at very low concentrations and, thereby, pose a potential threat to public and animal health. PMID- 26111809 TI - Approach to using mechanism-based structure activity relationship (SAR) analysis to assess human health hazard potential of nanomaterials. AB - With the increasing use and development of engineered nanoparticles in electronics, consumer products, pesticides, food and pharmaceutical industries, there is a growing concern about potential human health hazards of these materials. A number of studies have demonstrated that nanoparticle toxicity is extremely complex, and that the biological activity of nanoparticles will depend on a variety of physicochemical properties such as particle size, shape, agglomeration state, crystal structure, chemical composition, surface area and surface properties. Nanoparticle toxicity can be attributed to nonspecific interaction with biological structures due to their physical properties (e.g., size and shape) and biopersistence, or to specific interaction with biomolecules through their surface properties (e.g., surface chemistry and reactivity) or release of toxic ions. The toxic effects of most nanomaterials have not been adequately characterized and currently, there are many issues and challenges in toxicity testing and risk assessment of nanoparticles. Based on the possible mechanisms of action and available in vitro and in vivo toxicity database, this paper proposes an approach to using mechanism-based SAR analysis to assess the relative human health hazard/risk potential of various types of nanomaterials. PMID- 26111810 TI - Ethanol-extracted propolis enhances BBN-initiated urinary bladder carcinogenesis via non-mutagenic mechanisms in rats. AB - Ethanol-extracted propolis (EEP) is used for medical, dietetic and cosmetic purposes. In this study, the effects of EEP on urinary bladder carcinogenesis, its underlying mechanism and in vivo genotoxicity were investigated. In experiment 1, rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 2 or 4 weeks followed by dietary administration of 0.125, 0.25, 0.5 or 1% EEP for 4 or 32 weeks, respectively. At week 6, the mRNA levels of top2a, cyclin D1 and survivin were significantly elevated in the 0.5 and 1% EEP groups. At week 36, the incidence and multiplicity of urothelial carcinomas and total tumors were markedly elevated in all EEP groups. In experiment 2, rats were fed basal diet or the 1% EEP diet for 13 weeks without carcinogen initiation. Increases in urinary precipitate, cell proliferation and incidence of simple hyperplasia were observed in the 1% EEP group. In experiment 3, dietary administration of 2.5% EEP to gpt delta rats for 13 weeks did not induce any obvious mutagenicity in the urinary bladder urothelium. Taken together, EEP enhanced BBN-initiated rat urinary bladder carcinogenesis in a non-genotoxic manner through increasing formation of urinary precipitate, enhancing cell proliferation and inhibiting apoptosis during the early stages of carcinogenesis. PMID- 26111811 TI - Right-sided colon cancer and left-sided colorectal cancers respond differently to cetuximab. AB - INTRODUCTION: Right-sided colon cancer (RSCC) and left-sided colorectal cancer (LSCRC) differ with respect to their biology and genomic patterns. This study aimed to examine whether the primary tumor location is associated with the response to cetuximab in patients with metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC treated with cetuximab and standard chemotherapy as first- or second-line treatments were compared with randomly chosen patients who were treated with chemotherapy alone between 2005 and 2013. The main outcome measures were the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). The differences in the outcome were analyzed by using the chi-squared test, Student's t test, and Kaplan-Meier method. RESULTS: The treatment results of 206 patients with mCRC treated with cetuximab and standard chemotherapy as first- or second-line treatments were compared with those of 210 patients who were treated with chemotherapy alone. As a first-line treatment, cetuximab with chemotherapy was associated with a significantly higher ORR (49.4 % vs. 28.6 %, P = 0.005) as well as longer PFS (9.1 vs. 6.2 months, P = 0.002) and OS (28.9 vs. 20.1 months, P = 0.036) than chemotherapy alone in patients with LSCRC. However, cetuximab neither improved the ORR (36.4 % vs. 26.2 %, P = 0.349) nor prolonged PFS (5.6 vs. 5.7 months, P = 0.904) or OS (25.1 vs. 19.8 months, P = 0.553) in patients with RSCC. As a second-line treatment, cetuximab exhibited a tendency to improve the ORR (23.5 % vs. 10.2 %, P = 0.087) and prolong PFS (4.9 vs. 3.5 months, P = 0.064), and it significantly prolonged OS (17.1 vs. 12.4 months, P = 0.047) compared with chemotherapy alone in the patients with LSCRC. In contrast, as a second-line treatment, cetuximab neither improved the ORR (7.1 % vs. 11.4 %, P = 0.698) nor prolonged PFS (3.3 vs. 4.2 months, P = 0.761) or OS (13.4 vs. 13.0 months, P = 0.652) in patients with RSCC. CONCLUSIONS: The addition of cetuximab to chemotherapy in both first- and second-line treatments of mCRC may only benefit patients with primary LSCRC. PMID- 26111812 TI - Metformin in breast cancer - an evolving mystery. AB - Metformin, a diabetes drug with well-established side effect and safety profiles, has been widely studied for its anti-tumor activities in a number of cancers, including breast cancer. But its mechanism of action in the clinical arena remains elusive. In a window of opportunity trial of metformin in non-diabetic breast cancer patients, Dowling and colleagues examined both the direct actions of the drug on cancer cells (as mediated by AMP kinase), as well as its indirect actions (as mediated by circulating insulin). The data suggest that short-term administration of metformin in this setting has anti-tumor effects significantly involving the indirect, insulin-dependent pathway. The role of the direct pathway remains to be determined. This study represents an important step forward in establishing one of several possible mechanisms for metformin, information that will be useful in determining candidate biomarkers to evaluate in large clinical trials of metformin, such as the ongoing NCIC CTG MA.32 trial of adjuvant metformin. The potential significance of these data for metformin in the treatment of breast cancer is discussed here. PMID- 26111813 TI - Successful use of pre and post-operative ECMO for pulmonary endarterectomy, mitral valve replacement and myomectomy in a patient with chronic thromboembolic pulmonary hypertension and hypertrophic cardiomyopathy. AB - As a salvage strategy, extracorporeal membrane oxygenation (ECMO) permits the recovery of end-organ perfusion, whilst allowing the surgeon time for patient reassessment and surgical planning. We report upon the first known case in which VA ECMO was instituted as peri-operative supportive therapy for a young patient, in-extremis, with surgically correctable Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Hypertrophic Cardiomyopathy (HOCM). PMID- 26111814 TI - Applying a typology of health worker migration to non-EU migrant doctors in Ireland. AB - BACKGROUND: Research on health worker migration in the Irish context has categorized migrant health workers by country or region of training (for example, non-EU nurses or doctors) or recruitment mechanism (for example, actively recruited nurses). This paper applies a new typology of health worker migrants - livelihood, career-oriented, backpacker, commuter, undocumented and returner migrants (European Observatory on Health Systems and Policies and WHO, vol. 2:129 152, 2014) - to the experiences of non-EU migrant doctors in Ireland and tests its utility for understanding health worker migration internationally. METHODS: The paper draws on quantitative survey (N = 366) and qualitative interview (N = 37) data collected from non-EU migrant doctors in Ireland between 2011 and 2013. RESULTS: Categorizing non-EU migrant doctors in Ireland according to the typology (European Observatory on Health Systems and Policies and WHO, vol. 2:129-152, 2014) offers insight into their differing motivations, particularly on arrival. Findings suggest that the career-oriented migrant is the most common type of doctor among non-EU migrant doctor respondents, accounting for 60 % (N = 220) of quantitative and 54 % (N = 20) of qualitative respondents. The authors propose a modification to the typology via the addition of two additional categories - the family migrant and the safety and security migrant. CONCLUSIONS: Employing a typology of health worker migration can facilitate a more comprehensive understanding of the migrant medical workforce, a necessary prerequisite for the development of useful policy tools (European Observatory on Health Systems and Policies and WHO, vol. 2:129-152, 2014). The findings indicate that there is some fluidity between categories, as health worker motivations change over time. This indicates the potential for policy levers to influence migrant health worker decision-making, if they are sufficiently "tuned in" to migrant health worker motivation. PMID- 26111815 TI - Knowledge and attitudes of school teachers, preschool teachers and students in teacher training about epilepsy and emergency management of seizures. AB - PROBLEM: School and preschool teachers play a key role in the care of children with epilepsy. Yet, data about their knowledge on epilepsy are scarce. METHODS: Assessment of knowledge and attitudes towards epilepsy in teachers by conducting a questionnaire survey in Leipzig and Blankenburg, Germany, from August 2013 to January 2014. RESULTS: 1243 questionnaires were completed by 302 school teachers, 883 preschool teachers, 56 students and two unclassified participants. Of the respondents, 140 (11%) stated to have already been actively involved in an epilepsy emergency situation, another 148 (12%) as observers. Only 214 (17%) of respondents felt sufficiently prepared for an emergency. A rescue medication had already been applied by 79 (6%) of respondents; only 186 respondents (15%) stated they would be willing to administer a prescribed rescue medication under any circumstances. In response to an open-ended question about the most common fatal outcomes of a seizure, status epilepticus and drowning were rarely mentioned. 233 (19%) of respondents assumed that epileptic seizures cannot result in death. 606 (49%) of respondents were concerned about the legal repercussions to an incorrect response to a seizure.129/403 (32%) of teachers with >20 years of professional experience claimed never to have had a child suffering from epilepsy in their care, even though the prevalence of childhood epilepsy indicates that they should. In total, 1066 (86%) respondents expressed a desire to gain more knowledge on epilepsy. CONCLUSIONS: Training programmes for teachers should be established. Furthermore, a clear legal regulatory framework needs to be set up. PMID- 26111817 TI - Response to 'supervisor or mentor: is there a difference? Implications for paediatric practice'. PMID- 26111816 TI - Prevalence and associated harm of engagement in self-asphyxial behaviours ('choking game') in young people: a systematic review. AB - OBJECTIVE: To assess the prevalence of engagement in self-asphyxial (risk-taking) behaviour (SAB) ('choking game') and associated morbidity and mortality in children and young people up to age 20. DESIGN: Systematic literature review. SEARCH STRATEGY: Electronic database search of MEDLINE, Embase, PsycINFO, CINAHL, PubMed, Web of Science Core Collection, BIOSIS citation index and the Cochrane register with no language or date limits applied. References of key papers were reviewed, and experts were contacted to identify additional relevant papers. ELIGIBILITY CRITERIA: Systematic reviews, cross-sectional, cohort and case control studies, and case reports examining SAB with regard to individuals aged 0 20 years, without explicitly stated autoerotic, suicidal or self-harm intentions were included. RESULTS: Thirty-six relevant studies were identified, and SAB was reported in 10 countries. In North America, France and Colombia, awareness of SAB ranged from 36% to 91% across studies/settings, and the median lifetime prevalence of engagement in SAB was 7.4%. Six studies identified the potential for SAB to be associated with engagement in other risk behaviours. Ninety-nine fatal cases were reported. Of the 24 cases described in detail, most occurred when individuals engaged in SAB alone and used a ligature. CONCLUSIONS: The current evidence on SAB among young people is limited, and stems predominantly from North America and France. Awareness of SAB among young people is high, and engagement varies by setting. Further research is needed to understand the level of risk and harm associated with SAB, and to determine the appropriate public health response. PMID- 26111818 TI - The epidemiology of Kawasaki disease: a global update. AB - Kawasaki disease (KD) is a childhood vasculitis and the most frequent cause of paediatric acquired heart disease in North America, Europe and Japan. It is increasingly recognised in rapidly industrialising countries such as China and India where it may replace rheumatic heart disease as the most common cause of acquired heart disease in children. We review the current global epidemiology of KD and discuss some public health implications. PMID- 26111819 TI - Discussing overweight in primary care. PMID- 26111820 TI - Using a Root Cause Analysis Curriculum for Practice-Based Learning and Improvement in General Surgery Residency. AB - OBJECTIVE: To describe and evaluate a root cause analysis (RCA)-based educational curriculum for quality improvement (QI) practice-based learning and implementation in general surgery residency. DESIGN: A QI curriculum was designed using RCA and spaced-learning approaches to education. The program included a didactic session about the RCA methodology. Resident teams comprising multiple postgraduate years then selected a personal complication, completed an RCA, and presented the findings to the Department of Surgery. Mixed methods consisting of quantitative assessment of performance and qualitative feedback about the program were used to assess the value, strengths, and limitations of the program. SETTING: Urban tertiary academic medical center. PARTICIPANTS: General surgery residents, faculty, and medical students. RESULTS: An RCA was completed by 4 resident teams for the following 4 adverse outcomes: postoperative neck hematoma, suboptimal massive transfusion for trauma, venous thromboembolism, and decubitus ulcer complications. Quantitative peer assessment of their performance revealed proficiency in selecting an appropriate case, defining the central problem, identifying root causes, and proposing solutions. During the qualitative feedback assessment, residents noted value of the course, with the greatest limitation being time constraints and equal participation. CONCLUSION: An RCA-based curriculum can provide general surgery residents with QI exposure and training that they value. Barriers to successful implementation include time restrictions and equal participation from all involved members. PMID- 26111821 TI - A 19-Year Record of Training Haitian Residents in Otorhinolaryngology and Cervicofacial Surgery. AB - OBJECTIVES: Since 1996, 1 to 4 annual training missions have been carried out to train Haitian otorhinolaryngology (ENT) and cervicofacial surgery residents by the association Liens Otorhinolaryngology Ayti (LOA). Until 1996, ENT was practiced and taught by ophthalmologists. The aim of this article is to describe the contributions and limitations of LOA in training of Haitian resident physicians and the creation of the ENT specialty in Haiti. DESIGN: Retrospective analysis of clinical consultation and surgical interventions records and didactics carried out during missions from 1996 through 2014. PARTICIPANTS: A total of 37 missions were made during the 19-year period in which 29 senior ENT specialists participated, with an average of 3.37 missions per physician. RESULTS: A total of 10,300 consultations and 173 surgical procedures were made jointly by a senior LOA physician and a Haitian resident physician. Totally 16 Haitian ENT residents were trained, 81% of whom are still practicing in Haiti. ENT became a surgical specialty in 2001 after the nomination of a Haitian ENT specialist as Assistant Director of the ENT-Ophthalmology service. The latter benefitted from dual training by LOA in Haiti and abroad. CONCLUSION: The Haitian population experiences significant difficulties with access to medical care owing to very low number of resident medical personnel. LOA's work has contributed over 19 years to the training of ENT physicians now practicing in Haiti and to the creation of a local ENT specialty. PMID- 26111822 TI - e-Learning in Surgical Education: A Systematic Review. AB - OBJECTIVE: e-Learning involves the delivery of educational content through web based methods. Owing to work-hour restrictions and changing practice patterns in surgery, e-learning can offer an effective alternative to traditional teaching. Our aims were to (1) identify current modalities of e-learning, (2) assess the efficacy of e-learning as an intervention in surgical education through a systematic review of the literature, and (3) discuss the relevance of e-learning as an educational tool in surgical education. This is the first such systematic review in this field. DESIGN: A systematic search of MEDLINE and EMBASE was conducted for relevant articles published until July 2014, using a predefined search strategy. The database search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 38 articles were found which met the inclusion criteria. In these studies, e-learning was used as an intervention in 3 different ways: (1) to teach cases through virtual patients (18/38); (2) to teach theoretical knowledge through online tutorials, or other means (18/38); and (3) to teach surgical skills (2/38). Nearly all of the studies reviewed report significant knowledge gain from e-learning; however, 2 in 3 studies did not use a control group. CONCLUSIONS: e-Learning has emerged as an effective mode of teaching with particular relevance for surgical education today. Published studies have demonstrated the efficacy of this method; however, future work must involve well designed randomized controlled trials comparing e-learning against standard teaching. PMID- 26111823 TI - The Generic Error Rating Tool: A Novel Approach to Assessment of Performance and Surgical Education in Gynecologic Laparoscopy. AB - OBJECTIVE: Global rating scales are commonly used to rate surgeons' skill level. However, these tools lack granularity required for specific skill feedback. Recently, an alternative framework has been developed that is designed to measure technical errors during laparoscopy. The purpose of the present study was to gather validity evidence for the Generic Error Rating Tool (GERT) in gynecologic laparoscopy. DESIGN: Video recordings of total laparoscopic hysterectomies were analyzed by 2 blinded reviewers using the GERT and the Objective Structured Assessment of Technical Skills (OSATS) scale. Several sources of validity were examined according to the unitary framework of validity. Main outcomes were interrater and intrarater reliability regarding total number of errors and events. Further, surgeons were grouped according to OSATS scores (OSATS >= 28 = high performers and OSATS < 28 = low performers), and the number of errors and events was compared between groups. Correlation analysis between GERT and OSATS scores was performed. Lastly, error distribution within procedure steps was explored and compared between high- and low-performing surgeons. SETTING: University teaching hospital. PARTICIPANTS: A total of 20 anonymized video recordings of total laparoscopic hysterectomies. RESULTS: Interrater and intrarater reliability was high (intraclass correlation coefficient >0.95) for total number of errors and events. Low performers made significantly more errors than high performers did (median = 49.5 [interquartile range: 34.5-66] vs median = 31 [interquartile range: 16.75-35.25], p = 0.002). There was a significant negative correlation between individual OSATS scores and total number of errors (Spearman rho = -0.76, p < 0.001, and rho = -0.88, p < 0.001, for raters 1 and 2, respectively). Error distribution varied between operative steps, and low performers made more errors in some steps, but not in others. CONCLUSION: GERT allows for objective and reproducible assessment of technical errors during gynecologic laparoscopy and could be used for performance analysis and personalized surgical education and training. PMID- 26111825 TI - Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid. AB - The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic, electrophilic alkylating reagents. Although the Chan-Lam reaction has been widely applied in the arylation of heteroatom nucleophiles, O-alkylation with boronic acids is rare. We report a Cu-catalyzed nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds in air with no additional oxidant. An isotope-labeling study supports an oxidative cross-coupling mechanism, in analogy to that proposed for Chan-Lam arylation. PMID- 26111824 TI - Time dependency of foamy virus evolutionary rate estimates. AB - BACKGROUND: It appears that substitution rate estimates co-vary very strongly with their timescale of measurement; the shorter the timescale, the higher the estimated value. Foamy viruses have a long history of co-speciation with their hosts, and one of the lowest estimated rates of evolution among viruses. However, when their rate of evolution is estimated over short timescales, it is more reminiscent of the rapid rates seen in other RNA viruses. This discrepancy between their short-term and long-term rates could be explained by the time dependency of substitution rate estimates. Several empirical models have been proposed and used to correct for the time-dependent rate phenomenon (TDRP), such as a vertically-translated exponential rate decay model and a power-law rate decay model. Nevertheless, at present, it is still unclear which model best describes the rate dynamics. Here, we use foamy viruses as a case study to empirically describe the phenomenon and to determine how to correct rate estimates for its effects. Four empirical models were investigated: (i) a vertically-translated exponential rate decay model, (ii) a simple exponential rate decay model, (iii) a vertically-translated power-law rate decay model, and (iv) a simple power-law rate decay model. RESULTS: Our results suggest that the TDRP is likely responsible for the large discrepancy observed in foamy virus short-term and long-term rate estimates, and the simple power-law rate decay model is the best model for inferring evolutionary timescales. Furthermore, we demonstrated that, within the Bayesian phylogenetic framework, currently available molecular clocks can severely bias evolutionary date estimates, indicating that they are inadequate for correcting for the TDRP. Our analyses also suggest that different viral lineages may have different TDRP dynamics, and this may bias date estimates if it is unaccounted for. CONCLUSIONS: As evolutionary rate estimates are dependent on their measurement timescales, their values must be used and interpreted under the context of the timescale of rate estimation. Extrapolating rate estimates across large timescales for evolutionary inferences can severely bias the outcomes. Given that the TDRP is widespread in nature but has been noted only recently the estimated timescales of many viruses may need to be reconsidered and re-estimated. Our models could be used as a guideline to further improve current phylogenetic inference tools. PMID- 26111826 TI - Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. AB - OBJECTIVE: The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon beta-1a (IFNbeta-1a) in patients with relapsing-remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. METHODS: Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNbeta-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous fingolimod 0.5 mg and pooled IFN-switch groups. RESULTS: Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0-EOS: 0.17 vs 0.27). After switching to fingolimod (M0-12 vs M13-EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. CONCLUSIONS: These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNbeta-1a to fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834. PMID- 26111827 TI - An extended assistantship for final-year students. AB - BACKGROUND: Many students feel unprepared for clinical practice after completing their medical school training. There is evidence that a brief shadowing period improves student confidence and patient safety, but there is currently little evidence on the impact of a longer shadowing period. A 10-week student assistantship (SA) for final-year students was implemented for Year 5 undergraduates at the University of Bristol in 2011. This study investigated the impact of the SA on student confidence. METHODS: All final-year medical students at the University of Bristol in the academic year 2012-13 (n = 248) were contacted with an online questionnaire at the start of the SA. They were asked about confidence in a range of domains. Further questionnaires were sent at the end of the SA, and again once the students had qualified as foundation doctors. Descriptive statistical analysis was performed. Many students feel unprepared for clinical practice RESULTS: A total of 37 students responded to the pre assistantship questionnaire, 62 to the post-assistantship questionnaire, and 13 to the questionnaire sent once students had qualified. Self-assessed confidence improved in all areas when the pre- and post-assistantship scores were compared, in particular prescribing, assessing and managing unwell patients, and aspects of death and dying. DISCUSSION: Our findings suggest that a prolonged assistantship period improves knowledge and skills in a range of domains relevant to becoming a junior doctor, and could be considered within medical schools as a way to address established areas of poor confidence in new graduates. Larger studies are needed to provide more robust evidence for these initial findings. PMID- 26111829 TI - Curcumin alleviates lung injury in diabetic rats by inhibiting nuclear factor kappaB pathway. AB - Curcumin is a polyphenolic compound that is extracted from Curcuma longa. It has broad anti-inflammation and anti-tumor activities. Curcumin was previously reported to exert beneficial effects on diabetes. However, the effect of curcumin on diabetes-induced lung injury is not yet clear. In this study, the effects of curcumin on lung injury induced by diabetes was explored using quantitative real time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry and electrophoretic mobility shift assay. The results of this study showed that curcumin reduced oxidative stress level, inhibited the synthesis of nitric oxide and prostaglandin E2, and reduced inflammatory responses in the lungs of diabetic rats, thereby alleviating diabetes-induced lung injury. Further study of the mechanism revealed that curcumin inhibited the activation of nuclear factor (NF)-kappaB which is a key player in inflammatory responses. In summary, our study demonstrated that curcumin inhibited the activation of NF-kappaB in the lungs of diabetic rats, thus reducing pulmonary inflammatory responses and oxidative stress, and ultimately relieving diabetes induced lung injury. This study suggests that curcumin may be a promising agent to alleviate diabetic lung injury and also provides theoretical foundation for the development of diabetes therapy. PMID- 26111830 TI - Type 2 diabetes mellitus in Danish children and adolescents in 2014. AB - BACKGROUND/OBJECTIVE: The global increase in childhood obesity has in some countries been followed by an increase in type 2 diabetes mellitus (T2DM); however, the prevalence of T2DM among Danish children and adolescents is currently unknown. The aims of this cross-sectional study were to determine the prevalence of T2DM in children and adolescents in Denmark together with status on treatment, metabolic control, and late diabetic complications. METHODS: Individuals were identified in the Danish Registry for Diabetes in Children and Adolescents (DanDiabKids), and clinical information regarding these was obtained from the respective pediatric departments. RESULTS: In total, seven young individuals (three boys) with T2DM were identified, according to the American Diabetes Association (ADA)/International Society of Pediatric and Adolecent Diabetes (ISPAD) guidelines, leading to a prevalence of T2DM at 0.6/100 000 inhabitants in Denmark. Only three of the patients had hyperglycemic symptoms at diagnosis. One boy was overweight and six were obese (two boys). Currently, no patients fulfill the treatment target of glycosylated hemoglobin (HbA1c) <7.0% (53 mmol/mol) according to the guidelines for treatment of diabetes. CONCLUSIONS: In 2014, there is no increasing prevalence of T2DM in children and adolescents in Denmark. Nevertheless, the current treatment regimen is not satisfying, as none of the patients truly fulfill the treatment target. PMID- 26111828 TI - MKP1 phosphatase mediates G1-specific dephosphorylation of H3Serine10P in response to DNA damage. AB - Histone mark, H3S10 phosphorylation plays a dual role in a cell by maintaining relaxed chromatin for active transcription in interphase and condensed chromatin state in mitosis. The level of H3S10P has also been shown to alter on DNA damage; however, its cell cycle specific behavior and regulation during DNA damage response is largely unexplored. In the present study, we demonstrate G1 cell cycle phase specific reversible loss of H3S10P in response to IR-induced DNA damage is mediated by opposing activities of phosphatase, MKP1 and kinase, MSK1 of the MAP kinase pathway. We also show that the MKP1 recruits to the chromatin in response to DNA damage and correlates with the decrease of H3S10P, whereas MKP1 is released from chromatin during recovery phase of DDR. Furthermore, blocking of H3S10 dephosphorylation by MKP1 inhibition impairs DNA repair process and results in poor survival of WRL68 cells. Collectively, our data proposes a pathway regulating G1 cell cycle phase specific reversible reduction of H3S10P on IR induced DNA damage and also raises the possibility of combinatorial modulation of H3S10P with specific inhibitors to target the cancer cells in G1-phase of cell cycle. PMID- 26111831 TI - Physical Compatibility of Calcium Chloride and Sodium Glycerophosphate in Pediatric Parenteral Nutrition Solutions. AB - BACKGROUND: Calcium and phosphate precipitation is an ongoing concern when compounding pediatric parenteral nutrition (PN) solutions. Considerable effort has been expended in producing graphs, tables, and equations to guide the practitioner in prescribing PN that will remain stable. Calcium gluconate is preferred over calcium chloride when compounding PN because of its superior compatibility with inorganic phosphates. PN solutions containing calcium gluconate carry a higher aluminum load than equivalent solutions compounded with calcium chloride, leading to increased potential for aluminum toxicity. This study tested the solubility of calcium chloride in PN solutions compounded with an organic phosphate component, sodium glycerophosphate (NaGP), in place of sodium phosphate. METHODS: Five PN solutions were compounded by adding calcium chloride at 10, 20, 30, 40, and 50 mEq/L and corresponding concentrations of NaGP at 10, 20, 30, 40, and 50 mmol/L. Each of the 5 solutions was compounded using 1.5% and 4% amino acids, cysteine, and lipids. The physical stability was evaluated by visual inspection (precipitation, haze, and color change). Solutions were evaluated microscopically for any microcrystals using U.S. Pharmacopeia <788> standards. RESULTS: Compatibility testing showed no changes in the PN solution in any of the concentrations tested. Calcium chloride was found to be physically compatible with NaGP in PN at the tested concentrations. CONCLUSION: Utilization of NaGP in PN solutions would eliminate the need for precipitation curves and allow for the use of calcium chloride. Compounding with NaGP and calcium chloride allows the practitioner a mechanism for reducing the aluminum load in PN. PMID- 26111832 TI - Clinical Management of Patients With Parenteral Nutrition-Dependent Short Bowel Syndrome During Teduglutide Therapy. AB - BACKGROUND: Patients with intestinal failure, who are dependent on parenteral nutrition (PN) to supplement their limited absorption of dietary nutrients, are subject to complications associated with long-term PN therapy. Medication therapy that results in improved dietary nutrient absorption may enable these patients to reduce or even become independent from PN therapy and its related complications. The glucagon-like peptide 2 (GLP-2) analogue teduglutide was approved for use in such patients by the U.S. Food and Drug Administration in 2012. PURPOSE: The purpose of this article is to describe the experience of 7 patients with PN dependent intestinal failure who were treated with teduglutide by a single center that had been involved in the teduglutide clinical trials. RESULTS: Two patients who were treated during the clinical trials and 5 others who were treated since teduglutide came to market in the United States are described. Protocols used to prepare and monitor patients with this drug and PN weaning and adverse event outcomes are presented. CONCLUSIONS: While some patients had uncomplicated PN reduction, others experienced various complications. Careful monitoring of patients' clinical course is needed during drug therapy. PMID- 26111833 TI - UK doctors head home from Ebola frontline. PMID- 26111834 TI - Effect of Topical Insulin on Second-Degree Burns in Diabetic Rats. AB - The healing process is complex in diabetic wounds, and the healing mechanism of burn wounds is different from that of incisional or excisional wounds. Data from our previous study indicated that topical insulin cream reduced wound closure time in diabetic rats. Our aim was to investigate the effect of topical insulin cream on wound healing following second-degree burns in control and diabetic rats. Rats were divided into four groups: control (nondiabetic) rats treated with placebo (CP), control (nondiabetic) rats treated with topical insulin cream (CI), diabetic rats treated with placebo (DP), and diabetic rats treated with topical insulin cream (DI). The wounds were assessed at 4 time points (1, 7, 14, and 26 days) post-wounding for morphometric analysis of wound sections stained with hematoxylin/eosin, alpha-smooth muscle actin, and Picrosirius red to evaluate general aspects of the wound, inflammatory infiltrate, blood vessels, and Types I and III collagen fibers. Histological analysis showed that topical insulin cream increased the inflammatory cell infiltrate in the DI group (at 7 and 14 days postburn, p < .05) and blood vessels (at 14 days postburn, p < .05) to levels similar to those of groups CP and CI. Wounds treated with topical insulin cream (CI and DI groups) showed significantly stronger staining for fibrillar collagen than wounds of the DP group. The use of topical insulin may reduce the duration of the inflammatory phase; improve wound reepithelialization, tissue granulation, and wound contraction; and increase collagen deposition in second-degree burns in healthy and diabetic animals. PMID- 26111835 TI - [Why history of medicine?]. PMID- 26111836 TI - [Antike Anatomien]. AB - One still wonders today at the anatomical precision with which various ancient authors, like Homer, depict the inner body. How was it possible to get such a precise knowledge, at a period when medicine was not particularly famous for its scientific achievements? The history of the beginnings of western anatomy reveals a surprising variety: its progress, until the tremendous technical fulfilments of contemporary anatomical imaging, has been neither linear, nor spontaneous, nor even necessary. Before becoming one of the epistemological bedrocks of medicine, its history reveals itself filled with accidents, ruptures, contingencies, and actors who contributed to modify its course. PMID- 26111837 TI - [William Harvey revisited ]. AB - William Harvey's discovery of the circulation of the blood is often described as a product of the Scientific Revolution of the Seventeenth Century. Modern research has, however, shown thatHarvey followed the Aristotelian research tradition and thus tried to reveal the purpose of the organs through examination of various animals. His publication of 1628 has to be read as an argument of natural philosophy, or, more precisely, as a series of linked observations, experiments and philosophical reasonings from which the existence of circulation has to be deduced as a logical consequence. Harvey did not consider experiments as superior to philosophical reasoning nor intended he to create a new system of medicine. He believed in the vitality of the heart and the blood and rejected Francis Bacon's empirism and the mechanistic rationalism of Descartes. Harvey's contribution and originality lied less in his single observations and experiments but in the manner how he linked them with critical reasoning and how he accepted, presented and defended the ensuing radical findings. PMID- 26111838 TI - [Beyond the asylum -An other view on the history of psychiatry in the modern age]. AB - If one thinks medicine, madness and the past, one image immediately pops into mind: that of the mental asylum. Following the famous work by Michel Foucault, Madness and Civilization: A History of Insanity in the Age of Reason, many historians have thus considered that the medicalization of insanity in the modern age had mostly led to a "great confinement" and a greater segregation of all individuals deemed mentally unfit during the "asylum era': However, new research demonstrates that this classic narrative of the psychiatric past needs to be revised. It discloses that, ever since the 191h century, a whole other medical culture existed as a challenge to asylums, a culture that advocated the integration of the mad and fought to disassociate psychiatry from the dominant model of confinement all throughout the occidental world. This article aims at presenting the results of these historical works that depict another aspect of the psychiatric history, exploring "boarding out" practices, instead of asylum ones. PMID- 26111839 TI - [The construction of a medical discipline and its challenges: Orthopedics in Switzerland during the 19th and 20th centuries]. AB - During the 19th century, numerous figures, with different qualifications, claimed to practice orthopedics: doctors, surgeons, inventors of equipment and instruments, and other empiricists. They performed certain types of techniques, massages, surgical operationsand/or fitted prostheses. The polysemous notion of orthopedics had created conflicts of interest that would reach their height at the end of the 19th century. The integration of orthopedics into the training at the university level enhanced its proximity to surgery, a discipline that has dominated the so-called modern medicine. During the 20th century, various medical branches defend the legitimacy of certain orthopedic practices, thereby threating to a degree the title itself of this specialization. By examining the challenges that have shaped the history of orthopedics in Switzerland, this article also seeks to shed light on the strategies that were implemented in adopting a medical and technical discipline within a transforming society. PMID- 26111840 TI - [The traveling image in neurological textbooks (1850-1920)]. AB - Images have always played an important part in neurology. From the early days of the discipline, images, in the form of drawings and photographs, are included in textbooks and travel all around the Western world. They have a role to play in the diffusion, authority and standardization of the neurological discipline. This paper describes the world-wide circulation of a medical image through textbooks. PMID- 26111841 TI - [Negotiating light therapy. Kellogg versus Finsen, and the controversy about the health effects of light rays around 1900]. AB - Western medicine has produced different rationales for the application of light rays to cure diseases in the 201h century. Since the 1980s, physicians have used bright light for treating mental disorders. In the interwar period, however, physicians regarded ultraviolet rays rather than bright light as medically relevant. This view goes back to the 1890s, when the physician (and later Nobel Price laureate) Niels R. Finsen started treating skin tuberculosis with light rays. However, Finsen was not the only physician who utilized the new electric light to develop effective therapies. Famous American inventor of the breakfast cereal and eugenicists, John Harvey Kellogg used incandescent lamps to heat a sweatbox. Consequently, two different therapeutic schools emerged from these therapeutic experiments. This article shows how these two schools negotiated the use of light therapy and how a specific idea of medically interesting light rays emerged thereby. PMID- 26111842 TI - [Constant or break? On the relations between human genetics and eugenics in the Twentieth Century]. AB - The history of human genetics has been a neglected topic in history of science and medicine for a long time. Only recently, have medical historians begun to pay more attention to the history of human heredity. An important research question deals with the interconnections between human genetics and eugenics. This paper addresses this question: By focusing on a Swiss case study, the investigation of the heredity of goiter, I will argue that there existed close but also ambiguous relations between heredity research and eugenics in the twentieth century. Studies on human heredity often produced evidence that challenged eugenic aims and ideas. Concurrently, however, these studies fostered visions of genetic improvement of human populations. PMID- 26111843 TI - [Consumption and Control: How Vitamin C could become a Cure-All]. AB - Artificial vitamin C has become a bulk product. To explain how ascorbic acid could enter everyday life, one less has to look at medical necessities than at the dynamic interplay of production, promotion, and health care policy. Hence, this contribution focuses on the complex interactions of health concepts, diagnostic instruments and the physician's gaze necessary to endow ascorbic acid with a medical indication. On the one hand, this reveals the differences between a "purely scientific" and a "medical-biological" point of view. On the other hand, as man last but not least is what he eats, this points to the fact that nutrition and parts of it always are soaked with health policy and moral. PMID- 26111844 TI - [Hospital Infections, Antibiotics and the Emergence of Resistance in English Hospitals, 1930-1960]. AB - This paper examines the history of hospital infections, the clinical introduction of antibiotics and the emergence of antibiotic resistant disease strains in English hospitals between 1930 and 1960. It argues that infection has been an almost constant problem for the modern, curative hospital. The arrival first of sulphonamides and later of antibiotics provided a cost-effective, readily available counter-measure which proved to be highly effective in the short term. The longer term consequence, however, was the emergence of antibiotic resistant strains. Calls for a rational use of antibiotics, voiced from 1952, remained unheard. The problem culminated in the crisis around Staph 80/81, a strain of Staphyloccocus Aureus resistant to all available antibiotics at the time. The development of methicillin and the implementation of stricter infection control regimes allowed the problem to recede around 1960 after an intense period of historical change from the end of the war onwards. PMID- 26111845 TI - [Peptic ulcer disease and helicobacter pylori: How we know what we know]. AB - The bacterium Helicobacter pylori is one of the main causes of peptic ulcers. But how was this causal relationship demonstrated? A historical and philosophical analysis of a series of studies conducted during the 1980s can elucidate the question. In the beginning, a mere correlation between the newly discovered bacterium and peptic ulcers was found in gastric biopsies. It remained an open question whether the bacterium caused the disease, or whether it constituted merely an opportunistic infection. Yet determining the direction of causality was difficult in the absence of an animal model: Even though gastritis was observed in a courageous self-experiment involving a swallowed bacterial culture, tf!e significance of the individual case was small. The failings of the self experiment could only be rectified by a randomised, placebo-controlled trial which met the requirements of Koch's third postulate. Moreover, it was necessary to gain an initial understanding of the mechanism by which the causal relationship between H. pylori and peptic ulcers is mediated: How, forexample, does the bacterium survive in the acid environment of the stomach? The study of the case from the perspective of the history and philosophy of science illustrates how medical knowledge is established incrementally. PMID- 26111846 TI - Temporal trends in classical and alternative flame retardants in bird eggs from Donana Natural Space and surrounding areas (south-western Spain) between 1999 and 2013. AB - Several halogenated flame retardants were detected in black kite, white stork and greater flamingo unborn eggs from Donana Natural Space (Spain) collected in 1999, 2003, 2011 and 2013. The main components of Penta-BDE commercial mixture (BDE-47, -99 and -100) showed a decrease in the studied time interval, concurring with the ban of this mixture in the European Union (EU) in 2006. On the other hand, BDE 209, the main component of Deca-BDE mixture showed a clear trend in black kites but further monitoring is needed since its production ceased at the end of 2013. Besides, even if Dechlorane Plus (DP) was proposed by the EU as an alternative to BDE-209 no time trends were observed. Furthermore, total concentrations of PBDEs (classical FRs) are still higher than concentrations of hexabromocyclododecane (HBCD) and alternative FRs halogenated norbornenes (HNs), which are theoretically substitutes of the already banned PBDEs. PMID- 26111848 TI - Complex cooperative breeders: Using infant care costs to explain variability in callitrichine social and reproductive behavior. AB - The influence of ecology on social behavior and mating strategies is one of the central questions in behavioral ecology and primatology. Callitrichines are New World primates that exhibit high behavioral variability, which is widely acknowledged, but not always systematically researched. Here, I examine the hypothesis that differences in the cost of infant care among genera help explain variation in reproductive traits. I present an integrative approach to generate and evaluate predictions from this hypothesis. I first identify callitrichine traits that vary minimally and traits that are more flexible (e.g., have greater variance or norm of reaction), including the number of males that mate with a breeding female, mechanisms of male reproductive competition, number of natal young retained, and the extent of female reproductive suppression. I outline how these more labile traits should vary along a continuum of infant care costs according to individual reproductive strategies. At one end of the spectrum, I predict that groups with higher infant care costs will show multiple adult males mating and providing infant care, high subordinate female reproductive suppression, few natal individuals delaying dispersal, and increased reproductive output by the dominant female -with opposite predictions under low infant costs. I derive an estimate of the differences in ecological and physiological infant care costs that suggest an order of ascending costs in the wild: Cebuella, Callithrix, Mico, Callimico, Saguinus, and Leontopithecus. I examine the literature on each genus for the most variable traits and evaluate a) where they fall along the continuum of infant care costs according to their reproductive strategies, and b) whether these costs correspond to the ecophysiological estimates of infant care costs. I conclude that infant care costs can provide a unifying explanation for the most variable reproductive traits among callitrichine genera. The approach presented can be used to generate predictions and motivate researchers to unravel complexity in callitrichine social and reproductive behavior. PMID- 26111847 TI - Old measures and new scores in spinal muscular atrophy patients. AB - INTRODUCTION: A recent Rasch analysis performed on the Hammersmith Functional Motor Scale-Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items. METHODS: We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients. RESULTS: The mean 12-month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar. CONCLUSIONS: The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items. PMID- 26111849 TI - Erratum to: Halolamina rubra sp. nov., a haloarchaeon isolated from non-purified solar salt. PMID- 26111850 TI - Flavobacterium notoginsengisoli sp. nov., isolated from the rhizosphere of Panax notoginseng. AB - Two novel bacterial strains, designated SYP-B540(T) and SYP-B556, were isolated from rhizospheric soil of Panax notoginseng located at Yunnan Province, China. Both strains were Gram-staining negative, aerobic, non-motile, elongated rod shaped and yellow coloured. They grew optimally at 28 degrees C and pH 7.0. Analysis of 16S rRNA gene sequences showed that the two strains shared 99.8 % sequence similarity to each other, but lower than 97.6 % to the other known species of the genus Flavobacterium. The predominant respiratory quinone for the two strains was MK-6, and the major fatty acids were iso-C15:0 and summed Feature 3 (comprising 16:1 omega7c and/or 16:1 omega6c). The polar lipids consisted of phosphatidylethanolamine, two unidentified polar lipids and three unidentified amino-phospholipids. The DNA G+C contents of strains SYP-B540(T) and SYP-B556 were 33.3 and 32.7 mol%, respectively. In addition, the DNA-DNA hybridization values of strains SYP-B540(T) and SYP-B556 to their closest phylogenetic neighbors were significantly lower than 70 %. On the basis of the polyphasic taxonomy studies, strains SYP-B540(T) and SYP-B556 represent a novel species of the genus Flavobacterium, for which the name Flavobacterium notoginsengisoli sp. nov. is proposed. The type strain is SYP-B540(T) (=KCTC 32505(T) = NBRC 110012(T) = BCRC 80724(T)). PMID- 26111851 TI - Lysobacter agri sp. nov., a bacterium isolated from soil. AB - A bacterial strain, designated as THG-SKA3(T), was isolated from field soil of Kyung Hee University, South Korea. Cells of the isolate were observed to be Gram negative, aerobic, rod-shaped and motile by gliding. The strain was found to grow optimally at 28 degrees C, at pH 7 and in absence of NaCl. Based on 16S rRNA gene sequence comparisons, strain THG-SKA3(T) shared highest sequence similarity with Lysobacter niastensis KACC 11588(T) followed by Lysobacter panacisoli KACC 17502(T), Lysobacter enzymogenes LMG 8762(T) and Lysobacter oryzae KCTC 22249(T). The G+C content of THG-SKA3(T) was determined to be 68.9 mol%. The DNA-DNA relatedness values between strain THG-SKA3(T) and its closest phylogenetic neighbors were below 25.0 %.The major polar lipids of strain THG-SKA3(T) were determined to be diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. The predominant respiratory quinone was identified as ubiquinone 8 (Q-8). The major cellular fatty acids were identified as branched chain iso-C15:0, iso-C16:0 and unsaturated iso-C17:1 omega9c. On the basis of polyphasic data presented, it is evident that strain THG-SKA3(T) represents a novel species of the genus Lysobacter, for which the name Lysobacter agri sp. nov. (type strain THG-SKA3(T) = KACC 18283(T) = CSCTCC AB 2015126(T)) is proposed. PMID- 26111852 TI - Catellatospora tagetis sp. nov., isolated from the root of a marigold (Tagetes erecta L.). AB - A Gram-stain positive, non-motile, mesophilic actinomycete, designated strain NEAU-YJC4(T) was isolated from the root of a marigold (Tagetes erecta L.) collected in Heilongjiang Province, northeast China, and characterized using a polyphasic approach. Morphological and chemotaxonomic properties of strain NEAU YJC4(T) were consistent with the description of the genus Catellatospora. 16S rRNA gene sequence similarity studies showed that strain NEAU-YJC4(T) belongs to the genus Catellatospora, being most closely related to Catellatospora bangladeshensis JCM 12949(T) (98.7 %). Phylogenetic analysis based on 16S rRNA gene sequences demonstrated that strain NEAU-YJC4(T) formed a monophyletic clade with the closest relative. A combination of DNA-DNA hybridization results and some phenotypic characteristics indicated that strain NEAU-YJC4(T) can be distinguished from C. bangladeshensis JCM 12949(T). Therefore, it is proposed that strain NEAU-YJC4(T) represents a novel species of the genus Catellatospora, for which the name Catellatospora tagetis sp. nov. is proposed. The type strain is NEAU-YJC4(T) (=CGMCC 4.7176(T) = JCM 30053(T)). PMID- 26111853 TI - [Experience in nephron-sparing surgery in patients with small renal tumors]. AB - BACKGROUND: Nephron -sparing surgery is currently the treatment of choice for surgical removal of solid renal tumours smaller than 7 cm, in the case of a solitary kidney, bilateral renal tumours or the presence of chronic renal failure. MATERIAL AND METHODS: An observational, descriptive, retrospective and cross-sectional study was conducted. The variables evaluated were: age at diagnosis, gender, intraoperative blood loss, operative time, preoperative tumour size, hospital stay, pathology report, pTNM classification, Fuhrman nuclear grade, pre- and post-operative creatinine, monitoring for cancer. All were analysed using SPSS v 22. RESULTS: The study included 28 patients, 14 male and 14 women, with a mean age 52.3 years. The approach was lumbotomy in all patients. The mean hospital stay was 4.1 days. Mean perioperative bleeding loss was 380.3 ml. The mean preoperative creatinine was 0.96 mg/dl, with a post-operative mean of 1.12 mg/dl. Histopathology reported, 23 clear cell tumours, 2 angiomyolipomas, 2 oncocytomas, and 1 haemorrhagic cyst. Tumour staging was performed on 14 patients, with 13 patients T1bN0M0, and 1 patient T2aN0M0. In clear cell tumours, Fuhrman nuclear grade 2 was present in 16 patients and 7 patients were Fuhrman grade 3. CONCLUSION: Nephron sparing surgery is the choice procedure of choice in patients with small renal tumours, with good functional results without significant alteration in renal function. Outcome is optimal, with a low incidence of complications. PMID- 26111854 TI - [Prognostic factors related to mortality in newborns with necrotising enterocolitis]. AB - BACKGROUND: Necrotizing enterocolitis is the most frequent and severe acquired gastrointestinal disease in newborns and still has high mortality. There are few published papers about prognostic factors of death in our country. OBJECTIVE: To know the factors associated with death in patients with necrotizing enterocolitis. METHODS: Retrospective, descriptive, comparative study with a case control design was conducted on patients with necrotizing enterocolitis during a 5-year period. RESULTS: Deceased patients had significantly lower platelet counts compared to survivors (P=0.022) and the prognostic factors associated with mortality were anaemia (P=0.006, OR = 15.62), stage III of necrotizing enterocolitis (P<0.001, OR = 47.5), to require surgical treatment (P<0.001, OR = 47.5), to have intestinal necrosis (P=0.001, OR = 48.5) or perforation (P=0.016, OR =24.25), to have medical complications, specifically intravascular disseminated coagulation (P<.001, RR = 98), and multi-organ failure (P<0.001, RR = 2). It was also found that patients with gastrointestinal symptoms and diagnosis of necrotising enterocolitis when they were hospitalized were more likely to have surgical treatment. CONCLUSIONS: We must be aware of the factors associated with mortality, as well as those associated with surgical treatment to reduce overall mortality for this condition. PMID- 26111855 TI - Pd size effect on the gas sensing properties of Pd-loaded SnO2 in humid atmosphere. AB - Pd particles of different nanosizes were loaded on the SnO2 surface by using different Pd precursors for the purpose of investigating the Pd size effect on gas sensing properties in humid atmosphere. One kind of Pd-loaded SnO2 nanoparticle was characterized by smaller Pd particles (2.6 nm) with high dispersion, while another kind was characterized by larger Pd particles (5-10 nm) with low dispersion. It was found that both kinds of Pd on the SnO2 surface let the mainly adsorbed oxygen species change from O(-) to O(2-) in humid atmosphere at 350 degrees C. In addition, the water vapor poisoning effect on electric resistance and sensor response was greatly reduced by loading Pd. Interestingly, for the CO response at 350 degrees C, Pd-SnO2 with small Pd size showed almost constant sensor response with varying humidity (0.5-4 vol % H2O). While the CO response of Pd-SnO2 with large Pd size even increased with increasing amount of water vapor. Moreover, the former CO response was increased from 300 to 350 degrees C, but the later response decreased with increase in operating temperature. These behaviors were analyzed by temperature programed reduction (TPR) in H2 and CO atmospheres, and they were supported by the different catalytic activities of different nanosized Pd particles. PMID- 26111858 TI - Shades of grey: the conundrum of implantable defibrillators in individuals with advanced CKD. PMID- 26111859 TI - Implantable cardioverter-defibrillators in patients with CKD: a propensity matched mortality analysis. AB - BACKGROUND AND OBJECTIVES: Benefits of transvenous implantable cardioverter defibrillators (ICDs) in prevention of sudden cardiac death among the general population are proven. However, the benefit of ICDs remains unclear in CKD. A propensity-matched analysis was conducted to examine the survival benefits of ICDs placed for primary prevention in those with CKD not on dialysis (eGFR<60 ml/min per 1.73 m(2)). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Cleveland Clinic CKD registry was utilized to identify individuals who had an echocardiogram at the institution (between 2001 and October 2011). A propensity score of the likelihood of receiving an ICD was developed with the following variables: demographics, comorbid conditions, use of cardioprotective medications, eGFR, left ventricular ejection fraction, and ventricular arrhythmia. One-to-one greedy matching was used with 0.1 caliper width to match patients with and without an ICD. A Cox proportional hazards model was used to examine survival of matched patients with and without an ICD. RESULTS: This study included 1053 ICD patients and 9435 potential controls. Of 1053 ICD patients (60%), 631 were matched to the control group. During a median follow-up of 2.9 years (25th and 75th percentiles, 1.5, 4.7), 578 patients died. After adjusting for covariates, the hazard of mortality among propensity-matched patients was 0.69 (95% confidence interval [95% CI], 0.59 to 0.82) for the ICD group compared with the non-ICD group. A significant interaction was found between ICDs and eGFR (P=0.04). Presence of an ICD was associated with a lower risk of death among those with eGFRs of 45-59 ml/min per 1.73 m(2) (hazard ratio [HR], 0.58; 95% CI, 0.44 to 0.77) and 30-44 ml/min per 1.73 m(2) (HR, 0.65; 95% CI, 0.50 to 0.85), but not among those with eGFRs<30 ml/min per 1.73 m(2) (HR, 0.98; 95% CI, 0.71 to 1.35). CONCLUSIONS: Transvenous ICDs placed for primary prevention are associated with a survival benefit in those with stage 3 CKD, but not in those with stage 4 CKD. PMID- 26111857 TI - CKD as a Model for Improving Chronic Disease Care through Electronic Health Records. AB - Electronic health records have the potential to improve the care of patients with chronic medical conditions. CKD provides a unique opportunity to show this potential: the disease is common in the United States, there is significant room to improve CKD detection and management, CKD and its related conditions are defined primarily by objective laboratory data, CKD care requires collaboration by a diverse team of health care professionals, and improved access to CKD related data would enable identification of a group of patients at high risk for multiple adverse outcomes. However, to realize the potential for improvement in CKD-related care, electronic health records will need to provide optimal functionality for providers and patients and interoperability across multiple health care settings. The goal of the National Kidney Disease Education Program Health Information Technology Working Group is to enable and support the widespread interoperability of data related to kidney health among health care software applications to optimize CKD detection and management. Over the course of the last 2 years, group members met to identify general strategies for using electronic health records to improve care for patients with CKD. This paper discusses these strategies and provides general goals for appropriate incorporation of CKD-related data into electronic health records and corresponding design features that may facilitate (1) optimal care of individual patients with CKD through improved access to clinical information and decision support, (2) clinical quality improvement through enhanced population management capabilities, (3) CKD surveillance to improve public health through wider availability of population-level CKD data, and (4) research to improve CKD management practices through efficiencies in study recruitment and data collection. Although these strategies may be most effectively applied in the setting of CKD, because it is primarily defined by laboratory abnormalities and therefore, an ideal computable electronic health record phenotype, they may also apply to other chronic diseases. PMID- 26111860 TI - How to transform a metabolic syndrome score into an insulin sensitivity value? AB - BACKGROUND: The metabolic syndrome (MetS) predicts cardiovascular risk and incident type 2 diabetes mellitus. The presence of a MetS is defined by the clustering of >=3 out of 5 cardiometabolic criteria (hyperglycemia; hypertension; enlarged waist; low high-density lipoprotein-cholesterol; and hypertriglyceridemia), each of which is connected with insulin resistance. It is not known whether the severity of MetS, ranked from the sextet of scores range [0/5 to 5/5], is linearly related to reduced insulin sensitivity (IS) and/or lesser hyperbolic product across the glycemic spectrum. PATIENTS AND METHODS: A total of 839 adults (54 normoglycemic; 785 with abnormal glucose homeostasis, among whom 711 type 2 diabetes mellitus) had insulin sensitivity assessed together with their cardiometabolic phenotype. RESULTS: There was a significant gradient according to interval-scale MetS score in insulinemia; body mass index; (visceral) fat; hepatic steatosis; and macroangiopathy. There was an inverse linear relationship between increasing MetS scores and decreased insulin sensitivity, allowing to define an insulin resistance-predicting linear equation: IS (%) = [-15.1 * MetS score] + 109.4 (R(2) = 0.221). For each MetS category, mean IS values did not significantly differ between groups of patients across the glycemic spectrum. The hyperbolic product (beta-cell function * IS) and/or its loss rate were inversely related to MetS severity. CONCLUSION: Insulin sensitivity is linearly and inversely related to MetS severity across the 6 scores. This novel way to exploit information intrinsic to the MetS criteria provides an easy and low cost means to quantify insulin sensitivity across the glycemic spectrum. Moreover, a higher MetS score is associated with lesser residual insulin secretion, and faster B-cell function loss. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26111861 TI - Birth of nine normal healthy babies following transfer of blastocysts derived from human single-pronucleate zygotes. AB - PURPOSE: The purpose of this study is to examine the clinical outcomes of blastocysts derived from human single-pronucleate (1PN) embryos after conventional in vitro fertilization (cIVF) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: This was a retrospective study at a reproductive center of a hospital. To evaluate embryo quality and clinical outcomes, cIVF or ICSI cycles with one or more 1PN embryos were compared with same cycles with 2PN embryos (control cycles). RESULTS: A total of 623 cycles (426 cIVF cycles and 197 ICSI cycles) were treated with cIVF or ICSI. The single pronuclear status rate was similar between cIVF (22.1 %) and ICSI (25.1 %) cycles. Although the development rates of 1PN embryos on day 3 and day 5/6 in cIVF were significantly higher than those in ICSI, those of 1PN embryos in cIVF were significantly lower compared to 2PN embryos (p < 0.01). Nonetheless, the ongoing pregnancy rates achieved with 1PN blastocysts in 1PN embryos did not significantly differ from the control group. Thirty-three transfer cycles with 33 blastocysts derived from 1PN embryos in cIVF resulted in nine deliveries with no newborn malformations; however, no implantation was observed in three ICSI cycles. CONCLUSION: Although the blastocyst formation rate of 1PN embryos was significantly lower than 2PN embryos in cIVF and ICSI cycles, 1PN blastocysts in cIVF, and not from ICSI, demonstrated an adequate ongoing pregnancy rate. These results suggested that 1PN blastocysts in cIVF are available for clinical use and may lead to an increase in the chance of pregnancy in patients receiving assisted reproductive technology with 1PN embryos. PMID- 26111862 TI - Testicular injection of busulfan for recipient preparation in transplantation of spermatogonial stem cells in mice. AB - Intraperitoneal busulfan injections are used to prepare recipients for spermatogonial stem cell (SSC) transplantation but they are associated with haematopoietic toxicity. Testicular injections of busulfan have been proposed to overcome this limitation. To date, testicular injections have not been studied in the mouse model. Therefore, in the present study we used ICR mice as recipients for SSC transplantation and prepared these mice by testicular injection of busulfan on both sides (2, 3, 4 or 6mgkg-1 per side). Following this, donor germ cells expressing red fluorescent protein (RFP) from transgenic C57BL/6J male mice were transplanted into recipients via the efferent duct on Days 16-17 after busulfan treatment. Positive control mice were prepared by intraperitoneal injection of 40mgkg-1 busulfan and negative control mice were treated with bilateral testicular injection of 50% dimethyl sulfoxide. On Day 49 after transplantation, recipient mice that were RFP-positive by in vivo imaging were mated with ICR female mice. Donor-derived germ cell colonies with red fluorescence were observed on Day 60 after transplantation, and donor-derived offspring were obtained. The results demonstrated that endogenous germ cells were successfully eliminated in the seminiferous tubules via testicular busulfan administration, and that exogenous SSCs successfully undergo spermatogenesis in the testes of recipient mice prepared by testicular injections of busulfan. In addition to its effects on recipient preparation, this method was safe in rodents and could possibly be adapted for use in other species. PMID- 26111863 TI - Rivaroxaban Induces Mucosal Healing in a Rat Model of Trinitrobenzene Sulfonic Acid-Induced Colitis. AB - OBJECTIVE: This study was designed to identify the effect of rivaroxaban, a direct factor Xa inhibitor, on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. MATERIALS AND METHODS: Twenty-four female Wistar rats were divided into 4 groups of 6 each. Group 1 received TNBS + rivaroxaban, group 2 received TNBS + methylprednisolone, group 3 received TNBS and group 4 received a saline enema. Colitis was induced in the rats by the intracolonic administration of TNBS. Rivaroxaban and methylprednisolone were given by oral gavage daily for 7 days. The rats were killed 7 days after the induction of colitis. RESULTS: Rivaroxaban and methylprednisolone significantly reduced gross damage and histopathological scores. Rivaroxaban was more effective than methylprednisolone in terms of microscopic mucosal healing. Rivaroxaban attenuated the accumulation of malonyldialdehyde (MDA) and transforming growth-factor beta1 (TGF-beta1) and the activities of myeloperoxidase (MPO), matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1. Methylprednisolone reduced only the activity of MPO and the accumulation of MDA and TGF-beta1. Superoxide dismutase activity showed a restoration to normal levels after rivaroxaban and methylprednisolone administration. CONCLUSIONS: Rivaroxaban showed a therapeutic effect in the TNBS model of experimental colitis, and it seemed to be at least as effective as methylprednisolone. This effect may be brought about by the inhibition of oxidative stress and metalloproteinase activity associated with tissue injury and remodeling. PMID- 26111864 TI - Nuclear membrane localization during pollen development and apex-focused polarity establishment of SYP124/125 during pollen germination in Arabidopsis thaliana. AB - KEY MESSAGE: Establishment of apex-polarity. Elongation of the pollen tube is a highly coordinated process involving polarized secretion of cell wall and membrane materials to the apical region. We investigated changes in the localization of soluble NSF attachment proteins (SNAREs) in developing pollen grains and the pollen tube for transgenic Arabidopsis expressing pollen-specific plasma-membrane Qa-SNAREs (SYP124, 125 and 131) fused with the green fluorescent protein (GFP). The expression of SYP124 and SYP125 was firstly detected in the microspore nuclear membrane during pollen mitosis II. Although SYP124, 125 and 131 accumulated throughout the cytosol in the mature pollen grain, GFP-SYP124 and GFP-SYP125 were highly concentrated in the apical or subapical regions of the elongating pollen tube with slightly different localization patterns, whereas GFP SYP131 was uniformly localized to the plasma membrane of the pollen tube. The apex-focused polarity of GFP-SYP125 was established coincident with formation of a Ca(2+) gradient before pollen germination. These results suggest that SNAREs function differentially in the same cells and that at least two distinct membrane transport pathways are involved in the pollen development and the pollen tube germination and elongation. PMID- 26111865 TI - Novel Mutations in HESX1 and PROP1 Genes in Combined Pituitary Hormone Deficiency. AB - BACKGROUND/AIMS: The HESX1 gene is essential in forebrain development and pituitary organogenesis, and its mutations are the most commonly identified genetic cause of septo-optic dysplasia (SOD). The PROP1 gene is involved in anterior pituitary cell lineage specification and is commonly implicated in non syndromic combined pituitary hormone deficiency (CPHD). We aimed to assess the involvement of HESX1 and PROP1 mutations in a cohort of patients with SOD and CPHD. METHODS: Six patients with sporadic SOD and 16 patients with CPHD from 14 pedigrees were screened for mutations in HESX1 and PROP1 genes by exon sequencing. Half of the CPHD patients had variable associated clinical characteristics, such as hearing loss, orofacial cleft, kidney disorder or developmental delay. Novel variants were evaluated in silico and verified in SNP databases. RESULTS: A novel heterozygous p.Glu102Gly mutation in the HESX1 gene and a novel homozygous p.Arg121Thr mutation in the PROP1 gene were detected in 2 pedigrees with CPHD. A small previously reported deletion in PROP1 c.301_302delAG was detected in a separate patient with CPHD, in heterozygous state. No mutations were identified in patients with SOD. CONCLUSIONS: Our results expand the spectrum of mutations implicated in CPHD. The frequency of 15% of the PROP1 mutations in CPHD was low, likely due to the clinical heterogeneity of the cohort. PMID- 26111866 TI - Towards instantaneous cellular level bio diagnosis: laser extraction and imaging of biological entities with conserved integrity and activity. AB - The prospect for spatial imaging with mass spectroscopy at the level of the cell requires new means of cell extraction to conserve molecular structure. To this aim, we demonstrate a new laser extraction process capable of extracting intact biological entities with conserved biological function. The method is based on the recently developed picosecond infrared laser (PIRL), designed specifically to provide matrix-free extraction by selectively exciting the water vibrational modes under the condition of ultrafast desorption by impulsive vibrational excitation (DIVE). The basic concept is to extract the constituent protein structures on the fastest impulsive limit for ablation to avoid excessive thermal heating of the proteins and to use strongly resonant 1-photon conditions to avoid multiphoton ionization and degradation of the sample integrity. With various microscope imaging and biochemical analysis methods, nanoscale single protein molecules, viruses, and cells in the ablation plume are found to be morphologically and functionally identical with their corresponding controls. This method provides a new means to resolve chemical activity within cells and is amenable to subcellular imaging with near-field approaches. The most important finding is the conserved nature of the extracted biological material within the laser ablation plume, which is fully consistent with in vivo structures and characteristics. PMID- 26111868 TI - Vitamin D Supplementation Does Not Improve the Severity or the Resolution of Ultraviolet B-Induced Acute Erythema. AB - BACKGROUND: Whether vitamin D supplementation alleviates the severity of ultraviolet B (UVB)-induced erythema and/or facilitates its resolution remains undetermined. OBJECTIVE: To study the effect of oral vitamin D on UVB-induced erythema and its resolution in fair-skinned subjects. METHODS: UVB-induced erythema was quantified using a Chroma Meter(r) in 50 volunteers 48 h before and 10 days after the random administration of 200,000 IU vitamin D (n = 40) or placebo (n = 10). Resolution of erythema in both groups was assessed by chromametry 24, 48, and 72 h after vitamin D administration. RESULTS: No statistical difference between erythema values before and after administration in the vitamin D-supplemented group (p = 0.44) or the placebo group (p = 0.34) was noted. No statistical difference was evident between both groups with respect to resolution of erythema (p = 0.30). CONCLUSION: Oral vitamin D supplementation neither improves protection against UVB-induced erythema nor facilitates its resolution. PMID- 26111867 TI - Blood pressure and prognosis in patients with incident heart failure: the Diet, Cancer and Health (DCH) cohort study. AB - BACKGROUND: Our objective was to test the hypothesis that elevated blood pressure (BP) is associated with increased risk of stroke, bleeding and death in patients with incident heart failure (HF). METHODS: We conducted a prospective cohort study among subjects who were participants in the Diet, Cancer and Health study, born in Denmark, aged 50-64 years at recruitment. We assessed stroke (ischemic stroke or systemic embolic events), major bleeding, death and the composite endpoint according to degree of BP control in patients with incident HF. BP was assessed prior to HF at cohort entry. RESULTS: Of the whole cohort of 55,748 subjects, n = 2159 (35 % female) had incident HF, of which 12 % had treatment for hypertension. Median follow-up after incident HF was 3.5 years. High systolic (SBP), diastolic (DBP) and pulse (PP) pressures were associated with an increased risk of stroke, major bleeding and the composite endpoint. For death and stroke/death, the relation appeared U-shaped for SBP and DBP. When comparing the highest quartile group (Q4) to first quartile group (Q1), SBP (Q4: SBP >163 mmHg) was associated with significantly higher adjusted hazard rate ratio (HR) for stroke (HR 1.46, 95 % CI 1.00-2.14) and major bleeding (HR 1.68, 95 % CI 1.12 2.53). For DBP (Q4: DBP >94 mmHg), adjusted HR was significantly higher for major bleeding (HR 1.63, 95 % CI 1.13-2.38). The highest quartile of pulse pressure (Q4: PP >74 mmHg) was associated with non-significantly higher risk of stroke (HR 1.40, 95 % CI 0.94-2.06). CONCLUSION: We have shown for the first time that amongst a population with incident HF, higher baseline systolic, diastolic and pulse pressure levels were associated with a higher rate of adverse events. Our data support the importance for optimised BP control, as part of the holistic management of HF patients. PMID- 26111869 TI - A radiolucent chair for sitting-posture radiographs in non-ambulatory children: use in biplanar digital slot-scanning. AB - EOS imaging (EOS System; EOS imaging, Paris, France) enables fast 2-D/3-D imaging of children in standing load-bearing position. Non-ambulatory children with neuromuscular scoliosis need evaluation of their spinal balance while in a normal daily position. We designed a customized chair fitting the EOS patient-area dimensions to obtain images in natural sitting postures. The chair is a 360 degrees rotating orthopaedic chair made of fully radiolucent polyethylene and equipped with an adjustable headrest and three-point belts. Out of 41 consecutive patients, 36 (88%, 95% confidence interval 74-96%) had successful imaging. In most patients with severe neuromuscular trunk deformities, the EOS system combined with our chair was useful for assessing preoperative trunk collapse, pelvic obliquity and postoperative corrections in all planes. This specific device changed our daily practice for the assessment of spinal deformities in non ambulatory patients. PMID- 26111870 TI - Glutaric aciduria type 1: neuroimaging features with clinical correlation. AB - BACKGROUND: Glutaric aciduria type 1 is a rare neurometabolic disease with high morbidity. OBJECTIVE: To describe the MR imaging abnormalities in glutaric aciduria type 1 and to identify any association between the clinical and imaging features. MATERIALS AND METHODS: MRI scans of 29 children (mean age: 16.9 months) with confirmed diagnosis of glutaric aciduria type 1 were retrospectively reviewed. Gray matter and white matter scores were calculated based on a previously published pattern-recognition approach of assessing leukoencephalopathies. Hippocampal formation and opercular topography were assessed in relation to the known embryological basis. MRI scores were correlated with morbidity score. RESULTS: The most consistent MRI abnormality was widened operculum with dilatation of the subarachnoid spaces surrounding underdeveloped frontotemporal lobes. Incomplete hippocampal inversion was also seen. The globus pallidus was the most frequently involved gray matter structure (86%). In addition to the central tegmental tract, white matter abnormalities preferentially involved the central and periventricular regions. The morbidity score correlated with the gray matter abnormality score (P = 0.004). Patients with dystonia had higher gray matter and morbidity scores. CONCLUSION: Morbidity is significantly correlated with abnormality of gray matter, rather than white matter, whether secondary to acute encephalopathic crisis or insidious onset disease. PMID- 26111871 TI - Current methods for reducing intussusception: external manual reduction with US assistance. PMID- 26111872 TI - Peritoneal Dialysis for Chronic Congestive Heart Failure. AB - Maladaptive responses between a failing heart and the kidneys ultimately lead to permanent chronic kidney disease, referred to as cardiorenal syndrome type 2. In this narrative review, we discuss the pathophysiological pathways in the progression of cardiorenal failure and review the current evidence on peritoneal dialysis as a treatment strategy in cardiorenal syndrome type 2. A patient with heart failure can present with clinical symptoms related to venous congestion even in the absence of end-stage renal disease. Diuretics remain the cornerstone for the treatment of fluid overload related to heart failure. However, with chronic use, diuretic resistance can supervene. When medical therapy is no longer able to relieve congestive symptoms, ultrafiltration might be needed. Patients with heart failure tolerate well the gentle rate of fluid removal through peritoneal dialysis. Recent publications suggest a positive impact of starting peritoneal dialysis in patients with cardiorenal syndrome type 2 on the hospitalisation rate, functional status and quality of life. PMID- 26111873 TI - The House of Orthopaedics. PMID- 26111874 TI - Advances in Surgical Management of Intra-articular Calcaneus Fractures. AB - Intra-articular calcaneus fractures are commonly sustained after high-energy trauma, and a variety of techniques exists for anatomic reduction and surgical fixation. Traditional approaches using an extended L-shaped lateral incision with lateral plating for open reduction and internal fixation have relatively high complication rates. Common complications include hematoma formation, skin edge necrosis, wound breakdown, and superficial or deep infection. As a result, less invasive techniques have been developed in recent years, including limited incision sinus tarsi open reduction and internal fixation, percutaneous fixation, and arthroscopic-assisted fixation. These techniques are associated with lower complication rates and equivalent clinical and radiographic outcomes in certain fracture patterns and patient populations. PMID- 26111875 TI - Closed Sagittal Band Injury of the Metacarpophalangeal Joint. AB - Although it is an uncommon injury, traumatic rupture of the sagittal band often results in subluxation or dislocation of the extensor digitorum communis tendon. The radial sagittal band prevents ulnar subluxation of the extensor tendon at the metacarpophalangeal joint. Injury may result from a direct blow to the hand or from relatively low-energy mechanisms. Symptoms range from metacarpophalangeal joint pain and edema to dislocation of the extensor tendon. Associated injuries include collateral ligament sprains, capsular injury, and osteochondral fractures. Many acute injuries can be managed nonsurgically with extension splints. Optimal management of subacute or chronic injuries remains undefined. Surgical management consists of repair or reconstruction of the radial sagittal band. Numerous adjunctive surgical techniques have been described to prevent subluxation of the extensor tendon. PMID- 26111876 TI - Female Athlete Triad: Past, Present, and Future. AB - After the passage of Title IX in 1972, female sports participation skyrocketed. In 1992, the female athlete triad was first defined; diagnosis required the presence of an eating disorder, amenorrhea, and osteoporosis. However, many athletes remained undiagnosed because they did not meet all three of these criteria. In 2007, the definition was modified to a spectrum disorder involving low energy availability (with or without disordered eating), menstrual dysfunction, and low bone mineral density. With the new definition, all three components need not be present for a diagnosis of female athlete triad. Studies using the 1992 definition of the disorder demonstrated a prevalence of 1% to 4% in athletes. However, in certain sports, many female athletes may meet at least one of these criteria. The actual prevalence of athletes who fall under the "umbrella" diagnosis of the female athlete triad remains unknown. PMID- 26111877 TI - Transcatheter arterial embolization of hypervascular tumors with HepaSphere: prospective multicenter open label clinical trial of microspheres in Japan. AB - PURPOSE: To evaluate the feasibility and safety of transcatheter arterial embolization (TAE) with the use of HepaSphere microspheres for hypervascular tumors. MATERIALS AND METHODS: This was a prospective multicenter open label clinical trial involving six institutions in Japan. TAE was performed with the HepaSphere microspheres for hypervascular tumors in various locations. The endpoint of the study was the feasibility and safety of the procedure. The feasibility and safety were evaluated according to technical success and adverse events, respectively. Adverse events that were related to TAE were evaluated by using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Twenty-four patients were enrolled. The technical success rate was 100 % (24/24). Twenty-two (92 %) patients developed a total of 50 symptomatic adverse events, including 30 grade 1 events, 17 grade 2 events, and 3 grade 3 events. The most frequent adverse event was fever with an incidence of 63 %, followed by abdominal pain (25 %). CONCLUSION: TAE for hypervascular tumors with the HepaSphere microspheres was feasible and rarely caused major adverse events. TRIAL REGISTRATION: This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111534). PMID- 26111878 TI - CT findings of omental pregnancy: a case report. AB - Omental pregnancy is an extremely rare and dangerous form of ectopic pregnancy which can be very difficult to diagnose radiologically. We report the case of an 18-year-old girl with secondary omental pregnancy who was assessed by use of contrast-enhanced computed tomography (CT). For the first time, we report the contrast-enhanced CT features of omental pregnancy. Inhomogeneous mild enhancement was observed, which is different from other kinds of ectopic pregnancy, for which enhancement is often substantial. Possible reasons for the discrepancy are discussed, as also is differential diagnosis of omental pregnancy. PMID- 26111879 TI - Judgments of learning index relative confidence, not subjective probability. AB - The underconfidence-with-practice (UWP) effect is a common finding in calibration studies concerned with judgments of learning (JOLs) elicited on a percentage scale. The UWP pattern is present when, in a procedure consisting of multiple study-test cycles, the mean scale JOLs underestimate the mean recall performance on Cycle 2 and beyond. Although this pattern is present both for items recalled and unrecalled on the preceding cycle, to date research has concentrated mostly on the sources of UWP for the latter type of items. In the present study, we aimed to bridge this gap. In three experiments, we examined calibration on the third of three cycles. The results of Experiment 1 demonstrated the typical pattern of higher recall and scale JOLs for previously recalled items than for unrecalled ones. More importantly, they also revealed that even though the UWP effect was found for items previously recalled both once and twice, its magnitude was greater for the former class of items. Experiments 2 and 3, which employed a binary betting task and a binary 0 %/100 % JOL task, respectively, demonstrated that people can accurately predict future recall for previously recalled items with binary decisions. In both experiments, the UWP effect was absent for both items recalled once and twice. We suggest that the sensitivity of scale JOLs, but not binary judgments, to the number of previous recall successes strengthens the claim of Hanczakowski, Zawadzka, Pasek, and Higham (Journal of Memory and Language 69:429-444, 2013) that scale JOLs reflect confidence in, rather than the subjective probability of, future recall. PMID- 26111880 TI - The Dual Antiplatelet Therapy Trial after the FDA Update: Noncardiovascular Deaths, Cancer and Optimal Treatment Duration. AB - BACKGROUND: The landmark Dual Antiplatelet Therapy (DAPT) trial revealed an impressive reduction of stent thrombosis and myocardial infarction after prolonged 30-month DAPT compared to the conventional 12-month regimen. However, aside from the expected extra bleeding risks, more cancers and noncardiovascular deaths (NCVD) were observed in the 30-month DAPT arm. OBJECTIVE: We aimed to comprehend the totality of DAPT trial evidence in the light of the FDA medical review. RESULTS: A significant excess of solid cancers that was picked up after prasugrel treatment in the TRITON trial (Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes) and later observed with vorapaxar treatment in the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) has now been confirmed by the FDA DAPT review for 30-month therapy with prasugrel [hazard ratio (HR) 1.3] and clopidogrel (HR 1.2). The latest randomized evidence with antiplatelet agents rejected the drug-specific cancer risks, clearly indicating the class effect. The NCVD risks were elevated after treatment with both thienopyridines, but were more prominent after clopidogrel treatment (HR 1.91) than prasugrel treatment (HR 1.17). About half of the NCVD were considered to be caused by cancers occurring after the 24 months of extended antiplatelet therapy. Impression: The DAPT trial confirmed that long term antiplatelet therapy is associated with cancer that contributes to NCVD. Based on the full disclosure of cancer data by the DAPT study, it can be reflected that the optimal duration of antiplatelet therapy with thienopyridines should be limited to no more than 2 years. This duration allows the preservation of most vascular benefits while avoiding additional cancers and NCVD. (c) 2015 S. Karger AG, Basel. PMID- 26111881 TI - Dabigatran for the treatment of venous thromboembolism. AB - Venous thromboembolism (VTE) is a major cause of morbidity and mortality, and individuals with a first VTE are at risk of recurrent VTE. VTE treatment is divided into three phases: a first short phase of acute (traditionally parenteral) anticoagulation, followed by a second maintenance phase with an oral anticoagulant, which may be continued into a third extended maintenance phase in patients considered to be at increased risk of recurrent VTE. Vitamin K antagonists are effective oral anticoagulants but have well-known limitations; non-vitamin K oral anticoagulants including dabigatran etexilate (DE) were therefore developed. DE was approved for VTE treatment on the basis of an extensive clinical trial program that evaluated DE during both the maintenance phase and the extended maintenance phase of VTE treatment. This article provides a comprehensive overview of DE in VTE treatment, from its preclinical characteristics and pharmacokinetic properties to its efficacy and safety in major clinical trials. PMID- 26111882 TI - Single-copy gene based 50 K SNP chip for genetic studies and molecular breeding in rice. AB - Single nucleotide polymorphism (SNP) is the most abundant DNA sequence variation present in plant genomes. Here, we report the design and validation of a unique genic-SNP genotyping chip for genetic and evolutionary studies as well as molecular breeding applications in rice. The chip incorporates 50,051 SNPs from 18,980 different genes spanning 12 rice chromosomes, including 3,710 single-copy (SC) genes conserved between wheat and rice, 14,959 SC genes unique to rice, 194 agronomically important cloned rice genes and 117 multi-copy rice genes. Assays with this chip showed high success rate and reproducibility because of the SC gene based array with no sequence redundancy and cross-hybridisation problems. The usefulness of the chip in genetic diversity and phylogenetic studies of cultivated and wild rice germplasm was demonstrated. Furthermore, its efficacy was validated for analysing background recovery in improved mega rice varieties with submergence tolerance developed through marker-assisted backcross breeding. PMID- 26111883 TI - Effect of ethanol induced mild stress on post-thawed bull sperm quality. AB - This study was performed to investigate the effect of sub-lethal exposure of bull semen to ethanol on the post-thaw spermatozoa quality. Semen samples (n=24, 6 ejaculates/bull) from 4 Holstein bulls were collected and pooled. Pooled samples were divided into 4 equal parts and each part was frozen after being diluted with Optidyl(r) extender containing 0 (O-E0), 0.03 (O-E3), 0.09 (O-E9) and 0.15 (O E15) % (v/v) absolute ethanol. Sperm motility and velocity, plasma membrane integrity and functionality, mitochondrial activity, malondialdehyde concentration, and apoptosis status were evaluated after thawing. A higher percentage of total motility was observed in the O-E9 group as compared to the O E0, O-E3 and O-E15 groups (p<0.05). Also, plasma membrane integrity was higher (p<0.05) in the O-E9 group compared to the O-E3, and O-E15 groups. However, the difference between the O-E9 and O-E0 groups was not significant (p>0.05). In terms of the proportion of sperm abnormality and plasma membrane functionality no differences (p>0.05) were observed between the groups. Our results revealed that malondialdehyde level was lower in ethanol treated (O-E3, O-E9 and O-E15) groups compared to the O-E0 group (p<0.05). Furthermore, the percentage of live spermatozoa with active mitochondria was higher in the O-E9 and O-E15 groups compared to the O-E0 and O-E3 groups (p<0.05). The O-E3 and O-E9 groups resulted in the highest and lowest percentage of apoptotic spermatozoa, respectively (p<0.05). The results of this study demonstrate that supplementation of semen extender with sub-lethal concentration of ethanol influences post-thawed bull sperm quality in a dose dependent manner. PMID- 26111884 TI - Quantification of recombinant immunotoxin delivery to solid tumors allows for direct comparison of in vivo and in vitro results. AB - Solid tumors present challenges for delivery of protein therapeutics; current methods cannot quantify the functional effects of these agents. RG7787 (anti mesothelin recombinant immunotoxin) is highly cytotoxic to pancreatic cancer cell lines, but with limited activity in vivo. To investigate this discrepancy, we developed a flow cytometry method to quantify the amount of RG7787 internalized per cell in tumors and used it to analyze tumor responses by determining the number of molecules of RG7787 internalized per cell in vivo and comparing it to that needed to kill cells in vitro. At a maximum tolerated dose of 7.5 mg/kg, tumor cells in vivo internalized a wide range of RG7787 with the average amount equivalent to the amount that induced growth arrest in vitro. However, 20% of cells accumulated 20,300 ITs per cell, sufficient to kill cells in vitro. At 2.5 mg/kg the top 20% of cells internalized enough RG7787 to only induce growth arrest. These data are in agreement with tumor responses; 22% regression following a 7.5 mg/kg dose and growth stabilization following 2.5 mg/kg. Comparing amounts of RIT delivered in vivo and in vitro can explain tumor responses and should facilitate the development of more active immunotoxins and other antibody based agents. PMID- 26111885 TI - FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. AB - Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5), and contributes to the beneficial effects of exercise on metabolism. Here we report the therapeutical effects of FNDC5/irisin on metabolic derangements and insulin resistance in obesity, and show the lipolysis effect of irisin and its signal molecular mechanism. In obese mice, lentivirus mediated FNDC5 overexpression enhanced energy expenditure, lipolysis and insulin sensitivity, and reduced hyperlipidemia, hyperglycemia, hyperinsulinism, blood pressure and norepinephrine levels; it increased hormone-sensitive lipase (HSL) expression and phosphorylation, and reduced perilipin level and adipocyte diameter in adipose tissues. Subcutaneous perfusion of irisin reduced hyperlipidemia and hyperglycemia, and improved insulin resistance. Either FNDC5 overexpression or irisin perfusion only induced a tendency toward a slight decrease in body weight in obese mice. In 3T3-L1 adipocytes, irisin enhanced basal lipolysis rather than isoproterenol-induced lipolysis, which were prevented by inhibition of adenylate cyclase or PKA; irisin increased the HSL and perilipin phosphorylation; it increased PKA activity, and cAMP and HSL mRNA levels, but reduced perilipin expression. These results indicate that FNDC5/irisin ameliorates glucose/lipid metabolic derangements and insulin resistance in obese mice, and enhances lipolysis via cAMP-PKA-HSL/perilipin pathway. FNDC5 or irisin can be taken as an effective therapeutic strategy for metabolic disorders. PMID- 26111886 TI - Diagnosis of Stroke-Associated Pneumonia: Recommendations From the Pneumonia in Stroke Consensus Group. AB - BACKGROUND AND PURPOSE: Lower respiratory tract infections frequently complicate stroke and adversely affect outcome. There is currently no agreed terminology or gold-standard diagnostic criteria for the spectrum of lower respiratory tract infections complicating stroke, which has implications for clinical practice and research. The aim of this consensus was to propose standardized terminology and operational diagnostic criteria for lower respiratory tract infections complicating acute stroke. METHODS: Systematic literature searches of multiple electronic databases were undertaken. An evidence review and 2 rounds of consensus consultation were completed before a final consensus meeting in September 2014, held in Manchester, United Kingdom. Consensus was defined a priori as >=75% agreement between the consensus group members. RESULTS: Consensus was reached for the following: (1) stroke-associated pneumonia (SAP) is the recommended terminology for the spectrum of lower respiratory tract infections within the first 7 days after stroke onset; (2) modified Centers for Disease Control and Prevention (CDC) criteria are proposed for SAP as follows-probable SAP: CDC criteria met, but typical chest x-ray changes absent even after repeat or serial chest x-ray; definite SAP: CDC criteria met, including typical chest x ray changes; (3) there is limited evidence for a diagnostic role of white blood cell count or C-reactive protein in SAP; and (4) there is insufficient evidence for the use of other biomarkers (eg, procalcitonin). CONCLUSIONS: Consensus operational criteria for the terminology and diagnosis of SAP are proposed based on the CDC criteria. These require prospective evaluation in patients with stroke to determine their reliability, validity, impact on clinician behaviors (including antibiotic prescribing), and clinical outcomes. PMID- 26111887 TI - Methods of Implementation of Evidence-Based Stroke Care in Europe: European Implementation Score Collaboration. AB - BACKGROUND AND PURPOSE: Differences in stroke care and outcomes reported in Europe may reflect different degrees of implementation of evidence-based interventions. We evaluated strategies for implementing research evidence into stroke care in 10 European countries. METHODS: A questionnaire was developed and administered through face-to-face interviews with key informants. Implementation strategies were investigated considering 3 levels (macro, meso, and micro, eg, policy, organization, patients/professionals) identified by the framing analysis, and different settings (primary, hospital, and specialist) of stroke care. Similarities and differences among countries were evaluated using the categorical principal components analysis. RESULTS: Implementation methods reported by >=7 countries included nonmandatory policies, public financial incentives, continuing professional education, distribution of educational material, educational meetings and campaigns, guidelines, opinion leaders', and stroke patients associations' activities. Audits were present in 6 countries at national level; national and regional regulations in 4 countries. Private financial incentives, reminders, and educational outreach visits were reported only in 2 countries. At national level, the first principal component of categorical principal components analysis separated England, France, Scotland, and Sweden, all with positive object scores, from the other countries. Belgium and Lithuania obtained the lowest scores. At regional level, England, France, Germany, Italy, and Sweden had positive scores in the first principal component, whereas Belgium, Lithuania, Poland, and Scotland showed negative scores. Spain was in an intermediate position. CONCLUSIONS: We developed a novel method to assess different domains of implementation in stroke care. Clear variations were observed among European countries. The new tool may be used elsewhere for future contributions. PMID- 26111888 TI - White Matter Lesions Double the Risk of Post-Thrombolytic Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Cerebral white matter lesions (WMLs), a surrogate for small-vessel disease, are common in patients with stroke and may be related to an increased intracranial bleeding risk after intravenous thrombolysis in acute ischemic stroke. We aimed to investigate the risk of symptomatic intracerebral hemorrhage (sICH) in the presence of WMLs in a large cohort of ischemic stroke patients treated with intravenous thrombolysis. METHODS: We included 2485 consecutive patients treated with intravenous thrombolysis at the Helsinki University Central Hospital. WMLs were scored according to 4 previously published computed tomography visual rating scales from all baseline head scans. A sICH was classified according to the European Cooperative Acute Stroke Study II criteria. The associations of sICH with nominal, ordinal, and continuous variables were analyzed in a univariate binary regression model and adjusted in multivariate binary regression models. RESULTS: In univariate and multivariate regression analyses, all 4 tested visual WML rating scales (as continuous variables or dichotomized at different cutoff points) were associated with increased risk of sICH. In binary analyses, WML doubled the bleeding risk: the odds ratios of all 4 visual rating scales ranged from 2.22 (95% confidence interval, 1.49-3.30) to 2.70 (1.87-3.90) in univariable and from 2.00 (1.26-3.16) to 2.62 (1.71-4.02) in multivariable analyses. The multivariable-adjusted odds ratio for the association of high load of WMLs with remote parenchymal hemorrhage was 4.11 (2.38-7.10). CONCLUSIONS: WMLs visible on computed tomography are associated with a more than doubled risk of sICH in patients treated with intravenous thrombolysis for acute ischemic stroke. PMID- 26111889 TI - Letter by Zuo and Xu Regarding Article, "Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats". PMID- 26111890 TI - Retrobulbar Spot Sign Predicts Thrombolytic Treatment Effects and Etiology in Central Retinal Artery Occlusion. AB - BACKGROUND AND PURPOSE: Transorbital sonography may help establish diagnosis of central retinal artery occlusion (CRAO). Next to Doppler sonographic proof of CRAO, an intra-arterial spot sign can be detected in some cases. We hypothesized that it reflects calcified components. It may be associated with embolization from atherosclerotic plaques and may negatively influence thrombolysis. METHODS: Prospective monocenter study of 46 patients with ophthalmologically confirmed CRAO. Systemic tissue-type plasminogen activator thrombolysis was performed when appropriate. All patients received etiologic workup. RESULTS: CRAO was confirmed by Doppler in all patients. Fifty-nine percent of patients with arterio-arterial embolization were spot sign-positive compared with 20% from cardiac source (P<0.05) and none with vasculitis. Eleven patients underwent thrombolysis. Clinically relevant visual improvement was only found in absence of a spot sign (P<0.05). CONCLUSIONS: Transbulbar ultrasound is valuable for initial diagnosis and diagnostic workup of CRAO. In the light of inconsistent results of previous thrombolysis trials, ultrasound may identify patients more likely to benefit from thrombolytic treatment. PMID- 26111892 TI - Response to Letter Regarding Article, "Relevance of Blood-Brain Barrier Disruption After Endovascular Treatment of Ischemic Stroke: Dual-Energy Computed Tomographic Study". PMID- 26111894 TI - Response to Letter Regarding Article, "Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats". PMID- 26111893 TI - Ischemic Stroke Tissue-Window in the New Era of Endovascular Treatment. PMID- 26111895 TI - Functional Anatomy and Oncologic Barriers of the Larynx. AB - Laryngeal barriers to tumor spread are a product of laryngeal development, anatomic barriers, and enzymatic activity. Supraglottic and glottic/subglottic development is distinct and partially explains the metastatic behavior of laryngeal carcinoma. Dense connective tissues and elastic fibers provide anatomic barriers within the larynx. Laryngeal cartilage contains dense cartilage, enzyme inhibitors, and an intact perichondrium making it relatively resistant to tumor invasion; however, focal areas of vulnerability are created by ossified cartilage and natural interruptions in the perichondrium. Local inflammation and the enzymatic interplay between tumor and host are important factors in the spread of laryngeal tumor. PMID- 26111891 TI - Rare Coding Variation and Risk of Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage has a substantial genetic component. We performed a preliminary search for rare coding variants associated with intracerebral hemorrhage. METHODS: A total of 757 cases and 795 controls were genotyped using the Illumina HumanExome Beadchip (Illumina, Inc, San Diego, CA). Meta-analyses of single-variant and gene-based association were computed. RESULTS: No rare coding variants were associated with intracerebral hemorrhage. Three common variants on chromosome 19q13 at an established susceptibility locus, encompassing TOMM40, APOE, and APOC1, met genome-wide significance (P<5e-08). After adjusting for the APOE epsilon alleles, this locus was no longer convincingly associated with intracerebral hemorrhage. No gene reached genome wide significance level in gene-based association testing. CONCLUSIONS: Although no coding variants of large effect were detected, this study further underscores a major challenge for the study of genetic susceptibility loci; large sample sizes are required for sufficient power except for loci with large effects. PMID- 26111896 TI - Renaissance for low shrinking resins: all-in-one solution by bi-functional vinylcyclopropane-amides. AB - A low volume shrinking vinylcyclopropane (VCP) monomer, showing both a high reactivity and a low viscosity, was obtained by applying a sterically hindered and isomeric spacer element, incorporating intermolecular amide hydrogen bonds. The resulting properties locate this VCP system in a pronounced range that so far no other efficient and radical polymerizable resin could enter. PMID- 26111897 TI - Antibody tagged gold nanoparticles as scattering probes for the pico molar detection of the proteins in blood serum using nanoparticle tracking analyzer. AB - We report a rapid one-step immunoassay to detect protein using antibody conjugated gold nanoparticles (AbGNPs) where the targeted protein concentration was determined by analyzing the gold nanoparticle aggregation caused by antibody antigen interactions using nanoparticles tracking analysis (NTA) technique. The sandwich structure constituting the binding of the targeted human IgG to the gold nanoparticle conjugates with goat anti human monoclonal IgG (AbGNPs) was confirmed by transmission electron microscopy. The binding of human IgG (antigen, mentioned hence forth as AT) induce AbGNPs to form dimers or trimers through a typical antibody-antigen-antibody sandwich structure that can be analyzed for the sensitive determination on the basis of change in hydrodynamic diameter of AbGNPs. By this method the minimum detectable concentration of AT is found to be below 2pg/ml. We expect that a significant change in the hydrodynamic diameter of AbGNP could form the basis for the rapid one-step immunoassay development. PMID- 26111898 TI - Cytocompatibility of Si-incorporated TiO2 nanopores films. AB - Si-incorporated TiO2 nanopores films were prepared by anodization and silicon plasma immersion ion implantation. The microstructure and phase composition of the films were investigated by scanning electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The hydrophilicity of the films was evaluated using water contact angle measurement and MG63 cells were cultured on the films to investigate the cytocompatibility. The results showed that the concentration and depth of silicon on the Si-incorporated TiO2 nanopores films increased with the duration time of implantation. Both the as-annealed and Si incorporated nanopores films exhibited good hydrophilicity and cytocompatibility, while the TiO2 nanopores films implanted silicon for 1.0h showed higher proliferation rate and vitality of MG63 cells than others, indicating a great potential application for titanium implants. PMID- 26111899 TI - Persistent, severe post-thrombolysis angioedema: Simple management of a difficult problem. AB - Post-thrombolysis orolingual angioedema in the setting of managing acute stroke is reported in the literature as most often being mild and self-limiting. We present a case of severe angioedema resulting in persistent macroglossia, representing a different end of the spectrum of disease than that referenced in the literature. Despite the severity of the tongue edema in our case, it did resolve with a relatively simple intervention. In addition to highlighting that post-thrombolysis angioedema can be potentially life threatening, this report reviews the pathophysiology of this condition and discusses management options for macroglossia in this setting. PMID- 26111900 TI - Optimizing the affinity and specificity of ligand binding with the inclusion of solvation effect. AB - Solvation effect is an important factor for protein-ligand binding in aqueous water. Previous scoring function of protein-ligand interactions rarely incorporates the solvation model into the quantification of protein-ligand interactions, mainly due to the immense computational cost, especially in the structure-based virtual screening, and nontransferable application of independently optimized atomic solvation parameters. In order to overcome these barriers, we effectively combine knowledge-based atom-pair potentials and the atomic solvation energy of charge-independent implicit solvent model in the optimization of binding affinity and specificity. The resulting scoring functions with optimized atomic solvation parameters is named as specificity and affinity with solvation effect (SPA-SE). The performance of SPA-SE is evaluated and compared to 20 other scoring functions, as well as SPA. The comparative results show that SPA-SE outperforms all other scoring functions in binding affinity prediction and "native" pose identification. Our optimization validates that solvation effect is an important regulator to the stability and specificity of protein-ligand binding. The development strategy of SPA-SE sets an example for other scoring function to account for the solvation effect in biomolecular recognitions. PMID- 26111901 TI - Enantioselective construction of a 2,2'-bisindolylmethane scaffold via catalytic asymmetric reactions of 2-indolylmethanols with 3-alkylindoles. AB - A chiral phosphoric acid-catalyzed asymmetric reaction of 2-indolylmethanols with 3-alkylindoles has been established, which constructed a biologically important 2,2'-bisindolylmethane scaffold in high yields and good enantioselectivities (up to 98% yield, 94:6 er). This protocol not only provides an efficient method for constructing a 2,2'-bisindolylmethane framework in an enantioselective form, but also promotes the development of 2-indolylmethanol-involved catalytic asymmetric transformations. PMID- 26111902 TI - Safety of living kidney donation: another brick in the wall...and a solid (physiologic) one. PMID- 26111903 TI - Quality training, quality board examinations, quality nephrologists. PMID- 26111904 TI - APOL1 and kidney disease: new insights leading to novel therapies. PMID- 26111905 TI - The myth of the future burden of CKD in United States. PMID- 26111906 TI - Discontinuation of eculizumab treatment in atypical hemolytic uremic syndrome: an update. PMID- 26111908 TI - Beyond the last battle: a viewpoint from the frontiers of transplantation. PMID- 26111907 TI - In reply to 'the myth of the future burden of CKD in United States'. PMID- 26111909 TI - Quiz page: an unusual cause of nephrotic syndrome. PMID- 26111910 TI - Sulfated polysaccharides from Cyclocarya paliurus reduce H2O2-induced oxidative stress in RAW264.7 cells. AB - In this study, two sulfated polysaccharides (S-CP1-4 and S-CP1-8) from Cyclocarya paliurus were produced by chlorosulfonic acid-pyridine method. Hydrogen peroxide (H2O2) was used to develop an oxidative stress model in the mouse macrophage cell line RAW264.7. Effects of the two sulfated polysaccharides on H2O2-induced oxidative stress were investigated. The results showed that S-CP(1-8) improved the viability of the H2O2-induced stressed RAW264.7 cells, as well as inhibited the lipid oxidation as determined by the level of malondialdehyde (MDA). Meanwhile, treatment with S-CP(1-4) increased superoxide dismutase (SOD) activity in these cells. The sulfated polysaccharides were found to have a better protective effect against H2O2-induced oxidative stress as compared to the native polysaccharide. Scanning electron microscopy also showed a significant change in the surface morphology of sulfated polysaccharides, but the degradation of main chain of polysaccharides was unconspicuous according to the results of monosaccharide composition. In addition, the sulfated polysaccharides had noticeable DPPH radical scavenging activity. In summary, our results demonstrated that H2O2 was able to induce oxidative stress in RAW264.7 cells, and sulfated group might play an important role in resistance to H2O2-induced oxidative damage. PMID- 26111911 TI - A versatile chitosan/ZnO nanocomposite with enhanced antimicrobial properties. AB - Porous chitosan membrane was fabricated by casting method using silica particles. Simultaneously nano ZnO was synthesized by green-synthesis method using tung ting oolong tea extract. Chitosan membrane was combined with nano ZnO in order to increase its antimicrobial activity. Through observations obtained from various techniques such as XRD, SEM, FT-IR, UV-visible and fluorescence emission analyses, chitosan was seen to be able to incorporate nano ZnO in the nanocomposite membrane. A blue shift (from 360 to 335 nm) was observed in the UV visible spectrum of nanocomposite and fluorescence emission intensity of nanocomposite was considerably lower than that of nano ZnO. Gram negative organism Klebsiella planticola (MTCC2727) and Gram positive organism Bacillus substilis (MTCC3053) were used to test the antibacterial and antifouling activities of newly synthesized nanocomposite chitosan/ZnO membrane. The nanocomposite chitosan/ZnO membrane promisingly inhibited the bacterial growth when compared with as-synthesized chitosan. Gram negative K. planticola (MTCC2727) was comparatively more susceptible for inhibition than that of Gram positive Bacillus substilis (MTCC3053). In conclusion, nanocomposite obtained in this study showed enhanced antibacterial and antifouling activities. We believed that the enhanced physical properties of nanocomposite achieved by incorporating nano ZnO in the chitosan matrix could be beneficial in various applications. PMID- 26111912 TI - Biophysical insight into the anti-amyloidogenic behavior of taurine. AB - In this work, we investigated the inhibitory ability of taurine on the aggregation of Human serum albumin (HSA) and also examined how it controls the kinetic parameters of the aggregation process. We demonstrated the structural alterations in the HSA after binding to the taurine at 65 degrees C by exploiting various biophysical techniques. UV-vis spectroscopy was used to check the turbidometric changes in the protein. Thioflavin T fluorescence kinetics was subjected to explore kinetic parameters comparing the amyloid formation in the presence of varying concentration of taurine. Further, Congo red binding and ANS binding assays were performed to determine the inhibitory effect of taurine on HSA fibrillation process and surface hydrophobicity modifications occurring before and after the addition of taurine with protein, respectively. Far UV CD and Dynamic Light Scattering (DLS) confirmed that taurine stabilized the protein alpha-helical structure and formed complex with HSA which is further supported by differential scanning calorimetry (DSC). Moreover, microscopic imaging techniques were also done to analyze the morphology of aggregation formed. Taurine is also capable of altering the cytotoxicity of the proteinaceous aggregates. Molecular docking study also deciphered the possible residues involved in protein and drug interaction. PMID- 26111913 TI - Diagnosis of Severe Carpal Tunnel Syndrome Using Nerve Conduction Study and Ultrasonography. AB - This study investigated the correlation between nerve conduction study and ultrasonographic findings for assessment of the usefulness of ultrasonography in determining carpal tunnel syndrome severity. Hands of adults with carpal tunnel syndrome were assessed using ultrasound and nerve conduction studies and grouped according to median nerve cross-sectional area (CSA). There were significant differences (p < 0.01) in mean median nerve CSA between controls, patients with median sensory nerve conduction velocity <=40 m/s and patients with absent sensory nerve action potential and between controls, patients with median nerve distal motor latency >=4.5 ms and patients with absent compound muscle action potentials of the abductor pollicis brevis. This is the first report to define median nerve CSA cutoff values (18 mm(2)) for determining carpal tunnel syndrome severity in patients with absent compound muscle action potentials of the abductor pollicis brevis. Median nerve CSA values below the cutoff values should prompt clinicians to consider other disorders, such as cervical compressive myelopathy. PMID- 26111914 TI - Chronic obstructive pulmonary disease and coronary disease: COPDCoRi, a simple and effective algorithm for predicting the risk of coronary artery disease in COPD patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is often associated with cardiovascular artery disease (CAD), representing a potential and independent risk factor for cardiovascular morbidity. Therefore, the aim of this study was to identify an algorithm for predicting the risk of CAD in COPD patients. METHODS: We analyzed data of patients afferent to the Cardiology ward and the Respiratory Diseases outpatient clinic of Tor Vergata University (2010-2012, 1596 records). The study population was clustered as training population (COPD patients undergoing coronary arteriography), control population (non-COPD patients undergoing coronary arteriography), test population (COPD patients whose records reported information on the coronary status). The predicting model was built via causal relationship between variables, stepwise binary logistic regression and Hosmer-Lemeshow analysis. The algorithm was validated via split-sample validation method and receiver operating characteristics (ROC) curve analysis. The diagnostic accuracy was assessed. RESULTS: In training population the variables gender (men/women OR: 1.7, 95%CI: 1.237-2.5, P < 0.05), dyslipidemia (OR: 1.8, 95%CI: 1.2-2.5, P < 0.01) and smoking habit (OR: 1.5, 95%CI: 1.2-1.9, P < 0.001) were significantly associated with CAD in COPD patients, whereas in control population also age and diabetes were correlated. The stepwise binary logistic regressions permitted to build a well fitting predictive model for training population but not for control population. The predictive algorithm shown a diagnostic accuracy of 81.5% (95%CI: 77.78-84.71) and an AUC of 0.81 (95%CI: 0.78 0.85) for the validation set. CONCLUSIONS: The proposed algorithm is effective for predicting the risk of CAD in COPD patients via a rapid, inexpensive and non invasive approach. PMID- 26111915 TI - Uptake and Acceptability of Information and Communication Technology in a Community-Based Cohort of People Who Inject Drugs: Implications for Mobile Health Interventions. AB - BACKGROUND: Mobile phone and Internet-based technologies are increasingly used to disseminate health information and facilitate delivery of medical care. While these strategies hold promise for reducing barriers to care for medically underserved populations, their acceptability among marginalized populations such as people who inject drugs is not well-understood. OBJECTIVE: To understand patterns of mobile phone ownership, Internet use and willingness to receive health information via mobile devices among people who inject drugs. METHODS: We surveyed current and former drug injectors participating in a longitudinal cohort study in Baltimore, Maryland, USA. Respondents completed a 12-item, interviewer administered questionnaire during a regular semi-annual study visit that assessed their use of mobile technology and preferred modalities of receiving health information. Using data from the parent study, we used logistic regression to evaluate associations among participants' demographic and clinical characteristics and their mobile phone and Internet use. RESULTS: The survey was completed by 845 individuals, who had a median age of 51 years. The sample was 89% African-American, 65% male, and 33% HIV-positive. Participants were generally of low education and income levels. Fewer than half of respondents (40%) indicated they had ever used the Internet. Mobile phones were used by 86% of respondents. Among mobile phone owners, 46% had used their phone for text messaging and 25% had accessed the Internet on their phone. A minority of respondents (42%) indicated they would be interested in receiving health information via phone or Internet. Of those receptive to receiving health information, a mobile phone call was the most favored modality (66%) followed by text messaging (58%) and Internet (51%). CONCLUSIONS: Utilization of information and communication technology among this cohort of people who inject drugs was reported at a lower level than what has been estimated for the general U.S. POPULATION: Our findings identify a potential barrier to successful implementation of mobile health and Internet-based interventions for people who inject drugs, particularly those who are older and have lower levels of income and educational attainment. As mobile communication technology continues to expand, future studies should re-examine whether mHealth applications become more accessible and accepted by socioeconomically disadvantaged groups. PMID- 26111916 TI - Long-term survival of adults with cardiogenic shock after venoarterial extracorporeal membrane oxygenation. AB - PURPOSE: This study was designed to examine the long-term survival of patients who survived to be weaned from venoarterial extracorporeal membrane oxygenation (VA ECMO) and to determine which factors present at initiation and during ECMO predict long-term survival. We further sought to develop the preliminary long term outcome after VA ECMO score that would predict patient outcome and to assess its accuracy at various time points. METHODS: We conducted a retrospective, observational cohort study of all patients with cardiogenic shock treated with VA ECMO at the Alfred Hospital, Australia, from January 2007 until February 2013. Overall, 125 patients underwent ECMO, and 104 patients were successfully weaned and formed the study population, with a median follow-up of 21 months (range, 0 84). RESULTS: Survival rates of those weaned from ECMO at 3 months, 12 months, and 2 years were 87%, 79%, and 71%, respectively, corresponding to overall survival rates at 3 months of 90 (72%) of 124; at 12 months, 80 (65%) of 122; and 24 months, 57 (57%) of 100. Ischemic heart disease, higher lactate and higher bilirubin at initiation of VA ECMO, and a longer duration of renal replacement therapy during ECMO were all independently associated with decreased length of survival. Long-term survival was found to be highly related to the number of these risk factors present up to 2 years afterward. CONCLUSION: Good long-term survival can be achieved in patients who have been successfully weaned from VA ECMO. The factors present at initiation and during ECMO can relate to altered risk of long-term survival. PMID- 26111917 TI - Risk stratification in acute pulmonary embolism with heart-type fatty acid binding protein: A meta-analysis. AB - OBJECTIVE: Heart-type fatty acid-binding protein (H-FABP) has emerged as a new biomarker in risk stratification of patients with acute pulmonary embolism (PE). We performed a meta-analysis of studies in patients with acute PE to assess the prognostic value of elevated H-FABP for short-term adverse outcomes. DATA SOURCE: Two independent reviewers systematically searched PubMed, EMBASE, and Cochrane Database until June 2014. DATA SELECTION: Studies were searched using MeSH word "fatty acid-binding protein" and "pulmonary embolism." Prospective studies were included if those were done on patients with acute PE and if serum H-FABP assay was done. DATA EXTRACTION: Relevant data on study design, year of publication, patient population, inclusion criteria, exclusion criteria, mean age, sex, type of H-FABP assay, cutoff of H-FABP used, and outcomes were extracted. The primary end point was 30-day complicated clinical course and PE-related mortality. The secondary end point was right ventricular dysfunction (RVD). A random-effects model was used to pool study results. DATA SYNTHESIS: Nine studies, including 1680 patients, reported data on the 30-day complicated clinical course. Elevated H-FABP was significantly associated with the increased risk of 30-day complicated clinical course (odds ratio [OR], 17.67; 95% confidence interval [CI], 6.02 51.89; I(2) = 80%). Similarly, 6 studies, including 676 patients, reported 30-day mortality data. Elevated H-FABP was associated with increased risk of 30-day PE related mortality (OR, 32.94; 95% CI, 8.80-123.21, I(2) = 53%). The risk of RVD was significantly higher in patients with elevated H-FABP as compared with patients with normal H-FABP (OR, 2.57; 95% CI, 1.05-6.33, I(2) = 57%). The prognostic sensitivity and specificity of H-FABP were 71% and 74% in predicting 30-day complicated clinical course and were 90% and 70% in predicting 30-day mortality. CONCLUSION: This meta-analysis indicates that elevated H-FABP levels are associated with increased risk of 30-day complicated clinical course, mortality, and RVD. PMID- 26111918 TI - Costs and Resource Utilization Associated With Anemia and Rash in Chronic Hepatitis C Patients Treated With Direct-Acting Antiviral Agents in the United States. AB - PURPOSE: The addition of 2 direct-acting antiviral (DAA) agents, telaprevir and boceprevir, to peginterferon and ribavirin therapy significantly improves sustained virologic response rates in patients treated for chronic hepatitis C virus (CHC) but is associated with a higher risk of adverse events (AEs), including anemia and rash. Using a large administrative claims database, this study compared the health care resource utilization and costs among CHC patients who developed anemia and/or rash while receiving DAA-based therapies (telaprevir and boceprevir) versus those who did not develop anemia or rash. Adjusted costs were compared by using regression analysis. METHODS: Adult patients with >=1 CHC diagnosis and a prescription for boceprevir or telaprevir were selected from a US based claims database. The date of the first DAA fill after May 13, 2011, was defined as the index date. Patients were required to have continuous eligibility and no claims for hepatitis B treatment during the 6 months before (baseline) and 12 months after (study period) the index date. Patients were categorized into 4 cohorts based on the development of anemia only, rash only, both anemia and rash (anemia/rash), or neither anemia nor rash (NAR) while receiving DAA-based therapies. Baseline characteristics and study period health care utilization and costs were compared by using univariate statistics between cohorts that developed anemia only, rash only, or anemia/rash and the cohort that did not develop anemia or rash. Adjusted costs were compared by using multivariable regressions. FINDINGS: A total of 2862 patients were identified and categorized into 4 cohorts: 1204 anemia only, 131 rash only, 188 anemia/rash, and 1339 NAR patients. During the study period, patients developing anemia and/or rash incurred significantly more outpatient, dermatologist, and total medical visits compared with the NAR cohort. The anemia-only and anemia/rash cohorts also had significantly more inpatient, emergency department, and hematologist visits, as well as significantly higher adjusted total medical costs ($18,285 and $21,435 vs $11,253), total drug costs ($76,723 and $79,689 vs $63,001), and non-CHC drug costs ($10,391 and $10,475 vs $2437). The rash-only cohort had comparable adjusted total medical and drug costs. IMPLICATIONS: CHC patients who developed anemia while receiving DAA-based therapies incurred significantly higher resource utilization and costs compared with those who did not. The study highlights the need for new CHC treatment regimens that are associated with fewer and less severe AEs, particularly anemia. PMID- 26111919 TI - Combining lived experience with the facilitation of enquiry-based learning: a 'trigger' for transformative learning. AB - What is known on the subject The values underpinning recovery-orientated practice are recited in the literature and influential in the content of mental health nurse education internationally. However, scepticism exists regarding the degree to which students' assimilate the principles of recovery into their practice due to the troublesome and challenging nature of learning at a transformational level, also known as threshold concept learning. Evaluation suggests that this combination of educational approaches positively influences students' prior understandings, beliefs and values in relation to the prospect for people with significant mental health problems to recover. The components of threshold concepts are useful as a deductive framework for the evaluation of educational initiatives which attempt to initiate transformative learning. While this forum clearly holds significant potential for student development, support and preparation is needed for both the student and the facilitator in order to enable the possibility of learning which influences attitudes, beliefs and practice. The aim of this paper is to discuss the potential for combining lived experience of mental distress with the facilitation of enquiry-based learning (EBL) to act as a trigger for transformative learning in the context of promoting the understanding of mental health 'recovery' in nurse education.The values underpinning recovery orientated practice are recited in the literature and influential in mental health nurse education internationally. However, scepticism exists regarding the degree to which students assimilate into their practice. An open-ended was distributed to a cohort of pre-registration nursing students receiving the co facilitated EBL (n = 112). Data demonstrated how the specific attributes of this educational approach were identified by students as impacting positively on ill informed preconceptions, understanding of complex theory and their future practice. Results were considered in light of the identification of 'recovery' as a 'threshold concept' and offered evidence to support the value of this specific educational forum in the promotion of learning which is transformative, integrative, bounded and at times troublesome. Support and significant preparation is needed for both the student and the facilitator in order to enable the possibility of transformatory learning. PMID- 26111920 TI - Investigating the performance and cost-effectiveness of the simple ultrasound based rules compared to the risk of malignancy index in the diagnosis of ovarian cancer (SUBSONiC-study): protocol of a prospective multicenter cohort study in the Netherlands. AB - BACKGROUND: Estimating the risk of malignancy is essential in the management of adnexal masses. An accurate differential diagnosis between benign and malignant masses will reduce morbidity and costs due to unnecessary operations, and will improve referral to a gynecologic oncologist for specialized cancer care, which improves outcome and overall survival. The Risk of Malignancy Index is currently the most commonly used method in clinical practice, but has a relatively low diagnostic accuracy (sensitivity 75-80% and specificity 85-90%). Recent reports show that other methods, such as simple ultrasound-based rules, subjective assessment and (Diffusion Weighted) Magnetic Resonance Imaging might be superior to the RMI in the pre-operative differentiation of adnexal masses. METHODS/DESIGN: A prospective multicenter cohort study will be performed in the south of The Netherlands. A total of 270 women diagnosed with at least one pelvic mass that is suspected to be of ovarian origin who will undergo surgery, will be enrolled. We will apply the Risk of Malignancy Index with a cut-off value of 200 and a two-step triage test consisting of simple ultrasound-based rules supplemented -if necessary- with either subjective assessment by an expert sonographer or Magnetic Resonance Imaging with diffusion weighted sequences, to characterize the adnexal masses. The histological diagnosis will be the reference standard. Diagnostic performances will be expressed as sensitivity, specificity, positive and negative predictive values and likelihood ratios. DISCUSSION: We hypothesize that this two-step triage test, including the simple ultrasound-based rules, will have better diagnostic accuracy than the Risk of Malignancy Index and therefore will improve the management of women with adnexal masses. Furthermore, we expect this two-step test to be more cost-effective. If the hypothesis is confirmed, the results of this study could have major effects on current guidelines and implementation of the triage test in daily clinical practice could be a possibility. TRIAL REGISTRATION: ClinicalTrials.gov: registration number NCT02218502. PMID- 26111921 TI - Emergency Department Visits and Head Computed Tomography Utilization for Concussion Patients From 2006 to 2011. AB - OBJECTIVES: Concussion is the most common type of mild traumatic brain injury for which patients present to the emergency department (ED). It is critical to understand the contemporary epidemiology of concussion and rates of head computed tomography (CT) use in head-injured patients to inform education of evidence based clinical practice guidelines to emergency medicine providers. METHODS: This was a cross-sectional analysis of the Nationwide Emergency Department Sample (NEDS) for years 2006 to 2011, representing a stratified probability sample of all U.S. hospital-based EDs. Patients of all ages with concussion diagnoses were included, and those with intracranial hemorrhages or prolonged loss of consciousness were excluded. Descriptive and bivariate statistics were summarized for patient demographics, injury mechanism, Injury Severity Scores (ISS), and concussion incidence rates, based on U.S. Census Bureau population estimates. RESULTS: There were 756,214,762 (weighted) ED visits in the NEDS between 2006 and 2011, of which 0.5% received diagnoses of concussion. The national incidence rate of concussion visits increased 22.6% from 195 visits per 100,000 person-years in 2006 to 239 visits per 100,000 person-years in 2011. The incidence of concussion visits increased by 28.1% from 2006 to 2011 overall (580,573 to 743,994) and within all age group categories. The rate of head CT use in patients diagnosed with concussion increased 35.7% (range = 34.5% to 46.8%) for the entire group from 2006 to 2011 (p < 0.0001). The injury severity of patients' injuries decreased over time (66.4% ISS < 5 in 2006 and 75% in 2011; p < 0.0001), while the proportion of discharged patients increased over time (78.1% in 2006 and 86.6% in 2011; p < 0.0001). CONCLUSIONS: ED visits for concussions have increased over time, with a corresponding increase in head CT utilization despite a decrease in injury severity. Increased visits may be due to more concussion awareness and recognition of subtle injuries. Evidence-based clinical practice guidelines for neuroimaging in head-injured patients and management of concussion should be reinforced to emergency medicine providers. PMID- 26111922 TI - Kaatsu training to enhance physical function of older adults with knee osteoarthritis: Design of a randomized controlled trial. AB - As the U.S. population ages, efficacious interventions are needed to manage pain and maintain physical function among older adults with osteoarthritis (OA). Skeletal muscle weakness is a primary contributory factor to pain and functional decline among persons with OA, thus interventions are needed that improve muscle strength. High-load resistance exercise is the best-known method of improving muscle strength; however high-compressive loads commonly induce significant joint pain among persons with OA. Thus interventions with low-compressive loads are needed which improve muscle strength while limiting joint stress. This study is investigating the potential of an innovative training paradigm, known as Kaatsu, for this purpose. Kaatsu involves performing low-load exercise while externally applied compression partially restricts blood flow to the active skeletal muscle. The objective of this randomized, single-masked pilot trial is to evaluate the efficacy and feasibility of chronic Kaatsu training for improving skeletal muscle strength and physical function among older adults. Participants aged >= 60 years with physical limitations and symptomatic knee OA will be randomly assigned to engage in a 3-month intervention of either (1) center-based, moderate-load resistance training, or (2) Kaatsu training matched for overall workload. Study dependent outcomes include the change in 1) knee extensor strength, 2) objective measures of physical function, and 3) subjective measures of physical function and pain. This study will provide novel information regarding the therapeutic potential of Kaatsu training while also informing about the long-term clinical viability of the paradigm by evaluating participant safety, discomfort, and willingness to continually engage in the intervention. PMID- 26111923 TI - Dose timing of D-cycloserine to augment cognitive behavioral therapy for social anxiety: Study design and rationale. AB - The use of D-cycloserine (DCS) as a cognitive enhancer to augment exposure-based cognitive-behavioral therapy (CBT) represents a promising new translational research direction with the goal to accelerate and optimize treatment response for anxiety disorders. Some studies suggest that DCS may not only augment extinction learning but could also facilitate fear memory reconsolidation. Therefore, the effect of DCS may depend on fear levels reported at the end of exposure sessions. This paper presents the rationale and design for a randomized controlled trial examining the relative efficacy of tailoring DCS administration based on exposure success (i.e. end fear levels) during a 5-session group CBT protocol for social anxiety disorder (n = 156). Specifically, tailored post session DCS administration will be compared against untailored post-session DCS, untailored pre-session DCS, and pill placebo in terms of reduction in social anxiety symptoms and responder status. In addition, a subset of participants (n = 96) will undergo a fear extinction retention experiment prior to the clinical trial in which they will be randomly assigned to receive either DCS or placebo prior to extinguishing a conditioned fear. The results from this experimental paradigm will clarify the mechanism of the effects of DCS on exposure procedures. This study aims to serve as the first step toward developing an algorithm for the personalized use of DCS during CBT for social anxiety disorder, with the ultimate goal of optimizing treatment outcome for anxiety disorders. PMID- 26111924 TI - On developing a pragmatic strategy for clinical trials: A case study of hepatocellular carcinoma. AB - Randomised controlled trials (RCTs) with sufficiently high statistical power are not always feasible for patients when the administration of the treatment is burdensome. Nevertheless, useful information concerning the relative effectiveness of the Test and Standard therapies, may be gleaned from under powered trials, non-randomised comparative studies and/or clinician's beliefs: the latter possibly additionally providing some suggestion of the strength of evidence required in order to adopt the Test therapy into clinical practice. In such circumstances, a Bayesian synthesis may be useful in quantifying the evidence of treatment effectiveness. In this article, we aim to present a Bayesian approach for synthesizing the cumulative evidence of the use of adjuvant hepatic intra-arterial iodine-131-lipiodol (I131L) following curative resection in hepatocellular carcinoma (HCC) patients. We constructed a posterior distribution using the information from two small RCTs, three non-randomised comparative studies, three single arm studies and the views of investigators on the use of I131L. This distribution enables calculation of the probability that the Test therapy is more effective than the Standard by a pre-stipulated amount. If this is very high, then for example, one may conclude the Test may replace the Standard therapy. If it is not, then the Standard would be retained for clinical use. Despite a strong early indication of the effectiveness of I131L, the evolving evidence over a 10-year period became more sceptical of its value. Although highly recommended, difficulties of implementing a Bayesian approach in this context are highlighted. PMID- 26111925 TI - A novel colourimetric technique to assess chewing function using two-coloured specimens: Validation and application. AB - OBJECTIVES: Chewing efficiency may be evaluated using cohesive specimen, especially in elderly or dysphagic patients. The aim of this study was to evaluate three two-coloured chewing gums for a colour-mixing ability test and to validate a new purpose built software (ViewGum(c)). METHODS: Dentate participants (dentate-group) and edentulous patients with mandibular two-implant overdentures (IOD-group) were recruited. First, the dentate-group chewed three different types of two-coloured gum (gum1-gum3) for 5, 10, 20, 30 and 50 chewing cycles. Subsequently the number of chewing cycles with the highest intra- and inter-rater agreement was determined visually by applying a scale (SA) and opto electronically (ViewGum(c), Bland-Altman analysis). The ViewGum(c) software determines semi-automatically the variance of hue (VOH); inadequate mixing presents with larger VOH than complete mixing. Secondly, the dentate-group and the IOD-group were compared. RESULTS: The dentate-group comprised 20 participants (10 female, 30.3+/-6.7 years); the IOD-group 15 participants (10 female, 74.6+/ 8.3 years). Intra-rater and inter-rater agreement (SA) was very high at 20 chewing cycles (95.00-98.75%). Gums 1-3 showed different colour-mixing characteristics as a function of chewing cycles, gum1 showed a logarithmic association; gum2 and gum3 demonstrated more linear behaviours. However, the number of chewing cycles could be predicted in all specimens from VOH (all p<0.0001, mixed linear regression models). Both analyses proved discriminative to the dental state. CONCLUSION: ViewGum(c) proved to be a reliable and discriminative tool to opto-electronically assess chewing efficiency, given an elastic specimen is chewed for 20 cycles and could be recommended for the evaluation of chewing efficiency in a clinical and research setting. CLINICAL SIGNIFICANCE: Chewing is a complex function of the oro-facial structures and the central nervous system. The application of the proposed assessments of the chewing function in geriatrics or special care dentistry could help visualising oro-functional or dental comorbidities in dysphagic patients or those suffering from protein-energy malnutrition. PMID- 26111926 TI - Peptide-functionalized zirconia and new zirconia/titanium biocermets for dental applications. AB - OBJECTIVE: Titanium materials have been functionalized with biomolecules as a modern strategy to incorporate bioactive motifs that will expand and improve their biomedical applications. Here, we have biofunctionalized biomaterials based on zirconia of much interest for dentistry: the widely used bioceramic 3Y-TZP and a newly developed 3Y-TZP/Ti biocermet. METHODS: The biosurfaces were activated, silanized, and functionalized with coatings made of oligopeptides. Surface activation by plasma or alkaline-etching was optimized. The surfaces were coated by tethering a purposely-designed RGD-containing peptide. We selected this oligopeptide as a model peptide to validate the effectiveness of the biofunctionalization process. Successful treatments after each step of the process were assessed by surface physical and chemical characterization with water contact angles and XPS, respectively. Coatings' stability was evaluated after 2h sonication in water. Pre-osteoblasts adhesion on the functionalized surfaces was also studied. RESULTS: 10-min air-plasma treatment effectively activated all types of materials with no detrimental effects on the material structure and hardness. Nitrogen XPS-peak confirmed that RGD-peptides were chemically-attached on the silanized samples. This was further confirmed by visualizing the functionalized surfaces with flourescence-labelled RGD-peptides before and after ultrasonication. Furthermore, RGD-functionalized surfaces significantly enhanced osteoblast adhesion on all types of substrates, which demonstrated their successful bioactivation. CONCLUSIONS: We successfully developed stable functional biocoatings on zirconia and biocermets made of oligopeptides. Surface bioactivation of zirconia-containing components for dental implant applications will enable their improved clinical performance by incorporating signalling oligopeptides to accelerate osseointegration, improving permucosal sealing, and/or incorporating antimicrobial properties to prevent peri implant infections. PMID- 26111927 TI - Effect of different storage conditions on the physical properties of bleached enamel: An in vitro vs. in situ study. AB - OBJECTIVES: Evaluate the effect of different storage conditions on bleached enamel using Knoop microhardness (KHN) and colour variation. METHODS: Forty-eight tooth blocks were divided into four groups (n=12), based on storage media (SM): purified water (PW), artificial saliva (AS), natural saliva (NS), in situ (IS). Three whitening sessions were carried out using 35% hydrogen peroxide, with a week interval. Colour and KHN measurements were taken before the samples were placed in the SM (t1), after 24h in the SM (t2), and after 24h at the end of the bleaching treatment (t3). Two extra samples from each group were analysed using a scanning electron microscope (SEM). KHN results were analysed by PROC-MIXED and Tukey-Kramer test (alpha=0.05), and colour changes were evaluated using DeltaL, Deltaa, Deltab, DeltaE between the different times Delta1(t1-t2), Delta2(t2-t3) using the Kruskal-Wallis test and Dunn's test (alpha=0.05). RESULTS: Significant statistical difference was noted in KHN at t3, with the lowest values found for PW. As for colour analysis in DeltaE2 and Deltab2, IS showed values that were statistically lower when compared to AS. Likewise, there were differences between PW and AS in relation to IS when evaluating DeltaL2. In addition, NS showed similar values to IS. CONCLUSIONS: The storage conditions had different effects on the physical properties of bleached enamel. NS was the only SM that showed similar behaviour to IS. CLINICAL SIGNIFICANCE: NS proved an effective SM in the protection and recovery of damage caused by bleaching and is a viable SM for in vitro studies. PMID- 26111928 TI - Expression changes of microRNA-1 and its targets Connexin 43 and brain-derived neurotrophic factor in the peripheral nervous system of chronic neuropathic rats. AB - BACKGROUND: MicroRNAs (miRNAs) are involved in the neuroplastic changes which induce and maintain neuropathic pain. However, it is unknown whether nerve injury leads to altered miRNA expression and modulation of pain relevant target gene expression within peripheral nerves. In the present study, expression profiles of miR-1 and the pain-relevant targets, brain derived neurotrophic factor (BDNF) and Connexin 43 (Cx43), were studied in peripheral neuropathic pain, which was induced by chronic constriction injury (CCI) of the sciatic nerve in rats. The expression of miR-1 was investigated in the sciatic nerve, dorsal root ganglion (DRG) and the ipsilateral spinal cord by qPCR. Changes of BDNF and Cx43 expression patterns were studied using qPCR, Western blot analysis, ELISA and immunohistochemistry. RESULTS: In sciatic nerves of naive rats, expression levels of miR-1 were more than twice as high as in DRG and spinal cord. In neuropathic rats, CCI lead to a time-dependent downregulation of miR-1 in the sciatic nerve but not in DRG and spinal cord. Likewise, protein expression of the miR-1 targets BDNF and Cx43 was upregulated in the sciatic nerve and DRG after CCI. Immunohistochemical staining revealed an endoneural abundancy of Cx43 in injured sciatic nerves which was absent after Sham operation. CONCLUSIONS: This study demonstrates that CCI leads to a regulation of miRNAs (miR-1) in the peripheral nervous system. This regulation is associated with alterations in the expression and localization of the miR-1 dependent pain-relevant proteins BDNF and Cx43. Further studies will have to explore the function of miRNAs in the context of neuropathic pain in the peripheral nervous system. PMID- 26111929 TI - Carcinogenicity of lindane, DDT, and 2,4-dichlorophenoxyacetic acid. PMID- 26111931 TI - Misconceptions in the assessment of cough peak flow measurements for extubation or decanulation protocols. PMID- 26111930 TI - Healing activity of Casearia sylvestris Sw. in second-degree scald burns in rodents. AB - BACKGROUND: Every year thousands of people are victims of burns, mainly scald burns. Many of these victims have small size wounds and superficial partial thickness and do not seek specialized medical care. As in Brazil Casearia sylvestris Sw., popularly known as guacatonga is widely used for its analgesic, antiseptic and anti-inflammatory activities, this study sought to evaluate the effects of its hydroalcoholic extract in healing process of burns injuries. METHODS: The obtained extract was validated applying a thin layer chromatography and sophisticated validation method using Bothrops jararacussu snake venom that is necrotic and inflammatory, and by which guacatonga extract was able to neutralize the irreversible neuromuscular blockade induced by the venom. After induction of the scald injury, the animals were treated daily with saline solution spray; spray containing extract; biofilm; or biofilm impregnated with extract. RESULTS: Significant differences were observed between the four groups studied considering: extension of the healing area, neovascularization, fibroblast proliferation, and epithelialization. CONCLUSION: The anti inflammatory and bactericidal effects of C. sylvestris Sw. suggests a potential therapeutic benefit in the treatment of inflammatory conditions in second-degree scald burn injuries, as well as, counteracting against the in vitro paralysis induced by B. jararacussu venom. PMID- 26111933 TI - Learning in underserved UK areas: a novel approach. AB - BACKGROUND: There is an insufficient number of medical students intending to pursue general practitioner (GP) careers. The undergraduate curriculum has traditionally prioritised teaching in large hospital settings despite most National Health Service patient contact occurring in primary care. Primary care is faced with providing health care for an ageing population with high levels of co-morbidities. Patients who live in deprived areas suffer many disadvantages affecting their health and additionally tend to be underserved. Globally, there has been an initiative to provide medical students with extended clinical placements in rural and remote areas. These placements have identified many beneficial outcomes; however, little is known about placements in other underserved, deprived areas. This paper describes an innovative pilot programme to address these issues. CONTEXT: The North East of England has a large proportion of the most deprived communities and worst health care outcomes in England. In Teesside, Phase 1 Medicine at Durham University provides the pre clinical curriculum. Durham students then join Newcastle University for Phase 2 Medicine, the clinical years. INNOVATION: The Difficult and Deprived Areas Programme (DDAP) places fourth-year students in general practice and community settings in post-industrial, deprived areas for 14 weeks, thus adopting and applying principles from rural initiatives (continuity and immersion) to other deprived settings. The DDAP allows students to learn about psychosocial determinants of health and to pursue community interests whilst gaining an excellent clinical grounding. There is an insufficient number of medical students intending to pursue general practitioner careers IMPLICATIONS: The DDAP provides a model for educators seeking to implement initiatives in similar underserved, deprived settings, which may potentially alleviate GP workforce shortages. PMID- 26111934 TI - Circulating irisin levels are associated with lipid and uric acid metabolism in a Chinese population. AB - Irisin is a novel hormone secreted by skeletal muscle after exercise, which may ameliorate insulin resistance. In this study, we aimed to explore the relationship between circulating irisin levels and type 2 diabetes mellitus (T2DM) as well as related metabolic traits in a Chinese population. A total of 203 subjects were recruited. Of these, 68 subjects with normal glucose tolerance (NGT), 63 subjects with impaired glucose regulation (IGR) and 72 subjects with new-onset T2DM. Circulating irisin levels were measured by enzyme-linked immunosorbent assay (ELISA). Detailed clinical investigations and biochemistry measurements were carried out in all of the subjects. Multivariate linear regression analysis was performed to assess the association between irisin levels and related metabolic characteristics. All subjects were classified into normal weight and overweight/obese subgroups according to body mass index (BMI). No significant differences in circulating irisin levels were identified among the three groups (P = 0.9741). After adjusting for covariates, multiple linear regression analysis revealed that serum irisin level was independently and significantly associated with total cholesterol (P = 0.0005), low-density lipoprotein cholesterol (P = 0.0014), fasting fatty acids (P = 0.0402) and uric acid (P = 0.0062). By dividing the serum irisin levels into three tertile groups, the values of total cholesterol, low-density lipoprotein cholesterol, fasting fatty acids and uric acid were all increased significantly with the increase of irisin (P < 0.05). Moreover, serum irisin levels remain closely related to total cholesterol in both normal weight and overweight/obese subgroups. Our study suggests that circulating irisin concentrations are significantly associated with lipid and uric acid metabolism in a Chinese population. PMID- 26111932 TI - Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial. AB - INTRODUCTION: Multimodality therapy, including preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy (CCRT) involving XELOX regimen (oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma. METHODS: We randomly assigned patients to the TME group (TME without preoperative CCRT) or CCRT + TME group (TME with preoperative CCRT). The primary endpoint was disease-free survival (DFS); the secondary endpoints were overall survival (OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months. RESULTS: A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 % (P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 % (P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT + TME groups were 71.3 % and 70.0 % (P = 0.849), respectively. In the TME group, 16 (17.0 %) patients were proven to have pTNM stage I disease after surgery. In the CCRT + TME group, 32 (35.6 %) patients achieved a pathologic complete response (pCR). CONCLUSIONS: Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high pCR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted. CLINICAL TRIAL REGISTRATION NUMBER: Chi CTR-TRC-08000122. PMID- 26111935 TI - Ethnic differences in the incidence of type 1 diabetes in Norway: a register based study using data from the period 2002-2009. AB - BACKGROUND: Few studies have looked at variation in type 1 diabetes incidence between immigrant groups within a country. OBJECTIVE: To investigate differences in incidence rates of childhood-onset type 1 diabetes between immigrant groups and ethnic Norwegians, and their contribution to the number of incident cases of type 1 diabetes in Norway. SUBJECTS: The study includes 2221 individuals with newly onset type 1 diabetes diagnosed during 2002-2009 in children of 0-14 yr in Norway registered in the nationwide and population-based Norwegian Childhood Diabetes Registry. METHODS: Incident cases were classified in seven groups based on country of maternal birth and three age groups. Statistics Norway provided the corresponding population sizes. Incidence rates were compared by Poisson regression. RESULTS: The overall incidence rate was 34.0 cases per 100,000 person years (95% CI: 32.6, 35.5). There were large variations in incidence across the immigrant groups (p < 0.001), ranging from 6.8 per 100,000 person-years (95% CI: 1.9-17.5) for South/East Asians to 26.0 cases per 100,000 person-years (95% CI: 11.9-49.3) for sub-Saharan Africans. The differences remained significant after adjusting for age and gender. CONCLUSIONS: There are large variations in the rate of incidence of type 1 diabetes across the ethnic groups, and several immigrant groups have significantly lower incidence than ethnic Norwegians. Immigrant groups contributed ca. 5% of the total cases of type 1 diabetes and influence the overall incidence in Norway only to a small extent. PMID- 26111936 TI - Avian influenza virus exhibits distinct evolutionary dynamics in wild birds and poultry. AB - BACKGROUND: Wild birds are the major reservoir hosts for influenza A viruses, occasionally transmitting to other species such as domesticated poultry. Despite an abundance of genomic data from avian influenza virus (AIV), little is known about whether AIV evolves differently in wild birds and poultry, although this is critical to revealing the dynamics and time-scale of viral evolution. In particular, because environmental (water-borne) transmission is more common in wild birds, which may reduce the number of replications per unit time, it is possible that evolutionary rates are systematically lower in wild birds than in poultry. RESULTS: We estimated rates of nucleotide substitution in two AIV subtypes that are strongly associated with infections in wild birds - H4 and H6 - and compared these to rates in the H5N1 subtype that has circulated in poultry for almost two decades. Our analyses of three internal genes confirm that H4 and H6 viruses are evolving significantly more slowly than H5N1 viruses, suggesting that evolutionary rates of AIV are reduced in wild birds. This result was verified by the analysis of a poultry-associated H6 lineage that exhibited a markedly higher substitution rate than those H6 viruses circulating in wild birds. Interestingly, we also observed a significant difference in evolutionary rate between H4 and H6, despite frequent reassortment rate among them. CONCLUSIONS: AIV experiences markedly different evolutionary dynamics between wild birds and poultry. These results suggest that rate heterogeneity among viral subtypes and ecological groupings should be taken into account when estimating evolutionary rates and divergence times. PMID- 26111937 TI - Genome-scale resources for Thermoanaerobacterium saccharolyticum. AB - BACKGROUND: Thermoanaerobacterium saccharolyticum is a hemicellulose-degrading thermophilic anaerobe that was previously engineered to produce ethanol at high yield. A major project was undertaken to develop this organism into an industrial biocatalyst, but the lack of genome information and resources were recognized early on as a key limitation. RESULTS: Here we present a set of genome-scale resources to enable the systems level investigation and development of this potentially important industrial organism. Resources include a complete genome sequence for strain JW/SL-YS485, a genome-scale reconstruction of metabolism, tiled microarray data showing transcription units, mRNA expression data from 71 different growth conditions or timepoints and GC/MS-based metabolite analysis data from 42 different conditions or timepoints. Growth conditions include hemicellulose hydrolysate, the inhibitors HMF, furfural, diamide, and ethanol, as well as high levels of cellulose, xylose, cellobiose or maltodextrin. The genome consists of a 2.7 Mbp chromosome and a 110 Kbp megaplasmid. An active prophage was also detected, and the expression levels of CRISPR genes were observed to increase in association with those of the phage. Hemicellulose hydrolysate elicited a response of carbohydrate transport and catabolism genes, as well as poorly characterized genes suggesting a redox challenge. In some conditions, a time series of combined transcription and metabolite measurements were made to allow careful study of microbial physiology under process conditions. As a demonstration of the potential utility of the metabolic reconstruction, the OptKnock algorithm was used to predict a set of gene knockouts that maximize growth-coupled ethanol production. The predictions validated intuitive strain designs and matched previous experimental results. CONCLUSION: These data will be a useful asset for efforts to develop T. saccharolyticum for efficient industrial production of biofuels. The resources presented herein may also be useful on a comparative basis for development of other lignocellulose degrading microbes, such as Clostridium thermocellum. PMID- 26111938 TI - Uncoupling of endothelial nitric oxide synthase in cerebral vasculature of Tg2576 mice. AB - In this study, we tested the hypothesis that reduced bioavailability of tetrahydrobiopterin (BH4) is a major mechanism responsible for pathogenesis of endothelial dysfunction in cerebral microvessels of transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (APP) (Tg2576 mice). Endothelial nitric oxide synthase (eNOS) protein expression was significantly increased in cerebral vasculature of Tg2576 mice. In contrast, bioavailability of BH4 was significantly reduced (p < 0.05). Moreover, superoxide anion production was increased in cerebral microvessels of Tg2576 mice (p < 0.05). Incubation with NOS inhibitor, Nomega-nitro-L-arginine methyl ester, decreased superoxide anion indicating that uncoupled eNOS is most likely the source of superoxide anion. Increasing BH4 bioavailability either exogenously by BH4 supplementation or endogenously by treatment with the selective peroxisome proliferator-activated receptor--delta activator GW501516 (2 mg/kg/day, 14 days) attenuated eNOS uncoupling and decreased superoxide anion production in cerebral microvessels of Tg2576 mice (p < 0.05). Treatment with GW501516 restored the biological activity of endothelial nitric oxide in cerebral microvessels of Tg2576 mice, as indicated by the increased nitrite/nitrate content and 3,5-cyclic guanosine monophosphate levels (p < 0.05). Our studies indicate that sub-optimal BH4 bioavailability in cerebral vasculature is an important contributor to oxidant stress and endothelial dysfunction in Tg2576 mouse model of Alzheimer's disease. Existing evidence suggests that Abeta peptides-induced up-regulation of expression and activity of NADPH oxidase causes increased production of superoxide anion (.O2(-)). .O2(-) can also be converted to hydrogen peroxide (H2O2) by enzymatic activity of superoxide dismutase (SOD) or spontaneous dismutation. Elevation of .O2(-) and H2O2 might cause oxidation of tetrahydrobiopterin (BH4) to dihydrobiopterin (BH2) and subsequent uncoupling of endothelial nitric oxide synthase (eNOS) (a) thus reducing levels of nitric oxide (NO) and 3',5'-cyclic guanosine monophosphate (cGMP). Supplementation of BH4 or activation of PPARdelta prevents detrimental effects of eNOS uncoupling by restoring bioavailability of BH4 and scavenging of .O2(-), respectively (b). Activation of PPARdelta also increases expression of catalase thereby inactivating H2O2. Generation of H2O2 by uncoupled eNOS in cerebral microvessels of Tg2576 mice is hypothetical. PMID- 26111940 TI - Chlorhexidine Anaphylaxis Masquerading as Septic Shock. AB - Chlorhexidine is a commonly used antiseptic and disinfectant in the health-care setting. Its usage has increased in recent years with intensive campaigns and infection control guidelines to combat hospital-acquired infections. As a result, patients and health-care workers (HCW) are exposed to increasing chlorhexidine usage. In recent years, adverse reactions to chlorhexidine ranging from allergic contact dermatitis, photosensitivity, fixed drug eruptions, urticaria and anaphylactic shock have been reported. Most have been isolated case reports on adverse reactions occurring in healthy individuals or HCW. We report a case of anaphylactic shock caused by applying chlorhexidine cleansing solution and masquerading as septic shock from left-leg necrotising fasciitis. PMID- 26111939 TI - A Cluster-Randomized Trial of a Centralized Clinical Pharmacy Cardiovascular Risk Service to Improve Guideline Adherence. AB - BACKGROUND: Numerous studies have demonstrated the value of including pharmacists in team-based care to improve adherence to cardiovascular (CV) guidelines, medication adherence, and risk factor control. However, there is limited information on whether these models can be successfully implemented more widely in diverse settings and populations. The purpose of this study is to evaluate whether a centralized, web-based cardiovascular risk service (CVRS) managed by clinical pharmacists will improve guideline adherence in multiple primary care medical offices with diverse geographic and patient characteristics. METHODS: This study is a prospective trial in 20 primary care offices stratified by the percent of under-represented minorities and then randomized to either the CVRS intervention or usual care. The intervention will last for 12 months and all subjects will have research visits at baseline and 12 months. The primary outcome is the difference in guideline adherence between groups. Data will also be abstracted from the medical record at 24 months to determine if the intervention effect is sustained after it is discontinued. CONCLUSIONS: Patient enrollment will continue through 2016, with results expected in 2019. This study will provide information on whether a distant, centralized CVRS can be implemented in large numbers of medical offices, if it is effective in diverse populations, and if there is a long-term sustained effect. PMID- 26111941 TI - A novel therapeutic approach for LPIN1 mutation-associated rhabdomyolysis--The Austrian experience. AB - INTRODUCTION: Lipin 1 gene (LPIN1) mutations lead to cellular energy deficiency and cause up to 50% of the rhabdomyolysis episodes seen in pediatric patients. These episodes are associated with poor prognosis, as treatment options have been limited. We propose a novel therapeutic strategy based on prevention and early treatment of catabolism. METHODS: Five patients were diagnosed with LPIN1 mutations. They were instructed to maintain high caloric intake in situations possibly leading to catabolism such as viral infections or excessive physical activity. When an episode of rhabdomyolysis occurred, patients were treated with intravenous high-concentration glucose at first symptoms. RESULTS: The therapeutic strategies described limited the number of rhabdomyolyis episodes, and the duration of episodes was reduced from 7-10 days, as reported in the literature, to 5 days. CONCLUSION: In this small series, patients with LPIN1 mutations appear to have benefited from prevention and early treatment of catabolism. PMID- 26111943 TI - A General Route to Robust Nacre-Like Graphene Oxide Films. AB - Artificial nacre-like composite films of graphene oxide (GO) with a variety of commercially available water-soluble polymers were fabricated by a gel-film transformation (GFT) technique. The blending of a polymer into the aqueous dispersion of GO can modulate the interaction between GO sheets. Typically, the attraction force between polymer and GO sheets overcomes the dominant hydration and electrostatic repulsive forces between GO sheets, promoting the gelation of GO. Cast drying the resultant GO hydrogel containing small amounts of polymer (1 20 wt % relative to GO depending on the intrinsic structures of polymers) generates layered GO composite films with tensile strengths over 200 MPa and failure strains larger than 3.0%, which are higher than those of natural nacre and most nacre-like GO films. These results indicate that GO/polymer composite hydrogels are excellent precursors for nacre-like GO films and that the GFT approach is a general route toward the large-scale fabrication of nacre-like GO films with unique combinations of high strength and high toughness. PMID- 26111944 TI - Case report: Limb-threatening femoral vein thrombosis in a healthy carpet fitter: Carpet fitter's thrombosis. AB - OBJECTIVE: To report a case of femoral vein thrombosis in a carpet fitter and to highlight this as an occupational hazard. METHOD: Case presentation and literature review. RESULTS: An otherwise fit 21-year-old carpet fitter with no past medical history presented with acute thrombosis of his left common femoral, superficial femoral and great saphenous veins. Attempted catheter directed thrombolysis was unsuccessful. Due to severe pain and the threat of venous gangrene he was treated by emergency surgical thrombectomy with excision of chronic venous scarring and vein-patch repair that led to resolution of his symptoms. CONCLUSIONS: Deep vein thrombosis is typically associated with factors such as increasing age and prolonged periods of immobility; however, certain 'active' occupations can increase its risk. Crouched and cramped working conditions including repetitive active movement with flexed hips and knees can predispose to increased risk of venous thromboembolism. PMID- 26111942 TI - Physical activity, mindfulness meditation, or heart rate variability biofeedback for stress reduction: a randomized controlled trial. AB - In contemporary western societies stress is highly prevalent, therefore the need for stress-reducing methods is great. This randomized controlled trial compared the efficacy of self-help physical activity (PA), mindfulness meditation (MM), and heart rate variability biofeedback (HRV-BF) in reducing stress and its related symptoms. We randomly allocated 126 participants to PA, MM, or HRV-BF upon enrollment, of whom 76 agreed to participate. The interventions consisted of psycho-education and an introduction to the specific intervention techniques and 5 weeks of daily exercises at home. The PA exercises consisted of a vigorous intensity activity of free choice. The MM exercises consisted of guided mindfulness meditation. The HRV-BF exercises consisted of slow breathing with a heart rate variability biofeedback device. Participants received daily reminders for their exercises and were contacted weekly to monitor their progress. They completed questionnaires prior to, directly after, and 6 weeks after the intervention. Results indicated an overall beneficial effect consisting of reduced stress, anxiety and depressive symptoms, and improved psychological well being and sleep quality. No significant between-intervention effect was found, suggesting that PA, MM, and HRV-BF are equally effective in reducing stress and its related symptoms. These self-help interventions provide easily accessible help for people with stress complaints. PMID- 26111945 TI - Superior Disembedding Performance in Childhood Predicts Adolescent Severity of Repetitive Behaviors: A Seven Years Follow-Up of Individuals With Autism Spectrum Disorder. AB - Previous research suggests that individuals with autism spectrum disorder (ASD) show a detail-focused cognitive style. The aim of the current longitudinal study was to investigate whether this detail-focused cognitive style in childhood predicted a higher symptom severity of repetitive and restrictive behaviors and interests (RRBI) in adolescence. The Childhood Embedded Figures Test (CEFT) and the Autism Diagnostic Observation Schedule (ADOS) were administered in 87 children with ASD at the age of 6-12 years old (T1), and the ADOS was readministered 7 years later when the participants were 12-19 years old (T2). Linear regression analyses were performed to investigate whether accuracy and reaction time in the complex versus simple CEFT condition and performance in the complex condition predicted T2 ADOS RRBI calibrated severity scores (CSS), while taking into consideration relevant covariates and ADOS RRBI CSS at T1. The CEFT performance (accuracy in the complex condition divided by the time needed) significantly predicted higher ADOS RRBI CSS at T2 (DeltaR(2) = 15%). This finding further supports the detail-focused cognitive style in individuals with ASD, and shows that it is also predictive of future RRBI symptoms over time. PMID- 26111946 TI - Prevalence of cranial autonomic parasympathetic symptoms in chronic migraine: Usefulness of a new scale. AB - BACKGROUND: Cranial autonomic symptoms (CAS) seem to appear in around half of migraine patients. OBJECTIVE: Our aim was to analyse the prevalence and profile of CAS, mainly of cranial autonomic parasympathetic symptoms (CAPS), in a series of patients with chronic migraine (CM) according the new criteria for autonomic symptoms in the current IHS classification. PATIENTS AND METHODS: We recruited consecutive CM patients attending our headache clinic. Five CPAS were surveyed: lacrimation, conjunctival injection, eyelid oedema, ear fullness and nasal congestion. They were graded as 0 (absent), 1 (present and mild) and 2 (present and conspicuous); therefore the score in this CAPS scale ranges from 0 to 10 points. As a cranial autonomic sympathetic symptom (CSAS), we also asked about the presence of ptosis. RESULTS: We interviewed 100 CM patients. Their mean age was 45 years (18-63 years); 93 were females. Eighteen had no CAPS, while 82 reported at least one CAPS. There were only six patients with scores higher than 5, the mean and median CAPS being 2.1 and 2, respectively. Prevalence of CAPS was lacrimation (49%), conjunctival injection (44%), eyelid oedema (39%), ear fullness (30%) and nasal congestion (20%). Ptosis was reported by 42. CONCLUSION: These results, by using for the first time an easy quantitative scale, confirm that (mild) CAPS are not the exception but the rule in CM patients. The score in this CAPS scale could be of help as a further endpoint in clinical trials or to be correlated with potential biomarkers of parasympathetic activation in primary headaches. PMID- 26111947 TI - Contribution of behavioural science to antibiotic stewardship. PMID- 26111949 TI - A comparison of two commercially available ELISA methods for the quantification of human plasma heat shock protein 70 during rest and exercise stress. AB - This study compared resting and exercise heat/hypoxic stress-induced levels of plasma extracellular heat shock protein 70 (eHSP70) in humans using two commercially available enzyme-linked immunosorbent assay (ELIS)A kits. EDTA plasma samples were collected from 21 males during two separate investigations. Participants in part A completed a 60-min treadmill run in the heat (HOT70; 33.0 +/- 0.1 degrees C, 28.7 +/- 0.8 %, n = 6) at 70 % VO2max. Participants in part B completed 60 min of cycling exercise at 50 % VO2max in either hot (HOT50; 40.5 degrees C, 25.4 relative humidity (RH)%, n = 7) or hypoxic (HYP50; fraction of inspired oxygen (FIO2) = 0.14, 21 degrees C, 35 % RH, n = 8) conditions. Samples were collected prior to and immediately upon termination of exercise and analysed for eHSP70 using EKS-715 high-sensitivity HSP70 ELISA and new ENZ-KIT-101 Amp'd(TM) HSP70 high-sensitivity ELISA. ENZ-KIT was superior in detecting resting eHSP70 (1.54 +/- 3.27 ng . mL(-1); range 0.08 to 14.01 ng . mL(-1)), with concentrations obtained from 100 % of samples compared to 19 % with EKS-715 assay. The ENZ-KIT requires optimisation prior to running samples in order to ensure participants fall within the standard curve, a step not required with EKS 715. Using ENZ-KIT, a 1:4 dilution allowed for quantification of resting HSP70 in 26/32 samples, with a 1:8 (n = 3) and 1:16 (n = 3) dilution required to determine the remaining samples. After exercise, eHSP70 was detected in 6/21 and 21/21 samples using EKS-715 and ENZ-KIT, respectively. eHSP70 was increased from rest after HOT70 (p < 0.05), but not HOT50 (p > 0.05) or HYP50 (p > 0.05) when analysed using ENZ-KIT. It is recommended that future studies requiring the precise determination of resting plasma eHSP70 use the ENZ-KIT (i.e. HSP70 Amp'd((r)) ELISA) instead of the EKS-715 assay, despite additional assay development time and cost required. PMID- 26111950 TI - Resisting the Resistance in Cancer: Cheminformatics Studies on Short- Path Base Excision Repair Pathway Antagonists Using Supervised Learning Approaches. AB - Survival of cells and maintenance of genome depend on detection and repair of damaged DNA through intricate mechanisms. Cancer treatment relies on chemotherapy or radiation therapy that kills neoplastic cells by causing immense damage to the DNA. In many cases, escalated DNA repair mechanism leads to resistance against these therapies and therefore, there is a need to expand the interest in developing drugs that can sensitize the cells to such therapies by interfering with the DNA repair mechanism. Several studies have suggested a link between over expression of the primary mammalian enzyme, Apurinic/Apyrimidinic Endonuclease (APE1), responsible for abasic (or AP) site removal in the DNA and resistance of these cells to cancer therapy, whereas APE1 down-regulation sensitizes the cells to DNA damaging agents. Thus, the current treatment efficacy can be improved by aiding to selective sensitization of cancer cells and protection of normal cells. In the present study, we have used machine learning based approach by selecting assorted compounds with known activity for APE1 and constructed a range of in silico predictive classification models to discriminate between the inhibitors and non-inhibitors. These models can be applied to numerous other unscreened compounds to select the ones which are more likely to be the inhibitors for APE1. We have further found the common molecular substructures which were associated with the molecular activity of the compounds using a substructure search approach. PMID- 26111951 TI - Oxygen diffusion in marine-derived tissue engineering scaffolds. AB - This paper addresses the computation of the effective diffusivity in new bioactive glass (BG) based tissue engineering scaffolds. High diffusivities facilitate the supply of oxygen and nutrients to grown tissue as well as the rapid disposal of toxic waste products. The present study addresses required novel types of bone tissue engineering BG scaffolds that are derived from natural marine sponges. Using the foam replication method, the scaffold geometry is defined by the porous structure of Spongia Agaricina and Spongia Lamella. These sponges present the advantage of attaining scaffolds with higher mechanical properties (2-4 MPa) due to a decrease in porosity (68-76%). The effective diffusivities of these structures are compared with that of conventional scaffolds based on polyurethane (PU) foam templates, characterised by high porosity (>90%) and lower mechanical properties (>0.05 MPa). Both the spatial and directional variations of diffusivity are investigated. Furthermore, the effect of scaffold decomposition due to immersion in simulated body fluid (SBF) on the diffusivity is addressed. Scaffolds based on natural marine sponges are characterised by lower oxygen diffusivity due to their lower porosity compared with the PU replica foams, which should enable the best oxygen supply to newly formed bone according the numerical results. The oxygen diffusivity of these new BG scaffolds increases over time as a consequence of the degradation in SBF. PMID- 26111952 TI - Ambulatory Blood Pressure Monitoring and Body Mass Index: Good but Not Standardized! PMID- 26111953 TI - Xerosis and pruritus as major EGFRI-associated adverse events. AB - PURPOSE: The objective of this sub-analysis of the BeCet study (NCT01136005) was to examine health-related quality of life (HRQoL) of patients experiencing dermatological adverse events (AEs) during the first 6 weeks of epidermal growth factor receptor inhibitor (EGFRI) treatment. METHODS: Patients (n = 85) treated with EGFRI completed five questionnaires during the first 6 weeks of treatment. 77 patients provided enough data for the sub-analysis. Experienced AEs were reported in the Dermatological Reactions Targeted Therapy-Patients (DERETT-P), a symptom experience diary for patients treated with targeted therapy. The impact of EGFRI-associated dermatological adverse events on HRQoL was examined using four HRQoL questionnaires; the Functional Assessment of Cancer Therapy-EGFRI (FACT-EGFRI-18), the Functional Assessment of Cancer Therapy-General (FACT-G), the 36-Item Short Form Health Survey (SF-36), and the Skindex-16. RESULTS: During the first 6 weeks of EGFRI treatment, physical discomfort was the most significantly affected domain. In the entire study population, xerosis (dry skin) (22.3 %) and pruritus (itchy skin) (16.9 %) were reported as the most impactful AEs. For patients experiencing a papulopustular eruption (acneiform rash) pruritus (24.2 %), xerosis (18.9 %), and papulopustular eruption (6.3 %) were reported as the most impactful AEs. Papulopustular eruption, xerosis, and pruritus all showed a significant negative effect on HRQoL, displayed in FACT EGFRI-18 scores. CONCLUSIONS: In addition to papulopustular eruption, xerosis and pruritus are major EGFRI-associated dermatological AEs with an impact on HRQoL, which warrant more attention in clinical practice and research. PMID- 26111954 TI - Management of the respiratory distress symptom cluster in lung cancer: a randomised controlled feasibility trial. AB - BACKGROUND: Breathlessness, cough and fatigue are distressing symptoms for patients with lung cancer. There is evidence that these three symptoms form a discreet symptom cluster. This study aimed to feasibly test a new non pharmacological intervention for the management of the Respiratory Distress Symptom Cluster (breathlessness-cough-fatigue) in lung cancer. METHOD: This was a multi-centre, randomised controlled non-blinded parallel group feasibility trial. Eligible patients (patients with primary lung cancer and 'bothered' by at least two of the three cluster symptoms) received usual care plus a multicomponent intervention delivered over two intervention training sessions and a follow-up telephone call or usual care only. Follow-up was for 12 weeks, and end-points included six numerical rating scales for breathlessness severity, Dyspnoea-12, Manchester Cough in Lung Cancer scale, FACIT-Fatigue scale, Hospital Anxiety and Depression scale, Lung Cancer Symptom Scale and the EQ-5D-3L, collected at baseline, week 4 and week 12. RESULTS: One hundred seven patients were randomised over 8 months; however, six were removed from further analysis due to protocol violations (intervention group n = 50 and control group n = 51). Of the ineligible patients (n = 608), 29 % reported either not experiencing two or more symptoms or not being 'bothered' by at least two symptoms. There was 29 % drop out by week 4, and by week 12, a further two patients in the control group were lost to follow-up. A sample size calculation indicated that 122 patients per arm would be needed to detect a clinically important difference in the main outcome for breathlessness, cough and fatigue. CONCLUSIONS: The study has provided evidence of the feasibility and acceptability of a new intervention in the lung cancer population and warrants a fully powered trial before we reach any conclusions. The follow-on trial will test the hypothesis that the intervention improves symptom cluster of breathlessness, cough and fatigue better than usual care alone. Full economic evaluation will be conducted in the main trial. PMID- 26111955 TI - Improving psychosocial outcomes for caregivers of people with poor prognosis gastrointestinal cancers: a randomized controlled trial (Family Connect). AB - PURPOSE: This study investigated the effectiveness of a structured telephone intervention for caregivers of people diagnosed with poor prognosis gastrointestinal cancer to improve psychosocial outcomes for both caregivers and patients. METHODS: Caregivers of patients starting treatment for upper gastrointestinal or Dukes D colorectal cancer were randomly assigned (1:1) to the Family Connect telephone intervention or usual care. Caregivers in the intervention group received four standardized telephone calls in the 10 weeks following patient hospital discharge. Caregivers' quality of life (QOL), caregiver burden, unmet supportive care needs and distress were assessed at 3 and 6 months. Patients' QOL, unmet supportive care needs, distress and health service utilization were also assessed at these time points. RESULTS: Caregivers (128) were randomized to intervention or usual care groups. At 3 months, caregiver QOL scores and other caregiver-reported outcomes were similar in both groups. Intervention group participants experienced a greater sense of social support (p = .049) and reduced worry about finances (p = .014). Patients whose caregiver was randomized to the intervention also had fewer emergency department presentations and unplanned hospital readmissions at 3 months post-discharge (total 17 vs. 5, p = .01). CONCLUSIONS: This standardized intervention did not demonstrate any significant improvements in caregiver well-being but did result in a decrease in patient emergency department presentations and unplanned hospital readmissions in the immediate post-discharge period. The trend towards improvements in a number of caregiver outcomes and the improvement in health service utilization support further development of telephone-based caregiver-focused supportive care interventions. PMID- 26111956 TI - Comparison of effectiveness of biosimilar filgrastim (NivestimTM), reference Amgen filgrastim and pegfilgrastim in febrile neutropenia primary prevention in breast cancer patients treated with neo(adjuvant) TAC: a non-interventional cohort study. AB - PURPOSE: Biosimilars are supported by limited clinical data at the time of approval. Recently, NivestimTM, a biosimilar of reference of filgrastim, was approved for prevention of chemotherapy-related febrile neutropenia (FN). To add clinical experience to this new biosimilar, we performed a study to compare the effectiveness of NivestimTM with reference filgrastim and pegfilgrastim in FN prevention in patients receiving high-risk FN chemotherapy. METHODS: This is a comparative cohort study, with retrospective data collection. Three cohorts were identified according to the type of primary prophylaxis employed over different time periods: reference filgrastim (2004-2006), pegfilgrastim (2007-2008) and biosimilar filgrastim (2011-2012). The study included female patients with early breast cancer that received FN primary prophylaxis during (neo)adjuvant docetaxel/doxorubicin/cyclophosphamide (TAC). RESULTS: Reference filgrastim cohort included 147 patients and pegfilgrastim and biosimilar filgrastim cohorts 139 and 134 patients, respectively. FN rates per patient/cycle were 16 % (95 % confidence interval (CI) 10.2-22.5 %)/3 % (95 % CI 2.1-4.7 %) in the reference filgrastim group, 9 % (95 % CI 4.5-14.6 %)/2 % (95 % CI 1.3-3.6 %) in the pegfilgrastim group and 16 % (95 % CI 10.0-22.9 %)/4 % (95 % CI 2.5-5.3 %) in the biosimilar filgrastim cohort. The median absolute neutrophil count (ANC) at FN presentation was lower in the biosimilar group in comparison with reference filgrastim. FN episodes with ANC < 100 cells/MUL were more frequent in the biosimilar group (50 %) when compared with reference filgrastim (4 %) and pegfilgrastim (6 %). No differences concerning FN complications were seen, with the exception of more chemotherapy delays in the biosimilar group when compared with pegfilgrastim. CONCLUSION: No differences in biosimilar effectiveness were detected. The clinical relevance of the profound neutropenia found in the biosimilar cohort needs further attention. PMID- 26111959 TI - Targeting B16 tumors in vivo with peptide-conjugated gold nanoparticles. AB - This study examines the effects of polyethylene glycol (PEG) and peptide conjugation on the biodistribution of ultrasmall (2.7 nm) gold nanoparticles in mice bearing B16 melanoma allografts. Nanoparticles were delivered intravenously, and biodistribution was measured at specific timepoints by organ digestion and inductively coupled plasma mass spectrometry. All major organs were examined. Two peptides were tested: the cyclic RGD peptide (cRGD, which targets integrins); and a recently described peptide derived from the myxoma virus. We found the greatest specific tumor delivery using the myxoma peptide, with or without PEGylation. Un PEGylated cRGD performed poorly, but PEGylated RGD showed a significant transient collection in the tumor. Liver and kidney were the primary targets of all constructs. None of the particles were able to cross the blood-brain barrier. Although it was able to deliver Au to B16 cells, the myxoma peptide did not show any cytotoxic activity against these cells, in contrast to previous reports. These results indicate that the effect of passive targeting by PEGylation and active targeting by peptides can be independent or combined, and that they should be evaluated on a case-by-case basis when designing new nanosystems for targeted therapies. Both myxoma peptide and cRGD should be considered for specific targeting to melanoma, but a thorough investigation of the cytotoxicity of the myxoma peptide to different cell lines remains to be performed. PMID- 26111957 TI - Effect of single doses of IV palonosetron, up to 2.25 mg, on the QTc interval duration: a double-blind, randomized, parallel group study in healthy volunteers. AB - PURPOSE: The use of serotonin type 3 (5-HT3) receptor antagonists (RAs) in the prevention of nausea and vomiting caused by emetogenic chemotherapy is part of a comprehensive management strategy for patients undergoing chemotherapy. Electrocardiographic effects have been reported in patients after intravenous administration of 5-HT3 RAs. The present study investigated the electrocardiogram (ECG) profile of the 5-HT3 RA palonosetron following International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E14 Guidelines. METHODS: A total of 221 healthy subjects (101 females, 120 males) were randomized in this phase I, double-blind, double-dummy, parallel group study and assigned to one of five treatments: placebo, palonosetron (0.25, 0.75, or 2.25 mg), or moxifloxacin (400 mg). ECGs were recorded for 24 h pre-dosing until 48 h post-dose. The primary endpoint was the placebo time-matched and baseline-subtracted individual QTc interval prolongation (DeltaDeltaQTcI). RESULTS: The QTc interval was not prolonged after administration of palonosetron (DeltaDeltaQTcI upper confidence interval was <10 ms for all time points in all palonosetron treatment groups). Assay sensitivity was confirmed with the expected change in the QTc interval after administration of the positive control moxifloxacin. CONCLUSIONS: Palonosetron, even at supratherapeutic doses, has no effect on cardiac repolarization as measured by the QTc interval in a validated controlled clinical trial. PMID- 26111958 TI - Plasma Levels of Interleukin 12 Family Cytokines and Their Relevant Cytokines in Adult Patients with Chronic Immune Thrombocytopenia before and after High-Dose Dexamethasome Treatment. AB - OBJECTIVE: We aimed to investigate the expression of interleukin 12 (IL-12) family cytokines (IL-12, IL-23, IL-27 and IL-35) and their relevant cytokines (IFN-gamma, IL-4, IL-17A and IL-10) in patients with chronic immune thrombocytopenia (cITP) as well as the effect of high-dose dexamethasone (HD-DXM) treatment on this expression. MATERIALS AND METHODS: DXM was administered orally at a dose of 40 mg per day for 4 consecutive days to 38 patients with cITP. We measured the plasma levels of IL-12p70, IL-23, IL-27, IFN-gamma, IL-4 and IL-17A before and after treatment and also in 36 matched healthy controls, by means of FlowCytomixTM technology. The plasma levels of IL-10 and IL-35 were measured by enzyme-linked immunosorbent assay. RESULTS: Significantly higher plasma levels of IL-12p70, IL-23, IL-27, IFN-gamma and IL-17A were observed in cITP patients than in controls (p < 0.01), and after HD-DXM treatment, these levels decreased significantly (p < 0.01). However, significantly lower plasma levels of IL-4, IL 10 and IL-35 were observed in cITP patients than in controls (p < 0.01); after the HD-DXM treatment, these levels had increased significantly in the cITP patients (p < 0.01). Moreover, the cytokine levels of patients who attained a complete response returned to the levels of normal controls (p > 0.05) but were not corrected in the patients who had no response (p < 0.01). CONCLUSIONS: The patients with cITP had abnormal expression of the IL-12 family cytokines and their relevant cytokines levels, and HD-DXM treatment corrected the derangement of plasma cytokines. Measuring cytokine levels may help in the clinical assessment of cITP. PMID- 26111960 TI - Synthetic chromosomes. AB - What a living organism looks like and how it works and what are its components all this is encoded on DNA, the genetic blueprint. Consequently, the way to change an organism is to change its genetic information. Since the first pieces of recombinant DNA have been used to transform cells in the 1970s, this approach has been enormously extended. Bigger and bigger parts of the genetic information have been exchanged or added over the years. Now we are at a point where the construction of entire chromosomes becomes a reachable goal and first examples appear. This development leads to fundamental new questions, for example, about what is possible and desirable to build or what construction rules one needs to follow when building synthetic chromosomes. Here we review the recent progress in the field, discuss current challenges and speculate on the appearance of future synthetic chromosomes. PMID- 26111961 TI - Diagnostic accuracy of anti-MCV and anti-CCP antibodies in rheumatoid arthritis: A meta-analysis. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic performance of anti-mutated citrullinated vimentin (anti-MCV) and anti-cyclic citrullinated peptide (anti-CCP) antibodies in rheumatoid arthritis (RA). METHODS: We searched the Medline, Embase, and Cochrane library databases and performed two meta analyses on the diagnostic accuracy of anti-MCV and anti-CCP in patients with RA compared to healthy controls. RESULTS: We identified 12 studies that included a total of 2003 RA patients and 831 healthy controls for the meta-analysis. The pooled sensitivity and specificity of anti-MCV were 68.6% [95% confidence interval (CI) 66.6-79.7] and 94.2% (95% CI 92.4-96.7) and those of anti-CCP were 61.7% (95% CI 59.5-63.8) and 97.1% (95% CI 96.7-98.1), respectively. Anti-MCV PLR, NLR, and DOR were 12.99 (95% CI 8.013-21.27), 0.297 (95% CI 0.238-0.369), and 47.78 (95% CI 28.59-79.84), and those for anti-CCP were 16.71 (95% CI 11.42 24.47), 0.378 (95% CI 0.325-0.439), and 54.20 (95% CI 31.65-92.82), respectively. The AUC of anti-MCV was 0.886, and its Q* index was 0.817, indicating modest accuracy, while the AUC of anti-CCP was 0.946, and its Q* index was 0.885. The sensitivity of anti-MCV was significantly higher than that of anti-CCP in the diagnosis of RA (difference 0.069, 95% CI 0.039-0.098, p < 0.0001), but the specificity of anti-MCV was lower than that of anti-CCP (difference -0.029, 95% CI -0.051 to -0.006, p = 0.012). The Q* index of anti-MCV was significantly lower than that of anti-CCP (difference -0.068, 95% CI -0.070 to -0.065, p < 0.0001). CONCLUSION: Our meta-analysis demonstrates that anti-MCV is more sensitive but less specific, and has lower diagnostic accuracy than anti-CCP in RA, although anti-MCV and anti-CCP showed comparable high PLRs. PMID- 26111962 TI - Increasing Incidence of Juvenile Thyrotoxicosis in Denmark: A Nationwide Study, 1998-2012. AB - AIM: The aim of this study was to determine in a Danish nationwide study whether the incidence rate (IR) of thyrotoxicosis in children below 15 years of age has increased between 1998 and 2012 and to compare the results with previously published national data from 1982 to 1988. Furthermore, we intended to conduct a descriptive study of children diagnosed with Graves' disease (GD) between 2008 and 2012. METHODS: Children diagnosed with thyrotoxicosis between 1998 and 2012 were identified through the Danish National Patient Registry. All medical records were reviewed to verify the diagnosis. Additional data were collected on children diagnosed with GD in 2008-2012. RESULTS: In total, 237 patients with juvenile thyrotoxicosis (JT) were identified. The overall IR in 1998-2012 was 1.58/100,000 person-years and has increased significantly from 0.79/100,000 person-years in 1982-1988 (p < 0.001). The IR has continued to increase during the recent 15 years (1.31-1.83/100,000 person-years), with a 12.5% increase with each 5-year time period. The IR increased with age and female sex (p < 0.001). The descriptive study included 79 children with GD, presenting with a wide spectrum of clinical features. Remission occurred in 13.9%. CONCLUSION: The IR of JT has increased significantly since 1982-1988 and has continued to increase during the recent 15 years. The overall IR was 1.58/100,000 person-years during 1998-2012. PMID- 26111963 TI - Amino Acid and Peptide Utilization Profiles of the Fluoroacetate-Degrading Bacterium Synergistetes Strain MFA1 Under Varying Conditions. AB - Synergistetes strain MFA1 is an asaccharolytic ruminal bacterium isolated based on its ability to degrade fluoroacetate, a plant toxin. The amino acid and peptide requirements of the bacterium were investigated under different culturing conditions. The growth of strain MFA1 and its fluoroacetate degradation rate were enhanced by peptide-rich protein hydrolysates (tryptone and yeast extract) compared to casamino acid, an amino acid-rich protein hydrolysate. Complete utilization and preference for arginine, asparagine, glutamate, glycine, and histidine as free amino acids from yeast extract were observed, while the utilization of serine, threonine, and lysine in free form and peptide-bound glutamate was stimulated during growth on fluoroacetate. A predominant peptide in yeast extract preferentially utilized by strain MFA1 was partially characterized by high-liquid performance chromatography-mass spectrometry as a hepta-glutamate oligopeptide. Similar utilization profiles of amino acids were observed between the co-culture of strain MFA1 with Methanobrevibacter smithii without fluoroacetate and pure strain MFA1 culture with fluoroacetate. This suggests that growth of strain MFA1 could be enhanced by a reduction of hydrogen partial pressure as a result of hydrogen removal by a methanogen or reduction of fluoroacetate. PMID- 26111964 TI - Sediment Ammonia-Oxidizing Microorganisms in Two Plateau Freshwater Lakes at Different Trophic States. AB - Both ammonia-oxidizing archaea (AOA) and bacteria (AOB) can contribute to ammonia biotransformation in freshwater lake ecosystems. However, the factors shaping the distribution of sediment AOA and AOB in plateau freshwater lake remains unclear. The present study investigated sediment AOA and AOB communities in two freshwater lakes (hypertrophic Dianchi Lake and mesotrophic Erhai Lake) on the Yunnan Plateau (China). A remarkable difference in the abundance, diversity, and composition of sediment AOA and AOB communities was observed between Dianchi Lake and Erhai Lake. AOB usually outnumbered AOA in Dianchi Lake, but AOA showed the dominance in Erhai Lake. Organic matter (OM), total nitrogen (TN), and total phosphorus (TP) might be the key determinants of AOB abundance, while AOA abundance was likely influenced by the ration of OM to TN (C/N). AOA or AOB community structure was found to be relatively similar in the same lake. TN and TP might play important roles in shaping sediment AOA and AOB compositions in Dianchi Lake and Erhai Lake. Moreover, Nitrososphaera-like AOA were detected in Dianchi Lake. Nitrosospira- and Nitrosomonas-like AOB were dominant in Dianchi Lake and Erhai Lake, respectively. Sediment AOA and AOB communities in Dianchi Lake and Erhai Lake were generally regulated by trophic state. PMID- 26111965 TI - Economic benefits of the Mediterranean-style diet consumption in Canada and the United States. AB - BACKGROUND: The Mediterranean-style diet (MedDiet) is an established healthy eating behavior that has consistently been shown to favorably impact cardiovascular health, thus likely improving quality of life and reducing costs associated with cardiovascular disease (CVD). Data on the economic benefits of MedDiet intakes are, however, scarce. OBJECTIVE: The objective of this study was to estimate the annual healthcare and societal cost savings that would accrue to the Canadian and American public, independently, as a result of a reduction in the incidence of CVD following adherence to a MedDiet. DESIGN: A variation in cost-of-illness analysis entailing three stages of estimations was developed to 1) identify the proportion of individuals who are likely to adopt a MedDiet in North America, 2) assess the impact of the MedDiet intake on CVD incidence reduction, and 3) impute the potential savings in costs associated with healthcare and productivity following the estimated CVD reduction. To account for the uncertainty factor, a sensitivity analysis of four scenarios, including ideal, optimistic, pessimistic, and very-pessimistic assumptions, was implemented within each of these stages. RESULTS: Significant improvements in CVD-related costs were evident with varying MedDiet adoption and CVD reduction rates. Specifically, CAD $41.9 million to 2.5 billion in Canada and US $1.0-62.8 billion in the United States were estimated to accrue as total annual savings in economic costs, given the 'very-pessimistic' through 'ideal' scenarios. CONCLUSIONS: Closer adherence to dietary behaviors that are consistent with the principles of the MedDiet is expected to contribute to a reduction in the monetary burdens of CVD in Canada, the United States, and possibly other parts of the world. PMID- 26111966 TI - Indicators of dietary patterns in Danish infants at 9 months of age. AB - BACKGROUND: It is important to increase the awareness of indicators associated with adverse infant dietary patterns to be able to prevent or to improve dietary patterns early on. OBJECTIVE: The aim of this study was to investigate the association between a wide range of possible family and child indicators and adherence to dietary patterns for infants aged 9 months. DESIGN: The two dietary patterns 'Family Food' and 'Health-Conscious Food' were displayed by principal component analysis, and associations with possible indicators were analysed by multiple linear regressions in a pooled sample (n=374) of two comparable observational cohorts, SKOT I and SKOT II. These cohorts comprised infants with mainly non-obese mothers versus infants with obese mothers, respectively. RESULTS: A lower Family Food score indicates a higher intake of liquid baby food, as this pattern shows transition from baby food towards the family's food. Infants, who were younger at diet registration and had higher body mass index (BMI) z-scores at 9 months, had lower Family Food pattern scores. A lower Family Food pattern score was also observed for infants with immigrant/descendant parents, parents who shared cooking responsibilities and fathers in the labour market compared to being a student, A lower Health-Conscious Food pattern score indicates a less healthy diet. A lower infant Health-Conscious Food pattern score was associated with a higher maternal BMI, a greater number of children in the household, a higher BMI z-score at 9 months, and a higher infant age at diet registration. CONCLUSIONS: Associations between infant dietary patterns and maternal, paternal, household, and child characteristics were identified. This may improve the possibility of identifying infants with an increased risk of developing unfavourable dietary patterns and potentially enable an early targeted preventive support. PMID- 26111967 TI - Treatment Time or Convection Volume in HDF: What Drives the Reduced Mortality Risk? AB - BACKGROUND/AIMS: Treatment time is associated with survival in hemodialysis (HD) patients and with convection volume in hemodiafiltration (HDF) patients. High volume HDF is associated with improved survival. Therefore, we investigated whether this survival benefit is explained by treatment time. METHODS: Participants were subdivided into four groups: HD and tertiles of convection volume in HDF. Three Cox regression models were fitted to calculate hazard ratios (HRs) for mortality of HDF subgroups versus HD: (1) crude, (2) adjusted for confounders, (3) model 2 plus mean treatment time. As the only difference between the latter models is treatment time, any change in HRs is due to this variable. RESULTS: 114/700 analyzed individuals were treated with high-volume HDF. HRs of high-volume HDF are 0.61, 0.62 and 0.64 in the three models, respectively (p values <0.05). Confidence intervals of models 2 and 3 overlap. CONCLUSION: The survival benefit of high-volume HDF over HD is independent of treatment time. PMID- 26111968 TI - Protective efficacy of two novel DNA vaccines expressing Toxoplasma gondii rhomboid 4 and rhomboid 5 proteins against acute and chronic toxoplasmosis in mice. AB - OBJECTIVES: To evaluate the protective efficacy of two novel DNA vaccines expressing Toxoplasma gondii rhomboid 4 (ROM4) and rhomboid 5 (ROM5) proteins against acute and chronic toxoplasmosis. METHODS: DNA vaccines (pVAX-TgROM5 and pVAX-TgROM4) were constructed and their immunogenicity evaluated in Kunming mice. RESULTS: Mice vaccinated with pVAX-TgROM5 or pVAX-TgROM4 elicited strong Th1-type humoral and cellular responses, with higher level of IgG antibody titers (the predominance of IgG2a production), and increased levels of CD4(+) and CD8(+) T cells and cytokines IFN-gamma, IL-2, IL-12 (p70) and IL-23. Mice vaccinated with pVAX-TgROM5 (11 days) showed a significantly longer survival time compared with controls (8 days) (p < 0.05) after lethal challenge. Brain cyst numbers of mice vaccinated with pVAX-TgROM5 and pVAX-TgROM4 reduced significantly (p < 0.05) (72.04 and 44.08%, respectively) compared with control groups after chronic challenge. CONCLUSION: The pVAX-TgROM5 showed a better protective efficacy against acute and chronic toxoplasmosis compared to pVAX-TgROM4. PMID- 26111969 TI - MiR-19a regulates PTEN expression to mediate glycogen synthesis in hepatocytes. AB - MiR-19a, a member of mir-17-92 microRNA clusters, has been demonstrated to promote cell proliferation and angiogenesis via regulating the PI3K/AKT pathway, the major insulin signaling pathway. However, whether miR-19a plays an important role in glycogen synthesis in hepatocytes remains unknown. Here, we define the impact of miR-19a on glycogen synthesis and IL-6-induced reduced glycogenesis in hepatocytes and its underlying mechanisms. Our studies indicate that miR-19a was down-regulated in the livers of db/db mice and mice injected with IL-6, as well as mouse NCTC 1469 hepatocytes and HEP 1-6 hepatocytes treated by IL-6. We found that over-expression of miR-19a in NCTC 1469 cells and HEP 1-6 cells led to increased activation of the AKT/GSK pathway and synthesis of glycogen, whereas down-regulation of miR-19a impaired AKT/GSK phosphorylation and glycogenesis. Over-expression of miR-19a ameliorated IL-6-induced reduced glycogen synthesis in hepatocytes. Moreover, we identified PTEN as the target of miR-19a by a luciferase assay. Down-regulation of PTEN rescued the effects of miR-19a suppression on the activation of the AKT/GSK pathway and improved glycogenesis in NTC 1469 cells. These findings show for the first time that miR-19a might activate the AKT/GSK pathway and glycogenesis via down-regulation of PTEN expression. PMID- 26111971 TI - Effects of Postoperative Continuous Femoral Nerve Block Analgesia with Braun Continuous Peripheral Nerve Block Catheter Set versus Novel Needle-Over-Cannula after Total Knee Arthroplasty. AB - BACKGROUND: The aim of this study was to compare the novel needle-over-cannula vs. the Braun continuous peripheral nerve block catheter set (Contiplex A) in postoperative analgesics after total knee arthroplasty (TKA). MATERIAL AND METHODS: Sixty patients undergoing total knee arthroplasty were randomly assigned to Braun continuous peripheral nerve block catheter set group (Braun Group, n=30) or the novel needle-over-cannula group (Cannula Group, n=30). All the patients in the 2 groups received continuous femoral nerve block (CFNB) for postoperative analgesics. RESULTS: We found no significant difference in analgesic effect between the 2 groups. The time of catheter or cannula insertion was shorter in the Cannula Group than in the Braun Group. Four (13.32%) out of 30 patients had failed catheter insertions in the Braun Group compared to none in the Cannula Group. Twelve (46%) out of 26 patients in the Braun Group had serious local anesthetic leakage at puncture sites during 12 h compared to none in the Cannula Group. CONCLUSIONS: The novel needle-over-cannula is effective, convenient, and safe in CFNB after TKA. PMID- 26111970 TI - Epidemiological Paradox or Immigrant Vulnerability? Obesity Among Young Children of Immigrants. AB - According to the "immigrant epidemiological paradox," immigrants and their children enjoy health advantages over their U.S.-born peers--advantages that diminish with greater acculturation. We investigated child obesity as a potentially significant deviation from this paradox for second-generation immigrant children. We evaluated two alternate measures of mother's acculturation: age at arrival in the United States and English language proficiency. To obtain sufficient numbers of second-generation immigrant children, we pooled samples across two related, nationally representative surveys. Each included measured (not parent-reported) height and weight of kindergartners. We also estimated models that alternately included and excluded mother's pre-pregnancy weight status as a predictor. Our findings are opposite to those predicted by the immigrant epidemiological paradox: children of U.S.-born mothers were less likely to be obese than otherwise similar children of foreign born mothers; and the children of the least-acculturated immigrant mothers, as measured by low English language proficiency, were the most likely to be obese. Foreign-born mothers had lower (healthier) pre-pregnancy weight than U.S.-born mothers, and this was protective against their second-generation children's obesity. This protection, however, was not sufficiently strong to outweigh factors associated or correlated with the mothers' linguistic isolation and marginal status as immigrants. PMID- 26111972 TI - Characterization of tailless functions during Drosophila optic lobe formation. AB - Brain development goes through phases of proliferative growth and differentiation to ensure the formation of correct number and variety of neurons. How and when naive neuroepithelial cells decide to enter a differentiation pathway remains poorly understood. In the Drosophila visual system, four optic ganglia emerge from neuroepithelia of the inner (IPC) and outer (OPC) proliferation centers. Here we demonstrate that the orphan nuclear receptor Tailless (Tll) is a key factor for the development of all optic ganglia. We describe tll expression during larval optic lobe development in unprecedented detail and find a spatiotemporally dynamic pattern. In the larval OPC, symmetrically dividing neuroepithelial cells transform into asymmetrically dividing medulla neuroblast and into lamina precursor cells in a precisely regulated fashion. Using genetic manipulations we found that tll is required for proper neuroepithelium morphology and neuroepithelial cell survival. We show that tll regulates the precise timing of the transition from neuroepithelial cells to medulla neuroblasts. In particular, however, we demonstrate that tll has a crucial role for the specification of lamina precursor cells. We propose that the Tll/Tlx transcription factors have an evolutionary conserved role in regulating neural precursor cell states in the Drosophila optic lobe and in the mammalian retina. PMID- 26111973 TI - Myocardial Function by Two-Dimensional Speckle Tracking Echocardiography and Activin A May Predict Mortality in Patients with Carcinoid Intestinal Disease. AB - OBJECTIVES: Myocardial fibrosis causes deterioration of myocardial function in carcinoid intestinal disease (CID). We assessed the ability of myocardial function and various biomarkers to predict mortality in patients with CID. METHODS: A total of 71 patients with small intestinal carcinoid tumours were included, and underwent echocardiography at baseline. Systolic function was assessed by two-dimensional speckle tracking echocardiography as left ventricular (LV) and right ventricular (RV) strain, and as mitral annular displacement (MAD), by tissue Doppler imaging. Parameters of diastolic function, the amount of liver metastases, and various biomarkers were also analysed. RESULTS: During 1,274 +/- 368 days of follow-up, 18 patients (25%) died. Of the 53 survivors, 46 patients (87%) were available for follow-up echocardiography. Baseline LV strain and MAD was reduced in those who died compared to those who survived (p < 0.001). Baseline plasma levels of activin A were markedly higher in patients who died during follow-up than those who survived (p = 0.001). In multivariate Cox hazard models (A, B, C and D), LV strain, age, the amount of liver metastases, MAD, and activin A were independent predictors of mortality. CONCLUSION: Assessment of myocardial function by echocardiography, and the biomarker activin A, can be very useful in the risk stratification of patients with CID. (c) 2015 S. Karger AG, Basel. PMID- 26111974 TI - Anti-atherosclerotic effects of the glucagon-like peptide-1 (GLP-1) based therapies in patients with type 2 Diabetes Mellitus: A meta-analysis. AB - This study assessed the effect of GLP-1 based therapies on atherosclerotic markers in type 2 diabetes patients. 31 studies were selected to obtain data after multiple database searches and following inclusion and exclusion criteria. Age and BMI of the participants of longitudinal studies were 59.8 +/- 8.3 years and 29.2 +/- 5.7 kg/m(2) (Mean+/-SD). Average duration of GLP-1 based therapies was 20.5 weeks. Percent flow-mediated diameter (%FMD) did not change from baseline significantly but when compared to controls, %FMD increased non significantly following GLP-1-based therapies (1.65 [-0.89, 4.18]; P = 0.2; REM) in longitudinal studies and increased significantly in cross sectional studies (2.58 [1.68, 3.53]; P < 0.00001). Intima media thickness decreased statistically non-significantly by the GLP-1 based therapies. GLP-1 based therapies led to statistically significant reductions in the serum levels of brain natriuretic peptide (-40.16 [-51.50, -28.81]; P < 0.0001; REM), high sensitivity c-reactive protein (-0.27 [-0.48, -0.07]; P = 0.009), plasminogen activator inhibitor-1 ( 12.90 [-25.98, 0.18]; P=0.05), total cholesterol (-5.47 [-9.55, -1.39]; P = 0.009), LDL-cholesterol (-3.70 [-7.39, -0.00]; P = 0.05) and triglycerides ( 16.44 [-25.64, -7.23]; P = 0.0005) when mean differences with 95% CI in the changes from baselines were meta-analyzed. In conclusion, GLP-1-based therapies appear to provide beneficial effects against atherosclerosis. More randomized data will be required to arrive at conclusive evidence. PMID- 26111975 TI - Correlation of histopathologic features of ductal carcinoma in situ of the breast with the oncotype DX DCIS score. AB - The Oncotype DX Breast Cancer Assay for ductal carcinoma in situ is used to determine local recurrence risk in patients with ductal carcinoma in situ. The results help select patients with low-risk ductal carcinoma in situ who could forgo radiation therapy after conservative surgery. The genes assessed include five proliferation genes, progesterone receptor (PR), and GSTM-1. Our objective was to determine if PR, mitotic counting, or any other pathologic feature of ductal carcinoma in situ could predict the Oncotype DX DCIS Score. We identified 46 cases of ductal carcinoma in situ with a Oncotype DX DCIS Score. In addition to information obtained from routine pathology, we counted mitotic figures in the ductal carcinoma in situ and noted presence of dense chronic inflammatory infiltrate surrounding ductal carcinoma in situ. We found that PR >= 90% (P = 0.004), mitotic count <= 1 (P = 0.045), estrogen receptor >= 90% (P = 0.046), and low nuclear grade (P < 0.0001) were associated with a low score. Dense chronic inflammation surrounding ductal carcinoma in situ was associated with a high score (P = 0.034).All 13 cases with PR >= 90%, <= 1 mitotic figure and absence of dense chronic inflammation around ductal carcinoma in situ had a low score (100% specificity). A low score was not observed in any case with at least two of the following--negative PR, >1 mitotic figure, and/or presence of dense chronic inflammation around ductal carcinoma in situ (100% specificity). Our study suggests using a combination of PR (>= 90% vs negative) with mitotic count in ductal carcinoma in situ (<= 1 vs >1) and dense chronic inflammation around ductal carcinoma in situ one could predict the Oncotype DX DCIS score. Mitotic counting and evaluation of immune response might provide prognostic information in ductal carcinoma in situ. PMID- 26111976 TI - Intratumoral morphologic and molecular heterogeneity of rhabdoid renal cell carcinoma: challenges for personalized therapy. AB - Rhabdoid histology in clear-cell renal cell carcinoma is associated with a poor prognosis. The prognosis of patients with clear-cell renal cell carcinoma may also be influenced by molecular alterations. The aim of this study was to evaluate the association between histologic features and salient molecular changes in rhabdoid clear-cell renal cell carcinoma. We macrodissected the rhabdoid and clear-cell epithelioid components from 12 cases of rhabdoid clear cell renal cell carcinoma. We assessed cancer-related mutations from eight cases using a clinical next-generation exome-sequencing platform. The transcriptome of rhabdoid clear-cell renal cell carcinoma (n=8) and non-rhabdoid clear-cell renal cell carcinoma (n=37) was assessed by RNA-seq and gene expression microarray. VHL (63%) showed identical mutations in all regions from the same tumor. BAP1 (38%) and PBRM1 (13%) mutations were identified in the rhabdoid but not in the epithelioid component and were mutually exclusive in 3/3 cases and 1 case, respectively. SETD2 (63%) mutations were discordant between different histologic regions in 2/5 cases, with mutations called only in the epithelioid and rhabdoid components, respectively. The transcriptome of rhabdoid clear-cell renal cell carcinoma was distinct from advanced-stage and high-grade clear-cell renal cell carcinoma. The diverse histologic components of rhabdoid clear-cell renal cell carcinoma, however, showed a similar transcriptomic program, including a similar prognostic gene expression signature. Rhabdoid clear-cell renal cell carcinoma is transcriptomically distinct and shows a high rate of SETD2 and BAP1 mutations and a low rate of PBRM1 mutations. Driver mutations in clear-cell renal cell carcinoma are often discordant across different morphologic regions, whereas the gene expression program is relatively stable. Molecular profiling of clear-cell renal cell carcinoma may improve by assessing for gene expression and sampling tumor foci from different histologic regions. PMID- 26111977 TI - Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases. AB - Intraductal tubulopapillary neoplasm is a well-established entity in the pancreas. A similar, if not identical, tumor occurs also in the biliary tract. We conducted a multicenter study of 20 such lesions, focusing on their clinicopathologic characteristics and molecular profile. Biliary intraductal tubulopapillary neoplasms were seen in patients in their 60s (mean 62 years). The tumors were intrahepatic 70%, extrahepatic 10%, and perihilar 20%; mean tumor size was 6.9 cm. Histologically, all intraductal tubulopapillary neoplasms showed, in addition to their typical tubular pattern, solid areas (70%) or abortive papillae (50%). Necrosis was common (85%), predominantly focal (40%), and with 'comedocarcinoma-like pattern' in 40%. Immunohistochemically, these neoplasms were characterized by the expression of MUC1 (80%) and MUC6 (30%) and by the absence of MUC2 and MUC5AC. Associated invasive carcinomas were present in 16 (80%), mainly conventional tubular adenocarcinoma (50%). The molecular alterations observed included CDKN2A/p16 (intraductal components 44%, invasive 33%) and TP53 (intraductal components 17%, invasive 9%). Mutations in KRAS (intraductal 6%, invasive 0%), PIK3CA (intraductal 6%, invasive 0%), and loss of SMAD4/DPC4 (intraductal 7%, invasive 0%) were rare. No alterations/mutations were identified in IDH1/2, BRAF, GNAS, EGFR, HER2, and beta-catenin. Follow-up information was available for 17 patients (85%) with mean follow-up 44 months. Overall combined survival rates showed favorable prognosis: 1 year 100%, 3 years 90%, and 5 years 90%. In conclusion, despite the relatively high incidence of invasive carcinoma (80%), available follow-up suggests that biliary intraductal tubulopapillary neoplasms have an indolent behavior. Molecular analyses highlight the low prevalence of alterations of common oncogenic signaling pathways in intraductal tubulopapillary neoplasm. Further studies using whole-exome sequencing are required to discover yet unknown molecular changes and to understand the carcinogenesis of intraductal tubulopapillary neoplasms. PMID- 26111979 TI - Li[Li0.2Ni 0.16Mn 0.56Co 0.08]O 2 Nanoparticle/Carbon Composite Using Polydopamine Binding Agent for Enhanced Electrochemical Performance. AB - Li[Li0.2Ni0.16Mn0.56Co0.08]O2 nanoparticles were composited with carbon (Super P) in order to achieve an enhanced rate capability. A polydopamine pre-coating layer was introduced to facilitate the adhesion between Super P and pristine nanoparticles. The Super P particles were dispersed on the surface of Li[Li0.2Ni0.16Mn0.56Co0.08]O2 powders. The composite samples that were heat treated in a N2 atmosphere showed increased capacity and enhanced rate capability, which was caused by the improved electronic conductivity owing to the presence of carbon. However, the composite samples that were heat-treated in air did not present these carbon-related effects clearly. The capacity changes observed during the first several cycles may be due to the oxygen deficiency of the structure caused by the heat-treatment process. PMID- 26111980 TI - Stability of peptide drugs in the colon. AB - This study was the first to investigate the colonic stability of 17 peptide molecules (insulin, calcitonin, glucagon, secretin, somatostatin, desmopressin, oxytocin, Arg-vasopressin, octreotide, ciclosporin, leuprolide, nafarelin, buserelin, histrelin, [D-Ser(4)]-gonadorelin, deslorelin, and goserelin) in a model of the large intestine using mixed human faecal bacteria. Of these, the larger peptides - insulin, calcitonin, somatostatin, glucagon and secretin - were metabolized rapidly, with complete degradation observed within 5 min. In contrast, a number of the smaller peptides - Arg-vasopressin, desmopressin, oxytocin, gonadorelin, goserelin, buserelin, leuprolide, nafarelin and deslorelin - degraded more slowly, while octreotide, histrelin and ciclosporin were seen to be more stable as compared to the other small peptides under the same conditions. Peptide degradation rate was directly correlated to peptide lipophilicity (logP); those peptides with a higher logP were more stable in the colonic model (R(2)=0.94). In the absence of human faecal bacteria, all peptides were stable. This study highlights the impact of the colonic environment - in particular, the gut microbiota - on the metabolism of peptide drugs, and identifies potential peptide candidates for drug delivery to the colon. PMID- 26111978 TI - Evaluation of NF-kappaB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions. AB - Nuclear factor-kappaB (NF-kappaB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-kappaB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n=533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-kappaB subunits. Expression of p50, p52, p65, RELB, and c Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-kappaB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free survival (PFS) (P=0.0170), singular expression of the remaining NF-kappaB subunits alone did not show significant prognostic impact in the overall DLBCL cohort. Expression of p52/RELB was associated with better overall survival (OS) and PFS (P=0.0307 and P=0.0247). When cases were stratified into GCB- and ABC-DLBCL, p52 or p52/RELB dimer expression status was associated with better OS and PFS (P=0.0134 and P=0.0124) only within the GCB subtype. However, multivariate analysis did not show p52 expression to be an independent prognostic factor. Beneficial effect of p52 in GCB-DLBC appears to be its positive correlation with CD30 and negative correlation with BCL2 expression. Gene expression profiling (GEP) showed that p52(+) GCB-DLBCL was distinct from p52(-) GCB-DLBCL. Collectively, our data suggest that DLBCL patients with p52 expression might not benefit from therapy targeting the NF-kappaB pathway. PMID- 26111981 TI - Drug resistance mutations 18 months after discontinuation of nevirapine-based ART for prevention of mother-to-child transmission of HIV in Malawi. AB - OBJECTIVES: The objective of this study was to determine the prevalence of drug resistance mutations among HIV-positive women in Malawi 18 months after discontinuing nevirapine-based ART for the prevention of mother-to-child transmission. PATIENTS AND METHODS: HIV-infected antiretroviral-naive (except for single-dose nevirapine) pregnant Malawian women receiving a nevirapine-based triple antiretroviral regimen from Week 25 of gestation until 6 months of breastfeeding were included in this analysis. Drug resistance was assessed in HIV DNA 24 months post-partum and at baseline (before the initiation of treatment). In patients with resistance, the presence of mutations was also evaluated in the corresponding plasma samples. RESULTS: Seven out of 42 (16.7%) women studied had archived drug resistance at Month 24 [six cases had NNRTI-associated mutations and two cases the M184I mutation]. In four cases, resistance mutations were already present at baseline (all NNRTI mutations). In three cases, there was an emergence of 'new' resistance (also present in the plasma in one case). Of the 35 women without resistance mutations at Month 24, only one subject had resistance mutations at baseline. Baseline resistance was significantly more common among women with mutations at 24 months compared with those harbouring a WT virus (4/7 versus 1/35, P < 0.001). CONCLUSIONS: Among women who had discontinued drugs 6 months post-partum, only 3/42 (7.1%) had accumulated new resistance mutations in HIV-DNA 2 years after delivery. These findings are reassuring in terms of the safety of the Option B strategy for the prevention of HIV mother-to-child transmission. PMID- 26111982 TI - Treatment of a ruptured aneurysm involved in a double origin of the posterior inferior cerebellar artery. AB - Double origin of the posterior inferior cerebellar artery (DOPICA) is a rare anatomical variation, and can be associated with intracranial aneurysm formation. We describe a 66-year-old woman case of a ruptured aneurysm involved in a DOPICA. We performed aneurysmal coil embolization for the ruptured aneurysm involved in the cranial channel of DOPICA, but the aneurysm relapsed two months later. We subsequently performed internal trapping of the cranial channel because of well visualization of the distal flow by the balloon occlusion test. Endovascular trapping of a channel is one of the effective treatments of an aneurysm involved in DOPICA. PMID- 26111983 TI - Endovascular treatment of pulsatile tinnitus associated with transverse sigmoid sinus aneurysms and jugular bulb anomalies. AB - Pulsatile tinnitus of vascular origin may arise in arterial or venous structures. Many authors have reported the association of pulsatile tinnitus with anomalies of dural venous sinuses and the jugular bulb. In such circumstances, mainly concomitantly with disabling tinnitus, endovascular treatment has been successfully employed. We describe here a new case of jugular bulb diverticulum associated with transverse sigmoid sinus stenosis, in a patient presenting with disabling pulsatile tinnitus. She was treated with dural sinus stenting and selective embolization of the diverticulum. In addition, we performed a literature review aiming to identify possible risk factors for developing the symptoms, as well as the safety and results of endovascular treatment. PMID- 26111984 TI - Radiculo-pial spinal arteriovenous fistulas treated with coils: Report of two cases. AB - Spinal pial arteriovenous fistulas (SPAVFs) are rare lesions that present more frequently in young patients. Lesions located on radiculo-pial arteries without involvement of the anterior spinal artery are even rarer. SPAVFs may present with mass effect, venous congestion or hemorrhage. Most often, treatment is performed either by surgery or endovascularly with fluid embolic material. Use of microcoils has not been reported for this condition.We present two cases of radiculo-pial high-flow SPAVFs in two patients in their early 30 s. One patient presented with abrupt headache without proof of hemorrhage and the other one with trigeminal neuralgia resulting from dilated posterior fossa draining veins remote from the fistula. Both patients were successfully treated with endovascular shunt closure using microcoils with resolution of symptoms and disappearance of the dilated veins at follow-up.With recent advances in microcatheter technology, distal navigation and microcoil embolization offers another option for these cases that may be safer than fluid embolic material. PMID- 26111985 TI - Flat-detector computed tomography evaluation in an experimental animal aneurysm model after endovascular treatment: A pilot study. AB - We compared flat-detector computed tomography angiography (FD-CTA) to multislice computed tomography (MS-CTA) and digital subtracted angiography (DSA) for the visualization of experimental aneurysms treated with stents, coils or a combination of both.In 20 rabbits, aneurysms were created using the rabbit elastase aneurysm model. Seven aneurysms were treated with coils, seven with coils and stents, and six with self-expandable stents alone. Imaging was performed by DSA, MS-CTA and FD-CTA immediately after treatment. Multiplanar reconstruction (MPR) was performed and two experienced reviewers compared aneurysm/coil package size, aneurysm occlusion, stent diameters and artifacts for each modality.In aneurysms treated with stents alone, the visualization of the aneurysms was identical in all three imaging modalities. Residual aneurysm perfusion was present in two cases and visible in DSA and FD-CTA but not in MS CTA. The diameter of coil-packages was overestimated in MS-CT by 56% and only by 16% in FD-CTA compared to DSA (p < 0.05). The diameter of stents was identical for DSA and FD-CTA and was significantly overestimated in MS-CTA (p < 0.05). Beam/metal hardening artifacts impaired image quality more severely in MS-CTA compared to FD-CTA.MS-CTA is impaired by blooming and beam/metal hardening artifacts in the visualization of implanted devices. There was no significant difference between measurements made with noninvasive FD-CTA compared to gold standard of DSA after stenting and after coiling/stent-assisted coiling of aneurysms. FD-CTA may be considered as a non-invasive alternative to the gold standard 2D DSA in selected patients that require follow up imaging after stenting. PMID- 26111986 TI - Endovascular treatment of posterior communicating artery aneurysms in the presence of the fetal variant of posterior cerebral artery. AB - Posterior communicating artery (PcomA) aneurysms in the presence of the fetal variant of posterior cerebral artery (PCA) often pose technical challenges for endovascular treatment because of a greater potential for ischemic injury with the fetal PCA compromise. The purpose of this study was to assess the feasibility and results of endovascular treatment for these lesions. We retrospectively reviewed our experience and results of endovascular treatments for a series of nine consecutive patients with PcomA aneurysms occurring at the origin of fetal PCAs at the Department of Neurosurgery of Southwest Hospital, Chongqing, China, between June 2011 and June 2014. Depending on the angiographic findings, location and shape of the aneurysms, various therapeutic strategies were used including coiling by single or double microcatheter, balloon remodeling technique, and single or Y-stenting technique. Overall, fetal PCA was preserved patent in all cases, and complete or near complete occlusion was achieved in 8/9 cases. There was no procedure-related morbidity or mortality. With the exception of one patient who died of pneumonia 6 weeks after treatment, no clinical evidence of neurologic deterioration and hemorrhagic complication was seen during the follow up period in the remaining 8 patients. Our experience suggests that endovascular treatment is relatively safe and technically feasible in most patients with PcomA aneurysms in the presence of fetal PCA using multiple strategies. PMID- 26111987 TI - Endovascular treatment of bifurcation intracranial aneurysms with the WEB SL/SLS: 6-month clinical and angiographic results. AB - BACKGROUND: The WEB device is a recent intrasaccular flow disruption technique developed for the treatment of wide-necked intracranial aneurysms. To date, a single report on the WEB Single-Layer (SL) treatment of intracranial aneurysms has been published with 1-months' safety results. The aim of this study is to report our experience and 6-month clinical and angiographic follow-up of endovascular treatment of wide-neck aneurysm with the WEB SL. METHODS: Ten patients with 10 unruptured wide-necked aneurysms were prospectively enrolled in this study. Feasibility, intraoperative and postoperative complications, and outcomes were recorded. Immediate and 6-month clinical and angiographic results were evaluated. RESULTS: Failure of WEB SL placement occurred in two cases. Eight aneurysms were successfully treated using one WEB SL without additional treatment. Three middle cerebral artery, four anterior communicating artery, and one basilar artery aneurysms were treated. Average dome width was 7.5 mm (range 5.4-10.7 mm), and average neck size was 4.9 mm (range 2.6-6.5 mm). No periprocedural complication was observed, and morbi-mortality at discharge and 6 months was 0.0%. Angiographic follow-up at 6 months demonstrated complete aneurysm occlusion in 2/8 aneurysms, neck remnant in 5/8 aneurysms, and aneurysm remnant in 1/8 aneurysm. CONCLUSIONS: From this preliminary study, treatment of bifurcation intracranial aneurysms using WEB SL is feasible. WEB SL treatment seems safe at 6 months; however, the rate of neck remnants is not negligible due to compression of the WEB SL. Further technical improvements may be needed in order to ameliorate the occlusion in the WEB SL treatment. PMID- 26111988 TI - Visible light promoted hydration of alkynes catalyzed by rhodium(III) porphyrins. AB - Visible light promoted hydration of a wide scope of alkynes to ketones catalyzed by rhodium(III) porphyrin complexes was described. The key intermediate beta carbonyl alkyl was observed and independently synthesized. The rate of photolysis is over two orders of magnitude faster than that of the thermal process. PMID- 26111989 TI - Effects of whole-body vibration training with quadriceps strengthening exercise on functioning and gait parameters in patients with medial compartment knee osteoarthritis: a randomised controlled preliminary study. AB - OBJECTIVE: To compare the effects of whole-body vibration training (WBVT) with quadriceps strengthening exercise (QSE) with QSE alone on functioning and gait parameters in patients with medial compartment knee osteoarthritis. DESIGN: Randomised controlled preliminary study. SETTING: Department of Rehabilitation Medicine, West China Hospital, Chengdu, Sichuan, People's Republic of China. SUBJECTS: Thirty-nine patients with medial compartment knee osteoarthritis. INTERVENTIONS: Participants were assigned at random to one of two groups. MAIN MEASURES: Visual analogue scale (VAS) for pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), timed up and go test (TUG), 6-minute walk distance test (6MWD), and three-dimensional gait analysis during level walking at baseline, 12 weeks and 16 weeks (follow-up). RESULTS: Compared with baseline, significant improvements in VAS, all WOMAC scales, TUG, 6MWD and all spatiotemporal parameters were seen in both the WBVT+QSE group and the QSE alone group at 12 and 16 weeks. However, the WBVT+QSE group showed greater improvements than the QSE alone group in WOMAC scales (physical function), TUG, 6MWD and cadence at 12 weeks. No differences were found between the WBVT+QSE and QSE alone groups in VAS, WOMAC scales (pain, stiffness), kinematic and kinetic gait parameters, and other spatiotemporal parameters at 12 weeks and 16 weeks. CONCLUSION: Over a 3-month period, WBVT in combination with QSE improved symptoms, physical function and spatiotemporal parameters in patients with medial compartment knee osteoarthritis, and led to greater improvement than QSE alone in WOMAC scales (physical function), TUG, 6MWD and cadence. PMID- 26111990 TI - Photodynamic Antimicrobial Chemotherapy (PACT) in osteomyelitis induced by Staphylococcus aureus: Microbiological and histological study. AB - Osteomyelitis is an inflammation either of medullar spaces or of the surface of cortical bones, which represents a bacterial infection. Photodynamic Antimicrobial Chemotherapy (PACT) is a treatment based on a cytotoxic photochemical reaction that induces a series of metabolic reactions and culminates in bacterial suppression. Such effect led to the idea that it could be used as a treatment of osteomyelitis. Following approval by the Animal Experimentation Committee of the School of Dentistry of the Federal University of Bahia, the present randomized study used eighty Wistar rats with the aim to evaluate, by microbiological and histological analysis, the effects of Photodynamic Antimicrobial Chemotherapy - PACT on tibial surgical bone defects in rats infected by Staphylococcus aureus. The animals were divided in groups: Control (non-infected); Control Osteomyelitis Induction; Saline solution; Photosensitizer; Red Laser and PACT - on this group, a diode laser (40mW; lambda660nm ?=0.04cm(2), CW, 10J/cm(2)) was used in combination with 5MUg/ml of toluidine blue as the photosensitizer. On the microbiological study, immediately after treatment, the PACT group presented a bacterial reduction of 97.4% (p<0.001). Thirty days after treatment, there was a bacterial reduction of more than 99.9% (p<0.001). In the histological study, it was observed that the PACT group demonstrated an intense presence of osteocytes and absence of bone sequestration and micro-abscesses. The PACT using toluidine blue was effective in reducing the number of S. aureus enabling a better quality bone repair. PMID- 26111991 TI - Fluorescence kinetics of Trp-Trp dipeptide and its derivatives in water via ultrafast fluorescence spectroscopy. AB - Ultrafast fluorescence dynamics of Tryptophan-Tryptophan (Trp-Trp/Trp2) dipeptide and its derivatives in water have been investigated using a picosecond resolved time correlated single photon counting (TCSPC) apparatus together with a femtosecond resolved upconversion spectrophotofluorometer. The fluorescence decay profiles at multiple wavelengths were fitted by a global analysis technique. Nanosecond fluorescence kinetics of Trp2, N-tert-butyl carbonyl oxygen-N' aldehyde group-l-tryptophan-l-tryptophan (NBTrp2), l-tryptophan-l-tryptophan methyl ester (Trp2Me), and N-acetyl-l-tryptophan-l-tryptophan methyl ester (NATrp2Me) exhibit multi-exponential decays with the average lifetimes of 1.99, 3.04, 0.72 and 1.22ns, respectively. Due to the intramolecular interaction between two Trp residues, the "water relaxation" lifetime was observed around 4ps, and it is noticed that Trp2 and its derivatives also exhibit a new decay with a lifetime of ~100ps, while single-Trp fluorescence decay in dipeptides/proteins shows 20-30ps. The intramolecular interaction lifetime constants of Trp2, NBTrp2, Trp2Me and NATrp2Me were then calculated to be 3.64, 0.93, 11.52 and 2.40ns, respectively. Candidate mechanisms (including heterogeneity, solvent relaxation, quasi static self-quenching or ET/PT quenching) have been discussed. PMID- 26111992 TI - Synthesis and evaluation of galacto-noeurostegine and its 2-deoxy analogue as glycosidase inhibitors. AB - An epimer of the known glycosidase inhibitor noeurostegine, galacto noeurostegine, was synthesised in 21 steps from levoglucosan and found to be a potent, competitive and highly selective galactosidase inhibitor of Aspergillus oryzae beta-galactosidase. Galacto-noeurostegine was not found to be an inhibitor of green coffee bean alpha-galactosidase, yeast alpha-glucosidase and E. coli beta-galactosidase, whereas potent but non-competitive inhibition against sweet almond beta-glucosidase was established. The 2-deoxy-galacto-noeurostegine analogue was also prepared and found to be a less potent inhibitor of the same enzymes. PMID- 26111993 TI - Facile Preparation of Ultrasmall Void Metallic Nanogap from Self-Assembled Gold Silica Core-Shell Nanoparticles Monolayer via Kinetic Control. AB - A facile preparation of ultrasmall 1-2 nm void metallic nanogaps on various solid substrates is proposed by utilizing the self-assembly of a uniform gold-silica core-shell nanoparticle monolayer at interfaces and chemical etching. The ultrasmall void metallic nanogap shows key advantages such as a strong near-field enhancement and free diffusion of analytes to the gap, which are useful in molecular sensing and monitoring. PMID- 26111994 TI - US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. PMID- 26111995 TI - Functional characterizations of IPS-1 in CIK cells: Potential roles in regulating IFN-I response dependent on IRF7 but not IRF3. AB - IPS-1, as the sole adaptor of RIG-I and MDA5, plays a central role in innate antiviral immunity. In this study, we investigated potential roles of IPS-1 in innate immunity and the domain-requirement of IPS-1 for its signaling in grass carp (Ctenopharyngodon idella). Overexpression experiment showed that CiIPS-1 mediated IFN-I signal possibly dependent on CiIRF7 but not CiIRF3. Post GCRV challenge, CiIPS-1 could enhance antiviral immune responses. CARD and TM domains were crucial for antiviral function of CiIPS-1, and TRAF motif played an assistant role. PRO domain seemed as a negative regulator but was pivotal for the initiation of CiIFN-I and CiMx1. Post viral/bacterial PAMPs stimulation, CiIPS-1 mediated signaling was tightly controlled. CARD domain of CiIPS-1 could significantly elicit poly I:C/LPS/PGN-mediated signaling. PRO domain negatively regulated CiIRF7 and CiIFN-I but was indispensable for inductions of CiMx1 and CiIL-1beta. TRAF motif and TM domain regulated the signaling presumably in a cooperative fashion. Post poly I:C stimulation, TRAF motif negatively regulated CiIRF7, CiIFN-I and CiIL-1beta at a relative early time while TM domain functioned at a relative late time. TRAF motif was indispensable for the production of CiMx1, while TM domain slightly negatively regulated the expression. Post LPS and PGN stimulation, TRAF motif excited an assistant and persistent negative role on CiIFN-I, CiIRF7 and CiIL-1beta induction, but was crucial for induction of CiMx1. TM domain slightly negatively regulated LPS- and PGN-triggered signaling. Taken together, CiIPS-1 not only exerted important functions in antiviral immune response but also participated in viral/bacterial PAMPs-triggered immune response which was tightly controlled to prevent harmful effects resulting from excessive activation. This study provided novel insights into the pivotal role of IPS-1 in innate immunity. PMID- 26111996 TI - Nasal vaccination of young rainbow trout (Oncorhynchus mykiss) against infectious hematopoietic necrosis and enteric red mouth disease. AB - Determining the earliest age at which farmed fish can be successfully vaccinated is a very important question for fish farmers. Nasal vaccines are novel mucosal vaccines that prevent aquatic infectious diseases of finfish. The present study investigates the ontogeny of the olfactory organ of rainbow trout by histology and aims to establish the earliest age for vaccination against infectious hematopoietic necrosis (IHN) and enteric red mouth (ERM) disease using the nasal route. Rainbow trout (Oncorhynchus mykiss) were vaccinated intranasally (I.N) at three different ages: 1050 degrees days (DD) (group A); 450 DD (group B); and 360 DD (group C), or 70, 30 and 24 days post-hatch (dph), respectively. The mean weights of groups A, B and C were 4.69 g, 2.9 g and 2.37 g, respectively. Fish received either a live attenuated IHN virus vaccine, ERM formalin killed bacterin or saline (mock vaccinated). Fish were challenged to the corresponding live pathogen 28 days post-vaccination. IHN vaccine delivery at 360 DD resulted in 40% mortality likely due to residual virulence of the vaccine. No mortality was observed in the ERM nasal delivery groups. Following challenge, very high protection rates against IHN virus were recorded in all three age groups with survivals of 95%, 100% and 97.5% in groups A, B and C, respectively. Survival against ERM was 82.5%, 87.5% and 77.5% in groups A, B and C, respectively. Survival rates did not differ among ages for either vaccine. Our results indicate the feasibility and effectiveness of nasal vaccination as early as 360 DD and vaccination-related mortalities when a live attenuated viral vaccine was used in the youngest fish. PMID- 26111997 TI - Exploring erythropoiesis of common carp (Cyprinus carpio) using an in vitro colony assay in the presence of recombinant carp kit ligand A and erythropoietin. AB - The use of in vitro colony assays in mammals has contributed to identification of erythroid progenitor cells such as burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E) progenitors, and serves to examine functions of erythropoietic growth factors like Erythropoietin (Epo) and Kit ligand. Here, we established an in vitro colony-forming assay capable of investigating erythropoiesis in carp (Cyprinus carpio), cloned and functionally characterized recombinant homologous molecules Epo and Kit ligand A (Kitla), and identified three distinct erythroid progenitor cells in carp. Recombinant carp Epo induced the formation of CFU-E-like and BFU-E-like erythroid colonies, expressing erythroid marker genes, beta-globin, epor and gata1. Recombinant carp Kitla alone induced limited colony formation, whereas a combination of Kitla and Epo dramatically enhanced erythroid colony formation and colony cell growth, as well as stimulated the formation of thrombocytic/erythroid colonies expressing not only erythroid markers but also thrombocytic markers, cd41 and c-mpl. Utilizing this colony assay to examine the distribution of distinct erythroid progenitor cells in carp, we demonstrated that carp head and trunk kidney play a primary role in erythropoiesis, while the spleen plays a secondary. Furthermore, we showed that presumably bi-potent thrombocytic/erythroid progenitor cells localize principally in the trunk kidney. Our results indicate that teleost fish possess mechanisms of Epo- and Kitla-dependent erythropoiesis similar to those in other vertebrates, and also help to demonstrate the diversity of erythropoietic sites among vertebrates. PMID- 26111998 TI - Complement regulatory protein genes in channel catfish and their involvement in disease defense response. AB - Complement system is one of the most important defense systems of innate immunity, which plays a crucial role in disease defense responses in channel catfish. However, inappropriate and excessive complement activation could lead to potential damage to the host cells. Therefore the complement system is controlled by a set of complement regulatory proteins to allow normal defensive functions, but prevent hazardous complement activation to host tissues. In this study, we identified nine complement regulatory protein genes from the channel catfish genome. Phylogenetic and syntenic analyses were conducted to determine their orthology relationships, supporting their correct annotation and potential functional inferences. The expression profiles of the complement regulatory protein genes were determined in channel catfish healthy tissues and after infection with the two main bacterial pathogens, Edwardsiella ictaluri and Flavobacterium columnare. The vast majority of complement regulatory protein genes were significantly regulated after bacterial infections, but interestingly were generally up-regulated after E. ictaluri infection while mostly down regulated after F. columnare infection, suggesting a pathogen-specific pattern of regulation. Collectively, these findings suggested that complement regulatory protein genes may play complex roles in the host immune responses to bacterial pathogens in channel catfish. PMID- 26111999 TI - Role of Penaeus monodon hemocyte homeostasis associated protein (PmHHAP) in regulation of caspase-mediated apoptosis. AB - The viral responsive protein, PmHHAP, plays an important role in the control of hemocyte homeostasis in shrimps during viral infection. In this study, we further investigate the role of PmHHAP in the regulation of hemocyte apoptosis. RNA interference (RNAi) mediated gene silencing was used to suppress the PmHHAP expression and the change in hemocyte apoptosis was determined in the knockdown shrimp. Within circulating hemocytes, PmHHAP knockdown increased the number of annexin V-positive apoptotic cells and the combined caspase-3/-7 activity and induced the characteristic apoptotic DNA ladder. Furthermore, PmHHAP down regulation was accompanied by significantly altered expression of apoptosis related proteins including the effector caspases, PmCaspase and PmCasp. Yeast two hybrid and co-immunoprecipitation assays showed that PmHHAP binds to the p20 domain of PmCasp. Moreover, the recombinant PmHHAP protein was able to reduce the caspase activity in the actinomycin D-treated hemocyte cells and rPmCasp-treated hemocyte cells. Taken together, our data indicate that PmHHAP regulates hemocyte homeostasis by inhibits apoptotic cell death through caspase activation. PMID- 26112000 TI - To complete its replication cycle, a shrimp virus changes the population of long chain fatty acids during infection via the PI3K-Akt-mTOR-HIF1alpha pathway. AB - White spot syndrome virus (WSSV), the causative agent of white spot disease (WSD), is a serious and aggressive shrimp viral pathogen with a worldwide distribution. At the genome replication stage (12 hpi), WSSV induces a metabolic rerouting known as the invertebrate Warburg effect, which boosts the availability of energy and biosynthetic building blocks in the host cell. Here we show that unlike the lipogenesis that is seen in cancer cells that are undergoing the Warburg effect, at 12 hpi, all of the long chain fatty acids (LCFAs) were significantly decreased in the stomach cells of WSSV-infected shrimp. By means of this non-selective WSSV-induced lipolysis, the LCFAs were apparently diverted into beta-oxidation and used to replenish the TCA cycle. Conversely, at 24 hpi, when the Warburg effect had ceased, most of the LCFAs were significantly up regulated and the composition was also significantly altered. In crayfish these changes were in a direction that appeared to favor the formation of WSSV virion particles. We also found that, at 24 hpi, but not at 12 hpi, the PI3K-Akt-mTOR HIF1alpha pathway induced the expression of fatty acid synthase (FAS), an enzyme which catalyzes the conversion of acetyl-CoA into LCFAs. WSSV virion formation was impaired in the presence of the FAS inhibitor C75, although viral gene and viral DNA levels were unaffected. WSSV therefore appears to use the PI3K-Akt-mTOR pathway to induce lipid biosynthesis at 24 hpi in order to support viral morphogenesis. PMID- 26112001 TI - Relationship Between Prebiopsy Multiparametric Magnetic Resonance Imaging (MRI), Biopsy Indication, and MRI-ultrasound Fusion-targeted Prostate Biopsy Outcomes. AB - BACKGROUND: Increasing evidence supports the use of magnetic resonance imaging (MRI)-ultrasound fusion-targeted prostate biopsy (MRF-TB) to improve the detection of clinically significant prostate cancer (PCa) while limiting detection of indolent disease compared to systematic 12-core biopsy (SB). OBJECTIVE: To compare MRF-TB and SB results and investigate the relationship between biopsy outcomes and prebiopsy MRI. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of a prospectively acquired cohort of men presenting for prostate biopsy over a 26-mo period. A total of 601 of 803 consecutively eligible men were included. INTERVENTIONS: All men were offered prebiopsy MRI and assigned a maximum MRI suspicion score (mSS). Men with an MRI abnormality underwent combined MRF-TB and SB. OUTCOMES: Detection rates for all PCa and high-grade PCa (Gleason score [GS] >=7) were compared using the McNemar test. RESULTS AND LIMITATIONS: MRF-TB detected fewer GS 6 PCas (75 vs 121; p<0.001) and more GS >=7 PCas (158 vs 117; p<0.001) than SB. Higher mSS was associated with higher detection of GS >=7 PCa (p<0.001) but was not correlated with detection of GS 6 PCa. Prediction of GS >=7 disease by mSS varied according to biopsy history. Compared to SB, MRF-TB identified more GS >=7 PCas in men with no prior biopsy (88 vs 72; p=0.012), in men with a prior negative biopsy (28 vs 16; p=0.010), and in men with a prior cancer diagnosis (42 vs 29; p=0.043). MRF-TB detected fewer GS 6 PCas in men with no prior biopsy (32 vs 60; p<0.001) and men with prior cancer (30 vs 46; p=0.034). Limitations include the retrospective design and the potential for selection bias given a referral population. CONCLUSIONS: MRF-TB detects more high-grade PCas than SB while limiting detection of GS 6 PCa in men presenting for prostate biopsy. These findings suggest that prebiopsy multiparametric MRI and MRF-TB should be considered for all men undergoing prostate biopsy. In addition, mSS in conjunction with biopsy indications may ultimately help in identifying men at low risk of high-grade cancer for whom prostate biopsy may not be warranted. PATIENT SUMMARY: We examined how magnetic resonance imaging (MRI)-targeted prostate biopsy compares to traditional systematic biopsy in detecting prostate cancer among men with suspicion of prostate cancer. We found that MRI-targeted biopsy detected more high-grade cancers than systematic biopsy, and that MRI performed before biopsy can predict the risk of high-grade cancer. PMID- 26112002 TI - Establishment of NE asymmetry-targeting of membrane proteins to the inner nuclear membrane. AB - The inner nuclear membrane (INM) represents a specialized subdomain of the endoplasmic reticulum (ER). The INM houses a unique set of integral membrane proteins that perform key functions in the organization of intranuclear architecture, control of gene expression and coupling of the nucleus to the cytoskeleton. However, the molecular mechanism of membrane protein sorting from the ER to the INM has remained enigmatic. Recently, novel approaches combining visual kinetic assays and computational modeling were used to define the requirements of trafficking to the INM in human cells. These studies reveal that nuclear retention, diffusional mobility in the ER as well as the number and architecture of NPCs are major determinants of INM targeting, collectively lending support to a diffusion-retention-based mechanism. PMID- 26112003 TI - Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study. AB - BACKGROUND: The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. METHODS: A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians' confidence before and after knowing the Recurrence Score value, and physicians' perception of the assay were recorded. RESULTS: Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians' confidence improved significantly. CONCLUSION: These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies. PMID- 26112004 TI - Phase I/II Study of Weekly Oraxol for the Second-Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer. AB - BACKGROUND: Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC). METHODS: In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m(2) per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated. RESULTS: In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m(2). In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade >=3) were neutropenia and diarrhea. CONCLUSION: Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC. PMID- 26112005 TI - Menacalc, a quantitative method of metastasis assessment, as a prognostic marker for axillary node-negative breast cancer. AB - BACKGROUND: Menacalc is an immunofluorescence-based, quantitative method in which expression of the non-invasive Mena protein isoform (Mena11a) is subtracted from total Mena protein expression. Previous work has found a significant positive association between Menacalc and risk of death from breast cancer. Our goal was to determine if Menacalc could be used as an independent prognostic marker for axillary node-negative (ANN) breast cancer. METHODS: Analysis of the association of Menacalc with overall survival (death from any cause) was performed for 403 ANN tumors using Kaplan Meier survival curves and the univariate Cox proportional hazards (PH) model with the log-rank or the likelihood ratio test. Cox PH models were used to estimate hazard ratios (HRs) for the association of Menacalc with risk of death after adjustment for HER2 status and clinicopathological tumor features. RESULTS: High Menacalc was associated with increased risk of death from any cause (P=0.0199, HR (CI)=2.18 (1.19, 4.00)). A similarly elevated risk of death was found in the subset of the Menacalc cohort which did not receive hormone or chemotherapy (n=142) (P=0.0052, HR (CI)=3.80 (1.58, 9.97)). There was a trend toward increased risk of death with relatively high Menacalc in the HER2, basal and luminal molecular subtypes. CONCLUSIONS: Menacalc may serve as an independent prognostic biomarker for the ANN breast cancer patient population. PMID- 26112006 TI - Primary synovial sarcoma of the right heart involving the tricuspid valve in an elderly Chinese woman: a case report. AB - Described herein is a 51-year-old woman with abdominal discomfort who was found to have a pericardial effusion and a large mass in her right heart by computed tomography scan and who then underwent tumour resection surgery. The tumour was so extensive that it involved the right atrium, the right ventricle and the tricuspid valve, and encompassed the right coronary artery. The patient had no significant medical history, and no tumour was found at any other site. The morphology of the tumour mimicked carcinosarcoma, exhibiting mixed epithelioid and spindle elements and it was difficult to differentiate the diagnosis even by immunohistochemical stains. Then, the final diagnosis of primary biphasic synovial sarcoma of the heart was established based on the finding of SS18 rearrangement. This is a highly intriguing rare case that may represent a diagnostic pitfall, particularly regarding frozen section. The patient will receive chemotherapy, and we will pursue follow-up. PMID- 26112007 TI - Acute Hyperglycemia Impairs Vascular Function in Healthy and Cardiometabolic Diseased Subjects: Systematic Review and Meta-Analysis. AB - OBJECTIVES: Controversy exists over the effect of acute hyperglycemia on vascular function. In this systematic review, we compared the effect of acute hyperglycemia on endothelial and vascular smooth muscle functions across healthy and cardiometabolic diseased subjects. APPROACH AND RESULTS: A systematic search of MEDLINE, EMBASE, and Web of Science from inception until July 2014 identified articles evaluating endothelial or vascular smooth muscle function during acute hyperglycemia and normoglycemia. Meta-analyses compared the standardized mean difference (SMD) in endothelial and vascular smooth muscle functions between acute hyperglycemia and normoglycemia. Subgroup analyses and metaregression identified sources of heterogeneity. Thirty-nine articles (525 healthy and 540 cardiometabolic subjects) were analyzed. Endothelial function was decreased (39 studies; n=1065; SMD, -1.25; 95% confidence interval, -1.52 to -0.98; P<0.01), whereas vascular smooth muscle function was preserved (6 studies; n=144; SMD, 0.07; 95% confidence interval, -0.30 to 0.16; P=0.55) during acute hyperglycemia compared with normoglycemia. Significant heterogeneity was detected among endothelial function studies (P<0.01). A subgroup analysis revealed that endothelial function was decreased in the macrocirculation (30 studies; n=884; SMD, -1.40; 95% confidence interval, -1.68 to -1.12; P<0.01) but not in the microcirculation (9 studies; n=181; SMD, -0.63; 95% confidence interval, -1.36 to 0.11; P=0.09). Similar results were observed according to health status. Macrovascular endothelial function was inversely associated with age, blood pressure, and low-density lipoprotein cholesterol and was positively associated with the postocclusion interval of vascular assessment. CONCLUSIONS: To our knowledge, this is the first systematic review and meta-analysis of its kind. In healthy and diseased subjects, we found evidence for macrovascular but not microvascular endothelial dysfunction during acute hyperglycemia. PMID- 26112009 TI - Carotid arterial stiffness and risk of incident cerebral microbleeds in older people: the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study. AB - OBJECTIVE: Age and high blood pressure are major risk factors for cerebral microbleeds (CMBs). However, the underlying mechanisms remain unclear and arterial stiffness may be important. We investigated whether carotid arterial stiffness is associated with incidence and location of CMBs. APPROACH AND RESULTS: In the prospective, population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik study, 2512 participants aged 66 to 93 years underwent a baseline brain MRI examination and carotid ultrasound in 2002 to 2006 and returned for a repeat brain MRI in 2007 to 2011. Common carotid arterial stiffness was assessed using a standardized protocol and expressed as carotid arterial strain, distensibility coefficient, and Young elastic modulus. Modified Poisson regression was applied to relate carotid arterial stiffness parameters to CMB incidence. During a mean follow-up of 5.2 years, 463 people (18.4%) developed new CMBs, of whom 292 had CMBs restricted to lobar regions and 171 had CMBs in a deep or infratentorial region. After adjusting for age, sex, and follow-up interval, arterial stiffness measures were associated with incident CMBs (risk ratio per SD decrease in carotid arterial strain, 1.11 [95% confidence interval, 1.01-1.21]; per SD decrease in natural log-transformed distensibility coefficient, 1.14 [1.05-1.24]; and per SD increase in natural log-transformed Young elastic modulus, 1.13 [1.04-1.23]). These measures were also significantly associated with incident deep CMBs (1.18 [1.02-1.37]; 1.24 [1.08-1.42]; and 1.23 [1.07-1.42]) but not with lobar CMBs. When further adjusted for blood pressure and other baseline vascular risk factors, carotid plaque, prevalent CMBs, subcortical infarcts, and white matter hyperintensities, the associations persisted. CONCLUSIONS: Our findings support the hypothesis that localized increases in carotid arterial stiffness may contribute to the development of CMBs, especially in a deep location attributable to hypertension. PMID- 26112008 TI - Fibroblast Growth Factor 23 Is Associated With Carotid Plaque Presence and Area: The Northern Manhattan Study. AB - OBJECTIVE: Elevated fibroblast growth factor 23 (FGF23), a hormone that regulates phosphate homeostasis, has been associated with mortality, cardiovascular events, and stroke, and to arterial calcification in chronic kidney disease, but its role in atherosclerosis is unclear and population-based studies are lacking. We hypothesized that elevated FGF23 would associate with carotid plaque presence, area, and echogenicity in the race/ethnically diverse community-based Northern Manhattan Study (NOMAS) sample. APPROACH AND RESULTS: There were 1512 stroke-free NOMAS participants with FGF23 and 2-dimensional carotid ultrasound data (mean age, 68+/-9 years; 61% women; 62% Hispanic, 18% black, and 18% white). We used multivariable linear and logistic regression to evaluate FGF23, continuously and by quintiles, as a correlate of carotid plaque, plaque area (cubic root transformed), and echogenicity adjusting for sociodemographic and vascular risk factors. Participants with FGF23 levels in the top quintile were more likely to have carotid plaque (odds ratio, 1.49; 95% confidence interval, 1.02-2.19; P=0.04) and larger plaque area (beta=0.32 mm(2), 95% confidence interval, 0.10 0.53 mm(2); P=0.004) than those in the lowest quintile, adjusting for estimated glomerular filtration rate, demographics, and vascular risk factors. Linear regression models also showed that log transformed FGF23 (LnFGF23) associated with greater odds of plaque presence (odds ratio, 1.26 per LnFGF23; 95% confidence interval, 1.01-1.58; P=0.04), and plaque area (beta=0.19 mm(2) per LnFGF23; 95% confidence interval, 0.07-0.31 mm(2); P=0.002). CONCLUSIONS: Higher FGF23 associated with greater likelihood and burden of carotid atherosclerosis independent of CKD. Atherosclerosis may be a mechanism through which FGF23 increases cardiovascular events and stroke. PMID- 26112010 TI - Both MC1 and MC3 Receptors Provide Protection From Cerebral Ischemia-Reperfusion Induced Neutrophil Recruitment. AB - OBJECTIVE: Neutrophil recruitment is a key process in the pathogenesis of stroke, and may provide a valuable therapeutic target. Targeting the melanocortin (MC) receptors has previously shown to inhibit leukocyte recruitment in peripheral inflammation, however, it is not known whether treatments are effective in the unique cerebral microvascular environment. Here, we provide novel research highlighting the effects of the MC peptides on cerebral neutrophil recruitment, demonstrating important yet discrete roles for both MC1 and MC3. APPROACH AND RESULTS: Using intravital microscopy, in 2 distinct murine models of cerebral ischemia-reperfusion (I/R) injury, we have investigated MC control for neutrophil recruitment. After global I/R, pharmacological treatments suppressed pathological neutrophil recruitment. MC1 selective treatment rapidly inhibited neutrophil recruitment while a nonselective MC agonist provided protection even when coadministered with an MC3/4 antagonist, suggesting the importance of early MC1 signaling. However, by 2-hour reperfusion, MC1-mediated effects were reduced, and MC3 anti-inflammatory circuits predominated. Mice bearing a nonfunctional MC1 displayed a transient exacerbation of neutrophil recruitment after global I/R, which diminished by 2 hours. However importantly, enhanced inflammatory responses in both MC1 mutant and MC3 (-/-) mice resulted in increased infarct size and poor functional outcome after focal I/R. Furthermore, we used an in vitro model of leukocyte recruitment to demonstrate these anti-inflammatory actions are also effective in human cells. CONCLUSIONS: These studies reveal for the first time MC control for neutrophil recruitment in the unique pathophysiological context of cerebral I/R, while also demonstrating the potential therapeutic value of targeting multiple MCs in developing effective therapeutics. PMID- 26112011 TI - Foamy monocytes form early and contribute to nascent atherosclerosis in mice with hypercholesterolemia. AB - OBJECTIVE: To examine infiltration of blood foamy monocytes, containing intracellular lipid droplets, into early atherosclerotic lesions and its contribution to development of nascent atherosclerosis. APPROACH AND RESULTS: In apoE(-/-) mice fed Western high-fat diet (WD), >10% of circulating monocytes became foamy monocytes at 3 days on WD and >20% of monocytes at 1 week. Foamy monocytes also formed early in blood of Ldlr(-/-)Apobec1(-/-) (LDb) mice on WD. Based on CD11c and CD36, mouse monocytes were categorized as CD11c(-)CD36(-), CD11c(-)CD36(+), and CD11c(+)CD36(+). The majority of foamy monocytes were CD11c(+)CD36(+), whereas most nonfoamy monocytes were CD11c(-)CD36(-) or CD11c( )CD36(+) in apoE(-/-) mice on WD. In wild-type mice, CD11c(+)CD36(+) and CD11c( )CD36(+), but few CD11c(-)CD36(-), monocytes took up cholesteryl ester-rich very low-density lipoproteins (CE-VLDLs) isolated from apoE(-/-) mice on WD, and CE VLDL uptake accelerated CD11c(-)CD36(+) to CD11c(+)CD36(+) monocyte differentiation. Ablation of CD36 decreased monocyte uptake of CE-VLDLs. Intravenous injection of DiI-CE-VLDLs in apoE(-/-) mice on WD specifically labeled CD11c(+)CD36(+) foamy monocytes, which infiltrated into nascent atherosclerotic lesions and became CD11c(+) cells that were selectively localized in atherosclerotic lesions. CD11c deficiency reduced foamy monocyte infiltration into atherosclerotic lesions. Specific and consistent depletion of foamy monocytes (for 3 weeks) by daily intravenous injections of low-dose clodrosome reduced development of nascent atherosclerosis. CONCLUSIONS: Foamy monocytes, which form early in blood of mice with hypercholesterolemia, infiltrate into early atherosclerotic lesions in a CD11c-dependent manner and play crucial roles in nascent atherosclerosis development. PMID- 26112012 TI - Increased high-density lipoprotein cholesterol levels in mice with XX versus XY sex chromosomes. AB - OBJECTIVE: The molecular mechanisms underlying sex differences in dyslipidemia are poorly understood. We aimed to distinguish genetic and hormonal regulators of sex differences in plasma lipid levels. APPROACH AND RESULTS: We assessed the role of gonadal hormones and sex chromosome complement on lipid levels using the four core genotypes mouse model (XX females, XX males, XY females, and XY males). In gonadally intact mice fed a chow diet, lipid levels were influenced by both male-female gonadal sex and XX-XY chromosome complement. Gonadectomy of adult mice revealed that the male-female differences are dependent on acute effects of gonadal hormones. In both intact and gonadectomized animals, XX mice had higher HDL cholesterol (HDL-C) levels than XY mice, regardless of male-female sex. Feeding a cholesterol-enriched diet produced distinct patterns of sex differences in lipid levels compared with a chow diet, revealing the interaction of gonadal and chromosomal sex with diet. Notably, under all dietary and gonadal conditions, HDL-C levels were higher in mice with 2 X chromosomes compared with mice with an X and Y chromosome. By generating mice with XX, XY, and XXY chromosome complements, we determined that the presence of 2 X chromosomes, and not the absence of the Y chromosome, influences HDL-C concentration. CONCLUSIONS: We demonstrate that having 2 X chromosomes versus an X and Y chromosome complement drives sex differences in HDL-C. It is conceivable that increased expression of genes escaping X-inactivation in XX mice regulates downstream processes to establish sexual dimorphism in plasma lipid levels. PMID- 26112013 TI - The effects of pegylated interferon-alpha and ribavirin on liver and serum concentrations of activin-A and follistatin in normal Wistar rat: a preliminary report. AB - BACKGROUND: Activin-A and follistatin regulate the liver and the immune system. AIMS: To measure the effects of treatment with pegylated-interferon-alpha (Peg IFN-alpha) and ribavirin on the concentrations of mature activin-A and follistatin in serum and liver tissue homogenates in rats. METHODS: A total of 28 male Wistar rats were divided equally into four groups as follow: 'Control group' (n = 7), 'PEG only group' consisted of those that only received a weekly injection of Peg-IFN-alpha (6 ug/rat) for 4 weeks, 'RBV only group' received ribavirin only (4 mg/rat/day) orally for 35 days and the last group received both Peg-IFN-alpha and ribavirin 'PEG & RBV group'. The concentrations of candidate proteins in serum and liver samples were measured using ELISA. RESULTS: Pegylated interferon-alpha decreased activin-A and increased follistatin significantly in serum and liver of 'PEG only' and 'PEG & RBV' groups compared with the 'Control' and 'RBV only' groups (P < 0.05). There was no significant difference between the 'RBV only' and 'Control' groups (P > 0.05) in the concentrations of candidate proteins. A significant positive correlations between serum and liver activin-A (r = 0.727; P = 0.02 * 10(-3)) and follistatin (r = 0.540; P = 0.01) was also detected. CONCLUSION: Pegylated-interferon-alpha modulates the production of activin-A and follistatin by the liver, which is reflected and can be detected at the serum level. Further studies are needed to explore the role of Peg-IFN-alpha based therapy on the production of activins and follistatin by the liver and immune cells. PMID- 26112014 TI - Why are some people more successful at lifestyle change than others? Factors associated with successful weight loss in the BeWEL randomised controlled trial of adults at risk of colorectal cancer. AB - BACKGROUND: The BeWEL (BodyWEight and physicaL activity) randomised controlled trial demonstrated that a weight management programme offered in the colorectal cancer screening setting was effective. However, the differential responses of participants to the programme were notable. This study aimed to explore the factors associated with success and to identify implications for future programme design. METHODS: Analyses were conducted of quantitative data (n = 148) from the BeWEL intervention group to compare demographic and psychosocial characteristics and lifestyle changes in those who met and exceeded the target 7% weight loss ('super-achievers') with those who achieved only 'moderate' or 'low' amounts of weight loss (2-7% loss, or <2% loss, respectively). In-depth qualitative interviews (n = 24) explored in detail the motivations, actions, pathways to weight loss and circumstances of study participants. RESULTS: Over the 12 month intervention period, mean percentage weight loss of super-achievers (n = 33) was 11.5%, compared with moderate-achievers (n = 58) who lost 4.2%, and low-achievers (n = 57) who gained 0.8%. Compared to other groups, super- achievers increased their fruit and vegetable intake (p < 0.01) and physical activity (step count, p < 0.01). 'Super-achievers' did not differ in baseline demographic characteristics from other participants. However, significantly fewer reported that their activities were limited by physical and emotional health and they were more likely to perceive their current diet as harmful. Qualitative analyses found no consistent patterns among super-achievers in relation to some factors identified as important in previous studies, such as social support. However, super achievers shared several characteristics such as determination and consistency in their engagement with the intervention, receptivity to new information and prompts, previous positive experience of changing health behaviours, being motivated by early success, making changes routine, and an ability to devise and apply strategies for dealing with setback and 'relapse' triggers. CONCLUSIONS: Successful lifestyle change depends on active engagement as well as effective intervention ingredients. Weight loss interventions are likely to be more effective where they can adapt to participants' differing characteristics and needs, while also providing core elements likely to build success. PMID- 26112016 TI - The receptor proteins: pivotal roles in selective autophagy. AB - Autophagy is a highly regulated and multistep biological process whereby cells under metabolic, proteotoxic, or other stresses remove dysfunctional organelles and/or misfolded/polyubiquitinated proteins by shuttling them via specialized structures called autophagosomes to the lysosome for degradation. Although autophagy is generally considered to be a non-selective process, accumulating evidence suggests that it can also selectively degrade specific target cargoes. These selective targets include proteins, mitochondria, and even invading bacteria. The discovery and characterization of autophagic adapters, such as p62/Sequestosome 1 (SQSTM1) and Neighbor of BRCA1 gene 1 (NBR1), have provided mechanistic insights into selective autophagy. These receptors are all able to act as cargo receptors for the degradation of ubiquitinated substrates. This review mainly summarizes the most up-to-date findings regarding the key receptor proteins that play important roles in regulating selective autophagy. PMID- 26112015 TI - Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases. AB - BACKGROUND: To understand the contribution of Mendelian mutations to the burden of undiagnosed diseases that are suspected to be genetic in origin, we developed a next-generation sequencing-based multiplexing assay that encompasses the ~3000 known Mendelian genes. This assay, which we term the Mendeliome, comprises 13 gene panels based on clinical themes, covering the spectrum of pediatric and adult clinical genetic medicine. We explore how these panels compare with clinical whole exome sequencing (WES). RESULTS: We tested 2357 patients referred with suspected genetic diagnoses from virtually every medical specialty. A likely causal mutation was identified in 1018 patients, with an overall clinical sensitivity of 43 %, comparing favorably with WES. Furthermore, the cost of clinical-grade WES is high (typically more than 4500 US dollars), whereas the cost of running a sample on one of our panels is around 75-150 US dollars, depending on the panel. Of the "negative" cases, 11 % were subsequently found by WES to harbor a likely causal mutation in a known disease gene (largely in genes identified after the design of our assay), as inferred from a representative sample of 178. Although our study population is enriched for consanguinity, 245 (24 %) of solved cases were autosomal dominant and 35 (4 %) were X-linked, suggesting that our assay is also applicable to outbred populations. CONCLUSIONS: Despite missing a significant number of cases, the current version of the Mendeliome assay can account for a large proportion of suspected genetic disorders, and provides significant practical advantages over clinical WES. PMID- 26112017 TI - A lentiviral vector-based therapeutic vaccine encoding Ag85B-Rv3425 potently increases resistance to acute tuberculosis infection in mice. AB - Few treatment options for multidrug-resistant tuberculosis (TB) and extensively drug-resistant TB call attention to the development of novel therapeutic approaches for TB. Therapeutic vaccines are promising candidates because they can induce antigen-specific cellular immune responses, which play an important role in the elimination of Mycobacterium tuberculosis (MTB). In this study, a novel lentiviral vector therapeutic vaccine for delivering MTB-specific fusion protein Ag85B-Rv3425 was constructed. Results showed that one single-injection of this recombinant lentivirus vaccine could trigger antigen-specific Th1-type immune responses in mice. More importantly, mice with acute infection benefited a lot from a single-dose administration of this vaccine by markedly reduced MTB burdens in lungs and spleens as well as attenuated lesions in lungs compared with untreated mice. These results displayed good prospects of this novel vaccine for the immunotherapy of TB. PMID- 26112018 TI - APOL1 genetic variants, chronic kidney diseases and hypertension in mixed ancestry South Africans. AB - BACKGROUND: The frequencies of apolipoprotein L1 (APOL1) variants and their associations with chronic kidney disease (CKD) vary substantially in populations from Africa. Moreover, available studies have used very small sample sizes to provide reliable estimates of the frequencies of these variants in the general population. We determined the frequency of the two APOL1 risk alleles (G1 and G2) and investigated their association with renal traits in a relatively large sample of mixed-ancestry South Africans. APOL1 risk variants (G1: rs60910145 and rs73885319; G2: rs71785313) were genotyped in 859 African mixed ancestry individuals using allele-specific TaqMan technology. Glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. RESULTS: The frequencies of rs73885319, rs60910145 and rs71785313 risk alleles were respectively, 3.6%, 3.4%, and 5.8%, resulting in a 1.01% frequency of the APOL1 two-risk allele (G1:G1 or G1:G2 or G2:G2). The presence of the two-risk allele increased serum creatinine with a corresponding reduction in eGFR (either MDRD or CKD-EPI based). In dominant and log-additive genetic models, significant associations were found between rs71785313 and systolic blood pressure (both p <= 0.025), with a significant statistical interaction by diabetes status, p = 0.022, reflecting a negative non-significant effect in nondiabetics and a positive effect in diabetics. CONCLUSIONS: Although the APOL1 variants are not common in the mixed ancestry population of South Africa, the study does provide an indication that APOL1 variants may play a role in conferring an increased risk for renal and cardiovascular risk in this population. PMID- 26112019 TI - Non-enzymatic cyclic oxygenated metabolites of omega-3 polyunsaturated fatty acid: Bioactive drugs? AB - Non-enzymatic oxygenated metabolites derived from polyunsaturated fatty acids (PUFA) are formed in vivo through free radical reaction under oxidative stress conditions. It has been over twenty-five years since the discovery of cyclic oxygenated metabolites derived from arachidonic acid (20:4 n-6), the isoprostanes, and since then they have become biomarkers of choice for assessing in vivo OS in humans and animals. Chemical synthesis of n-3 PUFA isoprostanoids such as F3-Isoprostanes from eicosapentaenoic acid (20:5 n-3), and F4 Neuroprostanes from docosahexaenoic acid (22:6 n-6) unravelled novel and unexpected biological properties of such omega-3 non-enzymatic cyclic metabolites as highlighted in this review. PMID- 26112021 TI - Reply: Breast Cancer Staging: To Which Women Should 18F-FDG PET/CT Be Offered? PMID- 26112020 TI - 18F-Fluoromisonidazole Quantification of Hypoxia in Human Cancer Patients Using Image-Derived Blood Surrogate Tissue Reference Regions. AB - (18)F-fluoromisonidazole ((18)F-FMISO) is the most widely used PET agent for imaging hypoxia, a condition associated with resistance to tumor therapy. (18)F FMISO equilibrates in normoxic tissues but is retained under hypoxic conditions because of reduction and binding to macromolecules. A simple tissue-to-blood (TB) ratio is suitable for quantifying hypoxia. A TB ratio threshold of 1.2 or greater is useful in discriminating the hypoxic volume (HV) of tissue; TBmax is the maximum intensity of the hypoxic region and does not invoke a threshold. Because elimination of blood sampling would simplify clinical use, we tested the validity of using imaging regions as a surrogate for blood sampling. METHODS: Patients underwent 20-min (18)F-FMISO scanning during the 90- to 140-min interval after injection with venous blood sampling. Two hundred twenty-three (18)F-FMISO patient studies had detectable surrogate blood regions in the field of view. Quantitative parameters of hypoxia (TBmax, HV) derived from blood samples were compared with values using surrogate blood regions derived from the heart, aorta, or cerebellum. In a subset of brain cancer patients, parameters from blood samples and from the cerebellum were compared for their ability to independently predict outcome. RESULTS: Vascular regions of heart showed the highest correlation to measured blood activity (R(2) = 0.84). For brain studies, cerebellar activity was similarly correlated to blood samples. In brain cancer patients, Kaplan-Meier analysis showed that image-derived reference regions had predictive power nearly identical to parameters derived from blood, thus obviating the need for venous sampling in these patients. CONCLUSION: Simple static analysis of (18)F-FMISO PET captures both the intensity (TBmax) and the spatial extent (HV) of tumor hypoxia. An image-derived region to assess blood activity can be used as a surrogate for blood sampling in quantification of hypoxia. PMID- 26112022 TI - PET Imaging of Tumor-Associated Macrophages with 89Zr-Labeled High-Density Lipoprotein Nanoparticles. AB - Tumor-associated macrophages (TAMs) are increasingly investigated in cancer immunology and are considered a promising target for better and tailored treatment of malignant growth. Although TAMs also have high diagnostic and prognostic value, TAM imaging still remains largely unexplored. Here, we describe the development of reconstituted high-density lipoprotein (rHDL)-facilitated TAM PET imaging in a breast cancer model. METHODS: Radiolabeled rHDL nanoparticles incorporating the long-lived positron-emitting nuclide (89)Zr were developed using 2 different approaches. The nanoparticles were composed of phospholipids and apolipoprotein A-I (apoA-I) in a 2.5:1 weight ratio. (89)Zr was complexed with deferoxamine (also known as desferrioxamine B, desferoxamine B), conjugated either to a phospholipid or to apoA-I to generate (89)Zr-PL-HDL and (89)Zr-AI HDL, respectively. In vivo evaluation was performed in an orthotopic mouse model of breast cancer and included pharmacokinetic analysis, biodistribution studies, and PET imaging. Ex vivo histologic analysis of tumor tissues to assess regional distribution of (89)Zr radioactivity was also performed. Fluorescent analogs of the radiolabeled agents were used to determine cell-targeting specificity using flow cytometry. RESULTS: The phospholipid- and apoA-I-labeled rHDL were produced at 79% +/- 13% (n = 6) and 94% +/- 6% (n = 6) radiochemical yield, respectively, with excellent radiochemical purity (>99%). Intravenous administration of both probes resulted in high tumor radioactivity accumulation (16.5 +/- 2.8 and 8.6 +/ 1.3 percentage injected dose per gram for apoA-I- and phospholipid-labeled rHDL, respectively) at 24 h after injection. Histologic analysis showed good colocalization of radioactivity with TAM-rich areas in tumor sections. Flow cytometry revealed high specificity of rHDL for TAMs, which had the highest uptake per cell (6.8-fold higher than tumor cells for both DiO@Zr-PL-HDL and DiO@Zr-AI-HDL) and accounted for 40.7% and 39.5% of the total cellular DiO@Zr-PL HDL and DiO@Zr-AI-HDL in tumors, respectively. CONCLUSION: We have developed (89)Zr-labeled TAM imaging agents based on the natural nanoparticle rHDL. In an orthotopic mouse model of breast cancer, we have demonstrated their specificity for macrophages, a result that was corroborated by flow cytometry. Quantitative macrophage PET imaging with our (89)Zr-rHDL imaging agents could be valuable for noninvasive monitoring of TAM immunology and targeted treatment. PMID- 26112023 TI - In Vivo Cancer Dual-Targeting and Dual-Modality Imaging with Functionalized Quantum Dots. AB - Semiconductor quantum dots (QDs), after surface modification to provide water solubility and biocompatibility, have a promising future in biomedical applications. In this study, a dual receptor-targeting dual-modality PET/near infrared fluorescence (NIRF) probe was developed for accurate assessment of the pharmacokinetics and tumor-targeting efficacy of QDs. METHODS: QDs were modified by beta-Glu-RGD-BBN (RGD is arginine-glycine-aspartate acid, and BBN is bombesin) peptides and then labeled with (18)F via the 4-nitrophenyl-2-(18)F fluoropropionate prosthetic group. Cytotoxicity and cell-binding assay of QD-RGD BBN were performed with PC-3 cells. In vivo dual-modality PET/NIRF imaging of prostate tumor-bearing mice was investigated using QD-RGD-BBN and 2-(18)F fluoropropionyl-QD-RGD-BBN ((18)F-FP-QD-RGD-BBN). An in vivo biodistribution study of (18)F-FP-QD-RGD-BBN was performed on normal mice. RESULTS: QD-RGD-BBN exhibited strong red luminescence (600-800 nm) with the same maximum fluorescence wavelength (705 nm) as QD705 and slightly lower toxicity than that of QD705 in PC 3 cells at concentrations of greater than 30 MUg/mL. Uptake of QD-RGD-BBN in PC-3 cells showed no significant decrease in the presence of an excess amount of dimer arginine-glycine-aspartate acid (RGD2) or bombesin(7-14) (BBN) peptide but was blocked significantly in the presence of an excess amount of NH2-RGD-BBN. Dual function PET/NIRF imaging is able to accurately assess the biodistribution and tumor-targeting efficacy of the (18)F-labeled functionalized QDs. CONCLUSION: The functionalized QD probe has great potential as a universal dual-targeting probe for detecting tumors in living subjects, opening up a new strategy for the development of multitargeting multimodality (18)F-labeled QD probes with improved tumor-targeting efficacy. PMID- 26112024 TI - Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. AB - In prostate cancer with biochemical failure after therapy, current imaging techniques have a low detection rate at the prostate-specific antigen (PSA) levels at which targeted salvage therapy is effective. (11)C-choline and (18)F fluoromethylcholine, though widely used, have poor sensitivity at low PSA levels. (68)Ga-PSMA (Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga-N,N'-bis[2-hydroxy-5 (carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid]) has shown promising results in retrospective trials. Our aim was to prospectively compare the detection rates of (68)Ga-PSMA versus (18)F-fluoromethylcholine PET/CT in men who were initially managed with radical prostatectomy, radiation treatment, or both and were being considered for targeted therapy. METHODS: A sample of men with a rising PSA level after treatment, eligible for targeted treatment, was prospectively included. Patients on systemic treatment were excluded. (68)Ga PSMA, (18)F-fluoromethylcholine PET/CT, and diagnostic CT were performed sequentially on all patients between January and April 2015, and the images were assessed by masked, experienced interpreters. The findings and their impact on management were documented, together with the results of histologic follow-up when feasible. RESULTS: In total, 38 patients were enrolled. Of these, 34 (89%) had undergone radical prostatectomy and 4 (11%) had undergone radiation treatment. Twelve (32%) had undergone salvage radiation treatment after primary radical prostatectomy. The mean PSA level was 1.74 +/- 2.54 ng/mL. The scan results were positive in 26 patients (68%) and negative with both tracers in 12 patients (32%). Of the 26 positive scans, 14 (54%) were positive with (68)Ga-PSMA alone, 11 (42%) with both (18)F-fluoromethylcholine and (68)Ga-PSMA, and only 1 (4%) with (18)F-fluoromethylcholine alone. When PSA was below 0.5 ng/mL, the detection rate was 50% for (68)Ga-PSMA versus 12.5% for (18)F fluoromethylcholine. When PSA was 0.5-2.0 ng/mL, the detection rate was 69% for (68)Ga-PSMA versus 31% for (18)F-fluoromethylcholine, and when PSA was above 2.0, the detection rate was 86% for (68)Ga-PSMA versus 57% for (18)F fluoromethylcholine. On lesion-based analysis, (68)Ga-PSMA detected more lesions than (18)F-fluoromethylcholine (59 vs. 29, P < 0.001). The tumor-to-background ratio in positive scans was higher for (68)Ga-PSMA than for (18)F fluoromethylcholine (28.6 for (68)Ga-PSMA vs. 9.4 for (18)F-fluoromethylcholine, P < 0.001). There was a 63% (24/38 patients) management impact, with 54% (13/24 patients) being due to (68)Ga-PSMA imaging alone. Histologic follow-up was available for 9 of 38 patients (24%), and 9 of 9 (68)Ga-PSMA-positive lesions were consistent with prostate cancer ((68)Ga-PSMA was true-positive). The lesion positive on (18)F-fluoromethylcholine imaging and negative on (68)Ga-PSMA imaging was shown at biopsy to be a false-positive (18)F-fluoromethylcholine finding ((68)Ga-PSMA was true-negative). CONCLUSION: In patients with biochemical failure and a low PSA level, (68)Ga-PSMA demonstrated a significantly higher detection rate than (18)F-fluoromethylcholine and a high overall impact on management. PMID- 26112025 TI - Assessment of Traumatic Brain Injury by Increased 64Cu Uptake on 64CuCl2 PET/CT. AB - Copper is a nutritional trace element required for cell proliferation and wound repair. METHODS: To explore increased copper uptake as a biomarker for noninvasive assessment of traumatic brain injury (TBI), experimental TBI in C57BL/6 mice was induced by controlled cortical impact, and (64)Cu uptake in the injured cortex was assessed with (64)CuCl2 PET/CT. RESULTS: At 24 h after intravenous injection of the tracer, uptake was significantly higher in the injured cortex of TBI mice (1.15 +/- 0.53 percentage injected dose per gram of tissue [%ID/g]) than in the uninjured cortex of mice without TBI (0.53 +/- 0.07 %ID/g, P = 0.027) or the cortex of mice that received an intracortical injection of zymosan A (0.62 +/- 0.22 %ID/g, P = 0.025). Furthermore, uptake in the traumatized cortex of untreated TBI mice (1.15 +/- 0.53 %ID/g) did not significantly differ from that in minocycline-treated TBI mice (0.93 +/- 0.30 %ID/g, P = 0.33). CONCLUSION: Overall, the data suggest that increased (64)Cu uptake in traumatized brain tissues holds potential as a new biomarker for noninvasive assessment of TBI with (64)CuCl2 PET/CT. PMID- 26112026 TI - Repeatability of Tumor SUV Quantification: The Role of Variable Blood SUV. PMID- 26112027 TI - Progress on eliminating neglected tropical diseases is too slow, report warns. PMID- 26112028 TI - Remote Ischemic Conditioning for Preventing Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions/Coronary Angiography: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: It is uncertain whether remote ischemic conditioning (RIC) has a protective effect on contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI)/coronary artery angiography (CAG). We performed a meta-analysis of randomized controlled trials (RCTs) to assess the effect of RIC on CI-AKI in such patients. METHODS: PubMed, MEDLINE, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials databases were searched for RCTs that assessed the effect of RIC on CI-AKI in patients undergoing PCI/CAG. RESULTS: Ten RCTs with 1389 patients (RIC group, 757 and control, 632) were included. The RIC group significantly exerted a lower risk of CI-AKI compared to the controls (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.34-0.77, P = .001), and they had the similar effect on major adverse cardiovascular events within 1 year (OR = 0.36, 95% CI = 0.20-0.66, P < .001). The RIC reduced the rates of death within 30 days, but this was not significant (OR = 0.16, 95% CI = 0.02-1.34, P = .091). The RIC was associated with a significantly lower incidence of CI-AKI in patients following elective PCI/CAG (OR = 0.54, 95% CI = 0.33-0.87, P = .011). The RIC before not after the intervention was effective in reducing the occurrence of CI-AKI (OR: 0.37 vs 1.05, P = .022). The RIC of the upper arm has statistically significant effect on protecting CI-AKI but not that of the lower limb (OR: 0.41 vs 1.41, P = .004). The effect of RIC on CI-AKI was similar between patients with a mean estimated glomerular filtration rate <60 mL/min/1.73 m(2) and those with mean rates >=60 (OR: 0.23 vs 0.41, P = .333). CONCLUSION: The RIC reduced the incidence of CI-AKI in those receiving PCI/CAG. And RIC of the upper arm significantly reduced the risk of CI-AKI but not RIC of the lower limb in patients undergoing PCI/CAG. PMID- 26112030 TI - Older Adults' Perceptions of Fall Detection Devices. AB - A third of adults over the age of 65 are estimated to fall at least once a year. Perhaps as dangerous as the fall itself is the time spent after a fall if the person is unable to move. Although there are many devices available to detect when a person has fallen, little is known about the opinions of older adults regarding these fall detection devices (FDDs). We conducted five focus groups with 27 older adults. Transcripts from sessions were coded to generate themes that captured participants' perceptions. Themes were identified that related to two topics of interest: (a) personal influences on the participants' desire to have a FDD, including perceived need, participant values, and cost, and (b) participant recommendations regarding specific features and functionalities of these devices such as automation, wearable versus non-wearable devices, and device customization. Together, these themes suggest ways in which FDDs may be improved so that they are suitable for their intended population. PMID- 26112029 TI - The center for expanded data annotation and retrieval. AB - The Center for Expanded Data Annotation and Retrieval is studying the creation of comprehensive and expressive metadata for biomedical datasets to facilitate data discovery, data interpretation, and data reuse. We take advantage of emerging community-based standard templates for describing different kinds of biomedical datasets, and we investigate the use of computational techniques to help investigators to assemble templates and to fill in their values. We are creating a repository of metadata from which we plan to identify metadata patterns that will drive predictive data entry when filling in metadata templates. The metadata repository not only will capture annotations specified when experimental datasets are initially created, but also will incorporate links to the published literature, including secondary analyses and possible refinements or retractions of experimental interpretations. By working initially with the Human Immunology Project Consortium and the developers of the ImmPort data repository, we are developing and evaluating an end-to-end solution to the problems of metadata authoring and management that will generalize to other data-management environments. PMID- 26112031 TI - Initial Validity Analysis of the Emergency Medicine Milestones. AB - OBJECTIVES: The Accreditation Council for Graduate Medical Education (ACGME) Milestones describe behavioral markers for the progressive acquisition of competencies during residency. As a key component of the Next Accreditation System, all residents are evaluated for the acquisition of specialty-specific Milestones. The objective was to determine the validity and reliability of the emergency medicine (EM) Milestones. METHODS: The ACGME and the American Board of Emergency Medicine performed this single-event observational study. The data included the initial EM Milestones performance ratings of all categorical EM residents submitted to the ACGME from October 31, 2013, to January 6, 2014. Mean performance ratings were determined for all 23 subcompetencies for every year of residency training. The internal consistency (reliability) of the Milestones was determined using a standardized Cronbach's alpha coefficient. Exploratory factor analysis was conducted to determine how the subcompetencies were interrelated. RESULTS: EM Milestone performance ratings were obtained on 100% of EM residents (n = 5,805) from 162 residency programs. The mean performance ratings of the aggregate and individual subcompetency scores showed discrimination between residency years, and the factor structure further supported the validity of the EM Milestones. The reliability was alpha = 0.96 within each year of training. CONCLUSIONS: The EM Milestones demonstrated validity and reliability as an assessment instrument for competency acquisition. EM residents can be assured that this evaluation process has demonstrated validity and reliability; faculty can be confident that the Milestones are psychometrically sound; and stakeholders can know that the Milestones are a nationally standardized, objective measure of specialty-specific competency acquisition. PMID- 26112032 TI - Resilience in families in which a member has been diagnosed with schizophrenia. AB - Due to the extensive focus of the literature on the burden placed on families in which a member has been diagnosed with a mental illness such as schizophrenia, there is a need to identify factors that may help these families to be resilient and adapt to their crisis. The aim of this study was to identify family resilience qualities in families in which a member has been diagnosed with schizophrenia. The study comprised 42 families, represented by 33 parents and 9 siblings of the diagnosed family member. Families were recruited from three support groups within the Cape Metropolitan area, Western Cape, South Africa. Qualitative data were obtained through an open-ended question and quantitative data were collected with seven self-report questionnaires. The following family resilience qualities were identified: family income; finding support in their community; family togetherness; family communication style during crises; affirming and supportive communication patterns; family hardiness; commitment to the family; reframing crises as a challenge; and an internal locus of control within the family. The findings may be used by professionals and support group facilitators to enhance the resilience and functioning of families living with a member with schizophrenia. ACCESSIBLE SUMMARY: With approximately 1% of the world's population diagnosed with schizophrenia, it is clear that many families are affected when a member has been diagnosed. There is a need to identify factors that may help these families to be resilient. The aim of this study was to identify family resilience qualities in families in which a member has been diagnosed with schizophrenia. The following family resilience qualities were identified as resources that helped them to adapt to the many challenges put to them: family income, finding support in their community, the availability of hospitals, churches and professionals, family togetherness, family communication, family hardiness, commitment to the family, reframing crises as a challenge, and an internal locus of control within the family. Due to the limited studies on resilience in families in which a member has been diagnosed with schizophrenia, we suggest that the current study may contribute to this literature and provide a more comprehensive look at resilience in these families. Furthermore, the current study may contribute to knowledge about factors and resources that are associated with resilience in families in which a member has been diagnosed with schizophrenia. Finally, the findings of this study may be used in interventions to help families from different cultures and socio-economic statuses to adapt and hence be resilient. PMID- 26112033 TI - Assessing the waddle: An evaluation of a 3-point gait score system for ducks. AB - Impaired walking ability is an economically important welfare problem that affects poultry raised for meat production, including Pekin ducks. To gain a better understanding of the impacts of walking impairments on duck production, and to identify contributing variables and plausible remedies, an accurate measure of walking ability must first be defined. The viability of a 3-point gait score system for characterizing the walking abilities of Pekin ducks was evaluated. Specifically, we examined whether the qualitative gait score categories corresponded to quantitative gait parameter measures, and evaluated the inter- and intra-rater reliabilities of the gait score system. Commercial Pekin ducks aged 13 to 14 d (14 d; 248 ducks), 20 to 21 d (21 d; 350 ducks), and 30 to 32 d (31 d; 368 ducks), were video recorded and gait scored using a 3-point system (GS0 = best gait; GS2 = poor gait) as they crossed a Tekscan((r)) gait analysis system. Gait structure parameters were calculated based on 4 steps made by each duck. The most prominent differences were observed at 21 d and 31 d of age between the ducks with GS0 and GS2, with GS2 scoring ducks walking a shorter total distance, having greater differences in the amount of pressure applied to the right versus left leg, and the amount of time spent standing on 2 feet between steps. Gait score reliabilities were calculated separately for observers who received minimal training (M, N = 10) and those who viewed and discussed the sample cases (V, N = 13). Both groups assessed the gait of ducks from video footage. Inter-rater reliability (Fleiss kappa) was lowest for 14 d old ducks (M: k = 0.47, T: k = 0.62), and best for the 32 d old ducks (V: k = 0.75; T: k = 0.8). Overall, intra-rater reliabilities (Pearson's correlation) were high and were unaffected by the scorer's level of training (M: r = 0.87; V: r = 0.87; t21 = 0.43). The results indicate that a 3-point gait score system is a promising tool for assessing the walking ability of ducks at 21 d of age and older. PMID- 26112034 TI - Effects of color of light on preferences, performance, and welfare in broilers. AB - Broiler houses are mainly lit by fluorescent light. With the expected continued increase in energy prices, the interest in less energy consuming light sources is growing. The light-emitting diode (LED) is an energy-saving alternative. The aims of the present 2 studies were to examine 1) the preference for LED color temperature and effects on behavior, and 2) effects of LED color temperature on performance and welfare of male broilers (Ross 308). Two color temperatures were investigated: neutral-white (4,100 K) and cold-white (6,065 K). First, 6 groups of 6-day-old chicks were housed in pens consisting of 2 lightproof compartments with a pop-hole between allowing chicks to move freely between compartments. Number of broilers in each compartment and their behavior were recorded every 15 min on 6 d. A preference for 6,065 K was found (P < 0.001). On d 16, 28, and 34, more time was spent in the 6,065 K treatment (P < 0.03), whereas indifference between treatments was found on d 4, 10, and 22 (P > 0.07). Second, each of the 2 light conditions was applied to 6 groups of 75 chicks. BW and feed consumption were registered weekly. On d 34, we scored gait, foot pad dermatitis, and hock burns in 15 individuals/pen. At slaughter (d 35), cold carcass weight was recorded from all individuals, while yields of different body parts were collected from 9 individuals/group. Broilers from the 6,065 K treatment were 67.4 +/- 19.2 g heavier on the day of slaughter (P = 0.0009), whereas no difference was found at other ages (P > 0.12). Feed intake was found to be similar for the 2 treatments (P = 0.52). Pectoralis minor was 4.1 +/- 1.9 g heavier in the 6,065 K treatment (P = 0.03). There was no difference between the light treatments in any of the welfare parameters. We conclude from the results that of the 2 color temperatures examined, the most suitable for use in commercial broiler houses is 6,065 K. PMID- 26112035 TI - The inhibitory effects of gga-miR-199-3p, gga-miR-140-3p, and gga-miR-221-5p in Marek's disease tumorigenesis. AB - Marek's disease (MD) is lymphoproliferative neoplastic disease in chickens, which is caused by Marek's disease virus (MDV). Our previous study profiled microRNA (miRNA) transcriptome in MD lymphoma, and found that gga-miR-199-3p, gga-miR-140 3p, and gga-miR-221-5p were down-regulated in MD lymphoma. In this study, we further investigated their differential expression between MDV-infected spleens and noninfected spleens at 4, 7, 14, 21, and 28 d postinfection (dpi) to elucidate whether deregulation of them was specific to late tumor transformation phase or not. The results showed that gga-miR-199-3p was down-regulated at 14 and 28 dpi, and the expression of gga-miR-140-3p was decreased at 14 dpi, which indicated that deregulation of these miRNAs appeared since early stage of MD tumor transformation. Additionally, the inhibitory effects of gga-miR-199-3p, gga miR-140-3p, and gga-miR-221-5p on MDV-transformed lymphoid cell line (MSB1) cells proliferation were observed, which suggested that these miRNAs acted as MD tumor suppressors. Their aberrant expression at early tumor transformation phase and suppressive role in cell proliferation indicated that they were involved in MD lymphoma transformation, and might play crucial roles in MD tumorigenesis. PMID- 26112036 TI - Cooking frozen Turkey: duration, yield and stuffing alterations with solid-state starting temperature. AB - Frozen pre-stuffed turkeys from 12 week females were conductively cooked at 163 degrees C to an 85 degrees C internal breast end-point. Bread cubes having 50% added water filled crop and body cavity to 20% of weight the turkeys were then frozen. Each of 4 treatments employed 7 carcasses: one was thawed to +5 degrees C with repetitions at -5, -15, and -25 degrees C enabling a regression analysis. Time to attain breast end-point was 44 min when the starting temperature was +5 degrees C, which increased to 63 min at -5 degrees C, and 69 min at -25 degrees C (P < 0.001, Q: quadratic). Thigh temperatures averaged 77 degrees C. Crop stuffing was 80 degrees C when cooking was initiated at +5 degrees C and increased to 84 degrees C as the starting temperatures fell to -25 degrees C (P < 0.01, Q). Body cavity stuffing reached 65 degrees C when the carcass had been thawed prior to cooking, thereafter decreasing to 59 and 60 degrees C when at -5 and -15 degrees C, respectively, before returning to 65 degrees C for the -25 degrees C case (P < 0.01, C: cubic). Total carcass loss was 18.8% when cooking was initiated at +5 degrees C. This increased to 22.6% at -25 degrees C (P < 0.01, Q). Total drip after cooking averaged 23.7% however, the percentage of fat in the drip increased from 51.1% when using +5 degrees C, to 57.2% with carcasses at -25 degrees C (P < 0.05, Q). The stuffing gained in weight, which could be attributed to associated water when thawed, as opposed to frozen (147 vs. 102g, P < 0.05, Q). Stuffing moisture was less when the carcasses had been frozen than if cooked after thawing, particularly for crop (59.4% using +5 degrees C vs. 55.8% frozen, P < 0.05, Q). Fat dominated the DM: increase, which was similar among treatments and both locations (22.6%). Stuffing CP: increased with +5 degrees C carcasses on thawing compared to frozen carcasses, particularly for crop (15.1 vs. 13.2% DM, P < 0.05, Q from +5 to -5 degrees C, respectively). Changes in part yield and meat composition were minor. Heat for ice to change to liquid was the primary basis for alterations when cooking from the frozen state, while cavity stuffing consistently failed to attain a safe temperature. PMID- 26112037 TI - Evaluation of White Striping prevalence and predisposing factors in broilers at slaughter. AB - White striping ( WS: ) is an alteration of breast and thigh muscles of broiler chickens characterized by the presence of white striations parallel to the direction of muscle fibers. This study was performed to evaluate the prevalence and the predisposing factors to WS in commercial broilers of different weight reared in northern Italy. Fifty seven broiler flocks, including animals of medium and heavy-weight, were grossly evaluated at slaughter for the presence of WS. For each flock, breeding data (mean BW at slaughter, ADG, sex, color of skin and fat, genetic line, age, antibiotic treatment, and prevalence of deep pectoral myopathy) were collected and statistically analyzed to assess their correlation with WS. Histology of breast fillets affected by different grades of WS was performed to evaluate potential differences between medium- and heavy-weight broilers. The overall prevalence of WS in medium- and heavy-weight broilers (mean BW 2.59 +/- 0.13 kg and 3.64 +/- 0.34 kg, respectively) was 70.2 +/- 7.9% and 82.51 +/- 8.5%, respectively, while the percentage of severe WS was 13.3 +/- 7.1% and 25.7 +/- 12.8%, respectively. A strong correlation was found between presence of WS, BW at slaughter, and ADG (Pearson correlation = 0.69, P < 0.01; Pearson correlation = 0.67, P < 0.01). WS also closely correlated with the prevalence of deep pectoral myopathy (Spearman's Rho slaughterhouse 1 = 0.74, Spearman's Rho slaughterhouse 2 = 0.51, P < 0.01). No correlation was found between genetics or sanitary status of the flock and WS. Histology confirmed that breasts with WS lesions were affected by a polyphasic degenerative and necrotizing myopathy, and that the lesions, as expected, were more severe in heavy-weight broilers. In conclusion, WS is a major concern in commercial meat poultry reared in Italy, affecting more severely heavier broilers, and it is mainly related to the BW and ADG of animals. PMID- 26112038 TI - In ovo injection of prebiotics and synbiotics affects the digestive potency of the pancreas in growing chickens. AB - The purpose of the study was to examine the effect of 2 prebiotics and 2 synbiotics on the digestive potency of pancreas in 1-, 3-, 7-, 14-, 21-, and 34 day-old cockerels. Prebiotics (inulin and Bi2tos) and synbiotics (inulin + Lactococcus lactis subsp. lactis and Bi2tos + Lactococcus lactis subsp. cremoris) were injected in ovo into the air cell on the 12th d embryonic development. Their application increased the activity of amylase, lipase, and trypsin in the pancreas. The most pronounced changes were observed at the end of the investigated rearing period (d 34). The strongest stimulative effects on amylase were shown by both synbiotics, on lipase synbiotic Bi2tos + Lactococcus lactis subsp. cremoris, and on trypsin all the used prebiotics and synbiotics. Simultaneously, neither the absolute nor the relative mass of the pancreas in comparison to control group were changed. Also, the injected in ovo compounds did not cause a deterioration in the posthatching condition of the chicken liver, as determined by measurement of the activity of marker enzymes in the blood (alanine aminotransferase and aspartate aminotransferase). Treatment with the prebiotics and synbiotics did not change the feed conversion ratio but Bi2tos (galacto oligosaccharide) and inulin (fructan) + Lactococcus lactis subsp. lactis significantly increased final BW. PMID- 26112039 TI - Efficacy of 25-OH Vitamin D3 prophylactic administration for reducing lameness in broilers grown on wire flooring. AB - Bacterial chondronecrosis with osteomyelitis (BCO) is the most common cause of lameness in commercial broilers. Growing broilers on wire flooring provides an excellent experimental model for reproducibly triggering significant levels of lameness attributable to BCO. In the present study we evaluated the efficacy of adding HyD (25-OH vitamin D3) to the drinking water as a preventative/prophylactic treatment for lameness. Broiler chicks were reared on 5 x 10 ft flat wire floor panels within 6 environmental chambers. Three chambers were supplied with tap water (Control group) and the remaining chambers were supplied with HyD (HyD group: 0.06 mL HyD solution/L water; dosing based on the HyD Solution label to provide 33.9 MUg 25-OHD3/L) from d 1 through 56. Feed was provided ad libitum and was formulated to meet or exceed minimum standards for all ingredients, including 5,500 IU vitamin D3/kg. Lameness initially was detected on d 28, and the cumulative incidence of lameness on d 56 was higher in the Control group than in the HyD group (34.7 vs. 22.7%, respectively; P = 0.03; Z-test of proportions; chambers pooled). The most prevalent diagnoses for lame birds were osteochondrosis and osteomyelitis (BCO) of the proximal femora (52%) and tibiae (79%), accompanied by minor incidences of tibial dyschondroplasia (0.33%), spondylolisthesis, or kinky back (0.67%), and twisted legs (1%). Broilers that survived to d 56 without developing lameness did not differ in BW when compared by group within a gender. The wire flooring model imposes a rigorous, sustained challenge that undoubtedly is much more severe than typically would be experienced by broilers under normal commercial conditions. Therefore the encouraging response to HyD supplementation in the present study supports the potential for 25-OH vitamin D3 to attenuate outbreaks of lameness caused by BCO in commercial broiler flocks. PMID- 26112040 TI - Feed form and energy concentration of the diet affect growth performance and digestive tract traits of brown-egg laying pullets from hatching to 17 weeks of age. AB - The influence of feed form and energy concentration of the diet on growth performance and the development of the gastrointestinal tract (GIT) was studied in brown-egg laying pullets. Diets formed a 2 x 5 factorial with 2 feed forms (mash vs. crumbles) and 5 levels of energy differing in 50 kcal AMEn/kg. For the entire study (0 to 17 wk of age) feeding crumbles increased ADFI (52.9 vs. 49.7 g; P < 0.001) and ADG (12.7 vs. 11.6 g; P < 0.001) and improved feed conversion ratio (FCR; 4.18 vs. 4.27; P < 0.001). An increase in the energy content of the diet decreased ADFI linearly (P < 0.001) and improved FCR quadratically (P < 0.01) but energy intake (kcal AMEn/d) was not affected. BW uniformity was higher (P < 0.05) in pullets fed crumbles than in those fed mash but was not affected (P > 0.05) by energy content of the diet. At 5, 10, and 17 wk of age, the relative weight (RW, % BW) of the GIT and the gizzard, and gizzard digesta content were lower (P < 0.05 to P < 0.001) and gizzard pH was higher (P < 0.05 to P < 0.001) in pullets fed crumbles than in pullets fed mash. Energy concentration of the diet did not affect any of the GIT variables studied. In summary, feeding crumbles improved pullet performance and reduced the RW of the GIT and gizzard, and increased gizzard pH at all ages. An increase in the energy content of the diet improved FCR from 0 to 17 wk of age. The use of crumbles and the increase in the AMEn content of the diet might be used adventageously when the objetive is to increase the BW of the pullets. However, crumbles affected the development and weight of the organs of the GIT, which might have negative effects on feed intake and egg production at the beginning of the egg laying cycle. PMID- 26112042 TI - Domain-specific model selection for structural identification of the Rab5-Rab7 dynamics in endocytosis. AB - BACKGROUND: Given its recent rapid development and the central role that modeling plays in the discipline, systems biology clearly needs methods for automated modeling of dynamical systems. Process-based modeling focuses on explanatory models of dynamical systems; it constructs such models from measured time-course data and formalized modeling knowledge. In this paper, we apply process-based modeling to the practically relevant task of modeling the Rab5-Rab7 conversion switch in endocytosis. The task is difficult due to the limited observability of the system variables and the noisy measurements, which pose serious challenges to the process of model selection. To address these issues, we propose a domain specific model selection criteria that take into account knowledge about the necessary properties of the simulated model behavior. RESULTS: In a series of modeling experiments, we compare the results of process-based modeling obtained with different model selection criteria. The first is the standard maximum likelihood criterion based solely on least-squares model error. The second one is a parsimony-based criterion that also takes into account model complexity. We also introduce three domain-specific criteria based on domain expert expectations about the simulated behavior of an endocytosis model. According to the first criterion, 90 of the candidate models are indistinguishable. Furthermore, taking into account the complexity of the model does not lead to better model selection. However, the use of domain-specific criteria results in a remarkable improvement over the other two model selection criteria. CONCLUSIONS: We demonstrate the applicability of process-based modeling to the task of modeling the Rab5-Rab7 dynamics in endocytosis. Our experiments show that the domain-specific criteria outperform the standard domain-independent criteria for model selection. We also find that some of the model structures discarded as implausible in previous studies lead to the expected Rab5-Rab7 switch behavior. PMID- 26112041 TI - A group randomized controlled trial integrating obesity prevention and control for postpartum adolescents in a home visiting program. AB - BACKGROUND: Adolescence represents a critical period for the development of overweight that tracks into adulthood. This risk is significantly heightened for adolescents that become pregnant, many of whom experience postpartum weight retention. The aim of this study was to evaluate Balance Adolescent Lifestyle Activities and Nutrition Choices for Energy (BALANCE), a multicomponent obesity prevention intervention targeting postpartum adolescents participating in a national home visiting child development-parent education program. METHODS: A group randomized, nested cohort design was used with 1325 adolescents, 694 intervention and 490 control, (mean age = 17.8 years, 52 % underrepresented minorities) located across 30 states. Participatory methods were used to integrate lifestyle behavior change strategies within standard parent education practice. Content targeted replacement of high-risk obesogenic patterns (e.g. sweetened drink and high fat snack consumption, sedentary activity) with positive behaviors (e.g. water intake, fruit and vegetables, increased walking). Parent educators delivered BALANCE through home visits, school based classroom-group meetings, and website activities. Control adolescents received standard child development information. Phase I included baseline to posttest (12 months); Phase II included baseline to follow-up (24 months). RESULTS: When compared to the control group, BALANCE adolescents who were >=12 weeks postpartum were 89 % more likely (p = 0.02) to maintain a normal BMI or improve an overweight/obese BMI by 12 months; this change was not sustained at 24 months. When compared to the control group, BALANCE adolescents significantly improved fruit and vegetable intake (p = .03). In stratified analyses, water intake improved among younger BALANCE teens (p = .001) and overweight/obese BALANCE teens (p = .05) when compared to control counterparts. There were no significant differences between groups in sweetened drink and snack consumption or walking. CONCLUSION: Prevention of postpartum weight retention yields immediate health benefits for the adolescent mother and may prevent the early development or progression of maternal obesity, which contributes to the intergenerational transmission of obesity to her offspring. Implementing BALANCE through a national home visiting organization may hold promise for promoting positive lifestyle behaviors associated with interruption of the progression of maternal obesity. TRIAL REGISTRATION: Clinical Trials Registry NCT01617486 . PMID- 26112044 TI - Results From a European Multicenter Randomized Trial of Physical Activity and/or Healthy Eating to Reduce the Risk of Gestational Diabetes Mellitus: The DALI Lifestyle Pilot. AB - OBJECTIVE: Ways to prevent gestational diabetes mellitus (GDM) remain unproven. We compared the impact of three lifestyle interventions (healthy eating [HE], physical activity [PA], and both HE and PA [HE+PA]) on GDM risk in a pilot multicenter randomized trial. RESEARCH DESIGN AND METHODS: Pregnant women at risk for GDM (BMI >=29 kg/m2) from nine European countries were invited to undertake a 75-g oral glucose tolerance test before 20 weeks' gestation. Those without GDM were randomized to HE, PA, or HE+PA. Women received five face-to-face and four optional telephone coaching sessions, based on the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. Coaches received standardized training and an intervention toolkit. Primary outcome measures were GWG, fasting glucose, and insulin sensitivity (HOMA) at 35-37 weeks. RESULTS: Among the 150 trial participants, 32% developed GDM by 35-37 weeks and 20% achieved GWG <5 kg. HE women had less GWG (-2.6 kg [95% CI -4.9, 0.2]; P = 0.03) and lower fasting glucose (-0.3 mmol/L [-0.4, -0.1]; P = 0.01) than those in the PA group at 24-28 weeks. HOMA was comparable. No significant differences between HE+PA and the other groups were observed. CONCLUSIONS: An antenatal HE intervention is associated with less GWG and lower fasting glucose compared with PA alone. These findings require a larger trial for confirmation but support the use of early HE interventions in obese pregnant women. PMID- 26112043 TI - Epigenetic modifications of caveolae associated proteins in health and disease. AB - Caveolae are small, "omega-shaped" invaginations at the plasma membrane of the cell which are involved in a variety of processes including cholesterol transport, potocytosis and cell signalling. Within caveolae there are caveolae associated proteins, and changes in expression of these molecules have been described to play a role in the pathophysiology of various diseases including cancer and cardiovascular disease. Evidence is beginning to accumulate that epigenetic processes may regulate the expression of these caveolae related genes, and hence contribute to disease progression. Here, we summarize the current knowledge of the role of epigenetic modification in regulating the expression of these caveolae related genes and how this relates to changes in cellular physiology and in health and disease. PMID- 26112045 TI - Training for staff who support students. AB - BACKGROUND: Front-line administrative, academic and clinical teaching staff often find themselves providing pastoral and learning support to students, but they are often not trained for this role, and this aspect of their work is under acknowledged. CONTEXT: Staff participating in an action research study at two medical schools identified common concerns about the personal impact of providing student support, and of the need for professional development to carry out this responsibility. This need is magnified in clinical placement settings that are remote from on-campus services. INNOVATION: Informed by participatory action research, brief interactive workshops with multimedia training resources were developed, conducted and evaluated at eight health professional student training sites. These workshops were designed to: (1) be delivered in busy clinical placement and university settings; (2) provide a safe and inclusive environment for administrative, academic and clinical teaching staff to share experiences and learn from each other; (3) be publicly accessible; and (4) promote continued development and roll-out of staff training, adapted to each workplace (see http://www.uws.edu.au/meusupport). The workshops were positively evaluated by 97 participants, with both teaching and administrative staff welcoming the opportunity to discuss and share experiences. Staff supporting health professional students have shared, often unmet, needs for support themselves IMPLICATIONS: Staff supporting health professional students have shared, often unmet, needs for support themselves. Participatory action research can be a means for producing and maintaining effective training resources as well as the conditions for change in practice. In our workshops, staff particularly valued opportunities for guided discussion using videos of authentic cases to trigger reflection, and to collaboratively formulate student support guidelines, customised to each site. PMID- 26112047 TI - CXCL8 as a Potential Therapeutic Target for HIV-Associated Neurocognitive Disorders. AB - Chemokine CXCL8 is a low molecular weight neutrophil chemoattractant implicated in various neurodegenerative disorders including Alzheimer's disease and stroke. Increased expression of CXCL8 has been reported in serum, plasma and brain of human immunodeficiency virus (HIV)-1 infected individuals with neurocognitive impairment, indicating its role in neuroinflammation associated with HIV-1 infection of the brain. Since chemokines are critical in eliciting immune responses in the central nervous system (CNS), CXCL8 is of particular importance for being one of the first chemokines described in the brain. Activation of astrocytes and microglia by HIV-1 and virus associated proteins results in production of this chemokine in the brain microenvironment. Consequently, CXCL8 exerts its effect on target cells via Gprotein coupled receptors CXCR1 and CXCR2. Neutrophils are the main target cells for CXCL8; however, microglia and neurons also express CXCR1/CXCR2 and therefore are important targets for CXCL8-mediated crosstalk. The objective of this review is to focus on CXCL8 production, signaling and regulation in neuronal and glial cells in response to HIV-1 infection. We highlight the role of HIV-1 secreted proteins such as trans activator of transcription, envelope glycoprotein, negative regulatory factor and viral protein r in the regulation of CXCL8. We discuss dual role of CXCL8 in neurodegeneration as well as neuroprotection in the CNS. Thus, targeting CXCL8 through the development of CXCR1/CXCR2-based therapeutic strategies to either selectively agonize or antagonize receptors may be able to selectively promote neuroprotective and anti-inflammatory outcomes, leading to significant clinical applications in many neuroinflammatory CNS diseases, including HIV-associated neurocognitive disorders. PMID- 26112046 TI - Molecular and neuroendocrine mechanisms of cancer cachexia. AB - Cancer and its morbidities, such as cancer cachexia, constitute a major public health problem. Although cancer cachexia has afflicted humanity for centuries, its underlying multifactorial and complex physiopathology has hindered the understanding of its mechanism. During the last few decades we have witnessed a dramatic increase in the understanding of cancer cachexia pathophysiology. Anorexia and muscle and adipose tissue wasting are the main features of cancer cachexia. These apparently independent symptoms have humoral factors secreted by the tumor as a common cause. Importantly, the hypothalamus has emerged as an organ that senses the peripheral signals emanating from the tumoral environment, and not only elicits anorexia but also contributes to the development of muscle and adipose tissue loss. Herein, we review the roles of factors secreted by the tumor and its effects on the hypothalamus, muscle and adipose tissue, as well as highlighting the key targets that are being exploited for cancer cachexia treatment. PMID- 26112048 TI - Neonatal respiratory distress syndrome revealing a cervical bronchogenic cyst: a case report. AB - BACKGROUND: Bronchogenic cyst is a congenital malformation, rarely located in the cervical region and almost never involved in a neonate with acute respiratory distress in the delivery room. CASE PRESENTATION: A female newborn with respiratory distress syndrome caused by a large left cervical mass. Intubation was difficult due to tracheal deviation. Magnetic resonance imaging confirmed a left cervical cyst displacing the trachea and esophagus laterally. Surgical excision was performed via a cervical approach on the 5th day, and pathological examination revealed a bronchogenic cyst. The patient's course was complicated by left vocal cord paralysis and necrotic lesions in the glottic and subglottic regions; she required a tracheostomy on the 13th day. Inflammatory stenosis in the subglottic region required balloon dilation once, 20 days later. Proximal esophageal stenosis induced transient upper airway obstruction with salivary stasis. Decannulation was performed at 2 months and the patient was discharged 10 days later. CONCLUSION: A bronchogenic cyst can exceptionally obstruct the airways in the neonatal period. Surgical excision is necessary, but postoperative complications may occur if the cyst is in close contact with the trachea and esophagus, including necrotic and stenotic lesions of the upper aerodigestive tract. In those situations, tracheostomy may be necessary for mechanical ventilation weaning and the initiation of oral feeding. PMID- 26112049 TI - Immune microenvironment as a factor of breast cancer progression. AB - BACKGROUND: The rate of progression of the disease depends on various factors and the tumor microenvironment takes not the last place among them. One part of researchers argues that the presence of tumor-infiltrating leukocytes serves as a favorable marker of the disease. There exists a completely different point of view on the matter. The investigation of the effects of the inflammatory infiltration on the course of breast cancer process. METHODS: We found a pronounced inflammatory infiltration in the tumor microenvironment in 24 cases. Nineteen cases of IDC without inflammatory infiltration were used as a control group. Immunohistochemical reaction showed expression of ERalpha, PR, HER2/neu, E cadherin, Hsp90alpha, Bcl-2, CD3, CD79alpha, S100 and Myeloperoxidase receptors. Mathematical calculations were done using Microsoft Excel 2010 with 12.0.5 Attestat option. RESULTS: We have determined five variants of immune microenvironment: interstitial, trabecular, nodular, diffuse and mixed. We have established a direct correlation between the expression of ERalpha and PR and indirect correlation between the receptors of steroid hormones and HER2/neo in both groups of breast cancer. HER2/neo positive tumors in 100% of cases were accompanied by the presence of heat shock proteins. There was a combination of Bcl-2 presence with the steroid receptors expression in 90 % of cases. There was found the indirect correlation between the presence of B lymphocytes and expression of steroid receptors. CONCLUSIONS: The presence of B lymphocytes in an inflammatory infiltrate leads to the disappearance of estrogen receptors and progesterone receptors. It provokes the accumulation of Hsp90 in a cell. It contributes to the stabilization of HER2/neu receptors and most proteins that promote tumor progression. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1362330168161694. PMID- 26112051 TI - Decreased integrity of the fronto-temporal fibers of the left inferior occipito frontal fasciculus associated with auditory verbal hallucinations in schizophrenia. AB - Auditory verbal hallucinations (AVH) have been proposed to result from altered connectivity between frontal speech production regions and temporal speech perception regions. Whilst the dorsal language pathway, serviced by the arcuate fasciculus, has been extensively studied in relation to AVH, the ventral language pathway, serviced by the inferior occipito-frontal fasciculus (IOFF) has been rarely studied in relation to AVH. This study examined whether structural changes in anatomically defined subregions of the IOFF were associated with AVH in patients with schizophrenia. Diffusion tensor imaging scans and clinical data were obtained from the Australian Schizophrenia Research Bank for 113 schizophrenia patients, of whom 39 had lifetime experience of AVH (18 had current AVH, 21 had remitted AVH), 74 had no lifetime experience of AVH, and 40 healthy controls. Schizophrenia patients with a lifetime experience of AVH exhibited reduced fractional anisotropy (FA) in the fronto-temporal fibers of the left IOFF compared to both healthy controls and schizophrenia patients without AVH. In contrast, structural abnormalities in the temporal and occipital regions of the IOFF were observed bilaterally in both patient groups, relative to the healthy controls. These results suggest that while changes in the structural integrity of the bilateral IOFF are associated with schizophrenia per se, integrity reductions in the fronto-temporal fibers of the left IOFF may be specifically associated with AVH. PMID- 26112052 TI - Circulating resistin levels are early and significantly increased in deceased brain dead organ donors, correlate with inflammatory cytokine response and remain unaffected by steroid treatment. AB - INTRODUCTION: Resistin is a pro-inflammatory adipokine that increases after brain injury (trauma, bleeding) and may initiate an inflammatory response. Resistin was found increased in deceased, brain dead organ donors (DBD) and correlated with delayed graft function after kidney transplantation. The kinetics of resistin during brain death (BD), its impact on the inflammatory response and the influence of several donor variables on resistin levels are still unknown. METHODS: Resistin along with a panel of Th1/Th2 cytokines [interferon (IFN) gamma, interleukin (IL)-1beta, IL-2, IL-6, IL-8, IL10, IL-12, IL-13 and tumor necrosis factor (TNF)] was analyzed in 36 DBDs after the diagnosis of BD and before organ procurement and in 12 living kidney donors (LD). The cytokine levels and resistin were analyzed in relation to donor parameters including cause of death, donors' age and steroid treatment. RESULTS: Resistin levels were higher in DBDs both at BD diagnosis and before organ procurement compared to LD (p < 0.001). DBDs had significantly increased IL-1beta, IL-6, IL-8, IL-10 and TNF levels at both time points compared with LD. In DBDs, resistin at BD diagnosis correlated positively with IL-1beta (rs 0.468, p = 0.007), IL-6 (rs 0.511, p = 0.002), IL-10 (rs 0.372, p = 0.028), IL-12 (rs 0.398, p = 0.024), IL-13 (rs 0.397, p = 0.030) and TNF (rs 0.427, p = 0.011) at procurement. The cause of death, age over 60 and steroid treatment during BD did not affect resistin levels. However, steroid treatment significantly decreased pro-inflammatory cytokines IL-1beta, IL-8, TNF and IFN-gamma at the time of organ procurement. CONCLUSIONS: Resistin is increased early in DBDs, remains increased throughout the period of BD and correlates strongly with pro-inflammatory mediators. Resistin level, in contrast to cytokines, is not affected by steroid treatment. Resistin increase is related to the BD but is not influenced by age or cause of death. Resistin may be one of the initial triggers for the systemic inflammatory activation seen in DBDs. PMID- 26112050 TI - Improving care after colon cancer treatment in The Netherlands, personalised care to enhance quality of life (I CARE study): study protocol for a randomised controlled trial. AB - BACKGROUND: It is expected that in 2020 more than 17,000 cases of colorectal cancer will be diagnosed in The Netherlands. To date, patients are included in a surgeon-led follow-up programme whose main focus is recurrence detection. However, patients often experience multiple physical and psychosocial problems. Currently, these problems are not always encountered. More care by a generalist is suggested as a solution. Furthermore, patients prefer to undergo rehabilitation in their own environment and to be more involved in their own health care. eHealth applications might enhance this. Oncokompas(2.0) is an online self-management application which facilitates access to supportive care. This study aims to evaluate primary care follow-up and aftercare in comparison with secondary care follow-up and aftercare for patients with colon cancer. Second, the added value of Oncokompas(2.0) to care will be assessed. METHODS/DESIGN: This is a multi-centre 2 * 2 factorial randomised controlled trial with a calculated sample size of 300 patients. Patients with stage I, II, or III colon carcinoma are eligible. Patients will be randomly assigned in four groups: (1) usual follow-up visits and aftercare provided in secondary care, (2) usual follow-up visits and aftercare provided in secondary care with additional use of Oncokompas(2.0), (3) follow-up and aftercare in primary care, and (4) follow-up and aftercare in primary care with additional use of Oncokompas(2.0). The primary outcome is quality of life. Secondary outcomes include physical outcomes, psychosocial outcomes, number of investigations, referrals and related communication between secondary and primary care, (time of) recurrence detection and protocol adherence, attention to preventive care, self-management of patients, patient satisfaction, and preference of care at the end of the trial. Data collection will be done by questionnaires and extractions from electronic medical records. DISCUSSION: The results of this study will provide evidence, which has been scarce to date, on prominent general practitioner involvement in care for colon cancer patients after initial treatment. Also, it evaluates the efficacy of an eHealth application to enhance patient empowerment. DUTCH TRIAL REGISTER: NTR4860 (registered on 2 October 2014). PMID- 26112053 TI - A series of patients with minimal change nephropathy treated with rituximab during adolescence and adulthood. AB - BACKGROUND: The treatment of immune suppression dependent minimal change nephropathy (MCN) can be challenging and frequently leads to serious complications. In paediatric patients, successful treatment with rituximab is described in steroid-dependent MCN. There is limited information about the potential efficacy of rituximab for the treatment of MCN in adults and adolescence. We describe our experience with rituximab in adolescent and adult patients with immune suppression dependent MCN. RESULTS: Ten adolescents and adults with immune suppression dependent MCN and therapy related complications were treated with rituximab. At a mean age of 26 years, about 10.5 years after first presentation, they received two doses of rituximab (375 mg/m(2)). Maintenance immunosuppressive medication was stopped. After a mean follow-up of 43 months, three patients had four relapses. Three relapses were successfully retreated with rituximab again, after induction therapy with 60 mg prednisone per day. Rituximab was well tolerated and no infectious complications were recorded. CONCLUSION: Treatment with rituximab induces a long-term remission of immune suppression dependent MCN in adolescents and adults. A timely treatment with rituximab could be considered to limit side effects of immunosuppressive medication. PMID- 26112055 TI - CT volumetric analysis of pleural effusions: a comparison with thoracentesis volumes. AB - RATIONALE AND OBJECTIVES: The primary objective of this study was to compare computed tomography (CT) volumetric analysis of pleural effusions with thoracentesis volumes. The secondary objective of this study was to compare subjective grading of pleural effusion size with thoracentesis volumes. MATERIALS AND METHODS: This was a retrospective study of 67 patients with free-flowing pleural effusions who underwent therapeutic thoracentesis. CT volumetric analysis was performed on all patients; the CT volumes were compared with the thoracentesis volumes. In addition, the subjective grading of pleural effusion size was compared with the thoracentesis volumes. RESULTS: The average difference between CT volume and thoracentesis volume was 9.4 mL (1.3%) +/- 290 mL (30%); these volumes were not statistically different (P = .79, paired two-tailed Student's t-test). The thoracentesis volume of a "small," "moderate," and "large" pleural effusion, as graded on chest CT, was found to be approximately 410 +/- 260 cc, 770 +/- 270 mL and 1370 +/- 650 mL, respectively; the thoracentesis volume of a "small," "moderate," and "large" pleural effusion, as graded on chest radiograph, was found to be approximately 610 +/- 320 mL, 1040 +/- 460 mL, and 1530 +/- 830 mL, respectively. CONCLUSIONS: CT volumetric analysis is an accessible tool that can be used to accurately quantify the size of pleural effusions. PMID- 26112054 TI - From big data analysis to personalized medicine for all: challenges and opportunities. AB - Recent advances in high-throughput technologies have led to the emergence of systems biology as a holistic science to achieve more precise modeling of complex diseases. Many predict the emergence of personalized medicine in the near future. We are, however, moving from two-tiered health systems to a two-tiered personalized medicine. Omics facilities are restricted to affluent regions, and personalized medicine is likely to widen the growing gap in health systems between high and low-income countries. This is mirrored by an increasing lag between our ability to generate and analyze big data. Several bottlenecks slow down the transition from conventional to personalized medicine: generation of cost-effective high-throughput data; hybrid education and multidisciplinary teams; data storage and processing; data integration and interpretation; and individual and global economic relevance. This review provides an update of important developments in the analysis of big data and forward strategies to accelerate the global transition to personalized medicine. PMID- 26112056 TI - Reproducibility of VPCT parameters in the normal pancreas: comparison of two different kinetic calculation models. AB - RATIONALE AND OBJECTIVES: To assess the reproducibility of volume computed tomographic perfusion (VPCT) measurements in normal pancreatic tissue using two different kinetic perfusion calculation models at three different time points. MATERIALS AND METHODS: Institutional ethical board approval was obtained for retrospective analysis of pancreas perfusion data sets generated by our prospective study for liver response monitoring to local therapy in patients experiencing unresectable hepatocellular carcinoma, which was approved by the institutional review board. VPCT of the entire pancreas was performed in 41 patients (mean age, 64.8 years) using 26 consecutive volume measurements and intravenous injection of 50 mL of iodinated contrast at a flow rate of 5 mL/s. Blood volume(BV) and blood flow (BF) were calculated using two mathematical methods: maximum slope + Patlak analysis versus deconvolution method. Pancreas perfusion was calculated using two volume of interests. Median interval between the first and the second VPCT was 2 days and between the second and the third VPCT 82 days. Variability was assessed with within-patient coefficients of variation (CVs) and Bland-Altman analyses. Interobserver agreement for all perfusion parameters was calculated using intraclass correlation coefficients (ICCs). RESULTS: BF and BV values varied widely by method of analysis as did within-patient CVs for BF and BV at the second versus the first VPCT by 22.4%/50.4% (method 1) and 24.6%/24.0% (method 2) measured in the pancreatic head and 18.4%/62.6% (method 1) and 23.8%/28.1% (method 2) measured in the pancreatic corpus and at the third versus the first VPCT by 21.7%/61.8% (method 1) and 25.7%/34.5% (method 2) measured also in the pancreatic head and 19.1%/66.1% (method 1) and 22.0%/31.8% (method 2) measured in the pancreatic corpus, respectively. Interobserver agreement measured with ICC shows fair-to-good reproducibility. CONCLUSIONS: VPCT performed with the presented examinational protocol is reproducible and can be used for monitoring purposes. Best reproducibility was obtained with both methods for BF and with method 2 also for BV data for both follow-up studies. PMID- 26112057 TI - Effect of menstrual cycle phase on background parenchymal uptake at molecular breast imaging. AB - RATIONALE AND OBJECTIVES: The level of Tc-99m sestamibi uptake within normal fibroglandular tissue on molecular breast imaging (MBI), termed background parenchymal uptake (BPU), has been anecdotally observed to fluctuate with menstrual cycle. Our objective was to assess the impact of menstrual cycle phase on BPU appearance. MATERIALS AND METHODS: Premenopausal volunteers who reported regular menstrual cycles and no exogenous hormone use were recruited to undergo serial MBI examinations during the follicular and luteal phase. A study radiologist, blinded to cycle phase, categorized BPU as photopenic, minimal mild, moderate, or marked. Change in BPU with cycle phase was determined, as well as correlations of BPU with mammographic density and hormone levels. RESULTS: In 42 analyzable participants, high BPU (moderate or marked) was observed more often in luteal phase compared to follicular (P = .016). BPU did not change with phase in 30 of 42 participants (71%) and increased in the luteal phase compared to follicular in 12 (29%). High BPU was more frequent in dense breasts compared to nondense breasts at both the luteal (58% [15 of 26] vs. 13% [2 of 16], P = .004) and follicular phases (35% [9 of 26] vs. 6% [1 of 16], P = .061). Spearman correlation coefficients did not show any correlation of BPU with hormone levels measured at either cycle phase and suggested a weak correlation between change in BPU and changes in estrone and estradiol between phases. CONCLUSIONS: We observed variable effects of menstrual cycle on BPU among our cohort of premenopausal women; however, when high BPU was observed, it was most frequently seen during the luteal phase compared to follicular phase and in women with dense breasts compared to nondense breasts. PMID- 26112059 TI - Comparison of the Effectiveness and Prognostic Factors of Intravitreal Ranibizumab between Typical Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy over 24 Months of Follow-Up. AB - PURPOSE: To compare the response to ranibizumab between patients with typical neovascular age-related macular degeneration (tAMD) and those with polypoidal choroidal vasculopathy (PCV), and to determine the predictors for the outcomes. METHODS: Fifty-nine eyes from 59 consecutive patients (tAMD: 27 eyes, PCV: 32 eyes) were treated with three monthly ranibizumab injections followed by as needed retreatment. Best-corrected visual acuity (BCVA) and morphological parameters were evaluated over 24 months of follow-up. RESULTS: The mean BCVA in tAMD and PCV patients was significantly improved at 3 months (-0.22 and -0.09 logMAR units, respectively). The improvement in BCVA was sustained up to 24 months in tAMD (p = 0.01) but not in PCV patients. The significant predictor for good response to ranibizumab in tAMD patients was the improvement of BCVA at 3 months, whereas that in PCV patients was the anatomical resolution at 3 months. CONCLUSIONS: Ranibizumab is an effective therapy for tAMD and PCV over 24 months. The predictors for good outcome might be different between tAMD and PCV. PMID- 26112058 TI - Reference values for jitter recorded by concentric needle electrodes in healthy controls: A multicenter study. AB - INTRODUCTION: The aim of this study was to create reference values for jitter measured with concentric needle electrodes. METHODS: Operators worldwide contributed recordings from orbicularis oculi (OO), frontalis (FR), and extensor digitorum (ED) muscles in healthy controls. Criteria for acceptable signal quality were agreed upon in advance. Fifteen or 20 recordings of acceptable quality from each muscle were required for voluntary and electrical stimulation recordings, respectively. RESULTS: Recordings from 59 to 92 subjects were obtained for each muscle and activation type. Outlier limits for mean consecutive difference and individual jitter data for voluntary activation were: OO, 31 and 45 us; FR, 28 and 38 us; ED, 30 and 43 us; and for electrical stimulation they were: OO, 27 and 36 us; FR, 21 and 28 us; ED, 24 and 35 us. CONCLUSION: Reference jitter values from concentric needle electrode recordings were developed from signals of defined quality while seeking to avoid creating supernormal values. PMID- 26112060 TI - Intact Automatic Imitation and Typical Spatial Compatibility in Autism Spectrum Disorder: Challenging the Broken Mirror Theory. AB - A lack of imitative behavior is frequently described as a core feature of Autism Spectrum Disorder (ASD), and is consistent with claims of mirror neuron system dysfunction in these individuals. Previous research has questioned this characterization of ASD however, arguing that when tests of automatic imitation are used--which do not require higher-level cognitive processing--imitative behavior is intact or even enhanced in individuals with ASD. In Experiment 1, 60 adult individuals with ASD and a matched Control group completed an automatic imitation task in which they were required to perform an index or a middle finger lift while observing a hand making either the same, or the alternate, finger movement. Both groups demonstrated a significant imitation effect whereby actions were executed faster when preceded by observation of the same action, than when preceded by the alternate action. The magnitude of this "imitation effect" was statistically indistinguishable in the ASD and Control groups. Experiment 2 utilized an improved automatic imitation paradigm to demonstrate that, when automatic imitation effects are isolated from those due to spatial compatibility, increasing autism symptom severity is associated with an increased tendency to imitate. Notably, there was no association between autism symptom severity and spatial compatibility, demonstrating the specificity of the link between ASD symptoms and increased imitation. These results provide evidence against claims of a lack of imitative behavior in ASD, and challenge the "Broken Mirror Theory of Autism." PMID- 26112061 TI - Black Arsenic-Phosphorus: Layered Anisotropic Infrared Semiconductors with Highly Tunable Compositions and Properties. AB - New layered anisotropic infrared semiconductors, black arsenic-phosphorus (b AsP), with highly tunable chemical compositions and electronic and optical properties are introduced. Transport and infrared absorption studies demonstrate the semiconducting nature of b-AsP with tunable bandgaps, ranging from 0.3 to 0.15 eV. These bandgaps fall into the long-wavelength infrared regime and cannot be readily reached by other layered materials. PMID- 26112062 TI - Resistance of gastrointestinal nematodes to the most commonly used anthelmintics in sheep, cattle and horses in Spain. AB - The objective of this study was to evaluate the status of anthelmintic resistance (AR) in ruminants and horses in Spain. The efficacy of commonly used macrocyclic lactones (MLs) - ivermectin (IVM) and moxidectin (MOX) - was measured in sheep, cattle and horses. In addition, albendazole (ABZ) and levamisole (LEV) were evaluated in sheep and oxibendazole (OXI) and pyrantel (PYR) in horses. Efficacy was evaluated based on the difference between the arithmetic mean pre- and post treatment faecal egg count (in cattle and horses), or compared to an untreated control group (in sheep). AR was present when the percentage reduction in egg count was <95% and the lower 95% confidence interval (CI) was <90%; if only one of these two criteria was met, the finding was recorded as suspected AR (SAR). In horses, AR-PYR and OXI was considered when the percentage reduction in egg count was <= 90% and the lower 95% CI was <= 80%. For each animal species, at least 10 study sites were selected. AR to at least one of the drugs was detected in all 10 sheep flocks; the main parasite identified after treatment was Teladorsagia circumcincta. Moreover, in 5 flocks multidrug resistance was identified, on 4 farms to drugs from different families, on one farm to both MOX and IVM and on another farm to all drugs tested. In cattle, the efficacy of both MOX and IVM was 100% on 4 and 3 farms, respectively, and therefore 60% of these farms were considered to have AR or SAR to both MLs. The most frequent parasite identified after treatment was Trichostrongylus spp., although Ostertagia ostertagi was also identified after treatment on one farm. In contrast to ruminants, the 4 drugs evaluated in horses were highly efficacious against strongyles, with efficacies for the MLs and OXI between 95 and 100% and between 94 and 100% for PYR, although 3 herds were SAR against PYR. In conclusion, AR to at least one of the commonly used drugs was identified on all sheep flocks investigated in the northwest of Spain. The occurrence of AR to MLs in cattle was higher than expected but consistent with what was observed in sheep. In horses, all currently used drugs were confirmed as effective against strongyles. PMID- 26112063 TI - The relationships between dysfunctional attitudes, rumination, and non-somatic depressive symptomatology in newly diagnosed Asian cancer patients. AB - BACKGROUND: Given the high prevalence of cancer patients with comorbid depression, the present study sought to elucidate the relationships between two vulnerability factors, dysfunctional attitudes and rumination, and their influence on non-somatic depressive symptomatology in an Asian cohort of cancer patients. It was hypothesized that all variables of interest would be inter correlated, and that both dysfunctional attitudes and rumination would mediate one another in influencing non-somatic depressive symptoms. METHODS: A total of 194 recently diagnosed mixed-cancer patients in Singapore (Mage=49.2+/-9.2years; 68% women; 61% ethnically Chinese), without any comorbid psychiatric diagnosis, completed the Dysfunctional Attitudes Scale Form A, Rumination Responses Scale (comprising brooding and reflective rumination), and Hospital Anxiety and Depression Scale. RESULTS: Correlational analyses revealed that all variables were inter-correlated (rhos[194]=.35-.52). Bootstrapping mediation analyses controlling for gender and treatment received revealed that both brooding and reflective rumination mediated the relationship between dysfunctional attitudes and non-somatic depressive symptoms, and that dysfunctional attitudes also mediated the relationship between both brooding and reflective rumination and non somatic depressive symptoms. CONCLUSIONS: Findings suggest that, in cancer patients, both dysfunctional attitudes and rumination seem to act upon one other, in a feedback loop, to influence non-somatic depressive symptomatology. Clinicians may therefore have a wider range of treatments to choose from in managing cancer patients with depressive symptomatology. PMID- 26112064 TI - Effects of 72hours total sleep deprivation on male astronauts' executive functions and emotion. AB - BACKGROUND: To provide evidence for better understanding stressful situations, the present study was designed to investigate the specific physiological and psychological responses under stressful situations like social isolation and sleep deprivation. METHODS: Twelve healthy male adults (age: 18-30years old) who participated in our study were randomized to the 72hours of social isolation and 72hours of sleep deprivation experimental conditions. Performances (event-related potentials and physiological activities) on the Go/Nogo task which reflected the executive functions were accessed at baseline (pretest) and after 72-hour of the experiment (posttest). RESULTS: The results showed that compared to the social isolation, the participants got strengthened heart rate (HR), weakened HR variability and smaller amplitude of the P300 under the sleep deprivation condition; moreover, they had lower positive emotion and higher negative mood in the posttest. CONCLUSIONS: The present study indicated that sleep deprivation specifically influenced the intensity of task-relevant information processing, mood and vagal tone. PMID- 26112065 TI - Racial Differences in Minnesota Nursing Home Residents' Quality of Life: The Importance of Looking Beyond Individual Predictors. AB - OBJECTIVES: The aim of this study is to investigate racial differences in nursing home (NH) residents' quality of life (QOL) at the resident and facility levels. METHOD: We used hierarchical linear modeling to identify significant resident- and facility-level predictors for racial differences in six resident-reported QOL domains. Data came from the following: (a) resident-reported QOL (n = 10,929), (b) the Minimum Data Set, and (c) facility-level characteristics from the Minnesota Department of Human Services (n = 376). RESULTS: White residents reported higher QOL in five of six domains, but in full models, individual-level racial differences remained only for food enjoyment. On the facility level, higher percentage of White residents was associated with better scores in three domains, even after adjusting for all characteristics. DISCUSSION: Racial differences in QOL exist on individual and aggregate levels. Individual differences are mainly explained by health status. The finding that facility racial composition predicts QOL more than individual race underscores the importance of examining NH structural characteristics and practices. PMID- 26112066 TI - Age Differences in the Association Between Body Mass Index Class and Annualized Medicare Expenditures. AB - OBJECTIVE: The aim of the study is to assess the relationship between body mass index (BMI) class and Medicare claims among young-old (65-69), old (70-74), and old-old (75+) adults over a 10-year period. METHOD: We assessed costs by BMI class and age group among 9,300 respondents to the 1998 Health and Retirement Study (HRS) with linked 1998-2008 Medicare claims data. BMI was classified as normal (18.5-24.9), overweight (25-29.9), mild obesity (30-34.9), or severe obesity (35 or above). RESULTS: Annualized total Medicare claims adjusted for age, gender, ethnicity, education, and smoking history were 109% greater for severely obese young-old adults in comparison with normal weight young-old adults (US$9,751 vs. US$4,663). Total annualized claim differences between the normal weight and severely obese in the old and old-old groups were not statistically significant. DISCUSSION: Excess Medicare expenditures related to obesity may be concentrated among severely obese young-old adults. Preventing severe obesity among middle and older aged adults may have large cost implications for society. PMID- 26112067 TI - Recent progress in the drug development of coumarin derivatives as potent antituberculosis agents. AB - Tuberculosis (TB) is still a challenging worldwide health problem and mycobacterium tuberculosis (MTB) remains one of the most deadly human pathogens. TB is the second leading infectious cause of mortality today behind only HIV/AIDS. The impetus for developing new structural classes of antituberculosis drugs comes from the emergence of multi-drug resistant (MDR) strains. The development of MDR strains to commonly used drugs is due to, longer durations of therapy as results of resistance, and the resurgence of the disease in immune compromised patients. Therefore, there is an urgent need to explore new antitubercular (anti-TB) agents. Ironically, the low number of potentially new chemical entities which can act as anti-TB candidates is of great importance at present situation. Considering the severity of the problem, WHO has prepared a strategic plan in Berlin declaration 2007 to stop TB, globally. Among the oxygen heterocycles, coumarin derivatives are important motifs, which can be widely found in many natural products, and many of them displaying diverse biological activities. This spectacular spectrum of applications has intrigued organic and medicinal chemists for decades to explore the natural coumarins or their synthetic analogs for their applicability as anti-TB drugs. To pave the way for the future research, there is a need to collect the latest information in this promising area. In the present review, we collated published reports on coumarin derivatives to shed light on the insights on different types of methods reported for their preparations, characterizations and anti-TB applications, so that its full therapeutic potential class of compounds can be utilized for the treatment of tuberculosis. Therefore, the objective of this review is to focus on important coumarin analogs with anti-TB activities, and structure-activity relationships (SAR) for designing the better anti-TB agents. It is hoped that, this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic coumarin-based anti-TB drugs. PMID- 26112068 TI - Applications of a new type of poly(methyl methacrylate)/TiO2 nanocomposite as an antibacterial agent and a reducing photocatalyst. AB - A new type of poly(methyl methacrylate) (PMMA)/TiO2 nanocomposite film sensitized by ionic liquids with a low dosage of TiO2 nanoparticles was prepared based on a microemulsion method. The photocatalytic activity, via the photoreduction of 4 nitrophenole (4-NP) to 4-aminophenole (4-AP) by NaBH4, and the photocatalytic based antibacterial activity, for the destruction of Escherichia coli and Staphylococcus aureus, of the prepared nanocomposite film were investigated. The conditions for the maximum efficiency in the presence of visible light irradiation have been evaluated. The rate constant of the photoreduction of 4-NP to 4-AP was calculated and the maximum rate constant was found with the 0.01 wt% of TiO2 dosage in the photocatalyst and a solution pH of 7.5. The photocatalytic antibacterial maximum activity against Gram-negative bacteria was also obtained for the 0.01 wt% of TiO2 concentration of the photocatalyst. A notable result of this work is that PMMA/TiO2 nanocomposite films show efficient photocatalytic activity at very low loadings of TiO2, in contrast to other previous reports. PMID- 26112069 TI - The potential of decision support systems to improve risk assessment for pollen beetle management in winter oilseed rape. AB - BACKGROUND: The reliance on and extensive use of pyrethroid insecticides have led to pyrethroid resistance in pollen beetle (Meligethes aeneus). Widespread adoption of best practice in pollen beetle management is therefore needed. Decision support systems (DSSs) that identify the risk period(s) for pest migration can help to target monitoring and control efforts, but they must be accurate and labour efficient to gain the support of growers. Weather data and the phenology of pollen beetles in 44 winter oilseed rape crops across England over 4 years were used to compare the performance of two risk management tools: the DSS proPlant expert, which predicts migration risk according to a phenological model and local weather data, and 'rule-based advice', which depends on crop growth stage and a temperature threshold. RESULTS: Both risk management tools were effective in prompting monitoring that would detect breaches of various control thresholds. However, the DSS more accurately predicted migration start and advised significantly fewer days of migration risk, consultation days and monitoring than did rule-based advice. CONCLUSION: The proPlant expert DSS reliably models pollen beetle phenology. Use of such a DSS can focus monitoring effort to when it is most needed, facilitate the practical use of thresholds and help to prevent unnecessary insecticide applications and the development of insecticide resistance. PMID- 26112070 TI - Whole-genome sequencing of uropathogenic Escherichia coli reveals long evolutionary history of diversity and virulence. AB - Uropathogenic Escherichia coli (UPEC) are phenotypically and genotypically very diverse. This diversity makes it challenging to understand the evolution of UPEC adaptations responsible for causing urinary tract infections (UTI). To gain insight into the relationship between evolutionary divergence and adaptive paths to uropathogenicity, we sequenced at deep coverage (190*) the genomes of 19 E. coli strains from urinary tract infection patients from the same geographic area. Our sample consisted of 14 UPEC isolates and 5 non-UTI-causing (commensal) rectal E. coli isolates. After identifying strain variants using de novo assembly-based methods, we clustered the strains based on pairwise sequence differences using a neighbor-joining algorithm. We examined evolutionary signals on the whole-genome phylogeny and contrasted these signals with those found on gene trees constructed based on specific uropathogenic virulence factors. The whole-genome phylogeny showed that the divergence between UPEC and commensal E. coli strains without known UPEC virulence factors happened over 32 million generations ago. Pairwise diversity between any two strains was also high, suggesting multiple genetic origins of uropathogenic strains in a small geographic region. Contrasting the whole-genome phylogeny with three gene trees constructed from common uropathogenic virulence factors, we detected no selective advantage of these virulence genes over other genomic regions. These results suggest that UPEC acquired uropathogenicity long time ago and used it opportunistically to cause extraintestinal infections. PMID- 26112071 TI - Recent advances and perspectives in molecular epidemiology of Taenia solium cysticercosis. AB - Cysticercosis caused by accidental ingestion of eggs of Taenia solium is spreading all over the world through globalization and is one of the most neglected, neglected tropical diseases (NTDs) or neglected zoonotic diseases (NZDs). In the present study, the reason why T. solium cysticercosis has been neglected is discussed at first, and followed with an overview on the most recent advances and perspectives in molecular approaches for epidemiology of T. solium taeniasis/cysticercosis, since although taeniasis does not constitute recognized zoonoses, transmission and complete development are dependent on human definitive hosts. Main topics are discussions on (1) the two, Asian and Afro/American, genotypes of T. solium, (2) comparative analysis of mitochondrial (haploid) and nuclear (diploid) genes, and (3) the presence of hybrids of these two genotypes which indicates out-crossing of two genotypes in hermaphrodite tapeworms in Madagascar. Additional topics are on (4) the usefulness of phylogeographic analyses to discuss where the infection was acquired from, and (5) miscellaneous unsolved topics around these genetic diversity of T. solium. PMID- 26112073 TI - Magnetic resonance arthrography of the wrist with axial traction: An iconographic review. AB - Stress maneuvers inspired by arthroscopic techniques have been previously studied for MRA of shoulder, hip, knee and wrist. Axial traction in MRA of the wrist is advantageous to study intrinsic ligaments and cartilage, but seems useless to assess tendons or nerves disorders. Based on our experience and a well-chosen iconography, we would like to emphasize the contribution of axial traction in MRA of wrist disorders. PMID- 26112072 TI - The TatC component of the twin-arginine protein translocase functions as an obligate oligomer. AB - The Tat protein export system translocates folded proteins across the bacterial cytoplasmic membrane and the plant thylakoid membrane. The Tat system in Escherichia coli is composed of TatA, TatB and TatC proteins. TatB and TatC form an oligomeric, multivalent receptor complex that binds Tat substrates, while multiple protomers of TatA assemble at substrate-bound TatBC receptors to facilitate substrate transport. We have addressed whether oligomerisation of TatC is an absolute requirement for operation of the Tat pathway by screening for dominant negative alleles of tatC that inactivate Tat function in the presence of wild-type tatC. Single substitutions that confer dominant negative TatC activity were localised to the periplasmic cap region. The variant TatC proteins retained the ability to interact with TatB and with a Tat substrate but were unable to support the in vivo assembly of TatA complexes. Blue-native PAGE analysis showed that the variant TatC proteins produced smaller TatBC complexes than the wild type TatC protein. The substitutions did not alter disulphide crosslinking to neighbouring TatC molecules from positions in the periplasmic cap but abolished a substrate-induced disulphide crosslink in transmembrane helix 5 of TatC. Our findings show that TatC functions as an obligate oligomer. PMID- 26112074 TI - Pelvic trauma and vascular emergencies. AB - Pelvic ring injuries carry a high mortality rate, the main cause of which, in the first 24hours, is exsanguination. Injured patients are managed by a multidisciplinary damage-control strategy. Unstable patients should have instrumentalized hemostasis without delay. Arterial embolization is an effective way of achieving this and justifies this approach being permanently available in level 1 trauma-centers. After CT assessment of injuries, stable patients can undergo arterial embolization if active arterial bleeding or vascular damage is present. The embolization methods (selective or unselective) and agents used depend on the patient's hemodynamic stage and assessment of the injury whenever possible. PMID- 26112075 TI - Biochemical performance of native and introduced clam species living in sympatry: The role of elements accumulation and partitioning. AB - The present study reports metal and arsenic contamination in sediments, as well as element accumulation and partitioning in native (Ruditapes decussatus and Venerupis corrugata) and introduced (Ruditapes philippinarum) clam species living in sympatry at the Obidos lagoon (Portugal). The biochemical performance and the human health risks derived from the consumption of these species are also discussed. The results obtained showed that R. decussatus was the most abundant species in all the sampling sites, revealing that the introduced clam has not yet supplanted the native species. The concentration of elements was higher in areas with higher Total Organic Matter (TOM) and fines content, being Chromium (Cr), Copper (Cu) and Lead (Pb) the most abundant metals. Clams from these areas showed the highest concentration of elements but the lowest bioaccumulation levels. Furthermore, except for As, higher concentration of elements was found in clams insoluble fraction, the less toxic fraction to the organisms. Due to the low contamination levels and because elements, except As, were mainly allocated to the insoluble fraction, clams presented similar biochemical parameters among distinct areas, with no significant oxidative stress induced. Furthermore, clams from the Obidos lagoon represent a low health risk to human consumption since, except for As, their contamination levels were below the maximum permissible limits defined by international organizations. PMID- 26112076 TI - Population-level tuberculosis incidence in the ART era. PMID- 26112078 TI - beta-Blocker Therapy in the Era of Primary Percutaneous Intervention for ST Elevation Myocardial Infarction. AB - OBJECTIVES: With the present therapeutic advances in the era of primary percutaneous coronary intervention (PCI), the role of beta-blockers in ST elevation acute myocardial infarction (STEMI) has remained contentious. METHODS: We analyzed the data and clinical outcomes of 901 STEMI patients who had undergone primary PCI. We classified the patients into beta-blocker (n = 598) and non-beta-blocker groups (n = 303). RESULTS: The cumulative incidence of all-cause death was 10.0% in the beta-blocker group and 25.4% in the non-beta-blocker group (p < 0.001). The incidence of major adverse cardiac events (MACE) was 22.1% in the beta-blocker group and 34.3% in the non-beta-blocker group (p < 0.001). The relative hazard ratio (HR) of beta-blockers for all-cause death and MACE with low left ventricle ejection fraction (LVEF; <50%) was 0.55 [95% confidence interval (CI) 0.35-0.86, p = 0.009] and 0.75 (95% CI 0.51-1.09, p = 0.125), respectively. In patients with normal LVEF (>=50%), the relative HR of beta-blockers for death and MACE were 0.50 (95% CI 0.29-0.88, p = 0.016) and 0.75 (95% CI 0.51-1.12, p = 0.162), respectively. After propensity score matching of the difference of the baseline characteristics, the Kaplan-Meier survival curve demonstrated lower mortality in the beta-blocker group than in the non-beta-blocker group with both low LVEF and normal LVEF (p = 0.02 and p = 0.001, respectively). CONCLUSIONS: beta-Blockers have beneficial clinical outcomes in the era of primary PCI for STEMI, regardless of the LVEF. (c) 2015 S. Karger AG, Basel. PMID- 26112077 TI - Nationwide and regional incidence of microbiologically confirmed pulmonary tuberculosis in South Africa, 2004-12: a time series analysis. AB - BACKGROUND: South Africa has the highest incidence of tuberculosis in the world, largely resulting from a high population prevalence of HIV infection. We investigated the incidence of microbiologically confirmed pulmonary tuberculosis, and new cases of pulmonary tuberculosis registered for treatment, nationally and provincially in South Africa from 2004 to 2012, during which time there were changes in antiretroviral therapy (ART) coverage among individuals with HIV infection. METHODS: We identified cases of microbiologically confirmed pulmonary tuberculosis from 2004 to 2012 from the National Health Laboratory Service Corporate Data Warehouse. New cases registered for treatment were identified from National Department of Health electronic registries. A time series analysis, using autoregressive models, was undertaken on incidence of microbiologically confirmed pulmonary disease nationally and provincially; this trend was also examined relative to ART coverage of adults with HIV infection. FINDINGS: During the 9-year period, 3 523 371 cases of microbiologically confirmed pulmonary tuberculosis were recorded nationally. Annual incidence (per 100 000 population) increased from 650 (95% CI 648-652) in 2004 to 848 (845-850) in 2008, declining to 774 (771-776) by 2012 (9% decrease from 2008 to 2012). Incidence varied by age group, sex, and province. There was an inverse association between incidence of microbiologically confirmed disease and ART coverage among HIV-infected individuals nationally and provincially. Trends in incidence of tuberculosis cases registered for treatment mirrored those of microbiologically confirmed cases nationally and provincially; however, incidence of microbiologically confirmed cases was consistently higher than cases registered for treatment nationally and in seven of nine provinces. INTERPRETATION: Since its peak in 2008, the incidence of microbiologically confirmed pulmonary tuberculosis in South Africa had declined by 2012; this decline is associated with an increase in ART coverage. Future integration of registries for microbiologically confirmed cases and new cases registered for treatment would improve the assessment of the burden of pulmonary tuberculosis in South Africa. FUNDING: National Institute for Communicable Diseases: Division of the National Health Laboratory Service, South Africa. PMID- 26112080 TI - Liver toxicity in colorectal cancer patients treated with first-line FOLFIRI containing regimen: a single institution experience. AB - BACKGROUND: Chemotherapy-induced toxic liver injury is a relevant issue in the clinical management of patients affected with metastatic colorectal cancer (mCRC). This retrospective study evaluated patterns of liver toxicity in patients treated with FOLinic acid, Fluorouracil, IRInotecan (FOLFIRI)-based regimens. METHODS: One hundred and fifty-six mCRC patients treated at the University Campus Bio-Medico between January 2003 and January 2013 were included in this retrospective analysis. All patients received a FOLFIRI backbone-based chemotherapy. Basal liver enzymes levels were assessed before starting the treatment and before every therapy course. R ratio and the aspartate aminotransferase/alanine aminotransferase ratio were calculated. RESULTS: Ninety one patients were male versus 55 female, and the median age of the population was 62 years (range: 38-83). Most patients had liver involvement at the beginning of first-line regimen (101 patients, 64.74%) and 59 patients had received a previous 5-FU based therapy in the adjuvant setting (37.82%). Aspartate aminotransferase level (167.87 vs 41.05 U/l; p < 0.001), Alanine aminotransferase level (94.48 vs 39.80 U/l; p = 0.004) and alkaline phosphatase (289.0 vs 172.44 U/l; p = 0.02) were significantly increased during the first 3 months of treatment. In the entire population, the calculated R ratio was 3.96 (95% CI: 3.25-4.51). In all three regimens, the calculated R ratio was between 2 and 5, without any statistical differences. CONCLUSIONS: FOLFIRI-based hepatotoxicity has been indirectly defined as a mixed pattern injury in all three regimens evaluated. PMID- 26112081 TI - The straintronic spin-neuron. AB - In artificial neural networks, neurons are usually implemented with highly dissipative CMOS-based operational amplifiers. A more energy-efficient implementation is a 'spin-neuron' realized with a magneto-tunneling junction (MTJ) that is switched with a spin-polarized current (representing weighted sum of input currents) that either delivers a spin transfer torque or induces domain wall motion in the soft layer of the MTJ to mimic neuron firing. Here, we propose and analyze a different type of spin-neuron in which the soft layer of the MTJ is switched with mechanical strain generated by a voltage (representing weighted sum of input voltages) and term it straintronic spin-neuron. It dissipates orders of magnitude less energy in threshold operations than the traditional current-driven spin neuron at 0 K temperature and may even be faster. We have also studied the room-temperature firing behaviors of both types of spin neurons and find that thermal noise degrades the performance of both types, but the current-driven type is degraded much more than the straintronic type if both are optimized for maximum energy-efficiency. On the other hand, if both are designed to have the same level of thermal degradation, then the current-driven version will dissipate orders of magnitude more energy than the straintronic version. Thus, the straintronic spin-neuron is superior to current-driven spin neurons. PMID- 26112079 TI - Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses. AB - There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies. PMID- 26112082 TI - Acute Sensorineural Hearing Loss After Abuse of an Inhaled, Crushed Oxymorphone Extended-Release Tablet. AB - Oxymorphone, a semisynthetic MU-opioid receptor agonist, is the major active metabolite of oxycodone. It is a highly potent narcotic analgesic due to its high lipid solubility, which allows it to readily cross the blood-brain barrier and enter the central nervous system. It is available as both an immediate-release and extended-release (ER) formulation. Oxymorphone can be abused by injection or inhalation of crushed tablets; thus, in 2011, the manufacturer of ER oxymorphone reformulated the drug with crush-resistant technology to deter its misuse and abuse. We describe the case of a previously healthy, 24-year-old male who experienced reproducible acute subjective bilateral temporary hearing loss that occurred after inhalation of oxymorphone. He presented to the emergency department complaining of acute bilateral hearing loss after he reported snorting a crushed oxymorphone ER 30-mg tablet. Emergency department evaluation revealed obvious bilateral hearing loss as well as coincidental aspiration pneumonia. The patient's medical history revealed that he had experienced a similar episode of hearing loss after a previous episode of oxymorphone inhalation. His hearing loss began to improve 3 hours after presentation to the emergency department and was completely resolved by the following day. Use of the Naranjo adverse drug reaction probability scale revealed oxymorphone to be a probable cause of this patient's acute hearing loss (score of 6). The mechanism of action of opioid associated hearing loss (OAHL) is not completely understood, but it is thought to be due to disturbances within the cochlea, such as cochlear ischemia. To our knowledge, this is only the second published case report of acute reversible hearing loss following oxymorphone inhalation and the first published case report of reproducible OAHL. Since opioid misuse continues to be prevalent despite attempts at reformulations to make the drugs crush resistant, a high degree of clinical suspicion is needed to evaluate and treat patients who present with unique findings after episodes of substance abuse, especially those related to tamper-resistant formulations. PMID- 26112083 TI - Hyperbaric oxygen pre-treatment impairs anoxic tolerance but improves hyperglycemic tolerance in peripheral nerve. AB - Prior research has suggested that treatment with hyperbaric oxygen (HBO) may change energy metabolism in the peripheral nerve, potentially resulting in improved tolerance to hyperglycemia and anoxia. In this paper, the in vitro rat sciatic nerve model was used to explore the effects of a single 90 min treatment with either 1 or 3 atmospheres of: oxygen, nitrogen or air on the ability of the peripheral nerve to tolerate intermittent anoxia or hyperglycemia. After this treatment, the nerve was placed in a perfusion system where the nerve action potential (NAP) was continuously recorded over the duration of a 16 h experiment. The amplitude, paired pulse response, velocity and duration of the NAP were used as markers of peripheral nerve function. The perfusate contained either 5 mmol/L or 55 mmol/L glucose and was either continuously oxygenated or intermittently replaced by an oxygen free solution of identical composition. HBO treatment primarily affected the amplitude and duration of the NAP. HBO improved the NAP in continuously oxygenated nerves exposed to the 55 mmol/L glucose perfusate but not the 5 mmol/L. However, it worsened the NAP in nerves exposed to intermittent anoxia and increased the rate at which the amplitude of the NAP declined during anoxia. Pressure had an effect on the NAP only for oxygen but not nitrogen or air. The effect of the HBO treatment persisted more than 1 h after the end of the treatment. PMID- 26112085 TI - Introduction and Welcome. PMID- 26112091 TI - Sensorineural hearing loss following induction chemotherapy plus concurrent chemoradiotherapy for advanced nasopharyngeal carcinoma. AB - OBJECTIVE: To compare the incidence of sensorineural hearing loss between those treated with docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by carboplatin concurrent chemoradiotherapy and those treated with conventional concurrent chemoradiotherapy for advanced nasopharyngeal carcinoma. METHODS: Serial pure tone audiometry was conducted in 36 nasopharyngeal carcinoma patients who were randomised into 2 groups. The first group received docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by carboplatin concurrent chemoradiotherapy. The second group received conventional concurrent chemoradiotherapy. RESULTS: The incidence of sensorineural hearing loss at speech frequency in the first group was 10 per cent and in the second group was 50 per cent (p = 0.0027). Bone conduction thresholds were significantly increased after completion of the treatment at 2-4 kHz in the first group and at all frequencies in the second group. CONCLUSION: The docetaxel, cisplatin and 5-fluorouracil induction chemotherapy regimen followed by concurrent chemoradiotherapy was associated with a lower incidence of sensorineural hearing loss than conventional concurrent chemoradiotherapy. This regimen may be the preferred choice of treatment for hearing preservation. PMID- 26112092 TI - Chromosome Banding in Amphibia. XXXII. The Genus Xenopus (Anura, Pipidae). AB - Mitotic chromosomes of 16 species of the frog genus Xenopus were prepared from kidney and lung cell cultures. In the chromosomes of 7 species, high-resolution replication banding patterns could be induced by treating the cultures with 5 bromodeoxyuridine (BrdU) and deoxythymidine (dT) in succession, and in 6 of these species the BrdU/dT-banded chromosomes could be arranged into karyotypes. In the 3 species of the clade with 2n = 20 and 4n = 40 chromosomes (X. tropicalis, X. epitropicalis, X. new tetraploid 1), as well as in the 3 species with 4n = 36 chromosomes (X. laevis, X. borealis, X. muelleri), the BrdU/dT-banded karyotypes show a high degree of homoeology, though differences were detected between these groups. Translocations, inversions, insertions or sex-specific replication bands were not observed. Minor replication asynchronies found between chromosomes probably involve heterochromatic regions. BrdU/dT replication banding of Xenopus chromosomes provides the landmarks necessary for the exact physical mapping of genes and repetitive sequences. FISH with an X. laevis 5S rDNA probe detected multiple hybridization sites at or near the long-arm telomeric regions in most chromosomes of X. laevis and X. borealis, whereas in X. muelleri, the 5S rDNA sequences are located exclusively at the long-arm telomeres of a single chromosome pair. Staining with the AT base pair-specific fluorochrome quinacrine mustard revealed brightly fluorescing heterochromatic regions in the majority of X. borealis chromosomes which are absent in other Xenopus species. PMID- 26112093 TI - Protective effect of a novel Rho kinase inhibitor WAR-5 in experimental autoimmune encephalomyelitis by modulating inflammatory response and neurotrophic factors. AB - The Rho-kinase (ROCK) inhibitor Fasudil has proven beneficial in experimental autoimmune encephalomyelitis (EAE). Given the small safety window of Fasudil, we are looking for novel ROCK inhibitors, which have similar or stronger effect on EAE with greater safety. In this study, we report that WAR-5, a Y-27632 derivative, alleviates the clinical symptoms, attenuates myelin damage and reduces CNS inflammatory responses in EAE C57BL/6 mice at an extent similar to Fasudil, while exhibits less vasodilator and adverse reaction in vivo. WAR-5 inhibits ROCK activity, and selectively suppresses the expression of ROCK II in spleen, brain and spinal cord of EAE mice, especially in spinal cord, accompanied by decreased expression of Nogo. WAR-5 also regulates the imbalance of Th1/Th17 T cells and regulatory T cells, inhibits inflammatory microenvironment induced with NF-kappaB-IL-1beta pathway. Importantly, WAR-5 converts M1 toward M2 microglia/macrophages that are positively correlated with BDNF and NT-3 production. Taken together, WAR-5 exhibits therapeutic potential in EAE by more selectively inhibits ROCK II, with a greater safety than Fasudil, and is worthy of further clinical study to clarify its clinical value. PMID- 26112095 TI - S100P and HYAL2 as prognostic markers for patients with triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a group of very aggressive breast tumours, characterised by lack of expression of oestrogen receptor (ER), progesterone receptor (PR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2). Nevertheless, TNBCs show different clinical characteristics and are very diverse regarding prognostic outcome. So far, only a few prognostic markers for TNBC have been reported that could be helpful for therapeutic stratification. Here we have analysed the expression of S100P and HYAL2 using immunohistochemistry (IHC) in a TNBC cohort of 98 patients with a follow-up for recurrence and death. TNBC patients with high expression of both proteins showed significantly shorter progression-free survival (PFS) (mean PFS=35.9months, P=0.001) compared to TNBC patients with high expression levels of only one of the proteins (mean PFS=69.4months) and to TNBC patients with low expression of both proteins (mean PFS=83.3months). Moreover, multivariate Cox-regression model showed the combined expression of S100P and HYAL2 as independent prognostic factor for PFS (P=0.001). The expression of S100P and HYAL2 indicated similar prognostic effect to the overall survival (OS) of TNBC patients. In addition, high expression levels of both S100P and HYAL2 showed significant association with different clinicopathological characteristics, such as more recurrence events (P=0.004), and higher occurrence of metastasis (P=0.002). Our study proposes S100P and HYAL2 as potential prognostic markers for TNBC. PMID- 26112096 TI - Assessment of association between genetic variants in microRNA genes hsa-miR-499, hsa-miR-196a2 and hsa-miR-27a and prostate cancer risk in Serbian population. AB - Due to their potentially functional significance, genetic variants within microRNA genes have been recognized as candidates for cancer-related genetic biomarkers. Among the most extensively studied so far are rs3746444, rs11614913 and rs895819. Nevertheless, only few previous studies in Asian population analyzed the association of rs3746444 and rs11614913 with prostate cancer (PCa) risk, while rs895819 was not evaluated in relation to this issue. The aim of this study was to assess the possible association between these genetic variants and PCa risk and progression in Serbian population. 355 samples of peripheral blood were obtained from the patients with PCa and 353 samples from patients with benign prostatic hyperplasia (BPH). 312 volunteers derived from general population who gave samples of buccal swabs were included in the control group. Genotyping of rs3746444, rs11614913 and rs895819 was performed by using PCR-RFLP method, HRM analysis and allele-specific PCR, respectively. Allelic and genotypic associations were evaluated by unconditional linear (for serum PSA level in PCa patients) and logistic regression method with adjustment for age. Minor allele C of rs895819 was found to be associated with the increased risk of developing PCa under dominant (P=0.035; OR=1.38, 95%CI 1.02-1.86) and overdominant (P=0.04; OR=1.37, 95%CI 1.01-1.85) genetic model. Same genetic variant was found to be associated with the clinical stage of localized PCa, as well as with the presence of distant metastases. Allele G of rs3746444 was also shown to be associated with the decreased risk of PCa progression. According to our data, rs3746444 qualifies for a genetic variant potentially associated with PCa aggressiveness in Serbian population. Furthermore, our study provided the first evidence of association between rs895819 and PCa risk, as well as for its genetic association with the presence of distant metastases among PCa patients. PMID- 26112094 TI - Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). AB - Nonalcoholic steatohepatitis (NASH) is characterized by extensive hepatic monocyte infiltration and monocyte-derived macrophages have an important role in regulating the disease evolution. However, little is known about the functional changes occurring in liver macrophages during NASH progression. In this study, we investigated phenotypic and functional modifications of hepatic macrophages in experimental NASH induced by feeding C57BL/6 mice with a methionine-choline deficient (MCD) diet up to 8weeks. In mice with steatohepatitis liver F4/80 positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolated cells. At immunofluorescence these cells contained lipid vesicles positive for the apoptotic cell marker Annexin V suggesting the phagocytosis of apoptotic bodies derived from dead fat laden hepatocytes. Flow cytometry revealed that these enlarged macrophages expressed inflammatory monocyte (CD11b, Ly6C, TNF-alpha) markers. However, as compared to regular size macrophages the enlarged sub-set was characterized by an enhanced production of arginase-1 and of the anti-inflammatory mediators IL-10 and annexin A1. Similar vacuolated macrophages producing annexin A1 were also evident in liver biopsies of NASH patients. In mice with NASH, the accumulation of enlarged F4/80(+) cells paralleled with a decline in the expression of the macrophage M1 activation markers iNOS, IL-12 and CXCL10, while the levels of M2 polarization markers arginase-1 and MGL-1 were unchanged. Interestingly, the lowering of IL-12 expression mainly involved the macrophage sub-set with regular size. We conclude that during the progression of NASH fat accumulation within liver macrophages promotes the production of anti-inflammatory mediators that influence hepatic inflammatory responses. PMID- 26112098 TI - The Role of Topical Brimonidine Tartrate Gel as a Novel Therapeutic Option for Persistent Facial Erythema Associated with Rosacea. AB - Rosacea is a chronic inflammatory skin condition that commonly presents with persistent facial erythema with or without the coincident presence of flushing, telangiectasias, inflammatory papules or pustules, phymatous changes, or ocular involvement. Patients often present with a constellation of various signs and symptoms of the disease, and an individualized treatment plan should be tailored to a patient's unique clinical presentation. Previously available medications for rosacea have all targeted the inflammatory erythematous papules and pustules frequently associated with the disease, leaving a therapeutic gap for the common manifestation of persistent facial erythema. Brimonidine tartrate 0.33% gel was approved by the US Food and Drug Administration in August 2013 as the first medication available for the topical treatment of persistent facial erythema associated with rosacea. Brimonidine gel is a highly selective alpha2-adrenergic receptor agonist with potent vasoconstrictive effects, which leads to significant reduction of persistent facial erythema in the majority of patients when applied once daily. Based on large-scale clinical trials and post-marketing reports, brimonidine gel has maintained a good safety profile with a minority of patients experiencing adverse effects from its use, most of which are cutaneous in nature, mild-to-moderate in degree, occur early after initiation of treatment, often resolve spontaneously with continued use, and generally resolve after discontinuation of use. Among the reported adverse effects, two distinct manifestations of worsened erythema have been described. Brimonidine gel can be integrated into a treatment regimen along with concomitant therapies for facial papules and pustules with no increased risk of adverse events with combination therapy. Education about optimal application methods, setting reasonable expectations for treatment, and minimizing inflammation are important factors for the successful use of brimonidine gel as part of a patient's overall rosacea treatment regimen. PMID- 26112097 TI - Hypermethylation of FOXD3 suppresses cell proliferation, invasion and metastasis in hepatocellular carcinoma. AB - As a transcriptional repressor, forkhead box D3 (FOXD3) plays an important role in tumorigenesis and progression of several tumors. However, the function and methylation status of FOXD3 remain unknown in the progression of hepatocellular carcinoma (HCC). In this study, we found that FOXD3 was decreased in HCC tissues and correlated with differentiation, AFP and poor survival of HCC patients (p<0.05). Down-regulation of FOXD3 in HCC tissues was mainly due to promoter hypermethylation. In vitro and in vivo functional results showed that ectopic FOXD3 inhibited the proliferation, migration, epithelial-mesenchymal transition (EMT) and invasion in HepG2 and SMMC-7721 cells, and FOXD3 depletion in HepG2 and QGY-7701 cells showed the adverse effects (p<0.05). Moreover, FOXD3 was sufficient to suppress tumor growth and pulmonary metastatic potential in mice. Our findings suggest that down-regulation of FOXD3, due to promoter hypermethylation plays an important role in the progression of HCC and may be a promising prognostic biomarker for HCC patients. PMID- 26112100 TI - Intracellular synthesis of glutamic acid in Bacillus methylotrophicus SK19.001, a glutamate-independent poly(gamma-glutamic acid)-producing strain. AB - BACKGROUND: Bacillus methylotrophicus SK19.001 is a glutamate-independent strain that produces poly(gamma-glutamic acid) (gamma-PGA), a polymer of D- and L glutamic acids that possesses applications in food, the environment, agriculture, etc. This study was undertaken to explore the synthetic pathway of intracellular L- and D-glutamic acid in SK19.001 by investigating the effects of tricarboxylic acid cycle intermediates and different amino acids as metabolic precursors on the production of gamma-PGA and analyzing the activities of the enzymes involved in the synthesis of L- and D-glutamate. RESULTS: Tricarboxylic acid cycle intermediates and amino acids could participate in the synthesis of gamma-PGA via independent pathways in SK19.001. L-Aspartate aminotransferase, L-glutaminase and L-glutamate synthase were the enzymatic sources of L-glutamate. Glutamate racemase was responsible for the formation of D-glutamate for the synthesis of gamma-PGA, and the synthetase had stereoselectivity for glutamate substrate. CONCLUSION: The enzymatic sources of L-glutamate were investigated for the first time in the glutamate-independent gamma-PGA-producing strain, and multiple enzymatic sources of L-glutamate were verified in SK19.001, which will benefit efforts to improve production of gamma-PGA with metabolic engineering strategies. PMID- 26112099 TI - Treatment of HAE Attacks in the Icatibant Outcome Survey: An Analysis of Icatibant Self-Administration versus Administration by Health Care Professionals. AB - BACKGROUND: Icatibant, a selective bradykinin B2 receptor antagonist for the treatment of acute hereditary angio-oedema (HAE) attacks in adults, can be administered by health care professionals (HCPs) or self-administered. This analysis compared characteristics and outcomes of acute HAE attacks treated with self-administered and HCP-administered icatibant in a real-world setting. METHODS: The Icatibant Outcome Survey (Shire, Zug, Switzerland; NCT01034969) is an international observational study monitoring the safety and effectiveness of icatibant treatment. Descriptive retrospective analyses were performed (February 2008 to December 2012). RESULTS: Icatibant was used in 652 attacks in 170 patients with HAE type I/II. Most icatibant injections were self-administered (431/652, 68.5%). The proportion of self-treated attacks increased over time (40.3% in 2009 vs. 89.7% in 2012). The median time to administration was significantly shorter in self- versus HCP-treated attacks (1.5 vs. 2.4 h; p = 0.016). Earlier treatment (<2 h after onset) was significantly associated with a shorter median time to resolution (2.5 vs. 5.0 h; p = 0.032) and attack duration (3.0 vs. 14.0 h; p < 0.0001), regardless of administration method. Patients self administered icatibant for attacks of all severities; overall, 34.7% of severe and 30.2% of very severe attacks were HCP treated. Logistic regression analysis did not find use of long-term prophylaxis, attack location or gender to be predictive for self-administration. CONCLUSIONS: The proportion of HAE attacks treated with self-administered icatibant increased over time. Patients successfully self-administered icatibant for a wide variety of HAE attacks, demonstrating that icatibant is generally well tolerated and effective for self administration. Self-administration of icatibant provides a complementary option to HCP administration, enabling optimization of patient care. PMID- 26112101 TI - Dopamine-assisted synthesis of carbon-coated silica for PCR enhancement. AB - Polymerase chain reaction (PCR) has become one of the most popular methods to identify genomic information on cells and tissues as well as to solve crimes and check genetic diseases. Recently, the nanomaterials including nanocomposite and nanoparticles have been considered as a next generation of solution to improve both quality and productivity of PCR. Herein, taking into these demands, carbon coated silica was synthesized using silica particles via polymerization of biocompatible dopamine (PD) to form polydopamine (PDA) film and carbonization of PDA into graphitic structures. For further investigation of the effects of as prepared silica, PDA-coated silica (PDA silica), and carbonized PDA silica (C-PDA silica), two different types of genes were adopted to investigate the influences of them in the PCR. Furthermore, the strong interaction between the nanocomposites and PCR reagents including polymerase and primers enables regulation of the PCR performance. The effectiveness of the nanocomposites was also confirmed through adopting the conventional PCR and real-time PCR with two different types of DNA as realistic models and different kinds of analytical methods. These findings could provide helpful insight for the potential application in biosensors and biomedical diagnosis. PMID- 26112102 TI - Inter-laboratory verification of European pharmacopoeia monograph on derivative spectrophotometry method and its application for chitosan hydrochloride. AB - Inter-laboratory verification of European pharmacopoeia (EP) monograph on derivative spectrophotometry (DS) method and its application for chitosan hydrochloride was carried out on two generation of instruments (earlier GBC Cintra 20 and current technology TS Evolution 300). Instruments operate with different versions of Savitzky-Golay algorithm and modes of generating digital derivative spectra. For resolution power parameter, defined as the amplitude ratio A/B in DS method EP monograph, comparable results were obtained only with algorithm's parameters smoothing points (SP) 7 and the 2nd degree polynomial and those provided corresponding data with other two modes on TS Evolution 300 Medium digital indirect and Medium digital direct. Using quoted algorithm's parameters, the differences in percentages between the amplitude ratio A/B averages, were within accepted criteria (+/-3%) for assay of drug product for method transfer. The deviation of 1.76% for the degree of deacetylation assessment of chitosan hydrochloride, determined on two instruments, (amplitude (1)D202; the 2nd degree polynomial and SP 9 in Savitzky-Golay algorithm), was acceptable, since it was within allowed criteria (+/-2%) for assay deviation of drug substance, for method transfer in pharmaceutical analyses. PMID- 26112103 TI - Novel push-pull heterocyclic azo disperse dyes containing piperazine moiety: Synthesis, spectral properties, antioxidant activity and dyeing performance on polyester fibers. AB - Six novel push-pull azo disperse dyes were synthesized via classical azo coupling reaction using 2-amino-thiazolyl derivatives as the diazo components and 1-(4 bromobenzyl)-4-phenylpiperazine as a key coupling intermediate. The structures of the dyes and synthesized intermediate were confirmed by FT-IR, (1)H NMR, (13)C NMR and UV-vis analyses. The solvatochromic behavior of the dyes was studied in a set of 10 solvents of different polarity and considerable results were obtained. The prepared heterocyclic azo dyes were applied for dyeing polyester fibers and their dyeing properties were studied. The fastness properties of the dyed fabrics such as wash, light and rubbing fastness degrees were measured by standard methods. Investigation of antioxidant activity of compounds was carried out by ferric reducing antioxidant power (FRAP) method. The synthesized dyes exhibited significant antioxidant activities. PMID- 26112104 TI - Ab initio theoretical reinvestigation of the ground and excited state properties of silylated coumarins: Good candidates for solid state dye lasers and dye sensitized solar cells. AB - We present ab initio theoretical calculations of various properties of the ground and excited states of basic coumarin (1) and its derivatives: 4-methylcoumarin (2), 7-aminocoumarin (3), 7-amino-4-methylcoumarin or coumarin 120 (4), 4 trifluoromethylcoumarin (5), 7-amino-4-trifluoromethylcoumarin or coumarin 151 (6), silylated coumarin 120 (7) and silylated coumarin 151 (8). We calculate the following: (i) ground and excited state dipole moments (ii) energies and locations of HOMOs and LUMOs (iii) SCF total energies of ground state (iv) excitation energies with oscillator strengths for first six excited states (v) C=O and C-N bond lengths in ground and excited states (vi) ground state thermodynamic and electronic properties. The ground and excited state properties of coumarins 1-8 are obtained within the framework of density functional theory using B3LYP and long-range-corrected (LRC) omegaB97X-D functionals with 6 31G(d,p) basis set. A detailed comparative analysis of different photo physical and electronic properties of silylated and unsilylated coumarins is made. On the basis of theoretical results we find many interesting features of silylation process and we can conclude that silylation will result in better long-term photo and thermodynamic stability compared to its unsilylated counterpart due to increase in the values of thermodynamic parameters like SCF total energy, G(0) and H(0), etc. Therefore, silylated molecules may become good candidates for solid state dye lasers and dye sensitized solar cells. In contrast, we find that both the functional B3LYP and LRC-omegaB97X-D predict nearly the same results for electronic, thermodynamic and photo physical properties of studied coumarins 1-8 in their ground states but B3LYP hybrid functional severely overestimates excited state dipole moments, underestimates vertical excitation energies, oscillator strengths, C=O and C-N bond lengths of studied coumarins. On the basis of our theoretical results we conclude that LRC-omegaB97X-D functional must be used for prediction of excited state properties of a molecule. PMID- 26112105 TI - Substituent effects on anion sensing of salicylidene Schiff base derivatives: Tuning sensitivity and selectivity. AB - A series of colorimetric anion sensors using the salicylidene Schiff bases with different substituents, including electron donating group (tert-butyl, in sensor 2), conjugated group (naphthyl, in sensor 3) and electron withdrawing group (chlorine, in sensor 4), respectively, have been developed. The substituents can not only impact chromogenic signal output, but also tune the sensitivity and selectivity of the anion sensing by their specific electron push-pull features. In particular, both 1 (without substituent) and 2 show high selectivity for F(-) over Cl(-), Br(-), I(-), AcO(-) and H2PO4(-), but the sensitivity of 2 is poorer than 1 due to the effect of electron donating groups. Sensor 3 exhibits higher sensitivity for F(-) than 1, but it is disturbed by the weak response to AcO(-) and H2PO4(-). Sensor 4 has the highest sensitivity for F(-), but shows the significant response to AcO(-) and H2PO4(-), which also decreases the selectivity for F(-). Finally, analytical applications of 1 for the detection of F(-) in aqueous medium and toothpaste have been studied. PMID- 26112106 TI - Syntheses, crystallographic, mass-spectroscopic determination and antioxidant studies of Co(II), Ni(II) and Cu(II) complexes of a new imidazol based Schiff base. AB - A new imidazole-based Schiff base, 2-((1H-imidazol-4 yl)methyleneamino)benzylalcohol (HL) and corresponding analogous bis(2-((1H imidazol-4-yl)methyleneimino)benzylalcohol)metal(II) perchlorates (M: Co(1), Ni(2), Cu(3)) have prepared and characterized by elemental analyses, ESI-MS, IR, UV-Vis spectroscopies and conductivity measurements. X-ray single crystal structures of 1 and 2 have been also determined. Elemental analyses, spectroscopic and conductance data of 3 demonstrated similar structural features with these of crystallographically characterized complexes and based upon this relevances, HL ligands are neutrally coordinated to metal(II) ions in tridentate mode and all complexes are isostructural, dicathionic, contain perchlorate anions as complementary ions and, are in octahedral geometry with the formulae of [M(HL)2](ClO4)2 (for 3) and [M(HL)2](ClO4)2.H2O (for 1 and 2). Radical scavenging activities of the complexes have been evaluated by using DPPH, DMPD(+), and ABTS(+) assays. SC50 values (MUg/mL) of the complexes and standards on DPPH, DMPD(+), ABTS(+) follow the sequences, BHA (9.06+/-0.33)>CMPD3 (15.62+/ 0.52)>CMPD2 (17.43+/-0.29)>Rutin (21.65+/-0.60)>CMPD1 (25.67+/-0.51)>Trolox (28.57+/-0.37), Rutin>BHA>CMPD3>CMPD2>Trolox>CMPD1, and Trolox>BHA>CMPD3>CMPD2>Rutin>CMPD1 respectively. PMID- 26112107 TI - Reproductive Isolation of Ips nitidus and I. shangrila in Mountain Forests of Western China: Responses to Chiral and Achiral Candidate Pheromone Components. AB - Eastern Palearctic conifers are subject to frequent bark beetle outbreaks. However, neither the species responsible nor the semiochemicals guiding these attacks are well understood. Two high-mountain Ips species on Qinghai spruce, Picea crassifolia, I. shangrila and I. nitidus, are typical in this regard. Six synthetic candidate pheromone components that we earlier identified from hindguts of unmated males of these two Ips species were tested for field activity in Qinghai province, P. R. China. For I. nitidus, racemic ipsdienol ((+/-)-Id) could replace the naturally-produced blend of enantiomers containing 74% (-)-(S)-Id (74:26 S:R), in attractive ternary or binary blends. In contrast, sympatric I. shangrila were attracted mainly to blends including Id of opposite chirality, 97% (+)-(R)-Id. Of the verbenols, (-)-trans-verbenol was inactive for I. nitidus or inhibitory for I. shangrila, but (-)-cis-verbenol (cV) was a key component of the pheromone in both species. Two fully factorial experiments demonstrated that (+/ )-Id, cV, and 2-methyl-3-buten-2-ol (MB) are components of the aggregation pheromone of I. nitidus, whereas only (+)-Id and cV are essential components of the aggregation pheromone of I. shangrila. While MB is not necessary for attraction of I. shangrila, it is an active antagonist and likely functions in species isolation. A review of the pheromone production and responses in Palearctic Ips and Pseudoips showed that cV is more common than methylbutenols, and both elicit qualitatively variable responses. Ipsdienol is the most common component with variable chirality, and is a necessary, but often not sufficient, factor for determining pheromone specificity. PMID- 26112108 TI - Role of JNK and Contribution of p53 into Growth Potential of Mesenchymal Progenitor Cells In Vitro. AB - Specific JNK and p53 inhibitors stimulated the formation of fibroblast colonies (CFU-F) and clusters (ClFU-F) and increased proliferative activity of mesenchymal progenitor cells. No effects of inhibitors of JNK and p53 on differentiation of progenitor elements were revealed. PMID- 26112120 TI - Company Profiles. PMID- 26112117 TI - National Speakers. PMID- 26112121 TI - Spontaneous seizures in Kcna1-null mice lacking voltage-gated Kv1.1 channels activate Fos expression in select limbic circuits. AB - Mice lacking voltage-gated Kv1.1 channels as a result of deletion of the Kcna1 gene are an extensively utilized genetic model of human epilepsy and sudden unexpected death in epilepsy because of their frequent seizures and genotypic phenotypic similarity to the human condition. Ictal behaviors, electrophysiological recordings, and gene expression studies suggest limbic circuits are critical for epilepsy in Kcna1-null mice, but the exact brain networks recruited by seizures remain unknown. In this study, Fos protein expression patterns were used to map limbic brain regions with increased neuronal activity at baseline and during spontaneous seizures in Kcna1-null mice by comparing seizing and non-seizing knockouts and wild-type controls. Basal Fos levels were unchanged in non-seizing knockout mice compared to wild types for all brain regions examined except the dentate gyrus granule cell layer which exhibited a significant decrease in Fos-positive cells. Following seizures, Kcna1 null brains exhibited significantly increased Fos labeling in the basolateral amygdala and the dentate hilus region, but not in other principal cell layers of the hippocampal formation. The selective Fos activation in the amygdala following seizures suggests that extra hippocampal limbic circuits may be critically involved with seizure generation or spread in Kcna1-null mice. Fos protein expression patterns were analyzed using immunohistochemistry to provide the first map of brain regions recruited by spontaneous seizures in mice lacking Kv1.1 channels, an extensively used genetic model of epilepsy. Seizures significantly increased Fos expression in the amygdala and hilus by about fourfold, suggesting an important contribution by extrahippocampal networks to epilepsy in this model. PMID- 26112123 TI - The Effects of 17-Methoxyl-7-Hydroxy-Benzene-Furanchalcone on Pressure Overload Induced Cardiac Remodeling in Rats and the Endothelial Mechanisms Based on PGI2. AB - AIM: The primary objective of this study was to study the effects of 17-methoxyl 7-hydroxy-benzene-furanchalcone (MHBFC) on pressure overload-induced cardiac remodeling in rats, as well as the endothelial mechanisms based on PGI2. METHODS: Six weeks following surgery, rats were divided randomly into the following groups: a sham group, a model group, an MHBFC 12 mg/kg/day group (MHBFC 12), an indomethacin 2 mg/kg/day group (Indo 2), and an Indo 2+ MHBFC 12 group. The MS 4000 organism signal system was used to record the rats' hemodynamic indices. Additionally, the heart weight was determined, and the cardiac remodeling index was calculated. HE and Masson's stains were utilized to perform histological analyses; the immunofluorescence was used to observe the microvessel density of myocardial tissue; the colorimetric method was used to determine the hydroxyproline content of cardiac tissue; the ELISA method was used to measure the plasma PGI2 content; and transmission electron microscopy was used to observe the ultrastructure of the myocardium. RESULTS: A hyperdynamic circulation state, cardiac remodeling, decreased microvessel density and decreased plasma PGI2 content were each observed in the model group compared with the sham group, in which any changes in the above parameters were effectively reversed by MHBFC. Single-use Indo administration resulted in the progression of these pathophysiological changes; however, MHBFC prevented the worsening of these parameters. CONCLUSION: MHBFC significantly reverses pressure overload-induced cardiac remodeling, and its mechanism may partially contribute to the amelioration of endothelial cell function and the augmentation of PGI2 synthesis and secretion. PMID- 26112122 TI - A novel method for screening colorectal cancer by infrared spectroscopy of peripheral blood mononuclear cells and plasma. AB - BACKGROUND: Early detection of colorectal cancer (CRC) can reduce mortality and morbidity. Current screening methods include colonoscopy and stool tests, but a simple low-cost blood test would increase compliance. This preliminary study assessed the utility of analyzing the entire bio-molecular profile of peripheral blood mononuclear cells (PBMCs) and plasma using Fourier transform infrared (FTIR) spectroscopy for early detection of CRC. METHODS: Blood samples were prospectively collected from 62 candidates for CRC screening/diagnostic colonoscopy or surgery for colonic neoplasia. PBMCs and plasma were separated by Ficoll gradient, dried on zinc selenide slides, and placed under a FTIR microscope. FTIR spectra were analyzed for biomarkers and classified by principal component and discriminant analyses. Findings were compared among diagnostic groups. RESULTS: Significant changes in multiple bands that can serve as CRC biomarkers were observed in PBMCs (p = ~0.01) and plasma (p = ~0.0001) spectra. There were minor but statistically significant differences in both blood components between healthy individuals and patients with benign polyps. Following multivariate analysis, the healthy individuals could be well distinguished from patients with CRC, and the patients with benign polyps were mostly distributed as a distinct subgroup within the overlap region. Leave-one-out cross-validation for evaluating method performance yielded an area under the receiver operating characteristics curve of 0.77, with sensitivity 81.5% and specificity 71.4%. CONCLUSIONS: Joint analysis of the biochemical profile of two blood components rather than a single biomarker is a promising strategy for early detection of CRC. Additional studies are required to validate our preliminary clinical results. PMID- 26112124 TI - The longitudinal effects of neighbourhood social and material deprivation change on psychological distress in urban, community-dwelling Canadian adults. AB - OBJECTIVE: The purpose of this study was to assess how longitudinal changes in neighbourhood material and social deprivation affect distress outcomes in adult Canadians. STUDY DESIGN: This study used a prospective cohort approach. METHODS: We paired data from 2745 urban participants of Canada's National Population Health Survey-who completed the Kessler 6-Item psychological distress screening tool at baseline and follow-up-with neighbourhood social and material deprivation data from the census-based Pampalon Deprivation Index. Data were paired using participants' postal code. We conducted multiple linear regression models, which were stratified by baseline deprivation level and controlled for key confounders. RESULTS: Most participants lived in neighbourhoods that did not change drastically in social or material deprivation level during the six years between baseline and follow-up. We found that a worsening of material settings was significantly associated with worsening distress scores at follow-up. This finding is discussed in the context of existing literature, and made relevant for urban health research and policy. PMID- 26112125 TI - Retrospective review of administration of childhood primary vaccination schedule in an Irish tertiary neonatal intensive care unit. AB - AIMS: Quantify and evaluate administration of the routine childhood primary vaccination schedule in a tertiary neonatal intensive care unit (NICU). STUDY DESIGN: Retrospective review of paper record of vaccinations administered to inpatients in the NICU from 01/01/2001-30/11/2013. METHODS: Data were extracted from hospital records and institutional databases and analysed using SPSS for Mac version 21. Analysis was made based on gestational age, chronological age at time of administration of vaccine, corrected gestational age at time of vaccine administration and type of vaccine received. RESULTS: For all preterm (gestation < 37 weeks) babies that received the first '6in1' vaccination while an inpatient (n = 344): mean gestational age = 27.3 weeks (sd = 2.6 weeks); mean chronological age at time of vaccination = 9.4 weeks. For all preterm patients that received the second '6in1' vaccination while an inpatient (n = 19): mean gestational age = 25.6 weeks (sd = 1.63); mean chronological age at time of vaccination = 18.4 weeks. For all term (gestation >= 37 weeks) patients that received the first '6in1' vaccination while an inpatient (n = 9): mean gestational age = 40.1 weeks (sd = 1.9); mean chronological age at time of vaccination = 9.8 weeks. There were no reported adverse events to any of the vaccinations administered. CONCLUSION: It is safe for premature infants to receive the routine vaccination schedule in a NICU setting. PMID- 26112126 TI - What impact does community service learning have on medical students' appreciation of population health? AB - OBJECTIVES: The Bar Ilan Faculty of Medicine places public health as a priority in its medical curriculum, emphasizing its importance by strategically placing the required course as first on entry into medical school. Students are introduced to the importance of population health and community engagement through participatory community learning experiences. This study aims to examine how participatory community teaching methods impact students' understanding and attitudes towards community health. STUDY DESIGN: Mixed quantitative and qualitative design. METHODS: 75 first year students completed the required public health course utilizing participatory community methods, including community visits, Team Based Learning, an ethnic forum, and lifestyle medicine. Evaluation comprised skills assessment through project work, analysis of reflective notes and comparison of assessment scores with students in the previous year who experienced a formal lecture-only based curriculum. RESULTS: Students acquired public health skills, including conducting a needs assessment, searching for research evidence and designing an evaluation framework. Reflective notes revealed in-depth understanding not only of course aims, but an appreciation of the social determinants of health and the local community. Test marks indicated public health knowledge reached a comparable standard (83 +/- 7.3) to the previous year (85 +/- 9.3; P = 0.431). CONCLUSIONS: Participatory community learning equips students with public health skills, knowledge, and enhanced understanding of communities. It offers a way to effectively teach public health, while emphasizing the extended role and societal responsibilities of doctors. PMID- 26112127 TI - Global Governance for Health: how to motivate political change? AB - In this article, we address a central theme that was discussed at the Durham Health Summit: how can politics be brought back into global health governance and figure much more prominently in discussions around policy? We begin by briefly summarizing the report of the Lancet - University of Oslo Commission on Global Governance for Health: 'The Political Origins of Health Inequity' Ottersen et al. In order to provide compelling evidence of the central argument, the Commission selected seven case studies relating to, inter alia, economic and fiscal policy, food security, and foreign trade and investment agreements. Based on an analysis of these studies, the report concludes that the problems identified are often due to political choices: an unwillingness to change the global system of governance. This raises the question: what is the most effective way that a report of this kind can be used to motivate policy-makers, and the public at large, to demand change? What kind of moral or rational argument is most likely to lead to action? In this paper we assess the merits of various alternative perspectives: health as an investment; health as a global public good; health and human security; health and human development; health as a human right; health and global justice. We conclude that what is required in order to motivate change is a more explicitly political and moral perspective - favouring the later rather than the earlier alternatives just listed. PMID- 26112129 TI - Adaptation of the hypothalamus-pituitary-adrenal axis to daily repeated stress does not follow the rules of habituation: A new perspective. AB - Repeated exposure to a wide range of stressors differing in nature and intensity results in a reduced response of prototypical stress markers (i.e. plasma levels of ACTH and adrenaline) after an acute challenge with the same (homotypic) stressor. This reduction has been considered to be a habituation-like phenomenon. However, direct experimental evidence for this assumption is scarce. In the present work we demonstrate in adult male rats that adaptation of the hypothalamus-pituitary-adrenal (HPA) axis to repeated stress does not follow some of the critical rules of habituation. Briefly, adaptation was stronger and faster with more severe stressors, maximally observed even with a single exposure to severe stressors, extremely long-lasting, negatively related to the interval between the exposures and positively related to the length of daily exposure. We offer a new theoretical view to explain adaptation to daily repeated stress. PMID- 26112130 TI - Organization and evolution of parieto-frontal processing streams in macaque monkeys and humans. AB - The functional organization of the parieto-frontal system is crucial for understanding cognitive-motor behavior and provides the basis for interpreting the consequences of parietal lesions in humans from a neurobiological perspective. The parieto-frontal connectivity defines some main information streams that, rather than being devoted to restricted functions, underlie a rich behavioral repertoire. Surprisingly, from macaque to humans, evolution has added only a few, new functional streams, increasing however their complexity and encoding power. In fact, the characterization of the conduction times of parietal and frontal areas to different target structures has recently opened a new window on cortical dynamics, suggesting that evolution has amplified the probability of dynamic interactions between the nodes of the network, thanks to communication patterns based on temporally-dispersed conduction delays. This might allow the representation of sensory-motor signals within multiple neural assemblies and reference frames, as to optimize sensory-motor remapping within an action space characterized by different and more complex demands across evolution. PMID- 26112128 TI - The rat's not for turning: Dissociating the psychological components of cognitive inflexibility. AB - Executive function is commonly assessed by assays of cognitive flexibility such as reversal learning and attentional set-shifting. Disrupted performance in these assays, apparent in many neuropsychiatric disorders, is frequently interpreted as inability to overcome prior associations with reward. However, non-rewarded or irrelevant associations may be of considerable importance in both discrimination learning and cognitive flexibility. Non-rewarded associations can have greater influence on choice behaviour than rewarded associations in discrimination learning. Pathology-related deficits in cognitive flexibility can produce selective disruptions to both the processing of irrelevant associations and associations with reward. Genetic and pharmacological animal models demonstrate that modulation of reversal learning may result from alterations in either rewarded or non-rewarded associations. Successful performance in assays of cognitive flexibility can therefore depend on a combination of rewarded, non rewarded, and irrelevant associations derived from previous learning, accounting for some inconsistencies observed in the literature. Taking this combination into account may increase the validity of animal models and may also reveal pathology specific differences in problem solving and executive function. PMID- 26112132 TI - Circularly polarized luminescence under near-UV excitation and structural elucidation of a Eu complex. AB - A new chiral diketonate ligand based on carvone binds early lanthanides. The Eu complex displays high circularly polarized (g(lum) = 0.82) red luminescence under near-UV excitation in the solid state. This is the first report on such CPL activity in the solid state with a rigorous protocol to exclude artifacts. Paramagnetic NMR spectroscopy revealed the nature and structure of the active species. PMID- 26112134 TI - A Family History of Lethal Prostate Cancer and Risk of Aggressive Prostate Cancer in Patients Undergoing Radical Prostatectomy. AB - We investigated whether a family history of lethal prostate cancer (PCa) was associated with high-risk disease or biochemical recurrence in patients undergoing radical prostatectomy. A cohort of radical prostatectomy patients was stratified into men with no family history of PCa (NFH); a first-degree relative with PCa (FH); and those with a first-degree relative who had died of PCa (FHD). Demographic, operative and pathologic outcomes were analyzed. Freedom from biochemical recurrence was examined using Kaplan-Meier log rank. A multivariate Cox logistic regression analysis was also performed. We analyzed 471 men who underwent radical prostatectomy at our institution with known family history. The three groups had: 355 patients (75%) in NFH; 97 patients (21%) in FH; and 19 patients (4%) in FHD. The prevalence of a Gleason score >=8, higher pathologic T stage, and biochemical recurrence (BCR) rates did not significantly differ between groups. On Kaplan-Meier analysis there were no differences in short-term BCR rates (p = 0.212). In this cohort of patients undergoing radical prostatectomy, those with first-degree relatives who died of PCa did not have an increased likelihood of high-risk or aggressive PCa or shorter-term risk of BCR than those who did not. PMID- 26112133 TI - Insulin-like factor regulates neural induction through an IGF1 receptor independent mechanism. AB - Insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) signalling is required for normal embryonic growth and development. Previous reports indicated that the IGF/IGF1R/MAPK pathway contributes to neural induction and the IGF/IGF1R/PI3K/Akt pathway to eye development. Here, we report the isolation of insulin3 encoding a novel insulin-like ligand involved in neural induction. Insulin3 has a similar structure to pro-insulin and mature IGF ligands, but cannot activate the IGF1 receptor. However, similar to IGFs, Insulin3 induced the gene expression of an anterior neural marker, otx2, and enlarged anterior head structures by inhibiting Wnt signalling. Insulin3 are predominantly localised to the endoplasmic reticulum when otx2 is induced by insulin3. Insulin3 reduced extracellular Wnts and cell surface localised Lrp6. These results suggest that Insulin3 is a novel cell-autonomous inhibitor of Wnt signalling. This study provides the first evidence that an insulin-like factor regulates neural induction through an IGF1R-independent mechanism. PMID- 26112135 TI - Duodenal Electric Stimulation: Results of a First-in-Man Study. AB - BACKGROUND: The aim of this study was to demonstrate feasibility and safety of a new electric duodenal stimulation system (EDS, BALANCE) in humans. Secondary objectives were to evaluate the effect on glycemic control and weight loss in patients with obesity and type 2 diabetes mellitus (T2DM). METHODS: In an open labeled, prospective, single-arm, non-randomized multicenter study, 12 obese T2DM patients with a mean HbA1c of 8.0% received laparoscopic implantation of the BALANCE duodenal stimulating device. Adverse events, changes in glycemic control, cardiovascular parameters, and weight were collected. The follow-up period after implantation was 12 months. RESULTS: Device related severe adverse events did not occur. Mean HbA1c decreased by 0.8% (p = 0.02) and mean fasting blood glucose level (FBG) was reduced by 19% (p = 0.038) after the 12 months. Mean HDL level increased from 44 to 48 mg/dl (p = 0.033). CONCLUSIONS: EDS is a feasible and safe procedure. Positive effects on T2DM and some cardiovascular parameters (HDL, weight) were seen. However, further prospective randomized blinded studies are needed in order to evaluate the potential of this new minimally invasive method. PMID- 26112136 TI - Super-Obesity in the Elderly: Is Bariatric Surgery Justified? AB - Although the prevalence of obese elderly patients is increasing, the outcomes of bariatric surgery in this potentially high-risk cohort remain poorly understood, especially those relating to quality of life. Furthermore, there is no data on the efficacy of bariatric surgery in the super-obese elderly. We identified 50 consecutive patients undergoing bariatric surgery aged 60 years or over, and compared the outcomes of the super-obese (BMI >= 50; n = 26) with those of BMI < 50. Mean follow-up was 33 months. There were no significant differences between the groups in terms of comorbidities, operation-type and peri-operative complications. Mean percentage excess weight loss was comparable between the groups (56.7 vs. 58.8 %; p = 0.81), as was resolution of comorbidities and post operative quality of life (mean Bariatric Analysis and Reporting Outcome System (BAROS) 3.5 vs. 3.1; p = 0.64). PMID- 26112137 TI - Is Bariatric Surgery Effective in Reducing Comorbidities and Drug Costs? A Systematic Review and Meta-Analysis. AB - The aim of this study was to assess drug use and costs before and after bariatric surgery (BS). A systematic review of the literature was carried out using the MeSH terms obesity, bariatric surgery, and drug costs for searches of 10 electronic databases up to July 2014. Data were extracted from the 11 studies (37,720 patients) that fulfilled the inclusion criteria. Where applicable, data were pooled by meta-analysis. The average number of drugs per patient decreased from 3.9 +/- 1.86 before surgery to 1.75 +/- 1.85 after surgery. Mean reduction in total cost of drugs was 49.8 % over a follow-up duration of 6-72 months. BS is effective for the improvement or resolution of comorbidities and significantly reduces drug use and costs. PMID- 26112138 TI - Construction and expression of human scFv-Fc against interleukin-33. AB - Interleukin-33 (IL-33) is a member of the IL-1 family and the ligand of orphan ST2 molecules. IL-33 is widely expressed in multiple tissues and cells, and mainly involved in regulating Th2 immune and inflammatory responses. Inhibiting IL-33 signaling pathways relieves the symptoms of allergic inflammation, indicating that IL-33 is a potential target for the treatment of allergic diseases. In this study, the recombinant vectors SP-scFv-Fc/pcDNA3.1 and SP-scFv Fc/PMH3(EN) were constructed to express a human scFv-Fcs against IL-33. The size of the inserted SP-scFv-Fc was approximately 1540bp. The RT-PCR results showed that SP-scFv-Fcs were successfully transfected into CHO K1 cells. Western blot analysis indicated specific binding of the expressed scFv-Fcs fusion protein (approximately 60kDa under reduced condition) with a goat anti-human IgG1 Fc antibody. The expression level of the scFv-Fcs from SP-scFv-Fc/PMH3(EN) was higher than that from SP-scFv-Fc/pcDNA3.1. A single high-expressing cell line was selected after three rounds of screening and the fusion protein was expressed in a suspension culture in serum-free medium. The level of expression products reached 20mg/L and the expressed and purified scFvs was further characterized and analyzed for bioactivity and functionality. The recombinant vectors for eukaryotic expression of scFv-Fcs against IL-33 were successfully constructed and the expressed scFv-Fcs was shown to be a suitable candidate for the development of a new therapy for allergic and autoimmune diseases. PMID- 26112139 TI - Focal unilateral polymicrogyria and epilepsy surgery. PMID- 26112140 TI - The prognostic value of IL10 and TNF alpha functional polymorphisms in premenopausal early-stage breast cancer patients. AB - BACKGROUND: Interleukin-10 and tumor necrosis factor alpha play an important role in breast carcinogenesis. Genes, encoding those two cytokines, contain single nucleotide polymorphisms, which are associated with differential levels of gene transcription. This study analyzes single nucleotide polymorphisms in interleukin 10 and tumor necrosis factor alpha genes and their contribution to breast cancer phenotype, lymph node status and survival in a group of young Lithuanian women with early-stage breast cancer patients. RESULTS: We genotyped 100 premenopausal Eastern European (Lithuanian) patients with stage I-II breast cancer, <= 50 years old at the time of diagnosis, for interleukin 10 -592A > C, -819C > T and -1082A > G and tumor necrosis factor alpha -308G > A single nucleotide polymorphisms in the gene promoter region. We used the polymerase chain reaction, namely a restriction fragment length polymorphism method, for a SNP analysis. All genotypes were in Hardy-Weinberg equilibrium and had the same distribution as the HapMap CEU population. Holders of IL10 -592A > C heterozygous IL10 -592 AC genotype had a higher probability of estrogen receptor positive breast cancer phenotype than homozygous variants (P = 0.017). Phased ACC haplotype of IL10 polymorphisms was associated with younger age of diagnosis (P = 0.017). Of all the tested single nucleotide polymorphisms, only TNFalpha -308G > A has revealed a prognostic capability for breast cancer survival. GA genotype carriers, compared to GG, showed a significant disadvantage in progression-free survival (P = 0.005, adjusted hazard ratio (HR) = 4.631, 95 % confidence interval (CI) = 1.587 - 13.512), metastasis-free survival (P = 0.010, HR = 4.708, 95 % CI = 1.445 - 15.345) and overall survival (P = 0.037, HR = 4.829, 95 % CI = 1.098 - 21.243). CONCLUSIONS: According to our data, IL10 -1082A > G, -819 T > C, -592A > C polymorphisms and phased haplotypes have not revealed a prognostic value for breast cancer. On the contrary, the TNFalpha -308 polymorphism might modulate the risk and contribute to the identification of patients at a higher risk of breast cancer recurrence, metastasis and worse overall survival among young Lithuanian early-stage breast cancer patients. PMID- 26112141 TI - Fluid curtailment during childhood diarrhea: a countdown analysis. AB - BACKGROUND: The foundation of recommended diarrhea management in young children is increased fluids and continued feeding. This increase in fluids is necessary to replace those lost during diarrhea and ultimately prevent dehydration. There may be an opportunity to prevent deaths in children under five by discouraging the practice of reducing or curtailing fluids during diarrhea episodes across different settings worldwide. METHODS: We quantify and describe the extent of fluid curtailment in children with diarrhea in a selection of countries (Burkina Faso, Democratic Republic of Congo, Ethiopia, Nigeria, Tanzania, and Uganda) with high burden of diarrhea-related mortality with national cross sectional survey data. We examine the practice of fluid curtailment in these countries and its relationship to child and household traits and to characteristics of diarrhea management. RESULTS: The prevalence of fluid curtailment among children under five with diarrhea is strikingly high in these countries: 55 % in Nigeria, 49 % in Ethiopia, 44 % in Uganda, 37 % in Tanzania, 36 % in DR Congo and 32 % in Burkina Faso. Fluid curtailment is associated with giving less food, potentially worsening the impact of this harmful practice. Children who were reported to have had fluids curtailed during diarrhea episodes were also 3.51 (95 % confidence, 2.66 - 4.64) times more likely to be reported to have food withheld (alpha = 0.05; p < 0.001). Children who received care from non-governmental providers, and those who were breastfed were more likely to have their fluids curtailed, as were children with an unimproved water source. Children of poorer or less educated mothers and those living in rural areas are more likely to have curtailed fluids, compared to children of less poor or more educated mothers, or those living in urban areas. CONCLUSIONS: The harmful practice of curtailing fluids for a child with diarrhea is highly prevalent, representing an increased risk of dehydration and complications due to diarrhea, including death, especially for children in specific subgroups. PMID- 26112142 TI - Inequalities in health: definitions, concepts, and theories. AB - Individuals from different backgrounds, social groups, and countries enjoy different levels of health. This article defines and distinguishes between unavoidable health inequalities and unjust and preventable health inequities. We describe the dimensions along which health inequalities are commonly examined, including across the global population, between countries or states, and within geographies, by socially relevant groupings such as race/ethnicity, gender, education, caste, income, occupation, and more. Different theories attempt to explain group-level differences in health, including psychosocial, material deprivation, health behavior, environmental, and selection explanations. Concepts of relative versus absolute; dose-response versus threshold; composition versus context; place versus space; the life course perspective on health; causal pathways to health; conditional health effects; and group-level versus individual differences are vital in understanding health inequalities. We close by reflecting on what conditions make health inequalities unjust, and to consider the merits of policies that prioritize the elimination of health disparities versus those that focus on raising the overall standard of health in a population. PMID- 26112143 TI - Food security and nutrition in the Russian Federation - a health policy analysis. AB - BACKGROUND: In the Russian Federation (Russia), an elevated burden of premature mortality attributable to non-communicable diseases (NCDs) has been observed since the country's economic transition. NCDs are largely related to preventable risk factors such as unhealthy diets. OBJECTIVE: This health policy study's aim was to analyze past and current food production and nutritional trends in Russia and their policy implications for Russia's NCD burden. DESIGN: We examined food security and nutrition in Russia using an analytical framework of food availability, access to food, and consumption. RESULTS: Agricultural production declined during the period of economic transition, and nutritional habits changed from high-fat animal products to starches. However, per-capita energy consumption remained stable due to increased private expenditures on food and use of private land. Paradoxically, the prevalence of obesity still increased because of an excess consumption of unsaturated fat, sugar, and salt on one side, and insufficient intake of fruit and vegetables on the other. CONCLUSIONS: Policy and economic reforms in Russia were not accompanied by a food security crisis or macronutrient deprivation of the population. Yet, unhealthy diets in contemporary Russia contribute to the burden of NCDs and related avoidable mortality. Food and nutrition policies in Russia need to specifically address nutritional shortcomings and food-insecure vulnerable populations. Appropriate, evidence informed food and nutrition policies might help address Russia's burden of NCDs on a population level. PMID- 26112144 TI - Current Advances in L-DOPA and DOPA-Peptidomimetics: Chemistry, Applications and Biological Activity. AB - L-3,4-Dihydroxyphenylalanine [2-amino-3-(3,4-dihydroxyphenyl) propanoic acid (L DOPA) is a natural constituent of animal and plant tissue derived from post translational modification of the amino acid tyrosine. L-DOPA is modified during metabolism to catecholamine neurotransmitters, noradrenaline and adrenaline, which are characterized by different biological activities. L-DOPA has been the first drug of choice in the therapy of Parkinson's disease that is a progressive neurodegenerative disorder involving the loss of dopaminergic neurons of substantia nigra pars compacta. The social and economic impact of these diseases is very high due to the progressive aging of the population. This review focuses on the biological effect of LDOPA, as well as on the synthesis of L-DOPA derivatives and their application in central nervous system diseases. Among them, L-DOPA-containing peptides (L-DOPA-Pep) show important biological and pharmacological activities. For example, L-DOPA analogues of the alpha-factor interact with models of the G protein-coupled receptor, inhibit the oxidation of low-density lipoproteins, and are used for improving L-DOPA absorption in long term treatment of Parkinson's disease and as skin moisturizer in cosmetic compositions. Moreover, L-DOPA residues in proteins provide reactive tools for the preparation of adhesives and coatings materials. Usually, L-DOPA-Pep is prepared by traditional liquid or solid state procedures starting from simple amino acids. Recently, selective side-chain modifications of pre-formed peptides have also been reported both for linear and branched peptides. Here, we describe the recent advances in the synthesis of L-DOPA and dopa-peptidomimetics and their biological and pharmacological activities, focusing the attention on new synthetic procedures and biological mechanism of actions. PMID- 26112145 TI - Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches. AB - Asymmetric dimethylarginine (ADMA) is a competitive endogenous inhibitor of nitric oxide synthase with a key role in the pathophysiology of endothelial dysfunction, in the progression of atherosclerosis and in cardiovascular diseases. Statins, renin-angiotensin-aldosterone system inhibitors, blood glucose lowering agents, insulin sensitizers, beta-blockers, estrogen replacement therapy, antioxidants, complex B vitamins, L-arginine and acetylsalicylic acid have been evaluated for their ability to reduce ADMA levels or inhibit its actions. Despite the major beneficial effects of these agents in cardiovascular disease, research has shown that their favorable actions are only partially mediated by reducing ADMA levels or by bypassing its effect in nitric oxide synthesis. Novel therapeutic approaches targeting selectively ADMA are encouraging, but have only been tested in vitro or in animal studies and further research is needed in order to conclude on how therapeutic strategies modulating ADMA actions can affect atherosclerosis progression and cardiovascular diseases. PMID- 26112146 TI - Curious (Old and New) Antiviral Nucleoside Analogues with Intriguing Therapeutic Potential. AB - In the current context of antiviral drug development, which has been traditionally dominated by herpesviruses, human immunodeficiency virus (HIV) and hepatitis C virus (HCV), a new viral target has been recently gained unforeseen attention, Ebola virus. Ten nucleoside analogues, or categories thereof, are reviewed for their therapeutic potential as antiviral drugs: (i) BCX4430, a C nucleoside; (ii) 4'-azido-, 4'-cyano-, and 4'-ethynyl derivatives; (iii) 4' thionucleosides; (iv) cordycepin (3'-deoxyadeosine); (v) pyrazofurin, another C nucleoside; (vi) neplanocin A analogues; (vii) EICAR, a ribavirin analogue; (viii) GR-92938X, a double carboxamide; (ix) sofosbuvir (Solvaldi((r))), a 2'-C methylnucleoside; and (x) favipiravir (T-705), a pyrazine analogue. PMID- 26112147 TI - Epidemiology and clinical predictors of biphasic reactions in children with anaphylaxis. AB - BACKGROUND: Epidemiologic data regarding biphasic reactions in children with anaphylaxis are sparse. OBJECTIVE: To investigate the incidence and clinical predictors of biphasic reactions in children presenting to the emergency department (ED) with anaphylaxis. METHODS: A health records review of ED visits at 2 large Canadian academic pediatric EDs was conducted. All visits that satisfied anaphylaxis diagnostic criteria of the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network were included. Predictors of biphasic reaction were analyzed using univariate and multiple logistic regression analyses. RESULTS: Of 1,749 ED records reviewed, 484 visits met the study inclusion criteria. Seventy-one patients (14.7%) developed biphasic reactions. The median age was 6 years (interquartile range 2.7-10.1) and 51 (71.8%) were boys. Forty-nine of the 71 (69%) delayed reactions involved respiratory and/or cardiovascular manifestations and 35 (49%) were treated with epinephrine. Five independent predictors for biphasic reactions were found: age 6 to 9 years (odds ratio [OR] 3.60, 95% confidence interval [CI] 1.5-8.58), delay in presentation to the ED longer than 90 minutes after the onset of the initial reaction (OR 2.58, 95% CI 1.47-4.53), wide pulse pressure at triage (OR 2.92, 95% CI 1.69-5.04), treatment of the initial reaction with more than 1 dose of epinephrine (OR 2.7, 95% CI 1.12-6.55), and administration of inhaled beta agonists in the ED (OR 2.39, 95% CI 1.24-4.62). CONCLUSION: Biphasic reactions seem to be associated with the severity of the initial anaphylactic reactions. We identified clinical predictors that could ultimately be used to identify patients who would benefit from prolonged ED monitoring and enable better utilization of ED resources. PMID- 26112148 TI - Effect of heating and cooling combination therapy on patients with chronic low back pain: study protocol for a randomized controlled trial. AB - BACKGROUND: Clinicians often apply heating or cooling stimulation for treatment of musculoskeletal pain. However, scalding, frostbite and skin ulcers may occur from the excessive use of either therapy alone. Heating and cooling combination therapy may be a suitable alternative for treatment of musculoskeletal diseases, although insufficient research has documented the safety and efficacy of such therapy. The purpose of this clinical trial is to determine the efficacy and safety of heating and cooling combination therapy for treatment of chronic low back pain. METHODS/DESIGN: This is a multicenter, parallel-group, double-blinded, randomized controlled trial to evaluate the efficacy and safety of a heating and cooling combination therapeutic device (OCH-S100) in patients with chronic low back pain. Eighty participants with chronic low back pain will be recruited from two hospitals in South Korea (Dongguk University Ilsan Oriental Hospital and Dongguk University Bundang Oriental Hospital). Enrolled patients will be randomly divided into a treatment group and a sham group. Patients in both groups will be given 10 treatments (15 min per treatment) over 4 weeks. The protocol will consist of five cycles of heating/cooling therapy (maximum: 45 degrees C, minimum: 15 degrees C) in the treatment group, and five cycles of sham therapy (maximum: 1 degrees C above skin temperature, minimum: 1 degrees C below skin temperature) in the sham group. The primary outcome measure is change from baseline in the 100 mm Visual Analogue Scale (VAS) for pain after 4 weeks. There are six secondary outcome measures that consider disability or range of motion (ROM). DISCUSSION: This research will determine the efficacy and safety of heating and cooling combination therapy on chronic low back pain. The results of this trial may have important implications for the more widespread use of heating and cooling combination therapy for treatment of musculoskeletal pain. TRIAL REGISTRATION: NCT02289170 (14 October 2014). PMID- 26112149 TI - Analysis of Potential Binding Sites of 3,5,4'-Trihydroxystilbene (Resveratrol) and trans-3,3',5,5'-Tetrahydroxy-4'-methoxystilbene (THMS) to the GAPDH Molecule Using a Computational Ligand-Docking Method: Structural and Functional Changes in GAPDH Induced by the Examined Polyphenols. AB - The presented study analyzed potential binding sites of 3,5,4'-trihydroxystilbene (resveratrol, RSV) and its derivative, trans-3,3',5,5'-tetrahydroxy-4' methoxystilbene (THMS) to glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The effects of stilbene analogs on the structure of GAPDH were determined by fluorescence spectroscopy and zeta potential measurements. To what extent the studied compounds affect the activity of the enzyme was also assessed. A computational ligand-docking study showed that there are 11 potential binding sites of RSV and 8 such sites of THMS in the GAPDH molecule. While resveratrol does not significantly affect the activity of the dehydrogenase upon binding to it, THMS leads to approximately 10% inactivation of this enzyme. THMS has no effect on GAPDH inactivation induced by the superoxide anion radical, in contrast to resveratrol, which increases dehydrogenase inactivation. PMID- 26112150 TI - SonoGraphic monitoring of severe focal B-cell myositis of the anterior calf muscle responsive to rituximab. PMID- 26112151 TI - Cyclam glycoconjugates as lectin ligands and protective agents of metal-induced amyloid aggregation. AB - Transition metal ion complexes of a number of chelators have been widely investigated due to their biological properties. The sugar conjugation of metal complexes has resulted in improved properties of the systems, such as solubility and lectin recognition. In this paper, we report the synthesis, the characterization of new glucose and galactose conjugates of 1,4,8,11 tetraazacyclotetradecane (cyclam) and their Cu(II) complexes. The glycoconjugates were proved to be protective agents of metal-induced amyloid aggregation. The binding constants of the galactose conjugate KA1=(3.07+/-0.16)*10(7) and KA2=(2.13+/-0.04)*10(7)M(-1) with the lectin Ricinus communis agglutinin (RCA120) as a model of galactose-specific human lectin were obtained with surface plasmon resonance. PMID- 26112152 TI - Iron(II) porphyrins induced conversion of nitrite into nitric oxide: A computational study. AB - Nitrite reduction to nitric oxide by heme proteins was reported as a protective mechanism to hypoxic injury in mammalian physiology. In this study, the pathways of nitrite reduction to nitric oxide mediated by iron(II) porphyrin (P) complexes, which were generally recognized as models for heme proteins, were investigated by using density functional theory (DFT). In view of two type isomers of combination of nitrite and Fe(II)(P), N-nitro- and O-nitrito-Fe(II) porphyrin complexes, and two binding sites of proton to the different O atoms of nitrite moiety, four main pathways for the conversion of nitrite into nitric oxide mediated by iron(II) porphyrins were proposed. The results indicate that the pathway of N-bound Fe(II)(P)(NO2) isomer into Fe(III)(P)(NO) and water is similar to that of O-bound isomer into nitric oxide and Fe(III)(P)(OH) in both thermodynamical and dynamical aspects. Based on the initial computational studies of five-coordinate nitrite complexes, the conversion of nitrite into NO mediated by Fe(II)(P)(L) complexes with 14 kinds of proximal ligands was also investigated. Generally, the same conclusion that the pathways of N-bound isomers are similar to those of O-bound isomer was obtained for iron(II) porphyrin with ligands. Different effects of ligands on the reduction reactions were also found. It is notable that the negative proximal ligands can improve reactive abilities of N-nitro-iron(II) porphyrins in the conversion of nitrite into nitric oxide compared to neutral ligands. The findings will be helpful to expand our understanding of the mechanism of nitrite reduction to nitric oxide by iron(II) porphyrins. PMID- 26112153 TI - Thermodynamics of binding of a sulfonamide inhibitor to metal-mutated carbonic anhydrase as studied by affinity capillary electrophoresis. AB - By affinity capillary electrophoresis (ACE), the thermodynamic binding constants of a sulfonamide (SA) inhibitor to bovine carbonic anhydrase II (CA) and metal mutated variants (M-CAs) were evaluated. 1-(4-Aminosulfonylphenylazo)-2-naphthol 6,8-disulfonate was used as the SA in the electrophoretic buffer for ACE. The Scatchard analysis of the dependence of the electrophoretic mobility of native CA on the SA concentration provided the binding constant to be Kb=(2.29+/ 0.05)*10(6) M(-1) (at pH8.4, 25 degrees C). On the other hand, apoCA showed far smaller value [Kb=(3.76+/-0.14)*10(2) M(-1)], suggesting that the coordination of SA to the Zn(II) center controlled the binding thermodynamics. The ACE of M-CAs showed the same behaviors as native CA but with different Kb values. For example, Co-CA adopting the same tetrahedral coordination geometry as native CA exhibited the largest Kb value [(2.55+/-0.05)*10(6) M(-1)] among the M-CAs. In contrast, Mn and Ni-CA, which adopted the octahedral coordination geometry, had Kb values that were about two orders of magnitude lower. Because the hydrophobic cavity of CA around the active center pre-organized the orientation of SA, thereby fixing the ligating NH(-) moiety to the apex of the tetrahedron supported by three basal His3 of CA, metals such as Zn and Co at the center of M-CA gave the most stable CA-SA complex. However, pre-organization was not favored for octahedral geometry. Thus, pre-organization of SA was the key to facilitating the tetrahedral coordination geometry of the Zn(II) active center of CA. PMID- 26112154 TI - Aerobic interval training reduces inducible ventricular arrhythmias in diabetic mice after myocardial infarction. AB - Diabetes mellitus (DM) increases the risk of heart failure after myocardial infarction (MI), and aggravates ventricular arrhythmias in heart failure patients. Although exercise training improves cardiac function in heart failure, it is still unclear how it benefits the diabetic heart after MI. To study the effects of aerobic interval training on cardiac function, susceptibility to inducible ventricular arrhythmias and cardiomyocyte calcium handling in DM mice after MI (DM-MI). Male type 2 DM mice (C57BLKS/J Lepr (db) /Lepr (db) ) underwent MI or sham surgery. One group of DM-MI mice was submitted to aerobic interval training running sessions during 6 weeks. Cardiac function and structure were assessed by echocardiography and magnetic resonance imaging, respectively. Ventricular arrhythmias were induced by high-frequency cardiac pacing in vivo. Protein expression was measured by Western blot. DM-MI mice displayed increased susceptibility for inducible ventricular arrhythmias and impaired diastolic function when compared to wild type-MI, which was associated with disruption of cardiomyocyte calcium handling and increased calcium leak from the sarcoplasmic reticulum. High-intensity exercise recovered cardiomyocyte function in vitro, reduced sarcoplasmic reticulum diastolic calcium leak and significantly reduced the incidence of inducible ventricular arrhythmias in vivo in DM-MI mice. Exercise training also normalized the expression profile of key proteins involved in cardiomyocyte calcium handling, suggesting a potential molecular mechanism for the benefits of exercise in DM-MI mice. High-intensity aerobic exercise training recovers cardiomyocyte function and reduces inducible ventricular arrhythmias in infarcted diabetic mice. PMID- 26112155 TI - Cardiovascular magnetic resonance compatible physical model of the left ventricle for multi-modality characterization of wall motion and hemodynamics. AB - BACKGROUND: The development of clinically applicable fluid-structure interaction (FSI) models of the left heart is inherently challenging when using in vivo cardiovascular magnetic resonance (CMR) data for validation, due to the lack of a well-controlled system where detailed measurements of the ventricular wall motion and flow field are available a priori. The purpose of this study was to (a) develop a clinically relevant, CMR-compatible left heart physical model; and (b) compare the left ventricular (LV) volume reconstructions and hemodynamic data obtained using CMR to laboratory-based experimental modalities. METHODS: The LV was constructed from optically clear flexible silicone rubber. The geometry was based off a healthy patient's LV geometry during peak systole. The LV phantom was attached to a left heart simulator consisting of an aorta, atrium, and systemic resistance and compliance elements. Experiments were conducted for heart rate of 70 bpm. Wall motion measurements were obtained using high speed stereo photogrammetry (SP) and cine-CMR, while flow field measurements were obtained using digital particle image velocimetry (DPIV) and phase-contrast magnetic resonance (PC-CMR). RESULTS: The model reproduced physiologically accurate hemodynamics (aortic pressure = 120/80 mmHg; cardiac output = 3.5 L/min). DPIV and PC-CMR results of the center plane flow within the ventricle matched, both qualitatively and quantitatively, with flow from the atrium into the LV having a velocity of about 1.15 m/s for both modalities. The normalized LV volume through the cardiac cycle computed from CMR data matched closely to that from SP. The mean difference between CMR and SP was 5.5 +/- 3.7%. CONCLUSIONS: The model presented here can thus be used for the purposes of: (a) acquiring CMR data for validation of FSI simulations, (b) determining accuracy of cine-CMR reconstruction methods, and PMID- 26112157 TI - Becatamide Found in Houttuynia cordata Suppresses P-selectin Expression Via Inhibiting COX Enzyme, Not Increasing cAMP in Platelets. AB - Atherosclerosis is a well-known inflammatory cardiovascular disease. Recent studies suggested potential anti-atherosclerosis effects of becatamide found in Houttuynia cordata. Therefore, in this study, we investigated potential effect of becatamide (1) and its analogues (enferamide (2), veskamide (3), oretamide (4) and amkamide (5)) on cyclooxygenase (COX)-1 and -2 and the production of cyclic adenosine monophosphate (cAMP), which are critically involved in platelet activation. Among them, becatamide was the most potent compound able to inhibit COX-1 (IC50 = 0.27 um) and -2 (IC50 = 0.78 um) (p < 0.05). The decreasing order of COX-1 and -2 inhibition activity was becatamide > veskamide > enferamide > oretamide > amkamide. As a result of the inhibition, the production of thromboxane B2 and P-selectin expression were suppressed by 35% (p < 0.05) and 28% (p < 0.05), respectively, in mouse blood treated with becatamide (0.25 um). However, becatamide did not increase intracellular cAMP in platelets. Therefore, the suppression of P-selectin expression was not blocked by beta 2-adrenoceptor antagonists, suggesting that the COX inhibition is likely an underlying mechanism for the P-selectin suppression. In summary, becatamide may be a potent compound to inhibit platelet activation by inhibiting COX enzymes, not by increasing cAMP. Published 2015. This article is a U.S. Government work and is in the public domain in the USA. PMID- 26112156 TI - A Comprehensive Atlas of the Adult Mouse Penis. AB - Mice are routinely used to study the development of the external genitalia and, in particular, the process of male urethral closure. This is because misplacement of the male penile urethra, or hypospadias, is amongst the most common birth defects reported in humans. While mice present a tractable model to study penile development, several structures differ between mice and humans, and there is a lack of consensus in the literature on their annotation and developmental origins. Defining the ontology of the mouse prepuce is especially important for the relevance and interpretation of mouse models of hypospadias to human conditions. We have developed a detailed annotation of the adult mouse penis that addresses these differences and enables an accurate comparison of murine and human hypospadias phenotypes. Through MRI data, gross morphology and section histology, we define the origin of the mouse external and internal prepuces, their relationship to the single human foreskin as well as provide a comprehensive view of the various structures of the mouse penis and their associated muscle attachments within the body. These data are combined to annotate structures in a novel 3D adult penis atlas that can be downloaded, viewed at any angle, and manipulated to examine the relationship of various structures. PMID- 26112158 TI - Birth Weight Variability and Language Development: Risk, Resilience, and Responsive Parenting. AB - OBJECTIVE: This study examined whether birth weight variation within the normal range was associated with language ability at 36 months, and whether responsive parenting-the putative protective factor-buffered children from the risk of relatively low birth weight. METHODS: In all, 467 community mother-child dyads were followed longitudinally from birth. Receptive language was measured at 36 months. Responsive parenting was assessed through observed interactions at 18 months and examined as the hypothesized moderator. RESULTS: Controlling for confounds, both birth weight and responsive parenting positively predicted children's language skills. There was also a significant interaction between birth weight and responsive parenting-higher responsivity was associated with better language ability, and this link was especially pronounced for children at risk owing to relatively low birth weight. CONCLUSION: Normative differences in birth weight are a source of variability in children's language, but postnatal socialization factors such as parenting may buffer this risk. PMID- 26112159 TI - Abdominal Computed Tomography Utilization and 30-day Revisitation in Emergency Department Patients Presenting With Abdominal Pain. AB - OBJECTIVES: The objective was to explore which patient characteristics are associated with repeat emergency department (ED) visitation within 30 days of ED discharge for patients presenting with abdominal pain. METHODS: A retrospective, observational study was conducted at a single, academic, urban ED with over 85,000 annual visits. A consecutive sample of adult patients with a chief complaint of abdominal pain from January 2010 through December 2010 who were discharged following ED evaluation were included in the analysis. A logistic regression model was used to determine which patient-level factors, including computed tomography (CT) utilization, were associated with the primary outcome of ED revisit within 30 days. RESULTS: Of 80,619 total ED patient visits during the study period, 3,928 ED discharges with a chief complaint of abdominal pain were included. A total of 487 (12.4%) patients revisited the ED within 30 days. No deaths were recorded. CT imaging was associated with a lower 30-day revisit rate (odds ratio [OR] = 0.69, 95% confidence interval [CI] = 0.55 to 0.87) after controlling for multiple other patient-level factors associated with revisits. Increasing age (OR = 1.01, 95% CI = 1.00 to 1.02), increasing triage pain scores (OR = 1.13, 95% CI = 1.08 to 1.18), elevated triage heart rate (OR = 1.42, 95% CI = 1.07 to 1.89), low sodium levels (OR = 1.56, 95% CI = 1.07 to 2.23), and anemia (OR = 1.42, 95% CI = 1.04 to 1.95) were all associated with increased rate of return. CONCLUSIONS: Performance of an abdominal CT was associated with fewer 30 day revisits, suggesting that future measures of "imaging appropriateness" and "ED overuse" consider downstream utilization of health care resources in addition to the index visit. PMID- 26112160 TI - Treatment Resistant Epilepsy in Autism Spectrum Disorder: Increased Risk for Females. AB - The male:female ratio in autism spectrum disorder (ASD) averages greater than 4:1 while the male:female ratio of ASD with epilepsy averages less than 3:1. This indicates an elevated risk of epilepsy in females with ASD; yet, it is unknown whether phenotypic features of epilepsy and ASD differ between males and females with this comorbidity. The goal of this study is to investigate sex differences in phenotypic features of epilepsy and ASD in a prospective sample of 130 children and young adults with an initial ASD diagnosis and subsequent epilepsy diagnosis. All participants were characterized by standardized diagnostic inventories, parent/caregiver completed questionnaires, and medical/academic record review. Diagnostic classifications of epilepsy, ASD, and intellectual disability were performed by board certified neurologists and a pediatric neuropsychologist. Results demonstrated a lower male:female ratio (1.8:1) in individuals with ASD and treatment-resistant epilepsy relative to those with ASD and treatment-responsive epilepsy (4.9:1), indicating a higher risk of treatment resistant epilepsy in females. Mild neuroimaging abnormalities were more common in females than males and this was associated with increased risk of treatment resistance. In contrast, ASD symptom severity was lower in females compared with males. Findings distinguish females with ASD and epilepsy as a distinct subgroup at higher risk for a more severe epilepsy phenotype in the context of a less severe ASD phenotype. Increased risk of anti-epileptic treatment resistance in females with ASD and epilepsy suggests that comprehensive genetic, imaging, and neurologic screening and enhanced treatment monitoring may be indicated for this subgroup. Autism Res 2016, 9: 311-320. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 26112161 TI - Alteration of local adipose tissue trace element homeostasis as a possible mechanism of obesity-related insulin resistance. AB - The mechanisms of association between obesity and the related metabolic disturbances in general and insulin resistance in particular are extensively studied. Taking into account a key role of adipose tissue insulin resistance in the development of systemic obesity-related insulin resistance, the estimation of mechanisms linking increased adiposity and impaired insulin signaling in adipocytes will allow to develop novel prophylactic and therapeutic approaches to treatment of these states. A number of trace elements like chromium, zinc, and vanadium have been shown to take part in insulin signaling via various mechanisms. Taking into account a key role of adipocyte in systemic carbohydrate homeostasis it can be asked if trace element homeostasis in adipose tissue may influence regulatory mechanisms of glucose metabolism. We hypothesize that caloric excess through currently unknown mechanisms results in decreased chromium, vanadium, and zinc content in adipocytes. Decreased content of trace elements in the adipose tissue causes impairment of intra-adipocyte insulin signaling subsequently leading to adipose tissue insulin resistance. The latter significantly contributes to systemic insulin resistance and further metabolic disruption in obesity. It is also possible that decreased adipose tissue trace element content is associated with dysregulation of insulin-sensitizing and proinflammatory adipokines also leading to insulin resistance. We hypothesize that insulin resistance and adipokine dysbalance increase the severity of obesity subsequently aggravating alteration of adipose tissue trace element balance. Single indications of high relative adipose tissue trace element content, decreased Cr, V, and Zn content in obese adipose tissue, and tight association between fat tissue chromium, vanadium, and zinc levels and metabolic parameters in obesity may be useful for hypothesis validation. If our hypothesis will be confirmed by later studies, adipose tissue chromium, vanadium, and zinc content may be used as a prognostic biomarker of metabolic disturbances in obesity. Hypothetically, development and approbation of drugs increasing adipose tissue chromium, vanadium, and zinc content may help to achieve better metabolic control in obesity and obesity-related insulin resistance. However, stronger basis is required to prove our hypothesis. In particular, future studies should investigate the influence of obesity severity of adipose tissue trace element content, estimate the association between adipose tissue metals and metabolic parameters, and highlight the mechanisms involved in these changes. Both in vivo and in vitro studies are required to support the hypothesis. PMID- 26112162 TI - Fecal Calprotectin and serum chromogranin A as potential biomarkers of irritable bowel syndrome symptom severity. AB - Irritable bowel syndrome (IBS) is a disorder of the lower gastrointestinal (GI) tract, which manifests as abdominal pain and/or discomfort accompanied by altered bowel function, in the absence of structural pathology. The onset and precipitation of IBS is the result of an interaction among several factors, including psychological distress, altered GI sensation and processing of sensory information as well as GI inflammation. These factors have varying contributions to disorder etiology in different patients, and in line with that, there is now emerging evidence about a low-grade inflammation in a subgroup of IBS patients. Because IBS diagnosis is based on the ROME III criteria, with the exclusion of structural pathology, patients are often exposed to numerous invasive and unpleasant tests. In order to decrease the cost of repeated testing, while simultaneously alleviating patients' anxiety, research should be aimed at detecting cost-effective biomarkers. We hypothesize chromogranin A (CgA) and fecal Calprotectin (FC) could be used to eliminate possible organic causes of IBS symptoms. Also, we hypothesize FC could be helpful in detecting IBS patients with low-grade inflammation. Forty-eight outpatients with IBS (76% females) completed a set of psychosocial measures (HRQoL, STAI, BDI, VSI, SF-36), and their FC and CgA levels were obtained. We found elevated CgA levels in 4 patients, but CgA levels were not related to any of the psychological measures used. Elevated FC levels were found in 12 patients. FC levels significantly correlated with the physical component of health related quality of life (HRQoL) (r48=-.42, p<.01). In addition, one-way ANOVA's were performed to test possible differences in psychosocial measures depending on the patient's FC status. The analysis showed only one significant difference. Patients with the highest levels of FC had significantly lower physical component of HRQoL compared to the other two groups of patients. PMID- 26112164 TI - One little, too little: Counting Canada's indigenous people for improved health reporting. AB - The way state governments, worldwide, count or do not count Indigenous peoples has contributed to inconsistent reporting of Indigenous health statistics. To address unreliable reporting in Canada, we reviewed laws on Indian status and the development of a national Indian Registration System (IRS) to track Indian status and eligibility. With this information as a guide, we linked the IRS to the Manitoba provincial health registry systems and were able to identify individuals with Indian status for health reporting. To improve reporting, we identified individuals often missed in this type of linkage. For instance, we identified children and adult children who were eligible for Indian status but not yet registered. Equally as important, we identified individuals not eligible for Indian status but have Indian heritage and/or represent potential individual Indian status eligibility cases before the courts to right a historic form of identity sex discrimination that has made them invisible in Canadian society and health reporting. A familial kinship approach was used to identify Indian children and adult children typically missed when a strict legal entitlement criteria is used for data linkage. Our reflective socio-legal data linkage approach expanded the number of Indian peoples for health reporting purposes and demonstrated a feasible, inclusive way to report on the health of Indians in Canada. PMID- 26112163 TI - Quantitative analysis of mRNA expression levels and DNA methylation profiles of three neighboring genes: FUS1, NPRL2/G21 and RASSF1A in non-small cell lung cancer patients. AB - BACKGROUND: Tumor suppressor gene (TSG) inactivation plays a crucial role in carcinogenesis. FUS1, NPRL2/G21 and RASSF1A are TSGs from LUCA region at 3p21.3, a critical chromosomal region in lung cancer development. The aim of the study was to analyze and compare the expression levels of these 3 TSGs in NSCLC, as well as in macroscopically unchanged lung tissue surrounding the primary lesion, and to look for the possible epigenetic mechanism of TSG inactivation via gene promoter methylation. METHODS: Expression levels of 3 TSGs and 2 DNA methyltransferases, DNMT1 and DNMT3B, were assessed using real-time PCR method (qPCR) in 59 primary non-small cell lung tumors and the matched macroscopically unchanged lung tissue samples. Promoter methylation status of TSGs was analyzed using methylation-specific PCRs (MSP method) and Methylation Index (MI) value was calculated for each gene. RESULTS: The expression of all three TSGs were significantly different between NSCLC subtypes: RASSF1A and FUS1 expression levels were significantly lower in squamous cell carcinoma (SCC), and NPRL2/G21 in adenocarcinoma (AC). RASSF1A showed significantly lower expression in tumors vs macroscopically unchanged lung tissues. Methylation frequency was 38-76%, depending on the gene. The highest MI value was found for RASSF1A (52%) and the lowest for NPRL2/G21 (5%). The simultaneous decreased expression and methylation of at least one RASSF1A allele was observed in 71% tumor samples. Inverse correlation between gene expression and promoter methylation was found for FUS1 (rs = -0.41) in SCC subtype. Expression levels of DNMTs were significantly increased in 75-92% NSCLCs and were significantly higher in tumors than in normal lung tissue. However, no correlation between mRNA expression levels of DNMTs and DNA methylation status of the studied TSGs was found. CONCLUSIONS: The results indicate the potential role of the studied TSGs in the differentiation of NSCLC histopathological subtypes. The significant differences in RASSF1A expression levels between NSCLC and macroscopically unchanged lung tissue highlight its possible diagnostic role in lung cancer in situ recognition. High percentage of lung tumor samples with simultaneous RASSF1A decreased expression and gene promoter methylation indicates its epigenetic silencing. However, DNMT overexpression doesn't seem to be a critical determinate of its promoter hypermethylation. PMID- 26112166 TI - Effects of multisensory and motor stimulation on the behavior of people with dementia. AB - A quasi-experimental study using a pre-posttest design was conducted in four aged care facilities to assess the effects of a person-centred care (PCC) multisensory stimulation (MSS) and motor stimulation (MS) program, implemented by direct care workers, on the behaviors of residents with dementia. Data were collected at baseline and after the intervention through video recordings of morning care routines. Forty-five residents with moderate and severe dementia participated in the study. A total of 266 morning care routines were recorded. The frequency and duration of a list of behaviors were analyzed. The frequency of engagement in task decreased significantly ( p = .002) however, its duration increased ( p = .039). The duration of gaze directed at direct care workers improved significantly ( p = .014) and the frequency of closed eyes decreased ( p = .046). There was a significant decrease in the frequency of the expression of sadness. These results support the implementation of PCC-MSS and MS programs as they may stimulate residents' behaviors. PMID- 26112165 TI - Emergency medical service, nursing, and physician providers' perspectives on delirium identification and management. AB - Purpose of the study The study objective was to understand providers' perceptions regarding identifying and treating older adults with delirium, a common complication of acute illness in persons with dementia, in the pre-hospital and emergency department environments. Design and methods The authors conducted structured focus group interviews with separate groups of emergency medical services staff, emergency nurses, and emergency physicians. Recordings of each session were transcribed, coded, and analyzed for themes with representative supporting quotations identified. Results Providers shared that the busy emergency department environment was the largest challenge to delirium recognition and treatment. When describing delirium, participants frequently detailed hyperactive features of delirium, rather than hypoactive features. Participants shared that they employed no clear diagnostic strategy for identifying the condition and that they used heterogeneous approaches to treat the condition. To improve care for older adults with delirium, emergency nurses identified the need for more training around the management of the condition. Emergency medical services providers identified the need for more support in managing agitated patients when in transport to the hospital and more guidance from emergency physicians on what information to collect from the patient's home environment. Emergency physicians felt that delirium care would be improved if they could have baseline mental status data on their patients and if they had access to a simple, accurate diagnostic tool for the condition. Implications Emergency medical services providers, emergency nurses, and emergency physicians frequently encounter delirious patients, but do not employ clear diagnostic strategies for identifying the condition and have varying levels of comfort in managing the condition. Clear steps should be taken to improve delirium care in the emergency department including the development of mechanisms to communicate patients' baseline mental status, the adoption of a systematized approach to recognizing delirium, and the institution of a standardized method to treat the condition when identified. PMID- 26112167 TI - Decreasing spatial disorientation in care-home settings: How psychology can guide the development of dementia friendly design guidelines. AB - Alzheimer's disease results in marked declines in navigation skills that are particularly pronounced in unfamiliar environments. However, many people with Alzheimer's disease eventually face the challenge of having to learn their way around unfamiliar environments when moving into assisted living or care-homes. People with Alzheimer's disease would have an easier transition moving to new residences if these larger, and often more institutional, environments were designed to compensate for decreasing orientation skills. However, few existing dementia friendly design guidelines specifically address orientation and wayfinding. Those that do are often based on custom, practice or intuition and not well integrated with psychological and neuroscientific knowledge or navigation research, therefore often remaining unspecific. This paper discusses current dementia friendly design guidelines, reports findings from psychological and neuropsychological experiments on navigation and evaluates their potential for informing design guidelines that decrease spatial disorientation for people with dementia. PMID- 26112168 TI - The structure and interaction mechanism of a polyelectrolyte complex: a dissipative particle dynamics study. AB - The mechanism of complex formation of two oppositely charged linear polyelectrolytes dispersed in a solvent is investigated by using dissipative particle dynamics (DPD) simulation. In the polyelectrolyte solution, the size of the cationic polyelectrolyte remains constant while the size of the anionic chain increases. We analyze the influence of the anionic polyelectrolyte size and salt effect (ionic strength) on the conformational changes of the chains during complex formation. The behavior of the radial distribution function, the end-to end distance and the radius of gyration of each polyelectrolyte is examined. These results showed that the effectiveness of complex formation is strongly influenced by the process of counterion release from the polyelectrolyte chains. The radius of gyration of the complex is estimated using the Fox-Flory equation for a wormlike polymer in a theta solvent. The addition of salts in the medium accelerates the complex formation process, affecting its radius of gyration. Depending on the ratio of chain lengths a compact complex or a loosely bound elongated structure can be formed. PMID- 26112169 TI - How active ingredient localisation in plant tissues determines the targeted pest spectrum of different chemistries. AB - BACKGROUND: The efficacies of four commercial insecticides and of two research compounds were tested against aphids (Aphis craccivora and Myzus persicae), whiteflies (Bemisia tabaci) and red-spotted spider mites (Tetranychus urticae) in intrinsic (oral administration), curative (direct contact spray) and translaminar (arthropods infested on untreated leaf underside) assays. With a new translaminar model, the transport across the leaf cuticle and tissues and the electrochemical distribution of test compounds in cellular compartments and apoplast were calculated. RESULTS: The comparison of both information sets revealed that the intracellular localisation of active ingredients determines the performance of test compounds against different target pests because of different feeding behaviours: mites feed on mesophyll, and aphids and whiteflies mostly in the vascular system. Polar compounds have a slow adsorption into leaf cells and thus a favourable distribution into apoplast and xylem sap. Slightly lipophilic bases get trapped in vacuoles, which is a less suited place to control hemipteran pests but appropriate to control mites. Non-favourable cellular localisation led to a strong reduction in translaminar efficacy against phloem feeders. CONCLUSION: Prediction and optimisation of intracellular localisation of pesticides add valuable new information for targeted bioavailability and can indicate directions for improved pesticide design. PMID- 26112170 TI - The changing faces of IgG4-related disease: Clinical manifestations and pathogenesis. AB - Since the earliest reports in 2001, immunoglobulin G4 (IgG4)-related disease has been defined as an autoimmune systemic disease characterized by the lymphoplasmacytic infiltration of affected tissues leading to fibrosis and obliterative phlebitis along with elevated serum IgG4 levels. Prior to this unifying hypothesis, a plethora of clinical manifestations were considered as separate entities despite the similar laboratory profile. The pathology can be observed in virtually all organs and may thus be a challenging diagnosis, especially when the adequate clinical suspicion is not present or when obtaining a tissue biopsy is not feasible. Nonetheless, the most frequently involved organs are the pancreas and exocrine glands but these may be spared. Immunosuppressants lead to a prompt clinical response in virtually all cases and prevent histological sequelae and, as a consequence, an early differential diagnosis from other conditions, particularly infections and cancer, as well as an early treatment should be pursued. We describe herein two cases in which atypical disease manifestations were observed, i.e., one with recurrent neck lymph node enlargement and proptosis, and one with jaundice. Our understanding of the pathogenesis of IgG4-related disease is largely incomplete but data support a significant role for Th2 cytokines with the contribution of innate immunity factors such as Toll-like receptors, macrophages and basophils. Further, macrophages activated by IL4 overexpress B cell activating factors and contribute to chronic inflammation and the development of fibrosis. We cannot rule out the possibility that the largely variable disease phenotypes reflect different pathogenetic mechanisms and the tissue microenvironment may then contribute to the organ involvement. PMID- 26112172 TI - Precision-cut kidney slices (PCKS) to study development of renal fibrosis and efficacy of drug targeting ex vivo. AB - Renal fibrosis is a serious clinical problem resulting in the greatest need for renal replacement therapy. No adequate preventive or curative therapy is available that could be clinically used to target renal fibrosis specifically. The search for new efficacious treatment strategies is therefore warranted. Although in vitro models using homogeneous cell populations have contributed to the understanding of the pathogenetic mechanisms involved in renal fibrosis, these models poorly mimic the complex in vivo milieu. Therefore, we here evaluated a precision-cut kidney slice (PCKS) model as a new, multicellular ex vivo model to study the development of fibrosis and its prevention using anti fibrotic compounds. Precision-cut slices (200-300 MUm thickness) were prepared from healthy C57BL/6 mouse kidneys using a Krumdieck tissue slicer. To induce changes mimicking the fibrotic process, slices were incubated with TGFbeta1 (5 ng/ml) for 48 h in the presence or absence of the anti-fibrotic cytokine IFNgamma (1 ug/ml) or an IFNgamma conjugate targeted to PDGFRbeta (PPB-PEG-IFNgamma). Following culture, tissue viability (ATP-content) and expression of alpha-SMA, fibronectin, collagen I and collagen III were determined using real-time PCR and immunohistochemistry. Slices remained viable up to 72 h of incubation, and no significant effects of TGFbeta1 and IFNgamma on viability were observed. TGFbeta1 markedly increased alpha-SMA, fibronectin and collagen I mRNA and protein expression levels. IFNgamma and PPB-PEG-IFNgamma significantly reduced TGFbeta1 induced fibronectin, collagen I and collagen III mRNA expression, which was confirmed by immunohistochemistry. The PKCS model is a novel tool to test the pathophysiology of fibrosis and to screen the efficacy of anti-fibrotic drugs ex vivo in a multicellular and pro-fibrotic milieu. A major advantage of the slice model is that it can be used not only for animal but also for (fibrotic) human kidney tissue. PMID- 26112171 TI - miR-146a targets Fos expression in human cardiac cells. AB - miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-kappaB, a transcription factor induced by pro-inflammatory molecules (such as TNF-alpha) that is strongly related to the pathogenesis of cardiac disorders. The main goal of this study consisted of studying new roles of miR-146a in cardiac pathological processes caused by the pro-inflammatory cytokine TNF-alpha. Our results demonstrate that miR-146a transcript levels were sharply increased in cardiac ventricular tissue of transgenic mice with specific overexpression of TNF-alpha in the heart, and also in a cardiomyocyte cell line of human origin (AC16) exposed to TNF-alpha. Among all the in silico predicted miR-146a target genes, Fos mRNA and protein levels notably decreased after TNF alpha treatment or miR-146a overexpression. These changes correlated with a diminution in the DNA-binding activity of AP-1, the Fos-containing transcription factor complex. Interestingly, AP-1 inhibition was accompanied by a reduction in matrix metalloproteinase (MMP)-9 mRNA levels in human cardiac cells. The specific regulation of this MMP by miR-146a was further confirmed at the secretion and enzymatic activity levels, as well as after anti-miR-mediated miR-146a inhibition. The results reported here demonstrate that Fos is a direct target of miR-146a activity and that downregulation of the Fos-AP-1 pathway by miR-146a has the capacity to inhibit MMP-9 activity. Given that MMP-9 is an AP-1 target gene involved in cardiac remodeling, myocardial dysfunction and progression of heart failure, these findings suggest that miR-146a might be a new and promising therapeutic tool for treating cardiac disorders associated with enhanced inflammation in the heart. PMID- 26112173 TI - SUMOylation of Wor1 by a novel SUMO E3 ligase controls cell fate in Candida albicans. AB - Candida albicans is the most common human fungal pathogen, yet is a normal commensal resident of the human gut. CO(2) levels in the gut are much higher than in air, and it is known that elevated CO(2) concentration promotes C. albicans cells to undergo a phenotypic switch from white to opaque phase. Wor1, the master regulator of opaque cell formation, is required for both the white to opaque transition and opaque maintenance. To elucidate the regulatory mechanism of Wor1, we set out to identify Wor1-interacting proteins using a yeast two-hybrid screen. A SUMO E3 ligase named Wos1 (Wor1 SUMO-ligase 1) was identified to interact with Wor1 and regulate Wor1 SUMOylation. WOS1 expression is upregulated in response to high CO(2), and the induction by CO(2) is dependent on the transcription factor Flo8. Under high CO(2) conditions, Wos1 is required for the white to opaque switch and acts downstream of Flo8. At atmospheric CO(2) levels, overexpression of Wos1 enhances Wor1 SUMOylation and promotes the white to opaque switch. Wor1 is found to be SUMOylated at lysine 385, and loss of this mark by point mutation leads to a defect in CO(2) -mediated opaque cell induction. Together, our genetic and biological data show that Wos1-mediated Wor1 SUMOylation contributes to the regulation of CO(2) -induced white to opaque switching as well as heritable maintenance of the opaque cell type. PMID- 26112174 TI - Hospital audit of delayed transfusion after orthopaedic surgery. AB - BACKGROUND AND OBJECTIVES: To understand the mechanisms related to both the onset and correction of severe anaemia after orthopaedic surgery, we analysed all the full blood counts (FBCs) for patients on one orthopaedic ward during a one-year period in an academic hospital. METHODS: FBCs were screened and the medical records of those patients for whom a postoperative haemoglobin (Hb) concentration below 8 g/dL was recorded at least once were reviewed. The onset of postoperative anaemia was determined by calculating the various time intervals delineated by surgery, the time at which the transfusion threshold was reached and the time at which the lowest Hb level (nadir) and transfusion (if any) occurred. RESULTS: A total of 6573 FBCs drawn from 1255 patients were screened. The medical records of 74 consecutive patients with at least one Hb value < 8 g/dL were analysed. The postoperative Hb nadir was 7.4 (+/- 0.6) g/dL (mean - SD). The medians (IQR 25 75) of the calculated intervals were: (surgery - nadir): 72 (48-144) h, (nadir - transfusion): 7 (5-21) h and (transfusion threshold - transfusion): 26 (11-51) h. CONCLUSIONS: Delayed transfusion (defined as > 12 hours between the time at which the transfusion threshold was reached and actual transfusion) was observed in 57% of severely anaemic patients after orthopaedic surgery. PMID- 26112175 TI - Endovascular Repair of Saccular Ascending Aortic Aneurysm After Orthotopic Heart Transplantation Using an Investigational Zenith Ascend Stent-Graft. AB - PURPOSE: To report the use of an investigational stent-graft to treat an ascending aortic aneurysm in a patient with a heart transplant. CASE REPORT: A 48 year-old man presented with a 3.5*1.5-cm saccular aneurysm in the mid anterior ascending aorta, abutting the sternum. The patient's history was notable for placement of a left ventricular assist device followed by orthotopic heart transplantation 2 years prior to treat end-stage familial dilated cardiomyopathy. Under compassionate use, a custom-designed ascending aortic stent-graft (Zenith Ascend) was successfully delivered via an 18-F system and deployed just distal to the origin of the left main coronary artery under pulmonary artery catheter guided rapid ventricular pacing. The patient was discharged the next day, and 6 month follow-up was unremarkable. Imaging at 5 months showed an excluded aneurysm sac with no endoleak or migration. CONCLUSION: The ideal ascending aortic stent graft should be low profile, conformable to the arch anatomy, with short tip delivery system and a stepwise deployment mechanism that allows precise placement relative to the ostia of the coronary arteries and the innominate artery. This case illustrates the advancement of endovascular techniques to the most challenging segment of the aorta to decrease morbidity and mortality in high-risk patients. PMID- 26112176 TI - Effectiveness of a Toothpaste with Low Fluoride Content Combined with Trimetaphosphate on Dental Biofilm and Enamel Demineralization in situ. AB - OBJECTIVE: The aim of the present study was to evaluate in situ whether a toothpaste with low fluoride associated with sodium trimetaphosphate (TMP) would provide similar effect to that of a 1,100 ppm F toothpaste. DESIGN: This crossover double-blind study consisted of 4 phases (14 days each), during which 10 volunteers wore oral appliances containing 4 enamel bovine blocks. The cariogenic challenge was performed by the application of a 20% sucrose solution (6*/day). The toothpaste treatments (2*/day) were: placebo, 500 ppm F, 500 ppm F plus 1% TMP, and 1,100 ppm F. At the end, enamel mineral loss and biofilm composition were analyzed. RESULTS: The toothpaste with 500 ppm F plus 1% TMP showed the lowest mineral loss (p < 0.05). Regarding the fluoride and calcium concentrations in the enamel and in the biofilm, there were no significant differences between 500 ppm F plus 1% TMP, and 1,100 ppm F toothpastes (p > 0.569), but they were significantly different when compared to toothpaste with 500 ppm F (p < 0.050). CONCLUSION: The addition of 1% TMP to a low-fluoride toothpaste reduces enamel demineralization in situ similar to a 1,100 ppm F toothpaste. PMID- 26112177 TI - Phytoremediation potential of Arabidopsis with reference to acrylamide and microarray analysis of acrylamide-response genes. AB - Acrylamide (ACR) is a widely used industrial chemical. However, it is a dangerous compound because it showed neurotoxic effects in humans and act as reproductive toxicant and carcinogen in many animal species. In the environment, acrylamide has high soil mobility and may travel via groundwater. Phytoremediation is an effective method to remove the environmental pollutants, but the mechanism of plant response to acrylamide remains unknown. With the purpose of assessing remediation potentials of plants for acrylamide, we have examined acrylamide uptake by the model plant Arabidopsis grown on contaminated substrates with high performance liquid chromatography (HPLC) analysis. The result revealed that acrylamide could be absorbed and degraded by Arabidopsis. Further microarray analysis showed that 527 transcripts were up-regulated within 2-days under acrylamide exposure condition. We have found many potential acrylamide-induced genes playing a major role in plant metabolism and phytoremediation. PMID- 26112178 TI - Long-Term Off-Line Extracorporeal Photochemotherapy in Patients with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single Centre Analysis. AB - BACKGROUND: Extracorporeal photochemotherapy (ECP) for chronic lung allograft dysfunction (CLAD) has been reported as beneficial in a few short-term studies. OBJECTIVES: In this retrospective cohort study on 48 CLAD patients treated by ECP (off-line technique) for a period of >8 years (compared to 58 controls), we explored potential predictors of survival and response. METHODS: Failures were defined as a decrease in forced expiratory volume in 1 s (FEV1) of >10% from ECP initiation. RESULTS: ECP patients were enrolled between February 2003 and December 2013; 14 (29.2%) with restrictive allograft syndrome (RAS) and 34 with bronchiolitis obliterans syndrome. Grade 1 severity was indicated in 58.3%, grade 2 in 20.8%, and grade 3 in 20.8% of patients. The median follow-up was 65 months (cumulative 2,284.4 person-months). Twenty (41.7%) patients died, including 17 (85%) CLAD-related deaths. Among the controls, there were 42 deaths (72.4%), of which 32 (76.2%) were CLAD related, over a median of 51 months (cumulative 3,066.5 person-months; p = 0.09). Among ECP patients, the FEV1 slope flattened out after a decline in the initial months (slope -19 ml/month in months 0-6, +4 in months 36-48 and later; p = 0.001). RAS was associated with poorer survival, whereas a 'rapid decline in the previous 6 months' was not. No ECP side effects or complications were observed. CONCLUSION: Long-term ECP for CLAD is safe and reduces FEV1 decline over time; the RAS phenotype might show a poorer response. ECP deserves to be evaluated in a randomized controlled trial. PMID- 26112179 TI - Suspected cecal volvulus as a reason for abdominal pain after gastric bypass: a case series. PMID- 26112180 TI - How long should we make the biliopancreatic limb during Roux-en-Y gastric bypass? PMID- 26112181 TI - Comment on: Laparoscopic Roux-en-Y gastric bypass for failed gastric banding: outcomes in 642 patients. PMID- 26112182 TI - 1alpha,25-dihydroxyvitamin D3 stimulates human SOST gene expression and sclerostin secretion. AB - Sclerostin, the SOST gene product, is a negative regulator of bone formation and a positive regulator of bone resorption. In this study, treatment of human primary osteoblasts, including cells differentiated to an osteocyte-like stage, with 1alpha,25-dihydroxyvitaminD3 (1,25D) resulted in the dose-dependent increased expression of SOST mRNA. A similar effect was observed in human trabecular bone samples cultured ex vivo, and in osteocyte-like cultures of differentiated SAOS2 cells. Treatment of SAOS2 cells with 1,25D resulted in the production and secretion of sclerostin protein. In silico analysis of the human SOST gene revealed a single putative DR3-type vitamin D response element (VDRE) at position -6216 bp upstream of the transcription start site (TSS). This sequence was confirmed to have strong VDRE activity by luciferase reporter assays and electrophoretic mobility shift analysis (EMSA). Sequence substitution in the VDR/RXR half-sites abolished VDRE reporter activity and binding of nuclear proteins. A 6.3 kb fragment of the human proximal SOST promoter demonstrated responsiveness to 1,25D. The addition of the evolutionary conserved region 5 (ECR5), a known bone specific enhancer region, ahead of the 6.3 kb fragment increased basal promoter activity but did not increase 1,25D responsiveness. Site specific mutagenesis abolished the responsiveness of the 6.3 kb promoter to 1,25D. We conclude that 1,25D is a direct regulator of human SOST gene and sclerostin protein expression, extending the pathways of control of sclerostin expression. At least some of this responsiveness is mediated by the identified classical VDRE however the nature of the transcriptional regulation by 1,25D warrants further investigation. PMID- 26112183 TI - Human somatostatin receptor-3 distinctively induces apoptosis in MCF-7 and cell cycle arrest in MDA-MB-231 breast cancer cells. AB - Somatostatin (SST) mediates cytostatic and pro-apoptotic effects through five somatostatin receptors (SSTR1-5). The modest clinical benefits of SST analogs in cancers of different origin such as breast cancer are attributed to diminished SSTRs expression at tumor sites. In the present study, SSTR3 was overexpressed in MCF-7 and MDA-MB-231, and analyzed for downstream signaling molecules associated with cytostatic and cytotoxic effect. Cells overexpressing SSTR3 displayed inhibition of EGF induced proliferation and enhanced antiproliferative effect of SSTR3-specific agonist in comparison to non-transfected cells. SSTR3 overexpression in MCF-7 cells (R3-MCF-7) constitutively enhanced TUNEL staining, PARP-1 and p27(Kip1) expression suggesting apoptosis and cell-cycle arrest. Conversely, R3-MB-231 cells with SSTR3 overexpression exerted cytostatic and were devoid of any cytotoxic effects. The expression of PTP-1C and the status of ERK1/2, p38 and PI3K phosphorylation was modulated in a cell-specific manner. These findings provide new insights in understanding the antiproliferative role of SSTR3 in breast tumor biology. PMID- 26112184 TI - Expression, regulation and function of Hmgn3 during decidualization in mice. AB - Although Hmgn3 is involved in the regulation of development and cellular differentiation, its physiological roles on decidualization are still unknown. Here we showed that Hmgn3 was highly expressed in the decidua and decidualizing stromal cells. Overexpression of Hmgn3 variants, Hmgn3a or Hmgn3b, enhanced the expression of decidualization markers Prl8a2 and Prl3c1, whereas inhibition of Hmgn3 reduced their expression. Hmgn3 could mediate the effects of Hoxa10 and cAMP on the expression of Prl8a2 and Prl3c1. Further study found that Hmgn3 directed the process of decidualization through influencing the expression of Hand2. Progesterone could induce the expression of Hmgn3 in the ovariectomized mouse uterus, uterine epithelial cells and stromal cells. Knockdown of Hoxa10 with siRNA alleviated the induction of progesterone and cAMP on Hmgn3 expression. Simultaneously, siRNA-mediated down-regulation of Hmgn3 in the uterine stromal cells could attenuate the effects of progesterone, cAMP and Hoxa10 on the expression of Hand2. Collectively, Hmgn3 may play an important role during mouse decidualization. PMID- 26112185 TI - The LH/CG receptor activates canonical signaling pathway when expressed in Drosophila. AB - G-protein coupled receptors (GPCRs) and their ligands provide precise tissue regulation and are therefore often restricted to specific animal phyla. For example, the gonadotropins and their receptors are crucial for vertebrate reproduction but absent from invertebrates. In mammals, LHR mainly couples to the PKA signaling pathway, and CREB is the major transcription factor of this pathway. Here we present the results of expressing elements of the human gonadotropin system in Drosophila. Specifically, we generated transgenic Drosophila expressing the human LH/CG receptor (denoted as LHR), a constitutively active form of LHR, and an hCG analog. We demonstrate activation-dependent signaling by LHR to direct Drosophila phenotypes including lethality and specific midline defects; these phenotypes were due to LHR activation of PKA/CREB pathway activity. That the LHR can act in an invertebrate demonstrates the conservation of factors required for GPCR function among phylogenetically distant organisms. This novel gonadotropin model may assist the identification of new modulators of mammalian fertility by exploiting the powerful genetic and pharmacological tools available in Drosophila. PMID- 26112187 TI - Infection with human retroviruses other than HIV-1: HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4. AB - HIV-1 is the most prevalent retrovirus, with over 30 million people infected worldwide. Nevertheless, infection caused by other human retroviruses like HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4 is gaining importance. Initially confined to specific geographical areas, HIV-2, HTLV-1 and HTLV-2 are becoming a major concern in non-endemic countries due to international migration flows. Clinical manifestations of retroviruses range from asymptomatic carriers to life threatening conditions, such as AIDS in HIV-2 infection or adult T-cell lymphoma/leukemia or tropical spastic paraparesis in HTLV-1 infection. HIV-2 is naturally resistant to some antiretrovirals frequently used to treat HIV-1 infection, but it does have effective antiretroviral therapy options. Unfortunately, HTLV still has limited therapeutic options. In this article, we will review the epidemiological, clinical, diagnostic, pathogenic and therapeutic aspects of infections caused by these human retroviruses. PMID- 26112186 TI - Glycan complexity dictates microbial resource allocation in the large intestine. AB - The structure of the human gut microbiota is controlled primarily through the degradation of complex dietary carbohydrates, but the extent to which carbohydrate breakdown products are shared between members of the microbiota is unclear. We show here, using xylan as a model, that sharing the breakdown products of complex carbohydrates by key members of the microbiota, such as Bacteroides ovatus, is dependent on the complexity of the target glycan. Characterization of the extensive xylan degrading apparatus expressed by B. ovatus reveals that the breakdown of the polysaccharide by the human gut microbiota is significantly more complex than previous models suggested, which were based on the deconstruction of xylans containing limited monosaccharide side chains. Our report presents a highly complex and dynamic xylan degrading apparatus that is fine-tuned to recognize the different forms of the polysaccharide presented to the human gut microbiota. PMID- 26112188 TI - Thermo-stable carbon nanotube-TiO2 nanocompsite as electron highways in dye sensitized solar cell produced by bio-nano-process. AB - We produced a thermostable TiO2-(anatase)-coated multi-walled-carbon-nanotube (MWNT) nanocomposite for use in dye-sensitized solar cells (DSSCs) using biological supuramolecules as catalysts. We synthesized two different sizes of iron oxide nanoparticles (NPs) and arrayed the NPs on a silicon substrate utilizing two kinds of genetically modified cage-shaped proteins with silicon binding peptide aptamers on their outer surfaces. Chemical vapor deposition (CVD) with the vapor-liquid-solid phase (VLS) method was applied to the substrate, and thermostable MWNTs with a diameter of 6 +/- 1 nm were produced. Using a genetically modified cage-shaped protein with carbon-nanomaterials binding and Ti mineralizing peptides as a catalyst, we were able to mineralize a titanium compound around the surface of the MWNT. The products were sintered, and thin TiO2-layer-coated MWNTs nanocomoposites were successfully produced. Addition of a 0.2 wt% TiO2-coated MWNT nanocomposite to a DSSC photoelectrode improved current density by 11% and decreased electric resistance by 20% compared to MWNT-free reference DSSCs. These results indicate that a nanoscale TiO2-layer-coated thermostable MWNT structure produced by our mutant proteins works as a superior electron transfer highway within TiO2 photoelectrodes. PMID- 26112189 TI - Cumulative Blood Pressure in Early Adulthood and Cardiac Dysfunction in Middle Age: The CARDIA Study. AB - BACKGROUND: Cumulative blood pressure (BP) exposure may adversely influence myocardial function, predisposing individuals to heart failure later in life. OBJECTIVES: This study sought to investigate how cumulative exposure to higher BP influences left ventricular (LV) function during young to middle adulthood. METHODS: The CARDIA (Coronary Artery Risk Development in Young Adults) study prospectively enrolled 5,115 healthy African Americans and whites in 1985 and 1986 (baseline). At the year 25 examination, LV function was measured by 2 dimensional echocardiography; cardiac deformation was assessed in detail by speckle-tracking echocardiography. We used cumulative exposure of BP through baseline and up to the year 25 examination (millimeters of mercury * year) to represent long-term exposure to BP levels. Linear regression and logistic regression were used to quantify the association of BP measured repeatedly through early adulthood (18 to 30 years of age) up to middle age (43 to 55 years). RESULTS: Among 2,479 participants, cumulative BP measures were not related to LV ejection fraction; however, high cumulative exposure to systolic blood pressure (SBP) and diastolic blood pressure (DBP) were associated with lower longitudinal strain rate (both p < 0.001). For diastolic function, higher cumulative exposures to SBP and DBP were associated with low early diastolic longitudinal peak strain rate. Of note, higher DBP (per SD increment) had a stronger association with diastolic dysfunction compared with SBP. CONCLUSIONS: Higher cumulative exposure to BP over 25 years from young adulthood to middle age is associated with incipient LV systolic and diastolic dysfunction in middle age. PMID- 26112190 TI - The Strain of Detecting Early Target Organ Damage in Hypertension. PMID- 26112191 TI - Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort. AB - BACKGROUND: Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial. OBJECTIVES: This study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes. METHODS: Longitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011. RESULTS: Among 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99). CONCLUSIONS: After adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed. PMID- 26112192 TI - Digoxin: In the Cross Hairs Again. PMID- 26112193 TI - Clinical Differentiation Between Physiological Remodeling and Arrhythmogenic Right Ventricular Cardiomyopathy in Athletes With Marked Electrocardiographic Repolarization Anomalies. AB - BACKGROUND: Physiological cardiac adaptation to regular exercise, including biventricular dilation and T-wave inversion (TWI), may create diagnostic overlap with arrhythmogenic right ventricular cardiomyopathy (ARVC). OBJECTIVES: The goal of this study was to assess the accuracy of diagnostic criteria for ARVC when applied to athletes exhibiting electrocardiographic TWI and to identify discriminators between physiology and disease. METHODS: The study population consisted of athletes with TWI (n = 45), athletes without TWI (n = 35), and ARVC patients (n = 35). Subjects underwent electrocardiography (ECG), signal-averaged electrocardiography (SAECG), echocardiography, cardiac magnetic resonance imaging (CMRI), Holter monitoring, and exercise testing. RESULTS: There were no electrical, structural, or functional cardiac differences between athletes exhibiting TWI and athletes without TWI. When athletes were compared with ARVC patients, markers of physiological remodeling included early repolarization, biphasic TWI, voltage criteria for right ventricular (RV) or left ventricular hypertrophy, and symmetrical cardiac enlargement. Indicators of RV pathology included the following: syncope; Q waves or precordial QRS amplitudes <1.8 mV; 3 abnormal SAECG parameters; delayed gadolinium enhancement, RV ejection fraction <=45%, or wall motion abnormalities at CMRI; >1,000 ventricular extrasystoles (or >500 non-RV outflow tract) per 24 h; and symptoms, ventricular tachyarrhythmias, or attenuated blood pressure response during exercise. Nonspecific parameters included the following: prolonged QRS terminal activation; <=2 abnormal SAECG parameters; RV dilation without wall motion abnormalities; RV outflow tract ectopy; and exercise-induced T-wave pseudonormalization. CONCLUSIONS: TWI and balanced biventricular dilation are likely to represent benign manifestations of training in asymptomatic athletes without relevant family history. Diagnostic criteria for ARVC are nonspecific in such individuals. Comprehensive testing using widely available techniques can effectively differentiate borderline cases. PMID- 26112194 TI - Suspected ARVC in the Athlete: Do T-Wave Findings Really Help in Diagnosis? PMID- 26112195 TI - Choice of Estimated Glomerular Filtration Rate Equation Impacts Drug-Dosing Recommendations and Risk Stratification in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Interventions. AB - BACKGROUND: Multiple equations exist to estimate glomerular filtration rate (GFR); however, there is no consensus on which is superior for risk classification in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). OBJECTIVES: The goals of this study were to identify which equation to estimate GFR is superior for predicting adverse outcomes after PCI and to examine how equation selection would impact drug-dosing recommendations. METHODS: Estimated GFR (eGFR) was calculated with the Cockcroft-Gault, Modification of Diet in Renal Disease Study (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations for 128,805 patients undergoing PCI in the state of Michigan. Agreement between patient pre PCI eGFR estimates and resultant CKD stage classifications, their ability to discriminate post-procedural in-hospital clinical outcomes, and the impact of equation choice on dosing recommendations for commonly used antiplatelet and antithrombotic medications were investigated. RESULTS: CKD-EPI best discriminated post-PCI mortality by receiver operator characteristic analysis. There was wide variability in eGFR, which persisted after grouping by CKD stages. Reclassification by CKD-EPI resulted in net reclassification index improvement for acute kidney injury and new requirement for dialysis. Equation choice affected drug-dosing recommendations, with the formulas agreeing for only 50.3%, 40.0%, and 34.3% of potentially impacted patients for eGFR cutoffs of <60, <50, and <30 ml/min/1.73 m(2), respectively. CONCLUSIONS: Different eGFR equations result in CKD stage reclassification that has major clinical implications for predicting adverse outcomes after PCI and drug-dosing recommendations. Our results support the use of CKD-EPI for risk stratification among patients undergoing PCI. PMID- 26112196 TI - Estimating Renal Filtration, Drug Dosing, and Clinical Outcomes. PMID- 26112197 TI - Evolution of the American College of Cardiology/American Heart Association Clinical Guidelines. AB - BACKGROUND: The American College of Cardiology (ACC) and the American Heart Association (AHA) have been developing clinical guidelines to assist practicing clinicians. OBJECTIVES: The goal of this study was to evaluate changes in ACC/AHA guideline recommendations between 2008 and 2014. METHODS: The previous and current ACC/AHA guideline documents that were updated between 2008 and June 2014 were compared to determine changes in Class of Recommendation (COR) and Level of Evidence (LOE). Each recommendation was classified as new, dropped, revised, or unchanged, and the changes in evidence were examined. RESULTS: During the study period, 11 guideline documents (9 disease based and 2 interventional procedure based) were updated. The total number of recommendations decreased from 2,067 to 1,869 (321 fewer recommendations in disease-based guidelines and 123 additional recommendations in interventional procedure-based guidelines). The recommendation class distribution of the updated guidelines was 50.1% Class I (previously 50.8%), 39.4% Class II (previously 35.4%), and 10.4% Class III (previously 13.8%) (p = 0.001). The LOE distribution among updated versions was 15.0% for LOE: A (previously 13.3%), 50.8% for LOE: B (previously 41.4%), and 34.2% for LOE C (previously 45.3%) (p < 0.001). Among all guidelines, 859 recommendations were new, 1,339 were dropped, 881 were unchanged in COR and LOE, and 129 were revised. Of the revised guidelines, 75 recommendations had an increase in LOE (the majority from LOE: C to LOE: B); 34 recommendations had a decrease in LOE; and 20 recommendations had class changes. LOE increases were justified by introduction of new randomized controlled trials, new studies, and new meta-analyses. CONCLUSIONS: The ACC/AHA guideline recommendations are undergoing significant changes, becoming more evidence based and scientifically robust with a tendency to exclude recommendations with insufficient scientific evidence. PMID- 26112198 TI - Evolution of the ACC/AHA Clinical Practice Guidelines in Perspective: Guiding the Guidelines. PMID- 26112199 TI - Cardiovascular Health of Patients With Cancer and Cancer Survivors: A Roadmap to the Next Level. AB - Many existing and emerging cancer therapies have a significant effect on the cardiovascular health of patients with cancer and cancer survivors. This paper examines current aspects of interdisciplinary cardio-oncology clinical care delivery and education in the United States and outlines how these data provide a platform for future development of the field. We present the results of the nationwide survey on cardio-oncology services, practices, and opinions, conducted among chiefs of cardiology and program directors, which demonstrate ranges of clinical activities and identify significant interest for increased educational opportunities and expert training of cardiovascular physicians in this field. The survey respondents recognized clinical relevance but emphasized lack of national guidelines, lack of funds, and limited awareness and infrastructure as the main challenges for development and growth of cardio-oncology. We discuss potential solutions to unmet needs through interdisciplinary collaboration and the active roles of professional societies and other stakeholders. PMID- 26112201 TI - The Cardiovascular Specialty Board of the American Board of Internal Medicine. PMID- 26112200 TI - Finding the Gatekeeper to the Cardiac Catheterization Laboratory: Coronary CT Angiography or Stress Testing? AB - Functional capacity is a robust predictor of clinical outcomes, and stress testing is used in current practice paradigms to guide referral to invasive coronary angiography. However, invasive coronary angiography is driven by ongoing symptoms, as well as risk of adverse outcomes. The limitations of current functional testing-based paradigms might be avoided by using coronary computed tomographic angiography (CCTA) for exclusion of obstructive coronary artery disease. The growth of CCTA has been supported by comparative prognostic evidence with CCTA and functional testing, as well as radiation dose reduction. Use of CCTA for physiological evaluation of coronary lesion-specific ischemia may facilitate evaluation of moderate stenoses, designation of the culprit lesion, and prediction of benefit from revascularization. The potential of CCTA to serve as an effective gatekeeper to invasive coronary angiography will depend, in part, on the adoption of these new developments, as well as definition of the benefit of detecting high-risk plaque for guiding the management of selected patients. PMID- 26112202 TI - Vascular Medicine: The Eye Cannot See What the Mind Does Not Know. PMID- 26112203 TI - Remote Ischemic Conditioning Reduces Myocardial Infarct Size in STEMI Patients Treated by Thrombolysis. PMID- 26112204 TI - Are Phytosterols Responsible for the Low-Density Lipoprotein-Lowering Effects of Tree Nuts?: A Systematic Review and Meta-Analysis. PMID- 26112206 TI - When to Call It Severe Mitral Regurgitation? PMID- 26112205 TI - Reply: When to Call It Severe Mitral Regurgitation? PMID- 26112207 TI - Underutilization of High-Intensity Statin Therapy After Hospitalization for Coronary Heart Disease: A Cause for Concern, But a Few Words of Caution. PMID- 26112208 TI - Reply: Underutilization of High-Intensity Statin Therapy After Hospitalization for Coronary Heart Disease: A Cause for Concern, But a Few Words of Caution. PMID- 26112209 TI - Seeing is believing: good graphic design principles for medical research. AB - Have you noticed when you browse a book, journal, study report, or product label how your eye is drawn to figures more than to words and tables? Statistical graphs are powerful ways to transparently and succinctly communicate the key points of medical research. Furthermore, the graphic design itself adds to the clarity of the messages in the data. The goal of this paper is to provide a mechanism for selecting the appropriate graph to thoughtfully construct quality deliverables using good graphic design principles. Examples are motivated by the efforts of a Safety Graphics Working Group that consisted of scientists from the pharmaceutical industry, Food and Drug Administration, and academic institutions. PMID- 26112210 TI - Activation of imidazoline-I3 receptors ameliorates pancreatic damage. AB - Agmatine, an endogenous ligand of imidazoline receptors, is reported to exhibit anti-hyperglycaemic and many other effects. It has been established that the imidazoline I3 receptor is involved in insulin secretion. The current study characterizes the role of the imidazoline I3 receptor in the protection of pancreatic islets. The activity effect of agmatine against on streptozotocin (STZ)-induced (5 mmol/L) rat beta cell apoptosis was examined by using ApoTox-Glo triplex assay, live/dead cell double staining assay, flow cytometric analysis, and western blot. Imidazoline I3 receptors antagonist KU14R and the phospholipase C inhibitor named U73122 were treated in beta cells to investigate the potential signalling pathways. The serum glucose and recovery of insulin secretion were measured in STZ-treated rats after continuously injected agmatine. The apoptosis in rat beta cells was reduced by agmatine in a dose-dependent manner, cell viability was improved after treatment with agmatine and these effects were suppressed after the blockade of KU14R and U73122. Western blot analysis confirmed that agmatine could decrease caspase-3 expression and increase the p BAD levels. In STZ-treated rats, injection of agmatine for 4 weeks may significantly lower the serum glucose and recovery of insulin secretion. This improvement of pancreatic islets induced by agmatine was deleted by KU14R in vivo. Agmatine can activate the imidazoline I3 receptor linked with the phospholipase C pathway to induce cell protection against apoptosis induced by a low dose of STZ. This finding provides new insight into the prevention of early stage pancreatic islet damage. PMID- 26112211 TI - Engineered Deinococcus radiodurans R1 with NiCoT genes for bioremoval of trace cobalt from spent decontamination solutions of nuclear power reactors. AB - The aim of the present work was to engineer bacteria for the removal of Co in contaminated effluents. Radioactive cobalt ((60)Co) is known as a major contributor for person-sievert budgetary because of its long half-life and high gamma-energy values. Some bacterial Ni/Co transporter (NiCoT) genes were described to have preferential uptake for cobalt. In this study, the NiCoT genes nxiA and nvoA from Rhodopseudomonas palustris CGA009 (RP) and Novosphingobium aromaticivorans F-199 (NA), respectively, were cloned under the control of the groESL promoter. These genes were expressed in Deinococcus radiodurans in reason of its high resistance to radiation as compared to other bacterial strains. Using qualitative real time-PCR, we showed that the expression of NiCoT-RP and NiCoT-NA is induced by cobalt and nickel. The functional expression of these genes in bioengineered D. radiodurans R1 strains resulted in >60 % removal of (60)Co (>=5.1 nM) within 90 min from simulated spent decontamination solution containing 8.5 nM of Co, even in the presence of >10 mM of Fe, Cr, and Ni. D. radiodurans R1 (DR-RP and DR-NA) showed superior survival to recombinant E. coli (ARY023) expressing NiCoT-RP and NA and efficiency in Co remediation up to 6.4 kGy. Thus, the present study reports a remarkable reduction in biomass requirements (2 kg) compared to previous studies using wild-type bacteria (50 kg) or ion-exchanger resins (8000 kg) for treatment of ~10(5)-l spent decontamination solutions (SDS). PMID- 26112212 TI - Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels. AB - OBJECTIVE: Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressant-like effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated. METHODS: Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants). RESULTS: Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1 mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT. CONCLUSION: These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression. PMID- 26112213 TI - Lrig1 and CD44v3 Expression in the Human Folliculosebaceous Unit. PMID- 26112214 TI - Wnt5a attenuates Wnt3a-induced alkaline phosphatase expression in dental follicle cells. AB - Wnt signaling regulates multiple cellular events such as cell proliferation, differentiation, and apoptosis through beta-catenin-dependent canonical and beta catenin-independent noncanonical pathways. Canonical Wnt/beta-catenin signaling can promote the differentiation of dental follicle cells, putative progenitor cells for cementoblasts, osteoblasts, and periodontal ligament cells, toward a cementoblast/osteoblast phenotype during root formation, but little is known about the biological significance of noncanonical Wnt signaling in this process. We identified the expression of Wnt5a, a representative noncanonical Wnt ligand, in tooth root lining cells (i.e. precementoblasts/cementoblasts) and dental follicle cells during mouse tooth root development, as assessed by immunohistochemistry. Silencing expression of the Wnt5a gene in a dental follicle cell line resulted in enhancement of the Wnt3a (a representative canonical Wnt ligand)-mediated increase in alkaline phosphatase (ALP) expression. Conversely, treatment with recombinant Wnt5a inhibited the increase in ALP expression, suggesting that Wnt5a signaling functions as a negative regulator of canonical Wnt-mediated ALP expression of dental follicle cells. Wnt5a did not affect the nuclear translocation of beta-catenin as well as beta-catenin-mediated transcriptional activation of T-cell factor (Tcf) triggered by Wnt3a, suggesting that Wnt5a inhibits the downstream part of the beta-catenin-Tcf pathway. These findings suggest the existence of a feedback mechanism between canonical and noncanonical Wnt signaling during the differentiation of dental follicle cells. PMID- 26112215 TI - Endostatin induces proliferation of oral carcinoma cells but its effect on invasion is modified by the tumor microenvironment. AB - The turnover of extracellular matrix liberates various cryptic molecules with novel biological activities. Endostatin is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of collagen XVIII. Although there are a large number of studies on its anti-tumor effects, the molecular mechanisms are not yet completely understood, and the reasons why endostatin has not been successful in clinical trials are unclear. Research has mostly focused on its anti-angiogenic effect in tumors. Here, we aimed to elucidate how endostatin affects the behavior of aggressive tongue HSC-3 carcinoma cells that were transfected to overproduce endostatin. Endostatin inhibited the invasion of HSC-3 cells in a 3D collagen-fibroblast model. However, it had no effect on invasion in a human myoma organotypic model, which lacks vital fibroblasts. Recombinant endostatin was able to reduce the Transwell migration of normal fibroblasts, but had no effect on carcinoma associated fibroblasts. Surprisingly, endostatin increased the proliferation and decreased the apoptosis of cancer cells in organotypic models. Also subcutaneous tumors overproducing endostatin grew bigger, but showed less local invasion in nude mice xenografts. We conclude that endostatin affects directly to HSC-3 cells increasing their proliferation, but its net effect on cancer invasion seem to depend on the cellular composition and interactions of tumor microenvironment. PMID- 26112216 TI - Co-regulation of SREBP-1 and mTOR ameliorates lipid accumulation in kidney of diabetic mice. AB - SREBP-1 and mTOR have been proved to involve in renal lipid metabolism of diabetes mellitus. In the present study, we investigated the effect of co regulation of SREBP-1 and mTOR on renal lipid metabolism using diabetic mice and cultured renal tubular cells. The results showed that compared with those in high glucose-stimulated HKC cells single transfected with shRNA-SREBP-1 vector, the level of SREBP-1 protein were significantly reduced by 64.1% followed by decreased FASN mRNA, ACC mRNA, ADRP protein and lipid droplets in HKC cells co transfected with shRNA-SREBP-1 vector and kinase-dead mTOR vector. Furthermore, diabetic mice co-injected with shRNA-SREBP-1 vector and kinase-dead mTOR vector showed that renal SREBP-1 protein, FASN mRNA and ACC mRNA were respectively decreased by 34.6%, 45.9%, 22.0% in comparison with those in diabetic mice single injected with shRNA-SREBP-1 vector accompanied by reduced ADRP protein and triglyceride content. In the end our study suggests that co-regulation of SREBP-1 and mTOR in kidney of diabetic mice is more effective in lowering renal lipogenesis than only regulation of SREBP-1. PMID- 26112217 TI - Histone deacetylase inhibitor valproic acid promotes the induction of pluripotency in mouse fibroblasts by suppressing reprogramming-induced senescence stress. AB - Histone deacetylase inhibitor valproic acid (VPA) has been used to increase the reprogramming efficiency of induced pluripotent stem cell (iPSC) from somatic cells, yet the specific molecular mechanisms underlying this effect is unknown. Here, we demonstrate that reprogramming with lentiviruses carrying the iPSC inducing factors (Oct4-Sox2-Klf4-cMyc, OSKM) caused senescence in mouse fibroblasts, establishing a stress barrier for cell reprogramming. Administration of VPA protected cells from reprogramming-induced senescent stress. Using an in vitro pre-mature senescence model, we found that VPA treatment increased cell proliferation and inhibited apoptosis through the suppression of the p16/p21 pathway. In addition, VPA also inhibited the G2/M phase blockage derived from the senescence stress. These findings highlight the role of VPA in breaking the cell senescence barrier required for the induction of pluripotency. PMID- 26112219 TI - Estimation of the cost-effectiveness of apixaban versus vitamin K antagonists in the management of atrial fibrillation in Argentina. AB - Apixaban, a novel oral anticoagulant which has been approved for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation, reduces both ischemic and haemorrhagic stroke and produces fewer bleedings than vitamin K antagonist warfarin. These clinical results lead to a decrease in health care resource utilization and, therefore, have a positive impact on health economics of atrial fibrillation. The cost-effectiveness of apixaban has been assessed in a variety of clinical settings and countries. However, data from emergent markets, as is the case of Argentina, are still scarce.We performed a cost-effectiveness analysis of apixaban versus warfarin in non-valvular atrial fibrillation (NVAF) in patients suitable for oral anticoagulation in Argentina. A Markov-based model including both costs and effects were used to simulate a cohort of patients with NVAF. Local epidemiological, resource utilization and cost data were used and all inputs were validated by a Delphi Panel of local experts. We adopted the payer's perspective with costs expressed in 2012 US Dollars.The study revealed that apixaban is cost-effective compared with warfarin using a willingness to pay threshold ranging from 1 to 3 per capita Gross Domestic Product (11558 - 34664 USD) with an incremental cost-effectiveness ratio of 786.08 USD per QALY gained. The benefit is primarily a result of the reduction in stroke and bleeding events.The study demonstrates that apixaban is a cost-effective alternative to warfarin in Argentina. PMID- 26112218 TI - Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells. AB - Despite its wide use as a first-line therapeutic agent, gemcitabine has shown limited efficacy in advanced pancreatic cancer due to chemoresistance by as yet unidentified mechanisms. Our goal here was to identify molecular features involved in gemcitabine chemoresistance. Pyruvate kinase M2 (PKM2), a key enzyme of aerobic glycolysis, has recently emerged as an important therapeutic target for cancer treatment. It is involved in the metabolic reprogramming of cancer cells and has previously unexpected non-metabolic functions that are heavily involved in tumor growth and survival. Herein, we report that the chemoresistance of pancreatic cancer to gemcitabine was dependent on PKM2 expression and its non metabolic function. Knocking-down of PKM2 significantly enhanced gemcitabine induced cell apoptosis through the activation of caspase 3/7 and PARP cleavage, and this inhibitory activity was associated with p38-mediated activation of p53 phosphorylation at serine 46. Our findings support the potential of PKM2 as a novel target for gemcitabine chemoresistance and suggest the feasibility of combining gemcitabine and PKM2 inhibition for the improved chemotherapy of pancreatic cancer. PMID- 26112220 TI - Lessons learnt from a cluster-randomised trial evaluating the effectiveness of Self-Management Support (SMS) delivered by practice nurses in routine diabetes care. AB - OBJECTIVE: To evaluate the effectiveness of biopsychosocial Self-Management Support (SMS) delivered by practice nurses in routine diabetes care. DESIGN: A pragmatic cluster-randomised controlled trial within a hybrid effectiveness implementation study design. Practice nurses were cluster-randomised. SETTING: A regional care group in the Netherlands consisting of 77 family practices. The study involved practice nurses (n=40) providing care to approximately 4000 patients with diabetes. PARTICIPANTS: Patients with type 2 diabetes (n=264) selected by a self-administered questionnaire aimed at measuring emotional distress and diabetes-related reduced daily functioning. INTERVENTION: Practice nurses in the intervention arm (n=19) were trained to integrate SMS into their routine consultations. SMS included detection of patients with emotional distress and reduced daily functioning, and supporting them when needed through problem solving and reattribution techniques. Practice nurses in the control arm (n=21) provided usual care. MAIN OUTCOME MEASURES: The primary outcome measure was a dichotomised score on a Visual Analogue Scale that measured the perceived effect of diabetes on daily functioning. Secondary measures included patients' diabetes related distress, quality of life, autonomy and participation, self-efficacy, self-management and glycaemic control. Outcomes were measured at baseline and at 4-month and 12-month follow-ups. RESULTS: Only 16 of the 117 patients in the intervention arm (14%) who were found eligible by the posted research-driven screening questionnaire were detected by their practice nurses. Extra consultations for the self-management support were delivered to only 11 study participants. In the control arm, 147 patients received usual care. Multilevel analyses showed no significant differences in outcomes between the intervention and control arms. CONCLUSIONS: SMS in its present form was not effective. The research-driven screening to select trial participants appeared to be inconsistent with nurse-led detection in routine practice. Adequate follow-up moments need to be built in to overcome barriers resulting from tension between the implementation and effectiveness parts of hybrid studies. TRIAL REGISTRATION NUMBER: Current Controlled Trials NTR2764. PMID- 26112221 TI - Prayer or spiritual healing as adjuncts to conventional care: a cross sectional analysis of prevalence and characteristics of use among women. AB - OBJECTIVES: To determine the prevalence and characteristics of users of prayer or spiritual healing among women. DESIGN AND SETTING: This cross sectional study was conducted as a part of the Australian Longitudinal Study on Women's Health (ALSWH), a 20-year study that examines various factors affecting women's health and well-being. PARTICIPANTS: The sample used in the current study were women from the 1946-1951 cohort (n=9965) (59-64 years) who were surveyed in 2010. OUTCOME MEASURES: Use of prayer or spiritual healing; demographic factors and measures of health status. chi(2) Tests, analyses of variance (to determine associations) and a stepwise backward logistic regression model (for the most significant predictors) using a likelihood ratio test were used to determine the outcome measures. RESULTS: It is estimated that 26% of Australian women from the 1946-1951 cohort (aged 59-64 years) use prayer or spiritual healing on a regular basis. Women were significantly more likely to use prayer or spiritual healing if they were non-smokers, non-drinkers or low-risk drinkers, had symptoms of severe tiredness (OR 1.25; 95% CI 1.12 to 1.40), depression, (OR 1.30; 95% CI 1.11 to 1.53), anxiety (OR 1.33; 95% CI 1.15 to 1.53), diagnosed cancer (OR 1.84; 95% CI 1.28 to 2.65) or other major illnesses (OR 1.43; 95% CI 1.18 to 1.75) and used other complementary therapies. CONCLUSIONS: A significant proportion of adult women are using prayer or spiritual healing. Given that prayer or spiritual healing was significantly associated with health symptoms, chronic illnesses and positive health seeking behaviours, respect for prayer or spiritual healing practices is required within health care settings. Future research is recommended around specific populations using prayer or spiritual healing, reasons for their use and potential benefits on health related outcomes and general well-being. PMID- 26112222 TI - Is self-monitoring an effective option for people receiving long-term vitamin K antagonist therapy? A systematic review and economic evaluation. AB - OBJECTIVES: To investigate the clinical and cost-effectiveness of self-monitoring of coagulation status in people receiving long-term vitamin K antagonist therapy compared with standard clinic care. DESIGN: Systematic review of current evidence and economic modelling. DATA SOURCES: Major electronic databases were searched up to May 2013. The economic model parameters were derived from the clinical effectiveness review, routine sources of cost data and advice from clinical experts. STUDY ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) comparing self-monitoring versus standard clinical care in people with different clinical conditions. Self-monitoring included both self-management (patients conducted the tests and adjusted their treatment according to an algorithm) and self-testing (patients conducted the tests, but received treatment recommendations from a clinician). Various point-of-care coagulometers were considered. RESULTS: 26 RCTs (8763 participants) were included. Both self management and self-testing were as safe as standard care in terms of major bleeding events (RR 1.08, 95% CI 0.81 to 1.45, p=0.690, and RR 0.99, 95% CI 0.80 to 1.23, p=0.92, respectively). Self-management was associated with fewer thromboembolic events (RR 0.51, 95% CI 0.37 to 0.69, p <= 0.001) and with a borderline significant reduction in all-cause mortality (RR 0.68, 95% CI 0.46 to 1.01, p=0.06) than standard care. Self-testing resulted in a modest increase in time in therapeutic range compared with standard care (weighted mean difference, WMD 4.4%, 95% CI 1.71 to 7.18, p=0.02). Total health and social care costs over 10 years were L7324 with standard care and L7326 with self-monitoring (estimated quality adjusted life year, QALY gain was 0.028). Self-monitoring was found to have ~ 80% probability of being cost-effective compared with standard care applying a ceiling willingness-to-pay threshold of L20,000 per QALY gained. Within the base case model, applying the pooled relative effect of thromboembolic events, self-management alone was highly cost-effective while self-testing was not. CONCLUSIONS: Self-monitoring appears to be a safe and cost-effective option. TRIAL REGISTRATION NUMBER: PROSPERO CRD42013004944. PMID- 26112223 TI - Prevalence and predictors of initial oral antibiotic treatment failure in adult emergency department patients with cellulitis: a pilot study. AB - INTRODUCTION: Assessment of cellulitis severity in the emergency department (ED) setting is problematic. Given the lack of research performed to describe the epidemiology and management of cellulitis, it is unsurprising that heterogeneous antibiotic prescribing and poor adherence to guidelines is common. It has been shown that up to 20.5% of ED patients with cellulitis require either a change in route or dose of the initially prescribed antibiotic regimen. The current treatment failure rate for empirically prescribed oral antibiotic therapy in Irish EDs is unknown. The association of patient risk factors with treatment failure has not been described in our setting. Lower prevalence of community acquired methicillin-resistant Staphylococcus aureus-associated infection, differing antibiotic prescribing preferences and varying availability of outpatient intravenous therapy programmes may result in different rates of empiric antibiotic treatment failure from those previously described. METHODS AND ANALYSIS: Consecutive ED patients with cellulitis will be enrolled on a 24/7 basis from 3 Irish EDs. A prespecified set of clinical variables will be measured on each patient discharged on empiric oral antibiotic therapy. A second independent study recruiter will assess at least 10% of cases for each of the predictor variables. Follow-up by telephone call will occur at 14 days for all discharged patients where measurement of the primary outcome will occur. Our primary outcome is treatment failure, defined as a change in route of antibiotic administration from oral to intravenous antibiotic. Our secondary outcome is change in dose or type of prescribed antibiotic. A cohort of approximately 152 patients is required to estimate the proportion of patients failing oral antibiotic treatment with a margin of error of 0.05 around the estimate. ETHICS AND DISSEMINATION: Full ethics approval has been granted. An integrated dissemination plan, involving diverse clinical specialties and enrolled patients, is described. TRIAL REGISTRATION NUMBER: NCT 02230813. PMID- 26112224 TI - A pilot randomised controlled trial of personalised care after treatment for prostate cancer (TOPCAT-P): nurse-led holistic-needs assessment and individualised psychoeducational intervention: study protocol. AB - INTRODUCTION: Prostate cancer is common and the incidence is increasing, but more men are living longer after diagnosis, and die with their disease rather than of it. Nonetheless, specific and substantial physical, sexual, emotional and mental health problems often lead to a poor quality of life. Urology services increasingly struggle to cope with the demands of follow-up care, and primary care is likely to play the central role in long-term follow-up. The present phase II trial will evaluate the feasibility and acceptability of a nurse-led, person centred psychoeducational intervention, delivered in community or primary care settings. METHODS AND ANALYSIS: Prostate cancer survivors diagnosed in the past 9 48 months and currently biochemically stable will be identified from hospital records by their treating clinician. Eligible men would have either completed radical treatment, or would be followed up with prostate specific antigen monitoring and symptom reporting. We will recruit 120 patients who will be randomised to receive either an augmented form of usual care, or an additional nurse-led intervention for a period of 36 weeks. Following the health policy in Wales, the intervention is offered by a key worker, is promoting prudent healthcare and is using a holistic needs assessment. Outcome measures will assess physical symptoms, psychological well-being, confidence in managing own health and quality of life. Healthcare service use will be measured over 36 weeks. Feedback interviews with patients and clinicians will further inform the acceptability of the intervention. Recruitment, attrition, questionnaire completion rates and outcome measures variability will be assessed, and results will inform the design of a future phase III trial and accompanying economic evaluation. ETHICS AND DISSEMINATION: Ethics approval was granted by Bangor University and North Wales REC (13/WA/0291). Results will be reported in peer reviewed publications, at scientific conferences, and directly through national cancer and primary care networks. TRIAL REGISTRATION NUMBER: ISRCTN 34516019. PMID- 26112225 TI - Gastrointestinal Immune Response to the Shrimp Allergen Tropomyosin: Histological and Immunological Analysis in an Animal Model of Shrimp Tropomyosin Hypersensitivity. AB - BACKGROUND: Shellfish hypersensitivity is among the most common food allergies. A murine model of IgE-mediated shrimp allergy has been established in our laboratory. The aim of this study is to determine the intestinal histological changes and cytokine expression profile of this model sensitized with the major shellfish allergen tropomyosin. METHODS: Female Balb/c mice orally sensitized and challenged with recombinant tropomyosin were sacrificed. Continuous sections of duodenum, jejunum and ileum were prepared using the Swiss roll technique for histological and immunological analysis. Duodenal epithelial cell apoptosis and migration were examined. mRNA expression of IL-4, IL-6, IL-10, IL-13, IL-18 and IFN-gamma in intestinal tissue was measured via RT-PCR. RESULTS: In tropomyosin sensitized and challenged mice, an increased number of eosinophils, mast cells and goblet cells was found 24 h after challenge. There were also increased mast cell and goblet cell numbers at 72 h after challenge, but the level of eosinophils decreased. Differences compared with control mice are most prominent at the duodenum compared to the distal regions. In addition, TUNEL assay indicates a significantly higher apoptosis rate in sensitized mice sacrificed 72 h after challenge, and mRNA expression showed a biased Th2/Th1 cytokine profile and a higher level of murine mast cell protease 1. CONCLUSIONS: This study documented a multitude of histological and immunological changes in the gut in a murine model of shrimp allergy. Even without repetitive intragastric challenge, shrimp tropomyosin induces an increase in the number of inflammatory cells to varying degrees within the small intestine. This model provides an important tool for testing new therapeutic interventions. PMID- 26112226 TI - Potential use of microwave treatment on fresh-cut carrots: physical, chemical and microbiological aspects. AB - BACKGROUND: The effect of microwave treatments (900 and 750 W for 45 and 60 s) on the microbial, physicochemical and sensory properties of fresh-cut carrot slices and the contents of several bioactive compounds was studied. Carrot samples were stored for 7 days at 5 degrees C. RESULTS: The microwaving of fresh-cut carrots reduced the initial respiration rate (8.6 CO2 mL kg(-1) h(-1)) by 55-74% compared with untreated samples, although the rates then increased during storage. The initial pH (6.7), titratable acidity (0.036%), soluble solid content (8.2 degrees Brix) and shelf-life of the samples did not differ greatly from those of the untreated samples. Microwaving prevented the incipient whitening and surface dryness during storage. In general, no significant changes in phenylalanine ammonia lyase activity (5.5 umol t-cinnamic acid kg(-1) h(-1)), total phenolics (TP, 81.3 mg chlorogenic acid equivalent kg(-1) fresh weight (FW)) or total antioxidant capacity (TAC, 74.2 umol Trolox equivalent kg(-1) FW) were observed on the processing day or over storage. However, the mildest treatment (750 W for 45 s) caused TP and TAC enhancements of 118 and 394% respectively after 7 days of shelf-life. Microwave treatments reduced the initial microbial loads of the samples by up to 1.8 log units, although their microbial growth was greater than that of the untreated samples throughout storage. CONCLUSION: Mild microwave treatments such as 750 W/45 s and 750 W/60 s are a good sustainable alternative to the use of NaOCl; however, combining them with other sanitizing techniques is needed to control microbial growth throughout the shelf-life of fresh-cut carrot slices. PMID- 26112227 TI - New fluorescent metal-ion detection using a paper-based sensor strip containing tethered rhodamine carbon nanodots. AB - A strip of tethered rhodamine carbon nanodots (C-dots) was designed for selective detection of Al(3+) ion using a Forster resonance energy transfer (FRET)-based ratiometric sensing mechanism. The probe consisted of rhodamine B moieties immobilized on the surface of water-soluble C-dots. Upon exposure to Al(3+), the rhodamine moieties showed a much enhanced emission intensity via energy transfer from the C-dots under excitation at their absorption wavelength. The detection mechanism was related to the Al(3+)-induced ring-opening of rhodamine on C-dots through the chelation of the rhodamine 6G moiety with Al(3+), leading to a spectral overlap of the absorption of C-dots (donor) and the emission of ring opened rhodamine (acceptor). In addition, a paper-based sensor strip containing the tethered rhodamine C-dots was prepared for practical, versatile applications of Al(3+) sensing. The paper-based sensor could detect Al(3+) over other metal ions efficiently, even from a mixture of metal ions, with increased emission intensity at long-wavelength emission via FRET. Sensing based on FRET of C-dots is color-tunable, can be recognized with a naked eye, and may provide a new platform for specific metal-ion sensing. PMID- 26112228 TI - A systematic literature review and meta-analysis: The Theory of Planned Behavior's application to understand and predict nutrition-related behaviors in youth. AB - BACKGROUND: Efforts to reduce unhealthy dietary intake behaviors in youth are urgently needed. Theory-based interventions can be effective in promoting behavior change; one promising model is the Theory of Planned Behavior (TPB). PURPOSE: The aim of this study was to determine, using a systematic literature review, how the TPB has been applied to investigate dietary behaviors, and to evaluate which constructs are associated with dietary behavioral intentions and behaviors in youth. METHODS: Publications were identified by searching electronic databases, contacting experts in the field, and examining an evolving Internet based TPB-specific bibliography. Studies including participants aged 2-18years, all TPB constructs discernible and measured with a description of how the variables were assessed and analyzed, were published in English and peer-reviewed journals, and focused on nutrition-related behaviors in youth were identified. Accompanying a descriptive statistical analysis was the calculation of effect sizes where possible, a two-stage meta-analysis, and a quality assessment using tenants from the Consolidated Standards of Reporting Trials (CONSORT) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statements. RESULTS: Thirty-four articles, including three intervention studies, were reviewed. The TPB was most often used to evaluate healthy eating and sugary snack and beverage consumption. Attitude had the strongest relationship with dietary behavioral intention (mean r=0.52), while intention was the most common predictor of behavior performance (mean r=0.38; both p<0.001). All three interventions revealed beneficial outcomes when using the TPB (e.g. eta(2)=0.51 and ds=0.91, 0.89, and 0.79); extending the Theory with implementation intentions may enhance its effectiveness (e.g. eta(2)=0.76). CONCLUSIONS: Overall, the TPB may be an effective framework to identify and understand child and adolescent nutrition-related behaviors, allowing for the development of tailored initiatives targeting poor dietary practices in youth. However, support from the literature is primarily from observational studies and a greater effort towards examining these relationships within intervention studies is needed. PMID- 26112229 TI - Lifestyle intervention has a beneficial effect on eating behavior and long-term weight loss in obese adults. AB - OBJECTIVE: To investigate the change in eating behavior and the factors related with the change among successful dieters (maintained a weight loss of >=5% of original weight). METHODS: Obese adult subjects (21 male, 55 female) were randomized into three-year lifestyle intervention (n=59) and control groups (n=17). Eating behavior (cognitive restraint of eating, uncontrolled eating and emotional eating) was evaluated by the TFEQ-18 and motivation to lose weight and tolerance to problems by a separate questionnaire. Weight, height and body mass index were measured. RESULTS: Weight decreased more in the intervention group than in the control group (5.0% vs 0.6%, p=0.027). Cognitive restraint increased twice as much in the intervention group compared to the control group (16.0 vs. 7.0, p=0.044). The increment in cognitive restraint was positively associated with weight loss and high baseline motivation and tolerance to problems. Cognitive restraint increased in both successful (n=27) and unsuccessful dieters (n=32), but only the successful dieters were able to decrease uncontrolled eating in the long term. CONCLUSIONS: Our results showed that intensive lifestyle counseling improved cognitive restraint which was associated with enhanced weight loss among obese adults. Successful dieters also showed a long-term improvement of uncontrolled eating. Eating behavior should be evaluated and followed before and during lifestyle interventions in order to support the change, e.g. by finding methods to control eating at risk situations and strengthening motivation and tolerance to problems. PMID- 26112230 TI - Site Specific Interaction Between TiO2 Nanoparticles and Phenanthrimidazole-A First Principles Quantum Mechanical Study. AB - Understanding the interaction between the nanomaterials and bioactive molecules are of current interest due to the potential application of nanomaterial in biomedical field. The structural, electronic and optical properties of newly synthesised fluorophore 2-(4-methoxynaphthalen-1-yl)-1-phenyl-1H-phenanthro[9.10 d]imidazole have been investigated in detail. The imidazole absorbs strongly on the surface of TiO2 nanocrystals probably because of the chemical affinity of azomethine nitrogen atom of the imidazole, resulting in lowering the HOMO and LUMO energy levels. The TEM, SEM and EDX spectra confirm the adsorption of imidazole on the surface of TiO2 nanocrystals. The growth behavior and stability of small stoichiometric (TiO2)n clusters have been analysed by using density functional theory which reveals that clusters prefers three-dimensional structures. In addition, the interaction between the ground state structure of the (TiO2)n cluster and a single imidazole molecule have been studied. The calculated binding energy (Eb) and the energy gap (Eg) indicate that the imidazole molecule preferably binds to the Ti atom of the (TiO2)n clusters through its azomethine nitrogen atom; the binding energy is in range 5.24-7.89 eV. In order to understand the binding interaction with DNA docking study has been carried out. PMID- 26112231 TI - Spectroscopic Investigation of Interaction Between Carbon Quantum Dots and D Penicillamine Capped Gold Nanoparticles. AB - This study reports the interaction and energy transfer between fluorescent carbon quantum dots (CQDs) and D-Penicillamine capped gold nanoparticles (DPA-AuNPs). The CQDs was synthesized by a simple chemical oxidation method at room temperature. The prepared CQDs shows a strong fluorescence at lambda em = 430 nm when excited at lambda ex = 320 nm. The interaction of CQDs with DPA-AuNPs was characterized by fluorescence spectroscopy, Transmission Electron Microscopy (TEM) study and Dynamic Light Scattering (DLS) techniques. The fluorescence study shows the continuous quenching in the fluorescence intensity of CQDs in presence of increasing concentrations of DPA-AuNPs. The change in fluorescence spectra of CQDs in presence of increasing concentration of DPA-AuNPs and quenching are suggestive of a rapid adsorption of CQDs on the surface of DPA-AuNPs. The K sv , K, K q and n values were calculated and results indicated that the dynamic type of quenching takes place. The distance between donor and acceptor (r) is 6.07 nm which supports the energy transfer by Fluorescence Resonance Energy Transfer (FRET) phenomenon. The plausible mechanism for FRET is also discussed. PMID- 26112233 TI - How to optimize the use of biobanks from population-based cohorts in aging research. AB - In epidemiological cohorts, there is an increased interest for the implementation of biobanks. The potential role of biological determinants of diseases needs to be investigated before the onset of the event of interest in order to limit the problems encountered when examining biological determinants in classical case control studies. Biobank is now a very sophisticated system that consists of a programmed storage of biological material and related data. Our aim in this paper is to document how biobank constitution is useful for studying biological determinants of aging and to give some indications on methodological issues that can be helpful to optimize the constitution and use of biobanks in aging cohorts. Optimization of sampling through two-phase designs (nested case control or case cohort studies) allows better efficiency. These elements are, for most of them, not specific to aging populations but are useful more generally for the epidemiology of chronic diseases. Our purpose will be illustrated with some examples and results obtained in an ongoing aging cohort, the Three-City Study. PMID- 26112235 TI - Four steps toward the control of aging: following the example of infectious disease. AB - The biotechnological task of controlling human aging will evidently be complex, given the failure of all simple strategies for accomplishing this task to date. In view of this complexity, a multi-step approach will be necessary. One precedent for a multi-step biotechnological success is the burgeoning control of human infectious diseases from 1840 to 2000. Here we break down progress toward the control of infectious disease into four key steps, each of which have analogs for the control of aging. (1) Agreement about the fundamental nature of the medical problem. (2) Public health measures to mitigate some of the factors that exacerbate the medical problem. (3) Early biotechnological interventions that ward off the more tractable disease etiologies. (4) Deep understanding of the underlying biology of the diseases involved, leading in turn to comprehensive control of the medical problems that they pose. Achievement of all four of these steps has allowed most people who live in Western countries to live largely free of imminent death due to infectious disease. Accomplishing the equivalent feat for aging over this century should lead to a similar outcome for aging-associated disease. Neither infection nor aging will ever be entirely abolished, but they can both be rendered minor causes of death and disability. PMID- 26112234 TI - Development of depressive symptoms post hip fracture is associated with altered immunosuppressive phenotype in regulatory T and B lymphocytes. AB - Hip fracture is a common physical trauma in older adults that is also associated with a high incidence of new onset depression. The immune system declines with age and is also compromised by physical and psychological stress. This study examined whether hip fracture and depressive symptoms had additive effects upon the aged immune system that might contribute to poor health outcomes after hip fracture. We assessed the frequency of regulatory T cells, Tregs (CD4(+) CD25(+) Foxp3(+)) and IL10 production by CD4 T cells, and the frequency and IL10 production by regulatory B cells, Bregs (CD19(+) CD24(hi) CD38(hi)) in 101 hip fracture patients (81 female) 6 weeks after injury and 43 healthy age-matched controls (28 female). 38 hip fracture patients (37%) developed depressive symptoms. Hip fracture did not have an effect on circulating Tregs frequency but a significant reduction in the frequency of Bregs was observed in patients who developed depression compared with non-depressed patients (p = 0.001) or healthy controls (p < 0.001). Bregs also showed a significant decline in IL10 production in depressed hip fracture patients compared with controls (p = 0.04) and non depressed patients (p = 0.01). In contrast, there was an increase in IL10 production by CD4 T cells in hip fracture patients with new onset depression compared to hip fracture patients without depression (p = .04) and healthy controls (p = .02). We conclude that the reduced immunity associated with new onset depression post hip fracture could include a contribution by heightened Tregs function. PMID- 26112236 TI - Association Between Angiotensin-Converting Enzyme 2 and Coronary Artery Calcification in Patients on Maintenance Hemodialysis Therapy. AB - While all mechanisms that contribute to the pathogenesis of coronary artery calcification (CAC) are unknown, angiotensin-converting enzyme 2 (ACE2) may be involved in this process in maintenance hemodialysis (MHD) patients. The aim of this study was to investigate the association between ACE2 and CAC in patients on MHD therapy. Ninety patients on MHD therapy were involved in this prospective study. CAC was quantified by CAC score (CACs) using the Agatston method and a multi-slice CT scanner. Univariate and multivariate logistic regression were used to analyze the association between ACE2 and CACs. In the univariate analysis, CACs positively correlated with ACE2 (r = 0.666, P < 0.001). After adjusting for age, sex, smoking, hypertension, body mass index, diabetes mellitus, and hyperlipidemia, ACE2 levels continued to significantly and independently predict the presence of CAC. ROC curve analysis showed that the serum ACE2 level can predict the extent of CAC. These findings indicate that elevated serum ACE2 may be involved in vascular calcification in patients receiving MHD therapy. PMID- 26112237 TI - Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood glioma barrier. AB - Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFkappaB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance. PMID- 26112238 TI - Methods to estimate aspects of physical activity and sedentary behavior from high frequency wrist accelerometer measurements. AB - This investigation developed models to estimate aspects of physical activity and sedentary behavior from three-axis high-frequency wrist-worn accelerometer data. The models were developed and tested on 20 participants (n = 10 males, n = 10 females, mean age = 24.1, mean body mass index = 23.9), who wore an ActiGraph GT3X+ accelerometer on their dominant wrist and an ActiGraph GT3X on the hip while performing a variety of scripted activities. Energy expenditure was concurrently measured by a portable indirect calorimetry system. Those calibration data were then used to develop and assess both machine-learning and simpler models with fewer unknown parameters (linear regression and decision trees) to estimate metabolic equivalent scores (METs) and to classify activity intensity, sedentary time, and locomotion time. The wrist models, applied to 15-s windows, estimated METs [random forest: root mean squared error (rSME) = 1.21 METs, hip: rMSE = 1.67 METs] and activity intensity (random forest: 75% correct, hip: 60% correct) better than a previously developed model that used counts per minute measured at the hip. In a separate set of comparisons, the simpler decision trees classified activity intensity (random forest: 75% correct, tree: 74% correct), sedentary time (random forest: 96% correct, decision tree: 97% correct), and locomotion time (random forest: 99% correct, decision tree: 96% correct) nearly as well or better than the machine-learning approaches. Preliminary investigation of the models' performance on two free-living people suggests that they may work well outside of controlled conditions. PMID- 26112240 TI - Urinary excretion of lipid mediators in response to repeated eucapnic voluntary hyperpnea in asthmatic subjects. AB - Exercise-induced bronchoconstriction displays refractoriness manifested as a decreased response to repeated exercise challenge within hours. The refractoriness may be attenuated by inhibition of the biosynthesis of prostaglandins (PG). The aim of the study was to determine which PGs and other lipid mediators are excreted during the refractory period. First, 16 subjects with mild stable asthma performed two repeated 4-min challenges with eucapnic voluntary hyperpnea (EVH) 1 and 3 h apart. There was a similar degree of refractoriness in both protocols (~15% protection). The 1-h interval was too short to study mediator excretion because the urinary levels did not return to baseline before the second challenge. With the 3-h protocol, there was increased urinary excretion of cysteinyl-leukotrienes and metabolites of the mast cell product PGD2 after both challenges. Next, another eight subjects performed two 6 min challenges with EVH 3 h apart, which produced a greater bronchoconstrictor response than the 4-min protocol (30.0 +/- 5.4 vs. 17.7 +/- 1.5%; P = 0.0029) and a greater degree of refractoriness (~30%). Analysis by ultra-performance liquid chromatography triple quadrupole mass spectrometry confirmed excretion of the bronchoconstrictor cysteinyl-leukotrienes and PGD2 during both challenges. In addition, there was increased excretion of the bronchoprotective PGE2, and also of the main metabolite of PGI2. This is the first report of excretion of PGE2 and PGI2 during the refractory period to EVH challenge, suggesting that they may mediate the refractoriness. Maintained excretion of PGD2 and leukotriene E4 following the repeat challenge argues against mast cell mediator depletion as the mechanism of refractoriness. PMID- 26112241 TI - High-intensity interval training without weight loss improves exercise but not basal or insulin-induced metabolism in overweight/obese African American women. AB - The purpose of this randomized controlled clinical trial was to determine the effect of a 14-week high-intensity interval training (HIIT) intervention with weight stability on metabolic flexibility, insulin sensitivity, and cardiorespiratory fitness in sedentary, premenopausal, nondiabetic, overweight/obese African American women. Twenty-eight subjects were allocated to one of two groups: HIIT, which performed three sessions per week of four high intensity cycling intervals, or a control group (CON), which maintained their normal level of physical activity. Diet was controlled for all subjects to ensure weight stability. Pre- and postintervention (pre/post), subjects completed an incremental cycling test to limit of tolerance and, following a 10-day high-fat controlled feeding period, a euglycemic-hyperinsulinemic clamp to determine insulin sensitivity and substrate oxidation. Nine members of HIIT (age, 29 +/- 4 yr; body mass, 90.1 +/- 13.8 kg) and eleven members of CON (age, 30 +/- 7 yr; body mass, 85.5 +/- 10.7 kg) completed the study. HIIT experienced an increased limit of tolerance (post, 1,124 +/- 202 s; pre, 987 +/- 146 s; P < 0.05), gas exchange threshold (post, 1.29 +/- 0.34 liters/min; pre, 0.97 +/- 0.23 liters/min; P < 0.05), and fat oxidation at the same absolute submaximal work rate compared with CON (P < 0.05 for group-by-time interaction in all cases). However, changes in peak oxygen consumption (Vo2peak), insulin sensitivity, free fatty acid suppression during insulin stimulation, and metabolic flexibility were not different in HIIT compared with CON. High-intensity interval training with weight stability increased exercise fat oxidation and tolerance in subjects at risk for diabetic progression, but did not improve insulin sensitivity or fat oxidation in the postabsorptive or insulin-stimulated state. PMID- 26112239 TI - Mapping of spatial and temporal heterogeneity of plantar flexor muscle activity during isometric contraction: correlation of velocity-encoded MRI with EMG. AB - The aim of this study was to assess the correlation between contraction associated muscle kinematics as measured by velocity-encoded phase-contrast (VE PC) magnetic resonance imaging (MRI) and activity recorded via electromyography (EMG), and to construct a detailed three-dimensional (3-D) map of the contractile behavior of the triceps surae complex from the MRI data. Ten axial-plane VE-PC MRI slices of the triceps surae and EMG data were acquired during submaximal isometric contractions in 10 subjects. MRI images were analyzed to yield the degree of contraction-associated muscle displacement on a voxel-by-voxel basis and determine the heterogeneity of muscle movement within and between slices. Correlational analyses were performed to determine the agreement between EMG data and displacements. Pearson's coefficients demonstrated good agreement (0.84 < r < 0.88) between EMG data and displacements. Comparison between different slices in the gastrocnemius muscle revealed significant heterogeneity in displacement values both in-plane and along the cranio-caudal axis, with highest values in the mid-muscle regions. By contrast, no significant differences between muscle regions were found in the soleus muscle. Substantial differences among displacements were also observed within slices, with those in static areas being only 17-39% (maximum) of those in the most mobile muscle regions. The good agreement between EMG data and displacements suggests that VE-PC MRI may be used as a noninvasive, high-resolution technique for quantifying and modeling muscle activity over the entire 3-D volume of muscle groups. Application to the triceps surae complex revealed substantial heterogeneity of contraction-associated muscle motion both within slices and between different cranio-caudal positions. PMID- 26112242 TI - Effects of sleeping with reduced carbohydrate availability on acute training responses. AB - We determined the effects of "periodized nutrition" on skeletal muscle and whole body responses to a bout of prolonged exercise the following morning. Seven cyclists completed two trials receiving isoenergetic diets differing in the timing of ingestion: they consumed either 8 g/kg body mass (BM) of carbohydrate (CHO) before undertaking an evening session of high-intensity training (HIT) and slept without eating (FASTED), or consumed 4 g/kg BM of CHO before HIT, then 4 g/kg BM of CHO before sleeping (FED). The next morning subjects completed 2 h of cycling (120SS) while overnight fasted. Muscle biopsies were taken on day 1 (D1) before and 2 h after HIT and on day 2 (D2) pre-, post-, and 4 h after 120SS. Muscle [glycogen] was higher in FED at all times post-HIT (P < 0.001). The cycling bouts increased PGC1alpha mRNA and PDK4 mRNA (P < 0.01) in both trials, with PDK4 mRNA being elevated to a greater extent in FASTED (P < 0.05). Resting phosphorylation of AMPK(Thr172), p38MAPK(Thr180/Tyr182), and p-ACC(Ser79) (D2) was greater in FASTED (P < 0.05). Fat oxidation during 120SS was higher in FASTED (P = 0.01), coinciding with increases in ACC(Ser79) and CPT1 as well as mRNA expression of CD36 and FABP3 (P < 0.05). Methylation on the gene promoter for COX4I1 and FABP3 increased 4 h after 120SS in both trials, whereas methylation of the PPARdelta promoter increased only in FASTED. We provide evidence for shifts in DNA methylation that correspond with inverse changes in transcription for metabolically adaptive genes, although delaying postexercise feeding failed to augment markers of mitochondrial biogenesis. PMID- 26112243 TI - Trichostatin A, a histone deacetylase inhibitor, modulates unloaded-induced skeletal muscle atrophy. AB - Skeletal muscle atrophy is commonly associated with immobilization, ageing, and catabolic diseases such as diabetes and cancer cachexia. Epigenetic regulation of gene expression resulting from chromatin remodeling through histone acetylation has been implicated in muscle disuse. The present work was designed to test the hypothesis that treatment with trichostatin A (TSA), a histone deacetylase inhibitor, would partly counteract unloading-induced muscle atrophy. Soleus muscle atrophy (-38%) induced by 14 days of rat hindlimb suspension was reduced to only 25% under TSA treatment. TSA partly prevented the loss of type I and IIa fiber size and reversed the transitions of slow-twitch to fast-twitch fibers in soleus muscle. Unloading or TSA treatment did not affect myostatin gene expression and follistatin protein. Soleus protein carbonyl content remained unchanged, whereas the decrease in glutathione vs. glutathione disulfide ratio and the increase in catalase activity (biomarkers of oxidative stress) observed after unloading were abolished by TSA treatment. The autophagy-lysosome pathway (Bnip3 and microtubule-associated protein 1 light chain 3 proteins, Atg5, Gabarapl1, Ulk1, and cathepsin B and L mRNA) was not activated by unloading or TSA treatment. However, TSA suppressed the rise in muscle-specific RING finger protein 1 (MuRF1) caused by unloading without affecting the forkhead box (Foxo3) transcription factor. Prevention of muscle atrophy by TSA might be due to the regulation of the skeletal muscle atrophy-related MuRF1 gene. Our findings suggest that TSA may provide a novel avenue to treat unloaded-induced muscle atrophy. PMID- 26112244 TI - Reviewer's comment concerning "The prognostic ability of the STarT Back Tool was affected by episode duration" (by Lars Morso, Alice Kongsted, Lise Hestbaek, and Peter Kent: Eur Spine J (2015): doi:10.1007/s00586-015-3915-0. PMID- 26112245 TI - Reviewer's comment concerning "The surgical algorithm for the AOSpine thoracolumbar spine injury classification system" (by A.R. Vaccaro et al.: Eur Spine J, 2015; doi:10.1007/s00586-015-3982-2). PMID- 26112246 TI - Combined modified en bloc corpectomy with replacement of the aorta in curative interdisciplinary treatment of a large osteosarcoma infiltrating the aorta. AB - PURPOSE: We report a case of a large three-level spinal osteosarcoma infiltrating the adjacent aorta. This is the first case in which a combined modified three level en bloc corpectomy with resection and replacement of the adjacent aorta was successful as a part of interdisciplinary curative treatment. METHODS: Case report. RESULTS: The surgical procedure was performed as a two-step treatment. A heart lung machine (HLM) was not used, in order to avoid cerebral and spinal ischemia and to decrease the risk of hematogenous tumor metastases. Instead, a bypass from the left subclavian artery the distal descending aorta was used. We modified the en bloc corpectomy procedure, leaving a dorsal segment of the vertebral bodies to enable rapid surgery. The procedure was successful and the en bloc resection of the vertebral body with aortal resection could be achieved. Except for pallhypesthesia in the left dermatomes Th7-Th10, the patient does not have any postoperative neurologic deficits. CONCLUSION: Combined corpectomy with aortic replacement should be considered as a reasonable option in the curative treatment of osteosarcoma with consideration of the immense surgical risks. The use of an HLM is not necessary, especially considering the inherent risk of hematogenous tumor metastases. Modified corpectomy leaving a dorsal vertebral body segment was considered a reasonable variation since tumor-free margins could still be expected. PMID- 26112247 TI - Cement-augmented anterior odontoid screw fixation for osteoporotic type II odontoid fractures in elderly patients: prospective evaluation of 11 patients. AB - PURPOSE: Osteoporosis is considered to be a relative contraindication for anterior screw fixation of odontoid fractures because of reduced screw purchase. In the presence of osteoporosis, the most frequent mode of implant failure is via cut-out through the anterior wall of C2. Under in vitro conditions, cement augmented odontoid screws show significant biomechanical advantages as compared to non-augmented screws. Against this background, we present our prospectively collected data on cement-augmented anterior screw fixation of osteoporotic odontoid fractures in elderly patients. METHODS: 11 patients (8 female, 3 male, median age 83 years, range 73-89 years) with an isolated, osteoporotic type II odontoid fracture were treated. After closed reduction and standard anterior approach to the C2/3 level, a self-tapping, short-threaded 3.5-mm lag screw was placed. High-viscosity polymethylmethacrylate cement was injected via a cannulated Jamshidi needle into the base of the C2 vertebral body around the screw shaft and the screw was further tightened. Thin slice CT reconstructions for follow-up evaluation were done consistently postop and 12 months after surgery. RESULTS: Anatomic fracture reposition was achieved in all patients. Cement application was uneventful and well controllable. Cement leakage towards the fracture gap was not detectable. There were no major perioperative complications and no early revision surgeries. After 1 year, thin slice CT with three-dimensional reconstruction demonstrated solid osseous healing of the odontoid fracture in 8 out of 10 patients. CONCLUSIONS: Additional cement augmentation for anterior odontoid fracture repair is technically easy and safe. In elderly people with osteoporotic odontoid fractures, the procedure seems to be a useful supplementary option. PMID- 26112248 TI - Intermittent Stretching and Osteogenic Differentiation of Bone Marrow Derived Mesenchymal Stem Cells via the p38MAPK-Osterix Signaling Pathway. AB - AIMS: The relationship between the p38MAPK signaling pathway and osterix in osteogenic differentiation of BMMSCs subjected to intermittent stretching was investigated. METHODS: BMMSCs derived from C57BL/6J mice were divided into the following groups: 1) control, 2) stretch, and 3) SB203580+stretch (SB203580 is a p38MAPK signal pathway inhibitor). BMMSCs were exposed to an intermittent mechanical strain of 0.8% (8000MU strain) at 0.5 Hz, twice a day for 30 min each application. BMMSCs were harvested on days 1, 3, and 5 post-treatment. The expression of ALP, COL I, OCN, and osterix mRNA was assessed utilizing RT-PCR while the expression of P-p38MAPK and osterix protein was assessed by Western blot analysis. The osterix gene in mouse BMMSCs was knocked down using RNAi technology and its protein expression was also assessed by Western blot. RT-PCR was used to detect ALP, COL I, and OCN mRNA expression. RESULTS: Intermittent stretching was found to promote expression of ALP, COL I, OCN, and osterix mRNA. Silencing the osterix gene was found to reduce levels of ALP, COL I, and OCN mRNA. Western blot analysis demonstrated that the levels of osterix and P-p38MAPK proteins in the stretch group were significantly higher than in the control group (P<0.05). There was less expression of ALP, COL I, OCN, and osterix mRNA in the SB203580+stretch group than in the control and stretch groups. CONCLUSIONS: Data demonstrate that intermittent stretching promotes osteogenic differentiation of BMMSCs, and the p38MAPK-osterix pathway has an important role in the control of osteogenesis-related gene expression. PMID- 26112249 TI - Tetrachlorobenzoquinone triggers the cleavage of Bid and promotes the cross-talk of extrinsic and intrinsic apoptotic signalings in pheochromocytoma (PC) 12 cells. AB - Although there are few studies suggested PCP exposure induced developmental and behavioral disorders, however, the occurrence of neurotoxicity and PCP has not been firmly established. Tetrachlorobenzoquinone (TCBQ) is a reactive metabolite of environmental pollutant pentachlorophenol (PCP). To the best of our knowledge, there has no information regarding to the neurological toxic effect of TCBQ available. Here, we demonstrated that TCBQ induces cytotoxicity in pheochromocytoma PC12 cell line, and the mode-of-action analysis indicated the involvement of apoptotic signalings, such as the activation of caspase family proteins, the increased expressions of Fas and Fas-associated death domain (FADD), the loss of mitochondrial membrane potential (MMP), the release of cytochrome c (Cyt c) and the cleavage of the caspase substrates poly(ADP-ribose) polymerase (PARP). BI-6C9, a specific BH3-interacting domain death agonist (Bid) inhibitor, repressed TCBQ-induced Bid truncation, along with the activation of caspase 3 and the release of Cyt c, suggested the cross-talk of extrinsic and intrinsic apoptotic signalings. Furthermore, the inhibition of caspase 8 impaired TCBQ-induced the activation of caspase 3, as well as the release of Cyt c and the cleavage of Bid, suggesting caspase 8 acting as the upstream molecule of Bid, and TCBQ-induced apoptosis is initiated via caspase 8, leads to the activation of caspase 9/3 through Bid-mediated amplification loop. Finally, the pretreatment of antioxidant NAC ameliorated Fas, FADD and caspase 8/3 expressions, which illustrated that TCBQ-induced apoptotic signaling is ROS dependent. Taken together, these results indicated that the cleavage of Bid may play an important role in TCBQ-induced neurotoxicity which promotes the cross-talk of extrinsic and intrinsic apoptotic signalings in PC12 cells. PMID- 26112250 TI - Evaluation of Approaches to Deal with Low-Frequency Nuisance Covariates in Population Pharmacokinetic Analyses. AB - Clinical studies include occurrences of rare variables, like genotypes, which due to their frequency and strength render their effects difficult to estimate from a dataset. Variables that influence the estimated value of a model-based parameter are termed covariates. It is often difficult to determine if such an effect is significant, since type I error can be inflated when the covariate is rare. Their presence may have either an insubstantial effect on the parameters of interest, hence are ignorable, or conversely they may be influential and therefore non ignorable. In the case that these covariate effects cannot be estimated due to power and are non-ignorable, then these are considered nuisance, in that they have to be considered but due to type 1 error are of limited interest. This study assesses methods of handling nuisance covariate effects. The specific objectives include (1) calibrating the frequency of a covariate that is associated with type 1 error inflation, (2) calibrating its strength that renders it non-ignorable and (3) evaluating methods for handling these non-ignorable covariates in a nonlinear mixed effects model setting. Type 1 error was determined for the Wald test. Methods considered for handling the nuisance covariate effects were case deletion, Box-Cox transformation and inclusion of a specific fixed effects parameter. Non-ignorable nuisance covariates were found to be effectively handled through addition of a fixed effect parameter. PMID- 26112251 TI - Out-of-sync: disrupted neural activity in emotional circuitry during film viewing in melancholic depression. AB - While a rich body of research in controlled experiments has established changes in the neural circuitry of emotion in major depressive disorders, little is known as to how such alterations might translate into complex, naturalistic settings- namely involving dynamic multimodal stimuli with rich contexts, such as those provided by films. Neuroimaging paradigms employing dynamic natural stimuli alleviate the anxiety often associated with complex tasks and eschew the need for laboratory-style abstractions, hence providing an ecologically valid means of elucidating neural underpinnings of neuropsychiatric disorders. To probe the neurobiological signature of refined depression subtypes, we acquired functional neuroimaging data in patients with the melancholic subtype of major depressive disorder during free viewing of emotionally salient films. We found a marked disengagement of ventromedial prefrontal cortex during natural viewing of a film with negative emotional valence in patients with melancholia. This effect significantly correlated with depression severity. Such changes occurred on the background of diminished consistency of neural activity in visual and auditory sensory networks, as well as higher-order networks involved in emotion and attention, including bilateral intraparietal sulcus and right anterior insula. These findings may reflect a failure to re-allocate resources and diminished reactivity to external emotional stimuli in melancholia. PMID- 26112252 TI - Biomimetic self-assembling acylphthalocyanines. AB - We synthesized a series of biomimetic self-assembling phthalocyanines equipped with carbonyl groups as recognition motifs, a central zinc atom and diverse solubilizing alkyl chains mimicking for the first time with these robust pigments the natural chlorosomal bacteriochlorophylls. Upon self-assembly a very broad and red-shifted Q-band absorption extending to over 900 nm is put into evidence. PMID- 26112254 TI - Sitting and Activity Time in People With Stroke. AB - BACKGROUND: Excessive sitting time is linked to cardiovascular disease morbidity. To date, no studies have accurately measured sitting time patterns in people with stroke. OBJECTIVE: The purpose of this study was to investigate the amount and pattern of accumulation of sitting time, physical activity, and use of time in people with stroke compared with age-matched healthy peers. DESIGN: This study used an observational design. METHODS: Sitting time (total and time accumulated in prolonged, unbroken bouts of >=30 minutes) was measured with an activity monitor. Physical activity and daily energy expenditure were measured using an accelerometer and a multisensory array armband, respectively. All monitors had a 7-day wear protocol. Participants recalled 1 day of activity (during monitor wear time) using the Multimedia Activity Recall for Children and Adults. RESULTS: Sixty-three adults (40 with stroke and 23 age-matched healthy controls) participated. The participants (35% female, 65% male) had a mean age of 68.4 years (SD=10.0). Participants with stroke spent significantly more time sitting (X=10.9 h/d, SD=2.0) compared with controls (X=8.2 h/d, SD=2.0), with much of this sitting time prolonged (stroke group: X=7.4 h/d, SD=2.8; control group: X=3.7 h/d, SD=1.7). Participants with stroke accumulated most of their sitting time while watching television and in general quiet time, whereas control participants spent more time reading and on the computer. Physical activity and daily energy expenditure were lower in the stroke group compared with the control group. LIMITATIONS: A sample of convenience was used to select participants for the stroke and control groups, which may reduce the generalizability of results. CONCLUSIONS: Participants with stroke spent more time sitting and less time in activity than their age-matched peers. Further work is needed to determine whether reducing sitting time is feasible and leads to clinically important reductions in cardiovascular risk in this population. PMID- 26112253 TI - Socio-economic position as an intervention against overweight and obesity in children: a systematic review and meta-analysis. AB - Studies that investigated the association between socio-economic position (SEP) and obesity in children suggest inconsistent results. The aim of this study is to summarize and quantify the current evidence on SEP and risks of overweight and obesity in children aged 0-15 years. Relevant studies published between 1990 to Sep 4, 2014 were searched in Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews. Risk estimates from individual studies were pooled using random-effects models, according to lowest vs the highest SEP category. A total of 62 articles were included in the meta-analysis. The odds of both overweight risk and obesity risk were higher in the children with lowest SEP than in those with highest SEP (OR, 1.10, 95% CI: 1.03-1.17, and OR, 1.41, 95% CI: 1.29-1.55, respectively). Sub-group analyses showed that the inverse relationships between SEP and childhood overweight and obesity were only found in high-income countries and in more economic developed areas. In conclusion, our study suggests that children with lower SEP had higher risks of overweight and obesity, and the increased risks were independent of the income levels of countries. PMID- 26112256 TI - Functional Task Constraints Foster Enhanced Postural Control in Children With Cerebral Palsy. AB - BACKGROUND: Postural instability is a classical characteristic of cerebral palsy (CP), but it has not been examined during functional play activity. Recent work has demonstrated that when motor tasks are made functionally more relevant, performance improves, even in children with movement pathology. It is possible that in a disease state, the underlying control mechanisms that are associated with healthy physiology must be elicited. OBJECTIVE: The study objective was to explore the utility of the functional play task methodology as a more rich and interpretable approach to the quantification of postural instability in children with CP. DESIGN: Postural stability measures obtained from a cross-sectional cohort of children with CP (n=30) were compared with stability measures taken from children with typical development (n=30) during a single measurement period. METHODS: Postural stability data were obtained with a portable force platform system. Postural sway was quantified during a precision manual functional play task. A baseline condition (no task) also was included. Postural sway variability and postural sway regularity were analyzed with analyses of variance. RESULTS: There was an apparent difference in postural control (greater irregularity, greater sway variability) during quiet stance between children with CP and peers with typical development; this difference was mitigated during the performance of the precision functional play task. LIMITATIONS: A small and nonprobability sample of convenience may limit the findings of this study. CONCLUSIONS: The findings illustrate flexibility and adaptability in the postural control system despite the pathological features associated with CP. PMID- 26112255 TI - Virtual Sensorimotor Balance Training for Children With Fetal Alcohol Spectrum Disorders: Feasibility Study. AB - BACKGROUND: Diminished sensory adaptation has been associated with poor balance control for children with fetal alcohol spectrum disorders (FASD). A virtual reality system, Sensorimotor Training to Affect Balance, Engagement and Learning (STABEL), was developed to train sensory control for balance. OBJECTIVES: The purpose of this study was to examine the STABEL system in children with FASD and children with typical development (TD) to (1) determine the feasibility of the STABEL system and (2) explore the immediate effects of the STABEL system on sensory attention and postural control. DESIGN: This is a technical report with observational study data. METHODS: Eleven children with FASD and 11 children with TD, aged 8 to 16 years, completed 30 minutes of STABEL training. The children answered questions about their experience using STABEL. Sensory attention and postural control were measured pre- and post-STABEL training with the Multimodal Balance Entrainment Response system and compared using repeated-measures analysis of variance. RESULTS: All children engaged in game play and tolerated controlled sensory input during the STABEL protocol. Immediate effects post-STABEL training in both groups were increased postural sway velocity and some changes in entrainment gain. Children with FASD showed higher entrainment gain to vestibular stimuli. There were no significant changes in sensory attention fractions. LIMITATIONS: The small sample size, dose of STABEL training, and exploratory statistical analyses are study limitations, but findings warrant larger systematic study to examine therapeutic effects. CONCLUSIONS: Children completed the training protocol, demonstrating the feasibility of the STABEL system. Differences in postural sway velocity post-STABEL training may have been affected by fatigue, warranting further investigation. Limited immediate effects suggest more practice is needed to affect sensory attention; however, entrainment gain changes suggest the STABEL system provoked vestibular responses during balance practice. PMID- 26112257 TI - Out-of-Pocket Spending for Ambulatory Physical Therapy Services From 2008 to 2012: National Panel Survey. AB - BACKGROUND: Out-of-pocket (OOP) expenditures are incurred as insurers and employers shift some of the burden of health care costs onto consumers. As cost sharing increases, OOP expenditures could be a barrier to physical therapy care. OBJECTIVE: The purposes of this study were: (1) to identify factors associated with any OOP physical therapy spending and (2) to identify factors associated with higher spending among individuals incurring OOP costs. DESIGN: The study was a retrospective analysis using the 4 most recently available panels of data from the Medical Expenditure Panel Survey (MEPS) encompassing 2008-2012. METHODS: A data file containing episodes of physical therapy care for 2,189 people was created. Logistic regression was used to identify factors related to having an OOP expenditure. A multivariable generalized linear model was used to identify factors related to mean OOP expenditures. RESULTS: On average, an episode of care encompassed 9.9 visits, with mean total expenditures of $1,708 (median: $792). Fifty-four percent of episodes of care had an OOP expenditure. For individuals with OOP expenditures, the mean OOP expenditure for an episode of care was $351 (median: $144). Being female or non-Hispanic and having a higher income were associated with higher odds of incurring an OOP expenditure, whereas being in worse general health, >65 years of age, or nonwhite and having public funding were associated with lower odds of incurring an OOP expenditure. Amounts of OOP spending were higher in urban areas and in all census geographic regions relative to the Northeast region. LIMITATIONS: Estimates are based on household-reported survey data, limited to ambulatory care, and do not include institutionalized individuals. CONCLUSIONS: At 54%, the proportion of individuals with OOP expenditures for physical therapy is lower than for general medical care. Several predictors were found of having OOP expenditures and of the magnitude of those expenditures. PMID- 26112258 TI - Late diagnosis of posterior urethral valves. AB - CLINICAL PROBLEM: We diagnosed 8 patients with late-stage posterior urethral valves (PUV) between 1 and 14 years of age. Five patients complained of symptoms related to voiding dysfunction. The other 3 patients required urethrocystoscopy for other reasons (hypospadias fistulae, difficulty with catheterisation and high grade vesicoureteral reflux [VUR]). A second review of the first 2 patients' medical history showed voiding dysfunction symptoms. All patients underwent preoperative ultrasonography: 3 patients had normal results and 5 had renal or vesical disorders. The diagnosis was reached through voiding cystourethrogram (VCUG), and 4 patients underwent urodynamic studies. The diagnosis was confirmed by urethrocystoscopy, performing valve electrofulguration. We performed urethrocystoscopy during the check-ups at 3-6 weeks and observed no stenosis. The symptoms disappeared for all patients after 20 months of follow-up. The patient with VUR was cured. The ultrasounds showed no progression of the renal involvement and showed improvement in the vesical involvement. The velocimetries during check-ups presented curves within normal ranges. DISCUSSION: Most children with PUV are diagnosed through ultrasound during the neonatal period. Some patients present PUV at later ages with diverse symptoms, which impedes its diagnosis. We should suspect PUV in male patients with symptoms of voiding dysfunction, either when they have normal or pathological results from ultrasounds or VCUG. We recommend performing urethrocystoscopy to rule out urethral obstruction. PMID- 26112259 TI - Retrospective evaluation of prognostic indicators in dogs with head trauma: 72 cases (January-March 2011). AB - OBJECTIVE: To investigate the prognostic value of clinical and laboratory variables and scoring systems in dogs with head trauma. DESIGN: Retrospective study (January-March, 2011). SETTING: University teaching hospital. ANIMALS: Seventy-two client-owned dogs with a history of head trauma occurring <=5 days prior to hospital admission. Dogs were excluded if they had an unconfirmed history of trauma, preexisting neurologic disease, or insufficient data available in the medical record. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data from hospital admission were collected, including vital signs; blood pressure; pulse oximetry; venous blood gases and electrolyte concentrations; plasma lactate and blood glucose concentrations; PCV; total plasma protein concentration; activated clotting time; WBC count; and serum albumin, creatinine, total bilirubin, and BUN concentrations. Modified Glasgow Coma Scale (MGCS), mentation, and animal trauma triage (ATT) scores were also calculated. Treatment with mannitol, hypertonic saline (HS), corticosteroids, benzodiazepines, or phenobarbital, and requirement for endotracheal intubation were also recorded. Outcome was classified as survival or nonsurvival to hospital discharge. Decreased pulse oximetry, pH, bicarbonate concentration, or base excess, and increased potassium concentration, lactate concentration, BUN concentration, ATT score, or mentation score were risk factors for nonsurvival. Decreased MGCS score was the strongest predictor of nonsurvival; a score <= 11 was 84% sensitive and 73% specific for predicting nonsurvival. Dogs were more likely to die before discharge if they required HS or endotracheal intubation. CONCLUSIONS: Dogs that did not survive following head trauma were more likely to have poor perfusion, severe concurrent injuries reflected by increased ATT scores, severe traumatic brain injury as evidenced by decreased MGCS or increased mentation scores, or requirement for HS administration or endotracheal intubation. PMID- 26112260 TI - Assessment of gold and silver in assorted mobile phone printed circuit boards (PCBs): Original article. AB - Demand for gold and silver has been escalating with increasing usage of electronic equipment globally. Around 267.3 MT of gold and 7275 MT of silver are being consumed annually for manufacturing mobile phones, laptops and other electronic equipment. However, only 15% is recuperated from these equipment; the remainder lies in the storage yards or landfills. The waste comprise glass, plastics, wires, batteries, PCBs, metal casing, etc. The PCB is composed of precious metals, which creates immense purpose for recycling and recovery. This paper characterises and assesses the recoverable metallic fraction of gold and silver from PCBs of mobile phones. The methodology is based on dismantling of the mobile handset and subjecting the PCBs to roasting and acid digestion. The digested samples were analysed by atomic absorption spectroscopy and the content of gold and silver in the PCBs was to be found in the range of 0.009-0.017% and 0.25-0.79% by weight respectively. PMID- 26112261 TI - Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti cancer therapy. AB - BACKGROUND: Programmed cell death 1 (PD-1) is a key cell-surface receptor of CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote T-cell tolerance. As a crucial role in tumor immunity, PD-1 has been a focus of studies in anti-cancer therapy. It has been approved that tumors could exploit PD-1-dependent immune suppression for immune evasion. Considering the wide use of glucocorticoids (GCs) in anti-cancer therapy and their immunosuppressive effects, we explored whether GCs could influence the expression of PD-1. RESULTS: In our study, we used dexamethasone (DEX) as a model glucocorticoid and demonstrated that DEX could enhance PD-1 expression in a dose dependent manner. The effects were completely inhibited by the glucocorticoid receptor (GR) antagonist mifepristone (RU486), indicating that the effect of DEX on PD-1 is mediated through GR. We further found the sensitivity to DEX-induced upregulation of PD-1 expression had a significant difference between different T cell subsets, with memory T cells more susceptible to this effect. We also showed that DEX could suppress T cell functions via inhibition of cytokines production such as IL-2, IFN-gamma, TNF-alpha and induction of apoptosis of T cells. CONCLUSION: Our findings suggest a novel way by which DEX suppress the function of activated T lymphocytes by enhancing expression of PD-1 and provide an insight into the optimum clinical application of GCs. PMID- 26112262 TI - Association between iron deficiency and febrile seizures. AB - OBJECTIVE: The relationship between iron status and febrile seizures has been examined in various settings, mainly in the Developing World, with conflicting results. The aim of this study was to investigate any association between iron deficiency and febrile seizures (FS) in European children aged 6-60 months. DESIGN: Prospective, case-control study. SETTING: Greek population in Thessaloniki. PATIENTS: 50 patients with febrile seizures (cases) and 50 controls (children presenting with fever, without seizures). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Haematologic parameters (haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width), plasma iron, total iron-binding capacity, plasma ferritin, transferrin saturation and soluble transferrin receptors were compared in cases and controls. RESULTS: Plasma ferritin was lower (median [range]: 42.8 (3-285.7) vs 58.3 (21.4-195.3 ng/ml; p = 0.02) and Total Iron Binding Capacity (TIBC) higher (mean [Standard Deviation] 267 [58.9] vs 243 [58.45] MUg/dl, p = 0.04) in cases than in controls. Results were similar for 12 complex FS cases (ferritin 30 (3-121 vs 89 (41.8-141.5ng/lL; TIBC 292.92 [68.0] vs 232.08 [36.27] MUg/dL). Iron deficiency, defined as ferritin <30 ng/ml, was more frequent in cases (24%) than controls (4%; p = 0.004). Ferritin was lower and TIBC higher in 18 with previous seizures than in 32 with a first seizure although haemoglobin and mean cell haemoglobin concentration were higher. CONCLUSIONS: European children with febrile seizures have lower Ferritin than those with fever alone, and iron deficiency, but not anaemia, is associated with recurrence. Iron status screening should be considered as routine for children presenting with or at high risk for febrile seizures. PMID- 26112263 TI - Language comprehension in nonspeaking children with severe cerebral palsy: Neuroanatomical substrate? AB - BACKGROUND AND AIMS: To identify relations between brain abnormalities and spoken language comprehension, MRI characteristics of 80 nonspeaking children with severe CP were examined. METHODS: MRI scans were analysed for patterns of brain abnormalities and scored for specific MRI measures: white matter (WM) areas; size of lateral ventricles, WM abnormality/reduction, cysts, subarachnoid space, corpus callosum thinning and grey matter (GM) areas; cortical GM abnormalities, thalamus, putamen, globus pallidus and nucleus caudatus and cerebellar abnormalities. Language comprehension was assessed with a new validated instrument (C-BiLLT). RESULTS: MRI scans of 35 children were classified as a basal ganglia necrosis (BGN) pattern, with damage to central GM areas; in 60% of these children damage to WM areas was also found. MRI scans of 13 children were classified as periventricular leukomalacia (PVL) with little concomitant damage to central GM areas, 13 as malformations and 19 as miscellaneous. Language comprehension was best in children with BGN, followed by malformations and miscellaneous, and was poorest in PVL. Linear regression modelling per pattern group (malformations excluded), with MRI measures as independent variables, revealed that corpus callosum thinning in BGN and parieto-occipital WM reduction in PVL were the most important explanatory factors for poor language comprehension. No MRI measures explained outcomes in language comprehension in the miscellaneous group. CONCLUSIONS: Comprehension of spoken language differs between MRI patterns of severe CP. In children with BGN and PVL differences in language comprehension performance is attributed to damage in the WM areas. Language comprehension was most affected in children with WM lesions in the subcortical and then periventricular areas, most characteristic for children with PVL. PMID- 26112264 TI - The correlates of chronic disease-related health literacy and its components among men: a systematic review. AB - BACKGROUND: Chronic diseases drive the burden of disease in many societies, particularly among men. Lifestyle behaviours are strongly associated with chronic disease development, and in a number of countries men tend to engage in more risky behaviours, and have lower health knowledge and attention to prevention, than women. This study investigated the correlates of men's health literacy and its components about major lifestyle-related diseases, namely ischaemic heart disease and type 2 diabetes mellitus, to gain evidence to guide the development of policy and programs to improve men's health. METHODS: A systematic review was undertaken of observational studies that investigated men's health literacy and its components related to ischaemic heart disease or type 2 diabetes mellitus, and their associated risk factors. The Cumulative Index to Nursing and Allied Health Literature (CINAHL), MEDLINE, PsycINFO, Embase and the Cochrane Library databases were searched for articles published since 2003. The strength of the evidence was rated using the GRADE approach. RESULTS: After screening and review of 504 articles, the search elicited nine studies for inclusion: only one study examined health literacy (nutrition literacy). The majority of included studies focused on only one component of health literacy, namely knowledge (n = 7) and personal skills (confidence) (n = 1). Twenty correlates were identified, primarily relating to the knowledge component, with the strength of the evidence for only one correlate, education, graded as being of moderate quality. The evidence for all other correlates was graded as being of low quality. CONCLUSIONS: The limited body of research identified may have resulted from a lack of consensus about the definition of health literacy, and a concordant set of validated health literacy measures. Despite these limitations, broadening the search to include components of health literacy has identified that several factors are associated with men's knowledge and awareness of ischaemic heart disease and type 2 diabetes mellitus that will assist in the development of men's health promotion strategies. However, addressing the broader knowledge gaps and controversy in the health literacy field will deliver policy and program benefits to address these major contributors to the burden of disease among men. PMID- 26112265 TI - How urbanization affects the epidemiology of emerging infectious diseases. AB - The world is becoming more urban every day, and the process has been ongoing since the industrial revolution in the 18th century. The United Nations now estimates that 3.9 billion people live in urban centres. The rapid influx of residents is however not universal and the developed countries are already urban, but the big rise in urban population in the next 30 years is expected to be in Asia and Africa. Urbanization leads to many challenges for global health and the epidemiology of infectious diseases. New megacities can be incubators for new epidemics, and zoonotic diseases can spread in a more rapid manner and become worldwide threats. Adequate city planning and surveillance can be powerful tools to improve the global health and decrease the burden of communicable diseases. PMID- 26112266 TI - Evaluation of antibiotic prescription in the Lebanese community: a pilot study. AB - BACKGROUND: Antibiotics are considered among the most commonly prescribed drug classes in developing countries. Inappropriate prescription of antibiotics is a major public health concern and is related to the development of antimicrobial resistance. OBJECTIVE: This study aimed at assessing the appropriateness of antibiotic prescription by non-infectious disease physicians in a community setting in Lebanon. METHODS: A pilot cross-sectional study was undertaken on community pharmacy patients presenting with antibiotic prescription. It was performed over a period of 4 months in different regions of Lebanon. Participants answered a questionnaire inquiring about socio-demographic characteristics, medical conditions, symptoms that required medical attention, the doctor's diagnosis, the prescribed antibiotic, and whether laboratory tests were ordered to identify the causative organism or not. Data were analyzed using SPSS 17. RESULTS: We studied 270 patients (49.3% males and 50.7% females). This study showed that the most-prescribed antibiotics were the cephalosporins (82%) and that almost half of the illnesses for which antibiotics were prescribed were respiratory tract infections (41%). The study also showed that the choice of the prescribed antibiotic was appropriate in 61.5% of the studied cases, while the prescribed dose and the duration of the treatment were inaccurate in 52 and 64% of the cases, respectively. In addition, fever seemed to be a factor that influenced the physician's prescriptions, since the choice of drug conformity to guidelines increased from 53.7% (1 day of fever) to 88.9% (1 week of fever), and the dose prescription compliance to guidelines was higher (55.9%) for patients suffering from fever compared to those with no fever (38.1%). CONCLUSION: This study showed a high prevalence of inappropriate antibiotic prescriptions in Lebanon. Therefore, actions should be taken to optimize antibiotic prescription. PMID- 26112267 TI - Quantitative Proteomic and Phosphoproteomic Approaches for Deciphering the Signaling Pathway for Tension Wood Formation in Poplar. AB - Trees adjust their growth following forced changes in orientation to re-establish a vertical position. In angiosperms, this adjustment involves the differential regulation of vascular cambial activity between the lower (opposite wood) and upper (tension wood) sides of the leaning stem. We investigated the molecular mechanisms leading to the formation of differential wood types through a quantitative proteomic and phosphoproteomic analysis on poplar subjected to a gravitropic stimulus. We identified and quantified 675 phosphopeptides, corresponding to 468 phosphoproteins, and 3 763 nonphosphorylated peptides, corresponding to 1 155 proteins, in the differentiating xylem of straight-growing trees (control) and trees subjected to a gravitational stimulus during 8 weeks. About 1% of the peptides were specific to a wood type (straight, opposite, or tension wood). Proteins quantified in more than one type of wood were more numerous: a mixed linear model showed 389 phosphopeptides and 556 proteins to differ in abundance between tension wood and opposite wood. Twenty-one percent of the phosphoproteins identified here were described in their phosphorylated form for the first time. Our analyses revealed remarkable developmental molecular plasticity, with wood type-specific phosphorylation events, and highlighted the involvement of different proteins in the biosynthesis of cell wall components during the formation of the three types of wood. PMID- 26112268 TI - Secondary posterior interosseous nerve lesions associated with humeral fractures. AB - INTRODUCTION: Radial nerve lesions associated with humeral shaft fractures are the most common traumatic nerve lesions observed with long bone fractures. Secondary indirect posterior interosseous nerve (PIN) lesions can be associated with traumatic radial nerve palsy. The aim of this study was to identify cases of traumatic double-site radial nerve involvement through ultrasound (US). METHODS: Patients with traumatic radial nerve lesions referred to our laboratory from January 2010 to January 2014 were evaluated. RESULTS: Of the 35 patients, 18 had US evidence of a radial nerve lesion at the fracture site associated with secondary PIN involvement at the arcade of Frohse. CONCLUSIONS: Multiple-site nerve lesions are difficult to demonstrate through electrodiagnostic tests. In our case series, half of the patients with traumatic radial nerve damage had US evidence of PIN injury. Prospective studies with follow-up are needed to determine the clinical and prognostic relevance of this finding and the best therapeutic approach. PMID- 26112269 TI - Evolving Larger: Dosing Anti-Tuberculosis (TB) Drugs in an Obese World. AB - Current clinical practice guidelines recommend dosing anti-tuberculosis drugs according to ideal body weight and provide dosing caps for most first-line agents. However, this recommendation may be placing corpulent patients with tuberculosis at risk as increased total body weight is associated with an increased risk of clinical failure. Patients with diabetes are at an increased risk of developing tuberculosis and typically weigh more than patients with tuberculosis alone. All these factors in-combination stress the importance of evaluating the effect of weight on the pharmacokinetics of first-line anti tuberculosis drugs. Multiple studies suggest the use of total body weight based dosing for rifampin. Less data are available for pyrazinamide and ethambutol, but both appear to be candidates for total body weight based dosing. The study evaluating levofloxacin concluded that no adjustment is required. However, the larger variability in obese patients is concerning as to whether "one size fits all" dosing is optimal for levofloxacin. The vast majority of the isoniazid's pharmacokinetic variability is due to NAT2*4 status. However, more extensive analysis of slow and fast metabolizers is needed to determine the effect of weight within each subgroup. Moxifloxacin does not appear to be affected by weight, but doses of at least 800 mg are likely needed to optimize its pharmacokinetic/pharmacodynamic target attainment. Future pharmacokinetic evaluations should focus on recruiting a wide range of patient weights. These analyses should take advantage of the full weight distribution instead of arbitrarily dichotomizing patients into obese vs. non-obese persons. A subsequent evaluation of the safety and effectiveness of optimized dosing regimens is needed. PMID- 26112270 TI - Isolated dextrogastria in a newborn. PMID- 26112271 TI - Endometriosis with an acute colon obstruction: a case report. AB - INTRODUCTION: The presentation of an acute bowel obstruction caused by endometriosis in an emergency department setting is rare, as it usually presents through years of complaints in the absence of a distinct acute onset. In this report, we present a case of a patient who was familiar with abdominal complaints and eventually required emergency surgery to treat an acute bowel obstruction caused by endometriosis. Endometrioses present infrequently in the acute phase, and only a few cases in which emergency surgery was required have been described in the literature. CASE PRESENTATION: A 31-year-old Caucasian woman presented to the emergency room of our hospital with a distended abdomen, pain and nausea accompanied by a history of 14 years of chronic abdominal pain and constipation. An abdominal X-ray and subsequent computed tomographic scan showed a severely distended cecum of 9cm with stenosis in the sigmoid. Cecal blow-out was considered highly likely, and, during an emergency laparotomy, an obstructing process was found in the sigmoid. An oncologic resection of the sigmoid was performed with a primary anastomosis and loop ileostomy. A pathological examination revealed a tumor of 4cm in the sigmoid, which contained a tubelike structure with cytogenic stroma and the remains of focal bleeding. These are typical aspects of endometriosis. CONCLUSIONS: Infiltrating endometriosis is an invalidating disease that can be misdiagnosed for a wide range of other diseases. Emergency room physicians and surgeons should be aware that it can present as an acute obstruction and should be considered in diagnosing women of childbearing age. After initial colonoscopy, emergency surgery is the best therapeutic approach if there is a complete obstruction. PMID- 26112272 TI - Treatment of T3 laryngeal cancer in the Netherlands: a national survey. AB - BACKGROUND: Treatment strategies for T3 laryngeal carcinoma include radiotherapy (RT) with or without chemotherapy (CT) and sometimes surgery. We conducted a national survey to determine how T3 laryngeal carcinoma is currently being managed in the Netherlands. METHODS: A questionnaire on general treatment policy, also inquiring details on RT and CT, was sent to all 13 radiotherapy departments accredited for treatment of head and neck cancer (HNC) in the Netherlands. RESULTS: Twelve centers completed the questionnaire. All centers reported using RT with or without CT. Upfront laryngectomy is rarely performed. At 9/12 centers, CT is added to RT in cases with large tumors in T3N0 disease. Three centers use a volume criterion (3-6 cc); 6 centers don't specify "large" with such criteria. CT consists of cisplatin 3-weekly (7 centers) or weekly (2 centers), unless contra indicated or age; 6 centers use an age limit of 70 years. RT is given concomitantly with CT 5*/week except at the 2 centers where cisplatin weekly is combined with 6 fractions/week. In case of RT only, treatment is accelerated. Lymph node levels II-IV are treated electively. In T3N+ disease, 11/12 centers treat non-bulky T3N1 with RT only. Volume criteria for combined CT-RT are the same as above. Two centers perform an upfront neck dissection in case of (resectable) N3 disease; 10 centers treat T3N2-3 cancer with primary CT-RT, 2 centers don't use the N-stage criterion. Total RT dose is 68-70 Gy, the elective dose varies between 46 and 57.75 Gy. Eight centers use a simultaneous integrated boost technique. CONCLUSIONS: Treatment of T3 laryngeal cancer in the Netherlands is generally comparable, with CT-RT for voluminous T3N0 and most T3N+ tumors, but there are some differences between the centers in the use of chemotherapy and the dose-fractionation schemes. Therefore, the aim of the National Platform RT HNC is further standardization of RT dose, fractionation and delivery techniques. PMID- 26112273 TI - Transdermal fentanyl patch improves post-operative pain relief and promotes early functional recovery in patients undergoing primary total knee arthroplasty: a prospective, randomised, controlled trial. AB - INTRODUCTION: The aim of the present study was to evaluate the efficacy and safety of a 12.5 MUg/h transdermal fentanyl patch (TFP). MATERIALS AND METHODS: Fifty-two patients scheduled for primary total knee arthroplasty (TKA) were recruited in the study. They were randomly divided into two groups: patients provided with a transdermal fentanyl patch (Group TFP) and those provided with non-steroid anti-inflammatory drugs (Group NSAID). The patients in the TFP and NSAID groups had mean ages of 70.1 years (range 36-86 years) and 73.5 years (range 32-86 years), respectively. Post-operative pain intensity was measured using the visual analogue scale both at rest and during movement (mVAS). We also evaluated lower leg functional recovery and adverse events. RESULTS: The mean mVAS scores were not different between the two groups on post-operative day 4, but were significantly smaller in the TFP group than in the NSAID group on post operative days 7 (p = 0.0026) and 14 (p = 0.007). Muscle strength recovered faster in the TFP group than in the NSAID group, the percentage of pre-operative strength being significantly greater in the former than in the latter on post operative days 7 (p = 0.027) and 14 (p = 0.047). Furthermore, there were no remarkable adverse events in patients using TFP. CONCLUSION: We conclude that a 12.5 MUg/h TFP can improve post-operative pain relief and promotes early functional recovery following total knee arthroplasty. PMID- 26112274 TI - Fetal cardiac function in late-onset intrauterine growth restriction vs small-for gestational age, as defined by estimated fetal weight, cerebroplacental ratio and uterine artery Doppler. AB - OBJECTIVE: Among late-onset small fetuses, a combination of estimated fetal weight (EFW), cerebroplacental ratio (CPR) and mean uterine artery (UtA) pulsatility index (PI) can predict a subgroup of fetuses with poor perinatal outcome; however, the association of these criteria with fetal cardiac structure and function is unknown. Our aim was to determine the presence and severity of signs indicating cardiac dysfunction in small fetuses, classified as intrauterine growth-restricted (IUGR) or small-for-gestational age (SGA), according to EFW, CPR and UtA-PI. METHODS: A cohort of 209 late-onset small fetuses that were delivered > 34 weeks of gestation was divided in two categories: SGA (n = 59) if EFW was between the 3(rd) and 9(th) centiles with normal CPR and UtA-PI; and IUGR (n = 150) if EFW was < 3(rd) centile, or < 10(th) centile with a CPR < 5(th) centile and/or UtA-PI > 95(th) centile. The small population was compared with 150 appropriately grown fetuses (controls). Fetal cardiac morphometry and function were assessed by echocardiography using two-dimensional M-mode, conventional and tissue Doppler. RESULTS: Compared with controls, both IUGR and SGA fetuses showed larger and more globular hearts (mean left sphericity index +/ SD: controls, 1.8 +/- 0.3; SGA, 1.5 +/- 0.2; and IUGR, 1.6 +/- 0.3; P < 0.01) and showed signs of systolic and diastolic dysfunction, including decreased tricuspid annular plane systolic excursion (mean +/- SD: controls, 8.2 +/- 1.1; SGA, 7.4 +/- 1.2; and IUGR, 6.9 +/- 1.1; P < 0.001) and increased left myocardial performance index (mean +/- SD: controls, 0.45 +/- 0.14; SGA, 0.51 +/- 0.08; and IUGR, 0.57 +/- 0.1; P < 0.001). CONCLUSIONS: Despite a perinatal outcome comparable to that of normal fetuses, the population of so-defined SGA fetuses showed signs of prenatal cardiac dysfunction. This supports the concept that at least a proportion of them are not 'constitutionally small' and that further research is needed. PMID- 26112275 TI - Improving the Emergency Care Research Investigator Pipeline: SAEM/ACEP Recommendations. PMID- 26112276 TI - Neural evidence for competition-mediated suppression in the perception of a single object. AB - Multiple objects compete for representation in visual cortex. Competition may also underlie the perception of a single object. Computational models implement object perception as competition between units on opposite sides of a border. The border is assigned to the winning side, which is perceived as an object (or "figure"), whereas the other side is perceived as a shapeless ground. Behavioral experiments suggest that the ground is inhibited to a degree that depends on the extent to which it competed for object status, and that this inhibition is relayed to low-level brain areas. Here, we used fMRI to assess activation for ground regions of task-irrelevant novel silhouettes presented in the left or right visual field (LVF or RVF) while participants performed a difficult task at fixation. Silhouettes were designed so that the insides would win the competition for object status. The outsides (grounds) suggested portions of familiar objects in half of the silhouettes and novel objects in the other half. Because matches to object memories affect the competition, these two types of silhouettes operationalized, respectively, high competition and low competition from the grounds. The results showed that activation corresponding to ground regions was reduced for high- versus low-competition silhouettes in V4, where receptive fields (RFs) are large enough to encompass the familiar objects in the grounds, and in V1/V2, where RFs are much smaller. These results support a theory of object perception involving competition-mediated ground suppression and feedback from higher to lower levels. This pattern of results was observed in the left hemisphere (RVF), but not in the right hemisphere (LVF). One explanation of the lateralized findings is that task-irrelevant silhouettes in the RVF captured attention, allowing us to observe these effects, whereas those in the LVF did not. Experiment 2 provided preliminary behavioral evidence consistent with this possibility. PMID- 26112279 TI - Radiation protection during cardiac catherization: development of an improved lead apron for periinterventional echocardiography. PMID- 26112280 TI - Percutaneous septal ablation in a patient with recurrent outflow obstruction after previous surgical myectomy. PMID- 26112277 TI - Engineering structure and function using thermoresponsive biopolymers. AB - Self-assembly enables exquisite control at the smallest scale and generates order among macromolecular-building blocks that remain too small to be manipulated individually. Environmental cues, such as heating, can trigger the organization of these materials from individual molecules to multipartixcle assemblies with a variety of compositions and functions. Synthetic as well as biological polymers have been engineered for these purposes; however, biological strategies can offer unparalleled control over the composition of these macromolecular-building blocks. Biologic polymers are macromolecules composed of monomeric units that can be precisely tailored at the genetic level; furthermore, they can often utilize endogenous biodegradation pathways, which may enhance their potential clinical applications. DNA (nucleotides), polysaccharides (carbohydrates), and proteins (amino acids) have all been engineered to self-assemble into nanostructures in response to a change in temperature. This focus article reviews the growing body of literature exploring temperature-dependent nano-assembly of these biological macromolecules, summarizes some of their physical properties, and discusses future directions. PMID- 26112278 TI - Preliminary experience using milnacipran in patients with juvenile fibromyalgia: lessons from a clinical trial program. AB - BACKGROUND: There are no approved medications for juvenile fibromyalgia (JFM), a disorder that is often under-diagnosed. The effects of milnacipran, a drug approved for the management of fibromyalgia (FM) in adults, was assessed in a clinical trial program for JFM. METHODS: Patients, ages 13-17 years who met the Yunus and Masi criteria for JFM and/or 1990 American College of Rheumatology criteria for FM, were enrolled in a responder-enriched, randomized withdrawal trial. After receiving open-label milnacipran (8 weeks), patients with >=50 % improvement in pain underwent double-blind randomization (1:2) to either placebo or continuing treatment with milnacipran (8 weeks). All patients, including those who did not meet the randomization criteria for double-blind withdrawal, were allowed to enter an extension study with open-label milnacipran (up to 52 weeks). The primary endpoint was loss of therapeutic response (LTR) during the double blind period. Additional outcome measures included the Patient Global Impression of Severity (PGIS), Pediatric Quality of Life Inventory (PedsQL: Generic Core Scales, Multidimensional Fatigue Scale), and Multidimensional Anxiety Scale for Children (MASC). Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. RESULTS: The milnacipran program was terminated early due to low enrollment. Because only 20 patients were randomized into the double-blind withdrawal period, statistical analyses were not conducted for the LTR endpoint. However, 116 patients entered the open-label period of the initial study and 57 participated in the open-label extension study. Their experience provides preliminary information about the use of milnacipran in JFM patients. During both open-label periods, there were mean improvements in pain severity, PGIC, PedsQL, and MASC scores. No unexpected safety issues were detected. The most commonly reported treatment-emergent AEs were nausea, headache, vomiting, and dizziness. Mean increases in heart rate and blood pressure were observed, and were consistent with the AE profile in adults with FM. CONCLUSIONS: The open-label findings provide preliminary evidence that milnacipran may improve symptoms of JFM, with a safety and tolerability profile that is consistent with the experience in adult FM patients. Future trial designs for JFM should consider the relatively low recognition of this condition compared to adult FM and the difficulties with enrollment. TRIAL REGISTRATION: NCT01328002 ; NCT01331109. PMID- 26112281 TI - Socio-demographic patterns of physical activity and sedentary behaviour in Chile: results from the National Health Survey 2009-2010. AB - BACKGROUND: Surveillance of physical activity (PA) is essential for the development of health promotion initiatives. The aim of the present study was to examine the prevalence of PA and sedentary behaviour with respect to socio demographic factors in Chile. METHODS: A representative sample of 5434 adults aged >=15 years (59% women) who participated in the Chilean National Health Survey (2009-2010) were included. Socio-demographic data (age, sex, environment, education level, income level and smoking status) were collected for all participants. PA levels were assessed using the Global Physical Activity Questionnaire. RESULTS: 19.8% [95% CI: 18.1-21.6] of the Chilean population did not meet PA recommendations (>=600 MET min week(-1)). The prevalence of physical inactivity was higher in participants aged >=65 years, compared with the youngest age groups and was higher in women than in men. However, it was lower for participants with high, compared with low, education or income levels. The overall prevalence of sedentary risk behaviour (spending >4 h sitting per day) was 35.9% [95% CI: 33.7-38.2]. CONCLUSION: Physical inactivity correlates strongly with socio-demographic factors such as age, gender and educational level. Results identify social and economic groups to which future public health interventions should be aimed to increase PA in the Chilean population. PMID- 26112282 TI - Amyloid-like fibrils formed from intrinsically disordered caseins: physicochemical and nanomechanical properties. AB - Amyloid-like fibrils are studied because of their significance in understanding pathogenesis and creating functional materials. Amyloid-like fibrils have been studied by heating globular proteins at acidic conditions. In the present study, intrinsically disordered alpha-, beta-, and kappa-caseins were studied to form amyloid-like fibrils at pH 2.0 and 90 degrees C. No fibrils were observed for alpha-caseins, and acid hydrolysis was found to be the rate-limiting step of fibrillation of beta- and kappa-caseins. An increase of beta-sheet structure was observed after fibrillation. Nanomechanic analysis of long amyloid-like fibrils using peak-force quantitative nanomechanical atomic force microscopy showed the lowest and highest Young's modulus for beta-casein (2.35 +/- 0.29 GPa) and kappa casein (4.14 +/- 0.66 GPa), respectively. The dispersion with beta-casein fibrils had a viscosity more than 10 and 5 times higher than those of kappa-casein and beta-lactoglobulin, respectively, at 0.1 s(-1) at comparable concentrations. The current findings may assist not only the understanding of amyloid fibril formation but also the development of novel functional materials from disordered proteins. PMID- 26112283 TI - Daily respiratory training with large intrathoracic pressures, but not large lung volumes, lowers blood pressure in normotensive adults. AB - Inspiratory muscle training holds promise as a non-pharmacologic treatment that can improve respiratory muscle strength, reduce blood pressure, and improve autonomic balance in hypertensive patients. There is a gap in knowledge regarding the specific respiratory stimulus that gives rise to these favorable outcomes. We implemented five respiratory training protocols that differed in the magnitude and direction of the lung volumes and/or intrathoracic pressures generated by subjects in training. Normotensive adults were randomly assigned to each group and trained daily for 6 weeks. Pre-post and weekly measures of blood pressure showed significant declines in systolic [-8.96 mmHg (95% CI, 7.39-10.53)] and diastolic [-5.25 mmHg (95% CI, 3.67-6.83)] blood pressures for subjects who trained with large positive or negative intrathoracic pressures. Subjects who trained with modest intrathoracic pressures or large lung volumes saw no improvement in blood pressure (P > 0.3). Large intra-thoracic pressures are the specific respiratory stimulus underpinning breathing training related improvements in blood pressure. PMID- 26112285 TI - Monitoring techniques of the western corn rootworm are the precursor to effective IPM strategies. AB - BACKGROUND: The western corn rootworm (WCR) is economically the most important pest of maize in Croatia. To predict WCR adult population abundance and variability, traditional, genetic and morphometric monitoring of populations was conducted over time through each phase of the WCR invasion process in Croatia. RESULTS: Through traditional monitoring it was shown that WCR established their current population and reached economic densities after 14 years persisting in the study area. Regression-tree-based modelling showed that the best predictor of WCR adult abundance was the total amount of rainfall. Genetic monitoring indicated that genetic differentiation increased over time at the intrapopulation level, and morphometric monitoring indicated that wing morphotypes varied according to edaphic landscape changes. CONCLUSION: Traditional population metric surveys are important in WCR integrated pest management (IPM), as such surveys can be effectively used to predict population abundances. Novel-use monitoring techniques such as genetics and geometric morphometrics can be used to provide valuable information on variation within and among populations. The monitoring techniques presented herein provide sound data to assist in the understanding of both WCR ecology and population genetics and may provide more information than that currently available using traditional techniques (e.g. sticky traps), and as such these additional techniques should be written into IPM for WCR. PMID- 26112284 TI - Hemodynamic effects of high intensity interval training in COPD patients exhibiting exercise-induced dynamic hyperinflation. AB - Dynamic hyperinflation (DH) has a significant adverse effect on cardiovascular function during exercise in COPD patients. COPD patients with (n = 25) and without (n = 11) exercise-induced DH undertook an incremental (IET) and a constant-load exercise test (CLET) sustained at 75% peak work (WRpeak) prior to and following an interval cycling exercise training regime (set at 100% WRpeak with 30-s work/30-s rest intervals) lasting for 12 weeks. Cardiac output (Q) was assessed by cardio-bio-impedance (PhysioFlow, enduro, PF-O7) to determine Q mean response time (QMRT) at onset (QMRT(ON)) and offset (QMRT(OFF)) of CLET. Post rehabilitation only those patients exhibiting exercise-induced DH demonstrated significant reductions in QMRT(ON) (from 82.2 +/- 4.3 to 61.7 +/- 4.2 s) and QMRT(OFF) (from 80.5 +/- 3.8 to 57.2 +/- 4.9 s ). These post-rehabilitation adaptations were associated with improvements in inspiratory capacity, thereby suggesting that mitigation of the degree of exercise-induced DH improves central hemodynamic responses in COPD patients. PMID- 26112286 TI - The MinD homolog FlhG regulates the synthesis of the single polar flagellum of Vibrio alginolyticus. AB - FlhG, a MinD homolog and an ATPase, is known to mediate the formation of the single polar flagellum of Vibrio alginolyticus together with FlhF. FlhG and FlhF work antagonistically, with FlhF promoting flagellar assembly and FlhG inhibiting it. Here, we demonstrate that purified FlhG exhibits a low basal ATPase activity. As with MinD, the basal ATPase activity of FlhG can be activated and the D171A residue substitution enhances its ATPase activity sevenfold. FlhG-D171A localizes strongly at the cell pole and severely inhibits motility and flagellation, whereas the FlhG K31A and K36Q mutants, which are defective in ATP binding, do not localize to the poles, cannot complement a flhG mutant and lead to hyperflagellation. A strong polar localization of FlhF is observed with the K36Q mutant FlhG but not with the wild-type or D171A mutant FlhG. Unexpectedly, an Ala substitution at the catalytic residue (D60A), which abolishes ATPase activity but still allows ATP binding, only slightly affects FlhG functions. These results suggest that the ATP-dependent polar localization of FlhG is crucial for its ability to downregulate the number of polar flagella. We speculate that ATP hydrolysis by FlhG is required for the fine tuning of the regulation. PMID- 26112287 TI - Protective effect of a Protein Epitope Mimetic CCR10 antagonist, POL7085, in a model of allergic eosinophilic airway inflammation. AB - BACKGROUND: Potential involvement of the CCR10/CCL28 axis was recently reported in murine models of allergic asthma. If confirmed, blockade of the CCR10 receptor would represent an alternative to current asthma therapies. We evaluated the effect of a novel Protein Epitope Mimetic CCR10 antagonist, POL7085, in a murine model of allergic eosinophilic airway inflammation. METHODS: Mice were sensitized and challenged to ovalbumin. POL7085, a CCR10 antagonist (7.5 and 15 mg/kg), dexamethasone (1 mg/kg) or vehicle were administered intranasally once daily 1h before each allergen challenge. On day 21, airway hyperresponsiveness, bronchoalveolar lavage inflammatory cells and Th2 cytokines, and lung tissue mucus and collagen were measured. RESULTS: Allergen challenge induced airway hyperresponsiveness in vehicle-treated animals as measured by whole body barometric plethysmography, and eosinophilia in bronchoalveolar lavage. POL7085 dose-dependently and significantly decreased airway hyperresponsiveness (34 +/- 16 %) and eosinophil numbers in bronchoalveolar lavage (66 +/- 6 %). In addition, the highest dose of POL7085 used significantly inhibited lung IL-4 (85 +/- 4 %), IL-5 (87 +/- 2 %) and IL-13 (190 +/- 19 %) levels, and lung collagen (43 +/- 11 %). CONCLUSIONS: The Protein Epitope Mimetic CCR10 antagonist, POL7085, significantly and dose-dependently decreased allergen-induced airway hyperresponsiveness and airway inflammation after once daily local treatment. Our data give strong support for further investigations with CCR10 antagonists in asthmatic disease. PMID- 26112288 TI - Discrimination of Dental Caries Using Colorimetric Characteristics of Fluorescence Spectrum. AB - The feasibility of colorimetric parameters for the discrimination of the stages of dental caries based on a light-induced autofluorescence spectrum at a 405-nm excitation wavelength was investigated. The fluorescence spectra of 4 groups of tooth samples (10 sound, 10 early-stage decay, 14 established decay, and 10 severe decay), which were classified by the International Caries Detection and Assessment System, were experimentally measured in vitro. The carious lesion samples had an additional fluorescence peak at around 627 nm. The mathematical relation of the fluorescence spectrum and human color perception was established and computed. With increasing severity, the fluorescence color changed from green to yellow according to the colorimetric parameters of the CIE 1931 (x, y) chromaticity coordinates and dominant wavelengths. The results from a one-way ANOVA of the dominant wavelength showed a statistically significant difference among the 4 classified groups. The colorimetric parameters of the light-induced fluorescence spectrum can potentially be applied to evaluate the various carious levels. PMID- 26112289 TI - Data Safe Havens in health research and healthcare. AB - MOTIVATION: The data that put the 'evidence' into 'evidence-based medicine' are central to developments in public health, primary and hospital care. A fundamental challenge is to site such data in repositories that can easily be accessed under appropriate technical and governance controls which are effectively audited and are viewed as trustworthy by diverse stakeholders. This demands socio-technical solutions that may easily become enmeshed in protracted debate and controversy as they encounter the norms, values, expectations and concerns of diverse stakeholders. In this context, the development of what are called 'Data Safe Havens' has been crucial. Unfortunately, the origins and evolution of the term have led to a range of different definitions being assumed by different groups. There is, however, an intuitively meaningful interpretation that is often assumed by those who have not previously encountered the term: a repository in which useful but potentially sensitive data may be kept securely under governance and informatics systems that are fit-for-purpose and appropriately tailored to the nature of the data being maintained, and may be accessed and utilized by legitimate users undertaking work and research contributing to biomedicine, health and/or to ongoing development of healthcare systems. RESULTS: This review explores a fundamental question: 'what are the specific criteria that ought reasonably to be met by a data repository if it is to be seen as consistent with this interpretation and viewed as worthy of being accorded the status of 'Data Safe Haven' by key stakeholders'? We propose 12 such criteria. CONTACT: paul.burton@bristol.ac.uk. PMID- 26112290 TI - biRte: Bayesian inference of context-specific regulator activities and transcriptional networks. AB - In the last years there has been an increasing effort to computationally model and predict the influence of regulators (transcription factors, miRNAs) on gene expression. Here we introduce biRte as a computationally attractive approach combining Bayesian inference of regulator activities with network reverse engineering. biRte integrates target gene predictions with different omics data entities (e.g. miRNA and mRNA data) into a joint probabilistic framework. The utility of our method is tested in extensive simulation studies and demonstrated with applications from prostate cancer and Escherichia coli growth control. The resulting regulatory networks generally show a good agreement with the biological literature. AVAILABILITY AND IMPLEMENTATION: biRte is available on Bioconductor (http://bioconductor.org). CONTACT: frohlich@bit.uni-bonn.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26112291 TI - Real-time multi-view deconvolution. AB - In light-sheet microscopy, overall image content and resolution are improved by acquiring and fusing multiple views of the sample from different directions. State-of-the-art multi-view (MV) deconvolution simultaneously fuses and deconvolves the images in 3D, but processing takes a multiple of the acquisition time and constitutes the bottleneck in the imaging pipeline. Here, we show that MV deconvolution in 3D can finally be achieved in real-time by processing cross sectional planes individually on the massively parallel architecture of a graphics processing unit (GPU). Our approximation is valid in the typical case where the rotation axis lies in the imaging plane. AVAILABILITY AND IMPLEMENTATION: Source code and binaries are available on github (https://github.com/bene51/), native code under the repository 'gpu_deconvolution', Java wrappers implementing Fiji plugins under 'SPIM_Reconstruction_Cuda'. CONTACT: bschmid@mpi-cbg.de or huisken@mpi-cbg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26112292 TI - damidseq_pipeline: an automated pipeline for processing DamID sequencing datasets. AB - DamID is a powerful technique for identifying regions of the genome bound by a DNA-binding (or DNA-associated) protein. Currently, no method exists for automatically processing next-generation sequencing DamID (DamID-seq) data, and the use of DamID-seq datasets with normalization based on read-counts alone can lead to high background and the loss of bound signal. DamID-seq thus presents novel challenges in terms of normalization and background minimization. We describe here damidseq_pipeline, a software pipeline that performs automatic normalization and background reduction on multiple DamID-seq FASTQ datasets. AVAILABILITY AND IMPLEMENTATION: Open-source and freely available from http://owenjm.github.io/damidseq_pipeline. The damidseq_pipeline is implemented in Perl and is compatible with any Unix-based operating system (e.g. Linux, Mac OSX). CONTACT: o.marshall@gurdon.cam.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26112293 TI - Predicting tumor purity from methylation microarray data. AB - MOTIVATION: In cancer genomics research, one important problem is that the solid tissue sample obtained from clinical settings is always a mixture of cancer and normal cells. The sample mixture brings complication in data analysis and results in biased findings if not correctly accounted for. Estimating tumor purity is of great interest, and a number of methods have been developed using gene expression, copy number variation or point mutation data. RESULTS: We discover that in cancer samples, the distributions of data from Illumina Infinium 450 k methylation microarray are highly correlated with tumor purities. We develop a simple but effective method to estimate purities from the microarray data. Analyses of the Cancer Genome Atlas lung cancer data demonstrate favorable performance of the proposed method. AVAILABILITY AND IMPLEMENTATION: The method is implemented in InfiniumPurify, which is freely available at https://bitbucket.org/zhengxiaoqi/infiniumpurify. CONTACT: xqzheng@shnu.edu.cn or hao.wu@emory.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26112294 TI - Administrative Privatization and Employment Outcomes in the Implementation of Temporary Assistance to Needy Families. AB - BACKGROUND: Welfare reform in the 1990s encouraged states and localities to contract out cash assistance services to for-profit and nonprofit firms operating within the private sector. Although privatized welfare delivery was heralded in the wake of Temporary Assistance to Needy Families (TANF), scant empirical research evaluates welfare privatization and its potential relationship with administrative quality and program outcomes. OBJECTIVES: This study examines the relationship between administrative privatization and TANF program outcomes, including work participation activities, unsubsidized employment, employment closure, and monthly earnings, across a large sample of individual welfare clients in the state of Florida. RESULTS: The results of methodologically appropriate hierarchical linear models demonstrate that ownership variables seldom enhance the quality of TANF outcomes, suggesting that privatization alone is not an administrative panacea in human support services. Although direct privatization effects are often found to be substantively small and inconsistent in terms of service quality improvement, in closed-case models, there is evidence that nonprofit welfare delivery is associated with superior TANF employment closure outcomes. PMID- 26112295 TI - Long-term clinical outcomes of drug-eluting stents in diabetic patients with small vessels compared to larger vessel-7 years clinical follow-up. AB - OBJECTIVES: The aim of this study was to analyze the effectiveness of drug eluting stents (DES) in small vessels in patients with non-insulin-dependent (NIDDM) and insulin-dependent diabetes mellitus (IDDM). BACKGROUND: Several randomized trials have shown DES to significantly reduce the angiographic and clinical events in diabetic patients. However, there is insufficient data on similar outcomes in diabetics with small vessels. METHODS: We studied 258 consecutive diabetic patients (173 NIDDM and 85 IDDM) who underwent coronary stenting with DES, divided into 2 cohorts: group A (vessels<2.7mm): 163 patients, and group B (vessels>=2.7mm): 95 patients. We analyzed the major adverse cardiac events (MACE) [death, nonfatal myocardial infarction MI, and target lesion revascularization (TVR)] over a mean follow-up of 78.4+/-14.8months. RESULTS: Group A patients had: smaller reference diameter (2.4+/-0.31 versus 3.14+/-0.2mm, p=0.0001), longer lesions (19.3+/-9.5 versus 16.7+/-7.1mm, p=0.023), more complex lesions: (B2/C) (80.7 versus 52.6%, p<0.033), bifurcation lesions (25.8 versus 11.6%, p=0.007), diffuse disease (42.9 versus 26.3%, p=0.008), multivessel (32.5 versus 18.9%, p=0.019), eccentric lesions (57.1 versus 43.2%, p=0.031), more stents implanted (1.99+/-1.6 versus 1.7+/-1.3, p<0.0001), more overlapping stents (29.4 versus 13.7%, p=0.004) and more stents length (25.7+/-4.9 versus 20.2+/ 2.6, p<0.003). During the follow-up, both groups had overall similar MACE (10.4 versus 11.7%, p=0.9) with insignificant higher restenosis (9.2 versus 8.4%, p=0.832) and TVR (7.4 versus 6.4%, p=0.75) in group A. There was no difference in death (p=0.111) or MI (p=0.858). Both groups had similar stent thrombosis rate (1.2 versus 1.1%, p=0.899), angina events (10.4 versus 16.8%, p=0.137), abnormal stress thallium (14.1 versus 14.7%, p=0.890), and hospital days (2.91 versus 3.57, p=0.886). CONCLUSION: Despite complex angiographic characteristics, the use of DES in diabetic patients with small vessels showed favorable clinical outcomes and similar low TVR compared to those with large vessels. PMID- 26112296 TI - Combining balloon-assisted tracking and sheathless guiding catheter: unloosening the Gordian knot. AB - In a patient with a small-calibre radial artery and a 360 degrees radio-ulnar loop, we combined the balloon-assisted tracking (BAT) technique (used to track a catheter trough the loop) with the use of a 6.5FPB sheathless guiding catheter, in order to allow the extensive catheter manipulations needed for PCI despite the ongoing artery spasm. PMID- 26112297 TI - Complications with Endobronchial Ultrasound with a Guide Sheath for the Diagnosis of Peripheral Pulmonary Lesions. AB - BACKGROUND: Diagnostic bronchoscopy has been considered as a safe and effective procedure. Endobronchial ultrasound with a guide sheath (EBUS-GS) for the diagnosis of peripheral pulmonary lesions (PPLs) is becoming a common procedure, but reports about its safety are missing. OBJECTIVES: The aim of this study was to evaluate the safety profile of EBUS-GS for the diagnosis of PPLs. METHODS: All patients with PPLs who underwent EBUS-GS between September 2012 and August 2014 at the National Cancer Center Hospital were included. Postprocedural complications and the durability of devices were retrospectively reviewed. RESULTS: During the study period, EBUS-GS procedures were performed for 965 PPLs. The overall complication rate was 1.3% (13/965): 0.8% (8/965) for pneumothorax and 0.5% (5/965) for pulmonary infection. There was no significant hemorrhage, air embolism, tumor seeding or procedure-related death, and there was no breakage of the guide sheath. Only four radial probes were broken during the study period without any adverse reactions. CONCLUSIONS: EBUS-GS is a tolerable procedure, and the devices are durable. PMID- 26112298 TI - Obstructive Sleep Apnea Effects on the Right Ventricle and Beyond. PMID- 26112299 TI - Hypertension and Sleep Apnea. AB - Obstructive sleep apnea is more prevalent in patients with hypertension than in the general population and many with obstructive sleep apnea also have hypertension. Obstructive sleep apnea increases the risk of hypertension-related morbidities such as stroke, heart failure, and premature death. Are such associations coincidental or causal and if the latter, what are their implications for clinical practice? Despite compelling epidemiological and mechanistic links between obstructive sleep apnea and hypertension, the effect in clinical trials of the treatment of obstructive sleep apnea on blood pressure has been modest and variable. The purpose of this review is to summarize our present understanding of: (1) the relevant epidemiology and mechanisms that might be responsible for the bidirectional relationship between obstructive sleep apnea and hypertension; and (2) available evidence regarding the effect of treating obstructive sleep apnea on blood pressure. PMID- 26112300 TI - Heart Failure and Sleep Apnea. AB - Obstructive and central sleep apnea are far more common in heart failure patients than in the general population and their presence might contribute to the progression of heart failure by exposing the heart to intermittent hypoxia, increased preload and afterload, sympathetic nervous system activation, and vascular endothelial dysfunction. There is now substantial evidence that supports a role for fluid overload and nocturnal rostral fluid shift from the legs as unifying mechanisms in the pathogenesis of obstructive and central sleep apnea in heart failure patients, such that the predominant type of sleep apnea is related to the relative distribution of fluid from the leg to the neck and chest. Despite advances in therapies for heart failure, mortality rates remain high. Accordingly, the identification and treatment of sleep apnea in patients with heart failure might offer a novel therapeutic target to modulate this increased risk. In heart failure patients with obstructive or central sleep apnea, continuous positive airway pressure has been shown to improve cardiovascular function in short-term trials but this has not translated to improved mortality or reduced hospital admissions in long-term randomized trials. Other forms of positive airway pressure such as adaptive servoventilation have shown promising results in terms of attenuation of sleep apnea and improvement in cardiovascular function in short-term trials. Large scale, randomized trials are required to determine whether treating sleep apnea with various interventions can reduce morbidity and mortality. PMID- 26112302 TI - Sleep Apnea and Stroke. AB - Stroke is the second leading cause of death worldwide and often has devastating consequences for affected individuals in terms of chronic disability. Traditional risk factors such as age, male sex, ethnicity, hypertension, and atrial fibrillation explain 60%-80% of the risk of stroke. Obstructive sleep apnea (OSA) is highly prevalent in individuals who have had a stroke and its emerging role as a potential modifiable risk factor for stroke has been recognized in the most recent American Heart Association stroke guidelines, which recommend consideration of screening for and treatment of OSA in this regard. In this article we provide an overview of the current evidence-based knowledge related to stroke and sleep apnea. The main focus of this article is key pathophysiological mechanisms by which OSA might increase the risk for stroke. The effect of OSA on stroke outcomes and the efficacy of treatment of OSA on these outcomes is also discussed. PMID- 26112301 TI - Sleep-Disordered Breathing and Coronary Artery Disease. AB - Coronary artery disease (CAD) is one of the most frequent diseases in industrial nations. Despite significant advances in diagnosis and therapy, CAD and its long term consequences are important contributors to morbidity and mortality. Therefore, in addition to management of traditional CAD risk factors, there are continued efforts to evaluate other factors and comorbidities that might contribute to the development and progression of CAD. One such factor is sleep disordered breathing (SDB), which is characterized by repetitive apneas, arousals from sleep, and intermittent hypoxia. There is increasing evidence that SDB is a risk factor for CAD. In the early phase after myocardial infarction (MI) the heart might be in a vulnerable state sensitive to the negative consequences of SDB, including increased cardiac workload and endothelial dysfunction, which might ultimately lead to a mismatch between oxygen demand and supply. Despite successful percutaneous coronary intervention, patients with acute MI and SDB have prolonged myocardial ischemia, less salvaged myocardium, and impaired left and right ventricular remodelling compared with those without SDB, all of which predispose to heart failure. Suppression of SDB with positive airway pressure therapy in the early phase after MI is feasible. However, whether treatment of SDB with positive airway pressure will be an effective nonpharmacological treatment approach that will prevent the development of heart failure after MI remains to be determined and is the subject of current investigations. PMID- 26112303 TI - Should All Congestive Heart Failure Patients Have a Routine Sleep Apnea Screening? Pro. AB - Sleep-disordered breathing (SDB) is highly prevalent in heart failure (HF) patients. These breathing disturbances are independent predictors of increased morbidity and comorbid conditions that improve with SDB treatment. Considering the overlap between SDB-related and HF clinical symptoms reported by patients, objective tests need to be conducted for a diagnosis to be firmly established and to determine the type and severity of SDB that will dictate treatment alternatives. Considering the high success rate and diagnostic value of ambulatory monitoring techniques, they represent a practical, cost-effective, and accurate alternative to diagnosing SDB in HF patients. PMID- 26112304 TI - Should All Congestive Heart Failure Patients Have a Routine Sleep Apnea Screening? Con. AB - Sleep-disordered breathing (SDB) is one of the most common comorbidities in people with congestive heart failure (CHF). Although SDB has major cardiometabolic consequences, the attributable risk of SDB in asymptomatic CHF patients remains unclear. Whether early intervention using positive airway pressure would improve the prognosis in CHF patients is uncertain. As yet, there is insufficient evidence that routine polysomnography screening is cost-effective for asymptomatic CHF patients. Careful clinical risk evaluation and thoughtful use of limited-channel home sleep testing should be considered before the application of routine polysomnography in all CHF patients. PMID- 26112305 TI - When to Suspect Sleep Apnea and What to Do About It. AB - Obstructive sleep apnea (OSA), which is characterized by recurrent upper airway obstruction during sleep with resultant hypoxia-reoxygenation and sleep fragmentation, is prevalent among patients with cardiovascular disease. Refractory hypertension, nocturnal angina or arrhythmias, and stroke in particular should prompt consideration of OSA. The symptoms of OSA include snoring and excessive daytime sleepiness; risk factors include obesity and reduced upper airway dimensions. Up to 50% of patients with congestive heart failure (CHF) may manifest OSA, central sleep apnea-Cheyne-Stokes respiration (CSA-CSR), or both. Patients with CSA-CSR may present with fatigue, disrupted sleep, and paroxysmal nocturnal dyspnea. Objective sleep recording is required to document the nature and severity of sleep apnea. The gold standard is in laboratory overnight polysomnography (PSG), including monitoring of electroencephalography and other signals to determine sleep-wake state, and recording of body position, airflow, respiratory effort, and pulse oximetry. Portable cardiorespiratory recorders are now approved for diagnosis in patients without comorbidities. Full PSG is recommended for diagnosis in all other cases, although OSA and CSA-CSR can be identified from portable recorders in some patients with CHF and other conditions. The objectives of treatment are to improve symptoms, quality of life, and cardiovascular outcomes. The mainstay of treatment for moderate-to-severe OSA is positive airway pressure (PAP). Automated PAP devices may be used in uncomplicated OSA, whereas continuous fixed PAP is the treatment of choice for other patients with OSA, and may also treat a proportion of patients with CSA-CSR. A form of bi-level PAP known as adaptive servoventilation is effective in treating a majority of patients with CSA-CSR. PMID- 26112306 TI - Protein S-palmitoylation and cancer. AB - Protein S-palmitoylation is a reversible posttranslational modification of proteins with fatty acids, an enzymatic process driven by a recently discovered family of protein acyltransferases (PATs) that are defined by a conserved catalytic domain characterized by a DHHC sequence motif. Protein S-palmitoylation has a prominent role in regulating protein location, trafficking and function. Recent studies of DHHC PATs and their functional effects have demonstrated that their dysregulation is associated with human diseases, including schizophrenia, X linked mental retardation, and Huntington's Disease. A growing number of reports indicate an important role for DHHC proteins and their substrates in tumorigenesis. Whereas DHHC PATs comprise a family of 23 enzymes in humans, a smaller number of enzymes that remove palmitate have been identified and characterized as potential therapeutic targets. Here we review current knowledge of the enzymes that mediate reversible palmitoylation and their cancer-associated substrates and discuss potential therapeutic applications. PMID- 26112307 TI - Coxsackievirus A6: a new emerging pathogen causing hand, foot and mouth disease outbreaks worldwide. AB - Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the predominant pathogens causing outbreaks of hand, foot and mouth disease (HFMD) worldwide. Other human enterovirus A (HEV-A) serotypes tend to cause only sporadic HFMD cases. However, since a HFMD caused by coxsackievirus A6 broke out in Finland in 2008, CA6 has been identified as the responsible pathogen for a series of HFMD outbreaks in Europe, North America and Asia. Because of the severity of the clinical manifestations and the underestimated public health burden, the epidemic of CA6 associated HFMD presents a new challenge to the control of HFMD. This article reviewed the epidemic characteristics, molecular epidemiology, clinical features and laboratory diagnosis of CA6 infection. The genetic evolution of CA6 strains associated with HFMD was also analyzed. It indicated that the development of a multivalent vaccine combining EV71, CA16 and CA6 is an urgent necessity to control HFMD. PMID- 26112309 TI - Tuning the polarity of charge transport in InSb nanowires via heat treatment. AB - InSb nanowire (NW) arrays were prepared by pulsed electrodeposition combined with a porous template technique. The resulting polycrystalline material has a stoichiometric composition (In:Sb = 1:1) and a high length-to-diameter ratio. Based on a combination of Fourier transform infrared spectroscopy (FTIR) analysis and field-effect measurements, the band gap, the charge carrier polarity, the carrier concentration, the mobility and the effective mass for the InSb NWs was investigated. In this preliminary work, a transition from p-type to n-type charge transport was observed when the InSb NWs were subjected to annealing. PMID- 26112310 TI - A Bayesian methodology for detecting targeted genes under two related experiments. AB - Many gene expression data are based on two experiments where the gene expressions of the targeted genes under both experiments are correlated. We consider problems in which objectives are to find genes that are simultaneously upregulated/downregulated under both experiments. A Bayesian methodology is proposed based on directional multiple hypotheses testing. We propose a false discovery rate specific to the problem under consideration, and construct a Bayes rule satisfying a false discovery rate criterion. The proposed method is compared with a traditional rule through simulation studies. We apply our methodology to two real examples involving microRNAs; where in one example the targeted genes are simultaneously downregulated under both experiments, and in the other the targeted genes are downregulated in one experiment and upregulated in the other experiment. We also discuss how the proposed methodology can be extended to more than two experiments. PMID- 26112308 TI - Co-translational capturing of nascent ribosomal proteins by their dedicated chaperones. AB - Exponentially growing yeast cells produce every minute >160,000 ribosomal proteins. Owing to their difficult physicochemical properties, the synthesis of assembly-competent ribosomal proteins represents a major challenge. Recent evidence highlights that dedicated chaperone proteins recognize the N-terminal regions of ribosomal proteins and promote their soluble expression and delivery to the assembly site. Here we explore the intuitive possibility that ribosomal proteins are captured by dedicated chaperones in a co-translational manner. Affinity purification of four chaperones (Rrb1, Syo1, Sqt1 and Yar1) selectively enriched the mRNAs encoding their specific ribosomal protein clients (Rpl3, Rpl5, Rpl10 and Rps3). X-ray crystallography reveals how the N-terminal, rRNA-binding residues of Rpl10 are shielded by Sqt1's WD-repeat beta-propeller, providing mechanistic insight into the incorporation of Rpl10 into pre-60S subunits. Co translational capturing of nascent ribosomal proteins by dedicated chaperones constitutes an elegant mechanism to prevent unspecific interactions and aggregation of ribosomal proteins on their road to incorporation. PMID- 26112312 TI - Adenoviruses and acute respiratory infections in children living in an equatorial area of Brazil. AB - Human adenoviruses (HAdVs) are important respiratory pathogens, found in 2-27% of acute respiratory infection (ARI) cases. Few studies have analysed the diversity of species and types of HAdVs associated with ARI in Brazil. The purpose of this study was to determine the circulation patterns of the different HAdV species and respective types associated with ARI in children in the city of Fortaleza, northeastern Brazil. HAdVs were screened by an indirect immunofluorescence assay, and subsequently identified as species and types by PCR and sequencing of the hexon gene (HVR1-HVR6). Between 2001 and 2013, a total of 290 HAdV strains were detected, 190 of which were identified as belonging to the HAdV-B, -C and -E species. Seven types of HAdVs circulated in the studied population during the analysed period, with HAdV-3 being predominant. PMID- 26112311 TI - Computed tomography-guided percutaneous microwave ablation combined with osteoplasty for palliative treatment of painful extraspinal bone metastases from lung cancer. AB - OBJECTIVE: To retrospectively evaluate the efficacy and safety of microwave ablation (MWA) combined with osteoplasty in lung cancer patients with painful extraspinal bone metastases. MATERIALS AND METHODS: From January 2011 to July 2014, 26 lung cancer patients with 33 painful extraspinal bone metastases underwent percutaneous MWA combined with osteoplasty. Effectiveness was evaluated by visual analog scale (VAS) and daily morphine dose with a follow-up of 6 months. Complications were also recorded. RESULTS: Mean VAS score and morphine dose pre-procedure were 7.4 +/- 1.6 (range, 5-10) and 47.7 +/- 30.1 mg (range, 20 120 mg), respectively. Technical success and pain relief were achieved in all patients. Mean VAS scores and daily morphine doses post-procedure were as follows: 48 h, 1.7 +/- 1.2 (p < 0.001) and 29.6 +/- 16.1 mg (p = 0.003); 7 days, 1.9 +/- 1.7 (p < 0.001) and 16.1 +/- 12.0 mg (p < 0.001); 1 month, 1.5 +/- 0.9 (p < 0.001) and 10.8 +/- 10.9 (p < 0.001); 3 months, 0.9 +/- 0.7 (p < 0.001) and 8.4 +/- 9.2 mg (p < 0.001); and 6 months, 1.2 +/- 0.8 (p < 0.001) and 9.2 +/- 12.3 mg (p < 0.001). Complications were observed in eight patients (28%); among these, major complications were reported in two (7.7%) patients, one with local infection and the other with a bone fracture. The minor complication rate was 23.1% (6/26). CONCLUSION: MWA combination with osteoplasty appeared to be an effective and safe treatment for lung cancer patients with painful extraspinal bone metastases. PMID- 26112313 TI - Outcomes of Transobturator Tape Surgery with Safyre T(r) Slings for Female Stress Urinary Incontinence after 96 Months of Follow-Up. AB - BACKGROUND/AIMS: To report the outcomes of transobturator tape (TOT) surgery with Safyre T(r) (Promedon, Argentina) slings for female stress urinary incontinence (SUI) at a 96- month follow-up. METHODS: We conducted a clinical follow-up study of 153 patients diagnosed with SUI between January 2005 and December 2014. Patients were provided with detailed a priori information pertaining to the TOT procedure and were invited to attend follow-up visits at 1, 3, 12, 24, 48, 72 and 96 months. Follow-up visits included physical examination involving sling palpation, checking of the vaginal mucosa for erosion, cough test, as well as validated Urinary Distress Inventory-6 (UDI-6) and Incontinence Impact Questionnaire-7 (IIQ-7) questionnaires. RESULTS: The overall objective success rates, based on cough test results, were 91.3% at 12 months, 86.8% at 48 months and 77.6% at 96 months. Similarly, the overall subjective success rate, based on the validated UDI-6 and IIQ-7 scales, was 77.6% at 96 months. CONCLUSION: The cure rates achieved, following TOT treatment of SUI at 1-year follow-up, showed a statistically significant decline over an 8-year period, especially at months 48 and 96. (c) 2015 S. Karger AG, Basel. PMID- 26112316 TI - Characterization of the Genotypic Profile of Hepatitis Delta Virus: Isolation of HDV Genotype-1 in the Western Amazon Region of Brazil. AB - The hepatitis delta virus (HDV) is a hepatotropic subvirus that is dependent on the hepatitis B virus (HBV) and supplies the viral envelope containing the surface antigen of hepatitis B. Viral genetic diversity is related to the geographical origin of the isolates, and there are at least eight genotypes that are referred to as HDV-1 through HDV-8. HDV-3 is responsible for epidemics of severe and fulminant hepatitis, which are common in northeastern South America. HDV-3 is prevalent in the Brazilian Amazon and is associated with the increased aggressiveness of HDV infections. Although isolated, the characteristics of the clinical presentation of HDV-1 in the Amazon region have not yet been clearly reported. OBJECTIVE: This study aims to assess the genotypic and clinical characteristics of individuals with the HDV-1 genotype in the western Amazon region. METHODS: The HDV was genotyped by nested PCR-RFLP and sequencing from serum samples of 56 patients with HBV/HDV infection. The genotypes were correlated with the clinical characteristics presented by patients with HBV/HDV infection. RESULTS: A prevalence of 92.3% for the HDV-3 genotype (n = 48) and 7.6% (n = 4) for the HDV-1 genotype was observed. CONCLUSION: To date, this is the most extensive clinical study of HDV-1 genotype infections in the nonindigenous population of Western Amazonia. PMID- 26112315 TI - Indole trimers with antibacterial activity against Gram-positive organisms produced using combinatorial biocatalysis. AB - The I100V isoform of toluene-4-monooxygenase was used to catalyze the oxidative polymerization of anthranil and various indoles under mildly acidic conditions, favoring the production of trimers. Compounds produced in sufficient yield were purified and tested for their ability to inhibit the growth of B. anthracis, E. faecalis, L. monocytogenes, S. aureus, and in some cases, F. tularensis. 15 of the compounds displayed promising antibacterial activity (MIC < 5 ug/ml) against one or more of the strains tested, with the best MIC values being <0.8 ug/ml. All of these compounds had good selectivity, showing minimal cytotoxicity towards HepG2 cells. The structure was solved for six of the compounds that could be crystallized, revealing that minimally two classes of indole based trimers were produced. One compound class produced was a group of substituted derivatives of the natural product 2,2-bis(3-indolyl) indoxyl. The other group of compounds identified was classified as tryptanthrin-like compounds, all having multi-ring pendant groups attached at position 11 of tryptanthrin. One compound of particular interest, SAB-J85, had a structure that suggests that any compound, with a ring structure that can be activated by an oxygenase, might serve as a substrate for combinatorial biocatalysis. PMID- 26112314 TI - Treatment of traumatic brain injury with anti-inflammatory drugs. AB - Traumatic brain injury rapidly induces inflammation. This inflammation is produced both by endogenous brain cells and circulating inflammatory cells that enter from the brain. Together they drive the inflammatory response through a wide variety of bioactive lipids, cytokines and chemokines. A large number of drugs with anti-inflammatory action have been tested in both preclinical studies and in clinical trials. These drugs either have known anti-inflammatory action or inhibit the inflammatory response through unknown mechanisms. The results of these preclinical studies and clinical trials are reviewed. Recommendations are suggested on how to improve preclinical testing of drugs to make them more relevant to evaluate for clinical trials. PMID- 26112318 TI - Magnetically aligned iron oxide/gold nanoparticle-decorated carbon nanotube hybrid structure as a humidity sensor. AB - Functionalized carbon nanotubes (f-CNTs), particularly CNTs decorated with nanoparticles (NPs), are of great interest because of their synergic effects, such as surface-enhanced Raman scattering, plasmonic resonance energy transfer, magnetoplasmonic, magnetoelectric, and magnetooptical effects. In general, research has focused on a single type of NP, such as a metal or metal oxide, that has been modified on a CNT surface. In this study, however, a new strategy is introduced for the decoration of two different NP types on CNTs. In order to improve the functionality of modified CNTs, we successfully prepared binary NP decorated CNTs, namely, iron oxide/gold (Au) NP-decorated CNTs (IA-CNTs), which were created through two simple reactions in deionized water, without high temperature, high pressure, or harsh reducing agents. The physicochemical properties of IA-CNTs were characterized by ultraviolet/visible spectroscopy, Fourier transform infrared spectroscopy, a superconducting quantum interference device, scanning electron microscopy, and transmission electron microscopy. In this study, IA-CNTs were utilized to detect humidity. Magnetic IA-CNTs were aligned on interdigitated platinum electrodes under external magnetic fields to create a humidity-sensing channel, and its electrical conductivity was monitored. As the humidity increased, the electrical resistance of the sensor also increased. In comparison with various gases, for example, H2, O2, CO, CO2, SO2, and dry air, the IA-CNT-based humidity sensor exhibited high-selectivity performances. IA-CNTs also responded to heavy water (D2O), and it was established that the humidity detection mechanism had D2O-sensing capabilities. Further, the humidity from human out-breathing was also successfully detected by this system. In conclusion, these unique IA-CNTs exhibited potential application as gas detection materials. PMID- 26112317 TI - Monitoring the freshness of fish: development of a qPCR method applied to MAP chilled whiting. AB - BACKGROUND: Monitoring of early stages of freshness decay is a major issue for the fishery industry to guarantee the best quality for this highly perishable food matrix. Numerous techniques have been developed, but most of them have the disadvantage of being reliable only either in the last stages of fish freshness or for the analysis of whole fish. This study describes the development of a qPCR method targeting the torA gene harboured by fish spoilage microorganisms. torA encodes an enzyme that leads to the production of trimethylamine responsible for the characteristic spoiled-fish odour. RESULTS: A degenerate primer pair was designed. It amplified torA gene of both Vibrio and Photobacterium with good efficiencies on 7-log DNA dilutions. The primer pair was used during a shelf-life monitoring study achieved on modified atmosphere packed, chilled, whiting (Merlangius merlangus) fillets. The qPCR approach allows the detection of an increase of torA copies throughout the storage of fillets in correlation with the evolution of both total volatile basic nitrogen (-0.86) and trimethylamine concentrations (-0.81), known as spoilage markers. CONCLUSION: This study described a very promising, sensitive, reliable, time-effective, technique in the field of freshness characterisation of processed fish. PMID- 26112319 TI - Web-based prevention and treatment programmes for internalising problems in youth: encouraging findings in an expanding research field. PMID- 26112320 TI - SSRI antidepressants are not associated with cerebral microbleeds or ischaemic vascular lesions. PMID- 26112321 TI - Psychosocial therapy after self-harm associated with reduced repetition, suicide, and all-cause mortality in Denmark. PMID- 26112322 TI - A Secure Three-Factor User Authentication and Key Agreement Protocol for TMIS With User Anonymity. AB - Telecare medical information system (TMIS) makes an efficient and convenient connection between patient(s)/user(s) and doctor(s) over the insecure internet. Therefore, data security, privacy and user authentication are enormously important for accessing important medical data over insecure communication. Recently, many user authentication protocols for TMIS have been proposed in the literature and it has been observed that most of the protocols cannot achieve complete security requirements. In this paper, we have scrutinized two (Mishra et al., Xu et al.) remote user authentication protocols using smart card and explained that both the protocols are suffering against several security weaknesses. We have then presented three-factor user authentication and key agreement protocol usable for TMIS, which fix the security pitfalls of the above mentioned schemes. The informal cryptanalysis makes certain that the proposed protocol provides well security protection on the relevant security attacks. Furthermore, the simulator AVISPA tool confirms that the protocol is secure against active and passive attacks including replay and man-in-the-middle attacks. The security functionalities and performance comparison analysis confirm that our protocol not only provide strong protection on security attacks, but it also achieves better complexities along with efficient login and password change phase as well as session key verification property. PMID- 26112323 TI - Optimization of Aspergillus niger rock phosphate solubilization in solid-state fermentation and use of the resulting product as a P fertilizer. AB - A biotechnological strategy for the production of an alternative P fertilizer is described in this work. The fertilizer was produced through rock phosphate (RP) solubilization by Aspergillus niger in a solid-state fermentation (SSF) with sugarcane bagasse as substrate. SSF conditions were optimized by the surface response methodology after an initial screening of factors with significant effect on RP solubilization. The optimized levels of the factors were 865 mg of biochar, 250 mg of RP, 270 mg of sucrose and 6.2 ml of water per gram of bagasse. At this optimal setting, 8.6 mg of water-soluble P per gram of bagasse was achieved, representing an increase of 2.4 times over the non-optimized condition. The optimized SSF product was partially incinerated at 350 degrees C (SB-350) and 500 degrees C (SB-500) to reduce its volume and, consequently, increase P concentration. The post-processed formulations of the SSF product were evaluated in a soil-plant experiment. The formulations SB-350 and SB-500 increased the growth and P uptake of common bean plants (Phaseolus vulgaris L.) when compared with the non-treated RP. Furthermore, these two formulations had a yield relative to triple superphosphate of 60% (on a dry mass basis). Besides increasing P concentration, incineration improved the SSF product performance probably by decreasing microbial immobilization of nutrients during the decomposition of the remaining SSF substrate. The process proposed is a promising alternative for the management of P fertilization since it enables the utilization of low-solubility RPs and relies on the use of inexpensive materials. PMID- 26112324 TI - An Ime2-like mitogen-activated protein kinase is involved in cellulase expression in the filamentous fungus Trichoderma reesei. AB - OBJECTIVES: Eukaryotic mitogen-activated protein kinases (MAPKs) play crucial roles in transducing environmental and developmental signals inside the cell and regulating gene expression, however, the roles of MAPKs remain largely unknown in Trichoderma reesei. RESULTS: T. reesei ime2 (TrIme2) encodes an Ime2-like MAPK in T. reesei. The deletion of the TrIme2 gene led to 90% increase in cellulase activity against filter paper during earlier period time of cellulase induction as well as the extracellular protein production. Compared to the parent strain, the transcriptional levels of the three major cellulase genes cbh1,cbh2, egl1 were increased by about 9 times, 4 times, 2 times, respectively, at 8 h after cellulase induction in the DeltaTrIme2 mutant. In addition, the disruption of TrIme2 caused over 50% reduction of the transcript levels of cellulase transcriptional regulators cre1 and xyr1. CONCLUSION: TrIme2 functions in regulation of the expression of cellulase gene in T.reesei, and is a good candidate for genetically engineering of T. reesei for higher cellulase production. PMID- 26112325 TI - Production of novel types of antibacterial liamocins by diverse strains of Aureobasidium pullulans grown on different culture media. AB - OBJECTIVES: To compare production of antibacterial liamocins (polyol lipids) by diverse strains of Aureobasidium pullulans grown on different culture media. RESULTS: Liamocins produced by strains of A. pullulans have potential agricultural and pharmaceutical applications as antibacterials with specificity against Streptococcus spp. Six strains of A. pullulans were characterized for liamocin production on four different culture media. The choice of strain and culture medium affected growth, liamocin yields, and production of contaminating pigments. Best growth and highest liamocin yields were obtained using A. pullulans strain NRRL 50384 grown on a sucrose basal medium. Unexpectedly, the choice of strain and culture medium also affected the structure of liamocins produced, providing novel types of liamocins. Liamocins varied not only in the ratios of trimer and tetramer polyester tail groups, but also in the nature of the polyol headgroup, which could include mannitol, arabitol, or glycerol. CONCLUSIONS: The ability to conveniently produce novel types of liamocins in good yields will provide novel antibacterials for applied uses, and facilitate structure-function studies on the mechanism of antibacterial activity. PMID- 26112326 TI - Genome shuffling to generate recombinant yeasts for tolerance to inhibitors present in lignocellulosic hydrolysates. AB - OBJECTIVES: To investigate the use of genome shuffling to generate recombinants from previously generated hydrolysates-tolerant strains to improve tolerance of Saccharomyces cerevisiae to one or more inhibitory by-products present in lignocellulosic hydrolysates. RESULTS: Recombinants of previously evolved strains of S. cerevisiae were generated and analyzed for their relative performance in the individual inhibitors furfural, acetic acid, 5-(hydroxymethyl)-furfural (HMF) and in synthetic hydrolysates. One recombinant exhibited a 100 % fitness increase in the presence of HMF as compared to the wild-type diploid, while another stain exhibited a 13 % fitness increase in the presence of furfural. Furthermore, for one of these recombinants, these increases in fitness were specific to the inhibitor HMF and to synthetic hydrolysates rather than being due to a general increase in fitness. Mutations present in the evolved hydrolysates-tolerant mutants were identified via whole-genome resequencing. CONCLUSION: Recombinants of S. cerevisiae were produced with increased tolerance to inhibitory by-products present in hydrolysates of lignocellulosic biomass and identified potential genetic determinants associated with this phenotype. PMID- 26112327 TI - Sample end effects. AB - In high-resolution NMR spectroscopy, the variation of the magnetic field inside the sample has a measurable impact on lineshape. We present a model to calculate the moments of the internal field, as they relate to the current that should be set in the compensation coils to level the magnetic perturbations originating from the sample. We apply this model to common sample geometries, and discuss the practical implications for sample-limited applications. PMID- 26112328 TI - CW and pulsed electrically detected magnetic resonance spectroscopy at 263GHz/12T on operating amorphous silicon solar cells. AB - Here we describe a new high frequency/high field continuous wave and pulsed electrically detected magnetic resonance (CW EDMR and pEDMR) setup, operating at 263GHz and resonance fields between 0 and 12T. Spin dependent transport in illuminated hydrogenated amorphous silicon p-i-n solar cells at 5K and 90K was studied by in operando 263GHz CW and pEDMR alongside complementary X-band CW EDMR. Benefiting from the superior resolution at 263GHz, we were able to better resolve EDMR signals originating from spin dependent hopping and recombination processes. 5K EDMR spectra were found to be dominated by conduction and valence band tail states involved in spin dependent hopping, with additional contributions from triplet exciton states. 90K EDMR spectra could be assigned to spin pair recombination involving conduction band tail states and dangling bonds as the dominating spin dependent transport process, with additional contributions from valence band tail and triplet exciton states. PMID- 26112329 TI - Dexamethasone-suppressed cortisol awakening response predicts treatment outcome in posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) has been associated with several alterations in the neuroendocrine system, including enhanced cortisol suppression in response to the dexamethasone suppression test. The aim of this study was to examine whether specific biomarkers of PTSD predict treatment success in trauma focused psychotherapy. METHODS: Data were collected in the context of a randomized controlled trial comparing two forms of trauma-focused psychotherapy. Basal cortisol and dehydroepiandrosterone sulfate levels, and the response to the dexamethasone suppression test were assessed pre-treatment in 24 PTSD patients. Treatment success was measured by pre- to post-treatment decrease in self reported PTSD severity. RESULTS: A more suppressed cortisol curve after dexamethasone significantly predicted greater PTSD symptom decrease in trauma focused psychotherapy, independent of the effects of gender, pre-treatment PTSD symptom severity, and trauma history. Basal early morning cortisol and dehydroepiandrosterone sulfate did not predict treatment response. LIMITATIONS: The number of participants who completed the neuroendocrine measurements was small and a significant number of participants fulfilled criteria of co-morbid major depressive disorder. CONCLUSIONS: This study suggests the use of the dexamethasone-suppression test for the cortisol awakening response as a biomarker for treatment response to trauma-focused psychotherapy. Measures of HPA-axis sensitivity appear to be an important predictor of positive clinical response in PTSD patients, and may lead to biomarker-based treatment matching in the future. PMID- 26112330 TI - Bipolar disorder and self-stigma: A comparison with schizophrenia. AB - AIM: Even though numerous studies have focused on the effects of self-stigma on patients with schizophrenia, little is known about self-stigma of patients with bipolar disorder (BD). In this study, a self-administered scale of self stigmatising attitudes of patients with BD and schizophrenia was used to explore these attitudes, examine the potential differences between the two groups and study the factors that influence stigma within groups. METHODS: Self-stigma of 120 patients with schizophrenia and BD was assessed with the Self-stigma Questionnaire (SSQ) and the Stigma Inventory for Mental Illness (SIMI). Presence of clinical symptoms, overall functioning and level of self-esteem were also evaluated. RESULTS: Self-stigma is present in both groups but differs in its intensity. Patients with BD experience self-stigma in a lesser degree without affecting their social life or overall functioning. Patients with schizophrenia adopt more intense self-stigmatising attitudes leading to social exclusion and lower level of overall functioning. LIMITATIONS: The results are limited by the small sample size, whereas the inclusion of other questionnaires would broaden our insight to self-stigma. CONCLUSIONS: Self-stigma has a direct effect on overall functioning of patients with BD and schizophrenia tampering the clinical outcome of therapeutic interventions. Therefore, it should be incorporated in every treatment plan and be addressed as a clinical symptom of the mental illness. PMID- 26112331 TI - Reduced dopamine and glutamate neurotransmission in the nucleus accumbens of quinpirole-sensitized rats hints at inhibitory D2 autoreceptor function. AB - Dopamine from the ventral tegmental area and glutamate from several brain nuclei converge in the nucleus accumbens (NAc) to drive motivated behaviors. Repeated activation of D2 receptors with quinpirole (QNP) induces locomotor sensitization and compulsive behaviors, but the mechanisms are unknown. In this study, in vivo microdialysis and fast scan cyclic voltammetry in adult anesthetized rats were used to investigate the effect of repeated QNP on dopamine and glutamate neurotransmission within the NAc. Following eight injections of QNP, a significant decrease in phasic and tonic dopamine release was observed in rats that displayed locomotor sensitization. Either a systemic injection or the infusion of QNP into the NAc decreased dopamine release, and the extent of this effect was similar in QNP-sensitized and control rats, indicating that inhibitory D2 autoreceptor function is maintained despite repeated activation of D2 receptors and decreased dopamine extracellular levels. Basal extracellular levels of glutamate in the NAc were also significantly lower in QNP-treated rats than in controls. Moreover, the increase in NAc glutamate release induced by direct stimulation of medial prefrontal cortex was significantly lower in QNP-sensitized rats. Together, these results indicate that repeated activation of D2 receptors disconnects NAc from medial prefrontal cortex and ventral tegmental area. Repeated administration of the dopamine D2 receptor agonist quinpirole (QNP) induces locomotor sensitization. We found that the NAc of QNP-sensitized rats has reduced glutamate levels coming from prefrontal cortex together with a decreased phasic and tonic dopamine neurotransmission but a conserved presynaptic D2 receptor function. We suggest that locomotor sensitization is because of increased affinity state of D2 post-synaptic receptors. PMID- 26112332 TI - MiR-22 Suppresses BMP7 in the Development of Cirrhosis. AB - BACKGROUND/AIMS: New strategies for the prevention and treatment of cirrhosis are urgently needed for improving therapeutic outcome. A role of microRNAs (miRNAs) in the pathogenesis of cirrhosis has been recently acknowledged, whereas the exact involved miRNAs as well as the associated molecular signaling pathways have not been determined. Specifically, the studies on the relationship between miR-22 and bone morphogenic protein 7 (BMP7) in the development of cirrhosis are lacking. METHODS: We examined the correlation of the levels of miR-22 and bone morphogenic protein 7 (BMP7) in the liver biopsies from patients with cirrhosis. We examined overexpression or suppression of miR-22 on BMP7 in hepatocytes. We examined the binding of miR-22 to the 3'-UTR of BMP7 mRNA. Finally, in a carbon tetrachloride (CCl4)-induced cirrhosis model in mice, we gave mice adeno associated viruses carrying antisense of miR-22, and examined its effects on BMP7 levels and the hallmarks of cirrhosis. RESULTS: The levels of miR-22 and BMP7 in the liver biopsies from patients were strongly and inversely correlated. MiR-22 inhibited BMP7 expression in hepatocytes, through directly binding the 3'-UTR of BMP7 mRNA. Expression of antisense miR-22 significantly attenuated the levels of liver fibrosis, portal hypertension and sodium retention caused by CCl4, possibly through upregulation of BMP7. CONCLUSIONS: MiR-22 promotes the development of cirrhosis through BMP7 suppression. PMID- 26112333 TI - Reliable estimation of nociceptive withdrawal reflex thresholds. AB - BACKGROUND: Assessment of the nociceptive withdrawal reflex (NWR) is frequently applied to probe the excitability level of the spinal nociceptive circuitry. In humans, the NWR threshold (NWR-T) is often estimated by applying electrical stimulation over the sural nerve at the lateral malleolus. Such stimulation may be associated with substantial pain and discomfort rendering completion of the assessment infeasible. NEW METHOD: As an alternative to sural nerve stimulation, NWR-Ts were also estimated by electrical stimulation at the arch of the foot. Failure-rates and test-retest reliability of these two procedures were evaluated. A fully-automated interleaved up-down staircase procedure was used to estimate the NWR-T for both stimulation sites. NWRs were detected from EMG measured over the biceps femoris and tibialis anterior muscles, respectively. A total of three repeated measures were performed in two different sessions to evaluate the test retest reliability of the two methods using Bland-Altman agreement analysis. RESULTS: The failure rate of NWR-T estimation based on electrical stimulation of the sural nerve (29%) was substantially higher than when the NWR was elicited by stimulation at the arch of the foot (5%). COMPARISON WITH EXISTING METHOD: The analysis of test-retest reliability indicated that the two methods for NWR-T estimation were equally reliable for within-session comparisons, but stimulation at the arch of the foot enabled NWR-T estimation with superior between-session reliability CONCLUSIONS: These results support a paradigm shift within NWR-T estimation favoring stimulation at the arch of the foot. PMID- 26112334 TI - Non-invasive primate head restraint using thermoplastic masks. AB - BACKGROUND: The success of many neuroscientific studies depends upon adequate head fixation of awake, behaving animals. Typically, this is achieved by surgically affixing a head-restraint prosthesis to the skull. NEW METHOD: Here we report the use of thermoplastic masks to non-invasively restrain monkeys' heads. Mesh thermoplastic sheets become pliable when heated and can then be molded to an individual monkey's head. After cooling, the custom mask retains this shape indefinitely for day-to-day use. RESULTS: We successfully trained rhesus macaques (Macaca mulatta) to perform cognitive tasks while wearing thermoplastic masks. Using these masks, we achieved a level of head stability sufficient for high resolution eye-tracking and intracranial electrophysiology. COMPARISON WITH EXISTING METHOD: Compared with traditional head-posts, we find that thermoplastic masks perform at least as well during infrared eye-tracking and single-neuron recordings, allow for clearer magnetic resonance image acquisition, enable freer placement of a transcranial magnetic stimulation coil, and impose lower financial and time costs on the lab. CONCLUSIONS: We conclude that thermoplastic masks are a viable non-invasive form of primate head restraint that enable a wide range of neuroscientific experiments. PMID- 26112335 TI - Watching from a distance: A robotically controlled laser and real-time subject tracking software for the study of conditioned predator/prey-like interactions. AB - BACKGROUND: The physical distance between predator and prey is a primary determinant of behavior, yet few paradigms exist to study this reliably in rodents. NEW METHOD: The utility of a robotically controlled laser for use in a predator-prey-like (PPL) paradigm was explored for use in rats. This involved the construction of a robotic two-dimensional gimbal to dynamically position a laser beam in a behavioral test chamber. Custom software was used to control the trajectory and final laser position in response to user input on a console. The software also detected the location of the laser beam and the rodent continuously so that the dynamics of the distance between them could be analyzed. When the animal or laser beam came within a fixed distance the animal would either be rewarded with electrical brain stimulation or shocked subcutaneously. RESULTS: Animals that received rewarding electrical brain stimulation could learn to chase the laser beam, while animals that received aversive subcutaneous shock learned to actively avoid the laser beam in the PPL paradigm. Mathematical computations are presented which describe the dynamic interaction of the laser and rodent. COMPARISON WITH EXISTING METHODS: The robotic laser offers a neutral stimulus to train rodents in an open field and is the first device to be versatile enough to assess distance between predator and prey in real time. CONCLUSIONS: With ongoing behavioral testing this tool will permit the neurobiological investigation of predator/prey-like relationships in rodents, and may have future implications for prosthetic limb development through brain-machine interfaces. PMID- 26112336 TI - The brain cytokine levels are modulated by estrogen following traumatic brain injury: Which estrogen receptor serves as modulator? AB - The present study was designed to explore whether administration of estrogen affects brain cytokine levels in TBI. We also sought determine which one of type of classical estrogen receptors (ERs) is involved. Ovariectomized female rats were divided in to eight groups. Estrogen or vehicle was administered following TBI (E2 and oil groups). Antagonist of ER(ICI 182, 780) or vehicle was also administered following TBI (ICI and DMSO groups). The ICI or vehicle was administered either before induction of TBI and administration of estrogen (ICI+E2 and DMSO+E2 groups). TBI was induced by Marmarou's method. In addition to brain water content, the levels of brain proinflammatory and anti-inflammatory cytokines were measured 24 hours post- TBI. Present results demonstrated that, estrogen reduced TBI- induced brain edema. The antiedema effect of estrogen was attenuated by ICI. The brain measures of IL-1beta, IL-6 and TNF-alpha in TBI were also reduced by estrogen. The anti-inflammatory effect of estrogen was attenuated by ICI. The inhibition level of estrogen by ICI was 53.2%, 12.09% and 48.45% for IL-1beta, IL-6 and TNF-alpha, respectively. Estrogen also elevated IL-10 in TBI. ICI inversely controlled the effect of estrogen on IL-10, by 33.84%. This effect was not observed once ICI was used alone. The estrogen administration following TBI probably results in proinflammatory cytokines reduction, and inversely enhancement of anti-inflammatory cytokines. In our study, the neuroprotective effect of estrogen is proposed to be mediated by both ERalpha and ERalpha, and accordingly the inhibition of neuroprotective effect of estrogen by ICI. PMID- 26112337 TI - Complex angular momentum theory of state-to-state integral cross sections: resonance effects in the F + HD -> HF(v' = 3) + D reaction. AB - State-to-state reactive integral cross sections (ICSs) are often affected by quantum mechanical resonances, especially near a reactive threshold. An ICS is usually obtained by summing partial waves at a given value of energy. For this reason, the knowledge of pole positions and residues in the complex energy plane is not sufficient for a quantitative description of the patterns produced by resonance. Such description is available in terms of the poles of an S-matrix element in the complex plane of the total angular momentum. The approach was recently implemented in a computer code ICS_Regge, available in the public domain [Comput. Phys. Commun., 2014, 185, 2127]. In this paper, we employ the ICS_Regge package to analyse in detail, for the first time, the resonance patterns predicted for integral cross sections (ICSs) of the benchmark F + HD -> HF(v' = 3) + D reaction. The v = 0, j = 0, Omega = 0 -> v' = 3, j' = 0, 1, 2, and Omega' = 0, 1, 2 transitions are studied for collision energies from 58.54 to 197.54 meV. For these energies, we find several resonances, whose contributions to the ICS vary from symmetric and asymmetric Fano shapes to smooth sinusoidal Regge oscillations. Complex energies of metastable states and Regge pole positions and residues are found by Pade reconstruction of the scattering matrix elements. The accuracy of the ICS_Regge code, relation between complex energies and Regge poles, various types of Regge trajectories, and the origin of the J-shifting approximation are also discussed. PMID- 26112338 TI - Environmental enrichment and abstinence attenuate ketamine-induced cardiac and renal toxicity. AB - The current study was designed to investigate the effect of abstinence in combination with environmental enrichment (EE) on cardiac and renal toxicity induced by 2 weeks of ketamine self-administration (SA) in rodents. In Experiment 1, one group of rats underwent ketamine SA for 14 days. In Experiment 2, the animals completed 2 weeks of ketamine SA followed by 2 and 4 weeks of abstinence. In Experiment 3, animals underwent 14 days of ketamine SA and 4 weeks of abstinence in which isolated environment (IE) and EE was introduced. The corresponding control groups were included for each experiment. Two weeks of ketamine SA caused significant increases in organ weight, Apoptosis Stimulating Fragment/Kidney Injury Molecule-1, and apoptotic level of heart and kidney. The extended length of withdrawal from ketamine SA partially reduced toxicity on the heart and kidney. Finally, introduction of EE during the period of abstinence greatly promoted the effect of abstinence on ketamine-induced cardiac and renal toxicity. The interactive effect of EE and abstinence was promising to promote the recovery of cardiac and renal toxicity of ketamine. PMID- 26112341 TI - Extrinsic Origin of Persistent Photoconductivity in Monolayer MoS2 Field Effect Transistors. AB - Recent discoveries of the photoresponse of molybdenum disulfide (MoS2) have shown the considerable potential of these two-dimensional transition metal dichalcogenides for optoelectronic applications. Among the various types of photoresponses of MoS2, persistent photoconductivity (PPC) at different levels has been reported. However, a detailed study of the PPC effect and its mechanism in MoS2 is still not available, despite the importance of this effect on the photoresponse of the material. Here, we present a systematic study of the PPC effect in monolayer MoS2 and conclude that the effect can be attributed to random localized potential fluctuations in the devices. Notably, the potential fluctuations originate from extrinsic sources based on the substrate effect of the PPC. Moreover, we point out a correlation between the PPC effect in MoS2 and the percolation transport behavior of MoS2. We demonstrate a unique and efficient means of controlling the PPC effect in monolayer MoS2, which may offer novel functionalities for MoS2-based optoelectronic applications in the future. PMID- 26112342 TI - [Trans-oral intracranial stab wound with airway invasion]. PMID- 26112339 TI - Altered amygdala-prefrontal response to facial emotion in offspring of parents with bipolar disorder. AB - This study aimed to identify neuroimaging measures associated with risk for, or protection against, bipolar disorder by comparing youth offspring of parents with bipolar disorder versus youth offspring of non-bipolar parents versus offspring of healthy parents in (i) the magnitude of activation within emotional face processing circuitry; and (ii) functional connectivity between this circuitry and frontal emotion regulation regions. The study was conducted at the University of Pittsburgh Medical Centre. Participants included 29 offspring of parents with bipolar disorder (mean age = 13.8 years; 14 females), 29 offspring of non-bipolar parents (mean age = 13.8 years; 12 females) and 23 healthy controls (mean age = 13.7 years; 11 females). Participants were scanned during implicit processing of emerging happy, sad, fearful and angry faces and shapes. The activation analyses revealed greater right amygdala activation to emotional faces versus shapes in offspring of parents with bipolar disorder and offspring of non-bipolar parents than healthy controls. Given that abnormally increased amygdala activation during emotion processing characterized offspring of both patient groups, and that abnormally increased amygdala activation has often been reported in individuals with already developed bipolar disorder and those with major depressive disorder, these neuroimaging findings may represent markers of increased risk for affective disorders in general. The analysis of psychophysiological interaction revealed that offspring of parents with bipolar disorder showed significantly more negative right amygdala-anterior cingulate cortex functional connectivity to emotional faces versus shapes, but significantly more positive right amygdala left ventrolateral prefrontal cortex functional connectivity to happy faces (all P-values corrected for multiple tests) than offspring of non-bipolar parents and healthy controls. Taken together with findings of increased amygdala ventrolateral prefrontal cortex functional connectivity, and decreased amygdala anterior cingulate cortex functional connectivity previously shown in individuals with bipolar disorder, these connectivity patterns in offspring of parents with bipolar disorder may be risk markers for, rather than markers conferring protection against, bipolar disorder in youth. The patterns of activation and functional connectivity remained unchanged after removing medicated participants and those with current psychopathology from analyses. This is the first study to demonstrate that abnormal functional connectivity patterns within face emotion processing circuitry distinguish offspring of parents with bipolar disorder from those of non-bipolar parents and healthy controls. PMID- 26112343 TI - Type A intramural hematoma and hemopericardium secondary to penetrating atherosclerotic ulcer. PMID- 26112340 TI - The Wernicke conundrum and the anatomy of language comprehension in primary progressive aphasia. AB - Wernicke's aphasia is characterized by severe word and sentence comprehension impairments. The location of the underlying lesion site, known as Wernicke's area, remains controversial. Questions related to this controversy were addressed in 72 patients with primary progressive aphasia who collectively displayed a wide spectrum of cortical atrophy sites and language impairment patterns. Clinico anatomical correlations were explored at the individual and group levels. These analyses showed that neuronal loss in temporoparietal areas, traditionally included within Wernicke's area, leave single word comprehension intact and cause inconsistent impairments of sentence comprehension. The most severe sentence comprehension impairments were associated with a heterogeneous set of cortical atrophy sites variably encompassing temporoparietal components of Wernicke's area, Broca's area, and dorsal premotor cortex. Severe comprehension impairments for single words, on the other hand, were invariably associated with peak atrophy sites in the left temporal pole and adjacent anterior temporal cortex, a pattern of atrophy that left sentence comprehension intact. These results show that the neural substrates of word and sentence comprehension are dissociable and that a circumscribed cortical area equally critical for word and sentence comprehension is unlikely to exist anywhere in the cerebral cortex. Reports of combined word and sentence comprehension impairments in Wernicke's aphasia come almost exclusively from patients with cerebrovascular accidents where brain damage extends into subcortical white matter. The syndrome of Wernicke's aphasia is thus likely to reflect damage not only to the cerebral cortex but also to underlying axonal pathways, leading to strategic cortico-cortical disconnections within the language network. The results of this investigation further reinforce the conclusion that the left anterior temporal lobe, a region ignored by classic aphasiology, needs to be inserted into the language network with a critical role in the multisynaptic hierarchy underlying word comprehension and object naming. PMID- 26112344 TI - Beyond single behaviour theory: Adding cross-behaviour cognitions to the health action process approach. AB - OBJECTIVES: Commonly, health behaviour theories have been applied to single behaviours, giving insights into specific behaviours but providing little knowledge on how individuals pursue an overall healthy lifestyle. In the context of diet and physical activity, we investigated the extent to which cross behaviour cognitions, namely transfer cognitions and compensatory health beliefs, contribute to single behaviour theory. DESIGN: A total of 767 participants from two European regions (i.e., Germany n = 351, southern Europe n = 416) completed online questionnaires on physical activity and healthy dietary behaviour, behaviour-specific cognitions (i.e., self-efficacy, outcome expectancies, risk perception, intention, action planning, action control), as well as cross behaviour cognitions, namely transfer cognitions and compensatory health beliefs. METHODS: Nested path models were specified to investigate the importance of cross behaviour cognitions over and above behaviour-specific predictors of physical activity and healthy nutrition. RESULTS: Across both health behaviours, transfer cognitions were positively associated with intention and self-regulatory strategies. Compensatory health beliefs were negatively associated with intention. Action planning and action control mediated the effect of intentions on behaviour. CONCLUSIONS: Cross-behaviour cognitions contribute to single behaviour theory and may explain how individuals regulate more than one health behaviour. Statement of contribution What is already known on this subject? Cross behaviour cognitions are related to a healthy lifestyle. Compensatory health beliefs hinder the adoption of a healthy lifestyle. Transfer cognitions encourage the engagement in a healthy lifestyle. What does this study add? Transfer cognitions were positively associated with intentions, action planning, and action control over and above behaviour-specific cognitions. Compensatory health beliefs were related to intentions only. Both facilitating and debilitating cross behaviour cognitions need to be studied within a unified multiple behaviour research framework. PMID- 26112345 TI - Effects of dipyrone, meloxicam, or the combination on hemostasis in conscious dogs. AB - OBJECTIVE: To compare the effects of dipyrone, meloxicam, and of the combination of these drugs on hemostasis in dogs. DESIGN: Prospective, blinded, randomized crossover study. SETTING: Research laboratory at a veterinary teaching hospital. ANIMALS: Six adult dogs. INTERVENTIONS: Animals received 4 intravenous treatments with 15-day washout intervals: control (physiological saline, 0.1 mL/kg), meloxicam (0.2 mg/kg), dipyrone (25 mg/kg), and dipyrone-meloxicam (25 and 0.2 mg/kg, respectively). A jugular catheter was placed for drug injection and for collecting samples for whole blood platelet aggregation (WBPA) and thromboelastometry assays at baseline, 1, 2, 3, 5, and 8 hours after treatment administration. The percent change from baseline of lag time and of the area under the curve (AUC) of impedance changes in response to collagen-induced platelet activation were recorded during WBPA. Thromboelastometry-derived parameters included clotting time, clot formation time, alpha-angle, and maximum clot firmness. The buccal mucosal bleeding time was evaluated by a blinded observer at baseline, 1, 3, and 5 hours after treatment injection. MEASUREMENTS AND MAIN RESULTS: No significant changes in WBPA and thromboelastometry were recorded in the control treatment. Dipyrone significantly (P < 0.05) increased the lag time for 2 hours and decreased the AUC for 3 hours after injection. Meloxicam did not alter WBPA. Dipyrone-meloxicam significantly increased lag time for 2 hours and decreased the AUC for 5 hours after treatment injection. Experimental treatments did not differ from the control treatment for thromboelastometry and buccal mucosal bleeding time. CONCLUSIONS: While meloxicam does not alter hemostasis by the methods evaluated, dipyrone inhibits platelet aggregation for up to 3 hours. Meloxicam-dipyrone combination causes more prolonged inhibition of platelet function than dipyrone alone. Decreased platelet aggregation induced by dipyrone and dipyrone-meloxicam does not appear to impact the viscoelastic properties of the blood clot nor increase the risk of bleeding in dogs without preexisting hemostatic disorders. PMID- 26112346 TI - Heat-treated stainless steel felt as scalable anode material for bioelectrochemical systems. AB - This work reports a simple and scalable method to convert stainless steel (SS) felt into an effective anode for bioelectrochemical systems (BESs) by means of heat treatment. X-ray photoelectron spectroscopy and cyclic voltammetry elucidated that the heat treatment generated an iron oxide rich layer on the SS felt surface. The iron oxide layer dramatically enhanced the electroactive biofilm formation on SS felt surface in BESs. Consequently, the sustained current densities achieved on the treated electrodes (1 cm(2)) were around 1.5+/-0.13 mA/cm(2), which was seven times higher than the untreated electrodes (0.22+/-0.04 mA/cm(2)). To test the scalability of this material, the heat-treated SS felt was scaled up to 150 cm(2) and similar current density (1.5 mA/cm(2)) was achieved on the larger electrode. The low cost, straightforwardness of the treatment, high conductivity and high bioelectrocatalytic performance make heat-treated SS felt a scalable anodic material for BESs. PMID- 26112347 TI - The addition of ortho-hexagon nano spinel Co3O4 to improve the performance of activated carbon air cathode microbial fuel cell. AB - Commercial Co3O4 and ortho-hexagon spinel nano-Co3O4 (OHSNC) were doped in the AC at a different percentage (5%, 10% and 15%) to enhance the performance of microbial fuel cell (MFC). The maximum power density of MFC with 10% OHSNC doped cathode was 1500+/-14 mW m(-2), which was 97.36% and 41.24% higher than that with the bare AC air cathode and commercial Co3O4 respectively. The electrocatalytic behavior for their better performance was discussed in detail with the help of various structural and electrochemical techniques. The OHSNC was characterized via X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM). The results showed that the improved performance owed to the enhancement of both kinetics activity and the number of electron transfer in the ORR, and the internal resistance was largely reduced. Therefore, OHSNC was proved to be an excellent cathodic catalyst in AC air cathode MFC. PMID- 26112349 TI - Full-field in vitro measurements and in silico predictions of strain shielding in the implanted femur after total hip arthroplasty. AB - Alterations in bone strain as a result of implantation may contribute towards periprosthetic bone density changes after total hip arthroplasty. Computational models provide full-field strain predictions in implant-bone constructs; however, these predictions should be verified using experimental models wherever it is possible. In this work, finite element predictions of surface strains in intact and implanted composite femurs were verified using digital image correlation. Relationships were sought between post-implantation strain states across seven defined Gruen zones and clinically observed longer-term bone density changes. Computational predictions of strain distributions in intact and implanted femurs were compared to digital image correlation measurements in two regions of interest. Regression analyses indicated a strong linear correlation between measurements and predictions (R = 0.927 intact, 0.926 implanted) with low standard error (standard error = 38 uepsilon intact, 26 uepsilon implanted). Pre- to post-operative changes in measured and predicted surface strains were found to relate qualitatively to clinically observed volumetric bone density changes across seven Gruen zones: marked proximal bone density loss corresponded with a 50%-64% drop in surface strain, and slight distal density changes corresponded with 4%-14% strain increase. These results support the use of digital image correlation as a pre-clinical tool for predicting post-implantation strain shielding, indicative of long-term bone adaptations. PMID- 26112348 TI - Geometric parameterisation of pelvic bone and cartilage in contact analysis of the natural hip: an initial study. AB - Parameterised finite element models of the human hip have the potential to allow controlled analysis of the effect of individual geometric features on the contact mechanics of the joint. However, the challenge lies in defining a set of parameters which sufficiently capture the joint geometry in order to distinguish between individuals. In this study, a simple set of parameters to describe the geometries of acetabulum and cartilage in the hip were extracted from two segmentation-based models, which were then used to generate the parameterised finite element models for the two subjects. The contact pressure and contact area at the articular surface predicted from the parameterised finite element models were compared with the results from the segmentation-based models. The differences in the predicted results between the parameterised models and segmentation-based models were found to be within 11% across seven activities simulated. In addition, the parameterised models were able to replicate features of the contact pressure/area fluctuations over the loading cycle that differed between the two subjects. These results provide confidence that the parameterised approach could be used to generate representative finite element models of the human hip for contact analysis. Such a method has the potential to be used to systematically evaluate geometric features that can be captured from simple clinical measurements and provide a cost- and time-effective approach for stratification of the acetabular geometries in the patient population. PMID- 26112350 TI - A model-based approach of scatter dose contributions and efficiency of apron shielding for radiation protection in CT. AB - Given the contribution of scattered radiations to patient dose in CT, apron shielding is often used for radiation protection. In this study the efficiency of apron was assessed with a model-based approach of the contributions of the four scatter sources in CT, i.e. external scattered radiations from the tube and table, internal scatter from the patient and backscatter from the shielding. For this purpose, CTDI phantoms filled with thermoluminescent dosimeters were scanned without apron, and then with an apron at 0, 2.5 and 5 cm from the primary field. Scatter from the tube was measured separately in air. The scatter contributions were separated and mathematically modelled. The protective efficiency of the apron was low, only 1.5% in scatter dose reduction on average. The apron at 0 cm from the beam lowered the dose by 7.5% at the phantom bottom but increased the dose by 2% at the top (backscatter) and did not affect the centre. When the apron was placed at 2.5 or 5 cm, the results were intermediate to the one obtained with the shielding at 0 cm and without shielding. The apron effectiveness is finally limited to the small fraction of external scattered radiation. PMID- 26112352 TI - BABY EMPATHY: INFANT DISTRESS AND PEER PROSOCIAL RESPONSES. AB - Empathy is an important competence in our social world, a motivator of prosocial behavior, and thought to develop throughout the second year of life. The current study examined infants' responses to naturalistic peer distress to explore markers of empathy and prosocial behavior in young babies. Seventeen 8-month-old infants participated in a repeated measures design using the "babies-in-groups" paradigm, with maternal presence as the independent variable. Significant differences were found between response types: Gaze was the standard response to infant distress, followed by socially directed behaviors and affect, with self distress rarely occurring. Maternal presence was not found to impact the nature or frequency of babies' responses to peer distress. During distress episodes, babies looked preferentially at the distressed peer, then other mothers, and least to their own mother. Data revealed that infant responses to peer distress resulted in a successful cessation of that distress episode over one third of the time. Case studies are provided to illustrate the quantitative data. The results provided evidence of empathic concern and prosocial behavior in the first year of life, and provoke a challenge to developmental theories of empathy. PMID- 26112351 TI - A complete map of potential pathogenicity markers of avian influenza virus subtype H5 predicted from 11 expressed proteins. AB - BACKGROUND: Polybasic cleavage sites of the hemagglutinin (HA) proteins are considered to be the most important determinants indicating virulence of the avian influenza viruses (AIV). However, evidence is accumulating that these sites alone are not sufficient to establish high pathogenicity. There need to exist other sites located on the HA protein outside the cleavage site or on the other proteins expressed by AIV that contribute to the pathogenicity. RESULTS: We employed rule-based computational modeling to construct a map, with high statistical significance, of amino acid (AA) residues associated to pathogenicity in 11 proteins of the H5 type viruses. We found potential markers of pathogenicity in all of the 11 proteins expressed by the H5 type of AIV. AA mutations S-43(HA1)-D, D-83(HA1)-A in HA; S-269-D, E-41-H in NA; S-48-N, K-212-N in NS1; V-166-A in M1; G-14-E in M2; K-77-R, S-377-N in NP; and Q-48-P in PB1-F2 were identified as having a potential to shift the pathogenicity from low to high. Our results suggest that the low pathogenicity is common to most of the subtypes of the H5 AIV while the high pathogenicity is specific to each subtype. The models were developed using public data and validated on new, unseen sequences. CONCLUSIONS: Our models explicitly define a viral genetic background required for the virus to be highly pathogenic and thus confirm the hypothesis of the presence of pathogenicity markers beyond the cleavage site. PMID- 26112353 TI - Does academic assessment system type affect levels of academic stress in medical students? A cross-sectional study from Pakistan. AB - INTRODUCTION: Stress among medical students induced by academic pressures is on the rise among the student population in Pakistan and other parts of the world. Our study examined the relationship between two different systems employed to assess academic performance and the levels of stress among students at two different medical schools in Karachi, Pakistan. METHODS: A sample consisting of 387 medical students enrolled in pre-clinical years was taken from two universities, one employing the semester examination system with grade point average (GPA) scores (a tiered system) and the other employing an annual examination system with only pass/fail grading. A pre-designed, self-administered questionnaire was distributed. Test anxiety levels were assessed by The Westside Test Anxiety Scale (WTAS). Overall stress was evaluated using the Perceived Stress Scale (PSS). RESULTS: There were 82 males and 301 females while four did not respond to the gender question. The mean age of the entire cohort was 19.7 +/ 1.0 years. A total of 98 participants were from the pass/fail assessment system while 289 were from the GPA system. There was a higher proportion of females in the GPA system (85% vs. 59%; p < 0.01). Students in the pass/fail assessment system had a lower score on the WTAS (2.4 +/- 0.8 vs. 2.8 +/- 0.7; p = 0.01) and the PSS (17.0 +/- 6.7 vs. 20.3 +/- 6.8; p < 0.01), indicating lower levels of test anxiety and overall stress than in students enrolled in the GPA assessment system. More students in the pass/fail system were satisfied with their performance than those in the GPA system. CONCLUSION: Based on the present study, we suggest governing bodies to revise and employ a uniform assessment system for all the medical colleges to improve student academic performance and at the same time reduce stress levels. Our results indicate that the pass/fail assessment system accomplishes these objectives. PMID- 26112354 TI - The relationships among self-care, dispositional mindfulness, and psychological distress in medical students. AB - BACKGROUND: Past research suggests that medical students experience high levels of psychological distress. OBJECTIVE: The aim of the current study was to investigate the relationships among engagement in self-care behaviours, dispositional mindfulness, and psychological distress. METHODS: The sample consisted of 139 female and 68 male Australian medical students (N=207) aged 17 41 years (M=21.82, SD=3.62) across the 5 years of the Monash University medical course. Participants completed an online survey comprising a demographics questionnaire, the Five Facet Mindfulness Questionnaire, the Health-Promoting Lifestyle Profile II, and the Depression, Anxiety, and Stress Scales. RESULTS: Results revealed significant and interpretable multivariate correlations between distress and both mindfulness and self-care. Furthermore, the dispositional mindfulness observation subscale was found to be a significant moderator of the relationship between several dimensions of self-care and psychological distress. CONCLUSIONS: The present study points to the potential of self-care and mindfulness to decrease medical student distress and enhance well-being. PMID- 26112355 TI - Evaluation of the effect of natural and emotional stress of labor on lactation and breast-feeding. AB - BACKGROUND: The amount of stress experienced by both the mother and fetus during labor and delivery varies considerably and is likely to be different in primiparous and multiparous women as well as in those who receive analgesia during labor and those who do not receive. OBJECTIVE: In this study, we explored relations between stress during birth experience and lactogenesis of 100 women, who experienced vaginal delivery in Department of Obstetrics and Gynecology of University Hospital of Alexandroupolis. METHOD: Stress hormones (cortisol and glucose) were measured in serum (cord and maternal blood) immediately after delivery. Moreover, breast-feeding frequency on day 4, the time when the subjects first felt fullness in the breasts, milk volume on day 4 postpartum and duration of labor were recorded. Also, we recorded maternal exhaustion score during labor and positive and negative affects, posttraumatic stress score and mother-infant bonding rate, with the use of questionnaires. RESULTS: There were significant intercorrelations among the outcome variables. Mothers who experienced pain, exhaustion and negative feelings in a stressful and long labor had delayed onset of lactation. CONCLUSIONS: These results indicate that primiparity, long labor, stress to the mother and fetus during labor and delivery, negative affects and high score of posttraumatic stress are risk factors for delayed lactogenesis. PMID- 26112356 TI - Impact of endometriosis on quality of life, anxiety, and depression: an Austrian perspective. AB - PURPOSE: Several studies on the quality of life in patients with endometriosis have been performed with conflicting results. This cross-section survey examines the influence of endometriosis on the psychological well-being and the quality of life and the incidence of anxiety and depression among these patients, recruited from a tertiary care center in Austria. METHODS: Three standardized questionnaires of 62 patients with endometriosis were evaluated: status of health questionnaire (SF-36), hospital anxiety and depression scale (HADS-D), and endometriosis health profile (EHP-30). Quality of life status (EHP-30) was compared with published samples of the Oxford hospital and the Charite Berlin. Chi-square tests, independent sample t-tests, and one-way independent ANCOVA's were used to compare SF- 36 and HADS- D scores to 61 healthy controls. Pearson product-moment-correlation coefficients were used to investigate correlations between symptoms of depression and anxiety in the patient sample. RESULTS: Moderate to severe anxiety symptoms were found in 29 %; depressive symptoms were present in 14.5 % of the patients. Both symptoms occurred in 12.9 %. We found significant better values in all subscales of the EHP compared to the Oxford and Berlin samples. The control sample showed significant better subjective general health (p < 0.001), vitality (p < 0.001), mental health (p < 0.001), and better emotional role functioning (p < 0.001). Participants age significantly influenced mental health and emotional role functioning. CONCLUSIONS: The impact of endometriosis on life quality in our study was considerably less than in other studies but equivalent to other chronic medical conditions. It could be shown that endometriosis is influenced by biopsychosocial variables. However, the elevated presence of anxiety and depressive symptoms indicates the need of psychosomatic treatment of affective disorders to prevent manifestation. PMID- 26112357 TI - Correlation between VITOM((r)) videocolposcopy and histopathology for pathognomonic grading criteria. AB - OBJECTIVE: "Every colposcopic criterion must be mirrored by histopathology". We investigated the histomorphologic equivalent of four colposcopic criteria, which are associated with CIN 2 and/or CIN 3 and therefore called pathognomonic. PATIENTS AND METHODS: We diagnosed inner border sign, ridge sign, rag sign and/or cuffed gland openings using VITOM((r)) videocolposcopy in 255 patients which are consistent with major change. Histopathologic examination included immunohistochemical staining for p16, Ki 67 and stathmin-1 and micro-photographic documentation. RESULTS: The histopathologic pattern specific for each of the four pathognomonic colposcopic criteria was reproducibly identified: inner border sign showed a sharp demarcation between low- and high-grade CIN, in ridge sign high grade CIN adjoined directly the squamocolumnar junction, in rag sign, high-grade CIN was detached from stroma, and in cuffed gland openings, the entrance to a gland was rimmed by CIN, respectively. In 255 patients, the leading pathognomonic sign was inner border in 12.1 %, ridge in 34.1 %, rag in 18 %, and cuffed glands in 35.7 %, respectively. Inner border sign, ridge sign, rag sign and/or cuffed gland openings were associated with CIN 2 or 3 in 97, 98, 98 and 98 %, respectively. In 153 out of 255 patients, we found a combination of pathognomonic signs with ridge sign being the most frequent combined criterion (in 21 % of patients as second pathognomonic sign). CONCLUSION: The morphology of the four pathognomonic colposcopic criteria, inner border sign, ridge sign, rag sign and cuffed crypt openings, is reproduced in histopathology. These criteria are highly associated with CIN 2 or CIN 3. PMID- 26112358 TI - Associations of borderline personality with pain, problems with medications and suicidality in a community sample of chronic non-cancer pain patients prescribed opioids for pain. AB - OBJECTIVE: Borderline personality disorder (BPD) is common in patients with chronic non-cancer pain (CNCP). BPD patients often report worse pain and are more likely to abuse opioid medication. Although the prevalence of suicidality is high in both CNCP patients and those with BPD, no studies have examined the interrelationship of BPD, CNCP and suicidality. This article aims to examine the prevalence and associations of BPD in a large community sample of CNCP patients and the association with medication problems and suicidality. METHODS: Data from a national sample of 978 CNCP patients prescribed pharmaceutical opioids for CNCP. The screener from the International Classification of Diseases, version 10, International Personality Disorder Examination was used to identify patients with symptoms of BPD. RESULTS: One in five CNCP patients (19.1%) screened positive for BPD. BPD was associated with a number of demographic and clinical features, such as daily benzodiazepine use, and was independently associated with lifetime pharmaceutical opioid dependence [odds ratio (OR) 2.49, 95% confidence interval (95% CI) 1.42-4.38], past 12-month suicidal thoughts (OR 2.9, 95% CI 1.90-4.39) and lifetime suicide attempts (OR 3.19, 95% CI 2.16-4.72). CONCLUSIONS: BPD symptoms were prevalent among people prescribed opioids for CNCP and are associated with a number of adverse consequences. Further, those screening positive were at elevated risk of suicidal behaviors. Careful opioid prescription monitoring and appropriate referrals by clinicians are warranted in BPD with CNCP. PMID- 26112359 TI - Granulomatous Reaction to Pneumocystis jirovecii Diagnosed in a Bronchoalveolar Lavage: A Case Report. AB - BACKGROUND: Granulomatous reaction to Pneumocystis jirovecii is a rare but well known pathological finding encountered in the setting of immunosuppression, HIV infection being the most common cause. It can also potentially complicate the treatment of hematological malignancies, typically when drugs lowering the count and function of lymphocytes are used. Lung biopsy is considered the gold standard for the diagnosis of granulomatous P. jirovecii pneumonia, whereas the diffuse alveolar form is usually detected cytologically in bronchoalveolar lavage (BAL). CASE: A female patient pursuing R-CHOP chemotherapy for the treatment of multiple hematological malignancies developed a rapidly progressing dyspnea. Chest CT scans revealed a worsening of a known infiltrative lung disease thought to be secondary to her chemotherapy. Alterations compatible with a drug-induced interstitial lung disease and well-formed focally necrotizing granulomas were observed on an open lung biopsy, but no microorganism was identified with special stains. Eventually, a granulomatous reaction to P. jirovecii was found in a BAL and allowed appropriate treatment with rapid improvement of the dyspnea. CONCLUSION: Because granulomas are tissue-bound structures, they are rarely described in BAL. This article describes the first reported cytological diagnosis of a granulomatous reaction to P. jirovecii and the potential diagnostic interest of such a peculiar finding. PMID- 26112360 TI - Differential dosimetric benefit of proton beam therapy over intensity modulated radiotherapy for a variety of targets in patients with intracranial germ cell tumors. AB - BACKGROUND: We performed dosimetric comparisons between proton beam therapy and intensity modulated radiotherapy (IMRT) of intracranial germ cell tumors (ICGCTs) arising in various locations of the brain. MATERIALS: IMRT, passively scattered proton therapy (PSPT), and spot scanning proton therapy (SSPT) plans were performed for four different target volumes: the whole ventricle (WV), pineal gland (PG), suprasellar (SS), and basal ganglia (BG). Five consecutive clinical cases were selected from the patients treated between 2011 and 2014 for each target volume. Total 20 cases from the 17 patients were included in the analyses with three overlap cases which were used in plan comparison both for the whole ventricle and boost targets. The conformity index, homogeneity index, gradient index, plan quality index (PQI), and doses applied to the normal substructures of the brain were calculated for each treatment plan. RESULTS: The PQI was significantly superior for PSPT and SSPT than IMRT for ICGCTs in all locations (median; WV: 2.89 and 2.37 vs 4.06, PG: 3.38 and 2.70 vs 4.39, SS: 3.92 and 2.49 vs 4.46, BG: 3.01 and 2.49 vs 4.45). PSPT and SSPT significantly reduced the mean dose, and the 10 and 15 Gy dose volumes applied to the normal brain compared with IMRT (p <= 0.05). PSPT and SSPT saved significantly greater volumes of the temporal lobes and hippocampi (p < 0.05) in the SS and PG targets than IMRT. For tumors arising in the BG, PSPT and SSPT also saved greater volumes of the contralateral temporal lobes. CONCLUSIONS: PSPT and SSPT provide superior target volume coverage and saved more normal tissue compared with IMRT for ICGCTs in various locations. Future studies should assess whether the extent of normal tissue saved has clinical benefits in children with ICGCTs. PMID- 26112361 TI - DNA methylation differs between sister chromatids, and this difference correlates with the degree of differentiation potential. PMID- 26112362 TI - Emergency Medicine Milestones: The Next Step. PMID- 26112363 TI - Clinical significance of joint detection of mALB and NAG for early kidney damage in burn patients. AB - BACKGROUND: The aim of this study was to study the clinical significance of joint detection of mALB and NAG in early kidney damage in burn patients. METHODS: Forty five burn patients of different degrees were selected and divided into mild, moderate, severe, and heavy burns, and normal healthy controls according to their severity. Their b2- macroglobulin (b2-MG), a1-macroglobulin (a1-MG), mALB and N acetyl-b-D-NAG were tested for 3 days, 1 week, 2 weeks, 4 weeks after the burn, respectively. RESULTS: The urine concentration change b2-MG, a1-MG, MALB, and NAG are related to the area, depth and degree of the burn. The more serious the burn is, the higher the levels of mALB and NAG (P<0.001 or P<0.01) is. CONCLUSIONS: Early detection of mALB and NAG is helpful for early kidney damage diagnosis in burn patients to prevent further complications. PMID- 26112364 TI - Systematic analysis of glycerol: colourimetric screening and gas chromatography mass spectrometric confirmation. AB - Glycerol is a naturally occurring polyol in the human body, essential for several metabolic processes. It is widely used in the food, pharmaceutical, and medical industries and in clinical practice as a plasma volume expander (PVE). Athletes, however, may use glycerol to mask the presence of forbidden substances or to enhance performance, inclusively through hyperhydration achieved by glycerol ingestion with added fluid. These practices are considered doping, and are prohibited by the World Anti-Doping Agency (WADA). Therefore, glycerol was introduced in the prohibited list. Doping through glycerol ingestion can readily be identified by detection of elevated glycerol concentrations in urine. In this paper, a protocol for the fast detection of glycerol in urine is proposed. It consists of a previous visual colourimetric screening, followed by a quantitative/qualitative confirmation analysis by mass spectrometry. The screening procedure involves a reaction in which polyhydric alcohols are oxidized by periodate to formic acid and formaldehyde, which is detected by the addition of a fuchsin solution. For the subsequent qualitative/quantitative confirmation analysis, a gas chromatography-mass spectrometry based approach with a non deuterated internal standard and a drying step of only 10 min is proposed. The linear correlation was demonstrated within WADA's threshold range. The calculated RSD were 2.1% for within-day precision and 2.8% for between-day precision. The uncertainty estimation was calculated, and a value of 2.7% was obtained. The procedure may also be used for the analysis of other polyols in urine, as for example the PVE mannitol. PMID- 26112365 TI - Selective rather than universal screening for gestational diabetes mellitus? AB - OBJECTIVES: To estimate the proportion of women with gestational diabetes mellitus (GDM) who would be missed by selective versus universal screening and to describe their pregnancy outcomes. STUDY DESIGN: An observational cohort study in a single center performing universal screening for GDM with a 75 g oral glucose challenge test (OGTT) at 24-28 weeks gestation. We excluded women with pregestational or first trimester diabetes, those not screened and deliveries <34 weeks. Risk factors were age >= 35 years, BMI >= 25, family history of diabetes, GDM in a previous pregnancy or macrosomia in a previous pregnancy. Main outcomes were large for gestational age (LGA>90th centile for gestational age, adjusted for gender) and small for gestational age<10th centile. RESULTS: Among 2187 women screened, 309 (14%) had GDM, of whom 256 (83%) had one or more risk factors. The proportion of women who had GDM despite the absence of any risk factor was 2.4%. In multivariate analysis, LGA was significantly associated with GDM only in case of risk factors. Mean fasting blood glucose was lower in GDM without risk factors than in GDM with risk factors (87 +/- 1 mg/dl versus 94 +/- 14, p<0.001) and fewer required insulin (6% versus 26%, respectively, p<0.001). CONCLUSION: Selective screening would have missed one-sixth of GDM cases, but these cases seemed milder, with normal fasting blood glucose, and thus less likely to lead to perinatal complications. Whereas an opt-in approach relies heavily on accurate patient screening, we suggest that screening tests could be avoided in low-risk women by an opt-out approach. PMID- 26112366 TI - Penetration depth of focused beams in highly scattering media investigated with a numerical solution of Maxwell's equations in two dimensions. AB - The propagation of different focused beams (e.g., Gaussian or quasi-Bessel beams) through scattering media is studied. The finite-difference time-domain method, a numerical solution of Maxwell's equations, is applied to propagate the light beams in two dimensions. The focused beams are modeled by applying the angular spectrum of the plane waves method. The results show that weakly focused beams exhibit comparable performance to strongly focused beams in delivering focused light deep into scattering media. PMID- 26112367 TI - Raman spectroscopy of human skin: looking for a quantitative algorithm to reliably estimate human age. AB - The possibility of examining soft tissues by Raman spectroscopy is challenged in an attempt to probe human age for the changes in biochemical composition of skin that accompany aging. We present a proof-of-concept report for explicating the biophysical links between vibrational characteristics and the specific compositional and chemical changes associated with aging. The actual existence of such links is then phenomenologically proved. In an attempt to foster the basics for a quantitative use of Raman spectroscopy in assessing aging from human skin samples, a precise spectral deconvolution is performed as a function of donors' ages on five cadaveric samples, which emphasizes the physical significance and the morphological modifications of the Raman bands. The outputs suggest the presence of spectral markers for age identification from skin samples. Some of them appeared as authentic "biological clocks" for the apparent exactness with which they are related to age. Our spectroscopic approach yields clear compositional information of protein folding and crystallization of lipid structures, which can lead to a precise identification of age from infants to adults. Once statistically validated, these parameters might be used to link vibrational aspects at the molecular scale for practical forensic purposes. PMID- 26112368 TI - Toward a comprehensive interpretation of intravital microscopy images in studies of lung tissue dynamics. AB - Intravital microscopy (IVM) is a well-established imaging technique for real-time monitoring of microscale lung tissue dynamics. Although accepted as a gold standard in respiratory research, its characteristic image features are scarcely understood, especially when trying to determine the actual position of alveolar walls. To allow correct interpretation of these images with respect to the true geometry of the lung parenchyma, we analyzed IVM data of alveoli in a mouse model in comparison with simultaneously acquired optical coherence tomography images. Several IVM characteristics, such as double ring structures or disappearing alveoli in regions of liquid filling, could be identified and related to the position of alveoli relative to each other. Utilizing a ray tracing approach based on an idealized geometry of the mouse lung parenchyma, two major reflection processes could be attributed to the IVM image formation: partial reflection and total internal reflection between adjacent alveoli. Considering the origin of the reflexes, a model was developed to determine the true position of alveolar walls within IVM images. These results allow thorough understanding of IVM data and may serve as a basis for the correction of alveolar sizes for more accurate quantitative analysis within future studies of lung tissue dynamics. PMID- 26112369 TI - Multiview Hilbert transformation for full-view photoacoustic computed tomography using a linear array. AB - Due to their low cost, hand-held convenience, wide selection of bandwidths, and ultrasound imaging capability, linear ultrasonic transducer arrays have been widely studied for photoacoustic computed tomography (PACT). As linear-array PACT suffers from a limited view, full-view imaging requires either the transducer or the object to be rotated. So far, both the central frequencies and bandwidth of linear transducer arrays applied in full-view PACT are low, limiting the spatial resolutions of the reconstructed images. Here, we present a multiview high frequency PACT imaging system implemented with a commercial 40-MHz central frequency linear transducer array. By rotating the object through multiple angles with respect to the linear transducer array, we acquired full-view photoacoustic pressure measurements. Further, to quantify the unipolar initial pressures and overcome the limitations of the single-view Hilbert transformation, we developed a multiview Hilbert transformation method. The in-plane spatial resolution of this full-view linear-array PACT was quantified to be isotropically 60 MUm within a 10*10 mm2 field of view. The system was demonstrated by imaging both a leaf skeleton and a zebrafish in vivo. PMID- 26112371 TI - Peroral endoscopic myotomy in achalasia: Report on the first case performed in Mexico. PMID- 26112370 TI - Effects of intrinsic motivation on feedback processing during learning. AB - Learning commonly requires feedback about the consequences of one's actions, which can drive learners to modify their behavior. Motivation may determine how sensitive an individual might be to such feedback, particularly in educational contexts where some students value academic achievement more than others. Thus, motivation for a task might influence the value placed on performance feedback and how effectively it is used to improve learning. To investigate the interplay between intrinsic motivation and feedback processing, we used functional magnetic resonance imaging (fMRI) during feedback-based learning before and after a novel manipulation based on motivational interviewing, a technique for enhancing treatment motivation in mental health settings. Because of its role in the reinforcement learning system, the striatum is situated to play a significant role in the modulation of learning based on motivation. Consistent with this idea, motivation levels during the task were associated with sensitivity to positive versus negative feedback in the striatum. Additionally, heightened motivation following a brief motivational interview was associated with increases in feedback sensitivity in the left medial temporal lobe. Our results suggest that motivation modulates neural responses to performance-related feedback, and furthermore that changes in motivation facilitate processing in areas that support learning and memory. PMID- 26112372 TI - The fibroblast expression of RANKL in CoCrMo-particle-induced osteolysis is mediated by ER stress and XBP1s. AB - Particle-induced osteolysis is a major cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure and revision surgery. Although existing studies suggest that synovial fibroblasts present in the interfacial membrane are important targets of wear particles during bone resorption, the interaction mechanisms between the particles and fibroblasts remains elusive. In the present study, we investigated the effect of ER stress induced by CoCrMo particles (CoPs) in fibroblasts, calvarial resorption animal models and aseptic loosening clinical samples and its role in the stimulation of the RANKL expression. Our study further demonstrated that CoPs could induce significant ER stress in fibroblasts. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of RANKL in vitro and in vivo. Furthermore, in fibroblasts, downregulation of the expression of XBP1s, a signaling molecule of ER stress, significantly reduced the expression of RANKL induced by wear particles. Moreover, inhibition of ER stress or XBP1s both ameliorated the CoPs-induced osteolysis in animal models. Collectively, these results suggested that in particle-induced osteolysis, CoPs could stimulate fibroblasts to secret RANKL through ER stress and the signaling molecule XBP1s. Therefore, downregulating ER stress or the signaling molecule XBP1s of fibroblasts represents a potential therapeutic approach for treating particle induced peri-implant osteolysis. STATEMENT OF SIGNIFICANCE: For the first time, our study demonstrated that ER stress mediated the induction of RANKL expression by CoPs in fibroblasts and promoted particle-induced osteolysis. Furthermore, the upregulation of RANKL by CoPs in fibroblasts was mediated by the ER stress signaling molecule XBP1s. Both blocking ER stress and inhibiting the protein XBP1s by specific inhibitors resulted in downregulation of the expression of RANKL and amelioration of osteolysis induced by the implanted particles. Collectively, these findings suggest a possible mechanism underlying the RANKL expression induced by wear particles in fibroblasts, and downregulating ER stress and the XBP1s expression of fibroblasts represents a potential therapeutic approach for treating aseptic loosening. PMID- 26112373 TI - Enzyme-mediated hyaluronic acid-tyramine hydrogels for the propagation of human embryonic stem cells in 3D. AB - The propagation of human embryonic stem cells (hESCs) in three-dimensional (3D) scaffolds facilitates the cell expansion process and supplies pluripotent cells of high quality for broad-spectrum applications in regenerative medicine. Herein, we report an enzyme-mediated hyaluronic acid-tyramine (HA-Tyr) hydrogel that encapsulated and propagated hESCs in 3D. HA-Tyr hydrogels were formed by crosslinking the tyramine moieties with horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). By changing the HRP and H2O2 concentration, we prepared HA-Tyr hydrogels of different mechanical strength and studied the self-renewal properties of hESCs in these scaffolds. We observed that both the chemical composition and mechanical strength of substrates were important factors affecting cell proliferation and pluripotency. The HA-Tyr hydrogel with a compressive modulus of ~350Pa supported the proliferation of hESCs at the pluripotent state in both mTeSR1 medium and mouse embryonic fibroblast (MEF) conditioned medium. Immunohistochemical analyses revealed that hESCs proliferated well and formed spheroid structures in 3D, without undergoing apoptosis. The hESCs cultured in HA-Tyr hydrogels showed high expression of CD44 and pluripotency markers. These cells exhibited the capability to form cell derivatives of all three embryonic germ layers in vitro and in vivo. In addition, the genetic integrity of the hESCs was unaffected in the 3D cultivation system. STATEMENT OF SIGNIFICANCE: The scope of this study is to provide a stable 3D cultivation system for the expansion of human embryonic stem cells (hESCs) towards clinical applications. We report an enzyme mediated hyaluronic acid tyramine (HA-Tyr) hydrogel that encapsulated and propagated hESCs in 3D. Unlike other HA-based photo-crosslinked hydrogel systems reported, we investigated the effects of mechanical strength of hydrogels on the self-renewal properties of hESCs in 3D. Then, we characterized hESCs cultured in hydrogels with lower mechanical strength that best supported the self-renewal of hESCs. Hence, we demonstrated a reliable approach for the controlled propagation of hESCs in 3D. We believe that such an approach would facilitate the development of stem cell based therapy towards clinical applications. PMID- 26112374 TI - Self-assembled microbubbles as contrast agents for ultrasound/magnetic resonance dual-modality imaging. AB - In this work, superparamagnetic self-assembled microbubbles (SAMBs) consisting of "Poly(acrylic acid)-Iron oxide nanoparticles-Polyamine" sandwich-like shells and tetradecafluorohexane cores were fabricated by a template-free self-assembly approach. The SAMBs exhibit not only magnetic resonance (MR) T2 imaging functionality, but also ultrasound (US) image contrast, showing great potential as US/MR dual contrast agents. The diameters of the SAMBs can be tuned easily from 450nm to 1300nm by changing the precursor ratio, and this size variation directly affects their in vitro MRI and US signals. The SAMBs also exhibit in vivo contrast enhancement capabilities in rat liver with injection through portal vein, for both MR and US imaging. Additionally, the biodistribution of SAMBs over time suggests normal systemic metabolic activity through the spleen. The results show that the Fe content in rat liver reduces to a level of which Fe cannot be detected in 45days. The SAMBs exhibit no obvious damage to the primary organs of rat during the metabolic process, indicating their good biocompatibility in vivo. PMID- 26112375 TI - Changes in Occlusal Caries Lesion Management in France from 2002 to 2012: A Persistent Gap between Evidence and Clinical Practice. AB - A survey conducted in 2002 among French general dental practitioners (GPs) showed variations between treatment decisions and a tendency towards early restorative intervention for caries. The aims of the present questionnaire survey were to investigate, among a random sample of 2,000 French GPs, the management decisions for occlusal lesions in 2012 and to compare the results to those obtained in 2002. The response rate was 41.9%. The majority of the respondents (60.7%) would postpone their restorative decisions until the lesion was in the dentin, based on clinical and radiographic examinations. Almost 68% of the respondents suggested that the cavity preparation should be limited to the lesion (vs. a preparation extending to the occlusal fissure), and 81.6% chose composite as restorative material for the earliest lesion requiring restoration in a 20-year-old patient with his/her caries risk factors under control. Statistical analysis (chi(2) and logistic regression) showed that the management decisions were influenced by certain demographic characteristics (gender, clinical experience and participation in cariology courses). When comparing the 2002 and 2012 responses, it appears that even if French GPs still tend to intervene surgically for occlusal lesions, which could benefit from noninvasive care such as therapeutic sealants, the restorative threshold has been delayed to later stages of carious progression (p < 0.0001). Moreover, the 2012 respondents were less likely to open the fissure system than the 2002 respondents (p = 0.032), and less amalgam restorations would have been placed in 2012 (p < 0.0001). Furthermore, the results showed that the variability observed in 2002 toward caries management decisions was persisting in 2012. PMID- 26112376 TI - The training value of working with armed forces inpatients in psychiatry. AB - Over the last 10 years, the UK armed forces (UKAF) have been involved in operations worldwide. Mental health in the armed forces (AF) has been the subject of considerable interest in part because of a perceived added risk of psychological distress in this population. Inpatient psychiatric services are provided through partnerships with NHS hospitals. The Cavell Centre, Peterborough's acute inpatient psychiatric unit has up to four beds for service personnel, under the care of a civilian consultant psychiatrist and his AF Foundation Year 2 doctor (F2). This was the only Ministry of Defence (MoD) inpatient unit which had a training post for an AF doctor, but the post ended in August 2014 with the closure of MoD Hospital Unit Peterborough (MDHU(P)). This article outlines the differences in civilian and AF inpatient care and discusses the training value of AF doctors managing service personnel who are psychiatric inpatients. PMID- 26112377 TI - Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system, and it has been established that autoreactive T helper (Th) cells play a crucial role in its pathogenesis. Myelin basic protein (MBP) epitopes are major autoantigens in MS, and the sequence MBP87-99 is an immunodominant epitope. We have previously reported that MBP87-99 peptides with modifications at principal T-cell receptor (TCR) contact sites suppressed the induction of EAE symptoms in rats and SJL/J mice, diverted the immune response from Th1 to Th2 and generated antibodies that did not cross react with the native MBP protein. In this study, the linear and cyclic analogs of the MBP87-99 epitope, namely linear (Ala91,Ala96)MBP87-99 (P2) and cyclo(87-99)(Ala91,Ala96)MBP87-99 (P3), were evaluated for their binding to HLA-DR4, stability to lysosomal enzymes, their effect on cytokine secretion by peripheral blood mononuclear cells (PBMC) derived from MS patients or healthy subjects (controls), and their effect in rat EAE. P1 peptide (wild-type, MBP87-99) was used as control. P2 and P3 did not alter significantly the cytokine secretion by control PBMC, in contrast to P1 that induced moderate IL-10 production. In MS PBMC, P2 and P3 induced the production of IL-2 and IFN-gamma, with a simultaneous decrease of IL-10, whereas P1 caused a reduction of IL-10 secretion only. The cellular response to P3 indicated that cyclization did not affect the critical TCR contact sites in MS PBMC. Interestingly, the cyclic P3 analog was found to be a stronger binder to HLA-DR4 compared to linear P2. Moreover, cyclic P3 was more stable to proteolysis compared to linear P2. Finally, both P2 and P3 suppressed EAE induced by an encephalitogenic guinea pig MBP74-85 epitope in Lewis rats whereas P1 failed to do so. In conclusion, cyclization of myelin altered peptide ligand (Ala91,Ala96)MBP87-99 improved binding affinity to HLA-DR4, resistance to proteolysis and antigen-specific immunomodulation, rendering cyclo(87 99)(Ala91,Ala96)MBP87-99 an important candidate drug for MS immunotherapy. PMID- 26112378 TI - Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines. AB - A series of 16 simple long-chain alkyltriazoles and two novel alkylphosphocholine derivatives containing an azide moiety were evaluated in vitro for their leishmanicidal activity against. Among the 18 compounds tested, the eight most active compounds against promastigote forms were selected for further evaluation against amastigote forms. These compounds were also evaluated for their cytotoxicity against murine macrophages and tested as inhibitors of cysteine protease rCPB2.8, an important target for development of antileishmanial drugs. The mutagenicity of some of these compounds was also evaluated in prokaryotic and eukaryotic cells to assess any genetic effects of the leishmanicidal candidates. The compound 4, an alkylphosphocholine derivative, was found to be the most potent against amastigote forms with an IC50 of 3.81 MUM, comparable to that of pentamidine (IC50 = 6.62 MUM) and amphotericin B (IC50 = 6.10 MUM), two established leishmanicidal drugs. Compound 4 also exhibited the best selectivity index (SI) values of the series, demonstrating low toxicity against macrophages and a cLogP value higher than 5. Among the alkyltriazoles, compounds 13 and 14 were the most active against promastigote and amastigote forms. They were then evaluated for their mutagenicity in vitro; the mutagenicity index (MI) values were lower than 2, suggesting that these compounds are not mutagenic. PMID- 26112379 TI - Validation of photoplethysmography as a method to detect heart rate during rest and exercise. AB - Despite their enhanced marketplace visibility, validity of wearable photoplethysmographic heart rate monitoring is scarce. Forty-seven healthy participants performed seven, 6-min exercise bouts and completed a valid skin type scale. Participants wore an Omron HR500U (OHR) and a Mio Alpha (MA), two commercial wearable photoplethysmographic heart rate monitors. Data were compared to a Polar RS800CX (PRS). Means and error were calculated between devices using minutes 2-5. Compared to PRS, MA data was significantly different in walking, biking (2.41 +/- 3.99 bpm and 3.26 +/- 11.38 bpm, p < 0.05) and weight lifting (23.30 +/- 31.94 bpm, p < 0.01). OHR differed from PRS in walking (4.95 +/- 7.53 bpm, p < 0.05) and weight lifting (4.67 +/- 8.95 bpm, p < 0.05). MA during elliptical, stair climbing and biking conditions demonstrated a strong correlation between jogging speed and error (r = 0.55, p < 0.0001), and showed differences in participants with less photosensitive skin. PMID- 26112380 TI - Bronchoscopic Coil Treatment for Patients with Severe Emphysema: A Meta-Analysis. AB - BACKGROUND: Bronchoscopic coil treatment has been shown to improve pulmonary function, exercise capacity, and quality of life in patients with severe emphysema. OBJECTIVES: To perform a meta-analysis of the results of four independent European clinical trials investigating this coil therapy for emphysema. METHODS: Data on all patients included in the four European clinical trials were analyzed for efficacy and safety outcomes. RESULTS: A total of 2,536 coils were placed during 259 procedures in 140 patients. A total of 37 chronic obstructive pulmonary disease exacerbations and 27 pneumonias were recorded as serious adverse events up to 1 year after treatment. The pneumothorax rate was 6.4%. Both 6 and 12 months after treatment, significant (all p < 0.001) improvements were observed for: forced expiratory volume in 1 s [+0.08 liters (+/ 0.19) and +0.08 liters (+/-0.21)], residual volume [RV; -510 ml (+/-850) and -430 ml (+/-720)], 6-min walking distance [6MWD; +44.1 m (+/-69.8) and +38.1 m (+/ 71.9)], and St. George's Respiratory Questionnaire score [SGRQ; -9.5 points (+/ 14.3) and -7.7 points (+/-14.2)]. No differences in any outcome measures were observed between heterogeneous and homogeneous emphysema patients. Only a high baseline RV was found to be an independent predictor of successful treatment. CONCLUSIONS: Bronchoscopic coil treatment improves pulmonary function, 6MWD, and quality of life in patients with severe emphysema up to 1 year after treatment, independent of the distribution of the disease. PMID- 26112381 TI - Multiplicity in confirmatory clinical trials: a case study with discussion from a JSM panel. AB - An invited panel session was conducted in the 2012 Joint Statistical Meetings, San Diego, California, USA, to stimulate the discussion on multiplicity issues in confirmatory clinical trials for drug development. A total of 11 expert panel members were invited and 9 participated. Prior to the session, a case study was previously provided to the panel members to facilitate the discussion, focusing on the key components of the study design and multiplicity. The Phase 3 development program for this new experimental treatment was based on a single randomized controlled trial alone. Each panelist was asked to clarify if he or she responded as if he or she were a pharmaceutical drug sponsor, an academic panelist or a health regulatory scientist. PMID- 26112382 TI - C-kit is important for SOD1(G93A) mouse survival independent of mast cells. AB - Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease leading to progressive and lethal paralysis. The disease process is multi factorial and is characterized by selective motor neuron degeneration. Previous work demonstrated that the local concentration of various growth factors can influence motor neuron survival and disease progression. A potential role for c kit, a growth factor receptor present in the spinal cord, in ALS is unknown. To dissect the role of c-kit in ALS we interbred SOD1(G93A) mice with kit(w-sh/w-sh) mice, which have a 70% decrease in c-kit expression in the spinal cord. kit(w sh/w-sh) SOD1(G93A) mice have a reduced survival compared to SOD1(G93A) mice, while the amount of motor neurons at end stage is similar. By means of grip strength and nerve conductance analysis we show that kit(w-sh/w-sh) mice have diminished strength and slightly impaired compound muscle action potential latency, although the number of neurons is similar across genotypes. Decreasing kit gene expression in SOD1(G93A) mice is detrimental and our results imply that this effect is independent of mast cells, as tested by ketotifen administration. To conclude, our data expand on the protective role of growth factors in ALS, as decreasing c-kit by approximately 70% is detrimental in SOD1(G93A) mice. PMID- 26112383 TI - Sulforaphane rescues memory dysfunction and synaptic and mitochondrial alterations induced by brain iron accumulation. AB - Iron overload contributes to the development of neurodegeneration and the exacerbation of normal apoptosis rates, largely due to its participation in the Fenton reaction and production of reactive oxygen species (ROS). Mitochondria constitute the major intracellular source of ROS and the main target of attack by free radicals. They are dynamic organelles that bind (fusion) and divide (fission) in response to environmental stimuli, developmental status, and energy needs of the cells. Sulforaphane (SFN) is a natural compound that displays antioxidant and anti-inflammatory activities. This study aims to investigate the effects of SFN on memory deficits and changes in markers of mitochondrial function, DNM1L and OPA1, and the synaptic marker, synaptophysin, induced by neonatal iron treatment. Male rats received vehicle or carbonyl iron (30mg/kg) from the 12th to the 14th postnatal day. In adulthood, they were treated with saline or SFN (0.5 or 5mg/kg) for 14days every other day. Memory deficits were assessed using the object recognition task. DNM1L, OPA1, and synaptophysin levels in the hippocampus were quantified by Western blotting. Results showed that SFN was able to reverse iron-induced decreases in mitochondrial fission protein, DNM1L, as well as synaptophysin levels in the hippocampus, leading to a recovery of recognition memory impairment induced by iron. These findings suggest that SFN may be further investigated as potential agent for the treatment of cognitive deficits associated with neurodegenerative disorders. PMID- 26112384 TI - Probing three-dimensional sodiation-desodiation equilibrium in sodium-ion batteries by in situ hard X-ray nanotomography. AB - Materials degradation-the main limiting factor for widespread application of alloy anodes in battery systems-was assumed to be worse in sodium alloys than in lithium analogues due to the larger sodium-ion radius. Efforts to relieve this problem are reliant on the understanding of electrochemical and structural degradation. Here we track three-dimensional structural and chemical evolution of tin anodes in sodium-ion batteries with in situ synchrotron hard X-ray nanotomography. We find an unusual (de)sodiation equilibrium during multi electrochemical cycles. The superior structural reversibility during 10 electrochemical cycles and the significantly different morphological change features from comparable lithium-ion systems suggest untapped potential in sodium ion batteries. These findings differ from the conventional thought that sodium ions always lead to more severe fractures in the electrode than lithium ions, which could have impact in advancing development of sodium-ion batteries. PMID- 26112385 TI - Robust electromagnetic absorption by graphene/polymer heterostructures. AB - Polymer/graphene heterostructures present good shielding efficiency against GHz electromagnetic perturbations. Theory and experiments demonstrate that there is an optimum number of graphene planes, separated by thin polymer spacers, leading to maximum absorption for millimeter waves Batrakov et al (2014 Sci. Rep. 4 7191). Here, electrodynamics of ideal polymer/graphene multilayered material is first approached with a well-adapted continued-fraction formalism. In a second stage, rigorous coupled wave analysis is used to account for the presence of defects in graphene that are typical of samples produced by chemical vapor deposition, namely microscopic holes, microscopic dots (embryos of a second layer) and grain boundaries. It is shown that the optimum absorbance of graphene/polymer multilayers does not weaken to the first order in defect concentration. This finding testifies to the robustness of the shielding efficiency of the proposed absorption device. PMID- 26112386 TI - Population-specific evidence selection to support practice. PMID- 26112387 TI - Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology. AB - PURPOSE: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on (99m)Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images. METHODS: We performed retrospective dosimetry of the standard TheraSphere(r) treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50% and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on (99m)Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of (99m)Tc-MAA and (90)Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICSTM by Philips). STRATOSTM absorbed dose calculation was validated for (90)Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment. RESULTS: MAA and (90)Y biodistributions were not different (71% of cases), different in 23% and uncertain in 6%. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50%) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14%, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ~ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ~ 75 Gy. CONCLUSION: A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed. PMID- 26112388 TI - Feasibility and utility of re-treatment with (177)Lu-DOTATATE in GEP-NENs relapsed after treatment with (90)Y-DOTATOC. AB - PURPOSE: Peptide receptor radionuclide therapy (PRRT) is a valid therapy for grade 1/2 gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). Although a median progression-free survival (PFS) of more than 20 months is frequently observed, the majority of patients relapse after 2 - 3 years. In the present study, we investigated the use of low dosage re-treatment with (177)Lu-DOTATATE (Lu-PRRT) in patients with GEP-NENs who relapsed after treatment with (90)Y DOTATOC (Y-PRRT). METHODS: Upon tumour progression, 26 patients with a PFS of at least 12 months after Y-PRRT were consecutively enrolled in a phase II study of re-treatment with Lu-PRRT. All patients had preserved kidney and haematological parameters and received 14.8 - 18.5 GBq of Lu-PRRT in four or five cycles. The disease control rate (DCR), toxicity, PFS and prognostic factors were evaluated. RESULTS: Median total activity of Lu-PRRT was 16.5 GBq in five cycles. The DCR was 84.6%, median PFS was 22 months (95% CI 16 months - not reached) compared to 28 months (95% CI 20 - 36 months) after Y-PRRT. Tumour burden and number of liver metastases were important prognostic factors. Toxicity was mild after Lu-PRRT re treatment in the majority of patients, with only two patients with grade 2 and one with grade 3 bone marrow toxicity; one patient had grade 2 and one grade 3 renal toxicity. CONCLUSION: Patients with GEP-NEN who have previously responded to Y-PRRT are suitable candidates for Lu-PRRT re-treatment on progression. Although our sample size was limited, low-dosage Lu-PRRT was safe, and led to DCR and PFS rates comparable with those observed when Y-PRRT was used as primary treatment. PMID- 26112389 TI - Focal impairment in myocardial fatty acid imaging in the left anterior descending artery area, a strong predictor for cardiac death in hemodialysis patients without obstructive coronary artery disease. AB - PURPOSE: We investigated whether impaired patterns of myocardial fatty acid imaging were associated with cardiac death in dialysis patients without coronary lesions. METHODS: We prospectively enrolled 155 hemodialysis patients without obstructive coronary artery disease, who had been examined by single-photon emission computed tomography (SPECT) using the iodinated fatty acid analogue BMIPP. Uptake of BMIPP on SPECT was graded in 17 segments on a five-point scale (0, normal; 4, absent) and assessed as BMIPP summed scores. Of the enrolled 155 participants, we analyzed 95 who had BMIPP summed scores >= 6 (52 men and 43 women, 65 +/- 11 years). BMIPP scores >= 2 in >= 2 consecutive segments in SPECT were defined as focal, and the others as non-focal pattern. RESULTS: Of 95 participants analyzed, 42 (44.2 %) showed focal and 53 (55.8 %) non-focal type. During follow-up for 5.1 +/- 2.0 years, 42 died of cardiac events. The occurrence of cardiac death was higher in the focal than in the non-focal group (30/42 [71.4 %] versus 12/53 [22.6 %], p = 0.001). In stepwise Cox hazard analysis, focal pattern was associated with cardiac death (hazard ratio 2.266), independent of impairment of BMIPP SPECT (BMIPP summed scores >= 12). The predictive potential of BMIPP SPECT for cardiac death was higher (p < 0.001) in the left anterior descending artery area compared with other coronary territories. CONCLUSIONS: Focal impairment in myocardial fatty acid imaging in the left anterior descending area may strongly predict cardiac death in this population. PMID- 26112390 TI - Early Evolution of Human Respiratory Syncytial Virus ON1 Strains: Analysis of the Diversity in the C-Terminal Hypervariable Region of Glycoprotein Gene within the First 3.5 Years since Their Detection. AB - OBJECTIVE: Characterization of the phylogeny and diversity of human respiratory syncytial virus (HRSV) genotype ON1 that occurred during its early evolution (within the first 3.5 years since the detection of the first ON1 strains). ON1 strains have a 72-nucleotide-long in-frame duplication within the second hypervariable domain of the glycoprotein gene (HVR2). METHODS: All available HVR2 sequences of strains belonging to the ON1 genotype published prior to June 20, 2014 were collected. Multiple sequence alignments, phylogeny, phylogeography, sequence clustering and putative protein analyses were performed. RESULTS: The worldwide spread and diversification of ON1 strains are presented. Only in a minority of ON1 strains do the two replicas remain identical, and various ON1 strains possess common differences between the first and the second copy (segments A and B). Mutations of the progenitor sequence were more frequent in segment B, a higher overall diversity on the protein level and more putative glycosylation sites exist in segment B, and, unlike in segment A, positive selection acts on that protein region. CONCLUSIONS: The fast spread of the novel HRSV genotype ON1 has been accompanied by its rapid concurrent diversification. Differences in variability of the two replicas within HVR2 were detected, with C terminal replica being more variable. PMID- 26112391 TI - Trend of Japanese encephalitis in Uttar Pradesh, India from 2011 to 2013. AB - As indicated by the sporadic Japanese encephalitis (JE) cases reported from the districts of Uttar Pradesh (UP), India, the disease is endemic in the state despite the fact that a JE vaccination programme has been ongoing in the state since 2006. Hence, the present study was undertaken to study the annual trend of JE in UP during January 2011 to December 2013. CSF and/or serum samples collected from acute encephalitis syndrome (AES) cases were referred to the virology laboratory at King George's Medical University, Lucknow and were tested for anti JEV IgM antibodies by JEV MAC-ELISA kit. The study reveals that 26.9%, 9.9% and 14.8% of AES cases were positive for anti-JEV IgM in the years 2011, 2012 and 2013, respectively. Of the total JE confirmed cases, 30% were adults. Males were more commonly affected than females. A distinct peak of JE was seen in the monsoon and post-monsoon season, although sporadic cases were also reported in other months. JE vaccination by district in UP is discussed. This study reports that the proportion of JE positives in AES cases is decreasing in UP although the number of AES cases has not decreased. The study also discusses the probable causes of this decrease, including JE vaccination and natural periodicity due to herd immunity. PMID- 26112392 TI - Evaluation of Oxygen Supplementation Status as a Risk Factor Associated with the Development of Severe Retinopathy of Prematurity. AB - PURPOSE: The effects of oxygen supplementation status and other clinical risk factors on the development of severe retinopathy of prematurity (ROP) were evaluated. METHODS: Clinical records of 143 newborn infants with a gestational age of 32 weeks or less were reviewed. Severe ROP was diagnosed when photocoagulation due to progression to stage 3 was identified or when 'plus disease' developed. The factors were evaluated with univariate and multivariate logistic regression analyses between the groups with severe (n = 24) and non severe (n = 119) ROP. RESULTS: Gestational age, birth weight, duration of oxygen supplementation, duration of directional positive air pressure and maximum fraction of inspiratory oxygen (FiO2) were significantly associated with severe ROP in the univariate analyses. In the multivariate analysis, a longer duration of oxygen supplementation and a higher maximum FiO2 were revealed as significant risk factors associated with severe ROP. CONCLUSIONS: Duration of oxygen supplementation and maximum FiO2 required were important factors associated with severe ROP. PMID- 26112393 TI - Laser micro-dissection and qPCR for identifying specific HPV types responsible for malignancy in penile lesions. AB - The aim of the study was to identify specific human papillomavirus (HPV) type responsible for malignancy in penile tissue samples using laser micro-dissection and TaqMan quantitative real-time PCR (qPCR). The study was based on two pre malignant and seven malignant penile tissue samples and laser micro-dissection was performed on all. Genotyping was performed on whole tissue sections and laser micro-dissection samples using qPCR. Two whole tissue section samples were HPV negative while seven were HPV positive. In four samples that were single HPV infections with whole tissue section PCR, identical HPV types were confirmed with laser micro-dissection PCR. Clearly confirming that the single HPV type detected is responsible for malignancy. In two samples that had multiple HPV infections with whole tissue section PCR, only one HPV type with the highest viral load was detected with laser micro-dissection PCR, suggesting that the HPV type with the highest viral load is most likely the cause of that particular lesion. HPV 11 and/or HPV 16 were the only types detected with laser micro-dissection PCR in these cases, compared to multiple HPV types (HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 35, and HPV 39) initially detected with whole tissue section PCR. HPV 11 was associated with verrucous lesions while HPV 16 was associated with squamous cell carcinoma and PIN 3 lesions. This study confirms that laser micro-dissection and qPCR are essential tools in identifying the HPV types responsible for malignancy in penile lesions, particularly in samples with multiple infections. PMID- 26112394 TI - The Lifespan-Promoting Effect of Otophylloside B in Caenorhabditis elegans. AB - Aging is the major risk factor for many human diseases and degeneration. Thus, clinically effective medicine could delay the process of aging and aging-related diseases are desperately wanted. In traditional Chinese medicine (TCM), some were claimed to slow down aging. Qingyangshen (Cynanchum otophyllum schneid) is such a TCM. Here, we assayed the longevity effect of compound Otophylloside B (Ot B), a C-21 steroidal glycoside isolated from Qingyangshen, in Caenorhabditis elegans, which is a popular model for aging research. Our results showed that Ot B could modestly extend the lifespan of C. elegans, delay the age-related decline of body movement and improve the stress resistance. Further investigating the molecular mechanism of lifespan extension effect revealed that Ot B could activate the FOXO transcription factor DAF-16. Ot B could not further extend the lifespan of long lived mutant of insulin/IGF-1-like receptor (daf-2). In addition, Ot B also requires SIR-2.1 and CLK-1 which is an enzyme in ubiquinone synthesis, for lifespan extension. PMID- 26112395 TI - Ligand exchange procedure for bimetallic magnetic iron-nickel nanocrystals toward biocompatible activities. AB - Bimetallic magnetic iron-nickel (FeNi) nanocrystals (NCs) were synthesized through a one-pot synthetic wet chemistry method, and the morphology of the resulting NCs can be adjusted by changing the molar ratio of chemical attendees during the experimental processes. The obtained FeNi NCs can be redispersed in water medium though the phase works by using the ligand exchange procedures of cysteine (Cys), 5-aminovaleric acid (5AA), and glutathione (GSH), respectively. The synthesized NCs exhibited excellent magnetic properties with Hc (magnetic fields, ~10(-3) T) and MUa (initial permeability of up to 10(5)). Furthermore, linear sweep voltammetry (LSV) polarization curves revealed a low overpotential of -0.47, -0.44, and 0.15 V and a current of 105.7, 97.8, and 209 mA for the Cys , 5AA-, and GSH-FeNi NCs, respectively. This indicated a relatively high catalytic activity of these NCs in the hydrogen evolution reaction (HER). The different cell lines (AGS, HepG2, MG63, NCI-H460, and SK-MEL-2) exposed to FeNi NCs for 5 days exhibited >87% viability at concentrations of up to 50 MUg mL(-1), which was indicative of excellent biocompatibility. The resulting FeNi NCs offer a facile synthetic route to fabricate monodispersed NCs. The biocompatibility of these NCs should also enable their application in electrocatalysis and biological applications. PMID- 26112396 TI - Could miltefosine be used as a therapy for toxoplasmosis? AB - Toxoplasmosis is a zoonotic protozoal disease affecting more than a billion people worldwide. The shortfalls of the current treatment options necessitate the development of non-toxic and well-tolerated, efficient alternatives especially against the cyst form. The current study was undertaken to investigate, for the first time, the potential potency of miltefosine against Toxoplasma gondii infection in acute and chronic experimental toxoplasmosis. Results showed that there is no evidence of anti-parasitic activity of miltefosine against T. gondii tachyzoites in acute experimental toxoplasmosis. However, anti-parasitic activity of miltefosine against T. gondii cyst stage in chronic experimental toxoplasmosis could not be excluded as demonstrated by significant reduction in brain cyst burden. Moreover, considerable morphological changes in the cysts were revealed by light and electron microscopy study and also by amelioration of pathological changes in the brain. Future studies should focus on enhancement of anti toxoplasma activity of miltefosine against chronic toxoplasmosis using formulation based nanotechnology. To the best of our knowledge, this is the first study highlighting efficacy of miltefosine against chronic toxoplasmosis, thus, increasing the list of diseases that can be targeted by this drug. PMID- 26112397 TI - Parental emotional management benefits family relationships: A randomized controlled trial in Hong Kong, China. AB - There is a shortage of culturally appropriate, brief, preventive interventions designed to be sustainable and acceptable for community participants in nonwestern cultures. Parents' ability to regulate their emotions is an important factor for psychological well-being of the family. In Chinese societies, emotional regulation may be more important in light of the cultural desirability of maintaining harmonious family relationships. The objectives of our randomized controlled trial were to test the effectiveness of our Effective Parenting Programme (EPP) to increase the use of emotional management strategies (primary outcome) and enhance the parent-child relationship (secondary outcome). We utilized design characteristics that promoted recruitment, retention, and intervention sustainability. We randomized a community sample of 412 Hong Kong middle- and low-income mothers of children aged 6-8 years to the EPP or attention control group. At 3, 6 and 12- month follow up, the Effective Parent Program group reported greater increases in the use of emotion management strategies during parent-child interactions, with small to medium effect size, and lower negative affect and greater positive affect, subjective happiness, satisfaction with the parent-child relationship, and family harmony, compared to the control group, with small to medium effect size. Our results provided evidence of effectiveness for a sustainable, preventive, culturally appropriate, cognitive behaviorally-based emotion management program, in a non-clinical setting for Chinese mothers. TRIAL REGISTRATION: HKCTR-1190. PMID- 26112398 TI - Emphasizing Malleability in the biology of depression: Durable effects on perceived agency and prognostic pessimism. AB - Biological attributions for depression, which are currently ascendant, can lead to prognostic pessimism-the perception that symptoms are relatively immutable and unlikely to abate (Kvaale, Haslam, & Gottdiener, 2013; Lebowitz, Ahn, & Nolen Hoeksema, 2013). Among symptomatic individuals, this may have important clinical ramifications, as reduced confidence in one's own ability to overcome depression carries the risk of becoming a self-fulfilling prophecy. Previous research (Lebowitz, Ahn, et al., 2013) has demonstrated that educational interventions teaching symptomatic individuals about how the effects of genetic and neurobiological factors involved in depression are malleable and can be modified by experiences and environmental factors can reduce prognostic pessimism. While previous research demonstrated such effects only in the immediate term, the present research extends these findings by testing whether such benefits persist six weeks after the intervention. Indeed, among individuals who initially considered biological factors to play a major role in influencing their levels of depression, exposure to malleability-focused psychoeducation reduced levels of depression-related prognostic pessimism and stronger belief in their ability to regulate their moods. Critically, this benefit persisted six weeks after the intervention. Clinical implications of the findings are discussed. PMID- 26112400 TI - Work Environment-Related Factors in Obtaining and Maintaining Work in a Competitive Employment Setting for Employees with Intellectual Disabilities: A Systematic Review. AB - BACKGROUND: People with an intellectual disability value work as a significant part of their lives, and many of them want to participate in regular paid employment.Current estimates show that the number of people with ID who have some form of paid employment are very low, ranging from 9 to 40% across different countries,despite legislations. This review examines papers published in the past 20 years in an attempt to answer the following research question: 'What work environment-related factors contribute to obtaining or maintaining work in competitive employment for people with an intellectual disability?' METHOD: The databases of PubMed, PsycINFO,CINAHL, Embase and Web of Science were searched for relevant papers published between 1993 and 2013. All papers were independently screened by two researchers.Methodological quality of the studies was evaluated, and data on work environment-related factors stimulating employment for people with intellectual disabilities were extracted and grouped into categories. RESULTS: A total of 1932 articles were retrieved. After extensive screening for relevance and quality, 26 articles were included in this review. Four themes/categories with work environment related factors that could influence work participation were distinguished. Five studies were conducted on employers' decisions and opinions. Eight focused on job content and performance, and eight on workplace interaction and culture. Five studies evaluated support by job coaches. CONCLUSION: Despite ongoing legislation to promote participation of people with intellectual disabilities in the paid workforce, research in this area is still extremely scarce. In the past 20 years, very few studies have focused on work environment-related factors that can enhance competitive work for people with intellectual disabilities.This review shows that relevant work environment-related factors for obtaining and maintaining work in competitive employment include supporting the employers by paying specific attention to: employer's decisions, job content, integration and work culture and job coaches. PMID- 26112399 TI - Identification and characterization of a HEPN-MNT family type II toxin-antitoxin in Shewanella oneidensis. AB - Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. However, related studies in the ecologically and bioelectrochemically important strain Shewanella oneidensis are limited. Here, we show that SO_3166, a member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) superfamily, strongly inhibited cell growth in S. oneidensis and Escherichia coli. SO_3165, a putative minimal nucleotidyltransferase (MNT), neutralized the toxicity of SO_3166. Gene SO_3165 lies upstream of SO_3166, and they are co-transcribed. Moreover, the SO_3165 and SO_3166 proteins interact with each other directly in vivo, and antitoxin SO_3165 bound to the promoter of the TA operon and repressed its activity. Finally, the conserved Rx4-6H domain in HEPN family was identified in SO_3166. Mutating either the R or H abolished SO_3166 toxicity, confirming that Rx4-6H domain is critical for SO_3166 activity. Taken together, these results demonstrate that SO_3166 and SO_3165 in S. oneidensis form a typical type II TA pair. This TA pair plays a critical role in regulating bacterial functions because its disruption led to impaired cell motility in S. oneidensis. Thus, we demonstrated for the first time that HEPN-MNT can function as a TA system, thereby providing important insights into the understanding of the function and regulation of HEPNs and MNTs in prokaryotes. PMID- 26112402 TI - The effect of conservative treatment of urinary incontinence among older and frail older people: a systematic review. AB - BACKGROUND: urinary incontinence (UI) is a common symptom among older people, with a higher prevalence among frail older persons living in nursing homes. Despite consequences such as reduced health and quality of life, many older people do not seek help for their symptoms, resulting in missed opportunity for treatment. OBJECTIVE: the aim of this study was to investigate the evidence and the effect of conservative treatment of UI and the quality of life among older and frail older persons. METHODS: a systematic review of randomised controlled studies and prospective, non-randomised studies was conducted, evaluating interventions of conservative treatment of UI in an older population (65 years or older). A total of 23 studies fulfilled the inclusion criteria and 9 were of high or moderate quality. Fourteen studies were of low quality and were therefore excluded from the analysis. RESULTS: documented and effective conservative treatments are available even for older persons with UI. Pelvic muscle exercise, physical training in combination with ADL, prompted voiding and attention training, and help to toilet are important treatments. In some studies, however, the evidence of effectiveness is limited. CONCLUSIONS: this systematic review concludes that there are conservative treatments for UI for older and frail older persons that reduce leakage and increase quality of life. There is however a need for further high-quality studies. PMID- 26112401 TI - SH2-PLA: a sensitive in-solution approach for quantification of modular domain binding by proximity ligation and real-time PCR. AB - BACKGROUND: There is a great interest in studying phosphotyrosine dependent protein-protein interactions in tyrosine kinase pathways that play a critical role in many aspects of cellular function. We previously established SH2 profiling, a phosphoproteomic approach based on membrane binding assays that utilizes purified Src Homology 2 (SH2) domains as a molecular tool to profile the global tyrosine phosphorylation state of cells. However, in order to use this method to investigate SH2 binding sites on a specific target in cell lysate, additional procedures such as pull-down or immunoprecipitation which consume large amounts of sample are required. RESULTS: We have developed PLA-SH2, an alternative in-solution modular domain binding assay that takes advantage of Proximity Ligation Assay and real-time PCR. The SH2-PLA assay utilizes oligonucleotide-conjugated anti-GST and anti-EGFR antibodies recognizing a GST SH2 probe and cellular EGFR, respectively. If the GST-SH2 and EGFR are in close proximity as a result of SH2-phosphotyrosine interactions, the two oligonucleotides are brought within a suitable distance for ligation to occur, allowing for efficient complex amplification via real-time PCR. The assay detected signal across at least 3 orders of magnitude of lysate input with a linear range spanning 1-2 orders and a low femtomole limit of detection for EGFR phosphotyrosine. SH2 binding kinetics determined by PLA-SH2 showed good agreement with established far-Western analyses for A431 and Cos1 cells stimulated with EGF at various times and doses. Further, we showed that PLA-SH2 can survey lung cancer tissues using 1 MUl lysate without requiring phospho-enrichment. CONCLUSIONS: We showed for the first time that interactions between SH2 domain probes and EGFR in cell lysate can be determined in a microliter-scale assay using SH2-PLA. The obvious benefit of this method is that the low sample requirement allows detection of SH2 binding in samples which are difficult to analyze using traditional protein interaction assays. This feature along with short assay runtime makes this method a useful platform for the development of high throughput assays to determine modular domain-ligand interactions which could have wide-ranging applications in both basic and translational cancer research. PMID- 26112403 TI - The Winding Paths of the Lonesome Cowboy: Evidence for Mutual Influences Between Personality, Subjective Health, and Loneliness. AB - Prior research demonstrated influences of personality traits and their development on later status of subjective health and loneliness. In the present study, we intended to extend these findings by examining mutual influences between health-related characteristics and personality traits and their development over time. German adults were assessed at two time points across 15 years (NT1 = 654, NT2 = 271; Mage at Time 1 = 24.39, SD = 3.69). Data were analyzed with multivariate structural equation models and a multivariate latent change model. Neuroticism was found to predict later levels and the development of subjective health and loneliness. While subjective health likewise predicted later levels of Neuroticism, loneliness was found to be predictive of later levels as well as the development of Neuroticism, Extraversion, and Conscientiousness. Correlated changes indicated that developing a socially more desirable personality is associated with slower declines in subjective health and slower increases in loneliness. The findings indicate that characteristics related to an individual's health are reciprocally associated with personality traits. Thus, the study adds to the understanding of the development of personality and health-related characteristics. PMID- 26112404 TI - Children's age modulates the effect of part and whole practice in motor learning. AB - Motor skills can be learned by practicing the whole or part of a movement. In whole practice (WP), a skill is acquired by practicing the movement in its entirety, whereas in part practice (PP), a task is learned by practicing its components before combining them. However, the effectiveness of WP and PP in children is unclear. We, therefore, examined the effects of WP and PP on the learning of juggling among first-, third-, and fifth-graders. Children of each grade were pseudo-randomly assigned to the WP or PP group to learn cascade juggling in 6 days. After baseline assessments, the WP learners practiced three beanbag juggling. The PP learners practiced one-beanbag juggling on the first 2 days, two-beanbag juggling on the following 2 days, and three-beanbag juggling on the last 2 days. Practice consisted of 40 trials each day. Skill retention and transfer trials (juggling in the opposite direction) were measured 24h after training (number of catches). There was no significant difference between WP and PP in skill retention (WP: 1.28 +/- 0.73; PP: 1.42 +/- 046, p = .40) and transfer (WP: 1.31 +/- 0.78; PP: 1.37 +/- 0.55, p = .49). However, a time * grade * group interaction (p < .001) was observed in retention. Children of different grades received differential benefits from the WP and PP regimens. The fifth-graders learned better using WP, whereas the first- and third-graders showed better learning with PP. We discuss the three possible explanations for the results (neural maturity, explicit learning, and coordination capabilities). PMID- 26112405 TI - Minimal Invasive Suture-Tape Augmentation for Chronic Ankle Instability. AB - BACKGROUND: Although the modified Brostrom procedure has had excellent clinical results, postoperative complications such as skin irritation by suture material and problematic scar formation occur. This prospective study was performed to evaluate the clinical outcomes of mini-open ligament augmentation (internal brace technique) using suture tape for chronic ankle instability in a select cohort of patients. METHODS: Thirty-four young female patients with less than 70 kg of body weight were followed for more than 2 years after suture tape augmentation for lateral ankle instability. The clinical evaluation consisted of the Foot and Ankle Outcome Score (FAOS), Foot and Ankle Ability Measure (FAAM) score, Sefton grading system, and the period to return to various activities. Measurement of talar tilt angle and anterior talar translation was obtained from stress radiographs to evaluate the longevity of mechanical ankle stability. RESULTS: FAOS and FAAM scores had significantly improved to 92.5 points at final follow-up (P < .001). According to the Sefton grading, 31 cases (91.2%) achieved satisfactory functional results. The period to return to exercise was on average 10.2 weeks for jogging and 9.6 weeks for walking on uneven ground. The average subjective satisfaction score of patients was 93.8 points, and satisfaction with the scar was 98.5 points. Talar tilt angle and anterior talar translation had significantly improved to an average of 4.5 degrees and 4.1 mm, respectively, at final follow-up (P < .001). There were no complications such as skin irritation and wound infection, except for 1 case of chronic inflammation. CONCLUSIONS: Minimally invasive suture tape augmentation seems to be an effective alternative for young women with chronic ankle instability. Because there is a possibility of progressive elongation over time, the longevity of mechanical ankle stability and the proper indication for using the internal brace technique should be addressed in future studies. LEVEL OF EVIDENCE: Level IV, case series study. PMID- 26112406 TI - Suture Fixation of the Syndesmosis Using Readily Available Materials. PMID- 26112407 TI - Phosphatidylinositol Induces Caspase-Independent Apoptosis of Malignant Pleural Mesothelioma Cells by Accumulating AIF in the Nucleus. AB - BACKGROUND/AIMS: Phosphatidylinositol (PI) regulates a variety of cell processes. The present study investigated the antitumor action of 1,2-dioleoyl-sn-glycero-3 phospho-(1'-myo-inositol)(DOPI) and 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-myo inositol)(DPPI) on human malignant pleural mesothelioma (MPM) cell lines such as NCI-H28, NCI-H2052, NCI-H2452, and MSTO-211H cells. METHODS: MTT assay, TUNEL staining, flow cytometry using propidium iodide (PI) and annexin V (AV), enzymatic caspase assay, and nuclear staining using DAPI were carried out, and mitochondrial membrane potentials and intracellular distribution of apoptosis inducing factor (AIF) were monitored in cells with and without the siRNA silencing the Bid-targeted gene. RESULTS: Both DOPI and DPPI reduced cell viability for all the investigated MPM cell lines in a concentration (0.01-100 uM)-dependent manner. DOPI and DPPI significantly increased TUNEL-positive cells and the population of PI-negative/AV-positive and PI-positive/AV-positive cells, corresponding to early apoptosis and late apoptosis/secondary necrosis, respectively. DOPI and DPPI perturbed mitochondrial membrane potentials in MSTO 211H cells, but no significant activation of caspase-3, -4, -8, and -9 was obtained. DOPI and DPPI upregulated expression of Bid in MSTO-211H cells. DOPI and DPPI significantly increased nuclear localization of AIF without affecting expression of the mRNAs and proteins in MSTO-211H cells, which was inhibited by knocking-down Bid. In the DAPI staining, nuclear fragmentation and condensation were found. CONCLUSION: The results of the present study indicate that DOPI and DPPI facilitate Bid-mediated AIF release from the mitochondria, to accumulate AIF in the nucleus and induce caspase-independent apoptosis of MPM cells. PMID- 26112408 TI - Lipid-induced Muscle Insulin Resistance Is Mediated by GGPPS via Modulation of the RhoA/Rho Kinase Signaling Pathway. AB - Elevated circulating free fatty acid levels are important contributors to insulin resistance in the muscle and liver, but the underlying mechanisms require further elucidation. Here, we show that geranylgeranyl diphosphate synthase 1 (GGPPS), which is a branch point enzyme in the mevalonic acid pathway, promotes lipid induced muscle insulin resistance through activation of the RhoA/Rho kinase signaling pathway. We have found that metabolic perturbation would increase GGPPS expression in the skeletal muscles of db/db mice and high fat diet-fed mice. To address the metabolic effects of GGPPS activity in skeletal muscle, we generated mice with specific GGPPS deletions in their skeletal muscle tissue. Heterozygous knock-out of GGPPS in the skeletal muscle improved systemic insulin sensitivity and glucose homeostasis in mice fed both normal chow and high fat diets. These metabolic alterations were accompanied by activated PI3K/Akt signaling and enhanced glucose uptake in the skeletal muscle. Further investigation showed that the free fatty acid-stimulated GGPPS expression in the skeletal muscle was able to enhance the geranylgeranylation of RhoA, which further induced the inhibitory phosphorylation of IRS-1 (Ser-307) by increasing Rho kinase activity. These results implicate a crucial role of the GGPPS/RhoA/Rho kinase/IRS-1 pathway in skeletal muscle, in which it mediates lipid-induced systemic insulin resistance in obese mice. Therefore, skeletal muscle GGPPS may represent a potential pharmacological target for the prevention and treatment of obesity-related type 2 diabetes. PMID- 26112409 TI - Potential Prepore Trimer Formation by the Bacillus thuringiensis Mosquito specific Toxin: MOLECULAR INSIGHTS INTO A CRITICAL PREREQUISITE OF MEMBRANE-BOUND MONOMERS. AB - The insecticidal feature of the three-domain Cry delta-endotoxins from Bacillus thuringiensis is generally attributed to their capability to form oligomeric pores, causing lysis of target larval midgut cells. However, the molecular description of their oligomerization process has not been clearly defined. Here a stable prepore of the 65-kDa trypsin-activated Cry4Ba mosquito-specific toxin was established through membrane-mimetic environments by forming an ~200-kDa octyl beta-D-glucoside micelle-induced trimer. The SDS-resistant trimer caused cytolysis to Sf9 insect cells expressing Aedes-mALP (a Cry4Ba receptor) and was more effective than a toxin monomer in membrane perturbation of calcein-loaded liposomes. A three-dimensional model of toxin trimer obtained by negative-stain EM in combination with single-particle reconstruction at ~5 nm resolution showed a propeller-shaped structure with 3-fold symmetry. Fitting the three-dimensional reconstructed EM map with a 100-ns molecular dynamics-simulated Cry4Ba structure interacting with an octyl-beta-D-glucoside micelle showed relative positioning of individual domains in the context of the trimeric complex with a major protrusion from the pore-forming domain. Moreover, high-speed atomic force microscopy imaging at nanometer resolution and a subsecond frame rate demonstrated conformational transitions from a propeller-like to a globularly shaped trimer upon lipid membrane interactions, implying prepore-to-pore conversion. Real-time trimeric arrangement of monomers associated with L-alpha dimyristoylphosphatidylcholine/3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1 propanesulfonic acid bicelle membranes was also envisaged by successive high speed atomic force microscopy imaging, depicting interactions among three individual subunits toward trimer formation. Together, our data provide the first pivotal insights into the structural requirement of membrane-induced conformational changes of Cry4Ba toxin monomers for the molecular assembly of a prepore trimer capable of inserting into target membranes to generate a lytic pore. PMID- 26112410 TI - The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-kappaB Signaling via Partial Degradation of the NF-kappaB Subunit p100. AB - Partial degradation of the p100 subunit to generate p52 subunit is a hallmark of the alternative NF-kappaB pathway, which has been implicated in cancer. Here, we uncovered a role of the p97-Npl4-Ufd1 complex in mediating p100-to-p52 processing and therefore positively regulating the alternative NF-kappaB pathway. We observed an elevation of p97 mRNA levels in lymphoma patients, which positively correlates with NFKB2 expression, a downstream target gene of the alternative NF kappaB pathway. Moreover, NFKB2 mRNA levels were aberrantly down-regulated in patients with inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD), a disease caused by mutation of p97. Inactivation of p97 or depletion of the p97-Npl4-Ufd1 complex inhibits the processing of p100 into p52, decreasing transcription of the downstream target genes. Further analyses reveal that the p97-Npl4-Ufd1 complex interacts with F box and WD repeats protein SCF(betaTrCP) complex to regulate the partial degradation of p100, a process involving K48- and K11-linked ubiquitination. In line with this, in LPS-induced lung damage mice model, generation of p52 is significantly decreased in p97-KD mice compared with mock mice. Finally, abrogation of p97 ATPase activity by its specific inhibitor DBeQ, efficiently decreased proliferation of lymphoma cells. Collectively, our study revealed a regulatory role of the p97-Npl4-Ufd1 complex in regulating p100 partial degradation, highlighting the potential of p97 as a drug target for cancers with aberrant activation of the alternative NF-kappaB pathway. PMID- 26112411 TI - Kinetic Investigations of the Role of Factor Inhibiting Hypoxia-inducible Factor (FIH) as an Oxygen Sensor. AB - The hypoxia-inducible factor (HIF) hydroxylases regulate hypoxia sensing in animals. In humans, they comprise three prolyl hydroxylases (PHD1-3 or EGLN1-3) and factor inhibiting HIF (FIH). FIH is an asparaginyl hydroxylase catalyzing post-translational modification of HIF-alpha, resulting in reduction of HIF mediated transcription. Like the PHDs, FIH is proposed to have a hypoxia-sensing role in cells, enabling responses to changes in cellular O2 availability. PHD2, the most important human PHD isoform, is proposed to be biochemically/kinetically suited as a hypoxia sensor due to its relatively high sensitivity to changes in O2 concentration and slow reaction with O2. To ascertain whether these parameters are conserved among the HIF hydroxylases, we compared the reactions of FIH and PHD2 with O2. Consistent with previous reports, we found lower Km(app)(O2) values for FIH than for PHD2 with all HIF-derived substrates. Under pre-steady-state conditions, the O2-initiated FIH reaction is significantly faster than that of PHD2. We then investigated the kinetics with respect to O2 of the FIH reaction with ankyrin repeat domain (ARD) substrates. FIH has lower Km(app)(O2) values for the tested ARDs than HIF-alpha substrates, and pre-steady-state O2-initiated reactions were faster with ARDs than with HIF-alpha substrates. The results correlate with cellular studies showing that FIH is active at lower O2 concentrations than the PHDs and suggest that competition between HIF-alpha and ARDs for FIH is likely to be biologically relevant, particularly in hypoxic conditions. The overall results are consistent with the proposal that the kinetic properties of individual oxygenases reflect their biological capacity to act as hypoxia sensors. PMID- 26112412 TI - The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1.Ras related C3 Botulinum Toxin Substrate 1 (P-Rex1.Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells. AB - The P-Rex (phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of the Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion, and metastasis in several human cancers. The family is unique among Rho GEFs, as their activity is regulated by the synergistic binding of PIP3 and Gbetagamma at the plasma membrane. However, the molecular mechanism of this family of multi domain proteins remains unclear. We report the 1.95 A crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1.Rac1 interface revealed a critical role for this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. The structural data indicated that the PIP3/Gbetagamma binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gbetagamma releases inhibitory C-terminal domains to expose the Rac1 binding site. PMID- 26112413 TI - Induction of Plasmid Conjugation in Bacillus subtilis Is Bistable and Driven by a Direct Interaction of a Rap/Phr Quorum-sensing System with a Master Repressor. AB - Conjugation of plasmid pLS20 from Bacillus subtilis is limited to a time window between early and late exponential growth. Genetic evidence has suggested that pLS20-encoded protein RcoLS20 represses expression of a large conjugation operon, whereas Rap protein RapLS20 relieves repression. We show that RapLS20 is a true antirepressor protein that forms dimers in vivo and in vitro and that it directly binds to the repressor protein RcoLS20 in a 1:1 stoichiometry. We provide evidence that RapLS20 binds to the helix-turn-helix-containing domain of RcoLS20 in vivo, probably obstructing DNA binding of RcoLS20, as seen in competitive DNA binding experiments. The activity of RapLS20 in turn is counteracted by the addition of the cognate PhrLS20 peptide, which directly binds to the Rap protein and presumably induces a conformational change of the antirepressor. Thus, a Rap protein acts directly as an antirepressor protein during regulation of plasmid conjugation, turning on conjugation, and is counteracted by the PhrLS20 peptide, which, by analogy to known Rap/Phr systems, is secreted and taken back up into the cells, mediating cell density-driven regulation. Finally, we show that this switchlike process establishes a population heterogeneity, where up to 30% of the cells induce transcription of the conjugation operon. PMID- 26112414 TI - Re: Follow-up of women with previous gestational diabetes. PMID- 26112415 TI - Re: Coustan "Follow-up of women with previous gestational diabetes" (comment on Noctor et al. ATLANTIC-DIP: prevalence of metabolic syndrome and insulin resistance in women with previous gestational diabetes mellitus by International Association of Diabetes in Pregnancy Study Groups criteria. Acta Diabetol 2015;52:153-160). PMID- 26112416 TI - GPR39 receptors and actions of trace metals on pancreatic beta cell function and glucose homoeostasis. AB - AIMS: G-protein-coupled receptor 39 (GPR39) has been implicated in glucose homoeostasis, appetite control and gastrointestinal tract function. METHODS: This study used clonal BRIN-BD11 cells and mouse pancreatic islets to assess the insulin-releasing actions of trace metals believed to act via GPR39, and the second messenger pathways involved in mediating their effects. Micromolar concentrations of Zn(2+), Cu(2+), Ni(2+) and Co(2+) were examined under normoglycaemic and hyperglycaemic conditions. Mechanistic studies investigated changes of intracellular Ca(2+), cAMP generation and assessment of cytotoxicity by LDH release. Cellular localisation of GPR39 was determined by double immunohistochemical staining. RESULTS: All trace metals (7.8-500 umol/l) stimulated insulin release with Cu(2+) being the most potent in isolated islets, with an EC50 value of 87 MUmol/l. Zn(2+) was the most selective with an EC50 value of 125 MUmol/l. Enhancement of insulin secretion was also observed with Ni(2+) (179 MUmol/l) and Co(2+) (190 MUmol/l). These insulin-releasing effects were confirmed using clonal BRIN-BD11 cells which exhibited enhanced intracellular Ca(2+) (p < 0.05-p < 0.001) and cAMP generation (p < 0.05-p < 0.001) in response to trace metals. Oral administration of Zn(2+), Ni(2+) and Cu(2+) (50 umol/kg together with 18 mmol/kg glucose) decreased the glycaemic excursion (p < 0.05-p < 0.01) and augmented insulin secretion (p < 0.05-p < 0.01) in NIH Swiss mice. CONCLUSIONS: This study has demonstrated the presence of GPR39 and the insulinotropic actions of trace metals on BRIN-BD11 cells and pancreatic beta cells, together with their antihyperglycaemic actions in vivo. These data suggest that development of agonists capable of specifically activating GPR39 may be a useful new therapeutic approach for diabetes management. PMID- 26112417 TI - RNA Seq profiling reveals a novel expression pattern of TGF-beta target genes in human blood eosinophils. AB - Despite major advances in our understanding of TGF-beta signaling in multiple cell types, little is known about the direct target genes of this pathway in human eosinophils. These cells constitute the major inflammatory component present in the sputum and lung of active asthmatics and their numbers correlate well with disease severity. During the transition from acute to chronic asthma, TGF-beta levels rise several fold in the lung which drives fibroblasts to produce extracellular matrix (ECM) and participate in airway and parenchymal remodeling. In this report, we use purified blood eosinophils from healthy donors and analyze baseline and TGF-beta responsive genes by RNA Seq, and demonstrate that eosinophils (PBE) express 7981 protein-coding genes of which 178 genes are up regulated and 199 genes are down-regulated by TGF-beta. While 18 target genes have been previously associated with asthma and eosinophilic disorders, the vast majority have been implicated in cell death and survival, differentiation, and cellular function. Ingenuity pathway analysis revealed that 126 canonical pathways are activated by TGF-beta including iNOS, TREM1, p53, IL-8 and IL-10 signaling. As TGF-beta is an important cytokine for eosinophil function and survival, and pulmonary inflammation and fibrosis, our results represent a significant step toward the identification of novel TGF-beta responsive genes and provide a potential therapeutic opportunity by selectively targeting relevant genes and pathways. PMID- 26112418 TI - Lymphopenia-induced proliferation in the absence of functional Autoimmune regulator (Aire) induces colitis in mice. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in Autoimmune regulator (Aire), a transcriptional regulator of negative selection in thymus. However, Aire is also expressed in periphery, but the full range of Aire's peripheral function is unknown. Here, we transferred lymphocytes from wildtype donors into lymphopenic recipients with or without functional Aire. Following cell proliferation thus took place in Aire-sufficient or deficient environment. The wildtype lymphocytes hyperproliferated and induced disease in lymphopenic Aire(-/-) but not in Aire(+/+) recipients. The disease was characterized by diarrhea, inflammation, and colitis, and in some recipients pancreatitis, gastritis, and hepatitis was also found. Our results identify Aire as an important regulator of peripheral T cell homeostasis in gastrointestinal tissues. Given a suitable trigger the absence of peripheral Aire leads to dysregulated T cell proliferation and disease. PMID- 26112419 TI - Single molecule Forster resonance energy transfer studies of the effect of EndoS deglycosylation on the structure of IgG. AB - The bacterial enzyme EndoS specifically cleaves glycans bound to immunoglobulin G (IgG) molecules. Because this deglycosylation procedure leads to a diminished immune response, this enzyme has potential applications as a therapeutic for autoimmune disorders. Although the diminished immune response is attributed to a structural change in the Fc region of IgG antibodies, the specific nature of this structural change is not known due to the variety of results obtained by different experimental approaches. In order to better understand how EndoS deglycosylation impacts the structure of the Fc region of IgG antibodies, we have conducted single molecule Forster resonance energy transfer (FRET) studies of dye labeled, freely diffusing antibodies. A comparison of the FRET efficiency histograms obtained for glycosylated and EndoS deglycosylated antibodies indicates that the Fc region can take on a wider variety of structures upon deglycosylation. This is demonstrated by the presence of additional peaks in the FRET efficiency histogram for the deglycosylated case. PMID- 26112420 TI - Effects of interleukin-2 on bioelectric activity of rat atrial myocardium under normal conditions and during gradual stretching. AB - Using micro-electrode technique we studied the effects of interleukin-2 (50 ng/ml) on bio-electric activity of rat atrial myocardium under normal conditions and after gradual stretching of the tissue. It was shown that interleukin-2 caused increasing in the duration of action potential at the levels of 25, 50, and 90% re-polarization. Perfusion with interleukin-2 resulted in appearance of frequent rhythm patterns followed by smooth transient fragments of paroxysmal tachyarrhythmia pacing into normal rhythms. In the presence of interleukin-2, stretching of the tissue by 1.7 mN led to appearance of abnormal bio-electrical activity, predominantly in the lengthening of the duration of action potential at the levels of 90% re-polarization. Close observation of both interleukin-2 induced action potential duration to 90% of re-polarization, hump-like depolarization and stretch induced hump-like alteration, indicate existence of a link between the interleukin-2 and stretch induced mechanisms. PMID- 26112421 TI - Presenilin-1 familial Alzheimer's disease mutation alters hippocampal neurogenesis and memory function in CCL2 null mice. AB - Aberrations in hippocampal neurogenesis are associated with learning and memory, synaptic plasticity and neurodegeneration in Alzheimer's disease (AD). However, the linkage between them, beta-amyloidosis and neuroinflammation is not well understood. To this end, we generated a mouse overexpressing familial AD (FAD) mutant human presenilin-1 (PS1) crossed with a knockout (KO) of the CC-chemokine ligand 2 (CCL2) gene. The PS1/CCL2KO mice developed robust age-dependent deficits in hippocampal neurogenesis associated with impairments in learning and memory, synaptic plasticity and long-term potentiation. Neurogliogenesis gene profiling supported beta-amyloid independent pathways for FAD-associated deficits in hippocampal neurogenesis. We conclude that these PS1/CCL2KO mice are suitable for studies linking host genetics, immunity and hippocampal function. PMID- 26112423 TI - Links Between Single-Trial Changes and Learning Rate in Eyelid Conditioning. AB - The discovery of single-trial learning effects, where the presence or absence (or the number) of climbing fiber inputs produces measureable changes in Purkinje cell response and in behavior, represents a major breakthrough in cerebellar learning. Among other things, these observations provide strong links between climbing fiber-mediated plasticity and cerebellar learning. They also demonstrate that cerebellar learning is stochastic, with each instantiation of a movement producing a small increment or decrement in gain. The sum of the small changes give rise to the macroscopic properties of cerebellar learning. We used a relatively large data set from another example of cerebellar-dependent learning, classical conditioning of eyelid responses, to attempt a behavioral replication and extension of single-trial learning effects. As a normal part of training, stimulus-alone trials provide instances where the climbing fiber response would be omitted, similar to non-climbing-fiber trials (gain down) during smooth pursuit training. The consequences of the stimulus-alone trial on the amplitude and timing of the conditioned response on the following paired trials were examined. We find that the amplitude of the conditioned response during the trial after a stimulus-alone trial (no climbing fiber input) was measurably smaller than the amplitude on the previous trials, and this single-trial effect on amplitude is larger for longer interstimulus intervals. The magnitude of the single-trial effect parallels the rate of extinction at different interstimulus intervals supporting the previously observed link between single-trial effects and learning. PMID- 26112424 TI - Towards clinical computed ultrasound tomography in echo-mode: Dynamic range artefact reduction. AB - Computed ultrasound tomography in echo-mode (CUTE) allows imaging the speed of sound inside tissue using hand-held pulse-echo ultrasound. This technique is based on measuring the changing local phase of beamformed echoes when changing the transmit beam steering angle. Phantom results have shown a spatial resolution and contrast that could qualify CUTE as a promising novel diagnostic modality in combination with B-mode ultrasound. Unfortunately, the large intensity range of several tens of dB that is encountered in clinical images poses difficulties to echo phase tracking and results in severe artefacts. In this paper we propose a modification to the original technique by which more robust echo tracking can be achieved, and we demonstrate in phantom experiments that dynamic range artefacts are largely eliminated. Dynamic range artefact reduction also allowed for the first time a clinical implementation of CUTE with sufficient contrast to reproducibly distinguish the different speed of sound in different tissue layers of the abdominal wall and the neck. PMID- 26112425 TI - Detection and characterization of stainless steel SCC by the analysis of crack related acoustic emission. AB - In the paper the results of the acoustic emission (AE) based detection and characterization of stress-corrosion cracking (SCC) in stainless steel are presented. As supportive methods for AE interpretation, electrochemical noise, specimen elongation measurements, and digital imaging of the specimen surface were used. Based on the defined qualitative and quantitative time and power spectra characteristics of the AE bursts, a manual and an automatic procedure for the detection of crack related AE bursts were introduced. The results of the analysis of the crack related AE bursts indicate that the AE method is capable of detecting large scale cracks, where, apart from intergranular crack propagation, also some small ductile fractures occur. The sizes of the corresponding ductile fracture areas can be estimated based on a relative comparison of the energies of the detected AE bursts. It has also been shown that AE burst time and power spectra features can be successfully used for the automatic detection of SCC. PMID- 26112422 TI - The Errors of Our Ways: Understanding Error Representations in Cerebellar Dependent Motor Learning. AB - The cerebellum is essential for error-driven motor learning and is strongly implicated in detecting and correcting for motor errors. Therefore, elucidating how motor errors are represented in the cerebellum is essential in understanding cerebellar function, in general, and its role in motor learning, in particular. This review examines how motor errors are encoded in the cerebellar cortex in the context of a forward internal model that generates predictions about the upcoming movement and drives learning and adaptation. In this framework, sensory prediction errors, defined as the discrepancy between the predicted consequences of motor commands and the sensory feedback, are crucial for both on-line movement control and motor learning. While many studies support the dominant view that motor errors are encoded in the complex spike discharge of Purkinje cells, others have failed to relate complex spike activity with errors. Given these limitations, we review recent findings in the monkey showing that complex spike modulation is not necessarily required for motor learning or for simple spike adaptation. Also, new results demonstrate that the simple spike discharge provides continuous error signals that both lead and lag the actual movements in time, suggesting errors are encoded as both an internal prediction of motor commands and the actual sensory feedback. These dual error representations have opposing effects on simple spike discharge, consistent with the signals needed to generate sensory prediction errors used to update a forward internal model. PMID- 26112426 TI - Phantom evaluation of stacked-type dual-frequency 1-3 composite transducers: A feasibility study on intracavitary acoustic angiography. AB - In this paper, we present phantom evaluation results of a stacked-type dual frequency 1-3 piezoelectric composite transducer as a feasibility study for intracavitary acoustic angiography. Our previous design (6.5/30 MHz PMN-PT single crystal transducer) for intravascular contrast ultrasound imaging exhibited a contrast-to-tissue ratio (CTR) of 12 dB with a penetration depth of 2.5 mm. For improved penetration depth (>3 mm) and comparable contrast-to-tissue ratio (>12 dB), we evaluated a lower frequency 2/14 MHz PZT 1-3 composite transducer. Superharmonic imaging performance of this transducer and a detailed characterization of key parameters for acoustic angiography are presented. The 2/14 MHz arrangement demonstrated a -6 dB fractional bandwidth of 56.5% for the transmitter and 41.8% for the receiver, and produced sufficient peak-negative pressures (>1.5 MPa) at 2 MHz to induce a strong nonlinear harmonic response from microbubble contrast agents. In an in-vitro contrast ultrasound study using a tissue mimicking phantom and 200 MUm cellulose microvessels, higher harmonic microbubble responses, from the 5th through the 7th harmonics, were detected with a signal-to-noise ratio of 16 dB. The microvessels were resolved in a two dimensional image with a -6dB axial resolution of 615 MUm (5.5 times the wavelength of 14 MHz waves) and a contrast-to-tissue ratio of 16 dB. This feasibility study, including detailed explanation of phantom evaluation and characterization procedures for key parameters, will be useful for the development of future dual-frequency array transducers for intracavitary acoustic angiography. PMID- 26112427 TI - Energy transfer and spectroscopic characterization of a perylenetetracarboxylic diimide (PDI) hexamer. AB - We report a comprehensive study on a newly synthesized perylenetetracarboxylic diimide (PDI) hexamer together with its corresponding monomer and dimer by means of steady-state absorption and fluorescence as well as femtosecond broadband transient absorption measurements. The structure of the PDI hexamer is nearly arranged in a 3-fold symmetry by three identical and separated dimers. This unique structure makes the excited state energy relaxation processes more complex due to the existence of two different intramolecular interactions: a strong interaction between face-to-face PDIs in dimers and a relatively weak interaction between the three separated PDI dimers. The steady-state spectra and the ground state structural optimization show that the steric effect plays a dominant role in keeping the formation of the face-to-face stacked PDI-dimer within the PDI hexamer, indicating that some level of a pre-associated excimer had formed already in the ground state for the dimer in the hexamer. Femtosecond transient absorption experiments on the PDI hexamer reveal a fast (~200 fs) localization process and a sequential relaxation to a pre-associated excimer trap state from the delocalized exciton state with about 1.2 ps after the initially delocalized excitation. Meanwhile, excitation energy transfer among the three separated dimers within the PDI-hexamer is also revealed by the anisotropic femtosecond pump-probe transient experiments, where the hopping time is about 2.8 ps. A relaxed excimer state is further formed in 7.9 ps after energy hopping and conformational relaxation. PMID- 26112428 TI - Management of Locally Advanced Adenocarcinoma of the Esophagus and Gastroesophageal Junction: Finally a Consensus. AB - Opinion statement: Adenocarcinoma of the esophagus is increasing in incidence in Western nations leading to increased interest in and opportunity to study optimal management. Randomized trials have now robustly demonstrated the preoperative therapy with chemoradiotherapy and chemotherapy alone improves survival outcome for the bulk of curable patients, those with locally advanced T1N1M0 and T2-3 N0 1 M0 disease. Evidence suggests but does not confirm that radiation-containing regimens are more beneficial. Clinical staging is designed to exclude patients with T1N0M0 disease who may be treated with surgery alone and those with metastatic disease who may not benefit from intensive local therapy. The approach to clinical staging includes endoscopy with ultrasound and fine needle aspirate to assess local and regional disease, supplemented by CT and PET scanning primarily to exclude metastatic disease. Minimally invasive approaches to esophagectomy may be used with the goal of reducing complications, but there is no evidence that mortality or ultimate outcome is improved. PMID- 26112429 TI - Using white noise to gate organic transistors for dynamic monitoring of cultured cell layers. AB - Impedance sensing of biological systems allows for monitoring of cell and tissue properties, including cell-substrate attachment, layer confluence, and the "tightness" of an epithelial tissue. These properties are critical for electrical detection of tissue health and viability in applications such as toxicological screening. Organic transistors based on conducting polymers offer a promising route to efficiently transduce ionic currents to attain high quality impedance spectra, but collection of complete impedance spectra can be time consuming (minutes). By applying uniform white noise at the gate of an organic electrochemical transistor (OECT), and measuring the resulting current noise, we are able to dynamically monitor the impedance and thus integrity of cultured epithelial monolayers. We show that noise sourcing can be used to track rapid monolayer disruption due to compounds which interfere with dynamic polymerization events crucial for maintaining cytoskeletal integrity, and to resolve sub-second alterations to the monolayer integrity. PMID- 26112430 TI - Coexisting and mixing phenomena of thermoacoustic and magnetoacoustic waves in water. AB - Concurrent generation and mixing phenomenon of thermoacoustic (TA) and magnetoacoustic (MA) waves in water are predicted and observed. A theory unifying TA and MA is further put forward to analyze it. By scaling down the radio frequency in thermoacoustics to the low mega Hertz range and by incorporating appropriately a static magnetic field, TA and MA waves are simultaneously generated in the conductive matter. The two waves propagate concurrently in water and produce dynamic acoustic radiation force due to water absorption. Such dynamic radiation force vibrates the absorbing water and consequently yields acoustic emissions at the inter-modulation frequencies of TA and MA waves, creating mixing effect similar to that of vibro-acoustography. The mixing effect can be potentially utilized to mimic vibro-acoustography imaging without firing external ultrasound towards intrinsic dual-contrast (elasticity and conductivity) imaging. PMID- 26112431 TI - Tuberculosis in infants less than 3 months of age of Risaralda, Colombia. PMID- 26112432 TI - [Oncohematologic cancers and tuberculosis in a general hospital]. PMID- 26112433 TI - Strengthening the Reporting of Observational Studies in Epidemiology for respondent-driven sampling studies: "STROBE-RDS" statement. AB - OBJECTIVES: Respondent-driven sampling (RDS) is a new data collection methodology used to estimate characteristics of hard-to-reach groups, such as the HIV prevalence in drug users. Many national public health systems and international organizations rely on RDS data. However, RDS reporting quality and available reporting guidelines are inadequate. We carried out a systematic review of RDS studies and present Strengthening the Reporting of Observational Studies in Epidemiology for RDS Studies (STROBE-RDS), a checklist of essential items to present in RDS publications, justified by an explanation and elaboration document. STUDY DESIGN AND SETTING: We searched the MEDLINE (1970-2013), EMBASE (1974-2013), and Global Health (1910-2013) databases to assess the number and geographical distribution of published RDS studies. STROBE-RDS was developed based on STROBE guidelines, following Guidance for Developers of Health Research Reporting Guidelines. RESULTS: RDS has been used in over 460 studies from 69 countries, including the USA (151 studies), China (70), and India (32). STROBE RDS includes modifications to 12 of the 22 items on the STROBE checklist. The two key areas that required modification concerned the selection of participants and statistical analysis of the sample. CONCLUSION: STROBE-RDS seeks to enhance the transparency and utility of research using RDS. If widely adopted, STROBE-RDS should improve global infectious diseases public health decision making. PMID- 26112434 TI - Prospective evaluation of the incidence of wound infection in rattlesnake envenomation in dogs. AB - OBJECTIVE: To evaluate the incidence of wound infection following crotalidae envenomation in dogs and determine if the use of prophylactic antibiotics is warranted. DESIGN: Prospective observational study. SETTING: A 24-hour private practice specialty and emergency center in Murrieta, California. ANIMALS: One hundred and two dogs with acute rattlesnake envenomation. INTERVENTIONS: One hundred and forty-three consecutive cases of suspected acute rattlesnake envenomation were evaluated between March of 2012 and May of 2013. One hundred and two cases received no antimicrobials as part of management. Eight cases were placed on prophylactic antimicrobials by the primary care veterinarian prior to referral and were excluded. Two cases were excluded because they were initiated on antimicrobials during hospitalization for reasons unrelated to snakebite. Three cases involved cats and were excluded. Three patients died acutely near the time of presentation and were excluded. Twenty-one cases of suspected envenomation were excluded for lack of strong evidence of snakebite. Four cases were lost to follow-up and were excluded. Follow-up was conducted within 2 weeks either by phone or by direct inspection of the wound. RESULTS: Of the 102 patients included in the study only 1 infection developed. This patient developed an abscess subsequent to suspected compartment syndrome. CONCLUSION: The incidence of wound infection in rattlesnake envenomation is low, and the use of prophylactic antimicrobials is not recommended. The use of antimicrobials should be reserved for wounds with necrosis or abscess and the choice of antimicrobial should be based on a culture and sensitivity of the wound. PMID- 26112435 TI - [Keratinophilic fungi in soils of parks of Corrientes city, Argentina]. AB - BACKGROUND: The soil is a natural reservoir of keratinophilic fungi, which are a small but important group of filamentous fungi, some of which typically develop on keratinized tissues of living animals. There are numerous species of saprophytic fungi with recognized keratinophilic abilities, and several studies have been undertaken in order to link their presence to possible human disease. AIMS: To know the biota of geophilic fungi in general and of keratinophilic fungi particularly in soils from two public parks. METHODS: Soil samples from two public parks of Corrientes city, Argentina, were studied during two seasons, using the hook technique and serial dilutions for fungal isolation. RESULTS: Using the hook technique, 170 isolates were classified into 17 genera and 21 species, among which it is worth mentioning the presence of Microsporum canis. Shannon index for keratinophilic fungi in autumn was 2.27, and 1.92 in spring. By means of the serial dilutions technique, 278 fungi isolated were identified into 33 genera and 71 species. Shannon index in autumn was 3.9, and 3.5 in spring. CONCLUSIONS: The soils studied have particularly favorable conditions for the survival of pathogens and opportunistic geophilic fungi for humans and animals. PMID- 26112436 TI - MATERNAL MENTAL HEALTH MODERATES THE RELATIONSHIP BETWEEN OXYTOCIN AND INTERACTIVE BEHAVIOR. AB - Mothers with mood or anxiety disorders exhibit less optimal interactive behavior. The neuropeptide oxytocin (OT) has been linked to more optimal interactive behaviors in mothers without mental illness, and it may play a particularly beneficial role in mothers with mood or anxiety disorders given its antidepressant and anxiolytic functions. We compared the relationship between OT and interactive behavior in mothers with and without mental health problems. Participants included 20 women diagnosed with postpartum mood or anxiety disorders (clinical sample) and 90 women with low levels of depression and anxiety during pregnancy and postpartum (community sample). At 2 months' postpartum, blood was drawn to assess maternal OT levels, and mother-infant interaction was coded for maternal sensitivity, intrusiveness, remoteness, and depressiveness. Clinical mothers exhibited less sensitive, more intrusive, and more depressive interactive behaviors than did community mothers. The groups did not differ in OT levels. Mothers with higher OT levels were less intrusive with their infants. Higher OT levels were associated with less depressive interactive behavior only in clinical mothers. OT was associated with positive interactive behaviors in both groups. In clinical mothers, the calming and soothing effects of OT may promote more relaxed, energetic, and infant-focused interactive behaviors. PMID- 26112437 TI - Synthesis and evaluation of pyrrolotriazine based molecules as PI3 kinase inhibitors. AB - Over activation of the PI3K/Akt/mTOR pathway is found in most cancer tumor types. Controlled regulation of this pathway using PI3K inhibitors can provide therapeutic significance in cancer treatment. Herein, we report the synthesis and evaluation of pyrrolotriazine based novel small molecules as pan-PI3K inhibitors. The SAR studies based on in vitro potency along with microsomal metabolic stability screening, identified 18 as a preclinical lead found to be suitable for in vivo evaluation. The identified lead was also found to be a selective inhibitor of PI3K isoforms and mTOR when screened across a panel of 23 homologous kinases. PMID- 26112438 TI - Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators. AB - This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R) 19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia. PMID- 26112439 TI - Sustained inhibition of the NaV1.7 sodium channel by engineered dimers of the domain II binding peptide GpTx-1. AB - Many efforts are underway to develop selective inhibitors of the voltage-gated sodium channel NaV1.7 as new analgesics. Thus far, however, in vitro selectivity has proved difficult for small molecules, and peptides generally lack appropriate pharmacokinetic properties. We previously identified the NaV1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity via structure-guided analoging. To further understand GpTx-1 binding to NaV1.7, we have mapped the binding site to transmembrane segments 1-4 of the second pseudosubunit internal repeat (commonly referred to as Site 4) using NaV1.5/NaV1.7 chimeric protein constructs. We also report that select GpTx-1 amino acid residues apparently not contacting NaV1.7 can be derivatized with a hydrophilic polymer without adversely affecting peptide potency. Homodimerization of GpTx-1 with a bifunctional polyethylene glycol (PEG) linker resulted in a compound with increased potency and a significantly reduced off-rate, demonstrating the ability to modulate the function and properties of GpTx-1 by linking to additional molecules. PMID- 26112440 TI - Structure-activity relationship of N-benzenesulfonyl matrinic acid derivatives as a novel class of coxsackievirus B3 inhibitors. AB - A novel series of N-benzenesulfonyl matrinic amine/amide and matrinic methyl ether analogues were designed, synthesized and evaluated for their in vitro anti coxsackievirus B3 (CVB3) activities. The structure-activity relationship (SAR) studies revealed that introduction of a suitable amide substituent on position 4' could greatly enhance the antivirus potency. Compared to the lead compounds, the newly synthesized matrinic amide derivatives 21c-d and 21j exhibited stronger anti-CVB3 activities with lower micromolar IC50 from 2.5 MUM to 2.7 MUM, and better therapeutic properties with improved selectivity index (SI) from 63 to 67. The SAR results provided powerful information for further strategic optimization, and these top compounds were selected for the next evaluation as novel enterovirus inhibitors. PMID- 26112441 TI - An efficient approach for conversion of 5-substituted 2-thiouridines built in RNA oligomers into corresponding desulfured 4-pyrimidinone products. AB - An efficient approach for the desulfuration of C5-substituted 2-thiouridines (R5S2U) bound in the RNA chain exclusively to 4-pyrimidinone nucleoside (R5H2U) containing RNA products is proposed. This post-synthetic transformation avoids the preparation of a suitably protected H2U phosphoramidite, which otherwise would be necessary for solid-phase synthesis of the modified RNA. Optimization of the desulfuration, which included reaction stoichiometry, time and temperature, allowed to transform a set of ten R5S2U-RNAs into their R5H2U-RNA congeners in ca. 90% yield. PMID- 26112442 TI - Synthesis and biological evaluation of 3,5-disubstituted-4-alkynylisoxozales as a novel class of HSP90 inhibitors. AB - A series of 3,5-disubstitute-4-alkynylisoxazole derivatives were designed and synthesized through palladium(II)-copper(I) catalyzed Sonogashira cross-coupling reaction of an alkynyl moiety and an isoxazole scaffold as novel HSP90 inhibitors. The resultant compounds displayed moderate to potent binding affinity to HSP90 proteins, and also demonstrated good cell growth inhibitory activity against various cancer cell lines (A549, K562, MCF-7, DU145 and Hela). Some compounds (18d, 18e, 19a, 19d, 20c and 20q) show similar or better binding affinity towards HSP90alpha and HSP90beta comparing to NVP-AUY922. In addition, compounds 18e, 19a and 20q exhibited potent inhibitory activity against various human cancer cell lines. PMID- 26112443 TI - Design, synthesis and evaluation of MCH receptor 1 antagonists--Part I: Optimization of HTS hits towards an in vivo efficacious tool compound BI 414. AB - Despite recent approvals of anti-obesity drugs there is still a high therapeutic need for alternative options with higher efficacy in humans. As part of our MCH R1 antagonist program for the treatment of obesity, a series of biphenylacetamide HTS hits was evaluated. Several issues of the initial lead structures had to be resolved, such as potency, selectivity over related GPCRs and P-gp efflux limiting brain exposure in this series. We could demonstrate that all parameters can be significantly improved by structural modifications resulting in BI 414 as a potent and orally available MCH-R1 antagonist tool compound with acceptable in vivo efficacy in an animal model of obesity. PMID- 26112444 TI - The structural use of carbostyril in physiologically active substances. AB - Carbostyril (2-quinolinone, 2-quinolone) is an important structural component frequently used in natural products and in physiologically active substances including drugs. It is a 2-ring condensed heterocyclic compound containing several positions that can be replaced by arbitrary substituent groups and is used as a chemical building block, scaffold, fragment, and pharmacophore in drug design or discovery. Since the number of compounds that can be designed using carbostyril is exceedingly large, the steric structures of carbostyril derivatives can be adjusted to the unique, spatially oriented shape of, for example, the active sites of pharmaceutical target molecules. Moreover, the internal amide of the carbostyril unit exhibits distinctive features because of the fixed cis form of the lactam amide group. Because carbostyril has been used as a component in drugs and other bioactive compounds over time, carbostyril derivatives may improve absorption, distribution, metabolism, excretion, and toxicity (ADMET). Therefore, carbostyril derivatives have enormous potential. In this review, the potential and advantages of the use of carbostyril and its related molecular skeletons, such as 3,4-dihydrocarbostyril, are discussed by focusing on the physiologically active substances in which they are incorporated. PMID- 26112445 TI - Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors. AB - New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2 b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Depending on the functionalities and the size of these bicyclic head groups, potent inhibitors of RON tyrosine kinase with various level of selectivity against c-Met tyrosine kinase were obtained. PMID- 26112447 TI - Susceptibility to schizophrenia and insertion/deletion polymorphism in intron 3 of the XRCC4 gene. PMID- 26112446 TI - Ionic derivatives of betulinic acid exhibit antiviral activity against herpes simplex virus type-2 (HSV-2), but not HIV-1 reverse transcriptase. AB - Betulinic acid (1) has been modified to ionic derivatives (2-5) to improve its water solubility and biological activities. The binding properties of these derivatives with respect to human serum albumin (HSA) was examined and found to be similar to current anti-HIV drugs. These compounds did not inhibit HIV reverse transcriptase, however, 1, 2 and 5 inhibited herpes simplex type 2 (HSV-2) replication at concentrations similar to those reported for acyclovir (IC50 ~ 0.1 10 MUM) and with minimal cellular cytotoxicity. IC50 values for antiviral activity against HSV-2 186 were 1.6, 0.6, 0.9, 7.2, and 0.9 MUM for compounds 1 5, respectively. PMID- 26112448 TI - Dissociation and hallucinations in dyads engaged through interpersonal gazing. AB - Interpersonal gazing in dyads, when the two individuals in the dyad stare at each other in the eyes, is investigated in 20 healthy young individuals at low illumination for 10-min. Results indicate dissociative symptoms, dysmorphic face perceptions, and hallucination-like strange-face apparitions. Dissociative symptoms and face dysmorphia were correlated. Strange-face apparitions were non correlated with dissociation and dysmorphia. These results indicate that dissociative symptoms and hallucinatory phenomena during interpersonal-gazing under low illumination can involve different processes. Strange-face apparitions may characterize the rebound to "reality" (perceptual reality caused by external stimulus and hallucinatory reality caused by internal input) from a dissociative state induced by sensory deprivation. These phenomena may explain psychodynamic projections of the subject's unconscious meanings into the other's face. The results indicate that interpersonal gazing in dyads can be an effective tool for studying experimentally-induced dissociative symptoms and hallucinatory-like apparitions. PMID- 26112449 TI - Postcard intervention for depression in community-dwelling older adults: A randomised controlled trial. AB - Depression in older adults erodes their health, quality of life and the economy. Existing interventions are not feasible for broad application at the community. Postcard intervention only requires a few resources, and previous studies have shown its effectiveness for patients following drug overdose, self-harm and hospitalisation for major depression. The purpose of the present study is to evaluate the effectiveness of a postcard intervention. Participants were community-dwelling individuals, aged 65 or older, who eat meals alone and with the score of 4 or higher on the 15-item Geriatric Depression Scale (GDS-15). We enrolled 184 eligible participants, with 93 in the intervention and 91 in the control arm. Postcards were sent to participants once a month for eight months. Primary outcome was the GDS-15 score at post-intervention. Secondary outcomes were quality of life and activities of daily living. There was no significant difference in primary and secondary outcomes between completers of the intervention and the control arm. However, most of the participants who received intervention thought the intervention was effective. The postcard intervention for depression in community-dwelling elderly people in Japan is neither feasible nor effective. However, the descriptive results suggest that the intervention may be effective given different parameters. PMID- 26112450 TI - Patients with Gilles de la Tourette syndrome have widespread personality differences. AB - Only little is known about pathological personality traits in patients with Gilles de la Tourette syndrome (GTS). The aim of this study was to further investigate the prevalence of personality traits in adults with GTS. We used a variety of rating scales to assess not only personality traits, but also severity of tics, quality of life, and comorbidities (obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), depression), in a large group (n=50) of patients. Our major finding was that pathological personality traits are very common in patients with GTS encompassing a wide range of different personality traits, but most typically personality traits related to cluster C. Demand-anxious was the most common personality trait, while histrionic personality trait was absent. Patients' quality of life was more impaired by personality traits than comorbidities. Personality traits were more common in patients with comorbid OCD and depression, while comorbid ADHD had no influence. Our findings, therefore, corroborate the hypothesis that GTS plus OCD represents a more severe subtype of GTS, and support the assumption that OCD and depression, but not ADHD, are part of the GTS spectrum. PMID- 26112451 TI - Cytomorphometric and Morphological Analysis in Women with Trichomonas vaginalis Infection: Micronucleus Frequency in Exfoliated Cervical Epithelial Cells. AB - OBJECTIVES: The aim of this study was to explore the cytomorphometric and morphological effects of Trichomonas vaginalis in exfoliated epithelial cells. STUDY DESIGN: Ninety-six Pap-stained cervical smears were divided into a study group and two control groups as follows: T. vaginalis cases, a first control group with inflammation, and a second control group without inflammation. Micronucleated, binucleated, karyorrhectic, karyolytic, and karyopyknotic cells and cells with perinuclear halos per 1,000 epithelial cells were counted. Nuclear and cellular areas were evaluated in 70 clearly defined cells in each smear using image analysis. RESULTS: The frequencies of morphological parameters in the T. vaginalis cases were higher than the values of the two control groups, and the difference among groups was found to be significant (p < 0.05). The nuclear and cytoplasmic areas of epithelial cells were diminished in patients with trichomoniasis. The mean nucleus/cytoplasm ratio in T. vaginalis patients was higher than the value in the control groups, and the difference between the study group and control group 1 was significant. However, there was no statistically significant increase between the study group and control group 2. CONCLUSIONS: T. vaginalis exhibited significant changes in the cellular size and nuclear structure of the cells. The rising frequency of micronuclei, nuclear abnormalities, and changing nucleus/cytoplasm ratio may reflect genotoxic damage in trichomoniasis. PMID- 26112452 TI - PlantOrDB: a genome-wide ortholog database for land plants and green algae. AB - BACKGROUND: Genes with different functions are originally generated from some ancestral genes by gene duplication, mutation and functional recombination. It is widely accepted that orthologs are homologous genes evolved from speciation events while paralogs are homologous genes resulted from gene duplication events.With the rapid increase of genomic data, identifying and distinguishing these genes among different species is becoming an important part of functional genomics research. DESCRIPTION: Using 35 plant and 6 green algal genomes from Phytozome v9, we clustered 1,291,670 peptide sequences into 49,355 homologous gene families in terms of sequence similarity. For each gene family, we have generated a peptide sequence alignment and phylogenetic tree, and identified the speciation/duplication events for every node within the tree. For each node, we also identified and highlighted diagnostic characters that facilitate appropriate addition of a new query sequence into the existing phylogenetic tree and sequence alignment of its best matched gene family. Based on a desired species or subgroup of all species, users can view the phylogenetic tree, sequence alignment and diagnostic characters for a given gene family selectively. PlantOrDB not only allows users to identify orthologs or paralogs from phylogenetic trees, but also provides all orthologs that are built using Reciprocal Best Hit (RBH) pairwise alignment method. Users can upload their own sequences to find the best matched gene families, and visualize their query sequences within the relevant phylogenetic trees and sequence alignments. CONCLUSION: PlantOrDB ( http://bioinfolab.miamioh.edu/plantordb ) is a genome-wide ortholog database for land plants and green algae. PlantOrDB offers highly interactive visualization, accurate query classification and powerful search functions useful for functional genomic research. PMID- 26112453 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the Role of Somatostatin analogs: A Case Series. AB - OBJECTIVES: DIPNECH is a rare pre-neoplastic condition that often presents with a variety of non-specific pulmonary symptoms and sometimes seen in conjunction with pulmonary carcinoid tumors. There are very limited data on use of somatostatin analogs in patients with DIPNECH. We review the long-term outcomes of somatostatin analog therapy with regard to symptom control in patients with DIPNECH. MATERIALS/METHODS: Retrospective study out of our extensive registry of over 2000 neuroendocrine tumors identifies 184 pulmonary neuroendocrine tumors. Out of this, there were five histopathologically confirmed cases of DIPNECH. Appropriate institutional review board permission was taken for this analysis. RESULTS: All 5 patients were females, with a mean age at diagnosis was 65.5 years. Follow-up period includes 1-5 years. Cough was the presenting complaint in all five patients described as mostly dry, except for one patient who had productive early morning cough. Other symptoms seen in one of our patients included wheezing, flushing, and fluctuating blood pressure. No one reported weight loss, hemoptysis, and shortness of breath. One of our patients had a benign thyroid nodule and two patients had previous history of breast cancer. All five of our patients were histopathologically diagnosed by lung biopsy. 4 out of 5 patients were started on a somatostatin analog. All four patients reported drastic improvement in cough. One patient reported mild abdominal discomfort and diarrhea as side effects but remained on treatment. CONCLUSIONS: From our single institution review of neuroendocrine pulmonary tumor cases, we found only five cases of DIPNECH, which reaffirms rare nature of the pathology. It primarily affects females over 60 years with dry cough as the most common presenting symptom. Most of our patients responded to treatment with a somatostatin analog and had significant improvement in their presenting symptoms. Somatostatin analogs were well tolerated resulting in significant resolution of presenting symptoms in most of our patients. Further research is needed; however, a trial of somatostatin analogs should be considered in the treatment of patients with DIPNECH with responders being treated long term. PMID- 26112454 TI - Patients' experiences of changes in health complaints before, during, and after removal of dental amalgam. AB - In this article, we explore how patients with health complaints attributed to dental amalgam experienced and gave meaning to changes in health complaints before, during, and after removal of all amalgam fillings. We conducted semistructured qualitative interviews with 12 participants from the treatment group in a Norwegian amalgam removal trial. Interviews took place within a couple months of the final follow-up 5 years after amalgam removal. Using the NVivo9 software, we conducted an explorative and reflective thematic analysis and identified the following themes: Something is not working: betrayed by the body, You are out there on your own, Not being sure of the importance of amalgam removal, The relief experienced after amalgam removal, and To accept, to give up, or to continue the search. We discuss the findings in the context of patients' assigning meaning to illness experiences. PMID- 26112455 TI - Improving nurse practitioners' competence with genetics: Effectiveness of an online course. AB - PURPOSE: The purpose of this study was to assess the effectiveness of an online genetics course for improving nurse practitioners' knowledge, competence, and comfort with genetic principles and their application to clinical practice. DATA SOURCES: A genetics knowledge test and survey were administered to 232 nurse practitioner students, between 2011 and 2013, before and after completing a 15 week online genetics course taught by a multidisciplinary team of instructors at a private east coast U.S. university. The 65-item survey allowed participants to rate competence regarding genetic principles, diseases, and terminology, as well as comfort performing various clinical tasks related to genetics. The 21-item knowledge test contained multiple choice questions regarding core competencies in genetics. Paired t-tests were used to compare mean pre- and postscores. CONCLUSIONS: Participants significantly increased postcourse knowledge (p < .001) and comfort with genetic core competencies and clinical skills related to genetics (p < .001). This study demonstrates the effectiveness of an online genetics course for increasing nurse practitioners' knowledge, competence, and confidence with genetics and identifies specific topics educators should consider when designing curricula for nurse practitioners. IMPLICATIONS FOR PRACTICE: Findings from this study can improve genetics education for nurse practitioners, which will in turn improve patient health. PMID- 26112457 TI - In Focus: Plasma Medicine. PMID- 26112458 TI - Aggressive thyroid cancer: targeted therapy with sorafenib. AB - Sorafenib (Nexavar), is a multikinase inhibitor, which has demonstrated both antiproliferative and antiangiogenic properties in vitro and in vivo, inhibiting the activity of targets present in the tumoral cells (c-RAF [proto-oncogene serine/threonine-protein kinase], BRAF, (V600E)BRAF, c-KIT, and FMS-like tyrosine kinase 3) and in tumor vessels (c-RAF, vascular endothelial growth factor receptor [VEGFR]-2, VEGFR-3, and platelet-derived growth factor receptor beta). Sorafenib was initially approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma. Experimental studies have demonstrated that sorafenib has both antiproliferative and antiangiogenic properties in vitro and in vivo, against thyroid cancer cells. Furthermore, several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of sorafenib in patients with papillary, follicular and medullary aggressive thyroid cancer. The results of the different studies showed good clinical responses and stabilization of the disease and suggested that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies (such as radioiodine). Currently, USA Food and Drug Administration has approved the use of sorafenib for metastatic differentiated thyroid cancer. PMID- 26112459 TI - Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer. AB - Breast cancer is the most common cancer among females. Approximately 30% of cancer patients develop depression or depressive adaptation disorder within 5 years post diagnosis. Low grade inflammation and subsequent changes in neurotransmitter levels could be the pathophysiological link. In the current study we investigated the association of neurotransmitter precursor amino acids with a diagnosis of depression or state anxiety in 154 subjects suffering from breast cancer (BCA(+)), depression (DPR(+)), both or neither. Sociodemographic parameters, severity of depressive symptoms, and state anxiety (ANX) were recorded. Neopterin, kynurenine/tryptophan and phenylalanine/tyrosine were analysed by HPLC or ELISA. Significantly higher serum neopterin values were found in DPR(+) patients (p = 0.034) and in ANX(+) subjects (p = 0.008), as a marker of Th1-related inflammation. The phenylalanine/tyrosine ratio (index of the catecholamine pathway) was associated with the factors "breast cancer" and "depression" and their interaction (all p < 0.001); it was highest in the DPR(+)BCA(+) group. The kynurenine/tryptophan ratio (index of the serotonin pathway) was significantly associated with the factors "breast cancer" and "state anxiety" and their interaction (p < 0.001, p = 0.026, p = 0.02, respectively); it was highest in the ANX(+)BCA(+) group. In BCA(+) patients kynurenine/tryptophan ratios correlated with severity of state anxiety (r = 0.226, p = 0.048, uncorrected) and phenylalanine/tyrosine ratios with severity of depressive symptoms (r = 0.376, p < 0.05, corrected). In conclusion, levels of neurotransmitter precursor amino acids correlate with mental health, an effect which was much more pronounced in BCA(+) patients than in BCA(-) subjects. Aside from identifying underlying pathophysiological mechanisms, these results could be the basis for future treatment studies: in BCA(+) patients with depression the use of serotonin-noradrenaline reuptake inhibitors might be recommended while in those with predominant anxiety selective serotonin reuptake inhibitors might be the treatment of choice. PMID- 26112460 TI - Reasons Why Eligible Candidates Decline Left Ventricular Assist Device Placement. AB - BACKGROUND: A greater understanding of how beliefs and perceptions inform LVAD placement refusals can help ensure that standards for informed decision making are met. We report on the factors that influence refusal and what accounts for changes in decliners' decision-making process when, and if, that occurs. METHOD AND RESULTS: We identified candidates (8 bridge to transplant; 6 destination therapy, 7 without designation) who declined LVAD placement (n = 21), 11 of whom were identified prospectively from February 2014 to March 2015, and 10 of whom were identified retrospectively with the use of our program database. Of these 21 decliners, 11 candidates persistently declined LVAD placement, with a median time of 175 days elapsing between time of LVAD offer and March 4, 2015. Ten candidates declined for an average of 224 days before agreeing to LVAD placement. From March 2014 to March 2015, we conducted structured interviews with LVAD decliners. Interviews were audio recorded, transcribed verbatim, and analyzed quantitatively with the use of Atlas.ti. The findings reflect that refusal can evolve over time. Decliners report that their initial refusals were made reflexively, but the 10 decliners who ultimately opted for LVAD placement changed their decisions as symptoms worsened. Decliners have concerns about the impacts of LVAD treatment on mobility, and they distrust LVAD technology. Some decliners believe LVAD placement would affect their ability to receive a transplant. Finally, decliners believe that they are not sick enough for LVAD placement when they are stabilized with medical management. CONCLUSIONS: Decliners' perspectives are integral for improving informed consent and refusal processes. Our analysis revealed decliners' decision-making processes and factors influencing their decisions. We provide several clinically based practical recommendations based on our findings. PMID- 26112461 TI - Functions of plants long non-coding RNAs. AB - Long non-coding RNAs (lncRNAs) have been emerged as important players for various biological pathways, including dosage compensation, genomic imprinting, chromatin regulation, alternative splicing and nuclear organization. A large number of lncRNAs had already been identified by different approaches in plants, while the functions of only a few of them have been investigated. This review will summarize our current understanding of a wide range of plant lncRNAs functions, and highlight their roles in the regulation of diverse pathways in plants. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26112462 TI - Local field potentials are local events in the mouse auditory cortex. AB - Local field potentials (LFPs) and spikes (SPKs) sampled at the thalamocortical recipient layers represent the inputs from the thalamus and outputs to other layers. Previous studies have shown that SPK-constructed receptive fields (RFSPK) of cortical neurons are much smaller than LFP-constructed RFs (RFLFP). The difference in cortical RFLFP and RFSPK is therefore a plausible indication of local networking. The presence of a boarder RFLFP appears due to contamination, to some degree, from remote sites. Our studies of the mouse primary auditory cortex show that the best frequencies and minimum thresholds of RFSPK and RFLFP were similar. We also observed that the RFLFP area was only slightly larger than the RFSPK area, a very different finding from previous reports. The bandwidth of RFLFP was slightly broader than that of RFSPK at all levels. These data do not support the explanation that bioelectrical signals from distant sites impact on cortical LFP through volume conduction. That the cortical LFP represents a local event is further supported by comparisons of RFSPK and RFLFP after cortical inhibition by muscimol and cortical disinhibition by bicuculine. We conclude that the difference between RFSPK (output of cortical neurons) and RFLFP (input of cortical neurons) results from intracortical processing, including cortical lateral inhibition and excitation. PMID- 26112463 TI - DOTAP/DOPE ratio and cell type determine transfection efficiency with DOTAP liposomes. AB - The effects of lipid compositions on their physicochemical properties and transfection efficiencies were investigated. Four liposome formulations with different 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP) to dioleoylphosphatidylethanolamine (DOPE) weight ratios were investigated, that is, weight ratios 1:0 (T1P0), 3:1 (T3P1), 1:1 (T1P1), and 1:3 (T1P3). Mean sizes of liposomes were influenced by their lipid composition and the preparation concentration at the time of sonication. Zeta potentials of liposomes were inversely correlated with their liposome sizes. However, neither liposome sizes nor zeta potentials were correlated with transfection efficiency. The optimum composition of liposomes was cell-line dependent (T1P0 and T3P1 for Huh7 and AGS, T3P1 and T1P1 for COS7, and T1P1 and T1P3 for A549). The shape of lipoplexes was changed from lamellar to inverted hexagonal structure according to the increased ratio of DOPE, but there was no definite advantage of specific structure in transfection efficiency throughout all used cell lines. However, cellular internalization was consistently faster in T1P0, T3P1, T1P1 compared to T1P3 in all cell lines, suggesting the importance of endosomal escape. Our findings show that the transfection efficiency of DOTAP liposomes is mainly influenced by lipid composition and cell type, and not by size or zeta potential. PMID- 26112464 TI - Diffuse, non-polar electropermeabilization and reduced propidium uptake distinguish the effect of nanosecond electric pulses. AB - Ca2+ activation and membrane electroporation by 10-ns and 4-ms electric pulses (nsEP and msEP) were compared in rat embryonic cardiomyocytes. The lowest electric field which triggered Ca2+ transients was expectedly higher for nsEP (36 kV/cm) than for msEP (0.09 kV/cm) but the respective doses were similar (190 and 460 mJ/g). At higher intensities, both stimuli triggered prolonged firing in quiescent cells. An increase of basal Ca2+ level by >10 nM in cells with blocked voltage-gated Ca2+ channels and depleted Ca2+ depot occurred at 63 kV/cm (nsEP) or 0.14 kV/cm (msEP) and was regarded as electroporation threshold. These electric field values were at 150-230% of stimulation thresholds for both msEP and nsEP, notwithstanding a 400,000-fold difference in pulse duration. For comparable levels of electroporative Ca2+ uptake, msEP caused at least 10-fold greater uptake of propidium than nsEP, suggesting increased yield of larger pores. Electroporation by msEP started Ca2+ entry abruptly and locally at the electrode-facing poles of cell, followed by a slow diffusion to the center. In a stark contrast, nsEP evoked a "supra-electroporation" pattern of slower but spatially uniform Ca2+ entry. Thus nsEP and msEP had comparable dose efficiency, but differed profoundly in the size and localization of electropores. PMID- 26112465 TI - GLUT2 and TAS1R2 Polymorphisms and Susceptibility to Dental Caries. AB - OBJECTIVE: Dental caries is one of the most frequent multifactorial diseases. Among the numerous factors influencing the risk of caries, genetics plays a substantial role, with heritability ranging from 40 to 60%. Gene variants affecting taste preference and glucose transport were recently associated with caries risk. The aim of this study was to analyze two common polymorphisms in the sweet taste receptor (TAS1R2) and glucose transporter (GLUT2) genes in children with dental caries and healthy controls in the Czech population. METHODS: A total of 637 unrelated Caucasian children, aged 11-13 years, were included in this case control study. One hundred and fifty-five subjects were caries-free (with decayed/missing/filled teeth, DMFT = 0) and 482 children were caries-affected (DMFT >= 1). The TAS1R2 (Ile191Val, rs35874116) and GLUT2 (Thr110Ile, rs5400) genotypes were determined using the 5' nuclease TaqMan(r) assay for allelic discrimination. RESULTS: Compared with subjects with the common Thr allele, carriers of the Ile allele of GLUT2 had significantly more frequently dental caries (p < 0.05, OR = 1.639, 95% CI: 1.089-2.466). Similarly, children with the Val allele for the TAS1R2 Ile191Val polymorphism were more frequently affected by caries than children who carried the Ile allele (p < 0.05, OR = 1.413, 95% CI: 1.014-1.969). In contrast, no significant associations between GLUT2 and/or TAS1R2 polymorphisms and fillings were found, but allele frequencies of the TAS1R2 variant were marginally significantly different between children with DMFT = 0 and DMFT >=1 (p = 0.053, OR = 1.339, 95% CI: 0.996-1.799). However, no significant interaction between both genes and risk of dental caries was found. CONCLUSIONS: In conclusion, GLUT2 and TASR1 polymorphisms may influence the risk of caries in the Czech population. PMID- 26112467 TI - The 2- and 8-week effects of decompressive brace use in people with medial compartment knee osteoarthritis. AB - BACKGROUND: Knee osteoarthritis is a prevalent disease. Unloading the affected compartment using a brace is a treatment option. OBJECTIVES: To determine whether a decompressive knee brace alters loading in medial knee osteoarthritis following 2 and 8 weeks of use. STUDY DESIGN: Within subjects; pre- and post-testing. METHODS: A total of 15 individuals with medial knee osteoarthritis attended four sessions: baseline, fitting, 2 weeks after fitting (post), and 8 weeks after fitting (final). A gait analysis was performed at baseline (without knee brace), post and final. Knee adduction impulse, first and second peak knee adduction moment, knee motion, and walking velocity were calculated. Participants also recorded hours and steps taken while wearing the brace. RESULTS: On average, the brace was worn for more than 6 h/day. Through use of repeated-measures analysis of variance, it was determined that the knee adduction impulse and second peak knee adduction moment were reduced (p < 0.05) at post and final compared to baseline (36% and 34% reduction in knee adduction impulse, 26% reduction in second peak knee adduction moment for post and final, respectively). Furthermore, participants walked faster with increased knee motion during stance. CONCLUSION: The studied decompressive brace was effective in reducing potentially detrimental forces at the knee-knee adduction impulse and second peak knee adduction moment during the stance phase of gait. CLINICAL RELEVANCE: The data from this study suggest that use of a medial unloading brace can reduce potentially detrimental adduction moments at the knee. Clinicians should use this evidence to advocate for use of this noninvasive treatment for people presenting with medial knee osteoarthritis. PMID- 26112466 TI - Bee venom ameliorates lipopolysaccharide-induced memory loss by preventing NF kappaB pathway. AB - BACKGROUND: Accumulation of beta-amyloid and neuroinflammation trigger Alzheimer's disease. We previously found that lipopolysaccharide (LPS) caused neuroinflammation with concomitant accumulation of beta-amyloid peptides leading to memory loss. A variety of anti-inflammatory compounds inhibiting nuclear factor kappaB (NF-kappaB) activation have showed efficacy to hinder neuroinflammation and amyloidogenesis. We also found that bee venom (BV) inhibits NF-kappaB. METHODS: A mouse model of LPS-induced memory loss used administration of BV (0.8 and 1.6 MUg/kg/day, i.p.) to ICR mice for 7 days before injection of LPS (2.5 mg/kg/day, i.p.). Memory loss was assessed using a Morris water maze test and passive avoidance test. For in vitro study, we treated BV (0.5, 1, and 2 MUg/mL) to astrocytes and microglial BV-2 cells with LPS (1 MUg/mL). RESULTS: We found that BV inhibited LPS-induced memory loss determined by behavioral tests as well as cell death. BV also inhibited LPS-induced increases in the level of beta amyloid (Abeta), beta-and gamma-secretases activities, NF-kappaB and its DNA binding activity and expression of APP, and BACE1 and neuroinflammation proteins (COX-2, iNOS, GFAP and IBA-1) in the brain and cultured cells. In addition, pull down assay and molecular modeling showed that BV binds to NF-kappaB. CONCLUSIONS: BV attenuates LPS-induced amyloidogenesis, neuroinflammation, and therefore memory loss via inhibiting NF-kappaB signaling pathway. Thus, BV could be useful for treatment of Alzheimer's disease. PMID- 26112470 TI - Benchmarking Transcriptome Quantification Methods for Duplicated Genes in Xenopus laevis. AB - Xenopus is an important model organism for the study of genome duplication in vertebrates. With the full genome sequence of diploid Xenopus tropicalis available, and that of allotetraploid X. laevis close to being finished, we will be able to expand our understanding of how duplicated genes have evolved. One of the key features in the study of the functional consequence of gene duplication is how their expression patterns vary across different conditions, and RNA-seq seems to have enough resolution to discriminate the expression of highly similar duplicated genes. However, most of the current RNA-seq analysis methods were not designed to study samples with duplicate genes such as in X. laevis. Here, various computational methods to quantify gene expression in RNA-seq data were evaluated, using 2 independent X. laevis egg RNA-seq datasets and 2 reference databases for duplicated genes. The fact that RNA-seq can measure expression levels of similar duplicated genes was confirmed, but long paired-end reads are more informative than short single-end reads to discriminate duplicated genes. Also, it was found that bowtie, one of the most popular mappers in RNA-seq analysis, reports significantly smaller numbers of unique hits according to a mapping quality score compared to other mappers tested (BWA, GSNAP, STAR). Calculated from unique hits based on a mapping quality score, both expression levels and the expression ratio of duplicated genes can be estimated consistently among biological replicates, demonstrating that this method can successfully discriminate the expression of each copy of a duplicated gene pair. This comprehensive evaluation will be a useful guideline for studying gene expression of organisms with genome duplication using RNA-seq in the future. PMID- 26112468 TI - A systematic review of the effect of foot orthoses and shoe characteristics on balance in healthy older subjects. AB - BACKGROUND: Foot orthoses are used to optimize lower extremity function and can improve postural stability by enhancing the afferent somatosensory feedback available to the central nervous system. OBJECTIVE: The aim of this review was to evaluate the effect of foot orthoses on balance control in older subjects. STUDY DESIGN: Systematic review. METHODS: The search strategy was based on the Population Intervention Comparison Outcome method. A search was performed in PubMed, Science Direct, Google Scholar, and ISI Web of Knowledge databases by using selected keywords. A total of 22 articles were selected for final evaluation. RESULTS: The results demonstrated that older people should be advised to wear thin, hard-soled footwear with high collars to reduce the risk of falling. The findings for insoles demonstrated an increase in balance control via vibratory or magnetic insoles, but textured insoles do not appear to be beneficial for balance improvement. CONCLUSION: Foot orthoses improve postural stability via a somatosensory or biomechanical effect. Use of footwear with the proper features can be an appropriate intervention in order to increase the balance in the older population and reduce falls. CLINICAL RELEVANCE: Loss of balance is an important factor in increasing the risk of falling in older subjects. Foot orthoses can improve functional measures of stability in older adults. In this review, results from studies suggest a number of recommendations regarding the optimal footwear for older people to reduce the risk of falling. PMID- 26112471 TI - Streptozotocin diabetic mice display depressive-like behavior and alterations in the structure, neurotransmission and plasticity of medial prefrontal cortex interneurons. AB - Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes. PMID- 26112472 TI - The Relationship between Prenatal Antidepressant Use and the Decision to Breastfeed among Women Enrolled in a Randomized Exercise Intervention Trial. AB - BACKGROUND: Despite the numerous health benefits associated with breastfeeding, only 49% of postpartum women in the United States breastfeed at 6 months. Therefore, it is important to understand factors that may influence a woman's decision to breastfeed. OBJECTIVE: The purpose of this study was to examine the relationship between prenatal antidepressant use and the decision to breastfeed among postpartum women. METHODS: Participants were postpartum women (N = 87) who had participated in a randomized trial examining the efficacy of a 6-month exercise intervention for the prevention of postpartum depression (2009-2012). Participants were recruited from the upper Midwest and were at risk for postpartum depression. Participants completed telephone-based questionnaires assessing their prenatal antidepressant use and breastfeeding behavior. RESULTS: Seventeen percent of the participants took an antidepressant medication during pregnancy and 91% breastfed at birth. After controlling for baseline depressive symptoms, body mass index, and condition assignment, participants who were taking an antidepressant during pregnancy were less likely to initiate breastfeeding than participants who were not taking an antidepressant during pregnancy, beta = 2.042, P < .05 (odds ratio = 0.130; 95% confidence interval, 0.024-0.696). CONCLUSION: Our study indicates that prenatal antidepressant medication use may be a potential barrier to breastfeeding initiation. Additional research is needed to better understand the factors that play a role in the relationship between prenatal antidepressant use and breastfeeding initiation. PMID- 26112473 TI - "#discrimination": The Online Response to a Case of a Breastfeeding Mother Being Ejected from a UK Retail Premises. AB - BACKGROUND: Stigma is a significant barrier to breastfeeding. Internationally, mothers have reported stigma surrounding public breastfeeding. In the United Kingdom, the Equality Act 2010 gives women the right to breastfeed in public, including within private businesses. In April 2014, a woman who was breastfeeding in a UK sports shop was asked to leave, resulting in a localized protest by breastfeeding mothers. This resulted in the issue of public breastfeeding being highlighted in local, national, and social media. OBJECTIVE: To examine online opinion regarding breastfeeding in public and protesting about the right to breastfeed in public within the context of a single case. METHODS: Online user generated content relating to the case of Wioletta Komar was downloaded from Twitter and the comments section of a UK online news source, Mail Online. Data comprised 884 comments and 1210 tweets, collected within 24 hours of the incident. Semiotic and thematic analysis was facilitated by NVivo 10. RESULTS: Comments from Twitter were supportive (76%) or neutral (22%) regarding the protesting women and public breastfeeding. Conversely, Mail Online comments were mostly negative (85%). Mail Online posters questioned the legality of public breastfeeding, while Twitter comments acknowledged and supported women's legal right to breastfeed publicly. Many Mail Online commenters stated that they found it uncomfortable to watch breastfeeding or thought it was unnecessary to breastfeed in public. CONCLUSION: If the UK government is serious about increasing breastfeeding, interventions to promote public support for public breastfeeding are urgently required. PMID- 26112474 TI - Hyperbolic phonon-polaritons in boron nitride for near-field optical imaging and focusing. AB - Hyperbolic materials exhibit sub-diffractional, highly directional, volume confined polariton modes. Here we report that hyperbolic phonon polaritons allow for a flat slab of hexagonal boron nitride to enable exciting near-field optical applications, including unusual imaging phenomenon (such as an enlarged reconstruction of investigated objects) and sub-diffractional focusing. Both the enlarged imaging and the super-resolution focusing are explained based on the volume-confined, wavelength dependent propagation angle of hyperbolic phonon polaritons. With advanced infrared nanoimaging techniques and state-of-art mid infrared laser sources, we have succeeded in demonstrating and visualizing these unexpected phenomena in both Type I and Type II hyperbolic conditions, with both occurring naturally within hexagonal boron nitride. These efforts have provided a full and intuitive physical picture for the understanding of the role of hyperbolic phonon polaritons in near-field optical imaging, guiding, and focusing applications. PMID- 26112475 TI - Epididymosomes: a heterogeneous population of microvesicles with multiple functions in sperm maturation and storage. AB - Extracellular microvesicles present in the epididymal fluid have been named epididymosomes. Many epididymosome-associated proteins are transferred to spermatozoa during their maturation in the excurrent duct. Epididymosomes are heterogeneous, with their size varying between 50 and 250 nm. Two distinct population of epididymosomes characterized by different protein compositions and diameters have been isolated from the bovine epididymal fluid using different centrifugation protocols. One subpopulation of epididymosomes was characterized by CD9 and other tetraspanin partners. Transfer of proteins from these epididymosomes to maturing spermatozoa in co-incubation experiments was inhibited by antibodies against tetraspanin proteins. This suggests that this subpopulation of epididymosomes is involved in the acquisition of proteins involved in maturation by spermatozoa in the epididymis. The other population of epididymosomes was characterized by ELSPBP1 (epididymal sperm binding protein 1), known for its affinity for the phospholipid choline group. Flow cytometric analyses showed that ELSPBP1-positive epididymosomes only interacted with dying or dead epididymal spermatozoa in a Zn 2 + -dependent manner. BLVRA (biliverdin reductase) was identified as a partner of ELSPBP1. This enzyme reduces biliverdin to bilirubin: two molecules with powerful anti-oxidant properties. We hypothesize that BLVRA is involved in an ROS-scavenging mechanism protecting live epididymal spermatozoa against detrimental molecules (ROS) released by dying cells. Therefore, it appears that there are at least two epididymosome population with distinct functions: targeting specific proteins to transiting spermatozoa by tetraspanin-mediated membrane fusion, and protection of epididymal spermatozoa against ROS released from dying cells. Further work is needed to understand functions of epididymosomes in epididymal physiology and sperm maturation and storage. PMID- 26112476 TI - Long-term recovery of normal sexual function in testicular cancer survivors. AB - Testicular cancer (TC) is the most common solid cancer in men between the third and fourth decade of life. Due to successful treatment approaches, TC survivors (TCSs) have long life expectancy, but with numerous potential long-term sequelae, including sexual dysfunction. We investigated predictors of long-term normal sexual function (SF) recovery in TCSs. Sociodemographic, medical, and psychometric data were analyzed in 143 Caucasian-European TCSs, who underwent orchiectomy at a single institution. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF). Statistical models tested the association between predictors (including age at surgery, body mass index, CCI, and adjuvant therapy: radiotherapy [RT], chemotherapy [CT], CT followed by retroperitoneal lymph node dissection [RPLND] and RPLND alone) and the long-term recovery of normal SF (defined as IIEF-erectile function [EF] >=26, and sexual desire [SD], intercourse satisfaction [IS] orgasmic function [OF], and overall satisfaction [OS] domain scores in the upper tertiles). At a mean follow-up of 86 months, 35 (25.5%) TCSs had erectile dysfunction (ED), with 16 (11.2%) experiencing severe ED. Median time of EF recovery was 60, 60, and 70 months after CT, RT, and RPLND, respectively. Only adjuvant RT emerged as an independent predictor of nonrecovery of normal EF (HR: 0.55, P= 0.01). Neither adjuvant CT nor CT plus RPLND or RPLND alone significantly impaired the recovery of normal erections. Adjuvant therapy was not associated with impaired recovery of normal sexuality as a whole, considering the IIEF-SD, -OF, -IS, and OS domains. PMID- 26112477 TI - Salvage brachytherapy for locally recurrent prostate cancer after external beam radiotherapy. AB - External beam radiotherapy (EBRT) is a standard treatment for prostate cancer. Despite the development of novel radiotherapy techniques such as intensity modulated conformal radiotherapy, the risk of local recurrence after EBRT has not been obviated. Various local treatment options (including salvage prostatectomy, brachytherapy, cryotherapy, and high-intensity focused ultrasound [HIFU]) have been employed in cases of local recurrence after primary EBRT. Brachytherapy is the first-line treatment for low-risk and selected intermediate-risk prostate tumors. However, few studies have examined the use of brachytherapy to treat post EBRT recurrent prostate cancer. The purpose of this paper is to analyze the current state of our knowledge about the effects of salvage brachytherapy in patients who develop locally recurrent prostate cancer after primary EBRT. This article also introduces our novel permanent brachytherapy salvage method. PMID- 26112478 TI - New therapies for relapsed castration-resistant prostate cancer based on peptide analogs of hypothalamic hormones. AB - It is a pleasure to contribute our presentation at the International Prostate Forum of the Annual Meeting of the American Urological Association (AUA) to this special issue of the Asian Journal of Andrology. PMID- 26112480 TI - Implantation of AMS 700 LGX penile prosthesis preserves penile length without the need for penile lengthening procedures. AB - Implantation of an inflatable penile prosthesis (IPP) is a well-established definitive solution for erectile dysfunction when conservative treatments fail. Penile implants may shorten the penis. The AMS 700 LGX IPP is in common use but reports on its mechanical reliability, medium-term postsurgical patient satisfaction, and mean penile length preservation are lacking. We investigate the mean penile length, mechanical reliability, and patient satisfaction at 6 and 12 months after implantation of the AMS 700 LGX. This prospective study consecutively enrolled men undergoing first-time IPP implant surgery from February 2009 to April 2012. Stretched flaccid penile length, penile length at 50% and 100% of stiffness (P50 and P100) and International Index of Erectile Function (IIEF) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores, were measured at 6 and 12 months postsurgery. Of 45 patients who underwent AMS 700 LGX implantation (median age 61 years) and completed 6 months' follow-up, 36 (80%) completed the study. A significant difference in stretched flaccid penile length was seen between 6 and 12 months (P = 0.033). P100 was also significantly increased at 6 and 12 months, with a mean 10% increase (1.3 +/- 0.4 cm) from baseline to 12 months. Differences in mean IIEF scores at 6 and 12 months were significant for the desired domain (P = 0.0001) and for overall satisfaction (P = 0.002); however, mean EDITS scores at 6 and 12 months were not significantly improved. AMS 700 LGX is a powerful tool for preserving penile length in men undergoing penile prosthesis implantation. PMID- 26112479 TI - Hormone naive prostate cancer: predicting and maximizing response intervals. AB - Hormone naive advanced prostate cancer is subdivided into two disease states: biochemical recurrence and traditional M1 (metastatic) prostate cancer and characterized by no prior hormonal therapy or androgen deprivation therapy (ADT). In biochemical recurrence/prostate-specific antigen (PSA) recurrence, men should be risk-stratified based on their PSA doubling time, the Gleason score and the timing of the recurrence. In general, only men who are at high risk should be considered for early/immediate ADT although this is best done using shared decision with the patient. The type of ADT to be used in biochemical recurrence ranging from oral-only peripheral blockade (peripheral androgen deprivation) to complete hormonal therapy (combined androgen blockade [CAB]) remains in debate owing to lack of randomized controlled trials (RCT). However, there is good RCT support for use of intermittent hormonal therapy (IHT). There is also limited research on biomarker response (PSA and testosterone decline) to predict prognosis. On the other hand, in the setting of M1 hormone naive prostate cancer, there are many more RCT's to inform our decisions. CAB and gonadotrophin releasing hormone antagonists perhaps provide a slight efficacy advantage while IHT may be slightly inferior with minimal M1 disease. The PSA nadir at 7 months after starting ADT is a powerful prognostic tool for M1 patients. There is growing recognition that serum testosterone (T) control while on ADT is linked to the development of castrate-resistant prostate cancer. Especially for a M1 patient, maintaining a serum T below 20-30 ng dl-1 prolongs the response to ADT. Novel oral agents (abiraterone and enzalutamide) may soon find use in hormone naive disease and may alter the treatment landscape. Despite over 75 years of experience with ADT, many questions remain, and the field continues to evolve. PMID- 26112481 TI - Epididymosomes: transfer of fertility-modulating proteins to the sperm surface. AB - A variety of glycosylphosphatidylinositol (GPI)-linked proteins are acquired on spermatozoa from epididymal luminal fluids (ELF) during sperm maturation. These proteins serve roles in immunoprotection and in key steps of fertilization such as capacitation, acrosomal exocytosis and sperm-egg interactions. Their acquisition on sperm cells is mediated both by membrane vesicles (epididymosomes, EP) which were first reported to dock on the sperm surface, and by lipid carriers which facilitate the transfer of proteins associated with the membrane-free fraction of ELF. While the nonvesicular fraction is more efficient, both pathways are dependent on hydrophobic interactions between the GPI-anchor and the external lipid layer of the sperm surface. More recently proteomic and hypothesis-driven studies have shown that EP from several mammals carry transmembrane (TM) proteins, including plasma membrane Ca 2 + -ATPase 4 (PMCA4). Synthesized in the testis, PMCA4 is an essential protein and the major Ca 2 + efflux pump in murine spermatozoa. Delivery of PMCA4 to spermatozoa from bovine and mouse EP during epididymal maturation and in vitro suggests that the docking of EP on the sperm surface precedes fusion, and experimental evidence supports a fusogenic mechanism for TM proteins. Fusion is facilitated by CD9, which generates fusion-competent sites on membranes. On the basis of knowledge of PMCA4's interacting partners a number of TM and membrane-associated proteins have been identified or are predicted to be present, in the epididymosomal cargo deliverable to spermatozoa. These Ca 2 + -dependent proteins, undetected in proteomic studies, play essential roles in sperm motility and fertility, and their detection highlights the usefulness of the hypothesis-driven approach. PMID- 26112483 TI - From the epididymis to the egg: participation of CRISP proteins in mammalian fertilization. AB - Mammalian fertilization is a complex process that involves different steps of interaction between the male and female gametes. In spite of its relevance, the molecular mechanisms underlying this process still remain to be elucidated. The present review describes the contribution of our laboratory to the understanding of mammalian fertilization using Cysteine-RIch Secretory Proteins (CRISP) as model molecules. Substantial evidence obtained from in vitro assays and knockout models shows that epididymal CRISP1 associates with the sperm surface with two different affinities during maturation, and participates in the regulation of signaling pathways during capacitation as well as in both sperm-zona pellucida interaction and gamete fusion. These observations can be extended to humans as judged by our findings showing that the human homolog of the rodent protein (hCRISP1) is also involved in both stages of fertilization. Evidence supports that other members of the CRISP family secreted in the testis (CRISP2), epididymis (CRISP3-4) or during ejaculation (CRISP3) are also involved in sperm egg interaction, supporting the existence of a functional redundancy and cooperation between homolog proteins ensuring the success of fertilization. Together, our observations indicate that CRISP proteins accompany spermatozoa along their transit through both the male and female reproductive tracts. We believe these results not only contribute to a better mechanistic understanding of fertilization but also support CRISP proteins as excellent candidates for future research on infertility and contraception. PMID- 26112482 TI - Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice. AB - The development of the Wolffian/epididymal duct is crucial for proper function and, therefore, male fertility. The development of the epididymis is complex; the initial stages form as a transient embryonic kidney; then the mesonephros is formed, which in turn undergoes extensive morphogenesis under the influence of androgens and growth factors. Thus, understanding of its full development requires a wide and multidisciplinary view. This review focuses on mouse models that display abnormalities of the Wolffian duct and mesonephric development, the importance of these mouse models toward understanding male reproductive tract development, and how these models contribute to our understanding of clinical abnormalities in humans such as congenital anomalies of the kidney and urinary tract (CAKUT). PMID- 26112485 TI - Introduction of Dr. Andrew V Schally. PMID- 26112484 TI - Epididymitis: revelations at the convergence of clinical and basic sciences. AB - Acute epididymitis represents a common medical condition in the urological outpatient clinic. Mostly, epididymitis is caused by bacterial ascent through the urogenital tract, with pathogens originating either from sexually transmitted diseases or urinary tract infections. Although conservative antimicrobial therapy is possible in the majority of patients and is usually sufficient to eradicate the pathogen, studies have shown persistent oligozoospermia and azoospermia in up to 40% of these patients. Animal models of epididymitis are created to delineate the underlying reasons for this observation and the additional impairment of sperm function that is often associated with the disease. Accumulated data provide evidence of a differential expression of immune cells, immunoregulatory genes and pathogen-sensing molecules along the length of the epididymal duct. The evidence suggests that a tolerogenic environment exists in the caput epididymidis, but that inflammatory responses are most intense toward the cauda epididymidis. This is consistent with the need to provide protection for the neo antigens of spermatozoa emerging from the testis, without compromising the ability to respond to ascending infections. However, severe inflammatory responses, particularly in the cauda, may lead to collateral damage to the structure and function of the epididymis. Convergence of the clinical observations with appropriate animal studies should lead to better understanding of the immunological environment throughout the epididymis, the parameters underlying susceptibility to epididymitis, and to therapeutic approaches that can mitigate epididymal damage and subsequent fertility problems. PMID- 26112487 TI - External beam radiotherapy for localized prostate cancer. AB - Radiotherapy (XRT) is a curative treatment option for prostate cancer (PCa). Recent XRT technologies allow higher dose therapy that lead to increased local control with less adjacent tissue damage. Additionally, receiving neo-adjuvant or adjuvant hormonotherapy (HT) during radiation therapy increases the curative effect. The aim of this paper is to review the current literature and guidelines on external beam radiation therapy for PCa. However, brachytherapy and radiosurgery, a recently evolving relatively new technology for the radiotherapeutic management of localized PCa, are beyond the scope of this paper. PMID- 26112486 TI - Preventing aggressive prostate cancer with proven cardiovascular disease preventive methods. AB - Cardiovascular disease (CVD) has been the number one cause of death in the U.S. for 114 of the last 115 years. Risk factors for prostate cancer have primarily mirrored risk proven risk factors for CVD, especially aggressive disease. Obesity, dyslipidemia, glucose intolerance, metabolic syndrome, unhealthy dietary habits or caloric excess, lack of physical activity, and inflammation are just some of these shared risk factors. The evidence also suggests proven CVD preventive measures are identical to prostate cancer preventive measures, especially in regard to aggressive disease. Thus, apart from lifestyle measures that can encourage optimal heart and prostate health there are potentially several dietary supplements that need to be avoided in healthy men because they may also increase the risk of prostate cancer. However, there are also several low-cost, generic, safe in the appropriate individuals, and naturally derived agents that could reduce prostate cancer risk, and these can be discussed and remembered utilizing the acronym S.A.M. (statins, aspirin, and/or metformin). PMID- 26112488 TI - Active surveillance monitoring: the role of novel biomarkers and imaging. AB - "CANCER" is a disease state that leads to progressive illness that is uniformly fatal without treatment. Hippocrates invoked the Greek word karkinos, or "crab," to describe tumors he observed. For centuries, "CANCER" remained a disease that was recognized primarily in its locally advanced or metastatic stage, when it was almost uniformly fatal. PMID- 26112490 TI - The International Prostate Forum introduction and history. PMID- 26112489 TI - Risk calculators and updated tools to select and plan a repeat biopsy for prostate cancer detection. AB - Millions of men each year are faced with a clinical suspicion of prostate cancer (PCa) but the prostate biopsy fails to detect the disease. For the urologists, how to select the appropriate candidate for repeat biopsy is a significant clinical dilemma. Traditional risk-stratification tools in this setting such as prostate-specific antigen (PSA) related markers and histopathology findings have met with limited correlation with cancer diagnosis or with significant disease. Thus, an individualized approach using predictive models such as an online risk calculator (RC) or updated biomarkers is more suitable in counseling men about their risk of harboring clinically significant prostate cancer. This review will focus on the available risk-stratification tools in the population of men with prior negative biopsies and persistent suspicion of PCa. The underlying methodology and platforms of the available tools are reviewed to better understand the development and validation of these models. The index patient is then assessed with different RCs to determine the range of heterogeneity among various RCs. This should allow the urologists to better incorporate these various risk-stratification tools into their clinical practice and improve patient counseling. PMID- 26112491 TI - Physical and functional interaction between hepatitis C virus NS5A protein and ovarian tumor protein deubiquitinase 7B. AB - Hepatitis C virus (HCV) NS5A protein plays crucial roles in viral RNA replication, virus assembly, and viral pathogenesis. Although NS5A has no known enzymatic activity, it modulates various cellular pathways through interaction with cellular proteins. HCV NS5A (and other HCV proteins) are reportedly degraded through the ubiquitin-proteasome pathway; however, the physiological roles of ubiquitylation and deubiquitylation in HCV infection are largely unknown. To elucidate the role of deubiquitylation in HCV infection, an attempt was made to identify a deubiquitinase (DUB) that can interact with NS5A protein. An ovarian tumor protein (OTU), deubiquitinase 7B (OTUD7B), was identified as a novel NS5A binding protein. Co-immunoprecipitation analyses showed that NS5A interacts with OTUD7B in both Huh-7 and HCV RNA replicon cells. Immunofluorescence staining revealed that HCV NS5A protein colocalizes with OTUD7B in the cytoplasm. Moreover, HCV infection was found to enhance the nuclear localization of OTUD7B. The OTUD7B-binding domain on NS5A was mapped using a series of NS5A deletion mutants. The present findings suggest that the domain I of NS5A is important and the region from amino acid 121 to 126 of NS5A essential for the interaction. Either V121A or V124A mutation in NS5A disrupts the NS5A-OTUD7B interaction. The results of this in vivo ubiquitylation assay suggest that HCV NS5A enhances OTUD7B DUB activity. Taken together, these results suggest that HCV NS5A protein interacts with OTUD7B, thereby modulating its DUB activity. PMID- 26112492 TI - Comparison of hybrid FDG PET/MRI compared with PET/CT in colorectal cancer staging and restaging: a pilot study. AB - PURPOSE: We report our initial clinical experience from a pilot study to compare the diagnostic accuracy of hybrid PET/MRI with PET/CT in colorectal cancer and discuss potential PET/MRI workflow solutions for colorectal cancer. METHODS: Patients underwent both FDG PET/CT and PET/MRI (Ingenuity TF PET/MRI, Philips Healthcare) for rectal cancer staging or colorectal cancer restaging. The PET acquisition of PET/MRI was similar to that of PET/CT whereas the MRI protocol was selected individually based on the patient's medical history. One nuclear medicine physician reviewed the PET/CT studies and one radiologist reviewed the PET/MRI studies independently. The diagnostic accuracy of each modality was determined in consensus, using available medical records as a reference. RESULTS: Of the 12 patients enrolled, two were for initial staging and ten for restaging. The median scan delay between the two modalities was 60 min. The initial imaging was PET/CT in nine patients and PET/MRI in three patients. When PET/CT was performed first, the SUV values of the 16 FDG avid lesions were greater at PET/MRI than at PET/CT. In contrast, when PET/MRI was performed first, the SUV values of the seven FDG avid lesions were greater at PET/CT than at PET/MRI. PET/MRI provided more detailed T staging than PET/CT. On a per-patient basis, with both patient groups combined for the evaluation of N and M staging/restaging, the true positive rate was 5/7 (71%) for PET/CT and 6/7 (86%) for PET/MRI, and true negative rate was 5/5 (100%) for both modalities. On a per lesion basis, PET/CT identified 26 of 29 (90%) tumor lesions that were correctly detected by PET/MRI. Our proposed workflow allows for comprehensive cancer staging including integrated local and whole-body assessment. CONCLUSIONS: Our initial experience shows a high diagnostic accuracy of PET/MRI in T staging of rectal cancer compared with PET/CT. In addition, PET/MRI shows at least comparable accuracy in N and M staging as well as restaging to PET/CT. However, the small sample size limits the generalizability of the results. It is expected that PET/MRI would yield higher diagnostic accuracy than PET/CT considering the high soft tissue contrast provided by MRI compared with CT, but larger studies are necessary to fully assess the benefit of PET/MRI in colorectal cancer. PMID- 26112493 TI - [Rare diseases in Lebanon: diagnostic difficulties and therapy]. PMID- 26112494 TI - [Inborn metabolic disorders in Tunisia: challenges, experience and hopes]. PMID- 26112495 TI - [Cystic fibrosis: course of management in Algeria]. PMID- 26112496 TI - [Anonymous birth]. PMID- 26112497 TI - [Anonymous birth, a handover]. PMID- 26112498 TI - [The future of children born anonymously: the experience of an authorized adoption organization in France]. PMID- 26112499 TI - [The "ressort" workshop: when a child plays a role in the management of his kidney transplant]. PMID- 26112500 TI - [Compliance and patient education: an example of antivitamin K in pediatric cardiology]. PMID- 26112501 TI - [Migraines, tension headaches and chronic headache, how does one manage?]. PMID- 26112503 TI - [Relaxation, hypnosis, psychotherapy for headache: it truly works, under certain conditions!]. PMID- 26112502 TI - [Abdominal pain, vomiting, vertigo...this is unlike a migraine...although!]. PMID- 26112504 TI - [With the new vaccination schedule, is it easier to catch up?]. PMID- 26112505 TI - [Pharmacovigilance of vaccines]. PMID- 26112506 TI - [Pharmacovigilance of vaccines: distinguishing the truth from the false at the individual level]. PMID- 26112507 TI - [How to identify a renal emergency?]. PMID- 26112508 TI - [Hemolytic uremic syndrome in children]. PMID- 26112509 TI - [Parenthood and the disabled child]. PMID- 26112510 TI - [Exposure of the pregnant women and fetus to environmental pollutants: first results obtained from the national biosurveillance program (mothers included in the ELFE cohort)]. PMID- 26112511 TI - [Difficult vaccination schedules]. PMID- 26112512 TI - [HPV vaccine: what are we to believe?]. PMID- 26112513 TI - [Biotherapeutic agents and vaccines in pediatrics]. PMID- 26112514 TI - [Pseudohypoaldosteronism type I]. PMID- 26112515 TI - [Bartter and Gitelman syndromes]. PMID- 26112516 TI - [Hypophosphatemic rickets, a proximal tubular dysfunction!]. PMID- 26112517 TI - [Diagnosing an inborn metabolic error with consciousness disorders]. PMID- 26112518 TI - [Diagnosis and course to follow for metabolic acidosis]. PMID- 26112519 TI - [Diagnosis and course to follow for hepatic insufficiency]. PMID- 26112520 TI - [Diagnosis and course to follow for heart failure due to inborn metabolic diseases]. PMID- 26112521 TI - [What methods need another look for management of infections in premature infants?]. PMID- 26112522 TI - [When should enteral nutrition begin?]. PMID- 26112523 TI - [Realizations and challenges of childhood cancer in Africa: experiences of the Franco-African Group of Pediatric Oncology]. PMID- 26112524 TI - [The development of competence]. PMID- 26112525 TI - [Curing Burkitt lymphomas, from France to Africa]. PMID- 26112526 TI - [The treatment of nephroblastoma in Africa]. PMID- 26112527 TI - [Antibacterial resistance of community acquired infections: warnings and good news]. PMID- 26112528 TI - [Initial treatment of urinary tract infections with antibiotics: evolution or revolution?]. PMID- 26112529 TI - [Neonatal screening for severe combined immunodeficiency: the DEPISTREC study]. PMID- 26112530 TI - [Screening for severe congenital heart diseases by pulse oximetry in asymptomatic newborns]. PMID- 26112531 TI - [How to screen for metabolic diseases?]. PMID- 26112532 TI - [The distinctive features of the Guthrie test in neonatology]. PMID- 26112533 TI - [Why continue a special diet after 1 year of age?]. PMID- 26112534 TI - [What do one to three year old children eat: the results of the Nutri-Baby study]. PMID- 26112536 TI - [The child psychiatrist: what relationship does the psychiatrist have with the team?]. PMID- 26112535 TI - [What is the purpose of "growing-up milk?"]. PMID- 26112537 TI - [Care by the parents: problems and benefits]. PMID- 26112538 TI - [Parents and the program coordinator of PHARE-M help to improve the quality of care of cystic fibrosis]. PMID- 26112539 TI - [Sedation and analgesia for neonates in NICUs across Europe]. PMID- 26112540 TI - [Diagnosing pain in the neonate: why and how?]. PMID- 26112541 TI - [Lung diseases in the premature infant: physiopathology, therapy, and prevention]. PMID- 26112542 TI - [Non-invasive methods of pulmonary surfactant administration]. PMID- 26112543 TI - [Bronchopulmonary dysplasia in the newborn: physiopathology, treatment and prevention]. PMID- 26112544 TI - [The respiratory development of the premature infant: implications for follow up]. PMID- 26112545 TI - [Regurgitations]. PMID- 26112546 TI - [Diet therapy of functional diarrhea in the child]. PMID- 26112547 TI - [Dietary measures for constipation: always correct?]. PMID- 26112548 TI - [Myocardial function and endothelial dysfunction in sickle cell anemia]. PMID- 26112549 TI - [Does diarrhea justify or contradict the use of antibiotics?]. PMID- 26112550 TI - [What symptoms indicate a food allergy?]. PMID- 26112551 TI - [Diagnosing food allergies]. PMID- 26112552 TI - [Young LGBT are at risk of suicide and addictive behavior]. PMID- 26112553 TI - [Accommodating and caring for the homosexual adolescent: some tools for the practitioner]. PMID- 26112554 TI - [The role of the telephone]. PMID- 26112555 TI - [The heart and maternal or fetal diabetes]. PMID- 26112556 TI - [Heart disease in twin-twin transfusion syndrome in the era of laser surgery]. PMID- 26112557 TI - [Cardiovascular consequences of intrauterine growth restriction]. PMID- 26112558 TI - [The short child: from everyday life to adulthood]. PMID- 26112559 TI - [The adopted child]. PMID- 26112560 TI - [Between anxiolytics and sedation: what are we talking about?]. PMID- 26112561 TI - [Sedation without symptoms: what points of reference for pediatrics?]. PMID- 26112562 TI - [Macrophage activation syndrome: diagnosis and emergency management]. PMID- 26112563 TI - [Acute abdominal pain: when to think about a rare disease?]. PMID- 26112564 TI - [Feared complications in patients treated for inflammatory disease in the era of biotherapeutic products]. PMID- 26112565 TI - [The biology of dental development]. PMID- 26112566 TI - [Diseases revealed by the mouth]. PMID- 26112567 TI - [Dental care of the disabled child]. PMID- 26112568 TI - [The role of high-flow oxygen therapy for bronchiolitis]. PMID- 26112569 TI - [Asthma: the jungle of holding chambers]. PMID- 26112570 TI - [Use of an insulin pump in pediatrics: problems posed]. PMID- 26112571 TI - [Management of acute asthma]. PMID- 26112572 TI - [Puberty and inflammatory diseases]. PMID- 26112573 TI - [Puberty and cancer]. PMID- 26112574 TI - [Puberty and cystic fibrosis]. PMID- 26112575 TI - [Puberty and chronic kidney disease]. PMID- 26112577 TI - [Clinical decision making algorithms]. PMID- 26112576 TI - [Medical education: learning from an error]. PMID- 26112578 TI - [The state of Community Pediatrics residency]. PMID- 26112579 TI - [Early diagnosis of autism: clinical tools]. PMID- 26112580 TI - [Complications of autism]. PMID- 26112581 TI - [Can keeping a child connected to his life outside the hospital contribute to his care?]. PMID- 26112582 TI - [The Petits Princes Association recognizes the dreams of children and adolescents in collaboration with hospital teams]. PMID- 26112583 TI - [Supporting children with cancer: experience of the Smile at Life Association]. PMID- 26112584 TI - [Basic principles of diagnostic evaluation]. PMID- 26112585 TI - [Bias and factors of variation in diagnostic studies]. PMID- 26112586 TI - [How to use the STARD statement and the QUADAS-2 tool?]. PMID- 26112587 TI - [Understanding the difference between association and discrimination: examples from neonatology]. PMID- 26112588 TI - [Drug eruptions]. PMID- 26112589 TI - [Management of urinary incontinence in the adolescent athlete]. PMID- 26112590 TI - [Menstrual cycle and athletic performance: management of menstruation in competition]. PMID- 26112591 TI - [Introduction to arboviruses and viral hemorrhagic fevers in the child]. PMID- 26112592 TI - [Dengue in the child]. PMID- 26112593 TI - [Chikungunya in children]. PMID- 26112594 TI - [Risk-benefit of anti-reflux therapy in the premature infant]. PMID- 26112595 TI - [Prevention of allergies in utero and in the neonatal period]. PMID- 26112596 TI - Possible Clues to a Functional Cure for HIV Infection. PMID- 26112598 TI - Does the weather play a role in the spread of pandemic influenza? A study of H1N1pdm09 infections in France during 2009-2010. AB - Understanding patterns of influenza spread and persistence is crucial for pandemic preparedness. The H1N1pdm09 virus caused the first influenza pandemic of the 21st century which resulted in at least 18500 deaths. Based on laboratory confirmed primary-care case reports we investigated the role of weather conditions and socio-demographic variables in its initial spread and subsequent presence in France. Our findings suggest that low relative humidity and high population density were determinants in shaping the early spread of the virus at the national level. Those conditions also favoured the persistence of viral presence throughout the first 33 weeks of the pandemic. Additionally this persistence was significantly favoured by low insolation. These results confirm the increasingly recognized role of humidity in influenza dynamics and underlie the concomitant effect of insolation. Therefore climatic factors should be taken into account when designing influenza control and prevention measures. PMID- 26112599 TI - Organoid Models and Applications in Biomedical Research. AB - Recent technical advances in the stem cell field have enabled the in vitro generation of complex structures resembling whole organs termed organoids. Most of these approaches employ three-dimensional (3D) culture systems that allow stem cell-derived or tissue progenitor cells to self-organize into 3D structures. These systems evolved, methodologically and conceptually, from classical reaggregation experiments, showing that dissociated cells from embryonic organs can reaggregate and re-create the original organ architecture. Since organoids can be grown from human stem cells and from patient-derived induced pluripotent stem cells, they create significant prospects for modelling development and diseases, for toxicology and drug discovery studies, and in the field of regenerative medicine. Here, we outline historical advances in the field and describe some of the major recent developments in 3D human organoid formation. Finally, we underline current limitations and highlight examples of how organoid technology can be applied in biomedical research. PMID- 26112597 TI - Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium. AB - The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation. PMID- 26112600 TI - Carcinogenic ability quantification of human papilloma virus subtypes in eastern China. AB - Human papilloma virus (HPV) infection is a precursor of cervical cancer. This study aimed to introduce a method to quantify the risk of cervical cancer resulting from infection by different HPV subtypes, to help guide patient treatment. Nucleic acid molecule flow-through hybridization and gene chip technology were used to test 6,510 non-cervical cancer healthy volunteers (<=CIN I) and 204 cervical cancer patients (>=CIN-III) from Dongying City for 21 HPV subtypes (HPV-16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 6, 11, 42, 43, 44, 53, 66 and CP8304) in exfoliated cervical cells. The positive proportion of HPV subtypes was calculated, excluding or including patients with multiple subtype infections. The lower (L) and upper (H) limits of the carcinogenic risk score range were calculated, respectively. The values of carcinogenic index +/- uncertainty in the carcinogenic ability (CI +/- U) were also calculated. CI = (H + L)/2 represents the carcinogenic risk of the different subtypes, and U =(H - L)/2 represents the probability of each subtype being present in multiple infections. Infection rates were 15.87 and 96.57%, and HPV subtypes with high infection rates were HPV-16, 52, 58, 33, 18, and 31 and HPV-16, 31, 58, 18, 68, and 33 in the non-cervical cancer and cervical cancer groups, respectively. HPV subtypes with high risk of cervical cancer were HPV-31 (3.71 +/- 0.68), 51 (2.65 +/- 0.44), 18 (2.03 +/- 0.43), 68 (1.76 +/- 0.40), 58 (1.68 +/- 0.49), and 16 (1.39 +/- 0.33). We have provided a quantitative method for expressing HPV subtype carcinogenic risk. PMID- 26112601 TI - Two New Species of the Genus Criotettix Bolivar (Orthoptera: Tetrigidae), with a Key to the Species of the Genus from China. AB - Two new species of the tetrigid genus Criotettix Bolivar from China, namely Criotettix interruptaoides Deng & Zheng n. sp. and Criotettix shiwanshanensis Deng & Zheng n. sp. are described. An updated key to all known species of the genus from China is given. PMID- 26112602 TI - Correction to catalytic reaction processes revealed by scanning probe microscopy. PMID- 26112603 TI - E3 ubiquitin ligase Cbl-b suppresses human ORMDL3 expression through STAT6 mediation. AB - Orosomucoid 1-Like Protein 3 (ORMDL3) is an asthma candidate gene and Casitas B lineage lymphoma b (Cbl-b), an E3 ubiquitin ligase, is a critical factor in maintaining airway immune tolerance. However, the association of Cbl-b with ORMDL3 for asthma is unclear. Here, we show that expression of ORMDL3 is significantly increased and shows a strong linear correlation with decreased Cbl b in the peripheral blood of recurrent wheeze patients. To elucidate the molecular mechanisms underlying this correlation, we identified that Cbl-b suppressed the transcriptional activity and mRNA expression of ORMDL3 in vivo. Further investigation showed that phosphorylation of signal transducer and activator of transcription 6 (STAT6) was induced by interleukin 4 bound to the ORMDL3 promoter, while Cbl-b reduced the phosphorylation of STAT6. Our results show that Cbl-b suppresses human ORMDL3 expression through STAT6. PMID- 26112604 TI - Cep70 regulates microtubule stability by interacting with HDAC6. AB - Microtubules, highly dynamic components of the cytoskeleton, are involved in mitosis, cell migration and intracellular trafficking. Our previous work has shown that the centrosomal protein Cep70 regulates microtubule organization and mitotic spindle orientation in mammalian cells. However, it remains elusive whether Cep70 is implicated in microtubule stability. Here we demonstrate that Cep70 enhances microtubule resistance to cold or nocodazole treatment. Our data further show that Cep70 promotes microtubule stability by regulating tubulin acetylation, and plays an important role in stabilizing microtubules. Mechanistic studies reveal that Cep70 interacts and colocalizes with histone deacetylase 6 (HDAC6) in the cytoplasm. These findings suggest that Cep70 promotes microtubule stability by interaction with HDAC6 and regulation of tubulin acetylation. PMID- 26112605 TI - PKCdelta stabilizes TAp63 to promote cell apoptosis. AB - PKCdelta and p63 are respectively reported to play important roles in cell apoptosis. But there is no report on interaction between them in regulation of apoptosis. In the present study, we found that PKCdelta can directly associate and up-regulate TA isoforms of p63 (TAp63) proteins via increasing their stability. PKCdelta kinase activity and Thr157 site in TAp63 are crucial for this PKCdelta-induced accumulation of TAp63. PKCdelta can also enhance TAp63-mediated transcription and cell apoptosis. Taken together, our data indicate that PKCdelta phosphorylates TAp63 proteins at Thr157 to stabilize them and promote cell apoptosis. PMID- 26112606 TI - Entropic clocks in the service of electrical signaling: 'Ball and chain' mechanisms for ion channel inactivation and clustering. AB - Electrical signaling in the nervous system relies on action potential generation, propagation and transmission. Such processes are dynamic in nature and rely on precisely timed events associated with voltage-dependent ion channel conformational transitions between their primary open, closed and inactivated states and clustering at unique membrane sites. In voltage-dependent potassium (Kv) channels, fast inactivation and clustering processes rely on entropic clock chains as described by 'ball and chain' mechanisms, suggesting important roles for such chains in electrical signaling. Here, we consider evidence supporting the proposed 'ball and chain' mechanisms for Kv channel fast inactivation and clustering associated with intrinsically disordered N- and C-terminal regions of the protein, respectively. Based on this comparison, we delineate the requirements that argue for such a process and establish the thermodynamic signature of a 'ball and chain' mechanism. Finally, we demonstrate how 'chain' level alternative splicing of the Kv channel gene modulates the entropic clock based 'ball and chain' inactivation and clustering channel functions underlying changes in electrical signaling. As such, the Kv channel model system exemplifies how linkage between alternative splicing and intrinsic disorder enables functional diversity. PMID- 26112607 TI - Towards measuring neuroimage misalignment. AB - To enhance neuro-navigation, high quality pre-operative images must be registered onto intra-operative configuration of the brain. Therefore evaluation of the degree to which structures may remain misaligned after registration is critically important. We consider two Hausdorff Distance (HD)-based evaluation approaches: the edge-based HD (EBHD) metric and the Robust HD (RHD) metric as well as various commonly used intensity-based similarity metrics such as Mutual Information (MI), Normalised Mutual Information (NMI), Entropy Correlation Coefficient (ECC), Kullback-Leibler Distance (KLD) and Correlation Ratio (CR). We conducted the evaluation by applying known deformations to simple sample images and real cases of brain shift. We conclude that the intensity-based similarity metrics such as MI, NMI, ECC, KLD and CR do not correlate well with actual alignment errors, and hence are not useful for assessing misalignment. On the contrary, the EBHD and the RHD metrics correlated well with actual alignment errors; however, they have been found to underestimate the actual misalignment. We also note that it is beneficial to present HD results as a percentile-HD curve rather than a single number such as the 95-percentile HD. Percentile-HD curves present the full range of alignment errors and also facilitate the comparison of results obtained using different approaches. Furthermore, the qualities that should be possessed by an ideal evaluation metric were highlighted. Future studies could focus on developing such an evaluation metric. PMID- 26112608 TI - Involved-field radiotherapy for patients with mantle cell lymphoma. AB - INTRODUCTION: Retrospective analysis was performed at a single institution to assess the responsiveness of mantle cell lymphoma (MCL) to involved-field radiotherapy (IFRT). METHODS: All patients treated with IFRT to at least one site of MCL between 1998 and 2012 were included. There were 25 patients who received radiotherapy to 60 disease sites. Primary endpoint was overall response rate (ORR) infield for the first site of MCL treated per patient. Predictors of ORR were analysed for the primary endpoint. Time to local progression (TLP) infield and progression-free survival were calculated from the start of the first treatment course. Analysis of all sites collectively was also undertaken. Survival analysis was conducted by the Kaplan-Meier method. RESULTS: ORR rate was 84% for the first site treated per patient. Complete response and partial response rates were 68% and 16% respectively. Median TLP following radiotherapy to the first site was not reached. Infield control rate was 91% at 12 months (95% confidence interval 69-97%). When analysis was performed on all 60 sites, ORR was 85%. Symptomatic improvement occurred after IFRT to 93% of all sites. Systemic progression outside the radiotherapy field was the predominant form of failure following IFRT. CONCLUSION: Radiotherapy generally induced a clinical response at all levels of dose administered, ranging from 3 to 36 Gy. However, increased durability of local control was suggested with higher doses. Radiotherapy is an effective treatment for palliation of MCL with objective and symptomatic responses seen over a range of radiotherapy doses. PMID- 26112609 TI - Impact of Mood Spectrum Spirituality and Mysticism Symptoms on Suicidality in Earthquake Survivors with PTSD. AB - The aim of the present study was to explore the correlations between Spirituality/Mysticism/Psychoticism symptoms and suicidality in young adult survivors of the L'Aquila earthquake. The sample included 475 subjects recruited among high school seniors who had experienced the April 6, 2009, earthquake. Assessments included: Trauma and Loss Spectrum-Self Report and Mood Spectrum-Self Report (MOODS-SR). Mysticism/Spirituality dimension and suicidality were evaluated by means of some specific items of the MOOD-SR. The Spirituality/Mysticism/Psychoticism MOODS-SR factor score was significantly higher among subjects with PTSD diagnosis with respect to those without. Similarly, subjects with suicidal ideation, as well as those who committed a suicide attempt, reported significantly higher scores than those without. PMID- 26112610 TI - Thematic Analysis of Persian Documents in the Field of Quran Study and Medicine in National Scientific-Research Journals from 1992 to 2013 "An Opportunity for Evidence Based Decision Making". AB - Several documents have investigated the area of Quran study and medicine from different points of view; the present study has been assessing all the documents about Quran study and medicine, published in Iranian scientific-research journals, to create an opportunity of revising the interventions executed in this areas and targeting the decisions in order to draw a clear and more realistic vision. In this simple review study, scientific-research and general informative websites in the period of 1992-2013 were explored by taking advantage of critical keywords such as Islamic medicine and Islamic lifestyle. After the initial retrieval, 348 articles were finally ready for the evaluation process. Chi-square test was used to assess the significance of patterns differences between years of study. Minimum and maximum numbers of articles were published in 1992 (0.28 %) and 2011 (12.35 %), respectively. The level of execution of studies by using different methods was as follows: about 3.44 % qualitative, 29.59 % cross sectional descriptive-analytical, 30.45 % review, 1.14 % case-control, 17.52 % experimental, 3.73 % cohort methods and 12.93 % were performed by other methods. The most common subject study was "The effects of fasting and Ramadan on health" (21.83 %). The most important journals hosting this field articles were the journals of medicine and refinement (27.01 %), as well as the Quran and medicine (12.64 %), respectively. Chi-square test showed significant thematic differences during the 21 years of study. Based on the available evidences, the number of descriptive papers was yet more than the analytical, interventional and scientific-comparative articles. Also, the most studies had been reviewing the medical-Islamic documents. This reflects the need for revising the search strategies of Quran study and medicine. PMID- 26112611 TI - Pain Perception in Buddhism Perspective. AB - Dhamma, which Lord Buddha has presented to people after his enlightenment, analyzes every phenomenon and objects into their ultimate elements. The explanation of sensory system is also found in a part of Dhamma named Abhidhammapitaka, the Book of the Higher Doctrine in Buddhism. To find out the relationship between explanation of pain in the present neuroscience and the explanation of pain in Abhidhamma, the study was carried out by the use of a comprehensive review. The comparisons were in terms of peripheral stimulation, signal transmission, modulation, perception, suffering, determination and decision making for the responding to pain. We found that details of the explanation on pain mechanism and perception in Abhidhamma could associate well with our present scientific knowledge. Furthermore, more refinement information about the process and its function in particular aspects of pain perception were provided in Abhidhammapitaka. PMID- 26112612 TI - Why extra caution is needed in the case of depressed patients. PMID- 26112613 TI - Assent as an ethical imperative in the treatment of ADHD. AB - The American Academy of Paediatrics endorses obtaining assent when prescribing medications for attention-deficit/hyperactivity disorder (ADHD) in older children whenever possible. Studies indicate the concept of assent may not be well understood by clinicians, possibly effecting effective and widespread implementation. We argue that though the concept of assent continues to evolve, it is critical in the context of patient-centred care, shared decision-making and in supporting minors' transition to adulthood. Based on the principle of respect for young persons, we argue that obtaining assent is an ethical imperative when prescribing medication for ADHD. We highlight the instrumental benefits of obtaining assent in the paediatric clinical encounter when prescribing medications for treatment of ADHD. PMID- 26112614 TI - Stable nonpolar solvent droplet generation using a poly(dimethylsiloxane) microfluidic channel coated with poly-p-xylylene for a nanoparticle growth. AB - Applications of microfluidic devices fabricated in poly(dimethylsiloxane) (PDMS) have been limited to water-based analysis rather than nonpolar solvent based chemistry due to a PDMS swelling problem that occurs by the absorption of the solvents. The absorption and swelling causes PDMS channel deformation in shape, and changes the cross sectional area making it difficult to control the flow rate and concentrations of solution in PDMS microfluidic channels. We propose that poly-p-xylylene polymers (parylenes) are chemical vapors deposited on the surfaces of PDMS channels that alleviate the effect of solvents on the absorption and swelling. The parylene coated surface sustains 3 h with a small volumetric change (less than 22 % of PDMS swelling ratio). By generating an air-nonpolar solvent interface based on droplets in PDMS channel, we confirmed poly-p-xylylene coated PDMS microfluidic channels have the potential to be applicable to nanocrystal growth using nonpolar solvents. PMID- 26112615 TI - Recent strategies and progress in identifying host factors involved in virus replication. AB - Viruses are completely dependent on their host cells for the successful production of progeny viruses. At each stage of the viral life cycle an intricate interplay between virus and host takes place with the virus aiming to usurp the host cell for its purposes and the host cell trying to block the intruder from propagation. In recent years these interactions have been studied on a global level by systems biology approaches, such as RNA interference screens, transcriptomic or proteomic methodologies, and exciting new insights into the pathogen-host relationship have been revealed. In this review, we summarize the available data, give examples for important findings from such studies and point out current limitations and potential future directions. PMID- 26112616 TI - Discrepancy in Personality Perceptions Is Related to Relationship Satisfaction: Findings from Dyadic Latent Discrepancy Analyses. AB - The current study investigated discrepancies in self-, partner-, and meta perceptions of the Big Five traits and their associations with relationship satisfaction in intimate couples. The study was based on a subsample of the Swiss study "Co-Development in Personality: Longitudinal Approaches to Personality Development in Dyads Across the Life Span" (CoDiP) including cross-sectional data of 216 heterosexual couples. We adapted the Latent Congruence Model (LCM) for the study of discrepancies in personality perceptions in dyads. Beyond personality trait levels, the discrepancies between self- and partner-perceptions and between partner- and meta-perceptions of the Big Five traits were related to relationship satisfaction as actor and partner effects. In general, flattering and favorable partner-perceptions in relation to self- and meta-perceptions seem to positively contribute to relationship satisfaction. The present study implies that not only personality trait levels but also discrepancies between personality perceptions are important for understanding relationship satisfaction. PMID- 26112618 TI - Identification and Complications of Cosmetic Fillers: Sonography First. AB - Cosmetic fillers are frequently used these days for enhancing beauty and to treat wrinkles or sagging skin. However, information on the history of injections may be difficult to obtain, and there is a growing number of reports on complications with these agents. In contrast to other imaging techniques, sonography has been successfully used for detecting and identifying common types of cosmetic fillers and has become the first-line imaging modality to deal with these exogenous components. PMID- 26112617 TI - Conditionally Increased Acoustic Pressures in Nonfetal Diagnostic Ultrasound Examinations Without Contrast Agents: A Preliminary Assessment. AB - The mechanical index (MI) has been used by the US Food and Drug Administration (FDA) since 1992 for regulatory decisions regarding the acoustic output of diagnostic ultrasound equipment. Its formula is based on predictions of acoustic cavitation under specific conditions. Since its implementation over 2 decades ago, new imaging modes have been developed that employ unique beam sequences exploiting higher-order acoustic phenomena, and, concurrently, studies of the bioeffects of ultrasound under a range of imaging scenarios have been conducted. In 2012, the American Institute of Ultrasound in Medicine Technical Standards Committee convened a working group of its Output Standards Subcommittee to examine and report on the potential risks and benefits of the use of conditionally increased acoustic pressures (CIP) under specific diagnostic imaging scenarios. The term "conditionally" is included to indicate that CIP would be considered on a per-patient basis for the duration required to obtain the necessary diagnostic information. This document is a result of that effort. In summary, a fundamental assumption in the MI calculation is the presence of a preexisting gas body. For tissues not known to contain preexisting gas bodies, based on theoretical predications and experimentally reported cavitation thresholds, we find this assumption to be invalid. We thus conclude that exceeding the recommended maximum MI level given in the FDA guidance could be warranted without concern for increased risk of cavitation in these tissues. However, there is limited literature assessing the potential clinical benefit of exceeding the MI guidelines in these tissues. The report proposes a 3-tiered approach for CIP that follows the model for employing elevated output in magnetic resonance imaging and concludes with summary recommendations to facilitate Institutional Review Board (IRB)-monitored clinical studies investigating CIP in specific tissues. PMID- 26112619 TI - Utility of Sonoelastography in Differentiating Ruptured From Unruptured Epidermal Cysts and Implications for Patient Care. AB - OBJECTIVES: This study aimed to evaluate the correlation of sonoelastographic features between ruptured and unruptured epidermal cysts. METHODS: We performed a prospective survey of 27 patients with clinically suspected epidermal cysts diagnosed by excisional biopsy with prebiopsy sonography and real-time sonoelastography. We statistically evaluated the correlation between elastographic and histopathologic features. To measure the relative hardness on elastography, the Rinside/Routside ratio was used to show the ratio of the elasticity inside and outside the cyst, where the random value R was defined as the median red pixel intensity/(median red pixel intensity + median green pixel intensity + median blue pixel intensity). RESULTS: Only 24 of the 27 patients were enrolled. Among the 24 diagnosed epidermal cysts, 13 were unruptured cysts, and 11 were ruptured cysts based on histopathologic examination. There was no correlation between sonographically and histopathologically measured cyst diameters. The Rinside/Routside ratio was significantly higher in unruptured cysts than ruptured cysts (mean +/- SD, 1.16 +/- 0.15 versus 1.04 +/- 0.13; P = .047). All values below the cutoff point were considered to indicate ruptured cysts, and the cutoff value was set to 1.0919, which afforded sensitivity of 83.3% and specificity of 66.7%. CONCLUSIONS: Real-time sonoelastography is able to detect differences in tissue elasticity between ruptured and unruptured epidermal cysts. This study shows the utility of real-time sonoelastography, which has important implications for treatment planning. PMID- 26112620 TI - Assessment of the Postoperative Appearance of the Rotator Cuff Tendon Using Serial Sonography After Arthroscopic Repair of a Rotator Cuff Tear. AB - OBJECTIVES: The purpose of this study was to evaluate serial changes in sonographic findings of a rotator cuff tendon after rotator cuff repair. METHODS: Sixty-five arthroscopically repaired rotator cuff tears (43 full-thickness tears and 22 partial-thickness tears) were retrospectively included in this study. Serial sonographic examinations were performed at 5 weeks, 3 months, and 6 months after surgery. The sonographic findings of the repaired tendon were assessed for a recurrent tear, tendon thickness, morphologic tendon characteristics, vascularity, and bursitis at each time point. RESULTS: Four recurrent tears occurred within 3 months of surgery. The postoperative tendon thickness decreased from 5 weeks to 6 months after surgery (P = .001). There were significant changes in the morphologic tendon characteristics, including the echo texture, fibrillar pattern, and surface irregularity of the repaired tendon, from 5 weeks to 6 months after surgery (P < .001). Additionally, subacromial-subdeltoid bursitis and the vascularity of the repaired tendon decreased postoperatively over time. CONCLUSIONS: Serial sonography after arthroscopic rotator cuff repair was useful for monitoring the postoperative changes in a repaired tendon. The morphologic appearance of the repaired tendon and peritendinous soft tissue changes improved over time and nearly normalized within 6 months of surgery. PMID- 26112621 TI - Interobserver Reliability of Quantitative Muscle Sonographic Analysis in the Critically Ill Population. AB - OBJECTIVES: There is growing interest in the use of quantitative high-resolution neuromuscular sonography to evaluate skeletal muscles in patients with critical illness. There is currently considerable methodological variability in the measurement technique of quantitative muscle analysis. The reliability of muscle parameters using different measurement techniques and assessor expertise levels has not been examined in patients with critical illness. The primary objective of this study was to determine the interobserver reliability of quantitative sonographic measurement analyses (thickness and echogenicity) between assessors of different expertise levels and using different techniques for selecting the region of interest. METHODS: We conducted a cross-sectional observational study in neurocritical care and mixed surgical-medical intensive care units from 2 tertiary referral hospitals. RESULTS: Twenty diaphragm and 20 quadriceps images were evaluated. Images were obtained by using standardized imaging acquisition techniques. Quantitative sonographic measurements included muscle thickness and echogenicity analysis (either by the trace or square technique). All images were analyzed twice independently by 4 assessors of differing expertise levels. Excellent interobserver reliability was obtained for all measurement techniques regardless of expertise level (intraclass correlation coefficient, >0.75 for all comparisons). There was less variability between assessors for echogenicity values when the square technique was used for the quadriceps muscle and the trace technique for the diaphragm. CONCLUSIONS: Excellent interobserver reliability exists regardless of expertise level for quantitative analysis of muscle parameters on sonography in the critically ill population. On the basis of these findings, it is recommended that echogenicity analysis be performed using the square technique for the quadriceps and the trace technique for the diaphragm. PMID- 26112622 TI - Combination of Virtual Touch Tissue Imaging and Virtual Touch Tissue Quantification for Differential Diagnosis of Breast Lesions. AB - OBJECTIVES: Breast cancer is the second leading cause of death from cancer in women, and early detection is the key to successful treatment. Unfortunately, even with technological advances, the specificity of imaging modalities is still low. Therefore, we evaluated the value of a newly developed noninvasive technique, acoustic radiation force impulse imaging, for differentiating benign versus malignant breast lesions. METHODS: We prospectively examined 141 breast lesions in 122 patients. All lesions were classified according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) for mammography, BI-RADS for sonography, and Virtual Touch tissue imaging (VTI; Siemens Medical Solutions, Mountain View, CA) pattern. Internal and marginal shear wave velocity (SWV) values for the lesions were noted. The sensitivity, specificity, accuracy, and positive and negative predictive values for VTI and Virtual Touch tissue quantification (VTQ; Siemens Medical Solutions) were calculated. RESULTS: The marginal SWV values were statistically higher in malignant lesions (mean +/- SD, 5.41 +/- 1.37 m/s) than benign lesions (2.91 +/- 0.88 m/s; P < .001). When the SWV cutoff level was set at 4.07 m/s, and the higher of the internal and marginal values was adopted, the combination of VTI and VTQ showed 95.1% sensitivity, 99.0% specificity, and 97.8% accuracy. CONCLUSIONS: Breast Imaging Reporting and Data System category 4 lesions are the main focus of research for early detection of breast cancer. Unfortunately, BI RADS category 4 assessment covers a wide range of likelihood of malignancy (2% 95%). This wide range reflects the necessity for a more specific imaging modality. The combination of VTI and VTQ could increase the diagnostic performance of conventional sonography. PMID- 26112624 TI - Evaluation of Left Ventricular Regional Systolic Function Using Tissue Doppler Echocardiography After Mesenchymal Stem Cell Transplantation in Rabbits With Myocardial Infarction. AB - OBJECTIVES: The aim of this work was to assess left ventricular (LV) regional systolic function in rabbits with myocardial infarction after allogeneic mesenchymal stem cell (MSC) transplantation using quantitative tissue velocity imaging. METHODS: Thirty New Zealand White rabbits were assigned into 3 groups randomly: a sham-operated group (n = 10), a myocardial infarction (MI) group (n = 10), and a MSC transplantation group (n = 10). Mesenchymal stem cells (1 * 10(7) in total) were delivered into 5 spots around the left anterior descending artery (LAD) blood supply area via direct intramyocardial injections 1 hour after LAD ligation in the MSC group, whereas the MI group received the same amount of phosphate-buffered saline injections. Echocardiography was performed before LAD ligation and 1 day and 2 weeks after MSC transplantation, respectively. The peak systolic velocity (Vs) of each LV wall segment was measured. The myocardial slices were harvested for histologic staining after the last echocardiographic examination. RESULTS: The velocity curves for the LV myocardium before LAD ligation had a trend showing that the Vs value decreased gradually from basal to apical segments. The Vs values for the LV segments around the infarcted area in the MSC group decreased significantly compared with the sham group (P < .05) 1 day after MSC transplantation, whereas they increased significantly 2 weeks after MSC transplantation compared with 1 day after LAD ligation (P < .05). CONCLUSIONS: This study demonstrates that quantitative tissue velocity imaging may provide a promising approach to quantitatively assessing LV regional systolic function before and after MSC transplantation. PMID- 26112623 TI - Contrast Ultrasound Imaging Does Not Affect Heat Shock Protein 70 Expression in Cholesterol-Fed Rabbit Aorta. AB - OBJECTIVES: Diagnostic ultrasound imaging is enhanced by the use of circulating microbubble contrast agents (UCAs), but the interactions between ultrasound, UCAs, and vascular tissue are not fully understood. We hypothesized that ultrasound with a UCA would stress the vascular tissue and increase levels of heat shock protein 70 (Hsp70), a cellular stress protein. METHODS: Male New Zealand White rabbits (n = 32) were fed a standard chow diet (n = 4) or a 1% cholesterol, 10% fat, and 0.11% magnesium diet (n = 28). At 21 days, 24 rabbits on the cholesterol diet were either exposed to ultrasound (3.2-MHz f/3 transducer; 2.1 MPa; mechanical index, 1.17; 10 Hz pulse repetition frequency; 1.6 microseconds pulse duration; 2 minutes exposure duration at 4 sites along the aorta) with the UCA Definity (1* concentration, 1 mL/min; Lantheus Medical Imaging, North Billerica, MA) or sham exposed with a saline vehicle injection (n = 12 per group). Four rabbits on the cholesterol diet and 4 on the chow diet served as cage controls and were not exposed to ultrasound or restrained for blood sample collection. Animals were euthanized 24 hours after exposure, and aortas were quickly isolated and frozen in liquid nitrogen. Aorta lysates from the area of ultrasound exposure were analyzed for Hsp70 level by Western blot. Blood plasma was analyzed for cholesterol, Hsp70, and von Willebrand factor, a marker of endothelial function. RESULTS: Plasma total cholesterol levels increased to an average of 705 mg/dL. Ultrasound did not affect plasma von Willebrand factor, plasma Hsp70, or aorta Hsp70. Restraint increased Hsp70 (P < .001, analysis of variance). CONCLUSIONS: Restraint, but not ultrasound with the UCA or cholesterol feeding, significantly increased Hsp70. PMID- 26112625 TI - Low-Energy Ultrasound Treatment Improves Regional Tumor Vessel Infarction by Retargeted Tissue Factor. AB - OBJECTIVES: To enhance the regional antitumor activity of the vascular-targeting agent truncated tissue factor (tTF)-NGR by combining the therapy with low-energy ultrasound (US) treatment. METHODS: For the in vitro US exposure of human umbilical vein endothelial cells (HUVECs), cells were put in the focus of a US transducer. For analysis of the US-induced phosphatidylserine (PS) surface concentration on HUVECs, flow cytometry was used. To demonstrate the differences in the procoagulatory efficacy of TF-derivative tTF-NGR on binding to HUVECs with a low versus high surface concentration of PS, we performed factor X activation assays. For low-energy US pretreatment, HT1080 fibrosarcoma xenotransplant bearing nude mice were treated by tumor-regional US-mediated stimulation (ie, destruction) of microbubbles. The therapy cohorts received the tumor vessel infarcting tTF-NGR protein with or without US pretreatment (5 minutes after US stimulation via intraperitoneal injection on 3 consecutive days). RESULTS: Combination therapy experiments with xenotransplant-bearing nude mice significantly increased the antitumor activity of tTF-NGR by regional low-energy US destruction of vascular microbubbles in tumor vessels shortly before application of tTF-NGR (P < .05). Mechanistic studies proved the upregulation of anionic PS on the outer leaflet of the lipid bilayer of endothelial cell membranes by low-energy US and a consecutive higher potential of these preapoptotic endothelial cells to activate coagulation via tTF-NGR and coagulation factor X as being a basis for this synergistic activity. CONCLUSIONS: Combining retargeted tTF to tumor vessels with proapoptotic stimuli for the tumor vascular endothelium increases the antitumor effects of tumor vascular infarction. Ultrasound treatment may thus be useful in this respect for regional tumor therapy. PMID- 26112626 TI - Left Ventricular Ejection Time Derived From the Common Carotid Artery Doppler Waveform: Association With Left Ventricular Ejection Fraction and Prediction of Heart Failure. AB - OBJECTIVES: Left ventricular ejection time (LVET) is measured from blood pressure tracings as the interval from end diastole to the dicrotic notch and shows associations with left ventricular ejection fraction (LVEF) and heart failure. LVET can be measured on common carotid artery Doppler waveforms. We therefore studied the possible associations of common carotid artery LVET with LVEF measured by echocardiography and heart failure. METHODS: We performed a retrospective study of 110 patients who had transthoracic echocardiography and carotid Doppler evaluations within 1 day of each other. LVEF was determined by the biplane modified Simpson method. LVET was measured from left common carotid artery Doppler tracings. Linear regression was used to evaluate associations between LVET and LVEF. We also used logistic regression with LVEF of less than 40% as a cut point for heart failure to generate a receiver operating characteristic curve, estimate the area under the curve, and calculate sensitivity and specificity. RESULTS: LVET was associated with LVEF (P < .0001). The area under the curve of LVET for heart failure was 0.81 (95% confidence interval [CI], 0.72-0.87), and the sensitivity and specificity were 76.9% (95% CI, 65.4%-88.4%) and 65.5% (95% CI, 53.4%-77.8%), respectively, for LVET of 321 milliseconds. CONCLUSIONS: LVET measured on common carotid artery Doppler tracings decreases with LVEF and is strongly associated with prevalent heart failure. Based on what is known of blood pressure-measured LVET, common carotid artery Doppler waveform-derived LVET could be used to serially monitor cardiac function. PMID- 26112627 TI - A Predictive Model for Selecting Malignant Thyroid Nodules in Patients With Nondiagnostic or Indeterminate Fine-Needle Aspiration Cytologic Findings. AB - OBJECTIVES: The management of nodules with nondiagnostic or indeterminate fine needle aspiration cytologic findings remains challenging. This study evaluated the clinical differences, conventional sonographic findings, elastographic findings, and cytologic findings for predicting thyroid malignancy. METHODS: A total of 167 patients with a nondiagnostic or indeterminate thyroid fine-needle aspiration cytologic findings were enrolled in this study. The clinicopathologic and sonographic data from the patients were analyzed retrospectively to determine the independent predictive factors for thyroid malignancy. Then a scoring system was designed on the basis of statistically significant predictors. RESULTS: Fine needle aspiration cytologic findings, Thyroid Imaging Reporting and Data System categorization, and elastographic findings were independent predictive factors for thyroid cancer on multivariate analysis. The index points were statistically significant, with a score higher than 3 favoring malignant nodules with sensitivity of 79.37%, specificity of 85.85%, a positive predictive value of 76.9%, and a negative predictive value of 87.3%. CONCLUSIONS: For patients with nondiagnostic or indeterminate fine-needle aspiration cytologic findings, our scoring system for prediction of thyroid malignancy can be another choice. We suggest surgery for nodules with index points higher than 3. For nodules with index points of 3 or lower, observation and regular follow-up are recommended. PMID- 26112628 TI - Integrating Sonography Training Into Undergraduate Medical Education: A Study of the Previous Exposure of One Institution's Incoming Residents. AB - OBJECTIVES: Sonography is a crucial and versatile tool within the field of medicine. Recent advancements in technology have led to increased use of point-of care sonography. We designed a survey to assess prior point-of-care sonography training among incoming interns at an academic teaching hospital. METHODS: In 2012 and 2013, we surveyed incoming interns (n = 154 and 145, respectively) regarding point-of-care sonography training received during medical school. The survey questions included formal didactic sessions, bedside instruction, and the use of simulation technology. RESULTS: One-fourth (26.3% in 2012 and 23.4% in 2013) of responding interns reported having never done an ultrasound scan at the bedside. In 2012 and 2013, 55.0% and 55.6% of respondents reported never having done an ultrasound scan in a simulation center, respectively. Interns agreed that sonography education should be provided during medical school. On average, interns disagreed with the statement that sonography should be taught in residency only. There was no significant difference in the sex or general previous experience with sonography across both intern classes. CONCLUSIONS: Point-of-care sonography is inconsistently taught in medical school. The interns in our study also thought that sonography education should begin in medical school, and sonography should be taught by using simulation and at the bedside. PMID- 26112629 TI - Utility of Targeted Neonatal Echocardiography in the Management of Neonatal Illness. AB - OBJECTIVES: To describe the impact of targeted neonatal echocardiography on management of neonatal illness in a tertiary perinatal center neonatal intensive care unit (NICU). METHODS: We conducted a retrospective analysis of consecutive targeted neonatal echocardiographic studies that were performed over an 18-month period in a regional perinatal center NICU in Canada. All studies were performed with a cardiovascular ultrasound machine and transducer and read on a workstation with storage and analysis software. Reporting was done on a standardized document, and any management change resulting from targeted neonatal echocardiography was documented. RESULTS: A total of 303 consecutive targeted neonatal echocardiographic studies were performed on 129 neonates. The mean gestational age +/- SD was 27.8 +/- 4.3 weeks (range, 23-41 weeks), and the mean birth weight +/- SD was 1196 +/- 197 g (range, 490- 4500 g). The median number of studies per neonate was 2 (range, 1-8), with most repeated studies for a patent ductus arteriosus (PDA). The most common indication for echocardiography was assessment of a PDA (52.1%), followed by early global hemodynamic assessment of very low birth weight (16.2%) and pulmonary hypertension (12.2%). Of the 303 studies, 126 (41.5%) resulted in management changes. The contribution to management was significantly related to the timing of echocardiography. Around half of the echocardiographic examinations during first the week of life resulted in management changes, compared to 22% of studies after 1 week of age (P = .002). Patent ductus arteriosus management accounted for almost half of the interventions. CONCLUSIONS: Targeted neonatal echocardiography is a valuable tool in the NICU and can contribute substantially to hemodynamic management in the first week of life, PDA management in the first 2 weeks of life, and cases of hypotension or shock at any time during the hospital stay. PMID- 26112630 TI - Evaluating the Optimal Definition of Abnormal First-Trimester Uterine Artery Doppler Parameters to Predict Adverse Pregnancy Outcomes. AB - OBJECTIVES: To investigate the optimal definition of abnormal first-trimester uterine artery Doppler parameters associated with adverse pregnancy outcomes. METHODS: A prospective cohort of women with singleton gestations between 11 and 14 weeks consented to uterine artery Doppler measurements. Doppler parameters were measured bilaterally, and mean pulsatility index (PI) and resistive index (RI) values were calculated. The presence of notching was also determined. Each parameter was evaluated for prediction of preeclampsia, early preeclampsia (<34 weeks), preterm birth (<37 weeks), early preterm birth (<34 weeks), and small for gestational age (SGA; birth weight <10th percentile). Descriptive statistics evaluated the association between abnormal Doppler indices and outcomes. A receiver operating characteristic (ROC) analysis was used to define the best cutoff points for mean PI and RI. The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were calculated for bilateral notching and mean PI and RI percentiles. RESULTS: Of 1192 patients with complete outcome data, preeclampsia was seen in 8.4%, early preeclampsia in 1.8%, preterm birth in 12.9%, early preterm birth in 5.6%, and SGA in 8.5%. A mean PI above the 75th percentile (>1.91) was the best index for predicting early preeclampsia (sensitivity, 45.0%; specificity, 75.5%; NPV, 98.7%; ROC area, 0.65). A mean PI above the 75th percentile was also the best index for predictive early preterm birth (sensitivity, 40.0%; specificity, 76.0%; NPV, 95.5%; ROC area, 0.65). None of the parameters were significant for predicting SGA. CONCLUSIONS: A mean uterine PI above the 75th percentile is the most discriminative abnormal uterine artery Doppler parameter for predicting both early preeclampsia and early preterm birth. PMID- 26112631 TI - Cardiovascular System Sonographic Evaluation Algorithm: A New Sonographic Algorithm for Evaluation of the Fetal Cardiovascular System in the Second Trimester. AB - OBJECTIVES: To evaluate the reproducibility and feasibility of the new cardiovascular system sonographic evaluation algorithm for studying the extended fetal cardiovascular system, including the portal, thymic, and supra-aortic areas, in the second trimester of pregnancy (19-22 weeks). METHODS: We performed a cross-sectional study of pregnant women with healthy fetuses (singleton and twin pregnancies) attending our center from March to August 2011. The extended fetal cardiovascular system was evaluated by following the new algorithm, a sequential acquisition of axial views comprising the following (caudal to cranial): I, portal sinus; II, ductus venosus; III, hepatic veins; IV, 4-chamber view; V, left ventricular outflow tract; VI, right ventricular outflow tract; VII, 3-vessel and trachea view; VIII, thy-box; and IX, subclavian arteries. Interobserver agreement on the feasibility and exploration time was estimated in a subgroup of patients. The feasibility and exploration time were determined for the main cohort. Maternal, fetal, and sonographic factors affecting both features were evaluated. RESULTS: Interobserver agreement was excellent for all views except view VIII; the difference in the mean exploration time between observers was 1.5 minutes (95% confidence interval, 0.7-2.1 minutes; P < .05). In 184 fetuses (mean gestational age +/- SD, 20 +/- 0.6 weeks), the feasibility of all views was close to 99% except view VIII (88.7%). The complete feasibility of the algorithm was 81.5%. The mean exploration time was 5.6 +/- 4.2 minutes. Only the occiput anterior fetal position was associated with a lower frequency of visualization and a longer exploration time (P < .05). CONCLUSIONS: The cardiovascular system sonographic evaluation algorithm is a reproducible and feasible approach for exploration of the extended fetal cardiovascular system in a second-trimester scan. It can be used to explore these areas in normal and abnormal conditions and provides an integrated image of extended fetal cardiovascular anatomy. PMID- 26112632 TI - Sonography of the Optic Nerve Sheath Diameter for Detection of Raised Intracranial Pressure Compared to Computed Tomography: A Systematic Review and Meta-analysis. AB - OBJECTIVES: The diagnosis of raised intracranial pressure (ICP) is important in many critically ill patients. The optic nerve sheath is contiguous with the subarachnoid space; thus, an increase in ICP results in a corresponding increase in the optic nerve sheath diameter. The objective of this study was to assess the diagnostic accuracy of sonography of the optic nerve sheath diameter compared to computed tomography (CT) for predicting raised ICP. METHODS: We searched PubMed, EMBASE, and the Cochrane database from 1986 to August 2013 and performed hand searches. Two independent reviewers extracted data. Study quality was assessed by using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. We calculated kappa agreement for study selection and evaluated clinical and quality homogeneity before the meta-analysis. RESULTS: From 1214 studies, we selected 45 for full review. Twelve studies with 478 participants were included (kappa = 0.89). Ocular sonography yielded sensitivity of 95.6% (95% confidence interval [CI], 87.7%-98.5%), specificity of 92.3% (95% CI, 77.9%-98.4%), a positive likelihood ratio of 12.5 (95% CI, 4.16-37.5), and a negative likelihood ratio of 0.05 (95% CI, 0.02-0.14). Average quality according to the QUADAS tool was 7.4 of 11. There was moderate to high heterogeneity based on the prediction ellipse area and variance logit of sensitivity (2.1754) and specificity (2.6720). CONCLUSIONS: Ocular sonography shows good diagnostic test accuracy for detecting raised ICP compared to CT: specifically, high sensitivity for ruling out raised ICP in a low risk group and high specificity for ruling in raised ICP in a high-risk group. This noninvasive point-of-care method could lead to rapid interventions for raised ICP, assist centers without CT, and monitor patients during transport or as part of a protocol to reduce CT use. PMID- 26112633 TI - Saline Flush Test: Can Bedside Sonography Replace Conventional Radiography for Confirmation of Above-the-Diaphragm Central Venous Catheter Placement? AB - OBJECTIVES: Resuscitation often requires rapid vascular access via central venous catheters. Chest radiography is the reference standard to confirm central venous catheter placement and exclude complications. However, radiographs are often untimely. The purpose of this study was to determine whether dynamic sonographic visualization of a saline flush in the right side of the heart after central venous catheter placement could serve as a more rapid confirmatory study for above-the-diaphragm catheter placement. METHODS: A consecutive prospective enrollment study was conducted in the emergency departments of 2 major tertiary care centers. Adult patients of the study investigators who required an above-the diaphragm central venous catheter were enrolled during the study period. Patients had a catheter placed with sonographic guidance. After placement of the catheter, thoracic sonography was performed. The times for visualization of the saline flush in the right ventricle and sonographic exclusion of ipsilateral pneumothorax were recorded. Chest radiography was performed per standard practice. RESULTS: Eighty-one patients were enrolled; 13 were excluded. The mean catheter confirmation time by sonography was 8.80 minutes (95% confidence interval, 7.46-10.14 minutes). The mean catheter confirmation time by chest radiograph availability for viewing was 45.78 minutes (95% confidence interval, 37.03-54.54 minutes). Mean sonographic confirmation occurred 36.98 minutes sooner than radiography (P< .001). No discrepancy existed between sonographic and radiographic confirmation. CONCLUSIONS: Confirmation of central venous catheter placement by dynamic sonographic visualization of a saline flush with exclusion of pneumothorax is an accurate, safe, and more efficient method than confirmation by chest radiography. It allows the central line to be used immediately, expediting patient care. PMID- 26112634 TI - ERRATUM. PMID- 26112635 TI - The Ultrasound-Only Central Venous Catheter Placement and Confirmation Procedure. AB - The placement of a central venous catheter remains an important intervention in the care of critically ill patients in the emergency department. We propose an ultrasound-first protocol for 3 aspects of central venous catheter placement above the diaphragm: dynamic procedural guidance, evaluation for pneumothorax, and confirmation of the catheter tip location. PMID- 26112636 TI - Value of Intraoperative Sonography in Pancreatic Surgery. AB - The utility of intraoperative sonography for pancreatic disease has been well described for detection and evaluation of neoplastic and inflammatory pancreatic disease. Intraoperative sonography can help substantially reduce surgical time as well as decrease potential injury to tissues and major structures. Imaging with sonography literally at the point of care--the surgeon's scalpel--can precisely define the location of pancreatic lesions and their direct relationship with surrounding structures in real time during surgery. This article highlights our experience with intraoperative sonography at multiple institutional sites for both open and laparoscopic surgical procedures. We use intraoperative sonography for a wide range of pancreatic disease to provide accurate localization and staging of disease, provide guidance for enucleation of nonpalpable, nonvisible tumors, and in planning the most direct and least invasive surgical approach, avoiding injury to the pancreatic duct or other vital structures. PMID- 26112637 TI - Multiparametric Sonography of Testicular Hematomas: Features on Grayscale, Color Doppler, and Contrast-Enhanced Sonography and Strain Elastography. AB - We investigated the appearances of intratesticular hematomas on multiparametric sonography combining grayscale, color Doppler, and contrast-enhanced sonography and strain elastography. Over a 3-year period, 17 hematomas in 8 patients were analyzed. Blunt trauma (n = 7) and surgery (n = 1) were preceding events. Grayscale sonography showed well-defined oval or round predominantly hypoechoic and heterogeneous, peripherally (n = 13) or centrally (n = 4) located lesions. Three showed contrast enhancement of septations, and 4 showed peripheral lesion rim enhancement. On strain elastography, the mean strain ratio was 1.19 (range, 0.41-2.36), and elasticity score were 3 or lower (n = 13) and 5 (n = 4). Multiparametric sonography shows nonenhancement with contrast and predominantly "soft" elastographic properties and aids in the interpretation of the benign nature of intratesticular hematomas. PMID- 26112638 TI - Is the "I-Sign" in the 3-Vessel and Trachea View a Valid Tool for Prenatal Diagnosis of D-Transposition of the Great Arteries? AB - Prenatal diagnosis of D-transposition of the great arteries remains less frequent compared to other major congenital heart defects. In this study, we examined how often the 3-vessel and trachea view was abnormal in a large series of prenatally diagnosed cases of D-transposition of the great arteries. We found that an abnormal 3-vessel and trachea view in the shape of an "I" ("I-sign"), which represents an anteriorly displaced aorta, was present in all fetuses with D transposition of the great arteries when a 3-vessel and trachea view was successfully obtained. Therefore we believe that the 3-vessel and trachea view can be used to reliably detect D-transposition of the great arteries during prenatal sonography. PMID- 26112639 TI - Unexpected Inching Explained by an Ulnar Nerve Anatomic Variant Documented by Sonography. PMID- 26112640 TI - Cerebral Circulatory Arrest Detected by Transcranial Color-Coded Duplex Sonography: A Feasible Diagnosis for Intensivists. PMID- 26112641 TI - The devil is in the detail: estimating species richness, density, and relative abundance of tropical island herpetofauna. AB - BACKGROUND: One of the basic premises of drawing samples from populations is that the samples are representative of the populations. However, error in sampling is poorly recognized, and it goes unnoticed especially in community ecology. By combining traditional open quadrats used for sampling forest floor herpetofauna with intensive bounded quadrats, we explore the effect of sampling error on estimates of species richness, diversity, and density in the Andaman Islands. RESULTS: Fisher's alpha measure of species diversity and second order jackknife estimate of species richness were not sensitive to number of individuals sampled. Sampling error resulted in underestimation of density in both frogs and lizards. It influenced relative abundance of individual species resulting in underestimation of abundance of small or camouflaged species; and also resulted in low precision in lizard species richness estimates. CONCLUSIONS: Sampling error resulted in underestimation of abundance of small, fossorial or camouflaged species. Imperfect detection from less intensive sampling method results incorrect estimates of abundance of herpetofauna. Fisher's alpha for species diversity and second order jackknife for species richness were robust measures. These have strong implications on inferences made from previous studies as well as sampling strategies for future studies. It is essential that these shortfalls are accounted for while communities are sampled or when datasets are compared. PMID- 26112642 TI - Persistent Aortic Arch Hypoplasia After Coarctation Treatment Is Associated With Late Systemic Hypertension. AB - BACKGROUND: Mild transverse aortic arch (TAA) hypoplasia is common after coarctation treatment, but is considered benign in the absence of an arm-leg systolic blood pressure (SBP) difference. Hypertension (HTN) is a common long term morbidity after successful coarctation treatment. We examined whether mild TAA hypoplasia after coarctation treatment is associated with late systemic HTN. METHODS AND RESULTS: We retrospectively reviewed 92 patients (median age, 19.9 years; range, 4.9 to 57.8; 60% male) 14.1+/-10.3 years after successful coarctation treatment (surgery in 63, stent in 16, and balloon dilation in 13), excluding those with resting right arm-leg blood pressure gradient >20 mm Hg, atypical coarctation, and major associated heart defects. Minimum body-surface area (BSA)-adjusted TAA cross-sectional area (CSA) was calculated from cardiac magnetic resonance (CMR) images. On follow-up, 38 of 92 (41%) patients had systemic HTN using standard criteria. Systemic HTN was independently associated with smaller TAA CSA/BSA (P=0.006; odds ratio [OR], 6.41 per 0.5 cm(2)/m(2) decrease), higher age at CMR (P=0.03; OR, 1.57 per 5-year increase), and in a subset (n=61), higher arm-leg SBP difference during exercise (P=0.05; OR, 1.03 per 1-mm-Hg increase). Lower ratio of TAA diameter/descending aorta diameter was associated with a larger increase in right arm SBP during peak exercise (P=0.006; r(2)=0.11). CONCLUSIONS: Persistent mild aortic arch hypoplasia, even in the absence of an arm-leg SBP difference at rest, is associated with late systemic HTN. Further studies should be undertaken to determine whether more-aggressive arch reconstruction at initial repair can reduce the incidence of systemic HTN. PMID- 26112643 TI - Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes. AB - BACKGROUND/AIMS: Dysferlin plays a decisive role in calcium-dependent membrane repair in myocytes. Mutations in the encoding DYSF gene cause a number of myopathies, e.g. limb-girdle muscular dystrophy type 2B (LGMD2B). Besides skeletal muscle degenerative processes, dysferlin deficiency is also associated with cardiac complications. Thus, both LGMD2B patients and dysferlin-deficient mice develop a dilated cardiomyopathy. We and others have recently reported that dystrophin-deficient ventricular cardiomyocytes from mouse models of Duchenne muscular dystrophy show significant abnormalities in voltage-dependent ion channels, which may contribute to the pathophysiology in dystrophic cardiomyopathy. The aim of the present study was to investigate if dysferlin, like dystrophin, is a regulator of cardiac ion channels. METHODS AND RESULTS: By using the whole cell patch-clamp technique, we compared the properties of voltage dependent calcium and sodium channels, as well as action potentials in ventricular cardiomyocytes isolated from the hearts of normal and dysferlin deficient (dysf) mice. In contrast to dystrophin deficiency, the lack of dysferlin did not impair the ion channel properties and left action potential parameters unaltered. In connection with normal ECGs in dysf mice these results suggest that dysferlin deficiency does not perturb cardiac electrophysiology. CONCLUSION: Our study demonstrates that dysferlin does not regulate cardiac voltage-dependent ion channels, and implies that abnormalities in cardiac ion channels are not a universal characteristic of all muscular dystrophy types. PMID- 26112644 TI - The Surtsey Magma Series. AB - The volcanic island of Surtsey (Vestmannaeyjar, Iceland) is the product of a 3.5 year-long eruption that began in November 1963. Observations of magma-water interaction during pyroclastic episodes made Surtsey the type example of shallow to-emergent phreatomagmatic eruptions. Here, in part to mark the 50(th) anniversary of this canonical eruption, we present previously unpublished major element whole-rock compositions, and new major and trace-element compositions of sideromelane glasses in tephra collected by observers and retrieved from the 1979 drill core. Compositions became progressively more primitive as the eruption progressed, with abrupt changes corresponding to shifts between the eruption's four edifices. Trace-element ratios indicate that the chemical variation is best explained by mixing of different proportions of depleted ridge-like basalt, with ponded, enriched alkalic basalt similar to that of Iceland's Eastern Volcanic Zone; however, the systematic offset of Surtsey compositions to lower Nb/Zr than other Vestmannaeyjar lavas indicates that these mixing end members are as-yet poorly contained by compositions in the literature. As the southwestern-most volcano in the Vestmannaeyjar, the geochemistry of the Surtsey Magma Series exemplifies processes occurring within ephemeral magma bodies on the extreme leading edge of a propagating off-axis rift in the vicinity of the Iceland plume. PMID- 26112645 TI - Exciton intrachain transport induced by interchain packing configurations in conjugated polymers. AB - Based on a tight binding model combined with a nonadiabatic dynamics approach, we theoretically investigate the exciton intrachain transport in conjugated polymers with different interchain packing configurations. We construct two different interchain packing configurations, i.e. linear and exponential forms, and simulate the dynamical processes of the exciton transport in these systems. We find that, in both cases, there exists a distribution of driving force for exciton transport, which stems from the gradient of the exciton creation energy along the chains. This finding enriches the picture of exciton transport in polymers and provides a new idea to improve the exciton transport length in polymeric photovoltaic devices. PMID- 26112646 TI - Recombinant influenza virus carrying human adenovirus epitopes elicits protective immunity in mice. AB - Human adenoviruses (HAdVs) are known to cause a broad spectrum of diseases in pediatric and adult patients. As this time, there is no specific therapy for HAdV infection. This study used reverse genetics (RG) to successfully rescue a recombinant influenza virus, termed rFLU/HAdV, with the HAdV hexon protein antigenic epitope sequence inserted in the influenza non-structural (NS1) protein gene. rFLU/HAdV morphological characteristics were observed using electron microscopy. Furthermore, BALB/c mice immunized twice intranasally (i.n.) with 10(4) TCID50 or 10(5) TCID50 rFLU/HAdV showed robust humoral, mucosal, and cell mediated immune responses in vivo. More importantly, these specific immune responses could protect against subsequent wild-type HAdV-3 (BJ809) or HAdV-7 (BJ1026) challenge, showing a significant reduction in viral load and a noticeable alleviation of histopathological changes in the challenged mouse lung in a dose-dependent manner. These findings highlighted that recombinant rFLU/HAdV warrants further investigation as a promising HAdV candidate vaccine and underscored that the immuno-protection should be confirmed in primate models. PMID- 26112648 TI - Suramin inhibits chikungunya virus replication through multiple mechanisms. AB - Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes severe and often persistent arthritis. In recent years, millions of people have been infected with this virus for which registered antivirals are still lacking. Using our recently established in vitro assay, we discovered that the approved anti parasitic drug suramin inhibits CHIKV RNA synthesis (IC50 of ~5MUM). The compound inhibited replication of various CHIKV isolates in cell culture with an EC50 of ~80MUM (CC50>5mM) and was also active against Sindbis virus and Semliki Forest virus. In vitro studies hinted that suramin interferes with (re)initiation of RNA synthesis, whereas time-of-addition studies suggested it to also interfere with a post-attachment early step in infection, possibly entry. CHIKV (nsP4) mutants resistant against favipiravir or ribavirin, which target the viral RNA polymerase, did not exhibit cross-resistance to suramin, suggesting a different mode of action. The assessment of the activity of a variety of suramin-related compounds in cell culture and the in vitro assay for RNA synthesis provided more insight into the moieties required for antiviral activity. The antiviral effect of suramin-containing liposomes was also analyzed. Its approved status makes it worthwhile to explore the use of suramin to prevent and/or treat CHIKV infections. PMID- 26112647 TI - Chronic hepatitis B: A wave of new therapies on the horizon. AB - This year marks the 50th anniversary of the discovery of the Australia antigen (Blumberg et al., 1965), which in 1967 was identified to be the hepatitis B virus (HBV) surface antigen. Even though several antiviral medications have been in use for the management of chronic HBV infection for more than 20years, sustained clearance of HBsAg, similar to the sustained viral response (SVR) or cure in chronic hepatitis C, occurs in only a minority of treated patients. Moreover, even after 10years of effective suppression of HBV viremia with current therapy, there is only a 40-70% reduction in deaths from liver cancer. Recent success in developing antivirals for hepatitis C that are effective across all genotypes has renewed interest in a similar cure for chronic HBV infection. In this article, we review a wave of newly identified drug targets, investigational compounds and experimental strategies that are now under clinical evaluation or in preclinical development. The paper forms part of a symposium in Antiviral Research on "An unfinished story: From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." PMID- 26112649 TI - Propensity-matched analysis of minimally invasive mitral valve repair using a nationwide surgical database. AB - PURPOSE: The aim of this study was to compare the cases of minimally invasive mitral valve surgery (MICS-mitral) performed using right mini-thoracotomy (RT) with those performed using median sternotomy (MS). METHODS: Between 2008 and 2012, 6137 patients underwent isolated mitral valve repair at 210 institutions and were registered in the Japan Adult Cardiovascular Surgery Database. We compared 756 who underwent MICS-mitral via RT to 5381 MS patients and performed a one-to-one matched analysis based on the estimated propensity score. RESULTS: The in-hospital mortality was similar between both groups (RT vs. MS: 0.5 vs. 1.1%). Although the incidence of postoperative stroke, renal failure, and prolonged ventilation was similar, the number of patients with mediastinitis was greater in the MS group (RT vs. MS: 0 vs. 0.7%, p < 0.01). Reexploration for bleeding was more frequent in the RT group (RT vs. MS: 2.9 vs. 1.4%, p < 0.01). Mortality and morbidity occurred at a higher rate in low-volume institutions. The propensity analysis showed that the operation-related times were significantly longer in the RT group, while the length of hospital stay was shorter. In a propensity analysis of patients <60 years of age, there was no in-hospital mortality. CONCLUSIONS: MICS-mitral via RT was successful without compromising the clinical outcomes. Although the operation time and postoperative bleeding should be improved, an RT approach is safe in appropriately selected patients, especially those <60 years of age or treated in a high-volume center. PMID- 26112650 TI - Designing a study to evaluate the benefit of a biomarker for selecting patient treatment. AB - Biomarkers that predict the efficacy of treatment can potentially improve clinical outcomes and decrease medical costs by allowing treatment to be provided only to those most likely to benefit. We consider the design of a randomized clinical trial in which one objective is to evaluate a treatment selection marker. The marker may be measured prospectively or retrospectively using samples collected at baseline. We describe and contrast criteria around which the trial can be designed. An existing approach focuses on determining if there is a statistical interaction between the marker and treatment. We propose three alternative approaches based on estimating clinically relevant measures of improvement in outcomes with use of the marker. Importantly, our approaches accommodate the common scenario in which the marker-based rule for recommending treatment is developed with data from the trial. Sample sizes are calculated for powering a trial to assess these criteria in the context of adjuvant chemotherapy for the treatment of estrogen-receptor-positive, node-positive breast cancer. In this example, we find that larger sample sizes are generally required for assessing clinical impact than for simply evaluating if there is a statistical interaction between marker and treatment. We also find that retrospectively selecting a case-control subset of subjects for marker evaluation can lead to large efficiency gains, especially if cases and controls are matched on treatment assignment. PMID- 26112651 TI - Life with a stoma after curative resection for rectal cancer: a population-based cross-sectional study. AB - AIM: The aim of the investigation was to examine life with a stoma after rectal cancer surgery. METHOD: This was a population-based, cross-sectional study of patients with a stoma treated for rectal cancer from 2001 to 2007. A questionnaire was mailed to patients who had undergone abdominoperineal excision, Hartmann's procedure and anterior resection with a permanent stoma. RESULTS: Informative answers were obtained from 644 (88%) of 732 patients. Most (91%) managed the stoma on their own. There was an impact of the stoma on the quality of life in 68% of patients but this was minor in 50%. Leakage of the appliance was reported in 59%, and 58% of patients were disturbed by the smell of faeces. A parastomal hernia was reported in 57% and pain at the stoma site in 30%. There was no association between the impact of the stoma on the quality of life and gender, type of surgery, use of radiochemotherapy or the interval from surgery. CONCLUSION: Most patients reported little or no impact on quality of life resulting from the stoma, but many patients were disturbed by the smell or leakage of faeces. The parastomal hernia rate was extremely high. PMID- 26112652 TI - Financial Hardship--an Unwanted Consequence of Cancer Treatment. AB - The substantial economic burden of cancer is increasingly being shifted to patients. Financial burden experienced by patients as a result of medical treatment has an impact on their lifestyle choices, health behaviors, and quality of life. Variation in treatment recommendations based on the patients' economic status or affordability may be against the basic tenet of social justice and is a growing challenge for policy makers. This review summarizes the multifaceted constructs and current trends associated with financial hardship within the context of cancer care and healthcare economics focusing mainly on hematological malignancies but supplemented by nonhematological cancer and general medical literature. We also highlight the patient and physician perspectives about this issue and identify important areas for future research. We discuss the need for more proactive solutions so that patients can achieve good clinical outcomes, without catastrophic financial consequences for themselves and their families. PMID- 26112653 TI - Unique Case of Posterior Tibial Tendon Dysfunction After Stingray Strike. AB - BACKGROUND: Posterior tibial tendon dysfunction is a common cause of adult acquired flatfoot deformity. The cause of posterior tibial tendon dysfunction is often multifactorial and may include repetitive microtrauma, poor blood supply to the tendon, and, rarely, traumatic rupture. CASE DESCRIPTION: We present the case of a 69-year-old male with posterior tibial tendon dysfunction secondary to a stingray injury that occurred directly into the posterior tibial tendon. This injury led to an acquired adult flatfoot deformity that ultimately required surgical reconstruction. At the time of surgery, the posterior tibial tendon was severely degenerative at the site of skin penetration. LITERATURE REVIEW: Previous case reports of stingray injury describe full-thickness skin penetration with a subsequent inflammatory response and large zone of necrobiosis. This is the first reported case of stingray trauma and envenomation directly into tendon with subsequent tendon dysfunction. CLINICAL RELEVANCE: There are thousands of stingray injuries in the United States annually. Injuries vary in severity depending on the type of stingray, size of stingray, and depth and location of injury. For certain injuries, such as direct penetration into tendon, early irrigation and debridement may limit subsequent deficits caused by progressive tendon dysfunction. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case study. PMID- 26112654 TI - [Protect, and defend your health in the workplace too]. PMID- 26112655 TI - [Development of an instrument for the surveillance of quality indicators in specialized training in Preventive Medicine and Public Health]. AB - This study describes the process of developing an instrument intended for use in assessing satisfaction with the quality of training in preventive medicine and public health for resident physicians. To develop this instrument, the National Survey of Satisfaction with Medical Residency was adapted by an expert panel consisting of 23 resident physicians in preventive medicine and public health belonging to 9 autonomous communities in Spain. The adaptation of the survey to the specialty rotations included new dimensions and items and was evaluated with a 5-point Likert scale. The most important dimensions were planning and the achievement of specific objectives, supervision, delegation of responsibilities, resources and work environment, personal assessment, encouragement, support, and whether the rotation resulted in a publication or research project, etc. The development and utilization of this tool will enable future trainees in preventive medicine and public health to make an informed choice about their training itineraries. PMID- 26112656 TI - Efficacy of Tiotropium + Olodaterol in Patients with Chronic Obstructive Pulmonary Disease by Initial Disease Severity and Treatment Intensity: A Post Hoc Analysis. AB - INTRODUCTION: The once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting beta2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate-very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity. METHODS: 5162 patients were randomized and treated with olodaterol 5 ug, tiotropium 2.5 ug, tiotropium 5 ug, tiotropium + olodaterol 2.5/5 ug, or tiotropium + olodaterol 5/5 ug (all once daily via Respimat((r)) inhaler). Primary efficacy (lung function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids. RESULTS: Tiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3-4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0-3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline. CONCLUSIONS: Tiotropium + olodaterol 5/5 ug significantly improved FEV1 AUC0-3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 ug and tiotropium 5 ug alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease. FUNDING: Boehringer Ingelheim. TRIAL REGISTRATION: ClinicalTrials.gov numbers, NCT01431274 and NCT01431287. PMID- 26112657 TI - Efficacies of designer biochars in improving biomass and nutrient uptake of winter wheat grown in a hard setting subsoil layer. AB - In the Coastal Plains region of the United States, the hard setting subsoil layer of Norfolk soils results in low water holding capacity and nutrient retention, which often limits root development. In this region, the Norfolk soils are under intensive crop production that further depletes nutrients and reduces organic carbon (C). Incorporation of pyrolyzed organic residues or "biochars" can provide an alternative recalcitrant C source. However, biochar quality and effect can be inconsistent and different biochars react differently in soils. We hypothesized that addition of different designer biochars will have variable effects on biomass and nutrient uptake of winter wheat. The objective of this study was to investigate the effects of designer biochars on biomass productivity and nutrient uptake of winter wheat (Triticum aestivum L.) in a Norfolk's hard setting subsoil layer. Biochars were added to Norfolk's hard setting subsoil layer at the rate of 40 Mg ha(-1). The different sources of biochars were: plant-based (pine chips, PC); animal-based (poultry litter, PL); 50:50 blend (50% PC:50% PL); 80:20 blend (80% PC:20% PL); and hardwood (HW). Aboveground and belowground biomass and nutrient uptake of winter wheat varied significantly (p?0.0001) with the different designer biochar applications. The greatest increase in the belowground biomass of winter wheat over the control was from 80:20 blend of PC:PL (81%) followed by HW (76%), PC (59%) and 50:50 blend of PC:PL (9%). However, application of PL resulted in significant reduction of belowground biomass by about 82% when compared to the control plants. The average uptake of P, K, Ca, Mg, Na, Al, Fe, Cu and Zn in both the aboveground and belowground biomass of winter wheat varied remarkably with biochar treatments. Overall, our results showed promising significance for the treatment of a Norfolk's hard setting subsoil layer since designer biochars did improve both aboveground/belowground biomass and nutrient uptake of winter wheat. PMID- 26112658 TI - Impacts of propagating, frustrated and surface modes on radiative, electrical and thermal losses in nanoscale-gap thermophotovoltaic power generators. AB - The impacts of radiative, electrical and thermal losses on the performances of nanoscale-gap thermophotovoltaic (nano-TPV) power generators consisting of a gallium antimonide cell paired with a broadband tungsten and a radiatively optimized Drude radiator are analyzed. Results reveal that surface mode mediated nano-TPV power generation with the Drude radiator outperforms the tungsten radiator, dominated by frustrated modes, only for a vacuum gap thickness of 10 nm and if both electrical and thermal losses are neglected. The key limiting factors for the Drude- and tungsten-based devices are respectively the recombination of electron-hole pairs at the cell surface and thermalization of radiation with energy larger than the cell absorption bandgap. A design guideline is also proposed where a high energy cutoff above which radiation has a net negative effect on nano-TPV power output due to thermal losses is determined. It is shown that the power output of a tungsten-based device increases by 6.5% while the cell temperature decreases by 30 K when applying a high energy cutoff at 1.45 eV. This work demonstrates that design and optimization of nano-TPV devices must account for radiative, electrical and thermal losses. PMID- 26112659 TI - Mothers' appreciation of chromosomal microarray analysis for autism spectrum disorder. AB - PURPOSE: The aim of this study was to examine mothers' experiences with chromosomal microarray analysis (CMA) for a child with autism spectrum disorder (ASD). DESIGN AND METHODS: This is a descriptive qualitative study using thematic content analysis of in-depth interview with 48 mothers of children who had genetic testing for ASD. RESULTS: The principal theme, "something is missing," included missing knowledge about genetics, information on use of the results, explanations of the relevance to the diagnosis, and relevance to life-long care. Two subordinate themes were (a) disappreciation of the helpfulness of scientific information to explain the diagnosis, and (b) returning to personal experience for interpretation. PRACTICE IMPLICATIONS: The test "appreciated" in value when results could be linked to the phenotype. PMID- 26112660 TI - Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab. AB - Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen. PMID- 26112661 TI - In vitro dihydrouridine formation by tRNA dihydrouridine synthase from Thermus thermophilus, an extreme-thermophilic eubacterium. AB - Dihydrouridine (D) is formed by tRNA dihydrouridine synthases (Dus). In mesophiles, multiple Dus enzymes bring about D modifications at several positions in tRNA. The extreme-thermophilic eubacterium Thermus thermophilus, in contrast, has only one dus gene in its genome and only two D modifications (D20 and D20a) in tRNA have been identified. Until now, an in vitro assay system for eubacterial Dus has not been reported. In this study, therefore, we constructed an in vitro assay system using purified Dus. Recombinant T. thermophilus Dus lacking bound tRNA was successfully purified. The in vitro assay revealed that no other factors in living cells were required for D formation. A dus gene disruptant (Deltadus) strain of T. thermophilus verified that the two D20 and D20a modifications in tRNA were derived from one Dus protein. The Deltadus strain did not show growth retardation at any temperature. The assay system showed that Dus modified tRNA(Phe) transcript at 60 degrees C, demonstrating that other modifications in tRNA are not essential for Dus activity. However, a comparison of the formation of D in native tRNA(Phe) purified from the Deltadus strain and tRNA(Phe) transcript revealed that other tRNA modifications are required for D formation at high temperatures. PMID- 26112662 TI - THE WORKING MODEL OF THE CHILD INTERVIEW: STABILITY OF THE DISRUPTED CLASSIFICATION IN A COMMUNITY INTERVENTION SAMPLE. AB - The Working Model of the Child Interview (WMCI; C.H. Zeanah, D. Benoit, & M.L.Barton, 1986) assesses caregiver internal representation of his or her child and the relationship with the child, with a relatively new coding system for representations associated with disorganized attachment-WMCI-Disrupted (WMCI-D; A. Crawford & D. Benoit, 2009). In the present study, we investigated the stability of the WMCI-D classification using a sample of 62 mothers who completed the WMCI twice as part of their involvement in a randomized trial comparing an attachment-focused parent group to home visiting. Demographic information and measures of maternal sensitivity, parenting stress, and infant attachment also were obtained in the randomized trial. There was significant concordance between WMCI-D classifications over 8 months (from pretest to follow-up) (90% agreement; kappa = .79), with 61% of mothers remaining disrupted, 29% remaining not disrupted, 8% becoming disrupted, and 2% becoming not-disrupted. Compared to mothers with not-disrupted representations, mothers classified as disrupted had lower socioeconomic status, more parenting stress, and infants with less attachment security, ps < .05. These results suggest that the WMCI-D classification is stable over 8 months during infancy. The findings are consistent with research demonstrating stability for disorganized/unresolved/disrupted classifications, the validity of the WMCI-D classification, and the lack of intervention impact on disorganized attachment. PMID- 26112663 TI - [Inter-rater concordance of the "Nursing Activities Score" in intensive care]. AB - OBJECTIVE: To evaluate inter-rater concordance in the valuation of the "Nursing Activities Score". METHOD: Cross-sectional descriptive study conducted from December 2012 until June 2013 in a general intensive care unit with twelve beds. Three evaluator nurses, simultaneously and independently, through the patient daily charts, scored the nursing workload using Nursing Activities Score scale in all patients admitted over 18 years old. RESULTS: Three hundreds and thirty-nine records were collected. The intra-class correlation coefficient (ICC) between evaluators was 0.92 (0.89-0.94). A perfect concordance was obtained in 39.1% of the items, with 52.2% having a high, and 8.7% having lower concordance, corresponding to two of the items with multiple scoring options. Significant differences between two of the evaluators (P=.049) were found. CONCLUSIONS: Although the inter-rater concordance was high, more accurate records are needed to reduce the variability of the items with multiple options and to allow more accuracy in the interpretation and measurement of the data regarding nursing workload. PMID- 26112664 TI - One step forward, two steps back: The story of everolimus in advanced breast cancer. AB - There has been a substantial surge of 'targeted agents' in contemporary anticancer drug armamentarium and some of these agents have revolutionized the outcome of cancer patients. However, on contrary to the nomenclature, not all new targeted agents are selected based on presence of target molecules on the cancer cells. Drugs are typically approved based on demonstration of benefit in randomized controlled trials with regards to efficacy outcomes although both the 'benefits' and 'outcomes' are defined inconsistently. Surrogates that are not validated properly are often used as endpoints. Furthermore, new anticancer drugs are frequently associated with increased inconvenience to the patients and/or to the society due to added toxicity and cost. In this perspective article, emphasis is given to the above problems focusing on room for improvement in anticancer drug development. An illustration of a recently approved drug to treat advanced breast cancer, everolimus and a previously revoked drug bevacizumab is given. PMID- 26112665 TI - Consonant discrimination by Mandarin-speaking children with prelingual hearing impairment. AB - OBJECTIVES: Little is known about the consonant discrimination ability of Mandarin-speaking children with prelingual hearing impairment (HI) and fitted with hearing aids (HAs). The present study aimed to evaluate Mandarin consonant discrimination ability in children with HI, and explore the effects of unaided and aided hearing threshold, the age of first HA fitting and the duration of HA use on consonant discrimination ability. METHODS: Subjects were Mandarin-speaking children aged 5;4-12;6 years with profound HI (n=41), children aged 6;1-12;4 years with severe HI (n=26), and children aged 5;0-11;9 years with moderate HI (n=9). The Mandarin Consonant Discrimination Test was administered in six test conditions: -10, -5, 0, 5 and 10dB signal to noise ratios (S/Ns) and quiet. HAs were in the usual user's settings, adjusted to match the manufacturer prescribed settings and individual preferences, and the volume was set to comfortable listening level. RESULTS: The results revealed that /p(h)/-/t(h)/, /ts/-/ts/ and /z/-/l/ were the most difficult and /p/-/p(h)/, /t/-/t(h)/, /tc/-/tc(h)/ and /k/ /k(h)/ were the easiest consonant minimal pairs to discriminate in quiet both for children with profound HI and those with moderate to severe HI. In noise, no significant difference in performance was found among all consonant minimal pairs. A backward elimination stepwise multiple linear regressions revealed that unaided hearing level accounted for 25.4% of the variance in consonant discrimination performance in noise at 10dB S/N and 30.4% in quiet. However, aided hearing threshold, the age of first HA fitting and the duration of HA use did not significantly predict consonant discrimination ability both in quiet and in noise. CONCLUSIONS: Consonant discrimination performance of children with profound HI was poorer than those with moderate to severe HI. The ability to discriminate consonant pairs seems to depend on age of acquisition of the consonants. Although the age of first HA fitting and the duration of HA use were not correlated with consonant discrimination outcomes, this finding does not preclude the importance of early HA fitting. PMID- 26112672 TI - Cellular backpackers deliver lymphoma drugs. AB - Researchers have attached capsules containing the drug SN-38, a relative of irinotecan, to T cells. When infused into mice with a cancer similar to Burkitt lymphoma, the T cells entered the spleen, lymph nodes, and bone marrow where B cell tumors occurred, increasing the amount of drug reaching the tumors compared with other methods, and prolonging survival. PMID- 26112666 TI - Prevalence of cochlear dead regions in moderate to severe sensorineural hearing impaired children. AB - OBJECTIVES: To investigate the overall prevalence of cochlear dead regions in children with moderate to severe sensorineural hearing impairment. METHODS: Threshold-equalizing noise (or TEN) test was administered on thirty sensorineural hearing impaired children (8 girls, 22 boys), aged 5-14 years (mean+/-SD8.5+/ 2.8). RESULTS: Classifying by subject, 76% tested positive for cochlear dead regions in one or both ears at least at one frequency. Classifying by ears, 58.3% had dead regions at one frequency or more. Classifying by the number of frequencies were tested, 20% met the criteria for a dead region. The difference between mean absolute thresholds in two groups was statistically significant at 1000Hz and below (p<0.05). CONCLUSION: The results indicated a relatively high prevalence of dead regions in children with sensory neural hearing impairment, especially for frequencies at which the hearing loss exceeds 70dB HL. PMID- 26112673 TI - Effects of Intramuscular Injection of Autologous Immunoglobulin on Clinical Severity and Serum IgE Concentration in Patients with Atopic Dermatitis. AB - BACKGROUND/OBJECTIVE: The management of patients with atopic dermatitis (AD) is often difficult for both patients and physicians. We hypothesized that repeated intramuscular injections of autologous immunoglobulin can induce clinical improvement in patients with AD by correcting immune dysfunction. METHODS: Seventeen adult patients with severe AD were treated by intramuscular injection of 50 mg autologous immunoglobulin (mainly IgG with a purity >=97%) twice a week for 4 weeks. The standardized clinical severity scoring system for AD (SCORAD) value and serum IgE concentration were measured at baseline and at 4, 8, and 12 weeks. RESULTS: SCORAD values and serum IgE concentrations significantly decreased at 4, 8, and 12 weeks compared to baseline (p < 0.05). No significant side effects were observed. CONCLUSIONS: Repeated intramuscular injections of autologous immunoglobulin significantly decreased the clinical severity and serum IgE concentration in patients with severe AD. Further studies are required to evaluate the clinical significance of these findings. PMID- 26112674 TI - A biological tissue adhesive and dissolvent system for intraocular tumor plaque radiotherapy: an in vivo animal model experiment. AB - PURPOSE: To examine a novel biological adhesive and dissolvent system for plaque placement and removal using fibrin glue and urokinase, respectively, in an in vivo animal model. METHODS: The study was performed on 23 rabbit eyes. Of these, eight underwent a technical feasibility study and ultrasonographic plaque displacement measurements, nine were examined clinically and by magnetic resonance imaging and histopathology for tissue reaction to the biological substances used, and in six the impact of fibrin glue as an orbital space occupier on intraocular pressure was assessed. In an additional ex vivo experiment, the glue's radiation attenuating properties were tested using an oncology EDR2 film. RESULTS: Plaque horizontal movement throughout follow-up (7 10 days) was negligible (0.5 +/- 0.2 mm), and there was no tilting whatsoever. In the tissue response experiment, no adverse effects were recorded after application of fibrin or urokinase throughout the 21-day follow-up period. Interestingly, a circumscribed local inflammatory response was noted in tissue surrounding the fibrin glue, and persisted at 21 days. In the orbital space occupying experiment, application of 1 cc fibrin glue did not cause a significant elevation in intraocular pressure (IOP) (P = 0.06), and in the ex vivo experiment, there was no significant difference between radiation readings with and without glue separation of the radioactive sources and film (P = 0.065). CONCLUSIONS: The adhesive and dissolvent system was feasible and safe for plaque placement and removal. It may be superior to conventional surgical plaque placement methods in eliminating the relatively common risk of plaque tilting and complications due to scleral suturing. PMID- 26112676 TI - Serrated polyp of the duodenum. PMID- 26112677 TI - Ethics in publication. AB - Publication of scientific manuscripts remains our core method of sharing knowledge and advanced scientific inquiry. Pressures to publish for reasons other than pure discovery have the potential to corrupt this process. The core principles of scientific ethics outlined above provide guidance on how to maintain the integrity of our scientific process.We, as journal editors, are committed to the advancement of scientific knowledge and the ethical process of publication. We do the best we can to make sure that the articles we publish fulfill all the criteria of a well-conducted study. PMID- 26112675 TI - A comprehensive quantitative phosphoproteome analysis of rice in response to bacterial blight. AB - BACKGROUND: Rice is a major crop worldwide. Bacterial blight (BB) caused by Xanthomonas oryzae pv. oryzae (Xoo) has become one of the most devastating diseases for rice. It has been clear that phosphorylation plays essential roles in plant disease resistance. However, the role of phosphorylation is poorly understood in rice-Xoo system. Here, we report the first study on large scale enrichment of phosphopeptides and identification of phosphosites in rice before and 24 h after Xoo infection. RESULTS: We have successfully identified 2367 and 2223 phosphosites on 1334 and 1297 representative proteins in 0 h and 24 h after Xoo infection, respectively. A total of 762 differentially phosphorylated proteins, including transcription factors, kinases, epi-genetic controlling factors and many well-known disease resistant proteins, are identified after Xoo infection suggesting that they may be functionally relevant to Xoo resistance. In particular, we found that phosphorylation/dephosphorylation might be a key switch turning on/off many epi-genetic controlling factors, including HDT701, in response to Xoo infection, suggesting that phosphorylation switch overriding the epi-genetic regulation may be a very universal model in the plant disease resistance pathway. CONCLUSIONS: The phosphosites identified in this study would be a big complementation to our current knowledge in the phosphorylation status and sites of rice proteins. This research represents a substantial advance in understanding the rice phosphoproteome as well as the mechanism of rice bacterial blight resistance. PMID- 26112678 TI - Endoscopic suturing closure of large iatrogenic colonic perforation. PMID- 26112679 TI - Dedifferentiated liposarcoma presenting as a large rectal mass. PMID- 26112680 TI - EUS-guided internal drainage of a deep abdominal postoperative abscess after Whipple procedure. PMID- 26112682 TI - [Intraoperative verification of colorectal anastomotic integrity]. AB - Early postoperative anastomotic complications have serious clinical implications for the patients morbidity, mortality as well as long-term results. A number of measures can be undertaken to reduce the risk of anastomotic complications, including intraoperative colorectal anastomotic integrity assessment. Methods used to assess anastomotic reliability have gradually developed from basic mechanical techniques, direct visual endoluminal inspection, to microperfusion assessment of perianastomotic tissue. Moderate benefit in terms of reduced postoperative anastomotic complications has been shown with mechanical patency testing and partly with intraoperative endoscopic visualization of colorectal anastomoses. More recently, indocyanine green (ICG) fluorescence imaging methods have emerged as major contributions to anastomotic patency assessment and intraoperative decision making during surgical colorectal procedures including decreased numbers of ileostomies. PMID- 26112683 TI - [Treatment of gastrointestinal stromal tumors--a comprehensive view of the surgeon]. AB - INTRODUCTION: Gastrointestinal stromal tumors (GIST) are specific mesenchymal tumors of the gastrointestinal tract. Most of GISTs (95%) result from activating mutations in one of the receptor tyrosine kinase proteins (KIT). Tumor cells express this protein. GIST is most common in the stomach and small intestine, but may occur anywhere in the gastrointestinal tract and intra-abdominal soft tissues. The variety of its clinical presentations is related to localization of the tumor, its size and relationship to surrounding organs. Surgery is the first choice of treatment for patients with localized or potentially resectable tumors with the intention of R0 resection. Targeted therapy with imatinib (a selective inhibitor of the KIT protein) is the primary option for patients with metastatic GIST, as adjuvant treatment after surgery or neo-adjuvant therapy prior to surgery in indicated cases. This paper describes comprehensive therapy of GIST with an emphasis laid on the status of surgical treatment, and it highlights some controversial topics, e.g. the role of surgery for metastatic disease or neo adjuvant targeted therapy. CONCLUSION: GIST is a relatively rare tumor most commonly affecting the stomach and small intestine. Surgical treatment is not replaceable in the treatment strategy of this disease. The diagnostic-therapeutic approach to patients with GIST must be comprehensive. Due to prescribing restrictions of biological therapies, these patients are inevitably directed to specialized centers where surgical treatment should also be preferably provided. PMID- 26112684 TI - [Pancreatic metastases--diagnosis, radical surgery, complications and survival]. AB - INTRODUCTION: Although generally uncommon, pancreatic metastases are increasingly encountered in clinical practice. The benefit of pancreatic resections in this setting is unclear and still being discussed. Renal cell carcinoma is the most frequent primary tumour metastasing to the pancreas--R0 resections in cases of solitary metastases can be performed. Resections in malignant melanoma and ovarian cancer are rather considered as palliative. The aim of this study is to analyse our own set of patients operated on for metastases into the pancreas and evaluate the results of their surgical treatment. METHODS: We identified the patients operated on for metastases to the pancreas. Patient and tumour characteristics were summarized using descriptive statistics. RESULTS: A total of 9 patients (out of 312 patients undergoing resection for malignancy in the period of 2006-2014) with pancreatic metastases were analysed. All but one were asymptomatic; the symptomatic patient suffered from GI bleeding. All patients had a metachronous lesion with a median length of 12 years (421 years) between the initial operation and pancreatic resection. The most common metastasing tumour was renal cell carcinoma (77%) with the highest incidence occurring at the head of the pancreas (44%). The most frequent procedure used was the pylorus preserving pancreatic head resection (44%). The median operating time was 247 min, (126375 min). Six patients were complication free, the median of their hospital stay was 9.5 days (812 days). Complications included PPH type C and PF type B both of which required surgical intervention; however, PF type A required no intervention. No postoperative deaths occurred, multiple metastases were found in 4 patients with renal cell carcinoma metastases. The median of follow-up has been 11.5 months, (334 months). CONCLUSION: Survival after pancreatic resections due to renal cell carcinoma is favourable. Mortality is low and morbidity is similar to that associated with pancreatic resections due to other aetiologies, making surgery a valid and safe treatment option. Lifelong follow-up of patients after nephrectomy is advised. Resections in pancreatic metastases of malignant melanoma or ovarian carcinoma are considered as palliative, their indication being individual following interdisciplinary consultation. PMID- 26112685 TI - [Perspective of patients undergoing surgery for secondary peritonitis]. AB - INTRODUCTION: Peritonitis is a life-threatening disease with high mortality and morbidity. The prognosis depends on patient factors, the nature of the disease, and on diagnostic and therapeutic methods. The goal of our study was to perform a retrospective analysis of a group of patients with secondary peritonitis and to compare patients with non-stercoral peritonitis and those with stercoral peritonitis, and finally, to determine the prognostic value of the MPI prognostic index. METHODS: We analysed 124 patients who had undergone surgery for secondary peritonitis during the years 2012-2013. We divided the patients into two groups. Group A comprised patients with non-stercoral peritonitis and group B consisted of patients with stercoral peritonitis. We compared the two groups and predicted the peritonitis outcome using the Mannheim Peritonitis Index (MPI). RESULTS: The complete sample of 124 patients consisted of 70 men and 54 women. The average age of the patients was 63 years and the average length of hospitalization was 18 days. In total, 18 patients (15%) died during their hospitalization. The average MPI score was 19, which correlates to an 18% mortality rate prediction. In group A, which consisted of 68 patients with non-stercoral peritonitis, the average age was 59 years and the average length of hospitalization was 12 days. Two patients (3%) from this group died during hospitalization. The average MPI score was 9, which correlates to a 9% mortality rate prediction. In group B, which consisted of 56 patients with stercoral peritonitis, the average age was 67 years and the average length of hospitalization was 25 days. 16 patients (29%) from this group died during hospitalization. The average MPI score was 29, which correlates to a 31% mortality rate prediction. CONCLUSIONS: The outcome of our comparison between the two groups is that group A with non-stercoral peritonitis had a significantly lower mortality, lower number of complications and a shorter length of hospitalization. Both basic clinical data and sophisticated scoring systems can be used for mortality prediction in peritonitis. The Mannheim Peritonitis Index, a simple scoring system, proved to be useful in our study. PMID- 26112686 TI - [Intestinal volvulus caused by the ingestion of magnet balls: unexpected risk in children]. AB - INTRODUCTION: The occurrence of swallowed foreign bodies in the digestive system is a common problem in children with the highest incidence in children aged six months to five years. Most swallowed objects leave the human body per vias naturales while 10-20% of swallowed foreign bodies need to be removed with an endoscope. Serious and life-threatening situations are caused by the ingestion of foreign bodies in about 1% of all cases. CASE REPORT: The authors present a case of a two-year-old girl diagnosed with acute abdomen for which she was operated on. A small bowel volvulus and several intestinal fistulas were found intraoperatively. The cause of this finding was the ingestion of magnetic balls and a swallowed metal body drawn to them by magnetic force. CONCLUSION: If more than one magnetic body is ingested, it is necessary to admit the patient to hospital and to remove these foreign bodies using an endoscope. The position of the magnets which is not changing in a location inaccessible for an endoscope during 2448 hours is an indication for urgent operation. PMID- 26112687 TI - [Femoropopliteal deep vein thrombosis and popliteal artery pseudoaneurysm as a complication of multiple hereditary osteochondromatosis]. AB - Osteochondromas (exostoses) are the most common benign bone tumours. In most cases, osteochondroma occurs as a solitary lesion. Hereditary multiple osteochondromatosis is an autosomal dominant disorder manifested by multiple exostoses most commonly located at the metaphyses of long bones, the iliac crest, the ribs, the vertebral borders, and scapulas. Vascular complications of multiple osteochondromatosis are very rare, most frequently affecting the popliteal artery. The authors report the case of a 27-year-old female patient with hereditary multiple osteochondromatosis that was complicated by femoropopliteal deep vein thrombosis and giant popliteal artery pseudoaneurysm. PMID- 26112688 TI - [Endometriosis of the appendix presenting like acute appendicitis--a case report]. AB - INTRODUCTION: In general, pain in the lower right abdomen is the most frequent reason for hospital surgical admissions, acute appendicitis representing the most common cause of operation for acute abdomen. Timely appendectomy remains the only treatment in the early stages of inflammation and is usually uncomplicated, requiring only a short hospital stay. A differential diagnostic analysis necessitates a search for other, particularly long-term symptoms that might be driven to the background in cases of acute exacerbation. CASE REPORT: The case report presents a 38-year-old female patient who was admitted for lower right abdominal pain. Clinical examination and a blood test both suggested typical acute uncomplicated appendicitis, and therefore the patient underwent appendectomy. Haemorrhagic peritoneal fluid and nodularity of the appendix not typical for appendicitis was found. Oedema of the terminal ileum and a right adnexal tumour were a surprising finding. A more extensive surgical procedure involving ileocaecal resection and right-side adnexectomy was finally performed with regard to the intraoperative finding. The definitive diagnosis of appendiceal endometriosis, endometrial mass in the terminal intestine and ovarian endometriosis was established by histological evaluation. Long-term follow-up revealed microadenocarcinoma of cervix uteri. CONCLUSION: It is generally very difficult to confirm appendiceal endometriosis before operation, and revealing primary appendiceal endometriosis is virtually impossible. It is advisable to consider endometriosis in fertile women with chronic abdominal pain of unclear aetiology and gynaecological symptoms in their personal history. The best diagnostic and therapeutic method, respectively, is laparoscopy enabling exploration of the entire peritoneal cavity including the minor pelvis, and performing appendectomy as well as excision of suspicious endometrial lesions. The definitive diagnosis is usually established by histopathological evaluation. Gynaecological assessment and follow-up is highly recommended after surgery. PMID- 26112689 TI - Using the new hemostatic gelatin GELITA-SPON(r) RAPID3 to treat parenchymatous organs--a clinical observation. PMID- 26112690 TI - Matching on the disease risk score in comparative effectiveness research of new treatments. AB - PURPOSE: We use simulations and an empirical example to evaluate the performance of disease risk score (DRS) matching compared with propensity score (PS) matching when controlling large numbers of covariates in settings involving newly introduced treatments. METHODS: We simulated a dichotomous treatment, a dichotomous outcome, and 100 baseline covariates that included both continuous and dichotomous random variables. For the empirical example, we evaluated the comparative effectiveness of dabigatran versus warfarin in preventing combined ischemic stroke and all-cause mortality. We matched treatment groups on a historically estimated DRS and again on the PS. We controlled for a high dimensional set of covariates using 20% and 1% samples of Medicare claims data from October 2010 through December 2012. RESULTS: In simulations, matching on the DRS versus the PS generally yielded matches for more treated individuals and improved precision of the effect estimate. For the empirical example, PS and DRS matching in the 20% sample resulted in similar hazard ratios (0.88 and 0.87) and standard errors (0.04 for both methods). In the 1% sample, PS matching resulted in matches for only 92.0% of the treated population and a hazard ratio and standard error of 0.89 and 0.19, respectively, while DRS matching resulted in matches for 98.5% and a hazard ratio and standard error of 0.85 and 0.16, respectively. CONCLUSIONS: When PS distributions are separated, DRS matching can improve the precision of effect estimates and allow researchers to evaluate the treatment effect in a larger proportion of the treated population. However, accurately modeling the DRS can be challenging compared with the PS. PMID- 26112691 TI - Letter to the Editor Regarding The Use of Vancomycin Powder in Modern Spine Surgery: Systematic Review and Meta-Analysis of the Clinical Evidence. PMID- 26112693 TI - Genes involved in the pathogenesis of premature ovarian insufficiency. AB - Premature ovarian insufficiency (POI) is defined by the presence of primary or secondary amenorrhea, for at least 4 months, before the age of 40 years associated with follicle stimulating homone levels in menopausal range, exciding 40 UI/L. The diagnosis is confirmed by two blood sample at least 1 month to measure the level of FSH (over 40 UI/L) and level of estradiol (below 50 pmol/L). Ovarian follicular dysfunction and/or depletion of functional primordial follicles characterized this pathology. Abnormal bleeding patterns also include oligomenrrhea and polimenorrhea; because of these irregular menstrual cycles during adolescence, diagnosis could be difficult in young women. Excluding the cases in which an etiopathogenetic agent could be identified, such as in case of chemio- and radiotherapy or extensive surgery, women with autoimmune diseases and/or infections, the etiology of POI remains idiopathic. An important genetic component exists, supported by both a frequent recurring familiar event (20-30%) and the association with other different genetic disorders in particular the X chromosome defects and the implication of some different genes with significant functions in ovarian development. For most of the women the diagnosis of POI is unexpected because of there are no obvious signs or symptoms that precede the cessation of periods with a normal menstrual history, age of menarche and fertility prior to the onset of menopause. The diagnosis of POI has a deleterious psychological impact on the emotional sphere of the women affected: anger, depression, anxiety and sadness are common and the fact that the diagnosis coincides with infertility needs a psychological support. Oral hormonal replacement therapy (HRT) administration is not recommended as first choice of treatment because of the higher hormones concentration with respect to the real hormones necessity of the patients and transdermal HRT may be preferred in women with coagulation disturbances to relief symptoms and to improve to quality of life and the sexuality of these women until the age of 50 years old which is the median age of physiological menopause. Moreover it should be considered the associate comorbidities of POI such as bone loss, cardiovascular disease and endocrine disease. PMID- 26112692 TI - Rapid mapping of insertional mutations to probe cell wall regulation in Cryptococcus neoformans. AB - Random insertional mutagenesis screens are important tools in microbial genetics studies. Investigators in fungal systems have used the plant pathogen Agrobacterium tumefaciens to create tagged, random mutations for genetic screens in their fungal species of interest through a unique process of trans-kingdom cellular transconjugation. However, identifying the locations of insertion has traditionally required tedious PCR-based methods, limiting the effective throughput of this system. We have developed an efficient genomic sequencing and analysis method (AIM-Seq) to facilitate identification of randomly generated genomic insertions in microorganisms. AIM-Seq combines batch sampling, whole genome sequencing, and a novel bioinformatics pipeline, AIM-HII, to rapidly identify sites of genomic insertion. We have specifically applied this technique to Agrobacterium-mediated transconjugation in the human fungal pathogen Cryptococcus neoformans. With this approach, we have screened a library of C. neoformans cell wall mutants, selecting twenty-seven mutants of interest for analysis by AIM-Seq. We identified thirty-five putative genomic insertions in known and previously unknown regulators of cell wall processes in this pathogenic fungus. We confirmed the relevance of a subset of these by creating independent mutant strains and analyzing resulting cell wall phenotypes. Through our sequence based analysis of these mutations, we observed "typical" insertions of the Agrobacterium transfer DNA as well as atypical insertion events, including large deletions and chromosomal rearrangements. Initially applied to C. neoformans, this mutant analysis tool can be applied to a wide range of experimental systems and methods of mutagenesis, facilitating future microbial genetic screens. PMID- 26112694 TI - Interaction of intraocular lenses with fibronectin and human lens epithelial cells: Effect of chemical composition and aging. AB - The aim of this study is to investigate in vitro interactions between hydrophobic acrylate intraocular lenses (IOLs) and their biological environment. The influence of lens chemical composition and aging on fibronectin (FN) adsorption and on IOLs cytotoxicity on human lens epithelial cells was examined. Cytotoxicity of acrylate monomers used in IOLs manufacture was also investigated. Four different IOLs were included in the study: Acrysof((r)), Tecnis((r)), EnVista((r)), and iSert((r)). Implants were artificially aged in a xenon arc chamber to simulate 2 years of light exposure. Fibronectin adsorption on IOL surface was quantified using ELISA and correlated to surface roughness determined with AFM. Direct contact cytotoxicity was determined with the MTT assay and cell morphology was observed with light microscopy. Results showed that fibronectin adsorption did not differ significantly among IOLs, whatever their chemical composition. Moreover, aging conditions did not impact fibronectin adsorption. All IOLs were biocompatible even after applying 2-year aging conditions, with cell viability higher than 70%. Five acrylate monomers appeared to be toxic in the range of concentrations tested, but no monomer release from the IOLs could be detected during accelerated 2-year incubation with saline solution. This study did not reveal an influence of chemical composition and aging on protein adsorption and on biocompatibility. PMID- 26112695 TI - Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target. AB - BACKGROUND: Autophagy and genetic predisposition have been suggested to potentially play roles in the development of asthma. However, little is known about the role of autophagy in the pathogenesis of severe asthma. OBJECTIVE: We compared autophagy in the sputum granulocytes, peripheral blood cells (PBCs) and peripheral blood eosinophils (PBEs) between patients with severe asthma and those with non-severe asthma and investigated the functional effects of autophagy. METHODS: We enrolled 36 patients with severe asthma, 14 with non-severe asthma and 23 normal healthy controls in this study. Sputum granulocytes, PBCs and PBEs were isolated from each subject. Autophagy was evaluated based on the expression of microtubule-associated protein light chain 3 (LC3) by Western blot, confocal microscopy, transmission electron microscopy and flow cytometry. IL-8 levels were measured by ELISA. To induce autophagy, HL-60 cells, human primary small airway epithelial cells (SAECs) and A549 cells were treated with IL-5, IL-1beta and TNF alpha. To inhibit autophagy, PI3K inhibitors (LY29400 and 3-methyladenine [3-MA]) and hydroxychloroquine (HCQ) were used. Knockdown of ATG5 and Beclin-1 was performed in A549 cells, and the therapeutic effects of dexamethasone were evaluated. RESULTS: Higher autophagy levels were noted in sputum granulocytes, PBCs and PBEs from patients with severe asthma than from patients with non-severe asthma and healthy controls (P < 0.05 for all). IL-5 increased autophagy levels in both PBCs and PBEs (P < 0.05). 3-MA attenuated the increased expression of LC3 II and eosinophil cationic protein in HL-60 cells induced by IL-5 (P = 0.034 for both). Dexamethasone did not affect autophagy levels in PBEs. IL-1beta increased LC3-II expression and IL-8 production (P < 0.01) in SAECs, and this was attenuated by LY294002, 3-MA, HCQ and knockdown of ATG5 and Beclin-1 (in A549 cells) (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Autophagy could play a role in the pathogenesis of severe asthma. Autophagy modulation may be a novel therapeutic target for conventional therapy-resistant severe asthma. PMID- 26112696 TI - Granulocyte/Monocyte Adsorptive Apheresis in Moderate to Severe Ulcerative Colitis--Effective or Not? AB - BACKGROUND AND AIMS: Adsorptive granulocyte/monocyte apheresis (GMA) has shown promising efficacy in the treatment of patients with ulcerative colitis (UC). But a sham-controlled study was negative. A post-hoc analysis of this trial may haul out patients responding to GMA. METHODS: A total of 168 UC patients with a disease activity (DAI) between 6 and 11 were enrolled in this study. Out of 168 patients, 112 received GMA and 56 sham apheresis. The basis for this post hoc analysis is the clinical study report issued by Otsuka America Pharmaceutical. RESULTS: Baseline histology was available for 165 patients. Only 38% (63 of 165) of patients showed microscopic erosion/ulceration (group P). The remaining 62% of patients did not show microscopic erosion/ulceration (group A). The patients in group P showed significantly higher DAI, flexible proctosigmoidoscopy score and neutrophil infiltration into the colonic mucosa than those in group A (p = 0.0132, p = 0.0243 and p < 0.0001, respectively). Likewise, group P patients had a significantly (p = 0.0275) higher remission rate (11 of 46; 23.9%) when treated with GMA than with sham procedure (0 of 17; 0%). CONCLUSIONS: Patients in group P who had more active UC than those in group A showed clear clinical efficacy in response to GMA. We believe that true DAI should be specified for further randomized controlled trials. PMID- 26112697 TI - Paraganglioma and cyanotic congenital heart disease: The role of tisular hipoxia. PMID- 26112698 TI - Standard operating procedures for standardized mass rearing of the dengue and chikungunya vectors Aedes aegypti and Aedes albopictus (Diptera: Culicidae) - II Egg storage and hatching. AB - BACKGROUND: Management of large quantities of eggs will be a crucial aspect of the efficient and sustainable mass production of mosquitoes for programmes with a Sterile Insect Technique component. The efficiency of different hatching media and effectiveness of long term storage methods are presented here. METHODS: The effect on hatch rate of storage duration and three hatching media was analysed: deionized water, boiled deionized water and a bacterial broth, using Two-way ANOVA and Post hoc Tukey tests, and the Pearson correlation coefficient was used to find the effect on the proportion of collapsed eggs. Two long term storage methods were also tested: conventional storage (egg paper strips stored in zip lock bags within a sealed plastic box), and water storage (egg papers in a covered plastic cup with deionized water). Regression analyses were used to find the effect of water storage and storage duration on hatch rate. RESULTS: Both species hatched most efficiently in bacterial broth. Few eggs hatched in deionized water, and pre-boiling the water increased the hatch rate of Ae. aegypti, but not Ae. albopictus. A hatch rate greater than 80% was obtained after 10 weeks of conventional storage in Ae. aegypti and 11 weeks in Ae. albopictus. After this period, hatching decreased dramatically; no eggs hatched after 24 weeks. Storing eggs in water produced an 85% hatch rate after 5 months in both species. A small but significant proportion of eggs hatched in the water, probably due to combined effects of natural deoxygenation of the water over time and the natural instalment hatching typical of the species. CONCLUSIONS: The demonstrated efficiency of the bacterial broth hatching medium for both Ae. albopictus and Ae. aegypti facilitates mass production of these two important vector species in the same facility, with use of a common hatching medium reducing cost and operational complexity. Similarly the increased hatch rate of eggs stored in water would allow greater flexibility of egg management in a large programme over the medium term, particularly if oxygenation of the water by bubbling oxygen through the storage tray could be applied to prevent hatching during storage. PMID- 26112699 TI - Blood loss in primary total knee arthroplasty--body temperature is not a significant risk factor--a prospective, consecutive, observational cohort study. AB - BACKGROUND: Hypothermia related to anaesthesia and operating theatre environment is associated with increased blood loss in a number of surgical disciplines, including total hip arthroplasty. The influence of patient temperature on blood loss in total knee arthroplasty (TKA) has not been previously studied. METHODS: We recorded patient axillary temperature in the peri-operative period, up to 24 h post-operatively, and analysed the effect on transfusion rate and blood loss from a consecutive cohort of 101 patients undergoing primary TKA. RESULTS: No relationship between peri-operative patient temperature and blood loss was found within the recorded patient temperature range of 34.7-37.8 degrees C. Multivariable analysis found increasing age, surgical technique, type of anaesthesia and the use of anti-platelet and anticoagulant medications as significant factors affecting blood loss following TKA. CONCLUSION: Patient temperature within a clinically observed range does not have a significant impact on blood loss in primary TKA patients. As long as patient temperature is maintained within a reasonable range during the intra-operative and post operative periods, strategies other than rigid temperature control above 36.5 degrees C may be more effective in reducing blood loss following TKA. PMID- 26112700 TI - Facial pain/headache before and after surgery in patients with nasal polyposis. AB - CONCLUSION: Endoscopic surgery improved facial pain/headache and physical psychosocial impacts in patients with nasal polyposis. However, one fifth of patients still experienced residual pain after surgery, requiring neurologic counseling to look for the non-sinonasal cause of their symptoms. OBJECTIVE: Considering the limited amount of literature on facial pain/headache in patients with nasal polyposis, this prospective study assesses facial pain/headache and its impacts on the quality-of-life (QoL) before and after endoscopic surgery. METHODS: Facial pain/headache was assessed, using the DyNaChron questionnaire, in 107 patients with nasal polyposis 1 day prior to surgery and 6 weeks after surgery. All patients were operated on endoscopically on the bilateral ethmoidal labyrinths and olfactory clefts. RESULTS: Moderate or severe facial pain/headache was reported by 50% of the patients before surgery and by 20% after surgery. Post operatively, 79.44% of patients reported no/very mild pain (vs 47.66% pre operatively) and 20.56% moderate/severe pain (vs 52.33% pre-operatively). The pain was statistically reduced after surgery among patients with previous surgery (p = 0.0006). The scores of all analysed impacts of pain improved after surgery. However, patients with grade 1 polyps seemed to have less benefit from the surgery for facial pain/headache than those with more severe nasal polyposis. PMID- 26112701 TI - Polyploidy in Amphibia. AB - This review summarizes the current status of the known extant genuine polyploid anuran and urodelan species, as well as spontaneously originated and/or experimentally produced amphibian polyploids. The mechanisms by which polyploids can originate, the meiotic pairing configurations, the diploidization processes operating in polyploid genomes, the phenomenon of hybridogenesis, and the relationship between polyploidization and sex chromosome evolution are discussed. The polyploid systems in some important amphibian taxa are described in more detail. PMID- 26112702 TI - Vocal development during postnatal growth and ear morphology in a shrew that generates seismic vibrations, Diplomesodon pulchellum. AB - The ability of adult and subadult piebald shrews (Diplomesodon pulchellum) to produce 160Hz seismic waves is potentially reflected in their vocal ontogeny and ear morphology. In this study, the ontogeny of call variables and body traits was examined in 11 litters of piebald shrews, in two-day intervals from birth to 22 days (subadult), and ear structure was investigated in two specimens using micro computed tomography (micro-CT). Across ages, the call fundamental frequency (f0) was stable in squeaks and clicks and increased steadily in screeches, representing an unusual, non-descending ontogenetic pathway of f0. The rate of the deep sinusoidal modulation (pulse rate) of screeches increased from 75Hz at 3 4 days to 138Hz at 21-22 days, probably relating to ontogenetic changes in contraction rates of the same muscles which are responsible for generating seismic vibrations. The ear reconstructions revealed that the morphologies of the middle and inner ears of the piebald shrew are very similar to those of the common shrew (Sorex araneus) and the lesser white-toothed shrew (Crocidura suaveolens), which are not known to produce seismic signals. These results suggest that piebald shrews use a mechanism other than hearing for perceiving seismic vibrations. PMID- 26112703 TI - Post-traumatic epidural tension pneumocephalus: a case report. AB - INTRODUCTION: Pneumocephalus is usually a self-limiting condition commonly associated with neurosurgical interventions, head and facial trauma. In contrast, tension pneumocephalus is extremely rare, and considered a neurosurgical emergency. CASE PRESENTATION: We present a rare case of post-traumatic epidural tension pneumocephalus in a 30-year-old white man who deteriorated rapidly after a blunt head trauma. Imaging revealed a large, right temporoparietal epidural pneumocephalus with mass effect, most likely arising from a small defect in the mastoid sinus. A pre-existing mucocele was also suspected. Emergency burr hole evacuation was performed and he experienced full recovery, but more invasive treatment was eventually needed to resolve the condition. CONCLUSIONS: Epidural tension pneumocephalus is a rare and potentially life-threatening condition, but treatable with the right management. To the best of our knowledge, a post traumatic tension pneumocephalus caused by a pre-existing mucocele has not been reported in the literature. PMID- 26112705 TI - Trans-diaphragmatic left ventricular venting during peripheral venous-arterial extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) has proven to be an invaluable method of cardiopulmonary support in cases of severe cardiogenic shock. In an emergency, femoral artery and vein cannulation is the easiest and quickest access to initiate support. Often, with peripheral venous-arterial ECMO (VA ECMO), an inadequate reduction in left ventricular end-diastolic pressure (LVEDP) is present secondary to increased afterload from retrograde flow, inadequate RV drainage or persistent bronchial circulation. Elevated LVEDP has been known to be associated with poor myocardial recovery, LV thrombus formation and significant pulmonary edema. A cannulation strategy to achieve partial ventricular unloading is of paramount importance when considering ECMO support following cardiogenic shock to increase the potential for myocardial recovery. We present a novel case of emergent peripheral VA ECMO cannulation with a trans-diaphragmatic left ventricular (LV) vent in a 61-year-old, 79 kg male with end-stage liver disease and hepatitis B cirrhosis who suffered cardiac arrest during orthotopic liver transplantation. PMID- 26112704 TI - TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. AB - BACKGROUND: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. METHODS: We generated neuron-specific TNF deficient (NsTNF(-/-)) mice and compared outcomes of disease against TNF(f/f) control and global TNF(-/-) mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Intracerebral M. tuberculosis infection of TNF(-/-) mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF(-/-) mice were resistant to infection and presented with a phenotype similar to that in TNF(f/f) control mice. Impaired immunity in TNF(-/-) mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx. CONCLUSION: Our data show that neuron-derived TNF has a limited role in immune responses, but overall TNF production is necessary for protective immunity against CNS-TB. PMID- 26112706 TI - Structure and gating of the nuclear pore complex. AB - Nuclear pore complexes (NPCs) perforate the nuclear envelope and allow the exchange of macromolecules between the nucleus and the cytoplasm. To acquire a deeper understanding of this transport mechanism, we analyse the structure of the NPC scaffold and permeability barrier, by reconstructing the Xenopus laevis oocyte NPC from native nuclear envelopes up to 20 A resolution by cryo-electron tomography in conjunction with subtomogram averaging. In addition to resolving individual protein domains of the NPC constituents, we propose a model for the architecture of the molecular gate at its central channel. Furthermore, we compare and contrast this native NPC structure to one that exhibits reduced transport activity and unveil the spatial properties of the NPC gate. PMID- 26112707 TI - Frontier in Neurology Research Beyond Neurodegenerative Diseases. PMID- 26112708 TI - New Insights into Genotype-phenotype Correlations in Chinese Facioscapulohumeral Muscular Dystrophy: A Retrospective Analysis of 178 Patients. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD), a common autosomal dominant muscular disorder, is caused by contraction of the D4Z4 repeats on 4q35. The complicated genotype-phenotype correlation among different ethnic population remains a controversial subject. We aimed to refine this correlation in order to provide new information for genetic counseling. METHODS: Here, a cohort of 136 Chinese families including 178 affected individuals and 137 unaffected members were investigated. Genetic analyses were performed using the p13E-11, 4qA and 4qB probes after pulsed field gel electrophoresis separation and southern blotting. A 10-grade FSHD clinical severity scale was adopted for clinical assessment. The genotype-phenotype correlation was established by linear regression analyses. RESULTS: We observed a roughly inversed correlation between the short EcoRI fragment size and age-corrected clinical severity score in 154 symptomatic patients (P < 0.05). Compared to male patients, a significant higher proportion of females in both asymptomatic carriers and severe patients showed larger variation in the size of short EcoRI fragment. A high incidence (19/42, 45.2%) of asymptomatic (or minimally affected) carriers was found in familial members. CONCLUSIONS: Although the number of D4Z4 repeats is known as one of the critical influences on genotype-phenotype correlation, a majority of phenotypic spectrum was still incompatible with their heterozygous contraction of the D4Z4 repeat, especial in female cases. Our results suggest that there are multi-factors synergistically modulating the phenotypic expression. PMID- 26112709 TI - Clinical Characteristics, Radiological Features and Gene Mutation in 10 Chinese Families with Spinocerebellar Ataxias. AB - BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders that primarily cause the degeneration in the cerebellum, spinal cord, and brainstem. We study the clinical characteristics, radiological features and gene mutation in Chinese families with SCAs. METHODS: In this study, we investigated 10 SCAs Chinese families with SCA1, SCA3/Machado-Joseph disease (MJD), SCA7, SCA8. There were 27 people who were genetically diagnosed as SCA, of which 21 people showed clinical symptoms, and 6 people had no clinical phenotype that we called them presymptomatic patients. In addition, 3 people with cerebellar ataxia and cataracts were diagnosed according to the Harding diagnostic criteria but failed to be recognized as SCAs on genetic testing. Clinical characteristic analyses of each type of SCAs and radiological examinations were performed. RESULTS: We found that SCA3/MJD was the most common subtype in Han population in China, and the ratio of the pontine tegmentum and the posterior fossa area was negatively correlated with the number of cytosine adenine-guanine (CAG) repeats; the disease duration was positively correlated with the International Cooperative Ataxia Rating Scale score; and the CAG repeats number of abnormal alleles was negatively correlated with the age of onset. CONCLUSIONS: Collectively our study is a systematic research on SCAs in China, which may help for the clinical diagnosis and prenatal screening of this disease, and it may also aid toward better understanding of this disease. PMID- 26112710 TI - High-frequency Oscillations and the Seizure Onset Zones in Neocortical Epilepsy. AB - BACKGROUND: To study the characters of high-frequency oscillations (HFOs) in the seizure onset zones (SOZ) and the nonseizure onset zones (NSOZ) in the electrocorticography (ECoG) of patients with neocortical epilepsy. METHODS: Only patients with neocortical epilepsy who were seizure-free after surgery as determined with ECoG were included. We selected patients with normal magnetic resonance imaging before surgery in order to avoid the influence of HFOs by other lesions. Three minutes preictal and 10 min interictal ECoG as recorded in 39 channels in the SOZ and 256 channels in the NSOZ were analyzed. Ripples and fast ripples (FRs) were analyzed by Advanced Source Analysis software (ASA, The Netherlands). Average duration of HFOs was analyzed in SOZ and NSOZ separately. RESULTS: For ripples, the permillage time occupied by HFOs was 0.83 in NSOZ and 1.17 in SOZ during the interictal period. During preictal period, they were 2.02 in NSOZ and 7.93 in SOZ. For FRs, the permillage time occupied by HFOs was 0.02 in NSOZ and 0.42 in SOZ during the interictal period. During preictal period, they were 0.03 in NSOZ and 2 in SOZ. CONCLUSIONS: High-frequency oscillations are linked to SOZ in neocortical epilepsy. Our study demonstrates the prevalent occurrence of HFOs in SOZ. More and more burst of HFOs, especially FRs, means the onset of seizures. PMID- 26112711 TI - Repetitive Transcranial Magnetic Stimulation for the Treatment of Restless Legs Syndrome. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique used to alter cortex excitability that has been proposed as an efficient method for treating brain hyperexcitability or hypoexcitability disorders. The aim of this study was to investigate whether high-frequency rTMS could have any beneficial effects in restless legs syndrome (RLS). METHODS: Fourteen patients with RLS were given high-frequency rTMS (15 Hz, 100% motor threshold) to the leg representation motor cortex area of the frontal lobe for 14 sessions over 18 days. Patients were diagnosed according to the international criteria proposed by the International Restless Legs Syndrome Study Group in 2003. The International RLS Rating Scale (IRLS-RS), Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale were used to evaluate the severity of RLS, sleep quality, anxiety and depression, respectively. The scale scores were evaluated at four-time points (baseline, end of the 14 th session, and at 1- and 2-month posttreatment). One-way analysis of variance was used to compare scale scores at different time points. RESULTS: There was significant improvement in the IRLS-RS (from 23.86 +/- 5.88 to 11.21 +/ 7.23, P < 0.05), PSQI (from 15.00 +/- 4.88 to 9.29 +/- 3.91, P < 0.05), and HAMA (from 17.93 +/- 7.11 to 10.36 +/- 7.13, P < 0.05) scale scores at the end of 14 th session, with ongoing effects lasting for at least 2 months. CONCLUSIONS: High frequency rTMS can markedly alleviate the motor system symptoms, sleep disturbances, and anxiety in RLS patients. These results suggest that rTMS might be an option for treating RLS. PMID- 26112712 TI - Coexistence of High Fibrinogen and Low High-density Lipoprotein Cholesterol Levels Predicts Recurrent Cerebral Venous Thrombosis. AB - BACKGROUND: Cerebral venous thrombosis (CVT) may lead to serious neurological disorders; however, little is known about the risk factors for recurrent CVT. Our aim was to determine the association between elevated fibrinogen and decreased high-density lipoprotein cholesterol (HDL-C) levels with recurrent CVT. METHODS: This retrospective cohort study included participants if they had a first episode of objectively defined CVT and were admitted to Xuan Wu Hospital, Capital Medical University from August 2005 to September 2009. Demographic and clinical variables were collected, as well as laboratory parameters, including plasma fibrinogen and HDL-C. Patients with CVT were followed for recurrent symptomatic CVT. Follow-up was through the end of September 2010. Potential predictors of recurrence were analyzed using Cox survival analysis. RESULTS: At the end of the follow-up, 95 patients were eligible for the study. Twelve of 95 patients (12.6%) had recurred CVT. The median time of recurrence was 7 months (range: 1-39 months). Eight of these 12 (66.7%) experienced recurrence within the first 12 months after their initial CVT. The recurrence rate of CVT was 2.76 per 100 patient-years. Multivariate Cox regression analysis demonstrated that the coexistence of high fibrinogen (>4.00 g/L) and low HDL-C (<1.08 mmol/L) levels at baseline was the only independent predictor for recurrent CVT (hazard ratio: 4.69; 95% confidence interval: 1.10-20.11; P < 0.05). Of the twelve patients with recurrent CVT in our study, 7 (58.3%) had high fibrinogen plus low HDL-C levels. All 7 of these patients took warfarin for 3-12 months, and 6 of 7 had recurrent CVT after the discontinuation of anticoagulant treatment. CONCLUSIONS: Concomitant high fibrinogen and low HDL-C levels may be associated with recurrence of CVT. The effect of potential risk factors related to atherothrombosis on recurrent CVT should be closely monitored. PMID- 26112713 TI - F Wave Study in Amyotrophic Lateral Sclerosis: Assessment of Segmental Motoneuronal Dysfunction. AB - BACKGROUND: Dysfunctional spinal circuit may play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). The purpose of this study was to use F waves for assessment of segmental motoneuronal excitability following upper motor neuron (UMN) dysfunctions in ALS. METHODS: We studied the F waves of 152 ulnar nerves recorded from abductor digiti minimi in 82 patients with ALS. Two groups of hands were defined based on the presence or absence of pyramidal signs in the same upper limb. The group with pyramidal signs in the upper limbs was designated as the P group, and the group without pyramidal signs in the upper limbs was designated as the NP group. RESULTS: The mean (P < 0.001), median (P < 0.001) and maximum (P = 0.035) F wave amplitudes, mean (P < 0.001), median (P < 0.001) and maximum (P = 0.003) F/M amplitude ratio, index repeating neuron (P < 0.001) and index repeater F waves (P < 0.001) of the P group were significantly increased compared with the NP group. No significant differences were identified for F wave chronodispersion (P = 0.628), mean F wave latency (P = 0.151), minimum F wave latency (P = 0.211), maximum F wave latency (P = 0.199), F wave persistence (P = 0.738), F wave duration (P = 0.152), F wave conduction velocity (P = 0.813) and number of giant F waves (P = 0.072) between the two groups. CONCLUSIONS: In this study, increased F wave amplitude, F/M amplitude ratio and number of repeater F waves reflected enhanced segmental motoneuronal excitability following UMN dysfunctions in ALS. PMID- 26112714 TI - Variants of Interferon Regulatory Factor 5 are Associated with Neither Neuromyelitis Optica Nor Multiple Sclerosis in the Southeastern Han Chinese Population. AB - BACKGROUND: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are demyelinating disorders of the central nervous system. Interferon regulatory factor 5 (IRF5) is a common susceptibility gene to different autoimmune disorders. However, the association of IRF5 variants with NMO and MS patients has not been well studied. Therefore, we aimed to evaluate whether IRF5 variants were associated with NMO and MS in the Southeastern Han Chinese population. METHODS: Four single nucleotide polymorphisms (SNPs) were selected and genotyped by matrix assisted laser desorption/ionization time of flight mass spectrometry in 111 NMO patients, 145 MS patients and 300 controls from Southeastern China. RESULTS: None of these 4 SNPs was associated with NMO or MS patients. CONCLUSIONS: Our preliminary study indicates that genetic variants in IRF5 may affect neither NMO nor MS in the Southeastern Han Chinese population. Further studies with a large sample size and diverse ancestry populations are needed to clarify this issue. PMID- 26112715 TI - Mitochondrial DNA Haplogroups and the Risk of Sporadic Parkinson's Disease in Han Chinese. AB - BACKGROUND: Mitochondrial dysfunction is linked to the pathogenesis of Parkinson's disease (PD). However, the precise role of mitochondrial DNA (mtDNA) variations is obscure. On the other hand, mtDNA haplogroups have been inconsistently reported to modify the risk of PD among different population. Here, we try to explore the relationship between mtDNA haplogroups and sporadic PD in a Han Chinese population. METHODS: Nine single-nucleotide polymorphisms, which define the major Asian mtDNA haplogroups (A, B, C, D, F, G), were detected via polymerase chain reaction-restriction fragment length polymorphism or denaturing polyacrylamide gel electrophoresis in 279 sporadic PD patients and 510 matched controls of Han population. RESULTS: Overall, the distribution of mtDNA haplogroups did not show any significant differences between patients and controls. However, after stratification by age at onset, the frequency of haplogroup B was significantly lower in patients with early-onset PD (EOPD) compared to the controls (odds ratio [OR] =0.225, 95% confidence interval [CI]: 0.082-0.619, P = 0.004), while other haplogroups did not show significant differences. After stratification by age at examination, among subjects younger than 50 years of age: Haplogroup B also showed a lower frequency in PD cases (OR = 0.146, 95% CI: 0.030-0.715, P = 0.018) while haplogroup D presented a higher risk of PD (OR = 3.579, 95% CI: 1.112-11.523, P = 0.033), other haplogroups also did not show significant differences in the group. CONCLUSIONS: Our study indicates that haplogroup B might confer a lower risk for EOPD and people younger than 50 years in Han Chinese, while haplogroup D probably lead a higher risk of PD in people younger than 50 years of age. In brief, particular Asian mtDNA haplogroups likely play a role in the pathogenesis of PD among Han Chinese. PMID- 26112716 TI - Dopamine Agonists Exert Nurr1-inducing Effect in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease. AB - BACKGROUND: Nurr1 plays an essential role in the development, survival, and function maintenance of midbrain dopaminergic (DA) neurons, and it is a potential target for Parkinson's disease (PD). Nurr1 mRNA can be detected in peripheral blood mononuclear cells (PBMCs), but whether there is any association of altered Nurr1 expression in PBMC with the disease and DA drug treatments remains elusive. This study aimed to measure the Nurr1 mRNA level in PBMC and evaluate the effect of Nurr1 expression by DA agents in vivo and in vitro. METHODS: The mRNA levels of Nurr1 in PBMC of four subgroups of 362 PD patients and 193 healthy controls (HCs) using real-time polymerase chain reaction were measured. The nonparametric Mann-Whitney U-test and Kruskal-Wallis test were performed to evaluate the differences between PD and HC, as well as the subgroups of PD. Multivariate linear regression analysis was used to evaluate the independent association of Nurr1 expression with Hoehn and Yahr scale, age, and drug treatments. Besides, the Nurr1 expression in cultured PBMC was measured to determine whether DA agonist pramipexole affects its mRNA level. RESULTS: The relative Nurr1 mRNA levels in DA agonists treated subgroup were significant higher than those in recent-onset cases without any anti-PD treatments (de novo) (P < 0.001) and HC groups (P < 0.010), respectively. Furthermore, the increase in Nurr1 mRNA expression was seen in DA agonist and L-dopa group. Multivariate linear regression showed DA agonists, L-dopa, and DA agonists were independent predictors correlated with Nurr1 mRNA expression level in PBMC. In vitro, in the cultured PBMC treated with 10 MUmol/L pramipexole, the Nurr1 mRNA levels were significantly increased by 99.61%, 71.75%, 73.16% in 2, 4, and 8 h, respectively (P < 0.001). CONCLUSIONS: DA agonists can induce Nurr1 expression in PBMC, and such effect may contribute to DA agonists-mediated neuroprotection on DA neurons. PMID- 26112717 TI - The Natural Progression of Parkinson's Disease in a Small Cohort with 15 Drug naive Patients. AB - BACKGROUND: The studies of the natural progression of Parkinson's disease (PD) in Chinese populations have been lacking. To address this issue and obtain a preliminary data, we conducted a PD progression assessment in 15 adults with de novo PD from a nutritional intervention trial (NIT) cohort in Lin County China. METHODS: Using the Copiah County screening questionnaire and United Kingdom Parkinson's Disease Society Brain Bank diagnostic criteria, we surveyed the available NIT cohort members in 2000 and diagnosed 86 patients as PD. In 2010, we resurveyed all PD patients and confirmed definite PD diagnosis in 15 cases with the rest of them being dead (54); having probable (10) PD or vascular Parkinsonism (3); refusing to participate (2); or being away (2). In both surveys, we used Hoehn and Yahr (HY) scale and assessed the disease progression. Unified Parkinson's Disease Rating Scale (UPDRS) was added to the second survey. RESULTS: In 2010, the average disease duration for 15 definite PD patients was 13.6 +/- 7.3 years. Over a 10-year time span, 9 out of 15 patients remained at the same HY stage while the remaining 6 progressed. Rigidity (47% vs. 100%; P = 0.002) and postural instability (7% vs. 47%; P = 0.005) worsened significantly. The mean UPDRS motor scores in 2010 were 39.4 +/- 23.7. CONCLUSIONS: Overall worsening of motor function in PD seems to be the rule in this untreated cohort, and their rate of progression seemed to be slower than those reported in the western populations. PMID- 26112718 TI - Heterogeneity of Monosymptomatic Resting Tremor in a Prospective Study: Clinical Features, Electrophysiological Test, and Dopamine Transporter Positron Emission Tomography. AB - BACKGROUND: The relationship between monosymptomatic resting tremor (mRT) and Parkinson's disease (PD) remains controversial. In this study, we aimed to assess the function of presynaptic dopaminergic neurons in patients with mRT by dopamine transporter positron emission tomography (DAT-PET) and to evaluate the utility of clinical features or electrophysiological studies in differential diagnosis. METHODS: Thirty-three consecutive patients with mRT were enrolled prospectively. The Unified Parkinson's Disease Rating Scale and electromyography were tested before DAT-PET. Striatal asymmetry index (SAI) was calculated, and a normal DAT PET was defined as a SAI of <15%. Scans without evidence of dopaminergic deficits (SWEDDs) were diagnosed in patients with a subsequent normal DAT-PET and structural magnetic resonance imaging. RESULTS: Twenty-eight mRT patients with a significant reduction in uptake of DAT binding in the striatum were diagnosed with PD, while the remained 5 with a normal DAT-PET scan were SWEDDs. As for UPRDS, the dressing and hygiene score, walking in motor experiences of daily living (Part II) and motor examination (Part III) were significant different between two groups (P < 0.05 and P < 0.01, respectively). Bilateral tremor was more frequent in the SWEDDs group (P < 0.05). The frequency of resting tremor and the amplitude of postural tremor tend to be higher in the SWEDDs group (P = 0.08 and P = 0.05, respectively). CONCLUSIONS: mRT is heterogeneous in presynaptic nigrostriatal dopaminergic degeneration, which can be determined by DAT-PET brain imaging. Clinical and electrophysiological features may provide clues to distinguish PD from SWEDDs. PMID- 26112719 TI - Different Eukaryotic Initiation Factor 2Bepsilon Mutations Lead to Various Degrees of Intolerance to the Stress of Endoplasmic Reticulum in Oligodendrocytes. AB - BACKGROUND: Vanishing white matter disease (VWM), a human autosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is responsible for the initiation of protein synthesis by its guanine nucleotide exchange factor (GEF) activity. Mutations of eIF2B impair GEF activity at different degree. Previous studies implied improperly activated unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) participated in the pathogenesis of VWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types. METHODS: ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Arg113His, p. Arg269FNx01 or p. Ser610-Asp613del in eIF2Bepsilon. A representative UPR-PERK component of activating transcription factor 4 (ATF4) was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors. RESULTS: The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity of p. Arg269FNx01 group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-I and LC3-II in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants after ERS induction. CONCLUSIONS: GEF activities in different genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion mutants showed less tolerable to ERS. PMID- 26112720 TI - Nutrient Intakes of Pregnant Women and their Associated Factors in Eight Cities of China: A Cross-sectional Study. AB - BACKGROUND: During the last 3 decades, China has dramatic changes of the dietary pattern among its citizens, particularly in urban cities. This study aimed to determine the nutrient intake status and factors associated with nutrient intakes of urban Chinese pregnant women now-a-day. METHODS: The multistage stratified random sampling method was applied in the cross-sectional study. 479 women in three trimesters of pregnancy from eight cities of China were recruited. Nutrient intakes were evaluated with one 24 h dietary recall, and compared with the Chinese Dietary Reference Intakes (DRIs) 2013 for available nutrients. RESULTS: Most pregnant women had imbalanced macronutrient distribution with excessive energy derived from fat. Intakes of Vitamin A, B 6, calcium, magnesium, and selenium were below Chinese Recommended Nutrient Intake (RNI) and Estimated Average Requirements (EARs) in all trimesters. Most pregnant women took more folic acid in the first trimester with a significant decrease in the second and third trimester (P < 0.05). Shortfall in iron intake was found in the third trimester whereas some women may be at the risk of excessive iron intake. Intakes of thiamin met RNI in the first trimester but were below EAR in all trimesters. Trimester phasing was positively associated with most nutrients (P < 0.05). Prepregnancy body mass index was inversely associated with energy, fat, Vitamin C, and calcium intake (P < 0.05). Educational level and household income were positively associated with folic acid intake (P < 0.05). CONCLUSIONS: Current prenatal dietary choices of urban pregnant women in China are imbalanced in the nutrient intake when compared with national DRIs 2013, particularly in intakes of energy derived from fat and micronutrients. Appropriate dietary advice to pregnant women should promote a balanced diet with emphasis on avoidance of foods of high fat content and incorporation of foods that are good sources of the key micronutrients that are usually lacking in a regular pregnancy diet. Further research is needed to understand the eating habits and food patterns that contribute to this imbalanced diet in order to be able to effectively improve prenatal women's nutrient intake status. PMID- 26112721 TI - Safety and Efficacy of Low Dosage of Urokinase for Catheter-directed Thrombolysis of Deep Venous Thrombosis. AB - BACKGROUND: Catheter-directed thrombolysis (CDT) has been a mainstay in treating deep venous thrombosis (DVT). However, the optimal dosage of a thrombolytic agent is still controversial. The goal of this study was to evaluate the safety and efficacy of low dosage urokinase with CDT for DVT. METHODS: A retrospective analysis was performed using data from a total of 427 patients with DVT treated with CDT in our single center between July 2009 and December 2012. Early efficacy of thrombolysis was assessed with a thrombus score based on daily venography. The therapeutic safety was evaluated by adverse events. A venography or duplex ultrasound was performed to assess the outcome at 6 months, 1 year and 2 years postoperatively. RESULTS: The mean total dose of 3.34 (standard deviation [SD] 1.38) million units of urokinase was administered during a mean of 5.18 (SD 2.28) days. Prior to discharge, Grade III (complete lysis) was achieved in 154 (36%) patients; Grade II (50-99% lysis) in 222 (52%); and Grade I (50% lysis) in 51 (12%). The major complications included one intracranial hemorrhage, one hematochezia, five gross hematuria, and one pulmonary embolism. Moreover, no death occurred in the study. CONCLUSIONS: Treatment of low-dose catheter-directed thrombosis is an efficacious and safe therapeutic approach in patients with DVT offering good long-term outcomes and minimal complications. PMID- 26112722 TI - Survival Analysis of Hepatocellular Carcinoma: A Comparison Between Young Patients and Aged Patients. AB - BACKGROUND: To compare the clinicopathological features and prognosis between younger and aged patients with hepatocellular carcinoma (HCC). METHODS: We analyzed the outcome of 451 HCC patients underwent liver resection, transcatheter arterial chemoembolization and radiofrequency ablation, respectively. Then risk factors for aged and younger patients' survival were evaluated by multivariate analysis, respectively. RESULTS: The patients who were older than 55 years old were defined as the older group. The overall survival for aged patients was significantly worse than those younger patients. The younger patients had similar liver functional reserve but more aggressive tumor factors than aged patients. Cox regression analysis showed that the elevated levels of aspartate aminotransferase (AST) (Wald chi2 = 3.963, P = 0.047, hazard ratio [HR] =1.453, 95% confidence interval [CI]: 1.006-2.098), lower albumin (Wald chi2 = 12.213, P < 0.001, HR = 1.982, 95% CI: 1.351-2.910), tumor size (Wald chi2 = 8.179, P = 0.004, HR = 1.841, 95% CI: 1.212-2.797), and higher alpha-fetoprotein level (Wald chi2 = 4.044, P = 0.044, HR = 1.465, 95% CI: 1.010-2.126) were independent prognostic factors for aged patients, while only elevated levels of AST (Wald chi2 = 14.491, P < 0.001, HR = 2.285, 95% CI: 1.493-3.496) and tumor size (Wald chi2 = 21.662, P < 0.001, HR = 2.928, 95% CI: 1.863-4.604) were independent prognostic factors for younger patients. CONCLUSIONS: Age is a risk factor to determine the prognosis of patients with HCC. Aged patients who have good liver functional reserve are still encouraged to receive curative therapy. PMID- 26112723 TI - Randomized Controlled Study on Safety and Feasibility of Transfusion Trigger Score of Emergency Operations. AB - BACKGROUND: Due to the floating of the guideline, there is no evidence-based evaluation index on when to start the blood transfusion for patients with hemoglobin (Hb) level between 7 and 10 g/dl. As a result, the trigger point of blood transfusion may be different in the emergency use of the existing transfusion guidelines. The present study was designed to evaluate whether the scheme can be safely and effectively used for emergency patients, so as to be supported by multicenter and large sample data in the future. METHODS: From June 2013 to June 2014, patients were randomly divided into the experimental group (Peri-operative Transfusion Trigger Score of Emergency [POTTS-E] group) and the control group (control group). The between-group differences in the patients' demography and baseline information, mortality and blood transfusion-related complications, heart rate, resting arterial pressure, body temperature, and Hb values were compared. The consistency of red blood cell (RBC) transfusion standards of the two groups of patients with the current blood transfusion guideline, namely the compliance of the guidelines, utilization rate, and per capita consumption of autologous RBC were analyzed. RESULTS: During the study period, a total of 72 patients were recorded, and 65 of them met the inclusion criteria, which included 33 males and 32 females with a mean age of (34.8 +/- 14.6) years. 50 underwent abdomen surgery, 4 underwent chest surgery, 11 underwent arms and legs surgery. There was no statistical difference between the two groups for demography and baseline information. There was also no statistical differences between the two groups in anesthesia time, intraoperative rehydration, staying time in postanesthetic care unit, emergency hospitalization, postoperative 72 h Acute Physiologic Assessment and Chronic Health Evaluation II scores, blood transfusion-related complications and mortality. Only the POTTS-E group on the 1 st postoperative day Hb was lower than group control, P < 0.05. POTTS-E group was totally (100%) conformed to the requirements of the transfusion guideline to RBC infusion, which was higher than that of the control group (81.25%), P < 0.01.There were no statistical differences in utilization rates of autologous blood of the two groups; the utilization rates of allogeneic RBC, total allogeneic RBC and total RBC were 48.48%, 51.5%, and 75.7% in POTTS-E group, which were lower than those of the control group (84.3%, 84.3%, and 96.8%) P < 0.05 or P < 0.01. Per capita consumption of intraoperative allogeneic RBC, total allogeneic RBC and total RBC were 0 (0, 3.0), 2.0 (0, 4.0), and 3.1 (0.81, 6.0) in POTTS-E groups were all lower than those of control group (4.0 [2.0, 4.0], 4.0 [2.0, 6.0] and 5.8 [2.7, 8.2]), P < 0.05 or P < 0.001. CONCLUSIONS: Peri-operative Transfusion Trigger Score-E evaluation scheme is used to guide the application of RBC. There are no differences in the recent prognosis of patients with the traditional transfusion guidelines. This scheme is safe; Compared with doctor experience-based subjective assessment, the scoring scheme was closer to patient physiological needs for transfusion and more reasonable; Utilization rate and the per capita consumption of RBC are obviously declined, which has clinical significance and is feasible. Based on the abovementioned three points, POTTS-E scores scheme is safe, reasonable, and practicable and has the value for carrying out multicenter and large sample clinical researches. PMID- 26112724 TI - ApaI, BsmI, FokI, and TaqI Polymorphisms in the Vitamin D Receptor Gene and Parkinson's Disease. AB - BACKGROUND: The vitamin D receptor (VDR) gene has been identified as a candidate gene for susceptibility to Parkinson's disease (PD), but results from genetic association studies to date are inconsistent. Here, we conducted a meta-analysis of published case-control studies to evaluate the association of the extensively studied VDR ApaI (G/T), BsmI (G/A), FokI (C/T), and TaqI (T/C) gene polymorphisms with risk of PD. METHODS: Electronic search at PubMed, EMBASE, EBSCO, China National Knowledge Infrastructure, Weipu database, and Wanfang database was conducted to identify all relevant studies. Odds ratio (OR) with 95% confidence interval (CI) values was applied to evaluate the strength of the association. RESULTS: A total of seven studies with 2034 PD cases and 2432 controls were included in the meta-analysis following the inclusion and exclusion criteria. Overall, no significant association between ApaI, BsmI, and TaqI gene polymorphisms and PD susceptibility in all four genetic models was found (T vs. G: OR = 1.00, 95% CI: 0.89-1.12, P = 0.97; A vs. G: OR = 0.94, 95% CI: 0.77-1.15, P = 0.53; C vs. T: OR = 1.03, 95% CI: 0.85-1.25, P = 0.77) while a significant association between FokI (C/T) and PD risk was observed (C vs. T: OR = 1.41, 95% CI: 1.14-1.75, P = 0.001; CC vs. TT: OR = 2.45, 95% CI: 1.52-3.93, P = 0.0002; CT vs. TT: OR = 2.21, 95% CI: 1.38-3.52, P = 0.0009, CC vs. CT+TT: OR = 2.32, 95% CI: 1.49-3.61, P = 0.0002). CONCLUSIONS: Polymorphisms of ApaI, BsmI, and TaqI may not be associated with the susceptibility to PD while the FokI (C/T) polymorphism is possibly associated with increased PD risk. However, conclusions should be cautiously interpreted due to the relatively small number of studies included. PMID- 26112725 TI - Huntington Disease in Asia. AB - OBJECTIVE: The objective was to review the major differences of Huntington disease (HD) in Asian population from those in the Caucasian population. DATA SOURCES: Data cited in this review were obtained from PubMed database and China National Knowledge Infrastructure (CNKI) from 1994 to 2014. All the papers were written in English or Chinese languages, with the terms of Asia/Asian, HD, genotype, epidemiology, phenotype, and treatment used for the literature search. STUDY SELECTION: From the PubMed database, we included the articles and reviews which contained the HD patients' data from Asian countries. From the CNKI, we excluded the papers which were not original research. Due to the language's restrictions, those data published in other languages were not included. RESULTS: In total, 50 papers were cited in this review, authors of which were from the mainland of China, Japan, India, Thailand, Taiwan (China), Korea, and western countries. CONCLUSIONS: The lower epidemiology in Asians can be partly explained by the less cytosine-adenine-guanine repeats, different haplotypes, and CCG polymorphisms. For the physicians, atypical clinical profiles such as the initial symptom of ataxia, movement abnormalities of Parkinsonism, dystonia, or tics need to be paid more attention to and suggest gene testing if necessary. Moreover, some pathogenesis studies may help progress some new advanced treatments. The clinicians in Asian especially in China should promote the usage of genetic testing and put more effects in rehabilitation, palliative care, and offer comfort of patients and their families. The unified HD rating scale also needs to be popularized in Asia to assist in evaluating the progression of HD. PMID- 26112726 TI - Progress in Diagnosing Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes. AB - OBJECTIVE: Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. MELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well. DATA SOURCES: The data used in this review came from published peer review articles from October 1984 to October 2014, which were obtained from PubMed. The search term is "MELAS". STUDY SELECTION: Information selected from those reported studies is mainly based on the progress on clinical features, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS. RESULTS: MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging (MRI) can provide directional information on this disease. Muscle biopsy has meaningful value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the mutation m.3243A>G of the mitochondrial transfer RNA (Leu (UUR)) gene (MT-TL1). CONCLUSIONS: MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MRI, muscle biopsy, and genetics. PMID- 26112728 TI - Clinical and Laboratory Findings of Nonacute Neurobrucellosis. PMID- 26112727 TI - Currently Clinical Views on Genetics of Wilson's Disease. AB - OBJECTIVE: The objective of this study was to review the research on clinical genetics of Wilson's disease (WD). DATA SOURCES: We searched documents from PubMed and Wanfang databases both in English and Chinese up to 2014 using the keywords WD in combination with genetic, ATP7B gene, gene mutation, genotype, phenotype. STUDY SELECTION: Publications about the ATP7B gene and protein function associated with clinical features were selected. RESULTS: Wilson's disease, also named hepatolenticular degeneration, is an autosomal recessive genetic disorder characterized by abnormal copper metabolism caused by mutations to the copper-transporting gene ATP7B. Decreased biliary copper excretion and reduced incorporation of copper into apoceruloplasmin caused by defunctionalization of ATP7B protein lead to accumulation of copper in many tissues and organs, including liver, brain, and cornea, finally resulting in liver disease and extrapyramidal symptoms. It is the most common genetic neurological disorder in the onset of adolescents, second to muscular dystrophy in China. Early diagnosis and medical therapy are of great significance for improving the prognosis of WD patients. However, diagnosis of this disease is usually difficult because of its complicated phenotypes. In the last 10 years, an increasing number of clinical studies have used molecular genetics techniques. Improved diagnosis and prediction of the progression of this disease at the molecular level will aid in the development of more individualized and effective interventions, which is a key to transition from molecular genetic research to the clinical study. CONCLUSIONS: Clinical genetics studies are necessary to understand the mechanism underlying WD at the molecular level from the genotype to the phenotype. Clinical genetics research benefits newly emerging medical treatments including stem cell transplantation and gene therapy for WD patients. PMID- 26112729 TI - Is Syphilis a Potential New Factor of the POEMS Syndrome? PMID- 26112730 TI - Anti-Ma2 Paraneoplastic Encephalitis Associated with Ileal Lymphoma. PMID- 26112731 TI - Transoral Endoscopic Thyroidectomy with Central Neck Dissection. PMID- 26112732 TI - Impaired Hearing in Mitochondrial Disorders. PMID- 26112733 TI - Adolescent Drivers: Fine-Tuning Our Understanding. PMID- 26112734 TI - A Review of Hazard Anticipation Training Programs for Young Drivers. AB - PURPOSE: Poor hazard anticipation skills are a risk factor associated with high motor vehicle crash rates of young drivers. A number of programs have been developed to improve these skills. The purpose of this review was to assess the empirical literature on hazard anticipation training for young drivers. METHODS: Studies were included if they (1) included an assessment of hazard anticipation training outcomes; (2) were published between January 1, 1980 and December 31, 2013 in an English language peer-reviewed journal or conference proceeding; and (3) included at least one group that uniquely comprised a cohort of participants aged <21 years. Nineteen studies met inclusion criteria. RESULTS: Studies used a variety of training methods including interactive computer programs, videos, simulation, commentary driving, or a combination of approaches. Training effects were predominantly measured through computer-based testing and driving simulation with eye tracking. Four studies included an on-road evaluation. Most studies evaluated short-term outcomes (immediate or few days). In all studies, young drivers showed improvement in selected hazard anticipation outcomes but none investigated crash effects. CONCLUSIONS: Although there is promise in existing programs, future research should include long-term follow-up, evaluate crash outcomes, and assess the optimal timing of hazard anticipation training taking into account the age and experience level of young drivers. PMID- 26112735 TI - Young Drivers and Their Passengers: A Systematic Review of Epidemiological Studies on Crash Risk. AB - PURPOSE: A systematic review of the literature was conducted to appraise the evidence from epidemiological studies of crash risk in young drivers accompanied by passengers, compared with solo driving. METHODS: Databases searched were the Cochrane Library, Embase, Scopus, Transportation Research Information Services, and Web of Science for studies published between January 1, 1989 and August 1, 2013. Epidemiological studies were selected for review if they focused on crashes of young drivers (<=24 years old) and included both a no-passenger comparison group and some measure of exposure to enable calculation of estimates. RESULTS: Fifteen articles (17 studies) were selected; seven studies reported on fatal crashes and 10 on nonfatal or combined fatal/nonfatal crashes. Studies on fatal crashes showed increased risk, compared with solo driving, for young drivers with at least one passenger (significant estimates ranging from 1.24 to 1.89) and two or more passengers versus solo driving (1.70-2.92). Increased risk was also found for fatal crashes and for combined or nonfatal crashes with male versus female passengers (1.53-2.66) and for younger versus older drivers (1.42-3.14). CONCLUSIONS: Results more clearly indicated an increased risk for passenger presence in fatal crashes than that in nonfatal or combined fatal/nonfatal crashes. Findings of this review, based on correlational studies, support licensing policies that limit the presence and number of young passengers for young drivers. PMID- 26112736 TI - The Effect of Secondary Task Engagement on Adolescents' Driving Performance and Crash Risk. AB - PURPOSE: The purpose of this review was to synthesize the evidence of the effects of secondary task engagement on novice adolescent's driving performance and crash risk. METHODS: Searches of multiple databases were conducted using search terms related to secondary task engagement and teenage drivers. Articles were selected for inclusion if they were: written in English, an empirical study assessing the impact of secondary task engagement on driving, and included study participants who were licensed drivers between the ages of 14 and 17 years (if research was conducted in the United States) or within 18 months licensure in other countries. Thirty-eight abstracts were reviewed. RESULTS: Fifteen studies met the inclusion criteria. Most studies examined the effects of electronic device use as the secondary task. Effects were assessed using crash databases, simulator, instrumented vehicle, and naturalistic driving studies. Texting resulted in increased lane deviations and eyes off road time in simulated driving, whereas talking on a cell phone had little effect. Naturalistic studies, which use vehicle instrumentation to measure actual driving, found secondary tasks that required drivers to look away from the forward roadway also increased the risk of crashes and near-crashes for young novice drivers, whereas tasks that did not require eyes to be off the forward roadway (e.g., talking on cell phone) had no effect on crash risk. CONCLUSIONS: Methodological differences in the definition and measurement of driving performance make it difficult to directly compare findings, even among the limited number of studies conducted. Despite this, results suggest that secondary tasks degrade driving performance and increase risk only when they require drivers to look away from the forward roadway. Future research needs to focus more explicitly on the ways in which secondary task engagement influences drivers' behavior (e.g., interfering with information acquisition or manual control of the vehicle). This, along with the use of standard measures across studies, would build a more useful body of literature on this topic. PMID- 26112738 TI - Persistent natural infection of a Culex tritaeniorhynchus cell line with a novel Culex tritaeniorhynchus rhabdovirus strain. AB - Culex tritaeniorhynchus rhabdovirus (CTRV) is a mosquito virus that establishes persistent infection without any obvious cell death. Therefore, occult infection by CTRV can be present in mosquito cell lines. In this study, it is shown that NIID-CTR cells, which were derived from Cx. tritaeniorhynchus, are persistently infected with a novel strain of CTRV. Complete genome sequencing of the infecting strain revealed that it is genetically similar but distinct from the previously isolated CTRV strain, excluding the possibility of contamination. These findings raise the importance of further CTRV studies, such as screening of CTRV in other mosquito cell lines. PMID- 26112737 TI - Effectiveness of Parent-Focused Interventions to Increase Teen Driver Safety: A Critical Review. AB - PURPOSE: We critically reviewed recent parent-directed teen driving interventions to summarize their success in meeting stated goals; identify promising intervention components and knowledge gaps; aid in the selection, adaptation, and dissemination of effective interventions; and guide future research efforts. METHODS: We focused on interventions that included a direct parent component, explicitly stated outcomes related to the teen and/or their parents, were evaluated for parent or teen outcomes, targeted drivers younger than the age of 21 years, and had at least one evaluation study published since 1990 and in English. We conducted a comprehensive systematic search of 26 online databases between November 2013 and January 2014 and identified 34 articles representing 18 interventions. RESULTS: Several interventions-in particular, those that had an active engagement component, incorporated an in-vehicle data recorder system, and had a strong conceptual approach-show promise in improving parental supervisory behaviors during the learner and early independent phases, increasing teen driver skill acquisition, and reducing teens' risky driving behaviors. CONCLUSIONS: We identify essential characteristics of effective parent-involved teen driving interventions and their evaluation studies, propose a comprehensive and multitiered approach to intervention, and discuss several research areas and overarching issues for consideration. PMID- 26112739 TI - [Hindfoot osteotomies]. PMID- 26112740 TI - Controlling heterologous gene expression in yeast cell factories on different carbon substrates and across the diauxic shift: a comparison of yeast promoter activities. AB - BACKGROUND: Predictable control of gene expression is necessary for the rational design and optimization of cell factories. In the yeast Saccharomyces cerevisiae, the promoter is one of the most important tools available for controlling gene expression. However, the complex expression patterns of yeast promoters have not been fully characterised and compared on different carbon sources (glucose, sucrose, galactose and ethanol) and across the diauxic shift in glucose batch cultivation. These conditions are of importance to yeast cell factory design because they are commonly used and encountered in industrial processes. Here, the activities of a series of "constitutive" and inducible promoters were characterised in single cells throughout the fermentation using green fluorescent protein (GFP) as a reporter. RESULTS: The "constitutive" promoters, including glycolytic promoters, transcription elongation factor promoters and ribosomal promoters, differed in their response patterns to different carbon sources; however, in glucose batch cultivation, expression driven by these promoters decreased sharply as glucose was depleted and cells moved towards the diauxic shift. Promoters induced at low-glucose levels (P(HXT7), P(SSA1) and P(ADH2)) varied in induction strength on non-glucose carbon sources (sucrose, galactose and ethanol); in contrast to the "constitutive" promoters, GFP expression increased as glucose decreased and cells moved towards the diauxic shift. While lower than several "constitutive" promoters during the exponential phase, expression from the SSA1 promoter was higher in the post-diauxic phase than the commonly-used TEF1 promoter. The galactose-inducible GAL1 promoter provided the highest GFP expression on galactose, and the copper-inducible CUP1 promoter provided the highest induced GFP expression following the diauxic shift. CONCLUSIONS: The data provides a foundation for predictable and optimised control of gene expression levels on different carbon sources and throughout batch fermentation, including during and after the diauxic shift. This information can be applied for designing expression approaches to improve yields, rates and titres in yeast cell factories. PMID- 26112741 TI - SPAK and OSR1 Sensitivity of Excitatory Amino Acid Transporter EAAT3. AB - BACKGROUND/AIMS: Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no K(Lys)) kinases. The present study explored whether SPAK and/or OSR1 influence the excitatory amino acid transporter EAAT3, which accomplishes glutamate and aspartate transport in kidney, intestine and brain. METHODS: cRNA encoding EAAT3 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, wild-type OSR1, constitutively active (T185E)OSR1, WNK insensitive (T185A)OSR1 and catalytically inactive (D164A)OSR1. Glutamate-induced current was taken as measure of electrogenic glutamate transport and was quantified utilizing dual electrode voltage clamp. Furthermore, Ussing chamber was employed to determine glutamate transport in the intestine from gene-targeted mice carrying WNK insensitive SPAK (spak(tg/tg)) and from corresponding wild-type mice (spak(+/+)). RESULTS: EAAT3 activity was significantly decreased by wild-type SPAK and (T233E)SPAK, but not by (T233A)SPAK and (D212A)SPAK. SPAK decreased maximal transport rate without affecting significantly affinity of the carrier. Similarly, EAAT3 activity was significantly downregulated by wild-type OSR1 and (T185E)OSR1, but not by (T185A)OSR1 and (D164A)OSR1. Again OSR1 decreased maximal transport rate without affecting significantly affinity of the carrier. Intestinal electrogenic glutamate transport was significantly lower in spak(+/+) than in spak(tg/tg) mice. CONCLUSION: Both, SPAK and OSR1 are negative regulators of EAAT3 activity. PMID- 26112742 TI - Episodic detection of human papillomavirus within a longitudinal cohort of young women. AB - Redetection of a type-specific human papillomavirus (HPV) infection may represent reinfection. However, a growing body of literature suggests that reactivation of HPV is common and that episodic detection of a HPV infection may represent reactivation of a persistent virus. A cohort of prospectively followed adolescent women (N = 150), ages 14-17, was observed on average 6.4 years. The authors describe the redetection of 37 HPV types and associated factors of redetection of high-risk (HR) and low-risk (LR) types using Cox proportional hazard models. Of 1,248 HPV type-specific infections, 286 (22.9%) were associated with redetection after apparent clearance. Chlamydia infections (HR = 1.99 [95%CI, 1.15-3.49]) and non-condom use (HR = 1.1 [95%CI, 1.04-1.99]) were associated with increased redetection of HR-HPV infections. Oral contraceptive pills (HR = 2.73 [95%CI, 1.52-4.90]) and number of sexual partners (HR = 1.44 [95%CI, 1.04-1.99]) were associated with increased redetection of LR-HPV infections. Episodic detection of HPV is common for HR- and LR-HPV types. This finding and identified factors or redetection have clinical implications and enhances the understanding of HPV natural history. PMID- 26112743 TI - Human rhinovirus infections in hospitalized children: clinical, epidemiological and virological features. AB - Molecular epidemiology and clinical impact of human rhinovirus (HRV) are not well documented in tropical regions. This study compared the clinical characteristics of HRV to other common viral infections and investigated the molecular epidemiology of HRV in hospitalized children with acute respiratory infections (ARIs) in Vietnam. From April 2010 to May 2011, 1082 nasopharyngeal swabs were screened for respiratory viruses by PCR. VP4/VP2 sequences of HRV were further characterized. HRV was the most commonly detected virus (30%), in which 70% were diagnosed as either pneumonia or bronchiolitis. Children with single HRV infections presented with significantly higher rate of hypoxia than those infected with respiratory syncytial virus or parainfluenza virus (PIV)-3 (12.4% vs. 3.8% and 0%, respectively, P < 0.05), higher rate of chest retraction than PIV-1 (57.3% vs. 34.5%, P = 0.028), higher rate of wheezing than influenza A (63.2% vs. 42.3%, P = 0.038). HRV-C did not differ to HRV-A clinically. The genetic diversity and changes of types over time were observed and may explain the year-round circulation of HRV. One novel HRV-A type was discovered which circulated locally for several years. In conclusion, HRV showed high genetic diversity and was associated with significant morbidity and severe ARIs in hospitalized children. PMID- 26112745 TI - Pentoxifylline Treatment in Severe Acute Pancreatitis: A Pilot, Double-Blind, Placebo-Controlled, Randomized Trial. AB - In acute pancreatitis (AP) tumor necrosis factor-alpha mediates multi-organ failure; in animal models its blockade with pentoxifylline ameliorates AP. The efficacy of pentoxifylline in predicted severe AP (pSAP) was tested in a double blinded, randomized, control trial. Twenty-eight patients with pSAP were randomized within 72 hours of diagnosis to pentoxifylline or placebo. Baseline characteristics were similar in both groups. The pentoxifylline group had fewer intensive care unit admissions and shorter intensive care unit and hospital stays of longer than 4 days (all P < .05). Patients receiving pentoxifylline had no adverse effects. Pentoxifylline within 72 hours of pSAP is safe; a larger study of pentoxifylline in AP is needed to confirm efficacy. ClinicalTrials.gov number: NCT01292005. PMID- 26112744 TI - Hepatitis E virus in the countries of the Middle East and North Africa region: an awareness of an infectious threat to blood safety. AB - PURPOSE: Hepatitis E virus (HEV) is mainly transmitted through contaminated water supplies which make the virus endemic in developing countries including countries of the Middle East and North Africa (MENA) region. Recent reports suggest potential risk of HEV transmission via blood transfusion. METHODS: Related articles on HEV were collected by searching through the 25 countries of the MENA region using Pubmed and Medline within the past 14 years: January 2000-August 2014. RESULTS: One hundred articles were extracted, of which 25 were not eligible. The articles discussed the seroprevalence of HEV and HEV markers in 12 countries. Eight articles provided data on HEV in blood donors. The seroprevalence of HEV in the general MENA population ranged from 2.0 to 37.5% and was higher in males than in females. Prevalence increased with age, but exposure seems to be in early life. CONCLUSIONS: In the MENA region, the role of HEV as an infectious threat to blood safety is under-investigated. More data are needed to quantify the risk of transmission and to assess clinical outcomes. This requires, at least, surveillance screening of donors and recipients for HEV markers using sensitive and specific serological tests. At the present time, serious consideration should be given to selective screening for certain groups of patients (e.g., immunocompromised, pregnant women and others) who commonly require blood transfusion and are at high risk of hepatic failure or chronicity from HEV infection. PMID- 26112746 TI - Poly(thymine)-Templated Copper Nanoparticles as a Fluorescent Indicator for Hydrogen Peroxide and Oxidase-Based Biosensing. AB - Biomineralized fluorescent metal nanoparticles have attracted considerable interest in many fields by virtue of their excellent properties in synthesis and application. Poly(thymine)-templated fluorescent copper nanoparticles (T-CuNPs) as a promising nanomaterial has been exploited by us recently and displays great potential for signal transducing in biochemical analysis. However, the application of T-CuNPs is rare and still at an early stage. Here, a new fluorescent analytical strategy has been developed for H2O2 and oxidase-based biosensing by exploiting T-CuNPs as an effective signal indicator. The mechanism is mainly based on the poly(thymine) length-dependent formation of T-CuNPs and the probe's oxidative cleavage. In this assay, the probe T40 can effectively template the formation of T-CuNPs by a fast in situ manner in the absence of H2O2, with high fluorescent signal, while the probe is cleaved into short oligonucleotide fragments by hydroxyl radical (.OH) which is formed from the Fenton reaction in the presence of H2O2, leading to the decline of fluorescence intensity. By taking advantage of H2O2 as a mediator, this strategy is further exploited for oxidase-based biosensing. As the proof-of-concept, glucose in human serum has been chosen as the model system and has been detected, and its practical applicability has been investigated by assay of real clinical blood samples. Results demonstrate that the proposed strategy has not only good detection capability but also eminent detection performance, such as simplicity and low-cost, holding great potential for constructing effective sensors for biochemical and clinical applications. PMID- 26112747 TI - The effects of collaboration and minimal-group membership on children's prosocial behavior, liking, affiliation, and trust. AB - Recent theoretical work has highlighted potential links between interpersonal collaboration and group membership in the evolution of human sociality. Here we compared the effects of collaboration and minimal-group membership on young children's prosocial behavior (i.e., helping and resource allocation), liking, affiliation, and trust. In a design that matched as closely as possible these two ways of connecting with others, we showed that 5-year-olds' behavior was affected similarly by collaboration and minimal-group membership; both increased children's preference for their partners on multiple dimensions and produced overall effects of a similar magnitude. In contrast, 3.5-year-olds did not have a strong preference for either collaborators or minimal in-group members. Thus, both collaboration and minimal-group membership are similarly effective in their influence on children's prosocial behavior and social preferences. PMID- 26112748 TI - PTEN regulates IGF-1R-mediated therapy resistance in melanoma. AB - Inhibition of the mitogen-activated protein kinase (MAPK) pathway is a major advance in the treatment of metastatic melanoma. However, its therapeutic success is limited by the rapid emergence of drug resistance. The insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in melanomas developing resistance toward the BRAF(V) (600) inhibitor vemurafenib. Here, we show that hyperactivation of BRAF enhances IGF-1R expression. In addition, the phosphatase activity of PTEN as well as heterocellular contact to stromal cells increases IGF 1R expression in melanoma cells and enhances resistance to vemurafenib. Interestingly, PTEN-negative melanoma cells escape IGF-1R blockade by decreased expression of the receptor, implicating that only in melanoma patients with PTEN positive tumors treatment with IGF-1R inhibitors would be a suitable strategy to combat therapy resistance. Our data emphasize the crosstalk and therapeutic relevance of microenvironmental and tumor cell-autonomous mechanisms in regulating IGF-1R expression and by this sensitivity toward targeted therapies. PMID- 26112749 TI - Men Aged 15-44 in Need of Preconception Care. AB - OBJECTIVES: Preconception care for men focuses on prevention strategies implemented prior to conception of a first or subsequent pregnancy to improve pregnancy and infant outcomes. Little is known about U.S. men in need of preconception care. This analysis describes the proportion of men in need of preconception care and associations of these needs by background characteristics, related health conditions, access to care and receipt of services. METHODS: Data from men aged 15-44 in the National Survey of Family Growth 2006-2010 were analyzed to describe men in need of preconception care, based on future childbearing intentions and self and partner fecundity status (among sexually experienced only), and associated factors with these needs using weighted bivariate analyses. RESULTS: About 60 % of men are in need of preconception care. Higher prevalence of being in need was observed among men aged 15-29 than older; living in urban than non-urban settings; in school than not in school regardless of working status; not in a coresidential union than married or cohabiting; who were recent immigrants than U.S. born; and reporting never having had a child than >=1 child(ren). Men in need were overweight/obese (56 %), ever binge drank in the last year (58 %), and have high STI risk (21 %). The majority of men in need reported access to care in the last year (>70 %), but few reported receipt of services including STD/HIV testing (<20 %) or counseling (<11 %). CONCLUSIONS FOR PRACTICE: Findings from this analysis have implications for promoting preconception care among U.S. men. PMID- 26112750 TI - The Association Between Diabetes Mellitus Among American Indian/Alaska Native Populations with Preterm Birth in Eight US States from 2004-2011. AB - OBJECTIVES: Assess risk of preterm birth associated with diabetes mellitus (DM) among American Indian and Alaska Natives (AI/AN), a population with increased risk of DM and preterm birth, and examine whether this association differed by state of residence. METHODS: We used surveillance data from the Pregnancy Risk Assessment Monitoring System from 12,400 AI/AN respondents with singleton births in Alaska, Minnesota, Nebraska, New Mexico, Oklahoma, Oregon, Utah, and Washington from 2004-2011. We conducted multivariable logistic regression models to estimate the odds ratio adjusted for maternal age and prepregnancy BMI with all observations and then stratified by state. RESULTS: DM was reported in 5.92 % of the study population and preterm birth occurred in 8.95 % of births. Women with DM had 1.92 times higher odds of having a preterm birth than women without DM [95 % confidence interval (CI) 1.21-2.78]. After stratifying on state, women with DM in Nebraska had the greatest odds of preterm birth [aOR 6.63, (95 % CI 3.80-11.6)] while women in Alaska saw a protective effect from DM [aOR 0.17, (95 % CI 0.07-0.42)] compared to women without DM. CONCLUSION: Overall, AI/AN women with DM had significantly greater odds of preterm birth compared to AI/AN women without DM across states. Substantial differences in this association between states calls for increased public health efforts in high-risk areas as well as further research to assess whether differences are attributable to diagnosis, reporting, tribal, healthcare or lifestyle factors. PMID- 26112751 TI - Predicting Preterm Birth Among Women Screened by North Carolina's Pregnancy Medical Home Program. AB - OBJECTIVE: To determine which combination of risk factors from Community Care of North Carolina's (CCNC) Pregnancy Medical Home (PMH) risk screening form was most predictive of preterm birth (PTB) by parity and race/ethnicity. METHODS: This retrospective cohort included pregnant Medicaid patients screened by the PMH program before 24 weeks gestation who delivered a live birth in North Carolina between September 2011-September 2012 (N = 15,428). Data came from CCNC's Case Management Information System, Medicaid claims, and birth certificates. Logistic regression with backward stepwise elimination was used to arrive at the final models. To internally validate the predictive model, we used bootstrapping techniques. RESULTS: The prevalence of PTB was 11 %. Multifetal gestation, a previous PTB, cervical insufficiency, diabetes, renal disease, and hypertension were the strongest risk factors with odds ratios ranging from 2.34 to 10.78. Non Hispanic black race, underweight, smoking during pregnancy, asthma, other chronic conditions, nulliparity, and a history of a low birth weight infant or fetal death/second trimester loss were additional predictors in the final predictive model. About half of the risk factors prioritized by the PMH program remained in our final model (ROC = 0.66). The odds of PTB associated with food insecurity and obesity differed by parity. The influence of unsafe or unstable housing and short interpregnancy interval on PTB differed by race/ethnicity. CONCLUSIONS: Evaluation of the PMH risk screen provides insight to ensure women at highest risk are prioritized for care management. Using multiple data sources, salient risk factors for PTB were identified, allowing for better-targeted approaches for PTB prevention. PMID- 26112752 TI - Myocardial glucose uptake in patients with the m.3243A > G mutation in mitochondrial DNA. AB - Mitochondrial mutations impair glucose oxidation and increase glucose uptake in cell cultures and lead to cardiomyopathy in patients. Here we characterize cardiac glucose uptake in 14 patients with the m.3243A > G mutation in mitochondrial DNA. The 14 patients with m.3243A > G and 13 controls were similar in age, physical activity and body mass index. Ten patients had diabetes. Left ventricular glucose uptake per tissue mass (LVGU) was measured with 2-[(18) F]fluoro-2-deoxyglucose positron emission tomography during euglycemic hyperinsulinemia. Cardiac morphology and function were assessed with magnetic resonance imaging. We found that the LVGU was 25% lower in the patients than that in the controls (P = 0.029). LVGU was inversely correlated with mutation heteroplasmy, glycated haemoglobin and fasting lactate in patients. The seven patients with mutation heteroplasmy >= 49% had 44% lower LVGU than the seven patients with heteroplasmy < 49%. This difference remained significant after adjustment for concurrent free fatty acid concentration or glycated haemoglobin or glucose uptake in skeletal muscle or all (p < 0.048 [All]). Patients with m.3243A > G had a lower stroke volume and a higher heart rate than the controls, whereas cardiac output and work were similar. Myocardial glucose uptake is not increased but decreased with a threshold effect pattern in patients with the m.3243A > G mutation. The glucose hypometabolism adds to the impaired cardiac energetics and likely contributes to the progression of the mitochondrial cardiomyopathy. PMID- 26112754 TI - Synthesis and thermodynamics of Ag-Cu nanoparticles. AB - Metallic silver, copper, and Ag-Cu nanoparticles (NPs) have been produced by a chemical reduction method. The obtained nanoparticles were characterized by powder X-ray diffraction (XRD) and transmission electron microscopy (TEM). A side segregated configuration was observed for the one-pot synthesized Ag-Cu NPs, and the melting temperature depression of about 14 degrees C was found by differential scanning calorimetry (DSC). A comparison between the new experimental data, the literature data on Ag-Cu bimetallic NPs and the corresponding theoretical values obtained from the Ag-Cu nano-sized phase diagram was done, whereas the melting behaviour of Ag and Cu metal nanoparticles was discussed in the framework of the liquid layer model (LLM). PMID- 26112753 TI - Spider wrapping silk fibre architecture arising from its modular soluble protein precursor. AB - Spiders store spidroins in their silk glands as high concentration aqueous solutions, spinning these dopes into fibres with outstanding mechanical properties. Aciniform (or wrapping) silk is the toughest spider silk and is devoid of the short amino acid sequence motifs characteristic of the other spidroins. Using solution-state NMR spectroscopy, we demonstrate that the 200 amino acid Argiope trifasciata AcSp1 repeat unit contrasts with previously characterized spidroins, adopting a globular 5-helix bundle flanked by intrinsically disordered N- and C-terminal tails. Split-intein-mediated segmental NMR-active isotope-enrichment allowed unambiguous demonstration of modular and malleable "beads-on-a-string" concatemeric behaviour. Concatemers form fibres upon manual drawing with silk-like morphology and mechanical properties, alongside secondary structuring and orientation consistent with native AcSp1 fibres. AcSp1 structural stability varies locally, with the fifth helix denaturing most readily. The structural transition of aciniform spidroin from a mostly alpha-helical dope to a mixed alpha-helix/beta-sheet-containing fibre can be directly related to spidroin architecture and stability. PMID- 26112755 TI - Urinary Trypsin Inhibitor Attenuates Acute Lung Injury by Improving Endothelial Progenitor Cells Functions. AB - BACKGROUND: Urinary Trypsin Inhibitor (UTI) is involved in various aspects of tissue repair, regeneration and development. However, the potential role of UTI in protection against acute lung injury (ALI) remains largely unknown. In the present study, we demonstrated that UTI treatment could ameliorate ALI induced by oleic acid (OA) treatment in rabbit model. METHODS: Intravenous application of UTI (10000 U/kg/d) significantly improved the pathologies associated with OA induced ALI. The lungs were stained with hematoxylin and eosin to scored the lung injury. Peripheral blood mononuclear cells were isolated by density gradient centrifugation with Ficoll-Plaque Plus. The proliferation and ability of tube structure formation of EPCs were observed and the level of phosphorylated Akt protein expression and eNOS protein expression were assayed. RESULTS: Consistent with pathological scores, UTI treatment significantly reduced wet/dry ratio of OA injured lungs. A quantification of capillary density revealed that UTI treatment led to about 2 fold increase over uninjured control and about 1.5 fold increase over PBS treatment. The capacity for tube formation of EPCs on ECM gel was significantly reduced in the ALI group and recovered with UTI treatment. Quantification of western blot bands was summarized and showed that UTI treatment activates Akt/eNOS signaling. NO production could contribute to the improvement of EPCs function by UTI treatment. CONCLUSIONS: UTI-induced phosphorylation/activation of eNOS and Akt, increases the intracellular level of NO, thereby improving tube formation and proliferation function of EPCs. EPCs function is crucial for re-endothelialization after denuding injuries of arteries. PMID- 26112756 TI - TNF-alpha inhibition prevents cognitive decline and maintains hippocampal BDNF levels in the unpredictable chronic mild stress rat model of depression. AB - Previous findings have shown that patients with depression express higher levels of proinflammatory cytokines such as TNF-alpha and IL-6. We have recently found that Infliximab (a TNF-alpha inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress (UCMS) model of depression suggesting that inflammation might play an important role in depression. An increasing number of studies suggest that inflammation is also associated with cognitive impairments. The current study aimed to investigate the effect of UCMS on the cognitive performance of rats and their hippocampal BDNF levels and the effect of chronic Infliximab (5mg/kg/weekly, i.p.) treatment on these measures. Rats were subjected to different types of stressors daily for a period of 56 days to induce depression-like state. The UCMS resulted in impairments in spatial and emotional memory acquisition and retention with no effect on the level of locomotor activity. These behavioral effects of UCMS were accompanied by reduction in the level of BDNF in the CA1 and CA3 regions of the hippocampus. Chronic Infliximab treatment prevented the UCMS-induced cognitive impairments as well as the reduction in the levels of hippocampal brain-derived neurotrophic factor (BDNF). These results suggest that Infliximab improves the spatial and emotional memory impairments induced by chronic stress in rats likely through its effects on hippocampal function by modulating inflammation. PMID- 26112758 TI - Update on Severe Burn Management for the Intensivist. AB - Thermal injury of humans causes arguably the most severe perturbations in physiology that can be experienced. These physiologic derangements start immediately and can persist in some form until months or even years after the burn wounds are healed. Burn shock, marked activation of the systemic inflammatory response, multiple-organ failure, infection, and wound failure are just a few of the insults that may require management by the intensivist. The purpose of this article is to review recent advances in the critical care management of thermally injured patients. PMID- 26112757 TI - Chronic treatment with the vasopressin 1b receptor antagonist SSR149415 prevents the dysphoria associated with nicotine withdrawal in rats. AB - Nicotine addiction is a chronic brain disorder that is characterized by dysphoria upon smoking cessation and relapse after brief periods of abstinence. It has been hypothesized that the negative mood state associated with nicotine withdrawal is partly mediated by a heightened activity of brain stress systems. Animal studies suggest that blockade of vasopressin 1b (V1b) receptors diminishes high levels of drug intake in dependent animals and attenuates the emotional response to stressors. The goal of the present studies was to investigate the effect of acute and chronic treatment with the V1b receptor antagonist SSR149415 on the negative mood state associated with nicotine withdrawal in rats. An intracranial self stimulation (ICSS) procedure was used to assess mood states and nicotine dependence was induced using minipumps. The nicotinic receptor antagonist mecamylamine was used to precipitate withdrawal. Mecamylamine elevated the brain reward thresholds of the nicotine dependent rats, which reflects a negative mood state. Mecamylamine did not affect the brain reward thresholds of the saline treated control rats. Chronic treatment with SSR149415 completely prevented the elevations in brain reward thresholds associated with nicotine withdrawal while acute treatment only partly prevented nicotine withdrawal. These data suggest that chronic treatment with V1b receptor antagonists may prevent the dysphoria associated with smoking cessation and thereby improve relapse rates. PMID- 26112759 TI - Evaluation of Serum Lactate, Central Venous Saturation, and Venous-Arterial Carbon Dioxide Difference in the Prediction of Mortality in Postcardiac Arrest Syndrome. AB - INTRODUCTION: Tissue hypoperfusion and hypoxia markers predict mortality in critically ill patients. This study evaluates the ability of serum lactate, central venous oxygen saturation (Scvo 2), and venous-arterial carbon dioxide difference (GapCo 2) to predict mortality in patients with postcardiac arrest (post-CA) syndrome. METHODS: A prospective observational study of patients with post-CA in a tertiary teaching hospital. Serial assessments of lactate, lactate clearance (Clac), GapCo 2, and Scvo 2 in the first 72 hours post-CA were analyzed. Adults (>=18 years) patients resuscitated from CA were included. The primary end point was 28-day mortality and secondary end points were 24- and 72 hour mortality. RESULTS: A total of 54 patients were recruited, 33 (61,1%) of 54 were men, with a 28-day mortality of 75.9%. Cardiac arrest occurred in-hospital in 84.6% of survivors and 97.5% of nonsurvivors. Lactate and Clac were significantly associated with mortality at 28 days, yielding an area under the receiver-operating characteristic curve of 0.797 (lactate 6 hours) and 0.717 (Clac 6 hours) with a positive predictive value of 96% for lactate 6 hours (> 2.5 mmol/L) and 89.5% for Clac 6 hours (<50%). Survival analysis confirmed the difference between the groups from the 24th hour post-CA. Considering mortality at 24 hours, lactate, Clac, and Scvo 2 (immediately post-CA, 6 and 18 hours) were different between the groups. In mortality at 72 hours, lactate, Clac, Scvo 2 (48 hours), and GapCo 2 (36 and 48 hours) were associated with mortality. CONCLUSION: In post-CA syndrome, serum lactate and Clac were consistently able to predict mortality. PMID- 26112761 TI - Differential effects of behavioral interventions with a graded physical activity component in patients suffering from Chronic Fatigue (Syndrome): An updated systematic review and meta-analysis. AB - An updated systematic review and meta-analysis was conducted to (1) evaluate the effects of behavioral and psychological interventions containing a graded physical activity component upon fatigue severity, physical functioning, physical activity and psychological distress, and to (2) examine potential moderator effects of trial characteristics (type of control, setting, provider, length of treatment, psychological component, flexibility in physical activity, and minimal face to face patient-provider contact). Pertinent content of selected studies was extracted and rated on a scale of methodological quality. Sixteen randomized controlled trials (N=2004) were included in the meta-analyses. Significant small to medium effect sizes (Hedge's g=0.25 to g=0.66) were found for all outcomes at post-treatment (M=5.2months) and follow-up (M=11.7months), with the exception of physical activity at post-treatment (g=0.11). The largest effects were found for fatigue severity (g=0.61 to g=0.66). Subgroup analyses revealed that minimal contact interventions had additional beneficial effects upon fatigue (g=0.96) and depression (g=0.85). Interventions provided by psychologists-psychotherapists and interventions conducted in secondary-tertiary settings also resulted in more beneficial effects on fatigue. We found some indication of publication bias. The small number of studies and variability between them are limitations of this study. Future research should explore additional moderating effects in order to improve the effectiveness of interventions. PMID- 26112762 TI - Repurposing of rutin for the inhibition of norovirus replication. AB - Drug repurposing is a strategy employed to circumvent some of the bottlenecks involved in drug development, such as the cost and time needed for developing new molecular entities. Noroviruses cause recurrent epidemics and sporadic outbreaks of gastroenteritis associated with significant mortality and economic costs, but no treatment has been approved to date. Herein, a library of molecules previously used in humans was screened to find compounds with anti-noroviral activity. Antiviral testing for four selected compounds against murine norovirus infection revealed that rutin has anti-murine norovirus activity in cell-based assays. PMID- 26112760 TI - Dimensions of emotion dysregulation in anorexia nervosa and bulimia nervosa: A conceptual review of the empirical literature. AB - Several existing conceptual models and psychological interventions address or emphasize the role of emotion dysregulation in eating disorders. The current article uses Gratz and Roemer's (2004) multidimensional model of emotion regulation and dysregulation as a clinically relevant framework to review the extant literature on emotion dysregulation in anorexia nervosa (AN) and bulimia nervosa (BN). Specifically, the dimensions reviewed include: (1) the flexible use of adaptive and situationally appropriate strategies to modulate the duration and/or intensity of emotional responses, (2) the ability to successfully inhibit impulsive behavior and maintain goal-directed behavior in the context of emotional distress, (3) awareness, clarity, and acceptance of emotional states, and (4) the willingness to experience emotional distress in the pursuit of meaningful activities. The current review suggests that both AN and BN are characterized by broad emotion regulation deficits, with difficulties in emotion regulation across the four dimensions found to characterize both AN and BN, although a small number of more specific difficulties may distinguish the two disorders. The review concludes with a discussion of the clinical implications of the findings, as well as a summary of limitations of the existing empirical literature and suggestions for future research. PMID- 26112763 TI - Construction and characterization of a recombinant reticuloendotheliosis virus expressing enhanced green fluorescent protein. AB - Reticuloendotheliosis virus (REV) causes an immunosuppressive and oncogenic disease in chickens and other birds. In this study, based on an infectious clone of REV, named HLJR0901, a recombinant virus containing the enhanced green fluorescence protein (EGFP) gene was constructed by inserting the EGFP expression cassette downstream of the 3' terminus of the viral env gene. An EGFP-tagged REV that stably expresses EGFP was rescued. This visible recombinant REV could contribute to the further understanding of the molecular mechanism involved in the replication and pathogenicity of REV. PMID- 26112764 TI - Discovery of a novel circular DNA virus in the Forbes sea star, Asterias forbesi. AB - A single-stranded DNA (ssDNA) virus, Asterias forbesi-associated circular virus (AfaCV), was discovered in a Forbes sea star displaying symptoms of sea star wasting disease (SSWD). The AfaCV genome organization is typical of circular Rep encoding ssDNA (CRESS-DNA) viruses and is similar to that of members of the family Circoviridae. PCR-based surveys indicate that AfaCV is not clearly associated with SSWD, whereas the sea star-associated densovirus (SSaDV), recently implicated in SSWD in the Pacific, was prevalent in symptomatic specimens. AfaCV represents the first CRESS-DNA virus detected in echinoderms, adding to the growing diversity of these viruses recently recovered from invertebrates. PMID- 26112765 TI - Confidence bounds for nonlinear dose-response relationships. AB - An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve. It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated using a public dataset and simulations based on the Emax and sigmoid Emax models. PMID- 26112767 TI - The morphology of the foetal sigmoid colon in the African population: a possible predisposition to sigmoid volvulus. AB - AIM: This study aimed to determine the morphological types of the foetal sigmoid colon and establish if the anatomical predisposition to sigmoid volvulus is present in Black African foetuses. Sigmoid volvulus affects Black Africans in our province more frequently than other ethnic groups, and males more than females. Its aetiology remains speculative, with factors being proposed that do not suggest the pathogenetic mechanisms or the gender bias. Previous anatomical studies have suggested that Black Africans have a predisposition to sigmoid volvulus due to an elongated sigmoid colon. We investigated whether this phenomenon occurred during foetal development. METHOD: Foetuses were donated from local hospitals. Population groups were defined as Black African and non-African. After dissection, the anatomy of the sigmoid colon was described according to level of origin, classic or elongated type and shape (broad or narrow). RESULTS: A total of 296 Black African foetuses and 37 non-African foetuses were donated. The sigmoid colon in the majority of foetuses in all gestational age groups had a low level of origin. An elongated colon was seen in 68% of Black African and 17% of non-African foetuses (P < 0.0001). Among Black Africans there was a higher proportion of elongated sigmoid colon among male (73%) than female foetuses (62%) (P = 0.044). In foetuses with an elongated sigmoid colon the broad shape was more common in females than males and the long-narrow shape was more common in males (P = 0.038). CONCLUSION: The elongated sigmoid colon seen in Black Africans is present in utero and occurs more frequently in Black African males. A narrow shape is more common in male foetuses and the broad shape is more common in female foetuses. These anatomical features may be the cause of the predisposition to sigmoid volvulus in Black African adults. PMID- 26112768 TI - Variations in periplasmic loop interactions determine the pH-dependent activity of the hexameric urea transporter UreI from Helicobacter pylori: a molecular dynamics study. AB - BACKGROUND: Helicobacter pylori is an important factor in the development of diseases such as ulcer and gastric cancer. This bacterium uses a periplasmic transporter, UreI, to deliver urea to the intracelullar space, where later it is transformed into ammonia by the cytoplasmic enzyme urease to survive the acidic condition of the human stomach. The UreI transporter presents a pH-dependent activity, where this pH-dependence remains unknown at a structural level. Althought the existance of several protonable residues in the periplasmic loops are related to the pH-dependent activity, we find interesting to have a clear view of the conformational changes involved in this phenomena through a molecular dynamic study. RESULTS: Molecular dynamic simulations of the UreI transporter at three different pH conditions were performed, revealing two main pH-dependent conformations, which we present as the open and close states. We find that salt bridges between the periplasmic loops are crucial interactions that stabilize these conformations. Besides, a cooperative behaviour exists between the six subunits of the system that is necessary to fulfill the activity of this transporter. CONCLUSIONS: We found different pH-dependent conformations of the urea transporter UreI from Helicobacter pylori, which are related to salt-bridge interactions in the periplasmic regions. The behaviour of every channel in the system is not independent, given the existance of a cooperative behaviour through the formation of salt-bridges between the subunits of the hexameric system. We believe that our results will be related to the generation of new eradication therapies using this transporter as an attractive target, denoting that the knowledge of the possible pH-dependent conformations adopted for this transporter are important for the development of rational drug design approximations. PMID- 26112769 TI - Mathematical ability of first year undergraduate paramedic students-A before and after study. AB - BACKGROUND: An ability to accurately perform drug calculations unassisted is an essential skill for all health professionals, with various occupational-specific stressors exacerbating mathematical deficiencies. OBJECTIVES: The objective of this study was to determine the unaided mathematic ability of first year undergraduate paramedic students before and after mathematical and drug calculation tutorials. METHODS: Students were administered a questionnaire containing demographic, drug calculation and arithmetic questions during week one of the semester before the tutorials. During the semester students participated in three 2-hour tutorials which included both mathematical and drug calculation questions without assistance of computational devices. At the end of semester was a summative drug calculation examination of which five key questions were compared to similar questions from the first questionnaire. Descriptive statistics describe the demographic data with a paired t-test comparing the questionnaire and exam results. RESULTS: Drug calculation and mathematical ability was markedly improved following the tutorials, mean score of correct answers before 1.74 (SD 1.4) and after 4.14 (SD 0.93), p<0001. When comparing the correct results for the same question type, there were statistically significant differences in four of five different drug calculations: volume of drug drawn up 10 v 57 p<0.0001, infusion rate 29 v 31 p=0.717, drip rate 16 v 54 p<0.0001, volume from a syringe 30 v 59 p<0.0001, and drug dose 42 v 62 p<0.0001. Total errors reduced from 188 to 45. CONCLUSIONS: First year undergraduate paramedic students initially demonstrated a poor ability to complete mathematical and drug calculations without the assistance of computational devices. This improved significantly following appropriate education and practice. Further research is required to determine the retention of this ability over time. PMID- 26112770 TI - Faculty experiences with rapid integration of male nursing students within a patriarchal societal context. AB - BACKGROUND: In 2007, reforms by the Turkish government forced a rapid integration of male nursing students into previously all-female schools. The minimal amount of time for faculty preparation, little guidance from nursing leaders and the extant literature, and a societal context of patriarchy created unique challenges for faculty. OBJECTIVE: The purpose of this qualitative study was to explore and interpret the experiences of nursing faculty as they adapted to the sudden inclusion of men in schools of nursing. DESIGN: A qualitative descriptive study SETTINGS: Nine schools from six regions across Turkey PARTICIPANTS: 99 nursing faculty who were 22 to 55years of age, primarily female (97.8%), married (65.6%). METHODS: Focus groups were used to collect data. Data were analyzed using constant comparison and tripartite discussion. RESULTS: Analysis yielded three categories, seven themes, and seven subthemes describing variable experiences, perceptions, and adaptive strategies. CONCLUSIONS: The findings presented contradictions characterized by both optimism and concern following the rapid infusion of men into schools of nursing. Concerns primarily centered on the state of gender relations in a larger patriarchal society. The findings foster reflection and discourse as societies characterized by relatively rigid and traditional gender roles confront rapid cultural change and growing calls for diversity within nursing. PMID- 26112766 TI - A Clinical Approach to the Differential Diagnosis of Multiple Sclerosis. AB - The diagnostic criteria for multiple sclerosis (MS) rely on clinical, paraclinical, and radiographic findings of limited specificity. Many disorders mimic MS, and the decision of when to investigate an alternative diagnosis can be challenging. Reliance on extensive ancillary testing to exclude potential mimics, however, is unnecessary in most cases. Rather, recognition and rigorous interpretation of "classic" clinical and radiographic features of MS are often sufficient to establish the diagnosis. Misinterpretation of the clinical and radiographic diagnostic criteria for MS in the setting of more common diseases and syndromes and a lack of vigilance for "red flags" are important contributors to misdiagnosis. A clinical framework for the differential diagnosis of MS that emphasizes phenotypes atypical for MS and suggests diseases or syndromes in which they more commonly occur may be an important diagnostic guide for clinicians in contemporary practice. PMID- 26112771 TI - A case of a stomach gastrointestinal stromal tumor with extremely predominant cystic formation. AB - A 79-year-old male was referred to the hospital with a history of abdominal discomfort. Abdominal computed tomography revealed a cystic tumor with irregular wall thickness, approximately 50 mm in diameter, along the lesser curvature of the gastric body. Magnetic resonance imaging visualized the mass as signal hyperintense on T2-weighted imaging. Esophagogastroduodenoscopy showed a submucosal tumor with normal mucosa. Surgery was performed and the 60 * 50 * 50 mm mass was resected. The resected tumor comprised cystic and solid regions; the cystic region was filled by light bloody serous fluid. On histological examination, a solid region of the resected tumor showed a spindle-cell appearance. The diagnosis was gastric gastrointestinal stromal tumor (GIST) with predominant cystic formation. GISTs are usually solitary tumors, but in this case the tumor demonstrated extremely predominant cystic formation. Lesions with a hemorrhage or necrosis may form large cystic spaces. GISTs may show extensive cystic changes in response to tyrosine kinase inhibitor treatment; however, this patient had not undergone any such treatment before diagnosis. This represents an interesting case of a gastric GIST with predominant cystic formation occupying most of the tumor volume. Care should be taken to differentiate between GISTs and actual intra-abdominal cystic lesions. PMID- 26112772 TI - Inspiring medical students to love pathology. PMID- 26112773 TI - Preparation of Graphene-Modified Acupuncture Needle and Its Application in Detecting Neurotransmitters. AB - We report a unique nanosensing platform by combining modern nanotechnology with traditional acupuncture needle to prepare graphene-modified acupuncture needle (G AN), and using it for sensitive detection of neurotransmitters via electrochemistry. An electrochemical deposition method was employed to deposit Au nanoparticles (AuNPs) on the tip surface of the traditional acupuncture needle, while the other part of the needle was coated with insulation paste. Subsequently, the G-AN was obtained by cyclic voltammetry reduction of a graphene oxide solution on the surface of the AuNPs. To investigate the sensing property of the G-AN, pH dependence was measured by recording the open circuit potential in the various pH buffer solutions ranging from 2.0 to 10.0. What's more, the G AN was further used for detection of dopamine (DA) with a limit of detection of 0.24 MUM. This novel G-AN exhibited a good sensitivity and selectivity, and could realize direct detection of DA in human serum. PMID- 26112774 TI - Beyond positivism: Understanding and addressing childhood obesity disparities through a Critical Theory perspective. AB - PURPOSE: We apply Critical Theory to examine menu labeling with the aim of uncovering important implications for nursing practice, research, and policy. CONCLUSIONS: Our critical analysis uncovers barriers to menu labeling's effectiveness, particularly for vulnerable populations. Nurses must work to minimize the impact of these barriers and optimize the effectiveness of menu labeling, in order to strengthen the fight against obesity. PRACTICE IMPLICATIONS: We suggest changes, guided by this critical analysis, which can be implemented by nurses working in clinical practice, research, and policy. PMID- 26112776 TI - NARRATIVE AND META-ANALYTIC REVIEW OF INTERVENTIONS AIMING TO IMPROVE MATERNAL CHILD ATTACHMENT SECURITY. AB - Early secure maternal-child attachment relationships lay the foundation for children's healthy social and mental development. Interventions targeting maternal sensitivity and maternal reflective function during the first year of infant life may be the key to promoting secure attachment. We conducted a narrative systematic review and meta-analysis to examine the effectiveness of interventions aimed at promoting maternal sensitivity and reflective function on maternal-child attachment security, as measured by the gold standard Strange Situation (M. Ainsworth, M. Blehar, B. Waters, & S. Wall, 1978) and Q-set (E. Waters & K. Deane, 1985). Studies were identified from electronic database searches and included randomized or quasi-randomized controlled parallel-group designs. Participants were mothers and their infants who were followed up to 36 months' postpartum. Ten trials, involving 1,628 mother-infant pairs, were included. Examination of the trials that provided sufficient data for combination in meta-analysis revealed that interventions of both types increased the odds of secure maternal-child attachment, as compared with no intervention or standard intervention (n = 7 trials; odds ratio: 2.77; 95% confidence interval: 1.69, 4.53, n = 965). Of the three trials not included in the meta-analyses, two improved the likelihood of secure attachment. We conclude that interventions aimed at improving maternal sensitivity alone or in combination with maternal reflection, implemented in the first year of infants' lives, are effective in promoting secure maternal-child attachments. Intervention aimed at the highest risk families produced the most beneficial effects. PMID- 26112775 TI - Young women's views on testing for sexually transmitted infections and HIV as a risk reduction strategy in mutual and choice-restricted relationships. AB - AIM: The aim of this study was to identify relationship dynamics that influences the use of STI/HIV testing among young, urban African American women. BACKGROUND: Increasing STI/HIV testing is a key prevention strategy, but more research is needed to identify barriers to testing for young women such as intimate partner violence (IPV). METHODS: Thirty semi-structured interviews were conducted with African American women ages 18-24. Content analysis was used. RESULTS: Women in choice-restricted relationships were unable to negotiate safer sex practices and testing was viewed as the best option. Women in relationships where the desire to use condoms was mutual used STI and HIV testing as a sign of trust building that preceded unprotected sex. CONCLUSIONS: STI/HIV testing must be viewed as one strategy within a package of possible risk reduction. For those in choice restricted relationships, clinicians should screen patients for partner abuse and provide additional support and referrals as clinically appropriate. PMID- 26112777 TI - Effects of light touch on postural sway and visual search accuracy: A test of functional integration and resource competition hypotheses. AB - People often multi-task in their daily life. However, the mechanisms for the interaction between simultaneous postural and non-postural tasks have been controversial over the years. The present study investigated the effects of light digital touch on both postural sway and visual search accuracy for the purpose of assessing two hypotheses (functional integration and resource competition), which may explain the interaction between postural sway and the performance of a non postural task. Participants (n=42, 20 male and 22 female) were asked to inspect a blank sheet of paper or visually search for target letters in a text block while a fingertip was in light contact with a stable surface (light touch, LT), or with both arms hanging at the sides of the body (no touch, NT). The results showed significant main effects of LT on reducing the magnitude of postural sway as well as enhancing visual search accuracy compared with the NT condition. The findings support the hypothesis of function integration, demonstrating that the modulation of postural sway can be modulated to improve the performance of a visual search task. PMID- 26112778 TI - The role of task constraints in relating laboratory and clinical measures of balance. AB - This study tested the hypothesis that age-related postural control deficits are more clearly detected from force plate recordings when using postural control tasks with an explicitly defined goal as opposed to the frequently used quiet stance task. Eighteen older adults (over 65) and seventeen younger adults (under 30) stood on a force plate with visual feedback (VFB) of the center of pressure (COP) and without such visual feedback with eyes open (NVFB). In the VFB condition, online visual feedback about the COP was provided and participants maintained that feedback on a stationary visual target for 80s. We hypothesized that age-related difference in COP variability (standard deviation of COP position and average absolute maximum COP velocity; AAMV) would be more pronounced in the VFB than in the NVFB condition. In addition, we hypothesized that Berg balance scale (BBS) scores for older adults would correlate more strongly with the COP measures in the VFB condition than in the NVFB condition. Results showed that VFB enhanced age-related differences only for AAMV in anterior-posterior direction. Both age groups decreased postural sway when using VFB. Older adults increased AAMV with VFB while young adults did not, indicating that the task modified their postural control strategy stronger than in younger adults. BBS scores were correlated with the AAMV in both feedback conditions, while COP position variability was more clearly correlated with BBS in the VFB condition. These results suggest that the quiet stance task is sufficient to index balance function if velocity-based COP variables are utilized in the analysis. PMID- 26112779 TI - A proposal for an 'equal peer-review' statement. AB - To make the peer-review process as objective as possible, I suggest the introduction of an 'equal peer-review' statement that preserves author anonymity across the board, thus removing any potential bias related to nominal or institutional 'prestige'; this would guarantee an equal peer-review process for all authors and grant applicants. PMID- 26112781 TI - Complete Genome Sequences of Field Isolates of Mycobacterium bovis and Mycobacterium caprae. AB - Here we report the complete genome sequences of field isolates of Mycobacterium bovis and the related mycobacterial species, Mycobacterium caprae. The genomes of three M. bovis (MB1, MB3, MB4) and one M. caprae (MB2) field isolates with different virulence, prevalence, and host distribution phenotypes were sequenced. PMID- 26112780 TI - Effect of Weight Loss Induced by Intragastric Balloon Therapy on Cardiac Function in Morbidly Obese Individuals: A Pilot Study. AB - OBJECTIVE: The aim of the study was to investigate the effect of intragastric balloon therapy on left ventricular function and left ventricular mass in a cohort of morbidly obese patients. SUBJECTS AND METHODS: A prospective trial was performed in a cohort of 17 class II and class III morbidly obese individuals. The intragastric balloon was retained in the stomach for an average of 6 months. Conventional and tissue Doppler echocardiography were performed in all patients before and after the procedure. RESULTS: The mean age of the study participants was 36 +/- 10 years (range: 18-55). The mean body mass index was significantly decreased following the intragastric balloon insertion procedure (44 +/- 8 vs. 38 +/- 5, p < 0.001). The left ventricular mass index and left atrial volume index were significantly decreased following the procedure (112 +/- 21 vs. 93 +/- 17, p = 0.001 and 20 +/- 6 vs. 14 +/- 5, p = 0.02, respectfully). In addition, the ratio of mitral peak early diastolic velocity to tissue Doppler-derived peak diastolic velocity and tissue Doppler echocardiography-derived left ventricular myocardial performance index were decreased significantly following the procedure (9.5 +/- 1.9 vs. 7.7 +/- 1.5, p = 0.002 and 0.57 +/- 0.11 vs. 0.46 +/- 0.06, p = 0.001, respectively). CONCLUSIONS: Intragastric balloon therapy resulted in significant weight reduction in morbidly obese patients. This weight reduction was associated with improved left ventricular function. PMID- 26112782 TI - Draft Genome Sequence of the Rice Kernel Smut Tilletia horrida Strain QB-1. AB - Tilletia horrida is the most destructive fungal pathogen of rice (Oryza sativa L.). The 20,105,270-bp draft genome sequence of T. horrida strain QB-1 is reported here. Genes encoding proteins associated with key virulence factors were predicted, and this can provide information for understanding the pathogenic mechanisms in T. horrida. PMID- 26112783 TI - Complete Genome Sequences of Two Genetically Distinct Variants of Porcine Epidemic Diarrhea Virus in the Eastern Region of Thailand. AB - Porcine epidemic diarrhea virus (PEDV) has continued to cause sporadic outbreaks in Thailand since 2007. Previously, PEDV in Thailand was a new variant containing an insertion and deletion in the spike gene. Herein, full-length genome sequences are reported for two variants of PEDV isolates from pigs displaying diarrhea in Thailand. PMID- 26112784 TI - Draft Genome Sequences of Ciliovirus and Brinovirus from San Francisco Wastewater. AB - We report the draft genome sequences of ciliovirus and brinovirus, two members of a likely new family of RNA viruses assembled from San Francisco wastewater. Based on sequence alignments and a nonuniversal genetic code, we believe these to be the first described RNA viruses of ciliates; however, more work is necessary to confirm their host. PMID- 26112785 TI - Draft Genome Sequences of Leviviridae RNA Phages EC and MB Recovered from San Francisco Wastewater. AB - We report here the draft genome sequences of marine RNA phages EC and MB assembled from metagenomic sequencing of organisms in San Francisco wastewater. These phages showed moderate translated amino acid identity to other enterobacteria phages and appear to constitute novel members of the Leviviridae family. PMID- 26112786 TI - Complete Genome Sequence of Elizabethkingia meningoseptica, Isolated from a T Cell Non-Hodgkin's Lymphoma Patient. AB - An Elizabethkingia meningoseptica infection was detected at the end stage of a patient with T-cell non-Hodgkin's lymphoma. The complete genome of this isolated strain, FMS-007, was generated in one contig with a total size of 3,938,967 bp. A preliminary screening indicated that the genome contains drug resistance genes to aminoglycosides and beta-lactams. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (CRISPR/Cas) system with 16 direct repeats and 15 spacers was identified. PMID- 26112787 TI - Complete Genome Sequence of Leptospira interrogans Serovar Bratislava, Strain PigK151. AB - Leptospira interrogans serovar Bratislava infection occurs in multiple domestic and wildlife species and is associated with poor reproductive performance in swine and horses. We present the complete genome assembly of strain PigK151 comprising two chromosomes, CI (4.457 Mbp) and CII (358 kbp). PMID- 26112788 TI - Complete Genome Sequence of Edwardsiella tarda Isolate FL95-01, Recovered from Channel Catfish. AB - Edwardsiella tarda is a Gram-negative facultative anaerobe that has been isolated from fish, reptiles, amphibians, and mammals, including humans. This is a report of the complete and annotated genome of isolate FL95-01, recovered from channel catfish (Ictalurus punctatus). PMID- 26112789 TI - Whole-Genome Sequences of 15 Strains of Staphylococcus aureus subsp. aureus Isolated from Foodstuff and Human Clinical Samples. AB - The whole-genome sequences of 15 strains of Staphylococcus aureus (10 strains isolated from foodstuff samples in Switzerland and five from human clinical samples) were obtained by Illumina sequencing. Most strains fit within the known diversity for the species, but one (SA-120) possessed a higher G+C content and a higher number of genes than usual. PMID- 26112790 TI - Whole-Genome Sequencing of Brevundimonas diminuta XGC1, Isolated from a Tuberculosis Patient in Gujarat, India. AB - We report the draft genome of Brevundimonas diminuta strain XGC1, isolated from a tuberculosis-infected patient in Gujarat, India. This study also reveals that the B. diminuta XGC1 strain has acquired mutation to confer resistance to quinolone drugs. PMID- 26112791 TI - Draft Genome Sequence of Mycobacterium elephantis Strain Lipa. AB - We report the draft genome sequence of Mycobacterium elephantis strain Lipa from a sputum sample of a patient with pulmonary disease. This is the first draft genome sequence of M. elephantis, a rapidly growing mycobacterium. PMID- 26112792 TI - Draft Genome Sequence of Lactobacillus delbrueckii subsp. bulgaricus CRL871, a Folate-Producing Strain Isolated from a Northwestern Argentinian Yogurt. AB - Lactobacillus delbrueckii subsp. bulgaricus CRL871 is the first strain of L. delbrueckii subsp. bulgaricus reported as a folate-producing strain. We report the draft genome sequence of L. delbrueckii subsp. bulgaricus CRL871 (2,063,981 bp, G+C content of 49.1%). This strain is of great biotechnological importance to the dairy industry because it constitutes an alternative to folic acid fortification. PMID- 26112793 TI - Draft Genome Sequence of the Streptococcus pneumoniae Avery Strain A66. AB - We have used HiSeq 2000 technology to generate a draft genome sequence of Streptococcus pneumoniae strain A66. This is a common study strain used in investigations of pneumococcal bacterium-host interactions and was used in the seminal genetic studies of Avery et al. PMID- 26112794 TI - Draft Genome Sequences of Two Toxigenic Corynebacterium ulcerans Strains. AB - Here, we present the draft genome sequences of two toxigenic Corynebacterium ulcerans strains isolated from two different patients: one from a blood sample and the other from a scar exudate following surgery. Although these two strains harbor the diphtheria toxin gene tox, no full prophage sequences were found in the flanking regions. PMID- 26112795 TI - Draft Genome Sequence of Streptacidiphilus oryzae TH49T, an Acidophilic Actinobacterium Isolated from Soil. AB - The draft genome sequence of Streptacidiphilus oryzae strain TH49(T), an acidophilic actinobacterium, was obtained. The draft is composed of six scaffolds totaling 7.8 Mbp, and it contains 6,829 protein-coding genes and 91 RNA genes. Genes related to respiratory nitrate reduction, siderophore production, and biosynthesis of other secondary metabolites were identified. PMID- 26112796 TI - Stress among nurses working in emergency, anesthesiology and intensive care units depends on qualification: a Job Demand-Control survey. AB - BACKGROUND: The nurse stress literature reports an overwhelming culture of acceptance and expectation of work stressors, ironically linked to the control of the workplace to effectively and proactively manage stress. The stressors involved in delivering "stress management" have been well studied in nursing related workplaces, especially in acute care settings in accordance with the Karasek Job Demand-Control-Support (JDCS) model. However, little is known about the effects of specificity of an acute care unit and the level of qualifications on stress experienced by nurses. METHODS: A survey using the JDCS model was conducted among 385 nurses working in three different acute care units (anesthesiology, emergency and intensive care unit) from a university hospital. Specific questions explored variables such as gender, acute care units, level of qualification and working experience. RESULTS: Two hundred questionnaires were returned. A high level of job strain was highlighted without a gender effect and in the absence of isostrain. Nurses from acute care units were located in the high stress quadrant of the JDCS model. Conversely, other nurses were commonly located in the "active" quadrant. Independent of acute care settings, the highest level of education was associated with the highest job strain and the lowest level of control. CONCLUSIONS: In an acute care setting, a high level of education was a key factor for high job stress and was associated with a perception of a low control in the workplace, both of which may be predictors of adverse mental health. In particular, the lack of control has been associated with moral distress, a frequently reported characteristic of acute care settings. To enhance the personal and professional outcomes of the advanced registered nurses, strategies for supporting nurses manage daily stressors in acute care are urgently required. PMID- 26112797 TI - Shared Decision-making in the Emergency Department: Respecting Patient Autonomy When Seconds Count. AB - Shared decision-making (SDM), a collaborative process in which patients and providers make health care decisions together, taking into account the best scientific evidence available, as well as the patient's values and preferences, is being increasingly advocated as the optimal approach to decision-making for many health care decisions. The rapidly paced and often chaotic environment of the emergency department (ED), however, is a unique clinical setting that offers many practical and contextual challenges. Despite these challenges, in a recent survey emergency physicians reported there to be more than one reasonable management option for over 50% of their patients and that they take an SDM approach in 58% of such patients. SDM has also been selected as the topic on which to develop a future research agenda at the 2016 Academic Emergency Medicine consensus conference, "Shared Decision-making in the Emergency Department: Development of a Policy-relevant Patient-centered Research Agenda" (http://www.saem.org/annual-meeting/education/2016-aem-consensus-conference). In this paper the authors describe the conceptual model of SDM as originally conceived by Charles and Gafni and highlight aspects of the model relevant to the practice of emergency medicine. In addition, through the use of vignettes from the authors' clinical practices, the applicability of SDM to contemporary EM practice is illustrated and the ethical and pragmatic implications of taking an SDM approach are explored. It is hoped that this document will be read in advance of the 2016 Academic Emergency Medicine consensus conference, to facilitate group discussions at the conference. PMID- 26112799 TI - Capture, adaptation and artificial control of reproduction of Lophiosilurus alexandri: A carnivorous freshwater species. AB - The present study describes the capture adaptation and reproduction of wild Lophiosilurus alexandri broodstock in laboratory conditions. There were two periods when capturing was performed in natural habitats. The animals were placed in four tanks of 5m(3) with water temperatures at 28 degrees C with two tanks having sand bottoms. Thirty days after the temperature increased (during the winter) the first spawning occurred naturally, but only in tanks with sand on the bottom. During the breeding season, there were 24 spawning bouts with egg mass collections occurring as a result of the spawning bouts that occurred in the tanks. The hatching rates for eggs varied from 0% to 95%. The spawning bouts were mainly at night and on weekends. In the second reproductive period, the animals were sexed by cannulation and distributed in four tanks with all animals being maintained in tanks with sand on the bottom at 28 degrees C. During this phase, there were 36 spawning bouts. Findings in the present study contribute to the understanding of the reproductive biology of this endangered species during captivity. PMID- 26112800 TI - The uses and implications of standards in general practice consultations. AB - Quality standards play an increasingly important role in primary care through their inscription in various technologies for improving professional practice. While 'hard' biomedical standards have been the most common and debated, current quality development initiatives increasingly seek to include standards for the 'softer' aspects of care. This article explores the consequences of both kinds of quality standards for chronic care consultations. The article presents findings from an explorative qualitative field study in Danish general practice where a standardized technology for quality development has been introduced. Data from semi-structured interviews and observations among 17 general practitioners were analysed using an iterative analytical approach, which served to identify important variations in the uses and impacts of the technology. The most pronounced impact of the technology was observed among general practitioners who strictly adhered to the procedural standards on the interactional aspects of care. Thus, when allowed to function as an overall frame for consultations, those standards supported adherence to general recommendations regarding which elements to be included in chronic disease consultations. However, at the same time, adherence to those standards was observed to narrow the focus of doctor-patient dialogues and to divert general practitioners' attention from patients' personal concerns. Similar consequences of quality standards have previously been framed as manifestations of an inherent conflict between principles of patient centredness and formal biomedical quality standards. However, this study suggests that standards on the 'softer' aspects of care may just as well interfere with a clinical approach relying on situated and attentive interactions with patients. PMID- 26112801 TI - Engines of alternative objectivity: Re-articulating the nature and value of participatory mental health organisations with the Hearing Voices Movement and Stepping Out Theatre Company. AB - Through two case studies, the Hearing Voices Movement and Stepping Out Theatre Company, we demonstrate how successful participatory organisations can be seen as 'engines of alternative objectivity' rather than as the subjective other to objective, biomedical science. With the term 'alternative objectivity', we point to collectivisations of experience that are different to biomedical science but are nonetheless forms of objectivity. Taking inspiration from feminist theory, science studies and sociology of culture, we argue that participatory mental health organisations generate their own forms of objectivity through novel modes of collectivising experience. The Hearing Voices Movement cultivates an 'activist science' that generates an alternative objective knowledge through a commitment to experimentation, controlling, testing, recording and sharing experience. Stepping Out distinguishes itself from drama therapy by cultivating an alternative objective culture through its embrace of high production values, material culture, aesthetic standards. A crucial aspect of participatory practice is overcoming alienation, enabling people to get outside of themselves, encounter material worlds and join forces with others. PMID- 26112802 TI - Cytoplasmic genome types of European potatoes and their effects on complex agronomic traits. AB - BACKGROUND: Various wild species germplasm has been used in European potato breeding since the first introduction of potato (Solanum tuberosum L.) to Europe. As the plant cytoplasmic genome including chloroplast and mitochondrial genomes is transmitted only through the maternal parent, cytoplasmic markers are useful tools in breeding programs to determine cytoplasmic genome types and to trace maternal ancestors. The potato cytoplasmic genome can be distinguished into six distinct types (M, P, A, W, T, and D). Male sterility was found in genotypes with S. demissum-derived D-type cytoplasm and S. stoloniferum-derived W/gamma-type cytoplasm. These wild species were frequently used to incorporate superior pathogen resistance genes. As a result, the percentage of these two types is increasing unintentionally in the European germplasm pool. Other than cytoplasmic male sterility, little is known about effects of the cytoplasmic genome on complex agronomic traits in potato. RESULT: The cytoplasm types of 1,217 European potato cultivars and breeding clones were determined with type specific DNA markers. Most frequent were T- (59.4 %), D- (27.4 %), and W- (12.2 %) type cytoplasm, while A- (0.7 %) and M-type cytoplasm (0.3 %) was rare and P-type cytoplasm was absent. When comparing varieties with breeding clones, the former showed a relatively higher frequency of T-type and lower frequency of D- and W type cytoplasm. Correlation analysis of cytoplasm types and agronomic data showed that W/gamma-type cytoplasm was correlated with increased tuber starch content and later plant maturity. Correlation with quantitative resistance to late blight was observed for D-type and M-type cytoplasm. Both cytoplasm types had a positive effect on resistance. CONCLUSION: This study revealed and quantified the cytoplasmic diversity in the European potato germplasm pool. Knowledge of cytoplasm type is important for maintaining genetic diversity and managing the male sterility problem in breeding programs. This is the first comprehensive study to show correlations of distinct cytoplasmic genomes with complex agronomic traits in potato. Correlations particularly with tuber starch content and resistance to late blight provided new knowledge on cytoplasmic effects on these important traits, which can be exploited for genetic improvement of potato. PMID- 26112803 TI - Brain metastasis research: a late awakening. PMID- 26112804 TI - Prognostic scores for brain metastasis patients: use in clinical practice and trial design. AB - Brain metastases (BM) are the most serious neurological complication of cancer that results in significant morbidity and mortality in these patients. The most common primary malignancies that lead to BM include lung, breast and melanoma. Until recently the outcomes of patients with BM has been dismal. The current therapeutic options include surgery, whole brain radiation therapy (WBRT), stereotactic radiation (SRS), systemic therapy and symptom management only. Prognostic scores, a useful tool for BM patients, as an estimation of a patient's prognosis can guide tailored treatment for these patients. It is appropriate to recommend more aggressive approaches in patients with good performance status and limited disease and focus on symptom control and palliative measures when the disease is more advanced, or comorbidity preclude aggressive therapy. Due to vastly different outcomes, prognostic scores are important to stratify patients in clinical trials. A number of prognostic scoring systems for BM patients have been proposed that include Recursive Partitioning Analysis (RPA), the Score Index For Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), the Rotterdam system (ROTTERDAM), the Golden Grading System (GGS), 2 Rades classification (RADES), the Graded Prognostic Assessment (GPA) and the disease specific Graded Prognostic Assessment (ds-GPA). In this article, we will review the important prognostic scoring systems and their utility in clinical decision making and trial design. PMID- 26112805 TI - Neurosurgical and radiosurgical decision making in brain metastasis patients in the area of targeted therapies? AB - The incidence of brain metastases (BM) is increasing to date, mostly due to the actual improvement of cancer patient overall survival (OS) with the advent of targeted therapies. BM management has dramatically evolved over the last 15 years and uses varying strategies including more or less aggressive local treatments, sometimes combined with systemic therapies that led to an improvement of patient's survival and quality of life. The therapeutic decision is still a matter of debates among experts during multidisciplinary staff, taking into account established prognostic factors including patient's general condition (clinical and functional status of the patient), extra-cerebral disease status, characteristic of intracranial metastases and clinical and radiological presentation of BM. In this article, we reviewed evidence based data available in the literature on the local treatment of BM. PMID- 26112806 TI - Anaplastic lymphoma kinase inhibitors in brain metastases from ALK+ non-small cell lung cancer: hitting the target even in the CNS. AB - The paradigm shift occurring in non-small cell lung cancer (NSCLC) is encapsulated by the management of patients harboring oncogenic anaplastic lymphoma kinase (ALK) rearrangements. The unprecedented improvements in patient outcomes resulting from ALK-directed therapy have led to the appreciation of patterns of disease progression. Early studies have suggested that some tyrosine kinase inhibitors (TKIs), including ALK TKIs, inefficiently penetrated the blood brain barrier. With the increasing appreciation of the CNS as a sanctuary site in ALK TKI-treated patients, there is increasing focus and importance on the prevention and control of CNS metastases in ALK-rearranged NSCLC. The spectrum of CNS activity is variable among the currently available ALK TKI therapies and further studies are ongoing. In the following review we discuss the ability of current and future ALK inhibitors (ALK-i) to control and prevent CNS progression in patients with ALK-rearranged NSCLC. The potential implications for TKI sequencing and important future research directions are discussed. PMID- 26112807 TI - The inflammatory microenvironment in brain metastases: potential treatment target? AB - Brain metastases (BM) are frequent in cancer patients and are associated with high morbidity and mortality. The incidence of BM is increasing and only limited treatment strategies are available. Immunomodulatory agents are emerging as effective cancer therapeutics and a deeper understanding of the inflammatory microenvironment in BM might reveal new treatment possibilities. Although the brain has long been considered an 'immune-privileged' organ with limited capacity for inflammatory response, BM do contain tumor infiltrating lymphocytes (TILs). Moreover, dense infiltration with TIL showed an association with favorable patients' overall survival times. Microglia/macrophages were shown to be involved in the pivotal steps of BM formation by providing a "pre-metastatic niche" attracting BM initiating cells and to promote growth and survival of tumor cells in the CNS microenvironment. The anti-cytotoxic T lymphocyte antigen 4 (CTLA4) immune checkpoint inhibitor ipilimumab showed activity against melanoma BM in a clinical trial, thus providing proof of concept for effective therapeutic immunomodulation in patients with CNS metastases. Collectively, the available data show that BM harbors an active inflammatory microenvironment that may be exploited as treatment target. PMID- 26112809 TI - The emerging role of advanced neuroimaging techniques for brain metastases. AB - Brain metastases are an increasingly encountered and frightening manifestation of systemic cancer. More effective therapeutic strategies for the primary tumor are resulting in longer patient survival on the one hand while on the other, better brain tumor detection has resulted from increased availability and development of more precise brain imaging methods. This review focuses on the emerging role of functional neuroimaging techniques; magnetic resonance imaging (MRI) as well as positron emission tomography (PET), in establishing diagnosis, for monitoring treatment response with an emphasis on new targeted as well as immunomodulatory therapies and for predicting prognosis in patients with brain metastases. PMID- 26112808 TI - Genomic profiling of brain metastases: current knowledge and new frontiers. AB - Brain metastases (BM) constitute the majority of intracranial cancers and carry with them a dismal prognosis. Several common cancers have a particular predilection for spread to the brain, amongst them lung cancer, breast cancer, melanoma, renal cell carcinoma (RCC), and more rarely gastrointestinal (GI) cancers. While prognosis has historically been poor and multimodality treatment combining surgery and radiation therapy was the mainstay of treatment, the genomic revolution in cancer therapy is finding increasing applications in treatment of central nervous system (CNS) disease. Targeted therapy, combined with advances in the evaluation of BM for targetable mutations, is showing increased efficacy. Developments in the understanding of brain tropism and targetable signaling pathways in metastasis are elucidating entirely new treatment approaches. This review focuses on advances made in the understanding of the genomics of BM and how this may change the role of targeted therapeutics in this common complication of cancer. PMID- 26112810 TI - Strategies for preservation of memory function in patients with brain metastases. AB - BACKGROUND: Cognitive decline, particularly in memory, is a side effect seen in patients with brain metastases and when severe, can have a significant impact on their quality of life. It is most often the result of multiple intersecting etiologic factors, including the use of whole brain radiation therapy, effects of which, in part, are mediated by damage within the hippocampus. A variety of clinical factors and comorbidities may impact the likelihood and severity of this cognitive decline, and affected patients should be considered for evaluation in a comprehensive neuro-rehabilitation or "brain fitness" program. PREVENTION STRATEGIES OF NEUROCOGNITIVE DECLINE DUE TO WHOLE BRAIN RADIOTHERAPY (WBRT): Avoiding WBRT is warranted for some patients with brain metastases; particularly those <50 years old. However, when WBRT is clinically indicated, hippocampal avoidance WBRT (HA-WBRT) has been shown to significantly reduce memory decline compared to historical controls without compromising treatment efficacy. Additionally, the NMDA receptor antagonist memantine and renin-angiotensin aldosterone system (RAAS) blockers have shown promise as neuroprotective agents that could be used prophylactically with radiation. TREATMENT OF PATIENTS WITH NEUROCOGNITIVE DECLINE: After the onset of neurocognitive decline the treatment is largely symptom-driven, however simply screening for and treating depression, fatigue, anxiety, cognitive slowing, and other processes may alleviate some impairment. Stimulants such as methylphenidate may be useful in treating symptoms of fatigue and cognitive slowing. Other treatments including donepezil and cognitive rehabilitation have been extensively tested in the population at risk for dementia, although they have not been adequately studied in patients following cranial radiotherapy. An innovative hypothetical approach is the use of intranasal metabolic stimulants such as low dose insulin, which could be valuable in improving cognition and memory, by reversing impaired brain metabolic activity. CONCLUSIONS: Prevention of neurocognitive decline in patients with brain metastases requires a multimodal approach tailored to each patient's need, avoiding WBRT in some, altering the WBRT plan in others, and/or using neuroprotective prophylaxis in those in whom avoidance cannot be utilized. Likewise treatment will require a personalized combination of strategies optimized to address the patient's symptoms. PMID- 26112811 TI - Systemic therapies for melanoma brain metastases: which drug for whom and when? AB - Melanoma brain metastases are common, difficult to treat, and are associated with a poor prognosis. Historically, due to the poor activity of chemotherapeutic agents in melanoma, the management of brain metastases was centred on local treatments such as surgery, stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT) depending on the clinical presentation. New systemic therapies have now evolved; kinase inhibitors targeting BRAF mutated melanoma cells and activating checkpoint inhibitors that activate an immune anti-tumour response, resulting in significantly improved survival and quality of life for patients with metastatic melanoma and these drugs have demonstrated activity in melanoma brain metastases. As the landscape shifts to incorporate these new systemic agents with the available local therapies, further research into using appropriate combinations or sequences of various treatments, especially for active or progressing melanoma brain metastasis, is required. This review will examine the evidence for systemic therapies in patients with active melanoma brain metastasis (untreated or treated and progressed) and highlight active and evolving clinical trials in this challenging field. PMID- 26112812 TI - Management of neoplastic meningitis. AB - Leptomeningeal dissemination of tumor cells, also referred to as neoplastic meningitis, is most frequently seen in patients with late-stage cancer and mostly associated with a poor prognosis. Basically, neoplastic meningitis may affect all patients with a malignant tumor but is most common in patients affected by lung cancer, breast carcinoma, melanoma or hematologic neoplasms such as lymphoma and leukemia. Controlled clinical trials are largely lacking which results in various non-standardized treatment regimens. The presence of solid tumor manifestations in the CNS as well as the extracranial tumor load defines the most appropriate treatment approach. Radiation therapy, systemic chemotherapy and intrathecal treatment must be considered. For each patient, the individual situation needs to be carefully evaluated to determine the potential benefit as well as putative side effects associated with any therapy. A moderate survival benefit and particularly relief from pain and neurological deficits are the main treatment goals. Here, we summarize the management of patients with neoplastic meningitis and review the available treatment options. PMID- 26112813 TI - Expert consensus on image-guided radiofrequency ablation of pulmonary tumors- 2015 edition. PMID- 26112814 TI - Study on the pupal morphogenesis of Chrysomya rufifacies (Macquart) (Diptera: Calliphoridae) for postmortem interval estimation. AB - Chrysomya rufifacies (Macquart) is one of the most common species of blow flies at the scene of death in Southern China. Pupae are useful in postmortem interval (PMI) estimation due to their sedentary nature and longer duration of association with the corpse. However, to determine the age of a pupa is more difficult than that of a larva, due to the fact that morphological changes are rarely visible during pupal development. In this study, eggs of C. rufifacies were reared in climatic chambers under four different constant temperatures (20, 24, 28 and 32 degrees C each+/-1 degrees C, respectively) with same rearing conditions such as foodstuff, substrate, photoperiod and relative humidity. Ten duplicate pupae were sampled at 8-h intervals from prepupae to emergence under the different constant temperatures, respectively. The pupae were sampled, killed, fixed, dissected and with the puparium removed, the external morphological changes of the pupae were observed, recorded and photographed. The morphological characters of C. rufifacies pupae were described. Based on the visible external morphological characters during pupal morphogenesis at 28 degrees C+/-1 degrees C, the developmental period of C. rufifacies was divided into nine developmental stages and recorded in detailed description. Based on above-mentioned nine developmental stages, some visible external morphological characters were selected as indications for developmental stages. These indications mapped to 8-h sampling intervals at the four different constant temperatures were also described in this study. It is demonstrated that generally the duration of each developmental stage of C. rufifacies pupae is inversely correlated to appropriate developmental temperatures. This study provides relatively systematic pupal developmental data of C. rufifacies for the estimation of PMI. In addition, further work may improve by focus on other environmental factors, histological analysis, more thorough external examination by shortening sampling intervals, PAE (the Pupal Age Estimator) method and parasitic insects of C. rufifacies. PMID- 26112815 TI - The study of physical requirements for windsurfing specialty. AB - BACKGROUND: In order to prepare beginners to be windsurfing players, windsurf specific fitness training is necessary besides windsurfing skill training. The aim of this study was to clarify distinguish the difference in physical abilities between college windsurfers and age-matched college students without regular exercise, and to provide further training suggestions for a novice. METHODS: Eight windsurfers and a group of eight age and gender-matched students were involved in the present study. In this study, the ability of coordination, proprioception deficit, balance ability, maximum muscle strength, and muscle endurance for upper and lower limb were measured. RESULTS: The results showed windsurfers had significantly better coordination ability than the control group in both shoulders and the non-dominant knee. Besides, windsurfers had a significantly smaller sway area of the center of pressure in the balance test. The maximum knee isometric force in non-dominant limbs and upper limb muscle endurance also showed significantly better testing results for the windsurfers. CONCLUSIONS: This study verified that windsurfers have better physical capability especially in the non-dominant side limbs when compared to common health people. PMID- 26112816 TI - Mechanical and physiological analysis of minimalist versus traditionally-shod running. AB - BACKGROUND: It has been purported that minimalist running shoes allow runners to be more biomechanically and metabolically economical, but evidence supporting these claims remains equivocal. This study's aim was to measure oxygen consumption (VO2), heart rate (HR), pulmonary ventilation (VE) and electromyography (EMG) of gastrocnemius and tibialis anterior in 12 recreationally-trained, college-aged males during minimalist and shod running. METHODS: Participants ran at 70% VO2max on a treadmill in both minimalist and traditional shoes for six minutes each while VO2, HR, VE, EMG and steps taken were recorded. RESULTS: Results indicated no significant differences in VO2 (2.39+/-0.17 vs. 2.43+/-0.15 L/min), HR (156.59+/-2.99 vs. 157.13+/-3.86 bpm), VE (46.97+/-3.19 vs. 47.00+/-2.83 L/min), EMG in the tibialis anterior (2.02+/-0.28 vs. 1.79+/-0.20 mV), EMG in the gastrocnemius (1.97+/-0.36 vs. 2.03+/-0.37 mV) or steps taken (946.08+/-13.50 vs. 962.42+/-19.68 steps) between running in traditional and minimalist shoes, respectively. CONCLUSIONS: This study shows that there is no mechanical and physiological benefit when running wearing minimalist shoes as opposed to traditional shoes and warrants a cautious approach to transitioning to minimalist shoe use. PMID- 26112817 TI - Match intensity and heart rate predictors in top level basketball referees during men's Eurobasket. AB - BACKGROUND: The aims of this study were to determine the heart rate (HR) response of referees during men's Eurobasket Championship and identify relationships body composition and other match variables as predictor of HR. METHODS: Thirty-one elite basketball referees (REF, 40.4+/-4.3 years) were analyzed during a random sample of 38 matches in the 2013 men's Eurobasket Championship, one of the best basketball competitions in the World. The height, body mass, triceps, abdominal, supraspinale, subscapular, front thigh and medial calf skinfolds were measured. RESULTS: The result was that out of all 4 quarters of every game (Q1, Q2, Q3 and Q4), HR (bpm and % HRmax) in Q1 (164.2+/-13.9 bpm; 90.5+/-7.1%) was the highest (P<0.05). Likewise, Q2 (162.5+/-15.7 bpm; 90.5+/-7.1%) values were higher (P<0.05) than Q3 (158.5+/-13.2 bpm; 88.2+/-7.3%) and Q4 (158.4+/-13.4 bpm; 88.2+/ 7.5%). The study also showed that variables of triceps skinfold (beta: 1.33; P<0.000), years of experience (beta: -0.40; P<0.05) and fat mass (beta: -2.51; P<0.000) were the variables that significantly predicted the physical performance. CONCLUSIONS: In conclusion, the heart rate directly was associated with REF's anthropometric features and years of experience. However did not show any association with different match variables such as: total scores, differences scores among teams, duration of the match or ratio time/point ratio. PMID- 26112818 TI - Incidence and factors associated with injuries among adolescent players in an amateur soccer tournament in Nigeria. AB - BACKGROUND: The study was conducted to determine the incidence and risk factors associated with injuries among adolescents participating in an amateur soccer tournament in Ibadan, Nigeria. METHODS: A prospective study was conducted among 90 participants (66 players and 24 substitutes) from six all-male teams with each team comprising 11 players. A total of six matches, each lasting 60 minutes (132 player-hours) were played in the tournament. Players were observed during all matches and followed up for up to two weeks after the final match. The association between selected risk factors and injury occurence was assessed using chi2 test. RESULTS: Players mean age was 16.1 (+/-1.8) years. Twelve (13.3%) of the 90 players were involved in 15 injury events. The injury incidence was 113.6 injuries per 1000 player hours (95% CI: 56.1-171.1) and 12 (80.0%) of all injuries occurred within 15 minutes of the end of each half of the match. Injuries often affected the lower limb 10 (58.8%), and the upper limb 6 (35.3%). Common injuries sustained were abrasions, 11 (64.6%), sprains, 3 (17.6%) and contusions 2 (11.8%). Eighty percent of injuries were due to collision with another player. All injuries were slight to mild as all the injured players returned to practice or games within five days of sustaining the injury. Dominant playing foot (mainly left foot or both feet) was associated with a higher incidence of injuries (chi2=7.321; P=0.018). CONCLUSIONS: Injury incidence was relatively high although injuries were mild. Measures to minimize injuries following player-to-player contact would be beneficial for adolescent soccer players in our study setting. PMID- 26112819 TI - Bone turnover markers are associated with higher cortical porosity, thinner cortices, and larger size of the proximal femur and non-vertebral fractures. AB - Bone turnover markers (BTM) predict bone loss and fragility fracture. Although cortical porosity and cortical thinning are important determinants of bone strength, the relationship between BTM and cortical porosity has, however, remained elusive. We therefore wanted to examine the relationship of BTM with cortical porosity and risk of non-vertebral fracture. In 211 postmenopausal women aged 54-94 years with non-vertebral fractures and 232 age-matched fracture-free controls from the Tromso Study, Norway, we quantified femoral neck areal bone mineral density (FN aBMD), femoral subtrochanteric bone architecture, and assessed serum levels of procollagen type I N-terminal propeptide (PINP) and C terminal cross-linking telopeptide of type I collagen (CTX). Fracture cases exhibited higher PINP and CTX levels, lower FN aBMD, larger total and medullary cross-sectional area (CSA), thinner cortices, and higher cortical porosity of the femoral subtrochanter than controls (p<=0.01). Each SD increment in PINP and CTX was associated with 0.21-0.26 SD lower total volumetric BMD, 0.10-0.14 SD larger total CSA, 0.14-0.18 SD larger medullary CSA, 0.13-0.18 SD thinner cortices, and 0.27-0.33 SD higher porosity of the total cortex, compact cortex, and transitional zone (all p<=0.01). Moreover, each SD of higher PINP and CTX was associated with increased odds for fracture after adjustment for age, height, and weight (ORs 1.49; 95% CI, 1.20-1.85 and OR 1.22; 95% CI, 1.00-1.49, both p<0.05). PINP, but not CTX, remained associated with fracture after accounting for FN aBMD, cortical porosity or cortical thickness (OR ranging from 1.31 to 1.39, p ranging from 0.005 to 0.028). In summary, increased BTM levels are associated with higher cortical porosity, thinner cortices, larger bone size and higher odds for fracture. We infer that this is produced by increased periosteal apposition, intracortical and endocortical remodeling; and that these changes in bone architecture are predisposing to fracture. PMID- 26112820 TI - Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats. AB - Low-turnover bone disease is one of the bone abnormalities observed in patients with chronic kidney disease (CKD) and is recognized to be associated with low serum parathyroid hormone (PTH) level and skeletal resistance to PTH. Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood as renal dysfunction progresses in CKD patients. A recent in vitro study using an osteoblastic cell culture system suggests that IS has an important role in the pathogenesis of low bone turnover through induction of skeletal resistance to PTH. However, the effects of IS on the progression of low bone turnover have not been elucidated. In the present study, we produced rats with low bone turnover by performing parathyroidectomy (PTX) and fed these rats a diet containing indole, a precursor of IS, to elevate blood IS level from indole metabolism. Bone metabolism was evaluated by measuring histomorphometric parameters of secondary spongiosa of the femur. Histomorphometric analyses revealed significant decreases in both bone formation-related parameters and bone resorption-related parameters in PTX rats. In indole-treated PTX rats, further decreases in bone formation related parameters were observed. In addition, serum alkaline phosphatase activity, a bone formation marker, and bone mineral density of the tibia tended to decrease in indole-treated PTX rats. These findings strongly suggest that IS exacerbates low bone turnover through inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH. PMID- 26112822 TI - Prevalence of human papillomavirus in squamous cell carcinomas of the soft palate. PMID- 26112821 TI - Do case-only designs yield consistent results across design and different databases? A case study of hip fractures and benzodiazepines. AB - BACKGROUND: The case-crossover (CXO) and self-controlled case series (SCCS) designs are increasingly used in pharmacoepidemiology. In both, relative risk estimates are obtained within persons, implicitly controlling for time-fixed confounding variables. OBJECTIVES: To examine the consistency of relative risk estimates of hip/femur fractures (HFF) associated with the use of benzodiazepines (BZD) across case-only designs in two databases (DBs), when a common protocol was applied. METHODS: CXO and SCCS studies were conducted in BIFAP (Spain) and CPRD (UK). Exposure to BZD was divided into non-use, current, recent and past use. For CXO, odds ratios (OR; 95%CI) of current use versus non-use/past were estimated using conditional logistic regression adjusted for co-medications (AOR). For the SCCS, conditional Poisson regression was used to estimate incidence rate ratios (IRR; 95%CI) of current use versus non/past-use, adjusted for age. To investigate possible event-exposure dependence the relative risk in the 30 days prior to first BZD exposure was also evaluated. RESULTS: In the CXO current use of BZD was associated with an increased risk of HFF in both DBs, AORBIFAP = 1.47 (1.29-1.67) and AORCPRD = 1.55 (1.41-1.70). In the SCCS, IRRs for current exposure was 0.79 (0.72-0.86) in BIFAP and 1.21 (1.13-1.30) in CPRD. However, when we considered separately the 30-day pre-exposure period, the IRR for current period was 1.43 (1.31-1.57) in BIFAP and 1.37 (1.27-1.47) in CPRD. CONCLUSIONS: CXO designs yielded consistent results across DBs, while initial SCCS analyses did not. Accounting for event-exposure dependence, estimates derived from SCCS were more consistent across DBs and designs. PMID- 26112823 TI - Primary cutaneous CD4+ small-to-medium-sized pleomorphic T-cell lymphoma: a rare case report of infant. PMID- 26112824 TI - Polyunsaturated fatty acid metabolism in a marine teleost, Nibe croaker Nibea mitsukurii: Functional characterization of Fads2 desaturase and Elovl5 and Elovl4 elongases. AB - To reduce the requirement for fish oil in marine aquaculture, it would be advantageous to endow marine fish species with the capability for the endogenous biosynthesis of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). For this purpose, we have previously produced transgenic Nibe croaker (Nibea mitsukurii) carrying an elongase of very-long-chain fatty acids 2 (elovl2) gene isolated from Masu salmon (Oncorhynchus masou). However, fatty acid analysis revealed that 24:5n-3 accumulated in the liver of the transgenic fish, whereas the DHA level did not differ between non-transgenic and transgenic fish. Therefore, to select more effective enzymes for successful transgenic synthesis of DHA, understanding the endogenous DHA biosynthetic pathway in the Nibe croaker is considered to be important. The present study aimed to investigate the biochemical functions of the Elovl5, Elovl4 and Fads2 enzymes involved in the DHA biosynthetic pathway in the Nibe croaker. The results showed that both Elovl5 and Elovl4 were able to elongate C18 fatty acids to C22 fatty acids and that Fads2 had Delta6 desaturase activity toward C18 fatty acids and weak Delta8 desaturase activity toward C20 fatty acids. On the other hand, Fads2 was found to lack the ability to convert 24:5n-3 to 24:6n-3, a fatty acid that can directly be converted to DHA via beta-oxidation. PMID- 26112825 TI - Cloning and characterization of Na(+)/H(+) Exchanger isoforms NHE2 and NHE3 from the gill of Pacific dogfish Squalus suckleyi. AB - Na(+)/H(+) Exchanger (NHE) proteins mediate cellular and systemic homeostasis of sodium and acid and may be the major sodium uptake method for fishes. We cloned and sequenced NHE2 and NHE3 from the gill of the North Pacific Spiny Dogfish shark Squalus suckleyi and expressed them in functional form in NHE-deficient (AP 1) cell lines. Estimated IC50 for inhibition of NHE activity by amiloride and EIPA were 55 MUmol l(-1) and 4.8 MUmol l(-1), respectively, for NHE2 and 9 MUmol l(-1) and 24 MUmol l(-1), respectively, for NHE3. Phenamil at 100 MUmol l(-1) caused less than 16% inhibition of activity for each isoform. Although the IC50 are similar for the two isoforms, dfNHE2 is less sensitive than human NHE2 to inhibition by amiloride and EIPA, while dfNHE3 is more sensitive than human NHE3. These IC50 estimates should be considered when selecting inhibitor doses for fishes and for reinterpretation of previous studies that use these pharmacological agents. PMID- 26112827 TI - Epidemiology of asthma exacerbations and their relation with environmental factors in the Basque Country. PMID- 26112826 TI - Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine. AB - Initial velocity and product inhibition studies of Toxoplasma gondii adenosine kinase (TgAK, EC 2.7.1.20) demonstrated that the basic mechanism of this enzyme is a hybrid random bi-uni ping-pong uni-bi. Initial velocity studies showed an intersecting pattern, consistent with substrate-enzyme-co-substrate complex formation and a binding pattern indicating that binding of the substrate interferes with the binding of the co-substrate and vice versa. Estimated kinetic parameters were KAdo=0.002+/-0.0002 mM, KATP=0.05+/-0.008 mM, and Vmax=920+/-35 MUmol/min/mg protein. Ado exhibited substrate inhibition suggesting the presence of more than one binding site for Ado on the enzyme. ATP relieved substrate inhibition by Ado. Thus, Ado also binds to the ATP binding site. AMP was competitive with ATP, inferring that AMP binds to the same site as ATP. AMP, ADP and ATP were non-competitive with Ado, therefore, none of these nucleotides binds to the Ado binding site. Combining ATP with ADP was additive. Therefore, the binding of either ATP or ADP does not interfere with the binding of the other. It is concluded that for every ATP consumed, TgAK generates three new AMPs. These findings along with the fact that a wide range of nucleoside 5'-mono, di, and triphosphates could substitute for ATP as phosphate donors in this reaction may explain the efficient and central role played by TgAK in the utilization of Ado as the major source from which all other purines can be synthesized in T. gondii. PMID- 26112828 TI - Hippocampal place cells construct reward related sequences through unexplored space. AB - Dominant theories of hippocampal function propose that place cell representations are formed during an animal's first encounter with a novel environment and are subsequently replayed during off-line states to support consolidation and future behaviour. Here we report that viewing the delivery of food to an unvisited portion of an environment leads to off-line pre-activation of place cells sequences corresponding to that space. Such 'preplay' was not observed for an unrewarded but otherwise similar portion of the environment. These results suggest that a hippocampal representation of a visible, yet unexplored environment can be formed if the environment is of motivational relevance to the animal. We hypothesise such goal-biased preplay may support preparation for future experiences in novel environments. PMID- 26112829 TI - Electrospinning of PVA/chitosan nanocomposite nanofibers containing gelatin nanoparticles as a dual drug delivery system. AB - Nanofibrous core-sheath nanocomposite dual drug delivery system based on poly(vinyl alcohol) (PVA)/chitosan/lidocaine hydrochloride loaded with gelatin nanoparticles were successfully prepared by the electrospinning method. Gelatin nanoparticles were prepared by nanoprecipitation and were then loaded with erythromycin antibiotic agent with the average particle size of ~175 nm. The morphology of gelatin nanoparticles observed by field emission scanning electron microscopy (FE-SEM) was shown to be optimal at the concentration of 1.25 wt % of gelatin in aqueous phase by addition of 20 uL of glutaraldehyde 5% as the crosslinking agent. The nanoparticles were also characterized by dynamic light scattering, zeta potential measurement, and Fourier transform infrared spectroscopy (FTIR). The best bead free morphology for the PVA/chitosan nanofibrous mats were obtained at the solution weight ratio of 96/4. The nanofibrous mats were analyzed by swelling studies, FTIR and antibacterial tests. In vitro dual release profile of the core-sheath nanofibers was also studied within 72 h and showed the release efficiency equal to 84.69 and 75.13% for lidocaine hydrochloride and erythromycin, respectively. According to release exponent n, the release of lidocaine hydrochloride from the sheath part of the matrix is quasi-Fickian diffusion mechanism, while the release of erythromycin is based on anomalous or non-Fickian mechanisms. PMID- 26112830 TI - 2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3. AB - 2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-Mb terminal microdeletion could be narrowed down to the same ~ 200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37. PMID- 26112831 TI - Treatment outcomes of concurrent chemoradiotherapy for locally advanced sinonasal squamous cell carcinoma: A single-institution study. AB - CONCLUSIONS: CCRT is a potential treatment option for locally advanced sinonasal SCC in terms of organ preservation. OBJECTIVES: Concurrent chemoradiotherapy (CCRT) is increasingly used for patients with advanced head and neck cancer to preserve organ function and improve survival. In the present study, treatment outcomes were compared between surgery and post-operative radiotherapy (PORT) and CCRT in patients with locally advanced sinonasal squamous cell carcinoma (SCC). METHODS: The records of 30 patients with non-metastatic stage III and IV sinonasal SCC were retrospectively reviewed. Fifteen patients were treated with CCRT and 15 patients underwent PORT. RESULTS: The locoregional recurrence-free, distant metastasis-free, disease-free, disease-specific, and overall survival rates did not differ between PORT and CCRT groups. In addition, there were no significant differences in incidence rates of acute and chronic toxicities between the two groups. PMID- 26112832 TI - Molecular genetic variation and structure of Southeast Asian crocodile (Tomistoma schlegelii): Comparative potentials of SSRs versus ISSRs. AB - Tomistoma schlegelii, also referred to as the "false gharial", is one of the most exclusive and least known of the world's fresh water crocodilians, limited to Southeast Asia. Indeed, lack of economic value for its skin has led to neglect the biodiversity of the species. The current study aimed to investigate the mentioned case using 40 simple sequence repeat (SSR) primer pairs and 45 inter simple sequence repeat (ISSR) primers. DNA analysis of 17 T. schlegelii samples using the SSR and ISSR markers resulted in producing a total of 49 and 108 polymorphic bands, respectively. Furthermore, the SSR- and ISSR-based cluster analyses both generated two main clusters. However, the SSR based results were found to be more in line with the geographical distributions of the crocodile samples collected across the country as compared with the ISSR-based results. The observed heterozygosity (HO) and expected heterozygosity (HE) of the polymorphic SSRs ranged between 0.588-1 and 0.470-0.891, respectively. The present results suggest that the Malaysian T. schlegelii populations had originated from a core population of crocodiles. In cooperation with the SSR markers, the ISSRs showed high potential for studying the genetic variation of T. schlegelii, and these markers are suitable to be employed in conservation genetic programs of this endangered species. Both SSR- and ISSR-based STRUCTURE analyses suggested that all the individuals of T. schlegelii are genetically similar with each other. PMID- 26112834 TI - Kinetics and fracture resistance of lithiated silicon nanostructure pairs controlled by their mechanical interaction. AB - Following an explosion of studies of silicon as a negative electrode for Li-ion batteries, the anomalous volumetric changes and fracture of lithiated single Si particles have attracted significant attention in various fields, including mechanics. However, in real batteries, lithiation occurs simultaneously in clusters of Si in a confined medium. Hence, understanding how the individual Si structures interact during lithiation in a closed space is necessary. Here, we demonstrate physical and mechanical interactions of swelling Si structures during lithiation using well-defined Si nanopillar pairs. Ex situ SEM and in situ TEM studies reveal that compressive stresses change the reaction kinetics so that preferential lithiation occurs at free surfaces when the pillars are mechanically clamped. Such mechanical interactions enhance the fracture resistance of lithiated Si by lessening the tensile stress concentrations in Si structures. This study will contribute to improved design of Si structures at the electrode level for high-performance Li-ion batteries. PMID- 26112833 TI - Ubiquitin-specific proteases are differentially expressed throughout the Schistosoma mansoni life cycle. AB - BACKGROUND: The ubiquitination process can be reversed by deubiquitinating enzymes (DUBs). These proteases are involved in ubiquitin processing, in the recovery of modified ubiquitin trapped in inactive forms, and in the recycling of ubiquitin monomers from polyubiquitinated chains. The diversity of DUB functions is illustrated by their number and variety of their catalytic domains with specific 3D architectures. DUBs can be divided into five subclasses: ubiquitin C terminal hydrolases (UCHs), ubiquitin-specific proteases (USPs or UBPs), ovarian tumour proteases (OTUs), Machado-Joseph disease proteases (MJDs) and JAB1/MPN/Mov34 metalloenzymes (JAMMs). METHODS: Considering the role that the ubiquitin-proteasome system has been shown to play during the development of Schistosoma mansoni, our main goal was to identify and characterize SmUSPs. Here, we showed the identification of putative ubiquitin-specific proteases using bioinformatic approaches. We also evaluated the gene expression profile of representative USP family members using qRT-PCR. RESULTS: We reported 17 USP family members in S. mansoni that present a conservation of UCH domains. Furthermore, the putative SmUSP transcripts analysed were detected in all investigated stages, showing distinct expression during S. mansoni development. The SmUSPs exhibiting high expression profiles were SmUSP7, SmUSP8, SmUSP9x and SmUSP24. CONCLUSION: S. mansoni USPs showed changes in expression levels for different life cycle stages indicating their involvement in cellular processes required for S. mansoni development. These data will serve as a basis for future functional studies of USPs in this parasite. PMID- 26112835 TI - From farm to plate & beyond--A culture & context sensitive perspective for food safety. PMID- 26112836 TI - Bronchial asthma--Issues for the developing world. PMID- 26112837 TI - Antiviral activity of cystatin C against HIV. PMID- 26112838 TI - Impact of oral antidiabetic agents on bone metabolism. PMID- 26112839 TI - Survivin: A molecular biomarker in cancer. AB - Survivin, a member of the inhibitor of apoptosis (IAP) protein family that inhibits caspases and blocks cell death, is highly expressed in most cancers and is associated with a poor clinical outcome. Survivin has consistently been identified by molecular profiling analysis to be associated with high tumour grade cancers, different disease survival and recurrence. Polymorphisms in the survivin gene are emerging as powerful tools to study the biology of the disease and have the potential to be used in disease prognosis and diagnosis. The survivin gene polymorphisms have also been reported to influence tumour aggressiveness as well as survival of cancer patients. The differential expression of survivin in cancer cells compared to normal tissues and its role as a nodal protein in a number of cellular pathways make it a high target for different therapeutics. This review discusses the complex circuitry of survivin in human cancers and gene variants of survivin, and highlights novel therapy that targets this important protein. PMID- 26112840 TI - Fidaxomicin--the new drug for Clostridium difficile infection. AB - Clostridium difficile is one of the many aetiological agents of antibiotic associated diarrhoea and is implicated in 15-25 per cent of the cases. The organism is also involved in the exacearbation of inflammatory bowel disease and extracolonic manifestations. Due to increase in the incidence of C. difficile infection (CDI), emergence of hypervirulent strains, and increased frequency of recurrence, the clinical management of the disease has become important. The management of CDI is based on disease severity, and current antibiotic treatment options are limited to vancomycin or metronidazole in the developing countries. this review article briefly describes important aspects of CDI, and the new drug, fidaxomicin, for its treatment. Fidaxomicin is particularly active against C.difficile and acts by inhibition of RNA synthesis. Clinical trials done to compare the efficacy and safety of fidaxomicin with that of vancomycin in treating CDI concluded that fidaxomicin was non-inferior to vancomycin for treatment of CDI and that there was a significant reduction in recurrences. The bactericidal properties of fidaxomicin make it an ideal alternative for CDI treatment. However, fidaxomicin use should be considered taking into account the potential benefits of the drug, along with the medical requirements of the patient, the risks of treatment and the high cost of fidaxomicin compared to other treatment regimens. PMID- 26112842 TI - DHR-ICMR Guidelines for diagnosis & management of Rickettsial diseases in India. AB - Rickettsial diseases, caused by a variety of obligate intracellular, gram negative bacteria from the genera Rickettsia, Orientia, Ehrlichia, Neorickettsia, Neoehrlichia, and Anaplasma, belonging to the Alphaproteobacteria, are considered some of the most covert emerging and re-emerging diseases and are being increasingly recognized. Among the major groups of rickettsioses, commonly reported diseases in India are scrub typhus, murine flea-borne typhus, Indian tick typhus and Q fever. Rickettsial infections are generally incapacitating and difficult to diagnose; untreated cases have case fatality rates as high as 30-45 per cent with multiple organ dysfunction, if not promptly diagnosed and appropriately treated. The vast variability and non-specific presentation of this infection have often made it difficult to diagnose clinically. Prompt antibiotic therapy shortens the course of the disease, lowers the risk of complications and in turn reduces morbidity and mortality due to rickettsial diseases. There is a distinct need for physicians and health care workers at all levels of care in India to be aware of the clinical features, available diagnostic tests and their interpretation, and the therapy of these infections. Therefore, a Task Force was constituted by the Indian Council of Medical Research (ICMR) to formulate guidelines for diagnosis and management of rickettsial diseases. These guidelines include presenting manifestations, case definition, laboratory criteria (specific and supportive investigations) and treatment. PMID- 26112841 TI - Organ transplant & the psychiatrist: An overview. AB - Organ transplantation has emerged as the saving grace for those who are suffering from end organ disease. Advent of modern surgical procedures and immunosuppressants further decrease morbidity and mortality. Meta-analyses have shown that post-organ transplantation quality of life improves for social, physical and daily activity functioning, but not consistently for psychological health. Psychiatrists can play a useful role not only in selecting the best suitable candidate for the procedure by psychosocial screening but also to tackle post-operation psychological issues that trouble patients as well as caretakers and decrease their quality of life. Issues like selection of patients with psychiatric disorders and substance abuse for transplantation process and their treatment both pre- and post- operation, risky health behaviours, treatment adherence for immunosuppressants and psychological support for caretakers can be better addressed by a psychiatrist who is sensitive towards these issues. Prescribing various psychotropics and immunosuppressants in the background of impaired organ function and drug-drug interaction is further challenging. Thus, psychiatrists need to be knowledgeable about these issues and should be an integral part of organ transplantation team for overall better outcome. PMID- 26112843 TI - Evaluation of cystatin C activities against HIV. AB - BACKGROUND & OBJECTIVES: Several host defense proteins known to possess antimicrobial activities are present on mucosal surfaces and are consequently found in body fluids of vertebrates. Naturally occurring protease inhibitors like cystatins, especially cystatin C (cys C), are abundantly present in human seminal plasma. Although its antiviral activity against herpes simplex virus (HSV) has been demonstrated, the role of this protein against HIV is not well studied. Therefore, the aim of the present study was to evaluate the anti-HIV activities of cys C, which is present innately in the male reproductive tract. METHODS: Protein-protein interaction of cys C with various HIV proteins was studied using a commercially available HIV blot and specific interaction with HIV protease was studied by dot-blot technique using commercially available cys C. To purify biologically active cys C from human seminal plasma to be used for subsequent experiments, gel-permeation chromatography followed by affinity chromatography was used. The HIV infectivity inhibition activity of the purified cystatin C was tested in TZM-bl cells. To study its activity on HIV protease, time-course enzyme kinetics studies were performed using spectrometric assay. RESULTS: Cystatin C reacted with some HIV proteins including HIV protease. Biologically active cys C was purified using gel permeation chromatography followed by affinity chromatography. When tested in TZM-bl cells, purified cystatin C demonstrated HIV infectivity inhibitory activity (IC 50: 0.28 MUM). Enzyme kinetic studies demonstrated that it abrogated the action of HIV protease on its substrate. INTERPRETATION & CONCLUSIONS: The present data demonstrate that cystatin C possesses anti-HIV activities. Molecular models need to be designed with this protein which would assist towards prevention/ therapeutics against HIV. PMID- 26112844 TI - Effect of oral hypoglycaemic agents on bone metabolism in patients with type 2 diabetes mellitus & occurrence of osteoporosis. AB - BACKGROUND & OBJECTIVES: Type 2 diabetes mellitus (T2DM) is considered to be a protective factor against development of osteoporosis. But oral hypoglycaemic agents (OHA) are likely to increase the risk of osteoporosis. This study was carried out to evaluate the effect of various OHA on bone mineral density (BMD) in patients with T2DM. METHODS: Forty one patients (study group) with T2DM (mean age 51.9+/-5.5 yr; 31 females) receiving treatment with oral hypoglycaemic agents (OHA) [thiazolidinediones alone (n=14) or in combination with other OHA (n=27)] for a period of at least three consecutive years and 41 age- and gender-matched healthy controls (mean age 51.4+/-5.1 yr) were included in the study. A detailed clinical history was taken and all were subjected to physical examination and recording of anthropometric data. BMD was assessed for both patients and controls. RESULTS: The mean body mass index (kg/m [2] ) (26.5+/-4.90 vs 27.3 +/ 5.33) and median [inter-quartile range (IQR)] duration of menopause (yr) among women [6(2-12) vs 6(1-13)] were comparable between both groups. The bone mineral density (BMD; g/cm [2] ) at the level of neck of femur (NOF) (0.761+/-0.112 vs 0.762+/-0.110), lumbar spine antero-posterior view (LSAP) (0.849+/-0.127 vs 0.854+/-0.135); median Z-score NOF {0.100[(-0.850)-(0.550)] vs -0.200[(-0.800) (0.600)]}, LSAP {-1.200[(-1.700)-(-0.200)] vs -1.300 [(-1.85)-(-0.400)]} were also similar in study and control groups. Presence of normal BMD (9/41 vs 8/41), osteopenia (16/41 vs 18/41) and osteoporosis (16/41 vs 15/41) were comparable between the study and control groups. No significant difference was observed in the BMD, T-scores and Z-scores at NOF and LSAP among T2DM patients treated with thiazolidinediones; those treated with other OHA and controls. INTERPRETATION & CONCLUSIONS: The present findings show that the use of OHA for a period of three years or more does not significantly affect the BMD in patients with T2DM. PMID- 26112845 TI - Wealth related inequalities in self reported morbidity: Positional objectivity or epidemiological transition? AB - BACKGROUND & OBJECTIVES: Morbidity is self reported at a higher rate among the rich than the poor. However, objective measures suggest the contrary. We examined the role of epidemiological transition in wealth related inequalities in self reported morbidity (SRM). METHODS: We analyzed data of two States, Bihar and Kerala, from 60 [th] Round of National Sample Survey (NSS). Bivariate analysis was performed to study the associations between various socio-demographic variables and self-reported morbidity. A prediction model based on hierarchical logistic regression was developed to identify determinants of self-reported morbidity. RESULTS: In Bihar, acute morbidities (26 per 1000) were reported more often than chronic morbidities (19 per 1000) while in Kerala the reverse was true (89 acute and 123 chronic morbidities per 1000 person). In both the states, the rate of SRM showed an increasing trend from the poorest to the richest quintiles. The rising gradient in the odds of SRM across increasing socio-economic strata was more pronounced in Bihar [OR (richest)=2.52; 1.85-3.42] as compared to Kerala [OR (richest) =1.66; 1.37-2.0]. Moreover, this gradient was more on account of chronic diseases [OR (richest) =2.7; 1.8-4.0] for Bihar; [OR (richest) =1.6; 1.26 2.0 for Kerala] than the acute diseases [OR (richest) =1.82; 1.1-2.9 for Bihar]; [OR (richest) =1.4; 1.1-1.8 for Kerala]. INTERPRETATION & CONCLUSIONS: The present analysis shows that the epidemiologic transition results in higher prevalence and reporting of chronic ailments by the rich than the poor. This phenomenon is more evident in the early stages of transition. In later stages of transition, positional objectivity plays an important role to explain wealth related inequalities in SRM. PMID- 26112846 TI - Are Indian patients with juvenile-onset ankylosing spondylitis taller than reference population ? AB - BACKGROUND & OBJECTIVES: Paucity of growth retardation has been observed by us in patients with juvenile-onset ankylosing spondylitis (JAS) in a tertiary care health centre in south India. We, therefore, undertook this pilot study to assess and compare anthropometry of patients with JAS who were 15 yr and older with that of adult onset ankylosing spondylitis (AAS) and matching Indian reference population. METHODS: Consecutive male patients (December 2009- October 2012) with JAS and AAS fulfilling Modified New York Criteria were selected after applying inclusion and exclusion criteria. Demography and anthropometry were noted. Height of both patient groups as well as their parents and siblings were compared with that of the reference population. Mid-parental height and delta height were derived. Those with delta height of >8.5 cm were compared with the remaining. Multivariate logistic regression was done for variables that were found to be significant by chi-square in bivariate analysis. Similar analysis was done for BMI also. RESULTS: There was no significant difference in anthropometric variables between JAS and AAS groups. Twenty eight of the 30 (93.33%) JAS patients were taller as compared to the reference population. Twenty six (86.67%) AAS patients were taller than the reference population. The mean heights of JAS (170.67 +/- 6.94 cm) and AAS (168.2 +/- 5.94 cm) patients were significantly higher than the reference value of 163.11 cm; both p0 <0.001. Logistic regression revealed that tallness in JAS was associated positively with hypermobility (OR=23.46,95%CI 1.2-447.2, p0 =0.036). No significant association was detected for height in AAS and for BMI in both JAS and AAS groups. INTERPRETATION & CONCLUSIONS: No growth retardation was seen in patients with JAS in our study. Majority of patients with JAS and AAS were taller than reference population. The difference between mean height of JAS and AAS was not significant. Larger studies involving different populations are required to confirm these findings. PMID- 26112847 TI - Effect of alcoholic extract of Entada pursaetha DC on monosodium iodoacetate induced osteoarthritis pain in rats. AB - BACKGROUND & OBJECTIVES: Osteoarthritis (OA) is a degenerative disease characterized by joint pain and progressive loss of articular cartilage. Entada pursaetha has been traditionally used in the treatment of inflammatory disease, liver ailment, etc. In this study we investigated suppressive effect of ethanolic extract of E. pursaetha (EPE) on monosodium iodoacetate (MIA)-induced osteoarthritis pain and disease progression by histopathological changes in joints in a rat model. METHODS: OA was induced in right knee of rat by intra articular injection of 3 mg of MIA and characterized by pathological progression of disease and pain of affected joint. Spontaneous movements, mechanical, thermal and cold sensitivity were monitored at days 0 (before drug and MIA injection), 7, 14 and 21 of MIA administration. EPE (30, 100 and 300 mg/kg), vehicle or etoricoxib (10 mg/ kg; reference drug) were administered daily for 21 days by oral route. RESULTS: EPE at various doses significantly reduced mechanical, heat, cold hyperalgesia and increased the horizontal and vertical movements in intra articular MIA injected rats. EPE prevented the damage to cartilage structure and reduced the cellular abnormalities. Articular cartilage of rats treated with EPE at 300 mg/kg group was almost normal with well-developed smooth surface and chondrocytes were distributed individually or arranged in column. INTERPRETATION & CONCLUSIONS: The present findings showed that the EPE was not only able to mitigate pain and hyperalgesia but also inhibited MIA-induced cartilage degeneration in vivo. EPE may have the potential to become therapeutic modality in the treatment of osteoarthritis. However, further studies need to be done to confirm these findings in other models and clinical trials. PMID- 26112848 TI - Comparison of interferon gamma release assay & tuberculin skin tests for diagnosis of latent tuberculosis in patients on maintenance haemodialysis. AB - BACKGROUND & OBJECTIVES: Tuberculosis (TB) is a common infection in patients on haemodialysis. There is a definite role of treatment of latent TB (LTB) in these patients. However, diagnosis of LTB in these patients by tuberculin skin test (TST) is unreliable. There is suggestion that interferon gamma release assay (IGRA) will be more reliable test for diagnosis of LTB in this setting. Thus, we evaluated value of IGRA and TST for the diagnosis of LTB in patients on dialysis in an Indian setting. METHODS: Patients with end stage kidney disease on dialysis were included. Patients with active TB were excluded. Each patient was subjected to TST (induration of >=10 mm was taken as positive) and QuantiFERON TB Gold In Tube test (QFT-GIT) for diagnosis of LTB. RESULTS: A total of 185 patients were included; 129 (69.7%) were males and mean age was 36.7 +/- 12.3 yr. Past history of TB was present in 18 (9.7%) patients. One hundred and thirty four (72.4%) patients had scar of BCG vaccination. QFT-GIT test was positive in 66 (36%), TST in 32 (17%) and both in 13 (7%) patients. Of the 66 patients positive with QFT GIT, only 13 (19.6%) were positive for TST. Of the 32 patients positive with TST, only 13 (40.6%) were positive with QFT-GIT; 100 (54%) patients were negative for both the tests. Overall, 85 (45.9%) patients were positive for either of the two tests. Poor agreement was shown between the two methods. On logistic regression analysis, odds of QFT-GIT to be positive in patients with BCG vaccination was 1.23 and with history of TB 0.99, both being insignificant. odds of tuberculin skin test to be positive in patients with BCG vaccination was 1.04 and with history of TB 0.99, both again being insignificant. INTERPRETATION & CONCLUSIONS: Our findings showed that more number of patients (36%) on haemodialysis were positive for QuantiFERON Gold In-Tube test as compared to TST (17%). There was poor agreement between the two tests. No significant effect of BCG vaccination and history of TB in past was observed on both tests. PMID- 26112849 TI - Aetiology of childhood viral gastroenteritis in Lucknow, north India. AB - BACKGROUND & OBJECTIVES: Due to limited availability of data on viral aetiology of acute gastroenteritis in north India, the present study was planned to detect rotavirus, norovirus, sapovirus and astrovirus in stool samples of both in hospitalized and non-hospitalized children less than five years of age presenting with acute gastroenteritis. METHODS: A total of 278 stool samples from equal number of children were tested for rotavirus antigen using ELISA and for norovirus, sapovirus and astroviruses by reverse transcription (RT)-PCR. RESULTS: Of the 169 samples from hospitalized patients, rotavirus, norovirus, sapovirus and astrovirus were detected in 19.5, 2.3, 3.5 and 2.9 per cent samples, respectively. Of the 109 samples collected from the non-hospitalized patients, frequency of rotavirus and sapovirus detection was 9.1 and 1.8 per cent, respectively while norovirus and astrovirus were not detected. INTERPRETATION & CONCLUSIONS: Rotavirus was the most frequent cause of viral gastroenteritis in both hospitalized and non-hospitalized children. Maximum positivity of the viruses was seen in children less than two years of age. PMID- 26112850 TI - Profile of urinary tract infections in paediatric patients. AB - BACKGROUND & OBJECTIVES: This cross-sectional study was conducted at a tertiary care centre in Puducherry, south India, with the aim of finding the profile of the paediatric urinary tract infection (UTI), bacterial pathogens involved, and also to observe vesicoureteric reflux (VUR) and renal scarring in these patients. METHODS: A total of 524 paediatric patients <=13 yr, suspected to have UTI, were included in the study. Urine samples were collected, processed for uropathogen isolation and antibiotic susceptibility test was performed as per the Clinical and Laboratory Standards Institute (CLSI) guidelines. Thirty two culture proven children with UTI underwent micturating cysto-urethrography (MCU) and dimercaptosuccinic acid (DMSA) scanning was done for 69 children. RESULTS: o0 f the 524 children, 186 (35.4%) had culture proven UTI with 105 (56.4%) being infants, 50 (27.4%) between 1-5 yr, 30 (16.12%) between 5-13 yr and 129 (69.35%) males. Posterior urethral valve (PUV) was noted in three, hydronephrosis in one, VUR in 18 and renal scarring in 33. VUR as well as renal scarring were more in males >1 yr of age. A significant association (P=0.0054) was noted with a combined sensitivity and specificity of these investigations being 83 and 90 per cent, respectively of the MCU and DMSA scans for detecting VUR. Escherichia coli was the most common pathogen isolated, sensitive to nitrofurantoin, followed by cefoperazone-sulbactam, aminoglycosides and meropenem. INTERPRETATION & CONCLUSIONS: Our results indicate that UTI varies with age and gender and extensive evaluation is required in boys over one year of age with UTI. This study also highlights the better efficacy of aminoglycosides, cefoperazone sulbactam and nitrofurantoin in vitro compared with meropenem in Gram-negative uropathogens. PMID- 26112851 TI - Bayesian spatio-temporal model for tuberculosis in India. PMID- 26112852 TI - Performance of extended spectrum beta lactamases (ESBL) screening agar in various clinical specimens. PMID- 26112853 TI - Antimicrobial susceptibility pattern of vancomycin resistant enterococci to newer antimicrobial agents. PMID- 26112854 TI - External validity & non-probability sampling. PMID- 26112855 TI - Observational studies versus controlled clinical trials for efficacy & effectiveness of a drug. PMID- 26112857 TI - Caput medusae. PMID- 26112856 TI - Defining multidrug resistance in Gram-negative bacilli. PMID- 26112858 TI - Sirenomelia or mermaid syndrome. PMID- 26112859 TI - Tuberculosis - The usual suspect. PMID- 26112860 TI - Pooling Results by Means of Meta-Analysis. PMID- 26112861 TI - The Difference Is in What Is or Is Not Included. PMID- 26112862 TI - Metallic Hardware Not a Considered Complication. PMID- 26112863 TI - No Resident Left Behind: Statistical Illiteracy and What Lies Beyond the Abstract. PMID- 26112864 TI - The Association of Resting Heart Rate and Incident Hypertension: The Henry Ford Hospital Exercise Testing (FIT) Project. AB - BACKGROUND: Given that sympathetic tone is associated with hypertension, we sought to determine whether resting heart rate (RHR), as a surrogate for cardiac autonomic function, was associated with incident hypertension. METHODS: We analyzed 21,873 individuals without a history of hypertension who underwent a clinically indicated exercise stress test. Baseline RHR was assessed prior to testing and was categorized as <70, 70-85, and >85 beats-per-minute (bpm). Incident hypertension was defined by subsequent diagnosis codes for new-onset hypertension from three or more encounters. We tested for effect modification by age (<60 vs. >=60 years), sex, race, and history of coronary heart disease (CHD). RESULTS: Mean (+/-SD) age was 49 (+/-12) years, 55% were men and 21% were Black. Compared to the lowest RHR (<70 bpm) category, patients in the highest category (>85 bpm) were younger, more likely to be female, heavier, diabetic, and achieve lower metabolic equivalents (METS). Over a median of 4 years follow-up, there were 8,179 cases of incident hypertension. Compared to RHR <70 bpm, persons with RHR >85 bpm had increased risk of hypertension after adjustment for CHD risk factors, baseline blood pressure (BP), and METS (hazard ratio = 1.15 (95% confidence interval 1.08-1.23)). Age was an effect modifier (interaction P = 0.02), whereas sex, race, and CHD were not. In age-stratified analyses the relationship remained significant only in those younger than 60 years. CONCLUSION: Elevated RHR is an independent risk factor for incident hypertension, particularly in younger persons. Whether lifestyle modification or other strategies to reduce RHR can prevent incident hypertension in high-risk individuals warrants further study. PMID- 26112865 TI - Pesticides Exposure and Cardiovascular Hemodynamic Parameters Among Male Workers Involved in Mosquito Control in East Coast of Malaysia. AB - BACKGROUND: Research findings have linked exposure to pesticides to an increased risk of cardiovascular (CVS) diseases. Therefore, this study aimed to assess the impact of chronic mix-pesticides exposure on CVS hemodynamic parameters. METHODS: A total of 198 male Malay pesticide-exposed and 195 male Malay nonexposed workers were examined. Data were collected through exposure-matrix assessment, questionnaire, blood analyses, and CVS assessment. Explanatory variables comprised of lipid profiles, paraoxonase 1 (PON1), and oxidized low-density lipoprotein (ox-LDL). Outcome measures comprised of brachial and aortic diastolic blood pressure (DBP) and systolic BP (SBP), heart rate, and pulse wave velocity (PWV). Linear regressions identified the B coefficient showing how many units of CVS parameters are associated with each unit of covariates. RESULTS: Diazoxonase was significantly lower and ox-LDL was higher among pesticide-exposed workers than the comparison group. The final multivariate linear regression model revealed that age, body mass index (BMI), smoking, and pesticide exposure were independent predictors of brachial and aortic DBP and SBP. Pesticide exposure was also associated with heart rate, but not with PWV. Lipid profiles, PON1 enzymes, and ox-LDL showed no association with any of the CVS parameters. CONCLUSIONS: Chronic mix-pesticide exposure among workers involved in mosquito control has possible association with depression of diazoxonase and the increase in ox-LDL, brachial and aortic DBP and SBP, and heart rate. This study raises concerns that those using pesticides may be exposed to hitherto unrecognized CVS risks among others. If this is confirmed by further studies, greater efforts will be needed to protect these workers. PMID- 26112866 TI - Augmented Blood Pressure Variability in Hypertension Induced by Angiotensin II in Rats. AB - BACKGROUND: Augmented blood pressure (BP) variability is associated with cardiovascular diseases in some clinical conditions including hypertension. Drugs that effectively reduce BP variability need to be identified, while few animal models are currently available to study BP variability. Here, we report that hypertension induced by continuous infusion of angiotensin II (Ang II) was accompanied by increased BP variability in rats. METHODS: Ang II was subcutaneously infused at a rate of 240 pmol/kg/min into male Wistar rats undergoing intraperitoneal implantation of a transmitter connected to an abdominal aortic catheter. BP was continuously monitored via a telemetry system before and after the Ang II infusion in a conscious, unrestrained condition. BP variability was evaluated by coefficient of variation (CV) of BP levels measured every 15 minutes. In addition, spontaneously hypertensive and Wistar-Kyoto rats (SHR and WKY) were subjected to the BP monitoring experiment at 15 weeks of age. RESULTS: Both systolic and diastolic BP levels were significantly elevated following the Ang II infusion. Similarly, CVs of systolic and diastolic BP in the Ang II infusion group were significantly higher than in the vehicle group upon 1 and 2 weeks of the infusion. Meanwhile, CVs of systolic and diastolic BP of SHR were in a range similar to those of WKY despite significantly higher BP than in WKY. CONCLUSIONS: Hypertension induced by the continuous infusion of Ang II was accompanied by augmented BP variability in rats, an effect assumed to be at least in part, independent of BP elevation. PMID- 26112868 TI - Location of the inferior oblique muscle origin with reference to the lacrimal caruncle and its significance in oculofacial surgery. AB - PURPOSE: To identify the location of the inferior oblique muscle (IOM) origin with reference to the lacrimal caruncle in order to facilitate safer oculofacial surgery by preventing morbidity associated with IOM injury. METHODS: Thirty-seven intact orbits of 20 embalmed Asian cadavers were dissected. The location of the medial border of the IOM origin was determined with respect to the apex of the lacrimal caruncle. In addition, the size of the IOM origin and the anteroposterior distance from the inferior orbital rim to the anterior border of the IOM origin were measured. RESULTS: The IOM origin was located at a mean distance of 1.2 mm lateral and 11.2 mm inferior to the apex of the lacrimal caruncle. In half of the orbits, the IOM origin was situated just on the vertical line through the apex of the lacrimal caruncle. The mean length and width of the IOM origin were 4.3 and 2.7 mm, respectively. The mean anteroposterior distance from the inferior orbital rim to the IOM origin was 1.9 mm. CONCLUSIONS: The lacrimal caruncle is easily identifiable and a reliable external landmark for prediction of the IOM origin. The IOM origin is located approximately where the vertical line through the apex of the lacrimal caruncle intersects the inferior orbital rim. The findings of this anatomical study of the exact location of the IOM origin can help to improve the safety of oculofacial surgery. PMID- 26112867 TI - Cumulative Effects of Several Target Organ Damages in Risk Assessment in Hypertension. AB - BACKGROUND: The prognostic value of screening multiple target organ damages (TODs) in hypertensive subjects has not been extensively studied. We estimated the prognostic value of considering 3 TODs in estimating the 10-year survival in hypertensive subjects. METHODS: At baseline 1,848 out of a cohort of 1,963 hypertensive patients had a previous cardiovascular disease (CVD) or assessments of 3 TODs: Modification in Diet in Renal Disease (MDRD) <60ml/min or albuminuria >300mg/day, Sokolow index >3.5 mV, and advanced hypertensive retinopathy (grades 3 and 4 of Keith-Wagener-Barker classification). The cohort was divided into 5 groups: 0 TOD (N = 978), 1 TOD (N = 308), 2 TODs (N = 94), 3 TODs (N = 30), and previous CVD (N = 438). RESULTS: After 10 years of follow-up, we observed 418 deaths of which 254 from cardiovascular cause. The adjusted hazard ratios for the major cardiovascular risk factors showed a progressive risk associated with the number of TODs. For all-cause death, the hazard ratios [95% confidence intervals] vs. 0 TOD of the other 4 groups were 1.91 [1.39-2.63], 1.99 [1.28-3.10], 4.33 [2.42-7.72], and 3.09 [2.35-4.05], respectively. For cardiovascular death, the hazard ratios [95% confidence intervals] were of the same order of magnitude: 2.14 [1.38-3.32], 2.12 [1.15-3.89], 4.22 [1.83-9.72], and 4.24 [2.95-6.11], respectively. CONCLUSIONS: Our results indicate that hypertensive patients with several TODs had a worst outcome. Thus, it seems important to screen for multiple TODs in hypertension; especially check for severe hypertensive retinopathy in patients with left ventricular hypertrophy (LVH) and renal damage. PMID- 26112869 TI - Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus. AB - BACKGROUND/AIMS: Invasive fungal infections of the head and neck are rare life threatening infections where prompt diagnosis and intervention is critical for survival. The aim of this study is to determine the clinical characteristics and outcomes of invasive fungal disease of the sinus and orbit, and to compare mucormycosis and Aspergillus infection. METHODS: A retrospective review was conducted from a single tertiary care eye and ear hospital over 20 years (1994 2014). Twenty-four patients with a confirmed pathological diagnosis of invasive fungal disease of the sinus and/or orbit were identified and their medical records were reviewed. The main outcome measures were type of fungus, location of disease, mortality and visual outcome. RESULTS: Patients with orbital involvement had a higher mortality and higher likelihood of mucormycosis infection compared with those with sinus-only disease (78.6% vs 20%, p=0.01; 86% vs 30%, p=0.01, respectively). Patients with mucormycosis had a higher mortality (71%) than patients with Aspergillus (29%); however, this was not statistically significant (p=0.16). All patients with orbital involvement and/or mucormycosis infections were immunosuppressed or had inadequately controlled diabetes, and had a cranial neuropathy or ocular motility dysfunction. All five post-transplant patients with orbital infections died, while the two transplant patients with sinus infections survived. CONCLUSIONS: Patients with orbital fungal infections are more likely to be infected with mucormycosis compared with Aspergillus and have a higher mortality compared with infections sparing the orbit. History of transplant portends a dismal prognosis in orbital infections. Invasive fungal disease should be considered in any immunocompromised patient presenting with a new cranial neuropathy or ocular motility abnormality. PMID- 26112870 TI - Ophthalmic statistics note 7: multiple hypothesis testing-to adjust or not to adjust. PMID- 26112871 TI - Glaucoma in Asia: regional prevalence variations and future projections. AB - PURPOSE: To evaluate glaucoma prevalence and disease burden across Asian subregions from 2013 to 2040. METHODS: We conducted a systematic review and meta analysis of 23 population-based studies of 1318 primary open angle glaucoma (POAG) cases in 66,800 individuals and 691 primary angle closure glaucoma (PACG) cases in 72,767 individuals in Asia. Regions in Asia were defined based on United Nations' (UN) classification of macro-geographic regions. PubMed, Medline and Web of Science databases were searched for population-based glaucoma prevalence studies using standardised criteria published to 31 December 2013. Pooled glaucoma prevalence for individuals aged 40-80 years was calculated using hierarchical Bayesian approaches. Prevalence differences by geographic subregion, subtype and habitation were examined with random effects meta-regression models. Estimates of individuals with glaucoma from 2013 to 2040 were based on the UN World Population Prospects. RESULTS: In 2013, pooled overall glaucoma prevalence was 3.54% (95% credible interval (CrI) 1.83 to 6.28). POAG (2.34%, 95% CrI 0.96 to 4.55) predominated over PACG (0.73%, 95% CrI 0.18 to 1.96). With age and gender adjustment, PACG prevalence was higher in East than South East Asia (OR 5.55, 95% CrI 1.52 to 14.73), and POAG prevalence was higher in urban than rural populations (OR 2.11, 95% CrI 1.57 to 2.38). From 2013 to 2040, South Central Asia will record the steepest increase in number of glaucoma individuals from 17.06 million to 32.90 million compared with other Asian subregions. In 2040, South-Central Asia is also projected to overtake East Asia for highest overall glaucoma and POAG burden, while PACG burden remains highest in East Asia. CONCLUSIONS: Across the Asian subregions, there was greater glaucoma burden in South-Central and East Asia. Sustainable public health strategies to combat glaucoma in Asia are needed. PMID- 26112872 TI - Tumor necrosis factor-alpha enhances voltage-gated Na+ currents in primary culture of mouse cortical neurons. AB - BACKGROUND: Previous studies showed that TNF-alpha could activate voltage-gated Na(+) channels (VGSCs) in the peripheral nervous system (PNS). Since TNF-alpha is implicated in many central nervous system (CNS) diseases, we examined potential effects of TNF-alpha on VGSCs in the CNS. METHODS: Effects of TNF-alpha (1-1000 pg/mL, for 4-48 h) on VGSC currents were examined using whole-cell voltage clamp and current clamp techniques in primary culture of mouse cortical neurons. Expression of Nav1.1, Nav1.2, Nav1.3, and Nav1.6 were examined at both the mRNA and protein levels, prior to and after TNF-alpha exposure. RESULTS: TNF-alpha increased Na(+) currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. The observed effects of TNF-alpha on Na(+) currents were inhibited by pre-incubation with the NF-kappaB inhibitor BAY 11-7082 (1 MUM) or the p38 mitogen-activated protein kinases (MAPK) inhibitor SB203580 (1 MUM). CONCLUSIONS: TNF-alpha increases Na(+) currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-kappaB and p38 MAPK signal pathways in CNS neurons. PMID- 26112874 TI - [Research with big data: the European perspective]. AB - The article examines the impact that legislative developments in the European Union have had, still have and are continuing to have on cross-border access to microdata for research purposes. Therefore, we describe two competing aims: the tension between the ambitions of the EU to create a European Research Area within which research communities gain access to and share data across national boundaries; and the desire within the EU to establish a harmonious legislative framework that provides protection from the misuse of personal information. We attempt to examine which new developments at the EU level will have an impact upon research plans and the challenges researchers face when analysing big data. PMID- 26112873 TI - A novel navigation template for fixation of acetabular posterior column fractures with antegrade lag screws: design and application. AB - PURPOSE: To test whether a novel guide template we designed can facilitate accurate insertion of antegrade lag screws in the fixation of acetabular posterior column fractures. METHODS: We created virtual three-dimensional reconstruction models of the pelvis from CT scan data obtained from 96 adult patients without any bony problems. A virtual cylindrical implant was placed along the longitudinal axis of the acetabular posterior column passing through the ischial tuberosity. The diameter of cylindrical implant was augmented to 6.5 mm, and the direction was adjusted until the optimal screw path was found using the reverse engineering technique. The orifice of this cylinder from the iliac fossa was determined as the entry point for the antegrade lag screw. The anatomical parameters of the screw entry path were measured and saved in .stl format. The guide template was designed according to the acetabular morphology and the measured anatomical parameters before it was put into manufacture of a solid template with the rapid prototyping technique. The feasibility and accuracy of the guide template were tested in cadaveric pelvises. Finally, the guide template was used in real surgery for five patients. Furthermore, the time required for surgery was recorded. RESULTS: Under the guide of this navigation template, antegrade lag screws were successfully placed in the posterior column of the acetabulum in the cadaveric test. And five lag screws were successfully placed in five patients. The mean time of antegrade lag screw insertion required 5.8 (3-10) min. CONCLUSIONS: Antegrade lag screws can be more accurately put into the posterior column of the acetabulum with the help of this navigation template. PMID- 26112875 TI - [Laboratory practices: diagnostics and antibiotics resistance testing of Neisseria gonorrhoeae in Germany]. AB - Recent years have seen a world-wide increase in antimicrobial resistance (AMR) in cases of infection with Neisseria gonorrhoeae (NG). NG infection is not notifiable in Germany and there is a lack of information available about the spread and AMR of NG infections. The objective of the study was to provide information on diagnostic methods and AMR testing in cases of NG infections in German laboratories. A cross-sectional survey was undertaken in Germany between June and August 2013 using an online questionnaire. Laboratories performing NG diagnostics were identified and described with regard to the diagnostic methods used, the number of tests performed, the antibiotics tested and the AMR observed, in addition to general laboratory information. In total, 188 of the 521 participating laboratories performed NG diagnostics; these were included in the further statistical analysis. 92.6 % of the 188 laboratories performed culture. A median of 60 (IQR 15-270) samples per quarter (SPQ) were tested, with an overall positivity rate of 4.1 and 6.9 % among men. Most (82.1 %) of the 151 laboratories performing NG culture tested for AMR as well. The most frequently tested antibiotics were ciprofloxacin (94.8 %), penicillin (93.1 %), doxycycline (70.0 %) and ceftriaxone (67.2 %). The most frequently observed AMR ever were those against ciprofloxacin (87.1 %), penicillin (78.3 %), doxycycline (56.6 %) and azithromycin (35.1 %; all percentages refer to laboratories). The laboratories used different standards regarding susceptibility criteria. The emergence and spread of AMR shows that it is crucial to assess and monitor the scope and trends of multidrug-resistant gonorrhea. The data collected on diagnostic methods and AMR testing in cases of NG infections in German laboratories constitute an important basis for future monitoring. PMID- 26112876 TI - [Not Available]. PMID- 26112877 TI - Molecular Cytogenetic Analysis of Cucumis Wild Species Distributed in Southern Africa: Physical Mapping of 5S and 45S rDNA with DAPI. AB - Wild Cucumis species have been divided into Australian/Asian and African groups using morphological and phylogenetic characteristics, and new species have been described recently. No molecular cytogenetic information is available for most of these species. The crossability between 5 southern African Cucumis species (C. africanus, C. anguria, C. myriocarpus, C. zeyheri, and C. heptadactylus) has been reported; however, the evolutionary relationship among them is still unclear. Here, a molecular cytogenetic analysis using FISH with 5S and 45 S ribosomal DNA (rDNA) was used to investigate these Cucumis species based on sets of rDNA bearing chromosomes (rch) types I, II and III. The molecular cytogenetic and phylogenetic results suggested that at least 2 steps of chromosomal rearrangements may have occurred during the evolution of tetraploid C. heptadactylus. In step 1, an additional 45 S rDNA site was observed in the chromosome (type III). In particular, C. myriocarpus had a variety of rch sets. Our results suggest that chromosomal rearrangements may have occurred in the 45 S rDNA sites. We propose that polyploid evolution occurred in step 2. This study provides insights into the chromosomal characteristics of African Cucumis species and contributes to the understanding of chromosomal evolution in this genus. PMID- 26112878 TI - Within-herd prevalence thresholds for the detection of Mycobacterium avium subspecies paratuberculosis-positive dairy herds using boot swabs and liquid manure samples. AB - The control of Johne's disease requires the identification of Mycobacterium avium ssp. paratuberculosis (MAP)-positive herds. Boot swabs and liquid manure samples have been suggested as an easy-to-use alternative to sampling individual animals in order to diagnose subclinical Johne's disease at the herd level, but there is a need to evaluate performance of this approach in the field. Using a logistic regression model, this study aimed to calculate the threshold level of the apparent within-herd prevalence as determined by individual faecal culture, thus allowing the detection of whether a herd is MAP positive. A total of 77 boot swabs and 75 liquid manure samples were taken from 19 certified negative and 58 positive dairy herds. Faecal culture, three different polymerase chain reaction (PCR) methods and the combination of faecal culture with PCR were applied in order to detect MAP. For 50% probability of detection, a within-herd prevalence threshold of 1.5% was calculated for testing both matrices simultaneously by faecal culture and PCR, with the threshold increased to 4.0% for 90% probability of detection. The results encourage the use of boot swabs or liquid manure samples, or a combination both, for identifying MAP-positive herds and, to a certain extent, for monitoring certified Johne's disease-negative cattle herds. PMID- 26112879 TI - Interaction between Common Genetic Variants and Total Fat Intake on Low-Density Lipoprotein Peak Particle Diameter: A Genome-Wide Association Study. AB - BACKGROUND/AIM: Total fat intake has an important impact on the low-density lipoprotein (LDL) peak particle diameter (LDL-PPD) and may interact with nutrient sensitive single nucleotide polymorphisms (SNPs). The objective was to examine whether there is suggestive evidence of SNP * dietary fat intake interaction effects influencing the LDL-PPD in the Quebec Family Study (QFS) in order to generate hypotheses to be tested in larger studies. METHODS: SNPs from a genome wide association study (GWAS) using Illumina Human610-Quad BeadChip, total fat intake derived from a 3-day weighted food record, and SNP * total fat intake interaction effects were examined on LDL-PPD in 541 QFS subjects. RESULTS: The GWAS analyses 29 identified independent SNP * total fat intake interaction effects on the LDL-PPD at p < 10(-5), including SNPs in the following genes: ABCG2, CPA3, FNBP1, KCNQ3, NBAS, NCALD, OPRL1, NKAIN2, SH3BGRL2, SOX5, and SUSD4. CONCLUSIONS: This observational study suggests that multiple SNPs interact with dietary fat intake to influence variation in the LDL-PPD. PMID- 26112880 TI - [Is there an autism epidemic?]. PMID- 26112881 TI - Genetic mechanisms of parenting. AB - This article is part of a Special Issue "Parental Care". The complexities of parenting behavior in humans have been studied for decades. Only recently did we begin to probe the genetic and epigenetic mechanisms underlying these complexities. Much of the research in this field continues to be informed by animal studies, where genetic manipulations and invasive tools allow to peek into and directly observe the brain during the expression of maternal behavior. In humans, studies of adult twins who are parents can suggest dimensions of parenting that might be more amenable to a genetic influence. Candidate gene studies can test specific genes in association with parental behavior based on prior knowledge of those genes' function. Gene-by-environment interactions of a specific kind indicating differential susceptibility to the environment might explain why some parents are more resilient and others are more vulnerable to stressful life events. Epigenetic studies can provide the bridge often necessary to explain why some individuals behave differently from others despite common genetic influences. There is a much-needed expansion in parenting research to include not only mothers as the focus-as has been the case almost exclusively to date-but also fathers, grandparents, and other caregivers. PMID- 26112882 TI - Deconstructing the function of maternal stimulation in offspring development: Insights from the artificial rearing model in rats. AB - This article is part of a Special Issue on "Parental Care". Maternal behavior has an important function in stimulating adequate growth and development of the young. Several approaches have been used in primates and rodents to deconstruct and examine the influence of specific components of maternal stimulation on offspring development. These approaches include observational studies of typical mother-infant interactions and studies of the effects of intermittent or complete deprivation of maternal contact. In this review, we focus on one unique approach using rats that enables the complete control of maternal variables by means of rearing rat pups artificially without contact with the mother or litter, while maintaining stable nutrition, temperature and exposure to stressful stimuli. This artificial rearing model permits the removal and controlled replacement of relevant maternal and litter stimuli and has contributed valuable insights regarding the influence of these stimuli on various developmental outcomes. It also enables the analysis of factors implicated in social isolation itself and their long-term influence. We provide an overview of the effects of artificial rearing on behavior, physiology, and neurobiology, including the influence of replacing maternal tactile stimulation and littermate contact on these outcomes. We then discuss the relevance of these effects in terms of the maternal role in regulating different aspects of offspring development and implications for human research. We emphasize that artificial rearing of rats does not lead to a global insult of nervous system development, making this paradigm useful in investigating specific developmental effects associated with maternal stimulation. PMID- 26112883 TI - Combinatorial Sec pathway analysis for improved heterologous protein secretion in Bacillus subtilis: identification of bottlenecks by systematic gene overexpression. AB - BACKGROUND: Secretory expression of valuable proteins by B. subtilis and its related species has attracted intensive work over the past three decades. Although very high yields can be achieved with homologous proteins, production of heterologous proteins by B. subtilis is unfortunately not the straight forward. The Sec pathway is the major route for protein secretion in B. subtilis. Therefore, the aim of this work was to identify the bottlenecks of the Sec pathway and improve the secretion of heterologous proteins by molecular genetic techniques. RESULTS: Two alpha-amylases (AmyL and AmyS) both under the control of the P(HpaII) promoter and equipped with their native signal peptides SP(amyl) and SP(amyS) were successfully secreted with significantly different expression levels. To improve the secretion efficiency, 23 main genes or gene operons involved in or closely related to the Sec pathway were overexpressed singly by increasing an additional copy on the chromosome, and the overexpression of prsA enhanced the production of alpha-amylases (AmyL and AmyS) by 3.2- and 5.5-fold, respectively. With the induction by xylose of different concentrations, prsA overexpression level was optimized and the secretion efficiency of alpha-amylase was further improved. Moreover, combinatorial overexpression of prsA and nine screened genes or gene operons, respectively, was performed, and the overexpression of prsA combined with partial dnaK operon improved the alpha amylase activity of AmyL and AmyS by 160 and 173%, respectively, compared with the overexpression of prsA singly. Finally, the performance of the recombinant B. subtilis 1A237 was evaluated with the fed-batch fermentation in 7.5 L fermentor, and the level of secreted AmyL and AmyS reached 1,352 and 2,300 U/mL with the productivity of 16.1 U/mL h and 27.4 U/mL h, respectively. CONCLUSIONS: Our systematic gene overexpression approach was designed to investigate the bottleneck of Sec pathway in B. subtilis. The deficiency of PrsA lipoprotein and chaperones of DnaK series was main rate-limiting factors for heterologous proteins secretion. Systematic and deep insight into how components of Sec pathway interact with each other may be the key to improving the yield of heterologous proteins thoroughly. PMID- 26112884 TI - Modeling Suggests TRPC3 Hydrogen Bonding and Not Phosphorylation Contributes to the Ataxia Phenotype of the Moonwalker Mouse. AB - A gain-of-function mutation (T635A) in the transient receptor potential (TRP) channel TRPC3 results in abnormal channel gating and causes cerebellar ataxia in the dominant Moonwalker (Mwk) mouse mutant. However, the underlying molecular and structural mechanisms are unclear. Here, we used a combined approach of computational modeling and functional characterization of proposed TRPC3 mutants. Our findings support a mechanism by which the hydrogen bonding capability of threonine 635 plays a significant role in maintaining a stable, closed state channel. This capability is lost in the Mwk mutant, suggesting a structural basis for the disease-causing phenotype in the Mwk mouse. PMID- 26112887 TI - Pregnancy in women with congenital heart disease. AB - Congenital heart defects are the most common birth defects. Major advances in open-heart surgery have led to rapidly evolving cohorts of adult survivors and the majority of affected women now survive to childbearing age. The risk of cardiovascular complications during pregnancy and peripartum depends on the type of the underlying defect, the extent and severity of residual haemodynamic lesions and comorbidities. Careful individualized, multi-disciplinary pre pregnancy risk assessment and counselling, including assessment of risks in the offspring and estimation on long-term outcomes of the underlying heart defect, will enable informed decision making. Depending on the estimated risks, a careful follow-up plan during pregnancy as well as a detailed plan for delivery and postpartum care can reduce the risks and should be made by the multi-disciplinary team. PMID- 26112886 TI - Potent peroxisome proliferator-activated receptor-alpha agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome. AB - AIMS: Fibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-alpha LY518674 is known to substantially increase apolipoprotein A-I (apoA I) turnover without major impact on steady-state levels of apoA-I or high-density lipoprotein-cholesterol (HDL-C). We sought to determine whether therapy with a PPAR-alpha agonist impacts cholesterol efflux capacity, a marker of HDL function. METHODS AND RESULTS: Cholesterol efflux capacity was measured at baseline and after 8 weeks of therapy in a randomized, placebo-controlled trial involving participants with metabolic syndrome treated with either LY518674 100 MUg daily (n = 13) or placebo (n = 15). Efflux capacity assessment was quantified using a previously validated ex vivo assay that measures the ability of apolipoprotein-B depleted plasma to mobilize cholesterol from macrophages. LY518674 led to a 15.7% increase from baseline (95% CI 3.3-28.1%; P = 0.02, P vs. placebo = 0.01) in efflux capacity. The change in apoA-I production rate in the active treatment arm was strongly linked to change in cholesterol efflux capacity (r = 0.67, P = 0.01). CONCLUSIONS: Potent stimulation of PPAR-alpha leads to accelerated turnover of apoA-I and an increase in cholesterol efflux capacity in metabolic syndrome patients despite no change in HDL-C or apoA-I levels. This finding reinforces the notion that changes in HDL-C levels may poorly predict impact on functionality and thus has implications for ongoing pharmacologic efforts to enhance apoA-I metabolism. PMID- 26112888 TI - Coronary vascular regulation, remodelling, and collateralization: mechanisms and clinical implications on behalf of the working group on coronary pathophysiology and microcirculation. PMID- 26112885 TI - Intra-operative defibrillation testing and clinical shock efficacy in patients with implantable cardioverter-defibrillators: the NORDIC ICD randomized clinical trial. AB - AIMS: This trial was designed to test the hypothesis that shock efficacy during follow-up is not impaired in patients implanted without defibrillation (DF) testing during first implantable cardioverter-defibrillator (ICD) implantation. METHODS AND RESULTS: Between February 2011 and July 2013, 1077 patients were randomly assigned (1 : 1) to first time ICD implantation with (n = 540) or without (n = 537) DF testing. The intra-operative DF testing was standardized across all participating centres, and all ICD shocks were programmed to 40 J irrespective of DF test results. The primary end point was the average first shock efficacy (FSE) for all true ventricular tachycardia and fibrillation (VT/VF) episodes during follow-up. The secondary end points included procedural data, serious adverse events, and mortality. During a median follow-up of 22.8 months, the model-based FSE was found to be non-inferior in patients with an ICD implanted without a DF test, with a difference in FSE of 3.0% in favour of the no DF test [confidence interval (CI) -3.0 to 9.0%, Pnon-inferiority <0.001 for the pre-defined non-inferiority margin of -10%). A total of 112 procedure-related serious adverse events occurred within 30 days in 94 patients (17.6%) tested compared with 89 events in 74 patients (13.9%) not tested (P = 0.095). CONCLUSION: Defibrillation efficacy during follow-up is not inferior in patients with a 40 J ICD implanted without DF testing. Defibrillation testing during first time ICD implantation should no longer be recommended for routine left-sided ICD implantation. PMID- 26112889 TI - Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. AB - Sirtuins (Sirt1-Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation-all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFkappaB, Pcsk9, low density lipoprotein-receptor, PPARgamma, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD+, we anticipate that this field will move quickly from bench to bedside. PMID- 26112891 TI - Dissemination via the lymphatic or angiogenic route impacts the pathology, microenvironment and hypoxia-related drug response of lung metastases. AB - Complications associated with the development of lung metastases have a detrimental effect on the overall survival rate of many cancer patients. Preclinical models that mimic the clinical aspects of lung metastases are an important tool in developing new therapy options for these patients. The commonly used intravenous models only recapitulate dissemination of cancer cells to the lungs via the haematological route. Here we compared spontaneous and intravenous lung metastases of the highly metastatic KHT mouse fibrosarcoma cells after injecting KHT cells into the subcutaneous layer of the skin or directly into the tail vein. In contrast to the intravenous model, metastases spontaneously arising from the subcutaneous tumours disseminated most consistent with the lymph nodes/lymphatics route and were more hypoxic than the metastases observed following tail-vein administration and haematological spread. To ascertain whether this impacted on drug response, we tested the effectiveness of the hypoxia-sensitive cytotoxin AQ4N (Banoxantrone) in both models. AQ4N was more effective as an anti-metastatic drug in mice with subcutaneous KHT tumours, significantly reducing the metastatic score. Complementing the KHT studies, pathology studies in additional models of spontaneous lung metastases showed haematological (HCT116 intrasplenic implant) or mixed haematological/lymphatic (B16 intradermal implant) spread. These data suggest that preclinical models can demonstrate differing, clinically relevant dissemination patterns, and that careful selection of preclinical models is required when evaluating new strategies for targeting metastatic disease. PMID- 26112890 TI - Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: a retrospective registry study on 127,555 patients from the Nationwide OsMed Health DB Database. AB - AIMS: Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. METHODS AND RESULTS: We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62 0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52-0.94; P = 0.018). CONCLUSION: In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas. PMID- 26112892 TI - Biochemical characterization of FIKK8--A unique protein kinase from the malaria parasite Plasmodium falciparum and other apicomplexans. AB - FIKKs are protein kinases with distinctive sequence motifs found exclusively in Apicomplexa. Here, we report on the biochemical characterization of Plasmodium falciparum FIKK8 (PfFIKK8) and its Cryptosporidium parvum orthologue (CpFIKK) - the only member of the family predicted to be cytosolic and conserved amongst non Plasmodium parasites. Recombinant protein samples of both were catalytically active. We characterized their phosphorylation ability using an enzymatic assay and substrate specificities using an arrayed positional scanning peptide library. Our results show that FIKK8 targets serine, preferably with arginine in the +3 and -3 positions. Furthermore, the soluble and active FIKK constructs in our experiments contained an N-terminal extension (NTE) conserved in FIKK8 orthologues from other apicomplexan species. Based on our results, we propose that this NTE is an integral feature of the FIKK subfamily. PMID- 26112893 TI - Plasma pharmacokinetics of ceftiofur metabolite desfuroylceftiofur cysteine disulfide in holstein steers: application of nonlinear mixed-effects modeling. AB - Eight clinically normal and drug-naive Holstein steers were dosed with ceftiofur sodium at 2.2 mg/kg body weight intramuscularly. Doses were given at 24-h intervals for 5 days. Prior to the first dose and after all injections, blood samples were collected serially for determination of plasma concentrations of one of ceftiofur's main metabolites, desfuroylceftiofur cysteine disulfide (DCCD). A nonlinear mixed-effect model was used to analyze the plasma concentration data. A stochastic approximation expectation maximization (SAEM) algorithm in MONOLIX version 4.2.2 was used to approximate the likelihood of the nonlinear mixed effect model and to estimate the population parameters. In addition, simulation studies were conducted to justify the model and demonstrate how to interpret the model parameters given different scenarios. PMID- 26112895 TI - Testes transcriptome profiles of the anadromous fish Coilia nasus during the onset of spermatogenesis. AB - RNA-Seq technology has been widely applied to transcriptomics, genomics and functional gene study. Here, we performed de novo transcriptome sequencing to produce 23,842,172 clean reads representing a total of 4,815,798,404 (4.8 Gb) nucleotides from comprehensive transcript dataset for testis of Coilia nasus. Over 20 million Illumina reads were assembled into 194,636 unigenes, and 42,642 annotated genes were predicted by Blastx and ESTScan, respectively. Applying Blast analysis and functional annotation (e.g., GO, COG, SwissProt and KEGG) using the assembled gene models from catalogs of other species, we have sampled an extensive and diverse expressed gene catalog for C. nasus representing a large proportion of the genes involved in the onset of spermatogenesis. The results will provide a general clue to the potential spermatogenesis molecular mechanisms for this species. PMID- 26112894 TI - Supplementation of tributyrin improves the growth and intestinal digestive and barrier functions in intrauterine growth-restricted piglets. AB - BACKGROUND & AIMS: Intrauterine growth restriction (IUGR) neonates suffer from growth restriction. Tributyrin (TB), a pro-drug of butyrate, can facilitate the growth of animals. This study was to investigate the effects of TB supplementation on the growth of IUGR neonatal piglets. METHODS: Sixteen IUGR and 8 NBW (normal body weight) neonatal piglets were chosen, weaned at 7th day and fed basic milk diets (NBW and IUGR group) or the basic diets supplemented with 0.1% tributyrin (IT group, IUGR piglets fed with tributyrin) until day 21 (n = 8). The body weights of the piglets on days 0, 7, 10, 14, 17, and 20 were measured. The digestive enzyme activity, intestinal morphology, immunoglobulin levels and gene expression of IgG, FcRn and GPR41 in the small intestines were analyzed. RESULTS: The body weights of the piglets in the IUGR and IT group were similar, and both were lower than the NBW group on days 10 and 14. However, after day 17, the IT group exhibited improved (P < 0.05) body weights compared to that of the IUGR group. The piglets were sacrificed on day 21. Compared with the NBW piglets, IUGR impaired the development of immune organs and small intestines, impaired the intestinal villus morphology, decreased (P < 0.05) most of the tested intestinal digestive enzyme activities, decreased (P < 0.05) the ileal sIgA and IgG levels, and down-regulated (P < 0.05) the intestinal IgG and GPR41 expression. Piglets in the IT group exhibited a better-developed (P < 0.05) spleen and small intestines, improved intestinal villus morphology, increased (P < 0.05) intestinal villus surface areas, enhanced (P < 0.05) digestive enzyme activities, and up-regulated (P < 0.05) expression of IgG and GPR41 mRNA compared to those of the IUGR group. CONCLUSIONS: TB supplementation improves the growth and the intestinal digestive and barrier functions in IUGR piglets during the suckling period. PMID- 26112896 TI - A first insight into the spleen transcriptome of the notothenioid fish Lepidonotothen nudifrons: Resource description and functional overview. AB - In this study, we describe a de novo sequencing and assembly of the spleen transcriptome of Lepidonotothen nudifrons, a notothenioid fish widely distributed around the Antarctic Peninsula and the Scotia Arc. Sequences were generated on an Illumina MiSeq system and assembled to a total of 112,477 transcripts. Putative functional annotation was possible for more than 34% of the transcripts. This data will be relevant for future studies targeting the erythrocyte turnover, oxygen transport mechanism and immune system, which are key functional traits to investigate cold adaptation and thermal sensitivity of Antarctic notothenioids. PMID- 26112897 TI - RNA-Seq-based transcriptome analysis of Korean rose bitterling (Rhodeus uyekii) exposed to synthetic estrogen 17-alpha-ethinylestradiol (EE2). AB - The potential impact of natural and synthetic estrogens on aquatic ecosystems has become a subject of great interest in recent years. One synthetic estrogen, 17 alpha-ethinylestradiol (EE2), is present in municipal sewage discharges and causes gonad alterations in various fish species. To understand the possible damage caused by EE2, male Rhodeus uyekii were exposed to 100 ng/L EE2 for 7 days. RNA-Seq was performed to assess the effects of EE2 on gene expression in hepatic and skin tissues. The analysis revealed that EE2 induced the expression of various genes, including sex hormone genes, anti-Mullerian hormone, vitellogenin, and estrogen receptor alpha; cancer genes, breast cancer anti estrogen resistance protein 3, caveolin 2, and Smad2; and apoptotic genes, p53, Bcl-2, TNF-alpha, and WDR36. These results suggest that the synthetic estrogen EE2 disturbs the endocrine system and regulates both carcinogenic and apoptotic gene expressions in R. uyekii. PMID- 26112899 TI - Transitioning home: A four-stage reintegration hospital discharge program for adolescents hospitalized for eating disorders. AB - PURPOSE: Treatment for adolescents with eating disorders (ED) is multidimensional and extends after hospitalization. After participating in a four-step reintegration plan, treatment success including post-discharge community and social reintegration were examined from perspectives of patients, family members, and healthcare providers. DESIGN AND METHODS: Six pairs of patients and parents, and seven parents without their children were interviewed 2 to 30 months following discharge. RESULTS: All but two adolescents were enrolled in, or had completed school. Five worked in addition to school, and three completed army or national service. Twelve were receiving therapeutic care in the community. PRACTICE IMPLICATIONS: Adolescents with ED can benefit from a systematic reintegration program, and nurses should incorporate this into care plans. PMID- 26112898 TI - Imaging-based screening: maximizing benefits and minimizing harms. AB - Advanced imaging technologies play a central role in screening asymptomatic patients. However, the balance between imaging-based screening's potential benefits versus risks is sometimes unclear. Radiologists will have to address ongoing concerns, including high false-positive rates, incidental findings outside the organ of interest, overdiagnosis, and potential risks from radiation exposure. In this article, we provide a brief overview of these recurring controversies and suggest the following as areas that radiologists should focus on in order to tip the balance toward more benefits and less harms for patients undergoing imaging-based screening: interpretive variability, abnormal finding thresholds, and personalized, risk-based screening. PMID- 26112900 TI - Inactivation of Protein Tyrosine Phosphatases by Peracids Correlates with the Hydrocarbon Chain Length. AB - BACKGROUND/AIMS: Protein tyrosine phosphatases are crucial enzymes controlling numerous physiological and pathophysiological events and can be regulated by oxidation of the catalytic domain cysteine residue. Peracids are highly oxidizing compounds, and thus may induce inactivation of PTPs. The aim of the present study was to evaluate the inhibitory effect of peracids with different length of hydrocarbon chain on the activity of selected PTPs. METHODS: The enzymatic activity of human CD45, PTP1B, LAR, bacterial YopH was assayed under the cell free conditions, and activity of cellular CD45 in human Jurkat cell lysates. The molecular docking and molecular dynamics were performed to evaluate the peracids binding to the CD45 active site. RESULTS: Here we demonstrate that peracids reduce enzymatic activity of recombinant CD45, PTP1B, LAR, YopH and cellular CD45. Our studies indicate that peracids are more potent inhibitors of CD45 than hydrogen peroxide (with an IC50 value equal to 25 nM for peroctanoic acid and 8 uM for hydrogen peroxide). The experimental data show that the inactivation caused by peracids is dependent on hydrocarbon chain length of peracids with maximum inhibitory effect of medium-chain peracids (C8-C12 acyl chain), which correlates with calculated binding affinities to the CD45 active site. CONCLUSION: Peracids are potent inhibitors of PTPs with the strongest inhibitory effect observed for medium-chain peracids. PMID- 26112901 TI - Correlation between senescence-associated beta-galactosidase expression in articular cartilage and disease severity of patients with knee osteoarthritis. AB - AIM: The purposes of this study were to investigate senescence-associated beta galactosidase (SA-beta-Gal) levels in articular cartilage of knee osteoarthritis (OA) and the relationship with severity of the disease. METHODS: All the 50 cartilage tissues, including normal (controls) and OA cartilage were ascribed to four groups of normal, mild lesions, moderate lesions and severe lesions on the basis of the modified Mankin score. Immunohistochemistry was used to assess the SA-beta-Gal expression in articular cartilage. RESULTS: No SA-beta-Gal staining was observed in the normal articular cartilage samples. SA-beta-Gal staining was found in a subset of the chondrocytes close to the lesion site of mild, moderate and severe damaged knee OA cartilage. The percentage of SA-beta-Gal-positive chondrocytes in articular cartilage was 0% in controls, 13.00 +/- 5.77% in mild lesions, 31.65 +/- 6.91% in moderate lesions and 51.95 +/- 6.21% in severe lesions. SA-beta-Gal expression in mild lesions, moderate lesions and severe lesions was higher compared with that of controls (P < 0.0001). SA-beta-Gal expression in moderate lesions and severe lesions were higher with respect to mild lesion samples (P < 0.0001). SA-beta-Gal expression in severe lesions was elevated compared with those of moderate lesions (P < 0.0001). Subsequent analysis showed that articular cartilage SA-beta-Gal levels correlated with severity of disease (Spearman's rho = 0.94, P < 0.0001). CONCLUSION: SA-beta-Gal expression in articular cartilage is associated with progressive knee OA joint damage and is a potential indictor of disease severity. PMID- 26112902 TI - The combined treatment with novel platinum(II) complex and anti-MUC1 increases apoptotic response in MDA-MB-231 breast cancer cells. AB - New strategy of cancer's targeting treatment is combining monoclonal antibodies with chemotherapeutic agents. An important goal of targeted therapy appears to be a transmembrane glycoprotein type I-mucin 1 (MUC1), which is overexpressed in tumors of epithelial origin, especially in breast cancer. The goal of the study was to check the effect of monoclonal antibody against MUC1 with novel platinum(II) complex (Pt12) on selected aspects of apoptosis in human MDA-MB-231 breast cancer cells. The number of apoptotic and necrotic cells was measured using annexin V binding assay. The decrease of mitochondrial membrane potential (MMP) and DNA fragmentation was analyzed. Finally, the influence of novel platinum(II) complex (Pt12) used with anti-MUC1 on the concentration of selected markers of apoptosis such as Bax, caspase-8, -9, and caspase-3 was performed using ELISA. The results from combined treatment were compared with those obtained using monotherapy. In our study, we proved that anti-MUC1 used in combination with Pt12 strongly induced apoptosis in MDA-MB-231 breast cancer cell line. The effect was stronger than treatment with Pt12, cisplatin, anti-MUC1, and anti-MUC1 used with cisplatin. We also observed the highest decrease of MMP and the strongest DNA fragmentation after such a combined treatment. The results obtained from ELISA showed increased concentration of Bax, caspases-8, -9, -3 compared to monotherapy. Our study proved that Pt12 together with anti-MUC1 strongly induced apoptosis in estrogen-negative breast cancer cell line (MDA-MB 231). The apoptosis may go through extrinsic pathway associated with caspase-8 as well as intrinsic pathway connected with caspase-9. PMID- 26112903 TI - Angiotensin II directly impairs adipogenic differentiation of human preadipose cells. AB - Angiotensin II reduces adipogenic differentiation of preadipose cells present in the stroma-vascular fraction of human adipose tissue, which also includes several cell types. Because of the ability of non-adipose lineage cells in the stroma vascular fraction to respond to angiotensin II, it is not possible to unequivocally ascribe the anti-adipogenic response to a direct effect of this hormone on preadipose cells. Therefore, we used the human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell strain to investigate the consequences of angiotensin II treatment on adipogenic differentiation under serum-free conditions, by assessing expression of typical adipocyte markers perilipin and fatty acid-binding protein 4 (FABP4), at the transcript and protein level. Reverse transcription-polymerase chain reaction showed that perilipin and FABP4 transcripts were, respectively, reduced to 0.33 +/- 0.07 (P < 0.05) and 0.41 +/- 0.19-fold (P < 0.05) in SGBS cells induced to adipogenic differentiation in the presence of angiotensin II. Western Blot analysis corroborated reduction of the corresponding proteins to 0.23 +/- 0.21 (P < 0.01) and 0.46 +/- 0.30-fold (P < 0.01) the respective controls without angiotensin II. Angiotensin II also impaired morphological changes associated with early adipogenesis. Hence, we demonstrated that angiotensin II is able to directly reduce adipogenic differentiation of SGBS preadipose cells. PMID- 26112904 TI - Synergistic anticancer effects of combined gamma-tocotrienol and oridonin treatment is associated with the induction of autophagy. AB - gamma-Tocotrienol and oridonin are natural phytochemicals that display potent anticancer activity. Studies showed that combined treatment with subeffective doses of gamma-tocotrienol with oridonin resulted in synergistic autophagic and apoptotic effects in malignant +SA, but not normal CL-S1 mouse mammary epithelial cells in vitro. Specifically, combined treatment with low doses of gamma tocotrienol (8 uM) and oridonin (2 uM) for 24 h resulted in synergistic inhibition of +SA mammary cancer cells viability. This combination significantly enhanced the expression of autophagy cellular markers including the conversion of LC3B-I to LC3B-II, beclin-1, Atg3, Atg7, Atg5-Atg12, LAMP-1 and cathepsin-D, and pretreatment with the autophagy inhibitors 3-methyladenine (3-MA) or bafilomycin A1 (Baf1) blocked these effects. Furthermore, blockade of gamma-tocotrienol and oridonin-induced autophagy with 3-MA or Baf1 induced a modest, but significant reduction in cytotoxicity resulting from the combined treatment of these phytochemicals. The anticancer effects of combination treatment was also associated with a large suppression in Akt/mTOR mitogenic signaling and corresponding increase in the levels of apoptotic cellular marker including cleaved caspase-3 and PARP, and Bax/Bcl-2 ratio in these tumor cells. These effects were also found to be selective against cancer cells, since similar combined treatment with gamma-tocotrienol and oridonin did not induce autophagy or reduce viability of normal mouse CL-S1 mammary epithelial cells. These findings indicate that combined gamma-tocotrienol and oridonin-induced autophagy plays a role in mediating the synergistic anticancer effects of these phytochemicals. PMID- 26112905 TI - Myricetin inhibits proliferation and induces apoptosis and cell cycle arrest in gastric cancer cells. AB - Myricetin is a flavonoid that is abundant in fruits and vegetables and has protective effects against cancer and diabetes. However, the mechanism of action of myricetin against gastric cancer (GC) is not fully understood. We researched myricetin on the proliferation, apoptosis, and cell cycle in GC HGC-27 and SGC7901 cells, to explore the underlying mechanism of action. Cell Counting Kit (CCK)-8 assay, Western blotting, cell cycle analysis, and apoptosis assay were used to evaluate the effects of myricetin on cell proliferation, apoptosis, and the cell cycle. To analyze the binding properties of ribosomal S6 kinase 2 (RSK2) with myricetin, surface plasmon resonance (SPR) analysis was performed. CCK8 assay showed that myricetin inhibited GC cell proliferation. Flow cytometry analysis showed that myricetin induces apoptosis and cell cycle arrest in GC cells. Western blotting indicated that myricetin influenced apoptosis and cell cycle arrest of GC cells by regulating related proteins. SPR analysis showed strong binding affinity of RSK2 and myricetin. Myricetin bound to RSK2, leading to increased expression of Mad1, and contributed to inhibition of HGC-27 and SGC7901 cell proliferation. Our results suggest the therapeutic potential of myricetin in GC. PMID- 26112907 TI - Kinetics and mechanism of the reaction of perfluoro propyl vinyl ether (PPVE, C3F7OCH=CH2) with OH: assessment of its fate in the atmosphere. AB - Absolute rate coefficients for the reaction between OH radicals and perfluoro propyl vinyl ether (PPVE) were obtained using the technique of pulsed laser photolysis with the detection of OH radicals by laser induced fluorescence. Rate coefficients were measured over a range of temperatures (212-298 K) and at either 50 or 200 Torr bath-gas (N2 or N2/O2). The temperature dependence of the rate coefficient is given by k1(212-298 K) = (4.88 +/- 0.49) * 10(-13) exp[(564 +/- 10)/T] cm(3) molecule(-1) s(-1) with a value at room temperature of (3.4 +/- 0.3) * 10(-12) cm(3) molecule(-1) s(-1). No pressure dependence was observed, indicating that the reaction is at the high pressure limit under atmospheric conditions. The accuracy of the rate coefficient obtained was enhanced by on-line optical absorption measurements of PPVE at 184.95 nm using a value of sigma(184.95 nm) = (5.64 +/- 0.28) * 10(-18) cm(2) molecule(-1) determined in this work. An atmospheric lifetime of a few days for PPVE was calculated. Extensive quantum chemical calculations as a complement to the experimental work are presented in order to determine its probable tropospheric degradation mechanism. PMID- 26112908 TI - Temperature-independent polymer optical fiber evanescent wave sensor. AB - Although the numerous advantages of polymer optical fibers have been exploited in the fields of sensors and telecommunications, such fibers still experience a critical problem: the temperature dependency. Therefore, we explored the temperature-independent operation of a polymer fiber-optic evanescent wave sensor immersed in distilled water. We investigated variations in the surface morphology, deformation trajectory, refractive index, and weight of the fiber sensing region with varying water temperature. We also examined the spectral transmission and transmitted light intensity of fibers subjected to a heating cooling treatment. We observed that the light-transmission modes and sensitivity of the sensor were affected by changes in the surface morphology, diameter, and refractive index of the sensing region caused by changes in temperature. The transmitted light intensity of the sensor was maintained at a constant level after five cycles of the heating-cooling treatment, after which the fibers exhibited a smooth surface, low refractive index, and large fiber diameter. Consequently, we utilized the heating-cooling-treated fiber to realize a temperature-independent, U-shaped polymer fiber-optic evanescent wave sensor. The temperature independence was evaluated using glucose solutions in the range of 10 to 70 degrees C. The fabricated sensor showed significant temperature independence and high degree of consistency in measuring solutions. PMID- 26112906 TI - SVVYGLR motif of the thrombin-cleaved N-terminal osteopontin fragment enhances the synthesis of collagen type III in myocardial fibrosis. AB - Osteopontin (OPN) is involved in various physiological processes such as inflammatory and wound healing. However, little is known about the effects of OPN on these tissues. OPN is cleaved by thrombin, and cleavage of the N-terminal fragment exposes a SVVYGLR sequence on its C-terminus. In this study, we examined the effects of the thrombin-cleaved OPN fragments on fibroblasts and myocardial fibrosis, particularly the role of the SVVYGLR sequence. The recombinant thrombin cleaved OPN fragments (N-terminal fragment [N-OPN], C-terminal fragment [C-OPN], and the N-terminal fragment lacking the SVVYGLR sequence [DeltaSV N-OPN]) were added to fibroblasts, and the cellular motility, signal activity, and production of collagen were evaluated. A sustained-release gel containing an OPN fragment or SVVYGLR peptide was transplanted into a rat model of ischemic cardiomyopathy and the quantities and ratio of collagen type I (COL I) and type III (COL III) were estimated. N-OPN significantly promoted fibroblast migration. Smad signal activity, expression of smooth muscle actin (SMA), and the production of COL III were enhanced by N-OPN and SVVYGLR peptide. Conversely, DeltaSV N-OPN and C-OPN had no effect. In vivo, the expression level of N-OPN was associated with COL III distribution, and the COL III/COL I ratio was significantly increased by the sustained-release gel containing N-OPN or SVVYGLR peptide. The cardiac function was also significantly improved by the N-OPN- or SVVYGLR peptide-released gel treatment. The N-terminal fragment of thrombin-cleaved OPN-induced Smad signal activation, SMA expression, and COL III production, and its SVVYGLR sequence influences this function. PMID- 26112909 TI - Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial. AB - Seamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. PMID- 26112911 TI - Complex host genetic susceptibility to Staphylococcus aureus infections. AB - Understanding of the host genetic susceptibility to carriage of, and infections, due to Staphylococcus aureus, a nosocomial pathogen, is still in its nascent stages. Mouse models show variable susceptibility to S. aureus infections across mouse strains and disease models with roles for signaling pathways involving Toll like receptors (TLR-1, TLR-2, and TLR-6), interleukins (IL-4, IL-6, IL-10, and IL 13), chemokines [CXC ligand (CXCL)-1 and CXCL-2], and T helper (Th)1/Th2 responses. Genome-wide association studies (GWASs) for carriage in humans identified SNPs in IL4, DEFB1, CRP, and VDR for persistent nasal carriage. NR3C1 haplotypes may either enhance risk or provide protection from colonization. GWASs for all S. aureus diseases have suggested roles for DAPK3, a kinase, and XRN1, a nuclease, while CDON could have a role in complicated bacteremia. More studies are needed to identify host susceptibility genes along with confirmation from functional assays. PMID- 26112910 TI - Musical training, individual differences and the cocktail party problem. AB - Are musicians better able to understand speech in noise than non-musicians? Recent findings have produced contradictory results. Here we addressed this question by asking musicians and non-musicians to understand target sentences masked by other sentences presented from different spatial locations, the classical 'cocktail party problem' in speech science. We found that musicians obtained a substantial benefit in this situation, with thresholds ~6 dB better than non-musicians. Large individual differences in performance were noted particularly for the non-musically trained group. Furthermore, in different conditions we manipulated the spatial location and intelligibility of the masking sentences, thus changing the amount of 'informational masking' (IM) while keeping the amount of 'energetic masking' (EM) relatively constant. When the maskers were unintelligible and spatially separated from the target (low in IM), musicians and non-musicians performed comparably. These results suggest that the characteristics of speech maskers and the amount of IM can influence the magnitude of the differences found between musicians and non-musicians in multiple-talker "cocktail party" environments. Furthermore, considering the task in terms of the EM-IM distinction provides a conceptual framework for future behavioral and neuroscientific studies which explore the underlying sensory and cognitive mechanisms contributing to enhanced "speech-in-noise" perception by musicians. PMID- 26112912 TI - Lokiarchaeota: eukaryote-like missing links from microbial dark matter? AB - Identification and genome sequencing of novel organismal groups can reduce the gap between the sequenced minority and the unexplored majority. The recent discovery of phylum Lokiarchaeota promises understanding of biological history. Here we inquire if Lokiarchaeota truly represent ancient eukaryotic ancestors or just microbial dark matter of expanding archaeal diversity. PMID- 26112913 TI - Intracranial Injuries from Dog Bites in Children. AB - BACKGROUND/AIMS: Infants are especially at risk for intracranial injuries from dog bites due to their small stature and thin skull. Only 21 case reports have been published in the literature. We aim to add knowledge and treatment recommendations based on a more substantial sample. METHODS: Ten pediatric patients with a penetrating skull injury as a result of a dog bite, treated at our institution between 1992 and 2010, were identified and analyzed descriptively. A literature review of the 21 case reports was also conducted. RESULTS AND CONCLUSION: Early diagnosis and treatment can prevent complications from hemorrhage or infections. Based on our results, we recommend obtaining a head CT for all victims sustaining injuries to the head, early use of broad spectrum antibiotics, debridement and irrigation of tissue, and follow-up to identify late infectious complications. PMID- 26112915 TI - En bloc pancreaticoduodenectomy and colectomy for locally advanced right-sided colon cancer - a video vignette. PMID- 26112916 TI - Environmental drivers of phototrophic biofilms in an Alpine show cave (SW-Italian Alps). AB - The proliferation of lampenflora is a major threat for the conservation of show caves, since phototrophic organisms cause physical, chemical and aesthetic damage to speleothems. In this paper we examine the environmental factors influencing the presence and the growth of the three main photosynthetic groups composing phototrophic biofilms in the Bossea show cave (SW-Italian Alps). The presence and the primary production of cyanobacteria, diatoms and green algae were detected with BenthoTorch(r), an instrument for in situ measurement of chlorophyll a concentration that has never been used before in caves. By means of different techniques of regression analysis, we highlighted the response of the three photosynthetic groups to different environmental factors. Illuminance proved to be the main factor influencing positively both the probability of the presence and the productivity of the three groups. The presence of seeping water on the substrate and the distance from the cave entrance proved to play an important role in determining patterns of colonization. By means of GIS techniques, we provide thematic maps of the cave, providing a representation of pattern of the density of the three examined photosynthetic groups within different areas of the cave. The same approach may apply to other show caves, aiming at providing suggestions for the cave management (i.e. cleaning of the cave walls and positioning of artificial lights) and reduce impact caused by tourism. PMID- 26112914 TI - Chronobiology of bipolar disorder: therapeutic implication. AB - Multiple lines of evidence suggest that psychopathological symptoms of bipolar disorder arise in part from a malfunction of the circadian system, linking the disease with an abnormal internal timing. Alterations in circadian rhythms and sleep are core elements in the disorders, characterizing both mania and depression and having recently been shown during euthymia. Several human genetic studies have implicated specific genes that make up the genesis of circadian rhythms in the manifestation of mood disorders with polymorphisms in molecular clock genes not only showing an association with the disorder but having also been linked to its phenotypic particularities. Many medications used to treat the disorder, such as antidepressant and mood stabilizers, affect the circadian clock. Finally, circadian rhythms and sleep researches have been the starting point of the developing of chronobiological therapies. These interventions are safe, rapid and effective and they should be considered first-line strategies for bipolar depression. PMID- 26112917 TI - [Blood donation: Representations and issues associated with blood product collection]. AB - In order to answer to its aim of standardised self-sufficiency, the Etablissement francais du sang (main French national platform for blood donation) needs to know well the donors, what moves them, what motivates them, and the meaning that they give to their action. This knowledge allows the EFS to better understand the different sensitivities among donors, and therefore to improve the strategy regarding loyalty or/and newcomers. In this paper we follow, without attempting to be fully exhaustive, the evolution of the research regarding blood donation. The aim is to highlight the role played by social and historical representations regarding donation in general. In a given community, its norms, and its values influence both the image of donors as well as the meaning attached to the act itself of donation. Moreover, these norms have also influenced the way that research has tried to analyse this topic. The initial studies conducted in this field tried generally to understand the meaning and the symbolism attached to the act of blood donation. Later on, researchers started to focus on the assessment of notions such as generosity, and then solidarity. Nowadays, research is more focused on describing the population that gives blood. They are more scrutinised through their socio-demographic traits (who they are) than through the specific study of how they donate, the reasons behind the decision to act and the notion of satisfaction. PMID- 26112918 TI - Apical extrusion of sodium hypochlorite activated with two laser systems and ultrasonics: a spectrophotometric analysis. AB - BACKGROUND: The aim of the present study was to compare the effect of ultrasonically or laser (Nd:YAG or diode) activated irrigation on the irrigating solution extrusion compared to non-activated syringe irrigation. METHODS: Extracted mandibular premolar teeth (n = 48) with single canals were instrumented. The teeth were secured through the lid of an Eppendorf tube filled with 1.0 mL distilled water to collect the apically extruded irrigating solution. The teeth were randomly divided into four groups: non-activated syringe irrigation, diode laser, Nd:YAG laser and passive ultrasonic irrigation (PUI) using 2% NaOCl. The irrigating solution extruded through the apical foramen was collected in the Eppendorf tube and evaluated by a chemical reaction with using a spectrophotometer. The data was analyzed using one-way ANOVA and Tukey's post hoc test (alpha = 0.05). RESULTS: All the groups showed apically extruded irrigating solution. There were significant differences among the groups (p < 0.05). Nd:YAG laser activated irrigation showed greater extrusion (p < 0.05), while the non activated syringe irrigation showed less extrusion (p < 0.05). Only the difference between diode laser and PUI was not statistically significant (p > 0.05). CONCLUSION: Within the limitations of this in vitro study, the researchers concluded that non-activated syringe irrigation caused less apically extruded irrigating solution than PUI and LAI using Nd:YAG or diode lasers. PMID- 26112919 TI - Effect of moderate exercise-induced heat stress on carotid wave intensity. AB - INTRODUCTION: Exercise disrupts the interaction between the left ventricle and the vasculature, as measured by wave intensity (WI) analysis. However, the effect of exercise-induced heat stress on WI amplitude is unknown. WI measures are calibrated using brachial or carotid artery blood pressure, but the influence of calibration method on WI outcomes is unknown. PURPOSE: (1) To compare WI analysis during low and moderate exercise-induced heat stress; (2) to examine differences in carotid WI analysis based on calibration method. METHODS: Eleven healthy, young men (22 +/- 3 years) performed intermittent exercise in moderate- and low heat stress conditions. WI was assessed pre- and post-exercise on the right carotid artery, and calibrated with brachial and carotid blood pressures. RESULTS: A main effect of time was found for W1 when calibrated by brachial, but not carotid pressure. A time-by-condition interaction was observed for late systolic/early diastolic function (W2) in both brachial (p = 0.047) and carotid calibration methods (p = 0.042), where W2 increased following exercise-induced moderate-heat stress but decreased following low-heat stress. The elastic modulus exhibited a significant time-by-condition interaction (brachial p = 0.039; carotid p = 0.044), increasing following moderate-heat stress but decreasing following low-heat stress. Calibrations using carotid blood pressure significantly reduced WI amplitudes compared with brachial calibrations (p < 0.001). CONCLUSIONS: Arterial-ventricular coupling is affected in different ways following moderate and low exercise-induced heat stress. Wave amplitudes were lower (~13 %) following carotid calibration compared with brachial. PMID- 26112920 TI - The Prehospital Sepsis Screen: A Test in Search of an Application? PMID- 26112922 TI - Neutrophils Increase Oral Squamous Cell Carcinoma Invasion through an Invadopodia Dependent Pathway. AB - Neutrophils have recently been shown to promote invasion and correlate with a poor prognosis in different cancers, including head and neck squamous cell carcinomas. In this study, we analyze the effects of neutrophils in the invasion of oral squamous cell carcinoma (OSCC) using a combination of conditioned media, direct and indirect coculture of human peripheral blood neutrophils, and UMSCC47 cells (OSCC cell line). Invasion and matrix degradation were determined using a modified in vitro invasion assay and an invadopodia assay, respectively. UMSCC47 and neutrophil cocultures or conditioned media from cocultures increased UMSCC47 invasion, invadopodia formation, and matrix degradation. Further analysis revealed an increase in TNFalpha and IL8 in supernatants of cocultures compared with neutrophil or UMSCC47 cultures alone and that inhibition of TNFalpha and IL8 significantly decreased OSCC invasion. Our results show that neutrophils increase the invasiveness of OSCC through the activation of invadopodia and matrix degradation, suggesting a paracrine activation loop between the two cells. Importantly, the presence of neutrophils in the oral environment may modulate the clinical behavior of OSCC. PMID- 26112921 TI - Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade. AB - The identification of immunosuppressive factors within human tumor microenvironments, and the ability to block these factors, would be expected to enhance patients' antitumor immune responses. We previously established that an unidentified factor, or factors, present in ovarian tumor ascites fluids reversibly inhibited the activation of T cells by arresting the T-cell signaling cascade. Ultracentrifugation of the tumor ascites fluid has now revealed a pellet that contains small extracellular vesicles (EV) with an average diameter of 80 nm. The T-cell arrest was determined to be causally linked to phosphatidylserine (PS) that is present on the outer leaflet of the vesicle bilayer, as a depletion of PS-expressing EV or a blockade of PS with anti-PS antibody significantly inhibits the vesicle-induced signaling arrest. The inhibitory EV were also isolated from solid tumor tissues. The presence of immunosuppressive vesicles in the microenvironments of ovarian tumors and our ability to block their inhibition of T-cell function represent a potential therapeutic target for patients with ovarian cancer. PMID- 26112923 TI - Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-cell Therapy for Cancer. AB - Adoptive transfer of T cells engineered to express chimeric immunoreceptors is an effective strategy to treat hematologic cancers; however, the use of this type of therapy for solid cancers, such as ovarian cancer, remains challenging because a safe and effective immunotherapeutic target has not yet been identified. Here, we constructed and evaluated a novel redirected T-cell-based immunotherapy targeting human follicle-stimulating hormone receptor (FSHR), a highly conserved molecule in vertebrate animals with expression limited to gonadal tissues, ovarian cancer, and cancer-associated vasculature. Receptor ligand-based anti-FSHR immunoreceptors were constructed that contained small binding fragments from the ligand for FSHR, FSH, fused to T-cell transmembrane and T-cell signaling domains. Human T cells transduced to express anti-FSHR immunoreceptors were specifically immunoreactive against FSHR-expressing human and mouse ovarian cancer cell lines in an MHC-nonrestricted manner and mediated effective lysis of FHSR-expressing tumor cells, but not FSHR-deficient targets, in vitro. Similarly, the outgrowth of human ovarian cancer xenografts in immunodeficient mice was significantly inhibited by the adoptive transfer of FSHR-redirected T cells. Our experimental observations show that FSHR is a promising immunotherapeutic target for ovarian cancer and support further exploration of FSHR-targeted immune therapy approaches for patients with cancer. PMID- 26112924 TI - Selective and sensitive liquid chromatographic determination method of 5 hydroxyindoles with fluorous and fluorogenic derivatization. AB - A liquid chromatographic (LC) method with improved selectivity for the simultaneous determination of 5-hydroxyindoles (5-HIs; 5-hydroxytryptophan, 5 hydroxytryptamine, N-acetyl-5-hydroxytryptamine, 5-hydroxyindole-3-acetic acid, and 5-hydroxytryptophol) is described. This method involves precolumn derivatization with 4-(3',3',4',4',5',5',6',6',7',7',8',8',9',9',10',10',10' heptadecafluorodecyl)benzylamine (HFBA) and separation of the derivatives using a fluorous LC column. In this study, stable benzoxazole derivatives of 5-HIs with HFBA have been obtained by a simple derivatization procedure; their fluorescent properties enabled highly sensitive detection. In addition, only the HFBA derivatives of 5-HIs has been selectively retained on the fluorous LC column via fluorous interaction whereby perfluoroalkyl compounds show affinities with each other, while the non-fluorous compounds did not. The HFBA derivatives were separated within 30 min and the detection limits for 5-HIs in a 20-MUL injection volume were 1.2-14 fmol (S/N=3). Furthermore, this method was applied to the analysis of 5-HIs in the human plasma from healthy subjects. PMID- 26112925 TI - Liquid chromatography-quadrupole time-of-flight mass spectrometry for screening in vitro drug metabolites in humans: investigation on seven phenethylamine-based designer drugs. AB - Phenethylamine-based designer drugs are prevalent within the new psychoactive substance market. Characterisation of their metabolites is important in order to identify suitable biomarkers which can be used for better monitoring their consumption. Careful design of in vitro metabolism experiments using subcellular liver fractions will assist in obtaining reliable outcomes for such purposes. The objective of this study was to stepwise investigate the in vitro human metabolism of seven phenethylamine-based designer drugs using individual families of enzymes. This included para-methoxyamphetamine, para-methoxymethamphetamine, 4 methylthioamphetamine, N-methyl-benzodioxolylbutanamine, benzodioxolylbutanamine, 5-(2-aminopropyl) benzofuran and 6-(2-aminopropyl) benzofuran. Identification and structural elucidation of the metabolites was performed using liquid chromatography-quadrupole-time-of-flight mass spectrometry. The targeted drugs were mainly metabolised by cytochrome P450 enzymes via O-dealkylation as the major pathway, followed by N-dealkylation, oxidation of unsubstituted C atoms and deamination (to a small extent). These drugs were largely free from Phase II metabolism. Only a limited number of metabolites were found which was consistent with the existing literature for other phenethylamine-based drugs. Also, the metabolism of most of the targeted drugs progressed at slow rate. The reproducibility of the identified metabolites was assessed through examining formation patterns using different incubation times, substrate and enzyme concentrations. Completion of the work has led to a set of metabolites which are representative for specific detection of these drugs in intoxicated individuals and also for meaningful evaluation of their use in communities by wastewater based drug epidemiology. PMID- 26112926 TI - Global identification and quantitative analysis of chemical constituents in traditional Chinese medicinal formula Qi-Fu-Yin by ultra-high performance liquid chromatography coupled with mass spectrometry. AB - Qi-Fu-Yin (QFY), a classical traditional Chinese medicine formula, is proven to have significant neuroprotective effects by modern pharmacological studies. However, the chemical constituents of QFY have not been fully explored. In this study, an ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF MS) was developed for comprehensive analysis of chemical constituents in QFY. By using characteristic ions and fragmentation rules, a reliable identification of 156 compounds was described here, including 69 triterpene saponins, 23 oligosaccharide esters, 22 flavanoids, 9 alkaloids, 9 phenolic acids, 8 phthalides, 7 phenylethanoid glycosides, 3 xanthones, 3 sesquiterpene lactones, 2 ionones and 1 iridoid glycoside. Twenty-six major compounds were then determined in a single run by UHPLC coupled with triple quadrupole tandem mass spectrometry (QQQ MS) with fast positive/negative polarity switching. It allows for the acquisition of MS data in both ionization modes from a single run. The proposed method was then validated in terms of linearity, accuracy, precision and recovery. The overall recoveries for 26 analytes ranged from 91.35% to 109.58%, with RSDs ranging from 0.82% to 4.83%. In addition, the content of 26 analytes in QFY prepared by five batches of herbal materials was also analyzed. These results demonstrated that our present method was effective and reliable for comprehensive quality evaluation of QFY. Meanwhile, the study might provide the chemical evidence for revealing the material basis of its therapeutic effects. PMID- 26112927 TI - Determination of abacavir, tenofovir, darunavir, and raltegravir in human plasma and saliva using liquid chromatography coupled with tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry assay for the determination of abacavir (ABC), tenofovir (TFV), darunavir (DRV), and raltegravir (RAL) in human plasma and saliva was developed and validated to investigate the applicability of saliva as an appropriate specimen for therapeutic drug monitoring. As internal standards, TFV was chosen for ABC, ABC was chosen for TFV, RAL for DRV, and DRV for RAL. Sample preparation involved protein precipitation with acetonitrile, evaporation of solvent using a centrifugal evaporator, and reconstitution by dissolving the residue in mobile phase. Liquid chromatography was performed on a C18 reverse phase column (1.5 * 50 mm, 5 MUm) isocratically at a flow rate of 0.2 mL/min using 5mM formic acid-3% (v/v) acetonitrile as the mobile phase for ABC and TFV and 5mM formic acid-35% (v/v) acetonitrile as the mobile phase for DRV and RAL. The run time was 6 min, and the retention time was approximately 2.0 min for TFV, 2.5 min for RAL, and 4-4.5 min for ABC and DRV. Analytes were detected using tandem mass spectrometry in positive electrospray ionization mode. The precursor/product ion transitions (m/z) were 287.3/191.2 for ABC, 288.5/176.2 for TFV, 548.3/392.3 for DRV, and 445.3/109.5 for RAL, and were monitored on a triple quadrupole mass spectrometer operated in the multiple reaction monitoring mode. The linearity of the assay was assessed in the range 1-10,000 ng/mL for all four drugs. Within-run and between-run mean accuracy, precision, and the extraction recovery for all drugs were -14.5-18.1%, 1.2-13.1%, and 86.0-111.1%, respectively. The proposed assay is sufficiently sensitive and accurate to quantify these drugs in plasma and saliva, and is suitable for investigating the relationship between drug concentrations in plasma and saliva. PMID- 26112928 TI - A robust hybrid model integrating enhanced inputs based extreme learning machine with PLSR (PLSR-EIELM) and its application to intelligent measurement. AB - In this paper, a robust hybrid model integrating an enhanced inputs based extreme learning machine with the partial least square regression (PLSR-EIELM) was proposed. The proposed PLSR-EIELM model can overcome two main flaws in the extreme learning machine (ELM), i.e. the intractable problem in determining the optimal number of the hidden layer neurons and the over-fitting phenomenon. First, a traditional extreme learning machine (ELM) is selected. Second, a method of randomly assigning is applied to the weights between the input layer and the hidden layer, and then the nonlinear transformation for independent variables can be obtained from the output of the hidden layer neurons. Especially, the original input variables are regarded as enhanced inputs; then the enhanced inputs and the nonlinear transformed variables are tied together as the whole independent variables. In this way, the PLSR can be carried out to identify the PLS components not only from the nonlinear transformed variables but also from the original input variables, which can remove the correlation among the whole independent variables and the expected outputs. Finally, the optimal relationship model of the whole independent variables with the expected outputs can be achieved by using PLSR. Thus, the PLSR-EIELM model is developed. Then the PLSR EIELM model served as an intelligent measurement tool for the key variables of the Purified Terephthalic Acid (PTA) process and the High Density Polyethylene (HDPE) process. The experimental results show that the predictive accuracy of PLSR-EIELM is stable, which indicate that PLSR-EIELM has good robust character. Moreover, compared with ELM, PLSR, hierarchical ELM (HELM), and PLSR-ELM, PLSR EIELM can achieve much smaller predicted relative errors in these two applications. PMID- 26112929 TI - Optimal performance of networked control systems under the packet dropouts and channel noise. AB - The optimal tracking performance of single-input single-output (SISO) discrete time networked control systems (NCSs) with the packet dropouts and channel noise is studied in this paper. The communication channel is characterized by three parameters: the packet dropouts, channel noise and the encoding and decoding. The explicit expression of the optimal tracking performance is obtained by using the spectral factorization. It is shown that the optimal tracking performance dependents on the nonminimum phase zeros, unstable poles of the given plant, as well as the packet dropout probability, channel noise and the encoding and decoding. The optimal tracking performance is improved by two-parameter compensator. Finally, a typical example is given to illustrate the theoretical results. PMID- 26112930 TI - Three years of antibiotic consumption evaluation in French nursing homes. AB - OBJECTIVES: We had for aim to assess antibiotic consumption and to better understand their use in nursing homes so as to target messages on relevant practice procedures sent to prescribers. DESIGN: The MedQual network asked nursing homes with in-house pharmacies to participate in a retrospective collection of yearly antibiotic consumption data with an Excel((r)) spread sheet according to the Health Ministry recommendations. RESULTS: Fifty-two nursing homes participated in 2011, 2012, and 74 in 2013, accounting for 10% of the Pays de la Loire region's nursing homes and 15% of beds. The medians of total antibiotic consumption in daily-defined dose for 1000 patient-days were respectively 39 (32.4-49.0), 39.3 (34.4-52.9), and 44.8 (33.6-55.4). There was no significant difference between 2011 and 2013. Penicillins (J01C) were the most commonly used class with a median of 25.7 [IQ 18.8; 33.8] in 2011 and 30.4 [IQ 23.6; 41.3] in 2013. Quinolones (J01M) were the second most commonly used class with a median of 4.6 [IQ 2.9; 5.9] in 2011 and 3.8 [IQ 2.3; 6.5] in 2013, followed by the other beta-lactams (J01D) with a median of 2.5 [IQ 1.7; 4.5] in 2011 and 2,8 [IQ 1.7; 3.8] in 2013. CONCLUSION: The monitoring of antibiotic consumption in nursing homes in the Pays de la Loire Region since 2011 has allowed identifying inappropriate use and helped improve practices. No increase of overall consumption was observed in nursing homes but the distribution according to antibiotic class changed. The current objective is to extend this monitoring and to send personalized messages to prescribers. PMID- 26112931 TI - Implementing diabetes self-management education (DSME) in a Nigerian population: perceptions of practice nurses and dieticians. AB - Hyperglycaemic complication is the most common cause of hospitalization amongst diabetes patients in Nigeria. Research showed that diabetes self-management education (DSME) assists in controlling hyperglycaemia in diabetes patients. We assessed the opinions of practice nurses and dieticians on implementing DSME in a Nigerian population. 517 nurses and dieticians completed a self-administered questionnaire tool. Results showed that the majority of the participants agreed that DSME in a Nigerian population will assist patients (88.3%) and assist to reduce diabetes complications (91.4%). While only 34% of all participants believed that their establishments were prepared to implement DSME, a large proportion of the participants agreed that their work places do not have enough qualified health personnel (62.4%), educational facilities (65.8%) and economic resources (65.6%) to embark on DSME. These constitute significant barriers for effective DSME and demand that strategic investment in human and material resources for DSME is needed in this population of a developing country. PMID- 26112932 TI - The conceptual and clinical problems of paraneoplastic syndrome in oncology and internal medicine. AB - Symptomatology of oncological diseases consists not only of local symptoms caused by the primary malignancy or its metastases, but also by general systemic signs that are not directly connected with the tumor. These symptoms are mostly associated with auto-immunity or endocrine influences. In many cases, the source of paraneoplastic syndromes (PNS) is unknown. Nearly 15% of oncological patients demonstrate these syndromes but it is diagnosed much more rarely. The survey of the numerous PNS is offered. The significance of the PNS differs for oncologists and other physicians who encounter it in their practice. The reason of those differences, as well as the connection between PNS and cancer toxicity is discussed. The experience of antitoxic therapy (hemosorption, lymphosorption, enterosorption) used in our clinic in the previous years is overviewed. PMID- 26112933 TI - Overview on association of different types of leukemias with radiation exposure. AB - Exposure to ionizing radiation is associated with increasing risk of various types of hematological malignancies. The results of major studies on association of leukemias and radiation exposure of large populations in Japan and in Ukraine are analyzed. The patterns of different types of leukemia in 295 Chernobyl clean up workers diagnosed according to the criteria of up-to-date World Health Organization classification within 10-25 years following Chernobyl catastrophe are summarized. In fact, a broad spectrum of radiation-related hematological malignancies has been revealed both in Life Span Study in Japan and in study of Chernobyl clean-up workers in Ukraine. The importance of the precise diagnosis of tumors of hematopoietic and lymphoid tissues according to up-to-date classifications for elucidating the role of radiation as a causative factor of leukemias is emphasized. Such studies are of high importance since according to the recent findings, radiation-associated excess risks of several types of leukemias seem to persist throughout the follow-up period up to 55 years after the radiation exposure. PMID- 26112934 TI - Synergic carcinostatic effects of ascorbic acid and hyperthermia on Ehrlich ascites tumor cell. AB - AIM: In this study, we evaluated the carcinostatic effects of combined ascorbic acid (AsA) and a capacitive-resistive electric transfer (CRet) hyperthermic apparatus-induced hyperthermic treatment on Ehrlich ascites tumor (EAT) cells. MATERIALS AND METHODS: EAT cells were exposed to various AsA (0-10 mM) concentrations for 1 h; they subsequently underwent CRet treatment for 15 min at 42 degrees C. Cell viability was assessed by the WST-8 assay 24 h after the combined treatment. Reactive oxygen species involvement was evaluated using catalase and tempol; caspase-3/7 activation was determined by their fluorescent substrates; cell proliferation were estimated by time-lapse observation. The effect on the cell cycle was analyzed by flow cytometry. RESULTS: Combined AsA and CRet treatment synergistically suppressed cell viability compared with either treatment alone, and these synergistically carcinostatic effects were evident even at noncytotoxic concentrations of AsA alone (<= 2 mM). The carcinostatic effects of combined AsA and CRet treatment were attenuated in a dose-dependent manner by catalase addition, but not by the superoxide anion radical scavenger tempol. Time-lapse observation revealed that combined AsA and CRet treatment activated caspase-3/7 at 10-24 h after treatment, accompanied by significant cell growth suppression. Cell cycle analysis revealed that the rate of sub-G1-phase (apoptotic) cells was drastically increased at 12 h and 24 h, and that the G2/M phase cells gradually increased at 6-24 h after treatment. CONCLUSION: These results indicate that combined AsA and CRet treatment synergistically inhibits EAT cell growth through G2/M arrest and apoptosis induction via H2O2 generation at lower AsA concentrations; this carcinostatic effect cannot be exerted by AsA alone. PMID- 26112935 TI - Assessment of gold nanoparticle effect on prostate cancer LNCaP cells. AB - In recent years gold nanoparticles (AuNPs) have received considerable attention for various biomedical applications including diagnostics and targeted drug delivery. However, more research is still needed to characterize such aspects of their use in clinical oncology as permeability, retention and functional effect on tumor cells. AIMS: This study was designed to describe the effect of non functionalized AuNPs on LNCaP prostate cancer cells growth. MATERIAL AND METHODS: LNCaP cells were cultured in RPMI-1640 medium containing AuNPs covered by polyvinylpyrrolidone of average size 26.4 nm (10.0 MUg/ml). Counts of cells were calculated and their morphology was examined. RESULTS: AuNPs conglomerates have been visualized in cultured cells. After 4-day incubation in presence of AuNPs significant retardation of LNCaP cells growth was observed both in 5alpha dihydrotestosterone stimulated and non-stimulated cultures. No morphological changes of live LNCaP cells were seen in any experiment. CONCLUSION: Given absence of morphological changes in live cells and dribble and relatively constant numbers of dead cells, it was concluded that inhibitory effect of AuNPs on LNCaP cells growth was caused by alterations of proliferation. PMID- 26112936 TI - Aberrant expression of selenium-containing glutathione peroxidases in clear cell renal cell carcinomas. AB - AIM: To find putative diagnostic markers for clear cell renal cell carcinomas (ccRCC). MATERIAL AND METHODS: Quantitative polymerase chain reaction (Q-PCR), bisulfite treatment, methylation-specific PCR, analysis on cBioPortal for Cancer Genomics. RESULTS: We have found that expression of GPX1, GPX3, and GPX4 genes was decreased in ccRCC. We have shown that the number of alanine (GCG) repeats at the amino terminus of the GPX1 protein is variable. It was reported earlier that an allele that possess 5 alanine repeats is associated with the increased cancer risk. According to the obtained data, the allele with the 5 alanine repeats was also present in a group of healthy donors. Moreover, the frequency of alleles with repeats was similar among ccRCC patients and healthy individuals. We found that decreased expression of GPXs genes was not associated with promoter methylation. To provide other explanation, an analysis on the gene copy number was performed. We have found the heterozygous deletions for GPX1 gene, amplification for GPX3 gene, and no change in gene copy number for GPX4. CONCLUSIONS: Our data support the hypothesis that GPX1, GPX3, and GPX4 genes may play a role in ccRCC cancerogenesis and therefore they might be considered as putative diagnostic markers for ccRCC. PMID- 26112937 TI - Prognostic significance of MDM2 gene expression in childhood neuroblastoma. AB - AIM: To investigate the association of MDM2 expression at the mRNA levels in neuroblastoma with clinical features and unfavorable disease factors to determine the possibility of it usage as a prognostic marker of neuroblastoma. MATERIALS AND METHODS: Total RNA and DNA were extracted from tumor tissue samples of total 91 neuroblastoma patients (mean age: 39.45 +/- 4.81 months). MDM2 mRNA levels were detected with Q-PCR. TP53 gene deletion was detected with FISH method. MYCN amplification was detected with -Q-PCR analysis in fresh tumor samples and FISH in FFPE samples. RESULTS: We investigated the association of MDM2 mRNA expression with clinical outcome in neuroblastoma patients (n = 91). Kaplan - Meier curves showed a significant association of high MDM2 expression with poor event-free survival (p < 0.001). Clinical outcome of patients without MYCN amplification with low MDM2 expression was associated with better event-free survival than with high MDM2 expression (p < 0.001). Overexpression of MDM2 can be used as significant prognostic marker for patient stratification on risk groups and treatment optimization. CONCLUSION: Our results showed that the high expression of MDM2 at mRNA levels is an important factor of neuroblastoma prognosis. It may be a valuable additional molecular marker in guiding specific therapy in MYCN non amplified NB patients without TP53 gene deletion. PMID- 26112938 TI - Isolectins of phytohemagglutinin are able to induce apoptosis in HEp-2 carcinoma cells in vitro. AB - AIM: To study the effects of total phytohemagglutinin (PHA) and its isolectins on cell death and apoptosis in human HEp-2 carcinoma cells and to analyze the possible molecular mechanisms of lectin induced apoptosis. MATERIALS AND METHODS: The commercial preparation of the kidney beans (Phaseolus vulgaris) lectins and HEp-2 cells were used. Apoptosis index was determined using acridine orange and ethidium bromide staining. The expression levels of apoptosis mediator cleaved caspase-3 and proapoptotic Bax protein were studied by Western blot analysis. The gene expression levels were analyzed by qPCR. RESULTS: PHA and its isolectins induced apoptosis in HEp-2 cells accompanied by the increased expression of caspase-3 cleaved form, with PHA-E being the most effective. The treatment of HEp 2 cells with PHA or its isolectins resulted in a marked increase of Bax on both mRNA and protein levels. CONCLUSIONS: PHA and its isolectins were shown to induce the apoptosis in human HEp-2 carcinoma cells via increasing proapoptotic protein Bax and activating caspases-3. PMID- 26112939 TI - Pharmacological effect of aminoferrocene in mice with L1210 leukemia. AB - AIM: To study the cytostatic and some biological effects of aminoferrocene using mice with L1210 lymphoid leukemia. MATERIALS AND METHODS: Experiments were performed on BDF1 male mice (DBA/2, female * C57Bl/6, male) with transplantable L1210 lymphoid leukemia. Determination of antitumor activity of Benzyl-Fc Boron (Bn), it was injected intraperitoneally 6 times daily, starting on day 2 after L1210 leukemia cell transplantation. Doses of Bn such as 26; 260 and 2600 MUg/kg were used. The determination of intracellular content of cardiolipin, thiols, reactive oxygen species (ROS) and also analysis of Annexin V positivity and mitochondrial transmembrane potential (JC-1 staining) were performed with use of flow cytometry. The levels of "free iron" complexes, transferrin active forms and the rate of NO generation were measured by EPR-specroscopy. RESULTS: Six daily injections of Bn at a dose of 26 MUg/kg resulted in an increased survival of mice with L1210 leukemia by 28% (p < 0.05). Bn led to an increase of apoptotic cells number and ROS amount in leukemia cells. Besides, Bn caused a decrease of cardiolipin and nonprotein thiol compounds content. The membrane electrochemical potential of cell mitochondria was decreased also after Bn administration. Studies using EPR-spectroscopy revealed a significant increase in a level of "free iron", content of transferrin active species and generation rate of NO by inducible NO-synthase in L1210 cells after aminoferrocene administration. CONCLUSION: Our data indicate that Benzyl-Fc Boron can be promising candidate for realizing a new strategy of anticancer therapy with the use of ROS-inducing agents. PMID- 26112940 TI - Effect of dichloroacetate on Lewis lung carcinoma growth and metastasis. AB - A hallmark of malignancy is excessive tumor glycolysis, even in the presence of oxygen, which causes lactacidosis in the tumor microenvironment and favors tumor cell proliferation and survival. For this reason antimetabolic agents which target tumor cell metabolism are being researched extensively as promising anticancer drugs. AIM: To study the effect of lactacidosis on survival of Lewis lung carcinoma (LLC) cells at the conditions of nutritional substrate deficiency in vitro and evaluate antitumor and antimetastatic activity against LLC/R9 in vivo. MATERIALS AND METHODS: LLC variant LLC/R9 was used as experimental tumor model. Tumor cell viability was determined using trypan blue staining. Apoptosis level was counted with the use of Hoechst 33258 dye. Lactate content in the tumor tissue was evaluated by enzyme method with the use of lactate dehydrogenase. Reactive oxygen species was determined using 2.7-dichlorofluorescein diacetate. Effects of dichloroacetate (DCA) on the growth and metastasis of LLC/R9 were analyzed by routine procedures. Evaluation of DCA effect toward electron transport chain (ETC) components was performed using EPR. RESULTS: It has been shown that at the conditions of lactacidosis and glucose deficiency, LLC/R9 cell viability in vitro was higher by 30% (p < 0.05) and apoptosis level was triply lower (p < 0.05) than these indices at the conditions of glucose deficiency only. In mice with transplanted LLC/R9 tumors treated for 3 weeks per os with DCA at the total dose of 1.5 g/kg of body weight starting from the next day after tumor transplantation, the primary tumor volume was just by 30% lower than that in control group. At the same time, the number and volume of lung metastases in animals treated with DCA were by 59% (p < 0.05) and 94% (p < 0.05) lower, respectively, than these indices in the control group. DCA treatment resulted in nearly 30% increase (p < 0.05) of lactate content in tumor tissue compared to that in the control, but did not affect significantly the levels of heme iron complexes with NO (at g med = 2.007) in mitochondrial ETC proteins and Fe-S cluster proteins (at g = 1.94) in tumor cells. CONCLUSIONS: It has been shown that lactacidosis significantly promoted LLC/R9 cell survival at the conditions of glucose deficiency in vitro. If LLC/R9 developed in vivo, DCA as the compound with antilactacidosis activity did not suppress significantly the primary tumor growth but exerted significant antimetastatic activity. PMID- 26112941 TI - Cytotoxic activity of immune cells following administration of xenogeneic cancer vaccine in mice with melanoma B-16. AB - AIM: To study the effects of xenogeneic cancer vaccine (XCV) developed on the basis of nervous tissue antigen from rat embryo of late gestation period and protein-containing metabolite of Bacillus subtilis with molecular weight of 70 kDa, on specific and unspecific antitumor reactions of cellular and humoral chains of immune system, and to analyze possible mechanisms of its antimetastatic action. MATERIALS AND METHODS: XCV was administered triply with 3-day intervals after surgical removal of experimental melanoma V-16 in C57Bl/6 mice. Cytotoxic activity (CTA) of splenocytes against target cells K-562 as well as CTA of splenocytes, peritoneal macrophages (PM) and blood serum against melanoma V-16 target cells were determined using MTT test. The content of circulating immune complexes (CIC) in blood serum was evaluated by precipitation reaction. RESULTS: Immunologic effects of XCV vaccination in experimental animals with surgically removed melanoma B-16 in comparison with similarly treated unvaccinated mice were as follows: prevention of medium molecular weight CIC accumulation in blood serum during all observation period, significant increase (r < 0.05) of CTA of effectors of unspecific antitumor immunity (natural killer cells - NK - by 25.5 +/- 1.7 vs 12.5 +/- 5.4%, and PM - by 37.3 +/- 0.6 vs 32.0 +/- 0.9%, respectively) at 37(th) day after the surgery, and also preservation of functional activity of specific cytotoxic lymphocytes at the level of intact control. CONCLUSION: The results of the study allow propose that antimetastatic effect of XCV vaccination could be based on increased CTA of NK and PM, and preservation of CTL functional activity at late terms after surgical removal of B 16 primary tumors. PMID- 26112942 TI - Prevention of myelosuppression by combined treatment with enterosorbent and granulocyte colony-stimulating factor. AB - Hematotoxicity and its complication are the prominent limiting factors for rational treatment of malignancies. Granulocyte colony-stimulating factor (G-CSF) is used to increase granulocyte production. It has been shown previously that enterosorption causes prominent myeloprotective activity also. Still, no trial was performed to combine both of them. AIM: To study the influence of combination of enterosorption and pharmaceutical analogue of naturally occurring G-CSF (filgrastim) on bone marrow protection and the growth of grafted tumor in a case of injection of melphalan (Mel). MATERIALS AND METHODS: Mel injections were used for promotion of bone marrow suppression in rats. Carbon granulated enterosorbent C2 (IEPOR) was used for providing of enteral sorption detoxifying therapy. Filgrastim was used to increase white blood cells (WBC) count. RESULTS: The simultaneous usage of enterosorption and filgrastim had maximum effectiveness for restoring of all types of blood cells. WBC count was higher by 138.3% compared with the Mel group. The increase of platelets count by 98.5% was also observed. In the group (Mel + C2 + filgrastim) the absolute neutrophils count was twofold higher, in comparison with rats of Mel group. CONCLUSION: Simultaneous administration of G-CSF-analogue and carbonic enterosorbent C2 is a perspective approach for bone marrow protection, when the cytostatic drug melphalan is used. Such combination demonstrates prominent positive impact on restoring of all types of blood cells and had no influence on the antitumor efficacy. PMID- 26112943 TI - Use of elastography for cervical cancer diagnostics. AB - The aim of the study was to investigate the use of elastography for cervical cancer diagnostics. MATERIALS AND METHODS: The ultrasonic study with use of sonoelastography involved 87 patients with cervical pathology (cervicitis, n = 11; dysplasia, n = 14; cervical cancer, n = 62). RESULTS: At non-malignant pathology elastic types of elastograms prevailed while the tumors were characterized by images of stiff type formations. Present study has demonstrated an effectiveness of sonoelastography for valuation of tumor process invasion levels. At detection of tumor invasion into parametrium, the test sensitivity increased from 77.1 to 91.4%, specificity - from 85.1 to 96.2%, accuracy - from 80.6 to 93.5%; in case of tumor invasion into vagina these parameters correspondently changed: from 75.0 to 83.3%, from 76.9 to 88.4%, from 75.8 to 85.4%, respectively; and in case of uterus: from 82.9 to 85.3%, from 85.7 to 95.2%, from 83.8 to 88.7%, respectively. CONCLUSIONS: Inclusion of elastography into ultrasound examination of cervical pathologies could significantly improve diagnostic quality of the method. PMID- 26112944 TI - Lapatinib-based therapy for women with advanced/metastatic HER2 positive breast cancer. AB - BACKGROUND: Lapatinib alone or in combination with other agents, mostly capecitabine is used for patients with advanced/metastatic HER2 positive breast cancer (HER2(+)BC) after progression on trastuzumab based therapy. Here we report our experience with lapatinib based therapy in this setting. MATERIAL AND METHODS: 67 consecutive patients received lapatinib based therapy. 58 (86.6%) received lapatinib + capecitabine (LC), 7 (10.4%) with other agents and 2 (3.0%) as single agent lapatinib. Data was collected from patients' records retrospectively. RESULTS: Objective response to lapatinib based therapy in 64 evaluable patients was 64.0% in all patients and 64.0% in patients who received LC. Median progression free survival and overall survival were 10 and 27 months in all patients and 10 and 17 months in patients who received LC, respectively. 16 (24.0%) patients had dose delay > 1 week and/or dose reduction. CONCLUSION: Lapatinib based therapy is an effective treatment for women with advanced/metastatic HER2(+)BC after prior exposure to trastuzumab. It yields meaningful response rates, progression free and overall survival. Some patients require dose adjustments. PMID- 26112945 TI - Effect of polyamine metabolism inhibitors on Lewis lung carcinoma growth and metastasis. AB - AIM: To study the influence of polyamine metabolism inhibitors on the growth, metastasis and ornithine decarboxylase (ODC) activity of Lewis lung carcinoma. MATERIALS AND METHODS: Experiments were performed on female mice C57Bl/6 with Lewis lung carcinoma. Nomega-hydroxy-nor-arginine (nor-NOHA) and alpha difluoromethylornithine (DFMO) were used as arginase and ODC inhibitors, correspondently. Inhibition of tumor growth was calculated by comparison of tumor volume in the treated and control groups. The average number of metastases per animal in the group and the average volume of pulmonary metastases per animal in the group have been determined. Determination of ODC - the key enzyme of the polyamine synthesis - in the samples of experimental tumors was performed by method of Luqman S. RESULTS: Administration of DFMO or it's combination with nor NOHA resulted in the decrease of tumor growth rate, number and volume of lung metastases and was accompanied with reduced ODC activity in tumor tissue. CONCLUSION: Modifiers of polyamine metabolism may be considered as promising targeted cancer therapy. PMID- 26112946 TI - Survival rates of familial and sporadic prostate cancer patients. AB - AIM: To compare cancer-specific survival rates for familial and sporadic prostate cancer patients. MATERIALS AND METHODS: Gleason score and age at diagnosis of familial group and sporadic group were compared by chi(2) and t-test. Cancer specific survival rates were analyzed by the Kaplan - Meier method and compared by log-rank test. Statistically significant level was set at p < 0.05. RESULTS: Among 1175 prostate cancer patients, familial group consisted of 215 (18.3%) patients, the sporadic group consisted of 960 (81.7%) patients. The familial group patient's mean age at diagnosis (58.9 years old, 95% confidence interval (CI) 57.8-60.1) was significantly younger than that of sporadic group patients (67.2 years old, 95% CI 66.7-67.6) (p < 0.0001). Comparing Gleason score between familial group and sporadic group revealed no statistically significant difference. The analysis showed that 92% (95% CI 0.88-0.97) of familial group patients had a 10-year cancer-specific survival rates, which was a significantly better outcome than that of sporadic group with 69% (95% CI 0.60-0.78) 10-year cancer-specific survival rates (p = 0.0237). CONCLUSION: The study data demonstrate statistically significant difference between familial group and sporadic group concerning age and cancer-specific survival rates, but not Gleason score. PMID- 26112947 TI - Paraganglioma-like dermal melanocytic tumor: a rare skin lesion. PMID- 26112948 TI - Valentyn Leonidovych Ganul. PMID- 26112949 TI - Sergiy Petrovych Osinsky (1945-2015). PMID- 26112950 TI - Rs7193343 polymorphism in zinc finger homeobox 3 (ZFHX3) gene and atrial fibrillation: an updated meta-analysis of 10 case-control comparisons. AB - BACKGROUND: The previous genome-wide studies have shown that rs7193343 single nucleotide polymorphism (SNP) in zinc finger homeobox 3 (ZFHX3) gene correlate with risk of atrial fibrillation (AF). However, the distribution of this SNP differs significantly among various populations. The present study was to investigate whether combined evidence shows the association between ZFHX3 rs7193343 SNP and the risk of AF in various populations. METHODS: A systematic search of all studies published through Dec 2014 was conducted using the Medline, Embase, WanFang, ScienceDirect, CNKI, and OVID databases. The case-control studies that evaluated an association between rs7193343 SNP and risk of AF were identified. The association between the ZFHX3 rs7193343 SNP and AF susceptibility was assessed using genetic models. RESULTS: We collected 10 comparisons from six studies for rs7193343 SNP, including 1037 cases and 4310 controls in Asian, 5583 cases and 38215 controls in Caucasian, and then performed an updated meta analysis and subgroup analysis based on ethnicity. In overall population, the occurrence of AF was found to be associated with T-allelic of rs7193343 SNP in ZFHX3 (OR =1.17, 95% CI 1.10-1.26). In subgroup analysis, we observed there was significant association between T-allele of rs7193343 and risk of AF in Caucasian subgroups (OR =1.20, 95% CI 1.12-1.30), but no statistically significance (OR = 1.07, 95% CI 0.92-1.24) in Asian population. CONCLUSION: In Caucasian population, genetic variant rs7193343 SNP is associated with risk of AF in Caucasian population. However, no association is found in Asian population based on the current evidence. Further studies with larger sample size involving case-control populations with multiple ethnics are still required in the future. PMID- 26112952 TI - High resolution map of caenorhabditis elegans gap junction proteins. PMID- 26112951 TI - The molecular mechanism of the effect of sulfur dioxide inhalation on the potassium and calcium ion channels in rat aortas. AB - This study investigated the molecular mechanism of the effect of sulfur dioxide (SO2) on the expression of adenosine triphosphate (ATP)-sensitive potassium ion (K(+); KATP) channel, big-conductance calcium ion (Ca(2+))-activated K(+) (BKCa) channel, and L-type (L-Ca(2+)) channel subunits in rat aortas with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The results showed that the messenger RNA and protein levels of the KATP channel subunits Kir6.1, Kir6.2, and sulfonylurea receptor 2B (SUR2B) of rat aortas were significantly increased by SO2 at 14 mg/m(3), whereas the levels of SUR2A were not changed. SO2 at all the treated concentrations markedly raised the expression of the BKCa channel subunits alpha and beta1. SO2 at 14 mg/m(3) significantly decreased the expression of the L-Ca(2+) channel Cav1.2 and Cav1.3. The histological examination of rat aorta tissues showed moderate injury of tunica media in the presence of SO2 at 14 mg/m(3). These suggest that SO2 can activate the KATP and BKCa channels by upregulating the expression of Kir6.1, Kir6.2, SUR2B, BKCa alpha, and BKCa beta1, while inhibit the L-Ca(2+) channels by downregulating the expression of Cav1.2 and Cav1.3 in rat aortas. The molecular mechanism of SO2-induced vasorelaxant effect might be linked to the changes in expression of these channel subunits, which plays an important role in the pathogenesis of SO2-associated cardiovascular diseases. PMID- 26112955 TI - On the feasibility of growth-coupled product synthesis in microbial strains. AB - Enforcing obligate coupling of growth with synthesis of a desired product has become a key principle for metabolic engineering of microbial production strains. Various methods from stoichiometric and constraint-based modeling have been developed to calculate intervention strategies by which a given microorganism can only grow if it synthesizes a desired compound as a mandatory by-product. However, growth-coupled synthesis is not necessarily feasible for every compound of a metabolic network and no rigorous criterion is currently known to test feasibility of coupled product and biomass formation (before searching for suitable intervention strategies). In this work, we show which properties a network must fulfill such that strain designs guaranteeing coupled biomass and product synthesis can exist at all. In networks without flux bounds, coupling is feasible if and only if an elementary mode exists that leads to formation of both biomass and product. Setting flux boundaries leads to more complicated inhomogeneous problems. Making use of the concept of elementary (flux) vectors, a generalization of elementary modes, a criterion for feasibility can also be derived for this situation. We applied our criteria to a metabolic model of Escherichia coli and determined for each metabolite, whether its net production can be coupled with biomass synthesis and calculated the maximal (guaranteed) coupling yield. The somewhat surprising result is that, under aerobic conditions, coupling is indeed possible for each carbon metabolite of the central metabolism. This also holds true for most metabolites under anaerobic conditions but consideration of ATP maintenance requirements implies infeasibility of coupling for certain compounds. On the other hand, ATP maintenance may also increase the maximal coupling yield for some metabolites. Overall, our work provides important insights and novel tools for a central problem of computational strain design. PMID- 26112956 TI - An ensemble-guided approach identifies ClpP as a major regulator of transcript levels in nitric oxide-stressed Escherichia coli. AB - The importance of NO(?) to immunity is highlighted by the diversity of pathogens that require NO(?)-defensive systems to establish infections. Proteases have been identified to aid pathogens in surviving macrophage attack, inspiring us to investigate their role during NO(?) stress in Escherichia coli. We discovered that the elimination of ClpP largely impaired NO(?) detoxification by E. coli. Using a quantitative model of NO(?) stress, we employed an ensemble-guided approach to identify the underlying mechanism. Iterations of in silico analyses and corresponding experiments identified the defect to result from deficient transcript levels of hmp, which encodes NO(?) dioxygenase. Interestingly, the defect was not confined to hmp, as DeltaclpP imparted widespread perturbations to the expression of NO(?)-responsive genes. This work identified a target for anti infective therapies based on disabling NO(?) defenses, and demonstrated the utility of model-based approaches for exploring the complex, systems-level stress exerted by NO(?). PMID- 26112957 TI - The influence of chronic health problems and work-related factors on loss of paid employment among older workers. AB - BACKGROUND: With an ageing society and increasing retirement ages, it is important to understand how employability can be promoted in older workers with health problems. The current study aimed to determine whether (1) different chronic health problems predict transitions from paid employment to disability benefits, unemployment and early retirement, and (2) how work-related factors modify these associations. METHODS: Self-report questionnaire data was used from the Dutch longitudinal Study on Transitions in Employment, Ability and Motivation with 3 years of follow-up (2010-2013), among employees aged 45-64 years (N=8149). The influence of baseline chronic health problems and work-related factors on transitions from paid employment to disability benefits, unemployment and early retirement during follow-up was estimated in a competing risks proportional hazards model. Relative excess risk of transitions due to the interaction between chronic health problems and work-related factors was assessed. RESULTS: Severe headache, diabetes mellitus and musculoskeletal, respiratory, digestive and psychological health problems predicted an increased risk of disability benefits (HR range 1.78-2.79). Circulatory (HR=1.35) and psychological health problems (HR=2.58) predicted unemployment, and musculoskeletal (HR=1.23) and psychological health problems (HR=1.57) predicted early retirement. Work-related factors did not modify the influence of health problems on unemployment or early retirement. Psychosocial work-related factors, especially autonomy, modified the influence of health problems on disability benefits. Specifically, among workers with health problems, higher autonomy, higher support and lower psychological job demands reduced the risk of disability benefits by 82%, 49%, and 11%, respectively. CONCLUSIONS: All health problems affected disability benefits to a similar extent, but psychological health problems especially predicted unemployment and early retirement. For older workers with health problems, promoting an optimal work environment has the potential to contribute to sustainable employment. PMID- 26112958 TI - Expression and significance of cortactin and HDAC6 in human prostatic foamy gland carcinoma. AB - Cortactin, the cytoplasmic substrate of HDAC6, is known to play an actin cytoskeletal regulatory role which is implicated in the motility of cancer cells, and thus in cancer progression. Its activity is found to be regulated by HDAC6. However, the significance of cortactin and HDAC6 remains unclear in uncommon histologic variant human prostatic foamy gland carcinoma (PfCa). In this study, we aimed to identify the expression and potential role of cortactin and HDAC6 in PfCa. Therefore, 16 PfCa specimens containing 48 foci with distinctive lesions were collected to identify the status of cortactin and HDAC6 by immunohistochemistry. Their correlation between clinicopathological characteristics and prognostic values were further analysed. The effect of cortactin and HDAC6 on prostate cancer cell migration and invasion was then evaluated in IA8 cells. The results showed that expression of cortactin and HDAC6 was significantly higher in PfCa foci, compared to that of high-grade prostatic intraepithelial neoplasia (HGPIN) foci and benign foci (P < 0.05). Cortactin and HDAC6 were associated with poor prognosis of patients with PfCa (P < 0.05). Multivariable Cox regression analysis showed HDAC6 level was a significant prognostic factor for survival of patients with PfCa (beta = 1.200, Wald value = 7.282, P = 0.007, 95% CI = 1.389-7.941, P < 0.01, beta > 0). Both knocking down cortactin and inhibition of HDAC6 activity with tubacin reduced in vitro migration and invasion ability of IA8 cells substantially. Furthermore, HDAC6 has prognostic value for patients with PfCa. Dysregulation of cortactin and HDAC6 is implicated in the invasiveness and migration of prostate cancer cells. PMID- 26112959 TI - Clinical and Molecular Cytogenetic Characterization of a de novo Interstitial 1p31.1p31.3 Deletion in a Boy with Moderate Intellectual Disability and Severe Language Impairment. AB - Interstitial 1p deletions are rare events. Very few cases of 1p31.1p31.3 deletions characterized by variable phenotypes have been reported. No clear genotype-phenotype correlation has been determined yet. We present a child with a de novo interstitial 1p31.1p31.3 deletion, identified by array CGH, associated with intellectual disability and severe language impairment. The deleted region contains 20 OMIM genes, but we focused on GADD45A (MIM 126335; growth arrest- and DNA damage-inducible gene), LRRC7 (MIM 614453; leucine-rich repeat-containing protein 7), and NEGR1 (MIM 613173; neuronal growth regulator 1). We discuss whether these genes play a role in determining the phenotype of our patient in order to investigate the possibility of a genotype-phenotype correlation. PMID- 26112961 TI - Microbiological assay for the analysis of certain macrolides in pharmaceutical dosage forms. AB - Clarithromycin (CLA) and roxithromycin (ROX) are macrolide antibiotics with an expanded spectrum of activity that are commercially available as tablets. A microbiological assay, applying the cylinder-plate method and using a strain of Micrococcus luteus ATCC 9341 as test organism, has been used and validated for the quantification of two macrolide drugs; CLA and ROX in pure and pharmaceutical formulations. The validation of the proposed method was carried out for linearity, precision, accuracy and specificity. The linear dynamic ranges were from 0.1 to 0.5MUg/mL for both compounds. Logarithmic calibration curve was obtained for each macrolide (r>0.989) with statistically equal slopes varying from 3.275 to 4.038, and a percentage relative standard deviation in the range of 0.24-0.92%. Moreover, the method was applied successfully for the assay of the studied drugs in pharmaceutical tablet dosage forms. Recovery from standard addition experiments in commercial products was 94.71-96.91% regarding clarithromycin and 93.94-98.12% regarding roxithromycin, with a precision (%RSD) 1.32-2.11%. Accordingly, this microbiological assay can be used for routine quality control analysis of titled drugs in tablet formulations. PMID- 26112962 TI - [Familial severe hypertrophic cardiomyopathy and sudden cardiac death]. PMID- 26112960 TI - Characterisation of Dermanyssus gallinae glutathione S-transferases and their potential as acaricide detoxification proteins. AB - BACKGROUND: Glutathione S-transferases (GSTs) facilitate detoxification of drugs by catalysing the conjugation of the reduced glutathione (GSH) to electrophilic xenobiotic substrates and therefore have a function in multi-drug resistance. As a result, knowledge of GSTs can inform both drug resistance in, and novel interventions for, the control of endo- and ectoparasite species. Acaricide resistance and the need for novel control methods are both pressing needs for Dermanyssus gallinae, a highly economically important haematophagous ectoparasite of poultry. METHODS: A transcriptomic database representing D. gallinae was examined and 11 contig sequences were identified with GST BlastX identities. The transcripts represented by 3 contigs, designated Deg-GST-1, -2 and -3, were fully sequenced and further characterized by phylogenetic analysis. Recombinant versions of Deg-GST-1, -2 and -3 (rDeg-GST) were enzymically active and acaricide binding properties of the rDeg-GSTs were established by evaluating the ability of selected acaricides to inhibit the enzymatic activity of rDeg-GSTs. RESULTS: 6 of the identified GSTs belonged to the mu class, followed by 3 kappa, 1 omega and 1 delta class molecules. Deg-GST-1 and -3 clearly partitioned with orthologous mu class GSTs and Deg-GST-2 partitioned with delta class GSTs. Phoxim, permethrin and abamectin significantly inhibited rDeg-GST-1 activity by 56, 35 and 17% respectively. Phoxim also inhibited rDeg-2-GST (14.8%) and rDeg-GST-3 (20.6%) activities. CONCLUSIONS: Deg-GSTs may have important roles in the detoxification of pesticides and, with the increased occurrence of acaricide resistance in this species worldwide, Deg-GSTs are attractive targets for novel interventions. PMID- 26112963 TI - Chrysin attenuates cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity. AB - Chrysin (CHR) is a natural flavonoid and is present in high concentration in honey, propolis and many plant extracts. The aim of the present study was to evaluate the effects of CHR to reduce cardiomyocyte apoptosis and loss of intermediate filaments in a mouse model of mitoxantrone cardiotoxicity. Morphology of the cardiomyocytes was determined by optic and transmission electron microscopy and biochemistry methods. The expression of Bcl-2, Bax and Caspase-3 were assessed by immunofluorecence. Tunel assay was used to assess apoptosis in cardiomyocytes. In addition, the distribution of desmin protein was evaluated using immunohistochemistry. Our results show that MTX treatment significantly increased serum levels of creatine kinase isoenzyme (CK-MB), indicator of cardiac injury and withdrawn under CHR protection. Expression levels of Bcl-2 decreased, while those of Bax and caspase-3 increased following MTX treatment. 50 mg/kg of daily CHR intake reduced Bax and caspase-3 immunopositivity and restored Bcl-2 levels to a value comparable to the control. TUNEL (+) cardiomyocyte nuclei of MTX group showed typical signs of apoptosis which almost completely disappeared in response to 50 mg/kg CHR treatment. In parallel, an irregular distribution and a weak expression of desmin is associated with MTX induced cardiotoxic effects which was also restored by CHR treatment. In conclusion chrysin inhibits MTX-triggered cardiomyocyte apoptosis via multiple pathways, including decrease of the Bax/Bcl-2 ratio and caspase-3 expression along with preservation of the desmin disarray. PMID- 26112964 TI - Clinical factors indicating short nasal bone overlap. AB - CONCLUSION: It is important to take adequate precautions when performing septoplasty for elderly patients. OBJECTIVE: Septoplasty is the treatment of choice for deviation of the nasal septum. Saddle nose is a rare complication caused by damage to the keystone area. In this area, the nasal bone overlaps the upper lateral cartilages, so careful attention is needed when performing septoplasty to patients with short nasal bone overlap. Therefore, the factors associated with short nasal bone overlap were investigated to allow adequate precautions to be taken during surgery. METHOD: Computed tomography (CT) including the paranasal sinus region was performed in 177 patients. Data including sex, age, and the primary disease were obtained from their medical records. The degree of septal deviation and the bone overlap distance in the midline were measured using CT. RESULT: It was found that advancing age was significantly associated with shorter bone overlap distance in the midline. There was no significant association between the degree of septal deviation and nasal bone overlap distance in the midline. Furthermore, there was no significant difference in the overlap distance between nasal sinus diseases and other diseases, and between sexes. PMID- 26112965 TI - Phylogenetic Analysis Supports a Link between DUF1220 Domain Number and Primate Brain Expansion. AB - The expansion of DUF1220 domain copy number during human evolution is a dramatic example of rapid and repeated domain duplication. Although patterns of expression, homology, and disease associations suggest a role in cortical development, this hypothesis has not been robustly tested using phylogenetic methods. Here, we estimate DUF1220 domain counts across 12 primate genomes using a nucleotide Hidden Markov Model. We then test a series of hypotheses designed to examine the potential evolutionary significance of DUF1220 copy number expansion. Our results suggest a robust association with brain size, and more specifically neocortex volume. In contradiction to previous hypotheses, we find a strong association with postnatal brain development but not with prenatal brain development. Our results provide further evidence of a conserved association between specific loci and brain size across primates, suggesting that human brain evolution may have occurred through a continuation of existing processes. PMID- 26112966 TI - Comparative Analysis of the Shared Sex-Determination Region (SDR) among Salmonid Fishes. AB - Salmonids present an excellent model for studying evolution of young sex chromosomes. Within the genus, Oncorhynchus, at least six independent sex chromosome pairs have evolved, many unique to individual species. This variation results from the movement of the sex-determining gene, sdY, throughout the salmonid genome. While sdY is known to define sexual differentiation in salmonids, the mechanism of its movement throughout the genome has remained elusive due to high frequencies of repetitive elements, rDNA sequences, and transposons surrounding the sex-determining regions (SDR). Despite these difficulties, bacterial artificial chromosome (BAC) library clones from both rainbow trout and Atlantic salmon containing the sdY region have been reported. Here, we report the sequences for these BACs as well as the extended sequence for the known SDR in Chinook gained through genome walking methods. Comparative analysis allowed us to study the overlapping SDRs from three unique salmonid Y chromosomes to define the specific content, size, and variation present between the species. We found approximately 4.1 kb of orthologous sequence common to all three species, which contains the genetic content necessary for masculinization. The regions contain transposable elements that may be responsible for the translocations of the SDR throughout salmonid genomes and we examine potential mechanistic roles of each one. PMID- 26112969 TI - Sexual Violence Among Middle School Students: The Effects of Gender and Dating Experience. AB - Sexual violence has been increasingly recognized as a social, rather than strictly individual or family, problem. Unfortunately, providers and policymakers remain divided on the scope and causes of sexual violence, which limits their capacity to develop theory- and evidence-based responses. Such limitations are particularly pronounced in regards to children and adolescents. These youth are rarely addressed in the literature, and when they are, scholars tend to focus on adult victimization of children rather than children's victimization of their peers. This study investigates the prevalence of unwanted sexual contact among middle students. Data are from a sample of 1,371 students attending New York City public middle schools. Drawing from current antiviolence curricula and scholarly literature on sexual violence, gender and dating experience are used as predictors of victimization and perpetration; race, age, and prior exposure to antiviolence programming are included as controls. Data reveal that, while boys' violence towards girls comprises a substantial proportion of sexual violence in this population, same-sex violence and girls' violence towards boys are also prevalent. Analyses conclude with recommendations for future antiviolence programming based on these patterns. PMID- 26112970 TI - The Value of Incorporating Measures of Relationship Concordance When Constructing Profiles of Intimate Partner Homicides: A Descriptive Study of IPH Committed Within London, 1998-2009. AB - This article presents a profile of intimate partner homicides (IPH) committed within London incorporating a gendered comparison of the perpetrators' relationships. Data was sourced from the original police files for offenses committed in the capital between 1998 and 2009 ( N = 207; 173 male and 34 female perpetrators). In common with other international descriptive studies, the results indicate comparative differences between partners according to perpetrator gender in terms of age profiles, employment status, experience of mental health issues, intoxication at time of killing, and possession of criminal convictions. Gender-based IPH descriptive studies have tended to focus on a collation of either victim or perpetrator or relationship characteristics, often in isolation from one another. Assessments of how parties interact within fatal relationships are invariably absent, and yet, it is the relationship that forms the backdrop against which the fatal acts are perpetrated. This study, therefore, not only provides an insight into the profile of IPH committed within London where none had previously existed but also demonstrates the advantages of incorporating relationship concordance measures. The inclusion of such measures when researching IPH assists homicide investigators in understanding the dynamics taking place within the cohort of fatal relationships they police. It also provides researchers a useful platform to enhance understanding of this crucial aspect, for it is the relationship itself which is what defines IPH and distinguishes as a unique subset of homicide. PMID- 26112968 TI - Modulation of the molecular spintronic properties of adsorbed copper corroles. AB - The ability to modulate the spin states of adsorbed molecules is in high demand for molecular spintronics applications. Here, we demonstrate that the spin state of a corrole complex can be tuned by expanding its fused ring as a result of the modification to the d-pi interaction between the metal and ligand. A bicyclo[2.2.2]octadiene-fused copper corrole can readily be converted into a tetrabenzocorrole radical on an Au(111) substrate during the sublimation process. In the scanning tunnelling spectroscopy spectrum, a sharp Kondo resonance appears near the Fermi level on the corrole ligand of the tetrabenzocorrole molecule. In contrast, a non-fused-ring-expanded copper corrole molecule, copper 5,10,15 triphenylcorrole, shows no such Kondo feature. Mapping of the Kondo resonance demonstrates that the spin distribution of the tetrabenzocorrole molecule can be further modified by the rotation of the meso-aryl groups, in a manner that could lead to applications in molecular spintronics. PMID- 26112971 TI - Adverse Childhood Experiences Among Immigrants to the United States. AB - A growing number of studies have examined the "immigrant paradox" with respect to health behaviors in the United States. However, little research attention has been afforded to the study of adverse childhood experiences (ACE; neglect, physical and sexual abuse, and witnessing violence) among immigrants in the United States. The present study, using Waves I and II data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC), aims to address these gaps by comparing forms of ACE of first- and second-generation immigrants with native-born American adults in the United States. We also examined the latent structure of ACE among immigrants and conducted analyses to assess the psychiatric correlates of identified latent classes. With the exception of neglect, the prevalence of ACE was markedly higher among native-born Americans and second-generation immigrants compared with first-generation immigrants. Four latent classes were identified-limited adverse experience ( n = 3,497), emotional and physical abuse ( n = 1,262), family violence ( n = 358), and global adversity ( n = 246). The latter three classes evinced greater likelihood of being diagnosed with a mood, anxiety, personality, and substance use disorder, and to report violent and non-violent antisocial behavior. Consistent with prior research examining the associations between the immigrant paradox and health outcomes, results suggest that first-generation immigrants to the United States are less likely to have experienced physical and sexual abuse and witness domestic violence. However, likely due to cultural circumstances, first generation immigrants were more likely to report experiences that are deemed neglectful by Western standards. PMID- 26112967 TI - How Did Arthropod Sesquiterpenoids and Ecdysteroids Arise? Comparison of Hormonal Pathway Genes in Noninsect Arthropod Genomes. AB - The phylum Arthropoda contains the largest number of described living animal species, with insects and crustaceans dominating the terrestrial and aquatic environments, respectively. Their successful radiations have long been linked to their rigid exoskeleton in conjunction with their specialized endocrine systems. In order to understand how hormones can contribute to the evolution of these animals, here, we have categorized the sesquiterpenoid and ecdysteroid pathway genes in the noninsect arthropod genomes, which are known to play important roles in the regulation of molting and metamorphosis in insects. In our analyses, the majority of gene homologs involved in the biosynthetic, degradative, and signaling pathways of sesquiterpenoids and ecdysteroids can be identified, implying these two hormonal systems were present in the last common ancestor of arthropods. Moreover, we found that the "Broad-Complex" was specifically gained in the Pancrustacea, and the innovation of juvenile hormone (JH) in the insect linage correlates with the gain of the JH epoxidase (CYP15A1/C1) and the key residue changes in the binding domain of JH receptor ("Methoprene-tolerant"). Furthermore, the gain of "Phantom" differentiates chelicerates from the other arthropods in using ponasterone A rather than 20-hydroxyecdysone as molting hormone. This study establishes a comprehensive framework for interpreting the evolution of these vital hormonal pathways in these most successful animals, the arthropods, for the first time. PMID- 26112972 TI - The Reactive-Proactive Aggression Questionnaire: Validation Among a Portuguese Sample of Incarcerated Juvenile Delinquents. AB - The aim of the present study was to examine the psychometric properties of the Reactive-Proactive Aggression Questionnaire (RPQ) among a forensic sample of incarcerated male juvenile offenders ( N = 221). The Portuguese version of the RPQ demonstrated promising psychometric properties, namely, in terms of factor structure, internal consistency, convergent validity, discriminant validity, and concurrent validity that generally justifies its use among this population. Statistically significant associations were found with conduct disorder, age of criminal onset, age of first problem with the law, crime seriousness, physical violence use in committing crimes, alcohol use, cannabis use, cocaine/heroin use, and having unprotected sex. The findings provide additional support for the extension of the RPQ across different cultures, ethnic groups, and samples. PMID- 26112973 TI - Track My Health: a mobile application that allows patients to monitor their health. PMID- 26112974 TI - How Normal is a 'Normal' Heart in Fetuses and Infants with Down Syndrome? AB - BACKGROUND: Congenital heart disease is present in 44-56% of fetuses with Down syndrome (DS). There are, however, signs that hearts in DS without apparent structural heart defects also differ from those in the normal population. We aimed to compare the atrioventricular (AV) septum and valves in 3 groups: DS without AV septal defect (DS no-AVSD), DS with AVSD (DS AVSD) and control hearts. METHODS: The ventricular septum, membranous septum and AV valves were examined and measured in histological sections of 15 DS no-AVSD, 8 DS AVSD and 34 control hearts. In addition, the ventricular septum length was measured on ultrasound images of fetal (6 DS AVSD, 9 controls) and infant (10 DS no-AVSD, 10 DS AVSD, 10 controls) hearts. RESULTS: The membranous septum was 3 times larger in DS no-AVSD fetuses compared to control fetuses, and valve dysplasia was frequently (64%) observed. The ventricular septum was shorter in patients with DS both with and without AVSD, as compared to the control group. CONCLUSION: DS no-AVSD hearts are not normal as they have a larger membranous septum, shorter ventricular septum and dysplasia of the AV valves as compared to control hearts. PMID- 26112975 TI - Optimizing parameters of an open-source airway segmentation algorithm using different CT images. AB - BACKGROUND: Computed tomography (CT) helps physicians locate and diagnose pathological conditions. In some conditions, having an airway segmentation method which facilitates reconstruction of the airway from chest CT images can help hugely in the assessment of lung diseases. Many efforts have been made to develop airway segmentation algorithms, but methods are usually not optimized to be reliable across different CT scan parameters. METHODS: In this paper, we present a simple and reliable semi-automatic algorithm which can segment tracheal and bronchial anatomy using the open-source 3D Slicer platform. The method is based on a region growing approach where trachea, right and left bronchi are cropped and segmented independently using three different thresholds. The algorithm and its parameters have been optimized to be efficient across different CT scan acquisition parameters. The performance of the proposed method has been evaluated on EXACT'09 cases and local clinical cases as well as on a breathing pig lung phantom using multiple scans and changing parameters. In particular, to investigate multiple scan parameters reconstruction kernel, radiation dose and slice thickness have been considered. Volume, branch count, branch length and leakage presence have been evaluated. A new method for leakage evaluation has been developed and correlation between segmentation metrics and CT acquisition parameters has been considered. RESULTS: All the considered cases have been segmented successfully with good results in terms of leakage presence. Results on clinical data are comparable to other teams' methods, as obtained by evaluation against the EXACT09 challenge, whereas results obtained from the phantom prove the reliability of the method across multiple CT platforms and acquisition parameters. As expected, slice thickness is the parameter affecting the results the most, whereas reconstruction kernel and radiation dose seem not to particularly affect airway segmentation. CONCLUSION: The system represents the first open-source airway segmentation platform. The quantitative evaluation approach presented represents the first repeatable system evaluation tool for like-for-like comparison between different airway segmentation platforms. Results suggest that the algorithm can be considered stable across multiple CT platforms and acquisition parameters and can be considered as a starting point for the development of a complete airway segmentation algorithm. PMID- 26112976 TI - Preparation and Characterization of Monomodal Grapevine Virus A Capsid Protein. AB - Grapevine virus A (GVA), a flexible filament of approximately 800 nm in length is composed of capsid subunits that spontaneously assembles around a positive sense genomic RNA. In addition to encapsidation, plant viruses capsid proteins (CPs) participate in other processes throughout infection and GVA CP is involved in cell-to-cell translocation of the virus. A protocol was developed to obtain low molecular weight GVA-CP that is not prone to aggregation and spontaneous assembly and this was characterized by circular dichroism and dynamic light scattering. These results indicate the suitably of GVA-CP for X-ray crystallographic and NMR studies that should lead to the elucidation of the first three-dimensional structure of a flexible filamentous virus from the Betaflexiviridae family. PMID- 26112977 TI - Phosphoproteins with Stability Against All Urinary Phosphatases as Potential Biomarkers in Urine. AB - Urine, by accumulating all kinds of changes, was proposed to be a better source for biomarker discovery. As one of the most common post-translational modifications, phosphorylation plays a vital role in many biological activities. However, the urine phosphoproteome has been largely neglected due to the low abundance of phosphoproteins and the presence of various phosphatases in urine. The low level of background phosphorylation in urine is actually advantageous, as urinary phosphopeptides/proteins that are stable to the phosphatases present in urine have the potential to serve as valuable disease biomarkers. Using a TiO2 enrichment strategy, this study aimed to create a comprehensive proteomic profile of human urinary phosphoproteins and to characterize the changes in the urine phosphoproteome after incubation of urine with renal carcinoma cell lysates. In total, 106 urine phosphorylation sites corresponding to 64 proteins, including 80 previously unidentified human urine protein phosphorylation sites, were identified by mass spectrometry. Fifteen phosphopeptides, together averaging 47% of the total phosphopeptides, were found in samples from three individuals. Cellular proteins are potential source of biomarker in urine phosphorylated proteins. Addition of renal carcinoma cellular proteins to urine did not significantly change the phosphorylation level of urine proteins. But there were still a few phosphopeptides from cell lysates survived urinary phosphatases; such phosphopeptides represent potential biomarkers in urine. PMID- 26112978 TI - Construction and long term preservation of clonal transgenic silkworms using a parthenogenetic strain. AB - For the functional analysis of insect genes as well as for the production of recombinant proteins for biomedical use, clonal transgenic silkworms are very useful. We examined if they could be produced in the parthenogenetic strain that had been maintained for more than 40years as a female line in which embryogenesis is induced with nearly 100% efficiency by a heat shock treatment of unfertilized eggs. All individuals have identical female genotype. Silkworm transgenesis requires injection of the DNA constructs into the non-diapausing eggs at the preblastodermal stage of embryogenesis. Since our parthenogenetic silkworms produce diapausing eggs, diapause programing was eliminated by incubating ovaries of the parthenogenetic strain in standard male larvae. Chorionated eggs were dissected from the implants, activated by the heat shock treatment and injected with the transgene construct. Several transgenic individuals occurred in the daughter generation. Southern blotting analysis of two randomly chosen transgenic lines VTG1 and VTG14 revealed multiple transgene insertions. Insertions found in the parental females were transferred to the next generation without any changes in their sites and copy numbers, suggesting that transgenic silkworms can be maintained as clonal strains with homozygous transgenes. Cryopreservation was developed for the storage of precious genotypes. As shown for the VTG1 and VTG14 lines, larval ovaries can be stored in DMSO at the temperature of liquid nitrogen, transferred to Grace's medium during defrosting, and then implanted into larvae of either sex of the standard silkworm strains C146 and w1-pnd. Chorionated eggs, which developed in the implants, were dissected and activated by the heat shock to obtain females (nearly 100% efficiency) or by a cold shock to induce development to both sexes in 4% of the eggs. It was then possible to establish bisexual lines homozygous for the transgene. PMID- 26112979 TI - The prevalence of Type 2 diabetes and related complications in a nationally representative sample of adults aged 50 and over in the Republic of Ireland. AB - AIM: To investigate the prevalence of diagnosed Type 2 diabetes and its related complications in a nationally representative sample of older adults in the Republic of Ireland. METHODS: Cross-sectional analysis of a population-based sample of adults aged >= 50 years from the first wave of The Irish Longitudinal Study on Ageing (TILDA), (2009-2011). Diagnosed Type 2 diabetes prevalence was estimated by self-report or the use of oral hypoglycaemic agents. The prevalence of microvascular and macrovascular complications was determined by self-report. RESULTS: Diagnosed Type 2 diabetes prevalence was 8.4% [95% confidence interval (CI): 7.8-9.0%] and was higher among men [10.3% (95% CI: 9.4-11.2%)] than women [6.6% (95% CI: 5.9-7.5%)]; P <= 0.001. Among participants with diagnosed Type 2 diabetes, the overall prevalence of microvascular complications was 26.0% (95% CI: 22.4-30.0%) with no evidence of gender-specific differences (P = 0.7). The overall prevalence of macrovascular complications was 15.1% (95% CI: 12.2-18.4%) and was higher among men [17.8% (95% CI: 14.3-23.1%)] than women [11.4% (95% CI: 7.7-16.4%)]; P <= 0.001. CONCLUSIONS: In the absence of a national diabetes register, these findings provide a robust estimate of the national prevalence of diagnosed Type 2 diabetes and level of complications among adults aged 50 years and over in Ireland. PMID- 26112980 TI - Hyperglycemia and liver ischemia reperfusion injury: a role for the advanced glycation endproduct and its receptor pathway. AB - Although pretransplant diabetes is a risk factor for mortality post-liver transplant, the underlying mechanism has not been fully defined. In a murine liver partial warm ischemia model, we addressed the question of how diabetes/hyperglycemia impacted tissue inflammatory injuries against ischemia reperfusion (IR), focusing on the advanced glycation endproduct (AGE) and its receptor (RAGE) pathway. Our results showed that hepatocellular injury was exacerbated in streptozotocin-induced diabetic mice against IR, in association with hyper-inflammatory immune activation in livers. Serum levels of AGEs, but not HMGB1, were increased in diabetic mice in response to liver IR. Both RAGE antagonist peptides and small interfering RNA alleviated liver injuries and inhibited inflammatory immune activation against IR in diabetic, but not normal, mice. Kupffer cells (KCs)/macrophages, but not hepatocytes, from diabetic mice expressed significantly higher levels of RAGE, leading to their hyper inflammatory responsiveness to both TLR ligands and AGEs. In vitro, hyperglycemia increased macrophage RAGE expression and enhanced their TLR responses. Our results demonstrated that activation of the AGE-RAGE signaling pathway in KCs was responsible for hyper-inflammatory immune responses and exacerbated hepatocellular injuries in diabetic/hyperglycemic hosts against liver IR. PMID- 26112981 TI - [Clinical assessment of olfactory performance - why patient interviews are not enough : A report on lessons learned in planning studies with anosmic patients]. AB - BACKGROUND AND AIM: Olfactory dysfunction and loss of smell are mostly associated with an immense decrease in the quality of life. The aim of the presented study was to report on particularities in the acquisition of patients with olfactory dysfunction. METHODS: During July 2011 and May 2014 we were contacted by 300 potential patients with self-reported loss of smell, 95 (54 female, 41 male, mean age 53) of which were invited for clinical testing after phone interviews. RESULTS: Clinical smell testing revealed 46 patients with anosmia, 38 with hyposmia, and 11 with normosmia. Self-assessment of olfactory function only correlated with clinical scores if patients had nearly no olfactory function left. The ability of self-assessment of olfactory function was independent of age or sex. Further, most patients were not able to report on the reason for or the duration of their olfactory dysfunction. DISCUSSION: Our report shows that patients with olfactory dysfunction are hardly ever ably to assess their grade of performance reduction. Awareness among patients with a reduced sense of smell is of great general importance, since it can be an indicator of neurodegenerative diseases. This should especially be noted for patients older than 50 who are not able to indicate a reason for their loss of smell. PMID- 26112982 TI - The End of the International Reference Pricing System? AB - All 28 EU member states except Sweden and the UK apply international reference pricing (IRP), international price comparison, external reference pricing or cross-reference pricing. The attractiveness of using prices of other countries as a benchmark for decisions within a national price control is obvious. Alternative models for price and reimbursement decision making such as value-based pricing (VBP), i.e. cost-effectiveness analyses, are more complicated. However, IRP provides incentives for stakeholders to take action not in line with optimal (welfare-maximizing) pricing. IRP is costly for two reasons. First, manufacturers are incentivised to limit or delay access to new innovative treatments in countries with small markets and/or a low income, which can be costly in terms of loss of health. Second, all countries also experience a loss of welfare (health) because IRP reduces the opportunities for differential pricing (Ramsey pricing), i.e. using the fact that the ability and willingness to pay differs between countries. Thus, IRP results in less sales revenue to finance research and development of new innovative drugs. We can now observe that payers and manufacturers are engaged in different types of risk-sharing schemes, price volume negotiations, payback arrangements, confidential discounts, coverage with evidence developments, etc., all with the purpose of returning to the old model of price discrimination and Ramsey pricing. Shortly, real prices for use in IRP systems will cease to exist and, thus, we expect to soon see the end of IRP, a new system for price discrimination and an increasing demand for VBP. PMID- 26112983 TI - The contribution of PCR testing to influenza and pertussis notifications in Australia. AB - Influenza and pertussis are the two most common vaccine-preventable infections notified in Australia. We assessed the role of polymerase chain reaction (PCR) diagnosis in influenza and pertussis cases notified to the Australian National Notifiable Diseases Surveillance System (NNDSS). There were a total of 2 10 786 notified influenza cases (2001-2013) and 2 55 866 notified pertussis cases (1991 2013). After 1 January 2007, the majority of influenza and pertussis notifications were PCR-based (80.5% and 59.6%, respectively). Before 31 December 2006, PCR-based notifications were limited (29.1% and 11.7%, respectively). By 2013, PCR-based notifications had largely replaced all other diagnostic methods, with the exception of serology-based notifications in pertussis cases in adults aged ? 25 years. PMID- 26112984 TI - Vasodilator stress with adenosine and the gender preponderance for tolerability and manifestation of adverse symptoms: Is there a physiological basis? PMID- 26112985 TI - Intensification of ammonia removal from waste water in biologically active zeolitic ion exchange columns. AB - The use of nitrification filters for the removal of ammonium ion from waste-water is an established technology deployed extensively in municipal water treatment, in industrial water treatment and in applications such as fish farming. The process involves the development of immobilized bacterial films on a solid packing support, which is designed to provide a suitable host for the film, and allow supply of oxygen to promote aerobic action. Removal of ammonia and nitrite is increasingly necessary to meet drinking water and discharge standards being applied in the US, Europe and other places. Ion-exchange techniques are also effective for removal of ammonia (as the ammonium ion) from waste water and have the advantage of fast start-up times compared to biological filtration which in some cases may take several weeks to be fully operational. Here we explore the performance of ion exchange columns in which nitrifying bacteria are cultivated, with the goal of a "combined" process involving simultaneous ion-exchange and nitrification, intensified by in-situ aeration with a novel membrane module. There were three experimental goals. Firstly, ion exchange zeolites were characterized and prepared for comparative column breakthrough studies for ammonia removal. Secondly effective in-situ aeration for promotion of nitrifying bacterial growth was studied using a number of different membranes including polyethersulfone (PES), polypropylene (PP), nylon, and polytetra-fluoroethylene (PTFE). Thirdly the breakthrough performance of ion exchange columns filled with zeolite in the presence of aeration and in the presence of nitrifying bacteria was determined to establish the influence of biomass, and aeration upon breakthrough during ammonium ion uptake. The methodology adopted included screening of two types of the naturally occuring zeolite clinoptilolite for effective ammonia removal in continuous ion-exchange columns. Next, the performance of fixed beds of clinoptilolite in the presence of nitrifying bacteria is compared to that in columns in which only ion exchange is occurring. The aeration performance of each of the chosen membranes was compared experimentally using a newly developed membrane support module which is also described. Comparison of ammonia removal in columns equipped with in-situ aeration using each membrane was undertaken and the breakthrough characteristics determined. The results showed that ammonia removal in the presence of the nitrifiers was significantly intensified. Column operation with membrane aeration showed further enhancement of ammonia removal. The greatest enhancement was observed in the case of the polyethersulfone membrane (PES). It is concluded that combined nitrification and ion-exchange is significantly intensified in packed columns by in-situ aeration using a novel membrane module. There is significant potential for extending the ion-exchange cycle time and thus potential cost reduction. PMID- 26112986 TI - The use of gene arrays and corresponding connectivity mapping (Cmap) to identify novel anti-ageing ingredients. AB - OBJECTIVE: The need for effective 'anti-ageing' treatments, in particular for the management of photodamaged skin, prompted us to develop a novel method to identify new active ingredients. The model utilized a gene profiling study with corresponding connectivity mapping (Cmap) to identify novel anti-ageing compounds using all-trans retinoic acid (RA) as the lead compound due to its beneficial effect on photodamaged skin and skin firmness. METHOD: A vehicle-controlled clinical study including nine healthy Caucasian female volunteers aged 57 +/- 7 (mean +/- SEM) exhibiting photodamage on their lower outer forearms was conducted. The volunteers applied RA once daily on photodamaged skin for 7 days, and biopsies were subjected to Affymetrix gene arrays. Connectivity mapping (Cmap), examining hundreds of gene expression profiles, was run on the gene signature of RA-treated photodamaged skin to identify small bioactive compounds. RESULTS: Affymetrix gene array identified 19 genes significantly differentially expressed after application of RA. Corresponding Cmap analysis revealed six natural bioactive compounds including N-acetyl aspartic acid (A-A-A) showing similar activity to RA on the differentially expressed genes identified. CONCLUSION: Based on RA mimicking gene array activity, potential use within skincare on molecular size, safety assessment and sourcing, we identified the natural amino acid, A-A-A as a potential candidate to treat ageing skin. PMID- 26112987 TI - cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle. AB - Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation. PMID- 26112988 TI - Oncogenic acidic nuclear phosphoproteins ANP32C/D are novel clients of heat shock protein 90. AB - The acidic nuclear phosphoproteins (ANP32A-H) are an evolutionarily conserved family of proteins with diverse and sometimes opposing cellular functions. Here we show that the oncogenic family members ANP32C and ANP32D are associated in complexes containing the molecular chaperone Hsp90. The oncogenic ANP32C protein appears to be highly unstable with a rapid degradation (t1/2>30 min) occurring upon treatment of cells with cycloheximide. ANP32C was also found to be associated with oncogenic Hsp90 complexes by virtue of its ability to interact and be immunoprecipitated by the Hsp90 inhibitor PU-H71. Further studies treating cells with the Hsp90 inhibitors PU-H71 and 17-AAG showed atypical increased protein stability and prevention of ANP32C degradation compared to the Hsp90 client AKT. Cells overexpressing ANP32C or its mutant ANP32CY140H showed enhanced sensitivity to treatment with PU-H71 as demonstrated by CCK-8 and colony formation assays. Our results highlight that certain malignancies with ANP32C/D overexpression or mutation might be specifically targeted using Hsp90 inhibitors. PMID- 26112989 TI - Cirrhotic Multiorgan Syndrome. AB - Patients with cirrhosis and portal hypertension are at an increased risk of the development of circulatory dysfunction that may potentially result in multiple organ failure. Apart from the liver, this may involve the heart, lungs, kidneys, the immune system, the adrenal glands, and other organ systems. As the disease progresses, the circulation becomes hyperdynamic, and signs of cardiac, pulmonary, and renal dysfunction are observed, in addition to reduced survival. Infections and an altered cardiac function known as cirrhotic cardiomyopathy may be precipitators for the development of other complications such as hepatorenal syndrome. In patients with chronic organ dysfunction, various precipitating events may induce an acute-on-chronic renal failure and acute-on-chronic liver failure that negatively affect the prognosis. Future research on the pathophysiologic mechanisms of the complications and the precipitating factors is essential to understand the basics of the treatment of these challenging conditions. The aim of the present review is to focus on the development and precipitating factors of various organ failures in patients with decompensated cirrhosis. PMID- 26112992 TI - Lung Involvement in Rheumatic Disease: Introduction. PMID- 26112990 TI - Interactions of Hepatitis B Virus Infection with Nonalcoholic Fatty Liver Disease: Possible Mechanisms and Clinical Impact. AB - Hepatitis B virus (HBV) infection is a major etiology of chronic liver disease worldwide. In the past decade, nonalcoholic fatty liver disease (NAFLD) has emerged as a common liver disorder in general population. Accordingly, the patient number of chronic hepatitis B (CHB) concomitant with NAFLD grows rapidly. The present article reviewed the recent studies aiming to explore the relationship between CHB and NAFLD from different aspects, including the relevant pathogenesis of CHB and NAFLD, the intracellular molecular mechanisms overlaying HBV infection and hepatic steatosis, and the observational studies with animal models and clinical cohorts for analyzing the coincidence of the two diseases. It is concluded that although numerous cross-links have been suggested between the molecular pathways in HBV infection and NAFLD pathogenesis, regarding whether HBV infection can substantially interfere with the occurrence of NAFLD or vice versa in the patients, there is still far from a conclusive agreement. PMID- 26112994 TI - Impact of type 2 diabetes on the gene expression of bone-related factors at sites receiving dental implants. AB - This study evaluated the influence of type 2 diabetes mellitus (T2DM) on the gene expression of bone-related factors in alveolar bone tissue from sites designated to receive dental implants. Bone biopsies were harvested from sites of planned implants for 19 systemically healthy patients and 35 patients with T2DM (17 with better-controlled T2DM (glycated haemoglobin (HbA1c) levels <=8%) and 18 with poorly controlled T2DM (HbA1c levels >8%)). The mRNA levels of tumour necrosis factor alpha, transforming growth factor beta, receptor activator of the nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), runt-related transcription factor 2, alkaline phosphatase, bone sialoprotein (BSP), type I collagen (COL-I), and osteocalcin were evaluated by quantitative real-time polymerase chain reaction. T2DM up-regulates RANKL levels and the ratio of RANKL/OPG, whereas it down-regulates COL-I and BSP expression (P<0.05). Higher mRNA levels of RANKL/OPG were observed in the poorly controlled T2DM patients compared to those with better-controlled T2DM and systemically healthy patients (P<0.05). A lower amount of COL-I and BSP was detected in the biopsies from individuals with poorly controlled T2DM compared to systemically healthy patients (P<0.05). In conclusion, RANKL, RANKL/OPG, COL-I, and BSP are negatively affected in diabetics. Additionally, the patient's glycaemic status appears to modulate bone related genes in a different manner. PMID- 26112991 TI - Fibrosis Regression Explains Differences in Outcome in HIV-/HCV-Coinfected Patients with Cirrhosis After Sustained Virological Response. AB - BACKGROUND AND AIMS: Fibrosis regression (FR) after sustained virological response (SVR) should produce a better outcome in hepatitis C (HCV)-/HIV coinfected patients with liver cirrhosis, but there are no specific data in this issue. METHODS: We compared the incidence rate (IR) and the time to develop a liver complication and death in 133 cirrhotic patients according to SVR or/and FR. RESULTS: Of 42 patients with SVR, 23 (55%) had FR, in comparison with only 14 of the 91 (15%) without SVR. During a follow-up of 6.8 years (916.8 person years), the IR of death, liver-related death, and liver-related complications were 2.45, 0.61, and 1.22 per 100 persons/year among SVR/FR, and 7.6, 5.9, and 6.81 among non-SVR without FR (p < 0.01), respectively. SVR patients without FR had also a lower rate of liver-related complications (1.78 vs 3.25; p = 0.02), but a worse IR of death (5.36) and liver-related death (2.68) than non-SVR patients with FR (1.3, and 0.65; p < 0.01). Moreover, FR was associated with less hospital admissions and decreasing alpha-fetoprotein levels. In Cox analysis, only FR was associated with a lower risk of death (adjusted hazard ratio, HR 0.36; 95% CI 0.15-0.86), and liver-related death (HR 0.15; 95% CI 0.03-0.65), whereas both FR (HR 0.09; 95% CI 0.03-0.3, p < 0.01) and SVR (HR 0.24; 95% CI 0.07-0.87) decreased the risk of liver-related complications. CONCLUSION: Fibrosis regression after SVR is associated with the highest reduction in death of any cause, liver-related mortality, and liver-related complications in HIV /HCV-coinfected patients with cirrhosis. PMID- 26112995 TI - No differences in morphological characteristics between hyperplastic condyle and class III condyle. AB - The aim of this research was to compare the condylar morphology of patients with unilateral condylar hyperplasia (UCH) and patients with a class III skeletal relationship using cone beam computed tomography (CBCT). A prospective study was conducted on patients with facial asymmetry attending the division of oral and maxillofacial surgery of the study university in Chile. Fifteen patients with UCH and 15 with a class III skeletal relationship were selected. Linear measurements of the condylar processes were obtained at a scale of 1:1 using the software Ez3D Viewer Plus. Analysis of variance (ANOVA) and the paired t-test were used, considering P<0.05. Patients with UCH presented statistical differences between the hyperplastic condyle and non-hyperplastic condyle for anteroposterior and mediolateral diameters, condylar neck length, and ramus height. Patients with a class III skeletal relationship showed no differences between the right and left sides; the morphology of their condyles was similar to the condyles with hyperplasia and presented statistical differences when compared with the non hyperplastic condyles (one-way ANOVA, P<0.05). The condylar morphology of UCH patients could be related to the development of a class III skeletal relationship. These findings provide an insight into the possibility of some class III patients presenting bilateral condylar hyperplasia. PMID- 26112996 TI - Amino Acids Attenuate Insulin Action on Gluconeogenesis and Promote Fatty Acid Biosynthesis via mTORC1 Signaling Pathway in trout Hepatocytes. AB - BACKGROUND/AIMS: Carnivores exhibit poor utilization of dietary carbohydrates and glucose intolerant phenotypes, yet it remains unclear what are the causal factors and underlying mechanisms. We aimed to evaluate excessive amino acids (AAs) induced effects on insulin signaling, fatty acid biosynthesis and glucose metabolism in rainbow trout and determine the potential involvement of mTORC1 and p38 MAPK pathway. METHODS: We stimulated trout primary hepatocytes with different AA levels and employed acute administration of rapamycin to inhibit mTORC1 activation. RESULTS: Increased AA levels enhanced the phosphorylation of ribosomal protein S6 kinase (S6K1), S6, and insulin receptor substrate 1 (IRS-1) on Ser(302) but suppressed Akt and p38 phosphorylation; up-regulated the expression of genes related to gluconeogenesis and fatty acid biosynthesis. mTORC1 inhibition not only inhibited the phosphorylation of mTORC1 downstream targets, but also blunted IRS-1 Ser(302) phosphorylation and restored excessive AAs-suppressed Akt phosphorylation. Rapamycin also inhibited fatty acid biosynthetic and gluconeogenic gene expression. CONCLUSION: High levels of AAs up regulate hepatic fatty acid biosynthetic gene expression through an mTORC1 dependent manner, while attenuate insulin-mediated repression of gluconeogenesis through elevating IRS-1 Ser(302) phosphorylation, which in turn impairs Akt activation and thereby weakening insulin action. We propose that p38 MAPK probably also involves in these AAs-induced metabolic changes. PMID- 26112997 TI - Development and applications of the LFDFT: the non-empirical account of ligand field and the simulation of the f-d transitions by density functional theory. AB - Ligand field density functional theory (LFDFT) is a methodology consisting of non standard handling of DFT calculations and post-computation analysis, emulating the ligand field parameters in a non-empirical way. Recently, the procedure was extended for two-open-shell systems, with relevance for inter-shell transitions in lanthanides, of utmost importance in understanding the optical and magnetic properties of rare-earth materials. Here, we expand the model to the calculation of intensities of f -> d transitions, enabling the simulation of spectral profiles. We focus on Eu(2+)-based systems: this lanthanide ion undergoes many dipole-allowed transitions from the initial 4f(7)((8)S7/2) state to the final 4f(6)5d(1) ones, considering the free ion and doped materials. The relativistic calculations showed a good agreement with experimental data for a gaseous Eu(2+) ion, producing reliable Slater-Condon and spin-orbit coupling parameters. The Eu(2+) ion-doped fluorite-type lattices, CaF2:Eu(2+) and SrCl2:Eu(2+), in sites with octahedral symmetry, are studied in detail. The related Slater-Condon and spin-orbit coupling parameters from the doped materials are compared to those for the free ion, revealing small changes for the 4f shell side and relatively important shifts for those associated with the 5d shell. The ligand field scheme, in Wybourne parameterization, shows a good agreement with the phenomenological interpretation of the experiment. The non-empirical computed parameters are used to calculate the energy and intensity of the 4f(7)-4f(6)5d(1) transitions, rendering a realistic convoluted spectrum. PMID- 26112998 TI - Successful Treatment of Primary Cutaneous Mucormycosis Complicating Anti-TNF Therapy with a Combination of Surgical Debridement and Oral Posaconazole. AB - Lipid formulations of amphotericin B remain the first-line antifungal therapy for invasive mucormycosis. Posaconazole is an alternative for salvage therapy, but its use as primary therapy is not recommended due to the paucity of clinical data. Here we describe the case of a 57-year-old diabetic woman receiving etanercept and prednisone for the treatment of psoriatic arthritis who developed primary cutaneous mucormycosis after a minor gardening injury. Infection was successfully treated with aggressive surgical debridement followed by a 6-week course of the new delayed-release tablet formulation of posaconazole and temporary withholding of anti-TNF treatment. Primary antifungal therapy with posaconazole can be considered in selected cases of cutaneous mucormycosis. PMID- 26112999 TI - High thermopower of mechanically stretched single-molecule junctions. AB - Metal-molecule-metal junction is a promising candidate for thermoelectric applications that utilizes quantum confinement effects in the chemically defined zero-dimensional atomic structure to achieve enhanced dimensionless figure of merit ZT. A key issue in this new class of thermoelectric nanomaterials is to clarify the sensitivity of thermoelectricity on the molecular junction configurations. Here we report simultaneous measurements of the thermoelectric voltage and conductance on Au-1,4-benzenedithiol (BDT)-Au junctions mechanically stretched in-situ at sub-nanoscale. We obtained the average single-molecule conductance and thermopower of 0.01 G0 and 15 MUV/K, respectively, suggesting charge transport through the highest occupied molecular orbital. Meanwhile, we found the single-molecule thermoelectric transport properties extremely-sensitive to the BDT bridge configurations, whereby manifesting the importance to design the electrode-molecule contact motifs for optimizing the thermoelectric performance of molecular junctions. PMID- 26113000 TI - Effect of variation in hemorheology between human and animal blood on the binding efficacy of vascular-targeted carriers. AB - Animal models are extensively used to evaluate the in vivo functionality of novel drug delivery systems (DDS). However, many variations likely exist in vivo between the animals and human physiological environment that significantly alter results obtained with animal models relative to human system. To date, it is not clear if the variation in hemorheology and hemodynamics between common animal and human models affect the functionality of DDS. This study investigates the role of hemorheology of humans and various animal models in dictating the binding efficiency of model vascular-targeted carriers (VTCs) to the wall in physiological blood flows. Specifically, the adhesion of sLe(A)-coated nano- and micro-spheres to inflamed endothelial cells monolayers were conducted via a parallel plate flow chamber assay with steady and disturbed red blood cells (RBCs)-in-buffer and whole blood flows of common animal models. Our results suggest that the ratio of carrier size to RBC size dictate particle binding in blood flow. Additionally, the presence of white blood cells affects the trend of particle adhesion depending on the animal species. Overall, this work sheds light on some deviation in VTC vascular wall interaction results obtained with in vivo animal experimentation from expected outcome and efficiency in vivo in human. PMID- 26113001 TI - Charged supramolecular assemblies of surfactant molecules in gas phase. AB - The aim of this review is to critically analyze recent literature on charged supramolecular assemblies formed by surfactant molecules in gas phase. Apart our specific interest on this research area, the stimuli to undertake the task arise from the widespread theoretical and applicative benefits emerging from a comprehensive view of this topic. In fact, the study of the formation, stability, and physicochemical peculiarities of non-covalent assemblies of surfactant molecules in gas phase allows to unveil interesting aspects such as the role of attractive, repulsive, and steric intermolecular interactions as driving force of supramolecular organization in absence of interactions with surrounding medium and the size and charge state dependence of aggregate structural and dynamical properties. Other interesting aspects worth to be investigated are joined to the ability of these assemblies to incorporate selected solubilizates molecules as well as to give rise to chemical reactions within a single organized structure. In particular, the incorporation of large molecules such as proteins has been of recent interest with the objective to protect their structure and functionality during the transition from solution to gas phase. Exciting fall-out of the study of gas phase surfactant aggregates includes mass and energy transport in the atmosphere, origin of life and simulation of supramolecular aggregation in the interstellar space. Moreover, supramolecular assemblies of amphiphilic molecules in gas phase could find remarkable applications as atmospheric cleaning agents, nanosolvents and nanoreactors for specialized chemical processes in confined space. Mass spectrometry techniques have proven to be particularly suitable to generate these assemblies and to furnish useful information on their size, size polydispersity, stability, and structural organization. On the other hand molecular dynamics simulations have been very useful to rationalize many experimental findings and to furnish a vivid picture of the structural and dynamic features of these aggregates. Thus, in this review, we will focus on the most important achievements gained in recent years by both these investigative tools. PMID- 26113002 TI - Dural carotid-cavernous fistula presenting with confusion and expressive aphasia. AB - We report a patient who presented with confusion and expressive aphasia at the onset of a cortical venous reflux (CVR) related to a known dural carotid cavernous fistula (DCCF). CVR and venous congestion are rare findings in a DCCF, however, it is important to recognize these findings early to reduce the associated risks of venous hemorrhage and infarction. To our knowledge, no previous report has described an association of expressive aphasia with CVR from a DCCF. This patient highlights the potential for venous congestion secondary to CVR from a DCCF presenting with a constellation of symptoms, including confusion and expressive aphasia with corresponding MRI findings. Clinicians should consider a DCCF in the differential diagnosis of this clinical presentation, with corroborative imaging findings. PMID- 26113003 TI - Hypofractionated stereotactic radiotherapy for benign intracranial tumours of the cavernous sinus. AB - We present our experience with hypofractionated stereotactic radiotherapy (HSRT) using 15 fractions to treat benign conditions of the cavernous sinus (CS) and emphasise the outcome in terms of cranial nerve (CN) function and toxicity for long term safety and efficacy. We performed a retrospective review of prospectively collected data on 112 patients with benign tumours of the CS treated with HSRT between 1 January 1998 and 31 December 2009. While all tumours involved the CS, a separate analysis was undertaken for meningiomas and pituitary adenomas. The median follow-up was 77 months (range: 2.3-177). Fifty-seven patients (51%) had a diagnosis of meningioma and 55 (49%) had pituitary adenomas. Prior to HSRT, 82 patients (73%) underwent microsurgery. The median tumour volume was 6.6 cm(3) for meningiomas and 3.4 cm(3) for pituitary adenomas (interquartile range: 2.8-7.9), and the mean prescribed dose was 38 Gy (range: 37.5-40.0) to the tumour margin, delivered in 15 fractions. After HSRT, 57% of all preexisting cranial neuropathies either resolved or improved and 38% remained stable, whereas 5% deteriorated. The diagnosis of meningioma was the only variable associated with recovery of cranial neuropathy (p<0.001). Permanent CN complications occurred in three patients (3%). The 5 and 10 year actuarial freedom from progression for patients with meningiomas was 98% and 93%, respectively, and for patients with pituitary adenomas this was 96% and 96%, respectively. We demonstrate low rates of CN morbidity after HSRT and the possibility of resolution or improvement in CN function for common histologies involving the CS. PMID- 26113004 TI - Intraventricular foramen of Monro cavernous malformation. AB - We present a 64-year-old woman who was evaluated after being found unresponsive. Imaging revealed a foramen of Monro cavernoma resulting in hydrocephalus. Supratentorial cavernomas are most frequently found in the cerebral cortex, and although ventricular cavernomas do occur, they are rarely located in the foramen of Monro. Foramen of Monro cavernomas are extremely dangerous, requiring aggressive management when identified. PMID- 26113005 TI - Minimally invasive aortic valve replacement with a sutureless valve through a right anterior mini-thoracotomy versus transcatheter aortic valve implantation in high-risk patients. AB - OBJECTIVES: The aim of this study was to compare early outcomes and mid-term survival of high-risk patients undergoing minimally invasive aortic valve replacement through right anterior mini-thoracotomy (RT) with sutureless valves versus patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis. METHODS: From October 2008 to March 2013, 269 patients with severe aortic stenosis underwent either RT with perceval S sutureless valves (n = 178 patients, 66.2%) or TAVI (n = 91, 33.8%: 44 transapical and 47 trans femoral). Of these, 37 patients undergoing RT with the perceval S valve were matched to a TAVI group by the propensity score. RESULTS: Baseline characteristics were similar in both groups (mean age 79 +/- 6 years) and the median logistic EuroSCORE was 14% (range 9-20%). In the matched group, the in hospital mortality rate was 8.1% (n = 3) in the TAVI group and 0% in the RT group (P = 0.25). The incidence rate of stroke was 5.4% (n = 2) versus 0% in the TAVI and RT groups (P = 0.3). In the TAVI group, 37.8% (n = 14) had mild paravalvular leakage (PVL) and 27% (n = 10) had moderate PVL, whereas 2.7% (n = 1) had mild PVL in the RT group (P < 0.001). One- and 2-year survival rates were 91.6 vs 78.6% and 91.6 vs 66.2% in patients undergoing RT with the perceval S sutureless valve compared with those undergoing TAVI, respectively (P = 0.1). CONCLUSIONS: Minimally invasive aortic valve replacement with perceval S sutureless valves through an RT is associated with a trend of better early outcomes and mid-term survival compared with TAVI. PMID- 26113006 TI - Extended resection of sarcomas involving the mediastinum: a 15-year experience?. AB - OBJECTIVES: Sarcomas involving the mediastinum are rare and aggressive tumours with a poor prognosis. We reviewed our experience to evaluate outcomes and survival for patients who undergo surgical resection. METHODS: A retrospective review of 35 patients who underwent resection of sarcomas that involved the mediastinum at a single institution over a 15-year period was conducted. RESULTS: Fifteen patients (43%) had sarcomas originating from the great vessels, 15 (43%) the heart and 5 (15%) the chest wall. The most common subtype was leiomyosarcoma (n = 10, 29%). Twenty patients (57%) underwent resection of primary tumours, 11 (31%) of metastases and 4 (11%) of recurrences. Sixteen patients (46%) had Stage IV disease. An R0 resection was achieved in 17 patients (49%). Fourteen (40%) had an R1 resection and 4 (11%) an R2. Thirty cases (85%) were performed on cardiopulmonary bypass (CPB). Twenty-three patients (65%) required resection of adjacent structures. Eight cases (23%) were performed on an urgent basis. Morbidity and mortality were 37 and 6%, respectively. Overall median survival was 33 months (range 7-171 months). Median overall survival for Stage IV disease was 5 months compared with 27 months for all others (P = 0.26). Two-, 5- and 10-year survivals for the cohort were 50, 35 and 25%, respectively. Incomplete resection was associated with poor long-term survival. Median survival was 101 months for R0, 21 months for R1 and 9 months for R2 resection. CONCLUSIONS: CPB and concomitant resection of intrathoracic structures may be required for local tumour control in sarcomas that involve the mediastinum, and should not be considered contraindications to resection as they may offer the best opportunity for prolonged survival in selected cases. PMID- 26113008 TI - High Expressions of Lgr5 and ALDH1 in Primary Epithelial Ovarian Cancer Correlate with Advanced Tumor Stage and Grade as well as Poor Prognosis of the Patients. AB - BACKGROUND: The aim of our study was to investigate the clinical role of aldehyde dehydrogenase 1 (ALDH1) and leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) expressions in epithelial ovarian cancer (EOC) and their prognostic significance. METHODS: One hundred primary EOC samples were obtained for immunohistochemical analysis of ALDH1 and Lgr5 expressions. Correlation analysis was performed between ALDH1 or Lgr5 and clinical factors. RESULTS: High expression of ALDH1 and Lgr5 was identified in 71 and 55 cases of EOC tissues, respectively. The ALDH1 and Lgr5 expressions in EOC tissues were significantly higher as compared to the normal ovaries and benign ovarian tumors. High expression of ALDH1 and Lgr5 was strongly correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stages, higher tumor grades, and poor overall survival of the patients. CONCLUSIONS: Lgr5 and ALDH1 were highly expressed in EOC tissues, and correlated with different FIGO operation pathological stages and tumor grades, clinical outcome, and with each other. The combined use of ALDH1 and Lgr5 might be useful for the diagnosis and prognosis prediction of EOC patients. (c) 2015 S. Karger AG, Basel. PMID- 26113007 TI - Is arch form influenced by sagittal molar relationship or Bolton tooth-size discrepancy? AB - BACKGROUND: Orthodontic patients show high prevalence of tooth-size discrepancy. This study investigates the possible association between arch form, clinically significant tooth-size discrepancy, and sagittal molar relationship. METHODS: Pretreatment orthodontic casts of 230 Saudi patients were classified into one of three arch form types (tapered, ovoid, and square) using digitally scanned images of the mandibular arches. Bolton ratio was calculated, sagittal molar relationship was defined according to Angle classification, and correlations were analyzed using ANOVA, chi-square, and t-tests. RESULTS: No single arch form was significantly more common than the others. Furthermore, no association was observed between the presence of significant Bolton discrepancy and the sagittal molar relationship or arch form. Overall Bolton discrepancy is significantly more prevalent in males. CONCLUSIONS: Arch form in a Saudi patient group is independent of gender, sagittal molar relationship, and Bolton discrepancy. PMID- 26113009 TI - Half-peroneus-longus-tendon graft augmentation for unqualified hamstring tendon graft of anterior cruciate ligament reconstruction. AB - BACKGROUND: In some situations, harvested hamstring tendon grafts are not qualified for anterior cruciate ligament (ACL) reconstruction. This study aimed to present a reinforcing method with additional half peroneus longus tendon (half PLT) graft augmentation. METHODS: Eight cases underwent ACL reconstruction with unqualified hamstring tendon grafts (diameter <7 mm) and were salvaged by additional half-PLT graft augmentation. The pivot shift test and KT-1000 tests were performed 3 years after surgery. Functional evaluation of subjective International Knee Documentation Committee (IKDC) and Lysholm scores was also done. In addition, Foot and Ankle Disability Index (FADI) scores were used to evaluate the function of the ankle donor site. RESULTS: The diameter of unqualified four-strand hamstring tendon grafts was 6.2 mm on average (range, 6.0 6.5 mm). The average diameter of hamstring grafts with half-PLT augmentation was 9.6 mm (range, 9.5-10.0 mm). The pivot shift test was negative in all patients. No significant differences between normal and abnormal knees were found by KT 1000. The average IKDC score was 86.0 (range, 83 to 89), and the average Lysholm score was 84.4 (range, 80-90). The average FADI score for the donor sites of half PLT was 135.8 (range, 134-136). CONCLUSIONS: Additional half-PLT can successfully and safely reinforce unqualified hamstring tendon grafts for ACL reconstruction. PMID- 26113010 TI - Novel Insights into Osteoarthritis Joint Pathology from Studies in Mice. AB - Osteoarthritis causes tremendous individual suffering and staggering societal costs, but due to our limited understanding of the underlying molecular and cellular mechanisms, our avenues for treating this disease are very restricted. Recent years have seen a drastic increase in the use of genetically modified mice to characterize the pathophysiology of osteoarthritis. Many new players and mechanisms driving osteoarthritis pathogenesis have been elucidated, some of which might be strong candidates as therapeutic targets for the human disease. The current review summarizes key findings (selected subjectively by the authors) from mouse osteoarthritis studies over recent years. PMID- 26113011 TI - RS3PE: Clinical and Research Development. AB - Remitting seronegative symmetrical synovitis with pitting edema or RS3PE is a rare elderly-onset rheumatic syndrome. Although there are overlapping clinical manifestations between RS3PE, elderly-onset rheumatoid arthritis, and polymyalgia rheumatica, RS3PE has distinct characteristics. RS3PE can be associated with neoplasia and various rheumatic conditions, suggesting that it may be heterogeneous, and is considered as a paraneoplastic rheumatic disease. The pathogenesis of RS3PE may involve vascular endothelial growth factor and infection in RS3PE based upon limited data. Patients with RS3PE without concomitant malignancy respond well to small doses of glucocorticoids and carry good prognosis. PMID- 26113012 TI - HCV Treatments and Their Integration Into Rheumatology. AB - Hepatitis C virus (HCV) has been associated with distinct rheumatic syndromes including arthritis, sialadenitis, and cryoglobulinemic vasculitis (CV). The therapy of these HCV-associated syndromes includes antiviral therapy with or without the addition of immunosuppressives while clinical response is mainly seen in patients who clear the virus after antiviral therapy. Despite significant therapeutic advances, existing antiviral therapies with interferon-a (IFNa)-based schemes achieve viral eradication only in approximately half the patients. Recently, oral antivirals that target specific HCV proteins referred as direct acting antivirals (DAAs) have been developed and approved. Short-term (12-24 weeks) combination schemes with or without IFN ("IFN-free" regimens) including these inhibitors clear the virus in more than 90 % of treated patients. Here, we review current therapeutic options in HCV-associated rheumatic syndromes and the potential role of the newly available antivirals in an integrated therapeutic approach. PMID- 26113013 TI - Imaging in Giant Cell Arteritis. AB - Much progress has been made in the use of imaging as a diagnostic tool in giant cell arteritis (GCA), which assists in the management of patients where the initial diagnosis is unclear. This includes patients with atypical cranial symptoms, or with predominantly systemic, constitutional or limb symptoms. Ultrasound and magnetic resonance imaging are capable of visualising both the cranial and extracranial large vessel circulation, with vessel wall thickening and stenotic lesions being visualised. Computed tomographic angiography is helpful in visualising the aorta for aneurysm complicating GCA but can also detect vessel wall thickening in established large vessel vasculitis. PET-CT is a very sensitive test for early vascular inflammation in extracranial large vessel vasculitis, before aneurysmal or stenotic lesions have developed, of use in the patient with unexplained constitutional symptoms. The place of imaging in the follow-up of GCA is being investigated, and repeated imaging may be useful in select cases. Generally, vascular abnormalities become less defined once glucocorticoid treatment has been started, and therefore, imaging studies must be conducted early as part of a GCA fast-track assessment. PMID- 26113014 TI - Implementation of Functional Genomics for Bench-to-Bedside Transition in Osteoarthritis. AB - Collaborative work has led to the identification of robust osteoarthritis susceptibility genes. The translation of these gene deviations towards underlying biological mechanisms remains challenging yet necessary to allow the transition of these results in drug development and to applications in the clinic. Besides the availability of disease-relevant tissues which will contribute to a deeper insight into ongoing pathophysiological processes as result of the gene deviations, availability of respective cells will be key to establish in vitro models to further characterize genetic variants at a transcriptional and functional level. To allow exploration of effective use of drugs and biologicals such findings should eventually be further tested in in vivo models. In this review, we discuss possibilities for the implementation of an effective functional genomic pipeline for bench-to-bedside translation of identified susceptibility loci. PMID- 26113015 TI - Targeting male mosquito mating behaviour for malaria control. AB - Malaria vector control relies heavily on the use of Long-Lasting Insecticidal Nets (LLINs) and Indoor Residual Spraying (IRS). These, together with the combined drug administration efforts to control malaria, have reduced the death toll to less than 700,000 deaths/year. This progress has engendered real excitement but the emergence and spread of insecticide resistance is challenging our ability to sustain and consolidate the substantial gains that have been made. Research is required to discover novel vector control tools that can supplement and improve the effectiveness of those currently available. Here, we argue that recent and continuing progress in our understanding of male mating biology is instrumental in the implementation of new approaches based on the release of either conventional sterile or genetically engineered males. Importantly, further knowledge of male biology could also lead to the development of new interventions, such as sound traps and male mass killing in swarms, and contribute to new population sampling tools. We review and discuss recent advances in the behavioural ecology of male mating with an emphasis on the potential applications that can be derived from such knowledge. We also highlight those aspects of male mating ecology that urgently require additional study in the future. PMID- 26113017 TI - Cancer as a risk factor for stroke in atrial fibrillation patients receiving long term oral anticoagulant therapy. PMID- 26113016 TI - Diastolic dysfunction in spontaneous type 2 diabetes rhesus monkeys: a study using echocardiography and magnetic resonance imaging. AB - BACKGROUND: Diastolic heart failure is a common and deadly complication of diabetes mellitus, with the development of diabetic cardiomyopathy as one of the key determinants of the disease's complex pathology. The cause of the association is unknown and has no approved therapy strategies as of yet. However significant advances in this area may come from studies on suitable animal models. METHODS: A total of 25 male rhesus monkeys (12-16 years, 9-13 kg) were enrolled. Fifteen of them were diagnosed as spontaneous type 2 diabetes mellitus (T2DM, FPG >= 104 mg/dl, HbA1c: 4.7-5.5 %, diabetes duration: 1-4 years). The other 10 monkeys were non-diabetic (ND, FPG < 90 mg/dl). Echocardiography and cardiac magnetic resonance were used for evaluating the cardiac structure and function. One T2DM monkey with impaired diastolic function and another ND monkey were both sacrificed to gain the necessary pathology and protein expression studies displayed here. RESULTS: Six out of 15 T2DM rhesus monkeys were diagnosed with diastolic dysfunction (DD) by echocardiography. Additionally, no abnormalities were found in the group which we determined as the ND monkeys. The six DD monkeys all showed low e' velocity and decreased e'/a' ratio, among which three of them showing decreased E/A ratio and the other 3 having elevated E/A ratio, this appears to be similar to the impaired relaxation pattern and pseudonormal pattern found in human patients respectively. The EF and FS of monkeys with pseudonormal pattern decreased significantly compared with ND subjects. A CMR study showed that LVID at end systole of 5 DD monkeys is significantly longer than that of 3 ND monkeys. Of great interest, myocardium lesions and mitochondria impairments and increased expression of AGEs and caspase-3 were found in a sacrificed DD subject. CONCLUSION: The changes in the imaging and physiological markers of spontaneous T2DM rhesus monkeys are similar to those key markers found in human type 2 diabetes and diastolic dysfunction. This monkey model could help the medical community and us to understand the pathology of this debilitating disease and serve as a beginning to explore important measures to prevent and treat diabetic cardiomyopathy. PMID- 26113018 TI - Could MicroRNA polymorphisms influence warfarin dosing? A pharmacogenetics study on mir133 genes. AB - MicroRNAs are small single stranded molecules that play a crucial role in regulation of physiological and pathological processes. Recent studies showed that VKORC1 gene contains an highly evolutionary conserved binding site for mir 133. Moreover, in human hepatocytes mir-133 is constitutively co-expressed with VKORC1. Since VKORC1 protein is the target of warfarin treatment, the aim of this study was to verify if genetic variations in MIR133A1, MIR133A2 and MIR133B could contribute to warfarin dose variability. By direct sequencing, we identified 4 SNPs in MIR133A2 gene and 1 SNP in MIR133B gene. Three SNPs in MIR133A2 were in complete linkage disequilibrium and correlated with warfarin dose: indeed, for each SNP, patients carrying the GA or AA genotype required a MWWD significantly higher than the wildtype genotype (P=0.019). We also inferred the haplotypes in MIR133A2 gene. The GC haplotype required a MWWD significantly lower than AT haplotype (P=0.012). The multiple linear regression analysis confirmed that rs45547937 (as tag SNP) in MIR133A2 could be involved in warfarin dosing variability, (P=0.016). These results seem to suggest that also polymorphisms in miRNA precursors may potentially affects drug response variability. PMID- 26113019 TI - Evaluating Abdominal and Lower-Back Muscle Activity While Performing Core Exercises on a Stability Ball and a Dynamic Office Chair. AB - OBJECTIVE: The purpose of this study was to evaluate the ability of a dynamic office chair to activate the core muscles while participants performed exercises sitting on the chair compared to a stability ball. BACKGROUND: Prolonged sitting has become an accepted part of the modern office. However, epidemiological evidence suggests that sedentary postures are linked to many adverse effects on health. The concept of dynamic or active sitting is intended to promote movement while sitting to reduce the time spent in prolonged, static postures. METHODS: Sixteen participants performed four pelvic rotation exercises (front-back, side side, circular, and leg lift) on both a dynamic office chair and a stability ball. Muscle activity from 12 torso muscles were evaluated with surface electromyography. RESULTS: For all exercises, trunk muscle activity on the chair was comparable to that on a stability ball. The right external oblique was the only muscle to produce greater peak activity (p = .019) when using the ball compared to the chair (21.4 +/- 14.0 percent maximal voluntary excitations (%MVE) and 14.7 +/- 10.8 %MVE for the ball and chair, respectively). The left thoracic erector spinae produced greater average activity (p = .044) on the chair than on the ball. CONCLUSION: These findings suggest that this dynamic sitting approach could be an effective tool for core muscle activation while promoting movement and exercise while sitting at work. APPLICATION: Muscle activations on the dynamic chair are comparable to those on a stability ball, and dynamic office chairs can promote movement and exercise while sitting at work. PMID- 26113020 TI - The Diagnostic Performance of the Richmond Agitation Sedation Scale for Detecting Delirium in Older Emergency Department Patients. AB - OBJECTIVES: Delirium is frequently missed in older emergency department (ED) patients. Brief (<2 minutes) delirium assessments have been validated for the ED, but some ED health care providers may consider them to be cumbersome. The Richmond Agitation Sedation Scale (RASS) is an observational scale that quantifies level of consciousness and takes less than 10 seconds to perform. The authors sought to explore the diagnostic accuracy of the RASS for delirium in older ED patients. METHODS: This was a preplanned analysis of a prospective observational study designed to validate brief delirium assessments for the ED. The study was conducted at an academic ED and enrolled patients who were 65 years or older. Patients who were non-English-speaking, deaf, blind, comatose or had end-stage dementia were excluded. A research assistant (RA) and a physician performed the RASS at the time of enrollment. Within 3 hours, a consultation liaison psychiatrist performed his or her comprehensive reference standard assessment for delirium using Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) criteria. Sensitivities, specificities, and likelihood ratios with their 95% confidence intervals (CIs) were calculated. RESULTS: Of 406 enrolled patients, 50 (12.3%) had delirium diagnosed by the consult-liaison psychiatrist reference rater. When performed by the RA, a RASS other than 0 (RASS > 0 or < 0) was 84.0% sensitive (95% CI = 73.8% to 94.2%) and 87.6% specific (95% CI = 84.2% to 91.1%) for delirium. When performed by physician, a RASS other than 0 was 82.0% sensitive (95% CI = 71.4% to 92.6%) and 85.1% specific (95% CI = 81.4% to 88.8%) for delirium. Using a RASS > +1 or < -1 as the cutoff, the specificity improved to approximately 99% for both raters at the expense of sensitivity; the sensitivities were 22.0% (95% CI = 10.5% to 33.5%) and 16.0% (95% CI = 5.8% to 25.2%) in the RAs and physician raters, respectively. The positive likelihood ratio was 19.6 (95% CI = 6.5 to 59.1) when performed by the RA and 57.0 (95% CI = 7.3 to 445.9) when performed by the physician, indicating that a RASS > +1 or < -1 strongly increased the likelihood of delirium. The weighted kappa was 0.63, indicating moderate interobserver reliability. CONCLUSIONS: In older ED patients, a RASS other than 0 has very good sensitivity and specificity for delirium as diagnosed by a psychiatrist. A RASS > +1 or < -1 is nearly diagnostic for delirium, given the very high positive likelihood ratio. PMID- 26113021 TI - The mobility gap between older men and women: the embodiment of gender. AB - OBJECTIVES: To present the study design and baseline results of the longitudinal International Mobility in Aging Study (IMIAS) on gender differences in physical performance and mobility disability prevalence in five diverse societies. METHODS: Data are from surveys on random samples of people aged 65-74 years at Canadian (Kingston, Ontario; Saint-Hyacinthe, Quebec), Mediterranean (Tirana, Albania) and Latin American sites (Natal, Brazil; Manizales, Colombia) (N=1995). Mobility disability was defined as reporting difficulty in walking 400m or climbing stairs. Activities of daily living (ADL) disability was based on any self-reported difficulty in five mobility-related ADLs. The short physical performance battery (SPPB) was used to assess physical performance. Poisson regression models were fitted to estimate prevalence ratios. RESULTS: Age adjusted prevalence of low SPPB, mobility disability and ADL disability were higher in women than in men in all sites except for Kingston. After adjustment for education and income, gender differences in SPPB and ADL disability attenuated or disappeared in Saint-Hyacinthe and Manizales but remained large in Tirana and Natal and mobility disability remained more frequent in women than in men at all sites except Kingston. After further adjustment by chronic conditions and depressive symptoms, gender differences in mobility remained large at all sites except Kingston but only in Tirana did women have significantly poorer physical performance than men. DISCUSSION: Results provide evidence for gender as a risk factor to explain poorer physical function in women and suggest that moving toward gender equality could attenuate the gender gap in physical function in old age. PMID- 26113022 TI - Effect of a single injection of autologous conditioned serum (ACS) on tendon healing in equine naturally occurring tendinopathies. AB - INTRODUCTION: Autologous blood-derived biologicals, including autologous conditioned serum (ACS), are frequently used to treat tendinopathies in horses despite limited evidence for their efficacy. The purpose of this study was to describe the effect of a single intralesional injection of ACS in naturally occurring tendinopathies of the equine superficial digital flexor tendon (SDFT) on clinical, ultrasonographic, and histological parameters. METHODS: Fifteen horses with 17 naturally occurring tendinopathies of forelimb SDFTs were examined clinically and ultrasonographically (day 0). Injured tendons were randomly assigned to the ACS-treated group (n = 10) receiving a single intralesional ACS injection or included as controls (n = 7) which were either untreated or injected with saline on day 1. All horses participated in a gradually increasing exercise programme and were re-examined nine times at regular intervals until day 190. Needle biopsies were taken from the SDFTs on days 0, 36 and 190 and examined histologically and for the expression of collagen types I and III by immunohistochemistry. RESULTS: In ACS-treated limbs lameness decreased significantly until day 10 after treatment. Swelling (scores) of the SDFT region decreased within the ACS group between 50 and 78 days after treatment. Ultrasonographically, the percentage of the lesion in the tendon was significantly lower and the echogenicity of the lesion (total echo score) was significantly higher 78 and 106 days after intralesional ACS injection compared to controls. Histology revealed that, compared to controls, tenocyte nuclei were more spindle-shaped 36 days after ACS injection. Immunohistochemistry showed that collagen type I expression significantly increased between days 36 and 190 after ACS injection. CONCLUSIONS: Single intralesional ACS injection of equine SDFTs with clinical signs of acute tendinopathy contributes to an early significant reduction of lameness and leads to temporary improvement of ultrasonographic parameters of repair tissue. Intralesional ACS treatment might decrease proliferation of tenocytes 5 weeks after treatment and increase their differentiation as demonstrated by elevated collagen type I expression in the remodelling phase. Potential enhancement of these effects by repeated injections should be tested in future controlled clinical investigations. PMID- 26113024 TI - Homomorphic plant sex chromosomes are coming of age. AB - Sex chromosomes are a very peculiar part of the genome that have evolved independently in many groups of animals and plants (Bull ). Major research efforts have so far been focused on large heteromorphic sex chromosomes in a few animal and plant species (Chibalina & Filatov ; Zhou & Bachtrog ; Bellott et al. ; Hough et al. ; Zhou et al. ), while homomorphic (cytologically indistinguishable) sex chromosomes have largely been neglected. However, this situation is starting to change. In this issue, Geraldes et al. () describe a small (~100 kb long) sex-determining region on the homomorphic sex chromosomes of poplars (Populus trichocarpa and related species, Fig. ). All species in Populus and its sister genus Salix are dioecious, suggesting that dioecy and the sex chromosomes, if any, should be relatively old. Contrary to this expectation, Geraldes et al. () demonstrate that the sex-determining region in poplars is of very recent origin and probably evolved within the genus Populus only a few million years ago. PMID- 26113023 TI - iTRAQ-based quantitative proteomics analysis of rice leaves infected by Rice stripe virus reveals several proteins involved in symptom formation. AB - BACKGROUND: Rice plants infected by Rice stripe virus (RSV) usually leads to chlorosis and death of newly emerged leaves. However, the mechanism of RSV induced these symptoms was not clear. METHODS: We used an iTRAQ approach for a quantitative proteomics comparison of non-infected and infected rice leaves. RT qPCR and Northern blot analyses were performed for assessing the transcription of candidate genes. RESULTS: As a whole, 681 (65.8% downregulated, 34.2% upregulated infected vs. non-infected) differentially accumulated proteins were identified. A bioinformatics analysis indicated that ten of these regulated proteins are involved in chlorophyll biosynthesis and three in cell death processes. Subsequent RT-qPCR results showed that downregulation of magnesium chelatase was due to reduced expression levels of the genes encoding subunits CHLI and CHLD, which resulted in chlorophyll reduction involved in leaf chlorosis. Three aspartic proteases expressed higher in RSV-infected leaves than those in the control leaves, which were also implicated in RSV-induced cell death. Northern blot analyses of CHLI and p0026h03.19 confirmed the RT-qPCR results. CONCLUSIONS: The magnesium chelatase and aspartic proteases may be associated with RSV-induced leaf chlorosis and cell death, respectively. The findings may yield new insights into mechanisms underlying rice stripe disease symptom formation. PMID- 26113025 TI - Auditory-neurophysiological responses to speech during early childhood: Effects of background noise. AB - Early childhood is a critical period of auditory learning, during which children are constantly mapping sounds to meaning. But this auditory learning rarely occurs in ideal listening conditions-children are forced to listen against a relentless din. This background noise degrades the neural coding of these critical sounds, in turn interfering with auditory learning. Despite the importance of robust and reliable auditory processing during early childhood, little is known about the neurophysiology underlying speech processing in children so young. To better understand the physiological constraints these adverse listening scenarios impose on speech sound coding during early childhood, auditory-neurophysiological responses were elicited to a consonant-vowel syllable in quiet and background noise in a cohort of typically-developing preschoolers (ages 3-5 yr). Overall, responses were degraded in noise: they were smaller, less stable across trials, slower, and there was poorer coding of spectral content and the temporal envelope. These effects were exacerbated in response to the consonant transition relative to the vowel, suggesting that the neural coding of spectrotemporally-dynamic speech features is more tenuous in noise than the coding of static features-even in children this young. Neural coding of speech temporal fine structure, however, was more resilient to the addition of background noise than coding of temporal envelope information. Taken together, these results demonstrate that noise places a neurophysiological constraint on speech processing during early childhood by causing a breakdown in neural processing of speech acoustics. These results may explain why some listeners have inordinate difficulties understanding speech in noise. Speech-elicited auditory neurophysiological responses offer objective insight into listening skills during early childhood by reflecting the integrity of neural coding in quiet and noise; this paper documents typical response properties in this age group. These normative metrics may be useful clinically to evaluate auditory processing difficulties during early childhood. PMID- 26113026 TI - Hartmann's procedure and laparoscopic reversal versus primary anastomosis and ileostomy closure for left colonic perforation. AB - PURPOSE: Emergency surgical strategies for acute left-sided colonic perforation are evolving preferring primary anastomosis (PA) with ileostomy to Hartmann's procedure (HP) based on the morbidity and reversal rates. However, HP is still commonly performed. Hartmann's reversal is associated with considerable morbidity. It is of interest whether laparoscopic reversal results in a lower morbidity as retrospective data suggest. Here, we compared the combined morbidity rates for two surgical strategies: strategy A, HP followed by laparoscopic reversal, and strategy B, sigmoid resection with PA followed by ileostomy closure. METHODS: Prospectively collected data of all consecutive patients undergoing HP for benign left-sided colonic perforation between 2010 and 2014 were retrospectively compared to data of patients undergoing PA. Groups were matched for age and Charlson comorbidity index. Additionally, patients were analyzed for American Society of Anesthesiologists score, body mass index, and peritonitis stage. End points were morbidity, operation time, reversal rate, time to reversal, and length of hospital stay. RESULTS: The study included 32 patients for whom Hartmann's reversal was planned, along with 32 matched patients who underwent PA and diverting ileostomy. Median age was 75 and 72 years, Charlson score was 6 (4-9) and 6 (5-7), and patients classified by the American Society of Anesthesiologists (ASA) higher than III were 81 % in both groups. Combined major morbidity rates were 21 % for strategy A and 20 % for strategy B (p = 1.0). Combined comprehensive complication index was 16.4 +/- 14.1 and 12.3 +/- 19.1 (p = 0.08). HP reversal by laparoscopy was achieved in 71 %. The colostomy reversal rate was 75 % compared to ileostomy closure rate of 88 % (p = 0.34). CONCLUSIONS: Laparoscopic Hartmann's reversal is achievable in a high proportion of patients. Strategy B tends to have lower overall morbidity; meanwhile, major morbidity seems to be similar. Yet, in critically ill patients and in the absence of expertise of the surgeon on call, HP followed by elective laparoscopic reversal represents a viable alternative. PMID- 26113027 TI - Rational pharmacotherapy (RPT) in goutology: Define the serum uric acid target & treat-to-target patient cohort and review on urate lowering therapy (ULT) applying synthetic drugs. AB - A gout revolution is at hand as can be seen from the number of publications and our recent increase in a better understanding of gout regarding imaging, regarding pathogenetic involvement of crystals, cells and cytokines, as well as regarding new pharmacotherapeutic options. We should now focus on rational pharmacotherapy to significantly improve gout care. With modern combinations of xanthine oxidase inhibition PLUS uricosuric all serum urate concentrations can be targeted. The pharmacotherapeutic literature of synthetic urate lowering treatment is reviewed and a plea is given for rational pharmacotherapy combining different modes of action aiming at the rheumatologically predefined optimal serum urate concentrations instead of a more reluctant approach to just lower a serum urate to any lower level with a fixed dose allopurinol. PMID- 26113028 TI - Consumption of and satisfaction with health care among opioid users with chronic non-malignant pain. AB - BACKGROUND: Although persons with chronic pain are frequent users of the health care system, they report poor satisfaction with health care services. Participants with persistent opioid use in Nord-Trondelag Health Study (HUNT)3 report severe pain in spite of treatment. The aim of the study was to test the hypothesis that subjects with persistent opioid use have both a higher consumption of health care services and a poorer satisfaction than the remaining subjects reporting chronic pain. METHODS: This cross-sectional study was based on linkage of self-reported data from the substudy (10,238 were invited, 6927 met the inclusion criteria) of health care use in HUNT3; a population-based health survey during the years 2006-2008 and the complete national registers of the Norwegian Prescription Database and the Cancer Registry of Norway. Patients with chronic pain are stratified according to the level of opioid use as persistent users of opioids, intermittent users, and persons not using opioids. RESULTS: Persons with chronic non-malignant pain reported a higher consumption of all health care services compared to the control group. Consumption of health care services increased with increasing level of opioid use. Persons with persistent opioid use were highly satisfied with all health care services, although less satisfied than persons without chronic pain. CONCLUSIONS: Combined with previous findings of high levels of pain in spite of opioid treatment, the present findings indicate that symptomatic relief is not a prerequisite for patient satisfaction. The study shows higher patient satisfaction compared to previous studies. PMID- 26113029 TI - Drug-induced skin reactions: a pathologist viewpoint. AB - Cutaneous drug reactions are common adverse effects that occur in about 2-3% of the hospitalized patients. They have both immunologic and non-immunologic underlying mechanisms. These reactions are clinically and histologically similar to dermatoses. Their significant clinical indicators include: history of drug intake, atypical clinical features and improvement after cessation of the offending drugs. Their diagnostic histological clues include the presence of mixed histological patterns, apoptotic keratinocytes, eosinophils (dermis and epidermis), papillary dermal edema and extravasations of erythrocytes. However, no single clinical or histological feature is specific of drug eruptions. This work attempts to classify the histomorphologic reactions to various drugs in defined categories for assistance in morphologic diagnosis. PMID- 26113030 TI - Acute corneal toxicity of latanoprost with different preservatives. AB - PURPOSE: To investigate the corneal toxicity of Xalatan and three latanoprost generics using transepithelial electrical resistance (TER) and scanning electron microscopy (SEM). METHODS: Corneal TER changes after a 60-s exposure to Xalatan (latanoprost 0.005% preserved with 0.02% BAC), and latanoprost generics (Latanoprost PF BAC free, Latanoprost Nitten SB containing sodium benzoate and Latanoprost Towa containing 0.01% BAC with sodium chloride polysorbate 80 as additive) were measured in living rabbits. Corneal damage was also examined by SEM. Hank's balanced salt solution (HBSS) was used as a control. RESULTS: There was a significant decrease in the corneal TER after exposure of the cornea to Xalatan (p < 0.01) and all latanoprost generics (p < 0.01: Latanoprost PF, p < 0.05: Latanoprost Nitten SB, Latanoprost Towa) as compared to HBSS. All latanoprost generics showed less TER decrease in the corneal TER as compared to Xalatan (p < 0.01). SEM revealed that superficial cells of Xalatan-treated corneas were damaged and exhibited degenerated microvilli. Conversely, the superficial cells of corneas exposed to HBSS or all latanoprost generics appeared normal and had normal microvilli under SEM examinations. CONCLUSION: The corneal toxicity of Xalatan is greater than that of latanoprost generics. Xalatan contains 0.02% BAC, which may be responsible for the corneal toxicity. PMID- 26113032 TI - Post-traumatic osteonecrosis of the proximal humerus. AB - Post-traumatic osteonecrosis of the proximal humerus represents a challenging problem to the surgeon. It is commonly seen following multi-fragmentary fractures of the proximal humerus which may affect the long-term functional recovery after such injuries. This review summarises the current evidence on risk factors, reasons why estimating its epidemiology is difficult, the vascular supply of the humeral head, classification, and management options. PMID- 26113031 TI - Relation between E/e' ratio and NT-proBNP levels in elderly patients with symptomatic severe aortic stenosis. AB - BACKGROUND: Symptoms in the elderly patients with severe aortic stenosis (AS) and co-morbidities seem to lack in specificity. Therefore, objective parameters for increased left ventricular(LV) filling pressures are needed. The aim of this study was to investigate the correlation between the septal, lateral and average E/e' ratio and the value of the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP). METHODS: Two-hundred-fifty consecutive symptomatic patients (mean age 80 +/- 8 years, 52% men) with severe AS underwent transthoracic echocardiography and NT-proBNP measurement. RESULTS: In the overall population the septal E/e' (r = 0,459, r(2) = 0,21, P <0,0001), lateral E/e' (r = 0,322, r(2) = 0,10, P <0,0001), and the average E/e' (r = 0,432, r(2) = 0,18, P <0,0001) were all significantly correlated to NT-proBNP. After the exclusion of patients with confounders (more than mild aortic or mitral regurgitation, severe renal dysfunction, obesity or severe COPD) the septal E/e' (r = 0,584, r(2) = 0,34, P <0,0001), lateral E/e' (r = 0,377, r(2) = 0,14, P <0,0001), and the average E/e' (r = 0,487, r(2) = 0,24, P <0,0001) were all significantly better correlated to NT-proBNP. In obese patients no significant correlations were seen. Previous bypass surgery did not alter the correlations. CONCLUSIONS: In elderly patients with severe symptomatic AS there is a significant correlation between the E/e' ratio and NT-proBNP, in particular after exclusion of confounders. The correlation was best for the septal E/e' ratio and was preserved in patients with a history of bypass surgery. PMID- 26113033 TI - Using a modified Pauwels method to predict the outcome of femoral neck fracture in relatively young patients. AB - BACKGROUND: Pauwels classification has long been used in femoral neck fracture to measure the inclination of the fracture line and is still widely used. In recent years, however, some studies have contested the reliability of this measurement method. This study investigates modified measurement method to assess the inclination angle with assisted parameters to evaluate the correlation between the different angles and the incidences of loss of reduction, nonunion and avascular necrosis. PATIENTS AND METHODS: A retrospective study was conducted to analyse the clinical data of 209 relatively young patients (between 20 and 60 years old) with intracapsular femoral neck fracture fixed by inverted triangular screws between January 2004 and December 2010, including 111 males and 98 females, with an average age of 47.08+/-9.93 years. Using the modified measurement method, the pre-operative inclination angles of patients with intracapsular femoral neck fracture were analyzed. The measured angles were classified into three types: type I, <30 degrees; type II, 30-50 degrees; and type III, >50 degrees. RESULTS: With regard to loss of reduction, nonunion and avascular necrosis, there were no significant differences with respect to age, sex and fracture side. However, there were significant differences with respect to fracture type, reduction quality and different modified Pauwels types. In the multiple regression analysis, the factors associated with loss of reduction were the fracture type (odds ratio [OR]=7.22), reduction quality (anatomic vs unacceptable reduction, OR=0.11; acceptable vs unacceptable reduction, OR=0.23), and modified Pauwels type (type II vs type III, OR=0.36). The factors associated with fracture nonunion were the fracture type (OR=9.43), reduction quality (acceptable vs unacceptable reduction, OR=0.17) and modified Pauwels type (type II vs type III, OR=0.22). And the factors associated with avascular necrosis were the modified Pauwels type (type I vs type III, OR=0.15; type II vs type III, OR=0.36). CONCLUSIONS: A displaced fracture, poor reduction quality and high modified Pauwels type are noted risk factors for loss of reduction and fracture nonunion in the post-operative follow up of intracapsular femoral neck fracture. The modified Pauwels type is also noted a risk factor for avascular necrosis. Thus, this modified method is a useful tool for correcting the deficiencies of traditional Pauwels classification and predicting the outcome of femoral neck fractures. PMID- 26113034 TI - What is the underlying mechanism for the failure mode observed in the proximal femoral locking compression plate? A biomechanical study. AB - PURPOSE: Recently, several cases of clinical failure have been reported for the Proximal Femoral Locking Compression Plate (PF-LCP). The current study was designed to explore biomechanically the underlying mechanism and to determine whether the observed failure was due to technical error on insertion or to implant design. METHODS: A foam block model simulating an unstable intertrochanteric fracture was created for 3 study groups with 6 specimens each. Group C was correctly instrumented according to the manufacturer's guidelines. In Group P and Group A, the first or second proximal screw was placed with a posterior or anterior off-axis orientation by 2 degrees measured in the transversal plane, respectively. Each construct was cyclically tested until failure using a test setup and protocol simulating complex axial and torsional loading. Radiographs were taken prior to and after the tests. Force, number of cycles to failure and failure mode were compared. RESULTS: A screw deviation of 2 degrees from the nominal axis led to significantly earlier construct failure in Group P and Group A in comparison to Group C. The failure mode was characterised by loosening of the off-axis screw due to disengagement with the plate, resulting in loss of construct stiffness and varus collapse of the fracture. CONCLUSIONS: In our biomechanical test setup, the clinical failure modes observed with the PF LCP were reproducible. A screw deviation of 2 degrees from the nominal axis consistently led to the failure. This highlights how crucial is the accurate placement of locking screws in the proximal femur. PMID- 26113035 TI - Customized versus Population-Based Birth Weight References for Predicting Fetal and Neonatal Undernutrition. AB - OBJECTIVES: The aim of our study was to construct a model of customized birth weight curves based on a Spanish population and to compare the ability of this customized model to our population-based chart to predict a neonatal ponderal index (PI) <10th percentile. METHODS: We developed a model that can predict the 10th percentile for a fetus according to gestational age and gender as well as maternal weight, height, and age. We compared the ability of this customized model to that of our own population-based model to predict a neonatal PI <10th percentile. Data from a large database were used (32,854 live newborns, from 1993 through 2012). Only singleton pregnancies with a gestational age at delivery of 32-42 weeks were included. RESULTS: In the entire pregnant population, the customized method was superior to the population-based method for detecting newborns with a PI <10th percentile (sensitivity: 55 vs. 40.96%; specificity: 99.6 vs. 91.23%; positive predictive value: 11.49 vs. 9.55%, and negative predictive value: 98.84 vs. 98.55%, respectively). In pregnant women with a BMI >90th percentile, the sensitivity was 75%, compared to 50% in the population based method. In pregnant women with a height >90th percentile, the sensitivity was almost as high as in the population-based method (61.53 vs. 33.33%). CONCLUSION: The customized birth weight curve is superior to the population-based method for the detection of newborns with a PI <10th percentile. This is especially the case in women in the higher scales of height and weight as well as in preterm babies. PMID- 26113036 TI - Specificity and catalysis hardwired at the RNA-protein interface in a translational proofreading enzyme. AB - Proofreading modules of aminoacyl-tRNA synthetases are responsible for enforcing a high fidelity during translation of the genetic code. They use strategically positioned side chains for specifically targeting incorrect aminoacyl-tRNAs. Here, we show that a unique proofreading module possessing a D-aminoacyl-tRNA deacylase fold does not use side chains for imparting specificity or for catalysis, the two hallmark activities of enzymes. We show, using three distinct archaea, that a side-chain-stripped recognition site is fully capable of solving a subtle discrimination problem. While biochemical probing establishes that RNA plays the catalytic role, mechanistic insights from multiple high-resolution snapshots reveal that differential remodelling of the catalytic core at the RNA peptide interface provides the determinants for correct proofreading activity. The functional crosstalk between RNA and protein elucidated here suggests how primordial enzyme functions could have emerged on RNA-peptide scaffolds before recruitment of specific side chains. PMID- 26113037 TI - H2 S restores the cardioprotection from ischemic post-conditioning in isolated aged rat hearts. AB - This study explored the mechanisms underlying the recovery of myocardial protection from ischemic post-conditioning (PC) by exogenous hydrogen sulfide (H2 S) in aged rat hearts. We observed that ischemia/reperfusion (I/R) inhibited the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and promoted phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) in both young hearts and aged hearts. PC up-regulated ERK1/2 phosphorylations and down regulated p38 MAPK and JNK phosphorylations. Exogenous H2 S further enhanced the role of PC in the young hearts. In the aged hearts, PC failed to affect all these 3 MAPK members, while co-treatment with exogenous H2 S-induced ERK1/2 and reduced p38 MAPK and JNK phosphorylations. These results suggest that exogenous H2 S recovers PC-induced cardioprotection via MAPK pathway in the aged hearts. PMID- 26113038 TI - Residential exposure to traffic noise and risk for non-hodgkin lymphoma among adults. AB - Exposure to traffic noise may result in stress and sleep disturbances, which have been associated with impairment of the immune system. People with weakened immune systems are known to have a higher risk for non-Hodgkin lymphoma (NHL). We aimed to determine whether traffic noise was associated with risk for NHL in a nationwide case-control study. We identified 2753 cases aged 30-84 years with a primary diagnosis of NHL in Denmark between 1992 and 2010. For each case we selected two random population controls, matched on sex and year of birth. Road traffic and railway noise were calculated, and airport noise was estimated for all present and historical residential addresses of cases and controls from 1987 to 2010. Associations between traffic noise and risk for NHL were estimated using conditional logistic regression, adjusted for disposable income, education, cohabiting status and comorbidity. We found that a 5-year time-weighted mean of road traffic noise above 65 dB was associated with an 18% higher risk for NHL (95% confidence interval (CI) 1.01-1.37) when compared to road traffic noise below 55 dB, whereas for exposure between 55 and 65 dB no association was found (odds ratio: 0.98; 95% CI: 0.88-1.08). In analyzes of NHL subtypes, we found no association between road traffic noise and risk for T-cell lymphoma, whereas increased risks for B-cell lymphoma and unspecified lymphomas were observed at exposures above 65 dB. In conclusion, our nationwide study may indicate that high exposure to traffic noise is associated with higher NHL risk. PMID- 26113039 TI - Out of the shadows and into the spotlight: Social blunders fuel fear of self exposure in social anxiety disorder. AB - In a study designed to clarify and extend previous research on social blunders in social anxiety, 32 participants with social anxiety disorder (SAD), 25 anxious control (AC) participants with anxiety disorders other than SAD, and 25 healthy control (HC) participants with no history of anxiety problems estimated the costs of hypothetical blunders committed by either themselves or by others. Participants with SAD rated the costs of their own imagined blunders as highly inflated relative to both AC and HC participants. In contrast, for blunders participants imagined others committing, only SAD and healthy control participants' cost estimates differed from one another. Moreover, concerns about revealing self-flaws--and, in particular, about appearing socially incompetent- accounted for significant, unique variance in SAD participants' exaggerated cost estimates of self blunders, over and above symptoms of social anxiety and depression. These results enhance our understanding of how and why socially anxious individuals negatively appraise social blunders and help to clarify the potential function and role of social mishap exposures in the treatment of SAD. PMID- 26113040 TI - Mammary epithelial cell phagocytosis downstream of TGF-beta3 is characterized by adherens junction reorganization. AB - After weaning, during mammary gland involution, milk-producing mammary epithelial cells undergo apoptosis. Effective clearance of these dying cells is essential, as persistent apoptotic cells have a negative impact on gland homeostasis, future lactation and cancer susceptibility. In mice, apoptotic cells are cleared by the neighboring epithelium, yet little is known about how mammary epithelial cells become phagocytic or whether this function is conserved between species. Here we use a rat model of weaning-induced involution and involuting breast tissue from women, to demonstrate apoptotic cells within luminal epithelial cells and epithelial expression of the scavenger mannose receptor, suggesting conservation of phagocytosis by epithelial cells. In the rat, epithelial transforming growth factor-beta (TGF-beta) signaling is increased during involution, a pathway known to promote phagocytic capability. To test whether TGF-beta enhances the phagocytic ability of mammary epithelial cells, non-transformed murine mammary epithelial EpH4 cells were cultured to achieve tight junction impermeability, such as occurs during lactation. TGF-beta3 treatment promoted loss of tight junction impermeability, reorganization and cleavage of the adherens junction protein E-cadherin (E-cad), and phagocytosis. Phagocytosis correlated with junction disruption, suggesting junction reorganization is necessary for phagocytosis by epithelial cells. Supporting this hypothesis, epithelial cell E cad reorganization and cleavage were observed in rat and human involuting mammary glands. Further, in the rat, E-cad cleavage correlated with increased gamma secretase activity and beta-catenin nuclear localization. In vitro, pharmacologic inhibitors of gamma-secretase or beta-catenin reduced the effect of TGF-beta3 on phagocytosis to near baseline levels. However, beta-catenin signaling through LiCl treatment did not enhance phagocytic capacity, suggesting a model in which both reorganization of cell junctions and beta-catenin signaling contribute to phagocytosis downstream of TGF-beta3. Our data provide insight into how mammary epithelial cells contribute to apoptotic cell clearance, and in light of the negative consequences of impaired apoptotic cell clearance during involution, may shed light on involution-associated breast pathologies. PMID- 26113041 TI - HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation controlled mechanism. AB - Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response. PMID- 26113042 TI - The LIM protein Ajuba promotes adipogenesis by enhancing PPARgamma and p300/CBP interaction. AB - Adipocytes play a vital role in energy homeostasis and adipogenesis is a hierarchically regulated cellular differentiation process, in which the precursor mesenchymal stem cells are differentiated into mature adipocytes. Here, we report Ajuba is an important regulator of adipocyte differentiation by functioning as an obligate co-activator of PPARgamma. Ajuba binds the DNA-binding domain of PPARgamma via its preLIM region in a ligand-independent manner. Depletion of Ajuba in 3T3-L1 cells decreases PPARgamma target gene expression and results in delayed adipogenic differentiation. Conversely, stable overexpression of Ajuba in 3T3-L1 cells increases PPARgamma target gene expression and accelerates adipogenic differentiation. Mechanistic investigations demonstrate that Ajuba recruits p300/CBP via its LIM domain and facilitates p300/CBP binding to PPARgamma. Moreover, Ajuba, PPARgamma, p300/CBP can cooperatively occupy the PPARgamma target promoters and concomitantly increases histone acetylation at these loci. Collectively, these data suggest that Ajuba is a co-activator constitutively associated with PPARgamma and may be a potential therapeutic target for PPARgamma-mediated metabolic disorders. PMID- 26113044 TI - Efficacy of sclerotherapy with radio-opaque foam guided by digital subtraction angiography for the treatment of complex venous malformations of the head and neck. AB - Our aim was to evaluate the efficacy of sclerotherapy using radio-opaque foam and guided by digital subtraction angiography (DSA) for complex venous malformations in the head and neck in 11 selected patients between 2011 and 2013. The sclerosing foam was manufactured by the classic Tessari method and consisted of air, 1% polidocanol, and radio-opaque media iopromide (Ultravist((r))300) in a ratio of 7:2:1. We recorded the site and size of the lesion, time and duration of treatment, and therapeutic response. The lesions were on the face, cheek, temporal region, parotid region, neck, tongue, floor of the mouth, parapharyngeal space, and soft palate. The sclerosing foam was radio-opaque under DSA, and the mean (range) dose was 21 (3-65) ml. A mean (range) of 4 (2-7) treatments was required, and 10 of the 11 patients responded well. In 4 of the 11 cases the lesion resolved completely and in 6 there was a good response. Only one lesion recurred. Early complications included immediate swelling in injected areas, snoring, and pain on swallowing, but there were no air emboli or signs of cutaneous necrosis, and the complications were self-limiting. DSA-guided sclerotherapy with radio-opaque foam was safe and effective for the treatment of complex vascular malformations of the head and neck. PMID- 26113045 TI - Lichenoid eruption associated with use of an e-cigarette. PMID- 26113043 TI - KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer. AB - Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Kruppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras(LSL-G12D/+);Klf4(fl/fl) mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment. PMID- 26113046 TI - Endoscopic management of osteomas of the forehead. AB - Transcutaneous resection is the most common technique for the removal of facial lesions. In recent years, endoscopic techniques have been used in aesthetic surgery of the face, and have achieved good results. We know of few descriptions of this approach. We describe 9 patients who had endoscopic removal of osteomas of the forehead through a single 3 cm incision of the midline, which was concealed 2 cm behind the hairline. PMID- 26113047 TI - Lymph Node Yield in Colon Cancer: Individuals Can Make the Difference. AB - AIM: To investigate the influence of individual surgeons and pathologists on examining an adequate (i.e. >=10) number of lymph nodes in colon cancer resection specimens. PATIENTS AND METHODS: The number of lymph nodes was evaluated in surgically treated patients for colon cancer at our hospital from 2008 through 2010, excluding patients who had received neo-adjuvant treatment. The patient group consisted of 156 patients with a median age of 73 (interquartile range (IQR) 63-82 years) and a median of 12 lymph nodes per patient (IQR 8-15). In 106 patients (67.9%), 10 or more nodes were histopathologically examined. RESULTS: At univariate analysis, the examination of >=10 nodes was influenced by tumour size (p = 0.05), tumour location (p = 0.015), type of resection (p = 0.034), individual surgeon (p = 0.023), and pathologist (p = 0.005). Neither individual surgeons nor pathologists did statistically and significantly influence the chance of finding an N+ status. Age (p = 0.044), type of resection (p = 0.007), individual surgeon (p = 0.012) and pathologist (p = 0.004) were independent prognostic factors in a multivariate model for finding >=10 nodes. CONCLUSION: Though cancer staging was not affected in this study, individual efforts by surgeons and pathologists play a critical role in achieving optimal lymph node yield through conventional methods. PMID- 26113048 TI - Site-specific analysis of B-cell non-Hodgkin's lymphomas of the head and neck: A retrospective 10-year observation. AB - CONCLUSION: B-cell non-Hodgkin's lymphoma (B-NHL) in the head and neck most commonly affected the oropharynx and the cervical lymph node in sexagenarian patients, with more than 70% of these cases being diffuse large B-cell lymphoma (DLBCL). Accordingly, B-NHL should be considered one of the most important differential diagnoses of head and neck malignancies. OBJECTIVES: It has previously been reported that the majority of head and neck malignant lymphomas are B-NHLs. This analysis aimed to assess the site-specific profiles of B-NHL of the head and neck. METHODS: The medical records of patients with B-NHL of the head and neck diagnosed between January 2004 and December 2013 were retrospectively reviewed. The clinical parameters of these patients, including age, sex, site distribution, and histopathologic sub-type, were analyzed. RESULTS: A total of 153 cases (95 males; 58 females) were included in this analysis (male-to-female ratio = 1.64:1). The patient age at the time of diagnosis ranged from 30-92 years (median = 68 years). The oropharynx was the most commonly affected site (40.5%), followed by the cervical lymph nodes (33.3%). The most common histopathologic sub-type was DLBCL (71.9%), followed by follicular lymphoma (11.1%), and extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (9.2%). PMID- 26113049 TI - Diagnostic Value of Different Systematic Prostate Biopsy Methods in the Detection of Prostate Cancer with Ultrasonographic Hypoechoic Lesions--A Comparative Study. AB - OBJECTIVE: To assess if a less extended biopsy in the transperineal approach is sufficient for detection of prostate cancer (PC) in patients with hypoechoic lesions. METHODS: This was a prospective study of 167 consecutive patients with prostate hypoechoic lesion and who underwent transperineal ultrasound (TPUS) guided 12-core and hypoechoic lesion core biopsy between January 2012 and February 2013. RESULTS: PC was detected in 64.1% (107/167) of patients. The PC detection rate of the 12-core prostate biopsy scheme was the highest, but when including the hypoechoic lesion core, there was no difference between the 6- and 12-core schemes (all p > 0.05), irrespective of prostate volume or prostate specific antigen levels (all p > 0.05). CONCLUSIONS: A more limited biopsy scheme could be sufficient for the detection of PC if the hypoechoic lesion is sampled. PMID- 26113051 TI - Is onset of lactation delayed in women with diabetes in pregnancy? A systematic review. AB - AIM: To determine if women with diabetes in pregnancy have a delayed onset of lactation through a systematic review of the literature. METHODS: We searched databases including MEDLINE, Web of Science, PubMed, CINAHL Plus and PsychINFO for articles assessing diabetes in pregnancy and lactogenesis. Thirty-one articles were screened and 10 articles were included in the systematic review. We extracted data on diabetes in pregnancy and onset of lactation (secretory activation or lactogenesis II). RESULTS: The 10 studies examining the association between women with diabetes in pregnancy and delayed onset of lactation reported a significant delay in women with diabetes compared with women without diabetes. Two studies assessed the impact of metabolic control on lactogenesis, and found an association between poorer metabolic control and delayed onset of lactation. CONCLUSIONS: Although this review has found evidence of an association between women experiencing diabetes during pregnancy and delayed onset of lactation, the presence of many potential confounding factors need to be acknowledged. PMID- 26113050 TI - Putative calcium-binding domains of the Caenorhabditis elegans BK channel are dispensable for intoxication and ethanol activation. AB - Alcohol modulates the highly conserved, voltage- and calcium-activated potassium (BK) channel, which contributes to alcohol-mediated behaviors in species from worms to humans. Previous studies have shown that the calcium-sensitive domains, RCK1 and the Ca(2+) bowl, are required for ethanol activation of the mammalian BK channel in vitro. In the nematode Caenorhabditis elegans, ethanol activates the BK channel in vivo, and deletion of the worm BK channel, SLO-1, confers strong resistance to intoxication. To determine if the conserved RCK1 and calcium bowl domains were also critical for intoxication and basal BK channel-dependent behaviors in C. elegans, we generated transgenic worms that express mutated SLO-1 channels predicted to have the RCK1, Ca(2+) bowl or both domains rendered insensitive to calcium. As expected, mutating these domains inhibited basal function of SLO-1 in vivo as neck and body curvature of these mutants mimicked that of the BK null mutant. Unexpectedly, however, mutating these domains singly or together in SLO-1 had no effect on intoxication in C. elegans. Consistent with these behavioral results, we found that ethanol activated the SLO-1 channel in vitro with or without these domains. By contrast, in agreement with previous in vitro findings, C. elegans harboring a human BK channel with mutated calcium sensing domains displayed resistance to intoxication. Thus, for the worm SLO-1 channel, the putative calcium-sensitive domains are critical for basal in vivo function but unnecessary for in vivo ethanol action. PMID- 26113052 TI - Dissemination of clonally related multidrug-resistant Klebsiella pneumoniae in Ireland. AB - In October 2012, an outbreak of gentamicin-resistant, ciprofloxacin non susceptible extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae occurred in a neonatal intensive care unit in Ireland. In order to determine whether the outbreak strain was more widely dispersed in the country, 137 isolates of K. pneumoniae with this resistance phenotype collected from 17 hospitals throughout Ireland between January 2011 and July 2013 were examined. ESBL production was confirmed phenotypically and all isolates were screened for susceptibility to 19 antimicrobial agents and for the presence of genes encoding bla TEM, bla SHV, bla OXA, and bla CTX-M; 22 isolates were also screened for bla KPC, bla NDM, bla VIM, bla IMP and bla OXA-48 genes. All isolates harboured bla SHV and bla CTX-M and were resistant to ciprofloxacin, gentamicin, nalidixic acid, amoxicillin-clavulanate, and cefpodoxime; 15 were resistant to ertapenem, seven to meropenem and five isolates were confirmed as carbapenemase producers. Pulsed-field gel electrophoresis of all isolates identified 16 major clusters, with two clusters comprising 61% of the entire collection. Multilocus sequence typing of a subset of these isolates identified a novel type, ST1236, a single locus variant of ST48. Data suggest that two major clonal groups, ST1236/ST48 (CG43) and ST15/ST14 (CG15) have been circulating in Ireland since at least January 2011. PMID- 26113053 TI - Current controversies in the management of metastatic colorectal cancer. AB - The factors affecting the decisions for the treatment for patients with metastatic colorectal cancer (mCRC) are related to the patient, the tumor, and the treatment itself. Both cetuximab and panitumumab are anti-EGFR monoclonal antibody options for patients with RAS wild-type tumors. Several trials comparing these agents with bevacizumab are analyzed in this paper. The liver is the most common site of metastases in patients with CRC, and perioperative chemotherapy has been shown to yield benefits in this setting. In the second-line treatment for mCRC, maintenance with bevacizumab after progression following first-line treatment is convenient in some groups of patients with mCRC. Also, aflibercept has demonstrated benefits in response rate, progression-free survival, and overall survival in second-line treatment, whereas regorafenib provides benefits to patients progressing on all standard therapies. Several novel therapeutic options for patients with mCRC are under development, and these are discussed. PMID- 26113054 TI - AT-101 inhibits hedgehog pathway activity and cancer growth. AB - PURPOSE: AT-101 is considered as a putative pan-inhibitor of anti-apoptotic Bcl-2 family protein members acting as a BH3 mimetic. It is currently being investigated in phase I/II clinical trial in various types of cancers. In this study, using a series of in vitro and in vivo assays, we evaluated the effect of AT-101 on the hedgehog (Hh) signaling pathway activity and its anticancer ability. RESULTS: We found that AT-101 obviously blocked the Hh signaling pathway activity in response to ShhN-conditioned medium (ShhN CM). This inhibitory effect, to some extent, displayed selectivity against Hh signaling pathway. Furthermore, we identified that AT-101 potentially acted on smoothened (Smo) by sharing the same binding site with cyclopamine, a classical Hh signaling pathway inhibitor. Taking advantage of the patch+/-; p53-/- mouse medulloblastoma model, we observed that AT-101 significantly suppressed the Hh-driven medulloblastoma growth in vitro and in vivo. CONCLUSIONS: This study demonstrates that AT-101 significantly and selectively inhibits Hh pathway activity by potentially targeting Smo and consequently suppresses the growth of Hh-driven cancer. Therefore, this study reveals a novel molecular mechanism responsible for the anticancer action of AT-101 and contributes to the further development of AT-101 as an anticancer drug. PMID- 26113055 TI - Platform Therapy Compared with Natalizumab for Multiple Sclerosis: Relapse Rates and Time to Relapse Among Propensity Score-Matched US Patients. AB - BACKGROUND: Multiple sclerosis (MS) registry data, primarily from Europe, suggest that treatment with natalizumab delays time to relapse compared with platform therapy (interferon beta/glatiramer acetate). OBJECTIVE: This study uses US administrative claims data and propensity score matching (PSM) to compare relapse rates and time to relapse among patients with MS using either platform therapy or natalizumab. METHODS: Adults with MS receiving either platform therapy or natalizumab between January 1, 2009 and April 1, 2012 were identified in the Truven Health MarketScan((r)) Research Databases. Patients were included if they had 12 months of continuous enrollment both before and after the index date (the first claim for either drug cohort) and had 12 months of claims data suggesting consistent treatment adherence during the follow-up period. Characteristics used in PSM included demographics, selected comorbidities and concomitant medications, MS severity, baseline relapse rates, and expenditures. A relapse was defined as an MS-related hospitalization or corticosteroid use. RESULTS: A total of 882 patients were matched. Relapse occurred among significantly fewer patients in the natalizumab group (26.5%) than platform therapy (35.5%, p < 0.001) (hazard ratio 0.69; 95% CI 0.59-0.82). Relapses were also significantly later for those on natalizumab (308 vs 283 days without relapse, p < 0.001). CONCLUSION: Treatment with natalizumab was associated with a significantly lower risk and rate of MS relapse and longer MS relapse-free time compared with platform therapies. PMID- 26113056 TI - A Role for Histone H2B Variants in Endocrine-Resistant Breast Cancer. AB - Acquired resistance to aromatase inhibitors (AIs) remains a major clinical problem in the treatment of estrogen receptor-positive (ER+) breast cancer. We and others have previously reported widespread changes in DNA methylation using breast cancer cell line models of endocrine resistance. Here, we show that the histone variant HIST1H2BE is hypomethylated in estrogen deprivation-resistant C4 12 and long-term estrogen-deprived (LTED) cells compared with parental MCF-7 cells. As expected, this hypomethylation associates with increased expression of HIST1H2BE in C4-12 and LTED cells. Both overexpression and downregulation of HIST1H2BE caused decreased proliferation in breast cancer cell lines suggesting the need for tightly controlled expression of this histone variant. Gene expression analysis showed varied expression of HIST1H2BE in a large panel of breast cancer cell lines, without restriction to specific molecular subtypes. Analysis of HIST1H2BE messenger RNA (mRNA) expression in ER+ AI-treated breast tumors showed significantly higher expression in resistant (n = 19) compared with sensitive (n = 37) tumors (p = 0.01). Using nanostring analysis, we measured expression of all 61 histone variants in endocrine-resistant and endocrine sensitive tumors. We found significant overexpression of 22 variant histone genes in tumors resistant to AI therapy. In silico The Cancer Genome Atlas (TCGA) analysis showed frequent amplification of the HIST1 locus. In summary, our studies show, for the first time, that overexpression of histone variants might be important in endocrine response in ER+ breast cancer, and that overexpression is at least in part mediated via epigenetic mechanisms and amplifications. Future studies addressing endocrine response should include a potential role of these currently understudied histone variants. PMID- 26113057 TI - Snapshots of Conformational Changes Shed Light into the NtrX Receiver Domain Signal Transduction Mechanism. AB - Brucella abortus is an important pathogenic bacterium that has to overcome oxygen deficiency in order to achieve a successful infection. Previously, we proved that a two-component system formed by the histidine kinase NtrY and the response regulator NtrX is essential to achieve an adaptive response to low oxygen tension conditions. Even though the relevance of this signaling pathway has already been demonstrated in other microorganisms, its molecular activation mechanism has not yet been described in detail. In this article, we report the first crystal structures from different conformations of the NtrX receiver domain from B. abortus, and we propose a sequence of events to explain the structural rearrangements along the activation process. The analysis of the structures obtained in the presence of the phosphoryl group analog beryllofluoride led us to postulate that changes in the interface formed by the alpha4 helix and the beta5 strand are important for the activation, producing a reorientation of the alpha5 helix. Also, a biochemical characterization of the NtrX receiver domain enzymatic activities was performed, describing its autophosphorylation and autodephosphorylation kinetics. Finally, the role of H85, an important residue, was addressed by site-directed mutagenesis. Overall, these results provide significant structural basis for understanding the response regulator activation in this bacterial two-component system. PMID- 26113059 TI - Temporal dynamics of repetition suppression to individual faces presented at a fast periodic rate. AB - Periodic presentation of visual stimuli leads to a robust electrophysiological response on the human scalp exactly at the periodic stimulation frequency, a response defined as a "steady-state visual evoked potential" (SSVEP, Regan, 1966). However, recent studies have shown that SSVEPs over the (right) occipito temporal cortex are reduced when the same individual face is repeated at periodic rates of 3 to 9 Hz compared to when different faces are presented (Rossion, 2014). Here, we characterized the temporal dynamics of this repetition suppression effect. We presented different face identities at a rate of 5.88 Hz (stimulus onset asynchrony of 170 ms) for 15 s, followed by the repetition of the exact same face at this rate for 35 s. Compared to a stimulation sequence with different faces only, there was a large and specific decrease of the 5.88 Hz response when the same face was repeated at that rate. This effect was observed over the left and right occipito-temporal cortex, but not over medial occipital electrode sites where SSVEPs are typically measured. In the right hemisphere, this decrease occurred abruptly, i.e., within half a second following the introduction of the same-identity stimulation, with no further decrease until the end of the stimulation. These observations indicate that the SSVEP recorded over high-level visual areas to periodic stimulation is not steady but rather adapts immediately and fully following the repetition of the same individual face, supporting a bottom-up, stimulus-driven account of repetition suppression effects. PMID- 26113061 TI - Family carers' experience of the need for admission of their relative with an intellectual disability to an Assessment and Treatment Unit. AB - BACKGROUND: There is limited research that explores the experiences of family carers of individuals with an intellectual disability requiring admission to a specialist National Health Service Assessment and Treatment Unit. Accordingly, this study aimed to explore family carers' experience in respect of this phenomenon and their relationships with professionals at this time. METHODS: Interpretative phenomenological analysis was used. Six family carers (three mothers and three fathers) participated and were interviewed via the use of semi structured interviews. FINDINGS: Five major themes were developed to represent how carers made sense and gave meaning to their experience. They illustrate how this experience had a significant influence on their sense of value and self identity. It resulted in higher levels of anxiety, stress and uncertainty about the future of their relative and their identity as a carer. Significantly, professionals are identified as having a pivotal role in influencing how carers come to view their sense of self, identity, value and importance. CONCLUSION: The admission of their relative was a time of increased vulnerability for carers in respect of maintaining a sense of self-identity. Engaging with services and professionals had a major influence on situating them within the social structure that makes up the formal system of support. This had a pivotal role in influencing and determining how participants identified with their sense of self. PMID- 26113060 TI - Perinatal risk factors for acute myeloid leukemia. AB - Infectious etiologies have been hypothesized for acute leukemias because of their high incidence in early childhood, but have seldom been examined for acute myeloid leukemia (AML). We conducted the first large cohort study to examine perinatal factors including season of birth, a proxy for perinatal infectious exposures, and risk of AML in childhood through young adulthood. A national cohort of 3,569,333 persons without Down syndrome who were born in Sweden in 1973 2008 were followed up for AML incidence through 2010 (maximum age 38 years). There were 315 AML cases in 69.7 million person-years of follow-up. We found a sinusoidal pattern in AML risk by season of birth (P < 0.001), with peak risk among persons born in winter. Relative to persons born in summer (June-August), incidence rate ratios for AML were 1.72 (95 % CI 1.25-2.38; P = 0.001) for winter (December-February), 1.37 (95 % CI 0.99-1.90; P = 0.06) for spring (March-May), and 1.27 (95 % CI 0.90-1.80; P = 0.17) for fall (September-November). Other risk factors for AML included high fetal growth, high gestational age at birth, and low maternal education level. These findings did not vary by sex or age at diagnosis. Sex, birth order, parental age, and parental country of birth were not associated with AML. In this large cohort study, birth in winter was associated with increased risk of AML in childhood through young adulthood, possibly related to immunologic effects of early infectious exposures compared with summer birth. These findings warrant further investigation of the role of seasonally varying perinatal exposures in the etiology of AML. PMID- 26113062 TI - The effectiveness of Colourful Semantics on narrative skills in children with intellectual disabilities in Sri Lanka. AB - BACKGROUND: Children diagnosed with intellectual difficulties experience difficulties with narrative skills, due to limited syntactic knowledge. The Colourful Semantics approach with thematic roles and a colour coding system may encourage syntactic development in children experiencing intellectual disabilities. AIM: To evaluate the effectiveness of using the Colourful Semantics approach to develop narrative skills in Sri Lankan Tamil-speaking children diagnosed with intellectual difficulties. METHODS: Thirty Sri Lankan Tamil speaking children identified with intellectual difficulties were included. The Colourful Semantics approach was offered twice a week for 6 weeks, facilitated by the class teachers. Pre- and post-intervention narrative skill assessments were undertaken and analysed for content and syntactic structures. RESULTS: The results indicate positive changes post-intervention on the qualitative and quantitative narrative skills measures undertaken on content and syntactic structures. CONCLUSIONS AND IMPLICATIONS: The Colourful Semantics approach is an effective therapy approach to support development of narrative skills in children with intellectual difficulties. PMID- 26113063 TI - Culture Moderates Biases in Search Decisions. AB - Prior studies suggest that people often search insufficiently in sequential search tasks compared with the predictions of benchmark optimal strategies that maximize expected payoff. However, those studies were mostly conducted in individualist Western cultures; Easterners from collectivist cultures, with their higher susceptibility to escalation of commitment induced by sunk search costs, could exhibit a reversal of this undersearch bias by searching more than optimally, but only when search costs are high. We tested our theory in four experiments. In our pilot experiment, participants generally undersearched when search cost was low, but only Eastern participants oversearched when search cost was high. In Experiments 1 and 2, we obtained evidence for our hypothesized effects via a cultural-priming manipulation on bicultural participants in which we manipulated the language used in the program interface. We obtained further process evidence for our theory in Experiment 3, in which we made sunk costs nonsalient in the search task-as expected, cross-cultural effects were largely mitigated. PMID- 26113065 TI - Turbulent Times, Rocky Relationships: Relational Consequences of Experiencing Physical Instability. AB - What influences how people feel about and behave toward their romantic partners? Extending beyond features of the partners, relationship experiences, and social context, the current research examines whether benign, relationship-irrelevant factors-such as one's somatic experiences-can influence relationship perceptions and interpersonal behavior. Drawing on the embodiment literature, we propose that experiencing physical instability can undermine perceptions of relationship stability. Participants who experienced physical instability by sitting at a wobbly workstation rather than a stable workstation (Study 1), standing on one foot rather than two (Study 2), or sitting on an inflatable seat cushion rather than a rigid one (Study 3) perceived their romantic relationships to be less likely to last. Results were consistent with risk-regulation theory: Perceptions of relational instability were associated with reporting lower relationship quality (Studies 1-3) and expressing less affection toward the partner (Studies 2 and 3). These findings indicate that benign physical experiences can influence perceptions of relationship stability, exerting downstream effects on consequential relationship processes. PMID- 26113064 TI - Effects of Violent-Video-Game Exposure on Aggressive Behavior, Aggressive-Thought Accessibility, and Aggressive Affect Among Adults With and Without Autism Spectrum Disorder. AB - Recent mass shootings have prompted the idea among some members of the public that exposure to violent video games can have a pronounced effect on individuals with autism spectrum disorder (ASD). Empirical evidence for or against this claim has been missing, however. To address this issue, we assigned adults with and without ASD to play a violent or nonviolent version of a customized first-person shooter video game. After they played the game, we assessed three aggression related outcome variables (aggressive behavior, aggressive-thought accessibility, and aggressive affect). Results showed strong evidence that adults with ASD, compared with typically developing adults, are not differentially affected by acute exposure to violent video games. Moreover, model comparisons provided modest evidence against any effect of violent game content whatsoever. Findings from this experiment suggest that societal concerns that exposure to violent games may have a unique effect on adults with autism are not supported by evidence. PMID- 26113066 TI - Reply: To PMID 25339645. PMID- 26113067 TI - Topographic Diagnosis of Papillary Craniopharyngiomas: The Need for an Accurate MRI-Surgical Correlation. PMID- 26113068 TI - Longitudinal Mixed-Effect Model Analysis of the Association between Global and Tissue-Specific Brain Atrophy and Lesion Accumulation in Patients with Clinically Isolated Syndrome. AB - BACKGROUND AND PURPOSE: The relationship between lesion formation and brain atrophy development in the early phase of multiple sclerosis is unclear. We investigated the association between new lesion accumulation and brain atrophy progression in patients with clinically isolated syndrome over 48 months. MATERIALS AND METHODS: Patients with clinically isolated syndrome (n = 210) were evaluated with 1.5T MR imaging at baseline and at 6, 12, 24, 36, and 48 months as part of a multicenter observational study of early administration of intramuscular interferon beta-1a. Mixed-effect model analyses, adjusted for age, sex, and treatment status, investigated the association between accumulation of contrast-enhancing and T2 lesions and brain-volume percent changes in a 48-month period. RESULTS: In patients with clinically isolated syndrome, the average whole brain volume decreased 2.5%, the mean lateral ventricle volume increased 16.9%, and a mean of 7.7 new/enlarging T2 lesions accumulated over the follow-up period. Patients with clinically isolated syndrome who showed greater percentages of change in whole-brain, white and gray matter, cortical, and lateral ventricle volumes over the follow-up period had more severe lesion outcomes at baseline (all P < .007). There were significant associations between decreased individual brain-volume measures at baseline and greater percentages of change during follow up (P < .05). We found a significant association between the total cumulative number of new/enlarging T2 lesions and the evolution of whole-brain (P < .001), lateral ventricle (P = .007), gray matter and thalamic (P = .013), subcortical deep gray matter (P = .015), and cortical (P = .036) volumes over the follow-up period. CONCLUSIONS: Lesion accumulation and brain-volume changes occur simultaneously in the early phase of clinically isolated syndrome. More severe lesion and brain-volume outcomes at baseline were associated with greater development of brain atrophy over the follow-up period in patients with clinically isolated syndrome. PMID- 26113069 TI - Current Applications of MRI-Guided Laser Interstitial Thermal Therapy in the Treatment of Brain Neoplasms and Epilepsy: A Radiologic and Neurosurgical Overview. AB - Minimally invasive stereotactic tumor ablation is a viable option for the treatment of benign and malignant intracranial lesions. Although surgical excision constitutes first-line therapy for various brain pathologies, it can cause irreversible neurologic deficits. Additionally, many patients who may benefit from surgery do not qualify as surgical candidates due to multiple comorbidities. Recent advancements in laser interstitial thermal therapy, namely the ability to monitor ablation in real-time under MR imaging, have improved the safety and efficacy of the procedure. MRI-guided laser interstitial thermal therapy is currently used as a minimally invasive treatment for brain metastases, radiation necrosis, glioma, and epilepsy. This article will discuss the principles, suggested indications, complications, and imaging characteristics of MRI-guided laser interstitial thermal therapy as they pertain to the treatment of brain pathology. PMID- 26113070 TI - Timing-Invariant CT Angiography Derived from CT Perfusion Imaging in Acute Stroke: A Diagnostic Performance Study. AB - BACKGROUND AND PURPOSE: Timing-invariant (or delay-insensitive) CT angiography derived from CT perfusion data may obviate a separate cranial CTA in acute stroke, thus enhancing patient safety by reducing total examination time, radiation dose, and volume of contrast material. We assessed the diagnostic accuracy of timing-invariant CTA for detecting intracranial artery occlusion in acute ischemic stroke, to examine whether standard CTA can be omitted. MATERIALS AND METHODS: Patients with suspected ischemic stroke were prospectively enrolled and underwent CTA and CTP imaging at admission. Timing-invariant CTA was derived from the CTP data. Five neuroradiologic observers assessed all images for the presence and location of intracranial artery occlusion in a blinded and randomized manner. Sensitivity and specificity of timing-invariant CTA and standard CTA were calculated by using an independent expert panel as the reference standard. Interrater agreement was determined by using kappa statistics. RESULTS: We included 108 patients with 47 vessel occlusions. Overall, standard CTA and timing-invariant CTA provided similar high diagnostic accuracy for occlusion detection with a sensitivity of 96% (95% CI, 90%-100%) and a specificity of 100% (99%-100%) for standard CTA and a sensitivity of 98% (95% CI, 94%-100%) and a specificity of 100% (95% CI, 100%-100%) for timing-invariant CTA. For proximal large-vessel occlusions, defined as occlusions of the ICA, basilar artery, and M1, the sensitivity and specificity were 100% (95% CI, 100%-100%) for both techniques. Interrater agreement was good for both techniques (mean kappa value, 0.75 and 0.76). CONCLUSIONS: Timing-invariant CTA derived from CTP data provides diagnostic accuracy similar to that of standard CTA for the detection of artery occlusions in acute stroke. PMID- 26113072 TI - Injury of the Contralateral Lower Ascending Reticular Activating System by an Intracerebral Hemorrhage. PMID- 26113071 TI - MRI Tractography of Corticospinal Tract and Arcuate Fasciculus in High-Grade Gliomas Performed by Constrained Spherical Deconvolution: Qualitative and Quantitative Analysis. AB - BACKGROUND AND PURPOSE: MR imaging tractography is increasingly used to perform noninvasive presurgical planning for brain gliomas. Recently, constrained spherical deconvolution tractography was shown to overcome several limitations of commonly used DTI tractography. The purpose of our study was to evaluate WM tract alterations of both the corticospinal tract and arcuate fasciculus in patients with high-grade gliomas, through qualitative and quantitative analysis of probabilistic constrained spherical deconvolution tractography, to perform reliable presurgical planning. MATERIALS AND METHODS: Twenty patients with frontoparietal high-grade gliomas were recruited and evaluated by using a 3T MR imaging scanner with both morphologic and diffusion sequences (60 diffusion directions). We performed probabilistic constrained spherical deconvolution tractography and tract quantification following diffusion tensor parameters: fractional anisotropy; mean diffusivity; linear, planar, and spherical coefficients. RESULTS: In all patients, we obtained tractographic reconstructions of the medial and lateral portions of the corticospinal tract and arcuate fasciculus, both on the glioma-affected and nonaffected sides of the brain. The affected lateral corticospinal tract and the arcuate fasciculus showed decreased fractional anisotropy (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) and linear coefficient (z = 2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006) along with increased spherical coefficient (z = -2.51, n = 20, P = .006; z = 2.52, n = 20, P = .006). Mean diffusivity values were increased only in the lateral corticospinal tract (z = -2.53, n = 20, P = .006). CONCLUSIONS: In this study, we demonstrated that probabilistic constrained spherical deconvolution can provide essential qualitative and quantitative information in presurgical planning, which was not otherwise achievable with DTI. These findings can have important implications for the surgical approach and postoperative outcome in patients with glioma. PMID- 26113073 TI - Influence of facial skin ageing characteristics on the perceived age in a Russian female population. AB - OBJECTIVE: The desire for a youthful look remains a powerful motivator in the purchase of cosmetics by women globally. To develop an anti-ageing solution that targets the need of end consumers, it is critical to understand which signs of ageing really matter to them and which influence their age perception. To date, such research has not been performed in a Russian population. The aim of this work was to identify the signs of ageing that contribute the most to an 'older' or 'younger' look for Russian women aged 40 years old and above. METHODS: The age of 203 Russian female volunteers was estimated from their standard photographs by a total of 629 female naive assessors aged 20-65 years old. Perceived age data were related to 23 facial skin features previously measured using linear correlation coefficients. Differences in average severity of the correlating skin ageing features were evaluated between women perceived older and women perceived younger than their chronological age. Volunteers' responses to a ranking question on their key ageing skin concerns previously collected were analysed to provide an additional view on facial ageing from the consumer perspective. RESULTS: Nine facial skin ageing features were found to correlate the most with perceived age out of the 23 measured. Such results showed the importance of wrinkles in the upper part of the face (crow's feet, glabellar, under eye and forehead wrinkles), but also wrinkles in the lower half of the face associated with facial sagging (upper lip, nasolabial fold). Sagging was confirmed of key importance to female volunteers aged 41-65 years old who were mostly concerned by the sagging of their jawline, ahead of under eye and crow's feet wrinkle. The severity of hyperpigmented spots, red and brown, was also found to contribute to perceived age although to a weaker extent. CONCLUSION: By providing a clear view on the signs of ageing really matter to Russian women who are aged 40 years old and above, this research offers key information for the development of relevant anti ageing solutions specifically targeting their needs and their desire to achieve younger-looking skin. PMID- 26113074 TI - Recapitulation of in vivo-like paracrine signals of human mesenchymal stem cells for functional neuronal differentiation of human neural stem cells in a 3D microfluidic system. AB - Paracrine signals produced from stem cells influence tissue regeneration by inducing the differentiation of endogenous stem or progenitor cells. However, many recent studies that have investigated paracrine signaling of stem cells have relied on either two-dimensional transwell systems or conditioned medium culture, neither of which provide optimal culture microenvironments for elucidating the effects of paracrine signals in vivo. In this study, we recapitulated in vivo like paracrine signaling of human mesenchymal stem cells (hMSCs) to enhance functional neuronal differentiation of human neural stem cells (hNSCs) in three dimensional (3D) extracellular matrices (ECMs) within a microfluidic array platform. In order to amplify paracrine signaling, hMSCs were genetically engineered using cationic polymer nanoparticles to overexpress glial cell-derived neurotrophic factor (GDNF). hNSCs were cultured in 3D ECM hydrogel used to fill central channels of the microfluidic device, while GDNF-overexpressing hMSCs (GDNF-hMSCs) were cultured in channels located on both sides of the central channel. This setup allowed for mimicking of paracrine signaling between genetically engineered hMSCs and endogenous hNSCs in the brain. Co-culture of hNSCs with GDNF-hMSCs in the 3D microfluidic system yielded reduced glial differentiation of hNSCs while significantly enhancing differentiation into neuronal cells including dopaminergic neurons. Neuronal cells produced from hNSCs differentiating in the presence of GDNF-hMSCs exhibited functional neuron-like electrophysiological features. The enhanced paracrine ability of GDNF-hMSCs was finally confirmed using an animal model of hypoxic-ischemic brain injury. This study demonstrates the presented 3D microfluidic array device can provide an efficient co-culture platform and provide an environment for paracrine signals from transplanted stem cells to control endogenous neuronal behaviors in vivo. PMID- 26113075 TI - Lentiviral vector system for coordinated constitutive and drug controlled tetracycline-regulated gene co-expression. AB - Constitutive co-expression of cooperating transgenes using retroviral integrating vectors is frequently used for genetic modification of different cell types to establish therapeutic or cancer models. However, such approaches are unable to dissect the influence of dose, order and reversibility of transgene expression on the fate of newly developed therapeutic/malignant phenotypes. We present a modular lentiviral vector system, which provides expression of constitutive and inducible components. To demonstrate its functionality, we constitutively expressed the well-described transcription factor Meis1 followed by inducible co expression of collaborating partner Hoxa9 under the control of tetracycline responsive promoters in murine fibroblasts and primary hematopoietic progenitor cells (HPCs). Fluorescent markers to track transgene co-expression revealed tightly controlled, efficiently inducible and reversible but cell type dependent gene transfer over time. We demonstrated dose-dependent blockade of myeloid differentiation when both Meis1/Hoxa9 were concomitantly overexpressed in primary HPCs in vitro, but the absence of the transformed phenotype in non-induced samples or when Hoxa9 expression was down-regulated. This system combines the advantages of lentiviral gene transfer and the opportunity for drug-controlled co expression of multiple transgenes to dissect, among others, gene networks governing complex cell behavior, such as proto-oncogene dose-dependent leukemogenic pathways or collaborating mechanisms of genes enhancing competitive fitness of hematopoietic cells. PMID- 26113077 TI - Conditioning with rabbit versus horse ATG dramatically alters clinical outcomes in identical twins with severe aplastic anemia transplanted with the same allogeneic donor. AB - Severe aplastic anemia (SAA) is a rare disorder leading to bone marrow failure, which if left untreated, is invariably fatal. Conventional therapies with immunosuppressive therapy or allogeneic hematopoietic stem cell transplantation (HSCT) are highly effective. HSCT can offer a greater outcome in younger patients who have an available HLA match-related donor. Recent studies showing the addition of antithymocyte globulin (ATG) to the conditioning regimen improves engraftment and reduces the risk of graft-versus-host disease (GVHD).There are currently two ATG preparations in the USA, equine (or horse) and rabbit ATG. These agents are pharmacologically distinct, having significant differences in their pharmacokinetics and in vivo immunosuppressive effects [N Engl J Med 365(5):430-438, 2011]. Here, we report a case of two monozygotic twins with constitutional SAA that evolved to myelodysplastic syndrome (MDS) who both underwent allogeneic peripheral blood stem cell transplantation (PBSC) from the same single HLA antigen mismatched sibling donor with the only difference in the transplant regimen being the type of ATG used in the preparative regimen; one twin received horse ATG and the other received rabbit ATG during conditioning. This report emphasizes that dramatic differences in donor T cell chimerism and clinical outcomes including GVHD can occur as a consequence of the type of ATG that is utilized in the transplant conditioning regimen. These differences highlight that these agents should not be considered interchangeable drugs when used in this setting. PMID- 26113078 TI - Erratum: Family medicine model in Turkey: a qualitative assessment from the perspectives of primary care workers. PMID- 26113076 TI - Acute TNF-induced repression of cell identity genes is mediated by NFkappaB directed redistribution of cofactors from super-enhancers. AB - The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) is directly involved and required for the acute activation of the inflammatory gene program. Here, we show that the major transactivating subunit of NFkappaB, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high-occupancy sites within super-enhancers. Based on these data, we have developed models that, with high accuracy, predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super enhancers in a highly cell-type-specific manner. Our results propose a novel paradigm for NFkappaB-mediated repression, whereby NFkappaB selectively redistributes cofactors from high-occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes. PMID- 26113079 TI - Three-dimensional observation of Virchow-Robin spaces in the basal ganglia and white matter and their relevance to idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Virchow-Robin spaces (VRS) are brain perivascular spaces containing perforating arteries. Although enlarged VRS are associated with various disorders such as Alzheimer's disease, cerebrovascular disease, and head trauma, their functional role remains unclear. Using highly fluid-sensitive magnetic resonance imaging (MRI) sequences, fine morphological features of VRS and their relevance to idiopathic normal pressure hydrocephalus (iNPH) were investigated. METHODS: Three-dimensional constructive interference in steady state (3D-CISS) on 3 Tesla MRI was applied to 29 individuals. The morphology and number of VRS in the basal ganglia and white matter were compared between 20 patients with iNPH and nine age matched controls. The VRS number per hemisphere was classified into three grades: few, moderate, and abundant. RESULTS: Virchow-Robin spaces in the basal ganglia were curved, irregularly sized and shaped, and communicated with the cerebrospinal fluid in the subarachnoid space; they contained perforating arteries. VRS in the white matter were straight, smooth, homogeneously sized and shaped, and did not penetrate the cortex. Arteries were not seen in VRS of the white matter. White matter VRS were sparse in patients with iNPH. In contrast, basal ganglia VRS positively correlated with age. Postoperatively after shunt surgery, VRS in the white matter were mildly decreased in diameter, but not in number. No significant changes were noted in basal ganglia VRS. CONCLUSIONS: The present study revealed different morphological features of VRS in the basal ganglia and white matter. VRS in the basal ganglia were seen as genuine perivascular spaces; while neither communication with subarachnoid spaces nor arteries were seen in white matter VRS, even by 3D-CISS sequences and high resolution magnetic resonance angiography on 3T-MRI. White matter VRS were sparse in patients with iNPH and they were mildly decreased in diameter, but did not change in number after surgery. At present, it remains unclear whether the white matter VRS are dilated interstitial fluid spaces or cerebral amyloid angiopathy, or both. Further studies are necessary to elucidate the functional role of VRS in normal subjects and patients with iNPH. PMID- 26113080 TI - Improving search efficiency for systematic reviews of diagnostic test accuracy: an exploratory study to assess the viability of limiting to MEDLINE, EMBASE and reference checking. AB - BACKGROUND: Increasing numbers of systematic reviews evaluating the diagnostic test accuracy of technologies are being published. Currently, review teams tend to apply conventional systematic review standards to identify relevant studies for inclusion, for example sensitive searches of multiple bibliographic databases. There has been little evaluation of the efficiency of searching only one or two such databases for this type of review. The aim of this study was to assess the viability of an approach that restricted searches to MEDLINE, EMBASE and the reference lists of included studies. METHODS: A convenience sample of nine Health Technology Assessment (HTA) systematic reviews of diagnostic test accuracy, with 302 included citations, was analysed to determine the number and proportion of included citations that were indexed in and retrieved from MEDLINE and EMBASE. An assessment was also made of the number and proportion of citations not retrieved from these databases but that could have been identified from the reference lists of included citations. RESULTS: 287/302 (95 %) of the included citations in the nine reviews were indexed across MEDLINE and EMBASE. The reviews' searches of MEDLINE and EMBASE accounted for 85 % of the included citations (256/302). Of the forty-six (15 %) included citations not retrieved by the published searches, 24 (8 %) could be found in the reference lists of included citations. Only 22/302 (7 %) of the included citations were not found by the proposed, more efficient approach. CONCLUSIONS: The proposed approach would have accounted for 280/302 (93 %) of included citations in this sample of nine systematic reviews. This exploratory study suggests that there might be a case for restricting searches for systematic reviews of diagnostic test accuracy studies to MEDLINE, EMBASE and the reference lists of included citations. The conduct of such reviews might be rendered more efficient by using this approach. PMID- 26113081 TI - Bronchopulmonary Neuroendocrine Neoplasms and Their Precursor Lesions in Multiple Endocrine Neoplasia Type 1. AB - OBJECTIVE: The prevalence and clinical behavior of bronchopulmonary neuroendocrine tumors (bNET) associated with multiple endocrine neoplasia type 1 (MEN1) are not well defined. This study aimed to determine the prevalence, potential precursor lesions and prognosis of bNET in patients with MEN1. METHODS: A database of 75 prospectively collected MEN1 cases was retrospectively analyzed for bNET. Patient characteristics, imaging and treatment were evaluated. Resection specimens of operated patients were reassessed by two specialized pathologists. Available CT scans of the whole cohort were reviewed to determine the prevalence of bronchopulmonary nodules. RESULTS: Five of the 75 MEN1 patients (6.6%; 2 male, 3 female) developed histologically confirmed bNET after a median follow-up of 134 months. The median age at diagnosis of bNET was 47 years (range 31-67), and all patients were asymptomatic. Four patients underwent anatomic lung resections with lymphadenectomy; the remaining patient with multiple lesions had only a wedge resection of the largest bNET. Tumor sizes ranged from 7 to 32 mm in diameter, and all bNET were well differentiated. Two patients had lymph node metastases. Two of 4 reevaluated resection specimens revealed multifocal bNET, and 3 specimens showed tumorlets (up to 3) associated with multifocal areas of a neuroendocrine cell hyperplasia within the subsegmental bronchi. One bNET-related death (1.3%) occurred during long-term follow-up. Review of the available CT scans of the patients without proven bNET revealed small bronchopulmonary lesions (>=3 mm) in 16 of 53 cases (30.2%). CONCLUSIONS: bNET in MEN1 might be more common than previously recognized. Their natural course seems to be rather benign. Multifocal tumorlets and multifocal neuroendocrine cell hyperplasia might represent their precursor lesions. PMID- 26113082 TI - Detection of residual rifampicin in urine via fluorescence quenching of gold nanoclusters on paper. AB - BACKGROUND: Rifampicin or rifampin (R) is a common drug used to treat inactive meningitis, cholestatic pruritus and tuberculosis (TB), and it is generally prescribed for long-term administration under regulated dosages. Constant monitoring of rifampicin is important for controlling the side effects and preventing overdose caused by chronic medication. In this study, we present an easy to use, effective and less costly method for detecting residual rifampicin in urine samples using protein (bovine serum albumin, BSA)-stabilized gold nanoclusters (BSA-Au NCs) adsorbed on a paper substrate in which the concentration of rifampicin in urine can be detected via fluorescence quenching. The intensity of the colorimetric assay performed on the paper-based platforms can be easily captured using a digital camera and subsequently analyzed. RESULTS: The decreased fluorescence intensity of BSA-Au NCs in the presence of rifampicin allows for the sensitive detection of rifampicin in a range from 0.5 to 823 ug/mL. The detection limit for rifampicin was measured as 70 ng/mL. The BSA-Au NCs were immobilized on a wax-printed paper-based platform and used to conduct real-time monitoring of rifampicin in urine. CONCLUSION: We have developed a robust, cost-effective, and portable point-of-care medical diagnostic platform for the detection of rifampicin in urine based on the ability of rifampicin to quench the fluorescence of immobilized BSA-Au NCs on wax-printed papers. The paper-based assay can be further used for the detection of other specific analytes via surface modification of the BSA in BSA-Au NCs and offers a useful tool for monitoring other diseases. PMID- 26113083 TI - Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice. AB - GNAQ and GNA11 are heterotrimeric G protein alpha subunits, which are mutated in a mutually exclusive pattern in most cases of uveal melanoma, one of the most aggressive cancers. Here we introduce the first transgenic mouse model of uveal melanoma, which develops cancers induced by expression of oncogenic GNAQ(Q209L) under control of the Rosa26 promoter. Disease penetrance is 100% by 3 months of age, with 94% of mice also developing lung tumors. In this model, the Yap protein of the Hippo pathway is activated in the eyes, and blood vessels near the lesions in the head and lungs exhibit melanocytic invasion. While full transcription levels are not necessary for GNAQ(Q209L) to transform mouse melanocytes, we obtained suggestive evidence of a selective advantage for increased GNAQ(Q209L) expression in human tumors. Intriguingly, enforced expression of GNAQ(Q209L) progressively eliminated melanocytes from the interfollicular epidermis in adults, possibly explaining the near absence of GNAQ(Q209) mutations in human epithelial melanomas. The mouse model also exhibited dermal nevi and melanocytic neoplasms of the central nervous system, accompanied by impaired hearing and balance, identifying a novel role for GNAQ in melanocyte-like cells of the inner ear. Overall, this model offers a new tool to dissect signaling by oncogenic GNAQ and to test potential therapeutics in an in vivo setting where GNAQ(Q209L) mutations contribute to both the initiation and metastatic progression of uveal melanoma. PMID- 26113085 TI - Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rgammanull Immunodeficient Mice. AB - A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4(+) T cell-mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT 29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNgamma and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. PMID- 26113084 TI - Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function. AB - The "Warburg effect" describes a peculiar metabolic feature of many solid tumors, namely their increased glucose uptake and high glycolytic rates, which allow cancer cells to accumulate building blocks for the biosynthesis of macromolecules. During aerobic glycolysis, pyruvate is preferentially metabolized to lactate by the enzyme lactate dehydrogenase-A (LDH-A), suggesting a possible vulnerability at this target for small-molecule inhibition in cancer cells. In this study, we used FX11, a small-molecule inhibitor of LDH-A, to investigate this possible vulnerability in a panel of 15 patient-derived mouse xenograft (PDX) models of pancreatic cancer. Unexpectedly, the p53 status of the PDX tumor determined the response to FX11. Tumors harboring wild-type (WT) TP53 were resistant to FX11. In contrast, tumors harboring mutant TP53 exhibited increased apoptosis, reduced proliferation indices, and attenuated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WT TP53 tumors, with FX11 administration downregulating metabolic activity only in mutant TP53 tumors. Through a noninvasive quantitative assessment of lactate production, as determined by 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate, we confirmed that FX11 administration inhibited pyruvate-to-lactate conversion only in mutant TP53 tumors, a feature associated with reduced expression of the TP53 target gene TIGAR, which is known to regulate glycolysis. Taken together, our findings highlight p53 status in pancreatic cancer as a biomarker to predict sensitivity to LDH-A inhibition, with regard to both real-time noninvasive imaging by 13C MRS as well as therapeutic response. PMID- 26113086 TI - A Polymer-Based Antibody-Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy. AB - Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development. PMID- 26113087 TI - Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations. AB - Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of AID transgenic (AID Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of AID Tg mice. Using deep sequencing, we also detected Kras and c-Myc mutations in our analysis of the whole pancreas of AID Tg mice. In addition, Sanger sequencing confirmed the presence of Kras, c-Myc, and Smad4 mutations, with the typical mutational footprint of AID in precancerous lesions in AID Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC. PMID- 26113088 TI - Vaccine hesitancy and unfalsifiability. PMID- 26113089 TI - Oral health outcomes. PMID- 26113090 TI - Stainless steel crowns. PMID- 26113091 TI - Author's response. PMID- 26113092 TI - Unsatisfied patients. PMID- 26113093 TI - Authors' response. PMID- 26113094 TI - Selection bias. PMID- 26113095 TI - Author's response. PMID- 26113096 TI - Authors' response. PMID- 26113097 TI - Caries classification. PMID- 26113098 TI - Fracture resistance of computer-aided design and computer-aided manufacturing ceramic crowns cemented on solid abutments. AB - BACKGROUND: Because no information was found in the dental literature regarding the fracture resistance of all-ceramic crowns using CEREC (Sirona) computer-aided design and computer-aided manufacturing (CAD-CAM) system on solid abutments, the authors conducted a study. METHODS: Sixty synOcta (Straumann) implant replicas and regular neck solid abutments were embedded in acrylic resin and randomly assigned (n = 20 per group). Three types of ceramics were used: feldspathic, CEREC VITABLOCS Mark II (VITA); leucite, IPS Empress CAD (Ivoclar Vivadent); and lithium disilicate, IPS e.max CAD (Ivoclar Vivadent). The crowns were fabricated by the CEREC CAD-CAM system. After receiving glaze, the crowns were cemented with RelyX U200 (3M ESPE) resin cement under load of 1 kilogram. For each ceramic, one half of the specimens were subjected to the fracture resistance testing in a universal testing machine with a crosshead speed of 1 millimeter per minute, and the other half were subjected to the fractured resistance testing after 1,000,000 cyclic fatigue loading at 100 newtons. RESULTS: According to a 2-way analysis of variance, the interaction between the material and mechanical cycling was significant (P = .0001). According to a Tukey test (alpha = .05), the fracture resistance findings with or without cyclic fatigue loading were as follows, respectively: CEREC VITABLOCKS Mark II (405 N/454 N) was statistically lower than IPS Empress CAD (1169 N/1240 N) and IPS e.max CAD (1378 N/1025 N) (P < .05). The IPS Empress CAD and IPS e.max CAD did not differ statistically (P > .05). According to a t test, there was no statistical difference in the fracture resistance with and without cyclic fatigue loading for CEREC VITABLOCS Mark II and IPS Empress CAD (P > .05). For IPS e.max CAD, the fracture resistance without cyclic fatigue loading was statistically superior to that obtained with cyclic fatigue loading (P < .05). CONCLUSIONS: The IPS Empress CAD and IPS e.max CAD showed higher fracture resistance compared with CEREC VITABLOCS Mark II. The cyclic fatigue loading negatively influenced only IPS e.max CAD. PRACTICAL IMPLICATIONS: The CEREC VITABLOCS Mark II, IPS Empress CAD, and IPS e.max CAD ceramic crowns cemented on solid abutments showed sufficient resistance to withstand normal chewing forces. PMID- 26113100 TI - Evidence-based clinical practice guideline on the nonsurgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts. AB - BACKGROUND: A panel of experts convened by the American Dental Association Council on Scientific Affairs presents an evidence-based clinical practice guideline on nonsurgical treatment of patients with chronic periodontitis by means of scaling and root planing (SRP) with or without adjuncts. METHODS: The authors developed this clinical practice guideline according to the American Dental Association's evidence-based guideline development methodology. This guideline is founded on a systematic review of the evidence that included 72 research articles providing clinical attachment level data on trials of at least 6 months' duration and published in English through July 2014. The strength of each recommendation (strong, in favor, weak, expert opinion for, expert opinion against, and against) is based on an assessment of the level of certainty in the evidence for the treatment's benefit in combination with an assessment of the balance between the magnitude of the benefit and the potential for adverse effects. PRACTICAL IMPLICATIONS AND CONCLUSIONS: For patients with chronic periodontitis, SRP showed a moderate benefit, and the benefits were judged to outweigh potential adverse effects. The authors voted in favor of SRP as the initial nonsurgical treatment for chronic periodontitis. Although systemic subantimicrobial-dose doxycycline and systemic antimicrobials showed similar magnitudes of benefits as adjunctive therapies to SRP, they were recommended at different strengths (in favor for systemic subantimicrobial-dose doxycycline and weak for systemic antimicrobials) because of the higher potential for adverse effects with higher doses of antimicrobials. The strengths of 2 other recommendations are weak: chlorhexidine chips and photodynamic therapy with a diode laser. Recommendations for the other local antimicrobials (doxycycline hyclate gel and minocycline microspheres) were expert opinion for. Recommendations for the nonsurgical use of other lasers as SRP adjuncts were limited to expert opinion against because there was uncertainty regarding their clinical benefits and benefit-to-adverse effects balance. Note that expert opinion for does not imply endorsement but instead signifies that evidence is lacking and the level of certainty in the evidence is low. PMID- 26113099 TI - Systematic review and meta-analysis on the nonsurgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts. AB - BACKGROUND: Conduct a systematic review and meta-analysis on nonsurgical treatment of patients with chronic periodontitis by means of scaling and root planing (SRP) with or without adjuncts. METHODS: A panel of experts convened by the American Dental Association Council on Scientific Affairs conducted a search of PubMed (MEDLINE) and Embase for randomized controlled trials of SRP with or without the use of adjuncts with clinical attachment level (CAL) outcomes in trials at least 6 months in duration and published in English through July 2014. The authors assessed individual study bias by using the Cochrane Risk of Bias Tool and conducted meta-analyses to obtain the summary effect estimates and their precision and to assess heterogeneity. The authors used funnel plots and Egger tests to assess publication bias when there were more than 10 studies. The authors used a modified version of the US Preventive Services Task Force methods to assess the overall level of certainty in the evidence. RESULTS: The panel included 72 articles on the effectiveness of SRP with or without the following: systemic antimicrobials, a systemic host modulator (subantimicrobial-dose doxycycline), locally delivered antimicrobials (chlorhexidine chips, doxycycline hyclate gel, and minocycline microspheres), and a variety of nonsurgical lasers (photodynamic therapy with a diode laser, a diode laser, neodymium:yttrium aluminum-garnet lasers, and erbium lasers). CONCLUSIONS AND PRACTICAL IMPLICATIONS: With a moderate level of certainty, the panel found approximately a 0.5-millimeter average improvement in CAL with SRP. Combinations of SRP with assorted adjuncts resulted in a range of average CAL improvements between 0.2 and 0.6 mm over SRP alone. The panel judged the following 4 adjunctive therapies as beneficial with a moderate level of certainty: systemic subantimicrobial-dose doxycycline, systemic antimicrobials, chlorhexidine chips, and photodynamic therapy with a diode laser. There was a low level of certainty in the benefits of the other included adjunctive therapies. The panel provides clinical recommendations in the associated clinical practice guideline. PMID- 26113101 TI - Differences in disinfection protocols for root canal treatments between general dentists and endodontists: A Web-based survey. AB - BACKGROUND: The purpose of this study was to determine whether differences exist in disinfection protocols between endodontists and general dentists. METHODS: The authors sent an invitation to participate in a Web-based survey to 950 dentists affiliated with the Spanish Board of Dentistry. Participants responded to 9 questions about irrigation protocols and other factors related to disinfection during root canal therapy. RESULTS: A total of 238 (25.05%) study participants successfully completed and returned the surveys. Among these participants, 50% were general dentists and 50% were endodontists. The authors found no statistically significant differences in respondents' first choice of an irrigant solution (that is, sodium hypochlorite), but they noted statistically significant differences in the protocols used by general dentists and by endodontists in relation to the concentration of sodium hypochlorite (P = .0003), the use and type of irrigant used to remove the smear layer (P = 5.39 * 10(-10)), the use of adjuncts to irrigation (P = 5.98 * 10(-8)), the enlargement of the apical preparation when shaping a necrotic tooth (P = .001), and the maintenance of apical patency throughout the debridement and shaping procedure (P = .04). CONCLUSIONS: General dentists and endodontists embrace different disinfection protocols. The results of the survey demonstrated that endodontists keep up to date with protocols published in the literature, whereas general dentists use protocols learned during their dental training. Both groups of clinicians should be aware of the importance of disinfection techniques and their relationship to treatment outcomes. PRACTICAL IMPLICATIONS: Controlling microorganisms during a root canal treatment, especially in cases with necrotic pulp, is essential to improve treatment outcomes. Clinicians should update their protocols and also consider referring patients to a specialist when their protocols are based on traditional techniques, especially in those cases with necrotic pulp. PMID- 26113102 TI - Intraoral mass in the posterior maxillary vestibule. PMID- 26113103 TI - Limited evidence suggests no difference in implant failure rates among people with or without diabetes. PMID- 26113104 TI - What the ADA can learn from the NBA. PMID- 26113105 TI - Managing measles in dental practice: A forgotten foe makes a comeback. PMID- 26113106 TI - An analytical approach to adding an associate. PMID- 26113107 TI - Whose patient is he? PMID- 26113108 TI - Introduction: brain tumor immunotherapy. PMID- 26113109 TI - Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle. AB - AIMS: Cigarette smoke (CS) in active smokers and second-hand smoke exposure exacerbate respiratory disorders such as asthma and chronic bronchitis. While women are known to experience a more asthmatic response to CS than emphysema in men, there is limited information on the mechanisms of CS-induced airway dysfunction. We hypothesize that CS interferes with a normal (protective) bronchodilatory role of estrogens, thus worsening airway contractility. METHODS: We tested effects of cigarette smoke extract (CSE) on 17beta-estradiol (E2) signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM) obtained from lung samples of non-smoking female patients undergoing thoracic surgery. RESULTS: In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca(2+)]i) responses to 10uM histamine. Acute exposure to physiological concentrations of E2 decreased [Ca(2+)]i responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E2 on [Ca(2+)]i was blunted. Acute E2 exposure also decreased store-operated Ca(2+) entry and inhibited stromal interaction molecule 1 (STIM1) phosphorylation: effects blunted by CSE. Acute exposure to E2 increased cAMP, but less so in 24h CSE-exposed cells. 24h CSE exposure increased S-nitrosylation of ERalpha. Furthermore, 24h CSE-exposed bronchial rings showed increased bronchoconstrictor agonist responses that were not reduced as effectively by E2 compared to non-CSE controls. CONCLUSION: These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS. PMID- 26113110 TI - HIV-1 infection, but not syphilis or HBV infection, is a strong risk factor for anorectal condyloma in Asian population: a prospective colonoscopy screening study. AB - OBJECTIVE: To investigate the association between anorectal precancerous lesions, including condyloma, and sexually transmitted infections (STI) in Asian population. METHODS: This prospective study enrolled 2677 patients who underwent high-resolution colonoscopy for anorectal cancer screening. Anorectal lesions were diagnosed based on endoscopic findings and confirmed by biopsy. The association of HIV-1 infection, syphilis, and HBV infection with anorectal lesion was estimated by multivariate logistic regression. In HIV-1-infected patients (n=244), anal canal HPV-DNA was screened and genotyped. RESULTS: Although no malignancy was identified, anorectal condyloma was diagnosed in 32 (1.2%) male patients. 41% of anorectal condyloma cases had no specific lower GI symptoms. Multivariate analysis identified HIV-1 infection, but not syphilis or HBV infection, as an independent significant factor for condyloma (OR: 176.5, 95%CI 22.52-1383, p<0.001). In HIV-1 infected patients, positive type 16/18 HPV-DNA (OR: 4.766, 95%CI 1.838-12.36, p=0.001), lower CD4 cell count (per 100/MUl decrement, OR: 1.056, 95%CI 1.056-1.587, p=0.013), and current smoking (OR: 3.828, 95%CI 1.486-9.857, p=0.005) were independently associated with anorectal condyloma. CONCLUSIONS: HIV-1 infection, but not syphilis or HBV infection, was identified as a strong risk for anorectal condyloma. Anal HPV 16/18 was highly prevalent in patients with HIV-1 infection, especially in those with condyloma. PMID- 26113111 TI - Do oxidized zirconium femoral heads reduce polyethylene wear in cemented THAs? A blinded randomized clinical trial. AB - BACKGROUND: Charnley low-friction torque total hip arthroplasty (THA) remains the gold standard in THA. The main cause for failure is wear of the socket. Highly crosslinked polyethylene (HXLPE) has been associated with reduced wear rates. Also, oxidized zirconium has shown in vitro reduced wear rates. However, to our knowledge, there are no data comparing oxidized zirconium femoral heads with metal heads against HXLPE or ultrahigh-molecular-weight polyethylene (UHMWPE) when 22.25-mm bearings were used, which was the same size that performed so well in Charnley-type THAs. QUESTIONS/PURPOSES: We hypothesized that after a minimal 4 year followup (1) use of HXLPE would result in lower radiographic wear than UHMWPE when articulating with a stainless steel head or with an oxidized zirconium head; (2) use of oxidized zirconium would result in lower radiographic wear than stainless steel when articulating with UHMWPE and HXLPE; and (3) there would be no difference in terms of Merle d'Aubigne scores between the bearing couple combinations. METHODS: One hundred patients were randomized to receive cemented THA with either oxidized zirconium or a stainless steel femoral head. UHMWPE was used in the first 50 patients, whereas HXLPE was used in the next 50 patients. There were 25 patients in each of the four bearing couple combinations. All other parameters were identical in both groups. Complete followup was available in 86 of these patients. Femoral head penetration was measured using a validated computer-assisted method dedicated to all-polyethylene sockets. Clinical results were compared between the groups using the Merle d'Aubigne score. RESULTS: In the UHMWPE series, the median steady-state penetration rate from 1 year onward was 0.03 mm/year (range, 0.003-0.25 mm/year) in the oxidized zirconium group versus 0.11 mm/year (range, 0.03-0.29 mm/year) in the metal group (difference of medians 0.08, p < 0.001). In the HXLPE series, the median steady state penetration rate from 1 year onward was 0.02 mm/year (range, -0.32 to 0.07 mm/year) in the oxidized zirconium group versus 0.05 mm/year (range, -0.39 to 0.11 mm/year) in the metal group (difference of medians 0.03, p < 0.001). The Merle d'Aubigne scores were no different between the groups with a median of 18 in each of the groups (range, 16-18). CONCLUSIONS: This study demonstrated femoral head penetration was reduced by oxidized zirconium when compared with metal on both UHMWPE and HXLPE. However, apart the metal-UHMWE group, all other groups had a steady-state penetration rate well below the osteolysis threshold with a low difference between groups that might not be clinically important at this point. Longer-term followup is needed to warrant whether wear reduction will generate less occurrence of osteolysis and aseptic loosening. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 26113112 TI - Pioglitazone Identifies a New Target for Aneurysm Treatment: Role of Egr1 in an Experimental Murine Model of Aortic Aneurysm. AB - Peroxisome proliferator-activated receptor x03B3; agonists have been shown to inhibit angiotensin II (AngII)-induced experimental abdominal aortic aneurysms. Macrophage infiltration to the vascular wall is an early event in this pathology, and therefore we explored the effects of the peroxisome proliferator-activated receptor x03B3; agonist pioglitazone on AngII-treated macrophages. Using microarray-based expression profiling of phorbol ester-stimulated THP-1 cells, we found that a number of aneurysm-related gene changes effected by AngII were modulated following the addition of pioglitazone. Among those genes, polycystic kidney disease 1 (PKD1) was significantly up-regulated (multiple testing corrected p < 0.05). The analysis of the PKD1 proximal promoter revealed a putative early growth response 1 (EGR1) binding site, which was confirmed by chromatin immunoprecipitation (ChIP) and quantitative PCR. Further analysis of publicly available ChIP-sequencing data revealed that this putative binding site overlapped with a conserved EGR1 binding peak present in 5 other cell lines. Quantitative real-time PCR showed that EGR1 suppressed PKD1, while AngII significantly up-regulated PKD1, an effect counteracted by pioglitazone. Conversely, in EGR1 short hairpin RNA lentivirally transduced THP-1 cells, reduced EGR1 led to a significant up-regulation of PKD1, especially after treatment with pioglitazone. In vivo, deficiency of Egr1 in the haematopoietic compartment of mice completely abolished the incidence of CaCl2-induced aneurysm formation. PMID- 26113113 TI - Myeloproliferative neoplasm patient symptom burden and quality of life: evidence of significant impairment compared to controls. AB - The myeloproliferative neoplasms (MPN) including polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis (PMF) are rare diseases contributing to significant morbidity. Symptom management is a prime treatment objective but current symptom assessment tools have not been validated compared to the general population. The MPN-symptom assessment form (MPN-SAF), a reliable and validated clinical tool to assess MPN symptom burden, was administered to MPN patients (n = 106) and, for the first time, population controls (n = 124) as part of a UK case-control study. Mean symptom scores were compared between patients and controls adjusting for potential confounders. Mean patient scores were compared to data collected by the Mayo Clinic, USA on 1,446 international MPN patients to determine patient group representativeness. MPN patients had significantly higher mean scores than controls for 25 of the 26 symptoms measured (P < 0.05); fatigue was the most common symptom (92.4% and 78.1%, respectively). Female MPN patients suffered worse symptom burden than male patients (P < 0.001) and substantially worse burden than female controls (P < 0.001). Compared to the Mayo clinic patients, MPN-UK patients reported similar symptom burden but lower satiety (P = 0.046). Patients with PMF reported the worst symptom burden (88.3%); significantly higher than PV patients (P < 0.001). For the first time we report quality of life was worse in MPN-UK patients compared with controls (P < 0.001). PMID- 26113115 TI - Incorporating excluded solvent volume and physical dipoles for computing solvation free energy. AB - The solvation free energy described using the Born equation depends on the solute charge, solute radius, and solvent dielectric constant. However, the dielectric polarization derived from Gauss's law used in the Born equation differs from that obtained from molecular dynamics simulations. Therefore, the adjustment of Born radii is insufficient for fitting the solvation free energy to various solute conformations. In order to mimic the dielectric polarization surrounding a solute in molecular dynamics simulations, the water molecule in the first coordination shell is modeled as a physical dipole in a van der Waals sphere, and the intermediate water is treated as a bulk solvent. The electric dipole of the first shell water is modeled as positive and negative surface charge layers with fixed charge magnitudes, but with variable separation distance as derived from the distributions of hydrogen and oxygen atoms of water dictated by their orientational distribution functions. An equation that describes the solvation free energy of ions using this solvent scheme with a TIP3P water model is derived, and the values of the solvation free energies of ions estimated from this derived equation are found to be similar to those obtained from the experimental data. PMID- 26113114 TI - Sphingosine kinase 1 activation enhances epidermal innate immunity through sphingosine-1-phosphate stimulation of cathelicidin production. AB - BACKGROUND: The ceramide metabolite, sphingosine-1-phosphate (S1P), regulates multiple cellular functions in keratinocytes (KC). We recently discovered that production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), is stimulated via a NF-kappaB-dependent mechanism that is activated by S1P when S1P is generated by sphingosine kinase (SPHK) 1. OBJECTIVE: We investigated whether pharmacological modulation of SPHK1 activity, using a novel synthetic SPHK1 activator, (S)-methyl 2-(hexanamide)-3-(4-hydroxyphenyl) propanoate (MHP), stimulates CAMP expression. METHODS: MHP-mediated changes in both S1P and CAMP downstream mediators were analyzed in normal cultured human KC by qRT-PCR, Western immunoblot, ELISA, confocal microscopy for immunohistochemistry, HPLC and ESI-LC/MS/MS, and microbial pathogen invasion/colonization in a human epidermal organotypic model. RESULTS: Treatment with MHP directly activated SPHK1 and increased cellular S1P content in normal cultured human KC. Because MHP did not inhibit S1P lyase activity, which hydrolyses S1P, augumented S1P levels could be attributed to increased synthesis rather than blockade of S1P degradation. Next, we found that exogenous MHP significantly stimulated CAMP mRNA and protein production in KC, increases that were significantly suppressed by siRNA directed against SPHK1, but not by a scrambled control siRNA. NF-kappaB activation, assessed by nuclear translocation of NF-kappaB, occurred in cells following incubation with MHP. Conversely, pretreatment with a specific inhibitor of SPHK1 decreased MHP-induced nuclear translocation of NF-kappaB, and significantly attenuated the MHP-mediated increase in CAMP production. Finally, topical MHP significantly suppressed invasion of the virulent Staphylococcus aureus into murine skin explants. CONCLUSION: MHP activation of SPHK1, a target enzyme of CAMP production, can stimulate innate immunity. PMID- 26113116 TI - Theoretical investigation of the mechanism for the cycloaddition of CO2 to epoxides catalyzed by a magnesium(II) porphyrin complex. AB - The cycloaddition of CO2 to epoxides, catalyzed by Mg(TPP)/TBAI (TPP = tetraphenylporphyrin; TBAI = tetrabutylammonium iodide), was investigated using DFT methods. Epoxides with various substituents were studied to explore steric and electronic effects on the reaction mechanism. Computational results show that the cycloaddition proceeds according to a much easier mechanism in the presence of Mg(TPP) and TBAI than the mechanism that takes place when Mg(TPP) is used as the catalyst. A preference for the epoxide ring-opening to occur at the methine (Calpha) or methylene (Cbeta) carbon was noted. The ring-closing step leading to the formation of a five-membered carbonate is predicted to determine the reaction rate. For alkyl-substituted epoxides, the beta pathway is favorable since steric factors are dominant; for epoxides with a strongly electron-donating group and styrene oxide, the reaction is mainly controlled by electronic factors and proceeds along the alpha pathway. When the epoxide has a strongly electron withdrawing group (CF3), both steric and electronic effects play important roles. The calculated reactivity of epoxides with CO2 catalyzed by Mg(TPP)/TBAI is in good agreement with that observed experimentally. PMID- 26113117 TI - Acquired lymphoedema and cutaneous lymphangiectasia of abdominal skin following bilateral breast reduction and abdominoplasty. AB - We report two cases where the combination of breast reduction surgery and abdominoplasty led to lymphatic congestion clinically manifesting as lymphoedema and acquired cutaneous lymphangiectasia over the abdomen. These associations have not been previously reported, and clinicians need to be aware of them to obtain patients' consent for the procedure and to assist diagnosis and early intervention. PMID- 26113118 TI - Association between health literacy and medical care costs in an integrated healthcare system: a regional population based study. AB - BACKGROUND: Low health literacy is associated with higher health care utilization and costs; however, no large-scale studies have demonstrated this in the Veterans Health Administration (VHA). This research evaluated the association between veterans' health literacy and their subsequent VHA health care costs across a three-year period. METHODS: This retrospective study used a Generalized Linear Model to estimate the relative association between a patient's health literacy and VHA medical costs, adjusting for covariates. Secondary data sources included electronic health records and administrative data in the VHA (e.g., Medical and DCG SAS Datasets and DSS-National Data Extracts). Health literacy assessments and identifiers were electronically retrieved from the originating health system. Demographic and cost data were retrieved from the VHA centralized databases for the corresponding patients who had VHA use in all three years. RESULTS: In a study of 92,749 veterans with service utilization from 2007-2009, average per patient cost for those with inadequate and marginal health literacy was significantly higher ($31,581 [95 % CI: $30,186 - $32,975]; $23,508 [95 % CI: $22,749 - $24,268]) than adequate health literacy ($17,033 [95 % CI: $16,810 - $17,255]). Estimated three-year cost associated with veterans' with marginal and inadequate health literacy was $143 million dollars more than those with adequate health literacy. CONCLUSIONS: Analyses suggest when controlling for other person level factors within the VHA integrated healthcare system, lower health literacy is a significant independent factor associated with increased health care utilization and costs. This study confirms the association of lower health literacy with higher medical service utilization and pharmacy costs for veterans enrolled in the VHA. Confirmation of higher costs of care associated with lower health literacy suggests that interventions might be designed to remediate health literacy needs and reduce expenditures. These analyses suggest 17.2 % (inadequate & marginal) of the Veterans in this population account for almost one-quarter (24 %) of VA medical and pharmacy cost for this 3-year period. Meeting the needs of those with marginal and inadequate health literacy could produce potential economic savings of approximately 8 % of total costs for this population. PMID- 26113119 TI - Transthoracic Doppler for detection of stenoses in the three main coronary arteries by use of stenotic to prestenotic velocity ratio and aliased coronary flow. AB - AIMS: Our aim was to determine the feasibility and accuracy of diagnosing significant coronary artery stenoses using peak stenotic to prestenotic velocity ratio (pSPVR) measurements when compared with results from quantitative coronary angiography and coronary flow velocity reserve (CFVR) assessed by transthoracic echocardiography (TTE). METHODS AND RESULTS: One hundred and eight patients scheduled for coronary angiography were studied using transthoracic Doppler echocardiography. Stenoses were identified by local colour aliasing by colour flow Doppler, and further evaluated by pSPVR, using a pSPVR of >=2.0 as a cut-off for significant stenosis. When pSPVR could not be measured, local mosaic coronary flow pattern at Nyquist limit >=0.48 m/s was used. Sixty-five lesions suggestive of stenosis were found by TTE. Combining findings of pSPVR >=2.0 and local mosaic flow at Nyquist limit >=0.48 m/s, the sensitivity and specificity of demonstrating significant stenoses (diameter stenosis, 50-99%) in the left main coronary artery (LM), left anterior descending coronary (LAD), left circumflex coronary (Cx), and right coronary artery (RCA) were 75 and 98%, 74 and 95%, 40 and 87%, and 34 and 98%, respectively. The pSPVR did not differ significantly between arteries with reduced and normal CFVR, with a cut-off of CFVR <2.0. CONCLUSIONS: Findings of pSPVR >=2.0 or localized colour flow aliasing are useful in the non-invasive diagnosis of significant coronary disease in the three main coronary arteries, with high specificity for detecting significant stenoses. These findings showed high sensitivity for identifying significant stenoses in the LM and LAD, but showed lower ability to detect those lesions in the Cx and RCA. PMID- 26113120 TI - Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study. AB - AIMS: Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. METHODS AND RESULTS: Thirty-six (age 44 +/- 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison group' (n = 24, 6 DMD and 18 BMD). In the total MD carrier group, 17 (47%) MD carriers had at least one pathological CMR finding [5 (14%) with a reduced left ventricular ejection fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P = 0.008)--in spite of being significantly younger (40 +/- 11 vs. 50 +/- 16 years, P = 0.038). In the male MD comparison group, the same LGE pattern as in female carriers was seen, but with a significantly higher prevalence of cardiac abnormalities compared with their female carrier relatives constituting the female MD comparison group (75 vs. 27%; P = 0.003). CONCLUSION: Cardiac involvement is a frequent finding in female carriers of DMD, but less frequently observed in carriers of BMD. Those DMDc and BMDc with cardiac involvement demonstrate the same myocardial fibrosis pattern as their male counterparts with overt disease. PMID- 26113121 TI - Immediate and short-term effect of balloon mitral valvuloplasty on global and regional biventricular function: a two-dimensional strain echocardiographic study. AB - AIM: To assess the effect of balloon mitral valvuloplasty (BMV) on global and regional ventricular functions using 2D strain. METHODS AND RESULTS: Thirty-two patients with mitral stenosis (MS) and 30 healthy subjects underwent full echocardiographic examinations, including left ventricle (LV) and right ventricle (RV) regional and global longitudinal strain (GLS) measurements. In MS patients, measurements were repeated within 24 h and 3 months after BMV. Patients with MS had lower LV and RV GLS compared with control group (-16.5 +/- 2.7% vs. -21.0 +/- 1.5) and (-18.3 +/- 4.7 vs. -19.8 +/- 1.3), respectively. Significant decrease was noted in the basal and septal segments compared with the apical LV segments and RV free wall. BMV resulted in significant improvement in LV and RV GLS within 24 h post-BMV compared with baseline values (P = 0.0001 and 0.0002, respectively), an improvement which was maintained after 3 months. There was significant positive correlation between both LV and RV GLS at baseline and mitral valve mean pressure gradient and RV systolic pressure and significant inverse correlation between LV GLS and MVA. CONCLUSION: MS patients have subclinical LV and RV systolic dysfunction by GLS despite normal ejection fraction and fractional area change. BMV results in marked improvement in LV and RV GLS immediately post-BMV with trend towards normalization at follow-up after 3 months. A mixed aetiology theory involving a myocardial as well as a haemodynamic factor is believed to be the cause for this subclinical biventricular dysfunction and its improvement at short-term follow-up post-BMV. PMID- 26113122 TI - A cooperative approach to animal disease response activities: Analytical hierarchy process (AHP) and vvIBD in California poultry. AB - Very virulent infectious bursal disease virus (vvIBDv) was first detected in the United States at the end of 2008. Since its detection, Federal and State animal health officials, the poultry industry and the research/academic community have led response activities through a collaborative effort. By June 2011, much still remained unknown regarding the basic epidemiology and ecology of vvIBD in California, although there were a number of potential activities to fill this information gap. Available resources limited the ability to pursue all the activities, and responsible parties and stakeholders recognized the need to prioritize the activities. The analytic hierarchy process (AHP) is a useful multi criteria decision making methodology that incorporates qualitative information (in the form of judgments) with available quantitative information. This is especially useful when there is very limited quantitative information, such as in the situation with vvIBD in California. A commercial package that allows ready use of the AHP model was utilized for prioritizing activities, incorporating input from members from the three stakeholder groups: State and Federal animal health officials, poultry industry, and research/academia. Based on their inputs on 17 potential activities, the participants identified three priority activities; specifically determination of risk factors for re-emergence or re introduction at affected premises, development of a laboratory diagnostic test to screen for segment B of the vvIBDV genome and surveillance of other potential reservoirs (mealworms, rodents, beetles). In order to evaluate the ability of the AHP to respond to differences, a sensitivity analysis was done in order to evaluate changes in prioritization of activities. Changes in prioritization were noted demonstrating the plasticity of the model under different conditions. However, a 50% increase or decrease in weighting was necessary to affect the order of the three highest scoring activities. The use of a tool such as the AHP enables the development of a transparent, repeatable and flexible decision process, which can be useful in certain animal health response situations including the re-emergence of a previously eliminated disease or the introduction of a foreign animal disease. PMID- 26113124 TI - Stakeholders' engagement with Ebola therapy research in resource limited settings. AB - BACKGROUND: The current Ebola Virus Disease (EVD) outbreak in West Africa is the largest in history. As of February 18(th) 2015, 23,258 cases of EVD have been cumulatively reported from Nigeria, Senegal, Guinea, Liberia, Mali, Sierra Leone, Spain, the United Kingdom and the United States of America resulting in more than 9,000 deaths. It is therefore exigent to develop prevention and treatment therapies for EVD. DISCUSSION: Several new EVD treatments are in clinical development at this time. Based on lessons learned, four critical processes need to be implemented before clinical trials begin. First, all global EVD research need to be coordinated to promote data sharing and synergistic overlap, while reducing unnecessary duplication of efforts. The World Health Organization is well-placed to undertake such an endeavor. Second, governments of affected nations where trials are being proposed need to lead discussions regarding immediate access to any proven medications for epidemics. Also, governments need to leverage international resources to support and expand existing national expertise to jointly conduct high-caliber clinical research; and resources must be used to enhance local technical skills and expand existing personnel. Third, ethics committees must review protocols, monitor the research process, and work closely with research scientists to insure the ethical integrity of research throughout the trials. Fourth, community advisory boards (CAB) need to be formed, linked with existing community leadership structures and organized in conjunction with trial implementation. These community structures should work together with ethics committees to facilitate the study design, informed consent process, and study implementation. We must facilitate communication and mutual understanding between trial communities and research teams, and promote positive collaborations between all stakeholders engaged in EVD research. The community engagement process for EVD research is crucial to address myths and misconceptions, and to promote study volunteers' understanding of the research details. The collaboration between all stakeholders is crucial for continued long term partnership to address EVD outbreak and none of the stakeholders should be left behind in ongoing efforts to develop EVD therapies. PMID- 26113123 TI - Acute and subchronic exposure to air particulate matter induces expression of angiotensin and bradykinin-related genes in the lungs and heart: Angiotensin-II type-I receptor as a molecular target of particulate matter exposure. AB - BACKGROUND: Particulate matter (PM) adverse effects on health include lung and heart damage. The renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) endocrine systems are involved in the pathophysiology of cardiovascular diseases and have been found to impact lung diseases. The aim of the present study was to evaluate whether PM exposure regulates elements of RAAS and KKS. METHODS: Sprague Dawley rats were acutely (3 days) and subchronically (8 weeks) exposed to coarse (CP), fine (FP) or ultrafine (UFP) particulates using a particulate concentrator, and a control group exposed to filtered air (FA). We evaluated the mRNA of the RAAS components At1, At2r and Ace, and of the KKS components B1r, B2r and Klk-1 by RT-PCR in the lungs and heart. The ACE and AT1R protein were evaluated by Western blot, as were HO-1 and gammaGCSc as indicators of the antioxidant response and IL-6 levels as an inflammation marker. We performed a binding assay to determinate AT1R density in the lung, also the subcellular AT1R distribution in the lungs was evaluated. Finally, we performed a histological analysis of intramyocardial coronary arteries and the expression of markers of heart gene reprogramming (Acta1 and Col3a1). RESULTS: The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner. CP exposure induced Ace mRNA expression and regulated its protein in the lungs. Acute and subchronic exposure to FP and UFP induced the expression of At1r in the lungs and heart. All PM fractions increased the AT1R protein in a size dependent manner in the lungs and heart after subchronic exposure. The AT1R lung protein showed a time-dependent change in subcellular distribution. In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6. Moreover, exposure to all PM fractions increased coronary artery wall thickness. CONCLUSION: We demonstrate that exposure to PM induces the expression of RAAS and KKS elements, including AT1R, which was the main target in the lungs and the heart. PMID- 26113125 TI - Impact of overactive bladder on quality of life and resource use: results from Korean Burden of Incontinence Study (KOBIS). AB - BACKGROUND: To evaluate the impact of overactive bladder (OAB) on quality of life (QOL), resource use and productivity loss in patients recruited from six hospitals in Korea. METHODS: This cross-sectional survey recruited 625 OAB patients between July to December 2013. Patients were categorised into four groups based on the average number of urinary incontinence (UI) episodes over the past three days (0, 1, 2-3 and >=4 UI/day). QOL was measured using the Incontinence-Specific Quality of Life Instrument (I-QOL), the Overactive Bladder Questionnaire (OAB-q), and a generic health-related utility instrument (EQ-5D). Information on hospital and clinic visit frequency, and continence pads use were also collected. Work productivity was assessed using the Work Productivity and Activity Impairment (WPAI) questionnaire. Between group differences were assessed using ANOVA. Multivariable regression analyses were performed to examine the independent effects of OAB symptoms on QOL. RESULTS: Severity of UI showed a significant linear relationship with QOL, with clinically meaningful differences between each UI severity category. Compared to the dry category, patients in the most severe category (>=4 UI/day) had significantly lower I-QOL scores (69.8 vs 42.6; p < 0.0001), greater symptom bother on the OAB-q (30.4 vs 64.6; p < 0.0001), and poorer EQ-5D utility (0.848 vs 0.742; p < 0.001). Multivariable analyses showed that UI severity, frequency, urgency, and nocturia are independently associated with poorer QOL. Incontinence severity is also significantly associated with cost of incontinence pads (p < 0.0001), and a greater interference with work and regular activities (p = 0.001), however, no significant difference in hospital and clinic visits were observed. CONCLUSION: Severity of UI is a key contributor to the disease burden of OAB in Korean patients, even after taking into account the impact of other symptoms associated with OAB. PMID- 26113126 TI - The Dan Young Neonatal Surgical Unit audit: an audit of admissions and mortality rates pre- and post-amalgamation. AB - BACKGROUND AND AIMS: (1) To record the number of Index Surgical Cases (ISCs) admitted to the Royal Hospital for Sick Children (RHSC) Yorkill in 2012-2014. (2) To investigate if the amalgamation of the neonatal intensive care unit with the Dan Young Neonatal Surgical Unit in 2008 has impacted on the number of admissions and deaths. METHOD AND RESULTS: Data were collected from the ward admission books and the BadgerNet UK database. Reason for admission and outcome was recorded. Nonsurgical cases were categorised as 'miscellaneous'.The total number of admissions per year and the number of miscellaneous cases have been increasing since the amalgamation. There were no clinically significant differences in the number of babies with each ISC. The death rate was 1.8% in 2012, 2.9% in 2013 and 2.6% 2014. CONCLUSIONS: The unit now admits more miscellaneous babies and this has caused an increase in total admissions. Although the total number of deaths has increased, the death rates as a percentage of total admissions have now plateaued after an initial rise at the time of union. There has been no significant increase in the number of ISC deaths. Thus, it appears that the amalgamation has affected survival outcomes in the short term only. PMID- 26113127 TI - Risk and regulation in research. PMID- 26113128 TI - Animal research through a lens: transparency on animal research. PMID- 26113131 TI - Statement from the European Society of Vascular Surgery and the World Federation of Vascular Surgery Societies: Transatlantic Inter-Society Consensus Document (TASC) III and International Standards for Vascular Care (ISVaC). PMID- 26113130 TI - Robert B. Rutherford 29 July 1931-22 November 2013. PMID- 26113134 TI - Truncating mutation in intracellular phospholipase A1 gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54). AB - BACKGROUND: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum. RESULTS: A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP 12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity. CONCLUSION: This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders. PMID- 26113135 TI - Symptom Experience and Quality of Life in Children after Sport-Related Head Injuries: A Cross-Sectional Study. AB - BACKGROUND: Sports are a major cause of concussions, and little is known about the symptom experience and health-related quality of life (HRQL) in children who remain symptomatic for over 3 months following such head injuries. METHODS: A cross-sectional study of children aged 10-18 years was performed who were referred to the Neurosurgery Clinic at our centre following a head injury. Symptom experience was measured using the modified Concussion Symptom Scale, and HRQL was measured using the Pediatric Quality of Life Inventory (PedsQL). The Immediate Postconcussion Assessment and Cognitive Test (ImPACT) was administered to assess neurocognitive and neurobehavioural sequelae. RESULTS: Symptoms with the highest mean symptom scores on a Likert scale of 0-6 in 35 children at the time of assessment included headaches (3.1), poor concentration (2.7), memory problems (2.1), fatigue (2.1) and sensitivity to noise (2.0). Compared with normative data, children in this study had ImPACT summary scores between the 28th and 38th percentiles and a comparably low Cognitive Efficiency Index score. Mean scores for females were consistently statistically significantly lower (p < 0.05) than for males across all of the HRQL domains. Trouble falling asleep and memory problems explained 62% of the variance in the PedsQL total scores. CONCLUSIONS: Children continue to experience many symptoms at least 3 months following sport related head injuries that significantly impact their HRQL and neurocognitive abilities. PMID- 26113136 TI - Vps26B-retromer negatively regulates plasma membrane resensitization of PAR-2. AB - Retromer is a trimeric complex composed of Vps26, Vps29, and Vps35 and has been shown to be involved in trafficking and sorting of transmembrane proteins within the endosome. The Vps26 paralog, Vps26B, defines a distinct retromer complex (Vps26B-retromer) in vivo and in vitro. Although endosomally associated, Vps26B retromer does not bind the established retromer transmembrane cargo protein, cation-independent mannose 6-phosphate receptor (CI-M6PR), indicating it has a distinct role to retromer containing the Vps26A paralog. In the present study we use the previously established Vps26B-expressing HEK293 cell model to address the role of Vps26B-retromer in trafficking of the protease activated G-protein coupled receptor PAR-2 to the plasma membrane. In these cells there is no apparent defect in the initial activation of the receptor, as evidenced by release of intracellular calcium, ERK1/2 signaling and endocytosis of activated receptor PAR-2 into degradative organelles. However, we observe a significant delay in plasma membrane repopulation of the protease activated G protein-coupled receptor PAR-2 following stimulation, resulting in a defect in PAR-2 activation after resensitization. Here we propose that PAR-2 plasma membrane repopulation is regulated by Vps26B-retromer, describing a potential novel role for this complex. PMID- 26113137 TI - Scaling of cerebral blood perfusion in primates and marsupials. AB - The evolution of primates involved increasing body size, brain size and presumably cognitive ability. Cognition is related to neural activity, metabolic rate and rate of blood flow to the cerebral cortex. These parameters are difficult to quantify in living animals. This study shows that it is possible to determine the rate of cortical brain perfusion from the size of the internal carotid artery foramina in skulls of certain mammals, including haplorrhine primates and diprotodont marsupials. We quantify combined blood flow rate in both internal carotid arteries as a proxy of brain metabolism in 34 species of haplorrhine primates (0.116-145 kg body mass) and compare it to the same analysis for 19 species of diprotodont marsupials (0.014-46 kg). Brain volume is related to body mass by essentially the same exponent of 0.70 in both groups. Flow rate increases with haplorrhine brain volume to the 0.95 power, which is significantly higher than the exponent (0.75) expected for most organs according to 'Kleiber's Law'. By comparison, the exponent is 0.73 in marsupials. Thus, the brain perfusion rate increases with body size and brain size much faster in primates than in marsupials. The trajectory of cerebral perfusion in primates is set by the phylogenetically older groups (New and Old World monkeys, lesser apes) and the phylogenetically younger groups (great apes, including humans) fall near the line, with the highest perfusion. This may be associated with disproportionate increases in cortical surface area and mental capacity in the highly social, larger primates. PMID- 26113138 TI - Analysing avian eggshell pigments with Raman spectroscopy. AB - Avian eggshells are variable in appearance, including coloration. Here, we demonstrate that Raman spectroscopy can provide accurate diagnostic information about major eggshell constituents, including the pigments biliverdin and protoporphyrin IX. Eggshells pigmented with biliverdin showed a series of pigment diagnostic Raman peaks under 785 nm excitation. Eggshells pigmented with protoporphyrin IX showed strong emission under 1064 nm and 785 nm excitation, whereas resonance Raman spectra (351 nm excitation) showed a set of protoporphyrin IX informative peaks characteristic of protoporphyrin IX. As representative examples, we identified biliverdin in the olive green eggshells of elegant crested tinamous (Eudromia elegans) and in the blue eggshells of extinct upland moa (Megalapteryx didinus). This study encourages the wider use of Raman spectroscopy in pigment and coloration research and highlights the value of this technique for non-destructive analyses of museum eggshell specimens. PMID- 26113139 TI - siRNA transfection in larvae of the barnacle Amphibalanus amphitrite. AB - RNA interference (RNAi) provides an efficient and specific technique for functional genomic studies. Yet, no successful application of RNAi has been reported in barnacles. In this study, siRNA against p38 MAPK was synthesized and then transfected into A. amphitrite larvae at either the nauplius or cyprid stage, or at both stages. Effects of siRNA transfection on the p38 MAPK level were hardly detectable in the cyprids when they were transfected at the nauplius stage. In contrast, larvae that were transfected at the cyprid stage showed lower levels of p38 MAPK than the blank and reagent controls. However, significantly decreased levels of phosphorylated p38 MAPK (pp38 MAPK) and reduced settlement rates were observed only in 'double transfections', in which larvae were exposed to siRNA solution at both the nauplius and cyprid stages. A relatively longer transfection time and more larval cells directly exposed to siRNA might explain the higher efficiency of double transfection experiments. PMID- 26113140 TI - Mating for male-derived prostaglandin: a functional explanation for the increased fecundity of mated female crickets? AB - Direct benefits are considered to be the driving force of high female mating rates, yet species in which females do not receive material resources from males still experience increased fitness from mating frequently. One hypothesis suggests that substances within the ejaculate may boost survival or offspring production. If these materials are limiting to females, they will require continual renewal via mating and could provide a functional understanding of how high mating rates lead to increased female fitness. Using the Texas field cricket, Gryllus texensis, we investigated the sexual transfer of prostaglandin E2, an important mediator of invertebrate reproduction. We determined that like other gryllid species, males include significant quantities of prostaglandin E2 (PGE2) and its precursor molecule, arachidonic acid (AA), within the spermatophore. These components are passed to females during copulation and then stored within the spermatheca. We then tested the novel hypothesis that PGE2 is ephemerally available after mating and that females must frequently mate to maintain access to this limiting compound. We found that PGE2 within the spermatheca is indeed depleted through time, with only a small amount remaining 1 week after mating, but that its presence can be maintained at high quantities and for prolonged periods of time by remating. Our results support the hypothesis that high female mating rates increase the amount and availability of PGE2 throughout the breeding season, which could explain the positive relationship between female mating rate and fecundity. PMID- 26113141 TI - Haltere mechanosensory influence on tethered flight behavior in Drosophila. AB - In flies, mechanosensory information from modified hindwings known as halteres is combined with visual information for wing-steering behavior. Haltere input is necessary for free flight, making it difficult to study the effects of haltere ablation under natural flight conditions. We thus used tethered Drosophila melanogaster flies to examine the relationship between halteres and the visual system, using wide-field motion or moving figures as visual stimuli. Haltere input was altered by surgically decreasing its mass, or by removing it entirely. Haltere removal does not affect the flies' ability to flap or steer their wings, but it does increase the temporal frequency at which they modify their wingbeat amplitude. Reducing the haltere mass decreases the optomotor reflex response to wide-field motion, and removing the haltere entirely does not further decrease the response. Decreasing the mass does not attenuate the response to figure motion, but removing the entire haltere does attenuate the response. When flies are allowed to control a visual stimulus in closed-loop conditions, haltereless flies fixate figures with the same acuity as intact flies, but cannot stabilize a wide-field stimulus as accurately as intact flies can. These manipulations suggest that the haltere mass is influential in wide-field stabilization, but less so in figure tracking. In both figure and wide-field experiments, we observe responses to visual motion with and without halteres, indicating that during tethered flight, intact halteres are not strictly necessary for visually guided wing-steering responses. However, the haltere feedback loop may operate in a context-dependent way to modulate responses to visual motion. PMID- 26113142 TI - Small intestinal hydrolysis of plant glucosides: higher glucohydrolase activities in rodents than passerine birds. AB - Glycosides are a major group of plant secondary compounds characterized by one or more sugars conjugated to a lipophilic, possibly toxic aglycone, which is released upon hydrolysis. We compared small intestinal homogenate hydrolysis activity of three rodent and two avian species against four substrates: amygdalin and sinigrin, two plant-derived glucosides, the sugar lactose, whose hydrolysis models some activity against flavonoid and isoflavonoid glucosides, and the disaccharide sugar maltose (from starch), used as a comparator. Three new findings extend our understanding of physiological processing of plant glucosides: (1) the capacity of passerine birds to hydrolyze plant glucosides seems relatively low, compared with rodents; (2) in this first test of vertebrates' enzymic capacity to hydrolyze glucosinolates, sinigrin hydrolytic capacity seems low; (3) in laboratory mice, hydrolytic activity against lactose resides on the enterocytes' apical membrane facing the intestinal lumen, but activity against amygdalin seems to reside inside enterocytes. PMID- 26113143 TI - Characterising multi-level effects of acute pressure exposure on a shallow-water invertebrate: insights into the kinetics and hierarchy of the stress response. AB - Hydrostatic pressure is an important, ubiquitous, environmental variable of particular relevance in the marine environment. However, it is widely overlooked despite recent evidence that some marine ectotherms may be demonstrating climate driven bathymetric range shifts. Wide-ranging effects of increased hydrostatic pressure have been observed from the molecular through to the behavioural level. Still, no study has simultaneously examined these multiple levels of organisation in a single experiment in order to understand the kinetics, hierarchy and interconnected nature of such responses during an acute exposure, and over a subsequent recovery period. Here, we quantify the transcription of a set of previously characterised genes during and after acute pressure exposure in adults of the shrimp Palaemonetes varians. Further, we perform respiratory rate and behavioural analysis over the same period. Increases in expression of genes associated with stress and metabolism were observed during and after high pressure exposure. Respiratory rate increased during exposure and into the recovery period. Finally, differential behaviour was observed under elevated hydrostatic pressure in comparison to ambient pressure. Characterising generalised responses to acute elevated pressure is a vital precursor to longer term, acclimation-based pressure studies. Results provide a novel insight into what we term the overall stress response (OSR) to elevated pressure; a concept that we suggest to be applicable to other environmental stressors. We highlight the importance of considering more than a single component of the stress response in physiological studies, particularly in an era where environmental multi stressor studies are proliferating. PMID- 26113144 TI - Opportunities and limitations of bone marrow biopsy and bone marrow FDG-PET in lymphoma. AB - Bone marrow involvement in lymphoma may have prognostic and therapeutic consequences. Bone marrow biopsy (BMB) is the established method for the evaluation of the bone marrow. (18)F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) plays an important role in lymphoma staging, but its value in the assessment of the bone marrow and whether it can replace BMB is still a topic of debate and investigation. The purpose of this scientific communication is to provide an evidence-based overview about the opportunities and limitations of BMB and FDG-PET in the evaluation of the bone marrow in patients with lymphoma. This article first reviews the basic properties, opportunities and limitations of BMB and bone marrow FDG-PET, and then focuses on the clinical utility of BMB and bone marrow FDG-PET in three major lymphoma subtypes including Hodgkin lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. PMID- 26113145 TI - Change in pelvic organ support during pregnancy and the first year postpartum: a longitudinal study. AB - OBJECTIVE: To describe changes in pelvic organ support from mid pregnancy until 1 year postpartum among nulliparous pregnant women, and to examine whether delivery route affects changes in pelvic organ support. DESIGN: Prospective cohort study. SETTING: Akershus University Hospital in Norway. POPULATION: A cohort of 300 nulliparous pregnant women included at mid-pregnancy. METHODS: Pelvic organ support assessed at 21 and 37 weeks of gestation, and again at 6 weeks, 6 months, and 12 months postpartum, by the use of the Pelvic Organ Prolapse Quantification (POP-Q) system. Linear mixed model was used to assess longitudinal change in pelvic organ support. MAIN OUTCOME MEASURES: Prevalence of anatomic POP. Change in POP-Q variables over time and between delivery groups. RESULTS: The prevalence of anatomic POP ranged from 0 to 10%. Vaginal POP-Q points made a cranial shift from mid to late pregnancy, a caudal shift following delivery, and again a cranial shift after 6 weeks postpartum. Postpartum change was present following both vaginal and caesarean deliveries, but was more pronounced following vaginal delivery. The perineal body and genital hiatus became longer from mid to late pregnancy, and shortened after 6 weeks postpartum. At 12 months postpartum all POP-Q points, except cervix, had recovered to baseline in the vaginal delivery group. CONCLUSIONS: The prevalence of anatomic POP was low in this cohort. There was change in pelvic organ support both during pregnancy and following vaginal as well as caesarean delivery. The short-term ability to recover was good after the first pregnancy and delivery. TWEETABLE ABSTRACT: Pelvic organ support changes during pregnancy. A contribution to the risk of POP? PMID- 26113146 TI - The initial stage of reversal learning is impaired in mice hemizygous for the vesicular glutamate transporter (VGluT1). AB - Behavioral flexibility is a complex cognitive function that is necessary for survival in changeable environments. Patients with schizophrenia or Parkinson's disease often suffer from cognitive rigidity, reducing their capacity to function in society. Patients and rodent models with focal lesions in the prefrontal cortex (PFC) show similar rigidity, owing to the loss of PFC regulation of subcortical reward circuits involved in behavioral flexibility. The vesicular glutamate transporter (VGluT1) is preferentially expressed at modulatory synapses, including PFC neurons that project to components of the reward circuit (such as the nucleus accumbens, NAc). VGluT1(+/-) mice display behavioral phenotypes matching many symptoms of schizophrenia, and VGluT1 expression is reduced in the PFC of patients with schizophrenia and Parkinson's disease. Thus, it appears likely that VGluT1-expressing synapses from PFC play a key role in behavioral flexibility. To examine this hypothesis, we studied behavioral flexibility in VGluT1(+/-) mice by testing reversal learning in a visual discrimination task. Here, we show that VGluT1(+/-) mice acquired the initial visual discrimination at the same rate as controls. However, they failed to suppress responses to the previously rewarded stimulus following reversal of reward contingencies. Thus, our genetic disruption of modulatory glutamatergic signaling, including that arising from PFC, appears to have impaired the first stage of reversal learning (extinguishing responses to previously rewarded stimuli). Our data show that this deficit stems from a preservative phenotype. These findings suggest that glutamatergic regulation from the cortex is important for behavioral flexibility and the disruption of this pathway may be relevant in diseases such as schizophrenia. PMID- 26113147 TI - Sound Pressure Levels in 2 Veterinary Intensive Care Units. AB - BACKGROUND: Intensive care units (ICUs) in human hospitals are consistently noisy environments with sound levels sufficient to substantially decrease sleep quality. Sound levels in veterinary ICUs have not been studied previously, but environmental sound has been shown to alter activity in healthy dogs. HYPOTHESIS: Veterinary ICUs, like those in human medicine, will exceed international guidelines for hospital noise. ANIMALS: NA. METHODS: Prospective, observational study performed consecutively and simultaneously over 4 weeks in 2 veterinary ICUs. Conventional A-weighted sound pressure levels (equivalent continuous level [a reflection of average sound], the sound level that is exceeded 90% of the recording period time [reflective of background noise], and maximum sound levels) were continuously recorded and the number of spikes in sound >80 dBA were manually counted. RESULTS: Noise levels were comparable to ICUs in human hospitals. The equivalent continuous sound level was higher in ICU1 than in ICU2 at every time point compared, with greatest differences observed on week day (ICU1, 60.1 +/- 3.7 dBA; ICU2, 55.9 +/- 2.5 dBA, P < .001) and weekend nights (ICU1, 59.9 +/- 2.4 dBA; ICU2, 53.4 +/- 1.7 dBA, P < .0001) reflecting a 50% difference in loudness. Similar patterns were observed for the maximum and background noise levels. The number of sound spikes was up to 4 times higher in ICU1 (162.3 +/- 84.9 spikes) than in ICU2 (40.4 +/- 12.2 spikes, P = .001). CONCLUSIONS AND CLINICAL IMPORTANCE: These findings show that sound in veterinary ICUs is loud enough to potentially disrupt sleep in critically ill veterinary patients. PMID- 26113148 TI - Comparative analyses of plastid and AFLP data suggest different colonization history and asymmetric hybridization between Betula pubescens and B. nana. AB - Birches (Betula spp.) hybridize readily, confounding genetic signatures of refugial isolation and postglacial migration. We aimed to distinguish hybridization from range-shift processes in the two widespread and cold-adapted species B. nana and B. pubescens, previously shown to share a similarly east-west structured variation in plastid DNA (pDNA). We sampled the two species throughout their ranges and included reference samples of five other Betula species and putative hybrids. We analysed 901 individual plants using mainly nuclear high resolution markers (amplified fragment length polymorphisms; AFLPs); a subset of 64 plants was also sequenced for two pDNA regions. Whereas the pDNA variation as expected was largely shared between B. nana and B. pubescens, the two species were distinctly differentiated at AFLP loci. In B. nana, both the AFLP and pDNA results corroborated the former pDNA-based hypothesis that it expanded from at least two major refugia in Eurasia, one south of and one east of the North European ice sheets. In contrast, B. pubescens showed a striking lack of geographic structuring of its AFLP variation. We identified a weak but significant increase in nuclear (AFLP) gene flow from B. nana into B. pubescens with increasing latitude, suggesting hybridization has been most frequent at the postglacial expansion front of B. pubescens and that hybrids mainly backcrossed to B. pubescens. Incongruence between pDNA and AFLP variation in B. pubescens can be explained by efficient expansion from a single large refugium combined with leading-edge hybridization and plastid capture from B. nana during colonization of new territory already occupied by this more cold-tolerant species. PMID- 26113149 TI - Corrigendum. AB - The article Florence Nightingale (1820-1910) and Sir John Forbes (1787-1861): Neighbours in Old Burlington Street, Westminster (DOI: 10.1177/0967772013505051 ) by Robin Agnew, which appeared in the Journal of Medical Biography Volume 23, Issue 2, included a date error. On page 95 of the issue, 'promulgated by Auenbrugger in 1876 [...]' should be 'promulgated by Auenbrugger in 1761 [...]'. PMID- 26113150 TI - Corrigendum. AB - The article A Memoir of Sir John Forbes (1787-1861) (DOI: 10.1177/0967772013504859 ) by Robin Agnew, which appeared in the Journal of Medical Biography Volume 22, Issue 4, included a date error. On page 190 of the issue, 'Auenbrugger (1722-1821)' should be Auenbrugger (1722-1809)'. PMID- 26113151 TI - Photovoltaic properties of multilayered quantum dot/quantum rod-sensitized TiO2 solar cells fabricated by SILAR and electrophoresis. AB - A multilayered semiconductor sensitizer structure composed of three differently sized CdSe quantum rods (QRs), labeled as Q530, Q575, Q590, were prepared and deposited on the surface of mesoporous TiO2 nanoparticles by electrophoretic deposition (EPD) for photovoltaic applications. By varying the arrangement of layers as well as the time of EPD, the photoconversion efficiency was improved from 2.0% with the single layer of CdSe QRs (TiO2/Q590/ZnS) to 2.9% for multilayers (TiO2/Q590Q575/ZnS). The optimal EPD time was shorter for the multilayered structures. The effect of CdS quantum dots (QDs) deposited by successive ionic layer adsorption and reaction (SILAR) was also investigated. The addition of CdS QDs resulted in the enhancement of efficiency to 4.1% for the configuration (TiO2/CdS/Q590Q575/ZnS), due to increased photocurrent and photovoltage. Based on detailed structural, optical, and photoelectrical studies, the increased photocurrent is attributed to broadened light absorption while the increased voltage is due to a shift in the relevant energy levels. PMID- 26113152 TI - From warm to cold: migration of Adelie penguins within Cape Bird, Ross Island. AB - Due to their sensitivity to environmental change, penguins in Antarctica are widely used as bio-indicators in paleoclimatic research. On the basis of bio element assemblages identified in four ornithogenic sediment profiles, we reconstructed the historical penguin population change at Cape Bird, Ross Island, for the past 1600 years. Clear succession of penguin population peaks were observed in different profiles at about 1400 AD, which suggested a high probability of migration within this region. The succession was most obviously marked by a sand layer lasting from 1400 to 1900 AD in one of the analyzed profiles. Multiple physical/chemical parameters indicated this sand layer was not formed in a lacustrine environment, but was marine-derived. Both isostatic subsidence and frequent storms under the colder climatic condition of the Little Ice Age were presumed to have caused the abandonment of the colonies, and we believe the penguins migrated from the coastal area of mid Cape Bird northward and to higher ground as recorded in the other sediment profiles. This migration was an ecological response to global climate change and possible subsequent geological effects in Antarctica. PMID- 26113153 TI - Development and validation of the Medical Home Care Coordination Survey for assessing care coordination in the primary care setting from the patient and provider perspectives. AB - BACKGROUND: Community health centers are increasingly embracing the Patient Centered Medical Home (PCMH) model to improve quality, access to care, and patient experience while reducing healthcare costs. Care coordination (CC) is an important element of the PCMH model, but implementation and measurability of CC remains a problem within the outpatient setting. Assessing CC is an integral component of quality monitoring in health care systems. This study developed and validated the Medical Home Care Coordination Survey (MHCCS), to fill the gap in assessing CC in primary care from the perspectives of patients and their primary healthcare teams. METHODS: We conducted a review of relevant literature and existing care coordination instruments identified by bibliographic search and contact with experts. After identifying all care coordination domains that could be assessed by primary healthcare team members and patients, we developed a conceptual model. Potentially appropriate items from existing published CC measures, along with newly developed items, were matched to each domain for inclusion. A modified Delphi approach was used to establish content validity. Primary survey data was collected from 232 patients with care transition and/or complex chronic illness needs from the Community Health Center, Inc. and from 164 staff members from 12 community health centers across the country via mail, phone and online survey. The MHCCS was validated for internal consistency, reliability, discriminant and convergent validity. This study was conducted at the Community Health Center, Inc. from January 15, 2012 to July 15, 2014. RESULTS: The 13-item MHCCS - Patient and the 32-item MHCCS - Healthcare Team were developed and validated. Exploratory Structural Equation Modeling was used to test the hypothesized domain structure. Four CC domains were confirmed from the patient group and eight were confirmed from the primary healthcare team group. All domains had high reliability (Cronbach's alpha scores were above 0.8). CONCLUSIONS: Patients experience the ultimate output of care coordination services, but primary healthcare staff members are best primed to perceive many of the structural elements of care coordination. The proactive measurement and monitoring of the core domains from both perspectives provides a richer body of information for the continuous improvement of care coordination services. The MHCCS shows promise as a valid and reliable assessment of these CC efforts. PMID- 26113154 TI - On the Possibility of Habitable Trojan Planets in Binary Star Systems. AB - Approximately 60% of all stars in the solar neighbourhood (up to 80% in our Milky Way) are members of binary or multiple star systems. This fact led to the speculations that many more planets may exist in binary systems than are currently known. To estimate the habitability of exoplanetary systems, we have to define the so-called habitable zone (HZ). The HZ is defined as a region around a star where a planet would receive enough radiation to maintain liquid water on its surface and to be able to build a stable atmosphere. We search for new dynamical configurations-where planets may stay in stable orbits-to increase the probability to find a planet like the Earth. PMID- 26113156 TI - Phenotypic plasticity of sun and shade ecotypes of Stellaria longipes in response to light quality signaling, gibberellins and auxin. AB - Stellaria longipes plant communities (ecotypes) occur in several environmentally distinct habitats along the eastern slopes of southern Alberta's Rocky Mountains. One ecotype occurs in a prairie habitat at ~1000 m elevation where Stellaria plants grow in an environment in which the light is filtered by taller neighbouring vegetation, i.e. sunlight with a low red to far-red (R/FR) ratio. This ecotype exhibits a high degree of phenotypic plasticity by increasing stem elongation in response to the low R/FR ratio light signal. Another Stellaria ecotype occurs nearby at ~2400 m elevation in a much cooler alpine habitat, one where plants rarely experience low R/FR ratio shade light. Stem elongation of plants is largely regulated by gibberellins (GAs) and auxin, indole-3-acetic acid (IAA). Shoots of the prairie ecotype plants show increased IAA levels under low R/FR ratio light and they also increase their stem growth in response to applied IAA. The alpine ecotype plants show neither response. Plants from both ecotypes produce high levels of growth-active GA1 under low R/FR ratio light, though they differ appreciably in their catabolism of GA1. The alpine ecotype plants exhibit very high levels of GA8, the inactive product of GA1 metabolism, under both normal and low R/FR ratio light. Alpine origin plants may de-activate GA1 by conversion to GA8 via a constitutively high level of expression of the GA2ox gene, thereby maintaining their dwarf phenotype and exhibiting a reduced phenotypic plasticity in terms of shoot elongation. In contrast, prairie plants exhibit a high degree of phenotypic plasticity, using low R/FR ratio light mediated changes in GA and IAA concentrations to increase shoot elongation, thereby accessing direct sunlight to optimize photosynthesis. There thus appear to be complex adaptation strategies for the two ecotypes, ones which involve modifications in the homeostasis of endogenous hormones. PMID- 26113155 TI - Assembly of Slx4 signaling complexes behind DNA replication forks. AB - Obstructions to replication fork progression, referred to collectively as DNA replication stress, challenge genome stability. In Saccharomyces cerevisiae, cells lacking RTT107 or SLX4 show genome instability and sensitivity to DNA replication stress and are defective in the completion of DNA replication during recovery from replication stress. We demonstrate that Slx4 is recruited to chromatin behind stressed replication forks, in a region that is spatially distinct from that occupied by the replication machinery. Slx4 complex formation is nucleated by Mec1 phosphorylation of histone H2A, which is recognized by the constitutive Slx4 binding partner Rtt107. Slx4 is essential for recruiting the Mec1 activator Dpb11 behind stressed replication forks, and Slx4 complexes are important for full activity of Mec1. We propose that Slx4 complexes promote robust checkpoint signaling by Mec1 by stably recruiting Dpb11 within a discrete domain behind the replication fork, during DNA replication stress. PMID- 26113157 TI - Transgenic poplar expressing the pine GS1a show alterations in nitrogen homeostasis during drought. AB - Transgenic hybrid poplars engineered to express ectopically the heterologous pine cytosolic GS1a display a number of significant pleiotropic phenotypes including enhanced growth, enhanced nitrogen use efficiency, and resistance to drought stress. The present study was undertaken in order to assess mechanisms whereby ectopic expression of pine GS1a in transgenic poplars results in enhanced agronomic phenotypes. Microarray analysis using the Agilent Populus whole genome array has allowed identification of genes differentially expressed between wild type (WT) and GS transgenics in four tissues (sink leaves, source leaves, stems, and roots) under three growth conditions (well-watered, drought, and recovery). Analysis revealed that differentially expressed genes in functional categories related to nitrogen metabolism show a trend of significant down-regulation in GS poplars compared to the WT, including genes encoding nitrate and nitrite reductases. The down-regulation of these genes was verified using qPCR, and downstream effects were further tested using NR activity assays. Results suggest that higher glutamine levels in GS transgenics regulate nitrate uptake and reduction. Transcript levels of nitrogen-related genes in leaves, including GS/GOGAT cycle enzymes, aspartate aminotransferase, GABA shunt enzymes, photorespiration enzymes, asparagine synthetase, phenylalanine ammonia lyase, isocitrate dehydrogenase, and PII, were also assessed using qPCR revealing significant differences between GS poplars and the WT. Moreover, metabolites related to these differentially expressed genes showed alterations in levels, including higher levels of GABA, hydroxyproline, and putrescine in the GS transgenic. These alterations in nitrogen homeostasis offer insights into mechanisms accounting for drought tolerance observed in GS poplars. PMID- 26113158 TI - Melatonin in Arabidopsis thaliana acts as plant growth regulator at low concentrations and preserves seed viability at high concentrations. AB - Since the discovery of melatonin in plants, several roles have been described for different species, organs, and developmental stages. Arabidopsis thaliana, being a model plant species, is adequate to contribute to the elucidation of the role of melatonin in plants. In this work, melatonin was monitored daily by UHPLC MS/MS in leaves, in order to study its diurnal accumulation as well as the effects of natural and artificial light treatments on its concentration. Furthermore, the effects of exogenous application of melatonin to assess its role in seed viability after heat stress and as a regulator of growth and development of vegetative tissues were evaluated. Our results indicate that melatonin contents in Arabidopsis were higher in plants growing under natural radiation when compared to those growing under artificial conditions, and its levels were not diurnally-regulated. Exogenous melatonin applications prolonged seed viability after heat stress conditions. In addition, melatonin applications retarded leaf senescence. Its effects as growth promoter were dose and tissue dependent; stimulating root growth at low concentrations and decreasing leaf area at high doses. PMID- 26113159 TI - Brassinosteroids are involved in controlling sugar unloading in Vitis vinifera 'Cabernet Sauvignon' berries during veraison. AB - Sugar unloading in grape berries is a crucial step in the long-distance transport of carbohydrates from grapevine leaves to berries. Brassinosteroids (BRs) mediate many physiological processes in plants including carbohydrate metabolism. Here, 'Cabernet Sauvignon' (Vitis vinifera L.) grape berries cultivated in clay loam fields were treated with an exogenous BR (24-epibrassinolide; EBR), a BR synthesis inhibitor (brassinazole; Brz), Brz + EBR (sprayed with EBR 24 h after a Brz treatment), and deionized water (control) at the onset of veraison. The EBR treatment sharply increased the soluble sugars content in the berries, but decreased it in the skins. The EBR and Brz + EBR treatments significantly promoted the activities of both invertases (acidic and neutral) and sucrose synthase (sucrolytic) at various stages of ripening. The mRNA levels of genes encoding sucrose metabolic invertase (VvcwINV), and monosaccharide (VvHT3, 4, 5 and 6) and disaccharide (VvSUC12 and 27) transporters were increased by the EBR and/or Brz + EBR treatments. Generally, the effects of the Brz treatment on the measured targets contrasted with the effects of the EBR treatments. The EBR and Brz treatments inhibited the biosynthesis of the endogenous BRs 6 deoxocastastarone and castasterone. Both EBR and Brz + EBR treatments increased the brassinolide contents, down-regulated the expression of genes encoding BRs biosynthetic enzymes BRASSINOSTEROID-6-OXIDASE and DWARF1, (VvBR6OX1 and VvDWF1) and induced BR receptor gene BRASSINOSTEROID INSENSITIVE 1 (VvBRI1) expression in deseeded berries. Together, these results show that BRs are involved in controlling sugar unloading in grape berries during veraison. PMID- 26113160 TI - Biochemical characterization of an isoprene synthase from Campylopus introflexus (heath star moss). AB - Each year, plants emit terragram quantities of the reactive hydrocarbon isoprene (2-methyl-1,3-butadiene) into the earth's atmosphere. In isoprene-emitting plants, the enzyme isoprene synthase (ISPS) catalyzes the production of isoprene from the isoprenoid intermediate dimethylallyl diphosphate (DMADP). While isoprene is emitted from all major classes of land plants, to date ISPSs from angiosperms only have been characterized. Here, we report the identification and initial biochemical characterization of a DMADP-dependent ISPS from the isoprene emitting bryophyte Campylopus introflexus (heath star moss). The partially purified C. introflexus ISPS (CiISPS) exhibited a Km for DMADP of 0.37 +/- 0.28 mM, a pH optimum of 8.6 +/- 0.5, and a temperature optimum of 40 +/- 3 degrees C in vitro. Like ISPSs from angiosperms, the CiISPS required the presence of a divalent cation. However, unlike angiosperm ISPSs, the CiISPS utilized Mn(2+) preferentially over Mg(2+). Efforts are currently underway in our laboratory to further purify the CiISPS and clone the cDNA sequence encoding this novel enzyme. Our discovery of the first bryophyte ISPS paves the way for future studies concerning the evolutionary origins of isoprene emission in land plants and may help generate new bryophyte model systems for physiological and biochemical research on plant isoprene function. PMID- 26113161 TI - Bisphenol A affects germination and tube growth in Picea meyeri pollen through modulating Ca2+ flux and disturbing actin-dependent vesicular trafficking during cell wall construction. AB - Bisphenol A (BPA), a widespread pollutant, is reportedly harmful to humans, animals and plants. However, the effect of BPA on plant pollen tube growth, as well as the mechanism involved, remains unclear. Here, we report that BPA significantly inhibited Picea meyeri pollen germination and tube elongation in a dose-dependent manner. Transmission electron microscopy showed that BPA was detrimental to organelles such as mitochondria and Golgi apparatus. Non-invasive detection revealed that BPA inhibited extracellular Ca(2+) influx and promoted intracellular Ca(2+) efflux at the pollen tube tip, thereby inducing a dissipated Ca(2+) gradient. Fluorescence labeling showed that BPA disorganized actin filaments (AFs), which subsequently led to abnormal vesicle trafficking. Furthermore, BPA reduced the activity of acid phosphatase, a typical exocytosis enzyme. Moreover, Fourier transform infrared (FTIR) analysis and subsequent fluorescence labeling revealed that BPA induced an abnormal deposition of cell wall components, including pectins and callose. Taken together, our results indicate that BPA, a ubiquitous environmental pollutant, disturbs Ca(2+) flux in P. meyeri pollen tubes, thus disrupting AF organization, resulting in abnormal actin-dependent vesicle trafficking and further affecting the deposition of cell wall components. These findings provide new insight into the mechanism of BPA toxicity in pollen tube tip growth. PMID- 26113162 TI - An Early Warning Scoring System to Identify Septic Patients in the Prehospital Setting: The PRESEP Score. AB - OBJECTIVES: The objective was to develop and evaluate an early sepsis detection score for the prehospital setting. METHODS: A retrospective analysis of consecutive patients who were admitted by emergency medical services (EMS) to the emergency department of the Jena University Hospital was performed. Because potential predictors for sepsis should be based on consensus criteria, the following parameters were extracted from the EMS protocol for further analysis: temperature, heart rate (HR), respiratory rate (RR), oxygen saturation (SaO2 ), Glasgow Coma Scale score, blood glucose, and systolic blood pressure (sBP). Potential predictors were stratified based on inspection of Loess graphs. Backward model selection was performed to select risk factors for the final model. The Prehospital Early Sepsis Detection (PRESEP) score was calculated as the sum of simplified regression weights. Its predictive validity was compared to the Modified Early Warning Score (MEWS), the Robson screening tool, and the BAS 90-30-90. RESULTS: A total of 375 patients were included in the derivation sample; 93 (24.8%) of these had sepsis, including 60 patients with severe sepsis and 12 patients with septic shock. Backward model selection identified temperature, HR, RR, SaO2 , and sBP for inclusion in the PRESEP score. Simplified weights were as follows: temperature > 38 degrees C = 4, temperature < 36 degrees C = 1, HR > 90 beats/min = 2, RR > 22 breaths/min = 1, SaO2 < 92% = 2, and sBP < 90 mm Hg = 2. The cutoff value for a possible existing septic disease based on maximum Youden's index was >=4 (sensitivity 0.85, specificity 0.86, positive predictive value [PPV] 0.66, and negative predictive value [NPV] 0.95). The area under the receiver operating characteristic curve (AUC) of the PRESEP score was 0.93 (95% confidence interval [CI] = 0.89 to 0.96) and was larger than the AUC of the MEWS (0.93 vs. 0.77, p < 0.001). The PRESEP score surpassed MEWS and BAS 90 60-90 for sensitivity (0.74 and 0.62, respectively), specificity (0.75 and 0.83), PPV (0.45 and 0.51), and NPV (0.91 and 0.89). The Robson screening tool had a higher sensitivity and NPV (0.95 and 0.97), but its specificity and PPV were lower (0.43 and 0.32). CONCLUSIONS: The PRESEP score could be a valuable tool for identifying septic patients in the prehospital setting in the case of suspected infection. It should be prospectively validated. PMID- 26113163 TI - Superselective pseudo-continuous arterial spin labeling angiography. AB - PURPOSE: To evaluate the utility of a novel non-contrast enhanced, vessel selective magnetic resonance angiography (MRA) approach based on superselective pseudo-continuous arterial spin labeling (ASL) for the morphologic assessment of intracranial arteries when compared to a clinically used time-of-flight (TOF) MRA. MATERIALS AND METHODS: Three sets of selective ASL angiographies (right and left internal carotid artery, basilar artery) as well as one TOF data set were obtained from each of the five volunteers included in this study on a clinical 1.5T system. The depiction of arterial segments as well as their delineation was evaluated and independently analyzed by two radiologists. Additionally, the ASL angiography approach was performed in two patients suffering from arterio-venous malformations (AVM) in order to illustrate potential applications in a clinical setting. RESULTS: In both angiography techniques, intracranial arteries and their segments (distal branches up to A5 segments of the anterior cerebral arteries, M8 segments of the middle cerebral arteries, and P5 segments of the posterior cerebral arteries) were continuously depicted with excellent inter-reader agreement (kappa>0.81). In AVM patients, reconstructed images of the TOF angiography presented similar information about the size and shape of the AVM as did superselective ASL angiography. In addition, the acquired ASL angiograms of selected vessels allowed assessing the blood supply of individually labeled arteries to the AVM which could also be confirmed by digital subtraction angiography. CONCLUSION: Superselective ASL angiography makes it possible to visualize arterial trees of selected vessels, thereby, providing information about the macrovascular blood supply and flow territories of intracranial arteries. Similar image quality is achieved when compared to clinically used TOF angiography with respect to the identification and delineation of arterial segments. Initial application of superselective ASL angiography in two patients with AVM's demonstrates the ability to gather additional important information about feeding vessels and blood supply. PMID- 26113164 TI - Potential risk of residual cancer cells in the surgical treatment of initially unresectable pancreatic carcinoma after chemoradiotherapy. AB - BACKGROUND: With development of chemoradiotherapy for pancreatic carcinoma, borderline resectable or initially unresectable cases sometimes become operable after long-term intensive chemoradiotherapy. However, there is no established strategy for adjuvant surgery with respect to whether the surgical resection should be extensive or downsized accordingly with diminished disease areas following response to chemoradiotherapy. METHODS: The clinical and pathological aspects of 18 patients with initially unresectable pancreatic cancer who underwent adjuvant surgery after chemo(radio)therapy in our department from 2007 were evaluated. RESULTS: Overall survival from initial treatment was much better for patients with R0 resection than for patients with R1/2 resection. In two of three patients who had complete improvement of plexus (PL) invasion after chemo(radio)therapy, there had still remained pathological plexus invasion. It was shown that tumors did not shrink continuously from the tumor front, but parts remained discontinuously at the distal portion in the process of tumor regression by chemo(radio)therapy. CONCLUSIONS: In adjuvant surgery for patients with locally advanced pancreatic cancer, the potential risk of residual cancer in the regression area following chemoradiotherapy should be considered. Achieving R0 resection will lead to an improved prognosis, and it is necessary to consider how well the extent of resection is after a favorable response to chemoradiotherapy. PMID- 26113165 TI - Failure to launch: the self-regulating Md-MYB10 R6 gene from apple is active in flowers but not leaves of Petunia. AB - KEY MESSAGE: The Md - MYB10 R6 gene from apple is capable of self-regulating in heterologous host species and enhancing anthocyanin pigmentation, but the activity of MYB10 is dependent on endogenous protein partners. Coloured foliage due to anthocyanin pigments (bronze/red/black) is an attractive trait that is often lacking in many bedding, ornamental and horticultural plants. Apples (Malus * domestica) containing an allelic variant of the anthocyanin regulator, Md-MYB10 R6 , are highly pigmented throughout the plant, due to autoregulation by MYB10 upon its own promoter. We investigated whether Md-MYB10 R6 from apple is capable of functioning within the heterologous host Petunia hybrida to generate plants with novel pigmentation patterns. The Md-MYB10 R6 transgene (MYB10-R6 pro :MYB10:MYB10 term ) activated anthocyanin synthesis when transiently expressed in Antirrhinum rosea (dorsea) petals and petunia leaf discs. Stable transgenic petunias containing Md-MYB10 R6 lacked foliar pigmentation but had coloured flowers, complementing the an2 phenotype of 'Mitchell' petunia. The absence of foliar pigmentation was due to the failure of the Md-MYB10 R6 gene to self activate in vegetative tissues, suggesting that additional protein partners are required for Md-MYB10 to activate target genes in this heterologous system. In petunia flowers, where endogenous components including MYB-bHLH-WDR (MBW) proteins were present, expression of the Md-MYB10 R6 promoter was initiated, allowing auto-regulation to occur and activating anthocyanin production. Md-MYB10 is capable of operating within the petunia MBW gene regulation network that controls the expression of the anthocyanin biosynthesis genes, AN1 (bHLH) and MYBx (R3-MYB repressor) in petals. PMID- 26113166 TI - The prevalence of HSV-2 infection in HIV-1 discordant couples. AB - We aimed to investigate the prevalence and associated factors of HSV-2 discordance and concordance in HIV-1-discordant couples. This study used the baseline data from a cohort study of HIV-1-discordant couples in Dehong prefecture of Yunnan province, China. Of 954 participating couples, 42.4% were affected by HSV-2, of which 20.4% were HSV-2-concordant positive, 7.6% were HSV-2 discordant where the male was HSV-2 positive, and 14.4% were HSV-2 discordant where the female was HSV-2 positive. Compared to HSV-2-negative concordance, HSV 2 discordance with an HSV-2-positive male spouse was significantly associated with characteristics of the male spouse, including Han ethnicity and being in a second marriage. HSV-2 discordance with an HSV-2-positive female spouse was significantly associated with characteristics of the female spouse, including Han ethnicity, having engaged in commercial sex, having a sexual relationship of <3 years and being HIV-1 infected. Compared to HSV-2 discordance, HSV-2-positive concordance was significantly associated with an education level of middle school or higher for both spouses, a sexual relationship of ?3 years, more frequent sex and having an HIV-1-infected male spouse. The findings highlight the need for HSV 2 prevention and treatment efforts to reduce HSV-2 transmission in this population, and emphasize the importance of implementing prevention interventions early in couples' relationships. PMID- 26113168 TI - [Reproductive health care for women with spina bifida]. AB - OBJECTIVES: Few studies have focused on reproductive health care for women with spina bifida. This subject is rarely discussed, whether in patient groups or in the medical community. However, these patients need advice and a care that is appropriate to their condition. METHODS: In association with the spina bifida reference center of the University Hospital of Rennes, we have conducted a four year retrospective, observational study. Its aim was to analyze the characteristics of the patients' gynecological care and to adapt our practice to their needs. RESULTS: Forty-eight patients were included. We demonstrated an increased risk of precocious puberty, labia minora hypertrophy and genital prolapse. CONCLUSION: Some specific characteristics of the reproductive health care of patients with spina bifida are interesting to know. A study on a larger series of patients is needed to further analyze the obstetric, gynecological and sexological issues of these women. PMID- 26113169 TI - The effect of jugular bulb-vestibular aqueduct dehiscence on hearing and balance. AB - CONCLUSION: This study suggests that jugular bulb-vestibular aqueduct dehiscence (JBVAD) does not affect the hearing or balance functions of the inner ear. OBJECTIVES: Since JBVAD may cause impairment of the inner ear and induce hearing loss, tinnitus, and vertigo, this study was to investigate the effect of JBVAD on hearing and balance. METHOD: Patients undergoing temporal bone computed tomography (TBCT) scans from May 2013 to December 2013 at a tertiary referral hospital were reviewed. The topographic relationship between the jugular bulb (JB) and the vestibular aqueduct was assessed. The findings were classified as normal when there was always a bony structure between the two structures and as dehiscent when the bony coverage separating the two structures was absent. Clinical data were collected via electronic records and clinical follow-up. RESULTS: A total of 1313 out of 8325 patients were diagnosed with a HJB. Forty six patients showed JBVAD. The prevalence of dehiscence was 0.6% in patients undergoing temporal bone CT scans and 3.5% in patients with HJB. Of the 46 patients with JBVAD, 23 (50%) had sensorineural hearing loss, three (6.5%) had tinnitus, and two (4.3%) had vertigo. The correlation between JBVAD and these clinical symptoms did not achieve statistical significance. PMID- 26113170 TI - Development and application of an automated algorithm to identify a window of consecutive days of accelerometer wear for large-scale studies. AB - BACKGROUND: Some accelerometer studies ask participants to document in a daily log when the device was worn. These logs are used to inform the window of consecutive days to extract from the accelerometer for analysis. Logs can be missing or inaccurate, which can introduce bias in the data. To mitigate this bias, we developed a simple computer algorithm that used data within the accelerometer to identify the window of consecutive wear days. To evaluate the algorithm's performance, we compared how well it agreed to the window of days identified by visual inspection and participant logs. FINDINGS: Participants were older women (mean age 79 years) in a cohort study that aimed to examine the relationship of objective physical activity on cardiovascular health. The study protocol requested that participants wear an accelerometer 24 h per day over nine calendar days (to capture seven consecutive wear days) and to complete daily logs. A stratified sample with (n = 75) and without (n = 100) participant logs were selected. The Objective Physical Activity and Cardiovascular Health (OPACH) algorithm was applied to the accelerometer data to identify a window of up to seven consecutive wear days. Participant logs documented dates the device was first put on, worn, and removed. Using pre-established guidelines, two independent raters visually reviewed the accelerometer data and characterized the dates representing up to seven consecutive days of 24-h wear. Average agreement level between the two raters was 90%. The percent agreement was compared between the three methods. The OPACH algorithm and visual inspection had 83% agreement in identifying a window with the same total number of days, if one or more shifts in calendar dates were allowed. For visual inspection vs. logs and algorithm vs. logs, this agreement was 81 and 74%, respectively. CONCLUSION: The OPACH algorithm can be efficiently and readily applied in large-scale accelerometer studies for the identification of a window of consecutive days of accelerometer wear. This algorithm was comparable to visual inspection and participant logs and might provide a quicker and more cost-effective alternative to selecting which data to extract from the accelerometer for analysis. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00000611. PMID- 26113171 TI - Efficacy of Tailored Physical Activity or Chronic Pain Self-Management Programme on return to work for sick-listed citizens: A 3-month randomised controlled trial. AB - OBJECTIVES: The aim was to evaluate the efficacy of 'Tailored Physical Activity' (TPA) and a 'Chronic Pain Self-management Programme' (CPSMP) compared with a reference group (REF) on return to work after 3 months as sick-listed citizens with pain related to the back or the upper body. METHODS: Using a randomised controlled trial design all participants (n= 141) received health guidance for 1.5 hours and were randomised to TPA, CPSMP or REF. Characteristics of participants were collected from a questionnaire. The primary endpoint was proportion of participants returned to work as registered by the municipality and the co-primary endpoint was duration of the sickness absence period. Secondary outcomes consisted of pain, body mass index, aerobic capacity, grip strength, work ability and kinesiophobia. The trial was conducted in Sonderborg Municipality from March 2011 to October 2013. RESULTS: TPA was more effective on return to work than REF, while CPSMP only tended to be more effective than REF, and the primary outcome was the only between-groups significant difference. TPA participants also reached a highly significant reduction in pain from baseline to follow-up with no similar effect seen in CPSMP or REF. In contrast, no benefit of TPA and CPSMP was evident regarding work ability, kinesiophobia or physical capacity after 3 months of follow-up. CONCLUSIONS: The results suggest that TPA is a promising intervention to facilitate return to work and reduce pain among sick-listed citizens with pain related to the back or upper body compared to REF. PMID- 26113167 TI - Controversies Around Epidemiology, Diagnosis and Treatment of Clostridium difficile Infection. AB - Clostridium difficile infection is a major public health problem. However, in recent years the epidemiology, risk factors, diagnosis, and treatment of C. difficile infection have undergone a significant change. The incidence of C. difficile has increased, not only in the healthcare sector but also in the community. Hospital-acquired infection and community-acquired disease have different risk factors, with the latter occurring in children and younger individuals without a history of antibiotic use or previous infections. From a clinician's perspective, a quick efficient diagnosis is required for patient treatment; however, the old method of using enzyme immunoassays is insensitive and not very specific. Recent literature around diagnostic testing for C. difficile infection suggests using PCR or a two-step algorithm to improve sensitivity and specificity. More failures and recurrence with metronidazole have led to treatment algorithms suggesting its use for mild infections and switching to vancomycin if there is no clinical improvement. Alternatively, if signs and symptoms suggest severe infection, then oral vancomycin is recommended as a first line agent. The addition of a new but costly agent, fidaxomicin, has seen some disparity between the European and North American guidelines with regard to when it should be used. Lastly, rapid developments and good results with fecal microbial transplantation have also left clinicians wondering about its place in therapy. This article reviews the literature around some of the recent controversies in the field of C. difficile infection. PMID- 26113172 TI - Reported and intended behaviour towards those with mental health problems in the Czech Republic and England. AB - This is one of the first studies, which compares the level of stigmatizing behaviour in countries that used to be on the opposite sides of the Iron Curtain. The aim was to identify the prevalence of reported and intended stigmatizing behaviour towards those with mental health problems in the Czech Republic and to compare these findings with the findings from England. The 8-item Reported and Intended Behaviour Scale (RIBS) was used to assess stigmatising behaviour among a representative sample of the Czech population (n=1797). Results were compared with the findings of an analogous survey from England (n=1720), which also used the RIBS. The extent of reported behaviour (i.e., past and present experiences with those with mental health problems) was lower in the Czech Republic than in England. While 12.7% of Czechs reported that they lived, 12.9% that they worked, and 15.3% that they were acquainted with someone who had mental health problems, the respective numbers for England were 18.5%, 26.3% and 32.5% (P<0.001 in each of these items). On the other hand, the extent of intended stigmatizing behaviour towards those with mental health problems is considerably higher in the Czech Republic. Out of maximum 20 points attached to possible responses to the RIBS items 5-8, Czechs had a lower total score (x=11.0, SD=4.0) compared to English respondents (x=16.1, SD=3.6), indicating lower willingness to accept a person with mental health problems (P<0.001). The prevalence of stigmatizing behaviour in the Czech Republic is worrying. Both, further research and evidence based anti stigma interventions, should be pursued in order to better understand and decrease stigmatizing behaviour in the Czech Republic and possibly across the post-communist countries in Central and Eastern Europe. PMID- 26113173 TI - Comment on "Tumor necrosis factor-alpha antagonist therapy for concomitant rheumatoid arthritis and hepatitis C virus infection: a case series study". PMID- 26113175 TI - Characteristics of commercial and traditional village poultry farming in Mali with a focus on practices influencing the risk of transmission of avian influenza and Newcastle disease. AB - We aimed at characterizing commercial and traditional village poultry farming in Mali, with a focus on practices influencing the risk of transmission of avian influenza and Newcastle disease. Surveys were conducted in 2009-2011 in a study area covering approximately 98% of the Malian poultry population. Among the 282 commercial farms investigated, of which 64 had not been known by the government authorities, 83% were located within a 50km radius from the capitals of the country and regions and 54% had low biosecurity standard. Among the 152 randomly selected village household flocks investigated, characteristics were overall similar to those in other African countries but some differences were notable including a large flock size (median 44 poultry), a low presence of ducks and geese (11% and 1.1% of flocks, respectively), vaccination against Newcastle disease being common (49% of flocks), a low proportion of households selling sick and dead birds (0.7% and 0%, respectively) and limited cohabitation between poultry and humans at night. Our recommendations to limit the risk of disease transmission include (1) for commercial farms, to introduce compulsory farm registration and accreditation, to increase technical proficiency and access to credit for farms with low biosecurity, and to support poultry producer associations; (2) for village poultry, to promote better quarantine and management of sick and dead birds. Such detailed knowledge of country-specific characteristics of poultry production systems is essential to be able to develop more efficient disease risk management policies. PMID- 26113174 TI - A novel method to assess human population exposure induced by a wireless cellular network. AB - This paper presents a new metric to evaluate electromagnetic exposure induced by wireless cellular networks. This metric takes into account the exposure induced by base station antennas as well as exposure induced by wireless devices to evaluate average global exposure of the population in a specific geographical area. The paper first explains the concept and gives the formulation of the Exposure Index (EI). Then, the EI computation is illustrated through simple phone call scenarios (indoor office, in train) and a complete macro urban data long term evolution scenario showing how, based on simulations, radio-planning predictions, realistic population statistics, user traffic data, and specific absorption rate calculations can be combined to assess the index. Bioelectromagnetics. 36:451-463, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26113176 TI - Upregulated expression of NKG2D and its ligands give potential therapeutic targets for patients with thymoma. AB - The activating receptor NKG2D (natural killer group 2, member D) of natural killer (NK) cells promotes tumor immune surveillance by targeting ligands selectively induced on cancer cells, and thus having an important role in antitumor immune response. Because these ligands are not widely expressed on healthy adult tissue, NKG2D ligands may present as useful target for immunotherapeutic approaches in cancer. In this study, to elucidate the role of NKG2D-NKG2D ligand interaction in thymoma tissues and to evaluate the potential role of NKG2D ligands as therapeutic target for thymoma, we examined the expression of NKG2D and its specific ligands: MICA (major histocompatibility complex class I chain-related protein A), MICB (major histocompatibility complex class I chain-related protein B) and ULBP (UL16-binding protein) in 36 thymomas (6 subtype A, 6 subtype AB, 8 subtype B1, 5 subtype B2, 6 subtype B3 and 5 subtype C), 15 thymic atrophy and 8 thymic hyperplasia by immunohistochemistry and reverse transcription-real-time-PCR methods. We demonstrated that both mRNA and protein levels of NKG2D, MICA, MICB and ULBP were upregulated in six types of thymomas compared with those in atrophic thymus or proliferating thymus. Furthermore, the NKG2D ligands were found to be frequently coexpressed on thymoma cells. Furthermore, the expression of MICA, MICB and ULBP in subtype C was higher compared with those in subtype A, AB, B1, B2 and B3. Thus, we concluded that high expressions of NKG2D, MICA, MICB and ULBP1 were shown in patients with thymoma, and this may enhance the recognition function of NK cells to eliminate tumor cells. MICA, MICB and ULBP presented an attractive target for thymoma therapy. The abnormal expression of NKG2D, MICA, MICB and ULBP1 can provide us with evidence of the occurrence of thymoma and could also be used as a target in the treatment of thymoma. PMID- 26113177 TI - Length of Barrett's oesophagus and cancer risk: implications from a large sample of patients with early oesophageal adenocarcinoma. AB - OBJECTIVE: Although it is well understood that the risk of oesophageal adenocarcinoma increases with Barrett length, transition risks for cancer associated with different Barrett lengths are unknown. We aimed to estimate annual cancer transition rates for patients with long-segment (>=3 cm), short segment (>=1 to <3 cm) and ultra-short-segment (<1 cm) Barrett's oesophagus. DESIGN: We used three data sources to estimate the annual cancer transition rates for each Barrett length category: (1) the distribution of long, short and ultra short Barrett's oesophagus among a large German cohort with newly diagnosed T1 oesophageal adenocarcinoma; (2) population-based German incidence of oesophageal adenocarcinoma; and (3) published estimates of the population prevalence of Barrett's oesophagus for each Barrett length category. RESULTS: Among 1017 patients with newly diagnosed T1 oesophageal adenocarcinoma, 573 (56%) had long segment, 240 (24%) short-segment and 204 (20%) ultra-short-segment Barrett's oesophagus. The base-case estimates for the prevalence of Barrett's oesophagus among the general population were 1.5%, 5% and 14%, respectively. The annual cancer transition rates for patients with long, short and ultra-short Barrett's oesophagus were 0.22%, 0.03% and 0.01%, respectively. To detect one cancer, 450 patients with long-segment Barrett's oesophagus would need to undergo annual surveillance endoscopy; in short segment and ultra-short segment, the corresponding numbers of patients would be 3440 and 12,364. Similar results were obtained when applying US incidence data. CONCLUSIONS: The large number of patients, who need to undergo endoscopic surveillance to detect one cancer, raises questions about the value of surveillance endoscopy in patients with short segment or ultra-short segment of Barrett's oesophagus. PMID- 26113178 TI - In search for a disease-modifying treatment in irritable bowel syndrome. PMID- 26113179 TI - Adiabatic elimination-based coupling control in densely packed subwavelength waveguides. AB - The ability to control light propagation in photonic integrated circuits is at the foundation of modern light-based communication. However, the inherent crosstalk in densely packed waveguides and the lack of robust control of the coupling are a major roadblock toward ultra-high density photonic integrated circuits. As a result, the diffraction limit is often considered as the lower bound for ultra-dense silicon photonics circuits. Here we experimentally demonstrate an active control of the coupling between two closely packed waveguides via the interaction with a decoupled waveguide. This control scheme is analogous to the adiabatic elimination, a well-known procedure in atomic physics. This approach offers an attractive solution for ultra-dense integrated nanophotonics for light-based communications and integrated quantum computing. PMID- 26113180 TI - Comparative analysis of procoagulant and fibrinogenolytic activity of crude protease fractions of turmeric species. AB - ETHNAOPHARMACOLOGIAL RELEVANCE: Turmeric rhizome is a traditional herbal medicine, which has been widely used as a remedy to stop bleeding on fresh cuts and for wound healing by the rural and tribal population of India. AIM OF THE STUDY: To validate scientific and therapeutic application of turmeric rhizomes to stop bleeding on fresh cuts and its role in wound healing process. MATERIALS AND METHODS: The water extracts of thoroughly scrubbed and washed turmeric rhizomes viz., Curcuma aromatica Salisb., Curcuma longa L., Curcuma caesia Roxb., Curcuma amada Roxb. and Curcuma zedoria (Christm.) Roscoe. were subjected to salting out and dialysis. The dialyzed crude enzyme fractions (CEFs) were assessed for proteolytic activity using casein as substrate and were also confirmed by caseinolytic zymography. Its coagulant activity and fibrinogenolytic activity were assessed using human citrated plasma and fibrinogen, respectively. The type of protease(s) in CEFs was confirmed by inhibition studies using specific protease inhibitors. RESULTS: The CEFs of C. aromatica, C. longa and C. caesia showed 1.89, 1.21 and 1.07 folds higher proteolytic activity, respectively, compared to papain. In contrast to these, C. amada and C. zedoria exhibited moderate proteolytic activity. CEFs showed low proteolytic activities compared to trypsin. The proteolytic activities of CEFs were confirmed by caseinolytic zymography. The CEFs of C. aromatica, C. longa and C. caesia showed complete hydrolysis of Aalpha, Bbeta and gamma subunits of human fibrinogen, while C. amada and C. zedoria showed partial hydrolysis. The CEFs viz., C. aromatica, C. longa, C. caesia, C. amada and C. zedoria exhibited strong procoagulant activity by reducing the human plasma clotting time from 172s (Control) to 66s, 84s 88s, 78s and 90s, respectively. The proteolytic activity of C. aromatica, C. longa, C. caesia and C. amada was inhibited (>82%) by PMSF, suggesting the possible presence of a serine protease(s). However, C. zedoria showed significant inhibition (60%) against IAA and moderate inhibition (30%) against PMSF, indicating the presence of cysteine and serine protease(s). CONCLUSION: The CEFs of turmeric species exhibited strong procoagulant activity associated with fibrinogenolytic activity. This study provides the scientific credence to turmeric in its propensity to stop bleeding and wound healing process practiced by traditional Indian medicine. PMID- 26113181 TI - Ethnopharmacological knowledge of Shiraz and Fasa in Fars region of Iran for diabetes mellitus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study provides ethnopharmacological knowledge of traditional herbal healers from Shiraz and Fasa in Fars region (Iran) for treatment of diabetes mellitus. MATERIALS AND METHODS: Field surveys were carried out during September 2013-February 2014 in Shiraz and Fasa. The data were collected through structured questionnaire in Persian. All plant species recorded for the treatment of diabetes mellitus were sampled. Samples were identified by a botanist and obtained a voucher specimens number and deposited in the Shiraz School of Pharmacy Herbarium. The information such as scientific name, family, local name, medicinal use(s), parts used and preparation method were provided. Literature review on available data about antidiabetic effect of the addressed plant species was done to highlight gaps in current knowledge and propose the next steps. RESULTS: In total, 50 informants were interviewed. Totally 39 plant species were recommended by herbal healers, of which 28 are native to Iran. The most recommended plants for diabetes were Trigonella foenum graecam (28 Attars), Securigera securidaca (22 Attars), Vaccinium arctostaphylos (18 Attars). The most abundant families were Fabaceae, Asteraceae, Lamiaceae and Apiaceae. Plant parts used were mainly seeds, flowers, leaves and fruits. The most usual preparation methods were decoction, powder and distillation. Around 44% of all reported plants for diabetes are also in use for obesity management CONCLUSIONS: This study provided ethnopharmacological knowledge from Fars region in Iran for a specific disease and we have introduced important plant species which are recommended by local herbal healers for diabetes mellitus. For 23% of reported plants, clinical studies approved antidiabetic properties and for 61%, animal studies approved antidiabetic activity. PMID- 26113182 TI - Saussurea involucrata: A review of the botany, phytochemistry and ethnopharmacology of a rare traditional herbal medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea involucrata Matsum. & Koidz. is an endangered species of the Asteraceae family, growing in the high mountains of central Asia. It has been, and is, widely used in traditional Uyghur, Mongolian and Kazakhstan medicine as well as in Traditional Chinese Medicine as Tianshan Snow Lotus (Chinese: ). In traditional medical theory, S. involucrata can promote blood circulation, thereby alleviating all symptoms associated with poor circulation. It also reputedly eliminates cold and dampness from the body, diminishes inflammation, invigorates, and strengthens Yin and Yang. It has long been used to treat rheumatoid arthritis, cough with cold, stomach ache, dysmenorrhea, and altitude sickness in Uyghur and Chinese medicine. AIM OF THE REVIEW: To comprehensively summarize the miscellaneous research that has been done regarding the botany, ethnopharmacology, phytochemistry, biological activity, and toxicology of S. involucrata. METHOD: An extensive review of the literature was carried out. Apart from different electronic databases including SciFinder, Chinese National Knowledge Infrastructure (CNKI), ScienceDirect that were sourced for information, abstracts, full-text articles and books written in English and Chinese, including those traditional records tracing back to the Qing Dynasty. Pharmacopoeia of China and other local herbal records in Uighur, Mongolian and Kazakhstan ethnomedicines were investigated and compared for pertinent information. RESULTS: The phytochemistry of S. involucrata has been comprehensively investigated. More than 70 compounds have been isolated and identified; they include phenylpropanoids, flavonoids, coumarins, lignans, sesquiterpenes, steroids, ceramides, polysaccharides. Scientific studies on the biological activity of S. involucrata are equally numerous. The herb has been shown to have anti-neoplastic, anti-inflammatory, analgesic, anti-oxidative, anti fatigue, anti-aging, anti-hypoxic, neuroprotective and immunomodulating effects. Many have shown correlations to the traditional clinical applications in Traditional Chinese Medicine and medicines. The possible mechanisms of S. involucrata in treating various cancers are revealed in the article, these include inhibition of cancer cells by affecting their growth, adhesion, migration, aggregation and invasion, inhibition of epidermal growth factor receptor signaling in cancer cells, hindrance of cancer cell proliferation, causing cytotoxicity to cancer cells and promoting expression of tumor suppressor genes. Dosage efficacy is found to be generally concentration- and time dependent. However, studies on the correlation between particular chemical constituents and specific bioactivities are limited. CONCLUSION: In this review, we have documented the existing traditional uses of S. involucrata and summarized recent research into the phytochemistry and pharmacology of S. involucrata. Many of the traditional uses have been validated by phytochemical and modern pharmacological studies but there are still some areas where the current knowledge could be improved. Although studies have confirmed that S. involucrata has a broad range of bioactivities, further in-depth studies on the exact bioactive molecules and the mechanism of action are expected. Whether we should use this herb independently or in combination deserves to be clarified. The exact quality control as well as the toxicology studies is necessary to guarantee the stability and safety of the clinic use. The sustainable use of this endangered resource was also addressed. In conclusion, this review was anticipated to highlight the importance of S. involucrata and provides some directions for the future development of this plant. PMID- 26113183 TI - Effects of cell-cell contact and oxygen tension on chondrogenic differentiation of stem cells. AB - While cell condensation has been thought to enhance chondrogenesis, no direct evidence so far confirms that cell-cell contact itself increases chondrogenic differentiation of stem cells, since the change of cell-cell contact is usually coupled with those of other cell geometry cues and soluble factors in cell culture. The present study semi-quantitatively examined the effect of cell-cell contact in a decoupled way. We fabricated two-dimensional micropatterns with cell adhesive peptide arginine-glycine-aspartate (RGD) microdomains on a nonfouling poly(ethylene glycol) (PEG) hydrogel. Mesenchymal stem cells (MSCs) were well localized on the microdomains for a long time. Based on our micropattern design, single MSCs or cell clusters with given cell numbers (1, 2, 3, 6 and 15) and a similar spreading area per cell were achieved on the same substrate, thus the interference of soluble factor difference from cell autocrine and that of cell spreading area were ruled out. After 9-day chondrogenic induction, collagen II was stained to characterize the chondrogenic induction results; the mRNA expression levels of SOX9, collagen II, aggrecan, HIF-1alpha and collagen I were also detected. The statistics confirmed unambiguously that the extent of the chondrogenic differentiation increased with cell-cell contact, and even a linear relation between differentiation extent and contact extent was established within the examined range. The cell-cell contact effect worked under both hypoxia (5% O2) and normoxia (21% O2) conditions, and the hypoxia condition promoted the chondrogenic induction of MSCs on adhesive microdomains more efficiently than the normoxia condition under the same cell-cell contact extents. PMID- 26113186 TI - Potential antibacterial activity of triazine dendrimer: Synthesis and controllable drug release properties. AB - A novel sustained release delivery system of ciprofloxacin was developed. The system consists of a viscosity enhancer plus a penetration enhancer to overcome penetration barriers and loss due to wash-out and thus achieve the desired ciprofloxacin ocular absorption. A macromolecule of piperazine core 1,3,5 triazine dendrimer with eight molecules of ciprofloxacin drug as a surface moiety has been synthesized in five steps. Antibacterial activities of this compound have been investigated for Gram-positive and Gram-negative bacteria like Staphylococcus aureus (mtcc 737), Bacillus subtilis (mtcc 2063), Escherichia coli (mtcc-443), Pseudomonas aeruginosa (mtcc 741) and Proteus mirabilis (mtcc425). It was observed that the influence of hydrophobic and hydrophilic balance per repeat unit of these dendrimer has profound effects for antibacterial activities. The MIC value of the compound very lower at 100 MUg/mL(-1) when compared with standard ciprofloxacin at 500 MUg/mL(-1). The compound (10) exhibits five times higher activity against tested organisms when compared with ciprofloxacin as standard. The structures of the dendrimers were determined by means of MALDI-TOF MS, NMR and IR studies. The in vitro release of ciprofloxacin from obtained dendrimer was investigated. PMID- 26113184 TI - Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is caused by absence of the integral structural protein, dystrophin, which renders muscle fibres susceptible to injury and degeneration. This ultimately results in cardiorespiratory dysfunction, which is the predominant cause of death in DMD patients, and highlights the importance of therapeutic targeting of the cardiorespiratory system. While there is some evidence to suggest that restoring dystrophin in the diaphragm improves both respiratory and cardiac function, the role of the diaphragm is not well understood. Here using exon skipping oligonucleotides we predominantly restored dystrophin in the diaphragm and assessed cardiac function by MRI. This approach reduced diaphragmatic pathophysiology and markedly improved diaphragm function but did not improve cardiac function or pathophysiology, with or without exercise. Interestingly, exercise resulted in a reduction of dystrophin protein and exon skipping in the diaphragm. This suggests that treatment regimens may require modification in more active patients. In conclusion, whilst the diaphragm is an important respiratory muscle, it is likely that dystrophin needs to be restored in other tissues, including multiple accessory respiratory muscles, and of course the heart itself for appropriate therapeutic outcomes. This supports the requirement of a body-wide therapy to treat DMD. PMID- 26113187 TI - Synthesis and evaluation of N-analogs of 1,2-diarylethane as Helicobacter pylori urease inhibitors. AB - Therapies based on urease inhibition are now seriously considered as the first line of treatment for infections caused by Helicobacter pylori. However, the present inhibitors are ineffective or unstable in highly acidic gastric juice. Here, we report a series of benzylanilines as effective inhibitors of H. pylori urease. Out of the obtained twenty-one compounds, N-(3,4-dihydroxybenzyl)-4 nitroaniline (4) was evaluated in detail and shows promising features for development as anti-H. pylori agent. Excellent potency against urease in both cell-free extract and intact cell was observed at low concentrations of 4 (IC50=0.62 +/- 0.04 and 1.92 +/- 0.09 MUM), which showed over 29- and 54-fold increase in potency with respect to the positive control AHA. The SAR analysis revealed that protection of 3,4-dihydroxy group of 4 as methoxy or changes of 4 NO2 will result in a moderate to dramatic decrease in potency. PMID- 26113188 TI - BN/CC isosterism in borazaronaphthalenes towards phosphodiesterase 10A (PDE10A) inhibitors. AB - The application of BN/CC isosterism is explored as a method of expanding the scope of core scaffolds in biologically active compounds. The viability of potential drug candidates incorporating BN-heteroaromatic moieties was investigated through the synthesis of BN-substituted analogs to known phosphodiesterase (PDE10A) inhibitors, namely MP10 and a selection of N methylanilide analogs. These in some cases revealed unexpectedly potent and relatively stable derivatives, providing further support for the potential of BN incorporation in medicinal chemistry. PMID- 26113189 TI - Dietary delivery: a new avenue for microRNA therapeutics? AB - Many people carefully monitor their food choices, adhering to the philosophy that 'you are what you eat'. Recent research adds a new wrinkle to that old adage, suggesting that dietary small RNAs (sRNAs) can control the gene expression of the consumer and may provide an effective, noninvasive, and inexpensive therapy for many human diseases. PMID- 26113190 TI - A simple, physiologically-based model of sea turtle remigration intervals and nesting population dynamics: Effects of temperature. AB - Variation in the yearly number of sea turtles nesting at rookeries can interfere with population estimates and obscure real population dynamics. Previous theoretical models suggested that this variation in nesting numbers may be driven by changes in resources at the foraging grounds. We developed a physiologically based model that uses temperatures at foraging sites to predict foraging conditions, resource accumulation, remigration probabilities, and, ultimately, nesting numbers for a stable population of sea turtles. We used this model to explore several scenarios of temperature variation at the foraging grounds, including one-year perturbations and cyclical temperature oscillations. We found that thermally driven resource variation can indeed synchronize nesting in groups of turtles, creating cohorts, but that these cohorts tend to break down over 5-10 years unless regenerated by environmental conditions. Cohorts were broken down faster at lower temperatures. One-year perturbations of low temperature had a synchronizing effect on nesting the following year, while high temperature perturbations tended to delay nesting in a less synchronized way. Cyclical temperatures lead to cyclical responses both in nesting numbers and remigration intervals, with the amplitude and lag of the response depending on the duration of the cycle. Overall, model behavior is consistent with observations at nesting beaches. Future work should focus on refining the model to fit particular nesting populations and testing further whether or not it may be used to predict observed nesting numbers and remigration intervals. PMID- 26113191 TI - Insect models of illumination-invariant skyline extraction from UV and green channels. AB - Experiments have shown that the skyline is an important visual cue for navigating insects. However, the comparison between two snapshots collected at different times of day is a complex task due to possible illumination changes. In this study we examine whether the information from two different color channels (UV and green, which are also available for many insects) can be used to obtain an illumination-invariant separation between the sky and ground. We collected UV and green images of seven different scenes over entire days, in which natural and artificial objects are visible in front of the sky. With the collected data we want to find answers to the following two questions: 'Does UV/green contrast vision increase the quality of separation compared to UV-only vision?' and 'What yields a better performance: separation methods based on a fixed threshold (global separation techniques) or separation methods which adapt the threshold dependent on the input image (local separation techniques)?' We implemented several linear separation techniques and found that UV/green contrast only marginally increases the quality of global separation in comparison to UV-only, and that local separation techniques are superior to global separation techniques. PMID- 26113192 TI - When is emotional contagion adaptive? AB - Empathy plays an important role in animal social behavior. Since emotional contagion forms one of the bases of empathy, here we study conditions for emotional contagion to be adaptive, compared with other behavioral rules such as behavioral mimicry. We consider the situation where the focal individual (=observer) reacts to a behavior of another individual (=demonstrator). By emotional contagion one spontaneously copies the emotional state of the demonstrator and takes a behavior driven by that emotion. By behavioral mimicry, in contrast, one copies the behavior of the demonstrator itself. Through mathematical models we show that emotional contagion is adaptive when the environmental similarity between the demonstrator and the observer is intermediate. The advantage of adopting emotional contagion over behavioral mimicry increases when observing others' behavior is difficult or cognitively demanding. We show that emotional contagion is often a more flexible strategy than behavioral mimicry in order to cope with the living environment. In other words, emotional contagion often works as a better social learning strategy. These results suggest some ecological conditions that would favor the evolution of emotional contagion, and give a part of the explanations of why emotional contagion is frequently observed in group-living animals. PMID- 26113193 TI - A geminivirus betasatellite damages the structural and functional integrity of chloroplasts leading to symptom formation and inhibition of photosynthesis. AB - Geminivirus infection often causes severe vein clearing symptoms in hosts. Recently a betasatellite has emerged as a key regulator of symptom induction. To understand the host-betasatellite interactions in the process of symptom development, a systematic study was carried out involving symptoms induced by a betasatellite associated with radish leaf curl disease (RaLCB) in Nicotiana benthamiana. It has been found that betaC1 protein localized to chloroplasts of host cells, and RaLCB lacking betaC1, which failed to produce symptoms, had no effect on chloroplast ultrastructure. Vein flecking induced by transiently expressed betaC1 was associated with chloroplast ultrastructure. In addition, the betasatellite down-regulates expression of genes involved in chlorophyll biosynthesis as well as genes involved in chloroplast development and plastid translocation. Interestingly, the expression of key host genes involved in chlorophyll degradation remains unaffected. Betasatellite infection drastically reduced the numbers of active reaction centres and the plastoquinol pool size in leaves exhibiting vein clearing symptoms. Betasatellite-mediated impediments at different stages of chloroplast functionality affect the photosynthetic efficiency of N. benthamiana. To the best of the authors' knowledge, this is the first evidence of a chloroplast-targeting protein encoded by a DNA virus which induces vein clearing and structurally and functionally damages chloroplasts in plants. PMID- 26113194 TI - A comparison of light-harvesting performance of silicon nanocones and nanowires for radial-junction solar cells. AB - Silicon nanorod based radial-junction solar cells are competitive alternatives to traditional planar silicon solar cells. In various silicon nanorods, nanocone is always considered to be better than nanowire in light-absorption. Nevertheless, we find that this notion isn't absolutely correct. Silicon nanocone is indeed significantly superior over nanowire in light-concentration due to its continuous diameters, and thus resonant wavelengths excited. However, the concentrated light can't be effectively absorbed and converted to photogenerated carriers, since its propagation path in silicon nanocone is shorter than that in nanowire. The results provide critical clues for the design of silicon nanorod based radial junction solar cells. PMID- 26113195 TI - Accuracy of Fetal Echocardiography in the Differential Diagnosis between Truncus Arteriosus and Pulmonary Atresia with Ventricular Septal Defect. AB - OBJECTIVES: To report on the accuracy of fetal echocardiography in the distinction between truncus arteriosus communis (CAT) and pulmonary atresia with ventricular septal defect (PA-VSD) and to describe the association with extracardiac and chromosomal anomalies. METHODS: This was a retrospective study on 31 fetuses with a single arterial trunk overriding a VSD with a nonidentifiable right ventricle outflow tract with anterograde flow. Data on the type of cardiac defect, gestational age, characteristics of the arterial trunk valve, presence of additional vascular, chromosomal and extracardiac abnormalities and postnatal outcome were obtained. Misdiagnosed cases were reevaluated by four-dimensional spatiotemporal image correlation (4D-STIC) echocardiography. RESULTS: The overall diagnostic accuracy was 81% and increased to 93.5% with 4D-STIC. Chromosomal and extracardiac anomalies were detected in 40 and 27%, respectively. In the PA-VSD group, patent ductus arteriosus and major aortopulmonary collateral arteries (MAPCAs) were present in 70 and 50% of the cases, respectively, coexisting in 1 of 5 cases. MAPCAs were significantly associated with a right aortic arch and with a 22q11 microdeletion in 50% of cases. CONCLUSIONS: A prenatal distinction between CAT and PA-VSD can currently be achieved in most cases. MAPCAs should be actively searched for when PA-VSD is suspected, as they are associated with a higher risk of 22q11 microdeletion and potentially complicate postnatal treatment. PMID- 26113196 TI - Chronic total occlusion treated with coronary intervention by three-dimensional guidewire manipulation: an experimental study and clinical experience. AB - Three-dimensional (3D) wiring is one method for accurate guidewire control in chronic total occlusion (CTO) lesions during manipulation of CTO-specific stiff guidewires. However, the construction of a mental 3D image is difficult. We propose the idea of image patterns to allow immediate construction of 3D images from the two perpendicular angles of the X-ray system detector and report a case of CTO treated with 3D wiring. PMID- 26113197 TI - Reverse bent wiring with Crusade catheter can be a useful technique for penetrating an abrupt-type entry of coronary occlusion at branching ostium. AB - We encountered a case of chronic total in-stent occlusion which involving an abrupt-type entry at an obtuse marginal branching ostium. It is usually difficult to antegradely penetrate this kind of proximal fibrous cap. Therefore, we adopted a reverse bent wiring technique with a Crusade catheter and successfully completed all procedures. This technique is very simple but can be very effective in specific situations in daily percutaneous coronary intervention (PCI). Many PCI operators may empirically adopt this kind of wire manipulation technique. However, this kind of technique has never been officially reported to our knowledge. PMID- 26113199 TI - Decadal-scale rates of reef erosion following El Nino-related mass coral mortality. AB - As the frequency and intensity of coral mortality events increase under climate change, understanding how declines in coral cover may affect the bioerosion of reef frameworks is of increasing importance. Here, we explore decadal-scale rates of bioerosion of the framework building coral Orbicella annularis by grazing parrotfish following the 1997/1998 El Nino-related mass mortality event at Long Cay, Belize. Using high-precision U-Th dating and CT scan analysis, we quantified in situ rates of external bioerosion over a 13-year period (1998-2011). Based upon the error-weighted average U-Th age of dead O. annularis skeletons, we estimate the average external bioerosion between 1998 and 2011 as 0.92 +/- 0.55 cm depth. Empirical observations of herbivore foraging, and a nonlinear numerical response of parrotfish to an increase in food availability, were used to create a model of external bioerosion at Long Cay. Model estimates of external bioerosion were in close agreement with U-Th estimates (0.85 +/- 0.09 cm). The model was then used to quantify how rates of external bioerosion changed across a gradient of coral mortality (i.e., from few corals experiencing mortality following coral bleaching to complete mortality). Our results indicate that external bioerosion is remarkably robust to declines in coral cover, with no significant relationship predicted between the rate of external bioerosion and the proportion of O. annularis that died in the 1998 bleaching event. The outcome was robust because the reduction in grazing intensity that follows coral mortality was compensated for by a positive numerical response of parrotfish to an increase in food availability. Our model estimates further indicate that for an O. annularis dominated reef to maintain a positive state of reef accretion, a necessity for sustained ecosystem function, live cover of O. annularis must not drop below a ~5 10% threshold of cover. PMID- 26113200 TI - Daytime total sleep time relates to the association between acute traumatic brain injury and cognitive function recovery: Comment on Chiu et al. (2014). PMID- 26113198 TI - Serial changes of coronary endothelial function and arterial healing after paclitaxel-eluting stent implantation. AB - Several studies have shown coronary endothelial dysfunction and delayed arterial healing associated with first-generation drug-eluting stents. However, it remains unclear whether those issues persist for a longer term. We thus evaluated serial changes in endothelial function and intra-stent condition after paclitaxel eluting stents (PES) implantation. Eight patients with stable effort angina were assessed at 9 and over 24 months (1st and 2nd follow-up) after PES implantation. Endothelial function was evaluated with intracoronary infusion of acetylcholine (Ach). Vascular responses were quantitatively measured. Intra-stent condition was evaluated using angioscopy. We assessed (1) the degree of neointimal coverage over the stent (grade 0: no coverage to grade 3: full coverage); (2) presence of yellow intima inside the stent, and (3) existence of in-stent thrombus. Vasomotions proximal to the stent at 2nd follow-up significantly improved compared with 1st follow-up (p = 0.04), whereas vascular responses at the distal segment did not differ between 1st and 2nd follow-up (p = 0.19). From the angioscopic study, the average of coverage grading was comparable between the 2 points (0.9 +/- 0.8 vs. 1.3 +/- 1.0, p = 0.20). In addition, the incidence of yellow intima and in-stent thrombus did not differ between 1st and 2nd follow-up (yellow intima; 50 vs. 37.5 %, p = 1.0, thrombus; 75 vs. 50 %, p = 0.61). Endothelial dysfunction and delayed healing with PES could attenuate gradually, but these issues may persist over 24 months in some patients. PMID- 26113201 TI - A Two-Phase Pathogenetic Model of Depression after Stroke. AB - Depression is among the major long-term complications of cerebral stroke. Occurring in about 30% of all stroke survivors, 'poststroke depression' (PSD) is known to be associated with prolonged recovery, reduced quality of life, and increased mortality. Research over the past 25 years has enlarged our knowledge about organic and psychosocial risk factors, but their interaction is still unclear. In this paper, we start by reviewing and discussing pathogenetic PSD models that were proposed in the 1980s and 1990s. Based on these earlier approaches and on longitudinal research published since that time, a biphasic model is proposed that reflects the current knowledge on the emergence of PSD. The model integrates premorbid, stroke-related and psychosocial risk factors contributing to the emergence of PSD within the first 2 years after stroke. The distinction between 'reactive' and 'organic' PSD has been dropped, and groups of well-documented predictors are recommended for future research. Finally, we will outline possible implications of the model for prevention and therapy. PMID- 26113202 TI - Differential Proteomic Analysis of Syncytiotrophoblast Extracellular Vesicles from Early-Onset Severe Preeclampsia, using 8-Plex iTRAQ Labeling Coupled with 2D Nano LC-MS/MS. AB - AIMS: Previous studies have revealed that the increased shedding of syncytiotrophoblast extracellular vesicles (STBM) may lead to preeclampsia (PE). We aimed to identify the proteins carried by STBM and their potential pathological roles in early-onset severe PE. METHODS: In this study, we performed a differential proteomic analysis of STBM from early-onset severe PE patients, using iTRAQ isobaric tags and 2D nano LC-MS/MS. STBM were generated by the in vitro explant culture method, and then verified by electron microscopy and western blot analysis. RESULTS: A total of 18 533 unique peptides and 3 317 proteins were identified, 3 292 proteins were quantified. We identified 194 differentially expressed proteins in STBM from early-onset severe PE patients, 122 proteins were up-regulated and 72 proteins were down-regulated. Further bioinformatics analysis revealed that mitochondrion, transmembrane transport and transmembrane transporter activity were the most abundant categories in gene ontology (GO) annotation. Glycolysis/ gluconeogenesis, citrate cycle, fatty acid elongation, steroid hormone biosynthesis and oxidative phosphorylation were the five significantly represented pathways. Four differentially expressed proteins (siglec-6, calnexin, CD63 and S100-A8) related to inflammation, coagulation or immunoregulation were independently verified using western blot. CONCLUSIONS: The identification of key proteins carried by STBM may serve not only as a basis for better understanding and further exploring the etiology and pathogenesis of PE, but also as potential biomarkers and in providing targets for future therapy in PE, especially in early-onset severe PE(sPE). PMID- 26113203 TI - Development of a decision-making methodology to design a water quality monitoring network. AB - The number of water quality monitoring stations in the USA has decreased over the past few decades. Scarcity of observations can easily produce prediction uncertainty due to unreliable model calibration. An effective water quality monitoring network is important not only for model calibration and water quality prediction but also for resources management. Redundant or improperly located monitoring stations may cause increased monitoring costs without improvement to the understanding of water quality in watersheds. In this work, a decision-making methodology is proposed to design a water quality monitoring network by providing an adequate number of monitoring stations and their approximate locations at the eight-digit hydrologic unit codes (HUC8) scale. The proposed methodology is demonstrated for an example at the Upper Colorado River Basin (UCRB), where salinity is a serious concern. The level of monitoring redundancy or scarcity is defined by an index, station ratio (SR), which represents a monitoring density based on water quality load originated within a subbasin. By comparing the number of stations from a selected target SR with the available number of stations including the actual and the potential stations, the suggested number of stations in each subbasin was decided. If monitoring stations are primarily located in the low salinity loading subbasins, the average actual SR tends to increase, and vice versa. Results indicate that the spatial distribution of monitoring locations in 2011 is concentrated on low salinity loading subbasins, and therefore, additional monitoring is required for the high salinity loading subbasins. The proposed methodology shows that the SR is a simple and a practical indicator for monitoring density. PMID- 26113204 TI - Temporal change and its spatial variety on land surface temperature and land use changes in the Red River Delta, Vietnam, using MODIS time-series imagery. AB - Temporal changes in the land surface temperature (LST) in urbanization areas are important for studying an urban heat island (UHI) and regional climate change. This study examined the LST trends under different land use categories in the Red River Delta, Vietnam, using the Moderate Resolution Imaging Spectroradiometer (MODIS) LST product (MOD11A2) and land cover type product (MCD12Q1) for 11 years (2002-2012). Smoothened time-series MODIS LST data were reconstructed by the Harmonic Analysis of Time Series (HANTS) algorithm. The reconstructed LST (maximum and minimum temperatures) was assessed using the hourly air temperature dataset in two land-based meteorological stations provided by the National Climatic Data Center (NCDC). Significant correlation was obtained between MODIS LST and the air temperature for the daytime (R (2) = 0.73, root mean square error [RMSE] = 1.66 degrees C) and night time (R (2) = 0.84, RMSE = 1.79 degrees C). Statistical analysis also showed that LST trends vary strongly depending on the land cover type. Forest, wetland, and cropland had a slight tendency to decline, whereas cropland and urban had sharper increases. In urbanized areas, these increasing trends are even more obvious. This is undeniable evidence of the negative impact of urbanization on a surface urban heat island (SUHI) and global warming. PMID- 26113205 TI - Residual effect of pre-emergence herbicides on microbial activities in relation to mineralization of C, N and P in the Gangetic alluvial soil of West Bengal, India. AB - An experiment has been conducted under laboratory conditions to investigate the residual effect of three pre-emergence herbicides (thiobencarb, pendimethalin and pretilachlor) at fivefold field application rates (7.5, 10.0 and 2.5 kg a.i. ha( 1), respectively), on the changes of microbial activities and some biochemical processes in the Gangetic alluvial soil of West Bengal. Application of herbicides in general significantly increased microbial biomass resulting in greater mineralization of C, N and P in soil. The highest stimulation of microbial biomass C was recorded with thiobencarb (24.4%) followed by pendimethalin (23.4%). Microbial biomass N was highly induced under pretilachlor (54.5%) and thiobencarb (52.7%), while the stimulation of microbial biomass P was at par in the herbicide-treated soils. Compared to untreated control, the highest amount of organic C was retained with thiobencarb followed by pendimethalin. A similar trend was recorded with thiobencarb for total N, while pendimethalin induced exchangeable NH4 (+) and soluble NO3 (-) to the highest extent (42.2 and 34.5%, respectively). Regarding the availability of P in soil, pretilachlor manifested greater stimulation (33.1%) than thiobencarb (21.6%) and pendimethalin (11.4%). As compared to untreated control, thiobencarb harboured maximum number of bacteria (107.9%), while pretilachlor exerted the highest stimulations towards the proliferations of actinomycetes (132.6%) and fungi (149.5%) in soil. PMID- 26113206 TI - [A 17-year-old female patient with lower abdominal pain for 2 years]. PMID- 26113207 TI - Managing the safety of inhaled corticosteroids in COPD and the risk of pneumonia. AB - INTRODUCTION: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease. To estimate the association between ICS and pneumonia among users of ICS relative to non-ICS users and to examine whether this risk is dose related, class related and what's its association with the pneumonia-mortality or overall mortality. AREAS COVERED: Through a comprehensive literature search of MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception to February 2015, we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta analyses to generate summary estimates comparing ICS with non-ICS treatment on the risk of pneumonia. EXPERT OPINION: ICS alone or in combination with long acting beta-agonists are associated with an increased risk of pneumonia but have no effect on pneumonia related mortality. It is important to identify those patients to benefit the most from ICS, as those with frequent exacerbations, a severe airway obstruction, a positive bronchodilator test or a sputum eosinophilia despite treatment. PMID- 26113208 TI - Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study. AB - Tremor is a common side effect of tacrolimus correlated with peak-dose drug concentration. LCPT, a novel, once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ~30% dose reduction vs. immediate-release tacrolimus. In this phase 3b study, kidney transplant recipients (KTR) on a stable dose of tacrolimus and with a reported clinically significant tremor were offered a switch to LCPT. Tremor pre- and seven d post-conversion was evaluated by independent, blinded movement disorder neurologists using the Fahn-Tolosa-Marin (FTM) scale and by an accelerometry device; patients completed the QUEST (quality of life in essential tremor) and the Patient Global Impression of Change. There were 38 patients in the mITT population. A statistically and clinically significant improvement in tremor (FTM score, amplitude as measured by the accelerometry device and QOL [p-values < 0.05]) resulted post-conversion. Change in QUEST was significantly (p = 0.006) correlated (R = 0.44) with change in FTM; 78.9% of patients reported an improvement after switching to LCPT (p < 0.0005). To our knowledge this is the first trial in KTR that utilizes a sophisticated and reproducible measurement of tremor. Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose reduction of immediate-release tacrolimus for patients experiencing tremor. PMID- 26113209 TI - Glia-neuron interactions in the mammalian retina. AB - The mammalian retina provides an excellent opportunity to study glia-neuron interactions and the interactions of glia with blood vessels. Three main types of glial cells are found in the mammalian retina that serve to maintain retinal homeostasis: astrocytes, Muller cells and resident microglia. Muller cells, astrocytes and microglia not only provide structural support but they are also involved in metabolism, the phagocytosis of neuronal debris, the release of certain transmitters and trophic factors and K(+) uptake. Astrocytes are mostly located in the nerve fibre layer and they accompany the blood vessels in the inner nuclear layer. Indeed, like Muller cells, astrocytic processes cover the blood vessels forming the retinal blood barrier and they fulfil a significant role in ion homeostasis. Among other activities, microglia can be stimulated to fulfil a macrophage function, as well as to interact with other glial cells and neurons by secreting growth factors. This review summarizes the main functional relationships between retinal glial cells and neurons, presenting a general picture of the retina recently modified based on experimental observations. The preferential involvement of the distinct glia cells in terms of the activity in the retina is discussed, for example, while Muller cells may serve as progenitors of retinal neurons, astrocytes and microglia are responsible for synaptic pruning. Since different types of glia participate together in certain activities in the retina, it is imperative to explore the order of redundancy and to explore the heterogeneity among these cells. Recent studies revealed the association of glia cell heterogeneity with specific functions. Finally, the neuroprotective effects of glia on photoreceptors and ganglion cells under normal and adverse conditions will also be explored. PMID- 26113210 TI - Evidence for an enduring ischaemic penumbra following central retinal artery occlusion, with implications for fibrinolytic therapy. AB - The rationale behind hyperacute fibrinolytic therapy for cerebral and retinal arterial occlusion is to rescue ischaemic cells from irreversible damage through timely restitution of tissue perfusion. In cerebral stroke, an anoxic tissue compartment (the "infarct core") is surrounded by a hypoxic compartment (the "ischaemic penumbra"). The latter comprises electrically-silent neurons that undergo delayed apoptotic cell death within 1-6 h unless salvaged by arterial recanalisation. Establishment of an equivalent hypoxic compartment within the inner retina following central retinal artery occlusion (CRAO) isn't widely acknowledged. During experimental CRAO, electroretinography reveals 3 oxygenation based tissue compartments (anoxic, hypoxic and normoxic) that contribute 32%, 27% and 41% respectively to the pre-occlusion b-wave amplitude. Thus, once the anoxia survival time (~2 h) expires, the contribution from the infarcted posterior retina is irreversibly extinguished, but electrical activity continues in the normoxic periphery. Inbetween these compartments, an annular hypoxic zone (the "penumbra obscura") endures in a structurally-intact but functionally-impaired state until retinal reperfusion allows rapid recovery from electrical silence. Clinically, residual circulation of sufficient volume flow rate generates the heterogeneous fundus picture of "partial" CRAO. Persistent retinal venous hypoxaemia signifies maximal extraction of oxygen by an enduring "polar penumbra" that permeates or largely replaces the infarct core. On retinal reperfusion some days later, the retinal venous oxygen saturation reverts to normal and vision improves. Thus, penumbral inner retina, marginally oxygenated by the choroid or by residual circulation, isn't at risk of delayed apoptotic infarction (unlike hypoxic cerebral cortex). Emergency fibrinolytic intervention is inappropriate, therefore, once the duration of CRAO exceeds 2 h. PMID- 26113212 TI - Pharmacological approaches to retinitis pigmentosa: A laboratory perspective. AB - Retinal photoreceptors are highly specialized and performing neurons. Their cellular architecture is exquisitely designed to host a high concentration of molecules involved in light capture, phototransduction, electric and chemical signaling, membrane and molecular turnover, light and dark adaption, network activities etc. Such high efficiency and molecular complexity require a great metabolic demand, altogether conferring to photoreceptors particular susceptibility to external and internal insults, whose occurrence usually precipitate into degeneration of these cells and blindness. In Retinitis Pigmentosa, an impressive number of mutations in genes expressed in the retina and coding for a large varieties of proteins leads to the progressive death of photoreceptors and blindness. Recent advances in molecular tools have greatly facilitated the identification of the underlying genetics and molecular bases of RP leading to the successful implementation of gene therapy for some types of mutations, with visual restoration in human patients. Yet, genetic heterogeneity of RP makes mutation-independent approaches highly desirable, although many obstacles pave the way to general strategies for treating this complex disease, which remains orphan. The review will focus on treatments for RP based on pharmacological tools, choosing, among the many ongoing studies, approaches which rely on strong experimental evidence or rationale. For perspective treatments, new concepts are foreseen to emerge from basic studies elucidating the pathways connecting the primary mutations to photoreceptor death, possibly revealing common molecular targets for drug intervention. PMID- 26113213 TI - Stem cell based therapies for age-related macular degeneration: The promises and the challenges. AB - Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in developed countries. AMD is classified as either neovascular (NV AMD) or non-neovascular (NNV-AMD). Cumulative damage to the retinal pigment epithelium, Bruch's membrane, and choriocapillaris leads to dysfunction and loss of RPE cells. This causes degeneration of the overlying photoreceptors and consequential vision loss in advanced NNV-AMD (Geographic Atrophy). In NV-AMD, abnormal growth of capillaries under the retina and RPE, which leads to hemorrhage and fluid leakage, is the main cause of photoreceptor damage. Although a number of drugs (e.g., anti-VEGF) are in use for NV-AMD, there is currently no treatment for advanced NNV-AMD. However, replacing dead or dysfunctional RPE with healthy RPE has been shown to rescue dying photoreceptors and improve vision in animal models of retinal degeneration and possibly in AMD patients. Differentiation of RPE from human embryonic stem cells (hESC-RPE) and from induced pluripotent stem cells (iPSC-RPE) has created a potentially unlimited source for replacing dead or dying RPE. Such cells have been shown to incorporate into the degenerating retina and result in anatomic and functional improvement. However, major ethical, regulatory, safety, and technical challenges have yet to be overcome before stem cell-based therapies can be used in standard treatments. This review outlines the current knowledge surrounding the application of hESC RPE and iPSC-RPE in AMD. Following an introduction on the pathogenesis and available treatments of AMD, methods to generate stem cell-derived RPE, immune reaction against such cells, and approaches to deliver desired cells into the eye will be explored along with broader issues of efficacy and safety. Lastly, strategies to improve these stem cell-based treatments will be discussed. PMID- 26113211 TI - Molecular pathogenesis of retinal and choroidal vascular diseases. AB - There are two major types of ocular neovascularization that affect the retina, retinal neovascularization (NV) and subretinal or choroidal NV. Retinal NV occurs in a group of diseases referred to as ischemic retinopathies in which damage to retinal vessels results in retinal ischemia. Most prevalent of these are diabetic retinopathy and retinal vein occlusions. Subretinal and choroidal NV occur in diseases of the outer retina and Bruch's membrane, the most prevalent of which is age-related macular degeneration. Numerous studies in mouse models have helped to elucidate the molecular pathogenesis underlying retinal, subretinal, and choroidal NV. There is considerable overlap because the precipitating event in each is stabilization of hypoxia inducible factor-1 (HIF-1) which leads to upregulation of several hypoxia-regulated gene products, including vascular endothelial growth factor (VEGF), angiopoietin 2, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and several others. Stimulation of VEGF signaling and suppression of Tie2 by angiopoietin 2 and VE-PTP are critical for sprouting of retinal, subretinal, and choroidal NV, with perturbation of Bruch's membrane also needed for the latter. Additional HIF-1-regulated gene products cause further stimulation of the NV. It is difficult to model macular edema in animals and therefore proof-of-concept clinical trials were done and demonstrated that VEGF plays a central role and that suppression of Tie2 is also important. Neutralization of VEGF is currently the first line therapy for all of the above disease processes, but new treatments directed at some of the other molecular targets, particularly stabilization of Tie2, are likely to provide additional benefit for subretinal/choroidal NV and macular edema. In addition, the chronicity of these diseases as well as the implication of VEGF as a cause of retinal nonperfusion and progression of background diabetic retinopathy make sustained delivery approaches for VEGF antagonists a priority. PMID- 26113215 TI - Recombinant expression of four oxidoreductases in Phanerochaete chrysosporium improves degradation of phenolic and non-phenolic substrates. AB - Phanerochaete chrysosporium belongs to a group of lignin-degrading fungi that secretes various oxidoreductive enzymes, including lignin peroxidase (LiP) and manganese peroxidase (MnP). Previously, we demonstrated that the heterologous expression of a versatile peroxidase (VP) in P. chrysosporium recombinant strains is possible. However, the production of laccases (Lac) in this fungus has not been completely demonstrated and remains controversial. In order to investigate if the co-expression of Lac and VP in P. chrysosporium would improve the degradation of phenolic and non-phenolic substrates, we tested the constitutive co-expression of the lacIIIb gene from Trametes versicolor and the vpl2 gene from Pleurotus eryngii, and also the endogenous genes mnp1 and lipH8 by shock wave mediated transformation. The co-overexpression of peroxidases and laccases was improved up to five-fold as compared with wild type species. Transformant strains showed a broad spectrum in phenolic/non-phenolic biotransformation and a high percentage in synthetic dye decolorization in comparison with the parental strain. Our results show that the four enzymes can be constitutively expressed in a single transformant of P. chrysosporium in minimal medium. These data offer new possibilities for an easy and efficient co-expression of laccases and peroxidases in suitable basidiomycete species. PMID- 26113214 TI - Antioxidant activity of some Moroccan marine microalgae: Pufa profiles, carotenoids and phenolic content. AB - In order to promote Moroccan natural resources, this study aims to evaluate the potential of microalgae isolated from Moroccan coastlines, as new source of natural antioxidants. Different extracts (ethanolic, ethanol/water and aqueous) obtained from 9 microalgae strains were screened for their in vitro antioxidant activity using DPPH free radical-scavenging assay. The highest antioxidant potentials were obtained in Dunalliela sp., Tetraselmis sp. and Nannochloropsis gaditana extracts. The obtained results indicate that ethanol extract of all microalgae strains exhibit higher antioxidant activity, when compared to water and ethanol/water extracts. Therefore, total phenolic and carotenoid content measurement were performed in active ethanol extracts. The PUFA profiles of ethanol extracts were also determined by GC/MS analysis. The studied microalgae strains displayed high PUFA content ranging from 12.9 to 76.9 %, total carotenoids content varied from 1.9 and 10.8mg/g of extract and total polyphenol content varied from 8.1 to 32.0mg Gallic acid Equivalent/g of extract weight. The correlation between the antioxidant capacities and the phenolic content and the carotenoids content were found to be insignificant, indicating that these compounds might not be major contributor to the antioxidant activity of these microalgae. The microalgae extracts exerting the high antioxidant activity are potential new source of natural antioxidants. PMID- 26113216 TI - Engineering substrate specificity of succinic semialdehyde reductase (AKR7A5) for efficient conversion of levulinic acid to 4-hydroxyvaleric acid. AB - Engineering enzyme substrate specificity is a promising approach that can expand the applicability of enzymes for the biocatalytic production of industrial chemicals and fuels. In this study, succinic semialdehyde reductase (AKR7A5) was engineered for the conversion of levulinic acid to 4-hydroxyvaleric acid. Levulinic acid is a derivative of cellulosic biomass, and 4-hydroxyvaleric acid is a potential precursor to bio-polymers and fuels. Therefore, the enzymatic conversion of levulinic acid to 4-hydroxyvaleric acid is of special significance in that this conversion could provide a meaningful basis for the bio-production of useful chemicals from cellulosic biomass. In engineering the substrate specificity of the AKR7A5, a rational design approach with the aid of enzyme substrate interatomic contact analysis was applied. The Met13 residue was selected as a key mutation site, and substitutions of the residue with six hydrophobic amino acids were applied. As a result, four mutants with enhanced catalytic activity toward levulinic acid were obtained, and the most improved mutant, Met13Trp, exhibited a 7.0-fold increase in catalytic efficiency. Additionally, the structural effects of the positive mutations were investigated to analyze the structural basis for the enzyme substrate specificity with the target substrate. PMID- 26113217 TI - A Novel Approach for Overcoming Drug Resistance in Breast Cancer Chemotherapy by Targeting new Synthetic Curcumin Analogues Against Aldehyde Dehydrogenase 1 (ALDH1A1) and Glycogen Synthase Kinase-3 beta (GSK-3beta). AB - Breast cancer stem cells are well known to resist the traditional methods like chemo and radio therapy. Aldehyde dehydrogenase 1 (ALDHIA1) and glycogen synthase kinase-3 beta (GSK-3beta) are the two selected proteins for study, due to their overexpression and upregulation in breast cancer cells. Curcumin, the yellow pigment of the spice turmeric, is widely reported as an antioxidant and acts as a synergist along with traditional drugs. Under hypoxic conditions, it gets converted to free radical which causes apoptosis. Three naturally occurring curcuminoids, i.e. curcumin, demethoxycurcumin, and bisdemethoxycurcumin along with five derivatives/analogues of curcumin, viz. 4,4'-di-O-(carboxy-methyl) curcumin, 4-O-(2-hydroxyethyl)curcumin, 4,4'-di-O-allyl-curcumin, 4,4'-di-O (acetyl)-curcumin, and 3,3'-bisdemethylcurcumin were synthesized and evaluated for their anti-breast cancer potential by docking simulation and assessment of their antioxidant character, studied via 2, 2'-azinobis-(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS(.+)) radical cation scavenging assay, 2,2-diphenyl-1 picrylhydrazyl (DPPH.) radical, and ferric reducing ability potential (FRAP) assay. A co-relation between structure and activity of curcuminoids/its analogues and derivatives has been worked out. PMID- 26113218 TI - Electrospun Polycaprolactone Membrane Incorporated with Biosynthesized Silver Nanoparticles as Effective Wound Dressing Material. AB - Biosynthesized silver nanoparticles (AgNPs) incorporated polycaprolactone (PCL) nanomembrane was prepared by electrospinning as a cost-effective nanocomposite for application as an antimicrobial agent against wound infection. The nanocomposite membrane was characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) analysis and Scanning Electron microscopy (SEM). The hydrophilicity analysis of electrospun membranes as evaluated by water contact angle measurement showed the change of hydrophobicity of PCL to hydrophilic upon incorporation of silver nanoparticles. Better mechanical properties were also observed for PCL membrane due to the incorporation of silver nanoparticles and are highly supportive to explore its biomedical applications. Further antibacterial analysis of silver nanoparticle-incorporated PCL membrane against common wound pathogens coagulase-negative Staphylococcus epidermidis and Staphylococcus haemolyticus showed remarkable activity. As biosynthesized AgNPs are least explored for clinical applications, the current study is a promising cost-effective method to explore the development of silver nanoparticle-based electrospun nanocomposite to resist wound-associated infection. PMID- 26113219 TI - Industrial Production of 2,3-Butanediol from the Engineered Corynebacterium glutamicum. AB - The platform chemical 2,3-butanediol (2,3-BDO) is a valuable product that can be converted into several petroleum-based chemicals via simple chemical reactions. Here, we produced 2,3-BDO with the non-pathogenic and rapidly growing Corynebacterium glutamicum. To enhance the 2,3-BDO production capacity of C. glutamicum, we introduced budA encoding acetolactate decarboxylase from Klebsiella pneumoniae, a powerful 2,3-BDO producer. Additionally, budB (encoding alpha-acetolactate synthase) and budC (encoding acetoin reductase) were introduced from K. pneumoniae to reinforce the carbon flux in the 2,3-BDO production. Because budC had a negative effect on 2,3-BDO production in C. glutamicum, the budB and budA introduced strain, SGSC102, was selected for 2,3 BDO production, and batch culture was performed at 30 degrees C, 250 rpm and pH 6.86 with pure glucose, molasses, and cassava powder as carbon substrates. After batch culture, significant amount of 2,3-BDO (18.9 and 12.0 g/L, respectively) was produced from 80 g/L of pure glucose and cassava powder. PMID- 26113220 TI - Social network analysis of mating patterns in American black bears (Ursus americanus). AB - Nonrandom mating can structure populations and has important implications for population-level processes. Investigating how and why mating deviates from random is important for understanding evolutionary processes as well as informing conservation and management. Prior to the implementation of parentage analyses, understanding mating patterns in solitary, elusive species like bears was virtually impossible. Here, we capitalize on a long-term genetic data set collected from black bears (Ursus americanus) (N = 2422) in the Northern Lower Peninsula (NLP) of Michigan, USA. We identified mated pairs using parentage analysis and applied logistic regression (selection) models that controlled for features of the social network, to quantify the effects of individual characteristics, and spatial and population demographic factors on mating dynamics. Logistic regression models revealed that black bear mating was associated with spatial proximity of mates, male age, the time a pair had coexisted, local population density and relatedness. Mated pairs were more likely to contain older males. On average, bears tended to mate with nearby individuals to whom they were related, which does not support the existence of kin recognition in black bears. Pairwise relatedness was especially high for mated pairs containing young males. Restricted dispersal and high male turnover from intensive harvest mortality of NLP black bears are probably the underlying factors associated with younger male bears mating more often with female relatives. Our findings illustrate how harvest has the potential to disrupt the social structure of game species, which warrants further attention for conservation and management. PMID- 26113221 TI - Towards Single Biomolecule Imaging via Optical Nanoscale Magnetic Resonance Imaging. AB - Nuclear magnetic resonance (NMR) spectroscopy is a physical marvel in which electromagnetic radiation is charged and discharged by nuclei in a magnetic field. In conventional NMR, the specific nuclei resonance frequency depends on the strength of the magnetic field and the magnetic properties of the isotope of the atoms. NMR is routinely utilized in clinical tests by converting nuclear spectroscopy in magnetic resonance imaging (MRI) and providing 3D, noninvasive biological imaging. While this technique has revolutionized biomedical science, measuring the magnetic resonance spectrum of single biomolecules is still an intangible aspiration, due to MRI resolution being limited to tens of micrometers. MRI and NMR have, however, recently greatly advanced, with many breakthroughs in nano-NMR and nano-MRI spurred by using spin sensors based on an atomic impurities in diamond. These techniques rely on magnetic dipole-dipole interactions rather than inductive detection. Here, novel nano-MRI methods based on nitrogen vacancy centers in diamond are highlighted, that provide a solution to the imaging of single biomolecules with nanoscale resolution in-vivo and in ambient conditions. PMID- 26113222 TI - Usefulness of the Exhaled Breath Temperature Plateau in Asthma Patients. AB - BACKGROUND: Exhaled breath temperature (EBT) has recently been proposed as a noninvasive marker of bronchial inflammation in patients with asthma. However, the usefulness of EBT in everyday clinical practice is not well established. Results to date are contradictory and are mainly derived from small, pediatric populations. A comparison of results is further complicated by the use of different equipment and measurements. OBJECTIVE: We performed a comprehensive study to determine whether EBT is related to asthma control, disease severity, bronchial obstruction, or bronchial inflammation. METHODS: Sixty-nine patients on maintenance treatment for asthma were included in a cross-sectional study. At the same visit, we measured the EBT plateau (EBTp) using an X-halo Breath Thermometer (Delmedica, Singapore), the fraction of exhaled nitric oxide (FeNO), spirometry, and inflammatory cell count in induced sputum, and we administered the Asthma Control Test questionnaire. RESULTS: No significant differences were found between EBTp measurements and the level of asthma control, disease severity, bronchial obstruction, FeNO levels, or inflammatory asthma phenotypes. We found a significant difference between EBTp and gender. The EBTp was 34.07 degrees C (SD 0.74) in women and 34.38 degrees C (0.46) in men (p = 0.038). We also found a significant correlation between EBTp measurements and the induced sputum eosinophil count (R = -0.348, p = 0.003). CONCLUSIONS: The results of this study do not support the usefulness of the EBTp in asthma management in routine clinical practice. Further research using standardized methods is needed to determine the potential use of the EBTp measurement in asthma management. PMID- 26113223 TI - Outcomes of Neoadjuvant Chemotherapy without Radiation for Rectal Cancer. AB - AIM: The efficacy of neoadjuvant chemotherapy without radiation (NAC) in the treatment of rectal cancer remains unclear. This retrospective study was aimed at determining the pathological complete response rate and short-term outcomes of NAC in patients with locally advanced rectal cancer. PATIENTS AND METHODS: We collected data on 159 consecutive patients treated for rectal cancer (cT3/cT4a, cN+, and cM0 status) at five tertiary referral hospitals between 2005 and 2010. Pathological complete response (pCR) and safety were assessed as the main outcomes in 124 eligible patients comprising 15 who received NAC (NAC group) and 109 who received no neoadjuvant chemotherapy (non-NAC group). RESULTS: In the NAC group, 2 patients (13.3%) achieved a pCR (95% confidence interval: 1.7-40.5%) and 3 patients (20%) experienced grade 3/4 adverse events. No significant differences were found between the NAC and non-NAC groups in terms of short-term outcomes, including R0 proportion (100 vs. 96.3%, p = 0.45) and postoperative grade 3/4 complications (13.3 vs. 18.4%, p = 0.63). CONCLUSIONS: Neoadjuvant systemic chemotherapy without radiation appears to be safe, without worsening short-term outcomes, in patients with locally advanced rectal cancer. A further study is needed to verify these findings in larger samples. PMID- 26113224 TI - Grey scale texture analysis of endobronchial ultrasound mini probe images for prediction of benign or malignant aetiology. AB - BACKGROUND AND OBJECTIVE: Expert analysis of endobronchial ultrasound mini probe (EBUS-MP) images has established subjective criteria for discriminating benign and malignant disease. Minimal data are available for objective analysis of these images. The aim of this study was to determine if greyscale texture analysis could differentiate between benign and malignant lung lesions. METHODS: Digital EBUS-MP images with a gain setting of 10/19 and contrast setting of 4/8 from 2007 until 2012 inclusive were included. These images had an expert-defined region of interest (ROI) mapped. ROI were analysed for the following greyscale texture features: mean pixel value, difference between maximum and minimum pixel value, standard deviation of the mean pixel value, entropy, correlation, energy and homogeneity. Significant greyscale texture features differentiating benign from malignant disease were used by two physicians to assess a validation set. RESULTS: A total of 167 images were available. The first 85 lesions were used in the prediction set. Benign lesions had larger differences between maximum and minimum pixel values, larger standard deviations of the mean pixel values and higher entropy than malignant lesions (P < 0.0001 for all values). A total of 82 peripheral lesions were in the validation set. Physician 1 correctly classified 63/82 (76.8%) with a negative predictive value (NPV) for malignancy of 82% and positive predictive value (PPV) of 75%. Physician 2 correctly classified 62/82 (75.6%) with a NPV of 100% and PPV of 71.0%. CONCLUSIONS: Greyscale texture analysis of EBUS-MP images can help establish aetiology with a high NPV for malignancy. PMID- 26113225 TI - Doppler of the middle cerebral artery for the assessment of fetal well-being. PMID- 26113226 TI - Helping providers interpret cell-free fetal DNA testing. PMID- 26113227 TI - The importance of the cerebroplacental ratio in the evaluation of fetal well being in SGA and AGA fetuses. AB - The cerebroplacental ratio (CPR) is emerging as an important predictor of adverse pregnancy outcome, and this has implications for the assessment of fetal well being in fetuses diagnosed as small for gestational age (SGA) and those appropriate for gestational age close to term. Interest in this assessment tool has been rekindled because of recent reports associating an abnormal ratio with adverse perinatal events and associated postnatal neurological outcome. Fetuses with an abnormal CPR that are appropriate for gestational age or have late-onset SGA (>34 weeks of gestation) have a higher incidence of fetal distress in labor requiring emergency cesarean delivery, a lower cord pH, and an increased admission rate to the newborn intensive care unit when compared with fetuses with a normal CPR. Fetuses with early-onset SGA (<34 weeks of gestation) with an abnormal CPR have a higher incidence of the following when compared with fetuses with a normal CPR: (1) lower gestational age at birth, (2) lower mean birthweight, (3) lower birthweight centile, (4) birthweight less than the 10th centile, (5) higher rate of cesarean delivery for fetal distress in labor, (6) higher rate of Apgar scores less than 7 at 5 minutes, (7) an increased rate of neonatal acidosis, (8) an increased rate of newborn intensive care unit admissions, (9) higher rate of adverse neonatal outcome, and (10) a greater incidence of perinatal death. The CPR is also an earlier predictor of adverse outcome than the biophysical profile, umbilical artery, or middle cerebral artery. In conclusion, the CPR should be considered as an assessment tool in fetuses undergoing third-trimester ultrasound examination, irrespective of the findings of the individual umbilical artery and middle cerebral artery measurements. A CPR calculator is available at http://www.ajog.org/pb/assets/raw/Health%20Advance/journals/ymob/CPR/index.htm. PMID- 26113228 TI - Prevalence of methicillin-resistant Staphylococcus aureus colonization in HIV infected patients in Barcelona, Spain: a cross-sectional study. AB - BACKGROUND: Colonization by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has been found to be markedly more common in HIV infected individuals in the USA. Studies evaluating the prevalence MRSA colonization in HIV-infected populations in Europe are scarce. The aim of this study was to investigate the prevalence of MRSA colonization in a cohort of HIV infected patients in Barcelona, Spain. METHODS: Nasal and pharyngeal S. aureus carriage was assessed in a random sample of 190 patients from an outpatient HIV clinic. Nasal and pharyngeal swab specimens were obtained for staphylococcal culture from 190 and 110 patients respectively. All MRSA isolates were screened for Panton-Valentine leukocidin (PVL) genes by PCR. Molecular characterization of MRSA isolates was performed by multilocus sequence typing. Data related to HIV infection, healthcare exposure, and previously described risk factors for MRSA were collected from medical records and a questionnaire administered to each patient. RESULTS: The patients' characteristics were as follows: male, 83 %; median (IQR) age, 45 (39-49) years; intravenous drug users, 39 %; men who have sex with men, 32 %; heterosexual, 26 %; CD4 count, 528/MUL (IQR 351-740); on antiretroviral therapy, 96 %; and undetectable plasma viral load, 80 %. Sixty five patients (34 %) were colonized by S. aureus. MRSA colonization was found in 1 % and 2 % of nasal and pharyngeal samples respectively. No PVL positive MRSA strains were detected and all the MRSA isolates belonged to typical hospital acquired clones. CONCLUSIONS: Our data suggest that CA-MRSA colonization is not currently a problem in HIV-infected individuals in our area. PMID- 26113230 TI - Skin protection behaviour and sex differences in melanoma location in patients with multiple primary melanomas. AB - BACKGROUND/OBJECTIVES: Previous studies have shown that sunscreen usage, sun protection measures and self-examination rates in patients with single primary melanomas (SPM) are similar to that in the general population. This study hypothesises that these rates would be different in a population with multiple primary melanomas (MPM). We further hypothesise that there would be a sex difference in melanoma location in patients with MPM. The objectives of this study were to determine skin protection measures, self-examinations and melanoma location in a cohort of patients with MPM. METHODS: A survey was conducted on 137 patients with MPM examining their sun-protection measures, skin self-examination rates and medical and phenotypic characteristics. These data were combined with a review of their medical records to examine the patients' skin cancer history. RESULTS: Patients with MPM had higher rates of skin self-evaluation (74% vs 22%), sunscreen usage (70% vs 45%) and other sun-protection measures (95% vs 46%) than has been published for patients with a history of a SPM. We have also shown that women have a higher risk of developing melanomas on their arms (p < 0.01) and lower legs (p < 0.05) than men. CONCLUSIONS: This report showed the rates of skin self-examination, sunscreen usage and other sun-protection methods in patients with MPM is higher than in studies of patients with SPM. It also highlighted sex differences in terms of melanoma location for patients with MPM. Further studies to examine the cause of the differences in these forms of protective behaviour could help improve the utilisation of these important preventative measures in all patients. PMID- 26113229 TI - Cutaneous exposure to agglomerates of silica nanoparticles and allergen results in IgE-biased immune response and increased sensitivity to anaphylaxis in mice. AB - BACKGROUND: The skin is a key route of human exposure to nanomaterials, which typically occurs simultaneously with exposure to other chemical and environmental allergen. However, little is known about the hazards of nanomaterial exposure via the skin, particularly when accompanied by exposure to other substances. RESULTS: Repeated topical treatment of both ears and the shaved upper back of NC/Nga mice, which are models for human atopic dermatitis (AD), with a mixture of mite extract and silica nanoparticles induced AD-like skin lesions. Measurements of ear thickness and histologic analyses revealed that cutaneous exposure to silica nanoparticles did not aggravate AD-like skin lesions. Instead, concurrent cutaneous exposure to mite allergens and silica nanoparticles resulted in the low level production of allergen-specific IgGs, including both the Th2-related IgG1 and Th1-related IgG2a subtypes, with few changes in allergen-specific IgE concentrations and in Th1 and Th2 immune responses. In addition, these changes in immune responses increased the sensitivity to anaphylaxis. Low-level IgG production was induced when the mice were exposed to allergen-silica nanoparticle agglomerates but not when the mice exposed to nanoparticles applied separately from the allergen or to well-dispersed nanoparticles. CONCLUSIONS: Our data suggest that silica nanoparticles themselves do not directly affect the allergen specific immune response after concurrent topical application of nanoparticles and allergen. However, when present in allergen-adsorbed agglomerates, silica nanoparticles led to a low IgG/IgE ratio, a key risk factor of human atopic allergies. We suggest that minimizing interactions between nanomaterials and allergens will increase the safety of nanomaterials applied to skin. PMID- 26113231 TI - Pigment-dispersing factor signaling in the circadian system of Caenorhabditis elegans. AB - The neuropeptide pigment-dispersing factor (PDF) is important for the generation and entrainment of circadian rhythms in the fruitfly Drosophila melanogaster. Recently two pdf homologs, pdf-1 and pdf-2, and a PDF receptor, pdfr-1, have been found in Caenorhabditis elegans and have been implicated in locomotor activity. In this work, we have studied the role of the PDF neuropeptide in the circadian system of C. elegans and found that both pdf-1 and pdf-2 mutants affect the normal locomotor activity outputs. In particular, loss of pdf-1 induced circadian arrhythmicity under both light-dark (LD) and constant dark (DD) conditions. These defects can be rescued by a genomic copy of the pdf-1 locus. Our results indicate that PDF-1 is involved in rhythm generation and in the synchronization to LD cycles, as rhythmic patterns of activity rapidly disappear when pdf-1 mutants are recorded under both entrained and free-running conditions. The role of PDF-2 and the PDF receptors is probably more complex and involves the interaction between the two pdf paralogues found in the nematode. PMID- 26113232 TI - Oral nifedipine versus intravenous labetalol for severe hypertension during pregnancy: a systematic review and meta-analysis. AB - BACKGROUND: Oral nifedipine is recommended along with labetalol and hydralazine for treatment of severe hypertension during pregnancy by most authorities. Although nifedipine is cheap and easily administered, the usage pattern among health care providers suggests a strong preference for labetalol despite lack of evidence for the same. OBJECTIVES: To determine the efficacy and safety of oral nifedipine for treatment of severe hypertension of pregnancy compared with intravenous labetalol. SEARCH STRATEGY: We systematically searched for articles comparing oral nifedipine with intravenous labetalol for the treatment of severe hypertension during pregnancy in any language, over Medline, Cochrane Central Register of Clinical Trials and Google Scholar from inception till February 2014. SELECTION CRITERIA: We included all RCTs that compared intravenous labetalol with oral nifedipine for treatment of severe hypertension during pregnancy, addressing relevant efficacy and safety outcomes. DATA COLLECTION AND ANALYSIS: Eligible studies were reviewed, and data were extracted onto a standard form. We used Cochrane review manager software for quantitative analysis. Data were analysed using a fixed effect model. MAIN RESULTS: The pooled analysis of seven trials (four from developing countries) consisting of 363 woman-infant pairs showed that oral nifedipine was associated with less risk of persistent hypertension (RR 0.42, 95% CI 0.18-0.96) and reported maternal side effects (RR 0.57, 95% CI 0.35 0.94). However, on sensitivity analysis the outcome 'persistent hypertension' was no longer significant. Other outcomes did not reach statistical significance. CONCLUSION: Oral nifedipine is as efficacious and safe as intravenous labetalol and may have an edge in low resource settings. TWEETABLE ABSTRACT: Although studies to date are few in number and small, nifedipine shows promise for severe hypertension in pregnancy. PMID- 26113233 TI - Multilayered Thin Films from Boronic Acid-Functional Poly(amido amine)s As Drug Releasing Surfaces. AB - PURPOSE: To evaluate the potential of poly(amido amine)-based multilayered thin films in surface mediated drug release. METHODS: Multilayered thin films were prepared from copolymers of phenylboronic acid-functional poly(amido amine)s and chondroitin sulfate (ChS) in the presence of Alizarin Red S (ARS) as a reporter molecule. Multilayer buildup and ARS incorporation were evaluated with UV-vis spectroscopy. Glucose responsiveness of the multilayers was investigated. Finally, cellular uptake of ARS by COS-7 cells grown on the films was assessed. RESULTS: Multilayers based on alcohol containing polymers (ABOL-BA-PAA#ChS + ARS) displayed higher ARS incorporation than multilayers based on amine-containing polymers (DAB-BA-PAA#ChS + ARS). At physiological pH, a swift initial release of up to ~40% of the ARS content was observed during the first 12 h of incubation, followed by a much slower, gradual release of ARS. The multilayers were further evaluated by culturing COS-7 cells on top of multilayer-coated well plates. Cellular uptake of the fluorescent ARS-boronate ester was quantified through flow cytometry, and a maximum uptake of up to 30% was observed. Confocal microscopy confirmed the presence of ARS-boronate ester-containing particles in the nuclei of cells. CONCLUSIONS: The investigated multilayered thin films are effective in surface-mediated delivery of the model compound ARS. These multilayered surfaces are promising as drug-releasing delivery surface for coating stents, prostheses, and other implants. PMID- 26113235 TI - Potent Functional Immunogenicity of Plasmodium falciparum Transmission-Blocking Antigen (Pfs25) Delivered with Nanoemulsion and Porous Polymeric Nanoparticles. AB - PURPOSE: To evaluate functional immunogenicity of CHrPfs25. a malaria transmission blocking vaccine antigen, using nanoemulsion and porous polymeric PLGA nanoparticles. METHODS: CHrPfs25 was formulated with nanoemulsions (NE) and poly(D,L-lactide-co-glycolide) nanoparticles (PLGA-NP) and evaluated via IM route in mice. Transmission blocking efficacy of antibodies was evaluated by standard mosquito membrane feeding assay using purified IgG from immune sera. Physicochemical properties and stability of various formulations were evaluated by measuring poly-dispersity index, particle size and zeta potential. RESULTS: Mice immunized with CHrPfs25 using alum via IP and IM routes induced comparable immune responses. The highest antibody response was obtained with CHrPfs25 formulated in 4% NE as compared to 8% NE and PLGA-NP. No further increases were observed by combining NE with MPL-A and chitosan. One hundred percent transmission blocking activity was demonstrated at 400 MUg/ml of IgG for alum groups (both routes IP and IM), 4% NE and NE-MPL-A. Purified IgG from various adjuvant groups at lower doses (100 MUg/mL) still exhibited >90% transmission blocking activity, while 52-81% blocking was seen at 50 MUg/mL. CONCLUSION: Results suggest that CHrPfs25 delivered in various adjuvants/nanoparticles elicited strong functional immunogenicity in pre-clinical studies in mice. We are now continuing these studies to develop effective vaccine formulations for further evaluation of immune correlates of relative immunogenicity of CHrPfs25 in various adjuvants and clinical trials. PMID- 26113236 TI - Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer's Disease. AB - PURPOSE: H102, a novel beta-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD). METHODS: The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia. RESULTS: The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa. CONCLUSIONS: The H102 loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment. PMID- 26113237 TI - Inhalable Clarithromycin Microparticles for Treatment of Respiratory Infections. AB - PURPOSE: The aim of this work was to develop clarithromycin microparticles (CLARI MP) and evaluate their aerodynamic behavior, safety in bronchial cells and anti bacterial efficacy. METHODS: Microparticles containing clarithromycin were prepared as dry powder carrier for inhalation, using leucine and chitosan. CLARI MP were deposited on Calu-3 grown at air-interface condition, using the pharmaceutical aerosol deposition device on cell cultures (PADDOCC). Deposition efficacy, transport across the cells and cytotoxicity were determined. Anti antibacterial effect was evaluated against Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. RESULTS: Microparticles were of spherical shape, smooth surface and size of about 765 nm. Aerosolization performance showed a fine particle fraction (FPF) of 73.3%, and a mass median aerodynamic diameter (MMAD) of 1.8 MUm. Deposition on Calu-3 cells using the PADDOCC showed that 8.7 MUg/cm(2) of deposited powder were transported to the basolateral compartment after 24 h. The safety of this formulation is supported by the integrity of the cellular epithelial barrier and absence of toxicity, and the antimicrobial activity demonstrated for Gram positive and Gram negative bacteria. CONCLUSIONS: The appropriate aerodynamic properties and the excellent deposition on Calu-3 cells indicate that clarithromycin microparticles are suitable for administration via pulmonary route and are efficient to inhibit bacteria proliferation. PMID- 26113238 TI - Water-Hydrogel Binding Affinity Modulates Freeze-Drying-Induced Micropore Architecture and Skeletal Myotube Formation. AB - Freeze-dried hydrogels are increasingly used to create 3D interconnected micropores that facilitate biomolecular and cellular transports. However, freeze drying is often plagued by variance in micropore architecture based on polymer choice. We hypothesized that water-polymer binding affinity plays a significant role in sizes and numbers of micropores formed through freeze-drying, influencing cell-derived tissue quality. Poly(ethylene glycol)diacrylate (PEGDA) hydrogels with alginate methacrylate (AM) were used due to AM's higher binding affinity for water than PEGDA. PEGDA-AM hydrogels with larger AM concentrations resulted in larger sizes and numbers of micropores than pure PEGDA hydrogels, attributed to the increased mass of water binding to the PEGDA-AM gel. Skeletal myoblasts loaded in microporous PEGDA-AM hydrogels were active to produce 3D muscle-like tissue, while those loaded in pure PEGDA gels were localized on the gel surface. We propose that this study will be broadly useful in designing and improving the performance of various microporous gels. PMID- 26113239 TI - Locality preserving score for joint feature weights learning. AB - Locality preserving measurement criterion is frequently used for assessing the quality of features. However, locality preserving criterion based unsupervised feature selection algorithms have two widely acknowledged weaknesses: (1) The performance of feature selection heavily depends on the effectiveness of the similarity matrix, which is defined in the original space, and thus it is probably inconsistent with the one in the weighted space. (2) Greedy searching strategy neglects the correlation and redundancy among features. To alleviate these deficiencies, we propose a novel unsupervised feature selection algorithm by jointly learning adaptive nearest neighbors in the weighed space. An effective iterative algorithm is developed to solve the proposed formulation, where each iteration reduces to a convex subproblem which can be efficiently solved with some off-the-shelf toolboxes. The results of experiments on the UCI and face data sets demonstrate the effectiveness of the proposed algorithm, for outperforming many state-of-the-art unsupervised and supervised feature selection methods in terms of classification accuracy. PMID- 26113240 TI - Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities. AB - Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic subgroup. We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cytogenetics, and absence of prior treatment with intensive chemotherapy had a better outcome. 27 patients were allo-transplanted and achieved a 21-month median OS. Balanced 3q21 translocations were associated with a better response rate and overall survival. Outcome of patients with isolated EVI-1 overexpression was comparable to that of patients with chromosome 3q lesions. Thus, AML/MDS patients with 3q abnormalities appear to be a heterogeneous group in their response to AZA, and AZA may represent a suitable option in particular as a bridge to allogeneic transplantation. PMID- 26113242 TI - Colorimetric plasmon sensors with multilayered metallic nanoparticle sheets. AB - Colorimetric plasmon sensors for naked-eye detection of molecular recognition events have been proposed. Here, 3-layered Ag nanoparticle (NP) sheets on a Au substrate fabricated using the Langmuir-Schaefer method were utilized as the detection substrates. A drastic color change was observed following the binding of Au NPs via avidin-biotin interactions at less than 30% surface coverage. The color change was attributed not only to the localized surface plasmon resonance (LSPR) of the adsorbed Au NPs but also to the multiple light trapping effect derived from the stratified Au and Ag NPs, as predicted by a finite-difference time-domain (FDTD) simulation. This plasmonic multi-color has great potential in the development of simple and highly sensitive diagnostic systems. PMID- 26113241 TI - Immediate Discharge and Home Treatment With Rivaroxaban of Low-risk Venous Thromboembolism Diagnosed in Two U.S. Emergency Departments: A One-year Preplanned Analysis. AB - OBJECTIVES: The study hypothesis was that a target-specific anticoagulant would allow successful home treatment of selected patients with deep vein thrombosis (DVT) and pulmonary embolism (PE) diagnosed in two urban emergency departments (EDs). METHODS: A protocol was established for treating low-risk DVT or PE patients with rivaroxaban and clinic, follow-up at both 2 to 5 weeks, and 3 to 6 months. Patients were determined to be low-risk by using a modified version of the Hestia criteria, supplemented by additional criteria for patients with active cancer. Acceptable outcome rates were defined as venous thromboembolism (VTE) recurrence <= 2.1% or bleeding <= 9.4% during treatment. VTE recurrence required positive imaging of any VTE. The International Society of Thrombosis and Hemostasis definition of major or clinically relevant nonmajor bleeding was used. RESULTS: From March 2013 through April 2014, a total of 106 patients were treated. Seventy-one (68%) had DVT, 30 (28%) had PE, and five (3%) had both, representing 51% of all DVTs and 27% of all PEs diagnosed in both EDs during the period of study. The 106 patients have been followed for a mean (+/-SD) of 389 (+/-111) days (range = 213 to 594 days). No patient had VTE recurrence, and no patient had a major or clinically relevant bleeding event while on therapy (none of the 106, 0%, 95% confidence interval [CI] = 0% to 3.4%). However, three patients 2.8% (95% CI = 1% to 8%) had recurrent DVT after cessation of therapy. CONCLUSIONS: Patients diagnosed with VTE and immediately discharged from the ED while treated with rivaroxaban had a low rate of VTE recurrence and bleeding. PMID- 26113243 TI - Uncultivated thermophiles: current status and spotlight on 'Aigarchaeota'. AB - Meta-analysis of cultivation-independent sequence data shows that geothermal systems host an abundance of novel organisms, representing a vast unexplored phylogenetic and functional diversity among yet-uncultivated thermophiles. A number of thermophiles have recently been interrogated using metagenomic and/or single-cell genomic approaches, including members of taxonomic groups that inhabit both thermal and non-thermal environments, such as 'Acetothermia' (OP1) and 'Atribacteria' (OP9/JS1), as well as the exclusively thermophilic lineages 'Korarchaeota', 'Calescamantes' (EM19), 'Fervidibacteria' (OctSpA1-106), and 'Aigarchaeota' (HWCG-I). The 'Aigarchaeota', a sister lineage to the Thaumarchaeota, likely includes both hyperthermophiles and moderate thermophiles. They inhabit terrestrial, marine, and subsurface thermal environments and comprise at least nine genus-level lineages, several of which are globally distributed. PMID- 26113244 TI - Determination of radiography requirement in wrist trauma. AB - OBJECTIVES: The purpose of this study was to evaluate predetermined physical examination and function tests recommended to identify severe injury among patients presenting with wrist injury to the emergency department and to establish a reliable clinical decision rule capable of determining the need for radiography in wrist injuries. MATERIALS AND METHODS: This was a multicenter prospective derivation study of wrist injuries. All patients were assessed in terms of mechanism of trauma, inspection findings, heart rate, sensitivity at palpation, presence of pain with active movement, grasp strength, and functional tests using an examination form under main headings. Sensitivity, specificity, and positive and negative predictive values were expressed for each sign and each examination finding. RESULTS: One hundred nineteen adult patients were enrolled during the 6-month study period. Fracture was identified in 24.3% (n = 29). Presence of pain on the radial deviation, dorsal flexion, distal radioulnar drawer, and axial compression tests exhibited high sensitivity (82.8%, 89.7%, 82.8%, and 86.2%, respectively) and high negative predictive values (88.6%, 81.3%, 87.5%, and 93.6%, respectively) for wrist fracture. Sensitivity of 96.6% was observed when these 4 tests were evaluated together. CONCLUSIONS: The presence of one of these examination findings increases the likelihood of fracture and is adequate to recommend wrist radiography. In addition, there is a strong possibility of radiography being unnecessary if all 4 test results are negative in patients presenting with wrist injury, potentially preventing many nonessential radiographs being performed. PMID- 26113245 TI - Prognostic value of serum pregnancy-associated plasma protein A level at the initial ED presentation in elderly patients with CAP. AB - OBJECTIVE: This study aims to compare serum pregnancy-associated plasma protein A (PAPP-A) levels in surviving and nonsurviving elderly patients with community acquired pneumonia (CAP), investigating whether PAPP-A is correlated with CAP prediction scores and whether PAPP-A can successfully predict 28-day mortality rates in elderly patients. METHODS: This prospective, observational, single center, cross-sectional study was conducted at the emergency department (ED) of Celal Bayar University Hospital in Manisa, Turkey, between January and September 2014. All patients underwent follow-up evaluations 28 days after admission. The end point was defined as all-cause mortality. RESULTS: A total of 100 elderly patients (mean age, 77.3 +/- 7.6 years [range, 65-94 years]); 60% men) with CAP were enrolled in this study. All-cause mortality at the 28-day follow-up evaluation was 22%. Admission PAPP-A levels were significantly higher in nonsurvivors compared with 28-day survivors (10.3 +/- 4.5 vs 3.8 +/- 2.6 ng/mL, P < .001). A significant and positive correlation between admission PAPP-A levels and pneumonia severity index; confusion, oxygen saturation, respiratory rate, blood pressure, and age 75 years or older; and confusion, urea, respiratory rate, blood pressure, and age older than 65 years scores was found (r = .440, P < .001; r = .395, P < .001; and r = .359, P < .001, respectively). Moreover, we determined that the optimal PAPP-A cutoff for predicting 28-day mortality at the time of ED admission was 5.1 ng/mL, with 77.3% sensitivity and 77.9% specificity. CONCLUSIONS: Serum PAPP-A level is valuable for predicting mortality and the severity of the disease among elderly patients with CAP at ED admission. Thus, PAPP-A might play a further role in the clinical assessment of the severity of CAP. PMID- 26113246 TI - Association between cervical spine and skull-base fractures and blunt cerebrovascular injury. AB - INTRODUCTION: Blunt cerebrovascular injuries (BCVI) are associated with high morbidity and mortality and can lead to neurological deficits. The established criteria for patients undergoing CT angiography (CTA) for BCVI are broad, and can expose patients to radiation unnecessarily. This study aimed to examine the prevalence of BCVI in patients on CTA and determine presentations associated with the highest rates of BCVI. MATERIALS AND METHODS: With IRB approval, patients were selected for CTA screening for BCVI according to a predefined set of criteria at our hospital between 2007 and 2010. Patients were identified from our institution's trauma database. CTAs were retrospectively reviewed for BCVI including vasospasm and dissection. Electronic medical records were reviewed for clinical presentation and hospital course. RESULTS: Of 432 patients, vasospasm (n = 10) and/or dissection (n = 36) were found in 46 patients (10.6%). BCVI was associated with cervical spine and/or skull-base fracture in 40/46 patients (87%, P < 0.0001). Significant correlations were seen between dissection and fracture in 31/36 patients (86.2%, p < 0.0001) and between BCVI and both neurological deficits and fractures (27/44, P < 0.0001). CONCLUSION: BCVI was significantly associated with cervical and/or skullbase fractures and neurological deficits with coexistent fractures. Patients with these injuries should be prioritized for rapid CTA evaluation for BCVI. KEY POINTS: * CTA screening is important to identify patients with underlying BCVI * Cervical spine and/or skullbase fractures were significantly associated with BCVI * BCVI may occur in up to 11% of patients with blunt trauma injuries. PMID- 26113247 TI - Chikungunya and dengue virus infections during pregnancy: seroprevalence, seroincidence and maternal-fetal transmission, southern Thailand, 2009-2010. AB - Limited information is available on the seroprevalence of chikungunya virus (CHIKV) infection and maternal-fetal transmission incidence of CHIKV and dengue virus (DENV) infections during the 2008-2009 CHIKV outbreak in southern Thailand. A community-based post-epidemic seroprevalence study was conducted in parturient women admitted to the Thepa District Hospital in Songkhla Province, Thailand, for delivery from November 2009 to May 2010. The women were tested for chikungunya (CHIK) IgM/IgG and dengue (DEN) IgM/IgG. Cord blood samples were also tested for CHIK IgM or DEN IgM in women who tested positive for CHIK IgM or DEN IgM, respectively. The seroprevalence of CHIKV infection (CHIK IgM or IgG positive) was 227/319 (71.2%) with pre-outbreak seroprevalence (IgM-/IgG+) of 43.6% and the seroprevalence of DENV infection was 288/319 (90.3%). Complications during pregnancy, newborn outcomes and congenital anomalies were not different in those who had recent, remote or no CHIKV infections. None of the newborns whose mothers were CHIK or DEN IgM positive had cord blood positive for both CHIK and DEN IgM. In conclusion, both CHIKV and DENV are endemic in southern Thailand; during the recent CHIKV outbreak CHIK seroprevalence increased from 43.6% to 71.2%. PMID- 26113248 TI - Item Development and Face Validity of the Rheumatoid Arthritis Patient Priorities in Pharmacological Interventions Outcome Measures. AB - BACKGROUND: The assessment of rheumatoid arthritis (RA) is dominated by core sets and indices that have been developed by RA professionals. Previous research developed a set of eight priority treatment outcomes generated by patients to complement the professionally developed core sets for RA. OBJECTIVE: This study aimed to facilitate quantitative measurement of these outcomes. METHODS: Two consultation meetings with patient research partners diagnosed with RA (n = 18) were held to identify face validity in existing instruments (Phase 1) at the Bristol Royal Infirmary. Where validated measures did not exist, new numerical rating scales (NRS) were constructed and discussed at two focus groups with patients diagnosed with RA (n = 8) at the Bristol Royal Infirmary and the Royal National Hospital for Rheumatic Diseases (Phase 2). Feedback on the stem question, time frame, anchors and layout was recorded and transcribed verbatim. RESULTS: Of the eight priorities, existing NRS for pain, activities of daily living and fatigue were voted as acceptable (Phase 1), but new NRS were required for five priorities. The partners strongly recommended that the three separate domains of severity, effect and ability to cope in each measurement area be assessed, as in the existing validated fatigue NRS. Focus group participants (Phase 2) made significant contributions to the phrasing of questions, for example how to ensure 'mobility' could be uniformly understood and how changes in valued activities be judged appropriately. CONCLUSION: Through extensive patient feedback, 24 NRS were constructed based on priorities identified by patients and encompassing domains where existing questionnaires contain many more items and do not address three important concepts endorsed by patients: severity, effect and coping. The Rheumatoid Arthritis Patient Priorities in Pharmacological Interventions patient-reported outcome measures are now ready for the evaluation of comprehension, construct validity and sensitivity through an observational study. PMID- 26113249 TI - Patient-Centered Research to Support the Development of the Symptoms of Major Depressive Disorder Scale (SMDDS): Initial Qualitative Research. AB - BACKGROUND: Content valid, patient-reported outcome (PRO) measures of major depressive disorder (MDD) symptoms are needed to assess MDD treatment benefit. While a range of questionnaires are currently available to evaluate aspects of depression from the patient's perspective, their comprehensiveness and qualitative development histories are unclear. OBJECTIVE: The objective of this study was to describe the process and results of the preliminary qualitative development of a new symptom-based PRO measure intended to assess treatment benefit in MDD clinical trials. METHODS: Qualitative interviews were conducted with adult MDD patients in the USA who recently experienced a major depressive episode. Experienced interviewers conducted concept elicitation (CE) and cognitive interviews using semi-structured interview guides. The CE interview guide was used to elicit spontaneous reports of symptom experiences along with probing to further explore and confirm concepts. The cognitive interview guide was developed to evaluate concept relevance, understandability, and structure of the draft items, and to facilitate further instrument refinement. RESULTS: Forty patients participated in the CE interviews. A total of 3022 symptom codes, representing 84 different concepts were derived from the transcripts. Data from the CE interviews were considered alongside existing literature and clinical expert opinion during an item-generation process, leading to development of a preliminary version of the Symptoms of Major Depressive Disorder Scale (SMDDS). Fifteen patients participated in three waves of cognitive interviews, during which the SMDDS was further refined. CONCLUSIONS: The SMDDS is a 35-item PRO measure intended for use as an endpoint in MDD clinical trials to support medical product labeling. The SMDDS uses a 7-day recall period and verbal rating scales. It was developed in accordance with the US Food and Drug Administration (FDA)'s PRO Guidance and best practices. Qualitative interviews have provided evidence for content validity. Future quantitative studies will confirm the SMDDS's measurement properties and support FDA qualification. PMID- 26113250 TI - The readiness of the national health laboratory system in supporting care and treatment of HIV/AIDS in Tanzania. AB - BACKGROUND: Strong health laboratory systems and networks capable of providing high quality services are critical components of the health system and play a key role in routine diagnosis, care, treatment and disease surveillance. This study aimed to assess the readiness of the national health laboratory system (NHLS) and its capacity to support care and treatment of HIV/AIDS in Tanzania. METHODS: A documentary review was performed to assess the structure of the health system with reference to the status and capacity of the NHLS to support HIV diagnosis. Key informant interviews were also held with laboratory staff in all levels of the health care delivery system in four regions with different levels of HIV prevalence. Information sought included availability and utilization of laboratory guidelines, quality and the capacity of laboratories for diagnosis of HIV. RESULTS: The findings indicate that a well-established NHLS was in place. However, the coordination of HIV laboratory services was found to be weak. Forty six respondents were interviewed. In most laboratories, guidelines for HIV diagnosis were available but health care providers were not aware of their availability. Utilization of the guidelines for HIV diagnosis was higher at national level than at the lower levels. The low level of awareness and utilization of guidelines was associated with inadequate training and supervision. There was a shortage of human resource, mostly affecting the primary health care level of the system and this was associated with inequity in employment and training opportunities. Laboratories in public health facilities were better staffed and had more qualified personnel than private-owned laboratories. CONCLUSION: Tanzania has a well established national health laboratory network sufficient to support HIV care and treatment services. However, laboratories at the primary health care level are constrained by inadequate resources and operate within a limited capacity. Improving the laboratory capacity in terms of number of qualified personnel, staff training on the national guidelines, laboratory diagnostic tools and coordination should be given a higher priority. PMID- 26113251 TI - Infant death associated with maternal methamphetamine use during pregnancy and delivery: A case report. AB - The case described in this report is of a male infant who was found dead in a closet. His mother delivered the infant in the kitchen, left him wrapped in a towel, and called emergency medical services 4days after the delivery. At the autopsy, the growth suggests a full-term delivery, significant pathological findings were not observed, and the infant was estimated to be stillborn. After the autopsy, the police investigation discovered that the mother used a stimulant during the pregnancy and shortly before the rupture of the membrane. Toxicological analysis showed 1.60mg/L of methamphetamine in the blood, strongly suggesting that the fetal death was associated with this acute intoxication. Thus far, only a few cases of infant deaths have been reported in association with methamphetamine intoxication. The present case showed the highest blood concentration of methamphetamine compared to the past infant cases with this intoxication. PMID- 26113252 TI - Outcomes of consonant-vowel monosyllable perception and word recognition after cochlear implantation in elderly Japanese patients. AB - CONCLUSION: Performance in consonant-vowel (CV) monosyllable speech perception after cochlear implantation (CI) in the elderly (>= 65 years) is equivalent to that of young adults (18-64 years). Present data in the Japanese language supported the indication for CI in the elderly. Word recognition after CI was significantly lower in the elderly than young adults. OBJECTIVE: This study compared outcomes of monosyllable perception and word recognition after CI between elderly patients and young adults with post-lingual deafness. Age-related differences in CV monosyllable speech perception in Japanese were examined. METHODS: A retrospective chart review of 137 patients with post-lingual deafness who underwent CI at Okayama University Hospital during 1992-2014 [young adults aged 18-64 years (n = 96) and elderly aged >= 65 years (n = 41) at implantation] was conducted. CV monosyllable speech perception post-CI was compared among age groups (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, 80-89). CV monosyllable perception and word recognition scores post-CI were compared between the elderly and young adults. RESULTS: There was no significant difference in CV monosyllable speech perception among age groups. CV monosyllable speech perception in the elderly (61.4 +/- 25.5%) did not differ from that of young adults (65.9 +/- 24.8%). Word recognition scores were significantly lower in the elderly (64.3 +/- 28.1%) than young adults (80.4 +/- 25.9%) (p < 0.05). PMID- 26113253 TI - Acute kidney injury after transcatheter aortic valve replacement. PMID- 26113254 TI - Nuclear polarization by optical pumping in InP:Fe above liquid nitrogen temperature. AB - Hyperpolarized nuclear spins are observed in optically pumped iron-doped InP from 70K to 140K. (31)P NMR was carried out at 9.28T (159.8MHz) during optical excitation with circularly polarized light, using a laser diode (lambda~830nm) as a source. The enhancement of the nuclear spin polarization by optical pumping at 70K is estimated to be about 34 for those nuclei in the region of the sample absorbing light. This enhancement decreases with increasing temperature. As the direction of the enhanced nuclear spin polarization is found parallel or antiparallel to the travelling direction of the sigma(+) or sigma(-), the contact hyperfine interaction is dominant compared to the dipolar hyperfine interaction. PMID- 26113255 TI - Luminescent sensing and imaging of oxygen: fierce competition to the Clark electrode. AB - Luminescence-based sensing schemes for oxygen have experienced a fast growth and are in the process of replacing the Clark electrode in many fields. Unlike electrodes, sensing is not limited to point measurements via fiber optic microsensors, but includes additional features such as planar sensing, imaging, and intracellular assays using nanosized sensor particles. In this essay, I review and discuss the essentials of (i) common solid-state sensor approaches based on the use of luminescent indicator dyes and host polymers; (ii) fiber optic and planar sensing schemes; (iii) nanoparticle-based intracellular sensing; and (iv) common spectroscopies. Optical sensors are also capable of multiple simultaneous sensing (such as O2 and temperature). Sensors for O2 are produced nowadays in large quantities in industry. Fields of application include sensing of O2 in plant and animal physiology, in clinical chemistry, in marine sciences, in the chemical industry and in process biotechnology. PMID- 26113256 TI - Utility of the INECO frontal screening (IFS) in the detection of executive dysfunction in patients with relapsing-remitting multiple sclerosis (RRMS). AB - Several studies have reported that about 65 % of patients with relapsing remitting multiple sclerosis (RRMS) suffer from cognitive impairment, with executive dysfunction being the most frequently described. Even if several executive screening tests have been designed to specifically detect executive deficits, few studies have investigated their ability to tackle such dysfunction particularly in multiple sclerosis (MS). The aim of the present study was to evaluate the sensitivity and specificity of the INECO frontal screening (IFS) in the detection of executive dysfunction in patients with relapsing-remitting MS (RRMS). 54 patients with RRMS were included in the study. 34 presented executive dysfunction while 20 did not. 32 control subjects matched for age, sex, and educational level were also included. All were evaluated with the IFS and with a battery of classical executive tests. A patient was considered to have executive dysfunction if he/she scored a one and a half standard deviation below the control mean in at least one of the classical executive tests. Sensitivity and specificity of the IFS in its ability to detect executive dysfunction in MS was analyzed. Using a cut-off of 25.5 points, sensitivity of the IFS was 73.53 %, and specificity 78.13 % in differentiating controls from MS patients with executive dysfunction. The IFS showed excellent concurrent validity with executive tasks. The IFS can be considered a brief, easy-to-administer, cost-less tool for the detection of executive dysfunction in patients with RRMS. PMID- 26113257 TI - Properties of ultrathin cholesterol and phospholipid layers surrounding silicon carbide nanotube: MD simulations. AB - Computer simulation technique was used to study the dynamics of cholesterol and POPC phospholipid molecules forming a thin layer on the surface of the carbon and silicon-carbide nanotubes. Each nanotube was surrounded by an ultra-thin film formed by n lipid molecules, where n varies from 15 to 50. All studies were done for five temperatures, including physiological one (T=260, 285, 310, 335 and 360K). The influence of a nanotube on the dynamics of cholesterol or phospholipid molecules in a layer is presented and discussed. The water is ubiquitous in all biological milieus, where the cholesterol or lipids occur. Thus, simulations were performed in a water environment. Moreover, to show different behavior of lipids in systems with water the results were compared with the samples without it. The dynamical and structural observables, such as the mean square displacement, diffusion coefficient, radial distribution function, and activation energy were calculated to qualitatively investigate the behavior of cholesterol and phospholipid molecules in the layers. We observed remarkable differences between the cholesterol dynamics depending whether the ultrathin film surrounds carbon or silicon-carbide nanotube and whether the water environment appeared. PMID- 26113258 TI - Mimicking the niche: cytokines expand muscle stem cells. AB - Muscle stem cells (MuSCs) have long been considered to be potential therapeutic vehicles for diseases of muscle such as muscular dystrophies. A recent study published in Cell Research by Fu et al. reveals that recapitulating in vitro the in vivo microenvironment of MuSCs that occurs during muscle regeneration might be a major step towards translation. PMID- 26113259 TI - Copycat innate lymphoid cells dampen gut inflammation. AB - The mechanisms whereby the gut mucosa tolerates trillions of commensal bacteria without developing inflammation remain poorly understood. A recent Science article reveals that gut innate lymphoid cells constrain inflammatory T cell responses to commensal bacteria by adopting a strategy usually deployed by thymic epithelial cells to negatively select self-reactive T cells. PMID- 26113260 TI - Sustainability and dynamics of outcrop-to-outcrop hydrothermal circulation. AB - Most seafloor hydrothermal circulation occurs far from the magmatic influence of mid-ocean ridges, driving large flows of water, heat and solutes through volcanic rock outcrops on ridge flanks. Here we create three-dimensional simulations of ridge-flank hydrothermal circulation, flowing between and through seamounts, to determine what controls hydrogeological sustainability, flow rate and preferred flow direction in these systems. We find that sustaining flow between outcrops that penetrate less-permeable sediment depends on a contrast in transmittance (the product of outcrop permeability and the area of outcrop exposure) between recharging and discharging sites, with discharge favoured through less transmissive outcrops. Many simulations include local discharge through outcrops at the recharge end of an outcrop-to-outcrop system. Both of these characteristics are observed in the field. In addition, smaller discharging outcrops sustain higher flow rates than larger outcrops, which may help to explain how so much lithospheric heat is extracted globally by this process. PMID- 26113261 TI - Different post label delay cerebral blood flow measurements in patients with Alzheimer's disease using 3D arterial spin labeling. AB - PURPOSE: To evaluate cerebral blood flow (CBF) in patients with Alzheimer's disease (AD) using a three-dimensional pseudocontinuous arterial spin labeling (PCASL). We aimed to study the effects of different post label delay on the resulting CBF maps and to investigate the characteristics and clinical applications of brain perfusion. MATERIALS AND METHODS: Sixteen AD patients and nineteen healthy control subjects were recruited. 3D PCASL was performed using a 3.0 T MR scanner. ASL was performed twice with different post label delays (PLD). Comparisons of CBF were made between AD patients and healthy control subjects respectively with PLD of 1.5 s and PLD of 2.5 s. Relationship between the CBF values and cognition was investigated using correlation analysis. A receiver operating characteristic (ROC) curve was generated for CBF measurements in posterior cingulate region. RESULT: AD patients with PLD of 1.5 s showed lower CBF values primarily in bilateral temporal lobes, precuneus, middle and posterior cingulate gyri, left inferior parietal gyrus, left angular gyrus and left superior frontal gyrus. Lowered cerebral values were also observed in similar regions with PLD of 2.5 s, but the clusters of voxel were smaller. CBF values were associated with cognition scores in most of gyri mentioned above. CONCLUSION: Hypoperfusion areas were observed in AD patients. PLD of 1.5s was sufficient to display CBF. Considering the complicated AD pathology, multiple PLDs are strongly recommended. PMID- 26113262 TI - Nebulized colistin for treatment of ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: we still need to straighten out the dose! PMID- 26113263 TI - Early assessment of implementing evidence-based brief therapy interventions among secondary service psychiatric therapists. AB - This implementation study was part of the Ostrobothnia Depression Study, in Finland, which covered implementation of motivational interviewing (MI) and behavioral activation (BA) within regional public psychiatric secondary care. It aimed to evaluate the mid-term progress of implementation and related factors. Altogether, 80 therapists had been educated through the implementation program by the point of the mid-term evaluation. Eligible information for evaluation was gathered using two questionnaires (q1, q2) with a one-year interval. A total of 45 of the 80 therapists completed q1, 30 completed q2, and 24 completed both questionnaires. Professional education was the only background factor associated with adopting the interventions (q1: p=0.059, q2: p=0.023), with higher education indicating greater activity. On the basis of trends such as changes in overall usefulness score from q1 to q2, the most involved therapists were slightly more likely to adopt MI/BA. Our experience so far suggests that encouraging staff to begin using new interventions during education is very important. The Consolidated Framework for Implementation Research was found to be a useful tool for constructing the evaluation. PMID- 26113264 TI - Functional annotation of HOT regions in the human genome: implications for human disease and cancer. AB - Advances in genome-wide association studies (GWAS) and large-scale sequencing studies have resulted in an impressive and growing list of disease- and trait associated genetic variants. Most studies have emphasised the discovery of genetic variation in coding sequences, however, the noncoding regulatory effects responsible for human disease and cancer biology have been substantially understudied. To better characterise the cis-regulatory effects of noncoding variation, we performed a comprehensive analysis of the genetic variants in HOT (high-occupancy target) regions, which are considered to be one of the most intriguing findings of recent large-scale sequencing studies. We observed that GWAS variants that map to HOT regions undergo a substantial net decrease and illustrate development-specific localisation during haematopoiesis. Additionally, genetic risk variants are disproportionally enriched in HOT regions compared with LOT (low-occupancy target) regions in both disease-relevant and cancer cells. Importantly, this enrichment is biased toward disease- or cancer-specific cell types. Furthermore, we observed that cancer cells generally acquire cancer specific HOT regions at oncogenes through diverse mechanisms of cancer pathogenesis. Collectively, our findings demonstrate the key roles of HOT regions in human disease and cancer and represent a critical step toward further understanding disease biology, diagnosis, and therapy. PMID- 26113265 TI - Citrullination of myofilament proteins in heart failure. AB - AIMS: Citrullination, the post-translational conversion of arginine to citrulline by the enzyme family of peptidylarginine deiminases (PADs), is associated with several diseases, and specific citrullinated proteins have been shown to alter function while others act as auto-antigens. In this study, we identified citrullinated proteins in human myocardial samples, from healthy and heart failure patients, and determined several potential functional consequences. Further we investigated PAD isoform cell-specific expression in the heart. METHODS AND RESULTS: A citrullination-targeted proteomic strategy using data independent (SWATH) acquisition method was used to identify the modified cardiac proteins. Citrullinated-induced sarcomeric proteins were validated using two dimensional gel electrophoresis and investigated using biochemical and functional assays. Myocardial PAD isoforms were confirmed by RT-PCR with PAD2 being the major isoform in myocytes. In total, 304 citrullinated sites were identified that map to 145 proteins among the three study groups: normal, ischaemia, and dilated cardiomyopathy. Citrullination of myosin (using HMM fragment) decreased its intrinsic ATPase activity and inhibited the acto-HMM-ATPase activity. Citrullinated TM resulted in stronger F-actin binding and inhibited the acto-HMM ATPase activity. Citrullinated TnI did not alter the binding to F-actin or acto HMM-ATPase activity. Overall, citrullination of sarcomeric proteins caused a decrease in Ca(2+) sensitivity in skinned cardiomyocytes, with no change in maximal calcium-activated force or hill coefficient. CONCLUSION: Citrullination unique to the cardiac proteome was identified. Our data indicate important structural and functional alterations to the cardiac sarcomere and the contribution of protein citrullination to this process. PMID- 26113266 TI - Ultrastructure of the intercellular space in adult murine ventricle revealed by quantitative tomographic electron microscopy. AB - AIMS: Progress in tissue preservation (high-pressure freezing), data acquisition (tomographic electron microscopy, TEM), and analysis (image segmentation and quantification) have greatly improved the level of information extracted from ultrastructural images. Here, we combined these methods and developed analytical tools to provide an in-depth morphometric description of the intercalated disc (ID) in adult murine ventricle. As a point of comparison, we characterized the ultrastructure of the ID in mice heterozygous-null for the desmosomal gene plakophilin-2 (PKP2; mice dubbed PKP2-Hz). METHODS AND RESULTS: Tomographic EM images of thin sections of adult mouse ventricular tissue were processed by image segmentation analysis. Novel morphometric routines allowed us to generate the first quantitative description of the ID intercellular space based on three dimensional data. We show that complex invaginations of the cell membrane significantly increased the total ID surface area. In addition, PKP2-Hz samples showed increased average intercellular spacing, ID surface area, and membrane tortuosity, as well as reduced number and length of mechanical junctions compared with control. Finally, we observed membranous structures reminiscent of junctional sarcoplasmic reticulum at the ID, which were significantly more abundant in PKP2-Hz hearts. CONCLUSION: We have developed a systematic method to characterize the ultrastructure of the intercellular space in the adult murine ventricle and have provided a quantitative description of the structure of the intercellular membranes and of the intercellular space. We further show that PKP2 deficiency associates with ultrastructural defects. The possible importance of the intercellular space in cardiac behaviour is discussed. PMID- 26113273 TI - Inguinal seroma prevention after superficial circumflex iliac artery perforator flap harvest using non-microsurgical lympho-venous shunt. PMID- 26113274 TI - A systematic review of animal models for experimental neuroma. AB - Peripheral neuromas can result in an unbearable neuropathic pain and functional impairment. Their treatment is still challenging, and their optimal management is to be defined. Experimental research still plays a major role, but - although numerous neuroma models have been proposed on different animals - there is still no single model recognised as being the reference. Several models show advantages over the others in specific aspects of neuroma physiopathology, prevention or treatment, making it unlikely that a single model could be of reference. A reproducible and standardised model of peripheral neuroma would allow better comparison of results from different studies. We present a systematic review of the literature on experimental in vivo models, analysing advantages and disadvantages, specific features and indications, with the goal of providing suggestions to help their standardisation. Published models greatly differ in the animal and the nerve employed, the mechanisms of nerve injury and the evaluation methods. Specific experimental models exist for terminal neuromas and neuromas in continuity (NIC). The rat is the most widely employed animal, the rabbit being the second most popular model. NIC models are more actively researched, but it is more difficult to generate such studies in a reproducible manner. Nerve transection is considered the best method to cause terminal neuromas, whereas partial transection is the best method to cause NIC. Traditional histomorphology is the historical gold-standard evaluation method, but immunolabelling, reverse transcriptase-polymerase chain reaction (RT-PCR) and proteomics are gaining increasing popularity. Computerised gait analysis is the gold standard for motor recovery evaluation, whereas mechanical testing of allodynia and hyperalgesia reproducibly assesses sensory recovery. This review summarises current knowledge on experimental neuroma models, and it provides a useful tool for defining experimental protocols. Furthermore, it could help future research to define standard experimental model(s) of peripheral neuromas, allowing better comparison of results and improvement of our understanding of such a complex disease. PMID- 26113275 TI - The use of epidermal grafting for the management of acute wounds in the outpatient setting. PMID- 26113276 TI - Second intercostal internal mammary artery perforator (IMAP) fasciocutaneous flap as an alternative choice for the treatment of deep sternal wound infections (DSWI). AB - Sternal wound infections after sternotomy are associated with high morbidity, high mortality and escalating treatment costs. Repeated radical debridement - with the removal of any hardware - and wound conditioning are the prerequisites for reconstruction. Muscle and, less frequently, omentum flaps are usually used for reconstruction. However, these flaps are associated with considerable donor site morbidity, long operation times and aesthetic impairment. Fasciocutaneous flaps seem to be an alternative. This study presents our experience of using the second intercostal mammary artery fasciocutaneous perforator flap for defect closure in nine patients (mean age: 70.2 years). Following a retrospective chart review, we assessed data on patient demographics, the type of cardiac surgery, the prevalence of deep sternal wound infection (DSWI) risk factors, identified pathogens, surgery duration, hospitalization tim patients had undergone coronary artery bypass surgery, and two had valve replacements. The mean duration of surgery (121.4 +/- 39 min) was short. The patients had a mean body mass index (BMI) of 32.8 +/- 4.9 kg/m(2). An average flap size of 124 +/- 22 cm(2) sufficiently covered and obliterated each defect. One mediastinal haematoma required revision surgery. One wound dehiscence at the flap and two at the donor site were managed conservatively. Our experience reveals that a fasciocutaneous flap based on the second intercostal perforator of the internal mammary artery can be an alternative, quick-to-prepare flap for covering sternal defects. In adipose patients, it has sufficient bulk, and it is large enough to cover common sternal wounds. It also has low complication and morbidity rates, and it achieves an aesthetically pleasing result. PMID- 26113277 TI - Use of serratus fascia in stratticeTM and implant based breast reconstruction. PMID- 26113278 TI - Prominent ear correction: An effective technique for marking the cartilage with a needle and ink. PMID- 26113279 TI - Manson's point: A facial landmark to identify the facial artery. AB - INTRODUCTION: The anatomy of the facial artery, its tortuosity, and branch patterns are well documented. To date, a reliable method of identifying the facial artery, based on surface landmarks, has not been described. The purpose of this study is to characterize the relationship of the facial artery with several facial topographic landmarks, and to identify a location where the facial artery could predictably be identified. METHODS: Following institutional review board approval, 20 hemifacial dissections on 10 cadaveric heads were performed. Distances from the facial artery to the oral commissure, mandibular angle, lateral canthus, and Manson's point were measured. Distances were measured and confirmed clinically using Doppler examination in 20 hemifaces of 10 healthy volunteers. RESULTS: Manson's point identifies the facial artery with 100% accuracy and precision, within a 3 mm radius in both cadaveric specimens and living human subjects. Cadaveric measurements demonstrated that the facial artery is located 19 mm +/- 5.5 from the oral commissure, 31 mm +/- 6.8 from the mandibular angle, 92 mm +/- 8.0 from the lateral canthus. Doppler examination on healthy volunteers (5 male, 5 female) demonstrated measurements of 18 mm +/- 4.0, 50 mm +/- 6.4, and 79 mm +/- 8.2, respectively. CONCLUSIONS: The identification of the facial artery is critical for the craniofacial surgeon in order to avoid inadvertent injury, plan for local flaps, and in preparation of a recipient vessel for free tissue microvascular reconstruction. Manson's point can aid the surgeon in consistently indentifying the facial artery. PMID- 26113280 TI - Deep branch of the superficial circumflex iliac artery for backup. PMID- 26113281 TI - Does a mineral wristband affect balance? A randomized, controlled, double-blind study. AB - BACKGROUND: Having good balance is a facilitating factor in the performance of everyday activities. Good balance is also essential in various sport activities in order to both get results and prevent injury. A common measure of balance is postural sway, which can be measured both antero-posteriorly and medio-laterally. There are several companies marketing wristbands whose intended function is to improve balance, strength and flexibility. Randomized controlled trials have shown that wristbands with holograms have no effect on balance but studies on wristbands with minerals seem to be lacking. OBJECTIVE: The aim of this study was to investigate if the mineral wristband had any effect on postural sway in a group of healthy individuals. STUDY DESIGN: Randomized, controlled, double-blind study. MATERIAL/METHODS: The study group consisted of 40 healthy persons. Postural sway was measured antero-posteriorly and medio-laterally on a force plate, to compare: the mineral wristband, a placebo wristband, and without any wristband. The measurements were performed for 30 s, in four situations: with open eyes and closed eyes, standing on a firm surface and on foam. Analyses were made with multilevel technique. RESULTS: The use of wristband with or without minerals did not alter postural sway. Closed eyes and standing on foam both prolonged the dependent measurement, irrespective if it was medio-lateral or antero-posterior. Wearing any wristband (mineral or placebo) gave a small (0.22 0.36 mm/s) but not statistically significant reduction of postural sway compared to not wearing wristband. CONCLUSION: This study showed no effect on postural sway by using the mineral wristband, compared with a placebo wristband or no wristband. Wearing any wristband at all (mineral or placebo) gave a small but not statistically significant reduction in postural sway, probably caused by sensory input. PMID- 26113282 TI - Hashimoto's thyroiditis and papillary thyroid cancer: polyglandular hints. PMID- 26113284 TI - Optimal radiation fractionation for low-grade gliomas: Insights from a mathematical model. AB - We study optimal radiotherapy fractionations for low-grade glioma using mathematical models. Both space-independent and space-dependent models are studied. Two different optimization criteria have been developed, the first one accounting for the global effect of the tumor mass on the disease symptoms and the second one related to the delay of the malignant transformation of the tumor. The models are studied theoretically and numerically using the method of feasible directions. We have searched for optimal distributions of the daily doses dj in the standard protocol of 30 fractions using both models and the two different optimization criteria. The optimal results found in all cases are minor deviations from the standard protocol and provide only marginal potential gains. Thus, our results support the optimality of current radiation fractionations over the standard 6 week treatment period. This is also in agreement with the observation that minor variations of the fractionation have failed to provide measurable gains in survival or progression free survival, pointing out to a certain optimality of the current approach. PMID- 26113283 TI - Circadian redox oscillations and metabolism. AB - Circadian rhythms are 24h oscillations in physiology and behavior which allow organisms to anticipate and adapt to daily demands associated with the day/night cycle. The currently accepted model of the molecular clockwork is described as a transcriptional process composed of negative regulatory feedback loops. However, ample evidence underlines the important contribution of non-transcriptional and metabolic oscillations to cellular timekeeping. We summarize recent evidence pointing to the relationship between the transcriptional oscillator and metabolic redox state, with particular emphasis on the potential nodes of interaction. We highlight the intrinsic difficulty in segregating these two tightly coupled and interdependent processes, in living systems, and how disruption of their synchronicity impacts upon (patho)physiological processes as diverse as cardiovascular and metabolic disorders, aging, and cancer. PMID- 26113285 TI - Impact of the hypoxia inducible factor-1alpha (HIF-1alpha) pro582ser polymorphism and its gene expression on diabetic foot ulcers. AB - AIM: Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of series of genes and the primary factor mediating this response is the hypoxia-inducible factor-1alpha. This study was designed in order to examine the HIF-1alpha gene polymorphism, p582s (rs11549465) in Exon-12 of HIF-1alpha gene in diabetic subjects with and without foot ulcers (DFU) and to find its expression under these pathological conditions. METHODS: A total of 224 subjects from our tertiary care centre were included, which consists of healthy controls (N=66), type 2 diabetes mellitus (T2DM) (N=79) and T2DM with foot ulcers (DFU) (N=79). Allelic and genotypic comparisons between the different groups were evaluated by PCR-RFLP. The gene expression studies on selected samples (N=15 of each group) were done by Semi-quantitative real time PCR. RESULTS AND DISCUSSIONS: Genotype analysis showed a significant increase in presence of 'T' allele in T2DM & DFU when compared to that of control subjects. Allele wise analysis showed a higher frequency of 'T' allele in the T2DM (62.03%) when compared to that of control subjects (53.79%). Interestingly, semi-quantitative RT-PCR results showed decreased expression of HIF-1alpha gene on DFU when compared to that of T2DM and control subjects. CONCLUSION: Our findings predict that there is an association of HIF-1alpha gene polymorphism on foot ulcer patients when compare to that of healthy controls. Semi-quantitative real time studies showed decreased HIF-1alpha gene expression on foot ulcer patients suggesting its possible role on the pathogenesis. PMID- 26113286 TI - Prediction of plasma caffeine concentrations in young adolescents following ingestion of caffeinated energy drinks: a Monte Carlo simulation. AB - The fast-growing consumption of caffeinated energy drinks (CEDs) is linked to increasing reports of caffeine intoxication in adolescents. There is limited data available regarding plasma caffeine concentrations in this population after CED intake and the potential implications for caffeine-related toxicity. This study was an in silico population pharmacokinetic analysis of caffeine. Population pharmacokinetic model of oral caffeine was derived from a previous study of healthy male volunteers. Maximal plasma caffeine concentration (C max) profiles following ingestion of one or two servings of popular CEDs were predicted using Monte Carlo simulation and available population body weight data of 10-15-year old Korean adolescents. Caffeine C max values were positively correlated with the amount of caffeine ingested in CEDs and negatively correlated with body weight. The median (range) C max profiles varied from a low of 1.2 (0.5-2.6) mg/L to a concentration that is potentially associated with harmful caffeine-related effects of 25.4 (8.1-55.6) mg/L. A subgroup of female 10-11-year-old subjects exhibited the highest caffeine exposure profiles. CONCLUSION: These data indicate that CED ingestion can increase the risk of serious caffeine intoxication in young adolescents, particularly those with low body mass. WHAT IS KNOWN: * Excessive consumption of caffeine can lead to serious caffeine intoxication. * The risk of potential harmful caffeine intoxication after ingestion of caffeinated energy drinks (CED) has not been adequately evaluated in adolescents. WHAT IS NEW: * Predicted maximal plasma caffeine concentration profiles of adolescents with lower body weights showed an overlap with the ingested caffeine concentrations obtained from documented fatalities. * The present simulation based pharmacokinetic analysis demonstrates that CED ingestion could lead to potentially serious caffeine intoxication in this cohort. PMID- 26113287 TI - Structural, energetic, and dynamic insights into the abnormal xylene separation behavior of hierarchical porous crystal. AB - Separation of highly similar molecules and understanding the underlying mechanism are of paramount theoretical and practical importance, but visualization of the host-guest structure, energy, or dynamism is very difficult and many details have been overlooked. Here, we report a new porous coordination polymer featuring hierarchical porosity and delicate flexibility, in which the three structural isomers of xylene (also similar disubstituted benzene derivatives) can be efficiently separated with an elution sequence inversed with those for conventional mechanisms. More importantly, the separation mechanism is comprehensively and quantitatively visualized by single-crystal X-ray crystallography coupled with multiple computational simulation methods, in which the small apertures not only fit best the smallest para-isomer like molecular sieves, but also show seemingly trivial yet crucial structural alterations to distinguish the meta- and ortho-isomers via a gating mechanism, while the large channels allow fast guest diffusion and enable the structural/energetic effects to be accumulated in the macroscopic level. PMID- 26113288 TI - Increased Umbilical Artery Pulsatility Index in Third-Trimester Fetuses with Trisomy 21. AB - OBJECTIVE: To examine the umbilical arterial Doppler flow patterns in late third trimester fetuses with trisomy 21. METHODS: This is a retrospective study on fetuses with trisomy 21 that were evaluated after 33 weeks' gestation at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany. The umbilical and the middle cerebral artery (UA and ACM) pulsatility index (PI) measurements and the abdominal circumference were transformed into z-values. RESULTS: Forty-two fetuses met the study criteria. The mean gestational age at the time of the first and the second visit was 35.0 and 36.6 weeks, respectively. The mean UA PI was 1.31 and 1.38, which corresponds to z-values of 2.20 and 2.70. In 24 (57.1%) cases, both PI measurements were above the 95th centile. A linear regression analysis demonstrated that the mean of both UA PI was not dependent on the abdominal circumference or on any other examined maternal and pregnancy characteristics. The mean ACM PI at the first and the second visit was 1.62 and 1.48, respectively, corresponding to mean z-values of -0.59 and -0.75, and in none of the cases was it below the 5th centile. CONCLUSION: In half of the third trimester fetuses with trisomy 21, the resistance in the UA is increased - even in the absence of placental insufficiency. PMID- 26113289 TI - The moral imperative to continue gene editing research on human embryos. PMID- 26113290 TI - Digital volume correlation and micro-CT: An in-vitro technique for measuring full field interface micromotion around polyethylene implants. AB - Micromotion around implants is commonly measured using displacement-sensor techniques. Due to the limitations of these techniques, an alternative approach (DVC-MUCT) using digital volume correlation (DVC) and micro-CT (MUCT) was developed in this study. The validation consisted of evaluating DVC-MUCT based micromotion against known micromotions (40, 100 and 150 MUm) in a simplified experiment. Subsequently, a more clinically realistic experiment in which a glenoid component was implanted into a porcine scapula was carried out and the DVC-MUCT measurements during a single load cycle (duration 20 min due to scanning time) was correlated with the manual tracking of micromotion at 12 discrete points across the implant interface. In this same experiment the full-field DVC MUCT micromotion was compared to the full-field micromotion predicted by a parallel finite element analysis (FEA). It was found that DVC-MUCT micromotion matched the known micromotion of the simplified experiment (average/peak error=1.4/1.7 MUm, regression line slope=0.999) and correlated with the micromotion at the 12 points tracked manually during the realistic experiment (R(2)=0.96). The DVC-MUCT full-field micromotion matched the pattern of the full field FEA predicted micromotion. This study showed that the DVC-MUCT technique provides sensible estimates of micromotion. The main advantages of this technique are that it does not damage important parts of the specimen to gain access to the bone-implant interface, and it provides a full-field evaluation of micromotion as opposed to the micromotion at just a few discrete points. In conclusion the DVC MUCT technique provides a useful tool for investigations of micromotion around plastic implants. PMID- 26113291 TI - Factors that influence muscle shear modulus during passive stretch. AB - Although elastography has been increasingly used for evaluating muscle shear modulus associated with age, sex, musculoskeletal, and neurological conditions, its physiological meaning is largely unknown. This knowledge gap may hinder data interpretation, limiting the potential of using elastography to gain insights into muscle biomechanics in health and disease. We derived a mathematical model from a widely-accepted Hill-type passive force-length relationship to gain insight about the physiological meaning of resting shear modulus of skeletal muscles under passive stretching, and validated the model by comparing against the ex-vivo animal data reported in our recent work (Koo et al. 2013). The model suggested that resting shear modulus of a slack muscle is a function of specific tension and parameters that govern the normalized passive muscle force-length relationship as well as the degree of muscle anisotropy. The model also suggested that although the slope of the linear shear modulus-passive force relationship is primarily related to muscle anatomical cross-sectional area (i.e. the smaller the muscle cross-sectional area, the more the increase in shear modulus to result in the same passive muscle force), it is also governed by the normalized passive muscle force-length relationship and the degree of muscle anisotropy. Taken together, although muscle shear modulus under passive stretching has a strong linear relationship with passive muscle force, its actual value appears to be affected by muscle's mechanical, material, and architectural properties. This should be taken into consideration when interpreting the muscle shear modulus values. PMID- 26113292 TI - Strategic Targets in Acne: The Comedone Switch in Question. AB - The sequence of events and mechanisms leading to the development of the primary acne lesion, the comedone, is revisited. Recent knowledge obtained both from lineage tracing experiments in the mouse and the pilosebaceous response to xenobiotics in humans provides robust models for further understanding key biological events at the cellular roots of comedogenesis. The focus is set on the LRIG1+ sebaceous stem cells in the isthmus of the pilosebaceous duct. The master switch that transforms a normally functioning sebaceous gland into a microcomedone and the hierarchy of factors involved in this process are reviewed. The key strategic target in acne care appears to be the naive pilosebaceous follicle that is not involved yet in the acne cycle. The prevention of the comedone switch implies that the key switching factors are adequately controlled in the long term. PMID- 26113293 TI - Human circulating plasma DNA significantly decreases while lymphocyte DNA damage increases under chronic occupational exposure to low-dose gamma-neutron and tritium beta-radiation. AB - The blood plasma of healthy people contains cell-fee (circulating) DNA (cfDNA). Apoptotic cells are the main source of the cfDNA. The cfDNA concentration increases in case of the organism's cell death rate increase, for example in case of exposure to high-dose ionizing radiation (IR). The objects of the present research are the blood plasma and blood lymphocytes of people, who contacted occupationally with the sources of external gamma/neutron radiation or internal beta-radiation of tritium N = 176). As the controls (references), blood samples of people, who had never been occupationally subjected to the IR sources, were used (N = 109). With respect to the plasma samples of each donor there were defined: the cfDNA concentration (the cfDNA index), DNase1 activity (the DNase1 index) and titre of antibodies to DNA (the Ab DNA index). The general DNA damage in the cells was defined (using the Comet assay, the tail moment (TM) index). A chronic effect of the low-dose ionizing radiation on a human being is accompanied by the enhancement of the DNA damage in lymphocytes along with a considerable cfDNA content reduction, while the DNase1 content and concentration of antibodies to DNA (Ab DNA) increase. All the aforementioned changes were also observed in people, who had not worked with the IR sources for more than a year. The ratio cfDNA/(DNase1*Ab DNA * TM) is proposed to be used as a marker of the chronic exposure of a person to the external low-dose IR. It was formulated the assumption that the joint analysis of the cfDNA, DNase1, Ab DNA and TM values may provide the information about the human organism's cell resistivity to chronic exposure to the low-dose IR and about the development of the adaptive response in the organism that is aimed, firstly, at the effective cfDNA elimination from the blood circulation, and, secondly - at survival of the cells, including the cells with the damaged DNA. PMID- 26113294 TI - Metoprolol Inhibits Cardiac Apoptosis and Fibrosis in a Canine Model of Chronic Obstructive Sleep Apnea. AB - AIMS: Emerging evidence suggested that obstructive sleep apnea (OSA) was independently associated with the development of heart failure. In this study, we explored the influence of chronic OSA on left ventricular structural remodeling in canines, and the potential therapeutical role of metoprolol. METHODS: Chronic OSA model was established by stopping the ventilator and closing the airway for 4 h/day apnea-ventilation cycles every other day for 12 weeks while metoprolol (5 mg. kg(-1). day(-1)) were administered continuously. Norepinephrine concentration was measured by Enzyme Linked Immunosorbent Assay. Transmission electron microscopy, Hematoxylin and eosin, TUNEL and Masson trichrome staining were employed to detect the morphology, apoptosis and fibrosis of cardiomyocytes. Protein expression of apoptosis and fibrosis-related factors including apoptosis inducing factor (AIF), caspase 3, Bcl-2, Bax, alpha-smooth muscle actin (alpha SMA), transforming growth factor-beta1 (TGF-beta1), and p38 mitogen-activated protein kinase (MAPK) were examined by Western blotting. RESULTS: Norepinephrine concentration was markedly increased in chronic OSA dogs and reduced by metoprolol. Both the apoptotic ratio and collagen volume fraction were significantly increased in left ventricular myocytes of chronic OSA dogs, and was reversed by metoprolol. Moreover, chronic OSA-induced upregulation of AIF, cleaved caspase 3, Bax, alpha-SMA, and TGF-beta1 as well as downregulation of Bcl 2 was markedly recovered by metoprolol, which was mediated by p38 MAPK. CONCLUSION: Metoprolol protects against chronic OSA-induced cardiac apoptosis and fibrosis in left ventricular myocytes of canines, which may provide new potential strategy for drug therapy of OSA. PMID- 26113295 TI - Supporting quality public and patient engagement in health system organizations: development and usability testing of the Public and Patient Engagement Evaluation Tool. AB - OBJECTIVES: Only rudimentary tools exist to support health system organizations to evaluate their public and patient engagement (PPE) activities. This study responds to this gap by developing a generic evaluation tool for use in a wide range of organizations. METHODS: The evaluation tool was developed through an iterative, collaborative process informed by a review of published and grey literature and with the input of Canadian PPE researchers and practitioners. Over a 3-year period, structured e-mail, telephone and face-to-face exchanges, including a modified Delphi process, were used to produce an evaluation tool that includes core principles of high-quality engagement, expected outcomes for each principle and three unique evaluation questionnaires that were tested and revised with input from 65 end users. RESULTS: The tool is structured around four core principles of 'quality engagement': (i) integrity of design and process; (ii) influence and impact; (iii) participatory culture; and (iv) collaboration and common purpose. Three unique questionnaires were developed to assess each of these four evaluation domains from the following perspectives: (i) those who participate in PPE activities; (ii) those who plan, execute or sponsor PPE activities within organizations; and (iii) those who provide the leadership and capacity for PPE within their organizations. CONCLUSIONS: This is the first known collaboration of researchers and practitioners in the co-design of a comprehensive PPE evaluation tool aimed at three distinct respondent groups and for use in a wide range of health system organization settings. PMID- 26113296 TI - Simulation studies of circular muscle contraction, longitudinal muscle shortening, and their coordination in esophageal transport. AB - On the basis of a fully coupled active musculomechanical model for esophageal transport, we aimed to find the roles of circular muscle (CM) contraction and longitudinal muscle (LM) shortening in esophageal transport, and the influence of their coordination. Two groups of studies were conducted using a computational model. In the first group, bolus transport with only CM contraction, only LM shortening, or both was simulated. Overall features and detailed information on pressure and the cross-sectional area (CSA) of mucosal and the two muscle layers were analyzed. In the second group, bolus transport with varying delay in CM contraction or LM shortening was simulated. The effect of delay on esophageal transport was studied. For cases showing abnormal transport, pressure and CSA were further analyzed. CM contraction by itself was sufficient to transport bolus, but LM shortening by itself was not. CM contraction decreased the CSA and the radius of the muscle layer locally, but LM shortening increased the CSA. Synchronized CM contraction and LM shortening led to overlapping of muscle CSA and pressure peaks. Advancing LM shortening adversely influenced bolus transport, whereas lagging LM shortening was irrelevant to bolus transport. In conclusion, CM contraction generates high squeezing pressure, which plays a primary role in esophageal transport. LM shortening increases muscle CSA, which helps to strengthen CM contraction. Advancing LM shortening decreases esophageal distensibility in the bolus region. Lagging LM shortening no longer helps esophageal transport. Synchronized CM contraction and LM shortening seems to be most effective for esophageal transport. PMID- 26113297 TI - Hepatic TLR4 signaling in obese NAFLD. AB - Nonalcoholic fatty liver disease occurs frequently in the setting of metabolic syndrome, but the factors leading to nonalcoholic steatohepatitis (NASH) are not fully understood. This study investigated Toll-like receptor 4 (TLR4) signaling in human liver with the goal of delineating whether activation of this pathway segregates those with nonalcoholic fatty liver from those with NASH. Experiments were performed using liver biopsy tissue obtained from class III obese subjects undergoing bariatric surgery, and extended to an immortalized human hepatocyte HepaRG cell line and primary human hepatocytes. The bacterial endotoxin lipopolysaccharide (LPS) and total free fatty acid levels were significantly increased in plasma of NASH patients. TLR4 mRNA levels were significantly increased in subjects with NASH compared with NAFL as was interferon regulatory factor (IRF) 3 in the myeloid differentiation factor 88-independent signaling pathway. In HepaRG cells, nuclear factor-kappaB (NF-kappaB) nuclear translocation and functional activity increased following treatment with the fatty acid, palmitate, and following exposure to LPS compared with hepatocytes stimulated with a lipogenic treatment that induced de novo lipogenesis. Palmitate and LPS induction of NF-kappaB activity was partially attenuated by chemical- or small interfering RNA-mediated inhibition of TLR4. Expression of TLR4 and its downstream mediators was upregulated with palmitate and LPS. Similar results were observed using primary human hepatocytes from a lean donor. Interestingly, NF kappaB activity assays showed obese donor hepatocytes were resistant to chemical TLR4 inhibition. In conclusion, TLR4 expression is upregulated in a large cohort of NASH patients, compared with those with NAFL, and this occurs within the setting of increased LPS and fatty acids. PMID- 26113299 TI - Electrical neuromodulation at acupoint ST36 normalizes impaired colonic motility induced by rectal distension in dogs. AB - Electroacupuncture (EA) has been shown to improve impaired gastric motility and slow waves in both humans and animals. However, its effects on colonic motility have rarely been investigated. The aim of this study was to investigate the effects and underlying mechanisms of EA on impaired colonic motility induced by rectal distension (RD)in dogs. Colon contractions and transit were measured in various sessions with and without EA in hound dogs chronically placed with a colonic cannula. Colonic contractile activity was assessed by motility index (MI). Autonomic functions were determined by the spectral analysis of the heart rate variability derived from the electrocardiogram. It was found 1) RD suppressed colonic motility by 40.5% (10.8 +/- 0.9 with RD vs. 6.4 +/- 0.8 at baseline, P < 0.002). EA at ST36 normalized colonic contractions suppressed by RD (12.9 +/- 2.8, P < 0.002 vs. RD and P = 0.1 vs. control). 2) Administration of atropine blocked the ameliorating effect of EA on colon motility. 3) RD also delayed colonic transit (65.0 +/- 2.0% with RD vs. 86.0 +/- 1.9% without RD, P < 0.001) that was restored with EA (84.0 +/- 1.9%, P = 0.178 vs. control). 4) EA increased vagal activity suppressed by RD (0.37 +/- 0.07 with RD + EA vs. 0.09 +/ 0.03 with RD without EA, P < 0.001). In conclusion, RD inhibits colonic contractions and delays colonic transit in dogs; EA at ST36 restores the RD induced impairment in both colonic contraction and transit by enhancing vagal activity and mediated via the cholinergic pathway. PMID- 26113298 TI - Impact of SCP-2/SCP-x gene ablation and dietary cholesterol on hepatic lipid accumulation. AB - While a high-cholesterol diet induces hepatic steatosis, the role of intracellular sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) proteins is unknown. We hypothesized that ablating SCP-2/SCP-x [double knockout (DKO)] would impact hepatic lipids (cholesterol and cholesteryl ester), especially in high-cholesterol-fed mice. DKO did not alter food consumption, and body weight (BW) gain decreased especially in females, concomitant with hepatic steatosis in females and less so in males. DKO-induced steatosis in control-fed wild-type (WT) mice was associated with 1) loss of SCP-2; 2) upregulation of liver fatty acid binding protein (L-FABP); 3) increased mRNA and/or protein levels of sterol regulatory element binding proteins (SREBP1 and SREBP2) as well as increased expression of target genes of cholesterol synthesis (Hmgcs1 and Hmgcr) and fatty acid synthesis (Acc1 and Fas); and 4) cholesteryl ester accumulation was also associated with increased acyl-CoA cholesterol acyltransferase-2 (ACAT2) in males. DKO exacerbated the high-cholesterol diet induced hepatic cholesterol and glyceride accumulation, without further increasing SREBP1, SREBP2, or target genes. This exacerbation was associated both with loss of SCP-2 and concomitant downregulation of Ceh/Hsl, apolipoprotein B (ApoB), MTP, and/or L-FABP protein expression. DKO diminished the ability to secrete excess cholesterol into bile and oxidize cholesterol to bile acid for biliary excretion, especially in females. This suggested that SCP-2/SCP-x affects cholesterol transport to particular intracellular compartments, with ablation resulting in less to the endoplasmic reticulum for SREBP regulation, making more available for cholesteryl ester synthesis, for cholesteryl-ester storage in lipid droplets, and for bile salt synthesis and/or secretion. These alterations are significant findings, since they affect key processes in regulation of sterol metabolism. PMID- 26113301 TI - [Imaging in pediatric urology]. AB - BACKGROUND: For many years, sonography and the intravenous pyelogram (IVP) were the most important examination methods for the evaluation of the urinary tract in children. Both methods have their pros and cons: sonography provides ideal visualization of normal kidneys and the evaluation of the pelvicalyceal system. For detection or exclusion of renal scarring, however, this method is not well suited. It provides no information regarding kidney function. METHODS: With an IVP, it is possible to evaluate urinary excretion and, thus, indirectly assess kidney function. As this examination method involves radiation exposure and the necessity of a contrast agent, it should be avoided in the examination of children. The CT is an excellent examination method that can diagnose nearly all urological diseases in children or answer urological questions; however, a CT scan applies the highest radiation dose of all discussed methods. For this reason, examination via MRI is of increasing importance in uroradiology. Initially only the T2 sequences for the visualization of the urinary tract in children were applied. CONCLUSION: The current technical developments as well as the use of the contrast agent gadolinium and the antidiuretic agent furosemide allow an all-in-one evaluation of the kidneys and urinary tract. PMID- 26113300 TI - [Testosterone in the management of metastatic prostate cancer]. AB - Background Among all cancer types, prostate cancer (PCa) is the most prevalent cancer and is the third-leading cause of cancer-related death in men. The biologic function of the prostate is decisively influenced by testosterone and its metabolic product dihydrotestosterone. However, there is general uncertainty about the role of testosterone in metastatic castration-resistant prostate cancer (mCRPC). For many years, the androgen hypothesis had been accepted to explain the correlation between testosterone levels and the development or progression of PCa. However, extensive study analyses revealed contradictory results, leading to a reconsideration of the androgen hypothesis. High serum testosterone levels do not predispose to PCa development and low serum testosterone levels are not protective. The importance of testosterone levels in patients with mCRPC has been shown in several registration studies with new drugs, such as abiraterone acetate and enzalutamide. There is growing evidence suggesting a prognostic role of testosterone levels in mCRPC. PMID- 26113302 TI - [German validation of the Acute Cystitis Symptom Score]. AB - BACKGROUND: The Uzbek version of the Acute Cystitis Symptom Score (ACSS) was developed as a simple self-reporting questionnaire to improve diagnosis and therapy of women with acute cystitis (AC). The purpose of this work was to validate the ACSS in the German language. MATERIALS AND METHODS: The ACSS consists of 18 questions in four subscales: (1) typical symptoms, (2) differential diagnosis, (3) quality of life, and (4) additional circumstances. Translation of the ACSS into German was performed according to international guidelines. For the validation process 36 German-speaking women (age: 18-90 years), with and without symptoms of AC, were included in the study. Classification of participants into two groups (patients or controls) was based on the presence or absence of typical symptoms and significant bacteriuria (>= 10(3) CFU/ml). Statistical evaluations of reliability, validity, and predictive ability were performed. ROC curve analysis was performed to assess sensitivity and specificity of ACSS and its subscales. The Mann-Whitney's U test and t-test were used to compare the scores of the groups. RESULTS: Of the 36 German-speaking women (age: 40 +/- 19 years), 19 were diagnosed with AC (patient group), while 17 women served as controls. Cronbach's alpha for the German ACSS total scale was 0.87. A threshold score of >= 6 points in category 1 (typical symptoms) significantly predicted AC (sensitivity 94.7%, specificity 82.4%). There were no significant differences in ACSS scores in patients and controls compared to the original Uzbek version of the ACSS. CONCLUSION: The German version of the ACSS showed a high reliability and validity. Therefore, the German version of the ACSS can be reliably used in clinical practice and research for diagnosis and therapeutic monitoring of patients suffering from AC. PMID- 26113303 TI - A perspective on the evolution of germ-cell development and germinal mosaics of deleterious mutations. AB - In many animals a small number of primordial germ cells (PGCs) are set aside early in development, mitosis and mitochondrial DNA syntheses are arrested, transcription is stopped or reduced, and the PGCs migrate later to the emerging gonads and become germ cells. What could be the evolutionary advantage of sequestering non-dividing PGCs early in development? A commonly cited advantage is a reduction in the number of new deleterious mutations that would occur if there were additional divisions in PGCs early in development. We would like to add to this advantage the fact that these additional mutations in PGCs give rise to germinal mosaics (i.e., premeiotic clusters of mutation) in multiple progeny of the same individual, thus having a larger detrimental effect on the evolutionary fitness of their carriers. Here, we reviewed published studies providing evidence that germinal mosaics of deleterious mutant alleles are not rare, occur for all types of genetic damage, and have been observed in all tested organisms and in nature. We propose the hypothesis that PGC sequestration during early animal development may have evolved in part in response to selection for preventing the occurrence of premeiotic clusters of deleterious mutant alleles, and describe a series of predictions that would allow the assessment of the potential role of germinal mosaics on the evolution of PGC sequestration. PMID- 26113304 TI - Emerging drugs for the treatment of bone metastasis. AB - INTRODUCTION: Bone metastases are virtually incurable resulting in significant disease morbidity, reduced quality of life and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Increased understanding of the pathogenesis of bone disease has led to the discovery and clinical utility of bone-targeted agents other than bisphosphonates and denosumab, currently, the standard of care in this setting. AREAS COVERED: In this review, we present the recent advances in molecular targeted therapies focusing on therapies that inhibit bone resorption and/or stimulate bone formation and novel anti-tumoral agents that exerts significant effects on skeletal metastases, nowadays available in clinical practice or in phase of development. EXPERT OPINION: New emergent bone target therapies radium-223, mTOR inhibitors, anti-androgens have demonstrated the ability to increase overall survival in bone metastatic patients, other compounds, such as ET-1 and SRC inhibitors, up to now failed to clearly confirm in clinical trials their promising preclinical data. PMID- 26113305 TI - Orf virus inhibits interferon stimulated gene expression and modulates the JAK/STAT signalling pathway. AB - Interferons (IFNs) play a critical role as a first line of defence against viral infection. Activation of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway by IFNs leads to the production of IFN stimulated genes (ISGs) that block viral replication. The Parapoxvirus, Orf virus (ORFV) induces acute pustular skin lesions of sheep and goats and is transmissible to man. The virus replicates in keratinocytes that are the immune sentinels of skin. We investigated whether or not ORFV could block the expression of ISGs. The human gene GBP1 is stimulated exclusively by type II IFN while MxA is stimulated exclusively in response to type I IFNs. We found that GBP1 and MxA were strongly inhibited in ORFV infected HeLa cells stimulated with IFN-gamma or IFN-alpha respectively. Furthermore we showed that ORFV inhibition of ISG expression was not affected by cells pretreated with adenosine N1-oxide (ANO), a molecule that inhibits poxvirus mRNA translation. This suggested that new viral gene synthesis was not required and that a virion structural protein was involved. We next investigated whether ORFV infection affected STAT1 phosphorylation in IFN-gamma or IFN-alpha treated HeLa cells. We found that ORFV reduced the levels of phosphorylated STAT1 in a dose-dependent manner and was specific for Tyr701 but not Ser727. Treatment of cells with sodium vanadate suggested that a tyrosine phosphatase was responsible for dephosphorylating STAT1 p. ORFV encodes a factor, ORFV057, with homology to the vaccinia virus structural protein VH1 that impairs the JAK/STAT pathway by dephosphorylating STAT1. Our findings show that ORFV has the capability to block ISG expression and modulate the JAK/STAT signalling pathway. PMID- 26113306 TI - Decreased neutralizing antigenicity in IBV S1 protein expressed from mammalian cells. AB - We evaluated the antigenicity of recombinant infectious bronchitis virus (IBV) S1 protein expressed in mammalian cells. Recombinant S1 was expressed as a secreted protein fused with a trimerization motif peptide, then purified using Ni Sepharose. The purified protein was analyzed by Western blotting, mixed with oil adjuvant, and administered to 29-day-old specific-pathogen-free chickens. Six weeks after immunization, anti-IBV neutralizing titer and anti-S1 ELISA titer were determined; immunized chickens then were inoculated with IBV via the trachea and ciliary activity was observed. Results showed that the recombinant S1 protein was highly glycosylated, and the neutralizing antigenicity of recombinant S1 protein was lower than that of inactivated virus. However, anti-S1 ELISA indicated that the recombinant S1 protein induced antibodies against S1. These results suggest that the recombinant S1 may retain non-neutralizing epitopes but have unnatural glycosylation pattern and conformation, resulting in lacking neutralizing conformational epitopes. In conclusion, the neutralizing antigenicity of recombinant S1 protein expressed from mammalian cells was decreased, and was not sufficient to induce neutralizing antibodies. PMID- 26113307 TI - An analysis of original research contributions toward FDA-approved drugs. AB - Academic researchers shaped the landscape of drug discovery for nearly two centuries, and their efforts initiated programs for more than half of the US Food and Drug Administration (FDA)-approved new molecular entities (NMEs). During the first 50 years of the 20th century, contributions from industry-based discovery programs steadily increased, stabilizing near half of all first publications for NMEs. Although academia and industry have made similar contributions to the discovery of FDA-approved NMEs, there remains a substantial difference in the gap to-approval; on average, industry NMEs are 12 years closer to market at the time of the first publication. As more drug discovery efforts shift from industry to academia, including high-throughput screening resources, academia could have an increasingly crucial role in drug discovery. PMID- 26113308 TI - [Body weight and food consumption scores in adolescents from northeast Brazil]. AB - OBJECTIVE: The aim of the present study was to determine the prevalence of excess weight and analyze eating habits in relation to cardiovascular disease in adolescents from the city of Vitoria de Santo Antao, state of Pernambuco, northeast Brazil. METHODS: A cross-sectional study was carried out with male and female students (10-19 years old) enrolled at public and private schools in Vitoria de Santo Antao. Sociodemographic, anthropometric and lifestyle variables were collected. Food consumption was evaluated using a food frequency questionnaire and subsequently converted to monthly intake pattern scores, obtaining the intake distribution for a group of foods associated with the risk of developing cardiovascular disease and for a group of protective foods. The significance level for the statistical tests was set at 5.0%. RESULTS: The sample consisted of 2,866 students. The female gender accounted for 54.2% of the sample, and median age was 14 years (interquartile range: 12 to 16 years). The food intake scores showed greater dispersion in the group of protective foods (51.1%). Higher median scores for consumption of risk foods were found among adolescents whose mothers had more than nine years of schooling (p<0.001). CONCLUSIONS: Excess weight was prevalent among the students analyzed. The consumption of risk foods was only associated with maternal schooling, which shows the need for nutritional interventions directed at families, regardless of socioeconomic status. PMID- 26113309 TI - Protective Effects of Zinc Against Acute Arsenic Toxicity by Regulating Antioxidant Defense System and Cumulative Metallothionein Expression. AB - Arsenic (As), a toxic metalloid, is one of the major global concerns. The toxicity resulting from As exposure is linked to the generation of reactive oxygen intermediates during their redox cycling and metabolic activation processes that cause lipid peroxidation (LPO). Zinc (Zn), a redox-inactive metal, helps to maintain cellular functions because of its prominent role in antioxidant network through multiple mechanisms. The present study, therefore, explores the effectiveness of administered Zn to combat against acute As toxicity by analysis of antioxidant defense status, alkaline phosphatase (ALP) activity, histological profile, MT expression, and elemental status in rat liver. To achieve this goal, four experimental groups, one control and three receiving different metal supplementations, were chosen (group 1, control; group 2, Zn supplemented; group 3, As substituted; group 4, Zn + As supplemented). The levels of reduced glutathione (GSH) and activities of glutathione reductase (GR) and ALP were lowered, whereas LPO levels and activity of superoxide dismutase (SOD) were elevated with no significant change in catalase (CAT) activity. Histopathological changes were also observed in the As substituted group in comparison to the control. Particle-induced X-ray emission (PIXE) analysis showed decrease in Fe and S concentration in rat liver after As intoxication, whereas As was below detection limit, i.e., <1 ppm. Zn administration almost restored the antioxidants, ALP activity, histopathological changes, and elemental status. A cumulative increase in MT expression was found with the combined treatment of Zn and As. Also, Zn alone caused no significant change in the antioxidant defense system. It can be concluded that restoration of antioxidant activity and increased MT expression are the two independent protective mechanisms of Zn to reduce acute As toxicity. PMID- 26113310 TI - The Effect of Exposure to Cd and Pb in the Form of a Drinking Water or Feed on the Accumulation and Distribution of These Metals in the Organs of Growing Wistar Rats. AB - The degree of accumulation and distribution of Cd and Pb in the organs of young animals compared to the amount taken in with water or feed have not been thoroughly investigated yet. The experiment aimed to verify whether the source of toxic metals (feed, drinking water) administered to growing rats orally has an influence on the degree of accumulation of Cd and Pb in the organs (brain, spleen, lungs, heart, liver and kidneys). The rats received Cd and/or Pb respectively in the amount of 7 mg and/or 50 mg per 1 kg of feed or per 1 L of distilled water. The rats' organs accumulated in total about 0.5 % Cd and about 0.71 % Pb consumed with water and about 0.46 % Cd and about 0.63 % Pb taken in with feed. More than 60 % of Cd and more than 70 % of Pb absorbed by the studied organs was accumulated in the liver, and more than 30 % of Cd and 26-29 % of Pb in the kidneys and less than 1 % in other organs. The relationship between the distribution percentage of Cd in the studied organs can be presented as: liver > kidneys > brain > lungs > heart > spleen. The relationship between the distribution percentage of Pb can be presented as: liver > kidneys > brain > spleen > heart > lungs. Significantly (P < 0.05), more Cd and Pb were accumulated in total in the organs of rats receiving the metals in drinking water. PMID- 26113311 TI - Papillary Tumor of the Pineal Region: A Distinct Molecular Entity. AB - Papillary tumor of the pineal region (PTPR) is a neuroepithelial brain tumor, which might pose diagnostic difficulties and recurs often. Little is known about underlying molecular alterations. We therefore investigated chromosomal copy number alterations, DNA methylation patterns and mRNA expression profiles in a series of 24 PTPRs. Losses of chromosome 10 were identified in all 13 PTPRs examined. Losses of chromosomes 3 and 22q (54%) as well as gains of chromosomes 8p (62%) and 12 (46%) were also common. DNA methylation profiling using Illumina 450k arrays reliably distinguished PTPR from ependymomas and pineal parenchymal tumors of intermediate differentiation. PTPR could be divided into two subgroups based on methylation pattern, PTPR group 2 showing higher global methylation and a tendency toward shorter progression-free survival (P = 0.06). Genes overexpressed in PTPR as compared with ependymal tumors included SPDEF, known to be expressed in the rodent subcommissural organ. Notable SPDEF protein expression was encountered in 15/19 PTPRs as compared with only 2/36 ependymal tumors, 2/19 choroid plexus tumors and 0/23 samples of other central nervous system (CNS) tumor entities. In conclusion, PTPRs show typical chromosomal alterations as well as distinct DNA methylation and expression profiles, which might serve as useful diagnostic tools. PMID- 26113312 TI - Smart Probe for Tracing Cancer Therapy: Selective Cancer Cell Detection, Image Guided Ablation, and Prediction of Therapeutic Response In Situ. AB - Integrated diagnosis and therapy systems that can offer traceable cancer therapy are in high demand for personalized medicine. Herein, a pH-responsive polymeric probe containing tetraphenylsilole (TPS) with aggregation-induced emission characteristics and pheophorbide A (PheA) photosensitizer (PS) with aggregation caused quenching property for tracing the whole process of cancer therapy is reported. At physiological conditions (pH 7.4), the probe self-assembles into nanoparticles (NPs), which show weak fluorescence of PheA with low phototoxicity, but strong green fluorescence from TPS for probe self-tracking. Upon uptake by cancer cells and entrapment in lysosomes (pH 5.0), the NPs disassemble to yield weak emission of TPS but strong red fluorescence of PheA with restored phototoxicity for PS activation monitoring. Upon light irradiation, the generated reactive oxygen species can cause lysosomal disruption to trigger cell apoptosis. Meanwhile, the probe leaks to the cytoplasm (pH 7.2), where the TPS fluorescence is restored for in situ visualization of the therapeutic response. The probe design thus represents a novel strategy for traceable cancer therapy. PMID- 26113313 TI - Population pharmacokinetics of infliximab in patients with inflammatory bowel disease: potential implications for dosing in clinical practice. AB - BACKGROUND: Infliximab (IFX) is effective in the treatment of inflammatory bowel diseases (IBD). Currently, IFX is administered at fixed doses and intervals; however, costs are high and optimisation is necessary. Several publications indicate that IFX should be dosed on trough levels >=3.0 mg/L. For optimising IFX dosing, the use of a pharmacokinetic model is important. Population pharmacokinetics of IFX have been described earlier; however, these models were not used for dose optimising. AIMS: To develop a pharmacokinetic model for IFX in IBD patients that can be used for dose-optimisation of IFX and to predict serum trough levels in this population. METHODS: An observational retrospective study was performed in 42 IFX-treated IBD patients. Serum samples were drawn before infusion at T = 0, 2, 6, 14, 22 and 54 weeks and analysed for IFX and antibodies against IFX (ATI). Relevant covariates were recorded and a population pharmacokinetic model was developed. RESULTS: Individual plots created using the final model showed good correspondence between observed and model predicted values. Serum levels were influenced by ATI, disease activity, sex and albumin. Our results show that in patients without ATI target trough levels >=3.0 mg/L can be achieved by increasing dosing intervals from 8 to 12 weeks combined with a dose increase. This results in a reduction of 33% in concomitant costs. CONCLUSIONS: In IBD patients without ATI, trough level dosing based on longer intervals can reduce IFX therapy-related visits to the hospital with one-third. Trough level based dose intensification should always be justified by disease activity parameters. PMID- 26113314 TI - Portal/Superior Mesenteric Vein Reconstruction during Pancreatic Resection Using a Cryopreserved Arterial Homograft. AB - BACKGROUND: Portal-superior mesenteric vein (PV/SMV) resection during pancreatic resection has been widely applied in clinical practice. METHODS: From a prospective data base of pancreatic resections, patients undergoing PV/SMV resection and reconstruction with a cryopreserved arterial homograft were extracted with the aim of evaluating the safety, feasibility and reproducibility of the procedure. Data regarding patient demographics, preoperative staging, surgery, histopathology and postoperative outcomes were analyzed. RESULTS: Five patients were extracted in the last year. Indications for this technique were type IV-V degree of vein involvement and a 3.5 cm median length of vein infiltration. Median operative and clamping times were satisfactory (385 and 27 min, respectively), postoperative outcomes were good and there was no graft infection, thrombosis or stenosis occurred postoperatively and during the follow up period. CONCLUSION: The use of a cryopreserved arterial homograft for PV/SMV reconstruction after pancreatic resection seems to be a feasible, safe and easily reproducible surgical technique in high-volume specialized centers and can be added to the pool of surgical solutions in selected patients. PMID- 26113315 TI - Vascular Calcification Progression Is an Independent Predictor of Mortality in Patients on Haemodialysis. AB - BACKGROUND: We previously reported that vascular calcification (VC) score was associated with mortality in patients on haemodialysis (HD) and that a high serum level of parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23 were the only factors associated with VC progression. AIM: To assess the impact of VC progression on HD patient survival. METHODS: The study cohort including 85 HD patients studied between 2006 and 2007 and between 2009 and 2010 was divided into patients with VC progression (PG+, n = 38) and no-progression (PG-, n = 47), based on VC scores measured twice at 3-year intervals (VC1 and VC2). Patients were followed during 3 additional years. RESULTS: Kaplan-Meier analysis determined that PG+ displayed increased mortality (hazard ratio (HR): 2.4; 95% confidence interval (CI): 1.12-4.8; p = 0.03). This result was confirmed using a Cox proportional hazards model adjusted for age, dialysis duration, the VC1 score, and the mean FGF-23 and iPTH serum levels (HR: 2.7; 95% CI: 1.12-6.6; p = 0.02). CONCLUSION: VC progression is associated with poor survival in patients on HD, irrespective of a patient's baseline VC score. PMID- 26113316 TI - Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation. AB - Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated-donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft-versus-tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT. PMID- 26113317 TI - Current incidence of clinical kernicterus in preterm infants in Japan. AB - Clinical kernicterus in preterm infants has recently been reported in Japan, diagnosed on the basis of clinical findings during the neonatal and infancy periods. We investigated the incidence of clinical kernicterus in preterm infants <30 weeks gestational age (GA) based on a nationwide survey conducted in 233 certified educational facilities for neonatologists. The numbers of infants admitted and infants who died within 14 days after birth during 2011, and the number of infants who subsequently developed clinical kernicterus, were recorded. A total of 2720 infants were analyzed, representing 59% (2720/4623) of all preterm live births <30 weeks GA in Japan in 2011. Of these, 159 (5.8%) died within 14 days after birth, similar to the national rate. Five infants developed clinical kernicterus in infancy (5/2720, 0.18%). The current incidence of clinical kernicterus in Japan is therefore estimated at 1.8 per 1000 live births <30 weeks GA. PMID- 26113318 TI - Management of intestinal bleeding with single-dose cyclophosphamide in Henoch Schonlein purpura. AB - In these case series, we report on six children (3 girls, 3 boys) aged 5-13 years with Henoch-Schonlein purpura (HSP) who developed severe gastrointestinal (GI) bleeding resistant to both 2 mg/kg or pulse (10-30 mg/kg) i.v. methylprednisolone. All patients responded to single-dose (500 mg/m(2) ) i.v. cyclophosphamide (CPA) and none of them developed new GI bleeding after CPA treatment. No patients required surgical intervention. Single high-dose CPA may be beneficial in HSP with severe GI involvement, in which bleeding is non responsive to high-dose steroids. PMID- 26113319 TI - Cat-scratch disease with severe pleuritis in a 6-year-old girl. AB - We present the case of a 6-year-old girl with cat-scratch disease (CSD), who developed severe pleuritis without lymphadenitis. Bartonella henselae DNA was detected on real-time polymerase chain reaction (PCR) analysis of whole blood. This is the first report of CSD diagnosed on real-time PCR using whole blood. PMID- 26113320 TI - Pyoderma gangrenosum with systemic and pulmonary involvement in a toddler. PMID- 26113321 TI - Painless lumps in the proximal interphalangeal joints in tricho-rhino-phalangeal syndrome type 1. PMID- 26113322 TI - Racial differences of the tricuspid annular plane systolic excursion: Reply. PMID- 26113323 TI - Macroscopic hematuria caused by congenital portosystemic shunt and concomitant nutcracker syndrome. AB - Nutcracker syndrome (NCS) is an uncommon vascular abnormality that causes a variety of symptoms that range from asymptomatic microscopic hematuria to severe pelvic congestion. Congenital portosystemic shunt (CPSS) is an extremely rare anomaly that causes serious complications. Many cases of NCS and CPSS that have presented separately have been reported, but no cases of concomitant NCS and CPSS have been reported. We present a case of intermittent macroscopic hematuria in a patient with both NCS and CPSS. We diagnosed NCS on pressure gradient between the left renal vein (LRV) and the inferior vena cava. The presence of CPSS, which emerged from the LRV and connected to the extrahepatic portal vein, was confirmed on computed tomography. The interaction between NCS and CPSS resulted in mild intermittent macroscopic hematuria only, rather than the more common symptoms that occur when NCS or CPSS present separately. PMID- 26113324 TI - Chloroplast Biogenesis. PMID- 26113325 TI - BVA President celebrates creativity and innovation in Wales. PMID- 26113326 TI - Advanced Practitioner applications open for 2015. PMID- 26113327 TI - Referral practices express concern about potential restrictions on choice. PMID- 26113328 TI - Getting veterinary history 'out of the cupboards'. PMID- 26113329 TI - RCVS seeks views on revised Day 1 skills for veterinary nurses. PMID- 26113330 TI - FDA introduces 'final rule' on use of antibiotics in feed. PMID- 26113331 TI - Longer hours trialled for professional standards advice line. PMID- 26113332 TI - Advert highlights dangers of leaving dogs in hot cars. PMID- 26113333 TI - Pig disease charter launched. PMID- 26113334 TI - Cat videos leave viewers feline fine. PMID- 26113335 TI - Women in veterinary leadership. PMID- 26113336 TI - What is the true risk of imported dogs to the UK? PMID- 26113337 TI - Cross-border transport of rescue dogs may spread rabies in Europe. AB - Harmonisation of regulations in the European Union and the European Economic Area, as of January 1, 2012, has led to an increase in the number of rescue dogs imported to Norway from Eastern European countries, in particular Romania. Today the only requirements for dogs entering Norway are rabies vaccination and prophylactic Echinococcus multilocularis treatment. The aim of this study was to investigate the antibody levels to rabies virus in vaccinated rescue dogs and to examine if the dogs had sufficient antibody response according to the recommended titre >=0.5 IU/ml by the World Organisation for Animal Health (OIE). A significant proportion (53%, 95% CI (41% to 65%)) of imported rescue dogs from Eastern Europe were found to have inadequate titres after rabies vaccination. Moreover, 41 per cent of the dogs had antibody levels below or equal to 0.2 IU/ml, and among these, 14 dogs had titres <=0.1 IU/ml, which is considered negative in the fluorescent antibody virus neutralisation assay. This study indicates that the present regulation increases the risk of introducing rabies from member states where rabies is still prevalent to countries considered free from rabies. PMID- 26113338 TI - Towards a scholarship of primary health care. PMID- 26113339 TI - Ethical work climates in veterinary practices. PMID- 26113343 TI - Ensuring animal welfare is at the heart of research. PMID- 26113344 TI - Diary of a parliamentary intern. PMID- 26113347 TI - Susceptibility to antimicrobials of mastitis-causing Staphylococcus aureus, Streptococcus uberis and Str. dysgalactiae from New Zealand and the USA as assessed by the disk diffusion test. AB - OBJECTIVE: To compare the antimicrobial susceptibility patterns of three common mastitis pathogens (Staphylococcus aureus, Streptococcus uberis and Str. dysgalactiae) isolated from milk samples from New Zealand and the USA. METHODS: A total of 182 S. aureus, 126 Str. uberis and 89 Str. dysgalactiae isolates from New Zealand (107, 106 and 41, respectively) and the USA (75, 20 and 48, respectively) were assessed using the disk diffusion test. RESULTS: Susceptibility varied among the bacterial species. All isolates were susceptible to the amoxicillin-clavulanic acid combination. Resistance to lincomycin was most frequent (susceptibility of 8.6%) across all species. Non-susceptible (i.e. resistant or intermediate) isolates of S. aureus were identified for the three non-isoxazolyl penicillins (amoxicillin, ampicillin and penicillin: 20.6% and 36.0%) and lincomycin (99.9% and 94.6%) for NZ and the USA, respectively. Resistance to erythromycin (5.3%) and tetracyclines (6.7%) was detected only in isolates from the USA. There were differences in susceptibility between Str. uberis and Str. dysgalactiae; all streptococcal isolates demonstrated resistance to aminoglycosides (neomycin 52.4% and streptomycin 27.9%) and enrofloxacin (28%). Resistance of Str. dysgalactiae to tetracycline was almost 100.0% and to oxytetracycline 89.9%. CONCLUSION AND CLINICAL RELEVANCE: Most of the isolates tested were susceptible to most of the antimicrobials commonly used for treatment of bovine mastitis, with the exception of the lincosamides. Susceptibility to a selected class-representative antimicrobial and at the genus level should be interpreted with caution. Differences between NZ and the USA confirm the value of national surveys to determine the susceptibility patterns of mastitis pathogens. PMID- 26113348 TI - Surgical and postoperative events during permanent fistulation of sheep rumen by the Schalk and Amadon method. AB - OBJECTIVE: To describe and report on the course of events during and after surgical fistulation of sheep rumen by the Schalk and Amadon method and on improvements to address current trends in animal health, care and welfare. METHODS: A permanent re-entry fistula was created in 13 sheep using a method in which a fold of rumen is exteriorised and held by a metal clamp. Following surgery, sheep were monitored daily for any abnormalities for 4 weeks, then weekly for 6 months. RESULTS: Permanent fistulation was achieved in all 13 sheep; 2 sheep had minor complications: one during the surgery (rumen perforation) and one on the day after surgery (slipping of the metal clamp), but both recovered within 48 h with treatment. Over the 4 weeks post-surgery, 7 sheep had mildly elevated rectal temperatures, which resolved with non-steroidal anti-inflammatory drugs, systemic antibiotics and/or topical antiseptic cream. There was an 8-day variation among sheep in the time from surgery to creation of the fistula. CONCLUSION: Rumen fistulation of sheep by the Schalk and Amadon method, as described here, is a comparatively simple, safe and ethical procedure, with minimal effect on or complications for the animal. PMID- 26113349 TI - In vivo characterisation of two Australian isolates of Marek's disease virus including pathology, viral load and neuropathotyping based on clinical signs. AB - OBJECTIVE: To evaluate the pathogenicity of Australian Marek's disease virus (MDV) isolate MPF23 (1985) against the reference strain MPF57 based on pathology, viral load and neuropathotyping on the basis of clinical signs. PROCEDURE: Two MDV challenge isolates (MPF57 or MPF23) were administered to unvaccinated specific-pathogen free (SPF) layer chicks on day 5 after hatch at three challenge doses (500, 2000 or 8000 plaque-forming units (pfu)/chick). Mortality, body weight, immune organ weights, MDV load in peripheral blood lymphocytes (PBL) and clinical signs were measured to 56 days post challenge (dpc). RESULTS: MPF23 was the more pathogenic of the two viruses, inducing higher mortality (81% vs 62%) and incidence of MD lesions (100% vs 76%). MPF23 induced earlier, more sustained and more severe neurological signs in the period 26-56 dpc. However, there were few differences during the 0-23 dpc used in the neuropathotyping classification under test. The observed pattern during this earlier period classified both viruses as neuropathotype B, consistent with a very virulent pathotype. MDV load in PBL at 7 and 44 dpc did not differ between virus isolates, but the load at 7 dpc was significantly and negatively associated with time to euthanasia or death. CONCLUSION: MPF23 appears to be as, or more, virulent than the MDV strains isolated over the subsequent two decades. The neuropathotyping system developed in the USA did not clearly differentiate between the two isolates under test; however, extension of the period of assessment of clinical signs beyond 26 dpc did reveal clear differences. PMID- 26113350 TI - Cutaneous and systemic mycoses from infection with Lecanicillium spp. in captive Guthega skinks (Liopholis guthega). AB - BACKGROUND: Guthega skinks have been listed as critically endangered and are considered particularly vulnerable to extinction because of their isolation and restricted distribution. There is no information on their captive husbandry, or the diseases that affect them. CASE REPORT: Cutaneous and systemic mycosis from infection with Lecanicillium spp. was diagnosed in a captive colony of Guthega skinks (Liopholis guthega). Infection resulted in the death of five lizards. Diagnosis of infection was confirmed using a combination of histopathology, fungal culture and DNA sequencing from all affected animals. An additional four similarly affected individuals were successfully treated with a combination of voriconazole (10 mg/kg PO once daily) and shallow baths of benzalkonium chloride and polyhexamethylene biguanide hydrochloride (F10) (1 : 250, 20 min once daily). This is the first report of Lecanicillium spp. infection in reptiles. PMID- 26113351 TI - Concurrent idiopathic vestibular syndrome and facial nerve paralysis in a cat. AB - CASE REPORT: A 4-year-old male neutered Domestic Medium-hair cat was referred for right head tilt and ataxia of 2 weeks duration. On examination it was determined that the cat had right facial nerve paralysis and peripheral vestibular signs. Haematology and serum biochemical testing were performed in addition to magnetic resonance imaging of the brain and ears, and cerebrospinal fluid analysis. An underlying condition was not identified. A diagnosis of idiopathic vestibular syndrome and concurrent idiopathic right facial nerve paralysis was consequently made. The cat was re-evaluated over the following weeks and was determined to have complete resolution of clinical signs within 7 weeks. CONCLUSION: Vestibular dysfunction and concurrent facial nerve paralysis have previously been reported in the cat, but not of an idiopathic nature. PMID- 26113352 TI - Suspected intramedullary bone infarct subsequent to tibial plateau levelling osteotomy in a dog. AB - BACKGROUND: Bone infarction is a syndrome associated with disruption to the medullary blood supply of a long bone and may present as either a cause of lameness or, more commonly, an incidental finding. Bone infarction is a known complication of total hip replacement in the dog and may be associated with several other systemic diseases. CASE REPORT: A 3-year-old female desexed Labrador Retriever presented for acute lameness 4 weeks following tibial plateau levelling osteotomy (TPLO). Subsequent radiographs revealed an increase in medullary bone opacity, radiographically consistent with a medullary bone infarction. The lesion was followed with serial radiographs and appeared to spontaneously resolve. CONCLUSION: This is the first reported case of bone infarction following TPLO in the dog. Bone infarction should be considered as an unlikely but potential complication of TPLO. PMID- 26113353 TI - Serological evidence of Neospora caninum in alpacas from eastern Australia. AB - BACKGROUND: The aim of this study was to investigate if there was any serological evidence of Neospora caninum in alpaca populations in south-eastern Australia. METHODS AND RESULTS: Serum samples from 100 alpacas were collected from four farms. All serum samples were screened for N. caninum antibodies using a commercially available competitive ELISA. Of the 100 alpacas sampled, 3 were suspect seropositive for N. caninum. CONCLUSION: There is natural N. caninum seroprevalence in alpacas in south-eastern Australia; however, it remains undetermined whether or not this infection is currently contributing to reproductive failure in alpacas in Australia. PMID- 26113354 TI - How do we know when an animal is happy? PMID- 26113355 TI - Using free flaps for reconstruction during infections by mucormycosis: A case report and a structured review of the literature. AB - BACKGROUND: Mucormycosis is a very rare infection caused by fungi from the order Mucorales, it rarely involves the skin. We report a case of necrotizing fasciitis of the upper limb which required an aggressive surgical debridement, antifungal therapy and coverage of the defect with a free DIEP flap, a review of the literature was also done regarding indications of reconstruction with free flaps. CASE PRESENTATION: Here we present a case of cutaneous mucormycosis of the right upper limb in a 49-year-old immunocompetent woman after having an open fracture associated with massive contamination during a motor vehicle collision. In early postoperative period, she had multiple skin necrotic lesions. Serial surgical debridements were performed and ended up with interscapular-thoracic amputation associated with a total mastectomy. Following diagnosis confirmation of mucormycosis infection, the patient was started on antifungal therapy for several months. After disease control, the large defect was successfully covered by a DIEP flap. CONCLUSION: Cutaneous mucormycosis requires antifungal therapy along with aggressive debridement, reconstruction by a free flap seems to be a good solution to cover these large defects. PMID- 26113356 TI - Invasive therapies for primary postpartum haemorrhage: a population-based study in France. AB - OBJECTIVE: To describe the characteristics, management, and outcomes of women undergoing invasive therapies for primary postpartum haemorrhage (PPH). DESIGN: A population-based observational study. SETTING: All 106 maternity units of six French regions. POPULATION: A total of 146 781 women delivering between 2004 and 2006. METHODS: Prospective identification of women with PPH managed with invasive therapies, including uterine suture, pelvic vessel ligation, arterial embolisation, and hysterectomy. MAIN OUTCOME MEASURES: Rate of use and failure rate of invasive therapies, with 95% confidence intervals (95% CIs). RESULTS: An invasive therapy was used in 296 of 6660 women with PPH (4.4%, 95% CI 4.0-5.0), and in 0.2% of deliveries (95% CI 0.18-0.23). A hysterectomy was performed in 72/6660 women with PPH (1.1%, 95% CI 0.8-1.4%), and in 0.05% of deliveries (95% CI 0.04-0.06). A conservative invasive therapy was used in 262 women, including 183 (70%) who underwent arterial embolisation and 79 (30%) who had conservative surgery as the first-line therapy. Embolisation was more frequently used after vaginal than caesarean delivery, and when arterial embolisation was available on site. The failure rate of conservative invasive therapies was 41/262 (15.6%, 95% CI 11.5-20.6) overall, and was higher after surgical than after embolisation procedures, in particular for vaginal deliveries. CONCLUSIONS: Both maternal mortality as a result of obstetric haemorrhage and the rate of invasive therapies used for PPH are high in France. These findings suggest flaws in the initial management of PPH and/or the inadequate use of invasive procedures. TWEETABLE ABSTRACT: Maternal mortality as a result of haemorrhage and the rate of invasive therapies used for PPH are high in France. PMID- 26113358 TI - Ro/SSA autoantibody-positive pregnancy: reactions to serial fetal Doppler echocardiographic surveillance. AB - OBJECTIVE: The risk for congenital heart block (CHB) associated with maternal Ro/SSA autoantibodies is low, but the possibility of treating early stages of disease has seen the introduction of Doppler echocardiographic surveillance programs with serial examinations during the CHB susceptibility weeks of pregnancy. The aim of the present study was to understand how Ro/SSA autoantibody positive women having undergone Doppler echocardiographic surveillance programs and giving birth to children without CHB experienced their pregnancy and frequent ultrasound examinations. METHODS: A validated questionnaire based on data from an interview-study was distributed to Ro/SSA-positive women supervised with Doppler examinations during their pregnancy (n = 100). RESULTS: The response rate was 79%. The majority of the women (61%) reported that the increased number of ultrasound examinations influenced their pregnancy, but in a positive way, with qualified information and additional support from health care personnel in conjunction with the examinations. Further, the visits to the clinic provided opportunities to see the ultrasound picture of the expected infant. However, one third of the women also reported stress in relation to the examinations. CONCLUSIONS: Fetal echocardiographic surveillance holds many and predominantly positive effects for Ro/SSA-positive women during pregnancy in addition to the medical advantages. PMID- 26113357 TI - Surgery induced hypopituitarism in acromegalic patients: a systematic review and meta-analysis of the results. AB - PURPOSE: Hypopituitarism is a possible complication of the surgical treatment of acromegaly. However, there is a wide variability in the incidence rates of surgery-induced hypopituitarism. The purpose of this study was the systematic collection and synthesis of information on the incidence rates of hypopituitarism, panhypopituitarism, specific axis deficiencies and diabetes insipidus after surgery for acromegaly treatment. METHODS: We systematically reviewed all the papers that have reported pituitary deficits after surgery for acromegaly published up until December 2014, in the PubMed database. We identified 92 studies enrolling 6988 patients. A meta-analysis was performed to evaluate the incidence rates. We also performed several subgroup analyses to evaluate the impact of both surgical technique, and treatment prior to surgery, on the results. RESULTS: The weighted incidence rates were 12.79 % for hypopituitarism (95 % CI 9.88-16.00 %), 2.50 % for panhypopituitarism (95 % CI 1.24-4.15 %), 6.50 % for ACTH deficiency (95 % CI 4.07-9.44 %), 4.39 % for TSH deficiency (95 % CI 2.99-6.04 %), 6.70 % for FSH/LH deficiency (95 % CI 3.89 10.17 %), 14.95 % for GH deficiency (95 % CI 7.25-24.64 %), 10.05 % for transient (95 % CI 7.18-13.33 %) and 2.42 % for permanent diabetes insipidus (95 % CI 1.70 3.27 %). CONCLUSION: Our study provides new data on the incidence rates of hypopituitarism, specific pituitary axis deficiencies and diabetes insipidus after surgical treatment of acromegaly. Somatotroph function appears to be more prone to deficit than the other axes. However, there is a high heterogeneity between studies and several factors may influence the incidence of hypopituitarism. PMID- 26113359 TI - Borderline tuberculoid leprosy in childhood onset systemic lupus erythematosus patient. AB - Leprosy is a contagious and chronic systemic granulomatous disease caused by the bacillus Mycobacterium leprae. To our knowledge, no case of leprosy in a childhood-onset systemic lupus erythematosus (c-SLE) patient has been reported. For a period of 31 years, 312 c-SLE patients were followed at the Pediatric Rheumatology Unit of our University Hospital. One of them (0.3%) had tuberculoid leprosy skin lesions during the disease course and is here reported. A 10-year old boy from Northwest of Brazil was diagnosed with c-SLE based on malar rash, photosensitivity, oral ulcers, lymphopenia, proteinuria, positive antinuclear antibodies, anti-double-stranded DNA, anti-Sm and anti-Ro/SSA autoantibodies. He was treated with prednisone, hydroxychloroquine and intravenous cyclophosphamide, followed by mycophenolate mofetil. At 12-years-old, he presented asymmetric skin lesions characterized by erythematous plaques with elevated external borders and hypochromic center with sensory loss. Peripheral nerve involvement was not evidenced. No history of familial cases of leprosy was reported, although the region where the patient resides is considered to be endemic for leprosy. Skin biopsy revealed a well-defined tuberculoid form. A marked thickening of nerves was observed, often destroyed by granulomas, without evidence of Mycobacterium leprae bacilli. At that time, the SLEDAI-2K score was 4 and he had been receiving prednisone 15 mg/day, hydroxychloroquine 200 mg/day and mycophenolate mofetil 3 g/day. Paucibacillary treatment for leprosy with dapsone and rifampicine was also introduced. In conclusion, we have reported a rare case of leprosy in the course of c-SLE. Leprosy should always be considered in children and adolescents with lupus who present skin abnormalities, particularly with hypoesthesic or anesthesic cutaneous lesions. PMID- 26113360 TI - Alternations of salivary antioxidant enzymes in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic systemic inflammation. Oxidative stress may play a role in the pathogenesis of SLE. An increase in free radicals or an impaired antioxidant defense system in SLE causes oxidative stress. Therefore, oxidative damage plays an important role in the pathogenesis of SLE. Variations in antioxidant activity have been previously studied in serum of patients with this disease. However, salivary factors have not been evaluated. Considering that saliva, the noninvasive biological fluid, could be a reflection of the state of health, the purpose of this study was evaluation of peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT) activity in the saliva of patients with SLE. During the course of the practical part of the project, 30 patients with SLE and 30 healthy controls were selected to donate their saliva samples. After centrifugation of un-stimulated saliva, biological activity of POD, CAT and SOD were evaluated on their appropriate substrates using spectrophotometric methods and the results were statistically analyzed. The results showed that activities of antioxidant enzymes SOD and CAT were significantly reduced in saliva of SLE patients as compared to controls. The results suggest that antioxidant status was impaired in the saliva of SLE patients, and antioxidant status of saliva could be one of the non-invasive markers for SLE. PMID- 26113361 TI - Autoimmune thyroid disease in a cohort of Malaysian SLE patients: frequency, clinical and immunological associations. AB - Autoimmune thyroid disease (ATD) has been associated with other systemic autoimmune diseases. To date, there is limited data on thyroid disorders and autoimmune thyroid disease in Malaysia. The frequency of ATD among 189 systemic lupus erythematosus (SLE) patients was 6.3%, with 2.6% in the hyperthyroid group and 3.7% in the hypothyroid group. Hypothyroidism developed at a much younger mean age (24.3 years), suggesting that SLE might be a predisposing factor for the development of Hashimoto's thyroiditis. There was a higher rate of thyroid peroxidase antibody (TPO) positivity compared with anti-thyroglobulin antibody (Tg) in the hyperthyroid subgroup. This study also demonstrated a greater proportion of ATD patients who demonstrated high titres (>= 1:6400) of TPO compared with high titres of Tg. Although there was an association between ATD and the presence of anti-Ro/SSA and/or anti-La/SSB antibodies, the absence of sicca symptoms and negative Schirmer's tests suggest a lack of association with secondary Sjogren's syndrome. A novel association between ATD and antiphospholipid syndrome (APS) was detected in our cohort. Hence we propose that patients affected by APS be routinely screened for ATD. PMID- 26113362 TI - Osteoporosis imaging: effects of bone preservation on MDCT-based trabecular bone microstructure parameters and finite element models. AB - BACKGROUND: Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength due to a reduction of bone mass and deterioration of bone microstructure predisposing an individual to an increased risk of fracture. Trabecular bone microstructure analysis and finite element models (FEM) have shown to improve the prediction of bone strength beyond bone mineral density (BMD) measurements. These computational methods have been developed and validated in specimens preserved in formalin solution or by freezing. However, little is known about the effects of preservation on trabecular bone microstructure and FEM. The purpose of this observational study was to investigate the effects of preservation on trabecular bone microstructure and FEM in human vertebrae. METHODS: Four thoracic vertebrae were harvested from each of three fresh human cadavers (n=12). Multi-detector computed tomography (MDCT) images were obtained at baseline, 3 and 6 month follow-up. In the intervals between MDCT imaging, two vertebrae from each donor were formalin-fixed and frozen, respectively. BMD, trabecular bone microstructure parameters (histomorphometry and fractal dimension), and FEM-based apparent compressive modulus (ACM) were determined in the MDCT images and validated by mechanical testing to failure of the vertebrae after 6 months. RESULTS: Changes of BMD, trabecular bone microstructure parameters, and FEM-based ACM in formalin-fixed and frozen vertebrae over 6 months ranged between 1.0-5.6% and 1.3-6.1%, respectively, and were not statistically significant (p>0.05). BMD, trabecular bone microstructure parameters, and FEM-based ACM as assessed at baseline, 3 and 6 month follow-up correlated significantly with mechanically determined failure load (r=0.89-0.99; p<0.05). The correlation coefficients r were not significantly different for the two preservation methods (p>0.05). CONCLUSIONS: Formalin fixation and freezing up to six months showed no significant effects on trabecular bone microstructure and FEM-based ACM in human vertebrae and may both be used in corresponding in-vitro experiments in the context of osteoporosis. PMID- 26113363 TI - Erythropoietin therapy after allogeneic hematopoietic cell transplantation has no impact on long-term survival. PMID- 26113364 TI - Transcriptional slippage in the positive-sense RNA virus family Potyviridae. AB - The family Potyviridae encompasses ~30% of plant viruses and is responsible for significant economic losses worldwide. Recently, a small overlapping coding sequence, termed pipo, was found to be conserved in the genomes of all potyvirids. PIPO is expressed as part of a frameshift protein, P3N-PIPO, which is essential for virus cell-to-cell movement. However, the frameshift expression mechanism has hitherto remained unknown. Here, we demonstrate that transcriptional slippage, specific to the viral RNA polymerase, results in a population of transcripts with an additional "A" inserted within a highly conserved GAAAAAA sequence, thus enabling expression of P3N-PIPO. The slippage efficiency is ~2% in Turnip mosaic virus and slippage is inhibited by mutations in the GAAAAAA sequence. While utilization of transcriptional slippage is well known in negative-sense RNA viruses such as Ebola, mumps and measles, to our knowledge this is the first report of its widespread utilization for gene expression in positive-sense RNA viruses. PMID- 26113365 TI - Deficiency in mTORC1-controlled C/EBPbeta-mRNA translation improves metabolic health in mice. AB - The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of physiological adaptations in response to changes in nutrient supply. Major downstream targets of mTORC1 signalling are the mRNA translation regulators p70 ribosomal protein S6 kinase 1 (S6K1p70) and the 4E-binding proteins (4E-BPs). However, little is known about vertebrate mRNAs that are specifically controlled by mTORC1 signalling and are engaged in regulating mTORC1-associated physiology. Here, we show that translation of the CCAAT/enhancer binding protein beta (C/EBPbeta) mRNA into the C/EBPbeta-LIP isoform is suppressed in response to mTORC1 inhibition either through pharmacological treatment or through calorie restriction. Our data indicate that the function of 4E-BPs is required for suppression of LIP. Intriguingly, mice lacking the cis-regulatory upstream open reading frame (uORF) in the C/EBPbeta-mRNA, which is required for mTORC1 stimulated translation into C/EBPbeta-LIP, display an improved metabolic phenotype with features also found under calorie restriction. Thus, our data suggest that translational adjustment of C/EBPbeta-isoform expression is one of the key processes that direct metabolic adaptation in response to changes in mTORC1 activity. PMID- 26113367 TI - Reduced C/EBPbeta-LIP translation improves metabolic health. PMID- 26113368 TI - Thickness-dependent phase boundary in Sm-doped BiFeO3 piezoelectric thin films on Pt/Ti/SiO2/Si substrates. AB - Sm-doped BiFeO3 thin films were fabricated on platinized silicon substrates via a sol-gel method. Sm contents and thicknesses were varied in a wide range to investigate their effects on the phase structure and piezoelectricity. X-ray diffraction and Raman spectroscopy experiments revealed a rhombohedral to orthorhombic phase transition and the co-existence of both phases in a certain compositional vicinity. It is found that the proportion of a rhombohedral phase increased with film thickness at the compositions corresponding to the phase transition boundary, indicating the influence of the film thickness on the phase structure. The phase transition phenomenon and film thickness effect on the boundary were also studied by piezoresponse force microscopy. Based on the structure analysis and piezoelectric characterization results, a phase diagram of thickness versus composition was proposed, in which the morphotropic phase boundary was located at 9% to 11% in thinner Sm-doped films and shifted towards the Sm-rich side with increasing thickness. PMID- 26113366 TI - Parasite-induced ER stress response in hepatocytes facilitates Plasmodium liver stage infection. AB - Upon infection of a mammalian host, Plasmodium parasites first replicate inside hepatocytes, generating thousands of new parasites. Although Plasmodium intra hepatic development represents a substantial metabolic challenge to the host hepatocyte, how infected cells respond to and integrate this stress remains poorly understood. Here, we present proteomic and transcriptomic analyses, revealing that the endoplasmic reticulum (ER)-resident unfolded protein response (UPR) is activated in host hepatocytes upon Plasmodium berghei infection. The expression of XBP1s--the active form of the UPR mediator XBP1--and the liver specific UPR mediator CREBH is induced by P. berghei infection in vivo. Furthermore, this UPR induction increases parasite liver burden. Altogether, our data suggest that ER stress is a central feature of P. berghei intra-hepatic development, contributing to the success of infection. PMID- 26113369 TI - The Emergency Medicine Debate on tPA for Stroke: What Is Best for Our Patients? Efficacy in the First Three Hours. PMID- 26113371 TI - Adaptive Landscapes of Resistance Genes Change as Antibiotic Concentrations Change. AB - Most studies on the evolution of antibiotic resistance are focused on selection for resistance at lethal antibiotic concentrations, which has allowed the detection of mutant strains that show strong phenotypic traits. However, solely focusing on lethal concentrations of antibiotics narrowly limits our perspective of antibiotic resistance evolution. New high-resolution competition assays have shown that resistant bacteria are selected at relatively low concentrations of antibiotics. This finding is important because sublethal concentrations of antibiotics are found widely in patients undergoing antibiotic therapies, and in nonmedical conditions such as wastewater treatment plants, and food and water used in agriculture and farming. To understand the impacts of sublethal concentrations on selection, we measured 30 adaptive landscapes for a set of TEM beta-lactamases containing all combinations of the four amino acid substitutions that exist in TEM-50 for 15 beta-lactam antibiotics at multiple concentrations. We found that there are many evolutionary pathways within this collection of landscapes that lead to nearly every TEM-genotype that we studied. While it is known that the pathways change depending on the type of beta-lactam, this study demonstrates that the landscapes including fitness optima also change dramatically as the concentrations of antibiotics change. Based on these results we conclude that the presence of multiple concentrations of beta-lactams in an environment result in many different adaptive landscapes through which pathways to nearly every genotype are available. Ultimately this may increase the diversity of genotypes in microbial populations. PMID- 26113370 TI - Enzyme assays for synthesis and degradation of 2-5As and other 2'-5' oligonucleotides. AB - BACKGROUND: The 5'-triphosphorylated, 2'-5'-linked oligoadenylate polyribonucleotides (2-5As) are central to the interferon-induced antiviral 2-5A system. The 2-5As bind and activate the RNase L, an endoRNase degrading viral and cellular RNA leading to inhibition of viral replication. The 2-5A system is tightly controlled by synthesis and degradation of 2-5As. Whereas synthesis is mediated by the 2'-5' oligoadenylate synthetase family of enzymes, degradation seems to be orchestrated by multiple enzyme nucleases including phosphodiesterase 12, the ectonucleotide pyrophosphatase/phosphodiesterase 1 and the A-kinase anchoring protein 7. RESULTS: Here we present assay tools for identification and characterization of the enzymes regulating cellular 2-5A levels. A procedure is described for the production of 2'-5' oligoadenylates, which are then used as substrates for development and demonstration of enzyme assays measuring synthetase and nuclease activities, respectively. The synthetase assays produce only a single reaction product allowing for very precise kinetic assessment of the enzymes. We present an assay using dATP and the A(pA)3 tetramer core as substrates, which requires prior isolation of A(pA)3. A synthetase assay using either of the dNTPs individually together with NAD(+) as substrates is also presented. The nuclease reactions make use of the isolated 2'-5' oligoadenylates in producing a mixture of shorter reaction products, which are resolved by ion exchange chromatography to determine the enzyme activities. A purified human 2' 5' oligoadenylate synthetase and a purified human phosphodiesterase 12 along with crude extracts expressing those proteins, are used to demonstrate the assays. CONCLUSIONS: This paper comprises an assay toolbox for identification and characterization of the synthetases and nucleases regulating cellular 2-5A levels. Assays are presented for both enzyme families. The assays can also be used to address a broader cellular role of the OAS enzymes, based on the multiple substrate specificity intrinsic to these proteins. PMID- 26113372 TI - Shifting hepatitis B virus genotypes of acute hepatitis B patients in northeast Japan. AB - It has been reported that acute hepatitis B (AHB) patients with genotype A HBV (HBV/A) have been increasing since the 1990s in metropolitan areas in Japan. However, little is known about the trends of HBV genotypes in AHB patients in northeast Japan where genotype B HBV (HBV/B) prevails more than in other areas. In this study, we aimed to clarify the changes in the HBV genotypes and clinical characteristics of AHB patients in this area. HBV genotypes were determined by direct sequencing (n = 125) or enzyme immunoassay (n = 9) using serum samples from AHB patients including fulminant hepatitis in 1987-2014. Among 134 patients, 26 (19%), 33 (25%), and 75 (56%) patients were infected with HBV of genotypes A, B, and C, respectively. HBV/A emerged from 2001 and the percentage was increased gradually up to 48% in 2010-2014, whereas HBV/B was reduced from 40% in 1987-1994 to 10% in 2010-2014. Phylogenetic analysis showed that three major subgenotype A2 strains had come into this area serially. The levels of HBV DNA and prothrombin time were higher in HBV/A patients than other genotypes. This study could not show significant difference in the HBsAg-positive period among genotypes nor the effect of nucleoside analogues to shorten the HBsAg-positive period. A higher level of initial HBV DNA was associated with late disappearance of HBsAg. In conclusion, the percentage of HBV/A in AHB patients has been increasing in northeast Japan since 2001, which is later than metropolitan areas, whereas that of HBV/B is decreasing. PMID- 26113373 TI - Characterization of Cytomegalovirus Breakthrough Events in a Phase 2 Prophylaxis Trial of Letermovir (AIC246, MK 8228). AB - BACKGROUND: The efficacy of different letermovir (AIC246, MK8228) doses (60, 120, and 240 mg/day) against human cytomegalovirus (HCMV) was evaluated in a recent phase 2b dose-range-finding prophylaxis study in stem-cell transplant recipients. Here we report the genotypic and phenotypic characterization of 15 viral breakthroughs considered to be virological failures. METHODS: Direct sequencing of an HCMV open reading frame UL56 region that included amino acids 230-370 and thus encompassed all known letermovir resistance mutations was followed by marker transfer experiments to assess the impact of the identified sequence polymorphisms on viral fitness and susceptibility to letermovir. RESULTS: UL56 genotyping was successful for 12 of 15 patients. Six amino acid substitutions were detected in 5 patients. In 1 subject from the 60-mg-dose group, the known letermovir resistance mutation V236M was identified subsequent to a wild-type viremic episode. The remaining 5 sequence variants (L134V, S227I, Q228H, R410G, and D414N) were shown to be inert with regard to letermovir susceptibility, thus representing natural polymorphisms. CONCLUSIONS: Our findings represent the first case of a letermovir resistance mutation emerging in the clinic, apparently because of a suboptimal prophylactic dose (60 mg/day). This is in agreement with the trial's efficacy analyses, findings of which suggest that letermovir doses of 60 mg/day and 120 mg/day are suboptimal for prophylaxis whereas a dose of 240 mg/day appears to achieve complete suppression of viremia. PMID- 26113374 TI - Cerebral Palsy and Polymorphism of the Chemokine CCL18 in Very Preterm Children. AB - BACKGROUND: Prematurity and hereditary factors predispose to cerebral palsy (CP). Previously, low cord blood levels of the anti-inflammatory chemokine CCL18 have been found to be associated with risk of CP in preterm children. OBJECTIVES: To investigate the association between single nucleotide polymorphisms (SNPs) in CCL18 and susceptibility to CP, as well as the association between the SNPs and cord blood levels of CCL18. METHODS: The original population comprised very-low gestational-age (VLGA; <32 weeks) children from northern and central Finland (25 cases, 195 controls). Five CCL18 SNPs were genotyped and examined for associations with CP and cord blood CCL18. The replication population comprised Caucasian VLGA children from southern Finland and Canada (23 cases, 248 controls). RESULTS: In the original population, SNP rs2735835 was associated with CP; the minor allele A was underrepresented in cases compared to controls (OR = 0.42, 95% CI: 0.21-0.83, p = 0.01). This association remained significant after adjustment for multiple testing and risk factors of CP, and after combining the original and replication populations (OR = 0.52, 95% CI: 0.33-0.83, p = 0.005). Intraventricular hemorrhage (IVH) additively predicted CP. The Rs2015086 genotype was modestly associated with CCL18 concentration. CONCLUSIONS: A common CCL18 polymorphism together with IVH had an additive influence on CP susceptibility. Developmentally regulated CCL18, confined to primates, may be involved in the complex sequence of events leading to brain injury and predisposition to CP phenotype. PMID- 26113375 TI - Astrocyte activation and neurotoxicity: A study in different rat brain regions and in rat C6 astroglial cells. AB - The present study was conducted to investigate the effect of rotenone on astrocytes activation, their viability and its effect on neuronal death in different brain regions. Rotenone was injected in rat brain by intracerebroventricularly (bilateral) route at dose of 6 MUg and 12 MUg. In vitro C6 cells were treated with rotenone at concentration of 0.1, 0.25, 0.5, 1 and 2 MUM. Rotenone administration to rat brain caused significant astrocytes activation in frontal cortex, cerebellum, cerebellar nucleus, substantia nigra, hypothalamus and hippocampus regions of the rat brain. Rotenone administration also led to significant degeneration of cells in all the studied regions along with altered nuclear morphology assessed by hematoxylin-eosin and cresyl violet staining. Histological staining showed the significantly decreased number of cells in all the studied regions except cerebellar nucleus in dose and time dependant manner. Rotenone administration in the rat brain also caused significant decrease in glutathione levels and augmented nitrite levels. In vitro treatment of rotenone to astrocytic C6 cells caused significantly increased expression of glial fibrillar acidic protein (GFAP) and decreased viability in dose and time dependent manner. Rotenone treatment to C6 cells exhibited significant generation of reactive oxygen species, augmented nitrite level, impaired mitochondrial activity, apoptotic chromatin condensation and DNA damage in comparison to control cells. Findings showed that oxidative stress play a considerable role in rotenone induced astrocyte death that was attenuated with co treatment of antioxidant melatonin. In conclusion, results showed that rotenone caused significant astrocytes activation, altered nuclear morphology, biochemical alteration and apoptotic cell death in different rat brain regions. In vitro observations in C6 cells showed that rotenone treatment exhibited oxidative stress mediated apoptotic cell death, which was attenuated with co treatment of melatonin. PMID- 26113376 TI - Parascapular perforating flap to treat severe axillary hidradenitis suppurativa. PMID- 26113378 TI - Onychomadesis: A Rare Sequela of Hand, Foot, and Mouth Disease. PMID- 26113377 TI - Logarithmic spiral flap for circular or oval defects on the lateral surface of the nose and nasal ala: a series of 15 cases. AB - INTRODUCTION: A large number of flaps, particularly rotation and transposition flaps, have been described for the closure of skin defects left by oncologic surgery of the nose. The logarithmic spiral flap is a variant of the rotation flap. MATERIALS AND METHODS: We present a series of 15 patients with different types of skin tumor on the nose. The skin defect resulting from excision of the tumor by micrographic surgery was reconstructed using various forms of the logarithmic spiral flap. There are 3 essential aspects to flap design: commencement of the pedicle at the upper or lower border of the wound, a width of the distal end of the flap equal to the vertical diameter of the defect, and a progressive increase in the radius of the spiral from the distal end of the flap to its base. RESULTS: The cosmetic and functional results of surgical reconstruction were satisfactory, and no patient required additional treatment to improve scar appearance. CONCLUSION: The logarithmic spiral flap is useful for the closure of circular or oval defects situated on the lateral surface of the nose and nasal ala. The flap initiates at one of the borders of the wound as a pedicle with a radius that increases progressively to create a spiral. We propose the logarithmic spiral flap as an excellent option for the closure of circular or oval defects of the nose. PMID- 26113379 TI - Predictive Role of Admission Lactate Level in Critically Ill Patients with Acute Upper Gastrointestinal Bleeding. AB - BACKGROUND: The predictive role of lactate in critically ill patients with acute upper gastrointestinal bleeding (UGIB) remains to be elucidated. OBJECTIVE: The primary objective of this study was to assess the value of lactate level on admission to predict in-hospital death in patients with UGIB admitted to the intensive care unit (ICU). The secondary objective was to assess whether lactate level adds predictive value to the clinical Rockall score in these patients. METHODS: This was a retrospective cohort study that included 133 patients with acute UGIB admitted to the ICU. Inclusion criteria were age > 18 years and presence of UGIB on admission to the ICU. RESULTS: Mean age was 55.4 years old and 64.7% were male. The most common cause of gastrointestinal bleeding was peptic ulcer disease, followed by erosive esophagitis/gastritis. The in-hospital mortality was 22.6%. Median lactate level in survivors and nonsurvivors was 2.0 (interquartile range [IQR] 1.2-4.2 mmol/L) and 8.8 (IQR 3.4-13.3 mmol/L; p < 0.01), respectively. The receiver operating characteristic (ROC) area to predict in-hospital death for clinical Rockall score and lactate level (0.82) was significantly higher than the ROC area for the clinical Rockall score alone (0.69) (p < 0.01). CONCLUSIONS: In patients admitted to the ICU with acute UGIB, lactate level on admission has a high sensitivity but low specificity for predicting in-hospital death. Lactate level adds to the predictive value of the clinical Rockall score. Given its high sensitivity, lactate level can be used in addition to other prediction tools to predict outcomes in patients with UGIB. PMID- 26113380 TI - Child with Purpuric Rash on Feet. PMID- 26113381 TI - The vertical lobe of cephalopods: an attractive brain structure for understanding the evolution of advanced learning and memory systems. AB - In this review we show that the cephalopod vertical lobe (VL) provides a good system for assessing the level of evolutionary convergence of the function and organization of neuronal circuitry for mediating learning and memory in animals with complex behavior. The pioneering work of JZ Young described the morphological convergence of the VL with the mammalian hippocampus, cerebellum and the insect mushroom body. Studies in octopus and cuttlefish VL networks suggest evolutionary convergence into a universal organization of connectivity as a divergence-convergence ('fan-out fan-in') network with activity-dependent long term plasticity mechanisms. Yet, these studies also show that the properties of the neurons, neurotransmitters, neuromodulators and mechanisms of long-term potentiation (LTP) induction and maintenance are highly variable among different species. This suggests that complex networks may have evolved independently multiple times and that even though memory and learning networks share similar organization and cellular processes, there are many molecular ways of constructing them. PMID- 26113382 TI - Facultative thermogenesis during brooding is not the norm among pythons. AB - Facultative thermogenesis is often attributed to pythons in general despite limited comparative data available for the family. While all species within Pythonidae brood their eggs, only two species are known to produce heat to enhance embryonic thermal regulation. By contrast, a few python species have been reported to have insignificant thermogenic capabilities. To provide insight into potential phylogenetic, morphological, and ecological factors influencing thermogenic capability among pythons, we measured metabolic rates and clutch environment temperature differentials at two environmental temperatures-python preferred brooding temperature (31.5 degrees C) and a sub-optimal temperature (25.5 degrees C)-in six species of pythons, including members of two major phylogenetic branches currently devoid of data on the subject. We found no evidence of facultative thermogenesis in five species: Aspidites melanocephalus, A. ramsayi, Morelia viridis, M. spilota cheynei, and Python regius. However, we found that Bothrochilus boa had a thermal metabolic sensitivity indicative of facultative thermogenesis (i.e., a higher metabolic rate at the lower temperature). However, its metabolic rate was quite low and technical challenges prevented us from measuring temperature differential to make conclusions about facultative endothermy in this species. Regardless, our data combined with existing literature demonstrate that facultative thermogenesis is not as widespread among pythons as previously thought. PMID- 26113383 TI - Zero-inflated count models for longitudinal measurements with heterogeneous random effects. AB - Longitudinal zero-inflated count data arise frequently in substance use research when assessing the effects of behavioral and pharmacological interventions. Zero inflated count models (e.g. zero-inflated Poisson or zero-inflated negative binomial) with random effects have been developed to analyze this type of data. In random effects zero-inflated count models, the random effects covariance matrix is typically assumed to be homogeneous (constant across subjects). However, in many situations this matrix may be heterogeneous (differ by measured covariates). In this paper, we extend zero-inflated count models to account for random effects heterogeneity by modeling their variance as a function of covariates. We show via simulation that ignoring intervention and covariate specific heterogeneity can produce biased estimates of covariate and random effect estimates. Moreover, those biased estimates can be rectified by correctly modeling the random effects covariance structure. The methodological development is motivated by and applied to the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study, the largest clinical trial of alcohol dependence performed in United States with 1383 individuals. PMID- 26113384 TI - Distribution-free estimation of zero-inflated models with unobserved heterogeneity. AB - This paper presents a quasi-conditional likelihood method for the consistent estimation of both continuous and count data models with excess zeros and unobserved individual heterogeneity when the true data generating process is unknown. Monte Carlo simulation studies show that our zero-inflated quasi conditional maximum likelihood (ZI-QCML) estimator outperforms other methods and is robust to distributional misspecifications. We apply the ZI-QCML estimator to analyze the frequency of doctor visits. PMID- 26113385 TI - Cause-specific quantile residual life regression. AB - We propose a cause-specific quantile residual life regression where the cause specific quantile residual life, defined as the inverse of the cumulative incidence function of the residual life distribution of a specific type of events of interest conditional on a fixed time point, is log-linear in observable covariates. The proposed test statistic for the effects of prognostic factors does not involve estimation of the improper probability density function of the cause-specific residual life distribution under competing risks. The asymptotic distribution of the test statistic is derived. Simulation studies are performed to assess the finite sample properties of the proposed estimating equation and the test statistic. The proposed method is illustrated with a real dataset from a clinical trial on breast cancer. PMID- 26113386 TI - Modeling of correlated data with informative cluster sizes: An evaluation of joint modeling and within-cluster resampling approaches. AB - Joint modeling and within-cluster resampling are two approaches that are used for analyzing correlated data with informative cluster sizes. Motivated by a developmental toxicity study, we examined the performances and validity of these two approaches in testing covariate effects in generalized linear mixed-effects models. We show that the joint modeling approach is robust to the misspecification of cluster size models in terms of Type I and Type II errors when the corresponding covariates are not included in the random effects structure; otherwise, statistical tests may be affected. We also evaluate the performance of the within-cluster resampling procedure and thoroughly investigate the validity of it in modeling correlated data with informative cluster sizes. We show that within-cluster resampling is a valid alternative to joint modeling for cluster-specific covariates, but it is invalid for time-dependent covariates. The two methods are applied to a developmental toxicity study that investigated the effect of exposure to diethylene glycol dimethyl ether. PMID- 26113387 TI - Erythema multiforme after orf virus infection. PMID- 26113388 TI - The Psychiatrist as Leader-Teacher: Promoting Learning Beyond Residency. AB - In today's fast-paced, data-saturated, zero-tolerance practice environment, psychiatrists and other health care providers are expected to maintain clinical, fiscal, and administrative competence. The authors present a unique type of psychiatric leader-the leader-teacher-who incorporates teaching of these elements into day-to-day practice, enhancing lifelong learning for credentialed staff and increasing their confidence in managing complex clinical and administrative issues. Particular emphasis is placed on leader-teachers working in military environments. The article discusses the primary characteristics of this type of leader, including their tendency to (1) seek clarification, (2) distill information, (3) communicate guidance, and (4) catalogue products. The authors also address the advantages and disadvantages of being a leader-teacher and present several illustrative cases. PMID- 26113389 TI - Preoperative ultrasound ablation for borderline resectable pancreatic cancer: A report of 30 cases. AB - BACKGROUND AND OBJECTIVES: Currently, extended resection and preoperative neoadjuvant chemotherapy are the two main modalities for improvement of the resection rate and R0 resection rate of borderline resectable pancreatic cancer. The past few years, however, have witnessed some progress in the treatment of unresectable pancreatic cancer with high intensity focused ultrasound (HIFU). The aim of this study is twofold: first, to evaluate the feasibility and safety of HIFU ablation as a preoperative adjuvant therapy for borderline resectable pancreatic cancer, and second, to conduct pathological analyses to verify the safety and effectiveness of HIFU treatment of pancreatic cancer. METHODS: From January 2011 to December 2012, 30 patients with borderline resectable pancreatic cancer underwent HIFU ablation by Haifu Model-JC200 Focused Ultrasound Tumor Therapeutic System prior to radical surgery. The effect of pre-operative HIFU ablation was evaluated by post-HIFU functional imaging results, operation time of radical surgery, blood loss volume, R0 resection rate, postoperative 1-year survival rate and Ca199 curve. Postoperative pathological specimens were obtained for histological examination. RESULTS: All 30 patients with borderline resectable pancreatic cancer had completed the treatments and follow-ups. Functional image assessment after HIFU treatment showed a mean tumor ablation rate of (61.5+/ 24.3)%. 28 patients underwent radical resection of pancreatic cancer 7-9 days after HIFU treatment (23 cases underwent pancreaticoduodenectomy. 4 patients underwent pancreatectomy and 1 patient had total pancreatectomy). 7 patients underwent combined resection and reconstruction of portal-superior mesenteric vein (23.3%), with the resectability rate of 93.3%, the R0 resection rate of 92.7%, and the 1-year survival rate of 96.7%. The biological coagulative necrosis regions identified by the postoperative pathological examination matched well with the necrosis foci identified by post-operative functional imaging. CONCLUSION: The effectiveness of HIFU ablation of pancreatic tumors, as well as interstitial tissues within he main vascular spaces was confirmed by post operative pathological examinations. Based on these observations, we conclude that preoperative HIFU ablation of borderline resectable pancreatic cancer can significantly improve the resection rate, R0 resection rate, and reduce the difficulty and risk of surgery. Therefore, HIFU may be a valuable pre-operative adjunct therapy for resectable pancreatic cancer. However, the safety and the efficacy on the improvement of the surgery need to established with future multicenter, randomized studies. PMID- 26113390 TI - Using microbubble sonographic contrast agent to enhance the effect of high intensity focused ultrasound for the treatment of uterine fibroids. AB - OBJECTIVE: To evaluate the effects of the ultrasound contrast agent SonoVue in enhancing the ablative effects of Ultrasound-Guided high-intensity focused ultrasound (HIFU) on different sub-types of uterine fibroids. MATERIALS AND METHODS: In this study, 390 fibroids from 319 patients were retrospectively evaluated, among which 155 were treated with SonoVue and 235 were without SonoVue during HIFU ablation. The efficacy of HIFU was evaluated using magnetic resonance scanning (MRI) in all patients. RESULTS: The total ablation time to achieve the same non-perfused volume was significantly shortened with SonoVue. The average energy used and the acoustic energy for treating 1 mm(3) (EEF) was less when SonoVue is used as enhancing agent. The non-perfused volume (NPV) was measured by post-HIFU MRI and the mean fractional ablation was calculated. Mean NPV was 74% (range: 15%-100%) in the HIFU-only group and 75% (range: 17%-100%) in the HIFU+ SonoVue group. However, for T2 MRI low intensity signal fibroids, NPV in the SonoVue group reached 83% (range: 20%-100%) that was significantly higher than in the HIFU-only group, which was 76% (range: 15%-100%). No differences in adverse events were observed between the two groups. CONCLUSIONS: Our observations demonstrate that the use of therapeutic SonoVue during the HIFU procedure can significantly decrease the ablation time and the energy requirement for the treatment of the same fibroid volume in all types of fibroids. PMID- 26113391 TI - Acute kidney injury after transcatheter aortic valve replacement: a systematic review and meta-analysis. AB - BACKGROUND: The objective of this meta-analysis was to evaluate the risk of acute kidney injury (AKI) in patients who underwent transcatheter aortic valve replacement (TAVR). METHODS: A literature search was performed using MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and clinicaltrials.gov from inception through October, 2014. Studies that reported relative risks, ORs, or hazard ratios comparing the AKI risk in patients who underwent TAVR versus those who underwent surgical aortic valve replacement were included. We performed the pre-specified sensitivity analysis including only propensity score-based studies. Mortality risk was evaluated among the studies that reported AKI outcome. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random effect, generic inverse variance method. RESULTS: Three randomized controlled trials (RCTs) with 1,852 patients and 14 cohort studies with 3,113 patients were analyzed to assess the AKI risk in patients undergoing TAVR. The pooled RRs of AKI in patients undergoing TAVR were 0.65 (95% CI 0.36-1.15, I(2) = 75%) in the analysis of RCTs and propensity score-based studies and 0.76 (95% CI 0.44-1.34, I(2) = 79%) in the analysis of observational studies. Sensitivity analysis in RCTs and propensity score-based studies using a standard AKI definition demonstrated a significant association between TAVR and lower AKI risk (RR 0.35, 95% CI 0.25-0.50, I(2) = 0%). Our meta-analyses of RCTs and propensity score based studies did not find associations between TAVR and reduced risks of severe AKI requiring dialysis (RR 0.82, 95% CI 0.38-1.79, I(2) = 63%). CONCLUSIONS: Our meta-analysis demonstrates an association between TAVR and lower AKI risk. PMID- 26113392 TI - BRCA1/2 Mutation-associated Breast Cancer, Wide Local Excision and Radiotherapy or Unilateral Mastectomy: A Systematic Review. AB - AIMS: BRCA1/2 mutation carriers show reduced apoptotic response to ionising radiation leading to recent debate about the safety of wide local excision and radiotherapy. The aim of the current study was to determine if BRCA1/2 mutation carriers with breast cancer undergoing wide local excision and radiotherapy show increased ipsilateral and contralateral breast tumour recurrence and reduced survival compared with unilateral mastectomy. MATERIALS AND METHODS: Following a detailed literature search, the methodology, populations, biases and outcomes of ipsilateral breast tumour recurrence, contralateral breast tumour recurrence and survival were evaluated for 25 articles. RESULTS: No differences in outcomes were found between wide local excision and mastectomy. BRCA1/2 mutation status was predictive of contralateral breast cancer only. Radiotherapy reduces the risk of ipsilateral recurrence and confers no increase in contralateral recurrence. CONCLUSION: BRCA1/2 mutation status does not preclude treatment with wide local excision and radiotherapy. Given the retrospective studies with inherent flaws and small patient numbers, further large prospective trials are required. PMID- 26113393 TI - Bipyramid-templated synthesis of monodisperse anisotropic gold nanocrystals. AB - Much of the interest in noble metal nanoparticles is due to their plasmonic resonance responses and local field enhancement, both of which can be tuned through the size and shape of the particles. However, both properties suffer from the loss of monodispersity that is frequently associated with various morphologies of nanoparticles. Here we show a method to generate diverse and monodisperse anisotropic gold nanoparticle shapes with various tip geometries as well as highly tunable size augmentations through either oxidative etching or seed-mediated growth of purified, monodisperse gold bipyramids. The conditions employed in the etching and growth processes also offer valuable insights into the growth mechanism difficult to realize with other gold nanostructures. The high-index facets and more complicated structure of the bipyramid lead to a wider variety of intriguing regrowth structures than in previously studied nanoparticles. Our results introduce a class of gold bipyramid-based nanoparticles with interesting and potentially useful features to the toolbox of gold nanoparticles. PMID- 26113394 TI - Preparation by alkaline treatment and detailed characterisation of empty hepatitis B virus core particles for vaccine and gene therapy applications. AB - Hepatitis B virus (HBV) core (HBc) virus-like particles (VLPs) are one of the most powerful protein engineering tools utilised to expose immunological epitopes and/or cell-targeting signals and for the packaging of genetic material and immune stimulatory sequences. Although HBc VLPs and their numerous derivatives are produced in highly efficient bacterial and yeast expression systems, the existing purification and packaging protocols are not sufficiently optimised and standardised. Here, a simple alkaline treatment method was employed for the complete removal of internal RNA from bacteria- and yeast-produced HBc VLPs and for the conversion of these VLPs into empty particles, without any damage to the VLP structure. The empty HBc VLPs were able to effectively package the added DNA and RNA sequences. Furthermore, the alkaline hydrolysis technology appeared efficient for the purification and packaging of four different HBc variants carrying lysine residues on the HBc VLP spikes. Utilising the introduced lysine residues and the intrinsic aspartic and glutamic acid residues exposed on the tips of the HBc spikes for chemical coupling of the chosen peptide and/or nucleic acid sequences ensured a standard and easy protocol for the further development of versatile HBc VLP-based vaccine and gene therapy applications. PMID- 26113395 TI - Identification and expression of an uncharacterized Ly-6 gene cluster in zebrafish Danio rerio. AB - The Ly-6/uPAR/CD59/neurotoxin superfamily (Ly-6SF) identified in most metazoan has been shown to play important roles in different biological processes including immunity, cellular adhesion, and cell signaling. Members of this superfamily contain one or more conserved domains known as Ly-6/uPAR (LU) domain, which harbors 8 or 10 conserved cysteine residues forming 4-5 disulfide bonds. In this study, we reported the identification of a novel zebrafish Ly-6 gene cluster on chromosome 21, which consists of seven genes ly21.1, ly21.2, ly21.3, ly21.4, ly21.5, ly21.6, and ly21.7 and their spatiotemporal expression pattern during development. All the seven genes possess features typical of the Ly-6/neurotoxin superfamily, and phylogenetic analysis shows that these genes form a single cluster branching form other members of Ly-6 family, suggesting that the seven genes evolved by an event of intra-chromosome gene duplication. However, deduced Ly21.1-7 proteins share little homology with Ly-6 family proteins from other species, no orthologs are identified in vertebrates, including teleosts, hinting that ly21.1-7 genes are evolutionarily a novel addition to zebrafish. Expression analyses show that maternal mRNAs of ly21.1-7 genes are detected during early developmental stages, but later in development, they exhibit tissue-specific expression. Except for ly21.2 which is expressed in the skin ionocytes, all the remaining six genes are mainly expressed in the developing brain. PMID- 26113397 TI - Usability and Validity of a Battery of Computerised Cognitive Screening Tests for Detecting Cognitive Impairment. AB - BACKGROUND: Computerised cognitive screening (CCS) has the potential to detect cognitive impairment in the community, which is important for the early diagnosis of dementia. OBJECTIVE: The aim of this study was to investigate the ability of older adults with dementia to engage with smart phone and tablet technologies and to determine the accuracy of a battery of CCS tasks to detect cognitive impairment in comparison with the Montreal Cognitive Assessment (MoCA). METHODS: Patients with mild-moderate dementia (n = 40) attending a university-linked day hospital and normal controls (n = 20) completed (i) a questionnaire detailing the frequency and breadth of their technology use, (ii) three commercially available CCS tasks, and (iii) the MoCA. RESULTS: The three CCS tasks were completed by 85% (n = 34) of the patients with dementia and all controls; only 4 reported the task as 'hard'. Those with dementia scored significantly lower on the CCS than controls (p < 0.001). CCS scores correlated with total MoCA scores (r = 0.78, p < 0.01). Further, the CCS scores significantly predicted MoCA scores, controlling for the effects of age, gender, educational attainment, and frequency of technology use (beta = 0.71, p < 0.001), explaining 65.2% of the variance. Total CCS and MoCA scores (cut-off score <24) had similar sensitivity (94 and 95%, respectively) and accuracy (area under the curve 0.94 and 0.99, respectively, p = 0.5) in discriminating dementia from controls, though the CSS had lower specificity (60 vs. 100% for the MoCA). CONCLUSION: The participants had little difficulty self-administering the CCS, which is an oft-cited barrier to computerised testing in this population. Our results support the criterion and construct validity of a CCS versus the commonly used MoCA. Although further research is required, CCS for cognitive impairment may be useful in the community and, by prompting referral to specialist services, could lead to an earlier diagnosis of dementia. PMID- 26113396 TI - Plant miRNAs: biogenesis, organization and origins. AB - MicroRNAs, or miRNAs, are posttranscriptional regulators of gene expression. A wealth of observations and findings suggest highly complex, multicomponent, and intermingled pathways governing miRNA biogenesis and miRNA-mediated gene silencing. Plant miRNA genes are usually found as individual entities scattered around the intergenic and-to a much lesser extent-intragenic space, while miRNA gene clusters, formed by tandem or segmental duplications, also exist in plant genomes. Genome duplications are proposed to contribute to miRNA family expansions, as well. Evolutionarily young miRNAs retaining extensive homology to their loci of origin deliver important clues into miRNA origins and evolution. Additionally, imprecisely processed miRNAs evidence noncanonical routes of biogenesis, which may affect miRNA expression levels or targeting capabilities. Majority of the knowledge regarding miRNAs comes from model plant species. As ongoing research progressively expands into nonmodel systems, our understanding of miRNAs and miRNA-related pathways changes which opens up new perspectives and frontiers in miRNA research. PMID- 26113398 TI - A matter of scale: how emerging technologies are redefining our view of chromosome architecture. AB - The 3D folding of the genome and its relation to fundamental processes such as gene regulation, replication, and segregation remains one of the most puzzling and exciting questions in genetics. In this review, we describe how the use of new technologies is starting to revolutionize the field of chromosome organization, and to shed light on the mechanisms of transcription, replication, and repair. In particular, we concentrate on recent studies using genome-wide methods, single-molecule technologies, and super-resolution microscopy (SRM). We summarize some of the main concerns when employing these techniques, and discuss potential new and exciting perspectives that illuminate the connection between 3D genomic organization and gene regulation. PMID- 26113399 TI - Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain. AB - In humans, affective consequences of neuropathic pain, ranging from depression to anxiety and anhedonia, severely impair quality of life and are a major disease burden, often requiring specific medications. Depressive- and anxiety-like behaviors have also been observed in animal models of peripheral nerve injury. Dysfunctions in central nervous system monoamine transmission have been hypothesized to underlie depressive and anxiety disorders in neuropathic pain. To assess whether these neurons display early changes in their activity that in the long-term might lead to chronicization, maladaptive plasticity and affective consequences, we carried out in vivo extracellular single unit recordings from serotonin neurons in the dorsal raphe nucleus (DRN) and from dopamine neurons in ventral tegmental area (VTA) in the spared nerve injury (SNI) model of neuropathic pain in rats. Extracellular dopamine levels and the expression of dopamine D1, D2 receptors and tyrosine hydroxylase (TH) were measured in the nucleus accumbens. We report that, two weeks following peripheral nerve injury, discharge rate of serotonin DRN neurons and burst firing of VTA dopamine cells are enhanced, when compared with sham-operated animals. We also observed higher extracellular dopamine levels and reduced expression of D2, but not D1, receptors and TH in the nucleus accumbens. Our study confirms that peripheral neuropathy induces changes in the serotonin and dopamine systems that might be the early result of chronic maladaptation to persistent pain. The allostatic activation of these neural systems, which mirrors that already described as a consequence of stress, might lead to depression and anxiety previously observed in neuropathic animals but also an attempt to cope positively with the negative experience. PMID- 26113400 TI - From unilateral to bilateral parkinsonism: Effects of lateralization on dyskinesias and associated molecular mechanisms. AB - The mechanisms underlying lateralization and progression of motor symptoms from unilateral to bilateral in Parkinson's disease (PD) remain to be elucidated. In addition, the molecular mechanisms involved in levodopa-induced dyskinesias (LIDs) depending on lateralization and disease progression from unilaterally to bilateral have not been described yet. We investigated motor symptoms, LIDs and associated striatal molecular markers expression after unilateral left or right, and after a sequential bilateral 6-hydroxydopamine (6-OHDA)-induced nigrostriatal lesions in rats. Sequentially bilateral lesioned animals showed a bilateral increase in striatal preproenkephalin (PPE) mRNA without changes in pre prodynorphin (PDyn) mRNA expression. The increase in dyskinesias when parkinsonism becomes bilateral was mostly due to an increase in orolingual dyskinesias associated to a increase in PDyn mRNA expression. Right lesion induces, or facilitates when first-done, a greater level of LIDs and an increase in striatal PPE and PDyn mRNAs in the second lesioned side. We describe a new striatal molecular pattern that appears when parkinsonism becomes bilateral and the relevance of the lateralization for the development of LIDs. PMID- 26113401 TI - [Pathophysiology, epidemiology, clinical presentation, diagnosis and treatment options for autosomal dominant polycystic kidney disease]. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end-stage renal disease (ESRD) worldwide. Its prevalence is evaluated according to studies and population between 1/1000 and 1/4000 live births and it accounts for 6 to 8% of incident ESRD patients in developed countries. ADPKD is characterized by numerous cysts in both kidneys and various extrarenal manifestations that are detailed in this review. Clinico-radiological and genetic diagnosis are also discussed. Mutations in the PKD1 and PKD2 codifying for polycystin-1 (PC-1) and polycystin-2 (PC-2) are responsible for the 85 and 15% of ADPKD cases, respectively. In primary cilia of normal kidney epithelial cells, PC 1 and PC-2 interact forming a complex involved in flow- and cilia-dependant signalling pathways where intracellular calcium and cAMP play a central role. Alteration of these multiple signal transduction pathways leads to cystogenesis accompanied by dysregulated planar cell polarity, excessive cell proliferation and fluid secretion, and pathogenic interactions of epithelial cells with an abnormal extracellular matrix. The mass effect of expanding cyst is responsible for the decline in glomerular filtration rate that occurs late in the course of the disease. For many decades, the treatment for ADPKD aims to lessen the condition's symptoms, limit kidney damage, and prevent complications. Recently, the development of promising specific treatment raises the hope to slow the growth of cysts and delay the disease. Treatment strategies targeting cAMP signalling such as vasopressin receptor antagonists or somatostatin analogs have been tested successfully in clinical trials with relative safety. Newer treatments supported by preclinical trials will become available in the next future. Recognizing early markers of renal progression (clinical, imaging, and genetic markers) to identify high-risk patients and multidrug approaches with synergistic effects may provide new opportunities for the treatment of ADPKD. PMID- 26113404 TI - Microglia and necroptosis: The culprits of neuronal cell death in multiple sclerosis. AB - Multiple Sclerosis is an inflammatory demyelinating and degenerative disease of the central nervous system in which activated microglia contribute to oligodendroglial, neuronal, and axonal damage. A recent study (summarized here) provided evidence for a role of necroptosis in MS brain tissue based on reduced caspase-8 and increased expression of cFLIP in microglial cells. In addition, activation of RIPK1, RIPK3, and MLKL (molecules characteristic of necroptosis) was demonstrated in cortical lesions from MS brain specimens. Defective caspase-8 activity in microglia adds a new dimension to microglial role in MS and provides a potential therapeutic target in the progressive forms of the disease. PMID- 26113403 TI - Decreased serum level of IL-7 in patients with active Graves' disease. AB - BACKGROUND: Graves' disease (GD) is a common autoimmune disease which is one of the major causes of hyperthyroidism. Interleukin 7 (IL-7) has been recently reported to play an important role in various autoimmune diseases, but its role in the pathogenesis of GD has not been assessed. The aim of this study was to evaluate the levels of IL-7 and the soluble form of its receptor (sIL-7R) in the serum of GD patients, and to identify their association with disease activity. METHODS: A total of 37 GD patients were enrolled into the experimental group and 16 individuals into the control group. All patients were further classified into three subgroups: a GD-active group (hyperthyroidism and TRAb (thyroid stimulating hormone receptor antibody) >7.5 U/L) (N=15), a GD-inactive group (euthyreosis and TRAb<1 U/L) (N=8), and other GD patients (euthyreosis and TRAb>1 U/L) (N=14). Concentrations of IL-7 and sIL-7R were assayed with ELISA. Additionally, the relationship between IL-7 and sIL-7R serum concentrations with disease activity (free triiodothyronine [FT3], free thyroxine [FT4], thyroid stimulating hormone [TSH] and TRAb) was also analyzed. RESULTS: The serum concentrations of IL-7 in GD-active patients were significantly lower than those of the control group as well as the GD-inactive and GD-other groups. The serum level of IL-7 in GD patients negatively correlated with FT4 and TRAb concentrations. Moreover, no significant difference was observed in the serum level of sIL-7R in GD patients compared to the control group. CONCLUSIONS: These observations suggest that IL-7 may play a role in the pathogenesis of GD and may be associated with its clinical activity. To this end, the serum level of IL-7 could be an additional diagnostic biomarker predictive of the disease and could be particularly valuable for TRAb negative GD patients. PMID- 26113405 TI - The effects of ovariectomy and LPS-induced endotoxemia on resistin levels in female rats. AB - Resistin is involved in the inflammatory response, as well as in insulin resistance. In rodents, resistin levels are partially regulated by ovarian hormones. Thus, ovariectomy-induced changes in resistin levels and their response to lipopolysaccharide (LPS)-induced septic stress were evaluated. Ovariectomized (OVX) rats exhibited higher serum resistin concentrations and visceral and subcutaneous white adipose tissue (WAT) resistin mRNA levels than sham-operated (sham) rats under the saline-injected (basal) conditions. The serum resistin levels of the gonadal intact male rats were higher than those of the sham rats, whereas the serum resistin levels of the male and OVX rats did not differ. In both the sham and OVX rats, the serum resistin concentration and the resistin mRNA levels of WAT were increased by LPS injection. At 24h after the LPS injection, no difference was detected in the serum resistin concentrations or WAT mRNA resistin levels between the sham and OVX rats. These results suggest that ovarian hormones partially regulate the basal resistin levels of female rats. PMID- 26113402 TI - GM-CSF: An immune modulatory cytokine that can suppress autoimmunity. AB - GM-CSF was originally identified as a colony stimulating factor (CSF) because of its ability to induce granulocyte and macrophage populations from precursor cells. Multiple studies have demonstrated that GM-CSF is also an immune modulatory cytokine, capable of affecting not only the phenotype of myeloid lineage cells, but also T-cell activation through various myeloid intermediaries. This property has been implicated in the sustenance of several autoimmune diseases like arthritis and multiple sclerosis. In contrast, several studies using animal models have shown that GM-CSF is also capable of suppressing many autoimmune diseases such as Crohn's disease, Type-1 diabetes, Myasthenia gravis and experimental autoimmune thyroiditis. Knockout mouse studies have suggested that the role of GM-CSF in maintaining granulocyte and macrophage populations in the physiological steady state is largely redundant. Instead, its immune modulatory role plays a significant role in the development or resolution of autoimmune diseases. This is mediated either through the differentiation of precursor cells into specialized non-steady state granulocytes, macrophages and dendritic cells, or through the modulation of the phenotype of mature myeloid cells. Thus, outside of myelopoiesis, GM-CSF has a profound role in regulating the immune response and maintaining immunological tolerance. PMID- 26113406 TI - Impact of CARDIOrespiratory FITness on Arrhythmia Recurrence in Obese Individuals With Atrial Fibrillation: The CARDIO-FIT Study. AB - BACKGROUND: Obesity begets atrial fibrillation (AF). Although cardiorespiratory fitness is protective against incident AF in obese individuals, its effect on AF recurrence or the benefit of cardiorespiratory fitness gain is unknown. OBJECTIVES: This study sought to evaluate the role of cardiorespiratory fitness and the incremental benefit of cardiorespiratory fitness improvement on rhythm control in obese individuals with AF. METHODS: Of 1,415 consecutive patients with AF, 825 had a body mass index >=27 kg/m(2) and were offered risk factor management and participation in a tailored exercise program. After exclusions, 308 patients were included in the analysis. Patients underwent exercise stress testing to determine peak metabolic equivalents (METs). To determine a dose response, cardiorespiratory fitness was categorized as: low (<85%), adequate (86% to 100%), and high (>100%). Impact of cardiorespiratory fitness gain was ascertained by the objective gain in fitness at final follow-up (>=2 METs vs. <2 METs). AF rhythm control was determined using 7-day Holter monitoring and AF severity scale questionnaire. RESULTS: There were no differences in baseline characteristics or follow-up duration between the groups defined by cardiorespiratory fitness. Arrhythmia-free survival with and without rhythm control strategies was greatest in patients with high cardiorespiratory fitness compared to adequate or low cardiorespiratory fitness (p < 0.001 for both). AF burden and symptom severity decreased significantly in the group with cardiorespiratory fitness gain >=2 METs as compared to <2 METs group (p < 0.001 for all). Arrhythmia-free survival with and without rhythm control strategies was greatest in those with METs gain >=2 compared to those with METs gain <2 in cardiorespiratory fitness (p < 0.001 for both). CONCLUSIONS: Cardiorespiratory fitness predicts arrhythmia recurrence in obese individuals with symptomatic AF. Improvement in cardiorespiratory fitness augments the beneficial effects of weight loss. (Evaluating the Impact of a Weight Loss on the Burden of Atrial Fibrillation [AF] in Obese Patients; ACTRN12614001123639). PMID- 26113407 TI - miR-33a suppresses the nuclear translocation of beta-catenin to enhance gemcitabine sensitivity in human pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, partly due to its high level of drug resistance. beta-Catenin is critical for drug resistance in pancreatic cancer, which occurs through multiple mechanisms. Here, we observed that miR-33a targeted the 3'UTR of beta-catenin, inducing apoptosis and inhibiting the growth of human pancreatic cancer cells. Moreover, gemcitabine (GEM) treatment enhanced beta-catenin expression by reducing miR-33a expression in a dose-dependent manner. GEM-resistant MiaPaCa-2(res) cells with a low level of miR-33a expression and high level of beta-catenin expression adopted spindle shaped morphologies, similar to their morphologies during the epithelial-to mesenchymal transition (EMT), and their normal morphologies were restored by miR 33a overexpression. Furthermore, miR-33a downregulated beta-catenin nuclear translocation, decreasing the transcription of survivin, cyclin D1, and MDR-1, and the protein expression of slug, vimentin, and N-cadherin, thereby mediating sensitization to GEM. Thus, miR-33a might function as a tumor suppressor to downregulate beta-catenin expression, affecting cell growth, apoptosis, the EMT, and GEM resistance. PMID- 26113408 TI - High expression of CD39/ENTPD1 in malignant epithelial cells of human rectal adenocarcinoma. AB - The ectonucleotidase CD39 is pivotal in the conversion of immunostimulatory adenosine triphosphate (ATP) into immunosuppressive adenosine which potently inhibits host immune responses against cancer. This study investigated the expression level and prognostic significance of CD39 in human rectal adenocarcinoma. Our data demonstrated that CD39 staining strongly marked malignant epithelial cells where the protein and messenger RNA (mRNA) expression levels of CD39 were significantly increased compared with paracancerous controls. In addition to primary tumors, CD39 was also abundantly expressed in liver metastases and tumor-draining lymph nodes from metastatic rectal adenocarcinoma. Although patients with higher CD39 density in tumor cells were more likely to have favorable characteristics (early TNM and N stages) and overall survival, the singular parameter cannot be used as an independent factor for predicting patients' prognosis. Intriguingly, combined analysis of CD39 and CD73 expression was more efficient to foretell patient's outcome where patients with increased CD73 but decreased CD39 levels displayed a worst prognosis. Taken together, the current study revealed that malignant epithelial cells of human rectal adenocarcinoma strongly express CD39 that may play a potential role in the tumor invasion and metastasis. Although high expression of CD39 in tumor cells is correlated with favorable clinical outcome, the combination of CD39 and CD73 expression may have a better prognostic value. PMID- 26113409 TI - Interaction between TNFR1 and TNFR2 dominates the clinicopathologic features of human hypopharyneal carcinoma. AB - Although the expression of tumor necrosis factor receptors (TNFRs) has been associated with clinicopathologic features of some other cancers, their roles in hypopharyngeal squamous cell carcinoma (HPSCC) have not been documented. Forty five HPSCC specimens were analyzed for the expression of TNFR1 and TNFR2 and its relationship with clinicopathologic factors. Interaction between the two receptors and its effects on TNF-alpha was investigated by neutralizing TNFR1 and upregulation of TNFR2. The results indicated that, in HPSCC specimens, the expression of TNFR1 but not TNFR2 is associated with clinical staging, T stage, cervical lymph node metastasis, and histologic grade in HPSCC. In Fadu cells, when conjugating with its receptors, TNF-alpha mediates proliferation effects, and neutralizing TNFR1 and/or upregulating TNFR2 evokes proliferation-inhibiting and apoptosis-inducing effects and potentiates cisplatin (DDP)-induced growth inhibition and apoptosis induction. In conclusion, interaction of TNFR1 with TNFR2 determines the biological characters of HPSCC, and TNFR1 may dominate this process. Moreover, interaction between the two receptors plays important roles in determining the fates of HPSCC cells and thus may serve as a therapeutic target for developing new therapeutic strategies for HPSCC. PMID- 26113410 TI - High-mobility group nucleosome-binding protein 1 is a novel clinical biomarker in non-small cell lung cancer. AB - The involvement of alarmin high-mobility group nucleosome-binding protein 1 (HMGN1) in non-small cell lung cancer (NSCLC) is unknown. To address the presence of HMGN1 in the serum of different stages of NSCLC patients and healthy controls, we enrolled a consecutive sample of adult serum at diagnosis and correlated it with clinicopathologic outcomes. A total of 100 NSCLC patients and 23 healthy volunteers were enrolled from January 2012 through December 2013. Serum HMGN1 levels were determined by enzyme-linked immunosorbent assay (ELISA). Additionally, HMGN1 levels in 50 NSCLC patients with early-stage disease who received curative pneumonectomy were correlated with survivals. Kaplan-Meier plots were used to analyze the data. The patients with NSCLC were characterized by significantly higher serum levels of HMGN1 (0.4585 +/- 0.0640 ng/ml) compared to those in healthy controls (0.3578 +/- 0.0304 ng/ml). The serum HMGN1 levels were 0.4027 +/- 0.0271 ng/ml, 0.4604 +/- 0.0328 ng/ml, 0.5408 +/- 0.0459 ng/ml, and 0.4213 +/- 0.0341 ng/ml in patients with TNM stages I, II, IV, and IV, respectively (p < 0.001). There were significant differences among four groups (p < 0.001). Additionally, a positive correlation between serum HMGN1 and tumor stage was found in local disease, while serum HMGN1 level in metastatic NSCLC patients was significantly decreased. The Kaplan-Meier plots showed that patients with high serum HMGN1 had a poorer overall survival (OS) after curative pneumonectomy than those with low serum HMGN1 (p = 0.019). Inflammation triggered by alarmins plays a role in NSCLC pathogenesis. HMGN1 can serve as a useful clinical parameter for evaluating disease progression and predicting the outcomes for early-stage patients with NSCLC undergoing pneumonectomy. PMID- 26113411 TI - Tuning the Electronic Structure of Anatase Through Fluorination. AB - A highly fluorinated anatase lattice has been recently reported, providing a new class of materials whose general chemical formula is Ti(1-x)?(x)X(4x)O(2-4x) (X( ) = F(-) or OH(-)). To characterise the complex structural features of the material and the different F environments, we here apply a computational screening procedure. After deriving a polarisable force-field from DFT simulations, we screen in a step-wise fashion a large number of possible configurations differing in the positioning of the titanium vacancies (?) and of the fluorine atoms. At each step only 10% of the configurations are retained. At the end of the screening procedure, a configuration is selected and simulated using DFT-based molecular dynamics. This allows us to analyse the atomic structure of the material, which is strongly disordered, leading to a strong decrease (by 0.8 eV) of the band gap compared to conventional anatase. PMID- 26113412 TI - Inflammatory Macrophages Promotes Development of Diabetic Encephalopathy. AB - BACKGROUND/AIMS: Diabetes and Alzheimer's disease are often associated with each other, whereas the relationship between two diseases is ill-defined. Although hyperglycemia during diabetes is a major cause of encephalopathy, diabetes may also cause chronic inflammatory complications including peripheral neuropathy. Hence the role and the characteristics of inflammatory macrophages in the development of diabetic encephalopathy need to be clarified. METHODS: Diabetes were induced in mice by i.p. injection of streptozotocin (STZ). Two weeks after STZ injection and confirmation of development of diabetes, inflammatory macrophages were eliminated by i.p. injection of 20ug saporin-conjugated antibody against a macrophage surface marker CD11b (saporin-CD11b) twice per week, while a STZ-treated group received injection of rat IgG of same frequency as a control. The effects of macrophage depletion on brain degradation markers, brain malondialdehyde (MDA), catalase, superoxidase anion-positive cells and nitric oxide (NO) were measured. RESULTS: Saporin-CD11b significantly reduced inflammatory macrophages in brain, without affecting mouse blood glucose, serum insulin, glucose responses and beta cell mass. However, reduced brain macrophages significantly inhibited the STZ-induced decreases in brain MDA, catalase and superoxidase anion-positive cells, and the STZ-induced decreases in brain NO. CONCLUSION: Inflammatory macrophages may promote development of diabetic encephalopathy. PMID- 26113413 TI - Combined Treatment of an Amyotrophic Lateral Sclerosis Rat Model with Recombinant GOT1 and Oxaloacetic Acid: A Novel Neuroprotective Treatment. AB - BACKGROUND/AIM: The sporadic form of the disease affects the majority of amyotrophic lateral sclerosis (ALS) patients. The role of glutamate (Glu) excitotoxicity in ALS has been extensively documented and remains one of the prominent hypotheses of ALS pathogenesis. In light of this evidence, the availability of a method to remove excess Glu from brain and spinal cord extracellular fluids without the need to deliver drugs across the blood-brain barrier and with minimal or no adverse effects may provide a major therapeutic asset, which is the primary aim of this study. METHODS: The therapeutic efficacy of the combined treatment with recombinant Glu-oxaloacetate-transaminase (rGOT) and its co-factor oxaloacetic acid (OxAc) has been tested in an animal model of sporadic ALS. RESULTS: We found that OxAc/rGOT treatment provides significant neuroprotection to spinal cord motor neurons. It also slows down the development of motor weakness and prolongs survival. CONCLUSION: In this study we bring evidence that the administration of Glu scavengers to rats with sporadic ALS inhibited the massive death of spinal cord motor neurons, slowed the onset of motor weakness and prolonged survival. This treatment may be of high clinical significance for the future treatment of chronic neurodegenerative diseases. PMID- 26113414 TI - Transformation of apatite phosphorus and non-apatite inorganic phosphorus during incineration of sewage sludge. AB - The recovery of phosphorus from incinerated sewage sludge ash (SSA) is assumed to be economical. Transformation from non-apatite inorganic phosphorus (NAIP) to apatite phosphorus (AP), which has a higher bioavailability and more extensive industrial applications, was studied at 750-950 degrees C by sewage sludge incineration and model compound incineration with a calcium oxide (CaO) additive. Thermogravimetric differential scanning calorimetry analysis and X-ray diffraction measurements were used to analyze the reactions between NAIP with CaO and crystallized phases in SSA. High temperatures stimulated the volatilization of NAIP instead of AP. Sewage sludge incineration with CaO transformed NAIP into AP, and the percentage of AP from the total phosphorus reached 99% at 950 degrees C. Aluminum phosphate reacted with CaO, forming Ca2P2O7 and Ca3(PO4)2 at 750-950 degrees C. Reactions between iron phosphate and CaO occurred at lower temperatures, forming Ca(PO3)2 before reaching 850 degrees C. PMID- 26113415 TI - In-line coupling of an aptamer based miniaturized monolithic affinity preconcentration unit with capillary electrophoresis and Laser Induced Fluorescence detection. AB - A composite 30-cm capillary was prepared. The head of the capillary was a 1.5-cm original and miniaturized aptamer-based monolithic affinity support that was in line coupled to the end of the capillary used for capillary electrophoresis (CE) with laser induced fluorescence (LIF) detection. The device was used for the preconcentration, separation and quantification of ochratoxin A (OTA) as a test solute. The 1.5-cm preconcentration unit consists of a fritless affinity monolithic bonded with 5'-SH-modified oligonucleotide aptamers. A vinyl spacer was used for thiol-ene photoclick chemistry with a 5min irradiation at 365nm. Photografting allowed to confine the binding reaction to the desired silica monolithic segment, upstream the empty section of the CE capillary using an UV mask. The photografting procedure was optimized preparing 10-cm capillary monoliths for nano-LC. The retention factors of cationic solutes in ion-exchange nano-LC allowed to follow the aptamer binding on the monolith. The reproducibility of the photografting process was satisfactory with inter capillary variation lower than 10%. The aptamer bonding density can be increased by successive graftings of 100MUM aptamer concentration solution (5pmol/cm/grafting). The optimal conditions to successfully perform the in-line coupling (preconcentration, elution and separation of OTA) with the composite capillary were adjusted depending on individual requirements of each step but also insuring compatibility. Under optimized conditions, OTA was successfully preconcentrated and quantified down to 0.1pg (percolation of 2.65MUL of a 40ng/L OTA solution). A quantitative recovery of OTA (93+/-2%) was achieved in a single elution of 30pg percolated OTA amount. The reproducibility of the overall process was satisfactory with a relative standard deviation lower than 10% with negligible non-specific adsorption. This device was applied for the preconcentration and analysis of OTA in beer and wine at the ppb level within a total analysis time of 30min. PMID- 26113416 TI - NPM1 mutation is associated with leukemia cutis in acute myeloid leukemia with monocytic features. PMID- 26113417 TI - Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease. AB - Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20-30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon gamma production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease. PMID- 26113418 TI - Gradual increase in thrombogenicity of juvenile platelets formed upon offset of prasugrel medication. AB - In patients with acute coronary syndrome, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor like prasugrel is prescribed for one year. Here, we investigated how the hemostatic function of platelets recovers after discontinuation of prasugrel treatment. Therefore, 16 patients who suffered from ST-elevation myocardial infarction were investigated. Patients were treated with aspirin (100 mg/day, long-term) and stopped taking prasugrel (10 mg/day) after one year. Blood was collected at the last day of prasugrel intake and at 1, 2, 5, 12 and 30 days later. Platelet function in response to ADP was normalized between five and 30 days after treatment cessation and in vitro addition of the reversible P2Y12 receptor antagonist ticagrelor fully suppressed the regained activation response. Discontinuation of prasugrel resulted in the formation of an emerging subpopulation of ADP-responsive platelets, exhibiting high expression of active integrin alphaIIbbeta3. Two different mRNA probes, thiazole orange and the novel 5'Cy5-oligo-dT probe revealed that this subpopulation consisted of juvenile platelets, which progressively contributed to platelet aggregation and thrombus formation under flow. During offset, juvenile platelets were overall more reactive than older platelets. Interestingly, the responsiveness of both juvenile and older platelets increased in time, pointing towards a residual inhibitory effect of prasugrel on the megakaryocyte level. In conclusion, the gradual increase in thrombogenicity after cessation of prasugrel treatment is due to the increased activity of juvenile platelets. PMID- 26113420 TI - Impact of red cell distribution width on future risk of cancer and all-cause mortality among cancer patients - the Tromso Study. PMID- 26113419 TI - Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first line treatment of chronic myeloid leukemia. AB - Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (>= 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID- 26113421 TI - Management of nicotinamide N-methyltransferase overexpression: inhibit the enzyme or reduce nicotinamide intake? Reply to Zhou S, Li D, Zhou Y [letter]. PMID- 26113422 TI - In Search of Global Health Justice: A Need to Reinvigorate Institutions and Make International Law. AB - The recent outbreak of Ebola in West Africa has killed thousands of people, including healthcare workers. African responses have been varied and largely ineffective. The WHO and the international community's belated responses have yet to quell the epidemic. The crisis is characteristic of a failure to properly comply with the International Health Regulations 2005. More generally, it stems from a failure of international health justice as articulated by a range of legal institutions and instruments, and it should prompt us to question the state and direction of approaches to the governance of global public health. This paper queries what might be done to lift global public health as a policy arena to the place of prominence that it deserves. It argues that there are at least two critical reasons for the past, present and easily anticipated future failings of the global public health regime. After exploring those, it then articulates a new way forward, identifying three courses of action that might be adopted in realising better health outcomes and global health justice, namely value, institutional and legal reform. PMID- 26113423 TI - Enhancing cancer targeting and anticancer activity by a stimulus-sensitive multifunctional polymer-drug conjugate. AB - Undesirable physicochemical properties, low tumor targeting, insufficient cell internalization, acquired drug resistance, and severe side effects significantly limit the applications of anticancer drugs. In this study, to improve the tumor targeting and drug efficacy of the poorly water-soluble drug, doxorubicin (DOX), a novel drug delivery platform (PEG-ppTAT-DOX) was developed, which contained a polyethylene glycol (PEG), a matrix metalloproteinase 2 (MMP2)-sensitive peptide linker (pp), a cell penetrating peptide (TAT), and a model drug (doxorubicin). The prepared drug platform possessed several key features, including: (i) the nanoparticle formation via the self-assembly; (ii) prevention of the non-specific interaction via the PEGylation; (iii) tumor targeting via the MMP2-mediated PEG deshielding and exposure of the TAT; (iv) the TAT-mediated cell internalization; (v) the TAT-induced endosomal escape; (vi) the inhibition of P-glycoprotein mediated drug efflux; and (vii) the TAT-medicated nuclear translocation. These cooperative functions ensured the improved tumor targetability, enhanced tumor cell internalization, improved intracellular distribution, and potentiated anticancer activity. Compared to the multi-component nanocarriers, the proposed simple but multifunctional polymer-drug conjugate might have greater potential for tumor-targeted drug delivery and enhanced chemotherapy. PMID- 26113424 TI - A venous thromboembolism risk assessment model for patients with Cushing's syndrome. AB - Cushing's syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a 'CS-VTE score' from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age >=69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS VTE score >=4 high risk (85 %). Considering a score >=3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis. PMID- 26113425 TI - Functional imaging for pheochromocytoma-paraganglioma: a step closer to understanding its place in clinical practice. PMID- 26113426 TI - Ethanol-wet bonding technique: Clinical versus laboratory findings. AB - OBJECTIVES: This study evaluated the microtensile bond strength (MUTBS) and nanoleakage (NL) of dentin bonded interfaces produced with ethanol-wet and water wet bonding protocols under clinical and laboratory conditions. METHODS: The sample was composed of forty primary second molars in advanced exfoliation process. Occlusal cavities were prepared leaving a flat dentin surface on the pulpal floor. In half of the teeth, the water-wet protocol was followed using a three-step etch-and-rinse adhesive. In the other half, dentin was dehydrated with ascending ethanol solutions (50%, 70%, 80%, 95% and 3*100%), 15s each for the ethanol-bonding protocol. An experimental hydrophobic primer was used, followed by the neat adhesive application. Resin build-ups were prepared, stored for 24h, sectioned into sticks and tested in tensile mode (0.5mm/min). NL was performed for all groups. The MUTBS and NL data were submitted to two-way ANOVA and Kruskall-Wallis tests, respectively (alpha=0.05). RESULTS: Under clinical conditions, the highest MUTBS was observed for the water-wet bonding while under the laboratory setting, the highest MUTBS was obtained for the ethanol-wet bonding. Increased NL was observed in the water-wet bonding groups irrespective of the bonding condition. SIGNIFICANCE: The immediate benefits of the ethanol bonding observed in the laboratory setting was not confirmed when the same protocol was performed in vivo. However, as reduced nanoleakage was seen in adhesive interfaces produced with the ethanol-wet bonding technique, suggests that the hybrid layer may be more resistant to degradation. PMID- 26113427 TI - Ultra-high-molecular-weight polyethylene fiber reinforced dental composites: Effect of fiber surface treatment on mechanical properties of the composites. AB - OBJECTIVES: Poor interfacial adhesion between the fibers and resin matrix in the ultra high molecular weight polyethylene (UHMWPE) fiber reinforced composites (FRCs) is the main drawback of the composites. This study aims to evaluate the effect of corona and silane surface treatment of the fibers on the mechanical properties of the UHMWPE FRCs. METHODS: UHMWPE fibers were exposed to corona discharges for different periods of time (0s, 5s, 7s). The surface characteristics of the UHMWPE fibers were investigated by attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR), atomic force microscopy (AFM), scanning electron microscopy (SEM) and nanoindentation technique. The flexural strength and flexural modulus of the FRCs made of the treated fibers were determined on 2mm*2mm*25mm specimens. The fracture toughness (the critical stress intensity factor, KIC) of the composites was also evaluated using a three-point single edge notch beam (SENB) bending technique. Statistical analysis of the data was performed with ANOVA and the Tukey's post-hoc test. The fiber-resin interface and the fracture surface were investigated using SEM. RESULTS: The change in the surface mechanical properties and chemistry of the corona treated UHMWPE fibers were monitored. The fibers exposed to corona for 5s showed higher surface nanohardness. In the FRCs, the specimens reinforced with 5s corona treated silanized fibers showed higher mechanical properties (flexural modulus, flexural strength, and fracture toughness), SEM images revealed a better adhesion between the resin and fibers after 5s fiber corona treatment and silanization. SIGNIFICANCE: Corona and silane treatment of UHMWPE fibers provide dental FRCs with improved mechanical properties. PMID- 26113428 TI - The global threat of antimicrobial resistance--The need for standardized surveillance tools to define burden and develop interventions. PMID- 26113429 TI - Association between physical activity, participation in Physical Education classes, and social isolation in adolescents. AB - OBJECTIVE: To analyze the association between physical activity, participation in Physical Education classes, and indicators of social isolation among adolescents. METHODS: This was an epidemiological study based on secondary analysis of data from a representative sample of students (14-19 years) from public high schools (n=4,207). Data were collected through the questionnaire Global School-based Student Health Survey. The independent variables were the level of physical activity and enrollment in Physical Education classes, while the dependent variables were two indicators of social isolation (feeling of loneliness and having few friends). Descriptive and inferential procedures were used in the statistical analysis. RESULTS: Most of the adolescents were classified as insufficiently active (65.1%) and reported not attending Physical Education classes (64.9%). Approximately two in each ten participants reported feeling of loneliness (15.8%) and, in addition, about one in each five adolescents reported have only one friend (19.5%). In the bivariate analysis, a significantly lower proportion of individuals reporting social isolation was observed among adolescents who referred higher enrollment in Physical Education classes. After adjustment for confounding variables, binary logistic regression showed that attending Physical Education classes was identified as a protective factor in relation to the indicator of social isolation 'having few friends,' but only for girls. CONCLUSIONS: It was concluded that participation in Physical Education classes is associated with reduced social isolation among female adolescents. PMID- 26113430 TI - The antenna of a burrowing dragonfly larva, Onychogomphus forcipatus (Anisoptera, Gomphidae). AB - The larva of the dragonfly Onychogomphus forcipatus (Anisoptera, Gomphidae) has a burrowing lifestyle and antennae composed of four short and broad segments (scape, pedicel and a two-segmented flagellum). The present ultrastructural investigation revealed that different sensilla and one gland are located on the antenna. There is a great diversity of mechanoreceptors of different kinds. In particular club-shaped sensilla, sensilla chaetica, and tree-like sensilla show the typical structure of bristles, the most common type of mechanoreceptors, usually responding to direct touch, while numerous long thin thorny trichoid sensilla show a morphology recalling the structure of filiform hair mechanoreceptors. The latter ones are presumably important in larval Odonata for current detection and rheotactic orientation, especially in a burrowing species. On the smooth apical cuticle of the second flagellar segment, three structures are visible: (1) a small ellipsoidal pit hosting a convoluted peg, the morphology of which resembles that of a typical chemoreceptor (even if pores are lacking), (2) a couple of small pits (not investigated under TEM), and (3) one wide depression with spherical structures, the internal morphology of which lets us assume that it is a gland with unknown function. This is the first report of an antennal gland in palaeopteran insects. PMID- 26113431 TI - Uncovering head gland diversity in neotropical Polistinae wasps (Hymenoptera, Vespidae): comparative analysis and description of new glands. AB - Exocrine glands are involved in several wasp colony activities; however, the number of known glands in the Vespidae is rather low when compared to other social insect groups. The aim of this study is to survey the head of Neotropical social wasps and to provide a detailed comparative study of the glands found in the Polistinae. A total of 33 species distributed over 13 genera were studied with serial histological sections of the head, excluding the labiomaxillary complex. Additionally, the exoskeleton was explored using scanning electron microscopy looking for associated modifications. A total of eleven exocrine glands were observed, five are structures recorded for the first time for the Hymenoptera, three are new records for the Polistinae and three are previously known organs. The glands studied are: ocellar gland I, ocellar gland II, periocular gland, subantennal gland, hypopharyngeal gland, clypeal gland, posterobasal genal gland, ectal mandibular gland, mesal mandibular gland, intramandibular gland I, and intramandibular gland II. The widespread distribution of most of these glands suggests an origin prior to the evolution of the Polistinae. Our results highlight the importance of detailed morphological studies to unveil the significance of chemical communication in one of the most characteristic groups of social animals. PMID- 26113432 TI - Effectiveness of sofosbuvir-based regimens in genotype 1 and 2 hepatitis C virus infection in 4026 U.S. Veterans. AB - BACKGROUND: Real-world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. AIM: To assess sustained virological response (SVR) of sofosbuvir (SOF)-based regimens in routine medical practice. METHODS: Observational, intent-to-treat cohort analysis of genotype 1 and 2 HCV-infected veterans initiating SOF-based regimens with recommended treatment duration of 12 weeks. RESULTS: Four thousand and twenty-six veterans with genotype 1 (N = 3203) and genotype 2 (N = 823) comprise the cohort. SVR rates for genotype 1 were 66.8% for SOF + peginterferon + ribavirin (RBV), 75.3% for SOF + simeprevir (SIM), 74.1% for SOF + SIM + RBV and for genotype 2 were 79.0% for SOF + RBV. Genotype 1 patients were less likely to achieve SVR with BMI >=30 (OR 0.64, 95% CI 0.49 0.84, P < 0.001), a history of decompensated liver disease (OR 0.51, 95% CI 0.36 0.71, P < 0.001), treatment experience (OR 0.58, 95% CI 0.48-0.71, P < 0.001), APRI >2 (OR 0.44, 95% CI 0.36-0.55, P < 0.001) and with SOF + PEG + RBV compared with SOF + SIM (OR 0.50, 95% CI 0.40-0.62, P < 0.001). Age, sex, race/ethnicity, diabetes and genotype subtype did not predict SVR. Odds of achieving SVR with SOF + SIM + RBV did not differ compared with SOF + SIM (OR 1.03, 95% CI 0.75-1.44, P = 0.86). Genotype 2 patients were less likely to achieve SVR with prior treatment experience (OR 0.55, 95% CI 0.35-0.88, P = 0.009) and APRI >2 (OR 0.39, 95% CI 0.25-0.62, P < 0.001). CONCLUSIONS: In this real-world cohort, SVR rates were lower than in clinical trials. Genotype 1 and 2 HCV-infected patients with advanced liver disease by APRI >2 or FIB-4 > 3.25 were significantly less likely to achieve SVR. For genotype 1, a SOF + SIM +/- RBV regimen was associated with a higher likelihood of SVR. PMID- 26113433 TI - Anti-Social Behaviors Associated with Anabolic-Androgenic Steroid Use among Male Adolescents. AB - Anabolic-androgenic steroids (AAS) have been linked to a range of problematic behaviors, but AAS use is still sometimes portrayed as more benign than other forms of classical drug abuse. To address this issue, we compared the prevalence of anti-social behaviors among adolescent AAS users, non-AAS illicit drug users, and drug non-users. We examined 3 waves (2004, 2008, and 2012) of self-reported cross-sectional data from a secondary school survey conducted in Stockholm, Sweden (total n = 19,773; response percentage, 79.6%). Across all survey years, the risk ratios for virtually all measured anti-social behaviors were significantly higher among AAS users compared to non-AAS illicit drug users and to drug non-users. PMID- 26113434 TI - TB vaccines; promoting rapid and durable protection in the lung. AB - TB vaccine discovery has focused on IFN-gamma both for the selection of antigens and vaccine delivery strategies. Recent breakthroughs in our understanding of the requirements for immunological memory and the expression of immunity to TB in the lung now provide a framework for reconsidering that strategy. We will discuss the status of the TB vaccine field, recent insights into the role of central memory cells and the potential of tissue-resident memory cells in vaccine promoted protection against TB. PMID- 26113436 TI - Longitudinal association between neighborhood cohesion and depressive mood in old age: A Japanese prospective study. AB - Despite increasing evidence of the relationship between neighborhood cohesion and depressive mood, little is known about this longitudinal association in old age. This study examined the association between perceived neighborhood cohesion and depressive mood and the stress-buffering effect of perceived neighborhood cohesion on depressive mood among older Japanese people using the 2010 (baseline) and 2012 (follow-up) Hatoyama Cohort Study datasets. We analyzed 655 participants aged 65-84 at baseline. Although perceived neighborhood cohesion at baseline was not associated with depressive mood at follow-up, high neighborhood cohesion partially offset the deleterious effect of anticipated daily stressors on depressive mood. This effect was stronger for long-term residents of the neighborhood. Interventions to strengthen neighborhood cohesion may help reduce the deleterious effect of stressors on older residents' depressive mood. PMID- 26113435 TI - Potential of carbon nanotubes in algal biotechnology. AB - A critical mass of knowledge is emerging on the interactions between plant cells and engineered nanomaterials, revealing the potential of plant nanobiotechnology to promote and support novel solutions for the development of a competitive bioeconomy. This knowledge can foster the adoption of new methodological strategies to empower the large-scale production of biomass from commercially important microalgae. The present review focuses on the potential of carbon nanotubes (CNTs) to enhance photosynthetic performance of microalgae by (i) widening the spectral region available for the energy conversion reactions and (ii) increasing the tolerance of microalgae towards unfavourable conditions occurring in mass production. To this end, current understanding on the mechanisms of uptake and localization of CNTs in plant cells is discussed. The available ecotoxicological data were used in an attempt to assess the feasibility of CNT-based applications in algal biotechnology, by critically correlating the experimental conditions with the observed adverse effects. Furthermore, main structural and physicochemical properties of single- and multi-walled CNTs and common approaches for the functionalization and characterization of CNTs in biological environment are presented. Here, we explore the potential that nanotechnology can offer to enhance functions of algae, paving the way for a more efficient use of photosynthetic algal systems in the sustainable production of energy, biomass and high-value compounds. PMID- 26113437 TI - Newborn screening blood spot analysis in the UK: influence of spot size, punch location and haematocrit. AB - OBJECTIVE: In dried blood spot analysis, punch location and variations in applied sample volume and haematocrit can produce different measured concentrations of analytes. We investigated the magnitude of these effects in newborn screening in the UK. METHODS: Heparinized blood spiked with thyroid stimulating hormone (TSH), phenylalanine, tyrosine, leucine, methionine, octanoyl carnitine (C8), and immunoreactive trypsinogen (IRT) was spotted onto filter paper: (i) at a constant haematocrit of 50% at various volumes, and (ii) at a range of haematocrits using a constant volume. Subpunches (3.2 mm) of the dried blood spots were then analysed. RESULTS: Compared with a central punch from a 50 uL blood spot with 50% haematocrit, 10 uL spots can have significantly lower measured concentrations of all analytes, with decreases of 15% or more observed for leucine, methionine, phenylalanine, and tyrosine. Punching at the edge of a spot can increase measured concentrations up to 35%. Higher haematocrit decreased measured TSH and C8 yet increased amino acids and IRT by 15% compared with 50% haematocrit. Lower haematocrits had the opposite effect, but only with higher concentrations of some analytes. CONCLUSIONS: Differences in blood spot size, haematocrit and punch location substantially affect measured concentrations for analytes used in the UK newborn screening programme, and this could affect false positive and negative rates. To minimize analytical bias, these variables should be controlled or adjusted for where possible. PMID- 26113439 TI - Impact of bread making on fructan chain integrity and effect of fructan enriched breads on breath hydrogen, satiety, energy intake, PYY and ghrelin. AB - Recently, there has been considerable interest in the satiety inducing properties of inulin type fructans (ITF) as a tool for weight management. As a staple food, breads provide an excellent vehicle for ITF supplementation however the integrity of the ITF chains and properties upon bread making need to be assessed. Breads enriched with 12% fructooligosaccharides (FOS) and 12% inulin were baked and the degree of polymerisation of fructans extracted from the breads were compared to those of pure compounds. An acute feeding study with a single blind cross-over design was conducted with 11 participants to investigate the effect of ITF enriched breads on breath hydrogen, self-reported satiety levels, active ghrelin, total PYY and energy intake. Size exclusion chromatography indicated that little or no depolymerisation of inulin occurred during bread making, however, there was evidence of modest FOS depolymerisation. Additionally, ITF enriched breads resulted in increased concentrations of exhaled hydrogen although statistical significance was reached only for the inulin enriched bread (p = 0.001). There were no significant differences between bread types in reported satiety (p = 0.129), plasma active ghrelin (p = 0.684), plasma PYY (p = 0.793) and energy intake (p = 0.240). These preliminary results indicate that inulin enriched bread may be a suitable staple food to increase ITF intake. Longer intervention trials are required to assess the impact of inulin enriched breads on energy intake and body weight. PMID- 26113440 TI - Antiferromagnetically Coupled Dimeric Dodecacopper Supramolecular Architectures of Macrocyclic Ligands with a Symmetrical MU6-BO3(3-) Central Moiety. AB - Reactions between 2,6-diformyl-4-alkyl(R)-phenol (R = CH3 or C(CH3)3) and 1,3 diamino-2-hydroxypropane (1,3-DAP) in the presence of copper(II) salts (Cu(BF4)2.6H2O, Cu(ClO4)2.6H2O/H3BO3/Ar) and triethylamine (TEA) in a single pot result in self-assembly of dimeric dodecacopper supramolecular architectures of 30-membered hexatopic macrocyclic ligands (H6L4 and H6L5) with unique and fascinating structures having the BO3(3-) anion as the central species bonded to all six copper centers in a symmetrical fashion (MU6-BO3(3-)). A number of closely related macrocyclic hexacopper complexes are reported: {[Cu6(L4)(MU6 BO3)(MU-H2O)(C3H7NO)2(BF4)][BF4]2.3C3H7NO}2 (1) (DMF = C3H7NO), {[Cu6(L4)(MU6 BO3)(MU-C3H7NO)3][ClO4]3.3C3H7NO}2 (2), {[Cu6(L5)(MU6-BO3)(MU OH)(H2O)3(C3H7NO)][BF4]2.6C3H7NO.4C2H5OH.2H2O}2 (3), {[Cu6(L5)(MU6-BO3)(MU CH3OH)(CH3OH)2][ClO4]3.10H2O}2 (4), and {[Cu6(L5)(MU6-BO3)(MU-CH3CO2)(MU CH3O)(CH3OH)][BF4].13CH3OH.8H2O}2 (5). A polymeric side product {[Cu2(H2L2)(CH3OH)(BF4)][BF4]}n (6), involving a 2 + 2 macrocyclic ligand, was also isolated and structurally characterized. Complex 6 involves dinuclear copper(II) units linked through BF4(-) anions to form a novel 1D single-chain polymeric coordination compound. This appears to be the first report in which a central BO3(3-) species is linked to six copper(II) ions held together by a single macrocyclic ligand through three MU1,1-O(BO3(3-)) and three MU1,3-O(BO3(3 )) bridges. In complexes 1-5 the BO3(3-) is present in the center of the macrocyclic cavity and is bonded to all six metal centers arranged in a benzene like hexagonal array. In the hexagonal array there are alternate double (MU alkoxide and MU1,3-O(BO3(3-))) and (MU-phenoxide and MU1,1-O(BO3(3-))) bridges between the Cu(II) centers. The symmetrical hexa-bridging nature of MU6-BO3(3-) is unprecedented in transition metal complex chemistry, and along with alkoxide and phenoxide bridges in the equatorial plane provides effective pathways for an overall antiferromagnetic exchange interaction between six copper(II) centers. In 1, 3, and 5 the BO3(3-) moiety is produced in one step (synthetic) by an unusual copper(II)-macrocycle complex catalyzed hydrolysis of BF4(-) ion in methanol. In 2 and 4 the central species (BO3(3-)) comes from boric acid (H3BO3) which is added to reaction mixture of Cu(ClO4)2/H6L4/H6L5 under inert conditions to confirm the identity of the central species. PMID- 26113441 TI - Emodin prevents intima thickness via Wnt4/Dvl-1/beta-catenin signaling pathway mediated by miR-126 in balloon-injured carotid artery rats. AB - Neointimal proliferation after vascular injury is a key mechanism of restenosis, a major cause of percutaneous transluminal angioplasty failure and artery bypass occlusion. Emodin, an anthraquinone with multiple physiological activities, has been reported to inhibit proliferation of vascular smooth muscle cells (VSMCs) that might cause intimal arterial thickening. Thus, in this study, we established a rat model of balloon-injured carotid artery and investigated the therapeutic effect of emodin and its underlying mechanism. Intimal thickness was analyzed by hematoxylin and eosin staining. Expression of Wnt4, dvl-1, beta-catenin and collagen was determined by immunohistochemistry and/or western blotting. The proliferation of VSMC was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assay and electron microscopy. MicroRNA levels were quantified by real-time quantitative PCR. Emodin relieved injury-induced artery intimal thickness. Results of western blots and immunohistochemistry showed that emodin suppressed expression of signaling molecules Wnt4/Dvl-1/beta-catenin as well as collagen protein in the injured artery. In addition, emodin enhanced expression of an artery injury-related microRNA, miR-126. In vitro, MTT assay showed that emodin suppressed angiotensin II (AngII)-induced proliferation of VSMCs. Emodin reversed AngII-induced activation of Wnt4/Dvl-1/beta-catenin signaling by increasing expression of miR-126 that was strongly supported by transfection of mimic or inhibitor for miR-126. Emodin prevents intimal thickening via Wnt4/Dvl-1/beta-catenin signaling pathway mediated by miR-126 in balloon-injured carotid artery of rats. PMID- 26113442 TI - Is there a "magic" hemoglobin number? Clinical decision support promoting restrictive blood transfusion practices. AB - Blood transfusion has been identified as one of the most frequently performed therapeutic procedures, with a significant percentage of transfusions identified to be inappropriate. Recent key clinical trials in adults have provided Level 1 evidence to support restrictive red blood cell (RBC) transfusion practices. However, some advocates have attempted to identify a "correct" Hb threshold for RBC transfusion; whereas others assert that management of anemia, including transfusion decisions, must take into account clinical patient variables, rather than simply one diagnostic laboratory test. The heterogeneity of guidelines for blood transfusion by a number of medical societies reflects this controversy. Clinical decision support (CDS) uses a Hb threshold number in a smart Best Practices Alert (BPA) upon physician order, to trigger a concurrent utilization self-review for whether blood transfusion therapy is appropriate. This review summarizes Level 1 evidence in seven key clinical trials in adults that support restrictive transfusion practices, along strategies made possible by CDS that have demonstrated value in improving blood utilization by promoting restrictive transfusion practices. PMID- 26113443 TI - Prevalence of human papillomavirus types in cervical cancerous and precancerous lesions of Ecuadorian women. AB - Human Papillomavirus (HPV) is the most common sexually transmitted infection worldwide and it is responsible for most cases of uterine cancer. In Ecuador there is limited information about HPV types (and variants) in cancerous lesions; however, identifying the type-specific HPV prevalence in cervical lesions of women living in Ecuador is important to better predict the impact of HPV prophylactic vaccination in this country. We studied the prevalence of HPV types in cervical cancerous or precancerous lesions from 164 Ecuadorian women and found that 86.0% were HPV positive. The most common types were HPV16 (41.8%) and HPV58 (30.5%). Interestingly, HPV18 was detected only in 2.8% of the HPV-positive samples. Fifteen DNA sequences (genes E6 and L1) from 16 samples positive for HPV16 belonged to the European lineage, considered one of the least carcinogenic lineages, and 1 (6.25%) to the Asian-American lineage. Similar analysis in 12 HPV58 positive samples showed that 10 (83.3%) sequences grouped in sublineage A2, which belongs to the oldest HPV58 lineage, 1 belonged to A3 and 1 to lineage C. This study suggests that the currently used HPV vaccines (bivalent and tetravalent) may have lower effectiveness in Ecuador than in other geographic locations where HPV18 is more prevalent. PMID- 26113445 TI - Sleep promotes analogical transfer in problem solving. AB - Analogical problem solving requires using a known solution from one problem to apply to a related problem. Sleep is known to have profound effects on memory and information restructuring, and so we tested whether sleep promoted such analogical transfer, determining whether improvement was due to subjective memory for problems, subjective recognition of similarity across related problems, or by abstract generalisation of structure. In Experiment 1, participants were exposed to a set of source problems. Then, after a 12-h period involving sleep or wake, they attempted target problems structurally related to the source problems but with different surface features. Experiment 2 controlled for time of day effects by testing participants either in the morning or the evening. Sleep improved analogical transfer, but effects were not due to improvements in subjective memory or similarity recognition, but rather effects of structural generalisation across problems. PMID- 26113444 TI - More than one way to see it: Individual heuristics in avian visual computation. AB - Comparative pattern learning experiments investigate how different species find regularities in sensory input, providing insights into cognitive processing in humans and other animals. Past research has focused either on one species' ability to process pattern classes or different species' performance in recognizing the same pattern, with little attention to individual and species specific heuristics and decision strategies. We trained and tested two bird species, pigeons (Columba livia) and kea (Nestor notabilis, a parrot species), on visual patterns using touch-screen technology. Patterns were composed of several abstract elements and had varying degrees of structural complexity. We developed a model selection paradigm, based on regular expressions, that allowed us to reconstruct the specific decision strategies and cognitive heuristics adopted by a given individual in our task. Individual birds showed considerable differences in the number, type and heterogeneity of heuristic strategies adopted. Birds' choices also exhibited consistent species-level differences. Kea adopted effective heuristic strategies, based on matching learned bigrams to stimulus edges. Individual pigeons, in contrast, adopted an idiosyncratic mix of strategies that included local transition probabilities and global string similarity. Although performance was above chance and quite high for kea, no individual of either species provided clear evidence of learning exactly the rule used to generate the training stimuli. Our results show that similar behavioral outcomes can be achieved using dramatically different strategies and highlight the dangers of combining multiple individuals in a group analysis. These findings, and our general approach, have implications for the design of future pattern learning experiments, and the interpretation of comparative cognition research more generally. PMID- 26113446 TI - Cue-independent forgetting by intentional suppression - Evidence for inhibition as the mechanism of intentional forgetting. AB - People are able to intentionally forget unwanted memories through voluntary suppression, as revealed by the Think/No-think (TNT) paradigm. However, the nature of intentional forgetting is controversial. Findings that forgetting is independent of retrieval cues suggest that inhibitory control underlies intentional forgetting, but this result is also in line with an interference account. To resolve this controversy, we have directly contrasted the cue independent characteristic of suppression versus interference. A double-cue paradigm was used, in which two different cues were associated with the same target during initial memory formation. Only one cue-target association received further interference/suppression training. In the test phase, when both cues were used to retrieve the target, we found that interference caused memory impairment that was restricted to the trained cue-target association, while suppression induced forgetting that generalized to the independent cue-target association. Therefore, the effect of suppression differs from that of interference. The cue independent forgetting by voluntary suppression indicates that the target memory itself is inhibited, providing evidence that the underlying mechanism of suppression-induced forgetting is inhibitory control. PMID- 26113447 TI - Language exposure facilitates talker learning prior to language comprehension, even in adults. AB - Adults show a native language advantage for talker identification, which has been interpreted as evidence that phonological knowledge mediates talker learning. However, infants also show a native language benefit for talker discrimination, suggesting that sensitivity to linguistic structure due to systematic language exposure promotes talker learning, even in the absence of functional phonological knowledge or language comprehension. We tested this hypothesis by comparing two groups of English-monolingual adults on their ability to learn English and French voices. One group resided in Montreal with regular exposure to spoken French; the other resided in Storrs, Connecticut and did not have French exposure. Montreal residents showed faster learning and better retention for the French voices compared to their Storrs-residing peers. These findings demonstrate that systematic exposure to a foreign language bolsters talker learning in that language, expanding the gradient effect of language experience on talker learning to perceptual learning that precedes sentence comprehension. PMID- 26113449 TI - Rhetorical features facilitate prosodic processing while handicapping ease of semantic comprehension. AB - Studies on rhetorical features of language have reported both enhancing and adverse effects on ease of processing. We hypothesized that two explanations may account for these inconclusive findings. First, the respective gains and losses in ease of processing may apply to different dimensions of language processing (specifically, prosodic and semantic processing) and different types of fluency (perceptual vs. conceptual) and may well allow for an integration into a more comprehensive framework. Second, the effects of rhetorical features may be sensitive to interactions with other rhetorical features; employing a feature separately or in combination with others may then predict starkly different effects. We designed a series of experiments in which we expected the same rhetorical features of the very same sentences to exert adverse effects on semantic (conceptual) fluency and enhancing effects on prosodic (perceptual) fluency. We focused on proverbs that each employ three rhetorical features: rhyme, meter, and brevitas (i.e., artful shortness). The presence of these target features decreased ease of conceptual fluency (semantic comprehension) while enhancing perceptual fluency as reflected in beauty and succinctness ratings that were mainly driven by prosodic features. The rhetorical features also predicted choices for persuasive purposes, yet only for the sentence versions featuring all three rhetorical features; the presence of only one or two rhetorical features had an adverse effect on the choices made. We suggest that the facilitating effects of a combination of rhyme, meter, and rhetorical brevitas on perceptual (prosodic) fluency overcompensated for their adverse effects on conceptual (semantic) fluency, thus resulting in a total net gain both in processing ease and in choices for persuasive purposes. PMID- 26113448 TI - Poor judgment of distance between nociceptive stimuli. AB - Although pain is traditionally assumed to be poorly localized, recent work indicates that spatial acuity for nociception is surprisingly high. Here we investigated whether the nervous system can also accurately estimate the distance between two nociceptive stimuli. Estimating distance implies a metric representation of spatial relations, a property that underlies abilities such as perceiving the size of external objects. We presented pairs of simultaneous nociceptive or non-nociceptive somatosensory stimuli, and asked participants to judge the distance between them. Judgments of distance between nociceptive stimuli were much worse than judgments of distance between non-nociceptive tactile stimuli, even on skin regions where spatial acuity for nociception exceeded spatial acuity for touch. Control experiments ruled out explanations based on inaccurate localization of double nociceptive stimuli. Thus, the nervous system poorly represents the distance between two nociceptive stimuli. The dissociation between high spatial acuity and poor distance judgment in the nociceptive system may reflect a specialization for computing accurate spatial representations useful to protect the body, rather than to perceive the size of external objects. PMID- 26113450 TI - miR-181a promotes G1/S transition and cell proliferation in pediatric acute myeloid leukemia by targeting ATM. AB - PURPOSE: Abnormal expression of miRNAs is intimately related to a variety of human cancers. The purpose of this study is to confirm the expression of miR-181a and elucidate its physiological function and mechanism in pediatric acute myeloid leukemia (AML). METHODS: Pediatric AML patients and healthy controls were enrolled, and the expression of miR-181a and ataxia telangiectasia mutated (ATM) in tissues were examined using quantitative PCR. Moreover, cell proliferation and cell cycle were evaluated in several cell lines (HL60, NB4 and K562) by using flow cytometry after transfected with miR-181a mimics and inhibitors, or ATM siRNA and control siRNA. Finally, ATM as the potential target protein of miR-181a was examined. RESULTS: We found that miR-181a was significantly increased in pediatric AML, which showed an inverse association with ATM expression. Overexpressed miR-181a in cell lines significantly enhanced cell proliferation, as well as increased the ratio of S-phase cells by miR-181a mimics transfection in vitro. Luciferase activity of the reporter construct identified ATM as the direct molecular target of miR-181a. ATM siRNA transfection significantly enhanced cell proliferation and increased the ratio of S-phase cells in vitro. CONCLUSION: The results revealed novel mechanism through which miR-181a regulates G1/S transition and cell proliferation in pediatric AML by regulating the tumor suppressor ATM, providing insights into the molecular mechanism in pediatric AML. PMID- 26113451 TI - How staging of thin melanoma is changed after the introduction of TNM 7th edition: a population-based analysis. AB - INTRODUCTION: In 2009, the American Joint Committee on Cancer (AJCC) incorporated the tumor mitotic rate in the melanoma pathological TNM staging system. To investigate the effect of this change on the pT1 substaging of primary cutaneous melanomas, we reclassified the cases collected by a cancer registry according to the 6th and the 7th editions of AJCC melanoma staging. METHODS: Patients with pathological T1 melanoma diagnosed in the period 2000-2008 were selected from Tuscan Cancer Registry. The histological reports were reviewed and pT1 melanomas classified according to both the 6th and the 7th editions of the AJCC staging system. The shift of melanomas between pT1 substages was analyzed. RESULTS: Among the 242 pT1 melanomas collected in the study period and with mitotic index available, there were 202 (83 % of all pT1) and 175 (72 %) pT1a, according to the 6th and the 7th editions of the AJCC melanoma staging, respectively. When the 7th edition was used, 20 % of all pT1a melanomas shifted to pT1b, and 32 % of all pT1b melanomas shifted to pT1a. A poor level agreement between the two TNM staging systems, measured by the Cohen's kappa coefficient, was found (K = 0.37). CONCLUSIONS: The addition of mitotic activity to the pathological staging resulted in an increase in pT1b proportion and in a change in the classification of some cases. This modification could influence the clinical approach, with a different use of the sentinel lymph node biopsy, and underlines the role of mitosis evaluation in the management of thin melanoma patients. PMID- 26113452 TI - Determination of sex-based differences in serum gamma-linolenic [corrected] acid and dihomo-gamma-linolenic [corrected] acid using gas chromatography-mass spectrometry. AB - Because serum unsaturated fatty acids can provide useful information on disease diagnosis, the simultaneous determination of several fatty acids in small volumes of human serum would be beneficial for clinical applications. In the present study, serum fatty acids were extracted with n-heptane/chloroform from 10MUL of serum collected from 26 healthy Japanese subjects (11 men, ages 23-37 years; 15 women, ages 18-37 years) after deproteinization with perchloric acid, derivatization to their methyl ester using p-toluenesulfonic acid as an acid catalyst, and subsequent separation and measurement by gas chromatography-mass spectrometry (GC-MS) in the selected ion monitoring mode. Nine types of fatty acids (palmitoleic acid [PLA], oleic acid [OA], linoleic [corrected] acid [LA], gamma-linolenic acid [GLA], alpha-linolenic acid [ALA], dihomo-GLA [DGLA], arachidonic acid [AA], eicosapentaenoic acid [EPA], and docosahexaenoic acid [DHA]) were analyzed in the serum within 35 min by GC-MS. The concentrations of these fatty acids in serum ranged from 3.64+/-0.38MUM (GLA) to 413+/-26.3 MUM (LA). Among these nine fatty acids, GLA and DGLA levels were significantly lower in women than in men (p=0.0034 and 0.0012, respectively), suggesting that there may be sex-based differences in the biosynthetic production or metabolic processes of GLA and DGLA in humans. PMID- 26113453 TI - LC-MS/MS method for the simultaneous quantification of 11 compounds of Ginkgo biloba extract in lysates of mesangial cell cultured by high glucose. AB - The mesangial cell (MC) cultured with high glucose has been used to observe the protective effect of Ginkgo biloba extract (GBE) against diabetic nephropathy (DN), but the compounds interacting with cell are still unknown, which may be potential bioactive components. Based on this, the determination of GBE in MC lysates was proposed by high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) in this study. The MC was cultured with normal or high glucose with GBE for 4, 8, 12, 16, 24 and 48h. The harvested cell was extracted with 40% acetic acid in water and further analyzed by LC-MS/MS. All the validation data including linearity, intra-day and inter-day precision, limit of detection and quantification, matrix effect, and stability were within the required limits. The validated method was successfully applied to quantify 11 compounds of GBE in cell lysates. The results showed that high glucose prolonged the peak time of all observed 11 compounds and peak concentrations of bilobalide, ginkgolide C, ginkgolide B, quercetin, luteolin, kaempferol, isorhamnetin and genkwanin in cell lysates, which hinted that these compounds may be the potential bioactive components of GBE with preventive effect against DN. PMID- 26113454 TI - Characterization of Chinese rice wine taste attributes using liquid chromatographic analysis, sensory evaluation, and an electronic tongue. AB - To evaluate the taste characteristics of Chinese rice wine, wine samples sourced from different vintage years were analyzed using liquid chromatographic analysis, sensory evaluation, and an electronic tongue. Six organic acids and seventeen amino acids were measured using high performance liquid chromatography (HPLC). Five monosaccharides were measured using anion-exchange chromatography. The global taste attributes were analyzed using an electronic tongue (E-tongue). The correlations between the 28 taste-active compounds and the sensory attributes, and the correlations between the E-tongue response and the sensory attributes were established via partial least square discriminant analysis (PLSDA). E-tongue response data combined with linear discriminant analysis (LDA) were used to discriminate the Chinese rice wine samples sourced from different vintage years. Sensory evaluation indicated significant differences in the Chinese rice wine samples sourced from 2003, 2005, 2008, and 2010 vintage years in the sensory attributes of harmony and mellow. The PLSDA model for the taste-active compounds and the sensory attributes showed that proline, fucose, arabinose, lactic acid, glutamic acid, arginine, isoleucine, valine, threonine, and lysine had an influence on the taste characteristic of Chinese rice wine. The Chinese rice wine samples were all correctly classified using the E-tongue and LDA. The electronic tongue was an effective tool for rapid discrimination of Chinese rice wine. PMID- 26113455 TI - A simple high performance liquid chromatography method for quantitatively determining the reduced form of peroxiredoxin 2 and the mass spectrometric analysis of its oxidative status. AB - Peroxiredoxins (Prxs) are a family of thiol peroxidases, which have been suggested to serve as biomarkers for diseases caused by oxidative stress. In this study, we established a high performance liquid chromatography (HPLC) method for quantifying the amount of Prx2 in red blood cells (RBCs). RBC proteins were separated using HPLC, and a single peak was detected that matched that produced by recombinant Prx2. Under improved conditions, the calibration curve for Prx2 (reduced form) was linear over the range of 0.5-20.0MUg with a correlation coefficient of 0.999. The minimum detectable level of the recombinant Prx2 was 0.2MUg, with a signal-to-noise ratio of 3 per 20MUl of injection volume. SDS-PAGE and mass spectrometric analysis showed that the proteins comprising the peak were almost exclusively Prx2. Further high-resolution analysis using nanoLC-MS/MS demonstrated that the oxidation sensitive, Cys-51 was carbamidomethylated by iodoacetamide-alkylation during in-gel digestion but was not modified with sulfinic acid (-SO2H) or sulfonic acid (-SO3H). These results indicated that the separated Prx2 was the reduced form and not the hyperoxidized form. These basic experiments allowed us to determine the relative amounts of native Prx2 in RBCs taken from healthy subjects. The average levels of Prx2 in male and female subjects were 7.28ng/mg and 8.29ng/mg, respectively, and no significant difference was observed between the sexes. Therefore, the HPLC method with UV detection described herein offers a convenient method to quantitatively determine the levels of reduced form of Prx2 and its oxidative decrease in human RBCs. PMID- 26113456 TI - Linkage of sleep-disordered breathing and acute aortic dissection with patent false lumen. AB - Sleep-disordered breathing (SDB) is known as a cardiovascular risk factor and has high prevalence in hypertension, which is a major risk factor of aortic dissection (AD). However, the impact of SDB on AD has not been fully clarified. The aim of this study is to elucidate the impact of SDB on AD, especially on the type of false lumen in AD. We enrolled twenty-three consecutive patients with acute AD (mean age: 66 +/- 13 years). All subjects were evaluated by an ambulatory polygraphic sleep monitoring within 1 month from the onset. AD was evaluated by axial images of computed tomography. We comparatively analyzed SDB and AD. 35 % of the subjects presented severe OSA (apnea-hypopnea index: AHI >=30). The patent false lumen group showed significantly higher systolic and diastolic blood pressure (BP) on arrival and AHI, and lower percutaneous oxygen saturation (SaO2) compared with those in the thrombosed false lumen group. The prevalence of severe SDB was higher in the patent false lumen group (60 vs 15 %, p = 0.039). Systolic BP on arrival was significantly correlated with AHI (r = 0.457, p = 0.033) and the minimum SaO2 (r = -0.537, p = 0.010). The present study revealed close linkage between SDB and AD, and a high prevalence of SDB among AD patients. Severe SDB was related to the development of AD, especially for the patent false lumen type through highly elevated BP which might be easily evoked in the presence of severe SDB. Repetitive occurrence of intrathoracic negative pressure also might influence the repair or closure of false lumen of AD, although the present analysis did not reach statistical significance. PMID- 26113457 TI - Axillary artery cannulation provides balanced cerebral oxygenation. AB - Deterioration of cerebral performance remains a major problem after cardiac surgery. Axillary artery cannulation can improve clinical outcome, but some experimental series show a malperfusion of the right hemisphere. The aim of our clinical study was to analyze the intraoperative investigation of cerebral oxygenation in two different arterial cannulation sites by use of near-infrared spectroscopic oximetry (NIRO). We compared retrospectively the cerebral saturation of 20 patients with aortic cannulation (group AoC) and 20 patients with right axillary artery cannulation (group AxC) during either valve, coronary artery bypass graft (CABG), combined procedures, or aortic surgery. Patients were monitored with bihemispheric NIRO (NIRO-200, Hamamatsu, Herrsching, Germany). The oxygenation data were calculated as tissue oxygenation index (TOI). And the cardiopulmonary bypass time was considered with special regard to potentially dangerous phases for cerebral desaturation like the starting of the extracorporeal circulation (ECC), cross-clamping, rewarming phase, aortic declamping, and stopping of ECC. Patients were then postoperatively evaluated by a standardized neurological examination. During the entire CPB time and the specific phases potentially at risk for cerebral desaturation, no statistically significant drop of cerebral oxygenation (>20 % for >60 s) was detected after aortic and right axillary artery cannulation, respectively. Furthermore, no significant difference in TOI was found comparing the left and right hemisphere in each group. Postoperatively 2 transient confusional syndromes (CS) were observed after aortic and 3 CS after axillary artery cannulation. Right axillary artery cannulation provides balanced cerebral oxygenation in both hemispheres during extracorporeal circulation and its specific phases potentially at risk for cerebral malperfusion. It might therefore reduce the risk of neurological injury by reduction of solid embolization and maintenance of balanced cerebral oxygenation. PMID- 26113458 TI - Does reducing ischemia time justify to catheterize firstly the culprit artery in every primary PCI? AB - No consensus exists about which coronary artery should be firstly catheterized in primary PCIs. Initial catheterization of the "culprit artery" could reduce reperfusion time. However, complete knowledge of coronary anatomy could modify revascularization strategy. The objective of the study was to analyze this issue in ST-elevation myocardial infarction patients undergoing primary PCI. PCIs were performed in 384 consecutive patients. Choice of ipsilateral approach (IA): starting with a guiding catheter for the angiography and PCI of the "culprit artery", or contralateral approach (CA): starting with a diagnostic catheter for the "non-culprit artery" and completing the angiography and PCI of the culprit with a guiding catheter was left to the operator. Differences between two approaches regarding reperfusion time, acute events or revascularization strategies were analyzed. There were no differences between two approaches regarding reperfusion time or clinical events. When the left coronary artery was responsible, IA was more frequent (76.4 vs 22.6 %), but when it was the right coronary artery, CA was preferred (20 vs 80 %); p < 0.0001. With CA, bare metal stents (BMS) were more used than drug eluting (DES) (60.8 vs 39.2 %) inversely than with IA (BMS 41.3 vs DES 59.7 %; p < 0.0001). With CA there were more patients with left main or multivessel disease in which revascularization was completed with non-urgent surgery (4.13 vs 2.4 %, p < 0.0001). Initial CA does not involve higher reperfusion time. Furthermore, overall knowledge of coronary anatomy offers more options in revascularization strategy and may imply a change in management. Despite the need to individualize each case, contralateral approach may be the first option with the exception of unstable patients. PMID- 26113459 TI - Mucosal immunization of BALB/c mice with DNA vaccines encoding the SEN1002 and SEN1395 open reading frames of Salmonella enterica serovar Enteritidis induces protective immunity. AB - Salmonella Enteritidis is the main cause of foodborne salmonellosis worldwide. The limited effectiveness of current interventions against this pathogen has been the main incentive to develop new methods for the efficient control of this infection. To investigate the use of DNA vaccines against S. Enteritidis in humans, immune responses stimulated by two plasmids containing the genes designated SEN1002, located in the pathogenicity island SPI-19 and encoding a Hcp protein involved in transport mechanisms, and SEN1395, located in the genomic island PhiSE14 and encoding a protein of a new superfamily of lysozymes, were evaluated. Humoral and cellular responses following intranasal immunization of two groups of BALB/c mice with the plasmids pV1002 and pV1395 plus adjuvant were evaluated and it was observed that the IgG2a/IgG1 ratios were sixfold higher than control groups. Both plasmids stimulated specific secretory IgA production. Increased proliferation of lymphocytes and IFN-gamma production were detected in both experimental groups. DNA-vaccinated mice developed protective immunity against a virulent strain of S. Enteritidis, with nearly 2 logs of protection level compared to the negative control values in the spleen. Therefore, DNA vaccines are efficient at stimulating cellular and humoral immune responses at systemic and mucosal levels. PMID- 26113460 TI - Using secure messaging to update medications list in ambulatory care setting. AB - This study analyzed patient adoption of secure messaging to update medication list in an ambulatory care setting. The objective was to establish demographic differences between users and non-users of secure messaging for medications list update. Efficiency of secure messaging for the updates was compared to fax and telephone based updates. METHODS: The study used a retrospective, cross-sectional study of patient medical records and pharmacy call logs at Mayo Clinic, Arizona from December 2012 to May 2013, approximately one year after organizing a pharmacy call center for medication updates. A subgroup analysis during a 2-week period was used to measure time to complete update. MAIN MEASURES: Main dependent variable is the frequency of medication list updates over the study duration. Technician time required for the update was also utilized. RESULTS: A total of 22,495 outpatient visits were drawn and 18,702 unique patients were included in the primary analysis. A total of 402 unique patients were included in sub-group analysis. Secure message response rate (49.5%) was statistically significantly lower than that for phone calls (54.8%, p<0.001). Time to complete the update was significantly higher for faxed medication lists (Wilcoxon rank-sum tests, p<0.001) when compared to those for secure message or phone. CONCLUSIONS: Around 50% of the patients respond to medication update requests before office visit when contacted using phone calls and secure messages. Given the demographic differences between users and non-users of patient portal, mixed mode communication with patients is likely to be the norm for the foreseeable future in outpatient settings. PMID- 26113461 TI - Perceptions of the feasibility and acceptability of a smartphone application for the treatment of binge eating disorders: Qualitative feedback from a user population and clinicians. AB - BACKGROUND: Binge eating, a major public health problem, is characterized by recurrent episodes of out-of-control eating in which an individual consumes an unusually large amount of food in a discrete time period. Limitations of existing treatments for binge eating (both in-person psychotherapy and guided self-help) indicate that smartphone applications (apps) may be an ideal alternative or enhancement. An app for binge eating could aid treatment dissemination, engagement, and/or compliance. However, no research to date has examined user perceptions of a therapeutic app for binge eating, which is critical for development. OBJECTIVES: The purposes of the current study were to conceptualize a potential app for binge eating and obtain feedback regarding feasibility and acceptability from target users (i.e., individuals with binge eating) and clinicians specializing in the treatment of binge eating. METHODS: Our team conceptualized a smartphone app that contained self-help material, functions to monitor behavior, and provisions of in-the-moment interventions. We presented this app (e.g., feature explanations, mock screen shots) through phone interviews with clinicians who specialize in the treatment of binge eating (n=10), and focus groups with individuals experiencing binge eating (n=11). Participants were asked to discuss customization, user burden, terminology, attrition, data visualization, comprehensiveness, reminders, feasibility, acceptability, and perceived effectiveness of the proposed app. Thematic analyses were conducted from qualitative data (e.g., audio recordings and interview notes) obtained via the focus groups and interviews. RESULTS: Results indicated that our proposed app would be highly feasible and acceptable to users and clinicians, though concerns about the degree of personalization and customizability were noted. CONCLUSIONS: The current study details highly specific feedback and ideas regarding essential app features from target users and clinicians. This information is critical for the development of future apps to treat binge eating. Ways in which data obtained from the current study may be generalized to the development of therapeutic apps for other psychological disorders is discussed. PMID- 26113462 TI - NHI-PharmaCloud in Taiwan--A preliminary evaluation using the RE-AIM framework and lessons learned. AB - OBJECTIVES: The aim of this article is to present the preliminary impact of a medication monitoring program, PharmaCloud, in Taiwan and analyze the embedded factors that have contributed to the performance thereof. This article also compared PharmaCloud with similar international programs in order to draw lessons learned. METHODS: The five domains of the RE-AIM framework - reach, effectiveness, adoption, implementation, and maintenance - were examined using qualitative and quantitative data. A difference-in-differences model was applied to analyze the quantitative impact of PharmaCloud on drug utilization and drug expenses. The qualitative impact was evaluated by document analysis based on field reports from the participating medical institutions. RESULTS: Reach and adoption: although all of the major hospitals adopted PharmaCloud and some of the hospitals had high inquiry rates, more time and incentives are needed to raise the overall inquiry rate. Effectiveness: during the study period of 3 months, the number of medications per prescription declined in the intervention group was 0.15 more than that of the general population, and the drug expense per person declined in the intervention group was NT $567 (US $18.9) more than that of the general population. The potential savings could be between 2% and 5% of the total pharmaceutical expenditure. Medication duplication was found to have decreased more in the intervention group. IMPLEMENTATION: a variety of innovations in care delivery are being developed in which the pharmacists play a more significant role. Maintenance: the embedded National Health Insurance would lend strong support for PharmaCloud to grow and thrive. CONCLUSION: PharmaCloud owes its effectiveness to the embedded National Health Insurance (NHI) program, which is universal and provides a comprehensive benefit package including more than 16,000 prescription drugs. An effective medication program is one that operates under the principle of universality and comprehensiveness, facilitates innovations, and has a substantial level of interoperability with the intra-hospital health information systems. PMID- 26113463 TI - Microarray Analysis in Glioblastomas. AB - Microarray analysis in glioblastomas is done using either cell lines or patient samples as starting material. A survey of the current literature points to transcript-based microarrays and immunohistochemistry (IHC)-based tissue microarrays as being the preferred methods of choice in cancers of neurological origin. Microarray analysis may be carried out for various purposes including the following: i. To correlate gene expression signatures of glioblastoma cell lines or tumors with response to chemotherapy (DeLay et al., Clin Cancer Res 18(10):2930-2942, 2012). ii. To correlate gene expression patterns with biological features like proliferation or invasiveness of the glioblastoma cells (Jiang et al., PLoS One 8(6):e66008, 2013). iii. To discover new tumor classificatory systems based on gene expression signature, and to correlate therapeutic response and prognosis with these signatures (Huse et al., Annu Rev Med 64(1):59-70, 2013; Verhaak et al., Cancer Cell 17(1):98-110, 2010). While investigators can sometimes use archived tumor gene expression data available from repositories such as the NCBI Gene Expression Omnibus to answer their questions, new arrays must often be run to adequately answer specific questions. Here, we provide a detailed description of microarray methodologies, how to select the appropriate methodology for a given question, and analytical strategies that can be used. Experimental methodology for protein microarrays is outside the scope of this chapter, but basic sample preparation techniques for transcript-based microarrays are included here. PMID- 26113464 TI - Extreme ultraviolet imaging of three-dimensional magnetic reconnection in a solar eruption. AB - Magnetic reconnection, a change of magnetic field connectivity, is a fundamental physical process in which magnetic energy is released explosively, and it is responsible for various eruptive phenomena in the universe. However, this process is difficult to observe directly. Here, the magnetic topology associated with a solar reconnection event is studied in three dimensions using the combined perspectives of two spacecraft. The sequence of extreme ultraviolet images clearly shows that two groups of oppositely directed and non-coplanar magnetic loops gradually approach each other, forming a separator or quasi-separator and then reconnecting. The plasma near the reconnection site is subsequently heated from ~1 to >=5 MK. Shortly afterwards, warm flare loops (~3 MK) appear underneath the hot plasma. Other observational signatures of reconnection, including plasma inflows and downflows, are unambiguously revealed and quantitatively measured. These observations provide direct evidence of magnetic reconnection in a three dimensional configuration and reveal its origin. PMID- 26113466 TI - Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure Function Analysis. AB - Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the beta-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Overexpression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities. IMPLICATIONS: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer. PMID- 26113465 TI - Using an in-vitro biofilm model to assess the virulence potential of bacterial vaginosis or non-bacterial vaginosis Gardnerella vaginalis isolates. AB - Gardnerella vaginalis is the most common species found in bacterial vaginosis (BV). However, it is also present in a significant proportion of healthy women and G. vaginalis vaginal colonization does not always lead to BV. In an effort to better understand the differences between G. vaginalis isolated from women with a positive (BV) versus a negative (non-BV) diagnosis of BV, we compared the virulence potential of 7 BV and 7 non-BV G. vaginalis isolates and assessed the virulence factors related to biofilm formation, namely: initial adhesion and cytotoxic effect, biofilm accumulation, susceptibility to antibiotics, and transcript levels of the known vaginolysin, and sialidase genes. Furthermore, we also determined the ability of G. vaginalis to displace lactobacilli previously adhered to HeLa cells. Our results showed that non-BV strains were less virulent than BV strains, as suggested by the lower cytotoxicity and initial adhesion to Hela cells. Significant differences in expression of known virulence genes were also detected, further suggesting a higher virulence potential of the BV associated G. vaginalis. Importantly, we demonstrated that BV associated G. vaginalis were able to displace pre-coated vaginal protective lactobacilli and we hypothesize this to be a trigger for BV development. PMID- 26113467 TI - How can we detect the low risk patients for ischemic etiology in heart failure population? PMID- 26113469 TI - Supernormal conduction revealed by extremely late atrial extrasystole during phase 3 right bundle branch block. PMID- 26113468 TI - Clinical outcomes of multiple chronic total occlusions in coronary arteries according to three therapeutic strategies: Bypass surgery, percutaneous intervention and medication. AB - BACKGROUND: Limited data exist regarding clinical outcomes of multiple chronic total occlusions (CTOs) according to therapeutic strategies, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), and medical treatment (MT). METHODS: From March 2003 to February 2012, a total of 2024 patients with at least one CTO were enrolled in retrospective, single-center registry. 393 patients with at least two CTOs were categorized based on the intention-to-treat principle. Propensity-score matching was performed. The primary outcome was major adverse cardiac and cerebral events (MACCE). RESULTS: Of 393 patients with multiple CTOs, 169 patients (43%) were referred for CABG, 130 (33%) for PCI, and 94 (24%) for MT. Median overall follow-up duration was 46.5 (interquartile range 22.7 to 74.6) months. After propensity-score matching analysis, CABG had lower rates of MACCE when compared with PCI (HR=0.43, 0.21 0.85, P=0.01) and MT (HR=0.10, 0.04-0.27, P<0.01). Rates of repeat revascularization was significantly lower in CABG, compared with PCI (HR=0.05, 0.01-0.40, P<0.01) and MT (HR=0.01, 0.00-0.54, P=0.02). CABG had similar rates of cardiac death compared with PCI group (HR=0.97, 0.37-2.53, P=0.95), but had significantly lower rates of cardiac death compared with MT (HR=0.24, 0.08-0.75, P=0.01). CONCLUSIONS: For management of multiple CTOs, MT alone was associated with higher incidence of cardiac death and MACCE compared with CABG. PCI was associated with higher incidence of MACCE, as driven by higher repeat revascularization rate. These findings suggest that CABG might be associated with better clinical outcome and considered as the preferred treatment strategy in patients with multiple CTOs. PMID- 26113470 TI - Impact of type of intervention for aortic valve replacement on heart rate variability. AB - BACKGROUND: It is known that coronary heart surgery leads to varying degrees of cardiac autonomic derangement, clinically detectable as depression of heart rate variability (HRV) parameters. Few studies report that also surgical replacement of the aortic valve (SAVR) may lead to HRV abnormalities, while very little is known about the autonomic effects obtained after less invasive aortic valve replacement techniques. The study aimed to evaluate HRV after SAVR and to compare it with two less invasive techniques, transapical (TaAVI) and tranfemoral (TfAVI) aortic valve implant. METHODS: Time-domain heart rate variability (HRV) parameters have been studied by 24-h Holter ECG in 129 patients after SAVR, in 63 patients after TfAVI and in 19 patients after TaAVI. RESULTS: All HRV parameters were significantly depressed in SAVR, while they were almost completely preserved in TfAVI patients; TaAVI cases showed a somehow intermediate behaviour [(SDNN respectively: 71.0+/-34.9 vs 95.9+/-29.5 (p<0.001) vs 84.4+/-32.6ms (p=ns)]. Mean heart rate during the 24-h Holter was 8% higher in SAVR patients than in both TfAVI and TaAVI patients. The reported results were not correlated with echocardiographic ejection fraction, or presence of abnormal glucose metabolism, or degree of anaemia or treatment with beta-blockers. CONCLUSIONS: SAVR leads to profound depression of some cardiac autonomic parameters, while less invasive procedures allow better preservation of HRV. In particular TfAVI does not induce any significant deterioration of HRV parameters and seems to be the strategy of valve implant with less impact on the cardiovascular autonomic system. PMID- 26113471 TI - Non-obstructive prosthetic heart valve thrombosis (NOPVT): Really a benign entity? AB - AIMS: To assess the effectiveness of different treatment strategies in patients with non-obstructive prosthetic valve thrombosis (NOPVT) during hospitalization and long-term follow-up. METHODS: NOPVT was diagnosed by transesophageal echocardiography. Resolution was defined as the disappearance or reduction of the thrombus under anticoagulation. All cases were first managed with optimization of anticoagulation. At discharge, patients received oral anticoagulation (OAC) alone or OAC and antiplatelet therapy (double treatment). Adverse events were defined as cardiovascular death, recurrence, thromboembolic events or major bleeding. RESULTS: From 1997 to 2012, 47 patients (mean age: 65years; women: 60%) were diagnosed with NOPVT (mitral valve: 97%). Previous poor anticoagulation control was documented in 66% of patients. Twenty-one patients (45%) were treated with unfractionated heparin (UFH), especially those with thrombus size >10mm (19/21). Optimization of OAC was performed in the remaining patients. Treatment failed in 13 (27.6%) patients, mostly in those who received UFH (10/13), requiring surgery (53.8%) or fibrinolysis (30.7%). Forty-two patients survived and, at discharge, 44% of patients received OAC alone and 56% the double treatment. At follow-up (median 23months; range 0.03-116months), 59.5% of patients presented cardiovascular events, however no differences in outcome were observed with double treatment or OAC alone (p=0.385). CONCLUSIONS: NOPVT is a high-risk complication, not only during hospitalization but also during follow-up. Optimization of anticoagulation is efficient in most patients except in thrombi >=10mm treated with UFH. The double treatment does not prevent adverse events or complications during follow-up. PMID- 26113472 TI - Mitochondrial m-calpain opens the mitochondrial permeability transition pore in ischemia-reperfusion. AB - BACKGROUND/OBJECTIVES: Opening of the mitochondrial permeability transition pore (mPTP) is involved in ischemia-reperfusion injury. Isoforms of Ca(2+)-activated cysteine proteases, calpains, are implicated in the development of myocardial infarction in ischemia-reperfusion. Growing evidence has revealed the presence of calpains in the mitochondria. We aimed to characterize mitochondrial calpains in the rat heart and to investigate the roles of calpains in mPTP opening after ischemia-reperfusion. METHODS AND RESULTS: Western blotting analysis showed the expression of MU-calpain, m-calpain and calpain 10 in mitochondria isolated from male Sprague-Dawley rats, but casein zymography detected only m-calpain activity. Subcellular fractionation of mitochondria demonstrated the distribution of m calpain to the matrix fraction. Addition of >500MUM of Ca(2+) to isolated mitochondria induced mitochondrial swelling, reflecting mPTP opening, and calpain activation. Ca(2+)-induced mitochondrial swelling was inhibited partially by the calpain inhibitor calpeptin. These results support a partial contribution of calpain in the opening of the mPTP. The addition of Ca(2+) to the mitochondria induced inactivation of complex I of the electron transport chain, and cleavage of the ND6 complex I subunit, which were inhibited by calpeptin. Mitochondria isolated from rat hearts that underwent 30min of coronary occlusion followed by 30min of reperfusion showed activation of mitochondrial calpains, ND6 cleavage, complex I inactivation, and mPTP opening, which were inhibited by pretreatment with calpain inhibitor 1. CONCLUSIONS: We demonstrated for the first time the presence of mitochondrial matrix m-calpain, and its contribution to complex I inactivation and mPTP opening after postischemic reperfusion in the rat heart. PMID- 26113473 TI - Human endothelial colony forming cells from adult peripheral blood have enhanced sprouting angiogenic potential through up-regulating VEGFR2 signaling. AB - BACKGROUND: Endothelial colony forming cells (ECFCs), a subtype of endothelial progenitor cells, have been studied as a promising cellular source for therapeutic angiogenesis. Although ECFCs are very similar to mature endothelial cells, details regarding the role of ECFCs during angiogenesis are not known. We compared the cellular and angiogenic properties of ECFCs and mature endothelial cells (HUVECs). METHODS: HUVECs were used as control. Quantitative RT-PCR, western blotting, immunofluorescence staining, flow cytometric analyses and angiogenic cytokine array were performed. 3D-microfluidic angiogenesis assay system was adopted for in vitro angiogenic potential. In vivo angiogenic potential was assessed by Matrigel plug assay. RESULTS: ECFCs had higher expression of activated endothelial tip cell markers (Dll4, CXCR4, CD34, and VCAM1) and arterial genes (DLL4 and CX40), but lower expression of venous and lymphatic genes (COUP-TFII and PROX1). In 3D-microfluidic angiogenesis assay system, ECFCs induced robust sprouting vascular structures. Co-cultivation of both ECFCs and HUVECs gave rise to lumen-formed hybrid vascular structures, with the resulting ECFCs predominantly localized to the tip portion. This finding suggests that the ECFC has a role as a sprouting endothelial tip cell. Interestingly, VEGF-A phosphorylated VEGFR2 and its downstream signaling molecules more strongly in ECFCs than in HUVECs. Even small amount of VEGF-A successfully induced the sprouting angiogenesis of ECFCs. Finally, co administration of ECFCs and human dermal fibroblasts successfully induced lumen formed maturated neovessels in vivo. CONCLUSION: ECFCs derived from adult peripheral blood had enhanced sprouting angiogenic potential in vitro and in vivo through up-regulation of the VEGFR2 signaling pathway. PMID- 26113474 TI - Spot urine albumin to creatinine ratio outperforms novel acute kidney injury biomarkers in patients with acute myocardial infarction. AB - BACKGROUND: Acute kidney injury (AKI) is a frequent complication in patients hospitalized for acute myocardial infarction (AMI), and is associated with in hospital and long-term morbidity and mortality. We prospectively assessed the diagnostic performance of spot urine albumin to creatinine ratio (uACR) in an adequately sized multicenter cohort of patients admitted to hospital with AMI. We further compared uACR to novel renal injury associated biomarkers regarding their diagnostic ability. METHODS: We enrolled 805 consecutive patients presenting with acute ST-elevation and non-ST elevation AMI. Patients were assessed for presence of AKI at 48h post-admission and at hospital discharge using the Acute Kidney Injury Network (AKIN), the Acute Dialysis Quality Initiative [Risk, Injury and Failure (RIFLE)] criteria and the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Blood and urine sampling for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), cystatin-C, and uACR assessment was performed during admission. RESULTS: The predictive accuracy of uACR was good (Area Under the Curve (AUC), 0.725; 95% CI 0.676-0.774) and was better compared to urine NGAL (P=0.007), urine (P<0.001) and plasma Cystatin-C (P=0.001). ROC analysis identified concentrations of >=66.7MUg/mg as having the best diagnostic accuracy. The use of uACR exhibited good discriminating ability independent to possible cofounders and additive regarding the use of novel biomarkers. CONCLUSIONS: The use of uACR can easily be applied in the clinical setting, allows for robust risk assessment and offers the potential to improve the management of AMI patients at risk for acute kidney injury. PMID- 26113475 TI - Urocortin 2 protects heart and kidney structure and function in an ovine model of acute decompensated heart failure: Comparison with dobutamine. AB - BACKGROUND: Renal dysfunction is a frequent complication and crucial determinant of outcome in acute decompensated heart failure (ADHF). The aim of the study was to assess urocortin 2 (Ucn2) as a short-term therapy in ADHF with a focus on its renal effects. Comparison was made with dobutamine to distinguish effects beyond pure inotropism. METHODS: Sheep with ADHF received a 2-day infusion of a vehicle control, Ucn2 or dobutamine (n=6/grp). RESULTS: Compared to controls, Ucn2 and dobutamine produced matched improvements in cardiac contractility and output and arterial pressure, whereas reductions in central venous and left atrial pressures were greater with Ucn2. Both agents comparably repressed ADHF-activated hormone systems with the exception of the natriuretic peptides, which fell significantly during dobutamine but not Ucn2. While Ucn2 and dobutamine increased creatinine clearance and urine volume similarly, only Ucn2 induced a significant natriuresis. Ucn2 also decreased collagen deposition in the heart and kidney and suppressed gene expression of collagen-1, transforming growth factor-beta1, components of the angiotensin system (angiotensinogen, angiotensin-converting enzyme, type-1 receptor) and markers of hypertrophy (GATA binding protein-4, beta myosin heavy chain), apoptosis (caspase3) and inflammation/injury (interleukin 18, cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) in these tissues, while increasing cardiac natriuretic peptide mRNA. In contrast, dobutamine produced reduced or opposite effects on expression of these factors. CONCLUSIONS: Ucn2 administration in ADHF has favorable effects on hemodynamics, the natriuretic peptides and tissue mediators of inflammation, fibrosis, apoptosis and hypertrophy that stand in contrast to dobutamine. These data support Ucn2's potential as a renoprotective therapeutic in this setting. PMID- 26113476 TI - Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney injury after cardiac bypass surgery. AB - BACKGROUND: Pre-operative GDF-15 plasma levels significantly improve the prognostic value of the EuroSCORE for mortality after cardiac surgery. However, despite the strong correlation between GDF-15 and renal function, no data are available regarding the potential interest of pre-operative GDF-15 levels to improve the prediction of acute kidney injury (AKI) after cardiac artery bypass graft (CABG) surgery. METHODS: All patients operated on by 2 surgeons for CABG surgery at our university hospital from September 2011 to March 2013 were screened for participation in this prospective, observational study. EXCLUSION CRITERIA: age <18years or >80years, previous atrial fibrillation/flutter, previous severe renal failure, previous cardiac surgery, emergency surgery. AKI was defined according to KDIGO criteria. GDF-15 levels in plasma were measured before induction and 12h after surgery. RESULTS: 134 patients were included in this study. 42 (31%) developed post-operative AKI. AKI patients had a significantly higher pre-operative log-GDF-15 level (OR=3.64; 95% CI=1.41-9.40, p=0.008), a lower pre-operative eGFR (OR=0.98; 95% CI=0.96-0.99; p=0.026), and most often underwent on-pump surgery (OR=2.60; 95% CI=1.14-5.96, p=0.024). On ROC curves, GDF-15 before induction was found to be the best pre-operative biomarker to predict AKI (AUC=0.83; CI=0.75-0.89), compared with eGFR (AUC=0.67; 95% CI=0.59-0.75), p=0.003 and NT-proBNP (AUC=0.62; CI=0.51-0.72), p<0.001. Pre operative GDF-15 was also significantly better than the EuroSCORE in predicting AKI (AUC 0.62, 95% CI=0.54-0.70), p<0.001. CONCLUSIONS: Pre-operative GDF-15 plasma levels are associated with post-operative AKI in CABG patients. If confirmed in larger cohorts, pre-operative GDF-15 may be of value to improve pre operative risk stratification among candidates for surgery. PMID- 26113477 TI - Cluster headache: a quasi-rare disorder needing a reappraisal. PMID- 26113478 TI - Discrepancy between guidelines for stroke prevention in atrial fibrillation and practice patterns in primary care. The nationwide French AFIGP survey. AB - BACKGROUND: General practitioners (GPs) play a pivotal role in the long-term management of patients with atrial fibrillation (AF), including anticoagulant prophylaxis for stroke prevention. AIMS: To investigate the antithrombotic prescription behaviours of GPs in France and compare them with the European Society of Cardiology (ESC) guidelines for stroke prevention, and to identify the major determinants of use of antithrombotic therapy. METHODS: We conducted a cross-sectional survey, using data from the French Longitudinal Patient Database, on the use of antithrombotic treatments for stroke prevention in 15,623 patients (>=18years of age) with AF who attended at least one GP consultation between July 2010 and June 2011. Data were collected on patient baseline characteristics, stroke risk factors, and prescription of antithrombotic drugs. RESULTS: The mean age was 74.6+/-11.1years, 59.5% were men, and 83.1% had a CHADS2 score>=1. Over half (52.6%) of the patients with a CHADS2 score>=1 received a vitamin K antagonist (alone or in combination with an antiplatelet), 19.3% received aspirin alone, and 23.4% received no antithrombotic therapy; 3.6% of the patients received dual antiplatelet therapy and 1.1% clopidogrel alone. Over half of the patients (56.3%) were treated in accordance with the ESC 2010 guidelines. Of the remaining patients, 19.4% received no treatment, 13.0% were inadequately treated, and 11.2% were over-treated. Factors associated with antithrombotic treatment were anti-arrhythmic therapy, higher stroke risk, presence of atherothrombotic disease, and use of non-steroidal anti-inflammatory drugs. Female gender was associated with a lower likelihood of antithrombotic treatment. CONCLUSIONS: In this large French study, approximately 45% of thromboembolic high-risk patients were either not treated or inadequately treated. Better compliance with evidence based guidelines is needed to reduce the burden of stroke in the AF population. PMID- 26113479 TI - Fully bioresorbable drug-eluting coronary scaffolds: A review. AB - Following the development of stents, then drug-eluting stents (DES), bioresorbable scaffolds are proposed as a third evolution in coronary angioplasty, aiming to reduce the incidence of restenosis and stent thrombosis and to restore vascular physiology. At least 16 such devices are currently under development, but published clinical data were available for only three of them in September 2014. The first device is Abbott's BVS((r)), a poly-L-lactic acid (PLLA)-based everolimus-eluting device, which has been tested in a registry and two non-randomized trials. Clinical results seem close to what is expected from a modern DES, but possibly with more post-procedural side-effects. Two randomized trials versus DES are underway. This device is already marketed in many European countries. The second device is Elixir's DESolve((r)), a PLLA-based novolimus eluting device, which has been evaluated in two single-arm trials. Results are not widely different from those expected from a DES. The third device is Biotronik's DREAMS((r)), a metallic magnesium-based paclitaxel-eluting device, which has been assessed in an encouraging single-arm trial; its second version is currently undergoing evaluation in a single-arm trial. The available results suggest that the technological and clinical development of bioresorbable scaffolds is not yet complete: their possible clinical benefits are still unclear compared with third-generation DES; the impact of arterial physiology restoration has to be assessed over the long term; and their cost-effectiveness has to be established. From the perspective of a health technology assessment, there is no compelling reason to hasten the clinical use of these devices before the results of ongoing randomized controlled trials become available. PMID- 26113480 TI - Platelet effect of prasugrel and ticagrelor in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Recent studies have suggested that ticagrelor 90mg twice daily provides stronger platelet inhibition than prasugrel 10mg once daily in acute coronary syndrome patients undergoing percutaneous coronary intervention. OBJECTIVES: To compare the effects of ticagrelor 90 mg twice daily and prasugrel 10mg once daily on platelet reactivity in patients with ST-segment elevation myocardial infarction (STEMI), using: the VerifyNow((r)) P2Y12 (VN-P2Y12) assay, expressed in P2Y12 reaction units (PRU); measurement of the vasodilator stimulated phosphoprotein platelet reactivity index (VASP-PRI; %); and light transmission aggregometry (LTA), expressed as residual platelet aggregation (RPA; %). METHODS: Platelet reactivity was evaluated prospectively using the three assays 30 days after primary PCI in 118 patients with STEMI on a maintenance dose of prasugrel 10mg once daily (n=60) or ticagrelor 90mg twice daily (n=58). RESULTS: On-treatment platelet reactivity, assessed by the VN-P2Y12 assay, was lower for ticagrelor compared with prasugrel (20.91 +/- 4.59 PRU vs. 43.50+/-6.98 PRU; P=0.008) but was not significantly different when using the more specific VASP-PRI assay (13.05 +/- 1.61% vs. 17.44 +/- 1.97%; P=0.09) or RPA assessed by LTA (10.49 +/- 1.44% vs. 7.20 +/- 1.27%; P=0.09). CONCLUSIONS: The difference in platelet reactivity between ticagrelor and prasugrel varies according to the platelet function test in patients with STEMI. The differences observed may be related more to the tests than to the drugs used. PMID- 26113481 TI - A critical appraisal of the guidelines from France, the UK, Europe and the USA for the management of hypertension in adults. AB - Hypertension is the leading cause of death in developed countries; its management is the subject of guidelines that are regularly reviewed and updated. However, the guidelines from France, the UK, Europe and the USA differ. Some recommendations are graded, whereas others are not. All recommendations emphasize the role of alternative methods for clinical measurement of blood pressure, such as ambulatory blood pressure measurement (ABPM) or self-measurement. The UK guideline recommends that the diagnosis of hypertension should be established by ABPM. The USA guideline recommends a target of <= 150/90 mmHg for patients aged >60 years. The French guideline recommends that the target blood pressure remains at <140/90 mmHg, with <150 mmHg for patients aged >80 years. Systolic blood pressure between 130 and 139 mmHg and diastolic blood pressure <90 mmHg are recommended for diabetic patients and those with chronic kidney disease. The French Society of Hypertension (SFHTA) guideline is unique in recommending a dedicated consultation to announce the diagnosis to the patient. In the French and European guidelines, diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARBs) remain indicated as first-line therapy for hypertension; if the target blood pressure is not achieved, they recommend combining two active substances. The UK guideline recommends ACE inhibitors or ARBs as first-line therapy for patients aged <55 years; calcium antagonists are advised for patients aged >55 years and for black patients. The USA guideline advises treating non black patients, including those with diabetes, with thiazides, calcium antagonists, ACE inhibitors or ARBs; for black patients, including those with diabetes, it recommends thiazide and calcium antagonists. PMID- 26113482 TI - Decreased serum cell-free DNA levels in rheumatoid arthritis. AB - PURPOSE: Recent studies have demonstrated that serum/plasma DNA and RNA molecules in addition to proteins can serve as biomarkers. Elevated levels of these nucleic acids have been found not only in acute, but also in chronic conditions, including autoimmune diseases. The aim of this study was to assess cell-free DNA (cfDNA) levels in sera of rheumatoid arthritis (RA) patients compared to controls. METHODS: cfDNA was extracted from sera of patients with early and established RA, relapsing-remitting multiple sclerosis patients (RRMS) and healthy subjects, and its concentration was determined by quantitative PCR using two amplicons, Alu115 and beta-actin205, corresponding to Alu repetitive elements and the beta-actin single-copy gene, respectively. Serum DNase activity was measured by a single radial enzyme diffusion method. RESULTS: Reduced levels of cfDNA were observed in patients with established RA in comparison with healthy controls, early RA patients and RRMS patients. There were no significant differences in cfDNA concentration between healthy controls, early RA and RRMS patients. Total DNase activity appeared to be similar in the sera of all tested groups. CONCLUSIONS: Our results demonstrate that cfDNA levels are strongly reduced in the sera of established RA patients, which is not caused by changes in DNase activity. Measurement of cfDNA can distinguish established RA patients from early RA patients. Thus, cfDNA may serve as a biomarker in RA. PMID- 26113483 TI - Structural and Physical Basis for Anti-IgE Therapy. AB - Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcepsilonRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcepsilonRI and omalizumab binding sites in the Cepsilon3 domain, but crystallographic studies show FcepsilonRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-A omalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcepsilonRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcepsilonRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcepsilonRI. PMID- 26113484 TI - Functional (psychogenic) movement disorders associated with normal scores in psychological questionnaires: A case control study. AB - OBJECTIVE: Functional movement disorders (FMDs) fall within the broader category called functional neurological symptom disorder (FNSD). New DSM-5 criteria for FNSD no longer require the presence of a 'psychological conflict' suggesting that some patients with FMD may not have obvious psychological comorbidity. We studied patients with FMD in comparison to patients with a neurological movement disorder (MD) and healthy controls (HC) to identify whether there is a subgroup of patients with FMD who have normal psychological test scores. METHODS: We assessed self-rated measures of depression/anxiety (SCL-90), dissociation and personality disorder (PDQ-4) in patients attending neurological clinics and healthy controls. The proportion of patients scoring within normal ranges was determined, and the levels of somatic and psychological symptoms were compared between the three groups. RESULTS: Among the FMD group, 39% (20/51) scored within the normal range for all measures compared to 38% (13/34) of MD subjects and 89% (47/53) of healthy controls. There were no differences in overall scores in the SCL-90 and PDQ-4 between FMD and MD patients. FMD patients also did not differ from controls on a self-rated measure of personality pathology. CONCLUSION: Our data show that a substantial proportion of patients with FMD score within the normal range in psychological questionnaires, lending some support to the new DSM-5 criteria. PMID- 26113485 TI - [Medial knee osteoarthritis with juxta-articular tibial varus deformity: combined single condylar knee arthroplasty with open high tibial osteotomy]. PMID- 26113486 TI - Does the level of socioeconomic deprivation at the location of cardiac arrest in an English region influence the likelihood of receiving bystander-initiated cardiopulmonary resuscitation? AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a leading cause of mortality. Administration of cardiopulmonary resuscitation (CPR) by a bystander witnessing a cardiac arrest has been shown to increase the likelihood of return of spontaneous circulation and survival. This study analyses the association between the socioeconomic status of the location where a person suffers a cardiac arrest and the proportion of victims with OHCA receiving bystander CPR. METHODS: Retrospective analysis of all OHCAs occurring in North East England from 1 January 2011 to 31 December 2011: data obtained from the North East Cardiac Arrest Network Registry. RESULTS: Of 3179 OHCAs with an attempt at resuscitation, 623 patients received bystander-initiated CPR (19.6%). From quintile (Q) 1 to Q5 (most deprived to least deprived), bystander-initiated CPR rates increased from 14.5% to 23.3% (p for trend <0.001). Patients in the least deprived quintile were significantly more likely to receive bystander-initiated CPR when compared with those in the most deprived quintile (OR=1.78, 95% CI 1.32 to 2.39, p<=0.001). CONCLUSIONS: Increasing socioeconomic status at the location of cardiac arrest is positively associated with the likelihood of bystander CPR for OHCA in this region of England. PMID- 26113487 TI - Delays to initial reduction attempt are associated with higher failure rates in anterior shoulder dislocation: a retrospective analysis of factors affecting reduction failure. AB - INTRODUCTION: Little is understood about the relationship between delay to treatment and initial reduction success for anterior shoulder dislocation. Our study examines whether delays to initial treatment, from injury and hospital presentation, are associated with higher reduction failure rates for anterior shoulder dislocation. METHODS: A retrospective database and chart review was performed for patients undergoing intravenous sedation for attempted reduction of anterior shoulder dislocation in the emergency department (ED). Stepwise regression analysis was performed to identify predictors of reduction failure. Key variables analysed were the duration of the wait in the ED, the interval between the time of injury and first intervention and the interval from time of injury to arrival at the ED. Possible confounding variables analysed included age, gender, dose of sedative agent, qualifications of the reducing physician and whether the dislocated shoulder was recurrent. RESULTS: The duration of the intervals from injury to first reduction attempt and from arrival at the ED to first reduction attempt were both independent predictors of a higher reduction failure rate (OR=1.07, 95% CI 1.02 to 1.13; OR=1.19, 95% CI 1.05 to 1.34). Every interval of 10 min increased the odds of a failed reduction attempt by 7% and 19%, respectively. Overall, shoulder reduction was successful during the initial sedation event in 97 cases (92%) and unsuccessful in nine cases (8%). CONCLUSIONS: Delays to first reduction attempt either from the time of injury or within the ED are associated with a lower reduction success rate for anterior shoulder dislocations. PMID- 26113488 TI - The Sponsor Alliance Inventory: Assessing the Therapeutic Bond Between 12-Step Attendees and Their Sponsors. AB - AIMS: Within 12-step mutual-help organizations (MHOs), a sponsor plays a key recovery-specific role analogous to a 'lay therapist', serving as a role model, support and mentor. Research shows that attendees who have a sponsor have higher rates of abstinence and remission from substance use disorder (SUD), yet, while myriad formal psychotherapy studies demonstrate the therapeutic significance of the alliance between patients and professional clinicians on treatment outcomes, very little is known about the influence of the 'therapeutic alliance' between 12 step members and their sponsor. Greater knowledge about this key 12-step relationship could help explain greater degrees of 12-step effects. To bridge this gap, this study sought to develop and test a measure assessing the 12-step sponsee-sponsor therapeutic alliance--the Sponsor Alliance Inventory (SAI). METHOD: Young adults (N = 302) enrolled in a prospective effectiveness study who reported having a 12-step sponsor during the study (N = 157) were assessed at treatment entry, and 3, 6 and 12 months later on the SAI, their 12-step MHO attendance, involvement and percent days abstinent (PDA). RESULTS: Principal axis extraction revealed a single, 10-item, internally consistent (alpha's >= 0.95) scale that explained the majority of variance and was largely invariant to primary substance, gender and time. Criterion validity was also supported with higher SAI scores predicting greater proximal 12-step attendance, involvement and PDA. CONCLUSION: The SAI may serve as a brief, valid measure to assess the degree of sponsee-sponsor 'therapeutic alliance' within 12-step communities and may help augment explanatory models estimating the effects of MHOs on recovery outcomes. PMID- 26113489 TI - Prediction of Long-Term Outcomes in Young Adults with a History of Adolescent Alcohol-Related Hospitalization. AB - AIMS: Empirical data concerning the long-term psychosocial development of adolescents admitted to inpatient treatment with alcohol intoxication (AIA) are lacking. The aim of this study was to identify the factors that, at the time of admission, predict future substance use, alcohol use disorders (AUD), mental health treatment, delinquency and life satisfaction. METHODS: We identified 1603 cases of AIA treated between 2000 and 2007 in one of five pediatric departments in Germany. These former patients were invited to participate in a telephone interview. Medical records were retrospectively analyzed extracting potential variables predicting long-term outcomes. RESULTS: Interviews were conducted with 277 individuals, 5-13 [mean 8.3 (SD 2.3)] years after treatment, with a response rate of 22.7%; of these, 44.8% were female. Mean age at the interview was 24.4 (SD 2.2) years. Logistic and linear regression models revealed that being male, using illicit substances and truancy or runaway behavior in adolescence predicted binge drinking, alcohol dependence, use of illicit substances and poor general life satisfaction in young adulthood, explaining between 13 and 24% of the variance for the different outcome variables. CONCLUSIONS: This naturalistic study confirms that known risk factors for the development of AUD also apply to AIA. This finding facilitates targeted prevention efforts for those cases of AIA who need more than the standard brief intervention for aftercare. PMID- 26113490 TI - The Socioeconomic Differences in Alcohol-Related Harm and the Effects of Alcohol Prices on Them: A Summary of Evidence from Finland. AB - AIMS: We make a case study of Finland to study the connections between socioeconomic status, alcohol use, related harm and possibilities for intervention by means of alcohol pricing. METHODS: A review of Finnish studies on the topic. RESULTS: The socioeconomic differences in severe alcohol-related harm were great, and in the past two decades, these differences have widened. Alcohol related mortality has also strongly contributed to both the level and widening of socioeconomic differences in life expectancy. Both in 2004, when alcohol prices were abruptly cut, and in the longer term with more gradual changes in lowest prices of alcohol, the lowest socioeconomic groups were most affected in absolute but not so clearly in relative-terms, particularly among men. However, these effects are sometimes weak, not fully consistent by gender and across different measures of harm. CONCLUSIONS: The large and increasing socioeconomic differences in alcohol-related harm in Finland underline the importance of reducing these differences. The finding that particularly among men the impact of reduced alcohol prices on health has often in absolute terms been the greatest in the lower socioeconomic groups suggests that policies aimed at keeping the price of alcoholic beverages high may help to both minimize the overall level of alcohol related health problems and to reduce absolute inequalities. PMID- 26113492 TI - Brief report: Ethnic identity and aggression in adolescence: a longitudinal perspective. AB - Ethnic identity has been found to relate to many positive psychological outcomes, such as self-esteem and well-being, but little has been said about negative social outcomes such as aggression, nor have these relations been tested across time. The current study examined the concurrent and longitudinal relations between ethnic identity and peer nominated aggression at two time points with a two-year interval (8th and 10th grades) in a sample of 125 Israeli adolescents with an immigration background (56.8% girls). As hypothesized, ethnic identity related negatively to aggression at both T1 and T2. In addition, ethnic identity predicted a relative decrease in future aggression. Given these findings, the article suggests the importance of strengthening ethnic identity through interventions and educational programs. PMID- 26113491 TI - Understanding Lay Assessments of Alcohol Use Disorder: Need for Treatment and Associated Stigma. AB - AIMS: Three-quarters of people with an alcohol use disorder in the USA never receive treatment. Our understandings of who receives care are informed by sociological perspectives, theories and models, each of which discuss the role of lay people's understanding of illness. However, comparatively little work has been done to unpack the cognitive processes underlying lay assessment. In the context of the Framework Integrating Normative Influences on Stigma (FINIS), we aim to understand key factors guiding lay people's stigmatizing attitudes, perceptions and assessments of alcohol use disorder behaviors. METHODS: Lay people read a vignette depicting a male or female adult with a diagnosable alcohol use disorder, along with either a causal life-event explanation for the alcohol use disorder behaviors or no explanation. They then made judgments of the need for treatment, psychological abnormality and the stigma they felt toward the person depicted. RESULTS: Causal life-event explanations decreased lay judgments of the need for treatment, psychological abnormality and stigma. CONCLUSIONS: The results suggest that the availability of a causal life-event explanation may have a complex effect on lay judgments, decreasing the likelihood of recommending treatment for alcohol use disorders, yet simultaneously reducing stigmatizing perceptions (and presumably social distance). PMID- 26113493 TI - Rational design and evolutional fine tuning of Saccharomyces cerevisiae for biomass breakdown. AB - Conferring biomass hydrolysis activity on yeast through genetic engineering has paved the way for the development of groundbreaking processes for producing liquid fuels and commodity chemicals from lignocellulosic biomass. However, the overproduction and misfolding of heterologous and endogenous proteins can trigger cellular stress, increasing the metabolic burden and retarding growth. Improving the efficiency of lignocellulosic breakdown requires engineering of yeast secretory pathway based on system-wide metabolic analysis as well as DNA constructs for enhanced cellulase gene expression with advanced molecular biology tools. Also, yeast is subjected to severe stress due to toxic compounds generated during lignocellulose pretreatment in consolidated saccharification and fermentation processes. The prospect for development of robust yeast strains makes combining evolutionary and rational engineering strategies. PMID- 26113495 TI - Multiplexed detection of viral infections using rapid in situ RNA analysis on a chip. AB - Viral infections are a major cause of human disease, but many require molecular assays for conclusive diagnosis. Current assays typically rely on RT-PCR or ELISA; however, these tests often have limited speed, sensitivity or specificity. Here, we demonstrate that rapid RNA FISH is a viable alternative method that could improve upon these limitations. We describe a platform beginning with software to generate RNA FISH probes both for distinguishing related strains of virus (even those different by a single base) and for capturing large numbers of strains simultaneously. Next, we present a simple fluidic device for reliably performing RNA FISH assays in an automated fashion. Finally, we describe an automated image processing pipeline to robustly identify uninfected and infected samples. Together, our results establish RNA FISH as a methodology with potential for viral point-of-care diagnostics. PMID- 26113497 TI - Corrigendum. AB - Kue, J., Thorburn, S., & Keon, K. L. (2015). Research challenges and lessons learned from conducting community-based research with the Hmong community. Health Promotion Practice, 16(3), 411-418. doi:10.1177/1524839914561515 The authors would like to note the following funding information for the above-mentioned article: The project described in the article was supported by Award Number R21CA139147 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. PMID- 26113496 TI - A Community Health Worker Intervention for Diabetes Self-Management Among the Tz'utujil Maya of Guatemala. AB - Despite the high prevalence of diabetes in rural Guatemala, there is little education in diabetes self-management, particularly among the indigenous population. To address this need, a culturally relevant education intervention for diabetic patients was developed and implemented in two rural communities in Guatemala. An evaluative research project was designed to investigate if the structured, community-led diabetes self-management intervention improved selected health outcomes for participants. A one-group, pretest-posttest design was used to evaluate the effectiveness of the educational intervention by comparing measures of health, knowledge, and behavior in patients pre- and postintervention. A survey instrument assessed health beliefs and practices and hemoglobin A1c (HgA1c) measured blood glucose levels at baseline and 4 months post initiation of intervention (n = 52). There was a significant decrease (1.2%) in the main outcome measure, mean HgA1c from baseline (10.1%) and follow-up (8.9%; p = .001). Other survey findings were not statistically significant. This study illustrates that a culturally specific, diabetes self-management program led by community health workers may reduce HgA1c levels in rural populations of Guatemala. However, as a random sample was not feasible for this study, this finding should be interpreted with caution. Limitations unique to the setting and patient population are discussed in this article. PMID- 26113498 TI - Detection of asymmetric glaucomatous damage using automated pupillography, the swinging flashlight method and the magnified-assisted swinging flashlight method. AB - PURPOSE: To determine the sensitivity and specificity of various methods of detecting a relative afferent pupillary defect (RAPD) in patients with glaucoma related diagnoses. PATIENTS AND METHODS: Patients underwent RAPD evaluation using the swinging flashlight method (SFM), the magnifier-assisted SFM, and pupillography using the Konan RAPDx. Main outcome measures were sensitivity and specificity of three methods of RAPD evaluation in detecting visual field mean deviation (MD), cup to disc ratio (CDR), disc damage likelihood scale (DDLS), and retinal nerve fiber layer (RNFL) asymmetry. RESULTS: Eighty-one consecutive patients from the Wills Eye Hospital glaucoma service were enrolled, 60 with glaucoma and 21 with ocular hypertension or glaucoma suspect. Thirty-one percent of subjects had MD asymmetry>5 dB, 19.7% had CDR asymmetry>=0.20, 26.7% had DDLS asymmetry>=2, and 38.2% had RNFL asymmetry>10 microns. Sensitivity values for pupillography were 93.3% (95% CI, 68.1-99.8) for detecting MD asymmetry, 80.0% (95% CI, 51.9-95.7) for CDR asymmetry, 100.0% (95% CI, 73.5-100.0) for DDLS asymmetry, and 69.2% (95% CI, 38.6-90.9) for RNFL asymmetry. Specificity values were 41.2% (95% CI, 24.7-59.3) for detecting MD asymmetry, 32.8% (95% CI, 21.3 46.0) for CDR asymmetry, 33.3% (95% CI, 18.0-51.8) for DDLS asymmetry, and 42.9% (95% CI, 21.8-66.0) for RNFL asymmetry. Pupillography amplitude score was correlated with MD asymmetry (r2=0.41, P<0.001) and area under the curve was 0.84. CONCLUSION: Automated pupillography had higher sensitivity and lower specificity in detecting MD, CDR, DDLS, and RNFL asymmetry. Within the bounds of the cohort tested, this method had limited case-finding ability. PMID- 26113499 TI - New and emerging technologies for the treatment of inherited retinal diseases: a horizon scanning review. AB - The horizon scanning review aimed to identify new and emerging technologies in development that have the potential to slow or stop disease progression and/or reverse sight loss in people with inherited retinal diseases (IRDs). Potential treatments were identified using recognized horizon scanning methods. These included a combination of online searches using predetermined search terms, suggestions from clinical experts and patient and carer focus groups, and contact with commercial developers. Twenty-nine relevant technologies were identified. These included 9 gene therapeutic approaches, 10 medical devices, 5 pharmacological agents, and 5 regenerative and cell therapies. A further 11 technologies were identified in very early phases of development (typically phase I or pre-clinical) and were included in the final report to give a complete picture of developments 'on the horizon'. Clinical experts and patient and carer focus groups provided helpful information and insights, such as the availability of specialised services for patients, the potential impacts of individual technologies on people with IRDs and their families, and helped to identify additional relevant technologies. This engagement ensured that important areas of innovation were not missed. Most of the health technologies identified are still at an early stage of development and it is difficult to estimate when treatments might be available. Further, well designed trials that generate data on efficacy, applicability, acceptability, and costs of the technologies, as well as the long term impacts for various conditions are required before these can be considered for adoption into routine clinical practice. PMID- 26113501 TI - Insertion of sequential glaucoma drainage implant in a piggyback manner. AB - PURPOSE: This pilot study, the first of its type, was conducted to determine the clinical outcome of a sequential glaucoma drainage implant (GDI) inserted in piggyback manner, that is into the bleb of a primary GDI. METHODS: This was a retrospective chart study with a minimum 1-year follow-up involving 16 eyes of 14 uncontrolled glaucoma patients who had previously undergone sequential GDI performed using a technique to convert a one-plate into a two-plate implant system. Surgical success was defined as intraocular pressure (IOP) <21 mm Hg with at least a 30% reduction in IOP from baseline on two consecutive follow-up visits, IOP >5 mm Hg on two consecutive follow-up visits, and neither reoperation of glaucoma nor loss of light perception vision. RESULTS: The mean +/-SD baseline IOP was 29.2+/-5.2 mm Hg, and the mean postoperative IOP was 17.3+/-3.4 mm Hg, with a mean pressure drop of 39.4+/-10.4% (P<0.001). Life-table analysis showed an 88% success rate after 12 months of follow-up. The mean preoperative best corrected visual acuity (BCVA) was 0.2+/-0.2 logMAR (Snellen equivalent 6/9.5), compared with 0.3+/-0.3 logMAR postoperatively (Snellen equivalent 6/12; P=0.497). Postoperative complications included a flat anterior chamber and choroidal detachment (one eye), uveitis and cataract (one eye), diplopia (one eye), and worsening of pre-existing pseudophakic bullous keratopathy (one eye). CONCLUSIONS: In glaucoma eyes with useful vision the piggyback GDI seems to provide a significant IOP lowering with minimal complications in patients in whom an initial GDI had failed to control the IOP. PMID- 26113502 TI - Diverse clinical phenotypes associated with a nonsense mutation in FAM161A. AB - PURPOSE: Mutations in the FAM161A gene have been reported in association with autosomal recessive retinitis pigmentosa (arRP) in several ethnic populations. This study aimed to assess the prevalence of FAM161A-related retinopathy in a British cohort and to characterise the phenotype associated with mutations in this gene. METHODS: The FAM161A coding region and intron-exon boundaries were screened by Sanger sequencing in 120 retinitis pigmentosa (RP) patients (with likely autosomal recessive inheritance) in whom mutations in other known major RP genes have been ruled out by commercially available testing. Homozygosity mapping was performed in one consanguineous family, and high-throughput sequencing of candidate genes was performed to identify disease-associated changes. Clinical assessment of affected individuals included perimetry testing, fundus autofluorescence imaging, and optical coherence tomography. RESULTS: Two patients of British origin with a homozygous mutation in FAM161A (c.1309A>T, p.Arg437*) were identified by Sanger sequencing. Homozygosity mapping and subsequent high throughput sequencing analysis identified a further family of Pakistani origin with the same genotype. Clinical examination of affected members of these families revealed that this mutation was associated with a diverse clinical phenotype, ranging from mild disease with preservation of central acuity to severe visual impairment. CONCLUSIONS: Homozygosity for the c.1309A>T, p.Arg437* variant in FAM161A is a relatively common cause of arRP. The mutation occurs in diverse ethnic populations, associated with typical retinitis pigmentosa with disease onset usually in the second or third decade of life. PMID- 26113500 TI - A review of therapies for diabetic macular oedema and rationale for combination therapy. AB - Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO. A comprehensive review of clinical trials related to DMO and their outcomes was completed. Where phase III randomised control trials were available, these were referenced, if not available, phase II trials have been included. PMID- 26113503 TI - Long-term outcomes of phakic patients with diabetic macular oedema treated with intravitreal fluocinolone acetonide (FAc) implants. AB - PURPOSE: Diabetic macular oedema (DMO) is a leading cause of blindness in working age adults. Slow-release, nonbioerodible fluocinolone acetonide (FAc) implants have shown efficacy in the treatment of DMO; however, the National Institute for Health and Care Excellence recommends that FAc should be used in patients with chronic DMO considered insufficiently responsive to other available therapies only if the eye to be treated is pseudophakic. The goal of this analysis was to examine treatment outcomes in phakic patients who received 0.2 MUg/day FAc implant. METHODS: This analysis of the phase 3 FAME (Fluocinolone Acetonide in Diabetic Macular Edema) data examines the safety and efficacy of FAc implants in patients who underwent cataract extraction before (cataract before implant (CBI) group) or after (cataract after implant (CAI) group) receiving the implant. The data were further examined by DMO duration. RESULTS: Best corrected visual acuity (BCVA) after 36 months was comparable in the CAI and CBI groups. Both the percentage of patients gaining >= 3 lines of vision and mean change in BCVA letter score were numerically greater in the CAI group. In addition, most patients who underwent cataract surgery experienced a net gain in BCVA from presurgery baseline as well as from original study baseline. CONCLUSIONS: These data support the use of 0.2 MUg/day FAc implants in phakic as well as in pseudophakic patients. These findings will serve as a pilot for design of future studies to evaluate the potential protective effect of FAc implants before cataract surgery in patients with DMO and cataract. PMID- 26113504 TI - Comparison of two- and three-point sutures for advancing the levator aponeurosis in Asian eyelids. AB - PURPOSE: To compare the functional and cosmetic outcomes of two- and three-point sutures for advancing the levator aponeurosis in blepharoptosis surgery on Asians. PATIENTS AND METHODS: This retrospective study examined 60 Asian patients with blepharoptosis who had undergone advancement of the levator aponeurosis: 34 patients (46 eyelids) had ptosis correction using the two-point suture technique and 26 patients (41 eyelids) had ptosis correction using the three-point suture technique. The postoperative marginal reflex distance (MRD1), lid height difference, and eyelid contour were evaluated. RESULTS: Twenty-seven (79.4%) of the 34 patients in the two-point group and 19 (73.1%) of 26 patients in the three point group had a postoperative MRD1 of 2-4 mm, lids within 0.5 mm of each other, and a satisfactory eyelid contour; this difference was not significant. The rate of reoperation did not differ significantly between the two groups. CONCLUSION: Two- and three-point sutures for advancing the levator aponeurosis were equally effective for correcting blepharoptosis in Asians. PMID- 26113505 TI - Species-specific mercury bioaccumulation in a diverse fish community. AB - Mercury bioaccumulation models developed for fish provide insight into the sources and transfer of Hg within ecosystems. Mercury concentrations were assessed for 16 fish species of the western reach of Lake Diefenbaker, Saskatchewan, Canada. For top predators (northern pike, Esox Lucius; walleye, Sander vitreum), Hg concentrations were positively correlated to delta(15)N, and delta(15)N to fish age, suggesting that throughout life these fish fed on organisms with increasingly higher trophic values and Hg concentrations. However, fish mass and/or age were the principal parameters related to Hg concentrations for most species. For 9 common species combined, individual variation in Hg concentration was explained in declining order of importance by fish mass, trophic position (delta(15)N), and fish age. Delta (15)N value was not the leading variable related to Hg concentration for the assemblage, probably because of the longevity of lower--trophic-level species (3 species >= 20 yr), substantial overlap in Hg concentration and delta(15)N values for large-bodied fish up to 3000 g, and complex relationships between Hg concentration and delta(15)N among species. These results suggest that the quantity of food (and Hg) consumed each year and converted to fish mass, the quantity of Hg bioaccumulated over years and decades, and trophic position were significant determinants of Hg concentration in Lake Diefenbaker fish. PMID- 26113506 TI - Increased detection of Aedes albopictus in Belgium: no overwintering yet, but an intervention strategy is still lacking. AB - In 2013 and 2014, routine surveillance for invasive mosquito species was implemented in Belgium at 13 potential points of entry. Following the introduction of Aedes (Stegomyia) albopictus (Skuse 1895) to Belgium via a used tyre import company (Vrasene, Province of East Flanders) in July 2013, one female and 17 larvae were collected outdoors during a period of intensive surveillance in summer and autumn 2013, but no control measures were implemented. Although climatic conditions were suitable during the winter of 2013-2014, this reproducing population did not overwinter. Lack of genetic variation, incomplete diapause adaptation and egg desiccation due to long dry periods during diapause or competition with endemic species are possible reasons. More studies on the diapause/longevity of Ae. albopictus eggs in northern temperate climatic conditions and on the competition with endemic species in western and central Europe are warranted to assess the potential for this invasive mosquito to overwinter. Furthermore, following the detection of four Ae. albopictus larvae in a shipment of lucky bamboo at the port of Antwerp in August 2014, one female, one male, 11 pupae and six larvae were collected at the destined lucky bamboo company (Lochristi, Province of East Flanders) in autumn 2014. In this case, immediate control measures were successfully implemented at the nursery. Because of increasing threats and the absence of an invasive mosquito species control policy in Belgium, the need for a permanent vector surveillance and control plan has never been so high. PMID- 26113507 TI - Monitoring artemisinin resistance in Plasmodium falciparum: comparison of parasite clearance time by microscopy and real-time PCR and evaluation of mutations in Pfatpase6 gene in Odisha state of India. AB - Antimalarial drug resistance including artemisinin resistance in Plasmodium falciparum malaria is a major concern in combating malaria throughout the world. Delayed parasite clearance time (PCT) is indicative of emergence of artemisinin resistance. Herein, PCT has been monitored with the help of gold standard technique microscopy accompanied by a more sensitive real-time assay for academic purpose. After the administration of artemisinin based combination therapy, artesunate + sulfadoxine pyrimethamine (AS + SP), all the subjects were followed up to day 42 for monitoring the therapeutic efficacy of AS + SP in Bisra Community Health Centre (CHC), Sundergarh district in the state of Odisha in India. Further, representative samples were analyzed for L263E, E431K, A623E and S769N SNPs in Pfatpase6 gene and copy number polymorphisms in Pfmdr1 gene. Though all the samples were found parasite negative according to microscopy by the end of day 3 and attained adequate clinical and parasitological response (ACPR) at the end of day 42, real-time PCR showed day 3 positivity in 12 of the total analyzed samples (n = 43). This was further validated by end-point diagnostic PCR and correlated with high initial parasite load. E431K mutation was observed in 2 of the 12 samples (16.7 %) while the controls (n = 18) were all wild. L263E, A623E and S769N were wild in all the analyzed samples (n = 30). Pfmdr1 copy number analysis showed no change in the said trait. Conclusively, real-time PCR could support microscopy for better monitoring of PCT and may provide as an additional but useful research tool for artemisinin resistance studies. PMID- 26113508 TI - Efficacy of cyantraniliprole fly bait against housefly (Musca domestica L.) under laboratory conditions. AB - Novel and effective baits are needed to manage pest housefly populations and avoid the development of insecticide resistance. In this study, we bioassayed the efficacy of Zyrox(r), a novel fly bait containing a novel 0.5 % cyantraniliprole insecticide, to kill adult houseflies under laboratory conditions. We found that Zyrox(r) killed a significantly greater proportion of flies than the current competing fly bait, QuickBayt(r), after a 24-h exposure. The cumulative mortalities of houseflies were up to 96.36 % and 92.57 % for Zyrox(r) and 78.88 % and 68.76 % for QuickBayt(r) in no-choice and choice tests, respectively. Our results suggested that there was negligible behavioral resistance to both fly baits but revealed that Zyrox(r) appeared to work slower than QuickBayt(r) (at a 3-h exposure, proportionally fewer flies were killed by Zyrox(r) than by QuickBayt(r)). Importantly, we found that the efficacy of Zyrox(r) did not diminish with the age of the bait (up to 90 days old). In actual knockdown time (KDT) feeding bioassay, the results showed that Zyrox(r) knocked down flies significantly slower (11.97 min for females; 12.30 min for males) than QuickBayt(r) (1.89 min for females; 2.24 min for males). These results reveal the high efficacy of Zyrox(r) bait to kill adult flies and suggest that it is a promising slow-action bait for management of houseflies. PMID- 26113509 TI - Spatial covariation of local abundance among different parasite species: the effect of shared hosts. AB - Within any parasite species, abundance varies spatially, reaching higher values in certain localities than in others, presumably reflecting the local availability of host resources or the local suitability of habitat characteristics for free-living stages. In the absence of strong interactions between two species of helminths with complex life cycles, we might predict that the degree to which their abundances covary spatially is determined by their common resource requirements, i.e. how many host species they share throughout their life cycles. We test this prediction using five trematode species, all with a typical three-host cycle, from multiple lake sampling sites in New Zealand's South Island: Stegodexamene anguillae, Telogaster opisthorchis, Coitocaecum parvum, Maritrema poulini, and an Apatemon sp. Pairs of species from this set of five share the same host species at either one, two, or all three life cycle stages. Our results show that when two trematode species share the same host species at all three life stages, they show positive spatial covariation in abundance (of metacercarial and adult stages) across localities. When they share hosts at two life stages, they show positive spatial covariation in abundance in some cases but not others. Finally, if two trematode species share only one host species, at a single life stage, their abundances do not covary spatially. These findings indicate that the extent of resource sharing between parasite species can drive the spatial match-mismatch between their abundances, and thus influence their coevolutionary dynamics and the degree to which host populations suffer from additive or synergistic effects of multiple infections. PMID- 26113510 TI - First ultrastructural observations on gastritis caused by Physaloptera clausa (Spirurida: Physalopteridae) in hedgehogs (Erinaceus europeaus). AB - Ultrastructural changes of gastritis due to infection with Physaloptera clausa in 12 fresh carcasses of euthanized European hedgehogs (Erinaceus europaeus) collected from different part of Urmia, Iran, in which they were highly populated with this animal, six females and six males were subjected to detail necropsy with special reference to the stomach. Macroscopic changes of stomach were recorded and some of the worms collected. Based on number of parasites present in the stomach, they were divided into light infection, mild infection, and severe infection. Parasites were collected, and worms identification of the species was confirmed on the basis of light microscope examination with reference to keys. Tissues fixed in 3% glutaraldehyde, post-fixed in 1% osmium tetroxide and processed and plastic embedded; ultrathin sections of 60-70 nm were cut and stained with uranyl acetate and lead citrate; electron microscopic observations showed that, in light infection some changes were observed in gastric cells such as dilatation and vesiculation of the endoplasmic reticulum, large numbers of lipid granules, mitochondrial swelling, nuclear chromatin margination, and some nucleus showed washed out appearance. Other cells showed some alterations in mitochondria, dilatation of smooth endoplasmic reticulum, loss of both free and bound ribosomes, vesiculation in cytoplasm, and increase Golgi apparatus and secretory vesicles. The inflammatory cells including lymphocytes, macrophages, mast cells, and predominantly eosinophils were identified. In moderate infection, the cellular pattern of gastric mucosa replaced with inflammatory cells. The marked increase of macrophages and other inflammatory cell was observed. A particular finding in our study was the presence of globule leukocyte in the moderate stage. Moreover, scant formation and distribution of collagen fibers as well as fibroblasts were also noted. In severe infection, the most obvious observation was marked distribution of collagen fibers around the mucosal cells. The fibroblastic cells with elongated nucleus and extensive indentation were noticed. In conclusion, the result of our study revealed P. clausa could be a cause of gastritis and according to cellular pattern of inflammatory reaction, with the increase of worm burden and development of infection, chronic gastritis was stabilized. Present investigation documented the ultrastructural changes during verminous gastritis in hedgehogs. PMID- 26113511 TI - Transcription Analysis of the Beta-Glucosidase Precursor in Wild-Type and l-4i Mutant Bombyx mori (Lepidoptera: Bombycidae). AB - Lethal fourth-instar larvae (l-4i) mutant of Bombyx mori, a recently discovered novel mutant, die from energy depletion due to genetic mutation. Beta-glucosidase is a common digestive enzyme that hydrolyzes cellulose in the diet to provide energy. In this study, the mRNA expression profiles of B. mori beta-glucosidase precursor (BmpreBG) were characterized by reverse transcription polymerase chain reaction and quantitative real-time polymerase chain reaction. The transcription level of BmpreBG varied in different tissues and developmental stages, except in the pupa and moth, which are the no-diet period. Remarkably, the mRNA expression level of BmpreBG was sharply reduced in l-4i but not in the wild type, which suggested that the digestive function of the mutant was severely damaged. This was consistent with the l-4i phenotypic traits of not eating mulberries, lack of energy, and ultimate death. 5'-rapid amplification of cDNA ends showed, for the first time, that BmpreBG has a 160-bp 5'-untranslated region. These findings suggested that B. mori beta-glucosidase precursor was involved in the death process of l-4i mutant larvae. PMID- 26113512 TI - Survival of Coelaenomenodera lameensis (Coleoptera: Chrysomelidae) in Relation to the Physical Characteristics of Different Oil Palm (Elaeis sp.) Breeding Populations. AB - The edibility of different Elaeis sp. breeding populations present in Benin was tested for the leaf miner Coelaenomenodera lameensis Berti (Coleoptera: Chrysomelidae), a major oil palm pest in Africa. Experiments carried out in sleeves revealed the oviposition capacities of females and the mortality rates for the different developmental stages by comparing the populations found on two breeding populations of Elaeis oleifera (HBK) Cortes, four of Elaeis guineensis Jacquin and four (E. guineensis * E. oleifera) * E. guineensis backcrosses. Females laid their eggs similarly on all breeding populations, with a preference for the E. guineensis La Me origin. The average hatching rate reached 80% for the La Me origin as opposed to 28% for the Deli origin. The mortality rates for the larval instars were greater on E. oleifera, on certain backcrosses and on the Deli origin of E. guineensis. Development at the second- and third- larval instars was the most affected, with a mortality rate of three to five times greater than that seen on La Me. Epidermis and cuticle measurements indicated which breeding populations were suitable or unsuitable for the development of C. lameensis. E. guineensis, with its thin epidermis (12 um) and cuticle (2 um), proved to be highly susceptible to C. lameensis attacks. On the other hand, E. oleifera, which is very resistant, exhibited a thicker epidermis (17 um) and cuticle (4 um). The breeding populations were thus classified according to the positive or negative influence they exerted on the insect's egg laying and feeding. PMID- 26113513 TI - Aphicidal Activity of an Ageraphorone Extract From Eupatorium adenophorum Against Pseudoregma bambucicola (Homoptera: Aphididae, Takahashi). AB - The bamboo aphid, Pseudoregma bambucicola, is an important insect pest of bamboo that affects normal bamboo growth and induces sooty molds. The control of P. bambucicola involves the application of chemicals, such as imidacloprid, to which many species are resistant. In this study, we isolate a novel botanical pesticide (9-oxo-10,11-dehydro-ageraphorone) from an Eupatorium adenophorum(Asteraceae: Compositae) petroleum ether extract and test the aphicidal activity of this compound against P. bambucicola in laboratory bioassay and field-based experiments. This ageraphorone compound at a concentration of 2 mg/ml caused 73.33% mortality (corrected mortality [Subtracted the mortality of the negative control]: 70%) of P. bambucicola by laboratory bioassay within 6 h. Even at lower concentrations, this compound caused greater 33% mortality (corrected mortality: 30%) of aphids. Field experiments with naturally infested bamboo plants showed that two applications of 2 mg/ml ageraphorone to infested plants completely cleared infestations within 30 d. These effects were similar to those of the positive control (imidacloprid). These results reveal that 9-oxo-10,11-dehydro ageraphorone exhibits significant aphicidal activity against bamboo aphids. We suggest that future research be directed at developing this ageraphorone compound from E. adenophorum as an aphicidal agent for biocontrol. PMID- 26113514 TI - A cluster of invasive meningococcal disease revealed by the characterization of a novel serogroup B meningococcal clone. AB - The incidence of invasive infections due to Neisseria meningitidis in Israel is about 1/100 000 population annually. Three cases of meningococcal meningitis were reported in employees at a single plant; the first case appeared in March 2013 and the second and third cases appeared in December, almost 9 months later. N. meningitidis serogroup B was isolated from cerebrospinal fluid samples. Multilocus sequence typing assigned the three meningococcal isolates to ST10418, a new sequence type and a member of the ST32 clonal complex. The clonality was confirmed by performance of pulsed-field gel electrophoresis. Post-exposure antibiotic prophylaxis was administered to close contacts of the first case. Upon the diagnosis of the additional two cases, post-exposure prophylaxis was administered to all the plant employees. This report demonstrates the importance of combining public health measures and advanced laboratory studies to confirm clonality and to prevent further disease spread in a closed setting. PMID- 26113515 TI - Temperature affects the silicate morphology in a diatom. AB - Silica deposition by diatoms, a common component of the phytoplankton, has attracted considerable interest given the importance in ecology and materials science. There has recently been a great deal of research into the biological control of biosilicifcation, yet the in vivo physical and chemical effects have not been quantitatively investigated. We have grown the marine diatom Thalassiosira pseudonana in batch culture at three temperatures (14 degrees , 18 degrees , and 23 degrees C). We observed three distinct temperature-dependent growth phases. The morphology of silica was investigated using scanning electron microscopy followed by image analysis and supervised learning. The silica in the valves of the same species showed different structures: a mesh-like pattern in silicon-rich cultures and a tree-like pattern in silicon-limited cultures. Moreover, temperature affected this silica pattern, especially in silicon-limited cultures. We conclude that cells grown at 14 degrees C and 18 degrees C divide more successfully in Si-limited conditions by developing a tree-like pattern (lower silicification). PMID- 26113516 TI - Developing new models of shared primary and specialist HIV care in the UK: a survey of current practice. AB - HIV care in the UK is led by hospital-based specialists with limited general practitioner (GP) involvement. As GPs have expertise in some non-microbial HIV associated co-morbidities (e.g. cardiovascular disease), and more people are disclosing their HIV status to their GPs, there could be benefits in sharing HIV care. We describe contemporary models of shared HIV care in relevant developed world settings to inform future shared HIV care in the UK. An interview survey of key informants was used to explore experiences and models of shared care, and identify promoting and inhibiting factors. We interviewed ten key informants from six shared care models. There were three broad categories of shared care, with varying degrees of GP involvement. Strong clinical leadership in primary care, good professional relationships and communication, and tailored GP training were facilitators. Barriers included stigma, confidentiality concerns, and low prevalence of HIV outside major conurbations. Contemporary shared HIV care models have emerged organically and seem to work when grounded in good collaboration between a small number of dedicated GPs and specialist units. We propose two models for further study which may only be feasible in high HIV caseload practices. User acceptability, clinical and cost effectiveness must be considered. PMID- 26113517 TI - Early syphilis affects markers of HIV infection. AB - The objective of this study was to investigate if early syphilis infection affects markers of HIV infection; CD4 T cells and viral load (VL). A retrospective study was performed on 160 HIV-positive patients (111 receiving antiretroviral therapy [ART] and 49 without ART). Early syphilis diagnosis was made in HIV patients during their follow-up at the HIV/AIDS Unit at a Greek Dermatology and Venereology Unit. The patients' blood tests were available at the time of diagnosis, as well as before and 12 weeks after early syphilis diagnosis. CD4 T cell counts and VL levels were measured. It was found that syphilis infection had a negative impact on the CD4 T cell counts in both groups, with reduced CD4 T cell counts observed in 84.6% (99/111) and 79.5% (39/49) of patients receiving and not receiving ART, respectively. After treatment for syphilis, CD4 T cell counts returned to pre-treatment levels in most patients, especially those receiving ART. There was a slight and transient VL increase. Patients receiving ART had a 27% increase in VL, compared to 71.4% among patients not receiving ART. Although the VL increase was slight (41-14,000 copies/ml) in the group under treatment, 4-5% (5/111) patients did not return to pre-treatment levels. Moreover, viral mutations associated with treatment resistance were identified in these patients. Early syphilis accelerates and complicates the progression of HIV infection. Early diagnosis and treatment of syphilis may prevent infection-associated complications in most instances. Consequently, prevention of syphilis and other sexually transmitted infections is of great importance for patients infected with HIV. PMID- 26113518 TI - A case of primary adrenal diffuse large B-cell lymphoma in HIV. AB - Primary adrenal diffuse large B-cell lymphoma in HIV is a very rare, highly aggressive extra-nodal lymphoma. There is only one previous case reported in the literature. Our patient presented with isolated bilateral adrenal masses with no lymphadenopathy or visceral involvement, which made the diagnosis challenging. PMID- 26113519 TI - Characterization of FSH signalling networks in bovine cumulus cells: a perspective on oocyte competence acquisition. AB - Understanding the mechanisms regulating oocyte developmental competence is essential to enhance the clinical efficiency of assisted reproduction. FSH orchestrates the acquisition of oocyte competence, both in vivo and in vitro. Multiple pathways are implicated in FSH signalling; however, their precise coordination remains unresolved. A robust system to investigate FSH signalling is oocyte in vitro maturation (IVM) and we have previously demonstrated better bovine embryo development after FSH addition for the first 6 h during IVM. Using this model, we investigated FSH signalling in cumulus through transcriptomic and pharmacological tools. We demonstrate modulation of cumulus transcriptome by FSH mainly through protein kinase A (PKA) and epidermal growth factor (EGF) pathways. Differentially expressed transcripts were implicated in cumulus expansion, steroidogenesis, cell metabolism and oocyte competence. FSH required rouse sarcoma oncogene (SRC) for EGF receptor transactivation. PKA and EGF pathway crosstalk was investigated using extracellular signal-regulated kinases (ERK1/2) phosphorylation as the functional end-point. FSH enhanced ERK1/2 activation by the EGF pathway with a simultaneous diminution through PKA. More specifically, FSH increased dual specific phosphatase (DUSP1) transcripts via PKA although DUSP1 protein did not change since EGF was required to prevent degradation. Our findings implicate FSH in PKA and EGF pathway activation, which interact to maintain appropriate levels of ERK1/2 phosphorylation and eventually cumulus expansion, metabolism and steroidogenesis. Moreover, considering the implication of the EGF pathway in GDF9 and BMP15 actions, our findings suggest that FSH may have a role in modulation of the cumulus response to oocyte-secreted factors. This information has implications for improvement of IVM and hence oocyte developmental competence. PMID- 26113521 TI - FSH treatment of male idiopathic infertility improves pregnancy rate: a meta analysis. AB - INTRODUCTION: The aim of this study is to comprehensively evaluate whether FSH administration to the male partner of infertile couples improves pregnancy rate, spontaneously and/or after assisted reproductive techniques (ART). METHODS: Meta analysis of controlled clinical trials in which FSH was administered for male idiopathic infertility, compared with placebo or no treatment. Randomization was not considered as an inclusion criterion. RESULTS: We found 15 controlled clinical studies (614 men treated with FSH and 661 treated with placebo or untreated). Concerning the type of FSH, eight studies used recombinant FSH, whereas seven studies used purified FSH. Nine studies evaluated spontaneous pregnancy rate, resulting in an overall odds ratio (OR) of about 4.5 (CI: 2.17 9.33). Eight studies evaluated pregnancy rate after ART, showing a significant OR of 1.60 (CI: 1.08-2.37). Sub-dividing studies according to the FSH preparations (purified/recombinant), pregnancy rate improvement remained significant for each preparation. Eleven studies considered sperm quality after FSH treatment, finding a significant improvement of sperm concentration (2.66*10(6)/ml, CI: 0.47-4.84), but not of concentration of sperm with progressive motility (1.22*10(6)/ml, CI: 0.07 to 2.52). Three trials evaluated testicular volume, showing a non significant increase in men treated (1.35 ml, CI: -0.44 to 3.14). CONCLUSION: The results of controlled clinical trials available in the literature indicate an improvement of pregnancy rate after FSH administration to the male partner of infertile couples, both spontaneously and after ART. However, the heterogeneity of studies, the high risk of bias and the lack of precise criteria to guide FSH administration limit the strength of these results. Future studies should be designed to identify the markers of FSH response which are helpful in the decision-making process. Meanwhile, the use of FSH in the treatment of male infertility should be cautious. PMID- 26113522 TI - Mesenchymal stem cell implantation in knee osteoarthritis: an assessment of the factors influencing clinical outcomes. AB - BACKGROUND: Several clinical studies have reported on cell-based treatment using mesenchymal stem cells (MSCs) for cartilage regeneration in knee osteoarthritis (OA). However, little is known about the factors that influence the clinical outcomes after surgery. PURPOSE/HYPOTHESIS: This study aimed to investigate the clinical outcomes of MSC implantation in patients with knee OA and assess the factors that are associated with clinical outcomes. The hypothesis was that factors may exist that could influence clinical outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 49 patients (55 knees) were retrospectively evaluated after MSC implantation for knee OA. The inclusion criteria were patients who had an isolated full-thickness cartilage lesion and Kellgren-Lawrence OA grade 1 or 2. Clinical outcomes were measured with the International Knee Documentation Committee (IKDC) score, Tegner activity score, and patients' overall satisfaction with the surgery. Statistical analyses were performed to determine the effect of different factors on the clinical outcome. RESULTS: The mean pre- and postoperative IKDC and Tegner activity scores significantly improved from 37.7 +/- 6.3 to 67.3 +/- 9.5 (IKDC) and from 2.2 +/- 0.7 to 3.8 +/- 0.7 (Tegner) (P < .001 for both). Twenty-four patients reported their overall satisfaction with the surgery as excellent (43.6%), 17 as good (30.9%), 11 as fair (20.0%), and 3 as poor (5.5%). There were significant differences in clinical outcomes at the final follow-up among the age and lesion size groups (P < .05 for all). Multivariate analyses showed high prognostic significance related to patient age and lesion size, and scatter plots suggested a cutoff age of 60 years and a cutoff lesion size of 6.0 cm(2) for the optimum identification of poor clinical outcomes (P < .05 for both). CONCLUSION: The clinical outcomes of MSC implantation for knee OA are encouraging. Patient age and lesion size are important factors that affect clinical outcomes; thus, these may serve as a basis for preoperative surgical decisions. Cutoff points exist for the risk of clinical failure in patients older than 60 years and those with a lesion size larger than 6.0 cm(2). PMID- 26113523 TI - Identification and mapping stripe rust resistance gene YrLM168a using extreme individuals and recessive phenotype class in a complicate genetic background. AB - The identification and characterization of resistance genes effective against stripe rust of wheat is beneficial for modern wheat breeding programs. Molecular markers to such genes facilitate their deployment. The variety Milan has resistance that is effective against the predominant stripe rust races in the Sichuan region. Two resistant and two susceptible F8 lines from a cross between Milan and the susceptible variety Chuannong 16 were used to investigate inheritance of the Milan resistance. Three F2 populations were developed from crosses between the resistant lines and their susceptible sibling lines (LM168a * LM168c, LM168c * LM168a, LM168b * LM168d) and used for genetic analysis and molecular mapping of the genes for resistance. The stripe rust resistance in LM168a and LM168b was conferred by a single dominant gene, temporarily designated as YrLM168a. Forty-five extreme susceptible plants from the F2 families of LM168d * LM168b were genotyped with 836 simple sequence repeat (SSR) markers to map YrLM168a. YrLM168a was mapped in chromosome 6BL. The nearest flanking markers Xwmc756 and Xbarc146 were 4.6 and 4.6 cM away from the gene at both sides, respectively. The amplification results of twenty extreme resistant (IT 0) and susceptible (IT 4) F2 plants of LM168c * LM168a and LM168a * LM168c with marker Xwmc756 further validated the mapping results. The study suggested that extreme individuals and recessive phenotype class can be successfully used for mapping genes, which should be efficient and reliable. In addition, the flanking markers near YrLM168a should be helpful in marker-assisted breeding. PMID- 26113524 TI - Treatment of emphysema using bronchoscopic lung volume reduction coil technology: an update on efficacy and safety. AB - In the last decade several promising bronchoscopic lung volume reduction (BLVR) treatments were developed and investigated. One of these treatments is BLVR treatment with coils. The advantage of this specific treatment is that it works independently of collateral flow, and also shows promise for patients with a more homogeneous emphysema disease distribution. Seven years ago, the very first patients were treated with BLVR coil treatment and currently large randomized, controlled trials are underway. The aim of this article is to review the available literature and provide an update on the current knowledge on the efficacy and safety of BLVR treatment with coils. PMID- 26113525 TI - Cytotoxicity and genotoxicity of urban particulate matter in mammalian cells. AB - Ambient air particulate matter (PM)-associated reactive oxygen species (ROS) have been linked to a variety of altered cellular outcomes. In this study, three different PM samples from diesel exhaust particles (DEPs), urban dust standard reference material SRM1649a and air collected in Manchester have been tested for their ability to oxidise DNA in a cell-free assay, to increase intracellular ROS levels and to induce CYP1A1 gene expression in mammalian cells. In addition, the cytotoxicity and genotoxicity of PM were assessed using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and alkaline comet assay, respectively. All PM samples catalysed the Fenton reaction in a cell-free assay, but only DEP resulted in the generation of ROS as measured by dichlorodihydrofluorescein diacetate oxidation in mammalian cells. However, there was no evidence that increased ROS was a consequence of polycyclic aromatic hydrocarbon metabolism via CYP1A1 induction as urban dust, the Manchester dust samples but not DEP-induced CYP1A1 expression. Urban dust was more cytotoxic in murine embryonic fibroblasts (MEFs) than the other PM samples and also induced expression of GADD45a in the GreenScreen Human Cell assay without S9 activation suggesting the presence of a direct-acting genotoxicant. Urban dust and DEP produced comparable levels of DNA damage, as assessed by the alkaline comet assay, in MEFs at higher levels than those induced by Manchester PM. In conclusion, results from the cytotoxic and genotoxic assays are not consistent with ROS production being the sole determinant of PM-induced toxicity. This suggests that the organic component can contribute significantly to this toxicity and that further work is required to better characterise the extent to which ROS and organic components contribute to PM-induced toxicity. PMID- 26113527 TI - Invariance of measures to understand decision-making for pursuing living donor kidney transplant. AB - Living donor kidney transplant is the ideal treatment option for end-stage renal disease; however, the decision to pursue living donor kidney transplant is complex and challenging. Measurement invariance of living donor kidney transplant Decisional Balance and Self-Efficacy across gender (male/female), race (Black/White), and education level (no college/college or higher) were examined using a sequential approach. Full strict invariance was found for Decisional Balance and Self-Efficacy for gender and partial strict invariance was found for Decisional Balance and Self-Efficacy across race and education level. This information will inform tailored feedback based on these constructs in future intervention studies targeting behavior change among specific demographic subgroups. PMID- 26113528 TI - Forgiveness and health-related quality of life in older people: Adaptive cognitive emotion regulation strategies as mediators. AB - This study examined whether adaptive cognitive emotion regulation strategies mediate the relationship between forgiveness and health-related quality of life in a sample of 350 Spanish people aged 55 years and older. Positive refocusing and positive reappraisal strategies partially mediated the relation between forgiveness and mental health. Thus, focusing on planning partially mediated the relation between forgiveness and physical health. Our findings contribute to an emerging understanding of the underlying coping process between forgiveness and health outcomes and might provide preliminary insight for potential intervention for increasing quality of life via the promotion of forgiveness and adaptive coping in the elderly. PMID- 26113529 TI - Targeted immunotherapy in Hodgkin lymphoma. AB - In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13. PMID- 26113530 TI - Toward optimizing pomalidomide therapy in MM patients. AB - In this issue of Blood, Sehgal et al report on the clinical and pharmacodynamics analysis of pomalidomide dosing strategies in multiple myeloma (MM) and their impact on immune activation and cereblon targets. The particular novelty of this study lies in the direct correlation of immune effects triggered by pomalidomide with clinical responses in MM patients. Results of this study will stimulate many additional studies. PMID- 26113531 TI - Ebf1 in DNA repair and leukemogenesis. AB - In this issue of Blood, Prasad et al provide evidence for a new role for the B lineage transcriptional regulator early B-cell factor 1 (Ebf1) during early B cell development and B-cell acute lymphoblastic leukemia (B-ALL). PMID- 26113532 TI - Arginine addiction in AML. AB - In this issue of Blood, Miraki-Moud et al demonstrate that the majority of acute myeloid leukemias (AMLs) have low expression of argininosuccinate synthetase-1 (ASS1), rendering AML cell lines and primary AML blasts dependent on exogenous arginine and sensitized to arginine deprivation. PMID- 26113533 TI - CLEC-2: the inside story. PMID- 26113534 TI - Syk and tired of current chronic GVHD therapies. AB - In this issue of Blood, Flynn et al1 provide key data that lend further support to the development of clinical trials of spleen tyrosine kinase (Syk) inhibition for more effective chronic graft-versus-host disease (cGVHD) treatment. PMID- 26113535 TI - Foxc2 enhances proliferation and inhibits apoptosis through activating Akt/mTORC1 signaling pathway in mouse preadipocytes. AB - Forkhead box C2 (Foxc2) protein is a transcription factor in regulation of development, metabolism, and immunology. However, the regulatory mechanisms of Foxc2 on proliferation and apoptosis of preadipocytes are unclear. In this study, we found that high-fat-diet-induced obesity elevated the expression of Foxc2 and cyclin E after 6 weeks. Additionally, Foxc2 suppressed preadipocyte differentiation, increased cell counts and augmented G1-S transition of preadipocytes, along with the elevation of cyclin E expression and the reduction levels of p27 and p53. Furthermore, Foxc2 knockdown reduced early apoptotic cells with accompanying reduction of mitochondrial membrane potential and increased fragmentation of genomic DNA. We show that Foxc2 reduces the expression of Bax, caspase-9, and caspase-3 in both serum-starved and palmitic acid-induced cell apoptotic models, which confirms the anti-apoptotic role of Foxc2. Moreover, the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)C1 signaling pathway and the ERK/mTORC1 signaling pathway were activated along with preadipocyte proliferation in response to Foxc2 overexpression, whereas apoptosis marker genes were downregulated during this process. Those effects were blocked by the interference of Foxc2 or signal pathways specific inhibitors. These data collectively reveal that Foxc2 enhances proliferation of preadipocytes and inhibits apoptosis of preadipocytes by activating the Akt/mTORC1 and ERK/mTORC1 signaling pathways. PMID- 26113536 TI - Insufficient glucose supply is linked to hypothermia upon cold exposure in high fat diet-fed mice lacking PEMT. AB - Mice that lack phosphatidylethanolamine N-methyltransferase (Pemt(-/-) mice) are protected from high-fat (HF) diet-induced obesity. HF-fed Pemt(-/-) mice show higher oxygen consumption and heat production, indicating that more energy might be utilized for thermogenesis and might account for the resistance to diet induced weight gain. To test this hypothesis, HF-fed Pemt(-/-) and Pemt(+/+) mice were challenged with acute cold exposure at 4 degrees C. Unexpectedly, HF-fed Pemt(-/-) mice developed hypothermia within 3 h of cold exposure. In contrast, chow-fed Pemt(-/-) mice, possessing similar body mass, maintained body temperature. Lack of PEMT did not impair the capacity for thermogenesis in skeletal muscle or brown adipose tissue. Plasma catecholamines were not altered by Pemt genotype, and stimulation of lipolysis was intact in brown and white adipose tissue of Pemt(-/-) mice. HF-fed Pemt(-/-) mice also developed higher systolic blood pressure, accompanied by reduced cardiac output. Choline supplementation reversed the cold-induced hypothermia in HF-fed Pemt(-/-) mice with no effect on blood pressure. Plasma glucose levels were ~50% lower in HF-fed Pemt(-/-) mice compared with Pemt(+/+) mice. Choline supplementation normalized plasma hypoglycemia and the expression of proteins involved in gluconeogenesis. We propose that cold-induced hypothermia in HF-fed Pemt(-/-) mice is linked to plasma hypoglycemia due to compromised hepatic glucose production. PMID- 26113538 TI - Campbell's Law: implications for health care. AB - Campbell's Law is a well-known social science dictum describing the potential ill effects of using a quantitative measure both as a target and an indicator to drive decision making. Campbell's Law states that using a measure in this way tends to distort its usefulness to achieve the desired goal while driving participants to adopt corrupt practices. There is evidence of Campbell's Law at play in various industries, including health care. Fortunately, the deleterious effects of Campbell's Law can be successfully mitigated. The two main mitigation strategies involve either keeping the goals of a functioning system separated from the metrics used to assess progress towards that goal, or ensuring the proper safeguards are in place to combat the corrupting pressures. PMID- 26113537 TI - Manganese lipoxygenase of F. oxysporum and the structural basis for biosynthesis of distinct 11-hydroperoxy stereoisomers. AB - The biosynthesis of jasmonates in plants is initiated by 13S-lipoxygenase (LOX), but details of jasmonate biosynthesis by fungi, including Fusarium oxysporum, are unknown. The genome of F. oxysporum codes for linoleate 13S-LOX (FoxLOX) and for F. oxysporum manganese LOX (Fo-MnLOX), an uncharacterized homolog of 13R-MnLOX of Gaeumannomyces graminis. We expressed Fo-MnLOX and compared its properties to Cg MnLOX from Colletotrichum gloeosporioides. Electron paramagnetic resonance and metal analysis showed that Fo-MnLOX contained catalytic Mn. Fo-MnLOX oxidized 18:2n-6 mainly to 11R-hydroperoxyoctadecadienoic acid (HPODE), 13S-HPODE, and 9(S/R)-HPODE, whereas Cg-MnLOX produced 9S-, 11S-, and 13R-HPODE with high stereoselectivity. The 11-hydroperoxides did not undergo the rapid beta fragmentation earlier observed with 13R-MnLOX. Oxidation of [11S-(2)H]18:2n-6 by Cg-MnLOX was accompanied by loss of deuterium and a large kinetic isotope effect (>30). The Fo-MnLOX-catalyzed oxidation occurred with retention of the (2)H label. Fo-MnLOX also oxidized 1-lineoyl-2-hydroxy-glycero-3-phosphatidylcholine. The predicted active site of all MnLOXs contains Phe except for Ser(348) in this position of Fo-MnLOX. The Ser348Phe mutant of Fo-MnLOX oxidized 18:2n-6 to the same major products as Cg-MnLOX. Our results suggest that Fo-MnLOX, with support of Ser(348), binds 18:2n-6 so that the proR rather than the proS hydrogen at C-11 interacts with the metal center, but retains the suprafacial oxygenation mechanism observed in other MnLOXs. PMID- 26113539 TI - Transcultural nursing promoting peace through practice and scholarship. PMID- 26113540 TI - Marginalized People Locked in "Chinese Handcuffs". PMID- 26113542 TI - Sepsis: Medical errors in Poland. AB - Health, safety and medical errors are currently the subject of worldwide discussion. The authors analysed medico-legal opinions trying to determine types of medical errors and their impact on the course of sepsis. The authors carried out a retrospective analysis of 66 medico-legal opinions issued by the Wroclaw Department of Forensic Medicine between 2004 and 2013 (at the request of the prosecutor or court) in cases examined for medical errors. Medical errors were confirmed in 55 of the 66 medico-legal opinions. The age of victims varied from 2 weeks to 68 years; 49 patients died. The analysis revealed medical errors committed by 113 health-care workers: 98 physicians, 8 nurses and 8 emergency medical dispatchers. In 33 cases, an error was made before hospitalisation. Hospital errors occurred in 35 victims. Diagnostic errors were discovered in 50 patients, including 46 cases of sepsis being incorrectly recognised and insufficient diagnoses in 37 cases. Therapeutic errors occurred in 37 victims, organisational errors in 9 and technical errors in 2. In addition to sepsis, 8 patients also had a severe concomitant disease and 8 had a chronic disease. In 45 cases, the authors observed glaring errors, which could incur criminal liability. There is an urgent need to introduce a system for reporting and analysing medical errors in Poland. The development and popularisation of standards for identifying and treating sepsis across basic medical professions is essential to improve patient safety and survival rates. Procedures should be introduced to prevent health-care workers from administering incorrect treatment in cases. PMID- 26113543 TI - Appeals against detention in excessive security (outcomes of appeals against detention in conditions of excessive security in Scotland). AB - The Mental Health (Care and Treatment) (Scotland) Act 2003 introduced the right for patients in high-security psychiatric care to appeal against detention in conditions of excessive security. A previous study examined the first 100 patients to appeal under this provision. In this study we compare them with the next cohort of 110 patients to lodge an appeal, finding, contrary to expectations, no change in patient characteristics or the outcome of their appeals. The clinical, legal and demographic features of successful and unsuccessful appellants, who made up 38% and 27% of the 110 patients, respectively, were also compared. Those patients with the support of their responsible medical officer and those already included on a transfer list had a significantly better chance of success (p = 0.00). It was also found that a history of excessive alcohol consumption was associated with successful appeals (p = 0.002). A diagnosis of learning disability was associated with unsuccessful appeals (p = 0.018), though the sub-sample was very small. These findings are important given the forthcoming extension of this right of appeal to other levels of security. PMID- 26113544 TI - Non-terrorist suicidal death by oral explosion: A rare case from India. AB - Suicidal deaths involving explosives are rare. Their occurrence depends on both the availability of materials and the victim's expertise in handling explosive material. We report here a rare case from India of non-terrorist suicidal death involving explosives. The victim was around 25 years old, a blaster by occupation. He committed suicide by detonating dynamite in his mouth. The materials he used to operate this explosion were found near his body at the crime scene. There was characteristic bilateral symmetrical laceration around the oral cavity. Considering all the facts of the case in relation to history, location, nature, distribution and extent of injuries and recovered material at crime scene enables the cause and manner of death to be ascertained. PMID- 26113545 TI - A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy. AB - Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin kappa locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomib-based treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology. PMID- 26113546 TI - A nephrology guide to reading and using systematic reviews of observational studies. AB - Systematic reviews are an ideal way of summarizing evidence from primary studies. While systematic reviews of randomized trials are broadly used to summarize benefits and harms of interventions, systematic reviews of observational studies are useful to summarize data on prevalence of risk factors in a population, distribution of outcomes or associations of different risk factors with outcomes. Also, systematic reviews can be useful to clarify potential reasons for conflicting data found in primary studies and explore sources of heterogeneity (variation in primary study data) to better understand epidemiological data and generate hypotheses for candidate interventions to improve outcomes. Summarizing data from observational studies in systematic reviews is a powerful tool to distil existing prognostic evidence in specific settings and inform patients and healthcare providers. In this article, we describe how to critically appraise the methods, interpret the results and apply the findings of a systematic review of observational (prognostic) studies. PMID- 26113549 TI - Research Trends in Adapted Physical Activity Quarterly From 2004 to 2013. AB - The purpose of this documentary analysis was to examine trends in research published in Adapted Physical Activity Quarterly (APAQ) over a 10-yr span. A total of 181 research articles published from 2004 to 2013 were coded and analyzed using the following categories: first-author country affiliation, theoretical framework, intervention, research methods, disability categories, and topical focus. Results indicate high frequencies of nonintervention and group design studies, as well as a low frequency of studies that describe a theoretical or conceptual framework. Trends in disability of participants and topical focus reflect current interests of researchers publishing in APAQ. While some scholars have suggested that changes in research on adapted physical activity would occur, the results of this analysis suggest that many of these categories remain largely unchanged for research published in APAQ. This study calls attention to similarities between the results of the current analysis and previous ones. PMID- 26113550 TI - Coaches' Perceptions of Team Cohesion in Paralympic Sports. AB - The purpose of this study was to investigate Paralympic coaches' perceptions of team cohesion. Seven head coaches of summer and winter Canadian Paralympic sport teams participated in the study. Four participants coached individual sports and 3 coached team sports. Data were collected using semistructured interviews and analyzed using thematic analysis. The results addressed the coaches' perceptions of cohesion in the Paralympic sport setting and strategies used to foster cohesion with their teams. Participants described using techniques and strategies for enhancing cohesion that were similar to those in nondisability sport, such as task-related activities, goal setting, and regularly communicating with their athletes. They also listed how cohesion was distinct to the Paralympic setting, such as the importance of interpersonal activities to build social cohesion. The implications of these results for coaching athletes with a disability are also presented. PMID- 26113551 TI - Application of the Transtheoretical Model to Physical Activity in Deaf Individuals. AB - The current study used the transtheoretical model (TTM) as a guiding theoretical framework to assess differences in processes of change, decisional balance, and self-efficacy among deaf individuals with different levels of physical activity. Overall, 146 participants (M age = 26.4 yr, SD = 4.28) completed anonymous questionnaires assessing the dimensions of the TTM, stages of change, processes of change, decisional balance, and self-efficacy. Analysis of variance showed that both experiential and behavioral processes of change were higher in the preparation, action, and maintenance stages than in the other stages. Accordingly, the benefits of physical activity participation were stronger in the preparation stage, whereas the costs were more evident in the precontemplation stage. Finally, self-efficacy at the preparation stage was higher than in the other stages. The findings revealed how different stages of physical activity participation can be explained through the TTM, and the implications for physical activity intervention are discussed. PMID- 26113552 TI - Psychological Preparation for Paralympic Athletes: A Preliminary Study. AB - Since the first Paralympics in 1960 there has been an increase in social and scientific interest in Paralympic athletes' personality, their preparation, and their sport results. During the last 20 yr, researchers and practitioners have been focused on psychological-skills programs for athletes with disabilities. The purpose of this article was to describe a psychological-preparation program for Israeli Paralympic athletes. Two subprograms, the learning-modification application approach and the Simulation Training Exercise Program, were adapted to athletes' disability and sport demands. Two case studies, from table tennis and sailing (Sonar 3-person keelboat), are described to demonstrate how systematic sport psychology preparation can be effectively integrated into the training process of Paralympic athletes. Some recommendations for Paralympic athletes are presented. PMID- 26113556 TI - Private sector must improve customer experience, conference hears. PMID- 26113553 TI - Comparing the Well-Being of Para and Olympic Sport Athletes: A Systematic Review. AB - This systematic review included 12 studies that compared the well-being of Para and Olympic sport athletes. Meta-analyses revealed that Para athletes, compared with Olympic sport athletes, had lower levels of self-acceptance, indicated by athletic identity, d = 0.47, 95% confidence interval (CI) [0.77, 0.16], and body image perceptions, d = 0.33, 95% CI [0.59, 0.07], and differed from Olympic sport athletes in terms of their motivation, indicated by a greater mastery-oriented climate, d = 0.74, 95% CI [0.46, 1.03]. Given an inability to pool the remaining data for meta-analysis, individual standardized mean differences were calculated for other dimensions of psychological and subjective well-being. The results have implications for professionals and coaches aiming to facilitate the well-being needs of athletes under their care. Future research would benefit from incorporating established models of well-being based on theoretical rationale combined with rigorous study designs. PMID- 26113558 TI - Hippocampal Dose With Radiosurgery for Multiple Intracranial Targets: The Rationale for Proactive Beam Shaping. AB - Stereotactic radiosurgery provides conformal treatment of intracranial lesions, but when multiple lesions are treated, cumulative dose to structures such as the hippocampi may be increased. We analyzed hippocampal dose for patients treated with radiosurgery for multiple brain metastases. We then investigated a means to minimize hippocampal dose. We randomly selected 8 patients treated with single session, frame-based radiosurgery for 6 to 12 intracranial metastases. Standard planning was employed to deliver 16 to 20 Gy to each lesion without hippocampal avoidance. Each case was replanned using the software's dynamic shaping function to minimize direct beam hippocampal irradiation, while maintaining conformality and target coverage. With standard planning, the maximum hippocampal dose varied from 0.8 to 9.0 Gy but was >3 Gy only when a lesion was <10 mm from the hippocampus. There was no clear correlation between hippocampal dose and the number or the total volume of lesions. Replanning with direct beam avoidance decreased the mean hippocampal dose by an average of 35% but increased treatment time by a mean of 20%. Sparing was most pronounced when the closest lesion was in close proximity to the hippocampus. This is the first study reporting hippocampal dose for multilesion intracranial radiosurgery. It illustrates that when multiple intracranial targets are treated with radiosurgery, substantial hippocampal dose can result. Active beam shielding and optimization can lower hippocampal dose, especially with lesions <10 mm from the hippocampus. These results raise the prospect that the risk of neurocognitive side effects may be further decreased with a hippocampal-sparing approach. PMID- 26113557 TI - pH-weighted molecular imaging of gliomas using amine chemical exchange saturation transfer MRI. AB - BACKGROUND: Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water. METHODS: First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients. RESULTS: z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001). CONCLUSION: Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies. PMID- 26113559 TI - Overexpression of TRIM25 in Lung Cancer Regulates Tumor Cell Progression. AB - Lung cancer is one of the most common causes of cancer-related deaths worldwide. Although great efforts and progressions have been made in the study of the lung cancer in the recent decades, the mechanism of lung cancer formation remains elusive. To establish effective therapeutic methods, new targets implied in lung cancer processes have to be identified. Tripartite motif-containing 25 has been associated with ovarian and breast cancer and is thought to positively promote cell growth by targeting the cell cycle. However, whether tripartite motif containing 25 has a function in lung cancer development remains unknown. In this study, we found that tripartite motif-containing 25 was overexpressed in human lung cancer tissues. Expression of tripartite motif-containing 25 in lung cancer cells is important for cell proliferation and migration. Knockdown of tripartite motif-containing 25 markedly reduced proliferation of lung cancer cells both in vitro and in vivo and reduced migration of lung cancer cells in vitro Meanwhile, tripartite motif-containing 25 silencing also increased the sensitivity of doxorubicin and significantly increased death and apoptosis of lung cancer cells by doxorubicin were achieved with knockdown of tripartite motif-containing 25. We also observed that tripartite motif-containing 25 formed a complex with p53 and mouse double minute 2 homolog (MDM2) in both human lung cancer tissues and in lung cancer cells and tripartite motif-containing 25 silencing increased the expression of p53. These results provide evidence that tripartite motif containing 25 contributes to the pathogenesis of lung cancer probably by promoting proliferation and migration of lung cancer cells. Therefore, targeting tripartite motif-containing 25 may provide a potential therapeutic intervention for lung cancer. PMID- 26113560 TI - A Call to Action to Bring Safer Parenteral Micronutrient Products to the U.S. Market. AB - The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) started an intensive review of commercially available parenteral vitamin and trace element (TE) products in 2009. The chief findings were that adult multi-TE products currently available in the United States (U.S.) provide potentially toxic amounts of manganese, copper, and chromium, and neonatal/pediatric multi-TE products provide potentially toxic amounts of manganese and chromium. The multivitamin products appeared safe and effective; however, a separate parenteral vitamin D product is needed for those patients on standard therapy who continue to be vitamin D depleted and are unresponsive to oral supplements. The review process also extended to parenteral choline and carnitine. Although choline and carnitine are not technically vitamins or trace elements, choline is an essential nutrient in all age groups, and carnitine is an essential nutrient in infants, according to the Food and Nutrition Board of the Institute of Medicine. A parenteral choline product needs to be developed and available. Efforts are currently under way to engage the U.S. Food and Drug Administration (FDA) and the parenteral nutrient industry so A.S.P.E.N.'s recommendations can become a commercial reality. PMID- 26113561 TI - Nutrition Management of Cystic Fibrosis in the 21st Century. AB - Despite significant advancements made in life expectancy over the past century, cystic fibrosis remains a life-threatening genetic disease that affects the gastrointestinal tract, and it has significant impact on the nutrition status of those with the disease. Nutrition management includes a high-calorie/high-fat diet, pancreatic enzyme replacement therapy, vitamin and mineral replacement, and enteral support as needed. As patients are living longer, clinicians may encounter patients with cystic fibrosis in obstetrician offices, endocrine clinics, or hospital settings, owing to lung transplantation or for treatment for distal intestinal obstruction syndrome. PMID- 26113562 TI - Enteral Nutrition in Chronic Liver Disease: Translating Evidence Into Practice. AB - Malnutrition is prevalent in individuals with chronic liver disease and occurs as a result of inadequate nutrient intake, altered metabolism, and malabsorption. Although limited data show benefits of enteral nutrition (EN) in this population, patients with chronic liver disease often have inadequate oral intake and are potential candidates for EN. The goals of the EN, type and severity of liver disease, and access for EN will influence the decision to initiate EN. This paper summarizes EN studies in patients with liver disease and provides practical tips regarding patient selection, EN access, and EN formula choices. Two case studies illustrate the principles and challenges of providing EN to patients with cirrhosis. The paper concludes with suggested parameters for an EN feeding protocol and recommendations for future research. PMID- 26113563 TI - Endovascular treatment of unruptured ophthalmic artery aneurysms: clinical usefulness of the balloon occlusion test in predicting vision outcomes after coil embolization. AB - BACKGROUND: Endovascular coil embolization for ophthalmic artery (OphA) aneurysms has the latent risk of occlusion of the OphA during the procedure, which can lead to loss of vision. We report clinical and angiographic results of endovascular treatment of OphA aneurysms together with the efficacy of the balloon occlusion test (BOT). METHODS: From August 2005 to December 2013, 31 consecutive patients with 33 OphA aneurysms were treated in our institution. The patients were classified into two groups according to the location of the OphA within the aneurysmal sac. The BOT was performed in 28 patients using a hypercompliant balloon before endovascular coiling. Collateral circulation between the external carotid artery and the OphA was examined and visual function tests were performed before and after treatment. Patient demographics, angiographic and clinical outcomes were reviewed. RESULTS: Among the 28 patients who underwent the BOT, intact collateral circulation was demonstrated in 26 (92.9%) patients and complete occlusion of the OphA was obtained in three patients after coiling. Retrograde filling of the OphA with choroidoretinal blush was observed on post procedural angiography and no specific visual symptoms were reported during the follow-up period. Complete embolization was achieved in 30 lesions (96.8%) and only five patients (16.1%) had minor recanalization. CONCLUSIONS: Endovascular treatment of OphA aneurysms can be performed safely and effectively in conjunction with BOT. The BOT may give useful information to predict visual outcome in patients whose OphA is likely to be threatened by the coiling procedure and to determine the optimal treatment strategy. PMID- 26113564 TI - Smokers are more likely to quit as smoking prevalence decreases, study shows. PMID- 26113565 TI - Breath of hospitality. AB - In this paper we outline the possibilities of an ethic of care based on our self affection and subjectivity in the ethical spaces between-two. In this we first refer to three Irigarayan concepts - breath, silence and listening from the third phase of her philosophy, and discuss them within the methodological framework of an ethics of intersubjectivity and interiority. Together with attentiveness, we analyse them as four categories of our ethical becoming. Furthermore, we argue that self-affection is based on our inchoate receptivity for the needs of the other(s) and is thus dialectical in its character. In this we critically confront some epistemological views of our ethical becoming. We wind up this paper with a proposal for an ethics towards two autonomous subjects, based on care and our shared ethical becoming - both as signs of our deepest hospitality towards the other. PMID- 26113567 TI - Parents, Teach Your Children Well. PMID- 26113566 TI - AARC Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients. AB - Aerosolized medications are used as airway clearance therapy to treat a variety of airway diseases. These guidelines were developed from a systematic review with the purpose of determining whether the use of these medications to promote airway clearance improves oxygenation and respiratory mechanics, reduces ventilator time and ICU stay, and/or resolves atelectasis/consolidation compared with usual care. Recombinant human dornase alfa should not be used in hospitalized adult and pediatric patients without cystic fibrosis. The routine use of bronchodilators to aid in secretion clearance is not recommended. The routine use of aerosolized N acetylcysteine to improve airway clearance is not recommended. Aerosolized agents to change mucus biophysical properties or promote airway clearance are not recommended for adult or pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough. Mucolytics are not recommended to treat atelectasis in postoperative adult or pediatric patients, and the routine administration of bronchodilators to postoperative patients is not recommended. There is no high-level evidence related to the use of bronchodilators, mucolytics, mucokinetics, and novel therapy to promote airway clearance in these populations. PMID- 26113568 TI - Mechanical Insufflation-Exsufflation: The Good, the Bad, and the Ugly. PMID- 26113569 TI - A Paradox Defined? PMID- 26113570 TI - Are New Airway Devices for Percutaneous Dilatational Tracheostomy Really Needed? PMID- 26113571 TI - Are New Devices for Percutaneous Dilatational Tracheostomy Really Needed? Yes. PMID- 26113573 TI - Endovascular repair of proximal para-anastomotic aneurysms after previous open abdominal aortic aneurysm reconstruction. AB - OBJECTIVE: To evaluate the safety, efficacy and durability of endovascular repair for proximal para-anastomotic aneurysms after previous open abdominal aortic aneurysms prosthetic reconstruction and share our experience. METHODS: We retrospectively reviewed the data of all patients with previous open abdominal aortic aneurysms prosthetic reconstruction who underwent endovascular repair for proximal para-anastomotic aneurysms between May 2003 and January 2013 in our center (Nuremberg South Hospital). Key clinical outcomes included technical success rate, peri-operative morbidity and mortality, mid-term complications, reinterventions and open conversion rates. RESULTS: Totally, 24 patients of proximal para-anastomotic aneurysm were treated by endovascular repair. Successful deployments of stent graft were achieved in all patients (100%). Median hospital stay was 6.7 days. One patient had minor type Ia endoleak and one patient developed wound infection. There were no early open conversions and deaths. During a median follow-up of 43 months (range, 7-67 months), computed tomography angiography revealed type Ia endoleaks in four patients (16.7%). The overall reintervention and open conversion rates during follow-up were 16.7% (4/24) and 4.2% (1/24), respectively. Estimates of freedom from reintervention were 91.7% at 1 year, 87.1% at 3 years and 80.9% at 5 years. There was significant difference in freedom from reintervention between proximal para anastomotic aneurysms patients treated with tube and unibody bifurcated stent grafts (p = 0.034). The cumulative mortality rate was 12.5% (3/24), actuarial analysis for all patients estimated survival rates of 95.8% at 1 year and 87.3% at 5 years. CONCLUSIONS: Proximal para-anastomotic aneurysms are severe complications after abdominal aortic aneurysm open reconstruction. Closer follow up and prompt treatment are necessary. Endovascular treatment for proximal para anastomotic aneurysms is effective, safe and durable. Unibody bifurcated stent graft proved to be suitable for most proximal para-anastomotic aneurysms with various anatomical features. PMID- 26113574 TI - Protocol for prevention of spinal cord ischemia after thoracoabdominal aortic surgery. AB - OBJECTIVE: This manuscript was written to present a systemic protocol for the prevention, early detection, and treatment of spinal cord ischemia following open and endovascular thoracoabdominal aortic operations. METHODS: This protocol was a collaborative effort between surgeons, anesthesiologists and intensivists. It was implemented at our institution in November 2007. Nurses are trained to prevent, rapidly detect and ultimately aid in the treatment of spinal cord ischemia. RESULTS: Implementation of this protocol has aided in prevention, detection and treatment of spinal cord ischemia in patients after open and endovascular thoracoabdominal aortic operations. CONCLUSION: Standardized care and reliance on trained nursing staff to monitor for symptoms following thoracoabdominal aortic operations are safe and aid in the rapid detection, treatment and reversal of spinal cord ischemia. PMID- 26113575 TI - Fossil fuel companies and climate change: the case for divestment. PMID- 26113576 TI - Pakistan authorities trade blame as heatwave deaths exceed 800. PMID- 26113577 TI - Protective, elective lung irradiation in non-metastatic Ewing's sarcoma. AB - Ewing's sarcoma in childhood is a disease from family of the peripheral primitive neuroectodermal tumours. For a period of 16 y (1984-2000), 34 children with Ewing's sarcoma were treated and followed in our department. Twenty-seven of these patients were without distant metastases. Complex treatment was applied to all these patients-chemotherapy VACA (vincristine, actinomycin D, cyclophosphamide, adriamycin), local radiotherapy to a total dose of 50-56 Gy +/- surgery. After, a local tumour control was achieved in 11 children with non metastatic Ewing's sarcoma, elective whole lung irradiation to a total dose of 12 15 Gy was applied. Our experience in these 11 patients with non-metastatic Ewing's sarcoma, in whom elective lung irradiation was applied, showed significant reduction in the lung metastases, improved free of disease survival and overall survival. The achieved good treatment results necessitate extending this treatment approach through defining the risk groups of patients, suitable for elective lung radiotherapy combined with chemotherapy in non-metastatic Ewing's sarcoma. PMID- 26113578 TI - Internal exposure to uranium in a pooled cohort of gaseous diffusion plant workers. AB - Intakes and absorbed organ doses were estimated for 29 303 workers employed at three former US gaseous diffusion plants as part of a study of cause-specific mortality and cancer incidence in uranium enrichment workers. Uranium urinalysis data (>600 000 urine samples) were available for 58 % of the pooled cohort. Facility records provided uranium gravimetric and radioactivity concentration data and allowed estimation of enrichment levels of uranium to which workers may have been exposed. Urine data were generally recorded with facility department numbers, which were also available in study subjects' work histories. Bioassay data were imputed for study subjects with no recorded sample results (33 % of pooled cohort) by assigning department average urine uranium concentration. Gravimetric data were converted to 24-h uranium activity excretion using department average specific activities. Intakes and organ doses were calculated assuming chronic exposure by inhalation to a 5-um activity median aerodynamic diameter aerosol of soluble uranium. Median intakes varied between 0.31 and 0.74 Bq d(-1) for the three facilities. Median organ doses for the three facilities varied between 0.019 and 0.051, 0.68 and 1.8, 0.078 and 0.22, 0.28 and 0.74, and 0.094 and 0.25 mGy for lung, bone surface, red bone marrow, kidneys, and liver, respectively. Estimated intakes and organ doses for study subjects with imputed bioassay data were similar in magnitude. PMID- 26113579 TI - Milestone Survival: A Potential Intermediate Endpoint for Immune Checkpoint Inhibitors. AB - Recent advancements in cancer immunotherapies offer diverse strategies for cancer treatment. Among the most promising approaches is the blockade of immune checkpoint molecules to activate antitumor immunity. With targeted immunotherapies of new mechanisms of action come greater challenges in study design and statistical analysis, as well as the need for refining clinical trial endpoints. The long-term survival and delayed clinical effects demonstrated by these therapies could result in substantial prolongation of study duration and loss of statistical power if these key attributes are not accounted for in the study design and statistical analyses. In the Brookings Conference on Clinical Cancer Research held in Washington, DC, in November 2013, several intermediate clinical endpoints, including milestone overall survival, were proposed for the evaluation of cancer immunotherapies to take into account the possibility of delayed treatment effect and to better characterize the clinical activity profile of such agents, particularly immune checkpoint inhibitors. In this manuscript, the use of milestone survival is described as a potential efficacy endpoint for immune checkpoint inhibitors in late-stage drug development that could potentially mitigate the challenge of accelerating the drug development process when the strength of this class of agents is derived from long-term follow-up. PMID- 26113581 TI - An unusual cause of febrile hepatitis. AB - We describe the case of a 51-year-old man with recently diagnosed ulcerative colitis who developed fever and elevated liver enzymes as well as cholestasis a few weeks after starting treatment with mesalazine. As no obvious cause was found and fever persisted, liver biopsy was performed and revealed granulomatous hepatitis. The patient recovered completely after cessation of mesalazine, so that a drug-induced granulomatous hepatitis after exclusion of other differential diagnoses in an extensive work up was assumed. The present case demonstrates that even though drug-induced liver injury due to mesalazine is rare, it should be considered in unclear cases and lead to prompt discontinuation of mesalazine. PMID- 26113580 TI - Body Mass Index, PAM50 Subtype, and Outcomes in Node-Positive Breast Cancer: CALGB 9741 (Alliance). AB - BACKGROUND: Obesity at diagnosis is associated with poor prognosis in women with breast cancer, but few reports have been adjusted for treatment factors. METHODS: CALGB 9741 was a randomized trial of dose density and sequence of chemotherapy for node-positive breast cancer. All patients received doxorubicin, cyclophosphamide, and paclitaxel, dosed by actual body weight. Height and weight at diagnosis were abstracted from patient records, and the PAM50 assay was performed from archived specimens using the NanoString platform. Relationships between body mass index (BMI), PAM50, and recurrence-free and overall survival (RFS and OS) were evaluated using proportional hazards regression, adjusting for number of involved nodes, estrogen receptor (ER) status, tumor size, menopausal status, drug sequence, and dose density. All statistical tests were two-sided. RESULTS: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 additionally had subtype determination by PAM50. Median baseline BMI was 27.4kg/m(2). After 11 years of median follow-up, there were 619 RFS events and 543 deaths. Baseline BMI was a statistically significant predictor of RFS (adjusted hazard ratio [HR] for each five-unit increase in BMI = 1.08, 95% confidence interval [CI] = 1.02 to 1.14, P = .01) and OS (adjusted HR = 1.08, 95% CI = 1.01 to 1.14, P = .02) BMI and molecular phenotypes were independent prognostic factors for RFS, with no statistically significant interactions detected. CONCLUSIONS: BMI at diagnosis was a statistically significant prognostic factor in a group of patients receiving optimally dosed chemotherapy. Additional research is needed to determine the impact of weight loss on breast cancer outcomes and to evaluate whether this impact is maintained across tumor subtypes. PMID- 26113582 TI - Extensive gluteal haematoma after an intracapsular hip fracture in a patient on warfarin. AB - We describe a case of a patient on warfarin who developed an extensive haematoma after a hip hemiarthroplasty and was successfully treated with embolisation. This case highlights the importance of regular haematology input, careful consideration of a suitable surgical approach, close monitoring of postoperative wounds in patients on warfarin and the emerging role of embolisation. PMID- 26113583 TI - Fulminant amoebic enteritis that developed in the perinatal period. AB - We present a case of a 30-year-old postpartum woman who delivered by caesarean section at 34 weeks. On postoperative day 9, she was admitted to our hospital in shock. Emergency abdominal surgery was performed. Massive purulent ascites collected in the abdominal cavity and was associated with intestinal necrosis, which extended from the ascending colon to one-third of the descending colon. The necrotic lesion was excised, and an artificial anus was constructed at the ileum end. A histological finding on the 15th day indicated the possibility of amoebic enteritis, and the patient was started on metronidazole therapy. The diarrhoea improved dramatically after metronidazole treatment was started. The patient was able to walk unassisted on the 45th day and was subsequently discharged. Amoebic enteritis has been thought to be epidemic in developing countries, but today, the incidence of amoebic enteritis as a sexually transmitted disease is increasing in developed countries. PMID- 26113584 TI - Paediatric feather duvet hypersensitivity pneumonitis. AB - A previously well 12-year-old boy was admitted with a second insidious episode of dyspnoea, dry cough, anorexia, weight loss and chest pain. At admission, he had an oxygen requirement, significantly impaired lung function and reduced exercise tolerance. Initial forced expiratory volume in 1 s was 26%; a 3 min exercise test stopped at 1 min 50 when saturations dropped to 85%. CT scan showed ground-glass nodularity with lymphadenopathy. Bronchoalveolar lavage (BAL) for Pneumocystis carinii pneumonia and viruses were negative, and microbiology results for the BAL were reported in the absence of histology. This is because at the time the BAL samples were collected, a lung biopsy was performed. The biopsy was consistent with hypersensitivity pneumonitis. Echo was normal and CT pulmonary angiography negative. After taking a thorough history, exposure to feather duvets prior to each episode was elicited. IgG of avian precipitants was raised at 10.6 mgA/L (normal <10 mgA/L). Clinical improvement began with avoidance of exposure, while the boy was an inpatient. Antigen avoidance continued on discharge. He continues to improve since discharge. The condition was diagnosed as hypersensitivity pneumonitis secondary to exposure to antigens from feather duvets. PMID- 26113585 TI - Neuroborreliosis: the Guillain-Barre mimicker. AB - A 34-year-old woman presented to the medical admissions unit with progressive ascending weakness of her limbs and areflexia. Diagnosis of Guillain-Barre syndrome was suspected and she was started on intravenous immunoglobulins. Owing to a poor initial response, further exploratory history revealed travel to the New Forest and a possible tick bite; subsequent investigations confirmed positive serology for antibodies against Borrelia. The patient's weakness improved with intravenous ceftriaxone for neuroborreliosis, a manifestation of Lyme disease. With inpatient neurorehabilitation, she made good recovery and was able to mobilise with a stick from being completely bed bound 6 weeks after completion of her antibiotics. PMID- 26113586 TI - Giant cell tumour--a very rare differential for a lytic lesion of the medial condyle of the humerous. AB - Tumours are rare around the elbow joint, and giant cell tumours are especially rare in this region. A single case report of a giant cell involving the distal humerous was found in the literature and none were found involving the isolated medial condyle. We present a rare case of a 22-year-old woman with progressively increasing painful swelling in her left elbow over a period of 6 months. A plain radiograph revealed an expansile epiphyseometaphyseal, radiolucent lesion in the medial end of the distal humerous, with the rim being thin but still intact. The MRI of the elbow revealed a solid lesion in the medial aspect of the elbow with no breach of cortex. Biopsy of the lesion revealed multinucleated giant cells along with mononuclear cells consistent with a diagnosis of giant cell tumour. Extended curettage with bone cement was performed through an anterior approach. There has been no recurrence of the tumour in 2 years of follow-up; the patient has a good range of elbow movements of 20-110 degrees . PMID- 26113587 TI - Hodgkin's lymphoma in an adolescent previously treated with surgical resection of third ventricular juvenile pilocytic astrocytoma. AB - We present a case of a 19-year-old man with cervical lymphadenopathy diagnosed with classical Hodgkin's lymphoma 9 years after gross total resection of a third ventricular juvenile pilocytic astrocytoma (JPA). Chemotherapy or radiation therapy was not a part of his initial JPA treatment. Owing to his two primary neoplasms, genetic testing was performed, which revealed heterozygous polymorphisms of unknown significance for CDH1 and p53, and negative BRAF mutation analysis. Our case reports development of classical Hodgkin's lymphoma after JPA in the absence of antecedent radiation and/or chemotherapy, and identifiable genetic predisposition. PMID- 26113588 TI - A rare case of subcapsular liver haematoma following laparoscopic cholecystectomy. AB - Laparoscopic cholecystectomy is a commonly performed surgical procedure for the treatment of symptomatic cholelithiasis. As with all surgical procedures, it carries risk, with the most commonly reported complications including infection, bile leak and bleeding. One unusual complication is subcapsular liver haematoma, the diagnosis presented here. This is a rare occurrence; only a small number of cases have been reported in the literature and as yet no conclusive cause or management plan has been found. Iatrogenic liver trauma, the use of oral and intravenous non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants have all been named as possible contributing factors. Particularly, the use of ketorolac has been associated with four reported cases of subcapsular haematoma following laparoscopic cholecystectomy. The case reported here refutes that hypothesis, as neither NSAIDs nor anticoagulants were used during the treatment of this patient. PMID- 26113589 TI - Nodular trachea: tracheobronchopathia osteochondroplastica. AB - Tracheobronchopathia osteochondroplastica (TPO) is a rare disorder characterised by development of cartilaginous and bony nodules in the trachea. It usually affects elderly males with total prevalence of disease reported to be around 0.1%. Even though multiple theories and associations have been described, the exact cause of the disease remains unknown. Its presentation is non-specific with many cases being diagnosed incidentally. Chronic cough and dyspnoea are the most common presenting symptoms, but some cases may present with severe airway compromise. We present a case of a 70-year-old man with IgA lambda multiple myeloma, who was diagnosed with TPO by flexible bronchoscopy. PMID- 26113590 TI - Hemosuccus pancreaticus: a rare complication of chronic pancreatitis. AB - Hemosuccus pancreaticus is a very rare cause of gastrointestinal bleeding and it should be considered in every patient with history of chronic pancreatitis who presents with acute or intermittent gastrointestinal haemorrhage. A 54-year-old man with a history of chronic alcoholic pancreatitis was admitted to hospital for an acute exacerbation. During hospital stay, he presented with haematemesis and haemodynamic instability. Upper gastrointestinal endoscopy revealed a blood clot on Vater papilla. CT investigation showed a 4 cm cephalopancreatic pseudocyst and angiography identified a large pseudoaneurysm of the right gastroepiploic artery, bleeding into the pseudocyst-hemosuccus pancreaticus. Microcoil transcatheter embolisation was performed with success. PMID- 26113591 TI - Osteolipoma of floor of the mouth. AB - Lipomas are benign soft tissue tumours composed mainly of mature adipose tissue. Histological variants of lipomas have been named according to the type of tissue present and they include fibrolipoma, angiolipoma, osteolipoma, chondrolipoma and others. Osteolipoma, a classic lipoma with osseous metaplasia, is a very rare histological variant. Owing to the rarity of oral osteolipomas, we report an uncommon case of osteolipoma located on the floor of the mouth of a 20-year-old female patient and include a review of the literature. PMID- 26113592 TI - Spontaneous sphenopalatine pseudoaneurysm: recurrent epistaxis in a patient with cryptogenic vasculopathy. AB - We present a unique case of recurrent epistaxis secondary to a spontaneous sphenopalatine artery aneurysm in a young woman. This was investigated with an external carotid artery angiogram and subsequently treated successfully with endovascular embolisation of the aneurysm. PMID- 26113593 TI - A rare giant tubercle of Zuckerkandl with retrosternal extension encountered during total thyroidectomy. PMID- 26113594 TI - Xanthogranulomatous oophoritis mimicking malignancy: a diagnostic dilemma. AB - Xanthogranulomatous inflammation is a chronic condition in which the affected organ is replaced by lipid-filled macrophages with plasma cells, lymphocytes and neutrophils. It is very rare in the ovaries. A case of xanthogranulomatous oophoritis in a premenopausal multiparous woman presenting with abnormal uterine bleeding and adnexal mass whose clinical and imaging findings suggested malignancy is reported. PMID- 26113595 TI - Gynaecomastia: an unusual presenting symptom of bladder cancer. AB - A 74-year-old man presented to the outpatient clinic with painful gynaecomastia. A detailed physical examination to sort out possible causes of the gynaecomastia, including intracranial tumour, liver cirrhosis, hyperthyroidism, and adrenal and testicular tumour, was negative. No offending agent was found in his medication list. A CT scan of the head and ultrasound of the scrotum did not show any mass lesion. His serum beta-human chorionic gonadotropin (beta-hCG) and oestradiol levels were elevated. A CT scan of the abdomen and pelvis revealed bladder wall thickening with soft tissue mass. A cystoscopic biopsy confirmed transitional cell carcinoma with muscle invasion. The patient was started on chemotherapy but responded poorly. This case report describes the beta-hCG and oestradiol secreting transitional cell carcinoma of the bladder presenting as gynaecomastia in an older man. PMID- 26113596 TI - Intravenous immunoglobulin for antibody-mediated keratolimbal allograft rejection. AB - A 33-year-old woman with congenital aniridia presented with decreased vision in her right eye. Slit lamp examination revealed diffuse conjunctivalisation of the ocular surface with mild subepithelial fibrosis consistent with aniridic keratopathy secondary to limbal stem cell deficiency. She underwent limbal stem cell transplantation with cadaver donor tissue (keratolimbal allograft (KLAL) surgery) and received systemic immunosuppression. Despite optimal combination immunosuppressive therapy managed by a renal transplant specialist, 2 weeks after the KLAL, the patient developed intractable eye pain, conjunctival injection, dilation of the KLAL graft blood vessels and limbal haemorrhages. There were no epithelial defects noted. Donor-specific antibody testing was positive, and intravenous immunoglobulin therapy was initiated. There was immediate symptomatic and objective improvement. Fifteen months postoperatively, the patient's vision was 20/400 with a stable corneal epithelium and no evidence of inflammation. PMID- 26113597 TI - Getting a handle on complicated migraine. AB - We describe a case of a 45-year-old man who presented with a transient syndrome consisting of headache with neurological deficits. Neuroimaging including brain angiography was normal. Cerebrospinal fluid (CSF) analysis revealed an elevated protein and lymphocytic pleocytosis. The diagnosis of a syndrome of Headache and Neurological Deficits with CSF Lymphocytosis (HaNDL) was made after excluding all the other possible causes for the patient's presentation. He made an excellent recovery following a short course of naproxen sodium. PMID- 26113598 TI - Vasotropic light-chain amyloidosis and ischaemic cholangiopathy. AB - A 75-year-old woman was incidentally found to have deranged liver function tests (LFTs). She was well, apart from 2 years of dyspnoea. Investigations had revealed atrial fibrillation and a right pleural effusion, without identified aetiology. On examination, the only finding was a palpable liver edge. Initial blood and ultrasound screening suggested no cause. The patient underwent liver biopsy. Microscopy showed kappa-immunoglobulin light chains deposited exclusively in portal tracts, within blood vessel and bile duct walls. This pattern, although unusual, raised the possibility of kappa-light chain disease. Serum electrophoresis was normal, as were serum immunoglobulin values. Serum concentrations of kappa-light chains were elevated and microscopy of aspirated bone marrow found light-chain deposits with 10% plasmacytosis. Serum amyloid P (SAP) scintigraphy demonstrated splenic uptake. Myeloma, kappa-light chain, with light-chain amyloidosis was diagnosed. The patient has responded well to cyclophosphamide, bortazomib and dexamethasone chemotherapy, and her LFTs are now nearly normal. PMID- 26113599 TI - Kozhikode doctors plan court action over claims by homeopaths. PMID- 26113600 TI - 15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas. AB - The combination of pituitary adenomas (PA) and phaeochromocytomas (phaeo) or paragangliomas (PGL) is a rare event. Although these endocrine tumours may occur together by coincidence, there is mounting evidence that, in at least some cases, classical phaeo/PGL-predisposing genes may also play a role in pituitary tumorigenesis. A new condition that we termed '3Pas' for the association of PA with phaeo and/or PGL was recently described in patients with succinate dehydrogenase mutations and PAs. It should also be noted that the classical tumour suppressor gene, MEN1 that is the archetype of the PA-predisposing genes, is also rarely associated with phaeos in both mice and humans with MEN1 defects. In this report, we review the data leading to the discovery of 3PAs, other associations linking PAs with phaeos and/or PGLs, and the corresponding clinical and molecular genetics. PMID- 26113601 TI - Non-small cell lung cancer cell survival crucially depends on functional insulin receptors. AB - Insulin plays an important role as a growth factor and its contribution to tumor proliferation is intensely discussed. It acts via the cognate insulin receptor (IR) but can also activate the IGF1 receptor (IGF1R). Apart from increasing proliferation, insulin might have additional effects in lung cancer. Therefore, we investigated insulin action and effects of IR knockdown (KD) in three (NCI H292, NCI-H226 and NCI-H460) independent non-small cell lung cancer (NSCLC) cell lines. All lung cancer lines studied were found to express IR, albeit with marked differences in the ratio of the two variants IR-A and IR-B. Insulin activated the classical signaling pathway with IR autophosphorylation and Akt phosphorylation. Moreover, activation of MAPK was observed in H292 cells, accompanied by enhanced proliferation. Lentiviral shRNA IR KD caused strong decrease in survival of all three lines, indicating that the effects of insulin in lung cancer go beyond enhancing proliferation. Unspecific effects were ruled out by employing further shRNAs and different insulin-responsive cells (human pre-adipocytes) for comparison. Caspase assays demonstrated that IR KD strongly induced apoptosis in these lung cancer cells, providing the physiological basis of the rapid cell loss. In search for the underlying mechanism, we analyzed alterations in the gene expression profile in response to IR KD. A strong induction of certain cytokines (e.g. IL20 and tumour necrosis factor) became obvious and it turned out that these cytokines trigger apoptosis in the NSCLC cells tested. This indicates a novel role of IR in tumor cell survival via suppression of pro-apoptotic cytokines. PMID- 26113602 TI - Development of pheochromocytoma in ceramide synthase 2 null mice. AB - Pheochromocytoma (PCC) and paraganglioma are rare neuroendocrine tumors of the adrenal medulla and sympathetic and parasympathetic paraganglia, for which mutations in ~15 disease-associated genes have been identified. We now document the role of an additional gene in mice, the ceramide synthase 2 (CerS2) gene. CerS2, one of six mammalian CerS, synthesizes ceramides with very-long (C22-C24) chains. The CerS2 null mouse has been well characterized and displays lesions in several organs including the liver, lung and the brain. We now demonstrate that changes in the sphingolipid acyl chain profile of the adrenal gland lead to the generation of adrenal medullary tumors. Histological analyses revealed that about half of the CerS2 null mice developed PCC by ~13 months, and the rest showed signs of medullary hyperplasia. Norepinephrine and normetanephrine levels in the urine were elevated at 7 months of age consistent with the morphological abnormalities found at later ages. Accumulation of ceroid in the X-zone was observed as early as 2 months of age and as a consequence, older mice displayed elevated levels of lysosomal cathepsins, reduced proteasome activity and reduced activity of mitochondrial complex IV by 6 months of age. Together, these findings implicate an additional pathway that can lead to PCC formation, which involves alterations in the sphingolipid acyl chain length. Analysis of the role of sphingolipids in PCC may lead to further understanding of the mechanism by which PCC develops, and might implicate the sphingolipid pathway as a possible novel therapeutic target for this rare tumor. PMID- 26113603 TI - Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7 FH interval. AB - Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re sequenced 2.3 Mb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0*10(-5)) in the RGS7-FH interval in African Americans. In race combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7*10(-4)). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation. PMID- 26113604 TI - A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors. AB - Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERalpha. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment. PMID- 26113605 TI - 15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma. AB - The discovery of SDHD as a pheochromocytoma/paraganglioma susceptibility gene was the prismatic event that led to all of the subsequent work highlighting the key roles played by mitochondria in the pathogenesis of these tumors and other solid cancers. Alterations in the function of tricarboxylic acid cycle enzymes can cause accumulation of intermediate substrates and subsequent changes in cell metabolism, activation of the angiogenic pathway, increased reactive oxygen species production, DNA hypermethylation, and modification of the tumor microenvironment favoring tumor growth and aggressiveness. The elucidation of these tumorigenic mechanisms should lead to novel therapeutic targets for the treatment of the most aggressive forms of pheochromocytoma/paraganglioma. PMID- 26113606 TI - 15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma paraganglioma syndromes characterized by germline SDHB and SDHD mutations. AB - Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of alpha-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs. PMID- 26113607 TI - The state-of-play and future of platinum drugs. AB - The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects. PMID- 26113608 TI - Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. AB - Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18 28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3. PMID- 26113610 TI - Identification of occult tumors by whole-specimen mapping in solitary papillary thyroid carcinoma. AB - We undertook this study to estimate an accurate incidence and spread patterns of occult papillary thyroid carcinoma (PTC) in patients with a preoperative diagnosis of solitary PTC by using whole-specimen mapping of all specimens after a total thyroidectomy. Enrolled prospectively in this whole-thyroid mapping study are 82 consecutive patients who underwent a total thyroidectomy under a preoperative diagnosis of solitary PTC. All thyroidectomy specimens were serially sectioned in 2 mm thickness and whole-thyroid mapping was carried out for additional foci of occult PTC. The frequencies of occult lesions detected in the whole and contralateral lobe were determined, and clinicopathologic factors associated with multifocality were assessed. Whole-thyroid mapping revealed 66 occult PTC lesions missed by preoperative ultrasound in 37 (45.1%) of the 82 patients. The great majority (92.5%) of the occult PTC was smaller than 3 mm in size and 25 patients (30.5%) had contralateral lesions. We found that the male sex was an independent predictor of multifocality (odds ratio (OR), 3.00; 95% CI, 1.11-8.14), adjusting for preoperative findings. Analysis with pathologic parameters showed that the male sex (OR, 5.03; 95% CI, 1.68-15.08) and extrathyroidal extensions (OR, 3.03; 95% CI, 1.03-8.95) were associated with multifocal PTC. However, none of the clinicopathologic factors evaluated predicted contralateral PTC. Our study demonstrates the diagnostic limitations of ultrasound for the detection of multifocal PTC and the need to consider the possibility of occult lesions in the management of solitary PTC, especially in male patients. PMID- 26113609 TI - mPGES-1 in prostate cancer controls stemness and amplifies epidermal growth factor receptor-driven oncogenicity. AB - There is evidence that an inflammatory microenvironment is associated with the development and progression of prostate cancer (PCa), although the determinants of intrinsic inflammation in PCa cells are not completely understood. Here we investigated whether expression of intrinsic microsomal PGE synthase-1 (mPGES-1) enhanced aggressiveness of PCa cells and might be critical for epidermal growth factor receptor (EGFR)-mediated tumour progression. In PCa, overexpression of EGFR promotes metastatic invasion and correlates with a high Gleason score, while prostaglandin E2 (PGE2) has been reported to modulate oncogenic EGFR-driven oncogenicity. Immunohistochemical studies revealed that mPGES-1 in human prostate tissues is correlated with EGFR expression in advanced tumours. In DU145 and PC-3 cell lines expressing mPGES-1 (mPGES-1(SC) cells), we demonstrate that silencing or 'knock down' of mPGES-1 (mPGES-1(KD)) or pharmacological inhibition by MF63 strongly attenuates overall oncogenic drive. Indeed, mPGES-1(SC) cells express stem-cell-like features (high CD44, beta1-integrin, Nanog and Oct4 and low CD24 and alpha6-integrin) as well as mesenchymal transition markers (high vimentin, high fibronectin, low E-cadherin). They also show increased capacity to survive irrespective of anchorage condition, and overexpress EGFR compared to mPGES-1(KD) cells. mPGES-1 expression correlates with increased in vivo tumour growth and metastasis. Although EGFR inhibition reduces mPGES-1(SC) and mPGES-1(KD) cell xenograft tumour growth, we show that mPGES-1/PGE2 signalling sensitizes tumour cells to EGFR inhibitors. We propose mPGES-1 as a possible new marker of tumour aggressiveness in PCa. PMID- 26113612 TI - Histologic, Clinical, and Radiologic Findings of Alveolar Bone Expansion and Osteomyelitis of the Jaws in Cats. AB - The objective of this study was to characterize clinical, radiologic, and histologic patterns of alveolar bone expansion and osteomyelitis in cats. Based on case materials submitted as surgical biopsy specimens, alveolar bone pathology was diagnosed in 28 cats. These cats had a total of 37 oral lesions with clinical and radiologic changes that involved bone and/or teeth, including periodontitis, bone expansion, tooth resorption, and/or chronic osteomyelitis; 32 lesions were evaluated by histopathology. Canine teeth were affected in 19 cats (27 affected teeth), with bilateral lesions in 5 (26.3%) cats. The caudal premolar and/or molar regions were affected in 10 cats (10 affected sites). All biopsy sites evaluated by a review of clinical images and/or radiographs had evidence of periodontitis. Clinical photographs showed expansion of alveolar bone in 13 of 16 (81%) biopsy sites evaluated. Radiologically, rarifying osseous proliferation of alveolar bone was seen at 26 of 27 (96%) biopsy sites, and tooth resorption occurred at 15 of 18 (83%) sites. Histologically, the tissue samples from canine sites had compressed trabeculae of mature remodeled bone, loose fibrous stroma with paucicellular inflammation, and mild proliferation of woven bone. Tissue samples from the premolar/molar biopsy sites were often highly cellular with mixed lymphoplasmacytic and chronic suppurative inflammation, ulceration with granulation tissue, and robust proliferation of woven bone. Alveolar bone expansion and osteomyelitis in cats occurs in conjunction with periodontal inflammation and frequently with tooth resorption. PMID- 26113611 TI - Endocrine Pancreas in Cats With Diabetes Mellitus. AB - Pancreatic amyloidosis and loss of alpha and beta cells have been shown to occur in cats with diabetes mellitus, although the number of studies currently available is very limited. Furthermore, it is not known whether pancreatic islet inflammation is a common feature. The aims of the present study were to characterize islet lesions and to investigate whether diabetic cats have inflammation of the pancreatic islets. Samples of pancreas were collected postmortem from 37 diabetic and 20 control cats matched for age, sex, breed, and body weight. Histologic sections were stained with hematoxylin and eosin and Congo red; double labeled for insulin/CD3, insulin/CD20, insulin/myeloperoxidase, insulin/proliferating cell nuclear antigen, and glucagon/Ki67; and single labeled for amylin and Iba1. Mean insulin-positive cross-sectional area was approximately 65% lower in diabetic than control cats (P = .009), while that of amylin and glucagon was similar. Surprisingly, amyloid deposition was similar between groups (P = .408). Proliferation of insulin- and glucagon-positive cells and the number of neutrophils, macrophages, and T (CD3) and B (CD20) lymphocytes in the islets did not differ. The presence of T and B lymphocytes combined tended to be more frequent in diabetic cats (n = 8 of 37; 21.6%) than control cats (n = 1 of 20; 5.0%). The results confirm previous observations that loss of beta cells but not alpha cells occurs in diabetic cats. Islet amyloidosis was present in diabetic cats but was not greater than in controls. A subset of diabetic cats had lymphocytic infiltration of the islets, which might be associated with beta-cell loss. PMID- 26113613 TI - Characterization of Porcine Epidemic Diarrhea Virus Isolate US/Iowa/18984/2013 Infection in 1-Day-Old Cesarean-Derived Colostrum-Deprived Piglets. AB - Porcine epidemic diarrhea virus (PEDV) was first recognized in North America in April 2013 and has since caused devastating disease. The objective of this study was to characterize disease and viral detection associated with an original North American PEDV isolate inoculated in neonatal piglets. Thirty-six 1-day-old cesarean-derived and colostrum-deprived piglets were randomly assigned to the control (n = 16) or challenged group (n = 20); the latter were orogastrically inoculated with 1 ml of US/Iowa/18984/2013 PEDV isolate titered at 1 * 10(3) plaque-forming units per milliliter. Rectal swabs were collected from all piglets prior to inoculation and every 12 hours postinoculation (hpi) thereafter, with 4 control and 5 challenged piglets euthanized at 12, 24, 48, and 72 hpi. One piglet had a positive real-time quantitative polymerase chain reaction test on rectal swab at 12 hpi, and all remaining piglets were positive thereafter, with highest viral quantities detected at 24 and 36 hpi. Diarrhea was evident in 30% and 100% of challenged piglets at 18 and 24 hpi, respectively. Viral antigen was detected in enterocytes by immunohistochemistry in the duodenum and ileum of piglets euthanized at 12 hpi and was apparent throughout the small intestine of all piglets thereafter, with villus height:crypt depth ratios consistently below 4:1. Viremia was confirmed in 18 of 20 pigs at euthanasia. Clinical disease was severe and developed rapidly following infection with an original North American PEDV isolate, with lesions, viremia, and antigen detection possible by 12 hpi. PMID- 26113615 TI - Silent broken heart (Can shortness of breath be the only presentation of myocardial infarction?). AB - A 55-year-old previously healthy man was referred to our cardiology outpatient department (by the respiratory team) due to shortness of breath that started 2-3 months prior. He suddenly became breathless after changing a car wheel with no other associated symptoms. Specifically, he denied ever having had chest pain. His breathlessness got gradually worse preventing him from performing simple everyday activities, such as climbing stairs, and a couple of weeks before presentation, the patient noticed ankle oedema. He was an ex-smoker and drank 3-4 units of alcohol daily. There was a family history of hypertension. He worked as a contract manager in the construction industry. After clinical examination, a transthoracic echocardiogram was performed and the patient was admitted for further investigations. Clinical examination and investigation confirmed missed myocardial infarction with a complication of ventricular aneurysm. The patient was referred to cardiothoracic surgeons for surgical correction of the defect. PMID- 26113614 TI - Externalizing proneness and brain response during pre-cuing and viewing of emotional pictures. AB - Externalizing proneness, or trait disinhibition, is a concept relevant to multiple high-impact disorders involving impulsive-aggressive behavior. Its mechanisms remain disputed: major models posit hyperresponsive reward circuitry or heightened threat-system reactivity as sources of disinhibitory tendencies. This study evaluated alternative possibilities by examining relations between trait disinhibition and brain reactivity during preparation for and processing of visual affective stimuli. Forty females participated in a functional neuroimaging procedure with stimuli presented in blocks containing either pleasurable or aversive pictures interspersed with neutral, with each picture preceded by a preparation signal. Preparing to view elicited activation in regions including nucleus accumbens, whereas visual regions and bilateral amygdala were activated during viewing of emotional pictures. High disinhibition predicted reduced nucleus accumbens activation during preparation within pleasant/neutral picture blocks, along with enhanced amygdala reactivity during viewing of pleasant and aversive pictures. Follow-up analyses revealed that the augmented amygdala response was related to reduced preparatory activation. Findings indicate that participants high in disinhibition are less able to process implicit cues and mentally prepare for upcoming stimuli, leading to limbic hyperreactivity during processing of actual stimuli. This outcome is helpful for integrating findings from studies suggesting reward-system hyperreactivity and others suggesting threat-system hyperreactivity as mechanisms for externalizing proneness. PMID- 26113616 TI - Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion. AB - Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 MUg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and alpha- and gamma-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal gammaENaC[112-122] peptide concentrations nearly 20 fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and alphaENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal gammaENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies. PMID- 26113617 TI - Doctors and scientists urge Wellcome Trust to divest from fossil fuels. PMID- 26113621 TI - Don't ignore home grown medical systems. PMID- 26113618 TI - Genetic structure of the date palm (Phoenix dactylifera) in the Old World reveals a strong differentiation between eastern and western populations. AB - BACKGROUND AND AIMS: Date palms (Phoenix dactylifera, Arecaceae) are of great economic and ecological value to the oasis agriculture of arid and semi-arid areas. However, despite the availability of a large date palm germplasm spreading from the Atlantic shores to Southern Asia, improvement of the species is being hampered by a lack of information on global genetic diversity and population structure. In order to contribute to the varietal improvement of date palms and to provide new insights on the influence of geographic origins and human activity on the genetic structure of the date palm, this study analysed the diversity of the species. METHODS: Genetic diversity levels and population genetic structure were investigated through the genotyping of a collection of 295 date palm accessions ranging from Mauritania to Pakistan using a set of 18 simple sequence repeat (SSR) markers and a plastid minisatellite. KEY RESULTS: Using a Bayesian clustering approach, the date palm genotypes can be structured into two different gene pools: the first, termed the Eastern pool, consists of accessions from Asia and Djibouti, whilst the second, termed the Western pool, consists of accessions from Africa. These results confirm the existence of two ancient gene pools that have contributed to the current date palm diversity. The presence of admixed genotypes is also noted, which points at gene flows between eastern and western origins, mostly from east to west, following a human-mediated diffusion of the species. CONCLUSIONS: This study assesses the distribution and level of genetic diversity of accessible date palm resources, provides new insights on the geographic origins and genetic history of the cultivated component of this species, and confirms the existence of at least two domestication origins. Furthermore, the strong genetic structure clearly established here is a prerequisite for any breeding programme exploiting the effective polymorphism related to each gene pool. PMID- 26113622 TI - Vapor Store Owner Beliefs and Messages to Customers. AB - INTRODUCTION: Electronic cigarette (e-cigarette) use is becoming increasingly popular but little is known about the role of the local vapor store in promoting use and influencing customer attitudes and beliefs about vaping. METHODS: Thirty three vapor store owners were interviewed about their personal beliefs and attitudes about e-cigarettes and what they told customers about the health impact of using e-cigarettes. Interviews were recorded then transcribed, coded, and analyzed for themes. RESULTS: Vapor store owners used the internet to obtain information about vaping, most often from YouTube and industry sources. Owners often did not have the training to critically evaluate research studies posted on the internet. Owners promoted vaping as a healthier alternative to smoking and often compared it to a medical treatment. Owners considered ingredients in the e liquid as safe to use if it was safe to eat and discussed other foods vapor ingredients were found in. Owners also discussed the safety of secondhand vapor. Owners described the health impact of nicotine in e-liquid by comparing nicotine to caffeine and promoted the nicotine in e-liquid as coming from vegetables rather than tobacco. Finally, owners talked about vaping as a habit rather than a continued addiction to nicotine. CONCLUSIONS: Local store owners are an important source of health information for current and potential e-cigarette users but their messages to customers may be based on incomplete or misinterpreted information. Understanding local store owner messages to customers in addition to internet-based messages is an important area for future public health research. PMID- 26113620 TI - Hippocampal Shape Abnormalities Predict Symptom Progression in Neuroleptic-Free Youth at Ultrahigh Risk for Psychosis. AB - INTRODUCTION: Hippocampal abnormalities have been widely studied in schizophrenia spectrum populations including those at ultrahigh risk (UHR) for psychosis. There have been inconsistent findings concerning hippocampal morphology prior to and during the transition to psychosis, and little is known about how specific subregions are related to the symptom progression. METHODS: A total of 80 participants (38 UHR and 42 healthy controls) underwent a 3T MRI scan, as well as structured clinical interviews. Shape analysis of hippocampi was conducted with FSL/FIRST vertex analysis to yield a localized measure of shape differences between groups. A subgroup of the sample (24 UHR and 24 controls) also returned for a 12-month clinical follow-up assessment. RESULTS: The UHR group exhibited smaller hippocampal volumes bilaterally, and shape analysis revealed significant inversion in the left ventral posterior hippocampus in the UHR group. Greater inversion in this subregion was related to elevated symptomatology at baseline and increased positive symptoms, negative symptoms, and impaired tolerance to normal stress 12 months later. These results did not hold when left hippocampal volume was used as a predictor instead. DISCUSSION: This represents the first study to use vertex analysis in a UHR sample and results suggest that abnormalities in hippocampal shape appear to reflect underlying pathogenic processes driving the progression of illness. These findings suggest that examining shape and volume may provide an important new perspective for our conception of brain alterations in the UHR period. PMID- 26113624 TI - Hazy filling defect on coronary angiography: insights from optical coherence tomography. PMID- 26113625 TI - A 56 year old woman with syncope, weakness, and refractory hypotension. PMID- 26113626 TI - Will NICE guidance for employers improve workers' mental health? AB - BACKGROUND: The UK National Institute for Health and Clinical Excellence (NICE) has published guidance for employers on promoting mental wellbeing. A national audit in 2011 found wide variation between English National Health Service (NHS) trusts (organizations providing health care) in the implementation of this guidance, but it is not known whether fuller compliance with the guidance results in improved mental wellbeing of staff. AIMS: To explore whether there is an association between implementation of NICE guidance on mental wellbeing by NHS trusts in England and mental health outcomes as reported by staff. METHODS: A cross-sectional analysis relating mental health outcomes by trust from the NHS staff surveys in 2009 and 2010 to findings from the 2011 audit of compliance with NICE guidelines. RESULTS: NHS staff survey scores for mental health were significantly poorer in mental health and ambulance trusts than in acute trusts and mental health problems were significantly more frequent in London than in most other areas of England. Mental health scores tended to be better in trusts where the audit showed that staff health and wellbeing was a regular board agenda item, although not significantly so. There was no indication of better scores in trusts with policies on mental wellbeing or those that provided psychological therapies for staff. CONCLUSIONS: No clear relationship was found between implementation of the NICE guidance and self-reported mental health outcomes. There are several possible explanations for this finding which require further exploration. PMID- 26113627 TI - Use of Feedback-Oriented Online Exercises to Help Physiology Students Construct Well-Organized Answers to Short-Answer Questions. AB - Postsecondary education often requires students to use higher-order cognitive skills (HOCS) such as analysis, evaluation, and creation as they assess situations and apply what they have learned during lecture to the formulation of solutions. Summative assessment of these abilities is often accomplished using short-answer questions (SAQs). Quandary was used to create feedback-oriented interactive online exercises to help students strengthen certain HOCS as they actively constructed answers to questions concerning the regulation of 1) metabolic rate, 2) blood sugar, 3) erythropoiesis, and 4) stroke volume. Each exercise began with a SAQ presenting an endocrine dysfunction or a physiological challenge; students were prompted to answer between six and eight multiple-choice questions while building their answer to the SAQ. Student outcomes on the SAQ sections of summative exams were compared before and after the introduction of the online tool and also between subgroups of students within the posttool introduction population who demonstrated different levels of participation in the online exercises. While overall SAQ outcomes were not different before and after the introduction of the online exercises, once the SAQ tool had become available, those students who chose to use it had improved SAQ outcomes compared with those who did not. PMID- 26113628 TI - Flipped-Class Pedagogy Enhances Student Metacognition and Collaborative-Learning Strategies in Higher Education But Effect Does Not Persist. AB - In flipped-class pedagogy, students prepare themselves at home before lectures, often by watching short video clips of the course contents. The aim of this study was to investigate the effects of flipped classes on motivation and learning strategies in higher education using a controlled, pre- and posttest approach. The same students were followed in a traditional course and in a course in which flipped classes were substituted for part of the traditional lectures. On the basis of the validated Motivated Strategies for Learning Questionnaire (MSLQ), we found that flipped-class pedagogy enhanced the MSLQ components critical thinking, task value, and peer learning. However, the effects of flipped classes were not long-lasting. We therefore propose repeated use of flipped classes in a curriculum to make effects on metacognition and collaborative-learning strategies sustainable. PMID- 26113629 TI - Corrigendum to: Effectiveness of alcohol media literacy programmes: a systematic literature review. PMID- 26113630 TI - India's abortion law puts women at risk. PMID- 26113631 TI - Repetition Suppression in the Left Inferior Frontal Gyrus Predicts Tone Learning Performance. AB - Do individuals differ in how efficiently they process non-native sounds? To what extent do these differences relate to individual variability in sound-learning aptitude? We addressed these questions by assessing the sound-learning abilities of Dutch native speakers as they were trained on non-native tone contrasts. We used fMRI repetition suppression to the non-native tones to measure participants' neuronal processing efficiency before and after training. Although all participants improved in tone identification with training, there was large individual variability in learning performance. A repetition suppression effect to tone was found in the bilateral inferior frontal gyri (IFGs) before training. No whole-brain effect was found after training; a region-of-interest analysis, however, showed that, after training, repetition suppression to tone in the left IFG correlated positively with learning. That is, individuals who were better in learning the non-native tones showed larger repetition suppression in this area. Crucially, this was true even before training. These findings add to existing evidence that the left IFG plays an important role in sound learning and indicate that individual differences in learning aptitude stem from differences in the neuronal efficiency with which non-native sounds are processed. PMID- 26113632 TI - The impact of elevated carbon dioxide on the phosphorus nutrition of plants: a review. AB - BACKGROUND: Increasing attention is being focused on the influence of rapid increases in atmospheric CO2 concentration on nutrient cycling in ecosystems. An understanding of how elevated CO2 affects plant utilization and acquisition of phosphorus (P) will be critical for P management to maintain ecosystem sustainability in P-deficient regions. SCOPE: This review focuses on the impact of elevated CO2 on plant P demand, utilization in plants and P acquisition from soil. Several knowledge gaps on elevated CO2-P associations are highlighted. CONCLUSIONS: Significant increases in P demand by plants are likely to happen under elevated CO2 due to the stimulation of photosynthesis, and subsequent growth responses. Elevated CO2 alters P acquisition through changes in root morphology and increases in rooting depth. Moreover, the quantity and composition of root exudates are likely to change under elevated CO2, due to the changes in carbon fluxes along the glycolytic pathway and the tricarboxylic acid cycle. As a consequence, these root exudates may lead to P mobilization by the chelation of P from sparingly soluble P complexes, by the alteration of the biochemical environment and by changes to microbial activity in the rhizosphere. Future research on chemical, molecular, microbiological and physiological aspects is needed to improve understanding of how elevated CO2 might affect the use and acquisition of P by plants. PMID- 26113633 TI - Sugar composition of the pectic polysaccharides of charophytes, the closest algal relatives of land-plants: presence of 3-O-methyl-D-galactose residues. AB - BACKGROUND AND AIMS: During evolution, plants have acquired and/or lost diverse sugar residues as cell-wall constituents. Of particular interest are primordial cell-wall features that existed, and in some cases abruptly changed, during the momentous step whereby land-plants arose from charophytic algal ancestors. METHODS: Polysaccharides were extracted from four charophyte orders [Chlorokybales (Chlorokybus atmophyticus), Klebsormidiales (Klebsormidium fluitans, K. subtile), Charales (Chara vulgaris, Nitella flexilis), Coleochaetales (Coleochaete scutata)] and an early-diverging land-plant (Anthoceros agrestis). 'Pectins' and 'hemicelluloses', operationally defined as extractable in oxalate (100 degrees C) and 6 m NaOH (37 degrees C), respectively, were acid- or Driselase-hydrolysed, and the monosaccharides analysed chromatographically. One unusual monosaccharide, 'U', was characterized by (1)H/(13)C-nuclear magnetic resonance spectroscopy and also enzymically. KEY RESULTS: 'U' was identified as 3-O-methyl-D-galactose (3-MeGal). All pectins, except in Klebsormidium, contained acid- and Driselase-releasable galacturonate, suggesting homogalacturonan. All pectins, without exception, released rhamnose and galactose on acid hydrolysis; however, only in 'higher' charophytes (Charales, Coleochaetales) and Anthoceros were these sugars also efficiently released by Driselase, suggesting rhamnogalacturonan-I. Pectins of 'higher' charophytes, especially Chara, contained little arabinose, instead possessing 3 MeGal. Anthoceros hemicelluloses were rich in glucose, xylose, galactose and arabinose (suggesting xyloglucan and arabinoxylan), none of which was consistently present in charophyte hemicelluloses. CONCLUSIONS: Homogalacturonan is an ancient streptophyte feature, albeit secondarily lost in Klebsormidium. When conquering the land, the first embryophytes already possessed rhamnogalacturonan-I. In contrast, charophyte and land-plant hemicelluloses differ substantially, indicating major changes during terrestrialization. The presence of 3-MeGal in charophytes and lycophytes but not in the 'intervening' bryophytes confirms that cell-wall chemistry changed drastically between major phylogenetic grades. PMID- 26113634 TI - The importance of associations with saprotrophic non-Rhizoctonia fungi among fully mycoheterotrophic orchids is currently under-estimated: novel evidence from sub-tropical Asia. AB - BACKGROUND AND AIMS: Most fully mycoheterotrophic (MH) orchids investigated to date are mycorrhizal with fungi that simultaneously form ectomycorrhizas with forest trees. Only a few MH orchids are currently known to be mycorrhizal with saprotrophic, mostly wood-decomposing, fungi instead of ectomycorrhizal fungi. This study provides evidence that the importance of associations between MH orchids and saprotrophic non-Rhizoctonia fungi is currently under-estimated. METHODS: Using microscopic techniques and molecular approaches, mycorrhizal fungi were localized and identified for seven MH orchid species from four genera and two subfamilies, Vanilloideae and Epidendroideae, growing in four humid and warm sub-tropical forests in Taiwan. Carbon and nitrogen stable isotope natural abundances of MH orchids and autotrophic reference plants were used in order to elucidate the nutritional resources utilized by the orchids. KEY RESULTS: Six out of the seven MH orchid species were mycorrhizal with either wood- or litter decaying saprotrophic fungi. Only one orchid species was associated with ectomycorrhizal fungi. Stable isotope abundance patterns showed significant distinctions between orchids mycorrhizal with the three groups of fungal hosts. CONCLUSIONS: Mycoheterotrophic orchids utilizing saprotrophic non-Rhizoctonia fungi as a carbon and nutrient source are clearly more frequent than hitherto assumed. On the basis of this kind of nutrition, orchids can thrive in deeply shaded, light-limiting forest understoreys even without support from ectomycorrhizal fungi. Sub-tropical East Asia appears to be a hotspot for orchids mycorrhizal with saprotrophic non-Rhizoctonia fungi. PMID- 26113635 TI - When sexual meets apomict: genome size, ploidy level and reproductive mode variation of Sorbus aria s.l. and S. austriaca (Rosaceae) in Bosnia and Herzegovina. AB - BACKGROUND AND AIMS: Allopolyploidy and intraspecific heteroploid crosses are associated, in certain groups, with changes in the mating system. The genus Sorbus represents an appropriate model to study the relationships between ploidy and reproductive mode variations. Diploid S. aria and tetraploid apomictic S. austriaca were screened for ploidy and mating system variations within pure and sympatric populations in order to gain insights into their putative causalities. METHODS: Flow cytometry was used to assess genome size and ploidy level among 380 S. aria s.l. and S. austriaca individuals from Bosnia and Herzegovina, with 303 single-seed flow cytometric seed screenings being performed to identify their mating system. Pollen viability and seed set were also determined. KEY RESULTS: Flow cytometry confirmed the presence of di-, tri- and tetraploid cytotype mixtures in mixed-ploidy populations of S. aria and S. austriaca. No ploidy variation was detected in single-species populations. Diploid S. aria mother plants always produced sexually originated seeds, whereas tetraploid S. austriaca as well as triploid S. aria were obligate apomicts. Tetraploid S. aria preserved sexuality in a low portion of plants. A tendency towards a balanced 2m : 1p parental genome contribution to the endosperm was shared by diploids and tetraploids, regardless of their sexual or asexual origin. In contrast, most triploids apparently tolerated endosperm imbalance. CONCLUSIONS: Coexistence of apomictic tetraploids and sexual diploids drives the production of novel polyploid cytotypes with predominantly apomictic reproductive modes. The data suggest that processes governing cytotype diversity and mating system variation in Sorbus from Bosnia and Herzegovina are probably parallel to those in other diversity hotspots of this genus. The results represent a solid contribution to knowledge of the reproduction of Sorbus and will inform future investigations of the molecular and genetic mechanisms involved in triggering and regulating cytotype diversity and alteration of reproductive modes. PMID- 26113636 TI - Simultaneous determination of two amino bisphosphonates drugs by micellar electrokinetic chromatography. AB - A sensitive micellar electrokinetic chromatographic method with laser-induced fluorescence detection was developed for the determination of alendronate sodium (ALN) and pamidronate disodium (PAM) after derivatization with 4-chloro-7 nitrobenzo-2-oxa-1,3-diazole. The developed method was first used for the determination of ALN and PAM in pharmaceutical preparations. After optimization, baseline separation of the analytes could be obtained in <10 min in a running buffer composed of 10 mM sodium borate and 30 mM sodium dodecyl sulfate (pH 9.0) at a voltage of 15 kV with 25 degrees C cartridge temperature and the samples were injected by pressure (3447.5 Pa * 3 s). The method has linearity range of 0.05-70 ug/mL for the analytes (correlation coefficients: 0.9995 and 0.9997), the detection limits were 4 and 10 ng/mL for ALN and PAM, respectively. In intraday precision experiment, the relative standard deviation (RSD) values for migration time were 0.30% (ALN) and 0.27% (PAM), and the RSD values for peak areas were 1.19% (ALN) and 1.32% (PAM). The ranges of recovery were 95.5-101.8 and 94.6 105.3% for ALN and PAM, respectively. This method is not only rapid and accurate but also has the potential to be used for the quality control in pharmaceutical preparations of the two drugs. PMID- 26113637 TI - Circadian rhythms. Atomic-scale origins of slowness in the cyanobacterial circadian clock. AB - Circadian clocks generate slow and ordered cellular dynamics but consist of fast moving bio-macromolecules; consequently, the origins of the overall slowness remain unclear. We identified the adenosine triphosphate (ATP) catalytic region [adenosine triphosphatase (ATPase)] in the amino-terminal half of the clock protein KaiC as the minimal pacemaker that controls the in vivo frequency of the cyanobacterial clock. Crystal structures of the ATPase revealed that the slowness of this ATPase arises from sequestration of a lytic water molecule in an unfavorable position and coupling of ATP hydrolysis to a peptide isomerization with high activation energy. The slow ATPase is coupled with another ATPase catalyzing autodephosphorylation in the carboxyl-terminal half of KaiC, yielding the circadian response frequency of intermolecular interactions with other clock related proteins that influences the transcription and translation cycle. PMID- 26113638 TI - NEUROSCIENCE. Natural light-gated anion channels: A family of microbial rhodopsins for advanced optogenetics. AB - Light-gated rhodopsin cation channels from chlorophyte algae have transformed neuroscience research through their use as membrane-depolarizing optogenetic tools for targeted photoactivation of neuron firing. Photosuppression of neuronal action potentials has been limited by the lack of equally efficient tools for membrane hyperpolarization. We describe anion channel rhodopsins (ACRs), a family of light-gated anion channels from cryptophyte algae that provide highly sensitive and efficient membrane hyperpolarization and neuronal silencing through light-gated chloride conduction. ACRs strictly conducted anions, completely excluding protons and larger cations, and hyperpolarized the membrane of cultured animal cells with much faster kinetics at less than one-thousandth of the light intensity required by the most efficient currently available optogenetic proteins. Natural ACRs provide optogenetic inhibition tools with unprecedented light sensitivity and temporal precision. PMID- 26113639 TI - Plant science. Morphinan biosynthesis in opium poppy requires a P450 oxidoreductase fusion protein. AB - Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R) reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S) reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial based morphinan production. PMID- 26113640 TI - Ice sheets. Reverse glacier motion during iceberg calving and the cause of glacial earthquakes. AB - Nearly half of Greenland's mass loss occurs through iceberg calving, but the physical mechanisms operating during calving are poorly known and in situ observations are sparse. We show that calving at Greenland's Helheim Glacier causes a minutes-long reversal of the glacier's horizontal flow and a downward deflection of its terminus. The reverse motion results from the horizontal force caused by iceberg capsize and acceleration away from the glacier front. The downward motion results from a hydrodynamic pressure drop behind the capsizing berg, which also causes an upward force on the solid Earth. These forces are the source of glacial earthquakes, globally detectable seismic events whose proper interpretation will allow remote sensing of calving processes occurring at increasing numbers of outlet glaciers in Greenland and Antarctica. PMID- 26113641 TI - Circadian rhythms. A protein fold switch joins the circadian oscillator to clock output in cyanobacteria. AB - Organisms are adapted to the relentless cycles of day and night, because they evolved timekeeping systems called circadian clocks, which regulate biological activities with ~24-hour rhythms. The clock of cyanobacteria is driven by a three protein oscillator composed of KaiA, KaiB, and KaiC, which together generate a circadian rhythm of KaiC phosphorylation. We show that KaiB flips between two distinct three-dimensional folds, and its rare transition to an active state provides a time delay that is required to match the timing of the oscillator to that of Earth's rotation. Once KaiB switches folds, it binds phosphorylated KaiC and captures KaiA, which initiates a phase transition of the circadian cycle, and it regulates components of the clock-output pathway, which provides the link that joins the timekeeping and signaling functions of the oscillator. PMID- 26113643 TI - Curriculum development: Preparing trainees to care for children and adolescents with psychiatric disorders. AB - Family physicians provide care for about one-third of the children and adolescents in the United States, many of whom present with psychological concerns. Family physicians often do not recognize these psychological disorders and therefore do not diagnose or treat them. This report describes the implementation of a curriculum designed to increase family medicine trainees' level of awareness that children/adolescents experience psychiatric conditions. This goal is achieved through the addition of a clinical child/adolescent psychologist faculty member, resident self-assessment of training needs and subsequent development of didactic presentations to address these needs. The curriculum relies on the acquisition of child/adolescent psychiatric screeners, development of child/adolescent-focused bibliotherapy materials, and the development of a longitudinal behavioral sciences curriculum. To facilitate the screening of child/adolescent psychiatric disorders, a comprehensive collection of age-appropriate psychiatric screeners were compiled and made readily available in all precepting areas. To assist with the identification of specific child/adolescent psychiatric deficit areas, family medicine resident physicians were presented with an inventory of child/adolescent psychiatric, psychosocial, and behavioral topics, based upon American Academy of Family Practice guidelines and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition psychiatric disorders, and self-selected training deficiencies. PMID- 26113642 TI - HIV-1 ENVELOPE. Effect of the cytoplasmic domain on antigenic characteristics of HIV-1 envelope glycoprotein. AB - A major goal for HIV-1 vaccine development is the production of an immunogen to mimic native, functional HIV-1 envelope trimeric spikes (Env) on the virion surface. We lack a reliable description of a native, functional trimer, however, because of inherent instability and heterogeneity in most preparations. We describe here two conformationally homogeneous Envs derived from difficult-to neutralize primary isolates. All their non-neutralizing epitopes are fully concealed and independent of their proteolytic processing. Most broadly neutralizing antibodies (bnAbs) recognize these native trimers. Truncation of their cytoplasmic tail has little effect on membrane fusion, but it diminishes binding to trimer-specific bnAbs while exposing non-neutralizing epitopes. These results yield a more accurate antigenic picture than hitherto possible of a genuinely untriggered and functional HIV-1 Env; they can guide effective vaccine development. PMID- 26113644 TI - Loss of epigenetic silencing of the DUX4 transcription factor gene in facioscapulohumeral muscular dystrophy. AB - Current genetic and molecular evidence best supports an epigenetic mechanism for facioscapulohumeral muscular dystrophy (FSHD), whereby de-repression of the D4Z4 macrosatellite array leads to aberrant expression of the DUX4 transcription factor in skeletal muscle. This de-repression is triggered by either array contraction or (more rarely) by mutation of the SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) gene. Activation of DUX4 targets, including germline genes and several mammalian retrotransposons, then drives pathogenesis. A direct role for DUX4 mRNA in suppression of nonsense-mediated decay pathways has recently been demonstrated and may also contribute to muscle pathology. Loss of D4Z4 repression in FSHD is observed as hypomethylation of the array accompanied by loss of repressive chromatin marks. The molecular mechanisms of D4Z4 repression are poorly understood, but recent data have identified an Argonaute (AGO)-dependent siRNA pathway. Targeting this pathway by exogenous siRNAs could be a therapeutic strategy for FSHD. PMID- 26113646 TI - Digital PCR quantification of MGMT methylation refines prediction of clinical benefit from alkylating agents in glioblastoma and metastatic colorectal cancer. AB - BACKGROUND: O(6)-methyl-guanine-methyl-transferase (MGMT) silencing by promoter methylation may identify cancer patients responding to the alkylating agents dacarbazine or temozolomide. PATIENTS AND METHODS: We evaluated the prognostic and predictive value of MGMT methylation testing both in tumor and cell-free circulating DNA (cfDNA) from plasma samples using an ultra-sensitive two-step digital PCR technique (methyl-BEAMing). Results were compared with two established techniques, methylation-specific PCR (MSP) and Bs-pyrosequencing. RESULTS: Thresholds for MGMT methylated status for each technique were established in a training set of 98 glioblastoma (GBM) patients. The prognostic and the predictive value of MGMT methylated status was validated in a second cohort of 66 GBM patients treated with temozolomide in which methyl-BEAMing displayed a better specificity than the other techniques. Cutoff values of MGMT methylation specific for metastatic colorectal cancer (mCRC) tissue samples were established in a cohort of 60 patients treated with dacarbazine. In mCRC, both quantitative assays methyl-BEAMing and Bs-pyrosequencing outperformed MSP, providing better prediction of treatment response and improvement in progression free survival (PFS) (P < 0.001). Ability of methyl-BEAMing to identify responding patients was validated in a cohort of 23 mCRC patients treated with temozolomide and preselected for MGMT methylated status according to MSP. In mCRC patients treated with dacarbazine, exploratory analysis of cfDNA by methyl-BEAMing showed that MGMT methylation was associated with better response and improved median PFS (P = 0.008). CONCLUSIONS: Methyl-BEAMing showed high reproducibility, specificity and sensitivity and was applicable to formalin-fixed paraffin-embedded tissues and cfDNA. This study supports the quantitative assessment of MGMT methylation for clinical purposes since it could refine prediction of response to alkylating agents. PMID- 26113647 TI - Does activity of anticancer drugs in advanced cancer always translates in effectivity in early-stage high-risk disease? PMID- 26113645 TI - Application of single-cell genomics in cancer: promise and challenges. AB - Recent advances in single-cell genomics are opening up unprecedented opportunities to transform cancer genomics. While bulk tissue genomic analysis across large populations of tumour cells has provided key insights into cancer biology, this approach does not provide the resolution that is critical for understanding the interaction between different genetic events within the cellular hierarchy of the tumour during disease initiation, evolution, relapse and metastasis. Single-cell genomic approaches are uniquely placed to definitively unravel complex clonal structures and tissue hierarchies, account for spatiotemporal cell interactions and discover rare cells that drive metastatic disease, drug resistance and disease progression. Here we present five challenges that need to be met for single-cell genomics to fulfil its potential as a routine tool alongside bulk sequencing. These might be thought of as being challenges related to samples (processing and scale for analysis), sensitivity and specificity of mutation detection, sources of heterogeneity (biological and technical), synergies (from data integration) and systems modelling. We discuss these in the context of recent advances in technologies and data modelling, concluding with implications for moving cancer research into the clinic. PMID- 26113649 TI - Flaws in the trial design of IFCT-0802. PMID- 26113648 TI - High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer. AB - BACKGROUND: Conventional nutritional supplements are not or only partly successful in inducing protein accretion in advanced cancer, suggesting an attenuated anabolic response. To prevent muscle wasting and its deleterious consequences, generating an anabolic response is crucial. Dietary essential amino acids (EAA) have anabolic properties in other wasting diseases; however, data in advanced cancer are lacking. PATIENTS AND METHODS: In 13 patients with advanced nonsmall-cell lung cancer (NSCLC) (stage III and IV) and 11 healthy age-matched subjects, we measured protein synthesis and breakdown of the whole body, and net protein anabolism (difference between protein synthesis and breakdown) after intake of 14 g of free EAA with high leucine levels (EAA/leucine) versus a balanced amino acid mixture containing both EAA and non-EAA as present in whey protein, according to a randomized, double-blind, crossover design. RESULTS: Protein synthesis and net protein anabolism were higher after intake of the EAA/leucine than the balanced amino acid mixture (P < 0.001), independent of presence of cancer. A highly significant linear relationship between net protein anabolism and the amount of EAA available in the systemic circulation (R(2): 0.85, P < 0.001) was found in both groups. The presence of muscle or recent weight loss, systemic inflammatory response, or length of survival did not influence this relationship. High leucine levels in the EAA/leucine mixture was of no anabolic benefit. CONCLUSIONS: There is no anabolic resistance or attenuated anabolic potential to intake of 14 g of EAA/leucine or balanced amino acid mixture in advanced (mainly stage III) NSCLC. The high anabolic potential of dietary EAA in cancer patients is independent of their nutritional status, systemic inflammatory response or disease trajectory, suggesting a key role of EAA in new nutritional approaches to prevent muscle loss, thereby improving outcome of patients with advanced cancer. CLINICALTRAILSGOV: NCT01172314. PMID- 26113650 TI - Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy induced bone loss. AB - OBJECTIVES: Autophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models. METHODS: Systemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor kappa B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR. RESULTS: Selective deletion of Atg7 in monocytes from Atg7(fl/fl)_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7(fl/fl) littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy. CONCLUSIONS: Pharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use. PMID- 26113651 TI - Editorial Commentary: A Chance to Change the Paradigm of Outcome Assessment of Antimicrobial Stewardship Programs. PMID- 26113652 TI - Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR). AB - Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use. PMID- 26113654 TI - Editorial Commentary: The Impact of Opiate Substitution Therapy and Highly Active Antiretroviral Therapy on Mortality Risk Among People Who Inject Drugs. PMID- 26113653 TI - Aspergillus Polymerase Chain Reaction: Systematic Review of Evidence for Clinical Use in Comparison With Antigen Testing. AB - BACKGROUND: Aspergillus polymerase chain reaction (PCR) was excluded from the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions of invasive fungal disease because of limited standardization and validation. The definitions are being revised. METHODS: A systematic literature review was performed to identify analytical and clinical information available on inclusion of galactomannan enzyme immunoassay (GM-EIA) (2002) and beta-d-glucan (2008), providing a minimal threshold when considering PCR. Categorical parameters and statistical performance were compared. RESULTS: When incorporated, GM-EIA and beta-d-glucan sensitivities and specificities for diagnosing invasive aspergillosis were 81.6% and 91.6%, and 76.9% and 89.4%, respectively. Aspergillus PCR has similar sensitivity and specificity (76.8% 88.0% and 75.0%-94.5%, respectively) and comparable utility. Methodological recommendations and commercial PCR assays assist standardization. Although all tests have limitations, currently, PCR is the only test with independent quality control. CONCLUSIONS: We propose that there is sufficient evidence that is at least equivalent to that used to include GM-EIA and beta-d-glucan testing, and that PCR is now mature enough for inclusion in the EORTC/MSG definitions. PMID- 26113655 TI - Widespread Bordetella parapertussis Infections-Wisconsin, 2011-2012: Clinical and Epidemiologic Features and Antibiotic Use for Treatment and Prevention. AB - BACKGROUND: During October 2011-December 2012, concurrent with a statewide pertussis outbreak, 443 Bordetella parapertussis infections were reported among Wisconsin residents. We examined clinical features of patients with parapertussis and the effect of antibiotic use for treatment and prevention. METHODS: Patients with polymerase chain reaction results positive for B. parapertussis reported during October 2011-May 2012 were interviewed regarding presence and durations of pertussis-like symptoms and receipt of azithromycin treatment. Data regarding acute cough illnesses and receipt of azithromycin prophylaxis among parapertussis patient household members (HHMs) were also collected. Using multivariate repeated measures log-binomial regression analysis, we examined associations of treatment receipt by the HHM with the earliest illness onset and prophylaxis receipt among other HHMs with the presence of any secondary cough illnesses in the household. RESULTS: Among 218 patients with parapertussis, pertussis-like symptoms were frequently reported. Illness durations were significantly shorter among patients with treatment initiated 0-6 days after cough onset, compared with nonrecipients (median durations: 10 vs 19 days, P = .002). Among 361 HHMs from 120 households, compared with nonrecipients, prompt prophylaxis of HHMs was associated with no secondary cough illnesses (relative risk: 0.16; 95% confidence interval, .04 .69). CONCLUSIONS: Bordetella parapertussis infection causes pertussis-like illness that might be misclassified as pertussis if B. parapertussis testing is not performed. Prompt treatment might shorten illness duration, and prompt HHM prophylaxis might prevent secondary illnesses. Further study is needed to evaluate antibiotic effectiveness for preventing parapertussis and to determine risks and benefits of antibiotic use. PMID- 26113656 TI - The Effects of Opioid Substitution Treatment and Highly Active Antiretroviral Therapy on the Cause-Specific Risk of Mortality Among HIV-Positive People Who Inject Drugs. AB - BACKGROUND: Prior studies indicated opioid substitution treatment (OST) reduces mortality risk and improves the odds of accessing highly active antiretroviral therapy (HAART); however, the relative effects of these treatments for human immunodeficiency virus (HIV)-positive people who inject drugs (PWID) are unclear. We determine the independent and joint effects of OST and HAART on mortality, by cause, within a population of HIV-positive PWID initiating HAART. METHODS: Using a linked population-level database for British Columbia, Canada, we used time-to event analytic methods, including competing risks models, proportional hazards models with time-varying covariates, and marginal structural models, to identify the independent and joint effects of OST and HAART on all-cause as well as drug- and HIV-related mortality, controlling for covariates. RESULTS: Among 1727 HIV positive PWID, 493 (28.5%) died during a median 5.1 years (interquartile range, 2.1-9.1) of follow-up: 18.7% due to drug-related causes, 55.8% due to HIV-related causes, and 25.6% due to other causes. Standardized mortality ratios were 12.2 (95% confidence interval [CI], 9.8, 15.0) during OST and 30.0 (27.1, 33.1) during periods out of OST. Both OST (adjusted hazard, 0.34; 95% CI, .23, .49) and HAART (0.39 [0.31, 0.48]) decreased the hazard of all-cause mortality; however, individuals were at lowest risk of death when these medications were used jointly (0.16 [0.10, 0.26]). Both OST and HAART independently protected against HIV related death, drug-related death and death due to other causes. CONCLUSIONS: While both OST and HAART are life-saving treatments, joint administration is urgently needed to protect against both drug- and HIV-related mortality. PMID- 26113658 TI - Epidemiologic research with administrative databases: red herrings, false alarms and pseudo-epidemics. PMID- 26113657 TI - Cancer risk among parous women following assisted reproductive technology. AB - STUDY QUESTION: Do women who give birth after assisted reproductive technology (ART) have an increased risk of cancer compared with women who give birth without ART? SUMMARY ANSWER: Without correction, the results indicate an increase in overall cancer risk, as well as a 50% increase in risk of CNS cancer for women giving birth after ART, however the results were not significant after correcting for multiple analyses. WHAT IS KNOWN ALREADY: Studies regarding the effects of hormonal treatments involved with ART on subsequent cancer risk have provided inconsistent results, and it has also been suggested that infertility itself could be a contributory factor. STUDY DESIGN, SIZE, DURATION: A population-based cohort consisting of all women registered in the Medical Birth Registry of Norway as having given birth between 1 January 1984 and 31 December 2010 was assembled (n = 812 986). Cancers were identified by linkage to the Cancer Registry of Norway. Study subjects were followed from start of first pregnancy during the observational period until the first cancer, death, emigration, or 31 December 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the total study population (n = 806 248), 16 525 gave birth to a child following ART. Cox regression analysis computed hazard ratios (HR) and 95% confidence intervals (CI) comparing cancer risk between ART women and non-ART women; for overall cancer, and for cervical, ovarian, uterine, central nervous system (CNS), colorectal and thyroid cancers, and for malignant melanoma. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 22 282 cohort members were diagnosed with cancer, of which 338 were ART women and 21 944 non-ART women. The results showed an elevated risk in one out of seven sites for ART women. The HR for cancer of the CNS was 1.50 (95% CI 1.03- 2.18), and among those specifically subjected to IVF (without ICSI) the HR was 1.83 (95% CI 1.22-2.73). Analysis of risk of overall cancer gave an HR of 1.16 (95% CI 1.04 1.29). Among those who had delivered only one child by the end of follow-up, the HR for ovarian cancer was 2.00 (95% CI 1.08-3.65), and for those nulliparous at entry the HR was 1.80 (95% CI 1.04-3.11). However, all findings became non significant after correcting for multiple analyses. LIMITATIONS, REASONS FOR CAUTION: The results of elevated risk of overall cancer and CNS cancer lost significance when adjusting for multiple analyses, implying an important limitation of the study. The follow-up time was relatively short, especially for ART women. In addition, as the cohort was relatively young, there were few incident cancers, especially for some rarer cancer forms, such as uterine cancer. Risk assessments according to different causes of infertility could not be done. WIDER IMPLICATIONS OF THE FINDINGS: In light of the findings in the present study, further studies should be made on risk of CNS and ovarian cancer, and continued monitoring of all those treated with ART is encouraged. Our findings may only be generalizable to women who give birth after ART, and the risk for women who remain nulliparous after ART remains to be assessed. STUDY FUNDING/COMPETING INTEREST: The study was funded by the Norwegian National Advisory Unit on Women's Health. All authors claim no competing interests. PMID- 26113659 TI - Assisted reproduction and cancer risk: how useful are national databases? PMID- 26113660 TI - The war on error. PMID- 26113661 TI - Vascular endothelial growth factor (VEGF) regulation by hypoxia inducible factor 1 alpha (HIF1A) starts and peaks during endometrial breakdown, not repair, in a mouse menstrual-like model. AB - STUDY QUESTION: How is vascular endothelial growth factor (VEGF) expression regulated by hypoxia inducible factor 1 alpha (HIF1A) during menstruation? SUMMARY ANSWER: After progesterone (P4) withdrawal, HIF1A was activated and it directly up-regulated VEGF mRNA expression and this regulation was the highest during endometrium breakdown in the mouse menstrual-like model. WHAT IS KNOWN ALREADY: VEGF, an important angiogenic factor, is known to be essential for endometrial repair, particularly in angiogenesis and re-epithelialization. However, its upstream regulation has not been fully clarified. HIF1 is the first transcription factor response to hypoxia and is closely associated with angiogenesis; it is also an upstream regulator of VEGF mRNA. STUDY DESIGN, SIZE, DURATION: We investigated the changes in the expression of HIF1A and VEGF after P4 withdrawal and after HIF1A inhibition. The total number of mice used was 62. The treatment duration in the mouse menstrual-like model was 8 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: The mouse menstrual-like model and mouse and human decidual endometrial stromal cells were established to mimic menstruation. Protein and mRNA expressions of HIF1A and VEGF were investigated by immunohistochemistry, Western blot and quantitative PCR. The direct interaction between HIF1A and the Vegf promoter was also investigated by chromatin immunoprecipitation. HIF1A inhibition in vivo and in vitro was achieved by administration of an HIF1A inhibitor and by siRNA knockdown, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: HIF1A was translocated to the nucleus from 8 to 16 h after P4 withdrawal, while VEGF mRNA expression was the highest at 12 h. HIF1A directly bound to Vegf promoter during endometrial breakdown, which peaked at 12 h. HIF1A inhibition suppressed VEGF mRNA and protein expression in the mouse menstrual-like model and decidualized stromal cells. Inhibition of HIF1A also suppressed endometrial breakdown. LIMITATIONS, REASONS FOR CAUTION: Although HIF1A regulation of VEGF mRNA was confirmed in the mouse menstrual-like model and decidual endometrium stromal cells, the functional regulation of VEGF protein was not further determined. WIDER IMPLICATIONS OF THE FINDINGS: Here, we report that the functional regulation of VEGF was complicate in menstruation. We also report that HIF1A plays a key role in endometrial breakdown. STUDY FUNDING/COMPETING INTERESTS: The National Nature Science Foundation of China (No. 30901608), the National Basic Research Program of China (2010CB530403) and the National Science and Technology Support Program (No. 2012BAI32B05). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: This study is not a clinical trial. PMID- 26113662 TI - Epithelioid Osteosarcoma of the Maxilla: A Case Report and Review of the Literature. AB - Epithelioid osteosarcoma is an uncommon variant; only 4 cases have been reported in the jaw area, 2 of which were in the maxilla. A 22-year-old woman, in the eighth month of pregnancy, presented to the oral surgery clinic with a mass in the right maxilla that had rapidly expanded over the past 3 months. Computed tomography scans showed an ill-defined sclerotic destructive lesion that formed bone matrix in its soft tissue extension. Microscopic examination of the lesion revealed malignant epithelioid cells with osteoid deposits. The tumor cells were shown to have pale cytoplasm, vesicular nuclei, and prominent nucleoli and to undergo frequent mitosis. In addition, the tumor was positive for epithelial membrane antigen and vimentin and negative for AE1/AE3, Melan-A, CD30, synaptophysin, NSE, CD45, CD99, desmin, and myogenin. The final diagnosis was epithelioid osteosarcoma, which is a rare aggressive variant of osteosarcoma. Few cases of epithelioid osteosarcoma have been reported in the literature, and more studies are required to determine the clinical behavior of this tumor. PMID- 26113663 TI - Malignant Melanoma With Osteoclast-Like Differentiation. AB - Osteoclast-like giant cells are frequently encountered in nonskeletal malignancies; however, the evidence to date suggests that they represent a tissue response to the lesion rather than neoplastic differentiation. We describe a case of metastatic melanoma demonstrating osteoclast-like differentiation in the lung. The lung nodule was diagnosed as a metastatic melanoma by histological features and confirmed by immunohistochemistry. Resection specimen showed numerous multinucleated giant cells exhibiting osteoclast-like morphology dispersed throughout the lesion. Both the neoplastic melanocytes and giant cells were reactive for HMB-45, Melan-A, and S100. In addition, the multinucleated neoplastic giant cells were also reactive for the monocyte/macrophage lineage markers CD68 and CD163, and alkaline phosphatase, an enzyme present in normal osteoclasts. The neoplastic melanocytes and the multinucleated neoplastic giant cells were also reactive for microphthalmia-associated transcription factor, a protein required for the development of both melanocytes and osteoclasts. Collectively, a co-expression of monocyte/macrophage markers along with melanocytic markers and alkaline phosphatase in the multinucleated neoplastic giant cells in metastatic melanoma suggest that malignant melanocytes are capable of differentiating into osteoclast-like cells and consequently aid invasion into various structures and eliciting the aggressive behavior. PMID- 26113664 TI - Phyllodes Tumor of the Breast With Malignant Melanoma Component: A Case Report. AB - Phyllodes tumors of the breast display a wide variation in histological appearance and are classified into benign, borderline, and malignant categories based on a combination of histological parameters. These tumors may include a malignant heterologous component that is believed to originate through a process of multidirectional differentiation from a cancer stem cell. In these cases, the tumor is classified as a malignant phyllodes tumor. Among the heterologous elements that have been described in malignant phyllodes tumors are rhabdomyosarcoma, chondrosarcoma, osteosarcoma, liposarcoma and angiosarcoma. We present the first case of a phyllodes tumor with a malignant melanoma component in the breast of a 71-year-old lady, discussing the clinical implications of this diagnosis. PMID- 26113665 TI - Novel Pathologic Finding of Digital Soft Tissue Chondroma in a Child: A Case Report and Review of Literature. AB - Unlike osteochondromata that develop in the hand, soft tissue chondromata (STC) devoid of bone and tendinous attachments are exceedingly rare. They have been described in adult patients of middle age, though have not been previously reported in the pediatric population. We report the case of a 9-year-old female that presented with a tender digital mass 6 months following a minor hand injury. After an extensive workup, the mass was surgically excised and diagnosed as an STC. Our case is the first to identify a digital STC in a pediatric patient and expands on the pathologic differential diagnosis. While the true incidence in the pediatric population is unknown, STC should be included in the differential diagnosis when any patient, adult or child, presents with a digital mass. PMID- 26113666 TI - Mediastinal Mature Teratoma With Malignant Carcinomatous Transformation (Somatic Type Malignancy) With Metastatic Course. AB - We report the case of a 76-year-old patient presenting with an anterior mediastinal heterogeneous mass. Surgical biopsy revealed a solid and cystic lesion filled with hair. Pathological examination showed an atypical papillary epithelial lining without other germ cell tumor or immature teratoma associated. The final diagnosis was a mature teratoma of the mediastinum with somatic-type malignancy (carcinomatous transformation). After 8-month follow-up, subcutaneous and lymph node metastatic lesions of the carcinomatous component were identified. Subtyping of the malignant component within germ cell tumors is an important challenge for therapeutic options and prognosis. PMID- 26113667 TI - Thinking about Change: An Integrative Approach for Examining Cognition in a Changing World. AB - We are currently experiencing shifts in climate at rates not previously recorded. One important aspect of this change is a tendency toward extremes--extremes in temperature and moisture, both within and among years. Numerous studies focus on the physiological consequences of environmental change, especially in terms of ectothermic taxa's thermal regime and use of habitat. For many species, though, cognitive responses may be a means of response to environmental perturbation. However, the effects of environmental change on the general mechanisms of cognitive processes and their implications for larger phenomena are seldom examined. Moreover, at a larger scale, we do not fully understand the features of the environment that might select for cognitive enhancements or their mechanisms, making us unable to accurately predict which species might experience the most severe response to environmental change and in which environments. This symposium brought together scientists from numerous disciplines to examine the role of cognition in how organisms cope with changing environments. We cover topics from the perspectives of the physiological mechanisms underlying and driving cognition to the complexity of individual behavioral responses in changing environments to emergent large-scale processes influencing species' abilities to respond to such change. Our ultimate goals are to explore how animals use cognition to cope with rapid environmental change, how such coping mechanisms "scale up" to affect ecological and evolutionary patterns, and how we might determine which features of the environment have been (and will become) most important for the conservation of biodiversity. PMID- 26113668 TI - SSRI use and risk of fractures among perimenopausal women without mental disorders. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) were recently approved by the FDA to treat vasomotor symptoms associated with menopause. No prior study has directly examined whether fracture risk is increased among perimenopausal women who initiate SSRIs or among a population of women without mental disorders more generally. METHODS: Female patients without mental illness, aged 40-64 years, who initiated SSRIs were compared with a cohort who initiated H2 antagonists (H2As) or proton-pump inhibitors (PPIs) in 1998-2010, using data from a claims database. Standardised mortality ratio weighting was applied using the propensity score odds of treatment to adapt the distribution of characteristics among patients starting H2A/PPIs to the distribution among SSRI initiators. Poisson regression estimated risk differences and Cox proportional hazards regression the RR of fractures among new users of SSRIs versus H2A/PPIs. Primary analyses allowed for a 6-month lag period (ie, exposure begins 6 months after initiation) to account for a hypothesised delay in the onset of any clinically meaningful effect of SSRIs on bone mineral density. RESULTS: Fracture rates were higher among the 137,031 SSRI initiators compared with the 236,294 H2A/PPI initiators, with HRs (SSRI vs H2A/PPI) over 1, 2 and 5 years of 1.76 (95% CI 1.33 to 2.32), 1.73 (95% CI 1.33 to 2.24) and 1.67 (95% CI 1.30 to 2.14), respectively. CONCLUSIONS: SSRIs appear to increase fracture risk among middle aged women without psychiatric disorders, an effect sustained over time, suggesting that shorter duration of treatment may decrease fracture risk. Future efforts should examine whether this association pertains at lower doses. PMID- 26113669 TI - Depression and disability in people with podoconiosis: a comparative cross sectional study in rural Northern Ethiopia. AB - BACKGROUND: Little is known about depressive symptoms in podoconiosis despite the independent contribution of depression to worse health outcomes and disability in people with other chronic disorders. METHOD: Two-hundred and seventy-one individuals with podoconiosis and 268 healthy neighbours (individuals from the nearest household in any direction) were investigated for depressive symptoms using a validated Amharic version of the Patient Health Questionnaire (PHQ-9). The WHO Disability Assessment Schedule II (WHODAS II) tool was used to measure disability. Logistic regression and zero inflated negative binomial regression were used to identify factors associated with elevated depressive symptoms, and disability, respectively. RESULTS: Among study participants with podoconiosis, 12.6% (34/269) had high levels of depressive symptoms (scoring 5 or more points on the PHQ-9, on two assessments two weeks apart) compared to 0.7% (2/268) of healthy neighbours (p<0.001). Having podoconiosis and being older were significantly associated with increased odds of a high PHQ-9 score (adjusted odds ratios [AOR] 11.42; 95% CI: 2.44-53.44 and AOR 1.04; 95% CI: 1.00-1.08, respectively). Significant predictors of a higher disability score were having podoconiosis (WHODAS II multiplier value: 1.48; 95% CI: 1.39-1.58) and having a high PHQ-9 score (1.07; 95% CI: 1.06-1.08). CONCLUSION: We recommend integrating evidence-based treatments for depression into podoconiosis interventions. PMID- 26113670 TI - Objectively identified comorbidities in COPD: impact on pulmonary rehabilitation outcomes. PMID- 26113671 TI - Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis. AB - Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor beta1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form. PMID- 26113672 TI - Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes. AB - Several biomarkers have been used to assess sputum eosinophilia in asthma. It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes. We investigated the accuracy of biomarkers in detecting sputum eosinophilia (>=3%) in different adult asthma phenotypes.Levels of eosinophils in blood and sputum, exhaled nitric oxide fraction (FeNO) and total immunoglobulin (Ig)E from 336 adult patients, enrolled in three prospective observational clinical trials and recruited at five pulmonology outpatient departments, were analysed. Areas under the receiver operating characteristics curves (AUC) for detecting sputum eosinophilia were calculated and compared between severe and mild, obese and nonobese, atopic and nonatopic and (ex )smoking and never-smoking asthma patients.Sputum eosinophilia was present in 116 patients (35%). In the total group the AUC was 0.83 (95% CI 0.78-0.87) for blood eosinophils, 0.82 (0.77-0.87) for FeNO and 0.69 (0.63-0.75) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes. Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients.Blood eosinophils and FeNO had comparable diagnostic accuracy (superior to total IgE) in identifying sputum eosinophilia in adult asthma patients, irrespective of asthma phenotype such as severe, nonatopic, obese and smoking-related asthma. PMID- 26113673 TI - Airway bacteria and respiratory symptoms are common in ambulatory HIV-positive UK adults. PMID- 26113674 TI - Asthma, COPD and overlap syndrome: a longitudinal study in young European adults. AB - We compared risk factors and clinical characteristics, 9-year lung function change and hospitalisation risk across subjects with the asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), asthma or COPD alone, or none of these diseases.Participants in the European Community Respiratory Health Survey in 1991-1993 (aged 20-44 years) and 1999-2001 were included. Chronic airflow obstruction was defined as pre-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity=20 mg three times daily) for >=3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all cause death.Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary end-point event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58 1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile.In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event. PMID- 26113688 TI - Linking clinical phenotypes of chronic lung allograft dysfunction to changes in lung structure. AB - Chronic lung allograft dysfunction (CLAD) remains the major barrier to long-term success after lung transplantation. This report compares gross and microscopic features of lungs removed from patients receiving a redo-transplant as treatment for CLAD. Lungs donated by patients with either the bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) phenotype of CLAD and appropriate control lungs (eight per group) were air-inflated, frozen solid and kept frozen while a multi-detector computed tomography (MDCT) was obtained. The lung was then cut into 2-cm thick transverse slices and sampled for micro-CT and histopathology. The MDCT showed reduced lung volume with increased lung weight and density in RAS versus BOS and control (p<0.05). Although pre-terminal bronchioles were obstructed in both phenotypes, RAS lungs showed a reduction of pre-terminal bronchioles (p<0.01). Micro-CT and matched histopathology showed that RAS was associated with reduced numbers of terminal bronchioles/lung compared to BOS and controls (p<0.01), with expansion of the interstitial compartment and obliteration of the alveolar airspaces by fibrous connective tissue. RAS is associated with greater destruction of both pre-terminal and terminal bronchioles. Additionally, the interstitial compartments are expanded and alveolar airspaces are obliterated by accumulation of fibrous connective tissue. PMID- 26113689 TI - Bacterial community composition and diversity in an ancestral ant fungus symbiosis. AB - Fungus-farming ants (Hymenoptera: Formicidae, Attini) exhibit some of the most complex microbial symbioses because both macroscopic partners (ants and fungus) are associated with a rich community of microorganisms. The ant and fungal microbiomes are thought to serve important beneficial nutritional and defensive roles in these symbioses. While most recent research has investigated the bacterial communities in the higher attines (e.g. the leaf-cutter ant genera Atta and Acromyrmex), which are often associated with antibiotic-producing Actinobacteria, very little is known about the microbial communities in basal lineages, labeled as 'lower attines', which retain the ancestral traits of smaller and more simple societies. In this study, we used 16S amplicon pyrosequencing to characterize bacterial communities of the lower attine ant Mycocepurus smithii among seven sampling sites in central Panama. We discovered that ant and fungus garden-associated microbiota were distinct from surrounding soil, but unlike the situation in the derived fungus-gardening ants, which show distinct ant and fungal microbiomes, microbial community structure of the ants and their fungi were similar. Another surprising finding was that the abundance of actinomycete bacteria was low and instead, these symbioses were characterized by an abundance of Lactobacillus and Pantoea bacteria. Furthermore, our data indicate that Lactobacillus strains are acquired from the environment rather than acquired vertically. PMID- 26113691 TI - A 50-year-old man with dysuria. PMID- 26113692 TI - Solving reproducibility. PMID- 26113694 TI - INFECTIOUS DISEASES. Surviving Ebola survival. PMID- 26113695 TI - GENETICS. An enhanced view of gene control. PMID- 26113696 TI - OPTICS. Breaking the light barrier. PMID- 26113697 TI - Q&A. Tapping a nuclear test ban treasure-trove. PMID- 26113698 TI - The cancer test. PMID- 26113699 TI - Mission controller. PMID- 26113700 TI - Alan Stern's worldly ventures. PMID- 26113701 TI - SCIENTIFIC INTEGRITY. Self-correction in science at work. PMID- 26113703 TI - ECOLOGY. Ecological communities by design. PMID- 26113702 TI - SCIENTIFIC STANDARDS. Promoting an open research culture. PMID- 26113704 TI - MICROBIOTA. Mother's littlest helpers. PMID- 26113705 TI - MATERIALS SCIENCE. Bearing down on hydrogen. PMID- 26113706 TI - BIOGEOCHEMISTRY. Who can cleave DMSP? PMID- 26113707 TI - OPTICS. Topology, spin, and light. PMID- 26113708 TI - GENE REGULATION. A HUSH for transgene expression. PMID- 26113709 TI - Applying antibiotics lessons to antivirals. PMID- 26113710 TI - Response-Applying antibiotics lessons to antivirals. PMID- 26113711 TI - China legitimizes ivory, again. PMID- 26113712 TI - FUNGAL BIOGEOGRAPHY. Comment on "Global diversity and geography of soil fungi". AB - Tedersoo et al. (Research Article, 28 November 2014, p. 1078) present a compelling study regarding patterns of biodiversity of fungi, carried out at a scale unprecedented to date for fungal biogeographical studies. The study demonstrates strong global biogeographic patterns in richness and community composition of soil fungi. What concerns us with the study is what we do not see. Unfortunately, this study underestimates the fungal diversity of one key group of soil fungi due to reliance on a single primer with known flaws. PMID- 26113713 TI - ANIMAL COGNITION. Comment on "Number-space mapping in the newborn chick resembles humans' mental number line". AB - Rugani et al. (Reports, 30 January 3015, p. 534) tested 3-day-old domestic chicks using an innovative experimental setup and demonstrate the presence of the mental number line. We raise concerns regarding this conclusion by highlighting the possible loopholes in the experimental design and the data analysis procedures. We further suggest auxiliary experiments that can substantiate the authors' claim. PMID- 26113714 TI - ANIMAL COGNITION. Comment on "Number-space mapping in the newborn chick resembles humans' mental number line". AB - Rugani et al. (Reports, 30 January 2015, p. 534) presented evidence that domestic chicks employ a "mental number line." I argue that the hypothesis testing used to support this claim unjustifiably assumes that domestic chicks are unbiased when choosing between identical stimuli presented to their left and right. PMID- 26113715 TI - ANIMAL COGNITION. Response to Comments on "Number-space mapping in the newborn chick resembles humans' mental number line". AB - Mangalam and Karve raise concerns on whether our results demonstrate a mental number line, suggesting auxiliary experiments. Further data analyses show that their methodological concerns are not founded. Harshaw suggests that a side bias could have affected our results. We show that this concern is also unfounded. PMID- 26113716 TI - APPLIED OPTICS. Overcoming Kerr-induced capacity limit in optical fiber transmission. AB - Nonlinear optical response of silica imposes a fundamental limit on the information transfer capacity in optical fibers. Communication beyond this limit requires higher signal power and suppression of nonlinear distortions to prevent irreversible information loss. The nonlinear interaction in silica is a deterministic phenomenon that can, in principle, be completely reversed. However, attempts to remove the effects of nonlinear propagation have led to only modest improvements, and the precise physical mechanism preventing nonlinear cancellation remains unknown. We demonstrate that optical carrier stability plays a critical role in canceling Kerr-induced distortions and that nonlinear wave interaction in silica can be substantially reverted if optical carriers possess a sufficient degree of mutual coherence. These measurements indicate that fiber information capacity can be notably increased over previous estimates. PMID- 26113717 TI - OPTICS. Quantum spin Hall effect of light. AB - Maxwell's equations, formulated 150 years ago, ultimately describe properties of light, from classical electromagnetism to quantum and relativistic aspects. The latter ones result in remarkable geometric and topological phenomena related to the spin-1 massless nature of photons. By analyzing fundamental spin properties of Maxwell waves, we show that free-space light exhibits an intrinsic quantum spin Hall effect-surface modes with strong spin-momentum locking. These modes are evanescent waves that form, for example, surface plasmon-polaritons at vacuum metal interfaces. Our findings illuminate the unusual transverse spin in evanescent waves and explain recent experiments that have demonstrated the transverse spin-direction locking in the excitation of surface optical modes. This deepens our understanding of Maxwell's theory, reveals analogies with topological insulators for electrons, and offers applications for robust spin directional optical interfaces. PMID- 26113718 TI - 3D LITHOGRAPHY. Atomic gold-enabled three-dimensional lithography for silicon mesostructures. AB - Three-dimensional (3D) mesostructured semiconductors show promising properties and applications; however, to date, few methods exist to synthesize or fabricate such materials. Metal can diffuse along semiconductor surfaces, and even trace amounts can change the surface behavior. We exploited the phenomena for 3D mesoscale lithography, by showing one example where iterated deposition-diffusion incorporation of gold over silicon nanowires forms etchant-resistant patterns. This process is facet-selective, producing mesostructured silicon spicules with skeletonlike morphology, 3D tectonic motifs, and reduced symmetries. Atom-probe tomography, coupled with other quantitative measurements, indicates the existence and the role of individual gold atoms in forming 3D lithographic resists. Compared to other more uniform silicon structures, the anisotropic spicule requires greater force for detachment from collagen hydrogels, suggesting enhanced interfacial interactions at the mesoscale. PMID- 26113719 TI - HIGH-PRESSURE PHYSICS. Direct observation of an abrupt insulator-to-metal transition in dense liquid deuterium. AB - Eighty years ago, it was proposed that solid hydrogen would become metallic at sufficiently high density. Despite numerous investigations, this transition has not yet been experimentally observed. More recently, there has been much interest in the analog of this predicted metallic transition in the dense liquid, due to its relevance to planetary science. Here, we show direct observation of an abrupt insulator-to-metal transition in dense liquid deuterium. Experimental determination of the location of this transition provides a much-needed benchmark for theory and may constrain the region of hydrogen-helium immiscibility and the boundary-layer pressure in standard models of the internal structure of gas-giant planets. PMID- 26113720 TI - CORAL REEFS. Genomic determinants of coral heat tolerance across latitudes. AB - As global warming continues, reef-building corals could avoid local population declines through "genetic rescue" involving exchange of heat-tolerant genotypes across latitudes, but only if latitudinal variation in thermal tolerance is heritable. Here, we show an up-to-10-fold increase in odds of survival of coral larvae under heat stress when their parents come from a warmer lower-latitude location. Elevated thermal tolerance was associated with heritable differences in expression of oxidative, extracellular, transport, and mitochondrial functions that indicated a lack of prior stress. Moreover, two genomic regions strongly responded to selection for thermal tolerance in interlatitudinal crosses. These results demonstrate that variation in coral thermal tolerance across latitudes has a strong genetic basis and could serve as raw material for natural selection. PMID- 26113721 TI - PHOTOSYNTHESIS. A 12 A carotenoid translocation in a photoswitch associated with cyanobacterial photoprotection. AB - Pigment-protein and pigment-pigment interactions are of fundamental importance to the light-harvesting and photoprotective functions essential to oxygenic photosynthesis. The orange carotenoid protein (OCP) functions as both a sensor of light and effector of photoprotective energy dissipation in cyanobacteria. We report the atomic-resolution structure of an active form of the OCP consisting of the N-terminal domain and a single noncovalently bound carotenoid pigment. The crystal structure, combined with additional solution-state structural data, reveals that OCP photoactivation is accompanied by a 12 angstrom translocation of the pigment within the protein and a reconfiguration of carotenoid-protein interactions. Our results identify the origin of the photochromic changes in the OCP triggered by light and reveal the structural determinants required for interaction with the light-harvesting antenna during photoprotection. PMID- 26113722 TI - MARINE SULFUR CYCLE. Identification of the algal dimethyl sulfide-releasing enzyme: A missing link in the marine sulfur cycle. AB - Algal blooms produce large amounts of dimethyl sulfide (DMS), a volatile with a diverse signaling role in marine food webs that is emitted to the atmosphere, where it can affect cloud formation. The algal enzymes responsible for forming DMS from dimethylsulfoniopropionate (DMSP) remain unidentified despite their critical role in the global sulfur cycle. We identified and characterized Alma1, a DMSP lyase from the bloom-forming algae Emiliania huxleyi. Alma1 is a tetrameric, redox-sensitive enzyme of the aspartate racemase superfamily. Recombinant Alma1 exhibits biochemical features identical to the DMSP lyase in E. huxleyi, and DMS released by various E. huxleyi isolates correlates with their Alma1 levels. Sequence homology searches suggest that Alma1 represents a gene family present in major, globally distributed phytoplankton taxa and in other marine organisms. PMID- 26113723 TI - BRAIN CIRCUITS. A parvalbumin-positive excitatory visual pathway to trigger fear responses in mice. AB - The fear responses to environmental threats play a fundamental role in survival. Little is known about the neural circuits specifically processing threat-relevant sensory information in the mammalian brain. We identified parvalbumin-positive (PV(+)) excitatory projection neurons in mouse superior colliculus (SC) as a key neuronal subtype for detecting looming objects and triggering fear responses. These neurons, distributed predominantly in the superficial SC, divergently projected to different brain areas, including the parabigeminal nucleus (PBGN), an intermediate station leading to the amygdala. Activation of the PV(+) SC-PBGN pathway triggered fear responses, induced conditioned aversion, and caused depression-related behaviors. Approximately 20% of mice subjected to the fear conditioning paradigm developed a generalized fear memory. PMID- 26113724 TI - STRUCTURAL BIOLOGY. A Cas9-guide RNA complex preorganized for target DNA recognition. AB - Bacterial adaptive immunity uses CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas) proteins together with CRISPR transcripts for foreign DNA degradation. In type II CRISPR-Cas systems, activation of Cas9 endonuclease for DNA recognition upon guide RNA binding occurs by an unknown mechanism. Crystal structures of Cas9 bound to single-guide RNA reveal a conformation distinct from both the apo and DNA-bound states, in which the 10 nucleotide RNA "seed" sequence required for initial DNA interrogation is preordered in an A-form conformation. This segment of the guide RNA is essential for Cas9 to form a DNA recognition-competent structure that is poised to engage double-stranded DNA target sequences. We construe this as convergent evolution of a "seed" mechanism reminiscent of that used by Argonaute proteins during RNA interference in eukaryotes. PMID- 26113726 TI - The health of those who study health. PMID- 26113725 TI - RNA BIOCHEMISTRY. Factor-dependent processivity in human eIF4A DEAD-box helicase. AB - During eukaryotic translation initiation, the small ribosomal subunit, assisted by initiation factors, locates the messenger RNA start codon by scanning from the 5' cap. This process is powered by the eukaryotic initiation factor 4A (eIF4A), a DEAD-box helicase. eIF4A has been thought to unwind structures formed in the untranslated 5' region via a nonprocessive mechanism. Using a single-molecule assay, we found that eIF4A functions instead as an adenosine triphosphate dependent processive helicase when complexed with two accessory proteins, eIF4G and eIF4B. Translocation occurred in discrete steps of 11 +/- 2 base pairs, irrespective of the accessory factor combination. Our findings support a memory less stepwise mechanism for translation initiation and suggest that similar factor-dependent processivity may be shared by other members of the DEAD-box helicase family. PMID- 26113727 TI - EMBRYO DEVELOPMENT. BMP gradients: A paradigm for morphogen-mediated developmental patterning. AB - Bone morphogenetic proteins (BMPs) act in dose-dependent fashion to regulate cell fate choices in a myriad of developmental contexts. In early vertebrate and invertebrate embryos, BMPs and their antagonists establish epidermal versus central nervous system domains. In this highly conserved system, BMP antagonists mediate the neural-inductive activities proposed by Hans Spemann and Hilde Mangold nearly a century ago. BMPs distributed in gradients subsequently function as morphogens to subdivide the three germ layers into distinct territories and act to organize body axes, regulate growth, maintain stem cell niches, or signal inductively across germ layers. In this Review, we summarize the variety of mechanisms that contribute to generating reliable developmental responses to BMP gradients and other morphogen systems. PMID- 26113729 TI - Zika: another sexually transmitted infection? PMID- 26113728 TI - HEART DEVELOPMENT. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. AB - Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor. PMID- 26113731 TI - Ascending-to-descending aortic bypass graft for type B aortic interruption. PMID- 26113730 TI - How long-distance truck drivers and villagers in rural southeastern Tanzania think about heterosexual anal sex: a qualitative study. AB - OBJECTIVE: To explore ideas of truck drivers and villagers from rural Tanzania about heterosexual anal sex (HAS) and the associated health risks. METHODS: Qualitative study using 8 in-depth interviews (IDIs) and 2 focus group discussions (FGDs) with truck drivers and 16 IDIs and 4 FGDs with villagers from the Morogoro region. Study participants included 24 women and 46 men. Data analysis was performed thematically employing standard qualitative techniques. RESULTS: Reasons why men would practice HAS included sexual pleasure, the belief that anal sex is safer than vaginal sex, alternative sexual practice, exploration and proof of masculinity. Reasons why women would practice HAS included financial need, retaining a partner, alternative for sex during menses, pregnancy prevention and beauty enhancement because HAS is believed to 'fatten the female buttocks'. Most participants believed that condoms are not needed during HAS. This was linked to the ideas that infections only 'reside in wet places' (vagina) and that the anus is not 'conducive' for condom use; condoms reduce 'dryness' and 'friction' (pleasure) and may 'get stuck inside'. CONCLUSIONS: The study participants reported practices and ideas about HAS that put them at risk for HIV and sexually transmitted infections. Greater attention to education about HAS is urgently needed in Tanzania, where this sexual practice is still regarded as a taboo. This study offers useful information that could be included in sex education programmes. PMID- 26113732 TI - Utility of a preloaded fenestrated graft in thoracoabdominal aneurysm repair. AB - An 84-year-old man with a thoracoabdominal aortic aneurysm was treated using a fenestrated stent graft with a preloaded guidewire system under local anesthesia. He suffered from severe chronic obstructive pulmonary disease. We successfully placed 4 bridging stent grafts for perfusion of the celiac artery, superior mesenteric artery, and bilateral renal arteries via the 4 fenestrations. A preloaded wire system was used to insert a catheter into the celiac artery from the left brachial artery. Our findings indicate that a fenestrated stent graft with a preloaded wire system may expand the indication for treating thoracoabdominal aortic aneurysms in high-risk patients. PMID- 26113733 TI - Non-aneurysmal abdominal aortic rupture in a patient with Marfan syndrome. AB - Aortic rupture in the presence of aneurysmal disease is well understood and extensively described in the literature. However, aortic rupture in a non aneurysmal aorta is far less common. In the few reported cases, perforations are believed to result from a penetrating atheromatous ulcer of the aorta. We describe a rare case of non-aneurysmal aortic rupture in a 68-year-old man with Marfan syndrome and a history of proximal aortic surgery. The urgent need for hemorrhage control precluded any consideration of an endovascular repair. PMID- 26113734 TI - Unusual bronchial foreign body. AB - We present an unusual case of bronchial foreign body in an adult who presented with bronchiectasis more than two decades later. The patient was unaware of his accidental aspiration of the foreign body, and the final diagnosis was made intraoperatively. PMID- 26113735 TI - Cell salvage during coronary artery bypass surgery and allogenic blood exposure. AB - AIM: Our primary aim was to assess the impact of intraoperative cell saver usage on patient exposure to allogenic blood transfusion during elective coronary artery bypass. The secondary endpoint was the impact of cell savage on the units of blood and blood products transfused perioperatively. METHODS: A prospective observational cohort study with a historical cohort as a control group was performed in a single tertiary care center. One hundred and twenty-four patients undergoing primary on-pump coronary artery bypass grafting were included. Intraoperative cell salvage was performed in 60 patients (study group) but not in the control group (n = 64). Transfusion data, intensive care unit stay, hospital stay, and postoperative complications were evaluated in the cell saver and control groups. RESULTS: The number of patients exposed to allogenic red blood cell transfusion was significantly less in the study group (55% vs. 82.8%; p = 0.001) and the units per patient was also less in the study group (1.10 +/- 1.7 vs. 2.25 +/- 2.289 units; p = 0.002). However, there was no significant difference in terms of units of purified plasma fraction, platelets, or cryoprecipitate transfused. Intensive care unit stay, total hospital stay, number of reexplorations, complications, readmissions, and 28-day mortality were similar in both groups. CONCLUSIONS: Intraoperative cell salvage with a cell saver in patients undergoing primary elective coronary artery bypass decreases the proportion of patients exposed to allogenic red cell transfusions and the number of units of red blood cells transfused. PMID- 26113736 TI - Analytical imprecision of lactate dehydrogenase in primary serum tubes. AB - BACKGROUND: Previous studies showed high frequency of duplicate errors of lactate dehydrogenase (LDH) measurement in primary lithium-heparin blood tubes. We hence evaluated imprecision of LDH testing and frequency of replicate errors in primary serum samples centrifuged at two different speeds. METHODS: Serum samples were collected from 15 healthy subjects and centrifuged at either 1300 g or 2000 g. Serum LDH was then measured on Beckman Coulter AU5800 using the International Federation of Clinical Chemistry-recommended procedure. Complete blood cell count of top layer of serum supernatant was also performed using Advia 2120. Imprecision was calculated as coefficient of variation of 10 replicates of each serum tube, whereas the frequency of replicate errors was compared to the desirable specifications for imprecision. RESULTS: Mean LDH values were slightly but significantly higher in serum samples centrifuged at 2000 g rather than 1300 g, whereas blood cell counts were similar. The mean imprecision of LDH was more than double in samples centrifuged at 2000 g than in those centrifuged at 1300 g (8% versus 3%). The percentage of replicate measurements exceeding the desirable specifications was more than threefold higher in samples centrifuged at 2000 g than in those centrifuged at 1300 g (30% versus 9%; P < .001). CONCLUSIONS: The lower frequency of replicated errors in LDH measurement observed using serum samples centrifuged according to manufacturer's instruction suggests that assay precision in serum is better if samples are centrifuged at 1300 g rather than 2000 g when the International Federation of Clinical Chemistry-recommended procedure is used. PMID- 26113737 TI - The role of the clinical biochemist in detection of zinc-induced copper deficiency. AB - A middle-aged woman with neutropenia and ataxia was found to have raised plasma zinc and profoundly low plasma copper concentrations. When found that she had been prescribed 135 mg zinc/day for seven years, a diagnosis of zinc-induced copper deficiency was made. After the zinc prescription was stopped, her copper and zinc concentrations and neutropenia normalized but she only had partial improvement in neurological status. The diagnosis of zinc-induced copper deficiency can be facilitated by the laboratory through measurement of plasma zinc concentration in patients with a low plasma copper concentration. PMID- 26113738 TI - Improving clinical outcomes - towards patient-centred laboratory medicine. AB - Hard evidence of the specific contribution made by laboratory testing to patient outcomes and the delivery of health care is not easy to obtain. An understanding of the value of laboratory medicine, how that value can be measured and the various factors that influence it is vital to ensuring that laboratory services are provided and used optimally to improve patient care. To maximise the value of laboratory medicine, work is required to improve the utilisation of existing and new biomarkers, develop standard protocols for prospective patient-centred studies of biomarker clinical effectiveness or extra-analytical process effectiveness, benchmark existing and new tests in specified clinical situations with commonly accepted effectiveness measures, and define new roles for laboratory professionals that are focussed on optimising patient outcomes by adding value throughout the total testing process. This requires effective collaboration with clinical staff and a determination to accept patient outcome and patient experience as the primary measure of laboratory performance. PMID- 26113739 TI - Secrets from the microbiome: molecular biology meets microbiology meets histopathology...meets clinical biochemistry. AB - The microbiome is the collective term used to describe the bacteria, viruses, fungi and archaea that reside on and in the human body. The majority of these organisms are found within the large bowel. Mounting evidence suggests that changes in the microbiome may be associated with the development of colorectal cancer, a disease which affects 1.3 million people a year worldwide. Using colorectal cancer as an example, this article presents the inter-specialty collaborative approach to microbiome research and discusses the key role that clinical biochemistry is likely to play. PMID- 26113740 TI - Percutaneous transhepatic portal embolization using foam ethanolamine oleate and carbon dioxide (CO2): a pilot study. AB - BACKGROUND: Percutaneous transhepatic portal embolization (PTPE) can induce atrophy of the embolized- and hypertrophy of the residual area. These effects are advantageous in patients scheduled for extended hepatectomy. PURPOSE: To evaluate the clinical safety and effectiveness of foam sclerotherapy with foam ethanolamine oleate (EO) and carbon dioxide (CO2) for PTPE before hepatectomy. MATERIAL AND METHODS: We performed sclerotherapy for PTPE in 15 patients with: hepatocellular carcinoma (HHC; n = 9), bile duct carcinoma (n = 5), or metastatic liver tumor from colon cancer (n = 1). The foam contained 5% EO iopamidol (EOI) and CO2 at a 1:2 ratio. We compared the percentage of the pre- and post-PTPE future liver remnant (FLR) volumes and calculated the percent FLR volume (%FLR) increase after PTPE. RESULTS: The amount of EOI used (range, 14-20 mL; median, 16.8 mL) was based on the volume of the target portal vein. Technical success was achieved in 14 of 15 patients (93%); the other patient presented with computed tomography evidence of recanalization 1 week after PTPE. The FLR volume before and after portal vein embolization was 599 +/- 342 and 691 +/- 318 cm(3), respectively (P < 0.01); the mean %FLR volume increase was 29.5%. There was no significant difference in the mean platelet count, total bilirubin, total aspartate aminotransferase, and total creatinine before and after PTPE. One patient suffered intra-abdominal bleeding that required transcatheter arterial embolization. No other patients developed major complications higher than grade 3. CONCLUSION: Sclerotherapy using foam EOI and CO2 is clinically safe and effective for PTPE before hepatectomy. PMID- 26113741 TI - Regional dGEMRIC analysis in patients at risk of osteoarthritis provides additional information about activity related changes in cartilage structure. AB - BACKGROUND: Previously, a positive effect of exercise on cartilage structure was indicated with delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC). However, in that study only one full-thickness region of interest (ROI) in the medial femoral condyle was analyzed. PURPOSE: To improve the knowledge about exercise effects on cartilage structure by re-analyzing previous images with regional dGEMRIC analysis. MATERIAL AND METHODS: Thirty patients (age range, 38-50 years) with a previous medial meniscus resection were divided into three groups according to self-reported change in physical activity (PA) level in a 4-month exercise intervention study: Group I (n = 11), increased PA level; Group II (n = 13), no change in PA level; and Group III (n = 6), reduced PA level. dGEMRIC index was analyzed at inclusion and after 4 months. Anterior (less load) and posterior (more load) ROIs of medial and lateral femoral condyles were analyzed, as well as superficial and deep cartilage regions. RESULTS: Group I increased the dGEMRIC index in the posterior cartilage (P = 0.004). The increase was larger in the lateral (P = 0.005) than the medial compartment in both superficial and deep cartilage regions. The dGEMRIC index did not change in Group II. In Group III, the dGEMRIC index decreased in the medial posterior cartilage (P = 0.03). CONCLUSION: In patients with a previous medial meniscectomy, the beneficial effect of exercise varies between different locations within the joint, the largest improvement being observed in lateral posterior cartilage, i.e. the load-bearing cartilage in the compartment without a meniscus lesion. The effects of exercise do not seem to vary with cartilage depth. PMID- 26113742 TI - Magnetic resonance arthrography of the hip: prevalence of diagnoses not suspected by the referring physician and correlation with clinical examination and pain score. AB - BACKGROUND: Magnetic resonance arthrography (MRA) of the hip is the most sensitive imaging modality for intra-articular pathologies such as labral tears. PURPOSE: To evaluate the prevalence of non-suspected pathologies revealed by hip MRA and correlate them to physical examination/pain level. MATERIAL AND METHODS: All hip MRAs (2011-2013) were retrospectively evaluated for intra- and extra articular pathologies in consensus by two readers. A clinical score (0-7)/pain score (0-10) was calculated for each patient based on orthopedic test results extracted from referral forms/a telephone questionnaire. Patients were divided into four groups according to MRA findings: intra-articular expected (targeted) pathology only; intra-articular targeted and additional non-targeted (unexpected) pathology; non-targeted pathology; and no pathology. Pathologies prevalence/clinical score/pain score were compared between the groups. RESULTS: A total of 229 MRAs were included (127 men, 102 women; mean age, 36.5 +/- 14.17 years): 111(48.4%) patients had solely intra-articular targeted pathology. Significant non-targeted pathologies were detected in 76 (33%) patients (targeted and non-targeted, 51; non-targeted only 25). No significant pathology was detected in 42 patients (18%). Mean physical examination score was 2.77 +/- 1.77, range 0-7. There was no significant difference or correlation (r = 0.017, P = 0.804) between the clinical scores of the different MRA pathology groups. Pain score (143 patients) was significantly higher in the non-targeted pathology group compared to the targeted and non-targeted group (P = 0.04) and to the no pathology group (P = 0.04). There was no correlation between the physical examination score and the pain score (r = 0.017, P = 0.804). CONCLUSION: Unsuspected non-targeted pathologies were detected in 33% of hip MRA. Physical examination/pain level could not differentiate between patients. PMID- 26113743 TI - Realistic Survival Outcomes After Vasopressor Use in the Intensive Care Unit. AB - AIM: Patients in the intensive care unit (ICU) have significantly increased mortality rates. Frequently, clinicians are called upon to help families make decisions regarding aggressiveness of care. Having a realistic expectation of outcome is critical for these discussions. This article looked at survival and outcomes following initiation of vasopressors. METHODS: All patients admitted to the ICU between January and June 2011were included. Patients were classified into those who had been started on vasopressors (VP+) and those who had not (VP-). Outcomes of these groups including survival were calculated and compared. RESULTS: A total of 1023 patients were included: 169 in the VP+ group and 854 in the VP- group. The survival rate in the VP+ group was 29.6% compared to 92.0% in the VP- group. This was both clinically and statistically significant (P < .001). CONCLUSION: Patients started on vasopressors in the ICU have very poor outcomes. Being able to quantify this accurately is important to clinicians having discussions with family members. PMID- 26113744 TI - Digital inclusion: The concept and strategies for people with mental health difficulties. PMID- 26113746 TI - Vardeman, S. B. and Morris, M. D. (2013), "Majority Voting by Independent Classifiers can Increase Error Rates," The American Statistician, 67, 94-96: Comment by Baker, Xu, Hu, and Huang and Reply. PMID- 26113745 TI - Cell proliferation is reduced in the hippocampus in schizophrenia. AB - OBJECTIVE: The molecular and cellular basis of structural and functional abnormalities of the hippocampus found in schizophrenia is currently unclear. Postnatal neurogenesis contributes to hippocampal function in animal models and is correlated with hippocampal volume in primates. Reduced hippocampal cell proliferation has been previously reported in schizophrenia, which may contribute to hippocampal dysfunction. METHOD: We measured the cell proliferation marker, Ki67, in post-mortem hippocampal tissue from patients with schizophrenia (n = 10) and matched controls (n = 16). Ki67-labelled cells were counted within the dentate gyrus and hilus on sections taken from the anterior hippocampus. RESULTS: We replicated the finding of a significant reduction in Ki67+ cells/mm2 in schizophrenia cases compared to controls (t24 = 2.1, p = 0.023). In our relatively small sample, we did not find a relationship between Ki67+ cells and age overall, or between Ki67 + cells and duration of illness or antipsychotic treatment in people with schizophrenia. CONCLUSION: Our results confirm that reduced hippocampal cell proliferation may be present in schizophrenia. Restoring hippocampal neurogenesis may be a potential therapeutic target for the treatment of hippocampal dysfunction in schizophrenia. PMID- 26113747 TI - Methods for Handling Missing Secondary Respondent Data. AB - Secondary respondent data are underutilized because researchers avoid using these data in the presence of substantial missing data. We reviewed, critically evaluated, and tested potential solutions to this problem. Five strategies of dealing with missing partner data are reviewed: complete case analysis, inverse probability weighting, correction with a Heckman selection model, maximum likelihood estimation, and multiple imputation. Two approaches were used to evaluate the performance of these methods. First, we used data from the National Survey of Fertility Barriers (N = 1,666) to estimate a model predicting marital quality based on characteristics of women and their husbands. Second, we conducted a simulation based on these data testing the five methods and compared the results to estimates where the true value was known. We found that the maximum likelihood and multiple imputation methods were advantageous because they allow researchers to utilize all of the available information as well as produce less biased and more efficient estimates. PMID- 26113748 TI - Handling Missing Values in Longitudinal Panel Data With Multiple Imputation. AB - This article offers an applied review of key issues and methods for the analysis of longitudinal panel data in the presence of missing values. The authors consider the unique challenges associated with attrition (survey dropout), incomplete repeated measures, and unknown observations of time. Using simulated data based on 4 waves of the Marital Instability Over the Life Course Study (n = 2,034), they applied a fixed effect regression model and an event-history analysis with time-varying covariates. They then compared results for analyses with nonimputed missing data and with imputed data both in long and in wide structures. Imputation produced improved estimates in the event-history analysis but only modest improvements in the estimates and standard errors of the fixed effects analysis. Factors responsible for differences in the value of imputation are examined, and recommendations for handling missing values in panel data are presented. PMID- 26113749 TI - Perceptions of Cancer Clinical Research Among African American Men in North Carolina. AB - ACKNOWLEDGEMENTS: The authors are grateful to the men and women who participated in our Focus Groups and shared with us their very personal cancer experience. Their insight is valuable, and will inform and improve cancer care for future generations. The authors thank the Greensboro area Community Research Advocates - especially April Durr, Elvira Mebane, Marie McAdoo, Kathy Norcott, and Cindy Taylor - who assisted in the conduct of the study, including interpretation of results. They also thank Gratia Wright of First Research Group for her expertise in moderating and executing all of the focus groups, and Lindsey Haynes-Maslow for her assistance in responding to reviewer comments. The study was funded as a part of the Carolina Community Network program, funded by a grant from the National Cancer Institute (U01-CA114629). This study was reviewed and approved by the Institutional Review Board (IRB) at the University of North Carolina at Chapel Hill. OBJECTIVE: The problem of cancer health disparities is substantial. Clinical trials are widely advocated as a means of reducing disparities and bringing state-of-the-art care to the broader community, where most cancer care is delivered. This study sought to develop a better understanding of why disproportionately few African American men enroll in clinical trials given their substantial cancer burden. DESIGN: This study applied community-based participatory research (CBPR) methods to design and conduct four focus groups of African American male cancer survivors and their caregivers in North Carolina. RESULTS: Among major themes, participants expressed confusion about the relationship between clinical trials, treatment, and research: signifying patient confusion and misinterpretation of common clinical trial terminology. Social norms including gender barriers and generational differences remain problematic; participants often reported that men do not talk about health issues, are unwilling to go to the doctor, and exhibit misapprehension and distrust regarding trials. Participants perceived this misunderstanding as detrimental to community health and expressed the need for more clarity in clinical trials information and a more fundamental social openness and communication about cancer detection and treatment. CONCLUSION: Findings indicate the importance of clinical trial education in both traditional provider referral to trials and also in general patient navigation. To dispel pervasive misapprehension regarding placebos, clinical trial information should emphasize the role of standard care in modern cancer treatment trials. Many participants described willingness to participate in a trial upon physician recommendation, suggesting merit in improving patient physician communication through culturally competent terminology and trial referral systems. PMID- 26113752 TI - JANOS SZENTAGOTHAI. 31 October 1912 - 8 September 1994: Elected ForMemRs 20 April 1978. AB - Janos Szentagothai was an eminent, creative and renowned neuroscientist, who made pioneering and seminal discoveries contributing to our current understanding of brain functions. His vision of the brain as a network of specific populations of nerve cells, each engaging in selective operations and self-organizing into modules, has provided the framework and stimulus for generations of neuroscientists. His irrepressible curiosity and enthusiasm for the beauty in the organization of the brain never faded. He had a towering intellect and was a great humanist. Szentagothai was born in Budapest, Hungary, in 1912 and died in his native city in 1994. He was educated and worked in Hungary. During the six decades of his scientific activity, he made remarkably original and lasting contributions to the neurosciences, including the exploration of basic architectural features of many brain areas, the functional-anatomical bases of elementary brain operations such as reflex arcs, the vestibulo-ocular system, the brain control of hormonal regulation, general organizational principles of the neuraxis, the organization of the cerebellum and the modular organization of the neocortex. He left for posterity not only his discoveries, which have stood the test of time, but also a vigorous school of pupils as well as a large number of friends and admirers. Thanks to him neuroscience is one of the strongest scientific fields in Hungary today. PMID- 26113751 TI - [Regulation of uterine blood flow. II. Functions of estrogen and estrogen receptor alpha/beta in genomic and non-genomic actions of the uterine endothelium]. AB - Pregnancy is marked by changes and cardiovascular adaptations that are important for the maintenance and growth of the placenta and fetus. During this period, the uterine vascular adaptations manifest changes that can be classified as short or long term and they related to adaptations for vasodilation, angiogenic or remodeling. Estrogen and the classical estrogen receptors (ERs), ER-alpha and ER beta, have been shown to be partially responsible for facilitating this dramatic increase in uterine blood flow needed during pregnancy. This literature review discusses the basis for structural diversity and functional selectivity of ERs by estrogen, the role of ERs on the genomic and non-genomic effects in endothelial cells of uterine arteries (UAEC). These themes integrate scientific knowledge about the molecular regulation of UAEC to maintain the physiological increase in uteroplacental perfusion observed during normal pregnancy. PMID- 26113750 TI - [Regulation of uterine blood flow. I. Functions of estrogen and estrogen receptor alpha/beta in the uterine vascular endothelium during pregnancy]. AB - Estrogen and classical estrogen receptors (ERs), ER-alpha and ER-beta, have been shown to be partially responsible for short and long term uterine endothelial adaptations during pregnancy. The molecular and structural differences, together with the various effects caused by these receptors in cells and tissues, suggest that their function varies depending upon estrogen and estrogen receptor signaling. In this review, we discuss the role of estrogen and its classic receptors in the cardiovascular adaptations during pregnancy and the expression of ERs in vivo and in vitro in the uterine artery endothelium during the ovarian cycle and pregnancy, while comparing their expression in arterial endothelium from reproductive and non-reproductive tissues. These themes integrate current knowledge of this broad scientific field with various interpretations and hypothesis that related estrogenic effects by either one or both ERs. This review also includes the relationship with vasodilator and angiogenic adaptations required to modulate the dramatic physiological increase to the uteroplacental perfusion observed during normal pregnancy. PMID- 26113753 TI - Conscious Control over Action. AB - The extensive involvement of nonconscious processes in human behaviour has led some to suggest that consciousness is much less important for the control of action than we might think. In this article I push against this trend, developing an understanding of conscious control that is sensitive to our best models of overt (that is, bodily) action control. Further, I assess the cogency of various zombie challenges-challenges that seek to demote the importance of conscious control for human agency. I argue that though nonconscious contributions to action control are evidently robust, these challenges are overblown. PMID- 26113754 TI - Detector Calibration factor for interstitial in-vivo light dosimetry using isotropic detectors with scattering tip. AB - Isotropic detectors with spherical scattering tips are commonly used for in-vivo dosimetry of light fluence rate during photodynamic therapy (PDT). These detectors are typically calibrated in-air. It has been well established that the response of an isotropic detector is a function of the refractive index (n) of the surrounding medium when it is surrounded by an infinite medium of uniform n. However, there are few, if any, studies of the isotropic detector response when the detector is placed in a secondary medium, such as air, before it is placed inside the infinite uniform medium. This condition often arises when one places the isotropic detector inside an air-filled catheter which is then inserted into a turbid medium, such as tissue. We have performed theoretical and experimental studies to determine the correction factors in water (n = 1.33), which has a refractive index similar to that of tissue (n = 1.4). We found that the resulting correction factor is almost the same (within 20%) as the correction factor for the outermost medium (the water) rather than the immediate medium surrounding the isotropic detector (air). The detector correction factor is also a function of the index of refraction of the probe material. For a 1-mm diameter probe from CardioFocus, the detector correction factor varied from 1 (in air) to 1.09 (at air-water interface) to 1.49 (completely submerged in water). At the air-water interface the spherical bulb of the isotropic detector is placed half in air and half in water. For a 0.5-mm diameter probe from the same company, it varied from 1 (in air) to 1.32 (at air-water interface) to 1.87 (in water). For a 0.3-mm diameter probe from the same company, it varied from 1 (in air) to 1.32 (at air water interface) to 1.71 (in water). We have also found that the detector response changes by less than 10% when the detector position is varied from touching the catheter wall closest to the light source, to not touching, to touching the catheter wall farthest from the light source. The calibration factors between individual isotropic detectors of the same type varied within 5% for all detector types. Thus mean correction factor can be used for each individual isotropic detector of the same type. PMID- 26113755 TI - Study of light fluence rate distribution in photodynamic therapy using finite element method. AB - In photodynamic therapy (PDT), it is desirable to determine the light fluence distribution accurately for treatment planning. Earlier studies have shown heterogeneous distribution of optical properties in patients' prostates. Finiteelement method (FEM) is suitable for dealing with heterogeneous media and irregular geometries. Cylindrical diffusing fibers (CDFs) were modeled as linear sources of finite lengths, using the same parameters as those used in the treatments. Meshes were generated in the three-dimensional (3D) prostate geometry, reconstructed using transrectal ultrasound images of the prostate. Heterogeneous optical properties measured in the prostate were applied in the calculation and the refractive-index mismatch boundary condition was studied. Compared with the measurements, the FEM calculations using heterogeneous optical properties show better agreements than those using homogeneous optical properties. PMID- 26113756 TI - A Macro-Monte Carlo method for the simulation of diffuse light transport in tissue. AB - The Monte Carlo (MC) method of calculating light distributions in turbid media such as tissue has become the gold standard, especially in complex geometries and heterogeneous tissue. The utility of the MC method, however, is limited by is computational intensity. In an effort to reduce the time needed for MC calculations, we have adapted a macro-Monte Carlo (MMC) method (Neuenschwander, et al. 1995, Phys. Med. Biol. 40, 543-574) to the solution of tissue optics problems. Traditional MC routines trace individual photons step-by-step through the tissue. Instead, the MMC approach relies on a data set consisting of spheres in which the light absorbed in each voxel is pre-calculated using a traditional MC routine. At each MMC step, the pre-calculated absorbed light dose in the appropriate sphere, aligned to the current position and direction of the sphere, is recorded in the dose matrix. The position and direction of the photon exiting the sphere are chosen from the exit distribution of the pre-calculated sphere, and the process is repeated. By choosing the size of the pre-calculated sphere appropriately, arbitrarily complex boundary geometries can be simulated. We compare the accuracy and calculation time of the MMC method with a traditional MC algorithm for a variety of tissue optical properties and geometries. We find that the MMC algorithm can increase the speed of calculation by as much as two orders of magnitude, depending on the optical properties being simulated, without a significant loss in accuracy. PMID- 26113757 TI - Diffuse reflectance spectra measured in vivo in human tissues during Photofrin mediated pleural photodynamic therapy. AB - Optimal delivery of light in photodynamic therapy (PDT) requires not only optimal placement and power of light sources, but knowledge of the dynamics of light propagation in the tissue being treated and in the surrounding normal tissue, and of their respective accumulations of sensitizer. In an effort to quantify both tissue optical properties and sensitizer distribution, we have measured fluorescence emission and diffuse reflectance spectra at the surface of a variety of tissue types in the thoracic cavities of human patients. The patients studied here were enrolled in Phase II clinical trials of Photofrin-mediated PDT for the treatment of non-small cell lung cancer and cancers with pleural effusion. Patients were given Photofrin at dose of 2 mg per kg body weight 24 hours prior to treatment. Each patient received surgical resection of the affected lung and pleura. Patients received intracavity PDT at 630nm to a dose of 30 J/cm2, as determined by isotropic detectors sutured to the cavity walls. We measured the diffuse reflectance spectra before and after PDT in various positions within the cavity, including tumor, diaphragm, pericardium, skin, and chest wall muscle in 5 patients. The measurements we acquired using a specially designed fiber optic based probe consisting of one fluorescence excitation fiber, one white light delivery fiber, and 9 detection fibers spaced at distances from 0.36 to 7.8 mm from the source, all of which are imaged via a spectrograph onto a CCD, allowing measurement of radially-resolved diffuse reflectance and fluorescence spectra. The light sources for these two measurements (a 403-nm diode laser and a halogen lamp, respectively) were blocked by computer-controlled shutters, allowing sequential fluorescence, reflectance, and background acquisition. The diffuse reflectance was analyzed to determine the absorption and scattering spectra of the tissue and from these, the concentration and oxygenation of hemoglobin and the local drug uptake. The total hemoglobin concentration in normal tissues varied from 50 to 300 MUM, and the oxygen saturation was generally above 60%. One tumor measured exhibited higher hemoglobin concentration and lower saturation. PMID- 26113758 TI - In-vivo light dosimetry of interstitial PDT of human prostate. AB - We report results of in-vivo light dosimetry of light fluence (rate) in human prostate during photodynamic therapy (PDT). Measurements were made in-vivo at the treatment wavelength (732nm) in 15 patients in three to four quadrants using isotropic detectors placed inside catheters inserted into the prostate. The catheter positions are determined using a transrectal ultrasound (TRUS) unit attached to a rigid template with 0.5-cm resolution. Cylindrical diffusing fibers with various lengths are introduced into the catheters to cover the entire prostate gland. For the last four patients, distributions of light fluence rate along catheters were also measured using a computer controlled step motor system to move multiple detectors to different distances (with 0.1 mm resolution). To predict the light fluence rate distribution, a kernel-based model was used to calculate light fluence rate using either (a) the mean optical properties (assuming homogeneous optical properties) for all patients or (b) using distributions of optical properties measured for latter patients. Standard deviations observed between the calculations and measurements were 56% and 34% for (a) and (b), respectively. The study shows that due to heterogeneity of optical properties significant variations of light fluence rate were observed both intra and inter prostates. However, if one assume a mean optical properties (MUa = 0.3 cm-1, MUs' = 14 cm-1), one can predict the light fluence rate to within a maximum error 200% for 80% of the cases and a mean error of 105%. To improve the prediction of light fluence rate further would require determination of distribution of optical properties. PMID- 26113759 TI - Modeling light fluence rate distribution in optically heterogeneous prostate photodynamic therapy using a kernel method. AB - To accurately calculate light fluence rate distribution for light dosimetry in prostate photodynamic therapy (PDT), heterogeneity of optical properties has to be taken into account. Previous study has shown that a finite-element method (FEM) can be an efficient tool to deal with the optical heterogeneity. However, the calculation speed of the FEM is not suitable for real time treatment planning. In this paper, two kernel models are developed. Because the kernels are based on analytic solutions of the diffusion equation, calculations are much faster. We derived our extensions of kernel from homogeneous medium to heterogeneous medium assuming spherically symmetrical heterogeneity of optical properties. The kernel models are first developed for a point source and then extended for a linear source, which is considered a summation of point sources uniformly spaced along a line. The kernel models are compared with the FEM calculation. In application of the two kernel models to a heterogeneous prostate PDT case, both kernel models give improved light fluence rate results compared with those derived assuming homogeneous medium. In addition, kernel model 2 predicts reasonable light fluence rates and is deemed suitable for treatment planning. PMID- 26113760 TI - Two-dimensional/three dimensional Hybrid Interstitial Diffuse Optical Tomography of Human Prostate during Photodynamic Therapy: Phantom and Clinical Results. AB - We have developed an efficient Levenberg-Marquardt iterative algorithm utilizing a three-dimensional field measurements coupled to a two-dimensional optical property reconstruction scheme. This technique takes advantage of accurate estimation of light distribution in 3D forward calculation and reduced problem size and less computation time in 2D inversion. Important advances in terms of improving algorithm efficiency and accuracy include use of an iterative general minimum residual method (GMRES) for computing the field solutions, application of the dual mesh scheme and adjoint method for Jacobian construction, and implementation of normalization scheme to reduce the absorption-scattering cross talk. The synthetic measurement data were calculated for a cubic phantom containing a single absorption anomaly and a single scattering anomaly. The model had a background of MUa=0.03mm-1 and MUs'=1.4mm-1. The absorption and scattering anomalies have the MUa = 0.06 mm-1 and MUs' = 2.0 mm-1. Five sources and 72 detectors are used per slice. A typical human prostate is composed of 6 slices. The reconstruction images successfully recover the both anomalies with good localization. Experiment data from tissue simulated phantom are also presented. The clinical DOT imaging was performed before photodynamic therapy based on the protocol. The preliminary results showed the reconstructed prostate MUa varied between 0.025 and 0.07 mm-1 and MUs' ranged from 1.1 to 2 mm-1. These results show that this new 2D-3D hybrid algorithm consistently outperform the 2D-2D or 3D 3D counterparts. PMID- 26113761 TI - Integrated light dosimetry system for prostate photodynamic therapy. AB - A light dosimetry system is developed for prostate PDT, which integrates four main components: a light fluence rate calculation engine, an optimization tool for treatment planning, a light delivery system, and an in vivo light fluence rate measurement system. Three-dimensional light fluence rate distribution in a prostate is calculated using a kernel algorithm, which takes into account of heterogeneous optical properties. A Cimmino optimization algorithm is used to optimize the parameters of the cylindrical diffusing fibers (CDFs) to generate uniform PDT dose (or light fluence rate under uniform drug distribution) to cover the heterogeneous prostate. The light delivery system is composed of a 12-channel beamsplitter and the intensities of each channel (i.e., source) are controlled individually by programmable motorized attenuators. Our tests show that the light fluence rate calculation is fast and the accuracy is close to that of a finite element method model, and the approach that uses the treatment CDFs to determine optical properties, improves the accuracy of light fluence rate prediction. The light delivery system allows real time control of the light source intensities for both PDT dosimetry and PDT light delivery. Integrating the fast light fluence rate calculation, optimization, instant source intensity adjustment, and in vivo light fluence rate measurement, the dosimetry system is suitable for prostate PDT. PMID- 26113762 TI - Interstitial diffuse optical tomography using an adjoint model with linear sources. AB - An improved interstitial diffuse optical tomography (iDOT) system has been developed to characterize the optical properties of prostate gland during the photodynamic therapy (PDT). Multiple cylindrical light diffusers with different lengths (instead of point sources used in an earlier version) and isotropic detectors are introduced interstitially in the prostate gland in-vivo. During the data acquisition, linear sources and detectors are stepping into prostate sequentially controlled by a motorized system. A computerized multi-channel attenuator system is developed to automatically control the power strength of each linear source and on times to speed up data acquisition. Three dimensional optical properties are obtained by solving the inverse problem of steady-state diffusion equation based on an adjoint model with Moore-Penrose scheme. The convergence, accuracy and the speed of the algorithms are tested in mathematical phantoms and in prostate simulating phantoms with known optical properties. For comparison, the optical properties of tissue simulating phantoms are also reconstructed using iDOT with multiple isotropic point sources. Data acquisition time in iDOT using linear sources is at least 10 times faster than using the point sources with the total data acquisition time to be less than 1 minutes. Reconstruction results showed both algorithms can successfully recover the optical properties. Reconstruction using linear sources/detectors acquisition mode is 20 times faster than the point sources/detectors method (30 minutes vs. 4 hours on a 3.4 GHz Pentium PC with 4 GB memory). We have demonstrated that linear source/detector acquisition mode out-performs the point-source mode, and is more practical to be implemented in the clinical settings. PMID- 26113763 TI - Experimental Strategy to Discover Microbes with Gluten-degrading Enzyme Activities. AB - Gluten proteins contained in the cereals barley, rye and wheat cause an inflammatory disorder called celiac disease in genetically predisposed individuals. Certain immunogenic gluten domains are resistant to degradation by mammalian digestive enzymes. Enzymes with the ability to target such domains are potentially of clinical use. Of particular interest are gluten-degrading enzymes that would be naturally present in the human body, e.g. associated with resident microbial species. This manuscript describes a selective gluten agar approach and four enzyme activity assays, including a gliadin zymogram assay, designed for the selection and discovery of novel gluten-degrading microorganisms from human biological samples. Resident and harmless bacteria and/or their derived enzymes could potentially find novel applications in the treatment of celiac disease, in the form of a probiotic agent or as a dietary enzyme supplement. PMID- 26113764 TI - An information-theoretic approach to designing the plane spacing for multifocal plane microscopy. AB - Multifocal plane microscopy (MUM) is a 3D imaging modality which enables the localization and tracking of single molecules at high spatial and temporal resolution by simultaneously imaging distinct focal planes within the sample. MUM overcomes the depth discrimination problem of conventional microscopy and allows high accuracy localization of a single molecule in 3D along the z-axis. An important question in the design of MUM experiments concerns the appropriate number of focal planes and their spacings to achieve the best possible 3D localization accuracy along the z-axis. Ideally, it is desired to obtain a 3D localization accuracy that is uniform over a large depth and has small numerical values, which guarantee that the single molecule is continuously detectable. Here, we address this concern by developing a plane spacing design strategy based on the Fisher information. In particular, we analyze the Fisher information matrix for the 3D localization problem along the z-axis and propose spacing scenarios termed the strong coupling and the weak coupling spacings, which provide appropriate 3D localization accuracies. Using these spacing scenarios, we investigate the detectability of the single molecule along the z-axis and study the effect of changing the number of focal planes on the 3D localization accuracy. We further review a software module we recently introduced, the MUMDesignTool, that helps to design the plane spacings for a MUM setup. PMID- 26113765 TI - Monte Carlo simulation of inverse geometry x-ray fluoroscopy using a modified MC GPU framework. AB - Scanning-Beam Digital X-ray (SBDX) is a technology for low-dose fluoroscopy that employs inverse geometry x-ray beam scanning. To assist with rapid modeling of inverse geometry x-ray systems, we have developed a Monte Carlo (MC) simulation tool based on the MC-GPU framework. MC-GPU version 1.3 was modified to implement a 2D array of focal spot positions on a plane, with individually adjustable x-ray outputs, each producing a narrow x-ray beam directed toward a stationary photon counting detector array. Geometric accuracy and blurring behavior in tomosynthesis reconstructions were evaluated from simulated images of a 3D arrangement of spheres. The artifact spread function from simulation agreed with experiment to within 1.6% (rRMSD). Detected x-ray scatter fraction was simulated for two SBDX detector geometries and compared to experiments. For the current SBDX prototype (10.6 cm wide by 5.3 cm tall detector), x-ray scatter fraction measured 2.8-6.4% (18.6-31.5 cm acrylic, 100 kV), versus 2.1-4.5% in MC simulation. Experimental trends in scatter versus detector size and phantom thickness were observed in simulation. For dose evaluation, an anthropomorphic phantom was imaged using regular and regional adaptive exposure (RAE) scanning. The reduction in kerma-area-product resulting from RAE scanning was 45% in radiochromic film measurements, versus 46% in simulation. The integral kerma calculated from TLD measurement points within the phantom was 57% lower when using RAE, versus 61% lower in simulation. This MC tool may be used to estimate tomographic blur, detected scatter, and dose distributions when developing inverse geometry x-ray systems. PMID- 26113766 TI - Comparison of Specificity and Sensitivity of AMH and FSH in Diagnosis of Premature Ovarian Failure. AB - INTRODUCTION: Anti-Mullerian hormone represents the primitive follicular number and ovarian age. Low level of AMH is in relation to early menopausal state and decreased ovarian reserve. AMH level changes occur prior to FSH level in representing ovarian failure. The aim of this study is to compare sensitivity and specificity of AMH with FSH in diagnosis of POF. MATERIAL AND METHODS: This descriptive study is done on 96 patients referred to Dr. Rasekh Clinic. Serum level of AMH and FSH was measured at Day 3 (3rd day of menstrual cycle) and data were analyzed through SPSS 21 software. RESULTS: Results of AMH and FSH serum level indicate that AMH has more sensitivity (80% versus 28.57%) and almost equal specificity (78.89% versus 78.65%) compared with FSH. Also negative predictive value of AMH (98.61%) and FSH (87.5%) is different. But positive predictive value is the same (17.39%). Diagnostic accuracy of AMH is more than FSH and has significant differences. CONCLUSION: According to the results of this study, AMH serum level is more sensitive than FSH serum level. Also AMH has more negative predictive value. Besides, this hormone can be measured at any time of menstrual cycle, against FSH. AMH seems to be more useful in early diagnosis of POF. PMID- 26113767 TI - Infrared, Raman, and Ultraviolet Absorption Spectra and Theoretical Calculations and Structure of 2,3,5,6-Tetrafluoropyridine in its Ground and Excited Electronic States. AB - Infrared and Raman spectra of 2,3,5,6-tetrafluoropyridine (TFPy) were recorded and vibrational frequencies were assigned for its S0 electronic ground states. Ab initio and density functional theory (DFT) calculations were used to complement the experimental work. The lowest electronic excited state of this molecule was investigated with ultraviolet absorption spectroscopy and theoretical CASSCF calculations. The band origin was found to be at 35,704.6 cm-1 in the ultraviolet absorption spectrum. A slightly puckered structure with a barrier to planarity of 30 cm-1 was predicted by CASSCF calculations for the S1(pi,pi*) state. Lower frequencies for the out-of-plane ring bending vibrations for the electronic excited state result from the weaker bonding within the pyridine ring. PMID- 26113768 TI - Adenosine Receptors: The Contributions by John W. Daly. AB - John Daly played an important role in defining adenosine receptors as an important target for drug discovery. His systematic work characterized the effects of adenosine analogues on cyclic AMP in the brain that were antagonized by methylxanthines. He also played a decisive role in establishing these receptors as bona fide biochemical entities and contributed to the discovery of receptor heterogeneity. This brief review will cover some of his important early discoveries in the pharmacology and medicinal chemistry of adenosine receptors. PMID- 26113769 TI - Life-Span Differences in the Uses and Gratifications of Tablets: Implications for Older Adults. AB - This study extends Uses and Gratifications theory by examining the uses and gratifications of a new technological device, the tablet computer, and investigating the differential uses and gratifications of tablet computers across the life-span. First, we utilized a six-week tablet training intervention to adapt and extend existing measures to the tablet as a technological device. Next, we used paper-based and online surveys (N=847), we confirmed four main uses of tablets: 1) Information Seeking, 2) Relationship Maintenance, 3) Style, 4) Amusement and Killing time, and added one additional use category 5) Organization. We discovered differences among the five main uses of tablets across the life-span, with older adults using tablets the least overall. Builders, Boomers, GenX and GenY all reported the highest means for information seeking. Finally, we used a structural equation model to examine how uses and gratifications predicts hours of tablet use. The study provides limitations and suggestions for future research and marketers. In particular, this study offers insight to the relevancy of theory as it applies to particular information and communication technologies and consideration of how different periods in the life span affect tablet motivations. PMID- 26113770 TI - Making Full Use of the Longitudinal Design of the Current Population Survey: Methods for Linking Records Across 16 Months. AB - Data from the Current Population Survey (CPS) are rarely analyzed in a way that takes advantage of the CPS's longitudinal design. This is mainly because of the technical difficulties associated with linking CPS files across months. In this paper, we describe the method we are using to create unique identifiers for all CPS person and household records from 1989 onward. These identifiers-available along with CPS basic and supplemental data as part of the on-line Integrated Public Use Microdata Series (IPUMS)-make it dramatically easier to use CPS data for longitudinal research across any number of substantive domains. To facilitate the use of these new longitudinal IPUMS-CPS data, we also outline seven different ways that researchers may choose to link CPS person records across months, and we describe the sample sizes and sample retention rates associated with these seven designs. Finally, we discuss a number of unique methodological challenges that researchers will confront when analyzing data from linked CPS files. PMID- 26113771 TI - Check-All-That-Apply (CATA), Sorting, and Polarized Sensory Positioning (PSP) with Astringent Stimuli. AB - Multiple rapid sensory profiling techniques have been developed as more efficient alternatives to traditional sensory descriptive analysis. Here, we compare the results of three rapid sensory profiling techniques - check-all-that-apply (CATA), sorting, and polarized sensory positioning (PSP) - using a diverse range of astringent stimuli. These rapid methods differ in their theoretical basis, implementation, and data analyses, and the relative advantages and limitations are largely unexplored. Additionally, we were interested in using these methods to compare varied astringent stimuli, as these compounds are difficult to characterize using traditional descriptive analysis due to high fatigue and potential carry-over. In the CATA experiment, subjects (n=41) were asked to rate the overall intensity of each stimulus as well as to endorse any relevant terms (from a list of 13) which characterized the sample. In the sorting experiment, subjects (n=30) assigned intensity-matched stimuli into groups 1-on-1 with the experimenter. In the PSP experiment, (n=41) subjects first sampled and took notes on three blind references ('poles') before rating each stimulus for its similarity to each of the 3 poles. Two-dimensional perceptual maps from correspondence analysis (CATA), multidimensional scaling (sorting), and multiple factor analysis (PSP) were remarkably similar, with normalized RV coefficients indicating significantly similar plots, regardless of method. Agglomerative hierarchical clustering of all data sets using Ward's minimum variance as the linkage criteria showed the clusters of astringent stimuli were approximately based on the respective class of astringent agent. Based on the descriptive CATA data, it appears these differences may be due to the presence of side tastes such as bitterness and sourness, rather than astringent sub-qualities per se. Although all three methods are considered 'rapid,' our prior experience with sorting suggests it is best performed 1:1 with the experimenter, which makes sorting relatively less efficient than CATA or PSP. Based on the evaluation criteria used here, the choice of method depends on the time constraints of the experimenter and the need for descriptive terms to understand the sensory space of the samples. Accordingly, we recommend a mixed approach that combines CATA with a subsequent PSP task so that the product space can be well characterized before choosing poles for PSP. PMID- 26113772 TI - Working with communities to improve their eye health. PMID- 26113773 TI - How to empower communities to take action on improving eye health. PMID- 26113775 TI - Diseases at the back of the eye. PMID- 26113774 TI - Techniques to encourage people to take better care of their eye health. PMID- 26113776 TI - Improving quality by improving safety. PMID- 26113777 TI - Increasing sustainable cataract services in sub-Saharan Africa: an experimental initiative. PMID- 26113778 TI - The uncorrected refractive error challenge. PMID- 26113780 TI - Ensuring proper and safe use of the cryotherapy machine. PMID- 26113779 TI - Giving a health talk. PMID- 26113781 TI - Using a case study approach to document 'preferred practices' in mass drug administration for trachoma. PMID- 26113782 TI - PPP1R12A Copy Number Is Associated with Clinical Outcomes of Stage III CRC Receiving Oxaliplatin-Based Chemotherapy. AB - AIM: To investigate the correlation between PPP1R12A gene copy number and clinical outcomes of oxaliplatin-based regimen in stage III colorectal cancer (CRC). METHODS: A total of 139 paraffin-embedded tissue samples of stage III CRC patients who received oxaliplatin-based treatment after radical surgery were recruited. Genomic DNA was extracted and purified from paraffin-embedded sections. Quantitative PCR methods were used to detect the relative copy number (RCN) of PPP1R12A. RESULTS: Statistical analysis demonstrated that low PPP1R12A RCN was associated with poor RFS (HR = 2.186, 95% CI: 1.293-3.696; P = 0.003) and OS (HR = 2.782, 95% CI: 1.531-5.052; P < 0.001). Additionally, when patients were stratified according to subgroups of stage III and tumor location, poor RFS and OS were also observed in the low PPP1R12A RCN group with significance (RFS: IIIB HR = 2.870, P < 0.001; colon HR = 1.910, P = 0.037; OS: IIIB HR = 3.527, P < 0.001; IIIC HR = 2.662, P = 0.049; rectum HR = 4.229, P = 0.002). CONCLUSION: Our findings suggest the copy number of PPP1R12A can independently predict recurrence and overall survival of stage III colorectal cancer patients receiving oxaliplatin-based chemotherapy. PMID- 26113784 TI - Erratum: Inpatient Stroke Rehabilitation Outcomes in Korea Derived from the Korean Brain Rehabilitation Centers' Online Database System for the Years 2007 to 2011. AB - [This corrects the article on p. 644 in vol. 30, PMID: 25931798.]. PMID- 26113783 TI - Serum Levels of IL-1 beta , IL-6, TGF- beta , and MMP-9 in Patients Undergoing Carotid Artery Stenting and Regulation of MMP-9 in a New In Vitro Model of THP-1 Cells Activated by Stenting. AB - Inflammation plays an important role in the pathophysiological process after carotid artery stenting (CAS). Monocyte is a significant source of inflammatory cytokines in vascular remodeling. Telmisartan could reduce inflammation. In our study, we first found that, after CAS, the serum IL-1beta, IL-6, TGF-beta, and MMP-9 levels were significantly increased, but only MMP-9 level was elevated no less than 3 months. Second, we established a new in vitro model, where THP-1 monocytes were treated with the supernatants of human umbilical vein endothelial cells (HUVECs) that were scratched by pipette tips, which mimics monocytes activated by mechanical injury of stenting. The treatment enhanced THP-1 cell adhesion, migration and invasion ability, and the phosphorylation of ERK1/2 and Elk-1 and MMP-9 expression were significantly increased. THP-1 cells pretreated with PD98095 (ERK1/2 inhibitor) attenuated the phosphorylation of ERK1/2 and Elk 1 and upregulation of MMP-9, while pretreatment with telmisartan merely decreased the phosphorylation of Elk-1 and MMP-9 expression. These results suggested that IL-1beta, IL-6, TGF-beta, and MMP-9 participate in the pathophysiological process after CAS. Our new in vitro model mimics monocytes activated by stenting. MMP-9 expression could be regulated through ERK1/2/Elk-1 pathway, and the protective effects of telmisartan after stenting are partly attributed to its MMP-9 inhibition effects via suppression of Elk-1. PMID- 26113785 TI - Reducing Obesity Among People With Disabilities. AB - Achieving healthy weight for people with disabilities in the United States is a challenge. Obesity rates for adults and children with disabilities are significantly higher than for those without disabilities, with differences remaining even when controlling for other factors. Reasons for this disparity include lack of healthy food options for many people with disabilities living in restrictive environments, difficulty with chewing or swallowing food, medication use contributing to changes in appetite, physical limitations that can reduce a person's ability to exercise, constant pain, energy imbalance, lack of accessible environments in which to exercise or fully participate in other activities, and resource scarcity among many segments of the disability population. In order for there to be a coordinated national effort to address this issue, a framework needs to be developed from which research, policy, and practice can emerge. This paper reviews existing literature and presents a conceptual model that can be used to inform such a framework, provides examples of promising practices, and discusses challenges and opportunities moving forward. PMID- 26113786 TI - Non-locking Tetrahedral Finite Element for Surgical Simulation. AB - To obtain a very fast solution for finite element models used in surgical simulations low order elements such as the linear tetrahedron or the linear under integrated hexahedron must be used. Automatic hexahedral mesh generation for complex geometries remains a challenging problem, and therefore tetrahedral or mixed meshes are often necessary. Unfortunately the standard formulation of the linear tetrahedral element exhibits volumetric locking in case of almost incompressible materials. In this paper we extend the average nodal pressure tetrahedral element proposed by Bonet and Burton for a better handling of multiple material interfaces. The new formulation can handle multiple materials in a uniform way, with better accuracy, while requiring only a small additional computation effort. We discuss some implementation issues and show how easy an existing TLED (Total Lagrangian Explicit Dynamics) algorithm can be modified in order to support the new element formulation. The performance evaluation of the new element shows the clear improvement in reaction forces and displacements predictions compared to the average nodal pressure element in case of models consisting of multiple materials. PMID- 26113787 TI - Internet-based adherence interventions for treatment of chronic disorders in adolescents. AB - BACKGROUND: Treatment adherence is a ubiquitous challenge in medicine, particularly in the adolescent population with chronic disorders. Web-based adherence interventions may be particularly useful in adolescents, due to their familiarity with and frequent use of the Internet. OBJECTIVE: To review web-based interventions used to improve adherence to medication in adolescent patients with chronic disorders. METHODS: A PubMed search was performed for full-text, English, clinical trials in adolescents using keywords "adherence" or "compliance", "Internet" or "web", and "treatment" from inception until November 2014. Articles were selected if they involved using the Internet to provide support to adolescents to help improve their adherence to treatment, excluding those focused on solely providing medical services through the Internet and articles focusing on preventative care, rather than treatment of an illness. RESULTS: Fourteen studies were found concentrating on chronic adolescent disorders. Interventions included online surveys, physician chat lines, monitoring programs, and interactive programs. All interventions experienced either greater improvement in adherence or another disease control measure or no statistically significant difference compared with the control group (in-clinic visits). LIMITATIONS: Few clinical trials studying web-based interventions to improve adherence in adolescents were found. Due to not having one standard outcome measured in all of the studies, it was also difficult comparing the effectiveness of the interventions. CONCLUSION: Web-based interventions play a role in improving adherence in adolescents with chronic disorders by being more time saving and cost effective compared with in-clinic visits. Further research focusing on adherence interventions using the Internet is necessary to determine the ideal ways of utilizing the Internet to improve adherence in adolescents with chronic disorders. PMID- 26113788 TI - Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases. AB - The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses. In this review, we describe the endogenous inflammatory stimulators and signaling pathways in the brain. In particular, our group has focused on the JAK-STAT pathway, identifying anti-inflammatory targets and testing the effects of various anti-inflammatory drugs. This work has shown that the JAK-STAT pathway and its downstream are negatively regulated by phosphatases (SHP2 and MKP-1), inhibitory proteins (SOCS1 and SOCS3) and a nuclear receptor (LXR). These negative regulators are controlled at various levels (e.g. transcriptional, post-transcriptional and post-translational). Future study of these proteins could facilitate the manipulation of the inflammatory response, which plays ubiquitous, diverse and ambivalent roles under physiological and pathological conditions. PMID- 26113791 TI - Aberrant Thalamocortical Synchrony Associated with Behavioral Manifestations in Git1 (-/-) Mice. AB - Cross-talk between the thalamus and cortex has been implicated in attention but its pathogenic role in attention-deficit/hyperactivity disorder (ADHD) remains unknown. Here, I demonstrate that Git1 (-/-) mice, previously proposed as an animal model for ADHD, show abnormal theta oscillation in the thalamus. Multi electrode recordings revealed that Git1 (-/-) mice have hyper-synchrony of neural activities between the thalamus and cortex. The abnormal thalamic oscillation and thalamocortical synchrony in Git1 (-/-) mice were markedly reduced by amphetamine. In addition, ethosuximide ameliorates abnormal thalamic oscillation and ADHD-like hyperactivity shown in Git1 (-/-) mice. My study suggests critical roles of GIT1 and thalamocortical neural circuitry in ADHD. PMID- 26113790 TI - miR-Let7A Modulates Autophagy Induction in LPS-Activated Microglia. AB - Microglia regulate the secretion of various immunomediators in central nervous system diseases. Microglial autophagy is the crucial process for cell's survival and cytokine productions. Recent studies have reported that several microRNAs are involved in the autophagy system. miR-Let7A is such a microRNA that plays a role in various inflammation responses, and is magnified as a key modulator particularly in the autophagy system. In present study, we investigated whether miR-Let7A is involved in autophagy in activating microglia. Overexpression of miR Let7A in LPS-stimulated BV2 microglial cells promoted the induction of the autophagy related factors such as LC3II, Beclin1, and ATG3. Our results suggest a potential role of miR-Let7A in the autophagy process of microglia during CNS inflammation. PMID- 26113789 TI - Mitochondrial Dysfunction in Parkinson's Disease. AB - Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) with motor and nonmotor symptoms. Defective mitochondrial function and increased oxidative stress (OS) have been demonstrated as having an important role in PD pathogenesis, although the underlying mechanism is not clear. The etiopathogenesis of sporadic PD is complex with variable contributions of environmental factors and genetic susceptibility. Both these factors influence various mitochondrial aspects, including their life cycle, bioenergetic capacity, quality control, dynamic changes of morphology and connectivity (fusion, fission), subcellular distribution (transport), and the regulation of cell death pathways. Mitochondrial dysfunction has mainly been reported in various non-dopaminergic cells and tissue samples from human patients as well as transgenic mouse and fruit fly models of PD. Thus, the mitochondria represent a highly promising target for the development of PD biomarkers. However, the limited amount of dopaminergic neurons prevented investigation of their detailed study. For the first time, we established human telomerase reverse transcriptase (hTERT) immortalized wild type, idiopathic and Parkin deficient mesenchymal stromal cells (MSCs) isolated from the adipose tissues of PD patients, which could be used as a good cellular model to evaluate mitochondrial dysfunction for the better understanding of PD pathology and for the development of early diagnostic markers and effective therapy targets of PD. In this review, we examine evidence for the roles of mitochondrial dysfunction and increased OS in the neuronal loss that leads to PD and discuss how this knowledge further improve the treatment for patients with PD. PMID- 26113792 TI - Growth Differentiation Factor 15 Expression in Astrocytes After Excitotoxic Lesion in the Mouse Hippocampus. AB - Growth differentiation factor 15 (GDF15) is, a member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Although GDF15 is well established as a potent neurotrophic factor for neurons, little is known about its role in glial cells under neuropathological conditions. We monitored GDF15 expression in astrocyte activation after a kainic acid (KA)-induced neurodegeneration in the ICR mice hippocampus. In control, GDF15 immunoreactivity (IR) was evident in the neuronal layer of the hippocampus; however, GDF15 expression had increased in activated astrocytes throughout the hippocampal region at day 3 after the treatment with KA. LPS treatment in astrocytes dramatically increased GDF15 expression in primary astrocytes. In addition, LPS treatment resulted in the decrease of the IkappaB-alpha degradation and increase of the phosphorylation level of RelA/p65. These results indicate that GDF15 has a potential link to NF-kappaB activation, making GDF15 a valuable target for modulating inflammatory conditions. PMID- 26113793 TI - Curcumin Ameliorates Functional and Structural Abnormalities in Cisplatin-induced Neuropathy. AB - Peripheral neuropathy is one of the major side effects of cisplatin; however, effective treatments are lacking. Curcumin is a polyphenol found in the root of Curcuma longa and has been shown neuroprotective against several neurological diseases. Nevertheless, its effects on cisplatin neuropathy remain unclear. This study aimed to clarify this issue by inducing neuropathy in the rats with intraperitoneal injection of cisplatin 2 mg/kg twice a week for 5 consecutive weeks. Curcumin 200 mg/kg/day was given by gavage to a group of cisplatin-treated rats during these five weeks. The results showed that cisplatin induced thermal hypoalgesia in the 5(th) week which could be prevented by curcumin. In the 5(th) and 8(th) weeks, sciatic motor nerve conduction velocity was reduced in the cisplatin compared with the control groups. Curcumin significantly attenuated this deficit. Morphometric analysis of L4 dorsal root ganglia from the cisplatin group revealed nuclear and nucleolar atrophy including loss of neurons in the 8(th) week. These alterations were significantly blocked by curcumin. Moreover, curcumin also ameliorated the reduced myelin thickness in the sciatic nerve of cisplatin-treated rats. Taken together, our findings suggest the favorable effects of curcumin on both functional and structural abnormalities in cisplatin neuropathy. Future studies are needed to clarify the exact underlying mechanisms. PMID- 26113794 TI - The Effect of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Collagenase-Induced Intracerebral Hemorrhage Rat Model. AB - Intracerebral hemorrhage (ICH) is one of the devastating types of stroke. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have potential benefits in recovery from brain damage following ICH. This study aimed to identify the beneficial effects of hUCB-MSCs and investigate whether they have anti-inflammatory effects on the ICH brain via neurotrophic factors or cytokines. hUCB-MSCs were transplanted into a collagenase-induced ICH rat model. At 2, 9, 16, and 30 days after ICH, rotarod and limb placement tests were performed to measure behavioral outcomes. ICH rats were sacrificed to evaluate the volume of lesion using H&E staining. Immunostaining was performed to investigate neurogenesis, angiogenesis, and anti-apoptosis at 4 weeks after transplantation. Inflammatory factors (TNF-alpha, COX-2, microglia, and neutrophils) were analyzed by immunofluorescence staining, RT-PCR, and Western blot at 3 days after transplantation. hUCB-MSCs were associated with neurological benefits and reduction in lesion volume. The hUCB-MSCs-treated group tended to reveal high levels of neurogenesis, angiogenesis, and anti-apoptosis (significant for angiogenesis). The expression levels of inflammatory factors tended to be reduced in the hUCB-MSCs-treated group compared with the controls. Our study suggests that hUCB-MSCs may improve neurological outcomes and modulate inflammation associated immune cells and cytokines in ICH-induced inflammatory responses. PMID- 26113796 TI - Balo's Concentric Sclerosis Mimicking Cerebral Tuberculoma. AB - Balo's concentric sclerosis (BCS) is considered a rare variant of multiple sclerosis, which often mimics an intracranial neoplasm or abscess. We report the case of a 21-year-old woman presenting with BCS while undergoing treatment for pulmonary tuberculosis. Initial brain magnetic resonance imaging (MRI) findings were similar to those for cerebral tuberculoma, multiple metastases, or abscesses. However, the pathognomonic concentric sclerosis characteristic of BCS was seen on MRI. The antemortem confirmatory diagnosis of BCS was made by follow up MRI and a brain biopsy. It is suggested that BCS should be included in the differential diagnosis of cerebral tuberculoma, especially in developing countries with a high prevalence of tuberculosis. PMID- 26113795 TI - Chronic Antidepressant Treatment in Normal Mice Induces Anxiety and Impairs Stress-coping Ability. AB - Antidepressants are clinically used for patients with major depression. Antidepressant treatments in certain groups of patients are effective for relieving depression as well as anxiety disorder. However, it is not clearly known whether the use of current antidepressants in healthy persons is beneficial for upcoming depression- and anxiety-inducing life events. To address this question, normal mice were intraperitoneally administered with imipramine or fluoxetine for more than 2 weeks, and behaviors related to anxiety and depression were evaluated. Mice treated with imipramine or fluoxetine for more than 14 days exhibited significantly decreased immobility time in the forced swim test and tail suspension test, but these mice exhibited enhanced anxiety in several behavioral tests. Furthermore, chronic antidepressant treatments followed by sub threshold level of stress in normal mice profoundly aggravated antidepressant induced anxiety-like behaviors without further affecting depression-related behaviors. Chronic antidepressant treatments followed by sub-threshold level of stress produced swollen vesicles and ulcerations on the lips as well as a watery and inflammatory nose. Mice given chronic antidepressant treatments displayed intestinal abnormalities evidenced by a highly enlarged and inflamed small intestine full of defecation materials. These results suggest that chronic antidepressant treatment in normal mice provokes anxiety-like behaviors and impairs their stress-coping ability. PMID- 26113797 TI - Letter to the Editor: Hypothesis: Somatic Mosaicism and Parkinson Disease. PMID- 26113799 TI - Retention of the Cluster Core Structure during Ligand Exchange Reactions of Carboxylato-Substituted Metal Oxo Clusters. AB - The exchange of the carboxylato ligands of Zr4O2(methacrylato)12 in reactions with carboxylic acids proceeds with retention of the composition and structure of the cluster core. This was concluded from exchange/re-exchange experiments and from comparison of the IR bands of the cluster core of the original and ligand exchanged clusters. The IR bands were assigned on the basis of DFT calculations. Scrambling reactions between two Zr4O2(OOCR)12 clusters with different carboxylato ligands are a new way to prepare mixed-ligand oxo clusters. PMID- 26113800 TI - Rare earth element geochemistry of outcrop and core samples from the Marcellus Shale. AB - In this work, the geochemistry of the rare earth elements (REE) was studied in eleven outcrop samples and six, depth-interval samples of a core from the Marcellus Shale. The REE are classically applied analytes for investigating depositional environments and inferring geochemical processes, making them of interest as potential, naturally occurring indicators of fluid sources as well as indicators of geochemical processes in solid waste disposal. However, little is known of the REE occurrence in the Marcellus Shale or its produced waters, and this study represents one of the first, thorough characterizations of the REE in the Marcellus Shale. In these samples, the abundance of REE and the fractionation of REE profiles were correlated with different mineral components of the shale. Namely, samples with a larger clay component were inferred to have higher absolute concentrations of REE but have less distinctive patterns. Conversely, samples with larger carbonate fractions exhibited a greater degree of fractionation, albeit with lower total abundance. Further study is necessary to determine release mechanisms, as well as REE fate-and-transport, however these results have implications for future brine and solid waste management applications. PMID- 26113801 TI - Effect of Matrine on HPAC cell migration by down-regulating the expression of MT1 MMP via Wnt signaling. AB - AIM: This study sought to explore the exact mechanism of Matrine inhibited migration and invasion of human pancreatic cancer cells. METHODS: HPAC or Capan-1 cells were cultured in completed RPMI-1640 medium, contained with 50 MUg/ml Matrine or 0.05 MUg/ml docetaxel, respectively. Cell viability was evaluated by spectrophotometric analysis using MTT assay. Wound healing assay and transwell approach were used to detect the effects of Matrine on HPAC cell migration and invasion. Western Blot and RT-PCR were performed to detect the expressions of MT1 MMP, Wnt and beta-Catenin. CHIP assay was used to detect whether the MT1-MMP transcription activity correlated with Wnt signaling pathway. RESULTS: MTT results indicated that cell proliferration was inhibited by Matrine at a range of concentrations, especially at high dose. We further found that Matrine treatment significantly induced cell migration and invasion decreased. Interestingly, the expression of MT1-MMP decreased evidently upon Matrine treatment, paralleled with the expressions of Wnt and beta-Catenin detected by Western Blot and RT-PCR assay. Further analysis of MT1-MMP transcription activity revealed that Matrine reduced the expression of MT1-MMP mediated by Wnt signaling pathway. CONCLUSION: Matrine play a vital role in inhibiting HPAC cellular migration and invasion through down-regulating the expression of MT1-MMP via Wnt signaling pathway. PMID- 26113802 TI - Retraction: Hypericin-mediated photodynamic therapy induces apoptosis of myoloma SP2/0 cells depended on caspase activity in vitro. PMID- 26113803 TI - Nur77 deficiency leads to systemic inflammation in elderly mice. AB - BACKGROUND: Nur77, an orphan member of the nuclear receptor superfamily, has been implicated in the regulation of inflammation. However, the in vivo function of Nur77 remains largely unexplored. In the current study, we investigated the role of Nur77 in inflammation and immunity in mice. FINDINGS: We found that elderly 8 month-old Nur77-deficient mice (Nur77(-/-)) developed systemic inflammation. Compared to wild-type (WT) mice (Nur77(+/+)), Nur77(-/-) mice showed splenomegaly, severe infiltration of inflammatory cells in several organs including liver, lung, spleen and kidney, increased hyperplasia of fibrous tissue in the lung and enlargement of kidney glomeruli. Additionally, Nur77(-/-) mice had increased production of pro-inflammatory cytokines and immunoglobulin, and elicited pro-inflammatory M1-like polarization in macrophages as revealed by increased expression of CXCL11 and INDO, and decreased expression of MRC1. CONCLUSIONS: These in vivo observations provide evidence for a pivotal role for Nur77 in the regulation of systemic inflammation and emphasize the pathogenic significance of Nur77 in vivo. PMID- 26113804 TI - Retrospective cohort analysis comparing the incidence of deep vein thromboses between peripherally-inserted and long-term skin tunneled venous catheters in hemato-oncology patients. AB - BACKGROUND: The introduction of central venous catheters has advanced medical care, particularly in hemato-oncology. However these can be associated with an increased thrombotic risk. Previous studies have compared the rate of thrombotic events between peripherally- inserted (PICCs) and long term skin tunneled catheters (LTSTCs) noting fewer complications associated with the latter, though this has rarely translated into clinical practice. The objectives of our study was to compare the cumulative incidence of thrombotic events between peripherally inserted and long term skin tunneled venous catheters. PATIENTS/METHODS: We performed a retrospective, single center cohort analysis of patients with hematological malignancies who had either a PICC or LTSTC line inserted between January 2010 through January 2013. Cumulative incidences of thrombotic events were compared between the two groups, and post-thrombotic complications were also examined. RESULTS: 346 patients had a PICC inserted with cumulative incidence of symptomatic thrombosis of 5.8%, while 237 patients had a LTSTC inserted with a cumulative incidence of 1.7% (p = 0.003). Post-thrombotic complication rates, particularly infection, were higher in the PICC group compared to the LTSTC group (p = 0.597). CONCLUSIONS: Our study showed that the incidence of thrombotic events in hemato-oncology patients was significantly lower in those who had a LTSTC compared to PICC line. As the use of central venous lines increases in hemato-oncology patient care, a randomized trial comparing PICCs and LTSTCs is necessary to address which venous access is most appropriate in this cohort of patients, with minimal risk of morbidity and mortality. PMID- 26113806 TI - "Jeder Mensch hat einen Name": Legal and Ethical Dimensions of Human Experiments under National Socialism. AB - This paper considers whether it is right to identify by name victims of experiments abused either for psychiatric research, or for other types of experimentation in psychiatric hospitals and institutions. Similar questions arise as to whether it is possible to identify any of the persons for whom brains and other body parts were held for medical research and teaching. PMID- 26113805 TI - Rhabdomyolysis and exercise-associated hyponatremia in ultra-bikers and ultra runners. AB - BACKGROUND: Exercise-associated hyponatremia (EAH), rhabdomyolysis and renal failure appear to be a unique problem in ultra-endurance racers. METHODS: We investigated the combined occurrence of EAH and rhabdomyolysis in seven different ultra-endurance races and disciplines (i.e. multi-stage mountain biking, 24-h mountain biking, 24-h ultra-running and 100-km ultra-running). RESULTS: Two (15.4%) ultra-runners (man and woman) from hyponatremic ultra-athletes (n = 13) and four (4%) ultra-runners (four men) from the normonatremic group (n = 100) showed rhabdomyolysis following elevated blood creatine kinase (CK) levels > 10,000 U/L without the development of renal failure and the necessity of a medical treatment. Post-race creatine kinase, plasma and urine creatinine significantly increased, while plasma [Na(+)] and creatine clearance decreased in hyponatremic and normonatremic athletes, respectively. The percentage increase of CK was higher in the hyponatremic compared to the normonatremic group (P < 0.05). Post-race CK levels were higher in ultra-runners compared to mountain bikers (P < 0.01), in faster normonatremic (P < 0.05) and older and more experienced hyponatremic ultra-athletes (P < 0.05). In all finishers, pre-race plasma [K(+)] was related to post-race CK (P < 0.05). CONCLUSIONS: Hyponatremic ultra-athletes tended to develop exercise-induced rhabdomyolysis more frequently than normonatremic ultra-athletes. Ultra-runners tended to develop rhabdomyolysis more frequently than mountain bikers. We found no association between post-race plasma [Na(+)] and CK concentration in both hypo- and normonatremic ultra-athletes. PMID- 26113807 TI - Robust estimation of group-wise cortical correspondence with an application to macaque and human neuroimaging studies. AB - We present a novel group-wise registration method for cortical correspondence for local cortical thickness analysis in human and non-human primate neuroimaging studies. The proposed method is based on our earlier template based registration that estimates a continuous, smooth deformation field via sulcal curve constrained registration employing spherical harmonic decomposition of the deformation field. This pairwise registration though results in a well-known template selection bias, which we aim to overcome here via a group-wise approach. We propose the use of an unbiased ensemble entropy minimization following the use of the pairwise registration as an initialization. An individual deformation field is then iteratively updated onto the unbiased average. For the optimization, we use metrics specific for cortical correspondence though all of these are straightforwardly extendable to the generic setting: The first focused on optimizing the correspondence of automatically extracted sulcal landmarks and the second on that of sulcal depth property maps. We further propose a robust entropy metric and a hierarchical optimization by employing spherical harmonic basis orthogonality. We also provide the detailed methodological description of both our earlier work and the proposed method with a set of experiments on a population of human and non-human primate subjects. In the experiment, we have shown that our method achieves superior results on consistency through quantitative and visual comparisons as compared to the existing methods. PMID- 26113808 TI - Melanocortin receptor accessory proteins in adrenal disease and obesity. AB - Melanocortin receptor accessory proteins (MRAPs) are regulators of the melanocortin receptor family. MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency type 2. The role of its paralog melanocortin-2-receptor accessory protein 2 (MRAP2), which is predominantly expressed in the hypothalamus including the paraventricular nucleus, has recently been linked to mammalian obesity. Whole body deletion and targeted brain specific deletion of the Mrap2 gene result in severe obesity in mice. Interestingly, Mrap2 complete knockout (KO) mice have increased body weight without detectable changes to food intake or energy expenditure. Rare heterozygous variants of MRAP2 have been found in humans with severe, early-onset obesity. In vitro data have shown that Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affects receptor signaling. However, the mechanism by which Mrap2 regulates body weight in vivo is not fully understood and differences between the phenotypes of Mrap2 and Mc4r KO mice may point toward Mc4r independent mechanisms. PMID- 26113809 TI - Insights into the physiological role of CNS regeneration inhibitors. AB - The growth inhibitory nature of injured adult mammalian central nervous system (CNS) tissue constitutes a major barrier to robust axonal outgrowth and functional recovery following trauma or disease. Prototypic CNS regeneration inhibitors are broadly expressed in the healthy and injured brain and spinal cord and include myelin-associated glycoprotein (MAG), the reticulon family member NogoA, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs). These structurally diverse molecules strongly inhibit neurite outgrowth in vitro, and have been most extensively studied in the context of nervous system injury in vivo. The physiological role of CNS regeneration inhibitors in the naive, or uninjured, CNS remains less well understood, but has received growing attention in recent years and is the focus of this review. CNS regeneration inhibitors regulate myelin development and axon stability, consolidate neuronal structure shaped by experience, and limit activity-dependent modification of synaptic strength. Altered function of CNS regeneration inhibitors is associated with neuropsychiatric disorders, suggesting crucial roles in brain development and health. PMID- 26113811 TI - The effects of neuron morphology on graph theoretic measures of network connectivity: the analysis of a two-level statistical model. AB - We developed a two-level statistical model that addresses the question of how properties of neurite morphology shape the large-scale network connectivity. We adopted a low-dimensional statistical description of neurites. From the neurite model description we derived the expected number of synapses, node degree, and the effective radius, the maximal distance between two neurons expected to form at least one synapse. We related these quantities to the network connectivity described using standard measures from graph theory, such as motif counts, clustering coefficient, minimal path length, and small-world coefficient. These measures are used in a neuroscience context to study phenomena from synaptic connectivity in the small neuronal networks to large scale functional connectivity in the cortex. For these measures we provide analytical solutions that clearly relate different model properties. Neurites that sparsely cover space lead to a small effective radius. If the effective radius is small compared to the overall neuron size the obtained networks share similarities with the uniform random networks as each neuron connects to a small number of distant neurons. Large neurites with densely packed branches lead to a large effective radius. If this effective radius is large compared to the neuron size, the obtained networks have many local connections. In between these extremes, the networks maximize the variability of connection repertoires. The presented approach connects the properties of neuron morphology with large scale network properties without requiring heavy simulations with many model parameters. The two-steps procedure provides an easier interpretation of the role of each modeled parameter. The model is flexible and each of its components can be further expanded. We identified a range of model parameters that maximizes variability in network connectivity, the property that might affect network capacity to exhibit different dynamical regimes. PMID- 26113810 TI - Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update. AB - The blood-brain barrier (BBB) is a diffusion barrier that has an important role in maintaining a precisely regulated microenvironment protecting the neural tissue from infectious agents and toxins in the circulating system. Compromised BBB integrity plays a major role in the pathogenesis of retroviral associated neurological diseases. Human Immunodeficiency Virus (HIV) infection in the Central Nervous System (CNS) is an early event even before the serodiagnosis for HIV positivity or the initiation of antiretroviral therapy (ART), resulting in neurological complications in many of the infected patients. Macrophages, microglia and astrocytes (in low levels) are the most productively/latently infected cell types within the CNS. In this brief review, we have discussed about the effect of HIV infection and viral proteins on the integrity and function of BBB, which may contribute to the progression of HIV associated neurocognitive disorders. PMID- 26113813 TI - Not so bad: avoidance and aversive discounting modulate threat appraisal in anterior cingulate and medial prefrontal cortex. AB - The dorsal anterior cingulate (adACC) and dorsal medial prefrontal cortex (dmPFC) play a central role in the discrimination and appraisal of threatening stimuli. Yet, little is known about what specific features of threatening situations recruit these regions and how avoidance may modulate appraisal and activation through prevention of aversive events. In this investigation, 30 healthy adults underwent functional neuroimaging while completing an avoidance task in which responses to an Avoidable CS+ threat prevented delivery of an aversive stimulus, but not to an Unavoidable CS+ threat. Extinction testing was also completed where CSs were presented without aversive stimulus delivery and an opportunity to avoid. The Avoidable CS+ relative to the Unavoidable CS+ was associated with reductions in ratings of negative valence, fear, and US expectancy and activation. Greater regional activation was consistently observed to the Unavoidable CS+ during avoidance, which declined during extinction. Individuals exhibiting greater aversive discounting-that is, those more avoidant of immediate monetary loss compared to a larger delayed loss-also displayed greater activation to the Unavoidable CS+, highlighting aversive discounting as a significant individual difference variable. These are the first results linking adACC/dmPFC reactivity to avoidance-based reductions of aversive events and modulation of activation by individual differences in aversive discounting. PMID- 26113812 TI - Brain computer interface learning for systems based on electrocorticography and intracortical microelectrode arrays. AB - A brain-computer interface (BCI) system transforms neural activity into control signals for external devices in real time. A BCI user needs to learn to generate specific cortical activity patterns to control external devices effectively. We call this process BCI learning, and it often requires significant effort and time. Therefore, it is important to study this process and develop novel and efficient approaches to accelerate BCI learning. This article reviews major approaches that have been used for BCI learning, including computer-assisted learning, co-adaptive learning, operant conditioning, and sensory feedback. We focus on BCIs based on electrocorticography and intracortical microelectrode arrays for restoring motor function. This article also explores the possibility of brain modulation techniques in promoting BCI learning, such as electrical cortical stimulation, transcranial magnetic stimulation, and optogenetics. Furthermore, as proposed by recent BCI studies, we suggest that BCI learning is in many ways analogous to motor and cognitive skill learning, and therefore skill learning should be a useful metaphor to model BCI learning. PMID- 26113814 TI - Rapid prefrontal cortex activation towards aversively paired faces and enhanced contingency detection are observed in highly trait-anxious women under challenging conditions. AB - Relative to healthy controls, anxiety-disorder patients show anomalies in classical conditioning that may either result from, or provide a risk factor for, clinically relevant anxiety. Here, we investigated whether healthy participants with enhanced anxiety vulnerability show abnormalities in a challenging affective conditioning paradigm, in which many stimulus-reinforcer associations had to be acquired with only few learning trials. Forty-seven high and low trait-anxious females underwent MultiCS conditioning, in which 52 different neutral faces (CS+) were paired with an aversive noise (US), while further 52 faces (CS-) remained unpaired. Emotional learning was assessed by evaluative (rating), behavioral (dot probe, contingency report), and neurophysiological (magnetoencephalography) measures before, during, and after learning. High and low trait-anxious groups did not differ in evaluative ratings or response priming before or after conditioning. High trait-anxious women, however, were better than low trait anxious women at reporting CS+/US contingencies after conditioning, and showed an enhanced prefrontal cortex (PFC) activation towards CS+ in the M1 (i.e., 80-117 ms) and M170 time intervals (i.e., 140-160 ms) during acquisition. These effects in MultiCS conditioning observed in individuals with elevated trait anxiety are consistent with theories of enhanced conditionability in anxiety vulnerability. Furthermore, they point towards increased threat monitoring and detection in highly trait-anxious females, possibly mediated by alterations in visual working memory. PMID- 26113815 TI - Commentary: Feedback stabilizes propagation of synchronous spiking in cortical neural networks. PMID- 26113816 TI - A kinematic model for 3-D head-free gaze-shifts. AB - Rotations of the line of sight are mainly implemented by coordinated motion of the eyes and head. Here, we propose a model for the kinematics of three dimensional (3-D) head-unrestrained gaze-shifts. The model was designed to account for major principles in the known behavior, such as gaze accuracy, spatiotemporal coordination of saccades with vestibulo-ocular reflex (VOR), relative eye and head contributions, the non-commutativity of rotations, and Listing's and Fick constraints for the eyes and head, respectively. The internal design of the model was inspired by known and hypothesized elements of gaze control physiology. Inputs included retinocentric location of the visual target and internal representations of initial 3-D eye and head orientation, whereas outputs were 3-D displacements of eye relative to the head and head relative to shoulder. Internal transformations decomposed the 2-D gaze command into 3-D eye and head commands with the use of three coordinated circuits: (1) a saccade generator, (2) a head rotation generator, (3) a VOR predictor. Simulations illustrate that the model can implement: (1) the correct 3-D reference frame transformations to generate accurate gaze shifts (despite variability in other parameters), (2) the experimentally verified constraints on static eye and head orientations during fixation, and (3) the experimentally observed 3-D trajectories of eye and head motion during gaze-shifts. We then use this model to simulate how 2-D eye-head coordination strategies interact with 3-D constraints to influence 3-D orientations of the eye-in-space, and the implications of this for spatial vision. PMID- 26113817 TI - Electron microscopic tomography reveals discrete transcleft elements at excitatory and inhibitory synapses. AB - Electron microscopy has revealed an abundance of material in the clefts of synapses in the mammalian brain, and the biochemical and functional characteristics of proteins occupying synaptic clefts are well documented. However, the detailed spatial organization of the proteins in the synaptic clefts remains unclear. Electron microscope tomography provides a way to delineate and map the proteins spanning the synaptic cleft because freeze substitution preserves molecular details with sufficient contrast to visualize individual cleft proteins. Segmentation and rendering of electron dense material connected across the cleft reveals discrete structural elements that are readily classified into five types at excitatory synapses and four types at inhibitory synapses. Some transcleft elements resemble shapes and sizes of known proteins and could represent single dimers traversing the cleft. Some of the types of cleft elements at inhibitory synapses roughly matched the structure and proportional frequency of cleft elements at excitatory synapses, but the patterns of deployments in the cleft are quite different. Transcleft elements at excitatory synapses were often evenly dispersed in clefts of uniform (18 nm) width but some types show preference for the center or edges of the cleft. Transcleft elements at inhibitory synapses typically were confined to a peripheral region of the cleft where it narrowed to only 6 nm wide. Transcleft elements in both excitatory and inhibitory synapses typically avoid places where synaptic vesicles attach to the presynaptic membrane. These results illustrate that elements spanning synaptic clefts at excitatory and inhibitory synapses consist of distinct structures arranged by type in a specific but different manner at excitatory and inhibitory synapses. PMID- 26113819 TI - Pervasive Computing Technologies to Continuously Assess Alzheimer's Disease Progression and Intervention Efficacy. AB - Traditionally, assessment of functional and cognitive status of individuals with dementia occurs in brief clinic visits during which time clinicians extract a snapshot of recent changes in individuals' health. Conventionally, this is done using various clinical assessment tools applied at the point of care and relies on patients' and caregivers' ability to accurately recall daily activity and trends in personal health. These practices suffer from the infrequency and generally short durations of visits. Since 2004, researchers at the Oregon Center for Aging and Technology (ORCATECH) at the Oregon Health and Science University have been working on developing technologies to transform this model. ORCATECH researchers have developed a system of continuous in-home monitoring using pervasive computing technologies that make it possible to more accurately track activities and behaviors and measure relevant intra-individual changes. We have installed a system of strategically placed sensors in over 480 homes and have been collecting data for up to 8 years. Using this continuous in-home monitoring system, ORCATECH researchers have collected data on multiple behaviors such as gait and mobility, sleep and activity patterns, medication adherence, and computer use. Patterns of intra-individual variation detected in each of these areas are used to predict outcomes such as low mood, loneliness, and cognitive function. These methods have the potential to improve the quality of patient health data and in turn patient care especially related to cognitive decline. Furthermore, the continuous real-world nature of the data may improve the efficiency and ecological validity of clinical intervention studies. PMID- 26113820 TI - Socio-cognitive profiles for visual learning in young and older adults. AB - It is common wisdom that practice makes perfect; but why do some adults learn better than others? Here, we investigate individuals' cognitive and social profiles to test which variables account for variability in learning ability across the lifespan. In particular, we focused on visual learning using tasks that test the ability to inhibit distractors and select task-relevant features. We tested the ability of young and older adults to improve through training in the discrimination of visual global forms embedded in a cluttered background. Further, we used a battery of cognitive tasks and psycho-social measures to examine which of these variables predict training-induced improvement in perceptual tasks and may account for individual variability in learning ability. Using partial least squares regression modeling, we show that visual learning is influenced by cognitive (i.e., cognitive inhibition, attention) and social (strategic and deep learning) factors rather than an individual's age alone. Further, our results show that independent of age, strong learners rely on cognitive factors such as attention, while weaker learners use more general cognitive strategies. Our findings suggest an important role for higher-cognitive circuits involving executive functions that contribute to our ability to improve in perceptual tasks after training across the lifespan. PMID- 26113818 TI - Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction. AB - Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1) cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy (ADOA). Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction. PMID- 26113821 TI - A new paradigm for muscle contraction. AB - For the past 60 years, muscle contraction had been thought to be governed exclusively by the contractile filaments, actin, and myosin. This thinking explained most observations for concentric and isometric, but not for eccentric muscle contractions. Just over a decade ago, we discovered that eccentric contractions were associated with a force that could not be assigned to actin and myosin, but was at least in part associated with the filamentous protein titin. Titin was found to bind calcium upon activation, thereby increasing its structural stability, and thus its stiffness and force. Furthermore, there is increasing evidence that the proximal part of titin binds to actin in an activation- and force-dependent manner, thereby shortening its free length, thus increasing its stiffness and force. Therefore, we propose that muscle contraction involves three filaments, actin, myosin and titin, and that titin regulates force by binding calcium and by shortening its spring length by binding to actin. PMID- 26113823 TI - Perceived mathematical ability under challenge: a longitudinal perspective on sex segregation among STEM degree fields. AB - Students' perceptions of their mathematics ability vary by gender and seem to influence science, technology, engineering, and mathematics (STEM) degree choice. Related, students' perceptions during academic difficulty are increasingly studied in educational psychology, suggesting a link between such perceptions and task persistence. Despite interest in examining the gender disparities in STEM, these concepts have not been considered in tandem. In this manuscript, we investigate how perceived ability under challenge-in particular in mathematics domains-influences entry into the most sex-segregated and mathematics-intensive undergraduate degrees: physics, engineering, mathematics, and computer science (PEMC). Using nationally representative Education Longitudinal Study of 2002 (ELS) data, we estimate the influence of perceived ability under challenging conditions on advanced high school science course taking, selection of an intended STEM major, and specific major type 2 years after high school. Demonstrating the importance of specificity when discussing how gender influences STEM career pathways, the intersecting effects of gender and perceived ability under mathematics challenge were distinct for each scientific major category. Perceived ability under challenge in secondary school varied by gender, and was highly predictive of selecting PEMC and health sciences majors. Notably, women's 12th grade perceptions of their ability under mathematics challenge increased their probability of selecting PEMC majors over and above biology. In addition, gender moderated the effect of growth mindset on students' selection of health science majors. Perceptions of ability under challenge in general and verbal domains also influenced retention in and declaration of certain STEM majors. The implications of these results are discussed, with particular attention to access to advanced scientific coursework in high school and interventions aimed at enhancing young women's perceptions of their ability, in particular in response to the potentially inhibiting influence of stereotype threat on their pathways to scientific degrees. PMID- 26113822 TI - Social and Cultural Elements Associated with Neurocognitive Dysfunctions in Spinocerebellar Ataxia Type 2 Patients. AB - Spinocerebellar Ataxia Type 2 (SCA2) is a rare genetic disorder producing cerebellar degeneration and affecting motor abilities. Neuroimaging studies also show neurodegeneration in subcortical and cortical regions related to emotional and social processes. From social neuroscience, it is suggested that motor and social abilities can be influenced by particular cultural dynamics so, culture is fundamental to understand the effect of brain-related alterations. Here, we present the first analysis about the cultural elements related to the SCA2 disorder in 15 patients previously evaluated with neuroimaging and psychometric instruments, and their nuclear relationships distributed in six geographical and cultural regions in Mexico. Ethnographic records and photographic and video archives about the quotidian participant's routine were obtained from the patients, their relatives and their caregivers. The information was categorized and interpreted taking into consideration cultural issues and patients' medical files. Our analyses suggest that most of the participants do not understand the nature of the disease and this misunderstanding favors magic and non-medical explanations. Patients' testimonies suggest a decrease in pain perception as well as motor alterations that may be related to interoceptive dysfunctions. Relatives' testimonies indicate patients' lack of social and emotional interests that may be related to frontal, temporal, and cerebellar degeneration. In general, participants use their religious beliefs to deal with the disease and only a few of them trust the health system. Patients and their families are either openly rejected and ignored, tolerated or even helped by their community accordingly to different regional traits. We propose that ethnography can provide social representations to understand the patients' alterations, to formulate neurobiological hypotheses, to develop neurocognitive interventions, and to improve the medical approach to the disease. PMID- 26113824 TI - Emotional and social competencies and perceptions of the interpersonal environment of an organization as related to the engagement of IT professionals. AB - There is a dearth of research focused on the engagement of information technology (IT) professionals. This study analyzed the relationship between emotional and social competencies and the quality of the IT professional's perceptions of the interpersonal environment in an organization as they relate to employee engagement. Validated instruments were used and data was collected from 795 IT professionals in North America to quantitatively analyze the relationship between emotional and social competencies, role breadth self-efficacy (RBSE), with the quality of the IT professional's perceptions of the interpersonal environment, and those perceptions with employee engagement. The study results indicate that specific emotional and social competencies and RBSE relate differently to the quality of the perceptions of the interpersonal environment. The study also reveals how the quality of the IT professional's perceptions of the interpersonal environment relates to how much they engage in the organization. The findings indicate that the relationship between achievement orientation and the perceived interpersonal environment was positive and the relationship between influencing others and the perceived interpersonal environment was negative. Understanding such relationships offers much needed insight to practitioners and can benefit organizations that wish to increase the engagement of their IT professionals. The findings also can support practitioners to more effectively select and develop talent with the desired motives and traits. By doing so, organizations can experience increased employee satisfaction, engagement, and retention, resulting in higher productivity, quality, and profitability. PMID- 26113825 TI - GraphoGame - a catalyst for multi-level promotion of literacy in diverse contexts. AB - GraphoGame (GG) is originally a technology-based intervention method for supporting children with reading difficulties. It is now known that children who face problems in reading acquisition have difficulties in learning to differentiate and manipulate speech sounds and consequently, in connecting these sounds to corresponding letters. GG was developed to provide intensive training in matching speech sounds and larger units of speech to their written counterparts. GG has been shown to benefit children with reading difficulties and the game is now available for all Finnish school children for literacy support. Presently millions of children in Africa fail to learn to read despite years of primary school education. As many African languages have transparent writing systems similar in structure to Finnish, it was hypothesized that GG-based training of letter-sound correspondences could also be effective in supporting children's learning in African countries. In this article we will describe how GG has been developed from a Finnish dyslexia prevention game to an intervention method that can be used not only to improve children's reading performance but also to raise teachers' and parents' awareness of the development of reading skill and effective reading instruction methods. We will also provide an overview of the GG activities in Zambia, Kenya, Tanzania, and Namibia, and the potential to promote education for all with a combination of scientific research and mobile learning. PMID- 26113826 TI - Visual perception of order-disorder transition. AB - Our experience with the natural world, as composed of ordered entities, implies that perception captures relationships between image parts. For instance, regularities in the visual scene are rapidly identified by our visual system. Defining the regularities that govern perception is a basic, unresolved issue in neuroscience. Mathematically, perfect regularities are represented by symmetry (perfect order). The transition from ordered configurations to completely random ones has been extensively studied in statistical physics, where the amount of order is characterized by a symmetry-specific order parameter. Here we applied tools from statistical physics to study order detection in humans. Different sets of visual textures, parameterized by the thermodynamic temperature in the Boltzmann distribution, were designed. We investigated how much order is required in a visual texture for it to be discriminated from random noise. The performance of human observers was compared to Ideal and Order observers (based on the order parameter). The results indicated a high consistency in performance across human observers, much below that of the Ideal observer, but well-approximated by the Order observer. Overall, we provide a novel quantitative paradigm to address order perception. Our findings, based on this paradigm, suggest that the statistical physics formalism of order captures regularities to which the human visual system is sensitive. An additional analysis revealed that some order perception properties are captured by traditional texture discrimination models according to which discrimination is based on integrated energy within maps of oriented linear filters. PMID- 26113827 TI - Intransparent German number words complicate transcoding - a translingual comparison with Japanese. AB - Superior early numerical competencies of children in several Asian countries have (amongst others) been attributed to the higher transparency of their number word systems. Here, we directly investigated this claim by evaluating whether Japanese children's transcoding performance when writing numbers to dictation (e.g., "twenty five" -> 25) was less error prone than that of German-speaking children - both in general as well as when considering language-specific attributes of the German number word system such as the inversion property, in particular. In line with this hypothesis we observed that German-speaking children committed more transcoding errors in general than their Japanese peers. Moreover, their error pattern reflected the specific inversion intransparency of the German number-word system. Inversion errors in transcoding represented the most prominent error category in German-speaking children, but were almost absent in Japanese-speaking children. We conclude that the less transparent German number-word system complicates the acquisition of the correspondence between symbolic Arabic numbers and their respective verbal number words. PMID- 26113828 TI - Effects of auditory information on self-motion perception during simultaneous presentation of visual shearing motion. AB - Recent studies have found that self-motion perception induced by simultaneous presentation of visual and auditory motion is facilitated when the directions of visual and auditory motion stimuli are identical. They did not, however, examine possible contributions of auditory motion information for determining direction of self-motion perception. To examine this, a visual stimulus projected on a hemisphere screen and an auditory stimulus presented through headphones were presented separately or simultaneously, depending on experimental conditions. The participant continuously indicated the direction and strength of self-motion during the 130-s experimental trial. When the visual stimulus with a horizontal shearing rotation and the auditory stimulus with a horizontal one-directional rotation were presented simultaneously, the duration and strength of self-motion perceived in the opposite direction of the auditory rotation stimulus were significantly longer and stronger than those perceived in the same direction of the auditory rotation stimulus. However, the auditory stimulus alone could not sufficiently induce self-motion perception, and if it did, its direction was not consistent within each experimental trial. We concluded that auditory motion information can determine perceived direction of self-motion during simultaneous presentation of visual and auditory motion information, at least when visual stimuli moved in opposing directions (around the yaw-axis). We speculate that the contribution of auditory information depends on the plausibility and information balance of visual and auditory information. PMID- 26113829 TI - Lost or fond? Effects of nostalgia on sad mood recovery vary by attachment insecurity. AB - Nostalgia involves a fond recollection of people and events lost to time. Growing evidence indicates that nostalgia may ameliorate negative affective states such as loneliness and boredom. However, the effect of nostalgia on sadness is unknown, and there is little research on how social connectedness might impact nostalgia's effects. Grounded in a theoretical framework whereby people with lower levels of attachment insecurity benefit more from nostalgia, we exposed participants to a mortality-related sad mood and then randomly assigned them to reflect on a nostalgic or an ordinary event memory. We examined changes in mood and electrodermal activity (EDA) and found that nostalgic versus ordinary event memories led to a blunted recovery from sad mood, but that this effect was moderated by degree of attachment insecurity, such that participants with low insecurity benefited from nostalgia whereas people with high insecurity did not. These findings suggest that nostalgia's benefits may be tied to the degree of confidence one has in one's social relationships. PMID- 26113830 TI - The effect of relationship quality on individual perceptions of social responsibility in the US. AB - Social responsibility (SR) has been of continuing interest in the U.S. and around the world. Organizations make a wide variety of SR decisions that represent differing viewpoints. While a number of definitions of SR exist, many of these definitions indicate that SR decisions may be viewed as existing of various facets, such as legal/regulatory, financial/economic, ethical, environmental, and voluntary. While drivers of SR have been proposed, there has been limited research at a micro-level on how individuals perceive SR activities by the organizations where they work. Based on a prior qualitative study (Thornton and Byrd, 2013) that found SR decisions are related to several traits and influenced by relationships, a model was proposed and tested in this research. The traits found relevant in the qualitative research were conscientiousness, especially in the sense of being responsible, and self-efficacy. Relationship quality was assessed based on positive and negative emotional attractors as proposed in intentional change theory. Perceptions of individuals in management and non management showed that relationship quality mediated the effect of conscientiousness and general self-efficacy on the SR. Because there are multiple facets, the author made use of Carroll's (1991) pyramid of SR to identify activities that business owners and managers consider relevant. The findings indicate that conscientiousness is related to specific SR activities in the areas of legal/regulatory, ethical and discretionary dimensions while general self efficacy is related to financial/economic and legal/regulatory dimensions. The presence of relationship quality enhanced the effects of both conscientiousness and general self-efficacy on the various SR dimensions. This suggests that individuals perceived SR activities along different traits and that enhancing these traits might improve perceptions of SR decisions. PMID- 26113831 TI - Commentary on: Labels, cognomes, and cyclic computation: an ethological perspective. PMID- 26113833 TI - Auditory evoked potential: a proposal for further evaluation in children with learning disabilities. AB - The information presented in this paper demonstrates the author's experience in previews cross-sectional studies conducted in Brazil, in comparison with the current literature. Over the last 10 years, auditory evoked potential (AEP) has been used in children with learning disabilities. This method is critical to analyze the quality of the processing in time and indicates the specific neural demands and circuits of the sensorial and cognitive process in this clinical population. Some studies with children with dyslexia and learning disabilities were shown here to illustrate the use of AEP in this population. PMID- 26113832 TI - Current insights in the development of children's motor imagery ability. AB - Over the last two decades, the number of studies on motor imagery in children has witnessed a large expansion. Most studies used the hand laterality judgment paradigm or the mental chronometry paradigm to examine motor imagery ability. The main objective of the current review is to collate these studies to provide a more comprehensive insight in children's motor imagery development and its age of onset. Motor imagery is a form of motor cognition and aligns with forward (or predictive) models of motor control. Studying age-related differences in motor imagery ability in children therefore provides insight in underlying processes of motor development during childhood. Another motivation for studying age-related differences in motor imagery is that in order to effectively apply motor imagery training in children (with motor impairments), it is pertinent to first establish the age at which children are actually able to perform motor imagery. Overall, performance in the imagery tasks develops between 5 and 12 years of age. The age of motor imagery onset, however, remains equivocal, as some studies indicate that children of 5 to 7 years old can already enlist motor imagery in an implicit motor imagery task, whereas other studies using explicit instructions revealed that children do not use motor imagery before the age of 10. From the findings of the current study, we can conclude that motor imagery training is potentially a feasible method for pediatric rehabilitation in children from 5 years on. We suggest that younger children are most likely to benefit from motor imagery training that is presented in an implicit way. Action observation training might be a beneficial adjunct to implicit motor imagery training. From 10 years of age, more explicit forms of motor imagery training can be effectively used. PMID- 26113834 TI - A longitudinal study of the emerging self from 9 months to the age of 4 years. AB - The aim of this study was to investigate if children's early responsiveness toward social partners is developmentally related to their growing concept of self, as reflected in their mirror self-recognition (MSR) and delayed self recognition (DSR). Thus, a longitudinal study assessed infants' responsiveness (e.g., smiling, gaze) toward social partners during the still-face (SF) task and a social imitation game and related it to their emerging MSR and DSR. Thereby, children were tested at regular time points from 9 months to 4 years of age. Results revealed significant predictive relations between children's responsiveness toward a social partner in the SF task at 9 months and their MSR at 24 months. Further, interindividual differences in children's awareness of and responsiveness toward being imitated in a social imitation game at 12 months proved to be the strongest predictor of children's DSR at 4 years, while some additional variance was explained by MSR at 24 months and verbal intelligence. Overall, findings suggest a developmental link between children's early awareness of and responsiveness toward the social world and their later ability to form a concept of self. PMID- 26113836 TI - Bilingual children weigh speaker's referential cues and word-learning heuristics differently in different language contexts when interpreting a speaker's intent. AB - Past research has investigated how children use different sources of information such as social cues and word-learning heuristics to infer referential intents. The present research explored how children weigh and use some of these cues to make referential inferences. Specifically, we examined how switching between languages known (familiar) or unknown (unfamiliar) to a child would influence his or her choice of cue to interpret a novel label in a challenging disambiguation task, where a pointing cue was pitted against the mutual exclusivity (ME) principle. Forty-eight 3-and 4-years-old English-Mandarin bilingual children listened to a story told either in English only (No-Switch), English and Mandarin (Familiar-Switch), English and Japanese (Unfamiliar-Switch), or English and English-sounding nonsense sentences (Nonsense-Switch). They were then asked to select an object (from a pair of familiar and novel objects) after hearing a novel label paired with the speaker's point at the familiar object, e.g., "Can you give me the blicket?" Results showed that children in the Familiar-Switch condition were more willing to relax ME to follow the speaker's point to pick the familiar object than those in the Unfamiliar-Switch condition, who were more likely to pick the novel object. No significant differences were found between the other conditions. Further analyses revealed that children in the Unfamiliar Switch condition looked at the speaker longer than children in the other conditions when the switch happened. Our findings suggest that children weigh speakers' referential cues and word-learning heuristics differently in different language contexts while taking into account their communicative history with the speaker. There are important implications for general education and other learning efforts, such as designing learning games so that the history of credibility with the user is maintained and how learning may be best scaffolded in a helpful and trusting environment. PMID- 26113835 TI - Motor interference in interactive contexts. AB - Action observation and execution share overlapping neural substrates, so that simultaneous activation by observation and execution modulates motor performance. Previous literature on simple prehension tasks has revealed that motor influence can be two-sided: facilitation for observed and performed congruent actions and interference for incongruent actions. But little is known of the specific modulations of motor performance in complex forms of interaction. Is it possible that the very same observed movement can lead either to interference or facilitation effects on a temporally overlapping congruent executed action, depending on the context? To answer this question participants were asked to perform a reach-to-grasp movement adopting a precision grip (PG) while: (i) observing a fixation cross, (ii) observing an actor performing a PG with interactive purposes, (iii) observing an actor performing a PG without interactive purposes. In particular, in the interactive condition the actor was shown trying to pour some sugar on a large cup located out of her reach but close to the participant watching the video, thus eliciting in reaction a complementary whole-hand grasp. Notably, fine-grained kinematic analysis for this condition revealed a specific delay in the grasping and reaching components and an increased trajectory deviation despite the observed and executed movement's congruency. Moreover, early peaks of trajectory deviation seem to indicate that socially relevant stimuli are acknowledged by the motor system very early. These data suggest that interactive contexts can determine a prompt modulation of stimulus-response compatibility effects. PMID- 26113837 TI - The juggling paradigm: a novel social neuroscience approach to identify neuropsychophysiological markers of team mental models. AB - Since the discovery of the mirror neuron system in the 1980s, little, if any, research has been devoted to the study of interactive motor tasks (Goldman, 2012). Scientists interested in the neuropsychophysiological markers of joint motor action have relied on observation paradigms and passive tasks rather than dynamic paradigms and interactive tasks (Konvalinka and Roepstorff, 2012). Within this research scenario, we introduce a novel research paradigm that uses cooperative juggling as a platform to capture peripheral (e.g., skin conductance, breathing and heart rates, electromyographic signals) and central neuropsychophysiological (e.g., functional connectivity within and between brains) markers underlying the notion of team mental models (TMM). We discuss the epistemological and theoretical grounds of a cooperative juggling paradigm, and propose testable hypotheses on neuropsychophysiological markers underlying TMM. Furthermore, we present key methodological concerns that may influence peripheral responses as well as single and hyperbrain network configurations during joint motor action. Preliminary findings of the paradigm are highlighted. We conclude by delineating avenues for future research. PMID- 26113838 TI - The relationship between the development of response inhibition and intelligence in preschool children. AB - Building on the theoretical framework that intellectual behavior relies on one's ability to process both task-relevant and task-irrelevant information, this study aimed to empirically investigate the association of response inhibition with intelligence in preschool children's development. In a sample of 152 typically developing children aged between 3.6 and 6.6 years, we found evidence that suggests that inhibitory control is linked to age-related differences in intelligence. Stop-signal inhibition improved at a rate similar to the age related changes in Verbal IQ. Components of variance analyses revealed that stop signal reaction time predicted a larger proportion of the age-related variance in children's verbal intelligence than non-age-related variance. Results are discussed with respect to possible explanations for this intriguing relationship between response inhibition and the verbal aspects of intelligence. PMID- 26113839 TI - The numerology of gender: gendered perceptions of even and odd numbers. AB - Do numbers have gender? Wilkie and Bodenhausen (2012) examined this issue in a series of experiments on perceived gender. They examined the perceived gender of baby faces and foreign names. Arbitrary numbers presented with these faces and names influenced their perceived gender. Specifically, odd numbers connoted masculinity, while even numbers connoted femininity. In two new studies (total N = 315), we further examined the gendering of numbers. The first study examined explicit ratings of 1-digit numbers. We confirmed that odd numbers seemed masculine while even numbers seemed feminine. Although both men and women showed this pattern, it was more pronounced among women. We also examined whether this pattern holds for automatic as well as deliberated reactions. Results of an Implicit Association Test showed that it did, but only among the women. The implicit and explicit patterns of numerical gender ascription were moderately correlated. The second study examined explicit perceptions of 2-digit numbers. Again, women viewed odd numbers as more masculine and less feminine than even numbers. However, men viewed 2-digit numbers as relatively masculine, regardless of whether they were even or odd. These results indicate that women and men impute gender to numbers in different ways and to different extents. We discuss possible implications for understanding how people relate to and are influenced by numbers in a variety of real-life contexts. PMID- 26113840 TI - SDQ: discriminative validity and diagnostic potential. AB - The Strengths and Difficulties Questionnaire (SDQ) was designed to screen for behavioral problems in youths based on cutoff points that favor the instrument's diagnostic sensitivity. The present study aimed to analyze the discriminative validity of the SDQ to identify behavioral difficulties and prosocial resources in school-age children compared with the diagnostic data collected by the corresponding sections of the Development and Well-being Assessment (DAWBA). In addition, new cutoff points that value specificity were defined for the SDQ scales, exploring its diagnostic potential. This study was conducted in Brazil and assessed a community convenience sample that consisted of 120 children aged 6 12 years who were not under psychological/psychiatric treatment. The mothers of the participants also completed a sociodemographic questionnaire. Descriptive statistics were used to clinically characterize the sample. A ROC curve was used to assess the discriminant validity of the SDQ, and new cutoff points were established to maximize the instrument's specificity. The new cutoff points enabled a significant increase in specificity without a significant loss of sensitivity, which favors approaches based on measures of screening and diagnosis yet does not damage the instrument's screening capacity. The following increases were observed: 100% for the depressive disorder scale (cutoff point = 7), 95.1% for the generalized anxiety disorder scale (cutoff point = 7), 46.6% for the conduct disorder scale (cutoff point = 6), 19.2% for the hyperactive disorder scale (cutoff point = 8), and 27.6% for the antisocial personality disorder scale (cutoff point = 6). A cutoff point of 8 was applied to the prosocial behavior scale, which exhibited a 62.1% increase in specificity. The use of more specific cutoff points generated more accurate results and favored SDQ's use, particularly in contexts of care that require more precise and faster procedures for identification of problems. PMID- 26113841 TI - Neurological Impairment Linked with Cortico-Subcortical Infiltration of Diffuse Low-Grade Gliomas at Initial Diagnosis Supports Early Brain Plasticity. AB - Diffuse low-grade gliomas (DLGG) are slow-growing brain tumors that in spite of an indolent behavior at onset show a continuous expansion over time and inevitably transform into malignant gliomas. Extensive tumor resections may be performed with preservation of neurological function due to neuroplasticity that is induced by the slow tumor growth. However, DLGG prefer to migrate along subcortical pathways, and white matter plasticity is considerably more limited than gray matter plasticity. Whether signs of functional decompensating white matter that may be found as early as at disease presentation has not been systematically studied. Here, we examined 52 patients who presented with a DLGG at the time of radiological diagnosis. We found a significant correlation between neurological impairment and eloquent cortico-subcortical tumor localization, but not between neurological function and tumor volume. These results suggest that even small tumors invading white matter pathways may lack compensatory mechanisms for functional reorganization already at disease presentation. PMID- 26113842 TI - The presence of Epstein-Barr virus significantly impacts the transcriptional profile in immunodeficiency-associated Burkitt lymphoma. AB - Burkitt lymphoma (BL) is an aggressive neoplasm derived from mature, antigen experienced B-lymphocytes. Three clinical/epidemiological variants have been recognized, named sporadic, endemic and immunodeficiency-associated BL (ID-BL). Although they are listed within a unique entity in the current WHO Classification, recent evidence indicated genetic and transcriptional differences among the three sub-groups. Further, the presence of latently persisting Epstein Barr virus (EBV) has been associated with specific features in endemic and sporadic cases. In this study, we explored for the first time whether EBV infection could be related with a specific molecular profile in immunodeficiency associated cases. We studied 30 BL cases, including nine occurring in HIV positive patients (5 EBV-positive and 4 EBV-negative) by gene and microRNA (miRNA) expression profiling. We found that ID-BL presented with different profiles based on EBV presence. Specifically, 252 genes were differentially expressed, some of them being involved in intracellular signaling and apoptosis regulation. Furthermore, 28 miRNAs including both EBV-encoded (N = 18) and cellular (N = 10) ones were differentially regulated. Of note, genes previously demonstrated to be targeted by such miRNA were consistently found among differentially expressed genes, indicating the relevant contribution of miRNA to the molecular profile of the examined cases. Grippingly, 17 out of the 252 differentially expressed genes turned out to be potentially targeted by both cellular and EBV-encoded miRNA, suggesting a complex interaction and not excluding a potential synergism. In conclusion, we documented transcriptional differences based on the presence of EBV in ID-BL, and suggested a complex interaction between cellular and viral molecules in the determination of the global molecular profile of the tumor. PMID- 26113843 TI - From genome to toxicity: a combinatory approach highlights the complexity of enterotoxin production in Bacillus cereus. AB - In recent years Bacillus cereus has gained increasing importance as a food poisoning pathogen. It is the eponymous member of the B. cereus sensu lato group that consists of eight closely related species showing impressive diversity of their pathogenicity. The high variability of cytotoxicity and the complex regulatory network of enterotoxin expression have complicated efforts to predict the toxic potential of new B. cereus isolates. In this study, comprehensive analyses of enterotoxin gene sequences, transcription, toxin secretion and cytotoxicity were performed. For the first time, these parameters were compared in a whole set of B. cereus strains representing isolates of different origin (food or food poisoning outbreaks) and of different toxic potential (enteropathogenic and apathogenic) to elucidate potential starting points of strain-specific differential toxicity. While toxin gene sequences were highly conserved and did not allow for differentiation between high and low toxicity strains, comparison of nheB and hblD enterotoxin gene transcription and Nhe and Hbl protein titers revealed not only strain-specific differences but also incongruence between toxin gene transcripts and toxin protein levels. With one exception all strains showed comparable capability of protein secretion and so far, no secretion patterns specific for high and low toxicity strains were identified. These results indicate that enterotoxin expression is more complex than expected, possibly involving the orchestrated interplay of different transcriptional regulator proteins, as well as posttranscriptional and posttranslational regulatory mechanisms plus additional influences of environmental conditions. PMID- 26113844 TI - Examination of clinical and environmental Vibrio parahaemolyticus isolates by multi-locus sequence typing (MLST) and multiple-locus variable-number tandem repeat analysis (MLVA). AB - Vibrio parahaemolyticus is a leading cause of seafood-borne infections in the US. This organism has a high genetic diversity that complicates identification of strain relatedness and epidemiological investigations. However, sequence-based analysis methods are promising tools for these identifications. In this study, Multi-Locus Sequence Typing (MLST) and Multiple-Locus Variable-Number Tandem Repeat Analysis (MLVA) was performed on 58 V. parahaemolyticus isolates (28 of oyster and 30 of clinical origin), to identify differences in phylogeny. The results obtained by both methods were compared to Pulsed-Field Gel Electrophoresis (PFGE) patterns determined in a previous study. Forty-one unique sequence types (STs) were identified by MLST among the 58 isolates. Almost half of the isolates (22) belonged to a new ST and added to the MLST database. A ST could not be generated for 5 (8.6%) isolates, primarily due to an untypable recA locus. Analysis with eBURST did not identify any clonal complex among the strains analyzed and revealed 37 singeltons with 4 of them forming 2 groups (1 of them SLV, and the other a DLV). An established MLVA assay, targeting 12 total genes through three separate 4-plex PCRs, was successfully adapted to high resolution melt (HRM) analysis with faster and easier experimental setup; resulting in 58 unique melt curve patterns. HRM-MLVA was capable of differentiating isolates within the same PFGE cluster and having the same ST. Conclusively, combining the three methods PFGE, MLST, and HRM-MLVA, for the phylogenetic analysis of V. parahaemolyticus resulted in a high resolution subtyping scheme for V. parahaemolyticus. This scheme will be useful as a phylogenetic research tool and as an improved method for outbreak investigations for V. parahaemolyticus. PMID- 26113846 TI - Genetic Manipulation of NK Cells for Cancer Immunotherapy: Techniques and Clinical Implications. AB - Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression in vivo. Improving NK cell persistence in vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic. PMID- 26113845 TI - The ins and outs of RND efflux pumps in Escherichia coli. AB - Infectious diseases remain one of the principal causes of morbidity and mortality in the world. Relevant authorities including the WHO and CDC have expressed serious concern regarding the continued increase in the development of multidrug resistance among bacteria. They have also reaffirmed the urgent need for investment in the discovery and development of new antibiotics and therapeutic approaches to treat multidrug resistant (MDR) bacteria. The extensive use of antimicrobial compounds in diverse environments, including farming and healthcare, has been identified as one of the main causes for the emergence of MDR bacteria. Induced selective pressure has led bacteria to develop new strategies of defense against these chemicals. Bacteria can accomplish this by several mechanisms, including enzymatic inactivation of the target compound; decreased cell permeability; target protection and/or overproduction; altered target site/enzyme and increased efflux due to over-expression of efflux pumps. Efflux pumps can be specific for a single substrate or can confer resistance to multiple antimicrobials by facilitating the extrusion of a broad range of compounds including antibiotics, heavy metals, biocides and others, from the bacterial cell. To overcome antimicrobial resistance caused by active efflux, efforts are required to better understand the fundamentals of drug efflux mechanisms. There is also a need to elucidate how these mechanisms are regulated and how they respond upon exposure to antimicrobials. Understanding these will allow the development of combined therapies using efflux inhibitors together with antibiotics to act on Gram-negative bacteria, such as the emerging globally disseminated MDR pathogen Escherichia coli ST131 (O25:H4). This review will summarize the current knowledge on resistance-nodulation-cell division efflux mechanisms in E. coli, a bacteria responsible for community and hospital-acquired infections, as well as foodborne outbreaks worldwide. PMID- 26113847 TI - Type I Interferon Elevates Co-Regulatory Receptor Expression on CMV- and EBV Specific CD8 T Cells in Chronic Hepatitis C. AB - Hepatitis C virus (HCV) readily sets up persistence in a large fraction of infected hosts. Mounting epidemiological and immunological evidence suggest that HCV's persistence could influence immune responses toward unrelated pathogens and vaccines. Nonetheless, the fundamental contribution of the inflammatory milieu during persistent HCV infection in impacting immune cells specific for common pathogens such as CMV and EBV has not been fully studied. As the co-regulatory receptors PD-1, Tim-3, and 2B4 have all been shown to be vital in regulating CD8(+) T cell function, we assessed their expression on CMV/EBV-specific CD8(+) T cells from patients with chronic hepatitis C (CHC) and healthy controls ex vivo and upon stimulation with virus-specific peptides in vitro. Total and CMV/EBV specific CD8(+) T cells expressing PD-1, Tim-3, and 2B4 were highly enriched in patients with CHC compared to healthy individuals ex vivo. In vitro peptide stimulation further potentiated the differential co-regulatory receptor expression of PD-1, Tim-3, and 2B4, which then culminated in an enhanced functionality of CMV/EBV-specific CD8(+) T cells in CHC patients. Comprehensively analyzing plasma cytokines between the two cohorts, we observed that not only was IFNalpha-2a dominant among 21 other inflammatory mediators elevated in CHC patients but it also correlated with PD-1 and Tim-3 expressions ex vivo. Importantly, IFNalpha-2a further caused upregulation of these markers upon in vitro peptide stimulation. Finally, we could prospectively study patients receiving novel IFN-free antiviral therapy. Here, we observed that treatment induced clearance of HCV resulted in a partial reversion of the phenotype of CMV/EBV-specific CD8(+) T cells in patients with CHC. These data reveal an alteration of the plasma concentrations of IFNalpha-2a together with other inflammatory mediators during CHC, which appeared to pervasively influence co regulatory receptor expression on CMV/EBV-specific CD8(+) T cells. PMID- 26113848 TI - Carbohydrates in Cyberspace. PMID- 26113849 TI - Dynamic transcriptional profiling provides insights into tuberous root development in Rehmannia glutinosa. AB - Rehmannia glutinosa, an herb of the Scrophulariaceae family, is widely cultivated in the Northern part of China. The tuberous root has well-known medicinal properties; however, yield and quality are threatened by abiotic and biotic stresses. Understanding the molecular process of tuberous root development may help identify novel targets for its control. In the present study, we used Illumina sequencing and de novo assembly strategies to obtain a reference transcriptome that is relevant to tuberous root development. We then conducted RNA-seq quantification analysis to determine gene expression profiles of the adventitious root (AR), thickening adventitious root (TAR), and the developing tuberous root (DTR). Expression profiling identified a total of 6794 differentially expressed unigenes during root development. Bioinformatics analysis and gene expression profiling revealed changes in phenylpropanoid biosynthesis, starch and sucrose metabolism, and plant hormone biosynthesis during root development. Moreover, we identified and allocated putative functions to the genes involved in tuberous root development, including genes related to major carbohydrate metabolism, hormone metabolism, and transcription regulation. The present study provides the initial description of gene expression profiles of AR, TAR, and DTR, which facilitates identification of genes of interest. Moreover, our work provides insights into the molecular mechanisms underlying tuberous root development and may assist in the design and development of improved breeding schemes for different R. glutinosa varieties through genetic manipulation. PMID- 26113850 TI - RNA based viral silencing suppression in plant pararetroviruses. AB - The 35S promoter of cauliflower mosaic virus and that of other plant pararetroviruses gives rise to an RNA, which is both a pre-genome and a polycistronic mRNA. The 600 nucleotide long very structured leader of this RNA is also transcribed separately. The resulting 8S RNA is then converted to a double strand giving rise to a huge set of siRNAs, which suppress silencing. In this Mini-Review I discuss how this versatile stretch of 600 nts constitutes a masterpiece of evolution. PMID- 26113851 TI - Factors influencing somatic embryogenesis, regeneration, and Agrobacterium mediated transformation of cassava (Manihot esculenta Crantz) cultivar TME14. AB - Routine production of large numbers of transgenic plants is required to fully exploit advances in cassava biotechnology and support development of improved germplasm for deployment to farmers. This article describes an improved, high efficiency transformation protocol for recalcitrant cassava cultivar TME14 preferred in Africa. Factors that favor production of friable embryogenic calli (FEC) were found to be use of DKW medium, crushing of organized embryogenic structures (OES) through 1-2 mm sized metal wire mesh, washing of crushed OES tissues and short exposure of tyrosine to somatic embryos; and transformation efficiency was enhanced by use of low Agrobacterium density during co cultivation, co-centrifugation of FEC with Agrobacterium, germination of paramomycin resistant somatic embryos on medium containing BAP with gradual increase in concentration and variations of the frequency of subculture of cotyledonary-stage embryos on shoot elongation medium. By applying the optimized parameters, FEC were produced for cassava cultivar TME14 and transformed using Agrobacterium strain LBA4404 harboring the binary vector pCAMBIA2301. About 70-80 independent transgenic lines per ml settled cell volume (SCV) of FEC were regenerated on selective medium. Histochemical GUS assays confirmed the expression of gusA gene in transformed calli, somatic embryos and transgenic plants. The presence and integration of the gusA gene were confirmed by PCR and Southern blot analysis, respectively. RT-PCR analysis of transgenic plants confirmed the expression of gusA gene. This protocol demonstrates significantly enhanced transformation efficiency over existing cassava transformation protocols and could become a powerful tool for functional genomics and transferring new traits into cassava. PMID- 26113852 TI - Current insights into hormonal regulation of microspore embryogenesis. AB - Plant growth regulator (PGR) crosstalk and interaction with the plant's genotype and environmental factors play a crucial role in microspore embryogenesis (ME), controlling microspore-derived embryo differentiation and development as well as haploid/doubled haploid plant regeneration. The complexity of the PGR network which could exist at the level of biosynthesis, distribution, gene expression or signaling pathways, renders the creation of an integrated model of ME-control crosstalk impossible at present. However, the analysis of the published data together with the results received recently with the use of modern analytical techniques brings new insights into hormonal regulation of this process. This review presents a short historical overview of the most important milestones in the recognition of hormonal requirements for effective ME in the most important crop plant species and complements it with new concepts that evolved over the last decade of ME studies. PMID- 26113854 TI - Plant signaling networks involving Ca(2+) and Rboh/Nox-mediated ROS production under salinity stress. AB - Salinity stress, which induces both ionic and osmotic damage, impairs plant growth and causes severe reductions in crop yield. Plants are equipped with defense responses against salinity stress such as regulation of ion transport including Na(+) and K(+), accumulation of compatible solutes and stress-related gene expression. The initial Ca(2+) influx mediated by plasma membrane ion channels has been suggested to be crucial for the adaptive signaling. NADPH oxidase (Nox)-mediated production of reactive oxygen species (ROS) has also been suggested to play crucial roles in regulating adaptation to salinity stress in several plant species including halophytes. Respiratory burst oxidase homolog (Rboh) proteins show the ROS-producing Nox activity, which are synergistically activated by the binding of Ca(2+) to EF-hand motifs as well as Ca(2+)-dependent phosphorylation. We herein review molecular identity, structural features and roles of the Ca(2+)-permeable channels involved in early salinity and osmotic signaling, and comparatively discuss the interrelationships among spatiotemporal dynamic changes in cytosolic concentrations of free Ca(2+), Rboh-mediated ROS production, and downstream signaling events during salinity adaptation in planta. PMID- 26113853 TI - Quantitative description of ion transport via plasma membrane of yeast and small cells. AB - Modeling of ion transport via plasma membrane needs identification and quantitative understanding of the involved processes. Brief characterization of main ion transport systems of a yeast cell (Pma1, Ena1, TOK1, Nha1, Trk1, Trk2, non-selective cation conductance) and determining the exact number of molecules of each transporter per a typical cell allow us to predict the corresponding ion flows. In this review a comparison of ion transport in small yeast cell and several animal cell types is provided. The importance of cell volume to surface ratio is emphasized. The role of cell wall and lipid rafts is discussed in respect to required increase in spatial and temporary resolution of measurements. Conclusions are formulated to describe specific features of ion transport in a yeast cell. Potential directions of future research are outlined based on the assumptions. PMID- 26113856 TI - Single cell-type comparative metabolomics of epidermal bladder cells from the halophyte Mesembryanthemum crystallinum. AB - One of the remarkable adaptive features of the halophyte Mesembryanthemum crystallinum are the specialized modified trichomes called epidermal bladder cells (EBC) which cover the leaves, stems, and peduncle of the plant. They are present from an early developmental stage but upon salt stress rapidly expand due to the accumulation of water and sodium. This particular plant feature makes it an attractive system for single cell type studies, with recent proteomics and transcriptomics studies of the EBC establishing that these cells are metabolically active and have roles other than sodium sequestration. To continue our investigation into the function of these unusual cells we carried out a comprehensive global analysis of the metabolites present in the EBC extract by gas chromatography Time-of-Flight mass spectrometry (GC-TOF) and identified 194 known and 722 total molecular features. Statistical analysis of the metabolic changes between control and salt-treated samples identified 352 significantly differing metabolites (268 after correction for FDR). Principal components analysis provided an unbiased evaluation of the data variance structure. Biochemical pathway enrichment analysis suggested significant perturbations in 13 biochemical pathways as defined in KEGG. More than 50% of the metabolites that show significant changes in the EBC, can be classified as compatible solutes and include sugars, sugar alcohols, protein and non-protein amino acids, and organic acids, highlighting the need to maintain osmotic homeostasis to balance the accumulation of Na(+) and Cl(-) ions. Overall, the comparison of metabolic changes in salt treated relative to control samples suggests large alterations in M. crystallinum epidermal bladder cells. PMID- 26113855 TI - The olive knot disease as a model to study the role of interspecies bacterial communities in plant disease. AB - There is an increasing interest in studying interspecies bacterial interactions in diseases of animals and plants as it is believed that the great majority of bacteria found in nature live in complex communities. Plant pathologists have thus far mainly focused on studies involving single species or on their interactions with antagonistic competitors. A bacterial disease used as model to study multispecies interactions is the olive knot disease, caused by Pseudomonas savastanoi pv. savastanoi (Psv). Knots caused by Psv in branches and other aerial parts of the olive trees are an ideal niche not only for the pathogen but also for many other plant-associated bacterial species, mainly belonging to the genera Pantoea, Pectobacterium, Erwinia, and Curtobacterium. The non-pathogenic bacterial species Erwinia toletana, Pantoea agglomerans, and Erwinia oleae, which are frequently isolated inside the olive knots, cooperate with Psv in modulating the disease severity. Co-inoculations of these species with Psv result in bigger knots and better bacterial colonization when compared to single inoculations. Moreover, harmless bacteria co-localize with the pathogen inside the knots, indicating the formation of stable bacterial consortia that may facilitate the exchange of quorum sensing signals and metabolites. Here we discuss the possible role of bacterial communities in the establishment and development of olive knot disease, which we believe could be taking place in many other bacterial plant diseases. PMID- 26113857 TI - A cupin domain-containing protein with a quercetinase activity (VdQase) regulates Verticillium dahliae's pathogenicity and contributes to counteracting host defenses. AB - We previously identified rutin as part of potato root responses to its pathogen Verticillium dahliae. Rutin was directly toxic to the pathogen at doses greater than 160 MUM, a threshold below which many V. dahliae pathogenicity-related genes were up-regulated. We identified and characterized a cupin domain-containing protein (VdQase) with a dioxygenase activity and a potential role in V. dahliae potato interactions. The pathogenicity of VdQase knock-out mutants generated through Agrobacterium tumefasciens-mediated transformation was significantly reduced on susceptible potato cultivar Kennebec compared to wild type isolates. Fluorescence microscopy revealed a higher accumulation of flavonols in the stems of infected potatoes and a higher concentration of rutin in the leaves in response to the VdQase mutants as compared to wild type isolates. This, along with the HPLC characterization of high residual and non-utilized quercetin in presence of the knockout mutants, indicates the involvement of VdQase in the catabolism of quercetin and possibly other flavonols in planta. Quantification of Salicylic and Jasmonic Acids (SA, JA) in response to the mutants vs. wild type isolates revealed involvement of VdQase in the interference with signaling, suggesting a role in pathogenicity. It is hypothesized that the by-product of dioxygenation 2-protocatechuoylphloroglucinolcarboxylic acid, after dissociating into phloroglucinol and protocatechuoyl moieties, becomes a starting point for benzoic acid and SA, thereby interfering with the JA pathway and affecting the interaction outcome. These events may be key factors for V. dahliae in countering potato defenses and becoming notorious in the rhizosphere. PMID- 26113858 TI - Trichoderma reesei FS10-C enhances phytoremediation of Cd-contaminated soil by Sedum plumbizincicola and associated soil microbial activities. AB - This study aimed to explore the effects of Trichoderma reesei FS10-C on the phytoremediation of Cd-contaminated soil by the hyperaccumulator Sedum plumbizincicola and on soil fertility. The Cd tolerance of T. reesei FS10-C was characterized and then a pot experiment was conducted to investigate the growth and Cd uptake of S. plumbizincicola with the addition of inoculation agents in the presence and absence of T. reesei FS10-C. The results indicated that FS10-C possessed high Cd resistance (up to 300 mg L(-1)). All inoculation agents investigated enhanced plant shoot biomass by 6-53% of fresh weight and 16-61% of dry weight and Cd uptake by the shoots by 10-53% compared with the control. All inoculation agents also played critical roles in increasing soil microbial biomass and microbial activities (such as biomass C, dehydrogenase activity and fluorescein diacetate hydrolysis activity). Two inoculation agents accompanied by FS10-C were also superior to the inoculation agents, indicating that T. reesei FS10-C was effective in enhancing both Cd phytoremediation by S. plumbizincicola and soil fertility. Furthermore, solid fermentation powder of FS10-C showed the greatest capacity to enhance plant growth, Cd uptake, nutrient release, microbial biomass and activities, as indicated by its superior ability to promote colonization by Trichoderma. The solid fermentation powder of FS10-C might serve as a suitable inoculation agent for T. reesei FS10-C to enhance both the phytoremediation efficiency of Cd-contaminated soil and soil fertility. PMID- 26113862 TI - Transvaginal Drainage of Pelvic Abscesses and Collections Using Transabdominal Ultrasound Guidance. AB - Objectives. To evaluate clinical outcomes following transvaginal catheter placement using transabdominal ultrasound guidance for management of pelvic fluid collections. Methods. A retrospective review was performed for all patients who underwent transvaginal catheter drainage of pelvic fluid collections utilizing transabdominal ultrasound guidance between July 2008 and July 2013. 24 consecutive patients were identified and 24 catheters were placed. Results. The mean age of patients was 48.1 years (range = 27-76 y). 88% of collections were postoperative (n = 21), 8% were from pelvic inflammatory disease (n = 2), and 4% were idiopathic (n = 1). Of the 24 patients, 83% of patients (n = 20) had previously undergone a hysterectomy and 1 patient (4%) was pregnant at the time of drainage. The mean volume of initial drainage was 108 mL (range = 5 to 570). Catheters were left in place for an average of 4.3 days (range = 1-17 d). Microbial sampling was performed in all patients with 71% (n = 17) returning a positive culture. All collections were successfully managed percutaneously. There were no technical complications. Conclusions. Transvaginal catheter drainage of pelvic fluid collections using transabdominal ultrasound guidance is a safe and clinically effective procedure. Appropriate percutaneous management can avoid the need for surgery. PMID- 26113861 TI - A Robust and Fast Computation Touchless Palm Print Recognition System Using LHEAT and the IFkNCN Classifier. AB - Mobile implementation is a current trend in biometric design. This paper proposes a new approach to palm print recognition, in which smart phones are used to capture palm print images at a distance. A touchless system was developed because of public demand for privacy and sanitation. Robust hand tracking, image enhancement, and fast computation processing algorithms are required for effective touchless and mobile-based recognition. In this project, hand tracking and the region of interest (ROI) extraction method were discussed. A sliding neighborhood operation with local histogram equalization, followed by a local adaptive thresholding or LHEAT approach, was proposed in the image enhancement stage to manage low-quality palm print images. To accelerate the recognition process, a new classifier, improved fuzzy-based k nearest centroid neighbor (IFkNCN), was implemented. By removing outliers and reducing the amount of training data, this classifier exhibited faster computation. Our experimental results demonstrate that a touchless palm print system using LHEAT and IFkNCN achieves a promising recognition rate of 98.64%. PMID- 26113860 TI - Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality. AB - To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytical tools. With the advent of high throughput sequencing technologies, obtaining genome-wide population genetic data has become easier than ever before. We previously contributed the R package poppr specifically addressing issues with analysis of clonal populations. In this paper we provide several significant extensions to poppr with a focus on large, genome-wide SNP data. Specifically, we provide several new functionalities including the new function mlg.filter to define clone boundaries allowing for inspection and definition of what is a clonal lineage, minimum spanning networks with reticulation, a sliding-window analysis of the index of association, modular bootstrapping of any genetic distance, and analyses across any level of hierarchies. PMID- 26113859 TI - Targeting ATM-deficient CLL through interference with DNA repair pathways. AB - Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world and accounts for approximately 30% of adult leukemias and 25% of non-Hodgkin lymphomas. The median age at diagnosis is 72 years. During recent years numerous genetic aberrations have been identified that are associated with an aggressive course of the disease and resistance against genotoxic chemotherapies. The DNA damage-responsive proapoptotic ATM-CHK2-p53 signaling pathway is frequently mutationally inactivated in CLL either through large deletions on chromosome 11q (ATM) or 17p (TP53), or through protein-damaging mutations. Here, we focus on the role of ATM signaling for the immediate DNA damage response, DNA repair and leukemogenesis. We further discuss novel therapeutic concepts for the targeted treatment of ATM-defective CLLs. We specifically highlight the potential use of PARP1 and DNA-PKcs inhibitors for the treatment of ATM-mutant CLL clones. Lastly, we briefly discuss the current state of genetically engineered mouse models of the disease and emphasize the use of these preclinical tools as a common platform for the development and validation of novel therapeutic agents. PMID- 26113863 TI - Parkinsonism and Sjogren's Syndrome: A Fortuitous Association or a Shared Immunopathogenesis? AB - Background. The Sjogren Syndrome (SS) can include various manifestations of central nervous system impairment. Extrapyramidal signs are known to be very rare and unusually discovered on early onset in this pathology. Observation. A 46-year old woman with a history of progressive Parkinsonism for 6 years and a normal brain magnetic resonance imaging was partially improved with levodopa therapy. The later discovery of a sicca syndrome led to performing of further investigations, which revealed the presence of anti-SSA antibodies and a sialoadenitis of grade 4 according to Chisholm's classification on labial salivary gland biopsy. The diagnosis of primary SS was established and the adjunction of corticotherapy has remarkably improved Parkinson's signs without use of other immunosuppressive agents. Conclusion. Based on these findings, we discuss the hypothesis of either a causal link between SS and Parkinsonism or a fortuitous association of two distinct pathologies with or without a shared immunopathogenesis. PMID- 26113864 TI - Treatment of Oroantral Communication Using the Lateral Palatal Sliding Flap Technique. AB - Herein, we present a case of oroantral communication that was to be treated with clinical examination, tomography, and prototyping. A patient presented with oroantral communication with purulent exudation for 4 months, since the displacement of the dental implant and O-ring component to the maxillary sinus. Tomographic examination and prototyping revealed a 5 mm bone gap. The patient underwent local washes and antibiotic therapy. After local palpation, a bone defect detected by prototyping was suspected to be greater than that observed. For the surgery, a communication tunnel was made, and the bone defect was found to be 12 mm in diameter. A pedicle flap was raised on the palate, followed by sliding and suturing. No complications were observed during the postoperative period, and the suture was removed after a week. Four months later, communication did not resume, and the patient did not complain of pain, foul smelling, or purulent discharge and was satisfied with the outcome. The findings of this case suggest that the lateral sliding flap can be used as an efficient technique for closing oroantral communications. An accurate clinical examination is a critical tool that can be used instead of tomography and prototyping, which can be misleading. PMID- 26113867 TI - Effect of Sterols Isolated from Myrtillocactus geometrizans on Growth Inhibition of Colon and Breast Cancer Cells. AB - Objective. To explore the effect of peniocerol and macdougallin on HCT-15 and MCF 7 cells proliferation, cell cycle, apoptosis, and PARP cleavage. Methods. HCT-15 and MCF-7 cells were treated with various concentrations of peniocerol and macdougallin (10-80 MUM) during 24 or 48 h. Crystal Violet Assay was used to evaluate the inhibition effect. Cell cycle regulation was examined by a propidium iodide method. Cell apoptosis was detected through both Annexin-V FLUOS/PI double labeled cytometry assays and Western blot was applied to assess PARP cleavage. Results. Peniocerol and macdougallin induced growth inhibition and apoptosis in vitro in a time- and dose-dependent manner. Moreover, peniocerol and macdougallin induced arrest of cell cycle-dependent manner and increased the proportion of cells in G0/G1 phase. PARP cleavage in HCT-15 and MCF-7 cells was induced by treatment with peniocerol and macdougallin after 36 hours. Conclusions. Our results showed that the mechanism of cytotoxicity displayed by peniocerol and macdougallin is related to cell cycle arrest and apoptosis in both cell lines. This is a significant observation because it helps to understand the way some oxysterols isolated from Myrtillocactus geometrizans develop their biological activities against cancer cells. PMID- 26113865 TI - Making Blood: The Haematopoietic Niche throughout Ontogeny. AB - Approximately one-quarter of all cells in the adult human body are blood cells. The haematopoietic system is therefore massive in scale and requires exquisite regulation to be maintained under homeostatic conditions. It must also be able to respond when needed, such as during infection or following blood loss, to produce more blood cells. Supporting cells serve to maintain haematopoietic stem and progenitor cells during homeostatic and pathological conditions. This coalition of supportive cell types, organised in specific tissues, is termed the haematopoietic niche. Haematopoietic stem and progenitor cells are generated in a number of distinct locations during mammalian embryogenesis. These stem and progenitor cells migrate to a variety of anatomical locations through the conceptus until finally homing to the bone marrow shortly before birth. Under stress, extramedullary haematopoiesis can take place in regions that are typically lacking in blood-producing activity. Our aim in this review is to examine blood production throughout the embryo and adult, under normal and pathological conditions, to identify commonalities and distinctions between each niche. A clearer understanding of the mechanism underlying each haematopoietic niche can be applied to improving ex vivo cultures of haematopoietic stem cells and potentially lead to new directions for transplantation medicine. PMID- 26113866 TI - Electronic Health Record Analysis of the Primary Care of Adults with Intellectual and Other Developmental Disabilities. AB - BACKGROUND AND AIMS: Adults with intellectual and other developmental disabilities (IDD) are at risk for sub-optimal primary health care. Electronic Health Record (EHR) analyses are an under-utilized resource for studying the health and primary care of this population. METHODS: This was a case-control EHR analysis of adults with IDD provided primary care through the Cleveland Clinic between 2005 and 2008. The IDD cohort was identified by relevant ICD-9 codes in problem list and encounter diagnoses. A comparison cohort matched by age, sex, race, and insurance was also specified. Demographic, health and health service characteristics of the two cohorts were compared. FINDINGS: The IDD cohort consisted of 1267 individuals, mean age 39 years, 54% male, 78% Caucasian. Age, sex, racial, and health insurance characteristics were similar in the 2534 individuals in the comparison cohort. Individuals with IDD were significantly more likely to carry diagnoses of epilepsy, constipation, osteoporosis, obesity, and hyperlipidemia; but were significantly less likely to bear diagnoses of hypertension, diabetes, osteoarthritis, heart failure, coronary heart disease, and COPD. Despite a lower mean BMI, individuals with IDD were more likely to be labeled obese. Only genetic consultation rates were higher in the IDD cohort. DISCUSSION: Health services research related to persons with IDD is becoming more feasible as large health systems adopt EHRs. Further analyses from this dataset will investigate whether variations in disease rates in adults with IDD represent true differences in disease prevalence versus disparities in health care. PMID- 26113868 TI - Effects on Liver Lipid Metabolism of the Naturally Occurring Dietary Flavone Luteolin-7-glucoside. AB - Disruptions in whole-body lipid metabolism can lead to the onset of several pathologies such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs). The present study aimed at elucidating the molecular mechanisms behind the lipid-lowering effects of the flavone luteolin-7-glucoside (L7G) which we previously showed to improve plasma lipid profile in rats. L7G is abundant in plant foods of Mediterranean diet such as aromatic plants used as herbs. Results show that dietary supplementation with L7G for one week induced the expression of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and of its target gene carnitine palmitoyl transferase 1 (CPT-1) in rat liver. L7G showed a tendency to decrease the hepatic expression of sterol regulatory element-binding protein-1 (SREBP-1), without affecting fatty acid synthase (FAS) protein levels. Although SREBP-2 and LDLr mRNA levels did not change, the expression of HMG CoA reductase (HMGCR) was significantly repressed by L7G. L7G also inhibited this enzyme's in vitro activity in a dose dependent manner, but only at high and not physiologically relevant concentrations. These results add new evidence that the flavone luteolin-7-glucoside may help in preventing metabolic diseases and clarify the mechanisms underlying the beneficial health effects of diets rich in fruits and vegetables. PMID- 26113869 TI - Therapeutic Touch Has Significant Effects on Mouse Breast Cancer Metastasis and Immune Responses but Not Primary Tumor Size. AB - Evidence-based integrative medicine therapies have been introduced to promote wellness and offset side-effects from cancer treatment. Energy medicine is an integrative medicine technique using the human biofield to promote well-being. The biofield therapy chosen for study was Therapeutic Touch (TT). Breast cancer tumors were initiated in mice by injection of metastatic 66cl4 mammary carcinoma cells. The control group received only vehicle. TT or mock treatments were performed twice a week for 10 minutes. Two experienced TT practitioners alternated treatments. At 26 days, metastasis to popliteal lymph nodes was determined by clonogenic assay. Changes in immune function were measured by analysis of serum cytokines and by fluorescent activated cells sorting (FACS) of immune cells from the spleen and lymph nodes. No significant differences were found in body weight gain or tumor size. Metastasis was significantly reduced in the TT-treated mice compared to mock-treated mice. Cancer significantly elevated eleven cytokines. TT significantly reduced IL-1-a, MIG, IL-1b, and MIP-2 to control/vehicle levels. FACS demonstrated that TT significantly reduced specific splenic lymphocyte subsets and macrophages were significantly elevated with cancer. Human biofield therapy had no significant effect on primary tumor but produced significant effects on metastasis and immune responses in a mouse breast cancer model. PMID- 26113871 TI - Maternal intravenous fluids and postpartum breast changes: a pilot observational study. AB - BACKGROUND: The current breastfeeding initiation rate in Canada is approximately 87%. By one month, about 21% of women have stopped breastfeeding. Engorgement and edema in breast tissue can lead to breastfeeding challenges which may contribute to early weaning. The aims of this pilot research study were to explore the relationship between intrapartum intravenous fluids given to mothers and postpartum breast swelling in the first 10 days postpartum and to determine if a larger study was warranted and feasible. METHODS: A prospective, longitudinal, observational cohort pilot study with repeated measures and a within-subjects design was completed. Participants were first time mothers who have a single, healthy newborn and had a spontaneous vaginal birth. Daily data collection from admission into the study until postpartum day 10 took place. Descriptive statistics are reported and linear regression analysis was used to model the relationship between IV therapy and postpartum breast edema. RESULTS: Women who received intravenous fluids during labour had higher levels of breast edema postpartum and rated their breasts as firmer and more tender than women who did not receive intravenous fluids. Participants who had intravenous fluids described patterns of fullness that appeared to be related to edema as opposed to fullness associated with engorgement and lactogenesis II. CONCLUSIONS: The findings demonstrate that mothers in this pilot study who received intravenous fluids in labour and postpartum had higher levels of breast edema. These results suggest a larger study is warranted to more fully examine the effects of intravenous fluids on postpartum breast swelling. PMID- 26113870 TI - Children and youth with 'unspecified injury to the head': implications for traumatic brain injury research and surveillance. AB - BACKGROUND: The case definition for traumatic brain injury (TBI) often includes 'unspecified injury to the head' diagnostic codes. However, research has shown that the inclusion of these codes leads to false positives. As such, it is important to determine the degree to which inclusion of these codes affect the overall numbers and profiles of the TBI population. The objective of this paper was to profile and compare the demographic and clinical characteristics, intention and mechanism of injury, and discharge disposition of hospitalized children and youth aged 19 years and under using (1) an inclusive TBI case definition that included 'unspecified injury to the head' diagnostic codes, (2) a restricted TBI case definition that excluded 'unspecified injury to the head 'diagnostic codes, and (3) the 'unspecified injury to the head' only case definition. METHODS: The National Ambulatory Care Reporting System and the Discharge Abstract Database from Ontario, Canada, were used to identify cases between fiscal years 2003/04 and 2009/10. RESULTS: The rate of TBI episodes of care using the inclusive case definition for TBI (2,667.2 per 100,000) was 1.65 times higher than that of the restricted case definition (1,613.3 per 100,000). 'Unspecified injury to the head' diagnostic codes made up of 39.5 % of all cases identified with the inclusive case definition. Exclusion of 'unspecified injury to the head' diagnostic code in the TBI case definition resulted in a significantly higher proportion of patients in the intensive care units (p < .0001; 18.5 % vs. 22.2 %) and discharged to a non-home setting (p < .0001; 9.9 % vs. 11.6 %). CONCLUSION: Inclusion of 'unspecified injury to the head' diagnostic codes resulted in significant changes in numbers, healthcare use, and causes of TBI. Careful consideration of the inclusion of 'unspecified injury to the head' diagnostic codes in the case definition of TBI for the children and youth population is important, as it has implications for the numbers used for policy, resource allocation, prevention, and planning of healthcare services. This paper can inform future work on reaching consensus on the diagnostic codes for defining TBI in children and youth. PMID- 26113872 TI - Biases underlying species detection using fluorescent amplified-fragment length polymorphisms yielded from roots. AB - BACKGROUND: Roots of different plant species are typically morphologically indistinguishable. Of the DNA-based techniques, fluorescent amplified-fragment length polymorphisms (FAFLPs) are considered reliable, high throughput, inexpensive methods to identify roots from mixed species samples. False negatives, however, are not uncommon and their underlying causes are poorly understood. We investigated several sources of potential biases originating in DNA extraction and amplification. Specifically, we examined the effects of sample storage, tissue, and species on DNA yield and purity, and the effects of DNA concentration and fragment size on amplification of three non-coding chloroplast regions (trnT-trnL intergenic spacer, trnL intron, and trnL-trnF intergenic spacer). RESULTS: We found that sample condition, tissue and species all affected DNA yield. A single freeze-thaw reduces DNA yield, DNA yield is less for roots than shoots, and species vary in the amount of DNA yielded from extractions. The effects of template DNA concentration, species identity, and their interaction on amplicon yield differed across the three chloroplast regions tested. We found that the effect of species identity on amplicon production was generally more pronounced than that of DNA concentration. Though these factors influenced DNA yield, they likely do not have a pronounced effect on detection success of fragments and only underscore the restriction on the use of FAFLPs for measuring species presence rather than their abundance. However, for two of the regions tested-the trnT-trnL intergenic spacer and the trnL intron-size-based fragment competition occurred and the likelihood of detection was higher for smaller than larger fragments. This result reveals a methodological bias when using FAFLPs. CONCLUSIONS: To avoid potential bias with the use of FAFLPs, we recommend users check for the disproportionate absence of species detected belowground versus aboveground as a function of fragment size, and explore other regions, aside from the trnT-trnL intergenic spacer and trnL intron, for amplification. PMID- 26113873 TI - Electrical Neuroimaging with Irrotational Sources. AB - This paper discusses theoretical aspects of the modeling of the sources of the EEG (i.e., the bioelectromagnetic inverse problem or source localization problem). Using the Helmholtz decomposition (HD) of the current density vector (CDV) of the primary current into an irrotational (I) and a solenoidal (S) part we show that only the irrotational part can contribute to the EEG measurements. In particular we present for the first time the HD of a dipole and of a pure irrotational source. We show that, for both kinds of sources, I extends all over the space independently of whether the source is spatially concentrated (as the dipole) or not. However, the divergence remains confined to a region coinciding with the expected location of the sources, confirming that it is the divergence rather than the CDV that really defines the spatial extension of the generators, from where it follows that an irrotational source model (ELECTRA) is always physiologically meaningful as long as the divergence remains confined to the brain. Finally we show that the irrotational source model remains valid for the most general electrodynamics model of the EEG in inhomogeneous anisotropic dispersive media and thus far beyond the (quasi) static approximation. PMID- 26113874 TI - Lost in chemical space? Maps to support organometallic catalysis. AB - Descriptors calculated from molecular structures have been used to map different areas of chemical space. A number of applications for such maps can be identified, ranging from the fine-tuning and optimisation of catalytic activity and compound properties to virtual screening of novel compounds, as well as the exhaustive exploration of large areas of chemical space by automated combinatorial building and evaluation. This review focuses on organometallic catalysis, but also touches on other areas where similar approaches have been used, with a view to assessing the extent to which chemical space has been explored. Graphical abstractCartoon representation of a chemical space map. PMID- 26113875 TI - Dietary compounds galangin and myricetin suppress ovarian cancer cell angiogenesis. AB - Galangin and myricetin are flavonoids isolated from vegetables and fruits which exhibit anti-proliferative activity in human cancer cells. In this study, their anti-angiogenic effects were investigated with in vitro (HUVEC) and in vivo (CAM) models, which showed that galangin and myricetin inhibited angiogenesis induced by OVCAR-3 cells. The molecular mechanisms through which galangin and myricetin suppress angiogenesis were also studied. It was observed that galangin and myricetin inhibited secretion of the key angiogenesis mediator vascular endothelial growth factor (VEGF) and decreased levels of p-Akt, p-70S6K and hypoxia-inducible factor-1alpha (HIF-1alpha) proteins in A2780/CP70 and OVCAR-3 cells. Transient transfection experiments showed that galangin and myricetin inhibited secretion of VEGF by the Akt/p70S6K/ HIF-1alpha pathway. Moreover, a novel pathway, p21/HIF-1alpha/VEGF, was found to be involved in the inhibitory effect of myricetin on angiogenesis in OVCAR-3 cells. These data suggest that galangin and myricetin might serve as potential anti-angiogenic agents in the prevention of ovarian cancers dependent on new blood vessel networks. PMID- 26113876 TI - Wanderer, an interactive viewer to explore DNA methylation and gene expression data in human cancer. AB - BACKGROUND: The Cancer Genome Atlas (TCGA) offers a multilayered view of genomics and epigenomics data of many human cancer types. However, the retrieval of expression and methylation data from TCGA is a cumbersome and time-consuming task. RESULTS: Wanderer is an intuitive Web tool allowing real time access and visualization of gene expression and DNA methylation profiles from TCGA. Given a gene query and selection of a TCGA dataset (e.g., colon adenocarcinomas), the Web resource provides the expression profile, at the single exon level, and the DNA methylation levels of HumanMethylation450 BeadChip loci inside or in the vicinity of the queried gene. Graphic and table outputs include individual and summary data as well as statistical tests, allowing the comparison of tumor and normal profiles and the exploration along the genomic locus and across tumor collections. CONCLUSIONS: Wanderer offers a simple interface to straightforward access to TCGA data, amenable to experimentalists and clinicians without bioinformatics expertise. Wanderer may be accessed at http://maplab.cat/wanderer. PMID- 26113877 TI - Widespread intron retention diversifies most cancer transcriptomes. AB - BACKGROUND: Somatic mutations affecting components of the RNA splicing machinery occur with high frequencies across many tumor types. These mutations give rise to distinct alterations in normal splice site and exon recognition, such as unusual 3' splice site preferences, that likely contribute to tumorigenesis. METHODS: We analyzed genome-wide patterns of RNA splicing across 805 matched tumor and normal control samples from 16 distinct cancer types to identify signals of abnormal cancer-associated splicing. RESULTS: We found that abnormal RNA splicing, typified by widespread intron retention, is common across cancers even in the absence of mutations directly affecting the RNA splicing machinery. Almost all liquid and solid cancer types exhibited frequent retention of both alternative and constitutive introns relative to control normal tissues. The sole exception was breast cancer, where intron retention typified adjacent normal rather than cancer tissue. Different introns were preferentially retained in specific cancer types, although a small subset of introns enriched for genes encoding RNA splicing and export factors exhibited frequent retention across diverse cancers. The extent of intron retention correlated with the presence of IDH1 and IDH2 mutations in acute myeloid leukemia and across molecular subtypes in breast cancer. Many introns that were preferentially retained in primary cancers were present at high levels in the cytoplasmic mRNA pools of cancer cell lines. CONCLUSIONS: Our data indicate that abnormal RNA splicing is a common characteristic of cancers even in the absence of mutational insults to the splicing machinery, and suggest that intron-containing mRNAs contribute to the transcriptional diversity of many cancers. PMID- 26113878 TI - Synthesis of a hexasaccharide partial sequence of hyaluronan for click chemistry and more. AB - In the present work, the synthesis of a hexasaccharide partial sequence of hyaluronan equipped with a terminal azido moiety is reported. This hexasaccharide can be used for the attachment on surfaces by means of click chemistry and after suitable deprotection for biophysical studies. PMID- 26113879 TI - DNA display of glycoconjugates to emulate oligomeric interactions of glycans. AB - Glycans (carbohydrate portion of glycoproteins and glycolipids) frequently exert their function through oligomeric interactions involving multiple carbohydrate units. In efforts to recapitulate the diverse spatial arrangements of the carbohydrate units, assemblies based on hybridization of nucleic acid conjugates have been used to display simplified ligands with tailored interligand distances and valences. The programmability of the assemblies lends itself to a combinatorial display of multiple ligands. Recent efforts in the synthesis and applications of such conjugates are discussed. PMID- 26113880 TI - Special Issue on: Twelfth International Conference on Ontologies, Databases, and Applications of Semantics. PMID- 26113881 TI - Direct Electrochemical Addressing of Immobilized Alcohol Dehydrogenase for the Heterogeneous Bioelectrocatalytic Reduction of Butyraldehyde to Butanol. AB - Modified electrodes using immobilized alcohol dehydrogenase enzymes for the efficient electroreduction of butyraldehyde to butanol are presented as an important step for the utilization of CO2-reduction products. Alcohol dehydrogenase was immobilized, embedded in an alginate-silicate hybrid gel, on a carbon felt (CF) electrode. The application of this enzyme to the reduction of an aldehyde to an alcohol with the aid of the coenzyme nicotinamide adenine dinucleotide (NADH), in analogy to the final step in the natural reduction cascade of CO2 to alcohol, has been already reported. However, the use of such enzymatic reductions is limited because of the necessity of providing expensive NADH as a sacrificial electron and proton donor. Immobilization of such dehydrogenase enzymes on electrodes and direct pumping of electrons into the biocatalysts offers an easy and efficient way for the biochemical recycling of CO2 to valuable chemicals or alternative synthetic fuels. We report the direct electrochemical addressing of immobilized alcohol dehydrogenase for the reduction of butyraldehyde to butanol without consumption of NADH. The selective reduction of butyraldehyde to butanol occurs at room temperature, ambient pressure and neutral pH. Production of butanol was detected by using liquid-injection gas chromatography and was estimated to occur with Faradaic efficiencies of around 40 %. PMID- 26113882 TI - Broken vows and the next generation: Recognizing and helping when parental divorce is a spiritual trauma. AB - Recent national surveys show that older youth who have experienced parental divorce tend to disengage from organized religion but feel as close to God as peers from intact families. In this paper, we offer a conceptual model and concrete guidelines to help adults engage in sensitive, yet direct, dialogues with older youth about the spiritual dimensions of parental divorce. Based on a recent line of empirical research on the role of religion and spirituality for post-divorce adjustment, we argue that parental divorce can be experienced as a spiritual trauma where the event is interpreted as a sacred loss and desecration, and can also trigger painful spiritual struggles. Yet youth can also draw upon adaptive religious/spiritual methods to cope with the transition. We illustrate these psychospiritual processes using quotes from a study of college students who had experienced a parental divorce within the prior five years. We end with a list of questions that parents, pastoral counselors, clergy, and mental health professionals can draw upon to explore the intersection of faith and divorce with adolescents. PMID- 26113883 TI - Mental health literacy among secondary school students in North and Central Uganda: a qualitative study. AB - OBJECTIVES: There has been limited effort to explore young people's perceptions about mental illness in Uganda. For mental health programs targeting young people to succeed, it is important to incorporate their understanding of mental illness, their perceptions about causes of mental illness and their attitudes about mentally ill people. The objective of this study was to explore the mental health of young people in secondary schools in Northern and Central Uganda. SUBJECTS AND METHODS: This was a qualitative study where 24 focus group discussions (FGDs) were held with young people in secondary schools. Respondents aged 14-24 years were purposively selected from 4 secondary schools in the two regions. During the FGDs, young people's perceptions and understanding of three areas listed below were explored: meaning of mental health/mental illness; causes of mental illness and attitudes toward mental illness. Data management and analysis was done with the help of Atlas.ti, a-qualitative-analysis software. Thematic analysis approach was employed. RESULTS: FGD participants used concepts like a sound and normal mind, right thinking, normal behavior and normal thoughts to define mental health. Mental illness on the other hand was defined as loss of sense of reality, malfunctioning of the brain, impaired thinking and bizarre behavior. Young people attributed mental illness to; substance abuse (Marijuana, alcohol), witnessing traumatic events (seeing ones your relatives being killed, or being forced to participate in killing-frequently mentioned by young people in Northern Uganda); witch craft, effect of physical illness e.g. HIV/epilepsy, thinking too much, accidents and genetic explanations. They had mixed opinions about interacting with mentally ill individuals. Unpredictability and dangerousness were known to be a recurrent theme among people with negative views about mentally ill. Nonetheless, some FGD participants believed that the level of interaction with mentally ill persons depended on familiarity with mental illness and the severity of the symptoms. Similarly, there were mixed opinions regarding mental illness and work. Three main clusters of responses emerged. These were: i) "mentally ill people should not work"; ii) "mentally ill people should work but.."; iii) "mentally ill people should work like everyone else". CONCLUSIONS: Findings point to key gaps in the knowledge and attitudes of young people that need to be targeted by young-people-focused-interventions for mental health. In order for such interventions to succeed, young people must be able to recognize and respond appropriately to signs of distress, reduced functioning, and other early signs of poor mental health. PMID- 26113884 TI - A New Type of Electron Relay Station in Proteins: Three-Piece S:Pi?S<->S?Pi:S Resonance Structure. AB - A type of relay station for electron transfer in proteins, three-piece five electron bonding, is introduced in this paper, which is also first proposed here. The ab initio calculations predict the formation of S:Pi?S<->S?Pi:S resonance binding with an aromatic ring located in the middle of two sulfur-containing groups, which may participate in electron-hole transport in proteins. These special structures can lower the local ionization energies to capture electron holes efficiently and may be easily formed and broken because of their proper binding energies. In addition, the UV-vis spectra provide evidence of the formations of the three-piece five-electron binding. The cooperation of three adjacent pieces may be advantage to promote electron transfer a longer distance. PMID- 26113885 TI - Silver-Overgrowth-Induced Changes in Intrinsic Optical Properties of Gold Nanorods: From Noninvasive Monitoring of Growth Kinetics to Tailoring Internal Mirror Charges. AB - We investigate the effect of surfactant-mediated, asymmetric silver overgrowth of gold nanorods on their intrinsic optical properties. From concentration-dependent experiments, we established a close correlation of the extinction in the UV/vis/NIR frequency range and the morphological transition from gold nanorods to Au@Ag cuboids. Based on this correlation, a generic methodology for in situ monitoring of the evolution of the cuboid morphology was developed and applied in time-dependent experiments. We find that growth rates are sensitive to the substitution of the surfactant headgroup by comparison of benzylhexadecyldimethylammonium chloride (BDAC) with hexadecyltrimethylammonium chloride (CTAC). The time-dependent overgrowth in BDAC proceeds about 1 order of magnitude slower than in CTAC, which allows for higher control during silver overgrowth. Furthermore, silver overgrowth results in a qualitatively novel optical feature: Upon excitation inside the overlap region of the interband transition of gold and intraband of silver, the gold core acts as a retarding element. The much higher damping of the gold core compared to the silver shell in Au@Ag cuboids induces mirror charges at the core/shell interface as shown by electromagnetic simulations. Full control over the kinetic growth process consequently allows for precise tailoring of the resonance wavelengths of both modes. Tailored and asymmetric silver-overgrown gold nanorods are of particular interest for large-scale fabrication of nanoparticles with intrinsic metamaterial properties. These building blocks could furthermore find application in optical sensor technology, light harvesting, and information technology. PMID- 26113886 TI - [Bladder tumor in young patients: about 36 cases]. PMID- 26113887 TI - [Sinonasal Hemangiopericytoma: diagnostic and therapeutic challenge]. PMID- 26113888 TI - Conjunctival epidermoid carcinoma: a case report. PMID- 26113889 TI - Neglected rupture of the quadriceps tendon in a patient with chronic renal failure (case report and review of the literature). AB - Spontaneous ruptures of the quadriceps tendon are infrequent injuries, it is seen primarily in patients with predisposing diseases such as gout, rheumatoid arthritis and chronic renal failure. A 32-year-old man had a history of end stage renal disease and received regular hemodialysis treatment for more than 5 years. He was admitted in our service for total functional impotence of the right lower limb with knee pain after a common fall two months ago. The radiogram showed a ''patella baja" with suprapatellar calcifications. The ultrasound and MRI showed an aspect of rupture of the quadriceps tendon in its proximal end with retraction of 3 cm. Quadriceps tendon repair was performed with a lengthening plasty, and the result was satisfactory after a serial rehabilitation program. The diagnosis of quadriceps tendon ruptures needs more attention in patients with predisposing diseases. They should not be unknown because the treatment of neglected lesions is more difficult. We insist on the early surgical repair associated with early rehabilitation that can guarantee recovery of good active extension. PMID- 26113890 TI - Importance of extending the use of polymerase chain reaction in the diagnosis of venereal syphilis in a blood transfusion center in Burkina Faso, West Africa. AB - INTRODUCTION: Due to the existence of a variety of types of non-venereal syphilis caused by the related T. pallidum, regular serological testing such as Rapid Plasma Reagin (RPR) and Chemiluminescent Microparticle Immunoassay Technique (CMIA) are often unable to differentiate venereal syphilis from the non- venereal one, hence, the interest in the use of molecular biology testing for a confirmation diagnosis of syphilis caused by Treponema pallidum subspecies pallidum. OBJECTIVE: The study is designed to assess the effectiveness of PCR testing and serological methods in the diagnosis of Treponema pallidum subsp pallidum among blood donors in Burkina Faso. METHODS: The study included 6375 samples of volunteer blood donors from the regional blood transfusion center of Ouagadougou (CRTS/O). Among samples, 183 positive and 59 negative in RPR were analyzed to detect antibodies anti-T. pallidum subsp pallidum with a immunoassay method (CMIA) and were confirmed using the Polymerase Chain Reaction testing. RESULTS: In RPR, we obtained a prevalence rate of 2.9% (183/6375) for treponematosis. From the 183 RPR+ specimen, 108 (59%) were found CMIA+ and 11 (6%) were confirmed PCR+. While the 59 pattern RPR-; 31 (52.5%) were CMIA + including 3 (5.1%) tested PCR+. Seventy-five (75) samples RPR + /CMIA-; 2 (2.7%) were confirmed positive by PCR. All 28 samples RPR-/CMIA- were confirmed negative by PCR. CONCLUSION: PCR testing confirmed a low distribution of T. pallidum subsp pallidum in comparison to serological methods. Cross-reactions, existence of non venereal treponemal or immunological scars could account for the discrepancy between the results obtained. PMID- 26113891 TI - [Severe head and neck cellulitis, risk factors and severity criteria]. PMID- 26113892 TI - [Results of tubal plasty: ruslts of a Tunisian study]. PMID- 26113893 TI - Implementing primary health care-based PMTCT interventions: operational perspectives from Muhima cohort analysis (Rwanda). AB - INTRODUCTION: In countries with high burden of HIV, major programmatic challenges have been identified to preventing new infections among children and scaling up of treatment for pregnant mothers. We initiated this study to examine operational approaches that were used to enhance implementation of PMTCT interventions in Muhima health Centre (Kigali/Rwanda) from 2007 to 2010. METHODS: The prospective cohort study was conducted at Muhima health centre. A sample size of 656 was the minimum number required for the study. The main outcome was cumulative incidence of mother - to - child transmission of HIV-1 measured at 6 weeks of life among live born children. RESULTS: Among the 679 live born babies and followed up in this study, the overall cumulative rate of HIV-1 mother - to - child transmission observed was 3.2% at 6 weeks of age after birth. Disclosure of HIV status to partner was significantly associated with HIV-1 status of infants at 6 weeks of age (non-disclosure of HIV status adjusted odds ratio [AOR] 4.68, CI 1.39 to 15.77, p. CONCLUSION: The Muhima type of decentralized health facility offered an appropriate platform for implementation of PMTCT interventions, with the following operational features: family - centered approach; integrated service delivery for PMTCT/MCH interventions, task shifting; subsidized membership fees for people living with HIV, allowing for access to the community-based health insurance benefits. PMID- 26113894 TI - Assessing the prevalence of spina bifida and encephalocele in a Kenyan hospital from 2005-2010: implications for a neural tube defects surveillance system. AB - INTRODUCTION: Neural tube defects such as anencephaly, spina bifida, and encephalocele are congenital anomalies of the central nervous system. Data on the prevalence of neural tube defects in Kenya are limited. This study characterizes and estimates the prevalence of spina bifida and encephalocele reported in a referral hospital in Kenya from 2005-2010. METHODS: Cases were defined as a diagnosis of spina bifida or encephalocele. Prevalence was calculated as the number of cases by year and province of residence divided by the total number of live-births per province. RESULTS: From a total of 6,041 surgical records; 1,184 (93%) had reported diagnosis of spina bifida and 88 (7%) of encephalocele. Estimated prevalence of spina bifida and encephalocele from 2005-2010 was 3.3 [95% Confidence Interval (CI): 3.1-3.5] cases per 10,000 live-births. The highest prevalence of cases were reported in 2007 with 4.4 (95% CI: 3.9-5.0) cases per 10,000 live-births. Rift Valley province had the highest prevalence of spina bifida and encephalocele at 6.9 (95% CI: 6.3-7.5) cases per 10,000 live-births from 2005-2010. CONCLUSION: Prevalence of spina bifida and encephalocele is likely underestimated, as only patients seeking care at the hospital were included. Variations in regional prevalence could be due to referral patterns and healthcare access. Implementation of a neural tube defects surveillance system would provide a more thorough assessment of the burden of neural tube defects in Kenya. PMID- 26113895 TI - [Erythroblastic acute leukemia: report of seven cases]. PMID- 26113896 TI - Fetal nuchal translucency scan in Nigeria. AB - INTRODUCTION: To evaluate the performance of first trimester nuchal translucency scan screening among pregnant women in Nigeria. METHODS: A prospective observational and questionnaire based study involving 510 pregnant women between 11(+0) and 13(+6) weeks. Routine counselling and nuchal translucency measurement was conducted using the FMF, London guidelines. Chorionic villous sampling was done at NT >= 2.5 mm or >= 95th centile. RESULTS: Five hundred and ten out of 542 (94.1%) were analysed, mainly referred by health care workers (87.2%) and from predominantly private facilities (94.3%). The number of NT scans performed increased in successive years with corresponding decrease in the mean scanning time. Scan was successfully completed at first attempt in (96.5%), with mean scanning time of 28.3 minutes. Nuchal translucency increases with gestational but not maternal age. The median and 95th centile at 11(+0) week was 1.2mm and 1.7 mm and at 13(+6) weeks was 1.5 mm and 2.2 mm. Using a cut-off of >= 2.5 mm or >= 95th centile, 17 (3.3%) screened positive. Three out of the 17 had invasive testing and 2 (DR = 66.7%) were confirmed trisomy 21, with a false positive rate of 5.9%. Although majority (86.4%) were willing to have invasive testing, only few (3 or 17.6%) of the high risk group had testing. CONCLUSION: The study demonstrated that NT scan is feasible as a screening tool in pregnancy in Nigeria. Measures of improving utilization include wider dissemination of information, provision of dedicated NT clinics and manpower training. PMID- 26113897 TI - [Pseudotumoral form of chronic eosinophilic pneumopathy of fatal outcome]. PMID- 26113898 TI - [Tetraplegia revealing a severe pneumococcal meningomyelitis: about a case and literature review]. PMID- 26113899 TI - [Prevalence and factors associated with HIV and viral hepatitis B and C in the city of Bafoussam in Cameroon]. PMID- 26113900 TI - [Incomplete small bowel volvulus on common mesentery--a severe and rare complication in adults: report of 1 case]. PMID- 26113901 TI - [False traumatic intracranial arterial aneurysm]. PMID- 26113903 TI - [Sacrococcygeal teratoma: report of a case]. PMID- 26113902 TI - [Impact of antiretroviral therapy on the biological profile of HIV positive children followed-up at Yaounde University Hospital in Cameroon]. PMID- 26113907 TI - [Septic neuromeningeal metastases following a pneumococcal otitis]. PMID- 26113906 TI - [Squamous cell carcinomas of the scrotum: about 7 cases with review of the literature]. PMID- 26113905 TI - [Change in stature after pseudo-puberty early by 11beta hydroxylase deficiency in a girl of 7 years: report of a case and review of literature]. PMID- 26113904 TI - [Cold thoracic parietal abscess in immunocompetent individuals]. PMID- 26113908 TI - [Anterior transverse route in osteosynthesis of a type III fracture of the coronoid process in an adolescent: report of a case and literature review]. PMID- 26113909 TI - [Conjoined nerve root: about a case]. PMID- 26113910 TI - [Incidence of hepatocellular carcinoma in chronic infection with hepatitis B]. PMID- 26113911 TI - [Valvular heart disease in hospitals in Lome (Togo)]. PMID- 26113912 TI - [Strangulated obturator hernia: about two cases]. PMID- 26113913 TI - [Primitive omental appendagitis: a rare cause of abdominal pain]. PMID- 26113914 TI - [Dorsal liposarcoma: a rare clinical presentation]. PMID- 26113915 TI - [Study of knowledge, attitudes and practices in social reintegration of women victims of obstetric fistula: region of the far-North, Cameroon]. PMID- 26113916 TI - [Traumatic section of nonpregnant uterus in a highway traffic accident: report of a case]. PMID- 26113917 TI - [Rare ovarian tumors: report of a series of 11 cases of malignant non-epithelial ovarian tumors]. PMID- 26113918 TI - [Isolated latent scaphoid dislocation in children: report of a case]. PMID- 26113919 TI - Patterns and obstacles to oral antidiabetic medications adherence among type 2 diabetics in Ismailia, Egypt: a cross section study. AB - INTRODUCTION: Diabetes is a costly and increasingly common chronic disease. Effective management of diabetes to achieve glycemic control improves patient quality of life. Adherence rates to drug regimens in patients with type 2 diabetes are relatively low and vary widely between populations. There are many factors that could affect patient adherence to drug therapy. The aim of the present study was assessing patterns and obstacles to adherence of type 2 diabetic patients to their oral hypoglycemic drugs. METHODS: The present work is a descriptive cross section study, carried on type 2 diabetic patients who were on oral hypoglycemic drugs. Data concerning adherence to drugs was assessed using measure treatment adherence scale (MTA). RESULTS: A total of 372 (55.59% males and 44.41% females) patients with type-2 diabetes fulfilled the inclusion criteria and included in the study. Among the participants, 26.1% were found to have good adherence, 47.9% had a fair adherence, and 26% had poor adherence. CONCLUSION: The overall rate of medication adherence among the diabetic patients population was suboptimal and non-acceptable. Evaluation of adherence is vital for patients with diabetes in order to determine factors and barriers affecting the adherence and to manage them. PMID- 26113920 TI - Dural tear of unusual cause. AB - Epidural analgesia is highly recommended in cancer anorectal surgery. In addition to the fight against pain it provides some benefit in allowing early rehabilitation of patients. One of the risks of this practice is the dural tear creating a cerebrospinal fluid leak (CSF) in the epidural space (EPD). Clinical features the typical positional headache, a procession of various more or less severe symptoms: nausea, vomiting, dizziness, visual or hearing impairment or radicular pain. We report a dural of unusual cause secondary of the obstruction of tuohy catheter by vertebral cartilage. PMID- 26113921 TI - Recurrent testicular torsion after orchidopexy. PMID- 26113922 TI - [A randomized controlled trial: effect of wearing high-heeled shoes on the lower appendicular skeleton]. PMID- 26113923 TI - Supporting early career health investigators in Kenya: A qualitative study of HIV/AIDS research capacity building. AB - INTRODUCTION: Strategies to transfer international health research training programs to sub-Saharan African institutions focus on developing cadres of local investigators who will lead such programs. Using a critical leadership theory framework, we conducted a qualitative study of one program to understand how collaborative training and research can support early career investigators in Kenya toward the program transfer goal. METHODS: We used purposive sampling methods and a semi-structured protocol to conduct in-depth interviews with US (N = 5) and Kenyan (N = 5) independent investigators. Transcripts were coded using a two-step process, and then compared with each other to identify major themes. RESULTS: A limited local research environment, funding needs and research career mentorship were identified as major influences on early career researchers. Institutional demands on Kenyan faculty to teach rather than complete research restricted investigators' ability to develop research careers. This was coupled with lack of local funding to support research. Sustainable collaborations between Kenyan, US and other international investigators were perceived to mitigate these challenges and support early career investigators who would help build a robust local research environment for training. CONCLUSION: Mutually beneficial collaborations between Kenyan and US investigators developed during training mitigate these challenges and build a supportive research environment for training. In these collaborations, early career investigators learn how to navigate the complex international research environment to build local HIV research capacity. Shared and mutually beneficial resources within international research collaborations are required to support early career investigators and plans to transfer health research training to African institutions. PMID- 26113924 TI - Dislocation of a revision total knee arthroplasty: rare but serious complication. PMID- 26113925 TI - [Antenatal diagnosis of iniencephaly]. PMID- 26113926 TI - Cutaneous sarcoidosis simulating porokeratosis of Mibelli. AB - We report a skin localization of systemic sarcoidosis, which presented with lesions that resemble porokeratosis of Mibelli. Skin biopsy showed non-caseating sarcoidal granuloma. Whereas cutaneous sarcoidosis is present in up to one-third of cases and may present with a wide variety of lesions, our presentation is uncommon. Partial remission was obtained with hydroxychloroquine and prednisone. PMID- 26113927 TI - Evaluation of HIV antigen/antibody combination ELISAs for diagnosis of HIV infection in Dar Es Salaam, Tanzania. AB - INTRODUCTION: The aim of this study was to evaluate the performance of Enzygnost HIV Integral II antigen/antibody combination ELISAs in order to formulate HIV ELISA testing algorithms for the Ministry of Health and Social Welfare, Tanzania. METHODS: This was a laboratory-based evaluation of Enzygnost HIV Integral II Antibody/ Antigen, Murex HIV antigen/antibody and Vironostika HIV Uniform II antigen/antibody conducted between October 2011 and May 2012. RESULTS: A total of 600 blood samples were included in the evaluation. A total of 209/596 (35.1%) serum samples were confirmed HIV positive. Of these, the prevalence of HIV infection was 2.3% (3/130), 2.3% (3/127), 2.2% (3/139) and 100% (200/200) for VCT clients, ANC attendees, blood donors and CTC patients, respectively. Three hundred and eighty seven (64.9%) were HIV negative samples. Sensitivity was 100% (95% CI; 98.3-100%) for all the three HIV ELISAs. The specificity for the Enzygnost HIV Integral II and Murex was 100% (95% CI; 99.1-100%). The final specificity at repeat testing was 99.5% (95% CI; 98.2-99.9%) for Vironostika. Enzygnost HIV Integral II detected HIV infection seven days since first bleed. CONCLUSION: Initial testing using either Vironostika or Murex HIV antigen/antibody combination ELISA followed by testing of reactive samples on the Enzygnost HIV Integral II gave a sensitivity and specificity of 100% with reduced window period. Combination of two HIV antigen/antibody combination ELISAs can be used as an alternative confirmatory testing strategy for screening of donated blood at the National and Zonal blood transfusion centres and in lab diagnosis of HIV infection. PMID- 26113929 TI - [Posttraumatic hematoma of the Iliopsoas muscle with femoral nerve palsy: about a case report and review of literature]. PMID- 26113928 TI - Healthcare-associated infections in a Tunisian university hospital: from analysis to action. AB - INTRODUCTION: Our study was conducted, in university hospital center (UHC) Farhat Hached of Sousse (city in Tunisian center-east), within healthcare-associated infections (HAI) epidemiological surveillance (ES) program, based, among others, on HAI regular prevalence surveys. Our objectives are to resituate HAI prevalence rate and to identify their risk factors (RF) in order to adjust, in our hospital, prevention programs. METHODS: It is a transversal descriptive study, including all patients who had been hospitalized for at least 48 hours, measuring prevalence of HAI a "given day", with only one passage by service. Risk factors were determined using Epiinfo 6.0, by uni-varied analysis, then, logistic regression stepwise descending for the variables whose p. RESULTS: The study focused on 312 patients. Infected patients prevalence was 12.5% and that of HAI was 14.5%. Infections on peripheral venous catheter (PVC) dominated (42.2%) among all HAI identified. HAI significant RF were neutropenia (p < 10(-4)) for intrinsic factors, and PVC for extrinsic factors (p = 0,003). CONCLUSION: Predominance of infections on PVC should be subject of specific prevention actions, including retro-information strategy, prospective ES, professional practices evaluation and finally training and increasing awareness of health personnel with hygiene measures. Finally, development of a patient safety culture with personnel ensures best adherence to hygiene measures and HAI prevention. PMID- 26113930 TI - [A case of neglected fracture dislocation of the elbow with preservation of elbow function]. PMID- 26113931 TI - [Morel-Lavallee syndrome: an entity not to ignore]. PMID- 26113932 TI - [Contribution of computed tomography in the diagnosis of spinal tuberculosis about 496 cases in Abidjan]. PMID- 26113933 TI - [Management of complications of arteriovenous fistulas for chronic hemodialysis]. PMID- 26113934 TI - [Giant myxoma of the left atrium appended to the mitral valve]. PMID- 26113935 TI - [Tibial valgization osteotomy by medial opening-wedge filled with cement for femorotibial 38 varus-valgus gonarthrosis]. PMID- 26113936 TI - Coats disease. PMID- 26113937 TI - [Broncholithiasis: a rare complication of pulmonary tuberculosis]. PMID- 26113938 TI - Tuberous sclerosis complex presenting as pulmonary lymphangioleiomyomatosis--a clinicoradiological diagnosis. AB - Tuberous sclerosis complex (TSC) manifests predominantly as a neurocutaneous disorder. Lymphangioleiomyomatosis (LAM) is a rare pulmonary manifestation of TSC. Imaging evaluation plays an important role in the assessment of patients with tuberous sclerosis complex. In newly diagnosed patients, it helps not only to confirm the diagnosis of TSC, but also helps in identifying clinically significant complications. We describe the radiological findings in lungs and other organs in a middle aged female with TSC. PMID- 26113939 TI - [Amniotic bands syndrome and its diagnostic difficulties and management in Burkina Faso]. PMID- 26113940 TI - Prevalence of premarital sexual practice and associated factors among undergraduate health science students of Madawalabu University, Bale Goba, South East Ethiopia: institution based cross sectional study. AB - INTRODUCTION: Several studies in Sub- Saharan Africa have documented high and increasing premarital sexual activities among adolescents. Younger people face social, peer and cultural pressure to engage in premarital sex. As a result, significant numbers of adolescents are involved in sexual activities at an early age which exposes them to the risk of unintended pregnancy, early marriage, abortion and STIs/HIV/AIDS. This study was conducted to determine Prevalence of premarital sexual practice and associated factors among Health science students of Madawalabu University, Ethiopia. METHODS: A Descriptive cross sectional survey was employed and three hundred twenty four students were randomly selected after proportional allocation according to their level of education. Data were collected by a self-administered questionnaire and analyzed using SPSS Version 16. A stepwise logistic regression with forward method was used to identify independent predictors of premarital sexual practices at 95% CI and P value less than 0.05. RESULTS: Of respondents 181 (59.9%) who had a boy or girl friends; about 129 (42.7%) have had premarital sexual intercourse. Out of sexually active respondents, 85 (66.4%) had one sexual partner, 44 (33.6%) had two or more sexual partners. The average age of starting sexual intercourses was 18.4 +/- 2.14 years. Sixty three (20.9%) of respondents reported tobacco smoking and 117 (38.7%) reported consumption of alcohol consumption. CONCLUSION: Alcohol use, boarding, sex, educational level and discussion about sexuality were significantly associated with premarital sexual intercourses. So, there is the need to step up Reproductive health club at the university to bring behavior change among the students in order to detain the usual consequences of premarital sexual practices and risky sexual behavior. PMID- 26113941 TI - [Primary osteosarcoma of the thigh: about a case]. PMID- 26113942 TI - [A retrospective study of ovarian cancer with a median follow of 42 months]. PMID- 26113943 TI - [Unusual multifocal osteoarthritis tuberculosis in an immunocompetent patient]. PMID- 26113944 TI - [Pregnancy in chronic hemodialysis]. PMID- 26113945 TI - Foreign aid or foreign investments: call for a paradigm shift in mentality and nomenclature. AB - Funding for health care programs has over the years been an important challenge for health and health care services. However with the advent of financing, part of this problem was resolved. Through these investments, lives were saved, many destinies recovered and some obsolete systems reengineered. Major proofs of these expenditures are number of people reached and sometimes number of sites opened/supported, which in several cases, are not entirely verifiable. Sustainable development from these funds is limited, and far and in between. This is despite the fact that supports for health care and health care services have been ongoing for more than 60 years. As long as these funds are seen as aids to developing countries, they will continue to fail to achieve their primary objectives. But looking at these as investments in supported countries will significantly improve the outcome, health system impacts, as well as engineer sustainable health system strengthening and improvement. Such a re-branding will reduce the politics of support, improve effectiveness and efficiency in the use of the resources, and empower receiving nations towards better health systems. PMID- 26113946 TI - [Recurrent lupus enteritis improved by Azathioprine]. PMID- 26113947 TI - Jugular vein thrombosis due to Behcet disease. PMID- 26113948 TI - [Obstructive colloid cyst of the third ventricle]. PMID- 26113949 TI - [Lateral condylar fracture of the femur associated with sagittal vertical ipsilateral fracture of the patella]. PMID- 26113950 TI - The role of cytokines as inflammatory mediators in preeclampsia. AB - INTRODUCTION: This study is to determine the concentrations of IL-6, TNF alpha, and C reactive protein (CRP) in women with severe preeclampsia, and compare with those of gestational age- matched normotensive pregnant women and to correlate CRP levels with markers of organ damage in women with preeclampsia. METHODS: This was a case control study of fifty women with severe preeclampsia and fifty gestational age matched pregnant women with normal blood pressure. The women were drawn from The Antenatal Clinic of The Lagos University Teaching Hospital. Severe pre eclampsia was defined as systolic blood pressure >= 160 mmHg and/or diastolic blood pressure >= 110 mmHg and >= 2 + of proteinuria. After obtaining an informed consent, each participant completed a structured questionnaire. The questionnaire sought information on socio-demographic and clinical data. From each participant, mid-stream urine was collected for urinalysis and culture, and blood sample was collected for biochemical analysis. Comparisons of continuous variables and categorical variables were done using the Student's t test and Chi square test respectively. Correlation analysis was used to determine the associations between variables. Statistical significance was set at P. RESULTS: The women were similar in their socio demographic characteristics. There was a statistically significant difference in the systolic blood pressure (p < 0.0001), diastolic blood pressure ( p < 0.0001), uric acid ( p < 0.0001), AST ( p < 0.0001), ALP ( p < 0.0001), creatinine ( p < 0.0013), GGT ( p < 0.005), IL 6 ( p < 0.021), CRP ( p < 0.0002), and TNF alpha ( p < 0.023), between the group with severe preeclampsia and the group with normal blood pressure. This study also reports a significant association between CRP and systolic blood pressure, diastolic blood pressure, uric acid AST and ALP (p. CONCLUSION: The inflammatory cytokines, IL6, TNF alpha and CRP are elevated in severe preeclampsia and may mediate some of the clinical manifestations of the disorder. A role may exist for anti inflammatory agents in the management of women with preeclampsia. PMID- 26113951 TI - [Epidemiologic, clinical and pathologic aspects of melanoma CHU Yalgado Ouedraogo, Ouagadougou (Burkina Faso)]. PMID- 26113952 TI - Cholera: a comparison of the 2008-9 and 2010 outbreaks in Kadoma City, Zimbabwe. AB - INTRODUCTION: Kadoma City experienced cholera outbreaks in 2008-9, and 2010, affecting 6,393 and 123 people, respectively. A study was conducted to compare epidemiology of the cholera outbreaks. METHODS: A descriptive cross sectional study was conducted, analyzing line list data for the 2 outbreaks. Proportions, means were generated and compared using the Chi Square test at 5% level of significance. RESULTS: Cholera cases were similar by gender and age, with the 20 30 years group being most affected. Rimuka township contributed 80% and 100% of city cases in 2008-9 and 2010, respectively, p value = 0.000. In 2008-9, 91% of cholera cases presented within 2 days compared to 98% in 2010. Delay seeking treatment increased from 58% to 73% (p value = 0.001), with gender, and place equally affected. The 2010 outbreak evolved faster, resulting in higher proportion being managed in CTU. CFR was 2% in 2008-9, and 3.3% in 2010 (p value =0.31). CONCLUSION: The 2008-9 and 2010 cholera outbreaks were similar by age and gender. Rimuka Township was most affected by the outbreaks. There was worsening of delay seeking treatment. The 2010 outbreak was more rapid, leading to early opening of CTC. CFR was consistently above 1%. PMID- 26113953 TI - Chokeberry Anthocyanin Extract as Pancreatic beta-Cell Protectors in Two Models of Induced Oxidative Stress. AB - The aim of this study was to investigate the protective effects of a chokeberry anthocyanin extract (CAE) on pancreatic beta-cells (betaTC3) exposed to hydrogen peroxide- (H2O2-) and high glucose- (HG-) induced oxidative stress conditions. In order to quantify individual anthocyanins high performance liquid chromatography (HPLC) coupled to photodiode array (PDA) was used. The identification of the fragment ion pattern of anthocyanins was carried out by electrospray ionization mass spectrometry (LC-ESI-MS). The results showed that physiologically achievable concentrations of CAE (1, 5, and 10 MUM) protect betaTC3 against H2O2- and HG induced cytotoxicity. Antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were increased in pancreatic beta-cells pretreated with CAE compared to cells exposed to the prooxidant agents. GSH levels initially reduced after exposure to H2O2 and HG were restored by pretreatment with CAE. Insulin secretion in betaTC3 cells was enhanced by CAE pretreatment. CAE restored the insulin pool and diminished the intracellular reactive oxygen species level in glucose-induced stress condition in betaTC3 cells. These results demonstrate that anthocyanins from CAE were biologically active, showing a secretagogue potential and an antioxidative protection of enzymatic systems, conferring protection against H2O2 and glucose toxicity in betaTC3 cells. PMID- 26113955 TI - PTSD and Sexual Orientation: An Examination of Criterion A1 and Non-Criterion A1 Events. AB - This large-scale cross-sectional study compared posttraumatic stress disorder (PTSD) prevalence among White, Black, and Latino lesbian, gay and bisexual individuals (LGBs; n = 382) and compared them with heterosexual individuals (n = 126). Building on previous research, we relaxed the criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994), allowing non-Criterion A1 events such as ending a relationship, unemployment, homelessness, and separation from parents to qualify, and we assessed differences in PTSD prevalence between standard DSM-IV criteria and the relaxed criteria. Findings revealed that participants reporting a non Criterion A1 event were more likely than those reporting a Criterion A1 event to have symptoms diagnosable as PTSD. There was no significant difference in either DSM-IV or relaxed Criterion A1 PTSD prevalence between lesbian and gay, and heterosexual individuals or between bisexual and heterosexual individuals. Compared with White LGBs, Black and Latino LGBs had higher prevalence of PTSD with the relaxed Criterion A1 definition, but this was statistically significant only for Latinos. PMID- 26113954 TI - Optimisation of an Advanced Oxidation Protein Products Assay: Its Application to Studies of Oxidative Stress in Diabetes Mellitus. AB - Advanced oxidation protein products (AOPP) are reportedly elevated in the plasma of patients with a number of diseases, including diabetes mellitus, that involve oxidative stress. However, the accurate measurement of AOPP in human plasma is hampered by the formation of a precipitate following the addition of potassium iodide and glacial acetic acid according to the published assay procedure. Here we describe a modification of the AOPP assay which eliminates interference by precipitation and provides a robust, reliable, and reproducible protocol for the measurement of iodide oxidising capacity in plasma samples (intra-assay CV 1.7 5.3%, interassay CV 5.3-10.5%). The improved method revealed a significant association of AOPP levels with age (p < 0.05) and hypertension (p = 0.01) in EDTA-anticoagulated plasma samples from 52 patients with diabetes and 38 nondiabetic control subjects, suggesting a possible link between plasma oxidising capacity and endothelial and/or vascular dysfunction. There was no significant difference between AOPP concentrations in diabetic (74.8 +/- 7.2 MUM chloramine T equivalents) and nondiabetic (75.5 +/- 7.0 MUM chloramine T equivalents) individuals. PMID- 26113956 TI - Machine Learning Predictions of Molecular Properties: Accurate Many-Body Potentials and Nonlocality in Chemical Space. AB - Simultaneously accurate and efficient prediction of molecular properties throughout chemical compound space is a critical ingredient toward rational compound design in chemical and pharmaceutical industries. Aiming toward this goal, we develop and apply a systematic hierarchy of efficient empirical methods to estimate atomization and total energies of molecules. These methods range from a simple sum over atoms, to addition of bond energies, to pairwise interatomic force fields, reaching to the more sophisticated machine learning approaches that are capable of describing collective interactions between many atoms or bonds. In the case of equilibrium molecular geometries, even simple pairwise force fields demonstrate prediction accuracy comparable to benchmark energies calculated using density functional theory with hybrid exchange-correlation functionals; however, accounting for the collective many-body interactions proves to be essential for approaching the "holy grail" of chemical accuracy of 1 kcal/mol for both equilibrium and out-of-equilibrium geometries. This remarkable accuracy is achieved by a vectorized representation of molecules (so-called Bag of Bonds model) that exhibits strong nonlocality in chemical space. In addition, the same representation allows us to predict accurate electronic properties of molecules, such as their polarizability and molecular frontier orbital energies. PMID- 26113958 TI - Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells. AB - OBJECTIVE: Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-beta) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-beta on gliomas. METHODS: We engineered human MSCs to secret mouse IFN-beta (MSC-IFN-beta) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-beta treatment. RESULTS: In vitro, the combination of MSC-IFN-beta and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-beta and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. CONCLUSION: These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC IFN-beta and TMZ could be considered as a new option for the treatment of malignant gliomas. PMID- 26113957 TI - Understanding the Treatment Strategies of Intracranial Germ Cell Tumors: Focusing on Radiotherapy. AB - Intracranial germ cell tumors (ICGCT) occur in 2-11% of children with brain tumors between 0-19 years of age. For treatment of germinoma, relatively low radiation doses with or without chemotherapy show excellent 10 year survival rate of 80-100%. Past studies showed that neoadjuvant chemotherapy combined with focal radiotherapy resulted in unacceptably high rates of periventricular tumor recurrence. The use of generous radiation volume which covers the whole ventricular space with later boost treatment to primary site is considered as standard treatment of intracranial germinomas. For non-germinomatous germ cell tumors (NGGCT), 10-year overall survival rate is still much inferior than that of intracranial germinoma despite intensive chemotherapy and high-dose radiotherapy. Craniospinal radiotherapy combined with cisplatin-based chemotherapy provides the best treatment outcome for NGGCT; 60-70% of overall survival rate. There is a debate on the surgical role whether surgery can contribute to improved treatment outcome of NGGCT when added to combined chemoradiotherapy. Because higher dose of radiotherapy is required for treatment of NGGCT than for germinoma, it is tested whether whole ventricular irradiation can replace craniospinal irradiation in intermediate risk group of NGGCT to minimize radiation-related late toxicity in the recent studies. To minimize the treatment-related neural deficit and late sequelae while maintaining long-term survival rate of ICGCT patients, optimized administration of chemotherapy and radiotherapy should be selected. Use of technically upgraded radiotherapy modalities such as intensity-modulated radiotherapy or proton beam therapy is expected to bring an improved neurocognitive outcome with longitudinal assessment of the patients. PMID- 26113959 TI - Overexpressions of Vimentin and Integrins in Human Metastatic Spine Tumors. AB - OBJECTIVE: To comparatively investigate the expression of several integrins in specimens of human bone metastases and degenerative bone tissue. METHODS: Degenerative cancellous tissue was obtained from a sample of human degenerative spine. Thirteen human specimens were obtained from metastatic spine tumors, whose primary cancer was colon cancer (n=3), hepatocellular cancer (n=3), lung cancer (n=4), and breast cancer (n=3). The expression of vimentin and integrins alphav, beta1, and beta3 was assessed in metastatic and degenerative specimens by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Immunohistochemical staining showed that vimentin and integrin alphav was broadly expressed in all tissues examined. By contrast, integrin beta1 was weakly expressed only in 38.4% (5/13) of tissues. Integrin beta3 was consistently negative in all cases examined. qRT-PCR analysis showed that vimentin gene expression was higher in all metastatic specimens, as compared to degenerative bone. The gene expression of integrin alphav in breast specimen was significantly higher than others (p=0.045). The gene expression of integrin beta1 was also higher in all metastatic specimens than in degenerative bone tissue. The gene expression of integrin beta3 was variable. CONCLUSION: Spinal metastatic tumors have mesenchymal characteristics such as increased expression of vimentin. The increased expression of integrin alphav and beta1 in spine metastatic tumors suggests that adhesive molecules such as integrin may have implications for the prevention of spine metastasis. PMID- 26113960 TI - The Neuroprotective Effect of Kefir on Spinal Cord Ischemia/Reperfusion Injury in Rats. AB - OBJECTIVE: The main causes of spinal cord ischemia are a variety of vascular pathologies causing acute arterial occlusions. We investigated neuroprotective effects of kefir on spinal cord ischemia injury in rats. METHODS: Rats were divided into three groups : 1) sham operated control rats; 2) spinal cord ischemia group fed on a standard diet without kefir pretreatment; and 3) spinal cord ischemia group fed on a standard diet plus kefir. Spinal cord ischemia was performed by the infrarenal aorta cross-clamping model. The spinal cord was removed after the procedure. The biochemical and histopathological changes were observed within the samples. Functional assessment was performed for neurological deficit scores. RESULTS: The kefir group was compared with the ischemia group, a significant decrease in malondialdehyde levels was observed (p<0.05). Catalase and superoxide dismutase levels of the kefir group were significantly higher than ischemia group (p<0.05). In histopathological samples, the kefir group is compared with ischemia group, there was a significant decrease in numbers of dead and degenerated neurons (p<0.05). In immunohistochemical staining, hipoxia inducible factor-1alpha and caspase 3 immunopositive neurons were significantly decreased in kefir group compared with ischemia group (p<0.05). The neurological deficit scores of kefir group were significantly higher than ischemia group at 24 h (p<0.05). CONCLUSION: Our study revealed that kefir pretreatment in spinal cord ischemia/reperfusion reduced oxidative stress and neuronal degeneration as a neuroprotective agent. Ultrastructural studies are required in order for kefir to be developed as a promising therapeutic agent to be utilized for human spinal cord ischemia in the future. PMID- 26113961 TI - Comparative Analysis of Endovascular Stroke Therapy Using Urokinase, Penumbra System and Retrievable (Solitare) Stent. AB - BACKGROUND: Higher reperfusion rates have been established with endovascular treatment for acute ischemic stroke patients. There are limited data on the comparative performance of mechanical thrombectomy devices. This study aimed to analyse the efficacy and safety of the stent retriever device (Solitaire stent) by comparing procedure time, angiographic outcome, complication rate and long term clinical outcome with previous chemical thrombolysis and mechanical thrombectomy using penumbra system. METHODS: A retrospective single-center analysis was undertaken of all consecutive patients who underwent chemical thrombolysis and mechanical thrombectomy using Penumbra or Solitaire stent retriever from March 2009 to March 2014. Baseline characteristics, rate of successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b 3), symptomatic intracerebral hemorrhage, procedure time, mortality and independent functional outcomes (mRS <=2) at 3 month were compared across the three method. RESULTS: Our cohort included 164 patients, mechanical thrombectomy using stent retriever device had a significant impact on recanalization rate and functional independence at 3 months. In unadjusted analysis mechanical thrombectomy using Solitaire stent retriever showed higher recanalization rate than Penumbra system and chemical thrombolysis (75% vs. 64.2% vs. 49.4%, p=0.03) and higher rate of functional independence at 3 month (53.1% vs. 37.7% vs. 35.4%, p=0.213). In view of the interrelationships between all predictors of variables associated with a good clinical outcome, when the chemical thrombolysis was used as a reference, in multiple logistic regression analysis, the use of Solitaire stent retriever showed higher odds of independent functional outcome [odds ratio (OR) 2.62, 95% confidence interval (CI) 0.96-7.17; p=0.061] in comparison with penumbra system (OR 1.57, 95% CI 0.63-3.90; p=0.331). CONCLUSION: Our initial data suggest that mechanical thrombectomy using stent retriever is superior to the mechanical thrombectomy using penumbra system and conventional chemical thrombolysis in achieving higher rates of reperfusion and better outcomes. Randomized clinical trials are needed to establish the actual benefit to specific patient populations. PMID- 26113962 TI - Morphometric Study of the Anterior Thalamoperforating Arteries. AB - OBJECTIVE: To evaluate the morphometry of the anterior thalamoperforating arteries (ATPA). METHODS: A microanatomical study was performed in 79 specimens from 42 formalin-fixed adult cadaver brains. The origins of the ATPAs were divided into anterior, middle, and posterior segments according to the crowding pattern. The morphometry of the ATPAs, including the premammillary artery (PMA), were examined under a surgical microscope. RESULTS: The anterior and middle segments of the ATPAs arose at mean intervals of 1.75+/-1.62 mm and 5.86+/-2.05 mm from the internal carotid artery (ICA), and the interval between these segments was a mean of 3.17+/-1.64 mm. The posterior segment arose at a mean interval of 2.43+/-1.46 mm from the posterior cerebral artery (PCA), and the interval between the middle and posterior segments was a mean of 3.45+/-1.39 mm. The mean numbers of perforators were 2.66+/-1.19, 3.03+/-1.84, and 1.67+/-0.98 in the anterior, middle, and posterior segments, respectively. The PMA originated from the middle segment in 66% of cases. A perforator-free zone was located >2 mm from the ICA in 30.4% and >2 mm from the PCA in 67.1% of cases. CONCLUSION: Most perforators arose from the anterior and middle segments, within the anterior two thirds of the posterior communicating artery (PCoA). The safest perforator-free zone was located closest to the PCA. These anatomical findings may be helpful to verify safety when treating lesions around the PCoA and in the interpeduncular fossa. PMID- 26113963 TI - A Retrospective Analysis of Ventriculoperitoneal Shunt Revision Cases of a Single Institute. AB - OBJECTIVE: Ventriculoperitoneal (VP) shunt complication is a major obstacle in the management of hydrocephalus. To study the differences of VP shunt complications between children and adults, we analyzed shunt revision surgery performed at our hospital during the past 10 years. METHODS: Patients who had undergone shunt revision surgery from January 2001 to December 2010 were evaluated retrospectively by chart review about age distribution, etiology of hydrocephalus, and causes of revision. Patients were grouped into below and above 20 years old. RESULTS: Among 528 cases of VP shunt surgery performed in our hospital over 10 years, 146 (27.7%) were revision surgery. Infection and obstruction were the most common causes of revision. Fifty-one patients were operated on within 1 month after original VP shunt surgery. Thirty-six of 46 infection cases were operated before 6 months after the initial VP shunt. Incidence of shunt catheter fracture was higher in younger patients compared to older. Two of 8 fractured catheters in the younger group were due to calcification and degradation of shunt catheters with fibrous adhesion to surrounding tissue. CONCLUSION: The complications of VP shunts were different between children and adults. The incidence of shunt catheter fracture was higher in younger patients. Degradation of shunt catheter associated with surrounding tissue calcification could be one of the reasons of the difference in facture rates. PMID- 26113964 TI - A Ruptured Dermoid Cyst of the Cavernous Sinus Extending into the Posterior Fossa. AB - Supratentorial dermoid cysts are uncommon to develop in the cavernous sinus. We present a ruptured dermoid cyst of the cavernous sinus extending into the posterior fossa. The patient was a 32-year-old female who complained occipital headache, blurred vision, and tinnitus over 4 years. Brain magnetic resonance (MR) imaging revealed an enhanced tumor in the right cavernous sinus extending into the right temporal base and the posterior fossa with findings of ruptured cyst. Surgical resection was performed, and pathological findings were confirmed to be a dermoid cyst. We report a second case with ruptured dermoid cyst of the cavernous sinus extending into the posterior fossa. PMID- 26113965 TI - Bone Cement Dislodgement: One of Complications Following Bone Cement Augmentation Procedures for Osteoporotic Spinal Fracture. AB - Bone cement augmentation procedures have been getting more position as a minimally invasive surgical option for osteoporotic spinal fractures. However, complications related to these procedures have been increasingly reported. We describe a case of bone cement dislodgement following cement augmentation procedure for osteoporotic spinal fracture by reviewing the patient's medical records, imaging results and related literatures. A 73-year-old woman suffering back and buttock pain following a fall from level ground was diagnosed as an osteoporotic fracture of the 11th thoracic spine. Percutaneous kyphoplasty was performed for this lesion. Six weeks later, the patient complained of a recurrence of back and buttock pain. Radiologic images revealed superior dislodgement of bone cement through the 11th thoracic superior endplate with destruction of the lower part of the 10th thoracic spine. Staged anterior and posterior fusion was performed. Two years postoperatively, the patient carries on with her daily living without any significant disability. Delayed bone cement dislodgement can occur as one of complications following bone cement augmentation procedure for osteoporotic spinal fracture. It might be related to the presence of intravertebral cleft, lack of interdigitation of bone cement with the surrounding trabeculae, and possible damage of endplate during ballooning procedure. PMID- 26113966 TI - Spontaneous Spinal Subdural Hematoma with Simultaneous Cranial Subarachnoid Hemorrhage. AB - Spontaneous spinal subdural hematoma is reported at a rare level of incidence, and is frequently associated with underlying coagulopathy or those receiving anticoagulant or antiplatelet agents; some cases accompany concomitant intracranial hemorrhage. The spontaneous development of spinal subdural hemorrhage (SDH) is a neurological emergency; therefore, early diagnosis, the discontinuation of anticoagulant, and urgent surgical decompression are required to enable neurological recovery. In this report, we present a simultaneous spinal subdural hematoma and cranial subarachnoid hemorrhage, which mimicked an aneurysmal origin in a female patient who had been taking warfarin due to aortic valve replacement surgery. PMID- 26113967 TI - Delayed Pneumocephalus Following Fluoroscopy Guided Cervical Interlaminar Epidural Steroid Injection: A Rare Complication and Anatomical Considerations. AB - Cervical epidural steroid injection is indicated for radicular symptoms with or without axial neck pain. Complications are rare but can be serious. Here, we report the case of a 54-year-old man with cervical radicular pain who was treated with cervical epidural steroid injection. Injection was administered twice under fluoroscopic guidance with the loss-of-resistance technique using air to confirm the epidural space. After the second procedure, the patient complained of severe persistent headache and was diagnosed with pneumocephalus on brain computed tomography. The patient returned home without any neurological complication, after a few days of conservative treatment. Though, a fluoroscopic guidance cervical epidural injection is also known to diminish the risk of complications. Physicians should always keep in mind that it does not guarantee safety, particularly in the cervical region, related to its anatomical considerations. PMID- 26113968 TI - Infrequent Hemorrhagic Complications Following Surgical Drainage of Chronic Subdural Hematomas. AB - Chronic subdural hematomas mainly occur amongst elderly people and usually develop after minor head injuries. In younger patients, subdural collections may be related to hypertension, coagulopathies, vascular abnormalities, and substance abuse. Different techniques can be used for the surgical treatment of symptomatic chronic subdural hematomas : single or double burr-hole evacuation, with or without subdural drainage, twist-drill craniostomies and classical craniotomies. Failure of the brain to re-expand, pneumocephalus, incomplete evacuation, and recurrence of the fluid collection are common complications following these procedures. Acute subdural hematomas may also occur. Rarely reported hemorrhagic complications include subarachnoid, intracerebral, intraventricular, and remote cerebellar hemorrhages. The causes of such uncommon complications are difficult to explain and remain poorly understood. Overdrainage and intracranial hypotension, rapid brain decompression and shift of the intracranial contents, cerebrospinal fluid loss, vascular dysregulation and impairment of venous outflow are the main mechanisms discussed in the literature. In this article we report three cases of different post-operative intracranial bleeding and review the related literature. PMID- 26113969 TI - Unusual Position and Presentation of Frontobasal Meningoencephalocela. AB - We wish to show our experiance with threating a rare congenital brain malformation-encephalocele. It is a protusion of brain matter with greater incidence in the Far East. Our case is even more curious because of the site of occurrence-frontobasal. Most of encephalocele occur in the occipital region. In this article we report a case of a 57-year-old woman, without deformations on the face, which had epileptic seizures and in spite of receiving antiepileptic drug. She was also frequently treated for sinusitis. She never had rhinoliquorrhea, nor was she diagnosed to have meningitis. In the last few years she had difficulty breathing on her right nostril. After she was diagnosed with encephalocele and treated surgically her recovery was complete and she is without the seizures. PMID- 26113970 TI - Conformationally Strained trans-Cyclooctene with Improved Stability and Excellent Reactivity in Tetrazine Ligation. AB - Computation has guided the design of conformationally-strained dioxolane-fused trans-cyclooctene (d-TCO) derivatives that display excellent reactivity in the tetrazine ligation. A water soluble derivative of 3,6-dipyridyl-s-tetrazine reacts with d-TCO with a second order rate k2 366,000 (+/- 15,000) M-1s-1 at 25 degrees C in pure water. Furthermore, d-TCO derivatives can be prepared easily, are accessed through diastereoselective synthesis, and are typically crystalline bench-stable solids that are stable in aqueous solution, blood serum, or in the presence of thiols in buffered solution. GFP with a genetically encoded tetrazine containing amino acid was site-specifically labelled in vivo by a d-TCO derivative. The fastest bioorthogonal reaction reported to date [k2 3,300,000 (+/ 40,000) M-1s-1 in H2O at 25 degrees C] is described herein with a cyclopropane fused trans-cyclooctene. d-TCO derivatives display rates within an order of magnitude of these fastest trans-cyclooctene reagents, and also display enhanced stability and aqueous solubility. PMID- 26113971 TI - Sex differences of leukocytes DNA methylation adjusted for estimated cellular proportions. AB - BACKGROUND: DNA methylation, which is most frequently the transference of a methyl group to the 5-carbon position of the cytosine in a CpG dinucleotide, plays an important role in both normal development and diseases. To date, several genome-wide methylome studies have revealed sex-biased DNA methylation, yet no studies have investigated sex differences in DNA methylation by taking into account cellular heterogeneity. The aim of the present study was to investigate sex-biased DNA methylation on the autosomes in human blood by adjusting for estimated cellular proportions because cell-type proportions may vary by sex. METHODS: We performed a genome-wide DNA methylation profiling of the peripheral leukocytes in two sets of samples, a discovery set (49 males and 44 females) and a replication set (14 males and 10 females) using Infinium HumanMethylation450 BeadChips for 485,764 CpG dinucleotides and then examined the effect of sex on DNA methylation with a multiple linear regression analysis after adjusting for age, the estimated 6 cell-type proportions, and the covariates identified in a surrogate variable analysis. RESULTS: We identified differential DNA methylation between males and females at 292 autosomal CpG site loci in the discovery set (Bonferroni-adjusted p < 0.05). Of these 292 CpG sites, significant sex differences were also observed at 98 sites in the replication set (p < 0.05). CONCLUSIONS: These findings provided further evidence that DNA methylation may play a role in the differentiation or maintenance of sexual dimorphisms. Our methylome mapping of the effects of sex may be useful to understanding the molecular mechanism involved in both normal development and diseases. PMID- 26113972 TI - Co-administration with DNA encoding papillomavirus capsid proteins enhances the antitumor effects generated by therapeutic HPV DNA vaccination. AB - BACKGROUND: DNA vaccines have emerged as attractive candidates for the control of human papillomavirus (HPV)-associated malignancies. However, DNA vaccines suffer from limited immunogenicity and thus strategies to enhance DNA vaccine potency are needed. We have previously demonstrated that for DNA vaccines encoding HPV-16 E7 antigen (CRT/E7) linkage with calreticulin (CRT) linked enhances both the E7 specific CD8(+) T cell immune responses and antitumor effects against E7 expressing tumors. In the current study, we aim to introduce an approach to elicit potent CD4(+) T cell help for the enhancement of antigen-specific CD8(+) T cell immune responses generated by CRT/E7 DNA vaccination by using co administration of a DNA vector expressing papillomavirus major and minor capsid antigens, L1 and L2. RESULT: We showed that co-administration of vectors containing codon-optimized bovine papillomavirus type 1 (BPV-1) L1 and L2 in combination with DNA vaccines could elicit enhanced antigen-specific CD8(+) in both CRT/E7 and ovalbumin (OVA) antigenic systems. We also demonstrated that co administration of vectors expressing BPV-1 L1 and/or L2 DNA with CRT/E7 DNA led to the generation of L1/L2-specific CD4(+) T cell immune responses and L1 specific neutralizing antibodies. Furthermore, we showed that co-administration with DNA encoding BPV1 L1 significantly enhances the therapeutic antitumor effects generated by CRT/E7 DNA vaccination. In addition, the observed enhancement of CD8(+) T cell immune responses by DNA encoding L1 and L2 was also found to extend to HPV-16 L1/L2 system. CONCLUSION: Our strategy elicits both potent neutralizing antibody and therapeutic responses and may potentially be extended to other antigenic systems beyond papillomavirus for the control of infection and/or cancer. PMID- 26113973 TI - Pharmacokinetic analysis of the chronic administration of the inert gases Xe and Ar using a physiological based model. AB - BACKGROUND: New gas therapies using inert gases such as xenon and argon are being studied, which would require chronically administered repeating doses. The pharmacokinetics of this type of administration has not been addressed in the literature. METHODS: A physiologically based pharmacokinetics (PBPK) model for humans, pigs, mice, and rats has been developed to investigate the unique aspects of the chronic administration of inert gas therapies. The absorption, distribution, metabolism and excretion (ADME) models are as follows: absorption in all compartments is assumed to be perfusion limited, no metabolism of the gases occurs, and excretion is only the reverse process of absorption through the lungs and exhaled. RESULTS: The model has shown that there can be a residual dose, equivalent to constant administration, for chronic repeated dosing of xenon in humans. However, this is not necessarily the case for small animals used in pre-clinical studies. CONCLUSIONS: The use of standard pharmacokinetics parameters such as area under the curve would be more appropriate to assess the delivered dose of chronic gas administration than the gas concentration in the delivery system that is typically reported in the scientific literature because species and gas differences can result in very different delivered doses. PMID- 26113974 TI - Prevalence and antimicrobial susceptibility patterns of Salmonella isolates in association with hygienic status from butcher shops in Gondar town, Ethiopia. AB - BACKGROUND: Salmonella has been recognized as a major cause of food borne illness associated with meat products worldwide. The wide spread of antimicrobial resistant Salmonella has been a serious global human and animal health problem. The aims of this study were to estimate the prevalence and antimicrobial susceptibility pattern of Salmonella isolates from butcher shops of Gondar town, Ethiopia. METHODS: A cross-sectional study was conducted from February to June, 2013 in Gondar town. After receiving written consent from the study participants, raw meat and swab samples from butcher shops' utensils and meat handlers were collected and tested using standard bacteriological methods. The isolates were identified using colony characteristics, Gram-reaction, biochemical reaction and sugar tests. Antimicrobial susceptibility test was performed using Kirby-Bauer disc diffusion method. Check list was used to record general hygienic conditions and practices in the butcher shops. The data was entered and analyzed using SPSS version 20.0. RESULTS: Butcher shop premises and utensils sanitation and personnel's hygiene were poor. The overall prevalence of Salmonella was 17.3 %. Salmonella was detected in 32 (35.6 %) meat samples, 13 (23.2 %) hand swabs, 5 (9.1 %) knife swabs, and 3 (5.6 %) chopping board surface swabs. Of the total 53 Salmonella isolates subjected to antimicrobial susceptibility test, 47 (88.7 %), 35 (62.3 %), 19 (35.8 %), 17 (32.1 %) and 16 (30.2 %) of them exhibited resistance to Ampicillin, Amoxicillin, Nitrofuranthoin, Tetracycline, and Sulfamethoxazole-Trimethoprime, respectively. Furthermore; 15 (28.3 %) of the isolates were multidrug-resistant from which highest isolation was recorded from meat samples and 40 (75.5 %) isolates of Salmonella showed resistance to two or more antimicrobial agents tested. Interestingly, all of the isolates were susceptible to Gentamycin and Ceftriaxone. CONCLUSION: The general sanitary condition of the butcher shops and utensils used and personnel hygiene were not to the recommended standards. Contamination of meat, knives, and meat handlers hand with Salmonella was found high. Furthermore; multidrug-resistant Salmonella is circulating in the butchers' shop which is strong enough to warrant the revision of butcher shops sanitation policy and treatment regimen for infections implicated by Salmonella in the study area. Further in-depth study including serotyping and antimicrobial resistant gene identification is recommended. PMID- 26113975 TI - Athletic equipment microbiota are shaped by interactions with human skin. AB - BACKGROUND: Americans spend the vast majority of their lives in built environments. Even traditionally outdoor pursuits, such as exercising, are often now performed indoors. Bacteria that colonize these indoor ecosystems are primarily derived from the human microbiome. The modes of human interaction with indoor surfaces and the physical conditions associated with each surface type determine the steady-state ecology of the microbial community. RESULTS: Bacterial assemblages associated with different surfaces in three athletic facilities, including floors, mats, benches, free weights, and elliptical handles, were sampled every other hour (8 am to 6 pm) for 2 days. Surface and equipment type had a stronger influence on bacterial community composition than the facility in which they were housed. Surfaces that were primarily in contact with human skin exhibited highly dynamic bacterial community composition and non-random co occurrence patterns, suggesting that different host microbiomes-shaped by selective forces-were being deposited on these surfaces through time. However, bacterial assemblages found on the floors and mats changed less over time, and species co-occurrence patterns appeared random, suggesting more neutral community assembly. CONCLUSIONS: These longitudinal patterns highlight the dramatic turnover of microbial communities on surfaces in regular contact with human skin. By uncovering these longitudinal patterns, this study promotes a better understanding of microbe-human interactions within the built environment. PMID- 26113976 TI - Gut resistome development in healthy twin pairs in the first year of life. AB - BACKGROUND: The early life of the human host marks a critically important time for establishment of the gut microbial community, yet the developmental trajectory of gut community-encoded resistance genes (resistome) is unknown. We present a longitudinal study of the fecal antibiotic resistome of healthy amoxicillin-exposed and antibiotic-naive twins and their mothers during the first year of life. RESULTS: We extracted metagenomic DNA (mgDNA) from fecal samples collected from three healthy twin pairs at three timepoints (1 or 2 months, 6 or 7 months, and 11 months) and from their mothers (collected at delivery). The mgDNA was used to construct metagenomic expression libraries in an Escherichia coli host. These libraries were screened for antibiotic resistance, and functionally selected resistance genes were sequenced and annotated. A diverse fecal resistome distinct from the maternal resistome was apparent by 2 months of age, and infants' fecal resistomes included resistance to clinically important broad-spectrum beta-lactam antibiotics (e.g., piperacillin-tazobactam, aztreonam, cefepime) not found in their mothers. Dissemination of resistance genes among members of a given family was positively correlated with sharing of those same resistance genes between unrelated families, potentially identifying within family sharing as a marker of resistance genes emerging in the human community at large. Finally, we found a distinct developmental trajectory for a community encoded function: chloramphenicol resistance. All study subjects at all timepoints harbored chloramphenicol resistance determinants, but multidrug efflux pumps (rarely found in mothers) were the primary effectors of chloramphenicol resistance in young infants. Chloramphenicol acetyltransferases were more common in mothers than in infants and were found in nearly all the infants at later timepoints. CONCLUSIONS: Our results suggest that healthy 1-2-month-old infants' gut microbes harbor clinically relevant resistance genes distinct from those of their mothers, and that family-specific shared environmental factors early in life shape resistome development. PMID- 26113977 TI - One-step femtosecond laser patterning of light-trapping structure on dye sensitized solar cell photoelectrodes?. AB - Light-trapping patterns were constructed in TiO2 photoelectrodes for dye sensitized solar cells (DSSCs) by a one-step femtosecond laser structuring method that utilized ablation to create patterns at the surface of nanostructured TiO2 films. As a result, much more light was trapped in the photoelectrodes. Grating and orthogonal-grid patterns were studied, and the light trapping performance was optimized through the adjustment of pattern spacing, which was easily realized in the laser ablation process. With a 5-MUm-spacing orthogonal-grid pattern, DSSCs showed a highest photon-to-electron conversion efficiency of 9.32% under AM 1.5G, a 13.5% improvement compared to the same cell without laser ablation. This simple and universal laser ablation method could be used to process many kinds of nanomaterials, and could be applied for various devices with nanostructures. PMID- 26113978 TI - Immune monitoring technology primer: immunosequencing. AB - BACKGROUND: Profiling of the immune receptor repertoire is becoming increasingly relevant to the understanding and clinical management of cancer, autoimmunity, aging, and infectious disease. FINDINGS: A platform technology is described that provides comprehensive immune receptor profiling. CONCLUSION: Immunosequencing is a platform technology that allows the enumeration, specification and quantification of each and every B-and/or T-cell in any biologic sample of interest. It is based on bias-controlled multiplex PCR and high throughput sequencing and is highly accurate, standardized, and sensitive. PMID- 26113979 TI - TSH-secreting pituitary adenoma: benefits of pre-operative octreotide. AB - TSH-secreting pituitary adenomas are rare and the optimal investigation and management is uncertain. We describe a case of a 43 year-old woman with a TSH secreting pituitary adenoma, highlighting diagnostic testing and our use, pre operatively of somatostatin analogue therapy, which induced biochemical euthyroidism and a reduction in tumour size. LEARNING POINTS: The differential diagnosis of the syndrome of inappropriate TSH secretion is non-thyroidal illness, medications, assay interference due to heterophilic antibodies, thyroid hormone resistance and TSH-secreting pituitary adenoma.TRH stimulation test and triiodothyronine suppression test assist in differentiating thyroid hormone resistance and TSH-secreting pituitary adenoma.Somatostatin analogue therapy can induce biochemical euthyroidism and reduce tumour size. PMID- 26113980 TI - Pancreatic neuroendocrine tumors with transformation to insulinoma: an unusual presentation of a rare disease. AB - Approximately 35% of the pancreatic neuroendocrine tumors (pNETs) are functional, the most common of which is an insulinoma. Rarely can initially nonfunctioning tumor undergo biological transformation to a hormone-secreting tumor with subsequent changes in the clinical picture. We present here three unique patients with long-standing pNETs who developed life-threatening hyperinsulinemic hypoglycemia along with tumor progression. In two of the patients, everolimus (Afinitor) was administered in an attempt to control both tumor growth and hypoglycemia. In two cases everolimus therapy resulted in the abolishment of hypoglycemia and induced significant tumor regression; however these beneficial responses were transient. These cases highlight the exceptional ability of pNETs to change biological behavior in parallel with disease progression. Our experience concurs with recently published studies demonstrating the utility of everolimus for the control of both hypoglycemia and tumor progression. LEARNING POINTS: Nonfunctional pNET can gain new features such as insulin secretion with related morbidity.Gain of function in a previously nonfunctional pNET signifies tumor progression and is usually associated with poor prognosis.Everolimus proved to be a viable treatment for hypoglycemia in insulinoma patients and was also proven highly effective in the patients presented here.As disease progresses, the effect of everolimus on hypoglycemia wanes. We report for the first time the development of hypoglycemia during everolimus treatment. PMID- 26113981 TI - Adrenal insufficiency in a child following unilateral excision of a dual-hormone secreting phaeochromocytoma. AB - Phaeochromocytomas are a rare clinical entity, with dual hormone-secreting lesions particularly uncommon, seen in <1%. ACTH is the most common hormone co produced, and is potentially lethal if not diagnosed. We present the case of a previously well 10-year-old boy, who presented acutely with a hypertensive crisis and was found to have a unilateral, non-syndromic phaeochromocytoma. Medical stabilization of his hypertension was challenging, and took 3 weeks to achieve, before proceeding to unilateral adrenalectomy. Post-operatively the child experienced severe fatigue and was subsequently confirmed to have adrenal insufficiency. He improved markedly with hydrocortisone replacement therapy, which is ongoing 6 months post-operatively. In retrospect this likely represents unrecognized, sub-clinical ACTH-dependent Cushing's syndrome secondary to an ACTH/or precursor dual-hormone secreting phaeochromocytoma. At follow-up, his hypertension had resolved, there was no biochemical evidence of recurrence of the phaeochromocytoma, and genetic analysis was indicative of a sporadic lesion. LEARNING POINTS: Dual hormone secreting phaeochromocytomas with ACTH/or a precursor may cause secondary adrenal insufficiency following surgical removal.The concurrent features of Cushing's syndrome can be mild and easily overlooked presenting diagnostic and management pitfalls.As concomitant syndromes of hormone excess are rare in phaeochromocytomas; the diagnosis requires a high index of suspicion.Serial/diurnal cortisol levels, ACTH measurement +/- low dose dexamethasone suppression (when clinically stable, appropriate adrenergic blockade in place, and well supervised), can all be considered as needed. PMID- 26113982 TI - Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: a retrospective cohort study. AB - OBJECTIVE: We hypothesise that low 25-hydroxyvitamin D (25(OH)D) levels before hospitalisation are associated with increased risk of acute respiratory failure. DESIGN: Retrospective cohort study. SETTING: Medical and Surgical Intensive care units of two Boston teaching hospitals. PATIENTS: 1985 critically ill adults admitted between 1998 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure of interest was prehospital serum 25(OH)D categorised as <=10 ng/mL, 11-19.9 ng/mL, 20-29.9 ng/mL and >=30 ng/mL. The primary outcome was acute respiratory failure excluding congestive heart failure determined by International Classification of Diseases Ninth Edition (ICD-9) coding and validated against the Berlin Definition of acute respiratory sistress syndrome. Association between 25(OH)D and acute respiratory failure was assessed using logistic regression, while adjusting for age, race, sex, Deyo-Charlson Index and patient type (medical vs surgical). In the cohort, the mean age was 63 years, 45% were male and 80% were white; 25(OH)D was <=10 ng/mL in 8% of patients, 11-19.9 ng/mL in 24%, 20-29.9 ng/mL in 24% and >=30 ng/mL in 44% of patients. Eighteen per cent (n=351) were diagnosed with acute respiratory failure. Compared to patients with 25(OH)D >=30 ng/mL, patients with lower 25(OH)D levels had significantly higher adjusted odds of acute respiratory failure (<=10 ng/mL, OR=1.84 (95% CI 1.22 to 2.77); 11-19.9 ng/mL, OR=1.60 (95% CI 1.19 to 2.15); 20 29.9 ng/mL, OR=1.37 (95% CI 1.01 to 1.86)). CONCLUSIONS: Prehospital 25(OH)D was associated with the risk of acute respiratory failure in our critically ill patient cohort. PMID- 26113983 TI - Recommendations for management of diabetes during Ramadan: update 2015. AB - Since the first ADA working group report on the recommendations for management of diabetes during Ramadan in 2005 and our update in 2010, we received many inquiries asking for regular updates on information regarding education, nutritional habits and new oral and injectable agents that may be useful for the management of patients with diabetes during Ramadan. Patients can be stratified into their risk of hypoglycemia and/or complications prior to the start of the fasting period of Ramadan. Those at high risk of hypoglycemia and with multiple diabetic complications should be advised against prolonged fasting. Even in the lower hypoglycemia risk group, adverse effects may still occur. In order to minimize adverse side effects during fasting in patients with diabetes and improve or maintain glucose control, education and discussion of glucose monitoring and treatment regimens should occur several weeks prior to Ramadan. Agents such as metformin, thiazolidinediones and dipeptidyl peptidase-4 inhibitors appear to be safe and do not need dose adjustment. Most sulfonylureas may not be used safely during Ramadan except with extreme caution; besides, older agents, such as chlorpropamide or glyburide, should not be used. Reduction of the dosage of sulfonylurea is needed depending on the degree of control prior to fasting. Misconceptions and local habits should be addressed and dealt with in any educational intervention and therapeutic planning with patients with diabetes. In this regard, efforts are still needed for controlled prospective studies in the field of efficacy and safety of the different interventions during the Ramadan Fast. PMID- 26113984 TI - Impact of an individualized type 2 diabetes education program on clinical outcomes during Ramadan. AB - OBJECTIVE: To determine if individualized education before Ramadan results in a safer fast for people with type 2 diabetes. METHODS: Patients with type 2 diabetes who received care from participating clinics in Egypt, Iran, Jordan and Saudi Arabia and intended to fast during Ramadan 2014 were prospectively studied. Twelve clinics participated. Individualized education addressed meal planning, physical activity, blood glucose monitoring and acute metabolic complications and when deemed necessary, provided an individualized diabetes treatment plan. RESULTS: 774 people met study criteria, 515 received individualized education and 259 received usual care. Those who received individualized education were more likely to modify their diabetes treatment plan during Ramadan (97% vs 88%, p<0.0001), to perform self-monitoring of blood glucose at least twice daily during Ramadan (70% vs 51%, p<0.0001), and to have improved knowledge about hypoglycemic signs and symptoms (p=0.0007). Those who received individualized education also reduced their body mass index (-1.1+/-2.4 kg/m(2) vs -0.2+/-1.7 kg/m(2), p<0.0001) and glycated haemoglobin (-0.7+/-1.1% vs -0.1+/-1.3%, p<0.0001) during Ramadan compared those who received usual care. There were more mild (77% vs 67%, p=0.0031) and moderate (38% vs 19%, p<0.0001) hypoglycemic events reported by participants who received individualized education than those who received usual care, but fewer reported severe hypoglycemic events during Ramadan (23% vs 34%, p=0.0017). CONCLUSIONS: This individualized education and diabetes treatment program helped patients with type 2 diabetes lose weight, improve glycemic control and achieve a safer fast during Ramadan. PMID- 26113986 TI - Shared decision-making in selection of prosthetic aortic valve. PMID- 26113985 TI - Capsaicin may have important potential for promoting vascular and metabolic health. AB - Capsaicin, the phytochemical responsible for the spiciness of peppers, has the potential to modulate metabolism via activation of transient receptor potential vanilloid 1 (TRPV1) receptors, which are found not only on nociceptive sensory neurons, but also in a range of other tissues. TRPV1 activation induces calcium influx, and in certain tissues this is associated with increased activation or expression of key proteins such as endothelial nitric oxide synthase (eNOS), uncoupling protein 2 (UCP2), KLF2, PPARdelta, PPARgamma, and LXRalpha. The calcium influx triggered by TRPV1 activation in endothelial cells mimics the impact of shear stress in this regard, activating and increasing the expression of eNOS-but also increasing expression of cox-2, thrombomodulin, and nrf2 responsive antioxidant enzymes, while decreasing expression of proinflammatory proteins. Hence, dietary capsaicin has favourably impacted endothelium-dependent vasodilation in rodents. TRPV1-mediated induction of LXRalpha in foam cells promotes cholesterol export, antagonising plaque formation. Capsaicin-mediated activation of TRPV1-expressing neurons in the gastrointestinal tract promotes sympathetically mediated stimulation of brown fat, raising metabolic rate. The increased expression of UCP2 induced by TRPV1 activation exerts a protective antioxidant effect on the liver in non-alcoholic fatty liver disease, and on vascular endothelium in the context of hyperglycaemia. In rodent studies, capsaicin-rich diets have shown favourable effects on atherosclerosis, metabolic syndrome, diabetes, obesity, non-alcoholic fatty liver, cardiac hypertrophy, hypertension and stroke risk. Clinically, ingestion of capsaicin-or its less stable non-pungent analogue capsiate-has been shown to boost metabolic rate modestly. Topical application of capsaicin via patch was found to increase exercise time to ischaemic threshold in patients with angina. Further clinical studies with capsaicin administered in food, capsules, or via patch, are needed to establish protocols that are tolerable for most patients, and to evaluate the potential of capsaicin for promoting vascular and metabolic health. PMID- 26113987 TI - Thrombus aspiration in STEMI revisited: impact on coronary microcirculation? PMID- 26113988 TI - BAFF (B cell activating factor) transcript level in peripheral blood of patients with SLE is associated with same-day disease activity as well as global activity over the next year. AB - OBJECTIVES: Quantitating gene expression is a potential method of developing biomarkers in systemic lupus erythematosus (SLE). Because of the known pathological role of B cell activating factor (BAFF) in SLE, we explored the association between BAFF gene expression and clinical activity in SLE. METHODS: A total of 275 patients with SLE completed this phase of a prospective observational study. At entry into the study, the BAFF gene expression levels were determined in peripheral blood RNA. Serum concentration of BAFF protein was also measured. We then determined clinical associations with SLE disease history, SLE activity on the same day and SLE activity over the course of the next year. RESULTS: Elevated BAFF gene expression was associated with a history of more leucopenia and serologically with more autoantibodies (anti-dsDNA, anti-Sm, anti Ro, anti-La and anti-RNP) and low complement. Patients with higher amounts of BAFF transcript had higher measured levels of clinical disease activity. Initial high levels of BAFF gene expression also predicted increased disease activity over the course of the next year. In contrast, serum concentration of BAFF protein was not strongly associated with same-day global disease activity or with future disease activity. CONCLUSIONS: BAFF gene expression level is associated with clinical and serological SLE activity on the same day and predictive of clinical activity over the next year. BAFF gene expression is a better measure and predictor of SLE disease activity than the serum BAFF protein level. PMID- 26113990 TI - Evaluation of Idiopathic Choroidal Neovascularization with Indocyanine Green Angiography in Patients Undergoing Bevacizumab Therapy. AB - Purpose. To examine the clinical implications of change in choroidal neovascularization (CNV) size on indocyanine green (ICG) angiography in subjects with idiopathic CNV undergoing bevacizumab therapy. Methods. The charts of subjects with an idiopathic CNV treated by a modified PRN regimen with intravitreal bevacizumab over a 12-month period were retrospectively reviewed. Results. There were 34 subjects included in the analysis. Baseline CNV sizes of less than 1.0 mm(2) on ICG angiography correlated with complete CNV resolution (P = 0.0404), fewer injections delivered (P = 0.0002), and better Snellen visual acuity (P = 0.0098) at 12 months. Subjects that experienced a 33% or more reduction in CNV size on ICG angiography at 2 months had complete CNV resolution (P = 0.0047) and fewer injections (P < 0.0001) at 12 months compared to subjects that did not experience a 33% or more reduction in CNV size on ICG angiography at 2 months. Conclusions. Smaller baseline CNV size on ICG angiography resulted in better visual acuity and fewer injections at 12 months, and a reduction of 33% or more in CNV size after 2 months may predict a better clinical course in subjects with idiopathic CNV undergoing bevacizumab therapy. PMID- 26113991 TI - Ahmed Glaucoma Valve Implantation for Refractory Glaucoma in a Tertiary Hospital in Brazil. AB - Purpose. To evaluate the efficacy of Ahmed Glaucoma Valve (AGV) implantation in patients with refractory glaucoma in a tertiary hospital in Brazil. Methods. Retrospective case series of patients who underwent AGV implantation. Primary outcome was to assess the rate of failure, which was defined as intraocular pressure (IOP) in two consecutive visits greater than 18 or lower than 5 mmHg (criterion 1) or IOP greater than 15 or lower than 5 mmHg (criterion 2). The secondary outcome was to investigate risk factors for failure. Results. 112 eyes from 108 patients underwent AGV implantation between 2000 and 2012. Mean follow up time was 2.54 (+/-1.52) years. Kaplan-Meier survival analysis showed cumulative probabilities of success of 80.3%, 68.2%, and 47.3% at 1, 3, and 5 years using 18 mmHg as endpoint. When adopting 15 mmHg as endpoint, cumulative success rates were 80.3%, 60.7%, and 27.3% at 1, 3, and 5 years, respectively. Multivariate analysis with generalized estimating equations revealed that African American ancestry and early hypertensive phase were risk factors for failure (P = 0.001 and P = 0.002, resp.). Conclusion. A success rate of approximately 50% was obtained 5 years after the implantation of an AGV. African American ancestry and early hypertensive phase were associated with increased risk of failure. PMID- 26113992 TI - Pressure Measurement Techniques for Abdominal Hypertension: Conclusions from an Experimental Model. AB - Introduction. Intra-abdominal pressure (IAP) measurement is an indispensable tool for the diagnosis of abdominal hypertension. Different techniques have been described in the literature and applied in the clinical setting. Methods. A porcine model was created to simulate an abdominal compartment syndrome ranging from baseline IAP to 30 mmHg. Three different measurement techniques were applied, comprising telemetric piezoresistive probes at two different sites (epigastric and pelvic) for direct pressure measurement and intragastric and intravesical probes for indirect measurement. Results. The mean difference between the invasive IAP measurements using telemetric pressure probes and the IVP measurements was -0.58 mmHg. The bias between the invasive IAP measurements and the IGP measurements was 3.8 mmHg. Compared to the realistic results of the intraperitoneal and intravesical measurements, the intragastric data showed a strong tendency towards decreased values. The hydrostatic character of the IAP was eliminated at high-pressure levels. Conclusion. We conclude that intragastric pressure measurement is potentially hazardous and might lead to inaccurately low intra-abdominal pressure values. This may result in missed diagnosis of elevated abdominal pressure or even ACS. The intravesical measurements showed the most accurate values during baseline pressure and both high-pressure plateaus. PMID- 26113993 TI - Social Interaction and Collaboration among Oncology Nurses. AB - Collaboration is a complex process influenced by organizational, professional, interpersonal, and personal factors. Research has demonstrated that collaboration may also be influenced by social factors. Nurses spend much of their time working in collaborative teams, yet little is known about how they socially interact in practice. This qualitative case study explored nurse perceptions of social interaction in relation to collaboration. Data were collected using telephone interviews and documentary reviews from fourteen oncology nurses employed at one cancer center in Canada. Thematic analysis revealed two themes: knowing you is trusting you and formal and informal opportunities. Nurses reported that social interaction meant getting to know someone personally as well as professionally. Social interaction was enacted inside of work during breaks/meals and outside of work at planned events. Social interaction was facilitated by having a long-term current and/or previous professional and personal relationship. The barriers to social interaction included a lack of time to get to know each other, workload issues, and poor interpersonal skills. Findings suggest that social interaction is an important factor in the collaborative relationship among oncology nurses. Nurse leaders need to promote social interaction opportunities and facilitate educational sessions to improve social and interpersonal skills. PMID- 26113989 TI - Rational Combinations of Targeted Agents in AML. AB - Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many "synthetic lethal" strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies. PMID- 26113995 TI - Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease. AB - Peripheral nerve blockade (PNB) is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR). Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD). Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year-old female undergoing TKR. A Humate-P intravenous infusion was started and the patient was positioned supinely. Using sterile technique with ultrasound guidance, a Contiplex 18 Gauge Tuohy needle was advanced in plane through the fascia iliaca towards the femoral nerve. A nerve catheter was threaded through the needle and secured without complications. Postoperatively, a levobupivacaine femoral catheter infusion was maintained, and twice daily Humate P intravenous infusions were administered for 48 hours; enoxaparin thromboprophylaxis was initiated thereafter. The patient was discharged uneventfully on postoperative day 4. Given documentation of delayed, unheralded bleeding from PNB in coagulopathic patients, we recommend individualized PNB in vWD patients. Multidisciplinary team involvement is required to guide factor supplementation and thromboprophylaxis, as is close follow-up to elicit signs of bleeding throughout the delayed postoperative period. PMID- 26113996 TI - Instant Stent-Accentuated Three-Dimensional Optical Coherence Tomography Guided Selection of Proper Distal Cell for Side Branch Dilatation in Bifurcation Stenting. AB - In the bifurcation stenting, the distal rewiring for the side branch postdilatation confirmed by two-dimensional modalities may not lead to favorable results in some cases. If there are two distal cells divided by the link bridging from the carina, the rewiring through the larger distal cell may be recommended for the side branch postdilatation. Detailed confirmation of the rewired cell by the intraprocedural instant stent-accentuated three-dimensional optical coherence tomography is important. PMID- 26113994 TI - KV7 Channels Regulate Firing during Synaptic Integration in GABAergic Striatal Neurons. AB - Striatal projection neurons (SPNs) process motor and cognitive information. Their activity is affected by Parkinson's disease, in which dopamine concentration is decreased and acetylcholine concentration is increased. Acetylcholine activates muscarinic receptors in SPNs. Its main source is the cholinergic interneuron that responds with a briefer latency than SPNs during a cortical command. Therefore, an important question is whether muscarinic G-protein coupled receptors and their signaling cascades are fast enough to intervene during synaptic responses to regulate synaptic integration and firing. One of the most known voltage dependent channels regulated by muscarinic receptors is the KV7/KCNQ channel. It is not known whether these channels regulate the integration of suprathreshold corticostriatal responses. Here, we study the impact of cholinergic muscarinic modulation on the synaptic response of SPNs by regulating KV7 channels. We found that KV7 channels regulate corticostriatal synaptic integration and that this modulation occurs in the dendritic/spines compartment. In contrast, it is negligible in the somatic compartment. This modulation occurs on sub- and suprathreshold responses and lasts during the whole duration of the responses, hundreds of milliseconds, greatly altering SPNs firing properties. This modulation affected the behavior of the striatal microcircuit. PMID- 26113997 TI - Diagnostic Challenge in a Patient with Severe Anion Gap Metabolic Acidosis. AB - The approach to the patient with acute renal failure and elevated anion and osmolal gap is difficult. Differential diagnoses include toxic alcohol ingestion, diabetic or starvation ketoacidosis, or 5-oxoproline acidosis. We present a 76 year-old female with type 2 diabetes mellitus, who was found at home in a confused state. Laboratory analysis revealed serum pH 6.84, bicarbonate 5.8 mmol/L, pCO2 29 mmHg, anion gap 22.2 mmol/L, osmolal gap 17.4 mOsm/kg, elevated beta-hydroxybutyrate (4.2 mmol/L), random blood sugar 213 mg/dL, creatinine 2.1 mg/dL, and potassium 7.5 mmol/L with no electrocardiogram (EKG) changes. Fomepizole and hemodialysis were initiated for presumed ethylene glycol or methanol ingestion. Drug screens returned negative for ethylene glycol, alcohols, and acetaminophen, but there were elevated urine levels of acetone (11 mg/dL). The acetaminophen level was negative, and 5-oxoproline was not analyzed. After 5 days in the intensive care unit (ICU), her mental status improved with supportive care. She was discharged to a nursing facility. Though a diagnosis was not established, our patient's presentation was likely due to starvation ketosis combined with chronic acetaminophen ingestion. Acetone ingestion is less likely. Overall, our case illustrates the importance of systematically approaching an elevated osmolal and anion gap metabolic acidosis. PMID- 26113998 TI - Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature. AB - Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this disease's autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective. PMID- 26113999 TI - Carnitine Deficiency and Pregnancy. AB - We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID- 26114000 TI - Xanthogranulomatous Salpingooophoritis: The Youngest Documented Case Report. AB - Background. Xanthogranulomatous inflammation is an uncommon affection of the female genital tract. The youngest case reported of xanthogranulomatous salpingooophoritis in literature was by Shilpa et al. in 2013 in an eighteen-year old female. Case Report. We report a case of 2-year-old female child with right sided xanthogranulomatous salpingooophoritis presented as mass in abdomen. This is a case report of the youngest documented case of xanthogranulomatous salpingooophoritis in literature. As per abdominal examination, there was generalized distention of abdomen and a mass was palpable which was arising out of pelvis more on the right side. The ultrasonography (USG) abdomen and pelvis revealed a thick-walled mass measuring 9.2 cm * 6.0 cm * 7.6 cm in pelvis. We did right salpingooophorectomy of the patient. On histopathology, the diagnosis of xanthogranulomatous salpingooophoritis was confirmed. Conclusion. Clinical presentation, radiological appearance, and gross features of xanthogranulomatous lesions of ovary can mimic neoplastic lesions and lead to misdiagnosis. Though, it is very rare in pediatric age group, xanthogranulomatous salpingooophoritis as one of the differential diagnoses should be kept in mind while dealing with tuboovarian masses in this age group. PMID- 26114001 TI - Gonococcal Chorioamnionitis with Antepartum Fetal Death In Utero. AB - We report the case of a patient who developed gonococcal chorioamnionitis resulting in stillbirth at 28 + 4 weeks of pregancy. As this infection is rare and potentially serious, questions remain regarding occurrence and screening for Neisseria gonorrhoeae infection. PMID- 26114002 TI - Malignant Triton Tumors in Sisters with Clinical Neurofibromatosis Type 1. AB - Malignant triton tumors (MTTs) are rare and aggressive sarcomas categorized as a subgroup of malignant peripheral nerve sheath tumors (MPNSTs). MTTs arise from Schwann cells of peripheral nerves or existing neurofibromas and have elements of rhabdomyoblastic differentiation. We report the occurrence of MTTs in two sisters. The first patient is a 36-year-old female who presented with left sided chest wall swelling. She also had clinical features consistent with neurofibromatosis type 1 (NF-1). Debulking of the mass showed high-grade malignant peripheral nerve sheath tumor with skeletal muscle differentiation (MTT). The patient was treated with ifosfamide and adriamycin along with radiation. Four years after treatment, she still has no evidence of disease recurrence. Her sister subsequently presented to us at the age of 42 with left sided lateral chest wall pain. Imaging showed a multicompartmental retroperitoneal cystic mass with left psoas involvement. The tumor was resected and, similarly to her sister, it showed high-grade malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation (MTT). The patient was started on chemotherapy and radiation as described above. PMID- 26114003 TI - A New Variant of Posterior Canal Benign Paroxysmal Positional Vertigo: A Nonampullary or Common Crus Canalolithiasis. AB - Clockwise or counterclockwise, rotational, upbeating nystagmus is seen in patients with posterior canal benign paroxysmal positional vertigo during left or right head-hanging test, respectively. Rotating of nystagmus in opposite direction to the ear tested or even reversal of initial positioning rotational nystagmus is not usual and has never been reported before. We propose a new variant of posterior canal benign paroxysmal positional vertigo due to unusual behavior and location of the otoliths inside the membranous labyrinth. Unexpected rotational direction may lead to confusion about the site. The examiner should be aware of this abnormal or atypical variant of posterior canal benign paroxysmal positional vertigo. PMID- 26114004 TI - Visualizing Central Vessels of Hepatic Angiomyolipoma Devoid of Fat Using a 2D Multi-Breath-Hold Susceptibility-Weighted Imaging. AB - Epithelioid hepatic angiomyolipoma (Epi-HAML) is a rare benign mesenchymal tumor with malignant potential. Most of Epi-HAML contains no or only a minimal amount of adipose tissue and poses a diagnostic challenge. Central vessels are characteristic imaging finding of Epi-HAML, which usually were displayed by dynamic contrast imaging. In this paper, we displayed the central vessels of Epi HAML invisible on conventional MR images using a new developed abdominal susceptibility-weighted imaging (SWI). To the best of our knowledge, this is the first description for the role of SWI in characterization of Epi-HAML. PMID- 26114005 TI - Filiform Polyposis Secondary to Colonic Tuberculosis Presenting as Acute Colo Colonic Intussusception. AB - Filiform polyposis represents a rare but recognised manifestation on the varied spectrum of histopathology in colonic tuberculosis. We report a case of filiform polyposis secondary to colonic tuberculosis presenting as colo-colonic intussusception diagnosed on an abdominal computed tomography (CT) scan. The patient required urgent hemicolectomy and defunctioning ileostomy. Examination of the resected bowel lesions revealed filiform polyposis. Induced sputum samples from the patient grew Mycobacterium tuberculosis. The patient recovered well from the surgery and received treatment for tuberculosis. At last follow-up, he was awaiting the reversal of his ileostomy. The protean nature of histological findings in colonic tuberculosis and other current diagnostic challenges are discussed. The importance of maintaining a high index of suspicion for colonic tuberculosis and instituting early treatment is highlighted in this case. PMID- 26114006 TI - Huge Intravascular Tumor Extending to the Heart: Leiomyomatosis. AB - Intravenous leiomyomatosis (IVL) is a rare neoplasm characterized by histologically benign-looking smooth muscle cell tumor mass, which is growing within the intrauterine and extrauterine venous system. In this report we aimed to present an unusual case of IVL, which is originating from iliac vein and extended throughout to right cardiac chambers. A 49-year-old female patient, who was treated with warfarin sodium due to right iliac vein thrombosis, was admitted to our department with intermittent dyspnea, palpitation, and dizziness. Physical examination was almost normal except bilateral pretibial edema. On magnetic resonance venography, there was an intravenous mass, which is originated from right internal iliac vein and extended into the inferior vena cava. Transthoracic echocardiography and transesophageal echocardiography revealed a huge mass extending from the inferior vena cava through the right atrium, with obvious venous occlusion. Thoracic, abdominal, and pelvic MR showed an intravascular mass, which is concordant with leiomyomatosis. Surgery was performed through median sternotomy. A huge mass with 25-cm length and 186-gr weight was excised through right atrial oblique incision, on beating heart with cardiopulmonary bypass. Histopathologic assessment was compatible with IVL. Exact strategy for the surgical treatment of IVL is still controversial. We used one-stage approach, with complete resection of a huge IVL extending from right atrium to right iliac vein. In such cases, high recurrence rate is a significant problem; therefore it should be kept in mind. PMID- 26114007 TI - Unusual Variant of Coronal Bladder Duplication Associated with Glans Diphallia: A Case Report and Review of the Literature. AB - Bladder duplication is a rare congenital anomaly which occurs in the sagittal or coronal plane and it can be associated with other anomalies. It has been previously classified as complete duplication of the bladder and urethra or incomplete duplication with two bladders and common urethra. However, complete duplication of bladder with a single urethra has been rarely reported. Herein, we present a patient with a different variation of bladder duplication in the coronal plane with two urethras originating from the main bladder and associated glans diphallia. PMID- 26114008 TI - Trisacryl Gelatin Microembolism and Metastases in the Lung after Renal Artery Embolization and Nephrectomy for Renal Cell Carcinoma. AB - This is the first report, to our knowledge, of widespread, histologically confirmed trisacryl gelatin pulmonary microembolism after renal artery embolization (RAE). In addition, this is the first report of lung involvement by both metastatic renal cell carcinoma (RCC) and an embolic agent used for RAE. The patient was a 63-year-old woman who recently presented with both dyspnea on exertion and productive cough. Her past medical history included clear cell RCC, which was treated with preoperative trisacryl gelatin microsphere RAE and right nephrectomy 9 years earlier. Computed tomography of the chest showed multiple lung nodules, a mass-like density in the left lower lobe, and mediastinal and hilar lymphadenopathy. Wedge resections of the lung showed multiple foci of metastatic RCC and extensive involvement of the muscular pulmonary arteries by trisacryl gelatin microspheres. PMID- 26114009 TI - Visualizing a protein's sugars. PMID- 26114011 TI - Modifiable Risk Factors Affecting Outcomes: The Truth About Obesity. PMID- 26114012 TI - Treatment Considerations for the Management of Patients With Hormone Receptor Positive Metastatic Breast Cancer. AB - Breast cancer is among the most commonly diagnosed cancers in the United States. Despite treatment, 30% to 40% of women with early-stage or localized invasive breast cancer will eventually develop metastatic disease. Women with metastatic breast cancer (MBC) are living longer lives with the advent of new therapies. Currently, treatment for MBC can consist of a variety of approaches including chemotherapy, targeted therapy, and hormonal therapy, with disease-related, treatment-related, and patient-related factors guiding the selection and sequencing of these agents. In addition to controlling disease progression, strategies to improve or maintain quality of life are particularly important. For women with hormone receptor-positive disease, hormonal therapy is typically the first-line treatment of choice given the overall efficacy and favorable safety profiles of these agents; additional lines of other hormonal therapies are often administered upon disease progression. Other factors that must be considered by the practitioner to achieve optimal outcomes for the patient with MBC include the presence of comorbid illness and the educational, psychosocial, and supportive care needs of the patient. PMID- 26114010 TI - Cell totipotency: molecular features, induction, and maintenance. AB - In mammals, pluripotent stem cells can give rise to every cell type of embryonic lineage, and hold great potential in regenerative medicine and disease modeling. Guided by the mechanism underlying pluripotency, pluripotent stem cells have been successfully induced through manipulating the transcriptional and epigenetic networks of various differentiated cell types. However, the factors that confer totipotency, the ability to give rise to cells in both embryonic and extra embryonic lineages, still remain poorly understood. It is currently unknown whether totipotency can be induced and maintained in vitro. In this review, we summarize the current progress in the field, with the aim of providing a foundation for understanding the mechanisms that regulate totipotency. PMID- 26114013 TI - Improving Palliative Cancer Care. AB - Over a decade ago, the Institute of Medicine (IOM) presented Ensuring Quality Cancer Care in the United States, with recommendations for change (IOM, 1999). However, barriers to integrating palliative care (PC) to achieve high-quality care in cancer still remain. As novel therapeutic agents evolve, patients are living longer, and advanced cancer is now considered a chronic illness. In addition to complex symptom concerns, patients and family caregivers are burdened with psychological, social, and spiritual distress. Furthermore, data show that PC continues to be underutilized and inaccessible, and current innovative models of integrating PC into standard cancer care lack uniformity. The aim of this article is to address the existing barriers in implementing PC into our cancer care delivery system and discuss how the oncology advanced practice nurse plays an essential role in providing high-quality cancer care. We also review the IOM recommendations; highlight the work done by the National Consensus Project in promoting quality PC; and discuss a National Cancer Institute-funded program project currently conducted at a National Comprehensive Cancer Center, "Palliative Care for Quality of Life and Symptoms Concerns in Lung Cancer," which serves as a model to promote high-quality care for patients and their families. PMID- 26114014 TI - Using Technology to Advance Cancer Survivorship Programs. PMID- 26114015 TI - Ibrutinib in Relapsed or Refractory Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia. PMID- 26114016 TI - Clinical Management of Pancreatic Cancer. PMID- 26114017 TI - Use of Radiographic Criteria to Predict Outcomes Following Surgery for Pancreatic Cancer. PMID- 26114018 TI - Human Herpesvirus-6 Encephalitis After Hematopoietic Stem Cell Transplantation. PMID- 26114019 TI - Cancer Prediction Nomograms for Advanced Practitioners in Oncology. PMID- 26114020 TI - How Do You Triage Abdominal Pain in a Patient With Ovarian Cancer? PMID- 26114021 TI - Dual shear wave induced laser speckle contrast signal and the improvement in shear wave speed measurement. AB - Shear wave speed is quantitatively related to tissue viscoelasticity. Previously we reported shear wave tracking at centimetre depths in a turbid optical medium using laser speckle contrast detection. Shear wave progression modulates displacement of optical scatterers and therefore modulates photon phase and changes the laser speckle patterns. Time-resolved charge-coupled device (CCD) based speckle contrast analysis was used to track shear waves and measure the time-of-flight of shear waves for speed measurement. In this manuscript, we report a new observation of the laser speckle contrast difference signal for dual shear waves. A modulation of CCD speckle contrast difference was observed and simulation reproduces the modulation pattern, suggesting its origin. Both experimental and simulation results show that the dual shear wave approach generates an improved definition of temporal features in the time-of-flight optical signal and an improved signal to noise ratio with a standard deviation less than 50% that of individual shear waves. Results also show that dual shear waves can correct the bias of shear wave speed measurement caused by shear wave reflections from elastic boundaries. PMID- 26114022 TI - 4-D reconstruction of fluorescence molecular tomography using re-assembled measurement data. AB - Challenges remain in the reconstruction of dynamic (4-D) fluorescence molecular tomography (FMT). In our previous work, we implemented a fully 4-D FMT reconstruction approach using Karhunen-Loeve (KL) transformation. However, in the reconstruction processes, the input data were scan-by-scan fluorescence projections. As a result, the reconstruction interval is limited by the data acquisition time for scanning one circle projections, leading to a long time (typically >1 min). In this paper, we propose a new method to reduce the reconstruction interval of dynamic FMT imaging, which is achieved by re assembling the acquired fluorescence projection sequence. Further, to eliminate the temporal correlations within measurement data, the re-assembled projection sequence is reconstructed by the KL-based method. The numerical simulation and in vivo experiments are performed to evaluate the performance of the method. The experimental results indicate that after re-assembling measurement data, the reconstruction interval can be greatly reduced (~2.5 sec/frame). In addition, the proposed re-assembling method is helpful for improving reconstruction quality of the KL-based method. PMID- 26114023 TI - Accessing to arteriovenous blood flow dynamics response using combined laser speckle contrast imaging and skin optical clearing. AB - Laser speckle contrast imaging (LSCI) shows a great potential for monitoring blood flow, but the spatial resolution suffers from the scattering of tissue. Here, we demonstrate the capability of a combination method of LSCI and skin optical clearing to describe in detail the dynamic response of cutaneous vasculature to vasoactive noradrenaline injection. Moreover, the superior resolution, contrast and sensitivity make it possible to rebuild arteries-veins separation and quantitatively assess the blood flow dynamical changes in terms of flow velocity and vascular diameter at single artery or vein level. PMID- 26114024 TI - Attenuated infrared neuron stimulation response in cochlea of deaf animals may associate with the degeneration of spiral ganglion neurons. AB - HYPOTHESIS: We hypothesize that degenerated spiral ganglion neurons (SGNs) in guinea pigs reduces auditory brainstem responses evoked by pulsed infrared stimulation. BACKGROUND: Pulsed infrared laser excitation can directly evoke physiological responses in neuronal and other excitable cells in vivo and in vitro. Laser pulses could benefit patients with cochlear implants to stimulate the auditory system. METHODS: Pulsed infrared lasers were used to study evoked optical auditory brainstem responses (oABRs) in normal hearing and deafened animals. Aslo, the morphology and anatomy of SGNs in normal hearing and deafened guinea pigs were compared. RESULTS: By recording oABRs evoked by varying infrared laser pulse durations, it is suggested that degeneration of SGNs in deafened guinea pigs was associated with an elevated oABR threshold and with lower amplitudes. Moreover, oABR threshold decreased while amplitudes increased in both normal hearing and deafened animals as the pulse duration prolonged. Electron microscopy revealed that SGNs in deafened guinea pigs had swollen and vacuolar mitochondria, as well as demyelinated soma and axons. CONCLUSION: Infrared laser pulses can stimulate SGNs to evoke oABRs in guinea pigs. Deafened guinea pigs have elevated thresholds and smaller amplitude responses, likely a result of degenerated SGNs. Short pulse durations are more suitable to evoke responses in both normal hearing and deafened animals. PMID- 26114025 TI - Diffuse optical tomography using the one-way radiative transfer equation. AB - We present a computational study of diffuse optical tomography using the one-way radiative transfer equation. The one-way radiative transfer is a simplification of the radiative transfer equation to approximate the transmission of light through tissues. The major simplification of this approximation is that the intensity satisfies an initial value problem rather than a boundary value problem. Consequently, the inverse problem to reconstruct the absorption and scattering coefficients from transmission measurements of scattered light is simplified. Using the initial value problem for the one-way radiative transfer equation to compute the forward model, we are able to quantitatively reconstruct the absorption and scattering coefficients efficiently and effectively for simple problems and obtain reasonable results for complicated problems. PMID- 26114026 TI - Co-localized confocal Raman spectroscopy and optical coherence tomography (CRS OCT) for depth-resolved analyte detection in tissue. AB - We report the development of a combined confocal Raman spectroscopy (CRS) and optical coherence tomography (OCT) instrument (CRS-OCT) capable of measuring analytes in targeted biological tissues with sub-100-micron spatial resolution. The OCT subsystem was used to measure depth-resolved tissue morphology and guide the acquisition of chemically-specific Raman spectra. To demonstrate its utility, the instrument was used to accurately measure depth-resolved, physiologically relevant concentrations of Tenofovir, a microbicide drug used to prevent the sexual transmission of HIV, in ex vivo tissue samples. PMID- 26114027 TI - Acceleration of dynamic fluorescence molecular tomography with principal component analysis. AB - Dynamic fluorescence molecular tomography (FMT) is an attractive imaging technique for three-dimensionally resolving the metabolic process of fluorescent biomarkers in small animal. When combined with compartmental modeling, dynamic FMT can be used to obtain parametric images which can provide quantitative pharmacokinetic information for drug development and metabolic research. However, the computational burden of dynamic FMT is extremely huge due to its large data sets arising from the long measurement process and the densely sampling device. In this work, we propose to accelerate the reconstruction process of dynamic FMT based on principal component analysis (PCA). Taking advantage of the compression property of PCA, the dimension of the sub weight matrix used for solving the inverse problem is reduced by retaining only a few principal components which can retain most of the effective information of the sub weight matrix. Therefore, the reconstruction process of dynamic FMT can be accelerated by solving the smaller scale inverse problem. Numerical simulation and mouse experiment are performed to validate the performance of the proposed method. Results show that the proposed method can greatly accelerate the reconstruction of parametric images in dynamic FMT almost without degradation in image quality. PMID- 26114028 TI - Dynamic structure and protein expression of the live embryonic heart captured by 2-photon light sheet microscopy and retrospective registration. AB - We present an imaging and image reconstruction pipeline that captures the dynamic three-dimensional beating motion of the live embryonic zebrafish heart at subcellular resolution. Live, intact zebrafish embryos were imaged using 2-photon light sheet microscopy, which offers deep and fast imaging at 70 frames per second, and the individual optical sections were assembled into a full 4D reconstruction of the beating heart using an optimized retrospective image registration algorithm. This imaging and reconstruction platform permitted us to visualize protein expression patterns at endogenous concentrations in zebrafish gene trap lines. PMID- 26114029 TI - Influence of defocus on quantitative analysis of microscopic objects and individual cells with digital holography. AB - Digital holography offers a unique method for studying microscopic objects using quantitative measurements of the optical phase delays of transmitted light. The optical phase may be integrated across the object to produce an optical volume measurement, a parameter related to dry mass by a simple scaling factor. While digital holography is useful for comparing the properties of microscopic objects, especially cells, we show here that quantitative comparisons of optical phase can be influenced by the focal plane of the measurement. Although holographic images can be refocused digitally using Fresnel propagation, ambiguity can result if this aspect is not carefully controlled. We demonstrate that microscopic objects can be accurately profiled by employing a digital refocusing method to analyze phase profiles of polystyrene microspheres and red blood cells. PMID- 26114030 TI - Sensitive surface enhanced Raman scattering multiplexed detection of matrix metalloproteinase 2 and 7 cancer markers. AB - A surface enhanced Raman spectroscopy (SERS) based platform was developed for sensitive multiplexed detection of matrix metalloproteinases (MMP) (MMP-2 and MMP 7) with low limit of detection and high specificity. Detection is based on the virtue of enzymatic reaction where a peptide can be cleaved only by its corresponding enzyme. The platform comprises two components, a specialized SERS based bimetallic-film-over-nanosphere (BMFON) substrate and gold nanoparticles (AuNPs). The two components were functionalized such that binding between the two would occur through biotin-avidin-biotin complexation. Binding is hindered by MMP peptide chains conjugated onto the surfaces of the substrate and AuNPs, and can be removed only by cleaving the peptide chains with corresponding enzymes. Since AuNP binding sites become free after the peptides are cleaved, the number of binding sites for AuNPs onto the substrate would increase. By tagging the AuNPs, concentrations of MMP-specific enzymes can be quantified through examining intensities of signature SERS peaks of the tags. This cleave-and-bind mechanism was first validated by individual detection and quantification of MMP-2 and MMP 7. The platform was demonstrated to be able to sensitively detect concentrations of specific enzymes ranging from 1 ng/mL to 40 ug/mL, with close correlation between SERS intensity and concentrations. Finally, the multiplexed detection of MMP-2 and MMP-7 was demonstrated. The multiplexity of this platform provides a robust way to analyze diseases associated with MMP-2 and MMP-7 enzymes. Our work can be further developed as a clinical diagnostic tool to detect other MMP proteinase in bio-fluids samples, widening the number of biomarkers needed to characterize diseases better. PMID- 26114031 TI - Extended output phasor representation of multi-spectral fluorescence lifetime imaging microscopy. AB - In this paper, we investigate novel low-dimensional and model-free representations for multi-spectral fluorescence lifetime imaging microscopy (m FLIM) data. We depart from the classical definition of the phasor in the complex plane to propose the extended output phasor (EOP) and extended phasor (EP) for multi-spectral information. The frequency domain properties of the EOP and EP are analytically studied based on a multiexponential model for the impulse response of the imaged tissue. For practical implementations, the EOP is more appealing since there is no need to perform deconvolution of the instrument response from the measured m-FLIM data, as in the case of EP. Our synthetic and experimental evaluations with m-FLIM datasets of human coronary atherosclerotic plaques show that low frequency indexes have to be employed for a distinctive representation of the EOP and EP, and to reduce noise distortion. The tissue classification of the m-FLIM datasets by EOP and EP also improves with low frequency indexes, and does not present significant differences by using either phasor. PMID- 26114032 TI - Imaging translucent cell bodies in the living mouse retina without contrast agents. AB - The transparency of most retinal cell classes typically precludes imaging them in the living eye; unless invasive methods are used that deploy extrinsic contrast agents. Using an adaptive optics scanning light ophthalmoscope (AOSLO) and capitalizing on the large numerical aperture of the mouse eye, we enhanced the contrast from otherwise transparent cells by subtracting the left from the right half of the light distribution in the detector plane. With this approach, it is possible to image the distal processes of photoreceptors, their more proximal cell bodies and the mosaic of horizontal cells in the living mouse retina. PMID- 26114033 TI - An adaptive optics imaging system designed for clinical use. AB - Here we demonstrate a new imaging system that addresses several major problems limiting the clinical utility of conventional adaptive optics scanning light ophthalmoscopy (AOSLO), including its small field of view (FOV), reliance on patient fixation for targeting imaging, and substantial post-processing time. We previously showed an efficient image based eye tracking method for real-time optical stabilization and image registration in AOSLO. However, in patients with poor fixation, eye motion causes the FOV to drift substantially, causing this approach to fail. We solve that problem here by tracking eye motion at multiple spatial scales simultaneously by optically and electronically integrating a wide FOV SLO (WFSLO) with an AOSLO. This multi-scale approach, implemented with fast tip/tilt mirrors, has a large stabilization range of +/- 5.6 degrees . Our method consists of three stages implemented in parallel: 1) coarse optical stabilization driven by a WFSLO image, 2) fine optical stabilization driven by an AOSLO image, and 3) sub-pixel digital registration of the AOSLO image. We evaluated system performance in normal eyes and diseased eyes with poor fixation. Residual image motion with incremental compensation after each stage was: 1) ~2-3 arc minutes, (arcmin) 2) ~0.5-0.8 arcmin and, 3) ~0.05-0.07 arcmin, for normal eyes. Performance in eyes with poor fixation was: 1) ~3-5 arcmin, 2) ~0.7-1.1 arcmin and 3) ~0.07-0.14 arcmin. We demonstrate that this system is capable of reducing image motion by a factor of ~400, on average. This new optical design provides additional benefits for clinical imaging, including a steering subsystem for AOSLO that can be guided by the WFSLO to target specific regions of interest such as retinal pathology and real-time averaging of registered images to eliminate image post-processing. PMID- 26114034 TI - Mapping conduction velocity of early embryonic hearts with a robust fitting algorithm. AB - Cardiac conduction maturation is an important and integral component of heart development. Optical mapping with voltage-sensitive dyes allows sensitive measurements of electrophysiological signals over the entire heart. However, accurate measurements of conduction velocity during early cardiac development is typically hindered by low signal-to-noise ratio (SNR) measurements of action potentials. Here, we present a novel image processing approach based on least squares optimizations, which enables high-resolution, low-noise conduction velocity mapping of smaller tubular hearts. First, the action potential trace measured at each pixel is fit to a curve consisting of two cumulative normal distribution functions. Then, the activation time at each pixel is determined based on the fit, and the spatial gradient of activation time is determined with a two-dimensional (2D) linear fit over a square-shaped window. The size of the window is adaptively enlarged until the gradients can be determined within a preset precision. Finally, the conduction velocity is calculated based on the activation time gradient, and further corrected for three-dimensional (3D) geometry that can be obtained by optical coherence tomography (OCT). We validated the approach using published activation potential traces based on computer simulations. We further validated the method by adding artificially generated noise to the signal to simulate various SNR conditions using a curved simulated image (digital phantom) that resembles a tubular heart. This method proved to be robust, even at very low SNR conditions (SNR = 2-5). We also established an empirical equation to estimate the maximum conduction velocity that can be accurately measured under different conditions (e.g. sampling rate, SNR, and pixel size). Finally, we demonstrated high-resolution conduction velocity maps of the quail embryonic heart at a looping stage of development. PMID- 26114035 TI - In vivo quantitation of injected circulating tumor cells from great saphenous vein based on video-rate confocal microscopy. AB - The number of circulating tumor cell (CTC) in the peripheral blood of cancer patients can be a valuable biomarker for cancer diagnosis and treatment monitoring. In this study, we implemented a custom-design video-rate confocal microscopy system in capable of direct visualization of fast flowing CTC at great saphenous vein (GSV) of a live animal model in vivo. Continuous acquisition of video-rate images at GSV revealed the highly dynamic time-dependent changes in the number of intravenously injected circulating tumor cells. By extracting a calibration factor through the hemocytometric analysis of intravenously injected long-circulating red blood cells, we established a novel quantitation method for CTC in whole body blood in vivo. PMID- 26114036 TI - Unified approach for bioluminescence, Cerenkov, beta, X and gamma rays imaging. AB - The goal of this work is to demonstrate that a CCD-based system can be used as a unified device which allows visible, beta, X and gamma rays imaging. A system composed of a CCD coupled with lens mounted on a black light-tight box and a high resolution intensifying screen for the radiations conversion were used. In order to investigate the detection of different type of radiations in vitro and in vivo experiments were performed. The comparison of the results obtained with our prototype and those obtained with dedicated commercial devices showed a good agreement. PMID- 26114037 TI - Electrically tunable lens speeds up 3D orbital tracking. AB - 3D orbital particle tracking is a versatile and effective microscopy technique that allows following fast moving fluorescent objects within living cells and reconstructing complex 3D shapes using laser scanning microscopes. We demonstrated notable improvements in the range, speed and accuracy of 3D orbital particle tracking by replacing commonly used piezoelectric stages with Electrically Tunable Lens (ETL) that eliminates mechanical movement of objective lenses. This allowed tracking and reconstructing shape of structures extending 500 microns in the axial direction. Using the ETL, we tracked at high speed fluorescently labeled genomic loci within the nucleus of living cells with unprecedented temporal resolution of 8ms using a 1.42NA oil-immersion objective. The presented technology is cost effective and allows easy upgrade of scanning microscopes for fast 3D orbital tracking. PMID- 26114038 TI - Adaptive-optics SLO imaging combined with widefield OCT and SLO enables precise 3D localization of fluorescent cells in the mouse retina. AB - Adaptive optics scanning laser ophthalmoscopy (AO-SLO) has recently been used to achieve exquisite subcellular resolution imaging of the mouse retina. Wavefront sensing-based AO typically restricts the field of view to a few degrees of visual angle. As a consequence the relationship between AO-SLO data and larger scale retinal structures and cellular patterns can be difficult to assess. The retinal vasculature affords a large-scale 3D map on which cells and structures can be located during in vivo imaging. Phase-variance OCT (pv-OCT) can efficiently image the vasculature with near-infrared light in a label-free manner, allowing 3D vascular reconstruction with high precision. We combined widefield pv-OCT and SLO imaging with AO-SLO reflection and fluorescence imaging to localize two types of fluorescent cells within the retinal layers: GFP-expressing microglia, the resident macrophages of the retina, and GFP-expressing cone photoreceptor cells. We describe in detail a reflective afocal AO-SLO retinal imaging system designed for high resolution retinal imaging in mice. The optical performance of this instrument is compared to other state-of-the-art AO-based mouse retinal imaging systems. The spatial and temporal resolution of the new AO instrumentation was characterized with angiography of retinal capillaries, including blood-flow velocity analysis. Depth-resolved AO-SLO fluorescent images of microglia and cone photoreceptors are visualized in parallel with 469 nm and 663 nm reflectance images of the microvasculature and other structures. Additional applications of the new instrumentation are discussed. PMID- 26114039 TI - Second-harmonic generation microscopy of photocurable polymer intrastromal implants in ex-vivo corneas. AB - A custom adaptive-optics (AO) multiphoton microscope was used to visualize the corneal stroma after the insertion of a photocurable polymer material. A lamellar pocket was created and a certain amount of polymer in liquid form was injected. This turned into a rigid film after UV irradiation. Intact eyes were used as control. Tomographic and regular second harmonic generation (SHG) microscopy images were recorded from both control and corneas with polymer implants. In control corneas, the SHG signal decreased uniformly with depth. However, treated corneas exhibited an abrupt loss of SHG signal at the implant location. The use of AO increased the SHG levels and improved the visualization of the stroma, not only at deeper corneal layers but also beneath the implant. Moreover, the absence of SHG signal from the implant allowed its geometrical characterization (thickness and location). This technique offers a potential tool for non-invasive analysis of morphological changes in the cornea after surgery or treatment, and might be useful in future clinical environments. PMID- 26114040 TI - Optimizing light transport in scintillation crystals for time-of-flight PET: an experimental and optical Monte Carlo simulation study. AB - Achieving excellent timing resolution in gamma ray detectors is crucial in several applications such as medical imaging with time-of-flight positron emission tomography (TOF-PET). Although many factors impact the overall system timing resolution, the statistical nature of scintillation light, including photon production and transport in the crystal to the photodetector, is typically the limiting factor for modern scintillation detectors. In this study, we investigated the impact of surface treatment, in particular, roughening select areas of otherwise polished crystals, on light transport and timing resolution. A custom Monte Carlo photon tracking tool was used to gain insight into changes in light collection and timing resolution that were observed experimentally: select roughening configurations increased the light collection up to 25% and improved timing resolution by 15% compared to crystals with all polished surfaces. Simulations showed that partial surface roughening caused a greater number of photons to be reflected towards the photodetector and increased the initial rate of photoelectron production. This study provides a simple method to improve timing resolution and light collection in scintillator-based gamma ray detectors, a topic of high importance in the field of TOF-PET. Additionally, we demonstrated utility of our Monte Carlo simulation tool to accurately predict the effect of altering crystal surfaces on light collection and timing resolution. PMID- 26114041 TI - Miniaturized magnetic-driven scanning probe for endoscopic optical coherence tomography. AB - We designed and implemented a magnetic-driven scanning (MDS) probe for endoscopic optical coherence tomography (OCT). The probe uses an externally-driven tiny magnet in the distal end to achieve unobstructed 360-degree circumferential scanning at the side of the probe. The design simplifies the scanning part inside the probe and thus allows for easy miniaturization and cost reduction. We made a prototype probe with an outer diameter of 1.4 mm and demonstrated its capability by acquiring OCT images of ex vivo trachea and artery samples from a pigeon. We used a spectrometer-based Fourier-domain OCT system and the system sensitivity with our prototype probe was measured to be 91 dB with an illumination power of 850 MUW and A-scan exposure time of 1 ms. The axial and lateral resolutions of the system are 6.5 MUm and 8.1 MUm, respectively. PMID- 26114042 TI - Controlled light field concentration through turbid biological membrane for phototherapy. AB - Laser propagation through a turbid rat dura mater membrane is shown to be controllable with a wavefront modulation technique. The scattered light field can be refocused into a target area behind the rat dura mater membrane with a 110 times intensity enhancement using a spatial light modulator. The efficient laser intensity concentration system is demonstrated to imitate the phototherapy for human brain tumors. The power density in the target area is enhanced more than 200 times compared with the input power density on the dura mater membrane, thus allowing continued irradiation concentration to the deep lesion without damage to the dura mater. Multibeam inputs along different directions, or at different positions, can be guided to focus to the same spot behind the membrane, hence providing a similar gamma knife function in optical spectral range. Moreover, both the polarization and the phase of the input field can be recovered in the target area, allowing coherent field superposition in comparison with the linear intensity superposition for the gamma knife. PMID- 26114043 TI - Miniature, minimally invasive, tunable endoscope for investigation of the middle ear. AB - We demonstrate a miniature, tunable, minimally invasive endoscope for diagnosis of the auditory system. The probe is designed to sharply image anatomical details of the middle ear without the need for physically adjusting the position of the distal end of the endoscope. This is achieved through the addition of an electrowetted, tunable, electronically-controlled lens to the optical train. Morphological imaging is enabled by scanning light emanating from an optical coherence tomography system. System performance was demonstrated by imaging part of the ossicular chain and wall of the middle ear cavity of a normal mouse. During the experiment, we electronically moved the plane of best focus from the incudo-stapedial joint to the stapedial artery. Repositioning the object plane allowed us to image anatomical details of the middle ear beyond the depth of field of a static optical system. We also demonstrated for the first time to our best knowledge, that an optical system with an electrowetted, tunable lens may be successfully employed to measure sound-induced vibrations within the auditory system by measuring the vibratory amplitude of the tympanic membrane in a normal mouse in response to pure tone stimuli. PMID- 26114044 TI - Gated STED microscopy with time-gated single-photon avalanche diode. AB - Stimulated emission depletion (STED) microscopy provides fluorescence imaging with sub-diffraction resolution. Experimentally demonstrated at the end of the 90s, STED microscopy has gained substantial momentum and impact only in the last few years. Indeed, advances in many fields improved its compatibility with everyday biological research. Among them, a fundamental step was represented by the introduction in a STED architecture of the time-gated detection, which greatly reduced the complexity of the implementation and the illumination intensity needed. However, the benefits of the time-gated detection came along with a reduction of the fluorescence signal forming the STED microscopy images. The maximization of the useful (within the time gate) photon flux is then an important aspect to obtain super-resolved images. Here we show that by using a fast-gated single-photon avalanche diode (SPAD), i.e. a detector able to rapidly (hundreds picoseconds) switch-on and -off can improve significantly the signal-to noise ratio (SNR) of the gated STED image. In addition to an enhancement of the image SNR, the use of the fast-gated SPAD reduces also the system complexity. We demonstrate these abilities both on calibration and biological sample. The experiments were carried on a gated STED microscope based on a STED beam operating in continuous-wave (CW), although the fast-gated SPAD is fully compatible with gated STED implementations based on pulsed STED beams. PMID- 26114046 TI - Dermatopathology: An abridged compendium of words. A discussion of them and opinions about them. Part 8 (P-S). PMID- 26114045 TI - Photothermal optical lock-in optical coherence tomography for in vivo imaging. AB - Photothermal OCT (PTOCT) provides high sensitivity to molecular targets in tissue, and occupies a spatial imaging regime that is attractive for small animal imaging. However, current implementations of PTOCT require extensive temporal sampling, resulting in slow frame rates and a large data burden that limit its in vivo utility. To address these limitations, we have implemented optical lock-in techniques for photothermal optical lock-in OCT (poli-OCT), and demonstrated the in vivo imaging capabilities of this approach. The poli-OCT signal was assessed in tissue-mimicking phantoms containing indocyanine green (ICG), an FDA approved small molecule that has not been previously imaged in vivo with PTOCT. Then, the effects of in vivo blood flow and motion artifact were assessed and attenuated, and in vivo poli-OCT was demonstrated with both ICG and gold nanorods as contrast agents. Experiments revealed that poli-OCT signals agreed with optical lock-in theory and the bio-heat equation, and the system exhibited shot noise limited performance. In phantoms containing biologically relevant concentrations of ICG (1 ug/ml), the poli-OCT signal was significantly greater than control phantoms (p<0.05), demonstrating sensitivity to small molecules. Finally, in vivo poli-OCT of ICG identified the lymphatic vessels in a mouse ear, and also identified low concentrations (200 pM) of gold nanorods in subcutaneous injections at frame rates ten times faster than previously reported. This work illustrates that future in vivo molecular imaging studies could benefit from the improved acquisition and analysis times enabled by poli-OCT. PMID- 26114047 TI - Infiltrating basal cell carcinoma: a stellate peri-tumor dermatoscopy pattern as a clue to diagnosis. AB - BACKGROUND: Infiltrating basal cell carcinoma (BCC) has associated features that may be readily identified using dermatoscopy. OBJECTIVE: Investigate a stellate dermatoscopy pattern extending from the peripheral margin of infiltrating BCC. METHODS: A total of 741 consecutive cases of BCC were assessed retrospectively using non-polarized dermatoscopy. Following histopathologic examination, cases were categorized into six different BCC subtypes. Infiltrating cases numbered 107. This stellate feature was defined as a geometric star shaped pattern extending outwards from the circumferential peripheral edge of the tumor, and identified by white lines, vessels or uneven skin surface morphology. The percentages of infiltrating subtype within the tumor mass and tumor depth were compared, with and without the stellate pattern. RESULTS: Infiltrating BCC displayed the stellate pattern more than other BCC subtypes. Concordance between the two observers was almost perfect for white lines: Kappa coefficient of 0.87 (95% CI: 0.0.79-0.95) P<0.01 and substantial for vessels: Kappa coefficient of 0.71 95% CI: 0.59-0.84) P<0.01. Folds were only recorded in infiltrating cases (n=3). Compared to other BCC subtypes the stellate pattern had a sensitivity of 31.7% and specificity of 94.1%. A higher mean fraction of the tumor mass containing infiltrating subtype was found when comparing stellate pattern observed to stellate pattern not observed (P<0.01). No statistically significant association was found between the tumor depth with and without the stellate pattern. CONCLUSION: This study found a higher incidence of the stellate pattern within infiltrating BCC compared to the other BCC subtypes. As the percentage of the infiltrating subtype within the tumors increased the incidence of the stellate pattern also increased. PMID- 26114048 TI - Regarding a dermatoscopic pattern for infiltrating basal cell carcinoma. PMID- 26114050 TI - Dermoscopic patterns in patients with a clinical diagnosis of onychomycosis results of a prospective study including data of potassium hydroxide (KOH) and culture examination. AB - BACKGROUND: Onychomycosis is the most common nail disease, representing 50% of cases affecting the nail apparatus. The diagnosis is made by clinical examination along with the KOH exam of the nail and culture of the sample. However, not all dermatologists have access to a mycology lab. OBJECTIVE: To determine the correlation between KOH examination and dermoscopic patterns in patients with clinical diagnosis of onychomycosis. PATIENTS/METHODS: A descriptive, open, observational, prospective, cross-sectional study of 178 patients with clinical suspicion of onychomycosis was conducted. All patients underwent clinical examination, dermoscopy with a DermLite PHOTO dermatoscope (3Gen, San Juan Capistrano, CA, USA), KOH assessment and culture analysis. The most frequent dermoscopic patterns were identified and their correlation with the clinical subtype of onychomycosis was analyzed. RESULTS: The study included 178 patients with clinical suspicion of onychomycosis. Of these, 155 (87.1%) had positive direct KOH examination for onychomycosis. Eighty-seven patients (56.13%) presented with clinical onychomycosis pattern of total dystrophic onychomycosis (TDO), 67 (43.23%) with distal lateral subungual onychomycosis (DLSO), 1 (0.65%) with trachyonychia). Dermoscopic patterns of onychomycosis showed the following frequencies: the spiked pattern was present in 22 patients (14.19%), longitudinal striae pattern in 51 patients (32.9%) and linear edge pattern in 21 patients (13.55%). We identified a pattern described as "distal irregular termination" in 41 patients with TDO and 26 with DLSO. CONCLUSIONS: This is the fist study conducted in a Mexican population that uses dermoscopy as a diagnostic tool along with the KOH examination for the diagnosis of onychomycosis. Dermoscopy may be used as an important diagnostic tool when evaluating nail disease. However, it should not be used as the only diagnostic criteria for onychomycosis. PMID- 26114051 TI - Dermoscopic patterns in active and regressive lichen planus and lichen planus variants: a morphological study. PMID- 26114049 TI - Trends in dermoscopy use in the UK: results from surveys in 2003 and 2012. AB - BACKGROUND: Dermoscopy is a useful tool to aid diagnosis of pigmented and non pigmented skin lesions, as well as many other dermatological conditions. Use of dermoscopy is increasing worldwide, but to date, there are no reported data on attitudes of dermatologists in the United Kingdom (UK) towards dermoscopy. OBJECTIVE: To determine current attitudes of UK dermatologists towards dermoscopy and assess how these attitudes have changed over the last decade. METHODS: In October 2012, an online survey was sent to members of British Association of Dermatologists over a 12-week period. Data were subsequently compared with data from a similar UK nationwide paper questionnaire distributed to members in 2003. RESULTS: The 2003 survey collected 292 responses (uptake 42%), and in 2012 there were 209 responses (22%), predominantly from consultants and registrars. In 2012, 86% respondents reported increased use of dermoscopy over the previous decade with 98.5% of respondents reporting regular clinical use of dermoscopy, compared with 54% in 2003. Overall, 81% respondents in 2012 had received dermoscopy training, mainly from UK-based courses (62% of respondents) but increasingly via Internet-based resources (30% vs. 7% in 2003). However, 39% respondents lacked confidence when making a diagnosis based on their interpretation of dermoscopy findings. CONCLUSIONS: Over the last decade, use of dermoscopy has increased amongst UK dermatologists and the majority of respondents now employ dermoscopy in daily clinical practice. However, the use of dermoscopy in the dermatology community overall is not known and for those individuals there is a continued need for education. PMID- 26114052 TI - Appeasement never works. PMID- 26114053 TI - Trichilemmoma in continuity with pigmented basal cell carcinoma; with dermatoscopy and dermatopathology. AB - A case of trichilemmoma in continuity with a pigmented basal cell carcinoma is presented with dermatoscopy and dermatopathology. The distinction between the two lesions was evident dermatoscopically and was confirmed dermatopathologically. While trichilemmoma has been reported in association with basal cell carcinoma and dermatoscopy images of four previous cases of trichilemmoma have been published, no previous dermatoscopy image has been published of trichilemmoma associated with basal cell carcinoma. PMID- 26114054 TI - Malignant cylindroma in a patient with Brooke-Spiegler syndrome. AB - Malignant cylindroma (cylindromatous carcinoma, cylindrocarcinoma) is the malignant counterpart of benign cylindroma. It is a rare neoplasm, more often developing in the setting of multiple preexisting benign neoplasms. Herein we present an additional case of malignant transformation of the cylindroma diagnosed in an 83-year-old patient with known Brooke-Spiegler syndrome. PMID- 26114055 TI - Keratotic papules of palms and soles. PMID- 26114056 TI - Metaphoric and descriptive terminology in dermoscopy: Lessons from the cognitive sciences. PMID- 26114057 TI - Dermoscopic findings in a case of reactive perforating collagenosis. PMID- 26114058 TI - Benign dermoscopic parallel ridge pattern in plantar hyperpigmentation due to capecitabine. AB - We report the case of a 37-year-old woman (phototype II) who presented at our outpatient clinic with a two-month history of hyperpigmented plantar macules. Medical history revealed that the patient had taken capecitabine in the past three months as adjuvant chemotherapy for recurrent breast cancer. Dermoscopic examination of the plantar macules showed parallel ridge pattern with pigmentation in the furrows without obliteration of eccrine gland apertures. Besides in acral melanoma, parallel ridge pattern can also be observed in benign plantar lesions, such as congenital or acquired acral nevi, subcorneal hemorrhage, dye-related pigmentation and drug-induced hyperpigmentation, especially in patients with phototypes III-VI. The few reported cases of capecitabine-induced hyperpigmentation have been associated with hand and foot syndrome in patients with phototypes IV-V and palmar as well as plantar involvement. PMID- 26114059 TI - Painful purple nodule on the right thigh. PMID- 26114060 TI - A pigmented lesion with yellow-white globular-like structures-Answer. PMID- 26114061 TI - "Tape dermatoscopy": constructing a low-cost dermatoscope using a mobile phone, immersion fluid and transparent adhesive tape. AB - IMPORTANCE: Medical professionals and indeed the general public have an increasing interest in the acquisition of dermatoscopic images of suspect or ambiguous skin lesions. To this end, good dermatoscopic image quality and low costs are important considerations. OBSERVATIONS: Images of seven lesions (seborrheic keratosis, melanoma in-situ, blue and dermal nevus, basal cell carcinoma and two squamous cell carcinomas) were taken. A novel technique of "tape dermatoscopy" involved: Using immersion fluid (i.e., water, olive oil, disinfectant spray) placed on the flat or slightly elevated lesion;Covering the lesion with transparent adhesive tape with lateral tension;Using ambient indoor or outdoor lighting for illumination (rather than flash photography);Positioning a photographic device at an angle of approximately 45 degrees from the side of the lesion to avoid light reflection;Recording a focused image with a mobile phone or digital camera at a distance of approximately 25-30 cm from the lesion; andEnlarging the image on the screen of the device. Essential dermatoscopic features enabling a correct diagnosis were visible in 6 of the 7 lesions. 'Tape dermatoscopy" images of the lesions were compared to standard dermatoscopy (using a Fotofinder handyscope(r) in combination with a mobile phone). The latter confirmed the dermatoscopic features in six of seven lesions. CONCLUSIONS AND RELEVANCE: "Tape dermatoscopy" images can be recorded by medical personnel and even the general public without a dermatoscope. However, the limitations of this method are that images may be unfocused, exophytic tumors may be difficult to assess, excess pressure on tumoral blood vessels may lead to compression artefact, dermatoscopic features that are only visible under polarized light are unable to be detected (particularly "crystalline" or "chrysalis" structures) and tumors in certain anatomic locations may be difficult to assess (e.g., edges of nose, ears [demonstrated in one case], nails). Comparative prospective studies are necessary in order to test reproducibility of these preliminary findings, to establish special indications for the technique, and to develop guidelines for its effective use. PMID- 26114062 TI - Understanding the importance of dermatology training in undergraduate medical education. PMID- 26114063 TI - Review of Hayes' Practical Skin Cancer Surgery. PMID- 26114064 TI - Complete regression of a melanocytic nevus after epilation with diode laser therapy. AB - The use of lasers and intense pulsed light (IPL) technology has become an established practice in dermatology and aesthetic medicine. The use of laser therapy and IPL in the treatment of pigmented melanocytic lesions is a controversial issue. We report clinical, dermoscopic and histological changes of a completely regressed pigmented melanocytic nevus after hair removal treatment with the LightSheerTM Diode Laser (Lumenis Ltd, Yokneam, Israel). PMID- 26114065 TI - Segmental neurofibromatosis presenting with congenital excessive skin folds. AB - Segmental neurofibromatosis (SNF) is a rare type of neurofibromatosis (NF-1) resulting from post-zygotic somatic mutations in the neurofibromin gene that leads to mosaicism. Reported manifestations of SNF include neurofibromas, freckling, or cafe-au-lait spots limited to a single body region or limb. We present a 5-month-old male referred to our clinic for evaluation of congenital excessive skin folds on the back. A mildly erythematous, poorly demarcated soft plaque was noted, consisting of excessive skin folds. A cluster of light brown hyperpigmented macules was seen overlying the plaque. A punch biopsy of the plaque confirmed a diagnosis of neurofibroma. Further investigation ruled out other manifestations of NF-1. The early onset of our patient's neurofibroma and its gross appearance with redundant skin folds are all unusual features. To our knowledge, congenital excessive skin folds found in a single tumor have not been previously described in the literature as a manifestation of SNF. Clinicians should be educated about the possibility of congenital localized skin folds in association with SNF in order to identify the disease in infancy and monitor any changes in neurofibroma pathology. PMID- 26114066 TI - Radiation-induced basal cell carcinoma. AB - BACKGROUND: The treatment of tinea capitis using radiotherapy was introduced at the beginning of the twentieth century. A variety of cancers including basal cell carcinoma (BCC) are seen years after this treatment. OBJECTIVE: We sought to determine the clinical characteristics of BCCs among irradiated patients. METHODS: The clinical records of all patients with BCC in a clinic in north of Iran were reviewed. RESULTS: Of the 58 cases of BCC, 29 had positive history for radiotherapy in their childhood. Multiple BCCs were seen in 79.3% and 10.3% of patients with history and without history of radiotherapy, respectively. CONCLUSIONS: X-ray radiation is still a major etiologic factor in developing BCC in northern Iran. Patients with positive history for radiotherapy have higher rate of recurrence. PMID- 26114067 TI - Proton pump inhibitor-induced Sweet's syndrome: report of acute febrile neutrophilic dermatosis in a woman with recurrent breast cancer. AB - BACKGROUND: Sweet's syndrome, also referred to as acute febrile neutrophilic dermatosis, can either occur as an idiopathic disorder or associated with another condition, including cancer, or induced by exposure to a drug. Proton pump inhibitors selectively inhibit gastric parietal cell H+-K+-adenosine triphosphatase and are most commonly used for the treatment of gastroesophageal reflux disease. PURPOSE: Proton pump inhibitor-associated Sweet's syndrome is described in a woman with recurrent breast cancer. METHODS: PubMed was used to search the following terms, separately and in combination: acute febrile neutrophilic dermatosis, breast cancer, malignancy, paraneoplastic, proton pump inhibitor, and Sweet's syndrome. All papers were reviewed and relevant manuscripts, along with their reference citations, were evaluated. RESULTS: Proton pump inhibitors have previously been associated with cutaneous adverse reactions including maculopapular rash, subacute cutaneous lupus erythematosus and toxic epidermal necrolysis. However, drug-induced Sweet's syndrome has not been observed in patients receiving proton pump inhibitors. The reported woman developed Sweet's syndrome after initial exposure and subsequent repeat challenge to proton pump inhibitors; subsequent studies also observed recurrence of her breast cancer presenting as metastases to her stomach and bone. CONCLUSIONS: Drug induced Sweet's syndrome has most commonly been associated with granulocyte colony stimulating factor in oncology patients. Malignancy-associated Sweet's syndrome has been observed in patients with solid tumors, including breast cancer. Confirmation of proton pump inhibitor-induced Sweet's syndrome, by repeat challenge with another medication in the same class of drug, was observed in a woman with breast cancer; although the subsequent discovery of recurrent breast cancer presenting as gastric mucosa and vertebral metastases also raises the possibility of concurrent paraneoplastic Sweet's syndrome, her Sweet's syndrome symptoms and lesions resolved without recurrence while her recurrent metastatic visceral malignancy persisted. In summary, medication-associated Sweet's syndrome can occur in oncology patients and proton pump inhibitors should be added to the list of medications associated with the potential to cause drug-induced Sweet's syndrome. PMID- 26114068 TI - Nab-paclitaxel-associated photosensitivity: report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses. AB - BACKGROUND: Taxanes [paclitaxel, nab-paclitaxel (Abraxane, Celgene Corp, USA), and docetaxel]-used in the treatment of lung, breast, and head and neck cancers have been associated with cutaneous adverse effects, including photodermatoses. PURPOSE: We describe a woman with non-small cell lung cancer who developed a photodistributed dermatitis associated with her nab-paclitaxel therapy and review photodermatoses in patients receiving taxanes. MATERIALS AND METHODS: The features of a woman with a nab-paclitaxel-associated photodistributed dermatitis are presented and the literature on nab-paclitaxel-associated photosensitivity is reviewed. RESULTS: Our patient developed nab-paclitaxel-associated photodistributed dermatitis on the sun-exposed surfaces of her upper extremities, which was exacerbated with each course of nab-paclitaxel. Biopsies revealed an interface dermatitis and laboratory studies were negative for lupus erythematosus and dermatomyositis. Her condition improved following topical corticosteroid cream application and strict avoidance of sunlight. CONCLUSION: Chemotherapy can be associated with adverse mucocutaneous events, including dermatoses on sun exposed areas of the skin. Paclitaxel and nab-paclitaxel have both been associated with photodermatoses, including dermatitis, erythema multiforme, onycholysis, and subacute cutaneous lupus erythematosus. Strict avoidance of sun exposure, topical or oral corticosteroids, and/or discontinuation of the drug results in improvement with progressive resolution of symptoms and skin lesions. Development of photodermatoses is not an absolute contraindication to continuing chemotherapy, provided that the cutaneous condition resolves with dermatosis directed treatment and the patient avoids sun exposure. PMID- 26114069 TI - Infantile perianal pyramidal protrusion: a case report with dermoscopy and ultrasound findings. AB - Infantile perianal pyramidal protrusion, it is a rare benign cutaneous condition described in relatively recent times. It is considered to be under-reported in the pediatric literature because it is often mistaken for other conditions. The unawareness of this lesion may be responsible for an excessive concern both in physician and in parents, which leads to overly aggressive and unnecessary treatments. Thus its recognition has many implications regarding proper management and treatment. We report a typical presentation of IPPP in which the diagnosis was based on the use of non-invasive diagnostic tools and in particular of dermoscopy and ultrasonography. PMID- 26114070 TI - Frontotemporal hairline recession in a postmenopausal woman. PMID- 26114071 TI - Tinea capitis caused by Trichophyton tonsurans presenting as an obscure patchy hair loss due to daily antifungal shampoo use. AB - Tinea capitis is unusual and often misdiagnosed in healthy adults. We report a case of a healthy woman with a several-year history of asymptomatic, bizarre shaped, non-scarring alopecia. She had used over-the-counter ketoconazole shampoo regularly for a long time. An initial potassium hydroxide preparation showed negative result for fungal organism. The scalp biopsy revealed endothrix infection, and dermoscopic examination demonstrated the comma hair and corkscrew hair signs. The fungal culture showed Trichophyton tonsurans. The daily use of antifungal shampoo could be the important factor to conceal clinical and laboratory findings for diagnosis of T. tonsurans tinea capitis in our case, which required high clinical suspicion and histopathology and dermoscopic examinations. PMID- 26114073 TI - Cherry Picking in the 'Aina: Inequalities of Access to Dermatologic Care in Hawai'i. AB - There is evidence that people who are insured by Medicaid have difficulty accessing health care from private providers. This study documents access to dermatology care for a hypothetical patient insured by Medicaid in the State of Hawai'i. Posing as young Medicaid patient with a changing mole, we called all dermatologists listed on the American Academy of Dermatology website and requested an appointment to be seen. Only 23% of dermatologists contacted accept all Medicaid plans and an additional 12% accept some. Thus 65% of dermatologists called do not provide specialist care to Hawai'i's Medicaid population. PMID- 26114074 TI - A Serendipitous Find: A Case of Cholangiocarcinoma Identified Incidentally After Acute Liver Injury Due to Cascara sagrada Ingestion. AB - The use of anthranoid laxatives such as Cascara sagrada can, in rare instances, produce a hepatitis that resolves with discontinuation of the offending supplement. However, the clinical presentation of abdominal pain, jaundice, clay colored stools, and darkening urine can mimic the presentation of a variety of hepatobiliary illnesses, including cholangiocarcinoma. This case report describes a local patient diagnosed with an extrahepatic cholangiocarcinoma following workup for an acute hepatitis due to ingestion of large quantities of Cascara sagrada. PMID- 26114075 TI - Ethnic Differences in Withdrawal of Life Support After Intracerebral Hemorrhage. AB - Minorities are less likely to decide on withdrawal of life support (WOLS) after acute severe illness. However, the decision-making process for WOLS after intracerebral hemorrhage (ICH) among Native Hawaiians and other Pacific Islanders (NHOPI) has not been described. To address this gap in the literature, a retrospective study was conducted on consecutive spontaneous ICH patients admitted to a tertiary center in Honolulu between 2006 and 2010. The occurrence of WOLS and time-to-WOLS were the outcome measures. Unadjusted and multivariable logistic regression models were performed to determine associations between NHOPI ethnicity and WOLS. This study assessed 396 patients (18% NHOPI, 63% Asians, 15% non-Hispanic whites [NHW], 4% others) with ICH. NHOPI was associated with lower rate of WOLS than NHW in the univariate analysis (OR 0.35, 95% CI: 0.15, 0.80). However, NHOPI ethnicity was no longer significant when adjusted for age (OR 0.59, 95% CI: 0.25, 1.43) and in the fully adjusted model (OR 0.68, 95% CI: 0.20, 2.39). Although NHOPI with ICH were initially perceived to have less WOLS compared to NHW, this observed difference was largely driven by the younger age of NHOPI rather than from underlying cultural differences that are inherent to their ethnicity. PMID- 26114076 TI - Biostatistics and Data Management Core at the University of Hawai'i John A. Burns School of Medicine. PMID- 26114077 TI - Toward a Trauma-Informed System of Care in Hawai'i's Adult Mental Health Division. PMID- 26114079 TI - Optimization of phase contrast in bimodal amplitude modulation AFM. AB - Bimodal force microscopy has expanded the capabilities of atomic force microscopy (AFM) by providing high spatial resolution images, compositional contrast and quantitative mapping of material properties without compromising the data acquisition speed. In the first bimodal AFM configuration, an amplitude feedback loop keeps constant the amplitude of the first mode while the observables of the second mode have not feedback restrictions (bimodal AM). Here we study the conditions to enhance the compositional contrast in bimodal AM while imaging heterogeneous materials. The contrast has a maximum by decreasing the amplitude of the second mode. We demonstrate that the roles of the excited modes are asymmetric. The operational range of bimodal AM is maximized when the second mode is free to follow changes in the force. We also study the contrast in trimodal AFM by analyzing the kinetic energy ratios. The phase contrast improves by decreasing the energy of second mode relative to those of the first and third modes. PMID- 26114080 TI - Probing fibronectin-antibody interactions using AFM force spectroscopy and lateral force microscopy. AB - The first experiment showing the effects of specific interaction forces using lateral force microscopy (LFM) was demonstrated for lectin-carbohydrate interactions some years ago. Such measurements are possible under the assumption that specific forces strongly dominate over the non-specific ones. However, obtaining quantitative results requires the complex and tedious calibration of a torsional force. Here, a new and relatively simple method for the calibration of the torsional force is presented. The proposed calibration method is validated through the measurement of the interaction forces between human fibronectin and its monoclonal antibody. The results obtained using LFM and AFM-based classical force spectroscopies showed similar unbinding forces recorded at similar loading rates. Our studies verify that the proposed lateral force calibration method can be applied to study single molecule interactions. PMID- 26114081 TI - Nano-contact microscopy of supracrystals. AB - BACKGROUND: Highly ordered three-dimensional colloidal crystals (supracrystals) comprised of 7.4 nm diameter Au nanocrystals (with a 5% size dispersion) have been imaged and analysed using a combination of scanning tunnelling microscopy and dynamic force microscopy. RESULTS: By exploring the evolution of both the force and tunnel current with respect to tip-sample separation, we arrive at the surprising finding that single nanocrystal resolution is readily obtained in tunnelling microscopy images acquired more than 1 nm into the repulsive (i.e., positive force) regime of the probe-nanocrystal interaction potential. Constant height force microscopy has been used to map tip-sample interactions in this regime, revealing inhomogeneities which arise from the convolution of the tip structure with the ligand distribution at the nanocrystal surface. CONCLUSION: Our combined STM-AFM measurements show that the contrast mechanism underpinning high resolution imaging of nanoparticle supracrystals involves a form of nanoscale contact imaging, rather than the through-vacuum tunnelling which underpins traditional tunnelling microscopy and spectroscopy. PMID- 26114082 TI - Addition of Zn during the phosphine-based synthesis of indium phospide quantum dots: doping and surface passivation. AB - Zinc-doped InP(Zn) colloidal quantum dots (QDs) with narrow size distribution and low defect concentration were grown for the first time via a novel phosphine synthetic route and over a wide range of Zn doping. We report the influence of Zn on the optical properties of the obtained quantum dots. We propose a mechanism for the introduction of Zn in the QDs and show that the incorporation of Zn atoms into the InP lattice leads to the formation of Zn acceptor levels and a luminescence tail in the red region of the spectra. Using photochemical etching with HF, we confirmed that the Zn dopant atoms are situated inside the InP nanoparticles. Moreover, doping with Zn is accompanied with the coverage of the QDs by a zinc shell. During the synthesis Zn myristate covers the QD nucleus and inhibits the particle growth. At the same time the zinc shell leads to an increase of the luminescence quantum yield through the reduction of phosphorous dangling bonds. A scenario for the growth of the colloidal InP(Zn) QDs was proposed and discussed. PMID- 26114083 TI - PATHOGENESIS OF HEPATOCELLULAR CARCINOMA DEVELOPMENT IN NON ALCOHOLIC FATTY LIVER DISEASE. AB - Non-alcoholic fatty liver disease (NAFLD) is being recognized as an increasingly important contributor to the burden of hepatocellular carcinoma (HCC) worldwide. It is often accompanied by obesity and diabetes mellitus and is believed to be the hepatic representation of the metabolic syndrome. HCC development in NAFLD is multifactorial and complex. It is dependent on not only the well-described mechanisms noted in chronic liver injury, but also on the molecular derangements associated with obesity and dysmetabolism. These include adipocyte remodeling, adipokine secretion, lipotoxicity and insulin resistance. Recent advances focus on the importance of the gut-liver axis in accelerating the process of oncogenesis in NAFLD. The farnesoid X nuclear receptor (FXR) has been demonstrated to have important metabolic effects and its pharmacological activation by obeticholic acid has been recently reported to produce histological improvement in NASH. It is hoped that delineating the mechanisms of hepatic fibrosis and oncogenesis in NASH will lead to enhanced strategies for cancer prevention, surveillance and therapy in this population. PMID- 26114084 TI - PTEN sequence analysis in endometrial hyperplasia and endometrial carcinoma in Slovak women. AB - Phosphatase and tensin homolog (PTEN) is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa). ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3), complex hyperplasia (5), atypical complex hyperplasia (7), endometrioid carcinomas G1 (20) and G3 (5), and serous carcinoma (5) were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar. PMID- 26114085 TI - Radiographic Comparison of Lateral Lumbar Interbody Fusion Versus Traditional Fusion Approaches: Analysis of Sagittal Contour Change. AB - BACKGROUND: Lateral approach to lumbar fusion has been gaining popularity in recent years. With increasing awareness of the significance of sagittal balance restoration in spinal surgery, it is important to investigate the potential of this relatively new approach in correcting sagittal deformities in comparison to conventional approaches. The aim of this study was to evaluate sagittal contour changes seen in lateral lumbar interbody fusion and compare them with radiographic changes in traditional approaches to lumbar fusion. METHODS: Lumbar fusion procedures from January 2008 to December 2009 were reviewed. Four approaches were compared: anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), transforaminal interbody fusion (TLIF) and posterior spinal fusion (PSF). Standing pre-operative and 6-week post-operative radiographs were measured in terms of operative level, suprajacent and subjacent level, and regional lumbar lordosis (L1-S1) as well as operative level anterior (ADH) and posterior disc heights (PDH). T-test was used to analyze differences between and within different approaches (alpha=0.05). RESULTS: A total of 147 patients underwent lumbar fusion at 212 levels. Mean operative level segmental lordosis change after each procedure is as follows: ALIF 3.8 +/- 6.6 degrees (p < 0.01); LLIF 3.2 +/- 3.6 degrees (p<0.01); TLIF 1.9 +/- 3.9 degrees (p<0.01); and PSF 0.7 +/- 2.9 degrees (p =0.13). Overall lumbar lordosis change after each procedure is as follows: ALIF 4.2 +/- 5.8 degrees (p < 0.01); LLIF 2.5 +/- 4.1 degrees (p<0.01); TLIF 2.1 +/- 6.0 (p = 0.02); PSF -0.5 +/- 6.2 degrees (p = 0.66). There were no significant changes in the supradjcent and subjacent level lordosis in all approaches except in ALIF where a significant decrease in supradjecent level lordosis was seen. Mean ADH and PDH significantly increased for all approaches except in PSF where PDH decreased post-operatively. CONCLUSION: LLIF has the ability to improve sagittal contour as well as other interbody approaches and is superior to posterioronly approach in disc height restoration. However, ALIF provides the greatest amount of segmental and overall lumbar lordosis correction. LEVEL OF EVIDENCE: This is a Level III study. CLINICAL RELEVANCE: Regional lordosis correction may be effectively achieved with LLIF. This approach is a good addition to a surgeon's armamentarium in maintenance or restoration of normal lumbar sagittal alignment. PMID- 26114086 TI - Full Endoscopic Spinal Surgery Techniques: Advancements, Indications, and Outcomes. AB - Advancements in both surgical instrumentation and full endoscopic spine techniques have resulted in positive clinical outcomes in the treatment of cervical, thoracic, and lumbar spine pathologies. Endoscopic techniques impart minimal approach related disruption of non-pathologic spinal anatomy and function while concurrently maximizing functional visualization and correction of pathological tissues. An advanced understanding of the applicable functional neuroanatomy, in particular the neuroforamen, is essential for successful outcomes. Additionally, an understanding of the varying types of disc prolapse pathology in relation to the neuroforamen will result in more optimal surgical outcomes. Indications for lumbar endoscopic spine surgery include disc herniations, spinal stenosis, infections, medial branch rhizotomy, and interbody fusion. Limitations are based on both non spine and spine related findings. A high riding iliac wing, a more posteriorly located retroperitoneal cavity, an overly distal or proximally migrated herniated disc are all relative contra indications to lumbar endoscopic spinal surgery techniques. Modifications in scope size and visual field of view angulation have enabled both anterior and posterior cervical decompression. Endoscopic burrs, electrocautery, and focused laser technology allow for the least invasive spinal surgical techniques in all age groups and across varying body habitus. Complications include among others, dural tears, dysesthsia, nerve injury, and infection. PMID- 26114087 TI - Surgical management of Giant Lumbar Extradural Schwannoma: Report of 3 cases. AB - Standard surgical approach for extradural paraspinal tumours has been through a unilateral facetectomy, inter-transverse or retroperitoneal approach. Some of these approaches destabilise the spine and consequently require a fusion procedure. Access to these tumours through a minimal access route can decrease tissue damage, fasten post-operative recovery and obviate the need for a concomitant fusion procedure. However, proper case selection and adequate pre operative planning are important in choosing cases for a minimally invasive approach. We discuss three cases of giant extradural, paraspinal schwannomas. One case that was associated with listhesis along with the tumour situated more anteriorly and embedded in the psoas muscle was managed by lateral retroperitoneal route with simultaneous interbody graft followed by posterior interspinous stabilising device. The other two cases were managed by minimal access route using a 22mm fixed tubular retractor, one by a paramedian approach and one by far lateral approach. The technique and merits of the procedure are discussed. PMID- 26114088 TI - Ninety-day readmissions after degenerative cervical spine surgery: A single center administrative database study. AB - BACKGROUND: Unplanned hospital readmissions result in significant clinical and financial burdens to patients and the healthcare system. Readmission rates and causes have been investigated using large administrative databases which have certain limitations in data reporting and coding. The objective of this study was to provide a description of 90 day post-discharge readmissions following surgery for common degenerative cervical spine pathologies at a large-volume tertiary hospital. The study also compared the readmission rates of patients who underwent anterior- and posterior-approach procedures. METHODS: The administrative records from a single-center, high-volume tertiary institution were queried using ICD-9 codes for common cervical pathology over a three year period to determine the rate and causes of readmissions within the 90 days following the index surgery. RESULTS: A total of 768 patients underwent degenerative cervical spine surgery during the three year study period. Within 90 days of discharge, 24 (3.13%) patients were readmitted; 16 (2.06%) readmissions were planned for lumbar surgery; 8 (1.04%) readmissions were unplanned. 640 patients underwent procedures involving an anterior approach and 128 patients underwent procedures involving a posterior approach. There were 14 (2.17%) planned readmissions in the anterior group and 2 (1.5%) in the posterior group. The unplanned readmission rate was 0.63% (4 patients) and 3.13% (4 patients) in the anterior and posterior groups, respectively. (p=0.0343). CONCLUSION: The 90 day post-discharge unplanned readmission rate that followed elective degenerative cervical spine surgery was 1.04%. The unplanned readmission rate associated with posterior-approach procedures (3.13%) was significantly higher than that of anterior-approach procedures (0.63%). LEVEL OF EVIDENCE: IV. PMID- 26114089 TI - Spinous Process splitting Laminectomy: Clinical outcome and Radiological analysis of extent of decompression. AB - INTRODUCTION: Spinous process splitting laminectomy (SPSL) is a useful technique in achieving adequate decompression for lumbar canal stenosis, has the advantage of simultaneously decompressing multiple levels and minimising injury to the paraspinal muscles. Some concern has been expressed over the efficacy of this technique in decompressing lateral recesses. This study was undertaken to assess the clinical outcome of SPSL technique and radiologically assess the extent of decompression. PATIENTS AND METHODS: Thirty-nine consecutive patients treated by SPSL for degenerative lumbar spinal stenosis were methodically assessed for demographic data, clinical findings, Pre- and post-op VAS, JOA scores and spinal canal dimensions on imaging. Surgical technique for SPSL is described. RESULTS: The mean age of the patients was 66.9 yrs. The mean follow-up was 7.3 months. The mean pre- and post-operative VAS scores were 7.8 and 3.7, respectively. The mean pre- and post-operative JOA scores were 6.3 and 11.2, respectively. The mean JOA recovery rate was 57.3%. 77% of the patients were in the 'good' or 'excellent' McNab's grades at follow-up. Radiologic results were assessed separately at the 118 levels decompressed by the SPSL technique. The ratio increase for the spinal canal dimensions on post-operative images were as follows - Interfacet distance 116.6%; Effective AP distance-67.6%; Right lateral recess depth-165.1%; Right lateral recess angle-145.5%; Left lateral recess depth-149.3%; Left lateral recess angle-133.6%; Cross-sectional spinal canal area-163.8%. There was no worsening of pre-existing degenerative listhesis or scoliosis in any case. CONCLUSION: SPSL achieves effective central and lateral recess decompression, at the same time minimising injury to the paraspinal muscles thus reducing post operative pain and aiding in quicker mobilisation and recovery. It is an effective tool to treat multiple level spinal stenosis, especially in elderly patients who have pre-existing spinal deformities which can precipitate into frank instability after conventional procedures. PMID- 26114090 TI - Fellowship and Practice Composition Affect Surgical Decision Making in Patients with Adult Degenerative Scoliosis: Spinal Deformity versus Degenerative Spinal Surgeons. AB - BACKGROUND: For the Adult Degenerative Scoliosis (ADS) patient with radiculopathy, there is no clear data in the literature to guide the spine surgeon's decision making in choosing between limited decompression alone, short segment fusion, or longer arthrodesis of the deformity. This study investigates the differences in operative planning, for patients with ADS and radiculopathy, between two groups of spine surgeons based on fellowship experience and practice composition. METHODS: Six Degenerative Spine surgeons (Group 1) and 6 Spinal Deformity surgeons (Group 2) were shown 7 cases of patients with ADS and radiculopathy. Surgeons completed a questionnaire detailing their planned operative intervention including the number of fusion levels, if any, approach, choice of bone graft, and interbody device. Pearson Correlation was used to investigate the association between fellowship training, practice composition, number of levels fused, and other variables. Intraclass correlation (ICC) analysis was used to investigate the internal consistency among the groups. RESULTS: There was a direct correlation between fellowship deformity experience and practice composition (r=0.75, p<0.01), and between deformity practice composition and the number of planned fusion levels (r=0.90, p<0.001). Group 1 surgeons fused a mean 3.7 vertebral levels (range 0-6.7), while Group 2 surgeons fused a mean 10.8 levels (range 4-16.5). Group 2 surgeons fused a significantly greater number of levels for each case than degenerative surgeons on paired student t-test (p=0.002). Group 1 surgeons chose decompression alone more commonly than deformity surgeons (p<0.05). Group 2 surgeons had significantly higher group consistency by ICC analysis (p=0.004). CONCLUSIONS: Fellowship and practice composition influence the physician's surgical planning in ADS. There is a lack of standardized treatment paradigms for the management of radiculopathy in patients with ADS. PMID- 26114091 TI - Cancer Survivorship for Primary Care Annotated Bibliography. AB - Long-term cancer survivorship care is a relatively new and rapidly advancing field of research. Increasing cancer survivorship rates have created a huge population of long-term cancer survivors whose cancer-specific needs challenge healthcare infrastructure and highlight a significant deficit of knowledge and guidelines in transitional care from treatment to normalcy/prolonged survivorship. As the paradigm of cancer care has changed from a fixation on the curative to the maintenance on long-term overall quality of life, so to, has the delineation of responsibility between oncologists and primary care physicians (PCPs). As more patients enjoy long-term survival, PCPs play a more comprehensive role in cancer care following acute treatment. To this end, this annotated bibliography was written to provide PCPs and other readers with an up-to-date and robust base of knowledge on long-term cancer survivorship, including definitions and epidemiological information as well as specific considerations and recommendations on physical, psychosocial, sexual, and comorbidity needs of survivors. Additionally, significant information is included on survivorship care, specifically Survivorship Care Plans (SPCs) and their evolution, utilization by oncologists and PCPs, and current gaps, as well as an introduction to patient navigation programs. Given rapid advancements in cancer research, this bibliography is meant to serve as current baseline reference outlining the state of the science. PMID- 26114092 TI - Mental health interventions in schools 1: Mental health interventions in schools in high-income countries. AB - Mental health services embedded within school systems can create a continuum of integrative care that improves both mental health and educational attainment for children. To strengthen this continuum, and for optimum child development, a reconfiguration of education and mental health systems to aid implementation of evidence-based practice might be needed. Integrative strategies that combine classroom-level and student-level interventions have much potential. A robust research agenda is needed that focuses on system-level implementation and maintenance of interventions over time. Both ethical and scientific justifications exist for integration of mental health and education: integration democratises access to services and, if coupled with use of evidence-based practices, can promote the healthy development of children. PMID- 26114094 TI - Spatial Separation of Plk1 Phosphorylation and Activity. AB - Polo-like kinase 1 (Plk1) is one of the major kinases controlling mitosis and cell division. Plk1 is first recruited to the centrosome in S phase, then appears on the kinetochores in late G2, and at the end of mitosis, it translocates to the central spindle. Activation of Plk1 requires phosphorylation of T210 by Aurora A, an event that critically depends on the co-factor Bora. However, conflicting reports exist as to where Plk1 is first activated. Phosphorylation of T210 is first observed at the centrosomes, but kinase activity seems to be restricted to the nucleus in the earlier phases of G2. Here, we demonstrate that Plk1 activity manifests itself first in the nucleus using a nuclear FRET-based biosensor for Plk1 activity. However, we find that Bora is restricted to the cytoplasm and that Plk1 is phosphorylated on T210 at the centrosomes. Our data demonstrate that while Plk1 activation occurs on centrosomes, downstream target phosphorylation by Plk1 first occurs in the nucleus. We discuss several explanations for this surprising separation of activation and function. PMID- 26114095 TI - Corrigendum: "Training Global Oncologists: Addressing the Global Cancer Control Problem". AB - [This corrects the article on p. 80 in vol. 5, PMID: 25905040.]. PMID- 26114093 TI - The promise and challenge of ovarian cancer models. AB - The complexity and heterogeneity of ovarian cancer cases are difficult to reproduce in in vitro studies, which cannot adequately elucidate the molecular events involved in tumor initiation and disease metastasis. It has now become clear that, although the multiple histological subtypes of ovarian cancer are being treated with similar surgical and therapeutic approaches, they are in fact characterized by distinct phenotypes, cell of origin, and underlying key genetic and genomic alterations. Consequently, the development of more personalized treatment methodologies, which are aimed at improving patient care and prognosis, will greatly benefit from a better understanding of the key differences between various subtypes. To accomplish this, animal models of all histotypes need to be generated in order to provide accurate in vivo platforms for research and the testing of targeted treatments and immune therapies. Both genetically engineered mouse models (GEMMs) and xenograft models have the ability to further our understanding of key mechanisms facilitating tumorigenesis, and at the same time offer insight into enhanced imaging and treatment modalities. While genetic models may be better suited to examine oncogenic functions and interactions during tumorigenesis, patient-derived xenografts (PDXs) are likely a superior model to assess drug efficacy, especially in concurrent clinical trials, due to their similarity to the tumors from which they are derived. Genetic and avatar models possess great clinical utility and have both benefits and limitations. Additionally, the laying hen model, which spontaneously develops ovarian tumors, has inherent advantages for the study of epithelial ovarian cancer (EOC) and recent work champions this model especially when assessing chemoprevention strategies. While high-grade ovarian serous tumors are the most prevalent form of EOC, rarer ovarian cancer variants, such as small cell ovarian carcinoma of the hypercalcemic type and transitional cell carcinoma, or non-epithelial tumors, including germ cell tumors, will also benefit from the generation of improved models to advance our understanding of tumorigenic mechanisms and the development of selective therapeutic options. PMID- 26114096 TI - Diagnosis and History Taking in Children with Autism Spectrum Disorder: Dealing with the Challenges. PMID- 26114097 TI - Can biological structures be natural and sustainable capsules? PMID- 26114098 TI - Comparisons between Arabidopsis thaliana and Drosophila melanogaster in relation to Coding and Noncoding Sequence Length and Gene Expression. AB - There is a continuing interest in the analysis of gene architecture and gene expression to determine the relationship that may exist. Advances in high-quality sequencing technologies and large-scale resource datasets have increased the understanding of relationships and cross-referencing of expression data to the large genome data. Although a negative correlation between expression level and gene (especially transcript) length has been generally accepted, there have been some conflicting results arising from the literature concerning the impacts of different regions of genes, and the underlying reason is not well understood. The research aims to apply quantile regression techniques for statistical analysis of coding and noncoding sequence length and gene expression data in the plant, Arabidopsis thaliana, and fruit fly, Drosophila melanogaster, to determine if a relationship exists and if there is any variation or similarities between these species. The quantile regression analysis found that the coding sequence length and gene expression correlations varied, and similarities emerged for the noncoding sequence length (5' and 3' UTRs) between animal and plant species. In conclusion, the information described in this study provides the basis for further exploration into gene regulation with regard to coding and noncoding sequence length. PMID- 26114099 TI - Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression. AB - Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression. PMID- 26114100 TI - Biochemical and Molecular Phylogenetic Study of Agriculturally Useful Association of a Nitrogen-Fixing Cyanobacterium and Nodule Sinorhizobium with Medicago sativa L. AB - Seed inoculation with bacterial consortium was found to increase legume yield, providing a higher growth than the standard nitrogen treatment methods. Alfalfa plants were inoculated by mono- and binary compositions of nitrogen-fixing microorganisms. Their physiological and biochemical properties were estimated. Inoculation by microbial consortium of Sinorhizobium meliloti T17 together with a new cyanobacterial isolate Nostoc PTV was more efficient than the single rhizobium strain inoculation. This treatment provides an intensification of the processes of biological nitrogen fixation by rhizobia bacteria in the root nodules and an intensification of plant photosynthesis. Inoculation by bacterial consortium stimulates growth of plant mass and rhizogenesis and leads to increased productivity of alfalfa and to improving the amino acid composition of plant leaves. The full nucleotide sequence of the rRNA gene cluster and partial sequence of the dinitrogenase reductase (nifH) gene of Nostoc PTV were deposited to GenBank (JQ259185.1, JQ259186.1). Comparison of these gene sequences of Nostoc PTV with all sequences present at the GenBank shows that this cyanobacterial strain does not have 100% identity with any organisms investigated previously. Phylogenetic analysis showed that this cyanobacterium clustered with high credibility values with Nostoc muscorum. PMID- 26114101 TI - Phyloproteomic Analysis of 11780 Six-Residue-Long Motifs Occurrences. AB - How is it possible to find good traits for phylogenetic reconstructions? Here, we present a new phyloproteomic criterion that is an occurrence of simple motifs which can be imprints of evolution history. We studied the occurrences of 11780 six-residue-long motifs consisting of two randomly located amino acids in 97 eukaryotic and 25 bacterial proteomes. For all eukaryotic proteomes, with the exception of the Amoebozoa, Stramenopiles, and Diplomonadida kingdoms, the number of proteins containing the motifs from the first group (one of the two amino acids occurs once at the terminal position) made about 20%; in the case of motifs from the second (one of two amino acids occurs one time within the pattern) and third (the two amino acids occur randomly) groups, 30% and 50%, respectively. For bacterial proteomes, this relationship was 10%, 27%, and 63%, respectively. The matrices of correlation coefficients between numbers of proteins where a motif from the set of 11780 motifs appears at least once in 9 kingdoms and 5 phyla of bacteria were calculated. Among the correlation coefficients for eukaryotic proteomes, the correlation between the animal and fungi kingdoms (0.62) is higher than between fungi and plants (0.54). Our study provides support that animals and fungi are sibling kingdoms. Comparison of the frequencies of six-residue-long motifs in different proteomes allows obtaining phylogenetic relationships based on similarities between these frequencies: the Diplomonadida kingdoms are more close to Bacteria than to Eukaryota; Stramenopiles and Amoebozoa are more close to each other than to other kingdoms of Eukaryota. PMID- 26114102 TI - A Novel Injectable Magnesium/Calcium Sulfate Hemihydrate Composite Cement for Bone Regeneration. AB - OBJECTIVE: . A novel injectable magnesium/calcium sulfate hemihydrate (Mg/CSH) composite with improved properties was reported here. METHODS: Composition, setting time, injectability, compressive strength, and bioactivity in simulated body fluid (SBF) of the Mg/CSH composite were evaluated. Furthermore, the cellular responses of canine bone marrow stromal cells (cBMSCs) and bone formation capacity after the implantation of Mg/CSH in tibia defects of canine were investigated. RESULTS: Mg/CSH possessed a prolonged setting time and markedly improved injectability and mechanical property (p < 0.05). Mg/CSH samples showed better degradability than CSH in SBF after 21 days of soaking (p < 0.05). Moreover, the degrees of cell attachment, proliferation, and capability of osteogenic differentiation on the Mg/CSH specimens were higher than those on CSH, without significant cytotoxicity and with the increased proliferation index, ALP activity, and expression levels of integrin beta1 and Coll I in cBMSCs (p < 0.05). Mg/CSH enhanced the efficiency of new bone formation at the tibia defect area, including the significantly elevated bone mineral density, bone area fraction, and Coll I expression level (p < 0.05). CONCLUSIONS: The results implied that this new injectable bone scaffold exhibited promising prospects for bone repair and had a great potential in bone tissue engineering. PMID- 26114103 TI - Molecular Systematics of the Phoxinin Genus Pteronotropis (Otophysi: Cypriniformes). AB - The genus Pteronotropis is widely distributed along the gulf slope of eastern North America from Louisiana to Florida and rivers in South Carolina along the Atlantic slope. Pteronotropis have very distinctive, flamboyant coloration. The habitats most frequently associated with these species include heavily vegetated backwater bayous to small sluggish or flowing tannin-stained streams. Although Pteronotropis is recognized as a valid genus, no phylogenetic analysis of all the species has corroborated its monophyly. In recent years, four additional species have been either described or elevated from synonymy: P. merlini, P. grandipinnis, P. stonei, and P. metallicus, with the wide-ranging P. hypselopterus complex. To examine relationships within this genus and test its monophyly, phylogenetic analyses were conducted using two nuclear genes, recombination activating gene 1, RAG1, and the first intron of S7 ribosomal protein gene in both maximum parsimony and Bayesian analyses. In no analysis was Pteronotropis, as currently recognized, recovered as monophyletic without the inclusion of the currently recognized Notropis harperi, herein referred to as Pteronotropis. Two major clades are supported: one inclusive of P. hubbsi, P. welaka, and P. harperi and the second inclusive of P. signipinnis, P. grandipinnis, P. hypselopterus plus P. merlini sister to P. euryzonus, and P. metallicus plus P. stonei. PMID- 26114104 TI - Structural and Population Polymorphism of RT-Like Sequences in Avian Schistosomes Trichobilharzia szidati (Platyhelminthes: Digenea: Schistosomatidae). AB - Recently we developed the genus-specific markers of the avian schistosomes of the genus Trichobilharzia, the causative agents of human cercarial dermatitis. The 7 novel genome sequences of T. franki, T. regenti, and T. szidati revealed similarity with genome repeat region of African schistosome Schistosoma mansoni. In the present work we analyzed the 37 new T. szidati sequences to study intragenome variability and host specificity for the parasite from three localities of East Europe. DNAs were isolated from cercariae or single sporocysts obtained from 6 lymnaeid snails Lymnaea stagnalis and L. palustris from Belarus and Russia. All sequences formed three diverged groups, one of which consists of the sequences with multiple deletions; other groups involved two paralogous copies with stop codons and frameshift mutations. Strong association between geographical distribution and snail host specificity cannot be established. All studied sequences have homology with the reverse transcriptase domain (RT) of Penelope-like elements (PLE) of S. mansoni and S. japonicum and new members of RT family were identified. We proposed that three diverged groups RT sequences of T. szidati are results of duplication or transposition of PLE during parasite evolution. Implications of the retroelement dynamics in the life history of avian schistosomes are discussed. PMID- 26114105 TI - Signs of Selection in Synonymous Sites of the Mitochondrial Cytochrome b Gene of Baikal Oilfish (Comephoridae) by mRNA Secondary Structure Alterations. AB - Studies over the past decade have shown a significant role of synonymous mutations in posttranscriptional regulation of gene expression, which is particularly associated with messenger RNA (mRNA) secondary structure alterations. Most studies focused on prokaryote genomes and the nuclear genomes of eukaryotes while little is known about the regulation of mitochondrial DNA (mtDNA) gene expression. This paper reveals signs of selection in synonymous sites of the mitochondrial cytochrome b gene (Cytb) of Baikal oilfish or golomyankas (Comephoridae) directed towards altering the secondary structure of the mRNA and probably altering the character of mtDNA gene expression. Our findings are based on comparisons of intraspecific genetic variation patterns of small golomyanka (Comephorus dybowski) and two genetic groups of big golomyanka (Comephorus dybowskii). Two approaches were used: (i) analysis of the distribution of synonymous mutations between weak-AT (W) and strong-GC (S) nucleotides within species and groups in accordance with mutation directions from central to peripheral haplotypes and (ii) approaches based on the predicted mRNA secondary structure. PMID- 26114106 TI - New Developments in the Use of Biologics and Other Modalities in the Management of Lateral Epicondylitis. AB - Lateral epicondylitis is a common source of elbow pain. Though it is often a self limited condition, refractory lateral epicondylitis can lead to problems with activities of daily living and sometimes requires sick leave from work. Therefore prompt treatment is essential. Histopathologic studies have suggested that lateral epicondylitis is a tendinopathy, associated with apoptosis and autophagy, rather than a tendonitis associated with inflammation. Although corticosteroids have been used for short-term treatment, recent studies have suggested that they are not helpful and may even be harmful and delay healing in the treatment of lateral epicondylitis. Researchers have recently begun to investigate the use of biologics as potential treatment options for lateral epicondylitis. Autologous blood preparations including platelet rich plasma (PRP) and autologous whole blood injections (ABIs) have been proposed in order to deliver growth factors and other nutrients to the diseased tendon. Stem cell therapies have also been suggested as a method of improving tendon healing. This review discusses the current evidence for the use of PRP, ABI, and stem cell therapies for treatment of lateral epicondylitis. We also review the evidence for nonbiologic treatments including corticosteroids, prolotherapy, botulinum toxin A, and nitric oxide. PMID- 26114107 TI - Comparative Analysis of Apicoplast-Targeted Protein Extension Lengths in Apicomplexan Parasites. AB - In general, the mechanism of protein translocation through the apicoplast membrane requires a specific extension of a functionally important region of the apicoplast-targeted proteins. The corresponding signal peptides were detected in many apicomplexans but not in the majority of apicoplast-targeted proteins in Toxoplasma gondii. In T. gondii signal peptides are either much diverged or their extension region is processed, which in either case makes the situation different from other studied apicomplexans. We propose a statistic method to compare extensions of the functionally important regions of apicoplast-targeted proteins. More specifically, we provide a comparison of extension lengths of orthologous apicoplast-targeted proteins in apicomplexan parasites. We focus on results obtained for the model species T. gondii, Neospora caninum, and Plasmodium falciparum. With our method, cross species comparisons demonstrate that, in average, apicoplast-targeted protein extensions in T. gondii are 1.5-fold longer than in N. caninum and 2-fold longer than in P. falciparum. Extensions in P. falciparum less than 87 residues in size are longer than the corresponding extensions in N. caninum and, reversely, are shorter if they exceed 88 residues. PMID- 26114108 TI - A Database of Plastid Protein Families from Red Algae and Apicomplexa and Expression Regulation of the moeB Gene. AB - We report the database of plastid protein families from red algae, secondary and tertiary rhodophyte-derived plastids, and Apicomplexa constructed with the novel method to infer orthology. The families contain proteins with maximal sequence similarity and minimal paralogous content. The database contains 6509 protein entries, 513 families and 278 nonsingletons (from which 230 are paralog-free, and among the remaining 48, 46 contain at maximum two proteins per species, and 2 contain at maximum three proteins per species). The method is compared with other approaches. Expression regulation of the moeB gene is studied using this database and the model of RNA polymerase competition. An analogous database obtained for green algae and their symbiotic descendants, and applications based on it are published earlier. PMID- 26114109 TI - A Novel Restraining Device for Small Animal Imaging Exams: Validation in Rabbits. AB - OBJECTIVE: To develop, validate, and patent a Restraining Device for Small Animal Imaging Exams (RDSAIE) that allows exams to be comfortably conducted without risks to animals and professionals. METHODS: A RDSAIE with a mobile cover and shelf was built with transparent acrylic material. A total of six anesthetized rabbits were used to perform the following imaging exams of the skull: Cone Beam Computed Tomography, Magnetic Resonance Imaging, and Scintigraphy. RESULTS: The device showed great functionality and full visibility of the animal behavior, which remained fully stabilized and immobilized in either the horizontal or vertical position without the need for a person to remain in the test room to assist them. The procedures were performed without difficulty, and images of good resolution and without artifacts were obtained. CONCLUSION: The RDSAIE is comfortable, safe, efficient, and ergonomic. It allows the easy placement of animals in different body positions, including the vertical, the maintenance of postural stability, and full visibility. It may be constructed for animals heavier than 4 kg and it is adaptable for translational studies in anima nobile. PMID- 26114110 TI - Phylogeography of Pteronotropis signipinnis, P. euryzonus, and the P. hypselopterus Complex (Teleostei: Cypriniformes), with Comments on Diversity and History of the Gulf and Atlantic Coastal Streams. AB - The cyprinid genus Pteronotropis is endemic to southeastern Gulf of Mexico and Atlantic Ocean of North America. Never before has the genus been demonstrated to be monophyletic. We investigate both the phylogenetic relationships and the phylogeography of some species in the genus using mitochondrial ND2 sequences. In no analysis is the genus resolved as monophyletic if Notropis harperi is not included in the genus. Biogeographic and phylogeographic evaluations are conducted with Pteronotropis, including P. signipinnis, P. euryzonus, and the P. hypselopterus complex. Patterns of relationships and population genetic analyses support divergences within multiple clades both at the species level and within species that are tied to abiotic changes in the region. Replicated patterns across clades are observed, as well as patterns previously found in other taxa. Pteronotropis hypselopterus is likely not a natural grouping as populations from some drainages form clades more closely related to other species of the genus. The general patterns of relationships indicate likely cryptic species not currently recognized. Finally, the patterns of species relationships and clades and population structuring within species serve as another example of replicated divergences in the biodiversity east and west of the Mobile Bay. PMID- 26114111 TI - The Variability of the Order Burkholderiales Representatives in the Healthcare Units. AB - BACKGROUND AND AIM: The order Burkholderiales became more abundant in the healthcare units since the late 1970s; it is especially dangerous for intensive care unit patients and patients with chronic lung diseases. The goal of this investigation was to reveal the real variability of the order Burkholderiales representatives and to estimate their phylogenetic relationships. METHODS: 16S rDNA and genes of the Burkholderia cenocepacia complex (Bcc) Multi Locus Sequence Typing (MLST) scheme were used for the bacteria detection. RESULTS: . A huge diversity of genome size and organization was revealed in the order Burkholderiales that may prove the adaptability of this taxon's representatives. The following variability of the Burkholderiales in Russian healthcare units has been revealed: Burkholderiaceae (Burkholderia, Pandoraea, and Lautropia), Alcaligenaceae (Achromobacter), and Comamonadaceae (Variovorax). The Burkholderia genus was the most diverse and was represented by 5 species and 16 sequence types (ST). ST709 and 728 were transmissible and often encountered in cystic fibrosis patients and in hospitals. A. xylosoxidans was estimated by 15 genotypes. The strains of first and second ones were the most numerous. CONCLUSIONS: Phylogenetic position of the genus Lautropia with smaller genome is ambiguous. The Bcc MLST scheme is applicable for all Burkholderiales representatives for resolving the epidemiological problems. PMID- 26114112 TI - Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-kappaB Pathway. AB - Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-alpha. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-kappaB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-kappaB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-kappaB pathway activation. PMID- 26114113 TI - Lengths of Orthologous Prokaryotic Proteins Are Affected by Evolutionary Factors. AB - Proteins of the same functional family (for example, kinases) may have significantly different lengths. It is an open question whether such variation in length is random or it appears as a response to some unknown evolutionary driving factors. The main purpose of this paper is to demonstrate existence of factors affecting prokaryotic gene lengths. We believe that the ranking of genomes according to lengths of their genes, followed by the calculation of coefficients of association between genome rank and genome property, is a reasonable approach in revealing such evolutionary driving factors. As we demonstrated earlier, our chosen approach, Bubble-sort, combines stability, accuracy, and computational efficiency as compared to other ranking methods. Application of Bubble Sort to the set of 1390 prokaryotic genomes confirmed that genes of Archaeal species are generally shorter than Bacterial ones. We observed that gene lengths are affected by various factors: within each domain, different phyla have preferences for short or long genes; thermophiles tend to have shorter genes than the soil dwellers; halophiles tend to have longer genes. We also found that species with overrepresentation of cytosines and guanines in the third position of the codon (GC3 content) tend to have longer genes than species with low GC3 content. PMID- 26114114 TI - Association between ANKK1 (rs1800497) and LTA (rs909253) Genetic Variants and Risk of Schizophrenia. AB - Limited research has assessed associations between schizophrenia and genetic variants of the ankyrin repeat and kinase domain containing 1 (ANKK1) and lymphotoxin-alpha (LTA) genes among individuals of Middle Eastern ancestry. Here we present the first association study investigating the ANKK1 rs1800497 (T>C) and LTA rs909253 (A>G) single-nucleotide polymorphisms in an Egyptian population. Among 120 patients with DSM-IV and PANSS (Positive and Negative Syndrome Scale) assessments of schizophrenia and 100 healthy controls, we determined the genotypes for the polymorphisms using endonuclease digestion of amplified genomic DNA. Results confirmed previous findings from different ethnic populations, in that the rs1800497 and rs909253 polymorphisms were both associated with risk of schizophrenia. Differences between the genotypes of cases and controls were strongly significant (P = 0.0005 for rs1800497 and P = 0.001 for rs909253). The relative risk to schizophrenia was 1.2 (P = 0.01) for the C allele and 0.8 (P = 0.04) for the G allele. The CC, GG, and combined CC/AA genotypes were all more frequent in cases than in controls. These results support an association between ANKK1 and LTA genetic markers and vulnerability to schizophrenia and show the potential influence of just one copy of the mutant C or G allele in the Egyptian population. PMID- 26114115 TI - Multi-Leu PACE4 Inhibitor Retention within Cells Is PACE4 Dependent and a Prerequisite for Antiproliferative Activity. AB - The overexpression as well as the critical implication of the proprotein convertase PACE4 in prostate cancer progression has been previously reported and supported the development of peptide inhibitors. The multi-Leu peptide, a PACE4 specific inhibitor, was further generated and its capability to be uptaken by tumor xenograft was demonstrated with regard to its PACE4 expression status. To investigate whether the uptake of this inhibitor was directly dependent of PACE4 levels, uptake and efflux from cancer cells were evaluated and correlations were established with PACE4 contents on both wild type and PACE4-knockdown cell lines. PACE4-knockdown associated growth deficiencies were established on the knockdown HepG2, Huh7, and HT1080 cells as well as the antiproliferative effects of the multi-Leu peptide supporting the growth capabilities of PACE4 in cancer cells. PMID- 26114116 TI - Molecular Biogeography of Tribe Thermopsideae (Leguminosae): A Madrean-Tethyan Disjunction Pattern with an African Origin of Core Genistoides. AB - Thermopsideae has 45 species and exhibits a series of interesting biogeographical distribution patterns, such as Madrean-Tethyan disjunction and East Asia-North America disjunction, with a center of endemism in the Qinghai-Xizang Plateau (QTP) and Central Asia. Phylogenetic analysis in this paper employed maximum likelihood using ITS, rps16, psbA-trnH, and trnL-F sequence data; biogeographical approaches included BEAST molecular dating and Bayesian dispersal and vicariance analysis (S-DIVA). The results indicate that the core genistoides most likely originated in Africa during the Eocene to Oligocene, ca. 55-30 Ma, and dispersed eastward to Central Asia at ca. 33.47 Ma. The origin of Thermopsideae is inferred as Central Asian and dated to ca. 28.81 Ma. Ammopiptanthus is revealed to be a relic. Birth of the ancestor of Thermopsideae coincided with shrinkage of the Paratethys Sea at ca. 30 Ma in the Oligocene. The Himalayan motion of QTP uplift of ca. 20 Ma most likely drove the diversification between Central Asia and North America. Divergences in East Asia, Central Asia, the Mediterranean, and so forth, within Eurasia, except for Ammopiptanthus, are shown to be dispersals from the QTP. The onset of adaptive radiation at the center of the tribe, with diversification of most species in Thermopsis and Piptanthus at ca. 4-0.85 Ma in Tibet and adjacent regions, seems to have resulted from intense northern QTP uplift during the latter Miocene to Pleistocene. PMID- 26114117 TI - Ethnomedicinal Evaluation of Medicinal Plants Used against Gastrointestinal Complaints. AB - Aim of the present study was to document ethnomedicinal plants used against gastrointestinal complaints in five selected remote regions of Pakistan and to select potential medicinal plants for further in vitro and in vivo investigation. Data on ethnomedicinal plants and ethnographic profile of respondents was documented using semistructured questionnaires. The present study revealed utilization of 52 medicinal plants for the treatment of different gastrointestinal infections in studied regions. Apiaceae was the most dominant family reported to be used for the treatment of these infections (4 plants). Among all the plant parts fruit (24%), whole plants and leaves (23% each) were the most preferred plant parts used by the healers. Dosage of recipe was found to be related with the age of the patient. Highest degree of informant consensus was reported for vomiting, nausea (0.92 each), abdominal pain (0.9), and diarrhea (0.89). Withania coagulans scored highest FL value (86%) followed by Mentha longifolia and Melia azadirachta ranked second with FL value (75% each). Young generation was found to possess little traditional knowledge about utilizing plant recipes against these infections. Plants with high Fic and FL values should be subjected for further phytochemical and pharmacological investigation for scientific validation. PMID- 26114118 TI - miR-1322 Binding Sites in Paralogous and Orthologous Genes. AB - We searched for 2,563 microRNA (miRNA) binding sites in 17,494 mRNA sequences of human genes. miR-1322 has more than 2,000 binding sites in 1,058 genes with DeltaG/DeltaG m ratio of 85% and more. miR-1322 has 1,889 binding sites in CDSs, 215 binding sites in 5' UTRs, and 160 binding sites in 3' UTRs. From two to 28 binding sites have arranged localization with the start position through three nucleotides of each following binding site. The nucleotide sequences of these sites in CDSs encode oligopeptides with the same and/or different amino acid sequences. We found that 33% of the target genes encoded transcription factors. miR-1322 has arranged binding sites in the CDSs of orthologous MAMLD1, MAML2, and MAML3 genes. These sites encode a polyglutamine oligopeptide ranging from six to 47 amino acids in length. The properties of miR-1322 binding sites in orthologous and paralogous target genes are discussed. PMID- 26114119 TI - Effects of Atrazine on the Development of Neural System of Zebrafish, Danio rerio. AB - By comparative analysis of histomorphology and AChE activity, the changes of physiological and biochemical parameters were determined in zebrafish embryos and larvae dealt with atrazine (ATR) at different concentrations (0.0001, 0.001, 0.01, 0.1, and 1 mg/L). This study showed that the development of the sarcomere and the arrangement of white muscle myofibers were affected by ATR significantly and the length of sarcomere shortened. Further analysis of the results showed that the AChE activity in juvenile fish which was treated with ATR was downregulated, which can indicate that the innervation efficiency to the muscle was impaired. Conversely, the AChE activity in zebrafish embryos which was treated with ATR was upregulated. A parallel phenomenon showed that embryonic primary sensory neurons (Rohon-Beard cells), principally expressing AChE in embryos, survived the physiological apoptosis. These phenomena demonstrated that the motor integration ability of the zebrafish was damaged by ATR which can disturb the development of sensory neurons and sarcomere and the innervations of muscle. PMID- 26114120 TI - Diabetes Remission after Nonsurgical Intensive Lifestyle Intervention in Obese Patients with Type 2 Diabetes. AB - Partial or complete remission from type 2 diabetes was recently observed after bariatric surgeries. Limited data is available about the possibility of inducing diabetes remission through intensive weight reduction. We retrospectively evaluated diabetes remissions after one year of the Weight Achievement and Intensive Treatment (Why WAIT) program, a 12-week intensive program for diabetes weight management in real-world clinical practice. Among 120 obese patients with type 2 diabetes who completed the program, 88 patients returned for follow-up at one year. Nineteen patients (21.6%) had major improvement in their glycemic control, defined as achieving an A1C <6.5% after one year. Four patients (4.5%) achieved either partial or complete diabetes remission defined as A1C <6.5% and <5.7%, respectively, on no antihyperglycemic medications for one year; 2 achieved partial remission (2.3%) and 2 achieved complete remission (2.3%). At the time of intervention, patients who achieved diabetes remission had shorter diabetes duration (<5 years) and lower A1C (<8%) and were treated with fewer than 2 oral medications. They achieved a weight reduction of >7% after 12 weeks. These results indicate that a subset of obese patients with type 2 diabetes is appropriate for intensive lifestyle intervention with the aim of inducing diabetes remission. PMID- 26114121 TI - Optimal Hemoglobin A1c Levels for Screening of Diabetes and Prediabetes in the Japanese Population. AB - The aim of this study was to evaluate the utility of hemoglobin A1c (HbA1c) to identify individuals with diabetes and prediabetes in the Japanese population. A total of 1372 individuals without known diabetes were selected for this study. A 75 g oral glucose tolerance test (OGTT) was used to diagnose diabetes and prediabetes. The ability of HbA1c to detect diabetes and prediabetes was investigated using receiver operating characteristic (ROC) analysis. The kappa (kappa) coefficient was used to test the agreement between HbA1c categorization and OGTT-based diagnosis. ROC analysis demonstrated that HbA1c was a good test to identify diabetes and prediabetes, with areas under the curve of 0.918 and 0.714, respectively. Optimal HbA1c cutoffs for diagnosing diabetes and prediabetes were 6.0% (sensitivity 83.7%, specificity 87.6%) and 5.7% (sensitivity 60.6%, specificity 72.1%), respectively, although the cutoff for prediabetes showed low accuracy (67.6%) and a high false-negative rate (39.4%). Agreement between HbA1c categorization and OGTT-based diagnosis was low in diabetes (kappa = 0.399) and prediabetes (kappa = 0.324). In Japanese subjects, the HbA1c cutoff of 6.0% had appropriate sensitivity and specificity for diabetes screening, whereas the cutoff of 5.7% had modest sensitivity and specificity in identifying prediabetes. Thus, HbA1c may be inadequate as a screening tool for prediabetes. PMID- 26114122 TI - Secretory Products of Trichinella spiralis Muscle Larvae and Immunomodulation: Implication for Autoimmune Diseases, Allergies, and Malignancies. AB - Trichinella spiralis has the unique ability to make itself "at home" by creating and hiding in a new type of cell in the host body that is the nurse cell. From this immunologically privileged place, the parasite orchestrates a long-lasting molecular cross talk with the host through muscle larvae excretory-secretory products (ES L1). Those products can successfully modulate parasite-specific immune responses as well as responses to unrelated antigens (either self or nonself in origin), providing an anti-inflammatory milieu and maintaining homeostasis. It is clear, based on the findings from animal model studies, that T. spiralis and its products induce an immunomodulatory network (which encompasses Th2- and Treg-type responses) that may allow the host to deal with various hyperimmune-associated disorders as well as tumor growth, although the latter still remains unclear. This review focuses on studies of the molecules released by T. spiralis, their interaction with pattern recognition receptors on antigen presenting cells, and subsequently provoked responses. This paper also addresses the immunomodulatory properties of ES L1 molecules and how the induced immunomodulation influences the course of different experimental inflammatory and malignant diseases. PMID- 26114123 TI - NK and NKT Cell Depletion Alters the Outcome of Experimental Pneumococcal Pneumonia: Relationship with Regulation of Interferon-gamma Production. AB - Background. Natural killer (NK) and natural killer T (NKT) cells contribute to the innate host defense but their role in bacterial sepsis remains controversial. Methods. C57BL/6 mice were infected intratracheally with 5 * 10(5) cfu of Streptococcus pneumoniae. Animals were divided into sham group (Sham); pretreated with isotype control antibody (CON) group; pretreated with anti-asialo GM1 antibody (NKd) group; and pretreated with anti-CD1d monoclonal antibody (NKTd) group before bacterial challenge. Serum and tissue samples were analyzed for bacterial load, cytokine levels, splenocyte apoptosis rates, and cell characteristics by flow cytometry. Splenocyte miRNA expression was also analyzed and survival was assessed. Results. NK cell depletion prolonged survival. Upon inhibition of NKT cell activation, spleen NK (CD3-/NK1.1+) cells increased compared to all other groups. Inhibition of NKT cell activation led to higher bacterial loads and increased levels of serum and splenocyte IFN-gamma. Splenocyte miRNA analysis showed that miR-200c and miR-29a were downregulated, while miR-125a-5p was upregulated, in anti-CD1d treated animals. These changes were moderate after NK cell depletion. Conclusions. NK cells appear to contribute to mortality in pneumococcal pneumonia. Inhibition of NKT cell activation resulted in an increase in spleen NK (CD3-/NK1.1+) cells and a higher IFN-gamma production, while altering splenocyte miRNA expression. PMID- 26114125 TI - A Review of Myiasis in Iran and a New Nosocomial Case from Tehran, Iran. AB - BACKGROUND: Due to various climatic conditions in different parts of Iran, presenting of various kinds of human myiasis is expected. Despite of a few case series, most papers related to myiasis are case reports originated from various parts of Iran. This study discusses on different clinical features of myiasis in Iran and description of one case from Tehran as a representative to nosocomial infection in Iran. METHODS: The information needed for this descriptive study was derived mainly from the digital library of Tehran University of Medical Sciences. The larvae have been identified with observing on posterior spiracles, spines of their body and anal tubercles. RESULTS: Total number of reported myiasis cases from Iran is 77 which can be categorized clinically as furuncular, wound, ophthalmic, auricular, nasopharyngeal, oral, intestinal and genitourinary. Based on parasitological features, all myiasis agents in Iran are belonging to Calliphoridae, Sarcophagidae, Oestridae and Syrphidae flies. The case which is reporting in this paper can be mentioned as representative of nosocomial myiasis which it seems to be underreported because of some medicolegal reasons. CONCLUSION: Low number of investigations on various aspects of human myiasis, as well as incuriosity to report of the cases in disease reporting system of health minister, made the myiasis as a neglected disease. PMID- 26114126 TI - Seroepidemiologic Survey of Canine Visceral Leishmaniasis in Tehran and Alborz Provinces of Iran. AB - BACKGROUND: A two year seroepidemiological study was designed to find out the seroprevalence and risk factors of canine visceral leishmaniasis (CVL) among stray and owned dogs in Tehran and Alborz Provinces of Iran. METHODS: Blood samples of 602 dogs living in 11 counties of Tehran and Alborz Provinces were taken by venipuncture in 2008-2010. After separation of blood sera, anti leishmanial antibodies were detected by direct agglutination test (DAT). RESULTS: Overall, of the 408 and 194 serum samples collected randomly from dogs in 11 localities in Tehran and Alborz Provinces, 18/408 (4.41%) and 12/194 (6.18%) respectively were found positive. Among the localities, Shemiran in Tehran Province and Karaj In Alborz Province had the highest prevalence rates. No statistically significant differences were found between sex and living place but there was significant difference between living status (owned or stray) and CVL infection of dogs in Alborz Province (P= 0.018). The highest seroprevalence (7.5%) was found in dogs aged 3 to 5 years old. Only 20% of the seropositive dogs were symptomatic. CONCLUSION: Concerning possible human infections in Tehran and Alborz Provinces, both symptomatic and asymptomatic seropositive dogs should be considered as a risk. PMID- 26114124 TI - The Lung Immune Response to Nontypeable Haemophilus influenzae (Lung Immunity to NTHi). AB - Haemophilus influenzae is divided into typeable or nontypeable strains based on the presence or absence of a polysaccharide capsule. The typeable strains (such as type b) are an important cause of systemic infection, whilst the nontypeable strains (designated as NTHi) are predominantly respiratory mucosal pathogens. NTHi is present as part of the normal microbiome in the nasopharynx, from where it may spread down to the lower respiratory tract. In this context it is no longer a commensal and becomes an important respiratory pathogen associated with a range of common conditions including bronchitis, bronchiectasis, pneumonia, and particularly chronic obstructive pulmonary disease. NTHi induces a strong inflammatory response in the respiratory tract with activation of immune responses, which often fail to clear the bacteria from the lung. This results in recurrent/persistent infection and chronic inflammation with consequent lung pathology. This review will summarise the current literature about the lung immune response to nontypeable Haemophilus influenzae, a topic that has important implications for patient management. PMID- 26114127 TI - Molecular Survey on Detection of Leishmania Infection in Rodent Reservoirs in Jahrom District, Southern Iran. AB - BACKGROUND: Zoonotic Cutaneous Leishmaniasis (ZCL) is endemic in many parts of Iran. Recently its incidence is considerable in different parts of Jahrom district, in Fars Province, southern Iran. The aims of our study were to investigate the prevalence of leishmania infection, and identify and characterize the Leishmania species present, among the rodents by molecular methods in a new endemic focus of ZCL, in an urban and rural area of the Jahrom district, Fars Province, southern Iran. METHODS: From May to November 2010), 55 rodents in four regions of Jahrom focus were caught and checked for leishmania infection by the microscopical examination of liver, spleen, ears, and footpads' smears. RESULTS: Overall 18 Meriones persicus, 15 Tatera indica, 14 Mus musculus, and 8 Rattus rattus were caught. Totally, four (16.5%) and two (13.3%) of the Me. persicus and Ta. indica, but only one of Mu. musculus and Ra. rattus were found smear-positive for leishmania amastigotes, respectively. In the nested-PCR assay 8 (14.6%) smears were found positive for Leishmania major, none was found positive for any other Leishmania species. Sequencing based detection of Leishmania confirmed the microscopic and PCR findings. All positive specimens were shown 95-96% similarity with L. major Friedlin. CONCLUSION: Tatera indica and Me. persicus are incriminated as the main 'reservoir' hosts of L. major in the rural area of Jahrom, moreover, Mu. musculus and Ra. rattus have the minor but remarkable role in the maintenance of the disease in the urban regions of Jahrom focus. PMID- 26114128 TI - Chemical Composition, Larvicidal and Repellency Properties of Cionura erecta (L.) Griseb. Against Malaria Vector, Anopheles stephensi Liston (Diptera: Culicidae). AB - BACKGROUND: Application of plant derivatives have been suggested as alternative sources for mosquito control. METHODS: The root essential oil and methanol extract of Cionura erecta (L.) Griseb was tested under laboratory conditions for larvicidal and skin repelleny activities against Anopheles stephensi. The chemical compositions of essential oils were analyzed using gas chromatography- mass spectrometry. RESULTS: Among the five concentrations tested, the 320 ppm of essential oil and 1280 ppm of methanolic extract had the most toxic effects yielding 100% mortality. The LC50 values of C. erecta for both essential oil and methanolic extract were 77.30 and 250.38 ppm, respectively. A total of 19 compounds were identified in essential oil of root. The major components were detected in root essential oil including Cedren-9-one (7.89%), alpha cadinol (5.67%), eugenol (4.02%) and alpha muurolene (3.58%). The protection time of 50% solution of essential oil against bites of An. stephensi was 2.28 hour on white rabbit and the ED50 and ED90 values of the essential oil were 10.12 and 23.01 ppm respectively. CONCLUSION: The findings suggest that C. erecta oil has a potential source as larvicidal and repellency properties against An.stephensi. PMID- 26114129 TI - Efficacy of Different Sampling Methods of Sand Flies (Diptera: Psychodidae) in Endemic Focus of Cutaneous Leishmaniasis in Kashan District, Isfahan Province, Iran. AB - BACKGROUND: The aim of the study was to evaluate and compare the efficiency and practicality of seven trapping methods for adult phlebotominae sand flies. The results of this investigation provide information to determine the species composition and nocturnal activity pattern of different sand fly species. METHODS: The study was carried out in both plain region (about 5km far from northeast) and mountainous region (about 40km far from southwest of Kashan City). Seven traps were selected as sampling methods and sand flies were collected during 5 interval times starting July to September 2011 and from 8:00PM to 6:00AM in outdoors habitats. The traps include: sticky traps (4 papers for 2 hours), Disney trap, Malaise, CDC and CO2 light traps, Shannon traps (black and white nets) and animal-baited trap. RESULTS: A total of 1445 sand flies belonging to 15 species of Phlebotomus spp. and five of Sergentomyia spp. were collected. Females and males comprised 44.91% and 55.09% of catches, respectively. Of the collected specimens, Se. sintoni was found to be the most prevalent (37.86%) species, while Ph. papatasi, accounted for 31.76% of the sand flies. CONCLUSION: Disney trap and sticky traps exhibited the most productivity than other traps. In addition, in terms of the efficiency of sampling method, these two trapping methods appeared to be the most productive for both estimating the number of sand flies and the species composition in the study area. PMID- 26114130 TI - Fauna and Larval Habitats of Mosquitoes (Diptera: Culicidae) of West Azerbaijan Province, Northwestern Iran. AB - BACKGROUND: Several important diseases are transmitted by mosquitoes. Despite of the potential of the occurrence of some mosquito-borne diseases such as West Nile, dirofilariasis and malaria in the region, there is no recent study of mosquitoes in West Azerbaijan Province. The aim of this investigation was to study the fauna, composition and distribution of mosquitoes and the characteristics of their larval habitats in this province. METHODS: Larvae and adult collections were carried out from different habitats using the standard methods in twenty five localities of seven counties across West Azerbaijan Province. RESULTS: Overall, 1569 mosquitoes including 1336 larvae and 233 adults were collected from 25 localities. The details of geographical properties were recorded. Five genera along with 12 species were collected and identified including: Anopheles claviger, An. maculipennis s.l., An. superpictus, Culex pipiens, Cx. theileri, Cx. modestus, Cx. hortensis, Cx. mimeticus, Culiseta Longiareolata, Ochlerotatus caspius s.l., Oc. geniculatus and Uranotaenia unguiculata. This is the first record of Oc. geniculatus in the province. CONCLUSION: Due to the geographical location of the West Azerbaijan Province, it comprises different climatic condition which provides suitable environment for the establishment of various species of mosquitoes. The solidarity geographical, cultural and territorial exchanges complicate the situation of the province and its vectors as a threat for future and probable epidemics of mosquito-borne diseases. PMID- 26114131 TI - Differential Larval Toxicity and Oviposition Altering Activity of Some Indigenous Plant Extracts against Dengue and Chikungunya Vector Aedes albopictus. AB - BACKGROUND: Mosquitoes are well known as vectors of several disease causing pathogens. The extensive use of synthetic insecticides in the mosquito control strategies resulted to the development of pesticide resistance and fostered environmental deterioration. Hence in recent years plants become alternative source of mosquito control agents. The present study assessed the larvicidal and oviposition altering activity of six different plants species-Alstonia scholaris, Callistemon viminalis, Hyptis suaveolens, Malvastrum coromandelianum, Prosopis juliflora, Vernonia cinerea against Aedes albopictus mosquito in laboratory. METHODS: Leaf extracts of all the six plants species in five different solvents of various polarities were used in the range of 20-400ppm for larval bioassay and 50,100 and 200ppm for cage bioassay (for the study of oviposition behavior) against Ae. albopictus. The larval mortality data were recorded after 24 h and subjected to Probit analysis to determine the lethal concentrations (LC50), while OAI (Oviposition activity index) was calculated for oviposition altering activity of the plant extracts. RESULTS: Vernonia cinerea extract in acetone and C. viminalis extract in isopropanol were highly effective against Aedes albopictus larvae with LC50 value 64.57, 71.34ppm respectively. Acetone extract of P. juliflora found to be strong oviposition-deterrent which inhibited >2 fold egg laying (OAI-0.466) at 100ppm. CONCLUSION: Vernonia cinerea and C. viminallis leaf extracts have the potential to be used as larvicide and P. juliflora as an oviposition-deterrent for the control of Ae. albopictus mosquito. PMID- 26114132 TI - Distribution of Anopheles culicifacies and Detection of its Sibling Species E from Madhya Pradesh: Central India. AB - BACKGROUND: Anopheles culicifacies is an important vector of malaria in Southeast Asia, contributing to almost 70% of malaria cases in India. It exists as a complex of five morphologically indistinguishable species A, B, C, D and E with varied geographical distribution patterns. In India, 8% of the total population of Madhya Pradesh (Central India) contributes about 30% of total malaria cases, 60% of total falciparum cases and 50% of malaria deaths. An. culicifacies is the major malaria vector in this state. Vector control mainly relies on the proper identification and distribution of vector species exists in a particular area. The present study was carried out to identify the distribution of An. culicifacies sibling species in certain endemic district of Central India, Madhya Pradesh. METHODS: The An. culicifacies mosquitoes collected from the study districts were identified morphologically. The genomic DNA was isolated from the mosquitoes and subjected to Allele specific PCR targeting D3 domain of 28S ribosomal DNA. RESULTS: The mean prevalence of An. culicifacies during the study period was in the range of 8-120 per man per hour (PMH). From the study areas species B was identified from Jabalpur, Chindwara and Hoshangabad, Species C from Hoshangabad only, Species D from Narsinghpur and Khandwa and sibling species E from Mandla, Chindwara and Hoshangabad respectively. CONCLUSION: This is the first report to detect species E from Madhya Pradesh region which necessitate for reconsideration of species distribution of each An. culicifacies sibling species that would enable to develop required vector control strategies. PMID- 26114133 TI - Biodiversity of Aquatic Insects of Zayandeh Roud River and Its Branches, Isfahan Province, Iran. AB - BACKGROUND: Aquatic insects are the major groups of arthropods that spend some parts of their life cycle in the water. These insects play an important role for transmission of some human and animal diseases. There is few information about the aquatic insects fauna of Iran. METHODS: To study the aquatic insects fauna, adult, nymphal and larval collections were carried out from different habitats using the standard technique in Zayandeh Roud River, Isfahan Province,central Iran, during summer 2011. RESULTS: In total, 741 speimens of aquatic insects were collected and morphologically identified. They include 7 families and 12 genera representing 2 Orders. The order of Diptera (92.31%) and Coleoptera (7.69%). The families Culicidae, Syrphidae and Chironomidae from Diptera order, Gyrinidae, Dytiscidae, Haliplidae, Hydrophilidae from Coleoptera order were identified. CONCLUSION: Some aquatic insects play an important role for transmission of human and animal diseases. These insects also are important for biological control. Therefore ecological study on aquatic insects can provide information about ecology of insects in an area for any decision making. PMID- 26114134 TI - Anaplasma Infection in Ticks, Livestock and Human in Ghaemshahr, Mazandaran Province, Iran. AB - BACKGROUND: Anaplasmosis is an important issue for animal breeders in terms of economic losses as well as a health concern to human. Ticks are considered as the main vector of this disease. Lack of documented information about Anaplasma species in Iran was the scope of this study to determine the population of ticks and the presence of Anaplasma in ticks, domestic ruminants and also human beings in northern Iran. METHODS: A total of 101 unengorged hard ticks, 78 domestic ruminants and 40 human blood samples collected from Ghaemshahr, Mazandaran Province, northern Iran were tested by nested PCR against 16s rRNA gene of Anaplasma species. RESULTS: Positive PCR was found in 50 ticks, 28 sheep, 2 cattle, one goat, and 10 human specimens. Sequence analysis of the PCR products confirmed presence of A. ovis in two Rhipicephalus sanguineus and two Ixodes ricinus ticks, one human and 4 sheep samples. Moreover one Boophilus annulatus tick and one sheep sample were infected with A. bovis. Furthermore one sample of sheep was infected with A. centrale. CONCLUSION: This study is the first report of tick infection to A. ovis, A. bovis and human infection to A. ovis in Iran. The result of this study is a survey of Anaplasma infections from ticks, domestic animals and human in Iran which help to have appropriate prevention measures for anaplasmosis. PMID- 26114135 TI - Mosquito Fauna (Diptera: Culicidae) of Hamedan County, Western Iran. AB - BACKGROUND: This study aimed to identify and determine the larval and adult mosquitoes (Culicidae) fauna in Hamedan County, western Iran. METHODS: It was a cross-sectional study which took place in four area of the Hamedan County. Sampling methods for larvae, pupae and adults were dipping, hand catch, night catch and total catch. Larvae and adult mosquitoes collected and were sent to laboratory of Medical Entomology, Hamedan University of Medical Sciences, Hamedan, Iran for further identification to species level to determination of fauna. Data analysis was performed using SPSS software version19. RESULTS: Three genera and eight species of family Culicidae were collected and identified in Hamedan County, Hamedan Province, West Iran, during May to October 2013. These species included: Culex theileri, Cx. pipiens, Cx. antennatus, Culiseta subochrea, Cs. langiareolata, Anopheles superpictus, An. maculipennis and An. stephensi. The species Cx. antennatus and An. stephensi were reported for the first time in Hamedan County. CONCLUSION: An. stephensi and Cx. antennatus caught had not been previously recorded in Hamedan Province. Due to vast agricultural activities in the province which provides suitable environment for the establishment of various species of mosquitoes and since many of them are potential vectors of human and domesticated animal pathogens, their ecology needs to be studied extensively. PMID- 26114136 TI - Species Diversity and Distribution of Ticks (Acari: Ixodidae) in Zabol County, Eastern Iran. AB - BACKGROUND: Ticks are important vectors of human and animal pathogens. They are considered as main vectors for transmission of many viral, bacterial, rickettsial and parasitical pathogens. The aim of the present study was to find out species diversity of ticks, which infested the domestic ruminants in Zabol County, Eastern Iran in 2012. METHODS: Ticks were selected randomly from sheep, goats, cattle and camels. The ticks were collected from the body of infested animals and stored in 70% ethanol, then transported to the laboratory of Zabol University of Medical Sciences. Following examinations under stereomicroscope, ticks were identified using available taxonomic keys. RESULTS: In this study, a total number of 469 adult ticks (381 males and 88 females) were collected. Ticks were classified into 2 genera and 9 species including: Hyalomma dromedarii (17.3%), Hy. schulzei (1.8%), Hy. marginatum (0.5%), Hy. anatolicum excavatum (12.60%), Hy. anatolicum anatolicum (11.2%), Hy. asiaticum asiaticum (11.0%), Rhipicephalus sanguineus (21.2%), Rh. bursa (10.2%) and Rh. turacunis (13.911%). The frequency of genus Hyalomma (54.6%) was higher than Rhipicephalus. Rh. sanguineus was the predominant tick species and accounted for 21.26% of the ticks. The ratio of males was more than the female ticks. CONCLUSION: Hyalomma and Rhipicephalus species are commonly distributed in the study area. Further investigations are needed to identify the role of above tick species as vectors of pathogenic organisms. PMID- 26114137 TI - First Palaearctic Record of the Bird Parasite Passeromyia heterochaeta (Diptera: Muscidae) from the Iranian Persian Gulf Islands. AB - BACKGROUND: Passeromyia is a muscid genus previously known from the Old World Afrotropical and Oriental regions and eastwards from Australia and the West Pacific. The genus is known from nest-dwelling larvae which may be parasites of the nestlings. This study was aimed to identify of the Passeromyia species in the Iranian Persian Gulf Islands. METHODS: The flies were collected during April 2010 to March 2011 on the 4 Iranian Persian Gulf islands, Greater Tunb, Lesser Tunb, Abu-Mousa and Qeshm with fly bottle trap and entomological net. RESULTS: During this sampling, 18 representatives of P. heterochaeta, a species with free-living haematophagous larvae, have been collected. The species is reported herein from Greater Tunb, Lesser Tunb, Abu-Mousa and Qeshm islands. CONCLUSIONS: This is the first Palaearctic record of the species as well as the first report of the genus Passeromyia from the Palaearctic Region. PMID- 26114138 TI - First Record of the Mediterranean Recluse Spider Loxosceles rufescens (Araneae: Sicariidae) from Iran. AB - Loxosceles rufescens, commonly known as the Mediterranean Recluse or Mediterranean Fiddle-Back Spider is recorded from Iran for the first time. The genus Loxosceles contains 103 accepted species, two of them (including L. rufescens) are cosmopolitan. All Loxosceles species tested so far possess necrotic venoms, which is a unique characteristic among the Order Araneae. Considering this characteristic, it is of medical importance to determine a specific geographical distribution of these spiders. Collecting methods include visual inspection and direct hand collecting. All of the specimens were collected in Tehran. Six specimens of both sexes were collected from parks, houses and apartments. The characteristics of the genus, which are the unique arrangement of six eyes in three diads, the violin shaped mark on the cephalothorax, and the short tibia of adult male palpi with narrow base and it's embolus which is about as long as the width of the globular bulb were observed and recorded. Having the cytotoxicity of the venom and its urban distribution in mind, L. rufescens is probably among the more important spider species of Iran. Since there are no reports of loxoscelism from Iran, we assume that the bites are either infrequent or misdiagnosed. Therefore further studies are needed to clarify the medical importance degree of this species. PMID- 26114139 TI - Endoparasites of Wild Rodents in Southeastern Iran. AB - BACKGROUND: This study was aimed to collect wild rodents for endoparasites determination in some parts of Sistan and Baluchistan Province, southeastern Iran nearby Pakistan and Afghanistan countries. METHODS: A total of 100 wild rodents were captured alive with cage traps. Various samples were collected from blood and feces, also impression smear prepared from different organs. The samples were prepared by formalin-ether or stained with Giemsa, after that were examined under microscope. RESULTS: All the caught rodents (47 Tatera indica, 44 Meriones hurriana, 5 Gerbilus nanus and 4 Meriones libycus) were studied for endoparasites emphasizing to their zoonotic aspects. Endoparasites including Spirurida, Hymenolepis diminuta, Hymenolepis nana feraterna, Trichuris trichiura, Skerjabino taenia, Trichostrongylus spp, Entamoeba muris, Chilomastix mesnili and Leishmania spp were parasitologically identified. CONCLUSION: Among 9 genera or species of the identified parasites at least 5 of them have zoonotic and public health importance. PMID- 26114140 TI - Assessing the Susceptibility Status of Mosquitoes (Diptera: Culicidae) in a Dirofilariasis Focus, Northwestern Iran. AB - BACKGROUND: Mosquitoes are considered as the vectors of dirofilariasis and some vector borne disease in Iran. The objective of this study was to determine the susceptibility level of the vectors to various insecticides recommended by WHO for any control measures in an endemic area in northwestern Iran. METHODS: Mosquito larval and adult collections were carried out using different methods provided by WHO including dipping and hand catch techniques. The susceptibility level was assessed to DDT 4%, malathion 5%, propoxur 0.1%, deltamethrin 0.05% and lambda-cyhalothrin 0.05%. RESULTS: Totally, 749 adults and 5060 larvae of Culicidae mosquitoes were collected comprising seven species of adult and larvae, including: Anopheles claviger, An. maculipennis, An. sacharovi, Culex hortensis, Cx. pipiens, Cx. theileri and Culiseta longiaerolata. Frequency of larvae and adults of An. maculipennis was very low, so susceptibility tests on this species did not performed. Results showed that Cx. theileri, Cs. longiaerolata and Cx. pipiens were resistant to DDT 4%, lambda-cyhalothrin 0.05%, and propoxur 0.1% whereas found tolerant to deltamethrin 0.05% and malathion 5%. The LT50 and LT90 values for five insecticides were calculated. CONCLUSION: We suggest the same study in different parts of the world to obtain the data due to bionomic and susceptibility status of dirofilariasis vectors. This information will help the health authorities for monitoring and evaluation of control measures. PMID- 26114141 TI - Susceptibility of Culicidae Mosquitoes to Some Insecticides Recommended by WHO in a Malaria Endemic Area of Southeastern Iran. AB - BACKGROUND: According to the national strategy plan on monitoring of insecticides resistance, this study was carried out to determine the base line susceptibility of the Culicidae mosquitoes to the WHO-recommended insecticides in an endemic focus of malaria in southeastern Iran. METHODS: Larval collection was carried out by dipping method and adult collection occurred by suction tube from January to December 2010. The susceptibility test was assessed to DDT 4 %, malathion 5 %, propoxur 0.1 %, deltamethrin 0.05 %, lambda-cyhalothrin 0.05 %, and cyfluthrin 0.15 % at different interval times (discriminative dose) followed by 24 h recovery period. The LT50 and LT90 values were calculated for plotting the regression line using Microsoft office Excel software ver. 2007. RESULTS: Anopheles stephensi was quite resistant to DDT and showed susceptible or tolerant to other insecticides. The LT50 and LT90 values to DDT in this species were 29.07, and 98.26 minutes, respectively. Anopheles culicifacies and Anopheles dthali were found susceptible or tolerant to insecticides. Culex pipiens was found resistance to DDT, propoxur, lambda-cyhalothrin and cyfluthrin whereas observed susceptible to malathion and tolerant to deltamethrin. Ochlerotatus caspius sl. was resistant to DDT, whereas found susceptible to other insecticides. Culisita longiareolata was susceptible to deltamethrin, whereas tolerant to other insecticides. The LT50 and LT90 values of Cs. longiareolata to DDT were 17.82, and 51.26 minutes. CONCLUSION: We suggested the same study in different parts of the country for monitoring and evaluation of control measures. PMID- 26114142 TI - Aerobic Bacterial Community of American Cockroach Periplaneta americana,a Step toward Finding Suitable Paratransgenesis Candidates. AB - BACKGROUND: Cockroaches mechanically spread pathogenic agents, however, little is known about their gut microbiota. Identification of midgut microbial community helps targeting novel biological control strategies such as paratransgenesis. Here the bacterial microbiota of Periplaneta americana midgut, were identified and evaluated for finding proper paratransgenesis candidate. METHODS: Midgut of specimens were dissected and cultivated in different media. The bacterial isolates were then identified using the phenotypic and 16S-rRNA sequencing methods. RESULTS: The analytical profile index (API) kit showed presence of 11 bacterial species including: Escherichia coli, Shigella flexineri, Citrobacter freundii, E. vulneris, Enterobacter cloacae, Yersinia pseudotuberculosis, Y. intermedia, Leclericia adecarboxylata, Klebsiella oxytoca, K. planticola, and Rahnella aquatilis in the cockroach midguts. The first three species are potentially symbiotic whereas others are transient. The conventional plating method revealed presence of only four isolates of Salmonella, E. coli, and Proteus which in three cases mismatched with API and 16S-rRNA genotyping. The API correctly identified the four isolates as Shigella flexneri, Citrobacter freundii, and E. coli (n= 2). 16S-rRNA sequence analysis confirmed the API results; however the C. freundii sequence was identical with C. murliniae indicating lack of genetic variation in the gene between these two closely related species. CONCLUSION: A low number of potentially symbiotic bacteria were found in the American cockroach midguts. Among them Enterobacter cloacae is a potential candidate for paratransgenesis approach whereas other bacteria are pathogens and are not useful for the approach. Data analysis showed that identification levels increase from the conventional to API and to genotyping respectively. PMID- 26114143 TI - The Fauna and Ecology of Mosquitoes (Diptera: Culicidae) in Western Iran. AB - BACKGROUND: The aim of this study was to obtain new data which would be valuable to develop programs for future planning of mosquito controls in in western Iran. METHODS: Larvae and adult collections were carried out from different habitats using standard dipping and animal baited trap methods during May, June and July 2012 in two provinces (Kurdistan and Kermanshah) in the west of Iran. Characteristics of breeding places were studied based on the habitat type (River edge, Ground pool), water conditions (clear or turbid, stagnant or running), vegetation (With or without vegetation), water temperature, sunlight exposure (full or partial sunlight) and so on. RESULTS: Overall, 4081 third- and fourth instars larvae and 2013 Adult were collected. Five genera and eleven species of the family Culicidae were identified. Mosquitoes collected in larval and adult stages including, Anopheles maculipennis s.l. (4.1%, 4.42%), An. superpictus (1.35%,1.39%), An. turkhudi (1.75%,1.68%), Aedes vexans (2.5%, 8.78%), Culex hortensis (1.59%, 1.04%), Cx. mimeticus (5%, 2.38%), Cx. pipiens (16.5%, 8.15%), Cx. theileri (10%, 46.4%), Culiseta longiareolata (24%, 4.27%), and Cs. subochrea (24%, 4.27%) and Ochlerotatus caspius s.l. (9.1%, 21.46%). Culiseta longiareolata and Cs. subochrea found predominant species in larval collection, whereas Culex theileri was dominant in Adult collection. Anopheles turkhudi is reported for the first time in Kermanshah Province. CONCLUSION: Due to the geographical location of the two provinces, extensively studies with emphasis on mosquito ecology, to having comprehensive and up to date information is essential. PMID- 26114144 TI - Species Composition and Seasonal Activities of Malaria Vectors in an Area at Reintroduction Prevention Stage, Khuzestan, South-Western Iran. AB - BACKGROUND: The most part of Iran become malaria-free region and fall in prevention of re-introduction stage. These regions however are struggling with imported of malaria cases where malaria vectors exist. Therefore, understanding the situation of mosquito vectors is crucial. This study was carried out to find out the present situation of malaria vectors and malaria transmission potential in a malaria-free area. METHODS: The study was conducted in a malaria free area, Izeh County, Khuzestan Province during 12 months in 2011-2012. Five villages, including 2 in highlands and 3 in plain area, were selected randomly. The mosquito sampling methods were conducted using spray sheet and hand catch collection methods from indoor/outdoors, window trap and larvae collections. RESULTS: In total, 3352 female Anopheles were captured, 1826 mosquito from highland and 1526 from plain areas. Five species, An. stephensi, An. fluviatilis s.l., An. dthali, An. superpictus and An. pulcherrimus were identified. The seasonal activities were started from April to March. The abdominal conditions of collected mosquitoes from indoor/outdoor places pointed to exophilic propensity of An. fluviatilis.l. s.l. and endophilic behaviour for rest of the vectors. The results of window trap also confirmed these behaviors. The larval habitats of four species were widely dispersed and included spring, margin of rivers, irrigation channels, stagnant water and rice filed. CONCLUSION: Understanding the present situation of malaria vectors in free-malaria area is crucial particularly where is struggling with imported cases. The results of present study can be expanded to other area of northern Khuzestan for malaria vector control planning in reintroduction prevention stage. PMID- 26114145 TI - Resistance Mechanisms of Anopheles stephensi (Diptera: Culicidae) to Temephos. AB - BACKGROUND: Anopheles stephensi is a sub-tropical species and has been considered as one of the most important vector of human malaria throughout the Middle East and South Asian region including the malarious areas of southern Iran. Current reports confirmed An. stephensi resistance to temephos in Oman and India. However, there is no comprehensive research on mechanisms of temephos resistance in An. stephensi in the literature. This study was designed in order to clarify the enzymatic and molecular mechanisms of temephos resistance in this species. METHODS: Profile activities of alpha- and beta-esterases, mixed function oxidase (MFO), glutathione-S-transferase (GST), insensitive acetylcholinesterase, and para-nitrophenyl acetate (PNPA)-esterase enzymes were tested for An. stephensi strain with resistance ratio of 15.82 to temephos in comparison with susceptible strain. RESULTS: Results showed that the mean activity of alpha-EST, GST and AChE enzymes were classified as altered indicating metabolic mechanisms have considerable role in resistance of An. stephensi to temephos. Molecular study using PCR-RFLP method to trace the G119S mutation in ACE-1 gene showed lack of the mutation responsible for organophosphate insecticide resistance in the temephos-selected strain of An. stephensi. CONCLUSION: This study showed that the altered enzymes but not targets site insensitivity of ACE-1 are responsible for temephos resistance in An. stephensi in south of Iran. PMID- 26114146 TI - Morphological and Genotypic Variations among the Species of the Subgenus Adlerius (Diptera: Psychodidae, Phlebotomus) in Iran. AB - BACKGROUND: Female sand flies of subgenus Adlerius are considered as probable vectors of visceral leishmaniasis in Iran. The objective of this study was to determine the morphological and genotypic variations in the populations of this subgenus in the country. METHODS: Sand flies collected using sticky traps from 17 provinces during 2008-2010. The morphometric measurements were conducted with an Ocular Micrometer. Data was analyzed by SPSS. The Cytb gene was used to estimate population genetic diversity and identify the female specimens. UPGMA phenetic tree was used for DNA haplotypes of Cytb gene. RESULTS: Six species of subgenus Adlerius identified from which one species, P. (Adlerius) kabulensis, is new record. The identification key is provided for males. Results revealed the molecular systematic in the species of subgenus Adlerius and determine the relationship of three females of P. comatus, P. balcanicus and P. halepensis. CONCLUSION: The positions of three females and the males in the UPGMA tree are correct and the similarities among them confirm our results. The branches of each species are not genetically distinct which justify the overlapping morphological characters among them. Molecular sequencing of Cytb-mtDNA haplotypes can be used for female identification for different species of subgenus Adlerius in Iran. PMID- 26114147 TI - Hedgehogs (Erinaceus europaeus) as a Source of Ectoparasites in Urban-suburban Areas of Northwest of Iran. AB - BACKGROUND: Hedgehogs are small, nocturnal mammals which become popular in the world and have important role in transmission of zoonotic agents. Thus, the present study aimed to survey ectoparasite infestation from April 2010 to December 2011 in urban and suburban parts of Urmia and Tabriz Cities, Northwest of Iran. METHODS: A total number of 84 hedgehogs (40 females and 44 males) were examined. They have been carefully inspected for ectoparasites and collected arthropods were stored in 70% ethanol solution. The identification of arthropods was carried out using morphological diagnostic keys. RESULTS: The occurrence of ticks on hedgehogs was 23 (67.7%) with Rhipicephalus turanicus in Urmia and 11 (22%) as well as 1(2%) with Rh. turanicus and Hyalomma anatolicum anatolicum in Tabriz, respectively. One flea species, Archaeopsylla erinacei, was found with prevalence of 19 (55.9%) and 27 (54%) in Urmia and Tabriz Cities, respectively. Prevalence of infestation with Rh. turanicus and A. erinacei were not different (P> 0.05) between sexes of hedgehogs in two study areas. Highest prevalence of tick and flea infestation was in June in Urmia, whereas it was observed in August in Tabriz. Both tick and flea parasitizing hedgehogs showed seasonal difference in prevalence (P< 0.05) in Urmia, but it was not detected in Tabriz (P> 0.05). CONCLUSION: The result showed the high occurrence of ectoparasites in hedgehog population and according to the zoonotic potential of these animals as vector of some agents further studies are needed to investigate in different parts of Iran. PMID- 26114148 TI - Biological Activities and Composition of Ferulago carduchorum Essential Oil. AB - BACKGROUND: Ferulago carduchorum Boiss and Hausskn belongs to the Apiaceae family. This plant grows in west part of Iran that local people added it to dairy and oil ghee to delay expiration date and give them a pleasant taste. The aim of this study was to investigate the antioxidant, antimicrobial, acetyl cholinesterase inhibition, cytotoxic, larvicidal activities and composition of essential oil of F. carduchorum. METHODS: Acetyl cholinesterase (AChE) inhibitory, larvicidal activities and chemical composition of essential oil of F. carduchorum were investigated. Besides, antioxidant, antimicrobial and cytotoxic activities of essential oil were tested using DPPH, microdilution method and MTT assay, respectively. RESULTS: The major components of essential oil were (z)-beta ocimene (43.3%), alpha-pinene (18.23%) and bornyl acetate (3.98%). Among 43 identified components, monoterpenes were the most compounds (84.63%). The essential oil had noticeable efficiency against Candida albicans (MIC= 2340 MUg ml(-1)) and it was effective against Anopheles stephensi with LC50 and LC90 values of 12.78 and 47.43 ppm, respectively. The essential oil could inhibit AChE (IC50= 23.6 MUl ml(-1)). The essential oil showed high cytotoxicity on T47D, HEP G2 and HT-29 cell lines (IC50< 2 MUg ml(-1)). CONCLUSION: The essential oil of F. carduchorum collected from west of Iran had anti-Candida, larvicidal and cytotoxicity effects and should be further investigated in others in vitro and in vivo experimental models. PMID- 26114149 TI - Homology Modeling and Conformational Epitope Prediction of Envelope Protein of Alkhumra Haemorrhagic Fever Virus. AB - BACKGROUND: The aim of this study was to generate in silico 3D-structure of the envelope protein of AHFV using homology modeling method to further predict its conformational epitopes and help other studies to investigate its structural features using the model. METHODS: A 3D-structure prediction was developed for the envelope protein of Alkhumra haemorrhagic fever virus (AHFV), an emerging tick-borne flavivirus, based on a homology modeling method using M4T and Modweb servers, as the 3D-structure of the protein is not available yet. Modeled proteins were validated using Modfold 4 server and their accuracies were calculated based on their RSMDs. Having the 3D predicted model with high quality, conformational epitopes were predicted using DiscoTope 2.0. RESULTS: Model generated by M4T was more acceptable than the Modweb-generated model. The global score and P-value calculated by Modfold 4 ensured that a certifiable model was generated by M4T, since its global score was almost near 1 which is the score for a high resolution X-ray crystallography structure. Furthermore, itsthe P-value was much lower than 0.001 which means that the model is completely acceptable. Having 0.46 A rmsd, this model was shown to be highly accurate. Results from DiscoTope 2.0 showed 26 residues as epitopes, forming conformational epitopes of the modeled protein. CONCLUSION: The predicted model and epitopes for envelope protein of AHFV can be used in several therapeutic and diagnostic approaches including peptide vaccine development, structure based drug design or diagnostic kit development in order to facilitate the time consuming experimental epitope mapping process. PMID- 26114150 TI - A Case of Secondary Ophthalmomyiasis Caused by Chrysomya bezziana (Diptera: Calliphoridae). AB - Myiasis is the invasion of vertebrates' tissue by the larvae of a fly of the order Diptera. The objective of this paper is to present a rare case of secondary myiasis of ocular infestation by Chrysomya bezziana. A 55-year-old female from Sar village of Mazandaran Province, northern Iran), referred to Khatam Al-Anbia Hospital of Mashhad with extensive destruction of left orbital cavity. Existence of larvae was the major complaint in recent months. Some live larvae were removed from her destructed left eye. Primary diagnosis was myiasis of left upper lid (LUL) and suspected recurrent Basal cell carcinoma (BCC). The laboratory diagnosis was done in parasitology lab of Imam Reza Hospital of Mashhad and collected larvae were identified and confirmed to be larvae of the C. bezziana (Diptera: Calliphoridae). It is a case report of secondary ophtalmiomyiasis due to C. bezziana of a patient lives in Mazandaran Province. PMID- 26114151 TI - Nymphal Linguatulosis in Indian Crested Porcupines (Histrix Indica) in Southwest of Iran. AB - Linguatula serrata is one of the important zoonotic parasites. Carnivores serve as definitive host. The larvae existed in mesenteric lymph nodes (MLNs), liver, lungs, etc of intermediate herbivores. The definitive host becomes infected by ingesting viscera containing the infective nymphal stage. Humans may be infected with Linguatula either by ingestion of nymphs resulting in a condition called nasopharyngeal linguatulosis or Halzoun syndrome or by ingestion of infective eggs which develop in internal organs resulting in visceral linguatulosis. Indian crested porcupine (Hystrix indica) is a common rodent in Middle East. Based on some tradition, consumption of Histrix meat and viscera is common in some parts of Iran. The present study reports the occurrence of Linguatula serrata nymph in H. indica as a new intermediate host from southwest of Iran. PMID- 26114152 TI - Pharmacoeconomics of Antimalarials in Private-for-Profit (PFP) Drug-Outlets in Gulu and Kitgum Towns, Northern Uganda. AB - BACKGROUND: Clinically-diagnosed malaria is the leading cause of morbidity and mortality in Uganda accounting for 25 to 40% of outpatients, 15 to 20% of all hospital admissions, and 9 to 14% of all hospital deaths. This situation was exacerbated by The Lord's Resistance Army (LRA) rebellion in northern Uganda which completely ran down the health care system. While malaria remains the number one killer disease in northern Uganda, antimalarials are lacking in the public health facilities. Consequently, Private-for-profit drug-outlets have come up to help bridge the gap. However, the cost-effectiveness and treatment outcome ratings of antimalarials are not clear. Objective: To assess the pharmacoeconomics of malaria treatment in Private-for-profit (PFP) drug-outlets in Gulu Municipality and Kitgum Town Council. METHODOLOGY: This was a descriptive cross-sectional study sites were registered drug outlets. Study participants were drug-outlet owners, their employees, and malaria patients. We employed both purposive and random sampling methods to select the study participants. Data were collected using questionnaires and analysed using the SPSS computer package. RESULTS: Up to 91.1% of the respondents indicated that antimalarials are expensive. The prices varied from less than 5,000 to over 20,000 Ugandan shillings per dose (Exchange rate: 1$ = Ush 2,650). Fansidar and chloroquine were rated as being relatively cheap and ACTs expensive (Ush 11,000 to 15,000). Duration of treatment, frequency of administration, needles and syringes, raised the cost of some medicines. Most patients preferred cheap medicines (76.2%); those with low administration frequencies (77.5%); and those with short treatment duration (95%). Most patients (80.9%) buy antimalarials without testing, while 66.6% do not buy full doses. CONCLUSION: The cost benefit analysis of the use of antimalarials is unfavourable. The unit price of the medicines, their irrational use and the lack of professionals in the outlets together add up to high overall costs and poor treatment outcomes. PMID- 26114153 TI - Circulating endocannabinoids during hematopoietic stem cell transplantation: A pilot study. AB - OBJECTIVE: Hematopoietic stem cell transplantation (HCT) is a stressful and rigorous medical procedure involving significant emotional and immune challenges. The endocannabinoid (eCB) signaling system is involved in regulation of both the immune system and emotional reactivity, yet little is known about its function during HCT. We investigated the role of the eCB signaling system in a group of HCT recipients. METHODS: A total of 19 HCT recipients were enrolled and provided psychosocial data and blood samples at three peri-transplant time points: prior to transplant, hospital discharge, and approximately 100 days post-transplant. Psychosocial factors, inflammatory molecules, and the eCBs were determined and assessed for changes over this period and association with each other. RESULTS: HCT recipients demonstrated significant changes over the peri- transplant period in inflammatory molecules and psychosocial functioning, but not in circulating concentrations of the eCBs. Associations among these variables were most likely to be present pre-transplant and least likely to be present immediately post transplant, with depressive symptoms and inflammation most significantly associated. The eCB 2-arachidonoylglycerol (2-AG) was significantly, positively associated with both interleukin (IL)-6 and C-reactive protein (CRP) and negatively associated with depressive symptoms. CONCLUSIONS: The eCB signaling system may have alternative sources and regulatory mechanisms in addition to the immune system. Given the significant associations with inflammatory molecules and depressive symptoms in the peri- transplant period, it is important to better understand this system and its potential implications in the setting of complex and stressful medical procedures such as HCT. PMID- 26114154 TI - RhoA, a novel tumor suppressor or oncogene as a therapeutic target? PMID- 26114156 TI - Current perspectives on FOXA1 regulation of androgen receptor signaling and prostate cancer. AB - FOXA1 (also known as hepatocyte nuclear factor 3alpha, or HNF-3alpha) is a protein of the FKHD family transcription factors. FOXA1 has been termed as a pioneer transcription factor due to its unique ability of chromatin remodeling in which the chromatin can be decompacted to allow genomic access by nuclear hormone receptors, including androgen receptor (AR) and estrogen receptor (ER). In this review, we discuss our current understanding of FOXA1 regulation of prostatic and non-prostatic AR-chromatin targeting. We present an updated model wherein FOXA1:AR equilibrium in the nuclei defines prostatic AR binding profile, which is perturbed in prostate cancer with FOXA1 and/or AR de-regulation. Finally, we discuss recent efforts in exploring new horizons of AR-independent functions of FOXA1 in prostate cancer and interesting directions to pursue in future studies. PMID- 26114155 TI - Pancreatic cancer stromal biology and therapy. AB - Pancreatic cancer is one of the most lethal malignancies. Significant progresses have been made in understanding of pancreatic cancer pathogenesis, including appreciation of precursor lesions or premalignant pancreatic intraepithelial neoplasia (PanINs), description of sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and identification of major genetic and epigenetic events and the biological impact of those events on malignant behavior. However, the currently used therapeutic strategies targeting tumor epithelial cells, which are potent in cell culture and animal models, have not been successful in the clinic. Presumably, therapeutic resistance of pancreatic cancer is at least in part due to its drastic desmoplasis, which is a defining hallmark for and circumstantially contributes to pancreatic cancer development and progression. Improved understanding of the dynamic interaction between cancer cells and the stroma is important to better understanding pancreatic cancer biology and to designing effective intervention strategies. This review focuses on the origination, evolution and disruption of stromal molecular and cellular components in pancreatic cancer, and their biological effects on pancreatic cancer pathogenesis. PMID- 26114158 TI - Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV. AB - In recent years, chronic immune activation and systemic inflammation have emerged as hallmarks of HIV disease progression and mortality. Several studies indicate that soluble inflammatory biomarkers (sCD14, IL-6, IL-8, CRP and hyaluronic acid), as well as surface markers of T-cell activation (CD38, HLA-DR) independently predict progression to AIDS and mortality in HIV-infected individuals. While co-infections have been shown to contribute to immune activation, the impact of latent tuberculosis infection (LTBI), which is widely endemic in the areas most affected by the global AIDS epidemic, has not been evaluated. We hypothesized that both active and latent states of Mycobacterium tuberculosis co-infection contribute to elevated immune activation as measurable by these markers. In HIV-infected individuals with active, but not latent TB, we found elevated levels of soluble markers associated with monocyte activation. Interestingly, T-cell activation was elevated individuals with both latent and active TB. These results suggest that in the highly TB- and HIV-endemic settings of southern Africa, latent TB-associated T-cell activation may contribute to HIV disease progression and exacerbate the HIV epidemic. In addition, our findings indicate that aggressive campaigns to treat LTBI in HIV-infected individuals in high-burden countries will not only impact TB rates, but may also slow HIV progression. PMID- 26114157 TI - NKCC1 and NKCC2: The pathogenetic role of cation-chloride cotransporters in hypertension. AB - This review summarizes the data on the functional significance of ubiquitous (NKCC1) and renal-specific (NKCC2) isoforms of electroneutral sodium, potassium and chloride cotransporters. These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid, respectively. Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume. However, the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds. PMID- 26114159 TI - The Moderating Role of Smoking Amount Per Day on the Relations Between Anxiety Sensitivity, Smoking Dependence, and Cognitive-Affective Aspects of Smoking Among Treatment Seeking Smokers. AB - The current study examined the moderating effects of smoking amount per day on the relation between anxiety sensitivity and nicotine dependence, cigarette smoking outcome expectancies, and reasons for quitting smoking among 465 adult, treatment-seeking smokers (48% female; Mage = 36.6, SD = 13.5). Smoking amount per day moderated the relation between anxiety sensitivity and nicotine dependence, smoking expectancies for negative consequences and appetite control as well as intrinsic reasons for quitting. However, no moderating effect was evident for negative reinforcement expectancies. The form of the significant interactions indicated across dependent variables lower levels of smoking amount per day suppressed the relation between anxiety sensitivity and smoking related dependent variable, such that the positive relation of anxiety sensitivity to smoking dependence and cognitive-affective aspects of smoking is weaker in heavier smokers and more robust in lighter smokers. PMID- 26114160 TI - Cumulative effects of common genetic variants on risk of sudden cardiac death. AB - BACKGROUND: Genome-wide association studies and candidate-gene based approaches have identified multiple common variants associated with increased risk of sudden cardiac death (SCD). However, the independent contribution of these individual loci to disease risk is modest. OBJECTIVE: To investigate the cumulative effects of genetic variants previously associated with SCD risk. METHODS: A total of 966 SCD cases from the Oregon-Sudden Unexpected Death Study and 1,926 coronary artery disease controls from the Wellcome Trust Case-Control Consortium were investigated. We generated genetic risk scores (GRS) for each trait composed of variants previously associated with SCD or with abnormalities in specific electrocardiographic traits such as QRS duration, QTc interval and heart rate. GRSs were calculated using a weighted approach based on the number of risk alleles weighted by the beta coefficients derived from the original studies. We also compared the highest and lowest quintiles for the GRS composed of SCD SNPs. RESULTS: Increased cumulative risk was observed for a GRS composed of 14 SCD-SNPs (OR=1.17 [1.05-1.29], P = 0.002). The risk for SCD was 1.5 fold higher in the highest quintile when compared to the lowest quintile (OR = 1.46[1.11-1.92]). We did not observe significant associations with SCD for SNPs that determine electrocardiographic traits. CONCLUSIONS: A modest but significant effect on SCD risk was identified for a GRS composed of 14 previously associated SCD SNPs. While next generation sequencing methodology will continue to identify additional novel variants, these findings represent proof of concept for the additive effects of gene variants on SCD risk. PMID- 26114162 TI - Effect of Diamond Bur Grit Size on Composite Repair. AB - PURPOSE: This study investigated the effect of diamond bur grit size on the repair bond strength of fresh and aged resin composites. MATERIALS AND METHODS: Blocks of microhybrid composite (Opallis, FGM) were stored in distilled water at 37 degrees C for 24 h (fresh composite) or subjected to 5000 thermal cycles (aged composite). The surfaces were roughened using diamond-coated, flame-shaped carbide burs with medium grit (#3168), fine grit (#3168F), or extra-fine grit (#3168FF). The control group underwent no surface treatment. Surface roughness, water contact angle, and surface topography by scanning electron microscopy (SEM) were evaluated (n = 3). Samples were restored with resin composite and sectioned into beam-shaped specimens, which were subjected to microtensile bond testing. Failure modes were classified using a stereomicroscope. Data were statistically analyzed using the Student- Newman-Keuls test and two-way ANOVA, with significance set at p < 0.05. RESULTS: Higher surface roughness was observed for groups treated with the medium- and fine-grit burs; aged composites were rougher than fresh composites. The water contact angle formed on the aged composite was lower than that on the fresh composite. The highest repair bond strength was observed for the fine-grit bur group, and the lowest was recorded for control. Interfacial failures were more predominant. SEM images showed that the surfaces treated with fine- and extra-fine-grit burs had a more irregular topography. CONCLUSION: Surface roughening of fresh or aged resin composites with diamond burs improved retention of the repair material. Fine-grit burs generally performed better than medium- and extra-fine-grit burs. PMID- 26114161 TI - Effect of Unblinding on Participants' Perceptions of Risk and Confidence in a Large Double-Blind Clinical Trial of Chemotherapy for Breast Cancer. AB - IMPORTANCE: Blinding patients to treatment regimen is an important component of high-quality randomized clinical trials, although concern exists about how receipt of a placebo will affect participants' views, particularly among patients with cancer. OBJECTIVE: To determine whether unblinding of random assignment to placebo vs experimental agent in a large adjuvant breast cancer chemotherapy randomized clinical trial was associated with perception of greater chance of cancer recurrence and lower confidence in the decision to participate in the trial in participants who were randomized to placebo compared with those randomized to experimental therapy. DESIGN, SETTING, AND PARTICIPANTS: Serial telephone-based prospective survey substudy of all Eastern Cooperative Oncology Group Protocol 5103 (ECOG5103) participants enrolling between January 5 and June 8, 2010. In ECOG5103, patients were randomized to receive standard adjuvant chemotherapy for breast cancer with either placebo or bevacizumab for either approximately 6 or approximately 12 months. Treatment assignment was unblinded by 24 weeks, and then patients were surveyed. MAIN OUTCOMES AND MEASURES: Trial participants' self-reported perceived risk of recurrence and confidence in study participation. RESULTS: Of 571 patients in this substudy who started protocol therapy, 550 were still in the study at unblinding and 492 (89%) responded to the unblinding survey. At unblinding, 336 of 477 (70%) believed that they had at most a small risk of breast cancer recurrence, and 342 of 480 (71%) reported perceiving at most a small risk of serious problem with therapy; most reported feeling very informed (421 of 483 [87%]) and having high levels of confidence in their study participation (420 of 483 [87%]). The 102 participants who learned that they had been randomized to placebo did not have greater perception of chance of recurrence (P = .48) or fear of recurrence (P = .69), feel less informed (P = .86), or have lower confidence in trial participation (P = .31) compared with the 390 participants who had been randomized to experimental therapy. Patients who learned that they had been randomized to bevacizumab perceived higher risk of having a serious problem caused by treatment (P = .01). CONCLUSIONS AND RELEVANCE: In a placebo-controlled, double-blind randomized clinical trial of chemotherapy for breast cancer, unblinding to randomization allocation did not significantly affect most participants' views except for chance of a serious problem from experimental treatment, regardless of receipt of placebo or experimental anticancer therapy along with standard chemotherapy. PMID- 26114164 TI - Bond Strength of Resin Composite to Dentin with Different Adhesive Systems: Influence of Relative Humidity and Application Time. AB - PURPOSE: To investigate the influence of relative humidity and application time on bond strength to dentin of different classes of adhesive systems. MATERIALS AND METHODS: A total of 360 extracted human molars were ground to mid-coronal dentin. The dentin specimens were treated with one of six adhesive systems (Syntac Classic, OptiBond FL, Clearfil SE Bond, AdheSE, Xeno Select, or Scotchbond Universal), and resin composite (Filtek Z250) was applied to the treated dentin surface under four experimental conditions (45% relative humidity/application time according to manufacturers' instructions; 45% relative humidity/reduced application time; 85% relative humidity/application time according to manufacturers' instructions; 85% relative humidity/reduced application time). After storage (37 degrees C, 100% humidity, 24 h), shear bond strength (SBS) was measured and data analyzed with nonparametric ANOVA followed by Kruskal-Wallis tests and Mann-Whitney U-tests with Bonferroni-Holm correction for multiple testing (level of significance: alpha = 0.05). RESULTS: Increased relative humidity and reduced application time had no effect on SBS for Clearfil SE Bond and Scotchbond Universal (p = 1.00). For Syntac Classic, OptiBond FL, AdheSE, and Xeno Select there was no effect on SBS of reduced application time of the adhesive system (p >= 0.403). However, increased relative humidity significantly reduced SBS for Syntac Classic, OptiBond FL, and Xeno Select irrespective of application time (p <= 0.003), whereas for AdheSE, increased relative humidity significantly reduced SBS at recommended application time only (p = 0.002). CONCLUSION: Generally, increased relative humidity had a detrimental effect on SBS to dentin, but reduced application time had no effect. PMID- 26114163 TI - Influence of Curing Units and Indirect Restorative Materials on the Hardness of Two Dual-curing Resin Cements Evaluated by the Nanoindentation Test. AB - PURPOSE: To evaluate the hardness of a dual-curing self-adhesive resin cement (RelyX U200) and a conventional dual-curing resin cement (RelyX ARC) cured with different light curing units of different wavelengths (Elipar Freelight 2 LED [430 to 480 nm, conventional], Bluephase LED [380 to 515 nm, polywave], AccuCure 3000 Laser [488 nm]) by means of the nanoindentation test. MATERIALS AND METHODS: Bovine incisors were cleaned and then sectioned at the cementoenamel junction to remove the crown. After embedding in acrylic, dentin surfaces of the specimens were exposed and ground flat to standardize the surfaces. To simulate clinically placing indirect restorations, ceramic (IPS e.maxPress/Ivoclar Vivadent) or indirect composite resin (SR Adoro/Ivoclar Vivadent) slabs were cemented on dentin surfaces. The specimens were sectioned longitudinally at low speed under constant irrigation and then polished. In the positive control group, the cement was light cured without the interposition of indirect restorative material; in the negative control group, after the indirect restorative material was cemented, no light curing was performed, allowing only chemical polymerization of the cement. All specimens were stored in distilled water at 37 degrees C for 7 days. Nanoindentadion hardness of the cement layer was measured under a 100-mN load. Data were statistically analyzed using ANOVA and Tukey's test (p < 0.05). RESULTS: Although the self-adhesive cement is technically simple, conventional cement showed the best polymerization performance. The polywave LED technology did not differ significantly from other light-curing units. The hardness of the resin cements evaluated was negatively influenced by the interposition of an indirect restorative material; only the LEDs were able to maintain the same degree of cement polymerization when an indirect restorative material was used. CONCLUSION: The photoactivation step is required during the cementation of indirect restorations to ensure adequate polymerization of dual-curing resin cements. PMID- 26114165 TI - Bonding Effectiveness to Differently Sandblasted Dental Zirconia. AB - PURPOSE: To evaluate the effect of different mechanical pre-treatments on the bond durability to dental zirconia. MATERIALS AND METHODS: Fully sintered IPS e.max ZirCAD (Ivoclar Vivadent) blocks were randomly assigned to one of 4 groups: (1) kept as-sintered (control), (2) sandblasted with 50-MUm Al2O3(Danville), or tribochemically silica sandblasted using (3) CoJet (3M ESPE) and (4) SilJet (Danville). The zirconia specimens were additionally pre-treated chemically using a 10-MDP/silane ceramic primer (Clearfil Ceramic Primer, Kuraray Noritake). Two identically pre-treated zirconia blocks were bonded together using resin composite cement (RelyX Ultimate, 3M ESPE). The specimens were trimmed at the interface to a cylindrical hourglass shape and stored in distilled water (7 days, 37 degrees C), after which they were randomly tested as is or subjected to additional mechanical aging involving cyclic tensile stress (10 N, 10 Hz, 10,000 cycles). Subsequently, the microtensile bond strength was determined and SEM fractographic analysis performed. RESULTS: Weibull analysis revealed the highest Weibull scale and shape parameters when zirconia was tribochemically silica sandblasted using either CoJet or SilJet. The Weibull shape parameter of Al2O3 sandblasted zirconia was significantly reduced upon mechanical aging, but not when zirconia was tribochemically silica sandblasted. CONCLUSION: The mechanical surface pre-treatment of zirconia using tribochemical silica sandblasting (CoJet, SilJet) resulted in the most favorable bond durability of a resin-composite cement (RelyX Ultimate) to dental zirconia before and after aging. PMID- 26114166 TI - An unusual cause of bleeding from the duodenum: pyogenic granuloma. PMID- 26114167 TI - Endoscopic resection of a giant colonic lipoma causing severe anemia. PMID- 26114168 TI - Gastric Kaposi sarcoma in a double lung-transplanted patient. PMID- 26114169 TI - The helix sign in the peritoneal encapsulation syndrome: a new sign in a rare cause of bowel obstruction? PMID- 26114171 TI - Liver elastography - where are we now? PMID- 26114170 TI - Anemia in inflammatory bowel diseases is much more than levels of hemoglobin. PMID- 26114172 TI - The disappointing performance of the new "Magnetic Sphincters": a wrong idea or a wrong realization? PMID- 26114174 TI - Coping strategies and irrational beliefs as mediators of the health-related quality of life impairments in irritable bowel syndrome. AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a chronic and disabling gastrointestinal disorder. Although considerable research has underlined the influence of coping mechanisms as the determinants of the quality of life (QOL), only limited data are available regarding the specific coping mechanisms used by IBS patients to manage illness in daily life. Irrational cognitions are known to emerge in stressful situations such as chronic diseases, and it has been proposed to have implications in the QOL. The aim of this study was to explore the relationship between coping styles and irrational beliefs in predicting the effects of IBS symptoms on the health-related QOL (HRQOL). METHODS: A cross sectional study was performed at two tertiary gastroenterology centers. A sample of 70 consecutive IBS patients and 55 healthy controls was studied. All participants completed the Brief Cope Inventory, the Dysfunctional Attitudes Scale, the Short-Form Health Survey and a demographic questionnaire. RESULTS: All the HRQOL scores of the group with IBS were significantly lower than the HRQOL scores of the healthy group [Pillai's trace V = 0.404, F(8, 116) = 9.833, p < 0.001]. Irritable bowel syndrome patients used more problem-focused coping and avoidant-oriented coping than healthy subjects. The impact of IBS symptoms on HRQOL distress is mediated by irrational beliefs and avoidant oriented coping. CONCLUSIONS: Our findings highlight the role of irrational cognition and coping mechanisms in patients with IBS. The results underline the importance of the evaluation of psychological aspects of IBS with the possibility of having more tailored treatments for these patients. PMID- 26114173 TI - A single biopsy is valid for genetic diagnosis of eosinophilic esophagitis regardless of tissue preservation or location in the esophagus. AB - BACKGROUND & AIMS: A new gene expression profile test may distinguish eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD), but the optimal tissue preparation and biopsy location are unknown. We aimed to determine if formalin-fixed paraffin-embedded (FFPE) and RNA-later (RNAL) preserved specimens from newly diagnosed EoE patients have equivalent gene expression scores and whether scores vary by esophageal biopsy location. METHODS: We analyzed prospectively collected and banked esophageal biopsies from EoE patients and GERD controls. Paired FFPE and RNAL samples from the distal, mid, and proximal esophagus were used. RNA was extracted, and gene expression for a previously constructed 96 gene panel was quantified with a summary expression score. Scores were compared between EoE and GERD patients, between FFPE and RNAL samples, and between the different esophageal locations. RESULTS: A total of 72 samples, representing paired FFPE and RNAL specimens from 9 EoE cases and 3 GERD controls, were analyzed. Overall median gene expression scores were similar between FFPE and RNAL (238 vs 227; p=0.64), correlation was excellent between FFPE and RNAL (Spearman's rho=0.90; p<0.001), and there were no differences by biopsy level. Median gene scores distinguished EoE from controls (134 vs 402; p=0.02), and overall agreement between preservation methods and EoE case status was perfect (kappa=1.0; p<0.001). CONCLUSIONS: Gene expression scores were equivalent in FFPE and RNAL, and were also similar across three esophageal locations. This implies that a single biopsy in either FFPE or RNAL from anywhere in the esophagus may have the potential for genetic diagnosis of EoE. PMID- 26114175 TI - Does infliximab short infusion have a beneficial impact on the quality of life in patients with inflammatory bowel diseases? A single centre prospective evaluation. AB - BACKGROUND & AIMS: Infliximab (IFX) is an anti-tumor necrosis factor alpha agent used in inflammatory bowel diseases (IBD) therapy. Usually, it is administered over a 2-hour intravenous infusion. However, shortening the infusion duration to 1 hour has proved to be feasible and safe. In the present study we evaluated whether shortening the IFX infusion could affect the patients' quality of life (QoL) compared to the standard protocol. METHODS: Subjects affected by IBD receiving IFX were prospectively recruited. The main criterion to shorten the infusion was the absence of IFX-related adverse reactions during the previous three 2-h infusions. For each patient, demographic, clinical and anthropometric data were collected. A questionnaire investigating their overall/job/social/sexual QoL was administered. Ordinal regression was performed with odds ratios (OR) for significant independent variables. RESULTS: Eighty-one patients were included (46 with ulcerative colitis - UC, 35 with Crohn's disease CD). Sixteen received the 2-h infusion due to previous adverse reactions, and the remaining 65 underwent the 1-h schedule. Shortening the infusion to 1 hour determined a better QoL (OR=0.626). However, the QoL was negatively influenced by age (OR=1.023), female sex (OR=2.04) and severe disease activity (OR=7.242). One hour IFX infusion induced a better outcome on work (OR=0.588) and social (OR=0.643) QoL. Long-standing disease was correlated with a slightly better sexual QoL (OR=0.93). Conversely, older age (OR=1.046), severe clinical score (OR=15.579), use of other immunomodulators (OR=3.693) and perianal CD (OR=3.265) were related to an unsatisfactory sexual life. The total number of infusions (OR=0.891), proctitis (OR=0.062) or pancolitis (OR=0.1) minimized the perception of infusion-related side effects. CONCLUSION: The 1-h short infusion improves overall, social and job QoL, so that, when indicated, it should be recommended. PMID- 26114176 TI - Opportunistic colorectal cancer screening using colonoscopy. Comparative results between two historical cohorts in Bucharest, Romania. AB - BACKGROUND & AIMS: Even though Romania has one of the highest incidence and mortality in colorectal cancer (CRC) in Europe, there is currently no organized screening program. We aimed to assess the results of our opportunistic CRC screening using colonoscopy. METHODS: A single center retrospective study to include all opportunistic screening colonoscopies performed in two 18 month periods (2007-2008 and 2012-2013) was designed. All asymptomatic individuals without a personal or family history of adenoma or CRC and with complete colonoscopy performed in these two time periods were included. RESULTS: We included 1,807 individuals, 882 in the first period, 925 in the second period. There were 389 individuals aged below 50, 1,351 between 50 and 75 and 67 older than 75 years. There were 956 women (52.9%), with a mean age of 58.5 (median 59, range 23-97). The detection rates were 12.6% for adenomas (6.1% for advanced adenoma) and 3.4% for adenocarcinoma. Adenoma incidence (4.9% in subjects under 50, 14.7% in those aged 50 to 75, and 16.4% in those older than 75, p<0.0001) and size (6.3mm in subjects younger than 50, 9.2mm in those 50 to 75 and 10.8mm in those older than 75, p=0.015) significantly increased with age. Adenoma incidence increased in the second period (14.8% vs. 10.3%, p=0.005), while adenoma size decreased in the second period (8.4mm vs. 10mm, p=0.006). There were no procedure related complications. CONCLUSIONS: The neoplasia detection rate was 16% (12.6% adenoma, 3.4% adenocarcinoma). Adenoma incidence and size increased with age in both cohorts. In the second screening period significantly more and smaller adenomas were detected. PMID- 26114177 TI - Early Achievable Severity (EASY) index for simple and accurate expedite risk stratification in acute pancreatitis. AB - BACKGROUND: Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract associated with significant morbidity and mortality. The assessment of severity is crucial in the management of the disease. Current methods of risk stratification in AP have a limited value, as they provide little additional information thus delaying appropriate patient care. Early recognition of severe disease may prevent serious adverse events and improve patient management as well as overall clinical outcome. METHODS/DESIGN: The EASY trial is an observational, multicenter, prospective cohort study for establishing a simple, easy and accurate clinical scoring system for early prognostication of AP. Evaluation of simple attainable potential prognostic parameters obtained at admission (or not later than 6-12 hours afterwards) from patients diagnosed with AP will be performed to assess their potential correlation with the disease severity. The selected parameters that show the strongest correlation with severe disease course will be further utilized as potential early severity prognostic markers for prospective new patient stratification. Comparison of patients' clinical course with the obtained results of early risk stratification may validate the utilized parameters as prognostic markers. The trial has been (i) discussed and (ii) accepted in a distinguished international scientific meeting, (ii) receiving the relevant ethical approval (TUKEB: 30595-1/2014/EKU), (ii) registered at the ISRCTN registry which is a primary clinical trial registry recognized by WHO (Trial registration number: ISRCTN10525246). CONCLUSION: The EASY trial is designed to develop a simple and accurate clinical scoring system that can stratify patients with AP during the first 6-12 hours of hospitalization according to their risk for severe disease course. PMID- 26114178 TI - Coagulation Parameters in Wilson Disease. AB - BACKGROUND & AIMS: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Alterations of copper metabolism have been associated with changes in coagulation factors. The aim of the present study was the analysis of coagulation factors in WD patients. METHODS: 100 patients attending a tertiary WD outpatient clinic were analyzed in a prospective cross sectional cohort study. Out of peripheral venous blood samples coagulation factors were assessed including: full blood count, INR, partial thromboplastin time (PTT), clotting factors II, V, VII, VIII, IX, X, XI, XII, XIII, von Willebrand factor/-antigen, fibrinogen, antithrombin III, protein S, protein C, activated protein C (APC) resistance. Subgroup analyses of the blood tests were performed for sex, initial clinical presentation, WD treatment and liver function. RESULTS: Subgroup analysis by liver function showed decreased levels of factors II, V, VII and X. Subgroup analysis by gender or clinical course of the disease did not reveal significant coagulation changes. In patients treated with trientine significantly decreased levels of factors II, VII and antithrombin III and increased von Willebrand factor/-antigen levels were detected. Factor VIII levels were significantly reduced in patients receiving zinc. CONCLUSION: Although significant differences of some coagulation parameters in subgroup analysis were found, no clinically relevant alterations of the coagulation system in WD patients could be detected. PMID- 26114179 TI - Efficacy of Interferon A-2b monotherapy in Beta-thalassemics with chronic hepatitis C. AB - BACKGROUND & AIMS: Monotherapy with standard or pegylated interferon (PegIFN) remains the first-line treatment for HCV infection in patients with thalassemia major (betaTM), although its long-term impact is still unknown. We aimed to assess the efficacy of IFN-a2b/PegIFN-a2b (one or multiple treatment sessions) and the predictors for sustained virological response (SVR) in HCV-infected betaTM patients. METHODS: Between 11/1992 and 12/2013 [median follow-up: 165.5 months (8-237)], 48 betaTM HCV-infected patients [19 males, median age: 22 years (12-45)], received IFN-a2b (n=34) or PegIFN-a2b (n=14). Twenty-three patients (47.9%) had a previous splenectomy; 13/40 (32.5%) patients had Ishak stage >/=4 and 21/40 (52.5%) had siderosis grade 3-4. HCV-genotype was available in 36 patients (genotype 1: 47.2%, 2: 5.6%, 3: 25%, and 4: 22%). IL28B genotype was determined in 37 patients by means of in-house real-time PCR (CC: 27%, CT: 62.2%, TT: 10.8%). RESULTS: Totally, 15/48 (31.3%) achieved SVR following the first treatment and 18/48 (37.5%) after multiple courses. Splenectomy (p=0.01) and fibrosis grade >/=4 (p<0.05) were negative predictors for SVR (first course), whereas splenectomy (p<0.05) and age >18 (p<0.02) for SVR after multiple courses. In HCV-genotype 1/4 (n=25), none of the patients with CT or TT IL28B genotype achieved SVR compared to 50% of the CC patients (p=0.004). CONCLUSIONS: Interferon is an effective therapeutic option in HCV-infected betaTM patients. IL28B genotype was a strong predictor for SVR, together with splenectomy, age and fibrosis. PMID- 26114180 TI - Non-invasive distinction of non-alcoholic fatty liver disease using urinary volatile organic compound analysis: early results. AB - BACKGROUND & AIMS: Non-Alcoholic Fatty Liver Disease (NAFLD) is the commonest cause of chronic liver disease in the western world. Current diagnostic methods including Fibroscan have limitations, thus there is a need for more robust non invasive screening methods. The gut microbiome is altered in several gastrointestinal and hepatic disorders resulting in altered, unique gut fermentation patterns, detectable by analysis of volatile organic compounds (VOCs) in urine, breath and faeces. We performed a proof of principle pilot study to determine if progressive fatty liver disease produced an altered urinary VOC pattern; specifically NAFLD and Non-Alcoholic Steatohepatitis (NASH). METHODS: 34 patients were recruited: 8 NASH cirrhotics (NASH-C); 7 non-cirrhotic NASH; 4 NAFLD and 15 controls. Urine was collected and stored frozen. For assay, the samples were defrosted and aliquoted into vials, which were heated to 40+/-0.1 degrees C and the headspace analyzed by FAIMS (Field Asymmetric Ion Mobility Spectroscopy). A previously used data processing pipeline employing a Random Forrest classification algorithm and using a 10 fold cross validation method was applied. RESULTS: Urinary VOC results demonstrated sensitivity of 0.58 (0.33 - 0.88), but specificity of 0.93 (0.68 - 1.00) and an Area Under Curve (AUC) 0.73 (0.55 - 0.90) to distinguish between liver disease and controls. However, NASH/NASH-C was separated from the NAFLD/controls with a sensitivity of 0.73 (0.45 - 0.92), specificity of 0.79 (0.54 - 0.94) and AUC of 0.79 (0.64 - 0.95), respectively. CONCLUSIONS: This pilot study suggests that urinary VOCs detection may offer the potential for early non-invasive characterisation of liver disease using 'smell prints' to distinguish between NASH and NAFLD. PMID- 26114181 TI - Overview of biological therapy in ulcerative colitis: current and future directions. AB - The treatment of ulcerative colitis (UC) has changed over the last decade. It is extremely important to optimize the therapies which are available nowadays and commonly used in daily clinical practice, as well as to stimulate the search for more powerful drugs for the induction and maintenance of sustained and durable remission, thus preventing further complications. Therefore, it is mandatory to identify the patients' prognostic variables associated with an aggressive clinical course and to test the most potent therapies accordingly. To date, the conventional therapeutic approach based on corticosteroids, salicylates (sulfasalazine, 5-aminosalicylic acid) or immunosuppressive agents is commonly used as a first step to induce and to maintain remission. However, in recent years, knowledge of new pathogenetic mechanisms of ulcerative colitis have allowed us to find new therapeutic targets leading to the development of new treatments that directly target proinflammatory mediators, such as TNF-alpha, cytokines, membrane migration agents, cellular therapies. The aim of this review is to provide the most significant data regarding the therapeutic role of drugs in UC and to give an overview of biological and experimental drugs that will become available in the near future. In particular, we will analyse the role of these drugs in the treatment of acute flare and maintenance of UC, as well as its importance in mucosal healing and in treating patients at a high risk of relapse. PMID- 26114182 TI - Review of computed tomographic colonography from a surgeon's perspective. AB - New research has addressed many of the early concerns of computed tomographic colonography (CTC) and these studies are now beginning to shape clinical practices. A review of the literature demonstrates that the sensitivity of CTC in screening for large polyps (>/= 1cm) or cancers in the large intestine is as high as that of conventional optical colonoscopy, however, the sensitivity decreases with the diameter of the polyp. Despite this, CTC is well tolerated, more acceptable to patients than optical colonoscopy and therefore may improve colorectal cancer screening compliance. This review not only describes the diagnostic accuracy and sensitivity of CTC, and the evolving role of CTC as a primary colon cancer screening option, but also the recent studies that have demonstrated the additional value of CTC utilization for practicing clinicians. PMID- 26114183 TI - The role of Skp2 and its substrate CDKN1B (p27) in colorectal cancer. AB - Colorectal cancer is one of the most frequent cancers worldwide, having the fourth mortality rate among cancers in both sexes. Numerous studies are investigating the signalling pathways and different factors involved in the development and progression of colorectal cancer. It has recently been shown that the S-phase kinase-associated protein 2 (Skp2) overexpression plays an important role in the pathogenesis of colorectal cancer. We review the role of Skp2 and its ubiquitin-proteasome pathway in colorectal cancer. The F-box protein Skp2, a component of the SCF (Skp1-Cullin 1-F-box) E3 ubiquitin-ligase complex, has been shown to regulate cellular proliferation, cancer progression and metastasis by targeting several cell cycle regulators for ubiquitination and subsequent 26S proteasome degradation. The best known protein substrate of the Skp2 is the cyclin-dependent kinase inhibitor 1B (CDKN1B), also known as p27Kip1. Overexpression of Skp2 and loss of CDKN1B (p27) was strongly associated with aggressive tumor behavior and poor clinical outcome in a variety of cancers, including colorectal cancer. An efficient interaction between Skp2 and CDKN1B (p27) requires the presence of an essential activator of the SCF-Skp2 complex, the cyclin-dependent kinase subunit 1 (Cks1) cofactor. Alterations in the Skp2, Cks1 and CDKN1B (p27) expression have major effects on colorectal carcinogenesis and may serve as an important and independent prognostic marker. Furthermore, we highlight that Skp2 may be a promising therapeutic target for colorectal cancer, and development of Skp2 inhibitors would have a great impact on colorectal cancer therapy. PMID- 26114184 TI - Premalignant and malignant lesions of the heterotopic pancreas in the esophagus: a case report and review of the literature. AB - Heterotopic pancreas is a congenital pathology of the gastrointestinal tract, particularly rare in the esophagus. Both symptomatology and findings during preoperative examinations are non-specific and therefore do not often lead to an accurate diagnosis, which is usually revealed only by histopathological assessment of a resected specimen. We report an unusual case of a patient suffering from severe dysphagia caused by heterotopic pancreas in the distal esophagus with chronic inflammation and foci of premalignant changes. This article also reviews 14 adult cases of heterotopic pancreas in the esophagus previously reported in the literature, with the aim of determining the clinical features of this disease and possible complications including rare premalignant lesions and malignant transformation. Especially with regard to those complications, we suggest that both symptomatic and incidentally found asymptomatic lesions should be resected. PMID- 26114185 TI - Primary hepatic neuroendocrine tumor after 4 years tumor-free follow-up. AB - BACKGROUND: A primary hepatic neuroendocrine tumour (PHNET) is a very rare disease. The liver represents the preferential site for neuroendocrine tumors' metastases. CASE PRESENTATION: A 45-year old Caucasian female who presented with nausea, vomiting, diarrhea, accompanied by diffuse abdominal pain was found to have on contrast-enhanced computer tomography an encapsulated, partially cystic liver mass. The patient underwent an uneventful left atypical hepatic resection. Histopatological and immunohistochemical examination revealed a slowly growing (G1) hepatic neuroendocrine tumour. Post surgery, the specific neuroendocrine markers (serum Chromogranin A and 24h urinary 5 hydroxy-indolacetic acid) were within normal range. Further functional imaging investigations were performed. No other lesions were found making probable the diagnosis of PHNET. The patient is presently after 4 years of follow-up with no local recurrence or distant metastases. CONCLUSIONS: The diagnosis of PHNET is a medical challenge that requires a thorough long term follow-up in order to exclude an occult primary neuroendocrine tumour. PMID- 26114186 TI - A case of primary pancreatic non-Hodgkin B-cell lymphoma mimicking autoimmune pancreatitis. AB - Non Hodgkin lymphoma frequently involves the gastrointestinal tract, in particular the stomach and the small bowel. Rarely, it can also be a cause of pancreatic masses. Clinical presentation is often non-specific and may overlap with other pancreatic conditions such as carcinoma, neuroendocrine tumours and autoimmune pancreatitis. We report a case of primary pancreatic lymphoma in a young woman with jaundice, fever and abdominal pain mimicking autoimmune pancreatitis. Clinical evaluation included the abdominal Computed Tomography scan, Magnetic Resonance Imaging and an upper gastrointestinal endoscopy that revealed a large duodenal mass. Endoscopic biopsies were performed and eventually histological examination was coherent with a diagnosis of primary pancreatic lymphoma. PMID- 26114187 TI - Nephrotic syndrome after infliximab treatment in a patient with ulcerative colitis. AB - Tumor necrosis factor (TNF)-targeted therapies are increasingly used to treat a variety of inflammatory and autoimmune diseases. They are now used worldwide, and this class of medication has revolutionized the treatment of these diseases and the quality of life for patients but it also poses risk of developing various side effects including infections, exacerbation of some neurological manifestations, cutaneous lesions or induces antibody production. Renal complications are uncommon and poorly recognized. This report describes a probable case of infliximab-induced focal segmental glomerulosclerosis clinically presented as a severe nephrotic syndrome in a patient with ulcerative colitis. PMID- 26114189 TI - Clinical decompensation after achieving SVR with sofosbuvir, daclatasvir and ribavirin in a patient with recurrent HCV post-liver transplant. PMID- 26114188 TI - Primary peritoneal serous psammocarcinoma: a case report. AB - BACKGROUND: Psammocarcinomas (PCas) are rare epithelial tumors, usually originating in the ovaries or the peritoneum. These tumors are morphologically characterized by extensive psammomatous calcifications, invasiveness and low grade cytological features. CASE REPORT: We present the case of a 54-year-old woman who was referred to our department with an umbilical tumor and increasing abdominal girth. The patient had had an umbilical hernia for more than 20 years. The CA 125 level was normal. The CT scan showed small peritoneal nodules at the level of the Douglas pouch, including the posterior wall of the uterus, and the entire colon, as well as large nodules located on the caecum and the sigmoid colon. We performed partial enterectomy, total colectomy with ileo-rectal anastomosis, omentectomy, total histerectomy and bilateral adnexectomy, pelvic peritonectomy of the Douglas pouch. Pathology findings were consistent with F.I.G.O. stage IIIC peritoneal PCa. The patient received adjuvant chemotherapy with Taxol and Carboplatin. To date, twelve months after surgery, the follow-up shows no evidence of disease. CONCLUSION: Standardized treatment protocols are hindered by the rarity of the PCas. However, literature concludes that optimal debulking is mandatory, whereas the efficacy of adjuvant chemotherapy remains to be elucidated. PMID- 26114190 TI - Serum intestinal-fatty acid binding protein as a biomarker for refractory celiac disease. PMID- 26114191 TI - Mesalamine-induced fever: an important reminder to prescribers. PMID- 26114192 TI - The hypoglycemic effect of a polysaccharide (GLP) from Gracilaria lemaneiformis and its degradation products in diabetic mice. AB - Gracilaria lemaneiformis is cultivated on a large scale in China for industrial production of agarose, a natural polysaccharide, which has been shown to have many beneficial bioactivities such as antitumor, antiviral antioxidant activities, etc. In the present study, the hypoglycemic and antioxidant effects of a polysaccharide extracted from Gracilaria lemaneiformis (GLP; Mw, 121.89 kDa) and its chemically degraded products (GLP1 and GLP2: Mw, 57.02 and 14.29 kDa, respectively) were investigated in alloxan-induced diabetic mice. The intragastric administration of GLP, GLP1 and GLP2 for 21 days induced an obvious decrease (P < 0.05) in blood glucose levels in comparison with untreated diabetic mice. Furthermore, GLP, GLP1 and GLP2 caused evident increases (P < 0.05) in both ant i-oxidase (SOD and GSH-Px) activities and the total antioxidant capacity (T AOC) and a significant decrease (P < 0.05) in the level of malondialdehyde (MDA) in the liver, pancreas and kidney of diabetic mice. Even though GLP, GLP1 and GLP2 did not show any significant difference in the structure and sulfation levels, GLP1 demonstrated more potent effects than GLP and GLP2 at the same dose. Histopathological examination of the pancreas and kidney revealed that the damaged tissues induced by alloxan were repaired to a certain degree after the treatments of GLP, GLP1 and GLP2. PMID- 26114193 TI - A glucose biosensor based on glucose oxidase immobilized on three-dimensional porous carbon electrodes. AB - A novel glucose biosensor was developed by immobilizing glucose oxidase (GOD) on a three-dimensional (3D) porous kenaf stem-derived carbon (3D-KSC) which was firstly proposed as a novel supporting material to load biomolecules for electrochemical biosensing. Here, an integrated 3D-KSC electrode was prepared by using a whole piece of 3D-KSC to load the GOD molecules for glucose biosensing. The morphologies of integrated 3D-KSC and 3D-KSC/GOD electrodes were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The SEM results revealed a 3D honeycomb macroporous structure of the integrated 3D-KSC electrode. The TEM results showed some microporosities and defects in the 3D-KSC electrode. The electrochemical behaviors and electrocatalytic performance of the integrated 3D-KSC/GOD electrode were evaluated by cyclic voltammetry and electrochemical impedance spectroscopy. The effects of pH and scan rates on the electrochemical response of the biosensor have been studied in detail. The glucose biosensor showed a wide linear range from 0.1 mM to 14.0 mM with a high sensitivity of 1.73 MUA mM(-1) and a low detection limit of 50.75 MUM. Furthermore, the glucose biosensor exhibited high selectivity, good repeatability and reproducibility, and good stability. PMID- 26114194 TI - Ionic liquid-based zwitterionic organic polymer monolithic column for capillary hydrophilic interaction chromatography. AB - In the current study, a novel ionic liquid-based zwitterionic organic polymer monolithic column was developed by copolymerizing 1-vinyl-3-(butyl-4-sulfonate) imidazolium, acrylamide and N,N'-methylenebisacrylamide in a quaternary porogenic solvent consisting of formamide, dimethyl sulphoxide, polyethylene glycol 8000 and polyethylene glycol 10,000 for capillary hydrophilic interaction chromatography. The monolithic stationary phase was optimized by adjusting the amount of monomer in the polymerization solution along with the composition of porogenic solvent. The optimized monolith exhibited excellent selectivity and favorable retention for nucleosides and benzoic acid derivatives. The primary factors affecting the separation efficiency of the monolithic column (including acetonitrile content, pH, and buffer salt concentration in the mobile phase) have been thoroughly evaluated. Excellent reproducibility of the retention times for five nucleosides was achieved, with relative standard deviations of run-to-run (n = 3), column-to-column (n = 3) and batch-to-batch (n = 3) in the range of 0.18 0.48%, 2.33-4.20% and 3.07-6.50%, respectively. PMID- 26114195 TI - A new aluminium-ion battery with high voltage, high safety and low cost. AB - A new kind of Al-ion battery with carbon paper as the cathode, high-purity Al foil as the anode and ionic liquid as the electrolyte is proposed in this work. The significance of the presented battery is going to be an extremely high average voltage plateau of ca. 1.8 V vs. Al(3+)/Al. PMID- 26114196 TI - Challenging Plasma Cholesterol as a Risk Factor for Cardiovascular Disease. PMID- 26114197 TI - [Brucellosis is endemic]. PMID- 26114198 TI - [Appendicitis: perforation risks in the elderly]. PMID- 26114199 TI - [Sarcocystosis epidemic]. PMID- 26114200 TI - [Tungiasis present since the Incas]. PMID- 26114201 TI - Nursing research: Nurses know best. PMID- 26114202 TI - I2/KI-Mediated Oxidative N-N Bond Formation for the Synthesis of 1,5-Fused 1,2,4 Triazoles from N-Aryl Amidines. AB - An I2/KI-mediated oxidative N-N bond formation reaction is described. This new and environmentally benign approach allows for the convenient synthesis of a variety of 1,2,4-triazolo[1,5-a]pyridines and other 1,5-fused 1,2,4-triazoles from readily available N-aryl amidines in an efficient and scalable fashion. PMID- 26114206 TI - Temperature Dependence of Hydroxymethyl Group Rotamer Populations in Cellooligomers. AB - Empirical force fields for computer simulations of carbohydrates are often implicitly assumed to be valid also at temperatures different from room temperature for which they were optimized. Herein, the temperature dependence of the hydroxymethyl group rotamer populations in short oligosaccharides is investigated using molecular dynamics simulations and NMR spectroscopy. Two oligosaccharides, viz., methyl beta-cellobioside and beta-cellotetraose were simulated using three different carbohydrate force fields (CHARMM C35, GLYCAM06, and GROMOS 56Acarbo) in combination with different water models (SPC, SPC/E, and TIP3P) using replica exchange molecular dynamics simulations. For comparison, hydroxymethyl group rotamer populations were investigated for methyl beta cellobioside and cellopentaose based on measured NMR (3)JH5,H6 coupling constants, in the latter case by using a chemical shift selective NMR-filter. Molecular dynamics simulations in combination with NMR spectroscopy show that the temperature dependence of the hydroxymethyl rotamer population in these short cellooligomers, in the range 263-344 K, generally becomes exaggerated in simulations when compared to experimental data, but also that it is dependent on simulation conditions, and most notably properties of the water model. PMID- 26114207 TI - Guideline on aspects of cancer-related venous thrombosis. AB - The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). All the authors are consultants in haematology in the UK. A search was performed of PubMed and Embase using the term 'cancer' combined with 'thrombosis', 'treatment', 'prophylaxis' and 'clinical presentation'. The search covered articles published up until December 2014. Only human studies were included and articles not written in English were excluded. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH and the BCSH executive. The guideline was then reviewed by the sounding board of the British Society for Haematology (BSH). This comprises 50 or more members of the BSH who have reviewed the guidance and commented on the content and application to the UK setting. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN ATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the prevention and management of venous thromboembolism (VTE) in patients with cancer and to advise on an approach to screening for cancer in patients with unprovoked VTE in whom cancer was not initially suspected based on clinical grounds. PMID- 26114208 TI - Liposomal hydrogel formulation for transdermal delivery of pirfenidone. AB - CONTEXT: Pirfenidone (PFD) is an anti-fibrotic and anti-inflammatory agent indicated for the treatment of idiopathic pulmonary fibrosis (IPF). The current oral administration of PFD has several limitations including first pass metabolism and gastrointestinal irritation. OBJECTIVE: The aim of this study is to investigate the feasibility of transdermal delivery of PFD using liposomal carrier system. MATERIALS AND METHODS: PFD-loaded liposomes were prepared using soy phosphatidylcholine (SPC) and sodium cholate (SC). Encapsulation efficiency (EE) of PFD in liposomes was optimized using different preparation techniques including thin film hydration (TFH) method, direct injection method (DIM) and drug encapsulation using freeze-thaw cycles. In vitro drug release study was performed using dialysis membrane method. The skin permeation studies were performed using excised porcine ear skin model in a Franz diffusion cell apparatus. RESULTS AND DISCUSSION: The average particle size and zeta-potential of liposomes were 191 +/- 4.1 nm and -40.4 +/- 4.5 mV, respectively. The liposomes prepared by TFH followed by 10 freeze-thaw cycles showed the greatest EE of 22.7 +/- 0.63%. The optimized liposome formulation was incorporated in hydroxypropyl methyl cellulose (HPMC) hydrogel containing different permeation enhancers including oleic acid (OA), isopropyl myristate (IPM) and propylene glycol (PG). PFD-loaded liposomes incorporated in hydrogel containing OA and IPM showed the greatest flux of 10.9 +/- 1.04 MUg/cm(2)/h across skin, which was 5 fold greater compared with free PFD. The cumulative amount of PFD permeated was 344 +/- 28.8 MUg/cm(2) with a lag time of 2.3 +/- 1.3 h. CONCLUSION: The hydrogel formulation containing PFD-loaded liposomes can be developed as a potential transdermal delivery system. PMID- 26114209 TI - Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes, caffeine, warfarin, omeprazole, metoprolol and midazolam, in common marmosets (Callithrix jacchus). AB - 1. Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) composite, after single intravenous and oral administrations at doses of 0.20 and 1.0 mg kg(-1), respectively, to four male common marmosets were investigated. 2. The plasma concentrations of caffeine and warfarin decreased slowly in a monophasic manner but those of omeprazole, metoprolol and midazolam decreased extensively after intravenous and oral administrations, in a manner that approximated those as reported for pharmacokinetics in humans. 3. Bioavailabilities were ~100% for caffeine and warfarin, but <25% for omeprazole and metoprolol. Bioavailability of midazolam was 4% in marmosets, presumably because of contribution of marmoset P450 3A4 expressed in small intestine and liver, with a high catalytic efficiency for midazolam 1'-hydroxylation as evident in the recombinant system. 4. These results suggest that common marmosets, despite their rapid clearance of some human P450 probe substrates, could be an experimental model for humans and that marmoset P450s have functional characteristics that differ from those of human and/or cynomolgus monkey P450s in some aspects, indicating their importance in modeling in P450-dependent drug metabolism studies in marmosets and of further studies. PMID- 26114210 TI - Nucleobase Recognition by Truncated alpha-Hemolysin Pores. AB - The alpha-hemolysin (alphaHL) protein nanopore has been investigated previously as a base detector for the strand sequencing of DNA and RNA. Recent findings have suggested that shorter pores might provide improved base discrimination. New work has also shown that truncated-barrel mutants (TBM) of alphaHL form functional pores in lipid bilayers. Therefore, we tested TBM pores for the ability to recognize bases in DNA strands immobilized within them. In the case of TBMDelta6, in which the barrel is shortened by ~16 A, one of the three recognition sites found in the wild-type pore, R1, was almost eliminated. With further mutagenesis (Met113 -> Gly), R1 was completely removed, demonstrating that TBM pores can mediate sharpened recognition. Remarkably, a second mutant of TBMDelta6 (Met113 > Phe) was able to bind the positively charged beta-cyclodextrin, am7betaCD, unusually tightly, permitting the continuous recognition of individual nucleoside monophosphates, which would be required for exonuclease sequencing mediated by nanopore base identification. PMID- 26114211 TI - Transfusion in CMV seronegative T-depleted allogeneic stem cell transplant recipients with CMV-unselected blood components results in zero CMV transmissions in the era of universal leukocyte reduction: a U.K. dual centre experience. AB - OBJECTIVES: To establish rates of cytomegalovirus (CMV) transmission with use of CMV-unselected (CMV-U), leukocyte-reduced blood components transfused to CMV seronegative patient/CMV-seronegative donor (CMV neg/neg) allogeneic stem cell transplantation (SCT) recipients including those receiving T-depleted grafts. BACKGROUND: CMV infection remains a major cause of morbidity following SCT. CMV seronegative SCT recipients are particularly at risk of transfusion transmitted CMV (TT-CMV) and until recently they have received blood components from CMV seronegative donors with significant resource implications. Although leukocyte reduction of blood components is reported to minimise risk of TT-CMV, its efficacy in high-risk situations, such as in T-depleted transplant recipients, is unknown. METHODS: We retrospectively analysed the incidence of TT-CMV in CMV neg/neg allogeneic SCT recipients transfused with CMV-U, leukocyte-reduced blood components in two transplantation centres in the UK. Patients were monitored for CMV infection by weekly CMV polymerase chain reaction testing. Leukocyte reduction of blood components was in accordance with current UK standards. RESULTS: Among 76 patients, including 59 receiving in vivo T-depletion, no episodes of CMV infection were detected. Patients were transfused with 1442 CMV unselected, leukocyte-reduced components, equating to 1862 donor exposures. CONCLUSIONS: Our findings confirm the safety of leukocyte reduction as a strategy in preventing TT-CMV in high-risk allogeneic SCT recipients. PMID- 26114212 TI - Response to Roig-Romero. PMID- 26114213 TI - Improving assessment in small fiber neuropathy. AB - Interval measures at the impairment level addressing symptoms and at the activity/participation level addressing daily and social restrictions have not been developed for small fiber neuropathy (SFN). We developed an SFN-specific Rasch-built overall disability scale (SFN-RODS(c)), an activity/participation scale at the interval level. A preliminary SFN-RODS containing 146 activity/participation items was assessed twice (reliability studies) in 238 patients with SFN. The ordinal-based 13-item SFN-symptoms inventory questionnaire (SFN-SIQ(c)) and pain-visual-analogue-scale were also assessed (validity studies). The pre-SFN-RODS and SFN-SIQ data were subjected to the Rasch analyses. The pre-SFN-RODS did not meet Rasch model expectations. Based on requirements, such as misfit statistics, differential item functioning, and local dependency, items were systematically removed and model fit improved. Finally, a 32-item SFN RODS(c) scale was constructed that fulfilled all Rasch requirements, demonstrating acceptable reliability and validity scores. The 13-item SFN-SIQ(c) was successfully transformed to an interval Rasch-built measure fulfilling model's requirements. In conclusion, the 32-item SFN-RODS(c) is a disease specific interval measure suitable for detecting activity limitations and participation restrictions in patients with SFN. The 13-item SFN-SIQ(c) was transformed through Rasch to an interval measure. The use of these scales is recommended in future clinical interventional trials involving patients with SFN. PMID- 26114214 TI - The Feasibility of Collecting Patient Reported Pain Data Using a System Delivered Across Four Modes of Technology. PMID- 26114215 TI - Metrics for Assessing the Quality of Groundwater Used for Public Supply, CA, USA: Equivalent-Population and Area. AB - Data from 11,000 public supply wells in 87 study areas were used to assess the quality of nearly all of the groundwater used for public supply in California. Two metrics were developed for quantifying groundwater quality: area with high concentrations (km(2) or proportion) and equivalent-population relying upon groundwater with high concentrations (number of people or proportion). Concentrations are considered high if they are above a human-health benchmark. When expressed as proportions, the metrics are area-weighted and population weighted detection frequencies. On a statewide-scale, about 20% of the groundwater used for public supply has high concentrations for one or more constituents (23% by area and 18% by equivalent-population). On the basis of both area and equivalent-population, trace elements are more prevalent at high concentrations than either nitrate or organic compounds at the statewide-scale, in eight of nine hydrogeologic provinces, and in about three-quarters of the study areas. At a statewide-scale, nitrate is more prevalent than organic compounds based on area, but not on the basis of equivalent-population. The approach developed for this paper, unlike many studies, recognizes the importance of appropriately weighting information when changing scales, and is broadly applicable to other areas. PMID- 26114216 TI - Influence of Surgical Technique, Performance Status, and Peritonitis Exposure on Surgical Site Infection in Acute Complicated Diverticulitis: A Matched Case Control Study. AB - BACKGROUND: Acute generalized peritonitis secondary to complicated diverticulitis is a life-threatening condition; the standard treatment is surgery. Despite advances in peri-operative care, this condition is accompanied by a high peri operative complication rate (22%-25%). No definitive evidence is available to recommend a preferred surgical technique in patients with Hinchey stage III/IV disease. METHODS: A matched case-control study enrolling patients from four surgical units at Italian university hospital was planned to assess the most appropriate surgical treatment on the basis of patient performance status and peritonitis exposure, with the aim of minimizing the surgical site infection (SSI). A series of 1,175 patients undergoing surgery for Hinchey III/IV peritonitis in 2003-2013 were analyzed. Cases (n=145) were selected from among those patients who developed an SSI. THE CASE: control ratio was 1:3. Cases and control groups were matched by age, gender, body mass index, and Hinchey grade. We considered three surgical techniques: T1=Hartman's procedure; T2=sigmoid resection, anastomosis, and ileostomy; and T3=sigmoid resection and anastomosis. Six scoring systems were analyzed to assess performance status; subsequently, patients were divided into low, mild, and high risk (LR, MR, HR) according to the system producing the highest area under the curve. We classified peritonitis exposition as P1=<12 h; P2=12-24 h; P3=>24 h. Univariable and multivariable analyses were performed. RESULTS: The Apgar scoring system defined the risk groups according to performance status. Lowest SSI risk was expected when applying T3 in P1 (OR=0.22), P2 (OR=0.5) for LR and in P1 (OR=0.63) for MR; T2 in P2 (OR=0.5) in LR and in P1 (OR=0.61) in MR; T1 in P3 (OR=0.56) in LR; in P2 (OR=0.63) and P3 (OR=0.54) in MR patients, and in each P subgroup (OR=0.93;0.97;1.01) in HR. CONCLUSIONS: Pre-operative assessment based on Apgar scoring system integrated with peritonitis exposure in complicated diverticulitis may offer a ready-to-use tool for reducing SSI-related complications and applying appropriate treatment, reducing the need for disabling ostomy. PMID- 26114217 TI - The lubrication performance of the ceramic-on-ceramic hip implant under starved conditions. AB - Lubrication plays an important role in the clinical performance of the ceramic-on ceramic (CoC) hip implant in terms of reducing wear and avoiding squeaking. All the previous lubrication analyses of CoC hip implants assumed that synovial fluid was sufficiently supplied to the contact area. The aim of this study was to investigate the lubrication performance of the CoC hip implant under starved conditions. A starved lubrication model was presented for the CoC hip implant. The model was solved using multi-grid techniques. Results showed that the fluid film thickness of the CoC hip implant was affected by fluid supply conditions: with the increase in the supplied fluid layer, the lubrication film thickness approached to that of the fully blooded solution; when the available fluid layer reduced to some level, the fluid film thickness considerably decreased with the supplying condition. The above finding provides new insights into the lubrication performance of hip implants. PMID- 26114218 TI - The Effect of Tai Chi Chuan on Obstacle Crossing Strategy in Older Adults. AB - The purpose of this study was to determine the effect of Tai Chi Chuan on the strategies of obstacle-crossing behavior in older adults aged over 65 years. Fifteen Tai Chi group (TCG) participants were compared with 15 general group (GG) participants. Kinematic parameters (by Vicon motion analysis system) and ground reaction forces (by Kistler force plates) were synchronously recorded. A two-way mixed-design ANOVA (alpha = 0.05) was used to test the effects of the group and the obstacle height. The TCG performed significantly faster stride velocities, longer stride lengths, and shorter stride times than GG while crossing the obstacles. TCG could also produce significantly larger forward ground reaction forces to propel the body and were able to make a significantly greater flexion angle of the hip of the leading leg compared with the GG. It was concluded that the TCG adopted a different strategy with GG to cross the obstacles and completed the crossing behavior more effectively. PMID- 26114219 TI - Differential susceptibility of primary cultured human skin cells to hypericin PDT in an in vitro model. AB - Skin cancer is the most common cancer worldwide, and its incidence rate in South Africa is increasing. Photodynamic therapy (PDT) has been shown to be an effective treatment modality, through topical administration, for treatment of non-melanoma skin cancers. Our group investigates hypericin-induced PDT (HYP-PDT) for the treatment of both non-melanoma and melanoma skin cancers. However, a prerequisite for effective cancer treatments is efficient and selective targeting of the tumoral cells with minimal collateral damage to the surrounding normal cells, as it is well established that cancer therapies have bystander effects on normal cells in the body, often causing undesirable side effects. The aim of this study was to investigate the cellular and molecular effects of HYP-PDT on normal primary human keratinocytes (Kc), melanocytes (Mc) and fibroblasts (Fb) in an in vitro tissue culture model which represented both the epidermal and dermal cellular compartments of human skin. Cell viability analysis revealed a differential cytotoxic response to a range of HYP-PDT doses in all the human skin cell types, showing that Fb (LD50=1.75MUM) were the most susceptible to HYP-PDT, followed by Mc (LD50=3.5MUM) and Kc (LD50>4MUM HYP-PDT) These results correlated with the morphological analysis which displayed distinct morphological changes in Fb and Mc, 24h post treatment with non-lethal (1MUM) and lethal (3MUM) doses of HYP-PDT, but the highest HYP-PDT doses had no effect on Kc morphology. Fluorescent microscopy displayed cytoplasmic localization of HYP in all the 3 skin cell types and additionally, HYP was excluded from the nuclei in all the cell types. Intracellular ROS levels measured in Fb at 3MUM HYP-PDT, displayed a significant 3.8 fold (p<0.05) increase in ROS, but no significant difference in ROS levels occurred in Mc or Kc. Furthermore, 64% (p<0.005) early apoptotic Fb and 20% (p<0.05) early apoptotic Mc were evident; using fluorescence activated cell sorting (FACS), 24h post 3MUM HYP-PDT. These results depict a differential response to HYP-PDT by different human skin cells thus highlighting the efficacy and indeed, the potential bystander effect of if administered in vivo. This study contributes toward our knowledge of the cellular response of the epidermis to photodynamic therapies and will possibly enhance the efficacy of future photobiological treatments. PMID- 26114220 TI - A randomised trial to demonstrate the effectiveness of electronic messages on sun protection behaviours. AB - Message exposure is effective at changing a variety of health behaviours. Our aim was to improve sun protection habits of a volunteer sample. We conducted a randomised, non-blinded, investigator-initiated trial (from 1st June to 31st August in 2011) on the effect of an electronic text-message system on sun protection behaviours. The assessments of 149 healthy volunteer participants took place at the Clinical Department of Dermatology and Allergology at the University of Szeged in Hungary. Psychological and medical assessments were also made. Total motivation scores for adherence to sunscreen use improved at a nearly significant level (t=-1.954, p=0.054). The intervention group used sunscreens more often than the other groups according to their sun exposure diaries (F=8.173, p<0.05) and their interview results (F=3.44, p<0.05). Using electronic messages offers an effective method to improve sun protection behaviours. Our intervention is a cost effective method and it can easily be implemented at worksites. PMID- 26114221 TI - Nanostructured composite material graphite/TiO2 and its antibacterial activity under visible light irradiation. AB - The paper addresses laboratory preparation, characterization and in vitro evaluation of antibacterial activity of graphite/TiO2 nanocomposites. Composites graphite/TiO2 with various ratio of TiO2 nanoparticles (30wt.%, and 50wt.%) to graphite were prepared using a thermal hydrolysis of titanylsulfate in the presence of graphite particles, and subsequently dried at 80 degrees C. X-ray powder diffraction, transmission electron microscopy and Raman microspectroscopy served as phase-analytical methods distinguishing anatase and rutile phases in the prepared composites. Scanning and transmission electron microscopy techniques were used for characterization of morphology of the prepared samples. A developed modification of the standard microdilution test was used for in vitro evaluation of daylight induced antibacterial activity, using four common human pathogenic bacterial strains (Staphylococcus aureus, Escherichia coli, Enterococcus faecalis and Pseudomonas aeruginosa). Antibacterial activity of the graphite/TiO2 nanocomposites could be based mainly on photocatalytic reaction with subsequent potential interaction of reactive oxygen species with bacterial cells. During the antibacterial activity experiments, the graphite/TiO2 nanocomposites exhibited antibacterial activity, where differences in the onset of activity and activity against bacterial strains were observed. The highest antibacterial activity evaluated as minimum inhibitory concentration was observed against P. aeruginosa after 180min of irradiation. PMID- 26114222 TI - Biochemical traits and proteomic changes in postharvest flowers of medicinal chrysanthemum exposed to enhanced UV-B radiation. AB - The article studied UV-B effects on biochemical traits and proteomic changes in postharvest flowers of medicinal chrysanthemum. The experiment about UV-B effects on biochemical traits in flowers included six levels of UV-B treatments (0 (UV0), 50 (UV50), 200 (UV200), 400 (UV400), 600 (UV600) and 800 (UV800) MUWcm(-2)). UV400, UV600 and UV800 treatments significantly increased the contents of hydrogen peroxide, malondialdehyde and UV-B absorbing compounds, and the activity of phenylalanine ammonia lyase enzyme over the control. The contents of chlorogenic acid and flavone in flowers were significantly increased by UV-B treatments (except for UV50 and UV800). Two-dimensional gel electrophoresis was utilized to analyze proteomic changes in flowers with or without UV-B radiation. Results indicated that 43 protein spots (>1.5-fold difference in volume) were detected, including 19 spots with a decreasing trend and 24 spots with an increasing trend, and 19 differentially expressed protein spots were successfully indentified by MALDI-TOF MS. The indentified proteins were classified based on functions, the most of which were involved in photosynthesis, respiration, protein biosynthesis and degradation and defence. An overall assessment using biochemical and differential proteomic data revealed that UV-B radiation could affect biochemical reaction and promote secondary metabolism processes in postharvest flowers. PMID- 26114224 TI - Moho topography, ranges and folds of Tibet by analysis of global gravity models and GOCE data. AB - The determination of the crustal structure is essential in geophysics, as it gives insight into the geohistory, tectonic environment, geohazard mitigation, etc. Here we present the latest advance on three-dimensional modeling representing the Tibetan Mohorovicic discontinuity (topography and ranges) and its deformation (fold), revealed by analyzing gravity data from GOCE mission. Our study shows noticeable advances in estimated Tibetan Moho model which is superior to the results using the earlier gravity models prior to GOCE. The higher quality gravity field of GOCE is reflected in the Moho solution: we find that the Moho is deeper than 65 km, which is twice the normal continental crust beneath most of the Qinghai-Tibetan plateau, while the deepest Moho, up to 82 km, is located in western Tibet. The amplitude of the Moho fold is estimated to be ranging from -9 km to 9 km with a standard deviation of ~2 km. The improved GOCE gravity derived Moho signals reveal a clear directionality of the Moho ranges and Moho fold structure, orthogonal to deformation rates observed by GPS. This geophysical feature, clearly more evident than the ones estimated using earlier gravity models, reveals that it is the result of the large compressional tectonic process. PMID- 26114223 TI - Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit. AB - AIMS: The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo. METHODS: Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes. RESULTS: Tacrolimus clearance decreased gradually throughout the entire first year but only in CYP3A5*3/*3 homozygous recipients (25.6 +/- 11.1 l h(-1) at day 7; 17 +/- 9.1 l h(-1) at month 12; P < 0.001). In mixed model analysis, decreasing CYP3A4 activity, measured by apparent oral MDZ clearance (924 +/- 443 ml min(-1) at day 7 vs. 730 +/- 344 ml min(-1) at month 1; P < 0.001), explained 55.4% of the decline in tacrolimus clearance in the first month. CYP3A4 activity decreased by 18.9 ml min(-1) for every milligram of methylprednisolone dose tapering within the first month; beyond this point it remained stable. A gradual rise in haematocrit throughout the entire first year explained 31.7% of the decrease in tacrolimus clearance in the first month and 23.6% of the decrease between months 1 and 12. Cyclosporine clearance did not change over time. CONCLUSIONS: The maturation of tacrolimus disposition in the first year after renal transplantation observed in CYP3A5*3/*3 homozygous patients can partly be explained by a (steroid tapering-related) decline in CYP3A4 activity and a progressive increase in haematocrit. PMID- 26114225 TI - Extraction and Quantitation of Ketones and Aldehydes from Mammalian Cells Using Fluorous Tagging and Capillary LC-MS. AB - The extraction and quantitation of carbonyl metabolites from cell lysate was accomplished using a carbonyl-reactive fluorous tag and capillary liquid chromatography coupled to mass spectrometry (capLC-MS). Selective fluorous tagging for ketones and aldehydes provided a 30-fold increase in sensitivity using electrospray ionization MS. Separation of fluorous tagged carbonyl resulted in good separation of all components, and tandem MS was able to differentiate structural carbonyl isomers. The average limit of detection for carbonyl standards was 37 nM (range 1.5-250 nM), with linearity of R(2) > 0.99. Reproducibility for metabolites in cell lysate averaged 9% RSD. Human aortic endothelial cells (HAECs) were exposed to varying levels of glucose, and their carbonyl metabolite levels were quantified. Significant metabolite changes were seen in glycolysis and the propanoate pathway from a glucose challenge. Using an untargeted approach, 120 carbonyl metabolites were found to change in hyperglycemic HAECs. From this list of compounds, multiple metabolites from the pentose phosphate and tryptophan metabolic pathways were discovered. This system provides excellent sensitivity and quantitation of carbonyl metabolites without the need for isotope standards or labels. PMID- 26114226 TI - Quantitative Dose Dependency Analysis of Whole-Brain CT Perfusion Imaging. AB - PURPOSE: To quantitatively assess whether decreasing total radiation dose of the image acquisition protocol has an effect on cerebral CT perfusion values in patients with acute stroke. MATERIALS AND METHODS: This retrospective study was approved by the institutional ethics committee, and informed consent was waived. Twenty consecutive patients with ischemic stroke who underwent CT perfusion imaging with a 320-detector row CT scanner were included. A standard acquisition protocol was used, which was started 5 seconds after injection of a contrast agent, with a scan at 200 mAs, followed after 4 seconds by 13 scans, one every 2 seconds, at 100 mAs, and then five scans, one every 5 seconds, at 75 mAs. The total examination had an average effective dose of 5.0 mSv. For each patient, a patient-specific digital perfusion phantom was constructed to simulate the same protocol at a lower total dose (0.5-5.0 mSv, with stepped doses of 0.5 mSv). The lowest setting for which the maximum mean difference remained within 5% of the reference standard (at 5.0 mSv) was marked as the optimal setting. At the optimal setting, Pearson correlation coefficients were calculated to assess correlations with the reference values, and paired t tests were performed to compare the means. RESULTS: At 2.5 mSv, the maximum mean differences in values from those of the reference standard were 4.5%, 5.0%, and 1.9%, for cerebral blood flow, cerebral blood volume, and mean transit time, respectively. Pearson correlation coefficients of perfusion values for white matter and gray matter were 0.864 0.917, and all differences were significant (P < .0001). Paired t tests showed no significant differences between the reference standard and optimal settings (P = .089-.923). CONCLUSION: The total dose of a clinical cerebral CT perfusion protocol can be lowered to 2.5 mSv, with only minor quantitative effects on perfusion values. Dose reduction beyond this point resulted in overestimation of perfusion values. PMID- 26114227 TI - AIBp regulates mitotic entry and mitotic spindle assembly by controlling activation of both Aurora-A and Plk1. AB - We previously reported that Aurora-A and the hNinein binding protein AIBp facilitate centrosomal structure maintenance and contribute to spindle formation. Here, we report that AIBp also interacts with Plk1, raising the possibility of functional similarity to Bora, which subsequently promotes Aurora-A-mediated Plk1 activation at Thr210 as well as Aurora-A activation at Thr288. In kinase assays, AIBp acts not only as a substrate but also as a positive regulator of both Aurora A and Plk1. However, AIBp functions as a negative regulator to block phosphorylation of hNinein mediated by Aurora-A and Plk1. These findings suggest a novel AIBp-dependent regulatory machinery that controls mitotic entry. Additionally, knockdown of hNinein caused failure of AIBp to target the centrosome, whereas depletion of AIBp did not affect the localization of hNinein and microtubule nucleation. Notably, knockdown of AIBp in HeLa cells impaired both Aurora-A and Plk1 kinase, resulting in phenotypes with multiple spindle pole formation and chromosome misalignment. Our data show that depletion of AIBp results in the mis-localization of TACC3 and ch-TOG, but not CEP192 and CEP215, suggesting that loss of AIBp dominantly affects the Aurora-A substrate to cause mitotic aberrations. Collectively, our data demonstrate that AIBp contributes to mitotic entry and bipolar spindle assembly and may partially control localization, phosphorylation, and activation of both Aurora-A and Plk1 via hNinein during mitotic progression. PMID- 26114228 TI - Depression rating scales in Parkinson's disease: A critical review updating recent literature. AB - Depression is a prominent non-motor symptom in Parkinson's disease (PD). Assessing depression in PD remains a challenge due to the overlap of somatic symptoms between depression and PD. Other neuropsychiatric manifestations associated with PD, such as cognitive decline, also complicate assessment of depression. Therefore it is critical to investigate the validity of depression rating scales for use in PD. This will allow evaluation of observer- and self report instruments to be administered in neurologically ill geriatric populations such as PD, and identification of appropriate scales to use in cognitively challenged PD patients. The present review includes all studies examining the validity of depression rating scales in PD. It discusses the usefulness of 13 depression rating scales in PD. The clinician-rated and widely used HAMD-17 and the self-report GDS scales are recommended for screening and measuring severity of depression in PD. The GDS-15 may be a preferred choice due to its brevity and ease of use design for older adults. Other valid and reliable instruments to use in PD include self-rated scales, such as the HADS-D, HDI, and the BDI, and the observer-report, MADRS. The CSDD displayed satisfactory validity and reliability for identification of PD patients with and without dementia. The PHQ-2, PHQ-10, SDS, CES-D, UPDRS-Depression item, IDS-SR, and IDS-C each showed some evidence of validity or reliability, however further research on the psychometric properties of these scales when used in a PD population are required. PMID- 26114234 TI - Peer support and additional information in group medical consultations (GMCs) for BRCA1/2 mutation carriers: A randomized controlled trial. AB - BACKGROUND: Group medical consultations (GMCs) provide individual medical visits in the presence of <= 7 peer- patients. This study evaluated the efficacy of GMCs in the yearly breast cancer surveillance of BRCA mutation carriers. MATERIAL AND METHODS: This randomized controlled trial compared GMCs (intervention group, n = 63) with individual medical visits (control group, n = 59). Between-group differences on the primary outcomes distress and empowerment, were analyzed one week and three months after the visit. Feasibility is evaluated in terms of demand, acceptability and practicability. RESULTS: No between-group differences were found on primary outcomes. More themes were discussed in GMCs. Seventy-five percent of GMC-participants experienced peer support. Carriers reported significantly higher satisfaction with individual visits. GMCs were less time efficient. CONCLUSION: This is the first GMC study which reports results in favor of individual visits. The hereditary nature of the condition differentiates our study population from earlier studied GMC groups. Even though most participants experienced peer support and received more information, the lower patient satisfaction may be explained by the lack of individual time with the clinician and disruption of normal surveillance routines. As the need for peer support and additional information is present in a substantial part of carriers, future research should study the process of peer support. PMID- 26114235 TI - Binding of Starch Fragments to the Starch Branching Enzyme: Implications for Developing Slower-Digesting Starch. AB - Molecular weight distributions of starch branches affect functional properties, which can be controlled by engineering starch branching enzymes (SBEs). Molecular dynamics and docking approaches are used to examine interactions between SBE and starch fragments. In the native protein, three residues formed stable interactions with starch fragments in the central binding region; these residues may play key roles in substrate recognition. Fragments containing 5-12 glucose units interacted more tightly with SBE than smaller fragments, suggesting a minimal functional fragment size of 5, agreeing with experiment. Effects of three different point mutations on interactions with maltopentaose in the central binding region correlated well with experiment. Simulations indicate that SBE may template formation of the crystalline lamellae characteristic of native starch, consistent with the observation that crystalline lamellae formed by starch in a plant, are not necessarily the state of lowest free energy. The methodology will help develop starches with optimized functional properties. PMID- 26114236 TI - ALK-positive anaplastic large cell lymphoma presenting with hemophagocytic lymphohistiocytosis. PMID- 26114229 TI - Genome-wide association study of posttraumatic stress disorder in a cohort of Iraq-Afghanistan era veterans. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop after experiencing traumatic events. A genome-wide association study (GWAS) design was used to identify genetic risk factors for PTSD within a multi racial sample primarily composed of U.S. veterans. METHODS: Participants were recruited at multiple medical centers, and structured interviews were used to establish diagnoses. Genotypes were generated using three Illumina platforms and imputed with global reference data to create a common set of SNPs. SNPs that increased risk for PTSD were identified with logistic regression, while controlling for gender, trauma severity, and population substructure. Analyses were run separately in non-Hispanic black (NHB; n = 949) and non-Hispanic white (NHW; n = 759) participants. Meta-analysis was used to combine results from the two subsets. RESULTS: SNPs within several interesting candidate genes were nominally significant. Within the NHB subset, the most significant genes were UNC13C and DSCAM. Within the NHW subset, the most significant genes were TBC1D2, SDC2 and PCDH7. In addition, PRKG1 and DDX60L were identified through meta analysis. The top genes for the three analyses have been previously implicated in neurologic processes consistent with a role in PTSD. Pathway analysis of the top genes identified alternative splicing as the top GO term in all three analyses (FDR q < 3.5 * 10(-5)). LIMITATIONS: No individual SNPs met genome-wide significance in the analyses. CONCLUSIONS: This multi-racial PTSD GWAS identified biologically plausible candidate genes and suggests that post-transcriptional regulation may be important to the pathology of PTSD; however, replication of these findings is needed. PMID- 26114237 TI - Highly Uniform Perfluoropropane-Loaded Cerasomal Microbubbles As a Novel Ultrasound Contrast Agent. AB - Microbubbles are widely used as ultrasound contrast agents owing to their excellent echoing characteristics under ultrasound radiation. However, their short sonographic duration and wide size distribution still hinder their application. Herein, we present a hard-template approach to produce perfluoropropane-loaded cerasomal microbubbles (PLCMs) with uniform size and long sonographic duration. The preparation of PLCMs includes deposition of Si-lipids onto functionalized CaCO3 microspheres, removal of their CaCO3 cores and mild infusion of perfluoropropane. In vitro and in vivo experiments showed that PLCMs had excellent echoing characteristics under different ultrasound conditions. More importantly, PLCMs could be imaged for much longer than SonoVue (commercially used microbubbles) under the same ultrasound parameters and concentrations. Our results demonstrated that PLCMs have great potential for use as a novel contrast agent in ultrasound imaging. PMID- 26114238 TI - Contrasting association of circulating sCD14 with insulin sensitivity in non obese and morbidly obese subjects. AB - SCOPE: In experimental studies, moderate to high concentrations of sCD14 (serum cluster of differentiation 14 protein) prevent lipopolysaccharide (LPS)-induced systemic inflammation, while low concentrations may promote inflammation. Given that metabolic endotoxemia is thought to initiate high-fat diet-induced insulin resistance, we explored the association between sCD14 concentrations and insulin sensitivity in humans. METHODS AND RESULTS: Healthy non-obese (n = 12, BMI 26 +/- 5y), obese (n = 11, BMI 33.45 +/- 3.2) and morbidly obese participants (n = 38, BMI 45 +/- 7) underwent measurement of body composition (dual energy X-ray absorptiometry) and a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity (M value). Circulating sCD14 concentrations were measured by ELISA. Non-obese participants had lower circulating sCD14 concentrations compared to obese (p = 0.03). Circulating sCD14 concentrations were positively associated with percent body fat, waist circumference and white blood cell count and negatively associated with insulin sensitivity. In contrast, circulating sCD14 were positively associated with insulin sensitivity in morbidly obese participants. In regression analysis, insulin sensitivity (r = 0.52, p = 0.004) and fasting triglycerides (r = 0.49, p = 0.005) contributed independently to circulating sCD14 variance after controlling for age, sex and BMI in these morbidly obese subjects. CONCLUSION: These findings suggest that circulating sCD14 concentrations, through its compensatory (in non-obese subjects) or buffering role (in morbidly obese subjects), could exert an important role in modulating insulin sensitivity. PMID- 26114239 TI - Rapid Asymmetric Transfer Hydroformylation (ATHF) of Disubstituted Alkenes Using Paraformaldehyde as a Syngas Surrogate. AB - As an alternative to conventional asymmetric hydroformylation (AHF), asymmetric transfer hydroformylation (ATHF) by using formaldehyde as a surrogate for syngas is reported. A catalyst derived from commercially available [Rh(acac)(CO)2 ] (acac=acetylacetonate) and 1,2-bis[(2S,5S)-2,5-diphenylphospholano]ethane(1,5 cyclooctadiene) (Ph-BPE) stands out in terms of both activity and enantioselectivity. Remarkably, not only are high selectivities achievable, the reactions are very simple to perform, and higher enantioselectivity (up to 96 % ee) and/or turnover frequencies than those achievable by using the same catalyst (or other leading catalysts) can be obtained by using typical conditions for AHF. PMID- 26114240 TI - A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia. AB - OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia. METHOD: An international multicenter, randomized, double-blind, placebo-controlled trial was conducted between December 2011 and March 2014. Patients (N = 623) aged 18 to 70 years with schizophrenia (DSM-IV-TR criteria), experiencing an acute exacerbation, were randomized in a 1:1:1 ratio to receive gluteal intramuscular injection of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or matching placebo once monthly for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to day 85. The Clinical Global Impressions Improvement scale (CGI-I) score at day 85 was the secondary efficacy outcome. Safety and tolerability were assessed. RESULTS: The PANSS total score (mean +/- standard error [SE]) improved significantly from baseline to day 85 in the aripiprazole lauroxil 441 mg and 882 mg groups, with placebo-adjusted differences of -10.9 +/- 1.8 (P < .001) and -11.9 +/- 1.8 (P < .001), respectively. Significant (P <= .004) improvements in both active treatment groups were demonstrated as early as day 8 and continued throughout the treatment period. The proportion of patients who were very much or much improved on the CGI-I was significantly greater with aripiprazole lauroxil 441 mg and 882 mg treatment versus placebo (P < .001). The most common treatment-emergent adverse events were insomnia, akathisia, headache, and anxiety. The incidence of injection site reactions was low, predominantly described as injection site pain, and was associated with the first injection. CONCLUSIONS: Aripiprazole lauroxil demonstrated robust efficacy for treatment of patients experiencing acute exacerbation of schizophrenia. The improvement in psychotic symptoms was statistically significant and clinically meaningful. Symptom improvement occurred rapidly after initiation of aripiprazole lauroxil treatment and was maintained throughout the study. Both aripiprazole lauroxil 441 mg and 882 mg doses were well tolerated. These results support aripiprazole lauroxil as an important new treatment option for schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; Clinicaltrialsregister.eu identifier: 2012-003445-15. PMID- 26114241 TI - The Tibial Slope in Patients With Achondroplasia: Its Characterization and Possible Role in Genu Recurvatum Development. AB - BACKGROUND: Genu recurvatum, a posterior resting position of the knee, is a common lower extremity deformity in patients with achondroplasia and has been thought to be secondary to ligamentous laxity. To the best of our knowledge, the role of the tibial slope has not been investigated, and no studies describe the tibial slope in patients with achondroplasia. Our goals were to characterize the tibial slope in children and adults with achondroplasia, explore its possible role in the development of genu recurvatum, and compare the tibial slope in patients with achondroplasia to that in the general population. METHODS: We reviewed 252 lateral knee radiographs of 130 patients with achondroplasia seen at our clinic from November 2007 through September 2013. Patients were excluded if they had previous lower extremity surgery or radiographs with extreme rotation. We analyzed patient demographics and, on all radiographs, the tibial slope. We then compared the mean tibial slope to norms in the literature. Tibial slopes >90 degrees had an anterior tibial slope and received a positive prefix. Statistical analysis included intraclass and interclass reliability, Pearson correlation coefficient, and the Student t tests (significance, P<0.05). RESULTS: The overall mean tibial slope for the 252 knees was +1.32+/-7 degrees, which was significantly more anterior than the normal slopes reported in the literature for adults (7.2 to 10.7 degrees, P=0.0001) and children (10 to 11 degrees, P=0.0001). The Pearson correlation coefficient for mean tibial slope and age showed negative correlations of -0.4011 and -0.4335 for left and right knees, respectively. This anterior tibial slope produces proximal and posterior vector force components, which may shift the knee posteriorly in weightbearing. CONCLUSIONS: The mean tibial slope is significantly more anterior in patients with achondroplasia than in the general population; however, this difference diminishes as patients' age. An anterior tibial slope may predispose to a more posterior resting knee position, also known as genu recurvatum. LEVEL OF EVIDENCE: Level IV retrospective case series. PMID- 26114242 TI - Presentation of Adolescent Idiopathic Scoliosis: The Bigger the Kid, the Bigger the Curve. AB - BACKGROUND: It is our clinical suspicion that children with higher body mass index (BMIs) who are diagnosed with scoliosis tend to have larger curves on presentation. The purpose of this study was to determine the effect of BMI on severity of curve at initial presentation of adolescent idiopathic scoliosis. METHODS: This is a retrospective, descriptive cohort study of consecutive patients age 10 or greater referred to a single large tertiary care center with concern for spinal asymmetry. Patients were separated into 3 BMI categories as measured on the presenting visit: normal weight->=5th and <85th percentile, overweight->=85th and <95th percentile, and obese->=95th percentile. In addition to demographic information, data collected included BMI, curve magnitude, curve location, Risser stage, and where or by whom spinal asymmetry was noted. RESULTS: A total of 150 patients, 50 in each the normal weight, overweight, and obese categories, were included in this study. Average curve at presentation for normal weight patients was 18.1 degrees, for overweight patients 23.9 degrees (P=0.02), and for obese patients 24.5 degrees (P=0.02). As compared with the normal weight group, odds ratio of presenting with a curve of 40 degrees or above was 10.8 for the overweight group (95% confidence interval, 1.3-88.5, P=0.03) and 12.2 for the obese group (95% confidence interval, 1.5-99.8, P=0.02). Assuming a cut-off of 45 degrees as surgical range, no normal weight patients presented in surgical range (0%), but 7/50 (14%, P=0.01) overweight and 8/50 (16%, P<0.01) obese patients did. Moreover, higher BMI patients were significantly more likely to present at a higher degree of skeletally maturity, with an average Risser of 1.8 for normal weight patients, 2.7 (P=0.01) for overweight patients, and 2.9 (P=0.01) for obese patients. CONCLUSIONS: Overweight and obese patients with adolescent idiopathic scoliosis present at significantly larger curve magnitudes and significantly higher degrees of skeletal maturity. Moreover, these patients were significantly more likely to present with very large curves and, in our study, all patients presenting with a surgical range curve were either overweight or obese. LEVEL OF EVIDENCE: Level III-Retrospective case-control. PMID- 26114243 TI - Integrated Health Risk Assessment of Heavy Metals in Suxian County, South China. AB - The purpose of this study was to assess soil heavy metal contamination and the potential risk for local residents in Suxian county of Hunan Province, southern China. Soil, rice and vegetable samples from the areas near the mining industrial districts were sampled and analyzed. The results indicate that the anthropogenic mining activities have caused local agricultural soil contamination with As, Pb, Cu and Cd in the ranges of 8.47-341.33 mg/kg, 19.91-837.52 mg/kg, 8.41-148.73 mg/kg and 0.35-6.47 mg/kg, respectively. GIS-based mapping shows that soil heavy metal concentrations abruptly diminish with increasing distance from the polluting source. The concentrations of As, Pb, Cu and Cd found in rice were in the ranges of 0.02-1.48 mg/kg, 0.66-5.78 mg/kg, 0.09-6.75 mg/kg, and up to 1.39 mg/kg, respectively. Most of these concentrations exceed their maximum permissible levels for contaminants in foods in China. Heavy metals accumulate to significantly different levels between leafy vegetables and non-leafy vegetables. Food consumption and soil ingestion exposure are the two routes that contribute to the average daily intake dose of heavy metals for local adults. Moreover, the total hazard indices of As, Pb and Cd are greater than or close to the safety threshold of 1. Long-term As, Pb and Cd exposure through the regular consumption of the soil, rice and vegetables in the investigated area poses potential health problems to residents in the vicinity of the mining industry. PMID- 26114245 TI - The Role of Sister Cities' Staff Exchanges in Developing "Learning Cities": Exploring Necessary and Sufficient Conditions in Social Capital Development Utilizing Proportional Odds Modeling. AB - In the last half century former international adversaries have become cooperators through networking and knowledge sharing for decision making aimed at improving quality of life and sustainability; nowhere has this been more striking then at the urban level where such activity is seen as a key component in building "learning cities" through the development of social capital. Although mega-cities have been leaders in such efforts, mid-sized cities with lesser resource endowments have striven to follow by focusing on more frugal sister city type exchanges. The underlying thesis of our research is that great value can be derived from city-to-city exchanges through social capital development. However, such a study must differentiate between necessary and sufficient conditions. Past studies assumed necessary conditions were met and immediately jumped to demonstrating the existence of structural relationships by measuring networking while further assuming that the existence of such demonstrated a parallel development of cognitive social capital. Our research addresses this lacuna by stepping back and critically examining these assumptions. To accomplish this goal we use a Proportional Odds Modeling with a Cumulative Logit Link approach to demonstrate the existence of a common latent structure, hence asserting that necessary conditions are met. PMID- 26114246 TI - Dermal desmoplastic fibroblastoma presenting as a large sacral mass. AB - Desmoplastic fibroblastoma (collagenous fibroma) is a rare and recently recognised benign tumour. Most desmoplastic fibroblastomas arise in the subcutaneous tissue or skeletal muscle. Involvement of the dermis is extremely rare. We describe an unusual case of dermal desmoplastic fibroblastoma presenting as a large sacral mass in a 16-year-old male. An awareness of this entity is necessary to avoid confusion with other benign and malignant soft tissue neoplasms. PMID- 26114244 TI - Quantification of Protozoa and Viruses from Small Water Volumes. AB - Large sample volumes are traditionally required for the analysis of waterborne pathogens. The need for large volumes greatly limits the number of samples that can be processed. The aims of this study were to compare extraction and detection procedures for quantifying protozoan parasites and viruses from small volumes of marine water. The intent was to evaluate a logistically simpler method of sample collection and processing that would facilitate direct pathogen measures as part of routine monitoring programs. Samples were collected simultaneously using a bilayer device with protozoa capture by size (top filter) and viruses capture by charge (bottom filter). Protozoan detection technologies utilized for recovery of Cryptosporidium spp. and Giardia spp. were qPCR and the more traditional immunomagnetic separation-IFA-microscopy, while virus (poliovirus) detection was based upon qPCR versus plaque assay. Filters were eluted using reagents consistent with the downstream detection technologies. Results showed higher mean recoveries using traditional detection methods over qPCR for Cryptosporidium (91% vs. 45%) and poliovirus (67% vs. 55%) whereas for Giardia the qPCR-based methods were characterized by higher mean recoveries (41% vs. 28%). Overall mean recoveries are considered high for all detection technologies. Results suggest that simultaneous filtration may be suitable for isolating different classes of pathogens from small marine water volumes. More research is needed to evaluate the suitability of this method for detecting pathogens at low ambient concentration levels. PMID- 26114247 TI - Theoretical studies of the dependence of EPR parameters on local structure for the tetragonal Er(3+) centres in YVO4 and ScVO4. AB - The dependences of the EPR parameters on the local distortion parameters Deltatheta and DeltaR as well as the crystal-field parameters have been studied by diagonalizing the 364*364 complete energy matrices for a tetragonal Er(3+) centre in the YVO4 and ScVO4 crystals. The results show that the local distortion angle Deltatheta and the fourth-order crystal-field parameter A4 are most sensitive to the EPR g-factors g// and g?, whereas the local distortion length DeltaR and the second-order parameter A2 are less sensitive to the g-factors. Furthermore, we found that the abnormal EPR g-factors for the Er(3+) ion in the ScVO4 may be ascribed to the stronger nephelauxetic effect and covalent bonding effect, as a result of an expanded local distortion for the Er(3+) centre in the ScVO4 crystal. Simultaneously, the contributions of the J-J mixing effects from the terms of excited states to the EPR parameters have been evaluated quantitatively. PMID- 26114248 TI - The transformation of nepheline and albite into sodalite in pegmatitic mariupolite of the Oktiabrski Massif (SE Ukraine). AB - Sodalite, Na8Al6Si6Cl2, from a pegmatitic variety of mariupolite in the Oktiabrski Massif (SE Ukraine) was studied using electron microprobe, electron microscopy, spectroscopic cathodoluminescence and Raman techniques to determine its growth history during the evolution of the host rock. Three generations of the mineral were distinguished: (1) the oldest forms patches with a pink-violet cathodoluminescence colour, (2) a younger one, with a dark blue colour, forms the matrix of the crystals, and (3) the youngest generation forms veins with light blue cathodoluminescence in the older sodalite generations; all are undoubtedly secondary phases formed during the post-magmatic evolution of the host rock. The close spatial association of the sodalite with coexisting albite, nepheline, natrolite and K-feldspar, forming inclusions in each other, and the embayed contacts of sodalite with nepheline and albite, and the patchy appearance of sodalite under CL, together suggest that the two older sodalite varieties formed from the conversion of nepheline and albite under the action of Na-, Cl- and Al bearing, but Si undersaturated basic fluids released during cooling of the host. The excess of SiO2 (aq.) released as a result of albite metasomatism could be accommodated by natrolite occurring as tiny inclusions within the sodalite crystals. The youngest, veinlet, generation was probably formed via a fluid mediated dissolution-recrystallization process, perhaps simultaneously with the coexisting veins of natrolite. PMID- 26114249 TI - Metabolic plasticity of human T cells: Preserved cytokine production under glucose deprivation or mitochondrial restriction, but 2-deoxy-glucose affects effector functions. AB - The strong link between T-cell metabolism and effector functions is well characterized in the murine system but hardly investigated in human T cells. Therefore, we analyzed glycolytic and mitochondrial activity in correlation to function in activated human CD4 and CD8 T cells. Glycolysis was barely detectable upon stimulation but accelerated beyond 24 h, whereas mitochondrial activity was elevated immediately in both T-cell populations. Glucose deprivation or mitochondrial restriction reduced proliferation, had only a transient impact on "on-blast formation" and no impact on viability, IFN-gamma, IL-2, IL-4, and IL-10 production, whereas TNF was reduced. Similar results were obtained in bulk T cells and T-cell subsets. Elevated respiration under glucose restriction demonstrated metabolic flexibility. Administration of the glycolytic inhibitor 2 deoxy-glucose suppressed both glycolysis and respiration and exerted a strong impact on cytokine production that persisted for IFN-gamma after removal of 2 deoxy-glucose. Taken together, glycolytic or mitochondrial restriction alone compromised proliferation of human T cells, but barely affected their effector functions. In contrast, effector functions were severely affected by 2-deoxy glucose treatment. PMID- 26114250 TI - Lateralized Odontoid in Plain Film Radiography: Sign of Fractures? A Comparison Study with MDCT. AB - PURPOSE: To evaluate X-ray standards for the detection of odontoid fractures. SUMMARY OF BACKGROUND DATA: Cervical spine fractures are a common finding in emergency medicine, accounting for 1-3% of injuries. Involvement of the C1/C2 complex is found in 25% of cases, affecting the odontoid peg in 55-80%. Regarding the consequences of missed fractures, radiographic techniques built the groundwork for further treatment procedures. As standardized X-ray measurements have not been established, the incidence of unrecognized cervical spine fracture is expected to be up to 20%. The establishment of X-ray-based guidelines is also limited by the presumed low specificity and sensitivity of distance measurements caused by rotational distortion which leads to a rising popularity of CT. MATERIALS AND METHODS: 79 (age 60 +/- 26 yrs) patients with lateralization of the odontoid process on conventional plain film radiography (anteroposterior, lateral, and open mouth odontoid process view projection) were examined. The distance between the odontoid process and lateral mass of C1, angles of vertical odontoid line and basis of C2 were measured in the ap view. In the lateral view, dorsal alignment and atlantodental distance were assessed. MDCT examinations were used as a reference. Discriminatory power test was applied to assess significance. RESULTS: 8/79 (10.1%) odontoid process fractures were found. Diagnosis was achieved on conventional radiographs in 6 patients. Neither distance and angle measurements between odontoid and C1 nor the dorsal alignment of the vertebral bodies differed significantly between healthy and affected patients. CONCLUSION: Decentralization of the odontoid process is not necessarily an indirect sign for its fracture. In patients with suspected injury of the odontoid process, an MDCT scan might be the method of choice to rule out a fracture. KEY POINTS: Due to the wide physiological variety of odontoid process position, even a detailed metric analysis of cervical alignment and odontoid process angulation in X-ray scans is not able to facilitate the diagnosis of odontoid process fractures. In the case of cervical spine trauma, which necessitate medical imaging, a primary MDCT scan should be the method of choice. PMID- 26114251 TI - Prostate Imaging--An Update. AB - New technical and clinical developments of sonography and magnetic resonance imaging include improved detection, localization and staging as well as active surveillance of prostate cancer. Multiparametric MRI can best answer these typical clinical questions. However, ultrasound elastography seems to be suitable for the detection of significant prostate cancer as well. The structured reporting system for multiparametric MRI of the prostate according to PI-RADS Version 1 led to improved and reproducible diagnosis of prostate cancer. The new PI-RADS Version 2 aims to minimize the limitations of Version 1 and make PI-RADS standardization more globally acceptable. KEY POINTS: The detection, staging, and active monitoring of prostate cancer are common clinical questions. The best method for answering these questions is multiparametric MRI. Ultrasound elastography also seems to be suitable for the detection of significant prostate cancer. The new PI-RADS Version 2 claims to eliminate the limitations of PI-RADS Version 1 and to allow globally recognized standardized diagnostic reporting. PMID- 26114252 TI - ["Needles and pins". Self injury behavior by ingestion of numerous unusual sharp foreign bodies]. PMID- 26114253 TI - [Rare clinical course of epididymo-orchitis with subtotal testicular infarct]. PMID- 26114254 TI - [Cephalocele of the petrous apex: a rare etiology of trigeminal neuralgia]. PMID- 26114255 TI - Advances in ion mobility-mass spectrometry instrumentation and techniques for characterizing structural heterogeneity. AB - Over the last decade, the field of ion mobility-mass spectrometry (IM-MS) has experienced dramatic growth in its application toward ion structure characterization. Enabling advances in instrumentation during this time period include improved conformation resolution and ion sensitivity. Such advances have rendered IM-MS a powerful approach for characterizing samples presenting a diverse array of ion structures. The structural heterogeneity that can be interrogated by IM-MS techniques now ranges from samples containing mixtures of small molecules exhibiting a variety of structural types to those containing very large protein complexes and subcomplexes. In addition to this diversity, IM-MS techniques have been used to probe spontaneous and induced structural transformations occurring in solution or the gas phase. To support these measurement efforts, significant advances have been made in theoretical methods aimed at translating IM-MS data into structural information. These efforts have ranged from providing more reliable trial structures for comparison to the experimental measurements to dramatically reducing the time required to calculate collision cross sections for such structures. In this short review, recent advances in developments in IM-MS instrumentation, techniques, and theory are discussed with regard to their implications for characterization of gas- and solution-phase structural heterogeneity. PMID- 26114256 TI - Characterization of Mn-resistant endophytic bacteria from Mn-hyperaccumulator Phytolacca americana and their impact on Mn accumulation of hybrid penisetum. AB - Three hundred Mn-resistant endophytic bacteria were isolated from the Mn hyperaccumulator, Phytolacca americana, grown at different levels of Mn (0, 1, and 10mM) stress. Under no Mn stress, 90%, 92%, and 11% of the bacteria produced indole acetic acid (IAA), siderophore, and 1-aminocyclopropane-1-carboxylate (ACC) deaminase, respectively. Under Mn stress, 68-94%, 91-92%, and 21-81% of the bacteria produced IAA, siderophore, and ACC deaminase, respectively. Greater percentages of ACC deaminase-producing bacteria were found in the Mn-treated P. americana. Furthermore, the ratios of IAA- and siderophore-producing bacteria were significantly higher in the Mn treated plant leaves, while the ratio of ACC deaminase-producing bacteria was significantly higher in the Mn treated-roots. Based on 16S rRNA gene sequence analysis, Mn-resistant bacteria were affiliated with 10 genera. In experiments involving hybrid penisetum grown in soils treated with 0 and 1000mgkg(-1) of Mn, inoculation with strain 1Y31 was found to increase the root (ranging from 6.4% to 18.3%) and above-ground tissue (ranging from 19.3% to 70.2%) mass and total Mn uptake of above-ground tissues (64%) compared to the control. Furthermore, inoculation with strain 1Y31 was found to increase the ratio of IAA-producing bacteria in the rhizosphere and bulk soils of hybrid penisetum grown in Mn-added soils. The results showed the effect of Mn stress on the ratio of the plant growth-promoting factor-producing endophytic bacteria of P. americana and highlighted the potential of endophytic bacterium as an inoculum for enhanced phytoremediation of Mn-polluted soils by hybrid penisetum plants. PMID- 26114257 TI - Assessment of heavy metal pollution and human health risk in urban soils of steel industrial city (Anshan), Liaoning, Northeast China. AB - The purpose of this study was to determine the concentrations and health risk of heavy metals in urban soils from a steel industrial district in China. A total of 115 topsoil samples from Anshan city, Liaoning, Northeast China were collected and analyzed for Cr, Cd, Pb, Zn, Cu, and Ni. The geoaccumulation index (Igeo), pollution index (PI), and potential ecological risk index (PER) were calculated to assess the pollution level in soils. The hazard index (HI) and carcinogenic risk (RI) were used to assess human health risk of heavy metals. The average concentration of Cr, Cd, Pb, Zn, Cu, and Ni were 69.9, 0.86, 45.1, 213, 52.3, and 33.5mg/kg, respectively. The Igeo and PI values of heavy metals were in the descending order of Cd>Zn>Cu>Pb>Ni>Cr. Higher Igeo value for Cd in soil indicated that Cd pollution was moderate. Pollution index indicated that urban soils were moderate to highly polluted by Cd, Zn, Cu, and Pb. The spatial distribution maps of heavy metals revealed that steel industrial district was the contamination hotspots. Principal component analysis (PCA) and matrix cluster analysis classified heavy metals into two groups, indicating common industrial sources for Cu, Zn, Pb, and Cd. Matrix cluster analysis classified the sampling sites into four groups. Sampling sites within steel industrial district showed much higher concentrations of heavy metals compared to the rest of sampling sites, indicating significant contamination introduced by steel industry on soils. The health risk assessment indicated that non-carcinogenic values were below the threshold values. The hazard index (HI) for children and adult has a descending order of Cr>Pb>Cd>Cu>Ni>Zn. Carcinogenic risks due to Cr, Cd, and Ni in urban soils were within acceptable range for adult. Carcinogenic risk value of Cr for children is slightly higher than the threshold value, indicating that children are facing slight threat of Cr. These results provide basic information of heavy metal pollution control and environment management in steel industrial regions. PMID- 26114258 TI - A method to measure the ozone penetration factor in residences under infiltration conditions: application in a multifamily apartment unit. AB - Recent experiments have demonstrated that outdoor ozone reacts with materials inside residential building enclosures, potentially reducing indoor exposures to ozone or altering ozone reaction byproducts. However, test methods to measure ozone penetration factors in residences (P) remain limited. We developed a method to measure ozone penetration factors in residences under infiltration conditions and applied it in an unoccupied apartment unit. Twenty-four repeated measurements were made, and results were explored to (i) evaluate the accuracy and repeatability of the new procedure using multiple solution methods, (ii) compare results from 'interference-free' and conventional UV absorbance ozone monitors, and (iii) compare results against those from a previously published test method requiring artificial depressurization. The mean (+/-s.d.) estimate of P was 0.54 +/- 0.10 across a wide range of conditions using the new method with an interference-free monitor; the conventional monitor was unable to yield meaningful results due to relatively high limits of detection. Estimates of P were not clearly influenced by any indoor or outdoor environmental conditions or changes in indoor decay rate constants. This work represents the first known measurements of ozone penetration factors in a residential building operating under natural infiltration conditions and provides a new method for widespread application in buildings. PMID- 26114259 TI - TYPE 2 DIABETES IN PATIENTS WITH MAJOR DEPRESSIVE DISORDER: A META-ANALYSIS OF PREVALENCE ESTIMATES AND PREDICTORS. AB - BACKGROUND: Patients with depression may be at increased risk of type 2 diabetes mellitus (T2DM), which is a risk factor for cardiovascular diseases and premature mortality. We aimed to clarify the prevalence and predictors of T2DM in patients with major depressive disorder (MDD) and where possible compare the prevalence of T2DM in those with MDD versus general population controls. METHODS: We searched major electronic databases until December 2014 for studies reporting T2DM prevalence in patients with MDD. Two independent authors extracted data and completed methodological quality appraisal in accordance with the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. A random effects meta-analysis was utilized. RESULTS: The initial electronic database search resulted in 145 valid hits and 16 publications with clearly defined MDD (n = 15,8834; 31% male; mean age = 39-78 years) met the eligibility criteria. The overall prevalence of T2DM was 8.7% (95% confidence interval [CI] = 7.3-10.2%). Mean age of the MDD sample predicted a higher prevalence of T2DM (beta = 0.0411; 95% CI = 0.0032-0.079, P = .03; R2 = .22). A comparative meta-analysis revealed people with MDD (n = 154,366) had a higher risk of T2DM versus general controls (n = 2,098,063; relative risk [RR] = 1.49; 95% CI = 1.29-1.72; P < 0.001, N = 10). The RR (N = 3) focusing on age- and gender-matched general population controls (n = 103,555) was 1.36 (95% CI = 1.28-1.44; P < 0.001, n [MDD] = 10,895). CONCLUSIONS: T2DM is significantly more common in people with MDD compared with the general population. The current meta-analysis indicates that action is needed in order to curb the diabetes epidemic in this high-risk population. PMID- 26114260 TI - Study of the influence of over-the-counter vitamin supplement intake on urine fluorescence to optimize cancer detection by fluorescence cystoscopy. AB - Fluorescence cystoscopy (FC) efficiently enhances the detection and improves the therapeutic management of early bladder cancer. During an FC, about 150 ml of water is needed to inflate the bladder. The water is quickly diluted by urine which can be fluorescent. If this bladder washout fluid (BWF) becomes fluorescent, the FC images are frequently degraded. Unfortunately, it is unclear which elements of the diet may contribute to this background fluorescence. We propose to start this exploration with over-the-counter (OTC) vitamin supplements. To this end, we measured excitation-emission matrices of urine samples and the kinetics of modifications of urine fluorescence obtained from nine healthy volunteers before, during, and after intake of a commercially available OTC vitamin supplement. The pharmacokinetics shows that the BWF fluorescence values reach a maximum 8 to 10 h after vitamin intake. They decrease in the half-day that follows and reach values close to baseline ~1 day afterward. Based on these results, we conclude that, in order to avoid degradations of fluorescence images, it is likely best that the intake of OTC vitamin supplements be avoided during the week preceding an FC. PMID- 26114261 TI - Erratum: Clozapine-Related Negative Myoclonus Associated With Urinary Tract Infection. PMID- 26114263 TI - Photochemical behavior of antibiotics impacted by complexation effects of concomitant metals: a case for ciprofloxacin and Cu(II). AB - Many water bodies, especially those adjacent to aquaculture and livestock breeding areas, are contaminated by both antibiotics and transition metals. However, the effects of the interaction between antibiotics and transition metals on the environmental behavior and the ecotoxicology of antibiotics are largely unknown. We hypothesized that antibiotics may coordinately bind with metal ions, and this complexation may affect the environmental photochemical behavior of antibiotics. We took ciprofloxacin (CIP) and Cu(ii) as a case, and employed simulated sunlight experiments and density functional theory calculations to investigate the underlying reaction mechanisms. The results showed that monovalent cationic ciprofloxacin (H2CIP(+)) that is predominant in the normal pH range (6-9) of surface waters can chelate with hydrated Cu(ii) to form [Cu(H2CIP)(H2O)4](3+). Compared with H2CIP(+), [Cu(H2CIP)(H2O)4](3+) has different molecular orbitals, and atomic charge distribution. As a result, [Cu(H2CIP)(H2O)4](3+) showed dissimilar light absorption properties, slower direct photolytic rates, lower (1)O2 generation ability and weaker reactivity towards (1)O2. Due to the Cu(ii) complexation, the apparent photodegradation of H2CIP(+) was inhibited, and the photolytic pathways and product distribution were altered. This study implies that for an accurate ecological risk assessment of antibiotics under transition metal co-contamination conditions, the effects of metal complexation should be considered. PMID- 26114265 TI - Analysis of suspended solids transport processes in primary settling tanks. AB - The paper shows the results of a long-term research comprising FLUENT-based numerical modeling, in situ measurements and laboratory tests to analyze suspended solids (SS) transport processes in primary settling tanks (PSTs). The investigated PST was one of the rectangular horizontal flow PSTs at a large municipal wastewater treatment plant (WWTP) of a capacity of 500,000 population equivalent. Many middle-sized and large WWTPs are equipped with such PSTs. The numerical PST model was calibrated and validated based on the results of comprehensive in situ flow and SS concentration measurements from low (5 m/h) up to quite high surface overflow rates of 9.5 and 13.0 m/h and on settling and other laboratory tests. The calibrated and validated PST model was also successfully used for evaluation of some slight modifications of the inlet geometry (removing lamellas, installing a flocculation 'box', shifting the inlet into a 'bottom-near' or into a 'high' position), which largely affect PST behavior and performance. The investigations provided detailed insight into the flow and SS transport processes within the investigated PST, which strongly contributes to hydrodynamically driven design and upgrading of PSTs. PMID- 26114264 TI - Lichenoid reaction as a potential immune response marker of intratreatment histological response during successful vismodegib treatment for a giant basal cell carcinoma. AB - We report an 83 year-old patient with a 13 * 7.5 cm(2) basal cell carcinoma (BCC) successfully treated with the combination of vismodegib and minimal surgery. On Day 109, a 0.9 cm papule suspicious for residual BCC was seen centrally within a large pink atrophic plaque. This lesion was excised; pathology confirmed BCC with negative surgical margins. Simultaneously, suspecting noncontiguous histologic response, we performed 21 biopsies at the periphery of the pretreatment tumor location. Seventeen (17/21, 81%) revealed lichenoid dermatitis. No tumor was seen on any. We believe the lichenoid dermatitis observed is a novel finding for two reasons. First, it may be considered a marker of a positive intratreatment response. This may help guide clinicians on the optimal treatment duration of vismodegib to maximize efficacy and mitigate side effects. Second, we think it suggests an additional mechanism of vismodegib action, possibly via local immune effects. Further investigations are warranted. PMID- 26114266 TI - Evaluation of hydraulic performance indices for retention ponds. AB - Comprehensive hydraulic analysis of sediment retention ponds is commonly achieved through interpretation of residence time distribution and derivation of indices associated with short-circuiting and mixing. However, the availability of various indices indicates the need for careful selection of the most appropriate indices. This study compares some of the commonly used hydraulic performance indices, together with a new short-circuiting index, tau5, for five different flow regimes in a model sediment retention pond. The results show that tau5 was the best measure for short-circuiting. Among the mixing indices, only the Morril index correctly represented the physical behaviour of the experiments. In addition, two hydraulic efficiency indices, lambda and a moment index (MI) were assessed and showed a good correlation with the short-circuiting and mixing indices, but MI was more reproducible than lambda. Based on these results, this study recommends using tau5, Morril index and MI for analysis of hydraulic performance in sediment retention ponds. PMID- 26114267 TI - Influence of pH on hexavalent chromium reduction by Fe(II) and sulfide compounds. AB - Batch experiments were conducted to investigate the influence of pH on Cr(VI) reduction with Fe(II), sulfide and mixtures of Fe(II) and sulfide at pH 3.0-12.0. The results showed that Fe(II) could reduce Cr(VI) with a high removal of nearly 100% in the pH range of 3.0-9.0, while the reduction of Cr(VI) decreased to approximately 60% considering the oxygenation of Fe(II) at pH 12.0. The reaction between Cr(VI) and sulfide, however, was largely pH dependent. H2S was the main sulfide species with the Cr(VI) removal of ~80% at pH < 7.0, while sulfide mainly existed in the forms as HS(-) or S(2-) at pH >= 7.0, which had very limited removal of Cr(VI) (no more than 10%). The Cr(VI) removal by the mixtures of Fe(II) and sulfide was also compared with the sum of separate ones at different pH values. The sum of Cr(VI) removal by single Fe(II) and S(-II) was similar to that by the mixtures at pH 3.0-5.0 and pH 12.0, while the removal of Cr(VI) by the mixtures was observed to be more effective than the sum of the single-species removals at pH 7.0-9.0; the promoting effect was primarily attributed to the catalysis of ferric ion generated during the reduction process. PMID- 26114268 TI - Unexpected toxicity to aquatic organisms of some aqueous bisphenol A samples treated by advanced oxidation processes. AB - In this study, photocatalytic and catalytic wet-air oxidation (CWAO) processes were used to examine removal efficiency of bisphenol A from aqueous samples over several titanate nanotube-based catalysts. Unexpected toxicity of bisphenol A (BPA) samples treated by means of the CWAO process to some tested species was determined. In addition, the CWAO effluent was recycled five- or 10-fold in order to increase the number of interactions between the liquid phase and catalyst. Consequently, the inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated higher concentrations of some toxic metals like chromium, nickel, molybdenum, silver, and zinc in the recycled samples in comparison to both the single-pass sample and the photocatalytically treated solution. The highest toxicity of five- and 10-fold recycled solutions in the CWAO process was observed in water fleas, which could be correlated to high concentrations of chromium, nickel, and silver detected in tested samples. The obtained results clearly demonstrated that aqueous samples treated by means of advanced oxidation processes should always be analyzed using (i) chemical analyses to assess removal of BPA and total organic carbon from treated aqueous samples, as well as (ii) a battery of aquatic organisms from different taxonomic groups to determine possible toxicity. PMID- 26114270 TI - Influence of denitrification reactor retention time distribution (RTD) on dissolved oxygen control and nitrogen removal efficiency. AB - Low concentrations of dissolved oxygen (DO) are usually found in biological anoxic pre-denitrification reactors, causing a reduction in nitrogen removal efficiency. Therefore, the reduction of DO in such reactors is fundamental for achieving good nutrient removal. The article shows the results of an experimental study carried out to evaluate the effect of the anoxic reactor hydrodynamic model on both residual DO concentration and nitrogen removal efficiency. In particular, two hydrodynamic models were considered: the single completely mixed reactor and a series of four reactors that resemble plug-flow behaviour. The latter prove to be more effective in oxygen consumption, allowing a lower residual DO concentration than the former. The series of reactors also achieves better specific denitrification rates and higher denitrification efficiency. Moreover, the denitrification food to microrganism (F:M) ratio (F:MDEN) demonstrates a relevant synergic action in both controlling residual DO and improving the denitrification performance. PMID- 26114269 TI - Oxidative treatment of fentanyl compounds in water by sodium bromate combined with sodium sulphite. AB - As narcotic analgesics, fentanyl compounds have been commonly produced and widely used during surgical procedures. The residual and waste of fentanyl compounds have potential harmful impacts on the environment and human health. The oxidative degradation of fentanyl compounds by sodium bromate mixed systems was studied. Factors influencing the oxidation reaction, including molar ratio of NaBrO3/H(+)/SO3(2-), molar ratio of NaBrO3/fentanyl and pH, were investigated. Fentanyl, carfentanil and 3-methylfentanyl were able to be completely degraded in 30 minutes by a NaBrO3 mixed system under optimum conditions, the molar ratio of NaBrO3/H(+)/SO3(2-) equal to 20:3:10, the molar ratio of NaBrO3:fentanyl compounds 50:1 and pH = 4. Sufentanil was only able to be degraded by 74% under the same conditions. The degradation products of the fentanyl compounds detected and identified by gas chromatography/mass spectrometry suggested several possible degradation pathways. PMID- 26114271 TI - Optimizing the recovery of copper from electroplating rinse bath solution by hollow fiber membrane. AB - This study aimed to recover and remove copper from industrial model wastewater solution by non-dispersive solvent extraction (NDSX). Two mathematical models were developed to simulate the performance of an integrated extraction-stripping process, based on the use of hollow fiber contactors using the response surface method. The models allow one to predict the time dependent efficiencies of the two phases involved in individual extraction or stripping processes. The optimal recovery efficiency parameters were determined as 227 g/L of H2SO4 concentration, 1.22 feed/strip ratio, 450 mL/min flow rate (115.9 cm/min. flow velocity) and 15 volume % LIX 84-I concentration in 270 min by central composite design (CCD). At these optimum conditions, the experimental value of recovery efficiency was 95.88%, which was in close agreement with the 97.75% efficiency value predicted by the model. At the end of the process, almost all the copper in the model wastewater solution was removed and recovered as CuSO4.5H2O salt, which can be reused in the copper electroplating industry. PMID- 26114272 TI - Ammonia and phenol removal in an internal-circulate sequencing batch airlift reactor. AB - An internal-circulate sequencing batch airlift reactor (IC-SBAR) has been developed to evaluate the efficiency of phenol and ammonia removal in treating synthetic wastewater. This study examined the effect of operation cycle on this system. Results showed that above 97.0% removal efficiencies of ammonia and phenol were achieved, which indicated that ammonia and phenol removals were not related to operation cycle. The average removal efficiency of 91.7% for chemical oxygen demand (COD) was achieved when the static/aerobic/settling time was 240 min/440 min/40 min. It was found that COD removal efficiency increased due to the time of operation cycle being prolonged. The average removal efficiencies of total inorganic nitrogen (TIN) were 65.8, 69.3 and 68.9% when average TIN concentrations were 78.0, 97.6 and 88.4 mg/L, respectively, in the influent. A cycle study showed that most phenol was degraded by aerobic microbes. Increasing the static time from 120 to 240 min resulted in the accumulation of NO2(-)-N, which indicated that the structures of the nitrifying bacterial community were changed. PMID- 26114273 TI - Treatment of high organic content wastewater from food-processing industry with the French vertical flow constructed wetland system. AB - This study aimed at determining the treatment performances of a full-scale vertical flow constructed wetlands designed to treat wastewater from a food processing industry (cookie factory), and to study the influence of the organic loading rate. The full-scale treatment plant was designed with a first vertical stage of 630 m2, a second vertical stage of 473 m2 equipped with a recirculation system and followed by a final horizontal stage of 440 m2. The plant was commissioned in 2011, and was operated at different loading rates during 16 months for the purpose of this study. Treatment performances were determined by 24 hour composite samples. The mean concentration of the raw effluent was 8,548 mg.L(-1) chemical oxygen demand (COD), 4,334 mg.L(-1) biochemical oxygen demand (BOD5), and 2,069 mg.L(-1) suspended solids (SS). Despite low nutrients content with a BOD5/N/P ratio of 100/1.8/0.5, lower than optimum for biological degradation (known as 100/5/1), mean removal performances were very high with 98% for COD, 99% for BOD5 and SS for the two vertical stages. The increasing of the organic load from 50 g.m(-2).d(-1) COD to 237 g.m(-2).d(-1) COD (on the first stage) did not affect removal performances. The mean quality of effluent reached French standards (COD < 125 mg.L(-1), BOD5 < 25 mg.L(-1), SS < 35 mg.L(-1)). PMID- 26114274 TI - Modelling GAC adsorption of biologically pre-treated process water from hydrothermal carbonization. AB - Granular-activated carbon (GAC) adsorption of biologically pre-treated process waters from hydrothermal carbonization (HTC) of different materials was investigated. Overall, isotherms showed that most of the dissolved organic substances are strongly adsorbable while the non-adsorbable fractions are small. The equilibrium data were modelled by using five fictive components to represent the organic matter. Mean film transfer coefficients and mean intraparticle diffusivities were derived from short-column and batch kinetic test data, respectively. Breakthrough curves in GAC columns could be predicted satisfactorily by applying the film-homogeneous diffusion model and using the equilibrium and kinetic parameters determined from batch tests. Thus, the approach is suited to model GAC adsorption of HTC process water under technical scale conditions. PMID- 26114275 TI - The use of palm kernel shell (PKS) as substrate material in vertical-flow engineered wetlands for septage treatment in Malaysia. AB - In this study, the treatment of septage (originating from septic tanks) was carried out in a pilot-scale, two-staged, vertical-flow engineered wetland (VFEW). Palm kernel shells (PKS) were incorporated as part of the VFEW's substrate (B-PKS), to compare its organic matter (OM) and nitrogen (N) removal efficiency against wetlands with only sand substrates (B-SD). The results revealed satisfactory OM removal with >90% reduction efficiencies at both wetlands B-PKS and B-SD. No increment of chemical oxygen demand (COD) concentration was observed in the effluent of B-PKS. Ammonia load removal efficiencies were comparable (>91% and 95% in wetland B-PKS and B-SD, respectively). However, nitrate accumulation was observed in the effluent of B-SD where PKS was absent. This was due to the limited denitrification in B-SD, as sand is free of carbon. A lower nitrate concentration was associated with higher COD concentration in the effluent at B-PKS. This study has shown that the use of PKS was effective in improving the N removal efficiency in engineered wetlands. PMID- 26114276 TI - Removal of humic acid from composted hog waste by the white-rot fungus, Phanerochaete chrysosporium. AB - The potential hazards of humic acid (HA) associated with hog waste effluent, coupled with increasing awareness of environmental problems, have prompted many countries to control disposal of effluents into water bodies and to maximize removal of HA. Here we employed the white-rot fungus, Phanerochaete chrysosporium, to degrade the HA in composted hog waste effluent, evaluated by the response surface method. Preliminary experiments demonstrate that pH, temperature and quantity of inoculum are significant variables determining success of the fungus. In total, 13 experiments were conducted with three variables designated as A (pH), B (temperature) and C (inoculum amount). The optimal conditions for reduction of HA by P. chrysosporium are pH 6, 31.5 degrees C and an inoculum quantity of 5.86 g. Predicted and experimental results exhibit strong agreement, indicating efficiency in the model obtained by response surface method. Therefore, P. chrysosporium is an effective micro-organism for removal of HA from composted hog waste effluent. PMID- 26114277 TI - Long-term effects of engineered nanoparticles on enzyme activity and functional bacteria in wastewater treatment plants. AB - The pervasive use of engineered nanoparticles (NPs) in a wide range of fields raises concerns about their potential environmental impacts. Previous studies confirmed that some NPs had already entered wastewater treatment plants (WWTPs). Wastewater nutrient removal depends on the metabolisms of activated sludge bacteria and their related key enzymes. Therefore, this study compared the possible influences of Al2O3, SiO2, TiO2, and ZnO NPs on the key enzymes activities and microbial community structures involved in wastewater treatment facilities. It was found that long-term exposure to these NPs significantly affected the microbial communities and changed the relative abundances of key functional bacteria, such as ammonia-oxidizing bacteria. Also, the gene expressions and catalytic activities of essential enzymes, such as ammonia monooxygenase, nitrite oxidoreductase, nitrate reductase, and nitrite reductase, were decreased, which finally resulted in a lower efficiency of biological nitrogen removal. PMID- 26114278 TI - Reduction of start-up time through bioaugmentation process in microbial fuel cells using an isolate from dark fermentative spent media fed anode. AB - An electrochemically active bacteria Pseudomonas aeruginosa IIT BT SS1 was isolated from a dark fermentative spent media fed anode, and a bioaugmentation technique using the isolated strain was used to improve the start-up time of a microbial fuel cell (MFC). Higher volumetric current density and lower start-up time were observed with the augmented system MFC-PM (13.7 A/m(3)) when compared with mixed culture MFC-M (8.72 A/m(3)) during the initial phase. This enhanced performance in MFC-PM was possibly due to the improvement in electron transfer ability by the augmented strain. However, pure culture MFC-P showed maximum volumetric current density (17 A/m(3)) due to the inherent electrogenic properties of Pseudomonas sp. An electrochemical impedance spectroscopic (EIS) study, along with matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) analysis, supported the influence of isolated species in improving the MFC performance. The present study indicates that the bioaugmentation strategy using the isolated Pseudomonas sp. can be effectively utilized to decrease the start-up time of MFC. PMID- 26114279 TI - Bacterial community involved in the nitrogen cycle in a down-flow sponge-based trickling filter treating UASB effluent. AB - The bacterial community composition of a down-flow sponge-based trickling filter treating upflow anaerobic sludge blanket (UASB) effluent was investigated by pyrosequencing. Bacterial community composition considerably changed along the reactor and over the operational period. The dominant phyla detected were Proteobacteria, Verrucomicrobia, and Planctomycetes. The abundance of denitrifiers decreased from the top to the bottom and it was consistent with the organic matter concentration gradients. At lower loadings (organic and nitrogen loading rates), the abundance of anammox bacteria was higher than that of the ammonium-oxidizing bacteria in the upper portion of the reactor, suggesting that aerobic and anaerobic ammonium oxidation occurred. Nitrification occurred in all the compartments, while anammox bacteria prominently appeared even in the presence of high organic carbon to ammonia ratios (around 1.0-2.0 gCOD gN(-1)). The results suggest that denitrifiers, nitrifiers, and anammox bacteria coexisted in the reactor; thus, different metabolic pathways were involved in ammonium removal in the post-UASB reactor sponge-based. PMID- 26114280 TI - Anaerobic digestion of wastewater from the fruit juice industry: experiments and modeling. AB - Anaerobic digestion of wastewater from the fruit juice industry was carried out in a batch digester. To study the effect of the pH values as well as the nutrient medium on the fermentation process, different parameters were monitored under mesophilic temperature, such as cumulative biogas volume, chemical oxygen demand (COD), total sugar, and biomass growth. It was found that for all cases, the COD concentration decreased with time. The lowest value reached was obtained when the nutrient medium was added; it was about 110 g/L after 480 h. In such cases, the COD removal reached about 80%; the highest cumulative biogas volume of about 5,515.8 NmL was reached after 480 h testing; and the lowest value reached was about 2,862.3 NmL in the case of peach-substrate containing sodium sulfite. The addition of nutrient medium improved the cumulative biogas production as well as the COD abatement. Measurement of the biogas composition highlighted three gaseous components, namely, methane (56.52%), carbon dioxide (20.14%), and hydrogen sulfide (23.34%). The modified Gompertz equation and the first-order kinetic model were used to describe the cumulative biogas production and the organic matter removal, respectively. A good agreement was found between simulated and experimental data. PMID- 26114281 TI - Presence and persistence of wastewater pathogen Escherichia coli O157:H7 in hydroponic reactors of treatment wetland species. AB - Treatment wetlands (TWs) efficiently remove many pollutants including a several log order reduction of pathogens from influent to effluent; however, there is evidence to suggest that pathogen cells are sequestered in a subsurface wetland and may remain viable months after inoculation. Escherichia coli is a common pathogen in domestic and agricultural wastewater and the O157:H7 strain causes most environmental outbreaks in the United States. To assess attachment of E. coli to the TW rhizosphere, direct measurements of E. coli levels were taken. Experiments were performed in chemostats containing either Teflon nylon as an abiotic control or roots of Carex utriculata or Schoenoplectus acutus. Flow of simulated wastewater through the chemostat was set to maintain a 2 hour residence time. The influent was inoculated with E. coli O157:H7 containing DsRed fluorescent protein. Root samples were excised and analyzed via epifluorescent microscopy. E. coli O157:H7 was detected on the root surface at 2 hours after inoculation, and were visible as single cells. Microcolonies began forming at 24 hours post-inoculation and were detected for up to 1 week post-inoculation. Image analysis determined that the number of microcolonies with >100 cells increased 1 week post-inoculation, confirming that E. coli O157:H7 is capable of growth within biofilms surrounding wetland plant roots. PMID- 26114282 TI - High strength domestic wastewater treatment with submerged forward osmosis membrane bioreactor. AB - Forward osmosis membranes are less prone to fouling with high rejection of salts, and the osmotic membrane bioreactor (OMBR) can be considered as an innovative membrane technology for wastewater treatment. In this study, a submerged OMBR having a cellulose triacetate membrane, with the active layer facing the feed solution configuration, was operated at different organic loading rates (OLRs), i.e., 0.4, 1.2 and 2.0 kg-COD/(m(3).d) with chemical oxygen demand (COD) concentrations of 200 mg/L, 600 mg/L and 1,000 mg/L, respectively, to evaluate the performance on varying wastewater strengths. High organic content with sufficient amount of nutrients enhanced the biomass growth. High OLR caused more extrapolymeric substances production and less dewaterability. However, no significant differences in fouling trends and flux rates were observed among different OLR operational conditions. PMID- 26114283 TI - Evaluation of the simultaneous biogas upgrading and treatment of centrates in a high-rate algal pond through C, N and P mass balances. AB - The simultaneous capture of CO2 from biogas and removal of carbon and nutrients from diluted centrates in a 180 L high-rate algal pond (HRAP) interconnected to a 2.5 L absorption column were evaluated using a C, N and P mass balance approach. The experimental set-up was operated indoors at 75 MUE/m(2).s for 24 h/d at 20 days of hydraulic retention time for 2 months of steady state, and supported a C CO2 removal in the absorption column of 55 +/- 6%. Carbon fixation into biomass only accounted for 9 +/- 2% of the total C input, which explains the low biomass productivity recorded in the HRAP. In this context, the low impinging light intensity along with the high turbulence in the culture broth entailed a C stripping as CO2 of 49 +/- 5% of the total carbon input. Nitrification was the main NH4(+) removal mechanism and accounted for 47 +/- 2% of the inlet N-NH4(+), while N removal as biomass represented 14 +/- 2% of the total nitrogen input. A luxury P uptake was recorded, which resulted in a P-PO4(-3) biomass content over structural requirements (2.5 +/- 0.1%). Phosphorus assimilation corresponded to a 77 +/- 2% of the inlet dissolved P-PO4(-3) removed. PMID- 26114284 TI - Organic pollution removal from coke plant wastewater using coking coal. AB - Coke plant wastewater (CPW) is an intractable chemical wastewater, and it contains many toxic pollutants. This article presents the results of research on a semi-industrial adsorption method of coking wastewater treatment. As a sorbent, the coking coal (CC) was a dozen times less expensive than active carbon. The treatment was conducted within two scenarios, as follows: (1) adsorption after biological treatment of CPW with CC at 40 g L(-1); the chemical oxygen demand (COD) removal was 75.66%, and the concentration was reduced from 178.99 to 43.56 mg L(-1); (2) given an adsorption by CC of 250 g L(-1) prior to the biological treatment of CPW, the eliminations of COD and phenol were 58.08% and 67.12%, respectively. The CC that adsorbed organic pollution and was returned to the coking system might have no effect on both coke oven gas and coke. PMID- 26114285 TI - Corrigendum: Water Science and Technology 71 (4), 487-494: Full-scale phosphorus recovery from digested waste water sludge in Belgium - part I: technical achievements and challenges. PMID- 26114286 TI - Is Strain Elastography (IO-SE) Sufficient for Characterization of Liver Lesions before Surgical Resection--Or Is Contrast Enhanced Ultrasound (CEUS) Necessary? AB - AIM: To evaluate the diagnostic accuracy of IO-SE in comparison to IO-CEUS for the differentiation between malignant and benign liver lesions. MATERIAL AND METHODS: In a retrospective diagnostic study IO-CEUS and SE examinations of 49 liver lesions were evaluated and compared to histopathological examinations. Ultrasound was performed using a multifrequency linear probe (6-9 MHz). The loops of CEUS were evaluated up to 5 min. The qualitative characterization of IO-SE was based on a color coding system (blue = hard, red = soft). Stiffness of all lesions was quantified by a specific scaling of 0-6 (0 = low, 6 = high) using 7 ROIs (2 central, 5 peripheral). RESULTS: All malignant lesions displayed a characteristic portal venous washout and could be diagnosed correctly by IO-CEUS. 3/5 benign lesions could not be characterized properly either by IO-CEUS or IO-SE prior to resection. Thus for IO-CEUS sensitivity, specificity, positive and negative predictive value and accuracy were 100%, 40%, 94%, 100% and 94%. Lesion sizes were between 8 and 59 mm in diameter. Regarding the IO-SE, malignant lesions showed a marked variability. In qualitative analysis, 31 of the malignant lesions were blue colored denoting overall induration. Thirteen malignant lesions showed an inhomogenous color pattern with partial indurations. Two of the benign lesions also displayed overall induration. The other benign lesions showed an inhomogenous color mapping. Calculated sensitivity of the SE was 70.5%, specificity 60%, PPV 94%, NPV 18.75%, and accuracy 69%. CONCLUSION: IO-CEUS is useful for localization and characterization of liver lesions prior to surgical resection whereas IO-SE provided correct characterization only for a limited number of lesions. PMID- 26114288 TI - Correction: Paracoccidioides brasiliensis Interferes on Dendritic Cells Maturation by Inhibiting PGE2 Production. PMID- 26114287 TI - Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. AB - BACKGROUND: Several infectious diseases and therapeutic interventions cause gut microbe dysbiosis and associated pathology. We characterised the gut microbiome of children exposed to the helminth Schistosoma haematobium pre- and post treatment with the drug praziquantel (PZQ), with the aim to compare the gut microbiome structure (abundance and diversity) in schistosome infected vs. uninfected children. METHODS: Stool DNA from 139 children aged six months to 13 years old; with S. haematobium infection prevalence of 27.34% was extracted at baseline. 12 weeks following antihelminthic treatment with praziqunatel, stool DNA was collected from 62 of the 139 children. The 16S rRNA genes were sequenced from the baseline and post-treatment samples and the sequence data, clustered into operational taxonomic units (OTUs). The OTU data were analysed using multivariate analyses and paired T-test. RESULTS: Pre-treatment, the most abundant phyla were Bacteroidetes, followed by Firmicutes and Proteobacteria respectively. The relative abundance of taxa among bacterial classes showed limited variation by age group or sex and the bacterial communities had similar overall compositions. Although there were no overall differences in the microbiome structure across the whole age range, the abundance of 21 OTUs varied significantly with age (FDR<0.05). Some OTUs including Veillonella, Streptococcus, Bacteroides and Helicobacter were more abundant in children <= 1 year old compared to older children. Furthermore, the gut microbiome differed in schistosome infected vs. uninfected children with 27 OTU occurring in infected but not uninfected children, for 5 of these all Prevotella, the difference was statistically significant (p <0.05) with FDR <0.05. PZQ treatment did not alter the microbiome structure in infected or uninfected children from that observed at baseline. CONCLUSIONS: There are significant differences in the gut microbiome structure of infected vs. uninfected children and the differences were refractory to PZQ treatment. PMID- 26114289 TI - Orthodenticle Is Required for the Expression of Principal Recognition Molecules That Control Axon Targeting in the Drosophila Retina. AB - Parallel processing of neuronal inputs relies on assembling neural circuits into distinct synaptic-columns and layers. This is orchestrated by matching recognition molecules between afferent growth cones and target areas. Controlling the expression of these molecules during development is crucial but not well understood. The developing Drosophila visual system is a powerful genetic model for addressing this question. In this model system, the achromatic R1-6 photoreceptors project their axons in the lamina while the R7 and R8 photoreceptors, which are involved in colour detection, project their axons to two distinct synaptic-layers in the medulla. Here we show that the conserved homeodomain transcription factor Orthodenticle (Otd), which in the eye is a main regulator of rhodopsin expression, is also required for R1-6 photoreceptor synaptic-column specific innervation of the lamina. Our data indicate that otd function in these photoreceptors is largely mediated by the recognition molecules flamingo (fmi) and golden goal (gogo). In addition, we find that otd regulates synaptic-layer targeting of R8. We demonstrate that during this process, otd and the R8-specific transcription factor senseless/Gfi1 (sens) function as independent transcriptional inputs that are required for the expression of fmi, gogo and the adhesion molecule capricious (caps), which govern R8 synaptic-layer targeting. Our work therefore demonstrates that otd is a main component of the gene regulatory network that regulates synaptic-column and layer targeting in the fly visual system. PMID- 26114290 TI - Larvae and Nests of Six Aculeate Hymenoptera (Hymenoptera: Aculeata) Nesting in Reed Galls Induced by Lipara spp. (Diptera: Chloropidae) with a Review of Species Recorded. AB - Wetland species of aculeate Hymenoptera are poorly known, even though many of them may serve as diagnostic or flagship species in nature conservation. Here we examined 6,018 galls induced >=1 year prior their collection by the chloropid flies Lipara spp. The galls were collected at 34 sites in Central Europe. We examined 1,389 nests (4,513 individuals) of nine species, part of which were parasitized by one dipteran and two chrysidid parasitoid species. We describe the nests of seven dominant species and larvae of four species (Pemphredon fabricii, Trypoxylon deceptorium, Hoplitis leucomelana and Hylaeus pectoralis) and two parasitoids (Trichrysis cyanea and Thyridanthrax fenestratus, both in nests of Pemphredon fabricii and Trypoxylon deceptorium). All the species, but H. pectoralis, preferred robust galls at very thin stalks (induced typically by Lipara lucens) over the narrow galls on thick stalks. The larvae of P. fabricii and T. deceptorium resembled strongly their sibling species (Pemphredon lethifer and Trypoxylon attenuatum sensu lato, respectively). The larvae of T. fenestratus showed features different from those previously described. By hatching set of another 10,583 galls induced by Lipara spp. >=1 year prior their collection, we obtained 4,469 individuals of 14 nesting hymenopteran species, two cleptoparasites, three chrysidid and one dipteran parasitoid. Of these species, four new nesting species have been recorded for the first time in galls induced by Lipara spp.: Chelostoma campanularum, Heriades rubicola, Pseudoanthidium lituratum and Hylaeus incongruus. We also provide first records of their nest cleptoparasites Stelis breviuscula and Stelis ornatula, and the parasitoid Holopyga fastuosa generosa. Thyridanthrax fenestratus formed strong populations in nests of Pemphredon fabricii and Trypoxylon deceptorium, which are both newly recorded hosts for T. fenestratus. The descriptions provided here allow for the first time to identify the larvae of the most widespread central European aculeate hymenopteran reed gall specialists. PMID- 26114292 TI - Structure-Function Analysis of PPP1R3D, a Protein Phosphatase 1 Targeting Subunit, Reveals a Binding Motif for 14-3-3 Proteins which Regulates its Glycogenic Properties. AB - Protein phosphatase 1 (PP1) is one of the major protein phosphatases in eukaryotic cells. It plays a key role in regulating glycogen synthesis, by dephosphorylating crucial enzymes involved in glycogen homeostasis such as glycogen synthase (GS) and glycogen phosphorylase (GP). To play this role, PP1 binds to specific glycogen targeting subunits that, on one hand recognize the substrates to be dephosphorylated and on the other hand recruit PP1 to glycogen particles. In this work we have analyzed the functionality of the different protein binding domains of one of these glycogen targeting subunits, namely PPP1R3D (R6) and studied how binding properties of different domains affect its glycogenic properties. We have found that the PP1 binding domain of R6 comprises a conserved RVXF motif (R102VRF) located at the N-terminus of the protein. We have also identified a region located at the C-terminus of R6 (W267DNND) that is involved in binding to the PP1 glycogenic substrates. Our results indicate that although binding to PP1 and glycogenic substrates are independent processes, impairment of any of them results in lack of glycogenic activity of R6. In addition, we have characterized a novel site of regulation in R6 that is involved in binding to 14-3-3 proteins (RARS74LP). We present evidence indicating that when binding of R6 to 14-3-3 proteins is prevented, R6 displays hyper-glycogenic activity although is rapidly degraded by the lysosomal pathway. These results define binding to 14-3-3 proteins as an additional pathway in the control of the glycogenic properties of R6. PMID- 26114293 TI - Correction: Modeling of In-Utero and Intra-Partum Transmissions to Evaluate the Efficacy of Interventions for the Prevention of Perinatal HIV. PMID- 26114291 TI - De Novo Regulatory Motif Discovery Identifies Significant Motifs in Promoters of Five Classes of Plant Dehydrin Genes. AB - Plants accumulate dehydrins in response to osmotic stresses. Dehydrins are divided into five different classes, which are thought to be regulated in different manners. To better understand differences in transcriptional regulation of the five dehydrin classes, de novo motif discovery was performed on 350 dehydrin promoter sequences from a total of 51 plant genomes. Overrepresented motifs were identified in the promoters of five dehydrin classes. The Kn dehydrin promoters contain motifs linked with meristem specific expression, as well as motifs linked with cold/dehydration and abscisic acid response. KS dehydrin promoters contain a motif with a GATA core. SKn and YnSKn dehydrin promoters contain motifs that match elements connected with cold/dehydration, abscisic acid and light response. YnKn dehydrin promoters contain motifs that match abscisic acid and light response elements, but not cold/dehydration response elements. Conserved promoter motifs are present in the dehydrin classes and across different plant lineages, indicating that dehydrin gene regulation is likely also conserved. PMID- 26114294 TI - Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells. AB - Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184+/-0.045 mM, 0.665+/-0.007 mM, 2.347+/-0.010 mM and 1.885+/-0.015 mM (mean+/- standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti cancer activity in breast cancer. PMID- 26114295 TI - Estimating Gestational Age in Late Presenters to Antenatal Care in a Resource Limited Setting on the Thai-Myanmar Border. AB - Estimating gestational age in resource-limited settings is prone to considerable inaccuracy because crown-rump length measured by ultrasound before 14 weeks gestation, the recommended method for estimating gestational age, is often unavailable. Judgements regarding provision of appropriate obstetric and neonatal care are dependent on accurate estimation of gestational age. We determined the accuracy of the Dubowitz Gestational Age Assessment, a population-specific symphysis-fundal height formula, and ultrasound biometry performed between 16 and 40 weeks gestation in estimating gestational age using pre-existing data from antenatal clinics of the Shoklo Malaria Research Unit on the Thai-Myanmar border, where malaria is endemic. Two cohorts of women who gave birth to live singletons were analysed: 1) 250 women who attended antenatal care between July 2001 and May 2006 and had both ultrasound crown-rump length (reference) and a Dubowitz Gestational Age Assessment; 2) 975 women attending antenatal care between April 2007 and October 2010 who had ultrasound crown-rump length, symphysis-fundal measurements, and an additional study ultrasound (biparietal diameter and head circumference) randomly scheduled between 16 and 40 weeks gestation. Mean difference in estimated newborn gestational age between methods and 95% limits of agreement (LOA) were determined from linear mixed-effects models. The Dubowitz method and the symphysis-fundal height formula performed well in term newborns, but overestimated gestational age of preterms by 2.57 weeks (95% LOA: 0.49, 4.65) and 3.94 weeks (95% LOA: 2.50, 5.38), respectively. Biparietal diameter overestimated gestational age by 0.83 weeks (95% LOA: -0.93, 2.58). Head circumference underestimated gestational age by 0.39 weeks (95% LOA: -2.60, 1.82), especially if measured after 24 weeks gestation. The results of this study can be used to quantify biases associated with alternative methods for estimating gestational age in the absence of ultrasound crown-rump length to inform critical clinical judgements in this population, and as a point of reference elsewhere. PMID- 26114296 TI - "Attacks" or "Whistling": Impact of Questionnaire Wording on Wheeze Prevalence Estimates. AB - BACKGROUND: Estimates of prevalence of wheeze depend on questionnaires. However, wording of questions may vary between studies. We investigated effects of alternative wording on estimates of prevalence and severity of wheeze, and associations with risk factors. METHODS: White and South Asian children from a population-based cohort (UK) were randomly assigned to two groups and followed up at one, four and six years (1998, 2001, 2003). Parents were asked either if their child ever had "attacks of wheeze" (attack group, N=535), or "wheezing or whistling in the chest" (whistling group, N=2859). All other study aspects were identical, including questions about other respiratory symptoms. RESULTS: Prevalence of wheeze ever was lower in the attack group than in the whistling group for all surveys (32 vs. 40% in white children aged one year, p<0.001). Prevalence of other respiratory symptoms did not differ between groups. Wheeze tended to be more severe in the attack group. The strength of association with risk factors was comparable in the two groups. CONCLUSIONS: The wording of questions on wheeze can affect estimates of prevalence, but has less impact on measured associations with risk factors. Question wording is a potential source of between-study-heterogeneity in meta-analyses. PMID- 26114297 TI - Cost-Effectiveness Analysis of Universal Vaccination of Adults Aged 60 Years with 23-Valent Pneumococcal Polysaccharide Vaccine versus Current Practice in Brazil. AB - OBJECTIVE: To evaluate the cost-effectiveness of introducing universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) into the National Immunization Program (NIP) in Brazil. METHODS: Economic evaluation using a Markov model to compare two strategies: (1) universal vaccination of adults aged 60 years with one dose of PPV23 and 2) current practice (vaccination of institutionalized elderly and elderly with underlying diseases). The perspective was from the health system and society. Temporal horizon was 10 years. Discount rate of 5% was applied to costs and benefits. Clinical syndromes of interest were invasive pneumococcal disease (IPD) including meningitis, sepsis and others and pneumonia. Vaccine efficacy against IPD was obtained from a meta-analysis of randomized control trials and randomized studies, whereas vaccine effectiveness against pneumonia was obtained from cohort studies. Resource utilization and costs were obtained from the Brazilian Health Information Systems. The primary outcome was cost per life year saved (LYS). Univariate and multivariate sensitivity analysis were performed. RESULTS: The universal vaccination strategy avoided 7,810 hospitalizations and 514 deaths, saving 3,787 years of life and costing a total of USD$31,507,012 and USD$44,548,180, respectively, from the health system and societal perspective. The universal immunization would result in ICERs of USD$1,297 per LYS, from the perspective of the health system, and USD$904 per LYS, from the societal perspective. CONCLUSION: The results suggest that universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is a very cost-effective intervention for preventing hospitalization and deaths for IPD and pneumonia is this age group in Brazil. PMID- 26114299 TI - Correction: Estrogen Receptor beta2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1alpha in Prostate Cancer. PMID- 26114298 TI - Cortical and Subcortical Grey and White Matter Atrophy in Myotonic Dystrophies Type 1 and 2 Is Associated with Cognitive Impairment, Depression and Daytime Sleepiness. AB - OBJECTIVES: Central nervous system involvement is one important clinical aspect of myotonic dystrophy type 1 and 2 (DM1 and DM2). We assessed CNS involvement DM1 and DM2 by 3T MRI and correlated clinical and neuocognitive symptoms with brain volumetry and voxel-based morphometry (VBM). METHODS: 12 patients with juvenile or classical DM1 and 16 adult DM2 patients underwent 3T MRI, a thorough neurological and neuropsychological examination and scoring of depression and daytime sleepiness. Volumes of brain, ventricles, cerebellum, brainstem, cervical cord, lesion load and VBM results of the patient groups were compared to 33 matched healthy subjects. RESULTS: Clinical symptoms were depression (more pronounced in DM2), excessive daytime sleepiness (more pronounced in DM1), reduced attention and flexibility of thinking, and deficits of short-term memory and visuo-spatial abilities in both patient groups. Both groups showed ventricular enlargement and supratentorial GM and WM atrophy, with prevalence for more GM atrophy and involvement of the motor system in DM1 and more WM reduction and affection of limbic structures in DM2. White matter was reduced in DM1 in the splenium of the corpus callosum and in left-hemispheric WM adjacent to the pre- and post-central gyrus. In DM2, the bilateral cingulate gyrus and subgyral medio frontal and primary somato-sensory WM was affected. Significant structural functional correlations of morphological MRI findings (global volumetry and VBM) with clinical findings were found for reduced flexibility of thinking and atrophy of the left secondary visual cortex in DM1 and of distinct subcortical brain structures in DM2. In DM2, depression was associated with brainstem atrophy, Daytime sleepiness correlated with volume decrease in the middle cerebellar peduncles, pons/midbrain and the right medio-frontal cortex. CONCLUSION: GM and WM atrophy was significant in DM1 and DM2. Specific functional-structural associations related morphological changes to cognitive impairment, depression and daytime sleepiness, partly indicating involvement of complex neuronal networks. PMID- 26114300 TI - The Molecular and Genetic Basis of Repeatable Coevolution between Escherichia coli and Bacteriophage T3 in a Laboratory Microcosm. AB - The objective of this study was to determine the genomic changes that underlie coevolution between Escherichia coli B and bacteriophage T3 when grown together in a laboratory microcosm. We also sought to evaluate the repeatability of their evolution by studying replicate coevolution experiments inoculated with the same ancestral strains. We performed the coevolution experiments by growing Escherichia coli B and the lytic bacteriophage T3 in seven parallel continuous culture devices (chemostats) for 30 days. In each of the chemostats, we observed three rounds of coevolution. First, bacteria evolved resistance to infection by the ancestral phage. Then, a new phage type evolved that was capable of infecting the resistant bacteria as well as the sensitive bacterial ancestor. Finally, we observed second-order resistant bacteria evolve that were resistant to infection by both phage types. To identify the genetic changes underlying coevolution, we isolated first- and second-order resistant bacteria as well as a host-range mutant phage from each chemostat and sequenced their genomes. We found that first order resistant bacteria consistently evolved resistance to phage via mutations in the gene, waaG, which codes for a glucosyltransferase required for assembly of the bacterial lipopolysaccharide (LPS). Phage also showed repeatable evolution, with each chemostat producing host-range mutant phage with mutations in the phage tail fiber gene T3p48 which binds to the bacterial LPS during adsorption. Two second-order resistant bacteria evolved via mutations in different genes involved in the phage interaction. Although a wide range of mutations occurred in the bacterial waaG gene, mutations in the phage tail fiber were restricted to a single codon, and several phage showed convergent evolution at the nucleotide level. These results are consistent with previous studies in other systems that have documented repeatable evolution in bacteria at the level of pathways or genes and repeatable evolution in viruses at the nucleotide level. Our data are also consistent with the expectation that adaptation via loss-of-function mutations is less constrained than adaptation via gain-of-function mutations. PMID- 26114301 TI - Isolation and Characterization of a Novel Pathogenesis-Related Protein Gene (GmPRP) with Induced Expression in Soybean (Glycine max) during Infection with Phytophthora sojae. AB - Pathogenesis-related proteins (PR proteins) play crucial roles in the plant defense system. A novel PRP gene was isolated from highly resistant soybean infected with Phytophthora sojae (P. sojae) and was named GmPRP (GenBank accession number: KM506762). The amino acid sequences of GmPRP showed identities of 74%, 73%, 72% and 69% with PRP proteins from Vitis vinifera, Populus trichocarpa, Citrus sinensis and Theobroma cacao, respectively. Quantitative real time reverse transcription PCR (qRT-PCR) data showed that the expression of GmPRP was highest in roots, followed by the stems and leaves. GmPRP expression was upregulated in soybean leaves infected with P. sojae. Similarly, GmPRP expression also responded to defense/stress signaling molecules, including salicylic acid (SA), ethylene (ET), abscisic acid (ABA) and jasmonic acid (JA). GmPRP was localized in the cell plasma membrane and cytoplasm. Recombinant GmPRP protein exhibited ribonuclease activity and significant inhibition of hyphal growth of P. sojae 1 in vitro. Overexpression of the GmPRP gene in T2 transgenic tobacco and T2 soybean plants resulted in enhanced resistance to Phytophthora nicotianae (P. nicotianae) and P. sojae race 1, respectively. These results indicated that the GmPRP protein played an important role in the defense of soybean against P. sojae infection. PMID- 26114303 TI - Therapeutic and nutraceutical potential of rosmarinic acid-Cytoprotective properties and pharmacokinetic profile. AB - Rosmarinic acid (RA) is a natural polyphenolic antioxidant derived from many common herbal plants. This compound displays several important biological properties, including anti-inflammatory, antiviral, antibacterial, antidepressant, anticarcionogenic, and chemopreventive properties. The importance of its activities and its possible application in processed foods as a natural antioxidant has reached a new interest levels in recent years. The health effects of this polyphenol depend greatly on both its intakes and bioavailability. This review focuses on the importance of RA as a dietary supplement, and summarizes its pharmacokinetics and metabolism, including the factors that limit its oral bioavailability which leads to a lower therapeutic action. Further experimental investigations are needed to optimize and enhance the oral bioavailability of this natural compound which consequently will help increasing therapeutic efficacy of RA in vivo. PMID- 26114302 TI - Structural Basis of Specific Recognition of Non-Reducing Terminal N Acetylglucosamine by an Agrocybe aegerita Lectin. AB - O-linked N-acetylglucosaminylation (O-GlcNAcylation) is a reversible post translational modification that plays essential roles in many cellular pathways. Research in this field, however, is hampered by the lack of suitable probes to identify, accumulate, and purify the O-GlcNAcylated proteins. We have previously reported the identification of a lectin from the mushroom Agrocybe aegerita, i.e., Agrocybe aegerita lectin 2, or AAL2, that could bind terminal N acetylglucosamine with higher affinities and specificity than other currently used probes. In this paper, we report the crystal structures of AAL2 and its complexes with GlcNAc and GlcNAcbeta1-3Galbeta1-4GlcNAc and reveal the structural basis of GlcNAc recognition by AAL2 and residues essential for the binding of terminal N-acetylglucosamine. Study on AAL2 may enable us to design a protein probe that can be used to identify and purify O-GlcNAcylated proteins more efficiently. PMID- 26114304 TI - Domino One-Pot Process for the Synthesis of Isobenzofuran-1(3H)-ones via [Cu] Catalysis Using Water as the Green Solvent. AB - An efficient domino one-pot strategy via [Cu]-catalyzed intermolecular "cyanation" of o-bromobenzyl alcohols -> in situ intramolecular "nucleophilic attack" -> "hydrolysis" is presented, for the synthesis of isobenzofuran-1(3H) ones. Significantly, the reaction is successfully carried out under environmentally benign conditions, using water as sole green solvent. PMID- 26114305 TI - N-Coordinated Tin(II) Trifluoromethanesulfonates and Their Reactions with Transition Metal Carbonyls. AB - The syntheses of the compounds [L(1)SnCl][M(CO)5(SnCl3)] (3, M = W; 4, M = Cr), [L(1)SnCl]OTf (5), [L(1)SnCl][W(CO)5(SnCl2OTf)] (6), [L(1)SnOTf][OTf] (7), and [L(2)Sn(OTf)2] (8) with L(1) = {2,6-[(CH3)C?N(C6H3-2,6-(i)Pr2)2]C5H3N} (DIMPY) and L(2) = {2-[(CH3)C?N(C6H3-2,6-(i)Pr2)]-6-(CH3O)}C5H3N) is reported. The compounds were characterized by elemental analyses, (1)H, (13)C, (19)F, and (119)Sn NMR spectroscopy, electrospray ionization mass spectrometry, and single crystal X-ray diffraction analyses (3.1.5C7H8, 5.CH2Cl2, 7.C7H8, 8). For compounds 7 and 8, the experimental work is accompanied by density functional theory calculations. PMID- 26114306 TI - Quinoa: Nutritional, functional, and antinutritional aspects. AB - We have prepared a review of the physical-chemical composition and the functional and anti-nutritional properties of quinoa (Chenopodium quinoa Willd.). It is a plant of the Chenopodiaceae family, originally from the Andean regions, adaptable to different types of soils and climatic conditions. Its composition has attracted the attention of scientific community for its high nutritional value, being rich in proteins, lipids, fibers, vitamins, and minerals, with an extraordinary balance of essential amino acids. It is also gluten-free, a characteristic that enables its use by celiac patients. In spite of all these attributes, quinoa is not widely used by consumers due to the high cost of imported grain and little knowledge of its benefits. More studies are required to increase knowledge about this "pseudo-cereal" to demonstrate its functional and nutritional benefits and to study its anti-nutritional effects, since it presents high commercial value and excellent nutritional quality. PMID- 26114307 TI - Discovery of nitroaryl urea derivatives with antiproliferative properties. AB - A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC50 = 14.3 uM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development. PMID- 26114308 TI - 1-Substituted carbamoyl and thiocarbamoyl-4,5-dihydro-1H-pyrazoles as possible cytotoxic and antimicrobial agents. AB - Two series of 1-substituted carbamoyl and thiocarbomoyl derivatives were prepared by either treating the corresponding pyrazole with the appropriate isocyanate and isothiocyanate respectively, or alternatively by condensing the appropriate diketone with the proper substituted semicarbazide or thiosemicarbazide. The structures of the prepared compounds were fully determined by analytical and spectral methods. Preliminary biological screening of the prepared compounds revealed significant antibacterial and cytotoxic activities for some compounds. Compounds 4a2 and 4a3 were found to be the most active against the human colon carcinoma HT29 (11.8 and 7.5 MUg/mL, respectively) and human breast cancer MCF 7 (3.4 and 2.6 MUg/mL, respectively) cell lines. The structure-activity relationship (SAR) and in silico drug relevant properties (HBD, HBA, tPSA, cLog P, molecular weight, % ABS, drug-likeness and drug score) further confirmed that the compounds are potential lead compounds for future drug discovery study. PMID- 26114309 TI - Synthesis of 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides and their evaluation as ligands for NMDA receptor glycine binding site. AB - A series of 2-substituted 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1 dioxides were synthesized and evaluated for their affinity to the glycine binding site of the N-methyl-d-aspartate (NMDA) receptor. The binding affinity was determined by the displacement of radioligand [(3)H]MDL-105,519 from rat cortical membrane preparations. The most attractive structures in the search for prospective NMDA receptor ligands were identified to be 2-arylcarbonylmethyl substituted 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides. It has been demonstrated for the first time that the replacement of NH group in the ligand by sp(3) CH2 is tolerated. This finding may pave the way for previously unexplored approaches for designing new ligands of the NMDA receptor. PMID- 26114310 TI - Further in vitro biological activity evaluation of amino-, thio- and ester derivatives of avarol. AB - The acetylcholinesterase inhibitory and/or antitumour activities of amino-, thio- and ester-derivatives of avarol selected were evaluated for the first time at in vitro conditions. Avarol-3',4'-dithioglycol (1) and avarol-4' (3)mercaptopropionic acid (3) were shown to be the best inhibitors of the enzyme tested (0.50 ug and IC50 0.05 mM and 0.50 ug and IC50 0.12 mM, respectively), while 4'-tryptamine-avarone (9) and avarol-3'-(3)mercaptopropionic acid (2) exhibited the highest cytotoxicity against the human breast T-47D cancer cell line (IC50 0.66 ug/mL and 1.25 ug/mL, respectively). According to experimental data obtained, the sesquiterpenoid hydroquinone structure of bioactive avarol derivatives may inspire development of new pharmacologically useful substances to be used in the treatment of Alzheimer's disease and/or human breast tumour. PMID- 26114315 TI - The no-touch rubber hand paradigm and mirror-touch sensation: Support for the self-other theory of mirror-touch synesthesia. AB - We thoroughly enjoyed Ward and Banissy's Discussion Paper on mirror-touch synesthesia. The authors contrast two theories for explaining this phenomenon-the Threshold Theory and their Self-Other Theory. Ward and Banissy note that the Self Other Theory garners support from studies that have tested individuals with mirror-touch synesthesia using the rubber hand paradigm. In this Commentary, we provide further support for the Self-Other Theory by drawing on findings from control participants without mirror-touch synesthesia tested with two different no-touch rubber hand paradigms-one paradigm makes it easier while the other makes it more difficult to make the self-other distinction. PMID- 26114311 TI - Short Communication: HIV-1 Variants That Use Mouse CCR5 Reveal Critical Interactions of gp120's V3 Crown with CCR5 Extracellular Loop 1. AB - The CCR5 coreceptor amino terminus and extracellular (ECL) loops 1 and 2 have been implicated in HIV-1 infections, with species differences in these regions inhibiting zoonoses. Interactions of gp120 with CD4 and CCR5 reduce constraints on metastable envelope subunit gp41, enabling gp41 conformational changes needed for infection. We previously selected HIV-1JRCSF variants that efficiently use CCR5(Delta18) with a deleted amino terminus or CCR5(HHMH) with ECL2 from an NIH/Swiss mouse. Unexpectedly, the adaptive gp120 mutations were nearly identical, suggesting that they function by weakening gp120's grip on gp41 and/or by increasing interactions with ECL1. To analyze this and further wean HIV-1 from human CCR5, we selected variants using CCR5(HMMH) with murine ECL1 and 2 sequences. HIV-1JRCSF mutations adaptive for CCR5(Delta18) and CCR5(HHMH) were generally maladaptive for CCR5(HMMH), whereas the converse was true for CCR5(HMMH) adaptations. The HIV-1JRCSF variant adapted to CCR5(HMMH) also weakly used intact NIH/Swiss mouse CCR5. Our results strongly suggest that HIV-1JRCSF makes functionally critical contacts with human ECL1 and that adaptation to murine ECL1 requires multiple mutations in the crown of gp120's V3 loop. PMID- 26114316 TI - The sweet side of YAP/TAZ. PMID- 26114317 TI - The complete mitochondrial genome of the mysid shrimp, Neomysis japonica (Crustacea, Malacostraca, Mysida). AB - In this study, we determined the mitogenome sequence of Neomysis japonica (Crustacea, Malacostraca, Mysida), which is the first complete mitogenome sequence in the order Mysida. The mitogenome of N. japonica is 17,652 bp in length and contains 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and a control region (CR). Mitogenome analysis of N. japonica revealed a novel gene order that included inversions in three PCGs and five tRNAs, compared with H. americanus, the ancestral pancrustacean ground pattern. The results will be useful for the detailed study of mitogenome evolution and the phylogenetic relationships among the orders in the class Malacostraca. As seen from the phylogenetic tree, N. japonica belongs to the order Mysida within Malacostraca. PMID- 26114318 TI - Mitochondrial DNA deletions detected by Multiplex Ligation-dependent Probe Amplification. AB - The genetic diagnosis algorithm for mitochondrial (mt) diseases starts looking for deletions and common mutations in mtDNA. MtDNA's special features, such as large and variable genome copies, heteroplasmy, polymorphisms, and its duplication in the nuclear genome as pseudogenes (NUMTs), make it vulnerable to diagnostic misleading interpretations. Multiplex Ligation-dependent Probe Amplification (MLPA) is used to detect copy number variations in nuclear genes and its application on mtDNA has not been widely spread. We report three Kearns Sayre Syndrome patients and one Chronic Progressive External Ophthalmoplegia adult, whose diagnostic mtDNA deletions were detected by MLPA using a very low amount of DNA. This managed to "dilute" the NUMT interference as well as enhance MLPA's efficiency. By this report, we conclude that when MLPA is performed upon a reduced amount of DNA, it can detect effectively mtDNA deletions. We propose MLPA as a possible first step method in the diagnosis of mt diseases. PMID- 26114319 TI - Sequencing and analysis of the complete mitochondrial genome in Anopheles culicifacies species B (Diptera: Culicidae). AB - The complete mitochondrial genome sequence of Anopheles culicifacial species B was sequenced in this study. The length of the mitochondrial genome is 15 330 bp, which contains 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and a non-coding control region. The gene order and the gene composition are consistent with those previously reported for other mosquito species. The initiation codon of the PCGs complies with the ATN rule except for COI using TCG and ND5 using GTG as a start codon, and the termination codon is TAA or imcomplete, an only T. The total base composition is 40.4% A, 38.1% T, 12.4% C, and 9.1% G. The phylogenetic tree based on the sequences of 13 protein-coding genes showed that these species were classified into two clades, corresponding to the subgenus Cellia and subgenus Nyssorhynchus. An. culicifacies species B of Myzomyia Series was clustered with An. gambiae of Pyretophorus Series with a high bootstrap value of 100%. The complete mitogenome data can provide a basis for molecular identification and phylogenetic studies of mosquito species. PMID- 26114320 TI - The complete mitochondrial genome of an Antarctic moss Syntrichia filaris (Mull.Hal.) R.H. Zander. AB - The mitogenome of the Syntrichia filaris (GenBank accession number KP984758) has a total length of 106,343 bp and consists of 40 protein-coding genes, 3 ribosomal RNA (rRNA) and 24 transfer RNA. The mitochondrial structure and gene order was similar to other Bryophytes. Phylogenetic tree based on the combined analysis of amino acid sequences of 31 mitochondrial genes common in S. filaris, 17 Bryophyta and 3 Marchantiophyta, was well congruent with traditional species relationship of the moss order Pottiales. PMID- 26114321 TI - The complete chloroplast genome of salt cress (Eutrema salsugineum). AB - The complete chloroplast (cp) sequence of the salt cress (Eutrema salsugineum), a plant well-adapted to salt stress, was presented in this study. The circular molecule is 153,407 bp in length and exhibit a typical quadripartite structure containing an 83,894 bp large single copy (LSC) region, a 17,607 bp small single copy (SSC) region, and the two 25,953 bp inverted repeats (IRs). The salt cress cp genome contains 135 known genes, including 87 protein-coding genes, 8 ribosomal RNA genes, and 40 tRNA genes; 21 of these are located in the inverted repeat region. As expected, phylogenetic analysis support the idea that E. salsugineum is sister to Brassiceae species within the Brassicaceae family. PMID- 26114322 TI - The complete mitochondrial genome sequence of Wenxian Knobby Newt Tylototriton wenxianensis (Amphibia: Caudata). AB - We newly sequenced the mitochondrial genome of Tylototriton wenxianensis. The total length of the T. wenxianensis mitogenome is 16 265 bp, with GenBank accession number KR733683. It consists of 13 protein-coding genes (PCGs), two ribosomal RNA genes (rRNA), 22 transfer RNA genes (tRNA), and one control region (CR). Most of the genes are encoded on the H-strand, except for eight tRNA and ND6, which are encoded on the L-strand. Our mitogenomic phylogenetic tree showed that the relationships among the genera Tylototriton, Echinotriton, and Pleurodeles were well supported, and which is consistent with the previous molecular phylogeny. PMID- 26114323 TI - Complete mitogenomes of Guinean angelfish (Holacanthus africanus) and Rock beauty (Holacanthus tricolor) (Teleostei: Pomacanthidae). AB - In this study, we used the next-generation sequencing method to deduce two complete mitogenomes of Guinean angelfish (Holacanthus africanus) and Rock beauty (Holacanthus tricolor) for the first time. The assembled mitogenome, consisting of 16,819 bp and 16,625 bp in length, shows 87% similarity with each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes, and a non-coding control region of D-loop. The D-loop contains 1107 bp in H. africanus and 905 bp in H. tricolor and is located between tRNA-Pro and tRNA-Phe. The overall GC content is 46.2% for H. africanus and 45.6% for H. tricolor. The complete mitogenome of Guinean angelfish and Rock beauty deduced in this study provides essential and important DNA molecular data for further phylogenetic and evolutionary analysis for marine angelfish. PMID- 26114324 TI - Complete chloroplast genome of the Oriental white oak: Quercus aliena Blume. AB - The complete chloroplast (cp) genome sequence of the Oriental white oak: Quercus aliena Blume, the first sequenced member of the section Quercus, is reported in this study. The length of cp genome size is 160,921 bp, with 36.9% GC content. A pair of 25,841 bp inverted repeat regions (IRs) is separated by a 90,258 bp large single copy region (LSC) and an 18,980 bp small single copy region (SSC). This genome contains 115 unique genes, including 89 coding genes, four rRNA genes, and 39 tRNA genes. Border analysis of cp genome of Quercus aliena and other 10 most closely related cp genomes revealed that most Fagaceae species have high similarity either in structure or distribution of these genes except for Trigonobalanus doichangensis. PMID- 26114325 TI - Sequencing and analysis of the complete mitochondrial genome of Aedes albopictus (Diptera: Culicidae) in China. AB - The complete sequence of the mitochondrial genome of the Aedes albopictus (Diptera: Culicidae) is presented using traditional Sanger sequencing. Its mitogenome are 16,660 bp in length, consisting of 13 protein-coding genes, 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and a non-coding A + T rich region. As in other insects, most mitochondrial genes are encoded on the heavy strand, except for ND5, ND4, ND4L, ND1, two rRNA and eight tRNA genes, which are encoded on the light strand. The overall base composition on heavy strand was as follows - A: 40.1%, G: 8.2%, C: 11.9%, T: 39.8% and the A + T content 79.9%. The results of phylogenetic analyzes showed that the Ae. albopictus has closed relationship with the family Culicidae and order Diptera. PMID- 26114326 TI - Relationships between Cardiorespiratory and Muscular Fitness with Cardiometabolic Risk in Adolescents. AB - This study examined the independent relationships between cardiorespiratory and muscular fitness with cardiometabolic risk in adolescents. Subjects were 192 adolescents (118 boys), aged 15-17.5 years. The 2 m multi-stage fitness test assessed cardiorespiratory fitness and the counter movement jump assessed muscular fitness. Additional measures included interleukin-6, C-reactive protein, adiponectin, fibrinogen and plasminogen activator inhibitor-1. Regression analysis revealed that cardiorespiratory fitness was negatively related to cardiometabolic risk (beta = -0.014, p < 0.001). With additional adjustment for muscular fitness the relationship remained significant (beta = -0.015, p < 0.001). Muscular fitness was negatively related to cardiometabolic risk (beta = 0.021, p < 0.001) and remained significant after adjustment for cardiorespiratory fitness. Participants in the least-fit quartile for both cardiorespiratory and muscular fitness had significantly poorer cardiometabolic risk scores than those in the other quartiles. Findings revealed that muscular and cardiorespiratory fitness are significantly associated with cardiometabolic risk independently of one another. PMID- 26114327 TI - Radiation Dose-Rate Effects on Gene Expression in a Mouse Biodosimetry Model. AB - In the event of a nuclear accident or radiological terrorist attack, there will be a pressing need for biodosimetry to triage a large, potentially exposed population and to assign individuals to appropriate treatment. Exposures from fallout are likely, resulting in protracted dose delivery that would, in turn, impact the extent of injury. Biodosimetry approaches that can distinguish such low-dose-rate (LDR) exposures from acute exposures have not yet been developed. In this study, we used the C57BL/6 mouse model in an initial investigation of the impact of low-dose-rate delivery on the transcriptomic response in blood. While a large number of the same genes responded to LDR and acute radiation exposures, for many genes the magnitude of response was lower after LDR exposures. Some genes, however, were differentially expressed (P < 0.001, false discovery rate <5%) in mice exposed to LDR compared with mice exposed to acute radiation. We identified a set of 164 genes that correctly classified 97% of the samples in this experiment as exposed to acute or LDR radiation using a support vector machine algorithm. Gene expression is a promising approach to radiation biodosimetry, enhanced greatly by this first demonstration of its potential for distinguishing between acute and LDR exposures. Further development of this aspect of radiation biodosimetry, either as part of a complete gene expression biodosimetry test or as an adjunct to other methods, could provide vital triage information in a mass radiological casualty event. PMID- 26114329 TI - Defining the Biological Effectiveness of Components of High-LET Track Structure. AB - During space travel, astronauts are exposed to a wide array of high-linear energy transfer (LET) particles, with differing energies and resulting biological effects. Risk assessment of these exposures carries a large uncertainty predominantly due to the unique track structure of the particle's energy deposition. The complex damage elicited by high charge and energy (HZE) particles results from both lesions along the track core and from energetic electrons, delta rays, generated as a consequence of particle traversal. To better define how cells respond to this complex radiation exposure, a normal hTERT immortalized skin fibroblast cell line was exposed to a defined panel of particles carefully chosen to tease out track structure effects. Phosphorylation kinetics for several key double-strand break (DSB) response proteins (gamma-H2AX, pATF2 and pSMC1) were defined after exposure to ten different high-LET radiation qualities and one low-LET radiation (X ray), at two doses (0.5-2 Gy) and time points (2 and 24 h). The results reveal that the lower energy particles (Fe 300, Si 93 and Ti 300 MeV/u), with a narrower track width and higher number and intensity of delta rays, cause the highest degree of persistent damage response. The persistent gamma-H2AX signal at lower energies suggests that damage from these exposures are more difficult to resolve, likely due to the greater complexity of the associated DNA lesions. However, different kinetics were observed for the solely ATM mediated phosphorylations (pATF2 and pSMC1), revealing a shallow induction at early times and a higher level of residual phosphorylation compared to gamma H2AX. The differing phospho-protein profiles exhibited, compared to gamma-H2AX, suggests additional functions for these proteins within the cell. The strong correspondence between the predicted curves for energy deposition per nucleosome for each ion/energy combination and the persistent levels of gamma-H2AX indicates that the nature of energy distribution defines residual levels of gamma-H2AX, an indicator of unrepaired DSBs. Our results suggest that decreasing the energy of a particle results in more complex damage that may increase genomic instability and increase the risk of carcinogenesis. PMID- 26114328 TI - Examining the Effects of External or Internal Radiation Exposure of Juvenile Mice on Late Morbidity after Infection with Influenza A. AB - A number of investigators have suggested that exposure to low-dose radiation may pose a potentially serious health risk. However, the majority of these studies have focused on the short-term rather than long-term effects of exposure to fixed source radiation, and few have examined the effects of internal contamination. Additionally, very few studies have focused on exposure in juveniles, when organs are still developing and could be more sensitive to the toxic effects of radiation. To specifically address whether early-life radiation injury may affect long-term immune competence, we studied 14-day-old juvenile pups that were either 5 Gy total-body irradiated or injected internally with 50 MUCi soluble (137)Cs, then infected with influenza A virus at 26 weeks after exposure. After influenza infection, all groups demonstrated immediate weight loss. We found that externally irradiated, infected animals failed to recover weight relative to age matched infected controls, but internally (137)Cs contaminated and infected animals had a weight recovery with a similar rate and degree as controls. Externally and internally irradiated mice demonstrated reduced levels of club cell secretory protein (CCSP) message in their lungs after influenza infection. The externally irradiated group did not recover CCSP expression even at the two week time point after infection. Although the antibody response and viral titers did not appear to be affected by either radiation modality, there was a slight increase in monocyte chemoattractant protein (MCP)-1 expression in the lungs of externally irradiated animals 14 days after influenza infection, with increased cellular infiltration present. Notably, an increase in the number of regulatory T cells was seen in the mediastinal lymph nodes of irradiated mice relative to uninfected mice. These data confirm the hypothesis that early-life irradiation may have long-term consequences on the immune system, leading to an altered antiviral response. PMID- 26114330 TI - Serum Amyloid A as a Biomarker for Radiation Exposure. AB - There is a need for minimally invasive biomarkers that can accurately and quickly quantify radiation exposure. Radiation-responsive proteins have applications in clinical medicine and for mass population screenings after a nuclear or radiological incident where the level of radiation exposure and exposure pattern complicate medical triage for first responders. In this study, we evaluated the efficacy of the acute phase protein serum amyloid A (SAA) as a biomarker for radiation exposure using plasma from irradiated mice. Ten-week-old female C57BL6 mice received a 1-8 Gy single whole-body or partial-body dose from a Pantak X-ray source at a dose rate of 2.28 Gy/min. Plasma was collected by mandibular or cardiac puncture at 6, 24, 48 and 72 h or 1-3 weeks postirradiation. SAA levels were determined using a commercially available ELISA assay. Data was pooled to generate SAA MUg/ml threshold values correlating plasma SAA levels with radiation dose. SAA levels were statistically significant over control at all exposures between 2 and 8 Gy at 24 h postirradiation but not at 6, 48 and 72 h or 1-3 weeks postirradiation. SAA levels at 1 Gy were not significantly elevated over control at all time points. Total-body-irradiated (TBI) SAA levels at 24 h were used to generate a dose prediction model that successfully differentiated TBI mice into dose received cohorts of control/1 Gy and >= 2 Gy groups with a high degree of accuracy in a blind study. Dose prediction of partial-body exposures based on the TBI model correlated increasing predictive accuracy with percentage of body exposure to radiation. Our findings indicate that plasma SAA levels might be a useful biomarker for radiation exposure in a variety of total- and partial-body irradiation settings. PMID- 26114331 TI - Effects of Switching from Timolol to Brimonidine in Prostaglandin Analog and Timolol Combination Therapy. AB - PURPOSE: To assess the efficacy and safety of switching from timolol 0.5% to brimonidine 0.1% in patients with glaucoma treated with a prostaglandin analog (PGA) and timolol combination. METHODS: This prospective, open-label multicenter study enrolled patients with open-angle glaucoma or ocular hypertension who were being treated with a PGA and timolol. After baseline measurements, timolol was switched to brimonidine 0.1%, and patients were followed for 12 weeks. Patients visited at 4 and 12 weeks after switching. The main outcome measure was the change in intraocular pressure (IOP). For safety evaluations, hyperemia, formation of conjunctival follicles, superficial punctate keratopathy as a local side effect, blood pressure (BP), and heart rate (HR) were evaluated. RESULTS: One hundred seven patients participated in this study. Among them, 103 patients completed the study. The IOP values at baseline, 4 weeks, and 12 weeks after the transition were 15.7 +/- 2.7, 14.3 +/- 2.8, and 14.0 +/- 2.8 mmHg, respectively. IOP was significantly reduced at 4 and 12 weeks compared with baseline (p<0.001). There were no significant changes in hyperemia or follicle formation. The superficial punctate keratopathy score was significantly reduced at 12 weeks compared with baseline (p<0.05). Systolic and diastolic BP values were significantly reduced and HR significantly increased after switching (p<0.05). CONCLUSION: Switching from timolol 0.5% to brimonidine 0.1% may not change IOP in the combination use of timolol 0.5% and a PGA and was well tolerated by patients without severe ocular or systemic side effects. PMID- 26114332 TI - Synergetic catalytic effect of Cu2-xSe nanoparticles and reduced graphene oxide coembedded in electrospun nanofibers for the reduction of a typical refractory organic compound. AB - A new heterogeneous catalytic composite composed of nonstoichiometric Cu2-xSe nanoparticles (NPs) with high copper deficiency and graphene oxide (GO) is prepared by coembedding in electrospun nanofibers of a poly(vinylpyrrolidone) (PVP) support, wherein GO in the nanofibers is converted into reduced GO (rGO) via heat treatment. The as-prepared composite Cu2-xSe/rGO/PVP nanofibers have demonstrated superior catalytic activity toward the reduction of a refractory organic compound by taking 4-nitrophenol (4-NP) as an example. In the presence of NaBH4, the Cu2-xSe/rGO/PVP nanofibers display a synergetic effect between Cu2-xSe and rGO in PVP nanofibers compared to their independent components or corresponding nanofibers. Furthermore, the Cu2-xSe/rGO/PVP nanofibers exhibit a favorable water-stable property via heat treatment to solidify the hydrophilic PVP matrix, which makes the composite display good reusability, stability in aqueous solution, and separability from a water medium. This work not only presents a direct, convenient, and effective approach to doping semiconductor nanomaterials into polymer nanofibers but also provides fundamental routes for further investigations about the synergetic effect between different materials based on the platform of electrospun nanofibers. PMID- 26114333 TI - The Use of Vacuum-Assisted Closure and GranuFoam Silver(r) Dressing in the Management of Diabetic Foot Ulcer. AB - PURPOSE: The aim of this retrospective study was to evaluate the efficacy of vacuum-assisted closure (VAC) and GranuFoam Silver(r) dressing (KCI, San Antonio, TX) compared with conventional GranuFoam(r) dressing in the management of diabetic foot ulcers. PATIENTS AND METHODS: Twenty-one consecutive patients treated with conventional or silver-coated foam dressing were reviewed retrospectively. The wound duration was 6 mo. Group 1 (n=10) received conventional foam dressing (GranuFoam) and group 2 (n=11) received silver-coated foam dressing (GranuFoam Silver). The wound surface area, duration of treatment, bacteriology, and recurrence were compared between the groups. The mean age of the patients was 61.70+/-10.52 y in group 1 and 67.27+/-11.28 y in group 2. RESULTS: In group 1, the average surface area of the wounds was 45.30+/-46.96 cm2 and 18.40+/-23.48 cm2 in the pre-treatment and post-treatment periods, respectively. There was a statistically significant difference between two measurements (p=0.005). Average duration of the treatment was 25.50+/-27.13 d in this group. In group 2, average surface area of the wounds in the pre-treatment and post-treatment periods were 41.55+/-36.03 cm2 and 7.64+/-3.91 cm2, respectively. There was a statistically significant difference between two measurements (p=0.003). Average duration of the treatment was 10.09+/-3.51 d in this group. The patients treated with silver-impregnated polyurethane foam dressing had reduced recurrence (2 vs. 7 wounds, p=0.030) and increased number of the culture-negative cases at the end of the treatment. CONCLUSION: With the results of the study, it was concluded that VAC GranuFoam silver dressing can be superior to conventional GranuFoam dressing in reducing the recurrence rate of infected diabetic foot ulcers. PMID- 26114334 TI - Development of Plate Reader and On-Line Microfluidic Screening to Identify Ligands of the 5-Hydroxytryptamine Binding Protein in Venoms. AB - The 5-HT3 receptor is a ligand-gated ion channel, which is expressed in the nervous system. Its antagonists are used clinically for treatment of postoperative- and radiotherapy-induced emesis and irritable bowel syndrome. In order to better understand the structure and function of the 5-HT3 receptor, and to allow for compound screening at this receptor, recently a serotonin binding protein (5HTBP) was engineered with the Acetylcholine Binding Protein as template. In this study, a fluorescence enhancement assay for 5HTBP ligands was developed in plate-reader format and subsequently used in an on-line microfluidic format. Both assay types were validated using an existing radioligand binding assay. The on-line microfluidic assay was coupled to HPLC via a post-column split which allowed parallel coupling to a mass spectrometer to collect MS data. This high-resolution screening (HRS) system is well suitable for compound mixture analysis. As a proof of principle, the venoms of Dendroapsis polylepis, Pseudonaja affinis and Pseudonaja inframacula snakes were screened and the accurate masses of the found bioactives were established. To demonstrate the subsequent workflow towards structural identification of bioactive proteins and peptides, the partial amino acid sequence of one of the bioactives from the Pseudonaja affinis venom was determined using a bottom-up proteomics approach. PMID- 26114336 TI - Interactions of borderline personality disorder and anxiety disorders over 10 years. AB - OBJECTIVE: This report examines the relationship of DSM-IV borderline personality disorder (BPD) to anxiety disorders using data on the reciprocal effects of improvement or worsening of BPD and anxiety disorders over the course of 10 years. METHOD: We reliably and prospectively assessed borderline patients (n = 164) with DSM-IV-defined co-occurring generalized anxiety disorder (GAD; n = 42), panic disorder with agoraphobia (n = 39), panic disorder without agoraphobia (n= 36), social phobia (n = 48), obsessive-compulsive disorder (OCD; n = 36), and posttraumatic stress disorder (PTSD; n = 88) annually over a period of 10 years between 1997 and 2009. We used proportional hazards regression analyses to assess the effects of monthly improvement or worsening of BPD and anxiety disorders on each other's remission and relapse the following month. RESULTS: BPD improvement significantly predicted remission of GAD (hazard ratio [HR] = 0.65, P <.05) and PTSD (HR = 0.57, P < .05), whereas BPD worsening significantly predicted social phobia relapse (HR = 1.87, P < .05). The course of anxiety disorders did not predict BPD remission or relapse, except that worsening PTSD significantly predicted BPD relapse (HR = 1.90, P < .05). CONCLUSION: BPD negatively affects the course of GAD, social phobia, and PTSD. In contrast, the anxiety disorders, aside from PTSD, had little effect on BPD course. For GAD and social phobia, whose course BPD unidirectionally influences, we suggest prioritizing treatment for BPD, whereas BPD should be treated concurrently with panic disorders, OCD, or PTSD. We discuss state/trait issues in the context of our findings. PMID- 26114335 TI - A Highly Specific Monoclonal Antibody for Botulinum Neurotoxin Type A-Cleaved SNAP25. AB - Botulinum neurotoxin type-A (BoNT/A), as onabotulinumtoxinA, is approved globally for 11 major therapeutic and cosmetic indications. While the mechanism of action for BoNT/A at the presynaptic nerve terminal has been established, questions remain regarding intracellular trafficking patterns and overall fate of the toxin. Resolving these questions partly depends on the ability to detect BoNT/A's location, distribution, and movement within a cell. Due to BoNT/A's high potency and extremely low concentrations within neurons, an alternative approach has been employed. This involves utilizing specific antibodies against the BoNT/A-cleaved SNAP25 substrate (SNAP25197) to track the enzymatic activity of toxin within cells. Using our highly specific mouse monoclonal antibody (mAb) against SNAP25197, we generated human and murine recombinant versions (rMAb) using specific backbone immunoglobulins. In this study, we validated the specificity of our anti-SNAP25197 rMAbs in several different assays and performed side-by-side comparisons to commercially-available and in-house antibodies against SNAP25. Our rMAbs were highly specific for SNAP25197 in all assays and on several different BoNT/A-treated tissues, showing no cross-reactivity with full-length SNAP25. This was not the case with other reportedly SNAP25197-selective antibodies, which were selective in some, but not all assays. The rMAbs described herein represent effective new tools for detecting BoNT/A activity within cells. PMID- 26114337 TI - Exploiting Oligo(amido amine) Backbones for the Multivalent Presentation of Coiled-Coil Peptides. AB - The investigation of coiled coil formation for one mono- and two divalent peptide polymer conjugates is presented. Through the assembly of the full conjugates on solid support, monodisperse sequence-defined conjugates are obtained with defined positions and distances between the peptide side chains along the polymeric backbone. A heteromeric peptide design was chosen, where peptide K is attached to the polymer backbone, and coiled-coil formation is only expected through complexation with the complementary peptide E. Indeed, the monovalent peptide K polymer conjugate displays rapid coiled-coil formation when mixed with the complementary peptide E sequence. The divalent systems show intramolecular homomeric coiled-coil formation on the polymer backbone despite the peptide design. Interestingly, this intramolecular assembly undergoes a conformational rearrangement by the addition of the complementary peptide E leading to the formation of heteromeric coiled coil-polymer aggregates. The polymer backbone acts as a template bringing the covalently bound peptide strands in close proximity to each other, increasing the local concentration and inducing the otherwise nonfavorable formation of intramolecular helical assemblies. PMID- 26114338 TI - Kasabach-Merritt syndrome, kaposiform haemangioendothelioma and platelet blockade. PMID- 26114339 TI - Neurofibromatosis type 1: neurofibromas and sex. PMID- 26114340 TI - Development of anti-migraine therapeutics using the capsaicin-induced dermal blood flow model. AB - The efficacy of calcitonin gene-related peptide (receptor) (CGRP-(R)) blocking therapeutics in the treatment of acute migraine headache provided proof-of concept for the involvement of CGRP in the pathophysiology of this disorder. One of the major hurdles for the development of any class of drugs, including CGRP blocking therapeutics, is the early clinical development process during which toxic and inefficacious compounds need to be eliminated as early as possible in order to focus on the most promising molecules. At this stage, human models providing proof of target engagement, combined with safety and tolerability studies, are extremely valuable in focusing on those therapeutics that have the highest engagement from the lowest exposure. They guide the go/no-go decision making, establish confidence in the candidate molecule by de-risking toxicity and safety issues and thereby speed up the early clinical development. In this review the focus is on the so called 'capsaicin model' as a typical example of a target engagement biomarker used as a human model for the development of CGRP blocking therapeutics. By applying capsaicin onto the skin, TRPV1 channels are activated and a CGRP-mediated increase in dermal blood flow can be quantified with laser Doppler perfusion imaging. Effective CGRP blocking therapeutics in turn, display blockade of this response. The translation of this biomarker model from animals to humans is discussed as well as the limitations of the assay in predicting the efficacy of anti-migraine drugs. PMID- 26114341 TI - Inguinal Herniation of a Transplant Ureter: Lessons Learned From a Case of "Water Over the Bridge". AB - Inguinal herniation of the transplant ureter is rare, and there is a paucity of reports in the literature. Herniation is usually secondary to implanting a long redundant ureter and may be precipitated by its course over the spermatic cord. Most often, there is loss of the allograft owing to delayed presentation and chronic ureteric obstruction. Here, we report a case of inguinal herniation of a transplant ureter with obstruction and graft dysfunction. A 72-year-old man presented 9 years after deceased-donor kidney transplant, with progressive graft dysfunction and a symptomatic right inguinal hernia. A nephrostogram and subsequent surgery confirmed herniation of a loop of transplant ureter into the inguinal canal with a proximal dilated ureter and hydronephrosis. A long and redundant ureter had been anastomosed "over" the spermatic cord to the bladder during the original operation. The ureter was shortened by excising the distal segment, and the proximal dilated ureter was anastomosed to the bladder passing it "underneath" the spermatic cord. We used a Vicryl (polyglactin 910) mesh to repair the hernia. The graft function improved to baseline levels after the nephrostomy and remained stable after the surgery. This case emphasizes the need to keep the ureter short, and the importance of passing it underneath the spermatic cord before anastomosing to the bladder. Transplant and general surgeons should be aware of such presentations of graft dysfunction with inguinal hernia to avoid delayed diagnosis and graft loss. PMID- 26114342 TI - Ultrasound of the Fetal Veins Part 3: The Fetal Intracerebral Venous System. AB - The study of the intracerebral venous system in the fetus can only be achieved by means of high-resolution ultrasound equipment with sensitive color Doppler. In the past two decades, there has been a growing interest in the ultrasound examination of the fetal brain with few studies reporting on the brain vasculature during various stages of gestation. In comparison to other fetal venous systems, reports on the assessment of the fetal cerebral venous system are still scarce. This article presents a review on the fetal intracranial venous system with detailed discussions on the anatomy of the superficial and deep cerebral veins. Color Doppler of the main fetal cerebral veins to include the superior sagittal sinus, the straight sinus, the vein of Galen, the internal cerebral veins, the transverse sinuses and others is also discussed. Furthermore, this article highlights abnormal clinical conditions such as aneurysm of the vein of Galen, thrombosis of the dural sinus and variation in the course of some veins such as the straight sinus and falcine sinus. The role of pulsed Doppler examination in normal and growth-restricted fetuses is also discussed. PMID- 26114343 TI - Gastric Lesions: Demonstrated by Transabdominal Ultrasound After Oral Administration of an Echoic Cellulose-Based Gastric Ultrasound Contrast Agent. PMID- 26114344 TI - Prenatal Diagnosis of Anomalies of the Corpus Callosum over a 13-Year Period. AB - Purpose: The clinical use of detailed fetal neurosonography has increased over the past decade. This retrospective study explored the spectrum and frequency of different forms of corpus callosum anomalies (CCAs) in a level III center setting. Materials and Methods: Between 1999 and 2012, 48 907 detailed second and third trimester scans were performed. Among them, 140 (0.29 %) cases of CCA were diagnosed. We differentiated between complete and partial agenesis, hypoplastic corpus callosum (CC) and isolated and non-isolated forms. Results: The 140 cases with CCA included 107 with complete agenesis (76 %), 20 with partial agenesis (14 %) and 13 with a hypoplastic CC (9 %). Of them, 29 % (41/140) were isolated and 71 % (99/140) were non-isolated cases. Analysis of three time periods demonstrated an increase in the diagnosis of all types of CCA (1999 - 2004: n = 26; 2005 - 2008: n = 32; 2009 - 2012: n = 82), whereas the ratio between isolated and non-isolated types remained stable. The median gestational age at diagnosis was 25.0 weeks and did not change over the years. Non-isolated forms were associated with additional non-chromosomal cerebral anomalies in 22.2 % (22/99), extracerebral non-chromosomal malformations in 40.4 % (40/99), aneuploidies in 21.2 % (21/99), and syndromes in 16.2 % (16/99). All aneuploid fetuses except one showed cerebral or extracerebral malformations. Conclusion: The rise in prenatal diagnosis of CCA reflects the increased use of systematic fetal neurosonography over the years. Despite an overall increase in diagnosed cases, the relationship between isolated CCAs and complex forms remained stable. Since the percentage of coexisting anomalies is high, a detailed assessment by a specialist is recommended. PMID- 26114345 TI - Diagnosis of toxic alcohols: limitations of present methods. AB - CONTEXT: Methanol, ethylene glycol, diethylene glycol, and propylene glycol intoxications are associated with cellular dysfunction and an increased risk of death. Adverse effects can develop quickly; thus, there is a need for methods for rapidly detecting their presence. OBJECTIVE: To examine the value and limitations of present methods to diagnose patients with possible toxic alcohol exposure. METHODS: I searched MEDLINE for articles published between 1969 and 2014 using the terms: toxic alcohols, serum osmolality, serum osmol gap, serum anion gap, metabolic acidosis, methanol, ethylene glycol, diethylene glycol, propylene glycol, and fomepizole. Each article was reviewed for additional references. RESULTS: The diagnosis of toxic alcohol exposure is often made on the basis of this history and physical findings along with an increase in the serum osmol and anion gaps. However, an increase in the osmol and/or anion gaps is not always present. Definitive detection in blood requires gas or liquid chromatography, laborious and expensive procedures which are not always available. Newer methods including a qualitative colorimetric test for detection of all alcohols or enzymatic tests for a specific alcohol might allow for more rapid diagnosis. CONCLUSIONS: Exposure to toxic alcohols is associated with cellular dysfunction and increased risk of death. Treatment, if initiated early, can markedly improve outcome, but present methods of diagnosis including changes in serum osmol and anion gap, and use of gas or liquid chromatography have important limitations. Development of more rapid and effective tests for detection of these intoxications is essential for optimal care of patients. PMID- 26114346 TI - Acute behavioural disturbance associated with phenibut purchased via an internet supplier. AB - CONTEXT: Toxicity from recreational substances marketed for other purposes is a well-documented clinical entity. We present two cases of phenibut toxicity procured via the internet. CASE DETAILS: A 20-year-old female presented to the emergency department (ED) having used phenibut the prior day. The main finding was a decreased level of consciousness, however when roused she became delirious. Supportive care only was required with no specific intervention. The patient made a full recovery over a 24-hour period and admitted to use of phenibut purchased online. Plasma phenibut concentration was 29.7 MUg/ml. A 38-year-old male presented to ED with an agitated delirium. The prior evening he had used tetrahydrocannabinol or THC, alcohol and phenibut, the latter purchased via the internet. His behavioural state had a suboptimal response to parenteral sedation. He was subsequently intubated for airway protection in the context of ongoing sedation to optimally manage his behavioural state. Post extubation the next morning he admitted using phenibut. Plasma phenibut concentration was 36.5 MUg/ml. DISCUSSION: Altered mental status was the predominant manifestation of phenibut toxicity in these cases. Clinicians to be aware of how phenibut toxicity may present as the internet has widened access to such substances. PMID- 26114347 TI - The efficacy of prophylactic antibiotics in the management of children with kerosene-associated pneumonitis: a double-blind randomised controlled trial. AB - CONTEXT: Hydrocarbons, especially kerosene (paraffin), are the most common agents causing childhood poisoning in low and middle income countries (LMICs). Aspiration of kerosene causes an inflammatory sterile chemical pneumonitis, which may increase susceptibility to secondary lower respiratory tract bacterial infection. This study aimed to assess the efficacy of prophylactic antibiotics in the management of kerosene-associated pneumonitis in children and to identify risk factors associated with severity or outcome. METHODS: A double-blind placebo controlled trial of prophylactic antibiotics in the management of kerosene associated pneumonitis of children presenting to a referral hospital was performed from July 2010 to September 2011. Sequential children with a history of kerosene ingestion and mild respiratory illness were randomised to receive placebo or amoxicillin. Each child was followed-up at Day 3 and Day 5 post ingestion. The primary outcome measure was the number of treatment failures in each group, defined as any child who deteriorated within this time, necessitating a change in treatment regimen. Secondary outcome measures were length of hospital stay and symptoms and signs at follow-up. RESULTS: Seventy-four patients were enrolled. Thirty-five (47%) received placebo and 39 (53%) active treatment. There was no significant difference in treatment failures between placebo (3/35, 9%; 95% CI, 3-22) and active (2/39, 5%; 95% CI, 1-17) groups (relative risk, 0.60; 95% CI, 0.11-3.37). The median length of hospital stay was identical (placebo 0.5 days; IQR, 0-1.0 and active 0.5 days; IQR, 0.5-1.0). Symptoms and signs at Days 3 and 5 post-ingestion were similar. The only significant risk factor for treatment failure was residence in formal housing. Clinical severity at presentation was similar for treatment successes and failures. CONCLUSION: Prophylactic antibiotics do not improve the outcome in children with mild respiratory illness after kerosene ingestion. PMID- 26114348 TI - Effect of magnesium supplementation on blood pressure and vascular reactivity in nitric oxide synthase inhibition-induced hypertension model. AB - The aim of this study was to assess the effect of oral magnesium supplementation (Mg-supp) on blood pressure (BP) and possible mechanism in nitric oxide synthase (NOS) inhibition-induced hypertension model. Hypertension and/or Mg-supp were created by N-nitro-l-arginine methyl ester (25 mg/kg/day by drinking water) and magnesium-oxide (0.8% by diet) for 6 weeks. Systolic BP was measured weekly by tail-cuff method. The effects of hypertension and/or Mg-supp in thoracic aorta and third branch of mesenteric artery constriction and relaxation responses were evaluated. NOS-inhibition produced a gradually developing hypertension and the magnitude of the BP was significantly attenuated after five weeks of Mg-supp. The increased phenylephrine-induced contractile and decreased acetylcholine (ACh) induced dilation responses were found in both artery segments of hypertensive groups. Mg-supp was restored ACh-relaxation response in both arterial segments and also Phe-constriction response in thoracic aorta but not in mesenteric arteries. The contributions of NO, prostaglandins and K(+) channels to the dilator response of ACh were similar in the aorta of all the groups. The contribution of the NO to the ACh-mediated relaxation response of mesenteric arteries was suppressed in hypertensive rats, whereas this was corrected by Mg supp. The flow-mediated dilation response of mesenteric arteries in hypertensive rats failed and could not be corrected by Mg-supp. Whereas, vascular eNOS protein and magnesium levels were not changed and plasma nitrite levels were reduced in hypertensive rats. The results of this study showed that Mg-supp lowered the arterial BP in NOS-inhibition induced hypertension model by restoring the agonist induced relaxation response of the arteries. PMID- 26114349 TI - Circulating miR-21 and eNOS in subclinical atherosclerosis in patients with hypertension. AB - OBJECTIVES: The aim of this study is to evaluate the relationship of miR-21, nitric oxide (NOx) and endothelial nitric oxide synthase (eNOS) with subclinical atherosclerosis in carotid arteries by measuring carotid intima media thickness (CIMT) in patients with hypertension and healthy controls. DESIGN AND METHODS: A total of 28 hypertensive and 28 healthy controls were enrolled. MiR-21 expression was analyzed by quantitative reverse transcription-PCR and NOx, and eNOS levels were measured by ELISA assay. CIMT was evaluated by ultrasonography and CIMT >= 0.8 mm was accepted as increased CIMT (iCIMT). RESULTS: C-reactive protein (CRP) level, plasma miR-21 expression level and CIMT were found to be significantly higher in the hypertension group when compared to the control group (p = 0.009, p = 0.002 and p < 0.001, respectively). NOx and eNOS levels were significantly lower in the hypertension group compared to the control group (p < 0.001, both). MiR-21 level was positively correlated with the clinical systolic blood pressure, clinical diastolic blood pressure, CRP and CIMT. MiR-21 was also negatively correlated with NOx and eNOS. Eighteen patients with hypertension had iCIMT. MiR 21 and CRP levels were significantly higher (p < 0.001 and p = 0.001), whereas NOx and eNOS levels were significantly lower in patients with iCIMT (p < 0.001, both). CONCLUSION: The decreased levels of NOx and eNOS found in this study indicate the co-existence of endothelial dysfunction and hypertension once more. In the absence of microalbuminuria, the increased miR-21 expression in patients with iCIMT made us conclude that this miRNA might be involved in the early stages of atherosclerotic process in hypertensive patients. PMID- 26114350 TI - Arterial stiffness is increased in healthy subjects with a positive family history of hypertension. AB - A positive family history of hypertension is a risk factor for cardiovascular diseases. We investigated the value of pulse wave velocity (PWV) in healthy subjects with a positive family history of hypertension. 255 healthy subjects (M/F: 75/180) were divided into two groups according to without (group 1) or with (group 2) a positive family history of hypertension. Carotid-femoral pulse wave velocity (CF-PWV) was measured by Complior apparatus. Our results showed that CF PWV was significantly higher in group 2 than in group 1 (7.90 +/- 1.31 versus 7.32 +/- 1.15 m/s, p < 0.001). High-density lipoprotein cholesterol (HDL-C) was significantly higher in group 1 than in group 2. Multiple linear regressions showed that age, family history, GLU, and MAP were independent influencing factors of CF-PWV in the entire study group. Our present study showed PWV is significantly higher in healthy subjects with a positive family history of hypertension. Family history might play an important role in this process. PMID- 26114351 TI - Ideal cardiovascular health behaviors and factors prevent the development of hypertension in prehypertensive subjects. AB - BACKGROUND: Seven ideal health metrics were defined by AHA to monitor cardiovascular health. This study aimed to investigate the impact of ideal cardiovascular health behaviors and factors on the development of hypertension in prehypertensive subjects. METHODS: Thirty-two thousand eight-hundred and eighty seven participants with prehypertension were included in the study after excluding for preexisting stroke, myocardial infarction or malignancy. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals [CI] for the development of hypertension. RESULTS: During a follow-up of 52.2 months, 15,500 prehypertensive participants developed hypertension. The cumulative incidence of hypertension decreased with the number of ideal health metrics increased. It was 78.61%, 71.08%, 63.15%, 56.07% and 61.62% in prehypertensive individuals carrying <= 1, 2, 3, 4 and >= 5 ideal health behaviors or factors, respectively. After adjustment for age, gender, family history of hypertension, alcohol consumption, resting heart rate, plasma triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein, the risk ratios of incident hypertension in the subjects who carried 2, 3, 4, and >= 5 ideal health metrics were 0.833 (95%CI: 0.789-0.880), 0.710 (95%CI: 0.672-0.749), 0.604 (95%CI: 0.568 0.642), and 0.581 (95%CI: 0.524-0.643), respectively, in comparison to those with <= 1 ideal health metric. A similar trend was also observed in male and female populations. Poor health metrics, including body mass index, diet (salt intake), physical activity, total cholesterol, and smoking, were predictors for the development of hypertension in prehypertensive individuals. CONCLUSION: Ideal cardiovascular health behaviors and factors are protective factors to prevent the progression from prehypertension to hypertension. PMID- 26114352 TI - The impact of metabolic syndrome and hypertension on medical costs of patients with acute myocardial infarction at hospital. AB - OBJECTIVE: This study aimed to find out the impact of metabolic syndrome (MS) and hypertension on medical costs of patients with acute myocardial infarction (AMI) at hospital. METHODS: Patients with AMI at Qilu Hospital of Shandong University during January 2011 to May 2013 were separated into four groups according to whether with MS or history of hypertension. Comparison of medical costs, complication rate and cost-effectiveness ratio were analyzed. RESULTS: We found that total costs, each day costs, medical treatment costs, chemical examination costs and drug costs were significantly different in four groups. In variance analysis, MS led to high medical costs without significance. Hypertension was a significant factor influencing medical costs and lead to low medical costs. In multiple linear regression, we found that body mass index (BMI) and percutaneous coronary intervention (PCI) were important predictors of total costs and each day costs. With higher BMI and utilization rate of PCI, medical costs were increased. Trend of total costs in four groups is similar to that of the rate of PCI utilization. CONCLUSIONS: Metabolic syndrome has no impact on medical costs because of discordance in MS components. Hypertension will lead to lower PCI utilization rate, which results in less medical costs and bad hospital outcomes. PMID- 26114353 TI - Associations between blood pressure responses to acute stress and impaired renal function and serum uric acid level. AB - The study aimed to examine correlations between blood pressure (BP) responses to direct laryngoscopy and tracheal intubation and parameters of renal function, serum uric acid (SUA) level, and mean preoperative BP. Fifty-four patients (>= 40 years) who were scheduled for oral surgery were analyzed. General anesthesia was induced by the rapid sequence method without opioid analgesics. Systolic and diastolic BP (SBP, DBP) in the operation room were measured when an electrocardiogram, a BP cuff, and a pulse oximetry probe were attached to the patients (T1) and immediately after the trachea was intubated (T2). The DeltaSBP was defined as the difference between SBP at T2 and T1. The increasing rate of SBP (DeltaSBPr) was defined as DeltaSBP/SBP at T1. SBP at T2 was associated with increasing age (R = 0.44), serum creatinine (R = 0.32), SUA (R = 0.30), mean preoperative SBP and DBP (R = 0.54 and 0.37, respectively), and reduced estimated glomerular filtration rate (eGFR) (R = -0.44). Serum creatinine and SUA were positively associated, and eGFR was negatively associated with DeltaSBP (R = 0.36, 0.34, and -0.29) and DeltaSBPr (R = 0.39, 0.37, and -0.29). Multivariate regression analysis revealed that age and mean preoperative SBP was independently associated with SBP at T2, and serum creatinine was independently associated with DeltaSBP and DeltaSBPr. These findings suggested that elevated serum creatinine level, as well as elevated preoperative BP level, was associated with enhanced BP responses to acute stress in middle-aged to elderly patients. PMID- 26114354 TI - Resveratrol via activation of AMPK lowers blood pressure in DOCA-salt hypertensive mice. AB - OBJECTIVE: Resveratrol, a phytoalexin, is reported to activate AMP-activated protein kinase (AMPK) in vascular cells. Activation of AMPK induces vasorelaxation to lower blood pressure (BP). Whether resveratrol via activation of AMPK decreases, BP remains unknown. METHODS: Male wild-type (WT) mice and mice deficient in AMPKalpha2 (AMPKalpha2(-/-)) were fed with resveratrol (400 mg/kg). After 7 d, mice were implanted with deoxycorticosterone acetate (DOCA)-salt (150 mg/kg) for 35 d. BP was detected by the radiotelemetry method. Vessel contraction was determined by organ chamber. Active RhoA, Rho-associated kinase (ROCK) activity, phosphorylations of myosin light chain (MLC), and myosin phosphatase targeting subunit 1 (MYPT1) were assayed by western blot. RESULTS: Implantation of DOCA-salt dramatically increased systemic BPs (systolic BP and diastolic BP) in WT and AMPKalpha2(-/-) mice. However, treatment of resveratrol significantly decreased systemic BP in WT mice but not in AMPKalpha2(-/-) mice. In the organ chamber study, resveratrol inhibited agonist-induced vessel relaxation in WT mice aortas. Loss of AMPKalpha2 or AMPK inhibition by compound C reversed resveratrol suppressed vasoconstriction in isolated mice aortas. In cultured vascular smooth muscle cells (VSMCs), activation of AMPK by resveratrol inhibited phenylephrine enhanced MLC phosphorylation in a dose-dependent manner. CONCLUSIONS: Resveratrol via activation of AMPK lowers BP in DOCA-hypertensive mice through an AMPK/RhoA/ROCK2/MLCMLC pathway. PMID- 26114355 TI - Relationship between white blood cells and hypertension in Chinese adults: the Cardiometabolic Risk in Chinese (CRC) study. AB - Increased blood pressure was associated with increased white blood cell count (adjusted p < 0.001) in a community-based health examination survey of adults in China (n = 39 282; aged 18-93 years). Adjusted odds ratios (95% confidence intervals) for hypertension across white blood cell count quintiles were 1.00, 0.99 (0.89-1.09), 1.11 (1.01-1.22), 1.09 (0.99-1.20), and 1.19 (1.08-1.31) (p for trend < 0.001). Body mass index and white blood cell count had an additive effect on systolic blood pressure (p for interaction = 0.047). Therefore, white blood cell count could independently predict hypertension in Chinese adults. PMID- 26114356 TI - Prehypertension status, cardiometabolic risks, and decreased baroreflex sensitivity are linked to sympathovagal imbalance in salt-preferring individuals. AB - Salt preference has been reported to cause sympathovagal imbalance (SVI) and prehypertension. We investigated the role of inflammation, insulin resistance (IR), hyperlipidemia, and oxidative stress (OS) in genesis of SVI and cardiovascular (CV) risks in salt-preferring prehypertensives. The subjects were divided into no-salt-preferring (NSP, n = 87) and salt-preferring (SP, n = 89) group based on their preference for salted food. Body mass index (BMI), blood pressure (BP) variability parameters including baroreflex sensitivity (BRS), heart rate variability (HRV) indices, autonomic function tests, IR, lipid risk factors, inflammatory and OS markers, and renin were measured in both the groups. Based on the contribution of various cardiometabolic risks to low-frequency-high frequency (LF-HF) ratio of HRV, the marker of SVI was assessed by multiple regression analysis. Prediction of prehypertension status by the LF-HF ratio was assessed by bivariate logistic regression. BMI, heart rate, BP parameters, cardiac output, total peripheral resistance, LF-HF ratio, IR, atherogenic index, inflammatory, and OS markers were significantly increased, and BRS was significantly decreased in the SP group compared with the NSP group. There was an independent association of IR, atherogenic index, markers of inflammation and OS, and BRS with the LF-HF ratio in SP subjects, and the LF-HF ratio had significant prediction of prehypertension status in these subjects. It was concluded that IR, low-grade inflammation, atherogenic lipid profile, and OS contribute to SVI in SP subjects. Decreased BRS (the marker of CV risk) is linked to SVI, and SVI predicts prehypertension status in SP subjects. PMID- 26114357 TI - Sugar and artificially sweetened soda consumption linked to hypertension: a systematic review and meta-analysis. AB - BACKGROUND/OBJECTIVES: The risk of hypertension (HTN) in patients who regularly drink soda is controversial. The objective of this meta-analysis was to assess the associations between consumption of sugar and artificially sweetened soda and HTN. METHODS: A literature search was performed using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews from inception through January 2015. Studies that reported relative risks, odd ratios or hazard ratios comparing the risk of HTN in patients consuming a significant amount of either sugar or artificially sweetened soda versus those who did not consume soda were included. Pooled risk ratios (RR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method. RESULTS: Eight studies were included in our analysis to assess the association between consumption of sugar sweetened soda and HTN. The pooled RR of HTN in patients consuming sugar sweetened soda was 1.12 (95% CI, 1.03-1.23). Four studies were selected to assess the association between consumption of artificially sweetened soda and HTN. The pooled RR of HTN in patients consuming artificially sweetened soda was 1.15 (95% CI, 1.11-1.19). CONCLUSIONS: Our study demonstrates statistically significant associations between both sugar and artificially sweetened soda consumption and HTN. This finding may impact clinical management and primary prevention of HTN. PMID- 26114358 TI - Cytomegalovirus: Unusual Etiology of Lung Pseudotumor. PMID- 26114359 TI - Mercury uptake and phytotoxicity in terrestrial plants grown naturally in the Gumuskoy (Kutahya) mining area, Turkey. AB - This study investigated mercury (Hg) uptake and transport from the soil to different plant parts by documenting the distribution and accumulation of Hg in the roots and shoots of 12 terrestrial plant species, all of which grow naturally in surface soils of the Gumuskoy Pb-Ag mining area. Plant samples and their associated soils were collected and analyzed for Hg content by ICP-MS. Mean Hg values in the soils, roots, and shoots of all plants were 6.914, 460, and 206 ug kg(-1), respectively and lower than 1. The mean enrichment factors for the roots (ECR) and shoots (ECS) of these plants were 0.06 and 0.09, respectively and lower than 1. These results show that the roots of the studied plants prevented Hg from reaching the aerial parts of the plants. The mean translocation factor (TLF) was 1.29 and higher than 1. The mean TLF values indicated that all 12 plant species had the ability to transfer Hg from the roots to the shoots but that transfer was more efficient in plants with higher ECR and ECS. Therefore, these plants could be useful for the biomonitoring of environmental pollution and for rehabilitating areas contaminated by Hg. PMID- 26114361 TI - Remember the Jones Criteria? PMID- 26114360 TI - Molecular mechanisms of green tea polyphenols with protective effects against skin photoaging. AB - Whereas green tea has historically been consumed in high quantities in Northeast Asia, its popularity is also increasing in many Western countries. Green tea is an abundant source of plant polyphenols exhibiting numerous effects that are potentially beneficial for human health. Accumulating evidence suggests that green tea polyphenols confer protective effects on the skin against ultraviolet (UV) irradiation-induced acceleration of skin aging, involving antimelanogenic, antiwrinkle, antioxidant, and anti-inflammatory effects as well as prevention of immunosuppression. Melanin pigmentation in the skin is a major defense mechanism against UV irradiation, but pigmentation abnormalities such as melasma, freckles, senile lentigines, and other forms of melanin hyperpigmentation can also cause serious health and aesthetic issues. Furthermore, UV irradiation initiates the degradation of fibrillar collagen and elastic fibers, promoting the process of skin aging through deep wrinkle formation and loss of tissue elasticity. UV irradiation-induced formation of free radicals also contributes to accelerated photoaging. Additionally, immunosuppression caused by UV irradiation plays an important role in photoaging and skin carcinogenesis. In this review, we summarize the current literature regarding the antimelanogenic, antiwrinkle, antioxidant, and immunosuppression preventive mechanisms of green tea polyphenols that have been demonstrated to protect against UV irradiation-stimulated skin photoaging, and gauge the quality of evidence supporting the need for clinical studies using green tea polyphenols as anti-photoaging agents in novel cosmeceuticals. PMID- 26114362 TI - A 16-Year-Old Boy with Bilateral Hand and Foot Cramping and Numbness. PMID- 26114363 TI - Family Transitions: The Birth of a Two-Child Family. AB - I remember the morning we discovered we were expecting our second child. I was a second-year pediatric resident starting my rotation in the pediatric intensive care unit. I had just given birth to our first child 14 months earlier and was still overwhelmed, yet amazed, by the process of becoming a parent. Certainly we had always hoped for more than one child but this one was coming 9 months sooner than our grand plan. Being an older, nontraditional medical student, I was already significantly older than my colleagues in residency. I wondered anxiously how I was going to explain to my residency director and my fellow residents, who so graciously covered for me on my first maternity leave, that I was pregnant, yet again. Thankfully, 9 months later our second son was born healthy and vigorous. In those long, yet short 9 months, we discovered that our material needs would drastically change. We contemplated a new car that would accommodate two car seats safely and comfortably, and anticipated finding the room, in an already cramped living space, for both a toddler bed and a crib. Perhaps most important at the time, our nanny, who already did a wonderful job of caring for our eldest child, happily accepted the opportunity to now take care of both our children, at an additional cost. PMID- 26114364 TI - An 18-Month-Old Boy with Diarrhea and an Elevated Biochemical Parameter. PMID- 26114365 TI - A 14-Year-Old Girl with Slurred Speech, Aggressive Behavior, and Seizures. PMID- 26114366 TI - Pediatric Rheumatology. PMID- 26114367 TI - Demystifying the Positive Antinuclear Antibody Test in Children: A Clinical Review. AB - A 15-year-old girl presented with knee pain, associated with a positive antinuclear antibody (ANA). She denied joint swelling or morning stiffness and remained physically active despite the pain. A physical examination was unremarkable except for articular hypermobility. Laboratory results were also unremarkable. Therefore, the positive ANA was determined to be nonspecific, and not concerning. In the evaluation of children with musculoskeletal complaints, unusual rash, or fatigue, an ANA assessment is frequently considered. When is this test most likely to be useful? What is the appropriate follow up for a positive result? Which results are concerning for an autoimmune process? This article reviews the literature to address these practical concerns. Understanding the indications for ordering an ANA, and the correct interpretation of a positive ANA, may reduce unnecessary referrals and costly tests. Moreover, the misperception that a positive ANA indicates a rheumatologic disease can cause significant patient and parental anxiety. PMID- 26114368 TI - Juvenile Fibromyalgia: A Multidisciplinary Approach to Treatment. AB - A 14-year-old boy presented with months of severe widespread musculoskeletal pain. He was profoundly fatigued and unable to attend school. Laboratory evaluation, including complete blood count, comprehensive metabolic panel, inflammatory markers, and thyroid function, was unrevealing. Physical examination was also normal except for multiple tender points. The patient was diagnosed with juvenile primary fibromyalgia syndrome and referred for multidisciplinary treatment including physical therapy, exercise, and counseling, and his daily functioning gradually improves. Juvenile fibromyalgia is a complex syndrome that often severely limits patients' activities and can impede normal adolescent development. Effective treatment requires an understanding of the biologic, psychologic, and social factors contributing to the perpetuation of chronic pain. The author reviews the diagnostic criteria, pathophysiology, and treatment of juvenile fibromyalgia. Medications, particularly antidepressants and anticonvulsants, can be useful adjuncts to therapy. However, multimodal pain management including intensive physical therapy, exercise, counseling, and sleep hygiene is most effective in treating fibromyalgia. PMID- 26114369 TI - Systemic Juvenile Idiopathic Arthritis Complicated by Macrophage Activation Syndrome. AB - Systemic juvenile idiopathic arthritis (sJIA) is characterized by a large range of extra-articular manifestations in addition to joint inflammation. The child with sJIA usually presents with a spiking fever pattern, evanescent rash, and arthralgias/arthritis. Other features often present are lymphadenopathy, hepatosplenomegaly, and polyserositis. The systemic manifestations are frequently more prominent and severe than the arthritis. Laboratory studies reflect systemic inflammation with significant anemia, and elevation of acute phase reactants, platelets, and white blood cell count. Ferritin level is often strikingly high. The treatment of sJIA has evolved over the past decade with the improved understanding of the role of specific inflammatory cytokines in this disease. The medications employed to treat sJIA directly inhibit the actions of these cytokines. A major cause of morbidity and mortality of children with sJIA is the development of macrophage activation syndrome, which can cause unremitting fevers, pancytopenia, coagulopathy, and hepatic dysfunction. PMID- 26114370 TI - Great Vessels of Children: Takayasu's Arteritis. AB - Takayasu's arteritis (TA) is a granulomatous, large vessel vasculitis affecting primarily the aorta and its main branches. It is characterized by inflammation in the blood vessel wall, leading to either luminal occlusion or dilatation with aneurysm formation. The etiology of TA is unknown, but there seems to be a strong role for cell-mediated autoimmunity in the pathogenesis of this disease. TA most commonly presents in young women in their second and third decades of life, but has been reported in children as young as age 2 years. The symptoms can range from vague systemic complaints to catastrophic stroke. Angiography remains the gold standard for diagnosis, although computed tomography angiography and magnetic resonance angiography have been used as well. Corticosteroids are first line therapy, with various cytotoxic medications being used in refractory disease. Biologic agents targeting cytokines that are involved in disease pathogenesis have also been used successfully. In this article, we describe a patient with TA who responded to therapy with infliximab, an inhibitor of tumor necrosis factor. PMID- 26114371 TI - Neuropsychiatric Systemic Lupus Erythematosus in Children. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of antinuclear antibodies and other autoantibodies, as well as a clinical course that is characterized by flares and remissions. The clinical presentation is diverse, ranging from a mild disease characterized by rash and arthritis to a severe life-threatening disease involving multiple organs. Approximately 25% of children with SLE have neuropsychiatric manifestations of SLE, which are a major cause of morbidity and mortality. Neuropsychiatric symptoms may be the initial presentation of SLE in children. The mortality rate is relatively low, but morbidity may be significant and permanent damage can occur. This article discusses the importance, known pathophysiologic mechanisms, clinical approach, and evidence-based therapeutic options for the diagnosis and management of neuropsychiatric lupus erythematosus in children and adolescents. PMID- 26114372 TI - Dimensional Reduction From 2D Layer to 1D Band for Germanophosphates Induced by the "Tailor Effect" of Fluoride. AB - The "tailor effect" of fluoride, exclusively as a terminal rather than a bridge, was applied successfully to design low-dimensional structures in the system of transition metal germanophosphates for the first time. Two series of new compounds with low-dimensional structures are reported herein. K[M(II)Ge(OH)2(H0.5PO4)2] (M = Fe, Co) possess flat layered structures built from single chains of edge-sharing M(II)O6 and GeO6 octahedra interconnected by HPO4 tetrahedra. Their fluorinated derivatives, K4[M(II)Ge2F2(OH)2(PO4)2(HPO4)2].2H2O (M = Fe, Co), exhibit band structures of two four-membered ring germanium phosphate single chains sandwiched by M(II)O6 octahedra via corner-sharing. Both of these structures contain anionic chains of the condensation of four-membered rings built from alternating GeO4Phi2 (Phi = F, OH) octahedra and PO4 tetrahedra via sharing common GeO4Phi2 (Phi = F, OH) octahedra, the topology of which is the same as that of the mineral krohnkite [Na2Cu(SO4)2.2H2O]. Note that the switch from the two-dimensional layered structure to the one-dimensional band structure was performed simply by the addition of a small amount of KF.2H2O to the reaction mixture. This structural alteration arises from the incorporation of one terminal F atom to the coordination sphere of Ge, which breaks the linkage between the transition metal and germanium octahedra in the layer to form the band structure. PMID- 26114373 TI - Use of Caprylic Acid in Broiler Chickens: Effect on Campylobacter jejuni. AB - The effect of caprylic acid (CA) on Campylobacter jejuni in chickens was evaluated using two approaches: dietary supplementation or surface treatment of chilled chicken carcasses. To analyze the dietary effect of CA, individually housed broiler chickens (n = 48) were artificially infected with C. jejuni VFU612 (10(6) colony-forming units [CFU]/bird) on the 21st and 35th days of life. Dietary CA (2.5 and 5 g/kg of feed, fed throughout the entire experiment) significantly decreased C. jejuni shedding (p<0.05). However, the effect only lasted for 3-7 days after infection. The numbers of Campylobacter shed by the positive control birds reached its maximum on the 37th day of life, while on that same day, both Treatment I and Treatment II groups shed significantly lower (p<0.05) numbers of Campylobacter (by 0.8 and 1.8 log10 CFU/g, respectively). Also, peak shedding was delayed by 1 day in both treated groups. After euthanasia of each chicken on the 42nd day of life, no differences in Campylobacter counts in the crop, gizzard, ileum, and cecum were found between the positive control and the treated groups (p>0.05). Surface contamination of the chilled chicken halves was performed with C. jejuni VFU612 (clinical isolate) and CCM6214 (collection strain). Surface treatment with CA at 1.25 and 2.5 mg/mL for 1 min significantly reduced C. jejuni VFU612 contamination of chicken skin (p<0.05) by 0.29-0.53 and 1.14-1.58 log10 CFU/g of skin, respectively. Counts of C. jejuni CCM6214 were reduced by 0.68-1.65 log10 CFU/g of skin). In conclusion, dietary CA affected numbers of C. jejuni in the gastrointestinal contents of chickens, whereas surface treatment reduced C. jejuni contamination in processed chicken carcasses. PMID- 26114376 TI - Morphologically Aligned Cation-Exchange Membranes by a Pulsed Electric Field for Reverse Electrodialysis. AB - A low-resistance ion-exchange membrane is essential to achieve the high performance energy conversion or storage systems. The formation methods for low resistance membranes are various; one of the methods is the ion channel alignment of an ion-exchange membrane under a direct current (DC) electric field. In this study, we suggest a more effective alignment method than the process with the DC electric field. First, an ion-exchange membrane was prepared under a pulsed electric field [alternating current (AC) mode] to enhance the effectiveness of the alignment. The membrane properties and the performance in reverse electrodialysis (RED) were then examined to assess the membrane resistance and ion selectivity. The results show that the membrane electrical resistance (MER) had a lower value of 0.86 Omega cm(2) for the AC membrane than 2.13 Omega cm(2) observed for the DC membrane and 4.30 Omega cm(2) observed for the pristine membrane. Furthermore, RED achieved 1.34 W/m(2) of maximum power density for the AC membrane, whereas that for the DC membrane was found to be 1.14 W/m(2) [a RED stack assembled with CMX, used as a commercial cation-exchange membrane (CEM), showed 1.07 W/m(2)]. Thereby, the novel preparation process for a remarkable low resistance membrane with high ion selectivity was demonstrated. PMID- 26114374 TI - Obesity is associated with race/sex disparities in diabetes and hypertension prevalence, but not cardiovascular disease, among HIV-infected adults. AB - Race/sex differences are observed in cardiometabolic disease (CMD) risk and prevalence in the context of treated, chronic HIV infection, and these differences could be exacerbated by disparities in obesity prevalence. We sought to determine the effect of obesity on these disparities among people living with HIV. Prevalence of CMD (dyslipidemia, cardiovascular disorders, hypertension, diabetes, chronic kidney disease) was determined for patients seen at the University of Alabama at Birmingham HIV clinic between 7/2010 and 6/2011. Staged logistic regression was used to examine the impact of race/sex on comorbidities adjusting for key confounders including/excluding obesity (body mass index >=30 kg/m(2)). Of 1,800 participants, 77% were male, 54% were black, and 25% were obese. Obesity prevalence differed by race/sex: black women 49%, black men 24%, white women 24%, white men 15% (p<0.01). Compared to white men, other groups had reduced odds for dyslipidemia and cardiovascular disorders (p<0.01). Black men had increased odds for hypertension and chronic kidney disease, while black women had a nearly 2-fold increased odds for diabetes and hypertension (all at p<0.01). The associations of black women with diabetes and hypertension were attenuated when obesity was included in the models. Other group differences remained significant. Disparities in obesity prevalence do not explain race/sex differences in all CMD among people with HIV. Obesity accounted for associations with diabetes/hypertension for black women, who may benefit from weight reduction to decrease disease risk. Further investigations into the etiology and treatment of CMD in people living with HIV should consider unique race/sex treatment issues. PMID- 26114377 TI - Bilateral Asymmetry in Upper Extremities Is More Pronounced in Distal Compared to Proximal Joints. AB - The authors' aim was to compare spatial and temporal accuracy in proximal versus distal joints in upper extremities. Given the morphological differences in corticospinal and corticomotoneuronal projections for proximal and distal muscles, they hypothesized that bilateral asymmetry would be larger for distal than for proximal joints. Twelve participants performed isolated flexion extension movements with the shoulders and index fingers. Angular range of motion of finger and shoulder movements was kept constant. The results showed significant bilateral asymmetry for both proximal and distal joints for both spatial and temporal accuracy. More importantly, bilateral asymmetry was significantly larger for the index fingers than for the shoulders for both spatial and temporal variables, as hypothesized. These results at the behavioral level pave the way for further studies that combine direct measures of neural activation with behavioral measures to further illuminate the potential link between bilateral communication and laterality effects in motor performance. PMID- 26114378 TI - Topical Bevacizumab for the Treatment of Ocular Surface Squamous Neoplasia. AB - PURPOSE: To determine the efficacy and safety of topical bevacizumab treatment in patients with ocular surface squamous neoplasia (OSSN). METHODS: Six eyes of 6 patients with primary OSSN confirmed by impression cytology received topical 5 mg/mL bevacizumab 4 times daily for a period of 8 weeks. Patients were evaluated in 2-week intervals. Digital photography images were obtained at each visit and changes in the size of the lesions were analyzed by image analysis software. RESULTS: The mean age of the patients was 66 +/- 13 (+/- SD) years. Four tumors were nasal in origin and 2 tumors were temporal. The mean reduction observed in the lesion area was 43% +/- 24.2% (range, 20%-71%) in the first month and 68% +/- 29.7% (range, 42%-100%) in the second month when compared with the baseline area. Four patients required tumor excision at the end of the treatment period. Surgical treatment was not necessary in 2 patients due to complete disappearance of the tumor, which was confirmed by impression cytology. The visual acuity was stable in all patients and no systemic or visual side effects were observed during the study period. CONCLUSIONS: Topical bevacizumab is effective as a neoadjuvant therapy combined with surgical excision for the treatment of OSSN. Topical bevacizumab may be used before surgery to decrease the size of the excision. Excision may be unnecessary in responsive patients. PMID- 26114379 TI - Morning stiffness response with delayed-release prednisone after ineffective course of immediate-release prednisone. AB - OBJECTIVE: To assess morning stiffness in rheumatoid arthritis (RA) patients switched from immediate-release (IR) to delayed-release (DR) prednisone. METHOD: Circadian Administration of Prednisone in Rheumatoid Arthritis-1 (CAPRA-1) is a 12-week, randomized, multicentre, active-controlled study of morning stiffness that consisted of a double-blind phase and a 9-month open-label extension. Patients receiving IR prednisone with no significant improvement after the double blind study were switched to DR prednisone. Morning stiffness duration and median absolute and relative changes in pain and global assessment were evaluated (3, 6, and 9 months). RESULTS: In patients switched from IR to DR prednisone (n=110), statistically significant reductions in morning stiffness occurred over 3 months and were sustained for 9 months. Absolute reduction of morning stiffness was ~50 min with >40% relative reduction at each visit. Interleukin (IL)-6 levels were reduced by the same amount. Statistically significant and clinically meaningful mean reductions in morning stiffness were maintained at >67 min at each visit along with significant improvements in pain and patient global assessment. There was no evidence of tachyphylaxis seen over the 9-month study. CONCLUSIONS: Patients receiving disease-modifying anti-rheumatic drugs (DMARDs) and IR prednisone who had not had significant reductions in morning stiffness demonstrated statistically significant and clinically meaningful improvements when switched to DR prednisone. PMID- 26114380 TI - Intracellular cascade FRET for temperature imaging of living cells with polymeric ratiometric fluorescent thermometers. AB - Intracellular temperature plays a prominent role in cellular functions and biochemical activities inside living cells, but effective intracellular temperature sensing and imaging is still in its infancy. Herein, thermoresponsive double hydrophilic block copolymers (DHBCs)-based fluorescent thermometers were fabricated to investigate their application in intracellular temperature imaging. Blue-emitting coumarin monomer, CMA, green-emitting 7-nitro-2,1,3-benzoxadiazole (NBD) monomer, NBDAE, and red-emitting rhodamine B monomer, RhBEA, were copolymerized separately with N-isopropylacrylamide (NIPAM) to afford dye-labeled PEG-b-P(NIPAM-co-CMA), PEG-b-P(NIPAM-co-NBDAE), and PEG-b-P(NIPAM-co-RhBEA). Because of the favorable fluorescence resonance energy transfer (FRET) potentials between CMA and NBDAE, NBDAE and RhBEA, as well as the slight tendency between CMA and RhBEA fluorophore pairs, three polymeric thermometers based on traditional one-step FRET were fabricated by facile mixing two of these three fluorescent DHBCs, whereas exhibiting limited advantages. Thus, two-step cascade FRET among three polymeric fluorophores was further interrogated, in which NBD acted as a bridging dye by transferring energy from CMA to RhBEA. Through the delicate optimization of the molar contents of three polymeric components, a ~8.4 fold ratio change occurred in the temperature range of 20-44 degrees C, and the detection sensitivity improved significantly, reached as low as ~0.4 degrees C, which definitely outperformed other one-step FRET thermometers in the intracellular temperature imaging of living cells. To our knowledge, this work represents the first example of polymeric ratiometric thermometer employing thermoresponsive polymer-based cascade FRET mechanism. PMID- 26114381 TI - Red, green, blue equals 1, 2, 3: Digit-color synesthetes can use structured digit information to boost recall of color sequences. AB - Digit-color synesthetes report experiencing colors when perceiving letters and digits. The conscious experience is typically unidirectional (e.g., digits elicit colors but not vice versa) but recent evidence shows subtle bidirectional effects. We examined whether short-term memory for colors could be affected by the order of presentation reflecting more or less structure in the associated digits. We presented a stream of colored squares and asked participants to report the colors in order. The colors matched each synesthete's colors for digits 1-9 and the order of the colors corresponded either to a sequence of numbers (e.g., [red, green, blue] if 1 = red, 2 = green, 3 = blue) or no systematic sequence. The results showed that synesthetes recalled sequential color sequences more accurately than pseudo-randomized colors, whereas no such effect was found for the non-synesthetic controls. Synesthetes did not differ from non-synesthetic controls in recall of color sequences overall, providing no evidence of a general advantage in memory for serial recall of colors. PMID- 26114382 TI - Testing Refrigeration Trucks for the Emergency Evacuation of Companion Animals. AB - The purpose of this study was to quantify the changes in oxygen (O2) and carbon dioxide (CO2) in sealed refrigerator trucks scheduled to be used for transporting companion animals (dogs and cats) during an emergency evacuation. A total of 122 nonhuman animals (total weight = 1,248 kg) housed in individual crates were loaded into a 16-m refrigeration truck. Once they were loaded, the doors were closed and the percentages of O2 and CO2 were measured every 5 min by O2 and CO2 analyzers, and they were used to quantify the changes in gas pressure in the sealed truck. CO2 had a much higher-than-predicted increase, and O2 had a higher than-predicted decrease. These 2 pressures in combination with the functionality of the respiratory system will limit the animal's ability to load O2, and over time, they will initiate asphyxia or suffocation. Over time, the partial pressure of oxygen (PO2) in the sealed truck will decrease, causing hypoxia, and the partial pressure of carbon dioxide (PCO2) will increase, causing hypercapnia. PMID- 26114383 TI - RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production. AB - Human Cytomegalovirus (HCMV), an ubiquitous beta-herpesvirus, is a significant pathogen that causes medically severe diseases in immunocompromised individuals and in congenitally infected neonates. RhoB belongs to the family of Rho GTPases, which regulates diverse cellular processes. Rho proteins are implicated in the entry and egress from the host cell of mainly alpha- and gamma-herpesviruses, whereas beta-herpesviruses are the least studied in this regard. Here, we studied the role of RhoB GTPase during HCMV lytic infection. Microscopy analysis, both in fixed and live infected cells showed that RhoB was translocated to the assembly complex/compartment (AC) of HCMV, a cytoplasmic zone in infected cells where many viral structural proteins are known to accumulate and assembly of new virions takes place. Furthermore, RhoB was localized at the AC even when the expression of the late HCMV AC proteins was inhibited. At the very late stages of infection, cellular projections were formed containing RhoB and HCMV virions, potentially contributing to the successful viral spread. Interestingly, the knockdown of RhoB in HCMV-infected cells resulted in a significant reduction of the virus titer and could also affect the accumulation of AC viral proteins at this subcellular compartment. RhoB knockdown also affected actin fibers' structure. Actin reorganization was observed at late stages of infection originating from the viral AC and surrounding the cellular projections, implying a potential interplay between RhoB and actin during HCMV assembly and egress. In conclusion, our results demonstrate for the first time that RhoB is a constituent of the viral AC and is required for HCMV productive infection. PMID- 26114384 TI - Effect of pH on the Aggregation of alpha-syn12 Dimer in Explicit Water by Replica Exchange Molecular Dynamics Simulation. AB - The dimeric structure of the N-terminal 12 residues drives the interaction of alpha-synuclein protein with membranes. Moreover, experimental studies indicated that the aggregation of alpha-synuclein is faster at low pH than neutral pH. Nevertheless, the effects of different pH on the structural characteristics of the alpha-syn12 dimer remain poorly understood. We performed 500 ns temperature replica exchange molecular dynamics (T-REMD) simulations of two alpha-syn12 peptides in explicit solvent. The free energy surfaces contain ten highly populated regions at physiological pH, while there are only three highly populated regions contained at acidic pH. The anti-parallel beta-sheet conformations were found as the lowest free energy state. Additionally, these states are nearly flat with a very small barrier which indicates that these states can easily transit between themselves. The dimer undergoes a disorder to order transition from physiological pH to acidic pH and the alpha-syn12 dimer at acidic pH involves a faster dimerization process. Further, the Lys6-Asp2 contact may prevent the dimerization. PMID- 26114385 TI - Meta-Analysis of miR-146a Polymorphisms Association with Coronary Artery Diseases and Ischemic Stroke. AB - Coronary artery disease (CAD) and ischemic stroke (IS) are manifestations of atherosclerosis, with a high death rate. miR-146a is a microRNA that participates in the progress of CAD and IS. A single nucleotide polymorphism (SNP) in the precursor of miR-146a, rs2910164, was found to be associated with the risks of CAD and IS. However, the results were inconsistent and inconclusive. A meta analysis was performed to assess the relationship of rs2910164 and CAD as well as IS susceptibility. The database Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) were searched for related studies. Crude odds ratios with 95% confidence intervals were used to investigate the strength of the association by random- or fixed-effect model. A total of eight studies, with 3138 cases and 3097 controls were identified for the meta analysis. The results shows that rs2910164 is associated with the risk of CAD significantly in allelic model (OR = 0.86), homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying the GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large sample size group and in Koreans, under homozygous and dominant models. In conclusion, the current meta-analysis suggests lower risks of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS. PMID- 26114386 TI - Evidence for P-Glycoprotein Involvement in Cell Volume Regulation Using Coulter Sizing in Flow Cytometry. AB - The regulation of cell volume is an essential function that is coupled to a variety of physiological processes such as receptor recycling, excitability and contraction, cell proliferation, migration, and programmed cell death. Under stress, cells undergo emergency swelling and respond to such a phenomenon with a regulatory volume decrease (RVD) where they release cellular ions, and other osmolytes as well as a concomitant loss of water. The link between P glycoprotein, a transmembrane transporter, and cell volume regulation is controversial, and changes in cells volume are measured using microscopy or electrophysiology. For instance, by using the patch-clamp method, our team demonstrated that chloride currents activated in the RVD were more intense and rapid in a breast cancer cell line overexpressing the P-glycoprotein (P-gp). The Cell Lab Quanta SC is a flow cytometry system that simultaneously measures electronic volume, side scatter and three fluorescent colors; altogether this provides unsurpassed population resolution and accurate cell counting. Therefore, here we propose a novel method to follow cellular volume. By using the Coulter type channel of the cytometer Cell Lab Quanta SC MPL (multi-platform loading), we demonstrated a role for the P-gp during different osmotic treatments, but also a differential activity of the P-gp through the cell cycle. Altogether, our data strongly suggests a role of P-gp in cell volume regulation. PMID- 26114387 TI - Gene-Diet Interaction between SIRT6 and Soybean Intake for Different Levels of Pulse Wave Velocity. AB - Soybean is a common food for the Chinese people. We aimed to investigate the risk for brachial ankle pulse wave velocity (baPWV) with inflammatory-related SNPs and soybean. baPWV was measured, and 16 inflammatory-related SNPs located on ADIPOQ, CDH13, SIRT3, SIRT6, CXCL12, CXCR4, NOS1, PON1 and CDKN2B were genotyped in 1749 Chinese participants recruited from various communities. ADIPOQ rs12495941 (GT/TT vs. GG: crude OR = 1.27, p = 0.044) and SIRT6 rs107251 (CT/TT vs. CC: crude OR = 0.74, p = 0.009) were associated with abnormal baPWV (baPWV >= 1700 cm/s). After adjustment for conventional environmental risk factors, rs12495941 was associated with abnormal baPWV (GT/TT vs. GG: adjusted OR = 1.43, p = 0.011), but the association between rs107251 and abnormal baPWV was not significant (CT/TT vs. CC: adjusted OR = 0.83, p = 0.173). The interaction between rs107251 and soybean intake for different levels of baPWV was statistically significant (p = 0.017). Compared with a high level of soybean intake, a low level of soybean intake can significantly decrease the risk of abnormal baPWV in individuals of rs107251 CT/TT genotypes (<= 100 vs. > 100 g/week: adjusted OR = 0.542, p = 0.003). In this study, associations between ADIPOQ rs12495941, SIRT6 rs107251 and baPWV, as well as an interaction between SIRT6 rs107251 and soybean intake for different levels of baPWV were found. PMID- 26114388 TI - Atrazine Triggers DNA Damage Response and Induces DNA Double-Strand Breaks in MCF 10A Cells. AB - Atrazine, a pre-emergent herbicide in the chloro-s-triazine family, has been widely used in crop lands and often detected in agriculture watersheds, which is considered as a potential threat to human health. Although atrazine and its metabolites showed an elevated incidence of mammary tumors in female Sprague Dawley (SD) rats, no molecular evidence was found relevant to its carcinogenesis in humans. This study aims to determine whether atrazine could induce the expression of DNA damage response-related proteins in normal human breast epithelial cells (MCF-10A) and to examine the cytotoxicity of atrazine at a molecular level. Our results indicate that a short-term exposure of MCF-10A to an environmentally-detectable concentration of atrazine (0.1 ug/mL) significantly increased the expression of tumor necrosis factor receptor-1 (TNFR1) and phosphorylated Rad17 in the cells. Atrazine treatment increased H2AX phosphorylation (gammaH2AX) and the formation of gammaH2AX foci in the nuclei of MCF-10A cells. Atrazine also sequentially elevated DNA damage checkpoint proteins of ATM- and RAD3-related (ATR), ATRIP and phospho-Chk1, suggesting that atrazine could induce DNA double-strand breaks and trigger the DNA damage response ATR Chk1 pathway in MCF-10A cells. Further investigations are needed to determine whether atrazine-triggered DNA double-strand breaks and DNA damage response ATR Chk1 pathway occur in vivo. PMID- 26114389 TI - Structure and Principal Components Analyses Reveal an Intervarietal Fusion in Malaysian Mistletoe Fig (Ficus deltoidea Jack) Populations. AB - Genetic structure and biodiversity of the medicinal plant Ficus deltoidea have rarely been scrutinized. To fill these lacunae, five varieties, consisting of 30 F. deltoidea accessions were collected across the country and studied on the basis of molecular and morphological data. Molecular analysis of the accessions was performed using nine Inter Simple Sequence Repeat (ISSR) markers, seven of which were detected as polymorphic markers. ISSR-based clustering generated four clusters supporting the geographical distribution of the accessions to some extent. The Jaccard's similarity coefficient implied the existence of low diversity (0.50-0.75) in the studied population. STRUCTURE analysis showed a low differentiation among the sampling sites, while a moderate varietal differentiation was unveiled with two main populations of F. deltoidea. Our observations confirmed the occurrence of gene flow among the accessions; however, the highest degree of this genetic interference was related to the three accessions of FDDJ10, FDTT16 and FDKT25. These three accessions may be the genetic intervarietal fusion points of the plant's population. Principal Components Analysis (PCA) relying on quantitative morphological characteristics resulted in two principal components with Eigenvalue >1 which made up 89.96% of the total variation. The cluster analysis performed by the eight quantitative characteristics led to grouping the accessions into four clusters with a Euclidean distance ranged between 0.06 and 1.10. Similarly, a four-cluster dendrogram was generated using qualitative traits. The qualitative characteristics were found to be more discriminating in the cluster and PCA analyses, while ISSRs were more informative on the evolution and genetic structure of the population. PMID- 26114391 TI - Trends in aptamer selection methods and applications. AB - Aptamers are target specific ssDNA, RNA or peptide sequences generated by an in vitro selection and amplification method called SELEX (Systematic Evolution of Ligands by EXponential Enrichment), which involves repetitive cycles of binding, recovery and amplification steps. Aptamers have the ability to bind with a variety of targets such as drugs, proteins, heavy metals, and pathogens with high specificity and selectivity. Aptamers are similar to monoclonal antibodies regarding their binding affinities, but they offer a number of advantages over the existing antibody-based detection methods, which make the aptamers promising diagnostic and therapeutic tools for future biomedical and analytical applications. The aim of this review article is to provide an overview of the recent advancements in aptamer screening methods along with a concise description of the major application areas of aptamers including biomarker discovery, diagnostics, imaging and nanotechnology. PMID- 26114390 TI - Ginsenoside Rd Protects SH-SY5Y Cells against 1-Methyl-4-phenylpyridinium Induced Injury. AB - Ginsenoside Rd (GSRd), one of the main active monomer compounds from the medical plant Panax ginseng, has been shown to promote neuronal survival in models of ischemic cerebral damage. As an extending study, here we examined whether GSRd could exert a beneficial effect in an experimental Parkinson disease (PD) model in vitro, in which SH-SY5Y cells were injured by 1-methyl-4-phenylpyridinium (MPP+), an active metabolic product of the classical Parkinsonian toxin1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results, from the addition of different concentrations of GSRd (1, 10 and 50 MUM), showed that GSRd at 1 and 10 MUM could significantly attenuate MPP+-induced cell death. This protective effect may be ascribed to its ability to reduce intracellular reactive oxygen species levels, enhance antioxidant enzymatic activities, preserve the activity of respiratory complex I, stabilize the mitochondrial membrane potential and increase intracellular ATP levels. Additionally, the PI3K/Akt survival-signaling pathway was also involved in the protective effect of GSRd. Finally, using a mouse PD model in vivo, we also found that GSRd obviously reversed the loss of tyrosine hydroxylase-positive cells in substanitia nigra induced by MPTP. Thus, our findings demonstrated that GSRd showed a significant neuro-protective effect against experimental PD models, which may involve its antioxidant effects and mitochondrial function preservation. PMID- 26114392 TI - Corrosion chemistry closing comments: opportunities in corrosion science facilitated by operando experimental characterization combined with multi-scale computational modelling. AB - Recent advances in characterization tools, computational capabilities, and theories have created opportunities for advancement in understanding of solid fluid interfaces at the nanoscale in corroding metallic systems. The Faraday Discussion on Corrosion Chemistry in 2015 highlighted some of the current needs, gaps and opportunities in corrosion science. Themes were organized into several hierarchical categories that provide an organizational framework for corrosion. Opportunities to develop fundamental physical and chemical data which will enable further progress in thermodynamic and kinetic modelling of corrosion were discussed. These will enable new and better understanding of unit processes that govern corrosion at the nanoscale. Additional topics discussed included scales, films and oxides, fluid-surface and molecular-surface interactions, selected topics in corrosion science and engineering as well as corrosion control. Corrosion science and engineering topics included complex alloy dissolution, local corrosion, and modelling of specific corrosion processes that are made up of collections of temporally and spatially varying unit processes such as oxidation, ion transport, and competitive adsorption. Corrosion control and mitigation topics covered some new insights on coatings and inhibitors. Further advances in operando or in situ experimental characterization strategies at the nanoscale combined with computational modelling will enhance progress in the field, especially if coupling across length and time scales can be achieved incorporating the various phenomena encountered in corrosion. Readers are encouraged to not only to use this ad hoc organizational scheme to guide their immersion into the current opportunities in corrosion chemistry, but also to find value in the information presented in their own ways. PMID- 26114393 TI - Effects of N-Acetylcysteine Addition to University of Wisconsin Solution on the Rate of Ischemia-Reperfusion Injury in Adult Orthotopic Liver Transplant. AB - OBJECTIVES: One of the main concerns in liver transplant is the prolonged ischemia time, which may lead to primary graft nonfunction or delayed function. N acetylcysteine is known as a hepato-protective agent in different studies, which may improve human hepatocyte viability in steatotic donor livers. This study investigated whether N-acetylcysteine can decrease the rate of ischemia reperfusion syndrome and improve short-term outcome in liver transplant recipients. MATERIALS AND METHODS: This was a double-blind, randomized, control clinical trial of 115 patients. Between April 2012 and January 2013, patients with orthotopic liver transplant were randomly divided into 2 groups; in 49 cases N-acetylcysteine was added to University of Wisconsin solution as the preservative liquid (experimental group), and in 66 cases standard University of Wisconsin solution was used (control group). We compared postreperfusion hypotension, inotrope requirement before and after portal reperfusion, intermittent arterial blood gas analysis and potassium measurement, pathological review of transplanted liver, in-hospital complications, morbidity, and mortality. RESULTS: There was no significant difference between the groups regarding time to hepatic artery reperfusion, hospital stay, vascular complications, inotrope requirement before and after portal declamping, and blood gas analysis. Hypotension after portal reperfusion was significantly more common in experimental group compared with control group (P = .005). Retransplant and in hospital mortality were comparable between the groups. CONCLUSIONS: Preservation of the liver inside Univer-sity of Wisconsin solution plus N-acetylcysteine did not change the rate of ischemia reperfusion injury and short-term outcome in liver transplant recipients. PMID- 26114394 TI - Examining the association between posttraumatic stress disorder and attention deficit/hyperactivity disorder: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis examining the relationship between attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD). DATA SOURCES: We reviewed literature through PubMed and PsycINFO without a specified date range, utilizing the search (posttraumatic stress disorder OR PTSD) AND (ADHD OR attention deficit hyperactivity disorder OR ADD OR attention deficit disorder OR hyperkinetic syndrome OR minimal brain dysfunction). References from relevant articles were reviewed. STUDY SELECTION: We identified 402 articles; 28 met criteria. We included original human research in English that operationalized diagnoses of ADHD and PTSD, evaluated the relationship between the disorders, and included controls. We excluded articles that failed to differentiate ADHD or PTSD from nonspecific or subsyndromal deficits or failed to compare their relationship. DATA EXTRACTION: We extracted sample size, age, diagnostic methods, design, referral status, control type, and number of subjects with and without ADHD and PTSD alone and combined. We computed meta-analyses for 22 studies examining ADHD in PTSD and PTSD in ADHD using a random effects model and meta-analytic regression. We assessed for heterogeneity and publication bias and adjusted for intrastudy clustering. RESULTS: The relative risk (RR) for PTSD in ADHD was 2.9 (P < .0005); in samples using healthy controls, the RR was 3.7 (P = .001); and in samples using traumatized controls, the RR was 1.6 (P = .003). The RR for ADHD in PTSD was 1.7 (P < .0005); in samples using traumatized controls, the RR was 2.1 (P < .0005). The association was not significant in samples using psychiatric controls. CONCLUSIONS: Results indicate a bidirectional association between ADHD and PTSD, suggesting clinical implications and highlighting the need for neurobiological research that examines the mechanisms underlying this connection. PMID- 26114395 TI - Decay in survival motor neuron and plastin 3 levels during differentiation of iPSC-derived human motor neurons. AB - Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in Survival Motor Neuron 1 (SMN1), leading to degeneration of alpha motor neurons (MNs) but also affecting other cell types. Induced pluripotent stem cell (iPSC) derived human MN models from severe SMA patients have shown relevant phenotypes. We have produced and fully characterized iPSCs from members of a discordant consanguineous family with chronic SMA. We differentiated the iPSC clones into ISL-1+/ChAT+ MNs and performed a comparative study during the differentiation process, observing significant differences in neurite length and number between family members. Analyses of samples from wild-type, severe SMA type I and the type IIIa/IV family showed a progressive decay in SMN protein levels during iPSC MN differentiation, recapitulating previous observations in developmental studies. PLS3 underwent parallel reductions at both the transcriptional and translational levels. The underlying, progressive developmental decay in SMN and PLS3 levels may lead to the increased vulnerability of MNs in SMA disease. Measurements of SMN and PLS3 transcript and protein levels in iPSC-derived MNs show limited value as SMA biomarkers. PMID- 26114397 TI - Umbilical Microflora, Antiseptic Skin Preparation, and Surgical Site Infection in Abdominal Surgery. AB - BACKGROUND: Surgical site infections (SSI) following abdominal surgery are frequent and a major cause of postoperative morbidity and prolonged hospital stay. Besides antibiotic prophylaxis, antiseptic skin preparation is an important measure to prevent SSI. METHODS: Here we prospectively analyzed the effectiveness of antiseptic skin preparation in a cohort of 93 patients undergoing laparotomy, with special emphasis on the umbilical region. RESULTS: The microflora of the umbilicus contained a large number of resident (mostly staphylococci species and corynebacteria) and transient germs (including enterococci species). Following antiseptic skin preparation, bacteria could still be cultured from 24.7% of the patients' umbilici. In case of postoperative SSI, only one of seven SSI was caused by the microorganism that was present in the umbilicus before and after skin preparation. CONCLUSION: Antiseptic skin preparation fails to completely eradicate the microflora of the umbilical region in one quarter of the patients. However, at least in abdominal surgery, the vast majority of SSI are caused by intra-abdominal contamination rather than the skin microflora. PMID- 26114398 TI - Avoiding overfitting in the analysis of high-dimensional data with artificial neural networks (ANNs). AB - Complex data analysis is becoming more easily accessible to analytical chemists, including natural computation methods such as artificial neural networks (ANNs). Unfortunately, in many of these methods, inappropriate choices of model parameters can lead to overfitting. This study concerns overfitting issues in the use of ANNs to classify complex, high-dimensional data (where the number of variables far exceeds the number of specimens). We examine whether a parameter rho, equal to the ratio of the number of observations in the training set to the number of connections in the network, can be used as an indicator to forecast overfitting. Networks possessing different rho values were trained using as inputs either raw data or scores obtained from principal component analysis (PCA). A primary finding was that different data sets behave very differently. For data sets with either abundant or scant information related to the proposed group structure, overfitting was little influenced by rho, whereas for intermediate cases some dependence was found, although it was not possible to specify values of rho which prevented overfitting altogether. The use of a tuning set, to control termination of training and guard against overtraining, did not necessarily prevent overfitting from taking place. However, for data containing scant group-related information, the use of a tuning set reduced the likelihood and magnitude of overfitting, although not eliminating it entirely. For other data sets, little difference in the nature of overfitting arose from the two modes of termination. Small data sets (in terms of number of specimens) were more likely to produce overfit ANNs, as were input layers comprising large numbers of PC scores. Hence, for high-dimensional data, the use of a limited number of PC scores as inputs, a tuning set to prevent overtraining and a test set to detect and guard against overfitting are recommended. PMID- 26114399 TI - Postherpetic Wolf's isotopic response: possible contribution of resident memory T cells to the pathogenesis of lichenoid reaction. PMID- 26114400 TI - How effective and acceptable is Web 2.0 Balint group participation for general practitioners and general practitioner registrars in regional Australia? A pilot study. AB - OBJECTIVE: General practitioners (GPs) and general practice registrars report work-related stress. Balint groups may improve coping mechanisms. However, attendance at a face-to-face Balint group is difficult for rural doctors due to distance constraints. The study aim was to evaluate online Balint groups for rural doctors and determine effect size for a full-scale trial. DESIGN: A mixed methods approach, including a pre-post controlled trial and thematic analysis of qualitative data. SETTING: Rural primary care. PARTICIPANTS: Thirteen GPs and 8 general practice registrars completed the study. INTERVENTIONS: Balint groups were delivered over 8-9 fortnightly online sessions. GPs and GP registrars participated in separate groups. Data were collected on work-related affect, psychological medicine skills and professional isolation using the Warr's Work Related Affect Scale, the Psychological Medicine Inventory, and a professional isolation scale. MAIN OUTCOME MEASURES: Change scores on Warr's Work-Related Affect Scale, the Psychological Medicine Inventory, and a professional isolation scale. RESULTS: Balint participants' scores were significantly higher post intervention on the Psychological Medicine Inventory (mean 6.49 (+/-0.20) versus 5.43 (+/-0.26); P < 0.01) and Warr's Work-Related Affect (mean 4.09 (+/-0.09) versus 3.60 (+/-0.12); P < 0.01) scales than control group scores. Effect size on these scales ranged from 0.46 to 0.50. The greatest challenge was technical problems related to insufficient broadband speed. CONCLUSIONS: Online Balint groups appear to improve rural doctors' psychological medicine skills and work related affect. New data on effect size will inform a full-scale trial. Improved national broadband infrastructure may enhance online support opportunities for rural doctors. PMID- 26114401 TI - Safety assessment of a novel active ingredient, acetyl aspartic acid, according to the EU Cosmetics Regulation and the Scientific Committee on Consumer Safety guidelines. AB - OBJECTIVE: Acetyl aspartic acid (A-A-A) was proposed as a new novel active ingredient for use in cosmetics. The safety of A-A-A was assessed by following an in-house-developed 'New Ingredient Testing Strategy', which was designed in accordance with the Scientific Committee on Consumer Safety (SCCS) notes of guidance and the requirements of Annex I of the EU Cosmetics Regulation. The aim of the project was to determine whether A-A-A was safe for use in cosmetics and to determine a maximum permitted safe level in the formulations. METHODS: A literature review was conducted, consulting over 40 different information sources. This highlighted a number of gaps which required testing data. A-A-A was tested for phototoxicity according to OECD test guideline 432, skin irritation according to OECD test guideline 439 and eye irritation according to OECD test guideline 437. Dermal absorption of A-A-A was measured according to OECD test guideline 428 and was used to calculate the margin of safety (MoS). Finally, A-A A was tested in a human repeat insult patch test (HRIPT) and a 14-day in-use tolerance study. RESULTS: A-A-A was non-phototoxic and was non-irritating to skin and eyes in in vitro testing. Dermal absorption was calculated to be 5%. The MoS for A-A-A was 351, at a level of 5%, for all cosmetic product types, indicating no systemic safety toxicity concern. A-A-A at 5% under occlusive patch on a panel of 50 adult volunteers induced no skin irritation or allergic reaction in the HRIPT study. Finally, repeated application of A-A-A to the periocular area, twice per day for 14 days, in 21 female volunteers, demonstrated that 1% A-A-A was well tolerated following dermatological and ophthalmological assessment in a cosmetic formulation. CONCLUSION: A-A-A was assessed as safe by the cosmetic safety assessor for use in cosmetics at a level of 5% in all cosmetic product types, in line with the requirements of the EU Cosmetics Regulation and in accordance with the SCCS notes of guidance. PMID- 26114402 TI - Effect of bioreduced graphene oxide on anaerobic biotransformation of nitrobenzene in an anaerobic reactor. AB - Bioreduced graphene oxide (BRGO) has been proven to be capable of accelerating nitrobenzene (NB) biotransformation by anaerobic sludge (AS). To realize its application, in the present study, two continuous anaerobic reactors (R1 with BRGO/AS composite; R2 with AS) were employed to treat NB-containing wastewater during a long-term run. Compared with R2, the start-up time of R1 was shortened from 70 to 45 d and R1 exhibited better removal efficiency (87% of R1 and 74% of R2 with an influent NB concentration of 200 mg L(-1) at hydraulic retention time = 24 h, NaCl = 3%). Moreover, R1 exhibited better stability with over 81% NB removal efficiency within 90 d. Further study demonstrated that the presence of BRGO facilitated microorganisms to secrete extracellular polymeric substances, resulting in the higher electrochemical and dehydrogenase activities of R1 compared with those of R2. PMID- 26114404 TI - Novel Therapy With Ramelteon for Hypoactive Delirium: A Case Report. PMID- 26114403 TI - Experimental design and analysis and their reporting: new guidance for publication in BJP. PMID- 26114396 TI - Gold Nanoparticles for In Vitro Diagnostics. PMID- 26114405 TI - Intracellular distribution of cadmium during the growth of Abortiporus biennis on cadmium-amended media. AB - Heavy metals are difficult to remediate and traditional remedial processes are expensive, so bioremediation technology using bacteria, fungi, or plants is of interest. Many studies have demonstrated that basidiomycetes fungi are able to growth under heavy metals stress. In this study the distribution of cadmium (Cd) in Abortiporus biennis cells was studied. Cd accumulated especially within cytoplasm and its presence caused changes in the cytoplasm appearance, which became denser in comparison to the cytoplasm of control cells. Vacuolization of cytoplasm and periplasmic region in A. biennis cells was also observed. The growth rate of A. biennis was inhibited up to 75% during the growth on medium amended with 1 mmol/L cadmium oxide. The presence of Cd in growing media inhibited oxalic acid secretion by A. biennis, but oxalate concentration increased together with elevated Cd concentration in growing medium. The influence of initial pH of growing media on the accumulation of Cd by A. biennis was also observed. The highest accumulation of Cd in mycelium was detected during A. biennis growth on media with a pH of 6. Studies addressing metals uptake by fungi and metal distribution in fungal cells may allow these organisms to be applied in bioremediation processes more effectively or to be used as bioindicators of contaminated environmental pollutions. PMID- 26114406 TI - Screening of herbaceous plants for peat-enhanced rehabilitation of contaminated soil with oily sludge. AB - A batch pot experiment using nine herbaceous species were conducted for peat enhanced rehabilitation of contaminated soil with oily sludge in the initial contents of 0%, 1.3%, 7.4%, and 12.2%, respectively. The results showed that petroleum hydrocarbons removal, plant growth indices and enzyme activities varied depending on plant species and oil contents. Cotton, ryegrass and tall fescue were effective in the rehabilitation of oily sludge contaminated soils. The total petroleum hydrocarbon (TPH) removal ranged from 30.0% to 40.0% after 170 days of treatment. Plant biomass was shown to be the preferred indicator for screening phytoremediation plant because it was closely correlated with TPH removal and enzyme activities. Peat-enhanced plant rehabilitation could be a good strategy for the treatment of oily sludge contaminated saline soils. PMID- 26114407 TI - [Editorial]. PMID- 26114408 TI - [Progesterone for Prevention of Preterm Birth--Evidence-based Indications]. AB - BACKGROUND: The prevention and treatment of preterm birth remains an unsolved problem in modern obstetrics. Progesterone has a variety of actions on the myometrium and the cervix, among others inhibition of myometrial contractility and a cervix strengthening effect by inhibiting the production of proinflammatory cytokines and prostaglandins as well as by reducing the synthesis of proteins, which play a crucial role in initiating labour. Consequently, progesterone may be a promising candidate for the prevention of preterm birth. MATERIAL AND METHODS: We searched PubMed from 1956 to August 2014 using a combination of key words and text words related to preterm birth and progesterone. ('progesterone', progestins, 17-OHPC). The aim of the literature search was to determine evidence based indications for the use of progesterone in the prevention of preterm birth. RESULTS: (i) Patients with a singleton pregnancy and history of preterm birth should receive vaginal progesterone daily (200 mg capsule or 90 mg containing gel) from 16+0 to 36+0 weeks of gestation (alternatively 250 mg intramuscular 17 OHPC weekly): level of evidence 1a, grade of recommendation ++ . Prophylactic progesterone reduces the incidence of preterm birth <34 and <37 weeks of gestation and perinatal mortality significantly. (ii) Patients with singleton pregnancies and a sonographically short cervix (<=25 mm) before 24 weeks of gestation should receive vaginal progesterone daily (200 mg capsule or 90 mg containing gel) until 36+6 weeks of gestation: level of evidence 1a, grade of recommendation ++ . Prophylactic progesterone leads to a significant reduction in the incidence of preterm birth <28, <33, and <35 weeks of gestation and is associated with a significant reduction of neonatal morbidity. (III) There is a lack of evidence to recommend vaginal progesterone or intramuscular 17-OHPC for primary tocolysis or for "adjunctive" tocolysis (in combination with conventional tocolytic agents). (IV) There is a growing body of evidence that vaginal progesterone (400 mg/day) after successful tocolysis ("maintenance therapy") is a promising option for prolongation of pregnancy: level of evidence 1b, grade of recommendation +. (V) Data from the literature are insufficient to recommend progesterone in patients with preterm rupture of membranes or in the perioperative management of patients requiring transvaginal cervical cerclage. (VI) The vaginal administration of progesterone is well-tolerated by the patients and has only minor maternal side effects, whereas intramuscular injections of 17 OHPC are associated with a significant higher rate of side effects (e. g. local pain, nausea, diarrhoea). It is mandatory to inform patients on the off-label use of progesterone in pregnancy. DISCUSSION: Prophylactic progesterone administration is an evidence-based method for the prevention of preterm birth in women with a previous preterm birth and in pregnant women with a sonographically short cervix (<=25 mm) before 24 weeks of gestation. Vaginal progesterone is favoured over intramuscularly applied 17-OHPC, especially because of the lower rate of maternal side effects. Whether progesterone is an effective approach for the treatment of preterm birth as a tocolytic agent (primary, adjunctive) or for maintenance therapy after arrest of preterm labour has to be shown in further well-designed randomised and controlled trials with adequate statistical power. PMID- 26114410 TI - First human challenge testing of a pneumococcal vaccine. Double-blind randomized controlled trial. AB - RATIONALE: New vaccines are urgently needed to protect the vulnerable from bacterial pneumonia. Clinical trials of pneumonia vaccines are slow and costly, requiring tens of thousands of patients. Studies of pneumococcal vaccine efficacy against colonization have been proposed as a novel method to down-select between vaccine candidates. OBJECTIVES: Using our safe and reproducible experimental human pneumococcal colonization model, we aimed to determine the effect of 13 valent pneumococcal conjugate vaccine (PCV) on colonization. METHODS: A total of 100 healthy participants aged 18-50 years were recruited into this double-blind randomized placebo-controlled trial. They were randomly assigned to PCV (n = 49) or hepatitis A (control, n = 50) vaccination and inoculated with 80,000 CFU/100 MUl of Streptococcus pneumoniae (6B) per naris. MEASUREMENTS AND MAIN RESULTS: Participants were followed up for 21 days to determine pneumococcal colonization by culture of nasal wash. The PCV group had a significantly reduced rate of 6B colonization (10% [5 of 48]) compared with control subjects (48% [23 of 48]) (risk ratio, 0.22; confidence interval, 0.09-0.52; P < 0.001). Density of colonization was reduced in the PCV group compared with the control group following inoculation. The area under the curve (density vs. day) was significantly reduced in the PCV compared with control group (geometric mean, 259 vs. 11,183; P = 0.017). CONCLUSIONS: PCV reduced pneumococcal colonization rate, density, and duration in healthy adults. The experimental human pneumococcal colonization model is a safe, cost-effective, and efficient method to determine the protective efficacy of new vaccines on pneumococcal colonization; PCV provides a gold standard against which to test these novel vaccines. Clinical trial registered with ISRCTN: 45340436. PMID- 26114411 TI - Diffusion imaging of the vertebral bone marrow. AB - Diffusion-weighted MRI (DWI) of the vertebral bone marrow is a clinically important tool for the characterization of bone-marrow pathologies and, in particular, for the differentiation of benign (osteoporotic) and malignant vertebral compression fractures. DWI of the vertebral bone marrow is, however, complicated by some unique MR and tissue properties of vertebral bone marrow. Due to both the spongy microstructure of the trabecular bone and the proximity of the lungs, soft tissue, or large vessels, substantial magnetic susceptibility variations occur, which severely reduce the magnetic field homogeneity as well as the transverse relaxation time T*2 , and thus complicate MRI in particular with echoplanar imaging (EPI) techniques. Therefore, alternative diffusion-weighting pulse sequence types such as single-shot fast-spin-echo sequences or segmented EPI techniques became important alternatives for quantitative DWI of the vertebral bone marrow. This review first describes pulse sequence types that are particularly important for DWI of the vertebral bone marrow. Then, data from 24 studies that made diffusion measurements of normal vertebral bone marrow are reviewed; summarizing all results, the apparent diffusion coefficient (ADC) of normal vertebral bone marrow is typically found to be between 0.2 and 0.6 * 10-3 mm2 /s. Finally, DWI of vertebral compression fractures is discussed. Numerous studies demonstrate significantly greater ADCs in osteoporotic fractures (typically between 1.2 and 2.0 * 10-3 mm2 /s) than in malignant fractures or lesions (typically 0.7-1.3 * 10-3 mm2 /s). Alternatively, several studies used the (qualitative) image contrast of diffusion-weighted acquisitions for differentiation of lesion etiology: a very good lesion differentiation can be achieved, particularly with diffusion-weighted steady-state free precession sequences, which depict malignant lesions as hyperintense relative to normal appearing vertebral bone marrow, in contrast to hypointense or isointense osteoporotic lesions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26114412 TI - In vitro and in vivo effects of melatonin on sister chromatid exchange in human blood lymphocytes exposed to hypoxia. AB - OBJECTIVE: Many studies have shown that melatonin (MLT) has an anti-genotoxic effect in various tissues and cell lines. The aim of this study was to investigate the anti-genotoxic effect of MLT on normal human peripheral lymphocytes by assessing sister chromatid exchange (SCE) in vitro and in vivo. MATERIALS AND METHODS: Cells were treated with 50 and 200 MUM of MLT. The human volunteers (n = 20) for the in vivo study were administered a single dose of 3 mg MLT daily for 2 weeks. After sufficient time for its clearance, 1.5 mg of MLT daily was then administered to the same volunteers at same the period. RESULTS: Our results demonstrated the anti-genotoxic effect of MLT in human blood lymphocyte in vitro and in vivo. In vitro, hypoxia increased the SCE frequency compared to the control and both doses of MLT significantly decreased the SCE frequency in the hypoxic cells (p < 0.001). In vivo, oral administration of 3 mg MLT significantly increased the frequency of SCE, yet a small increase of SCE by hypoxia was found. Oral administration of 1.5 mg MLT showed no DNA damage but it had an anti-genotoxic effect. DISCUSSION AND CONCLUSION: MLT may prove useful for reducing the genotoxic effects of hypoxia in peripheral lymphocytes and suggest its possible role for ischemic diseases. PMID- 26114413 TI - 1,1'-Bis(pyrazol-3-yl)ferrocene: A Clip Ligand That Forms Supramolecular Aggregates and Prismatic Hexanuclear Coinage Metal Complexes. AB - Two ferrocene derivatives with appended pyrazole substituents, namely, 1,1'-bis(5 methyl-1H-pyrazol-3-yl)ferrocene (H2LH) and 1,1'-bis(5-trifluoromethyl-1H-pyrazol 3-yl)ferrocene (H2LF), were synthesized. In solid state they form distinct H bonded dimers with orthogonal (H2LH, C2 symmetry) or antiparallel (H2LF, C2h symmetry) arrangement of the two ferrocene/pyrazole hybrid molecules. Supramolecular dimerization was also detected in solution at low temperatures, though diffusion-ordered spectroscopy and variable-temperature NMR spectroscopy revealed several dynamic processes. Redox potentials of the ferrocene derivatives are affected by the nature of the pyrazole substituent (Me, CF3). In their deprotonated form [LR]2-, both ferrocene/pyrazole hybrids serve as ligands and form oligonuclear CuI, AgI, and AuI complexes that were identified by matrix assisted laser desorption ionization mass spectrometry. X-ray crystallography revealed the structures of Cu6L3H and Ag6L3F, which both contain two parallel and eclipsed [M(MU-pz)]3 metallamacrocycles (M = Cu, Ag) linked by three ferrocene units. MI...MI distances between the two triangular M3N6 decks are shorter in Ag6L3F (3.28-3.30 vs 3.44-3.51 A in the case of Cu6L3H), indicating substantial intramolecular closed-shell Ag(d10)-Ag(d10) interactions. However, Cu6L3H features close intermolecular Cu...Cu contacts as short as 3.37 A. Mossbauer data for both the ligands and complexes were collected, and electrochemical properties were measured; preliminary luminescence data are reported. PMID- 26114414 TI - Scholarly productivity and national institutes of health funding of foundation for anesthesia education and research grant recipients: insights from a bibliometric analysis. AB - BACKGROUND: The Foundation for Anesthesia Education and Research (FAER) grant program provides fellows and junior faculty members with grant support to stimulate their careers. The authors conducted a bibliometric analysis of recipients of FAER grants since 1987. METHODS: Recipients were identified in the FAER alumni database. Each recipient's affiliation was identified using an Internet search (keyword "anesthesiology"). The duration of activity, publications, publication rate, citations, citation rate, h-index, and National Institutes of Health (NIH) funding for each recipient were obtained using the Scopus (Elsevier, USA) and NIH Research Portfolio Online Reporting Tools (National Institutes of Health, USA) databases. RESULTS: Three hundred ninety seven individuals who received 430 FAER grants were analyzed, 79.1% of whom currently hold full-time academic appointments. Recipients published 19,647 papers with 548,563 citations and received 391 NIH grants totaling $448.44 million. Publications, citations, h-index, the number of NIH grants, and amount of support were dependent on academic rank and years of activity (P < 0.0001). Recipients who acquired NIH grants (40.3%) had greater scholarly output than those who did not. Recipients with more publications were also more likely to secure NIH grants. Women had fewer publications and lower h-index than men, but there were no gender-based differences in NIH funding. Scholarly output was similar in recipients with MD and PhD degrees versus those with MD degrees alone, but recipients with MD and PhD degrees were more likely to receive NIH funding than those with MDs alone. CONCLUSION: Most FAER alumni remain in academic anesthesiology and have established a consistent record of scholarly output that appears to exceed reported productivity for average faculty members identified in previous studies. PMID- 26114415 TI - Small tidal volumes, positive end-expiratory pressure, and lung recruitment maneuvers during anesthesia: good or bad? PMID- 26114416 TI - Continuous variable transformation in anesthesia: useful clinical shorthand, but threat to research. PMID- 26114417 TI - Economic and Time-Sensitive Issues Surrounding CCS: A Policy Analysis. AB - Are the existing global policies on combating global warming via the carbon capture and storage (CCS) method significant enough to curtail the temperature rise on time? We argue that it is already too late to have any reliance on CCS. The current status of CCS is that it is plagued by technical uncertainties, infrastructure, financial, and regulatory issues. The technology is far from maturity and, hence, commercialization. Simulations conducted in this work suggest that the relevance of CCS is completely defied if the annual emission growth rate is in excess of 2% between the years of 2015 and 2040. At such a growth rate, the annual emissions reduction between 2040 and 2100 will need to be in the vicinity of 5.5% by the year 2100. Considering an average annual emissions growth rate of 2.5% over the past decade, it seems unlikely that the emissions could be contained to a 2% growth level. CCS in its current shape and form is at odds with the economics of its implementation and the time in hand with which to play a significant role in a carbon mitigation strategy. There is an urgent need to rethink policies and strategies to combat global warming to at least some degree. PMID- 26114418 TI - Corrigendum. PMID- 26114419 TI - Sweet cherries from farm to table: A review. AB - In order to enable long-distance transportation and ensure that the fruit presents the requisite quality on arrival at markets, the cherry industry for direct consumption needs to prolong post-harvest shelf life. Sweet cherries are highly perishable, non-climacteric fruits with shelf life of 7-14 days in cold storage. Their shelf life is shortened by loss of firmness, color and flavor, stem discoloration, desiccation and mould growth. Various factors such as harvest time, proper handling and cooling practices and above all packaging, greatly influence the shelf life of cherries. One of the areas of research that has shown promise, and had success, is modified atmosphere packaging (MAP). It is one of the fastest growing packaging technologies and has many advantages for different food products. Properly designed modified atmosphere packs can be exploited to lower respiration rates and thus ripening of fruits which results in least changes in physiochemical parameters of sweet cherries during postharvest storage. This paper intended to review a broad spectrum of studies dealt with the use of MAP for preservation of sweet cherries cultivars with an interest for future research work. PMID- 26114420 TI - Bioavailability of beta-cryptoxanthin is greater from pasteurized orange juice than from fresh oranges - a randomized cross-over study. AB - SCOPE: Orange fruits and products thereof represent important dietary sources of carotenoids, particularly beta-cryptoxanthin. Since previous studies reported a positive effect of vegetable processing on carotenoid absorption, our objective was to compare the bioavailability of beta-cryptoxanthin from either fresh navel oranges (Citrus sinensis L. Osbeck) or pasteurized orange juice. METHODS AND RESULTS: The study was designed as a randomized 2-way cross-over study. Twelve volunteers consumed two meals delivering 744 MUg of beta-cryptoxanthin from either fresh navel oranges or pasteurized orange juice. Eight blood samples were collected over 9.5 h after test meal consumption and analyzed using HPLC-DAD. Additionally, carotenoid bioaccessibility was assessed after in vitro digestion of the same test foods. beta-cryptoxanthin bioavailability from pasteurized orange juice was 1.8-fold higher than from fresh oranges (P = 0.011). Similarly, mean absorption of the non-dose adjusted carotenoids lutein (P = 0.301), zeaxanthin (P = 0.216), and zeinoxanthin (P = 0.090) were slightly higher from orange juice, although not reaching statistical significance. The in vitro digestion revealed a 5.3-fold higher bioaccessibility of beta-cryptoxanthin from orange juice. Dietary fiber contents in the test foods were inversely associated with carotenoid bioavailability. CONCLUSION: Orange juice represents a more bioavailable source of beta-cryptoxanthin than fresh oranges. PMID- 26114421 TI - Comparison of bacterial leakage resistance of various root canal filling materials and methods: Confocal laser-scanning microscope study. AB - This study evaluated the bacterial leakage resistance and root canal lining efficacy of various root canal filling materials and methods by using confocal laser-scanning microscope (CLSM). Sixty extracted human premolars with mature apex and single root canal were randomly divided into 2 control groups and 4 experimental groups. Group CW was filled with continuous wave technique using gutta-percha and AH Plus sealer. Group GC was coated with AH-Plus sealer and then obturated with soften GuttaCore. Group GF was obturated using GuttaFlow and gutta percha. Group EM was filled with EndoSeal MTA and gutta-percha using ultrasonic vibration. The AH-Plus, GuttaFlow, and EndoSeal were labeled with Hoechst 33342 to facilitate fluorescence. The obturated root tip was incubated with Carboxyfluorescein diacetate succinimidyl ester (CFSE)-stained E. faecalis for 14 days. CLSM was performed to evaluate the sealer distribution and bacterial leakage for the apical 1-, 2-, 3-mm specimens. Statistically significant differences were determined by 1-way ANOVA with Tukey's post-hoc test and Pearson's correlation analysis. Group EM showed the better sealer distribution score than the other groups (p < 0.05). Group CW and group GC exhibited the less bacterial leakage than the group GF, while group EM showed the similar bacterial leakage score with the groups CW and GC. There was no significant correlation between the sealer distribution and bacterial leakage (p > 0.05). Under the conditions of this study, different root canal filling materials and methods showed different efficacy for canal distribution and bacterial leakage resistance. PMID- 26114422 TI - Studies on the Formation of Maillard and Caramelization Products from Glucosamine Incubated at 37 degrees C. AB - This experiment compared the in vitro degradation of glucosamine (GlcN), N acetylglucosamine, and glucose in the presence of NH3 incubated at 37 degrees C in phosphate buffer from 0.5 to 12 days. The reactions were monitored with UV-vis absorption and fluorescence emission spectroscopies, and the main products of degradation, quinoxaline derivatives of alpha-dicarbonyl compounds and condensation products, were determined using UHPLC-UV and Orbitrap mass spectrometry. GlcN produced two major dicarbonyl compounds, glucosone and 3 deoxyglucosone, ranging from 709 to 3245 mg/kg GlcN and from 272 to 4535 mg/kg GlcN, respectively. 3,4-Dideoxyglucosone-3-ene, glyoxal, hydroxypyruvaldehyde, methylglyoxal, and diacetyl were also detected in lower amounts compared to glucosone and 3-deoxyglucosone. Several pyrazine condensation products resulting from the reaction between dicarbonyls and GlcN were also identified. This study determined that GlcN is a significantly unstable molecule producing a high level of degradation products at 37 degrees C. PMID- 26114423 TI - The Relationship between Personality Dimensions and Resiliency to Environmental Stress in Orange-Winged Amazon Parrots (Amazona amazonica), as Indicated by the Development of Abnormal Behaviors. AB - Parrots are popular companion animals, but are frequently relinquished because of behavioral problems, including abnormal repetitive behaviors like feather damaging behavior and stereotypy. In addition to contributing to pet relinquishment, these behaviors are important as potential indicators of diminished psychological well-being. While abnormal behaviors are common in captive animals, their presence and/or severity varies between animals of the same species that are experiencing the same environmental conditions. Personality differences could contribute to this observed individual variation, as they are known risk factors for stress sensitivity and affective disorders in humans. The goal of this study was to assess the relationship between personality and the development and severity of abnormal behaviors in captive-bred orange-winged Amazon parrots (Amazona amazonica). We monitored between-individual behavioral differences in enrichment-reared parrots of known personality types before, during, and after enrichment deprivation. We predicted that parrots with higher scores for neurotic-like personality traits would be more susceptible to enrichment deprivation and develop more abnormal behaviors. Our results partially supported this hypothesis, but also showed that distinct personality dimensions were related to different forms of abnormal behavior. While neuroticism-like traits were linked to feather damaging behavior, extraversion-like traits were negatively related to stereotypic behavior. More extraverted birds showed resiliency to environmental stress, developing fewer stereotypies during enrichment deprivation and showing lower levels of these behaviors following re enrichment. Our data, together with the results of the few studies conducted on other species, suggest that, as in humans, certain personality types render individual animals more susceptible or resilient to environmental stress. Further, this susceptibility/resiliency can have a long-term effect on behavior, as evidenced by behavioral changes that persisted despite re-enrichment. Ours is the first study evaluating the relationship between personality dimensions, environment, and abnormal behaviors in an avian species. PMID- 26114424 TI - Overexpression of RhoH Permits to Bypass the Pre-TCR Checkpoint. AB - RhoH, an atypical small Rho-family GTPase, critically regulates thymocyte differentiation through the coordinated interaction with Lck and Zap70. Therefore, RhoH deficiency causes defective T cell development, leading to a paucity of mature T cells. Since there has been no gain-of-function study on RhoH before, we decided to take a transgenic approach to assess how the overexpression of RhoH affects the development of T cells. Although RhoH transgenic (RhoHtg) mice expressed three times more RhoH protein than wild-type mice, beta-selection, positive, and negative selection in the thymus from RhoHtg mice were unaltered. However, transgenic introduction of RhoH into Rag2 deficient mice resulted in the generation of CD4+ CD8+ (DP) thymocytes, indicating that overexpression of RhoH could bypass beta-selection without TCRbeta gene rearrangement. This was confirmed by the in vitro development of DP cells from Rag2-/-RhoHtg DN3 cells on TSt-4/Dll-1 stroma in an Lck dependent manner. Collectively, our results indicate that an excess amount of RhoH is able to initiate pre-TCR signaling in the absence of pre-TCR complexes. PMID- 26114425 TI - Reproductive Mode and the Evolution of Genome Size and Structure in Caenorhabditis Nematodes. AB - The self-fertile nematode worms Caenorhabditis elegans, C. briggsae, and C. tropicalis evolved independently from outcrossing male-female ancestors and have genomes 20-40% smaller than closely related outcrossing relatives. This pattern of smaller genomes for selfing species and larger genomes for closely related outcrossing species is also seen in plants. We use comparative genomics, including the first high quality genome assembly for an outcrossing member of the genus (C. remanei) to test several hypotheses for the evolution of genome reduction under a change in mating system. Unlike plants, it does not appear that reductions in the number of repetitive elements, such as transposable elements, are an important contributor to the change in genome size. Instead, all functional genomic categories are lost in approximately equal proportions. Theory predicts that self-fertilization should equalize the effective population size, as well as the resulting effects of genetic drift, between the X chromosome and autosomes. Contrary to this, we find that the self-fertile C. briggsae and C. elegans have larger intergenic spaces and larger protein-coding genes on the X chromosome when compared to autosomes, while C. remanei actually has smaller introns on the X chromosome than either self-reproducing species. Rather than being driven by mutational biases and/or genetic drift caused by a reduction in effective population size under self reproduction, changes in genome size in this group of nematodes appear to be caused by genome-wide patterns of gene loss, most likely generated by genomic adaptation to self reproduction per se. PMID- 26114426 TI - Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease. AB - The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO 1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes. PMID- 26114427 TI - Metabolomic Analysis of the Skeletal Muscle of Mice Overexpressing PGC-1alpha. AB - Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC 1alpha) is a coactivator of various nuclear receptors and other transcription factors whose expression increases in the skeletal muscle during exercise. We have previously made transgenic mice overexpressing PGC-1alpha in the skeletal muscle (PGC-1alpha-Tg mice). PGC-1alpha upregulates the expression of genes associated with red fibers, mitochondrial function, fatty acid oxidation, and branched chain amino acid (BCAA) degradation. However, global analyses of the actual metabolic products have not been investigated. In this study, we conducted metabolomic analysis of the skeletal muscle in PGC-1alpha-Tg mice by capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry. Principal component analysis and hierarchical cluster analysis showed clearly distinguishable changes in the metabolites between PGC-1alpha-Tg and wild-type control mice. Changes were observed in metabolite levels of various metabolic pathways such as the TCA cycle, pentose phosphate pathway, nucleotide synthesis, purine nucleotide cycle, and amino acid metabolism, including BCAA and beta alanine. Namely, metabolic products of the TCA cycle increased in PGC-1alpha-Tg mice, with increased levels of citrate (2.3-fold), succinate (2.2-fold), fumarate (2.8-fold), and malate (2.3-fold) observed. Metabolic products associated with the pentose phosphate pathway and nucleotide biosynthesis also increased in PGC 1alpha-Tg mice. Meanwhile, BCAA levels decreased (Val, 0.7-fold; Leu, 0.8-fold; and Ile, 0.7-fold), and Glu (3.1-fold) and Asp (2.2-fold) levels increased. Levels of beta-alanine and related metabolites were markedly decreased in PGC 1alpha-Tg mice. Coordinated regulation of the TCA cycle and amino acid metabolism, including BCAA, suggests that PGC-1alpha plays important roles in energy metabolism. Moreover, our metabolomics data showing the activation of the purine nucleotide pathway, malate-aspartate shuttle, as well as creatine metabolism, which are known to be active during exercise, further suggests that PGC-1alpha regulates metabolism in exercise. Thus, we demonstrated the roles of PGC-1alpha in the skeletal muscle at the metabolite level. PMID- 26114428 TI - Pseudomonas aeruginosa Biofilm Response and Resistance to Cold Atmospheric Pressure Plasma Is Linked to the Redox-Active Molecule Phenazine. AB - Pseudomonas aeruginosa is an important opportunistic pathogen displaying high antibiotic resistance. Its resistance is in part due to its outstanding ability to form biofilms on a range of biotic and abiotic surfaces leading to difficult to-treat, often long-term infections. Cold atmospheric plasma (CAP) is a new, promising antibacterial treatment to combat antibiotic-resistant bacteria. Plasma is ionized gas that has antibacterial properties through the generation of a mix of reactive oxygen and nitrogen species (RONS), excited molecules, charged particles and UV photons. Our results show the efficient removal of P. aeruginosa biofilms using a plasma jet (kINPen med), with no viable cells detected after 5 min treatment and no attached biofilm cells visible with confocal microscopy after 10 min plasma treatment. Because of its multi-factorial action, it is widely presumed that the development of bacterial resistance to plasma is unlikely. However, our results indicate that a short plasma treatment (3 min) may lead to the emergence of a small number of surviving cells exhibiting enhanced resistance to subsequent plasma exposure. Interestingly, these cells also exhibited a higher degree of resistance to hydrogen peroxide. Whole genome comparison between surviving cells and control cells revealed 10 distinct polymorphic regions, including four belonging to the redox active, antibiotic pigment phenazine. Subsequently, the interaction between phenazine production and CAP resistance was demonstrated in biofilms of transposon mutants disrupted in different phenazine pathway genes which exhibited significantly altered sensitivity to CAP. PMID- 26114430 TI - A Modelling Framework to Assess the Effect of Pressures on River Abiotic Habitat Conditions and Biota. AB - River biota are affected by global reach-scale pressures, but most approaches for predicting biota of rivers focus on river reach or segment scale processes and habitats. Moreover, these approaches do not consider long-term morphological changes that affect habitat conditions. In this study, a modelling framework was further developed and tested to assess the effect of pressures at different spatial scales on reach-scale habitat conditions and biota. Ecohydrological and 1D hydrodynamic models were used to predict discharge and water quality at the catchment scale and the resulting water level at the downstream end of a study reach. Long-term reach morphology was modelled using empirical regime equations, meander migration and 2D morphodynamic models. The respective flow and substrate conditions in the study reach were predicted using a 2D hydrodynamic model, and the suitability of these habitats was assessed with novel habitat models. In addition, dispersal models for fish and macroinvertebrates were developed to assess the re-colonization potential and to finally compare habitat suitability and the availability/ability of species to colonize these habitats. Applicability was tested and model performance was assessed by comparing observed and predicted conditions in the lowland Treene River in northern Germany. Technically, it was possible to link the different models, but future applications would benefit from the development of open source software for all modelling steps to enable fully automated model runs. Future research needs concern the physical modelling of long-term morphodynamics, feedback of biota (e.g., macrophytes) on abiotic habitat conditions, species interactions, and empirical data on the hydraulic habitat suitability and dispersal abilities of macroinvertebrates. The modelling framework is flexible and allows for including additional models and investigating different research and management questions, e.g., in climate impact research as well as river restoration and management. PMID- 26114429 TI - Dietary Lipid Levels Influence Lipid Deposition in the Liver of Large Yellow Croaker (Larimichthys crocea) by Regulating Lipoprotein Receptors, Fatty Acid Uptake and Triacylglycerol Synthesis and Catabolism at the Transcriptional Level. AB - Ectopic lipid accumulation has been observed in fish fed a high-lipid diet. However, no information is available on the mechanism by which dietary lipid levels comprehensively regulate lipid transport, uptake, synthesis and catabolism in fish. Therefore, the present study aimed to gain further insight into how dietary lipids affect lipid deposition in the liver of large yellow croaker(Larimichthys crocea). Fish (150.00+/-4.95 g) were fed a diet with a low (6%), moderate (12%, the control diet) or high (18%) crude lipid content for 10 weeks. Growth performance, plasma biochemical indexes, lipid contents and gene expression related to lipid deposition, including lipoprotein assembly and clearance, fatty acid uptake and triacylglycerol synthesis and catabolism, were assessed. Growth performance was not significantly affected. However, the hepato somatic and viscera-somatic indexes as well as plasma triacylglycerol, non esterified fatty acids and LDL-cholesterol levels were significantly increased in fish fed the high-lipid diet. In the livers of fish fed the high-lipid diet, the expression of genes related to lipoprotein clearance (LDLR) and fatty acid uptake (FABP11) was significantly up-regulated, whereas the expression of genes involved in lipoprotein assembly (apoB100), triacylglycerol synthesis and catabolism (DGAT2, CPT I) was significantly down-regulated compared with fish fed the control diet, and hepatic lipid deposition increased. In fish fed the low-lipid diet, the expression of genes associated with lipoprotein assembly and clearance (apoB100, LDLR, LRP-1), fatty acid uptake (CD36, FATP1, FABP3) and triacylglycerol synthesis (FAS) was significantly increased, whereas the expression of triacylglycerol catabolism related genes (ATGL, CPT I) was reduced compared with fish fed the control diet. However, hepatic lipid content in fish fed the low-lipid diet decreased mainly due to low dietary lipid intake. In summary, findings of this study provide molecular insight into the role of lipid deposition in the liver in response to different dietary lipid contents. PMID- 26114431 TI - Marine invertebrate lipases: Comparative and functional genomic analysis. AB - Lipases are key enzymes involved in lipid digestion, storage and mobilization of reserves during fasting or heightened metabolic demand. This is a highly conserved process, essential for survival. The genomes of five marine invertebrate species with distinctive digestive system were screened for the six major lipase families. The two most common families in marine invertebrates, the neutral an acid lipases, are also the main families in mammals and insects. The number of lipases varies two-fold across analyzed genomes. A high degree of orthology with mammalian lipases was observed. Interestingly, 19% of the marine invertebrate lipases have lost motifs required for catalysis. Analysis of the lid and loop regions of the neutral lipases suggests that many marine invertebrates have a functional triacylglycerol hydrolytic activity as well as some acid lipases. A revision of the expression profiles and functional activity on sequences in databases and scientific literature provided information regarding the function of these families of enzymes in marine invertebrates. PMID- 26114432 TI - Correction: cocor: A Comprehensive Solution for the Statistical Comparison of Correlations. PMID- 26114433 TI - Major Adverse Cardiovascular Events in Treated Periodontitis: A Population-Based Follow-Up Study from Taiwan. AB - BACKGROUND: The aim of the present study was to identify the long-term major adverse cardiovascular events (MACE) in treated periodontitis patients in Taiwan. METHODS: From the National Health Insurance Research Database (2001-2010), adult patients (>= 18 years) with treated periodontitis were identified. Comparison was made between patients with mild form and severe form of treated periodontitis after propensity score matching. The primary end point was the incidence of MACE. RESULTS: A total of 32,504 adult patients with treated periodontitis were identified between 2001 and 2010. After propensity score matching, 27,146 patients were preserved for comparison, including 13,573 patients with mild form and 13,573 patients with severe form of treated periodontitis. During follow-up, 728 individuals in mild treated periodontitis group and 1,206 individuals in severe treated periodontitis group had at least 1 MACE event. After adjustment for gender, hyperlipidemia, hypertension and diabetes mellitus, severe treated periodontitis was associated with a mildly but significantly increased risk of MACE among older patients > 60 years of age (incidence rate ratio, 1.26; 95% confidence interval, 1.08-1.46). No association was found among younger patients <= 60 years of age. CONCLUSIONS: Severe form of treated periodontitis was associated with an increased risk of MACE among older Taiwanese patients, but not among younger Taiwanese patients. We should put more efforts on the improvement of periodontal health to prevent further MACE. PMID- 26114435 TI - Correction: Indian Plant Germplasm on the Global Platter: An Analysis. PMID- 26114434 TI - Pseudomonas aeruginosa MifS-MifR Two-Component System Is Specific for alpha Ketoglutarate Utilization. AB - Pseudomonas aeruginosa is a Gram-negative, metabolically versatile opportunistic pathogen that elaborates a multitude of virulence factors, and is extraordinarily resistant to a gamut of clinically significant antibiotics. This ability, in part, is mediated by two-component regulatory systems (TCS) that play a crucial role in modulating virulence mechanisms and metabolism. MifS (PA5512) and MifR (PA5511) form one such TCS implicated in biofilm formation. MifS is a sensor kinase whereas MifR belongs to the NtrC superfamily of transcriptional regulators that interact with RpoN (sigma54). In this study we demonstrate that the mifS and mifR genes form a two-gene operon. The close proximity of mifSR operon to poxB (PA5514) encoding a beta-lactamase hinted at the role of MifSR TCS in regulating antibiotic resistance. To better understand this TCS, clean in-frame deletions were made in P. aeruginosa PAO1 creating PAO?mifS, PAO?mifR and PAO?mifSR. The loss of mifSR had no effect on the antibiotic resistance profile. Phenotypic microarray (BioLOG) analyses of PAO?mifS and PAO?mifR revealed that these mutants were unable to utilize C5-dicarboxylate alpha-ketoglutarate (alpha-KG), a key tricarboxylic acid cycle intermediate. This finding was confirmed using growth analyses, and the defect can be rescued by mifR or mifSR expressed in trans. These mifSR mutants were able to utilize all the other TCA cycle intermediates (citrate, succinate, fumarate, oxaloacetate or malate) and sugars (glucose or sucrose) except alpha-KG as the sole carbon source. We confirmed that the mifSR mutants have functional dehydrogenase complex suggesting a possible defect in alpha-KG transport. The inability of the mutants to utilize alpha-KG was rescued by expressing PA5530, encoding C5-dicarboxylate transporter, under a regulatable promoter. In addition, we demonstrate that besides MifSR and PA5530, alpha-KG utilization requires functional RpoN. These data clearly suggests that P. aeruginosa MifSR TCS is involved in sensing alpha-KG and regulating its transport and subsequent metabolism. PMID- 26114436 TI - Retention in HIV Care and Predictors of Attrition from Care among HIV-Infected Adults Receiving Combination Anti-Retroviral Therapy in Addis Ababa. AB - BACKGROUND: Patient retention in chronic HIV care is a major challenge following the rapid expansion of combination antiretroviral therapy (cART) in Ethiopia. OBJECTIVE: To describe the proportion of patients who are retained in HIV care and characterize predictors of attrition among HIV-infected adults receiving cART in Addis Ababa. METHOD: A retrospective analysis was conducted among 836 treatment naive patients, who started cART between May 2009 and April 2012. Patients were randomly selected from ten health-care facilities, and their current status in HIV care was determined based on routinely available data in the medical records. Patients lost to follow-up (LTFU) were traced by telephone. Kaplan-Meier technique was used to estimate survival probabilities of retention and Cox proportional hazards regression was performed to identify the predictors of attrition. RESULTS: Based on individual patient data from the medical records, nearly 80% (95%CI: 76.7, 82.1) of the patients were retained in care in the first 3 and half years of antiretroviral therapy. After successfully tracing more than half of the LTFU patients, the updated one year retention in care estimate became 86% (95% CI: 83.41%, 88.17%). In the multivariate Cox regression analyses, severe immune deficiency at enrolment in care/or at cART initiation and 'bed-ridden' or 'ambulatory' functional status at the start of cART predicted attrition. CONCLUSION: Retention in HIV care in Addis Ababa is comparable with or even better than previous findings from other resource-limited as well as EU/USA settings. However, measures to detect and enroll patients in HIV care as early as possible are still necessary. PMID- 26114437 TI - Crystal Structure, Cytotoxicity and Interaction with DNA of Zinc (II) Complexes with o-Vanillin Schiff Base Ligands. AB - Two new zinc complexes, Zn(HL1)2 (1) and [Zn2(H2L2)(OAc)2]2 (2) [H2L1 = Schiff base derived from o-vanillin and (R)-(+)-2-amino-3-phenyl-1-propanol, H3L2 = Schiff base derived from o-vanillin and 2-amino-2-ethyl-1,3-propanediol], have been synthesized and characterized by single crystal X-ray diffraction, elemental analyses, TG analyses, solid fluorescence, IR, UV-Vis and circular dichroism spectra. The structural analysis shows that complex 1 has a right-handed double helical chain along the crystallographic b axis. A homochiral 3D supramolecular architecture has been further constructed by intermolecular C-H... pi, O-H...O and C-H...O interactions. Complex 2 includes two crystallographically independent binuclear zinc molecules. The two binuclear zinc molecules are isostructural. The 2-D sheet supramolecular structure was formed by intermolecular hydrogen bonding interaction. The fluorescence of ligands and complexes in DMF at room temperature are studied. The interactions of two complexes with calf thymus DNA (CT-DNA) are investigated using UV-Vis, CD and fluorescence spectroscopy. The results show that complex 1 exhibits higher interaction with CT-DNA than complex 2. In addition, in vitro cytotoxicity of the complexes towards four kinds of cancerous cell lines (A549, HeLa, HL-60 and K562) were assayed by the MTT method. Investigations on the structures indicated that the chirality and nuclearity of zinc complexes play an important role on cytotoxic activity. PMID- 26114438 TI - Practical guidance and considerations for transitioning patients from oxcarbazepine or carbamazepine to eslicarbazepine acetate--Expert opinion. AB - There is currently a lack of guidance on methodology and special considerations for transitioning patients from oxcarbazepine (OXC) or carbamazepine (CBZ) to eslicarbazepine acetate (ESL), if deemed clinically necessary. An advisory panel of epilepsy experts was convened to share their experience on the use of adjunctive ESL in clinical practice and to provide practical recommendations to help address this gap. When changing over from OXC to ESL, an OXC:ESL dose ratio of 1:1 should be employed to calculate the ESL target dose, and the changeover can take place overnight. No changes to comedication are required. Since CBZ has a different mechanism of action to ESL and is a stronger inducer of cytochrome P450 (CYP) enzymes, the transitioning of patients from CBZ to ESL requires careful consideration on a patient-by-patient basis. In general, a CBZ:ESL dose ratio of 1:1.3 should be employed to calculate the ESL target dose, and patients should be transitioned over a minimum period of 1-2weeks. Special considerations include adjustment of titration schedule and target dose in elderly patients and those with hepatic or renal impairment and potential adjustment of comedications metabolized by CYP enzymes. In summary, due to structural distinctions between ESL, OXC, and CBZ, which affect mechanism of action and tolerability, there are clinical situations in which it may be appropriate to consider transitioning patients from OXC or CBZ to ESL. Changing patients over from OXC to ESL is generally more straightforward than transitioning patients from CBZ to ESL, which requires careful consideration. PMID- 26114440 TI - Therapeutic effect of methotrexate encapsulated in cationic liposomes (EndoMTX) in comparison to free methotrexate in an antigen-induced arthritis study in vivo. AB - OBJECTIVES: Cationic lipid complexes bind to angiogenic endothelial cells of solid tumours and microvessels of chronic inflammatory tissue. Methotrexate (MTX) is one of the drugs used in the therapy of rheumatoid arthritis (RA); it is applied systemically but can have serious side-effects. The aim of this study was to investigate the impact of MTX encapsulated in cationic liposomes (EndoMTX) in comparison to treatment with free MTX. METHOD: We used an antigen-induced arthritis (AiA) model and investigated the leucocyte- and platelet-endothelial cell interaction in arthritic female C57/Bl6 mice and in healthy controls. The arthritic animals were divided into four different groups receiving either trehalose, free MTX, EndoMTX placebo, or EndoMTX. These parameters and functional capillary density (FCD) were measured and assessed by intravital microscopy (IVM). We controlled clinical parameters such as the knee joint diameter (KJD) throughout the observation period. RESULTS: Animals treated with EndoMTX showed a significant and superior reduction in leucocyte- and platelet-endothelial cell interaction, FCD, and KJD. Free MTX or empty liposomes also showed a reduction in these parameters but not to a significant level. FCD decreased in the EndoMTX group in comparison to using free drugs or empty carrier-like liposomes. CONCLUSIONS: This study demonstrates the advantage of using MTX encapsulated in cationic liposomes in contrast to free and generic MTX, with a higher efficacy in anti-inflammatory and anti-angiogenic abilities. Targeting with cationic liposomes may be a promising treatment option and should be elucidated in further experiments regarding dose reduction and side-effects due to MTX usage. PMID- 26114439 TI - Phenotype of normal spirometry in an aging population. AB - RATIONALE: In aging populations, the commonly used Global Initiative for Chronic Obstructive Lung Disease (GOLD) may misclassify normal spirometry as respiratory impairment (airflow obstruction and restrictive pattern), including the presumption of respiratory disease (chronic obstructive pulmonary disease [COPD]). OBJECTIVES: To evaluate the phenotype of normal spirometry as defined by a new approach from the Global Lung Initiative (GLI), overall and across GOLD spirometric categories. METHODS: Using data from COPDGene (n = 10,131; ages 45 81; smoking history, >=10 pack-years), we evaluated spirometry and multiple phenotypes, including dyspnea severity (Modified Medical Research Council grade 0 4), health-related quality of life (St. George's Respiratory Questionnaire total score), 6-minute-walk distance, bronchodilator reversibility (FEV1 % change), computed tomography-measured percentage of lung with emphysema (% emphysema) and gas trapping (% gas trapping), and small airway dimensions (square root of the wall area for a standardized airway with an internal perimeter of 10 mm). MEASUREMENTS AND MAIN RESULTS: Among 5,100 participants with GLI-defined normal spirometry, GOLD identified respiratory impairment in 1,146 (22.5%), including a restrictive pattern in 464 (9.1%), mild COPD in 380 (7.5%), moderate COPD in 302 (5.9%), and severe COPD in none. Overall, the phenotype of GLI-defined normal spirometry included normal adjusted mean values for dyspnea grade (0.8), St. George's Respiratory Questionnaire (15.9), 6-minute-walk distance (1,424 ft [434 m]), bronchodilator reversibility (2.7%), % emphysema (0.9%), % gas trapping (10.7%), and square root of the wall area for a standardized airway with an internal perimeter of 10 mm (3.65 mm); corresponding 95% confidence intervals were similarly normal. These phenotypes remained normal for GLI-defined normal spirometry across GOLD spirometric categories. CONCLUSIONS: GLI-defined normal spirometry, even when classified as respiratory impairment by GOLD, included adjusted mean values in the normal range for multiple phenotypes. These results suggest that among adults with GLI-defined normal spirometry, GOLD may misclassify normal phenotypes as having respiratory impairment. PMID- 26114441 TI - Nonlinear processes reinforce extreme Indian Ocean Dipole events. AB - Under global warming, climate models show an almost three-fold increase in extreme positive Indian Ocean Dipole (pIOD) events by 2100. These extreme pIODs are characterised by a westward extension of cold sea surface temperature anomalies (SSTAs) which push the downstream atmospheric convergence further west. This induces severe drought and flooding in the surrounding countries, but the processes involved in this projected increase have not been fully examined. Here we conduct a detailed heat budget analysis of 19 models from phase 5 of the Coupled Model Intercomparison Project and show that nonlinear zonal and vertical heat advection are important for reinforcing extreme pIODs. Under greenhouse warming, these nonlinear processes do not change significantly in amplitude, but the frequency of occurrences surpassing a threshold increases. This is due to the projected weakening of the Walker circulation, which leads to the western tropical Indian Ocean warming faster than the east. As such, the magnitude of SSTAs required to shift convection westward is relatively smaller, allowing these convection shifts to occur more frequently in the future. The associated changes in wind and ocean current anomalies support the zonal and vertical advection terms in a positive feedback process and consequently, moderate pIODs become more extreme-like. PMID- 26114442 TI - Peak oxygen uptake, ventilatory efficiency and QRS-duration predict event free survival in patients late after surgical repair of tetralogy of Fallot. AB - OBJECTIVE: Patients with repaired tetralogy of Fallot (ToF) have an increased long-term risk of cardiovascular morbidity and mortality. Risk stratification in this population is difficult. Initial evidence suggests that cardiopulmonary exercise testing (CPET) may be helpful to risk-stratify patients with repaired ToF. METHODS AND RESULTS: We studied 875 patients after surgical repair for ToF (358 females, age 25.5 +/- 11.7 year, range 7-75 years) who underwent CPET between 1999 and 2009. During a mean follow-up of 4.1 +/- 2.6 years after CPET, 30 patients (3.4%) died or had sustained ventricular tachycardia (VT). 225 patients (25.7%) had other cardiac related events (emergency admission, surgery, or catheter interventions). On multivariable Cox regression-analysis, %predicted peak oxygen uptake (VO2 %) (p=0.001), resting QRS duration (p=0.030) and age (p<0.001) emerged as independent predictors of mortality or sustained VT. Patients with a peak VO2 <= 65% of predicted and a resting QRS duration >= 170 ms had a 11.4-fold risk of death or sustained VT. Ventilatory efficiency expressed as VE/VCO2 slope (p<0.001), peak VO2 % (p=.001), QRS duration (p=.001) and age (p=0.046) independently predicted event free survival. VE/VCO2 slope >= 31.0, peak VO2 % <= 65% and QRS duration >= 170 ms were the cut-off points with best sensitivity and specificity to detect an unfavorable outcome. CONCLUSIONS: CPET is an important predictive tool that may assist in the risk stratification of patients with ToF. Subjects with a poor exercise capacity in addition to a prolonged QRS duration have a substantially increased risk for death or sustained ventricular tachycardia, as well as for cardiac-related hospitalizations. PMID- 26114443 TI - Impaired two-dimensional global longitudinal strain of left ventricle predicts adverse long-term clinical outcomes in patients with acute myocardial infarction. PMID- 26114444 TI - Takotsubo cardiomyopathy and myopericarditis: Unraveling the inflammatory hypothesis. PMID- 26114445 TI - Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development. AB - BACKGROUND: In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis. METHODOLOGY/PRINCIPAL FINDINGS: Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 10(4) CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001. CONCLUSIONS/SIGNIFICANCE: Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis. PMID- 26114446 TI - Synthesis of New Styrylquinoline Cellular Dyes, Fluorescent Properties, Cellular Localization and Cytotoxic Behavior. AB - New styrylquinoline derivatives with their photophysical constants are described. The synthesis was achieved via Sonogashira coupling using the newly developed heterogeneous nano-Pd/Cu catalyst system, which provides an efficient synthesis of high purity products. The compounds were tested in preliminary fluorescent microscopy studies to in order to identify their preferable cellular localization, which appeared to be in the lipid cellular organelles. The spectroscopic properties of the compounds were measured and theoretical TD-DFT calculations were performed. A biological analysis of the quinolines that were tested consisted of cytotoxicity assays against normal human fibroblasts and colon adenocarcinoma cells. All of the compounds that were studied appeared to be safe and indifferent to cells in a high concentration range. The presented results suggest that the quinoline compounds that were investigated in this study may be valuable structures for development as fluorescent dyes that could have biological applications. PMID- 26114447 TI - Caffeine ameliorates high energy diet-induced hepatic steatosis: sirtuin 3 acts as a bridge in the lipid metabolism pathway. AB - The beneficial effect of caffeine-containing food on non-alcoholic fatty liver disease (NAFLD) has been widely reported. The aim of this study was to explore the effect of caffeine on hepatic steatosis. C57BL/6 mice were randomly assigned to a normal diet or a high energy diet (HED). Caffeine was given to HED mice by oral gavage. Body weights, lipids in the liver and liver damage were measured. Meanwhile, cAMP, SIRT3 or AMPK inhibitors were treated respectively before incubation with caffeine in oleate-treated HepG2 cells. SIRT3 was further silenced by siRNA to confirm the results. Caffeine significantly decreased the mass of fat tissues, lipids, ALT and AST levels in the liver of HED-treated mice. Caffeine increased the transformation of ADP to ATP and activated the cAMP/CREB/SIRT3/AMPK/ACC pathway in the liver. Nile red staining demonstrated that suppression of cAMP, SIRT3 or AMPK in oleate-treated HepG2 cells counteracted the effect of caffeine. Moreover, knocking down SIRT3 could down regulate AMPK and ACC phosphorylation by caffeine. These results demonstrate that caffeine could improve HED-induced hepatic steatosis by promoting lipid metabolism via the cAMP/CREB/SIRT3/AMPK/ACC pathway. SIRT3 functioned as a molecular bridge connecting caffeine and lipid metabolism. PMID- 26114449 TI - The role of sexual abuse on functional neuroimaging markers associated with major depressive disorder. AB - OBJECTIVES: Victims of child sexual abuse can develop depression and other mental health conditions that follow them well into adulthood. This study aimed to clarify the role of sexual abuse (SA) on functional imaging markers associated with MDD. METHODS: Thirty-seven patients with MDD only; and 13 patients with both MDD and SA and 43 healthy controls performed emotional attention shifting tasks during fMRI session. Clinical diagnoses were made by consultant psychiatrists based on the DSM-IV-TR criteria and diagnoses were confirmed using SCID-I. Magnetic resonance images were obtained with a Philips Achieva 3 Tesla MRI scanner. Short form childhood trauma questionnaire, Hamilton Rating Scale for Depression and Beck's Depression Inventory were also employed. Data were analysed with Statistical Parametric Mapping 8 (SPM8). RESULTS: Using the contrast judgment of emotion minus judgment of geometry following emotional neutral stimuli, patients with MDD showed significantly reduced activation in comparison to healthy controls in the area of the right fusiform gyrus. With the contrast judgment of emotion minus judgment of geometry following emotional negative stimuli, participants with MDD and SA showed significantly higher activation in the area of the left inferior parietal lobe in comparison to participants with MDD without SA. CONCLUSIONS: The history of sexual abuse affects functional neuroimaging markers associated with major depressive disorder. PMID- 26114448 TI - Ensemble Methods for MiRNA Target Prediction from Expression Data. AB - BACKGROUND: microRNAs (miRNAs) are short regulatory RNAs that are involved in several diseases, including cancers. Identifying miRNA functions is very important in understanding disease mechanisms and determining the efficacy of drugs. An increasing number of computational methods have been developed to explore miRNA functions by inferring the miRNA-mRNA regulatory relationships from data. Each of the methods is developed based on some assumptions and constraints, for instance, assuming linear relationships between variables. For such reasons, computational methods are often subject to the problem of inconsistent performance across different datasets. On the other hand, ensemble methods integrate the results from individual methods and have been proved to outperform each of their individual component methods in theory. RESULTS: In this paper, we investigate the performance of some ensemble methods over the commonly used miRNA target prediction methods. We apply eight different popular miRNA target prediction methods to three cancer datasets, and compare their performance with the ensemble methods which integrate the results from each combination of the individual methods. The validation results using experimentally confirmed databases show that the results of the ensemble methods complement those obtained by the individual methods and the ensemble methods perform better than the individual methods across different datasets. The ensemble method, Pearson+IDA+Lasso, which combines methods in different approaches, including a correlation method, a causal inference method, and a regression method, is the best performed ensemble method in this study. Further analysis of the results of this ensemble method shows that the ensemble method can obtain more targets which could not be found by any of the single methods, and the discovered targets are more statistically significant and functionally enriched. The source codes, datasets, miRNA target predictions by all methods, and the ground truth for validation are available in the Supplementary materials. PMID- 26114450 TI - Disseminated skin involvement in HIV-associated Burkitt lymphoma: a rare clinical feature with poor prognosis. PMID- 26114451 TI - Method for quantification of oils and sebum levels on skin using the Sebumeter((r)). AB - OBJECTIVE: The Sebumeter((r)) is widely used in both cosmetic and medical research, for measuring changes in sebum levels on skin. It is commonly reported that the units correlated to a mass of sebum on the skin in MUg cm(-2) ; however, validation for this has not been published. Also, its use for assessing the presence of other oily materials which are widely utilized in topical skincare products on skin has not been widely discussed. Determining a calibration scale and whether the response of the device is linear with the level of oils present enables quantification of the output of the device, and would validate the device for claims substantiation. METHODS: Different doses of a variety of oily materials (paraffin oil, white soft paraffin, capric-caprylic triglyceride, 350cSt silicone fluid and synthetic sebum) were applied to skin, and the Sebumeter((r)) used to collect and quantify them. The mass per square centimetre of the oily material delivered to the skin was then compared to the Sebumeter((r)) output to develop calibration curves for the different materials. Measurements were carried out on a single volunteer as this work was to verify the concept of quantitative oil assessment using the device. RESULTS: A linear correlation between the mass of the oily material and the Sebumeter((r)) output was seen for all the materials tested. However, the absolute response of the device was different for each material, and the output values did not directly give the mass of material on the skin in MUg cm(-2) . As part of the calibration, it was also demonstrated that to remove all the oily material from a given area of the skin required multiple 30-s applications of the Sebumeter((r)) cartridge. CONCLUSIONS: The Sebumeter((r)) is a precise analytical instrument capable of quantitative measurement of deposition of oily materials onto skin from topical products (down to the MUg cm(-2) level), as well as its traditional use of measuring sebum levels. However, the output values do not directly correlate with the mass of oil present, and generation of a calibration curve is necessary for any ingredient of interest to produce quantitative data for claim support and formulation development. PMID- 26114452 TI - Erratum. PMID- 26114454 TI - Healthy Habits for Children: Leveraging Existing Evidence to Demonstrate Value. AB - Healthy habits is a psychoeducational construct that refers to the preventive practice of analyzing and then adapting the sleep, physical, and eating routines of children in ways that enhance health and well-being. This approach is based on evidence that demonstrates the positive therapeutic value of engaging in proactive, healthful behaviors. In addressing healthy habits, occupational therapy practitioners have an opportunity to contribute to the Triple Aim of health care reform while demonstrating the value of occupational therapy in educational, medical, community, and other settings. PMID- 26114456 TI - Self-Administered, Home-Based SMART (Sensorimotor Active Rehabilitation Training) Arm Training: A Single-Case Report. AB - This single-case, mixed-method study explored the feasibility of self administered, home-based SMART (sensorimotor active rehabilitation training) Arm training for a 57-yr-old man with severe upper-limb disability after a right frontoparietal hemorrhagic stroke 9 mo earlier. Over 4 wk of self-administered, home-based SMART Arm training, the participant completed 2,100 repetitions unassisted. His wife provided support for equipment set-up and training progressions. Clinically meaningful improvements in arm impairment (strength), activity (arm and hand tasks), and participation (use of arm in everyday tasks) occurred after training (at 4 wk) and at follow-up (at 16 wk). Areas for refinement of SMART Arm training derived from thematic analysis of the participant's and researchers' journals focused on enabling independence, ensuring home and user friendliness, maintaining the motivation to persevere, progressing toward everyday tasks, and integrating practice into daily routine. These findings suggest that further investigation of self-administered, home based SMART Arm training is warranted for people with stroke who have severe upper-limb disability. PMID- 26114455 TI - Forced Aerobic Exercise Enhances Motor Recovery After Stroke: A Case Report. AB - OBJECTIVE: Previously, we demonstrated that forced aerobic exercise (FE) increases the pattern of neural activation in Parkinson's disease. We sought to evaluate whether FE, when coupled with repetitive task practice, could promote motor recovery poststroke. METHOD: A 46-yr-old man with ischemic stroke exhibited chronic residual upper-extremity deficits, scoring 35/66 on the Fugl-Meyer Assessment (FMA) at baseline. He completed 24 training sessions comprising 45 min of FE on a motorized stationary bicycle followed by 45 min of upper-extremity repetitive task practice. RESULTS: From baseline to end of treatment, the FMA score improved by 20 points, perceived level of recovery on the Stroke Impact Scale increased by 20 percentage points, and cardiovascular function measured by peak oxygen uptake improved 30%. These improvements persisted 4 wk after the intervention ceased. CONCLUSION: FE may be a safe and feasible rehabilitation approach to augment recovery of motor and nonmotor function while improving aerobic fitness in people with chronic stroke. PMID- 26114458 TI - Correlational Research to Examine the Relation Between Attachment and Sensory Modulation in Young Children. AB - This study investigated whether a relation exists between attachment and sensory modulation in young children. Participants were 68 children ages 3-6 yr recruited through the local community. Caregivers were asked to complete a standardized behavioral inventory of sensory modulation patterns, and parent-child interactions were observed in their home. The evaluator categorized these interactions on the basis of items related to attachment security and dependency. Results revealed modest correlations between attachment and sensory modulation: rs(66)=.28, p=.02. The capacity to predict sensory modulation function by attachment characteristics and the capacity to predict attachment characteristics by sensory modulation function was significant but small (p<.05). These findings supporting a relation between attachment and sensory modulation should be considered when assessing and planning treatment of children with problems in one or both of these areas. PMID- 26114457 TI - Assessment of Autism Symptoms During the Neonatal Period: Is There Early Evidence of Autism Risk? AB - OBJECTIVE: To define neonatal social characteristics related to autism risk. METHOD: Sixty-two preterm infants underwent neonatal neurobehavioral testing. At age 2 yr, participants were assessed with the Modified Checklist for Autism in Toddlers and Bayley Scales of Infant and Toddler Development, 3rd edition. RESULTS: Positive autism screening was associated with absence of gaze aversion, chi=5.90, p=01, odds ratio=5.05, and absence of endpoint nystagmus, chi=4.78, p=.02, odds ratio=8.47. Demonstrating gaze aversion was related to better language outcomes, t(55)=-3.07, p<=.003. Displaying endpoint nystagmus was related to better language outcomes, t(61)=-3.06, p=.003, cognitive outcomes, t(63)=-5.04, p<.001, and motor outcomes, t(62)=-2.82, p=.006. CONCLUSION: Atypical social interactions were not observed among infants who later screened positive for autism. Instead, the presence of gaze aversion and endpoint nystagmus was related to better developmental outcomes. Understanding early behaviors associated with autism may enable early identification and lead to timely therapy activation to improve function. PMID- 26114459 TI - Hand Strength, Handwriting, and Functional Skills in Children With Autism. AB - OBJECTIVE: To establish hand strength development trends in children with autism and to investigate correlations between grip and pinch strength, components of handwriting, and functional activities in children with and without autism. METHOD: Fifty-one children were divided into two groups: typically developing children and children on the autism spectrum. Each child completed testing for pinch and grip strength, handwriting legibility, pencil control, and independence in functional activities. RESULTS: The children with autism followed the same strength development trends as the typically developing children. Grip strength correlated with pencil control in both groups and with handwriting legibility in the typically developing children but not in the children with autism. Grip and pinch strength correlated with independence with functional activities in both groups. CONCLUSION: This study provides evidence that grip and pinch strength are important components in developing pencil control, handwriting legibility, and independence with functional fine motor tasks. PMID- 26114460 TI - Sensory Processing and Sleep in Typically Developing Infants and Toddlers. AB - OBJECTIVE: To explore the relationship between sensory processing patterns and sleep problems in typically developing infants and toddlers. METHOD: A retrospective chart review of 177 infants and toddlers from a community occupational therapy sleep clinic included descriptive and correlational analyses of data from the Infant/Toddler Sensory Profile and Brief Infant Sleep Questionnaire. RESULTS: More than half of participants (55%) demonstrated a pattern of increased sensory processing in one or more quadrants, with sensitivity being most common (36%). We found small but significant correlations between increased seeking and shorter daytime sleep duration (r=-.24, p=.002) and between increased sensitivity and longer time to settle to sleep (r=.27, p<.001). CONCLUSION: This study adds to recent literature linking sensory processing patterns to sleep problems and is the first to demonstrate this relationship in young, typically developing children. Results support the role of occupational therapy in addressing sleep difficulties in children. PMID- 26114461 TI - Sensory Sensitivity and Strategies for Coping With Pain. AB - OBJECTIVE: Our goal was to investigate the relationship between sensory processing styles and use of pain coping strategies in an experimental setting to understand individual differences in pain coping. METHOD: A cross-sectional design was used with a convenience sample of 116 healthy adults. Measures of sensory processing style and mood state were collected before participation in a cold pressor pain-inducement task, and measures of coping strategies were collected afterward. Multiple regression models were constructed to examine relationships between sensory processing and coping strategies. RESULTS: Sensory sensitivity and sensation avoiding were significantly associated with higher levels of catastrophizing. Sensation seeking was linked with active coping strategies, such as coping self-statements. Low registration was not significantly associated with any particular coping strategy after controlling for salient variables. CONCLUSION: This study highlights associations between sensory processing and pain coping strategies, which may inform more tailored approaches to clinical practice for people in pain. PMID- 26114462 TI - Hurricane Sandy, Disaster Preparedness, and the Recovery Model. AB - OBJECTIVE: Hurricane Sandy was the second largest and costliest hurricane in U.S. history to affect multiple states and communities. This article describes the lived experiences of 24 occupational therapy students who lived through Hurricane Sandy using the Recovery Model to frame the research. METHOD: Occupational therapy student narratives were collected and analyzed using qualitative methods and framed by the Recovery Model. Directed content and thematic analysis was performed using the 10 components of the Recovery Model. RESULTS: The 10 components of the Recovery Model were experienced by or had an impact on the occupational therapy students as they coped and recovered in the aftermath of the natural disaster. CONCLUSION: This study provides insight into the lived experiences and recovery perspectives of occupational therapy students who experienced Hurricane Sandy. Further research is indicated in applying the Recovery Model to people who survive disasters. PMID- 26114463 TI - Habits of the Sensory System and Mental Health: Understanding Sensory Dissonance. AB - OBJECTIVE: In occupational therapy, research has studied sensory function predominantly in relation to sensory disorders. There is a gap in the literature exploring how sensory experiences affect mental health. This study sought to provide a phenomenological understanding of how people relate experiences of sensory dissonance to their mental health. METHOD: Ten immigrants from Latin America participated in semistructured interviews and video observations of their occupational behavior. RESULTS: Participants' experiences of sensory dissonance provoked negative mental states and distress. Participants reported poor mental health following sensory experiences that were incongruent with their habits of sensing. They also intentionally used sensory anchors to induce positive mental states and connect with past occupational experiences. CONCLUSION: Occupational therapy practitioners should be mindful of how sensory environments can facilitate or impede intervention. Practitioners are encouraged to harness clients' sensory habits and use sensory anchors as a form of sensory scaffolding to facilitate therapeutic gains. PMID- 26114464 TI - Living Legends: Effectiveness of a Program to Enhance Sense of Purpose and Meaning in Life Among Community-Dwelling Older Adults. AB - OBJECTIVE: We investigated the therapeutic benefits (i.e., sense of purpose and meaning in life) of the Living Legends program, which includes life review writing and an intergenerational exchange, compared with life review writing alone, for community-dwelling older adults. METHOD: This study was a randomized controlled trial with a connected qualitative component. We analyzed quantitative data using independent-samples t tests and written descriptions of program experiences using Collaizi's qualitative methodology; we then used a triangulation protocol to integrate the qualitative and quantitative data. RESULTS: For participants in the writing workshop plus intergenerational exchange, sense of purpose and meaning in life increased significantly (p<.0001) compared with those in the writing workshop alone. Qualitative themes revealed additional program benefits. CONCLUSION: Living Legends enhanced participants' sense of purpose and meaning in life, a factor known to prevent cognitive loss and disability, compared with life review writing alone. PMID- 26114465 TI - Factors Affecting Readiness for Low Vision Interventions in Older Adults. AB - OBJECTIVE: We sought to identify factors that facilitate and inhibit readiness for low vision interventions in people with vision loss, conceptualized as readiness for change in the way they perform daily activities. METHOD: We conducted 10 semistructured interviews with older adults with low vision and analyzed the results using grounded theory concepts. RESULTS: Themes involving factors that facilitated change included desire to maintain or regain independence, positive attitude, and presence of formal social support. Themes related to barriers to change included limited knowledge of options and activity not a priority. Themes that acted as both barriers and facilitators were informal social support and community resources. CONCLUSION: This study provides insight into readiness to make changes in behavior and environment in older adults with vision loss. Study findings can help occupational therapy practitioners practice client-centered care more effectively and promote safe and satisfying daily living activity performance in this population. PMID- 26114466 TI - P-Drive: Implementing an Assessment of On-Road Driving in Clinical Settings and Investigating Its Internal and Predictive Validity. AB - We investigated (1) the psychometric properties of data gathered with the Performance Analysis of Driving Ability (P-Drive), an on-road assessment; (2) P Drive's predictive validity in relation to a summed decision of passing or failing a medical driving evaluation; and (3) the success of implementing P Drive. Drivers (N=99) with neurological impairment referred for a driving evaluation were observed on road and scored using P-Drive. Results showed evidence of person response validity and internal validity. P-Drive separated the drivers into four different strata (reliability coefficient=.92). A cutoff raw score of 81 was optimal, with sensitivity of 93% and specificity of 92%. Although only 9 occupational therapists (of 19 initially trained) contributed data for analysis, 17 reported using the assessment. Data gathered with P-Drive yielded evidence of excellent psychometric properties. Moreover, P-Drive was implemented successfully in clinical settings, although initial training to full implementation took longer than 1 yr. PMID- 26114467 TI - Upper-Limb Rehabilitation With Adaptive Video Games for Preschool Children With Developmental Disabilities. AB - OBJECTIVE: This study used a novel device to make video games accessible to children with developmental disabilities (DD) by modifying the training software and interfaces to enhance motor training. METHOD: In the pretest-posttest design, 20 children (13 boys, 7 girls; mean age=5.2 yr) with DD received adaptive upper limb motor rehabilitation consisting of fifteen 30-min individual sessions 3 times per week for 5 wk. RESULTS: Improvement in Beery-Buktenica Developmental Test of Visual Motor Integration and Peabody Developmental Motor Scales, Second Edition, scores for children with DD indicated significant differences between pretest and posttest. CONCLUSION: The rehabilitation device modified for the needs of children with DD is effective in improving visual-motor performance of children with DD. PMID- 26114468 TI - Developmental Test of Visual-Motor Integration (VMI): An Effective Outcome Measure for Handwriting Interventions for Kindergarten, First-Grade, and Second Grade Students? AB - We determined whether a widely used assessment of visual-motor skills, the Beery Buktenica Developmental Test of Visual-Motor Integration (VMI), is appropriate for use as an outcome measure for handwriting interventions. A two-group pretest posttest design was used with 207 kindergarten, first-grade, and second-grade students. Two well-established handwriting measures and the VMI were administered pre- and postintervention. The intervention group participated in the Size Matters Handwriting Program for 40 sessions, and the control group received standard instruction. Paired and independent-samples t tests were used to analyze group differences. The intervention group demonstrated significant improvements on the handwriting measures, with change scores having mostly large effect sizes. We found no significant difference in change scores on the VMI, t(202)=1.19, p=.23. Results of this study suggest that the VMI may not detect changes in handwriting related to occupational therapy intervention. PMID- 26114469 TI - Exploring Occupational Therapists' Perceptions of the Usefulness of Musculoskeletal Sonography in Upper-Extremity Rehabilitation. AB - OBJECTIVE: To identify the potential utility of musculoskeletal sonographic imaging in upper-extremity rehabilitation. METHOD: Two occupational therapists in an outpatient hand rehabilitation clinic were recruited by convenience, were trained in the use of sonography, and implemented sonographic imaging in their clinical practice. Qualitative data were obtained during and after the implementation period by means of questionnaires and interviews. Data collection, analysis, and interpretation were completed in an iterative process that culminated in a thematic analysis of the therapists' perceptions. RESULTS: The data indicate four potential areas of utility for musculoskeletal sonography in upper-extremity rehabilitation: (1) mastering anatomy and pathology, (2) augmenting clinical reasoning, (3) supplementing intervention, and (4) building evidence. CONCLUSION: Numerous potential uses were identified that would benefit both therapist and client. Further exploration of complexities and efficacy for increasing patient outcomes is recommended to determine best practices for the use of musculoskeletal sonography in upper-extremity rehabilitation. PMID- 26114470 TI - Research Opportunities in the Area of Adults With Neurodegenerative Diseases. AB - The American Occupational Therapy Association (AOTA) Evidence-Based Practice Project has developed a table summarizing the research opportunities on adults with neurodegenerative diseases. The table provides an overview of the current available evidence on interventions within the scope of occupational therapy practice and is based on the systematic reviews from the AOTA Evidence-Based Practice Guidelines Series. Researchers, students, and clinicians can use this information in developing innovative research to answer important questions within the occupational therapy field. PMID- 26114472 TI - Direct conversion of mouse fibroblasts to GABAergic neurons with combined medium without the introduction of transcription factors or miRNAs. AB - Degeneration or loss of GABAergic neurons frequently may lead to many neuropsychiatric disorders such as epilepsy and autism spectrum disorders. So far no clinically effective therapies can slow and halt the progression of these diseases. Cell-replacement therapy is a promising strategy for treatment of these neuropsychiatric diseases. Although increasing evidence showed that mammalian somatic cells can be directly converted into functional neurons using specific transcription factors or miRNAs via virus delivery, the application of these induced neurons is potentially problematic, due to integration of vectors into the host genome, which results in the disruption or dysfunction of nearby genes. Here, we show that mouse fibroblasts could be efficiently reprogrammed into GABAergic neurons in a combined medium composed of conditioned medium from neurotrophin-3 modified Olfactory Ensheathing Cells (NT3-OECs) plus SB431542, GDNF and RA. Following 3 weeks of induction, these cells derived from fibroblasts acquired the morphological and phenotypical GABAerigic neuronal properties, as demonstrated by the expression of neuronal markers including Tuj1, NeuN, Neurofilament-L, GABA, GABA receptors and GABA transporter 1. More importantly, these converted cells acquired neuronal functional properties such as synapse formation and increasing intracellular free calcium influx when treated with BayK, a specific activator of L-type calcium channel. Therefore, our findings demonstrate for the first time that fibroblasts can be directly converted into GABAergic neurons without ectopic expression of specific transcription factors or miRNA. This study may provide a promising cell source for the application of cell replacement therapy in neuropsychiatric disorders. PMID- 26114473 TI - RNase P Ribozymes Inhibit the Replication of Human Cytomegalovirus by Targeting Essential Viral Capsid Proteins. AB - An engineered RNase P-based ribozyme variant, which was generated using the in vitro selection procedure, was used to target the overlapping mRNA region of two proteins essential for human cytomegalovirus (HCMV) replication: capsid assembly protein (AP) and protease (PR). In vitro studies showed that the generated variant, V718-A, cleaved the target AP mRNA sequence efficiently and its activity was about 60-fold higher than that of wild type ribozyme M1-A. Furthermore, we observed a reduction of 98%-99% in AP/PR expression and an inhibition of 50,000 fold in viral growth in cells with V718-A, while a 75% reduction in AP/PR expression and a 500-fold inhibition in viral growth was found in cells with M1 A. Examination of the antiviral effects of the generated ribozyme on the HCMV replication cycle suggested that viral DNA encapsidation was inhibited and as a consequence, viral capsid assembly was blocked when the expression of AP and PR was inhibited by the ribozyme. Thus, our study indicates that the generated ribozyme variant is highly effective in inhibiting HCMV gene expression and blocking viral replication, and suggests that engineered RNase P ribozyme can be potentially developed as a promising gene-targeting agent for anti-HCMV therapy. PMID- 26114474 TI - Genome, Proteome and Structure of a T7-Like Bacteriophage of the Kiwifruit Canker Phytopathogen Pseudomonas syringae pv. actinidiae. AB - Pseudomonas syringae pv. actinidiae is an economically significant pathogen responsible for severe bacterial canker of kiwifruit (Actinidia sp.). Bacteriophages infecting this phytopathogen have potential as biocontrol agents as part of an integrated approach to the management of bacterial canker, and for use as molecular tools to study this bacterium. A variety of bacteriophages were previously isolated that infect P. syringae pv. actinidiae, and their basic properties were characterized to provide a framework for formulation of these phages as biocontrol agents. Here, we have examined in more detail phiPsa17, a phage with the capacity to infect a broad range of P. syringae pv. actinidiae strains and the only member of the Podoviridae in this collection. Particle morphology was visualized using cryo-electron microscopy, the genome was sequenced, and its structural proteins were analysed using shotgun proteomics. These studies demonstrated that phiPsa17 has a 40,525 bp genome, is a member of the T7likevirus genus and is closely related to the pseudomonad phages phiPSA2 and gh-1. Eleven structural proteins (one scaffolding) were detected by proteomics and phiPsa17 has a capsid of approximately 60 nm in diameter. No genes indicative of a lysogenic lifecycle were identified, suggesting the phage is obligately lytic. These features indicate that phiPsa17 may be suitable for formulation as a biocontrol agent of P. syringae pv. actinidiae. PMID- 26114475 TI - NLRP3 Inflammasome Activation by Viroporins of Animal Viruses. AB - Viroporins are a group of low-molecular-weight proteins containing about 50-120 amino acid residues, which are encoded by animal viruses. Viroporins are involved in several stages of the viral life cycle, including viral gene replication and assembly, as well as viral particle entry and release. Viroporins also play an important role in the regulation of antiviral innate immune responses, especially in inflammasome formation and activation, to ensure the completion of the viral life cycle. By reviewing the research progress made in recent years on the regulation of the NLRP3 inflammasome by viroporins of animal viruses, we aim to understand the importance of viroporins in viral infection and to provide a reference for further research and development of novel antiviral drugs. PMID- 26114477 TI - Malthusian Parameters as Estimators of the Fitness of Microbes: A Cautionary Tale about the Low Side of High Throughput. AB - The maximum exponential growth rate, the Malthusian parameter (MP), is commonly used as a measure of fitness in experimental studies of adaptive evolution and of the effects of antibiotic resistance and other genes on the fitness of planktonic microbes. Thanks to automated, multi-well optical density plate readers and computers, with little hands-on effort investigators can readily obtain hundreds of estimates of MPs in less than a day. Here we compare estimates of the relative fitness of antibiotic susceptible and resistant strains of E. coli, Pseudomonas aeruginosa and Staphylococcus aureus based on MP data obtained with automated multi-well plate readers with the results from pairwise competition experiments. This leads us to question the reliability of estimates of MP obtained with these high throughput devices and the utility of these estimates of the maximum growth rates to detect fitness differences. PMID- 26114478 TI - Neuroendocrine differentiation in breast carcinoma: clinicopathological features and outcome. AB - AIMS: Primary neuroendocrine (NE) breast carcinoma (BC) is an entity with a wide range of prevalence and poorly defined clinical behaviour. We evaluated the prevalence, clinicopathological features and clinical outcome of NEBC. METHODS AND RESULTS: Immunohistochemical staining for synaptophysin and chromogranin A was performed on whole sections from 1232 consecutive cases of invasive BC. We divided NEBC into focal (10-49% positive cells) and diffuse (>=50% positive cells) and compared the outcome of patients with NEBC with strictly matched non NEBC. A total of 128 BC showed NE differentiation (10.4%): 84 diffuse (6.8%) and 44 focal (3.6%). NE differentiation showed a significant association with T4 stage (P = 0.001), solid-papillary and mucinous histotype (P < 0.0001), G2 grading (P = 0.002), positive oestrogen receptor (ER) (P = 0.003) and progesterone receptor (PR) (P = 0.002). Almost 90% of NEBC were ER(+) /HER2(-) and more than half ER(+) /HER2(-) /Ki67>=14%. Kaplan-Meier analysis revealed that patients with NEBC showed worse disease-free survival (DFS) (P = 0.04) compared to matched non-NEBC. We did not find significant differences regarding clinicopathological features, DFS and CSS between diffuse and focal neuroendocrine BC. CONCLUSIONS: This study demonstrates that NEBC represents 7 10% of invasive BC and that NE differentiation does not affect the prognosis of BC in terms of CSS. PMID- 26114476 TI - Plant Translation Factors and Virus Resistance. AB - Plant viruses recruit cellular translation factors not only to translate their viral RNAs but also to regulate their replication and potentiate their local and systemic movement. Because of the virus dependence on cellular translation factors, it is perhaps not surprising that many natural plant recessive resistance genes have been mapped to mutations of translation initiation factors eIF4E and eIF4G or their isoforms, eIFiso4E and eIFiso4G. The partial functional redundancy of these isoforms allows specific mutation or knock-down of one isoform to provide virus resistance without hindering the general health of the plant. New possible targets for antiviral strategies have also been identified following the characterization of other plant translation factors (eIF4A-like helicases, eIF3, eEF1A and eEF1B) that specifically interact with viral RNAs and proteins and regulate various aspects of the infection cycle. Emerging evidence that translation repression operates as an alternative antiviral RNA silencing mechanism is also discussed. Understanding the mechanisms that control the development of natural viral resistance and the emergence of virulent isolates in response to these plant defense responses will provide the basis for the selection of new sources of resistance and for the intelligent design of engineered resistance that is broad-spectrum and durable. PMID- 26114480 TI - Phytoremediation potential of Lemna minor L. for heavy metals. AB - Phytoremediation potential of L. minor for cadmium (Cd), copper (Cu), lead (Pb), and nickel (Ni) from two different types of effluent in raw form was evaluated in a glass house experiment using hydroponic studies for a period of 31 days. Heavy metals concentration in water and plant sample was analyzed at 3, 10, 17, 24, and 31 day. Removal efficiency, metal uptake and bio-concentration factor were also calculated. Effluents were initially analyzed for physical, chemical and microbiological parameters and results indicated that municipal effluent (ME) was highly contaminated in terms of nutrient and organic load than sewage mixed industrial effluent (SMIE). Results confirmed the accumulation of heavy metals within plant and subsequent decrease in the effluents. Removal efficiency was greater than 80% for all metals and maximum removal was observed for nickel (99%) from SMIE. Accumulation and uptake of lead in dry biomass was significantly higher than other metals. Bio-concentration factors were less than 1000 and maximum BCFs were found for copper (558) and lead (523.1) indicated that plant is a moderate accumulator of both metals. Overall, L. minor showed better performance from SMIE and was more effective in extracting lead than other metals. PMID- 26114481 TI - Unconventional Heavy Oil Growth and Global Greenhouse Gas Emissions. AB - Enormous global reserves of unconventional heavy oil make it a significant resource for economic growth and energy security; however, its extraction faces many challenges especially on greenhouse gas (GHG) emissions, water consumption, and recently, social acceptability. Here, we question whether it makes sense to extract and use unconventional heavy oil in spite of these externalities. We place unconventional oils (oil sands and oil shale) alongside shale gas, coal, lignite, wood and conventional oil and gas, and compare their energy intensities and life cycle GHG emissions. Our results reveal that oil shale is the most energy intensive fuel among upgraded primary fossil fuel options followed by in situ-produced bitumen from oil sands. Lignite is the most GHG intensive primary fuel followed by oil shale. Based on future world energy demand projections, we estimate that if growth of unconventional heavy oil production continues unabated, the incremental GHG emissions that results from replacing conventional oil with heavy oil would amount to 4-21 Gt-CO2eq GtCO2eq over four decades (2010 by 2050). However, prevailing socio-economic, regional and global energy politics, environmental and technological challenges may limit growth of heavy oil production and thus its GHG emissions contributions to global fossil fuel emissions may be smaller. PMID- 26114479 TI - Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo. AB - Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool). In other processes, however, they appear to act differently (e.g. maintenance of foetal arterial identity) raising the questions of how similar DLL1 and DLL4 really are and which mechanism causes the apparent context-dependent divergence. By analysing mice that conditionally overexpress DLL1 or DLL4 from the same genomic locus (Hprt) and mice that express DLL4 instead of DLL1 from the endogenous Dll1 locus (Dll1Dll4ki), we found functional differences that are tissue-specific: while DLL1 and DLL4 act redundantly during the maintenance of retinal progenitors, their function varies in the presomitic mesoderm (PSM) where somites form in a Notch-dependent process. In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed. Transgenic DLL4 cannot replace DLL1 during somitogenesis and in heterozygous Dll1Dll4ki/+ mice, the Dll1Dll4ki allele causes a dominant segmentation phenotype. Testing several aspects of the complex Notch signalling system in vitro, we found that both ligands have a similar trans-activation potential but that only DLL4 is an efficient cis-inhibitor of Notch signalling, causing a reduced net activation of Notch. These differential cis-inhibitory properties are likely to contribute to the functional divergence of DLL1 and DLL4. PMID- 26114482 TI - Peripapillary Choroidal Thickness in Adult Chinese: The Beijing Eye Study. AB - PURPOSE: To measure peripapillary choroidal thickness (PPCT) and to assess its associations. METHODS: The population-based cross-sectional Beijing Eye Study 2011 included 3468 participants. Detailed medical and ophthalmic examinations were performed. We measured PPCT by spectral-domain optical coherence tomography (SD-OCT) with a 3.4-mm scan circle centered on the optic nerve head. RESULTS: Peripapillary choroidal thickness measurements were available for 3060 (88.2%) study participants with a mean age of 64.4 +/- 9.6 years (range, 50-93 years). Mean global PPCT was 134 +/- 53 MUm (range, 35-348 MUm). Peripapillary choroid was thickest in the superior region (155 +/- 60 MUm), followed by the temporal region (144 +/- 75 MUm; P < 0.001); nasal region (139 +/- 55 MUm; P < 0.001); and inferior region (110 +/- 45 MUm; P < 0.001). In multivariate analysis, thicker PPCT was associated with younger age (P < 0.001; standardized coefficient beta: 0.33; correlation coefficient B: -1.95; 95% confidence interval (CI): -2.25, 1.65); shorter axial length (P < 0.001; beta: -0.11; B: -5.39; 95% CI: -7.85, 2.93); smaller parapapillary alpha zone (P = 0.01; beta: -0.06; B: -5.46; 95% CI: -9.73, -1.19); and smaller beta zone (P < 0.001; beta: -0.14; B: -8.29; 95% CI: 11.12, -5.46); better best corrected visual acuity (logMAR; P = 0.002; beta: 0.05; B: -14.75; 95% CI: -28.59, -0.91), and higher prevalence of early age related macular degeneration (P = 0.04; beta: 0.05; B: 9.11; 95% CI: 0.42, 17.80) and intermediate age-related macular degeneration (P = 0.001; beta: 0.08; B: 10.90; 95% CI: 4.46, 17.33). It was not significantly (all P > 0.05) associated with blood pressure, blood concentration of lipids, intraocular pressure and prevalence of glaucoma, diabetic retinopathy, and retinal vein occlusions. The decrease of PPCT with longer axial length occurred predominantly in the temporal region. CONCLUSIONS: Peripapillary choroidal thickness is thickest superiorly and thinnest inferiorly. It decreases by 2 MUm per year of life and by 5 MUm per diopter of myopia. Thinner PPCT is correlated with larger parapapillary alpha and beta zones. The association of thinner PPCT with lower best corrected visual acuity may warrant further study. PMID- 26114483 TI - Behavioral Training as New Treatment for Adult Amblyopia: A Meta-Analysis and Systematic Review. AB - PURPOSE: New behavioral treatment methods, including dichoptic training, perceptual learning, and video gaming, have been proposed to improve visual function in adult amblyopia. Here, we conducted a meta-analysis of these methods to investigate the factors involved in amblyopia recovery and their clinical significance. METHODS: Mean and individual participant data meta-analyses were performed on 24 studies using the new behavioral methods in adults. Studies were identified using PubMed, Google Scholar, and published reviews. RESULTS: The new methods yielded a mean improvement in visual acuity of 0.17 logMAR with 32% participants achieving gains >= 0.2 logMAR, and a mean improvement in stereo sensitivity of 0.01 arcsec-1 with 42% of participants improving >=2 octaves. The most significant predictor of treatment outcome was visual acuity at the onset of treatment. Participants with more severe amblyopia improved more on visual acuity and less on stereo sensitivity than those with milder amblyopia. Better initial stereo sensitivity was a predictor of greater gains in stereo sensitivity following treatment. Treatment type, amblyopia type, age, and training duration did not have any significant influence on visual and stereo acuity outcomes. CONCLUSIONS: Our analyses showed that some participants may benefit from the new treatments; however, clinical trials are required to confirm these findings. Despite the diverse nature of the new behavioral methods, the lack of significant differences in visual and stereo sensitivity outcomes among them suggests that visual attention-a common element among the varied treatment methods-may play an important role in amblyopia recovery. PMID- 26114484 TI - How Many Visual Fields Are Required to Precisely Predict Future Test Results in Glaucoma Patients When Using Different Trend Analyses? AB - PURPOSE: To evaluate the minimum number of visual field (VF) tests required to precisely predict future VF results using ordinary least squares linear regression (OLSLR), quadratic regression, exponential regression, logistic regression, and M-estimator robust regression model. METHODS: Series of 15 VFs (Humphrey Field Analyzer 24-2 SITA standard) were analyzed from 247 eyes of 155 open-angle glaucoma patients. Future point-wise (PW) VF results and mean VF sensitivities were predicted with varying numbers of VFs in each regression method. RESULTS: In PW-OLSLR, as expected, the minimum absolute prediction error was obtained using the maximum number of VFs in the regression (14 VFs); mean absolute prediction error was equal to 2.4 +/- 0.9 dB. Ten VFs were required to reach the 95% confidence interval (CI) of the minimum absolute prediction error. Prediction errors associated with the exponential and quadratic regression models were significantly larger than those from PW-OLSLR, whereas errors from logistic regression were not significantly smaller than those from PW-OLSLR; however, the absolute prediction error from the M-estimator robust regression model was significantly smaller than those associated with PW-OLSLR (P < 0.01, paired Wilcoxon test). Like PW-OLSLR, 10 VFs were needed to obtain the minimum absolute prediction error of mean VF sensitivity, but there were no significant differences in errors using the different regression methods. CONCLUSIONS: Approximately 10 VFs, are needed to achieve an accurate prediction of PW VF sensitivity and mean sensitivity. Prediction error of PW VF sensitivity can be significantly minimized using the M-estimator robust regression model compared with conventional OLSLR. PMID- 26114485 TI - Associations Between Topical Ophthalmic Corticosteroids and Central Serous Chorioretinopathy: A Taiwanese Population-Based Study. AB - PURPOSE: To investigate the association between central serous chorioretinopathy (CSCR) and topical ophthalmic corticosteroid use. METHODS: Data were collected from the Longitudinal Health Insurance Database 2000, containing randomly selected medical claim data from 23 million residents in Taiwan. The study cohort comprised all patients diagnosed with CSCR between January 2001 and December 2010 (n = 2921) with a control group of patients (n = 17,526) matched to study patients according to age, sex, geographic region, and date of index medical care. Demographic characteristics, comorbidities, and corticosteroid use (topical ophthalmic, oral, nasal spray, injected, and inhaled) within 1 year before CSCR diagnosis were examined using univariate logistic regression. Student's t-test was used for continuous variables. Adjusted logistic regression was used to compare the odds ratio (OR) of the prognosis of CSCR patients with that of controls. RESULTS: In CSCR patients, we observed an increased prevalence of topical ophthalmic corticosteroid use (OR 6.328, 95% confidence interval [CI] 5.786-6.921, P < 0.0001). After adjusting for age, sex, geographic location of the patient's residence, hypertension, diabetes mellitus, hyperlipidemia, chronic renal disease, peptic ulcer, psychiatric disease, allergic respiratory disease, coronary artery disease, and corticosteroid use, conditional logistic regression analysis showed that CSCR patients were more likely to have used topical ophthalmic corticosteroids recently than the controls (OR 6.036, 95% CI 5.512 6.610, P < 0.0001). CONCLUSIONS: Results strongly support an association between recent topical ophthalmic corticosteroid use and CSCR. Thus, patients who require ophthalmic corticosteroids should be advised of the associated risk of developing CSCR. PMID- 26114486 TI - Expression of Angiogenic MicroRNAs in Endothelial Progenitor Cells From Type 1 Diabetic Patients With and Without Diabetic Retinopathy. AB - PURPOSE: MicroRNA (miR) expression in endothelial progenitor cells (EPCs) in type 1 diabetes (DM1) and its relation with different stages of diabetic retinopathy (DR) have not been reported to date. Our aim was to analyze miR-222, miR-221, and miR-126 expression in EPCs from DM1 patients with and without DR. METHODS: We included 41 patients with DR, 35 without DR, and 38 controls. Blood was collected for flow cytometry and EPC culture. Total RNA was extracted and purified and real time quantitative PCR was performed for miR expression in cultured EPCs. Relative changes in miR expression were analyzed with the 2-DeltaDeltaCT method. RESULTS: Circulating EPCs were reduced and miR-126 expression was increased in DM1 compared to controls (0.030 [interquartile range [IQR], 0.020-0.050] vs. 0.060 [IQR, 0.030-0.110], P = 0.004; 1.740 [IQR, 0.890-4.120] vs. 0.990 [IQR, 0.487 3.015], P = 0.047 respectively) without differences between patients with and without DR. Patients with DR had higher expression of miR-221 than those without DR (1.405 [IQR, 0.820-2.867] vs. 0.915 [IQR, 0.507-1.292], P = 0.019) without differences among degrees of DR. Circulating EPCs were reduced in patients on statins (0.010 [IQR, 0.010-0.050] vs. 0.045 [IQR, 0.020-0.087], P = 0.008), and miR-221 expression increased in patients on angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blocker (ARB) II (1.430 [IQR, 1.160-2.705] vs. 1.000 [IQR, 0.520-1.330], P = 0.021) compared to those without treatment. MicroRNA-126 expression was associated with body mass index (BMI; rho = -0.267, P = 0.026) and diastolic blood pressure (rho = -0.267, P = 0.034). MicroRNA-221 was associated with triglyceride concentration (rho = 0.296, P = 0.012). CONCLUSIONS: Circulating EPCs were reduced and miR-126 expression was increased in DM1 compared to controls. Patients with DR had higher expression of miR-221 than those without DR. The identification of biomarkers of diabetic complications might be useful for monitoring disease progression and potential therapeutic targets. PMID- 26114487 TI - Atypical Cadherin Fat1 Is Required for Lens Epithelial Cell Polarity and Proliferation but Not for Fiber Differentiation. AB - PURPOSE: The Fat family of atypical cadherins, originally identified in Drosophila, play diverse roles during embryogenesis and adult tissue maintenance. Among four mammalian members, Fat1 is essential for kidney and muscle organization, and is also essential for eye development; Fat1 knockout causes partial penetrant microphthalmia or anophthalmia. To account for the partial penetrance of the Fat1 phenotype, involvement of Fat4 in eye development was assessed. Lens phenotypes in Fat1 and 4 knockouts were also examined. METHODS: Fat1 and Fat4 mRNA expression was examined by in situ hybridization. Knockout phenotypes of Fat1 and Fat4 were analyzed by hematoxylin and eosin (H&E) and immunofluorescent staining. RESULTS: We found Fat4 knockout did not affect eye induction or enhance severity of Fat1 eye defects. Although Fat1 and Fat4 mRNAs are similarly expressed in the lens epithelial cells, only Fat1 knockout caused a fully penetrant lens epithelial cell defect, which was apparent at embryonic day 14.5 (E14.5). The columnar structure of the lens epithelial cells was disrupted and in some regions cell aggregates were formed. In these multilayered regions, apical cell junctions were fragmented and the apical-basal polarity was lost. EdU incorporation assay also showed enhanced proliferation in the lens epithelial cells. Interestingly, these defects were found mainly in the central zone of the epithelial layer. The lens epithelial cells of the germinative zone maintained their normal morphology and fiber differentiation occurred normally at the equator. CONCLUSIONS: These observations indicate that Fat1 is essential for lens epithelial cell polarity and proliferation but not for terminal differentiation. PMID- 26114488 TI - Regulation of Endothelin-1-Induced Trabecular Meshwork Cell Contractility by Latanoprostene Bunod. AB - PURPOSE: Previous in vivo studies demonstrated that latanoprostene bunod (LBN), a nitric oxide (NO)-donating prostaglandin F2alpha receptor agonist, results in greater intraocular pressure (IOP) lowering than latanoprost. The present series of investigations compared the effects of LBN and latanoprost on primary human trabecular meshwork cell (HTMC) contractility and underlying signaling pathways to determine whether LBN might mediate this additional IOP lowering via the conventional outflow pathway. METHODS: The effect of LBN (1-100 MUM) on HTMC cGMP levels was determined by ELISA with or without the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Endothelin-1 (ET-1) was used to induce HTMC contractility. To determine the effect of LBN on myosin light chain-2 (MLC-2) phosphorylation, HTMCs were pretreated with 10 to 60 MUM LBN for 1 hour and then ET-1 for 5 minutes. MLC-2 phosphorylation was determined by Western blotting. Effects of LBN (30 and 45 MUM) on ET-1-induced filamentous (F)-actin cytoskeletal stress fibers and the focal adhesion associated protein vinculin were determined by confocal microscopy. ET-1-induced HTMC monolayer resistance in the presence of LBN (45 MUM) was determined by electrical cell substrate impedance sensing, as an indicator of cell contractility. Latanoprost and SE 175 (an NO donor which releases NO on reductive transformation within the cells) were used as comparators in all studies. RESULTS: LBN (1-100 MUM) significantly increased cGMP levels in a dose-dependent manner, with a half maximal effective concentration (EC50) of 1.5 +/- 1.3 MUM, and with maximal effect similar to that of 100 MUM SE 175. In contrast, latanoprost caused a minimal increase in cGMP levels at 100 MUM only. The cGMP elevation induced by LBN or SE 175 was abolished by ODQ and was therefore sGC dependent. The two NO donors SE 175 and LBN elicited a reduction in ET-1-induced MLC-2 phosphorylation that was significantly greater than that mediated by latanoprost in HTMCs. SE 175 (100 MUM) and LBN (30 or 45 MUM) caused a dramatic reduction in ET-1-induced actin stress fibers and vinculin localization at focal adhesions, whereas 45 MUM latanoprost was without observable effect. SE 175 reduced ET-1-induced increases in HTMC resistance in a dose-dependent manner. A synergistic effect on reduction of HTMC resistance was observed when latanoprost and SE 175 doses were given together. LBN significantly reduced ET-1-induced HTMC monolayer resistance increases to a greater extent than latanoprost, indicating a greater reduction in cell contractility with LBN. CONCLUSIONS: LBN, SE 175, and latanoprost caused relaxation of ET-1-contracted HTMCs. The effect on HTMC relaxation observed with LBN was significantly greater in magnitude than that observed with latanoprost or SE 175. Data indicate that the NO-donating moiety of LBN mediates HTMC relaxation through activation of the cGMP signaling pathway and a subsequent reduction in MLC-2 phosphorylation. These findings suggest that increased conventional outflow facility may mediate the additional IOP-lowering effects of LBN over that of latanoprost observed in in vivo studies. PMID- 26114489 TI - iTRAQ-Based Quantitative Proteomic Analysis of Tear Fluid in a Rat Penetrating Keratoplasty Model With Acute Corneal Allograft Rejection. AB - PURPOSE: This study aimed to develop a greater understanding of the mechanisms underlying acute corneal allograft rejection by identifying differentially expressed tear proteins at defined stages and discovering potentially important proteins involved in the process. METHODS: The isobaric tags for relative and absolute quantitation (iTRAQ)-two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS) technique was used to identify tear proteins showing significant alterations in a rat penetrating keratoplasty model at different time points. Bioinformatics technology was applied to analyze the significant proteins, and a potential protein was verified by Western blotting. RESULTS: A total of 269 proteins were quantified, and 118 proteins were considered to be significantly altered by at least 2.0- or 0.5-fold. For gene ontology annotations, the top enrichments were neurological disease, free radical scavenging, cell death and survival, and cell movement. For pathway analyses, the top enrichments were LXR/RXR activation, acute phase response signaling, clathrin mediated endocytosis signaling, and coagulation system. Coronin-1A was verified as a potential protein involved in the early stage of acute corneal allograft rejection. CONCLUSIONS: This study first demonstrates that tear proteomics is a powerful tool for better understanding of the mechanisms underlying acute corneal rejection, and that coronin-1A in tears might be closely related to allograft rejection. PMID- 26114490 TI - Erratum. PMID- 26114491 TI - Restoration of Outer Retinal Layers After Aflibercept Therapy in Exudative AMD: Prognostic Value. AB - PURPOSE: To evaluate the outer retinal layer (ellipsoid zone [EZ] and external limiting membrane [ELM]) changes following intravitreal aflibercept injections in eyes with treatment-naive exudative age-related macular degeneration (eAMD) and to correlate these changes with fluid response and visual improvement. METHODS: A retrospective case series of 50 treatment-naive eAMD eyes followed-up for 18 months. All patients underwent regular comprehensive ophthalmic examinations. The presence of EZ disruption, ELM disruption, EZ swelling, subretinal hyper reflective exudation (SHE), central macular thickness (CMT), cystoid spaces, subretinal fluid, and pigmented epithelium detachment were evaluated by two different retinal specialists at baseline and final visits, and correlated with best corrected visual acuity (BCVA) improvement. RESULTS: At 18 months, BCVA, EZ disruption, ELM disruption, EZ swelling and SHE improved significantly (P = 0.001) at 18 months. Improvement of BCVA showed a statistically significant correlation with ELM restoration (P = 0.018), but not with EZ restoration (P = 0.581). Swelling of the EZ decreased from 72% of the cases at baseline to 30% in 18 months while SHE decreased from 52% to 6% in 18 months (P = 0.001). We observed a statistically significant (P = 0.001) reduction between the baseline and final value of CMT. CONCLUSIONS: Aflibercept is safe and effective in treating exudative AMD with the restoration of the outer retinal layers. Restoration of the EZ is not statistically correlated with the final BCVA, even though persistent EZ changes could be associated with irreversible decrease in vision. On the contrary, the final status of the ELM is directly correlated with final BCVA. Also, baseline changes in outer retinal layers, especially the ELM, appear to predict photoreceptor restoration and final BCVA, and must be comprehensively analyzed to enable and determine a future prognosis. PMID- 26114492 TI - Relationship Between Retinal Blood Flow and Serum Adiponectin Concentrations in Patients With Type 2 Diabetes Mellitus. AB - PURPOSE: To study the relationship between retinal microcirculation and serum adiponectin, an important adipocytokine secreted by adipocytes, concentrations in patients with type 2 diabetes mellitus. METHODS: Using a laser Doppler velocimetry system, we simultaneously measured the retinal blood flow (RBF) values and retinal vessel diameter and blood velocity in 64 consecutive Japanese patients (mean age +/- SD, 59.8 +/- 10.4 years) with type 2 diabetes with no or mild nonproliferative diabetic retinopathy. We compared the values with the RBF and serum adiponectin concentrations in these patients. The patients were divided into two groups based on sex (33 males, 31 females). RESULTS: The plasma adiponectin concentrations were correlated positively with the retinal vessel diameter (r = 0.480; P = 0.005), retinal blood velocity (r = 0.399; P = 0.02), and RBF (r = 0.518; P = 0.002) and correlated negatively with the retinal arterial vascular resistance (r = -0.598; P = 0.0002) in males, but not females, with type 2 diabetes with early-stage diabetic retinopathy. Multiple regression analysis showed that the plasma adiponectin level was independently and positively correlated with RBF and negatively correlated with retinal arterial vascular resistance. CONCLUSIONS: Our results indicated that a high concentration of serum adiponectin may be associated with increased RBF, probably via the increased blood velocity and dilated vessel diameter in males with type 2 diabetes with early-phase diabetic retinopathy. PMID- 26114493 TI - Unique Variants in OPN1LW Cause Both Syndromic and Nonsyndromic X-Linked High Myopia Mapped to MYP1. AB - PURPOSE: MYP1 is a locus for X-linked syndromic and nonsyndromic high myopia. Recently, unique haplotypes in OPN1LW were found to be responsible for X-linked syndromic high myopia mapped to MYP1. The current study is to test if such variants in OPN1LW are also responsible for X-linked nonsyndromic high myopia mapped to MYP1. METHODS: The proband of the family previously mapped to MYP1 was initially analyzed using whole-exome sequencing and whole-genome sequencing. Additional probands with early-onset high myopia were analyzed using whole-exome sequencing. Variants in OPN1LW were selected and confirmed by Sanger sequencing. Long-range and second PCR were used to determine the haplotype and the first gene of the red-green gene array. Candidate variants were further validated in family members and controls. RESULTS: The unique LVAVA haplotype in OPN1LW was detected in the family with X-linked nonsyndromic high myopia mapped to MYP1. In addition, this haplotype and a novel frameshift mutation (c.617_620dup, p.Phe208Argfs*51) in OPN1LW were detected in two other families with X-linked high myopia. The unique haplotype cosegregated with high myopia in the two families, with a maximum LOD score of 3.34 and 2.31 at theta = 0. OPN1LW with the variants in these families was the first gene in the red-green gene array and was not present in 247 male controls. Reevaluation of the clinical data in both families with the unique haplotype suggested nonsyndromic high myopia. CONCLUSIONS: Our study confirms the findings that unique variants in OPN1LW are responsible for both syndromic and nonsyndromic X-linked high myopia mapped to MYP1. PMID- 26114494 TI - High-dose oral intake of serotonin induces valvular heart disease in rabbits. PMID- 26114495 TI - Coronary artery fistulas and Brugada ECG pattern, a random association? PMID- 26114496 TI - Plasma miRNAs Effectively Distinguish Patients With Pancreatic Cancer From Controls: A Multicenter Study. AB - OBJECTIVES: To identify plasma microRNA (miRNA) markers of pancreatic cancer (PC). BACKGROUND: Accurate pretreatment diagnosis of PC remains challenging, whether plasma miRNAs could be used as biomarkers in PC remains unknown. METHODS: In this multiphase multicenter study, peripheral blood samples were obtained preoperatively in 3 phases: the discovery phase [7 patients with PC, 6 patients with chronic pancreatitis (CP), and 5 healthy volunteers (N)], the preliminary validation phase (29 patients with PC, 16 patients with CP, and 31 N), and the large sample validation phase (156 patients with PC, 65 N, 57 patients with CP, 27 patients with pancreatic neuroendocrine tumors, and 58 patients with other pancreatic tumors). The diagnostic values of the miRNAs were assessed and compared with cancer antigen 19-9 (CA19-9). RESULTS: The discovery phase demonstrated that 29 miRNAs were dysregulated in the patients with PC compared with the controls. In the preliminary validation phase, 13 miRNAs were shown to be dysregulated in the patients with PC and were selected for validation in a multicenter trial. MiR-486-5p exhibited diagnostic value in discriminating patients with PC from normal subjects or patients with CP, with area under the curve values of 0.861 and 0.707, respectively. MiR-938 exhibited diagnostic value in differentiating patients with PC from those with CP, pancreatic neuroendocrine tumors, and patients with other pancreatic tumors, with area under the curve values of 0.693, 0.660, and 0.618, respectively. In addition, we demonstrated that the value of miR-486-5p in discriminating patients with PC from normal subjects or patients with CP was comparable with that of CA19-9 (P = 0.602 and P = 0.230). CONCLUSIONS: This study identified several plasma miRNAs potentially suitable for distinguishing patients with PC from normal subjects or patients with other pancreatic tumors. PMID- 26114497 TI - Mechanisms of Fatal Cardiotoxicity following High-Dose Cyclophosphamide Therapy and a Method for Its Prevention. AB - Observed only after administration of high doses, cardiotoxicity is the dose limiting effect of cyclophosphamide (CY). We investigated the poorly understood cardiotoxic mechanisms of high-dose CY. A rat cardiac myocardial cell line, H9c2, was exposed to CY metabolized by S9 fraction of rat liver homogenate mixed with co-factors (CYS9). Cytotoxicity was then evaluated by 3-(4,5-dimethyl-2 thiazolyl)!2,5-diphenyl!2H-tetrazolium bromide (MTT) assay, lactate dehydrogenase release, production of reactive oxygen species (ROS), and incidence of apoptosis. We also investigated how the myocardial cellular effects of CYS9 were modified by acrolein scavenger N-acetylcysteine (NAC), antioxidant isorhamnetin (ISO), and CYP inhibitor beta-ionone (BIO). Quantifying CY and CY metabolites by means of liquid chromatography coupled with electrospray tandem mass spectrometry, we assayed culture supernatants of CYS9 with and without candidate cardioprotectant agents. Assay results for MTT showed that treatment with CY (125-500 MUM) did not induce cytotoxicity. CYS9, however, exhibited myocardial cytotoxicity when CY concentration was 250 MUM or more. After 250 MUM of CY was metabolized in S9 mix for 2 h, the concentration of CY was 73.6 +/- 8.0 MUM, 4-hydroxy-cyclophosphamide (HCY) 17.6 +/- 4.3, o-carboxyethyl-phosphoramide (CEPM) 26.6 +/- 5.3 MUM, and acrolein 26.7 +/- 2.5 MUM. Inhibition of CYS9-induced cytotoxicity occurred with NAC, ISO, and BIO. When treated with ISO or BIO, metabolism of CY was significantly inhibited. Pre-treatment with NAC, however, did not inhibit the metabolism of CY: compared to control samples, we observed no difference in HCY, a significant increase of CEPM, and a significant decrease of acrolein. Furthermore, NAC pre-treatment did not affect intracellular amounts of ROS produced by CYS9. Since acrolein seems to be heavily implicated in the onset of cardiotoxicity, any competitive metabolic processing of CY that reduces its transformation to acrolein is likely to be an important mechanism for preventing cardiotoxicity. PMID- 26114498 TI - Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans. AB - Furan, a possible human carcinogen, is found in heat treated foods and tobacco smoke. Previous studies have shown that humans are capable of converting furan to its reactive metabolite, cis-2-butene-1,4-dial (BDA), and therefore may be susceptible to furan toxicity. Human risk assessment of furan exposure has been stymied because of the lack of mechanism-based exposure biomarkers. Therefore, a sensitive LC-MS/MS assay for six furan metabolites was applied to measure their levels in urine from furan-exposed rodents as well as in human urine from smokers and nonsmokers. The metabolites that result from direct reaction of BDA with lysine (BDA-N(alpha)-acetyllysine) and from cysteine-BDA-lysine cross-links (N acetylcysteine-BDA-lysine, N-acetylcysteine-BDA-N(alpha)-acetyllysine, and their sulfoxides) were targeted in this study. Five of the six metabolites were identified in urine from rodents treated with furan by gavage. BDA-N(alpha) acetyllysine, N-acetylcysteine-BDA-lysine, and its sulfoxide were detected in most human urine samples from three different groups. The levels of N acetylcysteine-BDA-lysine sulfoxide were more than 10 times higher than that of the corresponding sulfide in many samples. The amount of this metabolite was higher in smokers relative to that in nonsmokers and was significantly reduced following smoking cessation. Our results indicate a strong relationship between BDA-derived metabolites and smoking. Future studies will determine if levels of these biomarkers are associated with adverse health effects in humans. PMID- 26114500 TI - An Evaluation of the Role the Internet Site Petfinder Plays in Cat Adoptions. AB - To better understand factors contributing to cat adoptions, this study was used to explore a possible association between an adoptable cat's popularity on Petfinder and the cat's length of availability for adoption at a managed-intake nonhuman animal shelter. This study was also used to examine factors associated with a cat's popularity on Petfinder and the percentage of adopters who visited Petfinder before making adoption decisions. One third of adopters surveyed visited Petfinder before adopting, and half of those had viewed their adopted cats' Petfinder profiles. The number of clicks per day that cats received on the site was negatively correlated with their length of availability. Age at adoption was positively correlated with length of availability and negatively correlated with number of clicks per day. Coat color was a strong predictor of number of clicks per day and length of availability. The only variable within the photographer's control significantly associated with number of clicks per day was whether the photos included toys. Although cats' physical characteristics are strong predictors of their popularity, strategic use of toys in cats' photographs may promote adoptions of cats who are typically overlooked. PMID- 26114501 TI - MamA as a Model Protein for Structure-Based Insight into the Evolutionary Origins of Magnetotactic Bacteria. AB - MamA is a highly conserved protein found in magnetotactic bacteria (MTB), a diverse group of prokaryotes capable of navigating according to magnetic fields - an ability known as magnetotaxis. Questions surround the acquisition of this magnetic navigation ability; namely, whether it arose through horizontal or vertical gene transfer. Though its exact function is unknown, MamA surrounds the magnetosome, the magnetic organelle embedding a biomineralised nanoparticle and responsible for magnetotaxis. Several structures for MamA from a variety of species have been determined and show a high degree of structural similarity. By determining the structure of MamA from Desulfovibrio magneticus RS-1 using X-ray crystallography, we have opened up the structure-sequence landscape. As such, this allows us to perform structural- and phylogenetic-based analyses using a variety of previously determined MamA from a diverse range of MTB species across various phylogenetic groups. We found that MamA has remained remarkably constant throughout evolution with minimal change between different taxa despite sequence variations. These findings, coupled with the generation of phylogenetic trees using both amino acid sequences and 16S rRNA, indicate that magnetotaxis likely did not spread via horizontal gene transfer and instead has a significantly earlier, primordial origin. PMID- 26114503 TI - Review of "It's All in Your Head: Context-Dependent Pain Processing in the Orbitofronal Cortex" by Sinha S, McGovern RA, Sheth SA, McKhann II, GM in Neurosurgery 76:N10-N11, 2015. PMID- 26114502 TI - Treatment of Chronic Experimental Autoimmune Encephalomyelitis with Epigallocatechin-3-Gallate and Glatiramer Acetate Alters Expression of Heme Oxygenase-1. AB - We previously demonstrated that epigallocatechin-3-gallate (EGCG) synergizes with the immunomodulatory agent glatiramer acetate (GA) in eliciting anti-inflammatory and neuroprotective effects in the relapsing-remitting EAE model. Thus, we hypothesized that mice with chronic EAE may also benefit from this combination therapy. We first assessed how a treatment with a single dose of GA together with daily application of EGCG may modulate EAE. Although single therapies with a suboptimal dose of GA or EGCG led to disease amelioration and reduced CNS inflammation, the combination therapy had no effects. While EGCG appeared to preserve axons and myelin, the single GA dose did not improve axonal damage or demyelination. Interestingly, the neuroprotective effect of EGCG was abolished when GA was applied in combination. To elucidate how a single dose of GA may interfere with EGCG, we focused on the anti-inflammatory, iron chelating and anti oxidant properties of EGCG. Surprisingly, we observed that while EGCG induced a downregulation of the gene expression of heme oxygenase-1 (HO-1) in affected CNS areas, the combined therapy of GA+EGCG seems to promote an increased HO-1 expression. These data suggest that upregulation of HO-1 may contribute to diminish the neuroprotective benefits of EGCG alone in this EAE model. Altogether, our data indicate that neuroprotection by EGCG in chronic EAE may involve regulation of oxidative processes, including downmodulation of HO-1. Further investigation of the re-dox balance in chronic neuroinflammation and in particular functional studies on HO-1 are warranted to understand its role in disease progression. PMID- 26114505 TI - Cranial Base and Posterior Cranial Vault Asymmetry After Open and Endoscopic Repair of Isolated Lambdoid Craniosynostosis. AB - BACKGROUND: Previous studies have shown that open cranial vault remodeling does not fully address the endocranial deformity. This study aims to compare endoscopic-assisted suturectomy with postoperative molding helmet therapy to traditional open reconstruction by quantifying changes in cranial base morphology and posterior cranial vault asymmetry. METHODS: Anthropometric measurements were made on pre- and 1-year postoperative three-dimensionally reconstructed computed tomography scans of 12 patients with unilateral lambdoid synostosis (8 open and 4 endoscopic-assisted). Cranial base asymmetry was analyzed using: posterior fossa deflection angle (PFA), petrous ridge angle (PRA), mastoid cant angle (MCA), and vertical and anterior-posterior (A-P) displacement of external acoustic meatus (EAM). Posterior cranial vault asymmetry was quantified by volumetric analysis. RESULTS: Preoperatively, patients in the open and endoscopic groups were statistically equivalent in PFA, PRA, MCA, and A-P EAM displacement. At 1 year postoperatively, open and endoscopic patients were statistically equivalent in all measures. Mean postoperative PFA for the open and endoscopic groups was 6.6 and 6.4 degrees, PRA asymmetry was 6.4 and 7.6%, MCA was 4.0 and 3.2 degrees, vertical EAM displacement was -2.3 and -2.3 millimeters, and A-P EAM displacement was 6.8 and 7.8 millimeters, respectively. Mean volume asymmetry was significantly improved in both open and endoscopic groups, with no difference in postoperative asymmetry between the 2 groups (P = 0.934). CONCLUSIONS: Patients treated with both open and endoscopic repair of lambdoid synostosis show persistent cranial base and posterior cranial vault asymmetry. The results of endoscopic-assisted suturectomy with postoperative molding helmet therapy are similar to those of open calvarial vault reconstruction. PMID- 26114506 TI - Total Auricular Rehabilitation: Combined Cosmetic and Functional Lateral Temporal Bone Reconstruction. AB - OBJECTIVE: The aim of the study was to describe 3 cases of total auricular rehabilitation, including the novel use of iliac crest bone grafts to support bone-anchored auricular prostheses. STUDY DESIGN: This study is a retrospective case series from a single institution. RESULTS: Three cases with large lateral temporal bone and soft tissue defects were successfully treated with total auricular rehabilitation. Rehabilitation included the following: soft tissue coverage with an anterolateral thigh microvascular free flap, iliac crest-free bone graft with staged placement of a bone-anchored auricular prosthesis into the bone graft, and audiologic rehabilitation with a bone-anchored hearing aid (BAHA). All of the cases with grafts and flaps survived and were without significant donor site morbidity. Bone-anchored hearing aid abutment skin overgrowth was seen in 2 cases and was revised under local anesthesia. All of the patients had expected functional recovery on postoperative audiologic testing. Each patient continues to consistently wear his/her auricular prosthesis and BAHA during 3 years of follow-up. CONCLUSIONS: Total auricular rehabilitation is a complex task involving reconstruction of extensive soft tissue defects, bony defects, and the hearing apparatus. Acceptable cosmetic and functional outcomes and high patient satisfaction is possible in committed patients. PMID- 26114507 TI - Clinical Implication of Heart Rate Variability in Obstructive Sleep Apnea Syndrome Patients. AB - Obstructive sleep apnea syndrome (OSAS) is a common disease with the prevalence of approximately 10% in general population, and this disease entity is considered to be highly related with the development of cerebrovascular and cardiovascular diseases. In the pathogenesis of cardiovascular disease, maintaining the homeostasis of autonomic nervous system (ANS) is critical. To evaluate the homeostasis of ANS, heart rate variability (HRV) is commonly used. The object of this study was to evaluate the homeostasis of ANS using the parameters of HRV and to elucidate the correlation between the parameters and apnea-hypopnea index (AHI). METHODS: Retrospective review of 806 patients was performed and 164 patients who were diagnosed as having OSAS by in-room polysomnography and met the criteria of age, sex, and body mass index were enrolled. The calculation of HRV parameters was executed using echocardiographic data from polysomnography. RESULTS: Between the control group (N = 81, AHI < 5) and OSAS patient group (N = 83, AHI > 15), standard deviation of NN (SDNN) intervals, SDNN index, HRV triangular index, very low frequency (VLF), low frequency (LF), 5-minute total power (TP), and low-frequency to high-frequency (LF/HF) ratio showed significant differences. In the correlation analysis between AHI and HRV parameters, only LF/HF ratio was proven to be significant. CONCLUSIONS: Elucidating the imbalance of ANS in OSAS patients was feasible by HRV and its parameters. PMID- 26114508 TI - Comparison of Autogenous and Alloplastic Cranioplasty Materials Following Impact Testing. AB - Alloplastic materials are often used when significant defects exist. Benefits include no donor site morbidity, relative ease of use, limitless supply, and predictable durability. Depending on the type of alloplast, limitations include a persistent risk of extrusion and infection. Of particular interest in relation to cranioplasties is the ability of the material to provide neuroprotection. The integrity and neuroprotective properties of autologous bone flaps, polymethylmethacrylate (PMMA), and high-density porous polyethylene (PP) were evaluated following impact testing. Three groups of New Zealand white rabbits (N = 4) underwent a cranioplasty with either a bone flap, PMMA, or PP. In the control group (N = 4), the animals had no cranioplasty. At the end of the eighth week, an impact was delivered to the center of each cranioplasty. At necropsy each cranium and brain was evaluated grossly and histologically. There was a statistical significant difference among groups for the severity of the hemorrhage (P = 0.022) and the grade of cranioplasty disruption (P = 0.0045). Autologous bone was found to be the weakest of the materials tested. In this group severe injury resulted at much lower energy levels than was observed in the control, PMMA, or PP groups. Both PMMA and PP were resistant to fracture and disruption. PMMA provided the greatest neuroprotection, followed by PP. Autologous bone provided the least protection with cranioplasty disruption and severe brain injury occurring in every patient. Brain injury patterns correlated with the degree of cranioplasty disruption regardless of the cranioplasty material. Regardless of the energy of impact, lack of dislodgement generally resulted in no obvious brain injury. PMID- 26114509 TI - Image-Guided Sinus Surgery in Sinonasal Pathologies With Skull Base/Orbital Erosion. AB - OBJECTIVE: The aim of the study was to review the use and outcomes of image guided sinus surgery (IGSS) in sinonasal pathologies with skull base/orbital erosion without intracranial or intraorbital extension. METHOD: A retrospective charts and medical records review was performed for 474 consecutive sinonasal surgeries performed by a single surgeon at tertiary, academic center from August 2010 to December 2013. RESULT: Fourteen subjects (mean age 27 years; 8 men and 6 women) were identified. Mucocele and tumor were the most common pathological indication for IGSS use in this case series. Orbital wall erosion was detected in 57%, skull base in 29%, and both sites in 14%. The average blood loss was 80 mL, the average operative time was 190 minutes, and the average hospital stay was 3 days. There was no major intra- or postoperative complications. Two patients required revision endoscopic sinus surgery. The mean follow-up was 14 months (range 8-36 months). CONCLUSION: Image-guided sinus surgery alone is safe and effective procedure for a variety of sinonasal pathologies with orbital and skull base erosion. PMID- 26114510 TI - Evaluation of Bone Height and Bone Mineral Density Using Cone Beam Computed Tomography After Secondary Bone Graft in Alveolar Cleft. AB - The purpose of this study was to assess the optimal timing of subsequent dental implant placement and orthodontics after alveolar bone grafting (ABG) in patients with unilateral complete clefts of the alveolar process. Iliac bone graft surgery was performed on 60 patients. Bone mineral density (BMD) and height of the ABG areas were assessed using cone beam computed tomography at 3 and 6 months postoperatively. The heights of the labial and palatal bone graft areas were classified using the modified Bergland classification. The study found that there was no change in BMD between 3 months (mean +/- SD: 406.51 +/- 71.28 Hounsfield units [HU]) and 6 months (409.53 +/- 46.37 HU; P = 0.381). Significant changes in the distribution of bone height classifications were observed in the labial and palatal sides of the ABG between 3 and 6 months (P = 0.025 for labial bone height, P = 0.008 for palatal bone height). These results indicate that the alveolar density remained stable between 3 and 6 months, whereas bone height level declined during that period after ABG, the latter indicating bone graft absorption over time. It is, therefore, suggested that subsequent orthodontic or dental implants be placed 3 months after ABG rather than at 6 months or later. PMID- 26114512 TI - Evaluation of the Cortical Bone Reaction Around of Implants Using a Single-Use Final Drill: A Histologic Study. AB - OBJECTIVES: This study was designed to compare the cortical bone reaction following traditional osteotomy or the use of a single-use final drill in the osseointegration of implants in the tibia of rabbits. MATERIALS AND METHODS: For this study, 48 conical implants, of standard surface type and design and manufactured by the same company, were inserted into the tibiae of 12 rabbits and removed after 30 or 60 days for histologic analysis. Two test groups were prepared according to the drill sequence used for the osteotomy at the preparation sites: in the control group was used a conventional drill sequence with several uses, whereas the test group (tesG) used a single-use final drill. The bone-to-implant contact and qualitative factors of the resulting cortical bone were assessed. RESULTS: Both techniques produced good implant integration. Differences in the linear bone-to-implant contact were observed between the drilling procedures as time elapsed in vivo, with the tesG appearing to have clinical advantages. Both groups exhibited new bone in quantity and in quality; however, the tesG exhibited a higher level of new bone deposition than the control group. CONCLUSIONS: Within the limitations of this study, the findings suggest that the use of a single-use final drill leads to better and faster organization of the cortical bone area during the evaluated period and may avoid the possible problems that can be caused by worn drills. PMID- 26114511 TI - Poly-D-L-Lactic Acid Membranes for Bone Regeneration. AB - PURPOSE: To histologically and histomorphometrically evaluate the biocompatibility and the biological properties of perforated and nonperforated poly-D-L-lactic acid (PDLLA) resorbable membranes, using a model of calvarial monocortical bone defects in domestic pigs. METHODS: A total of 6 10 * 10 * 10 mm circular calvarial bone defects were prepared in each of the 3 adult female large white domestic pigs and assigned to the following experimental groups: negative control, nonperforated membrane only, perforated membrane only, bone only, bone + nonperforated membrane, and bone + perforated membrane. The PDLLA membranes were fixed by PDLLA pins by means of an ultrasonic device. After 40 days, bone blocks containing the defects were harvested and histologically processed. RESULTS: A close contact between the PDLLA devices and the surrounding bone was found, and no trace of inflammatory tissue or signs of infection were detected. Bone regeneration occurred from the preexisting bone with a centripetal pattern. Incomplete bone filling was found in empty defects, whereas all sites filled with bone showed a complete bone formation, irrespectively of the presence and the type of membrane used. CONCLUSION: PDLLA membranes and pins showed to be highly biocompatible toward bone tissue and to do not interfere with the bone healing process of monocortical calvaria defects in domestic pigs. No adjunctive effect of PDLLA membranes, irrespectively of their perforated/nonperforated structure, could be evidenced in terms of bone regeneration under the present experimental conditions. Further studies are needed to investigate the regenerative potential of such devices in other clinically relevant models. PMID- 26114513 TI - The Frequency of Decreased Visual Acuity in Orbital Fractures. AB - The aim of this systematic review is to summarize and evaluate the effect of orbital fractures (blowout fractures and nonblowout fractures) on visual acuity. In PubMed search and Scopus search, the terms "orbital fracture OR maxillofacial injury OR facial trauma OR craniofacial fracture," and "visual acuity OR functional outcome OR visual outcome OR improving document of visual acuity OR blindness OR optic nerve neuropathy" were used, which resulted in 1634 and 1152 papers, respectively. Of the 2226 titles excluding 560 duplicated titles, 227 abstracts were reviewed. Of the 227 abstracts reviewed, the authors found 56 potentially relevant full-text articles, of which 5 studies met our inclusion criteria. The odds ratio and 95% confidence intervals from each study were abstracted. The statistical analysis was performed with review manager (The Nordic Cochrane Centre). A summary of 5 studies affirmed that 43 patients among 532 orbital fractures (8.1%) had decreased visual acuity. Twelve patients among 159 blowout fractures (7.5%) had decreased visual acuity. Thirty-one patients among 373 orbital fractures other than pure blowout fractures (8.3%) had decreased visual acuity. In orbital fractures other than pure blowout fractures, the frequency of decreased visual acuity was higher than pure blowout fractures (n = 532, odds ratio, 2.23, 95% confidence interval = 1.06-4.70). Surgeons should acknowledge this with patients before surgery. PMID- 26114514 TI - A Three-Dimensional Statistical Average Skull: Application of Biometric Morphing in Generating Missing Anatomy. AB - PURPOSE: The utilization of three-dimensional modeling technology in craniomaxillofacial surgery has grown exponentially during the last decade. Future development, however, is hindered by the lack of a normative three dimensional anatomic dataset and a statistical mean three-dimensional virtual model. The purpose of this study is to develop and validate a protocol to generate a statistical three-dimensional virtual model based on a normative dataset of adult skulls. METHOD: Two hundred adult skull CT images were reviewed. The average three-dimensional skull was computed by processing each CT image in the series using thin-plate spline geometric morphometric protocol. Our statistical average three-dimensional skull was validated by reconstructing patient-specific topography in cranial defects. The experiment was repeated 4 times. In each case, computer-generated cranioplasties were compared directly to the original intact skull. The errors describing the difference between the prediction and the original were calculated. RESULTS: A normative database of 33 adult human skulls was collected. Using 21 anthropometric landmark points, a protocol for three-dimensional skull landmarking and data reduction was developed and a statistical average three-dimensional skull was generated. Our results show the root mean square error (RMSE) for restoration of a known defect using the native best match skull, our statistical average skull, and worst match skull was 0.58, 0.74, and 4.4 mm, respectively. CONCLUSIONS: The ability to statistically average craniofacial surface topography will be a valuable instrument for deriving missing anatomy in complex craniofacial defects and deficiencies as well as in evaluating morphologic results of surgery. PMID- 26114515 TI - The Incidence and Topographic Distribution of Sutures Including Wormian Bones in Human Skulls. AB - OBJECTIVE: The Wormian Bones are accessory bones located within the cranial sutures and fontanelles. The present article examines the incidence of Wormian Bones and compares the number and topographic distribution between the sutures including Wormian Bones in skulls of West Anatolian Population. METHODS: One hundred fifty crania were examined. The parameters evaluated in the present study were as follows: the rate of skulls including Wormian Bones; the topographic distribution and frequencies of the sutures including Wormian Bones; the number of these sutures for each skull; the name and number of sutures that were bilaterally and symmetrically located on the right and left side of skull (paired sutures) and which coincidentally had Wormian Bones for each skull; the differences of frequencies between the paired sutures including Wormian Bones. RESULTS: The rate of skulls including Wormian Bones was determined as 59.3%. The maximum and minimum numbers of sutures, including Wormian Bones, were 6 in 1 skull and 1 in each of 30 skulls, respectively. The maximum and minimum rates of sutures that had Wormian Bones were found in left lambdoid 40.7% and right occipitomastoid 1.3% sutures, respectively. There was only a significant difference between the rate of right and left squamous sutures (P = 0.04). Forty five skulls were including 55 pairs of bilaterally and symmetrically located sutures that coincidentally had Wormian Bones in each pair. Each of 35 skulls had 1 pair of sutures including Wormian Bones and each of 10 skulls had 2 pairs. CONCLUSIONS: In the present study, the rate of Wormian Bones was determined as 59.3% in West Anatolian Population. This incidence rate is considerably lower than the other reports, and it may be as a result of racial variations. These divergent bones were more frequently found in left lambdoid sutures (40.7%) and less frequently in right occipitomastoid sutures (1.3%). This study may guide the investigators dealing with the neurosurgery, orthopedy, radiology, anatomy, and anthropology in their practice. PMID- 26114516 TI - Impact of Injury Mechanisms on Patterns and Management of Facial Fractures. AB - Mechanisms causing facial fractures have evolved over time and may be predictive of the types of injuries sustained. The objective of this study is to examine the impact of mechanisms of injury on the type and management of facial fractures at our Level 1 Trauma Center. The authors performed an Institutional Review Board approved review of our network's trauma registry from 2006 to 2010, documenting age, sex, mechanism, Injury Severity Score, Glasgow Coma Scale, facial fracture patterns (nasal, maxillary/malar, orbital, mandible), and reconstructions. Mechanism rates were compared using a Pearson chi2 test. The database identified 23,318 patients, including 1686 patients with facial fractures and a subset of 1505 patients sustaining 2094 fractures by motor vehicle collision (MVC), fall, or assault. Nasal fractures were the most common injuries sustained by all mechanisms. MVCs were most likely to cause nasal and malar/maxillary fractures (P < 0.01). Falls were the least likely and assaults the most likely to cause mandible fractures (P < 0.001), the most common injury leading to surgical intervention (P < 0.001). Although not statistically significant, fractures sustained in MVCs were the most likely overall to undergo surgical intervention. Age, number of fractures, and alcohol level were statistically significant variables associated with operative management. Age and number of fractures sustained were associated with operative intervention. Although there is a statistically significant correlation between mechanism of injury and type of facial fracture sustained, none of the mechanisms evaluated herein are statistically associated with surgical intervention. Clinical Question/Level of Evidence: Therapeutic, III. PMID- 26114517 TI - Sir William Arbuthnot Lane and His Contributions to Plastic Surgery. AB - Surgical subspecialties were just emerging at the turn of the 20th Century, before this time, general surgeons had to adjust their operative skills to address disorders throughout the body. Sir William Arbuthnot Lane was a British surgeon, whose restless mind led him to wander throughout the field of general surgery and beyond. Although controversial, he advanced in the repair of cleft lip and palate, introduced the "no touch" operative technique, internal fixation of fractures, and is credited as the first surgeon to perform open massage of the heart. During The Great War, he established the British Plastic Surgery unit at Sidcup and delegated the care of facial and jaw injuries to young Major Harold Gillies. Lane later founded The New Health Society, an organization that stimulated the natural food movement. Sadly, in his latter years Lane's thinking drifted further away from with the times and his professional credibility waned. Nevertheless, Lane's variegated life is of sufficient interest to deserve reassessment. PMID- 26114518 TI - Roles of Polycaprolactone Membrane on Guided Bone Formation in High-Speed Distraction of Experimental Design Cranium. AB - BACKGROUND: The aim of this research was to investigate whether covering of the distracted cranial bone segment with a polycaprolactone (PCL) membrane (guided bone formation) would accelerate the process of osteogenesis in high-speed distraction of adult rabbit. METHODS: Eighteen 24-weeks old, 3.0 to 3.5 kg, male New Zealand rabbits underwent routine gradual cranium distraction (group 1), distraction at high speed without the membrane (group 2), and distraction at high speed with a PCL membrane covering the cranium at the distraction gap (group 3). Five days after the cranial osteotomy, the distraction process was initiated at 3 mm per day (1.5 mm twice a day) in group 2 and group 3, and 1 mm per day (0.5 mm twice a day) in group 1 until 10 mm of length gain was achieved. At the consolidation 4 and 6 weeks, the bone mineral density was analyzed by a computerized tomography imaging protocol. The bone formation ratio of each group was compared with Hematoxylin and Eosin stain. The collagen formation of each group was analyzed by Massons' trichrome staining. RESULTS: Radiographic imaging and quantitative data indicated a significant increase in bone mineral density in group 1 and group 3 compared with group 2. Bone formation ratio in histologic analysis showed an increase in group 1 and group 3. Collagen synthesis in group 2 was significantly increased in distraction gap. In group 3, collagen fibers were significantly decreased underneath the PCL membrane. CONCLUSIONS: Polycaprolactone membrane covering the bone distraction gap provides an environment for faster bone formation in high-speed distraction. PMID- 26114519 TI - Communications Between the Trigeminal Nerve and the Facial Nerve in the Face: A Systematic Review. AB - The aim of the article is to elucidate the communications between the trigeminal nerve and facial nerve in the face. In a PubMed search, 328 studies were found using the terms 'trigeminal nerve, facial nerve, and communication.' The abstracts were read and 39 full-text articles were reviewed. Among them, 11 articles were analyzed. In the studies using dissection, the maxillary branch (V2) had the highest frequency (95.0% +/- 8.0%) of communication with the facial nerve, followed by the mandibular branch (V3) (76.7% +/- 38.5%). The ophthalmic branch (V1) had the lowest frequency of communication (33.8% +/- 19.5%). In a Sihler stain, all of the maxillary branches and mandibular branches had communications with the facial nerve and 85.7% (12/14 hemifaces) of the ophthalmic branches had communications. The frequency of communications between the trigeminal nerve and facial nerve were significantly higher (P = 0.00, t test) in the studies using a Sihler stain (94.7% +/- 1.1%) than the studies using dissection (76.9 +/- 35.8). The reason for the significantly higher frequency of trigeminal-facial communication in the studies using a Sihler stain is because of the limitation of the Sihler stain itself. This technique cannot differentiate the motor nerves from sensory nerves at the periphery, and a crossover can be misinterpreted as communication near to nerve terminal. PMID- 26114520 TI - Speech and Speech-Related Quality of Life After Late Palate Repair: A Patient's Perspective. AB - Many patients with cleft palate deformities worldwide receive treatment at a later age than is recommended for normal speech to develop. The outcomes after late palate repairs in terms of speech and quality of life (QOL) still remain largely unstudied. In the current study, questionnaires were used to assess the patients' perception of speech and QOL before and after primary palate repair. All of the patients were operated at a cleft center in northeast India and had a cleft palate with a normal lip or with a cleft lip that had been previously repaired. A total of 134 patients (7-35 years) were interviewed preoperatively and 46 patients (7-32 years) were assessed in the postoperative survey. The survey showed that scores based on the speech handicap index, concerning speech and speech-related QOL, did not improve postoperatively. In fact, the questionnaires indicated that the speech became more unpredictable (P < 0.01) and that nasal regurgitation became worse (P < 0.01) for some patients after surgery. A total of 78% of the patients were still satisfied with the surgery and all of the patients reported that their self-confidence had improved after the operation. Thus, the majority of interviewed patients who underwent late primary palate repair were satisfied with the surgery. At the same time, speech and speech-related QOL did not improve according to the speech handicap index-based survey. Speech predictability may even become worse and nasal regurgitation may increase after late palate repair, according to these results. PMID- 26114521 TI - The Supraorbital Keyhole Approach. AB - AIM: The major aim of the present anatomical study was to demonstrate the anatomical structures that can be visualized using the supraorbital keyhole approach, both endoscopically and microscopically, from an eyebrow incision to intracranial structures. Furthermore, it defines an optimal craniotomy for surgery. METHODS: Fine dissection was performed on each side of 5 formalin-fixed adult cadavers according to the surgical procedures of the supraorbital keyhole approach, and each step was documented both endoscopically and microscopically. Furthermore, the distance between the superior temporal line and the supraorbital notch/foramen was measured from the 10 total sides of the 5 cadavers and from the 118 sides of the 59 autopsies. RESULTS: Tumors and aneurysms of the anterior cranial fossa can be visualized during the supraorbital keyhole approach. The average distance between the superior temporal line and the supraorbital notch/foramen was measured. The distance obtained from the autopsies on the 25 females was 31.56 +/- 4.03 mm on the right side and 31.04 +/- 5.40 mm on the left side. The average distance obtained from the autopsies on the 34 males was 34.00 +/- 4.59 mm on the right side and 33.59 +/- 5.41 mm on the left side. There was no statistically significant difference between right and left in the female and male autopsies or between sexes. CONCLUSIONS: This anatomical study showed that structures in the anterior and middle cranial fossa can be reached via the supraorbital keyhole craniotomy approach with minimal brain retraction and adequate exposure and with minimal craniotomy size. PMID- 26114522 TI - Trigeminal Neuralgia: Evaluation of the Relationship Between the Region of Neuralgic Manifestation and the Site of Neurovascular Compression Under Endoscopy. AB - This study aimed to evaluate the relationship among the pain region, branches of trigeminal nerve, and the neurovascular compression (NVC) location. A total of 123 consecutive patients with trigeminal neuralgia (TN) underwent endoscope assisted microvascular decompression according to positive preoperative tomographic angiography. V2 alone was in 51 cases and V3 alone was in 64 cases. The location of NVC was classified into cranial, caudal, medial, or lateral sites. Some patients with multiple regions were recorded as medial + cranial, lateral + cranial, medial + caudal, and lateral + caudal. Twenty-eight (71.8%) of 39 patients with TN (V2) had their NVC at the medial site of the nerve. Twenty seven (64.3%) of 42 patients with TN (V3) had their NVC at the lateral site of the nerve. There was a statistically significant difference (P = 0.0011 < 0.01, chi2 test). Sixteen (69.6%) of 23 patients with TN(V2) had their NVC at the cranial site of the nerve. Thirty-four (69.4%) of 49 patients with TN (V3) had their NVC at the caudal site of the nerve. There was no statistical difference (P = 0.3097 > 0.01). Evaluation of the relationship between the pain region and the NVC location by endoscopic images during microvascular decompression is more accurate. The second branch is mostly distributed in the medial area, and third branch is mainly distributed in the lateral area. PMID- 26114523 TI - High-Energy Traumatic Maxillofacial Injury. AB - High-energy blunt or penetrating impact leads to great variability in facial injury patterns. Although the mechanism, pattern, and distribution of forces vary, the resultant damage to hard and soft tissues requires dedicated planning and execution of debridement and reconstructive procedures. This article evaluates the initial management of patients sustaining high-energy facial impact injuries resulting in one or more comminuted or displaced facial fractures, with accompanying severe facial lacerations and/or soft tissue defects and avulsion injuries. Seventy-three patients met the criteria for high-energy traumatic injuries at Jackson Memorial/University of Miami Medical Center between 2003 and 2013 and are included in this article. Thirty-nine patients sustained one or more gunshot wounds to the face, and 34 patients were involved in high-speed motor vehicle collisions; all patients met our criteria for high-energy trauma. The treatment protocol for these injuries involves meticulous surgical exploration and assessment, aggressive debridement, early definitive reduction/fixation, and reconstruction as necessary. PMID- 26114524 TI - New Pattern of Sutural Synostosis Associated With TWIST Gene Mutation and Saethre Chotzen Syndrome: Peace Sign Synostosis. AB - The authors present a new and unique pattern of sutural fusion "peace sign synostosis" (PSS) characterized by synostosis of the metopic, bicoronal, and sagittal sutures and associated with abnormalities of the TWIST1 gene known to be associated with Saethre-Chotzen syndrome (SCS). To do so, we performed a retrospective review of patients with bicoronal, metopic, and at least partial anterior sagittal synostoses at the Children's Hospital of Philadelphia and Seattle Children's Hospital. Patients' demographics, genetic analysis, perioperative and clinic notes were reviewed. Five patients were identified with PSS and abnormalities of TWIST1 consistent with SCS. One patient, with the longest follow-up of 7 years, underwent 5 intracranial procedures and required a ventriculoperitoneal (VP) shunt. The remaining 4 patients underwent posterior cranial vault distraction as the initial procedure, followed by anterior cranial vault remodeling. Two patients required a VP shunt. To conclude, synostosis of the metopic, bicoronal, and sagittal sutures (PSS) appears to be associated with SCS and produces a characteristic skull morphology that can be readily identified on physical examination. Early data suggest a high rate of reoperation, increased necessity for a VP shunt, and potential complications. Of note, this novel phenotype had not been previously observed at our respective institutions, reported in the literature, or observed in association with TWIST1 abnormalities as described in association with SCS. PMID- 26114525 TI - Assessment of the Facial Soft Tissue Thickness of the Patients Affected by Unilateral Cleft Lip and Palate Using Cone Beam Computed Tomography. AB - AIM: The aim of the study was to evaluate the soft tissue thickness of the patients affected by unilateral cleft lip and palate (UCLP) and to compare the findings with a matched control group without cleft using cone beam computed tomography (CBCT). METHODS: The study sample consisted of 66 patients (31 women and 35 men) divided into 2 groups as UCLP group (34 patients; 23 men and 11 women; 9 right sided and 25 left sided; mean age: 14.11 +/- 3.48 years) and control group (32 patients; 12 men and 20 women; mean age: 15.10 +/- 3.13 years) without any cleft. Angular angle between Nasion-A line and Nasion-B line (ANB), angle between Sella-Nasion line and Gonion-Menton line (SN-MP) and linear (glabella, nasion, rhinion, subnasale, labrale superius, stomion, labrale inferius, labiomentale, pogonion, and gnathion) measurements were done using CBCT. Student t test was performed to compare the variables between the groups. RESULTS: Soft tissue thickness values for men were higher in both groups, except for rhinion and glabella. Subnasale for women (P = 0.000), men (P = 0.006), and total samples (P = 0.000) and the variable of the labrale superius for men (P = 0.047) and total samples (P = 0.040) were found to be statistically significantly thinner in the UCLP group. SN-MP had significant affect on subnasale thickness (R = 15.8; Beta = -0.397; P = 0.001). CONCLUSION: Thickness of the subnasale and the labrale superius were found to be statistically significantly thinner in the UCLP group compared with the controls. PMID- 26114526 TI - Diagnostic Accuracy of Blood Glucose Measurements in Detecting Venous Compromise in Flaps. AB - Due to limitations of the current methods for monitoring flap circulation, newer methods with better diagnostic accuracy are needed. A drop in blood glucose levels within flap is a simple method that can be widely used; however, this method has been examined only in small cohorts. The objective of this study was to determine the diagnostic accuracy of blood glucose measurements within flaps in early detection of venous compromise. We sampled 127 pedicled and free flaps, including replants, performed on patients between 12 and 60 years of age. Within flap blood glucose measurements were performed using pinprick and a blood glucose meter at 0, 6, 12, 24 and 48 hours after operation. Daily examination for clinical signs of venous compromise was used to determine flap viability for up to 7th day after operation. Of the 127 flaps, 76 (60%) were performed on men and the mean age +/- standard deviation of the patients was 35.8 +/- 12.1 years. A cut-off value of 62 mg/dL was determined using a receiver operating characteristic curve. Using this cut-off value, the sensitivity and positive predictive values of within flap blood glucose for determining venous compromise were 90% and 91%, respectively, whereas the specificity and negative predictive values were 78% and 76%, respectively. The overall diagnostic accuracy of within flap blood glucose was 87%. We conclude that blood glucose measurement within flap has acceptable diagnostic accuracy and should be used for early detection of venous compromise. PMID- 26114527 TI - Shared Surgical Decision Making and Youth Resilience Correlates of Satisfaction With Clinical Outcomes. AB - The aim of this study was to identify factors associated with youth satisfaction with surgical procedures performed to address oral cleft or craniofacial conditions (CFCs). It was hypothesized that youth mental health, participation in decision making, perceived consequences of living with a CFC, and coping strategies would be associated with satisfaction with past surgeries. A total of 203 youth between the ages of 11 and 18 years (mean age = 14.5, standard deviation = 2.0, 61% male participants, 78% oral cleft) completed a series of questionnaires measuring depression, self-esteem, participation in decision making, condition severity, negative and positive consequences of having a CFC, coping, and satisfaction with past surgeries. Multiple regression analysis using boot-strapping techniques found that youth participation in decision making, youth perception of positive consequences of having a CFC, and coping accounted for 32% of the variance in satisfaction with past surgeries (P < 0.001). Youth age, sex, and assessment of condition severity were not significantly associated with satisfaction with surgical outcome. Depression, self-esteem, and negative consequences of having a CFC were not associated with satisfaction with past surgeries. Youth should be actively involved in the decision for craniofacial surgery. Youth who were more satisfied with their surgical outcomes also viewed themselves as having gained from the experience of living with a CFC. They felt that having a CFC made them stronger people and they believed that they were more accepting of others and more in touch with others' feelings because of what they had been through. PMID- 26114528 TI - Occurrence of Pneumatic Cavities Surrounding the Temporomandibular Joint. AB - OBJECTIVES: The aim of this study was to investigate the occurrence, the location, and the characteristics of the pneumatic cavities (PCAs) surrounding the temporomandibular joint (TMJ) by using cone-beam computed tomography. METHODS: A retrospective study was performed by using the three-dimensional data archives from Faculty of Dentistry, Bezmialem University, Istanbul, Turkey. The age and sex had been previously recorded for all of the patients. The location and the morphologic characteristics of the PCAs were documented. RESULTS: Pneumatic cavities were found in 18 patients (15%): 11 women (61%) and 7 men (39%). Eleven (57.9%) of the patients showed unilocular pneumatic air cells and 8 (42.1%) of them showed multilocular ones. The unilateral-to-bilateral ratio was 2.3:1. The age range was 8 to 76 years (mean 29.5 +/- 21.86 years), and the female-to-male ratio was 1.57:1. CONCLUSION: Cone-beam computed tomography provides images without superimposition that allows accurate and easy evaluation of the PCAs surrounding the TMJ. Our results suggest that the occurrence of PCAs is higher than has been previously reported; therefore, it is recommended for clinicians who are planning to perform TMJ surgery to think about the PCAs to understand the exact morphology for avoiding intraoperative complications. PMID- 26114529 TI - A Hypothesis for the Pathologic Mechanism of Idiopathic Exophthalmos Based on Computed Tomographic Evaluations. AB - The causes of idiopathic exophthalmos were still unknown. We used computed tomography to compare the orbital structures of patients with idiopathic exophthalmos and those of a healthy Japanese population. A total of 18 orbits (ranged 17-52 years) in idiopathic exophthalmos and 334 normal orbits (ranged 17 59 years) were included. On computed tomography, the eyeball and orbit sizes, lateral wall thickness and length, perpendicular distance from the interzygomatic line to the medial orbital rim, and the nasal cavity width were measured. No significant differences in eyeball or orbit sizes were found between the idiopathic exophthalmos and control groups (P > 0.05). In contrast, the mean lateral wall thickness of the idiopathic exophthalmos group was significantly thicker than that of the control group (P < 0.01). The lateral wall length was shorter with significant difference (P < 0.05). The perpendicular distance and the width of the nasal cavity in the idiopathic exophthalmos group were longer with significant difference (P < 0.05). The cause of idiopathic exophthalmos is compression of orbital contents by the medial wall expansion. The force of expansion of medial wall also influences the zygoma according to Wolff law. PMID- 26114530 TI - Severe Pediatric Midface Trauma: A Prospective Study of Growth and Development. AB - Severe pediatric facial trauma is characterized by multiple, comminuted, and unstable fractures, frequently necessitating operative intervention. Disruption of facial growth is a primary concern in the long-term sequelae of such conditions. Children suffering from midface fractures were followed over time in a long-term growth and development study. Lateral cephalograms at longest-term follow-up were traced, digitized, and averaged. Seven landmarks of the midface (A point, ANS, orbitale, bridge of nose, distal U6, upper lip, stomion superius) were identified for comparative measurements with age and sex-matched superimposed Bolton norms as controls. Differences in x and y axes between test and control metrics were measured. Clinical significance was defined as a 2-mm discrepancy from the norm. Statistical significance for each patient was determined using t tests of the x and y arrays of patient values versus normal controls. Seven patients met the inclusion criteria with mean age of 8.9 years at the time of injury. Mean cephalometric follow-up was 4.6 years (range 2-10 years). Six out of 7 patients (86%) showed clinically significant impairment in growth in horizontal (29%), vertical (29%), or both planes (29%). T Tests confirmed statistical significance (P <= 0.05) for all clinically significant differences. Mean deficiency in growth for all landmarks was 3.7 mm (range -4.0 to 13.7 mm) in the x axis and 2.9 mm (range -1.1 to 8.8 mm) in the y axis. Severe pediatric midface trauma often results in compromised bone growth and permanent facial deformity. New methodologies of management that better allow for growth are needed. PMID- 26114531 TI - Cyst Formation Following Rhinoplasty and Reconstruction With Diced Conchal Cartilage Wrapped in Mastoid Fascia Following Excision. PMID- 26114532 TI - The Effect of Subcutaneous Platelet-Rich Plasma Injection on Viability of Auricular Cartilage Grafts. AB - INTRODUCTION: Although cartilage grafts are frequently used for structural integrity and volume restoration, one of the main concerns dealing with cartilage grafting is gradual volume loss and unpredictable viability rates of cartilage grafts. Platelet-rich plasma (PRP) is a well known platelet concentrate reported to enhance cartilage repair and stimulates chondrocyte proliferation and matrix biosynthesis. The purpose of the current study was to investigate the effect of subcutaneous PRP injection on improving the viability of cartilage grafts. MATERIALS AND METHODS: Six circular cartilage grafts were obtained from auricular cartilages of 6 New Zealand white rabbits. Cartilage grafts were prepared in 3 forms: block, crushed, and crushed/wrapped with Surgicel (Surgical, Ethicon, Somerville, NJ). Grafts were placed to 6 dorsal subcutaneous pockets and pockets were closed. Autologous PRP was prepared and injected subcutaneously into the pockets of experiment groups. At the end of 8 weeks, cartilage grafts were removed. Cartilage mass reduction rates were measured. Resorption rates of cartilage grafts and formation of fibroelastic and bone tissue were microscopically evaluated. RESULTS: All of the cartilage grafts lost significant weight. Viability scores of block cartilages were higher than crushed cartilages. Although less weight loss rates and higher histopathologic scores were obtained in subcutaneously PRP injected cartilage graft groups, these results were not statistically significant. CONCLUSIONS: Although our study gives a new insight about increasing the viability of cartilage grafts, the subcutaneous PRP injection did not result in improving the viability of cartilage grafts in this experimental design. PMID- 26114533 TI - Deep Temporal Fascia Coverage of the Loading Weight in Paralytic Lagopthalmos Patients. AB - INTRODUCTION: Use of a weight for lagopthalmos secondary to facial nerve paralysis is the standard technique for achieving effective eyelid closure. However, because of thin and mobile skin of the eyelid and closely opposed implant, there is increased risk of complications such as implant visibility, contour deformity, and implant extrusion. SURGICAL TECHNIQUE: The authors describe a surgical technique involving coverage of the implanted weight with contralateral deep temporal fascia. The deep temporal fascia serves as a hammock to give an interventional barrier to prevent dehiscence of the pocket and extrusion of the ocular implant. It also provides camouflage to the irregular borders of the gold weight. RESULTS AND CONCLUSIONS: Autologous coverage of gold weight with deep temporal fascia provides an effective solution to commonly associated complications with the gold weights. The use of contralateral temporal fascia preserves the ipsilateral temporalis muscle for future facial nerve reconstruction. PMID- 26114534 TI - Are Mesenchymal Stem Cells Implanted in Lip Defect Capable of Returning Orbicularis Oris Muscle Function? AB - INTRODUCTION: This study aimed to evaluate the amount of orbicularis oris muscle formation and function after using scaffold-free cells and mesenchymal stem cells scaffold in repaired cleft lip of rats. METHODS: Forty male Wistar rats were used. A triangular cut (7 * 7 * 4 mm) was made on the upper lip of 30 rats and then divided into 3 equal groups. In the first group (control), the defected cuts were closed by routine surgical procedures. The second group consisted of cell scaffold and the third scaffold-free cells (5 * 5 * 3) in the area of the incision.Two months after restoration, muscle electromyography activity was examined alongside 10 normal rats and tissue samples were histologically examined. Data were analyzed statistically by SPSS software and ANOVA and the Kruskal-Wallis test. The significance level was considered at P < 0.05. RESULTS: Electromyography activity in second and third groups was not significantly different from each other and with normal muscle. The control group had, however, higher activity than normal muscle (P < 0.001). The amount of newly formed muscle tissue in the scaffold group had a clear statistical difference with the cell scaffold (P = 0.018) and control group (P < 0.001). Furthermore, the inflammatory reaction showed a significant statistical difference in the control and scaffold group (P = 0.001) and the scaffold and cell-scaffold groups (P = 0.007). There was no significant difference in the number of formed fibroblast cells and collagen tissue in the area between the 3 groups. CONCLUSIONS: The results of this study show that extracellular matrix scaffold can reduce tension in the repaired cleft lip area by increasing muscle formation and decreasing scar tissue contraction, confirming the benefits of this type of scaffold. PMID- 26114535 TI - Tips and Tricks in Transoral Robotic Surgery for Challenging Vascular Tumors. AB - Surgical removal of head-neck vascular neoplasms may have severe complications, although surgery remains a very important treatment modality. One of the most important aspects is to avoid the rupture of the tumor's capsule and to minimize functional complications, especially in the excision of benign tumors. The transoral robotic surgery allows removing lesions in challenging anatomical areas. Furthermore, the current robotic instrumentation does not allow a fine dissection of the structures and capsule rupture is a potential event. Here, the authors describe a minimally invasive technique using transoral robotic surgery for removal of vascular tumors in head-neck. Particular attention was given to the description of the diagnostic work up, the preoperative assessment and the surgical steps. No complications were encountered postoperatively. Transoral robotic surgery for vascular tumors appears to be a safe and feasible technique with minimal complications. PMID- 26114536 TI - Management of Severe Microstomia in a Ten-Week-Old Infant. AB - Microstomia is rarely seen in pediatric patients, but usually results from burns, trauma, or caustic ingestions. There have been multiple studies reporting various techniques for oral commissure reconstruction, but few reports in infants. The authors present another modification of previous techniques of microstomia repair performed in a 10-week-old infant using multiple z-plasties and bilateral mucosal rhomboid flaps. PMID- 26114537 TI - Chin Wing Osteotomy for Bilateral Goldenhar Syndrome Treated by "Chin Wing Mentoplasty": Aesthetic, Functional, and Histological Considerations. AB - Various treatment strategies have been proposed to perform the aesthetic surgical correction of asymmetric deformities of the mandible. These techniques range from relatively simple to complex procedures including bimaxillary surgery associated with complex mandibular osteotomies. The authors describe a patient with grade III Goldenhar syndrome, treated by a "chin wing" mentoplasty as described by Triaca. These situations are classically treated with a bilateral sagittal splint osteotomy (BSSO) in combination with mentoplasty. However, because of a good occlusion with Angle's class I relation, slight imbalance of the occlusal plane with good function of the mouth opening, the patient refused to be treated with a BSSO, hence, a chin wing mentoplasty was performed. Size and stability of bone regeneration were evaluated by histological examination and dynamic-volume computed tomography (CT). Mature bone in the grafted areas was detected by histology and CT scan with stable results and a significant increase of facial aesthetics 1 year after surgery. The authors also demonstrated that the chin wing technique provided a little but significant breathing improvement as detected on CT scans and lateral X-ray cephalograms by measuring the breathing area. Chin wing mentoplasty is a moderately invasive technique that is able to improve the aesthetics of the face and patient breathing. PMID- 26114538 TI - Adipose-Derived Stem Cells Improve Survival of Random Pattern Cutaneous Flaps in Radiation Damaged Skin. AB - BACKGROUND: Tissue ischemia and necrosis following surgery after radiotherapy on the skin and subcutaneous tissue are well known to all reconstructive surgeons. Nevertheless, there has been no report so far on local effects of adipose-derived stem cells (ADSCs) on random flap survival elevated in an irradiated rat dorsum. In this experimental study, we aimed to identify the effect of adipose tissue derived stem cell injection on random flap survival in irradiated tissues. METHODS: Adipose-derived stem cells were isolated from the groin region of Sprague-Dawley rats and expanded ex vivo for 3 passages. Animals were divided into 2: irradiated and nonirradiated and then again into ADSC injected and noninjected groups altogether 4 groups. After elevation of caudally based dorsal random skin flaps (10 cm long and 3 cm wide), Green fluorescent protein labeled ADSCs were then injected to the base of the pedicle. Radiotherapy was 20 Gy single dose applied during 8 weeks before surgery. At postoperative day 7, flap viability measurement and tissue harvest for histologic and immunocytochemical assessment were performed in all groups. RESULTS: We have observed increased flap viability in ADSCs injected irradiated group compared with control radiation group with small but not statistically significantly increase in vessel count per field. Mean survival rate of the flaps in groups A, B, C, and D were 40.46%, 60.07%, 40.90%, and 56.13%, respectively. There was a statistically significant vessel count difference between group B and group A and also with group D (P < 0.001). CONCLUSIONS: These findings suggest that ADSCs have a potential for enhancing the blood supply of random pattern skin flaps after radiation injury. This mechanism might be both neovascularization and vasodilation along with endothelial repair. Further studies are needed. PMID- 26114539 TI - The Microsurgical Anatomy of the Modified Presigmoid Trans-Partial Bony Labyrinth Approach. AB - OBJECTIVE: To investigate the surgical techniques of the modified presigmoid trans-partial bony labyrinth approach and the advantages in the exposure of the petroclival region and in the treatment of lesions in this area. METHODS: Between April and October of 2012, a study on modification of the surgical approach was performed on 15 cadaveric heads. On the basis of the traditional presigmoid approach, semicircular canals, and the petrous apex were partially resected. The detailed conditions of the exposure of important structures of the petroclival region were recorded. RESULTS: This approach provided a large operational space from the petroclival region to the posterior cavernous sinus. The range of presigmoid exposure (horizontal direction) was (19.41 +/- 1.58) mm, the exposure range of the inferior temporal (vertical direction) was (14.18 +/- 1.88) mm, the maximum exposure angle of the slope center depression was (60.54 degrees +/- 6.93 degrees ), and the depth of operation was (55.87 +/- 4.34) mm. The vertebral-basilar artery, anterior inferior cerebellar artery, superior cerebellar artery, ipsilateral III-X cranial nerves, contralateral VI cranial nerve, Meckel cave, and posterior cavernous sinus were well exposed. CONCLUSION: The modified presigmoid trans-partial bony labyrinth approach was able to achieve excellent exposure of deep surfaces of the petroclival region and the posterior part of the cavernous sinus and showed advantages including a large range of exposure, multiple axes of visualization, preservation of hearing and facial nerve function, and early devascularization of tumors. PMID- 26114541 TI - Use of Postoperative Palatal Obturator After Total Palatal Reconstruction With Radial Forearm Fasciocutaneous Free Flap. AB - A 67-year-old-male patient visited our hospital for a mass on the soft palate of approximately 5.0 * 6.0 cm in size. He was diagnosed with adenoid cystic carcinoma and reconstruction after total palate resection was planned. After ablative surgery, a radial forearm free flap procedure was successfully performed to cover the hard and soft palates. However, wound disruption occurred twice during the postoperative period. When a palate defect is reconstructed using a soft tissue free flap, flap drooping by gravitation and the flap itself can generate irregularity in the lower contour of the palate and, in the long-term, insufficiencies of velopharyngeal function, speech, and mastication. To complement such functional and aesthetic problems caused by flap drooping, conventional prosthetics and new operative techniques have been discussed. However, overcoming wound disruption caused by flap drooping in the acute postoperative period has not been discussed. In this case, the temporary use of a palatal obturator during the postoperative period was beneficial after soft tissue reconstruction of the palate. PMID- 26114543 TI - A task control theory of mirror-touch synesthesia. AB - Ward and Banissy's illuminating discussion of mirror-touch synesthesia (MTS) encourages research testing two alternatives to Threshold Theory: Their own Self Other Theory, and "Task Control Theory". MTS may be due to abnormal mirror activity plus a domain-general, rather than a specifically social, impairment in the ability to privilege processing of task-relevant over task-irrelevant information. PMID- 26114545 TI - Phylogeny and synonymous codon usage pattern of Papaya ringspot virus coat protein gene in the sub-Himalayan region of north-east India. AB - Sub-Himalayan West Bengal is favorable for the production of several fruits and vegetables. Papaya is one of the common plants cultivated in the area. Most of the papaya plants of the area are susceptible to Papaya ringspot virus (PRSV). Coat protein genes of 6 PRSV isolates of the area were sequenced following RT PCR. Phylogenetic study of the PRSV isolates showed about 80%-90% similarity with Cuban isolates. The codon usage pattern of our isolates was also analyzed, along with several other isolates. PRSV isolates of our study showed a preference for 8 putative optimal codons. Correspondence analysis of the genes of different isolates along the first 2 major axes were done, as the first 2 axes contributed more in shaping codon usage pattern. In the phylogenetic tree constructed by the neighbour-joining method, our isolates clustered together with the east Indian, north Indian, and Bangladeshi isolates. The diversity and codon usage pattern of the PRSV isolates of different regions were studied, and it was observed that the codon usage pattern of PRSV isolates is probably influenced by translational selection along with mutational bias. PMID- 26114544 TI - Mouse Tafazzin Is Required for Male Germ Cell Meiosis and Spermatogenesis. AB - Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These symptoms are the most significant clinical consequences of a disease, which is increasingly recognised to have a variable presentation. Mutation in the Taz gene in Xq28 is thought to be responsible for the condition, by altering mitochondrial lipid content and mitochondrial function. Male chimeras carrying a targeted mutation of Taz on their X-chromosome were infertile. Testes from the Taz knockout chimeras were smaller than their control counterparts and this was associated with a disruption of the progression of spermatocytes through meiosis to spermiogenesis. Taz knockout ES cells also showed a defect when differentiated to germ cells in vitro. Mutant spermatocytes failed to progress past the pachytene stage of meiosis and had higher levels of DNA double strand damage and increased levels of endogenous retrotransposon activity. Altogether these data revealed a novel role for Taz in helping to maintain genome integrity in meiosis and facilitating germ cell differentiation. We have unravelled a novel function for the Taz protein, which should contribute to an understanding of how a disruption of the Taz gene results in the complex symptoms underlying Barth Syndrome. PMID- 26114546 TI - Economic Assessment of FMDv Releases from the National Bio and Agro Defense Facility. AB - This study evaluates the economic consequences of hypothetical foot-and-mouth disease releases from the future National Bio and Agro Defense Facility in Manhattan, Kansas. Using an economic framework that estimates the impacts to agricultural firms and consumers, quantifies costs to non-agricultural activities in the epidemiologically impacted region, and assesses costs of response to the government, we find the distribution of economic impacts to be very significant. Furthermore, agricultural firms and consumers bear most of the impacts followed by the government and the regional non-agricultural firms. PMID- 26114547 TI - Effective Delivery of Endogenous Antioxidants Ameliorates Diabetic Nephropathy. AB - BACKGROUND: Diabetic nephropathy (DN) is thought to be partially due to the injury of renal cells and the renal micro-environment by free radicals. Free radial scavenging agents that inhibit free radical damage may well prevent the development of underlying conditions such as mesangial expansion (by inhibiting extracellular matrix expression) in these patients. METHODS: Using techniques for intra-cellular delivery of peptides, we made metallothionein (MT) and superoxide dismutase (SOD), potent endogenous antioxidants, readily transducible into cell membrane and tested their protective effect against the development of DN in OLETF rats. Herein, we study antioxidant peptides for their ability to prevent oxidative damage to primary rat mesangial cells (MCs), which are important constituents of renal glomeruli. RESULTS: Intraperitoneal administration of these antioxidants resulted in delivery to the kidney and decreased ROS and the expression of downstream signals in renal cells and postponed the usual progression to DN. In in vitro experiments, MT and SOD were efficiently transferred to MCs, and the increased removal of ROS by MT and SOD was proportional to the degree of scavenging enzymes delivered. MT and SOD decreased three major oxidative injuries (hyperglycemia, AGE and ROS exposure) and also injuries directly mediated by angiotensin II in MCs while changing downstream signal transduction. CONCLUSIONS: The protective effects of MT and SOD for the progression of DN in experimental animals may be associated with the scavenging of ROS by MT and SOD and correlated changes in signal transduction downstream. Concomitant administration of these antioxidant peptides may prove to be a new approach for the prevention and therapy of DN. PMID- 26114548 TI - A Comparative Transcriptome Analysis between Wild and Albino Yellow Catfish (Pelteobagrus fulvidraco). AB - Body colours are important and striking features for individual survival and reproductive success, in particular in vertebrates where mating behaviour and mate preference may be strongly influenced by non-normal phenotypes. Pigmentation disorders may be generated by disruption of one or many independent genes as well as by environmental factors. The first discovery of albino yellow catfish (Pelteobagrus fulvidraco Richardson) with golden skin colour from fish farms in China provides us valuable material to study the molecular mechanism underlying the abnormalities of pigmentation. In this study, transcriptome sequencing of fin tissues corresponding to the distinct body colours, wild type and mutant albino yellow catfish, were performed using Illumina sequencing technology. Based on next-generation sequencing technology and de novo assembly, we generated a transcriptome of P. fulvidraco. A number of genes differentially expressed between the wild types and albinos were identified, suggesting their contribution to the different phenotypes and fitness. However, non-synonymous mutations result from single nucleotide substitutions residing in coding regions may not contribute to such differences. Based on the high-throughput expression data generated for the two different types of P. fulvidraco, we found that alterations of expression pattern may be more common than non-synonymous mutations. The transcriptome of P. fulvidraco will be an invaluable resource for subsequent comparative genomics and evolutionary analyses of this economically important fish. PMID- 26114550 TI - Therapeutic potential of abalone and status of bioactive molecules: A comprehensive review. AB - Marine organisms are increasingly being investigated as sources of bioactive molecules with therapeutic applications as nutraceuticals and pharmaceuticals. In particular, nutraceuticals are gaining popularity worldwide owing to their therapeutic potential and incorporation in functional foods and dietary supplements. Abalone, a marine gastropod, contains a variety of bioactive compounds with anti-oxidant, anti-thrombotic, anti-inflammatory, anti-microbial, and anti-cancer activities. For thousands of years different cultures have used abalone as a traditional functional food believing consumption provides health benefits. Abalone meat is one of the most precious commodities in Asian markets where it is considered a culinary delicacy. Recent research has revealed that abalone is composed of many vital moieties like polysaccharides, proteins, and fatty acids that provide health benefits beyond basic nutrition. A review of past and present research is presented with relevance to the therapeutic potential of bioactive molecules from abalone. PMID- 26114549 TI - Transcriptome-based identification of new anti-inflammatory and vasodilating properties of the n-3 fatty acid docosahexaenoic acid in vascular endothelial cell under proinflammatory conditions [corrected]. AB - SCOPE: High intakes of n-3 fatty acids exert anti-inflammatory effects and cardiovascular protection, but the underlying molecular basis is incompletely defined. By genome-wide analysis we searched for novel effects of docosahexaenoic acid (DHA) on gene expression and pathways in human vascular endothelium under pro-inflammatory conditions. METHODS AND RESULTS: Human umbilical vein endothelial cells were treated with DHA and then stimulated with interleukin(IL) 1beta. Total RNA was extracted, and gene expression examined by DNA microarray. DHA alone altered the expression of 188 genes, decreasing 92 and increasing 96. IL-1beta changed the expression of 2031 genes, decreasing 997 and increasing 1034. Treatment with DHA before stimulation significantly affected the expression of 116 IL-1beta-deregulated genes, counter-regulating the expression of 55 genes among those decreased and of 61 among those increased. Functional and network analyses identified immunological, inflammatory and metabolic pathways as the most affected. Newly identified DHA-regulated genes are involved in stemness, cellular growth, cardiovascular system function and cancer, and included cytochrome p450 4F2(CYP4F2), transforming growth factor(TGF)-beta2, Cluster of Differentiation (CD)47, caspase recruitment domain(CARD)11 and phosphodiesterase(PDE)5alpha. CONCLUSIONS: Endothelial exposure to DHA regulates novel genes and related pathways. Such unbiased identification should increase our understanding of mechanisms by which n-3 fatty acids affect human diseases. PMID- 26114551 TI - The Role of MDR-Acinetobacter baumannii in Orthopedic Surgical Site Infections. AB - BACKGROUND: Gram-positive microorganisms were the main causative organisms of orthopedic surgical site infections (SSI); however the rising incidence of multiple drug resistant Acinetobacter baumannii (MDR-AB) infections in orthopedic operations causes a great concern because of their limited array of therapeutic options. OBJECTIVE: Our objective was to remark the changing microbiology in orthopedic SSI and to evaluate the MDR CHROMagar Acinetobacter media for screening of MDR-AB. METHODS: Aspirated pus samples were collected from infected wounds of 100 patients in the orthopedics unit of El-Helal Hospital, samples were cultured on conventional media and MDR CHROMagar Acinetobacter media, the reveled MDR-AB colonies were subjected to polymerase chain reaction (PCR) to detect blaOXA-51 like gene. RESULTS: Out of 100 infected wounds SSI cases represented 90/100 (90%) according to CDC 2013 definitions. Staphylococcus aureus was the dominant organism 40/90 (44.4%) (P value 0.038), all S. aureus isolates were methicillin-resistant Staphylococcus aureus (MRSA), followed by Klebsiella pneumoniae 22/90 (24.44%) and Acinetobacter 15/90 (16.67%). Implant was highly associated with SSI cases 80/90 (89%). Also, prolonged hospital stay>7 d was significantly associated with SSI 69/90 (77%) (p=0.001). CONCLUSION: Staphylococcus aureus was the main causative organism of orthopedic SSI (44.4%), whereas A. baumannii represented only (16.67%) of the causative organisms. MDR Acinetobacter CHROMagar reduced the turnaround time for screening of MDR-AB. PMID- 26114552 TI - Choosing the Most Effective Pattern Classification Model under Learning-Time Constraint. AB - Nowadays, large datasets are common and demand faster and more effective pattern analysis techniques. However, methodologies to compare classifiers usually do not take into account the learning-time constraints required by applications. This work presents a methodology to compare classifiers with respect to their ability to learn from classification errors on a large learning set, within a given time limit. Faster techniques may acquire more training samples, but only when they are more effective will they achieve higher performance on unseen testing sets. We demonstrate this result using several techniques, multiple datasets, and typical learning-time limits required by applications. PMID- 26114553 TI - Development of novel core-shell dual-mesoporous silica nanoparticles for the production of high bioavailable controlled-release fenofibrate tablets. AB - Novel core-shell dual-mesoporous silica nanoparticles (DMSN) were successfully prepared as a carrier in order to improve the dissolution of fenofibrate and obtain an oral highly bioavailable controlled-release drug delivery system using the osmotic pump technology. Fenofibrate was loaded into DMSN by an adsorption method. The solid state properties of fenofibrate in DMSN, before and after drug loading, were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption/desorption analysis (BET), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). In vitro release tests showed that DMSN increased the dissolution rate of fenofibrate and produced zero-order release in push-pull osmotic pump tablets (OPT). The relative bioavailability of OPT was 186.9% in comparison with the commercial reference product. In summary, osmotic pump technology in combination with solid dispersion technology involving nanometer materials is a promising way for achieving the oral delivery of poorly water-soluble drugs. PMID- 26114554 TI - Formulation, physicochemical characterization and in-vivo evaluation of ion sensitive metformin loaded-biopolymeric beads. AB - The demand on the controlled release of short acting antidiabetic drug, metformin (MT), has been increased dramatically. Thus, boosting the development of new sustained release formulations with contents of multi-micro-scaled particles. This paved the way for the preparation of MT-loaded Gellan gum (GG) microbeads through inotropic gelation technique. The prepared beads were characterized for the following parameters; yield and loading efficiency particle size, particles morphology and topography, swelling behavior, and in-vitro release studies. In view of any possible interactions, differential scanning calorimetry and infrared spectroscopy were performed. As an ultimate evaluation, the relative bioavailability of the sustained release beads was studied in healthy volunteers after oral administration in a fasted state compared to commercially available immediate and extended release tablets using a new validated HPTLC method for MT assay in urine. Results obtained revealed that the formulated Gellan beads were spherical in shape with less smooth surface in the micron range with high yield and entrapment efficiency. In-vitro release studies of the prepared beads were achieved up to 8 h. The prolonged release of MT can be explained through various factors among them; the swelling of the biopolymer and the ionic interaction between the drug and the GG. After oral administration, the AUC(0-24), t(1/2) and t(max) of the prepared beads were of 246.74 +/- 26.81 mg, 11.84 +/- 2.79 and 7.17 +/- 1.75 h, respectively, demonstrating its bioequivalence to the marketed products. In conclusion, the formulated GG microbeads exhibit potentials as an oral sustained release MT system. PMID- 26114555 TI - Varicella-zoster virus encephalomyelitis with a prominent demyelinating component. AB - The histopathologic presentation of varicella-zoster virus (VZV) infection of the central nervous system is varied and is not well understood. Here we report a case of VZV encephalomyelitis with prominent demyelinating pathology in a patient with a history of follicular lymphoma treated with allogeneic stem cell transplantation. The patient presented with waxing and waning bilateral limb weakness and mental status changes. MRI showed leptomeningeal, peripheral spinal cord and periventricular cerebral white matter lesions in the brain, and polymerase chain reaction on cerebrospinal fluid detected VZV DNA. The patient expired from developing atrial fibrillation that rapidly progressed to ventricular fibrillation 10 days after admission to our hospital. Autopsy revealed macrophage-rich areas of demyelination in the spinal cord and cerebrum with relative preservation of axons associated with inclusion bodies and positive immunostaining for VZV. This case represents a rare example of VZV encephalomyelitis presenting with a predominantly demyelinating, "multiple sclerosis-like" pathology. The clinical and histopathologic findings and relevant literature are presented and discussed. PMID- 26114557 TI - A Practical Torque Estimation Method for Interior Permanent Magnet Synchronous Machine in Electric Vehicles. AB - The torque output accuracy of the IPMSM in electric vehicles using a state of the art MTPA strategy highly depends on the accuracy of machine parameters, thus, a torque estimation method is necessary for the safety of the vehicle. In this paper, a torque estimation method based on flux estimator with a modified low pass filter is presented. Moreover, by taking into account the non-ideal characteristic of the inverter, the torque estimation accuracy is improved significantly. The effectiveness of the proposed method is demonstrated through MATLAB/Simulink simulation and experiment. PMID- 26114556 TI - Barriers and Potential Improvements for Needle and Syringe Exchange Programs (NSPs) in China: A Qualitative Study from Perspectives of Both Health and Public Security Sectors. AB - This study explores the acceptability, the barriers to the implementation of needle and syringe exchange programs (NSPs) and the potential improvement strategies in China from the perspectives of governmental health and public security officials. Purposive sampling was used for recruitment of participants who had been involved in NSPs implementation. Semi-Structured individual interviews were conducted in Mandarin to address three aspects of NSPs: (1) participants' attitudes towards NSPs, (2) participants' opinions on the effectiveness and barriers of NSPs, and (3) suggestions for improving the program. Content analysis was used to analyse the translated interview data. A total of 68 participants from 12 Hunan counties were interviewed (34 from each of the Bureau of Health and the Narcotic Division). Both groups recognised the importance and effectiveness of NSPs in HIV prevention, but public security officials regarded NSPs as a temporary intervention in place of punitive measures. Most health officials (32/34) regarded the main barriers to its implementation as administrative and structural, whereas participants from Narcotics Division (n=24) questioned the legitimacy of NSPs and concerned about the poor management of drug users' risk behaviours. Close cooperation between the health and public security sectors, engagement of the drug user community and an enabling policy environment were reportedly to be critical for potential improvements of NSPs in China. Misconceptions about NSPs encourage drug users' addictive behaviour, and an unclear leadership and insufficient support de motivate the participants from the Bureau of Health and the Narcotics Division to actively support the program implementation. PMID- 26114559 TI - [Hemi-prosthesis in femoral neck Fracture in the Elderly--OP video and our results]. AB - BACKGROUND: In geriatric patients with Pauwels II and III type femoral neck fractures, endoprosthesis is the therapy of choice. We want to demonstrate the operation technique of implantation of a hemiprosthesis (dual head prosthesis) by video in an 87-year-old female patient. In addition, we analyse the long-term results after surgery more than one year after endoprosthesis in patients with femoral neck fractures. METHOD: From 2007 to 2010, 219 public health insurance (AOK) patients with displaced femoral neck fractures were treated surgically at our hospital. This number of included patients puts us in the 97th percentile of all hospitals in Germany. Because the patients were publicly insured, all health information was available including completely retrospective post-hospital discharge as well as inpatient course and one-year mortality. RESULTS: There were 77 % female and 23 % male patients in the study with an average age of 83.5 years. In addition to the femoral neck injury, 19 % of the patients had an accompanying PCCL of 3, and 44 % had a PCCL of 4. 16 % suffered from heart failure, 23 % from diabetes, and 19 % from renal insufficiency. Time to surgery averaged one day post-injury. A dual head prosthesis (hemiprosthesis) was implanted in 81.4 % of cases, and a total joint prosthesis in 18.6 %. Average operative time skin to skin was 53 minutes. Average inpatient stay was 13 days. 71 % of patients could ambulate independently on discharge. Of the remaining patients, two-thirds were already not ambulating independently prior to the fracture. Hospital mortality averaged 6 % (national average 8.1 %), and 30-day and 90-day mortality rates were 6 % and 16.3 %. Within one year, 22.2 % of patients had died (national average 26.8 %), with a natural mortality probability of 7.1 % for an age of 83.5 years. 11 patients were re-admitted, for contralateral prosthetic implantation (n = 6) or revision after periprosthetic fracture (n = 4). 54.6 % of patients were admitted to hospital during the year for other diseases (national average 53.8 %). CONCLUSION: Endoprosthesis placement for displaced femoral neck fractures is a common, safe procedure. However, patients are old and have comorbidities. Despite recent decreases in hospital mortality, the risk of death remains more than twice as high within one year than that for uninjured patients of the same age. PMID- 26114560 TI - [Editorial for the Journal of Orthopaedics and Traumatology]. PMID- 26114561 TI - [Subtotal Segment Resection, Augmenting Angle-Stable Plate Osteosynthesis and Allogenic Bone Graft as Treatment Option for Juxtacortical Osteosarcoma in the Knee Region]. AB - Juxtacortical osteosarcomas are a group of rare primary bone tumours. They differ from medullary osteosarcomas in their anatomic location (outside of the corticalis), low metastasis rate and better prognosis. The only evidence-based treatment of juxtacortical osteosarcomas is the wide surgical resection. In this technical report we will introduce a new surgical technique, including the subtotal resection of the tumour-bearing bone segment, defect reconstruction by means of an augmenting fixed-angle plate osteosynthesis and homologous cancellous bone graft. If necessary, a subsequent plastic coverage of the soft tissue defect was performed. The technique will be presented by means of three illustrated cases of young patients with juxtacortical osteosarcomas in the proximity of the knee joint. Following diagnostic confirmation by means of an incision biopsy and tumour staging, the three patients underwent this new surgical technique. In the postoperative follow-up and re-staging, two to seven years after surgery, all patients were under complete remission, had functionally restored knee joints (Karnofsky score 90 % or higher) and showed good aesthetic results. The surgical technique described may therefore be an adequate alternative to the complete resection of the tumour-bearing bone segment with prosthetic reconstruction and should be considered on the basis of the illustrated functional results in individual cases. PMID- 26114562 TI - [Modular Neck in Primary Total Hip Replacement--A Justifiable Risk?]. AB - Modular necks are considered as a treatment option in primary total hip replacement aiming to allow a variable reconstruction of the hip joint. Concerns are related to increased failure and complication rates which may be associated with the additional modular interface. This interface is frequently affected by corrosion processes which may initiate premature failure of the entire implant. In this study the risk of modular necks as a clinical treatment option is evaluated. Based on register data and clinical studies modular necks should only be used with strict limitations for general treatment in primary total hip replacement. PMID- 26114563 TI - [Intraoperative Evaluation of Total Knee Arthroplasty: Anatomic and Kinematic Assessment with Trial Components]. AB - The intraoperative use of trial components in total knee arthroplasty (TKA) is of paramount importance to prevent inadequate ligament balance and to achieve optimal position of the definitive components. This review demonstrates an 8-step algorithm to assess the anatomy of the femoral, tibial and patellar component as well as the kinematics of the tibiofemoral and patellofemoral joints. Trial components allow an easy assessment of the anatomic fit of the final implants. Upon the trials insertion, bone coverage and the component overhang should be evaluated. The femoral rotation should be assessed using the transepicondylar axis and for the tibial component rotation assessment, the tibial tuberosity would be the most reliable bony landmark. Addressing the patella, sizing and bone coverage should be thoroughly evaluated. In order to restore physiological kinematics the remnants of the meniscus rim can be used to determine the correct reconstruction of the joint line. A tight extension gap results in limited extension, whereas a tight or unbalanced flexion gap leads to "booking" or "spin out" of the inlay. The POLO test (pull-out, lift- off) allows an easy assessment of the posterior cruciate ligament tension and the size of the flexion gap as well. To prevent postoperative dislocation and overstuffing, specific tests for correct patellar positioning and tracking support should be performed. The anatomy and kinematics of total knee arthroplasty have to be evaluated by trial components on a routine basis before inserting the final implants in order to identify implant positioning errors and inadequate ligament balance. PMID- 26114564 TI - [Surgical Techniques for Patella Replacement in Cases of Deficient Bone Stock in Revision TKA]. AB - The patella replacement in revision surgery is a challenge especially in cases of unsufficient bone stock. Depending on the extent of the bone defect, the following videos demonstrate different approaches: Video 1: bone sparing removal of the patella implant: onlay-type patella implants. Video 2: complete cortical bone rim of the patella, residual thickness between 6 to 10 mm: biconvex patella implant. Video 3 and 4: small defects of the cortical bone rim of the patella, residual thickness 1 to 5 mm (patella shell): gull-wing osteotomy, patella bone grafting techniques. Video 5: partial necrosis/defect of the patella shell with incomplete cortical bone rim: porous tantalum patella prosthesis. On account of the various surgical options for different bone defects of the patella, patellectomy and pure patelloplasty should be avoided to prevent functional shortcomings. PMID- 26114565 TI - [Avoidance of Patello-Femoral Overstuffing]. AB - Reconstruction of the patello-femoral compartment and by that avoidance of an overstuffing is one of the important steps for a successful TKA. A revision rate of around 15 % due to problems of the patello-femoral compartment demonstrates that this is not achieved in all cases. There can be many reasons for an overstuffing and also the symptoms can be very variable, showing sometimes a limited flexion, patello-femoral maltracking or anterior knee pain. Due to its relevance the following paper demonstrates the different reasons for a patello femoral overstuffing. Further possible solutions for avoidance of overstuffing are described. The reasons for patello-femoral overstuffing are multiple. The majority is caused on the femoral side, however additional patellar and tibial reasons exist. During positioning of the femora resection blocks, the distal resection plane (extension/flexion) as well as the AP block for sizing is crucial. For that a pre-op analysis and implant planning in the lateral view of the X-ray should be performed in order to optimise implant size and position. For the patella the correct resection height and plane are important to avoid an overstuffing. A lateral patella component position can be another reason for an overstuffing. In conclusion, it can be stated that an anatomic reconstruction of the patello-femoral compartment is an important part of TKA surgery. The avoidance of a patello-femoral overstuffing can be achieved by exact pre-op planning of the femoral component size and position, and by precise surgery with sufficient bone resection. PMID- 26114566 TI - [Management of Flexion Contracture in Primary Total Knee Arthroplasty]. AB - Flexion contracture is a common deformity of the arthritic knee. The present publication describes causes, clinical relevance and surgical technique in the presence of flexion contractures in total knee arthroplasty. Flexion contracture can be attributed to different causes. Basically it is a mismatch between flexion and extension gaps. Moderate and severe deformities have to be corrected by additional surgical interventions. In most cases soft tissue techniques with release of contracted structures, the removal of osteophytes and additional distal femoral bone resection are necessary. The goal of these interventions is to achieve full extension of the knee. During rehabilitation attention has to be paid to maintain it with intensive physical therapy. A remaining flexion contracture is associated with inferior functional outcome and persistent pain. PMID- 26114567 TI - [Tips and Tricks for Mobile Bearing Medial Unicondylar Knee Replacement]. AB - The term anteromedial osteoarthritis of the knee joint was first established in 1991 by White et al. and describes an isolated osteoarthritis of the medial tibiofemoral compartment with intact posterior tibial cartilage in patients with a functionally intact anterior cruciate ligament and occurs in about 30 % of all patients with clinically relevant gonarthrosis. In these patients, there is the possibility for minimally invasive unicondylar knee arthroplasty. One of the most commonly used prosthesis with long-term experience is the Oxford Uni knee prosthesis (Biomet UK Limited, Swindon, UK). The most recent phase of development of this prosthesis focused on improving the reliability of the instruments (Microplasty) which allows a more reproducible execution of the operation to help eliminate early failure due to surgical errors. In the following article, the essential surgical steps of minimally invasive implantation of the Oxford Uni with the Microplasty instrumentation in a patient with severe anteromedial osteoarthritis of the knee joint are demonstrated and explained. PMID- 26114568 TI - [Pilon Fractures]. AB - Pilon fractures are uncommon, representing approximately 5-10 % of all lower limb fractures. Pilon fractures are often associated with serious soft tissue injuries resulting in initial external fixation followed by internal fixation once the condition of the soft tissues has improved. Articular distal fractures of the tibia are classified as B3, C1, C2 and C3 fractures according to the AO Classification. Pilon fractures are usually the result of a high energy trauma. A low energy trauma such as a twisting injury of the ankle can also lead to a pilon fracture. Such low energy mechanisms of injury are rarely associated with significant soft tissue injury and can be immediately fixated internally. Pilon fractures are often associated with an unsatisfactory healing response. This is a result of a combination of factors including the severity of the trauma, the extent of the initial soft tissue injury and the accuracy of the articular surface reconstruction. PMID- 26114569 TI - Alopecia Areata Increases the Risk of Stroke: a 3-year Follow-Up Study. AB - The risk for stroke in alopecia areata (AA) patients is still unknown. This study aimed to investigate the risk for subsequent risk of a stroke in AA patients in a large-scale retrospective cohort study. We identified 3231 patients with AA included in the study group from 2004 to 2011 in the "Longitudinal Health Insurance Database 2000" in Taiwan. We randomly selected 16,155 matched patients as the comparison group. We individually tracked each patient for a 3-year period to identify patients who had received a diagnosis of stroke during the follow-up period. We found that incidence rates of stroke during the 3-year follow-up periods were 5.44 (95% confidence interval (CI) = 4.03~7.20) and 2.75 (95% CI = 2.30 ~ 3.27) per 1000 person-years for patients with and those without AA, respectively. Cox proportional hazard regressions showed that the adjusted hazard ratio for stroke for those patients with AA was 1.61 (95% CI = 1.13 ~ 2.30) within the follow-up period compared to the controls. We concluded that patients with AA were associated with a higher risk of stroke in the 3-year follow-up period. PMID- 26114572 TI - Recent Progress on Man-Made Inorganic Nanomachines. AB - The successful development of nanoscale machinery, which can operate with high controllability, high precision, long lifetimes, and tunable driving powers, is pivotal for the realization of future intelligent nanorobots, nanofactories, and advanced biomedical devices. However, the development of nanomachines remains one of the most difficult research areas, largely due to the grand challenges in fabrication of devices with complex components and actuation with desired efficiency, precision, lifetime, and/or environmental friendliness. In this work, the cutting-edge efforts toward fabricating and actuating various types of nanomachines and their applications are reviewed, with a special focus on nanomotors made from inorganic nanoscale building blocks, which are introduced according to the employed actuation mechanism. The unique characteristics and obstacles for each type of nanomachine are discussed, and perspectives and challenges of this exciting field are presented. PMID- 26114573 TI - Knowledge, Attitudes and Practices of Animal Bite Victims Attending an Anti rabies Health Center in Jimma Town, Ethiopia. AB - BACKGROUND: Rabies is an important but preventable cause of death in Ethiopia. We assessed the knowledge, attitudes and practices of animal bite victims attending an anti-rabies health center in Jimma Town, Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: Between July 2012 and March 2013 a cross-sectional questionnaire was administered to 384 bite victims or their guardians in the case of minors (aged <15 years). Factors associated with knowledge, attitudes and practices were evaluated using generalized linear models. Almost all participants (99%) were aware that rabies was transmitted by the bite or lick of a rabid dog, however only 20.1% identified "germs" as the cause of disease. A majority of participants stated rabies could be prevented by avoiding dog bites (64.6%) and confining dogs (53.9%); fewer (41.7%) recognized vaccination of dogs/cats as an important preventive strategy. Regarding attitudes, most (91.1%) agreed that medical evaluation should be sought as soon as possible. However, most (75.0%) also believed that traditional healers could cure rabies. Rural residence (adjusted odds ratio [OR] = 2.1, p = 0.015) and Protestant religion (OR = 2.4, p = 0.041) were independently associated with this belief. Among 186 participants who owned dogs, only 9 (4.8%) had ever vaccinated their dog and more than 90% of respondents indicated that their dog was free-roaming or cohabitated with the family. Only 7.0% of participants applied correct first aid following exposure, and the majority (47.7%) reported that the animal was killed by the community following the incident. Female sex and Muslim religion were independently associated with higher and lower practices scores, respectively, due largely to differences in animal management practices following the incident. CONCLUSIONS/SIGNIFICANCE: Although respondents demonstrated reasonably sound knowledge of rabies and its transmission, attitudes and practices were inconsistent with rabies prevention. Culturally- and gender-sensitive activities that promote proper first aid and healthcare seeking behavior as well as appropriate animal management, particularly in rural areas, are needed to prevent deaths associated with rabies in this setting. PMID- 26114571 TI - Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in Blastomyces dermatitidis. AB - In response to temperature, Blastomyces dermatitidis converts between yeast and mold forms. Knowledge of the mechanism(s) underlying this response to temperature remains limited. In B. dermatitidis, we identified a GATA transcription factor, SREB, important for the transition to mold. Null mutants (SREBDelta) fail to fully complete the conversion to mold and cannot properly regulate siderophore biosynthesis. To capture the transcriptional response regulated by SREB early in the phase transition (0-48 hours), gene expression microarrays were used to compare SREB? to an isogenic wild type isolate. Analysis of the time course microarray data demonstrated SREB functioned as a transcriptional regulator at 37 degrees C and 22 degrees C. Bioinformatic and biochemical analyses indicated SREB was involved in diverse biological processes including iron homeostasis, biosynthesis of triacylglycerol and ergosterol, and lipid droplet formation. Integration of microarray data, bioinformatics, and chromatin immunoprecipitation identified a subset of genes directly bound and regulated by SREB in vivo in yeast (37 degrees C) and during the phase transition to mold (22 degrees C). This included genes involved with siderophore biosynthesis and uptake, iron homeostasis, and genes unrelated to iron assimilation. Functional analysis suggested that lipid droplets were actively metabolized during the phase transition and lipid metabolism may contribute to filamentous growth at 22 degrees C. Chromatin immunoprecipitation, RNA interference, and overexpression analyses suggested that SREB was in a negative regulatory circuit with the bZIP transcription factor encoded by HAPX. Both SREB and HAPX affected morphogenesis at 22 degrees C; however, large changes in transcript abundance by gene deletion for SREB or strong overexpression for HAPX were required to alter the phase transition. PMID- 26114574 TI - Impact of Childhood Abuse on the Risk of Non-Suicidal Self-Injury in Mainland Chinese Adolescents. AB - BACKGROUND: Childhood abuse has been associated with significant increases in non suicidal self-injury (NSSI) behaviors in adolescents; however, only general definitions of this risk indicator have been examined. This study identified relationships between specific forms of childhood abuse and NSSI in mainland Chinese adolescents. METHOD: A total of 14,221 cases were retained from an epidemiological study involving adolescents from junior and senior middle schools. Information relating to the perpetrator, perceived harm, timing of exposure to different types of childhood abuse, and NSSI were obtained. Logistic regression was used to analyze relationships between each form of childhood abuse and NSSI. RESULTS: Approximately 51.0% of the students reported at least one abusive childhood experience. Nearly one in four students (24.9%) reported that they had engaged in NSSI in the past 12 months. Each type of childhood abuse, occurring at any time within the first 16 years of life, especially in situations of continuous exposure, was significantly associated with NSSI. A significant graded relationship was found between number of abusive childhood experiences and NSSI. Students maltreated by parents or others were at high risk of engaging in NSSI, the risk was greater in students maltreated by both; students who had been exposed to childhood abuse with no perceived harm still demonstrated an elevated risk for NSSI. The pattern of associations did not vary by gender. CONCLUSIONS: These findings suggest that experiencing any of various forms of childhood abuse should be considered a risk factor for NSSI during adolescence. Further research should focus upon psychosocial, neural, and genetic factors that might moderate or mediate the onset of NSSI in adolescents who have experienced childhood abuse. PMID- 26114575 TI - Hybrid in Silico/in Vitro Approach for the Identification of Angiotensin I Converting Enzyme Inhibitory Peptides from Parma Dry-Cured Ham. AB - The bioactivity assessment of foodborne peptides is currently a research area of great relevance, and, in particular, several studies are devoted to the antihypertensive effects through the inhibition of angiotensin I converting enzyme (ACE). In the present work, a straightforward workflow to identify inhibitory peptides from food matrices is proposed, which involves a hybrid in vitro/in silico tandem approach. Parma dry-cured ham was chosen as case study. In particular, the advantage of using the hybrid approach to identify active sequences (in comparison to the experimental trials alone) has been pointed out. Specifically, fractions obtained by in vitro gastrointestinal digestion of ham samples of 18 and 24 months of aging have been assessed for ACE inhibition. At the same time, the released peptidomic profiles, which cannot be entirely evaluated by using in vitro assays, have been screened for the inhibition by using an in silico model. Then, to identify novel inhibitory sequences, a series of strong candidates have been synthesized and assessed for their inhibitory activity through in vitro assay. On the one hand, the use of computational simulations appeared to be an effective strategy to find active sequences, as confirmed by in vitro analysis. On the other hand, strong inhibitory sequences were identified for the first time in Parma dry-cured ham (e.g., LGL and SFVTT with IC50 values of 145 and 395 MUM, respectively), which is a product of international dietary and economic relevance. Therefore, these findings demonstrate the usefulness of in silico methodologies coupled to in vitro tests for the identification of potentially bioactive peptides, and they give an important contribution to the study of the overall nutritional value of Parma ham. PMID- 26114576 TI - Annual Migration of Agrotis segetum (Lepidoptera: Noctuidae): Observed on a Small Isolated Island in Northern China. AB - Migration behavior of the turnip moth, Agrotis segetum (Lepidoptera: Noctuidae), is not well known by far. Here, we present the data from an 11-year study on A. segetum by means of searchlight trapping and ovarian dissection on Beihuang (BH) Island, which located in the center of the Bohai Strait in northern China. The data showed a large number of A. segetum flight across the strait each year, which provides direct evidence that A. segetum is a long-distance migrant, migrating at least 40-60 km to reach the trapping site. The migration period during 2003-2013 ranged from 115 to 172 d. Among the catches, the proportion of females was significantly higher than that of males in each month from May to September. Ovarian dissection showed that the proportion of mated females and the proportion of sexually mature females was significantly higher than that of unmated females and sexually immature females in early summer, respectively, but conversely in autumn. The early summer populations migrate in a south-north direction, which might undertake a long-distance flight on several successive nights. The autumn populations migrate in a north-south direction, which might originate not far from the trapping site. Based on these findings, the migratory physiology of A. segetum was discussed. PMID- 26114577 TI - The association between protective behavioral strategies and alcohol-related problems: An examination of race and gender differences among college drinkers. AB - This study examined race and gender differences in use of specific types of protective behavioral strategies (PBS) and the moderating effects of race and gender on the relationship between PBS use and alcohol problems, controlling for alcohol use, among a large sample of Asian, Black, and White college drinkers. There were significant racial and gender differences in the types of PBS used. Moderation analyses indicated that PBS were more protective for women than men against experiencing alcohol-related problems. There were no significant race effects or race-by-gender interaction effects on alcohol problems. Implementing PBS may be beneficial for all college students. PMID- 26114578 TI - Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay. AB - Lysosomal membrane permeabilization (LMP) contributes to tissue involution, degenerative diseases, and cancer therapy. Its investigation has, however, been hindered by the lack of sensitive methods. Here, we characterize and validate the detection of galectin puncta at leaky lysosomes as a highly sensitive and easily manageable assay for LMP. LGALS1/galectin-1 and LGALS3/galectin-3 are best suited for this purpose due to their widespread expression, rapid translocation to leaky lysosomes and availability of high-affinity antibodies. Galectin staining marks individual leaky lysosomes early during lysosomal cell death and is useful when defining whether LMP is a primary or secondary cause of cell death. This sensitive method also reveals that cells can survive limited LMP and confirms a rapid formation of autophagic structures at the site of galectin puncta. Importantly, galectin staining detects individual leaky lysosomes also in paraffin-embedded tissues allowing us to demonstrate LMP in tumor xenografts in mice treated with cationic amphiphilic drugs and to identify a subpopulation of lysosomes that initiates LMP in involuting mouse mammary gland. The use of ectopic fluorescent galectins renders the galectin puncta assay suitable for automated screening and visualization of LMP in live cells and animals. Thus, the lysosomal galectin puncta assay opens up new possibilities to study LMP in cell death and its role in other cellular processes such as autophagy, senescence, aging, and inflammation. PMID- 26114579 TI - A new method for determining the 3D spatial orientation of molar microwear. AB - Many types of behavioral and dietary information can be extracted from studies of tooth microwear. Some studies have even been successful at determining the overall directionality of microwear in order to establish gross masticatory movement (Williams et al., 2009, PNAS, 106, 11194-11199). However, microwear has never been successfully visualized in situ in 3 dimensions (3D), visualized virtually and quantified. The ability to accomplish this yields information on exact masticatory movement which can then be used to address any number of eco biological and physiological questions in extant and extinct organisms. In order to create 3D virtual reality (VR) representation of microwear, fossil molars from the Javanese Sangiran 7 (S7) Homo erectus tooth collection and from historic hunter/gatherer meta-populations were imaged, the microwear in 3 dimensions was extracted, this information was then placed back on VR representations of the molars and quantified. The methodology contained herein demonstrates the efficacy and importance of such a technique in determining gross masticatory movement in fossil and recent hominin molars. This methodology could, in theory, be applied to any organism which produces microwear on its dentition. Applications in the fields of dentistry, orthodontics, climatology and dietary and habitat reconstructions can also be envisioned. PMID- 26114580 TI - The Changing Strength and Nature of Fire-Climate Relationships in the Northern Rocky Mountains, U.S.A., 1902-2008. AB - Time-varying fire-climate relationships may represent an important component of fire-regime variability, relevant for understanding the controls of fire and projecting fire activity under global-change scenarios. We used time-varying statistical models to evaluate if and how fire-climate relationships varied from 1902-2008, in one of the most flammable forested regions of the western U.S.A. Fire-danger and water-balance metrics yielded the best combination of calibration accuracy and predictive skill in modeling annual area burned. The strength of fire-climate relationships varied markedly at multi-decadal scales, with models explaining < 40% to 88% of the variation in annual area burned. The early 20th century (1902-1942) and the most recent two decades (1985-2008) exhibited strong fire-climate relationships, with weaker relationships for much of the mid 20th century (1943-1984), coincident with diminished burning, less fire-conducive climate, and the initiation of modern fire fighting. Area burned and the strength of fire-climate relationships increased sharply in the mid 1980s, associated with increased temperatures and longer potential fire seasons. Unlike decades with high burning in the early 20th century, models developed using fire-climate relationships from recent decades overpredicted area burned when applied to earlier periods. This amplified response of fire to climate is a signature of altered fire-climate-relationships, and it implicates non-climatic factors in this recent shift. Changes in fuel structure and availability following 40+ yr of unusually low fire activity, and possibly land use, may have resulted in increased fire vulnerability beyond expectations from climatic factors alone. Our results highlight the potential for non-climatic factors to alter fire-climate relationships, and the need to account for such dynamics, through adaptable statistical or processes-based models, for accurately predicting future fire activity. PMID- 26114581 TI - HIV-1 genotypic drug resistance testing: digging deep, reaching wide? AB - For many years, population-based Sanger sequencing has been the golden standard for drug resistance testing within the routine follow-up of HIV-1 infected patients in resource-rich settings. Often, the data generated within this framework were subsequently used for research and surveillance purposes: to understand therapy response and to gain insights into epidemiological processes. Sanger sequencing was however ill suited for diagnostic and prognostic use in resource-limited settings (RLS) and therefore not broadly implemented. Next generation sequencing (NGS) technologies provide high-throughput approaches by the rapid acquisition of thousands to millions of short nucleotide sequences. Depending on the experimental design, the roll-out of NGS drug resistance testing at a larger scale is feasible, providing better characterization and understanding of the evolving population of viral variants within a patient and potentially improving the prognostic value of drug resistance testing. Whether the same will become true for RLS will largely depend on affordability and sample logistics, and this may affect other mutation-specific approaches. PMID- 26114582 TI - Agreement between touch-screen and paper-based patient-reported outcomes for patients with fibromyalgia: a randomized cross-over reproducibility study. AB - OBJECTIVES: To compare data based on computerized and paper versions of health status questionnaires (HSQs) for sampling patient-reported outcomes (PROs) in patients with fibromyalgia (FM). In addition, to examine associations between patient characteristics (age, education, computer experience) and differences between versions. Finally, to evaluate the acceptability of computer-based questionnaires among patients with FM. METHOD: The study population comprised female patients diagnosed with FM. All patients completed six HSQs: the Fibromyalgia Impact Questionnaire (FIQ), the Major Depression Inventory (MDI), the 36-item Short Form Health Survey (SF-36), the painDETECT questionnaire (PDQ), the Coping Strategies Questionnaire (CSQ), and the Generalized Anxiety Disorder Self-Assessment Questionnaire (GAD-10), both on paper and using a touch screen. One HSQ was tested at a time in a repeated randomized cross-over design. The two versions were completed with a 5-min interval and between each HSQ the participants had a 5-min break. Means, mean differences with 95% confidence intervals (CIs), medians, median differences, and intraclass correlation coefficients (ICCs) were calculated for all HSQs, including relevant subscales. Associations between patient characteristics and differences between versions were explored using Spearman's correlation coefficients. RESULTS: Twenty women, mean age 48.4 years, participated in the study. Except for one item, ICCs between touch-screen and paper versions of the HSQs examined indicated acceptable agreement (ICC = 0.71-0.99). Overall, mean and median differences revealed no differences between versions. No significant associations were observed for patient characteristics. None of the participants preferred paper questionnaires over computerized versions. CONCLUSIONS: The computerized HSQs using a touch screen gave comparable results to answers given on paper and were generally preferred by the participants. PMID- 26114583 TI - Amorphization and Directional Crystallization of Metals Confined in Carbon Nanotubes Investigated by in Situ Transmission Electron Microscopy. AB - The hollow core of a carbon nanotube (CNT) provides a unique opportunity to explore the physics, chemistry, biology, and metallurgy of different materials confined in such nanospace. Here, we investigate the nonequilibrium metallurgical processes taking place inside CNTs by in situ transmission electron microscopy using CNTs as nanoscale resistively heated crucibles having encapsulated metal nanowires/crystals in their channels. Because of nanometer size of the system and intimate contact between the CNTs and confined metals, an efficient heat transfer and high cooling rates (~10(13) K/s) were achieved as a result of a flash bias pulse followed by system natural quenching, leading to the formation of disordered amorphous-like structures in iron, cobalt, and gold. An intermediate state between crystalline and amorphous phases was discovered, revealing a memory effect of local short-to-medium range order during these phase transitions. Furthermore, subsequent directional crystallization of an amorphous iron nanowire formed by this method was realized under controlled Joule heating. High-density crystalline defects were generated during crystallization due to a confinement effect from the CNT and severe plastic deformation involved. PMID- 26114584 TI - Disruption of thioredoxin metabolism enhances the toxicity of transforming growth factor beta-activated kinase 1 (TAK1) inhibition in KRAS-mutated colon cancer cells. AB - Transforming growth factor beta-activated kinase 1 (TAK1) is critical for survival of many KRAS mutated colorectal cancer cells, and TAK1 inhibition with 5Z-7-oxozeaenol has been associated with oxidative stress leading to tumor cell killing. When SW 620 and HCT 116 human colon cancer cells were treated with 5uM 5Z-7-oxozeaenol, cell viability, growth, and clonogenic survival were significantly decreased. Consistent with TAK1 inhibition being causally related to thiol-mediated oxidative stress, 10mM N-acetylcysteine (NAC) partially reversed the growth inhibitory effects of 5Z-7-oxozeaenol. In addition, 5Z-7 oxozeaenol also increased steady-state levels of H2DCFDA oxidation as well as increased levels of total glutathione (GSH) and glutathione disulfide (GSSG). Interestingly, depletion of GSH using buthionine sulfoximine did not significantly potentiate 5Z-7-oxozeaenol toxicity in either cell line. In contrast, pre-treatment of cells with auranofin (Au) to inhibit thioredoxin reductase activity significantly increased levels of oxidized thioredoxin as well as sensitized cells to 5Z-7-oxozeaenol-induced growth inhibition and clonogenic cell killing. These results were confirmed in SW 620 murine xenografts, where treatment with 5Z-7-oxozeaenol or with Au plus 5Z-7-oxozeaenol significantly inhibited growth, with Au plus 5Z-7-oxozeaenol trending toward greater growth inhibition compared to 5Z-7-oxozeaenol alone. These results support the hypothesis that thiol-mediated oxidative stress is causally related to TAK1 induced colon cancer cell killing. In addition, these results support the hypothesis that thioredoxin metabolism is a critical target for enhancing colon cancer cell killing via TAK1 inhibition and could represent an effective therapeutic strategy in patients with these highly resistant tumors. PMID- 26114585 TI - Ancestral Chromatin Configuration Constrains Chromatin Evolution on Differentiating Sex Chromosomes in Drosophila. AB - Sex chromosomes evolve distinctive types of chromatin from a pair of ancestral autosomes that are usually euchromatic. In Drosophila, the dosage-compensated X becomes enriched for hyperactive chromatin in males (mediated by H4K16ac), while the Y chromosome acquires silencing heterochromatin (enriched for H3K9me2/3). Drosophila autosomes are typically mostly euchromatic but the small dot chromosome has evolved a heterochromatin-like milieu (enriched for H3K9me2/3) that permits the normal expression of dot-linked genes, but which is different from typical pericentric heterochromatin. In Drosophila busckii, the dot chromosomes have fused to the ancestral sex chromosomes, creating a pair of 'neo sex' chromosomes. Here we collect genomic, transcriptomic and epigenomic data from D. busckii, to investigate the evolutionary trajectory of sex chromosomes from a largely heterochromatic ancestor. We show that the neo-sex chromosomes formed <1 million years ago, but nearly 60% of neo-Y linked genes have already become non-functional. Expression levels are generally lower for the neo-Y alleles relative to their neo-X homologs, and the silencing heterochromatin mark H3K9me2, but not H3K9me3, is significantly enriched on silenced neo-Y genes. Despite rampant neo-Y degeneration, we find that the neo-X is deficient for the canonical histone modification mark of dosage compensation (H4K16ac), relative to autosomes or the compensated ancestral X chromosome, possibly reflecting constraints imposed on evolving hyperactive chromatin in an originally heterochromatic environment. Yet, neo-X genes are transcriptionally more active in males, relative to females, suggesting the evolution of incipient dosage compensation on the neo-X. Our data show that Y degeneration proceeds quickly after sex chromosomes become established through genomic and epigenetic changes, and are consistent with the idea that the evolution of sex-linked chromatin is influenced by its ancestral configuration. PMID- 26114587 TI - An Atlas of Network Topologies Reveals Design Principles for Caenorhabditis elegans Vulval Precursor Cell Fate Patterning. AB - The vulval precursor cell (VPC) fate patterning in Caenorhabditis elegans is a classic model experimental system for cell fate determination and patterning in development. Despite its apparent simplicity (six neighboring cells arranged in one dimension) and many experimental and computational efforts, the patterning strategy and mechanism remain controversial due to incomplete knowledge of the complex biology. Here, we carry out a comprehensive computational analysis and obtain a reservoir of all possible network topologies that are capable of VPC fate patterning under the simulation of various biological environments and regulatory rules. We identify three patterning strategies: sequential induction, morphogen gradient and lateral antagonism, depending on the features of the signal secreted from the anchor cell. The strategy of lateral antagonism, which has not been reported in previous studies of VPC patterning, employs a mutual inhibition of the 2 degrees cell fate in neighboring cells. Robust topologies are built upon minimal topologies with basic patterning strategies and have more flexible and redundant implementations of modular functions. By simulated mutation, we find that all three strategies can reproduce experimental error patterns of mutants. We show that the topology derived by mapping currently known biochemical pathways to our model matches one of our identified functional topologies. Furthermore, our robustness analysis predicts a possible missing link related to the lateral antagonism strategy. Overall, we provide a theoretical atlas of all possible functional networks in varying environments, which may guide novel discoveries of the biological interactions in vulval development of Caenorhabditis elegans and related species. PMID- 26114588 TI - Oxybutynin as a treatment for generalized hyperhidrosis: a randomized, placebo controlled trial. AB - BACKGROUND: Hyperhidrosis is a disorder that can impair quality of life. Localized treatments may be cumbersome and ineffective, and no systemic treatments have proven to be significantly beneficial. OBJECTIVES: To evaluate the effectiveness and tolerance of low-dose oxybutynin for hyperhidrosis. METHODS: We conducted a prospective, randomized, placebo-controlled trial. From June 2013 to January 2014, 62 patients with localized or generalized hyperhidrosis were enrolled. Oxybutynin was started at a dose of 2.5 mg per day and increased gradually to 7.5 mg per day. The primary outcome was defined as improvement of at least one point on the Hyperhidrosis Disease Severity Scale (HDSS). Dermatology Life Quality Index (DLQI) and tolerance were also reported. RESULTS: Most patients (83%) in our study had generalized hyperhidrosis. Oxybutynin was superior to placebo in improving the HDSS: 60% of patients treated with oxybutynin, compared with 27% of patients treated with placebo, improved at least one point on the HDSS (P = 0.009). The mean improvement in quality of life measured by DLQI was significantly better in the oxybutynin arm (6.9) than in the placebo arm (2.3). The most frequent side-effect was dry mouth, which was observed in 43% of the patients in the oxybutynin arm, compared with 11% in the placebo arm. CONCLUSIONS: Treatment with low-dose oxybutynin is effective in reducing symptoms of hyperhidrosis in generalized or localized forms. Side effects were frequent but minor and mainly involved dry mouth. PMID- 26114589 TI - What explains DRG upcoding in neonatology? The roles of financial incentives and infant health. AB - We use the introduction of diagnosis related groups (DRGs) in German neonatology to study the determinants of upcoding. Since 2003, reimbursement is based inter alia on birth weight, with substantial discontinuities at eight thresholds. These discontinuities create incentives to upcode preterm infants into classes of lower birth weight. Using data from the German birth statistics 1996-2010 and German hospital data from 2006 to 2011, we show that (1) since the introduction of DRGs, hospitals have upcoded at least 12,000 preterm infants and gained additional reimbursement in excess of 100 million Euro; (2) upcoding rates are systematically higher at thresholds with larger reimbursement hikes and in hospitals that subsequently treat preterm infants, i.e. where the gains accrue; (3) upcoding is systematically linked with newborn health conditional on birth weight. Doctors and midwives respond to financial incentives by not upcoding newborns with low survival probabilities, and by upcoding infants with higher expected treatment costs. PMID- 26114590 TI - DNA-based methodologies for the quantification of live and dead cells in formulated biocontrol products based on Pantoea agglomerans CPA-2. AB - Pantoea agglomerans strain CPA-2 is an effective biocontrol agent (BCA) against the major postharvest pathogens present on pome and citrus fruits. Dehydration, such as freeze-drying, spray-drying and fluidized bed drying is one of the best ways to formulate BCAs. In this work, the survival of CPA-2 cells after formulation was determined by dilution plating and molecular methods as qPCR alone and combined with a sample pretreatment with a propidium monoazide dye (PMA qPCR) and they were used to calculate treatment concentrations in efficacy trials on postharvest oranges. Furthermore, no significant differences in CPA-2 survival were observed as determined by dilution plating and PMA-qPCR after both the freeze drying and fluidized bed drying processes; however, an interesting significant difference was observed in the spray dried product comparing all quantitative methods. A difference of 0.48 and 2.17 log10 CFU or cells g/dw was observed among PMA-qPCR with qPCR and dilution plating, respectively. According to our study, dilution plating was shown to be an unreliable tool for monitoring the survival of CPA-2 after spray drying. In contrast, the combination of PMA and qPCR enabled a quick and unequivocal methodology to enumerate viable and VBNC CPA 2 cells under stress-dried conditions. Efficacy trials showed that, after 3 days, spray drying formulation rehydrated with 10% non-fat skimmed milk (NFSM) was as effective as fresh cells to control Penicillium digitatum in oranges. PMID- 26114591 TI - Reduction of Salmonella enterica on the surface of eggshells by sequential treatment with aqueous chlorine dioxide and drying. AB - The synergistic effects of sequential treatments with chlorine dioxide (ClO2) and drying in killing Salmonella enterica on the surface of chicken eggshells were investigated. Initial experiments were focused on comparing lethalities of sodium hypochlorite (NaOCl) and ClO2. Eggs surface-inoculated with S. enterica in chicken feces as a carrier were immersed in water, NaOCl (50 or 200 MUg/mL), or ClO2 (50 or 200 MUg/mL) for 1 or 5 min. For 1-min treatments, lethal activities of sanitizers were not significantly different (P>0.05). However, after treatment with ClO2 for 5 min, reductions of S. enterica were significantly greater (P<=0.05) than reductions after treatment with water or NaOCl. The effect of treatment of eggs with ClO2 or NaOCl, followed by drying at 43% relative humidity and 25 degrees C for 24 and 48 h, were determined. Populations of S. enterica decreased during drying, regardless of the type of sanitizer treatment. ClO2 treatment, compared to water or NaOCl treatments, resulted in additional reductions of ca. >1.3 log CFU/egg during drying. This indicates that sequential treatments with ClO2 and drying induced synergistic lethal effects against S. enterica on the surface of eggshells. These observations will be useful when selecting a sanitizer to control S. enterica on the surface of eggshells and designing an effective egg sanitization system exploiting the synergistic lethal effects of sanitizer and drying. PMID- 26114586 TI - Identification of Low-Risk Patients with Acute Symptomatic Pulmonary Embolism for Outpatient Therapy. AB - RATIONALE: Patients with acute symptomatic pulmonary embolism (PE) deemed to be at low risk for early complications might be candidates for partial or complete outpatient treatment. OBJECTIVES: To develop and validate a clinical prediction rule that accurately identifies patients with PE and low risk of short-term complications and to compare its prognostic ability with two previously validated models (i.e., the Pulmonary Embolism Severity Index [PESI] and the Simplified PESI [sPESI]) METHODS: Multivariable logistic regression of a large international cohort of patients with PE prospectively enrolled in the RIETE (Registro Informatizado de la Enfermedad TromboEmbolica) registry. MEASUREMENTS AND MAIN RESULTS: All-cause mortality, recurrent PE, and major bleeding up to 10 days after PE diagnosis were determined. Of 18,707 eligible patients with acute symptomatic PE, 46 (0.25%) developed recurrent PE, 203 (1.09%) bled, and 471 (2.51%) died. Predictors included in the final model were chronic heart failure, recent immobilization, recent major bleeding, cancer, hypotension, tachycardia, hypoxemia, renal insufficiency, and abnormal platelet count. The area under receiver-operating characteristic curve was 0.77 (95% confidence interval [CI], 0.75-0.78) for the RIETE score, 0.72 (95% CI, 0.70-0.73) for PESI (P < 0.05), and 0.71 (95% CI, 0.69-0.73) for sPESI (P < 0.05). Our RIETE score outperformed the prognostic value of PESI in terms of net reclassification improvement (P < 0.001), integrated discrimination improvement (P < 0.001), and sPESI (net reclassification improvement, P < 0.001; integrated discrimination improvement, P < 0.001). CONCLUSIONS: We built a new score, based on widely available variables, that can be used to identify patients with PE at low risk of short-term complications, assisting in triage and potentially shortening duration of hospital stay. PMID- 26114592 TI - Microbiological survey of raw and ready-to-eat leafy green vegetables marketed in Italy. AB - The presence of foodborne pathogens (Salmonella spp., Listeria monocytogenes, Escherichia coli O157:H7, thermotolerant Campylobacter, Yersinia enterocolitica and norovirus) in fresh leafy (FL) and ready-to-eat (RTE) vegetable products, sampled at random on the Italian market, was investigated to evaluate the level of risk to consumers. Nine regional laboratories, representing 18 of the 20 regions of Italy and in which 97.7% of the country's population resides, were involved in this study. All laboratories used the same sampling procedures and analytical methods. The vegetable samples were screened using validated real-time PCR (RT-PCR) methods and standardized reference ISO culturing methods. The results show that 3.7% of 1372 fresh leafy vegetable products and 1.8% of 1160 "fresh-cut" or "ready-to-eat" (RTE) vegetable retailed in supermarkets or farm markets, were contaminated with one or more foodborne pathogens harmful to human health. PMID- 26114593 TI - Diversity of black Aspergilli isolated from raisins in Argentina: Polyphasic approach to species identification and development of SCAR markers for Aspergillus ibericus. AB - Aspergillus section Nigri is a heterogeneous fungal group including some ochratoxin A producer species that usually contaminate raisins. The section contains the Series Carbonaria which includes the toxigenic species Aspergillus carbonarius and nontoxigenic Aspergillus ibericus that are phenotypically undistinguishable. The aim of this study was to examine the diversity of black aspergilli isolated from raisins and to develop a specific genetic marker to distinguish A. ibericus from A. carbonarius. The species most frequently found in raisins in this study were Aspergillus tubingensis (35.4%) and A. carbonarius (32.3%), followed by Aspergillus luchuensis (10.7%), Aspergillus japonicus (7.7%), Aspergillus niger (6.2%), Aspergillus welwitschiae (4.6%) and A. ibericus (3.1%). Based on inter-simple sequence repeat (ISSR) fingerprinting profiles of major Aspergillus section Nigri members, a sequence-characterized amplified region (SCAR) marker was identified. Primers were designed based on the conserved regions of the SCAR marker and were utilized in a PCR for simultaneous identification of A. carbonarius and A. ibericus. The detection level of the SCAR PCR was found to be 0.01 ng of purified DNA. The present SCAR-PCR is rapid and less cumbersome than conventional identification techniques and could be a supplementary strategy and a reliable tool for high-throughput sample analysis. PMID- 26114594 TI - Wait!!! No Steroids for this Asthma.... AB - BACKGROUND: Strongyloides stercoralis (SS) is a parasite seen in certain parts of the USA and in people from other endemic areas. In these patients steroids might precipitate or exacerbate asthma. Apart from worsening of asthma, serious complications like hyperinfection syndrome and even death can occur in these patients if treated with steroids. Treatment is either ivermectin or albendazole based on severity of the disease. Clinicians have to be very careful when prescribing steroids in patients presenting with an exacerbation of asthma from areas endemic for Strongyloides stercoralis. CASE REPORT: A young woman with history of asthma presented with complaints of nausea, vomiting, abdominal pain, wheezing, and dry cough. Physical examination revealed diffuse expiratory wheezing and mild diffuse abdominal pain without rebound or guarding. Laboratory results showed leukocytosis with eosinophilia. Stool studies showed Strongyloides stercoralis. Imaging revealed ground-glass opacities in the right upper and lower lobe along with an infiltrate in the lingular lobe on the left side. Bronchoscopy showed Strongyloides stercoralis. The patient was diagnosed with hyperinfection syndrome due to Strongyloides stercoralis most probably exacerbated by prednisone given for her asthma. Steroids were then discontinued and the patient was started on ivermectin. The patient improved with treatment. Repeat stool examination was negative for Strongyloides stercoralis. CONCLUSIONS: Clinicians have to be very careful when prescribing steroids in patients presenting with an exacerbation of asthma who are from areas endemic for Strongyloides stercoralis and should test for it (preferably with serology test) before starting treatment. PMID- 26114595 TI - Effects of ensemble complexity and perceptual similarity on rapid averaging of hue. AB - The ability to extract the mean of features from a rapidly viewed, heterogeneous array of objects has been demonstrated for a number of different visual properties. Few studies have previously investigated the rapid averaging of color; those that did had insufficient stimulus control or inappropriate methods. This study reports three experiments that directly test observers' ability to extract the mean hue from a rapidly presented, multielement color ensemble. In Experiment 1, ensembles varied in number of elements and number of colors. It was found that averaging was harder for ensembles with more colors but that changing the number of elements had no effect on accuracy, supportive of a distributed attention account of rapid color averaging. Experiment 2a manipulated the hue range present in any single ensemble (varying the perceptual difference between ensemble elements) while still varying the number of colors. Range had a strong effect on ability to pick the mean hue. Experiment 2b found no effect of color categories on the accuracy or speed of mean selection. The results indicate that perceptual difference of elements is the dominant factor affecting ability to average rapidly seen color ensembles. Findings are discussed both in the context of perception and memory of multiple colors and ensemble perception generally. PMID- 26114596 TI - Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. AB - Two parallel pathways produce cholesterol: the Bloch and Kandutsch-Russell pathways. Here we used stable isotope labeling and isotopomer analysis to trace sterol flux through the two pathways in mice. Surprisingly, no tissue used the canonical K-R pathway. Rather, a hybrid pathway was identified that we call the modified K-R (MK-R) pathway. Proportional flux through the Bloch pathway varied from 8% in preputial gland to 97% in testes, and the tissue-specificity observed in vivo was retained in cultured cells. The distribution of sterol isotopomers in plasma mirrored that of liver. Sterol depletion in cultured cells increased flux through the Bloch pathway, whereas overexpression of 24-dehydrocholesterol reductase (DHCR24) enhanced usage of the MK-R pathway. Thus, relative use of the Bloch and MK-R pathways is highly variable, tissue-specific, flux dependent, and epigenetically fixed. Maintenance of two interdigitated pathways permits production of diverse bioactive sterols that can be regulated independently of cholesterol. PMID- 26114597 TI - A mex3 homolog is required for differentiation during planarian stem cell lineage development. AB - Neoblasts are adult stem cells (ASCs) in planarians that sustain cell replacement during homeostasis and regeneration of any missing tissue. While numerous studies have examined genes underlying neoblast pluripotency, molecular pathways driving postmitotic fates remain poorly defined. In this study, we used transcriptional profiling of irradiation-sensitive and irradiation-insensitive cell populations and RNA interference (RNAi) functional screening to uncover markers and regulators of postmitotic progeny. We identified 32 new markers distinguishing two main epithelial progenitor populations and a planarian homolog to the MEX3 RNA-binding protein (Smed-mex3-1) as a key regulator of lineage progression. mex3 1 was required for generating differentiated cells of multiple lineages, while restricting the size of the stem cell compartment. We also demonstrated the utility of using mex3-1(RNAi) animals to identify additional progenitor markers. These results identified mex3-1 as a cell fate regulator, broadly required for differentiation, and suggest that mex3-1 helps to mediate the balance between ASC self-renewal and commitment. PMID- 26114599 TI - Taking a Chance or Playing It Safe: Reframing Risk Assessment Within the Surgeon's Comfort Zone. AB - OBJECTIVES: The purpose of this study was to explore how risk is perceived and experienced by the surgeon and how risk is actively managed in individual practice. BACKGROUND: Risk in surgery has been examined from system-wide and personality perspectives. Although these are important, little is known about the perspective of the individual surgeon. METHODS: A constructivist grounded theory study was conducted to explore surgeons' perspectives on risk in the context of their personal "Comfort Zones." Semistructured, 60-minute interviews were conducted with 18 surgeons who were purposively sampled for sex and subspecialty with a snowballing strategy applied to sample for differences in reputation (conservative vs aggressive). Data were collected and analyzed in an iterative manner until thematic saturation was reached. RESULTS: Surgeons described cases that were inside or outside of their personal comfort zones. When considering cases at the boundary of their comfort zones, participants described a variety of factors that could make them feel more or less comfortable. Specific strategies used to modulate this border were also described. Two perspectives on risk taking became apparent: the procedure-centric perspective described how surgeons viewed their colleagues whereas the surgeon-centric perspective described how surgeons viewed themselves. CONCLUSIONS: A framework for understanding surgeon's unique assessment of risk was elaborated. Increased awareness of the factors and strategies identified in this study can foster critical self-reflection by surgeons of their own risk assessments and those of their colleagues, and provide avenues for more explicit educational strategies for surgical training. PMID- 26114598 TI - Ventriculosternal Shunting for the Management of Hydrocephalus: Case Report of A Novel Technique. AB - BACKGROUND: Conventional cerebrospinal fluid diversion such as ventriculoperitoneal or ventriculoatrial shunting for the management of hydrocephalus is one of the commonest neurosurgical procedures. However, in selected patients, surgical options are limited when relative contraindications for these operations exist. A patient who underwent ventriculosternal shunting, a novel procedure, is presented with durable and successful outcomes. OBJECTIVE: To demonstrate the feasibility, durability, and safety of ventriculosternal shunting for the management of hydrocephalus. METHODS: A patient with end-stage renal failure and heart failure with recurrent pleural effusion suffered from post subarachnoid hemorrhage communicating hydrocephalus. Because of the need for continuous ambulatory peritoneal dialysis and the risk of introducing excessive cardiac preloading, conventional shunting was relatively contraindicated. Ventriculosternal shunting was performed by adopting the cancellous matrix of the sternum as the anatomic receptacle for intraosseous cerebrospinal fluid absorption. After placement of the ventricular catheter in the usual manner, the distal end was inserted into the sternum. RESULTS: There was demonstrable clinical and radiological improvement in hydrocephalus by ventriculosternal shunting. Cerebrospinal fluid intraosseous absorption by this novel procedure translated into both physical and cognitive recovery. The procedure was tolerable, effective, and durable, with the patient suffering no complications 3 years after the procedure. CONCLUSION: Ventriculosternal shunting for the management of hydrocephalus is a feasible, safe, and durable surgical treatment option for selected patients when conventional procedures are contraindicated. PMID- 26114600 TI - Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function. AB - Dietary polysaccharides provide various beneficial effects for our health. We investigated the protective effects of wild jujube (Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou) sarcocarp polysaccharides (WJPs) against experimental inflammatory bowel disease (IBD) by enabling enhanced intestinal barrier function. Colitis was induced in rats by the intrarectal administration of TNBS. We found that WJPs markedly ameliorated the colitis severity, including less weight loss, decreased disease activity index scores, and improved mucosal damage in colitis rats. Moreover, WJPs suppressed the inflammatory response via attenuation of TNF-alpha, IL-1beta, IL-6 and MPO activity in colitis rats. And then, to determine the effect of WJPs on the intestinal barrier, we measured the effect of WJPs on the transepithelial electrical resistance (TER) and FITC conjugated dextran permeability in Caco-2 cell stimulation with TNF-alpha. We further demonstrated that the alleviation of WJPs to colon injury was associated with barrier function by assembly of tight junction proteins. Moreover, the effect of WJPs on TER was eliminated by the specific inhibitor of AMPK. AMPK activity was also up-regulated by WJPs in Caco-2 cell stimulation with TNF-alpha and in colitis rats. This study demonstrates that WJPs protect against IBD by enabling enhanced intestinal barrier function involving the activation of AMPK. PMID- 26114601 TI - Additional patients with 4q deletion: Severe growth delay and polycystic kidney disease associated with 4q21q22 loss. AB - BACKGROUND: To the best of our knowledge, this is the third report concerning 4q21q22 deletions. In this report, we describe the cases of two girls with 4q deletion and polycystic kidney disease. G-banding confirmed the deletion in one patient but not in the other. METHODS: We describe the cases of two girls with 4q deletion and polycystic kidney disease. Chromosomal deletions were mapped to 4q21 22. One patient had a simple 4q contiguous gene deletion, whereas the other patient had a complicated chromosomal rearrangement. In patient 1, a smaller part of the 4q deletion was translocated to the 3p region. RESULTS: Fifty-four genes and 72 genes were deleted in patients 1 and 2, respectively. In both patients, 52 genes were consistently deleted. CONCLUSION: The present two patients had a similar phenotype, including severe growth and developmental retardation, and a characteristic facial appearance. The loss of RPKG2 and RASGEF1B causes severe growth defect. PKD2 loss causes kidney cysts. PMID- 26114602 TI - Source Apportionment of Elemental Carbon in Beijing, China: Insights from Radiocarbon and Organic Marker Measurements. AB - Elemental carbon (EC) or black carbon (BC) in the atmosphere has a strong influence on both climate and human health. In this study, radiocarbon ((14)C) based source apportionment is used to distinguish between fossil fuel and biomass burning sources of EC isolated from aerosol filter samples collected in Beijing from June 2010 to May 2011. The (14)C results demonstrate that EC is consistently dominated by fossil-fuel combustion throughout the whole year with a mean contribution of 79% +/- 6% (ranging from 70% to 91%), though EC has a higher mean and peak concentrations in the cold season. The seasonal molecular pattern of hopanes (i.e., a class of organic markers mainly emitted during the combustion of different fossil fuels) indicates that traffic-related emissions are the most important fossil source in the warm period and coal combustion emissions are significantly increased in the cold season. By combining (14)C based source apportionment results and picene (i.e., an organic marker for coal emissions) concentrations, relative contributions from coal (mainly from residential bituminous coal) and vehicle to EC in the cold period were estimated as 25 +/- 4% and 50 +/- 7%, respectively, whereas the coal combustion contribution was negligible or very small in the warm period. PMID- 26114603 TI - In vivo breath-hold (1) H MRS simultaneous estimation of liver proton density fat fraction, and T1 and T2 of water and fat, with a multi-TR, multi-TE sequence. AB - PURPOSE: To examine the intra-examination repeatability of proton density fat fraction (PDFF) and T1 and T2 of liver water and fat as estimated by a novel multi-repetition time (TR)-echo time (TE) (1) H magnetic resonance spectroscopy (MRS)-stimulated echo acquisition mode (STEAM) sequence that acquires 32 spectra for a range of TRs and TEs in single breath-hold. MATERIALS AND METHODS: Sixty seven subjects undergoing liver MRI examinations at 3T had three multi-TR-TE sequences acquired consecutively in a single session. This sequence was designed to allow accurate estimation of T1 and T2 of both water and fat, as well as PDFF, in a single breath-hold. A standard long-TR, multi-TE sequence was also acquired to allow comparison of estimated PDFF. Regression and interclass correlation (ICC) analyses were performed. RESULTS: There was strong agreement between PDFF estimated by the multi-TR-TE and long-TR, multi-TE sequences (slope 0.997; intercept -0.03; R = 0.997). The multi-TR-TE sequence had high repeatability for estimating PDFF (ICC = 0.999), water T2 (ICC = 0.920), water T1 (ICC = 0.845), and fat T2 (ICC = 0.760), and moderate repeatability for estimating fat T1 (ICC = 0.556). CONCLUSION: A novel multi-TR-TE sequence can estimate PDFF and water and fat T1 and T2 in a single breath-hold. Refinement may be needed to improve repeatability for fat T1 estimation. PMID- 26114604 TI - Perceptual Biases in Relation to Paranormal and Conspiracy Beliefs. AB - Previous studies have shown that one's prior beliefs have a strong effect on perceptual decision-making and attentional processing. The present study extends these findings by investigating how individual differences in paranormal and conspiracy beliefs are related to perceptual and attentional biases. Two field studies were conducted in which visitors of a paranormal conducted a perceptual decision making task (i.e. the face/house categorization task; Experiment 1) or a visual attention task (i.e. the global/local processing task; Experiment 2). In the first experiment it was found that skeptics compared to believers more often incorrectly categorized ambiguous face stimuli as representing a house, indicating that disbelief rather than belief in the paranormal is driving the bias observed for the categorization of ambiguous stimuli. In the second experiment, it was found that skeptics showed a classical 'global-to-local' interference effect, whereas believers in conspiracy theories were characterized by a stronger 'local-to-global interference effect'. The present study shows that individual differences in paranormal and conspiracy beliefs are associated with perceptual and attentional biases, thereby extending the growing body of work in this field indicating effects of cultural learning on basic perceptual processes. PMID- 26114605 TI - Correction: Effective Am(III)/Eu(III) separations using 2,6-bis(1,2,4-triazin-3 yl)pyridine (BTP) functionalised titania particles and hierarchically porous beads. AB - Correction for 'Effective Am(III)/Eu(III) separations using 2,6-bis(1,2,4-triazin 3-yl)pyridine (BTP) functionalised titania particles and hierarchically porous beads' by J. Veliscek-Carolan et al., Chem. Commun., 2015, DOI: 10.1039/c5cc03957f. PMID- 26114606 TI - Malignant sweat gland tumours: an update. AB - Cutaneous adnexal tumours can be a diagnostic challenge for the pathologist. This is particularly true in the case of tumours with sweat gland differentiation, due to a large number of rare entities, a multiplicity of names to designate the same neoplasms and consequent lack of consensus regarding their classification and nomenclature. In the traditional view, sweat gland tumours were divided into eccrine and apocrine. However, this has been challenged in recent years, and in fact many of these tumours may have both eccrine and apocrine variants. Some display more complex features and defy classification, due to the presence of other lines of differentiation, namely follicular and/or sebaceous (in the case of apocrine tumours, due to the close embryological relationship between apocrine glands, hair follicles and sebaceous glands). The present paper reviews and updates the basic concepts regarding the following malignant sweat gland tumours: apocrine carcinoma, porocarcinoma, hidradenocarcinoma, spiradenocarcinoma, cylindrocarcinoma, microcystic adnexal carcinoma and related entities, squamoid eccrine ductal carcinoma, digital papillary adenocarcinoma, primary cutaneous mucinous carcinoma, endocrine mucin-producing sweat gland carcinoma and primary cutaneous signet ring cell carcinoma. Particular emphasis is put in recent findings that may have implications in the diagnosis and management of these tumours. PMID- 26114607 TI - Effects of high Zn and Pb concentrations on Phragmites australis (Cav.) Trin. Ex. Steudel: Photosynthetic performance and metal accumulation capacity under controlled conditions. AB - The response of Phragmites australis (Cav.) Trin. Ex. Steudel to zinc (Zn) and lead (Pb) was studied separately in two hydroponic tests, during a three weeks experiment. The effects on ecophysiology and biomass partitioning were evaluated during the metal treatments and at the recovery, and total metal content and accumulation capacity in different plant organs were assessed. Zn and Pb had different effects on the overall measured parameters, highlighting different mechanism of action. In particular, Zn concentration was higher in roots and, being a micronutrient, it was translocated into leaves, producing a reduction of assimilation rate, stomatal conductance (-71.9 and -81.3% respect to the control plant respectively), and a strong down regulation of photosystems functionality both at PSII and PSI level. Otherwise, Pb was accumulated mainly in the more lignified tissue such as rhizomes, with slightly effect on gas exchange. Chlorophyll a fluorescence highlighted that Pb inhibits the electron transfer process at the PSI donor side, without recovery after the removal of the metal stress. Despite these physiological limitations, P. australis showed a high capacity to accumulate both metals, and only slight reduction of biomass, being therefore a suitable species for phytoremediation interventions. PMID- 26114608 TI - Pregnant women's view on the Swedish internet resource Drugs and Birth Defects intended for health care professionals. AB - INTRODUCTION: Pregnant women often have questions concerning fetal effects of drugs but there is limited reliable information specifically intended for them. This study investigated how pregnant women perceive and value the scientific resource Drugs and Birth Defects (www.janusinfo.se/fosterpaverkan) and compared their opinions with those of health care professionals. MATERIAL AND METHODS: Electronic questionnaire study. Pregnant women were recruited at their regular visits, and health care professionals via e-mail, at 10 antenatal clinics. Altogether, 275 pregnant women, 38 midwives and 30 physicians participated. RESULTS: Among the pregnant women, 81% found the information valuable, 70% that it was easy to understand, and 92% that it strengthened information from the staff. Concerning anxiety for negative fetal effects, 68% of the women answered that the anxiety decreased or was not influenced by the texts and 22% that it increased. Among physicians and midwives, 44% saw risks associated with pregnant women reading the texts and 24% answered that they would fully recommend them to use the database. The corresponding figures among pregnant women were 17 and 65%, respectively (P < 0.001). The professionals preferred, to a greater extent than pregnant women did, lay people to use a special edition. CONCLUSIONS: The majority of pregnant women seem to benefit from using a scientific resource on fetal impact of drugs intended for health care professionals. Some women are more worried after having read the information, but most of them still find it valuable. It is important that pregnant women who use the database can reach a medical professional to discuss the contents. PMID- 26114609 TI - Muscle force compensation among synergistic muscles after fatigue of a single muscle. AB - PURPOSE: The aim of this study was to examine control strategies among synergistic muscles after fatigue of a single muscle. It was hypothesized that the compensating mechanism is specific for each fatigued muscle. METHODS: The soleus (SOL), gastrocnemius lateralis (GL) and medialis (GM) were fatigued in separate sessions on different days. In each experiment, subjects (n = 11) performed maximal voluntary contractions prior to and after fatiguing a single muscle (SOL, GL or GM) while the voluntary muscle activity and torque were measured. Additionally, the maximal single twitch torque of the plantarflexors and the maximal spinal reflex activity (H-reflex) of the SOL, GL and GM were determined. Fatigue was evoked using neuromuscular stimulation. RESULTS: Following fatigue the single twitch torque decreased by -20.1%, -19.5%, and 23.0% when the SOL, GL, or GM, have been fatigued. The maximal voluntary torque did not decrease in any session but the synergistic voluntary muscle activity increased significantly. Moreover, we found no alterations in spinal reflex activity. CONCLUSIONS: It is concluded that synergistic muscles compensate each other. Furthermore, it seems that self-compensating mechanism of the fatigued muscles occurred additionally. The force compensation does not depend on the function of the fatigued muscle. PMID- 26114610 TI - Bayesian Sensitivity Analysis of a Cardiac Cell Model Using a Gaussian Process Emulator. AB - Models of electrical activity in cardiac cells have become important research tools as they can provide a quantitative description of detailed and integrative physiology. However, cardiac cell models have many parameters, and how uncertainties in these parameters affect the model output is difficult to assess without undertaking large numbers of model runs. In this study we show that a surrogate statistical model of a cardiac cell model (the Luo-Rudy 1991 model) can be built using Gaussian process (GP) emulators. Using this approach we examined how eight outputs describing the action potential shape and action potential duration restitution depend on six inputs, which we selected to be the maximum conductances in the Luo-Rudy 1991 model. We found that the GP emulators could be fitted to a small number of model runs, and behaved as would be expected based on the underlying physiology that the model represents. We have shown that an emulator approach is a powerful tool for uncertainty and sensitivity analysis in cardiac cell models. PMID- 26114611 TI - Protective Factors for Youth Exposed to Violence in Their Communities: A Review of Family, School, and Community Moderators. AB - This review provides a comprehensive investigation of the pattern and strength of findings in the literature regarding the environmental moderators of the relationship between exposure to community violence and mental health among children and adolescents. Twenty-nine studies met criteria for inclusion in our analysis of family, school, and community variables as moderators. Dependent variables included internalizing (e.g., anxiety, depression, posttraumatic stress disorder) and externalizing symptoms (e.g., aggression, substance use). Effect sizes for the interactions of exposure to violence and potential moderators were summarized by their patterns of protective processes. The majority of studies in the literature examined family characteristics as moderators of the exposure to violence-symptom relationship, rather than school- or community-level factors. Our results indicated more consistent patterns for (a) close family relationships and social support for internalizing symptoms and (b) close family relationships for externalizing symptoms. Overall, the most common type of protective pattern was protective-stabilizing, in which youth with higher levels of the environmental attribute demonstrate relative stability in mental health despite exposure to violence. We found no consistent evidence that parental monitoring-a dimension inversely associated with exposure to violence in prior studies moderated the relationship between exposure to violence and symptoms. The study emphasizes the importance of strengthening family support for young people's exposure to community violence; more research is needed to provide a solid evidence base for the role of school and community-level protective factors for youth exposed to violence. PMID- 26114613 TI - About the goal of a goals' goal theory. PMID- 26114614 TI - A Question of Love and Trust? The Role of Relationship Factors in Adolescent Sexual Decision Making. AB - OBJECTIVE: While representing only 25% of the sexually active population, 50% of all new sexually transmitted infections occur among young people mostly because of inconsistent condom use. Critically, the majority of adolescent sexual activity takes place in the context of romantic relationships; thus, it is important to understand how relationship factors may influence decision making about the use of protection. METHODS: We used a mixed-method approach to investigate the extent to which relationship length, degree of trust or love in the relationship, and frequency of intercourse influence both perceptions of the probability of condom use and self-reported condom use in the context of relationships among a diverse sample of high-risk adolescents (age 12-19 yr). RESULTS: Participants were least likely to use condoms if they were in relationships with high trust or love and high frequency of intercourse. Importantly, sexual experience status was a strong moderator of primary effects. CONCLUSION: The perspective of motivated cognition provides a useful theoretical framework to better understand adolescent decision making about condom use, particularly for sexually experienced youth. PMID- 26114615 TI - How Valid Is the Checklist for Autism Spectrum Disorder When a Child Has Apraxia of Speech? AB - OBJECTIVE: Our objective was to determine if the Checklist for Autism Spectrum Disorder (CASD) was inadvertently overemphasizing autism symptoms in a population of children without autism. METHODS: Children noted with communication delays were referred to both a developmental pediatrician and a speech and language pathologist for an apraxia and autism evaluation. All children who underwent both autism and apraxia evaluations and met rule-in or rule-out criteria for both diagnoses were included in the study, resulting in a sample size of 30. RESULTS: Our results show that 63.6% of children initially diagnosed with autism also had apraxia, 36.8% of children initially diagnosed with apraxia also had autism, 23.3% had neither, and 23.3% had both. Overall diagnostic accuracy for the CASD was 96.7%. Overall accuracy for the CASD for children without apraxia was 100% and accuracy for children with apraxia was 94.7%. Specificity for the CASD was 100%, while sensitivity was 90.9%. The PPV was 100% and the NPV was 95.0%. CONCLUSION: This study demonstrates that the CASD does not overemphasize autism symptoms in a population of children without autism. It also shows that autism and apraxia are highly comorbid. Thus, it is important to monitor all children diagnosed with apraxia for signs of autism and all children diagnosed with autism for signs of apraxia. This will help identify children as early as possible and allow them access to services appropriate to their needs. PMID- 26114616 TI - Engineering Polyelectrolyte Capsules with Independently Controlled Size and Shape. AB - Polyelectrolyte capsules (PECs) are a promising delivery system that has the ability to carry a large payload of a variety of cargoes. Controlling PEC properties is critical to understanding and tuning their cellular uptake efficiency, kinetics, and mechanism as well as their biodistribution in the body. The lack of a method to independently engineer PEC size, shape, and chemistry impedes both basic understanding of how physicochemical parameters affect PEC behavior in drug delivery and other applications, and the ability to optimize parameters for best function. Here, we report the successful fabrication of PECs having constant surface chemistry with independently controlled size and shape by combining soft organic templates created by the particle stretching method and a modified layer-by-layer (LBL) deposition process. Changing the template dispersion solution during LBL deposition from water to ethanol allowed us to overcome previous issues with organic templates, such as aggregation and template removal. These results will contribute not only to the basic study of the role of capsule shape and size on its function but also to the optimization of capsule properties for drug or imaging carriers, sensors, reactors, and other applications. PMID- 26114617 TI - Production of Calcaride A by Calcarisporium sp. in Shaken Flasks and Stirred Bioreactors. AB - Increased interest in marine resources has led to increased screening of marine fungi for novel bioactive compounds and considerable effort is being invested in discovering these metabolites. For compound discovery, small-scale cultures are adequate, but agitated bioreactors are desirable for larger-scale production. Calcarisporium sp. KF525 has recently been described to produce calcaride A, a cyclic polyester with antibiotic activity, in agitated flasks. Here, we describe improvements in the production of calcaride A in both flasks (13-fold improvement) and stirred bioreactors (200-fold improvement). Production of calcaride A in bioreactors was initially substantially lower than in shaken flasks. The cultivation pH (reduced from 6.8 to <5.4), carbon source (sucrose replacing glucose), C/N ratio and nature of mycelial growth (pellets or filaments) were important in improving calcaride A production. Up to 4.5 mg.g-1 biomass (85 mg.L-1) calcaride A were produced in the bioreactor, which was only slightly less than in shaken flasks (14 mg.g-1, 100 mg.L-1). The results demonstrate that a scalable process for calcaride A production could be developed using an iterative approach with flasks and bioreactors. PMID- 26114618 TI - Heme-nitrosyls: electronic structure implications for function in biology. AB - The question of why mammalian systems use nitric oxide (NO), a potentially hazardous and toxic diatomic, as a signaling molecule to mediate important functions such as vasodilation (blood pressure control) and nerve signal transduction initially perplexed researchers when this discovery was made in the 1980s. Through extensive research over the past two decades, it is now well rationalized why NO is used in vivo for these signaling functions, and that heme proteins play a dominant role in NO signaling in mammals. Key insight into the properties of heme-nitrosyl complexes that make heme proteins so well poised to take full advantage of the unique properties of NO has come from in-depth structural, spectroscopic, and theoretical studies on ferrous and ferric heme nitrosyls. This Account highlights recent findings that have led to greater understanding of the electronic structures of heme-nitrosyls, and the contributions that model complex studies have made to elucidate Fe-NO bonding are highlighted. These results are then discussed in the context of the biological functions of heme-nitrosyls, in particular in soluble guanylate cyclase (sGC; NO signaling), nitrophorins (NO transport), and NO-producing enzymes. Central to this Account is the thermodynamic sigma-trans effect of NO, and how this relates to the activation of the universal mammalian NO sensor sGC, which uses a ferrous heme as the high affinity "NO detection unit". It is shown via detailed spectroscopic and computational studies that the strong and very covalent Fe(II) NO sigma-bond is at the heart of the strong thermodynamic sigma-trans effect of NO, which greatly weakens the proximal Fe-NHis (or Fe-SCys) bond in six coordinate ferrous heme-nitrosyls. In sGC, this causes the dissociation of the proximally bound histidine ligand upon NO binding to the ferrous heme, inducing a significant conformational change that activates the sGC catalytic domain for the production of cGMP. This, in turn, leads to vasodilation and nerve signal transduction. Studies on ferrous heme-nitrosyl model complexes have allowed for a quantification of this thermodynamic sigma-trans effect of NO, through the use of high-resolution crystal structures, binding constant studies, single-crystal vibrational spectroscopy and density functional theory (DFT) calculations. These studies have further identified the singly occupied molecular orbital (SOMO) of the NO complexes as the key MO that mediates the thermodynamic sigma-trans effect of NO. In comparison to ferrous heme-nitrosyls, ferric heme-nitrosyls display thermodynamically much weaker Fe-NO bonds (from NO binding constants), but at the same time much stronger Fe-NO bonds in their ground states (from vibrational spectroscopy). Using spectroscopic investigations coupled to DFT calculations, this apparent contradiction has been rationalized with the involvement of at least three different electronic states in the binding/dissociation of NO to/from ferric hemes. This is of key significance for the release of NO from NO-producing enzymes like NOS, and further forms the basis for ferric hemes to serve as NO transporters in biological systems. PMID- 26114619 TI - Factors affecting the perception of whole-body vibration of occupational drivers: an analysis of posture and manual materials handling and musculoskeletal disorders. AB - Due to the high cost of conducting field measurements, questionnaires are usually preferred for the assessment of physical workloads and musculoskeletal disorders (MSDs). This study compares the physical workloads of whole-body vibration (WBV) and awkward postures by direct field measurements and self-reported data of 45 occupational drivers. Manual materials handling (MMH) and MSDs were also investigated to analyse their effect on drivers' perception. Although the measured values for WBV exposure were very similarly distributed among the drivers, the subjects' perception differed significantly. Concerning posture, subjects seemed to estimate much better when the difference in exposure was significantly large. The percentage of measured awkward trunk and head inclination were significantly higher for WBV-overestimating subjects than non overestimators; 77 and 80% vs. 36 and 33%. Health complaints in terms of thoracic spine, cervical spine and shoulder-arm were also significantly more reported by WBV-overestimating subjects (42, 67, 50% vs. 0, 25, 13%, respectively). Although more MMH was reported by WBV-overestimating subjects, there was no statistical significance in this study. PRACTITIONER SUMMARY: Self-reported exposures of occupational drivers are affected by many other cofactors, and this can result in misinterpretations. A comparison between field measurement and questionnaire was used to highlight the factors affecting the perception of drivers for whole-body vibration (WBV) exposure. Posture and musculoskeletal disorders influenced the perception of the similarly WBV-exposed drivers significantly. PMID- 26114620 TI - Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. AB - OBJECTIVE: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article. METHODS: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. RESULTS: We report elevated CLB and nCLB levels in these subjects. The mean (+/- standard deviation [SD]) increase in CLB levels was 60 +/- 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 +/- 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. SIGNIFICANCE: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment. PMID- 26114621 TI - Dynamics of inflammation biomarkers C-reactive protein, leukocytes, neutrophils, and CD64 on neutrophils before and after major surgical procedures to recognize potential postoperative infection. AB - BACKGROUND: Major trauma and soft tissue injuries result in a substantial activation of systemic immune response and post-traumatic complications such as postoperative infections. The aim was to assess the dynamics of expressed inflammatory biomarkers after surgery and to detect possible postoperative infection. METHODS: A total of 229 patients were included and separated into three different groups, depending on the procedure they underwent (colorectal, maxillofacial, open heart surgery). Biomarkers CD64 on neutrophils, C-reactive protein (CRP), count of leucocytes and neutrophils were measured to detect postoperative infection. RESULTS: The values of all biomarkers after surgery were generally elevated and had then dropped 48 h after the procedure. The levels were dependent on the type of operation and showed higher levels after more serious procedures. In the patients with postoperative infections the values were considerably higher. Moreover, biomarkers' cut-off values for positive infection were higher from patients who underwent surgery, compared to the cut-off values from patients with no surgical procedure. CD64 index was the only biomarker that could predict postoperative infection (p < 0.001). Other biomarkers could not statistically predict the infection. CONCLUSIONS: Newly acquired postoperative infection is difficult to diagnose using just biomarkers due to the strong activation of immune response. CD64 index with its slightly higher cut-off (> 1.27) is the only biomarker that could be used as a diagnostic tool to rapidly detect postoperative bacterial infection. PMID- 26114623 TI - Comments on the Article: "Meta-Analysis of Prevention of Surgical Site Infections after Incision Closure with Triclosan-Coated Sutures: Robustness to New Evidence". PMID- 26114622 TI - Nowhere to Go but Up: Impacts of Climate Change on Demographics of a Short-Range Endemic (Crotalus willardi obscurus) in the Sky-Islands of Southwestern North America. AB - Biodiversity elements with narrow niches and restricted distributions (i.e., 'short range endemics,' SREs) are particularly vulnerable to climate change. The New Mexico Ridge-nosed Rattlesnake (Crotalus willardi obscurus, CWO), an SRE listed under the U.S. Endangered Species Act within three sky islands of southwestern North America, is constrained at low elevation by drought and at high elevation by wildfire. We combined long-term recapture and molecular data with demographic and niche modeling to gauge its climate-driven status, distribution, and projected longevity. The largest population (Animas) is numerically constricted (N = 151), with few breeding adults (Nb = 24) and an elevated inbreeding coefficient (DeltaF = 0.77; 100 years). Mean home range (0.07 km2) is significantly smaller compared to other North American rattlesnakes, and movements are within, not among sky islands. Demographic values, when gauged against those displayed by other endangered/Red-Listed reptiles [e.g., Loggerhead Sea Turtle (Caretta caretta)], are either comparable or markedly lower. Survival rate differs significantly between genders (female 0.16). Plasma samples drawn 360 minutes after ROSC displayed a significant increase in sE-selectin, sL selectin, sI-CAM1, IL-1beta, IL-6, IL-10, and elastase compared to controls. In the CA animals, sE-selectin and elastase increased between 120 and 360 minutes after resuscitation (p < 0.007). Histological analysis revealed neuronal death in hippocampus layer CA1 360 min after resuscitation. CONCLUSION: When evaluated by SDF, the cerebral microcirculation appears unaffected in the early post-CA period despite hypotension, systemic inflammation, endothelial activation, and neuronal injury. PMID- 26114646 TI - Peptidoglycan Branched Stem Peptides Contribute to Streptococcus pneumoniae Virulence by Inhibiting Pneumolysin Release. AB - Streptococcus pneumoniae (the pneumococcus) colonizes the human nasopharynx and is a significant pathogen worldwide. Pneumolysin (Ply) is a multi-functional, extracellular virulence factor produced by this organism that is critical for pathogenesis. Despite the absence of any apparent secretion or cell surface attachment motifs, Ply localizes to the cell envelope of actively growing cells. We sought to characterize the consequences of this surface localization. Through functional assays with whole cells and subcellular fractions, we determined that Ply activity and its release into the extracellular environment are inhibited by peptidoglycan (PG) structure. The ability of PG to inhibit Ply release was dependent on the stem peptide composition of this macromolecule, which was manipulated by mutation of the murMN operon that encodes proteins responsible for branched stem peptide synthesis. Additionally, removal of choline-binding proteins from the cell surface significantly reduced Ply release to levels observed in a mutant with a high proportion of branched stem peptides suggesting a link between this structural feature and surface-associated choline-binding proteins involved in PG metabolism. Of clinical relevance, we also demonstrate that a hyperactive, mosaic murMN allele associated with penicillin resistance causes decreased Ply release with concomitant increases in the amount of branched stem peptides. Finally, using a murMN deletion mutant, we observed that increased Ply release is detrimental to virulence during a murine model of pneumonia. Taken together, our results reveal a novel role for branched stem peptides in pneumococcal pathogenesis and demonstrate the importance of controlled Ply release during infection. These results highlight the importance of PG composition in pathogenesis and may have broad implications for the diverse PG structures observed in other bacterial pathogens. PMID- 26114648 TI - Characterization of the Dielectric Constant in the Trichoderma reesei Cel7B Active Site. AB - An attempt is made to evaluate the dielectric constant of the Trichoderma reesei Cel7B active site. Through kinetic measurements, the pKa value of the catalytic acid E201 is determined. Mutations (away from E201) with net charge changes are introduced to perturb the E201 pKa. It is shown that the mutation with a +1 charge change (including G225R, G230R, and A335R) decreases the pKa of E201, whereas the mutation with a -1 charge change (including Q149E, A222D, G225D, and G230D) increases the pKa. This effect is consistent with the electrostatic interaction between the changed charge and the E201 side chain. The fitting of the experimental data yields an apparent dielectric constant of 25-80. Molecular dynamics simulations with explicit water molecules indicate that the high solvent accessibility of the active site contributes largely to the high dielectric constant. ONIOM calculations show that high dielectric constant benefits the catalysis through decreasing the energy of the transition state relative to that of the enzyme substrate complex. PMID- 26114649 TI - First-Principles Thermochemistry for the Thermal Decomposition of Titanium Tetraisopropoxide. AB - The thermal decomposition of titanium tetraisopropoxide (TTIP) is investigated using quantum chemistry, statistical thermodynamics, and equilibrium composition analysis. A set of 981 Ti-containing candidate species are proposed systematically on the basis of the thermal breakage of bonds within a TTIP molecule. The ground state geometry, vibrational frequencies and hindrance potentials are calculated for each species at the B97-1/6-311+G(d,p) level of theory. Thermochemical data are computed by applying statistical thermodynamics and, if unknown, the standard enthalpy of formation is estimated using balanced reactions. Equilibrium composition calculations are performed under typical combustion conditions for premixed flames. The thermodynamically stable decomposition products for different fuel mixtures are identified. A strong positive correlation is found between the mole fractions of Ti species containing carbon and the TTIP precursor concentration. PMID- 26114647 TI - PKC/ROS-Mediated NLRP3 Inflammasome Activation Is Attenuated by Leishmania Zinc Metalloprotease during Infection. AB - Parasites of the Leishmania genus infect and survive within macrophages by inhibiting several microbicidal molecules, such as nitric oxide and pro inflammatory cytokines. In this context, various species of Leishmania have been reported to inhibit or reduce the production of IL-1beta both in vitro and in vivo. However, the mechanism whereby Leishmania parasites are able to affect IL 1beta production and secretion by macrophages is still not fully understood. Dependent on the stimulus at hand, the maturation of IL-1beta is facilitated by different inflammasome complexes. The NLRP3 inflammasome has been shown to be of pivotal importance in the detection of danger molecules such as inorganic crystals like asbestos, silica and malarial hemozoin, (HZ) as well as infectious agents. In the present work, we investigated whether Leishmania parasites modulate NLRP3 inflammasome activation. Using PMA-differentiated THP-1 cells, we demonstrate that Leishmania infection effectively inhibits macrophage IL-1beta production upon stimulation. In this context, the expression and activity of the metalloprotease GP63 - a critical virulence factor expressed by all infectious Leishmania species - is a prerequisite for a Leishmania-mediated reduction of IL 1beta secretion. Accordingly, L. mexicana, purified GP63 and GP63-containing exosomes, caused the inhibition of macrophage IL-1beta production. Leishmania dependent suppression of IL-1beta secretion is accompanied by an inhibition of reactive oxygen species (ROS) production that has previously been shown to be associated with NLRP3 inflammasome activation. The observed loss of ROS production was due to an impaired PKC-mediated protein phosphorylation. Furthermore, ROS-independent inflammasome activation was inhibited, possibly due to an observed GP63-dependent cleavage of inflammasome and inflammasome-related proteins. Collectively for the first time, we herein provide evidence that the protozoan parasite Leishmania, through its surface metalloprotease GP63, can significantly inhibit NLRP3 inflammasome function and IL-1beta production. PMID- 26114650 TI - A reversed-phase HPLC-UV method developed and validated for simultaneous quantification of six alkaloids from Nicotiana spp. AB - A reversed-phase HPLC-UV method was developed, optimized, and validated for the separation and quantitation of six target alkaloids from leaves of Nicotiana species (nicotine, nornicotine, anatabine, anabasine, myosmine, and cotinine). A bidentate reversed-phase C18 column was used as stationary phase and an alkaline ammonium formate buffer and acetonitrile as mobile phase. The alkaloids were well separated in a short run time of 13min with mobile phase pH 10.5 and a small gradient of 9-13% acetonitrile, and detected using UV at 260nm. Peak parameters were acceptable for all six closely related alkaloids. The proposed method has enough linearity with correlation coefficient >0.999 within the investigated range for all tested alkaloids. Satisfactory precision was achieved for both intra- and inter-day assay, with RSD less than 2% for all alkaloid standards. Reproducibility was also within the acceptable range of RSD <2%. Limit of detection was 1.6MUg/mL for nicotine and below 1MUg/mL for all other alkaloids. The limit of quantification was 2.8 and 4.8MUg/mL for nornicotine and nicotine respectively, and below 2MUg/mL for all other alkaloids. The method was successfully applied for simultaneous analysis of alkaloids in leaves of Nicotiana benthamiana. PMID- 26114651 TI - Determination and pharmacokinetic studies of artesunate and its metabolite in sheep plasma by liquid chromatography-tandem mass spectrometry. AB - A rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneous quantify artesunate and its metabolite in sheep plasma. The plasma samples were prepared by liquid-liquid extraction. Chromatographic separation was achieved on a C18 column (250*4.6mm, 5MUm) using methanol: water (60:40, v/v) (the water included 1mM ammonium acetate, 0.1% formic acid, and 0.02% acetic acid) as the mobile phase. Mass detection was carried out using positive electrospray ionization in multiple reaction monitoring mode. The calibration curve was linear from 1ng/mL to 400ng/mL (r(2)=0.9992 for artesunate, r(2)=0.9993 for its metabolite). The intra- and inter-day accuracy and precision were within the acceptable limits of +/-10% at all concentrations for both artesunate and its metabolite. The recoveries ranged from 92% to 98% at the three concentrations for both. In summary, the LC-MS/MS metho described herein was fully successfully applied to pharmacokinetic studies of artesunate nanoemulsion after intramuscular delivery to sheep. PMID- 26114652 TI - Comparison of orthogonal chromatographic and lectin-affinity microarray methods for glycan profiling of a therapeutic monoclonal antibody. AB - The N-linked glycosylation of four lots of a marketed human therapeutic monoclonal antibody (mAb) was assessed by three orthogonal chromatographic methods and a commercial lectin microarray. For chromatography, the N-glycans were removed enzymatically from the mAbs using PNGase F. Native glycans were determined by HPAEC-PAD using a panel of 21 N-glycan standards and a multi-stage linear gradient eluent profile for sequential analyses of typical neutral and sialylated glycans in one chromatographic run. The monosaccharide contents of these glycans following acid hydrolysis were confirmed by HPAEC-PAD with monosaccharide standards. Glycosylation analysis by HILIC-FD after stoichiometric labelling with two different fluorescent tags (2-AA and 2-AB) enabled direct quantitation. The 2-AA- and 2-AB-labelled versions of the same glycan standard panel yielded distinctive separation profiles suitable for orthogonal identification of mAb glycans. Glycan profiling with the lectin microarray required partial denaturation of the intact mAbs to expose the sequestered Fc N glycans. Glycosylation fingerprints were obtained using a fluorescently labelled antibody directed against human IgG Fc. Fluorescence intensities from the fingerprints were deconvoluted with a proprietary algorithm to obtain semi quantitative "glycan structural class" information. Glycosylation analyses of the four mAb lots by these four methods, which separate and detect oligosaccharides according to different principles, provided complementary and corroboratory qualitative and quantitative information. The predominant N-linked structures were core-fucosylated asialo diantennary structures with varying galactosylation. There were also trace amounts of afucosyl and bisected glycans, but no detectable sialylation by any of the four methods. The therapeutic mAb demonstrated a high degree of consistency in the types and amounts of N-linked glycans in the four lots (<6% CV), and between all four analysis methods (<6% CV). The described methods are co-supported by the excellent quantitative agreement of their results, which is particularly notable considering the orthogonality of their separation and detection mechanisms. PMID- 26114653 TI - Online polar two phase countercurrent chromatography*high performance liquid chromatography for preparative isolation of polar polyphenols from tea extract in a single step. AB - Herein, we report an on-line two-dimensional system constructed by counter current chromatography (CCC) coupling with preparative high-performance liquid chromatography (prep-HPLC) for the separation and purification of polar natural products. The CCC was used as the first dimensional isolation column, where an environmental friendly polar two-phase solvent system of isopropanol and 16% sodium chloride aqueous solution (1:1.2, v/v) was introduced for low toxicity and favorable resolution. In addition, by applying the stop-and-go flow technique, effluents pre-fractionated by CCC was further purified by a preparative column packed with octadecyl silane (ODS) as the second dimension. The interface between the two dimensions was comprised of a 6-port switching valve and an electronically controlled 2-position 10-port switching valve connected with two equivalent holding columns. To be highlighted here, this rationally designed interface for the purpose of smooth desalination, absorption and desorption, successfully solved the solvent compatibility problem between the two dimensional separation systems. The present integrated system was successfully applied in a one-step preparative separation and identification of 10 pure compounds from the water extracts of Tieguanyin tea (Chinese oolong tea). In short, all the results demonstrated that the on-line 2D CCC*LC method is an efficient and green approach for harvesting polar targets in a single step, which showed great promise in drug discovery. PMID- 26114654 TI - Simultaneous determination of intracellular UDP-sugars in hyaluronic acid producing Streptococcus zooepidemicus. AB - Two chromatographic methods for the quantitative analysis of uridine diphosphate (UDP) sugars involved in hyaluronan pathway of Streptococcus zooepidemicus (SEZ) were developed and compared. The sample preparation protocol using centrifugation and extraction in hot ethanol was employed prior to the analyses. Separation was achieved using an anion exchange Spherisorb SAX column or a Shodex QA-825 column connected with a photodiode array (PDA) detector. To increase the throughput of the chromatography method employing the Spherisorb SAX column, the solid phase extraction (SPE) procedure was introduced. Method validation results displayed that limits of detection (LODs) of UDP-glucose (UDP-Glc), UDP-N-acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcA) calculated according to QC Expert software were in the low micromolar range and the coefficient of correlation (R(2)) was above 0.997. However, the analytical technique using the Spherisorb SAX column resulted in 80-90% recoveries and low LODs (<=6.19MUM), the Shodex QA 825 column showed better long-term stability and reproducible chromatographic properties (RSD<=5.60%). The Shodex QA-825 column was successfully used to monitor UDP-sugar levels during the growth rate of SEZ cells. PMID- 26114655 TI - Targeted Overexpression of alpha-Synuclein by rAAV2/1 Vectors Induces Progressive Nigrostriatal Degeneration and Increases Vulnerability to MPTP in Mouse. AB - Mutations, duplication and triplication of alpha-synuclein genes are linked to familial Parkinson's disease (PD), and aggregation of alpha-synuclein (alpha-syn) in Lewy bodies (LB) is involved in the pathogenesis of the disease. The targeted overexpression of alpha-syn in the substantia nigra (SN) mediated by viral vectors may provide a better alternative to recapitulate the neurodegenerative features of PD. Therefore, we overexpressed human wild-type alpha-syn using rAAV2/1 vectors in the bilateral SN of mouse and examined the effects for up to 12 weeks. Delivery of rAAV-2/1-alpha-syn caused significant nigrostriatal degeneration including appearance of dystrophic striatal neurites, loss of nigral dopaminergic (DA) neurons and dissolving nigral neuron bodies in a time-dependent manner. In addition, the alpha-syn overexpressed mice also developed significant deficits in motor function at 12 weeks when the loss of DA neurons exceeded a threshold of 50%. To investigate the sensitivity to neurotoxins in mice overexpressing alpha-syn, we performed an MPTP treatment with the subacute regimen 8 weeks after rAAV injection. The impact of the combined genetic and environmental insults on DA neuronal loss, striatal dopamine depletion, dopamine turnover and motor dysfunction was markedly greater than that of either alone. Moreover, we observed increased phosphorylation (S129), accumulation and nuclear distribution of alpha-syn after the combined insults. In summary, these results reveal that the overexpressed alpha-syn induces progressive nigrostriatal degeneration and increases the susceptibility of DA neurons to MPTP. Therefore, the targeted overexpression of alpha-syn and the combination with environmental toxins may provide valuable models for understanding PD pathogenesis and developing related therapies. PMID- 26114657 TI - Alcohol Use and Older Maori in Aotearoa. AB - This study investigated alcohol use, hazardous and binge drinking prevalence, and their relationships to socio-demographic variables in community dwelling older Maori adults in New Zealand. Alcohol use, hazardous drinking, and binge drinking were assessed with the AUDIT-C in a cross-sectional postal survey of 1042 older Maori people randomly selected from the New Zealand Electoral Roll. A total of 41.2% of all participants reported drinking at hazardous levels. Odds ratios from binomial logistic regression showed hazardous drinking was significantly more likely to occur among males, current smokers, and those with higher local self contained network scores. Binge drinking was reported by 19.6% of the sample, with odds ratios indicating that males, current smokers, and those with higher Maori cultural identification scores were significantly more likely to report binge drinking. The high rates of hazardous and binge drinking prevalence reported in the current study raise issues of concern when considering the health of older Maori people. Results indicate that social networks, gender, smoking status, and Maori cultural identification may influence hazardous and binge drinking alcohol use. However, limitations of the present study also highlight the need for more focused and in-depth research to be conducted with older Maori people to understand the sociocultural context in which alcohol use occurs. PMID- 26114656 TI - Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice. AB - Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-alpha, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-beta1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis. PMID- 26114658 TI - A novel autophagy/mitophagy inhibitor liensinine sensitizes breast cancer cells to chemotherapy through DNM1L-mediated mitochondrial fission. AB - Autophagy inhibition has been widely accepted as a promising therapeutic strategy in cancer, while the lack of effective and specific autophagy inhibitors hinders its application. Here we found that liensinine, a major isoquinoline alkaloid, inhibits late-stage autophagy/mitophagy through blocking autophagosome-lysosome fusion. This effect is likely achieved via inhibiting the recruitment of RAB7A to lysosomes but not to autophagosomes. We further investigated the effects of autophagy inhibition by liensinine on the therapeutic efficacy of chemotherapeutic drugs and found that cotreatment of liensinine markedly decreased the viability and increased apoptosis in breast cancer cells treated with various chemotherapeutic agents. Mechanistically, we found that inhibition of autophagy/mitophagy by liensinine enhanced doxorubicin-mediated apoptosis by triggering mitochondrial fission, which resulted from dephosphorylation and mitochondrial translocation of DNM1L. However, blocking autophagosome/mitophagosome formation by pharmacological or genetic approaches markedly attenuated mitochondrial fission and apoptosis in cells with combinatatorial treatment. Moreover, liensinine was synergized with doxorubicin to inhibit tumor growth in MDA-MB-231 xenograft in vivo. Our findings suggest that liensinine could potentially be further developed as a novel autophagy/mitophagy inhibitor, and a combination of liensinine with classical chemotherapeutic drugs could represent a novel therapeutic strategy for treatment of breast cancer. PMID- 26114660 TI - Synthesis of Cycloprodigiosin Identifies the Natural Isolate as a Scalemic Mixture. AB - The enantiomers of the natural product cycloprodigiosin were prepared using an expedient five-step synthetic sequence that takes advantage of a Schollkopf Barton-Zard (SBZ) pyrrole annulation with a chiral isocyanoacetate and a nitrocyclohexene derivative. Using chiral HPLC and X-ray crystallographic analyses of the synthetically prepared material and natural isolate (isolated from the marine bacterium Pseudoalteromonas rubra), naturally occurring cycloprodigiosin was determined to be a scalemic mixture occurring in an enantiomeric ratio of 83:17 (R)/(S) at C4'. PMID- 26114661 TI - Transcription profile of genes affected in response to pathological changes in drug-induced rat model of acute kidney injury. AB - OBJECTIVE: The objective of the present study was to examine the changes in the expression profile of certain genes in rat model of gentamicin-induced acute kidney injury (AKI) and to see whether time period and routes of administration affect their expression levels. METHODS: Rat AKI model was established with gentamicin injection using two different routes of administration and two different time periods. The models were evaluated through histopathological observations. Renal specific genes were selected on the basis of their role during kidney injury. These genes were analyzed through reverse transcriptase (RT) PCR. RESULTS: Marked disorganization of normal structure of proximal and distal tubules was observed in all the gentamicin-treated groups. Many tubules showed loss of brush border and presence of intratubular protein casts. Changes in gene expression levels were observed for kidney injury molecule (KIM-1), osteopontin, bone morphogenic protein-7 (BMP-7), extracellular signal-regulated kinases (ERK), stem cell factor (SCF) and IL-7 receptor with different levels of significance in the renal injury groups studied depending on the time period and route of administration. CONCLUSION: Gene expression seems to be dependent partly on the type of injury, route of administration and time period after induction of injury. An improved mechanistic understanding of gene regulation pathways in AKI may provide basis for potential therapeutic development. PMID- 26114662 TI - EDTA conditioning of dentine promotes adhesion, migration and differentiation of dental pulp stem cells. AB - AIM: To evaluate the effect of dentine conditioning on migration, adhesion and differentiation of dental pulp stem cells. METHODOLOGY: Dentine discs prepared from extracted human molars were pre-treated with EDTA (10%), NaOCl (5.25%) or H2 O. Migration of dental pulp stem cells towards pre-treated dentine after 24 and 48 h was assessed in a modified Boyden chamber assay. Cell adhesion was evaluated indirectly by measuring cell viability. Expression of mineralization-associated genes (COL1A1, ALP, BSP, DSPP, RUNX2) in cells cultured on pre-treated dentine for 7 days was determined by RT-qPCR. Nonparametric statistical analysis was performed for cell migration and cell viability data to compare different groups and time-points (Mann-Whitney U-test, alpha = 0.05). RESULTS: Treatment of dentine with H2 O or EDTA allowed for cell attachment, which was prohibited by NaOCl with statistical significance (P = 0.000). Furthermore, EDTA conditioning induced cell migration towards dentine. The expression of mineralization associated genes was increased in dental pulp cells cultured on dentine after EDTA conditioning compared to H2 O-pre-treated dentine discs. CONCLUSIONS: EDTA conditioning of dentine promoted the adhesion, migration and differentiation of dental pulp stem cells towards or onto dentine. A pre-treatment with EDTA as the final step of an irrigation protocol for regenerative endodontic procedures has the potential to act favourably on new tissue formation within the root canal. PMID- 26114663 TI - Association between Dopamine Receptor D2 (DRD2) Variations rs6277 and rs1800497 and Cognitive Performance According to Risk Type for Psychosis: A Nested Case Control Study in a Finnish Population Sample. AB - BACKGROUND: There is limited research regarding the association between genes and cognitive intermediate phenotypes in those at risk for psychotic disorders. METHODS: We measured the association between established psychosis risk variants in dopamine D2 receptor (DRD2) and cognitive performance in individuals at age 23 years and explored if associations between cognition and these variants differed according to the presence of familial or clinical risk for psychosis. The subjects of the Oulu Brain and Mind Study were drawn from the general population based Northern Finland 1986 Birth Cohort (NFBC 1986). Using linear regression, we compared the associations between cognitive performance and two candidate DRD2 polymorphisms (rs6277 and rs1800497) between subjects having familial (n=61) and clinical (n=45) risk for psychosis and a random sample of participating NFBC 1986 controls (n=74). Cognitive performance was evaluated using a comprehensive battery of tests at follow-up. RESULTS: Principal components factor analysis supported a three-factor model for cognitive measures. The minor allele of rs6277 was associated with poorer performance on a verbal factor (p=0.003) but this did not significantly interact with familial or clinical risk for psychosis. The minor allele of rs1800497 was associated with poorer performance on a psychomotor factor (p=0.038), though only in those at familial risk for psychotic disorders (interaction p=0.049). CONCLUSION: The effect of two DRD2 SNPs on cognitive performance may differ according to risk type for psychosis, suggesting that cognitive intermediate phenotypes differ according to the type (familial or clinical) risk for psychosis. PMID- 26114664 TI - Bio-inspired synthesis of hybrid silica nanoparticles templated from elastin-like polypeptide micelles. AB - The programmed self-assembly of block copolymers into higher order nanoscale structures offers many attractive attributes for the development of new nanomaterials for numerous applications including drug delivery and biosensing. The incorporation of biomimetic silaffin peptides in these block copolymers enables the formation of hybrid organic-inorganic materials, which can potentially enhance the utility and stability of self-assembled nanostructures. We demonstrate the design, synthesis and characterization of amphiphilic elastin like polypeptide (ELP) diblock copolymers that undergo temperature-triggered self assembly into well-defined spherical micelles. Genetically encoded incorporation of the silaffin R5 peptide at the hydrophilic terminus of the diblock ELP leads to presentation of the silaffin R5 peptide on the coronae of the micelles, which results in localized condensation of silica and the formation of near monodisperse, discrete, sub-100 nm diameter hybrid ELP-silica particles. This synthesis method, can be carried out under mild reaction conditions suitable for bioactive materials, and will serve as the basis for the development and application of functional nanomaterials. Beyond silicification, the general strategies described herein may also be adapted for the synthesis of other biohybrid nanomaterials as well. PMID- 26114665 TI - Comparison of HIV Virologic Failure Rates Between Patients with Variable Adherence to Three Antiretroviral Regimen Types. AB - Medication adherence is a major determinant of antiretroviral (ARV) treatment success and a significant challenge for HIV-positive patients, yet a well-defined adherence threshold to maintain virologic suppression on current ARV regimens remains unclear. The present study evaluated 1915 Kaiser Permanente Southern California HIV-positive patients on one of three regimen types: (1) emtricitabine tenofovir-efavirenz (FTC-TDF-EFV); (2) emtricitabine-tenofovir (FTC-TDF) and raltegravir (RAL); and (3) FTC-TDF and a boosted protease inhibitor, either darunavir (DRV) or atazanavir (ATV), to compare virologic failure rates between patients with varying levels of adherence to the regimens. Medication possession ratios (MPRs) were calculated to determine adherence, and HIV RNA PCR levels drawn 12-18 months after the initial pharmacy claim for the measured drug were used to determine virologic failure, which was defined as two consecutive HIV RNA PCR measurements >=200 copies/mL. Adherence was inversely related to virologic failure, with an 80-90% MPR threshold resulting in no more than 3.5% virologic failure rate. In comparison, >=90% MPR yielded no more that 1.1% virologic failure rate. Although the gold-standard adherence threshold for older ARV regimens has been 95%, an 80-90% MPR appears sufficient to maintain virologic suppression in patients treated with these three ARV regimen types. PMID- 26114666 TI - Numerical and comparative three-dimensional structural analysis of peripheral nerve fibres in epidermis of patients with atopic dermatitis. PMID- 26114668 TI - Much debated controversies of diffuse low-grade gliomas. PMID- 26114671 TI - Human feature-based attention consists of two distinct spatiotemporal processes. AB - In human and nonhuman primates, goal-directed behavior requires the selection of relevant pieces of information from the multitude of simultaneous sensory inputs. Feature-based attention (FBA) plays a crucial role in this selection by improving the neuronal representation of an attended stimulus feature. Of particular interest for understanding the neuronal mechanisms behind FBA is the processing fate of spatially unattended stimuli, either sharing the attended feature attribute or belonging to the attended or to a nonattended feature dimension. Using a wide range of cue/stimulus combinations, we investigated event-related potentials from the human brain, recorded under conditions of different feature attention but constant visual stimulation. We found that neural processing of visual stimuli sharing the dimension or the attribute of the attended target is associated with two distinct spatiotemporal processes, particularly prominent during the selection negativity period. Dimension-based modulation of neural signals first emerged over frontal electrode sites, and temporally preceded and accompanied attribute-specific FBA effects at occipital, parieto-occipital, and parietal electrodes. The findings suggest a process of FBA that not only increases responses of those neurons particularly tuned to the attended attribute but also modulates activity in the cortical module that is selective for the feature dimension to which the attended attribute belongs. PMID- 26114672 TI - Ground-based inhibition: Suppressive perceptual mechanisms interact with top-down attention to reduce distractor interference. AB - Successful attentional function requires inhibition of distracting information (e.g., Deutsch & Deutsch, 1963). Similarly, perceptual segregation of the visual world into figure and ground entails ground suppression (e.g., Likova & Tyler, 2008; Peterson & Skow, 2008). Here, we ask whether the suppressive processes of attention and perception-distractor inhibition and ground suppression-interact to more effectively insulate task performance from interfering information. We used a variant of the Eriksen flanker paradigm to assess the efficacy of distractor inhibition. Participants indicated the right/left orientation of a central arrow, which could be flanked by congruent, neutral, or incongruent stimuli. We manipulated the degree to which the ground region of a display was suppressed and measured the influence of this manipulation on the efficacy with which participants could inhibit responses from incongruent flankers. Greater ground suppression reduced the influence on target identification of interfering, incongruent information, but not that of facilitative, congruent information. These data are the first to show that distractor inhibition interacts with ground suppression to improve attentional function. PMID- 26114673 TI - Interobject grouping facilitates visual awareness. AB - In organizing perception, the human visual system takes advantage of regularities in the visual input to perceptually group related image elements. Simple stimuli that can be perceptually grouped based on physical regularities, for example by forming an illusory contour, have a competitive advantage in entering visual awareness. Here, we show that regularities that arise from the relative positioning of complex, meaningful objects in the visual environment also modulate visual awareness. Using continuous flash suppression, we found that pairs of objects that were positioned according to real-world spatial regularities (e.g., a lamp above a table) accessed awareness more quickly than the same object pairs shown in irregular configurations (e.g., a table above a lamp). This advantage was specific to upright stimuli and abolished by stimulus inversion, meaning that it did not reflect physical stimulus confounds or the grouping of simple image elements. Thus, knowledge of the spatial configuration of objects in the environment shapes the contents of conscious perception. PMID- 26114674 TI - Processing reafferent and exafferent visual information for action and perception. AB - A recent study suggests that reafferent hand-related visual information utilizes a privileged, attention-independent processing channel for motor control. This process was termed visuomotor binding to reflect its proposed function: linking visual reafferences to the corresponding motor control centers. Here, we ask whether the advantage of processing reafferent over exafferent visual information is a specific feature of the motor processing stream or whether the improved processing also benefits the perceptual processing stream. Human participants performed a bimanual reaching task in a cluttered visual display, and one of the visual hand cursors could be displaced laterally during the movement. We measured the rapid feedback responses of the motor system as well as matched perceptual judgments of which cursor was displaced. Perceptual judgments were either made by watching the visual scene without moving or made simultaneously to the reaching tasks, such that the perceptual processing stream could also profit from the specialized processing of reafferent information in the latter case. Our results demonstrate that perceptual judgments in the heavily cluttered visual environment were improved when performed based on reafferent information. Even in this case, however, the filtering capability of the perceptual processing stream suffered more from the increasing complexity of the visual scene than the motor processing stream. These findings suggest partly shared and partly segregated processing of reafferent information for vision for motor control versus vision for perception. PMID- 26114675 TI - Binocular correspondence and the range of fusible horizontal disparities in the central visual field. AB - Binocular disparities underlie precise stereoscopic depth perception but only over a finite range. At large disparities, objects appear diplopic, and depth perception is degraded. Measurements of the range of horizontal disparities for which single vision is experienced have previously been restricted to the horizontal plane of regard. We extended these mappings, in two experiments, to the upper and lower visual fields and eccentric meridians. In Experiment 1, we measured empirical corresponding points and fusional limits at identical elevations in the median plane for 20 participants. We observed a vertical shear in binocular correspondence consistent with a backward inclined empirical vertical horopter and the fusional range centered upon it. In Experiment 2, we mapped the vertical horopter and fusional limits for a second set of elevations in the median plane and at two additional eccentricities and found a similar pattern of results as in Experiment 1. For 23 of 25 participants in this study, we found that the relationship between measurements of the vertical horopter and fusional range is similar to the established relationship between Panum's fusional range and the horizontal horopter. Our data replicate previous findings that the vertical horopter is inclined top back. We are the first to illustrate that the fusional range of horizontal disparities is approximately centered upon the vertical horopter in the median plane and along eccentric meridians. PMID- 26114667 TI - Separable Crossover-Promoting and Crossover-Constraining Aspects of Zip1 Activity during Budding Yeast Meiosis. AB - Accurate chromosome segregation during meiosis relies on the presence of crossover events distributed among all chromosomes. MutSgamma and MutLgamma homologs (Msh4/5 and Mlh1/3) facilitate the formation of a prominent group of meiotic crossovers that mature within the context of an elaborate chromosomal structure called the synaptonemal complex (SC). SC proteins are required for intermediate steps in the formation of MutSgamma-MutLgamma crossovers, but whether the assembled SC structure per se is required for MutSgamma-MutLgamma dependent crossover recombination events is unknown. Here we describe an interspecies complementation experiment that reveals that the mature SC is dispensable for the formation of Mlh3-dependent crossovers in budding yeast. Zip1 forms a major structural component of the budding yeast SC, and is also required for MutSgamma and MutLgamma-dependent crossover formation. Kluyveromyces lactis ZIP1 expressed in place of Saccharomyces cerevisiae ZIP1 in S. cerevisiae cells fails to support SC assembly (synapsis) but promotes wild-type crossover levels in those nuclei that progress to form spores. While stable, full-length SC does not assemble in S. cerevisiae cells expressing K. lactis ZIP1, aggregates of K. lactis Zip1 displayed by S. cerevisiae meiotic nuclei are decorated with SC associated proteins, and K. lactis Zip1 promotes the SUMOylation of the SC central element protein Ecm11, suggesting that K. lactis Zip1 functionally interfaces with components of the S. cerevisiae synapsis machinery. Moreover, K. lactis Zip1-mediated crossovers rely on S. cerevisiae synapsis initiation proteins Zip3, Zip4, Spo16, as well as the Mlh3 protein, as do the crossovers mediated by S. cerevisiae Zip1. Surprisingly, however, K. lactis Zip1-mediated crossovers are largely Msh4/Msh5 (MutSgamma)-independent. This separation-of function version of Zip1 thus reveals that neither assembled SC nor MutSgamma is required for Mlh3-dependent crossover formation per se in budding yeast. Our data suggest that features of S. cerevisiae Zip1 or of the assembled SC in S. cerevisiae normally constrain MutLgamma to preferentially promote resolution of MutSgamma-associated recombination intermediates. PMID- 26114676 TI - Expectations accelerate entry of visual stimuli into awareness. AB - How do expectations influence transitions between unconscious and conscious perceptual processing? According to the influential predictive processing framework, perceptual content is determined by predictive models of the causes of sensory signals. On one interpretation, conscious contents arise when predictive models are verified by matching sensory input (minimizing prediction error). On another, conscious contents arise when surprising events falsify current perceptual predictions. Finally, the cognitive impenetrability account posits that conscious perception is not affected by such higher level factors. To discriminate these positions, we combined predictive cueing with continuous flash suppression (CFS) in which the relative contrast of a target image gradually increases over time. In four experiments we established that expected stimuli enter consciousness faster than neutral or unexpected stimuli. These effects are difficult to account for in terms of response priming, pre-existing stimulus associations, or the attentional mechanisms that cause asynchronous temporal order judgments (of simultaneously presented stimuli). Our results further suggest that top-down expectations play a larger role when bottom-up input is ambiguous, in line with predictive processing accounts of perception. Taken together, our findings support the hypothesis that conscious access depends on verification of perceptual predictions. PMID- 26114677 TI - Modulation of early ERPs by accurate categorization of objects in scenes. AB - The categorization of objects within natural scenes is carried out in a sequence of stages, which may build on the detection of perceptual regularities in the visual appearance of objects or may represent a more semantic level of categorization. Here, we examined the neural correlates of correct categorization of objects in scenes, using natural scenes which were equalized in color and spectral amplitude, and controlled in terms of spatial coherence. Event-related potentials (ERPs) were used to track the early stages of visual processing. Participants viewed degraded (phase-scrambled) versions of natural scenes and then categorized them as depicting animals or people. At an intermediate scrambling level, a negative-going occipitotemporal ERP modulation by categorization accuracy was observed, beginning approximately 150 ms after stimulus onset; at more degraded levels, no ERP modulation was observed. These results suggest that this early negative-going ERP modulation reflects processing of perceptual evidence which is predictive of later correct categorization, even when low-level differences in color, spectral amplitude, and spatial coherence are balanced or controlled. PMID- 26114679 TI - Release of crowding by pattern completion. AB - In crowding, target perception deteriorates in the presence of flanking elements. Crowding is classically explained by low-level mechanisms such as pooling or feature substitution. However, we have previously shown that perceptual grouping between the target and flankers, rather than low-level mechanisms, determines crowding. There are many grouping cues that can determine crowding, such as low- and high-level feature similarity, low- and high-level pattern regularity, and good Gestalt. Here we show that pattern completion, another grouping cue that is important for crowding in foveal vision, is also important in peripheral vision. We also describe computer simulations that show how pattern completion, and crowding in general, can be partly explained by recurrent processing. PMID- 26114678 TI - Single neural code for blur in subjects with different interocular optical blur orientation. AB - The ability of the visual system to compensate for differences in blur orientation between eyes is not well understood. We measured the orientation of the internal blur code in both eyes of the same subject monocularly by presenting pairs of images blurred with real ocular point spread functions (PSFs) of similar blur magnitude but varying in orientations. Subjects assigned a level of confidence to their selection of the best perceived image in each pair. Using a classification-images-inspired paradigm and applying a reverse correlation technique, a classification map was obtained from the weighted averages of the PSFs, representing the internal blur code. Positive and negative neural PSFs were obtained from the classification map, representing the neural blur for best and worse perceived blur, respectively. The neural PSF was found to be highly correlated in both eyes, even for eyes with different ocular PSF orientations (rPos = 0.95; rNeg = 0.99; p < 0.001). We found that in subjects with similar and with different ocular PSF orientations between eyes, the orientation of the positive neural PSF was closer to the orientation of the ocular PSF of the eye with the better optical quality (average difference was ~10 degrees ), while the orientation of the positive and negative neural PSFs tended to be orthogonal. These results suggest a single internal code for blur with orientation driven by the orientation of the optical blur of the eye with better optical quality. PMID- 26114680 TI - Synchronous motion modulates animacy perception. AB - Visual motion serves as a cue for high-level percepts. The present study reports novel modulation of animacy perception through synchronous motion. A target dot moving along a random trajectory was presented. The trajectory was generated based on a variant of 1/f noise; hence, the dot could be perceived as animate. Participants were asked to rate the strength of perceived animacy and perceived intention from the target dot. Several task-irrelevant dots surrounding the target were also presented. Results indicated that perceived animacy and intention were drastically weakened when surrounding dots created synchronous motion with the target dot as compared to when surrounding dots did not create synchronous motion. A series of follow-up experiments replicated these results and revealed specific characteristics of this modulation. The present findings suggest synchronous visual motion serves as a strong modulator of animacy perception. PMID- 26114681 TI - Weber's law in grasping. PMID- 26114682 TI - What determines the relationship between color naming, unique hues, and sensory singularities: Illuminations, surfaces, or photoreceptors? AB - The relationship between the sensory signal of the photoreceptors on one hand and color appearance and language on the other hand is completely unclear. A recent finding established a surprisingly accurate correlation between focal colors, unique hues, and so-called singularities in the laws governing how sensory signals for different surfaces change across illuminations. This article examines how this correlation with singularities depends on reflectances, illuminants, and cone sensitivities. Results show that this correlation holds for a large range of illuminants and for a large range of sensors, including sensors that are fundamentally different from human photoreceptors. In contrast, the spectral characteristics of the reflectance spectra turned out to be the key factor that determines the correlation between focal colors, unique hues, and sensory singularities. These findings suggest that the origins of color appearance and color language may be found in particular characteristics of the reflectance spectra that correspond to focal colors and unique hues. PMID- 26114684 TI - Engaging patiently. PMID- 26114683 TI - Encoding attentional states during visuomotor adaptation. AB - We recently showed that visuomotor adaptation acquired under attentional distraction is better recalled under a similar level of distraction compared to no distraction. This paradoxical effect suggests that attentional state (e.g., divided or undivided) is encoded as an internal context during visuomotor learning and should be reinstated for successful recall (Song & Bedard, 2015). To investigate if there is a critical temporal window for encoding attentional state in visuomotor memory, we manipulated whether participants performed the secondary attention-demanding task concurrently in the early or late phase of visuomotor learning. Recall performance was enhanced when the attentional states between recall and the early phase of visuomotor learning were consistent. However, it reverted to untrained levels when tested under the attentional state of the late phase learning. This suggests that attentional state is primarily encoded during the early phase of learning before motor errors decrease and reach an asymptote. Furthermore, we demonstrate that when divided and undivided attentional states were mixed during visuomotor adaptation, only divided attention was encoded as an internal cue for memory retrieval. Therefore, a single attentional state appears to be primarily integrated with visuomotor memory while motor error reduction is in progress during learning. PMID- 26114685 TI - Oral cancer: Who best to detect oral cancer? PMID- 26114686 TI - Oral tuberculosis lesions. PMID- 26114687 TI - Jaw problems: Update on ARONJ. PMID- 26114688 TI - Sun bed dangers: Ain't no sunshine. PMID- 26114689 TI - Ulceration: More on aphthous ulceration. PMID- 26114690 TI - When Jonathan met Jimmy. PMID- 26114691 TI - NHS dentistry 'not fit for purpose' in 10 years' time. PMID- 26114692 TI - Waterloo and its dental legacy. PMID- 26114694 TI - Which? report finds one in three practices 'refusing new patients'. PMID- 26114697 TI - Biological agents: what they are, how they affect oral health and how they can modulate oral healthcare. AB - Biological agents - biologics, biologicals or biopharmaceuticals - are any medicinal product manufactured in, or extracted from, a biological source. They are often generated by DNA recombinant biotechnology and several dozen therapeutic monoclonal antibodies (mAbs) are now marketed for a variety of indications, increasingly in the management of inflammatory immune-mediated disorders, transplantation rejection and cancer treatments. Immunomodulatory mAbs are expensive, must be given by injection or infusion and can have adverse effects but are increasingly used and can be highly effective agents. This paper reviews these agents and their increasing relevance to oral science and healthcare. PMID- 26114702 TI - A multicentre, multicycle audit of the prescribing practices of three paediatric dental departments in the North of England. AB - BACKGROUND: Odontogenic infections are frequently treated with antimicrobials. The inappropriate use of these medications has led to bacterial resistance and the development of species which are resistant to the antimicrobials currently available. This has serious implications for global public health. AIM: A multicycle clinical audit was carried out to compare the prescribing practices of three paediatric dental departments in the North of England. RESULTS: Results revealed deficiencies in prescribing practices in all three centres. Following education and the provision of an aide-memoire in subsequent cycles, improvements were seen in appropriateness of prescribing, increasing from 28% in the first cycle, to 71% in the third cycle. PMID- 26114703 TI - Predictive value of the admissions process and the UK Clinical Aptitude Test in a graduate-entry dental school. AB - AIM: To assess the association between admissions performance and the UK Clinical Aptitude Test (UKCAT), and subsequent achievement within a graduate-entry dental school. METHOD: The study was conducted at the University of Aberdeen Dental School between 2010 and 2014. Student demographics, pre-admission scores (PAS), Universities and Colleges Admissions Service (UCAS) tariffs, multiple mini interview (MMI) grades, UKCAT scores and percentiles were correlated with academic performance reported as the University Common Assessment Scale (0-20). STATISTICS: Data were analysed by Pearson correlation and multiple regression (IBM((r)) SPSS((r)) Statistics 21). RESULTS: Data were obtained for 71 students (F: 44; M: 27). Student age, MMI, UKCAT scores and UKCAT percentiles demonstrated a correlation with CAS scores (r(2) = 0.119, P = 0.001, r(2) = 0.136, P = 0.001, r(2) = 0.077, P = 0.019 and r(2) = 0.118, P = 0.001, respectively). CONCLUSIONS: This study suggests that student age, candidate performance at MMI and the UKCAT might be a predictor of academic achievement for graduate-entry dental students. PMID- 26114704 TI - Reduction of temporomandibular joint dislocation: an ancient technique that has stood the test of time. AB - The first known recorded evidence for the reduction of a mandibular joint dislocation is documented in a papyrus dated to c. 1500 BC that originated from ancient Egypt. This same technique was later discussed by Hippocrates in Greece and the Hippocratic corpus is referred to in early Islamic writings. It is detailed in medieval European texts and eventually was incorporated into modern dental and medical practice. Today, mandibular joint dislocation is probably not that common but to be included in an important ancient Egyptian treatise, predominately concerned with trauma to the head and neck, could suggest it was a more frequent occurrence in antiquity. This could relate to the heavy tooth wear, frequent antemortem tooth loss and the related sequelae of severe malocclusion and overclosure evident in many surviving ancient Egyptian skulls. PMID- 26114705 TI - Challenges facing NHS dental contract reforms: Pilot exit. AB - This article covers the move forwards from pilot to prototype in the National Health Service (NHS) dental contract reform in England. The current status of the pilot and prototype schemes are summarised and some of the challenges for those practices who will be exiting the pilots discussed. PMID- 26114721 TI - Peter Davey. PMID- 26114722 TI - Denis Reid. PMID- 26114723 TI - Richard Gorham. PMID- 26114726 TI - Committee Opinion No. 640: Cell-free DNA Screening for Fetal Aneuploidy. AB - Noninvasive prenatal screening that uses cell-free DNA from the plasma of pregnant women offers tremendous potential as a screening method for fetal aneuploidy. A number of laboratories have validated different techniques for the use of cell-free DNA as a screening test for fetal aneuploidy. All tests have a high sensitivity and specificity for trisomy 18 and trisomy 21, regardless of which molecular technique is used. Women whose results are not reported, indeterminate, or uninterpretable (a "no call" test result) from cell-free DNA screening should receive further genetic counseling and be offered comprehensive ultrasound evaluation and diagnostic testing because of an increased risk of aneuploidy. Patients should be counseled that cell-free DNA screening does not replace the precision obtained with diagnostic tests, such as chorionic villus sampling or amniocentesis and, therefore, is limited in its ability to identify all chromosome abnormalities. Cell-free DNA screening does not assess risk of fetal anomalies such as neural tube defects or ventral wall defects. Patients who are undergoing cell-free DNA screening should be offered maternal serum alpha fetoprotein screening or ultrasound evaluation for risk assessment. The cell-free DNA screening test should not be considered in isolation from other clinical findings and test results. Management decisions, including termination of the pregnancy, should not be based on the results of the cell-free DNA screening alone. Patients should be counseled that a negative cell-free DNA test result does not ensure an unaffected pregnancy. Given the performance of conventional screening methods, the limitations of cell-free DNA screening performance, and the limited data on cost-effectiveness in the low-risk obstetric population, conventional screening methods remain the most appropriate choice for first-line screening for most women in the general obstetric population. PMID- 26114724 TI - Histone variants as emerging regulators of embryonic stem cell identity. AB - Dynamic regulation of chromatin structure is an important mechanism for balancing the pluripotency and cell fate decision in embryonic stem cells (ESCs). Indeed ESCs are characterized by unusual chromatin packaging, and a wide variety of chromatin regulators have been implicated in control of pluripotency and differentiation. Genome-wide maps of epigenetic factors have revealed a unique epigenetic signature in pluripotent ESCs and have contributed models to explain their plasticity. In addition to the well known epigenetic regulation through DNA methylation, histone posttranslational modifications, chromatin remodeling, and non-coding RNA, histone variants are emerging as important regulators of ESC identity. In this review, we summarize and discuss the recent progress that has highlighted the central role of histone variants in ESC pluripotency and ESC fate, focusing, in particular, on H1 variants, H2A variants H2A.X, H2A.Z and macroH2A and H3 variant H3.3. PMID- 26114727 TI - Committee Opinion No. 641: Human Papillomavirus Vaccination. AB - Human papillomavirus (HPV) is associated with the development of anogenital cancer (including cervical, vaginal, vulvar, penile, and anal), oropharyngeal cancer, and genital warts. Human papillomavirus vaccination can significantly reduce the incidence of anogenital cancer and genital warts. Despite the benefits of HPV vaccines, only approximately one third of girls in the recommended age group have received all three vaccines. Compared with other vaccines recommended in the same age bracket, HPV vaccination rates in the United States are unacceptably low. It is crucial that obstetrician-gynecologists and other providers educate parents and patients on the benefits and safety of HPV vaccination. The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend routine vaccination with HPV vaccine for girls and boys. The nanovalent HPV vaccine is recommended by the Advisory Committee on Immunization Practices and was licensed by the U.S. Food and Drug Administration in December 2014 for girls and boys aged 11-12 years. PMID- 26114725 TI - Intramolecular ex vivo Fluorescence Resonance Energy Transfer (FRET) of Dihydropyridine Receptor (DHPR) beta1a Subunit Reveals Conformational Change Induced by RYR1 in Mouse Skeletal Myotubes. AB - The dihydropyridine receptor (DHPR) beta1a subunit is essential for skeletal muscle excitation-contraction coupling, but the structural organization of beta1a as part of the macromolecular DHPR-ryanodine receptor type I (RyR1) complex is still debatable. We used fluorescence resonance energy transfer (FRET) to probe proximity relationships within the beta1a subunit in cultured skeletal myotubes lacking or expressing RyR1. The fluorescein biarsenical reagent FlAsH was used as the FRET acceptor, which exhibits fluorescence upon binding to specific tetracysteine motifs, and enhanced cyan fluorescent protein (CFP) was used as the FRET donor. Ten beta1a reporter constructs were generated by inserting the CCPGCC FlAsH binding motif into five positions probing the five domains of beta1a with either carboxyl or amino terminal fused CFP. FRET efficiency was largest when CCPGCC was positioned next to CFP, and significant intramolecular FRET was observed for all constructs suggesting that in situ the beta1a subunit has a relatively compact conformation in which the carboxyl and amino termini are not extended. Comparison of the FRET efficiency in wild type to that in dyspedic (lacking RyR1) myotubes revealed that in only one construct (H458 CCPGCC beta1a CFP) FRET efficiency was specifically altered by the presence of RyR1. The present study reveals that the C-terminal of the beta1a subunit changes conformation in the presence of RyR1 consistent with an interaction between the C terminal of beta1a and RyR1 in resting myotubes. PMID- 26114728 TI - RNA sequencing supports distinct reactive oxygen species-mediated pathways of apoptosis by high and low size mass fractions of Bay leaf (Lauris nobilis) in HT 29 cells. AB - Anti-proliferative and pro-apoptotic effects of Bay leaf (Laurus nobilis) in mammalian cancer and HT-29 adenocarcinoma cells have been previously attributed to effects of polyphenolic and essential oil chemical species. Recently, we demonstrated differentiated growth-regulating effects of high (HFBL) versus low molecular mass (LFBL) aqueous fractions of bay leaf and now confirm by comparative effects on gene expression, that HFBL and LFBL suppress HT-29 growth by distinct mechanisms. Induction of intra-cellular lesions including DNA strand breakage by extra-cellular HFBL, invoked the hypothesis that iron-mediated reactive oxygen species with capacity to penetrate cell membrane, were responsible for HFBL-mediated effects, supported by equivalent effects of HFBL in combination with gamma radiation. Activities of HFBL and LFBL were interpreted to reflect differentiated responses to iron-mediated reactive oxygen species (ROS), occurring either outside or inside cells. In the presence of LFBL, apoptotic death was relatively delayed compared with HFBL. ROS production by LFBL mediated p53-dependent apoptosis and recovery was suppressed by promoting G1/S phase arrest and failure of cellular tight junctions. In comparison, intra-cellular anti-oxidant protection exerted by LFBL was absent for extra-cellular HFBL (likely polysaccharide-rich), which potentiated more rapid apoptosis by producing DNA double strand breaks. Differentiated effects on expression of genes regulating ROS defense and chromatic condensation by LFBL versus HFBL, were observed. The results support ferrous iron in cell culture systems and potentially in vivo, can invoke different extra-cellular versus intra-cellular ROS-mediated chemistries, that may be regulated by exogenous, including dietary species. PMID- 26114730 TI - Mathematical Modeling of Nitrous Oxide Production during Denitrifying Phosphorus Removal Process. AB - A denitrifying phosphorus removal process undergoes frequent alternating anaerobic/anoxic conditions to achieve phosphate release and uptake, during which microbial internal storage polymers (e.g., Polyhydroxyalkanoate (PHA)) could be produced and consumed dynamically. The PHA turnovers play important roles in nitrous oxide (N2O) accumulation during the denitrifying phosphorus removal process. In this work, a mathematical model is developed to describe N2O dynamics and the key role of PHA consumption on N2O accumulation during the denitrifying phosphorus removal process for the first time. In this model, the four-step anoxic storage of polyphosphate and four-step anoxic growth on PHA using nitrate, nitrite, nitric oxide (NO), and N2O consecutively by denitrifying polyphosphate accumulating organisms (DPAOs) are taken into account for describing all potential N2O accumulation steps in the denitrifying phosphorus removal process. The developed model is successfully applied to reproduce experimental data on N2O production obtained from four independent denitrifying phosphorus removal study reports with different experimental conditions. The model satisfactorily describes the N2O accumulation, nitrogen reduction, phosphate release and uptake, and PHA dynamics for all systems, suggesting the validity and applicability of the model. The results indicated a substantial role of PHA consumption in N2O accumulation due to the relatively low N2O reduction rate by using PHA during denitrifying phosphorus removal. PMID- 26114729 TI - Disease state changes and safety of long-term donepezil hydrochloride administration in patients with Alzheimer's disease: interim results from the long-term, large-scale J-GOLD study in Japan. AB - BACKGROUND: There have been very few long-term studies involving a large study population; existing studies usually have no more than a few hundred patients with Alzheimer's disease. For these reasons, there are no detailed investigations regarding changes in activities of daily living evaluated by the Functional Assessment Staging Test (FAST). METHODS: A long-term, large-scale observational study of donepezil hydrochloride (Aricept((r)); Eisai Co., Ltd, Tokyo, Japan) is currently in progress. Its objective is to investigate disease state changes associated with the long-term administration of this drug and its safety in patients with Alzheimer's disease. In this report, data collected over a maximum of 24 months were compiled. Efficacy was assessed using FAST and a cognitive function test (Mini-Mental State Examination or the Hasegawa's Dementia Scale Revised). RESULTS: The percentages of patients whose FAST stage improved or remained the same compared to at the start of donepezil hydrochloride administration (baseline) were 91.1% at 6 months, 83.0% at 12 months, 79.5% at 18 months, and 74.8% at 24 months. Multivariate logistic regression analysis was conducted to investigate factors that affect the improvement and maintenance or exacerbation of FAST at 24 months. 'Independence level in the daily life of elderly with dementia' and 'duration of illness' were identified as variables that affected the improvement and maintenance or exacerbation of FAST. Cognitive function improved significantly at 12 weeks and at 6 months compared to baseline, maintained baseline levels at 12 months and at 18 months, and decreased significantly at 24 months compared to baseline. CONCLUSIONS: This is the largest prospective study involving Alzheimer's disease patients in Japan, and we believe it is an important study that shows the reality of daily clinical practice. PMID- 26114732 TI - Correction: Facile rotation around a silicon-phosphorus double bond enabled through coordination to tungsten. AB - Correction for 'Facile rotation around a silicon-phosphorus double bond enabled through coordination to tungsten' by Nora C. Breit et al., Chem. Commun., 2015, DOI: 10.1039/c5cc04247j. PMID- 26114731 TI - Inter-study reproducibility of left ventricular torsion and torsion rate quantification using MR myocardial feature tracking. AB - BACKGROUND: To determine the inter-study reproducibility of MR feature tracking (MR-FT) derived left ventricular (LV) torsion and torsion rates for a combined assessment of systolic and diastolic myocardial function. METHODS: Steady-state free precession (SSFP) cine LV short-axis stacks were acquired at 9:00 (Exam A), 9:30 (Exam B), and 14:00 (Exam C) in 16 healthy volunteers at 3 Tesla. SSFP images were analyzed offline using MR-FT to assess rotational displacement in apical and basal slices. Global peak torsion, peak systolic and peak diastolic torsion rates were calculated using different definitions ("twist", "normalized twist" and "circumferential-longitudinal (CL) shear angle"). Exam A and B were compared to assess the inter-study reproducibility. Morning and afternoon scans were compared to address possible diurnal variation. RESULTS: The different methods showed good inter-study reproducibility for global peak torsion (intraclass correlation coefficient [ICC]: 0.90-0.92; coefficient of variation [CoV]: 19.0-20.3%) and global peak systolic torsion rate (ICC: 0.82-0.84; CoV: 25.9-29.0%). Conversely, global peak diastolic torsion rate showed little inter study reproducibility (ICC: 0.34-0.47; CoV: 40.8-45.5%). Global peak torsion as determined by the CL shear angle showed the best inter-study reproducibility (ICC: 0.90;CoV: 19.0%). MR-FT results were not measurably affected by diurnal variation between morning and afternoon scans (CL shear angle: 4.8 +/- 1.4 degrees , 4.8 +/- 1.5 degrees , and 4.1 +/- 1.6 degrees for Exam A, B, and C, respectively; P = 0.21). CONCLUSION: MR-FT based derivation of myocardial peak torsion and peak systolic torsion rate has high inter-study reproducibility as opposed to peak diastolic torsion rate. The CL shear angle was the most reproducible parameter independently of cardiac anatomy and may develop into a robust tool to quantify cardiac rotational mechanics in longitudinal MR-FT patient studies. PMID- 26114733 TI - Oxidative Stress in Caenorhabditis elegans: Protective Effects of Spartin. AB - Troyer syndrome is caused by a mutation in the SPG20 gene, which results in complete loss of expression of the protein spartin. We generated a genetic model of Troyer syndrome in worms to explore the locomotor consequences of a null mutation of the Caenorhabditis elegans SPG20 orthologue, F57B10.9, also known as spg-20. Spg-20 mutants showed decreased length, crawling speed, and thrashing frequency, and had a shorter lifespan than wild-type animals. These results suggest an age-dependent decline in motor function in mutant animals. The drug paraquat was used to induce oxidative stress for 4 days in the animals. We measured survival rate and examined locomotion by measuring crawling speed and thrashing frequency. After 4 days of paraquat exposure, 77% of wild-type animals survived, but only 38% of spg-20 mutant animals survived. Conversely, animals overexpressing spg-20 had a survival rate of 95%. We also tested lifespan after a 1 hour exposure to sodium azide. After a 24 hour recovery period, 87% of wild type animals survived, 57% of spg-20 mutant animals survived, and 82% of animals overexpressing spg-20 survived. In the behavioral assays, spg-20 mutant animals showed a significant decrease in both crawling speed and thrashing frequency compared with wild-type animals. Importantly, the locomotor phenotype for both crawling and thrashing was rescued in animals overexpressing spg-20. The animals overexpressing spg-20 had crawling speeds and thrashing frequencies similar to those of wild-type animals. These data suggest that the protein F57B10.9/SPG-20 might have a protective role against oxidative stress. PMID- 26114734 TI - Kidney microcirculation response to adenosine stimulation in renal artery stenosis. AB - The purpose of this study was to assess the vasoconstrictive effects of adenosine in the kidney microcirculation in hypertensive patients with renal artery stenosis (RAS). Twelve patients with resistant hypertension and moderate RAS were selected for the study. In all patients, systolic, diastolic and mean translesional pressure gradients, distal pressure (Pd), aortic pressure (Pa) and Pd/Pa ratio were measured using a pressure guidewire at baseline and after intrarenal bolus administration of 400 MUg adenosine. We observed significant changes in mean translesional pressure gradient and systolic Pd after pharmacological stimulation. The results suggest that in hypertensive patients with RAS, vasomotor activity of the kidney microcirculation may be preserved. PMID- 26114735 TI - Use of a high-sensitivity troponin T assay in the assessment and disposition of patients attending a tertiary Australian emergency department: a cross-sectional pilot study. AB - OBJECTIVE: We examined the disposition and outcomes of patients presenting to the ED with symptoms suggestive of acute coronary syndrome undergoing measurement of troponin T using a highly sensitive assay. METHODS: Troponin T (TnT) was measured in 204 consecutive patients (mean age = 65 [+/-18] years, 55% men) presenting to the ED with symptoms suggestive of acute coronary syndrome. RESULTS: Ninety-four patients predominantly had chest pain, 34 had dyspnoea and the remainder had various symptoms. Overall, 96 patients had TnT >14 ng/L (upper reference limit), of whom 31 were admitted to the cardiology service (26 had final cardiac diagnosis [five ST-elevation MI, 10 non-ST-elevation MI, one unstable angina and 10 other cardiac]). Among these 96 patients, 41 had chronic kidney disease, 17 had heart failure and seven had sepsis. At 30 days, death rates among patients who had TnT >14 ng/L with non-cardiac diagnoses and in patients who had TnT >14 ng/L with a cardiac diagnosis were 6.6% and 2.9% (P = 0.652); no death and/or MI occurred in patients with normal TnT levels. At late follow up (median 6.8 months) that was obtained in 189 (93% of 204) patients, four had MI and 14 died (three cardiac deaths). CONCLUSIONS: Despite high-sensitivity TnT assay having a high sensitivity and specificity for myocardial necrosis, the majority of unselected consecutive patients attending ED in whom TnT levels were elevated did not have an acute coronary syndrome. Our pilot study suggests that a larger study is needed to provide evidence to modify management algorithms. PMID- 26114736 TI - Equine allogeneic umbilical cord blood derived mesenchymal stromal cells reduce synovial fluid nucleated cell count and induce mild self-limiting inflammation when evaluated in an lipopolysaccharide induced synovitis model. AB - REASONS FOR PERFORMING STUDY: Improvement has been reported following intra articular (i.a.) injection of mesenchymal stromal cells (MSCs) in several species. These observations have led to the use of i.a. MSCs in equine practice with little understanding of the mechanisms by which perceived improvement occurs. OBJECTIVES: To evaluate the effect of i.a. allogeneic umbilical cord blood (CB-) derived MSCs using a lipopolysaccharide (LPS) induced synovitis model. We hypothesised that i.a. CB-MSCs would reduce the inflammatory response associated with LPS injection. STUDY DESIGN: Randomised, blinded experimental study. METHODS: Feasibility studies evaluated i.a. LPS or CB-MSCs alone into the tarsocrural joint. In the principal study, middle carpal joint synovitis was induced bilaterally with LPS and then CB-MSCs were injected into one middle carpal joint. Lameness, routine synovial fluid analysis, and synovial fluid biomarkers were evaluated at 0, 8, 24, 48 and 72 h. RESULTS: LPS injection alone resulted in transient lameness and signs of inflammation. In joints untreated with LPS, injection of 30 million CB-MSCs resulted in mild synovitis that resolved without treatment. Mild (grade 1-2) lameness in the CB-MSC-treated limb was observed in 2 horses and severe lameness (grade 4) in the 3rd, 24 h post injection. Lameness did not correlate with synovitis induced by CB-MSC injection. Simultaneous injection of LPS and CB-MSCs resulted in significant reduction in synovial fluid total nucleated, neutrophil and mononuclear cell numbers compared with contralateral LPS-only joints. No difference was detected in other parameters associated with synovial fluid analysis or in synovial fluid biomarkers. The incidence of lameness was only different from baseline at 8 h, where horses were lame in CB-MSC limbs. CONCLUSIONS: Allogeneic CB-MSCs reduced synovial fluid cell populations and stimulated mild self-limiting inflammation in the synovitis model. Continued evaluation of the effects of i.a. CB-MSC therapy on synovitis in horses is needed to evaluate anti- and proinflammatory properties of CB-MSCs. Immediate interests are dose, timing of treatment, and treatment frequency. PMID- 26114737 TI - Relationship between prolactin, breast cancer risk, and antipsychotics in patients with schizophrenia: a critical review. AB - OBJECTIVE: A recent meta-analysis showed that breast cancer probably is more common in female patients with schizophrenia than in the general population (effect size = 1.25, P < 0.05). Increasing experimental and epidemiological data have alerted researchers to the influence of prolactin (PRL) in mammary carcinogenesis. We therefore investigated the possible relationship between antipsychotic-induced hyperprolactinemia (HPRL) and breast cancer risk in female patients with schizophrenia. METHOD: A literature search (1950 until January 2015), using the MEDLINE database, was conducted for English-language published clinical trials to identify and synthesize data of the current state of knowledge concerning breast cancer risk (factors) in women with schizophrenia and its (their) relationship between HPRL and antipsychotic medication. RESULTS: Although an increasing body of evidence supports the involvement of PRL in breast carcinogenesis, results of human prospective studies are limited, equivocal, and correlative (with risk ratios ranging from 0.70 to 1.9 for premenopausal women and from 0.76 to 2.03 for postmenopausal women). Moreover, these studies equally do not take into account the local production of PRL in breast epithelium, although amplification or overexpression of the local autocrine/paracrine PRL loop may be a more important mechanism in tumorigenesis. Until now, there is also no conclusive evidence that antipsychotic medication can increase the risk of breast malignancy and mortality. CONCLUSION: Other breast risk factors than PRL, such as nulliparity, obesity, diabetes mellitus, and unhealthy lifestyle behaviours (alcohol dependence, smoking, low physical activity), probably are of greater relevance in individual breast cancer cases within the population of female patients with schizophrenia. PMID- 26114738 TI - Efficacy of Deferasirox (Exjade(r)) in Modulation of Iron Overload in Patients with beta-Thalassemia Intermedia. AB - Because of insufficient erythropoiesis, peripheral hemolysis and increased gastrointestinal iron absorption, iron overload is still a matter of debate in beta-thalassemia intermedia (beta-TI) patients, which can be overcome using iron chelators. However, data on use of iron chelators in beta-TI patients is highly restricted. The aim of this study was to evaluate the efficacy of oral administration of deferasirox (Exjade((r)) or DFX) by assessment of serum ferritin levels in beta-TI patients. In this quasi-experimental study, 50 beta-TI patients with serum ferritin levels >1000 ng/mL were selected and received oral DFX for 12 consecutive months. Iron overload was measured by checking serum ferritin levels every 2 months and the results were compared with the baseline level. The mean serum ferritin was decreased during 1 year of chelation therapy without any toxic effect. Although the difference between baseline ferritin and ferritin levels at the end of second month was not remarkable (p = 0.88), a significant reduction in serum ferritin was observed after 4 (p = 0.01), 6 (p = 0.001), 8 (p < 0.001), 10 (p < 0.001) and 12 months (p < 0.001) of chelation therapy compared to its baseline levels. There was no correlation between baseline ferritin levels and age (p = 0.574). In addition, no statistically significant difference was observed about change in serum ferritin levels after 6 and also 12 months of therapy between patients who had undergone splenectomy and those who did not (p = 0.796 and 0.859, respectively). Iron chelation therapy with DFX is safe and effective in reducing serum ferritin levels in beta-TI patients who suffer from side effects of iron overload. PMID- 26114739 TI - A Mixed-Methods Study of Pain-related Quality of Life in Sickle Cell Vaso Occlusive Crises. AB - The quality of care for sickle cell disease patients hospitalized with a vaso occlusive crisis (VOC) is poor, resulting in staggeringly high healthcare resource utilization. To evaluate in-patient care for VOC, we conducted a mixed methods study of all adult sickle cell disease patients admitted with a VOC from 2010-2012. We quantitatively assessed the quality of care for all patients, and qualitatively studied a subset of frequently admitted patients. In total, there were 182 admissions from 57 unique patients. The median length of stay was 6 days and the 30-day readmission rate was 34.0%. We identified red blood cell transfusion and patient controlled analgesia use as predictors of increased length of stay. Interestingly, unlike prior findings, younger patients (18-30 years old) did not have increased healthcare resource utilization. Moreover, older age appeared to increase readmission rate and enhance the effect of patient controlled analgesia use on length of stay. Interviews of high healthcare resource utilizers revealed significant deficiencies in pain management and a strong desire for individualized care. This is the first study to examine in patient predictors of acute healthcare resource utilization in sickle cell disease patients and to correlate them with qualitative perspectives of high healthcare resource utilizers. PMID- 26114740 TI - Optimal Manual Exchange Transfusion Protocol for Sickle Cell Disease: A Retrospective Comparison of Two Comprehensive Care Centers in the United Kingdom and Canada. AB - Chronic red blood cell (RBC) transfusion is employed for a wide range of sickle cell disease complications, ranging from primary and secondary stroke prophylaxis to prevention of painful vaso-occlusive episodes. Currently different methods are employed by centers for chronic transfusion that include simple, automated and partial manual RBC exchange transfusion. A retrospective cohort study of two different manual RBC exchange transfusion methods was conducted between two comprehensive care centers in Toronto, ON, Canada and London, United Kingdom in 19 and 21 sickle cell disease adults, respectively. London used a weight-based protocol, while Toronto used a unit-based method. Our results indicated that sickle cell disease patients utilizing a weight-based method are more often unable to achieve the prescribed Hb S (HBB: c.20A > T) target compared to the unit-based method (90.0 vs. 53.0% in the weight-based and unit-based methods, respectively, p = 0.0123). On multivariable logistic regression, none of the covariates examined was found to influence the ability to achieve the prescribed Hb S target after accounting for the exchange transfusion method. Mean interval of exchange sessions, session duration, total units of packed RBC, volume of blood used by body weight each year, the mean post exchange hematocrit [or packed cell volume (PCV)] and ferritin change were similar in both cohorts. In conclusion, the unit-based method was more effective at maintaining the prescribed Hb S target. PMID- 26114741 TI - Novel 31.2 kb alpha0 Deletion in a Palestinian Family with alpha-Thalassemia. AB - A previously unknown alpha(0) deletion, designated - -(DANE), was found in three generations of a Danish family of Palestinian origin. Six patients were heterozygous and three patients had deletional Hb H (beta4) disease with a compound heterozygosity for the common -alpha(3.7) (rightward) deletion. Multiplex ligation-dependent probe amplification (MLPA) supplemented by repeated polymerase chain reaction (PCR) amplification identified the 5' and 3' breakpoints in the alpha-globin gene cluster. This novel 31.2 kb deletion (NG_000006.1: g.8800_40007del31208) leads to the removal of the HBZ, HBA2 and HBA1 genes. PMID- 26114743 TI - Factors that Affect Nonurgent Emergency Department Visits in a Publicly Insured Pediatric Population: An Observational Study. AB - BACKGROUND: Publicly insured children have high rates of nonurgent emergency department visits (LAVs). The factors that drive consumption of these services are unknown. METHODS: Demographics, emergency department visits, hospitalizations, missed preventative care appointments, zip code, and asthma status as factors for LAVs were determined by univariate, multivariate, and classification/regression tree analysis. Subjects were publicly insured and received care between March 1 and December 31, 2011. RESULTS: A total of 4,387 children were identified; 856 (19.5%) had at least 1 nonurgent and 1,173 (26.7%) had at least 1 urgent emergency department visit; 526 (12%) missed >=2 primary care appointments and 779 children had asthma. By univariate analysis, at least one high acuity emergency department visit, hospitalization during the study period, and asthma were directly associated with LAVs; age was inversely related. Multivariate and classification tree analyses identified children younger than 31.5 months with at least 1 high acuity emergency department visit as the highest risk group (0.807 visits per patient; 95% confidence interval: 0.699-0.916, p < .00001). Missed appointments, asthma status, hospitalizations, zip code of residence, and gender were not significant factors. CONCLUSIONS: Young age and at least one high acuity emergency department visit are associated with high rates of nonurgent emergency department use among publicly insured children. PMID- 26114745 TI - Control Strategy Scenarios for the Alien Lionfish Pterois volitans in Chinchorro Bank (Mexican Caribbean): Based on Semi-Quantitative Loop Analysis. AB - Ecological and eco-social network models were constructed with different levels of complexity in order to represent and evaluate management strategies for controlling the alien species Pterois volitans in Chinchorro bank (Mexican Caribbean). Levins's loop analysis was used as a methodological framework for assessing the local stability (considered as a component of sustainability) of the modeled management interventions represented by various scenarios. The results provided by models of different complexity (models 1 through 4) showed that a reduction of coral species cover would drive the system to unstable states. In the absence of the alien lionfish, the simultaneous fishing of large benthic epifaunal species, adult herbivorous fish and adult carnivorous fish could be sustainable only if the coral species present high levels of cover (models 2 and 3). Once the lionfish is added to the simulations (models 4 and 5), the analysis suggests that although the exploitation or removal of lionfish from shallow waters may be locally stable, it remains necessary to implement additional and concurrent human interventions that increase the holistic sustainability of the control strategy. The supplementary interventions would require the implementation of programs for: (1) the restoration of corals for increasing their cover, (2) the exploitation or removal of lionfish from deeper waters (decreasing the chance of source/sink meta-population dynamics) and (3) the implementation of bans and re-stocking programs for carnivorous fishes (such as grouper) that increase the predation and competition pressure on lionfish (i.e. biological control). An effective control management for the alien lionfish at Chinchorro bank should not be optimized for a single action plan: instead, we should investigate the concurrent implementation of multiple strategies. PMID- 26114746 TI - Use of hierarchical Bayesian framework in MTS studies to model different causes and novel possible forms of acquired MTS. AB - An integrative account of MTS could be cast in terms of hierarchical Bayesian inference. It may help to highlight a central role of sensory (tactile) precision could play in MTS. We suggest that anosognosic patients, with anesthetic hemisoma, can also be interpreted as a form of acquired MTS, providing additional data for the model. PMID- 26114747 TI - Unexpected Changes in Functionality and Surface Coverage for Au Nanoparticle PEI Conjugates: Implications for Stability and Efficacy in Biological Systems. AB - Cationic polyethylenimine conjugated gold nanoparticles (AuNP-PEI) are a widely studied vector for drug delivery and an effective probe for interrogating NP-cell interactions. However, an inconsistent body of literature currently exists regarding the reproducibility of physicochemical properties, colloidal stability, and efficacy for these species. To address this gap, we systematically examined the preparation, stability, and formation mechanism of PEI conjugates produced from citrate-capped AuNPs. We considered the dependence on relative molar mass, Mr, backbone conformation, and material source. The conjugation mechanism of Au PEI was probed using attenuated total reflectance FTIR and X-ray photoelectron spectroscopy, revealing distinct fates for citrate when interacting with different PEI species. The differences in residual citrate, PEI properties, and sample preparation resulted in distinct products with differentiated stability. Overall, branched PEI (25 kDa) conjugates exhibited the greatest colloidal stability in all media tested. By contrast, linear PEI (25 kDa) induced agglomeration. Colloidal stability of the products was also observed to correlate with displaced citrate, which supports a glaring knowledge gap that has emerged regarding the role of this commonly used carboxylate species as a "place holder" for conjugation with ligands of broad functionalities. We observed an unexpected and previously unreported conversion of amine functional groups to quaternary ammonium species for 10 kDa branched conjugates. Results suggest that the AuNP surface catalyzes this conversion. The product is known to manifest distinct processes and uptake in biological systems compared to amines and may lead to unintentional toxicological consequences or decreased efficacy as delivery vectors. Overall, comprehensive physicochemical characterization (tandem spectroscopy methods combined with physical measurements) of the conjugation process provides a methodology for elucidating the contributing factors of colloidal stability and chemical functionality that likely influence the previously reported variations in conjugate properties and biological response models. PMID- 26114748 TI - The Prognostic Impact of Histopathological Variants in Patients with Advanced Urothelial Carcinoma. AB - PURPOSE: This study investigated the prognostic role of histopathological variants in patients with advanced urothelial carcinoma (UC) who were treated with systemic chemotherapy. MATERIALS AND METHODS: We conducted a retrospective analysis of patients with unresectable and/or metastatic UC who underwent systemic chemotherapy between January 1997 and December 2013 in Kaohsiung Chang Gung Memorial Hospital. Histopathological types were categorized as pure UC (PUC) and variants of UC (VUC). The overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier analyses and Cox proportional regression models. RESULTS: A total of 206 patients were enrolled; 53 of the patients (25.7%) had histopathological variants. The most common variant was squamous differentiation (68%). Compared with patients with PUC, patients with VUC significantly exhibited upper urinary tract origin (75% vs 52%, P = .008), chronic renal insufficiency (40% vs 23%, P = .03), and carboplatin-based chemotherapy (28% vs 10%, P = .003). According to univariate analysis, the median OS for PUC patients was significantly higher than that for VUC patients (15.9 vs 11.3 months, P = .007). The median PFS for patients who received first-line chemotherapy was 6.1 and 3.8 months for PUC patients and VUC patients, respectively (P = .004). Multivariate analysis revealed that VUC (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.16-2.40, P = .006), an age <= 60 years (HR 0.70, 95% CI 0.49-0.99, P = .045) and presence of visceral metastasis (HR 1.54, 95% CI 1.11-2.13, P = .009) were independent factors facilitating OS prediction. CONCLUSIONS: The presence of histopathological variants indicates poor survival outcomes in patients with metastatic UC. Accordingly, VUC should be integrated into and considered an independent factor in a predictive model of survival. PMID- 26114749 TI - Chemosensory Perception of Predators by Larval Amphibians Depends on Water Quality. AB - The acquisition of sensory information by animals is central to species interactions. In aquatic environments, most taxa use chemical cues to assess predation risk and other key ecological factors. A number of laboratory studies suggest that anthropogenic pollutants can disrupt chemoreception, even when at low, non-toxic concentrations, but there are few tests of whether real-world variation in water quality affects chemoreception. Here we investigate whether chemosensory perception of predators by the gray treefrog, Hyla versicolor, depends on water quality. We evaluated the anti-predator response of anuran tadpoles housed in water collected from three sites that represent strong contrasts in the concentration and types of dissolved solids: de-chlorinated tap water, water from an impaired stream, and treated wastewater effluent. Behavioral assays were conducted in laboratory aquaria. Chemical cues associated with predation were generated by feeding tadpoles to dragonfly predators held in containers, and then transferring aliquots of water from dragonfly containers to experimental aquaria. Tadpoles housed in tap water responded to predator cues with an activity reduction of 49%. Tadpoles housed in stream water and wastewater effluent responded to predator cues by reducing activity by 29% and 24% respectively. The results of factorial ANOVA support the hypothesis that the response to predator cues depended on water type. These results show that alteration of the chemical environment can mediate chemical perception of predators in aquatic ecosystems. Because most aquatic species rely on chemoreception to gather information on the location of food and predators, any impairment of sensory perception likely has important ecological consequences. PMID- 26114750 TI - Genetic and Non-Genetic Inheritance of Natural Antibodies Binding Keyhole Limpet Hemocyanin in a Purebred Layer Chicken Line. AB - Natural antibodies (NAb) are defined as antibodies present in individuals without known antigenic challenge. Levels of NAb binding keyhole limpet hemocyanin (KLH) in chickens were earlier shown to be heritable, and to be associated with survival. Selective breeding may thus provide a strategy to improve natural disease resistance. We phenotyped 3,689 white purebred laying chickens for KLH binding NAb of different isotypes around 16 weeks of age. Heritabilities of 0.12 for the titers of total antibodies (IgT), 0.14 for IgM, 0.10 for IgA, and 0.07 for IgG were estimated. We also estimated high, positive genetic, and moderate to high, positive phenotypic correlations of IgT, IgM, IgA, and IgG, suggesting that selective breeding for NAb can be done on all antibody isotypes simultaneously. In addition, a relatively substantial non-genetic maternal environmental effect of 0.06 was detected for IgM, which may reflect a transgenerational effect. This suggests that not only the genes of the mother, but also the maternal environment affects the immune system of the offspring. Breaking strength and early eggshell whiteness of the mother's eggs were predictive for IgM levels in the offspring, and partly explained the observed maternal environmental effects. The present results confirm that NAb are heritable, however maternal effects should be taken into account. PMID- 26114751 TI - "Just Another Tool for Online Studies" (JATOS): An Easy Solution for Setup and Management of Web Servers Supporting Online Studies. AB - We present here "Just Another Tool for Online Studies" (JATOS): an open source, cross-platform web application with a graphical user interface (GUI) that greatly simplifies setting up and communicating with a web server to host online studies that are written in JavaScript. JATOS is easy to install in all three major platforms (Microsoft Windows, Mac OS X, and Linux), and seamlessly pairs with a database for secure data storage. It can be installed on a server or locally, allowing researchers to try the application and feasibility of their studies within a browser environment, before engaging in setting up a server. All communication with the JATOS server takes place via a GUI (with no need to use a command line interface), making JATOS an especially accessible tool for researchers without a strong IT background. We describe JATOS' main features and implementation and provide a detailed tutorial along with example studies to help interested researchers to set up their online studies. JATOS can be found under the Internet address: www.jatos.org. PMID- 26114752 TI - The Impact of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on Rates of Malignancy for Fine-Needle Aspiration Diagnostic Categories. AB - BACKGROUND: Increased recognition of the indolent nature of noninvasive follicular variant of papillary thyroid carcinoma (NFVPTC) along with greater insight into the molecular alterations of these tumors has prompted endocrine pathologists to question whether these tumors warrant a diagnosis of carcinoma. However, a change in terminology would affect the rates of malignancy of fine needle aspiration (FNA) diagnostic categories. Therefore, the aim of this study was to determine the percentage decrease in associated risk of malignancy for each FNA diagnostic category if NFVPTCs were no longer termed carcinomas. METHODS: We evaluated a cohort of 655 FNAs with subsequent resection specimens over a 22-month time period. The diagnoses of the preceding FNAs were recorded according to the Bethesda System for Reporting Thyroid Cytopathology. For cases with more than one preceding FNA, the FNA diagnosis associated with the highest risk of malignancy was identified. Slides for all resection specimens with a diagnosis of FVPTC were reviewed to identify noninvasive tumors. By definition, all of these tumors were encapsulated, partially encapsulated, or well circumscribed and lacked any indication of infiltrative growth, capsular penetration, or lymphovascular invasion. RESULTS: Our cohort of 655 FNAs with subsequent resection specimens included 53 (8.1%) nondiagnostic (ND), 167 (25.5%) benign, 97 (14.8%) atypia/follicular lesion of undetermined significance (AUS/FLUS), 88 (13.4%) suspicious for follicular neoplasm (SFN), 94 (14.4%) suspicious for malignancy (SUS), and 156 (23.8%) malignant cases (POS). Surgical resections demonstrated benign findings in 309 (47.2%) and malignant tumors in 346 (52.8%), including 85 NFVPTCs accounting for 24.6% of malignancies. Our rates of malignancy for ND, benign, AUS/FLUS, SFN, SUS, and POS were 18.9%, 13.2%, 39.2%, 45.5%, 87.2%, and 98.7%, respectively. If NFVPTC were no longer termed carcinoma, these rates would drop to 17.0% (10% decrease), 5.4% (59% decrease), 21.6% (45% decrease), 37.5% (18% decrease), 45.7% (48% decrease), and 93.6% (5% decrease), respectively. CONCLUSION: Our findings demonstrate that if terminology were changed and NFVPTCs were not considered carcinomas, the rates of malignancy for FNA diagnostic categories would be substantially decreased, with the most clinically significant decrease seen in the SUS category, which demonstrated a relative decrease of nearly 50%. PMID- 26114753 TI - Habitat Fragmentation Intensifies Trade-Offs between Biodiversity and Ecosystem Services in a Heathland Ecosystem in Southern England. AB - While habitat fragmentation represents a major threat to global biodiversity, its impacts on provision of ecosystem services are largely unknown. We analysed biodiversity value and provision of multiple ecosystem services in 110 fragments of lowland heathland ecosystems in southern England, in which vegetation dynamics have been monitored for over 30 years. Decreasing fragment size was found to be associated with a decrease in biodiversity and recreational values, but an increase in relative carbon storage, aesthetic value and timber value. The trade off between either biodiversity or recreational values with the other ecosystem services therefore became more pronounced as heathland size decreased. This was attributed to a higher rate of woody succession in smaller heathland fragments over the past three decades, and contrasting values of different successional vegetation types for biodiversity and provision of ecosystem services. These results suggest that habitat fragmentation can reduce the potential for developing "win win" solutions that contribute to biodiversity conservation while also supporting socio-economic development. Approaches to multi-purpose management of fragmented landscapes should therefore consider the potential trade offs in ecosystem services and biodiversity associated with fragmentation, in order to make an effective contribution to sustainable development. PMID- 26114754 TI - LPS-Induced G-CSF Expression in Macrophages Is Mediated by ERK2, but Not ERK1. AB - Granulocyte colony-stimulating factor (G-CSF) selectively stimulates proliferation and differentiation of neutrophil progenitors which play important roles in host defense against infectious agents. However, persistent G-CSF production often leads to neutrophilia and excessive inflammatory reactions. There is therefore a need to understand the mechanism regulating G-CSF expression. In this study, we showed that U0126, a MEK1/2 inhibitor, decreases lipopolysaccharide (LPS)-stimulated G-CSF promoter activity, mRNA expression and protein secretion. Using short hairpin RNA knockdown, we demonstrated that ERK2, and not ERK1, involves in LPS-induced G-CSF expression, but not LPS-regulated expression of TNF-alpha. Reporter assays showed that ERK2 and C/EBPbeta synergistically activate G-CSF promoter activity. Further chromatin immunoprecipitation (ChIP) assays revealed that U0126 inhibits LPS-induced binding of NF-kappaB (p50/p65) and C/EBPbeta to the G-CSF promoter, but not their nuclear protein levels. Knockdown of ERK2 inhibits LPS-induced accessibility of the G-CSF promoter region to DNase I, suggesting that chromatin remodeling may occur. These findings clarify that ERK2, rather than ERK1, mediates LPS-induced G CSF expression in macrophages by remodeling chromatin, and stimulates C/EBPbeta dependent activation of the G-CSF promoter. This study provides a potential target for regulating G-CSF expression. PMID- 26114755 TI - Hierarchical phrase-based grammatical analysis of language samples from Cantonese speaking children with and without autism. AB - The present study made a reference to Zhu Dexi's phrase-based grammar approach to analyse Cantonese utterances hierarchically into 14 syntactic structures (SS). A total of 68 speech samples from Cantonese-speaking children with and without Autism Spectrum Disorder (ASD) were collected. The mean length of utterance in words (MLUw), the number of syntactic structures (NOSS), the number of different syntactic structures (NODSS) and the flexibility of syntactic structures (FSS) of the samples were calculated. Comparisons among four groups of typically developing (TD) children revealed that all the indexes show developmental changes across age stages. Comparisons between ASD subjects and their age-matched (AM) and MLUw-matched (MM) normal peers were done. MLUw, NOSS and NODSS and FSS could be used to distinguish autistic children from their AM normal peers, but only FSS could be used to distinguish ASD from MM groups qualitatively and quantitatively. The lack of production of SP, V1O/SV2 and Coord1Coord2 with low FSS may be one of the factors that will affect ASD children's further syntactic development. PMID- 26114756 TI - Potential Role of Circulating microRNA-21 for Hepatocellular Carcinoma Diagnosis: A Meta-Analysis. AB - BACKGROUND: Circulating microRNA-21 (miR-21) is known to be aberrantly expressed in hepatocellular carcinoma (HCC) patients, and this implies that microRNA-21 is a promising and novel indicator of HCC. However, a systematic evaluation of the performance of microRNA-21 as a diagnostic marker for HCC has yet to be conducted. Therefore, the test performance of circulating miR-21 for HCC was assessed in this study. METHODS: Three common international databases and a Chinese electronic database were used to search for literature on the diagnostic accuracy of microRNA-21 for HCC. The pooled results included the sensitivity and specificity of microRNA-21 for HCC detection and were analyzed with a random effect model. The area under summary receiver operating characteristic curve (AUC) was used to estimate overall test performance. RESULTS: A total of 339 HCC patients and 338 controls without HCC from four published studies were eligible for the meta-analysis and included in our study. The test performance of circulating miR-21 in HCC detection was assessed with the summary estimates of sensitivity and specificity, which were 81.2% (95% CI: 70.8% to 88.4%) and 84.8% (95% CI: 75.1% to 91.2%), respectively. The value of AUC was 0.90 (95% CI: 0.87 to 0.92). Significant inter-study heterogeneity was detected by our analysis, and sub-group analyses suggested that the type of control group was probably a source of heterogeneity. CONCLUSIONS: Our current findings suggested that circulating miR-21 can serve as a potential co-biomarker for early-stage HCC diagnosis. Thorough large-scale studies are needed to confirm the generalizability of our findings. PMID- 26114758 TI - Streptococcus oligofermentans Inhibits Streptococcus mutans in Biofilms at Both Neutral pH and Cariogenic Conditions. AB - Homeostasis of oral microbiota can be maintained through microbial interactions. Previous studies showed that Streptococcus oligofermentans, a non-mutans streptococci frequently isolated from caries-free subjects, inhibited the cariogenic Streptococcus mutans by the production of hydrogen peroxide (HP). Since pH is a critical factor in caries formation, we aimed to study the influence of pH on the competition between S. oligofermentans and S. mutans in biofilms. To this end, S. mutans and S. oligofermentans were inoculated alone or mixed at 1:1 ratio in buffered biofilm medium in a 96-well active attachment model. The single- and dual-species biofilms were grown under either constantly neutral pH or pH-cycling conditions. The latter includes two cycles of 8 h neutral pH and 16 h pH 5.5, used to mimic cariogenic condition. The 48 h biofilms were analysed for the viable cell counts, lactate and HP production. The last two measurements were carried out after incubating the 48 h biofilms in buffers supplemented with 1% glucose (pH 7.0) for 4 h. The results showed that S. oligofermentans inhibited the growth of S. mutans in dual-species biofilms under both tested pH conditions. The lactic acid production of dual-species biofilms was significantly lower than that of single-species S. mutans biofilms. Moreover, dual-species and single-species S. oligofermentans biofilms grown under pH cycling conditions (with a 16 h low pH period) produced a significantly higher amount of HP than those grown under constantly neutral pH. In conclusion, S. oligofermentans inhibited S. mutans in biofilms not only under neutral pH, but also under pH-cycling conditions, likely through HP production. S. oligofermentans may be a compelling probiotic candidate against caries. PMID- 26114757 TI - Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes. AB - High rates of error-prone replication result in the rapid accumulation of genetic diversity of RNA viruses. Recent studies suggest that mutation rates are selected for optimal viral fitness and that modest variations in replicase fidelity may be associated with viral attenuation. Arthropod-borne viruses (arboviruses) are unique in their requirement for host cycling and may necessitate substantial genetic and phenotypic plasticity. In order to more thoroughly investigate the correlates, mechanisms and consequences of arbovirus fidelity, we selected fidelity variants of West Nile virus (WNV; Flaviviridae, Flavivirus) utilizing selection in the presence of a mutagen. We identified two mutations in the WNV RNA-dependent RNA polymerase associated with increased fidelity, V793I and G806R, and a single mutation in the WNV methyltransferase, T248I, associated with decreased fidelity. Both deep-sequencing and in vitro biochemical assays confirmed strain-specific differences in both fidelity and mutational bias. WNV fidelity variants demonstrated host-specific alterations to replicative fitness in vitro, with modest attenuation in mosquito but not vertebrate cell culture. Experimental infections of colonized and field populations of Cx. quinquefaciatus demonstrated that WNV fidelity alterations are associated with a significantly impaired capacity to establish viable infections in mosquitoes. Taken together, these studies (i) demonstrate the importance of allosteric interactions in regulating mutation rates, (ii) establish that mutational spectra can be both sequence and strain-dependent, and (iii) display the profound phenotypic consequences associated with altered replication complex function of flaviviruses. PMID- 26114759 TI - Identification and electrophysiological evaluation of 2-methylbenzamide derivatives as Nav1.1 modulators. AB - Voltage-gated sodium channels (Nav) are crucial to the initiation and propagation of action potentials (APs) in electrically excitable cells, and during the past decades they have received considerable attention due to their therapeutic potential. Here, we report for the first time the synthesis and the electrophysiological evaluation of 16 ligands based on a 2-methylbenzamide scaffold that have been identified as Nav1.1 modulators. Among these compounds, N,N'-(1,3-phenylene)bis(2-methylbenzamide) (3a) has been selected and evaluated in ex-vivo experiments in order to estimate the activation impact of such a compound profile. It appears that 3a increases the Nav1.1 channel activity although its overall impact remains moderate. Altogether, our preliminary results provide new insights into the development of small molecule activators targeting specifically Nav1.1 channels to design potential drugs for treating CNS diseases. PMID- 26114760 TI - Encapsulation of vegetable oils as source of omega-3 fatty acids for enriched functional foods. AB - Polyunsaturated omega-3 fatty acids (PUFAs), a functional component present in vegetable oils, are generally recognized as being beneficial to health. Omega-3 PUFAs are rich in double bonds and unsaturated in nature; this attribute makes them highly susceptible to lipid oxidation and unfit for incorporation into long shelf life foods. The microencapsulation of oils in a polymeric matrix (mainly polysaccharides) offers the possibility of controlled release of the lipophilic functional ingredient and can be useful for the supplementation of foods with PUFAs. The present paper provides a literature review of different vegetable sources of omega-3 fatty acids, the functional effects of omega-3 fatty acids, different microencapsulation methods that can possibly be used for the encapsulation of oils, the properties of vegetable oil microcapsules, the effect of encapsulation on oxidation stability and fatty acid composition of vegetable oils, and the incorporation of long-chain omega-3 polyunsaturated fatty acids in foods. PMID- 26114761 TI - Incidence of and Risk Factors for Mastoiditis after Intensity Modulated Radiotherapy in Nasopharyngeal Carcinoma. AB - PURPOSE: To report the incidence of and risk factors for mastoiditis after intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Retrospective analysis of pretreatment and follow-up magnetic resonance imaging (MRI) data for 451 patients with NPC treated with IMRT at a single institution. The diagnosis of mastoiditis was based on MRI; otomastoid opacification was rated as Grade 0 (none), 1 (mild), 2 (moderate) or 3 (severe) by radiologists blinded to clinical outcome. This study mainly focused on severe mastoiditis; patients were divided into three groups: the G0M (Grade 0 mastoiditis before treatment) group, G1-2M (Grade 1 to 2 mastoiditis before treatment) group and G3M (Grade 3 mastoiditis before treatment) group. The software SAS9.3 program was used to analyze the data. RESULTS: For the entire cohort, the incidence of Grade 3 mastoiditis was 20% before treatment and 31%, 19% and 17% at 3, 12 and 24 months after radiotherapy, respectively. In the G0M group, the incidence of severe mastoiditis was 0% before treatment and 23%, 15% and 13% at 3, 12 and 24 months after radiotherapy, respectively. Multivariate analysis revealed T category (OR=0.68, 95% CI = 0.469 to 0.984), time (OR=0.668, 95% CI = 0.59 to 0.757) and chemotherapy (OR=0.598, 95% CI = 0.343 to 0.934) were independent factors associated with severe mastoiditis in the G0M group after treatment. CONCLUSIONS: Mastoiditis, as diagnosed by MRI, occurs as a progressive process that regresses and resolves over time in patients with NPC treated using IMRT. PMID- 26114762 TI - Development of a Novel Rabies Simulation Model for Application in a Non-endemic Environment. AB - Domestic dog rabies is an endemic disease in large parts of the developing world and also epidemic in previously free regions. For example, it continues to spread in eastern Indonesia and currently threatens adjacent rabies-free regions with high densities of free-roaming dogs, including remote northern Australia. Mathematical and simulation disease models are useful tools to provide insights on the most effective control strategies and to inform policy decisions. Existing rabies models typically focus on long-term control programs in endemic countries. However, simulation models describing the dog rabies incursion scenario in regions where rabies is still exotic are lacking. We here describe such a stochastic, spatially explicit rabies simulation model that is based on individual dog information collected in two remote regions in northern Australia. Illustrative simulations produced plausible results with epidemic characteristics expected for rabies outbreaks in disease free regions (mean R0 1.7, epidemic peak 97 days post-incursion, vaccination as the most effective response strategy). Systematic sensitivity analysis identified that model outcomes were most sensitive to seven of the 30 model parameters tested. This model is suitable for exploring rabies spread and control before an incursion in populations of largely free-roaming dogs that live close together with their owners. It can be used for ad-hoc contingency or response planning prior to and shortly after incursion of dog rabies in previously free regions. One challenge that remains is model parameterisation, particularly how dogs' roaming and contacts and biting behaviours change following a rabies incursion in a previously rabies free population. PMID- 26114763 TI - Swabbing Surgical Sites Does Not Improve the Detection of Staphylococcus aureus Carriage in High-Risk Surgical Patients. AB - BACKGROUND: A major risk factor for the development of surgical site infections is Staphylococcus aureus carriage. Compared with non-carriers, S. aureus carriers have up to a 14-fold greater risk for post-surgical infections. Pre-operative screening for S. aureus carriage is controversial. Yet, targeted screening in high-risk patients or from clinically relevant sites may be beneficial. We aimed to determine whether S. aureus detection in high-risk surgical patients would be increased by culturing surgical sites, in addition to the nares, vs. nares-only culturing. METHODS: Adults undergoing pre-operative evaluations in orthopedic and neurosurgical clinics were eligible for participation. For each subject, specimens were collected from the anterior nares and from the proposed surgical site. Samples were inoculated onto methicillin-resistant S. aureus-selective chromogenic agar plates and blood agar plates. RESULTS: Of 150 subjects, 80 (53.3%) were women and 70 (46.7%) men. The mean age was 61 years and 77/150 (51.3%) had a BMI>=30. Culture results were available for 147/150 subjects. Of the 147 surgical site cultures, 54 (36.7%), 51 (34.7%), and 28 (19.0%) were collected from knee, hip, and lumbar sites, respectively; the remaining 14 (9.5%) were from cervical, thoracic, or infra-clavicular sites. Overall, 35/147 (23.8%) nasal cultures grew S. aureus; 29/147 (19.7%) grew methicillin-susceptible S. aureus (MSSA), and 6/147 (4.1%) grew methicillin-resistant S. aureus (MRSA). Only 2/147 (1.4%) surgical site cultures grew S. aureus; both grew MSSA and MSSA was cultured also from the nasal swabs of these subjects. Using nasal culture+surgical site culture as "true positive," the percentage of additional S. aureus carriers detected by the addition of surgical site screening was zero as compared to nasal screening alone. CONCLUSIONS: The detection of S. aureus carriage in high-risk surgical patients is not improved by swabbing surgical sites in addition to the nares. PMID- 26114765 TI - Sampling and Pooling Methods for Capturing Herd Level Antibiotic Resistance in Swine Feces using qPCR and CFU Approaches. AB - The aim of this article was to define the sampling level and method combination that captures antibiotic resistance at pig herd level utilizing qPCR antibiotic resistance gene quantification and culture-based quantification of antibiotic resistant coliform indicator bacteria. Fourteen qPCR assays for commonly detected antibiotic resistance genes were developed, and used to quantify antibiotic resistance genes in total DNA from swine fecal samples that were obtained using different sampling and pooling methods. In parallel, the number of antibiotic resistant coliform indicator bacteria was determined in the same swine fecal samples. The results showed that the qPCR assays were capable of detecting differences in antibiotic resistance levels in individual animals that the coliform bacteria colony forming units (CFU) could not. Also, the qPCR assays more accurately quantified antibiotic resistance genes when comparing individual sampling and pooling methods. qPCR on pooled samples was found to be a good representative for the general resistance level in a pig herd compared to the coliform CFU counts. It had significantly reduced relative standard deviations compared to coliform CFU counts in the same samples, and therefore differences in antibiotic resistance levels between samples were more readily detected. To our knowledge, this is the first study to describe sampling and pooling methods for qPCR quantification of antibiotic resistance genes in total DNA extracted from swine feces. PMID- 26114766 TI - Oceanographic Conditions Limit the Spread of a Marine Invader along Southern African Shores. AB - Invasive species can affect the function and structure of natural ecological communities, hence understanding and predicting their potential for spreading is a major ecological challenge. Once established in a new region, the spread of invasive species is largely controlled by their dispersal capacity, local environmental conditions and species interactions. The mussel Mytilus galloprovincialis is native to the Mediterranean and is the most successful marine invader in southern Africa. Its distribution there has expanded rapidly and extensively since the 1970s, however, over the last decade its spread has ceased. In this study, we coupled broad scale field surveys, Ecological Niche Modelling (ENM) and Lagrangian Particle Simulations (LPS) to assess the current invaded distribution of M. galloprovincialis in southern Africa and to evaluate what prevents further spread of this species. Results showed that all environmentally suitable habitats in southern Africa have been occupied by the species. This includes rocky shores between Rocky Point in Namibia and East London in South Africa (approx. 2800 km) and these limits coincide with the steep transitions between cool-temperate and subtropical-warmer climates, on both west and southeast African coasts. On the west coast, simulations of drifting larvae almost entirely followed the northward and offshore direction of the Benguela current, creating a clear dispersal barrier by advecting larvae away from the coast. On the southeast coast, nearshore currents give larvae the potential to move eastwards, against the prevalent Agulhas current and beyond the present distributional limit, however environmental conditions prevent the establishment of the species. The transition between the cooler and warmer water regimes is therefore the main factor limiting the northern spread on the southeast coast; however, biotic interactions with native fauna may also play an important role. PMID- 26114764 TI - Compliance to Cell Phone-Based EMA Among Latino Youth in Outpatient Treatment. AB - Outpatient treatment practices for adolescent substance users utilize retrospective self-report to monitor drug use. Cell phone-based ecological momentary assessment (CEMA) overcomes retrospective self-report biases and can enhance outpatient treatment, particularly among Latino adolescents, who have been understudied with regard to CEMA. This study explores compliance to text message-based CEMA with youth (n = 28; 93% Latino) in outpatient treatment. Participants were rotated through daily, random, and event-based CEMA strategies for 1-month periods. Overall compliance was high (>80%). Compliance decreased slightly over the study period and was less during random versus daily strategies and on days when alcohol use was retrospectively reported. Findings suggest that CEMA is a viable monitoring tool for Latino youth in outpatient treatment, but further study is needed to determine optimal CEMA strategies, monitoring time periods, and the appropriateness of CEMA for differing levels of substance use. PMID- 26114767 TI - Interpregnancy Intervals in the United States: Data From the Birth Certificate and the National Survey of Family Growth. AB - OBJECTIVE: To describe data on interpregnancy intervals (IPI), defined as the timing between a live birth and conception of a subsequent live birth, from a subset of jurisdictions that adopted the 2003 revised birth certificate. Because this information is available among revised jurisdictions only, the national representativeness of IPI and related patterns to the entire United States were assessed using the 2006-2010 National Survey of Family Growth (NSFG). METHODS: Birth certificate data are based on 100% of births registered in 36 states and the District of Columbia that adopted the 2003 revised birth certificate in 2011 (83% of 2011 U.S. births). The "Date of last live birth" item on the birth certificate was used to calculate months between the birth occurring in 2011 and the previous birth. These data were compared with pregnancy data from a nationally representative sample of women from the 2006-2010 NSFG. RESULTS: Jurisdiction-specific median IPI ranged from 25 months (Idaho, Montana, North Dakota, South Dakota, Utah, and Wisconsin) to 32 months (California) using birth certificate data. Overall, the distribution of IPI from the birth certificate was similar to NSFG for IPI less than 18 months (30% and 29%), 18 to 59 months (50% and 52%), and 60 months or more (21% and 18%). Consistent patterns in IPI distribution by data source were seen by age at delivery, marital status, education, number of previous live births, and Hispanic origin and race, with the exception of differences in IPI of 60 months or more among non-Hispanic black women and women with a bachelor's degree or higher. PMID- 26114768 TI - Infrared Laser Spectroscopy of the L-Shaped Cl-HCl Complex Formed in Superfluid (4)He Nanodroplets. AB - Chlorine atoms, generated through the thermal decomposition of Cl2, are solvated in superfluid helium nanodroplets and clustered with HCl molecules. The H-Cl stretching modes of these clusters are probed via infrared laser spectroscopy. A band centered at ~2880.8 cm(-1) is assigned to the binary Cl-HCl complex on the basis of HCl pressure dependence and difference mass spectra. The band lies in the "free" HCl stretching region, implying that the complex is not hydrogen bound. Furthermore, the breadth of the band (~2 cm(-1) fwhm) is consistent with an assignment to a predominantly b-type component of the H-Cl stretch, as the dominant b-type selection rules and A rotational constant allow for high energy rotational excitations that efficiently couple to droplet excitations, resulting in fast rotational deactivation. Despite the lack of rotational fine structure, which would verify the assignment, the observed band is consistent with the stabilization of a weakly bound complex having an approximately L-shaped geometry. Frequency computations for a rigid, L-shaped complex reveal that the transition dipole moment vector points almost entirely along the b inertial axis; indeed, the signal-to-noise ratio in our experiment precluded the observation of an a-type component of the HCl stretching band for the complex. No bands were observed that could be assigned to a linear H-bonded Cl-HCl complex. Additionally, we located bands that are consistent with the formation of Cl2-HCl, Cl2-(HCl)2, and Cl-(HCl)2. Two vibrations of the Cl-(HCl)2 complex were found, and harmonic frequencies and intensities computed for a cyclic structure are consistent with the observations. PMID- 26114769 TI - Correction: Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment. PMID- 26114770 TI - Quantitative Mass Density Image Reconstructed from the Complex X-Ray Refractive Index. AB - We demonstrate a new analytical X-ray computed tomography technique for visualizing and quantifying the mass density of materials comprised of low atomic number elements with unknown atomic ratios. The mass density was obtained from the experimentally observed ratio of the imaginary and real parts of the complex X-ray refractive index. An empirical linear relationship between the X-ray mass attenuation coefficient of the materials and X-ray energy was found for X-ray energies between 8 keV and 30 keV. The mass density image of two polymer fibers was quantified using the proposed technique using a scanning-type X-ray microbeam computed tomography system equipped with a wedge absorber. The reconstructed mass density agrees well with the calculated one. PMID- 26114771 TI - Study of the forced degradation behavior of prasugrel hydrochloride by liquid chromatography with mass spectrometry and liquid chromatography with NMR detection and prediction of the toxicity of the characterized degradation products. AB - Prasugrel was subjected to forced degradation studies under conditions of hydrolysis (acid, base, and neutral), photolysis, oxidation, and thermal stress. The drug showed liability in hydrolytic as well as oxidative conditions, resulting in a total of four degradation products. In order to characterize the latter, initially mass fragmentation pathway of the drug was established with the help of mass spectrometry/time-of-flight, multiple stage mass spectrometry and hydrogen/deuterium exchange data. The degradation products were then separated on a C18 column using a stability-indicating volatile buffer method, which was later extended to liquid chromatography-mass spectrometry studies. The latter highlighted that three degradation products had the same molecular mass, while one was different. To characterize all, their mass fragmentation pathways were established in the same manner as the drug. Subsequently, liquid chromatography nuclear magnetic resonance (NMR) spectroscopy data were collected. Proton and correlation liquid chromatography with NMR spectroscopy studies highlighted existence of diastereomeric behavior in one pair of degradation products. Lastly, toxicity prediction by computer-assisted technology (TOPKAT) and deductive estimation of risk from existing knowledge (DEREK) software were employed to assess in silico toxicity of the characterized degradation products. PMID- 26114772 TI - Trigeminal neuralgia: pleonasm and miscalculation. PMID- 26114775 TI - Corrigendum. PMID- 26114777 TI - Chelation for autism spectrum disorder (ASD). AB - BACKGROUND: It has been suggested that the severity of autism spectrum disorder (ASD) symptoms is positively correlated with the level of circulating or stored toxic metals, and that excretion of these heavy metals, brought about by the use of pharmaceutical chelating agents, results in improved symptoms. OBJECTIVES: To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms. SEARCH METHODS: We searched the following databases on 6 November 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including three trials registers. In addition we checked references lists and contacted experts. SELECTION CRITERIA: All randomised controlled trials of pharmaceutical chelating agents compared with placebo in individuals with ASD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data. We did not conduct a meta-analysis, as only one study was included. MAIN RESULTS: We excluded nine studies because they were non-randomised trials or were withdrawn before enrolment. We included one study, which was conducted in two phases. During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three-day course of oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms. AUTHORS' CONCLUSIONS: This review included data from only one study, which had methodological limitations. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed. PMID- 26114778 TI - A new approach to determining net impulse and identification of its characteristics in countermovement jumping: reliability and validity. AB - Examining a countermovement jump (CMJ) force-time curve related to net impulse might be useful in monitoring athletes' performance. This study aimed to investigate the reliability of alternative net impulse calculation and net impulse characteristics (height, width, rate of force development, shape factor, and proportion) and validate against the traditional calculation in the CMJ. Twelve participants performed the CMJ in two sessions (48 hours apart) for test retest reliability. Twenty participants were involved for the validity assessment. Results indicated intra-class correlation coefficient (ICC) of >= 0.89 and coefficient of variation (CV) of <= 5.1% for all of the variables except for rate of force development (ICC = 0.78 and CV = 22.3%). The relationship between the criterion and alternative calculations was r = 1.00. While the difference between them was statistically significant (245.96 +/- 63.83 vs. 247.14 +/- 64.08 N s, p < 0.0001), the effect size was trivial and deemed practically minimal (d = 0.02). In conclusion, variability of rate of force development will pose a greater challenge in detecting performance changes. Also, the alternative calculation can be used practically in place of the traditional calculation to identify net impulse characteristics and monitor and study athletes' performance in greater depth. PMID- 26114779 TI - Evaluation of the DSM-5 severity indicator for binge eating disorder in a clinical sample. AB - OBJECTIVE: This study tested the new DSM-5 severity criterion for binge eating disorder (BED) based on frequency of binge-eating in a clinical sample. This study also tested overvaluation of shape/weight as an alternative severity specifier. METHOD: Participants were 834 treatment-seeking adults diagnosed with DSM-5 BED using semi-structured diagnostic and eating-disorder interviews. Participants sub-grouped based on DSM-5 severity levels and on overvaluation of shape/weight were compared on demographic and clinical variables. RESULTS: Based on DSM-5 severity definitions, 331 (39.7%) participants were categorized as mild, 395 (47.5%) as moderate, 83 (10.0%) as severe, and 25 (3.0%) as extreme. Analyses comparing three (mild, moderate, and severe/extreme) severity groups revealed no significant differences in demographic variables or body mass index (BMI). Analyses revealed significantly higher eating-disorder psychopathology in the severe/extreme than moderate and mild groups and higher depression in moderate and severe/extreme groups than the mild group; effect sizes were small. Participants characterized with overvaluation (N = 449; 54%) versus without overvaluation (N = 384; 46%) did not differ significantly in age, sex, BMI, or binge-eating frequency, but had significantly greater eating-disorder psychopathology and depression. The robustly greater eating-disorder psychopathology and depression levels (medium-to-large effect sizes) in the overvaluation group was observed without attenuation of effect sizes after adjusting for ethnicity/race and binge-eating severity/frequency. CONCLUSIONS: Our findings provide support for overvaluation of shape/weight as a severity specifier for BED as it provides stronger information about the severity of homogeneous groupings of patients than the DSM-5 rating based on binge-eating. PMID- 26114781 TI - Xylitol and caries prevention. AB - DATA SOURCES: Cochrane Oral Health Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL, Web of Science Conference Proceedings, Proquest Dissertations and Theses, US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the WHO Clinical Trials Registry Platform for ongoing trials. No language or year restrictions were used. STUDY SELECTION: Randomised controlled trials assessing the effects of xylitol products on dental caries in children and adults. DATA EXTRACTION AND SYNTHESIS: Two review authors independently screened the results of the electronic searches, extracted data and assessed the risk of bias of the included studies. Authors were contacted where possible for missing data or clarification where feasible. For continuous outcomes, means and standard deviations were used to obtain the mean difference and 95% confidence interval (CI). Continuous data was used to calculate prevented fractions (PF) and 95% CIs to summarise the percentage reduction in caries. For dichotomous outcomes, reported risk ratios (RR) and 95% CIs were used. As there were fewer than four studies included in the meta analysis, a fixed effect model was used. RESULTS: Ten studies were included with a total of 5903 participants. One study was assessed as being at low risk of bias, two were assessed as unclear risk of bias with seven at high risk of bias. Over 2.5-3 years, low quality evidence demonstrated that with 4216 children analysed, a fluoride toothpaste with 10% xylitol (exact dosage unsure) reduced caries by 13% when compared to a fluoride only toothpaste. (PF -0.13, 95% CI 0.18 to -0.08. Remaining evidence of the use of xylitol in children has risk of bias and uncertainty of effect and was therefore insufficient to determine a benefit from xylitol. Four studies reported that there were no adverse effects from any of the interventions. Two studies reported similar rates of adverse effects between study arms. The remaining studies either mentioned adverse effects but did not report any usable data, or did not mention them at all. Adverse effects include sores in the mouth, cramps, bloating, constipation, flatulence and loose stool or diarrhoea. CONCLUSIONS: Low quality evidence suggested that fluoride toothpaste containing xylitol may be more effective than fluoride-only toothpaste for preventing caries in the permanent teeth of children. The effect estimate should be interpreted with caution due to high risk of bias and the fact that it was derived from two studies that were carried out by the same authors in the same population. The remaining evidence was low to very low quality and is insufficient to determine whether any other xylitol containing products can prevent caries in infants, older children or adults. PMID- 26114780 TI - The Dimerization State of the Mammalian High Mobility Group Protein AT-Hook 2 (HMGA2). AB - The mammalian high mobility group protein AT-hook 2 (HMGA2) is a chromosomal architectural transcription factor involved in cell transformation and oncogenesis. It consists of three positively charged "AT-hooks" and a negatively charged C-terminus. Sequence analyses, circular dichroism experiments, and gel filtration studies showed that HMGA2, in the native state, does not have a defined secondary or tertiary structure. Surprisingly, using combined approaches of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) chemical cross-linking, analytical ultracentrifugation, fluorescence resonance energy transfer (FRET), and mass spectrometry, we discovered that HMGA2 is capable of self-associating into homodimers in aqueous buffer solution. Our results showed that electrostatic interactions between the positively charged "AT-hooks" and the negatively charged C-terminus greatly contribute to the homodimer formation. PMID- 26114782 TI - Mother-to-child transmission of Streptococcus mutans. AB - DATA SOURCES: PubMed, the Cochrane Library databases and the Virtual Health Library were searched from January 1950, with a manual search of the reference lists of the included studies. STUDY SELECTION: Duplicate papers, case reports, case series, descriptive studies, review articles, opinion articles and letters were excluded along with studies on children with oral defects, and ongoing preventative/restorative treatment and mothers who used antimicrobial substances. Two authors independently screened the title and abstract of all identified records, with consensus if required by a third author. A PECO (E= exposure) strategy was used to assess the eligibility of identified papers: observational human studies whose subjects were mother and child pairs; P contaminated by S.mutans; E comparison according to the presence and absence of S.mutans; C and whether there is vertical transmission (as defined by molecular analyses); O. DATA EXTRACTION AND SYNTHESIS: Included studies were assessed for risk of bias. Two researchers extracted data on the methods, participants and outcomes, and the authors were contacted when it was necessary to clarify details. The percentage of transmission before and after the year 2000 was evaluated using the t-test and the molecular analysis technique was evaluated using ANOVA. A cumulative meta analysis based on the publication year was performed, combining studies that assessed mother/child bionomy (pairs) and presented the percentage of transmission. RESULTS: Thirty-six cross-sectional studies were included, with the age of the children varying among the studies from three weeks to 15 years. All but one of the studies confirmed the vertical transmission of S. mutans from mother to child by genetic methods. The pooled cumulative meta-analysis demonstrated vertical transmission of S. mutans from mother to child (p<0.01) and showed a tendency of reduction in the percentage of vertical transmission compared with the year the studies were published.There was no significant difference in the transmission rate according to the type of technique used (p=0.39; ANOVA test). Quality assessment found that twenty-eight studies had bias such as confounding factors. All of the studies included were cross-sectional studies and therefore none was randomised. There were no reports of blinding in the selected studies although some studies evaluated the testing accuracy and repeatability or calibration; all included microbiological repetition. CONCLUSIONS: There is scientific evidence of vertical transmission of S. mutans from mother to child as there was an association between S. mutans strains in mothers and their respective children. PMID- 26114783 TI - Maternal xylitol and mutans streptococci transmission. AB - DATA SOURCES: PubMed, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials databases and the ClinicalTrials.gov registry were searched with related articles'. Experts were contacted and a manual search of reference lists was undertaken. STUDY SELECTION: Randomised or quasi-randomised controlled trials that evaluated the maternal use of xylitol gum on Mutans Streptococci (MS) colonisation in infants. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed data extraction with a third reviewer asked to resolve any disagreements. Cochrane risk of bias tool was used to assess the quality of studies. Two reviewers independently appraised the methodological quality. The primary outcome measure was presence of MS in the saliva or plaque of infants, with the secondary outcome measure being occurrence of dental decay. RESULTS: 11 studies published between 2000 and 2012 involving a total of 601 patients were included. Sample sizes ranged from 60 to 195 and the daily dose of xylitol consumption ranged from 1.95g to 5.28g. Follow-up ranged from six months to 120 months. There was a significant difference between the two groups, with infants in the control group experiencing greater incidences of MS in their plaque or saliva. Risk ratios were 0.44 (95% CI: 0.08-2.40) at 6-9 months, 0.54 (95% CI: 0.39-0.73) at 12-18 months, 0.60 (95% CI: 0.34-1.08) at 24 months, 0.56 (95% CI: 0.40-0.79) at 36 months and 0.61 (95% CI: 0.48-0.76) at 60 months. Caries data could not be pooled. CONCLUSIONS: Xylitol consumption by mothers with high MS levels was associated with a significant reduction in the mother-to-child transmission of salivary MS. These findings are based on evidence that may have suffered from biases. PMID- 26114784 TI - Caries prevention - little evidence for use of chlorhexidine varnishes and gels. AB - DATA SOURCES: Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and CINAHL. STUDY SELECTION: Randomised controlled trials (RCTs) comparing the effects of chlorhexidine-containing oral products with no treatment or placebo on dental caries, and comparing the effects of one chlorhexidine-containing oral product with another were considered. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted trial data and assessed risk of bias. Owing to the clinical diversity of the included studies with respect to age, composition of intervention, and variation in outcome measures and follow-up, meta-analysis was not carried out. A narrative synthesis was presented. RESULTS: Eight trials were included. Six were at high risk of bias and two at unclear risk. Six trials compared chlorhexidine varnish with placebo or no treatment. Data from two trials (690 patients) one using 10% chlorhexidine varnish and the other, 40%, showed that this led to an increase in the DMFS increment in the varnish group of 0.53 (95% CI; -0.47 to 1.53). Only one trial involving 496 patients and using 10% chlorhexidine varnish provided usable data for elevated mutans streptococci levels > 4 with RR 0.93 (95% CI; 0.80 to 1.07). Two trials (487 patients) compared 0.12% chlorhexidine gel with no treatment in the primary dentition. The presence of new caries gave rise to a 95% confidence interval that was compatible with either an increase or a decrease in caries incidence (RR 1.00, 95% CI 0.36 to 2.77). CONCLUSIONS: The authors found little evidence from the eight trials on varnishes and gels included in this review to either support or refute the assertion that chlorhexidine is more effective than placebo or no treatment in the prevention of caries or the reduction of mutans streptococci levels in children and adolescents. There were no trials on other products containing chlorhexidine such as sprays, toothpastes, chewing gums or mouthrinses. Further high quality research is required, in particular evaluating the effects on both the primary and permanent dentition and using other chlorhexidine-containing oral products. PMID- 26114785 TI - Insufficient evidence that slow-release fluoride devices reduce caries. AB - DATA SOURCES: Cochrane Oral Health Group's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, US National Institutes of Health Trials Register and World Health Organisation (WHO) International Clinical Trials Registry Platform. STUDY SELECTION: Parallel randomised controlled trials (RCTs) of any type of slow-release fluoride device irrespective of publication status, language or blinding were considered. Split mouth studies were excluded. DATA EXTRACTION AND SYNTHESIS: Standard Cochrane methods were followed with at least two reviewers independently undertaking all the key steps. RESULTS: Only one trial which was considered to be at high risk of bias was included. The trial included 174 children with 132 available for two year examination. However statistical analysis was performed on only the 63 children (31 in intervention group, 32 in control group) who had retained the beads (retention rate was 47.7% at two years). Among these 63 children, caries increment was reported to be statistically significantly lower in the intervention group than in the control group (DMFT: mean difference -0.72, 95% confidence interval (CI) -1.23 to -0.21; DMFS: mean difference -1.52, 95% CI 2.68 to -0.36 (very low quality evidence)). Although this difference was clinically significant, it only holds true for those children who retained the fluoride beads; over 50% of the children did not retain the beads. Adverse effects were not reported. CONCLUSIONS: There is insufficient evidence to determine the caries-inhibiting effect of slow-release fluoride glass beads. The body of evidence available is of very low quality and there is a potential overestimation of benefit to the average child. The applicability of the findings to the wider population is unclear; the study had included children from a deprived area that had low levels of fluoride in drinking water, and were considered at high risk of carries. In addition, the evidence was only obtained from children who still had the bead attached at two years (48% of all available children); children who had lost their slow-release fluoride devices earlier might not have benefited as much from the devices. PMID- 26114786 TI - Adjunctive tests cannot replace scalpel biopsy for oral cancer diagnosis. AB - DATA SOURCES: Medline, the Cochrane Diagnostic Test Accuracy Studies Register, the Cochrane Oral Health Groups Trials Register, Embase and MEDION. STUDY SELECTION: Two of the reviewers independently assessed titles abstracts and extracted data. Cross-sectional diagnostic test accuracy studies (or consecutive series) and randomised studies of diagnostic test accuracy that reported the diagnostic test accuracy of vital staining, oral cytology, light-based detection and oral spectroscopy, blood or saliva analysis used as an adjunct to conventional oral examination in detecting PMD or oral squamous cell carcinoma of the lip or oral cavity were considered. Scalpel, punch or fine needle aspiration biopsy with histological diagnosis was the reference test. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using a modified version of QUADAS-2. Meta analysis was used to combine the results of studies for each index test using the bivariate approach to estimate the expected values of sensitivity and specificity. Meta-regressionanalysis was undertaken to explore possible sources of heterogeneity. RESULTS: Forty-one studies, recruiting 4002 patients were included. No single study could be classified as being at low risk of bias across all domains. Fourteen studies evaluated vital staining, 13 studies oral cytology and 13 studies light-based detection or oral spectroscopy, while six studies assessed two combined index tests. There were no eligible diagnostic accuracy studies evaluating blood or salivary sample analysis. CONCLUSIONS: The overall quality of the included studies was poor. None of the adjunctive tests can be recommended as a replacement for the currently used standard of a scalpel biopsy and histological assessment. Given the relatively high values of the summary estimates of sensitivity and specificity for cytology, this would appear to offer the most potential. Combined adjunctive tests involving cytology warrant further investigation. PMID- 26114787 TI - Little evidence for the effectiveness of chemiluminescence and autofluorescent imaging devices as oral cancer screening adjuncts. AB - DATA SOURCES: Medline/PubMed. STUDY SELECTION: Primary studies where an optical device was used for investigation, screening or as a diagnostic tool for OSCC or OPMD were considered. DATA EXTRACTION AND SYNTHESIS: Data were abstracted by two reviewers independently and the biological plausibility, technical feasibility and diagnostic performance assessed. RESULTS: Twenty-five studies were included, 13 involving the use of chemiluminescence and 12 using autofluorescence with some using both. Chemiluminescence showed sensitivity at detecting any OPMDs and oral cancer, but preferentially detects leukoplakia and may fail to spot red patches. The additive use of toluidine blue may improve specificity. Tissue autofluorescence is sensitive at detecting white, red and white and red patches, and the area of fluorescence visualisation loss often extends beyond the clinically visible lesion. However, in addition to OPMDs, it may detect erythematous lesions of benign inflammation resulting in false-positive test results. CONCLUSIONS: In agreement with previous reviews, there is inadequate evidence to draw valid conclusions on the effectiveness of chemiluminescence and autofluorescent imaging devices as screening adjuncts. There is limited evidence for their use in primary care, and these tools are better suited to specialist clinics in which there is a higher prevalence of disease and where experienced clinicians may better discriminate between benign and malignant lesions. PMID- 26114788 TI - Low level laser therapy may reduce risk of oral mucositis. AB - DATA SOURCES: Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CINHAL, Web of Science, Scopus, LILACS, Conference proceedings of the International Society of Paediatric Oncology, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology and Oncology, and Multinational Association of Supportive Care in Cancer and the reference lists of identified studies. STUDY SELECTION: Two reviewers independently selected studies for inclusion with randomised controlled trials (RCTs) and quasi-RCTs being considered. DATA EXTRACTION AND SYNTHESIS: Data were extracted using a specifically developed form and study quality was assessed using the Cochrane risk of bias tool. Dichotomous outcomes data were synthesised using the risk ratio (RR) and 95% confidence interval (CI). Continuous outcomes measured using different scales were synthesised using the standardised mean difference (SMD) while those using the same scale were synthesised using the weighted mean difference (WMD). RESULTS: Eighteen RCTs involving 1144 patients were included. Four trials were considered to be at low risk of bias across all domains. Prophylactic LLLT reduced the overall risk of severe mucositis (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.20 to 0.67; P = 0.001). Compared to placebo/no therapy LLLT also reduced the following outcomes; severe mucositis at the time of anticipated maximal mucositis RR = 0.34, (95% CI; 0.20 to 0.59); overall mean grade of mucositis SMD -1.49, (95% CI; -2.02 to -0.95); duration of severe mucositis WMD -5.32, 95% (CI; -9.45 to -1.19) and incidence of severe pain (RR 0.26, 95% CI; 0.18 to 0.37). CONCLUSIONS: Prophylactic LLLT reduced severe mucositis and pain in patients with cancer and HSCT recipients. Future research should identify the optimal characteristics of LLLT and determine feasibility in the clinical setting. PMID- 26114789 TI - Antibiotic use at dental implant placement. AB - DATA SOURCES: Cochrane Oral Health Groups Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OVID and EMBASE via OVID. Databases were searched with no language or date restrictions. STUDY SELECTION: Two authors independently reviewed the titles and the abstracts for inclusion. Disagreements were resolved by discussion. If needed, a third author was consulted. Included were randomised clinical trials with a follow-up of at least three months which evaluated the use of prophylactic antibiotic compared to no antibiotic or a placebo and examined different antibiotics of different doses and durations in patients undergoing dental implant placement. The outcomes were implant failure (considered as implant mobility, removal of implant due to bone loss or infection) and prosthesis failure (prosthesis could not be placed). DATA EXTRACTION AND SYNTHESIS: Standard Cochrane methodology procedures were followed. Risk of bias was completed independently and in duplicate by two review authors. Results were expressed as risk ratios (RRs) using a random-effects model for dichotomous outcomes with 95% confidence intervals (CI). The statistical unit was the participant and not the prosthesis or implant. Heterogeneity including both clinical and methodological factors was investigated. RESULTS: Six randomised clinical trials with 1162 participants were identified for the review. Three trials compared 2 g of preoperative amoxicillin versus placebo (927 participants). One trial compared 3 g of preoperative amoxicillin versus placebo (55 participants). Another trial compared 1 g of preoperative amoxicillin plus 500 mg four times a day for two days versus no antibiotic (80 participants). An additional trial compared four groups: (1) 2 g of preoperative amoxicillin; (2) 2 g of preoperative amoxicillin plus 1 g twice a day for seven days; (3) 1 g of postoperative amoxicillin twice a day for seven days and (4) no antibiotics (100 participants). The overall body of the evidence was considered moderate.The meta analysis of the six trials showed a statistically significant higher number of implant failures in the group not receiving antibiotics, RR= 0.33 (95% CI; 0.16 to 0.67) P = 0.0002.The number needed to treat for one additional benefit outcome (NNTB) to prevent one person having an implant failure is 25 (95% CI; 14 to 100) based on an implant failure of 6% in participants not receiving antibiotics.There was borderline statistical significance for prosthesis failures (RR= 0.44 (95%CI; 0.19 to 1.00) with no statistically significant differences for infections or adverse events. No conclusive information for the different durations of antibiotics could be determined. CONCLUSIONS: There is statistically significant evidence suggesting that a single dose of 2 g or 3 g of amoxicillin given orally is beneficial in reducing dental implant failure in ordinary conditions. No significant adverse events were reported. It is still unknown whether post operative antibiotics are beneficial and which antibiotic is more effective. PMID- 26114790 TI - Antibiotic prophylaxis for dental implant placement? AB - DATA SOURCES: Electronic searches without time or language restrictions were performed in PubMed, Web of Science and the Cochrane Oral Health Group trials Register. A vast manual search was done in many dental implant-related journals. Reference lists were scanned for possible additional studies. Ongoing clinical trials were also searched. STUDY SELECTION: Titles and abstracts of the reports identified were read independently by the three authors. Disagreements were resolved by discussion. Rejected studies were recorded with the reasons for exclusion. The inclusion criteria included clinical human studies, either randomised or not, comparing the implant failure/survival rates in any group of patients receiving antibiotic prophylaxis versus not receiving antibiotics prior to implant placement. Case reports and non-human studies were excluded. Implant failure was considered as complete loss of the implant. DATA EXTRACTION AND SYNTHESIS: Data were extracted by the authors. Study risk of bias was assessed. Implant failure and post-operative infection were the outcomes measured, both dichotomous outcomes. Results were expressed using fixed or a random effect model depending on the heterogeneity calculated using an I(2) statistical test. The estimate of relative effect was expressed in risk ratio (RR) with 95% confidence interval. Number needed to treat (NNT) was calculated and sensitivity analysis was performed to detect differences among the studies considered to have high a risk of bias. RESULTS: Fourteen trials were included in the review and evaluated a total of 14,872 implants. Of the fourteen studies included in the review eight were randomised clinical trials, four were controlled clinical trials and two were retrospective studies. Seven studies had both patients and operators/outcome assessors blinded to the tested intervention. Nine studies had short follow-ups; six of them with a follow-up of four months, one of five months and two of six months.The antibiotic regimen was variable: seven studies did not use post-op antibiotics in all patients. Seven studies used amoxicillin as the antibiotic of choice. Ten studies had patients rinse with antimicrobial solutions as well.Among the fourteen studies, 8603 implants were placed in patients receiving antibiotics, 304 failures (3.53%) were recorded; 6269 implants were placed in patients not receiving antibiotics or receiving placebo, with 396 failures recorded (6.32%).From eight articles that provided the information about post operative infection there were 25 occurrences of infection in 1000 patients receiving antibiotics (2.5%) and 29 episodes in 770 patients not receiving antibiotics (3.8%).Some studies involved grafting procedures and a portion of the patients (in nine studies) were smokers.The test of overall effect for implant failure rate showed that the difference between the procedures with or without antibiotic is statistically significant: RR 0.55, 95% confidence interval (CI) 0.41 to 0.75, p value 0.0002, a relative risk reduction (RRR) of 45% and the number needed to treat (NNT) of 50 (95% CI 33-100).For the post operative infection outcome, the results of the meta-analysis showed no statistically significant results; RR 0.84, 95 % confidence interval 0.49-1.44, and a p value of 0.52.The results did not differ in the sensitivity analysis when removing the high risk of bias studies. For the implant failure, the results were RR 0.37, 95% CI 0.19-0.72, p value 0.003, and for the 'post operative infection' outcome the results were RR 0.78, 95% CI 0.38-1.39. p value 0.33. The funnel plot to calculate publication bias showed asymmetry for the studies reporting implant failure, while the studies reporting post-operative infection the funnel plot did not show asymmetry. CONCLUSIONS: The evidence from the review suggests that a prophylactic antibiotic regimen reduces failure of dental implants placed under ordinary conditions. However, there are no apparent differences in the occurrence of post-operative infections in patients receiving or not receiving antibiotics.The results have to be interpreted with caution due to the presence of several cofounding factors in the studies. PMID- 26114791 TI - Review suggests higher failure rates for dental implants placed in fresh extraction sites. AB - DATA SOURCES: PubMed, Web of Science and Cochrane Oral Health Group Trials. Register databases supplemented by hand searching a range of dental implants related journals. STUDY SELECTION: Randomised and non-randomised studies comparing implant failure rates in any group of patients receiving dental implants being inserted in fresh extraction sockets compared to the insertion in healed sites were considered. DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Newcastle-Ottawa scale (NOS). Implant failure (complete loss of implant) and postoperative infection were the dichotomous outcomes measures evaluated, with marginal bone loss as a continuous outcome. RESULTS: Seventy three publications were included, five were randomised controlled trials, 26 clinical controlled trials and 42 retrospective studies. The 73 studies included a total of 8241 dental implants inserted in fresh extraction sockets, with 330 failures (4.00%), and 19,410 implants inserted in healed sites, with 599 failures. A random effects meta-analysis (73 studies) found the relative risk of implant failures in fresh socket sites compared to healed sites was RR= 1.58 (95% CI; 1.27 1.95) for the maxilla only RR= 1.61 (95% CI; 0.97 2.66); mandible only RR= 2.15 (95% CI; 0.62-7.47). For implants supporting single crown restoration RR= 2.05 (95% CI; 1.36-3.11) and RR= 1.42 (95% CI; 0.71- 2.83) for those with a full arch prosthesis.There were 31 controlled studies (CCTs) and randomised controlled studies (RCTs) that included 2021 implants inserted in fresh sockets with 96 failures (4.75%) and 2759 implants were inserted in healed sites with 49 failures (1.59%). The relative risk of implant failures in fresh socket sites compared to healed sites was RR= 2.27 (95% CI; 1.57-3.29). CONCLUSIONS: The results of the present review should be interpreted with caution due to the presence of uncontrolled confounding factors in the included studies, most of them not randomised trials. Within the limitations of the existing investigations, the present study suggests that the insertion of dental implants in fresh extraction sockets affects the implant failure rates. PMID- 26114792 TI - Large overjet may double the risk of dental trauma. AB - DATA SOURCES: Medline/PubMed, SCOPUS and Google Scholar. DATA EXTRACTION AND SYNTHESIS: Studies were split according to the type of teeth and the overjet threshold used, thus obtaining three subsets; primary teeth - overjet threshold 3 4 mm; permanent teeth - overjet threshold 3-4 mm and permanent teeth - overjet threshold 6 +/- 1 mm. Pooled odds ratios for TDI were estimated for each dataset. RESULTS: Fifty-four studies were included involving patients from five continents. The adjusted pooled odds ratios were 2.31 (95%CI; 1.01-5.27) for primary teeth with 3-4 mm overjet; 2.01 (95%CI; 1.39-2.91) for permanent teeth with 3-4 mm overjet and 2.24 (95%CI; 1.56-3.21) for permanent teeth with 6 +/- 1 mm overjet. CONCLUSIONS: The present meta-analysis of observational studies showed that large overjet may double or even triple the risk for TDI to anterior primary and permanent teeth and that, at global level, large overjet is partly responsible for 100-300 million TDIs. PMID- 26114793 TI - The impact of malocclusion and its treatment on the oral health related quality of life of adults, assessed using the Oral Health Impact Profile (OHIP-14). AB - DATA SOURCES: PubMed, Medline and Embase via OVID were searched up to November 2013. This was supplemented by a hand search of the reference lists of all relevant publications and recently published review articles. The search was restricted to the English language. STUDY SELECTION: Two review authors independently searched and selected the studies. Interventional or observational studies of individuals aged 15 years and above with either a malocclusion, or those who had undergone treatment for a malocclusion, were included. Studies must have included a control group without a malocclusion (for assessment of malocclusion impact), or a control group requiring treatment for correction of malocclusion (to assess the impact of treating malocclusion). Oral health related quality of life (OHRQoL) had to be measured using OHIP-14. DATA EXTRACTION AND SYNTHESIS: Two review authors independently carried out data abstraction and methodological quality assessment. Studies were divided into three groups based on the type of comparison groups; with and without malocclusion (independent design), the same group of individuals before and after treatment (pre-post design), and an orthodontically treated group with a group requiring treatment (treated-untreated groups design). For each group, data were pooled if the same type and details of OHIP-14 scores were reported. A Q test, I(2) test and random effects model were used. Begg and Egger tests and funnel plots were used to measure bias, including publication bias. RESULTS: Twenty-five studies were included; eleven studies had an independent design, ten studies were classed as pre-post studies, and four studies were categorised as demonstrating a treated untreated groups design. Data from four of the independently designed studies, which included a total of 892 patients, were pooled and a meta-analysis conducted. The data from three of the pre-post designed studies, with a total of 110 patients, were also pooled in a separate meta-analysis. The standardised mean difference (SMD) in OHIP-14 total score in the independently designed studies was 0.84 (95% CI: 0.25 to 1.43) and in the pre-post design group was 1.29 (95% CI: 0.67 to 1.92). The studies in both meta-analyses demonstrated statistically significant levels of heterogeneity. There was also evidence of publication bias in the meta-analysis conducted using the independently designed studies. CONCLUSIONS: There are currently no high quality studies in the form of longitudinal or randomised controlled trials to assess the impact of malocclusion and its associated treatment on OHIP-14 scores respectively. Results from existing studies, which are predominantly cross-sectional, suggest that OHIP-14 scores are significantly lower in individuals without a malocclusion, indicating higher levels of OHRQoL. Similarly, longitudinal studies have shown that OHIP-14 scores are significantly lower after patients have received treatment for their malocclusion. The small number of trials, and their associated methodological concerns, limits the validity and reliability of the meta-analyses conducted, and the results obtained must be subjected to further scrutiny and confirmation. PMID- 26114794 TI - Chlorhexidine mouthwash more effective than dentifrice or gel. AB - DATA SOURCES: Medline, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL). STUDY SELECTION: Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) in adults 18 years of age comparing CHX DF/gel with CHX MW written in English or Dutch were considered. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently selected studies, abstracted data and assessed risk of bias. Where possible, a meta-analysis was performed. Difference in means values between test and control at both baseline and end was calculated using a fixed-effects model. RESULTS: Five RCTs were included, four had a parallel design and one was a cross-over trial. Three studies showed a positive score in favour of the mouthwash. Three studies contributed to a meta-analysis of the effect on 'de novo' plaque formation. There was a difference in means of 0.27 [95% CI: 0.14; 0.39] (P < 0.0001) in favour of CHX MW. One study assessed tooth staining finding more staining with the use of CHX MW compared to the CHX DF/gel. CONCLUSIONS: Chlorhexidine gel can be successfully formulated and will inhibit plaque growth to some degree, but not to the same extent, as a CHX MW. When CHX DF/gel is used in a non-brushing model, it is significantly less effective in plaque inhibition compared to CHX MW. Based on one study when CHX gel was applied with a finger after brushing, it is significantly more effective on plaque scores and the gingival index. The only brushing study also with a long follow-up showed that there is no significant difference between CHX DF and CHX MW. However, as a corollary, significantly more tooth discoloration was observed with the CHX MW. Altogether, the data show that when daily oral hygiene cannot be performed, CHX MW is the first product of choice. PMID- 26114799 TI - Effects of Pleiotrophin on endothelial and inflammatory cells: Pro-angiogenic and anti-inflammatory properties and potential role for vascular bio-prosthesis endothelialization. AB - PURPOSE: One of the limitations emerged with both synthetic and degradable vascular grafts is the lack of endothelialization after implantation that is known to be the main reason leading to unfavourable outcomes. It emerges the need to find new strategies to promote a rapid endothelialization of the scaffold. Pleiotrophin is a growth/differentiation cytokine for various cell type. We here evaluated the effect of Pleiotrophin on endothelial cells (EC), monocytes and macrophages that have been shown as key cells promoting neovascularization. MATERIAL/METHODS: EA.hy926 endothelial cells, THP-1 monocytes and PMA differentiated macrophages were treated with Pleiotrophin (10 and 100ng/ml). VEGF, Flk-1, Nrp-1, COX-2, ICAM-1 and TGFbeta expression were detected by Western Blot, IL-10, MCP-1 and TNFalpha levels by ELISA. Chemotaxis was performed in Boyden chambers. Wound healing was performed by scratch wound assay. RESULTS: Pleiotrophin induces in EC the expression of VEGF and its receptors Flk-1 and Nrp 1 and improves the migratory capacity. In THP-1 monocytes, Pleiotrophin induces the expression of VEGF and its receptor Nrp-1 and decreases the levels of COX-2 and TNFalpha. In PMA-differentiated macrophages COX-2 expression was significantly reduced by Pleiotrophin, while IL-10 and TGFbeta were increased. CONCLUSIONS: Pleiotrophin acts as an angiogenesis 'driver' by promoting the creation of a pro-angiogenic environment, a migratory behaviour in EC and a pro regenerative alternative phenotype in macrophages. Our results suggest that Pleiotrophin might be considered for vascular prosthesis engineering. PMID- 26114800 TI - A 2013/2014 northern hemisphere season surface antigen inactivated trivalent influenza vaccine--Assessing the immunogenicity and safety in an open label, uncontrolled study. AB - The present study evaluated the safety and immunogenicity of the 2013/2014 trivalent surface antigen inactivated subunit seasonal influenza virus vaccine Fluvirin(r) in healthy adults (18 - <= 60 years) and elderly (>60 years). The vaccine contained 15 ug haemagglutinin protein from each of influenza A/California/7/2009 (H1N1)pdm09-like strain, A/Victoria/361/2011 (H3N2)-like strain and B/Massachusetts/2/2012-like strain (B/Yamagata) as recommended by the WHO in the 2013/2014 Northern Hemisphere season. Antibody response to each influenza antigen after vaccination was measured prior to vaccination and 21 d after by single radial hemolysis (SRH) assay or hemagglutination inhibition (HI) assay in accordance with Guidance CPMP/BWP/214/96. 125 subjects (61 adults and 64 elderly) were enrolled in the study. Pre-vaccination protective antibody levels (SRH area >= 25 mm(2)) against A(H1N1), A(H3N2) and the B strain were detected in 17%, 20% and 57% of adults and in 36%, 20% and 55% of elderly, respectively, Post vaccination, SRH area >= 25 mm(2) was detectable in 95%, 82% and 92% in adult and in 80%, 84% and 92% of the elderly subjects for A(H1N1), A(H3N2) and the B strain, respectively. Geometric mean ratio (GMR) was higher in adult subjects (2.62-7.62) than in elderly subjects (2.33-3.42). All three CHMP licensure criteria were met for all strains contained in the vaccine for both age groups. The most frequently reported solicited local and systemic reactions were pain at the injection side, headache and fatigue. In conclusion, the vaccine demonstrated a good immunogenicity and an acceptable safety profile in both adults and elderly. PMID- 26114801 TI - Deterministic control of mean alignment and elongation of neuron-like cells by grating geometry: a computational approach. AB - Neuron-like cells are driven by their surrounding environment through local topography. A causal mechanotransductive web of topography-force relationships influences and controls complex cellular phenomena such as growth and alignment. This work aimed to provide a computational framework able to model the behaviour of neuron-like (PC12) cells on gratings, accounting for the twofold ability of topographical cues to simultaneously align and enhance the growth of cells. In particular, starting from the mechanical behaviour of the growth cone and filopodia, the effect of grating geometry (e.g., the periodicity and the size of grooves and ridges) on the neuritic mean alignment angle and on the outgrowth rate of cells was explored through theoretical tools and combinatorial simulations, which were able to predict (R(2) > 0.9) experimental data in a time range of 72-120 hours. PMID- 26114802 TI - MFN2 deletion of exons 7 and 8: founder mutation in the UK population. AB - Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot-Marie Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi-dominant kindreds have also been described. We previously reported a deletion of exons 7 and 8 resulting in nonsense-mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives were collected. MFN2 Sanger sequencing, multiplex ligation probe amplification, and haplotype analysis were performed. A severe early-onset CMT phenotype was seen in all cases: progressive distal weakness, wasting, and sensory loss from infancy or early childhood. Optic atrophy (four of five) and wheelchair dependency in childhood were common (four of five). All were compound heterozygous for a deletion of exons 7 and 8 in MFN2 with another previously reported pathogenic mutation (Phe216Ser, Thr362Met, and Arg707Trp). Carrier parents and relatives were unaffected (age range: 24-82 years). Haplotype analysis confirmed that the deletion had a common founder in all families. PMID- 26114803 TI - Gap formation following climatic events in spatially structured plant communities. AB - Gaps play a crucial role in maintaining species diversity, yet how community structure and composition influence gap formation is still poorly understood. We apply a spatially structured community model to predict how species diversity and intraspecific aggregation shape gap patterns emerging after climatic events, based on species-specific mortality responses. In multispecies communities, average gap size and gap-size diversity increased rapidly with increasing mean mortality once a mortality threshold was exceeded, greatly promoting gap recolonization opportunity. This result was observed at all levels of species richness. Increasing interspecific difference likewise enhanced these metrics, which may promote not only diversity maintenance but also community invasibility, since more diverse niches for both local and exotic species are provided. The richness effects on gap size and gap-size diversity were positive, but only expressed when species were sufficiently different. Surprisingly, while intraspecific clumping strongly promoted gap-size diversity, it hardly influenced average gap size. Species evenness generally reduced gap metrics induced by climatic events, so the typical assumption of maximum evenness in many experiments and models may underestimate community diversity and invasibility. Overall, understanding the factors driving gap formation in spatially structured assemblages can help predict community secondary succession after climatic events. PMID- 26114804 TI - Hydroboration of Arynes Formed by Hexadehydro-Diels-Alder Cyclizations with N Heterocyclic Carbene Boranes. AB - N-Heterocyclic carbene boranes (NHC-boranes) hydroborate arynes formed in situ by the hexadehydro-Diels-Alder (HDDA) reactions of triyne precursors. The reaction directly provides functionalized arylborane compounds. The unique feature of the NHC-boranes compared to other boranes is that they hydroborate only the aryne product and not the triyne precursor. PMID- 26114806 TI - Differential inflammatory response of dental pulp explants and fibroblasts to saliva. AB - AIM: To investigate the inflammatory response of dental pulp fibroblasts and the respective explants to whole saliva. METHODOLOGY: Explants from human and porcine dental pulp tissue and isolated dental pulp fibroblasts were used to investigate the inflammatory response to sterile saliva. Cytokine and chemokine expression was assessed by RT-PCR. Western blot analysis and pharmacologic inhibitors were used to determine the involvement of signalling pathways. RESULTS: Dental pulp explants of human and porcine origin exposed to human saliva exhibited no major changes of IL-6 and IL-8 mRNA expression (P > 0.05). In contrast, isolated porcine and human dental pulp fibroblasts, when stimulated with human saliva, exhibited a vastly increased expression of IL-6 and IL-8 mRNA (P < 0.05). In pulp fibroblasts, saliva also increased the expression of other cytokines and chemokines via activation of NFkappaB, ERK and p38 signalling. Notably, a significantly reduced inflammatory response was elicited when pulp fibroblasts were transiently exposed to saliva. CONCLUSIONS: Saliva has a potential impact on inflammation of dental pulp fibroblasts in vitro but not when cells are embedded in the intrinsic extracellular matrix of the explant tissue. PMID- 26114805 TI - The Utility of Systolic and Diastolic Echocardiographic Parameters for Predicting Coronary Artery Disease Burden as Defined by the SYNTAX Score. AB - BACKGROUND: Early identification of high-grade ischemia based on echocardiographic diastolic abnormalities may be clinically useful in the acute coronary syndrome (ACS) setting. This could provide the clinician with an awareness of the burden of coronary artery disease (CAD) before angiography is performed to allow for early intervention of suspected ischemic lesions. The objective of the study was to assess whether 2D transthoracic echocardiography (TTE)-derived tissue Doppler imaging parameters can predict the severity of CAD in comparison with the cardiac catheterization-derived SYNTAX score. METHODS: A retrospective study of 74 stable angina or patients with ACS was performed in 2012 at a single tertiary care center. In all study subjects, TTE and angiography were performed within 6 months of each other without revascularization in the interim. RESULTS: The study population included a total of 74 patients (mean age 67 +/- 12 years) with 77% presenting with an ACS. The median SYNTAX score was 24.0 (6.0-35.0). The E-wave velocity was higher, and deceleration time (DT) was lower in the high SYNTAX group in comparison with the low/intermediate SYNTAX group (P = 0.045 and P = 0.001, respectively). Septal mitral annular S' was lower in the high SYNTAX group (P = 0.02). After multivariate analysis, E/A ratio (OR 0.03, 95% 0.00-0.36, P = 0.0067), DT (OR 0.93, 95% CI 0.89-0.97, P = 0.0001) and septal annular S'-wave velocity (OR 0.34, 95% CI 0.16-0.71, P = 0.0038) remained strong predictors of a high SYNTAX score. CONCLUSION: Early identification of systolic and diastolic dysfunction based on echocardiographic parameters may be of important clinical significance for predicting CAD burden prior to invasive angiography. PMID- 26114807 TI - Diagnosis of tinea pedis by the Dermatophyte Test Strip. PMID- 26114808 TI - Latitudinal distributions of activities in atmospheric aerosols, deposition fluxes, and soil inventories of 7Be in the East Asian monsoon zone. AB - Activities of atmospheric aerosols, bulk deposition fluxes, and undisturbed soil inventories of (7)Be were investigated in China's East Asian monsoon zone at various latitudes ranging from 23.8 degrees N to 43.5 degrees N. The annual latitudinal distributions of (7)Be concentrations in aerosols follow a distribution pattern which looks similar to a normal distribution with the maxima occurring in the mid-latitude region. Simultaneous measurements of (7)Be at various latitudes suggest that atmospheric circulation may play an important role in the latitudinal distributions of (7)Be in surface air. Latitude and wet precipitation are the main factors controlling the bulk (7)Be depositional fluxes. Significant seasonal variations in (7)Be depositional fluxes in Beijing, a mid-latitude city, were observed with the highest flux in summer and the lowest in winter, whereas less seasonality were found in the high- and the low-latitude cities. The highest (7)Be inventory in undisturbed soils in summer also occurred at a mid-latitudinal area in the East Asian monsoon zone. Precipitation is the main factor controlling the (7)Be soil inventory in Qingdao with the highest values occurring in autumn followed by summer. PMID- 26114809 TI - Sequence-activity relationship, and mechanism of action of mastoparan analogues against extended-drug resistant Acinetobacter baumannii. AB - The treatment of some infectious diseases can currently be very challenging since the spread of multi-, extended- or pan-resistant bacteria has considerably increased over time. On the other hand, the number of new antibiotics approved by the FDA has decreased drastically over the last 30 years. The main objective of this study was to investigate the activity of wasp peptides, specifically mastoparan and some of its derivatives against extended-resistant Acinetobacter baumannii. We optimized the stability of mastoparan in human serum since the specie obtained after the action of the enzymes present in human serum is not active. Thus, 10 derivatives of mastoparan were synthetized. Mastoparan analogues (guanidilated at the N-terminal, enantiomeric version and mastoparan with an extra positive charge at the C-terminal) showed the same activity against Acinetobacter baumannii as the original peptide (2.7 MUM) and maintained their stability to more than 24 h in the presence of human serum compared to the original compound. The mechanism of action of all the peptides was carried out using a leakage assay. It was shown that mastoparan and the abovementioned analogues were those that released more carboxyfluorescein. In addition, the effect of mastoparan and its enantiomer against A. baumannii was studied using transmission electron microscopy (TEM). These results suggested that several analogues of mastoparan could be good candidates in the battle against highly resistant A. baumannii infections since they showed good activity and high stability. PMID- 26114810 TI - Synthesis of 3,4-diaminobenzoyl derivatives as factor Xa inhibitors. AB - The coagulation factor Xa (FXa) plays a central role in the blood coagulation cascade. Recent studies have shown that FXa is a particularly attractive target for the development of oral antithrombotic agents. In view of the excellent pharmaceutical properties of 1,2-phenylenediamine-based FXa inhibitors and the reported structure-activity relationship (SAR) analysis of FXa inhibitors, we designed and synthesized a series of 3,4-diaminobenzoyl-based FXa inhibitors. Intensive SAR studies on this new series led to the discovery of 3,4-dimethoxyl substituted compound 7b. 7b is a highly potent, selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. PMID- 26114811 TI - Synthesis, antiplasmodial activity and mechanistic studies of pyrimidine-5 carbonitrile and quinoline hybrids. AB - A series of hybrids comprising of 5-cyanopyrimidine and quinoline moiety were synthesized and tested for in vitro antiplasmodial activity against NF54 and Dd2 strains of Plasmodium falciparum. Hybrid bearing m-nitrophenyl substituent at C-4 of pyrimidine displayed the highest antiplasmodial activity [IC50 = 56 nM] against the CQ(R) (Dd2) strain, which is four-fold greater than CQ. PMID- 26114812 TI - Identification of N-acylhydrazone derivatives as novel lactate dehydrogenase A inhibitors. AB - Glycolysis is drastically increased in tumors and it is the main route to energy production with a minor use of oxidative phosphorylation. Among the key enzymes in the glycolytic process, LDH is emerging as one of the most interesting targets for the development of new inhibitors. In this context, in the present work, we carried out a virtual screening procedure followed by chemical modifications of the identified structures according to a "hit-to-lead" process. The effects of the new molecules were preliminary probed against purified human LDH-A. The compounds active at low micromolar level were additionally characterized for their activity on some cellular metabolic processes by using Raji human cell line. Within the series, 1 was considered the best candidate, and a more detailed characterization of its biological properties was performed. In Raji cells exposed to compound 1 we evidenced the occurrence of effects usually observed in cancer cells after LDH-A inhibition: reduced lactate production and NAD/NADH ratio, apoptosis. The flow cytometry analysis of treated cells also showed cell cycle changes compatible with effects exerted at the glycolytic level. Finally, in agreement with the data obtained with other inhibitors or by silencing LDH-A expression, compound 1 was found to increase Raji cells response to some commonly used chemotherapeutic agents. Taken together, all these finding are in support of the LDH-A inhibiting activity of compound 1. PMID- 26114813 TI - Design, synthesis, nitric oxide release and antibacterial evaluation of novel nitrated ocotillol-type derivatives. AB - Nitric oxide (NO) and its auto-oxidation products are known to disrupt normal bacterial function and NO releasing molecules have the potential to be developed as antibacterial leads in drug discovery. We have designed and synthesized a series of novel nitrated compounds by combining NO releasing groups with ocotillol-type triterpenoids, which have previously demonstrated activity only against Gram-positive bacteria. The in vitro NO release capacity and antibacterial activity were sequentially evaluated and the data showed that most of the synthesized compounds could release nitric oxide. Compound 16a, 17a and 17c, with nitrated aliphatic esters at C-3 position, displayed higher NO release than other analogues, correlating to their good antibacterial activity, in which 17c demonstrated broad-spectrum activity against both Gram positive and -negative bacteria, as well as excellent synergism at sub-minimum inhibitory concentration when using with kanamycin and chloramphenicol. Furthermore, the epifluorescent microscopic study indicated that the ocotillol-type triterpenoid core may induce NO release on the bacterial membrane. Our results demonstrate that nitrated substitutions at C-3 of ocotillol-type derivatives could provide an approach to expand their antibacterial spectrum, and that ocotillol-type triterpenoids may also be developed as appropriate carriers for NO donors in antibacterial agent discovery with low cytotoxicity. PMID- 26114814 TI - Positive attitude toward life, emotional expression, self-rated health, and depressive symptoms among centenarians and near-centenarians. AB - OBJECTIVES: Favorable attitudes, emotions, personality characteristics, and self rated health have been associated with successful aging in late life. However, less is known regarding these constructs and their relationships to mental health outcomes in the oldest old persons. This study examined cross-sectional relationships of these psychological factors to depressive symptoms in centenarians and near-centenarians. METHODS: A selected sample of Ashkenazi Jewish older adults aged 98-107 (n = 54, 78% female) without significant cognitive impairment participated. Cognitive function was assessed by Mini-Mental Status Examination, positive attitude toward life and emotional expression by the Personality Outlook Profile Scale (POPS), self-rated health by participants' subjective rating of their present health, and depressive symptoms by the Geriatric Depression Scale. RESULTS: Results demonstrated inverse associations of the positive attitude toward life domain of the POPS and self-rated health with participants' levels of depressive symptoms even after adjusting for the effects of history of medical illnesses, cognitive function, and demographic variables. Additionally, participants with high levels of care showed higher levels of depressive symptoms. Path analysis supported the partially mediating role of positive attitude toward life in the relationship between self-rated health and depressive symptoms. CONCLUSION: These findings emphasized the important roles of positive attitudes and emotions as well as self-rated health in mental health outcomes in the oldest old. Although, limited by its cross-sectional design, findings suggest these psychological factors may exert protective effects on mental health outcomes in advanced age. PMID- 26114815 TI - Hydroquinone and Quinone-Grafted Porous Carbons for Highly Selective CO2 Capture from Flue Gases and Natural Gas Upgrading. AB - Hydroquinone and quinone functional groups were grafted onto a hierarchical porous carbon framework via the Friedel-Crafts reaction to develop more efficient adsorbents for the selective capture and removal of carbon dioxide from flue gases and natural gas. The oxygen-doped porous carbons were characterized with scanning electron microscopy, transmission electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, and Raman spectroscopy. CO2, CH4, and N2 adsorption isotherms were measured and correlated with the Langmuir model. An ideal adsorbed solution theory (IAST) selectivity for the CO2/N2 separation of 26.5 (298 K, 1 atm) was obtained on the hydroquinone-grafted carbon, which is 58.7% higher than that of the pristine porous carbon, and a CO2/CH4 selectivity value of 4.6 (298 K, 1 atm) was obtained on the quinone grafted carbon (OAC-2), which represents a 28.4% improvement over the pristine porous carbon. The highest CO2 adsorption capacity on the oxygen-doped carbon adsorbents is 3.46 mmol g(-1) at 298 K and 1 atm. In addition, transient breakthrough simulations for CO2/CH4/N2 mixture separation were conducted to demonstrate the good separation performance of the oxygen-doped carbons in fixed bed adsorbers. Combining excellent adsorption separation properties and low heats of adsorption, the oxygen-doped carbons developed in this work appear to be very promising for flue gas treatment and natural gas upgrading. PMID- 26114816 TI - Femtosecond-Assisted Arcuate Keratotomy for the Correction of Postkeratoplasty Astigmatism: Vector Analysis and Accuracy of Laser Incisions. AB - PURPOSE: To assess the clinical and refractive outcomes of femtosecond-assisted arcuate keratotomy in postkeratoplasty patients, and the accuracy of the incisions, using optical coherence tomography. METHODS: This is a retrospective study of patients with high postkeratoplasty astigmatism. Patients with a minimum of 4 diopters (D) of postkeratoplasty regular astigmatism were included. The main outcome measures were corrected distance visual acuity, keratometry, corneal topography, and the depth of corneal incisions. Arcuate keratotomy procedures were performed using the IntraLase Femtosecond laser. The depth of keratotomies was set to 75% of the thinnest pachymetry. RESULTS: Twenty eyes of 20 patients were recruited in this study. The mean age at surgery was 51 years, and the mean follow-up period was 17 +/- 7.9 months. The corrected distance visual acuity improved significantly from 20/60 preoperatively to 20/41 after surgery (P = 0.004). The mean preoperative and postoperative spherical equivalents were -4.34 +/- 2.91 D and -4.44 +/- 3.64 D, respectively (P = 0.49). The mean keratometric cylinder decreased from 9.45 +/- 2.97 D (range, 4.2-15.2 D) to 4.64 +/- 2.79 D (range, 1.4-11.8 D) (P < 0.001). There was no statistical difference between the mean surgical-induced astigmatism and the mean target-induced astigmatism (P = 0.313). The mean difference between the scheduled and actual incision depth was 10.5 +/- 22.2 MUm (P = 0.057). No complications occurred during the procedures. CONCLUSIONS: Femtosecond-assisted keratotomy seems to be a safe and efficient technique for the reduction of large amounts of corneal astigmatism. Although overcorrection and undercorrection may occur, the visual outcome is satisfactory. Optical coherence tomography analysis reports a good predictability of the depth of incisions. PMID- 26114817 TI - Intraoperative Optical Coherence Tomography for Enhanced Depth Visualization in Deep Anterior Lamellar Keratoplasty From the PIONEER Study. AB - PURPOSE: Deep anterior lamellar keratoplasty (DALK) is a challenging procedure that often results in conversion to penetrating keratoplasty. Preservation of Descemet membrane (DM) relies on indirect visualization of surgical planes. We describe a technique for enhanced visualization of key steps in DALK with intraoperative optical coherence tomography. METHODS: Using a microscope-mounted spectral domain optical coherence tomography system, high-resolution images of various steps were obtained. RESULTS: Specifically, images were obtained of the trephination depth and proximity of the cannula tract to DM. Other key steps such as air cannula placement, assessment of the DM position and integrity after attempted big-bubble delivery, and assessment of graft-host apposition were readily visualized. The presence of intrastromal emphysema after air injection decreased visualization of deeper structures. CONCLUSIONS: Intraoperative optical coherence tomography allows visualization of depth-dependent anatomy and changes from specific surgical interventions during DALK not appreciated with the en face operating microscope view and has the potential to facilitate big-bubble delivery. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02423161. PMID- 26114818 TI - Long-Term Results of the Boston Keratoprosthesis for Unilateral Corneal Disease. AB - PURPOSE: To report the results of unilateral implantation of a Boston keratoprosthesis (BKPro) in patients with good visual acuity in the fellow eye. METHODS: A retrospective analysis of 37 eyes of 37 patients who underwent an optical BKPro and had a preoperative best-corrected visual acuity (BCVA) of 20/40 or better in the fellow eye at Wills Eye Hospital from September 2005 to November 2013 was performed. Patients were excluded if they had less than 1 year of postoperative follow-up. RESULTS: The mean follow-up after BKPro implantation was 31.7 months (range, 12-78 months; SD, 21). Twenty-eight patients underwent a BKPro for failed penetrating keratoplasty, and 9 patients underwent a primary BKPro. The most common complications were elevated intraocular pressure and retroprosthetic membrane formation in 16 eyes (43%) each. The mean final BCVA (1.0 +/- 0.8 logMAR; median, 1.0 logMAR) was statistically better than the mean preoperative BCVA (1.8 +/- 0.2 logMAR; median, 1.8 logMAR) (P < 0.001). The probability of postoperative BCVA of 20/200 or better was 54.1% with an average 45.1 +/- 4.7 (confidence interval: 35.9-54.3) months of follow-up. The probability of postoperative BCVA of 20/40 or better was 37.8% with an average 51.8 +/- 4.9 (confidence interval: 42.0-61.5) months of follow-up. CONCLUSIONS: Half of the patients in our study achieved the minimum visual acuity required for binocular functioning, whereas one-third of the patients achieved a BCVA somewhat similar to that of the contralateral eye. The complications were similar to those reported previously with good retention of the device. BKPro implantation is a reasonable option for patients with good vision in the fellow eye. PMID- 26114819 TI - Keratopathy in Autoimmune Polyendocrinopathy Syndrome Type 1. AB - PURPOSE: To report the spectrum of phenotypes in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)-related keratopathy. METHODS: In this retrospective observational case series, 6 patients followed for APS1 were included. Data collected included family history, age at presentation, and systemic and ophthalmic manifestations. The 14 coding exons of the autoimmune regulator (AIRE) gene were sequenced. RESULTS: The age at the onset of keratopathy ranged from 4 to 20 years. The ocular symptoms varied from mild photophobia to severe pain, and visual acuity was from light perception to 20/20 Snellen equivalent. Heterogeneous corneal involvement was observed, ranging from minimal superficial punctate staining to severe stromal scarring with deep corneal neovascularization. The severity of ophthalmic findings was uncorrelated to that of systemic manifestations. The genetic analyses identified 2 novel mutations (c.173C>A in exon 2 and c.892G>T in exon 8) and 4 known mutations (c.62C>T in exon 1, c.415C>T in exon 3, c.1096-1G>A in intron 9, and c.1193delC in exon 10) in the AIRE gene. In patients with identical AIRE mutations, including within a sib-pair, heterogeneous phenotypes were observed. CONCLUSIONS: Keratopathy can be an early and severe manifestation of APS1, which contributes to the global prognosis of the disease. Its mechanisms remain to be elucidated. PMID- 26114820 TI - Treatment of Refractory Keratitis After a Boston Type I Keratoprosthesis With Corneal Collagen Cross-Linking. AB - PURPOSE: To report a patient with refractory keratitis after a Boston type I keratoprosthesis treated with corneal collagen cross-linking (CXL). METHODS: Case report. RESULTS: A 29-year-old man with a history of chemical burn in the left eye underwent keratoprosthesis implantation. He developed infectious keratitis 4 months after surgery, which did not respond to topical antibiotics. The patient underwent corneal CXL with a shield covering the keratoprosthesis optic. Three weeks after CXL, the infiltration completely resolved. CONCLUSIONS: Corneal CXL might be beneficial in the treatment of refractory keratitis in patients with the Boston type I keratoprosthesis. PMID- 26114821 TI - Tear Film and Serum Prolidase Activity and Oxidative Stress in Patients With Keratoconus. AB - PURPOSE: To determine and compare the serum and tear film prolidase activity (PA) between patients with keratoconus and healthy subjects. Also, we aimed to evaluate the serum oxidative stress level and the correlation with serum PA in patients with keratoconus. METHODS: This prospective, comparative clinical study included 31 patients with keratoconus and 33 age-matched and sex-matched control subjects. All participants underwent a detailed ophthalmologic examination. Serum and tear samples were obtained from all participants. Tears and serum PA and serum oxidative stress markers were measured. RESULTS: No significant differences in demographic characteristics were detected between groups (P > 0.05). The serum PA was significantly lower in the keratoconus group than in the control group (895.6 +/- 198.7 vs. 1145.9 +/- 285.4 U/L, P < 0.001). A tear film comparison showed that PA was lower in the keratoconus group than in the control group; however, this difference was not significant (3075.4 +/- 672.2 vs. 3225.8 +/- 903.2 U.L-1.g-1 protein, P = 0.45). Oxidative stress markers, such as total oxidant status and oxidative stress index, were found to be significantly higher in the keratoconus group (P < 0.001). CONCLUSIONS: The serum PA was found to be lower in patients with keratoconus than in the controls. Additionally, serum oxidative stress markers were found to be higher than those of the controls. Thus, prolidase and systemic oxidative stress may have a role in the pathogenesis of keratoconus. PMID- 26114822 TI - Comparison of Morphological and Functional Meibomian Gland Characteristics Between Daily Contact Lens Wearers and Nonwearers. AB - PURPOSE: The aim of the study was to investigate the relationship between daily soft contact lens (CL) wear and various signs of ocular involvement. We focused on comprehensive meibomian gland (MG) evaluation, including both functional and morphological parameters of the MGs. METHODS: The ocular surface and MG characteristics were evaluated in 41 daily soft CL users and 31 age-matched non lens wearers. We analyzed the MG function (meibum quality and meibum expressibility) and morphology (meibography) and evaluated lid margin alterations. We also correlated our findings with self-reported ocular symptoms and tear film abnormalities (tear film breakup time and Schirmer test values). RESULTS: CL use was associated with abnormal meibum quality [higher meibum quality score, odds ratio (OR) = 2.7, 95% confidence interval (CI), 1.3-5.6, P = 0.0057], more frequent bulbar (OR = 3.6, 95% CI, 1.5-8.2, P = 0.0028) and palpebral (OR = 2.4, 95% CI, 1.1-5.1, P = 0.028) conjunctival hyperemia, lid margin telangiectasia (OR = 6.0, 95% CI, 2.4-14.6, P < 0.00001), rounding (OR = 9.3, 95% CI, 1.1-81.0, P = 0.04), notching (OR = 3.9, 95% CI, 1.2-12.4, P = 0.019), hyperemia (OR = 4.3, 95% CI, 1.3-14.1, P = 0.015) of the posterior lid margin, orifice plugging (OR = 4.8, 95% CI, 1.3-17.1, P = 0.015), and retroplacement (OR = 0.8, 95% CI, 0.4-1.9, P = 0.037) after adjustment for age and sex in a logistic regression model. Lid margin abnormality and meibum quality scores strongly positively correlated with the duration of CL wear. These associations remained significant after adjustment for age and sex (P = 0.00003 and P = 0.01, respectively). CONCLUSIONS: CL wear may predispose individuals to meibomian gland dysfunction, which is not usually investigated unless significant symptoms are present. Therefore, we recommend to routinely examine CL wearers for meibomian gland dysfunction manifestations and to introduce specific prophylaxis if required. PMID- 26114823 TI - Anterior Segment Optical Coherence Tomography-Guided Management Algorithm for Descemet Membrane Detachment After Intraocular Surgery. AB - PURPOSE: To evaluate the role of anterior segment optical coherence tomography (ASOCT) in the detection and management of Descemet membrane detachment (DMD) in cases of persistent corneal edema after intraocular surgery. An ASOCT-guided new algorithm for the management of such DMDs is described. METHODS: Thirty-seven consecutive cases of persistent corneal edema of more than 2-week duration after intraocular surgery were included. All cases referred had no response to medical therapy. ASOCT was performed in all eyes. DMDs that were in the superior half of the cornea with a planar configuration alone were managed using intracameral air, and those with scrolled edges were managed using intracameral 14% perfluoropropane (C3F8). DMDs that were in the inferior half of the cornea with planar or scrolled edges were managed using intracameral C3F8 injection. The parameters evaluated were the type and morphology of DMD, resolution of DMD, and best-corrected visual acuity. RESULTS: Using ASOCT, DMD was found to be present in 25 eyes. All cases had planar edges, and 52% (13/25) cases had scrolled edges. In 48% (12/25) cases, DMD was peripheral. Descemetopexy with intracameral air or 14% C3F8 gas showed resolution in all cases with the mean time to resolution being 16.0 +/- 7.1 days. CONCLUSIONS: ASOCT is a useful tool for timely diagnosis, characterization, and management of DMD in cases of nonresolving postoperative corneal edema. A new algorithm for intracameral injection of air or C3F8 in these cases helps to defer corneal transplantation. PMID- 26114824 TI - Subjective Discomfort Symptoms Are Related to Low Corneal Temperature in Patients With Evaporative Dry Eye. AB - PURPOSE: To measure the corneal temperature in patients with dry eye (DE) and to correlate the values with subjective discomfort symptoms. METHODS: Twenty-four patients with DE (scored as DEWS severity grade 2 to 3) and 15 age-matched normal control subjects were enrolled. Subjective symptoms of discomfort were scored with an Ocular Surface Disease Index questionnaire, and a 100-mm horizontal visual analog scale (VAS) technique was used to measure symptom intensity. Schirmer I test, tear film breakup time (TFBUT), and Oxford grade scoring were performed in all subjects. Dynamic infrared noncontact thermal imaging (Tomey TG 1000) was used to measure the central corneal temperature (CCT). After training, subjects were asked to maintain their eyes forcedly open and to signal the discomfort onset time (DOT). The temperature was measured at eye opening (T0) and every second during 10 seconds of sustained eye opening (T10). The first discomfort sensation onset time (DOT) was also recorded. Temperature values were correlated with the clinical tests, Ocular Surface Disease Index, VAS, and DOT, and data were statistically evaluated (significance P < 0.05). RESULTS: The corneal temperature immediately after eye opening was significantly lower in patients with DE than in controls, in correlation to the subject age, VAS, and TFBUT. A 3-phase cooling profile in patients with DE and a point of highest decrease (HD) in both groups were identified. DOT occurred earlier in patients with DE than in controls (5.9 vs. 15.9 seconds) and was strongly correlated to the VAS, TFBUT, and CCT-HD. CONCLUSIONS: Subjective sensation of discomfort occurred earlier in patients with DE than in controls, in correlation to low corneal temperatures and enhanced tear evaporation. PMID- 26114825 TI - Supplementary, Sulcus-Fixated Intraocular Lens in the Treatment of Spherical and Astigmatic Refractive Errors in Pseudophakic Eyes After Keratoplasty. AB - PURPOSE: To evaluate the efficacy, refractive outcomes, and complications of supplementary intraocular lens (IOL) implantation in pseudophakic eyes after keratoplasty. METHODS: This is a retrospective review of pseudophakic postkeratoplasty eyes after implantation of a custom-designed, sulcus-fixated, supplementary "piggyback" IOL to correct refractive errors. The outcome measures included preoperative and postoperative uncorrected distance visual acuity (UDVA), spectacle-corrected distance visual acuity (CDVA), refractive correction, and complications. RESULTS: This study evaluated 10 eyes (10 patients) with previous penetrating or deep anterior lamellar keratoplasty with a mean follow-up period of 12.2 +/- 10.7 months (range, 2-33 months). All eyes showed improved UDVA postoperatively with 70% achieving >=20/40. Median UDVA (logarithm of the minimum angle of resolution) improved from 1.2 (20/280, range 20/70-20/2000) preoperatively to 0.3 (20/40, range 20/20-20/60) postoperatively at the latest follow-up visit (P < 0.01). Five eyes (50%) had improvement in CDVA by at least 1 line of Snellen acuity with all eyes achieving >=20/40 and 70% achieving >=20/25. Median CDVA (logarithm of the minimum angle of resolution) was 0.2 (20/30, range 20/20-20/50) preoperatively compared with 0.1 (20/25, range 20/20-20/40) postoperatively (P = 0.03). In 8 eyes that received toric secondary IOLs, the mean refractive astigmatism decreased by 84% from 5.7 diopters (D) (range, 4-9 D) to 0.9 D (range, 0.2-3.0 D) (P = 0.01). Postoperative refractive astigmatism was +/-1 D of predicted astigmatism for 7 of 8 eyes. No eyes lost any lines of UDVA or CDVA, and there were no keratoplasty rejection/failure events. CONCLUSIONS: Implantation of a supplementary, sulcus-based IOL is an effective approach to reduce spherical and astigmatic refractive errors in pseudophakic eyes after keratoplasty. PMID- 26114826 TI - Inhibitory Effect of Topical Aflibercept on Corneal Neovascularization in Rabbits. AB - PURPOSE: To examine the inhibitory effect of topical aflibercept [vascular endothelial growth factor (VEGF) trapR1R2] on corneal neovascularization (NV) in rabbits. METHODS: Corneal NV was induced in 24 eyes of 12 rabbits. Seven days after a silk suture in the corneal stroma, the rabbits were divided into 4 groups of 6 eyes each. Two groups were treated with topical aflibercept at 2 different concentrations: 2 mg/0.5 mL (0.1%, group 1) and 2 mg/5 mL (0.01%, group 2). The other 2 groups were treated with topical bevacizumab 2.5 mg/1 mL (0.1%, group 3) and topical balanced salt solution (group 4, control). The concentration of VEGF and placental growth factor (PIGF) messenger RNA (mRNA) was measured by reverse transcriptase-polymerase chain reaction. RESULTS: The surface area of NV was significantly smaller in the treatment groups compared with that of the control group. The expression of VEGF mRNA was 0.227 in 0.1% aflibercept (group 1), 0.811 in 0.01% aflibercept (group 2), and 0.495 in 0.1% bevacizumab (group 3). There was a significant decrease in the VEGF concentration in all 3 treatment groups compared with the control group, 1.491 (P = 0.031, <0.05). In the 0.01% aflibercept group, the difference was less than that of the 0.1% aflibercept and 0.1% bevacizumab groups. There was no significant difference in the 0.1% aflibercept and 0.1% bevacizumab groups. The expression of PIGF mRNA was 0.791 in 0.1% aflibercept (group 1), 0.743 in 0.01% aflibercept (group 2), 1.194 in 0.1% bevacizumab (group 3), and 1.458 in the control group. The expression of PIGF mRNA was significantly decreased in the 0.1% aflibercept and 0.01% aflibercept groups. CONCLUSIONS: Topical aflibercept may have an inhibitory effect on corneal NV in rabbits. PMID- 26114827 TI - Management and Prevention of Herpes Zoster Ocular Disease. AB - Herpes zoster (HZ) is caused by reactivation of latent varicella zoster virus (VZV) in people who have had chicken pox, usually resulting in a painful, unilateral, dermatomal, vesicular rash. Herpes zoster ophthalmicus occurs when the first division of cranial nerve V is involved. HZ is common, with approximately 1 million new cases per year in the United States, and occurs in 1 in 3 persons. Although the rate of HZ increases with age, over half of all cases occur under the age of 60 years. Complications of herpes zoster ophthalmicus include eye disease, postherpetic neuralgia (PHN), and strokes. VZV has also been found in temporal arteritis biopsies. There is growing evidence that HZ is followed by chronic active VZV infection contributing to these complications. In view of this, and the efficacy of suppressive antiviral treatment in reducing recurrent herpes simplex keratitis, a randomized controlled trial of suppressive valacyclovir to reduce new or worsening anterior segment disease and/or PHN is needed. The zoster vaccine (ZV) is safe and effective in reducing the burden of illness, severity of PHN, and incidence of HZ. It is Centers for Disease Control and Prevention recommended for persons aged 60 years and above without impaired cellular immunity, and Food and Drug Administration approved for those aged 50 and older. It is most effective in preventing HZ in recipients in their 50s. Because of underusage of the ZV, it has not impacted the epidemiology of the disease. Barriers to its use include cost, variable reimbursement, frozen storage, and lack of a strong recommendation by doctors. PMID- 26114828 TI - Evolution of Endothelial Keratoplasty: Where Are We Headed? AB - In less than 10 years, the proportion of endothelial keratoplasty (EK) procedures has increased from less than 5% of the corneal grafts in the United States to over half. EK has made corneal grafts safer and provides better and more predictable visual results than standard full-thickness penetrating keratoplasty. Descemet membrane endothelial keratoplasty in particular has dramatically reduced the risk of rejection, allowing reduction in topical corticosteroid use, resulting in a lower incidence of steroid-induced intraocular pressure elevation. By removing the confounding effects of ocular surface disease, which is exacerbated by the sutures and anesthetic corneas associated with full-thickness grafts, EK has revealed that the greatest risk factor for graft failure is filtration surgery, particularly aqueous shunts. As the use of glaucoma filtering tubes continues to increase, they may become a leading cause of corneal decompensation. PMID- 26114829 TI - Contemporary Treatment Paradigms in Keratoconus. AB - The past 20 years have witnessed an explosion in our knowledge of keratoconus, accompanied by a radical transformation of management options. A 2-hit hypothesis proposes an underlying genetic predisposition coupled with external environmental factors, including eye rubbing and atopy. The variable prevalence and natural history have been better defined including significant cone progression in middle age. Therefore, current management must include early diagnosis, regular monitoring, and treatment of environmental cofactors. Spectacles and contact lenses remain fundamental to the optical management of keratoconus. Intrastromal corneal ring segments have been increasingly used, providing improvement in the corneal shape, corrected visual acuity, and contact lens wear. However, like contact lenses, intrastromal corneal ring segments do not treat the underlying disease process. Therefore, current approaches must also consider treatments to minimize keratoconus progression. Fortunately, there is increasing evidence that corneal collagen crosslinking will halt or slow progression in most cases. Until relatively recently, penetrating keratoplasty was the preferred intervention for advanced keratoconus, with long-term success in the region of 90%; however, the greatest risk of failure remains endothelial allograft rejection. Deep anterior lamellar keratoplasty has emerged in the new millennium as a preferred approach to conserve the host endothelium and avoid rejection. Nonetheless, the overall superiority of deep anterior lamellar keratoplasty compared with penetrating keratoplasty, in terms of optical and survival benefits, is still debated. This perspective provides an overview of our current knowledge of keratoconus and current management options. A step-ladder approach to managing keratoconus is outlined to provide the practitioner with a contemporary management paradigm. PMID- 26114831 TI - Urine collection in young children. PMID- 26114830 TI - Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder. AB - OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6 month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment. PMID- 26114833 TI - Does the Concentration of Oxidative and Inflammatory Biomarkers Differ by Haptoglobin Genotype in Type 1 Diabetes? AB - The haptoglobin (Hp) 2 allele directly predicts coronary artery disease in type 1 diabetes, potentially due to its decreased antioxidative/anti-inflammatory properties. We measured the concentrations of oxidative/inflammatory biomarkers (urinary 15-isoprostane F(2t) [IsoP], alpha- and gamma-tocopherol, tumor necrosis factor alpha [TNF-alpha], high-sensitivity C-reactive protein [hsCRP], white blood cell [WBC] count, fibrinogen, and adiponectin) thrice during 20 years of follow-up among 454 individuals with childhood-onset type 1 diabetes (mean baseline age, 28 years and diabetes duration, 19 years). Differences in biomarkers by Hp were assessed both at baseline (i.e., the first time point of measurements) and over time (with mixed models). No differences by Hp were observed at baseline with the exception of a significant trend toward higher IsoP concentrations with the number of Hp 2 alleles (p=0.01). In multivariable mixed models, the concentrations of IsoP (beta=0.05, p=0.01) and WBC count (beta=0.20, p=0.06) overtime increased incrementally with the number of Hp 2 alleles. No other biomarker assessed related to Hp. Reported elevated IsoP and WBC count concentrations over time among Hp 2 allele carriers lead to the hypothesis that the antioxidative and anti-inflammatory capacity of the Hp 2 is inferior to that of the Hp 1 allele in type 1 diabetes. PMID- 26114834 TI - Automated analysis protocol for high resolution BOLD-fMRI mapping of the fingertip somatotopy in brodmann area 3b. AB - BACKGROUND: To introduce a standardized and automatized method for functional MRI (fMRI) examinations of the cortical sensory somatotopy in large samples for investigations of the fingertip somatotopy in the primary somatosensory cortex. METHODS: At 3 Tesla, T2* (spin-spin relaxation time) weighted images (gradient echo echo planar imaging, voxel size 1.5 * 1.5 * 2 mm3) were acquired during stimulation of the finger tips for thumb, index and middle finger on both hands, in a group of 18 healthy participants. In addition, structural T1 weighted (magnetization prepared rapid gradient echo, isotropic voxel size 1 mm) and MR angiography (time of flight, voxel size 0.26 * 0.26 * 0.5 mm3) images were recorded. Boundary based register served to combine movement correction and registration in FreeSurfer Functional analysis stream (FS-Fast), resulting in fine scale corrections, as revealed with FSL Possum (FSL FMRIB Software Library Physics-Oriented Simulated Scanner for Understanding MRI) simulations. Automated data analysis was achieved by inclusion of cytoarchitectonic probability maps for calculation of functional activation in Brodmann area 3b. Draining vessel artifacts were identified using the peak value approach and the MR-angiography. Distances were computed as the shortest connection within the gray matter. RESULTS: The fMRI somatotopic maps agreed with the expected fingertip somatotopy in 63% of the investigated subjects, an improvement of 34% compared with FS-Fast. Artifacts have been removed completely. Adjacent fingertips showed average distances of 8 +/- 4.3 mm, and between thumb and middle finger 13.4 +/- 4.8 mm was found. Distances for both hands were similar as expected from the characteristics of the fingertip spatial tactile resolution. CONCLUSION: The introduced evaluation procedure allowed automated analysis of the fingertip representation in excellent agreement with preceding results. PMID- 26114835 TI - An empirical assessment of the "healthy prisoner hypothesis". AB - Lower mortality among inmates, compared to the general population, is typically ascribed to access to health care during incarceration and the low risk of death due to homicide, accidents, and drug overdose. In this study, we test an alternative explanation based on selection of healthy individuals into jails and prisons-"the healthy prisoner hypothesis." According to this hypothesis, inmates have to be healthy to commit crimes and become incarcerated, which explains why they experience lower mortality than comparable segments of the general population. Using ten waves of data from the National Longitudinal Survey of Youth 1997, we compare individuals who become incarcerated the following year to those who do not on four measures of health-depression, self-rated health, functional limitations, and injury or illness requiring medical attention. Results from matched samples indicate that future inmates are hardly ever in significantly better health the year prior to their incarceration. These findings strongly suggest that the paradoxical mortality advantage of inmates is not due to health selection. PMID- 26114836 TI - Clinical assessment of arterial stiffness with cardio-ankle vascular index: theory and applications. AB - Arterial stiffness is often assessed in clinical medicine, because it is not only an important factor in the pathophysiology of blood circulation but also a marker for the diagnosis and the prognosis of cardiovascular diseases. Many parameters have so far been proposed to quantitatively represent arterial stiffness and distensibility, such as pressure-strain elastic modulus (Ep), stiffness parameter (beta), pulse wave velocity (PWV), and vascular compliance (Cv). Among these, PWV has been most frequently applied to clinical medicine. However, this is dependent on blood pressure at the time of measurement, and therefore it is not appropriate as a parameter for the clinical evaluation of arterial stiffness, especially for the studies on hypertension. On the contrary, stiffness parameter beta is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiffness index called cardio-ankle vascular index (CAVI). Although this index is obtained from the PWV between the heart and the ankle, it is essentially similar to the stiffness parameter beta, and therefore it does not depend on blood pressure changes during the measurements. CAVI is being extensively used in clinical medicine as a measure for the evaluation of cardiovascular diseases and risk factors related to arteriosclerosis. In the present article, we will explain the theoretical background of stiffness parameter beta and the process to obtain CAVI. And then, the clinical utility of CAVI will be overviewed by reference to recent studies. PMID- 26114837 TI - Prevalence and prognosis of prodromal Alzheimer's disease as assessed by magnetic resonance imaging and 18F-fluorodeoxyglucose-positron emission tomography in a community: reanalysis from the Osaki-Tajiri Project. AB - BACKGROUND: Dubois et al. proposed the criteria for prodromal Alzheimer's disease (AD) to detect dementia in its very early stage. Because detection requires magnetic resonance imaging and (18) F-fluorodeoxyglucose-positron emission tomography (PET), the prevalence and prognosis have not been fully investigated. METHODS: Our database included 346 healthy participants (Clinical Dementia Rating (CDR) 0), 119 with questionable dementia (CDR 0.5), and 32 dementia participants (CDR 1+) and was applied to investigate the prevalence of prodromal AD. Forty four CDR 0.5 participants (37%) were randomly selected to undergo (18) F fluorodeoxyglucose-PET. The same percentage was applied to select 128 CDR 0 and 12 CDR 1 + participants (total: n = 184) to calculate the prevalence. A neuroradiologist classified the PET images in a blinded manner based on the criteria of Silverman et al. Participants were considered to have prodromal AD if they exhibited 'parietal/temporal +/- frontal hypometabolism' (PET) with hippocampal atrophy (magnetic resonance imaging). RESULTS: Eighteen CDR 0.5 participants (40.9%) met the criteria for prodromal AD, which was a prevalence rate of 9.8% among older adults aged >= 65 years. Thirteen prodromal AD participants (72%) converted to AD during the 5-year follow-up period. DISCUSSION: The concept and criteria for prodromal AD are useful for predicting which subjects in a community will convert to AD. PMID- 26114838 TI - Preference for language of instruction of an English language learner with autism. AB - OBJECTIVE: To use a preference assessment to identify the preferred language of instruction (English or Spanish) for a child with autism living in a Spanish speaking home and receiving school services in English only. METHODS: We used a concurrent chains method to evaluate the participant's preference for English or Spanish instruction. Colored microswitches represented English instruction, Spanish instruction and no instruction (control). Switch presses resulted in instruction and reinforcement in either English or Spanish, or no instruction and no reinforcement. After session 10, switches were reprogrammed to control for color bias. RESULTS: The participant chose Spanish instruction most frequently. CONCLUSIONS: The participant preferred to receive instruction in Spanish. These data support previous research indicating the importance of child preference when individualizing educational programs for children with autism and that language of instruction is an important variable when working with children with autism who experience multiple languages across home and school. PMID- 26114840 TI - Design of Fe3O4@SiO2@Carbon Quantum Dot Based Nanostructure for Fluorescence Sensing, Magnetic Separation, and Live Cell Imaging of Fluoride Ion. AB - A robust reusable fluoride sensor comprised of a receptor in charge of the chemical recognition and a fluorophore responsible for signal recognition has been designed. Highly fluorescent carbon quantum dot (CD) and magnetically separable nickel ethylenediaminetetraacetic acid (EDTA) complex bound-silica coated magnetite nanoparticle (Fe3O4@SiO2-EDTA-Ni) have been used as fluorophore and fluoride ion receptor, respectively. The assay is based on the exchange reaction between the CD and F(-), which persuades the binding of fluoride to magnetic receptor. This method is highly sensitive, fast, and selective for fluoride ion in aqueous solution. The linear response range of fluoride (R(2) = 0.992) was found to be 1-20 MUM with a minimum detection limit of 0.06 MUM. Excellent magnetic property and superparamagnetic nature of the receptor are advantageous for the removal and well quantification of fluoride ion. The practical utility of the method is well tested with tap water. Because of high sensitivity, reusability, effectivity, and biocompatibility, it exhibits great promise as a fluorescent probe for intracellular detection of fluoride. PMID- 26114839 TI - The association between quitting smoking and weight gain: a systematic review and meta-analysis of prospective cohort studies. AB - This systematic review and meta-analysis aimed to quantify weight gain after smoking cessation and the difference in weight gain between quitters and continuing smokers. Five electronic databases were searched before January 2015. Population-based prospective cohort studies were included if they recorded the weight change of adult smokers from baseline (before smoking cessation) to follow up (at least 3 months after cessation). Thirty-five cohort studies were identified, including 63,403 quitters and 388,432 continuing smokers. The mean weight gain was 4.10 kg (95% confidence interval [CI]: 2.69, 5.51) and body mass index (BMI) gain was 1.14 kg m(-2) (95% CI: 0.50, 1.79) among quitters. Compared with continuing smoking, quitting smoking was significantly associated with absolute weight (adjusted mean difference [MD]: 2.61 kg; 95% CI: 1.61, 3.60) and BMI gain (adjusted MD: 0.63 kg m(-2) ; 95% CI: 0.46, 0.80). Subgroup analyses using geographic region found that the difference in weight gain was considerably greater in studies from North America than from Asia. Follow-up length was identified as a source of heterogeneity, such that studies with longer follow-up showed greater difference in weight gain. Effective strategies are needed to encourage smokers to quit irrespective of potential weight gain and to help quitters avoid excess weight gain. PMID- 26114841 TI - Reliability of Ischemic Index Grading in Common Retinal Vascular Diseases. AB - BACKGROUND AND OBJECTIVE: Retinal nonperfusion is closely associated with vision threatening complications such as neovascularization and macular edema. The purpose of this study is to investigate the reliability of a calculated ischemic index (ISI) by means of intergrader and intragrader agreement on ultrawide-field fluorescein angiography (UWFFA) in common retinal vascular diseases. PATIENTS AND METHODS: Eight trained graders evaluated 15 UWFFA images provided digitally and re-graded on a different day. They included five eyes with diabetic retinopathy (DR), five with branch retinal vein occlusion (BRVO), and five with central retinal vein occlusion (CRVO). To assess intergrader and intragrader agreement and variability among different diseases, the replicate inter- and intragrader standard deviations (SDs) and coefficients of variation (CVs) were calculated. RESULTS: Mean ISI was 46% for images of DR, 26% for images of BRVO, and 61.3% for images of CRVO. Combined intragrader and intergrader replicate SDs were 17.8% for DR, 3.8% for BRVO and 13.0% for CRVO. Combined intragrader and intergrader replicate coefficients of variation were 38.6% (percent of mean ISI) for DR, 14.7% for BRVO, and 21.2% for CRVO. CONCLUSION: Intergrader and intragrader variability was high when assessing DR. This may be due to the chronic nature of DR progression, which can lead to patchy areas of ischemia. Intergrader and intragrader variability was better for CRVO and best for BRVO. This may be due to the acute or subacute nature of retinal vein occlusions. PMID- 26114842 TI - Centralized Reading Center Improves Quality in a Real-World Setting. AB - BACKGROUND AND OBJECTIVE: Diabetic retinopathy (DR) screening is standard of care, but its utility diminishes unless high quality is maintained. This project describes the improvement in diagnostic accuracy achieved at a large health maintenance organization by implementing a centralized reading center. PATIENTS AND METHODS: Data were extracted from the electronic health records of patients with diabetes who underwent DR screening between January 1, 2009, and December 31, 2013, at 13 medical centers. Certified ophthalmic assistants and technicians were trained to read DR images under the supervision of a retinal specialist. This program was pilot-tested prior to full implementation. RESULTS: DR prevalence among the 13 centers in 2009 was 10.1%, far below the national average. After implementation, prevalence increased to 22.1%. The program also resulted in improved access to follow-up. CONCLUSION: The results demonstrate the value of a reading center in decreasing diagnostic error and achieving other improvements in a real-world setting. PMID- 26114843 TI - Quality and Diagnostic Utility of Mydriatic Smartphone Photography: The Smartphone Ophthalmoscopy Reliability Trial. AB - BACKGROUND AND OBJECTIVE: Establish quality and diagnostic utility of mydriatic smartphone ophthalmoscopy (SO) fundus images compared to fundus camera (FC) images. PATIENTS AND METHODS: In this prospective, cross-sectional study, 94 consecutive patients in an urban eye emergency department underwent SO and FC fundus imaging via one of three study arms: medical student 1 (MS1), medical student 2 (MS2), and ophthalmology resident (OR). Images of 188 eyes were graded for overall quality by two masked reviewers, and observed critical fundus findings were compared to dilated fundus examination documentation. RESULTS: SO images were higher quality in the OR arm than in the MS1 and MS2 arms (P < .017). There were no differences in FC image quality between photographers (all P > .328). In the OR arm, SO images detected 74.3% of critical fundus findings, whereas FC images detected 77.1%. CONCLUSION: SO produces fundus images approaching the quality and diagnostic utility of traditional FC photographs. PMID- 26114844 TI - Quantification of Change in Pigment Epithelial Detachment Volume and Morphology After Transition to Intravitreal Aflibercept in Eyes With Recalcitrant Neovascular AMD: 18-Month Results. AB - BACKGROUND AND OBJECTIVE: To quantitatively evaluate the change in pigment epithelial detachment (PED) morphology on spectral-domain optical coherence tomography (SD-OCT) 18 months after the transition to intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) with PED recalcitrant to monthly intravitreal bevacizumab or ranibizumab. PATIENTS AND METHODS: Retrospective case series examining patients with neovascular AMD who had a persistent fibrovascular or serous PED on SD-OCT. PED volume was calculated by manually outlining the PED on individual OCT slices of the raster scan and multiplying by the pixel dimensions. RESULTS: Eleven eyes of 10 patients who had received an average of 25.7 +/- 20.1 (range: 6 to 70) prior bevacizumab or ranibizumab injections over a period of 26.6 +/- 19.8 months (range: 4 to 63) were included. PED volume decreased with aflibercept from 0.687 +/- 0.837 mm(3) to 0.562 +/- 0.705 mm(3) (P = .02), a decrease of 19% +/- 12.27%. CONCLUSION: After 18 months of aflibercept, recalcitrant PED volumes were reduced by 19% while preserving visual acuity in eyes with neovascular AMD. PMID- 26114845 TI - Current Infectious Endophthalmitis Rates After Intravitreal Injections of Anti Vascular Endothelial Growth Factor Agents and Outcomes of Treatment. AB - BACKGROUND AND OBJECTIVE: To assess the incidence and outcomes of infectious endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents. PATIENTS AND METHODS: Patient records at the Bascom Palmer Eye Institute (BPEI) from January 1, 2005, through December 31, 2014, were reviewed. The largest commercial claims and encounters database in the U.S. (MarketScan) was utilized to calculate the population-based endophthalmitis rate for 2011 to 2013. RESULTS: The population-based rate of endophthalmitis after anti-VEGF injections for 2011 to 2013 was 391/740,757 (0.053%). BPEI's rate was 20/121,285 (0.016%) during the study period: eight after bevacizumab (0.012%), six after ranibizumab (0.018%), and six after aflibercept (0.031%) injection. Nine BPEI cases (45%) were culture-positive: Streptococcus species (5), coagulase negative Staphylococcus (3), and non-anthracis Bacillus (1). Final visual acuity varied from 20/25 to no light perception. CONCLUSION: Endophthalmitis after anti VEGF injection was uncommon in our institution and in the population-based database. Treatment outcomes were variable but generally fared better in the culture-negative cases. PMID- 26114846 TI - Incontinentia Pigmenti: A Comprehensive Review and Update. AB - Incontinentia pigmenti (IP) is a rare syndrome with skin lesions, ocular abnormalities in the retina and elsewhere, central nervous system abnormalities, and teeth defects. The authors present an updated review of the literature, highlighting diagnosis, epidemiology, pathophysiology, clinical features, and management of IP. IP is an X-linked dominant syndrome with an incidence of 0.0025%; most patients are female. IP is caused by a mutation in the IKBKG gene, causing a loss of function of NF-kappabeta, leaving cells susceptible to apoptosis from intrinsic factors. The cardinal feature of IP is four stages of skin distinctive lesions. Of those with IP, 36.5% have detectable eye pathology and 60% to 90% of those have retinal issues. Peripheral avascularity and macular occlusive disease commonly occur. The authors performed a comprehensive review of Medline from 1947 to 2014. All papers mentioning IP in ophthalmologic journals were reviewed as well as applicable publications from other medical specialties. PMID- 26114847 TI - Ipilimumab-Associated Retinopathy. AB - Ipilimumab is a novel immunotherapeutic agent that improves survival in patients diagnosed with metastatic melanoma. With the rising incidence of melanoma, the use of this pharmacologic agent is increasing. However, ipilimumab can be associated with rare but serious systemic adverse events. While the mechanism of these systemic adverse events is immune-related dysfunction, the index case highlights a possible direct ocular adverse event associated with ipilimumab infusion resulting in bilateral serous retinal detachment. Close observation of ocular findings using multimodal imaging analysis can provide insights into possible pathophysiology of the condition and guide further management. PMID- 26114848 TI - Is Acute Zonal Occult Outer Retinopathy an Autoimmune Condition? A Case Report and Literature Review. AB - A 42-year-old woman with multiple sclerosis presented with focal decreased vision and photopsia in the left eye. Funduscopy and fluorescein angiography revealed focal chorioretinal atrophy, vascular attenuation, and bone spicules. Electroretinography revealed interocular reduction in b-wave amplitude, and Goldmann visual field perimetry studies revealed an inferior scotoma. The authors performed a literature review and conclude that the prevalence of acute zonal occult outer retinopathy in patients with autoimmune conditions may suggest that the condition is autoimmune in nature. Clinical history as well as funduscopic and retinal investigations are important in diagnosing acute zonal occult outer retinopathy. PMID- 26114849 TI - Multimodal Ultrawide-Field Imaging Features in Waardenburg Syndrome. AB - A 45-year-old woman was referred for bilateral irregular fundus pigmentation. Dilated fundus examination revealed irregular hypopigmentation posterior to the equator in both eyes, confirmed by fundus autofluorescence. A thickened choroid was seen on enhanced-depth imaging spectral-domain optical coherence tomography (EDI SD-OCT). Systemic evaluation revealed sensorineural deafness, telecanthus, and a white forelock. Further investigation revealed a first-degree relative with Waardenburg syndrome. Waardenburg syndrome is characterized by a group of features including telecanthus, a broad nasal root, synophrys of the eyebrows, piedbaldism, heterochromia irides, and deafness. Choroidal hypopigmentation is a unique feature that can be visualized with ultrawide-field fundus autofluorescence. The choroid may also be thickened and its thickness measured with EDI SD-OCT. PMID- 26114850 TI - Choroidal Involvement in Erdheim-Chester Disease. AB - Erdheim-Chester disease is a rare infiltrative disorder of non-Langerhans cell histiocytes, which affects multiple organs, including bone, heart, lungs, orbits, central nervous system (CNS), pituitary gland, and retroperitoneum. Bone affliction is almost universal in these patients and, to a lesser degree, the CNS, retroperitoneum, and other tissues. Eye involvement is typically retro orbital or periorbital. This case report describes a 48-year-old patient who presented with reduced vision in the left eye and no other complaints. Fundus examination revealed a choroidal mass in the macula. The authors believe that this might be the second case of choroidal involvement in Erdheim-Chester disease. PMID- 26114851 TI - Ocriplasmin-Induced Macular Hole Closure in the Absence of Vitreomacular Adhesion Release. AB - A 79-year-old man presented with a symptomatic, full-thickness macular hole with concurrent vitreomacular traction (VMT), stage 2. The patient was treated with a single injection of ocriplasmin. Within 1 week, the macular hole had closed, but there was persistence of vitreomacular traction. Two months after injection, the VMT released with sustained closure of the macular hole. The temporal course of macular hole closure antecedent to VMA release runs contrary to our current understanding of macular hole closure and warrants further research to decipher the mechanism by which ocriplasmin achieves its intended effect. PMID- 26114852 TI - Pars Plana Lensectomy After Femtosecond Laser-Assisted Cataract Surgery. AB - The use of femtosecond laser during cataract surgery is increasing, as it may potentially improve accuracy, safety and refractive outcomes. However, posterior capsule rupture with retained lens material can occur, necessitating vitreoretinal intervention. The authors report the first videographically documented case of removal of retained lens material after femtosecond laser assisted cataract surgery. PMID- 26114853 TI - Polycystic Ovary Syndrome and Central Serous Chorioretinopathy. AB - The authors report a case series of five women with the diagnosis of polycystic ovary syndrome (PCOS) (n = 4) or a first-degree relative with PCOS (n = 1) who presented with central serous chorioretinopathy (CSR). This report is the first to correlate PCOS and CSR on clinical presentation. Patients with PCOS often exhibit physical evidence of elevated androgens, such as testosterone, which recently has been linked to CSR. The authors suggest that women with CSR be investigated for PCOS if indicated clinically. In addition, further studies should investigate the relationship between the two disorders. PMID- 26114854 TI - Effects of a Multi-Disciplinary Lifestyle Intervention on Cardiometabolic Risk Factors in Young Women with Abdominal Obesity: A Randomised Controlled Trial. AB - BACKGROUND: Young women are under-represented in cardiovascular disease research, with obesity and cardiometabolic risk factor interventions generally targeting older adults. Furthermore, appropriate study designs for young women remain uncertain. This study aimed to assess the impact of a 12 week multi-disciplinary lifestyle intervention on cardiometabolic risk factors in premenopausal women with abdominal obesity. METHODS: Women aged 18-30 y with abdominal obesity [waist circumference (WC) >= 80 cm] were randomised to a 12 week lifestyle intervention (n = 26) of physical activity, nutrition education and cognitive behavioural therapy, or a wait-list control group (n = 17). Both groups completed anthropometric, biochemical, nutrition and fitness testing, at pre (0 weeks) and post (12 weeks), with intervention participants completed follow-up testing at 24 weeks. RESULTS: Results from a linear mixed model showed no between-group differences, other than increased physical activity in the intervention group, at post. In the intervention group alone, positive within-group changes were observed in WC, waist-hip-ratio (WHR), waist-height-ratio (WHtR), resting heart rate, blood pressure, predicted VO2max, and total energy intake. Most changes were maintained at 24 weeks post-intervention. Similar within-group improvements were observed in control participants in WC, WHR, WHtR, and systolic blood pressure but no changes were detected in physical activity and nutrition. CONCLUSIONS: Cardiometabolic risk factors were decreased as a result of a lifestyle intervention in young women with abdominal obesity. It is difficult to describe observations in the control group without greater understanding of the behaviour of wait-list participants. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612001017819. PMID- 26114855 TI - Within-Match PlayerLoadTM Patterns During a Simulated Soccer Match: Potential Implications for Unit Positioning and Fatigue Management. AB - PURPOSE: To assess the acute alterations in triaxial accelerometry (PlayerLoad [PL(VM)]) and its individual axial planes (anteroposterior PlayerLoad [PL(AP)], mediolateral PlayerLoad [PL(ML)], and vertical PlayerLoad [PL(V)]) during a standardized 90-min soccer match-play simulation (SAFT90). Secondary aims of the study were to assess the test-retest reliability and anatomical location of the devices. METHODS: Semiprofessional (n = 5) and university (n = 15) soccer players completed 3 trials (1 familiarization, 2 experimental) of SAFT90. PlayerLoad and its individual planes were measured continuously using micromechanical-electrical systems (MEMS) positioned at the scapulae (SCAP) and near the center of mass (COM). RESULTS: There were no between-halves differences in PL(VM); however, within-half increases were recorded at the COM, but only during the 1st half at the SCAP. Greater contributions to PL(VM) were provided by PL(V) and PL(ML) when derived from the SCAP and COM, respectively. PL(VM) (COM 1451 +/- 168, SCAP 1029 +/- 113), PL(AP) (COM 503 +/- 99, SCAP 345 +/- 61), PL(ML) (COM 712 +/- 124, SCAP 348 +/- 61), and PL(V) (COM 797 +/- 184, SCAP 688 +/- 124) were significantly greater at the COM than at the SCAP. Moderate and high test-retest reliability was observed for PlayerLoad and its individual planes at both locations (ICC .80 .99). CONCLUSIONS: PlayerLoad and its individual planes are reliable measures during SAFT90 and detected within-match changes in movement strategy when the unit was placed at the COM, which may have implications for fatigue management. Inferring alterations in lower-limb movement strategies from MEMS units positioned at the SCAP should be undertaken with caution. PMID- 26114856 TI - Squamosal Suture Craniosynostosis Due to Hyperthyroidism Caused by an Activating Thyrotropin Receptor Mutation (T632I). AB - BACKGROUND: Congenital hyperthyroidism can be a cause of failure to thrive, hyperactivity, developmental delay, and craniosynostosis during infancy. Most commonly, the condition occurs in the setting of maternal autoimmune thyroid disease. Rarely, congenital hyperthyroidism can also occur secondary to activating mutations within the thyrotropin (TSH) receptor. PATIENT FINDINGS: A Hispanic male infant presented at age 6 months with severe thyrotoxicosis. At the time of presentation he was being evaluated for squamosal suture synostosis and he was noted to have significant developmental delays. SUMMARY: The patient's thyrotoxicosis was initially treated with antithyroid medication, and he subsequently underwent craniosynostosis repair leading to neurodevelopmental improvement. DNA from the patient and his parents was submitted for mutational analysis of exons 9 and 10 of the TSH receptor. He was found to carry a monoallelic transition 1895C>T in exon 10 that resulted in the substitution of threonine at position 632 by isoleucine (T32I). This mutation resulted in constitutive activation of the TSH receptor. Neither parent carried this mutation indicating that the child has acquired a de novo germline mutation. CONCLUSIONS: We report the first case of squamosal suture craniosynostosis in a patient with non-autoimmune hyperthyroidism. Squamosal suture craniosynotosis is rare, often has a subtle presentation, and should be considered in all patients with this condition because prompt treatment of hyperthyroidism and craniosynotosis repair can lead to normalization of neurodevelopment. PMID- 26114857 TI - What can errors tell us about specific language impairment deficits? Semantic and morphological cuing in a sentence completion task. AB - The lexical retrieval ability of children with specific language impairment (SLI) and children with typical language development was compared. Fifty Hebrew speaking children participated: 15 school-age with SLI, 20 typically developing, matched on age to the SLI group and 15 younger, typically developing matched on naming performance to the SLI group. Participants were tested in a sentence completion task with semantic cuing and with morphological cuing. SLI children performed poorer than the chronological-age group and similarly to the naming matched group. Error patterns showed a qualitative difference between the SLI and naming-matched groups. The results suggest that lexical retrieval of children with SLI is delayed and qualitatively different from that of typically developing children. PMID- 26114858 TI - Time-scale dependency of host plant biomass- and trait-mediated indirect effects of deer herbivory on a swallowtail butterfly. AB - Despite recent attempts to quantify the relative strength of density- and trait mediated indirect effects, rarely has the issue been properly addressed at the population level. Most research is based on short-term small-scale experiments in which behavioural and/or physiological responses prevail. Here, we estimated the time-scales during which density- and trait-mediated effects manifest, as well as the strength of these effects, using an interaction chain with three organisms (deer-plant-butterfly). A hierarchical Bayesian model was performed by using a long-term data set of deer density in the Boso Peninsula, central Japan (where local densities differ spatially and temporally) as well as densities of the swallowtail butterfly Byasa alcinous and its host plant Aristolochia kaempferi. The time-scale effect of deer on plant quantity and quality was estimated according to the degree of carry-over effects. The negative influence on leaf density showed a temporal saturation pattern over the long term, while the positive influence on leaf quality due to resprouting of leaves after deer browsing showed no clear temporal trend. The net indirect effect changed from positive to negative with time, with the negative density-mediated effect becoming prominent in the long term. Our novel approach is widely applicable in assessing the dynamic impacts of wildlife if the spatio-temporal variability of expansion and/or invasion history is known. PMID- 26114859 TI - Analyses of Developmental Rate Isomorphy in Ectotherms: Introducing the Dirichlet Regression. AB - Temperature drives development in insects and other ectotherms because their metabolic rate and growth depends directly on thermal conditions. However, relative durations of successive ontogenetic stages often remain nearly constant across a substantial range of temperatures. This pattern, termed 'developmental rate isomorphy' (DRI) in insects, appears to be widespread and reported departures from DRI are generally very small. We show that these conclusions may be due to the caveats hidden in the statistical methods currently used to study DRI. Because the DRI concept is inherently based on proportional data, we propose that Dirichlet regression applied to individual-level data is an appropriate statistical method to critically assess DRI. As a case study we analyze data on five aquatic and four terrestrial insect species. We find that results obtained by Dirichlet regression are consistent with DRI violation in at least eight of the studied species, although standard analysis detects significant departure from DRI in only four of them. Moreover, the departures from DRI detected by Dirichlet regression are consistently much larger than previously reported. The proposed framework can also be used to infer whether observed departures from DRI reflect life history adaptations to size- or stage-dependent effects of varying temperature. Our results indicate that the concept of DRI in insects and other ectotherms should be critically re-evaluated and put in a wider context, including the concept of 'equiproportional development' developed for copepods. PMID- 26114860 TI - Donepezil Regulates 1-Methyl-4-phenylpyridinium-Induced Microglial Polarization in Parkinson's Disease. AB - 1-Methyl-4-phenylpyridinium (MPP+) induces microglial activation and degeneration of dopaminergic (DAergic) neurons. Donepezil is a well-known acetylcholinesterase inhibitor used clinically to treat cognitive dysfunction in Alzheimer's disease (AD). In the present study, we tested the hypothesis that MPP+ promotes microglial M1 polarization and suppresses M2 polarization and that this can be restored by donepezil. Results indicate that MPP+ treatment in microglial BV2 cells promotes microglial polarization toward the M1 state. However, pretreatment with donepezil inhibited MPP+-induced M1 polarization in microglia by suppressing the release of interleukin (IL)-6, IL-1beta, or tumor necrosis factor (TNF) alpha. Importantly, we found that MPP+ inhibited microglial M2 polarization by suppressing expression of Arg-1, Fizz1, and Ym1, which was also rescued by pretreatment with donepezil. In addition, IL-4-mediated induction of anti inflammatory marker genes IL-10, IL-13, and transforming growth factor-beta2 (TGF beta2) were significantly attenuated by MPP+ in BV2 cells, which was restored by pretreatment with donepezil in a concentration-dependent manner. Mechanistically, we found that the addition of MPP+ reduced the intensity of phosphorylated signal transducer and activator of transcription 6 (STAT6) but not total STAT6 in IL-4 stimulated BV2 cells. Importantly, pretreatment of microglial BV2 cells with donepezil 3 h prior to administration of MPP+ rescued the reduction of STAT6 phosphorylation induced by MPP+. PMID- 26114861 TI - Gender Differences in the Inheritance Mode of RYR2 Mutations in Catecholaminergic Polymorphic Ventricular Tachycardia Patients. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the causes of sudden cardiac death in young people and results from RYR2 mutations in ~60% of CPVT patients. The inheritance of the RYR2 mutations follows an autosomal dominant trait, however, de novo mutations are often identified during familial analysis. In 36 symptomatic CPVT probands with RYR2 mutations, we genotyped their parents and confirmed the origin of the respective mutation. In 26 sets of proband and both parents (trio), we identified 17 de novo mutations (65.4%), seven from their mothers and only two mutations were inherited from their fathers. Among nine sets of proband and mother, five mutations were inherited from mothers. Four other mutations were of unknown origin. The inheritance of RYR2 mutations was significantly more frequent from mothers (n = 12, 34.3%) than fathers (n = 2, 5.7%) (P = 0.013). The mean ages of onset were not significantly different in probands between de novo mutations and those from mothers. Thus, half of the RYR2 mutations in our cohort were de novo, and most of the remaining mutations were inherited from mothers. These data would be useful for family analysis and risk stratification of the disease. PMID- 26114862 TI - The dual targeting of EGFR and ErbB2 with the inhibitor Lapatinib corrects high glucose-induced apoptosis and vascular dysfunction by opposing multiple diabetes induced signaling changes. AB - The epidermal growth factor receptors, EGFR and EGFR2 (ErbB2), appear important mediators of diabetes-induced vascular dysfunction. We investigated whether targeted dual inhibition of EGFR and ErbB2 with Lapatinib would be effective in treating diabetes-induced vascular dysfunction in a rat model of type 1 diabetes. In streptozotocin-induced diabetes, chronic 4-week oral or acute, ex vivo, administration of Lapatinib prevented the development of vascular dysfunction as indicated by the attenuation of the hyper-reactivity of the diabetic mesenteric vascular bed (MVB) to norephinephrine without correcting hyperglycemia. Chronic in vivo or acute ex vivo Lapatinib treatment also significantly attenuated diabetes-induced increases in phosphorylation of EGFR, ErbB2, ERK1/2, AKT, ROCK2 and IkB-alpha as well as normalized the reduced levels of phosphorylated FOXO3A, and eNOS (Ser1177) in the diabetic MVB. Similar results were observed in vascular smooth muscle cells (VSMCs) cultured in high glucose (25 mM) treated with Lapatinib or small interfering RNA (siRNA) targeting the ErbB2 receptor. Lapatinib also prevented high glucose-induced apoptosis in VSMC. Thus, Lapatinib corrects hyperglycemia-induced apoptosis and vascular dysfunction with concomitant reversal of diabetes or high glucose-induced signaling changes in EGFR/ErbB2 and downstream signaling pathways implying that targeted dual inhibition of EGFR/ErbB2 might be an effective vasculoprotective treatment strategy in diabetic patients. PMID- 26114864 TI - Fruit and vegetable consumption and risk of cardiovascular disease: A meta analysis of prospective cohort studies. AB - A meta-analysis of prospective cohort studies was conducted to examine the relation between fruit and vegetables (FV) consumption and the risk of cardiovascular disease (CVD). We searched PubMed and EMBASE up to June 2014 for relevant studies. Pooled relative risks (RRs) were calculated and dose-response relationship was assessed. Thirty-eight studies, consisting of 47 independent cohorts, were eligible in this meta-analysis. There were 1,498,909 participants (44,013 CVD events) with a median follow-up of 10.5 years. The pooled RR (95% confidence interval) of CVD for the highest versus lowest category was 0.83 (0.79 0.86) for FV consumption, 0.84 (0.79-0.88) for fruit consumption, and 0.87 (0.83 0.91) for vegetable consumption, respectively. Dose-response analysis showed that those eating 800 g per day of FV consumption had the lowest risk of CVD. Our results indicate that increased FV intake is inversely associated with the risk of CVD. This meta-analysis provides strong support for the current recommendations to consume a high amount of FV to reduce CVD risk. PMID- 26114863 TI - Molecular Dynamics of Channelrhodopsin at the Early Stages of Channel Opening. AB - Channelrhodopsin (ChR) is a light-gated cation channel that responds to blue light. Since ChR can be readily expressed in specific neurons to precisely control their activities by light, it has become a powerful tool in neuroscience. Although the recently solved crystal structure of a chimeric ChR, C1C2, provided the structural basis for ChR, our understanding of the molecular mechanism of ChR still remains limited. Here we performed electrophysiological analyses and all atom molecular dynamics (MD) simulations, to investigate the importance of the intracellular and central constrictions of the ion conducting pore observed in the crystal structure of C1C2. Our electrophysiological analysis revealed that two glutamate residues, Glu122 and Glu129, in the intracellular and central constrictions, respectively, should be deprotonated in the photocycle. The simulation results suggested that the deprotonation of Glu129 in the central constriction leads to ion leakage in the ground state, and implied that the protonation of Glu129 is important for preventing ion leakage in the ground state. Moreover, we modeled the 13-cis retinal bound; i.e., activated C1C2, and performed MD simulations to investigate the conformational changes in the early stage of the photocycle. Our simulations suggested that retinal photoisomerization induces the conformational change toward channel opening, including the movements of TM6, TM7 and TM2. These insights into the dynamics of the ground states and the early photocycle stages enhance our understanding of the channel function of ChR. PMID- 26114865 TI - Anterior Subcutaneous versus Submuscular Transposition of the Ulnar Nerve for Cubital Tunnel Syndrome: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To pool reliable evidences for the optimum anterior transposition technique in the treatment of cubital tunnel syndrome by comparing the clinical efficacy of subcutaneous and submuscular anterior ulnar nerve transposition. METHODS: A comprehensive search was conducted in PubMed MEDLINE, Cochrane Library, EMBASE, Web of Science, OVID AMED, EBSCO and potentially relevant surgical archives. Risk of bias of each included studies was evaluated according to Cochrane Handbook for Systematic Reviews of Interventions. The risk ratio (RR) and 95% confidence intervals (CI) were calculated for the clinical improvement in function compared to baseline. Heterogeneity was assessed across studies, and subgroup analysis was also performed based on the study type and follow-up duration. RESULTS: Three studies with a total of 352 participants were identified, and the clinically relevant improvement was used as the primary outcomes. Our meta-analysis revealed that no significant difference was observed between two comparison groups in terms of postoperative clinical improvement in those studies (RR 1.04, 95% CI 0.86 to 1.25, P = 0.72). Meanwhile, subgroup analyses by study type and follow-up duration revealed the consistent results with the overall estimate. Additionally, the pre- and postoperative motor nerve conduction velocities were reported in two studies with a total of 326 patients, but we could not perform a meta-analysis because of the lack of concrete numerical value in one study. The quality of evidence for clinical improvement was 'low' or 'moderate' on the basis of GRADE approach. CONCLUSIONS: Based on small numbers of studies with relatively poor methodological quality, the limited evidence is insufficient to identify the optimum anterior transposition technique in the treatment of cubital tunnel syndrome. The results of the present study suggest that anterior subcutaneous and submuscular transposition might be equally effective in patients with ulnar neuropathy at the elbow. Therefore, more high quality randomized controlled trials with standardized clinical improvement metrics are required to further clarify this topic and to provide reproducible pre- and postoperative objective outcomes. PMID- 26114866 TI - Determinants of Low Birth Weight in Malawi: Bayesian Geo-Additive Modelling. AB - Studies on factors of low birth weight in Malawi have neglected the flexible approach of using smooth functions for some covariates in models. Such flexible approach reveals detailed relationship of covariates with the response. The study aimed at investigating risk factors of low birth weight in Malawi by assuming a flexible approach for continuous covariates and geographical random effect. A Bayesian geo-additive model for birth weight in kilograms and size of the child at birth (less than average or average and higher) with district as a spatial effect using the 2010 Malawi demographic and health survey data was adopted. A Gaussian model for birth weight in kilograms and a binary logistic model for the binary outcome (size of child at birth) were fitted. Continuous covariates were modelled by the penalized (p) splines and spatial effects were smoothed by the two dimensional p-spline. The study found that child birth order, mother weight and height are significant predictors of birth weight. Secondary education for mother, birth order categories 2-3 and 4-5, wealth index of richer family and mother height were significant predictors of child size at birth. The area associated with low birth weight was Chitipa and areas with increased risk to less than average size at birth were Chitipa and Mchinji. The study found support for the flexible modelling of some covariates that clearly have nonlinear influences. Nevertheless there is no strong support for inclusion of geographical spatial analysis. The spatial patterns though point to the influence of omitted variables with some spatial structure or possibly epidemiological processes that account for this spatial structure and the maps generated could be used for targeting development efforts at a glance. PMID- 26114867 TI - Risk Factors for Low Birthweight in Zimbabwean Women: A Secondary Data Analysis. AB - BACKGROUND: Low birth weight (LBW) remains the main cause of mortality and morbidity in infants, and a problem in the care of pregnant women world-wide particularly in developing countries. The purpose of this study was to describe the socio-demographic, nutritional, reproductive, medical and obstetrical risk factors for delivering a live LBW infant at Harare Maternity Hospital, Zimbabwe. METHODS: A secondary data analysis from data obtained through a questionnaire and delivery records was conducted. Linear regression models with a complimentary log log link function were used to estimate the relative risks for all LBW, term LBW and preterm LBW. RESULTS: The frequency of LBW was 16.7%. Lack of prenatal care (adjusted relative risk [ARR] 1.69, 95% CI 1.44, 1.98), mother's mid-arm circumference below 28.5 cm, (ARR 1.35, 95% CI 1.19, 1.54) and rural residence (ARR 1.22, 95% CI 1.04, 1.40) increased the risk of LBW. Eclampsia, anemia, and ante-partum hemorrhage, were associated with LBW (ARR 2.64, 95% CI 1.30, 5.35; ARR = 2.63, 95% CI 1.16, 5.97; and ARR = 2.39, 95% CI 1.55, 3.68), respectively. Malaria increased the risk of LBW (ARR = 1.89, 95% CI 1.21, 2.96). Prenatal care, infant sex, anemia, antepartum hemorrhage, premature rapture of membranes and preterm labor were associated with the three LBW categories. History of abortion or stillbirth, history of LBW, malaria, eclampsia, and placenta Previa, were associated with all LBW and preterm LBW, while pregnancy induced hypertension, and number of children alive were associated with all LBW and term LBW. CONCLUSIONS: LBW frequency remains high and is associated with nutritive, reproductive, medical and obstetrical factors. Preterm LBW and term LBW have similar and also different risk factors. Understanding the role of different risk factors in these different LBW categories is important if the goal is to reduce LBW frequency, and its complications, in Zimbabwe. PMID- 26114869 TI - Are Adiponectin and Leptin Good Predictors of Surgical Infection after Colorectal Surgery? A Prospective Study. AB - BACKGROUND: Infections are the most frequent complication after colorectal surgery. It has been suggested that adipose tissue metabolism could be related to the risk of post-operative infection, but this could be partially related to the body-mass index. The aim of this study was to look for a relation between adipocytokine levels and the risk of post-operative infection and its type. METHODS: This prospective cohort study was conducted between March 2013 and March 2014 in two French teaching hospitals. Pre-operative plasma levels of adiponectin and leptin were measured in consecutive patients undergoing elective colorectal surgery. All infections in the 30 d following surgery were recorded. RESULTS: Among the 142 patients included, 29 (20.4%) presented a post-operative infection: 26 surgical site infections and three extra-abdominal infections. Adiponectin and leptin levels correlated weakly but substantially with the body mass index (rspearman=-0.26 and +0.31, respectively). While there was no substantial difference between patients with and those without post-operative infection for adiponectin, median pre-operative leptin was substantially greater in patients with post-operative infection (8.67 vs. 4.37 ng/mL, p=0.003). A substantial interaction was found between leptin and cancer. In patients operated on for cancer, the area under the receiver-operating characteristic (ROC) curve was lower than in patients with benign diseases (0.597 vs. 0.858, p=0.011). Similar results were observed for intra-abdominal infection and surgical site infection. CONCLUSION: Patients with greater levels of leptin before colorectal surgery have an increased risk of post-operative surgical infection. This effect is stronger in patients without cancer. Adiponectin levels are not related to the risk of infection in Western patients. PMID- 26114868 TI - Transcriptome Profile of the Response of Paracoccidioides spp. to a Camphene Thiosemicarbazide Derivative. AB - Paracoccidioidomycosis (PCM) is a systemic granulomatous human mycosis caused by fungi of the genus Paracoccidioides, which is geographically restricted to Latin America. Inhalation of spores, the infectious particles of the fungus, is a common route of infection. The PCM treatment of choice is azoles such as itraconazole, but sulfonamides and amphotericin B are used in some cases despite their toxicity to mammalian cells. The current availability of treatments highlights the need to identify and characterize novel targets for antifungal treatment of PCM as well as the need to search for new antifungal compounds obtained from natural sources or by chemical synthesis. To this end, we evaluated the antifungal activity of a camphene thiosemicarbazide derivative (TSC-C) compound on Paracoccidioides yeast. To determine the response of Paracoccidioides spp. to TSC-C, we analyzed the transcriptional profile of the fungus after 8 h of contact with the compound. The results demonstrate that Paracoccidioides lutzii induced the expression of genes related to metabolism; cell cycle and DNA processing; biogenesis of cellular components; cell transduction/signal; cell rescue, defense and virulence; cellular transport, transport facilities and transport routes; energy; protein synthesis; protein fate; transcription; and other proteins without classification. Additionally, we observed intensely inhibited genes related to protein synthesis. Analysis by fluorescence microscopy and flow cytometry revealed that the compound induced the production of reactive oxygen species. Using an isolate with down-regulated SOD1 gene expression (SOD1 aRNA), we sought to determine the function of this gene in the defense of Paracoccidioides yeast cells against the compound. Mutant cells were more susceptible to TSC-C, demonstrating the importance of this gene in response to the compound. The results presented herein suggest that TSC-C is a promising candidate for PCM treatment. PMID- 26114870 TI - 10q26.1 Microdeletion: Redefining the critical regions for microcephaly and genital anomalies. AB - Distal 10q deletion syndrome is a well-characterized chromosomal disorder consisting of neurodevelopmental impairment, facial dysmorphism, cardiac malformations, genital and urinary tract defects, as well as digital anomalies. Patients with interstitial deletions involving band 10q26.1 present a phenotype similar to the ones with the distal 10q deletion syndrome, which led to the definition of a causal 600 kb smallest region of overlap (SRO). In this report, we describe a male patient with an interstitial 4.5 Mb deletion involving exclusively the 10q26.1 segment. He had growth and psychomotor retardation, microcephaly, flat feet, micropenis, and cryptorchidism. The patient's deleted region does not overlap the 10q SRO. We reviewed the clinical phenotype of patients with similar deletions and suggest the presence of two new SROs, one associated with microcephaly, growth and psychomotor retardation, and the other associated to genital anomalies. Interestingly, we narrowed those regions to segments encompassing five and two genes, respectively. FGFR2, NSMCE4A, and ATE1 were suggested as candidates for facial dysmorphism, growth cessation, and heart defects, respectively. WDR11 was linked to idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Its haploinsufficiency could play a crucial role in the genital anomalies of these patients. PMID- 26114871 TI - Phosphorylation of the Peptidoglycan Synthase PonA1 Governs the Rate of Polar Elongation in Mycobacteria. AB - Cell growth and division are required for the progression of bacterial infections. Most rod-shaped bacteria grow by inserting new cell wall along their mid-section. However, mycobacteria, including the human pathogen Mycobacterium tuberculosis, produce new cell wall material at their poles. How mycobacteria control this different mode of growth is incompletely understood. Here we find that PonA1, a penicillin binding protein (PBP) capable of transglycosylation and transpeptidation of cell wall peptidoglycan (PG), is a major governor of polar growth in mycobacteria. PonA1 is required for growth of Mycobacterium smegmatis and is critical for M. tuberculosis during infection. In both cases, PonA1's catalytic activities are both required for normal cell length, though loss of transglycosylase activity has a more pronounced effect than transpeptidation. Mutations that alter the amount or the activity of PonA1 result in abnormal formation of cell poles and changes in cell length. Moreover, altered PonA1 activity results in dramatic differences in antibiotic susceptibility, suggesting that a balance between the two enzymatic activities of PonA1 is critical for survival. We also find that phosphorylation of a cytoplasmic region of PonA1 is required for normal activity. Mutations in a critical phosphorylated residue affect transglycosylase activity and result in abnormal rates of cell elongation. Together, our data indicate that PonA1 is a central determinant of polar growth in mycobacteria, and its governance of cell elongation is required for robust cell fitness during both host-induced and antibiotic stress. PMID- 26114874 TI - Births: Preliminary Data for 2014. AB - Objectives-This report presents preliminary 2014 data on U.S. births. Births are shown by age, live-birth order, race, and Hispanic origin of mother. Data on marital status, cesarean delivery, preterm births, and low birthweight are also presented. PMID- 26114872 TI - Acculturation and cigarette smoking in Hispanic women: A meta-analysis. AB - The present study was a random-effects model meta-analysis of 26 studies published between 1990 and 2010 (k = 32; n = 39,777) that (a) examined the association between acculturation and cigarette smoking in Hispanic women and (b) evaluated age, national origin, and measure and dimensionality (unidimensional vs. bidimensional) of acculturation as moderating variables. Results indicate a strong positive relationship and suggest larger effects of acculturation on cigarette smoking in women of Mexican descent as compared with women originating from other Latin American countries for current and lifetime smoking, as well as smoking overall. The effect of acculturation on cigarette smoking was larger in adults as compared with adolescents for current smoking and smoking overall. Few differences in effect size by measure or dimensionality of acculturation emerged. Results are discussed with regard to implications for future research and the measurement of acculturation. PMID- 26114873 TI - Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma. AB - Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin are well-known therapeutic targets for renal cell carcinoma (RCC). Sunitinib is an agent that targets VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to sunitinib, we identified interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC tumor tends to have sunitinib-resistant metastatic site. Next, we showed that sunitinib sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance. PMID- 26114875 TI - Characteristics of the Delayed or Refusal Therapy in Breast Cancer Patients: A Longitudinal Population-Based Study in Taiwan. AB - BACKGROUND: The evidence indicated breast cancer was a cancer with high survival rate. However, there were still some breast cancer patients delaying or refusing therapy. So we conducted a cohort study to explore the relationship between characteristics of breast cancer patients and delay or refusal of therapy within four months after cancer diagnosed. METHODS: This was a retrospective national population-based study from 2004 to 2010 in Taiwan. This study included 35,095 patients with new diagnosis breast cancer from Taiwan Cancer Registry Database. Several analysis methods, including t test, Chi-square test, generalized estimating equations of logistic regression analysis, and Cox proportional hazards model, were performed to explore the characteristics of these patients and the relative risk of mortality with delay or refusal of therapy. RESULTS: Our study showed that the overall survival rates were significantly different (p <0.05) between the breast cancer patients who delayed or refused therapy and those with treatment. The patients who delayed or refused therapy had lower 5 year overall survival rate compared with the treated group. The related factors included age, Charlson comorbidity index, cancer staging (OR = 1.30-19.69; p <0.05), other catastrophic illnesses or injuries and the level of diagnostic hospitals. However, the patients with different income levels and degree of urbanization in living area were not statistically significant factors. CONCLUSION: Our results demonstrated that age and cancer staging were the main patient characteristics affecting whether the patients delayed or refused therapy. The delay or refusal of treatment was associated with the level of diagnosing hospital. PMID- 26114877 TI - Terahertz Spectroscopy and Solid-State Density Functional Theory Calculations of Cyanobenzaldehyde Isomers. AB - Spectral signatures in the terahertz (THz) frequency region are mainly due to bulk vibrations of the molecules. These resonances are highly sensitive to the relative position of atoms in a molecule as well as the crystal packing arrangement. To understand the variation of THz resonances, THz spectra (2-10 THz) of three structural isomers: 2-, 3-, and 4-cyanobenzaldehyde have been studied. THz spectra obtained from Fourier transform infrared (FTIR) spectrometry of these isomers show that the resonances are distinctly different especially below 5 THz. For understanding the intermolecular interactions due to hydrogen bonds, four molecule cluster simulations of each of the isomers have been carried out using the B3LYP density functional with the 6-31G(d,p) basis set in Gaussian09 software and the compliance constants are obtained. However, to understand the exact reason behind the observed resonances, simulation of each isomer considering the full crystal structure is essential. The crystal structure of each isomer has been determined using X-ray diffraction (XRD) analysis for carrying out crystal structure simulations. Density functional theory (DFT) simulations using CRYSTAL14 software, utilizing the hybrid density functional B3LYP, have been carried out to understand the vibrational modes. The bond lengths and bond angles from the optimized structures are compared with the XRD results in terms of root-mean-square-deviation (RMSD) values. Very low RMSD values confirm the overall accuracy of the results. The simulations are able to predict most of the spectral features exhibited by the isomers. The results show that low frequency modes (<3 THz) are mediated through hydrogen bonds and are dominated by intermolecular vibrations. PMID- 26114876 TI - Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery. AB - BACKGROUND: Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC50 < 10 MUM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi. CONCLUSIONS/ SIGNIFICANCE: We have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs. PMID- 26114878 TI - Reducing Lead on the Landscape: Anticipating Hunter Behavior in Absence of a Free Nonlead Ammunition Program. AB - Lead is a neurotoxin that has been documented to affect many forms of wildlife, and has been identified as a limiting factor in a population of California Condors in Northern Arizona. The Arizona Game and Fish Department provides vouchers for free nonlead ammunition to hunters selected to hunt within the distribution of California Condors, with the intention of having fewer lead-laden offal piles available to California Condors. Although wildlife agencies may reasonably assume voucher programs motivate hunters into choosing nonlead ammunition, the lead reduction efforts attributable to the voucher program has not been empirically quantified. Our intention was to compare a control group of hunters to a treatment group of hunters within California Condor occupied areas. Both groups received educational materials regarding the deleterious effects of lead, but the treatment group also received a voucher for a free initial box of ammunition. About half of the control group used nonlead ammunition, compared to about three-fourths of the treatment group. Prominent barriers to adoption of nonlead ammunition included a general difficulty of obtaining it, obtaining it in the desired caliber, and its costliness. Frequently mentioned motivations for using nonlead was the exhortation to use it by the Department, and the desire to aid California Condor recovery by hunters. The disparate compliance rates found herein confirm and quantify the success of nonlead ammunition voucher programs, but underscore the importance of working to increase the supply of nonlead ammunition with the end of facilitating its procurement and reducing its cost. PMID- 26114880 TI - Development of nanotoxicology: implications for drug delivery and medical devices. AB - Current nanotoxicology research suffers from suboptimal in vitro models, lack of in vitro-in vivo correlations, variability within in vitro protocols, deficits in both material purity and physicochemical characterization. Reliable nanomaterial toxicity and mechanistic insights are required for health and toxicity risk assessments. Much in vitro toxicological data is inconclusive in designating whether nanomaterials for drug delivery and medical device implants are truly safe. A critique is presented to analyze the interface between toxicology and nanopharmaceuticals. Deficiencies of existing practices in toxicology are reviewed and useful emerging techniques (e.g., lab-on-a-chip, tissue engineering, atomic force microscopy, high-content analysis) are highlighted. Cross fertilization between disciplines will aid development of biocompatible delivery and implant platforms while improvements are being suggested for better translation of nanotoxicology. PMID- 26114879 TI - AIM2 Drives Joint Inflammation in a Self-DNA Triggered Model of Chronic Polyarthritis. AB - Mice lacking DNase II display a polyarthritis-like disease phenotype that is driven by translocation of self-DNA into the cytoplasm of phagocytic cells, where it is sensed by pattern recognition receptors. While pro-inflammatory gene expression is non-redundantly linked to the presence of STING in these mice, the contribution of the inflammasome pathway has not been explored. To this end, we studied the role of the DNA-sensing inflammasome receptor AIM2 in this self-DNA driven disease model. Arthritis-prone mice lacking AIM2 displayed strongly decreased signs of joint inflammation and associated histopathological findings. This was paralleled with a reduction of caspase-1 activation and pro-inflammatory cytokine production in diseased joints. Interestingly, systemic signs of inflammation that are associated with the lack of DNase II were not dependent on AIM2. Taken together, these data suggest a tissue-specific role for the AIM2 inflammasome as a sensor for endogenous DNA species in the course of a ligand dependent autoinflammatory condition. PMID- 26114881 TI - Elution-extrusion counter-current chromatography for the separation of two pairs of isomeric monoterpenes from Paeoniae Alba Radix. AB - In this work, a simple and efficient protocol for the rapid separation of two pairs of isomeric monoterpenes from Paeoniae Alba Radix was developed by combining macroporous resin and elution-extrusion counter-current chromatography. The crude extract was firstly subjected to a D101 macroporous resin column eluted with water and a series of different concentrations of ethanol. Then, effluents of 30 and 95% ethanol were collected as sample 1 and sample 2 for further counter current chromatography purification. Finally, a pair of isomers, 96 mg of compound 1 and 48 mg of compound 2 with purities of 91.1 and 96.2%, respectively, was isolated from 200 mg of sample 1. The other pair of isomers, 14 mg of compound 3 and 8 mg of compound 4 with purities of 93.6 and 88.9%, respectively, was isolated from 48 mg of sample 2. Their purities were analyzed by high performance liquid chromatography, and their chemical structures were identified by mass spectrometry and (1) H NMR spectroscopy. Compared to a normal counter current chromatography separation, the separation time and solvent consumption of elution-extrusion counter-current chromatography were reduced while the resolutions were still good. The established protocol is promising for the separation of natural products with great disparity of content in herbal medicines. PMID- 26114885 TI - The mechanics of American football cleats on natural grass and infill-type artificial playing surfaces with loads relevant to elite athletes. AB - This study quantified the mechanical interactions of 19 American football cleats with a natural grass and an infill-type artificial surface under loading conditions designed to represent play-relevant manoeuvres of elite athletes. Variation in peak forces and torques was observed across cleats when tested on natural grass (2.8-4.2 kN in translation, 120-174 Nm in rotation). A significant (p < 0.05) relationship was found between the peak force and torque on natural grass. Almost all of the cleats caused shear failure of the natural surface, which generated a divot following a test. This is a force-limiting cleat release mode. In contrast, all but one of the cleat types held fast in the artificial turf, resulting in force and torque limited by the prescribed input load from the test device (nom. 4.8 kN and 200 Nm). Only one cleat pattern, consisting of small deformable nubs, released on the artificial surface and generated force (3.9 kN) comparable to the range observed with natural grass. These findings (1) should inform the design of cleats intended for use on natural and artificial surfaces and (2) suggest a mechanical explanation for a higher lower-limb injury rate in elite athletes playing on artificial surfaces. PMID- 26114882 TI - Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. AB - Fibrillins are large extracellular macromolecules that polymerize to form the backbone structure of connective tissue microfibrils. Mutations in the gene for fibrillin-1 cause the Marfan syndrome, while mutations in the gene for fibrillin 2 cause Congenital Contractural Arachnodactyly. Both are autosomal dominant disorders, and both disorders affect musculoskeletal tissues. Here we show that Fbn2 null mice (on a 129/Sv background) are born with reduced muscle mass, abnormal muscle histology, and signs of activated BMP signaling in skeletal muscle. A delay in Myosin Heavy Chain 8, a perinatal myosin, was found in Fbn2 null forelimb muscle tissue, consistent with the notion that muscle defects underlie forelimb contractures in these mice. In addition, white fat accumulated in the forelimbs during the early postnatal period. Adult Fbn2 null mice are already known to demonstrate persistent muscle weakness. Here we measured elevated creatine kinase levels in adult Fbn2 null mice, indicating ongoing cycles of muscle injury. On a C57Bl/6 background, Fbn2 null mice showed severe defects in musculature, leading to neonatal death from respiratory failure. These new findings demonstrate that loss of fibrillin-2 results in phenotypes similar to those found in congenital muscular dystrophies and that FBN2 should be considered as a candidate gene for recessive congenital muscular dystrophy. Both in vivo and in vitro evidence associated muscle abnormalities and accumulation of white fat in Fbn2 null mice with abnormally activated BMP signaling. Genetic rescue of reduced muscle mass and accumulation of white fat in Fbn2 null mice was accomplished by deleting a single allele of Bmp7. In contrast to other reports that activated BMP signaling leads to muscle hypertrophy, our findings demonstrate the exquisite sensitivity of BMP signaling to the fibrillin-2 extracellular environment during early postnatal muscle development. New evidence presented here suggests that fibrillin-2 can sequester BMP complexes in a latent state. PMID- 26114883 TI - PD-L1 and Survival in Solid Tumors: A Meta-Analysis. AB - BACKGROUND: Numerous agents targeting PD-L1/PD-1 check-point are in clinical development. However, the correlation between PD-L1 expression and prognosis of solid tumor is still in controversial. Here, we elicit a systematic review and meta-analysis to investigate the potential value of PD-L1 in the prognostic prediction in human solid tumors. METHODS: Electronic databases were searched for studies evaluating the expression of PD-L1 and overall survival (OS) of patients with solid tumors. Odds ratios (ORs) from individual studies were calculated and pooled by using a random-effect model, and heterogeneity and publication bias analyses were also performed. RESULTS: A total of 3107 patients with solid tumor from 28 published studies were included in the meta-analysis. The median percentage of solid tumors with PD-L1 overexpression was 52.5%. PD-L1 overexpression was associated with worse OS at both 3 years (OR = 2.43, 95% confidence interval (CI) = 1.60 to 3.70, P < 0.0001) and 5 years (OR = 2.23, 95% CI = 1.40 to 3.55, P = 0.0008) of solid tumors. Among the tumor types, PD-L1 was associated with worse 3 year-OS of esophageal cancer, gastric cancer, hepatocellular carcinoma, and urothelial cancer, and 5 year-OS of esophageal cancer, gastric cancer and colorectal cancer. CONCLUSIONS: These results suggest that expression of PD-L1 is associated with worse survival in solid tumors. However, the correlations between PD-L1 and prognosis are variant among different tumor types. More studies are needed to investigate the clinical value of PD-L1 expression in prognostic prediction and treatment option. PMID- 26114886 TI - Determination of the degree of acetylation and the distribution of acetyl groups in chitosan by HPLC analysis of nitrous acid degraded and PMP labeled products. AB - Chitin is one of the most abundant polysaccharides on earth. It consists of repeating beta-1,4 linked N-acetylated glucosamine (A) units. Chitosan is an N deacetylated product of chitin. Chitosan and its derivatives have broad medical applications as drugs, nutraceuticals, or drug delivery agents. However, a reliable analytical method for quality control of medically used chitosans is still lacking. In current study, nitrous acid was used to cleave all glucosamine residues in chitosan into 2,5-anhydromannose (M) or M at the reducing end of di-, tri-, and oligosaccharides. PMP, i.e. 1-phenyl-3-methyl-5-pyrazolone, was used to label all the Ms. Online UV detection allowed quantification of all M-containing UV peaks whereas online MS analysis directly identified 11 different kinds of mono-, di-, tri-, and oligosaccharides that correlated each oligosaccharide with specific UV peak after HPLC separation. The DA (degree of acetylation) for chitosans was calculated based on the A/(A+M) value derived from the UV data. This newly developed method had several advantages for quality control of chitosan: 1. the experimental procedures were extensively optimized; 2. the reliability of the method was confirmed by online LC-MS analysis; 3. the DA value was obtainable based on the UV data after HPLC analysis, which was comparableto that of (1)H NMR and conductometric titration analyses; 4. finally and most importantly, this method could be used to obtain the DA as well as chemical acetylation/deacetylation mechanisms for chitosan by any laboratory equipped with a HPLC and an online UV detector. PMID- 26114887 TI - Synthesis of glycotriazololipids and observations on their self-assembly properties. AB - Various carbohydrate-anchored triazole-linked lipids prepared by solvent-free mechanochemical azide-alkyne click reaction, on analysis by TEM, have been found to spontaneously self-assemble in solvents leading to structures of interesting physicochemical attributes. Interestingly, analogous compounds based on different sugars (e.g., d-glucose, and d-galactose, as also d-lactose) assemble in patterns distinctly different from each other thus reiterating the fact that the structure of the sugar as well as that of the lipid are important factors that determine the size and shape of the supramolecular assembly formed. Besides, the molecular self-assembly was also found to be solvent-as well as temperature-dependent. PMID- 26114888 TI - Host-microbe interactions as a driver of acclimation to salinity gradients in brown algal cultures. AB - Like most eukaryotes, brown algae live in association with bacterial communities that frequently have beneficial effects on their development. Ectocarpus is a genus of small filamentous brown algae, which comprises a strain that has recently colonized freshwater, a rare transition in this lineage. We generated an inventory of bacteria in Ectocarpus cultures and examined the effect they have on acclimation to an environmental change, that is, the transition from seawater to freshwater medium. Our results demonstrate that Ectocarpus depends on bacteria for this transition: cultures that have been deprived of their associated microbiome do not survive a transfer to freshwater, but restoring their microflora also restores the capacity to acclimate to this change. Furthermore, the transition between the two culture media strongly affects the bacterial community composition. Examining a range of other closely related algal strains, we observed that the presence of two bacterial operational taxonomic units correlated significantly with an increase in low salinity tolerance of the algal culture. Despite differences in the community composition, no indications were found for functional differences in the bacterial metagenomes predicted to be associated with algae in the salinities tested, suggesting functional redundancy in the associated bacterial community. Our study provides an example of how microbial communities may impact the acclimation and physiological response of algae to different environments, and thus possibly act as facilitators of speciation. It paves the way for functional examinations of the underlying host microbe interactions, both in controlled laboratory and natural conditions. PMID- 26114889 TI - Non-cyanobacterial diazotrophs mediate dinitrogen fixation in biological soil crusts during early crust formation. AB - Biological soil crusts (BSCs) are key components of ecosystem productivity in arid lands and they cover a substantial fraction of the terrestrial surface. In particular, BSC N2-fixation contributes significantly to the nitrogen (N) budget of arid land ecosystems. In mature crusts, N2-fixation is largely attributed to heterocystous cyanobacteria; however, early successional crusts possess few N2 fixing cyanobacteria and this suggests that microorganisms other than cyanobacteria mediate N2-fixation during the critical early stages of BSC development. DNA stable isotope probing with (15)N2 revealed that Clostridiaceae and Proteobacteria are the most common microorganisms that assimilate (15)N2 in early successional crusts. The Clostridiaceae identified are divergent from previously characterized isolates, though N2-fixation has previously been observed in this family. The Proteobacteria identified share >98.5% small subunit rRNA gene sequence identity with isolates from genera known to possess diazotrophs (for example, Pseudomonas, Klebsiella, Shigella and Ideonella). The low abundance of these heterotrophic diazotrophs in BSCs may explain why they have not been characterized previously. Diazotrophs have a critical role in BSC formation and characterization of these organisms represents a crucial step towards understanding how anthropogenic change will affect the formation and ecological function of BSCs in arid ecosystems. PMID- 26114890 TI - A review of pregnancies complicated by congenital sacrococcygeal teratoma in the West Midlands region over an 18-year period: population-based, cohort study. AB - OBJECTIVES: To describe the epidemiology and outcomes of sacrococcygeal teratoma (SCT) and identify the factors affecting prognosis in a population-based cohort. METHODS: Analyses of fetal SCTs from a population-based congenital anomaly register between 1995 and 2012, linked to regional datasets. A systematic literature review was performed for published studies on perinatal SCT (1995 to 2012). RESULTS: Thirty-six confirmed SCT cases were identified, giving a total prevalence of 0.30 per 10 000 births (95%CI 0.20-0.39). Twenty-three cases (63.9%) were diagnosed prenatally. There were six false positive prenatal diagnoses, and the positive predictive value of ultrasound for SCT was 79.3%. Secondary complications in prenatally diagnosed cases were polyhydramnios (27.2%), fetal hydrops (9.1%) and rapidly growing tumour (54.0%). The perinatal (PNMR) and infant mortality rates were 333.3 per 1000 births and 285.7 per 1000 live births, respectively. All stillbirths and infant deaths occurred in cases diagnosed prenatally. Factors associated with higher PNMR in registerable births were solid, vascular tumour composition (1000), polyhydramnios (667), premature delivery (667) and rapidly growing tumour (454). In the systematic review, prenatal hydrops fetalis and prematurity were the most morbid association in SCT. CONCLUSION: Prenatal ultrasound was relatively sensitive and specific in diagnosing SCT with good survival rates in live-born cases. PMID- 26114891 TI - Structural and Mechanical Improvements to Bone Are Strain Dependent with Axial Compression of the Tibia in Female C57BL/6 Mice. AB - Strain-induced adaption of bone has been well-studied in an axial loading model of the mouse tibia. However, most outcomes of these studies are restricted to changes in bone architecture and do not explore the mechanical implications of those changes. Herein, we studied both the mechanical and morphological adaptions of bone to three strain levels using a targeted tibial loading mouse model. We hypothesized that loading would increase bone architecture and improve cortical mechanical properties in a dose-dependent fashion. The right tibiae of female C57BL/6 mice (8 week old) were compressively loaded for 2 weeks to a maximum compressive force of 8.8N, 10.6N, or 12.4N (generating periosteal strains on the anteromedial region of the mid-diaphysis of 1700 MUepsilon, 2050 MUepsilon, or 2400 MUepsilon as determined by a strain calibration), while the left limb served as an non-loaded control. Following loading, ex vivo analyses of bone architecture and cortical mechanical integrity were assessed by micro-computed tomography and 4-point bending. Results indicated that loading improved bone architecture in a dose-dependent manner and improved mechanical outcomes at 2050 MUepsilon. Loading to 2050 MUepsilon resulted in a strong and compelling formation response in both cortical and cancellous regions. In addition, both structural and tissue level strength and energy dissipation were positively impacted in the diaphysis. Loading to the highest strain level also resulted in rapid and robust formation of bone in both cortical and cancellous regions. However, these improvements came at the cost of a woven bone response in half of the animals. Loading to the lowest strain level had little effect on bone architecture and failed to impact structural- or tissue-level mechanical properties. Potential systemic effects were identified for trabecular bone volume fraction, and in the pre-yield region of the force-displacement and stress-strain curves. Future studies will focus on a moderate load level which was largely beneficial in terms of cortical/cancellous structure and cortical mechanical function. PMID- 26114892 TI - Identification of small molecule inhibitors of Zcchc11 TUTase activity. AB - The RNA-binding protein Lin28 regulates the expression of the let-7 family of microRNAs (miRNAs) during early embryonic development. Lin28 recruits the 3' terminal uridylyl transferase (TUTase) Zcchc11 (TUT4) and/or Zcchc6 (TUT7) to precursor let-7 RNA (pre-let-7) to selectively block let-7 biogenesis. Uridylated pre-let-7 is targeted for decay by the downstream exonuclease Dis3l2 thereby preventing processing to mature let-7. Activation of this oncogenic pathway via up-regulation of Lin28 expression promotes cellular transformation, drives tumorigenesis in mouse models, and is frequently observed in a wide variety of cancer. Recent proof-of-principle experiments showed that Zcchc11 knockdown inhibits the tumorigenicity of Lin28-expressing human cancer cells and established this enzyme as a possible new therapeutic target for human malignancies. However, there are currently no known pharmacological agents capable of targeting this novel enzyme. In this study we developed and applied a sensitive biochemical assay that monitors Zcchc11 activity. Using this assay we performed an automated high-throughput screen of ~ 15,000 chemicals to identify putative TUTase inhibitors. Several of these small molecules were validated as specific inhibitors of Zcchc11 activity. Our results demonstrate the feasibility of screening for TUTase inhibitors and present a relatively simple platform that can be exploited for future drug discovery efforts aimed at restoring let-7 expression in cancer. PMID- 26114894 TI - Two Ene-Yne Metathesis Approaches to the Total Synthesis of Amphidinolide P. AB - The total synthesis of amphidinolide P was achieved through two different ene-yne metathesis approaches. In each approach, the metathesis step was performed at late stages in the synthesis with all other functionality present. By forging two successful pathways to the synthesis of 1, some of the strengths and weaknesses of metathesis-intensive synthetic strategies were identified. PMID- 26114895 TI - Seasonal spatial heterogeneity of warming rates on the Tibetan Plateau over the past 30 years. AB - Based on temperature data from 79 meteorological stations, we estimate the warming rate by season on the Tibetan Plateau (TP) during 1984-2013. The warming rate was spatially heterogeneous across seasons over the past 30 years. The northern TP (NTP) experienced more warming than the southern TP (STP) (divided near 33 degrees N) in all seasons. The greatest north-south difference in warming was 0.70 +/- 0.11 degrees C for summer (June-August), while the smallest difference was 0.27 +/- 0.14 degrees C for the cold season (November-April). Such seasonal and spatial heterogeneity in the warming rate is consistent with the seasonal precipitation patterns of the NTP and the STP. One possible cause for this phenomenon is that more precipitation occurs in the STP than in the NTP (especially for summer), accompanied by more low cloud cover, which may have slowed the warming rate. Our results imply that dry regions on the TP will possibly experience greater temperature increase than wet regions under future global warming, and this will be more prominent in summer. PMID- 26114893 TI - Impairment measures versus inflammatory RODS in GBS and CIDP: a responsiveness comparison. AB - This study aimed to 'define responder' through the concept of minimum clinically important differences using the individually obtained standard errors (MCID-SE) and a heuristic 'external criterion' responsiveness method in patients with Guillain-Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). One hundred and fourteen newly diagnosed or relapsing patients (GBS: 55, CIDP: 59) were serially examined (1-year follow-up). The inflammatory Rasch-built overall disability scale (I-RODS), Rasch-transformed MRC sum score (RT-MRC), and Rasch-transformed modified-INCAT-sensory scale (RT mISS) were assessed. Being-a-responder was defined as having a MCID-SE cut-off >=1.96. Also, the correlations between patients' scores on each scale and the EuroQoL health-status 'thermometer' (external criterion) were determined (higher correlation indicated better responsiveness). In both diseases, the SEs showed a characteristic 'U'-shaped dynamic pattern across each scales' continuum. The number of patients showing a meaningful change were higher for the I-RODS > RT MRC > RT-mISS and were in GBS higher than CIDP patients. The MCID-SE concept using Rasch-transformed data demonstrated an individual pattern of 'being-a responder' in patients with immune-mediated neuropathies, and the findings were validated by the external criterion responsiveness method. The I-RODS showed greater responsiveness compared with the MRC and INCAT-sensory scales, and its use is therefore recommended in future trials in GBS and CIDP. PMID- 26114896 TI - Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of primary cardiac malignant fibrous histiocytoma. AB - We describe a case of primary cardiac malignant fibrous histiocytoma where live/real time three-dimensional transesophageal echocardiography added incremental value to the two-dimensional modalities. Specifically, the three dimensional technique allowed us to delineate the true extent and infiltration of the tumor, to identify characteristics of the tumor mass suggestive of its malignant nature, and to quantitatively assess the total tumor burden. PMID- 26114897 TI - Mechanical Testing of a Synthetic Canine Gastrocnemius Tendon Implant. AB - OBJECTIVE: To test a polyethylene terephthalate prosthesis (STIF, Chenove, France) for gastrocnemius tendon repair in dogs (cadaver model). STUDY DESIGN: In vitro mechanical study. ANIMALS: Pelvic limbs (n = 8) from 4 recently euthanatized adult dogs (weighing 30-45 kg). METHODS: Proximally the implant was sutured at the myotendinous junction of the gastrocnemius and distally secured in a 4.5 mm blind ending tunnel in the medullary cavity of the calcaneus using an interference screw (STIF, Chenove, France). Proximal and distal fixation were tested independently using an electrodynamic testing machine (Electropuls 3000, Instron, UK). RESULTS: Mean +/- SD failure loads for the proximal fixation (266.13 +/- 43.88 N) was significantly less than for the distal fixation (649.25 +/- 210.36 N; P = .042, paired t-test). Mean stiffness of the proximal and distal constructs were 19.08 +/- 8.16 N/mm and 139.76 +/- 24.51 N/mm, respectively. CONCLUSIONS: Failure loads exceeded the values reported after experimental repair of chronic gastrocnemius tendon injuries using other methods involving suturing tendon to bone. Failure of this repair method clinically is predicted to occur proximally at the level of the myotendinous junction. PMID- 26114898 TI - Author guidelines in dermatological journals discourage the use of the CAse REport guidelines. PMID- 26114899 TI - Decadal re-evaluation of contaminant exposure and productivity of ospreys (Pandion haliaetus) nesting in Chesapeake Bay Regions of Concern. AB - The last large-scale ecotoxicological study of ospreys (Pandion haliaetus) in Chesapeake Bay was conducted in 2000-2001 and focused on U.S. EPA-designated Regions of Concern (ROCs; Baltimore Harbor/Patapsco, Anacostia/middle Potomac, and Elizabeth Rivers). In 2011-2012, ROCs were re-evaluated to determine spatial and temporal trends in productivity and contaminants. Concentrations of p,p'-DDE were low in eggs and below the threshold associated with eggshell thinning. Eggs from the Anacostia/middle Potomac Rivers had lower total PCB concentrations in 2011 than in 2000; however, concentrations remained unchanged in Baltimore Harbor. Polybrominated diphenyl ether flame retardants declined by 40%, and five alternative brominated flame retardants were detected at low levels. Osprey productivity was adequate to sustain local populations, and there was no relation between productivity and halogenated contaminants. Our findings document continued recovery of the osprey population, declining levels of many persistent halogenated compounds, and modest evidence of genetic damage in nestlings from industrialized regions. PMID- 26114900 TI - Induction of bacterial antibiotic resistance by mutagenic halogenated nitrogenous disinfection byproducts. AB - Halogenated nitrogenous disinfection byproducts (N-DBPs) raise concerns regarding their mutagenicity and carcinogenicity threatening public health. However, environmental consequence of their mutagenicity has received less attention. In this study, the effect of halogenated N-DBPs on bacterial antibiotic resistance (BAR) was investigated. After exposure to bromoacetamide (BAcAm), trichloroacetonitrile (TCAN) or tribromonitromethane (TBNM), the resistance of Pseudomonas aeruginosa PAO1 to both individual and multiple antibiotics (ciprofloxacin, gentamicin, polymyxin B, rifampin, tetracycline, ciprofloxacin + gentamicin and ciprofloxacin + tetracycline) was increased, which was predominantly ascribed to the overexpression of efflux pumps. The mechanism of this effect was demonstrated to be mutagenesis through sequencing and analyzing antibiotic resistance genes. The same induction phenomena also appeared in Escherichia coli, suggesting this effect may be universal to waterborne pathogens. Therefore, more attention should be given to halogenated N-DBPs, as they could increase not only genotoxicological risks but also epidemiological risks of drinking water. PMID- 26114902 TI - Novel Wire-on-Plate Electrostatic Precipitator (WOP-EP) for Controlling Fine Particle and Nanoparticle Pollution. AB - A new wire-on-plate electrostatic precipitator (WOP-EP), where discharge wires are attached directly on the surface of a dielectric plate, was developed to ease the installation of the wires, minimize particle deposition on the wires, and lower ozone emission while maintaining a high particle collection efficiency. For a lab-scale WOP-EP (width, 50 mm; height, 20 mm; length, 180 mm) tested at the applied voltage of 18 kV, experimental total particle collection efficiencies were found as high as 90.9-99.7 and 98.8-99.9% in the particle size range of 30 1870 nm at the average air velocities of 0.50 m/s (flow rate, 30 L/min; residence time, 0.36 s) and 0.25 m/s (flow rate, 15 L/min; residence time, 0.72 s), respectively. Particle collection efficiencies calculated by numerical models agreed well with the experimental results. The comparison to the traditional wire in-plate EP showed that, at the same applied voltage, the current WOP-EP emitted 1-2 orders of magnitude lower ozone concentration, had cleaner discharge wires after heavy particle loading in the EP, and recovered high particle collection efficiency after the grounded collection plate was cleaned. It is expected that the current WOP-EP can be scaled up as an efficient air-cleaning device to control fine particle and nanoparticle pollution. PMID- 26114903 TI - The pretense debate. AB - In a number of publications, Alan Leslie and colleagues have developed a theory of the psychological mechanisms underlying pretense. This theory maintains that pretense is an early manifestation of "theory of mind" or "mindreading" - the capacity to attribute mental states to oneself and others. Nichols and Stich proposed an alternative theory of pretense on which pretense in young children does not require mindreading. Rather, they argued, young children have a behavioral understanding of pretense. In a lengthy critique, Friedman and Leslie made a persuasive case that the Nichols and Stich theory cannot account for the early emergence of children's capacity to engage in joint pretense and recognize pretense in others. In this paper, we set out a new "pretense game" theory of pretense that avoids the problems raised by Friedman and Leslie, and does not require that children who engage in joint pretense must have a theory of mind. We go on to argue that our pretense game theory can explain many of the facts about pretense that go unexplained in Leslie's theory. The central shortcoming of Leslie's theory is that it attempts to explain the production and recognition of pretense behavior by positing the existence of an innate concept, without explaining how this concept enables those who have it to recognize or produce pretense behavior. PMID- 26114901 TI - Interference control training for PTSD: A randomized controlled trial of a novel computer-based intervention. AB - Post-traumatic stress disorder (PTSD) is a chronic and debilitating condition characterized by persistent intrusive memories. Although effective treatments exist for PTSD, there is a need for development of alternative treatments. Diminished ability to control proactive interference may contribute to re experiencing symptoms and may be a novel intervention target. The present study tested an intervention designed to modify proactive interference control clinicaltrials.gov identifier: (NCT02139137). Forty-two women with PTSD were randomly assigned to a computerized cognitive training or a control condition. The impact of these programs on cognitive performance and symptoms was assessed. PTSD re-experiencing symptoms and interference control performance improved significantly more for individuals in the training group relative to those in the control group. Other PTSD and general distress symptoms improved equally over time in both groups. Cognitive training of this type may hold promise as a novel intervention for reducing PTSD symptoms, although the mechanism of action and implications for models of PTSD requires future study. PMID- 26114904 TI - Simulating the cross-linguistic pattern of Optional Infinitive errors in children's declaratives and Wh- questions. AB - One of the most striking features of children's early multi-word speech is their tendency to produce non-finite verb forms in contexts in which a finite verb form is required (Optional Infinitive [OI] errors, Wexler, 1994). MOSAIC is a computational model of language learning that simulates developmental changes in the rate of OI errors across several different languages by learning compound finite constructions from the right edge of the utterance (Freudenthal, Pine, Aguado-Orea, & Gobet, 2007; Freudenthal, Pine, & Gobet, 2006a, 2009). However, MOSAIC currently only simulates the pattern of OI errors in declaratives, and there are important differences in the cross-linguistic patterning of OI errors in declaratives and Wh- questions. In the present study, we describe a new version of MOSAIC that learns from both the right and left edges of the utterance. Our simulations demonstrate that this new version of the model is able to capture the cross-linguistic patterning of OI errors in declaratives in English, Dutch, German and Spanish by learning from declarative input, and the cross-linguistic patterning of OI errors in Wh- questions in English, German and Spanish by learning from interrogative input. These results show that MOSAIC is able to provide an integrated account of the cross-linguistic patterning of OI errors in declaratives and Wh- questions, and provide further support for the view, instantiated in MOSAIC, that OI errors are compound-finite utterances with missing modals or auxiliaries. PMID- 26114905 TI - Learning novel phonological neighbors: Syntactic category matters. AB - Novel words (like tog) that sound like well-known words (dog) are hard for toddlers to learn, even though children can hear the difference between them (Swingley & Aslin, 2002, 2007). One possibility is that phonological competition alone is the problem. Another is that a broader set of probabilistic considerations is responsible: toddlers may resist considering tog as a novel object label because its neighbor dog is also an object. In three experiments, French 18-month-olds were taught novel words whose word forms were phonologically similar to familiar nouns (noun-neighbors), to familiar verbs (verb-neighbors) or to nothing (no-neighbors). Toddlers successfully learned the no-neighbors and verb-neighbors but failed to learn the noun-neighbors, although both novel neighbors had a familiar phonological neighbor in the toddlers' lexicon. We conclude that when creating a novel lexical entry, toddlers' evaluation of similarity in the lexicon is multidimensional, incorporating both phonological and semantic or syntactic features. PMID- 26114907 TI - The yield of colonic biopsy in the evaluation of chronic unexplained diarrhea. AB - BACKGROUND AND AIMS: In clinical practice, colonoscopy is widely used for the workup of chronic unexplained diarrhea. The aim of this study was to determine the yield of colonic biopsy in such an endeavor. METHODS: In a computerized database of 130 204 patients evaluated for chronic diarrhea, we tested the influence of biopsy site, number of tissue fragments, patient symptoms, and indication on the outcome of histopathologic evaluation. RESULTS: The population comprised 69% women and 31% men aged (mean+/-SD) 52.8+/-17.4 years. In 19% of patients, histopathological analysis revealed various types of mucosal lesion, the most common being microscopic colitis (8.6%), ulcerative colitis (2.2%), Crohn's disease (0.6%), active colitis (5.0%), diverticulitis (0.1%), and colonic ischemia (0.5%). In 29% of patients, the colonoscopy also revealed the presence of colon polyps. Endoscopists tended to take significantly more tissue samples from endoscopically visible lesions than for random biopsies of macroscopically normal-appearing mucosa. CONCLUSION: Overall, these associations suggest that specific diagnoses lead to more biopsies, rather than more biopsies leading to more diagnoses. Colonoscopy is a successful tool in the workup of chronic diarrhea, yielding a definitive diagnosis in almost one-fifth of all patients. As an added benefit, it also contributes to cancer prevention through the incidental findings of colonic neoplasm. PMID- 26114906 TI - A 12-Week Physical and Cognitive Exercise Program Can Improve Cognitive Function and Neural Efficiency in Community-Dwelling Older Adults: A Randomized Controlled Trial. AB - OBJECTIVES: To investigate whether a 12-week physical and cognitive exercise program can improve cognitive function and brain activation efficiency in community-dwelling older adults. DESIGN: Randomized controlled trial. SETTING: Kyoto, Japan. PARTICIPANTS: Community-dwelling older adults (N = 48) were randomized into an exercise group (n = 24) and a control group (n = 24). INTERVENTION: Exercise group participants received a weekly dual task-based multimodal exercise class in combination with pedometer-based daily walking exercise during the 12-week intervention phase. Control group participants did not receive any intervention and were instructed to spend their time as usual during the intervention phase. MEASUREMENTS: The outcome measures were global cognitive function, memory function, executive function, and brain activation (measured using functional magnetic resonance imaging) associated with visual short-term memory. RESULTS: Exercise group participants had significantly greater postintervention improvement in memory and executive functions than the control group (P < .05). In addition, after the intervention, less activation was found in several brain regions associated with visual short-term memory, including the prefrontal cortex, in the exercise group (P < .001, uncorrected). CONCLUSION: A 12-week physical and cognitive exercise program can improve the efficiency of brain activation during cognitive tasks in older adults, which is associated with improvements in memory and executive function. PMID- 26114908 TI - Diagnostic accuracy of data on aspartate aminotransferase to platelets index might be false in the paper by Tafarel et al. PMID- 26114909 TI - Cirrhotic patients with large esophageal varices and older age have poor hemodynamic response to terlipressin. PMID- 26114910 TI - Bayesian network meta-analysis to evaluate interferon-free treatments in naive patients with genotype 1 hepatitis C virus infection. PMID- 26114911 TI - Oesophageal adenocarcinoma and atrophic gastritis. PMID- 26114912 TI - Response to: oesophageal adenocarcinoma and atrophic gastritis - different viewpoints on the junction. PMID- 26114914 TI - Word recognition in Alzheimer's disease: Effects of semantic degeneration. AB - Impairments of word recognition in Alzheimer's disease (AD) have been less widely investigated than impairments affecting word retrieval and production. In particular, we know little about what makes individual words easier or harder for patients with AD to recognize. We used a lexical selection task in which participants were shown sets of four items, each set consisting of one word and three non-words. The task was simply to point to the word on each trial. Forty patients with mild-to-moderate AD were significantly impaired on this task relative to matched controls who made very few errors. The number of patients with AD able to recognize each word correctly was predicted by the frequency, age of acquisition, and imageability of the words, but not by their length or number of orthographic neighbours. Patient Mini-Mental State Examination and phonological fluency scores also predicted the number of words recognized. We propose that progressive degradation of central semantic representations in AD differentially affects the ability to recognize low-imageability, low-frequency, late-acquired words, with the same factors affecting word recognition as affecting word retrieval. PMID- 26114917 TI - Black Carbon Contribution to Organic Carbon Stocks in Urban Soil. AB - Soil holds 75% of the total organic carbon (TOC) stock in terrestrial ecosystems. This comprises ecosystem-derived organic carbon (OC) and black carbon (BC), a recalcitrant product of the incomplete combustion of fossil fuels and biomass. Urban topsoils are often enriched in BC from historical emissions of soot and have high TOC concentrations, but the contribution of BC to TOC throughout the urban soil profile, at a regional scale is unknown. We sampled 55 urban soil profiles across the North East of England, a region with a history of coal burning and heavy industry. Through combined elemental and thermogravimetic analyses, we found very large total soil OC stocks (31-65 kg m(-2) to 1 m), exceeding typical values reported for UK woodland soils. BC contributed 28-39% of the TOC stocks, up to 23 kg C m(-2) to 1 m, and was affected by soil texture. The proportional contribution of the BC-rich fraction to TOC increased with soil depth, and was enriched in topsoil under trees when compared to grassland. Our findings establish the importance of urban ecosystems in storing large amounts of OC in soils and that these soils also capture a large proportion of BC particulates emitted within urban areas. PMID- 26114916 TI - Triclosan and prescription antibiotic exposures and enterolactone production in adults. AB - BACKGROUND: The gut microbiome plays an important role in the development of disease. The composition of the microbiome is influenced by factors such as mode of delivery at birth, diet and antibiotic use, yet the influence of environmental chemical exposures is largely unknown. The antimicrobial compound triclosan, found in many personal care products and widely detected in human urine, is an environmental exposure for which systemic microbiotic effects may be of particular interest. To investigate the relationship between triclosan and gut microflora, we assessed the association between triclosan and enterolactone, an intestinal metabolite that is produced via bacterial transformation of dietary lignans (seeds, nuts) and has known susceptibility to oral antibiotics. METHODS: We examined urinary triclosan and enterolactone for 2005-2008 U.S. National Health and Nutrition Examination Survey subjects, aged >=20 years (n=3041). We also examined the association between prescription antibiotic use and enterolactone to confirm its susceptibility to changes in bacterial composition of the body. Associations between natural log-transformed enterolactone and (1) detected vs. not detected (<2.3 ng/mL) triclosan, (2) triclosan quintiles (Q1 Q5), and (3) any vs. no antibiotics were estimated with multiple linear regression, adjusting for sex, age, race, body mass index, poverty income ratio, education, fiber intake, bowel movement frequency, cotinine and creatinine (n=2441). RESULTS: Triclosan was detected in 80% of subjects (range: <2.3-3620 ng/mL), while enterolactone was detected in >99% of subjects (range: <0.1-122,000 ng/mL). After adjustment, enterolactone was not associated with triclosan (detect vs. non-detect: beta= 0.07 (95% CI: -0.15, 0.30); Q5 (>=104.5 ng/mL) vs. Q1 (none): beta= 0.06 (95% CI: -0.21, 0.34)). In sex-stratified analyses, triclosan was associated with higher enterolactone in women (detect vs. non-detect: beta= 0.31 (95% CI: -0.07, 0.70), but not men beta= -0.18 (95% CI: -0.47, 0.11). However, any antibiotic use (n=112), as compared to no antibiotic use, was associated with significantly lower enterolactone (beta=-0.78 (95%CI: -1.22, 0.36)), with no sex-specific effects. This association was driven by inverse associations with the following antibiotic classes: macrolide derivatives, quinolones, sulfonamides, and lincomycin derivatives. CONCLUSIONS: Antibiotics, but not triclosan, are negatively associated with urinary enterolactone. Antibiotics may reduce enterolactone by killing certain gut bacteria. At levels detected in the U.S., triclosan does not appear to be acting similarly, despite broad antimicrobial properties. Additional study of determinants of triclosan exposure and enterolactone production may be needed to better understand positive associations among women. PMID- 26114918 TI - Diagnostic accuracy of algorithms to identify hepatitis C status, AIDS status, alcohol consumption and illicit drug use among patients living with HIV in an administrative healthcare database. AB - PURPOSE: This study aims to develop and evaluate diagnostic algorithms for AIDS, hepatitis C status, alcohol abuse and illicit drug use in the administrative healthcare database of the Province of Quebec, Canada (Regie de l'assurance maladie du Quebec (RAMQ)). METHODS: We selected HIV-positive patients contributing to both the RAMQ database and a local clinical database, which was used as gold standard. We developed algorithms to identify the diagnoses of interest in RAMQ using data from hospital discharge summaries and medical and pharmaceutical claims databases. We estimated and compared sensitivity, specificity, positive predictive and negative predictive values and area under receiver operating curve for each algorithm. RESULTS: Four hundred twenty patients contributed to both databases. Prevalence of conditions of interest in the clinical database was as follows: AIDS 233 (55%), hepatitis C infection 105 (25%), alcohol abuse 106 (25%), illicit drug use 144 (34%) and intravenous drug use 107 (25%). Sensitivity to detect AIDS, hepatitis C, alcohol abuse, illicit drug use and intravenous drug use was 46% [95%CI: 39-53], 26% [18-35], 50% [37 57], 64% [55-72] and 70% [61-79], respectively. Specificity to detect these conditions was 91% [86-95], 97% [94-98], 92% [88-95], 95% [92-97] and 90% [87 93], respectively. Positive predictive values were 87% [80-92], 71% [54-85], 68% [56-78], 87% [79-93] and 72% [62-80], respectively. Area under receiver operating curve varied from 0.62 [0.57-0.65] for hepatitis C to 0.80 [0.76-0.85] for intravenous drug use. CONCLUSIONS: Sensitivity was low to detect AIDS, alcohol abuse, illicit drug use and especially hepatitis C in RAMQ. Researchers must be aware of the potential for residual confounding and must consider additional methods to control for confounding. PMID- 26114919 TI - Technologies of the Self and Ethnographic Praxis. AB - The authors contributing to this special issue draw on Foucault's notion of technologies of the self: the means by which people operate on their own bodies and souls in pursuit of self-transformation, always according to particular regimes of value. Foucault's notion remains attractive to anthropology: the technologies are ethnographically visible, and they illustrate how power affects the intimate realms of social life. The authors in this issue take up three problems: (1) the process by which people craft new subjectivities, (2) the genealogy of the new technologies of the self now circulating in East Asia, and (3) the forms of governance and political rationality that they justify. The articles as a whole testify to the fruitful encounter between ethnographic praxis and Foucault's philosophical project. They also show how transnational movement and hybrid cultural forms inflect the strategies of governance associated with modern technologies of the self, especially those allied with biomedicine. PMID- 26114920 TI - Fried food and prostate cancer risk: systematic review and meta-analysis. AB - We performed systematic review and meta-analysis of published studies that investigated the potential association between fried food consumption and prostate cancer risk. Four case-control studies were finally selected for this systematic literature review, totaling 2579 cancer patients and 2277 matched controls. In two of these studies, the larger intake of fried food was associated with a 1.3- to 2.3-fold increased risk of prostate cancer, no significant association was found in another, whereas an inverse relationship was observed in the remaining. The meta-analysis of published data showed that larger intake of fried food was associated with a 35% (95% CI 17-57%) increased risk of prostate cancer. The results of this systematic literature review support the notion that larger intake of fried foods may have a role in increasing the risk of prostate cancer. PMID- 26114921 TI - Word-finding impairment in veterans of the 1991 Persian Gulf War. AB - Approximately one quarter of 1991 Persian Gulf War Veterans experience cognitive and physiological sequelae that continue to be unexplained by known medical or psychological conditions. Difficulty coming up with words and names, familiar before the war, is a hallmark of the illness. Three Gulf War Syndrome subtypes have been identified and linked to specific war-time chemical exposures. The most functionally impaired veterans belong to the Gulf War Syndrome 2 (Syndrome 2) group, for which subcortical damage due to toxic nerve gas exposure is the suspected cause. Subcortical damage is often associated with specific complex language impairments, and Syndrome 2 veterans have demonstrated poorer vocabulary relative to controls. 11 Syndrome 1, 16 Syndrome 2, 9 Syndrome 3, and 14 age matched veteran controls from the Seabees Naval Construction Battalion were compared across three measures of complex language. Additionally, functional magnetic resonance imaging (fMRI) was collected during a covert category generation task, and whole-brain functional activity was compared between groups. Results demonstrated that Syndrome 2 veterans performed significantly worse on letter and category fluency relative to Syndrome 1 veterans and controls. They also exhibited reduced activity in the thalamus, putamen, and amygdala, and increased activity in the right hippocampus relative to controls. Syndrome 1 and Syndrome 3 groups tended to show similar, although smaller, differences than the Syndrome 2 group. Hence, these results further demonstrate specific impairments in complex language as well as subcortical and hippocampal involvement in Syndrome 2 veterans. Further research is required to determine the extent of language impairments in this population and the significance of altered neurologic activity in the aforementioned brain regions with the purpose of better characterizing the Gulf War Syndromes. PMID- 26114922 TI - Distractor inhibition: Evidence from lateralized readiness potentials. AB - The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object based selective attention on the level of distractor representations. PMID- 26114923 TI - Uric acid and skin microvascular function: the Maastricht study. AB - OBJECTIVE: Microvascular dysfunction has been suggested as a possible underlying mechanism for the association between uric acid and various diseases, such as hypertension, renal disease and cardiomyopathies. We therefore analysed the association between serum uric acid and skin microvascular function, a model of generalized microvascular function. METHODS: A cross-sectional study was performed in 610 individuals [51.8% men; mean age 58.7 +/- 8.6 years; 23.6% with type 2 diabetes (by design)] from The Maastricht Study. We assessed skin capillary density (capillaries/mm) by capillaroscopy at baseline, after 4 min of arterial occlusion, and after 2 min of venous congestion. Capillary recruitment after arterial occlusion and during venous congestion was expressed as the absolute change in capillary density after recruitment and as the percentage change in capillary density from baseline. RESULTS: Crude linear regression analyses showed that serum uric acid [per +1 standard deviation (SD) of 74 MUmol/l] was not associated with baseline capillary density [beta = -0.21 (95% confidence interval, 95% CI -1.61 to 1.19) P = 0.765], while an inverse association was found between uric acid and absolute change in capillary density after arterial occlusion [beta = -1.15 (95% CI -2.36 to 0.06) P = 0.062] and during venous congestion [beta = -1.41 (95% CI -2.68 to -0.14) P = 0.029]. However, after adjustment for sex, age and glucose metabolism status, these associations were no longer statistically significant. In addition, we found no association between uric acid and percentage capillary recruitment after arterial occlusion [beta = -1.66 (95% CI -3.97 to 0.65) P = 0.159] or during venous congestion [beta = -2.02 (95% CI -4.46 to 0.42) P = 0.104] in unadjusted analyses; multivariable analyses gave similar results. CONCLUSION: These results do not support the hypothesis that generalized microvascular dysfunction (as estimated in skin microcirculation) is the underlying mechanism for the association between uric acid and cardiovascular and renal diseases. The possibility that uric acid is associated with microvascular dysfunction in specific end-organs, for example heart or kidney, needs further investigation. PMID- 26114924 TI - Predicting the neural effect of switching from donepezil to galantamine based on single-photon emission computed tomography findings in patients with Alzheimer's disease. AB - BACKGROUND: A number of neuroimaging studies have addressed the specific effect of treatment with cholinesterase inhibitors on the frontal lobe in patients with Alzheimer's disease (AD). However, the neural effects of cholinesterase inhibitors on both apathy and executive dysfunction remain unclear. We examined whether baseline regional cerebral blood flow, as determined by using single photon emission computed tomography, is capable of predicting changes in apathy and executive dysfunction in response to AD patients switching from donepezil to galantamine therapy. METHODS: We conducted a 24-week, prospective, open-label study of AD patients treated with galantamine who did not respond to previous treatment with donepezil. Single-photon emission computed tomography was performed at baseline, and behaviour and cognitive assessments including the Mini Mental State Examination, the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale, the Frontal Assessment Battery, the Neuropsychiatry Inventory Brief Questionnaire Form, and the Dysexecutive Questionnaire were conducted at three time points (baseline and after 12 and 24 weeks of galantamine therapy). RESULTS: After galantamine therapy, the Neuropsychiatry Inventory Brief Questionnaire Form scores (apathy, irritability, and aberrant motor symptoms) and the Dysexecutive Questionnaire score improved significantly. The single-photon emission computed tomography findings showed that lower baseline regional cerebral blood flow values in several frontal areas, including the dorsolateral and ventrolateral prefrontal cortex, the anterior cingulate, and the orbitofrontal cortex, predicted greater reductions in the score for apathy (distress) on the Neuropsychiatry Inventory Brief Questionnaire Form and the Dysexecutive Questionnaire score after patients switched from donepezil to galantamine therapy. CONCLUSIONS: Our study suggests that galantamine therapy, unlike donepezil, is characterized by a dual mechanism of action that may increase acetylcholine and the nicotinic receptor-modulation effect within the frontal lobe, both of which are associated with apathy and executive dysfunction in AD patients. PMID- 26114925 TI - Participation in extracurricular activities for children with and without siblings with autism spectrum disorder. AB - OBJECTIVE: To compare the number, frequency, enjoyment and performance in extracurricular activities of siblings of children with autism spectrum disorders (ASD) to their typically developing (TD) peers, and to identify differences between actual and desired participation. METHODS: A case-control study with 30 siblings of children with ASD and 30 siblings of TD children was conducted using the Paediatric Interest Profiles and a questionnaire. RESULTS: Siblings of children with ASD participated in fewer extracurricular activities than those with TD siblings. ASD symptoms were significantly associated with the sibling participating in fewer extracurricular activities. Children with TD siblings had higher enjoyment scores in relaxation activities than children with siblings with ASD. CONCLUSION: While results were mainly positive, some differences indicated that having a sibling with ASD may impact participation in extracurricular activities. Assessments of participation barriers, as well as support to minimise participation restrictions among siblings of children with ASD are required. PMID- 26114926 TI - Anion Recognition by Pyrylium Cations and Thio-, Seleno- and Telluro- Analogues: A Combined Theoretical and Cambridge Structural Database Study. AB - Pyrylium salts are a very important class of organic molecules containing a trivalent oxygen atom in a six-membered aromatic ring. In this manuscript, we report a theoretical study of pyrylium salts and their thio-, seleno- and telluro analogues by means of DFT calculations. For this purpose, unsubstituted 2,4,6 trimethyl and 2,4,6-triphenyl cations and anions with different morphologies were chosen (Cl-, NO3- and BF4-). The complexes were characterized by means of natural bond orbital and "atoms-in-molecules" theories, and the physical nature of the interactions has been analyzed by means of symmetry-adapted perturbation theory calculations. Our results indicate the presence of anion-pi interactions and chalcogen bonds based on both sigma- and pi-hole interactions and the existence of very favorable sigma-complexes, especially for unsubstituted cations. The electrostatic component is dominant in the interactions, although the induction contributions are important, particularly for chloride complexes. The geometrical features of the complexes have been compared with experimental data retrieved from the Cambridge Structural Database. PMID- 26114927 TI - Antibacterial Activity and Mechanism of Action of Sulfone Derivatives Containing 1,3,4-Oxadiazole Moieties on Rice Bacterial Leaf Blight. AB - In this study, sulfone derivatives containing 1,3,4-oxadiazole moieties indicated good antibacterial activities against rice bacterial leaf blight caused by the pathogen Xanthomonas oryzaepv. pv. oryzae (Xoo). In particular, 2 (methylsulfonyl)-5-(4-fluorobenzyl)-1,3,4-oxadiazole revealed the best antibacterial activity against Xoo, with a half-maximal effective concentration (EC50) of 9.89 MUg/mL, which was better than those of the commercial agents of bismerthiazole (92.61 MUg/mL) and thiodiazole copper (121.82 MUg/mL). In vivo antibacterial activity tests under greenhouse conditions and field trials demonstrated that 2-(methylsulfonyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole was effective in reducing rice bacterial leaf blight. Meanwhile, 2-(methylsulfonyl)-5 (4-fluorophenyl)-1,3,4-oxadiazole stimulate the increase in superoxide dismutase (SOD) and peroxidase (POD) activities in rice, causing marked enhancement of plant resistance against rice bacterial leaf blight. It could also improve the chlorophyll content and restrain the increase in the malondialdehyde (MDA) content in rice to considerably reduce the amount of damage caused by Xoo. Moreover, 2-(methylsulfonyl)-5-(4-fluorophenyl)-1,3,4-oxadiazole, at a concentration of 20 MUg/mL, could inhibit the production of extracellular polysaccharide (EPS) with an inhibition ratio of 94.52%, and reduce the gene expression levels of gumB, gumG, gumM, and xanA, with inhibition ratios of 94.88%, 68.14%, 86.76%, and 79.21%, respectively. PMID- 26114929 TI - Relationships Between Pacing Parameters and Performance of Elite Male 1500-m Swimmers. AB - PURPOSE: Pacing has a substantial effect on endurance performance. The authors characterize pacing and identify its parameters for optimal performance in 1500-m freestyle swimming. METHODS: Web sites provided 50-m lap and 1500-m race times for 330 swims of 24 elite male swimmers. Pacing for each swim was characterized with 7 parameters derived from a general linear model: linear and quadratic coefficients for the effect of lap number; reductions from predicted time for first, second, penultimate, and last laps; and lap-time variability. Scatter plots of race time vs each parameter for each swimmer were used to identify optimum values of parameters. RESULTS: Most scatterplots showed only weak relationships between the parameter and performance, but one-third to one-half of swimmers had an optimum value of the parameter that was substantially different from their mean value. A large improvement in performance time (1.4% +/- 0.9%, mean +/- SD) could be achieved generally by reversing the sign of the linear parameter to make the slowest lap occur earlier in the race. Small to moderate improvements might also accrue by changing the quadratic parameter, by making the first and second laps slower and the penultimate and last laps faster, and reducing lap-time variability. CONCLUSIONS: This approach to analysis of pacing may help improve performance in swimmers and other endurance athletes in sports with multiple laps, but data from many competitions are required. PMID- 26114930 TI - Colour polymorphism torn apart by opposing positive frequency-dependent selection, yet maintained in space. AB - Polymorphic warning signals in aposematic species are enigmatic because predator learning and discrimination should select for the most common coloration, resulting in positive frequency-dependent survival selection. Here, we investigated whether differential mating success could create sufficiently strong negative frequency-dependent selection for rare morphs to explain polymorphic (white and yellow) warning coloration in male wood tiger moths (Parasemia plantaginis). We conducted an experiment in semi-natural conditions where we estimated mating success for both white and yellow male moths under three different morph frequencies. Contrary to expectations, mating success was positively frequency-dependent: white morph males had high relative fitness when common, likewise yellow morph males had high relative fitness when instead they were common. We hence built a model parameterized with our data to examine whether polymorphism can be maintained despite two sources of positive frequency dependence. The model includes known spatial variation in the survival advantage enjoyed by the yellow morph and assumes that relative mating success follows our experimentally derived values. It predicts that polymorphism is possible under migration for up to approximately 20% exchange of individuals between subpopulations in each generation. Our results suggest that differential mating success combined with spatial variation in predator communities may operate as a selection mosaic that prevents complete fixation of either morph. PMID- 26114931 TI - Oligo(p-phenylene ethynylene) Electrolytes: A Novel Molecular Scaffold for Optical Tracking of Amyloids. AB - Finding new optical probes to detect and track amyloid protein aggregates is key to understanding and defeating the myriad of neurodegenerative and other diseases associated with these misfolded proteins. Herein we report that a series of fluorescent, soluble oligo(p-phenylene ethynylene)s (OPEs) are able to detect amyloids in vitro by massive binding-activated superluminescence, with low micromolar affinity and high selectivity for the amyloid conformer. The OPEs track the kinetics of amyloid fibril formation from native hen egg white lysozyme (HEWL) similarly to thioflavin T (ThT), and the dependence of binding affinity on OPE length supports the theory of a linear binding groove. We hypothesize, based on spectral properties, induced circular dichroism, and previous work in analogous systems, that the fluorescence turn-on mechanism is a combination of the reduction of static solvent-mediated quenching at the ethyl ester end groups of the phenylene ethynylene fluorophore and the formation of chiral J-type aggregates templated on the amyloid fibril surface. PMID- 26114932 TI - The effects of narrow-band middle infrared radiation in enhancing the antitumor activity of paclitaxel. AB - Paclitaxel is used as an adjuvant to enhance the effectiveness of ionization radiation therapy; however, high-energy radiation often damages the healthy cells surrounding cancer cells. Low-energy, middle-infrared radiation (MIR) has been shown to prevent tissue damage, and recent studies have begun combining MIR with paclitaxel. However, the cytotoxic effects of this treatment combination remain unclear, and the mechanism underlying its effects on HeLa cells has yet to be elucidated. This study investigated the effectiveness of treating HeLa human cervical cancer cells with a combination of paclitaxel for 48 h in conjunction with narrow-band MIR from 3.0 to 5.0 MUm. This combined treatment significantly inhibited the growth of HeLa cells. Specifically, results from Annexin V-FITC/PI apoptosis detection and cell mitochondrial membrane potential analyses revealed an increase in apoptotic cell death and a collapse of mitochondrial membrane potential. One possible mechanism underlying cellular apoptosis is an increase in oxidative stress. These preliminary findings provide evidence to support the combination of narrow-band MIR with paclitaxel as an alternative approach in the treatment of human cervical cancer. PMID- 26114933 TI - The importance of ATP-related compounds for the freshness and flavor of post mortem fish and shellfish muscle: A review. AB - ATP degradation is one of the most important biochemical changes in the post mortem muscle of fish and shellfish. This process has long been recognized as an accurate way to evaluate freshness of fish and shellfish product. This review updates and condenses the overall history and recent advances in understanding the role of ATP-related compounds in post-mortem fish and shellfish muscle including a discussion of key analytical methods, their use as a freshness indicator, their roles in flavor enhancement, the factors affecting their transitions, and the possible mechanisms responsible for their impact on flavor and freshness. Moreover, some challenges and future directions for research regarding ATP-related compounds in fish and shellfish flavor and freshness are presented. With increasing consumer demands for fresh products with extended shelf life, understanding the relationships between ATP-related compounds and their involvement in the freshness and umami taste is a prerequisite for assuring the high quality of fish and shellfish. PMID- 26114935 TI - Archaeal ribonuclease P proteins have potential for biotechnological applications where precise hybridization of nucleic acids is needed. AB - Fluorescence resonance energy transfer-based assay showed that archaeal ribonuclease P (RNase P) proteins significantly promoted DNA annealing and strand displacement. Moreover, we found that archaeal RNase P proteins could discriminate nucleotide exchanges in DNA chains via their activity accelerating DNA strand displacement, suggesting that they have potential for biotechnological application to genetic diagnosis. PMID- 26114934 TI - Investigation of Toll-Like Receptor-2 (2258G/A) and Interferon Gamma (+874T/A) Gene Polymorphisms among Infertile Women with Female Genital Tuberculosis. AB - BACKGROUND: Toll-like receptor 2 (TLR2) and interferon-gamma (IFN-gamma) coordinate with a diverse array of cellular programs through the transcriptional regulation of immunologically relevant genes and play an important role in immune system, reproductive physiology and basic pathology. Alterations in the functions of TLR2 2258G (guanine)/ A, IFN-gamma (+874T/A) and signalling molecules that result from polymorphisms are often associated with susceptibility or resistance, which may, in turn, establish the innate host response to various infectious diseases. Presently, we proposed to investigate the risk of common single nucleotide polymorphism (SNP) of TLR2 and IFN-gamma genes, for their effect on infertility in women with female genital tuberculosis (FGTB) and healthy women as controls. METHODOLOGY/PRINCIPAL FINDINGS: Genotyping of TLR2 and IFN-gamma gene polymorphisms was performed by amplification refractory mutation system multi gene/multi-primer polymerase chain reaction followed by restriction fragment length polymorphism in 175 FGTB patients and 100 healthy control women (HCW). The TLR2 polymorphism [adenine (A) allele] was observed in 57.7 and 58.0% of FGTB patients and HCW, respectively. The IFN-gamma (+874T/A) polymorphism (A allele) was significant in 74.3 and 71.0% of FGTB patients and HCW, respectively, while the odds ratios for the AA and TA genotypes for predisposition of FGTB were found to be 0.304 and 1.650 in HCW, respectively. The SNP of TLR2 was not associated with FGTB but the SNP of IFN-gamma was found to be associated with mycobacteria infections and to induce infertility. CONCLUSIONS/SIGNIFICANCE: At present, we hypothesize that infertile women with FGTB and HCW without tuberculosis (TB) have identical frequency of TLR variants, which may be adequate in the production of IFN-gamma in response to Mycobacterium tuberculosis infections. Thus, the study appears to be the first of its kind reporting a mutation in the IFN-gamma gene [+874 T (thymine) to A] responsible for susceptibility to TB infections and further inducing infertility. PMID- 26114936 TI - Antiviral Limonoids Including Khayanolides from the Trang Mangrove Plant Xylocarpus moluccensis. AB - Eight new khayanolides, named thaixylomolins G-N (1-8), two new phragmalins (9 and 10), and two new mexicanolides (11 and 12) were obtained from the seeds of the Trang mangrove plant Xylocarpus moluccensis. The absolute configurations of these limonoids, except for the stereocenter at C-6 of 11 and 12, were assigned by experimental and TDDFT calculated electronic circular dichroism spectra. The khayanolides may be classified into two subclasses, one of which has a C-2 carbonyl and a 3beta-acetoxy group, whereas the other possesses a 2beta-acetoxy and a C-3 carbonyl function. Khayanolides, rearranged phragmalin-type limonoids, are reported for the first time from plants of the mangrove genus Xylocarpus. The structure of moluccensin J, a known 30-ketophragmalin containing a Delta(8(14)) double bond, was revised to be a khayanolide, named thaixylomolin K. The antiviral activities of the isolates against pandemic influenza A virus (subtype H1N1) were tested by the assay of cytopathic effect inhibition. Three khayanolides, viz., thaixylomolins I, K, and M, exhibited moderate anti-H1N1 activities. The most potent one, thaixylomolin I (IC50 = 77.1 +/- 8.7 MUM), showed stronger inhibitory activity than that of the positive control, ribavirin (IC50 = 185.9 +/- 16.8 MUM). PMID- 26114937 TI - Homozygous 16p13.11 duplication associated with mild intellectual disability and urinary tract malformations in two siblings born from consanguineous parents. AB - The use of array-comparative genomic hybridization (array-CGH) in routine clinical work has allowed the identification of many new copy number variations (CNV). The 16p13.11 duplication has been implicated in various congenital anomalies and neurodevelopmental disorders, but it has also been identified in healthy individuals. We report a clinical observation of two brothers from related parents each carrying a homozygous 16p13.11 duplication. The propositus had mild intellectual disability and posterior urethral valves with chronic renal disease. His brother was considered a healthy child with only learning disabilities and poor academic performances. However, a routine medical examination at 25-years-old revealed a mild chronic renal disease and ureteropelvic junction obstruction. Furthermore, the father presented with a unilateral renal agenesis, thus it seemed that a "congenital anomalies of kidney and urinary tract" (CAKUT) phenotype segregated in this family. This may be related to the duplication, but we cannot exclude the involvement of additional genetic or non-genetic factors in the urological phenotype. Several cohort studies showed association between this chromosomal imbalance and different clinical manifestations, but rarely with CAKUT. The duplication reported here was similar to the larger one of 3.4 Mb previously described versus the more common of 1.6 Mb. It encompassed at least 11 known genes, including the five ohnologs previously identified. Our observation, in addition to expanding the clinical spectrum of the duplication provides further support to understanding the underlying pathogenic mechanism. PMID- 26114938 TI - Epidemiology of Imported Leishmaniasis in Italy: Implications for a European Endemic Country. AB - In the past decade, the number of imported leishmaniasis cases has increased in countries of Western Europe. The trend is associated with increasing travels, ecotourism activity, military operations and immigration. While in endemic countries leishmaniasis is usually well diagnosed, accurate patient history and parasite identification are necessary to distinguish between autochthonous and imported cases. This is particularly important, as new Leishmania species/genotypes may be introduced and transmitted by local phlebotomine vectors without appropriate surveillance, with unpredictable consequences. We report on the surveillance of imported leishmaniasis performed by the Leishmania Identification Reference Centre of Rome from 1986 through 2012, involving health care centres from 16/20 Italian regions. Suspected imported cases were analyzed and conclusions were based on clinical, epidemiological and diagnostic findings. Over the years, different parasite identification methods were employed, including MultiLocus Enzyme Electrophoresis and molecular techniques combining disease diagnosis (SSU rDNA nested-PCR) and Leishmania typing (nuclear repetitive sequence and ITS-1 PCR-RFLPs). A total of 105 imported cases were recorded (annual range: 0-20) of which 36 were visceral (VL) (16 HIV-coinfections) and 69 cutaneous (CL) cases; 85 cases (52 CL) were from the Old World and 20 (17 CL) from the New World. Eight Leishmania species were identified, of which 7 were exotic to Italy. VL importation until 1995 was associated with the spread of Mediterranean Leishmania-HIV co-infections in early 1990s. Following the introduction of HAART treatment, such cases became occasional in Italians but relatively frequent among immigrants. In contrast, a steady increase of CL cases was observed from different areas of the Old and New Worlds, that in recent years included mainly immigrants 'visiting friends and relatives' and Italian tourists. This positive trend likely depends on better diagnosis and reporting; however, we suspect that many CL cases remained unrecognized. Given the relatively low incidence of leishmaniasis importation, the risk of introduction of exotic parasites appears limited, although the detection of anthroponotic species requires attention. PMID- 26114939 TI - Drinking Among Native American and White Youths: The Role of Perceived Neighborhood and School Environment. AB - This study examined whether differences in the perceived neighborhood and school environments account for differences in drinking behavior among Native American and White youths. Findings indicate that being Native American was indirectly related to drinking through perceived school and community variables. Higher drinking rates among Native Americans appear to be accounted for by lower school involvement, weaker neighborhood antidrug norms, greater neighborhood disorganization, and lower levels of perceived police enforcement. Results of this study highlight the potential importance of perceived school and neighborhood environments in drinking behavior among youths. PMID- 26114941 TI - Effect of Brood Age on Nestling Diet and Prey Composition in a Hedgerow Specialist Bird, the Barred Warbler Sylvia nisoria. AB - The composition and quality of food provided to nestling birds influence their growth and development and offers key insight into the ecological requirements of birds. One bird species whose feeding ecology is poorly understood is the Barred Warbler (Sylvia nisoria), which utilizes semi-natural shrubby vegetation in agroecosystems. Because Barred Warbler nestlings vary greatly in body mass we hypothesised that diet and prey properties (size, diversity, taxonomic composition, and chitin content and resulting body hardness and digestibility) would differ as the nestlings aged. We quantified the diet based on faecal analysis, sampling faecal sacs from the nestlings pooled into three age classes: 2-3 days old, 4-6 d old, and 7-9 d old. Nestlings were provided a wide diversity of food and a strong relationship existed between food characteristics and nestling age. The youngest nestlings (2-3 d old) had the lowest values of each dietary characteristic (diversity, number and total biomass of prey, and individual prey weight), that were significantly lower than the oldest nestlings (7-9 d old). Nestlings aged 4-6 d exhibited intermediate dietary characteristics. Differences in dietary composition of the six major food types showed marked differences between the individual broods and age categories. Percentages of the number and biomass of soft-bodied prey were highest in the diet of 2-3 d and 4-6 d old nestlings, and decreased with increasing age, whereas the opposite trend was observed in the percentage of intermediately and heavily chitinised prey. Parent Barred Warblers probably preferentially select soft-bodied prey for the youngest nestlings, and satisfy the greater energy demands of the older ones by providing them with a greater variety of prey containing more chitin, as well as plant food. The provisioning of less-readily digestible prey to older nestlings suggests that as the quality of food decreases the quantity increases, implying that the youngest nestlings may be physiologically limited as regards their ability to digest more heavily chitinised prey. PMID- 26114940 TI - Curcumin Improves Amyloid beta-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway. AB - Curcumin, the most active component of turmeric, has various beneficial properties, such as antioxidant, anti-inflammatory, and antitumor effects. Previous studies have suggested that curcumin reduces the levels of amyloid and oxidized proteins and prevents memory deficits and thus is beneficial to patients with Alzheimer's disease (AD). However, the molecular mechanisms underlying curcumin's effect on cognitive functions are not well-understood. In the present study, we examined the working memory and spatial reference memory in rats that received a ventricular injection of amyloid-beta1-42 (Abeta1-42), representing a rodent model of Alzheimer's disease (AD). The rats treated with Abeta1-42 exhibited obvious cognitive deficits in behavioral tasks. Chronic (seven consecutive days, once per day) but not acute (once a day) curcumin treatments (50, 100, and 200 mg/kg) improved the cognitive functions in a dose-dependent manner. In addition, the beneficial effect of curcumin is accompanied by increased BDNF levels and elevated levels of phosphorylated ERK in the hippocampus. Furthermore, the cognition enhancement effect of curcumin could be mimicked by the overexpression of BDNF in the hippocampus and blocked by either bilateral hippocampal injections with lentiviruses that express BDNF shRNA or a microinjection of ERK inhibitor. These findings suggest that chronic curcumin ameliorates AD-related cognitive deficits and that upregulated BDNF-ERK signaling in the hippocampus may underlie the cognitive improvement produced by curcumin. PMID- 26114942 TI - Listening to Puns Elicits the Co-Activation of Alternative Homophone Meanings during Language Production. AB - Recent evidence suggests that lexical-semantic activation spread during language production can be dynamically shaped by contextual factors. In this study we investigated whether semantic processing modes can also affect lexical-semantic activation during word production. Specifically, we tested whether the processing of linguistic ambiguities, presented in the form of puns, has an influence on the co-activation of unrelated meanings of homophones in a subsequent language production task. In a picture-word interference paradigm with word distractors that were semantically related or unrelated to the non-depicted meanings of homophones we found facilitation induced by related words only when participants listened to puns before object naming, but not when they heard jokes with unambiguous linguistic stimuli. This finding suggests that a semantic processing mode of ambiguity perception can induce the co-activation of alternative homophone meanings during speech planning. PMID- 26114943 TI - Understanding Collective Discontents: A Psychological Approach to Measuring Zeitgeist. AB - Over the last decade, several countries around the world developed a collective sense of doom and gloom: Their Zeitgeist could be characterized as one of decline. Paradoxically, in some countries, such as the Netherlands, this collective discontent with society seems to exist despite high levels of individual well-being. Current psychological research informs us about why individuals would feel unduly optimistic, but does not account for a collective sense of decline. The present research develops a novel operationalization of Zeitgeist, referred to as a general factor Z. We conceptualize Zeitgeist as a collective global-level evaluation of the state (and future) of society. Three studies confirm that perceptions of the same societal problems at the personal and collective level differed strongly. Across these studies we found support for a hypothesized latent factor Z, underlying collective-level perceptions of society. This Z-factor predicted people's interpretation of new information about society that was presented through news stories. These results provide a first step in operationalizing and (ultimately) understanding the concept of Zeitgeist: collectively shared ideas about society. Implications for policy are discussed. PMID- 26114945 TI - A Fatty Acid Based Bayesian Approach for Inferring Diet in Aquatic Consumers. AB - We modified the stable isotope mixing model MixSIR to infer primary producer contributions to consumer diets based on their fatty acid composition. To parameterize the algorithm, we generated a 'consumer-resource library' of FA signatures of Daphnia fed different algal diets, using 34 feeding trials representing diverse phytoplankton lineages. This library corresponds to the resource or producer file in classic Bayesian mixing models such as MixSIR or SIAR. Because this library is based on the FA profiles of zooplankton consuming known diets, and not the FA profiles of algae directly, trophic modification of consumer lipids is directly accounted for. To test the model, we simulated hypothetical Daphnia comprised of 80% diatoms, 10% green algae, and 10% cryptophytes and compared the FA signatures of these known pseudo-mixtures to outputs generated by the mixing model. The algorithm inferred these simulated consumers were comprised of 82% (63-92%) [median (2.5th to 97.5th percentile credible interval)] diatoms, 11% (4-22%) green algae, and 6% (0-25%) cryptophytes. We used the same model with published phytoplankton stable isotope (SI) data for delta13C and delta15N to examine how a SI based approach resolved a similar scenario. With SI, the algorithm inferred that the simulated consumer assimilated 52% (4-91%) diatoms, 23% (1-78%) green algae, and 18% (1-73%) cyanobacteria. The accuracy and precision of SI based estimates was extremely sensitive to both resource and consumer uncertainty, as well as the trophic fractionation assumption. These results indicate that when using only two tracers with substantial uncertainty for the putative resources, as is often the case in this class of analyses, the underdetermined constraint in consumer-resource SI analyses may be intractable. The FA based approach alleviated the underdetermined constraint because many more FA biomarkers were utilized (n < 20), different primary producers (e.g., diatoms, green algae, and cryptophytes) have very characteristic FA compositions, and the FA profiles of many aquatic primary consumers are strongly influenced by their diets. PMID- 26114946 TI - The Impact of Newer Biological Disease Modifying Anti-Rheumatic Drugs on Cardiovascular Risk Factors: A 12-Month Longitudinal Study in Rheumatoid Arthritis Patients Treated with Rituximab, Abatacept and Tociliziumab. AB - OBJECTIVES: To assess whether treatment with one of three novel biological DMARDs; rituximab, abatacept or tocilizumab reduce cardiovascular disease (CVD) risk factors in patients with rheumatoid arthritis (RA). METHODS: This is an open, observational and prospective study with visits at baseline, 3, 6, and 12 months. Patients were assigned to receive rituximab, abatacept or tocilizumab according to clinical indications assessed by an independent rheumatologist. Disease activity was quantified by the disease activity score (DAS28) and extensive ultrasonography. CVD risk was assessed by total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), blood pressure and arterial stiffness measurements [pulse wave velocity (PWV) and augmentation index (AIx)]. Within group change in disease activity and CVD risk over 3 months was explored using paired samples bivariate tests. Predictors of change in CVD risk at 3 months were identified in linear regression models. Changes in CVD risk markers over the 12- month follow-up in patients receiving rituximab were assessed by mixed models repeated analyses. RESULTS: 24 patients on rituximab, 5 on abatacept and 7 on tocilizumab were included. At 3 months PWV was significantly reduced in the tocilizumab group only, but at 12 months rituximab patients showed a significant reduction in PWV. Reduced inflammation at 3 months was associated with increased TC and HDL-c in the entire cohort. CONCLUSION: Treatment with tocilizumab and rituximab reduces PWV, a marker of CVD risk, in patients with RA. PMID- 26114947 TI - TRIM30alpha Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING. AB - Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30alpha (TRIM30alpha) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30alpha augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30alpha-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30alpha interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30alpha promoted the degradation of STING via K48 linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30alpha is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING. PMID- 26114948 TI - Orthocaspases are proteolytically active prokaryotic caspase homologues: the case of Microcystis aeruginosa. AB - Caspases are a family of cysteine-dependent proteases known to be involved in the process of programmed cell death in metazoans. Recently, cyanobacteria were also found to contain caspase-like proteins, but their existence has only been identified in silico up to now. Here, we present the first experimental characterisation of a prokaryotic caspase homologue. We have expressed the putative caspase-like gene MaOC1 from the toxic bloom-forming cyanobacterium Microcystis aeruginosa PCC 7806 in Escherichia coli. Kinetic characterisation showed that MaOC1 is an endopeptidase with a preference for arginine in the P1 position and a pH optimum of 7.5. MaOC1 exhibited high catalytic rates with the kcat /KM value for Z-RR-AMC substrate of the order 10(6) M(-1) s(-1). In contrast to plant or metazoan caspase-like proteins, whose activity is calcium dependent or requires dimerisation for activation, MaOC1 was activated by autocatalytic processing after residue Arg219, which separated the catalytic domain and the remaining 55 kDa subunit. The Arg219Ala mutant was resistant to autoprocessing and exhibited no proteolytic activity, confirming that processing of MaOC1 is a prerequisite for its activity. Due to their structural and functional differences to other known caspase-like proteins, we suggest to name these evolutionary primitive proteins orthocaspases. PMID- 26114949 TI - Neuropsychological Profile of Children, Adolescents and Adults Experiencing Maltreatment: A Meta-analysis. AB - OBJECTIVE: Few studies have attempted to describe the range of cognitive impairments affecting people who have experienced child maltreatment. The aim of this meta-analysis was to examine the neuropsychological profile of these people and to determine the cognitive impacts of maltreatment from childhood to adulthood. METHOD: Fifty-two publications from 1970 to 2013 were included. RESULTS: The affected cognitive domains were working memory (g = -.65), attention (g = -.63), intelligence (g = -.56) and speed of processing (g = -.49). The impact of maltreatment was greater in young children (g = -.71) and less pronounced in adults (g = -.26). CONCLUSIONS: These results suggest that exposure to maltreatment has an impact on specific cognitive processes, regardless of age. PMID- 26114950 TI - Advanced Evaluation Strategies for Protein-Imprinted Polymer Nanobeads. AB - Molecularly imprinted polymers (MIPs) are synthetic affinity matrices capable of selective binding a specific target molecule. A strategy for competitive selectivity studies is developed providing information on the selective binding properties of MIPs in complex matrices. Batch rebinding experiments entail the target protease, two other proteins, and MIP nanobeads. The protease is inhibited by addition of pepstatin thus quenching the degradation of the other proteins. The proteins are analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The relevance of competitive selectivity studies for the evaluation of MIP performance is further emphasized by comparison to single protein rebinding experiments. PMID- 26114951 TI - Real-time distortion correction of spiral and echo planar images using the gradient system impulse response function. AB - PURPOSE: MRI-guided interventions demand high frame rate imaging, making fast imaging techniques such as spiral imaging and echo planar imaging (EPI) appealing. In this study, we implemented a real-time distortion correction framework to enable the use of these fast acquisitions for interventional MRI. METHODS: Distortions caused by gradient waveform inaccuracies were corrected using the gradient impulse response function (GIRF), which was measured by standard equipment and saved as a calibration file on the host computer. This file was used at runtime to calculate the predicted k-space trajectories for image reconstruction. Additionally, the off-resonance reconstruction frequency was modified in real time to interactively deblur spiral images. RESULTS: Real time distortion correction for arbitrary image orientations was achieved in phantoms and healthy human volunteers. The GIRF-predicted k-space trajectories matched measured k-space trajectories closely for spiral imaging. Spiral and EPI image distortion was visibly improved using the GIRF-predicted trajectories. The GIRF calibration file showed no systematic drift in 4 months and was demonstrated to correct distortions after 30 min of continuous scanning despite gradient heating. Interactive off-resonance reconstruction was used to sharpen anatomical boundaries during continuous imaging. CONCLUSIONS: This real-time distortion correction framework will enable the use of these high frame rate imaging methods for MRI-guided interventions. Magn Reson Med 75:2278-2285, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26114952 TI - Editors' note. PMID- 26114954 TI - A Generalizable Brain-Computer Interface (BCI) Using Machine Learning for Feature Discovery. AB - This work describes a generalized method for classifying motor-related neural signals for a brain-computer interface (BCI), based on a stochastic machine learning method. The method differs from the various feature extraction and selection techniques employed in many other BCI systems. The classifier does not use extensive a-priori information, resulting in reduced reliance on highly specific domain knowledge. Instead of pre-defining features, the time-domain signal is input to a population of multi-layer perceptrons (MLPs) in order to perform a stochastic search for the best structure. The results showed that the average performance of the new algorithm outperformed other published methods using the Berlin BCI IV (2008) competition dataset and was comparable to the best results in the Berlin BCI II (2002-3) competition dataset. The new method was also applied to electroencephalography (EEG) data recorded from five subjects undertaking a hand squeeze task and demonstrated high levels of accuracy with a mean classification accuracy of 78.9% after five-fold cross-validation. Our new approach has been shown to give accurate results across different motor tasks and signal types as well as between subjects. PMID- 26114955 TI - Three-Dimensional Muscle Architecture and Comprehensive Dynamic Properties of Rabbit Gastrocnemius, Plantaris and Soleus: Input for Simulation Studies. AB - The vastly increasing number of neuro-muscular simulation studies (with increasing numbers of muscles used per simulation) is in sharp contrast to a narrow database of necessary muscle parameters. Simulation results depend heavily on rough parameter estimates often obtained by scaling of one muscle parameter set. However, in vivo muscles differ in their individual properties and architecture. Here we provide a comprehensive dataset of dynamic (n = 6 per muscle) and geometric (three-dimensional architecture, n = 3 per muscle) muscle properties of the rabbit calf muscles gastrocnemius, plantaris, and soleus. For completeness we provide the dynamic muscle properties for further important shank muscles (flexor digitorum longus, extensor digitorum longus, and tibialis anterior; n = 1 per muscle). Maximum shortening velocity (normalized to optimal fiber length) of the gastrocnemius is about twice that of soleus, while plantaris showed an intermediate value. The force-velocity relation is similar for gastrocnemius and plantaris but is much more bent for the soleus. Although the muscles vary greatly in their three-dimensional architecture their mean pennation angle and normalized force-length relationships are almost similar. Forces of the muscles were enhanced in the isometric phase following stretching and were depressed following shortening compared to the corresponding isometric forces. While the enhancement was independent of the ramp velocity, the depression was inversely related to the ramp velocity. The lowest effect strength for soleus supports the idea that these effects adapt to muscle function. The careful acquisition of typical dynamical parameters (e.g. force-length and force-velocity relations, force elongation relations of passive components), enhancement and depression effects, and 3D muscle architecture of calf muscles provides valuable comprehensive datasets for e.g. simulations with neuro-muscular models, development of more realistic muscle models, or simulation of muscle packages. PMID- 26114956 TI - Three Gorges Dam: Impact of Water Level Changes on the Density of Schistosome Transmitting Snail Oncomelania hupensis in Dongting Lake Area, China. AB - BACKGROUND: Schistosomiasis remains an important public health issue in China and worldwide. Oncomelania hupensis is the unique intermediate host of schistosoma japonicum, and its change influences the distribution of S. japonica. The Three Gorges Dam (TGD) has substantially changed the ecology and environment in the Dongting Lake region. This study investigated the impact of water level and elevation on the survival and habitat of the snails. METHODS: Data were collected for 16 bottomlands around 4 hydrological stations, which included water, density of living snails (form the Anxiang Station for Schistosomiasis Control) and elevation (from Google Earth). Based on the elevation, sixteen bottomlands were divided into 3 groups. ARIMA models were built to predict the density of living snails in different elevation areas. RESULTS: Before closure of TGD, 7 out of 9 years had a water level beyond the warning level at least once at Anxiang hydrological station, compared with only 3 out of 10 years after closure of TGD. There were two severe droughts that happened in 2006 and 2011, with much fewer number of flooding per year compared with other study years. Overall, there was a correlation between water level changing and density of living snails variation in all the elevations areas. The density of living snails in all elevations areas was decreasing after the TGD was built. The relationship between number of flooding per year and the density of living snails was more pronounced in the medium and high elevation areas; the density of living snails kept decreasing from 2003 to 2014. In low elevation area however, the density of living snails decreased after 2003 first and turned to increase after 2011. Our ARIMA prediction models indicated that the snails would not disappear in the Dongting Lake region in the next 7 years. In the low elevation area, the density of living snails would increase slightly, and then stabilize after the year 2017. In the medium elevation region, the change of the density of living snails would be more obvious and would increase till the year 2020. In the high elevation area, the density of living snails would remain stable after the year 2015. CONCLUSION: The TGD influenced water levels and reduced the risk of flooding and the density of living snails in the study region. Based on our prediction models, the density of living snails in all elevations tends to be stabilized. Control of S. japonica would continue to be an important task in the study area in the coming decade. PMID- 26114957 TI - Profound parental bias associated with chromosome 14 acquired uniparental disomy indicates targeting of an imprinted locus. AB - Acquired uniparental disomy (aUPD) is a common finding in myeloid malignancies and typically acts to convert a somatically acquired heterozygous mutation to homozygosity. We sought to identify the target of chromosome 14 aUPD (aUPD14), a recurrent abnormality in myeloid neoplasms and population cohorts of elderly individuals. We identified 29 cases with aUPD14q that defined a minimal affected region (MAR) of 11.2 Mb running from 14q32.12 to the telomere. Exome sequencing (n=7) did not identify recurrently mutated genes, but methylation-specific PCR at the imprinted MEG3-DLK1 locus located within the MAR demonstrated loss of maternal chromosome 14 and gain of paternal chromosome 14 (P<0.0001), with the degree of methylation imbalance correlating with the level of aUPD (r=0.76; P=0.0001). The absence of driver gene mutations in the exomes of three individuals with aUPD14q but no known haematological disorder suggests that aUPD14q may be sufficient to drive clonal haemopoiesis. Analysis of cases with both aUPD14q and JAK2 V617F (n=11) indicated that aUPD14q may be an early event in some cases but a late event in others. We conclude that aUPD14q is a recurrent abnormality that targets an imprinted locus and may promote clonal haemopoiesis either as an initiating event or as a secondary change. PMID- 26114958 TI - A Land-Use Perspective for Birdstrike Risk Assessment: The Attraction Risk Index. AB - Collisions between aircraft and birds, birdstrikes, pose a serious threat to aviation safety. The occurrence of these events is influenced by land-uses in the surroundings of airports. Airports located in the same region might have different trends for birdstrike risk, due to differences in the surrounding habitats. Here we developed a quantitative tool that assesses the risk of birdstrike based on the habitats within a 13-km buffer from the airport. For this purpose, we developed Generalized Linear Models (GLMs) with binomial distribution to estimate the contribution of habitats to wildlife use of the study area, depending on season. These GLMs predictions were combined to the flight altitude of birds within the 13-km buffer, the airport traffic pattern and the severity indices associated with impacts. Our approach was developed at Venice Marco Polo International airport (VCE), located in northeast Italy and then tested at Treviso Antonio Canova International airport (TSF), which is 20 km inland. Results from the two airports revealed that both the surrounding habitats and the season had a significant influence to the pattern of risk. With regard to VCE, agricultural fields, wetlands and urban areas contributed most to the presence of birds in the study area. Furthermore, the key role of distance of land-uses from the airport on the probability of presence of birds was highlighted. The reliability of developed risk index was demonstrated since at VCE it was significantly correlated with bird strike rate. This study emphasizes the importance of the territory near airports and the wildlife use of its habitats, as factors in need of consideration for birdstrike risk assessment procedures. Information on the contribution of habitats in attracting birds, depending on season, can be used by airport managers and local authorities to plan specific interventions in the study area in order to lower the risk. PMID- 26114959 TI - rMCP-2, the Major Rat Mucosal Mast Cell Protease, an Analysis of Its Extended Cleavage Specificity and Its Potential Role in Regulating Intestinal Permeability by the Cleavage of Cell Adhesion and Junction Proteins. AB - Mast cells of the rat intestinal mucosa express three chymotryptic enzymes named rMCP-2, -3 and 4. rMCP-2, the most abundant of these enzymes, has been shown to increase the permeability of the intestinal epithelium, most likely by cleavage of cell adhesion and junction proteins and thereby play a role in intestinal parasite clearance. However, no target for this effect has yet been identified. To address this question we here present its extended cleavage specificity. Phage display analysis showed that it is a chymase with a specificity similar to the corresponding enzyme in mice, mMCP-1, with a preference for Phe or Tyr in the P1 position, and a general preference for aliphatic amino acids both upstream and downstream of the cleavage site. The consensus sequence obtained from the phage display analysis was used to screen the rat proteome for potential targets. A few of the most interesting candidate substrates were cell adhesion and cell junction molecules. To see if these proteins were also susceptible to cleavage in their native conformation we cleaved 5 different recombinant cell adhesion and cell junction proteins. Three potential targets were identified: the loop 1 of occludin, protocadherin alpha 4 and cadherin 17, which indicated that these proteins were at least partly responsible for the previously observed prominent role of rMCP-2 in mucosal permeability and in parasite clearance. PMID- 26114960 TI - Silencing of DNase Colicin E8 Gene Expression by a Complex Nucleoprotein Assembly Ensures Timely Colicin Induction. AB - Colicins are plasmid-encoded narrow spectrum antibiotics that are synthesized by strains of Escherichia coli and govern intraspecies competition. In a previous report, we demonstrated that the global transcriptional factor IscR, co dependently with the master regulator of the DNA damage response, LexA, delays induction of the pore forming colicin genes after SOS induction. Here we show that IscR is not involved in the regulation of nuclease colicins, but that the AsnC protein is. We report that AsnC, in concert with LexA, is the key controller of the temporal induction of the DNA degrading colicin E8 gene (cea8), after DNA damage. We demonstrate that a large AsnC nucleosome-like structure, in conjunction with two LexA molecules, prevent cea8 transcription initiation and that AsnC binding activity is directly modulated by L asparagine. We show that L asparagine is an environmental factor that has a marked impact on cea8 promoter regulation. Our results show that AsnC also modulates the expression of several other DNase and RNase colicin genes but does not substantially affect pore forming colicin K gene expression. We propose that selection pressure has "chosen" highly conserved regulators to control colicin expression in E. coli strains, enabling similar colicin gene silencing among bacteria upon exchange of colicinogenic plasmids. PMID- 26114961 TI - Effects of changes in intracellular iron pool on AlkB-dependent and AlkB independent mechanisms protecting E.coli cells against mutagenic action of alkylating agent. AB - An Escherichia coli hemH mutant accumulates protoporphyrin IX, causing photosensitivity of cells to visible light. Here, we have shown that intracellular free iron in hemH mutants is double that observed in hemH(+) strain. The aim of this study was to recognize the influence of this increased free iron concentration on AlkB-directed repair of alkylated DNA by analyzing survival and argE3 -> Arg(+) reversion induction after lambda>320 nm light irradiation and MMS-treatment in E. coli AB1157 hemH and alkB mutants. E.coli AlkB dioxygenase constitutes a direct single-protein repair system using non-hem Fe(II) and cofactors 2-oxoglutarate (2OG) and oxygen (O2) to initiate oxidative dealkylation of DNA/RNA bases. We have established that the frequency of MMS induced Arg(+) revertants in AB1157 alkB(+)hemH(-)/pMW1 strain was 40 and 26% reduced comparing to the alkB(+)hemH(-) and alkB(+)hemH(+)/pMW1, respectively. It is noteworthy that the effect was observed only when bacteria were irradiated with lambda>320 nm light prior MMS-treatment. This finding indicates efficient repair of alkylated DNA in photosensibilized cells in the presence of higher free iron pool and AlkB concentrations. Interestingly, a 31% decrease in the level of Arg(+) reversion was observed in irradiated and MMS-treated hemH(-)alkB(-) cells comparing to the hemH(+)alkB(-) strain. Also, the level of Arg(+) revertants in the irradiated and MMS treated hemH(-) alkB(-) mutant was significantly lower (by 34%) in comparison to the same strain but MMS-treated only. These indicate AlkB independent repair involving Fe ions and reactive oxygen species. According to our hypothesis it may be caused by non-enzymatic dealkylation of alkylated dNTPs in E. coli cells. In in vitro studies, the absence of AlkB protein in the presence of iron ions allowed etheno(epsilon) dATP and epsilondCTP to spontaneously convert to dAMP and dCMP, respectively. Thus, hemH(-) intra cellular conditions may favor Fe-dependent dealkylation of modified dNTPs. PMID- 26114962 TI - The Effects of Irreversible Electroporation on the Achilles Tendon: An Experimental Study in a Rabbit Model. AB - BACKGROUND: To evaluate the potential effects of irreversible electroporation ablation on the Achilles tendon in a rabbit model and to compare the histopathological and biomechanical changes between specimens following electroporation ablation and radiofrequency ablation. METHODS: A total of 140 six month-old male New Zealand rabbits were used. The animals were randomly divided into two groups, 70 in the radiofrequency ablation group and 70 in the electroporation group. In situ ablations were applied directly to the Achilles tendons of rabbits using typical electroporation (1800 V/cm, 90 pulses) and radiofrequency ablation (power control mode) protocols. Histopathological and biomechanical evaluations were performed to examine the effects of electroporation ablation and radiofrequency ablation over time. RESULTS: Both electroporation and radiofrequency ablation produced complete cell ablation in the target region. Thermal damage resulted in tendon rupture 3 days post radiofrequency ablation. In contrast, electroporation-ablated Achilles tendons preserved their biomechanical properties and showed no detectable rupture at this time point. The electroporation-ablated tendons exhibited signs of recovery, including tenoblast regeneration and angiogenesis within 2 weeks, and the restoration of their integral structure was evident within 12 weeks. CONCLUSIONS: When applying electroporation to ablate solid tumors, major advantage could be that collateral damage to adjacent tendons or ligaments is minimized due to the unique ability of electroporation ablation to target the cell membrane. This advantage could have a significant impact on the field of tumor ablation near vital tendons or ligaments. PMID- 26114963 TI - Potential Clinical Uses of CDK Inhibitors: Lessons from Synthetic Lethality Screens. AB - Developments in genetic and genomic technology have produced vast quantities of data that are gradually yielding new insights into fundamental cellular and molecular processes. In particular, they have revealed some differences between normal and transformed cells that could potentially be exploited to develop targeted, personalized cancer therapies with unprecedented efficiencies. This review summarizes recent findings from synthetic lethality (SL) screens against cyclin-dependent kinases (CDKs) that can be targeted with small molecule kinase inhibitors. SL screens can be used to identify cancers sensitive to CDK inhibitors. Several SL partners of specific CDKs have been identified, including MYC, K-Ras, VHL, PI3K, and PARP, all of which are discussed in the review. CDK inhibitors have been in clinical trials for nearly 20 years and it has become clear that effective therapy using these compounds will require careful selection of patients with respect to the specific molecular phenotype of their disease. PMID- 26114965 TI - Outcome measures in neuromuscular disease: is the world still flat? AB - Valid, responsive, and meaningful outcome measures for the measurement of the impairment, activity limitations, and quality of life in patients with neuromuscular disease are crucial to identify the natural history of disease and benefits of therapy in clinical practice and trials. Although understanding of many aspects of neuromuscular diseases has advanced dramatically, the development of outcome measures has received less attention. The scales developed from Rasch theory by the PeriNomS Group represent the biggest significant shift in thought in neuromuscular outcome measures for decades. There remain problems with many of them, and further developments are required. However, incorporating them into our outcome sets for daily use and in clinical trials will lead to the more efficient capture of meaningful change and will result in better assessment of individuals and groups of patients in both clinical trials and neurological practice. PMID- 26114964 TI - A minimalist biosensor: Quantitation of cyclic di-GMP using the conformational change of a riboswitch aptamer. AB - Cyclic di-GMP (c-di-GMP) is a second messenger that is important in regulating bacterial physiology and behavior, including motility and virulence. Many questions remain about the role and regulation of this signaling molecule, but current methods of detection are limited by either modest sensitivity or requirements for extensive sample purification. We have taken advantage of a natural, high affinity receptor of c-di-GMP, the Vc2 riboswitch aptamer, to develop a sensitive and rapid electrophoretic mobility shift assay (EMSA) for c di-GMP quantitation that required minimal engineering of the RNA. PMID- 26114966 TI - Plasmonic Toroidal Dipolar Response under Radially Polarized Excitation. AB - Plasmonic toroidal resonance has attracted growing interests because of its low loss electromagnetic properties and potential high sensitive nanophotonic applications. However, the realization in a metamaterial requires three dimensional complicated structural design so far. In this paper, we design a simple metal-dielectric-metal (MIM) sandwich nanostructure, which exhibits a strong toroidal dipolar resonance under radially polarized excitation. The toroidal dipole moment as the dominant contribution for the scattering is demonstrated by the mirror-image method and further analyzed by Lagrangian hybridization model. The proposed toroidal configuration also shows a highly tolerant for misalignment between the structure center and the incident light focus. Our study proves the way for the toroidal plasmonic application with the cylindrical vector beams. PMID- 26114967 TI - Borinic Acid Catalyzed, Regioselective Chloroacylations and Chlorosulfonylations of 2,3-Epoxy Alcohols. AB - In the presence of a borinic acid derived catalyst, 2,3-epoxy alcohols undergo couplings with acyl and sulfonyl chlorides. This transformation directly generates O-acylated or O-sulfonylated chlorohydrin diols, with significant levels of regioselectivity for both the ring-opening and O-functionalization steps. PMID- 26114968 TI - Percutaneous thermal ablation for primary hepatocellular carcinoma: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Percutaneous thermal ablation using radiofrequency ablation (RFA) and microwave ablation (MWA) are both widely available curative treatments for hepatocellular carcinoma. Despite significant advances, it remains unclear which modality results in better outcomes. This meta-analysis of randomized controlled trials (RCT) and observational studies was undertaken to compare the techniques in terms of effectiveness and safety. METHODS: Electronic reference databases (Medline, EMBASE and Cochrane Central) were searched between January 1980 and May 2014 for human studies comparing RFA and MWA. The primary outcome was the risk of local tumor progression (LTP). Secondary outcomes were complete ablation (CA), overall survival, and major adverse events (AE). The ORs were combined across studies using the random-effects model. RESULTS: Ten studies (two prospective and eight retrospective) were included, and the overall LTP rate was 13.6% (176/1298). There was no difference in LTP rates between RFA and MWA [OR (95% CI): 1.01(0.67-1.50), P = 0.9]. The CA rate, 1- and 3-year overall survival and major AE were similar between the two modalities (P > 0.05 for all). In subgroup analysis, there was no difference in LTP rates according to study quality, but LTP rates were lower with MWA for treatment of larger tumors [1.88(1.10-3.23), P = 0.02]. There was no significant publication bias or inter study heterogeneity (I(2) < 50% and P > 0.1) observed in any of the measured outcomes. CONCLUSION: Overall, both RFA and MWA are equally effective and safe, but MWA may be more effective compared to RFA in preventing LTP when treating larger tumors. Well-designed, larger, multicentre RCTs are required to confirm these findings. PMID- 26114969 TI - Association of Gestational Age at Birth with Reasons for Subsequent Hospitalisation: 18 Years of Follow-Up in a Western Australian Population Study. AB - BACKGROUND: Preterm infants are at a higher risk of hospitalisation following discharge from the hospital after birth. The reasons for rehospitalisation and the association with gestational age are not well understood. METHODS: This was a retrospective birth cohort study of all live, singleton infants born in Western Australia between 1st January 1980 and 31st December 2010, followed to 18 years of age. Risks of rehospitalisation following birth discharge by principal diagnoses were compared for gestational age categories (<32, 32-33, 34-36, 37-38 weeks) and term births (39-41 weeks). Causes of hospitalisations at various gestational age categories were identified using ICD-based discharge diagnostic codes. RESULTS: Risk of rehospitalisation was inversely correlated with gestational age. Growth-related concerns were the main causes for rehospitalisation in the neonatal period (<1 month of age) for all gestational ages. Infection was the most common reason for hospitalisation from 29 days to 1 year of age, and up to 5 years of age. Injury-related hospitalisations increased in prevalence from 5 years to 18 years of age. Risk of rehospitalisation was higher for all preterm infants for most causes. CONCLUSIONS: The highest risks of rehospitalisation were for infection related causes for most GA categories. Compared with full term born infants, those born at shorter GA remain vulnerable to subsequent hospitalisation for a variety of causes up until 18 years of age. PMID- 26114970 TI - Computed Tomography Determined Changes in Position of the Urogenital System After CO2 Insufflation to Determine Optimal Positioning for Abdominal Laparoscopy. AB - OBJECTIVE: To evaluate changes, using computed tomography (CT), in position of the urogenital system before and after CO2 abdominal insufflation for the most commonly used body positions to determine the optimal laparoscopic approach. STUDY DESIGN: Experimental study. ANIMALS: Healthy intact female Beagles (n = 6) of similar age, weight, and body condition score. METHODS: Dogs had urinalysis, peripheral blood smear, and abdominal ultrasonography. Pre-insufflation (PrI) CT scans were performed in ventrodorsal routine (VDR), ventrodorsal Trendelenburg (VDT), left lateral (LL) and right lateral (RL) recumbency, and repeated post insufflation (PoI). Pre-determined measurements were made on PrI and PoI scans and differences compared. RESULTS: The position of the uterus and ovaries was mainly determined by gravitational effects and the attachment of the suspensory ligament. VDT provided best exposure of the uterine body. The kidneys remained in the non-dependent part of the abdomen when the dog was positioned in the opposite lateral position. The bladder remained in the ventral part of the abdomen in all positions. CONCLUSIONS: The best approach to the kidney and associated ovary and uterine horn would be the opposite lateral position to the side being approached. For ovariohysterectomy, this would require the dog to be rotated into each lateral position for the left and right uterine horn and ovary. VDT was best to access the bladder and uterine body. PMID- 26114971 TI - Prioritizing the global research agenda in psoriasis: an International Psoriasis Council Delphi consensus exercise. PMID- 26114972 TI - Resolution of Adsorption and Partition Components of Organic Compounds on Black Carbons. AB - Black carbons (BCs) may sequester non-ionic organic compounds by adsorption and/or partition to varying extents. Up to now, no experimental method has been developed to accurately resolve the combined adsorption and partition capacity of a compound on a BC. In this study, a unique "adsorptive displacement method" is introduced to reliably resolve the adsorption and partition components for a solute-BC system. It estimates the solute adsorption on a BC by the use of an adsorptive displacer to displace the adsorbed target solute into the solution phase. The method is validated by tests with uses of activated carbon as the model carbonaceous adsorbent, soil organic matter as the model carbonaceous partition phase, o-xylene and 1,2,3-trichlorobenzene as the reference solutes, and p-nitrophenol as the adsorptive displacer. Thereafter, the adsorption partition resolution was completed for the two solutes on selected model BCs: four biochars and two National Institute of Standards and Technology (NIST) standard soots (SRM-2975 and SRM-1650b). The adsorption and partition components resolved for selected solutes with given BCs and their dependences upon solute properties enable one to cross-check the sorption data of other solutes on the same BCs. The resolved components also provide a theoretical basis for exploring the potential modes and extents of different solute uptakes by given BCs in natural systems. PMID- 26114973 TI - Measurings. PMID- 26114974 TI - Do Sequential Compression Devices Really Reduce the Risk of Venous Thromboembolism in Plastic Surgery Patients? PMID- 26114975 TI - Reply: Chasing Michelangelo Buonarroti's Greatness. PMID- 26114976 TI - Endoscopic Thoracodorsal Neurectomy for Correction of Animation Deformity following Latissimus Dorsi-Based Breast Reconstruction. PMID- 26114977 TI - Follicular fluid alterations in endometriosis: label-free proteomics by MS(E) as a functional tool for endometriosis. AB - Endometriosis is a chronic gynecological condition that affects 10-32% of women of reproductive age and may lead to infertility. The study of protein profiles in follicular fluid may assist in elucidating possible biomarkers related to this disease. For this, follicular fluid samples were obtained from women with tubal factor or minimal male factor infertility who had pregnancy outcomes after in vitro fertilization (IVF) treatment (control group, n = 10), women with endometriosis (endometriosis group, n = 10), along with the endometrioma from these same patients were included (endometrioma group, n = 10). For proteomic analysis, samples were pooled according to their respective groups and normalized to protein content. Proteins were analyzed by in tandem mass spectrometry (MS(E)) Spectra processing and the ProteinLynx Global Server v.2.5. was used for database searching. Data was submitted to the biological network analysis using Cytoscape 2.8.2 with ClueGO plugin. As a result, 535 proteins were identified among all groups. The control group differentially or uniquely expressed 33 (6%) proteins and equal expression of 98 (18%) proteins was observed in the control and endometriosis groups of which 41 (7%) proteins were further identified and/or quantified. Six (1%) proteins were observed in both the endometriosis and endometrioma groups, but 212 (39%) proteins were exclusively identified and/or quantified in the endometrioma group. There were 9 (1%) proteins observed in both the control and endometrioma groups and there were 139 (25%) proteins common among all three groups. Distinct differences among the protein profiles in the follicular fluid of patients included in this study were found, identifying proteins related to the disease progression and IVF success. Thus, some pathways related to endometriosis are associated with the presence of specific proteins, as well as the absence of others. This study provides a first step to the development of more sensitive diagnostic tests and treatment. PMID- 26114978 TI - Conformance to Depression Process Measures of Medicare Part B Beneficiaries in Primary Care Settings. AB - OBJECTIVES: To evaluate conformance to depression screening, management, and outcome quality indicators and to evaluate individual characteristics associated with conformance to these indicators. DESIGN: Cross-sectional study using electronic health record (EHR) data. SETTING: Thirty-four clinics in one healthcare system. PARTICIPANTS: Medicare beneficiaries aged 65 and older with at least one primary care visit between September 2010 and August 2012 (N = 5,000). MEASUREMENTS: Seven measures, current as of 2013, were found for which all the necessary specifications were available in the EHR: general screening, screening within 4 months of diagnosis, screening after stroke, screening after heart disease, depression reassessment, depression response, and depression remission. Multilevel logistic regression analyses were used to determine factors associated with conformance. RESULTS: Screening for depression in Medicare beneficiaries was low (17%). Conformance to measures varied from 10% for the depression response measure to 77% for the depression remission measure. In the adjusted regression analyses for the general screening (adjusted odds ratio (AOR) = 1.45, 95% confidence interval (CI) = 1.01-2.08), depression reassessment (AOR = 4.19, 95% CI = 1.16-15.19), and screening after heart disease (AOR = 5.57, 95% CI = 1.37 22.57) measures, black participants were more likely to be given care that conformed to the numerator criteria than white participants. A strong site effect was found, with 90% of the depression screens being administered at three sites. CONCLUSION: Only a small proportion of Medicare beneficiaries received the recommended screening and follow-up care needed to conform to the quality measures for depression in the primary care setting. Further evaluation of measures of depression care should be conducted before these measures are implemented widely. PMID- 26114979 TI - Predictive Accuracy of Intraocular Lens Power Calculation: Comparison of Optical Low-Coherence Reflectometry and Immersion Ultrasound Biometry. AB - PURPOSE: To evaluate the accuracy of intraocular lens (IOL) power calculation using an optical low-coherence reflectometry (OLCR) biometer and to compare the results with those obtained with an immersion ultrasound biometry (IUB). METHODS: Biometric measurements were obtained with OLCR and IUB combined with automated keratometry before cataract surgery. The mean prediction error (MPE) and the mean absolute error (MAE) were calculated for five various IOL formulas (SRK II, SRK/T, Holladay, Hoffer Q, and Haigis), and the two different biometry methods were compared. RESULTS: Optical low-coherence reflectometry measured a slightly longer axial length (mean difference, 0.05 mm; P<0.001) and a shallow anterior chamber depth (mean difference, 0.12 mm; P<0.001). With OLCR, the MPEs (+/-SD) calculated by the SRK II, SRK/T, Holladay, Hoffer Q, and Haigis formulas were 0.04 +/- 0.53, -0.04 +/- 0.56, -0.03 +/- 0.53, -0.04 +/- 0.56, and -0.02 +/- 0.56, respectively (P<0.0001). The mean differences (+/- SD) for MAE were statistically significant between OLCR and IUB; SRK II (0.47 +/- 0.44 vs. 0.61 +/ 0.49, P<0.0001), SRK/T (0.39 +/- 0.4 vs. 0.49 +/- 0.45, P=0.0004), Holladay (0.37 +/- 0.37 vs. 0.47 +/- 0.41, P<0.0001), Hoffer Q (0.4 +/- 0.39 vs. 0.5 +/- 0.43, P<0.0001), and Haigis (0.4 +/- 0.39 vs. 0.7 +/- 0.51, P<0.0001). CONCLUSION: The OLCR produces a more predictable refractive outcome than IUB, with patients' spherical equivalent being more likely to be closer to their target refraction. PMID- 26114980 TI - Distress tolerance in social versus solitary college student drinkers. AB - Low distress tolerance has been an inconsistent predictor of alcohol-related consequences in college students, but its relationships to depression and coping motives for alcohol have received stronger support. Research on college students who drink heavily in isolation suggests that this population is more likely to have a greater number and severity of alcohol-related problems, depression, and coping motives. Solitary heavy drinkers were therefore hypothesized to have lower distress tolerance than other drinkers. This study examined differences in self reported and behavioral distress tolerance across two groups of university students: those who endorsed heavy solitary drinking (20.1%) versus those who endorsed other types of drinking. Students completed a self-report measure (Distress Intolerance Self-Report, or DISR) and behavioral measure of distress tolerance (Paced Auditory Serial Addition Test, or PASAT). Students who reported drinking heavily in isolation differed from other students on the DISR, F(1, 132) = 4.645, p = .033, eta(2) = .034, but not on the PASAT, F(1, 132) = 0.056, p = .813. These students also endorsed more coping motives for alcohol. Distress tolerance did not predict drinking consequences directly, yet a mediation model linking distress tolerance to consequences through coping motives supports previous findings of distress tolerance as a distal, indirect predictor of drinking problems. The unique characteristics of solitary binge drinkers and the significance of distress tolerance as an indirect predictor of alcohol-related consequences are discussed. PMID- 26114982 TI - GC/MS profiling, in vitro anti-leptospiral and haemolytic activities of Boesenbergia rotunda (L.) Mansf. used as a medicinal plant by Nicobarese of Andaman and Nicobar Islands. AB - Leaves of the plant Boesenbergia rotunda are used by the Nicobarese tribe of Andaman and Nicobar Islands, India, to prepare traditional medicine for treating fever, headache and body ache. In the present investigation, methanol fraction of these leaves were analysed by GC/MS that revealed the presence of 25 compounds. The anti-leptospiral activity of methanol crude extract was determined by both microdilution and macrodilution methods. The MICs of the extract were tested against 24 pathogenic leptospiral strains and ranged between 62.5-125 MUg/mL in both microdilution and macrodilution. The range of MBCs was 250 and 500 MUg/mL in macrodilution and microdilution respectively. The crude extract was subjected to cytotoxic studies and found to have negligible or no haemolytic activity, exhibiting IC50 values of greater than 4 mg/mL. Further in vivo studies are needed to investigate the pharmacological and toxicological properties of Boesenbergia rotunda, before it can be considered as a new anti-leptospiral agent. PMID- 26114981 TI - Friend or foe: Personal use and friends' use of protective behavioral strategies and spring break drinking. AB - The present study examined associations between use of protective behavioral strategies (PBS) by college students and their friends and drinking-related outcomes during Spring Break (SB). Moreover, this study examined the influence of friends' own PBS use on participants' PBS use during SB. Participants included college students (N = 694) and their nominated friends (N = 131) who were part of a larger study of SB drinking. Data were collected via web-based surveys that participants and friends took after SB, which assessed SB PBS, drinking, and related negative consequences. Results indicated that higher levels of Serious Harm Reduction (SHR) strategies and Limiting/Stopping (LS) strategies were associated with increased consumption, higher likelihood of experiencing any consequences, and an increased number of consequences. A different pattern emerged for Manner of Drinking (MD) strategy use; participants utilizing higher levels of MD strategies drank less and had fewer consequences. LS and MD strategies used by the participant's friends appeared to have less of an impact on the participant's drinking outcomes. However, greater friends' use of SHR strategies was associated with increased alcohol use by the participant, but not with consequences. Greater friends' use of SHR strategies was associated with greater SHR strategy use by the participant. Friends' LS and MD strategies were not associated with participant drinking, consequences, or PBS. These findings highlight the potential utility of interventions that focus on drinking behaviors on specific high-risk occasions for those at risk as well as for their friends. PMID- 26114983 TI - Spinal and Epidural Anesthesia in Patients With Recent Stable Fractures of Vertebral Column. AB - BACKGROUND: The use of central neuraxial block (CNB) in patients with spinal injuries with or without spinal cord injury continues to be a contentious issue due to paucity of evidence supporting or refuting its use. There are only a few case reports reporting the use of the technique in these patients. We performed a retrospective record review of patients who underwent neuraxial blockade for lower limb orthopedic surgery in the presence of coexisting recent spine injury (defined as spine injury within 1 month) to assess the occurrence of postoperative deterioration of spinal cord function or occurrence of new spinal cord dysfunction. MATERIALS AND METHODS: The hospital records of patients with recent stable traumatic fractures of the vertebral column who underwent lower limb orthopedic surgery under CNB from January 2010 to December 2013 were reviewed. Data collected included age, sex, level of fracture, number of vertebrae injured, presence of neurological deficits, interval between injury and surgery, number of surgeries, level of CNB, number of vertebral segments between the site of injury and CNB, position of patient used for CNB and surgery, and perioperative adverse hemodynamic events. All patients underwent detailed postoperative neurological examination and any deterioration or occurrence of new spinal cord dysfunction was noted. RESULTS: Nineteen patients underwent 21 CNBs for lower limb orthopedic procedures. There were 12 men and 7 women. Thoracolumbar area (18/19) was the commonest site of fractures. Two patients had neurological deficits due to cervical spine trauma. More than 50% of the patients had multiple bone fractures and nearly 30% had associated nonorthopedic trauma. Six patients underwent surgery within the first week (4 to 7 d) after trauma. In 80% of the patients, there was a gap of atleast 2 vertebrae between the level of injury and CNB administration. There were no perioperative adverse hemodynamic events requiring prolonged inotropic support. None of the patients had neurological deterioration or new changes. CONCLUSIONS: Spinal and epidural anesthesia in patients with recent stable fractures of the spine was not associated with adverse neurological events. The findings of this study may be particularly relevant to patients with recent stable vertebral fractures who require surgery but present with conditions that place them at high risk for general anesthesia. PMID- 26114984 TI - Venous Air Embolism: New Observations. PMID- 26114985 TI - Sudden Bradycardia and Hypotension in Neurosurgery: Trigeminocardiac Reflex (TCR) and More. PMID- 26114986 TI - Surgical site infections after abdominal surgery: incidence and risk factors. A prospective cohort study. AB - BACKGROUND: Abdominal surgeries have high rates of surgical site infections (SSIs), contributing to increased morbidity and mortality and costs for hospitalization. The aim of this study was to determine the SSI incidence rates and risk factors after abdominal surgeries. METHODS: This prospective cohort study included all patients undergoing abdominal surgeries between 2005 and 2007 in the Western Galilee Medical Center in Nahariya, Israel. SSI incidence rates were calculated per 100 operations. Odds ratios (ORs) were estimated for each risk factor using univariate and multivariate analyses by logistic regression models. RESULTS: Among 302 patients in the study cohort, the total SSI incidence rate was 22.2%. The univariate analysis defined 13 variables significantly associated with SSI: age > 60 years, lower functional status, diabetes mellitus, congestive heart failure, immunocompromising underlying disease, treatment with chemotherapy and other immunosuppressive medications, impaired immune system open cholecystectomy, laparotomy, an American Society of Anesthesiologists (ASA) score > 2, drain insertion, and 'dirty wound' classification. In multivariate regression analysis, treatment with immunosuppressive medications (OR = 2.5, 95% confidence interval (CI) = 1.099-143.443), open cholecystectomy (OR = 2.25, 95% CI = 2.242-40.109), and dirty wound classification (OR = 2.179, 95% CI = 3.80 20.551) were significantly associated with SSI. CONCLUSIONS: The significant risk factors defined should be addressed preoperatively to decrease the risk for SSI. Wound surveillance in the post-discharge period is necessary for correct estimation of SSI rates. PMID- 26114987 TI - Paradoxical response preceding control of Scedosporium apiospermum mycetoma with posaconazole treatment. AB - Mycetoma is a chronic granulomatous infection that is difficult to treat, notably when due to fungi such as Scedosporium apiospermum. Recent antifungal agents could be an option, but cases are rarely reported, and none with posaconazole. Paradoxical responses, defined as initial clinical worsening despite appropriate treatment, are common in tuberculosis but rare in deep mycoses in non immunocompromised hosts. Hence, paradoxical responses in context other than mycobacterial infection in an immunocompromised host could provide insights into the pathophysiology and the optimal strategy for treatment. We report the first case of a mycetoma caused by S. apiospermum with bone involvement treated with posaconazole, and the paradoxical response observed at the beginning of the treatment. As with mycobacterial infections, a paradoxical response in deep mycosis could represent the earliest marker of therapeutic efficacy. PMID- 26114988 TI - Low prevalence of peripheral arterial disease in a cross-sectional study of Danish HIV-infected patients. AB - BACKGROUND: Patients infected with human immunodeficiency virus (HIV) appear to be at increased risk of cardiovascular disease (CVD). The ankle-brachial index (ABI) is a well-established screening tool for peripheral arterial disease (PAD) and future cardiovascular events in the general population. However, controversies exist on the prevalence of PAD among HIV-infected patients. In this study we aimed to measure the prevalence of PAD among HIV-infected patients and compare the ABI with carotid intima-media thickness (cIMT) and other known CVD risk predictors. METHODS: We prospectively included HIV-infected patients from an outpatient clinic at the Department of Infectious Diseases, Hvidovre University Hospital, Denmark. We assessed the ABI pre- and post-exercise with a threshold for PAD defined as ABI <= 0.9. All patients had cIMT measured at the far wall of the distal common carotid artery. RESULTS: Of 102 patients included (mean age 52 years, 75% male, 94% receiving antiretroviral therapy (ART), 33% active smokers), 1 had a pre-exercise ABI <= 0.9 and in addition 3 patients had a post-exercise ABI <= 0.9. We found a poor correlation between ABI and traditional CVD risk factors other than body mass index. In contrast, a strong correlation was found between cIMT and traditional risk factors. Values of post-exercise ABI and cIMT were not correlated. The current ART did not influence ABI values. CONCLUSIONS: We found a low prevalence of PAD in HIV-infected patients. ABI did not correlate with CVD risk factors or cIMT. Based on these results ABI does not seem valuable as a screening tool for CVD among HIV-infected patients. PMID- 26114989 TI - Gait speed in older people: an easy test for detecting cognitive impairment, functional independence, and health state. AB - BACKGROUND: With ageing, physical and cognitive functions become impaired. Analyzing and determining the association between both functions can facilitate the prevention and diagnosis of associated problems. Some previous works have proposed batteries of physical performance tests to determine both physical and cognitive functions. However, only a few studies have used the gait speed (GS) test as a tool to evaluate parameters representative of health in the elderly such as functionality, mobility, independence, autonomy, and comorbidity. Therefore, the aim of this study was to determine the association between physical and cognitive functions in older people (over 65 years old) and to detect the most appropriate physical test to assess cognitive impairment, functional independence, comorbidity, and perceived health in this population. METHODS: One hundred six older adults (38 men, 68 women) participated voluntarily in this cross-sectional study. To assess the physical function handgrip strength, GS, 30-s chair stand tests, and body composition analysis were performed. To evaluate cognitive function, the Mini-Mental State Examination, Barthel index, and Charlson index were employed. No significant differences (P >= 0.05) between sexes were found. RESULTS: Multiple regression analysis of the Mini-Mental State Examination and physical fitness variables, adjusted for age and sex, indicates that GS is a predictor of Mini-Mental State Examination score (R(2) = 0.138). CONCLUSION: The results showed that GS is an important predictor of functional capacity (physical and cognitive function) in adults over 65 years old. PMID- 26114990 TI - Cervicomedullary tumors in children. AB - OBJECT: Cervicomedullary tumors (CMTs) represent a heterogeneous group of intrinsic neoplasms that are typically low grade and generally carry a good prognosis. This single-institution study was undertaken to document the outcomes and current treatment philosophy for these challenging neoplasms. METHODS: The charts of all pediatric patients with CMTs who received treatment at St. Jude Children's Research Hospital between January 1988 and May 2013 were retrospectively reviewed. Demographic, surgical, clinical, radiological, pathological, and survival data were collected. Treatment-free survival and overall survival were estimated, and predictors of recurrence were analyzed. RESULTS: Thirty-one children (16 boys, 15 girls) with at least 12 months of follow-up data were identified. The median age at diagnosis was 6 years (range 7 months-17 years) and the median follow-up was 4.3 years. Low-grade tumors (Grade I or II) were present in 26 (84%) patients. Thirty patients underwent either a biopsy alone or resection, with the majority of patients undergoing biopsy only (n = 12, 39%) or subtotal resection (n = 14, 45%). Only 4 patients were treated solely with resection; 21 patients received radiotherapy alone or in combination with other treatments. Recurrent tumor developed in 14 children (45%) and 4 died as a result of their malignancy. A high-grade pathological type was the only independent variable that predicted recurrence. The 5- and 10-year treatment-free survival estimates are 64.7% and 45.3%, respectively. The 5- and 10-year overall survival estimate is 86.7%. CONCLUSIONS: Children with CMTs typically have low grade neoplasms and consequently long-term survival, but high risk of recurrence. Therapy should be directed at achieving local tumor control while preserving and even restoring neurological function. PMID- 26114991 TI - Surgical treatment of adolescent idiopathic scoliosis in the United States from 1997 to 2012: an analysis of 20,346 patients. AB - OBJECT: Adolescent idiopathic scoliosis (AIS) can cause substantial morbidity and may require surgical intervention. In this study, the authors aimed to evaluate US trends in operative AIS as well as patient comorbidities, operative approach, in-hospital complications, hospital length of stay (LOS), and hospital charges in the US for the period from 1997 to 2012. METHODS: Patients with AIS (ICD-9-CM diagnosis codes 737.30) who had undergone spinal fusion (ICD-9-CM procedure codes 81.xx) from 1997 to 2012 were identified from the Kids' Inpatient Database. Parameters of interest included patient comorbidities, operative approach (posterior, anterior, or combined anteroposterior), in-hospital complications, hospital LOS, and hospital charges. RESULTS: The authors identified 20, 346 patients in the age range of 0-21 years who had been admitted for AIS surgery in the defined study period. Posterior fusions composed 63.4% of procedures in 1997 and 94.1% in 2012 (r = 0.95, p < 0.01). The mean number of comorbidities among all fusion groups increased from 3.0 in 1997 to 4.2 in 2012 (r = 0.92, p = 0.01). The percentage of patients with complications increased from 15.6% in 1997 to 22.3% in 2012 (r = 0.78, p = 0.07). The average hospital LOS decreased from 6.5 days in 1997 to 5.6 days in 2012 (r = -0.86, p = 0.03). From 1997 to 2012, the mean hospital charges (adjusted to 2012 US dollars) for surgical treatment of AIS more than tripled from $55,495 in 1997 to $177,176 in 2012 (r = 0.99, p < 0.01). CONCLUSIONS: Over the 15-year period considered in this study, there was an increasing trend toward using posterior-based techniques for AIS corrective surgery. The number of comorbid conditions per patient and thus the medical complexity of patients treated for AIS have increased. The mean charges for the treatment of AIS have increased, with a national bill over $1.1 billion per year in 2012. PMID- 26114992 TI - SMARCE1 mutations in pediatric clear cell meningioma: case report. AB - Clear cell meningioma (CCM) is an uncommon variant of meningioma. The authors describe a case of a pediatric CCM localized to the lumbar spine. After resection, sequencing revealed an inactivating mutation in the SWI/SNF chromatin remodeling complex subunit SMARCE1, with loss of the second allele in the tumor. The authors present a literature review of this mutation that is associated with CCM and a family history of spine tumors. PMID- 26114993 TI - Pediatric spinal injury in the US: epidemiology and disparities. AB - OBJECT: In the US, race and economic status have pervasive associations with mechanisms of injury, severity of injury, management, and outcomes of trauma. The goal of the current study was to examine these relationships on a large scale in the setting of pediatric spinal injury. METHODS: Admissions for spinal fracture without or with spinal cord injury (SCI), spinal dislocation, and SCI without radiographic abnormality were identified in the Kids' Inpatient Database (KID) and the National Trauma Data Bank (NTDB) registry for 2009. Patients ranged in age from birth up to 21 years. Data from the KID were used to estimate nationwide annual incidences. Data from the NTDB were used to describe patterns of injury in relation to age, race, and payor, with corroboration from the KID. Multiple logistic regression was used to model rates of mortality and spinal fusion. RESULTS: In 2009, the estimated incidence of hospital admission for spinal injury in the US was 170 per 1 million in the population under 21 years of age. The incidence of SCI was 24 per 1 million. Incidences varied regionally. Adolescents predominated. Patterns of injury varied by age, race, and payor. Black patients were more severely injured than patients of other races as measured by Injury Severity Scale scores. Among black patients with spinal injury in the NTDB, 23.9% suffered firearm injuries; only 1% of white patients suffered firearm injuries. The overall mortality rate in the NTDB was 3.9%. In a multivariate analysis that included a large panel of clinical and nonclinical factors, black race retained significance as a predictor of mortality (p = 0.006; adjusted OR 1.571 [1.141 2.163]). Rates of spinal fusion were associated with race and payor in the NTDB data and with payor in the KID: patients with better insurance underwent spinal fusion at higher rates. CONCLUSIONS: The epidemiology of pediatric spinal injury in the US cannot be understood apart from considerations of race and economic status. PMID- 26114994 TI - Safety of neuroangiography and embolization in children: complication analysis of 697 consecutive procedures in 394 patients. AB - OBJECT: The safe treatment of children using catheter-based angiography and embolization poses unique challenges because of the technical factors regarding the size and fragility of access and target vessels, as well as unique pediatric cerebrovascular pathologies. The complication rates for neurointerventional procedures in children have not been established. METHODS: The records of a consecutive cohort of pediatric patients who underwent neuroangiography and/or embolization between 2007 and 2013 were reviewed retrospectively to identify both intraprocedural and postprocedural complications. Demographic and clinical risk factors were analyzed with a multivariate logistic regression model. RESULTS: The 697 consecutive procedures consisted of 429 diagnostic angiograms and 268 embolizations (mean age of patients 11.1 years; range 4 days to 18 years; 217 females). There were 130 intracranial, 122 extracranial, and 16 spinal embolizations. Pathologies included 28 intracranial arteriovenous malformations (AVMs), 12 spinal AVMs, 19 aneurysms, 29 vein of Galen malformations, 29 dural arteriovenous fistulas, 96 extracranial AVMs, 39 tumors, 3 strokes, and 13 others. Overall, 2 intraprocedural and 1 postprocedural complication (0.7%) occurred in the diagnostic group, all of which were nonneurological events. In the embolization group, 7 intraprocedural and 11 postprocedural complications (6.7%) were observed. Of these complications, 15 were nonneurological events (5.6%), 1 was a short-term neurological event (0.4%), and 2 were long-term neurological events (0.7%). CONCLUSIONS: Neither the technical challenges posed by children's access and target vessels nor the unique neuro-vascular pathologies seen in children need result in an elevated morbidity rate related to neuroangiography and embolization. At a dedicated high-volume center, the complication rates may be lower than those for comparable procedures performed in adults. PMID- 26114995 TI - Adverse outcomes of pregnancy in women with non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease in the world, but little is known about its potential association with pregnancy outcomes. We aimed to investigate pregnancy outcomes in NAFLD. METHODS: The Swedish Medical Birth Register (MBR) was used to identify births between 1992 and 2011 (N = 1 960 416). By linkage with the National Patient Register, we identified women with a diagnosis of NAFLD. The MBR was then used to identify outcomes: gestational diabetes, pre-eclampsia, Caesarean section, Apgar score <7 at 5 min, preterm birth (<37 weeks), low birth weight (<2500 g), infants born small for gestational age and congenital malformations. As controls, we used women with no diagnosis for NAFLD divided into two groups; with and without polycystic ovary syndrome (PCOS). Poisson regression was used to estimate relative risks (RRs) adjusted for maternal age, smoking status and body mass index at early pregnancy, parity and prepregnancy diabetes. RESULTS: We identified 110 pregnancies in women with NAFLD. Using women without a diagnosis of NAFLD or PCOS as controls; NAFLD was associated with gestational diabetes [adjusted RRs 2.78; 95% confidence interval (CI): 1.25-6.15], pre-eclampsia (aRR 1.95; 95% CI 1.03-3.70), Caesarean section (aRR 1.52; 95% CI 1.19-1.94), preterm birth (aRR 2.50; 95% CI 1.38-4.55) and with low birth weight (aRR 2.40; 95% CI 1.21-4.78). CONCLUSION: Women with a diagnosis of NAFLD prior to giving birth have increased risks for adverse pregnancy outcome independently of body mass index and diabetes, and should be carefully monitored during antenatal care. PMID- 26114996 TI - Case Management with a Diabetes Team Using Home Telemedicine: Acceptance of Treatment Recommendations by Primary Care Providers in IDEATel. AB - BACKGROUND: The Informatics for Diabetes Education and Telemedicine (IDEATel) project demonstrated that a telemedicine intervention can improve glycemic, lipid, and blood pressure control. The focus of the current study was to evaluate factors associated with primary care providers' (PCPs') decision on whether to follow recommendations from the remote diabetes team in Upstate New York. MATERIALS AND METHODS: In the intervention group, diabetes educators videoconferenced with patients monthly to download and review glucose and blood pressure readings, diabetes-related issues, and laboratory data. These were reviewed with an endocrinologist, and recommendations to change therapy were sent to the PCPs. At annual visits, participants completed the Diabetes Symptom Checklist-Type 2 symptom severity score and Impact of Telemedicine surveys. RESULTS: Factors that increase the acceptance rate of IDEATel recommendations included longer time in the study (p=0.0052), changing medication dose as opposed to starting or stopping a medication (p<0.0001), adjusting glucose-lowering agents compared with antihypertensive or antilipid medications (p<0.0001), higher total Diabetes Symptom Checklist-Type 2 symptom severity score (p=0.045), greater number of glucose readings submitted by participants (p=0.014), and high score on surveys measuring impact of telemedicine on patient's knowledge, adherence, and satisfaction (p=0.0023). CONCLUSIONS: Recommendations for change in glycemic control medications, delivered remotely by a diabetes team to PCPs, were better accepted over time. Results support the use of a team-based telemedicine program to help PCPs improve diabetes care. PMID- 26114997 TI - Oral Presence of Carbohydrate and Caffeine in Chewing Gum: Independent and Combined Effects on Endurance Cycling Performance. AB - The oral presence of carbohydrate (CHO) and caffeine (CAF) may independently enhance exercise performance, but their influence on performance during prolonged exercise is less known. AIM: To determine the independent and combined effects of CHO and CAF administered in chewing gum during a cycling time trial (TT) after prolonged exercise. METHOD: Eleven male cyclists (32.2 +/- 7.5 y, 74.3 +/- 6.8 kg, 60.2 +/- 4.0 mL . kg-1 . min-1 VO2peak) performed 4 experimental trials consisting of 90-min constant-load cycling at 80% of their second ventilatory threshold (207 +/- 30 W), followed immediately by a 20-km TT. Under double blinded conditions, cyclists received placebo (PLA), CHO, CAF, or a combined CHO+CAF chewing gum at 0-, 5-, 10-, and 15-km points of the TT. RESULTS: Overall TT performance was similar across experimental and PLA trials (%mean difference +/- 90%CL 0.2% +/- 2.0%, 0.4% +/- 2.2%, 0.1% +/- 1.8% for CHO, CAF, and CHO+CAF). Compared with PLA, mean power output tended to be higher in the first 2 quarters of the TT with CHO (1.6% +/- 3.1% and 0.8% +/- 2.0%) and was substantially improved in the last 2 quarters during CAF and CHO+CAF trials (4.2% +/- 3.0% and 2.0% +/- 1.8%). There were no differences in average heart rate (ES <0.2) and only small changes in blood glucose (ES 0.2), which were unrelated to performance. Blood lactate was substantially higher post-TT for CAF and CHO+CAF (ES >0.6). CONCLUSION: After prolonged constant-load cycling, the oral presence of CHO and CAF in chewing gum, independently or in combination, did not improve overall performance but did influence pacing. PMID- 26114998 TI - Canine olfaction and electronic nose detection of volatile organic compounds in the detection of cancer: a review. AB - Olfactory cancer detection shows promise as an affordable, precise, and noninvasive way to screen for cancer. This review focuses on two methods of olfactory cancer detection: first, the ability of canines to differentiate between cancerous and healthy individuals through the use of biological samples and second, electronic nose technology that uses chemical sensors to detect known biomarkers in exhaled breath. This review summarizes and critiques past research and outlines future directions to improve understanding of both canine olfaction and electronic nose technology. PMID- 26114999 TI - The developmental race between maturing host plants and their butterfly herbivore - the influence of phenological matching and temperature. AB - Interactions between herbivorous insects and their host plants that are limited in time are widespread. Therefore, many insect-plant interactions result in a developmental race, where herbivores need to complete their development before plants become unsuitable, while plants strive to minimize damage from herbivores by outgrowing them. When spring phenologies of interacting species change asymmetrically in response to climate warming, there will be a change in the developmental state of host plants at the time of insect herbivore emergence. In combination with altered temperatures during the subsequent developmental period, this is likely to affect interaction strength as well as fitness of interacting species. Here, we experimentally explore whether the combined effect of phenological matching and thermal conditions influence the outcome of an insect host interaction. We manipulated both developmental stages of the host plants at the start of the interaction and temperature during the subsequent developmental period in a model system of a herbivorous butterfly, Anthocharis cardamines, and five of its Brassicaceae host plant species. Larval performance characteristics were favoured by earlier stages of host plants at oviposition as well as by higher developmental temperatures on most of the host species. The probability of a larva needing a second host plant covered the full range from no influence of either phenological matching or temperature to strong effects of both factors, and complex interactions between them. The probability of a plant outgrowing a larva was dependent only on the species identity. This study demonstrates that climatic variation can influence the outcome of consumer-resource interactions in multiple ways and that its effects differ among host plant species. Therefore, climate warming is likely to change the temporal match between larval and plant development in some plant species, but not in the others. This is likely to have important implications for host plant use and possibly influence competitive relationships. PMID- 26115000 TI - FEM simulation of tapered cap floating sleeve antenna for hepatocellular carcinoma therapy. AB - Malignant liver tumors are the sixth most common and deadly cancer in the world and the third most common cause of cancer mortality. Hepatocellular carcinoma (primary liver cancer) is one of the most common malignancies worldwide with one of the highest mortality rates. Microwave ablation (MWA) is a new, promising, and multidisciplinary technology designed to destroy unhealthy tissue of various natures by radiating electromagnetic waves with microwave antennas. The finite element method (FEM) has been used in the present work to generate the simulated models of tapered cap floating sleeve antenna for validation of its design concepts, because FEM allows modeling of complex geometries that cannot be solved by analytical methods or finite difference models. The performances have been evaluated in terms of objective metrics, ablation zone, antenna matching, power absorption and SAR pattern. PMID- 26115001 TI - Fruit consumption and adiposity status in adults: A systematic review of current evidence. AB - The aim of this review was to update current understanding of the potential association between fruit consumption and adiposity status in adult populations. Electronic databases were searched from January 1, 1997 to the search date of August 15, 2014, retrieving 4382 abstracts that were reviewed for eligibility: randomized controlled trial (RCT) or prospective cohort (PC), published in English, assessing the effect of whole fruit or fruit juice consumption on adiposity in healthy adult populations. Quality ratings for the 11 included RCTs were either positive (n = 2), neutral (n = 8), or negative (n = 1), while the six included PCs were either positive (n = 4) or neutral (n = 2). Consumption of whole fruit was found to contribute to a reduced risk for long-term weight gain in middle-aged adults. Experimental trials suggest this beneficial effect of whole fruit is mediated by a reduction in total energy intake. Fruit juice, however, had an opposing effect, promoting weight gain over the long term. This review reinforces national food-based dietary guidelines, encouraging the consumption of whole fruits and replacing fruit juices with plain water, as part of a broader set of dietary strategies to reduce total dietary energy intake in adult populations. PMID- 26115002 TI - OMIP-026: Phenotypic analysis of B and plasma cells in rhesus macaques. PMID- 26115003 TI - Poly-Electrophilic Sesquiterpene Lactones from Vernonia amygdalina: New Members and Differences in Their Mechanism of Thiol Trapping and in Bioactivity. AB - In addition to known compounds, the leaves of Vernonia amygdalina afforded the new sesquiterpene lactones 14-O-methylvernolide (2), 3'-deoxyvernodalol (6), and vernomygdalin (8). These and related compounds were evaluated for modulation of a series of thiol trapping-sensitive transcription factors (NF-kappaB, STAT3, and Nrf2), involved in the maintenance of the chronic inflammatory condition typical of human degenerative diseases. Vernolide (1) emerged as a potent inhibitor of STAT3 and NF-kappaB and showed cytostatic activity toward the prostate cancer cell line DU45, arresting the cell cycle at the S phase. The exomethylene lactones are characterized by multiple Michael acceptor sites, as exemplified by vernolide (1) and vernodalol (5). By using the nuclear magnetic resonance-based cysteamine assay, the most reactive thiophilic site could be identified in both compounds, and competitive experiments qualified vernolide (1) as being more thiophilic than vernodalol (5), in agreement with the results of the pharmacological assays. PMID- 26115004 TI - Pathways to Drinking Among Hispanic/Latino Adolescents: Perceived Discrimination, Ethnic Identity, and Peer Affiliations. AB - We examined whether discrimination experienced by Hispanic/Latino adolescents is associated (a) directly with adolescent alcohol use or (b) indirectly with adolescent alcohol use via mediation by ethnic identity and/or peer associations. Data were drawn from an NIAAA-funded randomized controlled trial evaluating the efficacy of a Guided-Self Change intervention for Hispanic/Latino youth with alcohol and interpersonal violence problems (R01 AA12180; see Wagner et al., 2014). The current sample included 371 Hispanic/Latino teenagers (mean age = 16.3 years [SD = 1.37]; 38% female). Using structural equation modeling (SEM), results revealed that perceived discrimination was indirectly related to alcohol consumption through positive (non-drinking) peer affiliations. Additionally, ethnic identity was found to moderate the relationship between discrimination and positive peer affiliation. These findings further our understanding about how discrimination and ethnic identity interact, as well as provide directions for how the effectiveness of prevention models may be enhanced for reducing underage drinking among Hispanic/Latino adolescents. PMID- 26115005 TI - The Association between Obstructive Sleep Apnea and Metabolic Markers and Lipid Profiles. AB - PURPOSE: The purpose of this study was to investigate the association between apnea-hypopnea index (AHI) and metabolic markers and whether the elevated risk of Metabolic Syndrome (MetS) is related to Obstructive Sleep Apnea (OSA). METHODS: This cross-sectional study recruited 246 male bus drivers from one transportation company in Taiwan. Each participant was evaluated by a polysomnography (PSG) test and by blood lipids examination. Severity of OSA was categorized according to the apnea-hypopnea index (AHI). RESULTS: The results showed that a 73.3% prevalence of MetS in OSA (AHI > 15) and a 80.0% prevalence of MetS in severe OSA (AHI > 30) were found. After adjusting for confounding variables, an increased level of Body Mass Index (BMI) and two non-MetS cardiovascular risk factors, total cholesterol/HDL-C ratio and TG/HDL-C ratio was significantly associated with AHI in subjects with severe OSA. MetS was about three times to be present in subjects with severe OSA, even adjusted for BMI. CONCLUSIONS: The findings showed a high prevalence of MetS in OSA among professional drivers, especially in the severe group category. BMI was the major contributing factor to OSA. However, the present study did not find a sensitive clinical marker of a detrimental metabolic profile in OSA patients. PMID- 26115006 TI - Structural and Biochemical Characterization of AidC, a Quorum-Quenching Lactonase with Atypical Selectivity. AB - Quorum-quenching catalysts are of interest for potential application as biochemical tools for interrogating interbacterial communication pathways, as antibiofouling agents, and as anti-infective agents in plants and animals. Herein, the structure and function of AidC, an N-acyl-l-homoserine lactone (AHL) lactonase from Chryseobacterium, is characterized. Steady-state kinetics show that zinc-supplemented AidC is the most efficient wild-type quorum-quenching enzymes characterized to date, with a kcat/KM value of approximately 2 * 10(6) M( 1) s(-1) for N-heptanoyl-l-homoserine lactone. The enzyme has stricter substrate selectivity and significantly lower KM values (ca. 50 MUM for preferred substrates) compared to those of typical AHL lactonases (ca. >1 mM). X-ray crystal structures of AidC alone and with the product N-hexanoyl-l-homoserine were determined at resolutions of 1.09 and 1.67 A, respectively. Each structure displays as a dimer, and dimeric oligiomerization was also observed in solution by size-exclusion chromatography coupled with multiangle light scattering. The structures reveal two atypical features as compared to previously characterized AHL lactonases: a "kinked" alpha-helix that forms part of a closed binding pocket that provides affinity and enforces selectivity for AHL substrates and an active site His substitution that is usually found in a homologous family of phosphodiesterases. Implications for the catalytic mechanism of AHL lactonases are discussed. PMID- 26115007 TI - Estimating reflex responses in large populations of motor units by decomposition of the high-density surface electromyogram. AB - KEY POINTS: Reflex responses of single motor units have been used for the study of spinal circuitries but the methods employed are invasive and limited to the assessment of a relatively small number of motor units. We propose a new approach to investigate reflexes on individual motor units based on high-density surface electromyography (HDsEMG) decomposition. The decomposition of HDsEMG has been previously validated in voluntary isometric contractions but never during reflex activities. The use of HDsEMG decomposition for reflex studies at the individual motor unit level, during constant force contractions, with excitatory and inhibitory stimuli, was validated here by the comparison of results with concurrently recorded intramuscular EMG signals. The validation results showed that HDsEMG decomposition allows an accurate quantification of reflex responses for a large number of individual motor units non-invasively, for both excitatory and inhibitory stimuli. ABSTRACT: We propose and validate a non-invasive method that enables accurate detection of the discharge times of a relatively large number of motor units during excitatory and inhibitory reflex stimulations. High density surface electromyography (HDsEMG) and intramuscular EMG (iEMG) were recorded from the tibialis anterior muscle during ankle dorsiflexions performed at 5%, 10% and 20% of the maximum voluntary contraction (MVC) force, in nine healthy subjects. The tibial nerve (inhibitory reflex) and the peroneal nerve (excitatory reflex) were stimulated with constant current stimuli. In total, 416 motor units were identified from the automatic decomposition of the HDsEMG. The iEMG was decomposed using a state-of-the-art decomposition tool and provided 84 motor units (average of two recording sites). The reflex responses of the detected motor units were analysed using the peri-stimulus time histogram (PSTH) and the peri-stimulus frequencygram (PSF). The reflex responses of the common motor units identified concurrently from the HDsEMG and the iEMG signals showed an average disagreement (the difference between number of observed spikes in each bin relative to the mean) of 8.2 +/- 2.2% (5% MVC), 6.8 +/- 1.0% (10% MVC) and 7.5 +/- 2.2% (20% MVC), for reflex inhibition, and 6.5 +/- 4.1%, 12.0 +/- 1.8% and 13.9 +/- 2.4%, for reflex excitation. There was no significant difference between the characteristics of the reflex responses, such as latency, amplitude and duration, for the motor units identified by both techniques. Finally, reflex responses could be identified at higher force (4 of the 9 subjects performed contraction up to 50% MVC) using HDsEMG but not iEMG, because of the difficulty in decomposing the iEMG at high forces. In conclusion, single motor unit reflex responses can be estimated accurately and non-invasively in relatively large populations of motor units using HDsEMG. This non-invasive approach may enable a more thorough investigation of the synaptic input distribution on active motor units at various force levels. PMID- 26115010 TI - Skeletal Metastasis of Unknown Primary Origin at the Initial Visit: A Retrospective Analysis of 286 Cases. AB - BACKGROUND: Skeletal metastasis is a common metastatic event for several carcinomas, and the treatment for skeletal metastasis of unknown primary (SMUP) are a critical issue in cancer therapy. Making a diagnosis of the primary site is the most crucial step in the treatment of SMUP; however, the procedures are sometimes difficult and time-consuming, and the primary site often remains unknown. Therefore, to establish optimal diagnostic strategies and elucidate the overall survival rates of SMUP, we conducted this retrospective study. METHODS: We retrospectively analyzed the clinical data for 286 SMUP cases from a total of 2,641 patients with skeletal metastases who were treated between 2002 and 2014 at our initiations. RESULTS: The primary sites were identified in 254/286 patients (88.8%), while 32 (11.2%) primary sites were not detected by our diagnostic strategies. Lung cancer was identified in 72 (25.2%) cases, and was the most frequently observed primary lesion. The median survival time of the SMUP patients was 20.0 months, while the median survival times of solitary bone metastasis cases and multi-bone metastasis cases were 39.0 months and 16.0 months, respectively. The median survival times of prostate cancer cases was over 120 months, that of patients with primary lung cancers was 9.0 months and the median survival time of cases who were finally diagnosed with an unknown primary was 11.0 months. CONCLUSIONS: We believe that our study would contribute to establishing an optimal strategy for diagnosing the primary site in SMUP patients, and our data provide definite indications for the survival times for different SMUP situations. PMID- 26115011 TI - Electrochemical and Infrared Spectroscopic Studies Provide Insight into Reactions of the NiFe Regulatory Hydrogenase from Ralstonia eutropha with O2 and CO. AB - The regulatory hydrogenase (RH) from Ralstonia eutropha acts as the H2-sensing unit of a two-component system that regulates biosynthesis of the energy conserving hydrogenases of the organism according to the availability of H2. The H2 oxidation activity, which was so far determined in vitro with artificial electron acceptors, has been considered to be insensitive to O2 and CO. It is assumed that bulky isoleucine and phenylalanine amino acid residues close to the NiFe active site "gate" gas access, preventing molecules larger than H2 interacting with the active site. We have carried out sensitive electrochemical measurements to demonstrate that O2 is in fact an inhibitor of H2 oxidation by the RH, and that both H(+) reduction and H2 oxidation are inhibited by CO. Furthermore, we have demonstrated that the inhibitory effect of O2 arises due to interaction of O2 with the active site. Using protein film infrared electrochemistry (PFIRE) under H2 oxidation conditions, in conjunction with solution infrared measurements, we have identified previously unreported oxidized inactive and catalytically active reduced states of the RH active site. These findings suggest that the RH has a rich active site chemistry similar to that of other NiFe hydrogenases. PMID- 26115012 TI - Forest Gaps Inhibit Foliar Litter Pb and Cd Release in Winter and Inhibit Pb and Cd Accumulation in Growing Season in an Alpine Forest. AB - AIMS: The release of heavy metals (such as Pb and Cd) from foliar litter play an important role in element cycling in alpine forest ecosystems. Although natural forest gaps could play important roles in the release of heavy metals from foliar litter by affecting the snow cover during the winter and solar irradiation during the growing season, few studies have examined these potential roles. The objectives of this study were to document changes in Pb and Cd dynamics during litter decomposition in the center of gaps and under closed canopies and to investigate the factors that controlled these changes during the winter and growing seasons. METHODS: Senesced foliar litter from six dominant species, including Kangding willow (Salix paraplesia), Masters larch (Larix mastersiana), Mingjiang fir (Abies faxoniana), Alpine azalea (Rhododendron lapponicum), Red birch (Betula albosinensis) and Mourning cypress (Sabina saltuaria), was placed in litterbags and incubated between the gap center and closed canopy conditions in an alpine forest in the eastern region of the Tibetan Plateau. The litterbags were sampled at the snow formation stage, snow coverage stage, snow melt stage and during the growing season. The Pb and Cd concentrations in the sampled foliar litter were determined by acid digestion (HNO3/HClO4). IMPORTANT FINDINGS: Over one year of decomposition, Pb accumulation and Cd release from the foliar litter occurred, regardless of the foliar litter species. However, Pb and Cd were both released from the foliar litter during the winter and accumulated during the growing season. Compared with the gap center and the canopy gap edge, the extended gap edge and the closed canopy showed higher Pb and Cd release rates in winter and higher Pb and Cd accumulation rates during the growing season, respectively. Statistical analyses indicate that the dynamics of Pb were significantly influenced by frequent freeze-thaw cycles in winter and appropriate hydrothermal conditions during the growing season, the dynamics of Cd were strongly influenced by species and the presence of a forest gap at different decomposition stages. These results show that forest gaps could inhibit Pb and Cd release from foliar litter in the alpine forest of western Sichuan. In addition, a decrease in the snow depth in the winter warming scenario would promote the release of Pb during foliar litter decomposition. There exist some difference that may be influenced by litter quality, microenvironment and microtopography during litter decomposition. PMID- 26115013 TI - Characterization of Endothelial Progenitor Cell Interactions with Human Tropoelastin. AB - The deployment of endovascular implants such as stents in the treatment of cardiovascular disease damages the vascular endothelium, increasing the risk of thrombosis and promoting neointimal hyperplasia. The rapid restoration of a functional endothelium is known to reduce these complications. Circulating endothelial progenitor cells (EPCs) are increasingly recognized as important contributors to device re-endothelialization. Extracellular matrix proteins prominent in the vessel wall may enhance EPC-directed re-endothelialization. We examined attachment, spreading and proliferation on recombinant human tropoelastin (rhTE) and investigated the mechanism and site of interaction. EPCs attached and spread on rhTE in a dose dependent manner, reaching a maximal level of 56+/-3% and 54+/-3%, respectively. EPC proliferation on rhTE was comparable to vitronectin, fibronectin and collagen. EDTA, but not heparan sulfate or lactose, reduced EPC attachment by 81+/-3%, while full attachment was recovered after add back of manganese, inferring a classical integrin-mediated interaction. Integrin alphaVbeta3 blocking antibodies decreased EPC adhesion and spreading on rhTE by 39+/-3% and 56+/-10% respectively, demonstrating a large contribution from this specific integrin. Attachment of EPCs on N-terminal rhTE constructs N25 and N18 accounted for most of this interaction, accompanied by comparable spreading. In contrast, attachment and spreading on N10 was negligible. alphaVbeta3 blocking antibodies reduced EPC spreading on both N25 and N18 by 45+/-4% and 42+/-14%, respectively. In conclusion, rhTE supports EPC binding via an integrin mechanism involving alphaVbeta3. N25 and N18, but not N10 constructs of rhTE contribute to EPC binding. The regulation of EPC activity by rhTE may have implications for modulation of the vascular biocompatibility of endovascular implants. PMID- 26115014 TI - Pullulanase and Starch Synthase III Are Associated with Formation of Vitreous Endosperm in Quality Protein Maize. AB - The opaque-2 (o2) mutation of maize increases lysine content, but the low seed density and soft texture of this type of mutant are undesirable. Lines with modifiers of the soft kernel phenotype (mo2) called "Quality Protein Maize" (QPM) have high lysine and kernel phenotypes similar to normal maize. Prior research indicated that the formation of vitreous endosperm in QPM might involve changes in starch granule structure. In this study, we focused on analysis of two starch biosynthetic enzymes that may influence kernel vitreousness. Analysis of recombinant inbred lines derived from a cross of W64Ao2 and K0326Y revealed that pullulanase activity had significant positive correlation with kernel vitreousness. We also found that decreased Starch Synthase III abundance may decrease the pullulanase activity and average glucan chain length given the same Zpu1 genotype. Therefore, Starch Synthase III could indirectly influence the kernel vitreousness by affecting pullulanase activity and coordinating with pullulanase to alter the glucan chain length distribution of amylopectin, resulting in different starch structural properties. The glucan chain length distribution had strong positive correlation with the polydispersity index of glucan chains, which was positively associated with the kernel vitreousness based on nonlinear regression analysis. Therefore, we propose that pullulanase and Starch Synthase III are two important factors responsible for the formation of the vitreous phenotype of QPM endosperms. PMID- 26115015 TI - Pre-Pregnancy Body Mass Index, Gestational Weight Gain, and Birth Weight: A Cohort Study in China. AB - OBJECTIVE: To assess whether pre-pregnancy body mass index (BMI) modify the relationship between gestational weight gain (GWG) and child birth weight (specifically, presence or absence of low birth weight (LBW) or presence of absence of macrosomia), and estimates of the relative risk of macrosomia and LBW based on pre-pregnancy BMI were controlled in Wuhan, China. METHODS: From June 30, 2011 to June 30, 2013. All data was collected and available from the perinatal health care system. Logistic regression models were used to estimate the independent association among pregnancy weight gain, LBW, normal birth weight, and macrosomia within different pre-pregnancy BMI groups. We built different logistic models for the 2009 Institute of Medicine (IOM) Guidelines and Chinese-recommended GWG which was made from this sample. The Chinese-recommended GWG was derived from the quartile values (25th-75th percentiles) of weight gain at the time of delivery in the subjects which comprised our sample. RESULTS: For LBW children, using the recommended weight gain of the IOM and Chinese women as a reference, the OR for a pregnancy weight gain below recommendations resulted in a positive relationship for lean and normal weight women, but not for overweight and obese women. For macrosomia, considering the IOM's recommended weight gain as a reference, the OR magnitude for pregnancy weight gain above recommendations resulted in a positive correlation for all women. The OR for a pregnancy weight gain below recommendations resulted in a negative relationship for normal BMI and lean women, but not for overweight and obese women based on the IOM recommendations, significant based on the recommended pregnancy weight gain for Chinese women. Of normal weight children, 56.6% were above the GWG based on IOM recommendations, but 26.97% of normal weight children were above the GWG based on Chinese recommendations. CONCLUSIONS: A GWG above IOM recommendations might not be helpful for Chinese women. We need unified criteria to classify adult BMI and to expand the sample size to improve representation and to elucidate the relationship between GWG and related outcomes for developing a Chinese GWG recommendation. PMID- 26115016 TI - The Self-Assessment of Role-Performance and Activities of Daily Living Abilities (SARATM): Development and Clinical Utility of a Client-Centered Screening Tool and Outcome Measure. AB - This article describes the development and use of the Self-Assessment of Role performance and activities of daily living Abilities (SARATM), a standardized client-centered index of functional abilities. Developed in four phases, this article describes the initial development, pilot testing and revision, examination of psychometric properties, and finalization. Pilot studies found the SARATM to be reliable, valid, and responsive to change. The use of the SARATM in clinical practice and for outcome monitoring promotes client-centered goal setting and client-valued rehabilitation. It is a viable alternative to deficit focused measures. The SARATM is a promising new tool that warrants increased utilization and further research. PMID- 26115017 TI - Cysteine scanning reveals minor local rearrangements of the horizontal helix of respiratory complex I. AB - The NADH:ubiquinone oxidoreductase, respiratory complex I, couples electron transfer from NADH to ubiquinone with the translocation of protons across the membrane. The complex consists of a peripheral arm catalyzing the redox reaction and a membrane arm catalyzing proton translocation. The membrane arm is almost completely aligned by a 110 A unique horizontal helix that is discussed to transmit conformational changes induced by the redox reaction in a piston-like movement to the membrane arm driving proton translocation. Here, we analyzed such a proposed movement by cysteine-scanning of the helix of the Escherichia coli complex I. The accessibility of engineered cysteine residues and the flexibility of individual positions were determined by labeling the preparations with a fluorescent marker and a spin-probe, respectively, in the oxidized and reduced states. The differences in fluorescence labeling and the rotational flexibility of the spin probe between both redox states indicate only slight conformational changes at distinct positions of the helix but not a large movement. PMID- 26115019 TI - Usefulness of Two Clinical Chorioamnionitis Definitions in Predicting Neonatal Infectious Outcomes: A Systematic Review (Podcast). PMID- 26115018 TI - Immediate postpartum insertion of intrauterine device for contraception. AB - BACKGROUND: Women who want to start intrauterine contraception (IUC) during the postpartum period might benefit from IUC insertion immediately after delivery. Postplacental insertion greatly reduces the risk of subsequent pregnancy and eliminates the need for a return visit to start contraception. Without the option of immediate insertion, many women may never return for services or may adopt less effective contraception. OBJECTIVES: Our aim was to examine the outcomes of IUC insertion immediately after placenta delivery (within 10 minutes), especially when compared with insertion at other postpartum times. We focused on successful IUC placement (insertion), subsequent expulsion, and method use. SEARCH METHODS: We searched for trials until 1 April 2015. Sources included PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), POPLINE, Web of Science, EMBASE, LILACS, ClinicalTrials.gov, and ICTRP. For the original review, the authors contacted investigators to identify other trials. SELECTION CRITERIA: We sought randomized controlled trials (RCTs) with at least one treatment arm that involved immediate IUC placement (i.e., within 10 minutes of placenta delivery). Comparison arms could have included early postpartum insertion (from 10 minutes postplacental to hospital discharge) or standard insertion (during a postpartum visit). Trials could also have compared different IUC methods or insertion techniques. Delivery may have been vaginal or cesarean. Primary outcomes were placement (insertion), subsequent expulsion, and method use at study assessment. DATA COLLECTION AND ANALYSIS: For dichotomous outcomes, we used the Mantel-Haenszel odds ratio (OR) with 95% confidence interval (CI). Earlier studies primarily reported results as life-table rates. We aggregated trials in a meta-analysis if they had similar interventions and outcome measures. A sensitivity analysis included studies with moderate or high quality evidence and sufficient outcome data. MAIN RESULTS: We included 15 trials. Seven studies reported from 2010 to 2014 were added to eight from the original 2001 review. Newer trials compared immediate postplacental insertion versus early (10 minutes to 48 hours) or standard insertion (during the postpartum visit). Of four with full reports, three were small trials. The other three studies had conference abstracts. The eight early trials examined immediate insertion of different devices or insertion techniques. Most studies were published in the 1980s, some with limited reporting.Our sensitivity analysis included trials with sufficient outcome data and moderate or high quality evidence. Four newer trials comparing insertion times met the inclusion criteria. Two studies used the levonorgestrel releasing intrauterine system (LNG-IUS) after vaginal delivery. The other two trials placed IUC after cesarean section; one used the CuT 380A intrauterine device (IUD) and the other used the LNG-IUS.A pilot trial compared immediate insertion versus early or standard insertion. In groups comparing immediate versus early insertion (N = 30), all women had the LNG-IUS inserted. By six months, the groups had the same expulsion rate and did not differ significantly in IUC use.For immediate versus standard insertion, we conducted meta-analyses of four trials. Insertion rates did not differ significantly between study arms. However, the trial from Uganda showed insertion was more likely for the immediate group, although the estimate was imprecise. In the meta-analysis, expulsion by six months was more likely for the immediate group, but the confidence interval was wide (OR 4.89, 95% CI 1.47 to 16.32; participants = 210; studies = 4). IUC use at six months was more likely with immediate insertion than with standard insertion (OR 2.04, 95% CI 1.01 to 4.09; participants = 243; studies = 4). Study arms did not differ in use at 3 or 12 months in individual small trials. AUTHORS' CONCLUSIONS: Recent trials compared different insertion times after vaginal or cesarean delivery. Evidence was limited because studies with full reports generally had small sample sizes. Overall, the quality of evidence was moderate; abstracts and older studies had limited reporting. Ongoing trials will add to the evidence, although some are small. Trials of adequate power are needed to estimate expulsion rates and side effects.The benefit of effective contraception immediately after delivery may outweigh the disadvantage of increased risk for expulsion. Frequent prenatal visits during the third trimester provide the opportunity to discuss effective contraceptive methods and desired timing for initiation. Clinical follow-up can help detect early expulsion, as can educating women about expulsion signs and symptoms. PMID- 26115020 TI - Midpregnancy Cervical Length in Nulliparous Women and its Association with Postterm Delivery and Intrapartum Cesarean Delivery. AB - OBJECTIVE: To evaluate the association between midpregnancy cervical length and postterm delivery and cesarean delivery during labor. STUDY DESIGN: In a multicenter cohort study, cervical length was measured in low-risk singleton pregnancies between 16 and 22 weeks of gestation. From this cohort, we identified nulliparous women who delivered beyond 34 weeks and calculated cervical length quartiles. We performed logistic regression to compare the risk of postterm delivery and intrapartum cesarean delivery to cervical length quartiles, using the lowest quartile as a reference. We adjusted for induction of labor, maternal age, ethnicity, cephalic position, preexisting hypertension, and gestational age at delivery. RESULTS: We studied 5,321 nulliparous women. Women with cervical length in the 3rd and 4th quartile were more likely to deliver at 42(+0) to 42(+6) weeks (adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.07 3.79 and aOR 1.97, 95% CI 1.06-3.67, respectively). The frequency of intrapartum cesarean delivery increased with cervical length quartile from 9.4% in the 1st to 14.9% in the 4th quartile (p = 0.01). This increase was only present in intrapartum cesarean delivery because of failure to progress and not because of fetal distress. CONCLUSION: The longer the cervix at midtrimester the higher the risk of both postterm delivery and intrapartum cesarean delivery. PMID- 26115021 TI - Dynamic PCr and pH imaging of human calf muscles during exercise and recovery using (31) P gradient-Echo MRI at 7 Tesla. AB - PURPOSE: Simultaneous acquisition of spatially resolved (31) P-MRI data for evaluation of muscle specific energy metabolism, i.e., PCr and pH kinetics. METHODS: A three-dimensional (3D) gradient-echo sequence for multiple frequency selective excitations of the PCr and Pi signals in an interleaved sampling scheme was developed and tested at 7 Tesla (T). The pH values were derived from the chemical shift-induced phase difference between the resonances. The achieved spatial resolution was ~2 mL with image acquisition time below 6 s. Ten healthy volunteers were studied performing plantar flexions during the delay between (31) P-MRI acquisitions, yielding a temporal resolution of 9-10 s. RESULTS: Signal from anatomically matched regions of interest had sufficient signal-to-noise ratio to allow single-acquisition PCr and pH quantification. The Pi signal was clearly detected in voxels of actively exercising muscles. The PCr depletions were in gastrocnemius 42 +/- 14% (medialis), 48 +/- 17% (lateralis) and in soleus 20 +/- 11%. The end exercise pH values were 6.74 +/- 0.18 and 6.65 +/- 0.27 for gastrocnemius medialis and lateralis, respectively, and 6.96 +/- 0.12 for soleus muscle. CONCLUSION: Simultaneous acquisition of PCr and Pi images with high temporal resolution, suitable for measuring PCr and pH kinetics in exercise recovery experiments, was demonstrated at 7T. This study presents a fast alternative to MRS for quantifying energy metabolism of posterior muscle groups of the lower leg. Magn Reson Med 75:2324-2331, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26115022 TI - Hemorrhagic intramedullary solitary fibrous tumor of the conus medullaris: case report. AB - The differential diagnosis of spinal tumors is guided by anatomical location and imaging characteristics. Diagnosis of rare tumors is made challenging by abnormal features. The authors present the case of a 47-year-old woman who presented with progressive subacute right lower-extremity weakness and numbness of the right thigh. Physical examination further revealed an extensor response to plantar reflex on the right and hyporeflexia of the right Achilles and patellar reflexes. Magnetic resonance imaging of the lumbar spine demonstrated an 8-mm intramedullary exophytic nodule protruding into a hematoma within the conus medullaris. Spinal angiography was performed to rule out an arteriovenous malformation, and resection with hematoma evacuation was completed. Pathological examination of the resected mass demonstrated a spindle cell neoplasm with dense bundles of collagen. Special immunostaining was performed and a diagnosis of solitary fibrous tumor (SFT) was made. SFTs are mesenchymally derived pleural neoplasms, which rarely present at other locations of the body, but have been increasingly described to occur as primary neoplasms of the spine and CNS. The authors believe that this case is unique in its rare location at the level of the conus, and also that this is the first report of a hemorrhagic SFT in the spine. Therefore, with this report the authors add to the literature the fact that this variant of an increasingly understood but heterogeneous tumor can occur, and therefore should be considered in the differential of clinically similar tumors. PMID- 26115023 TI - Surgical outcomes of 156 spinal accessory nerve injuries caused by lymph node biopsy procedures. AB - OBJECT: Iatrogenic injuries to the spinal accessory nerve (SAN) are not uncommon during lymph node biopsy of the posterior cervical triangle (PCT). In this study, the authors review the operative techniques and surgical outcomes of 156 surgical repairs of the SAN following iatrogenic injury during lymph node biopsy procedures. METHODS: This retrospective study examines the authors' clinical and surgical experience with 156 patients with SAN injury between 1980 and 2012. All patients suffered iatrogenic SAN injuries during lymph node biopsy, with the vast majority (154/156, 98.7%) occurring in Zone I of the PCT. Surgery was performed on the basis of anatomical and electro-physiological findings at the time of the operation. The mean follow-up period was 24 months (range 8-44 months). RESULTS: Of the 123 patients who underwent graft or suture repair, 107 patients (87%) improved to Grade 3 functionality or higher using the Louisiana State University Health Science Center (LSUHSC) grading system. Neurolysis was performed in 29 patients (19%) when the nerve was found in continuity with recordable nerve action potential (NAP) across the lesion. More than 95% of patients treated by neurolysis with positive NAP recordings recovered to LSUHSC Grade 3 or higher. Forty-one patients (26%) underwent end-to-end repair, while 82 patients (53%) underwent graft repair, and Grade 3 or higher recovery was assessed for 90% and 85% of these patients, respectively. The average graft length used was 3.81 cm. Neurotization was performed in 4 patients, 2 of whom recovered to Grade 2 and 3, respectively. CONCLUSIONS: SAN injuries present challenges for surgical exploration and repair because of the nerve's size and location in the PCT. However, through proper and timely intervention, patients with diminished or absent function achieved favorable functional outcomes. Surgeons performing lymph node biopsy procedures in Zone I of the PCT should be aware of the potential risk of injury to the SAN. PMID- 26115024 TI - Microvascular anatomy of spinal dural arteriovenous fistulas: arteriovenous connections and their relationships with the dura mater. AB - OBJECT The microvascular anatomy of spinal dural arteriovenous fistulas (AVFs), especially the relationships of the vessels with the dura mater, has yet to be angiographically demonstrated in detail and proven histologically. METHODS From January 2012 through April 2014, a total of 7 patients with spinal dural AVFs in the thoracic region underwent open microsurgical obliteration at Tokyo Metropolitan Neurological Hospital. The microvascular anatomy of spinal dural AVFs was comprehensively assessed by using advanced microangiography, including 3D computer graphics and intraoperative indocyanine green video angiography, and by histological findings. RESULTS The 2 microangiography techniques revealed the spatial course and in vivo blood flow of the meningeal vessels and their relationships with the dura mater in sufficient detail. The meningeal branch of the intercostal artery split into multiple meningeal vessels on the outer dural surface adjacent to the root sleeve. After crossing the dura mater to the inner dural surface, these vessels gathered and joined a single intradural draining vessel. On the inner dural surface, the single draining vessel was fed by the surrounding multiple meningeal vessels, which appeared to be caput medusae. Histological findings revealed that the structure of the meningeal branch of the intercostal artery corresponded to that of a normal artery. The structure of intradural draining vessels corresponded to that of a vein modified by retrograde arterial inflow. On the inner dural surface, more than 1 meningeal artery gathered and joined with the proximal radiculomedullary vein. CONCLUSIONS Spinal dural AVFs are located on the inner dural surface, where multiple direct AV connections between more than 1 meningeal feeding artery and a single proximal radiculomedullary vein occur at the site where the vein connects to the dura mater. PMID- 26115025 TI - Minimally invasive resection of lumbar intraspinal synovial cysts via a contralateral approach: review of 13 cases. AB - OBJECT: The authors sought to determine patient-related outcomes after minimally invasive surgical (MIS) lumbar intraspinal synovial cyst excision via a tubular working channel and a contralateral facet-sparing approach. METHODS: All the patients with a symptomatic lumbar intraspinal synovial cyst who underwent surgery at the University of Iowa Hospitals and Clinics with an MIS excision via a contralateral approach were treated between July 2010 and August 2014. There was a total of 13 cases. Each patient was evaluated with preoperative neurological examinations, lumbar spine radiography, MRI, and visual analog scale (VAS) scores. The patients were evaluated postoperatively with neurological examinations and VAS and Macnab scores. The primary outcomes were improvement in VAS and Macnab scores. Secondary outcomes were average blood loss, hospital stay duration, and operative times. RESULTS: There were 5 males and 8 females. The mean age was 66 years, and the mean body mass index was 28.5 kg/m(2). Sixty-nine percent (9 of 13) of the cysts were at L4-5. Most patients had low-back pain and radicular pain, and one-third of them had Grade 1 spondylolisthesis. The mean (+/ SD) follow-up duration was 20.8 +/- 16.9 months. The mean Macnab score was 3.4 +/- 1.0, and the VAS score decreased from 7.8 preoperatively to 2.9 postoperatively. The mean operative time was 123 +/- 30 minutes, with a mean estimated blood loss of 44 +/- 29 ml. Hospital stay averaged 1.5 +/- 0.7 days. There were no complications noted in this series. CONCLUSIONS: The MIS excision of lumbar intraspinal synovial cysts via a contralateral approach offers excellent exposure to the cyst and spares the facet joint at the involved level, thus minimizing risk of instability, blood loss, operative time, and hospital stay. Prospective randomized trials with longer follow-up times and larger cohorts are needed to conclusively determine the superiority of the contralateral MIS approach over others, including open or ipsilateral minimally invasive surgery. PMID- 26115026 TI - Challenges in early operative approaches to intramedullary spinal cord tumors: Harvey Cushing's perspective. AB - Although Harvey Cushing was mostly known for his contributions to brain tumor surgery, he was also a pioneer in the development of spinal cord surgery. This lesser known facet of Cushing's career can provide a fresh and unique perspective into how the founders of neurosurgery surmounted early challenges in the field. The authors bring to light and examine for the first time Cushing's unpublished writing "Technique of Laminectomy" along with his first 3 documented intramedullary spinal cord tumor (IMSCT) cases at the Johns Hopkins Hospital. The authors draw lessons from the challenges in pathological classification, preoperative diagnosis, tumor localization, and surgical technique of that time. Although Cushing's attempts at exploration and resection of IMSCT as described here were of limited success, his ability to adapt his clinical and surgical technique to the challenges of the time, as well as develop skills to successfully manipulate the spinal cord during these exploratory procedures without the patients incurring neurological damage, postoperative infection, or complications, is a testament to his determination to advance the field and his meticulous operative technique. In spite of the limitations imposed on the pioneer neurosurgeons, Harvey Cushing and his contemporaries persevered through many of the challenges and built an essential part of neurosurgery's common story. PMID- 26115027 TI - Rechecking the Centrality-Lethality Rule in the Scope of Protein Subcellular Localization Interaction Networks. AB - Essential proteins are indispensable for living organisms to maintain life activities and play important roles in the studies of pathology, synthetic biology, and drug design. Therefore, besides experiment methods, many computational methods are proposed to identify essential proteins. Based on the centrality-lethality rule, various centrality methods are employed to predict essential proteins in a Protein-protein Interaction Network (PIN). However, neglecting the temporal and spatial features of protein-protein interactions, the centrality scores calculated by centrality methods are not effective enough for measuring the essentiality of proteins in a PIN. Moreover, many methods, which overfit with the features of essential proteins for one species, may perform poor for other species. In this paper, we demonstrate that the centrality-lethality rule also exists in Protein Subcellular Localization Interaction Networks (PSLINs). To do this, a method based on Localization Specificity for Essential protein Detection (LSED), was proposed, which can be combined with any centrality method for calculating the improved centrality scores by taking into consideration PSLINs in which proteins play their roles. In this study, LSED was combined with eight centrality methods separately to calculate Localization specific Centrality Scores (LCSs) for proteins based on the PSLINs of four species (Saccharomyces cerevisiae, Homo sapiens, Mus musculus and Drosophila melanogaster). Compared to the proteins with high centrality scores measured from the global PINs, more proteins with high LCSs measured from PSLINs are essential. It indicates that proteins with high LCSs measured from PSLINs are more likely to be essential and the performance of centrality methods can be improved by LSED. Furthermore, LSED provides a wide applicable prediction model to identify essential proteins for different species. PMID- 26115028 TI - The potential of the riboSNitch in personalized medicine. AB - RNA conformation plays a significant role in stability, ligand binding, transcription, and translation. Single nucleotide variants (SNVs) have the potential to disrupt specific structural elements because RNA folds in a sequence specific manner. A riboSNitch is an element of RNA structure with a specific function that is disrupted by an SNV or a single nucleotide polymorphism (SNP; or polymorphism; SNVs occur with low frequency in the population, <1%). The riboSNitch is analogous to a riboswitch, where binding of a small molecule rather than mutation alters the structure of the RNA to control gene regulation. RiboSNitches are particularly relevant to interpreting the results of genome-wide association studies (GWAS). Often GWAS identify SNPs associated with a phenotype mapping to noncoding regions of the genome. Because a majority of the human genome is transcribed, significant subsets of GWAS SNPs are putative riboSNitches. The extent to which the transcriptome is tolerant of SNP-induced structure change is still poorly understood. Recent advances in ultra high throughput structure probing begin to reveal the structural complexities of mutation-induced structure change. This review summarizes our current understanding of SNV and SNP-induced structure change in the human transcriptome and discusses the importance of riboSNitch discovery in interpreting GWAS results and massive sequencing projects. PMID- 26115030 TI - A Novel Locus for Ectodermal Dysplasia of Hair, Nail and Skin Pigmentation Anomalies Maps to Chromosome 18p11.32-p11.31. AB - Ectodermal dysplasias (EDs) are a large heterogeneous group of inherited disorders exhibiting abnormalities in ectodermally derived appendages such as hair, nails, teeth and sweat glands. EDs associated with reticulated pigmentation phenotype are rare entities for which the genetic basis and pathophysiology are not well characterized. The present study describes a five generation consanguineous Pakistani family segregating an autosomal recessive form of a novel type of ectodermal dysplasia. The affected members present with sparse and woolly hair, severe nail dystrophy and reticulate skin pigmentation. After exclusion of known gene loci related with other skin disorders, genome-wide linkage analysis was performed using Illumina HumanOmniExpress beadchip SNP arrays. We linked this form of ED to human chromosome 18p11.32-p11.31 flanked by the SNPs rs9284390 (0.113Mb) and rs4797100 (3.14 Mb). A maximum two-point LOD score of 3.3 was obtained with several markers along the disease interval. The linkage interval of 3.03 Mb encompassed seventeen functional genes. However, sequence analysis of all these genes did not discover any potentially disease causing-variants. The identification of this novel locus provides additional information regarding the mapping of a rare form of ED. Further research, such as the use of whole-genome sequencing, would be expected to reveal any pathogenic mutation within the disease locus. PMID- 26115029 TI - Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs. AB - The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti wing antibodies confer 90 and 100% protection, respectively, one hour post exposure in mice challenged with MARV. PMID- 26115031 TI - Monolayers of poly-L-lysine on mica--Electrokinetic characteristics. AB - Physicochemical properties of poly-l-lysine and its monolayers on mica were thoroughly investigated by dynamic light scattering, electrokinetic methods and atomic force microscopy. The hydrodynamic diameter of PLL was equal to 25.5 nm within a wide range of pH and ionic strength. The electrophoretic measurements revealed that the molecules are positively charged for pH<10.5. By exploiting the electrophoretic mobility data, theelectrokinetic charge on the PLL molecules and their zeta potential were calculated. PLL monolayers of controlled coverage were deposited on mica under diffusion-controlled conditions by varying PLL bulk concentration and adsorption time. The electrokinetic characteristics of the monolayers were acquired in situ via streaming potential measurements. These studies allowed to uniquely determine the zeta potential of the monolayers as a function of pH and ionic strength. In this way the isoelectric point of the monolayers can be determined in a more convenient way compared to bulk measurements disturbed by the PLL molecule interactions. The stability of the monolayers under flow conditions was quantitatively evaluated via streaming potential measurements. The adsorption constant and the binding energy depth of PLL molecules were determined for different ionic strengths. These parameters indicate that the PLL monolayers remain stable over prolonged times. PMID- 26115032 TI - Immediate and Long-Term Outcome of Acute H2S Intoxication Induced Coma in Unanesthetized Rats: Effects of Methylene Blue. AB - BACKGROUND: Acute hydrogen sulfide (H2S) poisoning produces a coma, the outcome of which ranges from full recovery to severe neurological deficits. The aim of our study was to 1--describe the immediate and long-term neurological effects following H2S-induced coma in un-anesthetized rats, and 2--determine the potential benefit of methylene blue (MB), a compound we previously found to counteract acute sulfide cardiac toxicity. METHODS: NaHS was administered IP in un-sedated rats to produce a coma (n = 34). One minute into coma, the rats received MB (4 mg/kg i.v.) or saline. The surviving rats were followed clinically and assigned to Morris water maze (MWM) and open field testing then sacrificed at day 7. RESULTS: Sixty percent of the non-treated comatose rats died by pulseless electrical activity. Nine percent recovered with neurological deficits requiring euthanasia, their brain examination revealed major neuronal necrosis of the superficial and middle layers of the cerebral cortex and the posterior thalamus, with variable necrosis of the caudate putamen, but no lesions of the hippocampus or the cerebellum, in contrast to the typical distribution of post-ischemic lesions. The remaining animals displayed, on average, a significantly less effective search strategy than the control rats (n = 21) during MWM testing. Meanwhile, 75% of rats that received MB survived and could perform the MWM test (P<0.05 vs non-treated animals). The treated animals displayed a significantly higher occurrence of spatial search than the non-treated animals. However, a similar proportion of cortical necrosis was observed in both groups, with a milder clinical presentation following MB. CONCLUSION: In conclusion, in rats surviving H2S induced coma, spatial search patterns were used less frequently than in control animals. A small percentage of rats presented necrotic neuronal lesions, which distribution differed from post-ischemic lesions. MB dramatically improved the immediate survival and spatial search strategy in the surviving rats. PMID- 26115034 TI - Assessment of Double Outlet Right Ventricle Associated with Multiple Malformations in Pediatric Patients Using Retrospective ECG-Gated Dual-Source Computed Tomography. AB - PURPOSE: To evaluate the feasibility and diagnostic accuracy of retrospective electrocardiographically (ECG)-gated dual-source computed tomography (DSCT) for the assessment of double outlet right ventricle (DORV) and associated multiple malformations in pediatric patients. MATERIALS AND METHODS: Forty-seven patients <10 years of age with DORV underwent retrospective ECG-gated DSCT. The location of the ventricular septal defect (VSD), alignment of the two great arteries, and associated malformations were assessed. The feasibility of retrospective ECG gated DSCT in pediatric patients was assessed, the image quality of DSCT and the agreement of the diagnosis of associated malformations between DSCT and transthoracic echocardiography (TTE) were evaluated, the diagnostic accuracies of DSCT and TTE were referred to surgical results, and the effective doses were calculated. RESULTS: Apart from DORV, 109 associated malformations were confirmed postoperatively. There was excellent agreement (kappa = 0.90) for the diagnosis of associated malformations between DSCT and TTE. However, DSCT was superior to TTE in demonstrating paracardiac anomalies (sensitivity, coronary artery anomalies: 100% vs. 80.00%, anomalies of great vessels: 100% vs. 88.57%, separate thoracic and abdominal anomalies: 100% vs. 76.92%, respectively). Combined with TTE, DSCT can achieve excellent diagnostic performance in intracardiac anomalies (sensitivity, 91.30% vs. 100%). The mean image quality score was 3.70 +/- 0.46 (kappa = 0.76). The estimated mean effective dose was < 1 mSv (0.88 +/- 0.34 mSv). CONCLUSIONS: Retrospective ECG-gated DSCT is a better diagnostic tool than TTE for pediatric patients with complex congenital heart disease such as DORV. Combined with TTE, it may reduce or even obviate the use of invasive cardiac catheterization, and thus expose the patients to a much lower radiation dose. PMID- 26115033 TI - Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood. AB - BACKGROUND: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk. OBJECTIVES: The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development. METHODS: Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression. RESULTS: Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (beta = 0.0014; 95% CI: -0.0023, -0.0005, p = 0.002), stronger in males (beta = -0.0024; 95% CI: -0.0038, -0.0009, p = 0.003) than in females (beta = -0.0009; 95% CI: 0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (beta = -0.0013; 95% CI: 0.0023, -0.0003, p = 0.01) DMR methylation, but primarily in females, (beta = 0.0017; 95% CI: -0.0029, -0.0006, p = 0.005) rather than in males, (beta = 0.0004; 95% CI: -0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (beta = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months. CONCLUSIONS: Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood. CITATION: Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL, Hoyo C. 2016. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect 124:666-673; http://dx.doi.org/10.1289/ehp.1408577. PMID- 26115035 TI - Snakebites in Two Rural Districts in Lao PDR: Community-Based Surveys Disclose High Incidence of an Invisible Public Health Problem. AB - BACKGROUND: The Lao PDR (Laos) is one of the least developed countries in Asia with an estimated 25% of the population living in poverty. It is the habitat of some highly venomous snakes and the majority of the population earns their living from agricultural activities. Under these circumstances the incidence of snakebites is expected to be high. METHODS: Two cross-sectional, community-based surveys were performed in Champone and Phin district, Savannakhet province, Lao PDR to estimate snakebite incidence. Multistage random sampling was used. In the first stage approximately 40% of all villages in each district were randomly selected. In the second stage 33% of all households in each village were randomly chosen. Members of the selected households were interviewed about snakebites during the previous 12 months. RESULTS: Thirty-five of 9856 interviewees reported a snakebite in a 12 month period in Champone district and 79 of 7150 interviewees in Phin district. The estimated incidence is 355 snakebites per 100,000 persons per year and 1105 per 100,000 in Champone and Phin district respectively. All snakebite victims received treatment by traditional healers or self-treatment at home and nobody went to a hospital. Incidence of snakebites, calculated on the basis of hospital records of 14 district hospitals and Savannakhet provincial hospital, ranged from 3 to 14 cases per 100,000 persons per year between 2012 and 2014. CONCLUSION: Incidence of snakebites is high in rural communities in Laos with significant regional differences. Poverty most likely contributes significantly to the higher number of snakebites in Phin district. Hospital statistics profoundly underestimates snakebite incidence, because the majority of snakebite victims receive only treatment by traditional healers or self-treatment in their village. There is an urgent need to train medical staff and students in management of snakebite patients and make snake antivenom available to cope effectively with this important public health problem in order to prevent fatalities and disabilities. PMID- 26115036 TI - Determination of free and glucosidically-bound volatiles in plants. Two case studies: L-menthol in peppermint (Mentha x piperita L.) and eugenol in clove (Syzygium aromaticum (L.) Merr. & L.M.Perry). AB - This study arises from both the today's trend towards exploiting plant resources exhaustively, and the wide quantitative discrepancy between the amounts of commercially-valuable markers in aromatic plants and those recovered from the related essential oil. The study addresses the determination of both the qualitative composition and the exhaustive distribution of free and glucosidically-bound L-menthol in peppermint aerial parts (Mentha x piperita L., Lamiaceae) and of eugenol in dried cloves (Syzygium aromaticum (L.) Merr. & L.M.Perry, Myrtaceae), two plants known to provide widely ranging essential oil yields. The two markers were investigated in essential oils and residual hydrodistillation waters, before and after enzymatic hydrolysis. Their amounts were related to those in the headspace taken as reference. The results showed that the difference between marker compound in headspace and in essential oil amounted to 22.8% for L-menthol in peppermint, and 16.5% for eugenol in cloves. The aglycones solubilised in the residual hydrodistillation waters were 7.2% of the headspace reference amount for L-menthol, and 13.3% for eugenol, respectively representing 9.3% and 15.9% of their amounts in the essential oil. The amount of L-menthol from its glucoside in residual hydrodistillation waters was 20.6% of that in the related essential oil, while eugenol from its glucoside accounted for 7.7% of the amount in clove essential oil. The yield of L-menthol, after submitting the plant material to enzymatic hydrolysis before hydrodistillation, increased by 23.1%, and for eugenol the increase was 8.1%, compared to the amount in the respective conventional essential oils. This study also aimed to evaluate the reliability of recently-introduced techniques that are little applied, if at all, in this field. The simultaneous use of high-concentration-capacity sample preparation techniques (SBSE, and HS-SPME and in-solution SPME) to run quali quantitative analysis without sample manipulation, and direct LC-MS glucoside analysis, provided cross-validation of the results. PMID- 26115038 TI - Codon-Optimized NADH Oxidase Gene Expression and Gene Fusion with Glycerol Dehydrogenase for Bienzyme System with Cofactor Regeneration. AB - NADH oxidases (NOXs) play an important role in maintaining balance of NAD+/NADH by catalyzing cofactors regeneration. The expression of nox gene from Lactobacillus brevis in Escherichia coli BL21 (BL21 (DE3)) was studied. Two strategies, the high AT-content in the region adjacent to the initiation codon and codon usage of the whole gene sequence consistent with the host, obtained the NOX activity of 59.9 U/mg and 73.3 U/mg (crude enzyme), with enhanced expression level of 2.0 and 2.5-folds, respectively. Purified NOX activity was 213.8 U/mg. Gene fusion of glycerol dehydrogenase (GDH) and NOX formed bifuctional multi enzymes for bioconversion of glycerol coupled with coenzyme regeneration. Kinetic parameters of the GDH-NOX for each substrate, glycerol and NADH, were calculated as Vmax(Glycerol) 20 MUM/min, Km(Glycerol) 19.4 mM, Vmax (NADH) 12.5 MUM/min and Km (NADH) 51.3 MUM, respectively, which indicated the potential application of GDH-NOX for quick glycerol analysis and dioxyacetone biosynthesis. PMID- 26115039 TI - The Val30Met familial amyloid polyneuropathy specific Rasch-built overall disability scale (FAP-RODS((c)) ). AB - Familial amyloid polyneuropathy (FAP) is a chronic debilitating multi-organic disorder, mainly assessed using ordinal-based impairment measures. To date, no outcome measure at the activity and participation level has been constructed in FAP. The current study aimed to design an interval activity/participation scale for FAP through Rasch methodology. A preliminary FAP Rasch-built overall disability scale (pre-FAP-RODS) containing 146 activity/participation items was assessed twice (interval: 2-4 week; test-retest reliability) in 248 patients with Val30Met FAP examined in Porto, Portugal, of which 65.7% have received liver transplantation. An ordinal-based 24-item FAP-symptoms inventory questionnaire (FAP-SIQ) was also assessed (validity purposes). The pre-FAP-RODS and FAP-SIQ data were subjected to Rasch analyses. The pre-FAP-RODS did not meet model's expectations. On the basis of requirements such as misfit statistics, differential item functioning, and local dependency, items were systematically removed until a final 34-item FAP-RODS((c)) was constructed fulfilling all Rasch requirements. Acceptable reliability/validity scores were demonstrated. In conclusion, the 34-item FAP-RODS((c)) is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FAP. The use of the FAP-RODS((c)) is recommended for future international clinical trials in patients with Val30Met FAP determining its responsiveness and its cross-cultural validation. Its expansion to other forms of FAP should also be focus of future clinical studies. PMID- 26115037 TI - Mouse models of colorectal cancer as preclinical models. AB - In this review, we discuss the application of mouse models to the identification and pre-clinical validation of novel therapeutic targets in colorectal cancer, and to the search for early disease biomarkers. Large-scale genomic, transcriptomic and epigenomic profiling of colorectal carcinomas has led to the identification of many candidate genes whose direct contribution to tumourigenesis is yet to be defined; we discuss the utility of cross-species comparative 'omics-based approaches to this problem. We highlight recent progress in modelling late-stage disease using mice, and discuss ways in which mouse models could better recapitulate the complexity of human cancers to tackle the problem of therapeutic resistance and recurrence after surgical resection. PMID- 26115040 TI - It's Not Easy Being Blue: Are There Olfactory and Visual Trade-Offs in Plant Signalling? AB - Understanding the signals used by plants to attract seed disperses is a pervasive quest in evolutionary and sensory biology. Fruit size, colour, and odour variation have long been discussed in the controversial context of dispersal syndromes targeting olfactory-oriented versus visually-oriented foragers. Trade offs in signal investment could impose important physiological constraints on plants, yet have been largely ignored. Here, we measure the reflectance and volatile organic compounds of a community of Malagasy plants and our results indicate that extant plant signals may represent a trade-off between olfactory and chromatic signals. Blue pigments are the most visually-effective--blue is a colour that is visually salient to all known seed dispersing animals within the study system. Additionally, plants with blue-reflecting fruits are less odiferous than plants that reflect primarily in other regions of the colour spectrum. PMID- 26115042 TI - Three-Component Functionalized Dihydropyridine Synthesis via a Formal Inverse Electron-Demand Hetero-Diels-Alder Reaction. AB - A mild three-component synthetic approach to versatile 2-amino-1,4 dihydropyridines from terminal alkynes, sulfonyl azides, and N-sulfonyl-1-aza-1,3 butadienes was successfully developed and relied on the in situ generation of metalated ynamide intermediates Ib to achieve a formal inverse electron-demand hetero-Diels-Alder reaction. Experimental results suggest that alkali metal cations (Li(+) and Cs(+) ions) might play a critical role to achieve the cycloaddition process. PMID- 26115041 TI - SNP rs2057482 in HIF1A gene predicts clinical outcome of aggressive hepatocellular carcinoma patients after surgery. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) plays an important role in tumor growth and metastasis. Genetic variations of HIF1A gene have been shown to influence the developing risk and prognosis in many types of human malignancies. However, their association with clinical outcomes of hepatocellular carcinoma (HCC) patients remains unclear. To investigate the predictive role of single nucleotide polymorphisms (SNPs) in HIF1A gene in HCC patients' outcomes, we genotyped three functional SNPs (rs2057482, rs1957757 and rs2301113) in HIF1A gene and assessed their associations with clinicopathological parameters and prognosis of 492 surgical HCC patients. The patients with variant alleles (CT+TT) of SNP rs2057482 had a significantly lower recurrence risk when compared with patients with the CC genotype. In stratified analysis, the protective effect of rs2057482 CT+TT genotype was more evident in patients with adverse strata, compared with patients with favorable strata. Additionally, strong joint predictive effect between rs2057482 genotypes and AFP level, stage or differentiation were observed. Functional assay also indicated the significant effect of rs2057482 on gene expression. In conclusion, SNP rs2057482 in HIF1A gene is significantly associated with clinical outcomes of Chinese HCC patients after surgery, especially in those with aggressive status, which warrants further validation in other patient populations. PMID- 26115043 TI - Correction: Genetic Mechanism of Human Neutrophil Antigen 2 Deficiency and Expression Variations. PMID- 26115044 TI - Efficacy and safety of bone marrow-derived cell transplantation for spinal cord injury: a systematic review and meta-analysis of clinical trials. AB - PURPOSE: Bone marrow-derived cells (BMDCs) for clinical transplantation were carried out many years in treating spinal cord injury (SCI) without a clear conclusion. This study aimed to evaluate the safety and efficacy of BMDC transplantation in treatment of SCI patients. METHOD: Electronic databases, including PubMed, EMBASE, MEDLINE, and the Cochrane library, were searched to identify clinical therapeutic trials studying the application of BMDC transplantation in SCI. RESULTS: Overall the quality of the 24 studies was low, including one Grade I level of evidence, six Grade II levels, three Grade III levels, and 14 Grade IV levels. With a maximum of six-yr follow-up, the procedure related complications were minor and temporary, without serious adverse events (p = 0, n = 594). AIS improvement rate was analyzed in favor of BMDCs 6.13 (95% CI, 3.0-12.51; p < 0.001). In patient with complete (AIS A) and chronic SCI, the application of cell transplantation numbers between n * (10(7) -10(8) ) seemed to be more beneficial (p < 0.05 for all groups). CONCLUSIONS: Based on short-medium terms following up, BMDC transplantation appears to be safe and valid in SCI patients, more effective in chronic and complete injury. Nonetheless, prospective, randomized trials in larger cohorts are still needed. PMID- 26115045 TI - Clinicopathological Features and Prognosis of Metaplastic Breast Carcinoma: Experience of a Major Chinese Cancer Center. AB - Metaplastic breast carcinoma (MBC) is a rare heterogeneous group of primary breast malignancies, with low hormone receptor expression and poor outcomes. To date, no prognostic markers for this tumor have been validated. The current study was undertaken to evaluate the clinicopathologic characteristics, the response to various therapeutic regimens and the prognosis of MBCs in a large cohort of patients from Tianjin Medical University Cancer Hospital in China. Ninety cases of MBCs diagnosed in our hospital between January 2000 and September 2014 were retrieved from the archives. In general, MBCs presented with larger size, a lower rate of lymph node metastasis, and demonstrated more frequent local recurrence/distant metastasis than 1,090 stage-matched cases of invasive carcinoma of no specific type (IDC-NST), independent of the status of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expressions. The five-year disease-free survival (DFS) of MBC was significantly worse than IDC-NST. Using univariate analysis, lymph node metastasis, advanced clinical stage at diagnosis, high tumor proliferation rate assessed by Ki-67 labeling, and epidermal growth factor receptor (EGFR) overexpression/gene amplification were associated significantly with reduced DFS, while decreased OS was associated significantly with lymph node metastasis and EGFR overexpression/gene amplification. With multivariate analysis, lymph node status was an independent predictor for DFS, and lymph node status and EGFR overexpression/gene amplification were independent predictors for OS. Histologic subtyping and molecular subgrouping of MBCs were not significant factors in prognosis. We also found that MBCs were insensitive to neoadjuvant chemotherapy, routine chemotherapy, and radiation therapy. This study indicates that MBC is an aggressive type of breast cancer with poor prognosis, and that identification and optimization of an effective comprehensive therapeutic regimen is needed. PMID- 26115048 TI - Correction: Dynamics and yielding of binary self-suspended nanoparticle fluids. PMID- 26115049 TI - Differentiated plasma cell myeloma presenting as a solitary spinal amyloidoma: a case report, possible pitfall and review to the literature. AB - OBJECTIVE: Solitary spinal amyloidoma is a rare entity. Amyloidomas consist of extracellular amyloid deposits with an insoluble beta-pleated proteinaceous material. Although amyloidomas are slow growing lesions, they may lead to a progressive spinal cord or nerve root compression. Moreover amyloidoma results in destruction of bone with consequence of progressive osteolysis. METHOD: This study is a case presentation and review of the literature and should point out the need to explore any underlying diseases to guarantee the best therapy for the affected patient. In this case report we present a female patient with high-level paraparesis and lumbar stenosis in L2-L3 with combined spondylolisthesis (ASIA Impairemet Scale C). Paraparesis increased shortly after lumbar osteosynthesis. Contrast-enhanced MRI of the thoracic spine revealed medullary compression at the D5 level due to an epidural and paraspinal mass with concomitant bone infiltration. Operative decompression followed. Histopathological examination initially revealed amyloidoma. Finally the lesion was classified as a plasma cell myeloma. RESULTS: Plasma cell myeloma may rarely present as a solitary amyloidoma in the initial pathological examination with the potential to cause spinal cord compression associated to osteolytic lesions of the spine. CONCLUSION: A thorough pathological work-up is mandatory in order to rule out differential diagnosis and exclude possible underlying diseases. PMID- 26115047 TI - Melanoma and non-melanoma skin cancers in hairy cell leukaemia: a Surveillance, Epidemiology and End Results population analysis and the 30-year experience at Memorial Sloan Kettering Cancer Center. AB - Few studies have examined melanoma and non-melanoma skin cancer (NMSC) incidence rates after a diagnosis of hairy cell leukaemia (HCL). We assessed 267 HCL patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and Surveillance, Epidemiology and End Results (SEER) data for melanoma and NMSC incidence rates after HCL. Incidence data from MSKCC patients demonstrated a 10 year combined melanoma and NMSC skin cancer rate of 11.3%, melanoma 4.4% and NMSC 6.9%. Molecular analysis of skin cancers from MSKCC patients revealed activating RAS mutations in 3/9 patients, including one patient with melanoma. Of 4750 SEER patients with HCL, 55 (1.2%) had a subsequent diagnosis of melanoma. Standardized incidence ratios (SIRs) did not show that melanoma was more common in HCL patients versus the general population (SIR 1.3, 95% CI 0.78-2.03). Analysis of SEER HCL patients diagnosed before and after 1990 (approximately before and after purine analogue therapy was introduced) showed no evidence of an increased incidence after 1990. A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients. PMID- 26115050 TI - Neck paraganglioma: head rotation maneuver on transcranial Doppler ultrasonography. PMID- 26115052 TI - Oceanic Sink and Biogeochemical Controls on the Accumulation of Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls in Plankton. AB - Polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) were measured in plankton samples from the Atlantic, Pacific, and Indian Oceans collected during the Malaspina circumnavigation cruise. The concentrations of PCDD/Fs and dl-PCBs in plankton averaged 14 and 240 pg gdw(-1), respectively, but concentrations were highly variable. The global distribution of PCDD/Fs and dl-PCBs was not driven by proximity to continents but significantly correlated with plankton biomass, with higher plankton phase PCDD/F and dl-PCB concentrations at lower biomass. These trends are consistent with the interactions between atmospheric deposition, biomass dilution, and settling fluxes of organic matter in the water column (biological pump), as key processes driving POPs plankton phase concentrations in the global oceans. The application of a model of the air-water-plankton diffusive exchange reproduces in part the influence of biomass on plankton phase concentrations and suggests future modeling priorities. The estimated oceanic sink (Atlantic, Pacific, and Indian Oceans) due to settling fluxes of organic matter bound PCDD/Fs and dl-PCBs is of 400 and 10,500 kg y(-1), respectively. The atmospheric inputs due to gross diffusive absorption and dry deposition are nearly 3 and 10 times larger for PCDD/Fs and dl-PCBs, respectively, than the oceanic sink. These observations suggest that the coupling of atmospheric deposition with water column cycling supports and drives the accumulation of dl PCBs and PCDD/Fs in plankton from the global oligotrophic oceans. PMID- 26115051 TI - Investigation of a Large Collection of Pseudomonas aeruginosa Bacteriophages Collected from a Single Environmental Source in Abidjan, Cote d'Ivoire. AB - Twenty two distinct bacteriophages were isolated from sewage water from five locations in the city of Abidjan, Cote d'Ivoire over a two-year period, using a collection of Pseudomonas aeruginosa strains with diverse genotypes. The phages were characterized by their virulence spectrum on a panel of selected P. aeruginosa strains from cystic fibrosis patients and by whole genome sequencing. Twelve virions representing the observed diversity were visualised by electron microscopy. The combined observations showed that 17 phages, distributed into seven genera, were virulent, and that five phages were related to temperate phages belonging to three genera. Some showed similarity with known phages only at the protein level. The vast majority of the genetic variations among virulent phages from the same genus resulted from seemingly non-random horizontal transfer events, inside a population of P. aeruginosa phages with limited diversity. This suggests the existence of a single environmental reservoir or ecotype in which continuous selection is taking place. In contrast, mostly point mutations were observed among phages potentially capable of lysogenisation. This is the first study of P. aeruginosa phage diversity in an African city and it shows that a large variety of phage species can be recovered in a limited geographical site at least when different bacterial strains are used. The relative temporal and spatial stability of the Abidjan phage population might reflect equilibrium in the microbial community from which they are released. PMID- 26115053 TI - Psoriasis and polycystic ovary syndrome: a new link in different phenotypes. AB - OBJECTIVE: Women affected by PCOS and psoriasis are more likely to have insulin resistance, hyperinsulinemia, reduced HDL cholesterol levels and a more severe degree of skin disease than those with psoriasis alone. The mechanism underlying this association between PCOS and psoriasis is currently unknown. The aim of the present study was to evaluate the features of psoriasis and the psoriasis severity scores in the different PCOS phenotypes and in age and body mass index (BMI)-matched psoriatic control patients. STUDY DESIGN: A cross-sectional study was performed on 150 psoriatic patients: 94 PCOS and 56 age- and BMI-matched controls. PCOS patients were diagnosed and divided into four phenotypes according to Rotterdam criteria: A - patients with complete phenotype with hyperandrogenism (H) plus oligoamenorrhea (O) plus polycystic ovary (PCO) on ultrasound examination; B - patients with H plus O (without PCO); C - patients with H plus PCO (ovulatory phenotype); D - patients with O plus PCO (without H). The patient's Psoriasis Area and Severity Index (PASI) as well as the Physician's Global Assessment (PGA) were calculated. A PASI score >=10 was correlated with common indicator of severe disease. A PGA >=4 was considered as a condition of moderate to severe disease. RESULTS: Among the four phenotypes investigated, the group with complete phenotype (H plus O plus PCO) had a higher prevalence of patients with patient's PASI >=10 compared to controls (Odds Ratio (OR) 4.71, 95% confidence intervals (CI) 1.59-13.95). The group with O plus PCO had a higher prevalence of patients with PGA >=4 compared to controls (OR 26.79, 95% CI 3.40 211.02) while the ovulatory group had a lower prevalence of patients with PGA >=4 (OR 0.06, 95% CI 0.01-0.51). CONCLUSIONS: The ovulatory phenotype displays a milder psoriasis form than other phenotypes while the phenotypes with oligoamenorrhea presented higher severity scores of disease than other phenotypes and control group. PMID- 26115054 TI - Thrombophilia and venous thromboembolism in pregnancy: a meta-analysis of genetic risk. AB - Three common polymorphic variants, namely Factor V Leiden (FVL), Prothrombin G20210A (PT G20210A) and Methylenetetrahydrofolate Reductase (MTHFR) C677T are candidate genes for venous thromboembolism (VTE) in pregnancy. We performed a literature review and meta-analysis of pertinent genetic association studies (GAS) in pregnancy, to quantify the genetic risk of VTE in pregnancy. We used the model-free approach of generalized odds ratio (ORG) to estimate gene-to-disease association and explored the mode of inheritance using the degree of dominance h index. Twelve case-control GAS studies provided the full genotype distributions for at least one candidate gene to assess the genetic risk. FVL was associated with a significant risk of VTE in pregnancy (ORG 7.28; 95% confidence interval 5.53-9.58) and a dominant mode of inheritance (h=0.76), that is the effect of heterozygous carriers will lie close to the homozygous mutant genotype. PT G20210A mutation was also associated with a significant VTE risk (ORG 5.43; 95% CI 3.66-8.03) and had an over-dominant mode of inheritance (h=1.5), suggesting that the effect of heterozygous carriers may exceed that of homozygous mutant. MTHFR C677T had no association with VTE risk in pregnancy (ORG 1.24; 95% CI 0.88 1.73). Our analysis provided robust data on VTE in pregnancy, relative to FVL and PT G20210A status and suggested that the genetic effects of heterozygous over homozygous carriers do not justify stratification of heterozygous as "lower risk" over homozygous mutants. On clinical grounds this may impact decisions to preferentially exclude heterozygous from anticoagulation prophylaxis. PMID- 26115055 TI - Safety and efficacy of manual syringe infusion of distending media for hysteroscopic procedures: a case-control study. AB - OBJECTIVES: Adverse events associated with large volumes of distending media in hysteroscopic procedures can be life-threatening. The aim of this study was to evaluate the safety and efficacy of manual syringe infusion (MI) of distending media for hysteroscopic procedures. STUDY DESIGN: Between January 2011 and December 2013, the medical records of all women who underwent hysteroscopic procedures using MI or the conventional pump-infusion method (PI, the control group) were reviewed. The Wilcoxon rank-sum test, the Chi-square test and the multivariate logistic regression analysis were employed for statistical analysis. RESULTS: The MI group (n=82) had a significantly lower average volume of infused fluid (1117 +/- 712 mL vs. 2216 +/- 1502 mL, respectively; p<0.001), less operative time (22.2 +/- 9.7 vs. 30.4 +/- 9.8 min, respectively; p<0.001) and lower postoperative abdominal pain scores (0.6 +/- 0.7 vs. 0.8 +/- 0.7, respectively; p=0.04) than the PI group (n=58). Subgroup analysis of women who underwent hysteroscopic myomectomy revealed a significantly lower amount of infused fluid for the MI group than for the PI group (1737 +/- 905 mL vs. 3441 +/ 1952 mL, respectively; p=0.001). Infused fluid amount (coefficient=0.08, p<0.001) was the only significant independent factor affecting fluid deficit, with a constant of 76.1. CONCLUSION: The MI method appears to be a safe and feasible method for delivering distending media during hysteroscopic procedures. PMID- 26115057 TI - Implementing a Lean Management System in Primary Care: Facilitators and Barriers From the Front Lines. AB - BACKGROUND: Although Lean management techniques are increasingly used in health care to improve quality and reduce costs, lessons about how to successfully implement this approach on the front lines of care delivery are not well documented. In this study, we highlight key facilitators and barriers to implementing Lean among frontline primary care providers. METHODS: This case study took place at a large, ambulatory care delivery system serving nearly 1 million patients. In-depth interviews were conducted with primary care physicians, staff, and administrators to identify key factors impacting Lean redesigns in primary care. RESULTS: Overall, staff engagement and performance management, sensitivity to the professional values and culture of medicine, and perceived adequacy of organizational resources were critical when introducing Lean changes. Specific drivers of change included empowerment of staff at all levels, visual display of performance metrics, and a culture of innovation and collaboration. Barriers included physician resistance to standardized work, difficulty transferring management responsibilities to non-physician staff, and time and staffing required for participating in improvement efforts. CONCLUSION: Although Lean offers a new approach to delivering care, the implementation process itself is both complex and crucial to success. Understanding early facilitators and barriers can maximize Lean's, potential to improve health care delivery. PMID- 26115056 TI - Effects of low dose oral contraceptive pill containing drospirenone/ethinylestradiol in patients with endometrioma. AB - OBJECTIVES: Low dose oral contraceptive pills (OCPs) that contain synthetic estrogen and progestin are often used to relieve chronic pelvic pain associated with endometriosis. We sought to evaluate the efficacy of drospirenone/ethinylestradiol (DRSP/EE) with low-dose estrogen in treating endometrioma. STUDY DESIGN: A prospective clinical study in six hospitals and one clinic in Japan was conducted. Forty-nine 23- to 45-year-old patients who suffered from endometriosis-associated dysmenorrhea were included in the study. The primary endpoint was the change in size of ovarian endometrioma as measured by transvaginal ultrasonography. The secondary endpoint was the change in dysmenorrhea as evaluated by VAS (visual analog scale) scores before treatment and at 3 and 6 cycles of treatment. In addition, serum CA125, anti-mullerian hormone (AMH), interleukin (IL)-6, and IL-8 were evaluated after 6 cycles of treatment. RESULTS: The maximum diameter and volume of the ovarian endometrioma significantly decreased after 3 and 6 cycles compared with pretreatment. VAS scores of dysmenorrhea pain were also reduced after 1, 3 and 6 cycles. A significant correlation between the reduced size of the endometrioma and the decline of VAS scores was found. The levels of serum CA125 and AMH concentration were decreased after 6 cycles. No significant changes were observed in serum IL-6 and IL-8. CONCLUSION: Low dose DRSP/EE therapy is a promising treatment not only to reduce the size of endometrioma but also for dysmenorrhea. PMID- 26115058 TI - Development and Validation of the CPO Scale, a New Instrument for Evaluation of Health Care Improvement Efforts. AB - OBJECTIVE: To develop and validate an instrument for guidance and evaluation of quality and safety improvement efforts in health care. CONTEXT: The instrument is based on the Plan-Do-Study-Act cycle and the 3 fundamental improvement questions regarding aims, measurement, and change-making. METHODS: An interdisciplinary team of improvement experts developed the Change Process and Outcome (CPO) scale. After studying the improvement literature, the scale was tested and refined on a sample of 5 projects. The CPO evaluation process and classification system was developed when evaluating 189 of the quality improvement projects of the Norwegian Medical Association by their final reports. The scale was validated by applying statistical testing to the evaluation results. RESULTS: The final CPO scale consists of 13 process items and 7 outcome items. Interrater reliability ranged from 0.53 to 0.79, and test-retest reliability was 0.82. Factor analyses with Varimax rotation identified 2 significant process domains: Aims/change making and Measurement/reporting, with Cronbach alpha values 0.88 and 0.95, respectively. The classification system produced 3 performance levels: successful, promising, and uncertain. CONCLUSION: The CPO scale shows good internal consistency, reliability, and validity for evaluating the success of quality improvement initiatives. PMID- 26115059 TI - Organizing for Quality Improvement in Health Care: An Example From Childhood Obesity Prevention. AB - Children in rural areas face higher rates of obesity than children in urban areas, and their clinicians face challenges with preventing and managing obesity and translation of evidence into practice. We evaluated how the quality improvement (QI) intervention, Healthy Eating Active Living TeleHealth Community of Practice (HEALTH COP), at 7 rural California clinics addressed these challenges. Focus group interviews with QI team members assessed their experiences and factors related to adoption of key changes. Key challenges were clinician and staff buy-in, changing ingrained clinical practices, and motivating patient and families. Facilitators were top-down organizational requirements for QI, linkages to local QI resources, involvement of clinical champions, alignment with existing practices, incorporating a learning system connecting similar clinics, and clear and consistent communication channels. Evaluations of QI interventions should include not only measurement of effectiveness but also identification of factors associated with change and interactions with organizational processes and contexts. PMID- 26115060 TI - Taking the Pulse of a Target Population: Assessing Change Readiness. AB - OBJECTIVE: Implementing change in a health care organization poses structural and cultural challenges. DESIGN: We developed a survey derived from an existing organizational change model and distributed it to the target population of an impending change initiative. RESULTS: The respondents (59.2% response rate) indicated that changes in communication protocols were necessary, believed that change would be possible, reported feeling supported during previous change efforts, and tended to think that their feedback had been valued in the past. CONCLUSIONS: The survey revealed that our target population was ready to change the ways in which it communicates about patient needs and care protocols. To increase the probability of successful implementation of an initiative to improve communication protocols on the unit, we will design our implementation strategy to provide both the process support and the training support that participants perceived to be lacking. IMPLICATIONS: By taking the "pulse" of the target population, change agents can identify more effective implementation strategies. PMID- 26115061 TI - Innovation in Stroke Care Quality: NIH Stroke Scale Change and Shewhart Charts. AB - Stroke care, admission through discharge, is a process that should lead to symptomatic improvement. Improvement or decline in conditions of patients with acute stroke during hospitalization can be measured by the National Institutes of Health Stroke Scale (NIH Stroke Scale or NIHSS) at both admission and discharge and may indicate the overall quality of acute stroke care for a patient and the stability of care in the system. Shewhart control charts were analyzed for 98 patients with stroke admissions in a random sample at a tertiary care stroke center to determine the feasibility of examining the NIHSS score change to detect statistical control or identify excess variance in outcomes. The study sample showed a mean improvement of 1.33 points from admission to discharge on the NIHSS. Three statistical outliers were found. Excess statistical variation clustered within a specific stroke team's tenure suggested a need for targeted education and examination for process redesign. Using the NIHSS and the Shewhart control charts identified a systematic process flaw that could be targeted to improve stroke outcomes and move the delivery system toward statistical control. PMID- 26115062 TI - Identifying Previously Undetected Harm: Piloting the Institute for Healthcare Improvement's Global Trigger Tool in the Veterans Health Administration. AB - BACKGROUND: Adverse event (AE) surveillance may be enhanced by the Institute for Healthcare Improvement's Global Trigger Tool (GTT). A pilot study of the GTT was conducted in one Veterans Health Administration (VA) facility to assess the rates, types, and harm of AEs detected and to examine the overlap in AE detection between the GTT and existing surveillance mechanisms. METHODS: GTT guidelines were followed and medical records were reviewed for 17 weeks of acute care hospitalizations. Investigators met monthly, first to adjudicate discordant reviewer categorizations of harm and later to categorize the AEs detected using standardized definitions. GTT-detected AEs were compared with incident reports, Patient Safety Indicators, and the VA Surgical Quality Improvement Program. RESULTS: Medical records were reviewed for 273 of 1980 eligible cases. Using the GTT, a total of 109 AEs were identified. More than 1 of 5 hospitalizations (21%) were associated with an AE. The majority of AEs detected (60%) were minor harms; there were no deaths attributable to medical care. Ninety-six of the 109 AEs (88%) were not detected by other measures. CONCLUSIONS: The GTT identified previously undetected AEs at one VA. The GTT has the potential to track AEs and guide quality improvement efforts in conjunction with existing AE surveillance mechanisms. PMID- 26115063 TI - A Qualitative Evaluation of Web-Based Cancer Care Quality Improvement Toolkit Use in the Veterans Health Administration. AB - BACKGROUND: Disease severity, complexity, and patient burden highlight cancer care as a target for quality improvement (QI) interventions. The Veterans Health Administration (VHA) implemented a series of disease-specific online cancer care QI toolkits. OBJECTIVES: To describe characteristics of the toolkits, target users, and VHA cancer care facilities that influenced toolkit access and use and assess whether such resources were beneficial for users. METHODS: Deductive content analysis of detailed notes from 94 telephone interviews with individuals from 48 VHA facilities. We evaluated toolkit access and use across cancer types, participation in learning collaboratives, and affiliation with VHA cancer care facilities. RESULTS: The presence of champions was identified as a strong facilitator of toolkit use, and learning collaboratives were important for spreading information about toolkit availability. Identified barriers included lack of personnel and financial resources and complicated approval processes to support tool use. CONCLUSIONS: Online cancer care toolkits are well received across cancer specialties and provider types. Clinicians, administrators, and QI staff may benefit from the availability of toolkits as they become more reliant on rapid access to strategies that support comprehensive delivery of evidence based care. Toolkits should be considered as a complement to other QI approaches. PMID- 26115064 TI - Causal Analysis of Emergency Department Delays. AB - BACKGROUND: Improvement teams make causal inferences, but the methods they use are based on statistical associations. This article shows how data and statistical models can be used to help improvement teams make causal inferences and find the root causes of problems. METHODS: This article uses attribution data, competing risk survival analysis, and Bayesian network probabilities to analyze excessive emergency department (ED) stays within one hospital. We use data recorded by ED clinicians that attributed the cause of excessive ED stays to 23 causes for the 70 049 ED visits between March 2011 and April 2014. We use competing risk survival analysis to identify contribution of each cause to the delay. We use Bayesian network models to analyze interaction among different causes of excessive stays and find the root causes of this problem. RESULTS: This article shows the utility of causal analysis to help improvement teams focus on the root causes of problems. For the example analyzed in the article, most causes for patients' excessive ED stays were related to the hospital operations outside the ED. Therefore, improvement projects inside the ED such as expanding ED, increasing staff at the ED, or improving operations are less likely to have a positive impact on reducing excessive ED stays. On the contrary, interventions that improve hospital occupancy (better discharge, expansion of beds, etc) or improve laboratory response times are more likely to result in positive outcomes. PMID- 26115068 TI - Effect of testicular spermatozoa on embryo quality and pregnancy in patients with non-obstructive azoospermia. AB - This study was performed to assess and compare the outcomes of testicular sperm extraction (TESE)-intracytoplasmic sperm injection (ICSI) using spermatozoa from fresh and frozen testicular tissue from men with subgroups of non-obstructive azoospermia (NOA). A total of 110 cycles of TESE-ICSI were performed. Patients were classified into one of the following NOA subgroups: hypospermatogenesis (HS), maturation arrest (MA), or Sertoli cell-only syndrome (SCO). Laboratory (fertilization, cleavage stage of embryo, and good quality embryo) and clinical (pregnancy, clinical pregnancy, implantation, and delivery) outcomes were assessed. No statistically significant differences were observed in any of the other measured parameters between the three subgroups of NOA. No significant differences in laboratory outcomes were observed between spermatozoa from fresh and frozen testicular spermatozoa; however, statistically significant differences were observed in the pregnancy and implantation rates between groups (p < 0.05). The outcomes of using spermatozoa retrieved from fresh testicular tissue in each of the three subgroups were also compared; although clinical outcomes showed low results, no significant differences were observed between the three subgroups. Similarly, no significant differences were observed in spermatozoa retrieved from frozen testicular tissue. Once spermatozoa have been successfully obtained, acceptable laboratory outcomes can be achieved for NOA, whether or not the spermatozoa are cryopreserved. However, satisfactory clinical outcomes may be more difficult to achieve as the results showed in each group of fresh and frozen testicular spermatozoa. Therefore, achieving acceptable clinical pregnancy results and efficient cryopreservation of testicular spermatozoa should be considered in patients with NOA. PMID- 26115069 TI - Effects of intensive lipid-lowering therapy on coronary plaques composition in patients with acute myocardial infarction: Assessment with serial coronary CT angiography. AB - BACKGROUND: Statins have been shown to possess favourable effects on the cardiovascular system with stabilization of the vulnerable plaque. We sought to assess the effects of early aggressive statin treatment on plaque composition in patients with acute myocardial infarction (AMI), using serial assessment with coronary CT-angiography (CTA). METHODS: In a prospective randomized blinded endpoint trial patients with AMI were randomized to an intensive lipid lowering treatment receiving statin loading with 80 mg rosuvastatin followed by 40 mg daily or standard statin therapy according to current guidelines. Patients were assessed with CTA at baseline and after 12 months with evaluation of plaque volume and composition. RESULTS: In total, 140 patients with AMI were randomized and plaque composition was assessed in 96 patients. In the intensive care group LDL-level was median 1.3 [0.9; 1.5] mmol/l at 12 months follow-up and 2.0 [1.7; 2.4] mmol/l in the usual care group, p < 0.001. Plaque volume increased over 12 months with 43.5 (+/-225.8) mm(3) in the intensive care group and 19.1 (+/-190.2) mm(3) in the usual care group, p = 0.57. Plaque composition changed over 12 months with an increase in total dense calcium volume by 11.1 (+/-39.6) mm(3), corresponding to a 23% increase, in the intensive care group and a decreased by 0.4 (+/-26.6) mm(3) in the usual care group, p < 0.001. Necrotic core volume increased 26.8 (+/-122.1) mm(3) in the intensive care group and 25.2 (+/-80.1) mm(3) in the usual care group, p = 0.94. CONCLUSIONS: Early aggressive lipid lowering therapy significantly increases dense calcium volume in patients with AMI. PMID- 26115070 TI - Reproducibility and biological variability of HDL's vascular functional assays. AB - BACKGROUND: Recent failures of clinical trials promoting HDL-elevating therapies have prompted research groups to focus on its functional activity in disease. Endothelial effects of HDL can be measured with in vitro cell assays. The reproducibility and biological relevance of these assays have not been explored both in healthy individuals and those at increased cardiovascular (CV) risk. METHODS: HDL dependent nitric oxide (NO) bioavailability, superoxide (SO) production and serum paraoxonase-1 (PON-1) activity were measured in 35 healthy adults (34.37 24-49) and 8 patients (43.56 37-49) suffering from a chronic inflammatory condition (periodontitis-PD). Assay reproducibility was assessed by independent technicians on consecutive days to determine inter and intra analyser variability for each assay. The 35 healthy individuals were further divided into young (n = 16) and middle aged (n = 19) groups and compared with regards to HDL functions. Within-subject biological variation of HDL function was determined in a sub-group of 25 healthy volunteers at intervals of one day and 1 month, and in 8 patients at intervals of one day and 1 week. Power curves were also generated to estimate the number of patients that would be required for HDL functional assays in a cross-over and parallel study design. RESULTS: NO bioavailability was the most reproducible assay in healthy adults (coefficient of variation = 1.72%, 1.92 - intra and inter respectively) and PD patients (CV = 4.4% and 5.5%). All measures demonstrated no statistical difference between young and healthy middle aged population. No single assay demonstrated significant variations over time, indicating that within patient variations are negligible. Our power curves for NO bioavailability and PON-1 activity suggest that low number of patients will be required to detect significant differences in HDL function in a cross over and parallel study design. CONCLUSION: This study suggests that in vitro HDL functional assays are reliable and can be used to assess HDL functionality in healthy and diseased populations. NO bioavailability was the most reproducible assay, but PON-1 activity remains the most practical for application in clinical trials due to its capacity for scale. PMID- 26115071 TI - Determining the characteristics of human atherosclerosis: A difficult but indispensable task providing the direction and proof of concept for pioneering atherosclerosis research in animal models. PMID- 26115072 TI - Screening and treatment of familial hypercholesterolemia - Lessons from the past and opportunities for the future (based on the Anitschkow Lecture 2014). AB - In this review, we discuss the screening and treatment of familial hypercholesterolemia (FH), an autosomal dominant inherited disease, characterized by severely increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary heart disease (CHD). Genetic family based cascade screening for FH was shown to be cost-effective and a screening program with such an approach was carried out in the Netherlands from 1994 to 2014. Over 64,000 persons have participated in this program of whom 40.3% were found to carry an FH causing mutation. We will discuss the results of this screening program, as well as the scientific opportunities it has provided. Currently, statins and ezetimibe are the only registered LDL-C lowering treatment options for FH patients. Many of them do not attain the treatment goals that are recommended by treatment guidelines. In this review, we will also provide a comprehensive overview of promising new modalities that could lower LDL-C in FH patients. PMID- 26115073 TI - Effects of a Multimodal Exercise Program on Physical Function, Falls, and Injuries in Older Women: A 2-Year Community-Based, Randomized Controlled Trial. AB - OBJECTIVES: To investigate the effects of multimodal supervised exercise on physical functioning, falls, and related injuries in older women. DESIGN: Two year randomized controlled trial. SETTING: Tampere, Finland. PARTICIPANTS: Women aged 70 to 80 who had fallen in the previous year (n = 409). INTERVENTION: Participants were randomly assigned to an exercise or control group (ClinicalTrial.gov NCT00986466). Exercisers participated in group exercise classes twice a week for 12 months and once a week for the subsequent 12 months and home exercises. Controls maintained their current physical activity. MEASUREMENTS: Physical functioning assessed at baseline and at 6-month intervals during the intervention. Falls and related injuries monitored with fall diaries. RESULTS: Intention-to-treat analyses showed that exercise led to significant improvements in physical functioning. Leg strength differed significantly between the groups (mean change: 14.1%, 95% confidence interval (CI) = 8.0 to 20.2 in exercisers; 1.6%, 95% CI = -4.5 to 7.7 in controls; P < .001). Chair stand time also differed significantly between groups (7.4%, 95% CI 3.8 to 10.8% in exercisers; 2.4%, 95% CI = -1.6 to 6.2) in controls; P = .02). Between-group differences were significant for fast walking speed (P = .003) and probability of completing the backward walking test (P < .001), favoring exercisers. Timed Up and-Go and grip strength did not differ between groups. There was no difference in the total falls incidence rate ratio (IRR = 1.0, 95% CI = 0.79 to 1.26), but exercisers were less likely to have medically attended injurious falls (IRR = 0.45, 95% CI = 0.27 to 0.78; P = .004). CONCLUSION: Twenty-four months of multimodal exercise enhanced physical functioning in women aged 70 to 80 with a history of falls. Although the total number of falls was not lower than in controls, the rate of medically attended injurious falls was more than 50% lower. PMID- 26115074 TI - Loss of Desmoglein 2 Contributes to the Pathogenesis of Crohn's Disease. AB - BACKGROUND: The intestinal epithelium of patients with Crohn's disease (CD) is characterized by defects in permeability and alterations in tight junction morphology sealing the paracellular cleft. Desmosomes are primarily considered to mediate strong intercellular cohesion. Because barrier properties of epithelial cells were shown to depend on the function of the desmosomal adhesion molecule desmoglein 2 (Dsg2), we here investigated the relevance of Dsg2 for CD. METHODS: Biopsies from the terminal ileum of 14 patients with CD and 12 healthy controls were investigated for changes in cell adhesion molecules. Two intestinal epithelial cell lines were used for functional studies. A tandem peptide modulating Dsg binding was applied to strengthen Dsg2 interaction. RESULTS: Dsg2 but not the adherens junction molecule E-cadherin was strongly reduced in the mucosa of patients with CD. TNF-alpha, a central cytokine in CD pathogenesis, led to loss of cell cohesion and increased permeability in cultured epithelial cells, which was paralleled by loss of Dsg2 at cell borders, reduction of the tight junction component claudin-1, and upregulation of claudin-2. These effects were mediated at least in part by increased activity of p38MAPK because inhibition of this kinase restored intercellular adhesion and blunted the permeability increase induced by TNF-alpha. Importantly, stabilizing desmosomal adhesion through tandem peptide ameliorated loss of barrier functions and prevented claudin-2 increase. CONCLUSIONS: We show an important role of p38MAPK-mediated regulation of desmosomal adhesion resulting in upregulation of claudin-2 in CD. Our data suggest peptide-mediated strengthening of impaired Dsg2 adhesion as a novel therapeutic approach in CD. PMID- 26115075 TI - GPx2 Induction Is Mediated Through STAT Transcription Factors During Acute Colitis. AB - BACKGROUND: The selenoprotein glutathione peroxidase 2 (GPx2) is highly expressed in the gastrointestinal epithelium. During inflammatory bowel disease and colorectal cancer, GPx2 expression is enhanced. METHODS: We analyzed GPx2 expression and transcriptional regulation during the different phases of dextran sulfate sodium (DSS)-induced colitis in mice and in cytokine-treated colorectal cancer cells. RESULTS: In the colon of DSS-treated mice, GPx2 was upregulated during the acute and recovery phase. In the latter, it was specifically localized in regenerating ki67-positive crypts next to ulcerations. In cultured cells, endogenous GPx2 expression and GPx2 promoter activity were enhanced by the anti inflammatory mediators 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and interleukin-22 (IL-22), while it was unaffected by classical proinflammatory cytokines like IL-1beta. Induction of GPx2 expression by 15d-PGJ2 was mediated through Nrf2. In contrast, in DSS-treated Nrf2-KO mice GPx2 expression remained upregulated during recovery, which appeared to be independent of Nrf2. IL-22 activates transcription factors of the signal transducers and activators of transcription (STAT) family. Therefore, we analyzed the GPx2 promoter for putative STAT-responsive elements and identified 4 of them. Point mutation of the binding element next to the transcription start completely abolished promoter activation after IL-22 treatment and after cotransfection of STAT expression plasmids. To show in vivo relevance of the obtained results, we performed immunohistochemistry for phospho-STAT3 and GPx2. Especially during acute colitis, GPx2 and nuclear STAT3 colocalized in inflamed areas. CONCLUSIONS: GPx2 is a novel target of STAT transcription factors. The upregulation of GPx2 by IL-22 indicates that GPx2 might be important for the resolution of inflammation. PMID- 26115076 TI - Isolation and characterisation of three new anthraquinone secondary metabolites from Symplocos racemosa. AB - Three new anthraquinone secondary metabolites were isolated from Symplocos racemosa, a small tree of family symplocaceae. The structures of compounds (1-3) were elucidated to be 1,4-dihydroxy-6-(ethoxymethyl)-8-propylanthracene-9,10 dione (1), 1,4-dihydroxy-6-(hydroxymethyl)-8-butylanthracene-9,10-dione (2) and 1,4-dihydroxy-6-(hydroxymethyl)-8-propyl anthracene-9,10-dione (3) using their spectral data, i.e. through IR, UV, (1)H NMR, (13)C NMR and two-dimensional (2D) NMR techniques including heteronuclear multiple quantum coherence, heteronuclear multiple bond correlation and correlation spectroscopy. PMID- 26115077 TI - Congenital Oculomotor Nerve Paresis With Isolated Cyclic Pupillary Spasms. AB - Cyclic oculomotor nerve paresis is a rare and usually congenital disorder. It is characterized by unilateral third nerve paresis with periodic spasms causing eyelid elevation, miosis, and contraction of 1 or more of the extraocular muscles innervated by the third nerve. We report a 20-month-old girl who presented initially with a congenital partial right third nerve paresis without ptosis. She subsequently developed isolated cyclic spasms of the pupil followed several months later by permanent partial ptosis. PMID- 26115079 TI - CORRIGENDA. PMID- 26115078 TI - A double substitution induced Ca(Mg0.8, Al0.2)(Si1.8, Al0.2)O6:Eu(2+) phosphor for w-LEDs: synthesis, structure, and luminescence properties. AB - A double substitution induced blue-emitting phosphor Ca(Mg0.8, Al0.2)(Si1.8, Al0.2)O6:Eu(2+) (CMAS:Eu(2+)) was successfully synthesized by a solid-state reaction process, and its structure and luminescence properties were investigated in detail. The crystal structure and chemical composition of the CMAS matrix were analyzed and determined based on Rietveld refinements and Energy Dispersive Spectroscopy (EDS). The composition-optimized CMAS:Eu(2+) exhibited a strong blue light, centered at 446 nm upon excitation at 365 nm with the Commission Internationale de L'Eclairage (CIE) coordinates of (0.144, 0.113). Under 380 nm excitation, the PL emission intensity area of the optimized phosphor was found to be 46.95% of that of the commercial BaMgAl10O17:Eu(2+) (BAM:Eu(2+)) phosphor and the quantum efficiency of the phosphor is 41.32%. The temperature-dependent PL studies have been investigated which show the thermal stability of the CMAS:Eu(2+) phosphor compared with that of the CaMgSi2O6:Eu(2+) (CMS:Eu(2+)) phosphor. PMID- 26115080 TI - A survey on the current status of pediatric nursing human resources in Sichuan province of China. AB - OBJECTIVE: To investigate the status of pediatric nurses in Sichuan province of China, and to compare the status with the national standards. METHODS: This study used a convenience sample of hospitals with pediatric departments in Sichuan province. A list of hospitals was obtained from the Health and Family Planning Commission of Sichuan province. Fifty hospitals with pediatric departments were selected to receive questionnaires. Thirty-nine hospitals responded and 38 responses were valid. Bed-to-nurse ratios were evaluated. The Wilcoxon signed rank test was used to compare the bed-to-nurse ratios among the studied hospitals and the Chinese national standard. RESULTS: In the 38 surveyed hospitals, the average bed-to-nurse ratio was 1:0.57 and the average physician-to-nurse ratio was 1:1.53. The average bed-to nurse ratio in the pediatric departments was 1:0.51. The average bed-to-nurse ratio in the pediatric inpatient wards was 1:0.40. There were significant differences in the average bed-to-nurse ratios in the pediatric departments (Z = -2.149, P = 0.032) and the pediatric inpatient wards (Z = -2.328, P = 0.020) between general hospitals and specialty hospitals. There were significant differences between the average bed-to-nurse ratios in tertiary-level hospitals (Z = -4.178, P < 0.0001) and the pediatric inpatient wards of the surveyed hospitals (Z = -4.518, P < 0.0001) and the national standard. CONCLUSION: There is a nursing shortage in tertiary-level hospitals and some grade-A specialty hospitals in Sichuan, China. The shortage is worse in pediatric inpatient wards, especially in the general hospitals and some grade-B specialty hospitals. Hospital administrations need to understand the situation and offer strategies to cope for routine nursing management as well as disaster management. PMID- 26115081 TI - Cognitive impairment before changes appear on [18F]-fluoro-D-glucose positron emission tomography images in a patient with possible early-stage cerebellar predominant multiple system atrophy. AB - Multiple system atrophy (MSA) is a sporadic, rapidly progressive neurodegenerative disorder characterized by autonomic dysfunction combined with parkinsonism or cerebellar ataxia. Patients with MSA typically suffer from cognitive disorders and rapid eye movement sleep behaviour disorder. 18 F fluorodeoxyglucose-positron emission tomography is used to assess MSA. However, the relationship between the clinical features and findings on 18 F fluorodeoxyglucose-positron emission tomography in patients with MSA has not yet been investigated. Here we report a case of possible early-stage cerebellar-type MSA. We concluded that cerebellar-type MSA or other factors, such as rapid eye movement sleep behaviour disorder or obstructive sleep apnoea cognitive impairment, could appear before changes are visible on 18 F-fluorodeoxyglucose positron emission tomography images. Additionally, we concluded that the cognitive impairment could derive from cerebellar-type MSA itself, not from other factors such as rapid eye movement sleep behaviour disorder or sleep apnoea syndrome. PMID- 26115082 TI - Effects of IGF2BP2, KCNQ1 and GCKR polymorphisms on clinical outcome in metastatic gastric cancer treated with EOF regimen. AB - AIM: The present study analyzed Type 2 diabetes mellitus (T2D)-related gene polymorphisms and their impacts on chemotherapeutic response and survival in patients with metastatic gastric cancer (MGC). PATIENTS & METHODS: This retrospective study enrolled 108 MGC patients treated with first-line EOF chemotherapy (epirubicin, oxaliplatin and 5-fluorouracil combination chemotherapy). Eleven single nucleotide polymorphisms of five T2D-related genes were determined. RESULTS: Among the 11 single nucleotide polymorphisms, three (IGF2BP2 rs4402960, IGF2BP2 rs6769511 and KCNQ1 rs163182) were significantly associated with disease control rate and two (GCKR rs780093 and rs780094) were significantly associated with progression-free and overall survival. CONCLUSION: Our results suggest IGF2BP2 and KCNQ1 polymorphisms might be independent predictors of chemotherapeutic response, while GCKR polymorphisms might be independent predictors of survival in MGC patients treated with first-line EOF chemotherapy. Original submitted 30 June 2014; revision submitted 15 April 2015. PMID- 26115083 TI - Pharmacogenetics in electroconvulsive therapy and adjunctive medications. AB - Electroconvulsive therapy (ECT) has shown apparent efficacy in treatment of patients with depression and other mental illnesses who do not respond to psychotropic medications or need urgent control of their symptoms. Pharmacogenetics contributes to an individual's sensitivity and response to a variety of drugs. Clinical insights into pharmacogenetics of ECT and adjunctive medications not only improves its safety and efficacy in the indicated patients, but can also lead to the identification of novel treatments in psychiatric disorders through understanding of potential molecular and biological mechanisms involved. In this review, we explore the indications of pharmacogenetics role in safety and efficacy of ECT and present the evidence for its role in patients with psychiatric disorders undergoing ECT. PMID- 26115084 TI - Role of cytochrome P450 2C8*3 (CYP2C8*3) in paclitaxel metabolism and paclitaxel induced neurotoxicity. AB - AIM: The CYP2C8*3 allele has been suggested as a risk factor for paclitaxel induced neuropathy but the data hitherto published are conflicting. MATERIALS & METHODS: In total 435 patients were investigated with respect to maximum neuropathy grade and accumulated paclitaxel dose. The enzymatic properties of CYP2C8.3 variant were analyzed using heterologous mammalian HEK293 cell expression system. RESULTS: No significant association between CYP2C8*3 allele and neuropathy was found, although a trend was observed. The paclitaxel and amodiaquine metabolism by CYP2C8.3 were found similar to CYP2C8.1, whereas CYP2C8.3 was more efficient in the metabolism of rosiglitazone. CONCLUSION: These results indicate a difference in substrate specificity between CYP2C8.1 and CYP2C8.3; however, the CYP2C8*3 allele has no major impact on paclitaxel metabolism in vitro or of paclitaxel-induced neuropathy in vivo. Original submitted on 6 February 2015; revision submitted on 9 April 2015. PMID- 26115085 TI - Combined Treatment Effects Using Bioactive-Coated Implants and Ceramic Granulate in a Rabbit Femoral Condyle Model. AB - BACKGROUND: Resolution of peri-implant defects resulting from implant placement in the freshly extracted site demands for a bone graft substitute that stimulates bone regeneration and hence facilitates implant integration. In view of this, the addition of silica to hydroxyapatite (HASi) could enhance the bioactive behavior of ceramic materials and implant surfaces coated with bioactive ceramics might benefit the interaction between bone and implant. PURPOSE: To evaluate the bone response to implants coated with hydroxyapatite-silica (HASi) or hydroxyapatite (HA) and either or not combined with HASi and HA ceramic bone substitute particles, respectively, on bone-to-implant contact (BIC) and bone formation using a rabbit femoral condyle implant model with a gap design. MATERIAL AND METHODS: A total of 32 custom-made, titanium implants (Ti: diameter 5 mm, length 8 mm) with two-sided gaps were fabricated and coated with either HASi or HA using pulsed laser deposition (PLD). The implants were installed bilaterally in the femoral condyles of 16 New Zealand white rabbits. According to a randomization protocol, one gap of HASi-coated and HA-coated implants was filled with HASi particles and HA particles, respectively, and the other gap was left empty. After an implantation period of 8 weeks, the retrieved specimens were analyzed via histology and histomorphometry (i.e., bone to implant contact [BIC] and bone volume [BV]). RESULTS: The BIC and BV around the implants were analysed for HASi- and HA-coated implants with and without the use of HASi and HA bone substitute material. Comparison of HASi- and HA-coated implants showed similar BIC for HASi- (55.7 + 11.0) and HA-coated implants (50.3 + 19.7). When coated implants were combined with bone substitute materials, HASi-coated and particle-filled implants showed higher BIC (64.3 +/- 6.8%) compared with HA-coated and HA-filled implants (54.5 +/- 10.9%). Similarly, the BV within the region of interest showed significantly higher values for the HASi-coated and HASi-filled implants (21.1 +/ 1.7%) compared with HA-coated and HA-filled implants (12.8 +/- 4.9%). CONCLUSIONS AND CLINICAL IMPLICATIONS: Within the limitations of this study, it can be concluded that silicon substitution in HA favors bone regeneration compared with HA, especially when used as bone substitute material. Further studies using different healing periods will elucidate the resorption pattern of HASi granules in comparison with HA. PMID- 26115086 TI - Hibiscus sabdariffa Leaf Extract Inhibits Human Prostate Cancer Cell Invasion via Down-Regulation of Akt/NF-kB/MMP-9 Pathway. AB - Hibiscus sabdariffa leaf has been previously shown to possess hypoglycemic, hypolipidemic, and antioxidant effects, and induce tumor cell apoptosis. However, the molecular mechanisms involved in the anticancer activity of H. sabdariffa leaf extract (HLE) are poorly understood. The object of the study was to examine the anti-invasive potential of HLE. First, HLE was demonstrated to be rich in polyphenols. The results of wound-healing assay and in vitro transwell assay revealed that HLE dose-dependently inhibited the migration and invasion of human prostate cancer LNCaP (lymph node carcinoma of the prostate) cells under non cytotoxic concentrations. Our results further showed that HLE exerted an inhibitory effect on the activity and expressions of matrix metalloproteinase-9 (MMP-9). The HLE-inhibited MMP-9 expression appeared to be a consequence of nuclear factor-kappaB (NF-kappaB) inactivation because its DNA-binding activity was suppressed by HLE. Molecular data showed all these influences of HLE might be mediated via inhibition of protein kinase B (PKB, also known as Akt)/NF-kB/MMP-9 cascade pathway, as demonstrated by the transfection of Akt1 overexpression vector. Finally, the inhibitory effect of HLE was proven by its inhibition on the growth of LNCaP cells and the expressions of metastasis-related molecular proteins in vivo. These findings suggested that the inhibition of MMP-9 expression by HLE may act through the suppression of the Akt/NF-kB signaling pathway, which in turn led to the reduced invasiveness of the cancer cells. PMID- 26115088 TI - Assessing Shortened Field-Based Heart-Rate-Variability-Data Acquisition in Team Sport Athletes. AB - PURPOSE: To compare the LnRMSSD and the LnRMSSD:RR values obtained during a 5-min stabilization period with the subsequent 5-min criterion period and to determine the time course for LnRMSSD and LnRMSSD:RR stabilization at 1-min analysis in elite team-sport athletes. PARTICIPANTS: 35 elite futsal players (23.9 +/- 4.5 y, 174.2 +/- 4.0 cm, 74.0 +/- 7.5 kg, 1576.2 +/- 396.3 m in the Yo-Yo test level 1). METHODS: The RR-interval recordings were obtained using a portable heart-rate monitor continuously for 10 min in the seated position. The 2 dependent variables analyzed were LnRMSSD and LnRMSSD:RR. To calculate the magnitude of the differences between time periods, effect-size (ES) analysis was conducted. To assess the levels of agreement, intraclass correlation coefficients (ICC) and Bland-Altman plots were used. RESULTS: The LnRMSSD and LnRMSSD:RR values obtained during the stabilization period (0-5 min) presented very large to nearly perfect ICCs with the values obtained during the criterion period (5-10 min), with trivial ESs. In the ultra-short-term analysis (ie, 1-min segments) the data showed slightly less accurate results, but only trivial to small differences with very large to nearly perfect ICCs were found. CONCLUSION: LnRMSSD and LnRMSSD:RR can be recorded in 5 min without traditional stabilization periods under resting conditions in team-sport athletes. The ultra-short-term analysis (1 min) also revealed acceptable levels of agreement with the criterion. PMID- 26115087 TI - Are You Sure? Confidence about the Satiating Capacity of a Food Affects Subsequent Food Intake. AB - Expectations about a food's satiating capacity predict self-selected portion size, food intake and food choice. However, two individuals might have a similar expectation, but one might be extremely confident while the other might be guessing. It is unclear whether confidence about an expectation affects adjustments in energy intake at a subsequent meal. In a randomized cross-over design, 24 subjects participated in three separate breakfast sessions, and were served a low-energy-dense preload (53 kcal/100 g), a high-energy-dense preload (94 kcal/100 g), or no preload. Subjects received ambiguous information about the preload's satiating capacity and rated how confident they were about their expected satiation before consuming the preload in its entirety. They were served an ad libitum test meal 30 min later. Confidence ratings were negatively associated with energy compensation after consuming the high-energy-dense preload (r = -0.61; p = 0.001). The same relationship was evident after consuming the low energy-dense preload, but only after controlling for dietary restraint, hunger prior to, and liking of the test meal (p = 0.03). Our results suggest that confidence modifies short-term controls of food intake by affecting energy compensation. These results merit consideration because imprecise caloric compensation has been identified as a potential risk factor for a positive energy balance and weight gain. PMID- 26115090 TI - Reduction of Carbon Dioxide in Filtering Facepiece Respirators with an Active Venting System: A Computational Study. AB - During expiration, the carbon dioxide (CO2) levels inside the dead space of a filtering facepiece respirator (FFR) increase significantly above the ambient concentration. To reduce the CO2 concentration inside the dead space, we attach an active lightweight venting system (AVS) comprising a one-way valve, a blower and a battery in a housing to a FFR. The achieved reduction is quantified with a computational-fluid-dynamics model that considers conservation of mass, momentum and the dilute species, CO2, inside the FFR with and without the AVS. The results suggest that the AVS can reduce the CO2 levels inside the dead space at the end of expiration to around 0.4% as compared to a standard FFR, for which the CO2 levels during expiration reach the same concentration as that of the expired alveolar air at around 5%. In particular, during inspiration, the average CO2 volume fraction drops to near-to ambient levels of around 0.08% with the AVS. Overall, the time-averaged CO2 volume fractions inside the dead space for the standard FFR and the one with AVS are around 3% and 0.3% respectively. Further, the ability of the AVS to vent the dead-space air in the form of a jet into the ambient - similar to the jets arising from natural expiration without a FFR - ensures that the expired air is removed and diluted more efficiently than a standard FFR. PMID- 26115089 TI - Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging. AB - ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3' untranslated region (3'UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3'RACE) provided evidence of novel 3' UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trait locus (eQTL). Analyses of RNA from human brains showed increased ABCC9 transcript levels in individuals with the risk genotype, corresponding with enrichment for a shorter 3' UTR which may be more stable than variants with the longer 3' UTR. MicroRNA transfection experiments yielded results compatible with the hypothesis that miR-30c causes down-regulation of SUR2 transcripts with the longer 3' UTR. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease. ABCC9 gene variants are associated with increased risk for hippocampal sclerosis of aging (HS-Aging--a prevalent brain disease with symptoms that mimic Alzheimer's disease). We describe novel ABCC9 variants in human brain, corresponding to altered 3'UTR length, which could lead to targeting by miR-30c. We also determined that the HS-Aging risk mutation is associated with variation in ABCC9 transcript expression. PMID- 26115091 TI - Regulation of Pro-Apoptotic Phosphorylation of Kv2.1 K+ Channels. AB - Caspase activity during apoptosis is inhibited by physiological concentrations of intracellular K+. To enable apoptosis in injured cortical and hippocampal neurons, cellular loss of this cation is facilitated by the insertion of Kv2.1 K+ channels into the plasma membrane via a Zn2+/CaMKII/SNARE-dependent process. Pro apoptotic membrane insertion of Kv2.1 requires the dual phosphorylation of the channel by Src and p38 at cytoplasmic N- and C-terminal residues Y124 and S800, respectively. In this study, we investigate if these phosphorylation sites are mutually co-regulated, and whether putative N- and C-terminal interactions, possibly enabled by Kv2.1 intracellular cysteine residues C73 and C710, influence the phosphorylation process itself. Studies were performed with recombinant wild type and mutant Kv2.1 expressed in Chinese hamster ovary (CHO) cells. Using immunoprecipitated Kv2.1 protein and phospho-specific antibodies, we found that an intact Y124 is required for p38 phosphorylation of S800, and, importantly, that Src phosphorylation of Y124 facilitates the action of the p38 at the S800 residue. Moreover, the actions of Src on Kv2.1 are substantially decreased in the non-phosphorylatable S800A channel mutant. We also observed that mutations of either C73 or C710 residues decreased the p38 phosphorylation at S800 without influencing the actions of Src on tyrosine phosphorylation of Kv2.1. Surprisingly, however, apoptotic K+ currents were suppressed only in cells expressing the Kv2.1(C73A) mutant but not in those transfected with Kv2.1(C710A), suggesting a possible structural alteration in the C-terminal mutant that facilitates membrane insertion. These results show that intracellular N-terminal domains critically regulate phosphorylation of the C-terminal of Kv2.1, and vice versa, suggesting possible new avenues for modifying the apoptotic insertion of these channels during neurodegenerative processes. PMID- 26115092 TI - Cardiovascular Outcomes of Sitagliptin in Type 2 Diabetic Patients with Acute Myocardial Infarction, a Population-Based Cohort Study in Taiwan. AB - BACKGROUND: The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients after acute myocardial infarction (AMI) has so far remained uncertain. METHODS: We analyzed data from the National Health Insurance Research Database (NHIRD), a government-operated, population-based database, from March 1st, 2009 to December 31st, 2011. Type 2 diabetic patients hospitalized for AMI were included in our study. We compared subjects using sitagliptin with comparison group to evaluate its cardiovascular safety and efficacy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, and ischemic stroke. RESULTS: We identified a total of 3,282 type 2 diabetic patients hospitalized for AMI (mean follow-up 1.15 years). Of these patients, 547 (16.7%) who were exposed to sitagliptin were defined as the sitagliptin group and 2,735 (83.3 %) who did not use sitagliptin were the comparison group. The incidence of primary composite cardiovascular outcomes was 9.50 per 100 person-years in the sitagliptin group and was 9.70 per 100 person-years in the comparison group (hazard ratio (HR), 0.97; 95% CI, 0.73 1.29, P=0.849). Compared to the non-sitagliptin group, the sitagliptin group had similar risks of all-cause mortality, hospitalization for heart failure (HF) or percutaneous coronary intervention (PCI) with a HR of 0.82 (95% CI, 0.61-1.11, P=0.195), 0.93 (95% CI, 0.67-1.29, P=0.660), and 0.93 (95% CI, 0.75-1.14, P=0.473), respectively. CONCLUSION: The use of sitagliptin in type 2 diabetic patients with recent AMI was not associated with increased risk of adverse cardiovascular events. PMID- 26115095 TI - Reversible Fluorescent Nanoswitch Based on Carbon Quantum Dots Nanoassembly for Real-Time Acid Phosphatase Activity Monitoring. AB - A reversible fluorescence nanoswitch by integrating carbon quantum dots nanoassembly and pyrophosphate ion is developed, and a reliable real-time fluorescent assay for acid phosphatase (ACP) activity is established on the basis of the fluorescence nanoswitch. Carbon quantum dots (CQDs) abundant in carboxyl groups on the surface, nickel(II) ion and pyrophosphate ion comprise the fluorescent nanoswitch, which operates in the following way: the nanoassembly consisting of CQDs and nickel ions can be triggered by pyrophosphate ion serving as an external stimulus. At the same time, the fluorescence nanoswitch switches between two fluorescence states (OFF and ON) accompanying shifts in their physical states aggregation and disaggregation. Based on the nanoswitch, the introduction of ACP leads to breakdown of pyrophosphate ions into phosphate ions and resultant fluorescence quenching due to catalytic hydrolysis of ACP toward pyrophosphate ions (PPi). Quantitative evaluation of ACP activity in a broad range from 18.2 U/L to 1300 U/L, with a detection limit of 5.5 U/L, can be achieved in this way, which endows the assay with sufficiently high sensitivity for practical detection in human serum and seminal plasma. PMID- 26115094 TI - Isocitrate dehydrogenase 1 Gene Mutation Is Associated with Prognosis in Clinical Low-Grade Gliomas. AB - Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan-Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p < 0.001), but not 1p/19q loss (p = 0.834), occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response. Isocitrate dehydrogenase 1 mutation was highly associated with O 6-methylguanine DNA methyltransferase promoter methylation and TP53 mutation. PMID- 26115093 TI - The Microbiota and Abundance of the Class 1 Integron-Integrase Gene in Tropical Sewage Treatment Plant Influent and Activated Sludge. AB - Bacteria are assumed to efficiently remove organic pollutants from sewage in sewage treatment plants, where antibiotic-resistance genes can move between species via mobile genetic elements known as integrons. Nevertheless, few studies have addressed bacterial diversity and class 1 integron abundance in tropical sewage. Here, we describe the extant microbiota, using V6 tag sequencing, and quantify the class 1 integron-integrase gene (intI1) in raw sewage (RS) and activated sludge (AS). The analysis of 1,174,486 quality-filtered reads obtained from RS and AS samples revealed complex and distinct bacterial diversity in these samples. The RS sample, with 3,074 operational taxonomic units, exhibited the highest alpha-diversity indices. Among the 25 phyla, Proteobacteria, Bacteroidetes and Firmicutes represented 85% (AS) and 92% (RS) of all reads. Increased relative abundance of Micrococcales, Myxococcales, and Sphingobacteriales and reduced pathogen abundance were noted in AS. At the genus level, differences were observed for the dominant genera Simplicispira and Diaphorobacter (AS) as well as for Enhydrobacter (RS). The activated sludge process decreased (55%) the amount of bacteria harboring the intI1 gene in the RS sample. Altogether, our results emphasize the importance of biological treatment for diminishing pathogenic bacteria and those bearing the intI1 gene that arrive at a sewage treatment plant. PMID- 26115096 TI - Repeat Diagnoses of Bethesda Category III Thyroid Nodules: What To Do Next? AB - OBJECTIVES: To assess the malignancy rates of thyroid nodules repeatedly classified as Bethesda category III on fine needle aspiration (FNA), and to suggest management guidelines for these lesions. METHODS: This is a retrospective study that included 395 thyroid nodules categorized as Bethesda III undergone either surgery or ultrasound (US) follow-up. There were 67 nodules classified a second time as Bethesda category III on repeat FNA. We compared malignancy rates, clinicopathologic and ultrasonographic characteristics between direct surgery and repeat FNA groups and between the initial and repeat Bethesda category III groups, each. And in the repeat Bethesda III group, clinicopathologic and US variables were compared between benign and malignant nodules. RESULTS: Incidence of concurrent cancer, underlying thyroiditis and positive BRAF mutation were significantly higher in 142 nodules with direct surgery than 243 nodules with repeat FNA (p < 0.05). Of the 395 nodules with Bethesda category III cytology on initial FNA, the malignancy rate was 59.5%. In 67 nodules with repeat Bethesda III classification, however, the malignancy rate was 73.1% (p < 0.05). However, none of the variables were significantly different between the initial Bethesda category III group and the repeat Bethesda category III group (p > 0.05). In the repeat Bethesda category III group, solid consistency, irregular/microlobulated margins, nonparallel shape, and number of suspicious findings or "suspicious malignant" US assessments were associated with a high malignancy rate (p < 0.05). On multivariate logistic regression analysis, the factor associated with malignancy in the repeat Bethesda category III group was irregular/microlobulated margin (odds ratio = 15.576; 95% CI, 2.097-115.6804, p = 0.007) with a sensitivity, specificity, positive and negative predictive values, and accuracy of 81.6%, 83.3%, 93.0%, 62.5% and 82.1%, respectively. CONCLUSION: Thyroid nodules with repeated Bethesda category III classification and irregular/microlobulated margins on US are at increased risk of malignancy, and operative management should be considered as opposed to repeat FNA. PMID- 26115097 TI - Probing the Residual Structure of the Low Populated Denatured State of ADA2h under Folding Conditions by Relaxation Dispersion Nuclear Magnetic Resonance Spectroscopy. AB - The structural characterization of low populated states of proteins with accuracy comparable to that achievable for native states is important for understanding the mechanisms of protein folding and function, as well as misfolding and aggregation. Because of the transient nature of these low populated states, they are seldom detected directly under conditions that favor folding. The activation domain of human procarboxypeptidase A2 (ADA2h) is an alpha/beta-protein that forms amyloid fibrils at low pH, presumably initiated from a denatured state with a considerable amount of residual structure. Here we used Carr-Parcell-Meiboom Gill relaxation dispersion (CPMG RD) nuclear magnetic resonance (NMR) spectroscopy to characterize the structure of the denatured state of the ADA2h I71V mutant under conditions that favor folding. Under these conditions, the lifetime of the denatured state of I71V ADA2h is on the order of milliseconds and its population is approximately several percent, which makes this mutant amenable to studies by CPMG RD methods. The nearly complete set of CPMG RD-derived backbone (15)N, (13)C, and (1)H NMR chemical shifts in the I71V ADA2h denatured state reveals that it retains a significant fraction (up to 50-60%) of nativelike alpha-helical structure, while the regions encompassing native beta-strands are structured to a much lesser extent. The nativelike alpha-helical structure of the denatured state can bring together hydrophobic residues on the same sides of alpha-helices, making them available for intra- or intermolecular interactions. CPMG RD data analysis thus allowed a detailed structural characterization of the ADA2h denatured state under folding conditions not previously achieved for this protein. PMID- 26115098 TI - Effect of Ang-2-VEGF-A Bispecific Antibody in Renal Cell Carcinoma. AB - The blockade of VEGF pathway has been clinically validated as an initial treatment for renal cell carcinoma (RCC). Angiopoietin-2 (Ang-2) has been indicated as a key regulator for angiogenesis escape. The effect of a novel bispecific antibody (A2V CrossMab) against both Ang-2 and VEGF was investigated in comparison with either factor. A2V CrossMab significantly reduced tumor volume, vessel density, and interstitial fluid pressure compared to either monotherapy of anti-VEGF or anti-Ang-2. Host-derived angiogenesis-related genes have been significantly down-regulated in A2V CrossMab group. These data demonstrate that A2V CrossMab has additive anti-tumor effect for the treatment of RCC. PMID- 26115099 TI - A Systematic Literature Review of Studies Analyzing Inequalities in Health Expectancy among the Older Population. AB - AIM: To collect, organize and appraise evidence of socioeconomic and demographic inequalities in health and mortality among the older population using a summary measure of population health: Health Expectancy. METHODS: A systematic literature review was conducted. Literature published in English before November 2014 was searched via two possible sources: three electronic databases (Web of Science, Medline and Embase), and references in selected articles. The search was developed combining terms referring to outcome, exposure and participants, consisting in health expectancy, socioeconomic and demographic groups, and older population, respectively. RESULTS: Of 256 references identified, 90 met the inclusion criteria. Six references were added after searching reference lists of included articles. Thirty-three studies were focused only on gender-based inequalities; the remaining sixty-three considered gender along with other exposures. Findings were organized according to two leading perspectives: the type of inequalities considered and the health indicators chosen to measure health expectancy. Evidence of gender-based differentials and a socioeconomic gradient were found in all studies. A remarkable heterogeneity in the choice of health indicators used to compute health expectancy emerged as well as a non uniform way of defining same health conditions. CONCLUSIONS: Health expectancy is a useful and convenient measure to monitor and assess the quality of ageing and compare different groups and populations. This review showed a general agreement of results obtained in different studies with regard to the existence of inequalities associated with several factors, such as gender, education, behaviors, and race. However, the lack of a standardized definition of health expectancy limits its comparability across studies. The need of conceiving health expectancy as a comparable and repeatable measure was highlighted as fundamental to make it an informative instrument for policy makers. PMID- 26115101 TI - Heat Generation/Absorption Effects in a Boundary Layer Stretched Flow of Maxwell Nanofluid: Analytic and Numeric Solutions. AB - Analysis has been done to investigate the heat generation/absorption effects in a steady flow of non-Newtonian nanofluid over a surface which is stretching linearly in its own plane. An upper convected Maxwell model (UCM) has been utilized as the non-Newtonian fluid model in view of the fact that it can predict relaxation time phenomenon which the Newtonian model cannot. Behavior of the relaxations phenomenon has been presented in terms of Deborah number. Transport phenomenon with convective cooling process has been analyzed. Brownian motion "Db" and thermophoresis effects "Dt" occur in the transport equations. The momentum, energy and nanoparticle concentration profiles are examined with respect to the involved rheological parameters namely the Deborah number, source/sink parameter, the Brownian motion parameters, thermophoresis parameter and Biot number. Both numerical and analytic solutions are presented and found in nice agreement. Comparison with the published data is also made to ensure the validity. Stream lines for Maxwell and Newtonian fluid models are presented in the analysis. PMID- 26115100 TI - Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration. AB - HIV Nef acts as an anti-autophagic maturation factor through interaction with beclin-1 (BECN1). We report that exposure of macrophages to infectious or non infectious purified HIV induces toll-like receptor 8 (TLR8) and BECN1 dependent dephosphorylation and nuclear translocation of TFEB and that this correlates with an increase in autophagy markers. RNA interference for ATG13, TFEB, TLR8, or BECN1 inhibits this HIV-induced autophagy. However, once HIV establishes a productive infection, TFEB phosphorylation and cytoplasmic sequestration are increased resulting in decreased autophagy markers. Moreover, by 7 d post infection, autophagy levels are similar to mock infected controls. Conversely, although Nef deleted HIV similarly induces TFEB dephosphorylation and nuclear localization, and increases autophagy, these levels remain elevated during continued productive infection. Thus, the interaction between HIV and TLR8 serves as a signal for autophagy induction that is dependent upon the dephosphorylation and nuclear translocation of TFEB. During permissive infection, Nef binds BECN1 resulting in mammalian target of rapamycin (MTOR) activation, TFEB phosphorylation and cytosolic sequestration, and the inhibition of autophagy. To our knowledge, this is the first report of a virus modulating TFEB localization and helps to explain how HIV modulates autophagy to promote its own replication and cell survival. PMID- 26115102 TI - 2D light scattering static cytometry for label-free single cell analysis with submicron resolution. AB - Conventional optical cytometric techniques usually measure fluorescence or scattering signals at fixed angles from flowing cells in a liquid stream. Here we develop a novel cytometer that employs a scanning optical fiber to illuminate single static cells on a glass slide, which requires neither microfluidic fabrication nor flow control. This static cytometric technique measures two dimensional (2D) light scattering patterns via a small numerical aperture (0.25) microscope objective for label-free single cell analysis. Good agreement is obtained between the yeast cell experimental and Mie theory simulated patterns. It is demonstrated that the static cytometer with a microscope objective of a low resolution around 1.30 MUm has the potential to perform high resolution analysis on yeast cells with distributed sizes. The capability of the static cytometer for size determination with submicron resolution is validated via measurements on standard microspheres with mean diameters of 3.87 and 4.19 MUm. Our 2D light scattering static cytometric technique may provide an easy-to-use, label-free, and flow-free method for single cell diagnostics. PMID- 26115103 TI - Utilizing Radiofrequency Identification Technology to Improve Safety and Management of Blood Bank Supply Chains. AB - INTRODUCTION: The importance of efficiency in the supply chain of perishable products, such as the blood products used in transfusion services, cannot be overstated. Many problems can occur, such as the outdating of products, inventory management issues, patient misidentification, and mistransfusion. The purpose of this article was to identify the benefits and barriers associated with radiofrequency identification (RFID) usage in improving the blood bank supply chain. MATERIALS AND METHODS: The methodology for this study was a qualitative literature review following a systematic approach. The review was limited to sources published from 2000 to 2014 in the English language. Sixty-five sources were found, and 56 were used in this research study. RESULTS: According to the finding of the present study, there are numerous benefits and barriers to RFID utilization in blood bank supply chains. RFID technology offers several benefits with regard to blood bank product management, including decreased transfusion errors, reduction of product loss, and more efficient inventory management. Barriers to RFID implementation include the cost associated with system implementation and patient privacy issues. CONCLUSIONS: Implementation of an RFID system can be a significant investment. However, when observing the positive impact that such systems may have on transfusion safety and inventory management, the cost associated with RFID systems can easily be justified. RFID in blood bank inventory management is vital to ensuring efficient product inventory management and positive patient outcomes. PMID- 26115105 TI - Catch and release of concanavalin A by a mannose-immobilized photoaffinity PEGA resin coupled with a cleavable disulfide linker. AB - A photoaffinity PEGA resin containing mannose as a ligand and disulfide as a cleavable linker was prepared. The resin was crosslinked to concanavalin A, a binding protein of mannose, by UV irradiation, and the protein was subsequently released by cleavage of the disulfide linker. PMID- 26115106 TI - Evidence-based regulation and accredited continuing medical education. PMID- 26115104 TI - Wolbachia Reduces the Transmission Potential of Dengue-Infected Aedes aegypti. AB - BACKGROUND: Dengue viruses (DENV) are the causative agents of dengue, the world's most prevalent arthropod-borne disease with around 40% of the world's population at risk of infection annually. Wolbachia pipientis, an obligate intracellular bacterium, is being developed as a biocontrol strategy against dengue because it limits replication of the virus in the mosquito. The Wolbachia strain wMel, which has been introduced into the mosquito vector, Aedes aegypti, has been shown to invade and spread to near fixation in field releases. Standard measures of Wolbachia's efficacy for blocking virus replication focus on the detection and quantification of virus in mosquito tissues. Examining the saliva provides a more accurate measure of transmission potential and can reveal the extrinsic incubation period (EIP), that is, the time it takes virus to arrive in the saliva following the consumption of DENV viremic blood. EIP is a key determinant of a mosquito's ability to transmit DENVs, as the earlier the virus appears in the saliva the more opportunities the mosquito will have to infect humans on subsequent bites. METHODOLOGY/PRINCIPAL FINDINGS: We used a non-destructive assay to repeatedly quantify DENV in saliva from wMel-infected and Wolbachia-free wild type control mosquitoes following the consumption of a DENV-infected blood meal. We show that wMel lengthens the EIP, reduces the frequency at which the virus is expectorated and decreases the dengue copy number in mosquito saliva as compared to wild-type mosquitoes. These observations can at least be partially explained by an overall reduction in saliva produced by wMel mosquitoes. More generally, we found that the concentration of DENV in a blood meal is a determinant of the length of EIP, saliva virus titer and mosquito survival. CONCLUSIONS/SIGNIFICANCE: The saliva-based traits reported here offer more disease-relevant measures of Wolbachia's effects on the vector and the virus. The lengthening of EIP highlights another means, in addition to the reduction of infection frequencies and DENV titers in mosquitoes, by which Wolbachia should operate to reduce DENV transmission in the field. PMID- 26115107 TI - A rater training protocol to assess team performance. AB - INTRODUCTION: Simulation-based methodologies are increasingly used to assess teamwork and communication skills and provide team training. Formative feedback regarding team performance is an essential component. While effective use of simulation for assessment or training requires accurate rating of team performance, examples of rater-training programs in health care are scarce. We describe our rater training program and report interrater reliability during phases of training and independent rating. METHODS: We selected an assessment tool shown to yield valid and reliable results and developed a rater training protocol with an accompanying rater training handbook. The rater training program was modeled after previously described high-stakes assessments in the setting of 3 facilitated training sessions. Adjacent agreement was used to measure interrater reliability between raters. RESULTS: Nine raters with a background in health care and/or patient safety evaluated team performance of 42 in-situ simulations using post-hoc video review. Adjacent agreement increased from the second training session (83.6%) to the third training session (85.6%) when evaluating the same video segments. Adjacent agreement for the rating of overall team performance was 78.3%, which was added for the third training session. Adjacent agreement was 97% 4 weeks posttraining and 90.6% at the end of independent rating of all simulation videos. DISCUSSION: Rater training is an important element in team performance assessment, and providing examples of rater training programs is essential. Articulating key rating anchors promotes adequate interrater reliability. In addition, using adjacent agreement as a measure allows differentiation between high- and low-performing teams on video review. PMID- 26115108 TI - Development and validation of a trustworthy multisource feedback instrument to support nurse appraisals. AB - INTRODUCTION: Nurse appraisal is well established in the Western world because of its obvious educational advantages. Appraisal works best with many sources of information on performance. Multisource feedback (MSF) is widely used in business and in other clinical disciplines to provide such information. It has also been incorporated into nursing appraisals, but, so far, none of the instruments in use for nurses has been validated. We set out to develop an instrument aligned with the UK Knowledge and Skills Framework (KSF) and to evaluate its reliability and feasibility across a wide hospital-based nursing population. METHODS: The KSF framework provided a content template. Focus groups developed an instrument based on consensus. The instrument was administered to all the nursing staff in 2 large NHS hospitals forming a single trust in London, England. We used generalizability analysis to estimate reliability, response rates and unstructured interviews to evaluate feasibility, and factor structure and correlation studies to evaluate validity. RESULTS: On a voluntary basis the response rate was moderate (60%). A failure to engage with information technology and employment-related concerns were commonly cited as reasons for not responding. In this population, 11 responses provided a profile with sufficient reliability to inform appraisal (G = 0.7). Performance on the instrument was closely and significantly correlated with performance on a KSF questionnaire. DISCUSSION: This is the first contemporary psychometric evaluation of an MSF instrument for nurses. MSF appears to be as valid and reliable as an assessment method to inform appraisal in nurses as it is in other health professional groups. PMID- 26115109 TI - Predictors of attrition for a sexual assault forensic examiner (SAFE) blended learning training program. AB - INTRODUCTION: Participant attrition is a major concern for online continuing education health care courses. The current study sought to understand what factors predicted health care professionals completing the online component of a sexual assault forensic examiner (SAFE) blended learning training program (12 week online course and 2-day in-person clinical skills workshop). METHODS: The study used a Web-based survey to examine participant characteristics, motivation, and external barriers that may influence training completion. Hierarchical logistic regression was utilized to examine the predictors of training completion, while the Cox proportional hazards (Cox PH) regression model helped determine the factors associated with the timing of participant attrition. RESULTS: Results show that 79.3% of the enrolled professionals completed the online component. The study also found that clinicians who work in rural communities and those who were interested in a 2-day clinical skills workshop were more likely to complete the online course. In terms of when attrition occurred, we found that participants who were motivated by the 2-day clinical workshop, those who worked in a rural community, and participants interested in the training program because of its online nature were more likely to complete more of the online course. DISCUSSION: Blending an online course with a brief in person clinical component may serve as a motivator for completing an online course because it provides the opportunity to develop clinical skills while receiving immediate feedback. Participant attrition appears to be less of a concern for rural clinicians because this modality can reduce their barriers to accessing continuing education. PMID- 26115110 TI - Can didactic continuing education improve clinical decision making and reduce cost of quality? Evidence from a case study. AB - INTRODUCTION: Administration of human serum albumin (HSA) solutions for the resuscitation of critically ill patients remains controversial. The objective of this study was to assess the effect of continuing medical education (CME) on health care professionals' clinical decision making with regard to HSA administration and the costs of quality (COQ). A quasi-experimental study of time series association of CME intervention with COQ and use of HSA solution was conducted at the Surgery Department of the Hospital Valjevo, Serbia. The CME contained evidence-based criteria for HSA solution administration in surgical patients. The preintervention period was defined as January 2009 to May 2011. CME was provided in June 2011, with the postintervention period June 2011 to May 2012. METHODS: Total mortality rate, the rate of nonsurgical mortality, the rate of surgical mortality, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and number of hospital days per hospitalized patient were collected for each month as quality indicators. Statistical analysis was performed by multivariate autoregressive integrated moving average (MARIMA) modeling. The specification of the COQ was performed according to a traditional COQ model. RESULTS: The CME intervention resulted in an average monthly reduction of the hospital days per hospitalized patient, the rate of sepsis patient mortality, index of irrational use of HSA solutions, and COQ for $593,890.77 per year. DISCUSSION: Didactic CME presenting evidence-based criteria for HSA administration was associated with improvements in clinical decisions and COQ. In addition, this study demonstrates that models combining MARIMA and traditional COQ models can be useful in the evaluation of CME interventions aimed at reducing COQ. PMID- 26115111 TI - Effectiveness of test-enhanced learning in continuing health sciences education: a randomized controlled trial. AB - BACKGROUND: Increasing concerns over the effectiveness and quality of continuing medical education (CME) programs has encouraged educators to use theoretically driven empirical research to improve the educational value of these activities. Within cognitive psychology, theories of learning and knowledge acquisition, such as test-enhanced learning (TEL), may be used to enhance the effectiveness of CME protocols and delivery. The present study examined whether the pedagogical benefits of testing can be observed in practicing physicians. METHODS: A total of 83 physicians were recruited following an education session on constipation management and were randomized to either (a) the test condition (n = 43), where learners wrote a short test consisting of 10 short-answer questions (SAQs), or (b) the study condition (n = 40), where learners studied the same information. Four weeks later, 56 (68%) physicians completed a final test with 10 new SAQs, with 27 being from the initial test condition and 29 belonging to the initial study condition. RESULTS: Performance on the final SAQ test was equivalent for both test (42.5%) and study-only (41.2%) conditions (p = .71). DISCUSSION: The null findings in the present study are inconsistent with previous research showing the pedagogical benefits of testing relative to studying. Given that most TEL research focuses on novice learners, who lack strong associative memory networks, it is possible that TEL is specific to novices and not generalizable to experts. Alternative explanations focus on the importance of repeated, distributed testing with feedback. PMID- 26115112 TI - A 3-armed randomized controlled trial of nurses' continuing education meetings on adverse drug reactions. AB - INTRODUCTION: Nurses' insufficient knowledge of adverse drug reactions is reported as a barrier to spontaneous reporting. Therefore, CE meetings could be utilized to enhance nurses' competencies. METHODS: In a 3-armed randomized controlled trial, 496 nurses, working in a tertiary medical center, were randomly allocated to a didactic lecture, brainstorming workshop, or the control group (delayed education). Similar instructors (2 clinical pharmacists) prepared and delivered the educational content to all 3 groups. Outcomes were declarative/procedural knowledge (primary outcome), participation rate, and satisfaction. Knowledge was evaluated using a validated researcher-made questionnaire in 3 time points: immediately before, immediately after, and 3 months after each session. Participants' satisfaction was assessed immediately after each meeting via a standard tool. Data were analyzed using appropriate parametric and nonparametric tests. RESULTS: Rate of participation was 37.7% for the lecture group and 47.5% for the workshop group. The workshop participants were significantly more satisfied in comparison with the lecture group (p < .05). Mean knowledge scores were similar at baseline in the 3 study groups (43-47). Immediately after the meeting, knowledge was significantly higher in the lecture group (79.1 +/- 11.9 vs 73.7 +/- 11.3; p = .01). At the follow-up, knowledge scores of the lecture and workshop groups were similar, while significantly higher than the control group. However, the reduction of knowledge score was significantly higher in the lecture group (-13.0 +/- 15.9% vs -5.7 +/- 15.1%, p = .02). DISCUSSION: Educational interventions can improve nurses' knowledge of adverse drug reactions. Short-term learning could be achieved with lecture, but the retention of knowledge will be enhanced by simple interactive techniques. PMID- 26115113 TI - The impact of CME on physician performance and patient health outcomes: an updated synthesis of systematic reviews. AB - INTRODUCTION: Since 1977, many systematic reviews have asked 2 fundamental questions: (1) Does CME improve physician performance and patient health outcomes? and (2) What are the mechanisms of action that lead to positive changes in these outcomes? The article's purpose is to synthesize the systematic review literature about CME effectiveness published since 2003. METHODS: We identified 8 systematic reviews of CME effectiveness published since 2003 in which primary research studies in CME were reviewed and physicians' performance and/or patient health outcomes were included as outcome measures. RESULTS: Five systematic reviews addressed the question of "Is CME Effective?" using primary studies employing randomized controlled trials (RCTs) or experimental design methods and concluded: (1) CME does improve physician performance and patient health outcomes, and (2) CME has a more reliably positive impact on physician performance than on patient health outcomes. The 8 systematic reviews support previous research showing CME activities that are more interactive, use more methods, involve multiple exposures, are longer, and are focused on outcomes that are considered important by physicians lead to more positive outcomes. DISCUSSION: Future research on CME effectiveness must take account of the wider social, political, and organizational factors that play a role in physician performance and patient health outcomes. We now have 39 systematic reviews that present an evidence-based approach to designing CME that is more likely to improve physician performance and patient health outcomes. These insights from the scientific study of CME effectiveness should be incorporated in ongoing efforts to reform systems of CME and health care delivery. PMID- 26115114 TI - Navigating knowledge to action: a conceptual map for facilitating translation of population health risk planning tools into practice. AB - A population health risk tool was created that estimates future diabetes risk and provides outputs that can inform practical and meaningful diabetes prevention strategies and support local decision making and planning. A project was designed to inform and understand knowledge translation and application of this novel tool in multiple health-related settings. Lacking published studies in this area, the authors conceived a conceptual map to guide the project that integrates and adapts elements from several planned action theories. This paper describes the rationale and basis for constructing the Population Health Planning Knowledge-to Action Model and elaborates on the 2 connected structures of the framework: the Tool Creation Path and the Action Cycle. Although created for an express purpose, this model has the potential to inform application of other tools. This work demonstrates how a research team can adapt and integrate existing frameworks to better align with novel real-world knowledge translation issues. Furthermore, the integration of a population risk tool to support health decision making highlights the interaction between continuing education and knowledge translation. PMID- 26115115 TI - Ten steps for setting up an online journal club. AB - Journal clubs have an extensive history that dates back to the time of Sir William Osler. They provide a venue to discuss the latest medical literature among groups of peers and are an innovative method for translating knowledge into practice within individual institutions. With advances in social media, journal clubs are poised to take an evolutionary step by harnessing digital connectivity. Online journal clubs are uniting hundreds of medical practitioners from around the world under the banner of one cause: enhancing knowledge translation of the medical literature without the limitations of geography. This article describes 10 steps for creating online journal clubs based on the experiences of a multidisciplinary team of clinicians and medical educators. PMID- 26115117 TI - Correction: Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort. PMID- 26115116 TI - Assessing Vegetation Cover Dynamics Induced by Policy-Driven Ecological Restoration and Implication to Soil Erosion in Southern China. AB - In the aftermath of the severe droughts and floods at the end of the 20th century, the Chinese government launched several ecological restoration projects, including the Natural Forest Protection Program in 1998 and the Grain-for-Green Program in 1999, to promote afforestation and reforestation to reduce surface runoff and consequent soil erosion nationwide. However, it is still unclear how vegetation has changed in southern China since the launch of these programs. In this study, we used the MODIS Enhanced Vegetation Index (EVI) to analyze the vegetation cover dynamics in southern China from 2000 to 2009 and evaluate the resulting effects of controlling soil erosion. Our observations indicate that 5.3% of the study area significantly increased and 0.98% significantly decreased in EVI value (p < 0.05). The spring EVI had largest increase in space. The conversions of croplands on steep slopes to forests resulting from national policies led to significant increases in EVI. The increase in EVI was not driven by annual average temperature and annual precipitation. By referencing ecological restoration statistical data and field observations, we showed that ecological restoration programs significantly improved vegetation cover in southern China. Increase in the area of farmland-converted forestlands has reduced soil erosion based upon monitoring sediment yields at hydrologic stations in the Yangtze River. This study displays the spatial patterns of trend in vegetation growth since the beginning of the 21st century in southern China and highlights the important role of China's afforestation program. PMID- 26115118 TI - Asynchrony between Host Plant and Insects-Defoliator within a Tritrophic System: The Role of Herbivore Innate Immunity. AB - The effects of asynchrony in the phenology of spring-feeding insect-defoliators and their host plants on insects' fitness, as well as the importance of this effect for the population dynamics of outbreaking species of insects, is a widespread and well-documented phenomenon. However, the spreading of this phenomenon through the food chain, and especially those mechanisms operating this spreading, are still unclear. In this paper, we study the effect of seasonally declined leafquality (estimated in terms of phenolics and nitrogen content) on herbivore fitness, immune parameters and resistance against pathogen by using the silver birch Betula pendula--gypsy moth Lymantria dispar--nucleopolyhedrovirus as the tritrophic system. We show that a phenological mismatch induced by the delay in the emergence of gypsy moth larvae and following feeding on mature leaves has negative effects on the female pupal weight, on the rate of larval development and on the activity of phenoloxidase in the plasma of haemolymph. In addition, the larval susceptibility to exogenous nucleopolyhydrovirus infection as well as covert virus activation were both enhanced due to the phenological mismatch. The observed effects of phenological mismatch on insect-baculovirus interaction may partially explain the strong and fast fluctuations in the population dynamics of the gypsy moth that is often observed in the studied part of the defoliator area. This study also reveals some indirect mechanisms of effect related to host plant quality, which operate through the insect innate immune status and affect resistance to both exogenous and endogenous virus. PMID- 26115120 TI - How Do Indian Substance Users Perceive Stigma Towards Substance Use Vis-A-Vis Their Family Members? AB - Perceived stigma towards substance use may determine family members' willingness to help in the treatment process of a substance user. This study aimed to compare the perceived stigma towards substance use among Indian substance users and their family members. Fifty dyads each of alcohol- and opioid-dependent men and their family members were recruited through purposive sampling. Perceived stigma was assessed using Perceived Stigma of Substance Abuse Scale (PSAS) in both the dependent men and the family members. PSAS scores of patients and the family members correlated with each other in both the alcohol- and opioid-dependent groups. Being currently employed predicted higher PSAS scores among patients, while being unmarried predicted higher PSAS scores among family members. PMID- 26115119 TI - The UL13 and US3 Protein Kinases of Herpes Simplex Virus 1 Cooperate to Promote the Assembly and Release of Mature, Infectious Virions. AB - Herpes simplex virus type 1 (HSV-1) encodes two bona fide serine/threonine protein kinases, the US3 and UL13 gene products. HSV-1 DeltaUS3 mutants replicate with wild-type efficiency in cultured cells, and HSV-1 DeltaUL13 mutants exhibit <10-fold reduction in infectious viral titers. Given these modest phenotypes, it remains unclear how the US3 and UL13 protein kinases contribute to HSV-1 replication. In the current study, we designed a panel of HSV-1 mutants, in which portions of UL13 and US3 genes were replaced by expression cassettes encoding mCherry protein or green fluorescent protein (GFP), respectively, and analyzed DNA replication, protein expression, and spread of these mutants in several cell types. Loss of US3 function alone had largely negligible effect on viral DNA accumulation, gene expression, virion release, and spread. Loss of UL13 function alone also had no appreciable effects on viral DNA levels. However, loss of UL13 function did result in a measurable decrease in the steady-state levels of two viral glycoproteins (gC and gD), release of total and infectious virions, and viral spread. Disruption of both genes did not affect the accumulation of viral DNA, but resulted in further reduction in gC and gD steady-state levels, and attenuation of viral spread and infectious virion release. These data show that the UL13 kinase plays an important role in the late phase of HSV-1 infection, likely by affecting virion assembly and/or release. Moreover, the data suggest that the combined activities of the US3 and UL13 protein kinases are critical to the efficient assembly and release of infectious virions from HSV-1-infected cells. PMID- 26115121 TI - Viruses Occur Incorporated in Biogenic High-Mg Calcite from Hypersaline Microbial Mats. AB - Using three different microscopy techniques (epifluorescence, electronic and atomic force microscopy), we showed that high-Mg calcite grains in calcifying microbial mats from the hypersaline lake "La Salada de Chiprana", Spain, contain viruses with a diameter of 50-80 nm. Energy-dispersive X-ray spectrometer analysis revealed that they contain nitrogen and phosphorus in a molar ratio of ~9, which is typical for viruses. Nucleic acid staining revealed that they contain DNA or RNA. As characteristic for hypersaline environments, the concentrations of free and attached viruses were high (>10(10) viruses per g of mat). In addition, we showed that acid treatment (dissolution of calcite) resulted in release of viruses into suspension and estimated that there were ~15 * 10(9) viruses per g of calcite. We suggest that virus-mineral interactions are one of the possible ways for the formation of nano-sized structures often described as "nanobacteria" and that viruses may play a role in initiating calcification. PMID- 26115122 TI - The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity. AB - MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair-related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair-related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR 124 overexpression, by binding of miR-124 to the 3c-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents. PMID- 26115123 TI - The 26S Proteasome Degrades the Soluble but Not the Fibrillar Form of the Yeast Prion Ure2p In Vitro. AB - Yeast prions are self-perpetuating protein aggregates that cause heritable and transmissible phenotypic traits. Among these, [PSI+] and [URE3] stand out as the most studied yeast prions, and result from the self-assembly of the translation terminator Sup35p and the nitrogen catabolism regulator Ure2p, respectively, into insoluble fibrillar aggregates. Protein quality control systems are well known to govern the formation, propagation and transmission of these prions. However, little is known about the implication of the cellular proteolytic machineries in their turnover. We previously showed that the 26S proteasome degrades both the soluble and fibrillar forms of Sup35p and affects [PSI+] propagation. Here, we show that soluble native Ure2p is degraded by the proteasome in an ubiquitin independent manner. Proteasomal degradation of Ure2p yields amyloidogenic N terminal peptides and a C-terminal resistant fragment. In contrast to Sup35p, fibrillar Ure2p resists proteasomal degradation. Thus, structural variability within prions may dictate their ability to be degraded by the cellular proteolytic systems. PMID- 26115126 TI - [Aortic valve endocarditis: diagnosis and therapy]. PMID- 26115125 TI - [Community acquired pneumonia: antibiotic monotherapy is not inferior to combination therapy]. PMID- 26115127 TI - [Symptomatic intracranial stenosis: pharmacological therapy is superior]. PMID- 26115128 TI - [Sauna bathing is beneficial for cardiac health-the more, the better [corrected]]. PMID- 26115129 TI - [COPD: pulmonary rehabilitation beneficial]. PMID- 26115130 TI - [35-year-old patient with unclear oral finding]. PMID- 26115131 TI - [Infectious disease medicine: change is not always progress]. PMID- 26115132 TI - [Current strategies against multi-drug resistant organisms]. AB - The global spread of multi-drug resistant organisms (MDRO) is a major threat to public health. Fighting MDRO spread requires a multi-faceted approach as summarized in the German Antibiotic Resistance Strategy (DART). In the hospital, this includes antibiotic stewardship concepts and strict infection control measures. Treatment of MDRO is sophisticated. Within the last years, several antibiotics with activity against MRSA were launched and facilitate an individual therapy according to site of infection and co-morbidities. In contrast, novel antibiotics against carbapenemase producing Gram-negatives are still lacking. Current studies have shown, that a colistin-based combination treatment can improve the prognosis in these patients. The following article reviews MDRO definitions, burden of disease, treatment options and general strategies against MDRO. PMID- 26115133 TI - [Staphylococcus aureus bacteremia - a distinct entity]. AB - Bacteremia caused by Methicillin-sensitive (MSSA) and Methicillin-resistant (MRSA) Staphyloccus aureus strains are common and severe infections associated with high mortality rates and specific characteristics in disease course, complications and therapy. In this review, we discuss current recommendations for the diagnosis and treatment of MSSA and MRSA bloodstream infections. We also highlight why infectious disease consultation improves the treatment and outcome of patients with SAB and should be considered as a standard of care. PMID- 26115134 TI - [How to do a stress echocardiography?]. AB - Stress echocardiography (SE) is a powerful functional imaging technique to assess cardiac performance under work conditions. The main indication is the detection of myocardial ischemia due to coronary artery disease (CAD), however it can also be used in patients with structural heart disease (e. g. valvular disease, hypertrophic obstructive cardiomyopathy). Dynamic or pharmacological (dobutamine / adenosine) modalities are available to induce cardiac stress, basically depending on the clinical problem and the patient's ability to exercise. Exercise on a treadmill or a semi-supine bicycle is the most physiological way to induce stress. Dobutamine stimulation is useful in patients who are unable to exercise and for detection of viable myocardium in hypo- or akinetic segments. Adenosin induced hyperaemia causes steal effects in myocardial segments with significant CAD. Main limitations of SE are the need for an appropriate acoustic window and the user-dependent variability with regard to the interpretation of the results. PMID- 26115135 TI - [77-year-old female with hyponatremia, pruritus and papulous exanthema]. AB - HISTORY AND CLINICAL FINDINGS: A 77 year old female patient was admitted for the evaluation of hyponatremia and a generalized papulous exanthema with severe pruritus. INVESTIGATIONS AND DIAGNOSIS: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) could be diagnosed as cause for hyponatremia. Biopsy of a soft tissue tumor revealed a T-cell lymphoma with widespread skelettal dissemination. TREATMENT AND COURSE: Chemotherapy caused a rapid response and improvement of general well-being. SIADH could be controlled by the specific vasopressin-2-receptor antagonist tolvaptan. CONCLUSIONS: In this patient, both the papulous exanthema and the SIADH are regarded as T-cell lymphoma-associated paraneoplastic syndromes. PMID- 26115136 TI - [Lung exercise: outpatient exercise program has long-term benefits on COPD]. AB - The positive influence of regular physical training on the course of many chronic diseases in different fields is well documented. Especially for obstructive respiratory diseases the benefit of lung exercise is convincing. An overview will be given in this work how lung exercise can be an effective form of therapy for pulmonary diseases. Actually the evidence of the efficacy of physical activity is particularly overwhelming in obstructive pulmonary diseases. Several clinical trials showed an enhancement in endurance and exercise capacity, quality of life and a decrease of dyspnea and disease-related symptoms. However in comparison to other disease groups, the benefits and awareness and therefore a widespread dissemination is still insufficient. Regular physical activity is an important, effective and also cost-effective component of the therapy of respiratory diseases and is sometimes even superior to a drug therapy. Enough reason to share this kind of therapy with our patients with pulmonary diseases. PMID- 26115137 TI - [Cardiac rehabilitation in patients with atrial fibrillation]. AB - The course of cardiac rehabilitation is often altered due to episodes of paroxysmal, predominantly postoperative atrial fibrillation. In symptomatic patients, a TEE-guided cardioversion - preferential DC shock - is indicated. In patients with persistent / permanent atrial fibrillation, a heart rate up to 110 / min and 170 / min at rest and during physical activity should, respectively, be tolerated. Therefore, training should not be quitted by heart rate but rather by load. The antithrombotic management is in addition a great task in treating patients with atrial fibrillation. With the exception of patients with a CHA2DS2 VASc-Score < 1, oral anticoagulation is indicated. Atrial fibrillation has little impact on social aspects, whereas the underlying heart disease and drug treatment (oral anticoagulation) has an important impact. PMID- 26115138 TI - [The lost art of abstaining: a consequence of industrialized health care]. PMID- 26115139 TI - [Speaking the language of the patient]. PMID- 26115140 TI - [GDF-15, MRproADM, CTproET1, and CTproAVP in patients with asymptomatic diastolic dysfunction]. AB - BACKGROUND: The role of biomarkers in asymptomatic diastolic dysfunction (DD) has not been investigated so far. The aim of the study was to evaluate the clinical associations and the diagnostic property of different biomarkers in patients with asymptomatic DD. METHODS: Within a population based observational study, healthy participants (50-85 years) with an LVEF >= 50 % and no cardiovascular risk factor were prospectively identified. Patients were classified as having either DD (grade >= 1, n = 103) or no DD (CON: n = 85). All patients underwent physical examination including medical history, six-minute-walk-testing, QoL (SF-36), comprehensive echocardiography and blood sampling to measure routine values and specified biomarkers (NTproBNP, MRproANP, GDF-15, MRproADM, CTproET1, CTproAVP). RESULTS: In the DD-group plasma concentration of GDF-15 (p = 0,002), MRproADM (p < 0,001), and CTproAVP (p = 0,003) were significantly higher than in the CON group. In contrast, NTproBNP (p = 0,390), MRproANP (p = 287), and CTproET1 (p = 0,393) did not differ. GDF-15, MRproADM and CTproAVP were significantly associated with the presence of DD. However, the significance of the seen associations was lost after multiple adjustments. NTproBNP, MRproANP, and MRproADM were significantly related to E / e' as a continuous measure of diastolic function. The significance of the seen associations was lost after multiple adjustments. In ROC analyses, none of the investigated biomarkers was able to relevantly improve the diagnosis of DD. CONCLUSION: In patients with asymptomatic DD plasma concentrations of GDF-15, MRproADM and CT-proAVP were significantly higher when compared with controls. In contrast, NTproBNP, MRproANP and CTproET1 did not differ. After adjustment for age, sex, BMI and renal function, no significant association between DD or E / e' and different biomarkers could be observed. Furthermore, none of the investigated biomarkers was able to substantially improve the diagnosis of DD. PMID- 26115141 TI - [Extent of rationing and overprovision in stationary care: results of a nationwide survey of German hospitals]. AB - BACKGROUND: Faced with economic pressure and with the insufficient funding of investments many hospitals are in deficit. However, there is little evidence whether these circumstances translate into rationing of services and which factors might be relevant in this context. Concerning the development of the number of patients it is also unclear, whether economic incentives lead to an overprovision of medical services. METHOD: Based on earlier studies and semi structured interviews with hospital executives professional group specific questionnaires were developed and sent to almost 5.000 chief physicians, hospital managers and directors of nursing. The response rate was 43 %. RESULTS: All respondents perceived considerable economic restrictions. In consequence, 46 % of chief physicians have rationed useful services or replaced them by cheaper less effective alternatives. Although rationing is a concern in all medical disciplines the intensity is modest. Moreover, the chief physicians perceived a tendency to overprovision - especially in orthopedy and cardiology. CONCLUSION: Due to financial restrictions of health funds and federal states the economic pressure will stay high. This implies political actions to prevent negative consequences for patient care. PMID- 26115142 TI - Primary Care: A New Context for the Scholarship of Practice Model. AB - Interest in the emerging role for occupational therapy in the primary care practice setting has increased due to implementation of the Patient Protection and Affordable Care Act (ACA), which intends to expand health care coverage to uninsured Americans while improving coordination of care, health outcomes, and cost savings. Expanding occupational therapy to encompass promotion of wellness and prevention in a primary care context provides an opportunity for occupational therapy. The purpose of this article is to describe the role of occupational therapy in primary care and how the Scholarship of Practice model can guide the development of occupation-based and evidence-based best practice in primary care. PMID- 26115143 TI - Exploring the Counteracting Mechanism of Trehalose on Urea Conferred Protein Denaturation: A Molecular Dynamics Simulation Study. AB - To provide the underlying mechanism of the inhibiting effect of trehalose on the urea denatured protein, we perform classical molecular dynamics simulations of N methylacetamide (NMA) in aqueous urea and/or trehalose solution. The site-site radial distribution functions and hydrogen bond properties indicate in binary urea solution the replacement of NMA-water hydrogen bonds by NMA-urea hydrogen bonds. On the other hand, in ternary urea and trehalose solution, trehalose does not replace the NMA-urea hydrogen bonds significantly; rather, it forms hydrogen bonds with the NMA molecule. The calculation of a preferential interaction parameter shows that, at the NMA surface, trehalose molecules are preferred and the preference for urea decreases slightly in ternary solution with respect to the binary solution. The exclusion of urea molecules in the ternary urea-NMA trehalose system causes alleviation in van der Waals interaction energy between urea and NMA molecules. Our findings also reveal the following: (a) trehalose and urea induced second shell collapse of water structure, (b) a reduction in the mean trehalose cluster size in ternary solution, and (c) slowing down of translational motion of solution species in the presence of osmolytes. Implications of these results for the molecular explanations of the counteracting mechanism of trehalose on urea induced protein denaturation are discussed. PMID- 26115144 TI - Investigating interactions between early life stress and two single nucleotide polymorphisms in HSD11B2 on the risk of schizophrenia. AB - BACKGROUND: To examine the risk of schizophrenia in a Danish population after exposure to early life stress, and whether this risk is modified by DNA sequence variation, specifically two single nucleotide polymorphisms (SNPs) (rs5479 and rs56303414) from the gene HSD11B2. This gene encodes the enzyme 11-beta hydroxysteroid dehydrogenase type 2 which converts active cortisol into inactive cortisone. METHODS: A two-stage analysis involving (1) a population-based cohort study, and (2) a nested case-control study using genotype information. Stage 1 included 1,141,447 people; here, we calculated incidence rate ratios (IRR) for the risk of schizophrenia among children of mothers who experienced loss or serious illness of close relatives before, during, and after pregnancy. In stage 2, we genotyped rs5479 and rs56303414 among 1275 schizophrenia cases and 1367 controls, and investigated interactions between genotypes and early life stress on the risk of schizophrenia. RESULTS: In stage 1, no increased risk of schizophrenia was found in offspring after exposure during pregnancy, but offspring exposed to early life stress at age 0-2 years had a significantly increased risk of schizophrenia (adjusted IRR 1.18, 95% confidence interval 1.07 1.31). For rs5479, the minor allele was nucleotide A, and the major allele was nucleotide C. No interaction was found between rs5479 and exposure during pregnancy. Individuals with the minor A allele of rs5479, however, had a significantly increased risk of schizophrenia after exposure to early life stress at age 3-9 years (adjusted IRR 2.06, 1.04-4.06). No interaction was found between rs56303414 and exposure in any of the time periods. CONCLUSION: No association was found between exposure to early life stress during pregnancy and schizophrenia in the offspring investigated, whereas individuals exposed to early life stress within the first two years of life had an increased risk. No interaction was found between HSD11B2 and exposure during pregnancy, but individuals with the A allele of rs5479 had an increased risk of schizophrenia after exposure at age 3-9 years. PMID- 26115145 TI - Thinking of attachments reduces noradrenergic stress response. AB - Although there is much evidence that activating mental representations of attachments figure is beneficial for psychological health and can reduce stress response, no research has directly investigated whether attachment activation can ameliorate hormonal stress response. This study investigated whether activating an attachment figure or a non-attachment figure following administration of a socially evaluated cold pressor test to elicit stress impacted on glucocorticoid and noradrenergic response. Participants (N = 61) provided baseline salivary samples, underwent a cold pressor test, then imagined an attachment or non attachment figure, and finally provided subsequent saliva samples. Participants who imagined a non-attachment figure had greater noradrenergic response following the stressor than those who imagined an attachment figure. These findings highlight that activating attachment representations can ameliorate the immediate noradrenergic stress response. PMID- 26115146 TI - Mobile phone-based interventions for improving contraception use. AB - BACKGROUND: Contraception provides significant benefits for women's and children's health, yet an estimated 225 million women had an unmet need for modern contraceptive methods in 2014. Interventions delivered by mobile phone have been demonstrated to be effective in other health areas, but their effects on use of contraception have not been established. OBJECTIVES: To assess the effects of mobile phone-based interventions for improving contraception use. SEARCH METHODS: We searched for randomised controlled trials (RCTs) of client provider interventions delivered by mobile phone to improve contraception use compared with standard care or another intervention. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Global Health, PsycINFO, POPLINE, Africa-Wide Information and Latin American Caribbean Health Sciences Literature (LILACS) from January 1993 to October 2014, as well as clinical trials registries, online mHealth resources and abstracts from key conferences. SELECTION CRITERIA: Randomised controlled trials of mobile phone-based interventions to improve any form of contraception use amongst users or potential users of contraception. Outcome measures included uptake of contraception, measures of adherence, pregnancy and abortion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts of studies retrieved using the search strategy and extracted data from the included studies. We calculated the Mantel-Haenszel risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, together with 95% confidence intervals (CIs). Differences in interventions and outcome measures did not permit us to undertake meta-analysis. MAIN RESULTS: Five RCTs met our inclusion criteria. Three trials aimed to improve adherence to a specific method of contraception amongst existing or new contraception users by comparing automated text message interventions versus standard care. Two trials aimed to improve both uptake and adherence, not limited to one method, in both users and non-users of contraception. No trials were at low risk of bias in all areas assessed.One trial in the USA reported improved self reported oral contraceptive (OC) continuation at six months from an intervention comprising a range of uni-directional and interactive text messages (RR 1.19, 95% CI 1.05 to 1.35). One trial in Cambodia reported increased self reported use of effective contraception at four months post abortion from an intervention comprising automated interactive voice messages and phone counsellor support (RR 1.39, 95% CI 1.17 to 1.66).One feasibility trial in the USA reported a lower mean number of days between scheduled and completed attendance for the first but not subsequent Depo-Provera appointments using clinic records from an intervention comprising reminders and healthy self management text messages (mean difference (MD) -8.60 days, 95% CI -16.74 to -0.46). Simple text message OC reminders had no effect on missed pills as assessed by electronic medication monitoring in a small trial in the USA (MD 0.5 missed pills, 95% CI -1.08 to 2.08). No effect on self reported contraception use was noted amongst isotretinoin users from an intervention that provided health information via two uni-directional text messages and mail (RR 1.26, 95% CI 0.84 to 1.89). One trial assessed potential adverse effects of the intervention and reported no evidence of road traffic accidents or domestic abuse. AUTHORS' CONCLUSIONS: Our review provides limited evidence that interventions delivered by mobile phone can improve contraception use. Whilst evidence suggests that a series of interactive voice messages and counsellor support can improve post-abortion contraception, and that a mixture of uni directional and interactive daily educational text messages can improve OC adherence, the cost-effectiveness and long-term effects of these interventions remain unknown. Further high-quality trials are required to robustly establish the effects of interventions delivered by mobile phone to improve contraception use. PMID- 26115147 TI - A technique for implantation of the CentriMag left ventricular assist device to allow ambulation and rehabilitation in patients with heart failure. AB - BACKGROUND: The therapeutic options for heart failure include inotropic agents, intraaortic balloon pumps, and left ventricular assist devices (LVAD). Implantable LVADs are not appropriate for all patients. The short-term devices require patients to stay in bed, connected to cannulas, which are usually inserted using a median sternotomy. This approach requires a subsequent sternotomy, midline cannulas (which can make sitting difficult), and immobility. We began using a right thoracotomy with cannulas placed through intercostal spaces for selected patients in need of temporary LVAD support. METHODS: This retrospective chart review examined our experience with CentriMag LVAD placement via right thoracotomy from August 2009 to June 2013. We reviewed the reasons for support, the degree of postoperative mobilization, and the outcomes of the patients treated in this manner. RESULTS: This approach was used in 6 patients. Four patients lacked financial or social support for a long-term, implantable LVAD. One patient was considered too ill to have an implantable LVAD placed, and one was treated with temporary support with hope for recovery from myocarditis. Five of these 6 patients were able to walk soon after LVAD implantation and initiate rehabilitation. One did not recover and had support withdrawn. Another suffered a stroke and had support withdrawn. Four of the 6 were transplanted successfully. CONCLUSIONS: CentriMag LVAD implantation via a right thoracotomy is a feasible approach that provides adequate hemodynamic support while allowing patients to ambulate, making subsequent cardiac transplantation less complicated by allowing the avoidance of a repeat sternotomy. PMID- 26115148 TI - Coronary embolism causing acute inferior wall and ventricular myocardial infarction in a patient with rheumatic valvular heart disease: treatment with thrombus aspiration. AB - An elderly man with rheumatic valvular heart disease and atrial fibrillation presented with acute myocardial infarction. A coronary angiogram revealed complete occlusion of the right coronary artery (RCA), and we therefore considered that a thrombus might have obstructed the ostium of the RCA. We used a guiding catheter and the syringe of an aspiration device to remove two large dark red thrombi. A subsequent angiogram revealed that blood flow through the RCA had recovered, and the endomembrane of the RCA was smooth, with no evidence of stenosis or residual thrombus. In this case, thrombus aspiration via a guiding catheter was efficacious for treating this type of coronary embolism. PMID- 26115149 TI - Antibiotic therapy did not prevent the rupture of mycotic aneurysm of the superior mesenteric artery. AB - Mycotic aneurysm of the superior mesenteric artery (SMA) is a rare complication of infective endocarditis. We report a case with infective endocarditis involving the aortic valve complicated by multiple septic embolisms. The patient was treated with antibiotics for 6 weeks. During preparation for surgical treatment, the patient developed acute abdominal pain and was diagnosed with a ruptured SMA aneurysm, which was successfully treated with an emergency operation of aneurysm ligation. The aortic valve was replaced 17 days later and the patient recovered uneventfully. In conclusion, we present a rare case with infective endocarditis (IE) complicated by SMA aneurysm. Antibiotic treatment did not prevent the rupture of SMA aneurysm. Abdominal pain in a patient with a recent history of IE should be excluded with ruptured aneurysm. PMID- 26115150 TI - Exclusion of thrombocytopenia as a contraindication for invasive radiofrequency ablation in a patient with paroxysmal atrial fibrillation by using magnesium anticoagulation instead of EDTA: another case of anticoagulant-induced pseudo thrombocytopenia. AB - Thrombocytopenia might be an exclusion criterion for invasive radiofrequency catheter ablation; therefore it is necessary to differentiate between pseudo thrombocytopenia and a low platelet count due to other etiologies.A 69-year-old female presented to the cardiology department with recurrent atrial fibrillation that was resistant to conventional drug treatment. The initial laboratory findings were within the normal ranges, except for low platelet counts that occurred without a specific bleeding history. The reason for thrombocytopenia was anticoagulant-induced in vitro aggregation of platelets in the presence of EDTA as well as in citrated blood samples. As recently communicated, magnesium anticoagulated blood samples prevent platelet aggregation in individuals with anticoagulant-associated pseudo-thrombocytopenia. Although its aggregation inhibiting effect is known from previous clinical observations, magnesium sulphate has not been introduced as an anticoagulant in analytical medicine.Based on our observations, blood anticoagulated with magnesium sulphate is recommended to verify low routine platelet counts before final clinical decisions are made. PMID- 26115151 TI - Thrombocytopenia associated with Perceval sutureless aortic valve replacement in elderly patients: a word of caution. AB - OBJECTIVE: The aim of this study was to report for the first time the phenomenon of thrombocytopenia associated with the use of sutureless aortic valve replacements (AVR), and try to find an explanation for its occurrence. METHODS: The data was collected retrospectively for all patients who had sutureless AVR (7 patients) and was compared to patients who underwent sutured AVR (22 patients) by the same surgeon between February 2012 and November 2013. RESULTS: Cardiopulmonary bypass and cross-clamp durations were shorter in the sutureless group (96.4 min, 70.6 min) compared to the sutured group (128.3 min, 97.3 min), (P = .04, P = .003) respectively. Mean transvalvular gradients were lower in the sutureless group (mean = 9.6 mmHg) compared to the sutured group (mean = 17.3 mmHg). Platelet levels were significantly lower in the Perceval patients compared to the Enable patients and sutured valves. Platelet transfusion was higher for sutureless valves (6.5 units versus 5.4 units for the sutured group, P = .63), especially the Perceval valve (7.6 units versus 5.3 for the Enable valve, P = .35), but was not statistically significant. Packed red blood cells (PRBCs) transfusion was significantly higher in the sutureless group (6 units versus 3.1 for the sutured group, P = .002). CONCLUSION: The implantation of sutureless aortic valves, especially the Perceval valve, was associated with a significant drop in platelet count postoperatively with slow recovery and higher PRBCs transfusion requirements. Extreme caution should be taken before the routine use of these valves in elderly patients who are already at risk of thrombocytopenia postoperatively. PMID- 26115152 TI - Oxygen fraction adjustment according to body surface area during extracorporeal circulation. AB - BACKGROUND: The inspiratory oxygen fraction (FiO2) is usually set between 60% and 100% during conventional extracorporeal circulation (ECC). However, this strategy causes partial oxygen pressure (PaO2) to reach hyperoxemic levels (>180 mmHg). During anesthetic management of cardiothoracic surgery it is important to keep PaO2 levels between 80-180 mmHg. The aim of this study was to assess whether adjusting FiO2 levels in accordance with body temperature and body surface area (BSA) during ECC is an effective method for maintaining normoxemic PaO2 during cardiac surgery. METHODS: After approval from the Ethics Committee of the University of Acibadem, informed consent was given from 60 patients. FiO2 adjustment strategies applied to the patients in the groups were as follows: FiO2 levels were set as 0.21 * BSA during hypothermia and 0.21 * BSA + 10 during rewarming in Group I; 0.18 * BSA during hypothermia and 0.18 * BSA + 15 during rewarming in Group II; and 0.18 * BSA during hypothermia and variable with body temperature during rewarming in Group III. Arterial blood gas values and hemodynamic parameters were recorded before ECC (T1); at the 10th minute of cross clamp (T2); when the esophageal temperature (OT) reached 34 degrees C (T3); when OT reached 36 degrees C (T4); and just before the cessation of ECC (T5). RESULTS: Mean PaO2 was significantly higher in Group I than in Group II at T2 and T3 (P = .0001 and P = .0001, respectively); in Group I than in Group III at T1 (P = .02); and in Group II than in Group III at T2, T3, and T4 (P = .0001 for all). CONCLUSION: Adjustment of FiO2 according to BSA rather than keeping it at a constant level is more appropriate for keeping PaO2 between safe level limits. However, since oxygen consumption of cells vary with body temperature, it would be appropriate to set FiO2 levels in concordance with the body temperature in the rewarming period. PMID- 26115153 TI - Off-pump pulmonary embolectomy. AB - Pulmonary embolism is a common clinical condition associated with high mortality. Surgical pulmonary embolectomy (SPE), despite having been in existence for over 100 years, is generally regarded as an option of last resort with high mortality rates. Prompt recognition of predictors of mortality, such as right ventricular stress on echocardiography, helps decision-making for immediate surgical pulmonary embolectomy prior to development of significant circulatory collapse, with promising results.We present a 71-year-old male, with recent intracranial bleed and acute massive bilateral pulmonary embolism. The patient underwent successful off-pump surgical pulmonary embolectomy. PMID- 26115154 TI - Surgical removal of guidewire entrapped within stent struts during percutaneous coronary angioplasty. AB - There has been a growing trend toward percutaneous coronary angioplasty for complex coronary artery lesions. Stent or guidewire break off or trapping within the coronary artery lumen is a rare complication, but it may have fatal consequences. In such cases, the entrapped device may be removed by either percutaneous route or surgical exploration. Here, we report a patient with guidewire entrapment within the struts of the intracoronary stent during primary percutaneous coronary angioplasty, which necessitated surgical removal and subsequent coronary artery bypass grafting (CABG). PMID- 26115155 TI - Mitral valve replacement in an adult with left pulmonary agenesis. AB - Pulmonary agenesis is associated with the absence of pulmonary vessels, bronchi, or parenchyma. This condition usually occurs between the 4th and 5th week of gestation during the embryonic phase. Etiopathogenic factors associated with pulmonary agenesis are not fully understood. In the literature, genetic and teratogenic factors, viral infections, and vitamin-A deficiency are shown to be associated with pulmonary agenesis [Malcon 2012]. This condition may be seen unilaterally or bilaterally. Although the precise rate of incidence is unknown, it is estimated to occur in one of every 10,000 to 12,000 live births [Yetim 2011]. There is a 1.3:1 female predominance with unilateral agenesis [Halilbasic 2013]. PMID- 26115156 TI - Primary cardiac synovial sarcoma originating from the mitral valve causing left ventricular outflow tract obstruction. AB - An 11-year-old boy was admitted due to different episodes of syncope and convulsion. Echocardiogram revealed a mass of 2 * 4 cm originating from the mitral subvalvular apparatus and more precisely from the antero-lateral papillary muscle, protruding in the left ventricle outflow tract causing intermittent obstruction. The patient underwent surgical excision of the left sided mass. Pathology confirmed the diagnosis of primary synovial sarcoma. At 6 months after the operation a small mass in the left ventricle of 1 * 1 cm was detected. The patient underwent reoperation consisting in radical resection of the subvalvular apparatus and mitral valve replacement. Histology confirmed that the mass was a cardiac synovial sarcoma. At 1 year after surgery the patient is doing well. PMID- 26115157 TI - Asymptomatic right circumflex aortic arch associated with ventricular septal defect and biscuspid aortic valve. AB - INTRODUCTION: Anomalies of the aortic arch are frequent congenital malformations, which rarely form partial or complete vascular rings. A rare form of vascular ring is the encircling, or circumflex, aortic arch. CASE REPORT: A 19-month-old boy, with no respiratory symptoms, was referred for ventricular septal defect (VSD) repair. Cardiac magnetic resonance imaging and echocardiography confirmed the perimembranous VSD, a bicuspid aortic valve with normal function, and showed a right-sided ascending aorta, bifurcating to the left behind the esophagus and trachea above the tracheal bifurcation, with a left-sided descending aorta, a left ligamentum arteriosum and aberrant left subclavian artery, realizing a circumflex aortic arch. The child underwent successful VSD repair and ligamentum arteriosum division, with an uneventful postoperative course. CONCLUSIONS: Previous reports have described the association of circumflex aortic arch with VSD, but there is no previous report of its association with VSD and bicuspid aortic valve. Patients are usually symptomatic either preoperatively, or after VSD repair. For this reason, division of the ligamentum arteriosum, to open the vascular ring and free the trachea and esophagus from compression, should be performed in patients undergoing cardiac surgery for associated malformations. PMID- 26115158 TI - Insertion of the intraaortic balloon pump via the ascending aorta or the aortic arch using the HEARTSTRING Proximal Seal System. AB - PURPOSE: The HEARTSTRING Proximal Seal System is used to avoid aortic clamping to insert the intraaortic balloon pump (IABP) in the ascending aorta or the aortic arch. This technique is used when calcification or atheroma prevents side clamping of the ascending aorta or the aortic arch. DESCRIPTION: A vein graft or a small-caliber vascular prosthesis for the later insertion of the IABP is sewn to the ascending aorta or the aortic arch using the HEARTSTRING Proximal Seal System. EVALUATION: In our department, this technique is applied whenever insertion of the IABP is not feasible via the femoral arteries. CONCLUSION: The technique allows the safe insertion of the IABP via the ascending aorta or the aortic arch. PMID- 26115159 TI - Ankaferd blood stopper decreases postoperative bleeding and number of transfusions in patients treated with clopidogrel: a double-blind, placebo controlled, randomized clinical trial. AB - BACKGROUND: The risk of reoperation due to bleeding after open heart surgery is 2.2%-4.2%. Patients who undergo reoperation have a two to six times greater mortality rate. Risk factors for reoperation include: older age, low body mass index, time on extracorporeal circulation, and emergency operations. In coronary artery bypass graft (CABG) patients who are treated preoperatively with antiplatelets, including clopidogrel, the source of postoperative bleeding may be difficult to detect. The aim of this study was to investigate the effectiveness of local Ankaferd blood stopper (ABS) to prevent mediastinal bleeding in CABG patients who were treated with clopidogrel and acetylsalicylic acid (ASA) preoperatively. METHODS: Twenty-five emergency CABG patients premedicated with clopidogrel and ASA as antiplatelet drugs were included in the study (Group 1). An additional twenty-five patients who were premedicated with the same antiplatelet agents were selected as a control group (Group 2). Preoperative clinical characteristics of the two groups were comparable. At the end of the surgery, 4-10 mL of ABS solution was sprayed on the mediastinal and epicardial tissue following protamine administration in Group1. We compared postoperative total mediastinal bleeding, reoperation rate and total blood and blood products transfused between the two groups. RESULTS: There was no mortality in either of the two groups. Mean postoperative bleeding was 430 mL in the ABS group, and 690 mL in the CG group (P = .044). In the ICU, bleeding in groups 1 and 2 was 610 mL and 980 mL, respectively (P = .025); total bleeding from the mediastinum was 830 mL and 1490 mL, respectively (P = .001) and the amount of autotransfusion was 210 mL and 400 mL (P = .003). Total transfusion of PRBCs in the operating room in groups 1 and 2 was 0.3 and 0.8, respectively (P = .003). No patients in the ABS group needed surgical revision due to severe bleeding or cardiac tamponade. CONCLUSION: The use of local ABS reduces bleeding, transfusion requirements of packed red blood cells, platelets and total blood units in patients premedicated with clopidogrel and ASA undergoing emergent CABG . PMID- 26115160 TI - Cord Blood Methylmercury and Fetal Growth Outcomes in Baltimore Newborns: Potential Confounding and Effect Modification by Omega-3 Fatty Acids, Selenium, and Sex. AB - BACKGROUND: Methylmercury (MeHg) may affect fetal growth; however, prior research often lacked assessment of mercury speciation, confounders, and interactions. OBJECTIVE: Our objective was to assess the relationship between MeHg and fetal growth as well as the potential for confounding or interaction of this relationship from speciated mercury, fatty acids, selenium, and sex. METHODS: This cross-sectional study includes 271 singletons born in Baltimore, Maryland, 2004-2005. Umbilical cord blood was analyzed for speciated mercury, serum omega-3 highly unsaturated fatty acids (n-3 HUFAs), and selenium. Multivariable linear regression models controlled for gestational age, birth weight, maternal age, parity, prepregnancy body mass index, smoking, hypertension, diabetes, selenium, n-3 HUFAs, and inorganic mercury (IHg). RESULTS: Geometric mean cord blood MeHg was 0.94 MUg/L (95% CI: 0.84, 1.07). In adjusted models for ponderal index, betaln(MeHg) = -0.045 (g/cm(3)) * 100 (95% CI: -0.084, -0.005). There was no evidence of a MeHg * sex interaction with ponderal index. Contrastingly, there was evidence of a MeHg * n-3 HUFAs interaction with birth length [among low n-3 HUFAs, betaln(MeHg) = 0.40 cm, 95% CI: -0.02, 0.81; among high n-3 HUFAs, betaln(MeHg) = -0.15, 95% CI: -0.54, 0.25; p-interaction = 0.048] and head circumference [among low n-3 HUFAs, betaln(MeHg) = 0.01 cm, 95% CI: -0.27, 0.29; among high n-3 HUFAs, betaln(MeHg) = -0.37, 95% CI: -0.63, -0.10; p-interaction = 0.042]. The association of MeHg with birth weight and ponderal index was affected by n-3 HUFAs, selenium, and IHg. For birth weight, betaln(MeHg) without these variables was -16.8 g (95% CI: -75.0, 41.3) versus -29.7 (95% CI: -93.9, 34.6) with all covariates. Corresponding values for ponderal index were -0.030 (g/cm(3)) * 100 (95% CI: -0.065, 0.005) and -0.045 (95% CI: -0.084, -0005). CONCLUSION: We observed an association of increased MeHg with decreased ponderal index. There is evidence for interaction between MeHg and n-3 HUFAs; infants with higher MeHg and n-3 HUFAs had lower birth length and head circumference. These results should be verified with additional studies. PMID- 26115162 TI - The influence of motivation on stress: is it stressful not to fit? AB - The present research elaborates on the regulatory fit hypothesis by investigating a biological stress marker in a motivational fit- and non-fit-situation. Recent stress theories lead to the assumption that the participants' stress level in fit situations remains constant or rather decreases, whereas under non-fit-conditions an increase of the stress activity is observed. We tested this hypothesis by assessment of salivary alpha-amylase (sAA), a saliva-based stress marker presumed to reflect noradrenergic activity. The results indicated that participants in a fit-situation show a decrease in sAA, whereas participants in a non-fit-situation demonstrate a contrary effect with an increase in sAA. These findings extend the concept of regulatory fit by illustrating that there are differences in sAA activity depending on whether participants are in a fit-situation. The experience of regulatory fit appears to be associated with a reduction of stress. PMID- 26115161 TI - HPA-axis stress reactivity in youth depression: evidence of impaired regulatory processes in depressed boys. AB - Given the link between youth depression and stress exposure, efforts to identify related biomarkers have involved examinations of stress regulation systems, including the hypothalamic-pituitary-adrenal (HPA) axis. Despite these vast efforts, the underlying mechanisms at play, as well as factors that may explain heterogeneity of past findings, are not well understood. In this study, we simultaneously examined separate components of the HPA-axis response (e.g. activation intensity, peak levels, recovery) to the Socially Evaluated Cold Pressor Test in a targeted sample of 115 youth (age 9-16), recruited to overrepresent youth with elevated symptoms of depression. Among youth who displayed a cortisol response to the task, depression symptoms were associated with higher peak responses but not greater rate of activation or recovery in boys only. Among those who did not respond to the task, depression symptoms were associated with greater cortisol levels throughout the visit in boys and girls. Results suggest that depression symptoms are associated with a more prolonged activation of the axis and impaired recovery to psychosocial stressors primarily in boys. We discussed two potential mechanistic explanations of the link between depression symptoms and the duration of activation: (1) inhibitory shift (i.e. point at which the ratio of inhibitory and excitatory input into the axis shifts from greater excitatory to greater inhibitory input) or (2) inhibitory threshold (i.e. level of cortisol exposure required to activate the axis' feedback inhibition system). PMID- 26115163 TI - Urokinase receptor-deficient mice mount an innate immune response to and clarify respiratory viruses as efficiently as wild-type mice. AB - The plasminogen activator receptor (uPAR) is required for lung infiltration by innate immune cells in respiratory bacterial infections. In order to verify if this held true for respiratory viruses, wild type (WT) and uPAR knockout (uPAR(-/ )) mice were inoculated intranasally with the human respiratory syncytial virus (HRSV) and the influenza A virus. At several days post-infection (dpi), viral titers in the lungs were determined while cell infiltrates in the bronchoalveolar lavage (BAL) were analyzed by flow cytometry. In the case of influenza A, body weight loss and mortality were also monitored. Only minor differences were observed between infected WT and uPAR(-/-) mice, primarily in influenza virus replication and pathology. These results indicate that uPAR does not play a major role in limiting virus replication or in orchestrating the innate immune response against HRSV or influenza infections in mice. This suggests that there are fundamental differences in the immune control of the viral infections studied here and those caused by bacteria. PMID- 26115164 TI - Lipid rafts both in cellular membrane and viral envelope are critical for PRRSV efficient infection. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) represents a significantly economical challenge to the swine industry worldwide. In this study, we investigated the importance of cellular and viral lipid rafts in PRRSV infection. First, we demonstrated that PRRSV glycoproteins, Gp3 and Gp4, were associated with lipid rafts during viral entry, and disruption of cellular lipid rafts inhibited PRRSV entry. We also showed the raft-location of CD163, which might contribute to the glycoproteins-raft association. Subsequently, raft disruption caused a significant reduction of viral RNA production. Moreover, Nsp9 was shown to be distributed in rafts, suggesting that rafts probably serve as a platform for PRRSV replication. Finally, we confirmed that disassembly of rafts on the virus envelope may affect the integrity of PRRSV particles and cause the leakage of viral proteins, which impaired PRRSV infectivity. These findings might provide insights on our understanding of the mechanism of PRRSV infection. PMID- 26115165 TI - Extracellular signal-regulated kinase (ERK) activation is required for porcine epidemic diarrhea virus replication. AB - Porcine epidemic diarrhea virus (PEDV) is a highly enteropathogenic coronavirus of swine that causes acute enteritis with high mortality in nursery piglets. To date, the cellular factors involved in PEDV replication have not been well defined. The extracellular signal-regulated kinase (ERK) that serves as a critical component of cellular signal transduction pathways to modulate a variety of cellular functions has been shown to regulate several viral infections. In the present study, we found that PEDV activates ERK1/2 early in infection independently of viral replication. The PEDV-induced ERK1/2 activation resulted in the phosphorylation of its downstream substrate Elk-1 in infected cells. Treatment with ERK inhibitors or ERK1/2 knockdown significantly suppressed viral progeny production. Inhibition of ERK activation also diminished viral protein expression and genomic and subgenomic RNA transcription. These findings indicate that the ERK signaling pathway plays an important role in the PEDV life cycle and beneficially contributes to viral infection. PMID- 26115166 TI - Three cardiovirus Leader proteins equivalently inhibit four different nucleocytoplasmic trafficking pathways. AB - Cardiovirus infections inhibit nucleocytoplasmic trafficking by Leader protein induced phosphorylation of Phe/Gly-containing nucleoporins (Nups). Recombinant Leader from encephalomyocarditis virus, Theiler's murine encephalomyelitis virus and Saffold virus target the same subset of Nups, including Nup62 and Nup98, but not Nup50. Reporter cell lines with fluorescence mCherry markers for M9, RS and classical SV40 import pathways, as well as the Crm1-mediated export pathway, all responded to transfection with the full panel of Leader proteins, showing consequent cessation of path-specific active import/export. For this to happen, the Nups had to be presented in the context of intact nuclear pores and exposed to cytoplasmic extracts. The Leader phosphorylation cascade was not effective against recombinant Nup proteins. The findings support a model of Leader dependent Nup phosphorylation with the purpose of disrupting Nup-transportin interactions. PMID- 26115167 TI - Co-infection of influenza A viruses of swine contributes to effective shuffling of gene segments in a naturally reared pig. AB - Following the 2009 H1N1 pandemic, surveillance activities have been accelerated globally to monitor the emergence of novel reassortant viruses. However, the mechanism by which influenza A viruses of swine (IAV-S) acquire novel gene constellations through reassortment events in natural settings remains poorly understood. To explore the mechanism, we collected 785 nasal swabs from pigs in a farm in Thailand from 2011 to 2014. H3N2, H3N1, H1N1 and H1N2 IAVs-S were isolated from a single co-infected sample by plaque purification and showed a high degree of diversity of the genome. In particular, the H1N1 isolates, possessing a novel gene constellation previously unreported in Thailand, exhibited greater variation in internal genes than H3N2 IAVs-S. A pair of isolates, designated H3N2-B and H1N1-D, was determined to have been initially introduced to the farm. These results demonstrate that numerous IAVs-S with various gene constellations can be created in a single co-infected pig via reassortment. PMID- 26115168 TI - Update: Accidental drownings, Active Component, U.S. Armed Forces, 2005-2014. AB - Service members are at risk for unintentional drownings during training, occupational activities, and off-duty recreation. During 2005-2014, there were 1,193 incident episodes of accidental drowning with a rate of 8.4 per 100,000 person-years. Approximately one in six (n=162; 13.6%) of drowning episodes resulted in death. The overall incidence rate of accidental drowning decreased during the surveillance period; however, the death rate remained relatively stable. Incidence rates overall and death rates were relatively high among service members who were male, young, and in either the Navy or Marine Corps. The percentage of cases that were fatal was greatest among black, non-Hispanic service members. The results of this report may be useful to increase awareness regarding the ongoing risks and effects of drowning-related episodes among U.S. service members. PMID- 26115169 TI - Risk of Mental Health Disorders Following an Initial Diagnosis of Postpartum Depression, Active Component, U.S. Armed Forces, 1998-2010. AB - Postpartum depression (PPD) is one of the most common psychiatric conditions of the postpartum period. Several studies have found an association between PPD and other mental health disorders. The Defense Medical Surveillance System (DMSS) was used to identify a cohort of primiparous service women with PPD between 1998 and 2010 and match them by month of delivery to a cohort of women without PPD. During the surveillance period, there were 5,203 incident cases of PPD with a crude rate of 44.9 per 1,000 person-years. Individuals in the PPD cohort, when compared to their matched controls, were at higher risk for subsequent depressive disorders (adjusted hazard ratio [HR]: 7.3 [95% CI: 5.2-10.3]), anxiety disorders (adjusted HR: 3.2 [95% CI: 2.5-4.0]), and bipolar disorders (adjusted HR: 4.7 [95% CI: 1.9 11.9]). There were higher rates of these mental health diagnoses among individuals who eventually left service. Early screening, support, and treatment are essential during this vulnerable postpartum time frame to preserve the female fighting force. PMID- 26115170 TI - Urinary Tract Infections in Active Component U.S. Armed Forces Women Before and After Routine Screening Pap Examination. AB - It has been suggested that Pap tests, when used as surrogate markers for routine pelvic examinations in asymptomatic women, may be associated with an increased short-term risk of urinary tract infections (UTIs). This retrospective cohort study used Defense Medical Surveillance System (DMSS) data from 2007 through 2013 to compare the incidence of UTIs in active component women before and after receiving a routine screening Pap examination. The pre-Pap (baseline) UTI incidence rate in this cohort was 105.9 per 1,000 person-years (p-yrs) compared to 129.8 per 1,000 p-yrs post-Pap; the rate ratio was 1.23 (95% CI: 1.18-1.27). The adjusted relative risk of UTI post-Pap was 1.14 (95% CI: 1.10-1.18) and the adjusted percentage of UTIs attributable to a Pap test in the post-exposure period was 12.2% (95% CI: 9.1-15.2). Routine Pap tests, when used as a surrogate marker for pelvic examination, may be a modifiable risk factor for UTI in active component U.S. military women. PMID- 26115171 TI - Diarrheal and Respiratory Illness Surveillance During US-RP Balikatan 2014. AB - Diarrheal and respiratory illness surveillance was conducted during the 2014 Republic of the Philippines-U.S. Exercise Balikatan in the Philippines. Seven stool and three respiratory specimens that met the inclusion criteria were collected. Diarrhea stool specimens were tested with commercial enzyme-linked immunosorbent assay kits and real-time polymerase chain reaction (PCR) for 12 viral, bacterial, and protozoan pathogens. Campylobacter, enterotoxigenic Escherichia coli (ETEC), and enteropathogenic Escherichia coli (EPEC) were detected in four of seven (57%), two of seven (29%), and four of seven (57%) specimens, respectively. There were co-infections of EPEC and ETEC in two cases and EPEC and Campylobacter spp. in one case. Respiratory samples were tested using RT-PCR. One of three samples was positive for influenza B. Laboratory-based surveillance is important in determining causative agents for illnesses experienced by military personnel during deployment. Development of vaccines for enteric diseases should be expedited to mitigate their impact on operational readiness. PMID- 26115172 TI - The Importance of Integration of Stakeholder Views in Core Outcome Set Development: Otitis Media with Effusion in Children with Cleft Palate. AB - BACKGROUND: Approximately 75% of children with cleft palate (CP) have Otitis Media with Effusion (OME) histories. Evidence for the effective management of OME in these children is lacking. The inconsistency in outcome measurement in previous studies has led to a call for the development of a Core Outcome Set (COS). Despite the increase in the number of published COS, involvement of patients in the COS development process, and methods to integrate the views of patients and health professionals, to date have been limited. METHODS AND FINDINGS: A list of outcomes measured in previous research was identified through reviewing the literature. Opinion on the importance of each of these outcomes was then sought from key stakeholders: Ear, Nose and Throat (ENT) surgeons, audiologists, cleft surgeons, speech and language therapists, specialist cleft nurses, psychologists, parents and children. The opinion of health professionals was sought in a three round Delphi survey where participants were asked to score each outcome using a bespoke online system. Parents and children were also asked to score outcomes in a survey and provided an in-depth insight into having OME through semi-structured interviews. The results of the Delphi survey, interviews and parent/patient survey were brought together in a final consensus meeting with representation from all stakeholders. A final set of eleven outcomes reached the definition of "consensus in" to form the recommended COS: hearing; chronic otitis media (COM); OME; receptive language skills; speech development; psycho social development; acute otitis media (AOM); cholesteatoma; side effects of treatment; listening skills; otalgia. CONCLUSIONS: We have produced a recommendation about the outcomes that should be measured, as a minimum, in studies of the management of OME in children with CP. The development process included input from key stakeholders and used novel methodology to integrate the opinion of healthcare professionals, parents and children. PMID- 26115174 TI - Variation in Population Synchrony in a Multi-Species Seabird Community: Response to Changes in Predator Abundance. AB - Ecologically similar sympatric species, subject to typical environmental conditions, may be expected to exhibit synchronous temporal fluctuations in demographic parameters, while populations of dissimilar species might be expected to show less synchrony. Previous studies have tested for synchrony in different populations of single species, and those including data from more than one species have compared fluctuations in only one demographic parameter. We tested for synchrony in inter-annual changes in breeding population abundance and productivity among four tern species on Coquet Island, northeast England. We also examined how manipulation of one independent environmental variable (predator abundance) influenced temporal changes in ecologically similar and dissimilar tern species. Changes in breeding abundance and productivity of ecologically similar species (Arctic Sterna paradisaea, Common S. hirundo and Roseate Terns S. dougallii) were synchronous with one another over time, but not with a species with different foraging and breeding behaviour (Sandwich Terns Thalasseus sandvicensis). With respect to changes in predator abundance, there was no clear pattern. Roseate Tern abundance was negatively correlated with that of large gulls breeding on the island from 1975 to 2013, while Common Tern abundance was positively correlated with number of large gulls, and no significant correlations were found between large gull and Arctic and Sandwich Tern populations. Large gull abundance was negatively correlated with productivity of Arctic and Common Terns two years later, possibly due to predation risk after fledging, while no correlation with Roseate Tern productivity was found. The varying effect of predator abundance is most likely due to specific differences in the behaviour and ecology of even these closely-related species. Examining synchrony in multi species assemblages improves our understanding of how whole communities react to long-term changes in the environment and suggests that changes in predator abundance may differentially affect populations of sympatric seabird species. PMID- 26115175 TI - ssDNA Pairing Accuracy Increases When Abasic Sites Divide Nucleotides into Small Groups. AB - Accurate sequence dependent pairing of single-stranded DNA (ssDNA) molecules plays an important role in gene chips, DNA origami, and polymerase chain reactions. In many assays accurate pairing depends on mismatched sequences melting at lower temperatures than matched sequences; however, for sequences longer than ~10 nucleotides, single mismatches and correct matches have melting temperature differences of less than 3 degrees C. We demonstrate that appropriately grouping of 35 bases in ssDNA using abasic sites increases the difference between the melting temperature of correct bases and the melting temperature of mismatched base pairings. Importantly, in the presence of appropriately spaced abasic sites mismatches near one end of a long dsDNA destabilize the annealing at the other end much more effectively than in systems without the abasic sites, suggesting that the dsDNA melts more uniformly in the presence of appropriately spaced abasic sites. In sum, the presence of appropriately spaced abasic sites allows temperature to more accurately discriminate correct base pairings from incorrect ones. PMID- 26115173 TI - Association genetics in Populus reveals the interactions between Pt-miR397a and its target genes. AB - Recent studies have revealed associations between single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes and diseases. However, association studies to decipher the interactions between miRNAs and their target genes remain to be conducted. Here, we investigated the association of growth and wood traits with SNPs in Pt-miR397a and its targets, in 261 individuals from a natural population of Populus tomentosa. Of the 57 SNPs identified in Pt-miR397a, three strongly affect its secondary stability, and SNPs in target sites in Pt-LAC20 and Pt-HSP40 changed the binding affinity of Pt-miR397a. Single-SNP association analysis revealed that SNPs in Pt-miR397a significantly associated with alpha-cellulose content and stem volume, and SNPs in target genes also associated with growth and wood-property traits. Multi-SNP association analysis with additive and dominant models found that SNPs in six potential target genes associated with at least one trait in common with Pt-miR397a, revealing a possible genetic interaction between Pt-miR397a and its targets. Furthermore, epistasis analysis revealed epistatic interactions between SNPs in Pt-miR397a and its target genes. Thus, our study indicated that SNPs in Pt-miR397a and six target genes affect wood formation and that association studies can reveal the interactions between miRNAs and their target genes. PMID- 26115176 TI - Tissue distribution study of columbianadin and its active metabolite columbianetin in rats. AB - Columbianadin, one of the main bioactive constituents of the roots of Angelica pubescens Maxim. f. biserrata Shan et Yuan, has been found to possess obvious pharmacological effects in previous studies. In this study, a valid and sensitive reverse-phase high-performance liquid chromatography (RP-HPLC) method was established and validated for the determination of columbianadin (CBN) and its active metabolite columbianetin (CBT) in rat tissue samples. Sample separation was performed on an RP-HPLC column using a mobile phase of MeOH-H2 O (75:25, v/v) at a flow rate of 1.0 mL/min. The UV absorbance of the samples was measured at the wavelength 325 nm. The calibration curves for CBN were linear over the ranges of 0.5-20 ug/g for brain, testes and muscle, 1.0-10.0 ug/g for stomach and intestine, and 0.2-20.0 ug/g for heart, liver, spleen, lung and kidney. The calibration curves for CBT were linear over the ranges of 0.5-25 ug/g for stomach and intestine, and 0.1-10.0 ug/g for heart, liver, spleen, lung and kidney. The analysis method was successfully applied to a tissue distribution study of CBN and CBT after intravenous administration of CBN to rats. The results of this study indicated that CBN could be detected in all of the selected tissues after i.v. administration. CBN was distributed to rat tissues rapidly and could be metabolized to CBT in most detected tissues. Of the detected tissues, heart had the highest uptake of CBN, which suggested that heart might be one of the main target tissues of CBN. Concentrations of CBT were obviously higher in the digestive system than in other assayed tissues. The information provided by this research is very useful for gaining knowledge of the capacities of CBN and CBT to access different tissues. PMID- 26115177 TI - Emerging techniques for assisting and accelerating food freezing processes: A review of recent research progresses. AB - Freezing plays an important role in food preservation and the emergence of rapid freezing technologies can be highly beneficial to the food industry. This paper reviews some novel food freezing technologies, including high-pressure freezing (HPF), ultrasound-assisted freezing (UAF), electrically disturbed freezing (EF) and magnetically disturbed freezing (MF), microwave-assisted freezing (MWF), and osmo-dehydro-freezing (ODF). HPF and UAF can initiate ice nucleation rapidly, leading to uniform distribution of ice crystals and the control of their size and shape. Specifically, the former is focused on increasing the degree of supercooling, whereas the latter aims to decrease it. Direct current electric freezing (DC-EF) and alternating current electric freezing (AC-EF) exhibit different effects on ice nucleation. DC-EF can promote ice nucleation and AC-EF has the opposite effect. Furthermore, ODF has been successfully used for freezing various vegetables and fruit. MWF cannot control the nucleation temperature, but can decrease supercooling degree, thus decreasing the size of ice crystals. The heat and mass transfer processes during ODF have been investigated experimentally and modeled mathematically. More studies should be carried out to understand the effects of these technologies on food freezing process. PMID- 26115178 TI - Source Apportionment of Background PAHs in the Peace-Athabasca Delta (Alberta, Canada) Using Molecular Level Radiocarbon Analysis. AB - The downstream accumulation of polycyclic aromatic hydrocarbons (PAHs) in the Peace-Athabasca Delta (PAD), an ecologically important landscape, is a key issue of concern given the rapid development of the oil sands industry in Northern Alberta, Canada. In addition to PAHs derived from industrial activity (i.e., oil sands mining) within the Athabasca watershed, however, forest fires and erosion of fossil fuel deposits within both the Athabasca and Peace watersheds are two potentially important natural sources of PAHs delivered to the PAD. Consequently, evaluating the environmental impact of mining activities requires a quantitative understanding of natural, background PAHs. Here, we utilize molecular-level natural-abundance radiocarbon measurements on an amalgamated sediment record from a Peace River flood-susceptible oxbow lake in the northern Peace sector of the PAD to quantitatively discriminate sources of naturally occurring alkylated PAHs (fossil and modern biomass). A radiocarbon mass balance quantified a predominantly natural petrogenic source (93% petrogenic, 7% forest fire) for alkylated PAHs during the past ~50 years. Additionally, a significant petrogenic component determined for retene, a compound usually considered a biomarker for softwood combustion, suggests that its use as a unique forest fire indicator may not be suitable in PAD sediments receiving Peace watershed-derived fluvial inputs. PMID- 26115180 TI - Acupuncture as a Treatment Modality in Dermatology: A Systematic Review. AB - OBJECTIVES: Acupuncture is a form of Traditional Chinese Medicine that has been used to treat a broad range of medical conditions, including dermatologic disorders. This systematic review aims to synthesize the evidence on the use of acupuncture as a primary treatment modality for dermatologic conditions. METHODS: A systematic search of MEDLINE, EMBASE, and the Cochrane Central Register was performed. Studies were limited to clinical trials, controlled studies, case reports, comparative studies, and systematic reviews published in the English language. Studies involving moxibustion, electroacupuncture, or blood-letting were excluded. RESULTS: Twenty-four studies met inclusion criteria. Among these, 16 were randomized controlled trials, 6 were prospective observational studies, and 2 were case reports. Acupuncture was used to treat atopic dermatitis, urticaria, pruritus, acne, chloasma, neurodermatitis, dermatitis herpetiformis, hyperhidrosis, human papillomavirus wart, breast inflammation, and facial elasticity. In 17 of 24 studies, acupuncture showed statistically significant improvements in outcome measurements compared with placebo acupuncture, alternative treatment options, and no intervention. CONCLUSIONS: Acupuncture improves outcome measures in the treatment of dermatitis, chloasma, pruritus, urticaria, hyperhidrosis, and facial elasticity. Future studies should ideally be double-blinded and standardize the control intervention. PMID- 26115179 TI - Engineered Trehalose Permeable to Mammalian Cells. AB - Trehalose is a naturally occurring disaccharide which is associated with extraordinary stress-tolerance capacity in certain species of unicellular and multicellular organisms. In mammalian cells, presence of intra- and extracellular trehalose has been shown to confer improved tolerance against freezing and desiccation. Since mammalian cells do not synthesize nor import trehalose, the development of novel methods for efficient intracellular delivery of trehalose has been an ongoing investigation. Herein, we studied the membrane permeability of engineered lipophilic derivatives of trehalose. Trehalose conjugated with 6 acetyl groups (trehalose hexaacetate or 6-O-Ac-Tre) demonstrated superior permeability in rat hepatocytes compared with regular trehalose, trehalose diacetate (2-O-Ac-Tre) and trehalose tetraacetate (4-O-Ac-Tre). Once in the cell, intracellular esterases hydrolyzed the 6-O-Ac-Tre molecules, releasing free trehalose into the cytoplasm. The total concentration of intracellular trehalose (plus acetylated variants) reached as high as 10 fold the extracellular concentration of 6-O-Ac-Tre, attaining concentrations suitable for applications in biopreservation. To describe this accumulation phenomenon, a diffusion reaction model was proposed and the permeability and reaction kinetics of 6-O-Ac Tre were determined by fitting to experimental data. Further studies suggested that the impact of the loading and the presence of intracellular trehalose on cellular viability and function were negligible. Engineering of trehalose chemical structure rather than manipulating the cell, is an innocuous, cell friendly method for trehalose delivery, with demonstrated potential for trehalose loading in different types of cells and cell lines, and can facilitate the wide spread application of trehalose as an intracellular protective agent in biopreservation studies. PMID- 26115181 TI - Relationship Between a Standardized Tackling Proficiency Test and Match-Play Tackle Performance in Semiprofessional Rugby League Players. AB - PURPOSE: This study examined the relationships between tackling ability, playing position, muscle strength and power qualities, and match-play tackling performance in semiprofessional rugby league players. METHODS: Sixteen semiprofessional rugby league players (mean +/- SD age 23.8 +/- 1.9 y) underwent tests for muscle strength and power. Tackling ability of the players was tested using video analysis of a standardized 1-on-1 tackling drill. After controlling for playing position, players were divided into "good tackler" or "poor tackler" groups based on the median split of the results of the 1-on-1 tackling drill. A total of 4547 tackles were analyzed from video recordings of 23 matches played throughout the season. RESULTS: Maximal squat was significantly associated with tackling ability (rS = .71, P < .05) and with the proportion of dominant tackles (rS = .63, P < .01). Forwards performed more tackles (P = .013, ES = 1.49), with a lower proportion of missed tackles (P = .03, ES = 1.38) than backs. Good tacklers were involved in a larger proportion of dominant tackles and smaller proportion of missed tackles than poor tacklers. CONCLUSIONS: These findings demonstrate that lower-body strength contributes to more effective tackling performance during both a standardized tackling assessment and match play. Furthermore, players with good tackling ability in a proficiency test were involved in a higher proportion of dominant tackles and missed a smaller proportion of tackles during match play. These results provide further evidence of the practical utility of an off-field tackling assessment in supplying information predictive of tackling performance in competition. PMID- 26115182 TI - Pupillary light reflex to light inside the natural blind spot. AB - When a light stimulus covers the human natural blind spot (BS), perceptual filling-in corrects for the missing information inside the BS. Here, we examined whether a filled-in surface of light perceived inside the BS affects the size of the short-latency pupillary light reflex (PLR), a pupil response mediated by a subcortical pathway for unconscious vision. The PLR was not induced by a red surface that was physically absent but perceptually filled-in inside the BS in the presence of a red ring surrounding it. However, a white large disk covering the BS unexpectedly induced a larger PLR than a white ring surrounding the BS border did, even though these two stimuli must be equivalent for the visual system, and trial-by-trial percepts did not predict PLR size. These results suggest that some physiological mechanism, presumably the retinal cells containing the photopigment melanopsin, receives the light projected inside the BS and enhances PLR. PMID- 26115183 TI - Emergency Department Overcrowding and Ambulance Turnaround Time. AB - OBJECTIVE: The aims of this study were to describe overcrowding in regional emergency departments in Seoul, Korea and evaluate the effect of crowdedness on ambulance turnaround time. METHODS: This study was conducted between January 2010 and December 2010. Patients who were transported by 119-responding ambulances to 28 emergency centers within Seoul were eligible for enrollment. Overcrowding was defined as the average occupancy rate, which was equal to the average number of patients staying in an emergency department (ED) for 4 hours divided by the number of beds in the ED. After selecting groups for final analysis, multi-level regression modeling (MLM) was performed with random-effects for EDs, to evaluate associations between occupancy rate and turnaround time. RESULTS: Between January 2010 and December 2010, 163,659 patients transported to 28 EDs were enrolled. The median occupancy rate was 0.42 (range: 0.10-1.94; interquartile range (IQR): 0.20 0.76). Overcrowded EDs were more likely to have older patients, those with normal mentality, and non-trauma patients. Overcrowded EDs were more likely to have longer turnaround intervals and traveling distances. The MLM analysis showed that an increase of 1% in occupancy rate was associated with 0.02-minute decrease in turnaround interval (95% CI: 0.01 to 0.03). In subgroup analyses limited to EDs with occupancy rates over 100%, we also observed a 0.03 minute decrease in turnaround interval per 1% increase in occupancy rate (95% CI: 0.01 to 0.05). CONCLUSIONS: In this study, we found wide variation in emergency department crowding in a metropolitan Korean city. Our data indicate that ED overcrowding is negatively associated with turnaround interval with very small practical significance. PMID- 26115184 TI - Carbon Dioxide Conversion to Methanol over Size-Selected Cu4 Clusters at Low Pressures. AB - The activation of CO2 and its hydrogenation to methanol are of much interest as a way to utilize captured CO2. Here, we investigate the use of size-selected Cu4 clusters supported on Al2O3 thin films for CO2 reduction in the presence of hydrogen. The catalytic activity was measured under near-atmospheric reaction conditions with a low CO2 partial pressure, and the oxidation state of the clusters was investigated by in situ grazing incidence X-ray absorption spectroscopy. The results indicate that size-selected Cu4 clusters are the most active low-pressure catalyst for catalytic CO2 conversion to CH3OH. Density functional theory calculations reveal that Cu4 clusters have a low activation barrier for conversion of CO2 to CH3OH. This study suggests that small Cu clusters may be excellent and efficient catalysts for the recycling of released CO2. PMID- 26115185 TI - Stabilization of Proteins and Noncovalent Protein Complexes during Electrospray Ionization by Amino Acid Additives. AB - Ionization of proteins and noncovalent protein complexes with minimal disturbance to their native structure presents a great challenge for biological mass spectrometry (MS). In living organisms, the native structure of intracellular proteins is commonly stabilized by solute amino acids (AAs) accumulated in cells at very high concentrations. Inspired by nature, we hypothesized that AAs could also pose a stabilizing effect on the native structure of proteins and noncovalent protein complexes during ionization. To test this hypothesis, here we explored MS response for various protein complexes upon the addition of free AAs at mM concentrations into the electrospray ionization (ESI) solution. Thermal activation of ESI droplets in the MS inlet capillary was employed as a model destabilizing factor during ionization. Our results indicate that certain AAs, in particular proline (Pro), pose considerable positive effect on the stability of noncovalent protein complexes in ESI-MS without affecting the signal intensity of protein ions and original protein-ligand equilibrium, even when added at the 20 mM concentration. The data suggest that the degree of protein stabilization is primarily determined by the osmolytic and ampholytic characteristics of AA solutes. The highest stability and visibility of noncovalent protein complexes in ESI-MS are achieved using AA additives with neutral isoelectric point, moderate proton affinity, and unfavorable interaction with the native protein state. Overall, our results indicate that the simple addition of free amino acids into the working solution can notably improve the stability and accuracy of protein analysis by native ESI-MS. PMID- 26115186 TI - Global Transcriptome Profiles of 'Meyer' Zoysiagrass in Response to Cold Stress. AB - A long green period is essential for a turfgrass species with high ornamental value and a wide area of use. Zoysiagrasses (Zoysia spp. Willd.) are perennial turfgrass species popular in tropical, subtropical and temperate zones, possessing many properties necessary to be economically useful turfgrass. They do not have a long green period because of cold sensitivity. A main focus in zoysiagrass research is to develop cold tolerant cultivars. Understanding the cold response in zoysiagrass is a fundamental area of research. In the present study, 'Meyer' zoysiagrass (Zoysia japonica), a widely cultivated variety in the genus, is used. We employed RNA-Seq to investigate genome-wide gene expression profiles in leaves under cold stress (4 degrees C). Using the Illumina sequencing platform, we obtained approximately 206 million high-quality paired-end reads from three libraries (0 h, 2 h, and 72 h cold treatment at 4 degrees C). After de novo assembly and quantitative assessment, 46,412 unigenes were generated with an average length of 998 bp and an N50 of 1,522 bp. A total of 25,644 (55.2%) unigenes were annotated by alignment with public protein databases including NR, SwissProt, KEGG and KOG. Differentially expressed genes (DEGs) were investigated using the RPKM method. A total of 756 DEGs were identified between 0 h and 2 h cold treatment, with 522 up-regulated and 234 down-regulated; and 5327 DEGs were identified between 0 h and 72 h-cold treatment, with 2453 up-regulated and 2874 down-regulated. The expression profile of 15 DEGs selected randomly was confirmed with qRT-PCR. The results suggest that cold stress can induce desiccation and oxidative stress, inhibit photosynthesis and substance transport. In response to the stress, genes involved in proline synthesis, in starch hydrolysis, in methionine and ascorbic acid metabolism, in SOD activity, and in DREBs response pathway were up-regulated. GA metabolism, ABA and JA stimulus response were affected under cold exposure. This is the first transcriptome sequencing of Z. japonica, providing a large set of sequence data as well as gene expression profiles under cold stress. It will improve our current understanding of the cold response of zoysiagrass and be beneficial in breeding research. PMID- 26115187 TI - Dynamics of JAK2 V617F allele burden of CD34+ haematopoietic progenitor cells in patients treated with ruxolitinib. PMID- 26115188 TI - Regional Anesthesia in Patients With Preexisting Neurologic Disease. AB - WHAT'S NEW: Since publication of initial recommendations in 2008, there is limited new information regarding the performance of regional anesthesia in patients with preexisting neurologic diseases. However, the strength of evidence has increased since 2008 regarding (1) the concern that diabetic nerves are more sensitive to local anesthetics and perhaps more susceptible to injury and (2) the concern that performing neuraxial anesthesia and analgesia in patients with preexisting spinal canal pathology may increase the risk of new or worsening neurologic symptoms. This increased evidence reinforces our initial recommendations. In addition, since the initial recommendations in 2008, the concept of postsurgical inflammatory neuropathy has been described and is potentially a contributor to postoperative neurologic dysfunction. PMID- 26115189 TI - Continuous Adductor Canal Versus Continuous Femoral Nerve Blocks: Relative Effects on Discharge Readiness Following Unicompartment Knee Arthroplasty. AB - BACKGROUND: We tested the hypothesis that, following unicompartment knee arthroplasty, a continuous adductor canal block decreases the time to reach 4 discharge criteria compared with a continuous femoral nerve block. METHODS: Subjects were randomized to either an adductor canal or femoral perineural catheter (2-day ropivacaine 0.2% infusion) in an unmasked fashion. The primary outcome was the time to attain 4 discharge criteria: (1) adequate analgesia; (2) intravenous opioid independence; (3) ability to independently stand, walk 3 m, return, and sit down; and (4) ambulate 30 m. RESULTS: Subjects with an adductor canal catheter (n = 15) reached all 4 criteria in a median of 35 hours (interquartile range, 24-43 hours), compared with 40 hours (interquartile range, 27-69 hours) for those with a femoral catheter (n = 15; Wilcoxon rank sum test: P = 0.46; log-rank test: P = 0.16). However, the percentages of subjects (adductor canal: femoral) who reached the 2 mobilization criteria were 27%:0% on postoperative day (POD) 0, 93%:53% on POD 1, and 100%:73% on POD 2. Of adductor canal subjects, 100% were discharge ready by POD 2, compared with only 73% of femoral subjects (P < 0.001). CONCLUSIONS: Compared with a continuous femoral nerve block, a continuous adductor canal block did not appreciably decrease the median number of hours to overall discharge readiness, yet did decrease the number of discrete days until discharge readiness. These results are applicable to only unicompartment knee arthroplasty and must be considered preliminary because of the limited sample size of this pilot study. PMID- 26115191 TI - Human Parechovirus 3 Meningitis and Fatal Leukoencephalopathy. AB - Human parechovirus 3 (HPeV3) is a picornavirus associated with neurologic disease in neonates. Human parechovirus 3 infection of preterm and term infants is associated with seizures and destructive periventricular white matter lesions. Despite unremarkable cerebrospinal fluid (CSF), HPeV3 RNA can be amplified from CSF and nasopharyngeal and rectal swabs. We report pathologic findings in 2 autopsy cases of infants with active HPeV3 infection. Both children were born approximately 1 month premature and were neurologically intact but, after a few weeks, developed seizures and radiologic evidence of white matter lesions. Neuropathologic examination demonstrated classic severe periventricular leukomalacia in the absence of an immune response. Human parechovirus 3 sequences were identified in RNA extracted from CSF, sera, and tissues. Human parechovirus 3 in situ hybridization detection of infected cells was limited to meninges and associated blood vessels in addition to smooth muscle of pulmonary vessels. Ultrastructural evaluation of meninges demonstrated dense core structures compatible with picornavirus virions. These findings suggest that encephalopathic changes are secondary to infection of meninges and potential compromise of vascular perfusion. Thus, parechovirus infection of vascular smooth muscle may be a more general pathogenic process. PMID- 26115190 TI - Remyelination After Cuprizone-Induced Demyelination Is Accelerated in Juvenile Mice. AB - Remyelination capacity decreases with age in adult mice, but data comparing remyelination capacity after toxic demyelination in developing mice versus adult mice are not available. We treated 3-week-old and adult C57BL/6 mice with cuprizone for 1 to 5 weeks and studied demyelination/remyelination and cellular reactions in the corpus callosum and motor cortex by histology, immunohistochemistry, and electron microscopy. We compared results between the 2 treated groups and age-matched controls. In juvenile mice, significant demyelination was detectable in the corpus callosum on Week 2 and in the motor cortex on Week 5. Oligodendrocyte loss, microglial activation, and acute axonal damage peaked on Week 2. Increased numbers of oligodendrocyte precursor cells were evident on Week 1, and remyelination was detectable on Week 3. Juvenile mice showed more rapid demyelination than adult mice, which may be related to greater vulnerability of oligodendrocytes, lower myelin content, or dose-dependent cuprizone effects. Earlier activation of microglia and proliferation of oligodendrocyte precursor cells probably contributed to accelerated remyelination and less pronounced axonal damage. Our data indicate that oligodendroglial regeneration and remyelination are enhanced in the maturing rodent brain compared with the young-adult rodent brain. PMID- 26115192 TI - Lack of Major Histocompatibility Complex Class I Upregulation and Restrictive Infection by JC Virus Hamper Detection of Neurons by T Lymphocytes in the Central Nervous System. AB - The human polyomavirus JC (JCV) infects glial cells in immunosuppressed individuals, leading to progressive multifocal leukoencephalopathy. Polyomavirus JC can also infect neurons in patients with JCV granule cell neuronopathy and JCV encephalopathy. CD8-positive T cells play a crucial role in viral containment and outcome in progressive multifocal leukoencephalopathy, but whether CD8-positive T cells can also recognize JCV-infected neurons is unclear. We used immunohistochemistry to determine the prevalence of T cells in neuron-rich areas of archival brain samples from 77 patients with JCV CNS infections and 94 control subjects. Neurons predominantly sustained a restrictive infection with expression of JCV regulatory protein T antigen (T Ag), whereas glial cells were productively infected and expressed both T Ag and the capsid protein VP1. T cells were more prevalent near JCV-infected cells with intact nuclei expressing both T Ag and VP1 compared with those expressing either protein alone. CD8-positive T cells also colocalized more with JCV-infected glial cells than with JCV-infected neurons. Major histocompatibility complex class I expression was upregulated in JCV infected areas but could only be detected in rare neurons interspersed with infected glial cells. These results suggest that isolated neurons harboring restrictive JCV infection do not upregulate major histocompatibility complex class I and thus may escape recognition by CD8-positive T cells. PMID- 26115193 TI - Disrupting NOTCH Slows Diffuse Intrinsic Pontine Glioma Growth, Enhances Radiation Sensitivity, and Shows Combinatorial Efficacy With Bromodomain Inhibition. AB - NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the gamma-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a gamma-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation. PMID- 26115194 TI - Controlled Growth and the Maintenance of Human Pluripotent Stem Cells by Cultivation with Defined Medium on Extracellular Matrix-Coated Micropatterned Dishes. AB - Here, we introduce a new serum-free defined medium (SPM) that supports the cultivation of human pluripotent stem cells (hPSCs) on recombinant human vitronectin-N (rhVNT-N)-coated dishes after seeding with either cell clumps or single cells. With this system, there was no need for an intervening sequential adaptation process after moving hPSCs from feeder layer-dependent conditions. We also introduce a micropatterned dish that was coated with extracellular matrix by photolithographic technology. This procedure allowed the cultivation of hPSCs on 199 individual rhVNT-N-coated small round spots (1 mm in diameter) on each 35-mm polystyrene dish (termed "patterned culture"), permitting the simultaneous formation of 199 uniform high-density small-sized colonies. This culture system supported controlled cell growth and maintenance of undifferentiated hPSCs better than dishes in which the entire surface was coated with rhVNT-N (termed "non patterned cultures"). Non-patterned cultures produced variable, unrestricted cell proliferation with non-uniform cell growth and uneven densities in which we observed downregulated expression of some self-renewal-related markers. Comparative flow cytometric studies of the expression of pluripotency-related molecules SSEA-3 and TRA-1-60 in hPSCs from non-patterned cultures and patterned cultures supported this concept. Patterned cultures of hPSCs allowed sequential visual inspection of every hPSC colony, giving an address and number in patterned culture dishes. Several spots could be sampled for quality control tests of production batches, thereby permitting the monitoring of hPSCs in a single culture dish. Our new patterned culture system utilizing photolithography provides a robust, reproducible and controllable cell culture system and demonstrates technological advantages for the mass production of hPSCs with process quality control. PMID- 26115195 TI - MODIS Based Estimation of Forest Aboveground Biomass in China. AB - Accurate estimation of forest biomass C stock is essential to understand carbon cycles. However, current estimates of Chinese forest biomass are mostly based on inventory-based timber volumes and empirical conversion factors at the provincial scale, which could introduce large uncertainties in forest biomass estimation. Here we provide a data-driven estimate of Chinese forest aboveground biomass from 2001 to 2013 at a spatial resolution of 1 km by integrating a recently reviewed plot-level ground-measured forest aboveground biomass database with geospatial information from 1-km Moderate-Resolution Imaging Spectroradiometer (MODIS) dataset in a machine learning algorithm (the model tree ensemble, MTE). We show that Chinese forest aboveground biomass is 8.56 Pg C, which is mainly contributed by evergreen needle-leaf forests and deciduous broadleaf forests. The mean forest aboveground biomass density is 56.1 Mg C ha-1, with high values observed in temperate humid regions. The responses of forest aboveground biomass density to mean annual temperature are closely tied to water conditions; that is, negative responses dominate regions with mean annual precipitation less than 1300 mm y-1 and positive responses prevail in regions with mean annual precipitation higher than 2800 mm y-1. During the 2000s, the forests in China sequestered C by 61.9 Tg C y-1, and this C sink is mainly distributed in north China and may be attributed to warming climate, rising CO2 concentration, N deposition, and growth of young forests. PMID- 26115197 TI - Incorporating phosphorus cycling into global modeling efforts: a worthwhile, tractable endeavor. AB - 324 I. 324 II. 325 III. 326 IV. 327 328 References 328 SUMMARY: Myriad field, laboratory, and modeling studies show that nutrient availability plays a fundamental role in regulating CO2 exchange between the Earth's biosphere and atmosphere, and in determining how carbon pools and fluxes respond to climatic change. Accordingly, global models that incorporate coupled climate-carbon cycle feedbacks made a significant advance with the introduction of a prognostic nitrogen cycle. Here we propose that incorporating phosphorus cycling represents an important next step in coupled climate-carbon cycling model development, particularly for lowland tropical forests where phosphorus availability is often presumed to limit primary production. We highlight challenges to including phosphorus in modeling efforts and provide suggestions for how to move forward. PMID- 26115198 TI - PETE Doctoral Institutions: Programs, Faculty, and Doctoral Students. AB - PURPOSE: The present study of doctoral physical education teacher education (D PETE) programs was part of a longitudinal study that provided an extensive description of demographics including: (a) doctoral program characteristics, (b) faculty, and (c) doctoral students/graduates. METHOD: This trend study incorporated 3 data sets (2005-2006, 2008-2009, and 2011-2012) that described the characteristics of D-PETE programs. Academic heads of D-PETE programs provided demographic information on their doctoral students, faculty, and institutional characteristics for the 2005-2006, 2008-2009, and 2011-2012 academic years and selected summary data from 1996-1997 through 2011-2012. RESULTS/CONCLUSION: As a result of this longitudinal data collection, the following trends were revealed. First, there was a decrease in the number of D-PETE programs and an increase of nontenured and part-time pedagogy faculty. Second, initial teacher licensure programs remained in existence at the vast majority of D-PETE programs. Third, funding for doctoral students at D-PETE programs was decreasing. Fourth, racial composition of doctoral graduates and current doctoral students remained largely skewed toward Caucasians. Fifth, there was a slight decline in the percentage of doctoral graduates entering higher education, but employment rates were exceptionally high. Sixth, non-U.S. doctoral students and ABDs were marketable in the United States. PMID- 26115196 TI - Accelerating the Translation of Nanomaterials in Biomedicine. AB - Due to their size and tailorable physicochemical properties, nanomaterials are an emerging class of structures utilized in biomedical applications. There are now many prominent examples of nanomaterials being used to improve human health, in areas ranging from imaging and diagnostics to therapeutics and regenerative medicine. An overview of these examples reveals several common areas of synergy and future challenges. This Nano Focus discusses the current status and future potential of promising nanomaterials and their translation from the laboratory to the clinic, by highlighting a handful of successful examples. PMID- 26115199 TI - Evaluation of Highly Porous Dental Implants in Postablative Oral and Maxillofacial Cancer Patients: A Prospective Pilot Clinical Case Series Report. AB - PURPOSE: The aim of this study was to evaluate the clinical efficacy of new porous tantalum trabecular metal (PTTM)-enhanced titanium dental implants used for the prosthodontic rehabilitation of postablative cancer patients. First-year interim results of a prospective clinical case series are presented. MATERIALS AND METHODS: A total of 25 PTTM-enhanced titanium implants were placed in both maxillas and mandibles of 6 patients, who met specific inclusion criteria. Resonance frequency analysis was conducted, and implant stability was recorded in Implant Stability Quotient (ISQ) values at implant placement and after 2, 4, 6, and 12 months of functional loading. Bone levels were calculated by digitally measuring the distance from the implant shoulder to the first bone-to-implant on periapical radiographs taken at surgery and after 2, 4, 6, and 12 months of functioning. RESULTS: Cumulative implant survival was 100% (n = 25/25). At implant placement and the 2-, 4-, 6- and 12-month monitoring appointments, mean ISQ values were 72.14 +/- 5.61 (range = 50-81), 64.39 +/- 8.12 (range = 44-74), 74.26 +/- 7.14 (range = 44-74), 76.84 +/- 7.65 (range = 60-83), and 78.13 +/- 4.14 (range = 64-84), respectively, and mean crestal marginal bone loss was 0.19 +/- 0.25, 0.22 +/- 0.4, 0.3 +/- 0.46, and 0.57 +/- 0.62 mm, respectively. CONCLUSIONS: PTTM-enhanced dental implants were clinically effective in the prosthetic rehabilitation of postoncological patients. Larger long-term follow-up studies will help to evaluate clinical efficacy of PTTM dental implants. PMID- 26115200 TI - Opening the cuebox: the information children and young adults generate and rely on when making inferences from memory. AB - We used a cue-generation and a cue-selection paradigm to investigate the cues children (9- to 12-year-olds) and young adults (17-year-olds) generate and select for a range of inferences from memory. We found that children generated more cues than young adults, who, when asked why they did not generate some particular cues, responded that they did not consider them relevant for the task at hand. On average, the cues generated by children were more perceptual but as informative as the cues generated by young adults. When asked to select the most informative of two cues, both children and young adults tended to choose a hidden (i.e., not perceptual) cue. Our results suggest a developmental change in the cuebox (i.e., the set of cues used to make inferences from memory): New cues are added to the cuebox as more cues are learned, and some old, perceptual cues, although informative, are replaced with hidden cues, which, by both children and young adults, are generally assumed to be more informative than perceptual cues. PMID- 26115201 TI - Severe childhood Guillain-Barre syndrome associated with Mycoplasma pneumoniae infection: a case series. AB - We report seven children with recent Mycoplasma pneumoniae infection and severe Guillain-Barre syndrome (GBS) that presented to two European medical centres from 1992 to 2012. Severe GBS was defined as the occurrence of respiratory failure, central nervous system (CNS) involvement, or death. Five children had GBS, one Bickerstaff brain stem encephalitis (BBE), and one acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP). The five patients with severe GBS were derived from an original cohort of 66 children with GBS. In this cohort, 17 children (26%) had a severe form of GBS and 47% of patients with M. pneumoniae infection presented with severe GBS. Of the seven patients in this case series, five were mechanically ventilated and four had CNS involvement (two were comatose). Most patients presented with non-specific clinical symptoms (nuchal rigidity and ataxia) and showed a rapidly progressive disease course (71%). Antibodies against M. pneumoniae were detected in all patients and were found to be intrathecally synthesised in two cases (GBS and BBE), which proves intrathecal infection. One patient died and only two patients recovered completely. These cases illustrate that M. pneumoniae infection in children can be followed by severe and complicated forms of GBS. Non-specific clinical features of GBS in such patients may predispose a potentially life-threatening delay in diagnosis. PMID- 26115202 TI - Suicidal ideation in Chinese patients with chronic obstructive pulmonary disease: a controlled study. AB - BACKGROUND: No study has been published on the prevalence of suicidal behaviour in older Chinese patients with chronic obstructive pulmonary disease (COPD). This study examined the 1-year prevalence of suicidal ideation in older Chinese COPD patients and explored its demographic and clinical correlates. METHODS: A consecutive sample of 143 COPD patients and 211 matched control subjects were recruited and interviewed using structured, standardized instruments. RESULTS: The 1-year prevalence of suicidal ideation in COPD patients and controls were 15.4% and 10.9%, respectively. In multivariate analyses, suicidal ideation was significantly associated with the severity of depressive symptoms in COPD patients. CONCLUSION: Suicidal ideation was not higher in COPD patients than in controls. PMID- 26115203 TI - Relationships Among Pain Quality, Pain Impact, and Overall Improvement in Patients with Postherpetic Neuralgia Treated with Gastroretentive Gabapentin. AB - OBJECTIVE: To determine the effect of gastroretentive gabapentin (G-GR) and describe relationships among pain quality, pain impact, and overall-improvement scores in patients with postherpetic neuralgia (PHN). METHODS: Analyses of integrated data from two Phase 3 studies in which PHN patients received once daily G-GR 1,800 mg (n = 356) or placebo (n = 363). Neuropathic pain scale (NPS) and brief pain inventory (BPI) were completed at baseline and Week 10; patients' global impression of change (PGIC) at Week 10. Regression analyses described relationships among changes in the NPS, BPI, and PGIC scores. RESULTS: Compared with placebo, G-GR patients had significant reductions from baseline in individual NPS measures except cold pain (P < 0.05); composite NPS scores (P <= 0.003); BPI pain scores (P < 0.05); three individual (mood, sleep, and enjoyment of life) and the average of BPI interference scores (P < 0.05). Clinically significant improvements in BPI interference scores (except walking ability) were positively correlated with reductions in BPI and NPS pain (except dull and cold pain), and with improvements on the PGIC. Reductions in pain qualities at Week 2, especially in NPS pain intensity, were significant (P <= 0.0001) predictors of improvements in three BPI interference scores, total NPS score, and PGIC. CONCLUSIONS: For patients with PHN, G-GR provided significant improvements in multiple measures of pain quality and pain-related functional impairment. There was a positive correlation between pain relief and improvement in patient function, with reduction in pain intensity among predictors of improvements in patients' lives. Such comprehensive analyses give an insight into numerous factors that may contribute to better management of PHN. PMID- 26115204 TI - Feasibility study of using laser-generated neutron beam for BNCT. AB - The feasibility of using a laser-accelerated proton beam to produce a neutron source, via (p,n) reaction, for Boron Neutron Capture Therapy (BNCT) applications has been studied by MCNPX Monte Carlo code. After optimization of the target material and its thickness, a Beam Shaping Assembly (BSA) has been designed and optimized to provide appropriate neutron beam according to the recommended criteria by International Atomic Energy Agency. It was found that the considered laser-accelerated proton beam can provide epithermal neutron flux of ~2*10(6) n/cm(2) shot. To achieve an appropriate epithermal neutron flux for BNCT treatment, the laser must operate at repetition rates of 1 kHz, which is rather ambitious at this moment. But it can be used in some BNCT researches field such as biological research. PMID- 26115205 TI - (19)F(alpha,n) thick target yield from 3.5 to 10.0 MeV. AB - Using a target of PbF2, the thick-target yield from the (19)F(alpha,n) reaction was measured from E(alpha)=3.5-10 MeV. From these results, we infer the thick target neutron yields from targets of F2 and UF6 over this same alpha-particle energy range. PMID- 26115206 TI - An emergency bioassay method for (210)Po in urine. AB - A rapid method was developed to efficiently measure (210)Po in urine samples in an emergency situation. Polonium-210 in small urine samples (10 mL) was spontaneously deposited on a stainless steel disc in 1 M HCl at room temperature for 4 h in a polyethylene bottle. The metallic disc was then counted for 4 h by alpha spectrometry. The developed method allowed the preparation of large sample batch in a short time. The method meets the requirements for an emergency bioassay procedure. PMID- 26115207 TI - Enantioseparation characteristics of tadalafil and its intermediate on chitin derived chiral stationary phases. AB - Due to the low solubility and swelling properties of chitin bis(arylcarbamate) in most organic solvents, the chiral stationary phases (CSPs) prepared from chitin derivatives can be analyzed with a wide range of solvents. In order to develop new CSPs of chitin derivatives with halogen groups, chitin was derivatized with three different phenyl isocyanates to obtain chitin bis(4 trifluoromethoxyphenylcarbamate), chitin bis(3-chloro-4-methylphenylcarbamate) and chitin bis(4-chloro-3-trifluoromethylphenylcarbamate). Then, the three chitin derivatives were coated on macroporous 3-aminopropyl-functionalized silica gel to obtain three CSPs 1-3 respectively. These CSPs showed good enantioseparation capabilities towards tadalafil and its intermediate. Therefore, these CSPs are potentially applied for the enantioseparation and determination of tadalafil and its intermediate. It was also found that the retention times of some enantiomers were prolonged in the presence of their diastereoisomers or structural analogues and as a result, the resolution was improved to some extent. Hence, in the enantioseparation of a compound with two chiral centers, the resolution is hopefully improved by adding a diastereoisomer or a structural analogue. PMID- 26115208 TI - Ophthalmic Diagnostic Tests and Ocular Findings in a Flock of Captive American Flamingos ( Phoenicopterus ruber ruber). AB - Seventeen adult captive American flamingos ( Phoenicopterus ruber ruber) (34 eyes) underwent a complete ocular examination, including assessment of menace response, pupillary light reflexes, dazzle reflex, palpebral and corneal reflexes, fluorescein staining, slit-lamp biomicroscopy, and direct ophthalmoscopy. Birds were randomly assigned to one of 2 groups for tear production and intraocular pressure measurements. Tear production was measured by modified Schirmer tear test I (n = 9 birds) or phenol red thread test (n = 8 birds), and intraocular pressure was measured indirectly by applanation (Tonopen XL) (n = 9 birds) or rebound (TonoVet) (n = 8 birds) tonometry. Conjunctival swab samples were taken from one randomly selected eye of all 17 birds to identify surface ocular microbial flora via aerobic bacterial culture. Additionally, 3 of the 17 birds were anesthetized for bilateral B-mode ocular ultrasonography examination to obtain axial globe measurements. Results showed that the menace response and dazzle reflex were absent in all birds. Sixteen of the 17 birds were free of significant ocular disease; a small cataract and pigment on the anterior lens capsule were noted in one eye of one bird. Mean +/- SD tear production was 12.3 +/- 4.5 mm/min (range, 4-20 mm/min) for modified Schirmer tear test I and 24.2 +/- 4.4 mm/15 s (range, 14-30 mm/15 s) for phenol red thread test. Modified Schirmer tear test I measurements were significantly lower than phenol red thread measurements (P < .001). Mean intraocular pressure was 16.1 +/- 4.2 mm Hg (range, 7-22 mm Hg) for Tonopen and 9.5 +/- 1.7 mm Hg (range, 7-13 mm Hg) for TonoVet. Tonopen measurements were significantly higher than TonoVet measurements (P < .001). An Enterococcus species (9/17 eyes; 53%) and a gram-positive coccus (7/17 eyes; 41%) were the bacteria most commonly isolated from conjunctival swab samples. Mean B-mode ultrasonographic globe measurements of 6 eyes (3 birds) were axial globe length, 13.8 +/- 0.16 mm; anterior chamber depth, 1.75 +/- 0.05 mm; lens thickness, 4.6 +/- 0.06 mm; vitreous body depth, 6.95 +/- 0.10 mm; and pecten dimensions, 5.1 +/- 0.38 mm length, 2.2 +/- 0.14 mm width. In summary, the prevalence of ocular lesions was low in this population of captive American flamingos. Results obtained from 2 types of tear and intraocular pressure measurement tests were significantly different, indicating that a single type of each diagnostic test should be consistently used. A modification of the standard Schirmer tear test or use of phenol red thread test is recommended due to the small flamingo eye. PMID- 26115209 TI - Histologic Evaluation of Critical Size Defect Healing With Natural and Synthetic Bone Grafts in the Pigeon ( Columba livia ) Ulna. AB - Fracture and bone segment loss are major clinical problems in birds. Achieving bone formation and clinical union in a fracture case is important for the survival of the bird. To evaluate the efficacy of bone grafts for defect healing in birds, 2 different bone grafts were investigated in the healing of a bone defect in 24 healthy pigeons ( Columba livia ). In each bird, a 1-cm critical size defect (CSD) was created in the left ulna, and the fracture was stabilized with external skeletal fixation (ESF). A graft of hydroxyapatite (HA) alone (n = 12 birds) or demineralized bone matrix (DBM) combined with HA (n = 12 birds) was implanted in the CSD. The CSD healing was evaluated at 3 endpoints: 3, 6, and 12 weeks after surgery. Four birds were euthanatized at each endpoint from each treatment group, and bone graft healing in the ulna CSD was evaluated by histologic examination. The CSD and graft implants were evaluated for quality of union, cortex development, and bone graft incorporation. Results showed no graft rejection in any bird, and all birds had connective tissue formation in the defect because of the bone graft application. These results suggest that bone defect healing can be achieved by a combination of osteoinductive and osteoconductive bone graft materials for clinical union and new bone regeneration in birds. The combination of DBM and HA resulted in a better quality bone graft (P < .05) than did HA alone, but there was no significant differences in cortex development or bone graft incorporation at 3, 6, or 12 weeks. From the results of this study, we conclude that HA bone grafts, alone or in combination with DBM, with external skeletal fixation is suitable and safe for bone defect and fracture treatment in pigeons. PMID- 26115210 TI - Cockatiel Transition From a Seed-based to a Complete Diet. AB - To determine the effects of diet transition in cockatiels ( Nymphicus hollandicus ), 14 cockatiels were transitioned over a 12-day period from a seed diet to one of 2 commercial diets advertised as nutritionally complete. Before the transition, cockatiels were fed a seed-based diet for 30 days. The transition strategy consisted of gradually increasing the ratio of complete diet : seed based diet over the 12-day period. True amino acid digestibility determined on each complete diet (diets A and B) demonstrated that both diets contained highly digestible amino acids. Diets differed in ingredient composition and particle size, analyzed nutrients, and method of processing (baked or extruded). Daily feed intake of seed-based and complete diets was measured. Periodically throughout and after transition, body weights were measured, and blood samples were collected for hematologic testing and plasma biochemical analysis. All cockatiels accepted the transition strategy irrespective of complete diet. Cockatiels transitioned to diet A consumed significantly more of the complete diet and less of the seed-based diet during periods of measurement throughout transition. Total feed intake was significantly greater for cockatiels fed diet B for 33% of the measurement periods (P < .05). Body weight was generally not affected during or after transition (P > .05). Hematologic and plasma biochemical values did not differ between cockatiels fed the 2 complete diets (P > .05). It may be speculated that cockatiels were more accepting of diet A during transition, and diet A more efficiently maintained body weight. PMID- 26115211 TI - Bilateral Granulomatous and Fibrinoheterophilic Otitis Interna due to Pseudomonas aeruginosa in a Captive Little Bustard ( Tetrax tetrax ). AB - A captive juvenile little bustard ( Tetrax tetrax ) was presented for acute onset of right head tilt and right circling. The bird failed to respond to supportive care and systemic antibiotic therapy. A bilateral granulomatous and fibrinoheterophilic otitis interna due to Pseudomonas aeruginosa was diagnosed postmortem by histopathologic examination and bacterial culture. In bustards, Pseudomonas species have been documented in the normal bacterial flora of the oropharynx and are frequently reported in upper respiratory tract infections. This is the first report of a peripheral vestibular syndrome due to P aeruginosa otitis interna in a bustard species. Pseudomonas aeruginosa should be included as a possible cause of otitis and peripheral vestibular syndrome in bustards. PMID- 26115212 TI - Bilateral Malignant Seminomas in Two Unrelated, Aged Trumpeter Hornbills (Bycanistes buccinator). AB - Seminomas occur infrequently in birds. Two cases of bilateral malignant seminomas in unrelated trumpeter hornbills (Bycanistes buccinator) are described. Case 1 was a 22-year-old trumpeter hornbill submitted for necropsy because of sudden death at a zoo in California. Postmortem examination revealed multiple masses within the body cavity, 2 of which replaced both testes. Case 2 was a 19-year-old trumpeter hornbill at a zoo in North Carolina that underwent exploratory surgery for a suspected gastrointestinal obstruction. Both testes were diffusely enlarged, compressing and replacing the adjacent kidneys. In both birds, the masses were composed of discrete, round to polyhedral cells, typical of seminomas. Examination of the ancestry of the hornbills showed they were unrelated to each other, suggesting a potential predisposition for these birds to develop seminomas. PMID- 26115214 TI - Atrioventricular Dissociation and Congestive Heart Failure in a Ring-Necked Pheasant ( Phasianus colchicus ). AB - The aim of this clinical report was to describe a case of complete atrioventricular dissociation in a 9-month-old, male ring-necked pheasant ( Phasianus colchicus ). The case was incidentally determined during the evaluation of electrocardiograms recorded from pheasants. There were no observed clinical symptoms in the bird before or after the electrocardiogram. The PR interval varied, and there was no association of the P waves and QRS complexes in the electrocardiogram. Although the ventricular rhythm was regular (130 beats/min), atrial rhythm was irregular (approximately 91 beats/min). Pathological examination showed there was left ventricular hypertrophy with degeneration of the mitral valve of the heart and well-marked congestion in the liver and lung. PMID- 26115213 TI - Use of a Vascular Access Port for Antibiotic Administration in the Treatment of Pododermatitis in a Chicken. AB - Bacterial culture and susceptibility testing results of a wound on the plantar aspect of the foot of a 4-year-old, male chicken with a class IV pododermatitis revealed a multidrug-resistant Escherichia coli bacterium, sensitive to only a few antibiotics including ceftazidime. Concerns over the volume and frequency of antibiotic injections, combined with the likely duration of treatment, led to the use of a vascular access port to facilitate intravenous antimicrobial therapy. The port was placed and maintained for 5 months without complication, and the infection was resolved. This case illustrates the feasibility and application of a vascular port in an avian patient requiring long-term intravenous therapy. PMID- 26115215 TI - Use of 3D Ultrasonography in Diagnosing Ovarian Adenocarcinoma in a Common Mynah ( Acridotheres tristis ). AB - A 12-year-old female common mynah ( Acridotheres tristis ) was examined because of dyspnea and coelomic enlargement. Abdominal radiographs revealed hepatomegaly and a coelomic mass of unknown origin. Both brightness mode (2-dimensional; 2D) and 3-dimensional (3D) ultrasonography were performed to identify the origin of the mass. Ultrasonographic findings distinguished the mass from the liver and revealed high vascularization of the mass and a moderate increase in echogenicity of the liver. Three-dimensional ultrasonographic histogram analysis of the mass was performed. The mynah was treated with supportive care but died after 3 days. Histopathologic examination showed ovarian adenocarcinoma, with concurrent mild to moderate hepatopathy. In diagnostic imaging using ultrasound in birds, 3D ultrasonography allows perspective images of the internal organs to be obtained and is potentially superior to 2D ultrasonography in evaluating irregularly shaped objects. PMID- 26115216 TI - Measurement of Tear Production Using the Phenol Red Thread Test in the Common Mynah ( Acridotheres tristis ). AB - To evaluate tear production in the common mynah ( Acridotheres tristis ) using the phenol red thread test (PRTT) and to make a comparison of measurements with the PRTT placed in the fornices of lower and upper eyelids, tear production of both eyes in 22 healthy adult captive mynah birds was evaluated. After positioning of threads in the fornices of upper and lower eyelids, the PRTT values of the birds were 17.5 +/- 3.1 mm/15 s and 19.2 +/- 2.5 mm/15 s, respectively. A significant difference was found between PRTT values for upper eyelids and lower eyelids (P = 0.01). This study provides novel data for normal reference ranges of PRTT values in healthy common mynah birds and shows that a difference is found depending on where the PRTT thread is placed. PMID- 26115217 TI - What Is Your Diagnosis? Coelomic Mass in a Mynah. PMID- 26115221 TI - Novel mechanism of transcriptional regulation of cell matrix protein through CREB. AB - The transcription mechanism(s) of renal cell matrix accumulation in diabetes does not explored. Phosphorylation of the transcription factor cAMP-responsive element binding protein (CREB) significantly increased in cells treated with high glucose (HG) compared to cell grown in normal glucose (NG). Cells pretreated with rapamycin before exposure to HG showed significant decrease phosphorylation of CREB, increase in AMPK activity and decrease protein/mRNA and promoter activity of fibronectin. In addition, cells transfected with siRNA against CREB showed significant increase in AMPK activity, decrease in protein/mRNA and promoter activity of fibronectin. Cells treated with HG showed nuclear localization of p CREB while pretreated cells with rapamycin reversed HG effect. Moreover, gel shift analysis shows increase binding of CREB to fibronectin promoter in cells treated with HG while cells pretreated with rapamycin reversed the effect of HG. Furthermore, db/db mice treated with rapamycin showed significant increase in AMPK activity, decrease in expression of p-CREB and protein/mRNA of fibronectin. Strong staining of fibronectin and p-CREB was detected in kidney cortex of db/db mice while treated mice with rapamycin reversed hyperglycemia effect. In summary, our data provide a novel mechanism of transcriptional regulation of fibronectin through CREB that may be used as therapeutic approach to prevent diabetes complications. PMID- 26115222 TI - Active Degradation Explains the Distribution of Nuclear Proteins during Cellular Senescence. AB - The amount of cellular proteins is a crucial parameter that is known to vary between cells as a function of the replicative passages, and can be important during physiological aging. The process of protein degradation is known to be performed by a series of enzymatic reactions, ranging from an initial step of protein ubiquitination to their final fragmentation by the proteasome. In this paper we propose a stochastic dynamical model of nuclear proteins concentration resulting from a balance between a constant production of proteins and their degradation by a cooperative enzymatic reaction. The predictions of this model are compared with experimental data obtained by fluorescence measurements of the amount of nuclear proteins in murine tail fibroblast (MTF) undergoing cellular senescence. Our model provides a three-parameter stationary distribution that is in good agreement with the experimental data even during the transition to the senescent state, where the nuclear protein concentration changes abruptly. The estimation of three parameters (cooperativity, saturation threshold, and maximal velocity of the reaction), and their evolution during replicative passages shows that only the maximal velocity varies significantly. Based on our modeling we speculate the reduction of functionality of the protein degradation mechanism as a possible competitive inhibition of the proteasome. PMID- 26115224 TI - Correction: Auxin-Mediated Transcriptional System with a Minimal Set of Components Is Critical for Morphogenesis through the Life Cycle in Marchantia polymorpha. PMID- 26115225 TI - Analytical methods for determination of anticoagulant rodenticides in biological samples. AB - Anticoagulant rodenticides belong to a heterogeneous group of compounds which are used to kill rodents. They bind to enzyme complexes responsible for recycling of vitamin K, thus producing impairment in coagulation process. Rodenticides are among the most common house hold toxicants and exhibit wide variety of toxicities in non-target species especially in human, dogs and cats. This article reviews published analytical methods reported in literature for qualitative and quantitative determination of anticoagulant rodenticides in biological specimens. These techniques include high performance liquid chromatography coupled with ultraviolet and florescence detectors, liquid chromatography electrospray ionization tandem mass spectrometry, liquid chromatography with high resolution tandem mass spectrometry, ultra performance liquid chromatography mass spectrometry, gas chromatography mass spectrometry, ion chromatography with fluorescence detection, ion chromatography electrospray ionization ion trap mass spectrometry and ion chromatography electrospray ionization tandem mass spectrometry. PMID- 26115223 TI - Trait Anticipatory Pleasure Predicts Effort Expenditure for Reward. AB - Research in motivation and emotion has been increasingly influenced by the perspective that processes underpinning the motivated approach of rewarding goals are distinct from those underpinning enjoyment during reward consummation. This distinction recently inspired the construction of the Temporal Experience of Pleasure Scale (TEPS), a self-report measure that distinguishes trait anticipatory pleasure (pre-reward feelings of desire) from consummatory pleasure (feelings of enjoyment and gratification upon reward attainment). In a university community sample (N = 97), we examined the TEPS subscales as predictors of (1) the willingness to expend effort for monetary rewards, and (2) affective responses to a pleasant mood induction procedure. Results showed that both anticipatory pleasure and a well-known trait measure of reward motivation predicted effort-expenditure for rewards when the probability of being rewarded was relatively low. Against expectations, consummatory pleasure was unrelated to induced pleasant affect. Taken together, our findings provide support for the validity of the TEPS anticipatory pleasure scale, but not the consummatory pleasure scale. PMID- 26115227 TI - Carbon monoxide poisoning as a cause of death in Wuhan, China: A retrospective six-year epidemiological study (2009-2014). AB - Carbon monoxide (CO) poisoning is a common cause of death globally, and case reports and empirical studies on CO poisoning are widely examined. However, to the authors' knowledge, CO poisoning deaths in the mainland China are scarcely studied. Therefore, this study aims to explore the incidence trend of CO poisoning deaths that occurred in Wuhan - a mega city in Central China - for a six-year period (2009-2014). This arguably is the first comprehensive study to provide an overall analysis of CO poisoning deaths that sampled the mainland Chinese population. Using the data provided by the legal physicians who are employed in nine districts of Wuhan, a total of 131 cases of CO poisoning that resulted in the death of 156 victims are collected. Out of the total, 76 cases (97 deaths) are classified as accidents, 49 cases (51 deaths) are suicides, three cases (four deaths) are homicides, one case (three deaths) is homicide-suicide, and one case (one death) is classified as undetermined. Male victims are found to be the dominant sex group (53.5%; N=83); with a mean age of 44.9 years, while female victims averagely aged 46.1 years. The highest death occurring month is in January, and followed by February and December. Coal or charcoal burning is found to be the major cause of suicide CO poisoning death (66.7%), while fire accident is the major cause of accidental CO poisoning death (60.8%) in Wuhan during the six-year period. PMID- 26115226 TI - Gunshot residue preservation in seawater. AB - Little is known about the persistence of gunshot residue (GSR) in soft tissue and bones during decomposition in marine environments. For a better understanding, qualitative and quantitative data were obtained on GSR retention on soft tissue and bony gunshot wounds (GSWs). A quantity of 36 fleshed and 36 defleshed bovine ribs were shot at contact range with 0.22 calibre hollow point ammunition using a Stirling 0.22 calibre long rifle. Bone specimens in triplicate were placed in three environments: submerged, intertidal and in supralittoral zone. Sets of triplicates were recovered on day 3, 10, 24 and 38, and analysed with scanning electron microscopy with energy dispersive X-ray spectrometry (SEM-EDX), and inductive coupled plasma mass spectrometry (ICP-MS). The SEM-EDX recorded GSR indicative particles surrounding the bullet entrance on all bone types (fleshed and defleshed) in all environments throughout the study. GSR-unique particles were only detected on the supralittoral bones. The ICP-MS analysis showed faster GSR loss on submerged than intertidal and supralittoral defleshed specimens. Fleshed specimens showed a faster GSR loss on intertidal than submerged and supralittoral specimens. In conclusion, the GSR disappeared faster from submerged and intertidal than non-submerged specimens. The difference of detection of GSR between analysed specimens (defleshed versus fleshed) disappeared upon defleshing. This study highlights the potential of finding evidence of GSR in a submerged body and the potential of microscopic and analytical methods for examining suspected GSW in highly decomposed bodies in marine habitats. PMID- 26115228 TI - New, clear fusion from the cellular perspective: Measuring cellular fusion in Saccharomyces cerevisiae by flow cytometry. PMID- 26115229 TI - Superior vena cava flow and intraventricular haemorrhage in extremely preterm infants. AB - OBJECTIVE: To evaluate the relationship between superior vena cava flow (SVCF) measurements within the first 24 h of life, and development of intraventricular haemorrhage (IVH) in extremely preterm infants. STUDY DESIGN: Single centre retrospective cohort study of 108 preterm infants born less than 28 weeks' gestation. Main outcome measure was degree of IVH at day 7 postnatal age. RESULTS: The mean GA of the study group was 25.4 weeks. Mean SVCF was lower (75 ml/kg/min) in infants later diagnosed with IVH (n = 46) compared to infants, who did not develop IVH (87.7 ml/kg/min, p = 0.055). PDA diameter was inversely associated with SVCF (p = 0.024) and reversal of flow in the descending aorta (p = 0.001). Sensitivity analysis did not confirm an independent association of SVCF with development of IVH [OR 0.990 (0.978-1.002), p = 0.115]. CONCLUSION: Our study describes early SVCF in extremely preterm infants is associated with the extent of ductal shunting, but insensitive in predicting IVH. PMID- 26115230 TI - Maternal and fetal HLA-G 14 bp gene polymorphism in pregnancy-induced hypertension, preeclampsia, intrauterine growth restricted and normal pregnancies. AB - OBJECTIVE: Trophoblast expression of Human Leukocyte Antigene-G (HLA-G) is essential for feto-maternal immune tolerance and successful placentation. There is contradicting evidence on the relationship between HLA-G polymorphisms and preeclampsia (PE), intrauterine growth restriction (IUGR) and pregnancy-induced hypertension (PIH). Here, we investigate the association between both maternal and fetal HLA-G 14 bp insertion/deletion polymorphism and obstetrical complications. METHODS: Clinical and genetic data of 282 women/fetuses (31 severe PE, 8 mild PE, 46 IUGR, 42 PIH and 155 controls) were analyzed both individually and jointly under a codominant, a dominant and a recessive model. RESULTS: HLA-G 14 bp polymorphism was not associated with obstetrical complications, considering the mother and fetus genotypes both jointly and individually. CONCLUSIONS: With this study we filled several gaps occurring in previous studies: we analyzed a very well-defined population of PE, PIH and IUGR pregnancies, considering both fetal and maternal HLA-G 14 bp polymorphism, individually and jointly. Our findings showed that fetal and maternal HLA-G 14 bp genotypes are not associated with increased risk for the development of obstetrical complications, suggesting that this polymorphism has no immuno-modulatory role in the development of PE, PIH or IUGR. PMID- 26115231 TI - Perinatal outcomes in singleton pregnancies with a single umbilical artery. AB - OBJECTIVE: To analyze perinatal outcomes in singleton pregnancies with a single umbilical artery (SUA) as an isolated finding with no other underlying disorders. METHODS: This retrospective observational study compared a group of pregnancies with SUA (n = 127) and a group with a normal 3-vessel umbilical cord (n = 27 752). The study variables comprised maternal and obstetric characteristics and perinatal outcomes. RESULTS: The frequency of SUA was 0.45%. Pregnancies with SUA ended more frequently with cesarean delivery, and had a higher risk that the indication for cesarean delivery was non-reassuring fetal heart rate (NRFHR). Neonates in the SUA group had a lower weight for gestational age, and a higher risk of low umbilical cord blood pH. CONCLUSION: Obstetricians should monitor fetal growth closely in pregnancies with SUA, and be alert to NRFHR during labor and delivery. PMID- 26115232 TI - Effects of lower back pain on postural equilibrium and fall risk during the third trimester of pregnancy. AB - OBJECTIVE: To evaluate the effects of lower back pain (LBP) on postural equilibrium and fall risk during the third trimester pregnancy period by comparing postural stability between pregnant with LBP and pregnant without LBP control women. METHODS: The study population comprised 68 women of 24-35 years in the third trimester of pregnancy. They were divided into Groups 1 (n = 30) and 2 (n = 38) according to the presence or absence of LBP, respectively. Postural stability were evaluated between groups using Tetrax Interactive Balance System posturography (Tetrax, Sunlight Medical Ltd, Tel Aviv, Israel) with eight sensory conditions. RESULTS: For eight different positions, pregnant patients with LBP showed significantly higher values of general stability index, Fourier transformation index (F1, F2-F4, F5-F6 and F7-F8) and fall index than controls. CONCLUSION: LBP has a negative effect on postural stability. Postural equilibrium decreases and fall risk increases in pregnant patients with LBP. PMID- 26115235 TI - Integrating research and practice: proceedings of the research track of the 2015 Alliance for Continuing Education in the Health Professions annual meeting. PMID- 26115233 TI - Engineered hydrophobic pocket of (S)-selective arylmalonate decarboxylase variant by simultaneous saturation mutagenesis to improve catalytic performance. AB - A bacterial arylmalonate decarboxylase (AMDase) catalyzes asymmetric decarboxylation of unnatural arylmalonates to produce optically pure (R) arylcarboxylates without the addition of cofactors. Previously, we designed an AMDase variant G74C/C188S that displays totally inverted enantioselectivity. However, the variant showed a 20,000-fold reduction in activity compared with the wild-type AMDase. Further studies have demonstrated that iterative saturation mutagenesis targeting the active site residues in a hydrophobic pocket of G74C/C188S leads to considerable improvement in activity where all positive variants harbor only hydrophobic substitutions. In this study, simultaneous saturation mutagenesis with a restricted set of amino acids at each position was applied to further heighten the activity of the (S)-selective AMDase variant toward alpha-methyl-alpha-phenylmalonate. The best variant (V43I/G74C/A125P/V156L/M159L/C188G) showed 9,500-fold greater catalytic efficiency kcat/Km than that of G74C/C188S. Notably, a high level of decarboxylation of alpha-(4-isobutylphenyl)-alpha-methylmalonate by the sextuple variant produced optically pure (S)-ibuprofen, an analgesic compound which showed 2.5-fold greater activity than the (R)-selective wild-type AMDase. PMID- 26115236 TI - Relationship among knowledge acquisition, motivation to change, and self-efficacy in CME participants. AB - INTRODUCTION: The relationship among an individual's sense of self-efficacy, motivation to change, barriers to change, and the implementation of improvement programs has been reported. This research reports the relationship among self efficacy, motivation to change, and the acquisition of knowledge in a continuing medical education (CME) activity. METHODS: The measure of individual sense of self-efficacy was a 4-item scale. The measure of motivation was a 6-item scale following on the work of Prochaska and colleagues. The knowledge acquisition was measured in a simple post measure. The participants were enrolled in a CME activity focused on HIV. RESULTS: The CME activities had a significant effect on knowledge. Preliminary analysis demonstrates a relationship among the self efficacy measure, the motivation to change measure, and global intent to change. Specifically, as reported earlier, the sense of efficacy in effecting change in the practice environment is predictive of a high level of motivation to change that, in turn, is predictive of formation of intent to change practice patterns. Interestingly, there were also relationships among the self-efficacy measure, the motivation to change measure, and knowledge acquisition. Finally, as expected, there was a significant relationship between knowledge and intent to change practice. DISCUSSION: Further inspection of the motivation to change construct suggests that it mediates the self-efficacy constructs' effect on intent as well as its effect on knowledge acquisition. This new finding suggests that the proximal construct motivation completely masks an important underlying causal relationship that appears to contribute to practice change as well as learning following CME-self-efficacy. PMID- 26115234 TI - Solution Structure of CCL19 and Identification of Overlapping CCR7 and PSGL-1 Binding Sites. AB - CCL19 and CCL21 are chemokines involved in the trafficking of immune cells, particularly within the lymphatic system, through activation of CCR7. Concurrent expression of PSGL-1 and CCR7 in naive T-cells enhances recruitment of these cells to secondary lymphoid organs by CCL19 and CCL21. Here the solution structure of CCL19 is reported. It contains a canonical chemokine domain. Chemical shift mapping shows the N-termini of PSGL-1 and CCR7 have overlapping binding sites for CCL19 and binding is competitive. Implications for the mechanism of PSGL-1's enhancement of resting T-cell recruitment are discussed. PMID- 26115237 TI - Knowledge transfer at point of care: investigating new strategies for implementing guideline recommendations. PMID- 26115238 TI - Comparative effectiveness in CME: evaluation of personalized and self-directed learning models. PMID- 26115239 TI - Context and terminology in continuing education: improving the use of interventions in quality improvement and research. PMID- 26115240 TI - Quality improvement education for venous thromboembolism (VTE) prevention in cancer. PMID- 26115241 TI - Competence assessments: to pair or not to pair, that is the question. PMID- 26115242 TI - A comprehensive process for identifying and managing conflicts of interest reduced perceived bias at a specialty society annual meeting. PMID- 26115243 TI - Preassessment of weight management practices by providers and patients from 2 community primary care clinic networks. PMID- 26115244 TI - CME effectiveness: utilizing outcomes assessments of 600+ CME programs to evaluate the association between format and effectiveness. PMID- 26115245 TI - Overview of the 2015 Alliance Research Track. PMID- 26115246 TI - Tailoring CME with chart audits linked to individual physician performance to improve rheumatoid arthritis quality measures. PMID- 26115247 TI - Educational outcomes in the era of the Affordable Care Act: impact of personalized education about non-small cell lung cancer. AB - INTRODUCTION: The Affordable Care Act is moving medical care-and medical education-toward a quality-driven environment. Quality medical education must be available when the health care provider is ready to learn, provide feedback, and maximize translation of knowledge from desk to clinic. To best accomplish these goals, medical education must be personalized to clinicians' needs. Research has defined multiple knowledge/performance gaps among oncologists who manage advanced non-small cell lung cancer (NSCLC). A study was conducted to determine the effectiveness with which a personalized learning approach for oncologists will diminish these gaps. METHODS: The authors undertook development, online distribution, and impact measurement of an NSCLC curriculum in which learners' responses to a preeducation self-assessment of knowledge, skills, and attitudes resulted in receipt of a personalized curriculum. Upon completion of the assessment, each learner received a personalized curriculum, which included up to 5 distinct activities selected to address identified knowledge and practice gaps. Feedback was provided at the completion of each activity. RESULTS: Ninety-two oncologists completed an individualized learning plan. Analysis shows that completion of the learning plan was associated with a high effect size (d = .70). Significant increases were seen in oncologists' ability to correctly identify the rationale for determining histological subtype (13% increase), prevalence of genetic abnormalities (21% increase, p = .04), appropriate use of maintenance therapy (31% increase, p = .01), and appropriate treatment regimens for squamous cell carcinoma (19% increase, p = .003) and of adenocarcinoma (44% increase, p < .001). DISCUSSION: This study demonstrates the feasibility and impact of a personalized targeted curriculum for improving the competence of oncologists treating patients with advanced NSCLC. PMID- 26115248 TI - FORAGES AND PASTURES SYMPOSIUM: Use of marginal lands and fibrous byproducts in efficient beef and dairy production systems. PMID- 26115249 TI - FORAGES AND PASTURES SYMPOSIUM: Improving efficiency of production in pasture- and range-based beef and dairy systems. AB - Despite overall increased production in the last century, it is critical that grazing production systems focus on improving beef and dairy efficiency to meet current and future global food demands. For livestock producers, production efficiency is essential to maintain long-term profitability and sustainability. This continued viability of production systems using pasture- and range-based grazing systems requires more rapid adoption of innovative management practices and selection tools that increase profitability by optimizing grazing management and increasing reproductive performance. Understanding the genetic variation in cow herds will provide the ability to select cows that require less energy for maintenance, which can potentially reduce total energy utilization or energy required for production, consequently improving production efficiency and profitability. In the United States, pasture- and range-based grazing systems vary tremendously across various unique environments that differ in climate, topography, and forage production. This variation in environmental conditions contributes to the challenges of developing or targeting specific genetic components and grazing systems that lead to increased production efficiency. However, across these various environments and grazing management systems, grazable forage remains the least expensive nutrient source to maintain productivity of the cow herd. Beef and dairy cattle can capitalize on their ability to utilize these feed resources that are not usable for other production industries. Therefore, lower-cost alternatives to feeding harvested and stored feedstuffs have the opportunity to provide to livestock producers a sustainable and efficient forage production system. However, increasing production efficiency within a given production environment would vary according to genetic potential (i.e., growth and milk potential), how that genetic potential fits the respective production environment, and how the grazing management fits within those genetic parameters. Therefore, matching cow type or genetic potential to the production environment is and will be more important as cost of production increases. PMID- 26115250 TI - FORAGES AND PASTURES SYMPOSIUM: Optimizing the use of fibrous residues in beef and dairy diets. AB - Increased corn prices over the past decade have altered land use away from traditional forage in favor of corn. Accordingly, beef and dairy producers have had to adopt nontraditional forage resources into their production systems, many of which have become available as a result of increased corn production. Corn residues have become more available due to increases in corn hectares and yield. The individual plant components (i.e., husk, leaf, and stem) vary in fiber digestibility (NDF digestibility estimates = 40.5, 31.4, and 0.6% +/- 0.8 for husk, leaf, and stalk, respectively). Stocking cattle to consume 3.6 kg forage/25.5 kg of grain allows cattle to graze selectively; selection of husks and leaves improves cattle performance. Byproducts of the wet and dry milling industries can be supplemented to calves grazing corn residues to provide protein and energy. Optimal gains were observed when these byproducts were supplemented at approximately 2.5 kg/d to 250-kg growing calves. Gestating beef cows do not require supplemental inputs when grazing corn residue, if stocked appropriately. Alkaline treatment of crop residues improves their feeding value. Concentrations of up to 20% harvested corn residue treated with calcium oxide can be included in finishing diets with an average of 1.3% reduction in G:F when diets contain 40% wet or modified distillers grains. Conversely, when untreated corn residues are included in similar finishing diets, G:F is reduced by 13.4%. Calcium oxide treated residues included in beef growing diets increases DMI and ADG without significant improvements in G:F. Calcium oxide treatment of corn residues has been evaluated in dairy diets by replacing corn or corn silage with variable results. Efficient use of nontraditional fiber sources, such as corn milling byproducts and corn residue, are critical to the future viability of ruminant animal production. PMID- 26115251 TI - FORAGES AND PASTURES SYMPOSIUM: Improving soil health and productivity on grasslands using managed grazing of livestock. AB - Beyond grazing, managed grasslands provide ecological services that may offer economic incentives for multifunctional use. Increasing biodiversity of plant communities may maximize net primary production by optimizing utilization of available light, water, and nutrient resources; enhance production stability in response to climatic stress; reduce invasion of exotic species; increase soil OM; reduce nutrient leaching or loading in surface runoff; and provide wildlife habitat. Strategically managed grazing may increase biodiversity of cool-season pastures by creating disturbance in plant communities through herbivory, treading, nutrient cycling, and plant seed dispersal. Soil OM will increase carbon and nutrient sequestration and water-holding capacity of soils and is greater in grazed pastures than nongrazed grasslands or land used for row crop or hay production. However, results of studies evaluating the effects of different grazing management systems on soil OM are limited and inconsistent. Although roots and organic residues of pasture forages create soil macropores that reduce soil compaction, grazing has increased soil bulk density or penetration resistance regardless of stocking rates or systems. But the effects of the duration of grazing and rest periods on soil compaction need further evaluation. Because vegetative cover dissipates the energy of falling raindrops and plant stems and tillers reduce the rate of surface water flow, managing grazing to maintain adequate vegetative cover will minimize the effects of treading on water infiltration in both upland and riparian locations. Through increased diversity of the plant community with alterations of habitat structure, grazing systems can be developed that enhance habitat for wildlife and insect pollinators. Although grazing management may enhance the ecological services provided by grasslands, environmental responses are controlled by variations in climate, soil, landscape position, and plant community resulting in considerable spatial and temporal variation in the responses. Furthermore, a single grazing management system may not maximize livestock productivity and each of the potential ecological services provided by grasslands. Therefore, production and ecological goals must be integrated to identify the optimal grazing management system. PMID- 26115252 TI - Some novel growth functions and their application with reference to growth in ostrich. AB - Four novel growth functions, namely, Pareto, extreme value distribution (EVD), Lomolino, and cumulative beta-P distribution (CBP), are derived, and their ability to describe ostrich growth curves is evaluated. The functions were compared with standard growth equations, namely, the monomolecular, Michaelis Menten (MM), Gompertz, Richards, and generalized MM (gMM). For this purpose, 2 separate comparisons were conducted. In the first, all the functions were fitted to 40 individual growth curves (5 males and 35 females) of ostriches using nonlinear regression. In the second, performance of the functions was assessed when data from 71 individuals were composited (570 data points). This comparison was undertaken using nonlinear mixed models and considering 3 approaches: 1) models with no random effect, 2) random effect incorporated as the intercept, and 3) random effect incorporated into the asymptotic weight parameter (Wf). The results from the first comparison showed that the functions generally gave acceptable values of R2 and residual variance. On the basis of the Akaike information criterion (AIC), CBP gave the best fit, whereas the Gompertz and Lomolino equations were the preferred functions on the basis of corrected AIC (AICc). Bias, accuracy factor, the Durbin-Watson statistic, and the number of runs of sign were used to analyze the residuals. CBP gave the best distribution of residuals but also produced more residual autocorrelation (significant Durbin Watson statistic). The functions were applied to sample data for a more conventional farm species (2 breeds of cattle) to verify the results of the comparison of fit among functions and their applicability across species. In the second comparison, analysis of mixed models showed that incorporation of a random effect into Wf gave the best fit, resulting in smaller AIC and AIC values compared with those in the other 2 approaches. On the basis of AICc, best fit was achieved with CBP, followed by gMM, Lomolino, and Richards functions, respectively. The exponential, MM, Pareto, and EVD equations produced negative values for initial weight (W0) if left unconstrained. The Gompertz equation, in spite of having a fixed inflection point and therefore being less flexible, gave accurate estimates of both W0 and Wf and an acceptable goodness of fit favored by having fewer parameters than the other sigmoidal functions. Nevertheless, all the sigmoidal functions appeared appropriate in describing the growth trajectory of male and female ostriches to a reasonable level of accuracy. PMID- 26115253 TI - Genetic evaluation using single-step genomic best linear unbiased predictor in American Angus. AB - Predictive ability of genomic EBV when using single-step genomic BLUP (ssGBLUP) in Angus cattle was investigated. Over 6 million records were available on birth weight (BiW) and weaning weight (WW), almost 3.4 million on postweaning gain (PWG), and over 1.3 million on calving ease (CE). Genomic information was available on, at most, 51,883 animals, which included high and low EBV accuracy animals. Traditional EBV was computed by BLUP and genomic EBV by ssGBLUP and indirect prediction based on SNP effects was derived from ssGBLUP; SNP effects were calculated based on the following reference populations: ref_2k (contains top bulls and top cows that had an EBV accuracy for BiW >=0.85), ref_8k (contains all parents that were genotyped), and ref_33k (contains all genotyped animals born up to 2012). Indirect prediction was obtained as direct genomic value (DGV) or as an index of DGV and parent average (PA). Additionally, runs with ssGBLUP used the inverse of the genomic relationship matrix calculated by an algorithm for proven and young animals (APY) that uses recursions on a small subset of reference animals. An extra reference subset included 3,872 genotyped parents of genotyped animals (ref_4k). Cross-validation was used to assess predictive ability on a validation population of 18,721 animals born in 2013. Computations for growth traits used multiple-trait linear model and, for CE, a bivariate CE BiW threshold-linear model. With BLUP, predictivities were 0.29, 0.34, 0.23, and 0.12 for BiW, WW, PWG, and CE, respectively. With ssGBLUP and ref_2k, predictivities were 0.34, 0.35, 0.27, and 0.13 for BiW, WW, PWG, and CE, respectively, and with ssGBLUP and ref_33k, predictivities were 0.39, 0.38, 0.29, and 0.13 for BiW, WW, PWG, and CE, respectively. Low predictivity for CE was due to low incidence rate of difficult calving. Indirect predictions with ref_33k were as accurate as with full ssGBLUP. Using the APY and recursions on ref_4k gave 88% gains of full ssGBLUP and using the APY and recursions on ref_8k gave 97% gains of full ssGBLUP. Genomic evaluation in beef cattle with ssGBLUP is feasible while keeping the models (maternal, multiple trait, and threshold) already used in regular BLUP. Gains in predictivity are dependent on the composition of the reference population. Indirect predictions via SNP effects derived from ssGBLUP allow for accurate genomic predictions on young animals, with no advantage of including PA in the index if the reference population is large. With the APY conditioning on about 10,000 reference animals, ssGBLUP is potentially applicable to a large number of genotyped animals without compromising predictive ability. PMID- 26115254 TI - Estimation of genetic parameters for udder traits in Hereford cattle. AB - The objective was to estimate genetic parameters for udder traits in Hereford cattle. American Hereford Association (AHA) members initially recorded an overall score based on all udder characteristics. In 2008, the Beef Improvement Federation established guidelines, which were subsequently adopted by the AHA, for evaluating udder suspension and teat size. Therefore, a female was scored for either overall score or udder suspension and teat size for a single lactation, and females may be evaluated for overall score for a parity and then for udder suspension and teat size at a later parity. In all cases, subjective scores were assigned at parturition and ranged from 1 to 9, with a score of 9 considered ideal. Records on 48,191 animals and a 3-generation pedigree with 126,814 animals were obtained from the AHA, Kansas City, MO. These records contained repeated observations for overall score (n = 73,469), suspension (n = 38,412), and teat size (n = 38,412). Because the distribution of scores for all traits peaked at 7, a linear approximation was used in the analysis. Data were modeled using a multiple-trait animal model with random effects of additive genetic and permanent environment, fixed effect of contemporary group (herd-year-season), and a linear covariate for age in days. Heritability estimates (SE) for overall score, suspension, and teat size were 0.32 (0.01), 0.32 (0.01), and 0.28 (0.01), respectively. Through genetic selection for these traits, beef producers could improve udder traits. Repeatability estimates (SE) for overall score, suspension, and teat size were 0.45 (0.005), 0.47 (0.01), and 0.44 (0.01), respectively. Producers should continue evaluating udder traits repeatedly throughout a cow's lifetime. The phenotypic correlation (SE) between suspension and teat size was 0.64 (0.004) with 57% of records for suspension and teat size having the same score for both traits. The genetic correlations (SE) between teat size and suspension, overall score and teat size, and overall score and suspension were 0.81 (0.01), 0.71 (0.03), and 0.69 (0.03), respectively, and selection for one trait should result in correlated responses in the other traits. In conclusion, traits were moderately repeatable with scores from a parity being informative for subsequent parities. Because overall score, udder suspension, and teat size were moderately heritable with strong, positive genetic correlations, genetic improvement for these traits can be achieved through selection. PMID- 26115255 TI - Estimation of the environmental dam-offspring correlation in beef cattle. AB - A long standing controversy in animal breeding is related to the strong negative estimates of the direct-maternal genetic correlation obtained when fitting data on maternally influenced traits. In this article, we focused on a model that introduces a new correlation parameter among dam-offspring records. The extant theory allows estimation of the parameter when dams have at most a single offspring. Our goal was to develop an inferential procedure in a more general setting. To do so, we applied a Bayesian approach and we showed that the estimation could be accomplished by introducing a Markov chain Monte Carlo (MCMC) step embedded into a regular Gibbs sampler program. The procedure was implemented by means of an MCMC algorithm known as the Griddy-Gibbs sampler, and a Fortran 90 library was created to accomplish the task. The computer program is available from http://www.agro.uba.ar/catedras/mg_animal/software/RDBLK. With this tool at hand, we applied the inferential procedure to weaning weight records on beef cattle calves from an Argentinean Hereford herd, and we estimated the marginal distribution of the environmental dam-offspring correlation parameter. The distribution was unimodal and symmetric with a mean value of -0.14 (+/-0.03) and a 95% high posterior density interval between -0.20 and -0.07, indicating that the model placed a huge mass on negative values of the parameter. Noticeably, the magnitude of the direct-maternal genetic correlation diminished from -0.61 to 0.37 with respect to the standard maternal animal model. This result reinforces the idea that environmental covariances among dam-offspring records may bias the estimate of the direct-maternal genetic correlation. PMID- 26115256 TI - A comparison of alternative random regression and reaction norm models for whole genome predictions. AB - Whole genome prediction (WGP) based on high density SNP marker panels is known to improve the accuracy of breeding value (BV) prediction in livestock. However, these accuracies can be compromised when genotype by environment interaction (G*E) exists but is not accounted for. Reaction norm (RN) and random regression (RR) models have proven to be useful in accounting for G*E in pre-WGP evaluations by modeling BV as linear or higher order functions of environmental or temporal covariates. We extend these RR/RN models based on several alternative specifications for SNP-specific intercepts and linear slopes on environmental covariates. One specification is based on bivariate normality (BVN) of SNP specific intercepts and slopes, whereas 2 others, IW-BayesA and based on inverted Wishart (IW) extensions IW-BayesB, are, respectively, bivariate Student t extensions of currently popular models without (BayesA) or with (BayesB) variable selection. We highlight alternative specifications based on the square root free Cholesky decomposition (CD) of SNP-specific variance-covariance (VCV) matrices in an attempt to better differentially model environmentally sensitive from environmentally robust QTL. Two CD specifications were considered with (CD BayesB) or without (CD-BayesA) any variable selection on intercept and slope effects. We compared each of the 5 models based on an RN simulation study. Six scenarios were considered based on differences in overall genetic correlations between SNP-specific intercept and slope effects as well as on heritabilities and numbers of environmentally robust versus sensitive QTL. In most scenarios, IW BayesA had the greatest accuracy, whereas CD-BayesB exhibited the greatest accuracy in low complexity architectures (i.e., low number of QTL). In an RR application of a Duroc * Pietrain resource population at Michigan State University, 5,271 SNP markers and 928 F2 animals with known pedigree were analyzed for backfat thickness at wk 10, 13, 16, 19, and 22. SNP-based RR methods had a 2.5% greater (P < 0.0001) cross-validation accuracy for predicting phenotypes than the SNP-based conventional BayesA/BayesB and/or pedigree based RR BLUP; however, none of the proposed RR models had performances that were different from each other. PMID- 26115257 TI - Genomic prediction for tick resistance in Braford and Hereford cattle. AB - One of the main animal health problems in tropical and subtropical cattle production is the bovine tick, which causes decreased performance, hide devaluation, increased production costs with acaricide treatments, and transmission of infectious diseases. This study investigated the utility of genomic prediction as a tool to select Braford (BO) and Hereford (HH) cattle resistant to ticks. The accuracy and bias of different methods for direct and blended genomic prediction was assessed using 10,673 tick counts obtained from 3,435 BO and 928 HH cattle belonging to the Delta G Connection breeding program. A subset of 2,803 BO and 652 HH samples were genotyped and 41,045 markers remained after quality control. Log transformed records were adjusted by a pedigree repeatability model to estimate variance components, genetic parameters, and breeding values (EBV) and subsequently used to obtain deregressed EBV. Estimated heritability and repeatability for tick counts were 0.19 +/- 0.03 and 0.29 +/- 0.01, respectively. Data were split into 5 subsets using k-means and random clustering for cross-validation of genomic predictions. Depending on the method, direct genomic value (DGV) prediction accuracies ranged from 0.35 with Bayes least absolute shrinkage and selection operator (LASSO) to 0.39 with BayesB for k-means clustering and between 0.42 with BayesLASSO and 0.45 with BayesC for random clustering. All genomic methods were superior to pedigree BLUP (PBLUP) accuracies of 0.26 for k-means and 0.29 for random groups, with highest accuracy gains obtained with BayesB (39%) for k-means and BayesC (55%) for random groups. Blending of historical phenotypic and pedigree information by different methods further increased DGV accuracies by values between 0.03 and 0.05 for direct prediction methods. However, highest accuracy was observed with single-step genomic BLUP with values of 0.48 for -means and 0.56, which represent, respectively, 84 and 93% improvement over PBLUP. Observed random clustering cross validation breed-specific accuracies ranged between 0.29 and 0.36 for HH and between 0.55 and 0.61 for BO, depending on the blending method. These moderately high values for BO demonstrate that genomic predictions could be used as a practical tool to improve genetic resistance to ticks and in the development of resistant lines of this breed. For HH, accuracies are still in the low to moderate side and this breed training population needs to be increased before genomic selection could be reliably applied to improve tick resistance. PMID- 26115258 TI - Genetic associations between scrotal circumference and female reproductive traits in Nelore cattle. AB - The objective of this study was to estimate genetic associations between scrotal circumference obtained at 12 (SC12; mean of 21.46 +/- 2.74 cm), 15 (SC15; mean of 25.31 +/- 3.19 cm), and 18 mo of age (SC18; mean of 26.77 +/- 2.95 cm) and reproductive traits measured directly in heifers (age at first calving [AFC]: mean of 1,062.06 +/- 114.79 d; heifer pregnancy at 16 mo of age [HP]: mean of 15.4 +/- 0.36%; and subsequent rebreeding of primiparous heifers [HR]: mean of 27.1 +/- 0.44%) using Bayesian inference to evaluate the possible inclusion of these traits as selection criteria in beef cattle breeding programs. Genetic gains comparisons were also estimated. A total of 53,683 data of Nelore animals born between 1990 and 2006, obtained from the livestock archive of Agropecuaria Jacarezinho Ltda. (Valparaiso, Sao Paulo, Brazil), were analyzed. Two-trait analysis provided heritability estimates of 0.35 +/- 0.08, 0.40 +/- 0.04, 0.37 +/ 0.03, 0.21 +/- 0.01, 0.55 +/- 0.03, and 0.17 +/- 0.03 for SC12, SC15, SC18, AFC, HP, and HR, respectively. The genetic correlations between scrotal circumference and AFC, HP, and HR were -0.42 +/- 0.12, 0.43 +/- 0.13, and -0.13 +/- 0.17, respectively, for SC12; -0.25 +/- 0.07, 0.26 +/- 0.07, and -0.11 +/- 0.10, respectively, for SC15; and -0.22 +/- 0.06, 0.39 +/- 0.06, and 0.11 +/- 0.09, respectively, for SC18. The direct selection response for HP was 0.12%, but when HP is indirectly selected based on the scrotal circumferences, the gains on these correlated responses were higher (0.16, 0.16, and 0.22%) for selection based on SC12, SC15, and SC18, respectively. These findings suggest that the selection of animals for larger scrotal circumference, particularly at 12 mo of age, should result in higher rates of HP and younger AFC of Nelore females. PMID- 26115259 TI - Genetic relationships between internal diseases diagnosed at slaughter and carcass traits in Japanese Black cattle. AB - The objective of this paper was to estimate the genetic parameters of certain internal diseases (multifocal necrosis in the liver [MNL], bovine abdominal fat necrosis [BFN], and inflammation of the large intestine [ILI]) and to investigate relationships between the internal diseases and carcass traits (carcass weight [CW], rib eye area [REA], rib thickness [RT], subcutaneous fat thickness, and beef marbling score [BMS]). Records of the internal diseases and the carcass traits of 5,788 Japanese Black cattle were used for this study. The data for all the diseases were recorded as binary data as to whether the disease was observed (1) or not (0). Genetic parameters were estimated using linear and threshold animal models. The prevalence rates of MNL, BFN, and ILI were 16.1, 23.0, and 6.8%, respectively, and heritability estimates +/- posterior SD were 0.18 +/- 0.06, 0.28 +/- 0.06, and 0.18 +/- 0.06, respectively. The genetic correlations of MNL with BFN and ILI were -0.23 (P = 0.19) and -0.49 (P < 0.05), respectively. In contrast, the correlation between BFN and ILI was positive and high (0.96; < 0.05). The phenotypic correlations of the internal diseases with the carcass traits were weak and not different from 0 except for those of BFN and ILI with CW, REA, and RT, which were all negative (P < 0.05) and ranged from -0.21 (ILI and CW) to -0.05 (BFN and RT). The genetic correlations of MNL with the carcass traits were all weak and not significant. In contrast, the genetic correlations of BFN and ILI with CW, REA, and RT were all negative and significant (P < 0.05) between BFN and CW (-0.36) and between BFN and RT (-0.33). However, the genetic correlations for BFN and ILI with BMS were all positive at 0.21 P( = 0.16) and 0.39 (P < 0.05), respectively. The estimated heritability of the internal diseases suggests that they can be genetically improved. Genetic relationships of BFN and ILI with meat quantity traits were favorable for beef cattle breeding, because lower disease liabilities were associated with improved CW, REA, and RT for BFN and ILI. However, rather strong and unfavorable genetic relationships were found between BFN or ILI and BMS, which is related to meat quality. This suggests that selection for animals with superior BMS would increasingly lead to animals with higher liability to the internal diseases. PMID- 26115260 TI - Relationships between day one piglet serum immunoglobulin immunocrit and subsequent growth, puberty attainment, litter size, and lactation performance. AB - Colostrum affects gut and uterine gland development in the neonatal piglet, suggesting that subsequent growth and reproductive performance may be affected. Measuring immunoglobulin in piglet serum using the immunoglobulin immunocrit on Day 1 of age provides a simple, inexpensive indication of the amount of colostrum acquired by the piglet in the first day of life. Relationships between serum immunoglobulin immunocrit measures and subsequent growth rates, age at puberty, incidence of puberty failure, litter size, and lactation performance were examined in pigs born and subsequently farrowing between 2009 and 2013. Immunoglobulin immunocrit measures were collected on 16,762 piglets on Day 1 of age. Of these piglets, BW measurements were available from 15,324 (7,684 males and 7,640 females) piglets at a range of ages from weaning to 200 d of age, allowing an assessment of growth rates. Age at puberty was recorded from a subset of 2,857 of the females after observing them for estrous behavior from approximately 170 to 250 d of age. To examine relationships between d 1 immunocrit and puberty failure, gilts with immunocrit measures that failed to reach puberty (n = 119) were matched with littermate gilts with immunocrit measures that achieved puberty (n = 167). Similarly, number born alive was collected on a subset (n = 799) of females from first to fourth parities for which d 1 immunocrits were measured on them as neonates. Finally, d 1 immunocrit effect on adult lactational competence was assessed by measuring litter average (offspring of 440 females) and litter average piglet preweaning growth rate (offspring of 774 females) in females where d 1 immunocrits were available from them as neonates. Results indicated that low d 1 immunocrits were subsequently associated with reduced growth (P < 0.01), increased age at puberty (P < 0.01), reduced number born alive (P < 0.05), reduced litter average immunocrit (P < 0.05), and reduced litter average preweaning growth rate during lactation (P < 0.05). This suggests that management efforts to improve the amount of colostrum ingested by neonatal piglets would result in beneficial changes in production efficiency, particularly for gilts destined for the breeding herd. It also suggests that the immunoglobulin immunocrit can be useful in monitoring colostrum ingestion to maximize the beneficial effects of colostrum on subsequent performance. PMID- 26115261 TI - Long term vitamin A restriction improves meat quality parameters and modifies gene expression in Iberian pigs. AB - Vitamin A is a key regulator of gene expression, influencing adipogenesis and lipid metabolism in animal tissues. This experiment was conducted to assess the effect of dietary vitamin A level and administration time on productive traits, intramuscular fat (IMF) content in ham muscles, tissue fatty acid composition, and expression of a panel of adipogenic and lipogenic candidate genes in Iberian pigs. Sixty piglets of 16.3 kg (SD = 2.5 kg) live weight (LW) were either fed a vitamin A-enriched diet (10,000 IU vitamin A/kg; CONTROL, n = 20) or a diet without supplemented vitamin A, applied from 16.3 kg (SD = 2.5 kg; early restriction group, ER, n = 20) or from an average weight of 35.8 kg (SD = 3.1 kg; late restriction group, LR, n = 20). Two slaughters were performed when pigs reached the averaged weights of 101.4 (SD = 4.1 kg) and 157.9 kg LW (SD = 7 kg) and samples from liver, heart, and backfat were obtained in both sacrifice times. In addition, ham subcutaneous fat and Semimembranosus (SM) and Biceps Femoris (BF) muscles were sampled at the last sacrifice. Dietary vitamin A level produced no effect on carcass traits in any of the harvests, while a small effect was observed on fatty acid composition in backfat at 101.4 kg LW. However, at 157.9 kg LW, the ER and LR groups showed higher MUFA content and lower SFA content in backfat, ham fat, and IMF (P < 0.01). In IMF, a decrease in n-6/n-3 PUFA ratio was observed in the restricted groups (P < 0.005). Intramuscular fat content in SM muscle was greater (P < 0.05) in the ER group than in the CONTROL and LR groups, while no difference was detected in BF muscle. Little effect of dietary vitamin A was observed in liver. Regarding changes in gene expression, ACSL4, CEBPB, and IGF1 genes were upregulated (P < 0.0001, P < 0.0001, and P < 0.05, respectively) in the ER group in hepatic tissue, whereas CRABPII and SCD genes were upregulated (P < 0.05) in the same group in adipose tissue. On the other hand, was downregulated ( < 0.05) in the ER group in adipose tissue. Results found in this experiment show that long-term restriction of dietary vitamin A has a positive effect on nutritional and sensorial parameters of ham meat. Moreover, gene expression results were consistent with the vitamin A transcriptional regulation of adipogenesis and lipogenesis and with the changes observed in meat and fat composition. PMID- 26115262 TI - Divergent selection for residual feed intake affects the transcriptomic and proteomic profiles of pig skeletal muscle. AB - Improving feed efficiency is a relevant strategy to reduce feed cost and environmental waste in livestock production. Selection experiments on residual feed intake (RFI), a measure of feed efficiency, previously indicated that low RFI was associated with lower feed intake, similar growth rate, and greater lean meat content compared with high RFI. To gain insights into the molecular mechanisms underlying these differences, 24 Large White females from 2 lines divergently selected for RFI were examined. Pigs from a low-RFI ("efficient") and high-RFI ("inefficient") line were individually fed ad libitum from 67 d of age (27 kg BW) to slaughter at 115 kg BW (n = 8 per group). Additional pigs of the high-RFI line were feed restricted to the daily feed intake of the ad libitum low RFI pigs (n = 8) to investigate the impact of selection independently of feed intake. Global gene and protein expression profiles were assessed in the LM collected at slaughter. The analyses involved a porcine commercial microarray and 2-dimensional gel electrophoresis. About 1,000 probes were differentially expressed (P < 0.01) between RFI lines. Only 10% of those probes were also affected by feed restriction. Gene functional classification indicated a greater expression of genes involved in protein synthesis and a lower expression of genes associated with mitochondrial energy metabolism in the low-RFI pigs compared with the high-RFI pigs. At the protein level, 11 unique identified proteins exhibited a differential abundance (P < 0.05) between RFI lines. Differentially expressed proteins were generally not significantly affected by feed restriction. Mitochondrial oxidative proteins such as aconitase hydratase, ATP synthase subunit alpha, and creatine kinase S-type had a lower abundance in the low-RFI pigs, whereas fructose-biphosphate aldolase A and glyceraldehyde-3-phosphate dehydrogenase, 2 proteins involved in glycolysis, had a greater abundance in those pigs compared with high-RFI pigs. Antioxidant proteins such as superoxide dismutase and glutathione peroxidase 3 at the mRNA level and peroxiredoxin-6 at the protein level were also less expressed in LM of the most efficient pigs, likely related to lower oxidative molecule production. Collectively, both the transcriptomic and proteomic approaches revealed a lower oxidative metabolism in muscle of the low-RFI pigs and all these modifications were largely independent of differences in feed intake. PMID- 26115263 TI - Effects of dietary energy on sexual maturation and sperm production in Holstein bulls. AB - In prepubertal bulls and heifers of dairy and beef breeds, puberty can be induced to occur earlier than typical with targeted high-energy diets due to precocious activation of the endocrine mechanisms that regulate puberty. Precocious activation of puberty in bulls intended for use in the AI industry has the potential to hasten and perhaps increase sperm production. It was hypothesized that feeding bulls a high-energy diet beginning at 8 wk of age would advance the prepubertal rise in LH and lead to advanced testicular maturation and age at puberty. From 58 to 230 +/- 0.3 d of age, Holstein bulls received either a high energy diet (HE;n = 9; targeted ADG 1.5 kg/d) or a control diet (CONT;n = 10; targeted ADG 0.75 kg/d). Thereafter, all bulls were fed a similar diet. The HE treatment increased LH secretion at 125 d of age, testosterone concentrations from 181 to 210 d, and scrotal circumference (SC) from 146 to 360 d of age relative to the CONT treatment. Beginning at 241 +/- 5 d of age, semen collection (artificial vagina) was attempted every 14 d in bulls from the HE (n = 8) and CONT (n = 7) treatment until each bull attained puberty (ejaculate containing 50 * 10 spermatozoa with 10% motility). To assess semen production as mature bulls, semen was collected thrice weekly beginning at 541 +/- 5 d of age until slaughter at 569 +/- 5 d of age. After slaughter, epididymal and testicular measurements were collected and testicular tissue was fixed to determine seminiferous tubule diameter. Age at puberty did not differ between treatments (310 +/- 35 d). Although testis and epididymal weight and testis volume were greater (P < 0.05) in the HE than the CONT treatment, sperm production of mature bulls did not differ between treatments. Diameter of seminiferous tubules also did not differ between treatments. We conclude that the HE advanced aspects of sexual maturation and increased testes size, but this was not reflected in hastened puberty or sperm production in the present experiment. PMID- 26115264 TI - Alteration of factors associated with hepatic gluconeogenesis in response to acute lipopolysaccharide in dairy goat. AB - Lipopolysaccharide (LPS) is a common pathogenic agent that causes many diseases and metabolic disorders. Hypoglycemia is often observed when animals are infected with LPS. To explore the influence of LPS on blood glucose and hepatic gluconeogenesis in goats, 12 goats were randomly assigned to 1 of 2 groups: the LPS-treated group (60 MUg/kg BW of LPS; jugular vein injections) or the control group (saline vehicle; jugular vein injections). Blood samples were collected from jugular veins at 0, 1, 2, 4, 6, and 8 h, and liver tissue samples were biopsied 8 h after the injections. The dynamic changes in blood glucose levels as well as key hepatic gluconeogenic enzyme mRNA and protein expression, ATP and ADP levels, and glutathione reductase (GR) activity were determined. The results showed that blood glucose levels in the LPS group were dramatically reduced after an initial, short-term increase. In liver tissue, the mRNA of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase 1 (PEPCK1;P < 0.05), fructose-1,6 bisphosphatase 1 (FBP1;P < 0.01), pyruvate carboxylase (PCB;P < 0.05), and acyl CoA synthetase short-chain family member 3 (ACSS3; < 0.01), in the related pathways and PPAR-gamma coactivator 1alpha (PGC-1alpha;P < 0.05) were decreased in the LPS group compared with those in the control group, whereas glucose-6 phosphatase (G6Pase-alpha) was not different (P > 0.05). The protein expression of PEPCK1 decreased (P < 0.01), whereas that of G6Pase-alpha increased (P < 0.05) significantly. The ratio of ADP to ATP ( < 0.05) and the activity of GR (P < 0.01) were markedly increased in the LPS group compared with those in controls. This research showed that LPS markedly affects and reduces blood glucose in dairy goats. The crucial reasons for the marked change in blood glucose are the altered expression of key gluconeogenic enzymes in different pathways and of essential factors associated with gluconeogenesis in the liver. PMID- 26115265 TI - Effects of fat-enriched diet and methionine on insulin sensitivity in lactating cows. AB - The hyperinsulinemic-euglycemic clamp (EGC) technique was used to investigate the effects of calcium salts of long-chain fatty acids (LCFA-Ca) and rumen-protected Met (RPM) on insulin sensitivity in the peripheral tissues of lactating cows. Six multiparous Holstein cows were used in a 3 * 3 Latin square experiment in each 14 d period. Dietary treatments were 0 (RPM0), 20 (RPM20), and 60 (RPM60) g/d of RPM, supplemented with a diet containing 1.5% of LCFA-Ca equal to 110% of the cows' ME requirement. And as a control for the 3 LCFA-Ca-containing diets, a dietary treatment without LCFA-Ca (Con) was also included. After a 10-d adaptation period, milk samples were collected for 4 d, and EGC experiments were performed on d 14 of each treatment period. Insulin solution was infused through a jugular vein catheter at a rate of 0.1, 0.2, 0.3, and 0.4 milliunits.kg BW 1.min-1 for 30 min and then at a rate of 0.5 milliunits.kg BW-1.min-1 for 60 min. Glucose solution was variably infused to maintain plasma glucose at steady state through the same catheter. Blood samples for measurements were taken using the contralateral catheter. Plasma total cholesterol, cholesterol ester, free cholesterol, and phospholipid concentrations in RPM0 and RPM20 were higher than those in Con, whereas the concentrations in RPM60 were low at the same degree of those in RPM0 (P < 0.05). Plasma Met concentration was greatest in RPM60 (P < 0.05). In the EGC experiment, the glucose infusion rate was greater in RPM60 than in RPM0 and RPM20 and an effective concentration of insulin resulting in 50% maximal glucose infusion rate was lower in RPM60 compared with RPM0 (P < 0.05), indicating that insulin sensitivity was intensified in RPM60. Although the insulin sensitivity evaluated from the EGC data in RPM0, RPM20, and RPM60 was not different from Con, a slight decline was observed in RPM0 and insulin sensitivity in RPM60 was higher than Con. Our results from the EGC experiment demonstrated that the feeding RPM lead to increased insulin sensitivity, which suggests that dietary Met affects lipid metabolism via insulin action in lactating dairy cows fed a LCFA-Ca-containing diet. PMID- 26115266 TI - Proteomic analysis of white and yellow seminal plasma in turkeys (Meleagris gallopavo). AB - Yellow semen syndrome (YSS) is endemic within domestic turkey populations. Yellow semen is of lower quality and, when used for insemination, results in reduced fertility and hatchability. Little is known about the etiology of YSS. The aim of this study was to compare the proteome of white and yellow seminal plasma of turkeys using 1) 2-dimensional difference gel electrophoresis (2D-DIGE) to quantify seminal plasma proteins and 2) matrix-assisted laser desorption/ionization mass spectrometry to identify the proteins that are differentially abundant in white and yellow seminal plasma. A total of 49 protein spots (30 upregulated and 19 downregulated) were differentially expressed in yellow seminal plasma compared with white seminal plasma. Transthyretin and serum albumin-like showed a 3-fold increase in seminal plasma from males with YSS, and the latter was validated using Western blot analysis. A 3-fold increase was observed for hemopexin-like and immunoglobulin light chain V-J-C region. Pantetheinase-like showed a 1.3-fold increase. Ovotransferrin, hepatocyte growth factor activator, cysteine-rich secretory protein 3-like, and ferritin heavy chain-like showed a significant decrease (at least a 1.3-fold decrease) in yellow semen. Further studies are necessary to evaluate the precise function of the above-mentioned proteins in YSS and to establish quality markers of turkey semen to predict the reproductive potential of individual turkeys. PMID- 26115267 TI - Impact of puberty status and melengestrol acetate supplementation before the breeding period on reproductive efficiency of Bos indicus beef heifers. AB - Two experiments were designed to evaluate the impact of puberty status and the administration of melengestrol acetate (MGA) before onset of the breeding period on ovulatory responses (Exp. 1) and conception rate after AI performed on estrus detection during 10 d and the pregnancy rate through 80 d of breeding period (Exp. 2) of pasture-grazed beef heifers. In Exp. 1, heifers (15 pubertal and 15 prepubertal) received 0.5 mg per heifer/d -1 of MGA over 14 d. No differences in the ovulatory responses were found 10 d after the MGA administration (pubertal = 46.7% vs. prepubertal P = 53.3%; P = 0.72). In Exp. 2, 368 heifers were randomly assigned to groups according to pubertal status and the MGA treatment. All heifers were inseminated on estrus detection for up 10 d after MGA administration and following exposure to bulls between 20 and 80 d. The MGA-treated heifers exhibited a greater AI service rate than control heifers (72.1 vs. 41.6%;P < 0.01); however, heifers receiving MGA had lower conception results following AI (51.6 vs. 71.4%; P = 0.01). In addition, MGA-treated heifers were more likely to have a corpus luteum in the middle of the breeding period (95.3 vs. 87.5%;P < 0.01), although the Cox proportional hazard of pregnancy rate was similar (P = 0.29) at the end of the breeding period. At onset of the breeding period, pubertal heifers presented a greater pregnancy rate following AI (pubertal P = 42.2% vs. prepubertal P = 24.9%; P = 0.01). Therefore, pubertal heifers seem to have greater overall reproductive efficiency than prepubertal heifers, particularly at the beginning of the breeding period. Interestingly, administration of MGA before the onset of the breeding period increased AI service rate but did not alter the rate of pregnancy throughout the breeding period of pasture-grazed beef heifers. PMID- 26115268 TI - Influence of estrus at fixed-time artificial insemination on early embryonic development in beef cattle. AB - It has been repeatedly demonstrated that estrous expression before fixed-time AI (TAI) results in increased pregnancy success. Therefore, the objective of this experiment was to determine if preblastocyst embryonic developmental characteristics differed from heifers that did or did not exhibit estrus before TAI. Beef heifers (n = 113) were synchronized using the 5-d CO-Synch + controlled internal drug release device with TAI on d 0. Before TAI, estrous expression was assessed twice daily. On d 6, single embryos were collected and visually evaluated to determine quality (International Embryo Transfer Society standards; 1-4, in which 1 = excellent/good and 4 = degenerate) and stage (1-9, in which 1 = unfertilized and 9 = expanded hatched blastocyst). Embryos were stained and evaluated to determine number of dead blastomeres, number of total blastomeres, and number of accessory sperm. Estrous expression before TAI did not affect the percent of embryos recovered (P = 0.59), number of dead cells (P = 0.99), or number of total cells (P = 0.25). However, heifers that exhibited estrus had increased mean (P = 0.03) and median accessory sperm numbers and (P = 0.01) percent live cells when compared with nonestrus heifers. Heifers that exhibited estrus also produced embryos that had a more advanced stage (P = 0.03) and improved quality (P = 0.04) when compared with those heifers not exhibiting estrus. When all heifers were evaluated, there was no correlation between circulating concentration of estradiol at TAI and embryo quality or embryo stage. There was a significant correlation between accessory sperm numbers and embryo quality (P = 0.01) and embryo stage (P < 0.01), such that as accessory sperm numbers increased, embryo quality and stage increased. In conclusion, exhibiting estrus before TAI resulted in improved embryo quality and advanced embryo stage on d 6 and increased the number of accessory sperm associated with the embryo. PMID- 26115269 TI - Effect of processing of rapeseed under defined conditions in a pilot plant on chemical composition and standardized ileal amino acid digestibility in rapeseed meal for pigs. AB - Five rapeseed meals (RSM) were produced from a single batch of rapeseed in a large-scale pilot plant under standardized conditions. The objective was to evaluate the effect of residence time in the desolventizer/toaster (DT) on chemical composition and standardized ileal digestibility (SID) of AA in RSM. Four RSM, with 48, 64, 76, and 93 min residence time and using unsaturated steam in the DT, referred to as RSM48, RSM64, RSM76, and RSM93, respectively, and 1 low glucosinolate RSM, which was subjected to sequential treatment with unsaturated steam, saturated steam, and dry heat in the DT, referred to as low-GSL RSM, were assayed. Six barrows (average initial BW = 22 +/- 1 kg) were surgically fitted with a T-cannula at the distal ileum. Pigs were allotted to a 5 * 6 row * column design with 5 diets and 5 periods. The 5 RSM were included in a cornstarch-casein based basal diet. In addition, basal ileal endogenous losses and SID of AA originating from casein were determined at the conclusion of the experiment in 2 additional periods by means of the regression method and using 3 graded levels of casein. The SID of AA in the 5 RSM was determined in difference to SID of AA originating from casein. The glucosinolates (GSL) were efficiently reduced, whereas NDF, ADF, ADL, and NDIN contents increased and reactive Lys (rLys) and Lys:CP ratio decreased as the residence time in the DT was increased from 48 to 93 min. The SID of most AA in RSM linearly decreased (P < 0.05) as the residence time in the DT increased from 48 to 93 min. Moreover, there was a linear decrease (P < 0.05) in SID of AA with increasing NDF, ADF, ADL, and NDIN contents in these RSM, whereas SID of AA linearly decreased (P < 0.05) with decreasing levels of GSL and rLys and a decreasing Lys:CP ratio. The decrease (P < 0.05) in SID of AA amounted from 3 up to 6 (percentage units) for most AA, except for SID of Cys and Lys, which decreased by 10 and 11%-units (P < 0.05), respectively, as the residence time in the DT was increased from 48 to 93 min. The SID in low-GSL RSM was for CP and most AA similar to RSM93 but lower ( < 0.05) compared to RSM48. It can be concluded that time and energy-intensive heat treatment results in lower contents of SID AA in RSM together with a reduction in GSL levels. The feed industry would most likely benefit from a rapid and accurate prediction of SID of AA, for example, based on content of NDIN, GSL, rLys or on Lys:CP ratio, in different batches of RSM used for feed manufacturing. PMID- 26115270 TI - Regression analysis to predict growth performance from dietary net energy in growing-finishing pigs. AB - Data from 41 trials with multiple energy levels (285 observations) were used in a meta-analysis to predict growth performance based on dietary NE concentration. Nutrient and energy concentrations in all diets were estimated using the NRC ingredient library. Predictor variables examined for best fit models using Akaike information criteria included linear and quadratic terms of NE, BW, CP, standardized ileal digestible (SID) Lys, crude fiber, NDF, ADF, fat, ash, and their interactions. The initial best fit models included interactions between NE and CP or SID Lys. After removal of the observations that fed SID Lys below the suggested requirement, these terms were no longer significant. Including dietary fat in the model with NE and BW significantly improved the G:F prediction model, indicating that NE may underestimate the influence of fat on G:F. The meta analysis indicated that, as long as diets are adequate for other nutrients (i.e., Lys), dietary NE is adequate to predict changes in ADG across different dietary ingredients and conditions. The analysis indicates that ADG increases with increasing dietary NE and BW but decreases when BW is above 87 kg. The G:F ratio improves with increasing dietary NE and fat but decreases with increasing BW. The regression equations were then evaluated by comparing the actual and predicted performance of 543 finishing pigs in 2 trials fed 5 dietary treatments, included 3 different levels of NE by adding wheat middlings, soybean hulls, dried distillers grains with solubles (DDGS; 8 to 9% oil), or choice white grease (CWG) to a corn-soybean meal-based diet. Diets were 1) 30% DDGS, 20% wheat middlings, and 4 to 5% soybean hulls (low energy); 2) 20% wheat middlings and 4 to 5% soybean hulls (low energy); 3) a corn-soybean meal diet (medium energy); 4) diet 2 supplemented with 3.7% CWG to equalize the NE level to diet 3 (medium energy); and 5) a corn-soybean meal diet with 3.7% CWG (high energy). Only small differences were observed between predicted and observed values of ADG and G:F except for the low-energy diet containing the greatest fiber content (30% DDGS diet), where ADG and G:F were overpredicted by 3 to 6%. Therefore, the prediction equations provided a good estimation of the growth rate and feed efficiency of growing-finishing pigs fed different levels of dietary NE except for the pigs fed the low-energy diet containing the greatest fiber content. PMID- 26115271 TI - Influence of dietary electrolyte balance on feed preference and growth performance of postweaned piglets. AB - A total of 672 male and female piglets (21 d postweaning; approximately 13 kg BW) were selected to be used in 3 different experiments to assess the influence of dietary electrolyte balance (dEB; Na + K - Cl, in mEq/kg of diet) on feed preference and growth performance. In Exp. 1, piglets were fed 4 isoenergetic diets differing in dEB level: 16, 133, 152, and 269 mEq/kg diets. Changes on dEB were obtained by changing the levels of sodium and chloride with calcium chloride, calcium carbonate, and sodium bicarbonate. Piglets fed the 16 and 133 mEq/kg diets achieved a greater ADG (P < 0.04), BW (P < 0.04), and apparent total tract digestibility of CP and Zn (P < 0.05) than did piglets fed the 269 mEq/kg diet. The 16 mEq/kg level also reduced blood total CO (P < 0.01), bicarbonate (P < 0.01), and base excess (P < 0.02) concentrations compared with the rest of the dietary treatments. Three diets differing in dEB were designed for Exp. 2 and 3: 16, 151, and 388 mEq/kg diets. In Exp. 2, greater ADFI (P = 0.03), BW (P = 0.02), ADG (P < 0.001), and G:F (P < 0.01) were observed for piglets fed the -16 mEq/kg diet than those fed the 388 mEq/kg diet. Subsequently, their short-term preference for these diets was assessed by using a 2-d choice-test protocol (30 min). Piglets preferred (P < 0.001) the 388 mEq/kg diet to the -16 mEq/kg diet, independently of the dietary treatment they received before. Pigs also preferred (P < 0.001) the 151 mEq/kg diet when compared with the -16 mEq/kg diet. Experiment 3 assessed the long-term preference and short-term consumption of the 16 and 388 mEq/kg diets. Similar to Exp. 2, animals showed a greater (P < 0.001) intake of the 388 mEq/kg diet than they did of the -16 mEq/kg diet during both the preference (14 d) and 1-feeder (2 h) tests conducted. Results show that low rather than high dEB levels optimize growth performance of piglets. When they have the opportunity to choose, piglets are unable to select the diet that optimizes their performance, either in short- or in long-term preference tests, showing also a greater short-term consumption of high instead of low dEB levels. PMID- 26115272 TI - The effects of dietary verbascoside on blood and liver oxidative stress status induced by a high n-6 polyunsaturated fatty acids diet in piglets. AB - Twenty-four weaned female Hypor piglets (10.9 +/- 0.1 kg mean BW) were used to evaluate the antioxidant effect of a natural extract, titrated in verbascoside, on blood and liver oxidative status in relation to a high intake of n-6 PUFA, inducing oxidative stress. Piglets were assigned to 1 of 3 experimental groups; the first group was fed a diet with 9% sunflower oil (T1) and the second received the sunflower oil diet supplemented with 5 mg of verbascoside/kg feed from Verbenaceae extract (Lippia spp.; T2). The third group was fed a control diet (CTR), in which an isoenergetic replacement of oil by starch was done. Blood samples were collected at the beginning and the end of the trial (30 d). At the end of the trial, the animals were slaughtered and the liver specimens were collected. Oxidative stress markers, including total antiradical activity, superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) activities, were determined in blood samples. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) plasma levels were also evaluated. Immunohistochemistry and western blot analyses were performed in liver to evaluate heat shock protein (Hsp) 70, Hsp90, and Kupffer and Ito cell activation. Liver activities of SOD, GPX, and CAT were also determined. Total antiradical activity in blood and red blood cells were affected (P < 0.01) by dietary treatments. The n-6 PUFA supplementation at a high dosage for 30 d induced oxidative stress, decreasing total antiradical activity in blood and red blood cells (CTR vs. T1 + T2; P < 0.01) and plasma CAT activity (CTR vs. T1 + T2; P = 0.088) and increasing ALT value (CTR vs. T1 + T2; P < 0.01). Also, in liver, the CAT and GPX activities tended to be lower in pigs fed n-6 PUFA diets than pigs fed a control diet (CTR vs. T1 + T2; = 0.090 and = 0.085, respectively). The liver samples presented a normal architecture and no Ito and Kupffer cell activations were observed. In liver, the SOD activity tended to be lower in the T1 group (P = 0.064) than in the CTR and T2 groups. Moreover, the level of Hsp70 was higher (P < 0.01) in the T1 group than the CTR and T2 groups. These data suggest that the dose of dietary verbascoside partially restores the antioxidant status of the liver without affecting the systemic responses to oxidative stress induced by a high-fat diet. PMID- 26115273 TI - Effect of type of fiber, site of fermentation, and method of analysis on digestibility of soluble and insoluble fiber in rabbits. AB - The effect of type of fiber, site of fermentation, method for quantifying insoluble and soluble dietary fiber, and their correction for intestinal mucin on fiber digestibility were examined in rabbits. Three diets differing in soluble fiber were formulated (8.5% soluble fiber, on DM basis, in the low soluble fiber [LSF] diet; 10.2% in the medium soluble fiber [MSF] diet; and 14.5% in the high soluble fiber [HSF] diet). They were obtained by replacing half of the dehydrated alfalfa in the MSF diet with a mixture of beet and apple pulp (HSF diet) or with a mix of oat hulls and soybean protein (LSF diet). Thirty rabbits with ileal T cannulas were used to determine ileal and fecal digestibility. Cecal digestibility was determined by difference between fecal and ileal digestibility. Insoluble fiber was measured as NDF, insoluble dietary fiber (IDF), and in vitro insoluble fiber, whereas soluble fiber was calculated as the difference between total dietary fiber (TDF) and NDF (TDF-NDF), IDF (TDF-IDF), and in vitro insoluble fiber (TDF-in vitro insoluble fiber). The intestinal mucin content was used to correct the TDF and soluble fiber digestibility. Ileal and fecal concentration of mucin increased from the LSF to the HSF diet group (P < 0.01). Once corrected for intestinal mucin, ileal and fecal digestibility of TDF and soluble fiber increased whereas cecal digestibility decreased (P < 0.01). Ileal digestibility of TDF increased from the LSF to the HSF diet group (12.0 vs. 28.1%; P < 0.01), with no difference in the cecum (26.4%), resulting in a higher fecal digestibility from the LSF to the HSF diet group (P < 0.01). Ileal digestibility of insoluble fiber increased from the LSF to the HSF diet group (11.3 vs. 21.0%; P < 0.01), with no difference in the cecum (13.9%) and no effect of fiber method, resulting in a higher fecal digestibility for rabbits fed the HSF diet compared with the MSF and LSF diet groups (P < 0.01). Fecal digestibility of NDF was higher compared with IDF or in vitro insoluble fiber (P < 0.01). Ileal soluble fiber digestibility was higher for the HSF than for the LSF diet group (43.6 vs. 14.5%;P < 0.01) and fiber method did not affect it. Cecal soluble fiber digestibility decreased from the LSF to the HSF diet group (72.1 vs. 49.2%; P < 0.05). The lowest cecal and fecal soluble fiber digestibility was measured using TDF-NDF (P < 0.01). In conclusion, a correction for intestinal mucin is necessary for ileal TDF and soluble fiber digestibility whereas the selection of the fiber method has a minor relevance. The inclusion of sugar beet and apple pulp increased the amount of TDF fermented in the small intestine. PMID- 26115274 TI - Effects of ractopamine and arginine dietary supplementation for sows on growth performance and carcass quality of their progenies. AB - The objective of this study was to evaluate the effects of ractopamine (Rac) and Arg fed to pregnant sows from d 25 to 53 of gestation on fetal muscle development as well as the performance and carcass characteristics of the progeny. One hundred sows were divided into 4 treatments including a control diet, the control plus 1% Arg, the control plus 20 mg/kg Rac, and the control diet supplemented with both additives at the same levels as those used separately. During the farrowing process the data evaluated were the weight of placenta to calculate the placental efficiency and the number of piglets born alive, stillborn, and mummified. To evaluate the fiber number and area, 12 male piglets from each treatment were euthanized to harvest semitendinosus muscle. During the lactation, the preweaning mortality, weaned weights, and number of piglets weaned per litter were evaluated. After weaning, the pig performance was evaluated until the slaughter following the sow treatment. At end of finishing phase, 1 male pig of each treatment replicate was selected to evaluation the carcass and pork quality. All variables measured were analyzed using the MIXED procedure of SAS and least squares means were compared using the Tukey test with P < 0.05. The control diet + supplementation of 1.0% of L-Arg + 20 mg/kg of ractopamine HCl from d 25 to 53 of gestation (Arg+Rac) treatment had a greater number of stillborn piglets (P = 0.014) than the control group. Piglet birth weights from sows fed Rac were 11% greater (P = 0.031) than those of piglets of the control treatment. The semitendinosus muscle fiber diameters of piglets at birth from sows that received Arg, Rac, and Arg+Rac were greater (P < 0.0001) than those of control piglets, and as consequence, the fiber number per square millimeter decreased (P < 0.0001). The final nursery BW of progeny from sows fed Arg and Rac individually were greater (P = 0.010) than those of progeny of the control group. At 110 d of age, in the beginning of the finisher 1 phase, pigs from Arg-fed sows were 1.9 kg heavier (P = 0.010) than pigs from the Arg+Rac-fed sows. The HCW were 2.97 and 1.64 kg heavier (P < 0.0001) for progeny of the Arg and Rac sows, respectively, compared with those of progeny of the control. In conclusion, the trial showed that the use of Rac for gestating sows increased the piglets' weight at birth. The size of muscular fiber was increased in the semitendinosus muscle of piglets originating from sows receiving Rac or Arg. However, the combination of both compounds did not have an additive effect in comparison with the control treatment but increased the stillbirth number. PMID- 26115275 TI - Xylanase increased the ileal digestibility of nonstarch polysaccharides and concentration of low molecular weight nondigestible carbohydrates in pigs fed high levels of wheat distillers dried grains with solubles. AB - The objective was to study the effect of a commercially available xylanase (CAX), an experimental xylanase (EX), and EX in combination with protease (EXP) on the degradation of nondigestible carbohydrates (NDC) and apparent ileal digestibility (AID) of nutrients in wheat distillers dried grains with solubles (wDDGS). The control and 3 enzyme diets contained 96% wDDGS supplemented with vitamins, minerals, L-lysine, and chromic oxide as a digestibility marker in addition to enzyme premix. Eight ileal cannulated pigs were fed 4 experimental diets containing 96% wDDGS-a control diet or 1 of 3 diets with CAX, EX, or EXP-in a double 4 * 4 Latin square design. The experimental period lasted 7 d; adaptation lasted 4 d, and the ileal digesta were collected for 8 h on d 5 and 7, when spot samples of feces were also collected. Digesta samples were analyzed for NDC, total and soluble nonstarch polysaccharides (NSP), low molecular weight (LMW) NDC, OM, CP, fat, starch, and marker. Compared with the control diet, addition of CAX, EX, and EXP increased the AID of arabinoxylan by 32 (P < 0.001), 28 (P = 0.001), and 24% (P = 0.004), respectively. In addition, EXP increased the AID of noncellulosic polysaccharide glucose by 21% compared with the control (P = 0.005). Compared with the control, addition of EX, EXP, and CAX decreased the concentration of soluble arabinoxylan in ileal digesta by 40 (P < 0.0001), 40 (P < 0.0001), and 21% (P = 0.022), respectively. Furthermore, addition of CAX, EXP, and EX increased the concentration of LMW arabinoxylan in ileal digesta by 40 (P = 0.0001), 36 (P = 0.0006), and 24% (P = 0.023), respectively, compared with the control. Addition of EX and EXP decreased the concentration of soluble NSP of ileal digesta by 25 (P = 0.001) and 26% (P < 0.001), respectively, compared with the control diet. Addition of CAX (P < 0.0001) and EXP (P = 0.013) increased the arabinose-to-xylose ratio in the insoluble arabinoxylan fraction in ileal digesta compared with the control diet, and CAX increased the uronic acid-to-xylose ratio of the ileal insoluble NSP fraction (P < 0.0001) compared with the control diet. Enzyme addition did not affect AID of OM, CP, starch, and fat (P > 0.3). In conclusion, addition of xylanases to wDDGS diets increased the ileal digestibility of NSP and generated LMW NDC components in the small intestine of pigs but did not affect ileal digestibility of nutrients in the current study. PMID- 26115276 TI - Effect of in vitro and in vivo 25-hydroxyvitamin D treatment on macrophages, T cells, and layer chickens during a coccidia challenge. AB - This article describes the in vitro and in vivo effects of a 25 hydroxycholecalciferol (25[OH]D) treatment in layer hens during a mixed coccidia challenge. HD11 cells (chicken macrophage cell line) were treated in vitro with a coccidia antigen or in a medium supplemented with either 1,25 dihydroxycholecalciferol (1,25[OH]2D) or 25(OH)D. HD11 cells treated in vitro with 200 nM of 1,25(OH)2D had increased nitrite production (P < 0.01) compared with HD11 cells treated with 0 or 200 nM of 25(OH)D. Treating HD11 cells with 25(OH)D decreased IL-10 mRNA by 1.7-fold, but 1,25(OH)2D treatment increased the amount of IL-10 mRNA by 2.7-fold (P < 0.01) compared with the group treated with 0 nM of 25(OH)D. Post-coccidial antigen stimulation, 25(OH)D or 1,25(OH)2D treatment decreased (P < 0.01) 1alpha-hydroxylase mRNA amounts in HD11 cells. Stimulating primary T cells in vitro with Concanavalin A (Con-A) decreased (P = 0.020) the 1alpha-hydroxylase mRNA amounts by 3-fold. ConA-B1-VICK cells (chicken T cell line) stimulated with 100 nM 1,25(OH)2D or with supernatants from HD11 cells treated with 25(OH)D plus lipopolysaccharide (LPS) had 1.3-fold less (P < 0.01) interferon (IFN)-gamma mRNA compared with the group treated with 25(OH)D. Layer birds were fed a basal diet supplemented with 25(OH)D at 6.25, 25, 50, or 100 MUg/kg, and at 21 d of age orally challenged with 1 * 10(5) live coccidia oocysts. Compared with birds fed similar levels of 25(OH)D and unchallenged with the coccidia oocyst, birds challenged with the coccidia oocyst had 15% reduced BW gain in the groups supplemented with either 6.25, 25, or 50 MUg/kg of 25(OH)D, but only a 4% reduced BW gain in birds fed 100 MUg/kg of 25(OH)D (P < 0.01). Birds fed 100 MUg/kg 25(OH)D had decreased (P = 0.012) CD8+ cell percentages in cecal tonsils in both coccidial oocyst challenged and unchallenged birds, compared with birds fed 6.25 MUg/kg 25(OH) and unchallenged with coccidial oocysts. At 15 d post-coccidia challenge, birds fed 100 MUg/kg 25(OH)D and challenged with coccidial oocysts had 17% more CD4+CD25+ cells (P = 0.018) in the cecal tonsil compared with the birds fed 100 MUg/kg 25(OH)D and unchallenged with coccidial oocysts. At d 6 post-coccidia challenge, birds fed 100 MUg/kg 25(OH)D had a 3.5-fold increase (P < 0.01) in IL-10 mRNA amounts in the cecal tonsils compared with birds fed 6.25 MUg/kg 25(OH)D. In conclusion, supplementing birds with 100 MUg/kg 25(OH)D could be a nutritional strategy to reduce the production losses post-coccidia challenge. PMID- 26115277 TI - The effects of feeding sorghum dried distillers grains with solubles on finishing pig growth performance, carcass characteristics, and fat quality. AB - The objective of this study was to determine the effects of feeding sorghum dried distillers grains with solubles (DDGS) in grain sorghum- or corn-based diets on pig growth performance, carcass characteristics, and carcass fat quality. A total of 288 finishing pigs (BW 58.8 +/- 4.43 kg; Line TR 4 * 1050, PIC, Hendersonville, TN) were used in a 73-d study. Pigs were allotted to 1 of 6 dietary treatments with 6 pens of 8 pigs per treatment. Treatments included grain sorghum-based diets with 0%, 15%, 30%, or 45% sorghum DDGS (29.0% CP, 7.2% ether extract); a grain sorghum-based diet with 30% corn DDGS (25.7% CP, 8.7% ether extract); and a corn-based diet with 30% corn DDGS. The diets were formulated to 0.95%, 0.83%, and 0.71% standardized ileal digestible Lys in phases 1, 2, and 3, respectively, and were not balanced for energy. On d 73, a subsample of 72 pigs (1 barrow and 1 gilt/pen) was harvested at Kansas State University's Meats Laboratory. Carcass traits were calculated, as well as 10th-rib LM color, marbling and firmness, and fat color score. Fat samples from the 10th rib were collected and analyzed for fatty acid profile, which was used to calculate iodine value (IV). The remaining pigs were transported to a commercial packing plant (Triumph Foods, St. Joseph, MO) for carcass measurement and jowl IV determinations. Overall, increasing the dietary sorghum DDGS reduced (linear, P < 0.01) ADG and increased (linear, P < 0.01) back fat IV. Pigs fed increasing sorghum DDGS had decreased 10th-rib fat a* (less red) and b* (less yellow; P < 0.01 and 0.06, respectively). No differences were observed in growth performance or back fat IV among pigs fed corn- or grain sorghum-based diets with 30% corn DDGS. Pigs fed the grain sorghum-based diet with 30% corn DDGS had fat color that was more yellow (b*; P < 0.03) than that of pigs fed the grain sorghum-based diet with 30% sorghum DDGS. Pigs fed the grain sorghum-based diet with 30% sorghum DDGS also had decreased back fat IV (P < 0.01) and fat that was whiter (L*; P < 0.02) than that of those fed the grain sorghum-based diet with corn DDGS. Pigs fed grain sorghum with 30% sorghum DDGS had lower (P < 0.01) back fat IV than pigs fed corn with 30% corn DDGS. Feeding a grain sorghum-based diet with increasing sorghum DDGS reduces ADG when diets are not balanced for energy but, when fed at 30% of the diet, produces firmer pork fat than feeding a corn-based diet with 30% corn DDGS, which may be preferred for pork export markets. PMID- 26115278 TI - Amino acid, phosphorus, and energy digestibility of Aspergillus niger fermented rapeseed meal fed to growing pigs. AB - Fermented rapeseed meal (FRSM) contains greater levels of protein and less glucosinolates, NDF, and phytic acid than rapeseed meal (RSM) and might be an attractive feedstuff for swine, but its nutritional value has been poorly characterized. The aim of this study was to evaluate the nutritional value of RSM fermented by for growing pigs. In Exp. 1, 6 barrows (21.20 +/- 1.47 kg initial BW) fitted with a T-cannula in the distal ileum were allotted to a repeated 3 * 3 Latin square with 3 diets and 3 periods per square to determine the apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of CP and AA. A N-free diet and 2 diets containing RSM or FRSM as the only source of AA were formulated. Results indicated that there was no difference in AID and SID of CP and most AA between FRSM and RSM. However, the AID of 2 indispensable AA (Lys and Met) and 3 dispensable AA (Asp, Gly, and Tyr) were greater (P < 0.05) for FRSM than for RSM. The SID of only 2 dispensable AA (Gly and Tyr) were greater (P < 0.05) for FRSM than for RSM. In Exp. 2, 16 barrows (32.57 +/- 2.67 kg initial BW) were allotted to 2 diets formulated to contain RSM or FRSM as the sole source of P to determine the apparent total tract digestibility (ATTD) of P. The ATTD and standardized total tract digestibility (STTD) of P in FRSM were 72.10 and 77.31%, respectively. These values were greater (P < 0.01) than in RSM (34.79 and 41.34%, respectively). In Exp. 3, 24 growing barrows (32.23 +/- 1.33 kg initial BW) were fed 3 diets with 8 replicate pigs per diet to measure concentration of DE and ME of FRSM. A corn diet consisting of 98.40% corn was formulated and 2 additional diets were formulated by mixing corn with 35% RSM or FRSM. The DE and ME in FRSM (2,887 and 2,650 kcal/kg of DM, respectively) were greater (P < 0.05) than those in RSM (2,609 and 2,328 kcal/kg of DM, respectively). In summary, solid-state fermentation of RSM by has a greater nutritional value than RSM and is a promising alternative high-quality protein source. PMID- 26115279 TI - Vitamin E and omega-3 fatty acids independently attenuate plasma concentrations of proinflammatory cytokines and prostaglandin E3 in Escherichia coli lipopolysaccharide-challenged growing-finishing pigs. AB - This study tested the hypothesis that vitamin E (Vit E) and omega-3 fatty acids will additively attenuate the production of proinflammatory cytokines and PGE2 in immune system-stimulated growing-finishing pigs. A total of 80 mixed sex pigs weighing 50.7 +/- 0.76 kg (mean +/- SE) were blocked and stratified based on sex and BW to a 2 * 2 factorial design with the respective factors being 1) without and with 300 IU Vit E and 2) without and with 25% replacement of tallow to linseed oil as a source of n-3 fatty acids. Each treatment consisted of 4 replicate pens with 5 pigs (3 barrows and 2 gilts) per pen. All pigs were challenged with an intramuscular injection of Escherichia coli lipopolysaccharide (LPS; O111:B4) twice weekly over the 6-wk experiment. After LPS challenge, pigs fed a diet supplemented with n-3 fatty acids had fewer (P < 0.05) white blood cells and tended to show both a reduced (P < 0.10) proportion of lymphocytes and IgG concentration compared with pigs fed a diet without any supplements. Supplementation of n-3 fatty acids reduced (P < 0.01 and P < 0.05) serum concentrations of cortisol and tumor necrosis factor alpha (TNF-alpha), respectively. The serum concentration of PGE2 was decreased (P < 0.05) with supplementation of both Vit E and n-3 fatty acids; however, the extent of the reduction was greater (P < 0.001) in pigs fed an n-3 fatty acid-supplemented diet. However, there were no additive effects of the combined supplementation of Vit E and n-3 fatty acids on serum concentrations of proinflammatory cytokines and PGE2. The results suggest that n-3 fatty acids independently attenuate production of TNF-alpha and PGE2 in immune system-stimulated growing-finishing pigs. PMID- 26115280 TI - Impact of dietary lipids on sow milk composition and balance of essential fatty acids during lactation in prolific sows. AB - Two studies were designed to determine the effects of supplementing diets with lipid sources of EFA (linoleic and alpha-linolenic acid) on sow milk composition to estimate the balance of EFA for sows nursing large litters. In Exp. 1, 30 sows, equally balanced by parity (1 and 3 to 5) and nursing 12 pigs, were fed diets supplemented with 6% animal-vegetable blend (A-V), 6% choice white grease (CWG), or a control diet without added lipid. Diets were corn-soybean meal based with 8% corn distiller dried grains with solubles and 6% wheat middlings and contained 3.25 g standardized ileal digestible Lys/Mcal ME. Sows fed lipid supplemented diets secreted greater amounts of fat (P = 0.082; 499 and 559 g/d for control and lipid-added diets, respectively) than sows fed the control diet. The balance of EFA was computed as apparent ileal digestible intake of EFA minus the outflow of EFA in milk. For sows fed the control diet, the amount of linoleic acid secreted in milk was greater than the amount consumed, throughout lactation. This resulted in a pronounced negative balance of linoleic acid (-22.4, -38.0, and -14.1 g/d for d 3, 10, and 17 of lactation, respectively). In Exp. 2, 50 sows, equally balanced by parity and nursing 12 pigs, were randomly assigned to a 2 * 2 factorial arrangement of diets plus a control diet without added lipids. Factors included linoleic acid (2.1% and 3.3%) and alpha-linolenic acid (0.15% and 0.45%). The different concentrations of EFA were obtained by adding 4% of different mixtures of canola, corn, and flaxseed oils to diets. The n-6 to n-3 fatty acid ratios in the diets ranged from 5 to 22. Increasing supplemental EFA increased (P < 0.001) milk concentrations of linoleic (16.7% and 20.8%, for 2.1% and 3.3% linoleic acid, respectively) and alpha-linolenic acid (P < 0.001; 1.1 and 1.9% for 0.15 and 0.45% alpha-linolenic acid, respectively). Increasing supplemental EFA increased the estimated balance of alpha-linolenic acid (P < 0.001; -0.2 and 5.3 g/d for 0.15% and 0.45% alpha-linolenic acid, respectively), but not linoleic acid (P = 0.14; -3.4 and 10.0 g/d for 2.1% and 3.3% linoleic acid, respectively). In conclusion, lipid supplementation to sow lactation diets improved milk fat secretion. The fatty acid composition of milk fat reflected the dietary supplementation of EFA. The net effect of supplemental EFA was to create a positive balance during lactation, which may prove to be beneficial for the development of nursing piglets and the subsequent reproduction of sows. PMID- 26115281 TI - Effect of dietary copper amount and source on copper metabolism and oxidative stress of weanling pigs in short-term feeding. AB - Forty-eight weanling barrows were used to determine the effects of amount and source of dietary Cu on Cu metabolism, oxidative stress in the duodenum, and VFA ratios in the cecum of weanling pigs in short-term feeding. At 21 d of age, newly weaned pigs were stratified by BW (7.03 +/- 1.20 kg) and equally assigned to 1 of the following dietary treatments: 1) control (5 mg supplemental Cu/kg diet from CuSO4), 2) 225 mg supplemental Cu/kg diet from CuSO4, or 3) 225 mg supplemental Cu/kg diet from tribasic Cu chloride (TBCC). Pigs were housed 2 pigs per pen and were fed a complex diet until harvest on d 11 and 12. During harvest, bile and liver were obtained for mineral analysis, and liver samples were obtained for analysis of mRNA expression of Cu regulatory proteins. Digesta of duodenum, proximal jejunum, and ileum were collected for soluble Cu analysis. Mucosal scrapings of duodenum, proximal jejunum, and ileum were obtained for analysis of mucosal Cu concentration and mRNA expression of Cu regulatory proteins. Duodenal mucosal scrapings were also collected for analysis of malondialdehyde (MDA). Pigs fed high Cu had markedly greater (P < 0.0001) Cu concentrations in the duodenal, proximal jejunal, and ileal mucosa than controls. Copper in the duodenal mucosa was greater (P = 0.003) in CuSO4 than TBCC pigs. Duodenal MDA concentrations were greater (P = 0.003) in CuSO4 vs. control pigs and tended (P = 0.06) to be greater than in TBCC pigs. Duodenal antioxidant 1 (Atox1) mRNA was downregulated (P < 0.01) in pigs fed high Cu compared to controls and was not affected by Cu source. Compared with control pigs, those fed CuSO4 and TBCC had greater (P < 0.001) liver and bile Cu concentrations. Liver Cu was also greater (P = 0.0007) in TBCC than CuSO4-fed pigs. Hepatic Cu transporting beta-polypeptide ATPase (Atp7b) was upregulated (P = 0.02) in the Cu-supplemented pigs compared with controls and did not differ among Cu sources. The acetate:propionate ratio in cecal contents was much greater in pigs supplemented with 225 mg Cu/kg diet than in controls. When fed at 225 mg Cu/kg diet, TBCC may cause less oxidative stress in the duodenum than CuSO4. Feeding weanling pigs increased Cu resulted in modulation of duodenal and liver at the transcription level. PMID- 26115282 TI - Effect of the particle size of maize, rice, and sorghum in extruded diets for dogs on starch gelatinization, digestibility, and the fecal concentration of fermentation products. AB - The influence of rice, maize, and sorghum raw material particle size in extruded dry dog food on the digestibility of nutrients and energy and the fecal concentration of fermentation products was investigated. Three diets with similar nutrient compositions were formulated, each with 1 starch source. Before incorporation into diets, the cereals were ground into 3 different particle sizes (approximately 300, 450, and 600 um); therefore, a total of 9 diets were in a 3 * 3 factorial arrangement (3 cereals and 3 particle sizes). Fifty-four beagle dogs (12.0 +/- 0.1 kg BW) were randomly assigned to the diets, with 6 dogs per diet. The digestibility was measured with the chromium oxide method. The data were evaluated with ANOVA considering the carbohydrate source, grinding effect, and interactions. The means were compared with the Tukey test and polynomial contrasts (P < 0.05). With the same grinding procedure, rice was reduced to smaller particles than other cereals. The cereal mean geometric diameter (MGD) was directly related to starch gelatinization (SG) during extrusion. For rice diets, the MGD and SG did not change nutrient digestibility (P > 0.05); only GE digestibility was reduced at the largest MGD (P < 0.01). For maize and sorghum diets, the total tract apparent nutrient digestibility was reduced for foods with greater MGD and less SG (P < 0.01). A linear reduction in nutrient digestibility according to cereal particle size was observed for sorghum (r2 < 0.72; P < 0.01). Higher concentrations of fecal total short-chain fatty acids (SCFA) were observed for sorghum diets (P < 0.05) than for other diets. The rice diets led to the production of feces with less lactate (P < 0.05). The increase in raw material MGD did not influence fecal SCFA for rice diets, but for the dogs fed maize and sorghum foods, an increase in propionate and butyrate concentrations were observed as MGD increased (P < 0.05). In conclusion, for dogs fed different particle sizes of the cereal starches in the extruded diets, the digestibility and fecal characteristics were affected, and this effect was ingredient dependent. PMID- 26115283 TI - Spray-dried chicken plasma improves intestinal digestive function and regulates intestinal selected microflora in weaning piglets. AB - One hundred forty-four 25-d-old weaning piglets with BW of 6.43 +/- 0.39 kg were used in a 28-d trail to evaluate the effects of dietary addition of spray-dried chicken plasma (SDCP) as a replacement for spray-dried porcine plasma (SDPP) on growth performance, nutrient digestibility, diarrhea incidence, small intestinal morphology, digestive enzyme activity, and microflora. Pigs were randomly allotted to 1 of 4 dietary treatments: 1) CON (control; a basal diet), 2) SDPP (containing 5% SDPP), 3) SDPP + SDCP (containing 2.5% SDPP and 2.5% SDCP), and 4) SDCP (containing 5% SDCP). Six pigs from each treatment were randomly selected to collect serum and intestinal samples. Compared with the CON group, both the SDPP and the SDPP + SDCP groups improved final BW of pigs (P < 0.05), but there were no differences among the SDPP, SDPP + SDCP, and SDCP groups. From d 1 to 14 and d 15 to 28, pigs fed the SDPP and SDPP + SDCP diets had a greater (P < 0.05) ADG than pigs fed the CON diet. During the overall period, both ADG and ADFI of pigs in the SDPP and SDPP + SDCP groups were improved (P < 0.05) compared with pigs in the CON group. Furthermore, pigs fed diets containing SDPP or SDCP had a greater (P < 0.05) apparent total tract digestibility (ATTD) of CP, ether extract, Ca, and ash and less (P < 0.05) incidence of diarrhea than pigs fed the CON diet. However, no differences were observed for ATTD and diarrhea incidence between the SDPP and SDCP groups. Compared with the CON group, duodenal villus height and the ratio of villi to crypt were increased (P < 0.05) in the SDPP, SDPP + SDCP, and SDCP groups and jejunal crypt depth was decreased in the SDPP + SDCP and SDCP groups (P < 0.05). Pigs in the SDPP group had greater (P < 0.05) activities of amylase, maltase, and trypsin than pigs in the CON group. However, no significant differences were observed between the SDCP and SDPP groups. Additionally, inclusion of SDCP in diet decreased (P < 0.05) the population of Escherichia coli. In conclusion, these results demonstrated that the addition of SDCP in pigs' diet had an effect similar to SDPP on improving growth performance through the promotion of the small intestinal development, increasing digestive enzymes activities, enhancing ATTD of nutrients, and decreasing diarrhea incidence. PMID- 26115284 TI - Effects of feed grade L-methionine on intestinal redox status, intestinal development, and growth performance of young chickens compared with conventional DL-methionine. AB - This study was conducted to test the effects of supplemental L-Met on redox status, gut development, and growth performance of young broiler chickens compared with DL-Met. A total of 888 (half male and half female) 1-d-old Ross 308 chickens were weighed and randomly allotted to 7 treatments in a randomized complete block design for 21 d, including a basal diet (BD), the BD + 0.095% L Met or DL-Met, the BD + 0.190% L-Met or DL-Met, and the BD + 0.285% L-Met or DL Met (representing 60, 70, 80, and 90% of the Met + Cys requirement). Feed disappearance and BW were recorded every 7 d. Liver and duodenum samples were collected on d 0, 7, and 21 to measure redox status and intestine morphology. On d 7, chicks fed a diet supplemented with either 0.285% L-Met or 0.285% DL-Met had increased (P < 0.05) concentrations of glutathione (GSH) and reduced (P < 0.05) protein carbonyl (PC) and malonedialdehyde contents in duodenum mucosa compared with chicks fed the BD. Chicks fed a diet supplemented with 0.285% L-Met had greater (P < 0.05) villus width compared with chicks fed a diet supplemented with 0.285% DL-Met. Chicks fed a diet supplemented with 0.285% L-Met had lower (P < 0.05) crypt depth and greater (P < 0.05) villus height:crypt depth ratio compared with chicks fed a diet supplemented with 0.285% DL-Met or the BD. On d 21, chicks fed a diet supplemented with 0.285% L-Met had increased (P < 0.01) concentrations of GSH and total antioxidant capacity (TAC) but reduced (P < 0.05) PC content in duodenum mucosa compared with chicks fed a diet supplemented with 0.285% DL-Met and the BD. Chicks fed a diet supplemented with 0.285% L-Met had greater (P < 0.05) villus height compared with chicks fed the BD. During the entire 21-d supplementation of either L-Met or DL-Met, ADG and G:F were enhanced (P < 0.01) compared with chicks fed the BD. Chicks fed diets supplemented with L-Met had greater (P < 0.05) ADG and G:F than chicks fed diets supplemented with DL-Met. The relative bioavailability of L-Met to DL-Met for ADG and G:F was 138.2 and 140.7%, respectively. Overall, supplementation of either L-Met or DL-Met has beneficial effects on villus development in association with increased GSH production and levels of TAC and reduced protein oxidation in duodenum. Supplementation of L-Met served a better function on redox status and development of the gut of chicks compared with DL-Met. Chicks fed diets with L-Met had better growth response than chicks fed diets with DL-Met. PMID- 26115285 TI - Effects of dietary soybean meal concentration on growth and immune response of pigs infected with porcine reproductive and respiratory syndrome virus. AB - An experiment was conducted to determine the effects of dietary soybean meal (SBM) concentration on the growth performance and immune response of pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Four experimental treatments included a 2 * 2 factorial arrangement of 2 dietary SBM concentrations, 17.5% (LSBM) or 29% (HSBM), and 2 levels of PRRSV infection, uninfected sham or PRRSV infected. Sixty-four weanling pigs of split sex (21 d of age, 7.14 +/- 0.54 kg) were individually housed in disease containment chambers. Pigs were provided a common diet for 1 wk postweaning before being equalized for BW and sex and allotted to 4 treatment groups with 16 replicate pigs per group. Pigs were fed experimental diets for 1 wk before receiving either a sham inoculation (sterile PBS) or a 1 * 10 50% tissue culture infective dose of PRRSV at 35 d of age (0 d postinoculation, DPI). Pig BW and feed intake were recorded weekly, and rectal temperatures were measured daily beginning on 0 DPI. Blood was collected on 0, 3, 7, and 14 DPI for determination of serum PRRSV load, differential complete blood cell counts, and haptoglobin and cytokine concentrations. Infection with PRRSV increased (P < 0.01) rectal temperatures of pigs throughout the infection period, with no influence of dietary SBM concentration. Pigs in the PRRSV-infected group had lower (P < 0.01) ADFI and G:F from 0 to 14 DPI compared with uninfected pigs. In the PRRSV-infected group, pigs fed HSBM tended to have improved ADG (P = 0.06) compared with pigs fed LSBM, whereas there was no influence of SBM concentration on growth of pigs in the uninfected group. At 14 DPI, PRRSV-infected pigs fed HSBM had a lower serum PRRSV load (P < 0.05), a higher (P = 0.02) hematocrit value, and a tendency for greater hemoglobin concentration (P = 0.09) compared with pigs fed LSBM. Serum haptoglobin and tumor necrosis factor-alpha concentrations of PRRSV-infected pigs were lower (P < 0.05) in pigs fed HSBM at 3 and 14 DPI, respectively, than in pigs fed LSBM. Overall, increasing the dietary SBM concentration modulated the immune response and tended to improve the growth of nursery pigs during a PRRSV infection. PMID- 26115286 TI - Peanut cake as a substitute for soybean meal in the diet of goats. AB - This study aimed to test the hypothesis that peanut cake can substitute for soybean meal in the feed of ruminants on the basis of the intake, performance, digestion, and serum urea and glucose concentration in crossbred Boer * indigenous goat kids. Forty intact vaccinated and dewormed crossbred Boer * indigenous goat kids (average age = 5 mo, average BW = 15.6 +/- 2.7 kg) were used. The goats were fed Tifton-85 (Cynodon dactylon) hay and concentrate mixes of corn bran, soybean meal, premix mineral, and peanut cake substituted for soybean meal at rates of 0.0%, 33.33%, 66.67%, and 100%. The animals were confined for 62 d, and the digestibility trial was performed from d 27 to 31 of confinement. Samples of orts and feces were quantified and collected from each animal during this period. On the d 32 of confinement, a blood sample was taken from animals to measure urea N and glucose. Data were analyzed with a regression model. Substitution of soybean meal with peanut cake in the diet of the animals resulted in a reduction in intake of DM (P = 0.02), CP (P = 0.03), NDF (P = 0.03), nonfiber carbohydrate (NFC; P = 0.01), and TDN (P = 0.02) and an increase in intake of ether extract (P < 0.001). The total and daily average weight gains decreased (P = 0.02) with substitution, whereas G:F was not influenced (P = 0.11). With the exception of ether extract digestibility, which increased (P < 0.001) with substitution, digestibility of DM (P = 0.13), OM (P = 0.18), CP (P = 0.54), NDF (P = 0.20), and NFC (P = 0.73) was not influenced by diets. The concentration of serum urea N was influenced quadratically by the postprandial time for treatments with 33.33%, 66.67%, and 100.00% substitution. Peanut cake is not a complete, equal substitute for soybean meal in goat feed. However, peanut cake may represent an eventual replacer able to reduce goat producers' dependence on traditional ingredients in the feed of growing goat kids. PMID- 26115287 TI - A comparison of nitrogen utilization and urea metabolism between Tibetan and fine wool sheep. AB - To study metabolic adaptation to harsh foraging conditions, an experiment was conducted to characterize and quantify N utilization efficiency and urea metabolism in Tibetan and fine-wool sheep fed 4 levels of dietary N (11.0, 16.7, 23.1, and 29.2 g N/kg DM) in 2 concurrent 4 * 4 Latin square designs. Urea kinetics were determined using continuous intrajugular infusions of 15N15N-urea. Urinary excretions of total N and urea N increased linearly (P < 0.001) with dietary N and were not different between breeds (P >= 0.37). Fecal N excretion increased with dietary N for Tibetan sheep but not for fine-wool sheep (linear dietary N * breed; P < 0.05). Nitrogen retention (both amount per day and percentage of N intake) increased with increasing dietary N concentration (P < 0.001), and the rates of increase were greater in fine-wool than in Tibetan sheep (linear dietary N * breed and cubic dietary N * breed; P < 0.05). In Tibetan sheep, N retention as a percentage of intake was greatest for diets containing 16.7 g N/kg DM, whereas it was maximal for fine-wool sheep when the diet contained 23.1 g N/kg DM. Urea N entry rate, urea N recycled to the gastrointestinal tract (GIT), and urea N returned to the ornithine cycle all increased with dietary N (P < 0.05), and all were greater in Tibetan than fine wool sheep for the 11.0 g N/kg DM diet but were greater in fine-wool than Tibetan sheep for the diet with 29.2 g N/kg DM (linear dietary N * breed; P < 0.05). Urea N excreted in feces, both amount and fraction of GIT entry rate, was less in Tibetan than fine-wool sheep for the 11.0 and 16.7 g N/kg DM diets but similar for diets with 23.1 or 29.2 g N/kg DM (linear dietary N * breed; P < 0.01). For the lowest-protein diet, the fraction of urea N production recycled to the GIT was greater in the Tibetan than fine-wool sheep (88% vs. 82%), but for the diet with 29.2 g N/kg DM it was greater for fine-wool than Tibetan sheep (46% vs. 39%; linear dietary N * breed; P < 0.05). Plasma urea N increased more rapidly in response to increasing dietary N concentration for fine-wool sheep than for Tibetan sheep (linear dietary N * breed; P < 0.05). Urea tubular load and the amount and percentage of urea reabsorbed by the kidney were greater in Tibetan than fine-wool sheep (P < 0.05). These results suggest that Tibetan sheep have mechanisms that allow them to utilize N more efficiently than the fine-wool sheep when dietary N is inadequate. PMID- 26115288 TI - Effect of concentrate feeder design on performance, eating and animal behavior, welfare, ruminal health, and carcass quality in Holstein bulls fed high concentrate diets. AB - A total of 240 Holstein bulls (121 +/- 2.0 kg initial BW; 99 +/- 1.0 d of age), from 2 consecutive fattening cycles, were randomly allocated in 1 of 6 pens and assigned to 1 of the 3 treatments consisting of different concentrate feeder designs: a control feeder with 4 feeding spaces (CF), a feeder with less concentrate capacity (CFL), and a single-space feeder with lateral protections (SF). Each pen had a straw feeder and a drinker. All animals were fed a high concentrate diet for ad libitum intake. Concentrate consumption was recorded daily using a computerized feeder, straw consumption was recorded weekly, and BW was recorded every 14 d. Animal behavior was registered on d 1, 3, 5, 8, and 14 and every 28 d by scan sampling. Eating behavior at concentrate feeders was filmed on d 12, 125, and 206. On d 7, 120, and 204, samples of rumen contents were collected for measurement of pH and VFA and blood samples were obtained to analyze NEFA, haptoglobin, glucose, and insulin. Animals were slaughtered after 223 d, and HCW and lesions of the rumen wall and liver were recorded. The accumulative concentrate consumption per animal tended (P = 0.09) to be greater with CF than with CFL and SF. Also, CV of concentrate consumption was greater (P < 0.01) for SF than for CF or CFL. However, feeder design did not influence the other performance and carcass data. Also, no differences among treatments in rumen wall evaluation and liver abscesses were observed. At 7 and 204 d of study, SF bulls had greater (P < 0.05) rumen pH compared with CF and CFL bulls. On d 7, the acetate to propionate ratio from SF was greater (P < 0.05) than for CFL or CF. At d 7, NEFA of SF were greater (P < 0.05) compared with CF and CFL. Bulls fed with CF have the greatest (P < 0.01) concentrate disappearance velocity followed by bulls fed with CFL and finally by bulls fed with SF, and this was associated with different feeding behaviors. Bulls on SF spent more time (P < 0.05) eating straw and exhibited fewer (P < 0.05) displacements at concentrate feeder than CF and CFL bulls. The CFL bulls exhibited (P < 0.01) more attempted mounts and tended (P = 0.10) to exhibit more completed mounts than CF bulls. In conclusion, both alternative feeder designs (CFL and SF) are good strategies to reduce total concentrate consumption without impairing performance, rumen health, or animal welfare in Holstein bulls fed high-concentrate diets. However, at the beginning, there was evidence that animals fed using SF had problems with adaptation. PMID- 26115289 TI - Effects of twenty percent alkaline-treated corn stover without or with yucca extract on performance and nutrient mass balance of finishing steers fed modified distillers grains-based diets. AB - Two experiments were conducted with 192 steers each (during the winter [November to May] or summer [June to October]) to evaluate 3 diets with or without Yucca schidigera extract in a 3 * 2 factorial on steer growth performance and N mass balance. One factor was diet (DM basis): 1) 5% untreated corn stover, 51% corn, and 40% modified distillers grains plus solubles (MDGS; CON); 2) 20% calcium oxide-treated corn stover (CaO added at 5% of stover DM), 40% MDGS, and 36% corn (TRT); or 3) 20% untreated corn stover, 40% MDGS, and 36% corn (NONTRT). The other factor was dietary extract at 0 (NOYE) or 1.0 g/d per steer (YE). No interaction between diet and YE was detected (P > 0.51) for growth performance and carcass traits in winter and only for DMI in summer. Final BW, ADG, DMI, or G:F were not different (P >= 0.28) between cattle fed CON and TRT, whereas cattle fed NONTRT had lesser ADG, HCW, and G:F compared to CON and TRT in the winter experiment. During the summer, final BW and ADG tended to be greater (P >= 0.07) for CON compared to TRT. Cattle fed TRT had reduced (P < 0.01) G:F compared to CON. No difference was observed (P >= 0.36) between YE and NOYE in the winter experiment for performance or carcass traits. In the summer, cattle fed YE had greater (P < 0.02) HCW, ADG, and DMI compared to NOYE. In the summer experiment, cattle fed YE had greater (P < 0.01) N intake, N excretion, and amount of N lost (kg/steer) compared to NOYE, but no difference (P = 0.33) was observed for percentage of N volatilized (% of excretion). Diet had no effect (P > 0.18) on amount (kg/steer) or percentage of N volatized in the winter or summer. All diets had similar amounts (P > 0.13) of DM and OM removed from the pen surface in both summer and winter. Feeding CaO-treated corn stover as a partial grain replacement had no impact on performance in winter but decreased G:F in summer. Although high fiber diets increased the amount of OM on pen surfaces, they did not impact N volatilized. Feeding a Y. schidigera extract did not affect N balance or manure characteristics. PMID- 26115290 TI - Effect of vitamin E supplementation or alfalfa grazing on fatty acid composition and expression of genes related to lipid metabolism in lambs. AB - The aim of this study was to investigate the effects of vitamin E (VE) supplementation and alfalfa grazing during fattening on fatty acid composition and mRNA expression of genes related to lipid metabolism in the LM of Rasa Aragonesa light lambs. After weaning, 48 lambs were kept indoors and fed a commercial concentrate and a VE supplemented concentrate (480 mg DL-alpha tocopheryl acetate/kg DM) for 0 (control [CON]), 10 (VE10d), 20 (VE20d), and 30 d (VE30d) before slaughtering at 22 to 24 kg. Simultaneously, 8 unweaned lambs grazed in alfalfa (154 mg alpha-tocopherol/kg DM) paddocks with their dams and supplemented with the commercial concentrate (ALF). Immediately after slaughter, LM was sampled to determine gene expression. After 24 h of cooling at 4 degrees C, LM was extracted to determine intramuscular fat (IMF) content and fatty acid composition. The IMF content did not differ with the dietary treatment ( = 0.212). Unweaned grazing alfalfa lambs had greater concentration of rumenic acid (C18:2 c9,t11; P < 0.001) and lower oleic acid (C18:1 c9; = 0.001) content and PUFA n-6:n-3 ratio (P < 0.001) but similar expression of genes implicated in lipid metabolism compared to the concentrate-fed lambs. Vitamin E supplementation did not modify muscle fatty acid composition; however, it increased the expression of FADS2 and ELOVL6, which are involved in desaturation of long-chain fatty acid and the elongation of SFA and MUFA. The results showed that a short period of VE supplementation, especially 10 (VE10d) and 20 d (VE20d), modified gene expression. Overall, the results showed that VE may be acting as a regulatory factor for transcriptional control of genes related to lipid metabolism in the muscle of Rasa Aragonesa light lambs (22-24 kg live weight and younger than 90 d old). PMID- 26115292 TI - Effect of precision feeding high- and low-quality forage with different rumen protein degradability levels on nutrient utilization by dairy heifers. AB - One approach to improving efficiency of protein and nitrogen use for optimal productivity in dairy heifers is to provide adequate levels of protein with differing rumen degradabilities. The objective of this experiment was to determine effects of manipulating RDP in diets of dairy heifers precision fed low and high-quality forage. Eight rumen-cannulated Holstein heifers (448 +/- 19 kg BW) were randomly used and assigned to an 85% forage diet with 2 forage qualities, low quality (LQ, 48% NDF) and high quality (HQ, 38% NDF), and to 4 RDP levels (62%, 68%, 74%, and 81% of CP as RDP) within forage quality administered according to a split-plot two 4 * 4 Latin square design (20-d periods). Similar N intake was provided (1.70 g N/kg BW0.75), and alterations of RDP levels were made by exchanging canola meal with heat-treated soy protein with slow-release urea. Heifers offered the HQ diet had greater apparent total tract DM and OM digestibilities than those fed the LQ diet. Apparent N digestibility tended to be higher for the HQ diet but was not affected by the levels of RDP in diets. No difference was observed for rumen VFA concentration between forage treatments, but acetate to propionate ratio was higher for LQ-fed heifers. No difference in rumen carbohydrate fermentation was detected with increasing levels of RDP. Feeding HQ forage improved DM, OM, and N apparent digestibility. Increasing RDP in LQ and HQ had no effects on apparent digestibility of any measured parameter or N dynamics in dairy heifers. PMID- 26115291 TI - Effect of rate of weight gain of steers during the stocker phase. IV. Rumen fermentation characteristics and expression of genes involved in substrate utilization for fatty acid synthesis in adipose tissues of growing-finishing beef cattle. AB - The objective of this study was to determine the impact of stocker production systems differing in growth rate on rumen fermentation characteristics and utilization of substrates for fatty acid synthesis in intramuscular (IM), subcutaneous (SC), and perirenal (PR) adipose tissues. Angus steers were assigned to 4 stocker cattle production systems in 2 consecutive years: 1) 1.0 kg/d of 40% CP cottonseed meal-based supplement while grazing dormant native range (CON), 2) ground corn/soybean meal-based supplement while grazing dormant native range fed at 1% of BW (CORN), 3) grazing wheat pasture at a high stocking rate to achieve a low rate of BW gain (LGWP), and 4) grazing wheat pasture at a low stocking rate for a high rate of BW gain (HGWP). Eight ruminally cannulated steers were used to determine rumen fermentation characteristics. Steers were harvested during the stocker phase at similar age (different carcass weight) in Exp. 1 (3 steers/treatment) or at similar carcass weight in Exp. 2 (4 steers/treatment). Adipose tissues were analyzed for mRNA expression of genes involved in glucose (solute carrier family 2, member 4 [GLUT4], glucose-6-phosphate dehydrogenase [G6PDH], phosphofructokinase, muscle [PFKM], and pyruvate kinase 2, muscle [PK2]), lactate (lactate dehydrogenase B [LDHB]), and acetate (acetyl-CoA synthetase, cytosol [ACSS2]) utilization for fatty acid synthesis. The acetate:propionate ratio was least (P < 0.05) for HGWP steers, intermediate for CORN and LGWP steers, and greatest for CON steers. At similar age, LGWP and HGWP steers tended (F-test; P < 0.15) to have greater (P < 0.10) G6PDH and ACSS2 mRNA expression than CON and CORN steers in SC and PR but not IM adipose tissue. Expression of PFKM and PK2 mRNA tended (F-test; P < 0.15) to be greater (P < 0.10) in HGWP than CON and LGWP steers in IM but not SC or PR adipose tissue. At similar HCW, expression of GLUT4 and G6PDH mRNA were greater (P < 0.10) in SC adipose tissue of LGWP and HGWP steers compared with CON and CORN steers but not in IM and PR adipose tissue. Expression of LDHB mRNA was lesser (P < 0.10) in SC adipose tissue but greater (P < 0.10) in PR adipose tissue of LGWP and HGWP steers compared with CON and CORN steers. These results indicate a shift toward glucose utilization in SC adipose tissue but a shift towards lactate utilization in PR adipose tissue. These results suggest that diet and changes in VFA profile can influence substrates utilized for fatty acid synthesis, but diet has a greater effect in SC than IM adipose tissue. PMID- 26115293 TI - Supplementation of monensin and Optimase to beef cows consuming low-quality forage during late gestation and early lactation. AB - Two experiments were designed to investigate the effects of feeding monensin and/or slow release urea with a fibrolytic feed enzyme (Optimase; Alltech, Inc., Nicholasville, KY) on performance, milk production, calf growth performance, and blood metabolites in beef cows. Spring-calving cows and heifers were used in a completely randomized design in Exp. 1 (N = 84; 534 +/- 68 kg initial BW) and Exp. 2 (N = 107; 508 +/- 72 kg initial BW). Exp. 1 supplements were formulated to meet cow protein requirements and fed daily and included 1) cottonseed meal with no monensin (control); or 2) monensin added to control to supply 200 mg per head per d (MON). In Exp. 2, experimental supplements included 1) cottonseed meal/wheat middlings (CS) fed at a rate to provide adequate DIP and CP according to , 2) the CS plus soybean hulls and 61 g per cow per d Optimase (OPT), 3) the CS plus monensin to supply 200 mg per cow per d (MON2), and 4) OPT plus MON2 (Combo). Cows were fed in last trimester through early lactation in Exp. 1 and during 2nd trimester in Exp. 2. Data were analyzed using the Mixed procedure in SAS with animal as the experimental unit. In Exp. 1, treatment did not affect cow BW or BCS change (P > 0.19). Calf birth BW was not affected by dam treatment (P = 0.24); however, calves from dams consuming MON weighed more (P < 0.04) at d 45 and at trial end. Calves also had greater (P = 0.04) ADG from birth to trial end. Milk production did not significantly differ among treatments (P > 0.41). In Exp. 2, mean cow BW and BCS were similar (P > 0.35) among treatments on d 90. However, from d 0 to 54, cows assigned to the OPT supplement gained less BCS (P = 0.02) compared with cows assigned to the CS supplement. Cumulative BCS gain was greater (P < 0.01) for CS-fed cows than for cows fed the OPT and MON2 supplements, although it was not significantly different for cows fed the Combo supplement. These studies indicate that the influence of monensin on cow BW and BCS change is inconsistent. The potential for monensin supplementation to positively impact calf performance during early lactation seems to be clearer. Replacing a portion of oilseed N in the supplement with Optimase may marginally reduce cow performance. Further research is needed to determine both the effects of monensin and the implications of combining monensin with Optimase on forage intake and cow performance at various stages of production. PMID- 26115294 TI - The intake of thermally processed soybean reduces the feedlot period of lambs independently of roughage to concentrate ratio. AB - The objective of this study was to evaluate the nutrient intake and performance of feedlot lambs using 2 roughage to concentrate ratios and 2 types of soybean, whole (WS) or thermally processed (PS). Twenty male noncastrated market lambs weighting 23.26 +/- 2.18 kg were used. The design was completely randomized in a factorial arrangement of 2 * 2. Diets were formulated with 50:50 and 20:80 of roughage to concentrate ratio on DM, and the thermal processing was realized in an autoclave at 120 degrees C during 1 h. The end of the experimental period was determined by animal BCS, that is, the animals were slaughtered with a BCS between 3 and 3.5. The animals fed with 50% of roughage spent more time consuming feed (P < 0.01) and ruminating (P < 0.01). Thermally processed soybean provided more time consuming (P < 0.05) and less leisure time (P < 0.05) compared with WS. Diet with 20% of roughage provided increased ADG (P < 0.01) and better feed conversion (FC; P < 0.01). The utilization of PS resulted in decreased feedlot period (FP; P< 0.01), increased ADG (P < 0.05), decreased DMI (P < 0.01), and consequently better FC (P < 0.01). Diet with PS decreased the intake of ADF (P < 0.01). There was interaction between the roughage to concentrate ratio and soybean, wherein the diet with 50% of roughage and WS provided increased intake of NDF (P < 0.05). The use of thermally processed soybean provided better performance of lambs, and when this feed is associated with higher concentrate proportion, it reduces the intake of fibrous fraction of the diet. PMID- 26115295 TI - Effect of grain type and processing index on growth performance, carcass quality, feeding behavior, and stress response of feedlot steers. AB - One hundred sixty crossbred steers (538 +/- 36 kg BW) were used in an 84-d experiment with a randomized block design to study the effects of wheat or barley grain processed to 2 different indices on growth performance, feeding behavior, carcass characteristics, stress, and temperament of finishing beef cattle. Treatments were a wheat-based diet (88.4% of diet DM; WH) and a barley-based diet (89% of diet DM; BA), processed to an index of either 75% (HI) or 85% (LO) of their original volume weight. Cattle were allocated to 16 feedlot pens (10 animals per pen, 4 pens per treatment), 8 of which were equipped with the GrowSafe system for monitoring feeding behavior. Flight speed, hair, and saliva samples were collected on d 1, 28, 56, and 84 to determine temperament, acute, and chronic stress. All steers were slaughtered at the end of the experiment, and carcass quality was evaluated. Cattle fed WH had a lower (P < 0.05) meal length and frequency of visits per meal and tended (P = 0.10) to have a lower DMI, meal size, and feeding time than those fed BA. The LO processing index increased (P = 0.05) DMI and reduced (P < 0.05) the G:F and the percentage of saleable meat of the carcass compared to HI. There was a trend (P = 0.09) for a grain * processing index interaction, where cattle fed BA-LO had a lower incidence of severe liver abscesses compared with cattle fed other treatments. Cattle fed WH had greater hair cortisol concentrations (P = 0.01) and flight speed (P < 0.01) than those fed BA. There was a trend (P = 0.07) for a grain * processing index interaction, where heifers fed WH-LO had a lower salivary cortisol than those fed other treatments. Results suggest that a LO processing index had a negative effect on feed efficiency and carcass performance and that the WH diet caused a range of effects on feed intake and behavior indicative of steers with greater excitability and chronic stress. PMID- 26115296 TI - Protection of polyunsaturated fatty acids against ruminal biohydrogenation: Pilot experiments for three approaches. AB - Three methods for protection of PUFA against biohydrogenation by ruminal microorganisms were evaluated. In method 1 a blend of ground flaxseed, calcium oxide, and molasses was processed through a dry extruder. In method 2, a blend of ground flaxseed, soybean meal, molasses, and baker's yeast was moistened and prewarmed, allowing enzymes from yeast to produce reducing sugars, and the mixture was subsequently processed through a dry extruder like in method 1. In method 3, ground flaxseed was embedded within a matrix of dolomitic lime hydrate (L-Flaxseed) as a protective barrier against biohydrogenation. Dolomitic lime was mixed with ground flaxseed, water was added, the mixture was blended in a high speed turbulizer, and the resulting material was then dried to form a granular matrix. Methods 1 and 2 were tested in 1 study (study 1), and method 3 was tested in 2 studies (studies 2 and 3). In study 1, 60 crossbred yearling steers (BW = 475 +/- 55 kg) were used in a randomized complete block design experiment. Steers were fed for 12 d with a diet consisting of 48.73% steam-flaked corn, 35% wet corn gluten feed, 12% corn silage, and 4.27% vitamins and minerals (Control). For the other 4 treatments, a portion of wet corn gluten feed was replaced with 5% of unprocessed or extruded mixtures as described for methods 1 and 2. Steers were weighed, and jugular blood samples were taken for analysis of long-chain fatty acids (LCFA) on d 0 and 12 of the study. Both methods failed to improve resistance of PUFA against biohydrogenation (P > 0.1). In study 2, in situ fatty acid disappearance was evaluated for ground flaxseed (Flaxseed) or L-Flaxseed using 6 ruminally fistulated Holstein steers. The proportion of alpha-linolenic acid (ALA) that was resistant to ruminal biohydrogenation was approximately 2 fold greater for L-Flaxseed than for Flaxseed (P < 0.05). In study 3, 45 steers (269 +/- 19.5 kg initial BW) were used in a randomized complete block design. Steers were fed diets containing 0% Flaxseed (No Flaxseed), and in treatments 2 and 3, a portion of flaked corn was replaced with Flaxseed or L-Flaxseed. Animals were weighed and blood samples were taken on d 0, 7, and 14 of the study, and LCFA were analyzed. The use of L-Flaxseed in study 3 increased plasma concentrations of ALA to more than 4 times the level observed in cattle fed unprotected flaxseed, suggesting the dolomitic lime hydrate was effective as a protective barrier against biohydrogenation. PMID- 26115297 TI - Effects of various dietary lipid additives on lamb performance, carcass characteristics, adipose tissue fatty acid composition, and wool characteristics. AB - Tasco (Ascophyllum nodosum; TA) was compared to canola (CO), flax (FO), and safflower oils (SO) for effects on performance, carcass characteristics, and fatty acid profiles of adipose tissue in skirt muscle (SM), subcutaneous and perirenal adipose tissues, and wool production and quality characteristics of Canadian Arcott lambs. Fifty-six lambs were randomly assigned to dietary treatments (n = 14 per treatment). Diets consisted of a pelleted, barley-based finishing diet containing either TA, CO, FO, or SO (2% of dietary DM). Feed deliveries and orts were recorded daily. Lambs were weighed weekly and slaughtered once they reached >= 45 kg BW. Carcass characteristics, rumen pH, and liver weights were determined at slaughter. Wool yield was determined on mid-side patches of 100 cm2 shorn at d 0 and on the day before slaughter (d 105 or 140). Dye-bands were used to determine wool growth, micrometer and staple length. Adipose tissues and SM samples were taken at slaughter and analyzed for FA profiles. No effects were observed on intake, growth, or carcass characteristics. A greater (P = 0.02) staple strength of lambs fed CO was the only effect observed in wool. Flax oil increased total n-3 and decreased the n-6/n-3 ratio in tissue FA profiles (P < 0.001) in comparison to other diets. Tasco increased (P <= 0.001) SFA/PUFA in all tissues, whereas concentrations of CLA c-9, t-11 were greatest with SO in all tissues (P <= 0.02), compared to other diets. These results suggest Tasco supplementation did not improve the n-3/n-6 or SFA/PUFA ratios of lamb adipose tissues compared to other dietary lipid additives. PMID- 26115298 TI - Determining the preference, in vitro digestibility, in situ disappearance, and grower period performance of steers fed a novel algae meal derived from heterotrophic microalgae. AB - A series of 3 experiments were conducted to determine the in vitro and in situ disappearance, preference, and performance of steers consuming increasing concentrations of a novel feedstuff called algae meal (ALG). In Exp. 1 and 2, 3 ruminally cannulated steers (998 +/- 103 kg BW) and 4 treatments were utilized: a dry-rolled corn-based diet (CON), or 15% ALG (A15), 30% ALG (A30), or 45% ALG (A45) as a DM replacement of corn. Experiment 1 was performed as a 3 * 6 unbalanced Latin square with six 5-d periods, and 6 paired diet combinations to determine steer preference, based on DMI for 4 h after feed delivery. Experiment 2 was conducted as a 3 * 4 unbalanced Latin square with 3 diets fed each period and four 14-d periods to determine in situ disappearance of ALG, soyhulls, corn, and hay as ALG increased in the diet. Experiment 3 utilized 48 individually fed steers (292 +/- 22.4 kg; n = 12) in a 55-d grower trial, stratified by BW into 1 of 4 dietary treatments: a control wet corn gluten feed-based diet with no ALG (ALG0), or 15% ALG (ALG15), 30% ALG (ALG30), or 45% ALG (ALG45) in place of wet corn gluten feed on a DM basis. Digestibility of ALG was greater (P < 0.001) than soyhulls at 24 h, but was similar (P = 0.82) at 48 h, with hay being least (P < 0.001) digestible at 24 and 48 h. In Exp. 1, the proportion of total DM consumed by steers during the 4-h postfeeding was affected (P = 0.01) by paired diet combination. Steers preferred A15 or A30 diets over the A45 diet (P <= 0.008); however, no difference in preference between CON and A45 was noted (P = 0.76). Steers tended (P = 0.09) to prefer A30 over CON, but A15 and CON were not different (P = 0.75). No other paired diet combinations altered (P >= 0.23) DMI. In Exp. 2, inclusion of ALG in the diet did not affect (P >= 0.12) rate of, or overall in situ disappearance of, corn, soyhulls, or ALG. In Exp. 3, ADG tended ( = 0.06) to increase as ALG increased in the diet. There was a linear increase ( < 0.001) in DMI as ALG increased in the diet, and as a result, G:F linearly decreased ( = 0.01). In summary, ready consumption of the novel algae meal by steers and support of growth in steers at up to 45% of the diet suggest the algae meal is a viable feedstuff for ruminants. PMID- 26115299 TI - Accounting for uncertainty in the quantification of the environmental impacts of Canadian pig farming systems. AB - The objective of the study was to develop a life cycle assessment (LCA) for pig farming systems that would account for uncertainty and variability in input data and allow systematic environmental impact comparisons between production systems. The environmental impacts of commercial pig production for 2 regions in Canada (Eastern and Western) were compared using a cradle-to-farm gate LCA. These systems had important contrasting characteristics such as typical feed ingredients used, herd performance, and expected emission factors from manure management. The study used detailed production data supplied by the industry and incorporated uncertainty/variation in all major aspects of the system including life cycle inventory data for feed ingredients, animal performance, energy inputs, and emission factors. The impacts were defined using 5 metrics-global warming potential, acidification potential, eutrophication potential (EP), abiotic resource use, and nonrenewable energy use-and were expressed per kilogram carcass weight at farm gate. Eutrophication potential was further separated into marine EP (MEP) and freshwater EP (FEP). Uncertainties in the model inputs were separated into 2 types: uncertainty in the data used to describe the system (alpha uncertainties) and uncertainty in impact calculations or background data that affects all systems equally (beta uncertainties). The impacts of pig production in the 2 regions were systematically compared based on the differences in the systems (alpha uncertainties). The method of ascribing uncertainty influenced the outcomes. In eastern systems, EP, MEP, and FEP were lower (P < 0.05) when assuming that all uncertainty in the emission factors for leaching from manure application was beta. This was mainly due to increased EP resulting from field emissions for typical ingredients in western diets. When uncertainty in these emission factors was assumed to be alpha, only FEP was lower in eastern systems (P < 0.05). The environmental impacts for the other impact categories were not significantly different between the 2 systems, despite their aforementioned differences. In conclusion, a probabilistic approach was used to develop an LCA that systematically dealt with uncertainty in the data when comparing multiple environmental impacts measures in pig farming systems for the first time. The method was used to identify differences between Canadian pig production systems but can also be applied for comparisons between other agricultural systems that include inherent variation. PMID- 26115300 TI - Performance and carcass characteristics of commercial feedlot cattle from a study of vaccine and direct-fed microbial effects on Escherichia col O157:H7 fecal shedding. AB - The objective of this study was to quantify cattle performance and carcass characteristics associated with administration of a siderophore receptor and porin proteins-based vaccine (VAC) and a direct-fed microbial (DFM), which were originally evaluated for their impact on O157:H7 fecal shedding in a commercial feedlot population. Cattle (P = 17,148) were randomly allocated into 40 pens grouped by allocation dates into 10 complete blocks; pens within block were randomly allocated to control, VAC, DFM, or VAC + DFM treatment groups in a 2 * 2 factorial design. The DFM (Bovamine) was fed daily at the labeled dose of 10 cfu/animal of Lactobacillus acidophilus for the duration of the intervention period (mean = 86.6 d). The VAC cattle were vaccinated on Days 0 and 21 whereas unvaccinated cattle were not given a placebo or rehandled on Day 21. Data were analyzed using general and generalized linear mixed models that accounted for the study design. Main effects of DFM and VAC are reported as there were no significant treatment interactions for any of the outcomes evaluated. Vaccinated cattle had lower total weight gain (P < 0.01), ADG (P = 0.03), and cumulative DMI during the intervention period (P < 0.01) compared with unvaccinated cattle, whereas the DFM increased total weight gain (P = 0.03) and G:F (P = 0.05) during the intervention period. Daily DMI was decreased (P < 0.01) in vaccinated pens compared with unvaccinated pens during a 5-d period immediately following revaccination. After the intervention period was completed, cattle were sorted following the standard operating procedure for the feedlot and all cattle were fed the DFM from that point until harvest. Each steer was individually identified through harvest. At harvest, vaccinated cattle had more total days on feed (P < 0.01) with a larger HCW (P = 0.01) than nonvaccinated cattle, whereas cattle not fed the DFM during the intervention period had a significantly larger HCW (P < 0.01) than those fed the DFM during the intervention period. We conclude that the use of these DFM and vaccine products have differential and independent effects on cattle performance and carcass characteristics in a commercial feedlot setting. Although the magnitude of these effects may vary among production systems, a more comprehensive understanding of the potential production costs of preharvest food safety pathogen control programs is essential if such programs are to be fully adopted in the industry. PMID- 26115301 TI - Genome wide transcriptomic analysis identifies pathways affected by the infusion of Clostridium perfringens culture supernatant in the duodenum of broilers in situ. AB - Clostridium perfringens type A is the main etiological factor for necrotic enteritis, a multifactorial enteric disease that penalizes performance, health, and welfare of poultry. Lack of knowledge of host responses and disease pathogenesis is slowing down progress on developing therapies for disease control. A combined genomewide and targeted gene approach was used to investigate pathways and biological functions affected by the infusion of C. perfringens culture supernatant in the duodenum of broilers in 2 experiments. An in situ isolated loop of duodenum was prepared in anesthetized broilers of 3 wk of age (Exp. 1) and was infused either with crude C. perfringens culture supernatant (n = 7; treated), positive for necrotic enteritis B-like toxin (NetB) as determined by a cytotoxicity assay, or with a control preparation (n = 6; control). Birds were maintained alive for 1 h and then euthanized for tissue recovery. The use of the Affymetrix chicken genome array on RNA samples from loop tissue showed top biological functions affected by culture supernatant infusion included cell morphology, immune cell trafficking, and cell death; pathways affected included death receptor signaling, inflammatory response, and nuclear factor (NF)-kappaB signaling. In a second in situ study (Exp. 2), broilers were maintained alive for 4 h to monitor temporal expression patterns of targeted genes. Duodenal tissue was removed at 0.5, 1, 2, and 4 h post-infusion with culture supernatant (n = 9) or a control preparation (n = 5) for histology and gene expression analysis. Genes encoding proinflammatory cytokines, such as interferon gamma (IFNgamma), cell trafficking, such as neuroblastoma 1 (NBL1) and B cell CLL/Lymphoma 6 (BCL6), and cell death, such as Fas cell surface death receptor (FAS) and GTPase IMAP family member 8 (GIMAP8), were differentially expressed in the duodenum of treated and control broilers (P < 0.05). We have demonstrated that C. perfringens culture supernatant (NetB positive) infusion resulted in histological and gene expression changes consistent with necrotic enteritis in the duodenum of broilers. In the absence of live bacteria, crude culture supernatant resulted in early immunomodulation, inflammation, and cell death in the duodenum. The pathways identified here can be targeted for the development of new drugs, vaccines, and novel therapies for necrotic enteritis in broilers. PMID- 26115302 TI - Technical note: Accuracy of an ear tag-attached accelerometer to monitor rumination and feeding behavior in feedlot cattle. AB - Early identification of sick cattle increases treatment success and decreases mortality. Continuous automated records of behavior can be used to identify sick cattle early in the disease process. The objective was to evaluate accuracy of an ear-attached accelerometer (SensOor) that quantified ear movements and estimated feeding and rumination time through a proprietary algorithm. Accelerometers were attached to the ear tag of 18 steers with an initial mean BW of 326 +/- 46 kg. The manufacturer's proprietary software was used to determine time spent "feeding," "ruminating," "active," and "resting." Direct visual observation was used to validate the accelerometer. Sensitivity, specificity, and predictive values were calculated for rumination and feeding separately. Repeated measures were accounted for using mixed model logistic regression. Single minutes of either feeding or rumination in a run of other behavior minutes were changed to the preceding behavior. Accuracy and precision of hourly recorded feeding and rumination times were assessed using the concordance correlation coefficient adjusted for repeated measurements. Sensitivity and specificity were 95 and 76% for feeding and 49 and 96% for rumination, respectively. Concordance correlation between observations and the sensor were 0.79 (95% CI: 0.61 to 0.85) and 0.44 (95% CI: 0.23 to 0.60) for feeding and rumination, respectively. There was large variability among steers, with concordance correlations ranging from 0.09 to 0.98 for rumination time and from 0.58 to 0.96 for feeding time. We conclude that the accelerometer is a promising monitoring system for feeding behavior. PMID- 26115303 TI - Comparison of feed additive technologies for preconditioning of weaned beef calves. AB - Our objective was to evaluate the response of weaned calves to different supplemental feed additives in a supplement to affect calf performance and mitigate stress response observed during weaning and preconditioning. At weaning in each of 2 yr, 160 Angus and Brangus calves (203 and 227 +/- 2.3 and 2.5 kg) were stratified by BW, sex, and breed and were randomly allotted to 1 of 4 treatments ( = 40 calves/treatment): 1) supplement without feed additives (control, CON), 2) supplemented with chlortetracycline, 350 mg/d (CTC), 3) supplemented with monensin, 175 mg/d (RUM), and 4) supplemented with rumen modifier, 5 g/d (ACT). Calves were held by treatment in 1 of 4 drylot pens for 7 d after weaning and were offered ad libitum access to hay and 2.27 kg/d of supplement before placement in one of thirty-two 0.8-ha pastures (5 calves/pasture). On pasture calves were supplemented with 2.27 kg/d (yr 1) or supplemented at 1.0% BW (yr 2). Calf BW and blood samples were collected following weaning (d 0, 1, 4, 7, 11 in yr 1; d 0, 1, 3, 7, 14 in yr 2), at the conclusion of the preconditioning period (d 50, 51 in yr 2), and after transportation (d 52, 55, 59, 65 in yr 2) for analysis of acute phase protein (APP) concentrations. In yr 2, after 44 d on pasture, calves were loaded on 2 semitrucks and transported for 24 h. On return, calves were placed in 4 pastures with hay and fed their respective supplements for 14 d. For each year, data were analyzed with the MIXED procedure of SAS. The model included the main effect of treatment, and pasture was the experimental unit. All variables quantified by day were analyzed using repeated measures. In yr 1, ACT and CTC had greater (P <0.05) 52-d ADG than RUM, whereas CON was intermediate. However, in yr 2, over the 50-d postweaning period there was no difference (P = 0.20; 0.52 kg/d) in ADG response among treatments. After transportation, 7- and 14-d ADG were improved (P < 0.05) for ACT and CTC compared with CON and RUM. In both years, postweaning plasma concentrations of haptoglobin were similar (P > 0.05) among treatments; however an effect of day after transport (P < 0.001) was observed. Feed cost of gain and income over production cost (P >= 0.15; mean = $0.51/kg and $73.51, respectively) were not different among treatments. Use of supplemental additives may improve calf performance during a preconditioning period of this duration, but no additive was effective at mitigating stress postweaning. Additives were equally effective in supporting calf growth performance during a posttransportation period. PMID- 26115304 TI - Fatty acid metabolism in lambs fed citrus pulp. AB - In the present study, we have hypothesized that replacing barley with high proportions of dried citrus pulp in a concentrate-based diet for lambs could increase the intake of unsaturated fatty acids and could reduce the rate of the ruminal biohydrogenation of PUFA, with a consequent improvement of the intramuscular fatty acid composition. To test this hypothesis, 26 Comisana lambs were divided into 3 groups and for 56 d were fed a barley-based concentrate diet (CON; 8 lambs) or 2 diets in which barley was replaced with 24% (CIT24; 9 lambs) or 35% (CIT35; 9 lambs) dried citrus pulp. An overall improvement of the fatty acid composition of LM from lambs fed citrus pulp-containing diets was found. The PUFA/SFA ratio was lower (P < 0.05) in the LM from lambs in the CON group compared with both the CIT24 and CIT35 groups. The thrombogenic index was lower (P < 0.05) in meat from lambs fed the CIT35 diet compared with those fed the CON diet. The CIT35 diet increased the proportion of C20:5 n-3 in the LM (P < 0.05), whereas the CIT24 diet enhanced that of C22:6 -3 (P < 0.05) compared with the CON diet. Some of these results might be explained considering that feeding the CIT24 and CIT35 diets increased the intake of total fatty acids (P < 0.05) and of C18:3 n-3 (P < 0.01) compared with feeding the CON treatment. On the other hand, phenolic compounds present in citrus pulp could have inhibited the ruminal biohydrogenation of PUFA. This is supported by the fact that regardless of the level of inclusion in the diet, citrus pulp increased the proportion of rumenic acid (P < 0.001) in LM compared with the CON diet. The plasma from lambs fed both CIT24 and CIT35 diets had a greater percentage of vaccenic acid (VA; < 0.001) compared with that from lambs fed the CON diet, and the CIT35 diet increased the proportion of rumenic acid in plasma compared with the CON treatment (P < 0.05). In the ruminal fluid, stearic acid (SA) tended to decrease, and the sum of CLA tended to increase (P = 0.09) with increasing level of citrus pulp in the diets. Furthermore, the SA/(SA + VA) ratio tended to be lower (P = 0.10) in the ruminal fluid from lambs fed the CIT35 diet compared with that of the CON group. In conclusion, our results support the hypothesis that replacing barley with citrus pulp in the diet of growing lambs improves intramuscular fatty acid composition and underline the need for specific studies to clarify the mechanisms by which feeding citrus pulp affects the fatty acid metabolism in ruminants. PMID- 26115305 TI - Feedlot performance and carcass traits of hairbreed ewe lambs in response to zilpaterol hydrochloride and soybean oil supplementation. AB - The aim of the present study was to evaluate the impact of zilpaterol hydrochloride (ZH; 0 or 10 mg/lamb daily) and soybean oil (SBO; 0 or 6%) supplementation on feedlot performance, carcass traits, and wholesale cut yield of 32 Dorper * Pelibuey ewe lambs (30.55 +/- 2. 57 kg of initial BW). Lambs were blocked by BW and randomly assigned to treatments under a randomized complete block design with a 2 * 2 factorial arrangement. After a 34-d feeding period, all ewes were slaughtered. No ZH * SBO interactions were detected (P >= 0.11) for the variables evaluated. In the overall feeding period and first 17 d of experiment, feedlot performance was not affected (P >= 0.26) by ZH supplementation, but from d 18 to 34, ZH increased (P <= 0.03) total gain, ADG, and G:F without affecting DMI (P = 0.58). Also, ZH increased (P <= 0.02) HCW, cold carcass weight, dressing percentage, LM area, and leg perimeter. Lung weight as percentage of final BW decreased (P = 0.05) whereas other noncarcass components and wholesale cut yields were not affected (P >= 0.06) by ZH supplementation. Inclusion of SBO did not affect (P >= 0.08) feedlot performance or wholesale cut yields. The LM pH at 24 h postmortem as well as liver and peritoneum percentages were decreased (P <= 0.05) by SBO supplementation, but no other carcass characteristics or noncarcass components were affected (P >= 0.08) by SBO. In conclusion, feedlot performance and carcass characteristics were not altered by the interaction of ZH * SBO. However, ZH alone increased the growth of ewes during the last 17 d of the feeding period. Likewise, carcass characteristics of economic importance (i.e., HCW, dressing percentage, LM area, and leg perimeter) increased with ZH supplementation. In general, feedlot performance, carcass traits, and wholesale cut yields were not altered by including 6% of SBO in the finishing diet of ewe lambs. PMID- 26115306 TI - Cow-calf reproductive, genetic, and nutritional management to improve the sustainability of whole beef production systems. AB - Optimizing efficiency in the cow-calf sector is an important step toward improving beef sustainability. The objective of the study was to use a model to identify the relative roles of reproductive, genetic, and nutritional management in minimizing beef production systems' environmental impact in an economically viable, socially acceptable manner. An economic and environmental diet optimizer was used to identify ideal nutritional management of beef production systems varying in genetic and reproductive technology use. Eight management scenarios were compared to a least cost baseline: average U.S. production practices (CON), CON with variable nutritional management (NUT), twinning cattle (TWN), early weaning (EW), sire selection by EPD using either on-farm bulls (EPD-B) or AI (EPD AI), decreasing the calving window (CW), or selecting bulls by EPD and reducing the calving window (EPD-CW). Diets to minimize land use, water use, and/or greenhouse gas (GHG) emissions were optimized under each scenario. Increases in diet cost attributable to reducing environmental impact were constrained to less than stakeholder willingness to pay for improved efficiency and reduced environmental impact. Baseline land use, water use, and GHG emissions were 188 m, 712 L, and 21.9 kg/kg HCW beef. The NUT scenario, which assessed opportunities to improve sustainability by altering nutritional management alone, resulted in a simultaneous 1.5% reduction in land use, water use, and GHG emissions. The CW scenario improved calf uniformity and simultaneously decreased land use, water use, and GHG emissions by 3.2%. Twinning resulted in a 9.2% reduction in the 3 environmental impact metrics. The EW scenario allowed for an 8.5% reduction in the 3 metrics. The EPD-AI scenario resulted in an 11.1% reduction, which was comparable to the 11.3% reduction achieved by EPD-B in the 3 metrics. Improving genetic selection by using AI or by purchasing on-farm bulls based on their superior EPD demonstrated clear opportunity to improve sustainability. When genetic and reproductive technologies were adopted, up to a 12.4% reduction in environmental impact was achievable. Given the modeling assumptions used in this study, optimizing nutritional management while concurrently improving genetic and reproductive efficiency may be promising avenues to improve productivity and sustainability of U.S. beef systems. PMID- 26115307 TI - Cattle grazing in semiarid forestlands: Habitat selection during periods of drought. AB - Climate change models are predicting increased frequency and severity of droughts in arid and semiarid environments, and these areas are responsible for much of the world's livestock production. Because cattle (Bos Taurus) grazing can impact the abundance, distribution, and ecological function of native plant and animal communities, it is important to understand how cattle might respond to increasingly arid conditions. Here, we evaluate changes in habitat selection by cattle across an 8-yr period as a function of rainfall and other environmental covariates. Using resource selection functions, we evaluated habitat selection based on 2 behaviors, stationary and mobile. Models revealed similarity in cattle habitat selection across years, with only modest changes in selection as a function of precipitation, despite marked seasonal and interannual differences in rainfall. Cattle preferred gentle slopes, forest edges, wet meadows, and areas near water as well as areas far from water on plateaus. Cattle avoided areas at intermediate distances from water, typically associated with steep slopes. As conditions became drier during the late season, cattle did not switch selection patterns but instead contracted their selection around water. Cattle also selected similar habitats whether they were mobile or stationary, possibly making microsite decisions therein. This consistent pattern of selection across years could be particularly problematic for riparian communities as climates become drier; however, it may also simplify cattle management, as range managers can focus vegetation monitoring efforts on riparian areas. Due to the uncertainty surrounding future climatic conditions, it is imperative that both range and wildlife managers develop long-term plans to continue managing these multiuse landscapes in an ecologically sustainable manner based on expected patterns of livestock grazing. PMID- 26115308 TI - Erratum. PMID- 26115309 TI - Reproducibility of Middle Cerebral Artery Stenosis Measurements by DSA: Comparison of the NASCET and WASID Methods. AB - PURPOSE: To evaluate the intra- and inter-observer variability of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) criteria for the evaluation of middle cerebral artery (MCA) stenosis using digital subtraction angiography (DSA). MATERIALS AND METHODS: DSA images of 114 cases with 131 stenotic MCAs were retrospectively analyzed. Two radiologists and a researcher measured the degree of MCA stenosis independently using both NASCET and WASID methods. To determine intra-observer agreement, all the observers reevaluated the degree of MCA stenosis 4 weeks later. The linear relation and coefficient of variation (CV) between the measurements made by the two methods were assessed by correlation coefficient and multi-factor analysis of variance (ANOVA), respectively. Intra- and inter-observer variability of the two methods was evaluated by intraclass correlation coefficient (ICC), Spearman's R value, Pearson correlation coefficient and Bland-Altman plots. RESULTS: Despite the fact that the degree of MCA stenosis measured by NASCET was lower than measured using the WASID method, there was good linear correlation between the measurements made by the two methods (for the mean measurements of the 3 observers, NASCET% = 0.891 * WASID% - 1.89%; ICC, Spearman's R value and Pearson correlation were 0.874, 0.855, and 0.874, respectively). The CVs of both intra- and inter-observer measurements of MCA stenosis using WASID were significantly lower than that using NASCET confirmed by the multi-factor ANOVA results, which showed only the measurement methods of MCA stenosis had significant effects on the CVs both in intra- and inter-observer measurements (both P values < 0.001). Intra-observer measurements showed good or excellent agreement with respect to WASID and NASCET evaluation (ICC, 0.656 to 0.817 and 0.635 to 0.761, respectively). Good agreement for the WASID evaluation (ICC, 0.592 to 0.628) and for the NASCET evaluation (ICC, 0.529 to 0.568) was observed for inter-observer measurements. Bland-Altman plots demonstrated that the WASID method had better reproducibility and intra-observer agreement than NASCET method for evaluating MCA stenosis. CONCLUSION: Both NASCET and WASID methods have an acceptable level of agreement; however, the WASID method had better reproducibility for the evaluation of MCA stenosis, and thus the WASID method may serve as a standard for measuring the degree of MCA stenosis. PMID- 26115315 TI - Postdischarge Communication Between Home Health Nurses and Physicians: Measurement, Quality, and Outcomes. AB - OBJECTIVES: To use natural language processing (NLP) of text from electronic medical records (EMRs) to identify failed communication attempts between home health nurses and physicians, to identify predictors of communication failure, and to assess the association between communication failure and hospital readmission. DESIGN: Retrospective cohort study. SETTING: Visiting Nurse Service of New York (VNSNY), the nation's largest freestanding home health agency. PARTICIPANTS: Medicare beneficiaries with congestive heart failure who received home health care from VNSNY after hospital discharge in 2008-09 (N = 5,698). MEASUREMENTS: Patient-level measures of communication failure and risk-adjusted 30-day all-cause readmission. RESULTS: Identification of failed communication attempts using NLP had high external validity (kappa = 0.850, P < .001). A mean of 8% of communication attempts failed per episode of home care; failure rates were higher for black patients and lower for patients from higher median income ZIP codes. The association between communication failure and readmission was not significant with adjustment for patient, nurse, physician, and hospital factors. CONCLUSION: NLP of EMRs can be used to identify failed communication attempts between home health nurses and physicians, but other variables mostly explained the association between communication failure and readmission. Communication failures may contribute to readmissions in more-serious clinical situations, an association that this study may have been underpowered to detect. PMID- 26115316 TI - Saccharomyces cerevisiae Eukaryotic Elongation Factor 1A (eEF1A) Is Methylated at Lys-390 by a METTL21-Like Methyltransferase. AB - The human methyltransferases (MTases) METTL21A and VCP-KMT (METTL21D) were recently shown to methylate single lysine residues in Hsp70 proteins and in VCP, respectively. The yet uncharacterized MTase encoded by the YNL024C gene in Saccharomyces cerevisiae shows high sequence similarity to METTL21A and VCP-KMT, as well as to their uncharacterized paralogues METTL21B and METTL21C. Despite being most similar to METTL21A, the Ynl024c protein does not methylate yeast Hsp70 proteins, which were found to be unmethylated on the relevant lysine residue. Eukaryotic translation elongation factor eEF1A in yeast has been reported to contain four methylated lysine residues (Lys30, Lys79, Lys318 and Lys390), and we here show that the YNL024C gene is required for methylation of eEF1A at Lys390, the only of these methylations for which the responsible MTase has not yet been identified. Lys390 was found in a partially monomethylated state in wild-type yeast cells but was exclusively unmethylated in a ynl024cDelta strain, and over-expression of Ynl024c caused a dramatic increase in Lys390 methylation, with trimethylation becoming the predominant state. Our results demonstrate that Ynl024c is the enzyme responsible for methylation of eEF1A at Lys390, and in accordance with prior naming of similar enzymes, we suggest that Ynl024c is renamed to Efm6 (Elongation factor MTase 6). PMID- 26115318 TI - What is the ideal ablation therapy for Barrett's esophagus? PMID- 26115317 TI - Racial/ethnic differences in associations between neighborhood socioeconomic status, distress, and smoking among U.S. adults. AB - Neighborhood disadvantage may increase smoking by increasing distress, while neighborhood affluence may reduce smoking by increasing positive affect. We examined whether relationships between neighborhood socioeconomic status (SES) and daily smoking operated through distress and positive affect. Simultaneous multivariate path models used pooled cross-sectional data from the 2000 and 2005 National Alcohol Surveys (15,963 respondents; weighted N = 10,753) and the 2000 Decennial Census. Multiple groups analysis assessed differences by gender and race/ethnicity. Covariates included neighborhood immigrant concentration and individual-level demographics. In the full sample, neighborhood disadvantage significantly increased smoking and neighborhood affluence significantly decreased smoking, with no indirect paths through either distress or positive affect. Unique among Hispanics, affluence resulted in decreased smoking indirectly through reduced distress. Relationships between affect and smoking also varied by race/ethnicity, with no significant differences by gender. Interventions targeting neighborhood socioeconomic status and distress may help reduce smoking, particularly for racial/ethnic minorities. PMID- 26115319 TI - Per-rectal diclofenac decreases the risk of post-ERCP pancreatitis: What about intramuscular diclofenac? PMID- 26115322 TI - [In Process Citation]. PMID- 26115323 TI - [In Process Citation]. PMID- 26115324 TI - [In Process Citation]. PMID- 26115325 TI - Video Comment on Haapamaki C et al. PMID- 26115326 TI - Video Comment on Bove V et al. PMID- 26115327 TI - Video Comment on Attam R et al. PMID- 26115328 TI - Scoring System for Mortality in Patients Diagnosed with and Treated Surgically for Differentiated Thyroid Carcinoma with a 20-Year Follow-Up. AB - BACKGROUND: Differentiated thyroid carcinoma (DTC) is associated with an increased mortality. Few studies have constructed predictive models of all-cause mortality with a high discriminating power for patients with this disease that would enable us to determine which patients are more likely to die. OBJECTIVE: To construct a predictive model of all-cause mortality at 5, 10, 15 and 20 years for patients diagnosed with and treated surgically for DTC for use as a mobile application. DESIGN: We undertook a retrospective cohort study using data from 1984 to 2013. SETTING: All patients diagnosed with and treated surgically for DTC at a general university hospital covering a population of around 200,000 inhabitants in Spain. PARTICIPANTS: The study involved 201 patients diagnosed with and treated surgically for DTC (174, papillary; 27, follicular). EXPOSURES: Age, gender, town, family history, type of surgery, type of cancer, histological subtype, microcarcinoma, multicentricity, TNM staging system, diagnostic stage, permanent post-operative complications, local and regional tumor persistence, distant metastasis, and radioiodine therapy. MAIN OUTCOME MEASURE: All-cause mortality. METHODS: A Cox multivariate regression model was constructed to determine which variables at diagnosis were associated with mortality. Using the model a risk table was constructed based on the sum of all points to estimate the likelihood of death. This was then incorporated into a mobile application. RESULTS: The mean follow-up was 8.8+/-6.7 years. All-cause mortality was 12.9% (95% confidence interval [CI]: 8.3-17.6%). Predictive variables: older age, local tumor persistence and distant metastasis. The area under the ROC curve was 0.81 (95% CI: 0.72-0.91, p<0.001). CONCLUSION: This study provides a practical clinical tool giving a simple and rapid indication (via a mobile application) of which patients with DTC are at risk of dying in 5, 10, 15 or 20 years. Nonetheless, caution should be exercised until validation studies have corroborated our results. PMID- 26115330 TI - Role for Occupational Therapy in Community Mental Health: Using Policy to Advance Scholarship of Practice. AB - Occupational therapists must be aware of professional and policy trends. More importantly, occupational therapists must be involved in efforts to influence policy both for the profession and for the people they serve (Bonder, 1987). Using the state of Illinois as an example, this article reviews the policies and initiatives that impact service decisions for persons with psychiatric disabilities as well as the rationale for including occupational therapy in community mental health service provision. Despite challenges in building a workforce of occupational therapists in the mental health system, this article makes the argument that the current climate of emerging policy and litigation combined with the supporting evidence provides the impetus to strengthen mental health as a primary area of practice. Implications for scholarship of practice related to occupational therapy services in community mental health programs for individuals with psychiatric disability are discussed. PMID- 26115329 TI - Divergent Activity Profiles of Type 1 Ryanodine Receptor Channels Carrying Malignant Hyperthermia and Central Core Disease Mutations in the Amino-Terminal Region. AB - The type 1 ryanodine receptor (RyR1) is a Ca2+ release channel in the sarcoplasmic reticulum of skeletal muscle and is mutated in several diseases, including malignant hyperthermia (MH) and central core disease (CCD). Most MH and CCD mutations cause accelerated Ca2+ release, resulting in abnormal Ca2+ homeostasis in skeletal muscle. However, how specific mutations affect the channel to produce different phenotypes is not well understood. In this study, we have investigated 11 mutations at 7 different positions in the amino (N)-terminal region of RyR1 (9 MH and 2 MH/CCD mutations) using a heterologous expression system in HEK293 cells. In live-cell Ca2+ imaging at room temperature (~25 degrees C), cells expressing mutant channels exhibited alterations in Ca2+ homeostasis, i.e., an enhanced sensitivity to caffeine, a depletion of Ca2+ in the ER and an increase in resting cytoplasmic Ca2+. RyR1 channel activity was quantitatively evaluated by [3H]ryanodine binding and three parameters (sensitivity to activating Ca2+, sensitivity to inactivating Ca2+ and attainable maximum activity, i.e., gain) were obtained by fitting analysis. The mutations increased the gain and the sensitivity to activating Ca2+ in a site-specific manner. The gain was consistently higher in both MH and MH/CCD mutations. Sensitivity to activating Ca2+ was markedly enhanced in MH/CCD mutations. The channel activity estimated from the three parameters provides a reasonable explanation to the pathological phenotype assessed by Ca2+ homeostasis. These properties were also observed at higher temperatures (~37 degrees C). Our data suggest that divergent activity profiles may cause varied disease phenotypes by specific mutations. This approach should be useful for diagnosis and treatment of diseases with mutations in RyR1. PMID- 26115331 TI - Color Tuning in Red/Green Cyanobacteriochrome AnPixJ: Photoisomerization at C15 Causes an Excited-State Destabilization. AB - Cyanobacteriochromes (CBCRs) are cyanobacterial phytochrome-like photoreceptors that carry a single or several GAF (cGMP phosphodiesterase/adenylyl cyclase/FhlA) domains in a repetitive manner. Unlike phytochromes that photoswitch between red absorbing 15Z Pr and far-red-absorbing 15E Pfr states, CBCRs exhibit a much wider spectral activity. One of the best-characterized CBCRs, the phototaxis regulator PixJ of Anabaena sp. PCC 7120, AnPixJ can adopt two thermally stable photoreversible states, a red-absorbing dark state (Pr) and a green-absorbing photoproduct (Pg). Cross-polarization magic-angle spinning (CP/MAS) NMR spectroscopy on AnPixJ assembled in vitro with uniformly (13)C- and (15)N-labeled phycocyanobilin (PCB) chromophore identifies changes of the electronic structure of the chromophore between the two states. Results are compared with the data from red- and far-red-absorbing forms of the complete sensory module of cyanobacterial phytochrome Cph1 aiming at a conceptual understanding of the distinct photoproduct (Pg vs Pfr) absorbances upon Pr photoconversion. The PCB chromophore in the Pr state of both photosensors exhibits very similar spectral features. The photoconversion of Cph1 and the red/green switching AnPixJ C15-Z/E photoisomerization result in a very similar chemical-shift difference (Deltadelta) pattern having, however, opposite sign. The persistence of this pattern confirms the identity of the photochemical isomerization process, while the difference in its sign demonstrates that the same electronic factors drive into opposite direction. It is proposed that the LUMO energy of the 15E photoproduct is stabilized in Cph1 but destabilized in AnPixJ leading to opposite color shifts upon phototransformation. PMID- 26115332 TI - A Structurally and Functionally Biomimetic Biphasic Scaffold for Intervertebral Disc Tissue Engineering. AB - Tissue engineering offers high hopes for the treatment of intervertebral disc (IVD) degeneration. Whereas scaffolds of the disc nucleus and annulus have been extensively studied, a truly biomimetic and mechanically functional biphasic scaffold using naturally occurring extracellular matrix is yet to be developed. Here, a biphasic scaffold was fabricated with collagen and glycosaminoglycans (GAGs), two of the most abundant extracellular matrix components in the IVD. Following fabrication, the scaffold was characterized and benchmarked against native disc. The biphasic scaffold was composed of a collagen-GAG co-precipitate making up the nucleus pulposus-like core, and this was encapsulated in multiple lamellae of photochemically crosslinked collagen membranes comprising the annulus fibrosus-like lamellae. On mechanical testing, the height of our engineered disc recovered by ~82-89% in an annulus-independent manner, when compared with the 99% recovery exhibited by native disc. The annulus-independent nature of disc height recovery suggests that the fluid replacement function of the engineered nucleus pulposus core might mimic this hitherto unique feature of native disc. Biphasic scaffolds comprised of 10 annulus fibrosus-like lamellae had the best overall mechanical performance among the various designs owing to their similarity to native disc in most aspects, including elastic compliance during creep and recovery, and viscous compliance during recovery. However, the dynamic mechanical performance (including dynamic stiffness and damping factor) of all the biphasic scaffolds was similar to that of the native discs. This study contributes to the rationalized design and development of a biomimetic and mechanically viable biphasic scaffold for IVD tissue engineering. PMID- 26115333 TI - LAHRI: Laparoscopic-Assisted Hydrostatic Reduction of Intussusception. AB - BACKGROUND/PURPOSE: Intussusception is the most common cause of bowel obstruction in children from 3 months to 3 years of age. In the absence of peritonitis, initial treatment is either hydrostatic or pneumatic reduction. If these measures fail, operative intervention is required. In nonreducible cases, we propose the use of intraoperative hydrostatic enema to achieve or confirm reduction. In this study we describe a cohort of patients who have undergone laparoscopic-assisted hydrostatic reduction of intussusception (LAHRI). MATERIALS AND METHODS: This is a retrospective cohort study of all patients undergoing LAHRI from the years 2011 to 2013. We performed LAHRI in seven children 4 months to 2 years of age. All patients had ileocolic intussusception that failed initial reduction by radiographic enema. With the patient under general anesthesia, saline enema reduction was facilitated by direct laparoscopic visualization. RESULTS: In 2 of the 7 cases, intussusception reduction was visually confirmed in real time, and only a laparoscopic camera port was required. In 1 patient, the bowel was extensively dilated, requiring mini-laparotomy for visualization. The enema, however, reduced the intussusception without any need for manual reduction. In the remaining 4 cases, minimal laparoscopic manipulation was required after the enema failed to completely reduce the intussusceptum, but enema was used to confirm reduction. No child required bowel resection. CONCLUSIONS: In cases of failed reduction by contrast enema, we have demonstrated LAHRI to be a successful treatment modality. The technique has the advantage of little to no bowel manipulation and has evolved into one performed via a single umbilical port. PMID- 26115334 TI - Psychopharmacologic treatment of dissociative fugue and PTSD in an Ethiopian refugee. AB - Despite widespread awareness of their frequent co-occurrence, little is known about treatment of individuals with comorbid posttraumatic stress disorder (PTSD) and dissociative disorders. Patients with dissociative disorders do not respond well to standard exposure therapy, and few psychopharmacologic trials exist. Fluoxetine proved ineffective for depersonalization disorder, but paroxetine showed efficacy in decreasing dissociative symptoms in PTSD patients. PMID- 26115336 TI - Risk Factors for Urinary Tract Infections in Cardiac Surgical Patients. AB - BACKGROUND: Risk factors for catheter-associated urinary tract infections (CAUTIs) in patients undergoing non-cardiac surgical procedures have been well documented. However, the variables associated with CAUTIs in the cardiac surgical population have not been clearly defined. Therefore, the purpose of this study was to investigate risk factors associated with CAUTIs in patients undergoing cardiac procedures. METHODS: All patients undergoing cardiac surgery at a single institution from 2006 through 2012 (4,883 patients) were reviewed. Patients with U.S. Centers for Disease Control (CDC) criteria for CAUTI were identified from the hospital's Quality Assessment database. Pre-operative, operative, and post operative patient factors were evaluated. Univariate and multivariable analyses were used to identify significant correlations between perioperative characteristics and CAUTIs. RESULTS: There were 55 (1.1%) documented CAUTIs in the study population. On univariate analysis, older age, female gender, diabetes mellitus, cardiogenic shock, urgent or emergent operation, packed red blood cell (PRBC) units transfused, and intensive care unit length of stay (ICU LOS) were all significantly associated with CAUTI [p<0.05]. On multivariable logistic regression, older age, female gender, diabetes mellitus, and ICU LOS remained significantly associated with CAUTI. Additionally, there was a significant association between CAUTI and 30-d mortality on univariate analysis. However, when controlling for common predictors of operative mortality on multivariable analysis, CAUTI was no longer associated with mortality. CONCLUSIONS: There are several identifiable risk factors for CAUTI in patients undergoing cardiac procedures. CAUTI is not independently associated with increased mortality, but it does serve as a marker of sicker patients more likely to die from other comorbidities or complications. Therefore, awareness of the high-risk nature of these patients should lead to increased diligence and may help to improve peri operative outcomes. Recognizing patients at high risk for CAUTI may lead to improved measures to decrease CAUTI rates within this population. PMID- 26115335 TI - Prenatal Phthalate, Perfluoroalkyl Acid, and Organochlorine Exposures and Term Birth Weight in Three Birth Cohorts: Multi-Pollutant Models Based on Elastic Net Regression. AB - BACKGROUND: Some legacy and emerging environmental contaminants are suspected risk factors for intrauterine growth restriction. However, the evidence is equivocal, in part due to difficulties in disentangling the effects of mixtures. OBJECTIVES: We assessed associations between multiple correlated biomarkers of environmental exposure and birth weight. METHODS: We evaluated a cohort of 1,250 term (>= 37 weeks gestation) singleton infants, born to 513 mothers from Greenland, 180 from Poland, and 557 from Ukraine, who were recruited during antenatal care visits in 2002-2004. Secondary metabolites of diethylhexyl and diisononyl phthalates (DEHP, DiNP), eight perfluoroalkyl acids, and organochlorines (PCB-153 and p,p'-DDE) were quantifiable in 72-100% of maternal serum samples. We assessed associations between exposures and term birth weight, adjusting for co-exposures and covariates, including prepregnancy body mass index. To identify independent associations, we applied the elastic net penalty to linear regression models. RESULTS: Two phthalate metabolites (MEHHP, MOiNP), perfluorooctanoic acid (PFOA), and p,p'-DDE were most consistently predictive of term birth weight based on elastic net penalty regression. In an adjusted, unpenalized regression model of the four exposures, 2-SD increases in natural log transformed MEHHP, PFOA, and p,p'-DDE were associated with lower birth weight: 87 g (95% CI: -137, -340 per 1.70 ng/mL), -43 g (95% CI: -108, 23 per 1.18 ng/mL), and -135 g (95% CI: -192, -78 per 1.82 ng/g lipid), respectively; and MOiNP was associated with higher birth weight (46 g; 95% CI: -5, 97 per 2.22 ng/mL). CONCLUSIONS: This study suggests that several of the environmental contaminants, belonging to three chemical classes, may be independently associated with impaired fetal growth. These results warrant follow-up in other cohorts. PMID- 26115337 TI - Effects of redox conditions on the control of arsenic mobility in shallow alluvial aquifers on the Venetian Plain (Italy). AB - The Venetian Plain is known for the occurrence of areas with high concentrations of arsenic in groundwater (greater than 400 MUg/L). The study area represents the typical residential, industrial and agricultural features of most Western countries and is devoid of hydrothermal, volcanic or anthropogenic sources of arsenic. The aim of the study is to model the arsenic mobilization and the water rock interaction by a complete hydrogeochemical investigation (analyses of filtered and unfiltered groundwater sediment mineralogy and geochemistry). The groundwater arsenic contamination and redox conditions are highly variable. Groundwaters with oxidizing and strongly reducing potentials have much lower arsenic concentrations than do mildly reducing waters. The grain size of the aquifer sediments includes gravels, sands and silty-clays. A continuous range of organic material concentrations is observed (from zero to 40%). The amount of sedimentary organic matter is highly correlated with the arsenic content of the sediments (up to 300 mg/kg), whereas no relationships are detectable between arsenic and other chemical parameters. The occurrence of arsenic minerals was observed as a peculiar feature under the scanning electron microscope. Arsenic and sulfur are the sole constituents of small tufts or thin crystals concentrated in small masses. These arsenic minerals were clearly observed in the peat sediments, in agreement with the geochemical modeling that requires very reducing conditions for their precipitation from the groundwater. The modeling suggests that, under oxidizing conditions, arsenic is adsorbed; moreover, a continuous decrease in the redox potential causes increasing desorption of arsenic. If the reducing conditions become more intense, the formation of As-S minerals would explain the lower concentration of arsenic measured in the strongly reducing groundwater. Even if As-sulfides are rare under low-temperature conditions, the anomalous abundance of reductants (organic matter) can locally stabilize As-S minerals, which can scavenge large quantities of groundwater arsenic. PMID- 26115338 TI - Salt in the wound: The interfering effect of road salt on acidified forest catchments. AB - Atmospheric acidic depositions have strongly altered the functioning and biodiversity of Central European forest ecosystems. Most impacts occurred until the end of the 20(th) century but the situation substantially improved thereafter caused by legal regulations in the late 1980's to reduce acidifying atmospheric pollution. Since then slow recovery from acidification has been observed in forested catchments and adjacent waters. However, trends of recovery are inconsistent and underlying mechanisms diminishing recovery are still poorly understood. We propose that the input of road salt can significantly affect acidity regime and acidification recovery of forest ecosystems. By comparing the discharge hydro-chemistry and plant community composition of springs fed by forested catchments with and without high levels of salt input over two decades we observed a significant suppression of recovery and elevated levels of nutrient leaching (K(+), Ca(2+) and Mg(2+)) in highly salt contaminated catchments. We show that the pollution of near-surface groundwater (interflow) by road salt application can have lasting effects on ecosystem processes over distances of several hundred metres apart from the salt emitting road. PMID- 26115339 TI - Impact assessment of emission management strategies of the pharmaceuticals Metformin and Metoprolol to the aquatic environment using Bayesian networks. AB - The issue of pharmaceuticals in the environment has caused increasing concern in the recent years and various strategies have been proposed to tackle this problem. This work describes a Bayesian network (BN)-based socio-ecological impact assessment of a set of measures aimed at reducing the entry of pharmaceuticals in the aquatic environment. The measures investigated were selected across three sectors: public health market, environmental politics and drug design innovation. The BN model was developed for two drugs, Metformin and Metoprolol, and it models the distribution of the Predicted Environmental Concentration (PEC) values as a function of different measures. Results show that the sensitivity of the PEC for the two drugs to the measures investigated reflects the distinct drug characteristics, suggesting that in order to ensure the successful reduction of a broad range of substances, a spectrum of measures targeting the entire lifecycle of a pharmaceutical should be implemented. Furthermore, evaluation of two scenarios reflecting different emission management strategies highlights that the integrated implementation of a comprehensive set of measures across the three sectors results in a more extensive reduction of the contamination. Finally, the BN provides an initial forecasting tool to model the PEC of a drug as a function of a combination of measures in a context-specific manner and possible adaptations of the model are proposed. PMID- 26115340 TI - Study on the Catalytic Activity of Noble Metal Nanoparticles on Reduced Graphene Oxide for Oxygen Evolution Reactions in Lithium-Air Batteries. AB - Among many challenges present in Li-air batteries, one of the main reasons of low efficiency is the high charge overpotential due to the slow oxygen evolution reaction (OER). Here, we present systematic evaluation of Pt, Pd, and Ru nanoparticles supported on rGO as OER electrocatalysts in Li-air cell cathodes with LiCF3SO3-tetra(ethylene glycol) dimethyl ether (TEGDME) salt-electrolyte system. All of the noble metals explored could lower the charge overpotentials, and among them, Ru-rGO hybrids exhibited the most stable cycling performance and the lowest charge overpotentials. Role of Ru nanoparticles in boosting oxidation kinetics of the discharge products were investigated. Apparent behavior of Ru nanoparticles was different from the conventional electrocatalysts that lower activation barrier through electron transfer, because the major contribution of Ru nanoparticles in lowering charge overpotential is to control the nature of the discharge products. Ru nanoparticles facilitated thin film-like or nanoparticulate Li2O2 formation during oxygen reduction reaction (ORR), which decomposes at lower potentials during charge, although the conventional role as electrocatalysts during OER cannot be ruled out. Pt-and Pd-rGO hybrids showed fluctuating potential profiles during the cycling. Although Pt- and Pd-rGO decomposed the electrolyte after electrochemical cycling, no electrolyte instability was observed with Ru-rGO hybrids. This study provides the possibility of screening selective electrocatalysts for Li-air cells while maintaining electrolyte stability. PMID- 26115341 TI - The Chemophytostabilisation Process of Heavy Metal Polluted Soil. AB - Industrial areas are characterised by soil degradation processes that are related primarily to the deposition of heavy metals. Areas contaminated with metals are a serious source of risk due to secondary pollutant emissions and metal leaching and migration in the soil profile and into the groundwater. Consequently, the optimal solution for these areas is to apply methods of remediation that create conditions for the restoration of plant cover and ensure the protection of groundwater against pollution. Remediation activities that are applied to large scale areas contaminated with heavy metals should mainly focus on decreasing the degree of metal mobility in the soil profile and metal bioavailability to levels that are not phytotoxic. Chemophytostabilisation is a process in which soil amendments and plants are used to immobilise metals. The main objective of this research was to investigate the effects of different doses of organic amendments (after aerobic sewage sludge digestion in the food industry) and inorganic amendments (lime, superphosphate, and potassium phosphate) on changes in the metals fractions in soils contaminated with Cd, Pb and Zn during phytostabilisation. In this study, the contaminated soil was amended with sewage sludge and inorganic amendments and seeded with grass (tall fescue) to increase the degree of immobilisation of the studied metals. The contaminated soil was collected from the area surrounding a zinc smelter in the Silesia region of Poland (pH 5.5, Cd 12 mg kg-1, Pb 1100 mg kg-1, Zn 700 mg kg-1). A plant growth experiment was conducted in a growth chamber for 5 months. Before and after plant growth, soil subsamples were subjected to chemical and physical analyses. To determine the fractions of the elements, a sequential extraction method was used according to Zeien and Brummer. Research confirmed that the most important impacts on the Zn, Cd and Pb fractions included the combined application of sewage sludge from the food industry and the addition of lime and potassium phosphate. Certain doses of inorganic additives decreased the easily exchangeable fraction from 50% to 1%. The addition of sewage sludge caused a decrease in fraction I for Cd and Pb. In combination with the use of inorganic additives, a mobile fraction was not detected and an easily mobilisable fraction was reduced by half. For certain combinations of metals, the concentrations were detected up to a few percent. The application of sewage sludge resulted in a slight decrease in a mobile (water soluble and easily exchangeable metals) fraction of Zn, but when inorganic additives were applied, this fraction was not detected. The highest degree of immobilisation of the tested heavy metals relative to the control was achieved when using both sewage sludge and inorganic additives at an experimentally determined dose. The sequential extraction results confirmed this result. In addition, the results proved that the use of the phytostabilisation process on contaminated soils should be supported. PMID- 26115342 TI - Motilin Stimulates Gastric Acid Secretion in Coordination with Ghrelin in Suncus murinus. AB - Motilin and ghrelin constitute a peptide family, and these hormones are important for the regulation of gastrointestinal motility. In this study, we examined the effect of motilin and ghrelin on gastric acid secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. We first established a gastric lumen-perfusion system in the suncus and confirmed that intravenous (i.v.) administration of histamine (1 mg/kg body weight) stimulated acid secretion. Motilin (0.1, 1.0, and 10 MUg/kg BW) stimulated the acid output in a dose-dependent manner in suncus, whereas ghrelin (0.1, 1.0, and 10 MUg/kg BW) alone did not induce acid output. Furthermore, in comparison with the vehicle administration, the co-administration of low-dose (1 MUg/kg BW) motilin and ghrelin significantly stimulated gastric acid secretion, whereas either motilin (1 MUg/kg BW) or ghrelin (1 MUg/kg BW) alone did not significantly induce gastric acid secretion. This indicates an additive role of ghrelin in motilin-induced gastric acid secretion. We then investigated the pathways of motilin/motilin and ghrelin-stimulated acid secretion using receptor antagonists. Treatment with YM 022 (a CCK-B receptor antagonist) and atropine (a muscarinic acetylcholine receptor antagonist) had no effect on motilin or motilin-ghrelin co administration-induced acid output. In contrast, famotidine (a histamine H2 receptor antagonist) completely inhibited motilin-stimulated acid secretion and co-administration of motilin and ghrelin induced gastric acid output. This is the first report demonstrating that motilin stimulates gastric secretion in mammals. Our results also suggest that motilin and co-administration of motilin and ghrelin stimulate gastric acid secretion via the histamine-mediated pathway in suncus. PMID- 26115343 TI - The Influence of Casing-Sand Adhesion on Cementing Bond Strength. AB - In the petroleum industry, one of the most serious problems encountered during cementing is the failure at the bonding interface. Many measures including casing sand adhesion have been developed to improve cementing bond strength. However, due to the lack of detailed study of the technique, many questions remain. The primary goal of this study is to investigate the influence of casing-sand adhesion on cementing bond strength, and to optimize parameters. An orthogonal experiment and a supplementary experiment were conducted. The results indicated that casing-sand adhesion can improve the cementing bond strength. The priority orders of key factors are: sand grain size, sand coverage, adhesive curing temperature and adhesive curing time. The optimal parameters recommended for application are: 1.6mm~1.9mm sand grain size, 60%~70% sand coverage, 30 degrees C curing temperature and 60 hours curing time. PMID- 26115344 TI - Obliquity Control On Southern Hemisphere Climate During The Last Glacial. AB - Recent paleoclimate reconstructions have challenged the traditional view that Northern Hemisphere insolation and associated feedbacks drove synchronous global climate and ice-sheet volume during the last glacial cycle. Here we focus on the response of the Patagonian Ice Sheet, and demonstrate that its maximum expansion culminated at 28,400 +/- 500 years before present (28.4 +/- 0.5 ka), more than 5,000 years before the minima in 65 degrees N summer insolation and the formally defined Last Glacial Maximum (LGM) at 21,000 +/- 2,000 years before present. To investigate the potential drivers of this early LGM (eLGM), we simulate the effects of orbital changes using a suite of climate models incorporating prescribed and evolving sea-ice anomalies. Our analyses suggest that Antarctic sea-ice expansion at 28.5 ka altered the location and intensity of the Southern Hemisphere storm track, triggering regional cooling over Patagonia of 5 degrees C that extends across the wider mid-southern latitudes. In contrast, at the LGM, continued sea-ice expansion reduced regional temperature and precipitation further, effectively starving the ice sheet and resulting in reduced glacial expansion. Our findings highlight the dominant role that orbital changes can play in driving Southern Hemisphere glacial climate via the sensitivity of mid latitude regions to changes in Antarctic sea-ice extent. PMID- 26115345 TI - Development of microbial spoilage and lipid and protein oxidation in rabbit meat. AB - This experiment aimed to determine microbial spoilage and lipid and protein oxidation during aerobic refrigerated (4 degrees C) storage of rabbit meat. Forty male New Zealand white rabbits were slaughtered according to the Halal slaughter procedure. The hind limbs were used for microbial analysis while the Longissimus lumborum m. was used for determination of lipid and protein oxidation. Bacterial counts generally increased with aging time and the limit for fresh meat (10(8)cfu/g) was reached at d 7 postmortem. Significant differences in malondialdehyde content were observed after 3d of storage. The thiol concentration significantly decreased with increase in aging time. The band intensities of myosin heavy chain and troponin T significantly reduced with increased refrigerated storage while actin remained relatively stable. This study thus proposes protein oxidation as a potential deteriorative change in refrigerated rabbit meat along with microbial spoilage and lipid oxidation. PMID- 26115346 TI - The use of atmospheric pressure plasma-treated water as a source of nitrite for emulsion-type sausage. AB - We investigated the possible use of atmospheric pressure plasma-treated water (PTW) as a nitrite source in curing process. Emulsion-type sausages were manufactured with PTW, celery powder containing nitrite, and synthetic sodium nitrite at a concentration of nitrite ion 70mgkg(-1). In terms of sausage quality, there were no noticeable effects of PTW on the total aerobic bacterial counts, color, and peroxide values of sausages compared with those of celery powder and sodium nitrite throughout 28days of storage at 4 degrees C. Sausage with added PTW had lower concentrations of residual nitrite compared to those of added celery powder and sodium nitrite during the storage period (P<0.05). The sensory properties of PTW-treated and sodium nitrite-treated sausages were not different, whereas the sausage with added celery powder received the lowest scores in taste and acceptability. From the results, it is concluded that PTW can be used as a nitrite source equivalent to a natural curing agent. PMID- 26115347 TI - Predicting meat quality traits of ovine m. semimembranosus, both fresh and following freezing and thawing, using a hand held Raman spectroscopic device. AB - Complementary studies were conducted to determine the potential for a Raman spectroscopic hand held device to predict meat quality traits of fresh lamb m. semimembranosus (topside) after ageing and freezing/thawing. Spectra were collected from 80 fresh muscles at 24h and 5d PM, another 80 muscles were measured at 24h, 5d and following freezing/thawing. Shear force, cooking loss, sarcomere length, colour, particle size, collagen content, pH24, pHu, purge and thaw loss were also measured. Results indicated a potential to predict pHu (R(2)cv=0.59), pH24 (R(2)cv=0.48) and purge (R(2)cv=0.42) using spectra collected 24h PM. L* could be predicted using spectra collected 24h (R(2)cv=0.33) or 5d PM (R(2)cv=0.33). This suggests that Raman spectroscopy is suited to identifying carcases which deviate from the normal metabolic processes and related meat quality traits. PMID- 26115348 TI - Exposure to Deepwater Horizon Crude Oil Burnoff Particulate Matter Induces Pulmonary Inflammation and Alters Adaptive Immune Response. AB - The "in situ burning" of trapped crude oil on the surface of Gulf waters during the 2010 Deepwater Horizon (DWH) oil spill released numerous pollutants, including combustion-generated particulate matter (PM). Limited information is available on the respiratory impact of inhaled in situ burned oil sail particulate matter (OSPM). Here we utilized PM collected from in situ burn plumes of the DWH oil spill to study the acute effects of exposure to OSPM on pulmonary health. OSPM caused dose-and time-dependent cytotoxicity and generated reactive oxygen species and superoxide radicals in vitro. Additionally, mice exposed to OSPM exhibited significant decreases in body weight gain, systemic oxidative stress in the form of increased serum 8-isoprostane (8-IP) levels, and airway inflammation in the form of increased macrophages and eosinophils in bronchoalveolar lavage fluid. Further, in a mouse model of allergic asthma, OSPM caused increased T helper 2 cells (Th2), peribronchiolar inflammation, and increased airway mucus production. These findings demonstrate that acute exposure to OSPM results in pulmonary inflammation and alteration of innate/adaptive immune responses in mice and highlight potential respiratory effects associated with cleaning up an oil spill. PMID- 26115350 TI - Carotenoid deposition in plant and animal foods and its impact on bioavailability. AB - Over the past decades, an enormous body of literature dealing with the natural deposition of carotenoids in plant- and animal-based foods has accumulated. Prominent examples are the large solid-crystalline aggregates in carrots and tomatoes or the lipid-dissolved forms in dairy products and egg yolk. Latest research has identified lipid-dissolved forms in a rare number of plant foods, such as tangerine tomatoes and peach palm fruit (Bactris gasipaes Kunth). In addition, liquid-crystalline forms were assumed in so-called tubular chromoplasts of numerous fruits, e.g., in papaya, mango, and bell pepper. The bioavailability of carotenoids from fresh and processed foods strongly depends on their genuine deposition form, since their effective absorption to the human organism requires their liberation from the food matrix and subsequent solubilization into mixed micelles in the small intestine. Consequently, a broad overview about the natural array of carotenoid deposition forms should be helpful to better understand and modulate their bioavailability from foods. Furthermore, naturally highly bioavailable forms may provide biomimetic models for the improved formulation of carotenoids in food supplements. Therefore, this review paper presents scientific evidence from human intervention studies associating carotenoid deposition forms with their bioavailability, thus suggesting novel technological and dietary strategies for their enhanced absorption. PMID- 26115349 TI - The Role of Storage Lipids in the Relation between Fecundity, Locomotor Activity, and Lifespan of Drosophila melanogaster Longevity-Selected and Control Lines. AB - The contribution of insect fat body to multiple processes, such as development, metamorphosis, activity, and reproduction results in trade-offs between life history traits. In the present study, age-induced modulation of storage lipid composition in Drosophila melanogaster longevity-selected (L) and non-selected control (C) lines was studied and the correlation between total body fat mass and lifespan assessed. The trade-offs between fecundity, locomotor activity, and lifespan were re-evaluated from a lipid-related metabolic perspective. Fewer storage lipids in the L lines compared to the C lines supports the impact of body fat mass on extended lifespan. The higher rate of fecundity and locomotor activity in the L lines may increase the lipid metabolism and enhance the lipolysis of storage lipids, reducing fat reserves. The correlation between neutral lipid fatty acids and fecundity, as well as locomotor activity, varied across age groups and between the L and C lines. The fatty acids that correlated with egg production were different from the fatty acids that correlated with locomotor activity. The present study suggests that fecundity and locomotor activity may positively affect the lifespan of D. melanogaster through the inhibition of fat accumulation. PMID- 26115352 TI - High Selectivity of Supported Ru Catalysts in the Selective CO Methanation-Water Makes the Difference. AB - The selectivity for CO methanation is a decisive aspect for the practical application of the methanation reaction for the removal of CO from CO2-rich H2 fuel gases produced via hydrocarbon reforming. We show that increasing the water content in the feed gas, up to technically relevant levels of 30%, significantly increases the selectivity of supported Ru catalysts compared with operation in (almost) dry gas, while in operando EXAFS measurements reveal a gradual decrease in the Ru particle size with increasing amounts of water in the gas feed. Consequences of these findings and related IR spectroscopic data for the mechanistic understanding and practical applications are outlined. PMID- 26115351 TI - Reasons for recent marijuana use in relation to use of other illicit drugs among high school seniors in the United States. AB - OBJECTIVES: Studies show that illicit cannabis (marijuana) use is related to use of other illicit drugs and that reasons for use are related to frequency of marijuana use. However, research is needed to examine whether specific reasons for marijuana use are associated with use of other illicit drugs. METHODS: Data from recent marijuana-using high school seniors were examined from 12 cohorts of Monitoring the Future (Weighted n = 6481) to examine whether reasons for recent marijuana use are associated with use of eight other illicit drugs. RESULTS: Using "to experiment" decreased odds of reporting use of each drug and using to decrease effects of other drugs increased odds of reporting use of each drug. In multivariable models, using marijuana "to experiment" decreased the odds for reporting use of hallucinogens other than LSD and narcotics other than heroin. Using marijuana for "insight" increased the odds for use of hallucinogens other than LSD, and use due to "boredom" increased the odds for reporting use of powder cocaine and hallucinogens other than LSD. Using marijuana to increase effects of other drugs increased odds of reporting use of each of the eight drugs, and using it to decrease other drug effects increased odds of reporting use of crack, hallucinogens other than LSD, and amphetamine/stimulants. CONCLUSIONS: This study helped identify illicit marijuana users who are more likely to report use of other illicit drugs. Prevention efforts need to focus on students who report certain reasons for marijuana use as they may be at risk for use of other illicit drugs. PMID- 26115355 TI - Childhood and Adolescent nodular lymphocyte predominant Hodgkin lymphoma - A review of clinical outcome based on the histological variants. AB - Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) comprises approximately 10-12% of all childhood Hodgkin lymphoma. As the majority have low stage disease recent years have seen a de-escalation of treatment intensity to avoid treatment related morbidity. This report evaluates treatment outcome in children with histopathological variants of nLPHL after therapy de-escalation. Biopsies from 60 patients were reviewed and histology categorized as typical (n = 47; 78%) or variant nLPHL (n = 13; 22%). Furthermore, presence of immunoglobulin D (IgD) expression by the lymphocyte predominant (LP) cells was assessed in 41 patients. Treatment outcomes were compared according to treatment received and histopathology of nLPHL. Compared to typical nLPHL, children with variant nLPHL had higher stage disease at diagnosis (stage III: 3/13; 23% vs. 3/47; 6%, P = 0.11), lower complete response rates (6/13; 46% vs. 38/47; 81%, P = 0.029) and higher relapse rates (2/13; 15% vs. 2/47; 4%, P = 0.20). Additionally, IgD expression by LP cells was associated with poorer treatment response and was more commonly seen in patients with variant nLPHL. (11/13; 85% vs. 15/28; 54%, P = 0.08). Variant histology appears to be indicative of a poorer prognosis in patients with early stage disease, and may be an important factor to take into account when moving towards reduced intensity treatment for nLPHL. PMID- 26115353 TI - Spatio-temporal Dynamics and Mechanisms of Stress Granule Assembly. AB - Stress granules (SGs) are non-membranous cytoplasmic aggregates of mRNAs and related proteins, assembled in response to environmental stresses such as heat shock, hypoxia, endoplasmic reticulum (ER) stress, chemicals (e.g. arsenite), and viral infections. SGs are hypothesized as a loci of mRNA triage and/or maintenance of proper translation capacity ratio to the pool of mRNAs. In brain ischemia, hippocampal CA3 neurons, which are resilient to ischemia, assemble SGs. In contrast, CA1 neurons, which are vulnerable to ischemia, do not assemble SGs. These results suggest a critical role SG plays in regards to cell fate decisions. Thus SG assembly along with its dynamics should determine the cell fate. However, the process that exactly determines the SG assembly dynamics is largely unknown. In this paper, analyses of experimental data and computer simulations were used to approach this problem. SGs were assembled as a result of applying arsenite to HeLa cells. The number of SGs increased after a short latent period, reached a maximum, then decreased during the application of arsenite. At the same time, the size of SGs grew larger and became localized at the perinuclear region. A minimal mathematical model was constructed, and stochastic simulations were run to test the modeling. Since SGs are discrete entities as there are only several tens of them in a cell, commonly used deterministic simulations could not be employed. The stochastic simulations replicated observed dynamics of SG assembly. In addition, these stochastic simulations predicted a gamma distribution relative to the size of SGs. This same distribution was also found in our experimental data suggesting the existence of multiple fusion steps in the SG assembly. Furthermore, we found that the initial steps in the SG assembly process and microtubules were critical to the dynamics. Thus our experiments and stochastic simulations presented a possible mechanism regulating SG assembly. PMID- 26115356 TI - The Oral Tolerance as a Complex Network Phenomenon. AB - The phenomenon of oral tolerance refers to a local and systemic state of tolerance induced in the gut after its exposure to innocuous antigens. Recent findings have shown the interrelationship between cellular and molecular components of oral tolerance, but its representation through a network of interactions has not been investigated. Our work aims at identifying the causal relationship of each element in an oral tolerance network, and also to propose a phenomenological model that's capable of predicting the stochastic behavior of this network when under manipulation. We compared the changes of a "healthy" network caused by "knock-outs" (KOs) in two approaches: an analytical approach by the Perron Frobenius theory; and a computational approach, which we describe within this work in order to find numerical results for the model. Both approaches have shown the most relevant immunological components for this phenomena, that happens to corroborate the empirical results from animal models. Besides explain in a intelligible fashion how the components interacts in a complex manner, we also managed to describe and quantify the importance of KOs that hasn't been empirically tested. PMID- 26115357 TI - DLISA: A DNAzyme-Based ELISA for Protein Enzyme-Free Immunoassay of Multiple Analytes. AB - A DNAzyme-based ELISA, termed DLISA, was developed as a novel protein enzyme free, triply amplified platform, combining a catalytic and molecular beacon (CAMB) system with a cation exchange reaction for ultrasensitive multiplex fluorescent immunosorbent assay. Classical ELISA, which employs protein enzymes as biocatalysts to afford amplified signals, suffers from poor stability caused by the irreversible denaturation of these enzymes under harsh conditions, such as heat and acidity. Compared with proteins, nucleic acids are more stable and adaptable, and they can be easily produced using a commercial DNA synthesizer. Moreover, the catalytic and cleavage activities of DNAzyme can be achieved in solution; thus, no enzyme immobilization is needed for detection. Taken together, these attributes suggest that a DNAzyme-based ELISA detection approach will be more robust than current ELISA assays. Importantly, the proposed triply amplified DLISA immunoassay method shows ultrasensitive detection of such targets as human IgG with a detection limit of 2 fg/mL (3 * 10(-17) M), which is well within the range of many important disease biomarkers. DLISA can also be used to construct a sensing array for simultaneous multiplexed detection. With these merits, this high-throughput, stable, simple, sensitive, and low-cost multiplex fluorescence immunoassay shows promise for applications in clinical diagnosis. PMID- 26115358 TI - Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. AB - OBJECTIVES: Administration of anti-CD19 chimeric antigen receptor (CAR)-modified T cells for B-cell malignancies has been remarkably effective in recent clinical trials. To investigate the critical parameters affecting efficacy and evaluated the safety of using CAR T cells targeting CD19 in B-lineage malignancies. We performed a systematic review of reported phase I clinical trials using CAR T cells targeting CD19 in B-lineage malignancies. METHODS: We searched Medline and Embase for studies on anti-CD19 CAR-modified T cells in patients with B-cell malignancies in October 2014. Univariate analyses were performed using the Kaplan Meier method, and a Cox regression model was used to determine the independent prognostic factors of progression-free survival (PFS). RESULTS: Six trials involving 50 patients were included in this review. After CAR T-cell infusion, the overall response rate was 48% (complete responses in 24%). The 6-month PFS and 1-year PFS were 43% and 27%, respectively. Statistically significant factors favorably influencing PFS were conditioning chemotherapy (P < 0.001), B-cell aplasia (P = 0.040), and durable persistence of CAR T cells (P = 0.013) in univariate analyses. After multivariate analysis, conditioning chemotherapy remained as an independent prognostic factor for PFS. The most common adverse events were fever, hypotension, rigor, fatigue, bacteremia, chill, dyspnea, and headache, but all were temporary and resolved. CONCLUSION: Anti-CD19 CAR-modified T cells have shown therapeutic efficacy in patients with B-lineage malignancies and were well tolerated in most patients. Conditioning chemotherapy is a prerequisite to improve the clinical outcome. PMID- 26115359 TI - Subacute Tissue Response to 3D Graphene Oxide Scaffolds Implanted in the Injured Rat Spinal Cord. AB - The increasing prevalence and high sanitary costs of lesions affecting the central nervous system (CNS) at the spinal cord are encouraging experts in different fields to explore new avenues for neural repair. In this context, graphene and its derivatives are attracting significant attention, although their toxicity and performance in the CNS in vivo remains unclear. Here, the subacute tissue response to 3D flexible and porous scaffolds composed of partially reduced graphene oxide is investigated when implanted in the injured rat spinal cord. The interest of these structures as potentially useful platforms for CNS regeneration mainly relies on their mechanical compliance with neural tissues, adequate biocompatibility with neural cells in vitro and versatility to carry topographical and biological guidance cues. Early tissue responses are thoroughly investigated locally (spinal cord at C6 level) and in the major organs (i.e., kidney, liver, lung, and spleen). The absence of local and systemic toxic responses, along with the positive signs found at the lesion site (e.g., filler effect, soft interface for no additional scaring, preservation of cell populations at the perilesional area, presence of M2 macrophages), encourages further investigation of these materials as promising components of more efficient material-based platforms for CNS repair. PMID- 26115360 TI - COMPLETE RESOLUTION OF LARGE RETINAL FOLD AFTER TRANSECTION OF RETROLENTAL MEMBRANE DURING LENS-SPARING VITRECTOMY FOR RETINOPATHY OF PREMATURITY: A 15-YEAR FOLLOW-UP. AB - PURPOSE: To describe the long-term anatomical and visual outcomes of a patient with retinopathy of prematurity characterized by a prominent retinal fold adherent to the posterior lens capsule, treated by lens-sparing vitrectomy with surgical transection of the retrolental membrane. CASE SUMMARY: A premature infant was born at a gestational age of 25 weeks and birthweight of 636 g. She developed threshold retinopathy of prematurity bilaterally and was subsequently treated with laser ablative therapy. The left eye responded favorably, with regression of neovascularization; however, the right eye progressed to Stage 4A with a prominent retinal fold adherent to the posterior lens capsule. The patient underwent lens-sparing vitrectomy with dissection of the retrolental membrane at postmenstrual age of 44 weeks. At 15-year follow-up, the patient has maintained a best-corrected visual acuity of 20/60 and, of note, demonstrated complete resolution of the previous retinal fold. CONCLUSION: Surgical treatment for retinopathy of prematurity was considerably advanced by the introduction of lens sparing vitrectomy techniques; however, cases developing retrolental membranes often persisted with poor visual outcomes, and lensectomy is conventionally performed. However, in select cases of Stage 4A retinopathy of prematurity, careful transection of retrolental membranes during lens-sparing vitrectomy using the appropriate technique may provide very good anatomical and visual outcomes. PMID- 26115361 TI - Gender, Relationships, and Elder Abuse: Assessing Aggression in Mother-Daughter Dyads. AB - The older adult population is growing rapidly, and with it comes a national concern for elder abuse. Elder abuse is an intentional act of harm or failure to provide care by a person in a trusted relationship with the elder. One relationship is often overlooked in both research and clinical practice as having special significance for elder abuse-that of the adult daughter-elderly mother. However, recent studies suggest that there are gender differences in the use of aggression, which challenge standard assessments of abuse and may be important for assessing mother-daughter relationships. In this narrative review article, the authors review the relevant literature on female-to-female aggression, with an emphasis on its application to mother-daughter relationships and elder abuse. Measurement tools are evaluated in light of the state of the science. The authors conclude with specific recommendations for clinical practice. PMID- 26115362 TI - Fuzzy Index to Evaluate Edge Detection in Digital Images. AB - In literature, we can find different metrics to evaluate the detected edges in digital images, like Pratt's figure of merit (FOM), Jaccard's index (JI) and Dice's coefficient (DC). These metrics compare two images, the first one is the reference edges image, and the second one is the detected edges image. It is important to mention that all existing metrics must binarize images before their evaluation. Binarization step causes information to be lost because an incomplete image is being evaluated. In this paper, we propose a fuzzy index (FI) for edge evaluation that does not use a binarization step. In order to process all detected edges, images are represented in their fuzzy form and all calculations are made with fuzzy sets operators and fuzzy Euclidean distance between both images. Our proposed index is compared to the most used metrics using synthetic images, with good results. PMID- 26115363 TI - The WUSCHEL-RELATED HOMEOBOX 3 gene PaWOX3 regulates lateral organ formation in Norway spruce. AB - In angiosperms, WUSCHEL-RELATED HOMEOBOX 3 (WOX3) genes are required for the recruitment of founder cells from the lateral domains of shoot meristems that form lateral regions of leaves. However, the regulation of the formation of lateral organs in gymnosperms remains unknown. By using somatic embryos of Norway spruce (Picea abies) we have studied the expression and function of PaWOX3 during embryo development. The mRNA abundance of PaWOX3 was determined by quantitative real-time PCR, and the spatial expression of PaWOX3 was analysed by histochemical beta-glucuronidase (GUS) assays and in situ mRNA hybridization. To investigate the function of PaWOX3, we analysed how downregulation of PaWOX3 in RNA interference lines affected embryo development and morphology. PaWOX3 was highly expressed in mature embryos at the base of each cotyledon close to the junction between the cotyledons, and in the lateral margins of cotyledons and needles, separating them into an adaxial and an abaxial side. Downregulation of the expression of PaWOX3 caused defects in lateral margin outgrowth in cotyledons and needles, and reduced root elongation. Our data suggest that the WOX3 function in margin outgrowth in lateral organs is conserved among the seed plants, whereas its function in root elongation may be unique to gymnosperms. PMID- 26115364 TI - Do Changes in Tympanic Temperature Predict Changes in Affective Valence During High-Intensity Exercise? AB - PURPOSE: Increased core (brain or body) temperature that accompanies exercise has been posited to play an influential role in affective responses to exercise. However, findings in support of this hypothesis have been equivocal, and most of the performed studies have been done in relation to anxiety. The aim of the present study was to investigate the effects of tympanic temperature on basic affect (i.e., pleasure-displeasure) in the course of a high-intensity exercise session. METHOD: One hundred seventy students performed a 10-min cycling exercise at an intensity of 80% to 85% of maximal heart rate. Heart rate, tympanic temperature, and self-reported pleasure (using the Feeling Scale [FS]) were measured twice during exercise at the end of the first minute (Min 1:00) and beginning of the last minute (Min 9:00). RESULTS: Small increases in tympanic temperature were noted from Min 1:00 to Min 9:00 (mean change value = +0.2 degrees C). Meanwhile, the FS scores changed in the opposite direction (mean change value = - 0.2 units). However, changes in temperature only poorly predicted changes in pleasure-displeasure (R(2) = .05 for the linear regression, R(2) = .08 for the curvilinear regression). CONCLUSIONS: Slight elevated tympanic temperature occurred during the 10-min cycling exercise, but it had a negligible effect on changes in pleasure ratings. The possibility that tympanic temperature is not a valid indicator of core temperature during exercise is discussed. PMID- 26115365 TI - Evaluation of a Push-Pull Approach for Aedes aegypti (L.) Using a Novel Dispensing System for Spatial Repellents in the Laboratory and in a Semi-Field Environment. AB - The increase in insecticide resistant mosquito populations necessitates the exploration of novel vector control intervention measures. Push-pull strategies for insect control have been successful when used in integrated crop pest management. Through the combinatory use of deterring and attracting stimuli, the abundance of insect pests can be changed in a given area. A push-pull strategy might also significantly reduce human-vector contacts and augment existing mosquito control strategies, e.g. through the combination of an attractive trapping system and a potent spatial repellent. Our approach includes the BG Sentinel (BGS) trap in combination with catnip oil (Nepeta cataria), a known spatial repellent for Aedes aegypti. To impart a deterrent effect on mosquitoes at a distance, a homogenous and continuous dispersal of volatile repellent compounds is crucial. We have developed a repellent dispensing system that is easy to use and provides a homogenous dispersal of repellent in an air curtain. The use of five 9 V fans and custom-made repellent sachets containing 10% catnip essential oil created a repellent loaded air curtain that provided coverage of an area of 2 m2 (1.2 x 1.65 m). Air was sampled at four different heights in the curtain and analysed via thermal desorption (TD) and consecutive gas chromatography-mass spectrometry (GC-MS). Nepetalactone, the main constituent of the oil, was detected in air at a concentration range of 80 to 100 MUg/m3 and the amounts were comparable at all four sampling positions. When a human volunteer was sitting behind the repellent curtain and a BGS trap was installed in front of the curtain in laboratory push-pull trials, Ae. aegypti landing collections decreased significantly by 50% compared to repellent-free controls. However, in a semi-field environment, comparable protective effects could not be achieved and further research on suitable repellent concentrations for outdoor implementation will be required. PMID- 26115366 TI - Measuring Computed Tomography Scanner Variability of Radiomics Features. AB - OBJECTIVES: The purpose of this study was to determine the significance of interscanner variability in CT image radiomics studies. MATERIALS AND METHODS: We compared the radiomics features calculated for non-small cell lung cancer (NSCLC) tumors from 20 patients with those calculated for 17 scans of a specially designed radiomics phantom. The phantom comprised 10 cartridges, each filled with different materials to produce a wide range of radiomics feature values. The scans were acquired using General Electric, Philips, Siemens, and Toshiba scanners from 4 medical centers using their routine thoracic imaging protocol. The radiomics feature studied included the mean and standard deviations of the CT numbers as well as textures derived from the neighborhood gray-tone difference matrix. To quantify the significance of the interscanner variability, we introduced the metric feature noise. To look for patterns in the scans, we performed hierarchical clustering for each cartridge. RESULTS: The mean CT numbers for the 17 CT scans of the phantom cartridges spanned from -864 to 652 Hounsfield units compared with a span of -186 to 35 Hounsfield units for the CT scans of the NSCLC tumors, showing that the phantom's dynamic range includes that of the tumors. The interscanner variability of the feature values depended on both the cartridge material and the feature, and the variability was large relative to the interpatient variability in the NSCLC tumors for some features. The feature interscanner noise was greatest for busyness and least for texture strength. Hierarchical clustering produced different clusters of the phantom scans for each cartridge, although there was some consistent clustering by scanner manufacturer. CONCLUSIONS: The variability in the values of radiomics features calculated on CT images from different CT scanners can be comparable to the variability in these features found in CT images of NSCLC tumors. These interscanner differences should be considered, and their effects should be minimized in future radiomics studies. PMID- 26115367 TI - Positron Emission Tomography/Magnetic Resonance Imaging for Local Tumor Staging in Patients With Primary Breast Cancer: A Comparison With Positron Emission Tomography/Computed Tomography and Magnetic Resonance Imaging. AB - OBJECTIVES: This study aimed to assess the diagnostic performance of integrated positron emission tomography (PET)/magnetic resonance imaging (MRI) of the breast for lesion detection and local tumor staging of patients with primary breast cancer in comparison to PET/computed tomography (CT) and MRI. MATERIALS AND METHODS: The study was approved by the local institutional review board. Forty nine patients with biopsy-proven invasive breast cancer were prospectively enrolled in our study. All patients underwent a PET/CT, and subsequently, a contrast-enhanced PET/MRI of the breast after written informed consent was obtained before each examination. Two radiologists independently evaluated the corresponding data sets (PET/CT, PET/MRI, and MRI) and were instructed to identify primary tumors lesions as well as multifocal/multicentric and bilateral disease. Furthermore, the occurrence of lymph node metastases was assessed, and the T-stage for each patient was determined. Histopathological verification of the local tumor extent and the axillary lymph node status was available for 30 of 49 and 48 of 49 patients, respectively. For the remaining patients, a consensus characterization was performed for the determination of the T-stage and nodal status, taking into account the results of clinical staging, PET/CT, and PET/MRI examinations. Statistical analysis was performed to test for differences in diagnostic performance between the different imaging procedures. P values less than 0.05 were considered to be statistically significant. RESULTS: Positron emission tomography/MRI and MRI correctly identified 47 (96%) of the 49 patients with primary breast cancer, whereas PET/CT enabled detection of 46 (94%) of 49 breast cancer patients and missed a synchronous carcinoma in the contralateral breast in 1 patient. In a lesion-by-lesion analysis, no significant differences could be obtained between the 3 imaging procedures for the identification of primary breast cancer lesions (P > 0.05). Positron emission tomography/MRI and MRI allowed for a correct identification of multifocal/multicentric disease in 3 additional patients if compared with PET/CT. For the definition of the correct T stage, PET/MRI and MRI showed identical results and were correct in significantly more cases than PET/CT (PET/MRI and MRI, 82%; PET/CT, 68%; P < 0.05). Furthermore, the calculated sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for the detection of nodal positive patients (n = 18) were 78%, 94%, 88%, 88%, and 88% for PET/CT; 67%, 87%, 75%, 82%, and 80% for MRI; and 78%, 90%, 82%, 88%, and 86% for PET/MRI, respectively. Differences between the imaging modalities were not statistically significant (P > 0.05). CONCLUSIONS: Integrated PET/MRI does not provide diagnostic advantages for local tumor staging of breast cancer patients in comparison to MRI alone. Positron emission tomography/MRI and MRI enable an improved determination of the local tumor extent in comparison to PET/CT, whereas all 3 imaging modalities offer a comparable diagnostic performance for the identification of axillary disease. PMID- 26115368 TI - Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina. AB - Vascular endothelial cell growth factor (VEGF) is increased in diabetic macular edema. Compound 49b, a novel beta-adrenergic receptor agonist, is protective in a type 1 diabetic rat model. We questioned whether Compound 49b could decrease VEGF levels, suggesting that Compound 49b may be effective against edema. Two-month diabetic rats received topical Compound 49b for 7 days only and/or insulin-like growth factor binding protein 3 (IGFBP-3) siRNA. We also measured endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)zeta and PKCdelta phosphorylation. Retinal endothelial cells (RECs) cultured in high glucose were treated with Compound 49b and IGFBP-3 siRNA for evaluation of the same signaling pathways. Compound 49b significantly decreased VEGF through increased IGFBP-3 in the diabetic retina. Compound 49b also reduced eNOS, PKCzeta and PKCdelta phosphorylation in the diabetic retina and REC. Compound 49b regulated a number of proteins involved in REC barrier properties. PMID- 26115369 TI - Using Plant Functional Traits and Phylogenies to Understand Patterns of Plant Community Assembly in a Seasonal Tropical Forest in Lao PDR. AB - Plant functional traits reflect different evolutionary responses to environmental variation, and among extant species determine the outcomes of interactions between plants and their environment, including other plant species. Thus, combining phylogenetic and trait-based information can be a powerful approach for understanding community assembly processes across a range of spatial scales. We used this approach to investigate tree community composition at Phou Khao Khouay National Park (18 degrees 14'-18 degrees 32'N; 102 degrees 38'- 102 degrees 59'E), Laos, where several distinct forest types occur in close proximity. The aim of our study was to examine patterns of plant community assembly across the strong environmental gradients evident at our site. We hypothesized that differences in tree community composition were being driven by an underlying gradient in soil conditions. Thus, we predicted that environmental filtering would predominate at the site and that the filtering would be strongest on sandier soil with low pH, as these are the conditions least favorable to plant growth. We surveyed eleven 0.25 ha (50x50 m) plots for all trees above 10 cm dbh (1221 individual trees, including 47 families, 70 genera and 123 species) and sampled soils in each plot. For each species in the community, we measured 11 commonly studied plant functional traits covering both the leaf and wood economic spectrum traits and we reconstructed a phylogenetic tree for 115 of the species in the community using rbcL and matK sequences downloaded from Genebank (other species were not available). Finally we compared the distribution of trait values and species at two scales (among plots and 10x10m subplots) to examine trait and phylogenetic community structures. Although there was strong evidence that an underlying soil gradient was determining patterns of species composition at the site, our results did not support the hypothesis that the environmental filtering dominated community assembly processes. For the measured plant functional traits there was no consistent pattern of trait dispersion across the site, either when traits were considered individually or when combined in a multivariate analysis. However, there was a significant correlation between the degree of phylogenetic dispersion and the first principle component axis (PCA1) for the soil parameters. Moreover, the more phylogenetically clustered plots were on sandier soils with lower pH. Hence, we suggest that the community assembly processes across our site may reflect the influence of more conserved traits that we did not measure. Nevertheless, our results are equivocal and other interpretations are possible. Our study illustrates some difficulties in combining trait and phylogenetic approaches that may result from the complexities of integrating spatial and evolutionary processes that vary at different scales. PMID- 26115371 TI - Recognition of fractional non-innocent feature of osmium coordinated 2,2' biimidazole or 2,2'-bis(4,5-dimethylimidazole) and their interactions with anions. AB - Mononuclear complexes [Os(II)(bpy)2(H2L1)](ClO4)2 ([](ClO4)2) and [Os(II)(bpy)2(H2L2)](ClO4)2 ([](ClO4)2) incorporating two free NH protons at the back face of the coordinated H2L, and deprotonated L(2-) bridged symmetric dinuclear complexes [(bpy)2Os(II)(MU-L1(2-))Os(II)(bpy)2)](ClO4)2 ([](ClO4)2) and [(bpy)2Os(II)(MU-L2(2-))Os(II)(bpy)2)](ClO4)2 ([](ClO4)2) (bpy = 2,2'-bipyridine, H2L1 = 2,2'-biimidazole and H2L2 = 2,2'-bis(4,5-dimethylimidazole)) have been characterised. Crystal structures of [](ClO4)2 and the meso (DeltaLambda) diastereomeric form of [](ClO4)2 have been determined. The crystal structure of [](ClO4)2 also reveals the hydrogen bonding interactions between its free acidic NH protons and the oxygen atoms of the perchlorate anion in the nearby asymmetric unit. Experimental and DFT/TD-DFT calculations have divulged the non-innocent feature of the doubly deprotonated L(2-) in (3+) and (3+), leading to the resonating formulation of {Os(II)(MU-L(2-))Os(III)} <-> {Os(II)(MU-L(-))Os(II)}, instead of a simple mixed valent situation {Os(II)(MU-L(2-))Os(III)}. The dinuclear complexes (3+) and (3+) display one broad and moderately intense near IR transition near 1000 nm corresponding to a mixed Os(dpi)/L(pi) -> Os(dpi)/L(pi*) MLLMCT (metal/ligand to ligand/metal charge transfer) transition. Different experimental studies have also established the interaction of (2+) and (2+) with the selective anions. PMID- 26115370 TI - Rasch-ionale for neurologists. AB - Outcome measures are considered the most important tools to monitor patients' outcome in both clinical and research settings. Measuring the clinical state of patients is a fundamental part of our daily clinical practice and research that sometimes is taken for granted. In peripheral neuropathies, there are many scales available, but most of these are at the ordinal level. This paper will systematically address the types of scales available (being nominal, ordinal, interval, or ratio data-based) in terms of their strengths and weaknesses. The differences between classical test theory-based and modern test method-based outcome measures will be addressed with emphasis on Rasch methodology. Various steps will be highlighted as part of the evaluation and construction of outcome measures using the Rasch method, with the aim to increase the knowledge and utility of this technique. We argue that Rasch-built outcome measures should be used for future studies in neuromuscular disorders and their method of construction could be easily extrapolated to other neurological illnesses. PMID- 26115372 TI - Effects of Transcranial Direct Current Stimulation (tDCS) on Pain Distress Tolerance: A Preliminary Study. AB - OBJECTIVE: Pain remains a critical medical challenge. Current treatments target nociception without addressing affective symptoms. Medically intractable pain is sometimes treated with cingulotomy or deep brain stimulation to increase tolerance of pain-related distress. Transcranial direct current stimulation (tDCS) may noninvasively modulate cortical areas related to sensation and pain representations. The present study aimed to test the hypothesis that cathodal ("inhibitory") stimulation targeting left dorsal anterior cingulate cortex (dACC) would increase tolerance to distress from acute painful stimuli vs anodal stimulation. METHODS: Forty healthy volunteers received both anodal and cathodal stimulation. During stimulation, we measured pain distress tolerance with three tasks: pressure algometer, cold pressor, and breath holding. We measured pain intensity with a visual-analog scale before and after each task. RESULTS: Mixed ANOVA revealed that mean cold pressor tolerance tended to be higher with cathodal vs anodal stimulation (P = 0.055) for participants self-completing the task. Pressure algometer (P = 0.81) and breath holding tolerance (P = 0.19) did not significantly differ. The pressure algometer exhibited a statistically significant order effect irrespective of stimulation polarity (all P < 0.008). Pain intensity ratings increased acutely after cold pressor and pressure algometer tasks (both P < 0.01), but not after breath holding (P = 0.099). Cold pressor pain ratings tended to rise less after cathodal vs anodal tDCS (P = 0.072). CONCLUSIONS: Although our primary results were nonsignificant, there is a preliminary suggestion that cathodal tDCS targeting left dACC may increase pain distress tolerance to cold pressor. Pressure algometer results are consistent with task-related sensitization. Future studies are needed to refine this novel approach for pain neuromodulation. PMID- 26115373 TI - Effect of Different Adjuvants on Protection and Side-Effects Induced by Helicobacter suis Whole-Cell Lysate Vaccination. AB - Helicobacter suis (H. suis) is a widespread porcine gastric pathogen, which is also of zoonotic importance. The first goal of this study was to investigate the efficacy of several vaccine adjuvants (CpG-DNA, Curdlan, Freund's Complete and Incomplete, Cholera toxin), administered either subcutaneously or intranasally along with H. suis whole-cell lysate, to protect against subsequent H. suis challenge in a BALB/c infection model. Subcutaneous immunization with Freund's complete (FC)/lysate and intranasal immunization with Cholera toxin (CT)/lysate were shown to be the best options for vaccination against H. suis, as determined by the amount of colonizing H. suis bacteria in the stomach, although adverse effects such as post-immunization gastritis/pseudo-pyloric metaplasia and increased mortality were observed, respectively. Therefore, we decided to test alternative strategies, including sublingual vaccine administration, to reduce the unwanted side-effects. A CCR4 antagonist that transiently inhibits the migration of regulatory T cells was also included as a new adjuvant in this second study. Results confirmed that immunization with CT (intranasally or sublingually) is among the most effective vaccination protocols, but increased mortality was still observed. In the groups immunized subcutaneously with FC/lysate and CCR4 antagonist/lysate, a significant protection was observed. Compared to the FC/lysate immunized group, gastric pseudo-pyloric metaplasia was less severe or even absent in the CCR4 antagonist/lysate immunized group. In general, an inverse correlation was observed between IFN-gamma, IL-4, IL-17, KC, MIP-2 and LIX mRNA expression and H. suis colonization density, whereas lower IL 10 expression levels were observed in partially protected animals. PMID- 26115374 TI - Degree Correlations Optimize Neuronal Network Sensitivity to Sub-Threshold Stimuli. AB - Information processing in the brain crucially depends on the topology of the neuronal connections. We investigate how the topology influences the response of a population of leaky integrate-and-fire neurons to a stimulus. We devise a method to calculate firing rates from a self-consistent system of equations taking into account the degree distribution and degree correlations in the network. We show that assortative degree correlations strongly improve the sensitivity for weak stimuli and propose that such networks possess an advantage in signal processing. We moreover find that there exists an optimum in assortativity at an intermediate level leading to a maximum in input/output mutual information. PMID- 26115375 TI - Comparing equilibrium and kinetic protein unfolding using time-resolved electrospray-coupled ion mobility mass spectrometry. AB - Protein unfolding intermediates are thought to play a critical role in conformational pathogenesis, acting as a 'gateway' to inactivation or pathogenic aggregation. Unfolding intermediates have long been studied either by populating partially-folded species at equilibrium using incresingly denaturing conditions, or by transiently populating 'kinetic' intermediates under fully denaturing conditions using a time-resolved approach (e.g. stopped-flow fluorescence). However, it is not clear that the folding intermediates populated under equilibrium conditions are comparable to intermediates transiently populated in kinetic experiments. In this work, we combine time-resolved electrospray (TRESI) with travelling wave Ion Mobility Spectrometry (IMS) for the first time to directly compare equilibrium and kinetic unfolding intermediates of cytochrome c. Our results show a high degree of correlation between all species populated under these substantially different regimes. PMID- 26115376 TI - Multifaceted control of adult SVZ neurogenesis by the vascular niche. AB - The subventricular zone is one of the 2 germinal niches of the adult brain where neural stem cells (NSC) generate new neurons and glia throughout life. NSC behavior is controlled by the integration of intrinsic signals and extrinsic cues provided by the surrounding microenvironment, or niche. Within the niche, the vasculature has emerged as a critical compartment, to which both neural stem cells and transit-amplifying progenitors are closely associated. A key function of the vasculature is to deliver blood-borne and secreted factors that promote proliferation and lineage progression of committed neural progenitors. We recently found that, in contrast to the established role of soluble cues, juxtacrine signals on vascular endothelial cells maintain neural stem cells in a quiescent and undifferentiated state through direct cell-cell interactions. In this perspective, we discuss how, through these apparently opposing signals, the vascular niche might coordinate stem cell decisions between maintenance and proliferation. PMID- 26115377 TI - Enantioselective Metabolism and Interference on Tryptophan Metabolism of Myclobutanil in Rat Hepatocytes. AB - Myclobutanil, (RS)-2-(4-chlorophenyl)-2-(1H-1, 2, 4-triazol-1-ylmethyl) hexanenitrile is a widely used triazole fungicide. In this study, enantioselective metabolism and cytotoxicity were investigated in rat hepatocytes by chiral HPLC-MS/MS and the methyl tetrazolium (MTT) assay, respectively. Furthermore, tryptophan metabolism disturbance in rat hepatocytes after myclobutanil exposure was also evaluated by target metabolomics method. The half life (t1/2) of (+)-myclobutanil was 10.66 h, whereas that for (-)-myclobutanil was 15.07 h. Such results indicated that the metabolic process of myclobutanil in rat hepatocytes was enantioselective with an enrichment of (-)-myclobutanil. For the cytotoxicity research, the calculated EC50 (12 h) values for rac myclobutanil, (+)- and (-)-myclobutanil were 123.65, 150.65 and 152.60 uM, respectively. The results of tryptophan metabolites profiling showed that the levels of kynurenine (KYN) and XA were both up-regulated compared to the control, suggesting the activation effect of the KYN pathway by myclobutanil and its enantiomers which may provide an important insight into its toxicity mechanism. The data presented here could be useful for the environmental hazard assessment of myclobutanil. PMID- 26115378 TI - Medical equipment libraries: implementation, experience and user satisfaction. AB - The hospital-wide pooling and sharing of certain types of medical equipment can lead to both significant improvements in patient safety and financial advantages when compared with a department or ward-level equipment ownership system. In September 2003, a Medical Equipment Loan Service (MELS) was established, focusing initially on infusion pumps. The aims and expected benefits included; improving availability of equipment for both patients and clinical users, managing and reducing clinical risk, reducing equipment diversity, improving equipment management and reducing the overall cost of equipment provision. A user survey was carried out in 2005 and repeated in 2011. The results showed wide and continued satisfaction with the service. The process and difficulties of establishing the service and its development to include additional types of equipment are described. The benefits of managing medical equipment which is in widespread general use, through a MELS as part of a Clinical Engineering Department, are presented. PMID- 26115379 TI - Correction: Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial. PMID- 26115380 TI - Impact of allowing pharmacists to independently renew prescriptions: A population based study. AB - OBJECTIVES: To study the impact of a 2009 policy change in British Columbia (BC) that allowed pharmacists to independently renew certain prescriptions for chronic conditions. DESIGN: Population-based analysis. SETTING: BC, Canada. PARTICIPANTS: All residents of BC (more than 3.9 million). INTERVENTION: Prescription drug use data were collected from the PharmaNet database. This database contains a record of all ambulatory prescription drug dispensations in BC including a variable indicating whether a pharmacist renewed the prescription. MAIN OUTCOME MEASURES: We studied pharmaceutical and physician insurance claims datasets for all BC residents for 2 years following the 2009 policy change. We assessed the number and types of drugs renewed by pharmacists, and whether these complied with the policy. Further, we matched pharmacist-renewed prescriptions to equivalent potentially renewable prescriptions and assessed the impact on ambulatory physician visits. RESULTS: Over the first 2 years, pharmacists renewed 150,950 prescriptions in BC. Almost one-half of these renewals did not appear to match the conditions set out in the new regulatory policy (n = 69,970, 47%). Those that did match the conditions (n = 80,980, 53%) represented a very small proportion of the 47 million prescriptions that pharmacists could have renewed (0.17%). The most frequently renewed medications were treatments for dyslipidemias, hypertension, diabetes, and gastroesophageal reflux disease. Pharmacist-renewed prescriptions were preceded by a 30% relative decrease in ambulatory physician visits in the week before dispensing, but there was also a 17% relative increase in visits in the week following the pharmacist-renewed prescription. CONCLUSION: Overall, the use of pharmacist renewals was very low and one-half of the renewals were not policy-concordant. Pharmacist renewals were associated with the intended reductions in physician visits before dispensing, but there was also an unintended increase in visits after dispensing. These findings suggest that future policies such as this one need to be differently designed and closely monitored. PMID- 26115381 TI - Differences in reporting Pearl Indices in the United States and Europe: Focus on a 91-day extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation. AB - BACKGROUND: Regulatory agencies in the United States (US) and Europe differ in requirements for defining pregnancies after the last dose of oral contraceptive, sometimes resulting in discrepant Pearl Indices (PIs) for the same product despite identical clinical data. This brief report highlights one such example, a 91-day extended-regimen combined oral contraceptive (COC). METHODS: The US- and European-based PI methodologies were compared for a 91-day extended-regimen COC consisting of 84 days of active levonorgestrel/EE 150 MUg/30 MUg tablets, followed by seven days of EE 10 MUg tablets in place of placebo. CONCLUSIONS: At the times of approval of the 91-day extended-regimen COC in the US and Europe, the requirements for defining 'on-treatment' pregnancies differed (14-day vs. 2 day rule, respectively). This difference resulted in a higher PI in the US- vs. European-based calculation (1.34 and 0.76, respectively). The differences in the PI should not be interpreted as the extended-regimen COC being less effective in preventing pregnancy in the US compared with Europe. PMID- 26115382 TI - Biomimetic modification of silicone tubes using sodium nitrite-collagen immobilization accelerates endothelialization. AB - Biomimetic coatings to increase endothelialization of blood-contacting materials in biomedical devices are promising to improve the biocompatibility of these devices. Although a stable extracellular matrix protein coating on a biomaterial's surface is a prerequisite for endothelial cell attachment, it also stimulates platelet adhesion. Therefore, antithrombotic additives, such as nitric oxide donors, to a stable protein coating might lead to successful endothelialization of a material's surface. We aimed to test whether immobilized bioactive nitrite and acidified nitrite-generating sodium nitrite-collagen conjugate on silicone tubes enhances endothelialization by increasing the number of endothelial cells as well as growth hormone production and by decreasing platelet adhesion. Stable collagen immobilization on acrylic acid-grafted silicone tubes decreased the water contact angle from 102 degrees to 56 degrees . Initial 25 uM sodium nitrite in conjugate resulted in maximal growth hormone production (2.5-fold increase) and endothelial cell number (1.8-fold increase) after 2 days. A 95% confluent endothelial cell monolayer on sodium nitrite collagen conjugate coating was obtained after 6 days. Maximum (2.7-fold) inhibition of platelet adhesion was reached with initial 500 uM sodium nitrite in conjugate. Our data showing that sodium nitrite-collagen conjugate coating with 25-50 uM sodium nitrite on silicone tubes increases the number of endothelial cells attached and inhibits platelet adhesion suggest that this coating is highly promising for use in blood-contacting parts of biomedical devices. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1311-1321, 2016. PMID- 26115383 TI - Amino acid analysis using chromatography-mass spectrometry: An inter platform comparison study. AB - The analysis of amino acids has become a central task in many aspects. While amino acid analysis has traditionally mainly been carried out using either gas chromatography (GC) in combination with flame ionization detection or liquid chromatography (LC) with either post-column derivatization using ninhydrin or pre column derivatization using o-phthalaldehyde, many of today's analysis platforms are based on chromatography in combination with mass spectrometry (MS). While derivatization is mandatory for the GC-based analysis of amino acids, several LC platforms have emerged, particularly in the dawn of targeted metabolite profiling using hydrophilic interaction liquid chromatography (HILIC) coupled to MS, allowing the analysis of underivatized amino acids. Among the numerous analytical platforms available for amino acid analysis today, we here compare three prominent approaches, being GC-MS and LC-MS after amino acid derivatization using chloroformate and HILIC-MS of underivatized amino acids. We compare and discuss practical issues as well as performance characteristics, e.g., the use of (13)C labeled internal standards, of the different platforms and present data on their practical implementation in our laboratory. Finally, we compare the real-life applicability of all three platforms for a complex biological sample. While all three platforms are very-well suited for the analysis of complex biological samples they all show advantages and disadvantages for some analytes as discussed in detail in this manuscript. PMID- 26115384 TI - Exclusive Breastfeeding Rates in Latin America. PMID- 26115385 TI - Focal Adhesion Proteins alpha- and beta-Parvin are Overexpressed in Human Colorectal Cancer and Correlate with Tumor Progression. AB - This study aims to address the role of focal adhesion proteins alpha- and beta parvin in human colorectal carcinoma (CRC). Expression of alpha- and beta-parvin was examined by immunohistochemistry and real-time RT-PCR in a series of human CRC. Parvins were overexpressed in CRC and their expression correlated significantly with tumor invasion, lymph node metastasis, and disease stage. A significant positive correlation of parvins protein expression with overexpression of integrin-linked kinase, p-AKT, and nuclear beta-catenin, as well as with downregulation of E-cadherin was also observed. In conclusion, overexpression of alpha- and beta-parvin seems to be implicated in human colorectal cancer progression. PMID- 26115389 TI - Treatment of afferent limb syndrome: novel approach with endoscopic ultrasound guided creation of a gastrojejunostomy fistula and placement of lumen-apposing stent. PMID- 26115388 TI - Nucleophilic Hydroxylation in Water Media Promoted by a Hexa-Ethylene Glycol Bridged Dicationic Ionic Liquid. AB - Hexaethylene glycol bis(3-hexaethylene glycol imidazolium) dimesylate ionic liquid (hexaEG-DHIM) was designed and prepared as a highly efficient promoter for the nucleophilic hydroxylation of alkyl halides to the corresponding alcohol products in neat water media. It was observed that hexaEG-DHIM promoter enhanced the nucleophilicity of water significantly in the reaction. In addition, the hexaEG-DHIM could be reused several times without loss of activity. Moreover, the hydroxylation reactions of base-sensitive and/or polar alkyl halide substrates proceeded highly chemoselectively in excellent yields. PMID- 26115390 TI - Stent migration into the peritoneal cavity following endoscopic ultrasound-guided hepaticogastrostomy. PMID- 26115386 TI - Effect of Structured Physical Activity on Sleep-Wake Behaviors in Sedentary Elderly Adults with Mobility Limitations. AB - OBJECTIVES: To evaluate the effect of structured physical activity on sleep-wake behaviors in sedentary community-dwelling elderly adults with mobility limitations. DESIGN: Multicenter, randomized trial of moderate-intensity physical activity versus health education, with sleep-wake behaviors prespecified as a tertiary outcome over a planned intervention period ranging from 24 to 30 months. SETTING: Lifestyle Interventions and Independence for Elders Study. PARTICIPANTS: Community-dwelling persons aged 70 to 89 who were initially sedentary and had a Short Physical Performance Battery score less than 10 (N = 1,635). MEASUREMENTS: Sleep-wake behaviors were evaluated using the Insomnia Severity Index (ISI) (>=8 defined insomnia), Epworth Sleepiness Scale (ESS) (>=10 defined daytime drowsiness), and Pittsburgh Sleep Quality Index (PSQI) (>5 defined poor sleep quality) administered at baseline and 6, 18, and 30 months. RESULTS: The randomized groups were similar in terms of baseline demographic variables, including mean age (79) and sex (67% female). Structured physical activity resulted in a significantly lower likelihood of having poor sleep quality (adjusted odds ratios (aOR) for PSQI >5 = 0.80, 95% confidence interval (CI) = 0.68-0.94), including fewer new cases (aOR for PSQI >5 = 0.70, 95% CI = 0.54 0.89), than health education but not in resolution of prevalent cases (aOR for PSQI <=5 = 1.13, 95% CI = 0.90-1.43). No significant intervention effects were observed for the ISI or ESS. CONCLUSION: Structured physical activity resulted in a lower likelihood of developing poor sleep quality (PSQI >5) over the intervention period than health education but had no effect on prevalent cases of poor sleep quality or on sleep-wake behaviors evaluated using the ISI or ESS. These results suggest that the benefit of physical activity in this sample was preventive and limited to sleep-wake behaviors evaluated using the PSQI. PMID- 26115391 TI - Endoscopic closure of tracheoesophageal fistula with submucosal dissection and a biosynthetic mesh. PMID- 26115392 TI - Microscopic (collagenous) colitis in a patient with a heart transplant. PMID- 26115393 TI - Hepatic subcapsular biloma complicating laparoscopic cholecystectomy. PMID- 26115394 TI - Effective use of the "clip-flap" method for the endoscopic submucosal dissection of a difficult-to-approach superficial gastric tumor. PMID- 26115395 TI - Closure of a cervical esophageal perforation with an over-the-scope clip. PMID- 26115396 TI - Endoscopic sclerotherapy with a high concentration of n-butyl-2-cyanoacrylate for anastomotic varices after choledochojejunostomy. PMID- 26115398 TI - Enteropathy-associated T-cell lymphoma: involvement of the gastrointestinal tract from the duodenum to the rectum. PMID- 26115397 TI - Definitive endoscopic pyloric exclusion with an over-the-scope clip. PMID- 26115399 TI - Hemospray rescue treatment of gastroenteric anastomotic bleeding. PMID- 26115400 TI - Heterotopic gastric mucosa mimicking a rectal submucosal tumor. PMID- 26115401 TI - Tracheo-esophageal fistula following spontaneous migration of a missed impacted denture. PMID- 26115402 TI - Innovative Technological Approach to Ebola Virus Disease Outbreak Response in Nigeria Using the Open Data Kit and Form Hub Technology. AB - The recent outbreak of Ebola Virus Disease (EVD) in West Africa has ravaged many lives. Effective containment of this outbreak relies on prompt and effective coordination and communication across various interventions; early detection and response being critical to successful control. The use of information and communications technology (ICT) in active surveillance has proved to be effective but its use in Ebola outbreak response has been limited. Due to the need for timeliness in reporting and communication for early discovery of new EVD cases and promptness in response; it became imperative to empower the response team members with technologies and solutions which would enable smooth and rapid data flow. The Open Data Kit and Form Hub technology were used in combination with the Dashboard technology and ArcGIS mapping for follow up of contacts, identification of cases, case investigation and management and also for strategic planning during the response. A remarkable improvement was recorded in the reporting of daily follow-up of contacts after the deployment of the integrated real time technology. The turnaround time between identification of symptomatic contacts and evacuation to the isolation facility and also for receipt of laboratory results was reduced and informed decisions could be taken by all concerned. Accountability in contact tracing was ensured by the use of a GPS enabled device. The use of innovative technologies in the response of the EVD outbreak in Nigeria contributed significantly to the prompt control of the outbreak and containment of the disease by providing a valuable platform for early warning and guiding early actions. PMID- 26115403 TI - New Metrics for Evaluating Viral Respiratory Pathogenesis. AB - Viral pathogenesis studies in mice have relied on markers of severe systemic disease, rather than clinically relevant measures, to evaluate respiratory virus infection; thus confounding connections to human disease. Here, whole-body plethysmography was used to directly measure changes in pulmonary function during two respiratory viral infections. This methodology closely tracked with traditional pathogenesis metrics, distinguished both virus- and dose-specific responses, and identified long-term respiratory changes following both SARS-CoV and Influenza A Virus infection. Together, the work highlights the utility of examining respiratory function following infection in order to fully understand viral pathogenesis. PMID- 26115404 TI - The Knowledge of Rehabilitation Professionals Concerning Fetal Alcohol Spectrum Disorders. AB - The purpose of this study was to explore rehabilitation professionals' knowledge regarding signs and symptoms, prevention, and intervention of fetal alcohol spectrum disorders (FASD). Participants were 111 rehabilitation practitioners (e.g., occupational therapy, physical therapy, and speech-language pathology practitioners) recruited through email using a quantitative online survey design with purposive, snowball sampling. Results showed the majority of participants' demonstrated accurate knowledge of the signs and symptoms of FASD. Since professionals who received formal education on FASD reported significantly higher feelings of preparedness to identify children with FASD and manage/coordinate intervention plans, this study suggests rehabilitation professionals may be better prepared to treat individuals with FASD if they participate in formal training. PMID- 26115405 TI - Thermodynamic Functions of Solvation of Hydrocarbons, Noble Gases, and Hard Spheres in Tetrahydrofuran-Water Mixtures. AB - Thermodynamic solvation properties of mixtures of water with tetrahydrofuran at 298 K are studied. The Gibbs free energies and enthalpies of solvation of n octane and toluene are determined experimentally. For molecular dynamics simulations of the binary solvent, we have modified a TraPPE-UA model for tetrahydrofuran and combined it with the SPC/E potential for water. The excess thermodynamic functions of neon, xenon, and hard spheres with two different radii are calculated using the particle insertion method. Simulated and real systems share the same characteristic trends for the thermodynamic functions. A maximum is present on dependencies of the enthalpy of solvation from the composition of solvent at 70-90 mol % water, making it higher than in both of the cosolvents. It is caused by a high enthalpy of cavity formation in the mixtures rich with water due to solvent reorganization around the cavity, which is shown by calculation of the enthalpy of solvation of hard spheres. Addition of relatively small amounts of tetrahydrofuran to water effectively suppresses the hydrophobic effect, leading to a quick increase of both the entropy and enthalpy of cavity formation and solvation of low polar molecules. PMID- 26115407 TI - Antipsychotic treatment and the risk of hip fracture in subjects with schizophrenia: a 10-year population-based case-control study. AB - BACKGROUND: To investigate the association between antipsychotic treatment and risk of hip fracture in subjects with schizophrenia. METHOD: Among patients with schizophrenia (ICD-9-CM code 295), 605 cases with hip fracture and 2,828 matched controls were identified from 2002 to 2011 using the National Health Insurance Research Database in Taiwan. The authors conducted a nested case-control study to investigate the association between antipsychotic treatment and risk of hip fracture in subjects with schizophrenia. The modifiable effects of age and gender were evaluated by stratified analysis. In addition, the effects of antipsychotic use, antipsychotic classes, and receptor-binding profiles of antipsychotics, individually, on hip fracture were estimated, and potential confounding factors were adjusted in subsequent analysis. Conditional logistic regressions were applied to determine the effect of antipsychotic treatment on hip fracture. RESULTS: Current antipsychotic use was associated with an increased risk for hip fracture (adjusted odds ratio [AOR] = 1.61; 95% CI, 1.24-2.10). Among current users, new users had a higher risk of hip fracture (AOR = 4.28; 95% CI, 1.76 10.36) than past users (AOR = 1.11; 95% CI, 0.79-1.56). In addition, a significant increased risk of hip fracture was noted in schizophrenia subjects with first-generation antipsychotic use (AOR = 1.59; 95%CI, 1.15-2.20) but not in those with second-generation antipsychotic use (AOR = 1.16; 95% CI, 0.91-1.48). CONCLUSIONS: These results extend previous findings and demonstrate an increased risk of hip fracture associated with antipsychotic use in schizophrenia subjects. Further investigation is needed to dissect the underlying mechanisms related to the effect of antipsychotic use on hip fracture in subjects at risk. PMID- 26115406 TI - Lipopolysaccharide-Induced CXCL10 mRNA Level and Six Stimulant-mRNA Combinations in Whole Blood: Novel Biomarkers for Bortezomib Responses Obtained from a Prospective Multicenter Trial for Patients with Multiple Myeloma. AB - To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients. PMID- 26115408 TI - Patterns of Irregular Burials in Western Europe (1st-5th Century A.D.). AB - BACKGROUND: Irregular burials (IB--burials showing features that contrast with the majority of others in their geographic and chronological context) have been the focus of archaeological study because of their relative rarity and enigmatic appearance. Interpretations of IB often refer to supposed fear of the dead or to social processes taking place in time-specific contexts. However, a comprehensive and quantitative analysis of IB for various geographical contexts is still lacking, a fact that hampers any discussion of these burials on a larger scale. METHODS: Here, we collected a bibliographic dataset of 375 IB from both Britain and Continental Europe, altogether spanning a time period from the 1st to the 5th century AD. Each burial has been coded according to ten dichotomous variables, further analyzed by means of chi-squared tests on absolute frequencies, non metric multidimensional scaling, and cluster analysis. RESULTS: Even acknowledging the limits of this study, and in particular the bias represented by the available literature, our results point to interesting patterns. Geographically, IB show a contrast between Britain and Continental Europe, possibly related to historical processes specific to these regions. Different types of IB (especially prone depositions and depositions with the cephalic extremity displaced) present a series of characteristics and associations between features that permit a more detailed conceptualization of these occurrences from a socio-cultural perspective that aids to elucidate their funerary meaning. CONCLUSIONS AND SIGNIFICANCE: Altogether, the present work stresses the variability of IB, and the need to contextualize them in a proper archaeological and historical context. It contributes to the discussion of IB by providing a specific geographic and chronological frame of reference that supports a series of hypotheses about the cultural processes possibly underlying their occurrence. PMID- 26115409 TI - Surgery for Glioblastoma: Impact of the Combined Use of 5-Aminolevulinic Acid and Intraoperative MRI on Extent of Resection and Survival. AB - BACKGROUND: There is rising evidence that in glioblastoma (GBM) surgery an increase of extent of resection (EoR) leads to an increase of patient's survival. Based on histopathological assessments tumor depiction of Gd-DTPA enhancement and 5-aminolevulinic-acid-fluorescence (5-ALA) might be synergistic for intraoperative resection control. OBJECTIVE: To assess impact of additional use of 5-ALA in intraoperative MRI (iMRI) assisted surgery of GBMs on extent of resection (EoR), progression free survival (PFS) and overall survival (OS). METHODS: We prospectively enrolled 33 patients with GBMs eligible for gross-total resection(GTR) and performed a combined approach using 5-ALA and iMRI. As a control group, we performed a retrospective matched pair assessment, based on 144 patients with iMRI-assisted surgery. Matching criteria were, MGMT promotor methylation, recurrent surgery, eloquent location, tumor size and age. Only patients with an intended GTR and primary GBMs were included. We calculated Kaplan Mayer estimates to compare OS and PFS using the Log-Rank-Test. We used the T-test to compare volumetric results of EoR and the Chi-Square-Test to compare new permanent neurological deficits (nPND) and general complications between the two groups. RESULTS: Median follow up was 31 months. No significant differences between both groups were found concerning the matching criteria. GTR was achieved significantly more often (p <0.010) using 5-ALA&iMRI (100%) compared to iMRI alone (82%). Mean EoR was significantly (p<0.004) higher in 5-ALA&iMRI-group (99.7%) than in iMRI-alone-group (97.4%) Rate of complications did not differ significantly between groups (21% iMRI-group, 27%5-ALA&iMRI-group, p<0.518). nPND were found in 6% in both groups. Median PFS (6 mo resp.; p<0.309) and median OS (iMRI:17 mo; 5-ALA&iMRI-group: 18 mo; p<0.708)) were not significantly different between both groups. CONCLUSION: We found a significant increase of EoR when combining 5-ALA&iMRI compared to use of iMRI alone. Maximizing EoR did not lead to an increase of complications or neurological deficits if used with neurophysiological monitoring in eloquent lesions. No final conclusion can be drawn whether a further increase of EoR benefits patient's progression free survival and overall survival. PMID- 26115411 TI - Transperitoneal Laparoscopic Approach to the Perinephric Area in Children: Technical Report and Lessons Learned. AB - PURPOSE: This study presents a technical report of a standardized approach to the perinephric area in a series of pediatric patients, demonstrating that whatever renal or suprarenal surgery is planned, this can be approached and accomplished laparoscopically with an identical or very similar port triangulation, thus facilitating the learning curve within the same surgical team. PATIENTS AND METHODS: All patients undergoing renal and adrenal gland surgery with a minimally invasive approach in the period from October 2008 to November 2013 were retrospectively reviewed and included in the study. Technical details and clinical outcomes are described. RESULTS: In total, 68 patients matched the inclusion criteria and were therefore retrospectively examined. No major intraoperative complication occurred. Two patients developed recurrent pelvic ureteric junction obstruction and were managed with double J stent positioning and laparoscopic dismembered pyeloplasty, respectively. Two patients presenting with adrenal mass experienced a moderate bleeding that could be treated conservatively. CONCLUSIONS: Thanks to the reproducibility of the procedure and on the grounds of the presented experience, we support the proposal that the transperitoneal laparoscopic approach to the kidney and the adrenal gland could represent a relatively easy and safe way to quickly achieve confidence and skill in the management of related diseases. PMID- 26115410 TI - Mechanisms Underlying Latent Disease Risk Associated with Early-Life Arsenic Exposure: Current Research Trends and Scientific Gaps. AB - BACKGROUND: Millions of individuals worldwide, particularly those living in rural and developing areas, are exposed to harmful levels of inorganic arsenic (iAs) in their drinking water. Inorganic As exposure during key developmental periods is associated with a variety of adverse health effects, including those that are evident in adulthood. There is considerable interest in identifying the molecular mechanisms that relate early-life iAs exposure to the development of these latent diseases, particularly in relationship to cancer. OBJECTIVES: This work summarizes research on the molecular mechanisms that underlie the increased risk of cancer development in adulthood that is associated with early-life iAs exposure. DISCUSSION: Epigenetic reprogramming that imparts functional changes in gene expression, the development of cancer stem cells, and immunomodulation are plausible underlying mechanisms by which early-life iAs exposure elicits latent carcinogenic effects. CONCLUSIONS: Evidence is mounting that relates early-life iAs exposure and cancer development later in life. Future research should include animal studies that address mechanistic hypotheses and studies of human populations that integrate early-life exposure, molecular alterations, and latent disease outcomes. PMID- 26115413 TI - Temporal Trends of In-Hospital Mortality in Patients Treated with Intra-Aortic Balloon Pumping: A Nationwide Population Study in Taiwan, 1998-2008. AB - Intra-aortic balloon pumping (IABP) is widely used for hemodynamic support in critical patients with cardiogenic shock (CS). We examined whether the in hospital mortality of patients in Taiwan treated with IABP has recently declined. We used Taiwan's National Health Insurance Research Database to retrospectively review the in-hospital all-cause mortality of 9952 (7146 men [71.8%]) 18-year-old and older patients treated with IABP between 1998 and 2008. The mortality rate was 13.84% (n = 1377). The urbanization levels of the hospitals, and the number of days in the intensive care unit, of hospitalization, and of IABP treatment, and prior percutaneous coronary intervention (PCI) were associated with mortality. Seven thousand six hundred thirty-five patients (76.72%) underwent coronary artery bypass grafting (CABG) surgery, and 576 (5.79%) underwent high risk PCI with IABP treatment. The number of patients treated with IABP significantly increased during this decade (ptrend < 0.0001), the in-hospital all cause mortality for patients treated with IABP significantly decreased (ptrend = 0.0243), but the in-hospital all-cause mortality of patients who underwent CABG and PCI plus IABP did not decrease. In conclusion, the in-hospital mortality rate of IABP treatment decreased annually in Taiwan during the study period. However, high-risk patients who underwent coronary revascularization with IABP had a higher and unstable in-hospital mortality rate. PMID- 26115412 TI - Matrix rigidity regulates the transition of tumor cells to a bone-destructive phenotype through integrin beta3 and TGF-beta receptor type II. AB - Cancer patients frequently develop skeletal metastases that significantly impact quality of life. Since bone metastases remain incurable, a clearer understanding of molecular mechanisms regulating skeletal metastases is required to develop new therapeutics that block establishment of tumors in bone. While many studies have suggested that the microenvironment contributes to bone metastases, the factors mediating tumors to progress from a quiescent to a bone-destructive state remain unclear. In this study, we hypothesized that the "soil" of the bone microenvironment, specifically the rigid mineralized extracellular matrix, stimulates the transition of the tumor cells to a bone-destructive phenotype. To test this hypothesis, we synthesized 2D polyurethane (PUR) films with elastic moduli ranging from the basement membrane (70 MPa) to cortical bone (3800 MPa) and measured expression of genes associated with mechanotransduction and bone metastases. We found that expression of Integrin beta3 (Ibeta3), as well as tumor produced factors associated with bone destruction (Gli2 and parathyroid hormone related protein (PTHrP)), significantly increased with matrix rigidity, and that blocking Ibeta3 reduced Gli2 and PTHrP expression. To identify the mechanism by which Ibeta3 regulates Gli2 and PTHrP (both are also known to be regulated by TGF beta), we performed Forster resonance energy transfer (FRET) and immunoprecipitation, which indicated that Ibeta3 co-localized with TGF-beta Receptor Type II (TGF-beta RII) on rigid but not compliant films. Finally, transplantation of tumor cells expressing Ibeta3 shRNA into the tibiae of athymic nude mice significantly reduced PTHrP and Gli2 expression, as well as bone destruction, suggesting a crucial role for tumor-produced Ibeta3 in disease progression. This study demonstrates that the rigid mineralized bone matrix can alter gene expression and bone destruction in an Ibeta3/TGF-beta-dependent manner, and suggests that Ibeta3 inhibitors are a potential therapeutic approach for blocking tumor transition to a bone destructive phenotype. PMID- 26115414 TI - Tigecycline in the Treatment of Patients with Necrotizing Skin and Soft Tissue Infections Due to Multiresistant Bacteria. AB - BACKGROUND: Necrotizing skin and soft tissue infections (NSTI) form a group of aggressive diseases that require radical debridement for infection control. Simultaneously, a high-dose broad spectrum antibiotic regimen needs to be initiated with control of septic complications in the intensive care setting. The aim of this work is to analyze the efficacy and safety of tigecycline in a subpopulation of hospitalized, severely ill surgical NSTI patients who were documented in a large multicenter non-interventional study on tigecycline use in routine clinical practice. METHODS: A total of 1,025 patients with severe infections including complicated skin and soft-tissue infections (cSSTI, n=163; 15,9%) were enrolled in a prospective multi-center non-interventional study. Patients were to receive an initial intravenous dose of 100 mg tigecycline, followed by 50 mg twice daily. Prospectively documented parameters included clinical findings, APACHE II score, microbiological and standard laboratory assessments, surgical measures, and clinical outcomes including adverse events. RESULTS: Of 163 patients were treated for cSSTI, with the largest subgroup being NSTI patients (n=50, 30.7% of all cSSTI, mean age 61 y, median APACHE II score 20). Forty-eight NSTI patients (96%) had at least one comorbidity. In 80% of patients, the treatment was started after previous antibiotic treatment had failed and in 34% resistant pathogens were isolated (28% methicillin resistant Staphyloccocus aureus [MRSA], 4% extended-spectrum-beta-lactamase (ESBL) producing bacteria, and 2% vancomycin-resistant Enterococci (VRE). Tigecycline was administered as a single agent in 32 patients; 17 received combination regimens. Data from one patient were not reported. Rates of clinical cure or improvement with tigecycline treatment were 90.2%. Two patients (4%) had drug related adverse events (one thrombocytopenia and one fever/chills); 10 patients (20%) died. CONCLUSIONS: Tigecycline alone or in combination therapy was an effective and safe antibiotic treatment in critically ill and antimicrobially pre treated patients with NSTI frequently caused by resistant pathogens. PMID- 26115415 TI - The Impact of IL28B Genotype and Liver Fibrosis on the Hepatic Expression of IP10, IFI27, ISG15, and MX1 and Their Association with Treatment Outcomes in Patients with Chronic Hepatitis C. AB - The strong impact of interleukin 28B (IL28B) polymorphisms on sustained virological response (SVR) after peginterferon and ribavirin treatment in patients with chronic hepatitis C (CHC) is well-known. We investigated IL28B variability and hepatic expression of IP10, IFI27, ISG15, and MX1 in CHC patients, the relation of each with their clinical characteristics, and how they associated with responses to combined therapy. Genotyping and gene expression analysis were conducted in a selected cohort of treatment-naive patients who underwent interferon and ribavirin treatment. Differential expression of IP10, IFI27, ISG15, and MX1 genes was assessed from pretreatment liver biopsies using quantitative PCR. Histopathological evaluation of liver specimens was performed on the basis of the Scheuer's modified scale. We showed that hepatic IFI27, ISG15, and MX1 expression was lower in the IL28B CC 12979860 and TT rs8099917 groups than in the CT-TT rs12979860 and TG-GG rs8099917 groups (P < 0.001). We found no differences in IP10 expression between the IL28B genotypes (P > 0.05); in contrast, IP10 expression was significantly affected by the progression of fibrosis (P = 0.007). We showed that the rs12979860 CC genotype was associated with successful treatment when compared to the rs12979860 CT-TT genotype (P = 0.004). Additionally, the expression levels of IP10, IFI27 and ISG15, but not MX1, were significantly higher in non-SVR patients than in SVR patients. The effect of variation in IL28B on the results of IFN-based treatment may be associated with changes in IFI27 and ISG15, but not with IP10. Silencing of IP10 is positive and independent from IL28B prediction of SVR, which is strongly associated with liver fibrosis in CHC patients. PMID- 26115416 TI - Microelectromechanically tunable multiband metamaterial with preserved isotropy. AB - We experimentally demonstrate a micromachined reconfigurable metamaterial with polarization independent characteristics for multiple resonances in terahertz spectral region. The metamaterial unit cell consists of eight out-of-plane deformable microcantilevers placed at each corner of an octagon ring. The octagon shaped unit cell geometry provides the desired rotational symmetry, while the out of-plane movable cantilevers preserves the symmetry at different configurations of the metamaterial. The metamaterial is shown to provide polarization independent response for both electrical inductive-capacitive (eLC) resonance and dipolar resonance at all states of actuation. The proposed metamaterial has a switching range of 0.16 THz and 0.37 THz and a transmission intensity change of more than 0.2 and 0.7 for the eLC and dipolar resonances, respectively for both TE and TM modes. Further optimization of the metal layer thickness, provides an improvement of up to 80% modulation at 0.57 THz. The simultaneously tunable dual band isotropic metamaterial will enable the realization of high performance electro-optic devices that would facilitate numerous terahertz applications such as compressive terahertz imaging, miniaturized terahertz spectroscopy and next generation high speed wireless communication possible in the near future. PMID- 26115418 TI - Experimental and DFT Studies Explain Solvent Control of C-H Activation and Product Selectivity in the Rh(III)-Catalyzed Formation of Neutral and Cationic Heterocycles. AB - A range of novel heterocyclic cations have been synthesized by the Rh(III) catalyzed oxidative C-N and C-C coupling of 1-phenylpyrazole, 2-phenylpyridine, and 2-vinylpyridine with alkynes (4-octyne and diphenylacetylene). The reactions proceed via initial C-H activation, alkyne insertion, and reductive coupling, and all three of these steps are sensitive to the substrates involved and the reaction conditions. Density functional theory (DFT) calculations show that C-H activation can proceed via a heteroatom-directed process that involves displacement of acetate by the neutral substrate to form charged intermediates. This step (which leads to cationic C-N coupled products) is therefore favored by more polar solvents. An alternative non-directed C-H activation is also possible that does not involve acetate displacement and so becomes favored in low polarity solvents, leading to C-C coupled products. Alkyne insertion is generally more favorable for diphenylacetylene over 4-octyne, but the reverse is true of the reductive coupling step. The diphenylacetylene moiety can also stabilize unsaturated seven-membered rhodacycle intermediates through extra interaction with one of the Ph substituents. With 1-phenylpyrazole this effect is sufficient to suppress the final C-N reductive coupling. A comparison of a series of seven membered rhodacycles indicates the barrier to coupling is highly sensitive to the two groups involved and follows the trend C-N(+) > C-N > C-C (i.e., involving the formation of cationic C-N, neutral C-N, and neutral C-C coupled products, respectively). PMID- 26115419 TI - The nutritional role of free sialic acid, a human milk monosaccharide, and its application as a functional food ingredient. AB - N-Acetyl-d-neuraminic acid (NANA), more commonly known by its trivial name sialic acid, is an endogenous human and ubiquitous nutritional monosaccharide. As a bound sugar at the terminal positions of glycans NANA is known to play important roles in many biological events. The data that exist on the occurrence of the free monosaccharide in breast milk and nutrition, however, are less commonly discussed. In most foods of animal origin, sialic acid occurs as a mixture of NANA and N-glycolyl-d-neuraminic acid (NGNA), a hydroxylated derivative of NANA that is not found in humans. The dietary intake of NGNA has been identified as a risk factor for long-term adverse health effects. Therefore, we present summaries on the biochemistry, metabolism, bioavailability, and the data on NANA and NGNA levels that occur in diverse foods. Finally, we discuss the emerging data demonstrating that free NANA is linked to positive nutritional effects including pronounced antioxidative properties. These data and the extremely high safety profile of NANA justify dietary enrichment at levels that correspond to the dietary intake of NANA in infants through breast milk. PMID- 26115420 TI - The Effects of Doming of the Diaphragm in Subjects With Short-Hamstring Syndrome: A Randomized Controlled Trial. AB - CONTEXT: Taking into account the complex structure of the diaphragm and its important role in the postural chain, the authors were prompted to check the effects of a diaphragm technique on hamstring flexibility. OBJECTIVE: To evaluate the effects of the doming-of-the-diaphragm (DD) technique on hamstrings flexibility and spine mobility. DESIGN: Randomized placebo-controlled trial. SETTING: University laboratory. PATIENTS: Sixty young adults with short-hamstring syndrome were included in this randomized clinical trial using a between-groups design. INTERVENTION: The sample was randomly allocated to a placebo group (n = 30) or an intervention group (n = 30). Duration, position, and therapist were the same for both treatments. MAIN OUTCOME MEASURES: Hamstring flexibility was assessed using the forward-flexion-distance (FFD) and popliteal-angle test (PAT). Spinal motion was evaluated using the modified Schober test and cervical range of movement. RESULTS: Two-way ANOVA afforded pre- to postintervention statistically significant differences (P < .001) in the intervention group compared with the placebo group for hamstring flexibility measured by the FFD (mean change 4.59 +/- 5.66 intervention group vs 0.71 +/- 2.41 placebo group) and the PAT (mean change intervention group 6.81 +/- 8.52 vs placebo group 0.57 +/- 4.41). Significant differences (P < .05) were also found in the modified Schober test (mean change intervention group -1.34 +/- 3.95 vs placebo group 1.02 +/- 3.05) and cervical range of movement. Significant between-groups differences (P < .05) were also found in all the variables measured. CONCLUSIONS: The DD technique provides sustained improvement in hamstring flexibility and spine mobility. PMID- 26115422 TI - PAX5 alterations in genetically unclassified childhood Precursor B-cell acute lymphoblastic leukaemia. AB - Here, we report a high incidence of PAX5 abnormalities observed in 32/68 (47%) of patients with genetically unclassified childhood precursor B-cell acute lymphoblastic leukaemia (pre-B ALL). Various deletions, gains, mutations and rearrangements of PAX5 comprised 45%, 12%, 29% and 14%, respectively, of the abnormalities found. 28% of patients showed more than one abnormality of the gene, implying bi-allelic impairment of PAX5. Novel PAX5-RHOXF2, PAX5-ELK3 and PAX5-CBFA2T2 rearrangements, which lead to aberrant expression of PAX5, were also identified. PAX5 rearrangements demonstrated a complex mechanism of formation including concurrent duplications/deletions of PAX5 and its partner genes. Finally, the splice variant c.1013-2A>G, seen in two patients with loss of one PAX5 allele, was confirmed to be germ-line in one patient and somatic in the other. PAX5 alterations were also found to be clinically associated with a higher white blood cell count (P = 0.015). These findings contribute to the knowledge of PAX5 alterations and their role in the pathogenesis of pre-B ALL. PMID- 26115421 TI - Cytokine Kinetics in the First Week of Tuberculosis Therapy as a Tool to Confirm a Clinical Diagnosis and Guide Therapy. AB - BACKGROUND: Many patients treated for tuberculosis (TB) in low and middle income countries are treated based on clinical suspicion without bacteriological confirmation. This is often due to lack of rapid simple accurate diagnostics and low healthcare provider confidence in the predictive value of current tests. We previously reported in an animal TB model that levels of host markers rapidly change in response to treatment initiation. METHODS: We assessed the potential of host biomarker kinetics of TB patients during the first two weeks of therapy to identify patients responding to treatment. Adult patients clinically diagnosed with and treated for TB, 29 in Nigeria and 24 in Nepal, were analyzed. RESULTS: Changes in concentrations of non-specific host biomarkers, particularly IP-10, in response to the first week of anti-TB therapy were strongly associated with bacteriological confirmation of TB. A decrease in IP-10 level of >300pg/ml between 0 and 7 days of treatment identified 75% of both smear-positive and smear negative culture positive patients and correctly excluded TB in all nine culture negative patients. CONCLUSIONS: Monitoring of early IP-10 responses to treatment could form the basis of a simplified assay and could help identify patients who were erroneously clinically diagnosed with TB or those infected with drug resistant strains on inappropriate treatment. We believe this approach may be particularly appropriate for difficult to diagnose patients, e.g. smear-negative HIV-positive, or those with extra-pulmonary TB, often treated without bacterial confirmation. PMID- 26115423 TI - Planning the International Competition Schedules for the Health of Elite Athletes: A 21-Year Retrospective Study Evaluating the Effectiveness and Economic Impact in an Olympic Sport. AB - BACKGROUND: The increased number of trips and competitions scheduled in the international agonistic calendars meets commercial demands while acting as a source of stress for the athletes. A model, developed in biathlons to monitor the so-called competition load, revealed an upward trend over time. The aim of this study was to evaluate, in a 21-year period, the effects of the International Biathlon Union's rescheduling of the competitive calendars to control the competition load, as well as its stability over time and the economic impact of this intervention. METHODS: For each season competition, the load factors from the international agonistic calendar (number of venues/events, competition days/distance) were considered, and the athletes' daily and maximal stress scores were calculated. The calendar rescheduling, which started in 2001, involved the length of competitions, number of resting days and frequency of travels. Data from the period pre (1994-2000) and post (2001-2007) the intervention, as well as follow-up (2008-2015), were compared and analyzed in relation to the federation's budget. RESULTS: The competition load and athletes' daily stress score progressively increased pre, plateaued post and remained stable in follow-up. Their annual variations within the final two periods were significantly lower than in the pre period, in spite of the higher average values. The maximal stress score decreased over time. The direct correlation between most of the competition load factors with the economic budget present in pre was lost in post and follow up. Similarly, the athletes' daily stress score had a stable trend in post and follow-up, while budget continued to increase. CONCLUSIONS: The management of an athlete's potential source of stress by an international federation stabilized the competition load over time, but it did not affect the budget. Furthermore, it uncoupled the relationship between the athlete's effort and federation income. PMID- 26115424 TI - Analysis of multipotent mesenchymal stromal cells used for acute graft-versus host disease prophylaxis. AB - BACKGROUND: Multipotent mesenchymal stromal cells (MSCs) are used for prophylaxis of acute graft-versus-host disease (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Not all samples of MSC are efficient for aGvHD prevention. The suitability of MSCs for aGvHD prophylaxis was studied. METHODS: MSCs were derived from the bone marrow (BM) of HCT donor and cultivated for no more than three passages. The characteristics of donor BM samples including colony-forming unit fibroblast (CFU-F) concentration, growth parameters of MSCs, and the relative expression levels (REL) of different genes were analyzed. MSCs were injected intravenously precisely at the moment of blood cell reconstitution. RESULTS: MSCs infusion induced a significant threefold decrease in aGvHD development and improved overall survival compared with the standard prophylaxis group. In ineffective MSC samples (9.4%), a significant decrease in total cell production and the REL of CSF1, FGFR1, and PDGFRB was observed. In all studied BM samples, the cumulative MSC production and CFU-F concentrations decreased with age. The expression levels of FGFR2, PPARG, and VEGF differed by age. CONCLUSIONS: A universal single indicator for the prediction of MSC eligibility for aGvHD prophylaxis was not identified. A multiparameter mathematical model for selecting MSC samples effective for the prevention of aGvHD was proposed. PMID- 26115431 TI - Knowledge and Practices of Pediatricians Regarding Functional Constipation in the State of Minas Gerais, Brazil. AB - OBJECTIVES: The aim of the study was to analyze the knowledge, approaches, and practices of pediatricians participating in a regional pediatric conference regarding functional constipation (FC) to identify knowledge gaps. METHODS: Cross sectional regional study based on a semistructured questionnaire related to the Rome III criteria and the participant profiles. RESULTS: Of 400 questionnaires distributed, 264 (66.0%) were completed. Most pediatricians (76.7%) did not recognize the Rome III criteria, but the majority did recognize the following risk factors for FC: low-fiber diet (97.8%), family history (86.6%), onset of toilet training (76.4%), and weaning (62.4%). Foods considered high in fiber were oats (95.7%), leafy vegetables (95.3%), and wheat bran (93.2%). Digital rectal examination was not performed by 57.7% of nongastroenterologists. Complementary examinations were ordered in 27.5% and 72.5% of patients by general pediatricians and pediatric gastroenterologists, respectively, although the sample of gastroenterologists was not representative. The most prescribed drugs by nongastroenterologists were mineral oil (72.6%), magnesium hydroxide (52.1%), lactulose (41.0%), and polyethylene glycol (25.2%). Pediatric gastroenterologists prescribed magnesium hydroxide (91.7%), polyethylene glycol (91.7%), and mineral oil (58.3%). Most pediatricians (70.0%) considered the average treatment duration to be less than 1 year, although gastroenterologists considered it to be more than 1 year (54.6%). CONCLUSIONS: The knowledge of pediatricians regarding FC is inadequate. Constipation may not receive the public health attention it deserves within pediatric residency programs. The authors suggest that better education regarding FC should be included in medical school and residency program curricula to improve patient care. PMID- 26115430 TI - Genetic Changes to a Transcriptional Silencer Element Confers Phenotypic Diversity within and between Drosophila Species. AB - The modification of transcriptional regulation has become increasingly appreciated as a major contributor to morphological evolution. However, the role of negative-acting control elements (e.g. silencers) in generating morphological diversity has been generally overlooked relative to positive-acting "enhancer" elements. The highly variable body coloration patterns among Drosophilid insects represents a powerful model system in which the molecular alterations that underlie phenotypic diversity can be defined. In a survey of pigment phenotypes among geographically disparate Japanese populations of Drosophila auraria, we discovered a remarkable degree of variation in male-specific abdominal coloration. In testing the expression patterns of the major pigment-producing enzymes, we found that phenotypes uniquely correlated with differences in the expression of ebony, a gene required for yellow-colored cuticle. Assays of ebony's transcriptional control region indicated that a lightly pigmented strain harbored cis-regulatory mutations that caused correlated changes in its expression. Through a series of chimeric reporter constructs between light and dark strain alleles, we localized function-altering mutations to a conserved silencer that mediates a male-specific pattern of ebony repression. This suggests that the light allele was derived through the loss of this silencer's activity. Furthermore, examination of the ebony gene of D. serrata, a close relative of D. auraria which secondarily lost male-specific pigmentation revealed the parallel loss of this silencer element. These results demonstrate how loss-of-function mutations in a silencer element resulted in increased gene expression. We propose that the mutational inactivation of silencer elements may represent a favored path to evolve gene expression, impacting morphological traits. PMID- 26115432 TI - Severe Erosive Esophagitis Associated With a Short Course of Ibuprofen. PMID- 26115434 TI - Excitation of Mesoscopic Plasmonic Tapers by Relativistic Electrons: Phase Matching versus Eigenmode Resonances. AB - We investigate the optical modes in three-dimensional single-crystalline gold tapers by means of electron energy-loss spectroscopy. At the very proximity to the apex, a broad-band excitation at all photon energies from 0.75 to 2 eV, which is the onset for interband transitions, is detected. At large distances from the apex, though, we observe distinct resonances with energy dispersions roughly proportional to the inverse local radius. The nature of these phenomena is unraveled by finite difference time-domain simulations of the taper and an analytical treatment of the energy loss in fibers. Our calculations and the perfect agreement with our experimental results demonstrate the importance of phase-matching between electron field and radiative taper modes in mesoscopic structures. The local taper radius at the electron impact location determines the selective excitation of radiative modes with discrete angular momenta. PMID- 26115435 TI - Acute Effects of a Therapeutic Mobility Device on Physical Activity and Heart Rate in Children With Down Syndrome. AB - PURPOSE: The purpose of this feasibility study was to provide an opportunity to increase physical activity (PA) and heart rate (HR) for children with Down syndrome (DS) during unstructured group exercise utilizing a riding device called the Power Pumper(r). METHOD: Twenty-four children aged 5 to 7 years old participated in this case-control study, including 12 children with DS and 12 children without DS. Those without DS participated as age-matched controls. A 30 min unstructured PA session utilizing the Power Pumper was provided to both groups on 2 occasions. HR and PA were measured at baseline and during both sessions. RESULTS: For children with DS, findings revealed a statistically significant increase in time spent in moderate-to-vigorous PA (MVPA), F(1, 15) = 16.503, p < .010, ES = 0.76, and a nonsignificant increase in HR (ES = 0.41) when comparing exercise session performance to baseline. For children without DS, findings revealed statistically significant increases in time spent in MVPA, F(1, 15) = 73.604, p < .010, ES = 0.94, and HR, F(1, 22) = 34.634, p < .010, ES = 0.69, between exercise and baseline. Total MVPA approached the recommended 60 min following device use. PA and HR differences between baseline and exercise were greater in magnitude for children without DS. CONCLUSION: By participating in unstructured exercise in a social environment using the Power Pumper, children with DS engaged in higher-intensity PA accompanied by a nonsignificant physiological response in HR. These outcomes support PA guidelines recommended by the National Association for Sport and Physical Education. This device supports 1 option for achieving 60 min of MVPA daily. PMID- 26115433 TI - Serum- and Glucocorticoid-Inducible Kinase-1 (SGK-1) Plays a Role in Membrane Trafficking in Caenorhabditis elegans. AB - The mammalian serum- and glucocorticoid-inducible kinase SGK1 regulates the endocytosis of ion channels. Here we report that in C. elegans sgk-1 null mutants, GFP-tagged MIG-14/Wntless, the sorting receptor of Wnt, failed to localize to the basolateral membrane of intestinal cells; instead, it was mis sorted to lysosomes. This effect can be explained in part by altered sphingolipid levels, because reducing glucosylceramide biosynthesis restored the localization of MIG-14::GFP. Membrane traffic was not perturbed in general, as no obvious morphological defects were detected for early endosomes, the Golgi apparatus, and the endoplasmic reticulum (ER) in sgk-1 null animals. The recycling of MIG 14/Wntless through the Golgi might be partially responsible for the observed phenotype because the subcellular distribution of two plasma membrane cargoes that do not recycle through the trans-Golgi network (TGN) was affected to a lesser degree. Consistently, knockdown of the ArfGEF gbf-1 altered the distribution of SGK-1 at the basolateral membrane of intestinal cells. In addition, we found that sgk-1(RNAi) induced unfolded protein response in the ER, suggesting at least an indirect role of SGK-1 early in the secretory pathway. We propose that SGK-1 function is required for lipid homeostasis and that it acts at different intracellular trafficking steps. PMID- 26115436 TI - Extracellular proteases are released by ciliates in defined seawater microcosms. AB - The biodegradation of proteins in seawater requires various proteases which are commonly thought to be mainly derived from heterotrophic bacteria. We, however, found that protists showed a high protease activity and continuously produced trypsin-type enzymes. The free-living marine heterotrophic ciliate Paranophrys marina together with an associated bacterium was isolated and used for microcosm incubation with different concentrations of killed bacteria as food for 10 days. The results showed that the co-existence of the ciliate with its associated bacterium produced a significant protease activity in both cell-associated and cell-free fractions while that in the associated bacterium only microcosm was negligible. The protease profiles are different between cell-associated and cell free fractions, and a trypsin-type enzyme hydrolyzing Boc-Val-Leu-Lys-MCA was detected throughout the period in the presence of ciliates. This suggests that ciliates release proteases into the surrounding environment which could play a role in protein digestion outside cells. It has been previously suggested that bacteria are the major transformers in seawater. We here present additional data which indicates that protists, or at least ciliates with their specific enzymes, are a potential player in organic matter degradation in water columns. PMID- 26115437 TI - High MIP-1beta Levels in Plasma Predict Long-Term Immunological Nonresponse to Suppressive Antiretroviral Therapy in HIV Infection. AB - BACKGROUND: HIV-infected patients who fail to reconstitute their CD4 T-cell counts during suppressive antiretroviral therapy (ART) have increased risk of both AIDS-related and non-AIDS-related morbidity and mortality. Improved understanding of immunological nonresponse (INR) is necessary to enable earlier clinical intervention. METHODS: In a cohort of 112 HIV-infected patients starting ART, we performed a serial analysis of 32 plasma-soluble markers, assessed by multiplex cytokine and enzyme immunoassay. Samples were drawn pre-ART and during the first 3 years of treatment, with a final observation time of 8.4 years (interquartile range, 7.0-10.7 years) on ART. Long-term INR (LT-INR) was defined as failure to reach a CD4 T-cell count >350 cells per microliter. Marker stability was evaluated by parallel analysis of samples from ART-naive and HIV seronegative controls. RESULTS: Baseline CD4 T-cell counts predicted subsequent LT-INR (n = 15) [odds ratio, 1.10 (95% confidence interval: 1.01 to 1.19) pr. 10 cells/MUL reduction in CD4 count, P = 0.030] in the cohort as a whole, but not in patients with baseline CD4 counts <200 cells per microliter (n = 78). LT-INR was best characterized by elevated plasma levels of the CC chemokine macrophage inflammatory protein 1beta (MIP-1beta), both at baseline (pre-ART) and during ART. In patients with baseline CD4 counts <200 cells per microliter, baseline MIP 1beta predicted LT-INR [odds ratio 1.23 (95% confidence interval: 1.02 to 1.47) per 10 pg/mL increase in MIP-1beta, P = 0.029]. CONCLUSIONS: Elevated pre-ART levels of MIP-1beta identified LT-INR patients who started ART at CD4 counts <200. INR was characterized by persistently high MIP-1beta during suppressive ART. Thus, MIP-1beta may be of use for early identification of LT-INR. PMID- 26115438 TI - Incidence of HIV Infection in Young Gay, Bisexual, and Other YMSM: The P18 Cohort Study. AB - CONTENT: HIV infections continue to rise in a new generation of young gay, bisexual, and other young men who have sex with men (YMSM) despite 3 decades of HIV prevention and recent biomedical technologies to deter infection. OBJECTIVES: To examine the incidence of HIV and the demographic, behavioral, and structural factors associated with incident infections. DESIGN: A prospective cohort study. PARTICIPANTS: Six hundred YMSM who were aged 18-19 years at baseline. RESULTS: At baseline, 6 prevalent cases of HIV were detected. Over the course of 36 months and 6 additional waves of data collection, we identified 43 (7.2%) incident cases of HIV. Incident infections were marginally higher among those residing in neighborhoods with higher rates of HIV prevalence. Using Cox proportional hazards models, we detected that hazard ratios (HRs) for time to HIV seroconversion were significantly higher for black YMSM (HR = 7.46) and mixed/other race YMSM (HR = 7.99), and older age at sexual debut with another man was associated with a lower risk of HIV seroconversion (HR = 0.50), whereas low perceived familial socioeconomic status was marginally associated with an increased risk for HIV seroconversion (HR = 2.45). CONCLUSIONS: These findings support the disparities for HIV that exist within the population of sexual minority men and suggest that we attend to behavioral, structural, and social conditions to effectively tailor HIV prevention for a new generation of YMSM with keen eyes to the conditions faced by racial and ethnic minority YMSM, which heightened their risk for acquiring HIV. PMID- 26115439 TI - Network Characteristics of People Who Inject Drugs Within a New HIV Epidemic Following Austerity in Athens, Greece. AB - BACKGROUND: Greece experienced an unprecedented increase in HIV cases among drug injectors in 2011 after economic crisis. Network-level factors are increasingly understood to drive HIV transmission in emerging epidemics. METHODS: We examined the relationship between networks, risk behaviors, and HIV serostatus among 1404 people who inject drugs in Athens, Greece. We generated networks using the chain referral structure within a large HIV screening program. Network proportions, the proportion of a respondent's network with a given characteristic, were calculated. Multiple logistic regression models were used to assess the relationship between network proportions and individual HIV seroprevalence, injection frequency and unprotected sex. RESULTS: Of note, 1030 networks were generated. Respondent HIV seroprevalence was associated with greater proportions of network members who were HIV infected (ie, those with >= 50% of network members HIV positive vs. those with no network members HIV positive) (AOR: 3.11; 95% CI: 2.10 to 4.62), divided drugs (AOR: 1.60; 95% CI: 1.10 to 2.35), or injected frequently (AOR: 1.50; 95% CI: 1.02 to 2.21). Homelessness was the only sociodemographic characteristic associated with a risk outcome measure--high frequency injecting (AOR: 1.41; 95% CI: 1.03 to 1.93). These associations were weaker for more distal second- and third-degree networks and not present when examined within random networks. CONCLUSIONS: Networks are an independently important contributor to the HIV outbreak in Athens, Greece. Network associations were strongest for the immediate network, with residual associations for distal networks. Homelessness was associated with high-frequency injecting. Prevention programs should consider including network-level interventions to prevent future emerging epidemics. PMID- 26115440 TI - SPIDER OR NO SPIDER? NEURAL CORRELATES OF SUSTAINED AND PHASIC FEAR IN SPIDER PHOBIA. AB - BACKGROUND: Processes of phasic fear responses to threatening stimuli are thought to be distinct from sustained, anticipatory anxiety toward an unpredicted, potential threat. There is evidence for dissociable neural correlates of phasic fear and sustained anxiety. Whereas increased amygdala activity has been associated with phasic fear, sustained anxiety has been linked with activation of the bed nucleus of stria terminalis (BNST), anterior cingulate cortex (ACC), and the insula. So far, only a few studies have focused on the dissociation of neural processes related to both phasic and sustained fear in specific phobia. We suggested that first, conditions of phasic and sustained fear would involve different neural networks and, second, that overall neural activity would be enhanced in a sample of phobic compared to nonphobic participants. METHODS: Pictures of spiders and neutral stimuli under conditions of either predicted (phasic) or unpredicted (sustained) fear were presented to 28 subjects with spider phobia and 28 nonphobic control subjects during functional magnetic resonance imaging (fMRI) scanning. RESULTS: Phobic patients revealed significantly higher amygdala activation than controls under conditions of phasic fear. Sustained fear processing was significantly related to activation in the insula and ACC, and phobic patients showed a stronger activation than controls of the BNST and the right ACC under conditions of sustained fear. Functional connectivity analysis revealed enhanced connectivity of the BNST and the amygdala in phobic subjects. CONCLUSIONS: Our findings support the idea of distinct neural correlates of phasic and sustained fear processes. Increased neural activity and functional connectivity in these networks might be crucial for the development and maintenance of anxiety disorders. PMID- 26115441 TI - Needs Assessment for Research Use of High-Throughput Sequencing at a Large Academic Medical Center. AB - Next Generation Sequencing (NGS) methods are driving profound changes in biomedical research, with a growing impact on patient care. Many academic medical centers are evaluating potential models to prepare for the rapid increase in NGS information needs. This study sought to investigate (1) how and where sequencing data is generated and analyzed, (2) research objectives and goals for NGS, (3) workforce capacity and unmet needs, (4) storage capacity and unmet needs, (5) available and anticipated funding resources, and (6) future challenges. As a precursor to informed decision making at our institution, we undertook a systematic needs assessment of investigators using survey methods. We recruited 331 investigators from over 60 departments and divisions at the University of Pittsburgh Schools of Health Sciences and had 140 respondents, or a 42% response rate. Results suggest that both sequencing and analysis bottlenecks currently exist. Significant educational needs were identified, including both investigator focused needs, such as selection of NGS methods suitable for specific research objectives, and program-focused needs, such as support for training an analytic workforce. The absence of centralized infrastructure was identified as an important institutional gap. Key principles for organizations managing this change were formulated based on the survey responses. This needs assessment provides an in-depth case study which may be useful to other academic medical centers as they identify and plan for future needs. PMID- 26115442 TI - Outcome measures in MMN revisited: further improvement needed. AB - The objectives of this study were to provide an overview of the outcome measures (OMs) applied in clinical trials in multifocal motor neuropathy (MMN) and to determine the responsiveness of a core set of selected OMs as part of the peripheral neuropathy outcome measures standardization (PeriNomS) study. The following OMs were serially applied in 26 patients with newly diagnosed or relapsing MMN, receiving intravenous immunoglobulin (assessments: T0/T3/T12 months): 14 muscle pairs MRC (Medical Research Council) scale, the Neuropathy Impairment Scale motor-subset, a self-evaluation scale, grip strength, and MMN RODS(c) (Rasch-built overall disability scale). All data, except the grip strength, were subjected to Rasch analyses before determining responsiveness. For grip strength, responsiveness was examined using a combined anchor- (SF-36 question-2) and distribution-based (1/2 * SD) minimum clinically important difference (MCID) techniques, determining the proportion of patients exceeding both the identified cut-offs. For the remaining scales, the magnitude of change for each patient on each scale was determined using the MCID related to the individual SE (responder definition: MCID-SE >= 1.96). Overall, a great assortment of measures has been used in MMN trials with different responsiveness definitions. For the selected OMs, responsiveness was poor and only seen in one fourth to one third of the patients, the grip strength being more responsive. Despite the efforts taken to standardize outcome assessment, further clinimetric responsiveness studies are needed in MMN. PMID- 26115443 TI - Assessment of Myocardial Fibrosis in Mice Using a T2*-Weighted 3D Radial Magnetic Resonance Imaging Sequence. AB - BACKGROUND: Myocardial fibrosis is a common hallmark of many diseases of the heart. Late gadolinium enhanced MRI is a powerful tool to image replacement fibrosis after myocardial infarction (MI). Interstitial fibrosis can be assessed indirectly from an extracellular volume fraction measurement using contrast enhanced T1 mapping. Detection of short T2* species resulting from fibrotic tissue may provide an attractive non-contrast-enhanced alternative to directly visualize the presence of both replacement and interstitial fibrosis. OBJECTIVE: To goal of this paper was to explore the use of a T2*-weighted radial sequence for the visualization of fibrosis in mouse heart. METHODS: C57BL/6 mice were studied with MI (n = 20, replacement fibrosis), transverse aortic constriction (TAC) (n = 18, diffuse fibrosis), and as control (n = 10). 3D center-out radial T2*-weighted images with varying TE were acquired in vivo and ex vivo (TE = 21 MUs-4 ms). Ex vivo T2*-weighted signal decay with TE was analyzed using a 3 component model. Subtraction of short- and long-TE images was used to highlight fibrotic tissue with short T2*. The presence of fibrosis was validated using histology and correlated to MRI findings. RESULTS: Detailed ex vivo T2*-weighted signal analysis revealed a fast (T2*fast), slow (T2*slow) and lipid (T2*lipid) pool. T2*fast remained essentially constant. Infarct T2*slow decreased significantly, while a moderate decrease was observed in remote tissue in post-MI hearts and in TAC hearts. T2*slow correlated with the presence of diffuse fibrosis in TAC hearts (r = 0.82, P = 0.01). Ex vivo and in vivo subtraction images depicted a positive contrast in the infarct co-localizing with the scar. Infarct volumes from histology and subtraction images linearly correlated (r = 0.94, P<0.001). Region-of-interest analysis in the in vivo post-MI and TAC hearts revealed significant T2* shortening due to fibrosis, in agreement with the ex vivo results. However, in vivo contrast on subtraction images was rather poor, hampering a straightforward visual assessment of the spatial distribution of the fibrotic tissue. PMID- 26115444 TI - Aza-macrocyclic complexes of the Group 1 cations - synthesis, structures and density functional theory study. AB - The Group 1 complexes, [M(Me6[18]aneN6)][BAr(F)] (M = Li-Cs; Me6[18]aneN6 = 1,4,7,10,13,16-hexamethyl-1,4,7,10,13,16-hexaazacyclooctadecane; BAr(F) = tetrakis{3,5-bis(trifluoromethyl)-phenyl}borate), are obtained in high yield by reaction of the macrocycle with M[BAr(F)] in anhydrous CH2Cl2 solution, and characterised spectroscopically ((1)H, (13)C{(1)H}, (7)Li, (23)Na, and (133)Cs NMR), by microanalysis and, for M = Li, K, and Rb, by single crystal X-ray analysis. The structures show N6-coordination to the metal ion; the small ionic radius for Li(+) leads to a puckered conformation. In contrast, the K(+) ion fits well into the N6 plane, with the [BAr(F)](-) anions above and below, leading to two K(+) species in the asymmetric unit (a hexagonal planar [K(Me6[18]aneN6)](+) cation and a '[K(Me6[18]aneN6)(kappa(1)-BAr(F))2](-) anion', with long axial KF interactions). The Rb(+) ion sits above the N6 plane, with two long axial RbF interactions in one cation and two long, mutually cis RbF interactions in the other. The unusual sandwich cations, [M(Me3tacn)2](+) (M = Na, K; distorted octahedral, N6 donor set) and half-sandwich cations [Li(Me3tacn)(thf)](+) (distorted tetrahedron, N3O donor set), [Li(Me4cyclen)(OH2)](+), and [Na(Me4cyclen)(thf)](+) (both distorted square pyramids with N4O donor sets) were also prepared (Me3tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane, Me4cyclen = 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane). Density functional theory (DFT) calculations, using the BP86 and B3LYP functionals, show that the accessibility of the [M(Me3tacn)2](+) sandwich cations depends strongly on the M(+) ionic radius, such that it is sufficiently large to avoid steric clashing between the Me groups of the two rings, and small enough to avoid very acute N-M N chelate angles. The calculations also show that coordination to the Group 1 cation involves significant donation of electron density from the p-orbitals on the N atoms of the macrocycle, rather than purely electrostatic interactions. PMID- 26115445 TI - Association of IFNL3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV/HCV-coinfected women. AB - African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN-lambda region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14 0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51 1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-lambda variants (HRs <= 0.44, P values <= 0.04). The lower risk of death among African American HIV/HCV-coinfected women is not explained by genetic variation in the IFN-lambda region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality. PMID- 26115446 TI - Understanding Confounding Effects in Linguistic Coordination: An Information Theoretic Approach. AB - We suggest an information-theoretic approach for measuring stylistic coordination in dialogues. The proposed measure has a simple predictive interpretation and can account for various confounding factors through proper conditioning. We revisit some of the previous studies that reported strong signatures of stylistic accommodation, and find that a significant part of the observed coordination can be attributed to a simple confounding effect--length coordination. Specifically, longer utterances tend to be followed by longer responses, which gives rise to spurious correlations in the other stylistic features. We propose a test to distinguish correlations in length due to contextual factors (topic of conversation, user verbosity, etc.) and turn-by-turn coordination. We also suggest a test to identify whether stylistic coordination persists even after accounting for length coordination and contextual factors. PMID- 26115448 TI - Genetically encoded voltage indicators for large scale cortical imaging come of age. AB - Electrical signals are fundamental to cellular sensing, communication and motility. In the nervous system, information is represented as receptor, synaptic and action potentials. Understanding how brain functions emerge from these electrical signals is one of the ultimate challenges in neuroscience and requires a methodology to monitor membrane voltage transients from large numbers of cells at high spatio-temporal resolution. Optical voltage imaging holds longstanding promises to achieve this, and has gained a fresh powerful momentum with the development of genetically encoded voltage indicators (GEVIs). With a focus on neuroimaging studies on intact mouse brains, we highlight recent advances in this field. PMID- 26115447 TI - Near-infrared fluorescent proteins engineered from bacterial phytochromes. AB - Near-infrared fluorescent proteins (NIR FPs), photoactivatable NIR FPs and NIR reporters of protein-protein interactions developed from bacterial phytochrome photoreceptors (BphPs) have advanced non-invasive deep-tissue imaging. Here we provide a brief guide to the BphP-derived NIR probes with an emphasis on their in vivo applications. We describe phenotypes of NIR FPs and their photochemical and intracellular properties. We discuss NIR FP applications for imaging of various cell types, tissues and animal models in basic and translational research. In this discussion, we focus on NIR FPs that efficiently incorporate endogenous biliverdin chromophore and therefore can be used as straightforward as GFP-like proteins. We also overview a usage of NIR FPs in different imaging platforms, from planar epifluorescence to tomographic and photoacoustic technologies. PMID- 26115449 TI - Aminophylline Injection Alleviates Pain in Postdural Puncture Headache. PMID- 26115450 TI - The Role of Transposable Elements in the Origin and Evolution of MicroRNAs in Human. AB - MicroRNAs (miRNAs) are crucial regulators of gene expression at the post transcriptional level in eukaryotes via targeting gene 3'-untranslated regions. Transposable elements (TEs) are considered as natural origins of some miRNAs. However, what miRNAs are and how these miRNAs originate and evolve from TEs remain unclear. We identified 409 TE-derived miRNAs (386 overlapped with TEs and 23 un-overlapped with TEs) which are derived from TEs in human. This indicates that the TEs play important roles in origin of miRNAs in human. In addition, we found that the proportions of miRNAs derived from TEs (MDTEs) in human are more than other vertebrates especially non-mammal vertebrates. Furthermore, we classified MDTEs into three types and found that TE head or tail sequences along with adjacent genomic sequences contribute to generation of human miRNAs. Our current study will improve the understanding of origin and evolution of human miRNAs. PMID- 26115452 TI - Histogram Analysis of Apparent Diffusion Coefficients for Occult Tonsil Cancer in Patients with Cervical Nodal Metastasis from an Unknown Primary Site at Presentation. AB - PURPOSE: To explore the added value of histogram analysis of apparent diffusion coefficient (ADC) values over magnetic resonance (MR) imaging and fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for the detection of occult palatine tonsil squamous cell carcinoma (SCC) in patients with cervical nodal metastasis from a cancer of an unknown primary site. MATERIALS AND METHODS: The institutional review board approved this retrospective study, and the requirement for informed consent was waived. Differences in the bimodal histogram parameters of the ADC values were assessed among occult palatine tonsil SCC (n = 19), overt palatine tonsil SCC (n = 20), and normal palatine tonsils (n = 20). One-way analysis of variance was used to analyze differences among the three groups. Receiver operating characteristic curve analysis was used to determine the best differentiating parameters. The increased sensitivity of histogram analysis over MR imaging and (18)F-FDG PET/CT for the detection of occult palatine tonsil SCC was evaluated as added value. RESULTS: Histogram analysis showed statistically significant differences in the mean, standard deviation, and 50th and 90th percentile ADC values among the three groups (P < .0045). Occult palatine tonsil SCC had a significantly higher standard deviation for the overall curves, mean and standard deviation of the higher curves, and 90th percentile ADC value, compared with normal palatine tonsils (P < .0167). Receiver operating characteristic curve analysis showed that the standard deviation of the overall curve best delineated occult palatine tonsil SCC from normal palatine tonsils, with a sensitivity of 78.9% (15 of 19 patients) and a specificity of 60% (12 of 20 patients). The added value of ADC histogram analysis was 52.6% over MR imaging alone and 15.8% over combined conventional MR imaging and (18)F-FDG PET/CT. CONCLUSION: Adding ADC histogram analysis to conventional MR imaging can improve the detection sensitivity for occult palatine tonsil SCC in patients with a cervical nodal metastasis originating from a cancer of an unknown primary site. PMID- 26115453 TI - U.S. National Diagnostic Reference Levels: Closing the Gap. PMID- 26115451 TI - White Matter Changes of Neurite Density and Fiber Orientation Dispersion during Human Brain Maturation. AB - Diffusion tensor imaging (DTI) studies of human brain development have consistently shown widespread, but nonlinear increases in white matter anisotropy through childhood, adolescence, and into adulthood. However, despite its sensitivity to changes in tissue microstructure, DTI lacks the specificity to disentangle distinct microstructural features of white and gray matter. Neurite orientation dispersion and density imaging (NODDI) is a recently proposed multi compartment biophysical model of brain microstructure that can estimate non collinear properties of white matter, such as neurite orientation dispersion index (ODI) and neurite density index (NDI). In this study, we apply NODDI to 66 healthy controls aged 7-63 years to investigate changes of ODI and NDI with brain maturation, with comparison to standard DTI metrics. Using both region-of interest and voxel-wise analyses, we find that NDI exhibits striking increases over the studied age range following a logarithmic growth pattern, while ODI rises following an exponential growth pattern. This novel finding is consistent with well-established age-related changes of FA over the lifespan that show growth during childhood and adolescence, plateau during early adulthood, and accelerating decay after the fourth decade of life. Our results suggest that the rise of FA during the first two decades of life is dominated by increasing NDI, while the fall in FA after the fourth decade is driven by the exponential rise of ODI that overcomes the slower increases of NDI. Using partial least squares regression, we further demonstrate that NODDI better predicts chronological age than DTI. Finally, we show excellent test-retest reliability of NODDI metrics, with coefficients of variation below 5% in all measured regions of interest. Our results support the conclusion that NODDI reveals biologically specific characteristics of brain development that are more closely linked to the microstructural features of white matter than are the empirical metrics provided by DTI. PMID- 26115454 TI - A Method for Remotely Sensing Vital Signs of Human Subjects Outdoors. AB - After chemical or nuclear leakage or explosions, finding survivors is a huge challenge. Although human bodies can be found by smart vehicles and drones equipped with cameras, it is difficult to verify if the person is alive or dead this way. This paper describes a continuous wave radar sensor for remotely sensing the vital signs of human subjects. Firstly, a compact and portable 24 GHz Doppler radar system is designed to conduct non-contact detection of respiration signal. Secondly, in order to improve the quality of the respiration signals, the self-correlation and adaptive line enhancer (ALE) methods are proposed to minimize the interferences of any moving objects around the human subject. Finally, the detection capabilities of the radar system and the signal processing method are verified through experiments which show that human respiration signals can be extracted when the subject is 7 m away outdoors. The method provided in this paper will be a promising way to search for human subjects outdoors. PMID- 26115455 TI - Creating TUIs Using RFID Sensors--A Case Study Based on the Literacy Process of Children with Down Syndrome. AB - Teaching children with intellectual disabilities is a big challenge for most parents and educators. Special education teachers use learning strategies to develop and enhance motivation for complex learning tasks. Literacy acquisition is an essential and life-long skill for a child with intellectual disabilities. In this context, technology can support specific strategies that will help children learn to read. This paper introduces a Tangible User Interface (TUI) system based on Radio Frequency Identification (RFID) technology to support literacy for children with Down syndrome. Our proposed system focuses on the integration of RFID tags in 3D printed objects and low cost toys. The paper describes the experience of using some materials covering the tags and the different problems related to the material and distance of radio wave propagation. The results of a preliminary evaluation in a special education institution showed that the system helps to improve the interaction between teachers and children. The use of a TUI seems to give a physical sensory experience to develop literacy skills in children with Down syndrome. PMID- 26115457 TI - Mass and Force Sensing of an Adsorbate on a Beam Resonator Sensor. AB - The mass sensing superiority of a micro-/nano-mechanical resonator sensor over conventional mass spectrometry has been, or at least is being firmly established. Because the sensing mechanism of a mechanical resonator sensor is the shifts of resonant frequencies, how to link the shifts of resonant frequencies with the material properties of an analyte formulates an inverse problem. Besides the analyte/adsorbate mass, many other factors, such as position and axial force, can also cause the shifts of resonant frequencies. The in situ measurement of the adsorbate position and axial force is extremely difficult if not impossible, especially when an adsorbate is as small as a molecule or an atom. Extra instruments are also required. In this study, an inverse problem of using three resonant frequencies to determine the mass, position and axial force is formulated and solved. The accuracy of the inverse problem solving method is demonstrated, and how the method can be used in the real application of a nanomechanical resonator is also discussed. Solving the inverse problem is helpful to the development and application of a mechanical resonator sensor for two reasons: reducing extra experimental equipment and achieving better mass sensing by considering more factors. PMID- 26115456 TI - Non-Invasive Optical Sensor Based Approaches for Monitoring Virus Culture to Minimize BSL3 Laboratory Entry. AB - High titers of infectious viruses for vaccine and diagnostic reference panel development are made by infecting susceptible mammalian cells. Laboratory procedures are strictly performed in a Bio-Safety Level-3 (BSL3) laboratory and each entry and exit involves the use of disposable Personnel Protective Equipment (PPE) to observe cell culture conditions. Routine PPE use involves significant recurring costs. Alternative non-invasive optical sensor based approaches to remotely monitor cell culture may provide a promising and cost effective approach to monitor infectious virus cultures resulting in lower disruption and costs. We report here the monitoring of high titer cultures of Human Immunodeficiency Virus-1 (HIV-1) and Herpes Simplex Virus-2 (HSV-2) remotely with the use of optical oxygen sensors aseptically placed inside the cell culture vessel. The replacement of culture media for cell and virus propagation and virus load monitoring was effectively performed using this fluorescent sensor and resulted in half the number of visits to the BSL3 lab (five versus ten). PMID- 26115458 TI - Two-Port Approach Compared to Standard Laparoscopic Radical Cystectomy. AB - BACKGROUND AND OBJECTIVES: Two-port laparoscopic radical cystectomy (LRC) using a multichannel platform through the umbilicus and one additional 10-mm in the right iliac fossa has been recently described. We compare the perioperative and early results of this technique with a cohort of patients simultaneously treated in our institution with four-port LRC and a 7 to 10 cm midline incision. MATERIALS AND METHODS: A matched-pair study comparing perioperative outcomes, postoperative visual analog pain scale (VAPS), and morbidity of two-port (n=30) and four-port (n=30) LRC. Preoperative and perioperative data analyzed and compared included demographics, type of urinary diversion, operative time, blood loss, transfusion requirements, decrease in serum hemoglobin, operative complications, analgesic needs, length of stay, number of nodes removed, and other pathologic information. Complications in the first 3 months were evaluated according to the Clavien-Dindo classification. RESULTS: There was no significant difference between the two groups regarding patient age, gender, body-mass index, American Society of Anesthesiologists (ASA) score, Charlson comorbidity index, tumor stage, percent of positive nodes, positive margin rate, number of nodes retrieved, proportion of neobladders, secondary carcinoma in situ, incidental prostate cancer, or need of systemic chemotherapy. Median operative time was 20 minutes higher in the two port procedure, but this difference was not statistically significant (p=0.2). Estimated blood loss and differential hemoglobin change were lower in the two port technique (each p=0.03), but no difference was detected regarding the intraoperative or postoperative transfusion rate. Length of hospital stay was also equivalent. Differences were not observed either in the number or severity of complications. VAPS at days 2, 3, and 5 was significantly lower for two-port LRC (p<0.01). CONCLUSIONS: Two-port LRC performed through an umbilical platform and an accessory 10-mm port seems technically equivalent to standard four-port LRC. Perioperative outcomes regarding hospital stay and complications are tantamount. Diminished blood loss and, especially, less postoperative pain favor the reduced-port approach in this complex urologic minimally invasive procedure. PMID- 26115459 TI - A Rodent Model of Chikungunya Virus Infection in RAG1 -/- Mice, with Features of Persistence, for Vaccine Safety Evaluation. AB - Chikungunya virus (CHIKV) is a positive sense, single stranded RNA virus in the genus Alphavirus, and the etiologic agent of epidemics of severe arthralgia in Africa, Asia, Europe and, most recently, the Americas. CHIKV causes chikungunya fever (CHIK), a syndrome characterized by rash, fever, and debilitating, often chronic arthritis. In recent outbreaks, CHIKV has been recognized to manifest more neurologic signs of illness in the elderly and those with co-morbidities. The syndrome caused by CHIKV is often self-limited; however, many patients develop persistent arthralgia that can last for months or years. These characteristics make CHIKV not only important from a human health standpoint, but also from an economic standpoint. Despite its importance as a reemerging disease, there is no licensed vaccine or specific treatment to prevent CHIK. Many studies have begun to elucidate the pathogenesis of CHIKF and the mechanism of persistent arthralgia, including the role of the adaptive immune response, which is still poorly understood. In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development. To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model. Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate. PMID- 26115460 TI - Nicotine replacement therapy, tobacco products, and electronic cigarettes in pharmacies in St. Louis, Missouri. AB - OBJECTIVES: To compare availability of nicotine replacement therapy (NRT), tobacco products, and electronic cigarettes (e-cigarettes) in pharmacies in St. Louis, MO. DESIGN: Cross-sectional study, on-site store audits of 322 pharmacies. SETTING: St. Louis, MO. PARTICIPANTS: 242 eligible community pharmacies located in the study area. INTERVENTION: Pharmacies were visited by trained research assistants who conducted a 5- to 10-minute store audit using a paper-based data collection tool. MAIN OUTCOME MEASURES: Availability, accessibility, and pricing of NRT as a function of neighborhood poverty rate and proportion of black residents as well as availability of tobacco products and e-cigarettes. RESULTS: NRT availability decreased as neighborhood poverty rate increased (P = 0.02). Availability without pharmacy personnel assistance also decreased with increasing poverty rate (r = -0.19; 95% CI = -0.06, -0.31) and higher percentage of black residents (r = -0.18; 95% CI = -0.06, -0.31). Prices were lower in neighborhoods with higher poverty rates (P = 0.02) and a higher percentage of black residents (P = 0.03). E-cigarettes were available in 43% of pharmacies, and their availability and price did not differ by poverty rate or percentage of black residents. CONCLUSION: Low access to NRT might perpetuate smoking disparities in disadvantaged and racially diverse neighborhoods. Study data support policies to ensure equal NRT access to reduce disparities. PMID- 26115461 TI - Investigating changes in the gas-phase conformation of Antithrombin III upon binding of Arixtra using traveling wave ion mobility spectrometry (TWIMS). AB - We validate the utility of ion mobility to measure protein conformational changes induced by the binding of glycosaminoglycan ligands, using the well characterized system of Antithrombin III (ATIII) and Arixtra, a pharmaceutical agent with heparin (Hp) activity. Heparin has been used as a therapeutic anticoagulant drug for several decades through its interaction with ATIII, a serine protease inhibitor that plays a central role in the blood coagulation cascade. This interaction induces conformational changes within ATIII that dramatically enhance the ATIII-mediated inhibition rate. Arixtra is the smallest synthetic Hp containing the specific pentasaccharide sequence required to bind with ATIII. Here we report the first travelling wave ion mobility mass spectrometry (TWIMS) investigation of the conformational changes in ATIII induced by its interaction with Arixtra. Native electrospray ionization mass spectrometry allowed the gentle transfer of the native topology of ATIII and ATIII-Arixtra complex. IM measurements of ATIII and ATIII-Arixtra complex showed a single structure, with well-defined collisional cross section (CCS) values. An average 3.6% increase in CCS of ATIII occurred as a result of its interaction with Arixtra, which agrees closely with the theoretical estimation of the change in CCS based on protein crystal structures. A comparison of the binding behavior of ATIII under both denaturing and non-denaturing conditions confirmed the significance of a folded tertiary structure of ATIII for its biological activity. A Hp oligosaccharide whose structure is similar to Arixtra but missing the 3-O sulfo group on the central glucosamine residue showed a dramatic decrease in binding affinity towards ATIII, but no change in the mobility behavior of the complex, consistent with prior studies that suggested that 3-O sulfation affects the equilibrium constant for binding to ATIII, but not the mode of interaction. In contrast, nonspecific binding by a Hp tetrasaccharide showed more complex mobility behavior, suggesting more promiscuous interactions with ATIII. The effect of collisional activation of ATIII and ATIII-Arixtra complex were also assessed, revealing that the binding of Arixtra provided ATIII with additional stability against unfolding. Overall, our results validate the capability of TWIMS to retain the significant features of the solution structure of a protein carbohydrate complex so that it can be used to study protein conformational changes induced by the binding of glycosaminoglycan ligands. PMID- 26115462 TI - Forceps versus snare polypectomies in colorectal cancer screening: are we adhering to the guidelines? AB - BACKGROUND AND STUDY AIMS: European guidelines for quality assurance in colorectal cancer screening recommend snare resection for polyps > 5 mm. The aim of this study was to investigate polypectomy technique according to lesion size and shape, and to assess adherence of endoscopists enrolled in the national quality assurance program to the European guidelines. PATIENTS AND METHODS: This cohort study included screening colonoscopies performed between 2007 and 2013 within a quality assurance program in Austria. Resection technique was analyzed according to lesion characteristics and endoscopy facility (private practices, hospitals, outpatient clinics) before publication of the EU guidelines (2007 - 2010) and adherence to the guidelines after publication (2011 - 2013). All surveillance colonoscopies and examinations with missing data were excluded. RESULTS: A total of 128 969 screening colonoscopies performed by 278 endoscopy units were included. The polyp detection rate was 39.6 % (n = 47 797) and 95.6 % of polyps were resected. Of polyps >= 5 mm, 46.0 % were resected using forceps and were therefore not treated in accordance with the guidelines. Forceps polypectomy of lesions 5 - 10 mm and > 10 mm decreased significantly in hospitals after implementation of the guidelines (both P < 0.0001). In private practices, there was no difference in forceps usage for polyps of 5 - 10 mm (P = 0.41) before and after the guidelines, and for polyps > 10 mm forceps usage even increased (P < 0.0001). Endoscopists' forceps removal rates for polyps >= 5 mm correlated significantly with respective adenoma detection rates (P = 0.0007, r p - 0.187) and cecal intubation rates (P = 0.0001, r p - 0.303). Among endoscopists in private practices, internists had slightly lower forceps removal rates for polyps >= 5 mm than surgeons, both before (47.2 % vs. 50.7 %; P = 0.014) and after publication of the guidelines (51.9 % vs. 53.5 %; P = 0.161). CONCLUSIONS: This study confirmed the importance of the European guidelines. The inclusion of adequate resection technique as a quality indicator in colorectal cancer screening programs is recommended. PMID- 26115463 TI - Transient aphasias after left hemisphere resective surgery. AB - OBJECT: Transient aphasias are often observed in the first few days after a patient has undergone resection in the language-dominant hemisphere. The aims of this prospective study were to characterize the incidence and nature of these aphasias and to determine whether there are relationships between location of the surgical site and deficits in specific language domains. METHODS: One hundred ten patients undergoing resection to the language-dominant hemisphere participated in the study. Language was evaluated prior to surgery and 2-3 days and 1 month postsurgery using the Western Aphasia Battery and the Boston Naming Test. Voxel based lesion-symptom mapping was used to identify relationships between the surgical site location assessed on MRI and deficits in fluency, information content, comprehension, repetition, and naming. RESULTS: Seventy-one percent of patients were classified as aphasic based on the Western Aphasia Battery 2-3 days postsurgery, with deficits observed in each of the language domains examined. Fluency deficits were associated with resection of the precentral gyrus and adjacent inferior frontal cortex. Reduced information content of spoken output was associated with resection of the ventral precentral gyrus and posterior inferior frontal gyrus (pars opercularis). Repetition deficits were associated with resection of the posterior superior temporal gyrus. Naming deficits were associated with resection of the ventral temporal cortex, with midtemporal and posterior temporal damage more predictive of naming deficits than anterior temporal damage. By 1 month postsurgery, nearly all language deficits were resolved, and no language measure except for naming differed significantly from its presurgical level. CONCLUSIONS: These findings show that transient aphasias are very common after left hemisphere resective surgery and that the precise nature of the aphasia depends on the specific location of the surgical site. The patient cohort in this study provides a unique window into the neural basis of language because resections are discrete, their locations are not limited by vascular distribution or patterns of neurodegeneration, and language can be studied prior to substantial reorganization. PMID- 26115464 TI - Kinetic evaluation of low-grade gliomas in adults before and after treatment with CCNU alone. AB - OBJECT: The aim of this study was to evaluate the impact of CCNU chemotherapy alone on low-grade glioma (LGG) growth dynamics. METHODS: The authors measured the evolution of the mean tumor diameter (MTD) in adult patients with LGG before (n=28 patients) and after (n=38 patients) CCNU administration. RESULTS: Natural (spontaneous) growth of LGG in the present study was 4.3 mm/year (range 2.1-6.6 mm/year). The median MTD decrease after CCNU was 5.1 mm/year (range 1-8.9 mm/year). MTD decrease was noted in 30 patients (late decrease in 4 patients, and ongoing decrease in 24 patients with oligodendroglial tumors and 2 with astrocytic tumors). The median duration it took for the MTD to decrease after initiation of CCNU treatment was 619 days (1038 days for oligodendroglial tumors vs 377 days for astrocytic tumors; p=0.003). CONCLUSIONS: These results show that CCNU as a single agent has a significant impact on LGG tumor growth. The impact of CCNU seems to be comparable to the previously reported impact of temozolomide therapy and of combined procarbazine, CCNU, and vincristine chemotherapy. PMID- 26115465 TI - Editorial: Not everything that matters can be measured and not everything that can be measured matters. PMID- 26115466 TI - Editorial: Clip or coil? Six years of follow-up in BRAT. PMID- 26115467 TI - The Barrow Ruptured Aneurysm Trial: 6-year results. AB - OBJECT: The authors report the 6-year results of the Barrow Ruptured Aneurysm Trial (BRAT). This ongoing randomized trial, with the final goal of a 10-year follow-up, compares the safety and efficacy of surgical clip occlusion and endovascular coil embolization in patients presenting with subarachnoid hemorrhage (SAH) from a ruptured aneurysm. The 1- and 3-year results of this trial have been previously reported. METHODS: In total, 500 patients with an SAH met the entry criteria and were enrolled in the study. Of these patients, 471 were randomly assigned to the treatments: 238 to surgical clipping and 233 to endovascular coiling. Six patients who died before treatment and 57 patients with nonaneurysmal SAHs were excluded, leaving a total of 408 patients who underwent clipping (209 assigned) or coiling (199 assigned). Whether to treat patients within the assigned group or to cross over patients to the other group was at the discretion of the treating physician; 38% (75/199) of the patients assigned to coiling were crossed over to clipping and 1.9% (4/209) assigned to clipping were crossed over to coiling. The outcome data were collected by a dedicated nurse practitioner. The primary outcome analysis was based on the assigned treatment group; poor outcome was defined as a modified Rankin Scale (mRS) score > 2 and was independently adjudicated. Six years after randomization, 336 (82%) of 408 patients who had been treated were available for examination. RESULTS: On the basis of an mRS score of > 2, and similar to the results at the 3-year follow-up, no significant difference in outcomes (p = 0.24) was detected between the 2 treatment groups. Complete aneurysm obliteration at 6 years was achieved in 96% (111/116) of the clipping group and in 48% (23/48) of the coiling group (p < 0.0001). In the period between the 3- and 6-year follow-ups, 3 additional patients assigned to coiling and none assigned to clipping received retreatment, for overall retreatment rates of 4.6% (13/280) for clipping and 16.4% (21/128) for coiling (p < 0.0001). When aneurysm location was considered, the 6-year results continued to match the previously reported results, with no difference in outcome for anterior circulation aneurysms at most time points. Of the anterior circulation aneurysms assigned to coiling treatment, 42% (70/168) were crossed over to clipping treatment. The outcomes for posterior circulation aneurysms continued to favor coiling. The randomization process was unexpectedly skewed, with 18 of 21 treated aneurysms of the posterior inferior cerebellar artery (PICA) being assigned to clipping, but even when PICA aneurysms were removed from the analysis, outcomes for the posterior circulation aneurysms still favored coiling. CONCLUSIONS: Although BRAT was statistically underpowered to detect small differences, these results suggest little difference in outcome between the 2 treatments for anterior circulation aneurysms. This was not the case for the posterior circulation aneurysms, where coil embolization appeared to provide a sustained advantage over clipping. Aneurysm obliteration rates in BRAT were significantly lower and retreatment rates significantly higher in the patients undergoing coiling than in those undergoing clipping. However, despite the fact that retreatment rates were higher after coiling, no recurrent hemorrhages were known to have occurred in patients undergoing coiling in BRAT who were followed up for 6 years. Sufficient questions remain about the relative benefits of the 2 treatment modalities to warrant further well-designed randomized trials. PMID- 26115468 TI - Skull base chondrosarcoma radiosurgery: report of the North American Gamma Knife Consortium. AB - OBJECT: Stereotactic radiosurgery (SRS) is a potentially important option for patients with skull base chondrosarcomas. The object of this study was to analyze the outcomes of SRS for chondrosarcoma patients who underwent this treatment as a part of multimodality management. METHODS: Seven participating centers of the North American Gamma Knife Consortium (NAGKC) identified 46 patients who underwent SRS for skull base chondrosarcomas. Thirty-six patients had previously undergone tumor resections and 5 had been treated with fractionated radiation therapy (RT). The median tumor volume was 8.0 cm3 (range 0.9-28.2 cm3), and the median margin dose was 15 Gy (range 10.5-20 Gy). Kaplan-Meier analysis was used to calculate progression-free and overall survival rates. RESULTS: At a median follow-up of 75 months after SRS, 8 patients were dead. The actuarial overall survival after SRS was 89% at 3 years, 86% at 5 years, and 76% at 10 years. Local tumor progression occurred in 10 patients. The rate of progression-free survival (PFS) after SRS was 88% at 3 years, 85% at 5 years, and 70% at 10 years. Prior RT was significantly associated with shorter PFS. Eight patients required salvage resection, and 3 patients (7%) developed adverse radiation effects. Cranial nerve deficits improved in 22 (56%) of the 39 patients who deficits before SRS. Clinical improvement after SRS was noted in patients with abducens nerve paralysis (61%), oculomotor nerve paralysis (50%), lower cranial nerve dysfunction (50%), optic neuropathy (43%), facial neuropathy (38%), trochlear nerve paralysis (33%), trigeminal neuropathy (12%), and hearing loss (10%). CONCLUSIONS: Stereotactic radiosurgery for skull base chondrosarcomas is an important adjuvant option for the treatment of these rare tumors, as part of a team approach that includes initial surgical removal of symptomatic larger tumors. PMID- 26115469 TI - Trigeminal neuralgia caused by fibrous bands: case illustration. PMID- 26115471 TI - The academic productivity and impact of the University of Toronto Neurosurgery Program as assessed by manuscripts published and their number of citations. AB - OBJECT: Recent works have assessed academic output across neurosurgical programs using various analyses of accumulated citations as a proxy for academic activity and productivity. These assessments have emphasized North American neurosurgical training centers and have largely excluded centers outside the United States. Because of the long tradition and level of academic activity in neurosurgery at the University of Toronto, the authors sought to compare that program's publication and citation metrics with those of established programs in the US as documented in the literature. So as to not rely on historical achievements that may be of less relevance, they focused on recent works, that is, those published in the most recent complete 5-year period. METHODS: The authors sought to make their data comparable to existing published data from other programs. To this end, they compiled a list of published papers by neurosurgical faculty at the University of Toronto for the period from 2009 through 2013 using the Scopus database. Individual author names were disambiguated; the total numbers of papers and citations were compiled on a yearly basis. They computed a number of indices, including the ih(5)-index (i.e., the number of citations the papers received over a 5-year period), the summed h-index of the current faculty over time, and a number of secondary measures, including the ig(5), ie(5), and i10(5)-indices. They also determined the impact of individual authors in driving the results using Gini coefficients. To address the issue of author ambiguity, which can be problematic in multicenter bibliometric analyses, they have provided a source dataset used to determine the ih(5) index for the Toronto program. RESULTS: The University of Toronto Neurosurgery Program had approximately 29 full-time surgically active faculty per year (not including nonneurosurgical faculty) in the 5-year period from 2009 to 2013. These faculty published a total of 1217 papers in these 5 years. The total number of citations from these papers was 13,434. The ih(5)-index at the University of Toronto was 50. CONCLUSIONS: On the basis of comparison with published bibliometric data of US programs, the University of Toronto ranks first in terms of number of publications, number of citations, and ih(5)-index among neurosurgical programs in North America and most likely in the world. PMID- 26115470 TI - Five-year institutional bibliometric profiles for 103 US neurosurgical residency programs. AB - OBJECT: Various bibliometric indices based on the citations accumulated by scholarly articles, including the h-index, g-index, e-index, and Google's i10 index, may be used to evaluate academic productivity in neurological surgery. The present article provides a comprehensive assessment of recent academic publishing output from 103 US neurosurgical residency programs and investigates intradepartmental publishing equality among faculty members. METHODS: Each institution was considered a single entity, with the 5-year academic yield of every neurosurgical faculty member compiled to compute the following indices: ih(5), cumulative h, ig(5), ie(5), and i10(5) (based on publications and citations from 2009 through 2013). Intradepartmental comparison of productivity among faculty members yielded Gini coefficients for publications and citations. National and regional comparisons, institutional rankings, and intradepartmental publishing equality measures are presented. RESULTS: The median numbers of departmental faculty, total publications and citations, ih(5), summed h, ig(5), ie(5), i10(5), and Gini coefficients for publications and citations were 13, 82, 716, 12, 144, 23, 16, 17, 0.57, and 0.71, respectively. The top 5 most academically productive neurosurgical programs based on ih(5)-index were University of California, San Francisco, University of California, Los Angeles, University of Pittsburgh, Brigham & Women's Hospital, and Johns Hopkins University. The Western US region was most academically productive and displayed greater intradepartmental publishing equality (median ih[5]-index = 18, median Ginipub = 0.56). In all regions, large departments with relative intradepartmental publishing equality tend to be the most academically productive. Multivariable logistic regression analysis identified the ih(5)-index as the only independent predictor of intradepartmental publishing equality (Ginipub <= 0.5 [OR 1.20, 95% CI 1.20-1.40, p = 0.03]). CONCLUSIONS: The ih(5) index is a novel, simple, and intuitive metric capable of accurately comparing the recent scholarly efforts of neurosurgical programs and accurately predicting intradepartmental publication equality. The ih(5)-index is relatively insensitive to factors such as isolated highly productive and/or no longer academically active senior faculty, which tend to distort other bibliometric indices and mask the accurate identification of currently productive academic environments. Institutional ranking by ih(5)-index may provide information of use to faculty and trainee applicants, research funding institutions, program leaders, and other stakeholders. PMID- 26115472 TI - Development of a 3D-printed external ventricular drain placement simulator: technical note. AB - In this paper, the authors present a physical model developed to simulate accurate external ventricular drain (EVD) placement with realistic haptic and visual feedbacks to serve as a platform for complete procedural training. Insertion of an EVD via ventriculostomy is a common neurosurgical procedure used to monitor intracranial pressures and/or drain CSF. Currently, realistic training tools are scarce and mainly limited to virtual reality simulation systems. The use of 3D printing technology enables the development of realistic anatomical structures and customized design for physical simulators. In this study, the authors used the advantages of 3D printing to directly build the model geometry from stealth head CT scans and build a phantom brain mold based on 3D scans of a plastinated human brain. The resultant simulator provides realistic haptic feedback during a procedure, with visualization of catheter trajectory and fluid drainage. A multiinstitutional survey was also used to prove content validity of the simulator. With minor refinement, this simulator is expected to be a cost effective tool for training neurosurgical residents in EVD placement. PMID- 26115473 TI - Edema following Gamma Knife radiosurgery for parasagittal and parafalcine meningiomas. AB - OBJECT: Stereotactic radiosurgery (SRS) has been shown to offer a high probability of tumor control for Grade I meningiomas. However, SRS can sometimes incite edema or exacerbate preexisting edema around the targeted meningioma. The current study evaluates the incidence, timing, and degree of edema around parasagittal or parafalcine meningiomas following SRS. METHODS: A retrospective review was undertaken of a prospectively maintained database of patients treated with Gamma Knife radiosurgery at the University of Virginia Health System. All patients with WHO Grade I parafalcine or parasagittal meningiomas with at least 6 months of clinical follow-up were identified, resulting in 61 patients included in the study. The median radiographic follow-up was 28 months (range 6-158 months). Rates of new or worsening edema were quantitatively assessed using volumetric analysis; edema indices were computed as a function of time following radiosurgery. Statistical methods were used to identify favorable and unfavorable prognostic factors for new or worsening edema. RESULTS: Progression-free survival at 2 and 5 years was 98% and 90%, respectively, according to Kaplan-Meier analysis. After SRS, new peritumoral edema occurred or preexisting edema worsened in 40% of treated meningiomas. The median time to onset of peak edema was 36 months post-SRS. Persistent and progressive edema was associated with 11 tumors, and resection was undertaken for these lesions. However, 20 patients showed initial edema progression followed by regression at a median of 18 months after radiosurgery (range 6-24 months). Initial tumor volume greater than 10 cm3, absence of prior resection, and higher margin dose were significantly (p<0.05) associated with increased risk of new or progressive edema after SRS. CONCLUSIONS: Stereotactic radiosurgery offers a high rate of tumor control in patients with parasagittal or parafalcine meningiomas. However, it can lead to worsening peritumoral edema in a minority of patients. Following radiosurgery, transient edema occurs earlier than persistent and progressive edema. Longitudinal follow-up of meningioma patients after SRS is required to detect and appropriately treat transient as well as progressive edema. PMID- 26115474 TI - Gruber, Gradenigo, Dorello, and Vail: key personalities in the historical evolution and modern-day understanding of Dorello's canal. AB - A century ago an ambitious young anatomist in Rome, Primo Dorello, who sought to understand the cause of abducent nerve palsy that often occurred in patients with severe middle ear infections, conducted intricate studies on the intracranial course of the nerve. In his findings, he identified that the abducent nerve passes through a narrow sinus near the apex of the petrous bone, which formed an osteofibrous canal. Dorello suggested that in this enclosed region the abducent nerve may be particularly vulnerable to compression due to the vascular edema accompanying the infection. Although his work was widely appreciated, it was not well received by all. Interestingly, Giuseppe Gradenigo, one of the most prominent Italian otologists of the early 20th century, who was known for his work on a triad of symptoms (Gradenigo's syndrome) that accompanies petrous apicitis, a result of severe middle ear infections, was obstinate in his criticism of Dorello's findings. Thus a scientific duel began, with a series of correspondence between these two academics-one who was relatively new to the otological community (Dorello) and one who was well reputed in that community (Gradenigo). The disagreement ultimately ebbed in 1909, when Dorello published a report in response to Gradenigo's criticisms and convinced Gradenigo to change his views. Today Dorello's canal is widely recognized as a key landmark in skull base surgery of the petroclival region and holds clinical significance due to its relation to the abducent nerve and surrounding vascular structures. Yet, although academics such as Dorello and Gradenigo are recognized for their work on the canal, it is important not to forget the others throughout history who have contributed to the modern-day understanding of this anatomical structure. In fact, although the level of anatomical detail found in Dorello's work was previously unmatched, the first description of the canal was made by the experienced Austrian anatomist Wenzel Leopold Gruber in 1859, almost 50 years prior to Dorello's landmark publication. Another critical figure in building the understanding of Dorello's canal was Harris Holmes Vail, a young otolaryngologist from Harvard Medical School, who in 1922 became the first person to describe Dorello's canal in the English language. Vail conducted his own detailed anatomical studies on cadavers, and his publication not only reaffirmed Dorello's findings but also immortalized the eponym used today-"Dorello's canal." In this article the authors review the life and contributions of Gruber, Dorello, Gradenigo, and Vail, four men who played a critical role in the discovery of Dorello's canal and paved the way toward the current understanding of the canal as a key clinical and surgical entity. PMID- 26115476 TI - Multifunctional Supramolecular Hybrid Materials Constructed from Hierarchical Self-Ordering of In Situ Generated Metal-Organic Framework (MOF) Nanoparticles. AB - A synergistic approach is described to engineer supramolecular hybrid materials based on metal-organic frameworks, encompassing HKUST-1 nanoparticles formed in situ, coexisting with an electrically conducting gel fiber network. The following findings are made: i) multistimuli-responsive structural transformation via reversible sol-gel switching and ii) radical conversion of a soft hybrid gel into a mechanically malleable, viscoelastic matter. PMID- 26115477 TI - An unusual urticarial eruption: Familial cold autoinflammatory syndrome. AB - This is a case of a 26-year-old Caucasian woman with a lifelong history of an episodic urticaria associated with arthralgia, precipitated by exposure to cold. She had no other significant past medical history. She reported several family members with a history of very similar episodic eruptions without definitive diagnoses. An examination showed an urticarial eruption over her limbs with no other systemic findings. A baseline full blood examination, serology and autoimmune screen were normal. A skin biopsy was consistent with urticaria, with dermal oedema and a perivascular infiltrate. Following genetic testing, she was found to be heterozygous for a mutation, p.Ala439Val in the NLRP3 gene, known to cause familial cold autoinflammatory syndrome (FCAS), which typically presents with urticaria, conjunctivitis and arthralgia, as described in this patient. FCAS is one subtype of a group of conditions known as cryopyrin-associated periodic syndromes (CAPS). CAPS are rare, autosomal dominant inherited conditions with a spectrum of phenotypes, characterised by increased interleukin-1beta release with subsequent local and systemic proinflammatory and pyrogenic effects. PMID- 26115478 TI - Inhibition of Vascular Endothelial Growth Factor Receptor 3 Reduces Migration of Gastric Cancer Cells. AB - Angiogenesis induced by proangiogenic molecules such as vascular endothelial growth factor (VEGF) is a key process in the progression and metastasis of gastric cancer. In this study, we investigated the role of VEGF-C/VEGF receptor 3 (VEGFR3) axis in cell proliferation and migration/invasion of human gastric cancer cells (hGCCs). VEGF-C did not enhance cell proliferation but increased cell migration/invasion by approximately ~50% in hGCCs (AGS and SNU-484). MAZ51, a VEGFR3 inhibitor, reduced the VEGF-C-induced increase in migration/invasion by ~30% (p < 0.05). These results suggest that VEGFR3 could be a therapeutic target for reducing the metastasis of gastric cancer cells. PMID- 26115475 TI - Nuclear membrane diversity: underlying tissue-specific pathologies in disease? AB - Human 'laminopathy' diseases result from mutations in genes encoding nuclear lamins or nuclear envelope (NE) transmembrane proteins (NETs). These diseases present a seeming paradox: the mutated proteins are widely expressed yet pathology is limited to specific tissues. New findings suggest tissue-specific pathologies arise because these widely expressed proteins act in various complexes that include tissue-specific components. Diverse mechanisms to achieve NE tissue-specificity include tissue-specific regulation of the expression, mRNA splicing, signaling, NE-localization and interactions of potentially hundreds of tissue-specific NETs. New findings suggest these NETs underlie tissue-specific NE roles in cytoskeletal mechanics, cell-cycle regulation, signaling, gene expression and genome organization. This view of the NE as 'specialized' in each cell type is important to understand the tissue-specific pathology of NE-linked diseases. PMID- 26115479 TI - DLK1 is a novel inflammatory inhibitor which interferes with NOTCH1 signaling in TLR-activated murine macrophages. AB - Delta-like protein 1 (DLK1) is a noncanonical ligand that inhibits NOTCH1 receptor activity and regulates multiple differentiation processes. In macrophages, NOTCH signaling increases TLR-induced expression of key pro inflammatory mediators. We have investigated the role of DLK1 in macrophage activation and inflammation using Dlk1-deficient mice and Raw 264.7 cells overexpressing Dlk1. In the absence of Dlk1, NOTCH1 expression is increased and the activation of macrophages with TLR3 or TLR4 agonists leads to higher production of IFN-beta and other pro-inflammatory cytokines, including TNF-alpha, IL-12, and IL-23. The expression of key proteins involved in IFN-beta signaling, such as IRF3, IRF7, IRF1, or STAT1, as well as cRel, or RelB, which are responsible for the generation of IL-12 and IL-23, is enhanced in Dlk1 KO macrophages. Consistently, Dlk1 KO mice are more sensitive to LPS-induced endotoxic shock. These effects seem to be mediated through the modulation of NOTCH1 signaling. TLR4 activation reduces DLK1 expression, whereas increases NOTCH1 levels. In addition, DLK1 expression diminishes during differentiation of human U937 cells to macrophages. Overall, these results reveal a novel role for DLK1 as a regulator of NOTCH-mediated, pro-inflammatory macrophage activation, which could help to ensure a baseline level preventing constant tissue inflammation. PMID- 26115480 TI - Matching Pursuit with Asymmetric Functions for Signal Decomposition and Parameterization. AB - The method of adaptive approximations by Matching Pursuit makes it possible to decompose signals into basic components (called atoms). The approach relies on fitting, in an iterative way, functions from a large predefined set (called dictionary) to an analyzed signal. Usually, symmetric functions coming from the Gabor family (sine modulated Gaussian) are used. However Gabor functions may not be optimal in describing waveforms present in physiological and medical signals. Many biomedical signals contain asymmetric components, usually with a steep rise and slower decay. For the decomposition of this kind of signal we introduce a dictionary of functions of various degrees of asymmetry--from symmetric Gabor atoms to highly asymmetric waveforms. The application of this enriched dictionary to Otoacoustic Emissions and Steady-State Visually Evoked Potentials demonstrated the advantages of the proposed method. The approach provides more sparse representation, allows for correct determination of the latencies of the components and removes the "energy leakage" effect generated by symmetric waveforms that do not sufficiently match the structures of the analyzed signal. Additionally, we introduced a time-frequency-amplitude distribution that is more adequate for representation of asymmetric atoms than the conventional time frequency-energy distribution. PMID- 26115482 TI - Using Range-Wide Abundance Modeling to Identify Key Conservation Areas for the Micro-Endemic Bolson Tortoise (Gopherus flavomarginatus). AB - A widespread biogeographic pattern in nature is that population abundance is not uniform across the geographic range of species: most occurrence sites have relatively low numbers, whereas a few places contain orders of magnitude more individuals. The Bolson tortoise Gopherus flavomarginatus is endemic to a small region of the Chihuahuan Desert in Mexico, where habitat deterioration threatens this species with extinction. In this study we combined field burrows counts and the approach for modeling species abundance based on calculating the distance to the niche centroid to obtain range-wide abundance estimates. For the Bolson tortoise, we found a robust, negative relationship between observed burrows abundance and distance to the niche centroid, with a predictive capacity of 71%. Based on these results we identified four priority areas for the conservation of this microendemic and threatened tortoise. We conclude that this approach may be a useful approximation for identifying key areas for sampling and conservation efforts in elusive and rare species. PMID- 26115484 TI - Land Use/Cover Change in the Middle Reaches of the Heihe River Basin over 2000 2011 and Its Implications for Sustainable Water Resource Management. AB - The Heihe River Basin (HRB) is a typical arid inland river basin in northwestern China. From the 1960s to the 1990s, the downstream flow in the HRB declined as a result of large, artificial changes in the distribution of water and land and a lack of effective water resource management. Consequently, the ecosystems of the lower reaches of the basin substantially deteriorated. To restore these degraded ecosystems, the Ecological Water Diversion Project (EWDP) was initiated by the Chinese government in 2000. The project led to agricultural and ecological changes in the middle reaches of the basin. In this study, we present three datasets of land use/cover in the middle reaches of the HRB derived from Landsat TM/ETM+ images in 2000, 2007 and 2011. We used these data to investigate changes in land use/cover between 2000 and 2011 and the implications for sustainable water resource management. The results show that the most significant land use/cover change in the middle reaches of the HRB was the continuous expansion of farmland for economic interests. From 2000 to 2011, the farmland area increased by 12.01%. The farmland expansion increased the water resource stress; thus, groundwater was over-extracted and the ecosystem was degraded in particular areas. Both consequences are negative and potentially threaten the sustainability of the middle reaches of the HRB and the entire river basin. Local governments should therefore improve the management of water resources, particularly groundwater management, and should strictly control farmland reclamation. Then, water resources could be ecologically and socioeconomically sustained, and the balance between upstream and downstream water demands could be ensured. The results of this study can also serve as a reference for the sustainable management of water resources in other arid inland river basins. PMID- 26115483 TI - Prenatal Exposure to NO2 and Ultrasound Measures of Fetal Growth in the Spanish INMA Cohort. AB - BACKGROUND: Air pollution exposure during pregnancy has been associated with impaired fetal growth. However, few studies have measured fetal biometry longitudinally, remaining unclear as to whether there are windows of special vulnerability. OBJECTIVE: The aim was to investigate the impact of nitrogen dioxide (NO2) exposure on fetal and neonatal biometry in the Spanish INMA study. METHODS: Biparietal diameter (BPD), femur length (FL), abdominal circumference (AC), and estimated fetal weight (EFW) were evaluated for up to 2,478 fetuses in each trimester of pregnancy. Size at 12, 20, and 34 weeks of gestation and growth between these points, as well as anthropometry at birth, were assessed by SD scores derived using cohort-specific growth curves. Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses for up to 2,415 fetuses. Associations were investigated by linear regression in each cohort and subsequent meta-analysis. RESULTS: A 10-MUg/m(3) increase in average exposure to NO2 during weeks 0-12 was associated with reduced growth at weeks 0-12 in AC ( 2.1%; 95% CI: -3.7, -0.6) and EFW (-1.6%; 95% CI: -3.0, -0.3). The same exposure was inversely associated with reduced growth at weeks 20-34 in BPD (-2.6%; 95% CI: -3.9, -1.2), AC (-1.8%; 95% CI: -3.3, -0.2), and EFW (-2.1%; 95% CI: -3.7, 0.2). A less consistent pattern of association was observed for FL. The negative association of this exposure with BPD and EFW was significantly stronger in smoking versus nonsmoking mothers. CONCLUSIONS: Maternal exposure to NO2 in early pregnancy was associated with reduced fetal growth based on ultrasound measures of growth during pregnancy and measures of size at birth. PMID- 26115485 TI - A Geographic Mosaic of Climate Change Impacts on Terrestrial Vegetation: Which Areas Are Most at Risk? AB - Changes in climate projected for the 21st century are expected to trigger widespread and pervasive biotic impacts. Forecasting these changes and their implications for ecosystem services is a major research goal. Much of the research on biotic responses to climate change has focused on either projected shifts in individual species distributions or broad-scale changes in biome distributions. Here, we introduce a novel application of multinomial logistic regression as a powerful approach to model vegetation distributions and potential responses to 21st century climate change. We modeled the distribution of 22 major vegetation types, most defined by a single dominant woody species, across the San Francisco Bay Area. Predictor variables included climate and topographic variables. The novel aspect of our model is the output: a vector of relative probabilities for each vegetation type in each location within the study domain. The model was then projected for 54 future climate scenarios, spanning a representative range of temperature and precipitation projections from the CMIP3 and CMIP5 ensembles. We found that sensitivity of vegetation to climate change is highly heterogeneous across the region. Surprisingly, sensitivity to climate change is higher closer to the coast, on lower insolation, north-facing slopes and in areas of higher precipitation. While such sites may provide refugia for mesic and cool-adapted vegetation in the face of a warming climate, the model suggests they will still be highly dynamic and relatively sensitive to climate driven vegetation transitions. The greater sensitivity of moist and low insolation sites is an unexpected outcome that challenges views on the location and stability of climate refugia. Projections provide a foundation for conservation planning and land management, and highlight the need for a greater understanding of the mechanisms and time scales of potential climate-driven vegetation transitions. PMID- 26115486 TI - Validation of Genotyping-By-Sequencing Analysis in Populations of Tetraploid Alfalfa by 454 Sequencing. AB - Genotyping-by-sequencing (GBS) is a relatively low-cost high throughput genotyping technology based on next generation sequencing and is applicable to orphan species with no reference genome. A combination of genome complexity reduction and multiplexing with DNA barcoding provides a simple and affordable way to resolve allelic variation between plant samples or populations. GBS was performed on ApeKI libraries using DNA from 48 genotypes each of two heterogeneous populations of tetraploid alfalfa (Medicago sativa spp. sativa): the synthetic cultivar Apica (ATF0) and a derived population (ATF5) obtained after five cycles of recurrent selection for superior tolerance to freezing (TF). Nearly 400 million reads were obtained from two lanes of an Illumina HiSeq 2000 sequencer and analyzed with the Universal Network-Enabled Analysis Kit (UNEAK) pipeline designed for species with no reference genome. Following the application of whole dataset-level filters, 11,694 single nucleotide polymorphism (SNP) loci were obtained. About 60% had a significant match on the Medicago truncatula syntenic genome. The accuracy of allelic ratios and genotype calls based on GBS data was directly assessed using 454 sequencing on a subset of SNP loci scored in eight plant samples. Sequencing depth in this study was not sufficient for accurate tetraploid allelic dosage, but reliable genotype calls based on diploid allelic dosage were obtained when using additional quality filtering. Principal Component Analysis of SNP loci in plant samples revealed that a small proportion (<5%) of the genetic variability assessed by GBS is able to differentiate ATF0 and ATF5. Our results confirm that analysis of GBS data using UNEAK is a reliable approach for genome-wide discovery of SNP loci in outcrossed polyploids. PMID- 26115488 TI - Seeking the best training model for difficult conversations in neonatology. AB - OBJECTIVES: We hypothesize that a formal simulation curriculum prepares neonatology fellows for difficult conversations better than traditional didactics. METHODS: Single-center neonatology fellowship graduates from 1999 to 2013 were sent a retrospective web-based survey. Some had been exposed to a Difficult Conversations curriculum (simulation group), others had not (no simulation group). The simulation group participated in one workshop annually, consisting of lecture, simulation, and debriefing. Scenarios were customized to year of training. Epoch comparisons were made between the simulation and no simulation groups. RESULTS: Self-rated baseline effectiveness at discussing difficult topics was not different. The simulation group reported more supervised family meetings and feedback after fellow-led meetings. Simulations were rated very positively. The simulation group reported increased comfort levels. Strategic pause and body positioning were specific communication skills more frequently acquired in the simulation group. In both groups, the highest ranked contributors to learning were mentor observation and clinical practice. In the simulation group, simulation and debriefing outranked didactics or other experiences. CONCLUSIONS: Simulation-based workshops improve communication skills in high stakes conversations. However, they do not substitute for mentor observation and experience. Establishing a structured simulation-based difficult conversations curriculum refines vital communication skills necessary for the high stakes conversations neonatologists direct in clinical practice. PMID- 26115487 TI - Differential miRNA Expression in Cells and Matrix Vesicles in Vascular Smooth Muscle Cells from Rats with Kidney Disease. AB - Vascular calcification is a complex process and has been associated with aging, diabetes, chronic kidney disease (CKD). Although there have been several studies that examine the role of miRNAs (miRs) in bone osteogenesis, little is known about the role of miRs in vascular calcification and their role in the pathogenesis of vascular abnormalities. Matrix vesicles (MV) are known to play in important role in initiating vascular smooth muscle cell (VSMC) calcification. In the present study, we performed miRNA microarray analysis to identify the dysregulated miRs between MV and VSMC derived from CKD rats to understand the role of post-transcriptional regulatory networks governed by these miRNAs in vascular calcification and to uncover the differential miRNA content of MV. The percentage of miRNA to total RNA was increased in MV compared to VSMC. Comparison of expression profiles of miRNA by microarray demonstrated 33 miRs to be differentially expressed with the majority (~ 57%) of them down-regulated. Target genes controlled by differentially expressed miRNAs were identified utilizing two different complementary computational approaches Miranda and Targetscan to understand the functions and pathways that may be affected due to the production of MV from calcifying VSMC thereby contributing to the regulation of genes by miRs. We found several processes including vascular smooth muscle contraction, response to hypoxia and regulation of muscle cell differentiation to be enriched. Signaling pathways identified included MAP-kinase and wnt signaling that have previously been shown to be important in vascular calcification. In conclusion, our results demonstrate that miRs are concentrated in MV from calcifying VSMC, and that important functions and pathways are affected by the miRs dysregulation between calcifying VSMC and the MV they produce. This suggests that miRs may play a very important regulatory role in vascular calcification in CKD by controlling an extensive network of post-transcriptional targets. PMID- 26115489 TI - Amniotic fluid as a source of multipotent cells for clinical use. AB - Amniotic fluid cells (AFC) from 2nd trimester amniocentesis have been found to be a source of multipotent stem cells which might overcome the limitations of expansion, histocompatibility, tumorigenesis, and ethical issues associated with using human embryonic cells, umbilical cord, cord blood, bone marrow, and induced pluripotent cells. Previous work by our group and others demonstrated multipotency and the ability to grow well in culture. However, all these studies were done in media containing fetal calf serum. We sought to observe the properties of AFC grown in serum-free media as that would be required for clinical transplantation in humans. Fresh samples were obtained from three patients, and each sample divided into a culture whose cells were not exposed to fetal calf serum, and the other half into a standard culture medium containing fetal calf serum. Doubling time and stem cell marker expression by flow cytometry were assessed. Differentiation to neural, osteoid, and chondrogenic lineages was induced using appropriate media and confirmed by fluorescent microscopy, histology, and immunohistochemistry. There were no statistically significant differences between cells grown serum-free and in standard media in any of these parameters. The data supports the possibility of clinical use of AFC in stem cell transplantation. PMID- 26115490 TI - Adolescent health and medicine: a global perspective on training adolescent health professionals. PMID- 26115491 TI - Adolescent medicine and health: a good investment. PMID- 26115492 TI - Accreditation of Adolescent Medicine as a pediatric sub-specialty: the Canadian experience and lessons learned. AB - The Royal College of Physicians and Surgeons of Canada (Royal College) has an extensive process for recognizing new specialties and subspecialties. Among other requirements, the process requests that the applicants demonstrate that sufficient scientific breadth and depth exists within the proposed field, that a unique field of clinical practice exists, and that there is a societal need for individuals with this distinct area of specialization. In 2004, a group of adolescent medicine specialists from across Canada started the application process for the field to become an accredited pediatric subspecialty. A 3-year process was undertaken to demonstrate the need for accreditation of this new and emerging discipline. In 2007, Adolescent Medicine became the 63rd discipline and a sub-specialty of Pediatrics. This paper provides an overview of the process that led to the accreditation of Adolescent Medicine by the Royal College and offers insights into the lessons learned from this Canadian experience. PMID- 26115493 TI - Adolescent and young adult medicine in Australia and New Zealand: towards specialist accreditation. AB - In Australia and New Zealand, a critical mass of academic and clinical leadership in Adolescent Medicine has helped advance models of clinical services, drive investments in teaching and training, and strengthen research capacity over the past 30 years. There is growing recognition of the importance of influencing the training of adult physicians as well as paediatricians. The Royal Australasian College of Physicians (RACP) is responsible for overseeing all aspects of specialist physician training across the two countries. Following advocacy from adolescent physicians, the RACP is advancing a three-tier strategy to build greater specialist capacity and sustain leadership in adolescent and young adult medicine (AYAM). The first tier of the strategy supports universal training in adolescent and young adult health and medicine for all basic trainees in paediatric and adult medicine through an online training resource. The second and third tiers support advanced training in AYAM for specialist practice, based on an advanced training curriculum that has been approved by the RACP. The second tier is dual training; advanced trainees can undertake 2 years training in AYAM and 2 years training in another area of specialist practice. The third tier consists of 3 years of advanced training in AYAM. The RACP is currently seeking formal recognition from the Australian Government to have AYAM accredited, a process that will be subsequently undertaken in New Zealand. The RACP is expectant that the accreditation of specialist AYAM physicians will promote sustained academic and clinical leadership in AYAM to the benefit of future generations of young Australasians. PMID- 26115494 TI - The foundations of interdisciplinary fellowship training in adolescent medicine in the United States. AB - The field of adolescent medicine, having developed from the specialty of Pediatrics, encompasses a holistic and developmental approach from its very origin. While its foundations were in medicine, early leaders in the field emphasized the importance of mental health care as well as nutrition, public health, and social justice. As the specialty became further established in the US with the creation of an academic society, board certification and training program accreditation, the interdisciplinary nature of adolescent medicine practice and training became formalized. This formal recognition brought with it strict guidelines with regards training and board certification. Despite the often Byzantinian training requirements, an interdisciplinary approach forms the core of adolescent medicine practice, and the incorporation of interdisciplinary training is a necessity for graduate medical education programs in the field of adolescent medicine. PMID- 26115495 TI - A different training model for adolescent medicine: a PhD program in Turkey, where adolescent medicine is not currently a sub-specialty at this stage. AB - Adolescent medicine is currently not a certified subspecialty by the Ministry of Health in Turkey. Until recently, no subspecialty education was available for pediatricians interested in pursuing a career in this field. To compensate for the lack of training opportunities in the field, to meet the needs of adolescents and to increase research and strengthen scientific knowledge in the area of adolescent medicine, a doctoral program was established in 2004 by the Division of Adolescent Medicine under the Institute of Child Health at Hacettepe University in Ankara. This paper discusses the opportunities provided by the program, describing the pros and cons of such a course and what the program aims to achieve. This unique program provides pediatricians with extended postgraduate, subspecialty education in adolescent health care. We believe that the adolescent medicine PhD program at Hacettepe University could be a model for educating health care professionals in this field in other countries where there are not established fellowship programs. PMID- 26115496 TI - LEAH interdisciplinary training program. AB - This article describes the Leadership Education in Adolescent Health (LEAH) interdisciplinary training program in the United States. The Maternal and Child Health Bureau authorized by legislation provides monies to train leaders in adolescent health through a competitive grant process. Currently, seven academic medical centers have funding to provide leadership in adolescent health (LEAH) training in five core disciplines: medicine, nursing, psychology, social work and nutrition. LEAH training programs both ensure high clinical competence in core disciplines serving adolescents and prepare trainees for leadership positions in adolescent health and public health care realms. Together, these programs trained almost 1000 long-term trainees across these five disciplines, and graduates from these programs are working in 45 of the 50 states within the United States. About 90% of these graduates are working with maternal and child/adolescent health populations, and almost all have held leadership positions in the areas of public health, advocacy, public policy, academic medical centers and/or clinical care settings. PMID- 26115497 TI - The globalization of training in adolescent health and medicine: one size does not fit all. AB - Adolescent medicine across the globe is practiced within a variety of healthcare models, with the shared vision of the promotion of optimal health outcomes for adolescents. In the past decade, there has been a call for transformation in how health professionals are trained, with recommendations that there be adoption of a global outlook, a multiprofessional perspective and a systems approach that considers the connections between education and health systems. Many individuals and groups are now examining how best to accomplish this educational reform. There are tensions between the call for globally accepted standards of education models and practice (a one-size fits all approach) and the need to promote the ability for education practices to be interpreted and transformed to best suit local contexts. This paper discusses some of the key considerations for 'importing' training program models for adolescent health and medicine, including the importance of cultural alignment and the utilization of best evidence and practice in health professions education. PMID- 26115498 TI - Opportunities and challenges in adolescent health training abroad: trainees' experience and perspective. AB - As the global adolescent population increases and as there is enhanced recognition internationally of the unique nature of the adolescent period, the need for specialized training in adolescent medicine for international physicians becomes more apparent. There are challenges in securing placement in an adolescent medicine fellowship program, as well as, on acceptance, challenges with acculturation to a new setting, socially, academically and clinically. During fellowship, international medical graduates (IMGs) are exposed to new opportunities such as learning best-practices and being mentored by experienced advocates and clinicians in the field of adolescent health and medicine. This paper considers recommendations for improving adolescent medicine fellowship programs with a focus on IMGs. PMID- 26115499 TI - Training international medical graduate clinical fellows: the challenges and opportunities for adolescent medicine programs. AB - Adolescent medicine achieved accreditation status first in the United States in 1994 and then in Canada in 2008 and even if it is not an accredited subspecialty in most other Western nations, it has still become firmly established as a distinct discipline. This has not necessarily been the case in some developing countries, where even the recognition of adolescence as a unique stage of human development is not always acknowledged. The program at SickKids in Toronto has prided itself in treating its international medical graduates (IMG) clinical fellows the same as their Canadian subspecialty residents by integrating them seamlessly into the training program. Although this approach has been laudable to a great extent, it may have fallen short in formally acknowledging and addressing the challenges that the IMG trainees have had to overcome. Moving forward, faculty must be trained and supports instituted that are geared specifically towards these challenges. This must be done on a formal basis to ensure both the success of the trainees as well as the overall enrichment of the fellowship training programs. PMID- 26115500 TI - Adolescent health in South America. AB - Since the 1950s, a significant amount of work has been done on behalf of the comprehensive health of young people in South America. This article focuses on the regional process of training health professionals to work with this age group. There are countries in which the growth of adolescent health training has been significant, others that have made progress but still have a narrower offer of teaching activities, and a few where only very basic and limited training is available. Latin American professional associations, scientific societies, and international organizations have also contributed to the education of the adolescent health work force. Although the training in the region has advanced in some countries to the point that there is specialization in adolescent medicine, much remains to be done. Certain regional conditions have contributed to the education of providers in adolescent care. The most important has been the existence of professionals who have been highly motivated to improve the health of young people. They have worked very hard and with great commitment to achieve this goal. There have also been important obstacles to educating professionals in adolescent care. Aside from the usual lack of funding, barriers have existed in the health care system and its providers, as well as the training entities and because of certain South American conditions. Finally, this article describes the regional adolescent medicine programs and the status of recognition of this specialty, and addresses the opportunities and challenges for adolescent health training. PMID- 26115501 TI - Adolescent health in Asia: insights from Singapore. AB - The introduction of adolescent medicine as a medical subspecialty in Singapore was a welcome in an evolving health care system that is unique in terms of both efficiency, in financing and the results achieved in community health outcomes. The Ministry of Health (MOH) already recognized the need to accommodate the health care concerns related to adolescent psychosocial health risk behaviors and an increased prevalence of young people living with chronic illness. The challenge for the pioneer team of physicians trained in adolescent medicine was to develop and sustain a model of care that integrated (i) core clinical services that include quality measures of care to adolescents; (ii) professional development and capacity building needing an expansive teaching agenda at every level of health education; (iii) strong inter-sectorial collaborations within hospital and community partners; and (iv) robust research and evaluation strategies that keep clinical practice relevant and evidence based. PMID- 26115502 TI - Adolescent health in the Caribbean region: insights from the Jamaican experience. AB - Adolescent health in Jamaica and the wider English-speaking Caribbean has over the past three decades advanced in achieving improved healthcare services for adolescents. The path taken to achieve success thus far is reviewed - including a historical perspective on the services offered, revision of the relevant policy and legislation frameworks, improved service delivery through education and training of relevant stakeholders and providers, improved youth participation, and sustained involvement of advocates. PMID- 26115503 TI - The role of Society for Adolescent Health and Medicine in training of health professionals. AB - The Society for Adolescent Health and Medicine (SAHM) was created by health professionals committed to identifying and better addressing the health needs of adolescents and young adults, and this work has continued for nearly 50 years. The society initially focused primarily on clinical education, but has evolved to include educational activities providing clinical, research, policy, advocacy, and professional development content. Strategies have included high-quality annual meetings designed to meet the educational needs of its multi-disciplinary membership, publishing an internationally recognized journal, and developing strategic collaborations to advocate for legitimacy of the field and reform in health profession education. Historically, SAHM has been most successful at increasing specialized training in the United States among physicians, and primarily pediatricians, likely driven by the nuances of the development of adolescent medicine in this country. Successes are often linked to strategic collaborations with other professional organizations, and have been facilitated by federally funded initiatives to improve adolescent and young adult health. Recent efforts to improve professional training are focused on the use of technology, and SAHM is also currently exploring strategies to directly reach adolescents, young adults, and their parents. As the society becomes increasingly multidisciplinary and international, members have extraordinary opportunities to learn from each other, build upon lessons learned, and collaborate. Descriptions of the history of SAHM's training-focused efforts, selected highlights, and current priorities will be used to illustrate this long-standing commitment to the training of health professionals. PMID- 26115504 TI - Structural Nested Mean Models to Estimate the Effects of Time-Varying Treatments on Clustered Outcomes. AB - In assessing the efficacy of a time-varying treatment structural nested models (SNMs) are useful in dealing with confounding by variables affected by earlier treatments. These models often consider treatment allocation and repeated measures at the individual level. We extend SNMMs to clustered observations with time-varying confounding and treatments. We demonstrate how to formulate models with both cluster- and unit-level treatments and show how to derive semiparametric estimators of parameters in such models. For unit-level treatments, we consider interference, namely the effect of treatment on outcomes in other units of the same cluster. The properties of estimators are evaluated through simulations and compared with the conventional GEE regression method for clustered outcomes. To illustrate our method, we use data from the treatment arm of a glaucoma clinical trial to compare the effectiveness of two commonly used ocular hypertension medications. PMID- 26115506 TI - Introducing the New Editor of Arthritis & Rheumatology, Richard J. Bucala, MD, PhD. PMID- 26115505 TI - Effects of 1-Methylnicotinamide (MNA) on Exercise Capacity and Endothelial Response in Diabetic Mice. AB - 1-Methylnicotinamide (MNA), which was initially considered to be a biologically inactive endogenous metabolite of nicotinamide, has emerged as an anti-thrombotic and anti-inflammatory agent with the capacity to release prostacyclin (PGI2). In the present study, we characterized the effects of MNA on exercise capacity and the endothelial response to exercise in diabetic mice. Eight-week-old db/db mice were untreated or treated with MNA for 4 weeks (100 mg.kg-1), and their exercise capacity as well as NO- and PGI2-dependent response to endurance running were subsequently assessed. MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile. However, insulin sensitivity was improved (P<0.01). In MNA-treated db/db mice, the time to fatigue for endurance exercise was significantly prolonged (P<0.05). Post-exercise Delta6-keto PGF1alpha (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals. In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA. In conclusion, we demonstrated for the first time that MNA improves endurance exercise capacity in mice with diabetes, and may also decrease the cardiovascular risk of exercise. PMID- 26115509 TI - Allergen-induced early and late asthmatic responses to inhaled seasonal and perennial allergens. AB - BACKGROUND: The allergen bronchoprovocation (ABP) test is a validated model to study asthma pathophysiology and response to treatments. The inhibitory effect of agents on the allergen-induced late asthmatic response (LAR) is a predictor of their efficacy in asthma treatment. However, it is difficult to predict the magnitude of a LAR, which may vary according to immune responsiveness and the type of allergen used for ABP. AIM: To determine the relationship between the magnitudes of early asthmatic response (EAR) and LAR in mild asthmatic subjects according to the type of allergen inhaled and its determinants. METHODS: This is a retrospective analysis of a large database of ABPs, all performed with a common standardized methodology. Patients were either challenged with house dust mites (HDMs), animals or pollens allergens. EAR was defined as a >= 20% fall in forced expiratory volume in 1 s (FEV1 ) < 3 h following ABP and LAR as a >= 15% fall in FEV1 between 3 and 7 h post-ABP. The ratio of EAR % fall in FEV1 /LAR % fall in FEV1 was compared between the groups of subjects according to the allergen used for ABP. RESULTS: Data from 290 subjects were analysed: 87 had an isolated EAR and 203 had a dual response (EAR + LAR). Dual responders had a significantly lower baseline PC20 , a more marked fall in FEV1 at EAR, and a trend towards higher baseline sputum eosinophil percentages. The ratio of EAR over LAR was significantly lower in HDM compared with pollen ABP, indicating a larger LAR for a similar EAR. No correlations were observed between the ratio of EAR over LAR and the various parameters recorded in the different groups analysed. CONCLUSION: Different mechanisms may be involved in modulating the magnitude of the LAR, according to the type of allergen. HDM seems to induce a stronger LAR than pollens, animal allergens being intermediary in this regard. PMID- 26115508 TI - A Pilot Study of Circulating Endothelial and Hematopoietic Progenitor Cells in Children With Sarcomas. AB - Utilizing a multiparametric flow cytometry protocol, we assessed various cell types implicated in tumor angiogenesis that were found circulating in the peripheral blood of children with sarcomas (cases) based on their cell surface antigen expression. Circulating endothelial cells (CECs), endothelial colony forming cells (ECFCs), and the ratio of 2 distinct populations of circulating hematopoietic stem and progenitor cells (CHSPCs), the proangiogenic CHSPCs (pCHSPCs) and nonangiogenic CHSPCs (nCHSPCs) were enumerated. Multiparametric flow cytometry was analyzed in cases at baseline and at 4 additional timepoints until the end of treatment and levels compared with each other and with healthy controls. At all timepoints, cases had significantly lower levels of CECs, but elevated ECFCs and a pCHSPC:nCHSPC ratio compared with controls (all P-values <0.05). There was no significant difference in any of the cell types analyzed based on tumor histology, stage (localized vs. metastatic), or tumor size. After treatment, only the CECs among the complete responders were significantly lower at end of therapy (P<0.01) compared with nonresponders, whereas the ECFCs among all cases significantly increased (P<0.05) compared with baseline. No decline in the pCHSPC:nCHSPC ratio was observed despite tumor response. On the basis of these results, a validation of CECs as prognostic biomarker is now warranted. PMID- 26115510 TI - Cancer Associated Fibroblast-Derived Hepatocyte Growth Factor Inhibits the Paclitaxel-Induced Apoptosis of Lung Cancer A549 Cells by Up-Regulating the PI3K/Akt and GRP78 Signaling on a Microfluidic Platform. AB - Tumor stroma and growth factors provide a survival environment to tumor cells and can modulate their chemoresistance by dysregulating several signal pathways. In this study, we fabricated a three-dimensional (3D) microfluidic chip using polydimethylsiloxane (PDMS) to investigate the impact of hepatocyte growth factor (HGF) from cancer-associated fibroblasts (CAF) on the Met/PI3K/AKT activation, glucose regulatory protein (GRP78) expression and the paclitaxel-induced A549 cell apoptosis. With a concentration gradient generator, the assembled chip was able to reconstruct a tumor microenvironment in vitro. We found high levels of HGF in the supernatants of CAF and the CAF matrix from the supernatants of activated HFL1 fibroblasts or HGF enhanced the levels of Met, PI3K and AKT phosphorylation and GRP78 expression in A549 cells cultured in a 3D cell chamber, which was abrogated by anti-HGF. Inhibition of Met attenuated the CAF matrix enhanced PI3K/AKT phosphorylation and GRP78 expression while inhibition of PI3K reduced GRP78 expression, but not Met phosphorylation in A549 cells. Inhibition of GRP78 failed to modulate the CAF matrix-enhanced Met/PI3K/AKT phosphorylation in A549 cells. Furthermore, inhibition of PI3K or GRP78 enhanced spontaneous and paclitaxel-induced A549 cell apoptosis. Moreover, treatment with the CAF matrix inhibited spontaneous and medium or high dose of paclitaxel-induced A549 cell apoptosis. Inhibition of PI3K or GRP78 attenuated the CAF matrix-mediated inhibition on paclitaxel-induced A549 cell apoptosis. Our data indicated that HGF in the CAF matrix activated the Met/PI3K/AKT and up-regulated GRP78 expression, promoting chemoresistance to paclitaxel-mediated apoptosis in A549 cells. Our findings suggest that the microfluidic system may represent an ideal platform for signaling research and drug screening. PMID- 26115512 TI - Heavy metal release due to aging effect during zero valent iron nanoparticles remediation. AB - Zero valent iron nanoparticles (nZVI) represent a promising agent for environmental remediation. Nevertheless, their application presents some limitations regarding their rapid oxidation and aggregation in the media. The aim of this study was to determine the effect that nZVI aging has in heavy metal remediation in water. Contaminants studied were Zn, Cd, Ni, Cu and Cr, which are typical elements found in ground and wastewater. Results show a high contaminant removal capacity by the nZVI in the first 2 h of reaction. Nevertheless, for longer reaction times, some of the metal ions that had already been adsorbed in the nZVI were delivered to the water. Cd and Ni show the maximum delivery percentages (65 and 27% respectively after 21 days of contact time). The starting delivery time was shortened when applying lower nZVI amounts. No re-dissolution of Cr was observed in any circumstance because it was the only element incorporated into the nanoparticles core, as TEM images showed. Contaminant release from nZVI is probably due to nanoparticles oxidation caused by aging, which produced a pH decrease and nZVI surface crystallization. PMID- 26115511 TI - The Prognostic Role of Para-Aortic Lymph Nodes in Patients with Colorectal Cancer: Is It Regional or Distant Disease? AB - INTRODUCTION: Visible para-aortic lymph nodes of >=2 mm in size are common metastatic patterns of colorectal cancer (CRC) seen on imaging. Their prognostic value, however, remains inconclusive. We aimed to assess the prognostic role of visible para-aortic lymph nodes (PALNs). METHODS: Patients with confirmed pathologic diagnosis of CRC were enrolled. Correlations among clinicopathologic variables were analyzed using the chi2 test. The Cox proportional hazards model was applied for univariate and multivariate analyses. Survival was estimated using the Kaplan-Meier method and log-rank test. A prognostic model for visible PALNs in CRC patients was established. RESULTS: In total, 4527 newly diagnosed CRC patients were enrolled. Patients with visible PALNs had inferior overall survival compared to those without visible PALNs (5-year overall survival, 67% vs. 76%, P = 0.015). Lymphovascular invasion (LVI) (hazard ratio = 1.865, P = 0.015); nodal disease (pN+) status (hazard ratio = 2.099, P = 0.006); elevated preoperative serum carcinoembryonic antigen (CEA) levels (hazard ratio = 2.263, P < 0.001); and visible PALNs >=10 mm (hazard ratio = 1.638, P = 0.031) were independent prognostic factors for patients with visible PALNs. If each prognostic factor scored one point, 5-year overall survival of lower- (prognostic score 0-1), intermediate- (prognostic score 2), and high- (prognostic score 3-4) risk groups were, 78%. 54%, and 25% respectively (P < 0.001). CONCLUSIONS: The prognostic model, which included LVI, pN+ status, preoperative serum CEA level, and the size of visible PALNs, could effectively distinguish the outcome of patients with visible PALNs. PMID- 26115513 TI - COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL. AB - BACKGROUND: Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo. METHODS: Thirty-six adults with PTSD were randomized to 24 weeks of double-blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models. RESULTS: The combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26-.63). Both treatments were well-tolerated, with significantly increased appetite but not weight gain in the combined treatment group. CONCLUSION: Findings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI. PMID- 26115515 TI - A Cycling Movement Based System for Real-Time Muscle Fatigue and Cardiac Stress Monitoring and Analysis. AB - In this study, we defined a new parameter, referred to as the cardiac stress index (CSI), using a nonlinear detrended fluctuation analysis (DFA) of heart rate (HR). Our study aimed to incorporate the CSI into a cycling based fatigue monitoring system developed in our previous work so the muscle fatigue and cardiac stress can be both continuously and quantitatively assessed for subjects undergoing the cycling exercise. By collecting electrocardiogram (ECG) signals, the DFA scaling exponent alpha was evaluated on the RR time series extracted from a windowed ECG segment. We then obtained the running estimate of alpha by shifting a one-minute window by a step of 20 seconds so the CSI, defined as the percentage of all the less-than-one alpha values, can be synchronously updated every 20 seconds. Since the rating of perceived exertion (RPE) scale is considered as a convenient index which is commonly used to monitor subjective perceived exercise intensity, we then related the Borg RPE scale value to the CSI in order to investigate and quantitatively characterize the relationship between exercise-induced fatigue and cardiac stress. Twenty-two young healthy participants were recruited in our study. Each participant was asked to maintain a fixed pedaling speed at a constant load during the cycling exercise. Experimental results showed that a decrease in DFA scaling exponent alpha or an increase in CSI was observed during the exercise. In addition, the Borg RPE scale and CSI were positively correlated, suggesting that the factors due to cardiac stress might also contribute to fatigue state during physical exercise. Since the CSI can effectively quantify the cardiac stress status during physical exercise, our system may be used in sports medicine, or used by cardiologists who carried out stress tests for monitoring heart condition in patients with heart diseases. PMID- 26115514 TI - Motor and Sensory Deficits in the teetering Mice Result from Mutation of the ESCRT Component HGS. AB - Neurons are particularly vulnerable to perturbations in endo-lysosomal transport, as several neurological disorders are caused by a primary deficit in this pathway. In this report, we used positional cloning to show that the spontaneously occurring neurological mutation teetering (tn) is a single nucleotide substitution in hepatocyte growth factor-regulated tyrosine kinase substrate (Hgs/Hrs), a component of the endosomal sorting complex required for transport (ESCRT). The tn mice exhibit hypokenesis, muscle weakness, reduced muscle size and early perinatal lethality by 5-weeks of age. Although HGS has been suggested to be essential for the sorting of ubiquitinated membrane proteins to the lysosome, there were no alterations in receptor tyrosine kinase levels in the central nervous system, and only a modest decrease in tropomyosin receptor kinase B (TrkB) in the sciatic nerves of the tn mice. Instead, loss of HGS resulted in structural alterations at the neuromuscular junction (NMJ), including swellings and ultra-terminal sprouting at motor axon terminals and an increase in the number of endosomes and multivesicular bodies. These structural changes were accompanied by a reduction in spontaneous and evoked release of acetylcholine, indicating a deficit in neurotransmitter release at the NMJ. These deficits in synaptic transmission were associated with elevated levels of ubiquitinated proteins in the synaptosome fraction. In addition to the deficits in neuronal function, mutation of Hgs resulted in both hypermyelinated and dysmyelinated axons in the tn mice, which supports a growing body of evidence that ESCRTs are required for proper myelination of peripheral nerves. Our results indicate that HGS has multiple roles in the nervous system and demonstrate a previously unanticipated requirement for ESCRTs in the maintenance of synaptic transmission. PMID- 26115517 TI - Spatial variation and sources of polycyclic aromatic hydrocarbons (PAHs) in surface sediments from the Yangtze Estuary, China. AB - The spatial distributions and sources of polycyclic aromatic hydrocarbons (PAHs) in surface sediments from the Yangtze Estuary were systematically analyzed. The results indicated significant spatial variations. The mean of ?PAHs in different sampling times in a year varied from 128.5 +/- 51.4 to 307.8 +/- 108.9 ng g(-1). Samples collected during the flood season showed higher PAH concentrations and larger PAH fluctuations compared with those collected during the dry season. This variation was mainly ascribed to the change in the river flow rate. Higher values of ?PAHs were observed in the inner estuary than the adjacent coastal area over a year because of diffusion and degradation effects. Analysis of PAH abundance revealed a predominant proportion of light PAHs with two to three rings, with phenanthrene being the most abundant. Based on principal component analysis, vehicular emissions, coal and biomass combustion were the main sources of PAHs. PMID- 26115516 TI - Grip strength comparison in immune-mediated neuropathies: Vigorimeter vs. Jamar. AB - The Jamar dynamometer and Vigorimeter have been used to assess grip strength in immune-mediated neuropathies, but have never been compared to each other. Therefore, we performed a comparison study between these two devices in patients with immune-mediated neuropathies. Grip strength data were collected in 102 cross sectional stable and 163 longitudinal (new diagnoses or changing condition) patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), gammopathy-related polyneuropathy (MGUSP), and multifocal motor neuropathy (MMN). Stable patients were assessed twice (validity/reliability studies). Longitudinal patients were assessed 3-5 times during 1 year. Responsiveness comparison between the two tools was examined using combined anchor-/distribution-based minimum clinically important difference (MCID) techniques. Patients were asked to indicate their preference for the Jamar or Vigorimeter. Both tools correlated highly with each other (rho = 0.86, p < 0.0001) and showed good intra-class correlation coefficients (Jamar [Right/Left hands]: ICC 0.997/0.96; Vigori: ICC 0.95/0.98). Meaningful changes were comparable between the two instruments, being higher in GBS compared to CIDP patients. In MGUSP/MMN poor responsiveness was seen. Significant more patients preferred the Vigorimeter. In conclusion, validity, reliability, and responsiveness aspects were comparable between the Jamar dynamometer and Vigorimeter. However, based on patients' preference, the Vigorimeter is recommended in future studies in immune-mediated neuropathies. PMID- 26115518 TI - Peer effects on obesity in a sample of European children. AB - This study analyzes peer effects on childhood obesity using data from the first two waves of the IDEFICS study, which applies several anthropometric and other measures of fatness to approximately 14,000 children aged two to nine participating in both waves in 16 regions of eight European countries. Peers are defined as same-sex children in the same school and age group. The results show that peer effects do exist in this European sample but that they differ among both regions and different fatness measures. Peer effects are larger in Spain, Italy, and Cyprus--the more collectivist regions in our sample--while waist circumference generally gives rise to larger peer effects than BMI. We also provide evidence that parental misperceptions of their own children's weight goes hand in hand with fatter peer groups, supporting the notion that in making such assessments, parents compare their children's weight with that of friends and schoolmates. PMID- 26115519 TI - Increased Maternal and Cord Blood Betatrophin in Gestational Diabetes. AB - AIM: The aim of the study was to compare maternal and cord blood levels of betatrophin--a new peptide potentially controlling beta cell growth--as well as in its mRNA expression in subcutaneous adipose tissue, visceral adipose tissue and placental tissue obtained from pregnant women with normal glucose tolerance (NGT) and gestational diabetes (GDM). METHODS: Serum betatrophin and irisin concentrations were measured by ELISA in 93 patients with GDM and 97 women with NGT between 24 and 28 week of gestation. Additionally, maternal and cord blood betatrophin and irisin, as well as their genes (C19orf80 and Fndc5) expression were evaluated in 20 patients with GDM and 20 women with NGT at term. RESULTS: In both groups, serum betatrophin concentrations were significantly higher in the patients with GDM than in the controls (1.91 [1.40-2.60] ng/ml vs 1.63 [1.21 2.22] ng/ml, p=0.03 and 3.45 [2.77-6.53] ng/ml vs 2.78 [2.16-3.65] ng/ml, p=0.03, respectively). Cord blood betatrophin levels were also higher in the GDM than in the NGT group (20.43 [12.97-28.80] ng/ml vs 15.06 [10.11-21.36] ng/ml, p=0.03). In both groups betatrophin concentrations in arterial cord blood were significantly higher than in maternal serum (p=0.0001). Serum irisin levels were significantly lower in the patients with GDM (1679 [1308-2171] ng/ml) than in the healthy women between 24 and 28 week of pregnancy (1880 [1519-2312] ng/ml, p=0.03). Both C19orf80 and Fndc5 mRNA expression in fat and placental tissue did not differ significantly between the groups studied. CONCLUSIONS: Our results suggest that an increase in maternal and cord blood betatrophin might be a compensatory mechanism for enhanced insulin demand in GDM. PMID- 26115520 TI - Prospective Randomized Trial Comparing Hepatic Venous Outflow and Renal Function after Conventional versus Piggyback Liver Transplantation. AB - BACKGROUND: This randomized prospective clinical trial compared the hepatic venous outflow drainage and renal function after conventional with venovenous bypass (n = 15) or piggyback (n = 17) liver transplantation. METHODS: Free hepatic vein pressure (FHVP) and central venous pressure (CVP) measurements were performed after graft reperfusion. Postoperative serum creatinine (Cr) was measured daily on the first week and on the 14th, 21st and 28th postoperative days (PO). The prevalence of acute renal failure (ARF) up to the 28th PO was analyzed by RIFLE-AKIN criteria. A Generalized Estimating Equation (GEE) approach was used for comparison of longitudinal measurements of renal function. RESULTS: FHVP-CVP gradient > 3 mm Hg was observed in 26.7% (4/15) of the patients in the conventional group and in 17.6% (3/17) in the piggyback group (p = 0.68). Median FHVP-CVP gradient was 2 mm Hg (0-8 mmHg) vs. 3 mm Hg (0-7 mm Hg) in conventional and piggyback groups, respectively (p = 0.73). There is no statistically significant difference between the conventional (1/15) and the piggyback (2/17) groups regarding massive ascites development (p = 1.00). GEE estimated marginal mean for Cr was significantly higher in conventional than in piggyback group (2.14 +/- 0.26 vs. 1.47 +/- 0.15 mg/dL; p = 0.02). The conventional method presented a higher prevalence of severe ARF during the first 28 PO days (OR = 3.207; 95% CI, 1.010 to 10.179; p = 0.048). CONCLUSION: Patients submitted to liver transplantation using conventional or piggyback methods present similar results regarding venous outflow drainage of the graft. Conventional with venovenous bypass technique significantly increases the harm of postoperative renal dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01707810. PMID- 26115522 TI - Association of the New York State Marriage Equality Act With Changes in Health Insurance Coverage. PMID- 26115521 TI - Total Hepatitis B Core Antigen Antibody, a Quantitative Non-Invasive Marker of Hepatitis B Virus Induced Liver Disease. AB - Non invasive immunologic markers of virus-induced liver disease are unmet needs. We tested the clinical significance of quantitative total and IgM-anti-HBc in well characterized chronic-HBsAg-carriers. Sera (212) were obtained from 111 HBsAg-carriers followed-up for 52 months (28-216) during different phases of chronic-HBV-genotype-D-infection: 10 HBeAg-positive, 25 inactive-carriers (HBV DNA<=2000IU/ml, ALT<30U/L), 66 HBeAg-negative-CHB-patients and 10 with HDV-super infection. In 35 patients treated with Peg-IFN+/-nucleos(t)ide-analogues (NUCs) sera were obtained at baseline, end-of-therapy and week-24-off-therapy and in 22 treated with NUCs (for 60 months, 42-134m) at baseline and end-of-follow-up. HBsAg and IgM-anti-HBc were measured by Architect-assays (Abbott, USA); total anti-HBc by double-antigen-sandwich-immune-assay (Wantai, China); HBV-DNA by COBAS-TaqMan (Roche, Germany). Total-anti-HBc were detectable in all sera with lower levels in HBsAg-carriers without CHB (immune-tolerant, inactive and HDV superinfected, median 3.26, range 2.26-4.49 Log10 IU/ml) versus untreated-CHB (median 4.68, range 2.76-5.54 Log10 IU/ml), p<0.0001. IgM-anti-HBc positive using the chronic-hepatitis-cut-off" (0.130-S/CO) were positive in 102 of 212 sera (48.1%). Overall total-anti-HBc and IgM-anti-HBc correlated significantly (p<0.001, r=0.417). Total-anti-HBc declined significantly in CHB patients with response to Peg-IFN (p<0.001) and in NUC-treated patients (p<0.001); the lowest levels (median 2.68, range 2.12-3.08 Log10 IU/ml) were found in long-term responders who cleared HBsAg subsequently. During spontaneous and therapy-induced fluctuations of CHB (remissions and reactivations) total- and IgM-anti-HBc correlated with ALT (p<0.001, r=0.351 and p=0.008, r=0.185 respectively). Total anti-HBc qualifies as a useful marker of HBV-induced-liver-disease that might help to discriminate major phases of chronic HBV infection and to predict sustained response to antivirals. PMID- 26115525 TI - Galvanic corrosion of nitinol under deaerated and aerated conditions. AB - Various studies have examined the corrosion rate of nitinol generally under deaerated conditions. Likewise, galvanic corrosion studies have typically involved deaerated solutions. This work addressed the effect of galvanic coupling on the corrosion current of electropolished nitinol in phosphate buffered saline and 0.9% sodium chloride under dearated and aerated conditions for times up to 24 h. Tests were performed on nitinol alone and coupled with MP35N in both the mechanically polished and passivated conditions. Aeration and galvanic coupling were found to have relatively little effect, indicating that the corrosion current is controlled by the anodic reaction. The current can be attributed entirely to Ni(2+) dissolution, which appears to be governed by solid-state mass transport of Ni(2+) through the passive oxide film. Because corrosion of EP nitinol is controlled by the anodic reaction, contact between EP nitinol and MP35N or other biomedical Co-Cr alloys is unlikely to result in significant galvanic effects in vivo. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1322-1327, 2016. PMID- 26115524 TI - Water Channels Aquaporin 4 and -1 Expression in Subependymoma Depends on the Localization of the Tumors. AB - BACKGROUND: We analyzed aquaporin 4 and -1 expression in subependymomas, benign and slow growing brain tumors WHO grade I. Ten subependymoma cases were investigated, five of the fossa inferior and five of the fossa superior. METHODS AND RESULTS: Using immunohistochemistry, we observed different aquaporin expression patterns depending on localization: aquaporin 4 and -1 were detected in infratentorial subependymomas in the entire tumor tissue. In contrast, supratentorial subependymomas revealed aquaporin 4 and -1 expression only in border areas of the tumor. PCR analyses however showed no difference in aquaporin 4 expression between all subependymomas independent of localization but at higher levels than in normal brain. In contrast, aquaporin 1 RNA levels were found to be higher only in infratentorial samples compared to supratentorial and normal brain samples. The reason for the different distribution pattern of aquaporin 4 in subependymomas still remains unclear. On the cellular level, aquaporin 4 was redistributed on the surface of the tumor cells, and in freeze fracture replicas no orthogonal arrays of particles were found. This was similar to our previous findings in malignant glioblastomas. From these studies, we know that extracellular matrix molecules within the tumor like agrin and its receptor alpha dystroglycan are involved in forming orthogonal arrays of particles. In subependymomas neither agrin nor alpha-dystroglycan were detected around blood vessels. CONCLUSIONS: Taken together, we show in this study that in the benign subependymomas aquaporins 1 and 4 are dramatically redistributed and upregulated. We speculate that extracellular environments of infra- and supratentorial subependymomas are different and lead to different distribution patterns of aquaporin 4 and -1. PMID- 26115523 TI - Access and Attitudes to HPV Vaccination amongst Hard-To-Reach Populations in Kenya. AB - BACKGROUND: Sub-Saharan Africa bears the greatest burden of cervical cancer. Human papillomavirus (HPV) vaccination programmes to prevent the disease will need to reach vulnerable girls who may not be able access health and screening services in the future. We conducted formative research on facilitators and barriers to HPV vaccination and potential acceptability of a future HPV vaccination programme amongst girls living in hard-to-reach populations in Kenya. METHODS: Stakeholder interviews with Ministry of Health staff explored barriers to and support for the uptake of HPV vaccination. A situation assessment was conducted to assess community services in Maasai nomadic pastoralist communities in Kajiado County and in Korogocho informal settlement in Nairobi city, followed by focus group discussions (n=14) and semi-structured interviews (n=28) with health workers, parents, youth, and community and religious leaders. These covered marriage, knowledge of cervical cancer and HPV, factors that might inhibit or support HPV vaccine uptake and intention to accept HPV vaccine if a programme was in place. RESULTS: Reported challenges to an HPV vaccination programme included school absenteeism and drop-out, early age of sex and marriage, lack of parental support, population mobility and distance from services. Despite little prior knowledge of cervical cancer and HPV, communities were interested in receiving HPV vaccination. Adequate social mobilisation and school-based vaccination, supplemented by out-reach activities, were considered important facilitating factors to achieve high coverage. There was some support for a campaign approach to vaccine delivery. CONCLUSIONS: Given the high level of support for a vaccine against cervical cancer and the experience of reaching pastoralist and slum-dwellers for other immunizations, implementing an HPV vaccine programme should be feasible in such hard-to-reach communities. This may require additional delivery strategies in addition to the standard school-based delivery, with vaccine offered at multiple venues, potentially through a campaign approach. PMID- 26115526 TI - Bioelectrochemically-assisted anaerobic composting process enhancing compost maturity of dewatered sludge with synchronous electricity generation. AB - Bioelectrochemically-assisted anaerobic composting process (AnCBE) with dewatered sludge as the anode fuel was constructed to accelerate composting of dewatered sludge, which could increase the quality of the compost and harvest electric energy in comparison with the traditional anaerobic composting (AnC). Results revealed that the AnCBE yielded a voltage of 0.60 +/- 0.02 V, and total COD (TCOD) removal reached 19.8 +/- 0.2% at the end of 35 d. The maximum power density was 5.6 W/m(3). At the end of composting, organic matter content (OM) reduction rate increased to 19.5 +/- 0.2% in AnCBE and to 12.9 +/- 0.1% in AnC. The fuzzy comprehensive assessment (FCA) result indicated that the membership degree of class I of AnCBE compost (0.64) was higher than that of AnC compost (0.44). It was demonstrated that electrogenesis in the AnCBE could improve the sludge stabilization degree, accelerate anaerobic composting process and enhance composting maturity with bioelectricity generation. PMID- 26115527 TI - Protozoan grazing reduces the current output of microbial fuel cells. AB - Several experiments were conducted to determine whether protozoan grazing can reduce current output from sediment microbial fuel cells. When marine sediments were amended with eukaryotic inhibitors, the power output from the fuel cells increased 2-5-fold. Quantitative PCR showed that Geobacteraceae sequences were 120 times more abundant on anodes from treated fuel cells compared to untreated fuel cells, and that Spirotrichea sequences in untreated fuel cells were 200 times more abundant on anode surfaces than in the surrounding sediments. Defined studies with current-producing biofilms of Geobacter sulfurreducens and pure cultures of protozoa demonstrated that protozoa that were effective in consuming G. sulfurreducens reduced current production up to 91% when added to G. sulfurreducens fuel cells. These results suggest that anode biofilms are an attractive food source for protozoa and that protozoan grazing can be an important factor limiting the current output of sediment microbial fuel cells. PMID- 26115528 TI - Optimization of a wet microalgal lipid extraction procedure for improved lipid recovery for biofuel and bioproduct production. AB - Methods to convert microalgal biomass to bio based fuels and chemicals are limited by several processing and economic hurdles. Research conducted in this study modified/optimized a previously published procedure capable of extracting transesterifiable lipids from wet algal biomass. This optimization resulted in the extraction of 77% of the total transesterifiable lipids, while reducing the amount of materials and temperature required in the procedure. In addition, characterization of side streams generated demonstrated that: (1) the C/N ratio of the residual biomass or lipid extracted (LE) biomass increased to 54.6 versus 10.1 for the original biomass, (2) the aqueous phase generated contains nitrogen, phosphorous, and carbon, and (3) the solid precipitate phase was composed of up to 11.2 wt% nitrogen (70% protein). The ability to isolate algal lipids and the possibility of utilizing generated side streams as products and/or feedstock material for downstream processes helps promote the algal biorefinery concept. PMID- 26115529 TI - Optimization of process configuration and strain selection for microalgae-based biodiesel production. AB - A mathematical model was developed for the design of microalgae-based biodiesel production system by systematically integrating all the production stages and strain properties. Through the hypothetical case study, the model suggested the most economical system configuration for the selected microalgae strains from the available processes at each stage, thus resulting in the cheapest biodiesel production cost, S$2.66/kg, which is still higher than the current diesel price (S$1.05/kg). Interestingly, the microalgae strain properties, such as lipid content, effective diameter and productivity, were found to be one of the major factors that significantly affect the production cost as well as system configuration. PMID- 26115530 TI - Spatially Confined Hybridization of Nanometer-Sized NiFe Hydroxides into Nitrogen Doped Graphene Frameworks Leading to Superior Oxygen Evolution Reactivity. AB - Nanometer-sized hydroxide active centers are uniformly and strongly hybridized into a graphene framework by means of defect-anchored nucleation and spatially confined growth, resulting in a superior electrocatalyst for oxygen evolution reaction. This family of strongly coupled complexes and the topology-assisted fabrication strategy is expected to open up new avenues of research. It sheds light on a novel branch of advanced nano-architectured materials. PMID- 26115531 TI - Subwavelength Gold Grating as Polarizers Integrated with InP-Based InGaAs Sensors. AB - There are currently growing needs for polarimetric imaging in infrared wavelengths for broad applications in bioscience, communications and agriculture, etc. Subwavelength metallic gratings are capable of separating transverse magnetic (TM) mode from transverse electric (TE) mode to form polarized light, offering a reliable approach for the detection in polarization way. This work aims to design and fabricate subwavelength gold gratings as polarizers for InP based InGaAs sensors in 1.0-1.6 MUm. The polarization capability of gold gratings on InP substrate with pitches in the range of 200-1200 nm (fixed duty cycle of 0.5) has been systematically studied by both theoretical modeling with a finite difference time-domain (FDTD) simulator and spectral measurements. Gratings with 200 nm lines/space in 100-nm-thick gold have been fabricated by electron beam lithography (EBL). It was found that subwavelength gold gratings directly integrated on InP cannot be applied as good polarizers, because of the existence of SPP modes in the detection wavelengths. An effective solution has been found by sandwiching the Au/InP bilayer using a 200 nm SiO2 layer, leading to significant improvement in both TM transmission and extinction ratio. At 1.35 MUm, the improvement factors are 8 and 10, respectively. Therefore, it is concluded that the Au/SiO2/InP trilayer should be a promising candidate of near infrared polarizers for the InP-based InGaAs sensors. PMID- 26115532 TI - Treatment preferences of psychotherapy patients with chronic PTSD. AB - OBJECTIVE: Patient treatment preference may moderate treatment effect in major depressive disorder (MDD) studies. Little research has addressed preference in posttraumatic stress disorder (PTSD); almost none has assessed actual patients' PTSD psychotherapy preferences. From a 14-week trial of chronic PTSD comparing prolonged exposure, relaxation therapy, and interpersonal psychotherapy, we report treatment preferences of the 110 randomized patients, explore preference correlates, and assess effects on treatment outcome. METHOD: Patients recruited between 2008 and 2013 with chronic DSM-IV PTSD (Clinician-Administered PTSD Scale [CAPS] score >= 50) received balanced, scripted psychotherapy descriptions prerandomization and indicated their preferences. Analyses assessed relationships of treatment attitudes to demographic and clinical factors. We hypothesized that patients randomized to preferred treatments would have better outcomes, and to unwanted treatment worse outcomes. RESULTS: Eighty-seven patients (79%) voiced treatment preferences or disinclinations: 29 (26%) preferred prolonged exposure, 29 (26%) preferred relaxation therapy, and 56 (50%) preferred interpersonal psychotherapy (Cochran Q = 18.46, P < .001), whereas 29 (26%) were disinclined to prolonged exposure, 18 (16%) to relaxation therapy, and 3 (3%) to interpersonal psychotherapy (Cochran Q = 22.71, P < .001). Several baseline clinical variables correlated with treatment preferences. Overall, treatment preference/disinclination did not predict change in CAPS score, treatment response, or dropout. Comorbidly depressed patients receiving unwanted treatment had worse final CAPS scores. CONCLUSION: These exploratory findings are the first relating patients' PTSD psychotherapy preferences to outcome. Despite explanations emphasizing prolonged exposure's greater empirical support, patients significantly preferred interpersonal psychotherapy. Preference subtly affected psychotherapy outcome; depression appeared an important moderator of the effect of unwanted treatment on outcome. Potential biases to avoid in future research are discussed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00739765. PMID- 26115533 TI - Prevention of peritendinous adhesions with electrospun polyethylene glycol/polycaprolactone nanofibrous membranes. AB - Postoperative adhesion formation is the major complication that could occur after acute tendon surgery. The application of an anti-adhesive membrane at the post surgical site is deemed as a potential way to solve this problem by preventing adhesive fibrotic tissue development. In this study, we fabricated electrospun composite poly(ethylene glycol) (PEG)/poly(caprolactone) (PCL) nanofibrous membrane (NFM) to prevent peritendinous adhesions, which could act as a barrier between the tendon and surrounding tissues, without interrupting mass transfer and normal tendon gliding. PCL/PEG NFMs of 0% PEG (PCL), 25% PEG (25PECL), 50% PEG (50PECL) and 75% PEG (75PECL) were prepared and characterized for physico chemical properties. The PCL NFM shows the lowest protein permeability while 25PECL NFM exhibited the largest fiber diameter, smallest pore size and the largest ultimate stress and strain. The 75PECL NFM had the lowest water contact angle and the highest Young's modulus. In vitro cell adhesion and migration experiments with fibroblasts indicate that all NFMs could prevent cell penetration, with 75PECL NFM having the least cell attachment. In vivo application of 75PECL NFM on the repaired site of rabbit flexor tendon rupture model demonstrated improved efficacy compared with the PCL NFM and a commercial anti-adhesion barrier (SeprafilmTM), from gross observation, histological analysis and functional assays. We concluded that 75PECL NFM could function as an effective anti-adhesion membrane after tendon surgery in a clinical setting. PMID- 26115534 TI - Interaction of poloxamine block copolymers with lipid membranes: Role of copolymer structure and membrane cholesterol content. AB - Interactions of X-shaped poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymers with cell membranes were investigated recording the pi-A isotherms of monolayer systems of dipalmitoylphosphatidylcholine (DPPC):cholesterol 100:0; 80:20 and 60:40 mol ratio and evaluating the capability of the copolymers to trigger haemolysis or to protect from haemolytic agents. Four varieties of poloxamine (Tetronic 904, 908, 1107 and 1307) were chosen in order to cover a wide range of EO and PO units contents and molecular weights, and compared to a variety of poloxamer (Pluronic P85). The pi-A isotherms revealed that the greater the content in cholesterol, the stronger the interaction of the block copolymers with the lipids monolayer. The interactions were particularly relevant at low pressures and low lipid proportions, mimicking the conditions of damaged membranes. Relatively hydrophobic copolymers bearing short PEO blocks (e.g., T904 and P85) intercalated among the lipids expanding the surface area (DeltaGexc) but not effectively sealing the pores. These varieties showed haemolytic behavior. Oppositely, highly hydrophilic copolymers bearing long PEO blocks (e.g., T908, T1107 and T1307) caused membrane contraction and outer leaflet sealing due to strong interactions of PEO with cholesterol and diamine core with phospholipids. These later varieties were not haemolytic and exerted a certain protective effect against spontaneous haemolysis for both intact erythrocytes and cholesterol-depleted erythrocytes. PMID- 26115535 TI - Monocyclic and bicyclic monoterpenes in air of German daycare centers and human biomonitoring in visiting children, the LUPE 3 study. AB - To investigate the assumed association between indoor air pollution with monoterpenes (MTps) and the internal MTp exposure of occupants, a comparative study was performed in daycare centers in two federal states of Germany. Three well-known monoterpenoid air pollutants, viz. alpha-pinene (alphaPN), Delta(3) carene (CRN), and R-limonene (LMN), were measured in indoor air in 45 daycare centers. Additionally, urine samples of 222 children visiting these facilities were collected in the evening after a full-day stay. Altogether 11 MTp metabolites were analyzed in the urine samples using a novel highly sensitive and selective gas chromatographic-tandem-mass spectrometric procedure. The medians (95th percentiles) of the MTp levels in indoor air were 9.1 MUg m(-3) (94 MUg m( 3)) for LMN, 2.6 MUg m(-3) (13 MUg m(-3)) for alphaPN, and <1.0 MUg m(-3) (3.2 MUg m(-3)) for CRN. None of the day care centers exceeded the German health precaution or hazard guide value. In spite of the low MTp air exposure, the urine analyses revealed an exposure to the three monoterpenes in almost all children. The median levels of MTp metabolites in urine were 0.11 mg L(-1) for LMN-8,9-OH, 0.10 mg L(-1) for LMN-1,2-OH, 49 MUg L(-1) for PA, 2.9 MUg L(-1) for POH, 5.2 MUg L(-1) for tCAR, and 4.1 MUg L(-1) for cCAR (LMN metabolites), 7.2 MUg L(-1) for MYR, 19 MUg L(-1) for tVER, and 19 MUg L(-1) for cVER (alphaPN metabolites), as well as 8.2 MUg L(-1) for CRN-10-COOH (CRN metabolite). Statistically significant and strong correlations among the urinary metabolites of each MTp were found. Moreover, statistical associations between LMN metabolites and the LMN indoor air levels were revealed. However, the weakness of the associations indicates a considerable impact of other MTp sources, e.g. diet and consumer products, on the internal exposure. PMID- 26115536 TI - Towards a non-animal risk assessment for anti-androgenic effects in humans. AB - Toxicology testing is undergoing a transformation from a system based on high dose studies in laboratory animals to one founded primarily on in vitro methods that evaluate changes in normal cellular signalling pathways using human-relevant cells or tissues. We review the tools and approaches that could be used to develop a non-animal safety assessment for anti-androgenic effects in humans, with a focus on the molecular initiating events (MIEs) that human disorders indicate critical for normal functioning of the hypothalamus-pituitary-testicular (HPT) axis. In vitro test systems exist which can be used to characterize the effects of test chemicals on some MIEs such as androgen receptor antagonism, inhibition of steroidogenic enzymes or 5alpha-reductase inhibition. When used alongside information describing the pharmacokinetics of a specific chemical exposure, these could be used to inform a pathways-based safety assessment. However, some parts of the HPT axis such as events occurring in the hypothalamus or pituitary are not well represented by accepted in vitro methods. In vitro tools to characterize perturbations in these events need to be developed before a fully integrated model of the HPT axis can be described. Knowledge gaps also exist which prevent us from using in vitro data to predict the type and severity of in vivo effect(s) that could arise from a given level of in vitro anti androgenic activity. This means that more work is needed to reliably link an MIE with an adverse outcome. However, especially for chemicals with low anti androgenic activity, human exposure data can be used to put in vitro mode of action data into context for risk-based safety decision-making. PMID- 26115538 TI - Selection and Evaluation of Reference Genes for Reverse Transcription Quantitative PCR Expression Studies in a Thermophilic Bacterium Grown under Different Culture Conditions. AB - The phylum Deinococcus-Thermus is a deeply-branching lineage of bacteria widely recognized as one of the most extremophilic. Members of the Thermus genus are of major interest due to both their bioremediation and biotechnology potentials. However, the molecular mechanisms associated with these key metabolic pathways remain unknown. Reverse-transcription quantitative PCR (RT-qPCR) is a high throughput means of studying the expression of a large suite of genes over time and under different conditions. The selection of a stably-expressed reference gene is critical when using relative quantification methods, as target gene expression is normalized to expression of the reference gene. However, little information exists as to reference gene selection in extremophiles. This study evaluated 11 candidate reference genes for use with the thermophile Thermus scotoductus when grown under different culture conditions. Based on the combined stability values from BestKeeper and NormFinder software packages, the following are the most appropriate reference genes when comparing: (1) aerobic and anaerobic growth: TSC_c19900, polA2, gyrA, gyrB; (2) anaerobic growth with varied electron acceptors: TSC_c19900, infA, pfk, gyrA, gyrB; (3) aerobic growth with different heating methods: gyrA, gap, gyrB; (4) all conditions mentioned above: gap, gyrA, gyrB. The commonly-employed rpoC does not serve as a reliable reference gene in thermophiles, due to its expression instability across all culture conditions tested here. As extremophiles exhibit a tendency for polyploidy, absolute quantification was employed to determine the ratio of transcript to gene copy number in a subset of the genes. A strong negative correlation was found to exist between ratio and threshold cycle (CT) values, demonstrating that CT changes reflect transcript copy number, and not gene copy number, fluctuations. Even with the potential for polyploidy in extremophiles, the results obtained via absolute quantification indicate that relative quantification is appropriate for RT-qPCR studies with this thermophile. PMID- 26115539 TI - The principles of whole-cell modeling. AB - Whole-cell models which comprehensively predict how phenotypes emerge from genotype promise to enable rational bioengineering and precision medicine. Here, we outline the key principles of whole-cell modeling which have emerged from our work developing bacterial whole-cell models: single-cellularity; functional, genetic, molecular, and temporal completeness; biophysical realism including temporal dynamics and stochastic variation; species-specificity; and model integration and reproducibility. We also outline the whole-cell model construction process, highlighting existing resources. Numerous challenges remain to achieving fully complete models including developing new experimental tools to more completely characterize cells and developing a strong theoretical understanding of hybrid mathematics. Solving these challenges requires collaboration among computational and experimental biologists, biophysicists, biochemists, applied mathematicians, computer scientists, and software engineers. PMID- 26115540 TI - Correction: Mapping of Replication Origins in the X Inactivation Center of Vole Microtus levis Reveals Extended Replication Initiation Zone. PMID- 26115537 TI - Pharmacokinetics of bisphenol A in humans following a single oral administration. AB - BACKGROUND: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA. OBJECTIVE: To reduce uncertainties about the metabolism and excretion of BPA in humans following oral administration. METHODS: We exposed six men and eight women to 100 MUg/kg bw of deuterated BPA (d6-BPA) by oral administration and conducted blood and urine analysis over a three day period. The use of d6-BPA allowed administered d6-BPA to be distinguished from background native (unlabeled) BPA. We calculated the rate of oral absorption, serum elimination, half-life, area under the curve (AUC), urinary excretion, and metabolism to glucuronide and sulfate conjugates. RESULTS: Mean serum total (unconjugated and conjugated) d6 BPA Cmax of 1711 nM (390 ng/ml) was observed at Tmax of 1.1 +/- 0.50h. Unconjugated d6-BPA appeared in serum within 5-20 min of dosing with a mean Cmax of 6.5 nM (1.5 ng/ml) observed at Tmax of 1.3 +/- 0.52 h. Detectable blood levels of unconjugated or total d6-BPA were observed at 48 h in some subjects at concentrations near the LOD (0.001-0.002 ng/ml). The half-times for terminal elimination of total d6-BPA and unconjugated d6-BPA were 6.4 +/- 2.0 h and 6.2 +/ 2.6h, respectively. Recovery of total administered d6-BPA in urine was 84-109%. Most subjects (10 of 14) excreted >90% as metabolites within 24h. CONCLUSIONS: Using more sensitive methods, our study expands the findings of other human oral pharmacokinetic studies. Conjugation reactions are rapid and nearly complete with unconjugated BPA comprising less than 1% of the total d6-BPA in blood at all times. Elimination of conjugates into urine largely occurs within 24h. PMID- 26115541 TI - Meeting Report: International Symposium on the Genetics of Aging and Life History II. AB - The second International Symposium on the Genetics of Aging and Life History was held at the campus of Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea, from May 14 to 16, 2014. Many leading scientists in the field of aging research from all over the world contributed to the symposium by attending and presenting their recent work and thoughts. The aim of the symposium was to stimulate international collaborations and interactions among scientists who work on the biology of aging. In the symposium, the most recent and exciting work on aging research was presented, covering a wide range of topics, including the genetics of aging, age-associated diseases, and cellular senescence. The work was conducted in various organisms, includingC. elegans, mice, plants, and humans. Topics covered in the symposium stimulated discussion of novel directions for future research on aging. The meeting ended with a commitment for the third International Symposium on the Genetics of Aging and Life History, which will be held in 2016. PMID- 26115543 TI - Reexamining Interstage Home Monitoring After the Norwood Operation. PMID- 26115542 TI - Metabolomics analysis identifies novel plasma biomarkers of cystic fibrosis pulmonary exacerbation. AB - BACKGROUND: Cystic fibrosis (CF) lung disease is characterized by infection, inflammation, lung function decline, and intermittent pulmonary exacerbations. However, the link between pulmonary exacerbation and lung disease progression remains unclear. Global metabolomic profiling can provide novel mechanistic insight into a disease process in addition to putative biomarkers for future study. Our objective was to investigate how the plasma metabolomic profile changes between CF pulmonary exacerbation and a clinically well state. METHODS: Plasma samples and lung function data were collected from 25 CF patients during hospitalization for a pulmonary exacerbation and during quarterly outpatient clinic visits. In collaboration with Metabolon, Inc., the metabolomic profiles of matched pair plasma samples, one during exacerbation and one at a clinic visit, were analyzed using gas and liquid chromatography coupled with mass spectrometry. Compounds were identified by comparison to a library of standards. Mixed effects models that controlled for nutritional status and lung function were used to test for differences and principal components analysis was performed. RESULTS: Our population had a median age of 27 years (14-39) and had a median FEV1 % predicted of 65% (23-105%). 398 total metabolites were identified and after adjustment for confounders, five metabolites signifying perturbations in nucleotide (hypoxanthine), nucleoside (N4-acetylcytidine), amino acid (N-acetylmethionine), carbohydrate (mannose), and steroid (cortisol) metabolism were identified. Principal components analysis provided good separation between the two clinical phenotypes. CONCLUSIONS: Our findings provide putative metabolite biomarkers for future study and allow for hypothesis generation about the pathophysiology of CF pulmonary exacerbation. PMID- 26115545 TI - Surgical Anatomy of the Whole Facial Nerve for Enabling Craniofacial and Regenerative Medicine Translational Research in Swine. PMID- 26115544 TI - Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement. AB - BACKGROUND: Aortic diameter is an imperfect predictor of aortic complications in connective tissue disorders (CTDs). Novel indicators of vascular phenotype severity such as aortic stiffness and vertebral tortuosity index have been proposed. We assessed the relation between aortic stiffness by cardiac MRI, surgical root replacement, and rates of aortic root dilation in children and young adults with CTDs. METHODS AND RESULTS: Retrospective analysis of cardiac MRI data on children and young adults with a CTD was performed to derive aortic stiffness measures (strain, distensibility, and beta-stiffness index) at the aortic root, ascending aorta, and descending aorta. Vertebral tortuosity index was calculated as previously described. Rate of aortic root dilation before cardiac MRI was calculated as change in echocardiographic aortic root diameter z score per year. In 83 CTD patients (median age, 24 years; range, 1-55; 17% <18 years of age; 60% male), ascending aorta distensibility was reduced in comparison with published normative values: median z score, -1.93 (range, -8.7 to 1.3; P<0.0001 versus normals). Over a median follow-up period of 2.7 years, there were no aortic dissections or deaths, but 16 of 83 (19%) patients underwent surgical aortic root replacement. In multivariable analysis, lower aortic root strain (P=0.05) and higher vertebral tortuosity index (P=0.01) were independently associated with aortic root replacement. Lower ascending aorta strain (P=0.02) was associated with a higher rate of aortic root dilation. CONCLUSIONS: Higher aortic stiffness is associated with higher rates of surgical aortic replacement and aortic root dilation in children and young adults with CTDs. PMID- 26115546 TI - Eptifibatide Salvage of Arterial Anastomotic Thrombosis in Lower Extremity Free Flap Reconstruction: A Case Report. PMID- 26115547 TI - In Situ Deactivation of Interleukin-6 Enhances Early Peripheral Nerve Regeneration in a Murine Injury Model. AB - BACKGROUND: Systemic alteration of interleukin-6 (IL-6) influences peripheral nerve regeneration. We investigated the potential influences of in situ (at the coaptation site) IL-6 modulation in a peripheral-nerve-transection/sciatic-nerve graft in vivo model. METHODS: We quantified the elongation of regenerating axons, the number of arborizing axons, and the number of branches per arborizing axon 7 days after the injury in mice expressing axonal fluorescent proteins (thy-1-YFP mice). Sciatic nerves from nonexpressing mice (C57Bl6 or IL-6(-/-) mice) were grafted into those expressing yellow fluorescent protein. We altered the in situ IL-6 concentration by loading a topical gelatin sponge with an inhibiting IL-6 receptor antibody or IL-6 combined with a soluble IL-6 receptor. Sciatic nerves from IL-6(-/-) mice were grafted into an additional group. The contralateral sham operated side served as control in all the groups. RESULTS: Axonal elongation increased significantly with the in situ application of the IL-6 receptor antibody, while topical IL-6 significantly reduced the regeneration distance. The number of arborizing axons increased significantly in nerves grafted from IL-6(-/ ) mice, whereas branches per arborizing axons remained stable. CONCLUSION: In situ IL-6 receptor inhibition and IL-6(-/-) nerve grafting enhance early peripheral nerve regeneration in an acute murine injury model. PMID- 26115548 TI - Exogenous malic and acetic acids reduce cadmium phytotoxicity and enhance cadmium accumulation in roots of sunflower plants. AB - There is increasing evidence showing that low molecular weight organic acids (LMWOA) are involved in heavy metal resistance mechanisms in plants. The aim of this study was to investigate the effects of exogenous malic (MA) or acetic (AA) acids on the toxicity and accumulation of cadmium (Cd) in sunflower (Helianthus annuus L.). For this purpose, plants were grown in hydroponics under controlled conditions. Single Cd stress (5 MUM Cd for 14 days) induced strong phytotoxic effects, as indicated by a decrease in all growth parameters, concentration of photosynthetic pigments, and root activity, as well as a high level of hydrogen peroxide (H2O2) accumulation. Exogenous MA or AA (250 or 500 MUM) applied to the Cd-containing medium enhanced the accumulation of Cd by the roots and limited Cd translocation to the shoots. Moreover, the MA or AA applied more or less reduced Cd phytotoxicity by increasing the growth parameters, photosynthetic pigment concentrations, decreasing accumulation of H2O2, and improving the root activity. Of the studied organic acids, MA was much more efficient in mitigation of Cd toxicity than AA, probably by its antioxidant effects, which were stronger than those of AA. Plant response to Cd involved decreased production of endogenous LMWOA, probably as a consequence of severe Cd toxicity. The addition of MA or AA to the medium increased endogenous accumulation of LMWOA, especially in the roots, which could be beneficial for plant metabolism. These results imply that especially MA may be involved in the processes of Cd uptake, translocation, and tolerance in plants. PMID- 26115549 TI - Overexpression of two R2R3-MYB genes from Scutellaria baicalensis induces phenylpropanoid accumulation and enhances oxidative stress resistance in transgenic tobacco. AB - MYB proteins are involved in many significant physiological and biochemical processes, including regulation of primary and secondary metabolism, flavonoid biosynthesis, response to various biotic and abiotic stresses, hormone synthesis and signal transduction. The functions of R2R3-MYB proteins in Scutellaria baicalensis Georgi under abiotic stress, however, has not been elucidated. To study the molecular mechanism by which MYB2 and MYB7 respond to abiotic stress in S. baicalensis, we analyzed the phenylpropanoid content, growth phenotype, antioxidant enzyme activity and flavonoid synthesis-associated gene expression in SbMYB2 or SbMYB7-overexpressing transgenic tobacco plants after treatment with NaCl, mannitol and abscisic acid (ABA). The transgenic tobacco showed a higher fresh weight than did the wild type (WT) tobacco. In contrast, antioxidant enzyme activity and flavonoid synthesis-related gene expression were markedly higher in WT tobacco after treatment with NaCl, mannitol and ABA, as compared to transgenic plants, This is likely because increased phenylpropanoid accumulation in transgenic tobacco plants played a central role in abiotic stress resistance. These results indicate that overexpression of SbMYB2 or SbMYB7 increased phenylpropanoid accumulation and enhanced NaCl, mannitol and ABA stresses tolerance in transgenic tobacco. PMID- 26115550 TI - Amplified and localized photoswitching of TiO2 by micro- and nanostructuring. AB - Fast photoswitching of wetting properties is important for the development of micro/nanofluidic systems and lab-on-a-chip devices. Here, we show how structuring the surface amplifies photoswitching properties. Atomic layer deposited titanium dioxide (TiO2) has phototunable hydrophilic properties due to its surface chemistry, but microscale overhang pillars and additional nanoscale topography can override the chemistry and make the surface superhydrophobic. Three switching processes are achieved simply by controlling the UV exposure time: from (1) rolling superhydrophobic to sticky superhydrophobic (Cassie-Baxter to Wenzel), (2) superhydrophobic to hydrophilic, and (3) superhydrophobic to superhydrophilic after 1, 5, and 10 min of UV exposure, respectively. We report the fastest reversible switching to date: 1 min of UV exposure is enough to promote a rolling-to-sticky transition, and mild heating (30 min at 60 degrees C) is sufficient for recovery. This performance is caused by a combination of the photoswitching properties of TiO2, the micropillar overhang geometry, and surface nanostructuring. We demonstrate that the switching also can be performed locally by introducing microwriting under a water droplet. PMID- 26115551 TI - Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection. AB - BACKGROUND: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance associated virus (RAV) and therapeutic outcomes have not been well-understood. METHODS: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy. RESULTS: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients. CONCLUSIONS: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy. PMID- 26115552 TI - Anodic, cathodic, and annihilation electrochemiluminescence emissions from hydrophilic conjugated polymer dots in aqueous medium. AB - Hydrophilic poly[2-methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) conjugated polymer dots (CP-dots) capped by Triton X-100 were synthesized. For the first time, the electrochemiluminescence (ECL) emission of CP-dots was investigated in aqueous solution. At the glassy carbon/water interface, the CP dots have excellent and multichannel ECL properties, such as having annihilation ECL activity in the absence of coreactants, and give bright anodic and cathodic ECL emission (590 nm) in the presence of tri-n-propylamine (TPrA) and peroxydisulfate (S2O8(2-)), respectively. The versatile ECL properties of the hydrophilic CP-dots combined with their low cytotoxicity, good biocompatibility, and easy bioconjugation may suggest promising applications of this new type of ECL nanomaterial in novel biosensing and bioimaging, and new types of light emitting devices. PMID- 26115553 TI - Phonons and elasticity in critically coordinated lattices. AB - Much of our understanding of vibrational excitations and elasticity is based upon analysis of frames consisting of sites connected by bonds occupied by central force springs, the stability of which depends on the average number of neighbors per site z. When z < zc ~ 2d, where d is the spatial dimension, frames are unstable with respect to internal deformations. This pedagogical review focuses on the properties of frames with z at or near zc, which model systems like randomly packed spheres near jamming and network glasses. Using an index theorem, N0 -NS = dN -NB relating the number of sites, N, and number of bonds, NB, to the number, N0, of modes of zero energy and the number, NS, of states of self stress, in which springs can be under positive or negative tension while forces on sites remain zero, it explores the properties of periodic square, kagome, and related lattices for which z = zc and the relation between states of self stress and zero modes in periodic lattices to the surface zero modes of finite free lattices (with free boundary conditions). It shows how modifications to the periodic kagome lattice can eliminate all but trivial translational zero modes and create topologically distinct classes, analogous to those of topological insulators, with protected zero modes at free boundaries and at interfaces between different topological classes. PMID- 26115554 TI - Vortex-aligned fullerene nanowhiskers as a scaffold for orienting cell growth. AB - A versatile method for the rapid fabrication of aligned fullerene C60 nanowhiskers (C60NWs) at the air-water interface is presented. This method is based on the vortex motion of a subphase (water), which directs floating C60NWs to align on the water surface according to the direction of rotational flow. Aligned C60NWs could be transferred onto many different flat substrates, and, in this case, aligned C60NWs on glass substrates were employed as a scaffold for cell culture. Bone forming human osteoblast MG63 cells adhered well to the C60NWs, and their growth was found to be oriented with the axis of the aligned C60NWs. Cells grown on aligned C60NWs were more highly oriented with the axis of alignment than when grown on randomly oriented nanowhiskers. A study of cell proliferation on the C60NWs revealed their low toxicity, indicating their potential for use in biomedical applications. PMID- 26115555 TI - Iron impurities as the active sites for peroxidase-like catalytic reaction on graphene and its derivatives. AB - We established four kinds of good dispersing systems of graphene and its derivatives with different structural characteristics to estimate their peroxidase-like activity. Besides graphene oxide (GO), it is demonstrated that defect-free graphene, low-oxygen graphene, and iron(III)-doped graphene oxide (GO Fe) are all capable of H2O2 activation to oxidize peroxidase substrates. As for defect-free graphene, the dispersibility in reaction medium exerts great impact on its catalytic activity and our further judgements concerning the nature of active sites. Improved stability and further exfoliation of defect-free graphene in reaction medium are beneficial to the access of reactants to active sites on the basal planes and enhance its peroxidase-like activity, which is superior to that of low-oxygen graphene and much higher than that of GO. In addition, their peroxidase-like activity can be greatly inhibited by the addition of iron chelators. Interestingly, the introduction of trace ferric ions into GO does not lead to an apparent change except for remarkable increase of its peroxidase-like activity. Therefore, we propose that the observed iron impurities rather than the doped nonmetallic heteroatoms play an important role in the peroxidase-like activity of graphene and its derivatives. In this light, saturated iron(III) was immobilized onto the oxygen-donor coordination of GO to immensely promote its activity. The peroxidase-like activity of the prepared GO-Fe was systematically evaluated by using 3,3',5,5'-tetramethylbenzidine and pyrogallol as peroxidase substrates and was compared to that of horseradish peroxidase and hemin. As a result, GO-Fe shows excellent peroxidase-like catalytic activity, which is comparable to that of hemin. Furthermore, GO-Fe was used for the quantitative detection of H2O2 and glucose. PMID- 26115556 TI - A time to serve. PMID- 26115557 TI - MyPlate celebrates 4 years. PMID- 26115559 TI - What is translational research? Concepts and applications in nutrition and dietetics. AB - This monograph is tenth in a series of articles focused on research design and analysis, and provides an overview of translational research concepts. Specifically, this article presents models and processes describing translational research, defines key terms, discusses methodological considerations for speeding the translation of nutrition research into practice, illustrates application of translational research concepts for nutrition practitioners and researchers, and provides examples of translational research resources and training opportunities. To promote the efficiency and translation of evidence-based nutrition guidelines into routine clinical-, community-, and policy-based practice, the dissemination and implementation phases of translational research are highlighted and illustrated in this monograph. PMID- 26115560 TI - A randomized trial on the effects of 2010 Dietary Guidelines for Americans and Korean diet patterns on cardiovascular risk factors in overweight and obese adults. AB - BACKGROUND: Dietary patterns that are considered healthy (eg, the Dietary Approaches to Stop Hypertension diet and Mediterranean diet) may be more successful in reducing typical cardiovascular disease risks compared to dietary patterns considered unhealthy (eg, energy-dense diets such as the typical American diet). OBJECTIVE: This study assessed the effects of a Korean diet, the 2010 Dietary Guidelines for Americans (DGA), and a typical American diet on cardiometabolic risk factors, including lipid levels and blood pressure, in overweight, non-Asian individuals in the United States with elevated low-density lipoprotein cholesterol. DESIGN/INTERVENTION: The study was a three-period crossover, controlled-feeding study from January 2012 to May 2012. Thirty-one subjects were randomly allocated to one of six possible sequential orders for consuming the three diets for 4 weeks, each separated by a 10-day break. Data analysis included 27 subjects on the Korean diet periods and 29 in the DGA and typical American diet periods. Subjects remained weight stable. MAIN OUTCOME MEASURES: Lipid profile, blood pressure, insulin, glucose, and 24-hour urinary sodium were determined at baseline and at the end of each diet period. STATISTICAL ANALYSES PERFORMED: The additive main effects multiplicative interactions model was used to test for a subject by diet interaction. Differences among diets were determined using a mixed-models procedure (PROC MIXED) with random intercept for each subject. RESULTS: Total cholesterol and low density lipoprotein cholesterol significantly decreased on Korean (P<0.0001 and P<0.01, respectively) and DGA (P<0.01 and P<0.05, respectively) diets, but not on the typical American diet. Although an unfavorable outcome, high-density lipoprotein cholesterol significantly decreased on all three diets (Korean: P<0.0001; DGA: P<0.0001; typical American: P<0.05). No diet had a significant effect on serum triglycerides, but a slight increase in triglycerides in the Korean and decrease in the DGA resulted in a significant difference between these two diets (P<0.01). All three diets caused modest decreases in systolic and diastolic blood pressure, which reached statistical significance for DGA only (P<0.05 and P<0.01, respectively). No diet had significant effect on fasting insulin, whereas fasting glucose decreased significantly on the Korean (P<0.01) and typical American (P<0.05) diets only. Urinary sodium output decreased significantly on DGA (P<0.0001). CONCLUSIONS: After a 4-week feeding period, Korean and DGA diet patterns resulted in positive changes in cardiovascular disease risk factors. PMID- 26115562 TI - Communications at the academy: where strategy and trending conspire to shape history. PMID- 26115561 TI - Practice paper of the academy of nutrition and dietetics: principles of productivity in food and nutrition services: applications in the 21st century health care reform era. AB - Food and nutrition services, along with the health care organizations they serve, are becoming increasingly complex. These complexities are driven by sometimes conflicting (if not polarizing) human, department, organization, and environment factors and will require that managers shift how they think about and approach productivity in the context of the greater good of the organization and, perhaps, even society. Traditional, single-factor approaches to productivity measurements, while still valuable in the context of departmental trend analysis, are of limited value when assessing departmental performance in the context of an organization's goals and values. As health care continues to change and new models of care are introduced, food and nutrition services managers will need to consider innovative approaches to improve productivity that are consistent with their individual health care organization's vision and mission. Use of process improvement tools such as Lean and Six Sigma as strategies for evaluating and improving food and nutrition services efficiency should be considered. PMID- 26115563 TI - Is vinegar an effective treatment for glycemic control or weight loss? PMID- 26115564 TI - The TGF-beta superfamily in dendritic cell biology. AB - The TGF-beta superfamily consists of a large group of pleiotropic cytokines that are involved in the regulation of many developmental, physiological and pathological processes. Dendritic cells are antigen-presenting cells that play a key role in innate and adaptive immune responses. Dendritic cells have a complex relationship with the TGF-beta cytokine superfamily being both source and targets for many of these cytokines. Some TGF-beta family members are expressed by dendritic cells and modulate immune responses, for instance through the induction of T cell polarization. Others play a crucial role in the development and function of the different dendritic cell subsets. This review summarizes the current knowledge on the role of TGF-beta family cytokines in dendritic cell biology, focusing on TGF-beta as well as on other, less characterized, members of these important immune mediators. PMID- 26115565 TI - Targeting ion channels in cystic fibrosis. AB - Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause a characteristic defect in epithelial ion transport that plays a central role in the pathogenesis of cystic fibrosis (CF). Hence, pharmacological correction of this ion transport defect by targeting of mutant CFTR, or alternative ion channels that may compensate for CFTR dysfunction, has long been considered as an attractive approach to a causal therapy of this life-limiting disease. The recent introduction of the CFTR potentiator ivacaftor into the therapy of a subgroup of patients with specific CFTR mutations was a major milestone and enormous stimulus for seeking effective ion transport modulators for all patients with CF. In this review, we discuss recent breakthroughs and setbacks with CFTR modulators designed to rescue mutant CFTR including the common mutation F508del. Further, we examine the alternative chloride channels TMEM16A and SLC26A9, as well as the epithelial sodium channel ENaC as alternative targets in CF lung disease, which remains the major cause of morbidity and mortality in patients with CF. Finally, we will focus on the hurdles that still need to be overcome to make effective ion transport modulation therapies available for all patients with CF irrespective of their CFTR genotype. PMID- 26115567 TI - European Code against Cancer 4th Edition: Alcohol drinking and cancer. AB - Alcohol consumption is the third leading risk factor for disease and mortality in Europe. The International Agency for Research on Cancer (IARC) Monographs provide strengthened evidence that the consumption of alcoholic beverages is causally associated with cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum and female breast, even for low and moderate alcohol intakes. The risk of cancer increases in a dose-dependent manner, and the higher the amount of alcohol consumed, the higher the risk of developing cancer. Several biological mechanisms explain the carcinogenicity of alcohol; among them, ethanol and its genotoxic metabolite acetaldehyde play a major role. Taking all this evidence into account, a recommendation of the 4th edition of the European Code against Cancer (ECAC) is: "If you drink alcohol of any type, limit your intake. Not drinking alcohol is better for cancer prevention." PMID- 26115568 TI - Frozen with fear: Conditioned suppression in a virtual reality model of human anxiety. AB - Freezing-like topographies of behavior are elicited in conditioned suppression tasks whereby appetitive behavior is reduced by presentations of an aversively conditioned threat cue relative to a safety cue. Conditioned suppression of operant behavior by a Pavlovian threat cue is an established laboratory model of quantifying the response impairment seen in anxiety disorders. Little is known however about how different response topographies indicative of conditioned suppression are elicited in humans. Here, we refined a novel virtual reality (VR) paradigm in which presentations of a threat cue of unpredictable duration occurred while participants performed an operant response of shooting and destroying boxes searching for hidden gold. The VR paradigm detected significant suppression of response topographies (shots, hits and breaks) for a Pavlovian threat cue relative to a safety cue and novel cue presentations. Implications of the present findings for translational research on appetitive and aversive conflict in anxiety disorders are discussed. PMID- 26115566 TI - Divergent brain functional network alterations in dementia with Lewy bodies and Alzheimer's disease. AB - The clinical phenotype of dementia with Lewy bodies (DLB) is different from Alzheimer's disease (AD), suggesting a divergence between these diseases in terms of brain network organization. To fully understand this, we studied functional networks from resting-state functional magnetic resonance imaging in cognitively matched DLB and AD patients. The DLB group demonstrated a generalized lower synchronization compared with the AD and healthy controls, and this was more severe for edges connecting distant brain regions. Global network measures were significantly different between DLB and AD. For instance, AD showed lower small worldness than healthy controls, while DLB showed higher small-worldness (AD < controls < DLB), and this was also the case for global efficiency (DLB > controls > AD) and clustering coefficient (DLB < controls < AD). Differences were also found for nodal measures at brain regions associated with each disease. Finally, we found significant associations between network performance measures and global cognitive impairment and severity of cognitive fluctuations in DLB. These results show network divergences between DLB and AD which appear to reflect their neuropathological differences. PMID- 26115569 TI - Dynamics of foraging trails in the Neotropical termite Velocitermes heteropterus (Isoptera: Termitidae). AB - Foraging behavior in termites varies with the feeding habits of each species but often occurs through the formation of well-defined trails that connect the nest to food sources in species that build structured nests. We studied the formation of foraging trails and the change in caste ratio during foraging in the termite Velocitermes heteropterus. This species is widespread in Cerrado vegetation where it builds epigeal nests and forages in open-air at night. Our aim was to understand the processes involved in the formation of foraging trails, from the exploration of new unmarked areas to the recruitment of individuals to food and the stabilization of traffic on the trails, as well as the participation of the different castes during these processes. Foraging trails were videotaped in the laboratory and the videos were then analyzed both manually and automatically to assess the flow of individuals and the caste ratio on the trails as well as to examine the spatial organization of traffic over time. Foraging trails were composed of minor workers, major workers, and soldiers. The flow of individuals on the trails gradually increased from the beginning of the exploration of new areas up to the discovery of the food. The caste ratio remained constant throughout the foraging excursion: major workers, minor workers and soldiers forage in a ratio of 8:1:1, respectively. The speed of individuals was significantly different among castes, with major workers and soldiers being significantly faster than minor workers. Overall, our results show that foraging excursions in V. heteropterus may be divided in three different phases, characterized by individual speeds, differential flows and lane segregation. PMID- 26115570 TI - Verruculides A and B, two new protein tyrosine phosphatase 1B inhibitors from an Indonesian ascidian-derived Penicillium verruculosum. AB - Two new merosesquiterpenes, verruculides A (1) and B (2), were isolated from a culture broth of the Indonesian ascidian-derived Penicillium verruculosum TPU1311, together with three known congeners, chrodrimanins A (3), B (4), and H (5). The structures of 1 and 2 were assigned on the basis of their spectroscopic data (1D and 2D NMR, HRMS, UV, CD, and IR). Compound 2 had a linear sesquiterpene moiety and was considered to be the derivative of the biosynthetic precursor for 1 and 3-5. Compounds 1, 3, and 5 inhibited the activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 8.4, 8.5, and 14.9 MUM, respectively. Compound 2 showed 40% inhibition at 23.1 MUM, while 4 was not active at 20.7 MUM. PMID- 26115571 TI - Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. AB - Sustained proliferative capacity is a hallmark of cancer. In mammalian cells proliferation is controlled by the cell cycle, where cyclin-dependent kinases (CDKs) regulate critical checkpoints. CDK4 and CDK6 are considered highly validated anticancer drug targets due to their essential role regulating cell cycle progression at the G1 restriction point. This review provides an overview of recent advances on cyclin dependent kinase inhibitors in general with special emphasis on CDK4 and CDK6 inhibitors and compounds under clinical evaluation. Chemical structures, structure activity relationships, and relevant preclinical properties will be described. PMID- 26115572 TI - New geranylated flavanones from the fruits of Paulownia catalpifolia Gong Tong with their anti-proliferative activity on lung cancer cells A549. AB - Three new geranylated flavanones, named as paucatalinone A (1), B (2), and isopaucatalinone B (3), were isolated from the fruits of Paulownia catalpifolia Gong Tong (Scrophulariaceae). Their structures were well determined by means of IR, MS, 1D and 2D NMR, and CD techniques. Paucatalinone A (1) is the first sample as a dimeric geranylated flavanone derivative isolated from natural products. Paucatalinone A (1) displayed good antiproliferative effects on human lung cancer cells A549 and resulted in a clear increase of the percentage of cells in G1 phase and a decrease in the percentage of cells in S and G2/M phases in comparison with control cells. PMID- 26115574 TI - A highly selective fluorescent probe for direct detection and isolation of mouse embryonic stem cells. AB - Stem cell research has gathered immense attention in the past decade due to the remarkable ability of stem cells for self-renewal and tissue-specific differentiation. Despite having numerous advancements in stem cell isolation and manipulation techniques, there is a need for highly reliable probes for the specific detection of live stem cells. Herein we developed a new fluorescence probe (CDy9) with high selectivity for mouse embryonic stem cells. CDy9 allows the detection and isolation of intact stem cells with marginal impact on their function and capabilities. PMID- 26115575 TI - Hide and seek: Identification and confirmation of small molecule protein targets. AB - Target identification and confirmation for small molecules is often the rate limiting step in drug discovery. A robust method to identify proteins addressed by small molecules is affinity chromatography using chemical probes. These usually consist of the compound of interest equipped with a linker molecule and a proper tag. Recently, methods emerged that allow the identification of protein targets without prior functionalization of the small molecule of interest. The digest offers an update on the newest developments in the area of target identification with special focus on confirmation techniques. PMID- 26115573 TI - Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4. AB - IRAK4 plays a key role in TLR/IL-1 signaling. Previous efforts identified a series of aminopyrimidine IRAK4 inhibitors that possess good potency, but modest kinase selectivity. Exploration of substituents at the C-2 and C-5 positions generated compounds that maintained IRAK4 potency and improved kinase selectivity. Additionally, it was found that the pyrimidine core could be replaced with a pyridine and still retain potency and kinase selectivity. The optimization efforts led to compound 26 which had an IRAK4 IC50 of 0.7 nM, an IC50 of 55 nM on THP-1 cells stimulated with LPS, a TLR4 agonist, and greater than 100-fold selectivity versus 96% of a panel of 306 kinases. PMID- 26115576 TI - Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin. AB - Previous studies on the natural product chlorofusin have shown that the full peptide and azaphilone structure are required for inhibition of the interaction between MDM2 and p53. In the current work, we utilized the cyclic peptide as a template and introduced an azidonorvaline amino acid in place of the ornithine/azaphilone of the natural product and carried out click chemistry with the resulting peptide. From this small library the first ever non-azaphilone containing chlorofusin analog with MDM2/p53 activity was identified. Further studies then suggested that the simple structure of the Fmoc-norvaline amino acid that had undergone a click reaction was also able to inhibit MDM2/p53 interaction. This is an example where studies of a natural product have led to the serendipitous identification of a new small molecule inhibitor of a protein protein interaction. PMID- 26115577 TI - Synthesis and biological evaluation of N-cyclopropylbenzamide-benzophenone hybrids as novel and selective p38 mitogen activated protein kinase (MAPK) inhibitors. AB - A series of hybrid molecules consisting of benzophenones and N-cyclopropyl-3 methylbenzamides were synthesized and biologically evaluated as novel p38 mitogen activated protein kinase (MAPK) inhibitors. In particular, we found that compound 10g displayed potent p38alpha MAPK inhibitory activity (IC50=0.027 MUM), high kinase selectivity, and significant anti-inflammatory activity in THP-1 monocyte cells. PMID- 26115578 TI - Efficacy and safety of beclomethasone dipropionate nasal aerosol in children with perennial allergic rhinitis. AB - BACKGROUND: Beclomethasone dipropionate (BDP) nasal aerosol (non-aqueous) is approved for management of seasonal and perennial allergic rhinitis (PAR) in adolescents and adults. OBJECTIVE: To evaluate the efficacy and safety of BDP nasal aerosol at 80 MUg/day in children with PAR. METHODS: This 12-week, phase 3, double-blinded, placebo-controlled, parallel-group study randomized 547 children (4-11 years old) with PAR to once-daily BDP nasal aerosol at 80 MUg/day or placebo. The primary end point was change from baseline in average morning and evening reflective total nasal symptom score (rTNSS) during the first 6 weeks of treatment in patients 6 to 11 years old. Changes from baseline in average morning and evening instantaneous TNSS (iTNSS) in children 6 to 11 years old and average rTNSS and iTNSS in children 4 to 11 years old were assessed during the first 6 weeks of treatment. RESULTS: Improvements were significantly greater with BDP nasal aerosol than with placebo during the first 6 weeks of treatment in children 6 to 11 years old in average morning and evening rTNSS and iTNSS (mean treatment difference -0.66 [P = .002] and -0.58 [P = .004], respectively). Improvements in average morning and evening rTNSS and iTNSS also were significantly greater in patients 4 to 11 years receiving BDP nasal aerosol than with placebo during the first 6 weeks of treatment (P = .002 and P = .004, respectively). Similar improvements were seen during 12 weeks of treatment. The safety profile of BDP nasal aerosol was comparable to that of placebo. CONCLUSION: The BDP nasal aerosol at 80 MUg/day in children 4 to 11 years old was well tolerated and effective in controlling nasal symptoms of PAR. TRIAL REGISTRATION: www.clinicaltrials.gov, identifier NCT01783548. PMID- 26115579 TI - Surgical treatment of periprosthetic femoral fractures following hip arthroplasty: our institutional experience. AB - PURPOSE: Periprosthetic fractures are one of the most serious complications after hip replacement. The aim of this retrospective study was to evaluate the clinical outcome of surgical treatment of periprosthetic femoral fractures following total hip arthroplasty using treatment algorithm of the Vancouver classification. MATERIALS AND METHODS: Fifty six periprosthetic femoral fractures operated on during the period December 2004-September 2013 were followed-up retrospectively. There were 40 women and 16 men with mean age at the time of surgery 64.7 years (41-88 years). The mean follow-up for the group was 5 years (range, 1-10 years). Periprosthetic fractures were classified according to the Vancouver classification. The clinical evaluation was performed with the Harris hip score, the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and Short Form 8 (SF-8). Bone healing, implant survival, pain, function and complications were recorded. Bone healing and implant stability were evaluated clinically and on plain radiographs. RESULTS: Uneventful bone healing was achieved in 52 cases. In two fractures (one type B1, one type C) nonunion and plate failure occurred. Two cemented stems were revised for aseptic loosening 6.5 and 7 years after fracture fixation. Uncontrollable prosthesis infection and sepsis in a rheumatoid (immunocompromised) patient required disarticulation of the involved extremity. DISCUSSION AND CONCLUSIONS: Periprosthetic femoral fractures are difficult to treat and require complex treatment approach according to risk assessment, fracture type, implant stability, bone stock and medical status of the patient. Using a treatment protocol of the Vancouver classification we obtained satisfactory outcome. PMID- 26115580 TI - Expanding indications of the horizontal belt plate: a technical note. AB - BACKGROUND: Although the standard treatment for articular fractures usually involves open anatomic reduction and internal fixation with the concept of absolute stability, achieving adequate fracture stabilisation in multifragmentary patterns is always challenging. Several anatomical implants were developed to increase stabilisation and improve clinical outcomes in articular fractures. However modern implants, especially in developing countries, are expensive and not always available for routine use. Horizontal rafting plate has recently emerged as an alternative technique to treat complex tibial plateau fractures using simple implants that function as a large washer. OBJECTIVE: This technical note aims to describe horizontal belt plate use for treatment of periarticular fractures including the tibial plateau, thereby expanding its initial indication. CONCLUSION: Horizontal belt plate is an effective, safe, and inexpensive treatment alternative for complex articular fractures. However, the surgeon must carefully analyse the fracture pattern to verify if the horizontal belt plate can be used alone or with traditional techniques. PMID- 26115582 TI - Lives without imagery - Congenital aphantasia. PMID- 26115581 TI - Prognostic factors of health-related quality of life in patients after tibial plafond fracture. A pilot study. AB - BACKGROUND: Tibial plafond fractures are a uncommon injury, and the outcomes described in literature are generally poor. The purposes were to determine the effect of the tibial plafond fractures on general health-related quality of life, and to examine the factors that influence these outcomes. METHODS: Retrospective study of 43 patients with average age of 45.6 (range 18-69) years who were also invited for a clinical and radiological reassessment. The primary outcome measure was quality of life assessed by the Short Form-36 questionnaire. Visual analogue scale for pain, and motion of both ankle and subtalar joints were also assessed. Radiological evaluation was performed to assess bone healing, fracture reduction quality, and tibial alignment. RESULTS: The mean follow-up at last visit was 8.1 (range, 4-12) years. Patients who had suffered plafond fracture had significantly poorer quality of life compared with age- and gender-matched general population of our country regardless of the treatment method used. Multivariate analyses showed that the age had influence on the emotional outcomes, educational level and fracture pattern on physical outcomes, and marital status, fracture reduction quality, and ankle motion on both physical and mental component summaries. CONCLUSION: Tibial plafond fractures have a significant negative impact on general health-related quality of life regardless of the operative treatment used which reflects injury severity. In addition, psychosocial characteristics of patients may influence the outcomes. PMID- 26115583 TI - Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy. AB - Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is an amyloid disorder in Icelandic families caused by an autosomal dominant mutation in the cystatin C gene. Mutant cystatin C forms amyloid deposits in brain arteries and arterioles which are associated with changes in the arterial wall structure, notably deposition of extracellular matrix proteins. In this post-mortem study we examined the neuroinflammatory response relative to the topographical distribution of cystatin C deposition, and associated haemorrhages, in the leptomeninges, cerebrum, cerebellum, thalamus, and midbrain of HCCAA patients. Cystatin C was deposited in all brain areas, grey and white matter alike, most prominently in arteries and arterioles; capillaries and veins were not, or minimally, affected. We also observed perivascular deposits and parenchymal focal deposits proximal to affected arteries. This study shows for the first time, that cystatin C does not exclusively form CAA and perivascular amyloid but also focal deposits in the brain parenchyma. Haemorrhages were observed in all patients and occurred in all brain areas, variable between patients. Microinfarcts were observed in 34.6% of patients. The neuroinflammatory response was limited to the close vicinity of affected arteries and perivascular as well as parenchymal focal deposits. Taken together with previously reported arterial accumulation of extracellular matrix proteins in HCCAA, our results indicate that the central nervous system pathology of HCCAA is characterised by the formation of a glial scar within and around affected arteries. PMID- 26115584 TI - Chronic constant light-induced hippocampal late-phase long-term potentiation impairment in vitro is attenuated by antagonist of D1/D5 receptors. AB - Previous study reported that chronic constant light exposure caused hippocampus dependent long-term memory deficit. However, the underlying cellular mechanism of this impairment is still unclear. Multiple lines of evidence indicated that long term potentiation (LTP) is a cellular model for memory formation. Here we found that, by recording of field excitatory postsynaptic potential (fEPSP) in vitro, chronic constant light (CCL, 3 weeks) exposure impaired the late long-term potentiation (L-LTP), but not early long-term potentiation (E-LTP) and basal transmission in Schaffer collateral (SC)-CA1 synapses of hippocampal slices from rats. Because L-LTP depends on D1/D5 receptors, we examined whether interference of D1/D5 receptors can modulate L-LTP of CCL rats. Bath application of D1/D5 receptors antagonist SCH23390 (1MUM) blocked L-LTP in control rats and attenuated the impaired L-LTP in CCL rats. In contrast, pre-incubation of D1/D5 receptors agonist SKF38393 (25MUM) occluded further L-LTP in control rats while exacerbated the L-LTP impairment in CCL rats. These results suggested that CCL-induced L-LTP impairment can be modulated by D1/D5 receptors. Our findings may contribute to the further understanding of synaptic plasticity mechanism underlying hippocampal long-term memory impairment induced by circadian rhythm disruption. PMID- 26115585 TI - Endothelial NOS activation induces the blood-brain barrier disruption via ER stress following status epilepticus. AB - The blood-brain barrier (BBB) maintains the unique brain microenvironment, which is separated from the systemic circulating system. Since the endoplasmic reticulum (ER) is an important cell organelle that is responsible for protein synthesis, the correct folding and sorting of proteins contributing to cell survivals, ER stress is a potential cause of cell damage in various diseases. Therefore, it would be worthy to explore the the relationship between the ER stress and BBB disruption during vasogenic edema formation induced by epileptogenic insults. In the present study, we investigated the roles of ER stress in vasogenic edema and its related events in rat epilepsy models provoked by pilocarpine-induced status epilepticus (SE). SE-induced eNOS activation induces BBB breakdown via up-regulation of GRP78 expression and dysfunction of SMI-71 (an endothelial BBB marker) in the piriform cortex (PC). In addition, caveolin-1 peptide (an eNOS inhibitor) effectively attenuated GRP78 expression and down-regulation of SMI-71. Taken together, our findings suggest that eNOS mediated ER stress may participate in SE-induced vasogenic edema formation. Therefore, the modulation of ER stress may be a considerable strategy for therapy in impairments of endothelial cell function. PMID- 26115586 TI - Colocalization of cannabinoid receptor 1 with somatostatin and neuronal nitric oxide synthase in rat brain hippocampus. AB - Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in different parts of the brain and functions as a neurotransmitter and neuromodulator. In the central nervous system (CNS), SST inhibits Ca(2+) influx and regulates neuronal excitability in the hippocampus, the brain region which plays a major role in seizure, as well as cognitive and memory function. Much like SST, cannabinoid receptor 1 (CB1 receptor) is also widely distributed in the CNS, associated with memory function ad exerts inhibitory effects on seizure. It is unknown whether overlapping functional activities of SST and CB1 receptor are also associated with coexpression in the hippocampus. In the present study, we determined the colocalization between SST and CB1 receptor in adult rat brain hippocampus. In the CNS, the majority of SST positive interneurons coexpress neuronal nitric oxide synthase (nNOS). Accordingly, colocalization studies were also performed to determine whether nNOS positive neurons display comparable colocalization with CB1 receptor. The findings suggested that SST and nNOS are expressed in most interneurons whereas CB1 receptor is present in both interneurons and projection neurons in hippocampal regions. The distinct neuronal populations either expressing CB1 receptor, SST and nNOS alone or colocalization were observed in a region specific manner. Taken together, the observations described here anticipate the possibility of crosstalk between somatostatin subtypes and CB1 receptor in regulation of physiological activities in the hippocampus. PMID- 26115587 TI - Configurationally-Coupled Protonation of Polyproline-7. AB - Structure and dynamics regulate protein function, but much less is known about how biomolecule-solvent interactions affect the structure-function relationship. Even less is known about the thermodynamics of biomolecule-solvent interactions and how such interactions influence conformational entropy. When transferred from propanol into 40:60 propanol:water under acidic conditions, a remarkably slow protonation reaction coupled with the conversion of the polyproline-I helix (PPI, having all cis-configured peptide bonds) into polyproline-II (PPII, all trans) helix is observed in this work. Kinetics and equilibrium measurements as a function of temperature allow determination of the thermochemistry and insight into how proton transfer is regulated in this system. For the proton-transfer process, PPI(+)(PrOH) + H3O(+) -> PPII(2+)(PrOH/aq) + H2O, we determine DeltaG = 20 +/- 19 kJ.mol(-1), DeltaH = -75 +/- 14 kJ.mol(-1), and DeltaS= -188 +/- 48 J.mol(-1).K(-1) for the overall reaction, and values of DeltaG(?) = 91 +/- 3 kJ.mol(-1), DeltaH(?) = 84 +/- 9 kJ.mol(-1), and DeltaS(?) = -23 +/- 31 J.mol( 1).K(-1) for the transition state. For a minor process, PPI(+)(PrOH) -> PPII(+)(PrOH/aq) without protonation, we determine DeltaG = -9 +/- 20 kJ.mol(-1), DeltaH = 64 +/- 14 kJ.mol(-1), and DeltaS= 247 +/- 50 J.mol(-1).K(-1). This thermochemistry yields DeltaG = -10 +/- 29 kJ.mol(-1), DeltaH = -139 +/- 20 kJ.mol(-1), and DeltaS= -435 +/- 70 J.mol(-1).K(-1) for PPII(+)(PrOH/aq) + H3O(+) -> PPII(2+)(PrOH/aq) +H2O. The extraordinarily slow proton transfer appears to be an outcome of configurational coupling through a PPI-like transition state. PMID- 26115588 TI - The development of depressive symptoms during medical internship stress predicts worsening vascular function. AB - OBJECTIVE: We sought to prospectively determine whether the onset of internship stress and any subsequent depression alters physiological markers of early vascular disease METHODS: We explored potential mechanisms linking stress and depression to vascular disease in a prospective cohort of 37 participants exposed to medical internship stress, an established precipitant of depressive symptomatology. RESULTS: Change in depressive symptom score from baseline over one year of internship stress was inversely correlated with change in the reactive hyperemia index (RHI), a measure of peripheral endothelial function (r=0.41, p=0.01). The change in depressive symptoms in the first six months of internship was similarly related to change in RHI over one year (r=0.38, p=0.02). While the development of depressive symptoms did not significantly impact changes in endothelial progenitor cells (EPCs), EPCs did significantly decrease with the year of internship stress (11.9 to 3.4cells/ml blood; p=0.01). CONCLUSION: Endothelial function may be a critical link between stress, depression, and cardiovascular disease and a feasible surrogate outcome for prospective studies. PMID- 26115589 TI - Physiological and performance effects of carbohydrate gels consumed prior to the extra-time period of prolonged simulated soccer match-play. AB - OBJECTIVES: The physiological and performance effects of carbohydrate-electrolyte gels consumed before the 30min extra-time period of prolonged soccer-specific exercise were investigated. DESIGN: Randomised, double-blind, crossover. METHODS: Eight English Premier League academy soccer players performed 120min of soccer specific exercise on two occasions while consuming fluid-electrolyte beverages before exercise, at half-time and 90min. Carbohydrate-electrolyte (0.7+/-0.1gkg( 1) BM) or energy-free placebo gels were consumed ~5min before extra-time. Blood samples were taken before exercise, at half-time and every 15min during exercise. Physical (15-m and 30-m sprint speed, 30-m sprint maintenance and countermovement jump height) and technical (soccer dribbling) performance was assessed throughout each trial. RESULTS: Carbohydrate-electrolyte gels improved dribbling precision (+29+/-20%) and raised blood glucose concentrations by 0.7+/-0.8mmoll(-1) during extra-time (both p<0.01). Supplementation did not affect sprint velocities (15m and 30m), 30-m sprint maintenance or dribbling speed as reductions compared to 0 15min values occurred at 105-120min irrespective of trial (all p<0.05). Plasma osmolality and blood sodium concentrations increased post-exercise vs. the opening 15min (p<0.05) but no effect of supplementation existed. Selected markers of physical performance (jump height, 30-m sprint velocity and 30-m repeated sprint maintenance) also reduced by >3% during half-time (all p<0.05). CONCLUSIONS: Carbohydrate-electrolyte gel ingestion raised blood glucose concentrations and improved dribbling performance during the extra-time period of simulated soccer match-play. Supplementation did not attenuate reductions in physical performance and hydration status that occurred during extra-time. PMID- 26115590 TI - Moderate-severely bothersome vasomotor symptoms are associated with lowered psychological general wellbeing in women at midlife. AB - OBJECTIVES: The extent to which menopause influences wellbeing is unclear. We investigated the association between moderate-severely bothersome vasomotor symptoms (VMS) and psychological general wellbeing in women, aged 40-65 years, taking into account socio-demographic and lifestyle factors. STUDY DESIGN/MAIN OUTCOME MEASURES: This was a cross-sectional survey of 2020 Australian women, aged 40-65 years, recruited from the community between July 2013 and March 2014. Wellbeing was assessed by the Psychological and General Wellbeing questionnaire (PGWB) and VMS by the Menopause-specific Quality of Life Questionnaire. RESULTS: Moderate-severely bothersome VMS had a strong significant negative association with psychological general wellbeing [regression coefficient (beta)=-8.17, 95% confidence interval (CI) -10.90 to -5.45]. Socio-demographic factors associated with lower wellbeing included being un-partnered (beta=-2.80, 95% CI -4.74 to 0.86), obese (beta=-5.46, 95% CI -7.24 to -3.68) and a smoker (beta=-3.47, 95% CI -6.10 to -0.84). Older age (beta=0.29, 95% CI 0.06-0.42) and participation in paid and/or volunteer work (beta=2.72, 95% CI 0.61-4.82) were positively associated with wellbeing. For those with insecure housing, being a carer was associated with better wellbeing. CONCLUSIONS: Moderate-severely bothersome VMS are significantly and independently negatively associated with psychological general wellbeing in women at midlife. This is an important consideration when assessing psychological wellbeing in women during this life phase. PMID- 26115592 TI - Caregiver profiles and determinants of caregiving burden in Ghana. AB - OBJECTIVES: Due to the growing elderly population, the high cost of care in Ghana and low coverage of the National Health Insurance Scheme, demands for family caregiving have become more imperative in Ghana than ever before. Many caregivers experience high burdens, yet literature on caregiving in Ghana is lacking. This study examined caregiver profiles and determinants of the burden of caregiving in Ghana. STUDY DESIGN: Cross-sectional study. METHODS: This study used data from Wave 1 of the World Health Organization (WHO) Study on Global Ageing and Adult Health (2007-2008). In total, 238 caregivers were analysed in the study. The burden of caregiving was measured using the WHO Impact of Caregiving Scale. Independent sample t-tests, correlations and analysis of variance were used to investigate associations between background characteristics and the burden of caregiving. Linear regression was used to examine determinants of the burden of caregiving. RESULTS: The mean age of caregivers was 61 years (standard deviation 14.5), and the male:female ratio was approximately equal. On average, approximately two adults per household required care. Less than five percent of caregivers received financial, emotional, health, physical and personal care support. Place of residence, provision of financial, health and physical support to care recipients, and receipt of financial, physical and health support were significant determinants of the burden of caregiving. CONCLUSIONS: This study found a mismatch between the number of people needing care and the number of people providing care. In order to improve the health of caregivers and care recipients, there is a need to provide financial support for caregivers. In addition, pro-caregiving government programmes and policies should be established. PMID- 26115591 TI - Low-dose 17-beta-estradiol cream for vaginal atrophy in a cohort without prolapse: Serum levels and vaginal response including tissue biomarkers associated with tissue remodeling. AB - OBJECTIVES: Describe the effect of 50 mcg vaginal 17-beta-estradiol (E2) cream on vaginal maturation, serum estrogen levels, atrophic symptoms, and biomarkers of oxidative stress and tissue remodeling in postmenopausal women without prolapse. METHODS: Seventeen women, 65 years or older, applied intravaginal E2 cream nightly for eight weeks, then twice weekly for eight weeks. Vaginal biopsies, serial blood draws, and atrophic symptoms were obtained at baseline, eight, and sixteen weeks. Changes in atrophic symptoms, vaginal maturation indices (VMI), and serum E2 were measured. Immunohistochemical staining characterized levels of transforming growth factor-beta (TGF-beta), nuclear factor kappa B (NFKB), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and thrombospondin (TSP). RESULTS: Serum E2 levels (pg/ml) were unchanged from baseline (mean (SD)) 7.7 (3.3) to eight 9.7 (5.7) and sixteen 8.7 (5.8) (p=0.24) weeks. VMI (mean (SD)) improved from baseline 34.2 (18.3) to eight 56.7 (13.1) and sixteen 54.5 (11.3) (p<0.001) weeks with no difference between eight and sixteen weeks. Vaginal dryness (p=0.03) and itching (p=0.02) improved. Tissue biomarker levels did not change (TGF-beta p=0.35, NFKB p=0.74, eNOS p=0.80, iNOS p=0.24, TSP p=0.80). DISCUSSION: Vaginal E2 improved atrophic symptoms and VMI without elevating serum E2. Tissue remodeling biomarkers did not change. PMID- 26115593 TI - High dose of TNF-alpha suppressed osteogenic differentiation of human dental pulp stem cells by activating the Wnt/beta-catenin signaling. AB - Dental pulp stem cells (DPSCs) were a clonogenic, highly proliferative cells capable of self-renewal and multi-lineage differentiation including chondrocytes, adipocytes, neural cells and osteoblasts, which make it an attractive choice for bone regeneration and repair of craniofacial defects. Recent studies showed that tumor necrosis factor alpha (TNF-alpha) may affect osteoclastogenesis and bone formation. However, the effect and mechanism of TNF-alpha on DPSCs is not clear. In this study, we found that low dose TNF-alpha promoted mineralization and high dose TNF-alpha suppressed osteogenic differentiation of DPSCs. Levels of ALP, Osteopontin, Osteocalcin, Osterix and Runx2 were up-regulated in DPSCs treated with TNF-alpha at low concentration, while down-regulated in DPSCs treated with TNF-alpha at high concentration. Blockade of Wnt/beta-catenin signaling reversed the inhibitory effect observed on osteogenic differentiation of DPSCs treated with TNF-alpha at high concentration. In addition, we did not detect any proliferative effect of TNF-alpha on DPSCs by cell cycle and cell counts analysis. In summary, our data suggested that high concentration TNF-alpha suppressed mineralization and mineralization-related gene expressions through the Wnt/beta-catenin signaling in DPSCs. Our findings may provide a foundation for autologous transplantation of DPSCs. PMID- 26115594 TI - Passage of time judgements. AB - The article discusses passage of time judgements (POTJs), judgements about how fast time seems to pass in some situation or during some event. It is argued that POTJs should be distinguished from duration judgements, and that the relation between the two remains to be identified. The article discusses (a) POTJs in laboratory situations and in the real world, (b) "feel judgements", the statement that a duration "feels longer" than a person knows it to be, (c) distortions of passage of time in emergency situations, (d) passage of time and ageing, and (e) determinants of POTJs, particularly the roles of information-processing/attention and arousal. PMID- 26115595 TI - Impacts on silkworm larvae midgut proteomics by transgenic Trichoderma strain and analysis of glutathione S-transferase sigma 2 gene essential for anti-stress response of silkworm larvae. AB - Lepidoptera is a large order of insects that have major impacts on humans as agriculture pests. The midgut is considered an important target for insect control. In the present study, 10 up-regulated, 18 down-regulated, and one newly emerged protein were identified in the transgenic Trichoderma-treated midgut proteome. Proteins related to stress response, biosynthetic process, and metabolism process were further characterized through quantitative real-time PCR (qPCR). Of all the identified proteins, the glutathione S-transferase sigma 2 (GSTs2) gene displayed enhanced expression when larvae were fed with Trichoderma wild-type or transgenic strains. Down regulation of GSTs2 expression by RNA interference (RNAi) resulted in inhibition of silkworm growth when larvae were fed with mulberry leaves treated with the transgenic Trichoderma strain. Weight per larva decreased by 18.2%, 11.9%, and 10.7% in the untreated control, ddH2O, and GFP dsRNA groups, respectively, at 24h, while the weight decrease was higher at 42.4%, 28.8% and 32.4% at 72 h after treatment. Expression of glutathione S transferase omega 2 (GSTo2) was also enhanced when larvae were fed with mulberry leaves treated with the transgenic Trichoderma strain. These results indicated that there was indeed correlation between enhanced expression of GSTs2 and the anti-stress response of silkworm larvae against Trichoderma. This study represents the first attempt at understanding the effects of transgenic organisms on the midgut proteomic changes in silkworm larvae. Our findings could not only broaden the biological control targets of insect at the molecular level, but also provide a theoretical foundation for biological safety evaluation of the transgenic Trichoderma strain. PMID- 26115596 TI - Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis. AB - Ginkgo biloba extract (GBE) is commonly used as a herbal supplement. The National Toxicology Program (NTP) study of GBE reported clear evidence of hepatocarcinogenicity in mice. To clarify the mode of action (MOA) for hepatocarcinogenesis by GBE, we investigated the involvement of the constitutive androstane receptor (CAR) in hepatocarcinogenesis induced by GBE using CAR knockout (CARKO) and wild type (WT) mice. We used the same lot of GBE that was used for the NTP study. In 1-week GBE dietary treatment, hepatocellular DNA replication was increased in WT mice but not in CARKO mice. In 4- or 13-week treatment, greater hepatic Cyp2b10 induction and hepatocellular hypertrophy were observed in WT mice, whereas these effects of GBE were much smaller in CARKO mice. In a two-stage hepatocarcinogenesis model initiated by diethylnitrosamine, 27-week treatment with GBE resulted in an increase of eosinophilic altered foci and adenomas in WT mice. By contrast, foci and adenomas were clearly less evident in CARKO mice. These results indicate that GBE-induced hepatocarcinogenesis is mainly CAR-mediated. Since CAR-mediated MOA for hepatocarcinogenesis in rodents is considered to be qualitatively implausible for humans, our findings would be helpful to evaluate the carcinogenic characterization of GBE to humans. PMID- 26115597 TI - Effectiveness of activated carbon and Egyptian montmorillonite in the protection against deoxynivalenol-induced cytotoxicity and genotoxicity in rats. AB - This study was conducted to prepare and characterize activated carbon (AC) and to evaluate its protective effect against deoxynivalenol (DON) toxicity in rats compared to Egyptian montmorillonite (EM). AC was prepared using a single-step chemical activation with phosphoric acid (H3PO4). The resulted AC has a high surface area and a high total pore volume. Male Sprague-Dawley rats were divided into 6 groups (n = 10) and treated for 3 weeks as follow: the control group, the groups fed AC or EM-supplemented diet (0.5% w/w), the group treated orally with DON (5 mg/kg b.w.) and the groups fed AC or EM-supplemented diet and treated with DON. Blood and liver samples were collected for different analyses. Treatment with DON increased liver function enzymes, lipid peroxidation, tumor necrosis factor alpha, DNA fragmentation, decreased hepatic glutathione content, up regulating mRNA Fas and TNF-alpha genes expression and increased micronucleated polychromatic erythrocytes and normochromatic erythrocytes in bone marrow. Co treatment of DON plus AC or EM succeeded to normalize the levels of the biochemical parameters, reduced the cytotoxicity of bone marrow and ameliorated the hepatic genotoxicity. Moreover, AC was more effective than EM and has a high affinity to adsorb DON and to reduce its cytotoxicity and genotoxicity. PMID- 26115598 TI - Genotoxicity evaluation of metformin and glimepiride by micronucleus assay in exfoliated urothelial cells of type 2 diabetes mellitus patients. AB - Micronucleus (MN) assay was performed on the exfoliated urothelial cells to detect the genotoxic effects of the anti-hyperglycemic drugs, metformin and glimepiride in T2DM patients and to use it as a biomarker for DNA damage by assessing the frequency of micronuclei in the exfoliated urothelial cells. A total of 201 subjects (147 T2DM patients & 54 Normal cases) were selected from diverse age groups (25-75 years) and the mean MN frequency was examined per 1000 cells in all the subjects. Relative to the control group (5.02 +/- 1.01), an increased MN frequency was observed in females (26.15 +/- 2.15) when compared to males (23.08 +/- 2.09) in T2DM patients. Further analysis showed that there was a profound increase in the number of MN in the patients using metformin alone (23.02 +/- 4.44), or combination of metformin & glimepiride (24.98 +/- 2.87) than to the subjects using glimepiride alone (17.52 +/- 3.28). It has been proven by this simple, reliable and non-invasive method that metformin has a potential role in causing genotoxicity and that the MN observed in exfoliated urothelial cells could be used as a reliable biomarker in monitoring the genotoxic risk of the anti-hyperglycemic drugs. PMID- 26115599 TI - Flow cytometry evaluation of in vitro cellular necrosis and apoptosis induced by silver nanoparticles. AB - Particles possess unique properties in the nanoscale, e.g., enhanced catalytic activity, high surface area, and light emission/absorption properties, that might result in interference with colorimetric in vitro cytotoxicity assays such as MTT, XTT or MTS. Alternatively, assays that do not use spectrophotometric detection, such as trypan blue exclusion or flow cytometry (FC) based assays, are less likely to be influenced by nanoparticle interference. The aim of this study was to evaluate FC assays to assess the cytotoxicity of three different sizes (10, 100, or 200 nm) of silver nanoparticles (AgNPs) at different mass concentrations (1, 25, or 50 ug/ml) in L-929 fibroblast cells. After 4 h and 24 h exposure, cell necrosis and apoptosis were assessed using 7-AAD and Annexin V dyes, respectively, with FC. The data indicate that cell necrosis and apoptosis in AgNP-exposed fibroblasts depends on dose, exposure time, and AgNP size. The data indicate that AgNPs produced a dose- and time-dependent decrease in cell viability; however, 10 nm AgNPs were significantly more toxic than larger-sized particles. Thus, standard FC assays can be utilized to assess apoptosis and necrosis in response to nanomaterial exposure. PMID- 26115600 TI - Immunohistochemical localization of GABAergic key molecules in the main olfactory bulb of the Korean roe deer, Capreolus pygargus. AB - Gamma-amino butyric acid (GABA) negatively regulates the excitatory activity of neurons and is a predominant neurotransmitter in the nervous system. The olfactory bulb, the main center in the olfactory system, is modulated by inhibitory interneurons that use GABA as their main neurotransmitter. The present study aimed to evaluate GABAergic transmission in the main olfactory bulb (MOB) of the Korean roe deer (Capreolus pygargus) by examining the immunohistochemical localization of GABAergic key molecules, including glutamic acid decarboxylase (GAD), vesicular GABA transporter (VGAT), GABA transporters (GATs; GAT-1 and GAT 3), and potassium sodium chloride co-transporter 2 (KCC2). GAD, VGAT, and KCC2 were expressed in the glomerular layer (GL), external plexiform layer (ePL), mitral cell layer (ML), and granule cell layer (GrL). Intense GAT-1 expression was observed in the GL; GAT-1 expression was discernible in the ePL, ML, and GrL. However, intense GAT-3 expression was extensively observed in all layers of the MOB. These results suggest that substantial GABAergic synapses are present in the GL, ePL, ML, and GrL. Furthermore, the released GABA may be removed by GAT-1 and GAT-3 in the GL, and the majority of GABA, which is present in the ePL to GrL, may undergo reuptake by GAT-3. This is the first morphological and descriptive study of GABAergic transmission in the MOB of Korean roe deer. PMID- 26115601 TI - Contributions of attention and elaboration to associative encoding in young and older adults. AB - Episodic memory declines during healthy aging, with a particular reduction in the ability to encode associations. We investigated the role of alternating attentional focus between two items of a pair in order to generate associative links, as well as working memory based elaborative processes in this age-related memory deficit. While their eye gaze behavior and ERPs were recorded, 19 young and 22 elderly (64-79 years) participants used interactive imagery to encode pairs of spatially separated objects. In a subsequent recognition test, older adults showed a larger reduction in associative than item memory, relative to young adults. For both age groups the number of eye gaze transitions between objects at encoding was correlated with associative recognition performance, suggesting that alternating attentional focus between items aids the generation of relational links necessary to encode associative memories. However, the relative time course of eye gaze transitions over the encoding interval for trials that were subsequently retrieved vs. forgotten differed between age groups. Furthermore, the ERPs of older adults exhibited strongly reduced frontal slow wave "subsequent memory effects", suggesting that they engaged to a lesser extent in working memory-based elaboration of the associative link. Based on these results, we propose that older adults exhibit a reduced tendency to generate and elaborate on internal representations of inter-item associative links. Rather, they use a less effective encoding strategy that disproportionally relies on the external stimulus display, resulting in lower associative memory performance. PMID- 26115602 TI - Does the speaker matter? Online processing of semantic and pragmatic information in L2 speech comprehension. AB - The present study investigated how pragmatic information is integrated during L2 sentence comprehension. We put forward that the differences often observed between L1 and L2 sentence processing may reflect differences on how various types of information are used to process a sentence, and not necessarily differences between native and non-native linguistic systems. Based on the idea that when a cue is missing or distorted, one relies more on other cues available, we hypothesised that late bilinguals favour the cues that they master during sentence processing. To verify this hypothesis we investigated whether late bilinguals take the speaker's identity (inferred by the voice) into account when incrementally processing speech and whether this affects their online interpretation of the sentence. To do so, we adapted Van Berkum, J.J.A., Van den Brink, D., Tesink, C.M.J.Y., Kos, M., Hagoort, P., 2008. J. Cogn. Neurosci. 20(4), 580-591, study in which sentences with either semantic violations or pragmatic inconsistencies were presented. While both the native and the non native groups showed a similar response to semantic violations (N400), their response to speakers' inconsistencies slightly diverged; late bilinguals showed a positivity much earlier than native speakers (LPP). These results suggest that, like native speakers, late bilinguals process semantic and pragmatic information incrementally; however, what seems to differ between L1 and L2 processing is the time-course of the different processes. We propose that this difference may originate from late bilinguals' sensitivity to pragmatic information and/or their ability to efficiently make use of the information provided by the sentence context to generate expectations in relation to pragmatic information during L2 sentence comprehension. In other words, late bilinguals may rely more on speaker identity than native speakers when they face semantic integration difficulties. PMID- 26115603 TI - Re-establishing the disrupted sensorimotor loop in deafferented and deefferented people: The case of spinal cord injuries. AB - Acting efficiently in the world depends on the activity of motor and somatosensory systems, the integration of which is necessary for the proper functioning of the sensorimotor loop (SL). Profound alterations of SL functioning follow spinal cord injury (SCI), a condition that brings about a disconnection of the body from the brain. Such disconnection creates a substantial deprivation of somatosensorial inputs and motor outputs. Consequent somatic deficits and motor paralysis affect the body below the lesion level. A complete restoration of normal functions of the SL cannot be expected until basic neuroscience has found a way to re-establish the interrupted neural connectivity. Meanwhile, studies should focus on the development of technical solutions for dealing with the disruption of the sensorimotor loop. This review discusses the structural and functional adaptive reorganization of the brain after SCI, and the maladaptive mechanisms that impact on the processing of body related information, which alter motor imagery strategies and EEG signals. Studies that show how residual functions (e.g. face tactile sensitivity) may help people to restore a normal body image are also reviewed. Finally, data on how brain and residual body signals may be used to improve brain computer interface systems is discussed in relation to the issue of how such systems may help SCI people to re-enter the world and interact with objects and other individuals. PMID- 26115604 TI - A Swarm Optimization approach for clinical knowledge mining. AB - BACKGROUND AND OBJECTIVES: Rule-based classification is a typical data mining task that is being used in several medical diagnosis and decision support systems. The rules stored in the rule base have an impact on classification efficiency. Rule sets that are extracted with data mining tools and techniques are optimized using heuristic or meta-heuristic approaches in order to improve the quality of the rule base. In this work, a meta-heuristic approach called Wind driven Swarm Optimization (WSO) is used. The uniqueness of this work lies in the biological inspiration that underlies the algorithm. METHODS: WSO uses Jval, a new metric, to evaluate the efficiency of a rule-based classifier. Rules are extracted from decision trees. WSO is used to obtain different permutations and combinations of rules whereby the optimal ruleset that satisfies the requirement of the developer is used for predicting the test data. The performance of various extensions of decision trees, namely, RIPPER, PART, FURIA and Decision Tables are analyzed. The efficiency of WSO is also compared with the traditional Particle Swarm Optimization. RESULTS: Experiments were carried out with six benchmark medical datasets. The traditional C4.5 algorithm yields 62.89% accuracy with 43 rules for liver disorders dataset where as WSO yields 64.60% with 19 rules. For Heart disease dataset, C4.5 is 68.64% accurate with 98 rules where as WSO is 77.8% accurate with 34 rules. The normalized standard deviation for accuracy of PSO and WSO are 0.5921 and 0.5846 respectively. CONCLUSION: WSO provides accurate and concise rulesets. PSO yields results similar to that of WSO but the novelty of WSO lies in its biological motivation and it is customization for rule base optimization. The trade-off between the prediction accuracy and the size of the rule base is optimized during the design and development of rule-based clinical decision support system. The efficiency of a decision support system relies on the content of the rule base and classification accuracy. PMID- 26115605 TI - [NaCl 0.9 % for volume substitution : blessing or curse?]. AB - The nonphysiological high chloride content of 0.9 % saline causes hyperchloremic acidosis and rapidly reduces renal perfusion in healthy volunteers-negative affects not seen with balanced crystalloids with low chloride content. Evidence from recently published studies strongly suggests that 0.9 % saline negatively effects outcome in surgical and critically ill patients. Major complications are the increased incidence of acute kidney injury and need for renal replacement therapy, as well as higher postoperative in-hospital mortality. Although implemented as the gold standard in many clinical guidelines, there are currently no data supporting the use of 0.9 % saline instead of modern balanced crystalloids. This is also and even particularly true for patients with hypokalemia and acute or chronic kidney injury. In-house training is an effective tool for sustainably raising the awareness of this issue among nursing and medical staff, and identifying alternative strategies to the use of NaCl 0.9 % in clinical practice. PMID- 26115606 TI - Water-soluble benzodiazepine prodrug/enzyme combinations for intranasal rescue therapies. AB - Benzodiazepines (BZDs), including diazepam (DZP) and midazolam (MDZ), are drugs of choice for rapid treatment of seizure emergencies. Current approved use of these drugs involves administration via either intravenous or rectal routes. The former requires trained medical personnel, while the latter is socially unacceptable for many patients and caregivers. In recent years, efforts have been made to formulate BZDs for nasal administration. Because of the low solubility of these molecules, organic vehicles have been used to solubilize the drugs in the nasal products under development. However, organic solvents are irritating, potentially resulting in injury to nasal tissue. Here we report preliminary studies supporting a strategy in which water-soluble BZD prodrugs and a suitable converting enzyme are coadministered in an aqueous vehicle. Diazepam and midazolam prodrugs were synthesized and were readily converted to their active forms by a protease from Aspergillus oryzae. Using a permeation assay based on monolayers of Madin-Darby canine kidney II-wild type cells, we found that enzymatically produced BZDs could be maintained at high degrees of supersaturation, enabling faster transport across the membrane than can be achieved using saturated solutions. This strategy not only obviates the need for organic solvents, but it also suggests more rapid absorption and earlier peak concentrations than can be otherwise achieved. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26115607 TI - Evidence for immunomodulation and apoptotic processes induced by cationic polystyrene nanoparticles in the hemocytes of the marine bivalve Mytilus. AB - Polymeric nanoparticles can reach the marine environment from different sources as weathering of plastic debris and nanowaste. Nevertheless, few data are available on their fate and impact on marine biota. Polystyrene nanoparticles (PS NPs) can be considered as a model for studying the effects of nanoplastics in marine organisms: recent data on amino-modified PS NPs (PS-NH2) toxicity in sea urchin embryos underlined that marine invertebrates can be biological targets of nanoplastics. Cationic PS NPs have been shown to be toxic to mammalian cells, where they can induce apoptotic processes; however, no information is available on their effects and mechanisms of action in the cells of marine organisms. In this work, the effects of 50 nm PS-NH2 were investigated in the hemocytes of the marine bivalve Mytilus galloprovincialis. Hemocytes were exposed to different concentrations (1, 5, 50 MUg/ml) of PS-NH2 suspension in ASW. Clear signs of cytoxicity were evident only at the highest concentrations (50 MUg/ml). On the other hand, a dose dependent decrease in phagocytic activity and increase in lysozyme activity were observed. PS-NH2 NPs also stimulated increase in extracellular ROS (reactive oxygen species) and NO (nitric oxide) production, with maximal effects at lower concentrations. Moreover, at the highest concentration tested, PS-NH2 NPs induced apoptotic process, as evaluated by Flow cytometry (Annexin V binding and mitochondrial parameters). The results demonstrate that in marine invertebrates the immune function can represent a significant target for PS-NPs. Moreover, in Mytilus hemocytes, PS-NH2 NPs can act through mechanisms similar to those observed in mammalian cells. Further research is necessary on specific mechanisms of toxicity and cellular uptake of nanoplastics in order to assess their impact on marine biota. PMID- 26115608 TI - Resurgence of canine parvovirus 2a strain in the domestic dog population from Argentina. AB - Ninety-three rectal swab samples were taken, from dogs suspected of canine parvovirus (CPV) infection and analyzed by PCR. A fragment of the VP2 gene, was amplified in 41 (44%) of them, resulting CPV positive samples. Sequencing analysis of these PCR products showed that 37 samples (90.2%) belonged to the CPV2c type, whereas four samples (9.8%) were identified as CPV2a, which has not been found since 2008. It was also found that 24 out of 37 CPV2c samples (65%), carried the mutation Thr440Ala, whereas this mutation was absent in the four CPV2a strains reported herein. Using phylogenetic analysis of the full length VP2 gene, which was amplified by PCR in six local samples, it was seen that CPV2a Argentine strains reported in this study, were genetically closer to a previous local CPV2a isolate (year 2003) and to a South African CPV2a strain, than to any of the recently reported Uruguayan CPV2a strains. The results obtained in this work, together with those reported previously in Uruguay strongly suggest that, in spite of the geographical proximity, wild type CPV strains undergo different evolutive pathways in each country, resulting in the prevalence of different strains in related dog populations. Further extensive epidemiological studies are needed in order to improve the understanding of CPV evolution. PMID- 26115609 TI - Rapid and specific detection of Yam mosaic virus by reverse-transcription recombinase polymerase amplification. AB - Yam mosaic virus (YMV; genus Potyvirus) is considered to cause the most economically important viral disease of yams (Dioscorea spp.) in West Africa which is the dominant region for yam production globally. Yams are a vegetatively propagated crop and the use of virus-free planting material forms an essential component of disease control. Current serological and PCR-based diagnostic methods for YMV are time consuming involving a succession of target detection steps. In this study, a novel assay for specific YMV detection is described that is based on isothermal reverse transcription-recombinase polymerase amplification (RT-exoRPA). This test has been shown to be reproducible and able to detect as little as 14 pg/MUl of purified RNA obtained from an YMV-infected plant, a sensitivity equivalent to that obtained with the reverse transcription-polymerase chain reaction (RT-PCR) in current general use. The RT-exoRPA assay has, however, several advantages over the RT-PCR; positive samples can be detected in less than 30 min, and amplification only requires a single incubation temperature (optimum 37 degrees C). These features make the RT-exoRPA assay a promising candidate for adapting into a field test format to be used by yam breeding programmes or certification laboratories. PMID- 26115610 TI - Mycotic abdominal aortic aneurysm after adjuvant therapy with bacillus Calmette Guerin in patients with urothelial bladder cancer: a rare but misinterpreted complication. AB - Bacillus Calmette-Guerin (BCG) therapy is often associated with side effects. The most feared is disseminated sepsis that may occur rarely with the development of mycotic aortic aneurysms. Twenty cases of patients treated with intravesical BCG complicated by mycotic abdominal aortic aneurysm have been reported in the literature, including 2 cases of the present study. Delayed vascular work-up represents a critical aspect. Mycotic aneurysms evidence a rapid progression. Primary care physicians and urologists should be sensitized to recognize unspecified symptoms such as potential clinical manifestations of a mycotic abdominal aortic aneurysm, even several months or years after BCG therapy. PMID- 26115611 TI - Mycotic Saccular Abdominal Aortic Aneurysm in an Infant after Cardiac Catheterization: A Case Report. AB - Abdominal aortic aneurysms (AAAs) are a rare entity in the pediatric population. Children with mycotic (infectious) AAA in particular are at risk of life threatening rupture due to their rapid expansion coupled with aortic wall thinning and deterioration. Here, we present the case of a 10-month-old infant with prior 2-staged repair for hypoplastic left heart syndrome that was incidentally discovered to have a mycotic AAA on abdominal ultrasound (US) for evaluation of renovascular hypertension. Before the time of evaluation with US, the infant had developed methicillin-resistant Staphylococcus aureus bacteremia 3 days after cardiac catheterization with percutaneous thoracic aortic balloon angioplasty. She had normal aortic contours on contrasted computed tomography scan of the abdomen approximately 2 weeks before the aforementioned US evaluation. This infant subsequently underwent open aneurysmorrhaphy with cryopreserved vein patch angioplasty with resolution of her aneurysmal segment. PMID- 26115612 TI - Open Surgical Repair of Aortoiliac Aneurysm, Left Pelvic Kidney and Right Kidney Malposition with Aberrant Vascularization, and Compressive Syndrome. AB - We present the case of a 65-year-old male patient with aortoiliac aneurysm associated with a congenital left pelvic kidney vascularized by left common iliac artery and right malposition kidney vascularized by 2 aberrant arteries, which sprout from the aneurysm. In addition, the patient had right iliacofemoral vein thrombosis caused by right iliac artery aneurysm compression. We faced the challenge of treating the patient while preserving renal function. PMID- 26115613 TI - Pharmacokinetics of adalimumab in Crohn's disease. PMID- 26115614 TI - Cloning, purification and characterization of a thermostable beta-galactosidase from Bacillus licheniformis strain KG9. AB - A thermo— and alkalitolerant Bacillus licheniformis KG9 isolated from Taşlıdere hot water spring in Batman/Turkey was found to produce a thermostable β—galactosidase. Phylogenetic analysis showed that the 16S rRNA gene from B. licheniformis strain KG9 was 99.9% identical to that of the genome sequenced B. licheniformis strain DSM 13. Analysis of the B. licheniformis DSM 13 genomic sequence revealed four putative β—galactosidase genes. PCR primers based on the genome sequence of strain DSM 13 were used to isolate the corresponding β—galactosidase genes from B. licheniformis strain KG9. The calculated molecular weights of the β—galactosidases I, II, III, and IV using sequencing data were 30, 79, 74, and 79 kDa, respectively. The genes were inserted into an expression vector and recombinant β—galactosidase was produced in Escherichia coli. Of the four β—galactosidase genes identified in strain KG9, three of them were expressed as active, intracellular enzymes in E. coli. One of the recombinant enzymes, β—galactosidase III, was purified and characterized. Optimal temperature and pH was determined to be at 60 oC and pH 6.0, respectively. Km was determined to be 1.3 mM and 13.3 mM with oNPG (ortho—nitrophenyl—β—D—galactopyranoside) and lactose as substrates, respectively, and Vmax was measured to 1.96 μmol/min and 1.55 μmol/min with oNPG and lactose, respectively. PMID- 26115615 TI - Re: Too hot to handle? Hot water bottle injuries in Sydney, Australia. PMID- 26115616 TI - Management of late extraneural recurrence of medulloblastoma without high-dose chemotherapy. PMID- 26115617 TI - Renal transplantation in infants. AB - Renal transplantation (RTx) has become an accepted mode of therapy in infants with severe renal failure. The major indications are structural abnormalities of the urinary tract, congenital nephrotic syndrome, polycystic diseases, and neonatal kidney injury. Assessment of these infants needs expertise and time as well as active treatment before RTx to ensure optimal growth and development, and to avoid complications that could lead to permanent neurological defects. RTx can be performed already in infants weighing around 5 kg, but most operations occur in infants with a weight of 10 kg or more. Perioperative management focuses on adequate perfusion of the allograft and avoidance of thrombotic and other surgical complications. Important long-term issues include rejections, infections, graft function, growth, bone health, metabolic problems, neurocognitive development, adherence to medication, pubertal maturation, and quality of life. The overall outcome of infant RTx has dramatically improved, with long-term patient and graft survivals of over 90 and 80 %, respectively. PMID- 26115618 TI - Adiponectin in children and young adults with focal segmental glomerulosclerosis. AB - BACKGROUND: Adiponectin is an adipokine that is elevated in kidney disease. Evidence suggests that adiponectin exerts a direct effect on the podocyte and may play a role in the pathogenesis of proteinuria. The objectives of this study were to characterize serum and urine adiponectin levels over time in patients with focal segmental glomerulosclerosis (FSGS) and to evaluate the role of baseline levels of adiponectin as a predictor of clinical remission. METHODS: This was a study of 60 individuals, ages 3-38 years, with steroid-resistant FSGS enrolled in the FSGS clinical trial. Serial measurements of serum and urine adiponectin were obtained at baseline and 26 and 52 weeks. RESULTS: Participants were of mean age 19.4 +/- 10.2 years (50% male, 33% black). Serum adiponectin (baseline mean 14.3 +/- 6.6 MUg/ml) and urine adiponectin:creatinine (Uadp/cr) (baseline mean 126.8 +/- 178.9 MUg/ml) directly correlated with proteinuria at all time points (r = 0.37-0.81; all p < 0.05). Proteinuria, hypoalbuminemia, and hyperlipidemia were significant independent predictors of greater serum adiponectin and Uadp/cr in multivariate analysis. Lower tertiles of baseline serum adiponectin were associated with greater response to treatment at 52 weeks when adjusted for age, sex, body mass index (BMI) z score, and estimated glomerular filtration rate (eGFR) [odds ratio (OR) 0.48; 95% confidence interval (CI) 0.26-0.91, p = 0.023). For log Uadp/cr, the OR for remission was 0.43 (95% CI 0.21-0.89, p = 0.02) at 52 weeks. However, when baseline urine protein:creatinine was added to the models, the relationships were no longer significant. CONCLUSIONS: Serum and urine adiponectin levels were directly associated with proteinuria and paralleled changes in proteinuria over time in children and young adults with FSGS. Although baseline adiponectin was lower in responders, response to treatment in patients with FSGS was not associated with serum and urine adiponectin levels but, rather, was related to proteinuria. PMID- 26115619 TI - Russell Wallace Chesney MD-a fond farewell. PMID- 26115621 TI - Attention-deficit/hyperactivity disorder Under Treatment Outcomes Research (AUTOR): a European observational study in pediatric subjects. AB - The ADHD Under Treatment Observational Research (AUTOR) study was a European prospective, observational study that assessed factors associated with changes in ADHD severity, estimated change from baseline in quality of life (QoL), and characterized changes in ADHD symptoms over a 2-year period as a function of baseline treatment. The primary objective was to identify factors associated with worsening in ADHD severity during a 2-year follow-up period for subjects aged 6 17 years, who were receiving the same pharmacotherapy for 3-8 months before enrollment and had a Clinical Global Impression (CGI)-ADHD-Severity score of mild/lower and a CGI-ADHD-Improvement score of improved/very much improved. Multivariate logistic regression examined the association of factors with worsening in ADHD. Mixed-model repeated measures regression analyzed QoL in terms of change from baseline in CHIP-CE PRF scores. There were 704 subjects analyzed. Variables associated with worsening ADHD severity were parental occupation, poorer school outcomes, and use of psychoeducation; baseline treatment was not significant. Among the secondary objectives, initial use of atomoxetine (vs. stimulants) was associated with a significant improvement on the CHIP-CE PRF total score, with an adjusted treatment difference of -6.0 (95 % CI -7.9, -4.1) at 24 months. Additionally, the odds of stability (CGI-ADHD-S <= 3 over the 2 year period) were significantly lower for subjects initially responding to stimulants compared with atomoxetine (OR 0.5; 95 % CI 0.3, 0.8). ADHD symptom worsening was associated with initial use of psychoeducation, parental occupation, and poorer school outcomes. Response to initial treatment with atomoxetine was associated with improved QoL over 2 years. PMID- 26115622 TI - Detection of Novel Mutation in Ccm3 Causes Familial Cerebral Cavernous Malformations. AB - Cerebral cavernous malformations are vascular lesions that usually involve brain micro-vessels. They can occur both in a sporadic form and familial one. Causes of familial forms are mutations at three loci: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. Here, we describe a novel CCM3 missense mutation (c.422T>G) detected in two Greek brothers showing multiple lesions at magnetic resonance imaging; to date, only the youngest is symptomatic. Bioinformatics tools showed this novel variant causes a loss of function in Pdcd10 protein due to its localization in the eighth helix and, particularly, affects Leu141, a highly conserved amino acid. Roles of Pdcd10 in angiogenesis regulation and its association with early development of cerebral cavernous malformations were also considered. PMID- 26115623 TI - LPS-Primed Release of HMGB-1 from Cortical Astrocytes is Modulated Through PI3K/AKT Pathway. AB - Studies have shown that LPS-preconditioned tolerant state could protect against brain injury to subsequent challenges. We hypothesized astrocytes were directly involved in the readjustment to confer neuroprotective effects with LPS pretreatment. High-mobility group box 1(HMGB-1) from LPS-preconditioned astrocytes, presumably serving as a positive regulator, might contribute to the favorable preconditioned effects. Furthermore, a potential cellular pathway (PI3K/AKT pathway), has been proposed for the active regulation of LPS-primed reactive astrocytes to secrete HMGB-1. In the present study, we used a low concentration of LPS to directly prime the astrocytes in vitro, and the subsequent astrocytic reactions, including cytokine secretion, the expression of transcription factors, and the release of HMGB-1 were examined after the blockade of the PI3K pathway. The data showed that LPS preconditioning could reduce some capacity of astrocytes to subsequent challenge in vitro. PI3K/AKT pathway was partially involved in the modulation of the release HMGB-1 from reactive astrocytes. These findings offer direct evidence supporting the flexible roles of astrocytes in mediating LPS-primed neuroprotection, and highlight additional targets for future attempts to modify the protective effects of astrocytes through LPS preconditioning. PMID- 26115624 TI - Ligustilide Ameliorates Inflammatory Pain and Inhibits TLR4 Upregulation in Spinal Astrocytes Following Complete Freund's Adjuvant Peripheral Injection. AB - Ligustilide is a major component of Radix Angelica Sinensis and reported to have anti-inflammatory and anti-nociceptive effects. Toll-like receptor 4 (TLR4) has been shown to be expressed in the spinal cord and be involved in inflammatory pain and neuropathic pain. Whether ligustilide can inhibit spinal TLR4 expression in inflammatory pain is still unknown. In the present study, we intravenously injected ligustilide daily for 4 days, with the first injection given at 1 h before complete Freund's adjuvant (CFA) injection. We tested the analgesic effect of ligustilide by behavioral test and checked the expression and distribution of TLR4 in the spinal cord by real-time quantitative PCR, Western blot, and immunofluorescence. Our data showed that repeated daily intravenous treatment with ligustilide alleviated CFA-induced heat hyperalgesia and mechanical allodynia. The same treatment also inhibited CFA-induced TLR4 mRNA and protein increase in the spinal cord. Immunofluorescence double staining showed that TLR4 was predominantly expressed in spinal astrocytes. In primary cultured astrocytes, ligustilide dose-dependently reduced lipopolysaccharide-induced upregulation of TLR4 mRNA expression. These data indicate that ligustilide treatment reduces TLR4 expression in spinal astrocytes and is an effective therapy for inflammatory pain. PMID- 26115625 TI - Recovery of motor coordination after exercise is correlated to enhancement of brain-derived neurotrophic factor in lactational vanadium-exposed rats. AB - Lactational exposure to vanadium can reduce the locomotor activity in adult animals. In this study, we investigated whether lactational vanadium exposure impairs the motor coordination and whether exercise ameliorates this dysfunction. Sprague-Dawley dams were treated with or without vanadium during lactation. The weaned male offspring were trained to treadmill running for 5 weeks and then examined their motor coordination on a rotarod. The neuroprotective effect of exercise was evaluated by the brain-derived neurotrophic factor (BDNF) in plasma and cerebellum. The results demonstrated that vanadium-exposed rats exhibited impaired motor coordination and reduced plasma and cerebellar BDNF levels. Treadmill running during childhood-adolescence prevented the impaired motor coordination in the lactational vanadium-exposed rats. The beneficial effect of treadmill running on motor coordination in the vanadium-exposed rats was correlated to the normalization of plasma and cerebellar BDNF levels, as well as the increased TrkB phosphorylation in the cerebellum. The result suggests that exercise may prevent the impairment of motor coordination in the lactational vanadium-exposed rats. PMID- 26115620 TI - Biomechanical assessment in models of glaucomatous optic neuropathy. AB - The biomechanical environment within the eye is of interest in both the regulation of intraocular pressure and the loss of retinal ganglion cell axons in glaucomatous optic neuropathy. Unfortunately, this environment is complex and difficult to determine. Here we provide a brief introduction to basic concepts of mechanics (stress, strain, constitutive relationships) as applied to the eye, and then describe a variety of experimental and computational approaches used to study ocular biomechanics. These include finite element modeling, direct experimental measurements of tissue displacements using optical and other techniques, direct experimental measurement of tissue microstructure, and combinations thereof. Thanks to notable technical and conceptual advances in all of these areas, we are slowly gaining a better understanding of how tissue biomechanical properties in both the anterior and posterior segments may influence the development of, and risk for, glaucomatous optic neuropathy. Although many challenging research questions remain unanswered, the potential of this body of work is exciting; projects underway include the coupling of clinical imaging with biomechanical modeling to create new diagnostic tools, development of IOP control strategies based on improved understanding the mechanobiology of the outflow tract, and attempts to develop novel biomechanically-based therapeutic strategies for preservation of vision in glaucoma. PMID- 26115626 TI - Association between two promoter polymorphisms (rs1893219 and rs1893220) of MC2R gene and intracerebral hemorrhage in Korean population. AB - The hypothalamic-pituitary-adrenal (HPA) axis has an important role in the pathogenesis of stroke. We investigated whether single nucleotide polymorphisms (SNPs) of melanocortin 2 receptor (MC2R), also known as adrenocorticotropic hormone (ACTH) receptor, were associated with the development of intracerebral hemorrhage (ICH) in Korean population. Two promoter SNPs [rs1893219 (-853A/G) and rs1893220 (-759G/T)] were genotyped in 145 ICH patients and 331 control subjects using direct sequencing. Multiple logistic regression models were used to determine odds ratios, 95% confidence intervals, and p-values. Two SNPs were associated with the development of ICH (rs1893219, p=0.003 in log-additive model, p=0.023 in dominant model, p=0.002 in recessive model; rs1893220, p=0.005 in log additive model, p=0.021 in dominant model, p=0.003 in recessive model). The frequencies of the G allele of rs1893219 and the T allele of rs1893220 were decreased in ICH group compared to control group (p=0.003 and p=0.004, respectively). The frequencies of the AG and GT haplotypes comprised of rs1893219 and rs1893220 were also significantly different between the ICH and control groups (p=0.0026 and p=0.0034, respectively). These data suggest that the MC2R gene may contribute to the development of ICH. PMID- 26115627 TI - Single nucleotide polymorphisms in the BDNF gene and suicide in the Slovenian sample. AB - In recent years, brain-derived neurotrophic factor (BDNF) and sequence variations within and near the BDNF gene have been studied for associations with various psychiatric disorders, including suicidal behavior. Since our previous work on completed suicide in Slavic population showed an association of the functional single nucleotide polymorphism (SNP) rs6265 in the BDNF gene, we decided to extend the investigation and test additional SNPs in the BDNF gene, rs7124442, rs10767664, rs962369, rs12273363, rs908867, rs1491850, and rs1491851, for association with completed suicide. Our study subjects were Caucasians, and included 486 suicide completers and 289 controls. The case/control comparisons of allele, genotype and haplotype frequency distributions were performed by means of Pearson's X(2) tests. Analyses of allele and genotype frequency distributions of the sudied SNPs did not reveal any significant differences between the controls and suicide completers. Haplotype analysis (rs7124442-rs10767664-rs962369 rs12273363-rs908867) showed an association of the haplotype C-A-T-C-C (p(corr)=0.038) with completed suicide, indicating that these SNPs on a haplotype level may play a role in completed suicide phenotype in our study sample. PMID- 26115628 TI - Management of Pulmonary Hypertension in Patients with Chronic Lung Disease. AB - Pulmonary hypertension (PH) is a common complication of chronic pulmonary diseases, especially in advanced disease, and is associated with greater mortality and worse clinical course. Patients with symptoms that exceed those expected by their pulmonary disease should be further evaluated by echocardiography. Confirmatory right heart catheterization is indicated in those conditions where the results of the hemodynamic assessment will determine treatment options. The treatment of choice for patients who are hypoxemic and have pulmonary hypertension associated with chronic lung disease is long-term oxygen therapy. Conventional vasodilators or drugs approved for pulmonary arterial hypertension are not recommended in patients with mild-to-moderate PH because they may impair gas exchange and because there is a lack of evidence supporting their efficacy. Patients with severe PH should be considered for referral to a center with expertise in PH and lung diseases. Ideally, these patients should be included in randomized controlled trials to determine which patients are more likely to derive benefit and which therapies are most likely to be successful. PMID- 26115629 TI - Quality of Life in Treatment-Resistant Hypertension. AB - Treatment-resistant hypertension (TRH) is an increasingly common and clinically challenging hypertension phenotype associated with adverse impact on cardiovascular events and death. Recent evidence, although limited, suggests that TRH may also adversely affect health-related quality of life (HrQoL) and other patient-reported outcomes. However, the precise mechanisms for this link remain unknown. A number of recent studies focusing on both the general hypertensive population and those with TRH suggest that patient awareness of difficult-to control blood pressure, chronically elevated blood pressure levels, and the use of aggressive medication regimens with attendant cumulative adverse effects may play significant roles. This review summarizes the existing literature on HrQoL in persons with TRH, highlights literature from the general hypertensive population with relevance to TRH, and discusses important remaining questions regarding HrQoL in persons with TRH. PMID- 26115630 TI - Antibody-drug conjugates for cancer therapy: The technological and regulatory challenges of developing drug-biologic hybrids. AB - Antibody-drug conjugates (ADCs) are a new class of therapeutic agents that combine the targeting ability of monoclonal antibodies (mAbs) with small molecule drugs. The combination of a mAb targeting a cancer-specific antigen with a cytotoxin has tremendous promise as a new type of targeted cancer therapy. Two ADCs have been approved and many more are in clinical development, suggesting that this new class of drugs is coming to the forefront. Because of their unique nature as biologic-small drug hybrids, ADCs are challenging to develop, from both the scientific and regulatory perspectives. This review discusses both these aspects in current practice, and surveys the current state of the art of ADC drug development. PMID- 26115631 TI - Efficacy of and risk of bleeding during pegylated interferon plus ribavirin treatment in HIV/HCV-coinfected patients with pretreatment thrombocytopenia. AB - The aim of this study was to assess the efficacy of and the risk of major bleeding during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients according to the pretreatment platelet count. Two hundred and seventy-four HCV/HIV-coinfected, previously naive individuals with compensated cirrhosis enrolled in one Spanish prospective cohort who received peg-IFN/RBV were included in this study. The frequency of severe bleeding and sustained virological response (SVR) rate were compared between patients with a pretreatment platelet count <=70,000/mm(3) and >70,000/mm(3), respectively. Sixty-one (22 %) patients had a baseline platelet count <=70,000/mm(3). The median (Q1-Q3) pretreatment platelet count was 58,000 (49,000-65,000) cells/mm(3) in the platelet <=70,000 group and 129,000 (102,500-166,000) cells/mm(3) in the platelet >70,000 group (p < 0.0001). Seventeen (28 %) subjects of the platelet <=70,000 group and 71 (33 %) patients of the platelet >70,000 group achieved SVR (p = 0.4). Only 2 (3.2 %) patients in the platelet <=70,000 group developed a severe hemorrhagic event, specifically esophageal variceal bleeding. The efficacy of therapy with peg IFN/RBV in HIV/HCV-coinfected patients with low pretreatment platelet counts is comparable to that found in the overall subset of subjects with compensated cirrhosis. The frequency of severe hemorrhagic events related with this therapy is low in this population. PMID- 26115632 TI - Genome-wide identification and characterization of five MyD88 duplication genes in Yesso scallop (Patinopecten yessoensis) and expression changes in response to bacterial challenge. AB - Myeloid differentiation factor 88 (MyD88) is a pivotal adaptor in the TLR/IL-1R signaling pathway, which plays an important role in activating the innate immune system. Although MyD88 genes have been identified in a variety of species, they have not been systematically characterized in scallops. In this study, five MyD88 genes were identified in Yesso scallop (Patinopecten yessoensis), PyMyD88-1, PyMyD88-2a, PyMyD88-2b, PyMyD88-3 and PyMyD88-4, which consisted of two pairs of tandem duplications located on the same chromosome. To our knowledge, this is the largest number of MyD88 genes found in an invertebrate. Phylogenetic and protein structural analyses were carried out to determine the identities and evolutionary relationships of these genes. PyMyD88s have highly conserved structures compared to MyD88 genes from other invertebrate species, except for PyMyD88-4, which contains only a DD domain, suggesting the evolutionarily conserved form of this particular gene member. We investigated the expression profiles of PyMyD88 genes at different developmental stages and in healthy adult tissues and hemocytes after Micrococcus luteus and Vibrio anguillarum infection using quantitative real time PCR (qRT-PCR). The expression of most PyMyD88s was significantly induced in the acute phase (3-6 h) after infection with both gram-positive (M. luteus) and gram-negative (V. anguillarum) bacteria, with much more dramatic changes in PyMyD88 expression being observed after V. anguillarum challenge. Collectively, the abundance of MyD88s and their specific expression patterns provide insight into their versatile roles in the response of the bivalve innate immune system to gram-negative bacterial pathogens. PMID- 26115634 TI - Bortezomib: A Review in Mantle Cell Lymphoma in Previously Untreated Patients Unsuitable for Stem-Cell Transplantation. AB - Bortezomib (Velcade((r))) is a proteasome inhibitor that is approved for the treatment of multiple myeloma and mantle cell lymphoma (MCL). This article reviews the efficacy and tolerability of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in the treatment of previously untreated MCL unsuitable for stem-cell transplantation, and overviews the pharmacology of bortezomib. In the large, randomized, assessor blinded, multinational LYM-3002 trial, induction therapy with VR-CAP improved progression-free survival significantly more than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) after a median follow up of 40 months in patients with newly diagnosed MCL ineligible or not considered for stem-cell transplantation. Complete response and certain other secondary endpoints were improved significantly more with VR-CAP than R-CHOP. Overall survival data were not mature at the time of assessment. The improved efficacy with VR-CAP was accompanied by an increased incidence of grade 3 or higher adverse events, particularly haematological adverse events. PMID- 26115633 TI - Cloning and characterization of a novel hemocyanin variant LvHMCV4 from shrimp Litopenaeus vannamei. AB - Recently, we found 3 variants of hemocyanin subunit with higher molecular weight in shrimp Litopenaeus vannamei (Named as LvHMCV1-3). In this study, a novel L. vannamei hemocyanin variant (Named as LvHMCV4) was further cloned and characterized. Bioinformatic analysis predicted that LvHMCV4 contains one open reading frame of 2137 bp and encodes a polypeptide of 678 amino acids. It shares 84-99% cDNA sequences identity to that of the classical form of L. vannamei hemocyanin (LvHMC, AJ250830.1) and LvHMCV1-3. LvHMCV4 possesses a conserved structure characteristic of the hemocyanin family and can be clustered into one branch along with other arthropod hemocyanins in a phylogenetic tree. Further, the full-length DNA of LvHMCV4 contains 2660 bp and two introns, which are located at the 80-538 bp and 2063-2227 bp regions, respectively. In addition, the mRNA transcript of LvHMCV4 was expressed highly in the hepatopancreas, lymphoid, brain and hemocytes, and weakly in the heart, intestine and gill, while no expression was found in the muscle, stomach and gut. Infection by Escherichia coli K12, Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio fluvialis, Streptococcus pyogenes or Staphylococcus aureus up-regulated significantly LvHMCV4 mRNA expression in the hepatopancreas. Furthermore, the recombinant protein of LvHMCV4 (rLvHMCV4) was prepared, which showed agglutination activities against six pathogenic bacteria at concentrations ranging from 15.6 to 125 MUg/ml. When co-injected with V. parahaemolyticus in L.vannamei, rLvHMCV4 significantly increased the survival rate after 48 h injection. Together, these studies suggested that hemocyanin variant, LvHMCV4, might be involved in shrimp resistance to pathogenic infection. PMID- 26115635 TI - Application of gold nanoparticles for gastrointestinal cancer theranostics: A systematic review. AB - Gold nanoparticles (GNPs) are readily synthesised structures that absorb light strongly to generate thermal energy which induces photothermal destruction of malignant tissue. This review examines the efficacy, potential challenges and toxicity from in vitro and in vivo applications of GNPs in oesophageal, gastric and colon cancers. A systematic literature search of Medline, Embase, Web of Science and Cochrane databases was performed using PRISMA guidelines. Two hundred and eighty-four papers were reviewed with sixteen studies meeting the inclusion criteria. The application of GNPs in eleven in vivo rodent studies with GI adenocarcinoma demonstrated excellent therapeutic outcomes but poor corroboration in terms of the cancer cells used, photothermal irradiation regimes, fluorophores and types of nanoparticles. There is compelling evidence of the translational potential of GNPs to be complimentary to surgery and feasible in the photothermal therapy of GI cancer but reproducibility and standardisation require development prior to GI cancer clinical trials. FROM THE CLINICAL EDITOR: Gold nanoparticles are one of the most potentially useful nanoparticles. This is especially true in cancer therapeutics because of their photothermal properties. In this comprehensive article, the authors reviewed the application and efficacy of gold nanoparticles in both the diagnosis and treatment of GI cancers. This review should provide a stimulus for researchers to further develop and translate these nanoparticles into future clinical trials. PMID- 26115636 TI - Time-controlled phagocytosis of asymmetric liposomes: Application to phosphatidylserine immunoliposomes binding HIV-1 virus-like particles. AB - Macrophage immune functions such as antibody-mediated phagocytosis are strongly impaired in individuals affected by HIV-1. Nevertheless, infected macrophages are still able to phagocytose apoptotic cells. For this reason, we recently developed antibody-decorated phosphatidylserine (PS)-containing liposomes that bind HIV-1 virus-like particles and, by mimicking apoptotic cells, are efficiently internalized by macrophages. In the context of an in vivo application, it would be extremely important to initially protect immunoliposomes from macrophages, in order to provide enough time to redistribute through the body and achieve maximum virus binding. To this end, we have designed asymmetric immunoliposomes in which the PS is initially confined to the inner leaflet and thus cannot be recognized by macrophages. Spontaneous PS flip-flop to the outer surface leads to a time delay in internalization by macrophages in vitro. Such a delay can be fine-tuned by altering the molecular composition of the immunoliposomes. FROM THE CLINICAL EDITOR: In the fight against HIV-1, macrophage plays an important role. Ironically, the phagocytic functions of these cells are often impaired by HIV-1. In this interesting article, the authors described the development of asymmetric liposomes, which would bind HIV-1 with prolonged systemic circulation, such that the clearance of virus by macrophages is enhanced. This system represents a promising effective approach to utilize the phagocytic capability of macrophages. PMID- 26115637 TI - Mesoporous silica nanoparticle delivery of chemically modified siRNA against TWIST1 leads to reduced tumor burden. AB - Growth and progression of solid tumors depend on the integration of multiple pro growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types. FROM THE CLINICAL EDITOR: Tumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field. PMID- 26115638 TI - Interaction of titanium dioxide nanoparticles with glucose on young rats after oral administration. AB - Titanium dioxide nanoparticles (TiO2 NPs) have a broad application prospect in replace with TiO2 used as a food additive, especially used in sweets. Understanding the interaction of TiO2 NPs with sugar is meaningful for health promotion. We used a young animal model to study the toxicological effect of orally administrated TiO2 NPs at doses of 0, 2, 10 and 50 mg/kg per day with or without daily consumption of 1.8 g/kg glucose for 30 days and 90 days. The results showed that oral exposure to TiO2 NPs and TiO2 NPs+glucose both induced liver, kidney, and heart injuries as well as changes in the count of white and red blood cells in a dose, time and gender-dependent manner. The toxicological interactions between orally-administrated TiO2 NPs and glucose were evident, but differed among target organs. These results suggest that it is necessary to limit dietary co-exposure to TiO2 NPs and sugar. FROM THE CLINICAL EDITOR: Nanotechnology has gained entrance in the food industry, with the presence of nanoparticles now in many food items. Despite this increasing trend, the potential toxic effects of these nanoparticles to human remain unknown. In this article, the authors studied titanium dioxide nanoparticles (TiO2 NPs), which are commonly used as food additive, together with glucose. The findings of possible adverse effects on liver, kidney, and heart might point to a rethink of using glucose and TiO2 NPs combination. PMID- 26115640 TI - Mitochondrial superoxide reduction and cytokine secretion skewing by carbon nanotube scaffolds enhance ex vivo expansion of human cord blood hematopoietic progenitors. AB - In this study, we report that surface functional groups of single walled carbon nanotubes (f-SWCNT) are critical for mediating survival and ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) in human umbilical cord blood (UCB). In comparison to amide (-O-NH2) and polyethylene-glycol (-PEG) functionalized SWCNT, carboxylic acid (-COOH) variants gave optimal viability support which correlated with maximal reduction of lethal mitochondrial superoxides in HSPC. Cytokine array illustrated that f-SWCNT-COOH maintained higher proportion of HSPC associated cytokines and minimal level of differentiation promoting factors. Transplantation of f-SWCNT-COOH expanded grafts in sub-lethally irradiated immunodeficient mice resulted in higher engraftment of HSPC in bone marrow compared to control when they were co transplanted with non-expanded cells from the same UCB. Expanded grafts mediated higher survival rate of mice compared to non-expanded grafts due to lower graft versus-host-disease which is likely a consequence of proportion of immune cells in the grafts. FROM THE CLINICAL EDITOR: Umbilical cord blood (UCB) is a potential source of hematopoietic stem and progenitor (HSPC) cells. One major hurdle for its clinical use is the insufficient yield of cell number. The authors in this study elegantly demonstrated the importance of various functional groups on single-walled carbon nanotubes (f-SWCNT) in enhancing ex vivo expansion of HSPC in UCB. The findings may pave a way for having UCB as a source for HSPC for clinical use in the future. PMID- 26115641 TI - In vitro experiments showing enhanced release of doxorubicin from Doxil(r) in the presence of ammonia may explain drug release at tumor site. AB - The anticancer nanodrug Doxil(r), a pegylated liposomal doxorubicin (PLD), accumulates at the tumor site due to the enhanced permeability and retention effect. However, the mechanism of doxorubicin release from the liposome within the tumor is unknown. We propose that ammonia produced at the tumor site by glutaminolysis enhances release. Using tumor cells in culture, we show that PLD, when ammonia is present, kills tumor cells with an efficacy similar to that of free doxorubicin, while PLD without ammonia and ammonia without PLD have very poor cytotoxicity. We confirm in tumor mouse models that ammonium/ammonia levels measured at the tumors are in the millimolar range, much higher than in the plasma of these mice. This is a new concept of stimulus-response, therapeutically efficacious drug release in tumors, with ammonia derived from tumor cell glutaminolysis acting as the stimulus. There may also be additional microenvironment-related variables that influence therapeutic efficacy. FROM THE CLINICAL EDITOR: The use of liposomal platform as a drug carrier has brought success to Doxil. Nonetheless, the underlying mechanism of drug release at tumor site and subsequent tumor killing was largely unknown. In this article, the authors demonstrated in their experiments that higher ammonia level in the tumor environment was the main mechanism for drug release. PMID- 26115639 TI - Movement of magnetic nanoparticles in brain tissue: mechanisms and impact on normal neuronal function. AB - Magnetic nanoparticles (MNPs) have been used as effective vehicles for targeted delivery of theranostic agents in the brain. The advantage of magnetic targeting lies in the ability to control the concentration and distribution of therapy to a desired target region using external driving magnets. In this study, we investigated the behavior and safety of MNP motion in brain tissue. We found that MNPs move and form nanoparticle chains in the presence of a uniform magnetic field, and that this chaining is influenced by the applied magnetic field intensity and the concentration of MNPs in the tissue. Using electrophysiology recordings, immunohistochemistry and fluorescent imaging we assessed the functional health of neurons and neural circuits and found no adverse effects associated with MNP motion through brain tissue. FROM THE CLINICAL EDITOR: Much research has been done to test the use of nanocarriers for gaining access across the blood brain barrier (BBB). In this respect, magnetic nanoparticles (MNPs) are one of the most studied candidates. Nonetheless, the behavior and safety of MNP once inside brain tissue remains unknown. In this article, the authors thus studied this very important subject. PMID- 26115642 TI - Nano-enabled drug delivery systems for brain cancer and Alzheimer's disease: research patterns and opportunities. AB - "Tech mining" applies bibliometric and text analytic methods to scientific literature of a target field. In this study, we compare the evolution of nano enabled drug delivery (NEDD) systems for two different applications - viz., brain cancer (BC) and Alzheimer's disease (AD) - using this approach. In this process, we derive research intelligence from papers indexed in MEDLINE. Review by domain specialists helps understand the macro-level disease problems and pathologies to identify commonalities and differences between BC and AD. Results provide a fresh perspective on the developmental pathways for NEDD approaches that have been used in the treatment of BC and AD. Results also point toward finding future solutions to drug delivery issues that are critical to medical practitioners and pharmaceutical scientists addressing the brain. FROM THE CLINICAL EDITOR: Drug delivery to brain cells has been very challenging due to the presence of the blood-brain barrier (BBB). Suitable and effective nano-enabled drug delivery (NEDD) system is urgently needed. In this study, the authors utilized "tech mining" tools to describe and compare various choices of delivery system available for the diagnosis, as well as treatment, of brain cancer and Alzheimer's disease. PMID- 26115643 TI - [Occupational chronic obstructive pulmonary diseases. Legal aspects and practical management]. AB - The existence of occupational chronic obstructive pulmonary diseases (COPD) is now well established. Since 1989, several regulations have been progressively introduced, allowing compensation for some cases of occupational COPD. Following a brief review of the main occupational causes of COPD, the authors describe the present context for compensation in France and the procedures to be followed to ensure that patient's interests are supported. PMID- 26115644 TI - Two fatal tiger attacks in zoos. AB - Two captive tiger attacks are presented that took place in Cologne and Munster zoos. Both attacks occurred when the handlers, intent on cleaning the enclosures, entered whilst the tigers accidently retained access to the location, and thus defended their territory against the perceived intruders. Both victims suffered fatal neck injuries from the bites. At Munster, colleagues managed to lure the tiger away from its victim to enable treatment, whilst the Cologne zoo tiger had to be shot in order to allow access to be gained. Whilst it was judged that human error led to the deaths of the experienced zookeepers, the investigation in Munster was closed as no third party was found to be at fault, whereas the Cologne zoo director was initially charged with being negligent. These charges were subsequently dismissed as safety regulations were found to be up to date. PMID- 26115645 TI - Integrating pharmacotherapy and psychotherapy. PMID- 26115646 TI - Early growth response gene (EGR)-1 regulates leukotriene D4-induced cytokine transcription in Hodgkin lymphoma cells. AB - Classical Hodgkin lymphoma (cHL) has a unique pathological feature characterized by a minority of malignant Hodgkin Reed-Sternberg (H-RS) cells surrounded by numerous inflammatory cells. Cysteinyl-leukotrienes (CysLTs) are produced by eosinophils, macrophages and mast cells in the HL tumor microenvironment. In the present study we have explored the signal transduction pathways leading to leukotriene (LT) D4 induced expression of cytokines in the Hodgkin lymphoma cell line L1236 and KM-H2. Stimulation of L1236 and KM-H2 cells with LTD4 led to a concentration- and time-dependent increase at the transcriptional level of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3) and CCL4. The expression of several transcription factors was induced upon stimulation of Hodgkin cell lines with LTD4. Among these, EGR-1 was required for cytokine production. Inhibition of EGR-1 expression using shEGR 1 transduced by lentivirus led to suppression of the expression of TNF-alpha and IL-6. The effect of LTD4 on the expression of transcription factors and cytokines were also blocked by the specific CysLT1 receptor antagonist zafirlukast. These results demonstrate that EGR-1 plays a critical role in LTD4-induced cytokine transcription in Hodgkin cell lines. PMID- 26115647 TI - Validation of a tandem mass spectrometry method using combined extraction of 37 oxylipins and 14 endocannabinoid-related compounds including prostamides from biological matrices. AB - There is a clinical need for more relevant coverage of bioactive lipids using smaller sample volumes. Therefore, we have validated a tandem mass spectrometry method for combined solid phase extraction of 37 compounds in the oxylipin (OxL) and 14 in the endocannabinoid (eCB) metabolome, as well as prostamides. The limits of quantification (LOQ) for compounds in the eCB metabolome were in the range 0.5-1000 fg on column, intraday accuracy and precision ranges (%) were 83 125 and 0.3-17, respectively, and interday accuracy and precision ranges (%) were 80-119 and 1.2-20, respectively, dependent upon the compound and the concentration studied. Corresponding values for OxL were 0.5 fg-4.2 pg on column (LOQ), 85-115% (inter- and intraday accuracy) and <5% (precision). The combined extraction method was successfully applied to tissues, cell extracts, human plasma and milk samples. A deeper study of levels in elk, pig and cow brain, as well as cow heart and liver revealed tissue and species-specific elevation of eicosanoids: arachidonate diols, 20-HETE and 12(S)-HEPE (cow liver), LTB4 (cow brain), and monohydroxy metabolites (HETEs), epoxides and 5-oxo-ETE in elk brain, which might be caused by factors of stress and/or post-mortem reactions in the tissues. PMID- 26115648 TI - Adult Congenital Heart Disease in Pregnancy. AB - With the success of modern surgical techniques for congenital heart disease, the population of women of childbearing age with congenital heart disease is growing. Because of the significant hemodynamic load of pregnancy, labor, and delivery, women with congenital heart disease require preconceptual risk assessment and expert multidisciplinary care throughout pregnancy. The aim of this review is to discuss the management of cardiovascular, obstetric, and fetal care issues that are commonly encountered during pregnancy in women with congenital heart disease. PMID- 26115649 TI - Pregnancy in Women With Solid-Organ Transplants: A Review. AB - IMPORTANCE: Advances in solid-organ transplantation have allowed many women to reach reproductive potential, and pregnancy is no longer a rarity for these women. OBJECTIVE: To identify (1) potential complications to allograft function posed by pregnancy, (2) expected perinatal outcomes in women with solid-organ transplants, (3) risks of potential immunosuppressant regimens, (4) safety of lactation, and (5) contraceptive options for women with solid-organ transplants. EVIDENCE ACQUISITION: Single-center, registry data, and previous systematic reviews were evaluated in women with solid-organ transplants to identify the objectives of this review. In addition, recommendations from public health organizations were examined in regard to safety of medications and contraceptive methods. RESULTS: Women with solid-organ transplants are at risk for premature birth, low birth weight, cesarean delivery, and hypertensive disorders of pregnancy. Most immunosuppressant regimens are safe; however, mycophenolate mofetil should be avoided. Lactation with tacrolimus, cyclosporine, azathioprine, and prednisone appears safe. Long-acting reversible contraceptive methods are safe and effective for transplant recipients. CONCLUSIONS: Many successful pregnancies have been achieved in women following transplantation; however, optimal perinatal outcomes require stable allograft function. RELEVANCE: As more women are becoming pregnant after organ transplantation, a review of obstetric recommendations and perinatal outcome is warranted. PMID- 26115650 TI - The prevalence of sleep-disordered breathing among survivors of acute pulmonary embolism. AB - BACKGROUND: Sleep-disordered breathing (SDB) is associated with prothrombotic effects that could lead to venous thromboembolic diseases. OBJECTIVE: The objective of this study is to clarify the prevalence of SDB among survivors of pulmonary embolism (PE). METHODS: One hundred six consecutive PE patients were prospectively evaluated by portable monitoring (PM). Nocturnal polysomnography was performed in all subjects who were diagnosed by PM to have an apnoea hypopnoea index (AHI) > 15/h or evidence of increased daytime sleepiness. RESULTS: The overall SDB prevalence in the study population was 58.5 %. Mild obstructive sleep apnoea (OSA) was diagnosed in 35.8 % of patients. Of the subjects, 12.3 % suffered from moderate OSA. In 10.4 % of study participants, OSA was found to be severe. High-risk PE was significantly more frequent among subjects with an AHI > 15/h (p = 0.005). CONCLUSION: OSA is a common comorbidity of PE and possibly represents an additional risk factor for hemodynamic instability in PE patients. PMID- 26115652 TI - Arteriovenous shunts and capillary blush as an early sign of basal ganglia infarction after successful mechanical intra-arterial thrombectomy in ischaemic stroke. AB - OBJECTIVES: Recent studies indicate an interest in early infarct assessment, mainly using post-interventional perfusion imaging. This work evaluated two specific angiographic signs for infarct prediction in the basal ganglia immediately after successful mechanical intra-arterial thrombectomy. METHODS: In this retrospective study, 57 consecutive patients (mean +/- SD age 67 +/- 15 years) with acute occlusion of the proximal anterior circulation who underwent mechanical thrombectomy of the M1 segment of the middle cerebral artery were included. Two separate angiographic signs, early venous drainage and capillary blush, were identified and analysed regarding their statistical significance for infarct prediction within the basal ganglia. RESULTS: Four patients were excluded due to parenchymal haemorrhage. Forty-four of 53 patients developed infarction of the basal ganglia. Sensitivity/specificity were 93%/27%, respectively, for the capillary blush sign and 88%/63%, respectively, for the early venous drainage sign. Combining both signs increased the sensitivity and specificity to 88% and 81%, respectively, and increased the positive predictive value to 95%. CONCLUSIONS: Both angiographic signs seem to predict the irreversible damage of tissue in the basal ganglia reliably despite successful recanalization of the middle cerebral artery in patients with ischaemic stroke. KEY POINTS: * Evaluation of success in neurointerventional procedures is mainly based on recanalization rates. * Two separate angiographic signs can predict infarction immediately after proximal MCA recanalization. * Combining both signs increases their specificity. PMID- 26115651 TI - The effect of partial sleep deprivation on computer-based measures of fitness to drive. AB - PURPOSE: Using a partial sleep deprivation paradigm, the aim of the study was to investigate the sensitivity of a computer-based test battery of fitness to drive to detect impairments related to sleepiness. METHODS: Forty-seven healthy subjects (34 females, mean age 26.0 +/- 6.8 years) participated in a counterbalanced within-subject design of two conditions: (i) normal night sleep and (ii) partial sleep deprivation (PSD) with 4 h time in bed. For the assessment of fitness to drive, we used a validated traffic psychological test battery. Moreover, well-established measures of sleepiness highly responsive to sleep deprivation were applied: the Karolinska Sleepiness Scale (KSS), pupillography (Pupil Unrest Index (PUI) as physiological sleepiness indicator) and two sustained attention tasks (psychomotor Vigilance Task and Mackworth Clock Test). RESULTS: Subjective and physiological sleepiness were significantly increased after PSD, accompanied by large (d > 1.50 for KSS) and medium (d = 0.55 for PUI) effect sizes. Sleepiness-related performance decrements were found in both sustained attention tasks (d = 0.59-0.77). Assessing driving-related ability, PSD induced decrements only in the test domain Reaction Test (reaction time d = 0.54 and motor time d = 0.45). All other subtests-as well as the overall judgement of fitness to drive-were not significantly affected by PSD. CONCLUSION: In contrast to established tests of sustained attention and subjective sleepiness, computer based test batteries of fitness to drive might lack sensitivity to core aspects of sleepiness as they mainly consist of short and stimulating subtests. Therefore, tasks that require sustained attention should be an essential part of traffic psychological test batteries when sleepiness is a potential issue. PMID- 26115653 TI - Combined reading of Contrast Enhanced and Diffusion Weighted Magnetic Resonance Imaging by using a simple sum score. AB - OBJECTIVE: To improve specificity of breast MRI by integrating Apparent Diffusion Coefficient (ADC) values with contrast enhanced MRI (CE-MRI) using a simple sum score. METHODS: Retrospective analysis of a consecutive series of patients referred to breast MRI at 1.5 T for further workup of breast lesions. Reading results of CE-MRI were dichotomized into score 1 (suspicious) or 0 (benign). Lesion's ADC-values (in *10-3 mm2/s) were assigned two different scores: ADC2: likely malignant (score +1, ADC <= 1), indeterminate (score 0, ADC >1- <= 1.4) and likely benign (score -1, ADC > 1.4) and ADC1: indeterminate (score 0, ADC <= 1.4) and likely benign (score -1, ADC > 1.4). Final added CE-MRI and ADC scores >0 were considered suspicious. Reference standard was histology and imaging follow-up of >24 months. Diagnostic parameters were compared using McNemar tests. RESULTS: A total of 150 lesions (73 malignant) were investigated. Reading of CE MRI showed a sensitivity of 100 % (73/73) and a specificity of 81.8 % (63/77). Additional integration of ADC scores increased specificity (ADC2/ADC1, P = 0.008/0.001) without causing false negative results. CONCLUSION: Using a simple sum score, ADC-values can be integrated with CE-MRI of the breast, improving specificity. The best approach is using one threshold to exclude cancer. KEY POINTS: ADC is used to assign levels of suspicion to breast lesions. ADC values >1.4 *10 (-3) mm (2) /s are likely benign and effectively rule out malignancy. ADC values below <=1*10 (-3) mm (2) /s) are likely malignant but may be false positive. CE-MRI (+1: suspicious, 0: benign) and ADC (0: indeterminate, -1: benign) scores are added. Sum scores >0 should be biopsied. PMID- 26115654 TI - Imaging of mesothelioma of tunica vaginalis testis. AB - OBJECTIVES: To describe the imaging findings in a series of patients with mesothelioma of the tunica vaginalis testis. METHODS: We reviewed clinical data, imaging findings and follow-up information in a series of 10 pathology-proven cases of mesothelioma (all had US; 2 had MR) of the tunica vaginalis. RESULTS: A variety of patterns could be observed, the most common (5/10) being a hydrocele with parietal, solid and hypervascular vegetations; one patient had a septated hydrocele with hypervascular walls; one had multiple, solid nodules surrounded by a small, physiological quantity of fluid; one a cystic lesion with thick walls and vegetations compressing the testis; two had a solid paratesticular mass. MR showed multiple small nodules on the surface of the tunica vaginalis in one case and diffuse thickening and vegetations in the other one; lesions had low signal intensity on T2-w images and were hypervascular after contrast injection. CONCLUSIONS: A preoperative diagnosis of mesotheliomas presenting as solid paratesticular masses seems very difficult with imaging. On the contrary, the diagnosis must be considered in patients in whom a hydrocele with parietal vegetations is detected, especially if these show high vascularity. KEY POINTS: Mesotheliomas of the tunica vaginalis are rare, often challenging to diagnose preoperatively. Most common finding is a complex hydrocele with hypervascular parietal vegetations. Septated hydrocele, nodules without hydrocele, a thick walled paratesticular cyst are less common. Preoperative diagnosis may allow aggressive surgical approach and, possibly, a better prognosis. PMID- 26115655 TI - Muscle MRI findings in facioscapulohumeral muscular dystrophy. AB - OBJECTIVES: Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. METHODS AND MATERIALS: Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). RESULTS: In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. CONCLUSIONS: In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. KEY POINTS: Muscle MRI identifies a specific pattern of muscle involvement in FSHD patients. Muscle MRI may predict FSHD in asymptomatic and severely affected patients. Muscle MRI of upper girdle better predicts FSHD. Muscle MRI may differentiate FSHD from other forms of muscular dystrophy. Muscle MRI may show the involvement of non-clinical testable muscles. PMID- 26115656 TI - Implementation of an electronic fingerprint-linked data collection system: a feasibility and acceptability study among Zambian female sex workers. AB - BACKGROUND: Patient identification within and between health services is an operational challenge in many resource-limited settings. When following HIV risk groups for service provision and in the context of vaccine trials, patient misidentification can harm patient care and bias trial outcomes. Electronic fingerprinting has been proposed to identify patients over time and link patient data between health services. The objective of this study was to determine 1) the feasibility of implementing an electronic-fingerprint linked data capture system in Zambia and 2) the acceptability of this system among a key HIV risk group: female sex workers (FSWs). METHODS: Working with Biometrac, a US-based company providing biometric-linked healthcare platforms, an electronic fingerprint-linked data capture system was developed for use by field recruiters among Zambian FSWs. We evaluated the technical feasibility of the system for use in the field in Zambia and conducted a pilot study to determine the acceptability of the system, as well as barriers to uptake, among FSWs. RESULTS: We found that implementation of an electronic fingerprint-linked patient tracking and data collection system was feasible in this relatively resource-limited setting (false fingerprint matching rate of 1/1000 and false rejection rate of <1/10,000) and was acceptable among FSWs in a clinic setting (2% refusals). However, our data indicate that less than half of FSWs are comfortable providing an electronic fingerprint when recruited while they are working. The most common reasons cited for not providing a fingerprint (lack of privacy/confidentiality issues while at work, typically at bars or lodges) could be addressed by recruiting women during less busy hours, in their own homes, in the presence of "Queen Mothers" (FSW organizers), or in the presence of a FSW that has already been fingerprinted. CONCLUSIONS: Our findings have major implications for key population research and improved health services provision. However, more work needs to be done to increase the acceptability of the electronic fingerprint-linked data capture system during field recruitment. This study indicated several potential avenues that will be explored to increase acceptability. PMID- 26115657 TI - Long-term results of therapeutic local anesthesia (neural therapy) in 280 referred refractory chronic pain patients. AB - BACKGROUND: Can the application of local anesthetics (Neural Therapy, NT) alone durably improve pain symptoms in referred patients with chronic and refractory pain? If the application of local anesthetics does lead to an improvement that far exceeds the duration of action of local anesthetics, we will postulate that a vicious circle of pain in the reflex arcs has been disrupted (hypothesis). METHODS: Case series design. We exclusively used procaine or lidocaine. The inclusion criteria were severe pain and chronic duration of more than three months, pain unresponsive to conventional medical measures, written referral from physicians or doctors of chiropractic explicitly to NT. Patients with improvement of pain who started on additional therapy during the study period for a reason other than pain were excluded in order to avoid a potential bias. Treatment success was measured after one year follow-up using the outcome measures of pain and analgesics intake. RESULTS: 280 chronic pain patients were included; the most common reason for referral was back pain. The average number of consultations per patient was 9.2 in the first year (median 8.0). After one year, in 60 patients pain was unchanged, 52 patients reported a slight improvement, 126 were considerably better, and 41 pain-free. At the same time, 74.1% of the patients who took analgesics before starting NT needed less or no more analgesics at all. No adverse effects or complications were observed. CONCLUSIONS: The good long term results of the targeted therapeutic local anesthesia (NT) in the most problematic group of chronic pain patients (unresponsive to all evidence based conventional treatment options) indicate that a vicious circle has been broken. The specific contribution of the intervention to these results cannot be determined. The low costs of local anesthetics, the small number of consultations needed, the reduced intake of analgesics, and the lack of adverse effects also suggest the practicality and cost-effectiveness of this kind of treatment. Controlled trials to evaluate the true effect of NT are needed. PMID- 26115658 TI - Global analyses of TetR family transcriptional regulators in mycobacteria indicates conservation across species and diversity in regulated functions. AB - BACKGROUND: Mycobacteria inhabit diverse niches and display high metabolic versatility. They can colonise both humans and animals and are also able to survive in the environment. In order to succeed, response to environmental cues via transcriptional regulation is required. In this study we focused on the TetR family of transcriptional regulators (TFTRs) in mycobacteria. RESULTS: We used InterPro to classify the entire complement of transcriptional regulators in 10 mycobacterial species and these analyses showed that TFTRs are the most abundant family of regulators in all species. We identified those TFTRs that are conserved across all species analysed and those that are unique to the pathogens included in the analysis. We examined genomic contexts of 663 of the conserved TFTRs and observed that the majority of TFTRs are separated by 200 bp or less from divergently oriented genes. Analyses of divergent genes indicated that the TFTRs control diverse biochemical functions not limited to efflux pumps. TFTRs typically bind to palindromic motifs and we identified 11 highly significant novel motifs in the upstream regions of divergently oriented TFTRs. The C terminal ligand binding domain from the TFTR complement in M. tuberculosis showed great diversity in amino acid sequence but with an overall architecture common to other TFTRs. CONCLUSION: This study suggests that mycobacteria depend on TFTRs for the transcriptional control of a number of metabolic functions yet the physiological role of the majority of these regulators remain unknown. PMID- 26115661 TI - Cosmetic Surgery National Data Bank Statistics. PMID- 26115659 TI - The prognostic impact of mutations in spliceosomal genes for myelodysplastic syndrome patients without ring sideroblasts. AB - BACKGROUND: Mutations in genes that are part of the splicing machinery for myelodysplastic syndromes (MDS), including MDS without ring sideroblasts (RS), have been widely investigated. The effects of these mutations on clinical outcomes have been diverse and contrasting. METHODS: We examined a cohort of 129 de novo MDS patients, who did not harbor RS, for mutations affecting three spliceosomal genes (SF3B1, U2AF1, and SRSF2). RESULTS: The mutation rates of SF3B1, U2AF1, and SRSF2 were 7.0 %, 7.8 %, and 10.1 %, respectively. Compared with previously reported results, these rates were relatively infrequent. The SRSF2 mutation strongly correlated with old age (P < 0.001), while the mutation status of SF3B1 did not affect overall survival (OS), progression-free survival (PFS), or acute myeloid leukemia (AML) transformation. In contrast, MDS patients with mutations in U2AF1 or SRSF2 exhibited inferior PFS. The U2AF1 mutation was associated with inferior OS in low-risk MDS patients (P = 0.035). The SRSF2 mutation was somewhat associated with AML transformation (P = 0.083). CONCLUSION: Our findings suggest that the frequencies of the SF3B1, U2AF1, and SRSF2 splicing gene mutations in MDS without RS were relatively low. We also demonstrated that the U2AF1 and SRSF2 mutations were associated with an unfavorable prognostic impact in MDS patients without RS. PMID- 26115662 TI - Detecting Adaptive Evolution in Phylogenetic Comparative Analysis Using the Ornstein-Uhlenbeck Model. AB - Phylogenetic comparative analysis is an approach to inferring evolutionary process from a combination of phylogenetic and phenotypic data. The last few years have seen increasingly sophisticated models employed in the evaluation of more and more detailed evolutionary hypotheses, including adaptive hypotheses with multiple selective optima and hypotheses with rate variation within and across lineages. The statistical performance of these sophisticated models has received relatively little systematic attention, however. We conducted an extensive simulation study to quantify the statistical properties of a class of models toward the simpler end of the spectrum that model phenotypic evolution using Ornstein-Uhlenbeck processes. We focused on identifying where, how, and why these methods break down so that users can apply them with greater understanding of their strengths and weaknesses. Our analysis identifies three key determinants of performance: a discriminability ratio, a signal-to-noise ratio, and the number of taxa sampled. Interestingly, we find that model-selection power can be high even in regions that were previously thought to be difficult, such as when tree size is small. On the other hand, we find that model parameters are in many circumstances difficult to estimate accurately, indicating a relative paucity of information in the data relative to these parameters. Nevertheless, we note that accurate model selection is often possible when parameters are only weakly identified. Our results have implications for more sophisticated methods inasmuch as the latter are generalizations of the case we study. PMID- 26115660 TI - Functional Near-Infrared Spectroscopy Evidence for Development of Prefrontal Engagement in Working Memory in Early Through Middle Childhood. AB - The neural underpinnings of working memory are hypothesized to develop incrementally across preschool and early school age, coinciding with the rapid maturation of executive function occurring during this period. This study investigates the development of prefrontal cortex function between the ages of 3 and 7. Children (n = 68) participated in a novel spatial working memory task while their middle and lateral prefrontal cortex (LPFC) was monitored using functional near infrared spectroscopy (fNIRS). We found increased activation of the LPFC when comparing working memory to rest. Greater LPFC increase was noted for longer compared with shorter delay periods. Increase in LPFC activation, accuracy, and response speed were positively correlated with child age, suggesting that developmental changes in prefrontal function might underlie effective development of executive function in this age range. PMID- 26115663 TI - Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies. AB - OBJECTIVE: To quantify the frequency and seriousness of adverse events in non oncology phase I studies with healthy participants. DESIGN: Meta-analysis of individual, healthy volunteer level data. SETTING: Phase I studies with healthy volunteers conducted between September 2004 and March 2011 at Pfizer's three dedicated phase I testing sites in Belgium, Singapore, and the United States. These included studies in which drug development was terminated. PARTICIPANTS: 11,028 participants who received the study drug in 394 distinct non-oncology phase I studies, which involved 4620 unique individuals. A total of 2460 (53.2%) participants were involved in only one study, whereas others participated in two or more studies. MAIN OUTCOME MEASURES: Adverse events classified as mild, moderate, and severe as well as serious adverse events-defined by the Food and Drug Administration as events that result in death, a life threatening event, admission to hospital, prolongation of existing hospital stay, a persistent or major disability, or a congenital anomaly or birth defect. Pfizer researchers of phase I trials determined adverse events, and serious adverse events were those filed with the FDA. RESULTS: Overall, 4000 (36.3%) participants who received the study drug experienced no adverse events and 7028 (63.7%) experienced 24,643 adverse events. Overall, 84.6% (n=20,840) of adverse events were mild and 1.0% (n=255) were severe. 34 (0.31%) serious adverse events occurred among the 11,028 participants who received the study agent, with no deaths or life threatening events. Of the 34 serious adverse events, 11 were related to the study drug and seven to study procedures, whereas 16 were unrelated to a study drug or procedure, including four that occurred when the participant was receiving a placebo. Overall, 24.1% (n=5947) of adverse events were deemed to be unrelated to the study drug. With a total of 143 (36%) studies involving placebo, 10.3% (n=2528) of all adverse events occurred among participants receiving placebo. The most common adverse events were headache (12.2%, n=3017), drowsiness (9.8%, n=2410), and diarrhea (6.9%, n=1698). Research on drugs for neuropsychiatric indications had the highest frequency of adverse events (3015 per 1000 participants). CONCLUSION: Among 11,028 healthy participants who received study drug in non-oncology phase I studies, the majority (85%) of adverse events were mild. 34 (0.31%) serious adverse events occurred, with no life threatening events or deaths. Half of all adverse events were related to the study drug or to procedures. Extrapolation of these data to other types of phase I studies, especially with biological agents, may not be warranted. PMID- 26115664 TI - Social movements and public health advocacy in action: the UK people's health movement. AB - There are growing calls within public health for researchers and practitioners working to improve and protect the public's health to become more involved in politics and advocacy. Such a move takes practitioners and researchers beyond the traditional, evidence-based public health paradigm, raising potential dilemmas and risks for those who undertake such work. Drawing on the example of the People's Health Movement, this short paper argues that advocacy and social movements are an essential component of public health's efforts to achieve great health equity. It outlines how the Scottish branch of the People's Health Movement sought to overcome potential tensions between public health evidence and advocacy by developing a regional manifesto for health via transparent and democratic processes which combine empirical and experiential evidence. We suggest that this is an illustrative example of how potential tensions between public health research and advocacy can be overcome, through bottom-up movements of solidarity and action. PMID- 26115666 TI - Migraine as a predictor of mortality: The HUNT study. AB - BACKGROUND: There is conflicting evidence for the association between migraine and increased mortality risk. The aim of this study was to investigate the relationship between migraine and non-migrainous headache, and all-cause mortality and cardiovascular mortality. METHODS: In this prospective population based cohort study from Norway, we used baseline data from the second Nord Trondelag Health Survey (HUNT2), performed between 1995 and 1997 in the County of Nord-Trondelag. These data were linked with a comprehensive mortality database with follow-up through the year 2011. A total of 51,853 (56% of invited) people were categorized based on their answers to the headache questions in HUNT2 (headache free, migraine or non-migrainous headache). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression. RESULTS: During the follow-up period 9408 died, 4321 of these from cardiovascular causes. There was no difference in all-cause mortality between individuals with migraine and non-migrainous headache compared to those without headache or between headache status and mortality by cardiovascular disease. There was, however, among men with migraine without aura a reduced risk of death by cardiovascular diseases (HR 0.72, 95% confidence interval 0.56-0.93). This relationship was not evident in women. CONCLUSION: In this large, prospective cohort study there was no evidence for a higher all-cause mortality or cardiovascular mortality among individuals with migraine. PMID- 26115667 TI - Systems modelling and simulation in health service design, delivery and decision making. AB - The ever increasing pressures to ensure the most efficient and effective use of limited health service resources will, over time, encourage policy makers to turn to system modelling solutions. Such techniques have been available for decades, but despite ample research which demonstrates potential, their application in health services to date is limited. This article surveys the breadth of approaches available to support delivery and design across many areas and levels of healthcare planning. A case study in emergency stroke care is presented as an exemplar of an impactful application of health system modelling. This is followed by a discussion of the key issues surrounding the application of these methods in health, what barriers need to be overcome to ensure more effective implementation, as well as likely developments in the future. PMID- 26115665 TI - INTERACTING DISCIPLINES: Cardiac natriuretic peptides and obesity: perspectives from an endocrinologist and a cardiologist. AB - Since their discovery in 1981, the cardiac natriuretic peptides (cNP) atrial natriuretic peptide (also referred to as atrial natriuretic factor) and brain natriuretic peptide have been well characterised in terms of their renal and cardiovascular actions. In addition, it has been shown that cNP plasma levels are strong predictors of cardiovascular events and mortality in populations with no apparent heart disease as well as in patients with established cardiac pathology. cNP secretion from the heart is increased by humoral and mechanical stimuli. The clinical significance of cNP plasma levels has been shown to differ in obese and non-obese subjects. Recent lines of evidence suggest important metabolic effects of the cNP system, which has been shown to activate lipolysis, enhance lipid oxidation and mitochondrial respiration. Clinically, these properties lead to browning of white adipose tissue and to increased muscular oxidative capacity. In human association studies in patients without heart disease higher cNP concentrations were observed in lean, insulin-sensitive subjects. Highly elevated cNP levels are generally observed in patients with systolic heart failure or high blood pressure, while obese and type-2 diabetics display reduced cNP levels. Together, these observations suggest that the cNP system plays a role in the pathophysiology of metabolic vascular disease. Understanding this role should help define novel principles in the treatment of cardiometabolic disease. PMID- 26115668 TI - Pain in Community-Dwelling Elderly African Americans. AB - OBJECTIVE: This study examines the type, severity, and correlates of pain among underserved elderly African Americans. METHOD: This cross-sectional study includes 400 non-institutionalized underserved aged African Americans, recruited from 16 African American churches located in South Los Angeles. RESULTS: Two thirds of our participants reported a level of pain of 5 or higher (on a scale of 0-10) for at least one of the pain items. Participants with severe level of pain showed a higher level of insomnia, depression, and deficiency in activity of daily living as well as a lower level of memory function and quality of physical and mental health. Also, level of pain is a statistically significant correlate of office-based physician visits and emergency department admission. CONCLUSION: Our findings encourage multidisciplinary and interdisciplinary interventions to include pharmacotherapy, psychological support, and physical rehabilitation, specifically on neuropathic pain among aged African Americans with multiple chronic conditions. PMID- 26115669 TI - Stapedectomy Effects on Tinnitus: Relationship of Change in Loudness to Change in Severity. AB - OBJECTIVE: To relate poststapedectomy change in tinnitus loudness to change in tinnitus severity. STUDY DESIGN: Prospective, within-subjects. SETTING: A single otology and neurotology subspecialty referral practice. SUBJECTS AND METHODS: Forty-nine subjects undergoing stapedectomy completed the study between January 2012 and October 2013. Tinnitus instruments, audiometric data, and demographic information were collected prior to and 1 and 6 months after surgery. Tinnitus loudness was assessed using an 11-point (0 = none; 5 = conversation level; 10 = jet engine) visual analog scale, and severity was measured using the validated Tinnitus Functional Index. The relationship between change in tinnitus loudness and change in tinnitus severity was evaluated using linear regression and receiver operating characteristic (ROC) analyses. RESULTS: A linear regression model of change in tinnitus loudness averaged for both ears on a visual analog scale (DeltaVASavg) versus change in Tinnitus Functional Index score (DeltaTFI) showed a strong correlation (DeltaTFI = 9.35 *DeltaVASavg; R = 0.64; P < .001). An ROC analysis identified DeltaVASavg between 1.5 and 2.0 as the optimal threshold for predicting a clinically significant change in tinnitus severity (DeltaTFI >= 13), with sensitivity and specificity of approximately 0.62 and a positive predictive value (PPV) of 0.64. CONCLUSION: For poststapedectomy patients, a VAS loudness change by 1.5 to 2.0 points averaged for both ears in bilateral tinnitus or ~3 points in unilateral tinnitus has a PPV ~0.64 for a clinically significant change in tinnitus severity. PMID- 26115670 TI - A Clinical Study of Pharyngolaryngectomy with Total Esophagectomy: Postoperative Complications, Countermeasures, and Prognoses. AB - OBJECTIVE: Patients with advanced hypopharyngeal or cervical esophageal cancer have a comparatively high risk of also developing thoracic esophageal cancer. Pharyngolaryngectomy with total esophagectomy is highly invasive, and few reports about it exist. We examined the postoperative complications and respective countermeasures and prognoses of patients who underwent pharyngolaryngectomy with total esophagectomy. STUDY DESIGN: Case series with chart review. SETTING: Department of Head and Neck Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Japan. SUBJECTS AND METHODS: We examined the postoperative complications and respective countermeasures and prognoses of 40 patients who underwent pharyngolaryngectomy with total esophagectomy in our hospital. RESULTS: Postoperative complications were observed in 23 patients (57.5%) and consisted of 8 groups: tracheal region necrosis in 5 patients; neck abscess formation/wound infection in 5; fistula in 4; tracheostomy suture leakage in 2; ileus in 2; lymphorrhea in 2; pulmonary complications in 2; and other complications, including hemothorax, tracheoinnominate artery fistula, temporary cardiac arrest due to intraoperative mediastinum operation, methicillin-resistant Staphylococcus aureus enteritis, and sepsis, in 1 patient each. A lethal complication-brachiocephalic vein hemorrhage due to tracheostomy suture leakage and hemorrhagic shock due to tracheoinnominate artery fistula-occurred in 2 (5%) patients. The crude 5-year survival rate was 48.6%. CONCLUSIONS: Serious postoperative complications were related to tracheostomaplasty. Although pharyngolaryngectomy with total esophagectomy is highly invasive, we believe that our outlined treatment method is the most appropriate for cases of advanced hypopharyngeal or cervical esophageal cancer that also requires concurrent surgery for esophageal cancer. PMID- 26115671 TI - Junctional abnormalities in human airway epithelial cells expressing F508del CFTR. AB - Cystic fibrosis (CF) has a profound impact on airway physiology. Accumulating evidence suggests that intercellular junctions are impaired in CF. We examined changes to CF transmembrane conductance regulator (CFTR) function, tight junctions, and gap junctions in NuLi-1 (CFTR(wt/wt)) and CuFi-5 (CFTR(DeltaF508/DeltaF508)) cells. Cells were studied at air-liquid interface (ALI) and compared with primary human bronchial epithelial cells. On the basis of fluorescent lectin binding, the phenotype of the NuLi-1 and CuFi-5 cells at week 8 resembled that of serous, glycoprotein-rich airway cells. After week 7, CuFi-5 cells possessed 130% of the epithelial Na(+) channel activity and 17% of the CFTR activity of NuLi-1 cells. In both cell types, expression levels of CFTR were comparable to those in primary airway epithelia. Transepithelial resistance of NuLi-1 and CuFi-5 cells stabilized during maturation in ALI culture, with significantly lower transepithelial resistance for CuFi-5 than NuLi-1 cells. We also found that F508del CFTR negatively affects gap junction function in the airway. NuLi-1 and CuFi-5 cells express the connexins Cx43 and Cx26. While both connexins were properly trafficked by NuLi-1 cells, Cx43 was mistrafficked by CuFi-5 cells. Cx43 trafficking was rescued in CuFi-5 cells treated with 4 phenylbutyric acid (4-PBA), as assessed by intracellular dye transfer. 4-PBA treated CuFi-5 cells also exhibited an increase in forskolin-induced CFTR mediated currents. The Cx43 trafficking defect was confirmed using IB3-1 cells and found to be corrected by 4-PBA treatment. These data support the use of NuLi 1 and CuFi-5 cells to examine the effects of F508del CFTR expression on tight junction and gap junction function in the context of serous human airway cells. PMID- 26115672 TI - Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake. AB - In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2 ), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2 [(18)F]fluoroglucose ((18)F-FDG) and 14-(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in (18)F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in (18)F-FTHA uptake (-2.1-fold, P < 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake. PMID- 26115673 TI - Leucine supplementation improves leptin sensitivity in high-fat diet fed rats. AB - BACKGROUND: Several studies have reported the favorable effect of leucine supplementation on insulin resistance or insulin sensitivity. However, whether or not leucine supplementation improves leptin sensitivity remains unclear. DESIGN: Forty-eight male Sprague-Dawley rats were fed with either a high-fat diet (HFD) or HFD supplemented with 1.5, 3.0, and 4.5% leucine for 16 weeks. At the end of the experiment, serum leptin level was measured by ELISA, and leptin receptor (ObR) in the hypothalamus was examined by immunohistochemistry. The protein expressions of ObR and leptin-signaling pathway in adipose tissues were detected by western blot. RESULTS: No significant differences in body weight and food/energy intake existed among the four groups. Serum leptin levels were significantly lower, and ObR expression in the hypothalamus and adipose tissues was significantly higher in the three leucine groups than in the control group. These phenomena suggested that leptin sensitivity was improved in the leucine groups. Furthermore, the expressions of JAK2 and STAT3 (activated by ObR) were significantly higher, and that of SOCS3 (inhibits leptin signaling) was significantly lower in the three leucine groups than in the control group. CONCLUSIONS: Leucine supplementation improves leptin sensitivity in rats on HFD likely by promoting leptin signaling. PMID- 26115675 TI - Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions. AB - Cortical superficial siderosis describes a distinct pattern of blood-breakdown product deposition limited to cortical sulci over the convexities of the cerebral hemispheres, sparing the brainstem, cerebellum and spinal cord. Although cortical superficial siderosis has many possible causes, it is emerging as a key feature of cerebral amyloid angiopathy, a common and important age-related cerebral small vessel disorder leading to intracerebral haemorrhage and dementia. In cerebral amyloid angiopathy cohorts, cortical superficial siderosis is associated with characteristic clinical symptoms, including transient focal neurological episodes; preliminary data also suggest an association with a high risk of future intracerebral haemorrhage, with potential implications for antithrombotic treatment decisions. Thus, cortical superficial siderosis is of relevance to neurologists working in neurovascular, memory and epilepsy clinics, and neurovascular emergency services, emphasizing the need for appropriate blood sensitive magnetic resonance sequences to be routinely acquired in these clinical settings. In this review we focus on recent developments in neuroimaging and detection, aetiology, prevalence, pathophysiology and clinical significance of cortical superficial siderosis, with a particular emphasis on cerebral amyloid angiopathy. We also highlight important areas for future investigation and propose standards for evaluating cortical superficial siderosis in research studies. PMID- 26115674 TI - Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. AB - See Moon (doi:10.1093/awv239) for a scientific commentary on this article.Traumatic brain injury frequently leads to long-term cognitive problems and physical disability yet remains without effective therapeutics. Traumatic brain injury results in neuronal injury and death, acute and prolonged inflammation and decreased blood flow. Drugs that block angiotensin II type 1 receptors (AT1R, encoded by AGTR1) (ARBs or sartans) are strongly neuroprotective, neurorestorative and anti-inflammatory. To test whether these drugs may be effective in treating traumatic brain injury, we selected two sartans, candesartan and telmisartan, of proven therapeutic efficacy in animal models of brain inflammation, neurodegenerative disorders and stroke. Using a validated mouse model of controlled cortical impact injury, we determined effective doses for candesartan and telmisartan, their therapeutic window, mechanisms of action and effect on cognition and motor performance. Both candesartan and telmisartan ameliorated controlled cortical impact-induced injury with a therapeutic window up to 6 h at doses that did not affect blood pressure. Both drugs decreased lesion volume, neuronal injury and apoptosis, astrogliosis, microglial activation, pro-inflammatory signalling, and protected cerebral blood flow, when determined 1 to 3 days post-injury. Controlled cortical impact-induced cognitive impairment was ameliorated 30 days after injury only by candesartan. The neurorestorative effects of candesartan and telmisartan were reduced by concomitant administration of the peroxisome proliferator-activated receptor gamma (PPARgamma, encoded by PPARG) antagonist T0070907, showing the importance of PPARgamma activation for the neurorestorative effect of these sartans. AT1R knockout mice were less vulnerable to controlled cortical impact-induced injury suggesting that the sartan's blockade of the AT1R also contributes to their efficacy. This study strongly suggests that sartans with dual AT1R blocking and PPARgamma activating properties have therapeutic potential for traumatic brain injury. PMID- 26115676 TI - Experimental subarachnoid haemorrhage results in multifocal axonal injury. AB - The great majority of acute brain injury results from trauma or from disorders of the cerebrovasculature, i.e. ischaemic stroke or haemorrhage. These injuries are characterized by an initial insult that triggers a cascade of injurious cellular processes. The nature of these processes in spontaneous intracranial haemorrhage is poorly understood. Subarachnoid haemorrhage, a particularly deadly form of intracranial haemorrhage, shares key pathophysiological features with traumatic brain injury including exposure to a sudden pressure pulse. Here we provide evidence that axonal injury, a signature characteristic of traumatic brain injury, is also a prominent feature of experimental subarachnoid haemorrhage. Using histological markers of membrane disruption and cytoskeletal injury validated in analyses of traumatic brain injury, we show that axonal injury also occurs following subarachnoid haemorrhage in an animal model. Consistent with the higher prevalence of global as opposed to focal deficits after subarachnoid haemorrhage and traumatic brain injury in humans, axonal injury in this model is observed in a multifocal pattern not limited to the immediate vicinity of the ruptured artery. Ultrastructural analysis further reveals characteristic axonal membrane and cytoskeletal changes similar to those associated with traumatic axonal injury. Diffusion tensor imaging, a translational imaging technique previously validated in traumatic axonal injury, from these same specimens demonstrates decrements in anisotropy that correlate with histological axonal injury and functional outcomes. These radiological indicators identify a fibre orientation-dependent gradient of axonal injury consistent with a barotraumatic mechanism. Although traumatic and haemorrhagic acute brain injury are generally considered separately, these data suggest that a signature pathology of traumatic brain injury-axonal injury-is also a functionally significant feature of subarachnoid haemorrhage, raising the prospect of common diagnostic, prognostic, and therapeutic approaches to these conditions. PMID- 26115678 TI - Kinetic changes of regulatory B10 cells in collagen-induced arthritis could be regulated by cytokines IFN-gamma and TGF-beta1. AB - OBJECTIVE: The status of B10 cells in patients with rheumatoid arthritis (RA) has not been consistently reported. In this study, we observed the kinetic changes of the B10 cells in collagen-induced arthritis (CIA) mice and the influence of multiple cytokines on the B10 cells to investigate the potential mechanism underlying the changes of B10 cells. METHODS: The kinetic changes of frequency and function of the CD19(+)CD1d(hi)CD5(+) cells in splenic cells were observed during the complete progress of CIA mice. The kinetic changes of cytokines IL-4, IL-6, IL-17A, IL-18, TNF-alpha, IFN-gamma and TGF-beta1 were also detected. Then influence of these cytokines on the status of B10 cells was investigated both in vitro and in vivo. RESULTS: The frequency and suppressive ability of the CD19(+)CD1d(hi)CD5(+) cells increased to its peak on the 14th day while gradually decreased subsequently. IFN-gamma showed a similar tendency with the CD19(+)CD1d(hi)CD5(+) cells, whereas IL-6, IL-17A, IL-18, TNF-alpha, and TGF beta1 reached its peak on the 28-35th day. In addition, IFN-gamma up-regulated while TGF-beta1 down-regulated the frequency and function of the CD19(+)CD1d(hi)CD5(+) cells both in vitro and in vivo. CONCLUSION: The B10 cells in CIA mice could be regulated by IFN-gamma and TGF-beta1, suggesting that the status of B10 cells in RA may be influenced by the balance of pro-inflammatory and anti-inflammatory factors, and the impaired B10 cells could be recovered in vitro by adequate treatment before being used for a therapeutic method in clinical practice. PMID- 26115679 TI - Tackling antibiotic resistance in febrile neutropenia: current challenges with and recommendations for managing infections with resistant Gram-negative organisms. AB - Multidrug resistant (MDR) Gram-negative bacteria (GNB) have emerged as important pathogens and a serious challenge in the management of neutropenic patients worldwide. The great majority of infections are caused by the Enterobacteriaceae (especially Escherichia coli and Klebsiella spp.) and Pseudomonas aeruginosa, and less frequently Acinetobacter spp. and Stenotrophomonas maltophilia. A broader spectrum empiric antibiotic regimen is usually recommended in patients with a history of prior bloodstream infection caused by a MDR GNB, in those colonized by a MDR GNB, and if MDR GNBs are frequently isolated in the initial blood cultures. In any situation, de-escalation to standard empiric regimen is advised if infection with MDR GNB is not documented. PMID- 26115677 TI - Intrinsic signature of essential tremor in the cerebello-frontal network. AB - Essential tremor is a movement disorder characterized by tremor during voluntary movements, mainly affecting the upper limbs. The cerebellum and its connections to the cortex are known to be involved in essential tremor, but no task-free intrinsic signatures of tremor related to structural cerebellar defects have so far been found in the cortical motor network. Here we used voxel-based morphometry, tractography and resting-state functional MRI at 3 T to compare structural and functional features in 19 patients with essential tremor and homogeneous symptoms in the upper limbs, and 19 age- and gender-matched healthy volunteers. Both structural and functional abnormalities were found in the patients' cerebellum and supplementary motor area. Relative to the healthy controls, the essential tremor patients' cerebellum exhibited less grey matter in lobule VIII and less effective connectivity between each cerebellar cortex and the ipsilateral dentate nucleus. The patient's supplementary motor area exhibited (i) more grey matter; (ii) a lower amplitude of low-frequency fluctuation of the blood oxygenation level-dependent signal; (iii) less effective connectivity between each supplementary motor area and the ipsilateral primary motor hand area, and (iv) a higher probability of connection between supplementary motor area fibres and the spinal cord. Structural and functional changes in the supplementary motor area, but not in the cerebellum, correlated with clinical severity. In addition, changes in the cerebellum and supplementary motor area were interrelated, as shown by a correlation between the lower amplitude of low frequency fluctuation in the supplementary motor area and grey matter loss in the cerebellum. The structural and functional changes observed in the supplementary motor area might thus be a direct consequence of cerebellar defects: the supplementary motor area would attempt to reduce tremor in the motor output by reducing its communication with M1 hand areas and by directly modulating motor output via its corticospinal projections.See Raethjen and Muthuraman (doi:10.1093/brain/awv238) for a scientific commentary on this article. PMID- 26115680 TI - Intraneural perineurioma of the digital nerve: a case report. PMID- 26115681 TI - Measurements of surgeons' exposure to ionizing radiation dose: comparison of conventional and mini C-arm fluoroscopy. AB - This study was performed to measure the equivalent scattered radiation dose delivered to susceptible organs while simulating orthopaedic surgery using conventional and mini C-arm fluoroscopy. In addition, shielding effects on the thyroid, thymus, and gonad, and the direct exposure delivered to the patient's hands were also compared. A conventional and mini C-arms were installed in an operating room, and a hand and an operator phantom were used to simulate a patient's hand and a surgeon. Photoluminescence dosimeters were used to measure the equivalent dose by scattered radiation arriving at the thyroid, thymus, and gonad on a whole-body phantom in the position of the surgeon. Equivalent scattered radiation doses were measured in four groups: (1) unshielded conventional C-arm group; (2) unshielded mini C-arm group; (3) lead-shielded conventional C-arm group; and (4) lead-shielded mini C-arm group. Equivalent scattered radiation doses to the unshielded group were significantly lower in the mini C-arm group than those in the conventional C-arm group for all organs. The gonad in the lead-shielded conventional C-arm group showed the highest equivalent dose among operator-susceptible organs, and radiation dose was reduced by approximately 96% compared with that in the unshielded group. Scattered radiation was not detected in any susceptible organ in the lead-shielded mini C-arm group. The direct radiation dose to the hand phantom measured from the mini C-arm was significantly lower than that measured from the conventional C-arm. The results show that the equivalent scattered radiation dose to the surgeon's susceptible organs and the direct radiation dose to a patient's hand can be decreased significantly by using a mini C-arm rather than a conventional C-arm. However, protective lead garments, such as a thyroid shield and apron, should be applied to minimize radiation exposure to susceptible organs, even during use of mini C arm fluoroscopy. PMID- 26115682 TI - In vivo flexor tendon forces generated during different rehabilitation exercises. AB - We measured in vivo forces in the flexor digitorum profundus and the flexor digitorum superficialis tendons during commonly used rehabilitation manoeuvres after flexor tendon repair by placing a buckle force transducer on the tendons of the index finger in the carpal canal during open carpal tunnel release of 12 patients. We compared peak forces for each manoeuvre with the reported strength of a flexor tendon repair. Median flexor digitorum profundus force (24 N) during isolated flexor digitorum profundus flexion and median flexor digitorum superficialis force (13 N) during isolated flexor digitorum superficialis flexion were significantly higher than during the other manoeuvres. Significantly higher median forces were observed in the flexor digitorum superficialis with the wrist at 30 degrees flexion (6 N) compared with the neutral wrist position (5 N). Median flexor digitorum profundus forces were significantly higher during active finger flexion (6 N) compared with place and hold (3 N). Place and hold and active finger flexion with the wrist in the neutral position or tenodesis generated the lowest forces; isolated flexion of these tendons generated higher forces along the flexor tendons. LEVEL OF EVIDENCE: III (controlled trial without randomization). PMID- 26115683 TI - Poor outcomes from use of the Artelon(r) biodegradable implant for the treatment of thumb carpo-metacarpal joint and scapho-trapezio-trapezoid osteoarthritis: a short report and brief review of literature. PMID- 26115684 TI - The role of proprioception and neuromuscular stability in carpal instabilities. AB - Carpal stability has traditionally been defined as dependent on the articular congruity of joint surfaces, the static stability maintained by intact ligaments, and the dynamic stability caused by muscle contractions resulting in a compression of joint surfaces. In the past decade, a fourth factor in carpal stability has been proposed, involving the neuromuscular and proprioceptive control of joints. The proprioception of the wrist originates from afferent signals elicited by sensory end organs (mechanoreceptors) in ligaments and joint capsules that elicit spinal reflexes for immediate joint stability, as well as higher order neuromuscular influx to the cerebellum and sensorimotor cortices for planning and executing joint control. The aim of this review is to provide an understanding of the role of proprioception and neuromuscular control in carpal instabilities by delineating the sensory innervation and the neuromuscular control of the carpus, as well as descriptions of clinical applications of proprioception in carpal instabilities. PMID- 26115685 TI - Visualization of RelB expression and activation at the single-cell level during dendritic cell maturation in Relb-Venus knock-in mice. AB - RelB is activated by the non-canonical NF-kappaB pathway, which is crucial for immunity by establishing lymphoid organogenesis and B-cell and dendritic cell (DC) maturation. To elucidate the mechanism of the RelB-mediated immune cell maturation, a precise understanding of the relationship between cell maturation and RelB expression and activation at the single-cell level is required. Therefore, we generated knock-in mice expressing a fusion protein between RelB and fluorescent protein (RelB-Venus) from the Relb locus. The Relb(Venus/Venus) mice developed without any abnormalities observed in the Relb(-/-) mice, allowing us to monitor RelB-Venus expression and nuclear localization as RelB expression and activation. Relb(Venus/Venus) DC analyses revealed that DCs consist of RelB( ), RelB(low) and RelB(high) populations. The RelB(high) population, which included mature DCs with projections, displayed RelB nuclear localization, whereas RelB in the RelB(low) population was in the cytoplasm. Although both the RelB(low) and RelB(-) populations barely showed projections, MHC II and co stimulatory molecule expression were higher in the RelB(low) than in the RelB(-) splenic conventional DCs. Taken together, our results identify the RelB(low) population as a possible novel intermediate maturation stage of cDCs and the Relb(Venus/Venus) mice as a useful tool to analyse the dynamic regulation of the non-canonical NF-kappaB pathway. PMID- 26115686 TI - Mutagenesis study to disrupt electrostatic interactions on the twofold symmetry interface of Escherichia coli bacterioferritin. AB - Ferritins and other cage proteins have been utilized as models to understand the fundamentals of protein folding and self-assembly. The bacterioferritin (BFR) from Escherichia coli, a maxi-ferritin made up of 24 subunits, was chosen as the basis for a mutagenesis study to investigate the role of electrostatic intermolecular interactions mediated through charged amino acids. Through structural and computational analyses, three charged amino acids R30, D56 and E60 which involved in an electrostatic interaction network were mutated to the opposite charge. Four mutants, R30D, D56R, E60H and D56R-E60H, were expressed, purified and characterized. All of the mutants fold into alpha-helical structures. Consistent with the computational prediction, they all show a lowered thermostability; double mutant D56R-E60H was found to be 16 degrees C less stable than the wild type. Except for the mutant E60H, all the other mutations completely shut down the formation of protein cages to favour the dimer state in solution. The mutants, however, retain their ability to form cage-like nanostructures in the dried, surface immobilized conditions of transmission electron microscopy. Our findings confirm that even a single charge-inversion mutation at the 2-fold interface of BFR can affect the quaternary structure of its dimers and their ability to self-assemble into cage structures. PMID- 26115687 TI - Expression, purification and enzymatic characterization of a recombinant human ubiquitin-specific protease 47. AB - In this study, the physicochemical and enzymatic properties of recombinant human ubiquitin (Ub)-specific protease (USP) 47, a novel member of the C19 family of de ubiquitinating enzymes (DUB), were characterized for the first time. Recombinant human USP47 was expressed in a baculovirus expression system and purified to homogeneity. The purified protein was shown to be a monomeric protein with a molecular mass of ~146 kDa on sodium dodecyl sulphate-polyacrylamide gel electrophoresis. USP47 released Ub from Ub-aminoacyl-4-metheylcoumaryl-7-amide and Ub-tagged granzyme B. The substitution of the potential nucleophile Cys109 with Ser severely abrogated the Ub-releasing activity of USP47, indicating that USP47 is indeed a cysteine DUB. An assay using Ub dimer substrates showed that the enzyme cleaved a variety of isopeptide bonds between 2 Ub molecules, including the Lys48- and Lys63-linked isopeptide bonds. USP47 also released a Ub moiety from Lys48- and Lys63-linked polyUb chains. Of the inhibitors tested, N ethylmaleimide, Zn ion and Ub aldehyde revealed a dose-dependent inhibition of USP47. In this study, clear differences in the enzymatic properties between USP47 and USP7 (the most closely related proteins among DUBs) were also found. Therefore, our results suggest that USP47 may play distinct roles in Ub-mediated cellular processes via DUB activity. PMID- 26115688 TI - Subtype-independent near full-length HIV-1 genome sequencing and assembly to be used in large molecular epidemiological studies and clinical management. AB - INTRODUCTION: HIV-1 near full-length genome (HIV-NFLG) sequencing from plasma is an attractive multidimensional tool to apply in large-scale population-based molecular epidemiological studies. It also enables genotypic resistance testing (GRT) for all drug target sites allowing effective intervention strategies for control and prevention in high-risk population groups. Thus, the main objective of this study was to develop a simplified subtype-independent, cost- and labour efficient HIV-NFLG protocol that can be used in clinical management as well as in molecular epidemiological studies. METHODS: Plasma samples (n=30) were obtained from HIV-1B (n=10), HIV-1C (n=10), CRF01_AE (n=5) and CRF01_AG (n=5) infected individuals with minimum viral load >1120 copies/ml. The amplification was performed with two large amplicons of 5.5 kb and 3.7 kb, sequenced with 17 primers to obtain HIV-NFLG. GRT was validated against ViroSeqTM HIV-1 Genotyping System. RESULTS: After excluding four plasma samples with low-quality RNA, a total of 26 samples were attempted. Among them, NFLG was obtained from 24 (92%) samples with the lowest viral load being 3000 copies/ml. High (>99%) concordance was observed between HIV-NFLG and ViroSeqTM when determining the drug resistance mutations (DRMs). The N384I connection mutation was additionally detected by NFLG in two samples. CONCLUSIONS: Our high efficiency subtype-independent HIV-NFLG is a simple and promising approach to be used in large-scale molecular epidemiological studies. It will facilitate the understanding of the HIV-1 pandemic population dynamics and outline effective intervention strategies. Furthermore, it can potentially be applicable in clinical management of drug resistance by evaluating DRMs against all available antiretrovirals in a single assay. PMID- 26115689 TI - Gill paracellular permeability and the osmorespiratory compromise during exercise in the hypoxia-tolerant Amazonian oscar (Astronotus ocellatus). AB - In the traditional osmorespiratory compromise, fish increase their effective gill permeability to O2 during exercise or hypoxia, and in consequence suffer unfavorable ionic and osmotic fluxes. However oscars, which live in the frequently hypoxic ion-poor waters of the Amazon, actually decrease ionic fluxes across the gills during acute hypoxia without changing gill paracellular permeability, and exhibit rapid paving over of the mitochondrial-rich cells (MRCs). But what happens during prolonged exercise? Gill paracellular permeability, ionic fluxes, and gill morphology were examined in juvenile oscars at rest and during aerobic swimming. Initial validation tests with urinary catheterized fish quantified drinking, glomerular filtration, and urinary flow rates, and confirmed that measurements of gill paracellular permeability as [(3)H]PEG-4000 clearances were the same in efflux and influx directions, but far lower than previously measured in comparably sized trout. Although the oscars achieved a very similar proportional increase (90%) in oxygen consumption (MO2) to trout during steady-state swimming at 1.2 body lengths sec(-1), there was no increase in gill paracellular permeability, in contrast to trout. However, oscars did exhibit increased unidirectional Na(+) efflux and net K(+) rates during exercise, but no change in drinking rate. There were no changes in MRC numbers or exposure, or other alterations in gill morphology during exercise. A substantial interlamellar cell mass (ILCM) that covered the lamellae to a depth of 30% was unchanged by 4 h of swimming activity. We conclude that a low branchial paracellular permeability which can be dissociated from changes in O2 flux, as well as the presence of the ILCM, may be adaptive in limiting ionoregulatory costs for a species endemic to ion-poor, frequently hypoxic waters. PMID- 26115690 TI - Long-term effect of pulsed high-intensity laser therapy in the treatment of post mastectomy pain syndrome: a double blind, placebo-control, randomized study. AB - We assess the long-term effect of pulsed high-intensity laser therapy (HILT) in the treatment of the post-mastectomy pain syndrome (PMPS). A total of 61 women participated in this study (30 in the laser group and 31 in the placebo laser group), with a mean age of 53.56 +/- 1.11 years. Patients who were randomly assigned to the laser group received HILT three times per week for 4 weeks, plus a routine physical therapy program (RPTP). The placebo laser group received placebo HILT plus RPTP. The outcomes measured were pain level by visual analog scale (VAS), shoulder range of motion (ROM), and quality of life (QOL). Statistical analysis was performed by ANOVA with repeated measures to compare the differences between baseline and post-treatment measurements and after 12 weeks of follow-up for both groups. The level of statistical significance was set at P < 0.05. Shoulder ROM significantly increased in the laser group after 4 weeks of treatment and after 12 weeks of follow-up compared with the placebo group. VAS results showed a significant decrease post-treatment in the laser group relative to the placebo group, and QOL results showed a significant improvement in the laser group compared with the placebo group and still improved after 12 weeks of follow-up. HILT combined with an RPTP appears to be more effective in patients with PMPS than a placebo laser procedure with RPTP. PMID- 26115691 TI - Evidence for and characterization of nervous necrosis virus infection in Pacific cod (Gadus macrocephalus). AB - A mortality rate higher than 90% was observed in a larva-rearing facility for Pacific cod, Gadus macrocephalus, in China. Larvae showing clinical signs of infection were collected. Initial suspicion of nervous necrosis virus (NNV) infection was confirmed by sequencing, absolute quantification real-time PCR (A qPCR), and electron microscopy. The nucleotide sequence of RNA2 was 1,375 bases long (GenBank no. KM576685), coding for a single ORF corresponding to the capsid protein from residues 21 to 1034. Phylogenetic analysis of the capsid protein sequence showed that PCNNV belongs to the barfin flounder NNV (BFNVV) genotype. An amino acid sequence alignment revealed 39 differences between the cold- and warm-resistant viral groups, suggesting that PCNNV evolved under temperature selection. The 3-D structure of the predicted capsid protein was modeled to identify potential epitopes, and the gene was expressed in Escherichia coli, yielding a protein with a molecular mass of 55 kDa. During PCNNV outbreaks, the viral copy number was found to reach 10(7) per ng of total RNA, which could be considered the lethal copy number of NNV in cod. The gonads, eggs, fertilized eggs and asymptomatic cod fry were all positive for PCNNV, indicating viral vertical transmission as the main source of the viral load. The amount of virus in the apparent healthy fry or survivors seemed to decrease gradually with development. These results might lead to efficient diagnostic methods to help farmers select NNV-free broodfish for cod breeding. PMID- 26115692 TI - Detection, discrimination and quantitation of 22 bluetongue virus serotypes using real-time RT-PCR with TaqMan MGB probes. AB - Bluetongue virus (BTV) is the etiological agent of bluetongue (BT) disease, a noncontagious insect-transmitted disease of international importance. To date, 26 BTV serotypes have been recognized worldwide. Methods to discriminate BTV serotypes in clinical samples are essential to epidemiological surveillance efforts and BTV vaccination programs. The BTV VP2 major outer capsid protein, encoded by genomic segment 2 (Seg-2), is the most highly variable BTV protein and is the primary determinant of the virus serotype. Here, we report the development of rapid and reliable real-time RT-PCR assays to detect and discriminate 22 BTV serotypes on the basis of VP2-encoding genomic sequences. Serotype-specific primers and probes detected only the targeted BTV serotype and displayed no cross amplification of off-target BTV serotypes or other closely related Reoviridae and Bunyaviridae family members. The real-time RT-PCR assays developed were highly sensitive, and the majority of serotype-specific reactions could detect template when present at >=10 copies. These BTV serotype-specific real-time RT-PCR assays represent a rapid, sensitive, and reliable method for the identification, differentiation and quantification of 22 BTV serotypes. PMID- 26115694 TI - The Effects of Biodiesel and Crude Oil on the Foraging Behavior of Rusty Crayfish, Orconectes rusticus. AB - Environmental pollutants, such as crude oil and other petroleum-based fuels, inhibit and limit an organism's ability to perceive a chemical stimulus. Despite the increased use of alternative fuels, such as biodiesel, there have been few studies investigating the impact of these chemicals on the behavior of aquatic organisms. The purpose of this study was to compare the sublethal effects of biodiesel and crude oil exposure on chemically mediated behaviors in a freshwater keystone species. Crayfish (Orconectes rusticus) were tested on their ability to respond appropriately to a positive chemical stimulus within a Y-maze choice paradigm. Behavior was quantified by measuring time spent finding an odor source, duration of time spent at the odor source, percentage of crayfish that found the odor source, and percentage of crayfish that chose the correct arm of the arena. Results indicated negative impacts of both biodiesel and crude oil on the ability of crayfish to locate the food source. However, there were no significant differences between behavioral performances when crayfish were exposed to crude oil compared with biodiesel. Thus, biodiesel and crude oil have equally negative effects on the chemosensory behavior of crayfish. These findings indicate that biodiesel has the potential to have similar negative ecological impacts as other fuel source toxins. PMID- 26115693 TI - Hepatitis A and E Viruses in Wastewaters, in River Waters, and in Bivalve Molluscs in Italy. AB - Several studies have reported the detection of hepatitis A (HAV) and E (HEV) virus in sewage waters, indicating a possibility of contamination of aquatic environments. The objective of the present study was to assess the occurrence of HAV and HEV in different water environments, following the route of contamination from raw sewage through treated effluent to the surface waters receiving wastewater discharges . Bivalve molluscan shellfish samples were also analyzed, as sentinel of marine pollution. Samples were tested by RT-PCR nested type in the VP1/2A junction for HAV, and in the ORF1 and ORF2 regions for HEV. Hepatitis A RNA was detected in 12 water samples: 7/21 (33.3%) raw sewage samples, 3/21 (14.3%) treated sewage samples, and 2/27 (7.4%) river water samples. Five sequences were classified as genotype IA, while the remaining 7 sequences belonged to genotype IB. In bivalves, HAV was detected in 13/56 samples (23.2%), 12 genotype IB and one genotype IA. Whether the presence of HAV in the matrices tested indicates the potential for waterborne and foodborne transmission is unknown, since infectivity of the virus was not demonstrated. HEV was detected in one raw sewage sample and in one river sample, both belonging to genotype 3. Sequences were similar to sequences detected previously in Italy in patients with autochthonous HEV (no travel history) and in animals (swine). To our knowledge, this is the first detection of HEV in river waters in Italy, suggesting that surface water can be a potential source for exposure . PMID- 26115695 TI - The effect of pupil dilation on AL-Scan biometric parameters. AB - The purpose of this study was to investigate the effects of pupil dilation on the parameters of the AL-Scan (Nidek Co., Ltd, Gamagori, Japan). We compared the measurements of axial length (AL), anterior chamber depth (ACD), central corneal keratometry reading, pupil diameter, and intraocular lens (IOL) power of 72 eyes of 72 healthy volunteers and patients scheduled for cataract surgery before and 45 min after instillation of cyclopentolate hydrochloride 1 % using the AL-Scan. Intraobserver repeatability was assessed by taking three consecutive recordings of ACD and AL. Only ACD readings were significantly different between predilation and postdilation (P < 0.001). The difference of the other measurements between two sessions was not statistically significant (P > 0.001). Only two cases in the study demonstrated changes in IOL power higher than 0.5 D. The intraobserver repeatability of both devices was good (CV values for ACD and AL were 0.16 and 0.20 %, respectively). Dilated pupil size did not affect the measurement of IOL power using the A-Scan optical biometer, but increase in ACD after dilation should be taken into account when performing refractive surgeries in which ACD is very important such as phakic anterior chamber IOL implantation. PMID- 26115696 TI - Early Childhood Trajectories of Conduct Problems and Callous-Unemotional Traits: The Role of Fearlessness and Psychopathic Personality Dimensions. AB - Children with early onset of conduct problems (CP) are at risk for long lasting psychosocial problems, especially if CP co-occurs with callous-unemotional (CU) traits. Joint trajectories of CP and CU traits during early childhood were identified using data from the SOFIA study, following 2031 children longitudinally from ages 3-5 to 5-7 years. The results showed that children exhibiting stable high CP and CU traits were characterized by high levels of fearlessness, and psychopathic traits, including grandiose-deceitfulness, and impulsivity, need for stimulation. Children with decreasing or increasing CP and CU traits were characterized by decreases and increases respectively in their levels of fearlessness and psychopathic traits. Children high on CP and low on CU traits exhibited lower levels of these dimensions. Thus, stability and change of fearlessness and psychopathic traits are associated with stability and change in CP and CU traits, making these temperamental and personality traits promising target candidates for early intervention. PMID- 26115698 TI - MAFB as a novel regulator of human adipose tissue inflammation. AB - AIMS/HYPOTHESIS: Dysregulated expression of metabolic and inflammatory genes is a prominent consequence of obesity causing insulin resistance and type 2 diabetes. Finding causative factors is essential to understanding progression of these pathologies and discovering new therapeutic targets. The transcription factor V maf musculoaponeurotic fibrosarcoma oncogene homologue B (MAFB) is highly expressed in human white adipose tissue (WAT). However, its role in the regulation of WAT function is elusive. We aimed to characterise MAFB expression and function in human WAT in the context of obesity and insulin resistance. METHODS: MAFB mRNA expression was evaluated in human WAT from seven cohorts with large inter-individual variation in BMI and metabolic features. Insulin-induced adipocyte lipogenesis and lipolysis were measured and correlated with MAFB expression. MAFB regulation during adipogenesis and the effects of MAFB suppression in human adipocytes was investigated. MAFB regulation by TNF-alpha was examined in human primary adipocytes and THP-1 monocytes/macrophages. RESULTS: MAFB expression in human adipocytes is upregulated during adipogenesis, increases with BMI in WAT, correlates with adverse metabolic features and is decreased after weight loss. MAFB downregulation decreases proinflammatory gene expression in adipocytes and interferes with TNF-alpha effects. Interestingly, MAFB is differentially regulated by TNF-alpha in adipocytes (suppressed) and THP 1 cells (upregulated). Further, MAFB is primarily expressed in WAT macrophages/monocytes and its expression correlates with macrophage and inflammatory markers. CONCLUSIONS/INTERPRETATION: Our findings indicate that MAFB is a regulator and a marker of adipose tissue inflammation, a process that subsequently causes insulin resistance. PMID- 26115699 TI - Human Extraintestinal Sarcocystosis: What We Know, and What We don't Know. AB - There are over 150 known Sarcocystis species, and at least one is capable of infecting and causing disease in man. Extraintestinal (muscular) sarcocystosis and intestinal sarcocystosis are the two known manifestations of disease in humans. In this series of six cases and review, we focus on the invasive extraintestinal ("muscular") form of sarcocystosis in humans. This disease, which until recently was rarely described, has become relevant particularly as an imported condition in travelers due to a recent series of outbreaks reported from Malaysia. Human intestinal sarcocystosis is ubiquitous across the globe. However, absolute numbers of probable and particularly confirmed cases are few, with only several hundred described to date. Characteristically, patients exhibit signs and symptoms either 1-2 weeks after exposure, or after 4-8 weeks. Whether people remain asymptomatic or develop disease apparently depends on the infecting species, host factors, and the inoculum size. The definitive host(s) remain uncertain, and identification of the animal reservoir(s) requires further research. A better understanding of the epidemiology of the disease, as well as its immunological determinants, is hampered by the lack of reliable serological diagnostic methods. Additionally, DNA seems to be contained very effectively within the encysted parasite, thereby rendering PCR detection unreliable. Physicians should suspect the condition in patients with suggestive symptoms and a possible history of exposure. Surveillance networks for imported infectious diseases are formidable tools to help detect and localize outbreaks. PMID- 26115697 TI - Traumatic and Adverse Attachment Childhood Experiences are not Characteristic of OCD but of Depression in Adolescents. AB - We investigated whether adverse attachment experience might contribute to the development of obsessive-compulsive disorder (OCD). We interviewed 100 adolescents, 25 each with primary OCD, depressive disorder (DD), OCD plus DD and general population controls (CTRs) using the adult attachment interview to assess attachment experiences (AEs), including traumatic and adverse AE (TAE). Adolescents with OCD, OCD+DD and DD had little evidence of secure base/safe haven parental behaviour and their childhood attachment needs judged to be rejected as compared to the controls. Overprotection was not characteristic of OCD, and parents using the child for their own needs (elevated levels of involving/role reversal) occurred only in DD, with low levels in OCD, OCD+DD and CTR. Traumatic experiences, often multiple, and/or attachment related were reported significantly more often in the DD group, and was less common in OCD+DD, CTR and particularly in the OCD group. In OCD, little TAE was reported and adverse AE were less serious and seem unlikely to contribute directly to OCD aetiology. In DD and to some degree in OCD+DD serious AE/TAE may have some etiological significance for the depressive states. PMID- 26115700 TI - A 2015 Update on Ventilator-Associated Pneumonia: New Insights on Its Prevention, Diagnosis, and Treatment. AB - Ventilator-associated pneumonia (VAP), an infection of the lower respiratory tract which occurs in association with mechanical ventilation, is one of the most common causes of nosocomial infection in the intensive care unit (ICU). VAP causes significant morbidity and mortality in critically ill patients including increased duration of mechanical ventilation, ICU stay and hospitalization. Current knowledge for its prevention, diagnosis and management is therefore important clinically and is the basis for this review. We discuss recent changes in VAP surveillance nomenclature incorporating ventilator-associated conditions and ventilator-associated events, terms recently proposed by the Centers for Disease Control. To the extent possible, we rely predominantly on data from randomized control trials (RCTs) and meta-analyses. PMID- 26115701 TI - Prevalence, Nature, Severity and Risk Factors for Prescribing Errors in Hospital Inpatients: Prospective Study in 20 UK Hospitals. AB - INTRODUCTION: It has been suggested that doctors in their first year of post graduate training make a disproportionate number of prescribing errors. OBJECTIVE: This study aimed to compare the prevalence of prescribing errors made by first-year post-graduate doctors with that of errors by senior doctors and non medical prescribers and to investigate the predictors of potentially serious prescribing errors. METHODS: Pharmacists in 20 hospitals over 7 prospectively selected days collected data on the number of medication orders checked, the grade of prescriber and details of any prescribing errors. Logistic regression models (adjusted for clustering by hospital) identified factors predicting the likelihood of prescribing erroneously and the severity of prescribing errors. RESULTS: Pharmacists reviewed 26,019 patients and 124,260 medication orders; 11,235 prescribing errors were detected in 10,986 orders. The mean error rate was 8.8 % (95 % confidence interval [CI] 8.6-9.1) errors per 100 medication orders. Rates of errors for all doctors in training were significantly higher than rates for medical consultants. Doctors who were 1 year (odds ratio [OR] 2.13; 95 % CI 1.80-2.52) or 2 years in training (OR 2.23; 95 % CI 1.89-2.65) were more than twice as likely to prescribe erroneously. Prescribing errors were 70 % (OR 1.70; 95 % CI 1.61-1.80) more likely to occur at the time of hospital admission than when medication orders were issued during the hospital stay. No significant differences in severity of error were observed between grades of prescriber. Potentially serious errors were more likely to be associated with prescriptions for parenteral administration, especially for cardiovascular or endocrine disorders. CONCLUSION: The problem of prescribing errors in hospitals is substantial and not solely a problem of the most junior medical prescribers, particularly for those errors most likely to cause significant patient harm. Interventions are needed to target these high-risk errors by all grades of staff and hence improve patient safety. PMID- 26115702 TI - SNX15 Regulates Cell Surface Recycling of APP and Abeta Generation. AB - Amyloid-beta (Abeta) peptide plays an essential role in the pathogenesis of Alzheimer's disease (AD) and is generated from amyloid-beta precursor protein (APP) through sequential proteolytic cleavages by beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase. Trafficking dysregulation of APP, BACE1, and gamma secretase may affect Abeta generation and disease pathogenesis. Sorting nexin 15 (SNX15) is known to regulate protein trafficking. Here, we report that SNX15 is abundantly expressed in mouse neurons and astrocytes. In addition, we show that although not affecting the protein levels of APP, BACE1, and gamma-secretase components and the activity of BACE1 and gamma-secretase, overexpression and downregulation of SNX15 reduce and promote Abeta production, respectively. Furthermore, we find that overexpression of SNX15 increases APP protein levels in cell surface through accelerating APP recycling, whereas downregulation of SNX15 has an opposite effect. Finally, we show that exogenous expression of human SNX15 in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Abeta pathology in the hippocampus and improve short-term working memory in the APPswe/PSEN1dE9 double transgenic AD model mice. Together, our results suggest that SNX15 regulates the recycling of APP to cell surface and, thus, its processing for Abeta generation. PMID- 26115703 TI - Prenatal Exposure of Cypermethrin Induces Similar Alterations in Xenobiotic Metabolizing Cytochrome P450s and Rate-Limiting Enzymes of Neurotransmitter Synthesis in Brain Regions of Rat Offsprings During Postnatal Development. AB - Oral administration of low doses of cypermethrin to pregnant Wistar rats led to a dose-dependent differences in the induction of xenobiotic-metabolizing cytochrome P450s (CYPs) messenger RNA (mRNA) and protein in brain regions isolated from the offsprings postnatally at 3 weeks that persisted up to adulthood. Similar alterations were observed in the expression of rate-limiting enzymes of neurotransmitter synthesis in brain regions of rat offsprings. These persistent changes were associated with alterations in circulating levels of growth hormone (GH), cognitive functions, and accumulation of cypermethrin and its metabolites in brain regions of exposed offsprings. Though molecular docking studies failed to identify similarities between the docked conformations of cypermethrin with CYPs and neurotransmitter receptors, in silico analysis identified regulatory sequences of CYPs in the promoter region of rate-limiting enzymes of neurotransmitter synthesis. Further, rechallenge of the prenatally exposed offsprings at adulthood with cypermethrin (p.o. 10 mg/kg * 6 days) led to a greater magnitude of alterations in the expression of CYPs and rate-limiting enzymes of neurotransmitter synthesis in different brain regions. These alterations were associated with a greater magnitude of decrease in the circulating levels of GH and cognitive functions in rechallenged offsprings. Our data has led us to suggest that due to the immaturity of CYPs in fetus or during early development, even the low-level exposure of cypermethrin may be sufficient to interact with the CYPs, which in turn affect the neurotransmission processes and may help in explaining the developmental neurotoxicity of cypermethrin. PMID- 26115705 TI - UVA illumination-induced optical coupling between tryptophan and natural dissolved organic matter. AB - Exposure of tryptophan (Trp) in aqueous solutions to UVA radiation resulted in decrease of Trp (C1) but generated an unknown fluorescent component (C2) with fluorescence emission maxima extending into wavelength range characteristic of humic substance (HS)-like material. The intensity of the two components (C1 and C2) could be operationally fit to linear functions of the illumination time t (0~40 h). However, C1 and C2 decreased and increased nonlinearly respectively in a mixture (Trp mixed with a reference sample of natural organic matter, i.e., NOM) which was exposed to the same UVA illumination, and the change of both C1 and C2 was faster than that in the absence of NOM. Moreover, the UV-Vis absorption maximum (ex = 278 nm) of Trp was faster removed for the mixture (after 5 h) than for Trp solutions without NOM (after 20 h). These observations suggested NOM-facilitated photobleaching of Trp and photoproduction of a new FDOM component under UVA illumination. Meanwhile, the fluorescence of the NOM in the absence of Trp was well represented by two HS-like components which decayed monotonically upon exposure to UVA light, while the photoinduced decay became nonmonotonic in the presence of Trp, and one component even increased with illumination during certain time window, indicating Trp-facilitated production of HS-like fluorescence signatures from NOM. The findings show that UVA-induced optical signature changes of tryptophan and HS-like materials are coupled and highlight the potential impact of absorption of solar UVA light by natural dissolved organic matter (DOM) on using the optical signatures to trace sources and sinks of DOM. PMID- 26115704 TI - E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion. AB - Desmosomes provide strong intercellular cohesion essential for the integrity of cells and tissues exposed to continuous mechanical stress. For desmosome assembly, constitutively synthesized desmosomal cadherins translocate to the cell cell border, cluster and mature in the presence of Ca(2+) to stable cell contacts. As adherens junctions precede the formation of desmosomes, we investigated in this study the relationship between the classical cadherin E cadherin and the desmosomal cadherin Desmoglein 3 (Dsg3), the latter of which is indispensable for cell-cell adhesion in keratinocytes. By using autoantibodies from patients with the blistering skin disease pemphigus vulgaris (PV), we showed in loss of function studies that E-cadherin compensates for effects of desmosomal disassembly. Overexpression of E-cadherin reduced the loss of cell cohesion induced by PV autoantibodies and attenuated activation of p38 MAPK. Silencing of E-cadherin abolished the localization of Dsg3 at the membrane and resulted in a shift of Dsg3 from the cytoskeletal to the non-cytoskeletal protein pool which conforms to the notion that E-cadherin regulates desmosome assembly. Mechanistically, we identified a complex consisting of extradesmosomal Dsg3, E cadherin, beta-catenin and Src and that the stability of this complex is regulated by Src. Moreover, Dsg3 and E-cadherin are phosphorylated on tyrosine residues in a Src-dependent manner and Src activity is required for recruiting Dsg3 to the cytoskeletal pool as well as for desmosome maturation towards a Ca(2+)-insensitive state. Our data provide new insights into the role of E cadherin and the contribution of Src signaling for formation and maintenance of desmosomal junctions. PMID- 26115706 TI - A trench study to assess transfer of pesticides in subsurface lateral flow for a soil with contrasting texture on a sloping vineyard in Beaujolais. AB - Subsurface lateral flow in both texture-contrast soils and catchments with shallow bedrock is suspected to be a non-point source of contamination of watercourses by pesticides used in agriculture. As a case study, the north of the Beaujolais region (eastern France) provides a favorable environment for such contamination due to its agro-pedo-climatic conditions. Environments seen in the Beaujolais region include intense viticulture, permeable and shallow soils, steep hillslopes, and storms that occur during the periods of pesticide application. Watercourse contamination by pesticides has been widely observed in this region, and offsite pesticide transport by subsurface lateral flow is suspected to be involved in diffuse and chronic presence of pesticides in surface water. In order to confirm and quantify the potential role of such processes in pesticide transfer, an automated trench system has been designed. The trench was set up on a steep farmed hillslope in a texture-contrast soil. It was equipped with a tipping bucket flow meter and an automatic sampler to monitor pesticide concentrations in lateral flow at fine resolution, by means of a flow-dependent sampling strategy. Four pesticides currently used in vine growing were studied to provide a range of mobility properties: one insecticide (chlorpyrifos-methyl) and three fungicides (spiroxamine, tebuconazole, and dimethomorph). With this system, it was possible to study pesticide concentration dynamics in the subsurface lateral flow, generated by substantial rainfall events following pesticide applications. The experimental design ascertained to be a suitable method in which to monitor subsurface lateral flow and related transfer of pesticides. PMID- 26115708 TI - Pronounced response of papillary craniopharyngioma to treatment with vemurafenib, a BRAF inhibitor. PMID- 26115707 TI - Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis. AB - OBJECTIVE: Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. DESIGN: Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. RESULTS: The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2) = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I(2) = 35 %, p value for heterogeneity = 0.16). CONCLUSIONS: The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs. PMID- 26115710 TI - [Introduction]. PMID- 26115709 TI - Impact of selective pituitary gland incision or resection on hormonal function after adenoma or cyst resection. AB - OBJECTIVE: With the resection of pituitary lesions, the anterior pituitary gland often obstructs transsphenoidal access to the lesion. In such cases, a gland incision and/or partial gland resection may be required to obtain adequate exposure. We investigate this technique and determine the associated risk of post operative hypopituitarism. METHODS: All patients who underwent surgical resection of a pituitary adenoma or Rathke cleft cyst (RCC) between July 2007 and January 2013 were analyzed for pre- and post-operative hormone function. The cohort of patients with gland incision/resection were compared to a case-matched control cohort of pituitary surgery patients. Total hypophysectomy patients were excluded from outcome analysis. RESULTS: Of 372 operations over this period, an anterior pituitary gland incision or partial gland resection was performed in 79 cases (21.2 %). These include 53 gland incisions, 12 partial hemi-hypophysectomies and 14 resections of thinned/attenuated anterior gland. Diagnoses included 64 adenomas and 15 RCCs. New permanent hypopituitarism occurred in three patients (3.8 %), including permanent DI (3) and growth hormone deficiency (1). There was no significant difference in the rate of worsening gland dysfunction nor gain of function. Compared to a control cohort, there was a significantly lower incidence of transient DI (1.25 vs. 11.1 %, p = 0.009) but no significant difference in permanent DI (3.8 vs. 4.0 %) in the gland incision group. CONCLUSION: Selective gland incisions and gland resections were performed in over 20 % of our cases. This technique appears to minimize traction on compressed normal pituitary gland during removal of large lesions and facilitates better visualization and removal of cysts, microadenomas and macroadenomas. PMID- 26115711 TI - [The molecular machinery of neurotransmitter secretion]. PMID- 26115712 TI - [The genes and proteins which control the process of secretion]. PMID- 26115713 TI - [The source of membrane fusion in the cell]. PMID- 26115714 TI - [Contribution of synaptic release mechanisms to the building of sensory maps]. AB - Numerous neurotransmitters have been implicated in neurodevelopmental processes. In addition, developing neurons show an abundance of vesicles in the growth cones, and express proteins of the SNARE complex early on. This has led to propose a role for vesicular fusion machinery in axonal growth and synapse formation. However, as the molecular machinery of vesicular fusion started to unveil, and knockouts for the major proteins of this complex were generated, it came as a surprise that none of these proteins was essential for the construction of brain architecture, although they were crucial for vital functions of the organism, leading to early mortality of exocytosis mutants. Because of this early death, conditional ablation of these genes in well-defined neuronal populations was necessary to study their role at later stages of neural circuit development, when activity-dependent mechanisms are best defined. Early studies showed that mutants of Munc18-1, a gene essential for both constitutive and calcium triggered release, were required for target dependent cell survival but not for axon growth or early refinement of topographic targeting, at least in the retinotectal system. Conditional knockout of the Rim1 and Rim2 genes allowed to interrogate more specifically the role of calcium-triggered release. Rims (rab interacting molecules) play a key role in the assembly of calcium channels and their coupling to the SNARE complex alters calcium-triggered release with little effect on constitutive release. When Rim1/Rim2 genes were ablated in the thalamus, layer IV neurons failed to organize into barrel structures, and to form the characteristic asymmetric distribution of their dendrites. More surprisingly, thalamocortical axons still organized in precise topographic maps and formed well differentiated synapses despite considerable reduction of calcium-induced synaptic release. However, this reduction in release probability altered axon targeting in the visual system where axons from both eyes compete for the same target. Thus, genetic tools targeting the exocytosis machinery are allowing to dissect more precisely the contribution of synaptic and non-synaptic mechanisms to activity dependent circuit wiring. PMID- 26115715 TI - [Phosphoinositides: lipidic essential actors in the intracellular traffic]. AB - Phosphoinositides (PPIn) are lipids involved in the vesicular transport of proteins between the different intracellular compartments. They act by recruiting and/or activating effector proteins and are thus involved in crucial cellular functions including vesicle budding, fusion and dynamics of membranes and regulation of the cytoskeleton. Although they are present in low concentrations in membranes, their activity is essential for cell survival and needs to be tightly controlled. Therefore, phosphatases and kinases specific of the various cellular membranes can phosphorylate/dephosphorylate their inositol ring on the positions D3, D4 and/or D5. The differential phosphorylation determines the intracellular localisation and the activity of the PPIn. Indeed, non phosphorylated phosphatidylinositol (PtdIns) is the basic component of the PPIn and can be found in all eukaryotic cells at the cytoplasmic face of the ER, the Golgi, mitochondria and microsomes. It can get phosphorylated on position D4 to obtain PtdIns4P, a PPIn enriched in the Golgi compartment and involved in the maintenance of this organelle as well as anterograde and retrograde transport to and from the Golgi. PtdIns phosphorylation on position D3 results in PtdIns3P that is required for endosomal transport and multivesicular body (MVB) formation and sorting. These monophosphorylated PtdIns can be further phosphorylated to produce bisphophorylated PtdIns. Thus, PtdIns(4,5)P2, mainly produced by PtdIns4P phosphorylation, is enriched in the plasma membrane and involved in the regulation of actin cytoskeleton and endocytosis. PtdIns(3,5)P2, mainly produced by PtdIns3P phosphorylation, is enriched in late endosomes, MVBs and the lysosome/vacuole and plays a role in endosome to vacuole transport. PtdIns(3,4)P2 is absent in yeast, cells and mainly produced by PtdIns4P phosphorylation in human cells; PtdIns(3,4)P2 is localised in the plasma membrane and plays an important role as a second messenger by recruiting specific protein kinases (Akt and PDK1). Finally the triple phosphorylated PPIn, PtdIns(3,4,5)P3 also absent in yeast, is produced by the phosphorylation of PtdIns(3,4)P2 and localized at the plasma membrane of human cells where it binds proteins via their PH domain. Interaction partners include members of the Arf (ADP-ribosylation factors) family, PDK1 (Phosphoinositide Dependent Kinase 1) and Akt. Therefore this last PPIn is essential for the control of cell proliferation and its deregulation leads to the development of numerous cancers. In conclusion, the regulation of PPIn phosphorylation/dephosphorylation is complex and needs to be very precisely regulated. Indeed phosphatases and kinases allow the maintenance of the equilibrium between the different forms. PPIn play a crucial role in numerous cellular functions and a loss in their synthesis or regulation results in severe genetic diseases. PMID- 26115716 TI - [The ESCRT complex: from endosomal transport to the development of multicellular organisms]. AB - Since its discovery more than 50 years ago, the endo-lysosomal system has emerged as a central integrator of different cellular activities. This vesicular trafficking apparatus governs processes as diverse as the transduction of stimuli by growth factor receptors, the recycling and secretion of signaling molecules and the regulation of cellular homeostasis through autophagy. Accordingly, dysfunctions of the vesicular transport machinery have been linked to a growing number of pathologies. In this review we take the "Endosomal Sorting Complex Required for Transport" (ESCRT) as an example to illustrate the multiple functions of an evolutionarily conserved endosomal transport machinery. We describe the major concepts that have emerged from the study of this machinery at the level of the development and the physiology of multi-cellular organisms. In particular, we highlight the essential contributions of ESCRT proteins on the regulation of three biological processes: the endocytic regulation of cell signaling, autophagy and its role in neuronal morphogenesis and finally the biogenesis and function of extracellular vesicles. PMID- 26115718 TI - Comprehensive analysis of SAUR gene family in citrus and its transcriptional correlation with fruitlet drop from abscission zone A. AB - Small auxin-up RNA (SAUR) gene family is large, and the members of which can be rapidly induced by auxin and encode highly unstable mRNAs. SAUR genes are involved in various developmental and physiological processes, such as leaf senescence, fruitlet abscission, and hypocotyl development. However, their modes of action in citrus remain unknown. Hereby, a systematic analysis of SAUR gene family in citrus was conducted through a genome-wide search. In this study, a total of 70 SAUR genes, referred to as CitSAURs, have been identified in citrus. The evolutionary relationship and the intro-exon organization were analyzed, revealing strong gene conservation and the expansion of particular functional genes during plant evolution. Expression analysis showed that the major of CitSAUR genes were expressed in at least one tissue and showed distinctive expression levels, indicating the SAUR gene family play important roles in the development and growth of citrus organs. However, there were more than 20 CitSAUR genes such as CitSARU36, CitSAUR37, and CitSAUR54 exhibiting very low expression level in all tissue tested. Twenty-three out of 70 CitSAUR genes were responded to indole-3-acetic acid (IAA) treatment, of which just CitSAUR19 was down regulated. Additionally, 14 CitSAUR genes exhibited distinct changes during fruitlet abscission, however just 5 of them including CitSAUR06, CitSAUR08, CitSAUR44, CitSAUR61, and CitSAUR64 were associated with fruitlet abscission. The current study provides basic information for the citrus SAUR gene family and will pave the way for deciphering the precise role of SAURs in citrus development and growth as well as fruitlet abscission. PMID- 26115717 TI - Intradiploic growing skull fracture: review of mechanisms and literature. AB - PURPOSE: A rare case of intradiploic growing fracture of the occipital bone is presented. Examination of this case and literature review was carried out to find significant specific features of such a rare condition. CASE: A 4-year-old boy was operated on for a huge occipital intradiploic growing skull fracture. His medical history, surgical management, and postoperative course are presented. LITERATURE REVIEW: A computer literature search using the Medline database revealed 31 well-documented cases. CONCLUSIONS: Special attention must be paid to skull fractures in childhood when occurring near CSF large spaces, especially if ventricle enlargement, suggesting that hydrocephalus is present. Surgeons should evaluate hydrocephalus before treating such lesions in order to improve surgical result and postoperative clinical evolution. PMID- 26115719 TI - Evaluation of cytotoxicity, morphological alterations and oxidative stress in Chinook salmon cells exposed to copper oxide nanoparticles. AB - The current study is aimed to study cytotoxicity and oxidative stress mediated changes induced by copper oxide nanoparticles (CuO NPs) in Chinook salmon cells (CHSE-214). To this end, a number of biochemical responses are evaluated in CHSE 214 cells which are as follows [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazoliumbromide] MTT, neutral red uptake (NRU), lactate dehydrogenase (LDH), protein carbonyl (PC), lipid peroxidation (LPO), oxidised glutathione (GSSG), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione sulfo-transferase (GST), superoxide dismutase (SOD), catalase (CAT), 8-Hydroxy-2' deoxyguanosine (8-OHdG) and reactive oxygen species (ROS), respectively. The 50% inhibition concentration (IC50) of CuO NPs to CHSE-214 cells after 24 h exposure was found to be 19.026 MUg ml(-1). Viability of cells was reduced by CuO NPs, and the decrease was dose dependent as revealed by the MTT and NRU assay. CHSE-214 cells exposed to CuO NPs induced morphological changes. Initially, cells started to detach from the surface (12 h), followed by polyhedric, fusiform appearance (19 h) and finally the cells started to shrink. Later, the cells started losing their cellular contents leading to their death only after 24 h. LDH, PC, LPO, GSH, GPx, GST, SOD, CAT, 8-OHdG and ROS responses were seen significantly increased with the increase in the concentration of CuO NPs when compared to their respective controls. However, significant decrease in GSSG was perceptible in CHSE-214 cells exposed to CuO NPs in a dose-dependent manner. Our data demonstrated that CuO NPs induced cytotoxicity in CHSE-214 cells through the mediation of oxidative stress. The current study provides a baseline for the CuO NPs-mediated cytotoxic assessment in CHSE-214 cells for the future studies. PMID- 26115720 TI - Reference gene selection for real-time quantitative PCR analysis on ovarian cryopreservation by vitrification in mice. AB - PURPOSE: To ensure the correct interpretation of the results of quantitative real time reverse transcription-polymerase chain reaction (qRT-PCR) from ovarian tissue cryopreserved by vitrification, it is critical to normalize expression levels to a reference gene with stable messenger RNA (mRNA) expression in the vitrified/warmed ovarian tissue. The aim of this work was to identify suitable reference genes for qRT-PCR analysis during ovarian cryopreservation by vitrification. METHODS: GeNorm, NormFinder, comparative Delta-CT, and BestKeeper were used to analyze the expression and stability of the 14 reference genes GAPDH, ABL1, ACTB, CDKN1A, GPER, GUSB, HPRT1, HSP90AB1, IPO8, PPIA, RPL4, RPL30, TBP, and UPAR. RESULTS: Our results indicated that ACTB and RPL4 were relatively stable reference genes in vitrified/warmed ovaries. PMID- 26115721 TI - Effect of eccentric contraction on satellite cell activation in human vastus lateralis muscle. AB - We compared the time-course of satellite cell (SC) activation between eccentric and concentric contractions in the vastus lateralis (VL) muscle after step exercise. Young adults participated in a 30-min step up/down exercise which mainly involved concentric contractions with the right VL muscle and eccentric contractions with the left VL muscle. The concentric and eccentric contraction phases of the VL muscles were identified by changes in the electromyogram (EMG) and knee joint angle. Biopsy samples were taken from both VL muscles at three time periods: before the exercise and 2 and 5 days after the exercise. We found that the numbers of SCs were significantly increased in the type IIa fibers of the left VL at 2 and 5 days after the exercise. The expression of both hepatocyte growth factor (HGF) and myogenic differentiation 1 (MyoD) mRNA had significantly increased in the left VL at 2 and 5 days after the exercise and in the right VL at 5 days after the exercise. The expression of transient receptor potential canonical (TRPC) 1 mRNA also increased in the left VL at 2 days after exercise. These results indicate that eccentric contraction can effectively activate SC proliferation for up to 5 days after exercise. Similar changes in HGF, MyoD and TRPC1 mRNA expression suggest that HGF/c-Met signal activation through cation influx has a major impact on skeletal muscle SC activation in response to eccentric exercise. PMID- 26115722 TI - Eight proteins play critical roles in RCC with bone metastasis via mitochondrial dysfunction. AB - Most kidney cancers are renal cell carcinomas (RCC). RCC lacks early warning signs and 70 % of patients with RCC develop metastases. Among them, 50 % of patients having skeletal metastases developed a dismal survival of less than 10 % at 5 years. Therefore, exploring the key driving proteins and pathways involved in RCC bone metastasis could benefit patients' therapy and prolong their survival. We examined the difference between the OS-RC-2 cells and the OS-RC-2 BM5 cells (subpopulation from OS-RC-2) of RCC with proteomics. Then we employed Western-blot, immunohistochemistry and the clinical database (oncomine) to screen and verify the key proteins and then we analyzed the functions and the related pathways of selected key proteins with system biology approaches. Our proteomic data revealed 26 significant changed spots (fold change <0.5 and >1.9, P < 0.05) between two cells. The Western blotting results validated for these identified spots were consistent with the proteomics'. From the public clinical database, 23 out of 26 proteins were connected with RCC metastases and 9 out of 23 with survival time directly (P < 0.05). Finally, only 8 out of 9 proteins had significantly positive results in tissues of RCC patients with bone metastasis compared with primary tumor (P < 0.05). System biology analyzing results showed these eight proteins mainly distributed in oxidative phosphorylation which indicates that mitochondria dysfunction played the critical role to regulate cells metastasis. Our article used a variety of experimental techniques to find eight proteins which abnormally regulated mitochondrial function to achieve a successful induction for RCC metastasis to bone. PMID- 26115723 TI - Image quality at low tube voltage (70 kV) and sinogram-affirmed iterative reconstruction for computed tomography in infants with congenital heart disease. AB - BACKGROUND: Lower tube voltage has advantages for CT angiography, such as improved contrast OBJECTIVE: To evaluate the image quality of low-voltage (70 kV) CT for congenital heart disease and the ability of sinogram-affirmed iterative reconstruction to improve image quality. MATERIALS AND METHODS: Forty-six children with congenital heart disease (median age: 109 days) were examined using dual-source CT. Scans were performed at 80 kV and 70 kV in 21 and 25 children, respectively. A nonionic iodinated contrast medium (300 mg I/ml) was used for the 80-kV protocol. The contrast medium was diluted to 75% (225 mgI/mL) with saline for the 70-kV protocol. Image noise was measured in the two protocols for each group by extracting the standard deviations of a region of interest placed on the descending aorta. We then determined whether sinogram-affirmed iterative reconstruction reduced the image noise at 70 kV. RESULTS: There was more noise at 70 kV than at 80 kV (29 +/- 12 vs 20 +/- 4.8; P < 0.01). Sinogram-affirmed iterative reconstruction with grade 4 strength settings improved the noise (20 +/ 5.9; P < 0.01) for the 70-kV group. CONCLUSION: Sinogram-affirmed iterative reconstruction improved the image quality of CT in congenital heart disease. PMID- 26115724 TI - Reply to Dr. Vazquez et al. regarding current methods for reducing intussusception: external manual reduction with US assistance. PMID- 26115725 TI - Survival and Growth of the Marine Polychaete, Neanthes arenaceodentata, Following Laboratory Exposure to Copper-Spiked Sediment. AB - Juvenile marine polychaetes, Neanthes arenaceodentata, were exposed for 28 days to copper (Cu)-spiked sediment at six concentrations ranging from 48.3 to 2380 mg Cu/kg dry sediment, plus control. Survival was reduced (p <= 0.05) at concentrations >=1190 mg Cu/kg. Growth was inhibited at Cu concentrations >=506 mg Cu/kg. Dose-response relationships yielded LC10 and LC50 estimates of 514 and 1230 mg Cu/kg, respectively. The growth effect EC50 estimate was 409 mg Cu/kg. Ranges for the no observable effect concentration and lowest observable effect concentration were 506-1190 mg Cu/kg for survival, and 230-506 mg Cu/kg for growth. Pore water concentrations of Cu were 38.7-65.8 ug Cu/L in exposures where toxic effects were observed, compared to a range of 15.1-22.4 ug Cu/L in exposures where significant effects were not evident. The results of the study were compared with empirical and mechanistic sediment quality guidelines for the protection of benthic organisms. PMID- 26115726 TI - Toxic Metals in Pelagic, Benthic and Demersal Fish Species from Mediterranean FAO Zone 37. AB - Fish represents a nutrient-rich food but, at the same time, is one of the most important contributor to the dietary intake of heavy metals. The aim of this study was to assess residual levels of Pb, Cd and Hg in different species, caught from FAO zones 37 1.3 and 37 2.2, particularly small pelagic, benthic and demersal fishes. The results obtained showed the absence of toxic metal in fishes from FAO zone 37 1.3. Relating to FAO zone 37 2.2, instead, in all samples we observed the absence of Pb, small concentrations of Cd (0.081+/-0.022 mg/kg) and higher Hg residual levels (0.252+/-0.033 mg/kg). Particularly, the trend of Cd contamination was similar in all species whereas Hg showed high levels in demersal, intermediate in pelagic and low in benthic species. However, only Cd concentrations exceed the MRL in mackerel, mullet, sea-bream fishes, according to Regulation CE n. 629/2008 and n. 488/2014. PMID- 26115727 TI - Current Treatment of Dyslipidemia: A New Paradigm for Statin Drug Use and the Need for Additional Therapies. AB - Coronary heart disease (CHD) is the leading cause of death in most countries, with the high prevalence currently driven by dual epidemics of obesity and diabetes. Statin drugs, the most effective, evidence-based agents to prevent and treat this disease, have a central role in management and are advised in all published guidelines. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol and assessment guidelines ('new ACC/AHA guidelines') emphasized global cardiovascular (CV) risk reduction as opposed to targeting low-density lipoprotein-cholesterol (LDL-C) levels, stressed the use of statins in two dose intensities, utilized a new risk calculator using pooled cohort equations, and lowered the risk cutoff for initiation of statin therapy. Although there were major strengths of the new ACC/AHA guidelines, substantial controversy followed their release, particulars of which are discussed in this review. They were generally regarded as improvements in an ongoing transition using evidenced-based data for maximum patient benefit. Several guidelines, other than the ACC/AHA guidelines, currently provide practitioners with choices, some depending on practice locations. Cholesterol control with statin drugs is used in all paradigms. However, some patients respond inadequately, approximately 15% are intolerant, and other factors prevent attaining cholesterol goals in as many as 40% of patients. Even after treatment, substantial residual risk for ongoing major events remains. Another readily available modality that can rival statin drugs in effectiveness is vast improvement in diet and lifestyle within the general population; however, despite great effort, existing programs to implement such changes have failed. Hence, despite unrivaled success, there is great need for additional drugs to prevent and treat CHD, whether as monotherapy or in combination with statin drugs. New American guidelines do not discuss or recommend any nonstatin drugs for CHD, and the US FDA has moved away from approving drugs based solely on changes in surrogates in the absence of clinical outcomes trials. Both have significantly altered the realities of developing pharmacotherapies and cardiology practice. PMID- 26115728 TI - Trelagliptin: First Global Approval. AB - Trelagliptin (Zafatek((r))) is an orally active dipeptidyl peptidase (DPP)-4 inhibitor developed by Takeda and approved in Japan for the treatment of type 2 diabetes mellitus (T2DM). Unlike other approved agents of its class, which are usually administered once daily, trelagliptin can be administered once weekly. Phase II development of trelagliptin was discontinued in the USA and EU, as Takeda considered that the costs associated with obtaining approval in these markets were prohibitive. This article summarizes the milestones in the development of trelagliptin leading to this first approval for T2DM. PMID- 26115729 TI - Clinical Challenges of Fecal Incontinence in the Elderly. AB - OPINION STATEMENT: Fecal incontinence (FI) is underreported, yet it is quite commonly experienced by the elderly patient. FI confers a significant direct and indirect burden on patients, their caregivers, and the health-care system. Due to the presence of multiple comorbid medical conditions in patients over 65 years of age and the number of medications taken by elderly patients, FI management poses several challenges to the treating physician. We emphasize the importance of a comprehensive history and physical exam with specific attention to diet, physical activity, cognitive function, medications, and comorbidities specific to patients in this age group. Symptomatic conservative therapy should be the first step in management. Evaluation of the underlying pathology causing FI and more invasive treatments should be considered in selected patients who are cognitively intact and can tolerate these procedures. PMID- 26115731 TI - Outcomes are improving for patients with carotid stenosis. PMID- 26115730 TI - APOE epsilon4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage. AB - OBJECTIVE: Genetic variants epsilon2/epsilon4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE epsilon4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association. METHODS: Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH. RESULTS: We observed 29 nonlobar ICH recurrences among 363 survivors. APOE epsilon4 was associated with recurrent nonlobar ICH (hazard ratio = 1.31; 95% confidence interval = 1.02-2.69; p = 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing low-density lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p = 0.027), as were decreasing HDL levels (p = 0.046). LDL levels modified the association of APOE epsilon4 with recurrent nonlobar ICH (mediation p < 0.05). No associations were identified between APOE epsilon2 and recurrent nonlobar ICH. CONCLUSION: APOE epsilon4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE epsilon4 in nonlobar ICH. PMID- 26115732 TI - Neuroanatomical foundations of naming impairments across different neurologic conditions. AB - The ability to name objects or abstract entities is an essential feature of speech and language, being commonly considered a central component of normal neurologic function. For this reason, the bedside testing of naming performance is part of the neurologic examination, especially since naming impairments can signify the early onset of a progressive disease or the occurrence of a more established problem. Modern neuroscience research suggests that naming relies on specific and distributed networks that operate in concert to support various processing stages, spanning from object recognition to spoken words. Likewise, studies evaluating the types of naming impairments in patients with neurologic conditions have contributed to the understanding of acquired forms of naming impairments and the underlying stages during normal language processing. In this article, we review the neurobiological mechanisms supporting naming, with a focus on the clinical application of these concepts. We provide an overview of the stages of cognitive processing that are hypothesized to support naming. For each stage, we explore the evidence revealing its neural basis, drawing parallels to clinical syndromes that commonly disrupt each stage. We review the patterns of naming impairment across various neurologic conditions, including classic language disorders, such as poststroke aphasia or primary progressive aphasia, as well as other diseases where language impairments may be subtle but helpful for the appropriate diagnosis. In this context, we provide a structured and practical guide for the bedside naming assessments rooted in modern neuroscience, aimed at supporting the evaluation and diagnosis of neurologic conditions that affect language. PMID- 26115733 TI - Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations. AB - OBJECTIVES: To describe the clinical and neurophysiologic patterns of patients with neuronal ceroid lipofuscinoses associated with CLN6 mutations. METHODS: We reviewed the features of 11 patients with different ages at onset. RESULTS: Clinical disease onset occurred within the first decade of life in 8 patients and in the second and third decades in 3. All children presented with progressive cognitive regression associated with ataxia and pyramidal and extrapyramidal signs. Recurrent seizures, visual loss, and myoclonus were mostly reported after a delay from onset; 7 children were chairbound and had severe dementia less than 4 years from onset. One child, with onset at 8 years, had a milder course. Three patients with a teenage/adult onset presented with a classic progressive myoclonic epilepsy phenotype that was preceded by learning disability in one. The EEG background was slow close to disease onset in 7 children, and later showed severe attenuation; a photoparoxysmal response (PPR) was present in all. The 3 teenage/adult patients had normal EEG background and an intense PPR. Early attenuation of the electroretinogram was seen only in children with onset younger than 5.5 years. Somatosensory evoked potentials were extremely enlarged in all patients. CONCLUSIONS: In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature. PMID- 26115734 TI - Temporal trends in safety of carotid endarterectomy in asymptomatic patients: systematic review. AB - OBJECTIVE: To systematically review temporal changes in perioperative safety of carotid endarterectomy (CEA) in asymptomatic individuals in trial and registry studies. METHODS: The MEDLINE and EMBASE databases were searched using the terms "carotid" and "endarterectomy" and "asymptomatic" from 1947 to August 23, 2014. Articles dealing with 50%-99% stenosis in asymptomatic individuals were included and low-volume studies were excluded. The primary endpoint was 30-day stroke or death and the secondary endpoint was 30-day all-cause mortality. Statistical analysis was performed using random-effects meta-regression for registry data and for trial data graphical interpretation alone was used. RESULTS: Six trials (n = 4,431 procedures) and 47 community registries (n = 204,622 procedures) reported data between 1983 and 2013. Registry data showed a significant decrease in postoperative stroke or death incidence over the period 1991-2010, equivalent to a 6% average proportional annual reduction (95% credible interval [CrI] 4%-7%; p < 0.001). Considering postoperative all-cause mortality, registry data showed a significant 5% average proportional annual reduction (95% CrI 3%-9%; p < 0.001). Trial data showed a similar visual trend. CONCLUSIONS: CEA is safer than ever before and high-volume registry results closely mirror the results of trials. New benchmarks for CEA are a stroke or death risk of 1.2% and a mortality risk of 0.4%. This information will prove useful for quality improvement programs, for health care funders, and for those re-examining the long-term benefits of asymptomatic revascularization in future trials. PMID- 26115735 TI - Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate. AB - OBJECTIVE: We aimed to decipher the molecular genetic basis of disease in a cohort of children with a uniform clinical presentation of neonatal irritability, spastic or dystonic quadriplegia, virtually absent psychomotor development, axonal neuropathy, and elevated blood/CSF lactate. METHODS: We performed whole exome sequencing of blood DNA from the index patients. Detected compound heterozygous mutations were confirmed by Sanger sequencing. Structural predictions and a bacterial activity assay were performed to evaluate the functional consequences of the mutations. Mass spectrometry, Western blotting, and protein oxidation detection were used to analyze the effects of selenoprotein deficiency. RESULTS: Neuropathology indicated laminar necrosis and severe loss of myelin, with neuron loss and astrogliosis. In 3 families, we identified a missense (p.Thr325Ser) and a nonsense (p.Tyr429*) mutation in SEPSECS, encoding the O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, which was previously associated with progressive cerebellocerebral atrophy. We show that the mutations do not completely abolish the activity of SEPSECS, but lead to decreased selenoprotein levels, with demonstrated increase in oxidative protein damage in the patient brain. CONCLUSIONS: These results extend the phenotypes caused by defective selenocysteine biosynthesis, and suggest SEPSECS as a candidate gene for progressive encephalopathies with lactate elevation. PMID- 26115736 TI - Unraveling the neuroimaging predictors for motor dysfunction in long-standing multiple sclerosis. AB - OBJECTIVE: To find the strongest neuroimaging predictors for motor dysfunction using conventional and quantitative imaging measures focusing on the corticospinal tract (CST) in a large cohort of patients with long-standing multiple sclerosis (MS). METHODS: In this cross-sectional study, a wide spectrum of neuroimaging measures at the whole-brain, cervical, and CST level were analyzed in 195 patients with MS and 54 healthy controls. Motor function was assessed using the Expanded Disability Status Scale (EDSS), 9-Hole Peg Test, Timed 25-Foot Walk Test, and Multiple Sclerosis Walking Scale. Associations between damage in different parts of the motor system and motor functioning were assessed using stepwise linear regression. RESULTS: Patients had an average disease duration of 19.98 (+/-6.99) years and a median EDSS score of 4 (range: 1.0-8.0). EDSS score was associated with number of infratentorial and cervical cord lesions, lesion volume in the CST, and mean upper cervical cord area (adjusted R(2) = 0.403). Timed 25-Foot Walk Test score was associated with number of infratentorial lesions and cerebellar volume (adjusted R(2) = 0.150), 9-Hole Peg Test score with number of infratentorial lesions and thickness of the cortex connected to the CST (adjusted R(2) = 0.245), and Multiple Sclerosis Walking Scale with number of infratentorial and cervical lesions, thickness of the cortex connected to the CST, and mean upper cervical cord area (adjusted R(2) = 0.354). CONCLUSIONS: Motor dysfunction in MS has a complex substrate that cannot be ascribed to a single neuroimaging finding, but is the consequence of infratentorial and spinal cord damage, as well as damage in the CST. PMID- 26115737 TI - Surgical resection strategies for locally advanced pancreatic cancer. AB - BACKGROUND: Despite all improvements in tumor diagnostics and treatment, pancreatic cancer is still the fourth leading cause of cancer-related death in the Western world. It is mostly diagnosed at a locally advanced or metastasized stage because of the lack of early symptoms. A radical margin-free surgical resection offers the only potential cure for locoregional disease. Over the last decades, several surgical strategies and techniques have evolved to optimize oncologic radical resections and thus to improve long-term outcome of patients. PURPOSE: The purpose of this review was to describe the various surgical strategies and techniques for locally advanced pancreatic cancer and to evaluate their influence on long-term outcome. CONCLUSIONS: Locally advanced pancreatic cancer should not generally be deemed unresectable. Various surgical techniques offer a good chance of margin-free tumor resection, even if surrounding organs or vessels are involved. Because of potentially higher peri- and postoperative morbidity rates, patients should be selected properly and are best treated in specialized high-volume centers. PMID- 26115738 TI - Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells. AB - The sodium/iodide symporter (NIS) is involved in iodide uptake and has been used for the diagnosis and treatment of thyroid cancer. Transfection of the NIS gene in A549 human lung cancer cells can induce radioactive iodine ((131)I) and radioactive technetium ((99m)Tc) uptake. The aim of the present study was to assess the role of NIS in (99m)Tc and (131)I uptake by the A549/DDP human cisplatin-resistant lung cancer cell line. To do so, recombinant adenovirus, adenovirus-enhanced green fluorescent protein-human NIS (Ad-eGFP-hNIS) and Ad eGFP-rat NIS (Ad-eGFP-rNIS) vectors were established. These vectors were transfected into A549/DDP cells and xenograft tumors in nude mice. Assessment of (99m)Tc and (131)I uptake was performed. Results showed that the transfection efficiency of Ad-eGFP-hNIS and Ad-eGFP-rNIS in A549/DDP cells was at least 90 % in all experiments, and that the uptake ability of (99m)Tc and (131)I was highly enhanced (14-18 folds for (99m)Tc, and 12-16 folds for (131)I). However, the radionuclide concentration in transfected NIS genes' A549/DDP cells reached a plateau within 30-60 min, indicating that NIS transport led rapidly to (99m)Tc and (131)I saturation in cells. In xenograft tumor models, uptake of (99m)TcO4 ( ) was obviously higher in the hNIS and rNIS groups compared with controls. In conclusion, these results support the hypothesis that A549/DDP cells can effectively uptake (99m)Tc and (131)I when transfected with the hNIS and rNIS gene. The rNIS or hNIS gene could be used as an effective method for the effective delivery of radioactive products to specific tissues for imagery and/or treatment. PMID- 26115739 TI - Evaluation of right atrial dysfunction in patients with corrected tetralogy of Fallot using 3D speckle-tracking echocardiography. Insights from the CSONGRAD Registry and MAGYAR-Path Study. AB - BACKGROUND: In recent studies, alterations in ventricular deformations were demonstrated in adult patients with corrected tetralogy of Fallot by three dimensional speckle-tracking echocardiography. The present study was designed to assess three-dimensional speckle-tracking echocardiography-derived right atrial volumetric and strain parameters in corrected tetralogy of Fallot. METHODS: A total of 17 patients with corrected tetralogy of Fallot were included in the study. Their results were compared with 18 age- and gender-matched healthy controls. Complete two-dimensional echocardiography and three-dimensional speckle tracking echocardiography were performed in all cases. RESULTS: Significantly increased right atrial volumes respecting heart cycle were detected in patients with corrected tetralogy of Fallot. Total and passive atrial emptying fractions proved to be significantly decreased in patients with corrected tetralogy of Fallot (26.4 +/- 12.4 % vs. 39.1 +/- 8.8 %, p = 0.001 and 11.2 +/- 6.8 % vs. 19.8 +/- 9.0 %, p = 0.003, respectively). Global and mean segmental peak longitudinal (17.3 +/- 9.2 % vs. 30.8 +/- 11.2 %, p = 0.0007 and 20.6 +/- 10.7 % vs. 34.4 +/- 10.5 %, p = 0.0005) and area strains (20.1 +/- 17.6 % vs. 41.0 +/- 19.8 %, p = 0.004 and 28.1 +/- 19.8 % vs. 49.1 +/- 19.7 %, p = 0.004) as well as global radial peak strain (-9.1 +/- 5.1 % vs. -15.0 +/- 10.0 %, p = 0.05) were reduced in patients with corrected tetralogy of Fallot compared with controls. CONCLUSIONS: The complexity of right atrial dysfunction can be demonstrated by three-dimensional speckle-tracking echocardiography in patients with corrected tetralogy of Fallot. PMID- 26115740 TI - Target lesion calcification and risk of adverse outcomes in patients with drug eluting stents. A meta-analysis. AB - BACKGROUND: Studies focusing on the relationship between calcified lesions and adverse outcomes in the drug-eluting stent (DES) era have presented inconsistent conclusions. The aim of this study was to assess the association between target lesion calcification and adverse outcomes in patients undergoing DES implantation. METHODS: A systematic search was conducted on Medline (Ovid SP, 1946 to 28 February 2014), Embase (Ovid SP, 1974 to 28 February 2014), and the Chinese Biomedical Literature Database (CBM, 1978 to 28 February 2014). Abstracts from the 2012 and 2013 scientific meetings of the American College of Cardiology and American Heart Association were manually searched. Hazard ratios (HRs) were pooled using a fixed or random effects model in the context of heterogeneity. RESULTS: A total of 13 studies comprising 66,361 patients were included. Target lesion calcification was associated with an increased risk of all-cause mortality (HR = 1.41; 95 % CI = 1.27-1.56), cardiac death (HR = 1.97; 95 % CI = 1.68-2.31), myocardial infarction (HR = 1.33; 95 % CI = 1.13-1.57), target lesion revascularization (TLR; HR 1.47, 95 % CI 1.18-1.83), stent thrombosis (HR 1.63, 95 % CI 1.36-1.96), and major cardiovascular events (HR 1.37, 95 % CI 1.19-1.58). The results proved robust in subgroup analyses for TLR and stent thrombosis. CONCLUSION: Calcified target lesions are risk factors for adverse outcomes in the DES era. Further studies focusing on comprehensive therapy in patients with coronary calcification are urgently needed. PMID- 26115741 TI - [Incidence of constipation in patients with outpatient opioid therapy]. AB - BACKGROUND: Constipation is a common complication in patients with opioid therapy. Additionally, patient-related risk factors also contribute to the development of constipation and these factors have to be integrated into an individualized treatment plan. OBJECTIVE: The aim of this study was to assess the incidence of constipation in patients with opioid therapy in an outpatient setting and to analyze the risk factors that contribute to the development of constipation. MATERIAL AND METHODS: This retrospective cohort study was conducted in two university affiliated outpatient departments at the Charite hospital in Berlin. The trial included all consecutively treated patients with opioid therapy of at least 4 weeks duration. The study was conducted from January 2013 to August 2013. Constipation was defined according to the Rome III criteria. RESULTS: Out of 1166 screened patients, altogether 171 patients were included with a median duration of opioid therapy of 5 years. The most common diagnoses were back pain, musculoskeletal pain and neuropathic pain. In 14% of the treated patients symptoms of constipation were detected and another 35% needed laxatives for symptom control resulting in an overall incidence of constipation of 49%. The remaining 51% of the patients did not use any laxatives and did not experience symptoms of constipation. Age and dosing of opioid therapy significantly increased the risk of consipation but duration of opioid therapy was not related to the incidence of constipation. DISCUSSION: The incidence of constipation in this population remains high although a relevant number of patients were intermittently free of symptoms without using laxatives. An individualized therapy plan and patient education seem to be important elements to control opioid-associated constipation. PMID- 26115742 TI - Does Stigma Towards Mental Illness Affect Initial Perceptions of Peer Providers? AB - Peers (i.e. people with lived experience of mental illness and/or addictions) are being hired in large numbers to offer support for people with serious mental illnesses, but little is known about how peer providers are viewed. The goal of this study was to measure reactions towards actors posed as peer providers. Half of study participants interacted with an actor portraying a psychiatrist and half interacted with an actor portraying a peer provider. Ratings such as liking, feeling comfortable, as well as time spent talking were measured. Participants did not report preferring actors in either condition and did not talk more or have less silence with actors in either condition. Participants also were equally willing to see actors portraying peer providers again in the future and recommend them to a family member. Among participants who had received mental health services, there was a trend towards viewing actors portraying peer providers as more friendly and effective. These positive initial perceptions suggest that stigma towards people with mental illness does not taint the initial perception of peer providers. PMID- 26115743 TI - [Caring communes and locally responsible communities. Model approaches to securing successful aging and care in the neighborhood]. AB - BACKGROUND: This article reports on two projects both concerned with how to initiate and support independent and satisfying aging in community settings and how to promote social participation in neighborhood solidarity in the future. The community plays an important role in this context, supporting independent living, social connectedness and individual well-being in old age. AIM: Against the background of demographic and social changes and the related social challenges, the pilot projects focused on the problems of how the process of aging, which from an individual perspective can be seen as a life period with declining mobility and reduced options for action, can be influenced in a positive way. MATERIAL AND METHODS: The article describes the key experiences in the context of the two pilot projects entitled "VEGA-locally responsible communities and individual well-being in old age" and "Care mix in locally responsible communities". It focuses on the process results and identifies potential barriers to the implementation of the projects. In addition, this article also emphasizes the opportunities and advantages of social networking in local communities. RESULTS AND CONCLUSION: Based on the action research approach, neighborhood specific results and need-based concepts have been developed, which have led to various subproject pathways for implementation. Among other results it was important that social networking and supportive neighborhood structures could be established, which are important conditions for sustainable anchoring in the residential quarter. Another important result was the fact that the communities as well as the different generations in the residential quarter were sensitized and activated for the topic "aging and well-being with social connectedness in local communities". PMID- 26115744 TI - [Successful aging in social environment and neighborhood]. PMID- 26115745 TI - Arthrodesis of proximal inter-phalangeal joint for hammertoe: intramedullary device options. AB - BACKGROUND: Proximal inter-phalangeal (PIP) joint arthrodesis today represents the standard treatment for structured hammertoes; however, recently, a lot of new intramedullary devices for the fixation of this arthrodesis have been introduced. The purpose of this work is to look at the currently available devices and to perform a review of the present literature. MATERIALS AND METHODS: A literature search of PubMed/Medline and Google Scholar databases, considering works published up until September 2014 and using the keywords: hammertoe, arthrodesis, PIP joint, fusion, intramedullary devices, and K-wire, was performed. The published papers were included in the present study only if they met the following inclusion criteria: English articles, arthrodesis of PIP joints for hammertoes with new generation intramedullary devices, series with n > 10. Studies using absorbable pins or screws that are considered as another kind of fixation that involved more than one articulation, as well as comments, letters to the editor, or newsletters were excluded. RESULTS: Nine publications were included. Of the patients' reports, 93-100 % were good or excellent concerning satisfaction. Radiological arthrodesis was achieved in 60.5-100 % of cases. Three of the publications compared the new devices with the K-wire. Of these three articles, two employed the traditional technique and one the buried technique. The AOFAS score, evaluated in three publications, showed a delta of 19, 45 and 58 points. Major complications, which required a secondary surgical revision, were between 0 and 8.6 %. The complications of the K-wire and the new devices were similar; also the reoperation rate was close to equal (maximal difference 2 %). On the other hand, these kinds of devices definitely have a higher price, compared to the K-wire. CONCLUSION: The use of these new devices provides good results; however, their high price is currently a problem. For this reason, cost benefit studies seem to be necessary to justify their use as standard treatment. PMID- 26115746 TI - Preventing lower back pain among caregivers. PMID- 26115747 TI - Neurobiological research in child and adolescent psychiatry: does the pendulum swing back to more attention on developmental psychopathology? PMID- 26115748 TI - Reappraisal of the clinical implications of adenosine triphosphate in terms of the prediction of reconnection sites in cases with electrical isolation of the pulmonary veins. AB - PURPOSE: Dormant conduction (DC) induced by intravenous adenosine triphosphate (ATP) after pulmonary vein (PV) isolation (PVI) could predict subsequent PV reconnection (RC) sites. This study aimed to investigate the relationship between the DC and RC sites during the long-term follow-up. METHODS: Ninety-one consecutive patients (62 males; mean age, 62 +/- 11 years) with symptomatic persistent (n = 18) or paroxysmal (n = 73) atrial fibrillation (AF) who underwent PVI were included in this study. After a successful PVI, we administered ATP to reveal the DC sites. In total, DC sites were observed in 46 (51%) patients, and all were left un-ablated after marking or tagging all of them using fluoroscopic images and a three-dimensional (3D) mapping system. After the follow-up period (14.8 +/- 3.6 months), AF recurred in 29 (32%) patients, all of whom had a DC in the initial ablation session, and underwent redo sessions. We divided the DC sites into three groups; in group A, the RC sites differed from the DC sites, in group B, the RC sites were identical to the DC sites, and in group C, the RC sites involved both DC and other sites. RESULTS: As a result, 20 (69%), 3 (11.5%), and 6 (19.5%) patients belonged to groups A, B, and C, respectively. Statistical analyses comparing the agreement between DC and the RC sites yielded a weak relationship. CONCLUSIONS: DC sites implying RC sites had a weak agreement, and other options to predict RC sites will be required to improve the clinical benefit of CA of AF. PMID- 26115750 TI - Intractable Diarrhea in Two Brothers: Late Diagnosis of Tufting Enteropathy in Adolescence. PMID- 26115749 TI - Psoriasiform Skin Lesions Are Caused by Anti-TNF Agents Used for the Treatment of Inflammatory Bowel Disease. AB - BACKGROUND: Tumor necrosis factor (TNF) antagonists used for the treatment of inflammatory bowel disease (IBD) have been associated with the development of psoriasiform skin lesions. We assessed the demographic and clinical characteristics associated with and outcomes of patients with anti-TNF-induced psoriasiform lesions. METHODS: Patients with Crohn's disease (CD) and ulcerative colitis (UC) receiving treatment with anti-TNF therapy (infliximab, adalimumab, or certolizumab pegol) at a tertiary referral center were identified using an IRB approved clinical data repository. Patients that developed psoriasiform skin lesions after initiation of anti-TNF therapy were included as cases. A group of anti-TNF-treated patients without drug-related psoriasiform lesions were identified as controls. The association between demographic and clinical variables and psoriasiform lesions was assessed using Chi-square analyses and multivariable logistic regression. RESULTS: Five hundred twenty-one patients with IBD undergoing treatment with anti-TNF therapy were identified; of these, 18 (3.5%) had psoriasiform lesions (16 CD and 2 UC). Seventy-two patients were identified as controls. Lesions developed a mean of 58 weeks (range 4-240 weeks) after starting anti-TNF therapy. The majority of patients were female and Caucasian (63 and 78%, respectively). Thirty-nine percent of patients had upper tract disease location. Forty-five patients (50%) were current or former smokers. Location of psoriasiform lesions included palmo-plantar (53%), trunk (47%), and scalp (53%), with 88% reporting involvement of >=2 locations. Treatment of psoriasiform lesions was instituted with topical therapy in eight patients and systemic therapy (+/- phototherapy) in five patients. Discontinuation of anti-TNF therapy was recommended in nine patients (50%); of those, three were retreated with a second anti-TNF agent and all had recurrence of psoriasiform lesions. When adjusted for multiple variables, upper GI tract disease was significantly associated with psoriasiform lesions. CONCLUSIONS: Anti-TNF-induced psoriasiform lesions developed in 3.5% of patients with IBD at a tertiary referral center. Similar to prior published studies, most patients were female, had involvement of the palmo-plantar and scalp regions, and did not have severe IBD activity. The presence of upper tract disease was associated with the development of psoriasiform lesions. Skin lesions led to discontinuation of anti-TNF therapy in 50% of patients. Based upon these results, IBD providers should educate patients about this adverse effect, refer to dermatology for treatment, and discuss alternative IBD therapeutic options early if a severe psoriasiform rash develops. PMID- 26115752 TI - Modulation of the intestinal microbiota and morphology of tilapia, Oreochromis niloticus, following the application of a multi-species probiotic. AB - The intestinal microbiota and morphology of tilapia (Oreochromis niloticus) were investigated after the application of a multi-species probiotic containing Lactobacillus reuteri, Bacillus subtilis, Enterococcus faecium and Pediococcus acidilactici (AquaStar((r)) Growout). Tilapia (55.03 +/- 0.44 g) were fed either a control diet or a probiotic diet (control diet supplemented with AquaStar((r)) Growout at 5 g kg(-1)). After four and eight weeks, culture-dependent analysis showed higher levels of lactic acid bacteria (LAB), enterococci and Bacillus spp. in the mucosa and digesta of fish fed AquaStar((r)) Growout. At week four, polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) revealed a higher similarity within the probiotic fed replicates than replicates of the control group; after eight weeks, the compositional dissimilarity of the microbiome profiles between the groups was greater than the dissimilarities within each group (P < 0.05). High-throughput sequencing revealed that the probiotic treatment significantly reduced the number of operational taxonomic units and species richness in the digesta. Significantly higher proportions of reads belonging to Proteobacteria and Cyanobacteria were detected in the control group whereas the probiotic-fed fish displayed a significantly higher abundance of reads assigned to the Firmicutes (which accounted for >99 % of reads). Bacillus, Cetobacterium and Mycobacterium were the dominant genera in the digesta of control fish whereas Bacillus, Enterococcus and Pediococcus were the largest constituents in probiotic-fed fish. The addition of AquaStar((r)) Growout to tilapia diets led to increased populations of intraepithelial leucocytes, a higher absorptive surface area index and higher microvilli density in the intestine. These data suggest that AquaStar((r)) Growout can modulate both the intestinal microbiota and morphology of tilapia. PMID- 26115751 TI - Infectious Gastroenteritis as a Risk Factor for Tropical Sprue and Malabsorption: A Case-Control Study. AB - BACKGROUND: Previous studies have linked an increase in functional and pathological gastrointestinal (GI) disorders following antecedent infectious gastroenteritis (IGE), yet studies of other chronic GI disorders such as tropical sprue (TS) and intestinal malabsorption (IM) are lacking. This study was performed to evaluate the association between documented IGE and the risk of TS and IM using a matched case-control study. METHODS: The odds of IGE (exposure) among subjects with TS and IM were compared to the odds of exposure in matched controls. Data were obtained from the Defense Medical Surveillance System. Incidence was estimated based on the number of active duty military personnel, and conditional logistic regression models were used to evaluate the relationship between IGE and TS/IM while adjusting for potential confounders. RESULTS: The overall incidence of TS and IM was 0.24 and 1.98 per 100,000 person-years, respectively. After adjusting for important covariates, prior IGE was associated with an increase in the odds of TS (odds ratio (OR) 36.64) and IM (OR 3.93) (p < 0.001). Other covariates demonstrating an increased risk were being of Caucasian race, having greater than high school education, and service in military branches other than the Army. CONCLUSION: Overall, this study demonstrates the first significant estimates that a case of antecedent IGE is associated with an increased risk of TS and IM in an active duty military population. Ultimately, acquisition of TS or IM has the potential to decrease operational efficiency, which may have a significant impact on deployed military missions. PMID- 26115753 TI - Epigenetics as an emerging tool for improvement of fungal strains used in biotechnology. AB - Filamentous fungi are today a major source of industrial biotechnology for the production of primary and secondary metabolites, as well as enzymes and recombinant proteins. All of them have undergone extensive improvement strain programs, initially by classical mutagenesis and later on by genetic manipulation. Thereby, strategies to overcome rate-limiting or yield-reducing reactions included manipulating the expression of individual genes, their regulatory genes, and also their function. Yet, research of the last decade clearly showed that cells can also undergo heritable changes in gene expression that do not involve changes in the underlying DNA sequences (=epigenetics). This involves three levels of regulation: (i) DNA methylation, (ii) chromatin remodeling by histone modification, and (iii) RNA interference. The demonstration of the occurrence of these processes in fungal model organisms such as Aspergillus nidulans and Neurospora crassa has stimulated its recent investigation as a tool for strain improvement in industrially used fungi. This review describes the progress that has thereby been obtained. PMID- 26115754 TI - Enhancing the utilization of host trehalose by fungal trehalase improves the virulence of fungal insecticide. AB - Entomopathogenic fungi proliferate in insect hemolymph by using host nutrients after penetrating the cuticle. To improve the virulence of the locust specific fungus, Metarhizium acridum, we genetically modified the fungus to overexpress ATM1, an endogenous hydrolase of trehalose, which is the main carbon source in insect hemolymph. Compared with the wild-type strain, Metarhizium acridum overexpressing ATM1 gene secreted more acid trehalase into locust hemolymph. The trehalose concentrations in locusts infected with the ATM1-overexpressing strain were 5.5 and 6.1 mmol/l, lower than that in locusts infected with the wild-type strain at 3 and 5 days post-inoculation, representing 44.5 and 60.7 % reduction, respectively. Correspondingly, overexpressing ATM1 accelerated the growth of Metarhizium acridum in host hemolymph, and the dose causing 50 % mortality (LD50) of the ATM1-overexpressing strain was reduced by 8.3-fold compared with the wild type strain, suggesting that increasing the utilization of host nutrients by pathogens could be a promising way to improve the virulence of biopesticides based on parasites of pests. PMID- 26115755 TI - Screening risk areas for sediment and phosphorus losses to improve placement of mitigation measures. AB - Identification of vulnerable arable areas to phosphorus (P) losses is needed to effectively implement mitigation measures. Indicators for source (soil test P, STP), potential mobilization by erosion (soil dispersion), and transport (unit stream power length-slope, LS) risks were used to screen the vulnerability to suspended solids (SS) and P losses in two contrasting catchments regarding topography, soil textural distribution, and STP. Soils in the first catchment ranged from loamy sand to clay loam, while clay soils were dominant in the second catchment. Long-term SS and total P losses were higher in the second catchment in spite of significantly lower topsoil STP. A higher proportion of areas in the second catchment were identified with higher risk due to the significantly higher risk of overland flow generation (LS) and a significantly higher mobilization risk in the soil dispersion laboratory tests. A simple screening method was presented to improve the placement of mitigation measures. PMID- 26115756 TI - Dissolution of Commercially Available Mesalamine Formulations at Various pH Levels. AB - INTRODUCTION: Mesalamine (5-aminosalicylic acid; 5-ASA) is recommended first-line therapy for mild-to-moderate ulcerative colitis. Many mesalamine formulations employ a pH-dependent release mechanism designed to maximize drug release in the colon. This study compared the in vitro release of 5-ASA from six commercially available mesalamine formulations at pH levels similar to those typically encountered in the human gastrointestinal tract. METHODS: The release of 5-ASA from six mesalamine formulations [Mesalazin-Kohlpharma (Kohlpharma, Germany), Mesalazin-Eurim (Eurimpharm, Germany), Mesalazina-Faes (Faes Farma, Spain), Mesalazine EC (Actavis B.V., Netherlands), Mesalazine EC 500 PCH (Pharmachemie B.V., Netherlands); multimatrix mesalamine (Shire US Inc., USA)] was monitored separately at three different pH levels [1.0 (2 h), 6.4 (1 h), and 7.2 (8 h)] using United States Pharmacopeia dissolution apparatus II. The dissolution percentage was calculated as a mean of 12 units for each formulation. RESULTS: At pH 1.0 and 6.4, <1 % of 5-ASA release was observed for each of the mesalamine formulations tested. At pH 7.2, complete release of 5-ASA occurred within 1 h for Mesalazine EC and Mesalazine EC 500 PCH, and within 2 h for Mesalazin-Kohlpharma, Mesalazin-Eurim, and Mesalazina-Faes; complete release of 5-ASA from multimatrix mesalamine occurred within 7 h. Little variability in rate of 5-ASA dissolution was observed between tablets of each formulation. CONCLUSION: At pH 7.2, 5-ASA release profiles were variable among the commercially available mesalamine formulations that were tested. PMID- 26115757 TI - Human Flesh Search Engine and Online Privacy. AB - Human flesh search engine can be a double-edged sword, bringing convenience on the one hand and leading to infringement of personal privacy on the other hand. This paper discusses the ethical problems brought about by the human flesh search engine, as well as possible solutions. PMID- 26115758 TI - An acute bout of aerobic exercise can protect immediate offline motor sequence gains. AB - The present study examined the efficacy of a short bout of moderately intensive exercise to protect knowledge of a newly acquired motor sequence. Previous work revealed that sleep-dependent offline gains in motor sequence performance are reduced by practicing an alternative motor sequence in close temporal proximity to the original practice with the target motor sequence. In the present work, a brief bout of exercise was inserted at two different temporal locations between practice of a to-be-learned motor sequence and the interfering practice that occurred 2 h later. At issue was whether exposure to exercise could reduce the impact of practice with the interfering task which was expected to be manifest as reemergence of offline gain observed in the case in which the learner is not exposed to the interfering practice. Acute exercise did influence the interfering quality of practice with an alternative motor sequence resulting in the return of broad offline gain. However, this benefit was immediate, emerging on the initial test trial, only when exercise was experienced some time after the original period of motor sequence practice and just prior to practice with the interfering motor sequence. Thus, while exercise can contribute to post-practice consolidation, there appears to be a fragile interplay between spontaneous memory consolidation occurring after task practice and the consolidation processes induced via exercise. PMID- 26115759 TI - Myoepithelial Carcinoma of the Nasopharynx: Report of a Rare Case and a Review of the Literature. AB - Salivary gland carcinomas are very rare in the nasopharynx, with the most frequent histologic types being adenoid cystic carcinoma, mucoepidermoid carcinoma and adenocarcinoma, not otherwise specified. Myoepithelial carcinoma (MECA) is a rare tumor of the salivary glands, and there are only three previously reported cases of nasopharyngeal MECA. The case presented is the fourth reported case of MECA in the nasopharynx. Due to the morphologic heterogeneity of MECA, immunohistochemistry is indispensable in ascertaining the diagnosis. MECA is a locally aggressive tumor, but the long-term prognosis of this tumor in the nasopharynx remains uncertain. In our case the tumor was unresectable and the patient was given chemo-radiotherapy. Despite this, residual tumor was seen on nasoscopy 5 months after initial diagnosis and was documented on a re-biopsy which displayed the same histomorphologic features as the original tumor. PMID- 26115761 TI - Potential programming of selected cardiometabolic risk factors at childhood by maternal polyunsaturated fatty acid availability in the MEFAB cohort. AB - BACKGROUND: Increasing evidence suggests that long-chain polyunsaturated fatty acid (LCPUFA) availability in utero could program later health. OBJECTIVE: The objective of the study was to explore whether prenatal LCPUFA availability could be involved in programming cardiometabolic disease risk at childhood. METHODS: Data of 242 mother-child pairs from the Maastricht Essential Fatty Acid Birth (MEFAB) cohort were used. Multi-variable linear regression analysis was applied to identify associations between maternal LCPUFA concentrations around weeks 11, 22 and 32 of pregnancy and at time of delivery and cardiometabolic risk factors of their children (glucose metabolism, blood lipids, and blood pressure) at age 7. RESULTS: Maternal eicosapentaenoic acid (20:5n-3) at week 11 of pregnancy was negatively associated with children's glucose (B=-0.34mmol/L; 95% CI: -0.56, 0.12). Positive associations were found between maternal linoleic acid (18:2n-6) at time of delivery and children's proinsulin (B=0.25pmol/L; 95% CI: 0.08, 0.41); maternal 3-docosapentaenoic acid (22:5n-3) at week 11 and children's total cholesterol (B=1.23mmol/L; 95% CI: 0.45, 2.01) and low-density-lipoprotein cholesterol (B=1.12mmol/L; 95% CI: 0.42, 1.82); and maternal osbond acid (22:5n 6) at week 22 and tetracosadienoic acid (24:2n-6) at week 32 and children's diastolic blood pressure (B=16.86mmHg; 95% CI: 7.63, 26.08 and B=17.75mmHg; 95% CI: 6.37, 29.94, respectively). CONCLUSION: Our findings suggest that maternal omega-6 (n-6) fatty acids may be of particular importance in relation to children's glucose metabolism and blood pressure, whereas omega-3 (n-3) fatty acids seem particularly related to blood lipids at childhood. In general, the strength of the associations appeared stronger with fatty acid concentrations in early pregnancy compared to late pregnancy. PMID- 26115760 TI - The Use of Green Leaf Membranes to Promote Appetite Control, Suppress Hedonic Hunger and Loose Body Weight. AB - On-going research aims at answering the question, which satiety signal is the most potent or which combination of satiety signals is the most potent to stop eating. There is also an aim at finding certain food items or food additives that could be used to specifically reduce food intake therapeutically. Therapeutic attempts to normalize body weight and glycaemia with single agents alone have generally been disappointing. The success of bariatric surgery illustrates the rationale of using several hormones to treat obesity and type-2-diabetes. We have found that certain components from green leaves, the thylakoids, when given orally have a similar rationale in inducing the release of several gut hormones at the same time. In this way satiety is promoted and hunger suppressed, leading to loss of body weight and body fat. The mechanism is a reduced rate of intestinal lipid hydrolysis, allowing the lipolytic products to reach the distal intestine and release satiety hormones. The thylakoids also regulate glucose uptake in the intestine and influences microbiota composition in the intestine in a prebiotic direction. Using thylakoids is a novel strategy for treatment and prevention of obesity. PMID- 26115762 TI - Psychological effects of calisthenic exercises on neuroinflammatory and rheumatic diseases. AB - BACKGROUND: The aim of this study was to evaluate the effects of calisthenic exercises on psychological status in patients with ankylosing spondylitis (AS) and multiple sclerosis (MS). METHODS: This study comprised 40 patients diagnosed with AS randomized into two exercise groups (group 1 = hospital-based, group 2 = home-based) and 40 patients diagnosed with MS randomized into two exercise groups (group 1 = hospital-based, group 2 = home-based). RESULTS: The exercise programme was completed by 73 participants (hospital-based = 34, home-based = 39). Mean age was 33.75 +/- 5.77 years. After the 8-week exercise programme in the AS group, the home-based exercise group showed significant improvements in erythrocyte sedimentation rates (ESR). The hospital-based exercise group showed significant improvements in terms of the Bath AS Metrology Index (BASMI) and Hospital Anxiety and Depression Scale-Anxiety (HADS-A) scores. After the 8-week exercise programme in the MS group, the home-based and hospital-based exercise groups showed significant improvements in terms of the 10-m walking test, Berg Balance Scale (BBS), HADS-A, and MS international Quality of Life (MusiQoL) scores. There was a significant improvement in the hospital-based and a significant deterioration in the home-based MS patients according to HADS-Depression (HADS-D) score. CONCLUSION: The positive effects of exercises on neurologic and rheumatic chronic inflammatory processes associated with disability should not be underestimated. PMID- 26115763 TI - Two-step production of gamma-aminobutyric acid from cassava powder using Corynebacterium glutamicum and Lactobacillus plantarum. AB - Production of gamma-aminobutyric acid (GABA) from crop biomass such as cassava in high concentration is desirable, but difficult to achieve. A safe biotechnological route was investigated to produce GABA from cassava powder by C. glutamicum G01 and L. plantarum GB01-21. Liquefied cassava powder was first transformed to glutamic acid by simultaneous saccharification and fermentation with C. glutamicum G01, followed by biotransformation of glutamic acid to GABA with resting cells of L. plantarum GB01-21 in the reaction medium. After optimizing the reaction conditions, the maximum concentration of GABA reached 80.5 g/L with a GABA productivity of 2.68 g/L/h. This is the highest yield ever reported of GABA production from cassava-derived glucose. The bioprocess provides the added advantage of employing nonpathogenic microorganisms, C. glutamicum and L. plantarum, in microbial production of GABA from cassava biomass, which can be used in the food and pharmaceutical industries. PMID- 26115765 TI - Anticancer activity of pyrithione zinc in oral cancer cells identified in small molecule screens and xenograft model: Implications for oral cancer therapy. AB - Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options, underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to identify novel anticancer agents for OSCC using quantitative high throughput assays for screening six chemical libraries consisting of 5170 small molecule inhibitors. In depth characterization resulted in identification of pyrithione zinc (PYZ) as the most effective cytotoxic agent inhibiting cell proliferation and inducing apoptosis in OSCC cells in vitro. Further, treatment with PYZ reduced colony forming, migration and invasion potential of oral cancer cells in a dose dependent manner. PYZ treatment also led to altered expression of several key components of the major signaling pathways including PI3K/AKT/mTOR and WNT/beta catenin in OSCC cells. In addition, treatment with PYZ also reduced expression of 14-3-3zeta, 14-3-3sigma, cyclin D1, c-Myc and pyruvate kinase M2 (PKM2), proteins identified in our earlier studies to be involved in development and progression of OSCCs. Importantly, PYZ treatment significantly reduced tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. Taken together, we demonstrate in vitro and in vivo efficacy of PYZ in OSCC. In conclusion, we identified PYZ in HTS assays and demonstrated in vitro and in vivo pre-clinical efficacy of PYZ as a novel anticancer therapeutic candidate in OSCC. PMID- 26115764 TI - Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors. AB - Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ~50% of ERalpha-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERalpha-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERalpha-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERalpha-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERalpha-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH1A1 (a marker of pluripotency in epithelial cancers which is absent in normal breast tissue) is increased in relapsing tumors, with a concurrent modification of its intra-cellular localization. Our data could be of value in the discrimination of patients susceptible to develop tamoxifen resistance and in the selection of optimized patient-tailored therapies. PMID- 26115767 TI - Discovery of precursor and mature microRNAs and their putative gene targets using high-throughput sequencing in pineapple (Ananas comosus var. comosus). AB - MicroRNAs (miRNAs) are a class of small, endogenous non-coding RNAs that negatively regulate gene expression, resulting in the silencing of target mRNA transcripts through mRNA cleavage or translational inhibition. MiRNAs play significant roles in various biological and physiological processes in plants. However, the miRNA-mediated gene regulatory network in pineapple, the model tropical non-climacteric fruit, remains largely unexplored. Here, we report a complete list of pineapple mature miRNAs obtained from high-throughput small RNA sequencing and precursor miRNAs (pre-miRNAs) obtained from ESTs. Two small RNA libraries were constructed from pineapple fruits and leaves, respectively, using Illumina's Solexa technology. Sequence similarity analysis using miRBase revealed 579,179 reads homologous to 153 miRNAs from 41 miRNA families. In addition, a pineapple fruit transcriptome library consisting of approximately 30,000 EST contigs constructed using Solexa sequencing was used for the discovery of pre miRNAs. In all, four pre-miRNAs were identified (MIR156, MIR399, MIR444 and MIR2673). Furthermore, the same pineapple transcriptome was used to dissect the function of the miRNAs in pineapple by predicting their putative targets in conjunction with their regulatory networks. In total, 23 metabolic pathways were found to be regulated by miRNAs in pineapple. The use of high-throughput sequencing in pineapples to unveil the presence of miRNAs and their regulatory pathways provides insight into the repertoire of miRNA regulation used exclusively in this non-climacteric model plant. PMID- 26115766 TI - Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV mediated gene therapy. AB - Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the treated twitcher mice was significantly prolonged and their neurobehavioral performance was improved. Taken together, our findings underscore the complexity of cerebellar neurodegeneration in GLD and highlight the potential effectiveness of gene therapy in mitigating neuropathological deficits in GLD and other neurodegenerative disorders in which Purkinje cells are involved. PMID- 26115768 TI - Role of 5-hydroxymethylcytosine in neurodegeneration. AB - The recent discovery of 5-hydroxymethylcytosine (5hmC), an epigenetic modifier and oxidation product of 5-methylcytosine (5mC), has broadened the scope and understanding of neural development and neurodegenerative diseases. By virtue of their functional groups, 5mC and 5hmC exert opposite effects on gene expression; the former is generally associated with gene silencing whereas the latter is mainly involved in up-regulation of gene expression affecting the cellular processes such as differentiation, development, and aging. Although DNA methylation plays an important role in normal neural development and neuroprotection, an altered pathway due to complex interaction with environmental and genetic factors may cause severe neurodegeneration. The levels of 5hmC in brain increase progressively from birth until death, while in patients with neurodegenerative disorders, the levels are found to be highly compromised. This article discusses the recent developments in the area of hydroxymethylation, with particular emphasis on the role of 5hmC in neurodegenerative diseases including Alzheimer's disease, Parkinson's diseases and Huntington's disease. We have also included recent findings on the role of 5hmC in brain tumors (gliomas). Despite compelling evidence on the involvement of 5hmC in neurodegeneration, it is yet to be established whether this epigenetic molecule is the cause or the effect of the onset and progression of neurodegenerative diseases. PMID- 26115769 TI - Molecular cloning, sequence characteristics, and tissue expression analysis of ECE1 gene in Tibetan pig. AB - Low air pressure and low oxygen partial pressure at high altitude seriously affect the survival and development of human beings and animals. ECE1 is a recently discovered gene that is involved in anti-hypoxia, but the full-length cDNA sequence has not been obtained. For a better understanding of the structure and function of the ECE1 gene and to study its effect in Tibetan pig, the cDNA of the ECE1 gene from the muscle of Tibetan pig was cloned, sequenced and characterized. The ECE1 full-length cDNA sequence consists of 2262 bp coding sequence (CDS) that encodes 753 amino acids with a molecular mass of 85,449 kD, 2 bp 5'UTR and 1507 bp 3'UTR. In addition, the phylogenetic tree analysis revealed that the Tibetan pig ECE1 has a closer genetic relationship and evolution distance with the land mammals ECE1. Furthermore, analysis by qPCR showed that the ECE1 transcript is constitutively expressed in the 10 tissues tested: the liver, subcutaneous fat, kidney, muscle, stomach, heart, brain, spleen, pancreas, and lung. These results serve as a foundation for further insight into the Tibetan pig ECE1 gene. PMID- 26115770 TI - IGFBP7 promotes hemocyte proliferation in small abalone Haliotis diversicolor, proved by dsRNA and cap mRNA exposure. AB - Insulin-like growth factor binding protein 7 (IGFBP7) binds IGFs with a low affinity, but in contrast, recognizes insulin with a high affinity. Many studies show that IGFBP7 involves several cellular processes of vertebrates and functions as a tumor suppressor gene in different tumors. However, the function of IGFBP7 in invertebrates is unclear. In this research, we studied the function of IGFBP7 in the proliferation of small abalone Haliotis diversicolor hemocytes by exposure to dsRNA or cap mRNA of saIGFBP7. We found that exposure to dsRNA or cap mRNA of saIGFBP7 could significantly affect the mRNA and protein expression of IGFBP7 in cultured small abalone hemocytes (p<0.05). There was a significant increase in hemocyte density and the number of adherent hemocytes after exposure to cap mRNA of saIGFBP7 (p<0.05). Similarly, exposure to dsRNA of saIGFBP7 could significantly decrease the hemocyte density and the number of adherent hemocytes (p<0.05). These findings suggest that IGFBP7 increases hemocyte growth. It is the first time to report the effect of IGFBP7 on the proliferation of marine invertebrate cells. PMID- 26115771 TI - Genome-wide identification of turnip mosaic virus-responsive microRNAs in non heading Chinese cabbage by high-throughput sequencing. AB - Turnip mosaic virus (TuMV) is the most prevalent viral pathogen infecting most cruciferous plants. MicroRNAs (miRNAs) are around 22 nucleotides long non-protein coding RNAs that play key regulatory roles in plants. Recent research findings show that miRNAs are involved in plant-virus interaction. However we know little about plant defense and viral offense system networks throughout microRNA regulation pathway. In this study, two small RNA libraries were constructed based on non-heading Chinese cabbage (Brassica campestris ssp. chinensis L. Makino, NHCC) leaves infected by TuMV and healthy leaves, and sequenced using the Illumina-Solexa high-throughput sequencing technology. A total of 86 conserved miRNAs belonging to 25 known miRNA families and 45 novel ones were identified. Among them, twelve conserved and ten new miRNAs were validated by real-time fluorescence quantitative PCR (qPCR). Differential expression analysis showed that 42 miRNAs were down-regulated and 27 miRNAs were up-regulated in response to TuMV stress. A total of 271 target genes were predicted using a bioinformatics approach, these genes are mainly involved in growth and resistance to various stresses. We further selected 13 miRNAs and their corresponding target genes to explore their expression pattern under TuMV and/or cold (4 degrees C) stresses, and the results indicated that some of the identified miRNAs could link TuMV response with cold response of NHCC. The characterization of these miRNAs could contribute to a better understanding of plant-virus interaction throughout microRNA regulation pathway. This can lead to finding new approach to defend virus infection using miRNA in Chinese cabbage. PMID- 26115772 TI - Classification and Tie2 mutations in spinal and soft tissue vascular anomalies. AB - Vascular anomalies included hemangiomas and vascular malformations (VMs). VMs are mediated by mutations in the endothelial cell-specific receptor tyrosine kinase Tie2 (TEK),which is essential for angiogenesis and vascular stabilization. We identified five types of Tie2 mutations in 80 patients with soft tissue or spinal VMs by PCR including the previously detected missense mutations 2690A>G (Y897C), 2740C>T (L914F), 2743C>T (R915C), and two nonsense mutations 2763G>A, 2688C>T, we identified Tie2 mutation in primary spinal VMs for the first time. Tie2 mutations were found to be absent in 33 patients with hemangiomas and DNA samples of VMs. In addition, we showed that Tie2 mRNA expression in spinal VMs was similar to soft tissue VMs, but obviously lower than infant hemangiomas (P<0.01). This study provides new insights into spinal VMs, the association of Tie2 and vascular anomalies needs to be further discussed. PMID- 26115773 TI - Frequency domain analysis of cerebral near infrared spectroscopy signals during application of an impedance threshold device in spontaneously ventilating volunteers. AB - Currently available near infrared spectroscopy (NIRS) devices are unable to discriminate between arterial and venous blood, a potential source of artifact. The purpose of this study was to test the hypothesis that oscillations in NIR signals at the respiratory and cardiac frequency could be attributed to venous and arterial blood, respectively, and thereby isolated. After written informed consent was obtained, a two-wavelength NIRS device was placed over the left frontal cortex in 20 volunteers. After 5 min of unimpeded spontaneous ventilation, an impedance threshold device (ITD, average resistance-7 cm H2O) was applied and an additional two minutes of data recorded. Tissue saturation (StO2) calculated at the ventilatory and cardiac frequencies was compared to non pulsatile StO2, before and after application of the ITD using spectral peak and power algorithms. The ITD increased non-pulsatile cerebral saturation by 3.6 %. The ITD had no discernable effect on pulsatile estimates of StO2 at either the ventilatory or cardiac frequencies. StO2 estimated at the NIRS spectral peak from 0.75 to 1.75 Hz was 24 % higher than non-pulsatile StO2 (p = 0.0013). There were no other significant differences between pulsatile and non-pulsatile algorithms in the estimation of StO2. In 64 % of cases, both the low (ventilator) and high (cardiac) frequency estimates of StO2 were either both larger or both smaller than non-pulsatile StO2, suggesting that they were interrogating the same vascular bed. Frequency domain analysis cannot reliably separate NIRS waveforms into arterial and venous components. PMID- 26115775 TI - Data Synthesis in Meta-Analysis may Conclude Differently on Cognitive Effect From Transcranial Direct Current Stimulation. PMID- 26115774 TI - Comparison of electrical velocimetry and cardiac magnetic resonance imaging for the non-invasive determination of cardiac output. AB - A novel algorithm of impedance cardiography referred to as electrical velocimetry (EV) has been introduced for non-invasive determination of cardiac output (CO). Previous validation studies yielded diverging results and no comparison with the non-invasive gold standard cardiac magnetic resonance imaging (CMR) has been performed. We therefore aimed to prospectively assess the accuracy and reproducibility of EV compared to CMR. 152 consecutive stable patients undergoing CMR were enrolled. EV measurements were taken twice before or after CMR in supine position and averaged over 20 s (AESCULON((r)), Osypka Medical, Berlin, Germany). Bland-Altman analysis showed insufficient agreement of EV and CMR with a mean bias of 1.2 +/- 1.4 l/min (bias 23 +/- 26 %, percentage error 51 %). Reproducibility was high with 0.0 +/- 0.3 l/min (bias 0 +/- 8 %, percentage error 15 %). Outlier analysis revealed gender, height, CO and stroke volume (SV) by CMR as independent predictors for larger variation. Stratification of COCMR in quintiles demonstrated a good agreement for low values (<4.4 l/min) with bias increasing significantly with quintile as high as 3.1 +/- 1.1 l/min (p < 0.001). Reproducibility was not affected (p = 0.71). Subgroup analysis in patients with arrhythmias (p = 0.19), changes in thoracic fluid content (p = 0.51) or left heart failure (p = 0.47) could not detect significant differences in accuracy. EV showed insufficient agreement with CMR and good reproducibility. Gender, height and increasing CO and SV were associated with increased bias while not affecting reproducibility. Therefore, absolute values should not be used interchangeably in clinical routine. EV yet may find its place for clinical application with further investigation on its trending ability pending. PMID- 26115778 TI - PubMLST.org--The new home for the Borrelia MLSA database. PMID- 26115776 TI - Concordance Between BeamF3 and MRI-neuronavigated Target Sites for Repetitive Transcranial Magnetic Stimulation of the Left Dorsolateral Prefrontal Cortex. AB - BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) is a common target for repetitive transcranial magnetic stimulation (rTMS) in major depression, but the conventional "5 cm rule" misses DLPFC in >1/3 cases. Another heuristic, BeamF3, locates the F3 EEG site from scalp measurements. MRI-guided neuronavigation is more onerous, but can target a specific DLPFC stereotaxic coordinate directly. The concordance between these two approaches has not previously been assessed. OBJECTIVE: To quantify the discrepancy in scalp site between BeamF3 versus MRI guided neuronavigation for left DLPFC. METHODS: Using 100 pre-treatment MRIs from subjects undergoing left DLPFC-rTMS, we localized the scalp site at minimum Euclidean distance from a target MNI coordinate (X - 38 Y + 44 Z + 26) derived from our previous work. We performed nasion-inion, tragus-tragus, and head circumference measurements on the same subjects' MRIs, and applied the BeamF3 heuristic. We then compared the distance between BeamF3 and MRI-guided scalp sites. RESULTS: BeamF3-to-MRI-guided discrepancies were <0.65 cm in 50% of subjects, <0.99 cm in 75% of subjects, and <1.36 cm in 95% of subjects. The angle from midline to the scalp site did not differ significantly using MRI-guided versus BeamF3 methods. However, the length of the radial arc from vertex to target site was slightly but significantly longer (mean 0.35 cm) with MRI guidance versus BeamF3. CONCLUSIONS: The BeamF3 heuristic may provide a reasonable approximation to MRI-guided neuronavigation for locating left DLPFC in a majority of subjects. A minor optimization of the heuristic may yield additional concordance. PMID- 26115779 TI - CaM and CML emergence in the green lineage. AB - Calmodulin (CaM) is a well-studied calcium sensor that is ubiquitous in all eukaryotes and contributes to signaling during developmental processes and adaptation to environmental stimuli. Among eukaryotes, plants have a remarkable variety of CaM-like proteins (CMLs). The expansion of genomic data sets offers the opportunity to explore CaM and CML evolution among the green lineage from algae to land plants. Database analysis indicates that a striking diversity of CaM and CMLs evolved in angiosperms during terrestrial colonization and reveals the emergence of new CML classes throughout the green lineage that correlate with the acquisition of novel biological traits. Here, we speculate that expansion of the CML family was driven by selective pressures to process environmental signals efficiently as plants adapted to land environments. PMID- 26115777 TI - Preliminary results of the Spanish Association of Urology National Registry in Active Surveillance for prostate cancer. AB - OBJECTIVES: To present a National Registry of patients with prostate cancer as monitored through active surveillance, with the intention of testing the hypothesis that cancer-specific mortality in very low-risk and low-risk patients is less than 5% at 15 years. MATERIAL AND METHODS: A multicentre observational study (AEU-PIEM/2014/0001) sponsored by the Spanish Association of Urology was conducted using their platform for multicentre studies. The clinical-pathological inclusion criteria were as follows: cT1a-cT3a, PSA <= 20 ng/ml, initial minimum biopsy of 10 cores, number of affected cores <= 3, 1st Gleason score of 3 and 2nd Gleason score <= 4 and a known prostate volume (in cc). A unified follow-up was not established for all recruiting centres; however, a survey was conducted that reflects the follow-up characteristics based on a number of tangible parameters that allow for their comparison. With the same philosophy of flexibility, the use of certain biomarkers and multiparametric MRI was not considered necessary for inclusion. RESULTS: We describe the Registry's characteristics and possibilities, as well as the preliminary results from the 324 patients included in its first 5 months of operation in the 15 recruiting centres. We also report the clinical pathological variables, biomarkers, radiodiagnosis technique and quality-of-life questionnaires considered for the database, as well as the possibilities for indefinite follow-up, remaining open to any active treatment recognized in clinical guidelines. CONCLUSIONS: The AEU-PIEM/2014/0001 represents an extremely useful tool for all Spanish urologists for multicentre clinical research. The registry will undoubtedly enable the dissemination of active surveillance of our patients in a more coordinated manner, thus maintaining the advantages of optimised opportunistic screening for prostate cancer without resulting in overtreatment. PMID- 26115780 TI - MicroProteins: small size-big impact. AB - MicroProteins (miPs) are short, usually single-domain proteins that, in analogy to miRNAs, heterodimerize with their targets and exert a dominant-negative effect. Recent bioinformatic attempts to identify miPs have resulted in a list of potential miPs, many of which lack the defining characteristics of a miP. In this opinion article, we clearly state the characteristics of a miP as evidenced by known proteins that fit the definition; we explain why modulatory proteins misrepresented as miPs do not qualify as true miPs. We also discuss the evolutionary history of miPs, and how the miP concept can extend beyond transcription factors (TFs) to encompass different non-TF proteins that require dimerization for full function. PMID- 26115781 TI - Plant cutin genesis: unanswered questions. AB - The genesis of cutin, the main lipid polymer present in the biosphere, has remained elusive for many years. Recently, two main approaches have attempted to explain the process of cutin polymerization. One describes the existence of an acyltransferase cutin synthase enzyme that links activated monomers of cutin in the outer cell wall, while the other shows that plant cutin is the final result of an extracellular nonenzymatic self-assembly and polymerizing process of cutin monomers. In this opinion article, we explain both models and suggest that they could be pieces of a more complex biological scenario. We also highlight their different characteristics and current limitations, and suggest a potential synergism of both hypotheses. PMID- 26115782 TI - Assessment of microtubule depolymerization property of flavonoids isolated from Tanacetum gracile in breast cancer cells by biochemical and molecular docking approach. AB - The chemical investigation of the bioactive nonpolar fractions of Tanacetum gracile afforded two flavonoid analogues namely, 5-hydroxy-3,6,7,3',4' pentamethoxyflavone (1) and 5,4'-dihydroxy-3,6,7,3',4'-tetramethoxyflavone (2) which were identical to the previously reported artemetin and chrysosplenetin respectively. The structure of the compounds was elucidated on the basis of spectroscopic evidences and they showed significant cytotoxic activity against human breast cancer cells (MCF-7 and T47D). Mechanism based study showed that the compounds modulated microtubule depolymerization by activating mitotic spindle checkpoint. Molecular docking at the colchicine binding pocket revealed that the compounds bind at alpha-beta interfacial site of tubulin, correlating binding interactions with probable inhibition mechanism. The study reveals important observations to generate improved flavonoids that leads to cell apoptosis. The compounds were also evaluated for absorption, metabolism and toxicity by online webserver admetSAR. The significant microtubule disassembling property and less toxicity paves way for consideration of the compounds as chemopreventive agents. PMID- 26115783 TI - Loss of mitochondrial transmembrane potential and glutathione depletion are not sufficient to account for induction of apoptosis by carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone in human leukemia K562 cells. AB - Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), an uncoupler of mitochondrial oxidative phosphorylation, inhibits cell proliferation and induces cell death with apoptotic features. It was reported that the cytotoxic effects of FCCP are preceded by a rapid glutathione (GSH) depletion with a subsequent loss of mitochondrial transmembrane potential (DeltaPsi). The GSH depletion was suggested as the cause of apoptosis in FCCP treated cells. This conclusion was further supported by the finding that all adverse effects of FCCP including cell death can be prevented by N-acetylcysteine (NAC) a precursor of GSH synthesis (Han and Park, 2011). Here, we argue that neither loss of DeltaPsi nor GSH depletion is sufficient to account for induction of apoptosis in FCCP treated leukemia K562 cells. Indeed, the lowest concentration of FCCP that brings about the permanent loss of DeltaPsi and the extensive decrease in GSH level induces cell death in minor population of cells. Only much higher concentrations of FCCP, that exceed the range to achieve permanent collapse of DeltaPsi, induce extensive apoptosis. The low proapoptotic activity of FCCP could be explained by hyperactivation of protein kinase B/Akt. A detailed LC/MS/MS analysis of cell extracts revealed extensive formation of FCCP adducts with GSH. This effect could explain the mechanism of GSH depletion, which is currently unknown. Although NAC induces an increase in the GSH pool, this effect is not crucial for abrogation of FCCP cytotoxicity. Indeed, the presence of NAC in the growth medium causes a rapid clearance of FCCP due to its quantitative conversion into the FCCP-NAC adduct, which is the real cause of abrogated FCCP cytotoxicity. PMID- 26115784 TI - Lipidomic fatty acid profile and global gene expression pattern in mammary gland of rats that were exposed to lard-based high fat diet during fetal and lactation periods associated to breast cancer risk in adulthood. AB - The persistent effects of animal fat consumption during pregnancy and nursing on the programming of breast cancer risk among female offspring were studied here. We have previously found that female offspring of rat dams that consumed a lard based high-fat (HF) diet (60% fat-derived energy) during pregnancy, or during pregnancy and lactation, were at a reduced risk of developing mammary cancer. To better understand the unexpected protective effects of early life lard exposure, we have applied lipidomics and nutrigenomics approaches to investigate the fatty acid profile and global gene expression patterns in the mammary tissue of the female offspring. Consumption of this HF diet during gestation had few effects on the mammary tissue fatty acids profile of young adult offspring, while exposure from gestation throughout nursing promoted significant alterations in the fatty acids profile. Major differences were related to decreases in saturated fatty acids (SFA) and increases in omega-6 polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and conjugated linolenic acid (CLA) concentrations. In addition several differences in gene expression patterns by microarray analysis between the control and in utero or in utero and during lactation HF exposed offspring were identified. Differential dependency network (DDN) analysis indicated that many of the genes exhibited unique connections to other genes only in the HF offspring. These unique connections included Hrh1 Ythdf1 and Repin1-Elavl2 in the in utero HF offspring, and Rnf213-Htr3b and Klf5 Chrna4 in the in utero and lactation HF offspring, compared with the control offspring. We conclude that an exposure to a lard-based HF diet during early life changes the fatty acid profile and transcriptional network in mammary gland in young adult rats, and these changes appear to be consistent with reduced mammary cancer risk observed in our previous study. PMID- 26115785 TI - New approaches for understanding the nuclear force balance in living, adherent cells. AB - Cytoskeletal forces are transmitted to the nucleus to position and shape it. Linkages mediated by the LINC (linker of nucleoskeleton and cytoskeleton) complex transfer these forces to the nuclear envelope. Nuclear position and shape can be thought to be determined by a balance of cytoskeletal forces generated by microtubule motors that shear the nuclear surface, actomyosin forces that can pull, push and shear the nucleus, and intermediate filaments that may passively resist nuclear decentering and deformation. Parsing contributions of these different forces to nuclear mechanics is a very challenging task. Here we review new approaches that can be used in living cells to probe and understand the nuclear force balance. PMID- 26115786 TI - [Problematic Internet use among teenagers in Sfax, Tunisia]. AB - Use of the Internet in Tunisian society and especially among teenagers has increased in recent years. While the use of Internet is primarily intended for research and communication, the Internet has also become an important part of teenager's life. Most people use the Internet in healthy and productive ways. However, some teenagers develop a problematic use of the Internet, which is a condition also known by the term of "Internet addiction". In Tunisia, the literature does not report data on problematic Internet use prevalence among Tunisian teenagers. PURPOSE: The aim of this study was to determine the prevalence of problematic Internet use among teenagers, in the urban area of Sfax. METHODS: This transversal study was carried out between the 15th January and the 15th February 2009. Participants were 600, first to third grade secondary school students, aged 14 to 20. They were recruited from seven secondary schools randomly selected in the urban area in Sfax City. The self-administered Young's 8 item questionnaire was used in this survey. Participants who scored five or more can be considered problematic Internet users. Finally, 587 valid data samples were collected, 263 (44%) males and 324 (56%) females. Eighty-five percent of the participants were in the 15-17 age range. The mean age was 16 years (+/-1.26). RESULTS: The prevalence of problematic Internet use was 18.05% (total of 587 students). The sex-ratio was 0.75. The problematic Internet use was not correlated with sex. The average time of Internet use per day among problematic Internet users was 4.5hours (+/-2.84) against 1.02hours (+/-1.56) among non problematic Internet users (P=0.000). DISCUSSION: In this study, the prevalence of problematic Internet use was higher than that reported in previous studies. Two facts can explain this: first, the use of the only self-administered questionnaire does not distinguish between a simple abuse and a problematic Internet use. A psychiatric examination is essential to support the diagnosis of problematic Internet use. Second, this study was conducted exclusively in an urban area where access to the Internet is easier than in rural areas. This study was not representative of teenagers in Sfax. The gender difference was consistent with the findings of prior research, as was the average time of Internet use per day among problematic Internet users. CONCLUSION: This study shows that problematic Internet use is frequent in our teenage population. A preventive outreach for youths, their families and health professionals is needed to limit the extension of this problem among young people. The existence of misuse of the Internet should not lead to avoiding this media. Reflections on how to moderate the relationship with the Internet are necessary; especially since Internet becomes an essential medium of information and communication. The current lack of Internet education in school curricula is also a shortage to fulfil. PMID- 26115787 TI - [Healing garden: Primary concept]. AB - Since ancient times the relationship between mankind and plants occupies medicine and philosophy. From the first tablets of herbal medicine to Asclepius gardens, those of cloisters and bimaristans to cosmological gardens in Asia, from the largest public park to asylum institutions of the nineteenth century, the garden is proposed as a place of care, a promoter of restoration of the human being. If the advent of technology and drugs have for a time relegated it to the level of empirical care, results in neuroscience ultimately provide it on a scientific basis. The early evolutionary theories, the Savanah theory from Orians, the biophilia hypothesis from Wilson, are relayed by the famous Ulrich' study showing the positive influence of a view of nature through the window on the recovery of in patients. Mechanisms leading stress regulation, level of attention and organisation, focus and fascination, are recognized at the origin of restoration processes. Human capacities to respond to the recuperating function of a natural environment connect to grounded behaviour for adaptation to natural selection process and survival. The mechanisms of our immune system are essential to maintain our vitality. Phyto-resonance, felt or unconsciously perceived in appearance, according to Shepard is an emotion that structures well beyond the archaic behaviour. Recovery, in terms of phenomenological experience of the presence, is a philosophical demonstration of the environmental i.e. multisensory, spatial and temporal approach. Its emotional and affective experience connects to the vitality and creativity. The phyto-resonance hypothesis according to the Konrad Neuberger's point of view induces strategies catering to all levels of the organisation of the human being. It confirms the multidisciplinary nature of hortitherapy and places the mechanism of relationships between man and plant at the centre of discipline. It is also a source of inspiration and inexhaustible work for caregivers. The phenomenological approach of the therapeutic garden is an art of hospitality, human relationships and care. The garden opens the door to our interiority and prepares the interpersonal meeting. The experience of presence, mobilizing internal resources, is an opening to the possibilities of the living world, allows entry into a slow but promising time. The reintroduction and rehabilitation of the garden setting in residential care is necessary. These benefits are open to all for a better efficacy of care. PMID- 26115788 TI - Three Turkish families with different transthyretin mutations. AB - Transthyretin (TTR)-related hereditary amyloidosis, also called familial amyloid polyneuropathy (FAP), is a rare autosomal dominant systemic disorder that presents with progressive axonal sensory, autonomic and/or motor neuropathies. The present report describes three families with three different TTR mutations who were followed from 1995 to 2014. Only one of these families expressed the Val30Met mutation, which is the most common mutation in endemic regions; all members of this family had late disease onset but varied severities and clinical presentations of the disease. The second family expressed the Thr49Ser mutation, which has not been well documented previously. Our limited experience obtained from these patients indicates that this mutation presents with autonomic neuropathy but a greater degree of cardiac involvement, especially fatal heart failure. The third mutation, Glu54Lys, has been identified as a cause of severe familial amyloid polyneuropathy; the family members with this mutation exhibited severe motor and autonomic neuropathy, early vitreous opacity, and fatal heart failure. Three of the patients with the Val30Met mutation were treated with tafamidis for longer than one year and cessation of the polyneuropathy resulted. However, a short trial of tafamidis in two patients with the Glu54Lys mutation, who showed severe systemic and neurological involvement, did not gain any clinical benefits. PMID- 26115789 TI - Discrete Global but No Focal Gray Matter Volume Reductions in Unmedicated Adult Patients With Attention-Deficit/Hyperactivity Disorder. AB - BACKGROUND: Gray matter reduction mainly in the anterior cingulate cortex, the basal ganglia, and the cerebellum has been reported in attention deficit/hyperactivity disorder (ADHD). Yet, respective data remain contradictory and inconclusive. To clarify if structural alteration in these brain areas can be verified in a large cohort of adult patients and if a history of stimulant medication has an effect on brain structure, magnetic resonance imaging was performed in the context of a clinical trial on the efficacy of group psychotherapy, clinical management, methylphenidate, and placebo (Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study Trial). METHODS: Between January 2007 and August 2010, 1480 patients from seven study centers across Germany, aged 18 to 58, were prescreened; 518 were assessed for eligibility; 433 were randomized; and 187 were eligible for neuroimaging. The control group included 121 healthy volunteers. Structural magnetic resonance imaging data sets were acquired. Following strict quality control, 131 patient and 95 control data sets could be analyzed. All patients were unmedicated for at least 6 months. The established method of voxel-based morphometry (VBM8 segmentation and diffeomorphic anatomical registration through exponentiated lie normalization) was used to assess global and regional brain volumes. RESULTS: Patients displayed subtle global cerebral volume reductions. There was no evidence of regional gray matter volume abnormalities. The inattentive ADHD subtype was linked to smaller volumes in the left dorsolateral prefrontal cortex. A history of previous medication did not modulate brain volumes. CONCLUSIONS: ADHD in adulthood is associated with global rather than regional volumetric abnormalities. Previous use of stimulant medication does not seem to modify subsequent brain volumes in a significant way. PMID- 26115791 TI - Challenges affecting access to cesarean delivery and strategies to overcome them in low-income countries. AB - BACKGROUND: Most maternal deaths occur in low-income countries where access to appropriate medical care is restricted. OBJECTIVES: To evaluate rates of cesarean deliveries and identify barriers to this mode of delivery in low-income countries. SEARCH STRATEGY: A review of Medline and PubMed was performed to identify reports published in English or French using the keywords "cesarean section," "maternal mortality," and "developing countries." SELECTION CRITERIA: Studies investigating the obstacles to cesarean delivery and plans to overcome them in low-income countries were included. DATA COLLECTION AND ANALYSIS: Data from included studies were extracted and analyzed. MAIN RESULTS: Studies from 16 countries in Sub-Saharan Africa were included. The average rate of cesarean delivery was 3.6% (range 1.5%-7.1%). The rate was negatively correlated with the maternal mortality ratio (r=-0.63; P=0.005), neonatal mortality rate (r=-0.81; P<0.001), and infant mortality rate (r=-0.80; P<0.001). Major barriers to achieving higher rates of cesarean deliveries include poverty, limited access to healthcare services, and a shortage of skilled providers. CONCLUSIONS: Maternal and infant mortality rates could be lowered by increasing access to cesarean delivery. Additional education of patients and providers, establishment of more heath facilities, and governmental support of obstetric care could help to reach this goal. PMID- 26115792 TI - Effects of alloying on oxidation and dissolution corrosion of the surface of gamma-Fe(111): a DFT study. AB - Effects of alloying elements in popular steels on the oxidation and dissolution corrosion of the surface of gamma-Fe(111) have been investigated by performing density functional theory calculations within the local density approximation. First, the segregation of alloying atoms as well as preferential adsorption sites for oxygen and water were carefully examined, and it was found that all of the alloying elements considered had a tendency to segregate to the surface, and that the most preferred adsorption sites were the hexagonal closed packed (hcp) site and the top site for oxygen and water, respectively. The adsorption energies that characterized the tendency for oxygen or water to be adsorbed on the alloy surface showed that all ten alloying elements (especially Cr, Si, and Cu) were able to inhibit the adsorption of oxygen, and that all of the alloying elements except for Nb, Mo, and Ti inhibited water adsorption. The electrode potentials, which indicate the electrochemical stabilities of the surfaces of the alloys, suggested that all of these alloying elements (especially Cr, Mo, and Si) were able to suppress the adsorption of oxygen and water on the investigated surfaces, except for Nb and Ti in the case of water adsorption. Density of states analysis further indicated that all ten alloying elements (especially Cr, Si, Mo, and Cu) enhanced the corrosion resistance of the fcc Fe substrate, except for Nb and Ti with respect to dissolution corrosion. PMID- 26115790 TI - Anhedonia, Reduced Cocaine Reward, and Dopamine Dysfunction in a Rat Model of Posttraumatic Stress Disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) co-occurs with substance use disorders at high rates, but the neurobiological basis of this relationship is largely unknown. PTSD and drug addiction each involve dysregulation of brain reward circuitry; therefore, the identification of pathology of the mesolimbic dopamine system may aid in understanding their functional relationship. Dopamine reward dysfunction also may be relevant to the mechanisms underlying the PTSD symptoms of anhedonia and emotional numbing. METHODS: Single-prolonged stress (SPS) was used as a rat model of PTSD, and a series of behavioral and neuropharmacologic assays were applied to assess the impact of SPS on reward, cocaine intake, and components of the striatal dopamine system. RESULTS: Exposure to SPS increased anhedonia-like behaviors and decreased the rewarding properties of cocaine compared with control handling. Altered cocaine intake during extended access self-administration sessions was observed in rats exposed to SPS, further suggesting a difference in the reinforcing properties of cocaine following severe stress. SPS reduced tissue content of dopamine and its metabolites in the striatum, as well as altered striatal dopamine transporter and D2, but not D1, receptor densities. CONCLUSIONS: These results support a role for altered dopaminergic transmission in reduced reward function in PTSD. Pathology of the dopamine system and the degradation of reward processes may contribute to PTSD symptomology and have implications for co-occurring psychiatric disorders such as substance abuse or depression. PMID- 26115793 TI - Spanish-Portuguese consensus statement on use of daylight-mediated photodynamic therapy with methyl aminolevulinate in the treatment of actinic keratosis. AB - INTRODUCTION: Daylight-mediated photodynamic therapy (PDT) is a new type of PDT that is as effective as conventional PDT in grade 1 and 2 actinic keratosis but with fewer adverse effects, resulting in greater efficiency. The climatic conditions in the Iberian Peninsula require an appropriately adapted consensus protocol. OBJECTIVE: We describe a protocol for the treatment of grade 1 and 2 actinic keratosis with daylight-mediated PDT and methyl aminolevulinate (MAL) adapted to the epidemiological and clinical characteristics of Spanish and Portuguese patients and the climatic conditions of both countries. METHODS: Twelve dermatologists from different parts of Spain and Portugal with experience in the treatment of actinic keratosis with PDT convened to draft a consensus statement for daylight-mediated PDT with MAL in these countries. Based on a literature review and their own clinical experience, the group developed a recommended protocol. RESULTS: According to the recommendations adopted, patients with multiple grade 1 and 2 lesions, particularly those at risk of developing cancer, are candidates for this type of therapy. Daylight-mediated PDT can be administered throughout the year, although it is not indicated at temperatures below 10 degrees C or at excessively high temperatures. Likewise, therapy should not be administered when it is raining, snowing, or foggy. The procedure is simple, requiring application of a sunscreen with a protection factor of at least 30 based exclusively on organic filters, appropriate preparation of the lesions, application of MAL without occlusion, and activation in daylight for 2hours. CONCLUSION: This consensus statement represents a practical and detailed guideline to achieve maximum effectiveness of daylight-mediated PDT with MAL in Spain and Portugal with minimal adverse effects. PMID- 26115794 TI - Census of Centers That Perform Mohs' Micrographic Surgery in Spain and Description of Their Activity: A Feasibility Study for the Mohs' Micrographic Surgery Registry of the Foundation of the Spanish Academy of Dermatology and Venereology. PMID- 26115795 TI - Bevacizumab in newly diagnosed ovarian cancer. PMID- 26115796 TI - Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. AB - BACKGROUND: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. METHODS: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. FINDINGS: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0.57, 95% CI 0.45 0.73; p<0.0001) and those assigned to pembrolizumab 10 mg/kg (0.50, 0.39-0.64; p<0.0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. INTERPRETATION: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. FUNDING: Merck Sharp & Dohme. PMID- 26115798 TI - The place of PD-1 inhibitors in melanoma management. PMID- 26115799 TI - [Radiological evaluation of congenital tumors]. AB - In this article, we consider tumors that are diagnosed during pregnancy or in the first three months of life. This is a heterogeneous group of neoplasms with special biological and epidemiological characteristics that differentiate them from tumors arising in children or adults. In the last two decades, the prenatal detection of congenital tumors has increased due to the generalized use of prenatal sonographic screening. Advances in imaging techniques, especially in fetal magnetic resonance imaging, have enabled improvements in the diagnosis, follow-up, clinical management, and perinatal treatment of these tumors. This image-based review of the most common congenital tumors describes their histologic types, locations, and characteristics on the different imaging techniques used. PMID- 26115800 TI - Cytotoxicity of anthraquinones from the roots of Pentas schimperi towards multi factorial drug-resistant cancer cells. AB - INTRODUCTION: Multidrug resistance in cancer represents a major problem in chemotherapy. The present study was designed to assess the cytotoxicity of anthraquinones from Pentas schimperi, namely damnacanthal (1), damnacanthol (2), 3-hydroxy-2-hydroxymethyl anthraquinone (3) and schimperiquinone B (4) against nine drug-sensitive and multidrug resistant (MDR) cancer cell lines. METHODS: The resazurin reduction assay was used to evaluate the cytotoxicity of the above compounds, whilst caspase-Glo assay was used to detect the activation of caspases enzymes by compounds 1 and 2. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species were all analyzed via flow cytometry. RESULTS: Anthraquinones 1 and 2 displayed cytotoxic effects with IC50 values below 81 MUM on all the nine tested cancer cell lines whilst 3 and 4 displayed selective activities. The recorded IC50 values for compounds 1 and 2 ranged from 3.12 MUM and 12.18 MUM (towards leukemia CCRF-CEM cells) and from 30.32 MUM and 80.11 MUM (towards gliobastoma U87MG.DeltaEGFR cells) respectively, and from 0.20 MUM (against CCRF-CEM cells) to 195.12 MUM (against CEM/ADR5000 cells) for doxorubicin. Compounds 1 and 2 induced apoptosis in CCRF-CEM leukemia cells, mediated by the disruption of the MMP and increase in ROS production. CONCLUSIONS: Anthraquinones from Pentas schimperi and mostly 1 and 2 are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug resistant cancers. PMID- 26115801 TI - The Utility of Dual-Energy Computed Tomographic Angiography for the Evaluation of Brain Aneurysms After Surgical Clipping: A Prospective Study. AB - OBJECTIVE: The purpose of this prospective study was to compare a novel dual energy computed tomographic angiography (DECTA) method for postoperative assessment of clipped brain aneurysms to detect aneurysm remnants and parent artery patency, with catheter-based digital subtraction angiography (DSA). METHODS: Patients who underwent microsurgical cerebral aneurysm repair were prospectively evaluated after surgery by both DECTA and conventional DSA. CTA was performed using a novel dual-energy method with single source and fast kilovoltage switching (Gemstone Spectral Imaging [GSI]). DSA was performed using biplanar cerebral angiography. An experienced neuroradiologist and a neurosurgeon, both blinded to the original radiologic results, reviewed the images. RESULTS: On DSA, 8 of 15 aneurysms (53%) had a remnant after clipping. All of these remnants were <2 mm except for 1. The only residual aneurysm >2 mm was clearly detected by GSI CTA. Of those 7 DSA-confirmed <2-mm remnants, 5 were detected by GSI CTA. Metal artifacts compromised the image quality in 2 patients. The sensitivity and specificity of GSI CTA for remnant aneurysm <2-mm detection in single clip-treated patients were 100%. In all patients, these were 71.4 % and 100%, respectively. GSI CTA was 100% sensitive and 77% specific to detect parent vessel compromise, with associated positive and negative predictive values of 60% and 100%, respectively. CONCLUSIONS: DECTA is a promising noninvasive alternative to conventional catheter-based angiography for identification of aneurysm remnants and assessment of adjacent arteries after surgical clipping of brain aneurysms treated by 2 or fewer clips. It allows for a more rapid image acquisition than DSA, is more cost effective, and is widely available at clinical centers. PMID- 26115802 TI - Aqueduct Stent Placement: Indications, Technique, and Clinical Experience. AB - OBJECTIVE: Complicated hydrocephalus, such as trapped fourth ventricle, is challenging. Aqueduct stent placement is a possible alternative to the conventional multiple shunts approach. This article discusses the indications, techniques, and clinical experiences of aqueduct stent placement. METHODS: We retrospectively analyzed a series of 10 consecutive patients with hydrocephalus and had aqueduct stent placement between February 2009 and May 2014. The clinical and imaging data were collected and the indications, technique, and clinical experience of aqueduct stent placement were analyzed and discussed. RESULTS: Among the 10 patients (mean age, 38 years; range, 5 months-69 years), 8 patients harbored an obstructive hydrocephalus caused by aqueductal obstruction. The underlying pathology consisted of intraventricular tumor in 3 patients, intraventricular cysticercosis in 2, and membranous or inflammatory obstruction in 3 patients. Two patients presented with trapped fourth ventricle, which resulted from Dandy-Walker malformation and shunt placement, respectively. Aqueduct stents were placed endoscopically in 8 patients, whereas the other 2 were placed microscopically. There were no deaths due to aqueduct stent placement. Postoperatively, all of the patients showed improvement or resolution of their symptoms. After an average follow-up period of 27 months (range, 1-51 months), recurrence of aqueductal obstruction has not been observed. In 1 patient, there was a complication of transient oculomotor paralysis after aqueduct stent placement. A stent migration was observed in 1 patient after remaining stable for 4 years. CONCLUSIONS: Aqueduct stent placement is technically feasible and can be useful in selected patients either with endoscopy or open surgery. PMID- 26115803 TI - Prognostic Factors in the Operative Management of Sacral Chordomas. AB - OBJECTIVE: Surgical resection of sacral chordomas offers the best long-term prognosis but has high rates of local recurrence, metastases, and mortality. Most prognostic studies are limited by low patient numbers, variation in treatment, follow-up, and prognostic variables studied. The objective of this study was to identify factors associated with recurrence, metastasis, and survival. METHODS: Retrospective review of 58 patients undergoing sacrectomy for chordoma with a mean age of 63 years (range: 41-80 years) and a mean follow-up of 45.3 months (range: 2-144 months). Data on prognostic variables and outcomes were collected. Forty-two patients underwent a combined anterior and posterior approach and 16 underwent a posterior-only approach. RESULTS: Twenty-six patients (44.8%) died during follow-up. Kaplan-Meier estimates for 5- and 10-year survival were 62% and 26%, respectively. Local recurrence occurred in 32 patients (51.7%) and metastases in 19 (32.7%). Adequacy of resection margins was the most important predictor of disease recurrence, metastases, and survival. Tumors >8 cm were associated with significantly increased risk of metastases and reduced survival (P < 0.05). Dedifferentiated disease and infiltration of the sacroiliac joints and/or adjacent musculature were also associated with reduced survival. Median survival was 23 months for patients with gluteus maximus invasion, 66 months for gluteus maximus and piriformis invasion, 67 months for piriformis invasion, and 90 months for patients with no muscle invasion. CONCLUSIONS: Patients with inadequate resection margins, tumors >8 cm, sacroiliac joint and/or musculature infiltration, and dedifferentiated disease have significantly worse oncologic outcomes. Involvement of gluteus maximus alone confers a higher risk of metastases and local recurrence than involvement of piriformis and gluteus maximus, or piriformis alone. PMID- 26115804 TI - Improvement of Long-term Results with Neoadjuvant Chemotherapy and Radiotherapy for Central Nervous System Germinoma. AB - OBJECTIVE: To evaluate the role of neoadjuvant chemotherapy and radiotherapy in the treatment of central nervous system germinomas in 38 patients who received definitive treatment and were followed-up >5 years between 1980 and 2009. METHODS: The median age at diagnosis and follow-up period were 16.5 years and 128.3 months, respectively. Treatment was irradiation alone or adjuvant platinum based chemotherapy followed by reduced-dose local irradiation. Seven patients progressed at 12.9-133.9 months and 1 died of disease 89.3 months after therapy initiation. RESULTS: The treatment strategies were divided into 3 groups: group A (1980-1988, n = 5), whole brain with local irradiation; group B (1989-2002, n = 16), chemotherapy with or without reduced irradiation dose; and group C (2003 2009, n = 17): neoadjuvant chemotherapy (3 courses) followed by 30.6 Gy of whole ventricle irradiation for patients with localized complete response, and additional local boost of 19.8 Gy for others. There were 7 recurrent cases, all in group B. The progression-free survival was significantly longer in groups A and C versus group B (P < 0.001). Decreased Karnofsky performance status was observed in 2 (40%), 6 (37.5%), and 0 cases in groups A-C, respectively. The main reasons for the good results in group C might be the neoadjuvant chemotherapy with whole ventricle radiotherapy and introduction of neuroendoscopy, especially for pineal lesions, resulting in a substantial reduction of time from the diagnosis to first treatment. CONCLUSIONS: Chemotherapy followed by whole ventricle radiotherapy, with or without local boost, and with use of neuroendoscopy results in good disease control without late complications in patients with germinomas. PMID- 26115805 TI - Experimental left pneumonectomy in pigs: procedure and management. AB - BACKGROUND: Because there is no detailed description of procedures and perioperative management of major pulmonary resections in swine, we reviewed our experience to delineate the most effective practice in performing left pneumonectomy. MATERIALS AND METHODS: Analysis of 11 consecutive left pneumonectomies. Animal data, operative reports, anesthesia records, and perioperative facts were evaluated. Follow-up information until postoperative day 60, methods of care-taking, therapy administration, and all the stabling aspects were systematically assessed. The investigation was aimed at highlighting those procedural steps or details which make the difference in optimizing the available resources (animals, instruments, and personnel). No statistical analysis was performed considering data characteristics and the descriptive nature of information. RESULTS: Surgery requires a median time of 2 h and 16 min; two operators and one anesthesiologist represent the basic team. Circulators' number depends on goals to accomplish. The most straightforward procedure requires careful dissection of the pulmonary ligament (limited view), pulmonary veins (low variability), pulmonary artery (delicate), and finally bronchus (no variability observed). The key factors for good anesthesia management have been identified: sedation by caregivers, preoxygenation before induction of general anesthesia, high respiratory rates with low tidal volume after pneumonectomy, and noninvasive ventilation after extubation. Antibiotic prophylaxis has been performed. Postoperative care must be continuous until animals are able to stand up, afterward "preventive noncurative," and always animal friendly. Ideas for minimally stressful therapy administration are helpful. CONCLUSIONS: After the delineation of this methodology, the compliance to a routine practice allowed us to reduce time, stress, and cost; quality and quantity of possible research increased. PMID- 26115806 TI - Long-term therapy with sorafenib is associated with pancreatic atrophy. AB - BACKGROUND: Although the short-term adverse effects of sorafenib are well known, few data exist on long-term toxicity. The objective of the present study was to investigate the prevalence of pancreatic atrophy among a cohort of patients with hepatocellular carcinoma (HCC) who were treated with sorafenib for >=2 y. METHODS: Between March 2007 and December 2013, 31 patients with HCC who were treated with sorafenib for >=2 y were identified. The effect of pancreatic atrophy and enhancement on incidence of adverse events, tumor response, and overall survival (OS) were assessed. RESULTS: Thirty-one patients with HCC were treated with sorafenib for >=2 y and met inclusion criteria; 11 patients (35.5%) were Barcelona-clinic liver cancer stage B, whereas 20 patients (64.5%) were Barcelona-clinic liver cancer stage C. Median duration of treatment with sorafenib was 35.2 mo. Pancreatic atrophy and a decrease in pancreatic enhancement occurred in 24 patients (77.4%) and 15 patients (48.4%), respectively. On the basis of the modified response evaluation criteria in solid tumors, four patients (12.9%) had a complete response, 10 patients (32.3%) had a partial response, and 17 patients (54.8%) had stable disease. Patients treated with sorafenib with pancreatic atrophy had a median OS of 49.4 mo (95% confidence interval, 41.2-57.5 mo) compared with 31.2 mo (95% confidence interval, 25.7-36.7 mo) among patients who did not develop pancreatic atrophy (P = 0.009). In contrast, survival was not associated with decreased versus normal enhancement of the pancreas (OS, 47.7 mo versus 41.7 mo, respectively; P = 0.739). CONCLUSIONS: Pancreatic atrophy occurred in many HCC patients after 2 y of treatment with sorafenib. Patients who experienced pancreatic atrophy had a better tumor response and OS. PMID- 26115807 TI - Intraoperative fluorescence image-guided pulmonary segmentectomy. AB - BACKGROUND: The intraoperative color and fluorescence-merged imaging system (ICFIS) is a new technology that may aid the demarcation of intersegmental borders during pulmonary segmentectomy. This study was performed to validate, for the first time, image-guided segmentectomy using ICFIS and to find the optimal dosage of fluorescent dye to ensure safe and sustained imaging during surgery. METHODS: Nine rabbits were subjected to pulmonary segmentectomy. These constituted three groups of three rabbits each. After ligation of the segmental pulmonary artery supplying the targeted segment, the rabbits were injected intravenously with indocyanine green (ICG) at a concentration of 0.3, 0.6, or 3.0 mg/kg, depending on their group assignment. The optimal dose was determined from the rabbit study and then used to guide ICFIS during pulmonary segmentectomy in five pigs. RESULTS: The fluorescent signal contrast ratios of the targeted area to the normal lung using ICG concentrations of 0.3, 0.6, or 3.0 mg/kg were 1.9 +/ 0.25, 2.0 +/- 0.17, and 2.1 +/- 0.06, respectively. The mean ICG washout times were 1, 3, and 6 min, respectively. Proceeding with an ICG concentration of 0.6 mg/kg, the mean washout time was found to be longer in pigs (15 min). This provided adequate time for successful ICFIS-guided segmentectomy in all five pigs, without the requirement for additional procedures for intersegmental plane demarcation. CONCLUSIONS: ICG image-guided segmentectomy using ICFIS enabled immediate visualization of the intersegmental planes. The washout time using the ICG dose determined in this study was long enough to ensure that visualization was sustained throughout the surgery. PMID- 26115808 TI - Benchmarking statewide trauma mortality using Agency for Healthcare Research and Quality's patient safety indicators. AB - BACKGROUND: Improving clinical outcomes of trauma patients is a challenging problem at a statewide level, particularly if data from the state's registry are not publicly available. Promotion of optimal care throughout the state is not possible unless clinical benchmarks are available for comparison. Using publicly available administrative data from the State Department of Health and the Agency for Healthcare Research and Quality (AHRQ) patient safety indicators (PSIs), we sought to create a statewide method for benchmarking trauma mortality and at the same time also identifying a pattern of unique complications that have an independent influence on mortality. METHODS: Data for this study were obtained from State of Florida Agency for Health Care Administration. Adult trauma patients were identified as having International Classification of Disease ninth edition codes defined by the state. Multivariate logistic regression was used to create a predictive inpatient expected mortality model. The expected value of PSIs was created using the multivariate model and their beta coefficients provided by the AHRQ. Case-mix adjusted mortality results were reported as observed to expected (O/E) ratios to examine mortality, PSIs, failure to prevent complications, and failure to rescue from death. RESULTS: There were 50,596 trauma patients evaluated during the study period. The overall fit of the expected mortality model was very strong at a c-statistic of 0.93. Twelve of 25 trauma centers had O/E ratios <1 or better than expected. Nine statewide PSIs had failure to prevent O/E ratios higher than expected. Five statewide PSIs had failure to rescue O/E ratios higher than expected. The PSI that had the strongest influence on trauma mortality for the state was PSI no. 9 or perioperative hemorrhage or hematoma. Mortality could be further substratified by PSI complications at the hospital level. CONCLUSIONS: AHRQ PSIs can have an integral role in an adjusted benchmarking method that screens at risk trauma centers in the state for higher than expected mortality. Stratifying mortality based on failure to prevent PSIs may identify areas of needed improvement at a statewide level. PMID- 26115809 TI - Endovascular management of traumatic peripheral arterial injuries. AB - BACKGROUND: Traumatic injuries to peripheral arterial vessels are increasingly managed with endovascular techniques. Early small series have suggested that endovascular therapy is feasible and decreases operative blood loss, but these data are limited. The purpose of this study was to evaluate the feasibility and outcomes of endovascular management of nonaortic arterial trauma. MATERIALS AND METHODS: We reviewed records of traumatic nonaortic arterial injuries presenting at an urban level 1 trauma center from December 2009-July 2013. Patients undergoing treatment in interventional radiology and patients whose injuries occurred >72 h before presentation were excluded. Demographics, indicators of injury severity, operative blood loss, transfusion requirements, and clinical outcome were compared between patients undergoing endovascular and open management using appropriate inferential statistics. RESULTS: During the study period, 17 patients underwent endovascular interventions and 20 had open surgery. There were 19 upper extremity and/or thoracic outlet arterial injuries, 15 lower extremity injuries and 11 pelvic injuries. Endovascular cases were completed using a vascular imaging C-arm in a standard operating room. Estimated blood loss during the primary procedure was significantly lower with endovascular management (150 versus 825 cc, P < 0.001). No differences were observed between cohorts in age, injury severity score, intensive care unit length of stay, arterial pH, transfusion requirements, inpatient complication rate, or mortality. CONCLUSIONS: Our experience with endovascular management demonstrates its feasibility with commonly available tools. Operative blood loss may be significantly decreased using endovascular techniques. Further study is needed to refine patient selection criteria and to define long-term outcomes. PMID- 26115810 TI - Intraoperative radiocolloid injection for sentinel node biopsy postneoadjuvant chemotherapy. AB - BACKGROUND: This study sought to determine significance of radiocolloid injection timing for sentinel node biopsy (SNB) after neoadjuvant chemotherapy (NAC). MATERIAL AND METHODS: A retrospective comparison of intraoperative (IRCI) and preoperative (PRCI) radiocolloid injection for SNB was performed in breast cancer patients who had completed NAC. The sentinel node identification rate (SNIDR) was tested for noninferiority by a two-proportion z-test. The differences between clinical demographics, pathologic demographics, and SNIDR were evaluated by Fisher exact test. The difference in the number of sentinel nodes removed was analyzed by two-sample t-test. RESULTS: In the 6-y study period, 120 SNB were performed after NAC: 84 received PRCI and 36 received IRCI. The two groups were similar except there were fewer clinical T2 and more clinical T3 and T4 with IRCI (P = 0.0008). The SNIDR was 92.9% with PRCI and 80.6% with IRCI. By two proportion z-test, IRCI was not "noninferior" (P = 0.5179). By Fisher exact test, the SNIDR of the two groups did not differ. The SNIDR differs only in patients who experience T downstaging (100% versus 80%, P = 0.0173). The mean number of lymph nodes removed was higher with IRCI: 3.38 versus 2.49 nodes (P = 0.0068). There were more positive SNB with IRCI: 32.1% versus 55.2%, (P = 0.0432). The incidence of nontherapeutic axillary dissection was similar between the two groups (3.6% for PRCI versus 5.6% for IRCI). CONCLUSIONS: IRCI for SNB after NAC may be inferior to PRCI. PMID- 26115811 TI - Differential impact of obesity and diabetes mellitus on survival after liver resection for colorectal cancer metastases. AB - BACKGROUND: Data on the potential effect of obesity and diabetes mellitus on survival after liver resection due to colorectal cancer (CRC) metastases are very limited. METHODS: Patients undergoing liver resection for CRC metastases in a European institution in 2004-2011 were retrospectively enrolled. Relevant data, such as body mass index, extent of resection, chemotherapy, and perioperative outcome, were collected from medical records. The relation of obesity and diabetes mellitus with overall and disease-free survival was assessed using adjusted Cox models. RESULTS: Thirty of 207 patients (14.4%) included in the study were obese (BMI >=30 kg/m(2)) and 25 (12%) had diabetes mellitus. Major hepatectomy was performed in 46%. Although both obese patients and those with diabetes had higher American Society of Anesthesiologist scores (P < 0.05 for both), neither obesity nor diabetes was significantly related to primary tumor characteristics, liver metastasis features, extent or radicality of resection, extrahepatic disease at hepatectomy, preoperative or postoperative oncologic therapy, or perioperative outcome (P > 0.05 for all). Patients were followed up for a median of 39 mo posthepatectomy (interquartile range, 13-56 mo). After adjustment for confounders, obesity was an independent predictor of improved (hazard ratio, 0.305, 95% confidence interval, 0.103-0.902) and diabetes of worse overall survival (hazard ratio, 3.298, 95% confidence interval, 1.306-8.330). Obese patients with diabetes had also worse disease-free survival compared with the rest of the cohort (P < 0.05). CONCLUSIONS: After hepatectomy for CRC metastases, obesity does not seem to be associated to poor outcome while diabetes mellitus has a negative impact on prognosis. PMID- 26115812 TI - The University of the West Indies Clinical Epidemiology Unit: collaborating to improve health. PMID- 26115813 TI - Good reliability and validity for a new utility instrument measuring the birth experience, the Labor and Delivery Index. AB - OBJECTIVES: To validate the Labor and Delivery Index (LADY-X), a new delivery specific utility measure. STUDY DESIGN AND SETTING: In a test-retest design, women were surveyed online, 6 to 8 weeks postpartum and again 1 to 2 weeks later. For reliability testing, we assessed the standard error of measurement (S.E.M.) and the intraclass correlation coefficient (ICC). For construct validity, we tested hypotheses on the association with comparison instruments (Mackey Childbirth Satisfaction Rating Scale and Wijma Delivery Experience Questionnaire), both on domain and total score levels. We assessed known-group differences using eight obstetrical indicators: method and place of birth, induction, transfer, control over pain medication, complications concerning mother and child, and experienced control. RESULTS: The questionnaire was completed by 308 women, 257 (83%) completed the retest. The distribution of LADY X scores was skewed. The reliability was good, as the ICC exceeded 0.80 and the S.E.M. was 0.76. Requirements for good construct validity were fulfilled: all hypotheses for convergent and divergent validity were confirmed, and six of eight hypotheses for known-group differences were confirmed as all differences were statistically significant (P-values: <0.001-0.023), but for two tests, difference scores did not exceed the S.E.M. CONCLUSION: The LADY-X demonstrates good reliability and construct validity. Despite its skewed distribution, the LADY-X can discriminate between groups. With the preference weights available, the LADY X might fulfill the need for a utility measure for cost-effectiveness studies for perinatal care interventions. PMID- 26115797 TI - Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. AB - BACKGROUND: The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. METHODS: ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I-IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb-IV), with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m(2) of body surface area) or the same chemotherapy regimen plus bevacizumab 7.5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. FINDINGS: Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48.9 months (IQR 26.6-56.2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44.6 months [95% CI 43.2 45.9] in the standard chemotherapy group vs 45.5 months [44.2-46.7] in the bevacizumab group; log-rank p=0.85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34.5 months [95% CI 32.0-37.0] with standard chemotherapy vs 39.3 months [37.0-41.7] with bevacizumab; log-rank p=0.03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49.7 months [95% CI 48.3-51.1]) in the standard chemotherapy group vs 48.4 months [47.0-49.9] in the bevacizumab group; p=0.20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. INTERPRETATION: Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. FUNDING: The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche. PMID- 26115814 TI - Mysterious hexagonal pyramids on the surface of Pyrobaculum cells. AB - In attempts to induce putative temperate viruses, we UV-irradiated cells of the hyperthermophilic archaeon Pyrobaculum oguniense. Virus replication could not be detected; however, we observed the development of pyramidal structures with 6 fold symmetry on the cell surface. The hexagonal basis of the pyramids was continuous with the cellular cytoplasmic membrane and apparently grew via the gradual expansion of the 6 triangular lateral faces, ultimately protruding through the S-layer. When the base of these isosceles triangles reached approximately 200 nm in length, the pyramids opened like flower petals. The origin and function of these mysterious nanostructures remain unknown. PMID- 26115816 TI - Expectation conversations about the very predictable events in advanced dementia. PMID- 26115815 TI - Novel endomorphin-1 analogs with C-terminal oligoarginine-conjugation display systemic antinociceptive activity with less gastrointestinal side effects. AB - In recent study, in order to improve the bioavailability of endomorphin-1 (EM-1), we designed and synthesized a series of novel EM-1 analogs by replacement of L Pro(2) by beta-Pro, D-Ala or Sar, together with C-terminal oligoarginine conjugation. Our results indicated that the introduction of D-Ala and beta-Pro in position 2, along with oligoarginine-conjugation, didn't significantly decrease the MU-affinity and in vitro bioactivity, and the enhancement of arginine residues did not markedly influence the MU-affinity of these analogs. All analogs displayed a significant enhancement of stability, which may be due to increased resistance to proline-specific enzymatic degradation. Moreover, following intracerebroventricular (i.c.v.) administration, analogs 1, 2, 4 and 5 produced significant antinociception and increased duration of action, with the ED50 values being about 1.8- to 4.2-fold less potent than that of EM-1. In addition, our results indicated that no significant antinociceptive activity of EM-1 was seen following subcutaneous (s.c.) injection, whereas analogs 1, 2, 4 and 5 with equimolar dose induced significant and prolonged antinociception by an opioid and central mechanism. Herein, we further examined the gastrointestinal transit and colonic propulsive latencies of EM-1 and its four analogs administered centrally and peripherally. I.c.v. administration of EM-1 and analogs 1, 2, 4 and 5 significantly delayed gastrointestinal transit and colonic bead propulsion in mice, but the inhibitory effects induced by these analogs were largely attenuated. It is noteworthy that no significant gastrointestinal side effects induced by these four analogs were observed after s.c. administration. Our results demonstrated that combined modifications of EM-1 with unnatural amino acid substitutions and oligoarginine-conjugation gave an efficient strategy to improve the analgesic profile of EM-1 analogs but with less gastrointestinal side effects when administered peripherally. PMID- 26115817 TI - Effectiveness of Robot Paro in Intramural Psychogeriatric Care: A Multicenter Quasi-Experimental Study. AB - BACKGROUND: Together with care professionals, specific psychogeriatric care applications were developed for the seal robot Paro. OBJECTIVES: This study aims to evaluate the outcomes of the developed Paro interventions, applying the robot in psychogeriatric care. DESIGN: A multicenter quasi-experimental time series ABAB study (n = 91) with within-subject comparison was conducted to assess both the short-term effects of the Paro interventions for therapeutic applications, and the facilitation of daily care activities by care providers. SETTING: Small scale care units (8-10 residents each), spread over 6 different locations, in 3 Dutch care institutions for intramural psychogeriatric care. PARTICIPANTS: A total of 91 patients with dementia, in all stages of dementia. INTERVENTION: Two user-centered intervention types were applied, one for therapeutic purposes and one for the facilitation of daily care activities. MEASUREMENTS: Effectiveness was measured with a goal attainment scale (IPPA) and a mood scale (Coop/Wonca), by means of a registration form. RESULTS: A total of 106 user-specific interventions were defined for 91 participants; 71 participants completed the study, 14 were men and 57 were women. All interventions combined show a significant effect (P < .001). CONCLUSION: Paro should be seen as a tool for care staff and not as a replacement of care. Successful implementation of Paro in daily intramural psychogeriatric care practice can increase the quality of care and the quality of life for the elderly. PMID- 26115818 TI - Response to the Letter to the Editor by Aaron Spital, "Is This Elderly Patient Dehydrated? Diagnostic Accuracy of Hydration Assessment Using Physical Signs, Urine, and Saliva Markers". PMID- 26115819 TI - Syncope: Definition, Epidemiology, and Classification. AB - Major progress has been made during the last 2 decades on the different aspects of syncope. Most of the progress is the consequence of the acceptance of a clear definition of what is and what is not syncope. However, although this definition is widely accepted by physicians who are "specialists" in syncope, it still remains unknown or challenged by many other physicians. This lack of awareness leads to multiple useless, costly, and painful examinations. The next step is therefore to disseminate the knowledge of this definition and the strategy for diagnosis of syncope. PMID- 26115820 TI - Initial Clinical Evaluation. AB - The initial evaluation of patients with transient loss of consciousness (LOC) comprises a detailed medical history, physical examination, and 12-lead electrocardiogram. Because there are many causes of syncopal and nonsyncopal LOC, an adequate method of taking the clinical history, which is the cornerstone of diagnosing patients with transient LOC, should be used. PMID- 26115821 TI - The Value of Tilt Testing and Autonomic Nervous System Assessment. AB - Tilt testing for the investigation of syncope was introduced in 1986. Since then, it has propagated worldwide as a routine test to determine the cause of transient loss of consciousness when that event has not been diagnosed by history, including that of a witness, physical examination, supine and erect blood pressures, and 12-lead electrocardiogram. Tilt testing allows reproduction of syncope with monitoring of physiologic parameters including electrocardiogram, beat-to-beat blood pressure, electroencephalogram, and middle cerebral artery blood-flow velocity. As a result, much has been learned about syncope. PMID- 26115822 TI - Value of Ambulatory Electrocardiographic Monitoring in Syncope. AB - Implantable loop recorders (ILRs) continuously monitor electrocardiographic signals and perform real-time analysis of heart rhythm for up to 36 months. ILRs are used to evaluate transitory loss of consciousness from possible arrhythmic origin, particularly unexplained syncope, and to evaluate difficult cases of epilepsy and unexplained falls, although current indications for their application in these areas are less clearly defined. This article analyzes the current indications for ILRs according the European Society of Cardiology guidelines on the management of syncope and the European Heart Rhythm Association guidelines on the use of implantable and external electrocardiogram loop recorders, and their limitations. PMID- 26115823 TI - Value of EP Study and Other Cardiac Investigations. AB - With the advent of implantable loop recorders capable of prolonged electrocardiographic monitoring, and following studies demonstrating the benefit of implantable cardioverter-defibrillator therapy in subgroups of patients with structural heart disease and depressed left ventricular function, the role of invasive cardiac electrophysiologic (EP) studies in patients with unexplained syncope has been substantially reduced. Nonetheless, in select high-risk patients presenting with unexplained syncope, EP studies still play an important role in identifying a diagnosis in these patients and assessing long-term risk of mortality. PMID- 26115824 TI - How to Differentiate Syncope from Seizure. AB - Convulsive syncope is a common cause of misdiagnosis in patients who present with a transient loss of consciousness. This misdiagnosis contributes significantly to the numbers of patients with a questionable diagnosis of epilepsy, and to those with apparently drug-resistant epilepsy. The most important step to an accurate diagnosis is a fastidious history. Inducing syncope with tilt table testing and documenting heart rate changes during events with implantable loop recorders have proved to be useful. These suggest the need for closer and ongoing collaboration among neurologists and cardiologists to provide optimal care for patients with the diagnostic dilemma of syncope or epileptic seizures. PMID- 26115825 TI - Risk Stratification of Patients Presenting with Transient Loss of Consciousness. AB - Important goals in the initial evaluation of patients with transient loss of consciousness include determining whether the episode was syncope and choosing the venue for subsequent care. Patients who have high short-term risk of adverse outcomes need prompt hospitalization for diagnosis and/or treatment, whereas others may be safely referred for outpatient evaluation. This article summarizes the most important available risk assessment studies and points out key differences among the existing recommendations. Current risk stratification methods cannot replace critical assessment by an experienced physician, but they do provide much needed guidance and offer direction for future risk stratification consensus development. PMID- 26115826 TI - Syncope in Children and Adolescents. AB - Most strategies for managing syncope in children reflect data from studies involving the adult population. In the future, there will be a great need for studies in children and adolescents suffering from recurrent syncope. To date, there has been no Food and Drug Administration-approved therapy for neurocardiogenic syncope (NCS), the most common cause of syncope in both adults and children. None of the clinical trials of pharmacotherapy in NCS has shown benefit over placebo. NCS should be considered a chronic condition, and the aim of the therapy should be to decrease recurrence of syncope rather than to completely eliminate it. PMID- 26115827 TI - Syncope in the Older Person. AB - Syncope in the older person carries a high morbidity, mortality, and health economic burden. While neurally mediated disorders and orthostatic hypotension account for the majority of syncopal episodes in this age group, around a third of causes are cardiac, predominantly arrhythmic. Clinicians need to be aware of the management of potential comorbid issues such as osteoporosis and cognitive impairment and if not in a position to act on them, ensure that appropriate specialist help is sought. Further work is needed to understand the pathophysiology and hence the management of syncope in the older patient, with ongoing studies helping to tease out some of the treatment controversies. PMID- 26115828 TI - Syncope as a Warning Symptom of Sudden Cardiac Death in Athletes. AB - Clinical evaluation of syncope in the athlete remains a challenge. Although benign mechanisms predominate, syncope may be arrhythmic and precede SCD. Exercise-induced syncope should be regarded as an important alarming symptom of an underlying cardiac disease predisposing to arrhythmic cardiac arrest. All athletes with syncope require a focused and detailed workup for underlying cardiac causes, either structural or electrical. Major aim is to identify athletes at risk and to protect them from SCD. Athletes with potentially life threatening etiologies of syncope should be restricted from competitive sports. PMID- 26115829 TI - Syncope in Hereditary Arrhythmogenic Syndromes. AB - Since the discovery of the first mutation causing long QT syndrome (LQTS) in 1995, the field of hereditary arrhythmogenic syndromes has expanded greatly. Today, these syndromes include LQTS, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. There is also evidence suggesting that the newly described malignant early repolarization syndrome also has a genetic cause. PMID- 26115830 TI - Syncope and Idiopathic (Paroxysmal) AV Block. AB - Syncope due to idiopathic AV block is characterized by: 1) ECG documentation (usually by means of prolonged ECG monitoring) of paroxysmal complete AV block with one or multiple consecutive pauses, without P-P cycle lengthening or PR interval prolongation, not triggered by atrial or ventricular premature beats nor by rate variations; 2) long history of recurrent syncope without prodromes; 3) absence of cardiac and ECG abnormalities; 4) absence of progression to persistent forms of AV block; 5) efficacy of cardiac pacing therapy. The patients affected by idiopathic AV block have low baseline adenosine plasma level values and show an increased susceptibility to exogenous adenosine. The APL value of the patients with idiopathic AV block is much lower than patients affected by vasovagal syncope who have high adenosine values. PMID- 26115831 TI - Syncope in Patients with Organic Heart Disease. AB - Patients with syncope and organic heart disease remain a small but important subset of those patients who experience transient loss of consciousness. These patients require thoughtful and complete evaluation in an attempt to better understand the mechanism of syncope and its relationship to the underlying disease, and to diagnose and treat both properly. The goal is to reduce the risk of further syncope, to improve long-term outcomes with respect to arrhythmic and total mortality, and to improve patients' quality of life. PMID- 26115832 TI - Syncope and Driving. AB - The occurrence of syncope while driving has obvious implications for personal and public safety. Neurally mediated syncope is the most common type of syncope in general and, thereby, also while driving. The presence of structural heart disease (reduced ejection fraction, previous myocardial infarction, significant congenital heart disease) potentially leads to high risk and should determine driving restrictions pending clarification of underlying heart disease and etiology of syncope. The clinical approach to syncope evaluation and recommendations for driving should not differ, whether or not the syncopal spell occurred while driving. PMID- 26115833 TI - Therapy for Syncope. AB - The diagnostic process in patients with syncope is not always easy and includes a detailed clinical history, physical examination and baseline electrocardiogram; according to the results of these initial approaches, some additional tests must be performed. Using this strategy, the cause of syncope is diagnosed in 60% to 80% of patients; in the remaining patients, risk stratification can be established to identify those patients at risk of having cardiac events or death at midterm follow-up. This article reviews the treatment of patients with syncope according to the different causes. PMID- 26115834 TI - The Role of the Syncope Management Unit. AB - Syncope is a common symptom, experienced by 15% of persons less than 18 years old and up to 23% of elderly nursing home residents, so it is important to consider optimizing strategies for the management of these patients. The strategy selected will inevitably differ from place to place. However, an organized structure offers more cost-effective care. This article discusses possible health care delivery models for syncope management and reviews the current status of the organization of syncope care, to show the value of a multidisciplinary approach to the organized management of patients with syncope. PMID- 26115835 TI - beta-Amyloid binding in elderly subjects with declining or stable episodic memory function measured with PET and [11C]AZD2184. AB - PURPOSE: Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and beta-amyloid using positron emission tomography (PET) and [(11)C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits. METHODS: Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [(11)C]AZD2184. The binding potential BP ND was calculated using linear graphical analysis with the cerebellum as reference region. RESULTS: The binding of [(11)C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP ND was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BP ND were ApoE epsilon4 allele carriers. CONCLUSIONS: We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits. PMID- 26115836 TI - Modulation of L-type Ca2+ channel activity by neuronal nitric oxide synthase and myofilament Ca2+ sensitivity in cardiac myocytes from hypertensive rat. AB - Neuronal nitric oxide synthase (nNOS) is important in cardiac protection in diseased heart. Recently, we have reported that nNOS is associated with myofilament Ca(2+) desensitization in cardiac myocytes from hypertensive rats. So far, the effect of myofilament Ca(2+) desensitization or nNOS on L-type Ca(2+) channel activity (I(Ca)) in cardiac myocyte is unclear. Here, we examined nNOS regulation of I(Ca) in left ventricular (LV) myocytes from sham and angiotensin II (Ang II)-induced hypertensive rats. Our results showed that basal I(Ca) was not different between sham and hypertension (from -60 to +40 mV, 0.1 Hz). S methyl-L-thiocitrulline (SMTC), a selective nNOS inhibitor, increased peak I(Ca) similarly in both groups. However, chelation of intracellular Ca(2+) [Ca(2+)]i with BAPTA increased I(Ca) and abolished SMTC-augmentation of I(Ca) only in hypertension. Myofilament Ca(2+) desensitization with butanedione monoxime (BDM), a myosin ATPase inhibitor, decreased I(Ca) in both groups but to a greater extent in hypertension. Intracellular BAPTA or nNOS inhibition reinstated I(Ca) in the presence of BDM to the basal level, suggesting Ca(2+)-dependent inactivation of I(Ca) by nNOS and greater vulnerability in hypertension. Increasing stimulation frequencies (2, 4 and 8 Hz) attenuated myofilament Ca(2+) sensitivity in sham and reduced peak ICa in both groups. Nevertheless, SMTC or BAPTA exerted no effect on I(Ca) at high frequencies in either group. These results suggest that nNOS attenuates I(Ca) via Ca(2+)-dependent mechanism and the vulnerability is greater in hypertension subject to myofilament Ca(2+) desensitization. nNOS or [Ca(2+)]i does not affect I(Ca) at high stimulation frequencies. The results were recapitulated with computer simulation. PMID- 26115837 TI - Fluoxetine suppresses calcium signaling in human T lymphocytes through depletion of intracellular calcium stores. AB - Selective serotonin reuptake inhibitors, such as fluoxetine, have recently been shown to exert anti-inflammatory and immunosuppressive effects. Although the effects on cytokine secretion, proliferation and viability of T lymphocytes have been extensively characterized, little is known about the mechanism behind these effects. It is well known that Ca(2+) signaling is an important step in the signaling transduction pathway following T cell receptor activation. Therefore, we investigated if fluoxetine interferes with Ca(2+) signaling in Jurkat T lymphocytes. Fluoxetine was found to suppress Ca(2+) signaling in response to T cell receptor activation. Moreover, fluoxetine was found to deplete intracellular Ca(2+) stores, thereby leaving less Ca(2+) available for release upon IP3- and ryanodine-receptor activation. The Ca(2+)-modifying effects of fluoxetine are not related to its capability to block the serotonin transporter, as even a large excess of 5HT did not abolish the effects. In conclusion, these data show that fluoxetine decreases IP3- and ryanodine-receptor mediated Ca(2+) release in Jurkat T lymphocytes, an effect likely to be at the basis of the observed immunosuppression. PMID- 26115838 TI - Research priorities in mesothelioma: A James Lind Alliance Priority Setting Partnership. AB - BACKGROUND: In the UK, despite the import and use of all forms of asbestos being banned more than 15 years ago, the incidence of mesothelioma continues to rise. Mesothelioma is almost invariably fatal, and more research is required, not only to find more effective treatments, but also to achieve an earlier diagnosis and improve palliative care. Following a debate in the House of Lords in July 2013, a package of measures was agreed, which included a James Lind Alliance Priority Setting Partnership, funded by the National Institute for Health Research. The partnership brought together patients, carers, health professionals and support organisations to agree the top 10 research priorities relating to the diagnosis, treatment and care of patients with mesothelioma. METHODS: Following the established James Lind Alliance priority setting process, mesothelioma patients, current and bereaved carers, and health professionals were surveyed to elicit their concerns regarding diagnosis, treatment and care. Research questions were generated from the survey responses, and following checks that the questions were currently unanswered, an interim prioritisation survey was conducted to identify a shortlist of questions to take to a final consensus meeting. FINDINGS: Four hundred and fifty-three initial surveys were returned, which were refined into 52 unique unanswered research questions. The interim prioritisation survey was completed by 202 responders, and the top 30 questions were taken to a final meeting where mesothelioma patients, carers, and health professionals prioritised all the questions, and reached a consensus on the top 10. INTERPRETATION: The top 10 questions cover a wide portfolio of research (including assessing the value of immunotherapy, individualised chemotherapy, second-line treatment and immediate chemotherapy, monitoring patients with pleural thickening, defining the management of ascites in peritoneal mesothelioma, and optimising follow-up strategy). This list is an invaluable resource, which should be used to inform the prioritisation and funding of future mesothelioma research. PMID- 26115839 TI - The impact of clinical characteristics on outcomes from maintenance therapy in non-small cell lung cancer: A systematic review with meta-analysis. AB - OBJECTIVES: Although maintenance therapy has been a routine treatment paradigm for advanced non-small cell lung cancer (NSCLC), there is currently lack of direct evidence to identify patients most likely to benefit from maintenance therapy for advanced NSCLC. MATERIALS AND METHODS: Trials comparing maintenance therapy with placebo or observation in NSCLC were identified. The primary endpoint was overall survival (OS) in trial population and predefined subgroups. Other endpoints included progression-free survival (PFS) in trial population and predefined subgroups, toxicities and health-related quality of life (QoL). RESULTS: 13 trials with 4960 patients were identified. Maintenance therapy yielded a statistically significant but clinically modest improvement in OS (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.78-0.89, P<0.001), without significant difference between switch and continuation strategy (HR, 0.83 vs. 0.86; Pinteraction=0.631). Patients with performance status (PS) of 0 derived more PFS benefit (HR, 0.52; 95% CI, 0.45-0.61) than those with PS of 1 (HR, 0.69; 95% CI, 0.63-0.76; Pinteraction=0.002). Patients with adenocarcinoma derived more PFS benefit (HR, 0.54; 95% CI, 0.46-0.64) than those with squamous cell carcinoma (HR, 0.85; 95% CI, 0.68-1.06; Pinteraction=0.001). Patients with activating epidermal growth factor receptor (EGFR) mutations derived more survival benefit than those with wild-type EGFR tumors in terms of OS (HR, 0.53 vs. 0.85, Pinteraction=0.086) and PFS (HR, 0.20 vs. 0.80, Pinteraction=0.003). Response to first-line therapy did not significantly predict additional benefit from maintenance therapy. Toxicities occurred more frequently in patients treated with maintenance therapy but health-related QoL was not adversely affected by maintenance therapy. CONCLUSION: Maintenance therapy with either a continuation or a switch strategy yields a statistically significant but clinically modest improvement in OS for patients with advanced NSCLC. Factors that may predict benefit from maintenance therapy (tumor histology, PS, or EGFR mutation status), as well as economic considerations should be taken into account before initiating maintenance therapy. PMID- 26115840 TI - Stigma- and non-stigma-related treatment barriers to mental healthcare reported by service users and caregivers. AB - Delayed treatment seeking for people experiencing symptoms of mental illness is common despite available mental healthcare. Poor outcomes are associated with untreated mental illness and caregivers may eventually need to seek help on the service user's behalf. More attention has recently focused on the role of stigma in delayed treatment seeking. This study aimed to establish the frequency of stigma- and non-stigma-related treatment barriers reported by 202 service users and 80 caregivers; to compare treatment barriers reported by service users and caregivers; and to investigate demographic predictors of reporting stigma-related treatment barriers. The profile of treatment barriers differed between service users and caregivers. Service users were more likely to report stigma-related treatment barriers than caregivers across all stigma-related items. Service users who were female, had a diagnosis of schizophrenia or with GCSEs (UK qualifications usually obtained at age 16) were significantly more likely to report stigma-related treatment barriers. Caregivers who were female or of Black ethnicities were significantly more likely to report stigma-related treatment barriers. Multifaceted approaches are needed to reduce barriers to treatment seeking for both service users and caregivers, with anti-stigma interventions being of particular importance for the former group. PMID- 26115841 TI - Health-related quality of life in posttraumatic stress disorder: 4 years follow up study of individuals exposed to urban violence. AB - Evidence suggests that Posttraumatic Stress Disorder (PTSD) is associated with substantially reduced Health-related quality of life (HRQoL). This study aimed to explore the impact of PTSD symptoms in HRQoL and its predictors in individuals exposed to urban violence. We follow-up a cohort of 267 individuals exposed to urban violence, derived from an epidemiological survey and clinical cases from an outpatient program of victims of violence, with and without PTSD, by assessing symptoms and other measures at two intervals, approximately 4 years apart. PTSD symptom severity was associated with poorer quality of life at baseline and at follow-up. Higher levels of depression and anxiety, new trauma experiences, more traumas in childhood and more PTSD arousal symptoms were all predictors of lower HRQoL over time. Results strongly suggest the need to assess HRQoL in addition to symptoms in order to assess the true severity of PTSD. These results have implications for the functional recovery in the treatment of PTSD. PMID- 26115842 TI - Allocentric but not egocentric visual memory difficulties in adults with ADHD may represent cognitive inefficiency. AB - Attention Deficit Hyperactivity Disorder (ADHD) has often been conceptualized as arising executive dysfunctions (e.g., inattention, defective inhibition). However, recent studies suggested that cognitive inefficiency may underlie many ADHD symptoms, according to reaction time and processing speed abnormalities. This study explored whether a non-timed measure of cognitive inefficiency would also be abnormal. A sample of 23 ADHD subjects was compared to 23 controls on a test that included both egocentric and allocentric visual memory subtests. A factor analysis was used to determine which cognitive variables contributed to allocentric visual memory. The ADHD sample performed significantly lower on the allocentric but not egocentric conditions. Allocentric visual memory was not associated with timed, working memory, visual perception, or mental rotation variables. This paper concluded by discussing how these results supported a cognitive inefficiency explanation for some ADHD symptoms, and discussed future research directions. PMID- 26115843 TI - Inhibition of GSK3beta by pharmacological modulation of sphingolipid metabolism occurs independently of ganglioside disturbance in a cellular model of Alzheimer's disease. AB - Accumulating evidence implicates ganglioside and/or related-sphingolipid disturbance in the pathogenesis of Alzheimer's disease (AD). However, it is not known whether these lipidic alterations are connected with other important features of AD, such as deregulated insulin/Akt/GSK3 signaling. In this study, we have treated neuroglioma cells expressing the double Swedish mutation of human amyloid precursor protein (H4APPsw) with several glycosphingolipid (GSL) modulating agents, and we have analyzed the impact of the aberrant ganglioside composition on the GSK3 activation state. We found that both ceramide analogs D- and L-PDMP (1-phenyl 2-decanoylamino-3-morpholino-1-propanol), which have opposite effects on ganglioside synthesis, selectively inhibited GSK3beta via Ser9 phosphorylation independently of the upstream insulin/Akt pathway. Conversely, the iminosugar N-butyldeoxynojirimycin (NB-DNJ) which displayed similar reduction of gangliosides as D-PDMP, did not affect the phosphorylation state of GSK3beta. Concurrently, while NB-DNJ did not modify the cellular ceramide content, both PDMP enantiomers strongly and equally reduced the levels of long-chain ceramide species. Altogether, our findings led us to hypothesize that the PDMP-induced altered ganglioside composition is not the principal mechanism involved in the inhibition of GSK3beta, but seems to implicate, at least in part, their ability to reduce ceramide levels. Nevertheless, this study provides new information regarding the possibilities to target GSK3beta through modulation of sphingolipid metabolism. PMID- 26115844 TI - Genes with minimal phylogenetic information are problematic for coalescent analyses when gene tree estimation is biased. AB - The development and application of coalescent methods are undergoing rapid changes. One little explored area that bears on the application of gene-tree based coalescent methods to species tree estimation is gene informativeness. Here, we investigate the accuracy of these coalescent methods when genes have minimal phylogenetic information, including the implementation of the multilocus bootstrap approach. Using simulated DNA sequences, we demonstrate that genes with minimal phylogenetic information can produce unreliable gene trees (i.e., high error in gene tree estimation), which may in turn reduce the accuracy of species tree estimation using gene-tree-based coalescent methods. We demonstrate that this problem can be alleviated by sampling more genes, as is commonly done in large-scale phylogenomic analyses. This applies even when these genes are minimally informative. If gene tree estimation is biased, however, gene-tree based coalescent analyses will produce inconsistent results, which cannot be remedied by increasing the number of genes. In this case, it is not the gene-tree based coalescent methods that are flawed, but rather the input data (i.e., estimated gene trees). Along these lines, the commonly used program PhyML has a tendency to infer one particular bifurcating topology even though it is best represented as a polytomy. We additionally corroborate these findings by analyzing the 183-locus mammal data set assembled by McCormack et al. (2012) using ultra-conserved elements (UCEs) and flanking DNA. Lastly, we demonstrate that when employing the multilocus bootstrap approach on this 183-locus data set, there is no strong conflict between species trees estimated from concatenation and gene-tree-based coalescent analyses, as has been previously suggested by Gatesy and Springer (2014). PMID- 26115845 TI - Assessing host-specificity of Escherichia coli using a supervised learning logic regression-based analysis of single nucleotide polymorphisms in intergenic regions. AB - Host specificity in E. coli is widely debated. Herein, we used supervised learning logic-regression-based analysis of intergenic DNA sequence variability in E. coli in an attempt to identify single nucleotide polymorphism (SNP) biomarkers of E. coli that are associated with natural selection and evolution toward host specificity. Seven-hundred and eighty strains of E. coli were isolated from 15 different animal hosts. We utilized logic regression for analyzing DNA sequence data of three intergenic regions (flanked by the genes uspC-flhDC, csgBAC-csgDEFG, and asnS-ompF) to identify genetic biomarkers that could potentially discriminate E. coli based on host sources. Across 15 different animal hosts, logic regression successfully discriminated E. coli based on animal host source with relatively high specificity (i.e., among the samples of the non target animal host, the proportion that correctly did not have the host-specific marker pattern) and sensitivity (i.e., among the samples from a given animal host, the proportion that correctly had the host-specific marker pattern), even after fivefold cross validation. Permutation tests confirmed that for most animals, host specific intergenic biomarkers identified by logic regression in E. coli were significantly associated with animal host source. The highest level of biomarker sensitivity was observed in deer isolates, with 82% of all deer E. coli isolates displaying a unique SNP pattern that was 98% specific to deer. Fifty three percent of human isolates displayed a unique biomarker pattern that was 98% specific to humans. Twenty-nine percent of cattle isolates displayed a unique biomarker that was 97% specific to cattle. Interestingly, even within a related host group (i.e., Family: Canidae [domestic dogs and coyotes]), highly specific SNP biomarkers (98% and 99% specificity for dog and coyotes, respectively) were observed, with 21% of dog E. coli isolates displaying a unique dog biomarker and 61% of coyote isolates displaying a unique coyote biomarker. Application of a supervised learning method, such as logic regression, to DNA sequence analysis at certain intergenic regions demonstrates that some E. coli strains may evolve to become host-specific. PMID- 26115847 TI - A systematic review of peroneal nerve palsy and recovery following traumatic knee dislocation. AB - PURPOSE: A common peroneal nerve (CPN) palsy has been reported to complicate knee dislocations in 5-40 % of patients. Patients who suffer from a persistent foot drop have significantly worse functional outcomes. Reports on prognostic factors for nerve recovery or treatment-specific functional outcomes remain sparse in the literature. METHODS: Two independent reviewers completed a search of Medline, Embase, PubMed and the Cochrane Library from 1946 to present. Motor strength was determined using the Medical Research Council (MRC) grading system or an equivalent description. A functional recovery was defined as an MRC >=3/5. RESULTS: The combined search of Medline, Embase, PubMed and the Cochrane Library identified 1528 abstracts. Thirteen articles met our inclusion/exclusion criteria. This included 214 CPN palsies. Functional recovery (MRC >=3/5) following complete CPN palsy was 38.4 %. Full recovery (MRC = 5/5) following partial CPN palsy was 87.3 %. Younger age was predictive of neurologic recovery. Recovery following isolated neurologic interventions ranged from 0 to 30 %. CONCLUSIONS: A vastly different prognosis can be expected for patients who suffer an incomplete versus a complete CPN palsy. The majority of patients with an incomplete palsy will achieve a full motor recovery while <40 % of patients with a complete motor palsy will regain the ability to dorsiflex at the ankle. While neurologic interventions show promise for the future, the outcomes in knee dislocation patients remain poor. The most predictable means of reestablishing antigravity dorsiflexion in a persistent CPN palsy is a posterior tibial tendon transfer. PMID- 26115846 TI - What Matters to Women When Making Decisions About Breast Cancer Chemoprevention? AB - PURPOSE: Despite the effectiveness of chemoprevention (tamoxifen and raloxifene) in preventing breast cancer among women at high risk for the disease, uptake is low. The objective of this study was to determine the tradeoff preferences for various attributes associated with chemoprevention among women not currently taking the drugs. METHODS: We used rating-based conjoint analysis to evaluate the relative importance of a number of attributes associated with chemoprevention, including risk of side effects, drug effectiveness, time needed to take the drugs, and availability of a blood test to see if the drugs were working in an Internet sample of women. We generated mean importance values and part-worth utilities for all attribute levels associated with taking chemoprevention. We then used multivariable linear regression to examine attribute importance scores controlling for participant age, race, Hispanic ethnicity, educational level, and a family history of breast cancer. RESULTS: Overall interest in taking chemoprevention was low among the 1094 women included in the analytic sample, even for the scenario in which participants would receive the greatest benefit and fewest risks associated with taking the drugs. Time needed to take the pill for it to work and 5-year risk of breast cancer were the most important attributes driving tradeoff preferences between the chemoprevention scenarios. CONCLUSIONS: Interest in taking chemoprevention among this sample of women at average risk was low. Addressing women's concerns about the time needed to take chemoprevention for it to work may help clinicians improve uptake of the drugs among those likely to benefit. PMID- 26115848 TI - Medial prefrontal cortex role in recognition memory in rodents. AB - The study of the neurobiology of recognition memory, defined by the integration of the different components of experiences that support recollection of past experiences have been a challenge for memory researches for many years. In the last twenty years, with the development of the spontaneous novel object recognition task and all its variants this has started to change. The features of recognition memory include a particular object or person ("what"), the context in which the experience took place, which can be the arena itself or the location within a particular arena ("where") and the particular time at which the event occurred ("when"). This definition instead of the historical anthropocentric one allows the study of this type of episodic memory in animal models. Some forms of recognition memory that require integration of different features recruit the medial prefrontal cortex. Focusing on findings from spontaneous recognition memory tasks performed by rodents, this review concentrates on the description of previous works that have examined the role that the medial prefrontal cortex has on the different steps of recognition memory. We conclude that this structure, independently of the task used, is required at different memory stages when the task cannot be solved by a single item strategy. PMID- 26115850 TI - Advancing implementation in maternal and newborn health: two decades of experience. PMID- 26115851 TI - Best practices for a successful MNCH partnership that an external evaluation could never find: experiences from the Maternal and Child Health Integrated Program. AB - Partnerships for maternal, newborn, and child health (MNCH) are increasingly prevalent, yet little has been published about the possible reasons for their success or failure. In this commentary, we assess the presence of four principles for a successful collaborative partnership-clear goals, clear roles, trust, and commitment-within the Maternal and Child Health Integrated Program (MCHIP), an MNCH partnership among eight implementing organizations that was funded by USAID from 2008 to 2014. MCHIP made substantial strides in developing clear goals and partner roles, and despite external constraints, to develop the trust and commitment needed to work in an interdependent manner. Future collaborative MNCH partnerships should pursue a shared understanding of these four principles as early and often as possible to ensure success. PMID- 26115849 TI - Identification and expression dynamics of three WUSCHEL related homeobox 13 (WOX13) genes in peanut. AB - WUSCHEL-related homeobox (WOX) genes play key roles in plant stem cell maintenance and development. WOX genes showed specific expression patterns which are important for their functions. WOX13 subfamily genes as the ancestor genes of this family were less studied in the past. In this study, we cloned three Arachis hypogaea (peanut) WOX13 (AhWOX13) subfamily genes from peanut: WOX13A and WOX13B1, 2. WOX13B1 encoded a same protein as WOX13B2, and there were only two base difference between these two genes. Differential expression patterns were observed for these three AhWOX13 subfamily genes in different tissues and developmental stages. Phylogenic trees analysis showed that these AhWOX13 subfamily genes were the most conserved WOX genes and belonged to the ancient clade of WOX family. This was also supported by the conserved motif analysis. Selective pressure analysis showed that the WOX family genes mainly underwent weak purifying selection (omega = 0.58097), while many positive mutations accumulated during the evolution history. Under the purifying selection, gene duplication event and loss of duplicated gene play important roles in the expansion and evolution of WOX family. PMID- 26115852 TI - Implementation of the Standards-Based Management and Recognition approach to quality improvement in maternal, newborn, and child health programs in low resource countries. AB - The Standards-Based Management and Recognition (SBM-R; Jhpiego, Baltimore, MD, USA) approach to quality improvement was developed by Jhpiego to respond to common challenges faced by health systems in low-resource settings, including poor pre-service education, lack of resources for conventional supervisory models, and weak health information systems. Since its introduction in Brazil in 1997, SBM-R has been implemented in approximately 30 countries and continues expanding to new places and service delivery areas. The present article: (1) describes key steps in the SBM-R methodology focusing on provider performance assessment using evidence-based standards; and (2) presents examples of improvements in provider performance in maternal, newborn, and child health care following SBM-R implementation derived from routine program data, quasi experimental evaluations, and in-depth case studies. SBM-R incorporates evidence based methods that are known to have positive effects on healthcare quality, including audit and feedback, educational outreach visits, and checklist usage; however, further rigorous research is needed to document the population-level impacts of the SBM-R approach. PMID- 26115853 TI - Task shifting in maternal and newborn health care: key components from policy to implementation. AB - Task shifting in various forms has been adopted extensively around the world in an effort to expand the reach of lifesaving services to the women, newborns, and families who need them. The emerging global literature, as well as Jhpiego's field experiences, supports the importance of addressing several key components that facilitate effective task shifting in maternal and newborn health care. These components include: (1) policy and regulatory support; (2) definition of roles, functions, and limitations; (3) determination of requisite skills and qualifications; (4) education and training; and (5) service delivery support, including management and supervision, incentives and/or remuneration, material support (e.g. commodities), and referral systems. Jhpiego's experiences with task shifting also provide illustrations of the complex interplay of these key components at work in the field. Task shifting should be considered as a part of the larger health system that needs to be designed to equitably meet the needs of mothers, newborns, children, and families. PMID- 26115854 TI - Jhpiego: model supporter of implementation science. PMID- 26115855 TI - Experiences engaging community health workers to provide maternal and newborn health services: implementation of four programs. AB - A paucity of skilled health providers is a considerable impediment to reducing maternal, infant, and under-five mortality for many low-resource countries. Although evidence supports the effectiveness of community health workers (CHWs) in delivering primary healthcare services, shifting tasks to this cadre from providers with advanced training has been pursued with overall caution-both because of difficulties determining an appropriate package of CHW services and to avoid overburdening the cadre. We reviewed programs in Rwanda, Afghanistan, Nigeria, and Nepal where tasks in delivery of health promotion information and distribution of commodities were transitioned to CHWs to reach underserved populations. The community-based interventions were complementary to facility based interventions as part of a comprehensive approach to increase access to basic health services. Drawing on these experiences, we illuminate commonalities, lessons learned, and factors contributing to the programs' implementation strategies to help inform practical application in other settings. PMID- 26115856 TI - Scaling up high-impact interventions: how is it done? AB - Building upon the World Health Organization's ExpandNet framework, 12 key principles of scale-up have emerged from the implementation of maternal and newborn health interventions. These principles are illustrated by three case studies of scale up of high-impact interventions: the Helping Babies Breathe initiative; pre-service midwifery education in Afghanistan; and advanced distribution of misoprostol for self-administration at home births to prevent postpartum hemorrhage. Program planners who seek to scale a maternal and/or newborn health intervention must ensure that: the necessary evidence and mechanisms for local ownership for the intervention are well-established; the intervention is as simple and cost-effective as possible; and the implementers and beneficiaries of the intervention are working in tandem to build institutional capacity at all levels and in consideration of all perspectives. PMID- 26115857 TI - Preparing the next generation of maternal and newborn health leaders: the maternal and newborn health champions initiatives. AB - A champion in health care can be defined as any health professional who has the requisite knowledge and skills in a relevant health field, who is respected by his/her peers and supported by his/her supervisors, and who takes the lead to promote or introduce evidence-based interventions to improve the quality of care. Jhpiego used a common approach during two distinct initiatives to identify individuals in Africa, Asia, and Latin America and the Caribbean whose expertise in their clinical service area and whose leadership capacity could be strengthened to enable them to serve as champions for maternal and newborn health (MNH). These champions have gone on to contribute to the improvement of MNH in their respective countries and regions. The lessons learned from this approach are shared so they can be used by other organizations to design leadership development strategies for MNH in low-resource countries. PMID- 26115858 TI - Essential basic and emergency obstetric and newborn care: from education and training to service delivery and quality of care. AB - Approximately 15% of expected births worldwide will result in life-threatening complications during pregnancy, delivery, or the postpartum period. Providers skilled in emergency obstetric and newborn care (EmONC) services are essential, particularly in countries with a high burden of maternal and newborn mortality. Jhpiego and its consortia partners have implemented three global programs to build provider capacity to provide comprehensive EmONC services to women and newborns in these resource-poor settings. Providers have been educated to deliver high-impact maternal and newborn health interventions, such as prevention and treatment of postpartum hemorrhage and pre-eclampsia/eclampsia and management of birth asphyxia, within the broader context of quality health services. This article describes Jhpiego's programming efforts within the framework of the basic and expanded signal functions that serve as indicators of high-quality basic and emergency care services. Lessons learned include the importance of health facility strengthening, competency-based provider education, global leadership, and strong government ownership and coordination as essential precursors to scale up of high impact evidence-based maternal and newborn interventions in low resource settings. PMID- 26115859 TI - A facility birth can be the time to start family planning: postpartum intrauterine device experiences from six countries. AB - Initiation of family planning at the time of birth is opportune, since few women in low-resource settings who give birth in a facility return for further care. Postpartum family planning (PPFP) and postpartum intrauterine device (PPIUD) services were integrated into maternal care in six low- and middle-income countries, applying an insertion technique developed in Paraguay. Facilities with high delivery volume were selected to integrate PPFP/PPIUD services into routine care. Effective PPFP/PPIUD integration requires training and mentoring those providers assisting women at the time of birth. Ongoing monitoring generated data for advocacy. The percentages of PPIUD acceptors ranged from 2.3% of women counseled in Pakistan to 5.8% in the Philippines. Rates of complications among women returning for follow-up were low. Expulsion rates were 3.7% in Pakistan, 3.6% in Ethiopia, and 1.7% in Guinea and the Philippines. Infection rates did not exceed 1.3%, and three countries recorded no cases. Offering PPFP/PPIUD at birth improves access to contraception. PMID- 26115860 TI - Evolution of malaria in pregnancy control: Jhpiego's 10-year contribution. AB - Malaria continues to be a life-threatening illness throughout Sub-Saharan Africa, with pregnant women and children being particularly vulnerable and an estimated 10 000 women and 200 000 newborns dying each year as a result of malaria in pregnancy (MIP). Since 2004, WHO has supported a three-pronged MIP approach: (1) intermittent preventive treatment with sulfadoxine-pyrimethamine; (2) use of insecticide-treated bed nets; and (3) effective case management. The present article identifies benchmarks in Jhpiego's 10-plus years of MIP experience at the regional and national levels that have contributed to its global MIP leadership and aligned programs and policies with global approaches toward malaria elimination. As countries continue to develop and expand MIP programming, support will continue to be essential in the following eight MIP program areas: integration, policy, capacity development, community engagement, quality assurance, commodities, monitoring and evaluation, and financing. PMID- 26115861 TI - RED for PMTCT: an adaptation of immunization's Reaching Every District approach increases coverage, access, and utilization of PMTCT care in Bondo District, Kenya. AB - Gaps exist in coverage, early access, and utilization of prevention of mother-to child transmission of HIV (PMTCT) services in Kenya. The Maternal and Child Health Integrated Program, led by Jhpiego, piloted an adaptation of immunization's Reaching Every District (RED) approach in Bondo District as a way of improving PMTCT care. Routine district-level monthly summary service delivery pre- and post-implementation data were analyzed. Marked improvements resulted in the proportion of HIV-infected and non-infected pregnant women completing four focused prenatal care visits, from 25% to 41%, and the proportion of HIV-exposed infants (HEIs) tested at six weeks, from 27% to 78% (P<0.001). The proportion of HEIs tested for HIV infection at 12months was 52%, while 77% of HEIs were issued antiretroviral prophylaxis by the end of the pilot. Implementation of RED for PMTCT demonstrated that PMTCT services can be delivered effectively in the context of the existing community strategy and resulted in increased coverage, access, and utilization of care for HIV-positive pregnant women and their children. PMID- 26115862 TI - Eyes on the prize: linking pre-service education to outcomes. PMID- 26115863 TI - Dissemination of the multidrug-resistant extended-spectrum beta-lactamase producing Escherichia coli O25b-ST131 clone and the role of house crow (Corvus splendens) foraging on hospital waste in Bangladesh. AB - Two hundred and thirty-eight faecal samples from crows foraging on hospital wastes were analysed for extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. ESBL-producing crow isolates were characterized and compared with 31 patient isolates. Among the crows, 59% carried ESBL producers. These included Escherichia coli, Klebsiella pneumoniae, Raoultella terrigena and Enterobacter cloacae harbouring the genes for CTX-M-1, CTX-M-15, CTX-M-55, CTX-M 79, and CTX-M-14. Human isolates carried only the CTX-M-15 gene. Two-thirds of crow E. coli isolates and all human E. coli isolates were multidrug resistant. Crows and patients shared E. coli sequence types, including the epidemic E. coli O25b-ST131 clone. The scavenging behaviour of crows at poorly managed hospital waste dumps made them potential reservoirs of antibiotic resistance, including ESBLs. PMID- 26115864 TI - De-escalation therapy among bacteraemic patients with community-acquired pneumonia. AB - There is no evidence supporting the use of de-escalation therapy (DET) among patients with community-acquired pneumonia (CAP). We assessed the outcomes associated with DET among bacteraemic CAP patients. We performed a secondary analysis of the Community-Acquired Pneumonia Organization database, which contains data on 660 bacteraemic patients hospitalized because of CAP in 35 countries (2001-2013). Exclusion criteria were death within 72 h from admission and an inappropriate empirical antibiotic regimen. DET was defined as changing an appropriate empirical broad-spectrum regimen to a narrower-spectrum regimen according to culture results within 7 days from hospital admission. Two study groups were identified: patients whose antibiotic therapy was de-escalated (the DET group), and patients whose antibiotic therapy was not de-escalated (the N-DET group). The primary study outcome was 30-day mortality. Two hundred and sixty-one bacteraemic CAP patients were included. Gram-positive bacteria were responsible for 88.1% of the cases (Streptococcus pneumoniae, 75.9%). Gram-negative bacteria were responsible for for 7.3% of the cases. DET was performed in 165 patients (63.2%). The N-DET group was characterized by a more severe presentation at admission. After adjustment for confounders, DET was not associated with an increased risk of 30-day mortality. DET seems to be safe among bacteraemic patients with CAP. Randomized clinical trials are warranted to further explore these findings. PMID- 26115865 TI - From the left to the right: 13-year experience in laparoscopic living donor liver transplantation. AB - Living Donors are the best theoretical candidates to benefit from the advantages of laparoscopy, but development was slow because of concerns about graft integrity and donor safety. Herein our 13-year experience in laparoscopic Living Donor Liver Transplantation (LDLT) is presented. Laparoscopic Left Lateral Section (LLLS) was performed in children receiver, while Laparoscopic Left Hepatectomy (LLH)-including or not the middle hepatic vein-and Laparoscopic Right Hepatectomy (LRH) in adults. Two senior surgeons were always involved for each procedure. All donors were first-degree relatives. From 2001 to 2014, 71 procedures were performed: 63 LLLS (88.7%, 6 LLH (8.4%), and 2 LRH (2.8%). Surgical procedures required a mean of 271.1 +/- 65.9, 318 +/- 40.2, and 480 +/- 0 min for LLLS, LLH, and LRH, respectively with a learning curve toward LLLH over the years (r = 0.09). Seven procedures (9.8%) required conversion. The mean hospital stay was 5.5 +/- 3.4, 5.3 +/- 0.6, and 8 +/- 0 days for LLLS, LLH, and LRH, respectively. Complications occurred in 11 patients (17.3%) undergoing LLLS: 8 (12.7%) grade I and 3 (4.7%) grade II, according to the Modified Clavien-Dindo classification. Laparoscopic liver resection for LDLT requires an equivalent and parallel expertise in open LDLT and LLR. If LLLS for LDLT is now in an exploration phase in highly specialized centers, LLH and LRH for LDLT in adults lack evidence and cannot be recommended for wide introduction. For laparoscopic LDLT beginners, LLLS offers optimal conditions. PMID- 26115868 TI - Role of cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) in regulating the trafficking and signaling of corticotropin-releasing factor receptor 1. AB - Corticotropin releasing factor (CRF) receptor1 (CRFR1) is associated with psychiatric illness and is a proposed target for the treatment of anxiety and depression. Like many G protein-coupled receptors (GPCRs), CRFR1 harbors a PDZ (PSD95/Disc Large/Zona Occludens 1)-binding motif at the end of its carboxyl terminal tail. The interactions of PDZ proteins with GPCRs are crucial for the regulation of their receptor function. In the present study, we characterize the interaction of the cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) with CRFR1. We show using co-immunoprecipitation that the two proteins interact in human embryonic kidney (HEK293) cells in a PDZ motif dependent manner. We find that the interaction occurs at the Golgi apparatus and that overexpression of CAL retains a proportion of CRFR1 in the intracellular compartment and prevents trafficking to the cell surface. We also demonstrate a significant reduction in the levels of receptor at the plasma membrane upon CAL overexpression, as well as a reduction in internalization. We find that the overexpression of CAL in HEK293 cells resulted in a significant decrease in CRF stimulated extracellular-regulated protein kinase 1/2 (ERK1/2) phosphorylation, but has no effect on cAMP signaling mediated by the receptor. This effect was dependent on an intact PDZ motif and knockdown of CAL expression using CAL siRNA results in a significant enhancement in ERK1/2 signaling. We show that CAL contributes to the regulation of CRFR1 glycosylation and utilize glycosylation deficient CRFR1 mutants to further examine the role of glycosylation in the cell surface trafficking of CRFR1. We find that the mutation of Asn residues 90 and 98 results in a reduction in cell surface CRFR1 that is comparable to the effect of CAL overexpression and that these mutants are retained in the Golgi apparatus. Mutation of Asn residues 90 and 98 also results in a decrease in the efficacy for CRF-stimulated cAMP formation mediated by CRFR1. Taken together, our data suggest that CAL can regulate the anterograde trafficking, the internalization as well as the signaling of CRFR1 via modulating the post-translational modifications that the receptor undergoes at the Golgi apparatus. PMID- 26115867 TI - Cochrane in CORR ((r)): Interventions for Treating Proximal Humeral Fractures in Adults (Review). PMID- 26115869 TI - [Not Available]. PMID- 26115866 TI - Highly Crosslinked-remelted versus Less-crosslinked Polyethylene in Posterior Cruciate-retaining TKAs in the Same Patients. AB - BACKGROUND: Concern regarding osteolysis attributable to polyethylene wear after TKA, particularly in younger patients, has prompted the introduction of highly crosslinked-remelted polyethylene (HXLPE) for TKAs. However, few in vivo comparative results of TKAs using HXLPE and less-crosslinked polyethylene inserts in the same patients are available, regarding fracture or failure of the locking mechanism of tibial polyethylene inserts or of osteolysis in patients younger than 60 years. QUESTIONS/PURPOSES: We wanted to determine whether (1) survivorship free from aseptic loosening in knees with HXLPE inserts was different from survivorship in knees with less-crosslinked polyethylene inserts, (2) the prevalence of fracture or failure of the locking mechanism of the tibial polyethylene insert was greater in knees with HXLPE than in those with less crosslinked polyethylene, and (3) the proportion of patients who had osteolysis develop was greater with HXLPE than with less-crosslinked polyethylene inserts. METHODS: One hundred seventy-one patients with a mean age of 58 +/- 8 years (range, 35-59 years) received posterior cruciate-retaining prostheses with a less crosslinked polyethylene tibial insert in one knee and a HXLPE tibial insert in the contralateral knee. From January 2007 to January 2010, we performed 366 same day bilateral simultaneous sequential posterior cruciate-retaining TKAs in 183 patients, of whom 171 (93%) participated in this study. All patients during this study period underwent posterior cruciate-retaining TKAs regardless of deformity of the knees and we did not perform posterior-stabilized TKAs during the same period. Patients who had bilateral end-stage osteoarthritis and were younger than 60 years were selected for inclusion. Six patients (4%) were lost to followup before 5 years. Twenty-six patients were males and 145 were females. The mean duration of followup was 6 years (range, 5-8 years). At each followup, patients were assessed for loosening of the components, fracture or failure of the locking mechanism of the polyethylene inserts, or osteolysis. RESULTS: The survival rate of the knee prosthesis at a mean of 5.8 years after surgery was 100% (95% CI, 0.95-1.00) in both groups for the endpoint aseptic loosening and 99.4% (95% CI, 0.95-1.00) in both groups for the endpoint revision. No knee in either group had fracture or failure of the locking mechanism of the tibial polyethylene insert, and none had osteolysis. CONCLUSIONS: With the numbers available, we found no clinically important differences between HXLPE and less-crosslinked polyethylene inserts in posterior cruciate-retaining TKAs. Given that HXLPE is newer, as-yet unproven, and more expensive than the proven technology (less-crosslinked polyethylene), we suggest not adopting HXLPE for clinical use until it shows superiority. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 26115870 TI - Ginsenoside-Rg1 induces angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a. AB - Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. Ginsenoside-Rg1 (Rg1), one of the most abundant active components of ginseng, has been demonstrated as an angiogenesis-stimulating compound in different models. There is increasing evidence implicating microRNAs (miRNAs), a group of non-coding RNAs, as important regulators of angiogenesis, but the role of microRNAs in Rg1-induced angiogenesis has not been fully explored. In this report, we found that stimulating endothelial cells with Rg1 could reduce miR-23a expression. In silico experiments predicted hepatocyte growth factor receptor (MET), a well-established mediator of angiogenesis, as the target of miR-23a. Transfection of the miR-23a precursor or inhibitor oligonucleotides validated the inverse relationship of miR-23a and MET expression. Luciferase reporter assays further confirmed the interaction between miR-23a and the MET mRNA 3'-UTR. Intriguingly, ginsenoside-Rg1 was found to increase MET protein expression in a time-dependent manner. We further demonstrated that ginsenoside-Rg1-induced angiogenic activities were indeed mediated through the down-regulation of miR-23a and subsequent up-regulation of MET protein expression, as confirmed by gain- and loss-of-function angiogenic experiments. In summary, our results demonstrated that ginsenoside-Rg1 could induce angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a. This study has broadened our understanding of the non-genomic effects of ginsenoside-Rg1, and provided molecular evidence that warrant further development of natural compound as novel angiogenesis-promoting therapy. PMID- 26115871 TI - A Novel Method of Axillary Venipuncture Using the Cephalic Vein as a Sole Anatomic Landmark. AB - The use of axillary venipuncture for pacemaker lead implantation has become a common technique. However, because of its relatively high complexity, it is still not the method of choice in most hospitals. As such, we propose an effective, simple, and safe technique for axillary venipuncture using only the cephalic vein as an anatomic landmark, with the possibility of selective cephalic contrast venography as a backup. A total of 108 patients were examined. After preparation of the cephalic vein, the puncture needle was inserted into the superficial pectoral muscle 1.5-2 cm medial to the cephalic vein and advanced in the direction parallel to the course of the cephalic vein. The needle was advanced up to 3-4 cm at an angle of 30 degrees relative to the body surface, applying gentle suction during advancement. If after 3 attempts the axillary vein was not accessed, the same process was repeated 3-4 cm medial to the cephalic vein. If this was not effective, contrast venography of the axillary vein through the cephalic vein was performed. In 92.6% of all cases, the axillary vein was cannulated without fluoroscopic control, and in 7.4% of cases, fluoroscopic control and selective contrast venography were needed. A novel technique for axillary venipuncture using the cephalic vein as a single landmark is a simple, effective, and safe tool for pacemaker lead implantation. In some cases, selective cephalic contrast venography is an elegant and effective addition. PMID- 26115872 TI - Prognostic Value of Oxygen Kinetics During Recovery From Cardiopulmonary Exercise Testing in Patients With Chronic Heart Failure. AB - BACKGROUND: Peak oxygen uptake (VO2peak) is a well-established prognostic marker in chronic heart failure (CHF). Cardiopulmonary exercise testing (CPET) provides physiological parameters other than VO2peak that might have prognostic value. We aimed at determining whether exercise recovery data kinetics have prognostic implications over VO2peak and Heart Failure Survival Score. METHODS: Exercise data from 200 consecutive CHF patients evaluated for possible heart transplantation and received CPET at our institution between 2004 and 2011 were analyzed. The rate of recovery of oxygen uptake (VO2) at 2 minutes after exercise (VO2-REC2) was calculated using the difference between VO2peak and VO2 at minute 2 of recovery and expressed as a percentage of VO2peak. The composite primary end point was the time from CPET to the first event including death, heart transplant, or mechanical heart implantation. RESULTS: Mean follow-up period was 1271 +/- 61 days during which there were 108 first events including 35 deaths, 66 heart transplants, and 7 mechanical heart implantations. The strongest prognostic factors in the univariate analysis were VO2-REC2, VO2peak, VO2 efficiency slope, and ventilation to carbon dioxide excretion ratio slope (all P < 0.0001). Multivariate analysis showed that VO2-REC2 (P < 0.0001), ventilation to carbon dioxide excretion ratio slope (P = 0.0022), use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (P = 0.0042), presence of a defibrillator (P = 0.0127), and mean arterial pressure (P = 0.0151) were independent predictors of event-free survival time. CONCLUSIONS: VO2-REC2 was the strongest prognostic marker of death, heart transplantation, and mechanical heart implantation in severe CHF. This finding should be confirmed prospectively. PMID- 26115873 TI - Cultural adaptation and validation of the Chinese version of the Fatigue Severity Scale in patients with major depressive disorder and nondepressive people. AB - PURPOSE: The aims of the study were to adapt the Fatigue Severity Scale to Chinese conditions and assess the psychometric properties of the Chinese version in patients with major depressive disorder (MDD) and nondepressive people. METHODS: A total of 101 patients with MDD and 94 nondepressive persons were included in this study. A forward and backward translation procedure was performed for developing a culturally acceptable Chinese version of the Fatigue Severity Scale (CFSS). Validity was assessed according to construct validity, internal consistency, concurrent validity, divergent validity, and contrasted group validity. RESULTS: The CFSS exhibited a one-factor structure in patients with MDD and the nondepressive participants. A 7-item version of CFSS and an 8 item version of the CFSS demonstrated better model fit than the original 9-item version in the patients with MDD and the nondepressive participants, respectively. In both participant groups, internal consistency values were within acceptable ranges. In addition, concurrent validity and divergent validity were confirmed in both groups. The average CFSS score of patients with MDD was significantly higher than that of the nondepressive participants. CONCLUSION: The 9-item CFSS is a valid instrument for assessing fatigue-related impairment in Chinese-speaking patients with MDD. However, the two reduced-item CFSS versions showed better psychometric properties than the original version in the patients with MDD and the nondepressive participants. PMID- 26115874 TI - Fibroblast Growth Factor Receptor Family Members as Prognostic Biomarkers in Head and Neck Squamous Cell Carcinoma: A Systematic Review. AB - BACKGROUND: Since head and neck cancer is characterized by poor survival rates, there is a demand for novel therapeutic targets and prognostic biomarkers. An upcoming therapeutic target is the fibroblast growth factor receptor (FGFR) family. However, their prognostic role in head and neck cancer remains unclear. OBJECTIVE: To systematically review current evidence on the prognostic value of FGFR family members in head and neck squamous cell carcinoma (HNSCC). METHODS: A systematic search of PubMed, Embase, and the Cochrane Library was performed for publications up to 14 May 2014. Two reviewers screened all articles and included prognostic studies on the molecular biomarkers FGFR1-5 in any type of HNSCC. Relevant studies were assessed on risk of bias using the Quality in Prognostic Studies (QUIPS) tool. Data on FGFR aberrations and survival outcome were extracted from relevant studies. The prognostic value of FGFR aberrations was compared among studies. RESULTS: The initial search yielded 1568 publications of which 12 fulfilled the inclusion criteria. Four studies reported FGFR1 gene amplification (9.3-17.4 %) and FGFR1 protein overexpression (11.8 %) in HNSCC. FGFR1 protein expression by cancer-associated fibroblasts correlated with poor survival outcome in one study (p < 0.01). Eight studies reported high rates of FGFR4 Gly388Arg polymorphisms (32.5-54.2 %) and FGFR4 protein overexpression (16 35 %), with varying correlations with survival. So far, no studies assessed the prognostic role of FGFR2, FGFR3, or FGFR5 in HNSCC. LIMITATIONS: Significant risk of bias has been identified among included studies. Therefore, cautious interpretation of the results is recommended. CONCLUSION: In conclusion, evidence was found for prognostic value of FGFR1 expression in cancer-associated fibroblasts in HNSCC. Prognostic evidence on the other FGFR family members in HNSCC is limited and conflicting. This emphasizes the need for future well conducted prognostic studies. PMID- 26115875 TI - Identification of the SOX5 gene as a novel IGH-involved translocation partner in BCL2-negative follicular lymphoma with t(12;14)(p12.2;q32). AB - Chromosome translocations involving the immunoglobulin heavy chain (IGH) gene locus at chromosome region 14q32 are often observed in B-cell lymphoid neoplasms. Of these, t(14;18)(q32;q21) results in juxtaposition of the IGH gene on chromosome 14 and the BCL2 gene on chromosome 18, leading to the overexpression of BCL2 anti-apoptotic protein, which plays a critical role in the development of follicular lymphoma (FL). However, BCL2 overexpression is not observed in approximately 10 % of FL, and the molecular pathogenesis of BCL2-negative FL has not been elucidated. Here, we identify the SRY-related high-morbidity-group (HMG) box 5 (SOX5) gene on chromosome 12p12 as a novel IGH-involved translocation partner in the case of BCL2-negative follicular lymphoma (FL) with a complex karyotype including t(12;14)(p12.2;q32) by long-distance inverse PCR. As a result of this translocation, the SOX5 gene is juxtaposed to the enhancer of the IGH gene; SOX5 overexpression in neoplastic cells was demonstrated by immunohistochemistry. The results of the present study suggest a role for SOX5 in the molecular pathogenesis of FL. PMID- 26115876 TI - Abdominal subcutaneous fat pad aspiration and bone marrow examination for the diagnosis of AL amyloidosis: the reliability of immunohistochemistry. AB - Tissue biopsy is essential for the diagnosis and typing of amyloidosis. Given its safety and ease, abdominal fat pad (AFP) is the first biopsy site of choice; bone marrow (BM) biopsy should additionally be performed to identify underlying plasma cell dyscrasia. The aim of the present study was to assess the usefulness of combined biopsy and immunohistochemical staining of AFP and BM tissues for the diagnosis and typing of amyloidosis. A total of 65 patients were examined. Congo red staining and immunohistochemical staining with antibodies were performed. Of 51 patients with systemic amyloidosis, 50 patients were examined with fat pad aspirates and 38 (76 %) cases were positive. All 51 patients were also examined by BM analysis and 25 (49 %) cases were positive. Including both AFP aspirates and BM specimens, 90 % of patients with systemic amyloidosis were Congo red positive. Of the 49 patients with AL amyloidosis, immunohistochemical stains were positive in 67.6 % of patients with AFP aspirates and in 50 % with BM specimens. Combining AFP aspirate and BM examination, immunohistochemical stains yielded positive stains for the corresponding circulating monoclonal immunoglobulin in 72.7 % of cases, and hence these analyses appear to be valuable in diagnosing the type of amyloidosis. PMID- 26115877 TI - Adiponectin is down-regulated in bone marrow interstitial fluid in hematological malignancy. AB - Adipokines play a role in carcinogenesis in a variety of malignancies. These findings were established with regard to serum adipokines and malignancies. However, the expression of adipokines in bone marrow fluid remains unclear, and an investigation of the correlation between bone marrow adipokines and hematological malignancy is needed. The present study was designed to detect adipokine concentrations, including adiponectin, leptin and resistin, in bone marrow interstitial fluid from patients with hematological malignancy and controlled counterparts. The correlations between adipokines, body mass index, clinical parameters, and hematological malignancy were assessed. A total of 80 bone marrow samples were assessed for values of adipokines, adiponectin, leptin and resistin. Patients with hematological malignancy had lower levels of adiponectin. Adiponectin from leukemia bone marrow expressed significantly low values. The adiponectin levels were inversely correlated with body mass index. In conclusion, adiponectin was decreased in bone marrow from patients with leukemia and negatively correlated with body mass index. PMID- 26115878 TI - Multi-modal intervention to reduce cardiovascular risk among hypertensive older adults: Design of a randomized clinical trial. AB - Persons aged over 65 years account for over 75% of healthcare expenditures and deaths attributable to cardiovascular disease (CVD). Accordingly, reducing CVD risk among older adults is an important public health priority. Functional status, determined by measures of physical performance, is an important predictor of cardiovascular outcomes in older adults and declines more rapidly in seniors with hypertension. To date, physical exercise is the primary strategy for attenuating declines in functional status. Yet despite the general benefits of training, exercise alone appears to be insufficient for preventing this decline. Thus, alternative or adjuvant strategies are needed to preserve functional status among seniors with hypertension. Prior data suggest that angiotensin converting enzyme inhibitors (ACEi) may be efficacious in enhancing exercise-derived improvements in functional status yet this hypothesis has not been tested in a randomized controlled trial. The objective of this randomized, double-masked pilot trial is to gather preliminary efficacy and safety data necessary for conducting a full-scale trial to test this hypothesis. Sedentary men and women >= 65 years of age with functional limitations and hypertension are being recruited into this 24 week intervention study. Participants are randomly assigned to one of three conditions: (1) ACEi plus exercise training, (2) thiazide diuretic plus exercise training, or (3) AT1 receptor antagonist plus exercise training. The primary outcome is change in walking speed and secondary outcomes consist of other indices of CV risk including exercise capacity, body composition, as well as circulating indices of metabolism, inflammation and oxidative stress. PMID- 26115879 TI - Study design, intervention, and baseline characteristics of a group randomized trial involving a faith-based healthy eating and physical activity intervention (Walk by Faith) to reduce weight and cancer risk among overweight and obese Appalachian adults. AB - BACKGROUND: Increased prevalence of overweight and obesity among Appalachian residents may contribute to increased cancer rates in this region. This manuscript describes the design, components, and participant baseline characteristics of a faith-based study to decrease overweight and obesity among Appalachian residents. METHODS: A group randomized study design was used to assign 13 churches to an intervention to reduce overweight and obesity (Walk by Faith) and 15 churches to a cancer screening intervention (Ribbons of Faith). Church members with a body mass index (BMI) ?25 were recruited from these churches in Appalachian counties in five states to participate in the study. A standard protocol was used to measure participant characteristics at baseline. The same protocol will be followed to obtain measurements after completion of the active intervention phase (12months) and the sustainability phase (24months). Primary outcome is change in BMI from baseline to 12months. Secondary outcomes include changes in blood pressure, waist-to-hip ratio, and fruit and vegetable consumption, as well as intervention sustainability. RESULTS: Church members (n=664) from 28 churches enrolled in the study. At baseline 64.3% of the participants were obese (BMI?30), less than half (41.6%) reported regular exercise, and 85.5% reported consuming less than 5 servings of fruits and vegetables per day. CONCLUSIONS: Church members recruited to participate in a faith-based study across the Appalachian region reported high rates of unhealthy behaviors. We have demonstrated the feasibility of developing and recruiting participants to a faith-based intervention aimed at improving diet and increasing exercise among underserved populations. PMID- 26115880 TI - Design and methods of the Gentle Cardiac Rehabilitation Study--A behavioral study of tai chi exercise for patients not attending cardiac rehabilitation. AB - INTRODUCTION: Cardiac rehabilitation (CR) programs reduce overall and cardiovascular mortality in patients with a history of acute coronary events or revascularization procedures, but only 30% of patients enroll in CR and attrition rates reach up to 60%. Tai chi, a mind-body practice based on light/moderate aerobic exercise accompanied by meditative components could be a possible exercise option for patients who do not attend CR. METHODS/DESIGN: Sixty patients will be randomized to a "LITE" condition (one tai chi session twice weekly for 12 weeks) or to a "PLUS" condition (one tai chi session 3 times weekly for 12 weeks, followed by maintenance classes 1-2 times weekly for an additional 12 weeks). Measurements will be conducted at baseline, 3-, 6-, and 9 months after enrollment. The primary outcome is to determine the feasibility, acceptability and safety of each dose. Secondary outcomes include estimates of effect size of each dose on accelerometry-assessed physical activity; the proportion of patients meeting current recommendations for physical activity; and measures of fitness, quality of life, body weight, and sleep. In addition, we will collect exploratory information on possible mediators (exercise self-efficacy, perceived social support, resilience, mindfulness, and depression). CONCLUSIONS: Findings from this pilot study will provide preliminary indications about the usefulness of tai chi as an exercise option for patients not attending traditional CR programs. Results will also shed light on the possible mechanisms by which tai chi practice may improve overall physical activity among patients with atherosclerotic coronary heart disease. PMID- 26115883 TI - Evaluation and identification of poly-microbial biofilms on natural green Gordal table olives. AB - This work examines the formation of poly-microbial communities adhered to the epidermis of natural green Gordal olives and the application of different methodologies for recovery and counting of the microorganisms embedded in olive biofilms. The fermentation process was physicochemical and microbiologically monitored for 90 days, at which, formation of true biofilms on the skin of fermented fruits was confirmed by scanning electron microscopy. Then, samples of olives were taken and treated with sonication, enzymes, mechanical homogenization with stomacher and ultrasonic bath for biofilm disaggregation. The use of the stomacher for 1 min was the most effective treatment to release the lactic acid bacteria (6.6 log10 cfu g(-1)), whereas sonication for 5 min was the most efficient method for quantification of yeasts (up to 3.5 log10 cfu g(-1)). Molecular identification of isolates obtained from natural Gordal olive biofilms revealed that Lactobacillus pentosus was the only species found among lactic acid bacteria, while Pichia membranifaciens was the dominant yeast species, with higher counts obtained for the bacteria. PMID- 26115882 TI - Pseudonocardia nematodicida sp. nov., isolated from mangrove sediment in Hainan, China. AB - Two aerobic, Gram-stain positive actinobacterial strains with nematicidal activity, designated HA11164(T) and HA12591, were isolated from mangrove sediments in Hainan, China. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strains HA11164(T) and HA12591 belong to the genus Pseudonocardia and are closely related to Pseudonocardia carboxydivorans (with the similarities of 98.30 and 98.24 %, respectively), Pseudonocardia alni (98.23 and 98.16 %, respectively) and Pseudonocardia antimicrobica (98.10 and 98.03 %, respectively). The major polar lipids of the strain HA11164(T), as a representative strain of the two strains, were found to consist of phosphatidylmethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, phosphatidylinositol, five unidentified glycolipids and four unidentified polar lipids. The predominant menaquinone of strain HA11164(T) was identified as MK-8 (H4), and the major fatty acids were identified as iso-C16:0, C17:1 omega10, C16:0 and C16:1 omega9. The G+C content of strain HA11164(T) was determined to be 74.9 mol%. The DNA-DNA relatedness values between strains HA11164(T) and P. alni, Pseudonocardia tropica, Pseudonocardia antarctica, P. carboxydivorans and Pseudonocardia parietis were 58.3, 56.2, 50.0, 57.1 and 46.0 %, respectively. Based on the results of this polyphasic study, strains HA11164(T) and HA12591 are considered to represent a novel species of the genus Pseudonocardia, for which the name Pseudonocardia nematodicida sp. nov. is proposed. The type strain is HA11164(T) (=CGMCC 4.7118(T) = DSM 45940(T)). PMID- 26115881 TI - Injecting risk behaviours following treatment for hepatitis C virus infection among people who inject drugs: The Australian Trial in Acute Hepatitis C. AB - BACKGROUND: A barrier to hepatitis C virus (HCV) treatment among people who inject drugs (PWID) has been a concern that interferon-based HCV treatment may increase injecting risk behaviours. This study evaluated recent (past month) injecting risk behaviours during follow-up among PWID that did and did not receive HCV treatment. METHODS: The Australian Trial in Acute Hepatitis C (ATAHC) was a prospective study of natural history and treatment of recent HCV infection. Analyses were performed using generalized estimating equations. RESULTS: Among 124 participants with a history of injecting drug use (median age 32 years), 69% were male, and 68% were treated for HCV infection. HCV treatment was not associated with an increase in recent injecting drug use (adjusted odds ratio (aOR) 1.06, 95% CI 0.93, 1.21) or recent used needle and syringe borrowing during follow-up (aOR 0.99, 95% CI 0.89, 1.08). HCV treatment was associated with a decrease in recent ancillary injecting equipment sharing during follow-up (aOR 0.85, 95% CI 0.74, 0.99). Further, among treated participants who remained in follow-up (n=24), ancillary injecting equipment sharing significantly decreased from 54% at enrolment to 17% during follow-up (P=0.012). CONCLUSIONS: HCV treatment was not associated with drug use or used needle and syringe borrowing during follow-up, but was associated with decreased ancillary injecting equipment sharing during follow-up. Programs to enhance HCV assessment and treatment among PWID should be expanded, given that HCV treatment does not lead to increases in injecting risk behaviours and has previously been demonstrated to be safe and effective among PWID. PMID- 26115884 TI - Single nucleotide polymorphisms of the EpCAM-coding gene TACSTD1 in patients with ovarian cancer and their potential translational aspects. AB - PURPOSE: EpCAM is overexpressed in many neoplasms including ovarian cancer. We screened the EpCAM-coding gene TACSTD1 for single nucleotide polymorphisms (SNPs), which could alter ovarian cancer risk, impact upon disease progression, or alter binding of the therapeutic EpCAM-binding antibody, catumaxomab. METHODS: DNA fragments of 10 healthy volunteers were analyzed to identify SNPs. Subsequently, DNA of ovarian cancer patients (n = 117) and age-matched healthy controls (n = 115) was genotyped by restriction fragment length polymorphism and pyrosequencing. TACSTD1 genotypes 4461T>C were cloned into a gene expression vector; Hek293 cells were subsequently used for stable transfection. FACS analysis of the transfected Hek293 cells was conducted with HO-3-the EpCAM binding site of catumaxomab-to determine antibody binding. RESULTS: One SNP was detected in exon 3 (4461T>C; rs1126497), resulting in an amino acid exchange at position 115 (Met115Thr). Another polymorphism was found in the 3'UTR (17225A>G; rs1421). Genotyping of patients and controls for these SNPs did not reveal significant differences in genotype distribution. Regarding 17225A>G, the homozygous AA-genotype was associated with diminished progression-free survival (PFS; p = 0.032). Overall survival, FIGO-stage, grading, and age did not differ significantly between genotypes. FACS analysis of transfected Hek293 cells overexpressing EpCAM 115Met/Thr showed binding of HO-3 to both proteins. CONCLUSIONS: The AA-genotype of 17225A>G seems to be associated with diminished PFS in ovarian cancer patients. The amino acid exchange resulting from 4461T>C does not appear to alter binding of HO-3, suggesting that treatment with catumaxomab can be offered to patients regardless of their TACSTD1-genotype. PMID- 26115885 TI - Fine particulate matter leads to reproductive impairment in male rats by overexpressing phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. AB - Maintenance of male reproductive function depends on normal sperm generation during which process Sertoli cells play a vital role. Studies found that fine particulate matter (PM) causes decreased male sperm quality, mechanism of which unestablished. We aim to investigate the definite mechanism of PM impairment on male reproduction. Male Sprague-Dawley rats were daily exposed to normal saline (NS) or PM2.5 with the doses of 9 mg/kg.b.w and 24 mg/kg.b.w. via intratracheal instillation for seven weeks. Reproductive function was tested by mating test and semen analysis after last exposure. Testes were collected to assess changes in histomorphology, and biomarkers including connexin 43 (Cx43), superoxide dismutase (SOD), phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (p-Akt). Male rats exposed to PM2.5 showed noticeable decreased fertility, significantly reduced sperm count, increased sperm abnormality rate and severe testicular damage in histomorphology. After PM2.5 exposure, the levels of Cx43 was significantly downregulated, and SOD was upregulated and downregulated significantly with different dose, respectively. Protein expression of PI3K and p-Akt dramatically enhanced, and the later one being located in Sertoli cells, the upward or declining trend was in dose dependent. PM2.5 exposure leads to oxidative stress impairment via PI3K/Akt signaling pathway on male reproduction in rats. PMID- 26115886 TI - Coordinated regulation of scopoletin at adipose tissue-liver axis improved alcohol-induced lipid dysmetabolism and inflammation in rats. AB - There is increasing evidence that alcohol-induced white adipose tissue (WAT) dysfunction contributes to disturbance of hepatic lipid metabolism. This study investigated the effects of scopoletin on lipid homeostasis and inflammation at the WAT and liver in chronic alcohol-fed rats. Rats were fed a liquid diet containing 5% alcohol with or without two doses of scopoletin (0.001% and 0.005%) for 8 weeks. Scopoletin decreased serum triglyceride and cytokines (TNFalpha and IL-6) levels and hepatic and WAT lipid levels, whereas it increased WAT adiponectin mRNA and serum adiponectin levels, up-regulated hepatic gene and protein expression of AdipoR2 and activated AMPK. Additionally, scopoletin inhibited the expression of lipogenic genes (SREBP-1c and Fasn) and increased the expression of fatty acid oxidative genes (PPARalpha, Acsl1, CPT, Acox, and Acaa1a) in both WAT and liver. Alcohol led to significant up-regulation of WAT lipolysis and hepatic Cidea gene expression, whereas it decreased the WAT Cidea gene level; however, scopoletin reversed these changes. Scopoletin significantly down-regulated TLR4 signaling genes such as MyD88, TRIF, NFkappaB, TNFalpha and IL-6 in WAT and liver. These results indicated that coordinated regulation of scopoletin at the WAT-liver axis may play an important role in improvement of alcohol-induced lipid dysregulation and inflammation. PMID- 26115888 TI - Suprascapular nerve compression due to rib osteochondroma: MR imaging features. PMID- 26115887 TI - Bioactive Functions of Milk Proteins: a Comparative Genomics Approach. AB - The composition of milk includes factors required to provide appropriate nutrition for the growth of the neonate. However, it is now clear that milk has many functions and comprises bioactive molecules that play a central role in regulating developmental processes in the young while providing a protective function for both the suckled young and the mammary gland during the lactation cycle. Identifying these bioactives and their physiological function in eutherians can be difficult and requires extensive screening of milk components that may function to improve well-being and options for prevention and treatment of disease. New animal models with unique reproductive strategies are now becoming increasingly relevant to search for these factors. PMID- 26115889 TI - Pitfalls and mimickers on (18)F-FDG-PET/CT in peritoneal carcinomatosis from colorectal cancer: An analysis from 37 patients. AB - BACKGROUND: Optimal selection is critical in patients with peritoneal carcinomatosis (PC) in whom curative cytoreductive surgery can be anticipated. (18)F-FDG-PET/CT may result in false-positive findings that may eliminate patients for whom cytoreductive surgery would be beneficial. OBJECTIVES: To determine the rate of false-positive findings on (18)F-FDG-PET/CT and clarify their causes in patients with suspected PC from colorectal cancer. METHODS: A retrospective analysis of 37 patients with suspected PC from colorectal cancer who had (18)F-FDG-PET/CT before cytoreductive surgery was performed to determine the rate and the causes of false-positive findings. (18)F-FDG-PET/CT was considered falsely positive when no tumor was found at surgery, histopathological analysis and follow-up. RESULTS: False-positive findings were observed in four patients, yielding a 11% (95%CI: 3-25%) false-positive rate on a per-patient basis. The causes of false-positives were elucidated in two patients (surgical mesh after umbilical hernia repair and one foreign body granuloma). CONCLUSION: False-positive findings on (18)F-FDG-PET/CT are observed in 11% of patients with suspected PC from colorectal cancer. Familiarity with false-positive findings would result in more accurate selection of patients candidates to cytoreductive surgery. PMID- 26115890 TI - Response to Bonnefon et al.: Limited 'kernels of truth' in facial inferences. PMID- 26115892 TI - Extreme clinical chemistry. PMID- 26115891 TI - [A self-report study of sexual victimization in Spanish community adolescents and at-risk groups]. AB - OBJECTIVE: To determine the extent of sexual victimization in four groups of Spanish adolescents based on their own reports. METHOD: An observational, cross sectional, multicenter study was conducted. Sexual victimization was assessed by seven questions included in the Juvenile Victimization Questionnaire. The samples were composed of 1,105 adolescents (mean age [M]=14.52, standard deviation [SD]=1.76) from seven secondary schools; 149 adolescents (M=14.28; SD=1.45) from 14 child and adolescent mental health centers; 129 adolescents (M=14.59, SD=1.62) institutionalized in 18 long-term (78.3%) and short-term (21.7%) residential centers belonging to the child protection system; and 101 adolescents (M=16.08, SD=0.99) recruited from three detention centers (77.2%) and five open regime teams or follow-up services for court orders for minors not requiring loss of freedom (22.8%). RESULTS: The extent of lifetime sexual victimization ranged from 14.7% of the adolescents in the community sample to 23.5% of youths attended in mental health services, 35.6% of youths involved in the juvenile justice system, and 36.4% of children protected by the child welfare system. Most of the victims were female, the only exception being the group of male victims from the juvenile justice system. CONCLUSIONS: Sexual victimization of children is widespread in Spain and its distribution differs depending on the group of children under study. PMID- 26115893 TI - Association between hypertriglyceridemia and protein oxidation and proinflammatory markers in normocholesterolemic and hypercholesterolemic individuals. AB - BACKGROUND: Although hypercholesterolemia is a well-established risk factor for coronary heart disease, evidence suggests that increased triglyceride (TG) concentrations are also an independent risk factor. TG concentrations >150mg/dl are observed nearly twice as often in subjects with atherosclerosis. We assessed the association between hypertriglyceridemia and protein oxidation and proinflammatory markers in normocholesterolemic and hypercholesterolemic individuals. METHODS: We included 127 volunteers enrolled in Cruz Alta, RS, Brazil. The patients were stratified based on total cholesterol and TG concentrations for analysis of associations with inflammation (high-sensitivity C reactive protein - hs-CRP), endothelial dysfunction (nitric oxide - NOx) and oxidative stress (advanced oxidation protein products - AOPPs; ischemia-modified albumin - IMA). Correlations between variables were determined and multiple regression analysis was employed to investigate whether some variables correlate with TG concentrations. RESULTS: Hypertriglyceridemia was related to oxidative stress and proinflammatory markers in individuals independent of total cholesterol concentrations. Moreover, the results indicate a stronger association of tested biomarkers with TG concentrations than with total cholesterol. The results indicate a positive correlation between oxidative stress and TG concentrations in the sera of hypercholesterolemia subjects. AOPPs and IMA concentrations were associated with the presence of hypertriglyceridemia in a manner that was independent of age, gender, hypertension and diabetes mellitus disease, smoking habits, sedentary lifestyle, BMI, waist circumference, LDL, HDL and total cholesterol concentrations. CONCLUSIONS: We speculate that TG concentrations can reflect the enhancement of protein oxidation and proinflammation. PMID- 26115894 TI - Metabolic annotation of 2-ethylhydracrylic acid. AB - Increased levels of the organic acid, 2-ethylhydracrylic acid (2-EHA) occur in urine of subjects with impaired L(+)-isoleucine metabolism. Chiral intermediates formed during isoleucine degradation are (S) enantiomers. Blockage of (S) pathway flux drives racemization of (2S, 3S) L(+)-isoleucine and its (2S, 3R) stereoisomer, L(+)-alloisoleucine. This non-protein amino acid is metabolized to (R)-2-methylbutyryl CoA via enzymes common to branched chain amino acid degradation. Subsequently, (R) intermediates serve as alternate substrates for three valine metabolic enzymes, generating 2-EHA. Once formed, 2-EHA accumulates because it is poorly recognized by distal valine pathway enzymes. Thus, urinary 2 EHA represents a biomarker of isoleucine pathway defects. 2-EHA levels are also increased in rats exposed to the industrial solvent, ethylene glycol monomethyl ether or the neurotoxin precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In these cases, a block in (S) pathway isoleucine catabolism occurs at the level of (S)-2-methylbutyryl CoA conversion to tiglyl CoA via inhibition of electron transferring flavoprotein/ubiquinone oxidoreductase dependent reactions. Elevated urinary 2-EHA in propionyl CoA carboxylase deficiency and methylmalonic aciduria results from a buildup of distal intermediates in the (S) pathway of isoleucine degradation. In Barth syndrome and dilated cardiomyopathy with ataxia syndrome, 2 EHA is a byproduct of impeded propionyl CoA entry into the Krebs cycle. PMID- 26115895 TI - Utilization of the O-arm after Ommaya reservoir placement. AB - The authors demonstrate the utility of portable intraoperative CT scans for the rapid identification of ventricular catheter tip location after Ommaya reservoir placement. The O-arm (Medtronic Sofamor Danek, Memphis, TN, USA) was utilized to confirm ventricular catheter placement intraoperatively. Conventionally, a postoperative CT scan is obtained prior to Ommaya reservoir use to ensure proper catheter placement. By obtaining these images intraoperatively, revisions may be performed without the need for an additional surgical procedure, and the reservoir may be utilized immediately postoperatively. PMID- 26115896 TI - Survival following Ommaya reservoir placement for neoplastic meningitis. AB - The objective of this study was to evaluate the outcomes of patients with neoplastic meningitis (NM) following Ommaya reservoir placement in order to determine whether any patient factors are associated with longer survival. NM is a devastating late manifestation of cancer, and given its dismal prognosis, identifying appropriate patients for Ommaya reservoir placement is difficult. The authors performed a retrospective review of 80 patients who underwent Ommaya reservoir placement at three medical centers from September 2001 through September 2012. The primary outcome was death. Differences in survival were assessed with Kaplan-Meier survival analyses. The Cox proportional hazards and logistic regression modeling were performed to identify factors associated with survival. The primary diagnoses were solid organ, hematologic, and primary central nervous system tumors in 53.8%, 41.3%, and 5%, respectively. The median overall survival was 72.5 days (95% confidence interval 36-122) with 30% expiring within 30 days and only 13.8% surviving more than 1 year. There were no differences in median overall survival between sites (p=0.37) despite differences in time from diagnosis of NM to Ommaya reservoir placement (p<0.001). Diagnosis of hematologic malignancy was inversely associated with death within 90 days (p=0.04; odds ratio 0.34), older age was associated with death within 90 days (p=0.05; odds ratio 1.5, per 10 year increase in age). The prognosis of NM remains poor despite the available treatment with intraventricular chemotherapy. There exists significant variability in treatment algorithms among medical centers and consideration of this variability is crucial when interpreting existing series of Ommaya reservoir use in the treatment of patients with NM. PMID- 26115897 TI - Surgical management of malignant cerebral edema secondary to immune reconstitution inflammatory syndrome from natalizumab-associated progressive multifocal encephalopathy. AB - We report a rare multiple sclerosis (MS) patient who developed malignant cerebral edema related to progressive multifocal encephalopathy (PML) immune reconstitution inflammatory syndrome (IRIS) after natalizumab discontinuation. The patient subsequently required a decompressive hemicraniectomy to reduce intracranial pressure and to avoid uncal herniation. PML is a demyelinating disease of the central nervous system (CNS) which affects oligodendrocytes and is caused by reactivation of latent John Cunningham virus. Natalizumab is a known risk factor (1 in 1000) for MS patients treated with this drug. Discontinuation of natalizumab treatment decreases the risk of PML progression, but a massive inflammatory response can occur after cell-mediated immune surveillance is reestablished in the CNS, causing immune reconstitution inflammatory syndrome (IRIS). Treatment of IRIS usually consists of steroids and plasma exchange to lessen the immune response, however, mortality has been reported at up to 29.4%, despite aggressive medical treatment. We discuss our management strategy with a review of the pertinent literature. PMID- 26115899 TI - Central retinal vein occlusion in a migraine patient. AB - We describe a 31-year-old woman with a history of migraines without aura, who presented to our emergency department due to a monocular visual disturbance. This was misdiagnosed as being related to her migraine, however, it was subsequently found to be caused by a central retinal vein occlusion. Patients suffering from migraine can experience visual disturbances in the form of auras. The neuropathological basis for this phenomenon is thought to be a spreading depression in the visual cortex, causing a hemifield active visual phenomenon. Missing the diagnosis of central retinal vein occlusion is common, especially in the setting of an initially normal fundoscopy examination. PMID- 26115900 TI - The Impact of Metabolic Syndrome on Clinical Outcomes After Everolimus-Eluting Stent Implantation. AB - As it is controversial whether metabolic syndrome (MetS) affects cardiovascular outcomes in patients who underwent percutaneous coronary intervention (PCI), we investigated the impact of MetS on clinical outcomes in patients who underwent PCI with everolimus-eluting stents (EESs). Patients who underwent PCI with EESs from 2009 to 2013 were included in this single-center, prospective cohort study. A composite event consisted of repeat revascularization, nonfatal myocardial infarction, and cardiac death. Of 903 patients observed for 4.9 years (median 1.8 years), 570 were diagnosed with MetS. The MetS group displayed more severe coronary artery disease and underwent more extensive PCIs than did the non-MetS group. The overall composite event rate was not significantly different between the MetS and the non-MetS group (11.9% vs 13.2%, p = 0.572). Kaplan-Meier survival analysis showed no significant difference in the event-free survival of the composite event between the 2 groups (p = 0.700). A multivariable Cox regression analysis showed that MetS was not associated with the composite event, whereas total stent length, decreased renal function, diabetes, and the absence of abdominal obesity were associated with the composite event. Abdominal obesity was associated with decreased risk of the composite event, alleviating unfavorable clinical outcomes of patients with diabetes in the MetS group. In conclusion, MetS has no impact on the clinical outcomes of patients who underwent PCI with EESs, although the MetS group exhibited more severe coronary artery disease and underwent more extensive PCIs. The paradoxical association between obesity and favorable clinical outcomes may explain this result. PMID- 26115898 TI - Use of multivariate linear regression and support vector regression to predict functional outcome after surgery for cervical spondylotic myelopathy. AB - This study introduces the use of multivariate linear regression (MLR) and support vector regression (SVR) models to predict postoperative outcomes in a cohort of patients who underwent surgery for cervical spondylotic myelopathy (CSM). Currently, predicting outcomes after surgery for CSM remains a challenge. We recruited patients who had a diagnosis of CSM and required decompressive surgery with or without fusion. Fine motor function was tested preoperatively and postoperatively with a handgrip-based tracking device that has been previously validated, yielding mean absolute accuracy (MAA) results for two tracking tasks (sinusoidal and step). All patients completed Oswestry disability index (ODI) and modified Japanese Orthopaedic Association questionnaires preoperatively and postoperatively. Preoperative data was utilized in MLR and SVR models to predict postoperative ODI. Predictions were compared to the actual ODI scores with the coefficient of determination (R(2)) and mean absolute difference (MAD). From this, 20 patients met the inclusion criteria and completed follow-up at least 3 months after surgery. With the MLR model, a combination of the preoperative ODI score, preoperative MAA (step function), and symptom duration yielded the best prediction of postoperative ODI (R(2)=0.452; MAD=0.0887; p=1.17 * 10(-3)). With the SVR model, a combination of preoperative ODI score, preoperative MAA (sinusoidal function), and symptom duration yielded the best prediction of postoperative ODI (R(2)=0.932; MAD=0.0283; p=5.73 * 10(-12)). The SVR model was more accurate than the MLR model. The SVR can be used preoperatively in risk/benefit analysis and the decision to operate. PMID- 26115901 TI - Predictors of Six-Month Mortality in BNP-Matched Acute Heart Failure Patients. AB - Natriuretic peptides have established prognostic value in heart failure (HF). The role of many other clinical and laboratory variables is still to be proved. The aim of this study was to assess prognostic determinants of death in acute HF in B type natriuretic peptide (BNP)-matched patients. We conducted a case-control study to assess prognostic predictors of 6-month mortality in acute HF. From a prospectively recruited population of hospital-admitted patients with acute HF, we retrospectively selected a convenience sample of age-, gender-, and admission BNP-matched patients who survived (controls) or died (cases) in the follow-up period. Prognostic predictors of death were analyzed using a Cox regression analysis. A multivariate model was built. Variables in the model included atrial fibrillation, hypertension, admission heart rate, systolic blood pressure, the New York Heart Association class, hemoglobin, urea, albumin, systolic dysfunction, ischemic etiology, prognostic-modifying therapy, and BNP decrease during hospitalization. We analyzed 224 patients: 112 surviving and 112 not surviving a 6-month period. Median age was 80 years, 42.9% of the patients were men, and 63.9% had systolic dysfunction. Patients surviving the first 6 months had higher admission systolic blood pressure and heart rate, higher hemoglobin, lower urea, and more often had >30% decrease in BNP during hospitalization; they were more often discharged on HF prognostic modifying therapy. However, in multivariate analysis, the only independent mortality predictor was BNP decrease: patients in whom BNP decreased >30% had an HR of death of 0.57 (0.37 to 0.89). In conclusion, in BNP-matched patients with acute HF, the only independent mortality predictor is BNP decrease. Other literature suggested death predictors do not seem independent of natriuretic peptides. PMID- 26115902 TI - Threat of alveolar echinococcosis to public health--a challenge for Europe. AB - Alveolar echinococcosis (AE) is a neglected 'malignant' parasitic disease. The European endemic area of Echinococcus multilocularis in foxes is larger than previously anticipated, and there is new evidence that both fox populations and the prevalence of E. multilocularis have increased in many areas, indicating increased pressure for infection with E. multilocularis eggs in intermediate and accidental hosts, including humans. This may result in more human AE cases within the next decades. Current numbers of both immunocompetent and immunocompromised AE patients, and the anticipated future increase, call for scaling-up research to rapidly improve the development and implementation of prevention measures, early diagnosis, and curative treatment of human AE. PMID- 26115903 TI - Factors predicting severe infections during chemotherapy in head and neck cancer patients. AB - CONCLUSIONS: The head and neck cancer patients with more co-morbidities and those dependent on tube feeding are at a high risk of severe infections during chemotherapy. Therefore, prophylaxis with colony-stimulating factors and/or antibiotics should be considered for those patients. OBJECTIVES: To investigate the risk factors for severe infection during chemotherapy in head and neck cancer patients. METHODS: A retrospective study was conducted of 129 patients with head and neck cancer who received taxane-based and platinum-based chemotherapy between 2008-2013. Logistic regression models were used to evaluate risk factors. RESULTS: Febrile neutropenia occurred in 50 patients out of the 129 (39%), severe infections occurred in 24 patients (19%), and bacteremia in two patients (2%). In univariate analysis, low serum albumin levels and tube feeding were significantly associated with severe infections (p = 0.015 and < 0.001, respectively). In multivariate analysis, the odds ratios for a higher modified Charlson co morbidity index and tube feeding were 2.80 and 9.74, respectively. These two were independent predictive factors for severe infections (p = 0.020 and 0.001, respectively). PMID- 26115904 TI - Evidence for mild sediment Pb contamination affecting leaf-litter decomposition in a lake. AB - Much work has focused on the effects of metal-contaminated sediment on benthic community structure, but effects on ecosystem functions have received far less attention. Decomposition has been widely used as an integrating metric of ecosystem function in lotic systems, but not for lentic ones. We assessed the relationship between low-level sediment lead (Pb) contamination and leaf-litter decomposition in a lentic system. We measured 30-day weight loss in 30 litter bags that were deployed along a Pb-contamination gradient in a cypress-forested lake. At each deployment site we also quantified macrobenthos abundance, dissolved oxygen, water depth, sediment organic content, sediment silt/clay content, and both total sediment and porewater concentrations of Cd, Cu, Ni, Pb and Zn. Principal components (PC) analysis revealed a negative relationship between Pb concentration and benthic macroinvertebrate abundance, and this covariation dominated the first PC axis (PC1). Subsequent correlation analyses revealed a negative relationship between PC1 and percent leaf-litter loss. Our results indicate that leaf-litter decomposition was related to sediment Pb and benthic macroinvertebrate abundance. They also showed that ecosystem function may be affected even where sediment Pb concentrations are mostly below threshold effects sediment quality guidelines--a finding with potential implications for sediment risk assessment. Additionally, the litter-bag technique used in this study showed promise as a tool in risk assessments of metal-contaminated sediments in lentic systems. PMID- 26115905 TI - The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. AB - BACKGROUND: Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which skin barrier function is disrupted in patients with AD remains unclear. OBJECTIVES: Taking into account the fact that the TH2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. METHODS: We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE 052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. RESULTS: IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. CONCLUSION: STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD. PMID- 26115906 TI - Early-term birth is a risk factor for wheezing in childhood: A cross-sectional population study. AB - BACKGROUND: Early term-born (37-38 weeks' gestation) infants have increased respiratory morbidity during the neonatal period compared with full term-born (39 42 weeks' gestation) infants, but longer-term respiratory morbidity remains unclear. OBJECTIVE: We assessed whether early term-born children have greater respiratory symptoms and health care use in childhood compared with full term born children. METHODS: We surveyed 1- to 10-year-old term-born children (n = 13,361). Questionnaires assessed respiratory outcomes with additional data gathered from national health databases. RESULTS: Of 2,845 eligible participants, 545 were early term-born and 2,300 were full term-born. Early term-born children had higher rates of admission to the neonatal unit (odds ratio [OR], 1.7; 95% CI, 1.2-2.5) and admission to the hospital during their first year of life (OR, 1.6; 95% CI, 1.2-2.1). Forty-eight percent of early term-born children less than 5 years old reported wheeze ever compared with 39% of full term-born children (OR, 1.5; 95% CI, 1.1-1.9), and 26% versus 17% reported recent wheezing (OR, 1.7; 95% CI, 1.3-2.4). Early term-born children older than 5 years reported higher rates of wheeze ever (OR, 1.4; 95% CI, 1.05-1.8) and recent wheezing over the last 12 months than full-term control subjects (OR, 1.4; 95% CI, 1.02-2.0). Increased rates of respiratory symptoms in early term-born children persisted when family history of atopy and delivery by means of cesarean sections were included in logistic regression models. CONCLUSION: Early term-born children had significantly increased respiratory morbidity and use of health care services when compared with full term-born children, even when stratified by mode of delivery and family history of atopy. PMID- 26115907 TI - School-Based Body Mass Index Screening and Parental Notification in Late Adolescence: Evidence From Arkansas's Act 1220. AB - PURPOSE: In 2003, Arkansas enacted Act 1220, one of the first comprehensive legislative initiatives aimed at addressing childhood obesity. One important provision of Act 1220 mandated that all children attending public schools be screened for their body mass index (BMI) and the information sent home to their parents. Since then, eight other states have adopted similar school-based BMI screening and notification policies. Despite their widespread adoption and implementation, there is a dearth of empirical studies evaluating such policies, particularly for adolescents. The aim of this study was to evaluate whether adolescents, who had been previously screened in early adolescence, experienced changes in their health outcomes if they continued to receive screening and reporting throughout late adolescence (11th and 12th grades). METHODS: Secondary data from the Centers for Disease Control's Youth Risk Behavior Survey were analyzed using the method of difference-in-differences. Changes in outcomes between 10th and 12th grade were compared between a group of students who received screenings throughout 11th and 12th grades versus a later comparison group who were exempt from screening and reporting requirements in 11th and 12th grades. RESULTS: BMI screening and parental notification during late adolescence, given prior screening and notification in early adolescence, was not significantly related to BMI-for-age z-scores, the probability of being in a lower weight classification or exercise and dietary intake behaviors. CONCLUSIONS: Exposing 11th and 12th graders to BMI screening and reporting, given that they had been exposed in prior grades, was not associated with adolescents' health outcomes. PMID- 26115908 TI - Adolescents' Perceptions of Risks and Benefits of Conventional Cigarettes, E cigarettes, and Marijuana: A Qualitative Analysis. AB - PURPOSE: Although rates of adolescent cigarette use have remained constant or decreased, rates of marijuana and e-cigarette use are rising. Knowledge and perceptions of risks and benefits of tobacco products impact adolescents' decisions to use these products. However, little is known regarding adolescents' knowledge and perceptions of risks of e-cigarettes and marijuana nor how these perceptions are formed. This study uses qualitative techniques to assess and compare adolescents' perceptions of the risks and benefits of cigarettes, e cigarettes, and marijuana. METHODS: Twenty-four adolescents (nine females and 15 males) from Northern California participated in six small-group discussions. Adolescents were asked what good or bad things might happen from using these products. To assess how perceptions and knowledge of risks and benefits were formed, participants were asked where and from whom they had learned about these products. RESULTS: Adolescents described negative consequences of cigarette use but were much less sure regarding risks of marijuana and e-cigarette use. Conversely, they described few benefits of cigarettes but described a number of benefits of e-cigarette and marijuana use. Adolescents described learning about these products from the media, from family and friends, and from the school environment. CONCLUSIONS: Adolescents have learned from multiple sources about risks of using cigarettes, but they receive much less and often incorrect information regarding marijuana and e-cigarettes, likely resulting in their positive and often ambivalent perceptions of marijuana and e-cigarettes. PMID- 26115909 TI - Longitudinal Associations Between Cybervictimization and Mental Health Among U.S. Adolescents. AB - PURPOSE: An emerging body of literature suggests that victims of bullying report detrimental mental health outcomes, such as depression and anxiety. The purpose of this study was to explore the relationship between cybervictimization, depression, and anxiety among school-aged youth over a 3-year time frame. METHODS: Students in Grades 6 through 12 at the initial wave of the study responded to survey items designed to assess their online experiences, including cybervictimization and self-reported depression and anxiety at three separate time points, over a 3-year period. In total, 559 school-aged youth participated in the study. RESULTS: Results suggest a reciprocal relationship between cybervictimization and depression and cybervictimization and anxiety. More specifically, depression at Time 1 predicted cybervictimization at Time 2, depression at Time 2 predicted cybervictimization at Time 3, and cybervictimization at Time 1 predicted depression at Time 3. Additionally, cybervictimization at Time 1 predicted anxiety at Time 2, cybervictimization at Time 2 predicted anxiety at Time 3, and anxiety at Time 1 predicted cybervictimization at Time 2. CONCLUSIONS: Based on the findings from this study, cybervictimization, depression, and anxiety seem to have a reciprocal relationship. Therefore, educational and mental health professionals should consider interventions that address adolescents' online experiences, while supporting mental health and social and emotional learning. PMID- 26115910 TI - Glucocorticoids: Dose-related effects on osteoclast formation and function via reactive oxygen species and autophagy. AB - Whether glucocorticoids directly enhance or interrupt osteoclastogenesis is still a controversial subject. In this study, we ascertained the dose-dependent positive effects of glucocorticoids on osteoclastogenesis in vivo and in vitro as well as investigated the mechanism in vitro. As the dose of glucocorticoids increased, osteoclastogenesis was stimulated at 0.1 MUM, a peak was achieved at 1 MUM and a corresponding decrease occurred at 10 MUM. Reactive oxygen species (ROS), which play a crucial role in osteoclastogenesis, and autophagy flux activity, a cellular recycling process, were consistently up-regulated along with the dose-dependent effects of the glucocorticoids on osteoclast formation and function. N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of the glucocorticoids on autophagy and osteoclastogenesis. Moreover, 3-methyladenine (3 MA), an autophagy inhibitor, interrupted osteoclastogenesis stimulation by the glucocorticoids. These results implied that with glucocorticoid administration, ROS and autophagy, as a downstream factor of ROS, played vital roles in osteoclast formation and function. 3-MA administration did not enhance ROS accumulation, so that autophagy had no effect on ROS induced by glucocorticoids. Our investigation demonstrated that glucocorticoids had dose-dependent positive effects on osteoclast formation and function via ROS and autophagy. These results provide support for ROS and autophagy as therapeutic targets in glucocorticoid related bone loss diseases such as glucocorticoid-induced osteoporosis. PMID- 26115912 TI - Introduction special issue. PMID- 26115913 TI - Time-dependent test characteristics of neck stiffness in patients suspected of nontraumatic subarachnoid haemorrhage. AB - BACKGROUND: Neck stiffness can be the only diagnostic clue for subarachnoid haemorrhage (SAH) at neurological examination in patients with a clinical suspicion of nontraumatic SAH who present with a normal level of consciousness and no focal neurologic deficits. Since the clinical impression is that neck stiffness may take several hours to develop, we determined time-dependent test characteristics of neck stiffness. METHODS: We retrieved the presence of neck stiffness from the medical records of consecutive patients presenting between 2005 and 2013 with a clinical suspicion of SAH, a normal level of consciousness and no focal neurologic deficits. Test characteristics with corresponding 95% confidence intervals (CIs) were calculated for the evaluation of neck stiffness <=6 h and 6-72 h after symptom onset for the diagnosis of nontraumatic SAH. In a secondary analysis, multiple imputation was used to account for missing values. RESULTS: 114 of 247 included patients were diagnosed with nontraumatic SAH. Neck stiffness at neurological examination performed <=6 h after symptom onset had a positive predictive value (PPV) of 90% (95% CI: 78%-97%) and negative predictive value (NPV) of 69% (95% CI: 59%-78%). Between 6 and 72 h after symptom onset the PPV was 76% (95% CI: 58%-89%) and NPV 91% (95% CI: 78%-98%). Multiple imputation to account for missing values yielded similar results. CONCLUSION: In patients with a normal level of consciousness without focal neurologic deficits the presence of neck stiffness is helpful but not pathognomic for the diagnosis of SAH. Moreover, the absence of neck stiffness does not rule out SAH, especially when evaluated <=6 h after symptom onset. PMID- 26115911 TI - Abdominal aortic calcification and risk of fracture among older women - The SOF study. AB - Data concerning the link between severity of abdominal aortic calcification (AAC) and fracture risk in postmenopausal women are discordant. This association may vary by skeletal site and duration of follow-up. Our aim was to assess the association between the AAC severity and fracture risk in older women over the short- and long term. This is a case-cohort study nested in a large multicenter prospective cohort study. The association between AAC and fracture was assessed using Odds Ratios (OR) and 95% confidence intervals (95%CI) for vertebral fractures and using Hazard Risks (HR) and 95%CI for non-vertebral and hip fractures. AAC severity was evaluated from lateral spine radiographs using Kauppila's semiquantitative score. Severe AAC (AAC score 5+) was associated with higher risk of vertebral fracture during 4 years of follow-up, after adjustment for confounders (age, BMI, walking, smoking, hip bone mineral density, prevalent vertebral fracture, systolic blood pressure, hormone replacement therapy) (OR=2.31, 95%CI: 1.24-4.30, p<0.01). In a similar model, severe AAC was associated with an increase in the hip fracture risk (HR=2.88, 95%CI: 1.00-8.36, p=0.05). AAC was not associated with the risk of any non-vertebral fracture. AAC was not associated with the fracture risk after 15 years of follow-up. In elderly women, severe AAC is associated with higher short-term risk of vertebral and hip fractures, but not with the long-term risk of these fractures. There is no association between AAC and risk of non-vertebral-non-hip fracture in older women. Our findings lend further support to the hypothesis that AAC and skeletal fragility are related. PMID- 26115914 TI - Familial forms of multiple sclerosis and neuromyelitis optica at an MS center in Rio de Janeiro State, Brazil. AB - OBJECTIVE: To describe familial forms of demyelinating diseases from an MS referral center in Rio de Janeiro State, Brazil. METHODS: A descriptive, cross sectional study was done to identify familial IIDD cases in Hospital da Lagoa, a public hospital where 75% of patients with IIDD who live in Rio de Janeiro state, located in the Southeast region of Brazil, are referred. The diagnoses of all consecutive patients followed in 2011 were reviewed to apply new diagnostic criteria (Wingerchuk et al., 2008). The diagnosis of IIDD was confirmed based on clinical history, neurological examination, MRI of the skull and spinal cord, CSF analysis and investigation of IgG NMO antibodies. The cases that had at least one other relative with IIDD were selected for the study. RESULTS: Familial forms were found only in the multiple sclerosis (MS) and neuromyelitis optica syndrome (NMOSD) categories. 23 MS families were identified, 60.86% with first degree kinship. It has a Caucasian preponderance, 90% of whom were white. The frequency of early onset was 15% and 20% of the MSf cases have progressive primary course. CONCLUSION: The frequency of familial cases of IIDD was 6.12% among MS patients and 2.8% in NMO spectrum syndromes. PMID- 26115915 TI - Characteristic location and growth patterns of functioning pituitary adenomas: correlation with histological distribution of hormone-secreting cells in the pituitary gland. AB - OBJECTIVE: To evaluate the correlation between the magnetic resonance imaging findings of functional pituitary adenomas and histological distribution of hormone-secreting cells in pituitary gland. METHODS: Forty-nine patients with pathologically confirmed functional micro and macro pituitary adenomas were retrospectively reviewed for its location and growth direction. RESULTS: Micro prolactin, micro-adrenocorticotropic hormone (ACTH), and micro-growth hormone (GH) producing adenomas showed specific location (P-value <.01). Macro-GH and macro-thyroid-stimulating hormone producing adenomas showed specific growth direction (P-value <.05), whereas macro-prolactin and macro-ACTH producing adenomas did not. CONCLUSION: The functional pituitary microadenomas' location and macroadenomas' growth pattern correlate well with histological distribution of hormone-secreting cells in pituitary gland. PMID- 26115916 TI - Protective effect of 14-3-3 antibodies on stressed neuroretinal cells via the mitochondrial apoptosis pathway. AB - BACKGROUND: Previous studies demonstrate changes of autoantibody concentrations against retinal and optic nerve head antigens in the serum of glaucoma patients in comparison to healthy persons. These antibodies belong to the natural autoimmunity. Previous studies showed up regulated, but also significantly down regulated autoantibody levels. These antibodies have the ability to influence protein profiles of neuroretinal cells and possibly hold neuroprotective potential, as we have been able to demonstrate before. Aim of this study was to analyse the serum and antibody effect of glaucoma patients on neuroretinal cells in more detail and also determine the impact of antibodies found down-regulated in glaucoma patients on the pathogenesis of the neurodegenerative disease glaucoma. METHODS: Neuroretinal cells (RGC-5) were incubated with serum either from glaucoma patients or healthy controls for 24 h. Mass spectrometric analysis was performed after cell lysis. Furthermore the neuroretinal cells were preincubated with different and concentrations of 14-3-3 antibodies (0.005, 0.1, 0.5, 1, 5 and 10 MUg/ml) and then stressed with H2O2, staurosporine or glutamate. Viability tests were performed with crystal violet and ROS tests with DCFH-DA. Antibody location in the cell after antibody incubation was performed with immunocytochemical methods. Additionally mass spectrometric analysis was performed with the cells after antibody incubation. RESULTS: Protein expression analysis with Maldi-Orbitrap MS showed changes in the expression level of regulatory proteins in cells incubated with glaucoma serum, e.g. an up-regulation of 14-3-3 and a down-regulation of Calmodulin. After preincubation of the cells with anti-14-3-3 antibody and stressing the cells, we detected an increase in viability of up to 22 % and a decrease in reactive oxygen species (ROS) of up to 31 %. Proteomic 1 analysis involvement of the mitochondrial apoptosis pathway in this protective effect and immunohistochemical analysis showed an antibody uptake in the cells. CONCLUSION: We found significant effects of serum antibodies on proteins of neuroretinal cells especially of the mitochondrial apoptosis pathway. Furthermore we detected a protective potential of antibodies down-regulated in glaucoma patients. The changed autoantibodies belong to the natural autoimmunity. We conclude that changes in the natural autoimmunity of patients with glaucoma can negatively impact regulatory functions. PMID- 26115918 TI - Evaluation of analgesic, anti-inflammatory, anti-depressant and anti-coagulant properties of Lactuca sativa (CV. Grand Rapids) plant tissues and cell suspension in rats. AB - BACKGROUND: Lactuca sativa (lettuce) has been traditionally used for relieving pain, inflammation, stomach problems including indigestion and lack of appetite. Moreover, the therapeutic significance of L. sativa includes its anticonvulsant, sedative-hypnotic and antioxidant properties. METHODS: In the present study, the MC (methanol and chloroform; 1:1) and aqueous extracts of seed and leaf along with cell suspension exudate were prepared. These extracts were explored for their analgesic, anti-inflammatory, antidepressant and anticoagulant effects by hot plate analgesic assay; carrageenan induced hind paw edema test, forced swimming test and capillary method for blood clotting respectively in a rat model. The results were analyzed using one-way Analysis of Variance (ANOVA) followed by Turkey multiple comparison test. RESULTS: Interestingly, the extracts and the cell suspension exudate showed dual inhibition by reducing pain and inflammation. The results indicated that the aqueous extracts of leaf exhibited highest analgesic and anti-inflammatory activities followed by leaf MC, cell suspension exudate, seed aqueous and seed MC extracts. The current findings show that aqueous and MC extracts of seed have the least immobility time in the forced swimming test, which could act as an anti-depressant on the central nervous system. The leaf extracts and cell suspension exudate also expressed moderate anti-depressant activities. In anticoagulant assay, the coagulation time of aspirin (positive control) and MC extract of leaf was comparable, suggesting strong anti-coagulant effect. Additionally, no abnormal behavior or lethality was observed in any animal tested. CONCLUSION: Taken together, L. sativa can potentially act as a strong herbal drug due to its multiple pharmaceutical effects and is therefore of interest in drug discovery and development of formulations. PMID- 26115919 TI - Endovascular repair of Stanford B aortic dissection using two stent grafts with different sizes. AB - OBJECTIVE: The objective of this study was to introduce a novel strategy for thoracic endovascular aortic repair of Stanford B aortic dissection using two stent graft implantation (TSI), in which the proximal stent and distal stent with different sizes are sequentially deployed, and to summarize our experience with this technique. METHODS: A retrospective study was conducted of 72 consecutive patients (61 men; mean age, 55 +/- 7 years; range, 41-67 years) with Stanford type B aortic dissection who underwent TSI treatment between January 2012 and May 2013. Among all patients, 43 (59.7%) involved the infrarenal aorta and 29 (40.3%) involved the whole thoracic and abdominal aorta; mean aortic involvement length was 226 +/- 13 mm (range, 182-312 mm). Eight cases were for acute dissection (within 2 weeks from onset of symptoms), 11 cases were for chronic dissection (>3 months after initial dissection), and 53 cases were for subacute dissection (between 2 weeks and 3 months). Twenty-two cases (30.6%) were uncomplicated type and 50 cases (69.4%) were complicated type. Follow-up was performed postoperatively at 1 month, 6 months, and yearly thereafter. Technique success, aorta morphology, and procedure-related complications were evaluated. RESULTS: Technical success was achieved in 100%; 72 pairs of stent grafts (144 thoracic stent grafts) and 10 left subclavian artery chimney stents were used. The mean aortic length coverage by the stent grafts was 197.6 +/- 20.3 mm, and mean taper diameter span was 7.5 +/- 1.8 mm. All patients were followed up from 6 to 16 months (mean, 10 +/- 4 months); 95.8% (69 of 72) had a thrombosed false lumen in the aortic coverage, and the true lumen expanded on average 57% +/- 11% (23% 100%). No significant changes were found in aortic diameters of the proximal and distal ends of the two stent grafts and the angles between centerlines of the distal end of the stent and the aorta during follow-up. Procedure-related complications included transient paraplegia (coverage of the left subclavian artery without revascularization and extensive coverage of aorta >220 mm) due to acute spinal cord ischemia (n = 1) and malapposition of the distal stent (primary tear closed, true lumen expansion led to oversize rate insufficient in distal stent diameter; n = 1). No death or malperfusion complications were observed during the perioperative period and follow-up. CONCLUSIONS: Short-term outcomes showed TSI to be a flexible and effective approach to accurately repair Stanford B aortic dissection that could potentially address the limitations of currently available stent grafts. Further prospective clinical studies are warranted to evaluate its long-term efficacy. PMID- 26115917 TI - Core oxidative stress response in Aspergillus nidulans. AB - BACKGROUND: The b-Zip transcription factor AtfA plays a key role in regulating stress responses in the filamentous fungus Aspergillus nidulans. To identify the core regulons of AtfA, we examined genome-wide expression changes caused by various stresses in the presence/absence of AtfA using A. nidulans microarrays. We also intended to address the intriguing question regarding the existence of core environmental stress response in this important model eukaryote. RESULTS: Examination of the genome wide expression changes caused by five different oxidative stress conditions in wild type and the atfA null mutant has identified a significant number of stereotypically regulated genes (Core Oxidative Stress Response genes). The deletion of atfA increased the oxidative stress sensitivity of A. nidulans and affected mRNA accumulation of several genes under both unstressed and stressed conditions. The numbers of genes under the AtfA control appear to be specific to a stress-type. We also found that both oxidative and salt stresses induced expression of some secondary metabolite gene clusters and the deletion of atfA enhanced the stress responsiveness of additional clusters. Moreover, certain clusters were down-regulated by the stresses tested. CONCLUSION: Our data suggest that the observed co-regulations were most likely consequences of the overlapping physiological effects of the stressors and not of the existence of a general environmental stress response. The function of AtfA in governing various stress responses is much smaller than anticipated and/or other regulators may play a redundant or overlapping role with AtfA. Both stress inducible and stress repressive regulations of secondary metabolism seem to be frequent features in A. nidulans. PMID- 26115920 TI - Mortality and complications after aortic bifurcated bypass procedures for chronic aortoiliac occlusive disease. AB - OBJECTIVE: Open surgery has given way to endovascular grafting in patients with aortoiliac occlusive disease. The growing use of endovascular grafts means that fewer patients with aortoiliac occlusive disease have open surgery. The declining open surgery caseload challenges the surgeon's operative skills, particularly because open surgery is increasingly used in those patients who are unsuitable for endovascular repair and hence technically more demanding. We assessed the early outcome after aortic bifurcated bypass procedures during two decades of growing endovascular activity and identified preoperative risk factors. METHODS: Data on patients with chronic limb ischemia were prospectively collected during a 20-year period (1993 to 2012). The data were obtained from the Danish Vascular Registry, assessed, and merged with data from The Danish Civil Registration System. RESULTS: We identified 3623 aortobifemoral and 144 aortobiiliac bypass procedures. The annual caseload fell from 323 to 106 during the study period, but the 30-day mortality at 3.6% (95% confidence interval [CI], 3.0-4.1) and the 30 day major complication rate remained constant at 20% (95% CI, 18-21). Gangrene (odds ratio [OR], 3.3; 95% CI, 1.7-6.5; P = .005) was the most significant risk factor for 30-day mortality, followed by renal insufficiency (OR, 2.5; 95% CI, 1.1-5.8; P = .035) and cardiac disease (OR, 2.1; 95% CI, 1.4-3.1; P < .001). Multiorgan failure, mesenteric ischemia, need for dialysis, and cardiac complications were the most lethal complications, with mortality rates of 94%, 44%, 38%, and 34%, respectively. CONCLUSIONS: Aortic bifurcated bypass is a high risk procedure. Although open surgery has increasingly given way to endovascular repair, 30-day outcomes have remained stable during the past decade. Thus, it is still acceptable to consider an aortic bifurcated bypass whenever endovascular management is not feasible. PMID- 26115921 TI - Surgical outcomes of vascular reconstruction in soft tissue sarcomas of the lower extremities. AB - BACKGROUND: Limb-sparing procedures are currently considered the standard treatment for lower limb soft tissue sarcoma (STS). Surgical excision combined with vascular resection may be necessary to provide an adequate safety margin and to improve the oncologic outcomes. In this scenario, vascular reconstruction is required to preserve limb function. We evaluated the long-term patency and survival outcomes of arterial and venous reconstruction after resecting lower limb STS in the largest single-center case series to date. METHODS: Between November 1995 and July 2014, 25 patients with lower limb STS and vascular invasion underwent surgical resection followed by arterial or venous reconstruction. Patients were followed up at regular outpatient visits, at which clinical examinations and duplex ultrasound mapping were performed to assess graft patency. RESULTS: A total of 44 revascularization procedures were performed. The median follow-up time for the arterial and venous groups combined was 25.2 months (range, 0.26-225.6 months). The 5-year survival probability was 42.1%. The graft occlusion rate was significantly higher after reconstruction with synthetic grafts than after reconstruction with saphenous vein substitutes (P = .02). The occlusion rate was not significantly different between arterial reconstruction and venous reconstruction (P > .05). CONCLUSIONS: Arterial and venous reconstruction is feasible after surgical resection of lower limb STS. Vascular reconstruction provides favorable long-term patency outcomes and low complication rates, allowing limb preservation and disease control in a select group of patients. Vascular reconstruction using venous grafts had a significantly higher patency rate than reconstruction with artificial venous substitutes. PMID- 26115923 TI - An infrarenal abdominal aortic aneurysm with severe neck stenosis. PMID- 26115922 TI - Preoperative beta-blockers do not improve cardiac outcomes after major elective vascular surgery and may be harmful. AB - OBJECTIVE: Routine initiation beta-blocker medications before vascular surgery is controversial due to conflicting data. The purpose of this analysis was to determine whether prophylactic use of beta-blockers before major elective vascular surgery decreased postoperative cardiac events or mortality. METHODS: The Society for Vascular Surgery Vascular Quality Initiative (SVS-VQI) data set was used to perform a retrospective cohort analysis of infrainguinal lower extremity bypass (LEB), aortofemoral bypass (AFB), and open abdominal aortic aneurysm (AAA) repair patients. Chronic (>30 days preoperatively) beta-blocker patients were excluded, and comparisons were made between preoperative (0-30 day) and no beta-blocker groups. Patients were risk stratified using a novel prediction tool derived specifically from the SVS-VQI data set. Propensity matched pairs and interprocedural specific risk stratification comparisons were performed. End points included in-hospital major adverse cardiac events (MACEs), including myocardial infarction (MI; defined as new ST or T wave electrocardiographic changes, troponin elevation, or documentation by echocardiogram or other imaging modality), dysrhythmia, and congestive heart failure, and 30-day mortality. RESULTS: The study analyzed 13,291 patients (LEB, 68% [n = 9047]; AFB, 11% [n = 1474]; and open AAA, 21% [n = 2770]); of these, 67.7% (n = 8999) were receiving beta-blockers at time of their index procedure. Specifically, 13.2% (n = 1753) were identified to have been started on a preoperative beta-blocker, 54.5% (n = 7426) were on chronic beta-blockers, and 32.3% (n = 4286) were on no preoperative beta-blockers. Among the three procedures, patients had significant demographic and comorbidity differences and thus were not combined. A 1:1 propensity-matched pairs analysis (1459 pairs) revealed higher rates of postoperative MI with preoperative beta-blockers (preoperative beta-blocker relative risk, 1.65; 95% confidence interval, 1.02 2.68; P = .05 vs no beta-blocker), with no difference in dysrhythmia, congestive heart failure, or 30-day mortality. When stratified into low-risk, medium-risk, and high-risk groups within each procedure, all groups of preoperative beta blocker patients had no difference or higher rates of MACEs and 30-day mortality, with the exception of high-risk open AAA patients, who had a lower rate of MI (odds ratio, 0.35; 95% confidence interval, 011-0.87; P = .04). CONCLUSIONS: Exclusive of high-risk open AAA patients, preoperative beta-blockers did not decrease rates of MACEs or mortality after LEB, AFB, or open AAA. Importantly, exposure to prophylactic preoperative beta-blockers increased the rates of some adverse events in several subgroups. Given these data, the SVS-VQI cannot support routine initiation of preoperative beta-blockers before major elective vascular surgery in most patients. PMID- 26115924 TI - Multiple aortic pseudoaneurysms in a patient with Behcet's disease. PMID- 26115925 TI - The prevalence of abdominal aortic aneurysm is consistently high among patients with coronary artery disease. AB - OBJECTIVE: Emerging evidence suggests high prevalence of abdominal aortic aneurysm (AAA) among patients with coronary disease. Accurate characterization of the association between coronary disease and AAA and of the actual prevalence of AAA among patients with angiography-verified coronary artery disease (CAD) is needed to evaluate the possible benefits of systematic screening for AAA. METHODS: We searched for studies that reported the association between AAA and CAD or coronary heart disease (CHD; wider phenotype definition) in the general population (randomized controlled trials, prospective population cohorts) and those that reported the prevalence of AAA among patients with angiography verified CAD through PubMed, Embase, and reference lists for the period between 1980 and 2014. Random-effects models were applied because of the high heterogeneity between included studies. RESULTS: Among the general population, 23 studies reported the association between CHD and the occurrence of subclinical AAA (positive ultrasound screening; meta-analyzed odds ratio of 2.38 with 95% confidence interval [CI] of 1.78-3.19; P = 4.1 * 10(-9)). According to four prospective studies, CHD is a strong predictor of future AAA events (fatal and nonfatal; meta-analyzed hazard ratio of 3.49 with 95% CI of 2.56-4.76; P = 2.4 * 10(-15)). Altogether, 10 studies reported the prevalence of AAA among patients with angiography-verified CAD or undergoing coronary artery bypass grafting. Among men, meta-analyzed prevalence was 9.5% (95% CI, 7.6%-11.7%). Among men undergoing coronary artery bypass grafting or with three-vessel disease, the prevalence was 11.4% (95% CI, 9.1%-13.9%). Among women, the prevalence was low (0.35%). CONCLUSIONS: The risk of subclinical AAA and future AAA events is high among patients with coronary disease. Screening for AAA among CAD patients by cardiologists would be easy and inexpensive, with possible benefits to survival and risk evaluation. PMID- 26115926 TI - Reply: To PMID 25053534. PMID- 26115927 TI - Regarding "Multiple overlapping uncovered stents as an alternative flow-diverting strategy in the management of peripheral and visceral aneurysms". PMID- 26115928 TI - Learning to fear depends on emotion and gaze interaction: The role of self relevance in fear learning. AB - Emotional learning is an adaptive function, however its psychological determinants are unclear. Here, we propose a new theoretical framework based on appraisal theories of emotion, which holds that emotional learning is modulated by a process of relevance detection. Testing the model, we predicted faster, larger acquisition and greater resistance to extinction of the conditioned response (CR) to self-relevant stimuli relative to stimuli with less relevance. We manipulated self-relevance through emotion and gaze direction of synthetic dynamic facial expressions during differential aversive conditioning. Results provided mixed evidence for our hypotheses. Critically, we revealed faster acquisition of the CR to angry faces with direct compared with averted gaze and greater resistance to extinction to fearful faces with averted relative to direct gaze. We conclude that the relevance detection hypothesis offers an appropriate theoretical framework allowing to (re)interpret existing evidence, incorporate our results, and propose a new research perspective in the study of emotional learning. PMID- 26115929 TI - [Knowledge, attitudes, and practices concerning rabies and post-exposure prophylactic measures at the Cheikh Anta Diop university in Dakar]. PMID- 26115930 TI - Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma. AB - PURPOSE: To determine the maximum recommended dose (RD) and pharmacokinetics of Myocet(r), a non-pegylated liposomal doxorubicin, in children. METHODS: Eligible patients were children with refractory high-grade glioma who had received prior chemotherapy and radiotherapy but no anthracyclines. Cohorts of at least three patients each received escalating doses of Myocet(r) starting at 60 mg/m(2) at 3 week intervals, administered intravenously over 1 h, and then doses were escalated to 75 mg/m(2) corresponding to the adult RD. Periodic blood samples were collected, and plasma doxorubicin and doxorubicinol concentrations were quantified to characterise the pharmacokinetics of Myocet(r). RESULTS: Between October 2010 and January 2013, 13 children aged 6-17 years were treated. In total, 27 courses were administered, at the 60 mg/m(2) dose level in seven patients without dose-limiting toxicity (DLT), and at 75 mg/m(2) in six patients of whom two experienced DLT (grade 4 neutropenia). The most common grade 3-4 toxicities reported for all courses were neutropenia (35 and 38 %, respectively), thrombocytopenia (12 and 4 %, respectively); and grade 3 vomiting, nausea, mucositis, and fever (4 % each). Mean estimates of central volume of distribution at steady state, clearance, and elimination half-life of doxorubicin were 24.8 L, 15 L/h/m(2), and 34.8 h, respectively, with a large interpatient variability. CONCLUSION: The RD of Myocet(r) administered every 3 weeks to paediatric patients was 60 mg/m(2). The efficacy of Myocet(r) in paediatric patients with high-grade glioma remains to be determined and should be studied in Phase II trials. PMID- 26115931 TI - Rapid acceleration of plant speciation during the Anthropocene. AB - Speciation rates need to be considered when estimating human impacts on the numbers of species on Earth, given that past mass extinctions have been followed by the accelerated origination of new taxa. Here, I suggest that the Anthropocene is already exhibiting a greatly accelerated plant speciation rate due to agriculture, horticulture, and the human-mediated transport of species, followed by hybridisation. For example, more new plant species have come into existence in Europe over the past three centuries than have been documented as becoming extinct over the same period, even though most new hybrid-origin species are likely to remain undetected. Current speciation rates are unusually high and they could be higher than during or after previous mass extinctions. PMID- 26115932 TI - Internal fertilization and sperm storage in cnidarians: a response to Orr and Brennan. PMID- 26115933 TI - Society for maternal and fetal medicine workshop on pregnancy as a window to future health: Clinical utility of classifying women with metabolic syndrome. AB - Women with preeclampsia, gestational diabetes, and obesity during pregnancy are at risk for medical complications later in life. Therefore, practitioners should identify those who can benefit from early diagnosis and interventions. Metabolic syndrome is a cluster of risk factors including hypertension, elevated triglycerides, low high-density lipoprotein cholesterol, glucose intolerance, and obesity, which also identifies those at risk for cardiovascular disease. Taking the time to classify women with the metabolic syndrome does not necessarily offer risk stratification superior to that offered by identifying the individual components. This article will offer conclusions regarding the need for busy obstetrician/gynecologists to make this classification. PMID- 26115934 TI - Lund-Mackay and modified Lund-Mackay score for sinus surgery in children with cystic fibrosis. AB - OBJECTIVE: Patients with cystic fibrosis (CF) frequently present with severe sinonasal disease often requiring radiologic imaging and surgical intervention. Few studies have focused on the relationship between radiologic scoring systems and the need for sinus surgery in this population. The objective of this study is to evaluate the Lund-Mackay (LM) and modified Lund-Mackay (m-LM) scoring systems in predicting the need for sinus surgery or revision surgery in patients with CF. METHODS: We performed a retrospective chart review of CF patients undergoing computed tomography (CT) sinus imaging at a tertiary care pediatric hospital from 1995 to 2008. Patient scans were scored using both the LM and m-LM systems and compared to the rate of sinus surgery or revision surgery. Receiver-operator characteristics curves (ROC) were used to analyze the radiological scoring systems. RESULTS: A total of 41 children with CF were included in the study. The mean LM score for patients undergoing surgery was 17.3 (+/-3.1) compared to 11.5 (+/-6.2) for those treated medically (p<0.01). For the m-LM, the mean score of patients undergoing surgery was 20.3 (+/-3.5) and 13.5 (+/-7.3) for those medically treated (p<0.01). Using a ROC curve with a threshold score of 13 for the LM, the sensitivity was 89.3% (95% CI of 72-98) and specificity of 69.2% (95% CI of 39-91). At an optimal score of 19, the m-LM system produced a sensitivity of 67.7% (95% CI of 48-84) and specificity of 84.6% (95% CI of 55-98). CONCLUSION: The modified Lund-Mackay score provides a high specificity while the Lund-Mackay score a high sensitivity for CF patients who required sinus surgery. The combination of both radiologic scoring systems can potentially predict the need for surgery in this population. PMID- 26115935 TI - Tracking tympanostomy tube outcomes in pediatric patients with otitis media using an electronic database. AB - OBJECTIVE: To implement and review a database for children with a diagnosis of otitis media (OM) to facilitate comparative outcomes and long-term prospective follow up of surgical outcomes. Specific aim is to review presenting symptoms, risk factors, tympanostomy tube outcomes and complications, and need for further procedures. METHODS: A web-based customized database was constructed to universally enroll all patients seen in consultation with a diagnosis of OM. Unique database fields include demographics, physical exam findings, risk factors, intervention, and long-term outcomes. Major surgical complications measured include: tympanic membrane perforation, retained tubes, chronic otorrhea, and cholesteatoma formation. RESULTS: Six hundred and thirty four unique patients have been prospectively enrolled. Five hundred and forty four tubes have been followed to extrusion. Outcomes demonstrate high prevalence of OM risk factors associated with surgical patients including: 63% in day care and 26% with a sibling requiring tympanostomy tubes. Complication rates; 1% developed perforations requiring surgical intervention, 2.6% required removal of retained tubes, 1% extruded early (<60 days), and 0.7% were surgically removed for other complications. Cholesteatoma was identified in 0.56%, all had ongoing chronic ear disease. CONCLUSIONS: Long-term, outcome driven investigations assessing the surgical management of OM are needed given the prevalence of this disease and the frequency of surgical intervention required. The current database represents the largest prospective cohort of patients enrolled and followed in this fashion and has generated data demonstrating a procedure associated with significant improvement in patient quality of life in the short-term with low complication rates in the long-term. This ongoing prospective investigation is providing data that have the potential to be important in treatment algorithms, procedure justification, and risk factor modification. PMID- 26115936 TI - Editorial Comment. PMID- 26115937 TI - Bilateral cartilage T2 mapping 9 years after Mega-OATS implantation at the knee: a quantitative 3T MRI study. AB - OBJECTIVE: To evaluate morphological and quantitative MR findings 9 years after autograft transfer of the posterior femoral condyle (Mega-OATS) and to correlate these findings with clinical outcomes. Quantitative MR measurements were also obtained of the contralateral knee and the utility as reference standard was investigated. DESIGN: Both knees of 20 patients with Mega-OATS osteochondral repair at the medial femoral condyle (MFC) were studied using 3T MRI 9 years after the procedure. MR-sequences included morphological sequences and a 2D multislice multiecho (MSME) spin echo (SE) sequence for quantitative cartilage T2 mapping. Cartilage segmentation was performed at the cartilage repair site and six additional knee compartments. Semi-quantitative MR observation of cartilage repair tissue (MOCART) scores and clinical Lysholm scores were obtained. Paired t tests and Spearman correlations were used for statistical analysis. RESULTS: Global T2-values were significantly higher at ipsilateral knees compared to contralateral knees (42.1 +/- 3.0 ms vs 40.4 +/- 2.6 ms, P = 0.018). T2-values of the Mega-OATS site correlated significantly with MOCART scores (R = -0.64, P = 0.006). The correlations between MOCART and Lysholm scores and between absolute T2-values and Lysholm scores were not significant (P > 0.05). However, higher T2 side-to-side differences at the femoral condyles correlated significantly with more severe clinical symptoms (medial, R = -0.53, P = 0.030; lateral, R = -0.51, P = 0.038). CONCLUSIONS: Despite long-term survival, 9 years after Mega-OATS procedures, T2-values of the grafts were increased compared to contralateral knees. Clinical scores correlated best with T2 side-to-side differences of the femoral condyles, indicating that intraindividual adjustment may be beneficial for outcome evaluation. PMID- 26115938 TI - Evaluation of Echinostoma liei worm, metacercaria and redia antigens for schistosomiasis control. AB - While chemotherepeutic drugs, such as praziquantel, oxamniquine and metrifonate, are currently considered safe and effective drugs for schistosomiasis treatment, reinfection occurs frequently after drug treatment. Thus, a vaccine is sought to provide long-term treatment. Antigens from worm, metacercaria and redia of Echinostoma liei (E. liei) were purified using CNBr-activated Sepharose column, then used for immunization of mice prior to infection with Schistosomiasis mansoni. Worm burden, hepatic and intestinal eggs and oogram count was significantly reduced and that was reflected in normalization of liver architecture. This referred to a significant increase in the tested immunoglobulin level (IgM, IgG1 and IgG2). PMID- 26115939 TI - The efficacies of 5 insecticides against hard ticks Hyalomma asiaticum, Haemaphysalis longicornis and Rhipicephalus sanguineus. AB - At present, chemical-based tick control strategies are still the most efficient and widely used methods in control of ticks and tick-borne diseases. In this study, the efficacies of lambda-cyhalothrin, beta-cypermethrin, emamectin benzoate, spirotetramat and hexaflumuron in vitro were evaluated against Hyalomma asiaticum, Haemaphysalis longicornis and Rhipicephalus sanguineus that are widespread and able to transmit a variety of human and animal diseases in China. The results showed that the LC (lethal concentration) 50 of lambda-cyhalothrin, beta-cypermethrin, emamectin benzoate, spirotetramat and hexaflumuron were 22.05, 107.35, 287.62, 432.25 and over 6250 mg/L to Hy. asiaticum engorged nymphs, respectively. The LC50 of lambda-cyhalothrin and beta-cypermethrin were each to 100.69 mg/L and 340.05 mg/L against Hy. asiaticum unfed adults. In addition, 50 mg/L of lambda-cyhalothrin could completely inhibit engorged females of the 3 tick species to lay eggs. These results indicate that lambda-cyhalothrin has the highest efficacy and broadest spectrum for against the 3 tick species. The present study provides some information for selecting chemical acaricides in control ticks and tick-borne-diseases, as well for preparing acaricide mixtures to improve killing efficacy, and retard the advent of tick-resistance of acaricides in China. PMID- 26115940 TI - Characterisation of iron regulatory protein 1A and 1B in the blood-feeding copepod Lepeophtheirus salmonis. AB - During its parasitic life stages, the marine ectoparasitic copepod Lepeophtheirus salmonis ingests large amounts of host blood, which contains high amounts of iron. Iron is an essential micronutrient, but also toxic in high dosages, and blood-feeding parasites like the salmon louse must thus possess an efficient system to handle the excess iron. Iron regulatory protein 1 and 2 (IRP1 and IRP2) are known to play crucial roles in this process, by regulating several proteins involved in iron transport and storage, depending on the cellular iron concentration. To gain knowledge about the regulation of the iron metabolism in salmon lice, two IRP homologues (LsIRP1A and LsIRP1B) were identified by sequence and predicted structure similarity to known IRPs in other species. In situ hybridisation revealed that LsIRP1A and LsIRP1B mRNAs were expressed in the ovaries, oviducts and vitellogenic oocytes of adult females. Transcription levels of LsIRP1A and LsIRP1B mRNAs did not differ significantly between the different developmental stages of the salmon louse. Adults in the absence of blood as a feed source had decreased levels of LsIRP1A, but not LsIRP1B mRNA. RNA binding experiments indicated the presence of functioning IRP in salmon lice. In order to explore the biological functions of LsIRP1A and LsIRP1B, the mRNAs of both proteins were knocked down by RNA interference (RNAi) in preadult females. The knockdown was confirmed by qRT-PCR. LsIRP1B knockdown lice produced less offspring than control lice due to slightly shorter egg strings and had decreased levels of transcripts involved in egg development. Knockdown of both LsIRP1A and LsIRP1B caused increased expression of a salmon louse Ferritin (LsFer). These results confirm that salmon lice have two IRP1 homologues, LsIRP1A and LsIRP1B, and might suggest a function in cellular iron regulation in the reproductive organs and eggs. PMID- 26115941 TI - Nitric oxide production increases during Toxoplasma gondii encephalitis in mice. AB - Toxoplasma gondii is an intracellular parasite with the potential of causing severe encephalitis among immunocompromised human and animals. The aim of this experimental study was to investigate the immunomodulatory and immunopathological role of nitric oxide (NO) in central nervous systems and to identify any correlation between toxoplasmosis neuropathology and investigate the consequences of the cellular responses protect against T. gondii. Mice were infected with ME49 strain T. gondii and levels of endothelial, neuronal and inducible nitric oxide synthase (eNOS, nNOS, iNOS), glial fibrillary acidic protein (GFAP) and neurofilament (NF) were examined in brain tissues by immunohistochemistry, during the development and establishment of a chronic infection at 10 30 and 60 days post infection. Results of the study revealed that the levels of eNOS (p < 0.05), nNOS (p < 0.05), iNOS (p < 0.005), GFAP (p < 0.005) and NF (p < 0.005) were remarkably higher in T. gondii-infected mice than in uninfected control. The most prominent finding from our study was 10 and 30 days after inoculation data indicating that increased levels of NO not only a potential neuroprotective role for immunoregulatory and immunopathological but also might be a molecular trigger of bradyzoite development. Furthermore, this findings were shown that high expressed NO origin was not only inducible nitric oxide synthase but also endothelial and neuronal. We demonstrated that activation of astrocytes and microglia/macrophages is a significant event in toxoplasma encephalitis (TE). The results also clearly indicated that increased levels of NO might contribute to neuropathology related with TE. Furthermore, expression of NF might gives an idea of the progress and critical for diagnostic significance of this disease. PMID- 26115942 TI - Alcohol Use and Unintended Sexual Consequences among Women Attending an Urban Sexually Transmitted Infections Clinic. AB - BACKGROUND: Although alcohol use has been linked with a variety of sexual behaviors, we lack an understanding of what precise events occur when women drink that may lead to emotional or physical harms. METHODS: To fill this gap, we qualitatively explored the unintended sexual events occurring while drinking among a particularly at-risk clinic population: urban women attending a public sexually transmitted infections (STI) clinic. This was a secondary data analysis of 20 semistructured, in-depth interviews conducted between December 2009 and August 2010 with 20 sexually active adult women attending the Baltimore City Health Department STI Clinic. We purposively sampled women presenting for care in the STI clinic who reported either binge drinking in the past 6 months or engaging in vaginal or anal intercourse while under the influence of alcohol. Interviews were analyzed using a grounded theory approach. RESULTS: Five major unintended sexual events emerged: sex with new partners; alternative sexual activities, including anal sex and "rough" sex; unprotected sex; blacked out sex or sex occurring during alcohol-related amnesia; and rape. Themes often overlapped, and sexual victimization was a common thread throughout multiple themes. An additional theme, alcohol and prey, largely occurring in bars and nightclubs, emerged as an important precursor to many of the unintended events described. CONCLUSIONS: Alcohol use was associated with a variety of--often dangerous--unintended sexual events. Our results highlight the link between alcohol use and sexual victimization and the need for intervention development to reduce the emotional and physical harms resulting from the unintended consequences of alcohol use. PMID- 26115944 TI - Audiovestibular disorders as autoimmune reaction in patients with melanoma. AB - Melanoma is an aggressive form of cancer derived from neuroectodermal melanocytes. Melanocytes are present in the skin and hair follicles, as well as in the eye (iris and choroids), the leptomeninges, the anal canal and the inner ear. In the inner ear melanocytes are found both in the intermediate layer of the stria vascularis of the cochlea and in the dark cells of the vestibular organs. They are believed to play an important role in the production of endolymphatic potentials and in the maintenance of normal volumes of the inner ear fluids. Recently, audiovestibular dysfunctions have been demonstrated in patients treated with immunotherapy for metastatic melanoma and have been related to an autoimmune attack on the normal melanocytes of the inner ear. Melanoma is an immunogenic tumor type frequently associated with spontaneous autoimmune manifestations which seem to be associated with better prognosis. The melanoma-associated antigens are also expressed in normal melanocytes in the skin, eye and ear. We hypothesize that inner ear melanocytes could be a target of an autoimmune process in patients affected by melanoma. The immune system could produce antibodies that cross-react with both the melanoma cells and the labyrinth melanocytes causing an altered homeostasis of endolymphatic liquids and provoking some labyrinthic disorders such as vertigo, hearing loss, aural fullness and tinnitus resembling or influencing Meniere's disease. In this perspective, audiovestibular disorders could be interpreted as an attempt by the individual immune system to develop anti-tumor response. In patients affected by melanoma an autoimmune genesis has already been advocated for ocular symptoms in melanoma-associated retinopathy, where the cross-reaction happens against retinal cells. A possible role of inner ear melanocytes should be considered as a potential cause of audiovestibular disorders. Further research is needed to demonstrate a connection between melanoma and labyrinth dysfunctions such as in melanoma-associated retinopathy. PMID- 26115943 TI - Patients do not have a consistent understanding of high risk for future fracture: a qualitative study of patients from a post-fracture secondary prevention program. AB - We examined fracture patients' understanding of "high" fracture risk after they were screened through a post-fracture secondary prevention program and educated about their risk verbally, numerically, and graphically. Our findings suggest that messages about fracture risk are confusing to patients and need to be modified to better suit patients' needs. INTRODUCTION: The aim of this study was to examine fracture patients' understanding of high risk for future fracture. METHODS: We conducted an in-depth qualitative study in patients who were high risk for future fracture. Patients were screened through the Osteoporosis Exemplary Care Program where they were educated about fracture risk: verbally told they were "high risk" for future fracture, given a numerical prompt that they had a >20 % chance of future fracture over the next 10 years, and given a visual graph highlighting the "high risk" segment. This information about fracture risk was also relayed to patients' primary care physicians (PCPs) and specialists. Participants were interviewed at baseline (within six months of fracture) and follow-up (after visit with a PCP and/or specialist) and asked to recall their understanding of risk and whether it applied to them. RESULTS: We recruited 27 patients (20 females, 7 males) aged 51-87 years old. Fractures were sustained at the wrist (n = 7), hip (n = 7), vertebrae (n = 2), and multiple or other locations (n = 11). While most participants recalled they had been labeled as "high risk" (verbal cue), most were unable to correctly recall the other elements of risk (numerical, graphical). Further, approximately half of the patients who recalled they were high risk did not believe that high risk applied, or had meaning, to them. Participants also had difficulty explaining what they were at risk for. CONCLUSIONS: Our results suggest that health care providers' messages about fracture risk are confusing to patients and that these messages need to be modified to better suit patients' needs. PMID- 26115945 TI - Multiple sclerosis and susceptibility to cardiovascular diseases: Implications of ethnicity-related interleukin-17A gene polymorphism? AB - There are conflicting findings on whether patients with MS are at more or less risk of vascular comorbidities as compared to the general population. The worldwide incidence and prevalence of cardiovascular diseases (CVD) in the MS patients has been reported to vary substantially by region. Inflammation and demyelination in MS seem to be due to an autoimmune process mediated by IL17 secreting Th17 cells. Genotypic and allelic frequencies of IL17A and IL17F gene polymorphisms seem to confer risk to MS across populations. Increased serum levels of TH17 cells and IL-17 have been connected with atherogenesis. Ethnic specific IL17A gene haplotypes have been associated with the risk of developing atherosclerosis and premature coronary artery disease. The co-occurrence of CVD with MS might be due to ethnicity-related IL-17 gene polymorphism implying geographic and population heterogeneities. Ethnic-specific IL17 gene polymorphism may explain the conflicting results both on the roles of IL17 and Th17 cells in atherosclerosis development and about the epidemiology of CVD in MS population across countries. Genomic and proteomic studies are required to assess the possibility to use polymorphisms of IL17 gene as biomarkers of racial susceptibility to CVD in MS. PMID- 26115946 TI - Reactivation of latently infected HIV-1 viral reservoirs and correction of aberrant alternative splicing in the LMNA gene via AMPK activation: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome. AB - Although the use of antiretroviral therapy (ART) has proven highly effective in controlling and suppressing HIV-1 replication, the persistence of latent but replication-competent proviruses in a small subset of CD4(+) memory T cells presents significant challenges to viral eradication from infected individuals. Attempts to eliminate latent reservoirs are epitomized by the 'shock and kill' approach, a strategy involving the combinatorial usage of compounds that influence epigenetic modulation and initiation of proviral transcription. However, efficient regulation of viral pre-mRNA splicing through manipulation of host cell splicing machinery is also indispensible for HIV-1 replication. Interestingly, aberrant alternative splicing of the LMNA gene via the usage of a cryptic splice site has been shown to be the cause of most cases of Hutchinson Gilford progeria syndrome (HGPS), a rare genetic condition characterized by an accelerated aging phenotype due to the accumulation of a truncated form of lamin A known as progerin. Recent evidence has shown that inhibition of the splicing factors ASF/SF2 (or SRSF1) and SRp55 (or SRSF6) leads to a reduction or an increase in progerin at both the mRNA and protein levels, respectively, thus altering the LMNA pre-mRNA splicing ratio. It is also well-established that during the latter stages of HIV-1 infection, an increase in the production and nuclear export of unspliced viral mRNA is indispensible for efficient HIV-1 replication and that the presence of ASF/SF2 leads to excessive viral pre-mRNA splicing and a reduction of unspliced mRNA, while the presence of SRp55 inhibits viral pre-mRNA splicing and aids in the generation and translation of unspliced HIV-1 mRNAs. The splicing-factor associated protein and putative mitochondrial chaperone p32 has also been shown to inhibit ASF/SF2, increase unspliced HIV-1 viral mRNA, and enhance mitochondrial DNA replication and oxidative phosphorylation. It is our hypothesis that activation of AMPK, a master regulator of cellular metabolism which has been shown to activate PKC-theta (theta) and is essential for T cell activation, may modulate the splicing activities of SRp55 as well as enhance a p32-mediated inhibition of ASF/SF2-induced alternative splicing, potentially correcting aberrant alternative splicing in the LMNA gene and reactivating latent viral HIV-1 reservoirs. Moreover, similar epigenetic modifications and cell cycle regulators also characterize the analogous stages of premature senescence in progeroid cells and latency in HIV-1 infected T cells. AMPK-activating compounds including metformin and resveratrol may thus embody a novel treatment paradigm linking the pathophysiology of HGPS with that of HIV-1 latency. PMID- 26115947 TI - Associations between peripheral vertigo and gastroesophageal reflux disease. AB - We hypothesize that peripheral vertigo is associated with gastroesophageal reflux disease (GERD). Two mechanisms could be considered - gastric acids may directly irritate the respiratory mucosa and cause inflammation, or Helicobacter pylori (H. pylori) could be present and cause local infection. Reflux material (Hydrochloric acid (HCl) and pepsin) could get into the middle ear via Eustachian tube and affect osseous structures directly. Disturbance of ossicles could cause tinnitus, which is more common for peripheral vertigo. H. pylori could also get in the esophagus and in the upper respiratory tract via gastroesophageal reflux, and could cause tympanosclerosis and fixation of ossicles. In our study group, 120 of 153 (78.4%) patients had gastroesophageal reflux disease (GERD). Diagnostic tests of H. pylori (rapid urease test or blood antibody test) were performed for 96 of 120 (80%) patients with GERD and were found positive for 32 of 96 (33.3%) patients. Peripheral vertigo was present in 93 of 120 (77.6%) patients with GERD compared to 33 of 126 (26%) patients without GERD (chi(2)=9.016, p=0.003). H. pylori and peripheral vertigo coexisted in 26 of 126 patients (20.6%) (OR 1.36; 95% CI 0.49-3.74, p=0.55). Our study demonstrated statistically significant association between peripheral vertigo and GERD but not between peripheral vertigo and H. pylori. Further more extensive investigations are needed in order to explore our hypothesis. PMID- 26115949 TI - Erratum to: Diagnostics of Tree Diseases Caused by Phytophthora austrocedri Species. PMID- 26115948 TI - Epidemiological status of kissing-bugs in South East Asia: A preliminary assessment. AB - Kissing-bugs (Triatominae) are being increasingly reported as a biting nuisance in SE Asia, with severe bite reactions sometimes leading to anaphylactic shock. In addition, they pose a risk for vector-borne transmission of trypanosomiasis, with potential diagnostic difficulties due to the range of trypanosome species in the region. Here, we review available information about Triatominae in Asia, and present additional comparisons using morphometry, cytogenetics, and new DNA sequence data, to clarify their relationship with each other and with the better known American species. We deduce that all Asian Triatominae have probably derived from forms originally spread during the 15-18th centuries on sailing ships, from the area that now forms the southern USA. PMID- 26115951 TI - Ethyl lactate as a greener alternative to acetonitrile in RPLC: a realistic appraisal. AB - Appropriate substitution of acetonitrile (ACN) in mobile phases for reversed phase liquid chromatography (RPLC) by low toxicity, ecologically friendly alternative solvents emerges as a greener approach in separation sciences. Ethyl lactate is considered as a green solvent in organic synthesis, industrial extraction processes and many other applicative fields. Its ability to substitute ACN in mobile phases for RPLC applications was barely investigated. The feasibility of such a replacement was tested for the separation of the mixture of 16 polycyclic aromatic hydrocarbons listed by the Environmental Protection Agency. The analytical approach was found to be achievable, with some compromises in terms of elution order, peak efficiency and UV detectability. Thermodynamic aspects of the chromatographic process were also comparatively assessed. Correlations between the elution order and some molecular descriptors were also discussed. PMID- 26115952 TI - The reduction in small ribosomal subunit abundance in ethanol-stressed cells of Bacillus subtilis is mediated by a SigB-dependent antisense RNA. AB - One of the best-characterized general stress responses in bacteria is the sigmaB mediated stress response of the Gram-positive soil bacterium Bacillus subtilis. The sigmaB regulon contains approximately 200 protein-encoding genes and 136 putative regulatory RNAs. One of these sigmaB-dependent RNAs, named S1136-S1134, was recently mapped as being transcribed from the S1136 promoter on the opposite strand of the essential rpsD gene, which encodes the ribosomal primary-binding protein S4. Accordingly, S1136-S1134 transcription results in an rpsD-overlapping antisense RNA (asRNA). Upon exposure of B. subtilis to ethanol, the S1136 promoter was found to be induced, while rpsD transcription was downregulated. By quantitative PCR, we show that the activation of transcription from the S1136 promoter is directly responsible for the downregulation of rpsD upon ethanol exposure. We also show that this downregulation of rpsD leads to a reduced level of the small (30S) ribosomal subunit upon ethanol stress. The activation of the S1136 promoter thus represents the first example of antisense transcription mediated regulation in the general stress response of B. subtilis and implicates the reduction of ribosomal protein abundance as a new aspect in the sigmaB dependent stress response. We propose that the observed reduction in the level of the small ribosomal subunit, which contains the ribosome-decoding center, may protect B. subtilis cells against misreading and spurious translation of possibly toxic aberrant peptides under conditions of ethanol stress. PMID- 26115953 TI - RNF17 blocks promiscuous activity of PIWI proteins in mouse testes. AB - PIWI proteins and their associated piRNAs protect germ cells from the activity of mobile genetic elements. Two classes of piRNAs-primary and secondary-are defined by their mechanisms of biogenesis. Primary piRNAs are processed directly from transcripts of piRNA cluster loci, whereas secondary piRNAs are generated in an adaptive amplification loop, termed the ping-pong cycle. In mammals, piRNA populations are dynamic, shifting as male germ cells develop. Embryonic piRNAs consist of both primary and secondary species and are mainly directed toward transposons. In meiotic cells, the piRNA population is transposon-poor and largely restricted to primary piRNAs derived from pachytene piRNA clusters. The transition from the embryonic to the adult piRNA pathway is not well understood. Here we show that RNF17 shapes adult meiotic piRNA content by suppressing the production of secondary piRNAs. In the absence of RNF17, ping-pong occurs inappropriately in meiotic cells. Ping-pong initiates piRNA responses against not only transposons but also protein-coding genes and long noncoding RNAs, including genes essential for germ cell development. Thus, the sterility of Rnf17 mutants may be a manifestation of a small RNA-based autoimmune reaction. PMID- 26115955 TI - Transtracheal ventilation with a novel ejector-based device (Ventrain) in open, partly obstructed, or totally closed upper airways in pigs. AB - BACKGROUND: Transtracheal access and subsequent jet ventilation are among the last options in a 'cannot intubate-cannot oxygenate' scenario. These interventions may lead to hypercapnia, barotrauma, and haemodynamic failure in the event of an obstructed upper airway. The aim of the present study was to evaluate the efficacy and the haemodynamic effects of the Ventrain, a manually operated ventilation device that provides expiratory ventilation assistance. Transtracheal ventilation was carried out with the Ventrain in different airway scenarios in live pigs, and its performance was compared with a conventional jet ventilator. METHODS: Pigs with open, partly obstructed, or completely closed upper airways were transtracheally ventilated either with the Ventrain or by conventional jet ventilation. Airway pressures, haemodynamic parameters, and blood gases obtained in the different settings were compared. RESULTS: Mean (SD) alveolar minute ventilation as reflected by arterial partial pressure of CO2 was superior with the Ventrain in partly obstructed airways after 6 min in comparison with traditional manual jet ventilation [4.7 (0.19) compared with 7.1 (0.37) kPa], and this was also the case in all simulated airway conditions. At the same time, peak airway pressures were significantly lower and haemodynamic parameters were altered to a lesser extent with the Ventrain. CONCLUSIONS: The results of this study suggest that the Ventrain device can ensure sufficient oxygenation and ventilation through a small-bore transtracheal catheter when the airway is open, partly obstructed, or completely closed. Minute ventilation and avoidance of high airway pressures were superior in comparison with traditional hand-triggered jet ventilation, particularly in the event of complete upper airway obstruction. PMID- 26115954 TI - Cognitive behavioral therapy for depression improves pain and perceived control in cardiac surgery patients. AB - BACKGROUND: Depression after cardiac surgery (CS) is associated with increased pain and decreased sleep quality. While cognitive behavioral therapy (CBT) aimed at depression is effective in relieving depressive symptoms after cardiac surgery, little is known about its ability to ameliorate other common postoperative problems that affect recovery and quality of life. AIMS: The purpose of this study was to evaluate the effects of CBT for depression on pain severity, pain interference, sleep, and perceived control in patients recovering from CS. METHODS: Depressed patients recovering from CS were randomized to receive either eight weeks of CBT or usual care. At baseline and post intervention, patients completed questionnaires for depressive symptoms, pain, sleep, and perceived control. Group comparisons were conducted using t-tests or chi square analysis. Repeated measures analysis was used to assess the effect of the intervention in changes over time. RESULTS: The sample (n=53) included 16.9% women and had a mean age of 67.8+/-9.2 years. CBT for depression increased perceived control (p<0.001) and decreased pain interference (p=0.02) and pain severity (p=0.03). Group effects remained significant (p<0.05) for perceived control and pain interference and a trend was observed for pain severity (p<0.10) after controlling for variables that differed at baseline. There were no group differences in sleep disturbance over time. CONCLUSIONS: A depression-focused CBT intervention yields benefits in other common postoperative problems, specifically improved perceived control and decreased pain in depressed cardiac surgery patients. PMID- 26115956 TI - An occult cause of dyspnoea. PMID- 26115957 TI - Crack tip shielding observed with high-resolution transmission electron microscopy. AB - The dislocation shielding field at a crack tip was experimentally proven at the atomic scale by measuring the local strain in front of the crack tip using high resolution transmission electron microscopy (HRTEM) and geometric phase analysis (GPA). Single crystalline (110) silicon wafers were employed. Cracks were introduced using a Vickers indenter at room temperature. The crack tip region was observed using HRTEM followed by strain measurements using GPA. The measured strain field at the crack tip was compressive owing to dislocation shielding, which is in good agreement with the strain field calculated from elastic theory. PMID- 26115959 TI - Critical Care Management of Bariatric Surgery Complications. AB - Obesity remains a major medical disease that often requires surgical intervention in morbidly obese patients. Surgical procedures have evolved and are performed routinely in most major medical centers. Outcomes are often dependent on patient characteristics, type of procedure, and preoperative planning. Risk stratification often depends on screening and optimizing known comorbidities often encountered in this patient population. A thorough understanding of the physiologic changes seen in obese patient and the commonly performed operations will allow the physician to perform optimal treatment strategies. PMID- 26115958 TI - Magnetic resonance spectroscopy of paragangliomas: new insights into in vivo metabolomics. AB - Paragangliomas (PGLs) can be associated with mutations in genes of the tricarboxylic acid (TCA) cycle. Succinate dehydrogenase (SDHx) mutations are the prime examples of genetically determined TCA cycle defects with accumulation of succinate. Succinate, which acts as an oncometabolite, can be detected by ex vivo metabolomics approaches. The aim of this study was to evaluate the potential role of proton magnetic resonance (MR) spectroscopy ((1)H-MRS) for identifying SDHx related PGLs in vivo and noninvasively. Eight patients were prospectively evaluated with single voxel (1)H-MRS. MR spectra from eight tumors (four SDHx related PGLs, two sporadic PGLs, one cervical schwannoma, and one cervical neurofibroma) were acquired and interpreted qualitatively. Compared to other tumors, a succinate resonance peak was detected only in SDHx-related tumor patients. Spectra quality was considered good in three cases, medium in two cases, poor in two cases, and uninterpretable in the latter case. Smaller lesions had lower spectra quality compared to larger lesions. Jugular PGLs also exhibited a poorer spectra quality compared to other locations. (1)H-MRS has always been challenging in terms of its technical requisites. This is even more true for the evaluation of head and neck tumors. However, (1)H-MRS might be added to the classical MR sequences for metabolomic characterization of PGLs. In vivo detection of succinate might guide genetic testing, characterize SDHx variants of unknown significance (in the absence of available tumor sample), and even optimize a selection of appropriate therapies. PMID- 26115960 TI - Morphological and molecular features of oral fluid-derived exosomes: oral cancer patients versus healthy individuals. AB - PURPOSE: Oral cancer (OC) patients are at high risk to develop recurrent disease or secondary primary cancers with no available biomarkers to detect these events until a visible lesion is readily present and diagnosed by biopsy. Exosomes secreted by cancer cells are involved in tumor growth, invasion and metastasis. We aimed to determine morphological and molecular differences between oral fluid (OF)-derived exosomes of OC patients and those isolated from healthy individuals (HI). METHODS: OF from OC patients (n = 36) and HI (n = 25) was initially assessed by nanoparticle tracking analysis (NTA). Following ultracentrifugation, exosomal pellets of OC patients and HI were morphologically examined by transmission electron microscopy and atomic force microscopy (AFM). Enzyme-linked immunosorbent assay (ELISA) and western blotting (WB) were used to analyze the expression of exosomal markers--CD9, CD81 and CD63. RESULTS: NTA showed that OC samples of OF had a significantly higher concentration of nanoparticles/ml (p = 0.01) and modal nanoparticle size (p = 0.002) compared to HI. The difference in size was structurally highlighted by AFM three-dimensional images applied on exosomal pellets. ELISA and WB showed differential expression of exosomal markers in OC exosomes compared to HI: lower expression of CD81 and CD9 in contrast to a higher expression of CD63 (~53 kDa). CONCLUSIONS: OF-derived exosomes from OC patients differ both morphologically and molecularly from exosomes present in HI. This study is a baseline that provides a starting point for finding exosomal biomarkers for early detection of malignant changes in high-risk patients without overt clinical signs/lesions. PMID- 26115962 TI - Fair Is Not Fair Everywhere. AB - Distributing the spoils of a joint enterprise on the basis of work contribution or relative productivity seems natural to the modern Western mind. But such notions of merit-based distributive justice may be culturally constructed norms that vary with the social and economic structure of a group. In the present research, we showed that children from three different cultures have very different ideas about distributive justice. Whereas children from a modern Western society distributed the spoils of a joint enterprise precisely in proportion to productivity, children from a gerontocratic pastoralist society in Africa did not take merit into account at all. Children from a partially hunter gatherer, egalitarian African culture distributed the spoils more equally than did the other two cultures, with merit playing only a limited role. This pattern of results suggests that some basic notions of distributive justice are not universal intuitions of the human species but rather culturally constructed behavioral norms. PMID- 26115961 TI - Analysis of IDH1-R132 mutation, BRAF V600 mutation and KIAA1549-BRAF fusion transcript status in central nervous system tumors supports pediatric tumor classification. AB - OBJECTIVE: Gliomas are the leading cause of cancer-related morbidity in children and comprise a clinical, histological and molecular heterogenous group of CNS tumors. Appropriate treatment of these tumors relies on correct classification into tumor types and malignancy grades. METHODS: We examined 170 (0-18 years) pediatric and 131 (19-35 years) young adult brain tumors including pilocytic astrocytomas (PAs), pilomyxoid astrocytomas (PMAs), diffuse astrocytomas (DAs), gangliogliomas, dysembryoplastic neuroepithelial tumors (DNTs) and pleomorphic xanthoastrocytomas (PXAs) for IDH1 and BRAF mutation/BRAF fusion gene status. The obtained data were compared to results in 464 (<35 years) adult brain tumors. In 32 tumors with an oligodendroglial or mixed glioma differentiation, additionally the LOH1p/19q status was determined. RESULTS: By combining immunohistochemistry and molecular methods, IDH1/2 mutations were observed in 6 pediatric, 35 young adult and 43 adult tumors of the astrocytic/oligodendroglial lineage. BRAF V600E mutations (20 pediatric, 7 young adults and 2 adults) were found mostly in gangliogliomas, PXAs, few astrocytomas and few DNTs. Except for one DA case, BRAF fusions (35 pediatric, 8 young adults and 2 adults) were restricted to PA and PMA and associated with age and infratentorial location. All mutations were mutually exclusive and always present in the primary tumor. Two-thirds of all pediatric samples harbored one of the three examined mutations. CONCLUSION: Combination of IDH1-R132, BRAF V600 and KIAA1549-BRAF fusion analysis is therefore a useful tool to increase diagnostic accuracy in pediatric gliomas. PMID- 26115964 TI - Optimization and Application of APCI Hydrogen-Deuterium Exchange Mass Spectrometry (HDX MS) for the Speciation of Nitrogen Compounds. AB - A systematic study was performed to investigate the utility of atmospheric pressure chemical ionization hydrogen-deuterium exchange mass spectrometry (APCI HDX MS) to identify the structures of nitrogen-containing aromatic compounds. First, experiments were performed to determine the optimized experimental conditions, with dichloromethane and CH(3)OD found to be good cosolvents for APCI HDX. In addition, a positive correlation between the heated capillary temperature and the observed HDX signal was observed, and it was suggested that the HDX reaction occurred when molecules were contained in the solvent cluster. Second, 20 standard nitrogen-containing compounds were analyzed to investigate whether speciation could be determined based on the different types of ions produced from nitrogen-containing compounds with various functional groups. The number of exchanges occurring within the compounds correlated well with the number of active hydrogen atoms attached to nitrogen, and it was confirmed that APCI HDX MS could be used to determine speciation. The results obtained by APCI HDX MS were combined with the subsequent investigation of the double bond equivalence distribution and indicated that resins of shale oil extract contained mostly pyridine type nitrogen compounds. This study confirmed that APCI HDX MS can be added to previously reported chemical ionization, electrospray ionization, and atmospheric pressure photo ionization-based HDX methods, which can be used for structural elucidation by mass spectrometry. PMID- 26115963 TI - Triazole analog 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4 bromophenylamino)-1-(4-chlorophenyl)ethanol induces reactive oxygen species and autophagy-dependent apoptosis in both in vitro and in vivo breast cancer models. AB - Autophagy is considered as an important cell death mechanism that closely interacts with other common cell death programs like apoptosis. Critical role of autophagy in cell death makes it a promising, yet challenging therapeutic target for cancer. We identified a series of 1,2,3-triazole analogs having significant breast cancer inhibition property. Therefore, we attempted to study whether autophagy and apoptosis were involved in the process of cancer cell inhibition. The lead molecule, 1-(1-benzyl-5-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)-2-(4 bromophenylamino)-1-(4-chlorophenyl)ethanol (T-12) induced significant cell cycle arrest, mitochondrial membrane depolarization, apoptosis and autophagy in MCF-7 and MDA-MB-231 cells. T-12 increased reactive oxygen species and its inhibition by N-acetyl-L-cysteine protected breast cancer cells from autophagy and apoptosis. Autophagy inhibitor, 3-methyladenine abolished T-12 induced apoptosis, mitochondrial membrane depolarization and reactive oxygen species generation. This suggested that T-12 induced autophagy facilitated cell death rather than cell survival. Pan-caspase inhibition did not abrogate T-12 induced autophagy, suggesting that autophagy precedes apoptosis. In addition, T-12 inhibited cell survival pathway signaling proteins, Akt, mTOR and Erk1/2. T-12 also induced significant regression of tumor with oral dose of as low as 10mg/kg bodyweight in rat mammary tumor model without any apparent toxicity. In presence of reactive oxygen species inhibitor (N-acetyl-L-cysteine) and autophagy inhibitor (chloroquine), T-12 induced tumor regression was significantly decreased. In conclusion, T-12 is a potent inducer of autophagy-dependent apoptosis in breast cancer cells both in vitro and in vivo and can serve as an important lead in development of new anti-tumor therapy. PMID- 26115965 TI - A deeper look into Comet--implementation and features. AB - The Comet database search software was initially released as an open source project in late 2012. Prior to that, Comet existed as the University of Washington's academic version of the SEQUEST database search tool. Despite its availability and widespread use over the years, some details about its implementation have not been previously disseminated or are not well understood. We address a few of these details in depth and highlight new features available in the latest release. Comet is freely available for download at http://comet ms.sourceforge.net or it can be accessed as a component of a number of larger software projects into which it has been incorporated. Graphical Abstract ?. PMID- 26115966 TI - Beyond Naphthenic Acids: Environmental Screening of Water from Natural Sources and the Athabasca Oil Sands Industry Using Atmospheric Pressure Photoionization Fourier Transform Ion Cyclotron Resonance Mass Spectrometry. AB - There is a growing need for environmental screening of natural waters in the Athabasca region of Alberta, Canada, particularly in the differentiation between anthropogenic and naturally-derived organic compounds associated with weathered bitumen deposits. Previous research has focused primarily upon characterization of naphthenic acids in water samples by negative-ion electrospray ionization methods. Atmospheric pressure photoionization is a much less widely used ionization method, but one that affords the possibility of observing low polarity compounds that cannot be readily observed by electrospray ionization. This study describes the first usage of atmospheric pressure photoionization Fourier transform ion cyclotron resonance mass spectrometry (in both positive-ion and negative-ion modes) to characterize and compare extracts of oil sands process water, river water, and groundwater samples from areas associated with oil sands mining activities. When comparing mass spectra previously obtained by electrospray ionization and data acquired by atmospheric pressure photoionization, there can be a doubling of the number of components detected. In addition to polar compounds that have previously been observed, low-polarity, sulfur-containing compounds and hydrocarbons that do not incorporate a heteroatom were detected. These latter components, which are not amenable to electrospray ionization, have potential for screening efforts within monitoring programs of the oil sands. PMID- 26115968 TI - Comparison of Internal Energy Distributions of Ions Created by Electrospray Ionization and Laser Ablation-Liquid Vortex Capture/Electrospray Ionization. AB - Recently a number of techniques have combined laser ablation with liquid capture for mass spectrometry spot sampling and imaging applications. The newly developed noncontact liquid-vortex capture probe has been used to efficiently collect material ablated by a 355 nm UV laser in a continuous flow solvent stream in which the captured material dissolves and then undergoes electrospray ionization. This sampling and ionization approach has produced what appears to be classic electrospray ionization spectra; however, the 'softness' of this sampling/ionization process versus simple electrospray ionization has not been definitely determined. In this work, a series of benzylpyridinium salts were employed as thermometer ions to compare internal energy distributions between electrospray ionization and the UV laser ablation/liquid-vortex capture probe electrospray combination. Measured internal energy distributions were identical between the two techniques, even with differences in laser fluence (0.7-3.1 J cm( 2)) and when using UV-absorbing or non-UV-absorbing sample substrates. These data, along with results from the analysis the biological molecules bradykinin and angiotensin III indicated that the ions or their fragments formed directly by UV laser ablation that survive the liquid capture/electrospray ionization process were likely to be an extremely small component of the total ion signal observed. Instead, the preponderate neutral molecules, clusters, and particulates ejected from the surface during laser ablation, subsequently captured and dissolved in the flowing solvent stream, then electrosprayed, were the principal source of the ion signal observed. Thus, the electrospray ionization process used controls the overall 'softness' of this technique. PMID- 26115967 TI - How Closely Related Are Conformations of Protein Ions Sampled by IM-MS to Native Solution Structures? AB - Here, we critically evaluate the effects of changes in the ion internal energy (E(int)) on ion-neutral collision cross sections (CCS) of ions of two structurally diverse proteins, specifically the [M + 6H](6+) ion of ubiquitin (ubq(6+)), the [M + 5H](5+) ion of the intrinsically disordered protein (IDP) apo metallothionein-2A (MT), and its partially- and fully-metalated isoform, the [CdiMT](5+) ion. The ion-neutral CCS for ions formed by "native-state" ESI show a strong dependence on E(int). Collisional activation is used to increase E(int) prior to the ions entering and within the traveling wave (TW) ion mobility analyzer. Comparisons of experimental CCSs with those generated by molecular dynamics (MD) simulation for solution-phase ions and solvent-free ions as a function of temperature provide new insights about conformational preferences and retention of solution conformations. The E(int)-dependent CCSs, which reveal increased conformational diversity of the ion population, are discussed in terms of folding/unfolding of solvent-free ions. For example, ubiquitin ions that have low internal energies retain native-like conformations, whereas ions that are heated by collisional activation possess higher internal energies and yield a broader range of CCS owing to increased conformational diversity due to losses of secondary and tertiary structures. In contrast, the CCS profile for the IDP apoMT is consistent with kinetic trapping of an ion population composed of a wide range of conformers, and as the E(int) is increased, these structurally labile conformers unfold to an elongated conformation. PMID- 26115969 TI - Cationic Xylene Tag for Increasing Sensitivity in Mass Spectrometry. AB - N-(2-(Bromomethyl)benzyl)-N,N-diethylethanaminium bromide, that we designate as CAX-B (cationic xylyl-bromide), is presented as a derivatization reagent for increasing sensitivity in mass spectrometry. Because of its aryl bromomethyl moiety, CAX-B readily labels compounds having an active hydrogen. In part, a CAX tagged analyte (CAX-analyte) can be very sensitive especially in a tandem mass spectrometer (both ESI and MALDI). This is because of facile formation of an analyte-characteristic first product ion (as a xylyl-based cation) from favorable loss of triethylamine as a neutral from the precursor ion. This loss is enhanced both by resonance stabilization of the xylyl cation, and by anchimeric assistance from the ortho hetero atom of the attached analyte. High intensity of a first product ion opens up the opportunity for a CAX-analyte to be additionally sensitive when it is prone to a secondary neutral loss from the analyte part. For example, we have derivatized and detected 160 amol of thymidine by CAX-tagging/LC MALDI-TOF/TOF-MS in this way, where the two neutral losses are triethylamine and deoxyribose. Other analytes detected at the amol level as CAX derivatives (as diluted standards) include estradiol and some nucleobases. The tendency for analytes with multiple active hydrogens to label just once with CAX (an advantage) is illustrated by the conversion of bisphenol A to a single product even when excess CAX-B is present. A family of analogous reagents with a variety of reactivity groups is anticipated as a consequence of replacing the bromine atom of CAX-B with various functional groups. PMID- 26115970 TI - Constitutive activities of estrogen-related receptors: Transcriptional regulation of metabolism by the ERR pathways in health and disease. AB - The estrogen-related receptors (ERRs) comprise a small group of orphan nuclear receptor transcription factors. The ERRalpha and ERRgamma isoforms play a central role in the regulation of metabolic genes and cellular energy metabolism. Although less is known about ERRbeta, recent studies have revealed the importance of this isoform in the maintenance of embryonic stem cell pluripotency. Thus, ERRs are essential to many biological processes. The development of several ERR knockout and overexpression models and the application of advanced functional genomics have allowed rapid advancement of our understanding of the physiology regulated by ERR pathways. Moreover, it has enabled us to begin to delineate the distinct programs regulated by ERRalpha and ERRgamma that have overlapping effects on metabolism and growth. The current review primarily focuses on the physiologic roles of ERR isoforms related to their metabolic regulation; therefore, the ERRalpha and ERRgamma are discussed in the greatest detail. We emphasize findings from gain- and loss-of-function models developed to characterize ERR control of skeletal muscle, heart and musculoskeletal physiology. These models have revealed that coordinating metabolic capacity with energy demand is essential for seemingly disparate processes such as muscle differentiation and hypertrophy, innate immune function, thermogenesis, and bone remodeling. Furthermore, the models have revealed that ERRalpha- and ERRgamma deficiency in mice accelerates progression of pathologic processes and implicates ERRs as etiologic factors in disease. We highlight the human diseases in which ERRs and their downstream metabolic pathways are perturbed, including heart failure and diabetes. While no natural ligand has been identified for any of the ERR isoforms, the potential for using synthetic small molecules to modulate their activity has been demonstrated. Based on our current understanding of their transcriptional mechanisms and physiologic relevance, the ERRs have emerged as potential therapeutic targets for treatment of osteoporosis, muscle atrophy, insulin resistance and heart failure in humans. PMID- 26115972 TI - [Kikuchi-Fujimoto's disease and adult-onset Still's disease. A rare co occurence]. AB - Kikuchi-Fujimoto's disease and adult-onset Still's disease are rare inflammatory conditions with overlapping clinical features. Adult-onset Still's disease causes high fevers, a typical salmon-colored rash, and joint pain. The principal symptom of Kikuchi's disease is cervical lymphadenopathy with typical histopathological features including extensive necrosis of the involved lymph nodes. Here, we report on a rare case of concurrent adult-onset Still's disease and Kikuchi Fujimoto syndrome in a young Caucasian patient. PMID- 26115971 TI - Subsequent mortality after hyperglycemic crisis episode in the non-elderly: a national population-based cohort study. AB - Hyperglycemic crisis episodes (HCEs)-diabetic ketoacidosis and the hyperosmolar hyperglycemic state-are the most serious acute metabolic complications of diabetes. We aimed to investigate the subsequent mortality after HCE in the non elderly diabetic which is still unclear. This retrospective national population based cohort study reviewed, in Taiwan's National Health Insurance Research Database, data from 23,079 non-elder patients (<=65 years) with new-onset diabetes between 2000 and 2002: 7693 patients with HCE and 15,386 patients without HCE (1:2). Both groups were compared, and follow-up prognoses were done until 2011. One thousand eighty-five (14.1%) patients with HCE and 725 (4.71%) patients without HCE died (P < 0.0001) during follow-up. Incidence rate ratios (IRR) of mortality were 3.24 times higher in patients with HCE than in patients without HCE (P < 0.0001). Individual analysis of diabetic ketoacidosis and hyperosmolar hyperglycemic state also showed the similar result with combination of both. After stratification by age, mortality was significant higher in the middle age (40-64 years) [IRR 3.29; 95% confidence interval (CI) 2.98-3.64] and young adult (18-39 years) (IRR 3.91; 95% CI 3.28-4.66), but not in the pediatric subgroup (<18 years) (IRR 1.28; 95% CI 0.21-7.64). The mortality risk was highest in the first month (IRR 54.43; 95% CI 27.98-105.89), and still high after 8 years (IRR 2.05; 95% CI 1.55-2.71). After adjusting for age, gender, and selected comorbidities, the mortality hazard ratio for patients with HCE was still four times higher than for patients without HCE. Moreover, older age, male gender, stroke, cancer, chronic obstructive pulmonary disease, congestive heart failure, and liver disease were independent mortality predictors. HCE significantly increases the subsequent mortality risk in the non-elderly with diabetes. Strategies for prevention and control of comorbidities are needed as soon as possible. PMID- 26115973 TI - [Systemic sclerosis. Current classification and diagnosis of organ involvement]. AB - Systemic sclerosis (SSc) is a rare, chronic inflammatory autoimmune disease with unknown etiology, which leads to deposition of collagen and extracellular matrix proteins in the skin and affected internal organs. The diagnosis of SSc is based on clinical, serological, and paraclinical examinations. In 2013 new criteria for the classification of systemic sclerosis, which also take early forms of SSc into consideration, were developed. A complete clinical and paraclinical examination is important for the oligosymptomatic early stages and the subsequent disease course of SSc in order to diagnose and timely treat a developing organ involvement. PMID- 26115974 TI - Development of a risk stratification system to guide treatment for female germ cell tumors. AB - OBJECTIVE: Due to their rarity, little is known about prognostic factors in female germ cell tumors (GCTs) or outcomes following systemic therapy. Management is largely based on studies of male GCT and epithelial ovarian cancer. METHODS: Chart review was performed for all females with GCT seen at Memorial Sloan Kettering Cancer Center (MSKCC) from 1990 to 2012. Patients receiving chemotherapy were stratified using a modification of the male IGCCCG risk system, and the classifier was correlated with outcome. RESULTS: Of 93 patients, 92 (99%) underwent primary surgery and 85 (92%) received chemotherapy. Modified IGCCCG classification was significantly associated with progression-free survival (PFS) and overall survival (OS), both when applied preoperatively and pre-chemotherapy (p<0.001 for all four analyses). Progression after initial chemotherapy (n=29) was detected by imaging in 14 (48%) patients, by serum tumor markers in 6 (21%) patients, and by multiple methods in the rest. Seven (29%) of 24 patients treated with salvage chemotherapy achieved long-term PFS, including 4/6 who received high dose chemotherapy (HDCT) as initial salvage versus 3/16 treated with other initial salvage regimens. The estimated 3-year OS rate was 84% (95% CI, 76-92%), with a trend favoring dysgerminoma over non-dysgerminoma histologies (p=0.12). CONCLUSIONS: Modified IGCCCG classification was prognostic for female GCT patients in this cohort and identified a poor-risk group who may benefit from more intensive first-line chemotherapy. Both imaging and tumor marker evaluation were important in identifying relapses after first-line chemotherapy. The majority of long-term remissions with salvage therapy were achieved with initial salvage HDCT. PMID- 26115975 TI - Glucocorticoid receptor activation inhibits chemotherapy-induced cell death in high-grade serous ovarian carcinoma. AB - OBJECTIVES: To test the hypothesis that glucocorticoid receptor (GR) activation increases resistance to chemotherapy in high-grade serous ovarian cancer (HGS OvCa) and that treatment with a GR antagonist will improve sensitivity to chemotherapy. METHODS: GR expression was assessed in OvCa cell lines by qRT-PCR and Western blot analysis and in xenografts and primary human tumors using immunohistochemistry (IHC). We also examined the effect of GR activation versus inhibition on chemotherapy-induced cytotoxicity in OvCa cell lines and in a xenograft model. RESULTS: With the exception of IGROV-1 cells, all OvCa cell lines tested had detectable GR expression by Western blot and qRT-PCR analysis. Twenty-five out of the 27 human primary HGS-OvCas examined expressed GR by IHC. No cell line expressed detectable progesterone receptor (PR) or androgen receptor (AR) by Western blot analysis. In vitro assays showed that in GR-positive HeyA8 and SKOV3 cells, dexamethasone (100nM) treatment upregulated the pro-survival genes SGK1 and MKP1/DUSP1 and inhibited carboplatin/gemcitabine-induced cell death. Concurrent treatment with two GR antagonists, either mifepristone (100nM) or CORT125134 (100nM), partially reversed these effects. There was no anti apoptotic effect of dexamethasone on chemotherapy-induced cell death in IGROV-1 cells, which did not have detectable GR protein. Mifepristone treatment alone was not cytotoxic in any cell line. HeyA8 OvCa xenograft studies demonstrated that adding mifepristone to carboplatin/gemcitabine increased tumor shrinkage by 48% compared to carboplatin/gemcitabine treatment alone (P=0.0004). CONCLUSIONS: These results suggest that GR antagonism sensitizes GR+ OvCa to chemotherapy induced cell death through inhibition of GR-mediated cell survival pathways. PMID- 26115976 TI - Hormone receptors as a marker of poor survival in epithelial ovarian cancer. AB - OBJECTIVE: Androgen receptor (AR), estrogen receptor alpha and beta (ERalpha, ERbeta), and progesterone receptor (PR) are potential therapeutic targets in epithelial ovarian cancer. In this study we evaluate the prognostic value of these hormone receptors in ovarian cancer patients. METHODS: In a prospective multicenter randomized controlled phase II trial 196 ovarian cancer patients were randomized to carboplatin/docetaxel+/-celecoxib. Of 121 patients sufficient tumor tissue was available for hormone receptor analysis. Tissue micro-arrays were stained for AR, ERalpha, ERbeta, and PR. Cluster analysis was performed to identify subgroups based on hormone receptor expression profile. Receptor expression was correlated to progression-free survival (PFS) and overall survival (OS) in uni- and multivariate analysis. RESULTS: AR, ERalpha, ERbeta, and PR were expressed in respectively 10%, 31%, 73%, and 19%. In patients with synchronous metastasis tissue available (n=69 patients), discordant receptor expression was observed in 9-32%. ERbeta-expression was associated with poor PFS and OS (hazard ratios 1.88 and 1.92). Clustering analysis revealed a subgroup with hormone receptor negative disease that had a favorable PFS and OS. CONCLUSION: Hormone receptors are expressed in the majority of ovarian cancer tumors and may serve as therapeutic targets. Clustering analysis can reveal subgroups with different outcome, which may prove valuable in selecting patients for endocrine therapy. PMID- 26115977 TI - A multicenter analysis of adjuvant therapy after surgery for stage IIIC endometrial adenocarcinoma: A Korean Radiation Oncology Group study (KROG 13-17). AB - OBJECTIVE: To investigate whether combined chemoradiotherapy (CTRT) confers a benefit for survival outcome over radiotherapy (RT) alone after primary surgery in patients with FIGO stage IIIC endometrial adenocarcinoma. METHODS: We conducted a multicenter retrospective study of patients with surgical stage IIIC endometrial cancer from 1990 to 2011. Adjuvant RT alone was performed in 85 patients (40.3%) and adjuvant CTRT in 126 patients (59.7%). Disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: Stage IIIC1 and stage IIIC2 accounted for 63% and 37%, respectively. FIGO IIIC2 had a higher recurrence rate than FIGO IIIC1 (38.5% vs. 29.3%, p=0.172). Five-year OS and DFS were lower in FIGO IIIC2 than FIGO IIIC1 (85.1% vs. 76.9%, p=0.417; 71.0% vs. 59.2%, p=0.108, respectively). Eighteen patients (13.5%) in stage IIIC1 developed PALN recurrence, whereas only one (3.3%) in stage IIIC2 had PALN recurrence (p=0.001). In multivariate analysis, predictors of DFS were parametrial invasion (HR, 3.49; 95% CI, 1.83-6.64; p<0.001), higher grade (HR, 2.78; 95% CI, 1.31-5.89; p=0.008), and >3 positive pelvic nodes (HR, 1.84; 95% CI, 1.11-3.05; p=0.019). Combined CTRT did not affect DFS or OS in IIIC1 and IIIC2 compared with RT alone. CONCLUSION: CTRT showed comparable survival outcome to RT alone. Half of relapses (46%) in stage IIIC1 occurred in PALN region, whereas relapse in stage IIIC2 primarily occurred in distant metastasis (90%). Future randomized studies are needed to determine which subgroup may be most likely to benefit from CCRT. PMID- 26115978 TI - The efficacy and safety of neoadjuvant chemotherapy in the treatment of locally advanced cervical cancer: A randomized multicenter study. AB - OBJECTIVE: This study sought to evaluate the toxicity and curative effect of irinotecan plus cisplatin neoadjuvant chemotherapy (NACT) for stage Ib2, IIa2, and IIb cervical cancer patients. METHODS: A total of 219 patients were randomly assigned to two groups: 109 patients were treated with 1-2 cycles of chemotherapy (NACT group), and 110 patients in the control group were treated directly with surgery (DS group). Patients in the NACT group were randomly assigned to two groups: 50 patients were treated with irinotecan plus cisplatin followed by surgery (IP group), and 59 patients were treated with paclitaxel plus cisplatin followed by surgery (TP group). Patients with pathological recurrence risk factors received post-operative radiotherapy. RESULTS: Survival analysis revealed no significant difference in disease-free survival (DFS) or overall survival (OS) between the NACT and DS groups. Analysis of clinicopathologic factors showed that the lymphovascular space invasion (LVSI) and deep stromal invasion rates were significantly lower in the NACT group. Grade 3/4 neutropenia and grade 3/4 diarrhea were both higher in the IP group than in the TP group. DFS and OS were similar in the IP and TP groups. Univariate analysis showed that LVSI was the only factor associated with DFS. CONCLUSION: NACT did not improve overall survival but did reduce the number of patients who received post-operative radiotherapy. NACT consisting of irinotecan plus cisplatin for cervical cancer showed similar efficacy and higher toxicity compared with the use of paclitaxel plus cisplatin, although the toxicity was tolerable. PMID- 26115979 TI - Patient Selection in Short Stay Total Hip Arthroplasty for Medicare Patients. AB - There is a trend towards shortening inpatient hospital stays following total hip arthroplasty (THA) in an effort to reduce healthcare costs and potentially decrease complications. The purpose of this study was to identify patients who are at risk for readmission, complications, and mortality after short stay THA. The Medicare sample (1997-2011) was used to identify THA patients with 1-2-day (Group A, n=2949) or 3-day (Group B, n=8707) stays. Complication risks were similar between groups, though there was a reduced risk for hospitalization for Group A (adjusted hazard ratio=0.90, P=0.029). These findings suggest that age and comorbidities, particularly diabetes and cardiovascular conditions, have the greatest effect on readmission and event risk after short stay THA. PMID- 26115980 TI - Reduced Blood Loss and Transfusion Rates: Additional Benefits of Local Infiltration Anaesthesia in Knee Arthroplasty Patients. AB - We hypothesised that local infiltration of anaesthesia (LIA) containing adrenaline may reduce peri-operative blood loss and transfusion requirements in primary total knee arthroplasty patients (TKA) when compared to simple patient control analgesia (PCA). In this retrospective cohort study there were 22 TKAs in the PCA group and 27 TKAs in the LIA group. There were no drains used or significant differences in demographics between groups. There was a statistically significant difference in blood loss (P = 0.003), between the LIA group (M = 942 ml, CI 829-1055), and the PCA group (M = 1314 ml, CI 1099-1527). Patients receiving PCA were 4.3 times more likely to require blood transfusion. Using the LIA technique reduces blood loss and risk of blood transfusion. PMID- 26115981 TI - Percutaneous Acetabuloplasty Compared With Open Reconstruction for Extensive Periacetabular Carcinoma Metastases. AB - For destructive metastatic periacetabular disease, options include open acetabular reconstruction or percutaneous cement acetabuloplasty (PA). We reviewed 28 consecutive patients with Harrington grade II or III lesions, 17 who underwent Harrington-type or anti-protrusio reconstruction and 11 who underwent PA. Primary outcome measures were performance status (PS), ambulatory status (0=unassisted ambulation, 1=assisted ambulation, 2=nonambulatory), and 10-point VAS score. The surgery group had better pain reduction than the PA group at 3 months (3.6 vs. 1.5 points, P=0.04), and a trend at final follow-up (3.8 vs. 1.4 points, P=0.06). Improvement in ambulatory status was better in the surgery group at 3 months only (0.53 vs. -0.14, P=0.03). Thus compared with PA, open reconstruction may provide improved pain relief and ambulation. PMID- 26115982 TI - Tranexamic Acid Benefits Total Joint Arthroplasty Patients Regardless of Preoperative Hemoglobin Value. AB - While tranexamic acid (TXA) reduces transfusion in total joint arthroplasty (TJA), it remains unclear whether there is a preoperative hemoglobin (Hgb) threshold above which it is no longer beneficial. 2100 primary TJA patients were retrospectively categorized by preoperative Hgb; 1161 (55%) received TXA. Transfusion rates decreased with TXA in all groups; with Hgb>15 the transfusion rate was 0.5% with TXA and 4.5% without (P=0.0086); with Hgb>11 the transfusion rate was 4.7% with TXA and 18.7% without (P<0.0001). Patients receiving TXA had a shorter LOS by 0.51 days (P<0.0001). Patients receiving a postoperative transfusion had a longer LOS by 0.69 days (P<0.0001). TXA should be considered in all TJA patients independent of preoperative Hgb level. PMID- 26115983 TI - Resection Technique Does Affect Resection Symmetry and Thickness of the Patella During Total Knee Arthroplasty: A Prospective Randomized Trial. AB - The purpose of this study was to evaluate the accuracy and efficiency of three patellar resection techniques: cutting guide, free hand with haptic feedback, and a novel technique utilizing four quadrant measurements. Ninety patients undergoing TKA were randomized to receive patellar resurfacing by one of the three study techniques. The novel four quadrant technique resulted in least post resection asymmetry (0.85 mm, P = 0.001). The most accurate methods for obtaining desired thickness were haptic feedback (0.66 mm mean discrepancy [MD]) and novel four quadrant technique (0.66 mm MD) followed by the patellar cutting guide (1.40 mm MD) (P < 0.001). Use of a patellar cutting guide resulted in increased patellar asymmetry and decreased accuracy in obtaining desired patellar thickness in this prospective trial. PMID- 26115984 TI - Metaphyseal Sleeves for Revision Total Knee Arthroplasty: Good Short-Term Outcomes. AB - Metaphyseal sleeve prostheses have shown promising results in the management of bone defects at revision TKA. We present a study of their use in aseptic revision TKA. Thirty-five revisions were included in 34 patients with wear or aseptic loosening indicated in 71% of cases. The majority of cases (63%) were AORI grade 2 or greater on the tibia or femur. Knee Society scores were excellent or good in 83% of patients with the same percentage having no or only mild pain. One patient suffered a sleeve-related complication with femoral condylar fractures three years postoperatively; these united with good outcomes. All radiographs were satisfactory; no patient required a further revision. We report good outcomes with the use of metaphyseal sleeves in revision TKA. PMID- 26115985 TI - Population Size Estimates for Men who Have Sex with Men and Persons who Inject Drugs. AB - Understanding geographic variation in the numbers of men who have sex with men (MSM) and persons who inject drugs (PWID) is critical to targeting and scaling up HIV prevention programs, but population size estimates are not available at generalizable sub-national levels. We analyzed 1999-2010 National Health and Nutrition Examination Survey data on persons aged 18-59 years. We estimated weighted prevalence of recent (past 12 month) male-male sex and injection drug use by urbanicity (the degree to which a geographic area is urban) and US census region and calculated population sizes. Large metro areas (population >=1,000,000) had higher prevalence of male-male sex (central areas, 4.4% of men; fringe areas, 2.5%) compared with medium/small metro areas (1.4%) and nonmetro areas (1.1%). Injection drug use did not vary by urbanicity and neither varied by census region. Three-quarters of MSM, but only half of PWID, resided in large metro areas. Two-thirds of MSM and two-thirds of PWID resided in the South and West. Efforts to reach MSM would benefit from being focused in large metro areas, while efforts to reach PWID should be delivered more broadly. These data allow for more effective allocation of funds for prevention programs. PMID- 26115986 TI - nextflu: real-time tracking of seasonal influenza virus evolution in humans. AB - Seasonal influenza viruses evolve rapidly, allowing them to evade immunity in their human hosts and reinfect previously infected individuals. Similarly, vaccines against seasonal influenza need to be updated frequently to protect against an evolving virus population. We have thus developed a processing pipeline and browser-based visualization that allows convenient exploration and analysis of the most recent influenza virus sequence data. This web-application displays a phylogenetic tree that can be decorated with additional information such as the viral genotype at specific sites, sampling location and derived statistics that have been shown to be predictive of future virus dynamics. In addition, mutation, genotype and clade frequency trajectories are calculated and displayed. AVAILABILITY AND IMPLEMENTATION: Python and Javascript source code is freely available from https://github.com/blab/nextflu, while the web-application is live at http://nextflu.org. CONTACT: tbedford@fredhutch.org. PMID- 26115987 TI - Measuring Alcohol Consumption in Population Surveys: A Review of International Guidelines and Comparison with Surveys in England. AB - AIMS: To review the international guidelines and recommendations on survey instruments for measurement of alcohol consumption in population surveys and to examine how national surveys in England meet the core recommendations. METHODS: A systematic search for international guidelines for measuring alcohol consumption in population surveys was undertaken. The common core recommendations for alcohol consumption measures and survey instruments were identified. Alcohol consumption questions in national surveys in England were compared with these recommendations for specific years and over time since 2000. RESULTS: Four sets of international guidelines and three core alcohol consumption measures (alcohol consumption status, average volume of consumption, frequency and volume of heavy episodic drinking) with another optional measure (drinking context) were identified. English national surveys have been inconsistent over time in including questions that provide information on average volume of consumption but have not included questions on another essential alcohol consumption measure, frequency of heavy episodic drinking. Instead, they have used questions that focus only on maximum volume of alcohol consumed on any day in the previous week. CONCLUSIONS: International guidelines provide consistent recommendations for measuring alcohol consumption in population surveys. These recommendations have not been consistently applied in English national surveys, and this has contributed to the inadequacy of survey measurements for monitoring vital aspects of alcohol consumption in England over recent years. PMID- 26115988 TI - Impulsivity as a Multifaceted Construct Related to Excessive Drinking Among UK Students. AB - AIMS: A substantial number of university students exceed alcohol guidelines. Impulsivity has been repeatedly implicated in heavy alcohol use, yet despite knowledge that impulsivity is multifaceted, there have previously been few studies applying multiple measures of self-report and behavioural impulsivity to examine the relationship with excessive student drinking. This results in a limited understanding of the relationship of various facets of impulsivity to student drinking. METHODS: Participants completed a comprehensive battery of impulsivity measures: the Barratt Impulsiveness Scale as a self-report index and the Stop Signal Task, Information Sampling Task and Monetary Choice Questionnaire as behavioural measures of three facets of impulsivity. Participants who exceeded UK drinking guidelines were compared to those who did not on measures of impulsivity. Hierarchical linear regression was then employed to test whether indices of impulsivity were associated with the average units consumed per week. RESULTS: Participants who exceeded UK guidelines reported increased impulsivity in facets of self-report impulsivity. They also displayed performance deficits in normal adjustment of Go responses on the Stop Signal Task. In the regression model, nonplanning impulsivity on the Barratt Impulsiveness Scale was seen to predict quantity of alcohol consumed per month. CONCLUSIONS: The study applies a comprehensive selection of behavioural and self-report measures of impulsivity and indicates that excessive drinkers are more impulsive in some but not all aspects. The results indicate that the wide range of deficits apparent in alcohol dependent individuals are not evident in this younger, heavy drinking population, but that specific performance and self-identified deficits are already apparent. PMID- 26115989 TI - Indole: a signaling molecule or a mere metabolic byproduct that alters bacterial physiology at a high concentration? AB - Indole is an organic compound that is widespread in microbial communities inhabiting diverse habitats, like the soil environment and human intestines. Measurement of indole production is a traditional method for the identification of microbial species. Escherichia coli can produce millimolar concentrations of indole in the stationary growth phase under nutrient-rich conditions. Indole has received considerable attention because of its remarkable effects on various biological functions of the microbial communities, for example, biofilm formation, motility, virulence, plasmid stability, and antibiotic resistance. Indole may function as an intercellular signaling molecule, like a quorum-sensing signal. Nevertheless, a receptor system for indole and the function of this compound in coordinated behavior of a microbial population (which are requirements for a true signaling molecule) have not yet been confirmed. Recent findings suggest that a long-known quorum-sensing regulator, E. coli's SdiA, cannot recognize indole and that this compound may simply cause membrane disruption and energy reduction, which can lead to various changes in bacterial physiology including unstable folding of a quorum-sensing regulator. Indole appears to be responsible for acquisition of antibiotic resistance via the formation of persister cells and activation of an exporter. This review highlights and summarizes the current knowledge about indole as a multitrophic molecule among bacteria, together with recently identified new avenues of research. PMID- 26115990 TI - Spirosoma montaniterrae sp. nov., an ultraviolet and gamma radiation-resistant bacterium isolated from mountain soil. AB - A Gram-negative, yellow-pigmented, long-rod shaped bacterial strain designated DY10(T) was isolated from a soil sample collected at Mt. Deogyusan, Jeonbuk province, South Korea. Optimum growth observed at 30 degrees C and pH 7. No growth was observed above 1% (w/v) NaCl. Comparative 16S rRNA gene sequence analysis showed that strain DY10(T) belonged to the genus Spirosoma and was distantly related to Spirosoma arcticum R2-35(T) (91.0%), Spirosoma lingual DSM 74(T) (90.8%), Spirosoma endophyticum EX36(T) (90.7%), Spirosoma panaciterrae DSM 21099(T) (90.5%), Spirosoma rigui WPCB118(T) (90.2%), Spirosoma spitsbergense DSM 19989(T) (89.8%), Spirosoma luteum DSM 19990(T) (89.6%), Spirosoma oryzae RHs22(T) (89.6%), and Spirosoma radiotolerans DG5A(T) (89.1%). Strain DY10(T) showed resistance to gamma and ultraviolet radiation. The chemotaxonomic characteristics of strain DY10(T) were consistent with those of the genus Spirosoma, with the quinone system with MK-7 as the predominant menaquinone, iso C15:0, C16:1 omega5c, and summed feature3 (C16:1 omega7c/C16:1 omega6c), and phosphatidylethanolamine as the major polar lipid. The G+C content of the genomic DNA was 53.0 mol%. Differential phenotypic properties with the closely related type strains clearly distinguished strain DY10(T) from previously described members of the genus Spirosoma and represents a novel species in this genus, for which the name Spirosoma montaniterrae sp. nov. is proposed. The type strain is DY10(T) (=KCTC 23999(T) =KEMB 9004-162(T) =JCM 18492(T)). PMID- 26115991 TI - Sphingosinicella ginsenosidimutans sp. nov., with ginsenoside converting activity. AB - The Gram-reaction-negative, strictly aerobic, non-motile, nonspore-forming, and rod-shaped bacterial strain designated BS11(T) was isolated from the compost and its taxonomic position was investigated by using a polyphasic approach. Strain BS11(T) grew optimally at 30-37 degrees C and at pH 7.0 in the absence of NaCl on nutrient agar. Strain BS11(T) displayed beta-glucosidase activity that was responsible for its ability to transform ginsenoside Rb1 (one of the dominant active components of ginseng) to Rd. On the basis of 16S rRNA gene sequence similarity, strain BS11(T) was shown to belong to the family Sphingomonadaceae and was related to Sphingosinicella vermicomposti YC7378(T) (96.3% sequence similarity), S. xenopeptidilytica 3-2W4(T) (96.2%), S. microcystinivorans Y2(T) (96.1%), and S. soli KSL-125(T) (95.9%). The G+C content of the genomic DNA was 64.9%. The major menaquinone was Q-10 and the major fatty acids were summed feature 7 (comprising C18:1 omega7c/omega9t/omega12t; 40.6%), C16:0 (22.5%), C17:1 omega6c (13.7%) and C17:0 (9.1%). DNA and chemotaxonomic data supported the affiliation of strain BS11(T) to the genus Sphingosinicella. Strain BS11(T) could be differentiated genotypically and phenotypically from the recognized species of the genus Sphingosinicella. The novel isolate therefore represents a novel species, for which the name Sphingosinicella ginsenosidimutans sp. nov. is proposed, with the type strain BS11(T) (=KACC 16619T =JCM 18201(T)). PMID- 26115992 TI - Flavisolibacter swuensis sp. nov. isolated from soil. AB - A Gram-staining-negative, non-motile, non-spore-forming, and rod-shaped bacterium designated as strain SR2-4-2(T) was isolated from soil in South Korea. Phylogenetic analysis based on 16S rRNA gene sequence of strain SR2-4-2(T) revealed that it belonged to the genus of Flavisolibacter, family of Chitinophagaceae, and class of Sphingobacteriia. It shared sequence similarities with Flavisolibacter ginsengisoli Gsoil 643(T) (96.4%), Flavisolibacter ginsengiterrae Gsoil 492(T) (96.3%), and Flavisolibacter rigui 02SUJ3(T) (93.0%). Chemotaxonomic data revealed that its predominant fatty acids were iso-C15:0 (26.4%) and iso-C17:0 3OH (10.7%). Its major polar lipid was phosphatidylethanolamine (PE) and its predominant respiratory quinone was MK-7. The G+C content of genomic DNA of the strain SR2-4-2(T) DNA was 45.0%. Based on the phylogenetic, chemotaxonomic, and phenotypic data, the strain SR2-4-2(T) (=JCM 19974(T) =KEMB 9004-156(T)) is classified as a type strain of a novel species for which the name of Flavisolibacter swuensis sp. nov. is proposed. PMID- 26115993 TI - Bacillus coreaensis sp. nov.: a xylan-hydrolyzing bacterium isolated from the soil of Jeju Island, Republic of Korea. AB - A xylan-degrading bacterium, designated as MS5(T) strain, was isolated from soil collected from the Jeju Island, Republic of Korea. Strain MS5(T) was Gram-stain positive, aerobic, and motile by polar flagellum. The major fatty acids identified in this bacterium were iso-C15:0 (32.3%), C16:0 (27.3%), and anteiso C15:0 (10.2%). A similarity search based on the 16S rRNA gene sequence revealed that the strain belongs to the class Bacilli and shared the highest similarity with the type strains Bacillus beringensis BR035(T) (98.7%) and Bacillus korlensis ZLC-26(T) (98.6%) which form a coherent cluster in a neighbor-joining phylogenetic tree. The DNA G+C content of strain MS5(T) was 43.0 mol%. The major menaquinone was MK-7 and the diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The DNADNA relatedness values between strain MS5(T) and two closely related species, B. beringensis BR035(T) and B. korlensis ZLC-26(T), were less than 70%. DNA-DNA relatedness analysis and 16S rRNA sequence similarity, as well as phenotypic and chemotaxonomic characteristics suggest that the strain MS5(T) constitutes a novel Bacillus species, for which the name Bacillus coreaensis sp. nov. is proposed. The type strain is MS5(T) (=DSM25506(T) =KCTC13895(T)). PMID- 26115994 TI - Arbuscular mycorrhizal fungal diversity, root colonization, and soil alkaline phosphatase activity in response to maize-wheat rotation and no-tillage in North China. AB - Monitoring the effects of no-tillage (NT) in comparison with conventional tillage (CT) on soil microbes could improve our understanding of soil biochemical processes and thus help us to develop sound management strategies. The objective of this study was to compare the species composition and ecological function of soil arbuscular mycorrhizal (AM) fungi during the growth and rotation of crops under NT and CT. From late June 2009 to early June 2010, 32 topsoil (0-15 cm) samples from four individual plots per treatment (CT and NT) were collected at both the jointing and maturation stages of maize (Zea mays L.) and wheat (Triticum aestivum L.) from a long-term experimental field that was established in an Aquic Inceptisol in North China in June 2006. The AM fungal spores were isolated and identified and then used to calculate species diversity indices, including the Shannon- Wiener index (H'), Evenness (E), and Simpson's index (D). The root mycorrhizal colonization and soil alkaline phosphatase activity were also determined. A total of 34 species of AM fungi within nine genera were recorded. Compared with NT, CT negatively affected the soil AM fungal community at the maize sowing stage, leading to decreases in the average diversity indices (from 2.12, 0.79, and 0.82 to 1.79, 0.72, and 0.74 for H', E, and D, respectively), root mycorrhizal colonization (from 28% to 20%), soil alkaline phosphatase activity (from 0.24 to 0.19 mg/g/24 h) and available phosphorus concentration (from 17.4 to 10.5 mg/kg) at the maize jointing stage. However, reductions in diversity indices of H', E, and D were restored to 2.20, 0.81, and 0.84, respectively, at the maize maturation stage. CT should affect the community again at the wheat sowing stage; however, a similar restoration in the species diversity of AM fungi was completed before the wheat jointing stage, and the highest Jaccard index (0.800) for similarity in the species composition of soil AM fungi between CT and NT was recorded at the wheat maturation stage. Our results also demonstrated that NT resulted in the positive protection of the community structure of AM fungi and played an important role in maintaining their functionality especially for maize seedlings. PMID- 26115995 TI - Biotransformation of (-)-alpha-pinene and geraniol to alpha-terpineol and p menthane-3,8-diol by the white rot fungus, Polyporus brumalis. AB - In this study, the monoterpenes, alpha-pinene and geraniol, were biotransformed to synthesize monoterpene alcohol compounds. Polyporus brumalis which is classified as a white rot fungus was used as a biocatalyst. Consequently alpha terpineol was synthesized from alpha-pinene by P. brumalis mycelium, after three days. Moreover, another substrate, the acyclic monoterpenoids geraniol was transformed into the cyclic compound, p-menthane-3, 8-diol (PMD). The main metabolites, i.e., alpha-terpineol and PMD, are known to be bioactive monoterpene alcohol compounds. This study highlights the potential of fungal biocatalysts for monoterpene transformation. PMID- 26115997 TI - Prevalence of avian influenza virus in wild birds before and after the HPAI H5N8 outbreak in 2014 in South Korea. AB - Since 2003, highly pathogenic avian influenza (HPAI) virus outbreaks have occurred five times in Korea, with four HPAI H5N1 outbreaks and one HPAI H5N8 outbreak. Migratory birds have been suggested to be the first source of HPAI in Korea. Here, we surveyed migratory wild birds for the presence of AI and compared regional AI prevalence in wild birds from September 2012 to April 2014 for birds having migratory pathways in South Korea. Finally, we investigated the prevalence of AI in migratory birds before and after HPAI H5N8 outbreaks. Overall, we captured 1617 migratory wild birds, while 18,817 feces samples and 74 dead birds were collected from major wild bird habitats. A total of 21 HPAI viruses were isolated from dead birds, and 86 low pathogenic AI (LPAI) viruses were isolated from captured birds and from feces samples. Spatiotemporal distribution analysis revealed that AI viruses were spread southward until December, but tended to shift north after January, consistent with the movement of migratory birds in South Korea. Furthermore, we found that LPAI virus prevalences within wild birds were notably higher in 2013-2014 than the previous prevalence during the northward migration season. The data from our study demonstrate the importance of the surveillance of AI in wild birds. Future studies including in-depth genetic analysis in combination with evaluation of the movement and ecology of migratory birds might help us to bridge the gaps in our knowledge and better explain, predict, and ultimately prevent future HPAI outbreaks. PMID- 26115996 TI - Anti-tumor effect of Cordyceps militaris in HCV-infected human hepatocarcinoma 7.5 cells. AB - Cordyceps extract has been reported to have various pharmacological activities including an anti-cancer effect. We investigated the inhibitory effect of Cordyceps militaris on hepatitis C virus-infected human hepatocarcinoma 7.5 cells (J6/JFH1-huh 7.5 cells). The huh7.5 cells with or without HCV infection were treated with various concentrations of ethanol extract of Cordyceps militaris (CME) for 48 h and the cytotoxicity was measured by CCK-8 assay. Both J6/JFH1 huh7.5 cells and huh7.5 cells were highly susceptible to CME. To examine the molecular mechanisms of the inhibitory effect on huh7.5 cells, the effect of CME on cell apoptosis was measured using flow cytometry and the expressions of p53, Bim, Bax, PARP, (cleaved) caspase-9, and (cleaved) caspase- 3 in huh 7.5 cells were detected by western blot assays. CME significantly increased early apoptosis and up-regulated the expression of Bim, Bax, cleaved PARP, cleaved caspase 9 and cleaved caspase-3. We also found the decrease of HCV Core or NS3 protein by CME in HCV-infected huh 7.5 cells. PMID- 26115998 TI - Development of a stringent ELISA protocol to evaluate anti-viral hemorrhagic septicemia virus-specific antibodies in olive flounder Paralichthys olivaceus with improved specificity. AB - Olive flounder were vaccinated with polyinosinic:polycytidylic acid [Poly (I:C)] to prevent viral hemorrhagic septicemia (VHS). Vaccine efficacy was verified by detection of anti- VHS virus (VHSV) antibodies using enzyme-linked immunosorbent assay (ELISA). In the study, ELISA absorbance values of the negative control group [Poly (I:C)-MEM10] were saturated when an ELISA protocol, that includes pretreatment of the fish sera with 5% skim milk, was used. However, the saturated OD values in the negative control did not correlate with a specific immune response against VHSV, because the group showed low survival rate (only 10%) following the VHSV challenge. Also, OD values of Poly (I:C)- VHSV group were high, and the group showed high survival rate (97.5%) against VHSV challenge test. It was suggested that the high OD values were possibly due to the presence of anti-fetal bovine serum (FBS) cross-reactivity. To compensate this, we subtracted the absorbance of infectious hematopoietic necrosis (IHNV)-Ag plates from those of the VHSV-Ag plates. However, the average value for the Poly (I:C) VHSV group (0.167) was lower than expected even though high survival rate. We used an advanced ELISA system to pre-treat fish sera with 5% skim milk and two novirhabdoviruses as capture antigens as well as 50% FBS. The corrected absorbance values for pre-treated fish sera from the negative control Poly (I:C) MEM10 and experimental Poly (I:C)-VHSV groups averaged 0.033 and 0.579, respectively. The specific VHSV antibody response of the vaccinated group was assessed using fish sera pretreated with skim milk and FBS and by calculating the corrected absorbance values from ELISA with two novirhabdovirus capture antigens. PMID- 26115999 TI - The Medical Staff Ride: an education tool for military medical leadership development. AB - This paper provides a description of the Medical Staff Ride as an educational tool for military medical leadership. It is based upon two Medical Staff Rides covering the Somme Campaign 1916 and the Normandy Campaign 1944. It describes the key educational activity 'The Stand' at which history and current issues are brought together through study of a particular location on the historical battlefield. The Medical Staff Ride can be divided into six distinct phases, each of which have common question sets for analysis by attendees. The Medical Staff Ride can be shown to have valuable educational outcomes that are efficient in time and cost, and effective in achieving personal learning. The supporting Readers for the two Medical Staff Rides covered by this paper are available as electronic supplement to this edition of the journal. PMID- 26116000 TI - Paediatric traumatic cardiac arrest: data from the Joint Theatre Trauma Registry. AB - BACKGROUND: Traumatic cardiac arrest (TCA) in children is associated with a low probability of survival and poor neurological outcome in survivors. Since 2003, over 600 seriously injured local national children have been treated at deployed UK military medical treatment facilities during the Iraq and Afghanistan conflicts. A number of these were in cardiac arrest after sustaining traumatic injuries. This study defined outcomes from paediatric TCA in this cohort. METHODS: A retrospective database review was undertaken using the UK Joint Theatre Trauma Registry. This includes UK military, coalition military, civilians and local security forces personnel who prompted trauma team activation. All children in this series were local nationals. Patients aged less than 18 years who presented between January 2003 and April 2014, and who underwent cardiopulmonary resuscitation, were included. RESULTS: 27 children with TCA were included. Four children survived to discharge from the medical treatment facility (14.8%), though limited data are available regarding the long-term neurological outcome in these patients. CONCLUSIONS: This study demonstrates that the outcomes for paediatric TCA in our military field hospitals were similar to other paediatric civilian and adult military studies, despite patients being injured by severe blast injuries. Further work is needed to define the optimal management of paediatric TCA. PMID- 26116001 TI - Olfr603, an orphan olfactory receptor, is expressed in multiple specific embryonic tissues. AB - BACKGROUND: Olfactory receptors were initially believed to be expressed specifically within the olfactory neurons. However, accumulating genome-scale data has recently demonstrated more extensive expression. There are hundreds of olfactory receptor family members and the realisation of their widespread expression provides an opportunity to reveal new biology. However, existing data is predominantly based on RT-PCR, microarray and RNA-seq approaches and the details of tissue and cell-type specific expression are lacking. RESULTS: As a proof of principle, we selected Olfr603 for expression analysis. We generated an antibody against a non-conserved epitope of Olfr603 and characterised its expression in E8.5-E12.5 mouse embryos using immunohistochemistry. This analysis demonstrated a dynamic pattern of expression in diverse cell types within the developing embryo unrelated to the olfactory system. Expression was detected in migrating neural crest, endothelial precursors and vascular endothelium, endocardial cells, smooth muscle, neuroepithelium and within the ocular tissues. This complex distribution does not conform to any apparent germ layer or tissue origin. CONCLUSIONS: This initial characterisation of Olfr603 expression highlights the potential for a broad role for this receptor in the development of many tissues. PMID- 26116003 TI - Epigenetic factors in the regulation of prospermatogonia and spermatogonial stem cells. AB - Appropriate regulation of epigenome within cells is crucial for the determination of cell fate and contributes to the lifelong maintenance of tissue homeostasis. Epigenomic re-establishment during embryonic prospermatogonia development and fine-tune of the epigenetic landscape in postnatal spermatogonial stem cells (SSCs) are two key processes required for functional male germ cell formation. Repression of re-activated transposons and male germline-specific epigenome establishment occur in prospermatogonia, whereas modulations of the epigenetic landscape is important for SSC self-renewal and differentiation to maintain the stem cell pool and support long-term sperm production. Here, we describe the impact of epigenome-related regulators and small non-coding RNAs as well as the influence of epigenome modifications that result from extrinsic signaling for controlling the decision between self-renewal, differentiation and survival in mouse prospermatogonia and SSCs. This article provides a review of epigenome related molecules involved in cell fate determination in male germ cells and discusses the intriguing questions that arise from these studies. PMID- 26116002 TI - Size-specific follicle selection improves mouse oocyte reproductive outcomes. AB - Encapsulated in vitro follicle growth (eIVFG) has great potential to provide an additional fertility preservation option for young women and girls with cancer or other reproductive health threatening diseases. Currently, follicles are cultured for a defined period of time and analyzed as a cohort. However, follicle growth is not synchronous, and culturing follicles for insufficient or excessive times can result in compromised gamete quality. Our objective is to determine whether the selection of follicles based on size, rather than absolute culture time, better predict follicle maturity and oocyte quality. Multilayer secondary mouse follicles were isolated and encapsulated in 0.25% alginate. Follicles were cultured individually either for defined time periods or up to specific follicle diameter ranges, at which point several reproductive endpoints were analyzed. The metaphase II (MII) percentage after oocyte maturation on day 6 was the highest (85%) when follicles were cultured for specific days. However, if follicles were cultured to a terminal diameter of 300-350 MUm irrespective of absolute time in culture, 93% of the oocytes reached MII. More than 90% of MII oocytes matured from follicles with diameters of 300-350 MUm showed normal spindle morphology and chromosome alignment, 85% of oocytes showed two pronuclei after IVF, 81% developed into the two-cell embryo stage and 38% developed to the blastocyst stage, all significantly higher than the percentages in the other follicle size groups. Our study demonstrates that size-specific follicle selection can be used as a non-invasive marker to identify high-quality oocytes and improve reproductive outcomes during eIVFG. PMID- 26116004 TI - Designing the microturbine engine for waste-derived fuels. AB - Presented paper deals with adaptation procedure of a microturbine (MGT) for exploitation of refuse derived fuels (RDF). RDF often possess significantly different properties than conventional fuels and usually require at least some adaptations of internal combustion systems to obtain full functionality. With the methodology, developed in the paper it is possible to evaluate the extent of required adaptations by performing a thorough analysis of fuel combustion properties in a dedicated experimental rig suitable for testing of wide-variety of waste and biomass derived fuels. In the first part key turbine components are analyzed followed by cause and effect analysis of interaction between different fuel properties and design parameters of the components. The data are then used to build a dedicated test system where two fuels with diametric physical and chemical properties are tested - liquefied biomass waste (LW) and waste tire pyrolysis oil (TPO). The analysis suggests that exploitation of LW requires higher complexity of target MGT system as stable combustion can be achieved only with regenerative thermodynamic cycle, high fuel preheat temperatures and optimized fuel injection nozzle. Contrary, TPO requires less complex MGT design and sufficient operational stability is achieved already with simple cycle MGT and conventional fuel system. The presented approach of testing can significantly reduce the extent and cost of required adaptations of commercial system as pre selection procedure of suitable MGT is done in developed test system. The obtained data can at the same time serve as an input for fine-tuning the processes for RDF production. PMID- 26116005 TI - Heavy element accumulation in Evernia prunastri lichen transplants around a municipal solid waste landfill in central Italy. AB - This paper presents the results of a biomonitoring study to evaluate the environmental impact of airborne emissions from a municipal solid waste landfill in central Italy. Concentrations of 11 heavy elements, as well as photosynthetic efficiency and cell membrane integrity were measured in Evernia prunastri lichens transplanted for 4months in 17 monitoring sites around the waste landfill. Heavy element contents were also determined in surface soils. Analytical data indicated that emissions from the landfill affected Cd, Co, Cr, Cu, Ni, Pb, Sb and Zn concentrations in lichens transplanted within the landfill and along the fallout direction. In these sites moderate to severe accumulation of these heavy elements in lichens was coupled with an increase in cell membrane damage and decrease in photosynthetic efficiency. Nevertheless, results indicated that landfill emissions had no relevant impact on lichens, as heavy element accumulation and weak stress symptoms were detected only in lichen transplants from sites close to solid waste. The appropriate management of this landfill poses a low risk of environmental contamination by heavy elements. PMID- 26116006 TI - Evaluation of the impact of lime softening waste disposal in natural environments. AB - Drinking water treatment residues (WTR), generated from the lime softening processes, are commonly reused or disposed of in a number of applications; these include use as a soil amendment or a subsurface fill. Recently questions were posed by the Florida regulatory community on whether lime WTR that contained a small percentage of other treatment additives could appropriately be characterized as lime WTR, in terms of total element content and leachability. A study was done using a broad range of leaching tests, including a framework of tests recently adopted by the United States-Environmental Protection Agency (EPA) and tests that were modified to account for scenario specific conditions, such as the presence of natural organic matter (NOM). The results of these additional leaching tests demonstrated that certain applications, including disposal in a water body with NOM or in placement anaerobic environment, did result in increased leaching of elements such as Fe, and that a site specific assessment should be conducted prior to using WTR in these types of applications. This study illustrates the importance of leaching test selection when attempting to provide an estimation of release in practice. Although leaching tests are just one component in a beneficial use assessment and other factors including aquifer and soil properties play a significant role in the outcome, leaching tests should be tailored to most appropriately represent the scenario or reuse application being evaluated. PMID- 26116007 TI - Extension of the sorting instructions for household plastic packaging and changes in exposure to bioaerosols at materials recovery facilities. AB - The aim of this study was to assess how extending the sorting instructions for plastic packaging would affect the exposure of workers working at materials recovery facility (MRF) to dust, endotoxins, fungi and bacteria, taking into consideration other factors that could have an influence on this exposure. Personal sampling was carried out at four MRFs during six sampling campaigns at each facility, both in sorting rooms and when the workers were involved in "mobile tasks" away from the rooms. The data was analysed by describing the extension of sorting instructions both using a qualitative variable (after vs before) and using data for the pots and trays recycling stream, including or excluding plastic film. Overall, before the extension of the sorting guidelines, the geometric mean of personal exposure levels in sorting rooms was 0.3mg/m(3) for dust, 27.7 EU/m(3) for endotoxins, 13,000 CFU/m(3) for fungi and 1800 CFU/m(3) for bacteria. When workers were involved in mobile tasks away from the rooms, these averages were 0.5mg/m(3), 25.7 EU/m(3), 28,000 CFU/m(3) and 5100 CFU/m(3) respectively.The application by households of instructions to include pots, trays and film with other recyclable plastic packaging led to an increase in exposure to endotoxins, fungi and bacteria at MRFs. For an increase of 0.5 kg per inhabitant per year in the pots, trays and film recycling stream, exposure in sorting rooms rose by a factor of 1.4-2.2, depending on the biological agent. Exposure during mobile tasks increased by a factor of 3.0-3.6. The age of the waste amplified the effect of the extension of sorting instructions on exposure to fungi, bacteria and endotoxins. Factors that had a significant influence on the exposure of workers to dust and/or bioaerosols included the presence of paper, newspapers and magazines in the sorted waste, the order in which incoming waste was treated and the quality of the ventilation system in the sorting rooms. The levels of exposure observed in this study highlight the need to implement appropriate preventive measures against bioaerosols at MRFs for dry waste. There are grounds to justify these preventive measures, both inside sorting rooms and for the MRF as a whole, regardless of whether the decision to extend sorting instructions for household plastic waste is adopted. PMID- 26116009 TI - Current status of solid waste management in small island developing states: A review. AB - This article reviews the current status of waste management in Small Island Developing States (SIDS) and the challenges that are faced in solid waste management. The waste generation rates of SIDS were compared within the three geographic regions namely Caribbean SIDS, Pacific SIDS and Atlantic, Indian Ocean, Mediterranean and South China (AIMS) SIDS and with countries of the Organisation for Economic Co-Operation and Development (OECD). Only Pacific SIDS had a waste generation rate less than 1kg/capita/day. The waste generation rates for the three SIDS regions averaged 1.29kg/capita/day while that for OECD countries was at a mean value of 1.35kg/capita/day. The waste compositions in the different SIDS regions were almost similar owing to comparable consumption patterns while these differed to a large extent with wastes generated in OECD countries. In SIDS, the major fraction of MSW comprised of organics (44%) followed by recyclables namely paper, plastics, glass and metals (total: 43%). In contrast, MSW in OECD countries consisted mainly of recyclables (43%) followed by organics (37%). This article also reviewed the other functional elements of the waste management systems in SIDS. Several shortcomings were noted in the process of waste collection, transfer and transport namely the fact of having outdated collection vehicles and narrow roads which are inaccessible. Among the waste management practices in SIDS, waste disposal via landfilling, illegal dumping and backyard burning were favoured most of the time at the expense of sustainable waste treatment technologies such as composting, anaerobic digestion and recycling. PMID- 26116008 TI - Integrated gasification and plasma cleaning for waste treatment: A life cycle perspective. AB - In the past, almost all residual municipal waste in the UK was landfilled without treatment. Recent European waste management directives have promoted the uptake of more sustainable treatment technologies, especially for biodegradable waste. Local authorities have started considering other options for dealing with residual waste. In this study, a life cycle assessment of a future 20MWe plant using an advanced two-stage gasification and plasma technology is undertaken. This plant can thermally treat waste feedstocks with different composition and heating value to produce electricity, steam and a vitrified product. The objective of the study is to analyse the environmental impacts of the process when fed with seven different feedstocks (including municipal solid waste, solid refuse fuel, reuse-derived fuel, wood biomass and commercial & industrial waste) and identify the process steps which contribute more to the environmental burden. A scenario analysis on key processes, such as oxygen production technology, metal recovery and the appropriate choice for the secondary market aggregate material, is performed. The influence of accounting for the biogenic carbon content in the waste from the calculations of the global warming potential is also shown. Results show that the treatment of the refuse-derived fuel has the lowest impact in terms of both global warming potential and acidification potential because of its high heating value. For all the other impact categories analysed, the two stage gasification and plasma process shows a negative impact for all the waste streams considered, mainly due to the avoided burdens associated with the production of electricity from the plant. The plasma convertor, key characteristic of the thermal process investigated, although utilising electricity shows a relatively small contribution to the overall environmental impact of the plant. The results do not significantly vary in the scenario analysis. Accounting for biogenic carbon enhanced the performance of biomass and refuse-derived fuel in terms of global warming potential. The main analysis of this study has been performed from a waste management perspective, using 1ton of waste as functional unit. A comparison of the results when 1kWhe of electricity produced is used as functional unit shows similar trends for the environmental impact categories considered. PMID- 26116010 TI - Race-based sexual stereotypes and their effects on sexual risk behavior in racially diverse young men who have sex with men. AB - Men who have sex with men (MSM) are disproportionately impacted by the HIV/AIDS epidemic in the United States. The epidemic is not evenly distributed across MSM, and young racial minority MSM experience the highest rate of new infections. Race based sexual stereotyping is not uncommon among MSM, and it may contribute to the isolation of racial minority sexual networks, which has been found to contribute to increased HIV incidence in Black MSM. The goals of these analyses were to describe the race-based sexual preferences and stereotypes of racially diverse young MSM (YMSM), and to examine whether endorsement of sexual stereotypes was associated with sexual risk behavior when having sex with partners of the stereotyped race. Data were taken from Crew 450, an ongoing longitudinal study of a syndemic of psychosocial health issues linked to HIV among YMSM in Chicago and surrounding areas. Analyses utilized data from three study waves, and longitudinal analyses were conducted with Hierarchical Linear Modeling. YMSM generally endorsed same-race preferences for sexual partners. Black partners were rated highest in displaying stereotypically dominant characteristics and in likelihood of taking the top/insertive sex role, while Latino partners were rated the highest in likelihood of sex being hot and passionate. White partners were rated lowest on each of these domains. Longitudinal analyses found that endorsement of these stereotypes had important implications for the rate of condomless receptive and insertive anal sex with racial minority partners. Findings suggest that sexual stereotypes may contribute to the isolation of racial minority sexual networks. PMID- 26116011 TI - The effect of antireflux surgery on laryngeal symptoms, findings and voice parameters. AB - The aim of this study was to evaluate the effect of laparoscopic antireflux surgery (LARS) on the laryngeal symptoms, physical findings and voice parameters of gastroesophageal reflux disease (GERD) patients with or without laryngopharyngeal reflux (LPR). Forty-one GERD patients predominantly with LPR symptoms (Group I) and twenty-six GERD patients without LPR symptoms (Group II) who had LARS were prospectively analysed before and 2 years after the surgery. Upper gastrointestinal endoscopy, 24-h ambulatory pH or MII-pH monitoring was performed in all cases. A reflux study group including specialists from five departments in a university hospital decided surgical indications. Patients were asked to fill out a validated LPR and voice quality questionnaire (Reflux Symptom Index and Voice Handicap Index-10). Laryngeal findings were evaluated and scored using a laryngoscopic grading scale [Reflux Finding Score (RFS)], by four blinded ENT specialists. GRBAS scale was done by a blinded otolaryngologist. Voice parameters were measured objectively via the Multi Dimensional Voice Programme (MDVP). The mean age was 45.8 +/- 8.5 for Group I (24 men) and 48.9 +/- 12.3 for Group II (16 men). The mean follow-up after LARS was 24.5 +/- 1.3 months for Group I and 25.2 +/- 1.1 months for Group II. The preoperative mean score of RSI was 22.8 +/- 7.4 vs. 11.2 +/- 6.6; RFS was 10.6 +/- 2.3 vs. 5.7 +/- 2.5 and VHI was 18.07 +/- 4.4 vs. 10.86 +/- 3.3 for Group I and II, respectively. The postoperative mean score of RSI was 12.9 +/- 6.4 vs. 8.4 +/- 4.5; RFS was 6.9 +/- 2.0 vs. 4.5 +/- 2.3 and VHI was 9.59 +/- 4.4 vs. 7.95 +/- 3.5 for Group I and II, respectively. Group I had significantly lower RSI and RFS scores following LARS compared to the preoperative scores. LARS successfully improved RFS, RSI and VHI in carefully selected patients with GERD, especially the signs and symptoms related to the larynx and voice. Although the indications for LARS are limited in patients with LPR symptoms, these results favor the decision-making period of LARS. PMID- 26116013 TI - Designing a biocompatible hydrogel for the delivery of mesalamine. AB - A new design for nanocomposite hydrogels based on cross-linked chitosan for the delivery of mesalamine is presented. To enhance drug loading in chitosan, the mineral montmorillonite was incorporated into the matrix. The exfoliated silica montmorillonite nanosheets form interactions with both chitosan and mesalamine, which affect the hydrogel's drug release mechanism and swelling properties. The impact of montmorillonite and glutaraldehyde concentrations on the hydrogel properties was investigated. In vitro drug-release studies detected slower release over short times when montmorillonite was introduced into the matrix. This study is the first to evaluate the influence of pH during mixing and on mixing duration. It was shown that lowering the pH during mixing delayed the release since the positively charged drug was better introduced between the montmorillonite layers, as confirmed by differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FTIR) analysis. All hydrogels showed prolonged sustained release of mesalamine over 24h in simulated colonic fluid (pH 7.4). When modeled, the mesalamine release profile suggests a complex release mechanism, involving adsorption of the drug to the montmorillonite and its diffusion. The results imply that chitosan-montmorillonite hydrogels can serve as potential drug carriers for controlled-release applications. PMID- 26116012 TI - Radiation induced oral mucositis: a review of current literature on prevention and management. AB - Oral mucositis (OM) is a major limiting acute side effect of radiotherapy for head and neck cancer. The spectrum of problems associated with mucositis includes oral pain, odynophagia, reduced oral intake, and secondary infections. Incidence of mucositis is increased with addition of concurrent chemotherapy as well as altered fractionation schedules. This leads to treatment interruption and suboptimal disease control. Hence, prevention as well as timely management of OM is necessary for optimum tumor control. We reviewed the English literature with key words "Radiation induced mucositis, Mucositis, Oral Mucositis" to find relevant articles describing incidence, pathophysiology, prophylaxis, and treatment of oral mucositis. Prevention and treatment of OM is an active area of research. Maintenance of oral hygiene is an important part in prevention of OM. A battery of agents including normal saline and alkali (soda bicarbonate) mouth washes, low level laser therapy, and benzydamine (non-steroidal analgesic and anti-inflammatory) have effectiveness in the prevention and treatment of radiation induced oral mucositis. Chlorhexidine mouth gargles are recommended for prevention of chemotherapy induced oral mucositis but is not recommended for radiotherapy associated mucositis. Treatment of co-existing infection is also important and both topical (povidone iodine) and systemic anti fungals should be used judiciously. Radiation induced oral mucositis is a common problem limiting the efficacy of radiation by increasing treatment breaks. Adequate prophylaxis and treatment may limit the severity of radiation mucositis and improve compliance to radiation which may translate in better disease control and survival. PMID- 26116014 TI - Microfluidic conceived Trojan microcarriers for oral delivery of nanoparticles. AB - In this study, we report on a novel method for the synthesis of poly(acrylamide) Trojan microparticles containing ketoprofen loaded poly(ethyl acrylate) or poly(methyl acrylate) nanoparticles. To develop these composite particles, a polymerizable nanoemulsion was used as a template. This nanoemulsion was obtained in an elongational-flow micromixer (MURMX) which was linked to a capillary-based microfluidic device for its emulsification into micron range droplets. Downstream, the microdroplets were hardened into Trojan particles in the size range of 213-308 MUm by UV initiated free radical polymerization. The nanoemulsion size varied from 98 -132 nm upon changes in surfactant concentration and number of operating cycles in MURMX. SEM and confocal microscopy confirmed the Trojan morphology. Under SEM it was observed that the polymerization reduced the size of the nanoemulsion down to 20-32 nm for poly(ethyl acrylate) and 10-15 nm for poly(methyl acrylate) nanoparticles. This shrinkage was confirmed by cryo TEM studies. We further showed that Trojan microparticles released embedded nanoparticles on contact with suitable media as confirmed by transmission electron microscopy. In a USP phosphate buffer solution of pH 6.8, Trojan microparticles containing poly(ethyl acrylate) nanoparticles released 35% of encapsulated ketoprofen over 24h. The low release of the drug was attributed to the overall low concentration of nanoparticles and attachment of some of nanoparticles to the poly(acrylamide) matrix. Thus, this novel method has shown possibility to develop Trojan particles convieniently with potential to deliver nanoparticles in the gastrointestinal tract. PMID- 26116015 TI - Enniatin-containing solutions for oromucosal use: Quality-by-design ex-vivo transmucosal risk assessment of composition variability. AB - Fusafungine, a mixture of the cyclic hexadepsipeptides enniatins, is currently on the market for the treatment of upper respiratory tract diseases because of its bacteriostatic and anti-inflammatory effects. In this study, a quality-by-design risk assessment was performed with two objectives: (i) investigate whether enniatins are able to permeate the mucosa and reach blood circulation, as the summary of product characteristics indicates this is not the case, and if so, to quantify their transmucosal kinetics and (ii) study the influence of excipient concentration variability on mucosal permeation. First, the concentration of the two main excipients isopropyl myristate and ethanol, known penetration enhancers, in several marketed samples was determined using GC-FID. Then, the transmucosal kinetics of the enniatins were quantitatively evaluated for different dose solutions, using porcine buccal mucosa in an ex-vivo in-vitro Franz diffusion cell set-up, with UHPLC-MS/MS bioanalytics. This study demonstrated that enniatins are capable of permeating the mucosa. However, no risk of a significant different transmucosal permeability with varying excipient concentrations was detected. PMID- 26116016 TI - Controlled release of a model vaccine by nanoporous ceramic microneedle arrays. AB - Current vaccination technology can advance from the use of novel ceramic nanoporous microneedle arrays (npMNA), where the material serves as a storage reservoir for vaccines. Moreover, npMNA will enhance vaccine efficacy by more precisely reaching skin dendritic cells, the kickstarters of T and B cell immunity. In the present study we assessed the efficacy of vaccination using npMNAs by in vivo application of OVA257-264 peptides mixed with agonistic anti CD40 antibodies as adjuvant. The induction of OVA-specific CD8(+) T cells via npMNA was comparable with the frequency induced via intradermal injection using needle-syringe. However, only when expanding the vaccination area by using two npMNAs the frequencies of induced IFN-gamma-specific effector CD8(+) T cells were comparable with those induced via needle-syringe injection. Analysis of vaccine release from npMNA in a human ex vivo skin explant model revealed that OVA257-264 peptides were indeed delivered intradermal, and release also increased by prolonging the npMNA application time on the human skin. Together, our studies demonstrate the potential of npMNA for vaccine delivery in human skin and in vivo induction of CD8(+) effector T cell responses. PMID- 26116017 TI - Differential behaviors of trastuzumab-sensitive and -resistant SKBR3 cells treated with menadione reveal the involvement of Notch1/Akt/FOXO1 signaling elements. AB - Given that HER2 serves as a putative target for therapy in HER2-positive breast cancer, intrinsic and/or acquired resistance to trastuzumab (T) has been proposed to be the major obstacle in treatments. In addition, chemoresistance is commonly attributed to increased antioxidant capacity. In that regard, we evaluated the effect of menadione (M) alone and/or its combination with trastuzumab on proliferation, intracellular GSH and ROS contents as well as HER2 and Notch1 signaling pathways in both trastuzumab-resistant (SKBR3(R)) and -sensitive SKBR3 (SKBR3(S)) cells. In spite of increased level of ROS and reduced level of GSH in M-treated SKBR3(S) cells, M-treated SKBR3(R) cells showed a decreased content of ROS and GSH compared to untreated cells. However, M/T co-treatment of SKBR3 cells indicated no effect on ROS content, while decreased the level of GSH compared to untreated control cells. Based on the extent of apoptosis, colony formation and wound healing assays, M alone, and/or in combination with T had a stronger inhibitory effect on proliferation of SKBR3(R) cells relative to SKBR3(S) cells. These effects might be due to the stronger effects of M and/or M/T on downregulation of p-Akt, Hes1, NICD, and upregulation of FOXO1 among SKBR3(R) cells relative to the sensitive SKBR3 cells. These findings would certainly shed light on some of the signaling factors involved in induction of trastuzumab resistance and would be of value in designing more efficient chemosensitization strategies. PMID- 26116018 TI - LPA signaling through LPA receptors regulates cellular functions of endothelial cells treated with anticancer drugs. AB - Lysophosphatidic acid (LPA) signaling via LPA receptors provides a variety of cellular functions, including angiogenesis. In this study, to assess an involvement of LPA receptors in cell motile activities of endothelial cells during chemotherapy, F-2 cells were treated with cisplatin (CDDP) and doxorubicin (DOX) at a concentration of 0.01 MUM every 24 h for at least 1 month. The treatment of CDDP and DOX inhibited the expression levels of the LPA receptor-1 (Lpar1), Lpar2, and Lpar3 genes in F-2 cells. The cell motile activities of CDDP and DOX treated cells were relatively lower than those of untreated cells. Next, we investigated whether cancer cells could stimulate the cell motile activities of F-2 cells treated with CDDP and DOX. For cell motility assay, CDDP- and DOX treated cells were co-cultured with pancreatic cancer PANC-1 cells. The cell motile activities of CDDP- and DOX-treated cells were significantly enhanced by the existence of PANC-1 cells, correlating with the LPA receptor expressions. In addition, the elevated cell motile activities were suppressed by the pretreatment of an autotaxin inhibitor S32826. These results suggest that LPA signaling via LPA receptors may regulate the cell motile activities of F-2 cells treated with anticancer drugs. PMID- 26116019 TI - Paradental cyst is an inclusion cyst of the junctional/sulcular epithelium of the gingiva: histopathologic and immunohistochemical confirmation for its pathogenesis. AB - OBJECTIVE: The aim of this study was to characterize the histologic and immunohistochemical profiles of paradental cyst-lining epithelia to clarify its histopathogenesis. STUDY DESIGN: Ten surgical specimens of paradental cysts were examined for clinical profiles and to determine the histopathologic characteristics of the lining epithelia. Immunohistochemical profiles for keratin (K) subtypes, as well as for perlecan, UEA-I lectin binding, and proliferating cell nuclear antigen (PCNA), were determined and compared. RESULTS: The paradental cyst was clinically characterized by its occurrence in young adults (mean age, 36.8 years; male, 42.8, female 27.8). Eight of the 10 cases arose in the retromolar area. The cyst wall was basically granulation tissue that was attached to the periodontal ligament space. Thin irregular anastomosing epithelial cords lined the cyst walls of immature granulation tissue with vascular dilation and hemorrhage. The intercellular space of the lining epithelia was widened with inflammatory cell infiltrates. Immunohistochemically, the lining was positive for K13, K14, K17, K19, UEA-I binding, and perlecan, suggesting its junctional/sulcular epithelial character. CONCLUSION: The results showed that the paradental cyst was lined by epithelial cells with characteristics of the junctional/sulcular epithelium. The cyst can thus be considered as a kind of inclusion cyst arising in the periodontal pocket, most frequently of the mandibular third molars of young adults. PMID- 26116020 TI - Investigating the addition of SiO2-CaO-ZnO-Na2O-TiO2 bioactive glass to hydroxyapatite: Characterization, mechanical properties and bioactivity. AB - Hydroxyapatite (Ca10(PO4)6(OH)2) is widely investigated as an implantable material for hard tissue restoration due to its osteoconductive properties. However, hydroxyapatite in bulk form is limited as its mechanical properties are insufficient for load-bearing orthopedic applications. Attempts have been made to improve the mechanical properties of hydroxyapatite, by incorporating ceramic fillers, but the resultant composite materials require high sintering temperatures to facilitate densification, leading to the decomposition of hydroxyapatite into tricalcium phosphate, tetra-calcium phosphate and CaO phases. One method of improving the properties of hydroxyapatite is to incorporate bioactive glass particles as a second phase. These typically have lower softening points which could possibly facilitate sintering at lower temperatures. In this work, a bioactive glass (SiO2-CaO-ZnO-Na2O-TiO2) is incorporated (10, 20 and 30 wt%) into hydroxyapatite as a reinforcing phase. X-ray diffraction confirmed that no additional phases (other than hydroxyapatite) were formed at a sintering temperature of 560 C with up to 30 wt% glass addition. The addition of the glass phase increased the % crystallinity and the relative density of the composites. The biaxial flexural strength increased to 36 MPa with glass addition, and there was no significant change in hardness as a function of maturation. The pH of the incubation media increased to pH 10 or 11 through glass addition, and ion release profiles determined that Si, Na and P were released from the composites. Calcium phosphate precipitation was encouraged in simulated body fluid with the incorporation of the bioactive glass phase, and cell culture testing in MC-3T3 osteoblasts determined that the composite materials did not significantly reduce cell viability. PMID- 26116021 TI - Evaluation of the biological tolerability of the starch-based medical device 4DryField(r) PH in vitro and in vivo a rat model. AB - PURPOSE: To evaluate in vitro cytotoxicity/biocompatibility as well as in vivo tolerability of the novel polysaccharide 4DryField(r) PH, certified for haemostasis and adhesion prevention. METHODS: In vitro cytotoxicity/viability testing according to ISO EN 10,993 using murine and human tumour cell lines incubated with 4DryField(r) PH (PlantTec Medical GmbH). Using a rat model the impact of 4DryField(r) PH on animals viability and in vivo effects were macro- and micropathologically assessed. RESULTS: In vitro testing revealed no cytotoxic effect of 4DryField(r) PH nor enhancement of viability to tumour cell lines. In vivo viability of rats was unimpaired by 4DryField(r) PH. Bodyweight loss in animals with abdominal injury plus treatment with 4DryField(r) PH was in the range of controls and less than in injured rats without treatment. At day 7 after surgery no formation of adhesions, neither macroscopic nor histological remnants nor signs of foreign body reaction were present in animals without injury. In animals with peritoneal injury and 4DryField(r) PH application, histopathological observation revealed minor residuals of polysaccharide in the depth of wound cavity embedded in a thickened subperitoneal layer; however, with a suggested intact neoperitoneum. The presence of mononuclear cells surrounding polysaccharide particles in varying states of degradation was observable as well. CONCLUSION: 4DryField(r) PH is not cytotoxic and does not enhance viability of tumour cell lines. High dose of 4DryField(r) PH of 1.09 g/kg bodyweight is well tolerated and reduces weight loss in animals with peritoneal injury. The biocompatibility of 4DryField(r) PH can be rated as being excellent. PMID- 26116022 TI - Treatment study of distal femur for parathyroid hormone (1-34) and beta tricalcium phosphate on bone formation in critical size defects in rats. AB - The objective of this study was to evaluate local bone formation following systemic administration of parathyroid hormone (1-34), a surgically implanted synthetic beta-tricalcium phosphate bone biomaterial serving as a matrix to support new bone formation. Twelve weeks after bilateral ovariectomy, all rats underwent bone defect in the distal femurs, and beta-tricalcium phosphate was implanted into critical sized defects. After defect operation, all animals were randomly divided into four groups and received following subcutaneous injections until death at four and eight weeks: sham rats (group ST); sham rats + parathyroid hormone, 30 ug/kg, three times a week (group SPT); OVX rats (group OT); and OVX rats + parathyroid hormone (group OPT). The distal femurs of rats were harvested for evaluation. The treatment group demonstrating the highest levels of new bone formation was the defects treated with parathyroid hormone as assessed by micro-computed tomography, biomechanical strength, and histological analysis for sham rats. Furthermore, parathyroid hormone showed a stronger effect on accelerating the degradation of beta-tricalcium phosphate. Osteoporosis can limit the function of parathyroid hormone and/or beta-tricalcium phosphate. The results from our study demonstrate that combination of parathyroid hormone and beta-tricalcium phosphate brings better effect to bone tissue repair in non osteoporosis and/or osteoporosis status. PMID- 26116023 TI - Editorial overview: Extremophiles: From extreme environments to highly stable biocatalysts. PMID- 26116024 TI - AtROS1 overexpression provides evidence for epigenetic regulation of genes encoding enzymes of flavonoid biosynthesis and antioxidant pathways during salt stress in transgenic tobacco. AB - In plants, epigenetic changes have been identified as regulators of developmental events during normal growth as well as environmental stress exposures. Flavonoid biosynthetic and antioxidant pathways play a significant role in plant defence during their exposure to environmental cues. The aim of this study was to unravel whether genes encoding enzymes of flavonoid biosynthetic and antioxidant pathways are under epigenetic regulation, particularly DNA methylation, during salt stress. For this, a repressor of silencing from Arabidopsis, AtROS1, was overexpressed in transgenic tobacco. Generated transgenics were evaluated to examine the influence of AtROS1 on methylation status of promoters as well as on coding regions of genes encoding enzymes of flavonoids biosynthesis and antioxidant pathways. Overexpression of AtROS1 increases the demethylation levels of both promoters as well as coding regions of genes encoding chalcone synthase, chalcone isomerase, flavanone 3-hydroxylase, flavonol synthase, dihydroflavonol 4 reductase, and anthocyanidin synthase of the flavonoid biosynthetic pathway, and glutathione S-transferase, ascorbate peroxidase, glutathione peroxidase, and glutathione reductase of the antioxidant pathway during control conditions. The level of demethylation was further increased at promoters as well as coding regions of these genes during salt-stress conditions. Transgenic tobacco overexpressing AtROS1 showed tolerance to salt stress that could have been due to the higher expression levels of the genes encoding enzymes of the flavonoid biosynthetic and antioxidant pathways. This is the first comprehensive study documenting the epigenetic regulation of flavonoid biosynthetic and antioxidant pathways during salt-stress exposure of plants. PMID- 26116025 TI - PtrABF of Poncirus trifoliata functions in dehydration tolerance by reducing stomatal density and maintaining reactive oxygen species homeostasis. AB - Abscisic acid-responsive element (ABRE)-binding factors (ABFs) play important roles in abiotic stress responses; however, the underlying mechanisms are poorly understood. In this study, it is reported that overexpression of Poncirus trifoliata PtrABF significantly enhanced dehydration tolerance. The transgenic lines displayed smaller stomatal apertures, reduced stomatal density/index, and lower expression levels of genes associated with stomatal development. PtrABF was found to interact with PtrICE1, a homologue of ICE1 (Inducer of CBF Expression 1) that has been shown to be critical for stomatal development. Microarray analysis revealed that a total of 70 genes were differentially expressed in the transgenic line, 42 induced and 28 repressed. At least two units of ABREs and coupling elements were present in the promoters of most of the induced genes, among which peroxidase and arginine decarboxylase were verified as bona fide targets of PtrABF. Transgenic plants exhibited higher antioxidant enzyme activities and free polyamine levels, but lower levels of reactive oxygen species (ROS) and malondialdehyde. Polyamines were revealed to be associated with ROS scavenging in the transgenic plants due to a modulation of antioxidant enzymes triggered by signalling mediated by H2O2 derived from polyamine oxidase (PAO)-mediated catabolism. Taken together, the results indicate that PtrABF functions positively in dehydration tolerance by limiting water loss through its influence on stomatal movement or formation and maintaining ROS homeostasis via modulation of antioxidant enzymes and polyamines through transcriptional regulation of relevant target genes. PMID- 26116026 TI - Differential molecular response of monodehydroascorbate reductase and glutathione reductase by nitration and S-nitrosylation. AB - The ascorbate-glutathione cycle is a metabolic pathway that detoxifies hydrogen peroxide and involves enzymatic and non-enzymatic antioxidants. Proteomic studies have shown that some enzymes in this cycle such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR), and glutathione reductase (GR) are potential targets for post-translational modifications (PMTs) mediated by nitric oxide-derived molecules. Using purified recombinant pea peroxisomal MDAR and cytosolic and chloroplastic GR enzymes produced in Escherichia coli, the effects of peroxynitrite (ONOO(-)) and S-nitrosoglutathione (GSNO) which are known to mediate protein nitration and S-nitrosylation processes, respectively, were analysed. Although ONOO(-) and GSNO inhibit peroxisomal MDAR activity, chloroplastic and cytosolic GR were not affected by these molecules. Mass spectrometric analysis of the nitrated MDAR revealed that Tyr213, Try292, and Tyr345 were exclusively nitrated to 3-nitrotyrosine by ONOO(-). The location of these residues in the structure of pea peroxisomal MDAR reveals that Tyr345 is found at 3.3 A of His313 which is involved in the NADP-binding site. Site directed mutagenesis confirmed Tyr345 as the primary site of nitration responsible for the inhibition of MDAR activity by ONOO(-). These results provide new insights into the molecular regulation of MDAR which is deactivated by nitration and S-nitrosylation. However, GR was not affected by ONOO(-) or GSNO, suggesting the existence of a mechanism to conserve redox status by maintaining the level of reduced GSH. Under a nitro-oxidative stress induced by salinity (150mM NaCl), MDAR expression (mRNA, protein, and enzyme activity levels) was increased, probably to compensate the inhibitory effects of S-nitrosylation and nitration on the enzyme. The present data show the modulation of the antioxidative response of key enzymes in the ascorbate-glutathione cycle by nitric oxide (NO)-PTMs, thus indicating the close involvement of NO and reactive oxygen species metabolism in antioxidant defence against nitro-oxidative stress situations in plants. PMID- 26116027 TI - Cyclic Ozone Exposure Induces Gender-Dependent Neuropathology and Memory Decline in an Animal Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a major cause of dementia in the elderly. Although early-onset (familial) AD is attributed to gene mutations, the cause for late onset (sporadic) AD, which accounts for 95% of AD cases, is unknown. In this study, we show that exposure of 6-week-old amyloid beta precursor protein (APP)/presenilin (PS1) overexpressing mice, a well-established animal model of AD, and nontransgenic littermates to a cyclic O3 exposure protocol, which mimics environmental exposure episodes, accelerated learning/memory function loss in male APP/PS1 mice but not in female APP/PS1 mice or nontransgenic littermates. Female APP/PS1 mice had higher brain levels of amyloid beta peptide (Abeta42) and Abeta40, compared with male APP/PS1 mice; O3 exposure, however, had no significant effect on brain Abeta load in either male or female mice. Our results further show that male APP/PS1 mice had lower levels of antioxidants (glutathione and ascorbate) and experienced augmented induction of NADPH oxidases, lipid peroxidation, and neuronal apoptosis upon O3 exposure, compared with female APP/PS1 mice. No significant effect of O3 on any of these parameters was detected in nontransgenic littermates. In vitro studies further show that 4 hydroxynonenal, a lipid peroxidation product which was increased in the plasma and cortex/hippocampus of O3-exposed male APP/PS1 mice, induced neuroblastoma cell apoptosis. Together, the results suggest that O3 exposure per se may not cause AD but can synergize with genetic risk factors to accelerate the pathophysiology of AD in genetically predisposed populations. The results also suggest that males may be more sensitive to O3-induced neuropathophysiology than females due to lower levels of antioxidants. PMID- 26116028 TI - Freshwater Planarians as an Alternative Animal Model for Neurotoxicology. AB - Traditional toxicology testing has relied on low-throughput, expensive mammalian studies; however, timely testing of the large number of environmental toxicants requires new in vitro and in vivo platforms for inexpensive medium- to high throughput screening. Herein, we describe the suitability of the asexual freshwater planarian Dugesia japonica as a new animal model for the study of developmental neurotoxicology. As these asexual animals reproduce by binary fission, followed by regeneration of missing body structures within approximately 1 week, development and regeneration occur through similar processes allowing us to induce neurodevelopment "at will" through amputation. This short time scale and the comparable sizes of full and regenerating animals enable parallel experiments in adults and developing worms to determine development-specific aspects of toxicity. Because the planarian brain, despite its simplicity, is structurally and molecularly similar to the mammalian brain, we are able to ascertain neurodevelopmental toxicity that is relevant to humans. As a proof of concept, we developed a 5-step semiautomatic screening platform to characterize the toxicity of 9 known neurotoxicants (consisting of common solvents, pesticides, and detergents) and a neutral agent, glucose, and quantified effects on viability, stimulated and unstimulated behavior, regeneration, and brain structure. Comparisons of our findings with other alternative toxicology animal models, such as zebrafish larvae and nematodes, demonstrated that planarians are comparably sensitive to the tested chemicals. In addition, we found that certain compounds induced adverse effects specifically in developing animals. We thus conclude that planarians offer new complementary opportunities for developmental neurotoxicology animal models. PMID- 26116030 TI - An evaluation of post-registration neuroscience focused education and neuroscience nurses' perceived educational needs. AB - BACKGROUND: People with complex neurological conditions require co-ordinated care provided by nurses educated in meeting service needs, understanding the pathophysiological processes of disease and the preparation to care for those with complex needs. However, evidence suggests that neuroscience specific education provision is largely unregulated and set outside of a cohesive professional development context. Furthermore, it largely seems to only address the induction phase into working within neurosciences. OBJECTIVES: To evaluate the nature of post-registration neuroscience focused education across Europe and neuroscience nurses' perceived educational needs. METHODS: Post qualifying nurses working in the field of neurosciences were invited to complete a self-reported 29 item on-line questionnaire that contained closed and open-ended questions exploring professional background, clinical and educational experience, educational opportunities available to them and their perspectives on their educational needs. RESULTS: 154 participants from fourteen countries across Europe completed the survey. 75% (n=110) of respondents had undertaken neuroscience focused education with the most accessible education opportunities found to be conferences 77% (n=96) and study days 69% (n=86). Overall, 52.6% of courses were multidisciplinary in nature, and 47.4% were exclusively nursing. Most identified that their courses were funded by their employer (57%, n=63) or partly funded by their employer. Results illustrate a significant variance across Europe, highlighting the need for more effective communication between neuroscience nurses across Europe. Implications for future education provision, recruitment/retention, and funding are discussed, resulting in recommendations for the future of neuroscience nursing. CONCLUSIONS: This study, the largest of its kind to survey neuroscience nurses, illustrates the absence of a cohesive career development pathway for neuroscience nurses in Europe. Nurses need quality assured specialist education to deliver high quality appropriate healthcare. PMID- 26116031 TI - Changing negative stereotypes regarding aging in undergraduate nursing students. AB - OBJECTIVE: The aim of this study was to explore the modification of stereotypes and myths regarding aging among third-year nursing students before and after undergoing an Aging Nursing course. METHOD: A within-subject repeated-measures descriptive study was conducted. The Negative Stereotypes Questionnaire about Aging (CENVE) was used. RESULTS: The overall prevalence of negative stereotypes was 62.0% pre-intervention (P1) and 12.3% post-intervention (P2) measured; these values were 63.5% (P1) and 9.2% (P2) for the health factor, 43.1% (P1) and 4.9% (P2) for the motivation and social factors and 58.3% (P1) and 3.8% (P2) for the character-personality factor. Paired Student's t tests confirmed that the differences were statistically significant. CONCLUSIONS: There was a high prevalence of negative stereotypes toward aging among the nursing students, even though they had conducted clinical practice and were in their third year. The course was demonstrated to be effective in modifying these stereotypes. The proper training of future professionals markedly contributes the dispensation of proper care and the eradication of ageism, which remains prevalent in the healthcare system. PMID- 26116029 TI - 4,4'-Methylenedianiline Alters Serotonergic Transport in a Novel, Sex-Specific Model of Pulmonary Arterial Hypertension in Rats. AB - Pulmonary arterial hypertension (PAH) is a cardiovascular disorder characterized by elevated pulmonary artery pressure as a result of arterial wall thickening. Patients are 3-4 times more likely to be women than men. This gender discrepancy demonstrates a need for an animal model with similar sex differences. 4,4' Methylenedianiline (DAPM) is an aromatic amine used industrially in the synthesis of polyurethanes. Chronic, intermittent treatment of male and female rats with DAPM resulted in medial hyperplasia of pulmonary arterioles, exclusively in females, coupled to increases in pulmonary arterial pressures. Significant increases in plasma levels of endothelin-1 (ET-1) and serotonin, but decreases in nitrite [Formula: see text], were observed in females treated with DAPM. A decrease was observed in the serum ratio of the estrogen metabolites 2 hydroxyestradiol (2-OHE1)/16alpha-hydroxyestrogen (16alpha-OHE1). In females, ET 1,[Formula: see text] , and 2-OHE1/16alpha-OHE1 were significantly correlated with peak pressure gradient, an indirect measure of pulmonary arterial pressure. Expression of the serotonin transport protein (SERT) was significantly higher in the arteries of DAPM-treated females. In vitro, DAPM induced human pulmonary vascular smooth muscle cell proliferation and serotonin uptake, both of which were inhibited by treatment with the estrogen receptor antagonist ICI 182,780 or the selective serotonin reuptake inhibitor fluoxetine. DAPM also induced the release of serotonin from human pulmonary endothelial cells in culture, which is blocked by ICI 182,780. Taken together, this suggests that DAPM-mediated dysregulation of serotonin transport is estrogen-receptor dependent. Thus, DAPM induced PAH pathology may be a new tool to clarify the sex selectivity of PAH disease pathogenesis. PMID- 26116032 TI - Towards identifying nurse educator competencies required for simulation-based learning: A systemised rapid review and synthesis. AB - OBJECTIVES: This paper presents the results of a systemised rapid review and synthesis of the literature undertaken to identify competencies required by nurse educators to facilitate simulation-based learning (SBL). DESIGN: An international collaboration undertook a protocol-based search, retrieval and critical review. DATA SOURCES: Web of Science, PubMed, CINAHL Plus, PsycInfo, ERIC, the Cochrane Library and Science Direct. The search was limited to articles published in English, 2002-2012. REVIEW METHODS: The search terms used: nurse*, learn*, facilitator, simula*, lecturer, competence, skill*, qualificat*, educator, health care, "patient simulation", "nursing education" and "faculty". The search yielded 2156 "hits", following a review of the abstracts, 72 full-text articles were extracted. These were screened against predetermined inclusion/exclusion criteria and nine articles were retained. Following critical appraisal, the articles were analyzed using an inductive approach to extract statements for categorization and synthesis as competency statements. RESULTS: This review confirmed that there was a modest amount of empirical evidence on which to base a competency framework. Those papers that provided descriptions of educator preparation identified simulation-based workshops, or experiential training, as the most common approaches for enhancing skills. SBL was not associated with any one theoretical perspective. Delivery of SBL appeared to demand competencies associated with planning and designing simulations, facilitating learning in "safe" environments, expert nursing knowledge based on credible clinical realism, reference to evidence-based knowledge and demonstration of professional values and identity. CONCLUSIONS: This review derived a preliminary competency framework. This needs further development as a model for educators delivering SBL as part of nursing curricula. PMID- 26116033 TI - Mifepristone label laws and trends in use: recent experiences in four US states. PMID- 26116034 TI - Nonsurgical permanent contraception for women: let's complete the job. PMID- 26116035 TI - [Obesity and complicated diverticular disease of the colon]. AB - BACKGROUND: The incidence of diverticular disease of the colon has been rising in recent years, and the associated factors are: low ingestion of fibre, age, lack of physical activity, and obesity. METHODS: A retrospective, descriptive, observational study was conducted on patients with the diagnosis of complicated diverticular disease requiring surgical or interventional treatment, for a period of 12 years. RESULTS: A total of 114 patients (72 males, and 42 females), age range 28-91 years. More than three-quarters (88 patients; 77.19%) had a body mass index (BMI) between 25 and 40 kg/m(2), and 26 patients (22.8%) had a BMI between 20 and 25 kg/m(2). Among the patients with BMI less than 25 kg/m(2), 12 patients had Hinchey 1 (46%), 8 Hinchey 2 (30.7%), 4 Hinchey 3 (15.4%), and two Hinchey 4 (7.7%). Of the patients with BMI greater than 25 kg/m(2), 19 patients had Hinchey 1 (21.6%), 24 Hinchey 2 (27.3%), 27 Hinchey 3 (30.7%), and 18 Hinchey 4 (20.45%). A statistically significant difference (P<0.001) was found between groups using Mann-Whitney U test. The BMI greater than 25 kg/m(2) as risk factor for complicated diverticular disease showed Odds Ratio of 3.4884 (95% confidence interval 1.27-9.55) with Z value of 2.44 (P=0.014). CONCLUSIONS: In this study, obesity was associated with an increased incidence and severity of complicated diverticular disease. PMID- 26116036 TI - [Scheduled hysterectomy vs. urgent hysterectomy in patients with placenta accreta in a high specialty medical unit]. AB - BACKGROUND: Patients with placenta accreta have a high frequency of complications and death risk. OBJECTIVE: The aim of this study was to compare the results of scheduled hysterectomy vs. urgent hysterectomy in patients with placenta accreta in a high specialty medical unit. MATERIAL AND METHODS: An observational, comparative, cross-sectional study was conducted by reviewing patient records with confirmed diagnostic of placenta accreta, who attended in a one year period. They were divided into 2 groups based on the type of surgery, scheduled or urgent. Descriptive statistics were applied, with comparisons using Student t test and chi squared tests. A value of P<.05 was considered significant. RESULTS: There were 4,592 births in the period of study, and 125 obstetric hysterectomies were performed, with 40 confirmed cases of accreta (8.7 per thousand births) with 20 in scheduled and 20 in urgent surgeries, with the most frequent type being placenta accreta. The mean maternal age was 32 years, with a mean of 5 hours operating time, total bleeding 3135 ml, and 3.5 units of packed cells transfused. There was no statistical difference when comparing these variables with re interventions, hypovolaemic shock, and intensive care unit admission. Caesarean hysterectomy with hypogastric artery ligation was the most frequent surgery performed. CONCLUSIONS: In this hospital, scheduled and urgent surgical treatment of patients with placenta accreta show similar results, probably because the constant availability of resources and the experience obtained by the multidisciplinary team in all shifts. Nevertheless, make absolutely sure to perform elective surgery while having all the necessary resources. PMID- 26116037 TI - [Telemetric monitoring reduces visits to the emergency room and cost of care in patients with chronic heart failure]. AB - BACKGROUND: Tele-cardiology is the use of information technologies that help prolong survival, improve quality of life and reduce costs in health care. Heart failure is a chronic disease that leads to high care costs. OBJECTIVE: To determine the effectiveness of telemetric monitoring for controlling clinical variables, reduced emergency room visits, and cost of care in a group of patients with heart failure compared to traditional medical consultation. MATERIAL AND METHODS: A randomized, controlled and open clinical trial was conducted on 40 patients with Heart failure in a tertiary care centre in north-western Mexico. The patients were divided randomly into 2 groups of 20 patients each (telemetric monitoring, traditional medical consultation). In each participant was evaluated for: blood pressure, heart rate and body weight. The telemetric monitoring group was monitored remotely and traditional medical consultation group came to the hospital on scheduled dates. All patients could come to the emergency room if necessary. RESULTS: The telemetric monitoring group decreased their weight and improved control of the disease (P=.01). Systolic blood pressure and cost of care decreased (51%) significantly compared traditional medical consultation group (P>.05). Admission to the emergency room was avoided in 100% of patients in the telemetric monitoring group. CONCLUSION: In patients with heart failure, the telemetric monitoring was effective in reducing emergency room visits and saved significant resources in care during follow-up. PMID- 26116038 TI - [Intestinal obstruction secondary to postoperative adhesion formation in abdominal surgery. Review]. AB - The development of intestinal obstruction after upper and lower abdominal surgery is part of the daily life of each every surgeon. Despite this, there are very few good quality studies that allow enable assessment of the frequency of intestinal obstruction to be assessed, even although postoperative adhesions are the cause of considerable direct and indirect morbidity and its prevention can be considered a public health problem. And yet, in Mexico, at this time, there is no validated recommendation validated on the prevention of adhesions, or more particularly, in connection with the use of a variety of anti-adhesion commercial products which have been marketed for at least a decade. Intraperitoneal adhesions develop between surfaces without peritoneum of the abdominal organs, mesentery, and abdominal wall. The most common site of adhesions is between the greater omentum and anterior abdominal wall previous. Despite the frequency of adhesions and their direct and indirect consequences, just there is only one published a recommendation (from gynaecological literature), regarding peritoneal adhesion prevention. As regards of colorectal surgery, performed more than 250,000 colorectal resections are performed annually in the United States, and from 24% to 35% of them will develop a complication. The clinical and economic financial burden of these complications is enormous, and surgeries colorectal surgery been specifically highlighted as a potential point prevention point of surgical morbidity. PMID- 26116039 TI - [Platelet-rich plasma in knee osteoarthritis treatment]. AB - The biological changes that commonly cause degenerative articular cartilage injuries in the knee are primarily associated to misalignment of the joint and metabolic changes related to age, as occurs in osteoarthritis. Furthermore, the capacity for cartilage self-regeneration is quite limited due to the lack of vascularity of the tissue. To date there is no ideal treatment capable to stimulate cartilage regeneration; thus there is a need to seek alternative therapies for the treatment of such conditions. The number of publications demonstrating the therapeutic and regenerative benefits of using platelet-rich plasma as a treatment for knee osteoarthritis has been increasing in recent years. In spite of encouraging results, there are still only a few randomised control studies with strong clinical evidence, lacking clarity on points such as the optimum formulation or the mechanism of action of platelet-rich plasma. Up to this point and based on the results of clinical studies, not all patients can benefit from this therapy. It is important to consider aspects such as the age and grade of cartilage degeneration. The aim of the present paper is to review the recent scientific literature on the treatment of knee osteoarthritis with platelet-rich plasma, and the biological bases of this therapy, as well as presenting the current opinion on this subject. PMID- 26116040 TI - The surgical management of symptomatic articular cartilage defects of the knee: Consensus statements from United Kingdom knee surgeons. AB - BACKGROUND: Symptomatic articular cartilage and osteochondral lesions in the knee are an important source of pain and disability, and may lead to osteoarthritis. There are several surgical treatments for the condition, with emerging data evaluating their clinical effectiveness and longer-term clinical outcome. Health care providers have challenged the indications for the use of expensive techniques and have been reluctant to authorize funding or reimbursement. METHODS: The UK Cartilage Consensus Meeting was convened, involving clinicians in the UK with experience in the treatment options, decision-making and evaluation of the literature on the subject. RESULTS: This paper reports the consensus of attendees regarding appropriate surgical options for managing articular cartilage defects in the knee, validated by a large cohort of surgeons in the UK who are active in the field of articular cartilage surgery. CONCLUSIONS: An evidence based United Kingdom Consensus of 104 clinicians on the surgical management of symptomatic articular cartilage lesions of the knee. Several techniques may be suitable for small defects. Cell therapy has the best evidence-based outcomes for larger defects. Responsible innovation, pooled data collection and improvement in physical therapies are important. Surgeons should have access to the most appropriate evidence-based therapies for first-line treatment. PMID- 26116041 TI - AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle. AB - Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation. PMID- 26116042 TI - Men and women have similarly shaped carpometacarpal joint bones. AB - Characterizing the morphology of the carpometacarpal (CMC) joint bones and how they vary across the population is important for understanding the functional anatomy and pathology of the thumb. The purpose of this paper was to develop a statistical shape model of the trapezium and first metacarpal bones to characterize the size and shape of the whole bones across a cohort of 50. We used this shape model to investigate the effects of sex and age on the size and shape of the CMC joint bones and the articulating surface area of the CMC joint. We hypothesized that women have similar shape trapezium and first metacarpal bones compared to men, following scaling for overall size. We also hypothesized that age would be a significant predictor variable for CMC joint bone changes. CT image data and segmented point clouds of 50 CMC bones from healthy adult men and women were obtained from an ongoing study and used to generate two statistical shape models. Statistical analysis of the principal component weights of both models was performed to investigate morphological sex and age differences. We observed sex differences, but were unable to detect any age differences. Between men and women the only difference in morphology of the trapezia and first metacarpal bones was size. These findings confirm our first hypothesis, and suggest that the women have similarly shaped trapezium and first metacarpal bones compared to men. Furthermore, our results reject our second hypothesis, indicating that age is a poor predictor of CMC joint morphology. PMID- 26116043 TI - Quadratus femoris: An EMG investigation during walking and running. AB - Dysfunction of hip stabilizing muscles such as quadratus femoris (QF) is identified as a potential source of lower extremity injury during functional tasks like running. Despite these assumptions, there are currently no electromyography (EMG) data that establish the burst activity profile of QF during any functional task like walking or running. The objectives of this study were to characterize and compare the EMG activity profile of QF while walking and running (primary aim) and describe the direction specific action of QF (secondary aim). A bipolar fine-wire intramuscular electrode was inserted via ultrasound guidance into the QF of 10 healthy participants (4 females). Ensemble curves were generated from four walking and running trials, and normalized to maximum voluntary isometric contractions (MVICs). Paired t-tests compared the temporal and amplitude EMG variables. The relative activity of QF in the MVICs was calculated. The QF displayed moderate to high amplitude activity in the stance phase of walking and very high activity during stance in running. During swing, there was minimal QF activity recorded during walking and high amplitudes were present while running (run vs walk effect size=4.23, P<0.001). For the MVICs, external rotation and clam produced the greatest QF activity, with the hip in the anatomical position. This study provides an understanding of the activity demands placed on QF while walking and running. The high activity in late swing during running may signify a synergistic role with other posterior thigh muscles to control deceleration of the limb in preparation for stance. PMID- 26116044 TI - The Biomechanics of eyelid tarsus tissue. AB - Reconstruction of the eyelid remains challenging due to the unique properties of the tarsal plate, which is a fibrocartilagenous structure within the eyelid providing structural support and physical form. There are no previous studies investigating the biomechanical properties of tarsus tissue, which is vital to the success of bioengineered tarsal substitutes. We therefore aimed to determine the biomechanical properties of human tarsus tissue, and used a CellScale BioTester 5000 (CellScale, Waterloo, Canada) to perform uniaxial tensile tests on ten samples of healthy eyelid tarsus. All samples were tested 'fresh' within two hours of harvest. A tensile preload of 50 mN was applied for 10 min before the sample was subjected to uniaxial tension under linear ramp displacement control. Maximum strain was 30% of the original tissue length and thirty dynamic cycles were performed at a strain rate of 1%/s using a triangular waveform. Of the samples tested, the mean (SD) width was 5.51 mm (1.45 mm) whilst mean thickness was 1.6mm (0.51 mm). The mean toe modulus was 0.14 (0.10) MPa, elastic modulus was 1.73 (0.61) MPa, with an extensibility of 15.8 (2.1)%, and phase angle of 6.4 degrees (2.4) degrees . After adjusting for the initial tissue slack, the maximum strain ranged from 23.8% to 30.0%. At maximum strain, it was observed that the linear region of the stress-strain curve was reached without the sample slipping out of the clamps. Our results establish a benchmark for native tarsus tissue, which can be used when evaluating tissue engineered tarsal substitutes in the future. PMID- 26116045 TI - Song plasticity over time and vocal learning in clay-colored thrushes. AB - Songbirds have been traditionally classified into close-ended or open-ended learning species according to the length of the sensitive period during which birds are able to memorize new vocalizations. Closed-ended learners are generally not capable of changing their song after the first year of life, while open-ended learners show song plasticity as adults. A few Turdus species have been suggested to be open-ended learners, but no long-term study has been conducted to investigate their song plasticity over time. We analyzed the songs of clay colored thrushes, T. grayi, over four successive breeding seasons to assess song plasticity in their syllable repertoires within and between breeding seasons. A total of 16,262 syllables were classified through visual inspection of spectrograms and multidimensional scaling analysis based on spectrogram correlations. On average, 563 +/- 153 (SD) syllables per male per breeding season were analyzed. Male repertoire size was 9-20 syllable types. Males were capable of modifying their syllable repertoire between the initial and final periods of the breeding season. Song plasticity within breeding seasons may be associated with imitation between neighboring males, suggesting song learning in males that were >=2 years old. This short-term plasticity is not enough, however, to explain the high proportion of change (mean = 65 % syllable types) in repertoire composition between breeding seasons in adult males. Song plasticity resulting from annual changes in repertoire composition could be explained by open-ended learning, but another mechanism, extended memory and re-expression, could also explain long-term plasticity. Experimental studies controlling the acoustic environment are needed to determine which mechanism is responsible for such a high level of song plasticity. PMID- 26116046 TI - Stem cell mobilization and collection from pediatric patients and healthy children. AB - Today, hematopoietic stem cell transplantation (HSCT) is a standard treatment for a variety of conditions in children, including certain malignancies, hemoglobinopathies, bone marrow failure syndromes, immunodeficiency and inborn metabolic disease. Two fundamentally different types of HSCT are categorized by the source of the stem cells. The first, autologous HSCT represents infusion of patient's own hematopoietic stem cells (HSCs) obtained from the patient; the second, allogeneic HSCT refers to the infusion of HSCs obtained from a donor via bone marrow harvest or apheresis. Bone marrow has been the typical source for HSCs for pediatric donors. Bone marrow harvest is a safe procedure mainly related to mild and transient side effects. Recently, a dramatically increased use of mobilized peripheral blood stem cells (PBSCs) in the autologous as well as allogeneic setting has been seen worldwide. There are limited data comparing mobilization regimens; also mobilization practices vary widely in children. The most commonly used approach includes granulocyte colony stimulating factor (G CSF) at 10 mg/kg/day as a single daily dose for 4 days before the day of leukapheresis. G-CSF induced pain was less reported in children compared to adult donors. For the collection, there are several technical problems, derived from the size of the patient or donor, which must be considered before and during the apheresis. Vascular access, extracorporeal circuit volume, blood flow rates are the main limiting factors for PBSC collection in small children. Most children younger than 12 years require central vascular access for apheresis; line placement may require either general anesthesia or conscious sedation and many of the complications arise from the central venous catheter. In this review, we discuss that the ethical considerations and some principals regarding children serving as stem cell donors and the commonest sources of HSCs are presented in children, together with a discussion of how to collect and process these cells. PMID- 26116047 TI - A 23 years audit of packed red blood cell consumption in a university hospital in a developing country. AB - BACKGROUND: There is paucity of information on the blood transfusion practice in developing countries. The current audit aims to find out the long term trend in the consumption of packed red blood cells (PRBCs) in a large Saudi teaching hospital in Riyadh MATERIALS AND METHODS: We analyzed the annual consumption of PRBCs from 1985 to 2007 in seven major hospital divisions (Medicine, General Surgery, Pediatrics, Obstetrics and Gynecology, Cardiac Surgery, Accident and Emergency and Renal Dialysis Unit) at the 850-bed King Khalid University Hospital (KKUH), Riyadh. RESULTS: Grand total consumption of PRBCs was 345,642 units. The consumption increased gradually and peaked in the year 1994, dropped to 30.4% 6 years later and then increased gradually thereafter, due to the expansion in the number of patients cared for in the Departments of Medicine, Cardiac Surgery and Accident and Emergency, while in the Department of Pediatrics the drop in consumption continued unabated. In the Renal Dialysis Unit consumption was minimal with the use of erythropoietin therapy. The crossmatch:transfusion ratio uncovered gross over-ordering of PRBCs and wastage of blood bank resources in most hospital divisions most notably in the Department of Obstetrics and Gynecology. CONCLUSION: The results obtained indicate clearly that there has been overuse of blood products that dropped markedly in years coinciding with the worldwide apprehension about the safety of transfusion therapy particularly HIV transmission. This factor in addition to the current implementation of strict guidelines is gradually improving transfusion practices in our institute. PMID- 26116048 TI - A comparative study of erectile function and use of erectile aids in high-risk prostate cancer patients after robot-assisted laparoscopic prostatectomy. AB - OBJECTIVE: Erectile function with and without use of erectile aids was compared in high-, intermediate- and low-risk prostate cancer patients at a mean of 3 years after robot-assisted laparoscopic prostatectomy (RALP). MATERIALS AND METHODS: A sample of 982 men who underwent RALP at Oslo University Hospital, Radiumhospitalet, between 2005 and 2010 was invited to complete a mailed questionnaire in 2011. The response rate was 79%, but only 609 patients did not have adjuvant treatment and reported on erection. The sample consisted of 29% high-risk, 40% intermediate-risk and 25% low-risk patients according to the preoperative D'Amico classification. Based on questionnaire data, two primary outcomes were defined: ability to have intercourse (sufficient erection), and use and effect of erectile aids. RESULTS: Sufficient erection with or without erectile aids was reported by 19% of the high-, 30% of the intermediate- and 19% of the low-risk group (not significant). Erectile aids were used by 48% of the sample, of whom 18% of the high-, 21% of the intermediate- and 14% of the low risk group reported sufficient erection (not significant). Papaverine injections were used by 21% and phosphodiesterase-5 inhibitors by 28% of the sample. Limitations were the lack of data on erection baseline and on penile rehabilitation. CONCLUSIONS: Nearly half of the sample used erectile aids, which significantly increased the proportion with sufficient erection in all risk groups after RALP. With and without the use of erectile aids, the proportions of patients with sufficient erection were 30% or less, with non-significant differences between groups. PMID- 26116049 TI - Risk factors for incisional hernia after hepatic resection for hepatocellular carcinoma in patients with liver cirrhosis. AB - BACKGROUND: The risk factors for incisional hernia (IH) and the association between liver fibrosis and IH after hepatic resection in patients with hepatocellular carcinoma (HCC) with liver cirrhosis (LC) are still unclear. We aimed to evaluate the rate of IH and to assess the effect of perioperative factors, including serum markers for liver fibrosis, on the risk of IH. METHODS: A total of 192 patients with HCC with LC who received hepatectomy were retrospectively analyzed. The primary end point was the incidence rate of IH and the secondary end points were associations between IH and 22 clinical factors. RESULTS: IH was diagnosed in 60 (31.3%) patients. The estimated incidence rates were 19.8% at 12 months, 32.5% at 36 months, and 38.8% at 60 months. In multivariable analysis, the presence of postoperative intractable ascites (odds ratio 24.83, P = .0003), abdominal wall closure by a single-layer mass closure with a continuous running suture (odds ratio 4.59, P = .0143), preoperative body mass index >= 25 kg/m(2) (odds ratio 3.36, P = .0025), and preoperative serum N terminal pro-peptide of type IV collagen 7S domain (P4NP 7S) levels >= 5 ng/mL (odds ratio 3.13, P = .0234) were independent risk factors. CONCLUSION: There are several risk factors for IH after hepatic resection in HCC patients with LC. Preoperative serum P4NP 7S levels >= 5 ng/mL are a useful predictive marker, and abdominal wall closure with a continuous running suture by a single-layer mass closure should be avoided. PMID- 26116050 TI - In vivo detection of catecholamines by magnetic resonance spectroscopy: A potential specific biomarker for the diagnosis of pheochromocytoma. PMID- 26116051 TI - A statewide analysis of specialized care for pediatric appendicitis. AB - BACKGROUND: Appendicitis is the most common operative disease in children, yet few data exist to support specialized care for childhood appendicitis. We hypothesized that children treated with specialized care are younger, have more severe disease, and experience equal or better outcomes. METHODS: Texas Blue Cross/Blue Shield claims data were reviewed for all children <18 years who underwent appendectomy for acute appendicitis from 2008 to 2012. Primary outcomes included adverse events, 30-day readmissions, and hospital duration of stay. chi(2), Fisher exact test, Student t test, and multivariate regression were performed. RESULTS: Of the 3,886 pediatric appendectomies, 894 (23%) were performed by pediatric surgeons and 1,558 (40%) were performed in children's hospitals. Children treated by pediatric surgeons were younger, had more severe disease, underwent fewer computed tomography (CT) examinations, and were hospitalized longer (all P < .05). Similarly, children treated in children's hospitals were younger, underwent fewer CTs, were more likely to undergo laparoscopic appendectomy, and were hospitalized longer (all P < .05). Specialized care did not predict adverse events or 30-day readmissions; however, specialized care was associated with longer duration of stay (P < .01). CONCLUSION: Privately insured children in Texas treated for appendicitis by pediatric surgeons or in children's hospitals were younger, had more severe disease, and were hospitalized longer but were less likely to undergo preoperative CT. PMID- 26116052 TI - A decade of investigations on groundwater arsenic contamination in Middle Ganga Plain, India. AB - Groundwater arsenic (As) load in excess of drinking limit (50 ug L(-1)) in the Gangetic Plains was first detected in 2002. Though the menace was known since about two decades from the downstream part of the plains in the Bengal Basin, comprising of Lower Ganga Plain and deltaic plains of Ganga-Brahmaputra-Meghna River system, little thought was given to its possible threat in the upstream parts in the Gangetic Plains beyond Garo-Rajmahal Hills. The contamination in Bengal Basin has become one of the extensively studied issues in the world and regarded as the severest case of health hazard in the history of mankind. The researches and investigations in the Gangetic Plains during the last decade (2003 2013) revealed that the eastern half of the plains, also referred as Middle Ganga Plain (MGP), is particularly affected by contamination, jeopardising the shallow aquifer-based drinking water supply. The present paper reviews researches and investigations carried out so far in MGP by various research institutes and government departments on wide array of issues of groundwater As such as its spatio-temporal variation, mobilisation paths, water level behaviour and flow regime, configuration of contaminated and safe aquifers and their recharge mechanism. Elevated conc. of groundwater As has been observed in grey and dark grey sediments of Holocene age (Newer Alluvium) deposited in a fluvio-lacustrine environment in the floodplain of the Ganga and most of its northern tributaries from Himalayas. Older Alluvium, comprising Pleistocene brownish yellow sediment, extending as deeper aquifers in Newer Alluvium areas, is low in groundwater As. Similarities and differences on issues between the MGP and the Bengal Basin have been discussed. The researches point towards the mobilisation process as reductive dissolution of iron hydroxide coating, rich in adsorbed As, mediated by microbial processes. The area is marked with shallow water level (<8.0 m below ground) with ample monsoonal recharge. The infiltrated rainwater and percolating water from surface water bodies carry organic carbon from sediments (particularly from the clay plugs in abandoned channels), abetting microbial processes, spread of anoxic front and release of As. PMID- 26116053 TI - Semen quality, testicular B-mode and Doppler ultrasound, and serum testosterone concentrations in dogs with established infertility. AB - Retrospective examination of breeding records enabled the identification of 10 dogs of normal fertility and 10 dogs with established infertility of at least 12 months of duration. Comparisons of testicular palpation, semen evaluation, testicular ultrasound examination, Doppler ultrasound measurement of testicular artery blood flow, and measurement of serum testosterone concentration were made between the two groups over weekly examinations performed on three occasions. There were no differences in testicular volume (cm(3)) between the two groups (fertile right testis = 10.77 +/- 1.66; fertile left testis = 12.17 +/- 2.22); (infertile right testis = 10.25 +/- 3.33; infertile left testis = 11.37 +/- 3.30), although the infertile dogs all had subjectively softer testes compared with the fertile dogs. Infertile dogs were either azoospermic or when they ejaculated, they had lower sperm concentration, sperm motility, and percentage of morphologically normal spermatozoa than fertile dogs. Furthermore, infertile dogs had reduced sperm membrane integrity measured via the hypoosmotic swelling test. Infertile dogs had significantly lower basal serum testosterone concentrations (1.40 +/- 0.62 ng/mL) than fertile dogs (1.81 +/- 0.87 ng/mL; P < 0.05). There were subjective differences in testicular echogenicity in some of the infertile dogs, and important differences in testicular artery blood flow with lower peak systolic and end-diastolic velocities measured in the distal supratesticular artery, marginal testicular artery, and intratesticular artery of infertile dogs (P < 0.05). Notably, resistance index and pulsatility index did not differ between infertile and fertile dogs. These findings report important differences between infertile and fertile dogs which may be detected within an expanded breeding soundness examination. PMID- 26116054 TI - Testicular perfusion after standing laparoscopic peritoneal flap hernioplasty in stallions. AB - Acquired inguinal herniation is a very common condition in stallions, usually leading to unilateral or bilateral castration to prevent future recurrence. Recently, several surgical techniques such as the standing laparoscopic peritoneal flap hernioplasty (SLPFH) have been developed to avoid herniation recurrence and also preserve the breeding activity of high economic value stallions. However, studies on SLPFH lack more comprehensive and systematic data about reproductive-related adverse effects and outcomes. The aim of this study was to evaluate whether SLPFH of the internal inguinal rings produces changes in the testicular blood flow in a 1-year follow-up. For that purpose, six healthy stallions were used and testicular blood flow was assessed before, 3, 6, and 12 months (T0, T3, T6, and T12) after the procedure. Blood flow was evaluated ultrasonographically, using the pulsed-wave color Doppler mode. Peak systolic velocity, end-diastolic velocity, the time-averaged maximum velocity, and the derived indexes (resistive index) and pulsatility index) of the testicular artery were measured in two localizations: in the spermatic cord and on the caudal epididymal edge of the testicle. On the spermatic cord, the peak systolic velocity of the testicular artery increased significantly at T12. However, on the epididymal edge location of the artery, the pulsatility and resistive indexes were decreased at T12 (P < 0.05). This pattern of blood flow was related to a hyperemic process. Furthermore, SLPFH might have compressed the spermatic cord, causing a slight occlusion of the testicular artery and triggering a compensatory hyperemia to compensate the deficit of blood flow that supplies the testes. The SLPFH of the internal inguinal ring affected the testicular perfusion in stallions in a 1 year follow-up, although there was no effect on sperm production during this time. The spectral Doppler ultrasound is a useful tool to asses the testicular perfusion after reproductive surgical procedure and provides information which anticipates vascular supply compromise of the stallion testicles. PMID- 26116055 TI - Nanomedicine and mammalian sperm: Lessons from the porcine model. AB - Biomedical nanotechnology allows us to engineer versatile nanosized platforms that are comparable in size to biological molecules and intracellular organelles. These platforms can be loaded with large amounts of biological cargo, administered systemically and act at a distance, target specific cell populations, undergo intracellular internalization via endogenous uptake mechanisms, and act as contrast agents or release cargo for therapeutic purposes. Over recent years, nanomaterials have been increasingly viewed as favorable candidates for intragamete delivery. Particularly in the case of sperm, nanomaterial-based approaches have been shown to improve the efficacy of existing techniques such as sperm-mediated gene transfer, loading sperm with exogenous proteins, and tagging sperm for subsequent sex- or function-based sorting. In this short review, we provide an outline of the current state of nanotechnology for biomedical applications in reproductive biology and present highlights from a series of our studies evaluating the use of specialized silica nanoparticles in boar sperm as a potential delivery vehicle into mammalian gametes. The encouraging data obtained already from the porcine model in our laboratory have formed the basis for ethical approval of similar experiments in human sperm, thereby bringing us a step closer toward the potential use of this novel technology in the clinical environment. PMID- 26116056 TI - Preselection of high and low ovulatory responders in sheep multiple ovulation and embryo transfer programs. AB - The present study evaluated the feasibility of carrying out an easy-to-handle and cost-efficient test for the preselection of high- and low-ovulatory responder ewes under superovulatory protocols. The test was based on the assessment of the number of ovulations obtained in response to the administration of a single-shot eCG treatment. The predictive value of the test was determined by comparing the number of ovulations with yields obtained in response to a multiple-dose FSH treatment. In addition, the study determined possible effects of follicular status at first FSH dose and their relationship with subsequent ovarian response. A total of 31 Merino ewes received hormonal treatment comprising the administration of 800 IU of eCG at the end of progestative treatment. Twenty three days later, multiple-dose FSH treatment (80-mg FSH, in six decreasing doses between Days 12 and 14 of a second progestative treatment) was applied to the same ewes. The study showed a significant relationship between the number of corpora lutea obtained in response to eCG treatment with respect to those obtained in response to FSH treatment (r = 0.791; P < 0.05), which resulted in 84% recurrence rate. The number of embryos was greater for high-responder in relation to low-responder ewes (7.2 +/- 3.7 and 4.0 +/- 3.9, respectively; P < 0.05), whereas rates of recovery and fertilization were similar between groups (P > 0.05). Hence, there was a tendency for a higher mean of grades 1 and 2 embryos in high-responder in relation to low-responder ewes (6.1 +/- 3.8 and 3.7 +/- 4.0, respectively; P < 0.1). No significant relationship was found between the number of corpora lutea in response to FSH treatment and the number of small and total follicles at first FSH dose (P > 0.05). However, a negative low relationship was found between the presence of large follicles and the ovulation rate in response to FSH treatment (r = -0.361; P < 0.05). In conclusion, the results show the feasibility of carrying out an easy-to-handle and cost-efficient procedure for the preselection of embryo donors. The procedure was based on high recurrence rate between hormonal treatments, which in turn accounts for a distinctive ewe ovulatory response. PMID- 26116057 TI - Collagen and matrix metalloproteinase-2 and -9 in the ewe cervix during the estrous cycle. AB - The cervical collagen remodeling during the estrous cycle of the ewe was examined. The collagen concentration determined by a hydroxyproline assay and the area occupied by collagen fibers (%C), determined by van Gieson staining, were assessed in the cranial and caudal cervix of Corriedale ewes on Days 1 (n = 6), 6 (n = 5), or 13 (n = 6) after estrous detection (defined as Day 0). In addition, the gelatinase activity by in situ and SDS-PAGE gelatin zymographies and matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9, respectively) expression by immunohistochemistry were determined. The collagen concentration and %C were lowest on Day 1 of the estrous cycle (P < 0.04), when MMP-2 activity was highest (P < 0.006) and the ratio of activated to latent MMP-2 trend to be highest (P = 0.0819). The MMP-2 activity was detected in 73% of the homogenized cervical samples, and its expression was mainly detected in active fibroblasts. By contrast, the MMP-9 activity was detected in 9% of the samples, and its scarce expression was associated with plasmocytes, macrophages, and lymphocytes. Matrix metalloproteinase-2 expression was maximal on Day 1 in the cranial cervix and on Day 13 in the caudal cervix and was lower in the cranial than in the caudal cervix (P < 0.0001). This time-dependent increase in MMP-2 expression that differed between the cranial and caudal cervix may reflect their different physiological roles. The decrease in the collagen content and increase in fibroblast MMP-2 activity in sheep cervix on Day 1 of the estrous cycle suggests that cervical dilation at estrus is due to the occurrence of collagen fiber degradation modulated by changes in periovulatory hormone levels. PMID- 26116058 TI - Use of B-mode ultrasonography for fetal sex determination in dogs. AB - Ultrasonographic determination of fetal sex in dogs has not previously been reported. The aim of this study was to describe a method for determination of intrauterine fetal sex using ultrasound. A cohort study was conducted in pregnant bitches to perform ultrasound examination of the fetal genitalia between the eighth and ninth week of gestation. Fetal sex was determined in utero by consensus agreement of two sonographers. Eighteen pregnant bitches were included in this study, and a total of 39 fetuses were evaluated. The accuracy of ultrasonography to determine the sex with a 95% confidence interval was 62.24% to female fetuses and 65.48% to male fetuses. The sonographic accuracy in determining fetal sex can be achieved at 100% when there are up to two fetuses in the litter; however, the accuracy of the technique reduces (66.7%) when more than three fetuses are present. This study describes the sonographic appearance of the external genitalia in canine fetuses in utero associated with a specific position of the fetus and reports that sex determination is possible between 55 and 58 days of gestation. PMID- 26116059 TI - Storage of sexed boar spermatozoa: Limits and perspectives. AB - Despite the great potential application of sex-sorted spermatozoa in swine, the technology is not practiced in the pig industry because of technical factors and species-specific issues. The susceptibility of boar spermatozoa to stresses induced by the sorting procedure, the relative slowness of the sex-sorting process together with the high sperm numbers required for routine artificial insemination in pig are some of the main factors limiting the commercial application of this technology in pigs. This review briefly describes the damage to spermatozoa during sex sorting, focusing on an additional limiting factor: increased susceptibility of sexed boar spermatozoa to injuries induced by liquid storage and cryopreservation that, in turn, impairs sperm quality leading to unsatisfactory results in vivo. Strategies to extend the lifespan of sex-sorted boar spermatozoa and to improve their fertilizing ability after liquid storage or cryopreservation need to be implemented before this technology can be used in pig farms. In this regard, encapsulation in barium alginate membranes could be a promising technique to optimize the in vivo use of sexed boar spermatozoa, by protecting, targeting, and controlling the release of sperm into the female genital tract. PMID- 26116060 TI - Transitioning HIV-infected children and adolescents into adult care: an Italian real-life experience. AB - As young people living with HIV age, transition to adult care is increasingly required. The aim of our study was to describe how a care transition program was developed in an HIV adult clinic in Genoa, Italy. This is a descriptive study including 45 HIV-infected patients who participated in the transition process from a pediatric unit to an adult Infectious Diseases Unit, which started in 2000. A dedicated day, patient-customized environment, psychological support, and all health services in one site were provided. In 2014, a survey form was created to investigate the efficacy of the transition. At survey compilation time, 38 patients (84.4%) were retained in care, 2 were lost to follow-up, 2 were transferred to another adult clinic, and 3 had died. We highlight the importance of planning the transition process and the role of the interprofessional team to guarantee a successful transition for HIV-infected children and adolescents. PMID- 26116061 TI - Doctors and the Etiquette of Mobile Device Use in Trauma and Orthopedics. AB - BACKGROUND: The etiquette surrounding the use of mobile devices, so-called "mobiquette," has been previously identified as a barrier to use in an educational context. OBJECTIVE: To investigate the influence of mobile device use on patient and staff opinions in the trauma and orthopedics department at a teaching hospital in Wales. METHODS: A survey of patients at the bedside and staff in their work environment was undertaken. Data included age, frequency of observed use, suspected main reason for use, and whether doctors' use of a mobile device positively or negatively influenced participants' opinions of them as a professional and as a person. RESULTS: A total of 59 patients and 35 staff responded. The modal age range was 40 to 54 years old. Most patients (78%) never see doctors using mobile devices in the workplace, compared with 3% of staff. The main reason for use was thought to be "communicating with colleagues" (48%) followed by "Internet use/applications for work reasons" (40%). Approximately 40% of patients' opinions of doctors were positively influenced by device use, compared with 82% of staff. This difference between patient and staff opinions was statistically significant for both professional (P<.001) and personal (P=.002) opinions. CONCLUSIONS: Patients are likely to have a negative opinion of doctors using mobile devices in the workplace. This can be balanced by the more positive opinions of colleagues. We advise doctors to remember "mobiquette" around patients. PMID- 26116062 TI - Can we use an early warning system for tricuspid regurgitation? PMID- 26116064 TI - Electrical nerve stimulation method for intraoperative localization of the inferior alveolar nerve within the mandible: a pilot study in rabbits. AB - The efficacy of the electrical nerve stimulation method for localizing the inferior alveolar nerve (IAN) within the mandibular bone was evaluated. Six New Zealand rabbits were used (both sides of the mandible). The IAN was stimulated through the mandibular bone and compound action potentials (CAPs) were recorded proximally from the main trunk of the nerve. Stimulation current pulse widths were set at 0.05, 0.1, 0.3, 0.5, and 1ms. The minimum current magnitude that generated a CAP with a criterion level (300mV peak-to-peak amplitude) was measured in the range of 0.05-5mA. Correlations between the distance of the IAN from the active electrode site and the minimum current magnitudes were studied for each pulse width. The correlation coefficients were 0.678, 0.807, 0.893, 0.851, and 0.890 for the pulse widths of 0.05, 0.1, 0.3, 0.5, and 1ms, respectively. The minimum current producing the criterion CAP response in the IAN was significantly (P<0.0001 for all pulse widths) and highly correlated with the distance between the stimulation site and the nerve. The results suggest that electrical nerve stimulation is a promising method that can be used for the localization of the IAN, especially during mandibular implant surgery. PMID- 26116063 TI - Reconstruction of mandibular vertical defects for dental implants with autogenous bone block grafts using a tunnel approach: clinical study of 50 cases. AB - The objective of this study was to evaluate the outcomes of mandibular vertical defect reconstruction with autologous bone and the use of a sub-periosteal tunnel approach in preparation for dental implant insertion. Forty-three consecutive patients with an atrophic posterior mandible were reconstructed using this method. Two thin laminae of cortical bone, obtained by splitting blocks harvested from the retromolar area, were fixed in a box-like framework containing cancellous and particulate bone. The goal was to achieve an alveolar ridge width of >=5.5mm and an effective bone height (EBH) of >=10.5mm for dental implant insertion (>=3.4mm diameter, >=9.5mm length). Fifty reconstruction procedures were performed. The mean EBH was 7.1+/-1.3mm pre-treatment and 12.3+/-1.1mm post treatment (mean increase 5.2+/-1.4mm). Complete graft loss was recorded in two cases; the remaining complications were minor. After a mean consolidation period of 3.5 months, 96 dental implants were placed. No failure of osseointegration was observed at follow-up (mean 32.9 months). The average bone height reduction was 0.9mm (graft vertical resorption 17.4%). Reconstruction of posterior mandibular vertical defects using two autogenous cortical bone blocks with particulate bone between them, combined with a tunnelling technique, provided good healing with no wound dehiscence and minimum resorption of the grafted bone, favouring a substantial vertical bone gain. PMID- 26116065 TI - Effect of sitting, standing, and supine body positions on facial soft tissue: detailed 3D analysis. AB - Medical imaging techniques require various body positions. Gravity causes changes in the facial soft tissue and acts in different directions according to the position of the head during imaging. The aim of this study was to evaluate the effect of positional changes on the facial soft tissue. The faces of subjects were scanned in the standing, sitting, and supine body positions. Differences in the positions were compared using the root mean square (RMS), mean absolute deviation (MAD), and mean signed distance (MSD). The displacement of 15 midsagittal and 20 bilateral landmarks was evaluated. The RMS, MAD, and MSD values of the sitting-standing comparison were significantly lower than those of the sitting-supine and standing-supine comparisons. There were no significant differences between the sitting-supine and standing-supine comparisons. Sixteen out of 135 measurements (12%) of the midsagittal landmarks and 94 out of 180 (52%) measurements of the bilateral landmarks showed significant displacements among the body positions. These results demonstrate a significant change in the facial soft tissue caused by body position. Furthermore, these data show the different susceptibilities of the facial soft tissue landmarks to the effect of body position along the x, y, and z axes. PMID- 26116066 TI - Effect of oral contraceptive use on the incidence of dry socket in females following impacted mandibular third molar extraction: a meta-analysis. AB - The aim of this comprehensive meta-analysis was to provide evidence-based data to test whether oral contraceptive (OC) use can promote the incidence of dry socket (DS) in females following impacted mandibular third molar extraction. PubMed, the Cochrane Library, and Elsevier Science Direct databases were searched. The pooled risk ratio (RR) with 95% confidence interval (CI) was calculated using fixed effects or random-effects model analysis. Heterogeneity among studies was evaluated with the Cochran test and I(2) statistic. Study quality was assessed with the Newcastle-Ottawa scale. Of 70 articles identified in the search, 12 reporting 16 clinical controlled trials were included in this study. The incidence of DS was significantly greater in the OC groups than in the control groups (RR 1.80, 95% CI 1.33-2.43). Subgroup analyses showed that the unit assessed (tooth or patient), the region in which the study was conducted, and the intervention were not related to the incidence of DS in females taking OC after impacted mandibular third molar extraction. The sensitivity analysis showed no significant change when any one study was excluded. Publication bias was also not detected. This study suggests that OC use may promote the incidence of DS in females following impacted mandibular third molar extraction. PMID- 26116067 TI - Point: Introducing Diversity Into a Medical Group: How to Do It and Why. PMID- 26116068 TI - When Vision Prevails: A History of the International Society for Strategic Studies in Radiology. PMID- 26116069 TI - Counterpoint: Diversity and Inclusion: Works in Progress. PMID- 26116070 TI - Anthocyanin-rich Seoritae extract ameliorates renal lipotoxicity via activation of AMP-activated protein kinase in diabetic mice. AB - BACKGROUND: Anthocyanins are major constituents of food colours and have been reported to possess anti-diabetic activities for potential medicinal use. The precise role of anthocyanins in diabetic nephropathy is poorly understood. We investigated whether anthocyanin-rich Seoritae extract (SE) can potentially prevent oxidative stress and lipotoxicity, which are the main causes of renal damage in diabetic nephropathy, via activation of AMP-activated protein kinase (AMPK) and the consequent effects on its target molecules. METHODS: Four groups of male C57BLKS/J db/m and db/db mice were used. Diabetic and non-diabetic mice were orally administered 10 mg/kg body weight SE daily for 12 weeks, starting at 8 weeks of age. RESULTS: db/db mice treated with anthocyanins showed decreased albuminuria. Anthocyanins ameliorated intra-renal lipid concentrations in db/db mice with improvement of glomerular matrix expansion and inflammation, which was related to increased phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma, and inhibited the activity of acetyl-CoA carboxylase and sterol regulatory element-binding protein 1. Anthocyanins reversed diabetes-induced increases in renal apoptosis and oxidative stress. In cultured human glomerular endothelial cells, anthocyanins prevented high glucose-induced oxidative stress and apoptosis through activation of AMPK in the same manner. CONCLUSIONS: The results revealed that anthocyanins ameliorated diabetic nephropathy in db/db mice via phosphorylation of AMPK, the major energy-sensing enzyme, and the consequent effects on its target molecules, which appeared to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney. PMID- 26116071 TI - Distance to parks and non-residential destinations influences physical activity of older people, but crime doesn't: a cross-sectional study in a southern European city. AB - BACKGROUND: Physical activity (PA) has numerous health benefits, but older adults live mostly sedentary lifestyles. The physical and social neighborhood environment may encourage/dissuade PA. In particular, neighborhood crime may lead to feeling unsafe and affect older adults' willingness to be physically active. Yet, research on this topic is still inconclusive. Older population, probably the age group most influenced by the neighborhood environment, has been understudied, especially in Southern Europe. In this study, we aimed to analyze the association between leisure-time physical activity (LTPA) in older adults and objective crime, alongside other neighborhood characteristics. METHODS: We obtained data from a population-based cohort from Porto (2005-2008) to assess LTPA. Only adults aged 65 years or more were included (n = 532). A Geographic Information System was used to measure neighborhood characteristics. Neighborhood crime was expressed as crime rates by category (incivilities, criminal offenses with and without violence and traffic crime). Neighborhood characteristics such as socioeconomic deprivation, land gradient, street density, transportation network, distance to parks, non-residential destinations and sport spaces were also included. Generalized Additive Models were fitted to estimate the association between neighborhood characteristics and the participation (being active vs. inactive) and frequency (min/day) of LTPA. RESULTS: Forty-six percent of the men and 61 % of the women did not engage in any kind of LTPA. Among the active participants, men spent on average 50.5 (35.2 Standard Deviation, SD) min/day in LTPA, whereas the average among women was 36.9 (35.1 SD) min/day (p < 0.001). Neighborhood crime was unrelated to the participation in, or frequency of, LTPA. On the other hand, two neighborhood characteristics - distance to the nearest park (beta = -0.0262, p = 0.029) and to the nearest non-residential destination (beta = -0.0735, p = 0.019) - were associated with time spent on LTPA, but only among active older women. No neighborhood characteristic was related to participation in LTPA. CONCLUSIONS: From a public health point of view, the provision of parks and non-residential destinations (shops, schools, cultural and worship places) might contribute to elevate PA levels of already active older women. On the other hand, in this setting, crime was not a big issue. PMID- 26116073 TI - Compartmentalization of iron between mitochondria and the cytosol and its regulation. AB - Iron is essential for life. Its coordinated distribution between intracellular compartments and the adaptation of iron uptake to intracellular demands are central for a balanced iron homeostasis. Mitochondria take center stage in cellular iron metabolism as they harbor the two major iron-utilizing pathways, the synthesis of heme and the biogenesis of iron-sulfur (Fe/S) proteins. Consistent with this central role, mitochondria are also critical regulators of cellular iron homeostasis. They directly influence cellular iron uptake and the status of iron-utilizing metabolic processes through iron-dependent co-factors or by control of gene expression. For all these aspects of cellular iron metabolism, the uptake of iron into mitochondria is critical. During the last decade, considerable progress has been made with respect to the functional characterization of mitochondrial iron acquisition and the identification of transporters involved. The model organism Saccharomyces cerevisiae has been especially useful for the elucidation of this process. Here, we summarize the recent advances in the mechanism of mitochondrial iron transport and the impact of mitochondria on the regulation of cellular iron homeostasis. PMID- 26116072 TI - Metabolomic and transcriptomic insights into how cotton fiber transitions to secondary wall synthesis, represses lignification, and prolongs elongation. AB - BACKGROUND: The morphogenesis of single-celled cotton fiber includes extreme elongation and staged cell wall differentiation. Designing strategies for improving cotton fiber for textiles and other uses relies on uncovering the related regulatory mechanisms. In this research we compared the transcriptomes and metabolomes of two Gossypium genotypes, Gossypium barbadense cv Phytogen 800 and G. hirsutum cv Deltapine 90. When grown in parallel, the two types of fiber developed similarly except for prolonged fiber elongation in the G. barbadense cultivar. The data were collected from isolated fibers between 10 to 28 days post anthesis (DPA) representing: primary wall synthesis to support elongation; transitional cell wall remodeling; and secondary wall cellulose synthesis, which was accompanied by continuing elongation only in G. barbadense fiber. RESULTS: Of 206 identified fiber metabolites, 205 were held in common between the two genotypes. Approximately 38,000 transcripts were expressed in the fiber of each genotype, and these were mapped to the reference set and interpreted by homology to known genes. The developmental changes in the transcriptomes and the metabolomes were compared within and across genotypes with several novel implications. Transitional cell wall remodeling is a distinct stable developmental stage lasting at least four days (18 to 21 DPA). Expression of selected cell wall related transcripts was similar between genotypes, but cellulose synthase gene expression patterns were more complex than expected. Lignification was transcriptionally repressed in both genotypes. Oxidative stress was lower in the fiber of G. barbadense cv Phytogen 800 as compared to G. hirsutum cv Deltapine 90. Correspondingly, the G. barbadense cultivar had enhanced capacity for management of reactive oxygen species during its prolonged elongation period, as indicated by a 138-fold increase in ascorbate concentration at 28 DPA. CONCLUSIONS: The parallel data on deep-sequencing transcriptomics and non-targeted metabolomics for two genotypes of single-celled cotton fiber showed that a discrete developmental stage of transitional cell wall remodeling occurs before secondary wall cellulose synthesis begins. The data showed how lignification can be transcriptionally repressed during secondary cell wall synthesis, and they implicated enhanced capacity to manage reactive oxygen species through the ascorbate-glutathione cycle as a positive contributor to fiber length. PMID- 26116074 TI - Evidence for functional and dynamic microcompartmentation of Cav-1/TRPV4/K(Ca) in caveolae of endothelial cells. AB - Ca(2+)-activated K(+) channels (KCa) play a pivotal role in the endothelium dependent hyperpolarization and regulation of vascular tone and blood pressure. For activation, KCa depend on an increase of intracellular calcium which is substantially mediated by Ca(2+)-permeable cation channels including the transient receptor potential V4 (TRPV4). It has been proposed that KCa and Ca(2+) permeable cation channels may be clustered in localized positions within the cell membrane to form functional units and that caveolae may constitute the scaffolding for such microcompartmental organization. Here, we sought to elucidate the composition and functional relevance of these microcompartments in vitro and in vivo. We show that TRPV4 and small-conductance KCa2.3 are enriched in caveolae of human microvascular endothelial cells. Using immunoprecipitation, immunocytology and superresolution microscopy, we found a caveolae-dependent association between caveolin-1, TRPV4 and small conductance KCa2.3, but not intermediate conductance KCa3.1, in endothelial cells under static condition. Mechanical stimulation of cells via exposure to shear stress led to a partial de novo colocalization of KCa3.1 with Cav-1 and TRPV4. In a mouse model of genetic Cav-1 deficiency, we found significantly reduced KCa-mediated currents as determined by patch-clamping in carotid artery endothelial cells (CAEC) from Cav 1(-/-) mice compared to wildtype. Functionally, Cav-1 deficiency was associated with impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation in response to shear stress and acetylcholine. In summary, our findings provide evidence for a dynamic microcompartmentation of TRPV4/KCa in caveolae of endothelial cells and highlight the importance of Cav-1 for endothelial KCa functions and flow-induced vasodilation. PMID- 26116075 TI - Fungal stress biology: a preface to the Fungal Stress Responses special edition. AB - There is currently an urgent need to increase global food security, reverse the trends of increasing cancer rates, protect environmental health, and mitigate climate change. Toward these ends, it is imperative to improve soil health and crop productivity, reduce food spoilage, reduce pesticide usage by increasing the use of biological control, optimize bioremediation of polluted sites, and generate energy from sustainable sources such as biofuels. This review focuses on fungi that can help provide solutions to such problems. We discuss key aspects of fungal stress biology in the context of the papers published in this Special Issue of Current Genetics. This area of biology has relevance to pure and applied research on fungal (and indeed other) systems, including biological control of insect pests, roles of saprotrophic fungi in agriculture and forestry, mycotoxin contamination of the food-supply chain, optimization of microbial fermentations including those used for bioethanol production, plant pathology, the limits of life on Earth, and astrobiology. PMID- 26116076 TI - Cdc14 phosphatase: warning, no delay allowed for chromosome segregation! AB - Cycling events in nature start and end to restart again and again. In the cell cycle, whose purpose is to become two where there was only one, cyclin-dependent kinases (CDKs) are the beginning and, therefore, phosphatases must play a role in the ending. Since CDKs are drivers of the cell cycle and cancer cells uncontrollably divide, much attention has been put into knocking down CDK activity. However, much less is known on the consequences of interfering with the phosphatases that put an end to the cell cycle. We have addressed in recent years the consequences of transiently inactivating the only master cell cycle phosphatase in the model yeast Saccharomyces cerevisiae, Cdc14. Transient inactivation is expected to better mimic the pharmacological action of drugs. Interestingly, we have found that yeast cells tolerate badly a relatively brief inactivation of Cdc14 when cells are already committed into anaphase, the first cell cycle stage where this phosphatase plays important roles. First, we noticed that the segregation of distal regions in the chromosome arm that carries the ribosomal DNA array was irreversibly impaired, leading to an anaphase bridge (AB). Next, we found that this AB could eventually be severed by cytokinesis and led to two different types of genetically compromised daughter cells. All these previous studies were done in haploid cells. We have now recently expanded this analysis to diploid cells and used the advantage of making hybrid diploids to study chromosome rearrangements and changes in the ploidy of the surviving progeny. We have found that the consequences for the genome integrity were far more dramatic than originally envisioned. PMID- 26116077 TI - Clinical applications for dual energy CT versus dynamic contrast enhanced CT in oncology. AB - Both Dual Energy CT (DECT) and Volume Perfusion CT (VPCT) have gained interest in recent years with several studies providing evidence of benefits for both in a variety of oncological settings. These technologies open a new spectrum of diagnostic opportunities aiming at an improved detection and characterization of suspected tumor lesions, early evaluation of therapy response and generally more accurate treatment monitoring. Here, we review and discuss current advances, beneficial aspects and potential shortcomings of both imaging modalities with regard to their clinical use in oncology. PMID- 26116078 TI - Local anaesthetic wound infiltration in addition to standard anaesthetic regimen in total hip and knee replacement: long-term cost-effectiveness analyses alongside the APEX randomised controlled trials. AB - BACKGROUND: The Arthroplasty Pain Experience (APEX) studies are two randomised controlled trials in primary total hip (THR) and total knee replacement (TKR) at a large UK orthopaedics centre. APEX investigated the effect of local anaesthetic wound infiltration (LAI), administered before wound closure, in addition to standard analgesia, on pain severity at 12 months. This article reports results of the within-trial economic evaluations. METHODS: Cost-effectiveness was assessed from the health and social care payer perspective in relation to quality adjusted life years (QALYs) and the primary clinical outcome, the WOMAC Pain score at 12-months follow-up. Resource use was collected from hospital records and patient-completed postal questionnaires, and valued using unit cost estimates from local NHS Trust finance department and national tariffs. Missing data were addressed using multiple imputation chained equations. Costs and outcomes were compared per trial arm and plotted in cost-effectiveness planes. If no arm was dominant (i.e., more effective and less expensive than the other), incremental cost-effectiveness ratios were estimated. The economic results were bootstrapped incremental net monetary benefit statistics (INMB) and cost-effectiveness acceptability curves. One-way deterministic sensitivity analyses explored any methodological uncertainty. RESULTS: In both the THR and TKR trials, LAI was the dominant treatment: cost-saving and more effective than standard care, in relation to QALYs and WOMAC Pain. Using the L20,000 per QALY threshold, in THR, the INMB was L1,125 (95 % BCI, L183 to L2,067) and the probability of being cost effective was over 98 %. In TKR, the INMB was L264 (95 % BCI, -L710 to L1,238), but there was only 62 % probability of being cost-effective. When considering an NHS perspective only, LAI was no longer dominant in THR, but still highly cost effective, with an INMB of L961 (95 % BCI, L50 to L1,873). CONCLUSIONS: Administering LAI is a cost-effective treatment option in THR and TKR surgeries. The evidence, because of larger QALY gain, is stronger for THR. In TKR, there is more uncertainty around the economic result, and smaller QALY gains. Results, however, point to LAI being cheaper than standard analgesia, which includes a femoral nerve block. TRIAL REGISTRATION: ISRCTN96095682 , 29/04/2010. PMID- 26116079 TI - Prevalence of Tinea capitis in school going children from Mathare, informal settlement in Nairobi, Kenya. AB - BACKGROUND: Tinea capitis is a common infection especially in poor resource settings. This study was aimed at determining the prevalence Tinea capitis in children from selected schools from an urban slum in Nairobi city of Kenya. METHODS: A cross-sectional study was carried out in 150 school going children during the period between May and September 2013. A questionnaire was administered and cultures of scalps, skin scrapping/hair stubs samples were performed and the etiological agents identified and confirmed. RESULTS: In a total of one hundred and fifty (150) children recruited 89 (59.3%) were males and 61 (40.7%) females aged between 3 and 14 years. The overall prevalence rates in dermatophytes infection was 81.3% (122/150) with etiological agents consisting Trichophyton spp. (61.3%), Microsporum spp. (13.3%) and Epidermophyton spp. (7.3%) infections with infections occurring either singly (56%), duo (38%) or tipple co-infections (6%). CONCLUSION: This study demonstrates a high prevalence of Tinea infections with Trichophyton tonsurans as the predominant etiological agent in school going children of the urban slums of Nairobi. PMID- 26116080 TI - A study on the performance and emission characteristics of esterified pinnai oil tested in VCR engine. AB - Biodiesel is a clean renewable fuel derived from vegetable oils and animal fats. It is biodegradable, oxygenated, non toxic and free from sulfur and aromatics. The biodiesel prepared from pinnai oil undergoes acid esterification followed by alkaline transesterification process. The fatty acid methyl esters components were identified using gas chromatography and compared with the standard properties. The properties of biodiesel are comparable with diesel. The yield of the biodiesel production depends upon the process parameters such as reaction temperature, pH, time duration and amount of catalyst. The yield of biodiesel by transesterification process was 73% at 55 degrees C. This fuel was tested in a variable compression ratio engine with blend ratios of B10 and B20. During the test runs the compression ratio of the engine was varied from 15:1 to 18:1 and the torque is adjusted from zero to maximum value of 22Nm. The performance characteristics such as the brake thermal efficiency, brake specific energy consumption and exhaust gas temperature of the engine are analyzed. The combustion characteristics of biodiesel like ignition delay, combustion duration and maximum gas temperature and the emission characteristics are also analyzed. The performance characteristics, combustion characteristics and engine emission are effective in the variable compression ratio engine with biodiesel and it is compared with diesel. PMID- 26116081 TI - Eplerenone's role in the management of complex cardiovascular disorders. AB - The accompanying special issue reviews the role of eplerenone and spironolactone in the management of various cardiovascular and renal conditions. PMID- 26116082 TI - Contextual Information Around the First Use of Electronic Cigarettes Among New Zealand Smokers and Recent Quitters. PMID- 26116083 TI - Food and Drug Administration Response to the ATTUD/SRNT Policy Statement on the Labeling of Nicotine Replacement Therapies. PMID- 26116084 TI - A Cross-Country Study of Smoking Cessation Assistance Utilization in 16 Low and Middle Income Countries: Data From the Global Adult Tobacco Survey (2008-2012). AB - INTRODUCTION: While it is clear that tobacco use has been increasing in developing countries, it is unclear whether smokers in these countries utilize cessation assistance to quit. We examined the extent to which smokers in developing countries use assistance when making a cessation attempt. METHODS: Data from the Global Adult Tobacco Survey of 16 low and middle income countries were analyzed. This nationally representative household survey collected data on assistance that smokers used to quit, such as provider advice, pharmacotherapy, and quit lines between 2008 and 2012. RESULTS: Use of any of the recommended assistance in the past 12 months varied greatly in lower middle income countries (4% to 27%), and to a lesser extent in upper middle income countries (5% to 18%). Counseling and pharmacotherapy were more commonly used than other types of assistance, though the prevalence was low across countries (counseling: 1% to 15%; pharmacotherapy: 1% to 27%). Quit lines were rarely used (0.1% to 1.5%). The average age of assistance users and nonusers was both around 40. In general, past users of cessation assistance tended to have higher education levels than nonusers. CONCLUSIONS: Cessation assistance is underused in these low and middle income countries. Tobacco control advocates in these countries should work on ways to promote use of cessation assistance to enhance quit rates. PMID- 26116085 TI - The Impact of Health Warning Labels for Swedish Snus Advertisements on Young Adults' Snus Perceptions and Behavioral Intentions. AB - INTRODUCTION: This study examined the impact of warning labels conveying the potential harms and addictiveness of Swedish snus and the potential-reduced harms of Swedish snus among young adult nonsmokers and smokers. METHODS: A convenience sample of young adults aged 18-30 residing in the United States (n = 517, 56% male, 33% smokers) participated in an online experiment. Participants completed baseline measures and were randomized to 1 of 5 experimental conditions where they viewed a Swedish snus ad with warning labels that varied by condition: (1) Control-no warning; (2) Addiction-warning conveying the addictiveness of snus; (3) Harm-warning communicating the potential harms of snus; (4) Harm Reduction warning conveying the potential-reduced harms of snus compared with cigarettes; (5) Harm Reduction Switch-warning communicating the potential-reduced harms of snus when switching completely from cigarettes to snus. Outcomes measured included perceived harms and addictiveness of snus, thoughts about not using snus, and intentions to use snus. RESULTS: Participants in the Harm Reduction and Harm Reduction Switch conditions perceived snus to be less harmful than cigarettes compared with the Control, Addiction, and Harm conditions. Nonsmokers in the Harm Reduction condition reported fewer thoughts about not using snus than nonsmokers in the Harm condition. CONCLUSIONS: Warnings conveying the potential reduced harms of Swedish snus compared with cigarettes generate perceptions that snus is less harmful than cigarettes and produce fewer thoughts about not using snus among nonsmokers. Such perceptions have been associated with snus use in prior studies. PMID- 26116086 TI - The Influence of Social Support on Smoking Cessation Treatment Adherence Among HIV+ Smokers. AB - INTRODUCTION: The high prevalence of smoking among people living with HIV is a significant problem. Nonadherence to smoking cessation pharmacotherapy is a barrier for successfully quitting. The current study investigated the extent to which social support variables impact adherence and cessation. METHODS: Participants were 444 HIV+ smokers who provided data on nicotine patch adherence, social support, and smoking. We conducted a path analysis to estimate (1) the effects of six social support indicators at baseline on nicotine patch adherence; (2) the effect of patch adherence on 7-day point prevalence smoking at 6-month follow-up; and (3) the indirect effects of social support indicators on 7-day point prevalence smoking at 6-month follow-up via patch adherence. RESULTS: The tested model demonstrated good fit as indicated by the comparative fit index, root mean square error of approximation, and weighted root mean square residual (0.94, 0.02, and 0.51, respectively). Path analysis results indicated greater social support network contact was associated with higher levels of nicotine patch adherence (beta = .13, P = .02), greater patch adherence was associated with a lower probability of 7-day point prevalence smoking at 6-month follow-up (beta = -.47, P < .001) and greater social support network contact (beta = -.06, P = .03) had a significant indirect effect on 7-day point prevalence smoking at 6 month follow-up via patch adherence. CONCLUSIONS: Findings have implications for smoking cessation interventions that seek to capitalize on the beneficial effects of social support. Such efforts should account for the role that frequency of contact may have on nicotine patch use and other treatment-related mechanisms. PMID- 26116087 TI - Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure. AB - A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer (P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively (P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT. PMID- 26116088 TI - Interferon-alpha: A Potentially Effective Treatment for Minimal Residual Disease in Acute Leukemia/Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation. AB - In this prospective clinical study, the safety and efficacy of preemptive interferon-alpha (IFN-alpha) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n = 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-alpha. A total of 22 patients received preemptive IFN-alpha; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-alpha group and 62.9% for the DLI group (P < .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-alpha group and 35.6% for the DLI group (P = .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-alpha group and 4.4% for the DLI group (P = .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-alpha group and 60.0% for the DLI group (P = .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly associated with poorer clinical outcomes. Thus, preemptive IFN-alpha may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT. PMID- 26116090 TI - Olfactory signal coding in an odor background. AB - Insects communicating with pheromones are confronted with an olfactory environment featuring a diversity of volatile organic compounds from plant origin. These volatiles constitute a rich and fluctuant background from which the information carried by the pheromone signal must be extracted. Thus, the pheromone receptor neurons must encode into spike trains the quality, intensity and temporal characteristics of the signal that are determinant to the recognition and localization of a conspecific female. We recorded and analyzed the responses of the pheromone olfactory receptor neurons of male moths to sex pheromone in different odor background conditions. We show that in spite of the narrow chemical tuning of the pheromone receptor neurons, the sensory input can be altered by odorant background. PMID- 26116089 TI - Analysis of the Effect of Race, Socioeconomic Status, and Center Size on Unrelated National Marrow Donor Program Donor Outcomes: Donor Toxicities Are More Common at Low-Volume Bone Marrow Collection Centers. AB - Previous studies have shown that risks of collection-related pain and symptoms are associated with sex, body mass index, and age in unrelated donors undergoing collection at National Marrow Donor Program centers. We hypothesized that other important factors (race, socioeconomic status [SES], and number of procedures at the collection center) might affect symptoms in donors. We assessed outcomes in 2726 bone marrow (BM) and 6768 peripheral blood stem cell (PBSC) donors collected between 2004 and 2009. Pain/symptoms are reported as maximum levels over mobilization and collection (PBSC) or within 2 days of collection (BM) and at 1 week after collection. For PBSC donors, race and center volumes were not associated with differences in pain/symptoms at any time. PBSC donors with high SES levels reported higher maximum symptom levels 1 week after donation (P = .017). For BM donors, black males reported significantly higher levels of pain (OR, 1.90; CI, 1.14 to 3.19; P = .015). No differences were noted by SES group. BM donors from low-volume centers reported more toxicity (OR, 2.09; CI, 1.26 to 3.46; P = .006). In conclusion, race and SES have a minimal effect on donation associated symptoms. However, donors from centers performing <= 1 BM collection every 2 months have more symptoms after BM donation. Approaches should be developed by registries and low-volume centers to address this issue. PMID- 26116091 TI - Retrieving relevant experiments: The case of microRNA microarrays. AB - Content-based retrieval of biological experiments in large public repositories is a recent challenge in computational biology and bioinformatics. The task is, in general, to search in a database using a query-by-example without any experimental meta-data annotation. Here, we consider a more specific problem that seeks a solution for retrieving relevant microRNA experiments from microarray repositories. A computational framework is proposed with this objective. The framework adapts a normal-uniform mixture model for identifying differentially expressed microRNAs in microarray profiling experiments. A rank-based thresholding scheme is offered to binarize real-valued experiment fingerprints based on differential expression. An effective similarity metric is introduced to compare categorical fingerprints, which in turn infers the relevance between two experiments. Two different views of experimental relevance are evaluated, one for disease association and another for embryonic germ layer, to discern the retrieval ability of the proposed model. To the best of our knowledge, the experiment retrieval task is investigated for the first time in the context of microRNA microarrays. PMID- 26116092 TI - Labetalol and cardiovascular consequences of cocaine use. PMID- 26116093 TI - "Brain sex differentiation" in teleosts: Emerging concepts with potential biomarkers. AB - "Brain sex differentiation" in teleosts is a contentious topic of research as most of the earlier reports tend to suggest that gonadal sex differentiation drives brain sex differentiation. However, identification of sex-specific marker genes in the developing brain of teleosts signifies brain-gonadal interaction during early sexual development in lower vertebrates. In this context, the influence of gonadotropin-releasing hormone (GnRH)-gonadotropin (GTH) axis on gonadal sex differentiation, if any requires in depth analysis. Presence of seabream (sb) GnRH immunoreactivity (ir-) in the brain of XY Nile tilapia was found as early as 5days post hatch (dph) followed by qualitative reduction in the preoptic area-hypothalamus region. In contrast, in the XX female brain a steady ir- of sbGnRH was evident from 15dph. Earlier studies using sea bass already implied the importance of hypothalamic gonadotropic axis completion during sex differentiation period. Such biphasic pattern of localization was also seen in pituitary GTHs using heterologous antisera in tilapia. However, more recent analysis in the same species could not detect any sexually dimorphic pattern using homologous antisera for pituitary GTHs. Detailed studies on the development of hypothalamo-hypophyseal-gonadal axis in teleosts focusing on hypothalamic monoamines (MA) and MA-related enzymes demonstrated sex-specific differential expression of tryptophan hydroxylase (Tph) in the early stages of developing male and female brains of tilapia and catfish. The changes in Tph expression was in agreement with the levels of serotonin (5-HT) and 5-hydroxytryptophan in the preoptic area-hypothalamus. Considering the stimulatory influence of 5-HT on GnRH and GTH release, it is possible to propose a network association between these correlates during early development, which may bring about brain sex dimorphism in males. A recent study from our laboratory during female brain sex development demonstrated high expression of tyrosine hydroxylase in correlation with catecholamine levels, brain aromatase and its related transcription factors such as fushi tarazu factor 1, Ftz-f1 and fork head box protein L2, foxl2. Taken together, gender differences in the levels of various transcripts provide new perspectives on brain sex differentiation in lower vertebrates. Sexually dimorphic or differentially expressing genes may play an essential role at the level of brain in response to gonadal differentiation, which might consequentially or causatively respond to gonadal sex. PMID- 26116094 TI - Therapeutic transdermal drug innovation from 2000 to 2014: current status and outlook. AB - The US Food and Drug Administration (FDA) approved the first transdermal drug over 35 years ago. Today, transdermal products represent a growing, multibillion dollar market. From 2000 to 2014, an average of 2.6 new transdermal drug were approved each year. However, only two of these approvals represented new molecular entities (NMEs). Furthermore, none of these approvals were designated for priority review by the FDA. Currently, transdermal drugs are limited in scope to fewer than 20 clinical indications. The past decade has seen significant safety, performance, and cost issues surrounding multiple transdermal drug products. As the field moves towards more complex drug-device combinations to overcome the natural barrier function of the skin, there will likely be more regulatory challenges, but also the potential for broader clinical scope. PMID- 26116095 TI - Treatment of Scaphoid Nonunion: A Systematic Review of the Existing Evidence. AB - PURPOSE: To determine by systematic review the optimal treatment of scaphoid nonunion. METHODS: We conducted a systematic review of the literature with a meta analysis of proportions to investigate the comparative effectiveness of different surgical techniques. RESULTS: A total of 48 publications (1,602 patients) met the eligibility criteria. Vascularized and nonvascularized bone grafts had an estimated union incidence of 92% and 88%, respectively. Distal radius and iliac crest bone grafts had similar union rates (89% and 87%, respectively) but harvesting of iliac crest bone grafts had more complications. Both screw and K wire fixation had a higher incidence of union (88% and 91%, respectively) than no fixation (79%). No approach was statistically different. Patients fixed with screws were mobilized earlier than those with K-wire fixation. CONCLUSIONS: Current evidence does not demonstrate a significantly superior method for the treatment of scaphoid nonunion. A multicenter randomized trial would be ideal but the large numbers that would be required may make this unrealistic. We recommend the continued reporting of series with specific assessments and outcome measures to optimize future comparisons in an attempt to determine the best management of scaphoid nonunion. CLINICAL RELEVANCE: The use of bone grafts and the methods of their fixation for scaphoid nonunion are debated issues in hand and wrist surgery, with multiple methods employed. There is no current consensus on optimal treatment. A meta-analysis of proportions of available data from recent studies was deemed the most appropriate way to assimilate the available evidence with the view to inform surgeons of the optimal treatment according to the evidence base. PMID- 26116096 TI - Tumor necrosis factor-alpha single nucleotide polymorphisms in juvenile systemic lupus erythematosus. AB - BACKGROUND: Juvenile systemic lupus erythematosus (JSLE) is a multi-system autoimmune disorder of unknown origin. Given the importance of the contribution of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), towards the pathogenesis of JSLE, this study was performed to assess TNFA gene polymorphisms in a case-control study. METHODS: Fifty nine patients with JSLE were enrolled in this study as case group and compared with healthy control subjects. The frequency of alleles, genotypes, and haplotypes of TNFA single nucleotide polymorphisms (SNPs) at positions -308 and -238 were evaluated, using polymerase chain reaction with sequence-specific primers method. RESULTS: The G allele at position -238 in TNFA promoter region was significantly more frequent in patients with JSLE than in the healthy controls (P value<0.001), while the frequency of A allele at the same position was significantly lower than controls. Furthermore, a significant positive association for G/G genotype at the same position was detected in patients' group compared with control subjects (P value<0.001). The GA haplotype of TNFA (positions -308, -238) was significantly less frequent in case group than in controls (P value<0.001), while GG was the most frequent haplotype for TNFA in the patient group, compared to controls (P value<0.01). CONCLUSIONS: Pro-inflammatory cytokine gene polymorphisms may influence susceptibility to JSLE. Particular TNFA gene variants are associated with JSLE and could be used as a genetic marker for susceptibility to JSLE. PMID- 26116097 TI - Thyroid Paraganglioma: "Naked" Nuclei as a Clue to Diagnosis on Imprint Cytology. AB - A cytologic diagnosis of paraganglioma of the thyroid is difficult to make because the thyroid gland is an unusual location for such a tumor and the cytologic findings overlap with other benign and malignant thyroid tumors. We report the case of a 28-year-old female presenting with a solitary mass of the right thyroid gland. A diagnosis of paraganglioma was made on the resected specimen. At the time of tumor resection, imprint cytology was performed. The imprint was hypercellular with cohesive sheets of round cells showing anisokaryosis and anisocytosis. Moreover, there was a second cell type consisting of oval nuclei with dispersed nuclear chromatin present within the sheets and separate as "naked" nuclei. By immunohistochemistry, the cohesive round cells were positive for chromogranin A, indicating chief cells. The naked nuclei were positive for S-100 protein, indicating sustentacular cells. To the best our knowledge, this is the first case report describing naked nuclei as a cytologic feature of paraganglioma. Identification of sustentacular cells provides a clue for the cytologic diagnosis of paraganglioma. PMID- 26116098 TI - The changing landscape for HIV-serodifferent couples desiring a child. PMID- 26116099 TI - Validation of metabolomic models for prediction of early-onset preeclampsia. AB - OBJECTIVE: We sought to perform validation studies of previously published and newly derived first-trimester metabolomic algorithms for prediction of early preeclampsia (PE). STUDY DESIGN: Nuclear magnetic resonance-based metabolomic analysis was performed on first-trimester serum in 50 women who subsequently developed early PE and in 108 first-trimester controls. Random stratification and allocation was used to divide cases into a discovery group (30 early PE and 65 controls) for generation of the biomarker model(s) and a validation group (20 early PE and 43 controls) to ensure an unbiased assessment of the predictive algorithms. Cross-validation testing on the different algorithms was performed to confirm their robustness before use. Metabolites, demographic features, clinical characteristics, and uterine Doppler pulsatility index data were evaluated. Area under the receiver operator characteristic curve (AUC), 95% confidence interval (CI), sensitivity, and specificity of the biomarker models were derived. RESULTS: Validation testing found that the metabolite-only model had an AUC of 0.835 (95% CI, 0.769-0.941) with a 75% sensitivity and 74.4% specificity and for the metabolites plus uterine Doppler pulsatility index model it was 0.916 (95% CI, 0.836-0.996), 90%, and 88.4%, respectively. Predictive metabolites included arginine and 2-hydroxybutyrate, which are known to be involved in vascular dilation, and insulin resistance and impaired glucose regulation, respectively. CONCLUSION: We found confirmatory evidence that first-trimester metabolomic biomarkers can predict future development of early PE. PMID- 26116100 TI - Feasibility and technical features of fetal brain magnetic resonance spectroscopy in 1.5 T scanners. PMID- 26116101 TI - Why the heart is like an orchestra and the uterus is like a soccer crowd. AB - The human uterus has no pacemaker or motor innervation, yet develops rhythmic, powerful contractions that increase intrauterine pressure to dilate the cervix and force the fetus through the pelvis. To achieve the synchronous contractions required for labor, the muscle cells of the uterus act as independent oscillators that become increasingly coupled by gap junctions toward the end of pregnancy. The oscillations are facilitated by changes in resting membrane potential that occur as pregnancy progresses. Reductions of potassium channels in the myocyte membranes in late pregnancy prolong myocyte action potentials, further facilitating transmission of signals and recruitment of neighboring myocytes. Late in pregnancy prostaglandin production increases leading to increased myocyte excitability. Also late in pregnancy myocyte actin polymerizes allowing actin myosin interactions that generate force, following myocyte depolarization, calcium entry, and activation of myosin kinase. Labor occurs as a consequence of the combination of increased myocyte to myocyte connectivity, increased depolarizations that last longer, and activated intracellular contractile machinery. During labor the synchronous contractions of muscle cells raise intrauterine pressure to dilate the cervix in a process distinct from peristalsis. The synchronous contractions occur in a progressively larger region of the uterine wall. As the size of the region increases with increasing connectivity, the contraction of that larger area leads to an increase in intrauterine pressure. The resulting increased wall tension causes myocyte depolarization in other parts of the uterus, generating widespread synchronous activity and increased force as more linked regions are recruited into the contraction. The emergent behavior of the uterus has parallels in the behavior of crowds at soccer matches that sing together without a conductor. This contrasts with the behavior of the heart where sequential contractions are regulated by a pacemaker in a similar way to the actions of a conductor and an orchestra. PMID- 26116102 TI - The association between cervical dysplasia, a short cervix, and preterm birth. AB - OBJECTIVE: We sought to determine whether cervical dysplasia in the absence of an excisional procedure is associated with an increased risk of preterm birth (PTB) and whether that risk is independent of the presence of a short cervix. STUDY DESIGN: This is a cohort study including women with a singleton pregnancy who underwent routine cervical length assessment between 18-23 6/7 weeks of gestation, stratified by cervical dysplasia (ie, no prior dysplasia, prior dysplasia but no excisional procedure, or prior excisional procedure). The frequency of a short cervix (<=2.5 cm) and PTB were compared between groups and multivariable analyses were performed to identify whether: (1) dysplasia alone or a prior excisional procedure was associated with PTB; and (2) whether these factors remained independently associated with PTB after adjusting for the presence of a short cervix. RESULTS: Of the 18,528 women who met inclusion criteria, 3023 (16.3%) had prior dysplasia alone and 1356 (7.3%) had a prior excisional procedure. The frequency of a short cervix for women without dysplasia, with prior dysplasia alone, or with a prior excisional procedure was 0.8%, 1.0%, and 2.2%, respectively (P < .001). The frequency of PTB, respectively, was 6.4%, 6.5%, and 8.4% (P < .001). After adjusting for potential confounding factors, prior excisional procedure but not prior dysplasia alone was associated with PTB. CONCLUSION: Having a prior cervical excisional procedure but not dysplasia alone is associated with an increased risk of PTB. This association is independent of the presence of a short cervix. PMID- 26116103 TI - Ultrasound follow up of an adnexal mass has the potential to save lives. AB - Ovarian cancer is among the most dreaded cancers since it is often found at a late stage where the opportunity for extended survival is poor. Ultrasound has been utilized in several ovarian cancer screening trials in asymptomatic women in order to detect ovarian cancer at early stages where survival rates are high. Efforts to improve screening for ovarian cancer are ongoing. While ovarian cancer screening in asymptomatic women is not recommended for clinical application currently, the care of women with adnexal masses found by ultrasound in clinical practice can benefit from close evaluation of the evidence obtained from large prospective ovarian cancer screening trials and by relating this evidence to recent advances in the understanding of different types of ovarian cancer. Post menopausal women who have an adnexal mass discovered by ultrasound have a much higher risk of developing ovarian cancer than women with normal ultrasound. The preponderance of reported evidence indicates that ultrasound monitoring of an adnexal mass is safe, cost effective and can achieve an improved positive predictive value in detecting ovarian cancer when ovarian abnormalities resolve during surveillance. Proposals to arbitrarily discontinue ultrasound monitoring can negatively impact patient care and generate medical-legal actions, especially because there is no evidence to support safe discontinuation. In this review, we outline a rationale for continuing ultrasound surveillance of ovarian abnormalities. PMID- 26116105 TI - Committee approves bill to boost NIH funding. AB - A U.S. House of Representatives committee approved the 21st Century Cures Act. If passed by Congress, the bill would boost funding for the NIH and FDA and introduce new strategies for accelerating the approval of drugs and devices. PMID- 26116106 TI - [A 55-year old Thai male patient with acute right upper quadrant abdominal pain]. AB - We report on a 55-year-old Thai male who presented during a visit to Germany with acute abdominal pain in the right upper quadrant and signs of cholestasis. The diagnosis of liver fluke infection (opisthorchiasis) was confirmed by the detection of the characteristic eggs of Opisthorchis viverrini in stool microscopy. The patient was treated with praziquantel. Opisthorchiasis is a common parasitic disease and major public health problem in Southeast Asia and in Eastern Europe. PMID- 26116107 TI - Detecting functional changes with [(18)F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy. AB - BACKGROUND: The multitargeting tyrosine kinase inhibitor (TKI) sunitinib is currently the first-line drug therapy for metastasizing renal cell carcinoma (RCC). TKIs have profound effects on tumor angiogenesis, leading to modifications of the tumor microenvironment. The goal of this study was to determine whether these treatment-induced changes can be detected with [(18)F]FAZA. METHODS: The present study utilized positron emission tomography (PET) to analyze tumor oxygenation status during and after sunitinib therapy in the murine Caki-1 RCC tumor model. Dynamic and static scans were performed, as well as ex vivo biodistributions at 3 h post injection (p.i.). Immunohistochemical analysis of tumor tissue was carried out for the quantification of pimonidazole binding and the hypoxia-associated factors CD-31, Ki-67, and Von Willebrand factor (VWF). In addition, in vitro cellular uptake studies were done to analyze the direct effects of sunitinib on the Caki-1 cells. RESULTS: During therapy with sunitinib (40 mg/kg/day), uptake of [(18)F]FAZA into Caki-1 mice decreased by 46 +/- 5% (n = 4; 5 days) at 3 h post injection (p.i.) during the first study and 22 +/- 5% (n = 8; 9 days) during the long-term study, indicating a decrease in the tumor's hypoxia level. However, when drug therapy was stopped, this effect was reversed completely, and the tumor [(18)F]FAZA uptake increased to 126 +/- 6% (n = 6) of the control tumor uptake, indicative of an even higher level of tumor hypoxia compared to the therapy starting point. Sunitinib had no direct effect on [(18)F]FAZA uptake into Caki-1 cells in vitro. CONCLUSION: [(18)F]FAZA PET could be used to monitor drug response during sunitinib therapy in RCC and may guide combination therapies based on the tumor's hypoxia status. PMID- 26116108 TI - Evaluation of efficacy of a new MEK inhibitor, RO4987655, in human tumor xenografts by [(18)F] FDG-PET imaging combined with proteomic approaches. AB - BACKGROUND: Inhibition of mitogen-activated protein kinase (MEK, also known as MAPK2, MAPKK), a key molecule of the Ras/MAPK (mitogen-activated protein kinase) pathway, has shown promising effects on B-raf-mutated and some RAS (rat sarcoma) activated tumors in clinical trials. The objective of this study is to examine the efficacy of a novel allosteric MEK inhibitor RO4987655 in K-ras-mutated human tumor xenograft models using [(18)F] FDG-PET imaging and proteomics technology. METHODS: [(18)F] FDG uptake was studied in human lung carcinoma xenografts from day 0 to day 9 of RO4987655 therapy using microPET Focus 120 (CTI Concorde Microsystems, Knoxville, TN, USA). The expression levels of GLUT1 and hexokinase 1 were examined using semi-quantitative fluorescent immunohistochemistry (fIHC). The in vivo effects of RO4987655 on MAPK/PI3K pathway components were assessed by reverse phase protein arrays (RPPA). RESULTS: We have observed modest metabolic decreases in tumor [(18)F] FDG uptake after MEK inhibition by RO4987655 as early as 2 h post-treatment. The greatest [(18)F] FDG decreases were found on day 1, followed by a rebound in [(18)F] FDG uptake on day 3 in parallel with decreasing tumor volumes. Molecular analysis of the tumors by fIHC did not reveal statistically significant correlations of GLUT1 and hexokinase 1 expressions with the [(18)F] FDG changes. RPPA signaling response profiling revealed not only down regulation of pERK1/2, pMKK4, and pmTOR on day 1 after RO4987655 treatment but also significant up-regulation of pMEK1/2, pMEK2, pC-RAF, and pAKT on day 3. The up-regulation of these markers is interpreted to be indicative of a reactivation of the MAPK and activation of the compensatory PI3K pathway, which can also explain the rebound in [(18)F] FDG uptake following MEK inhibition with RO4987655 in the K-ras-mutated human tumor xenografts. CONCLUSIONS: We have performed the first preclinical evaluation of a new MEK inhibitor, RO4987655, using a combination of [(18)F] FDG-PET imaging and molecular proteomics. These results provide support for using preclinical [(18)F] FDG-PET imaging in early, non invasive monitoring of the effects of MEK and perhaps other Ras/MAPK signaling pathway inhibitors, which should facilitate a wider implementation of clinical [(18)F] FDG-PET to optimize their clinical use. PMID- 26116109 TI - Feasibility and advantage of adding (131)I-MIBG to (90)Y-DOTATOC for treatment of patients with advanced stage neuroendocrine tumors. AB - BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an effective form of treatment for patients with metastatic neuroendocrine tumors (NETs). However, delivering sufficient radiation dose to the tumor to result in a high percentage of long-term tumor remissions remains challenging because of the limits imposed on administered activity levels by radiation damage to normal tissues. The goal of this study was to evaluate the dosimetric advantages of adding (131)I meta iodobenzylguanidine ((131)I-MIBG) to (90)Y DOTA Phe1-Tyr3-octreotide ((90)Y DOTATOC) in patients with advanced stage midgut NETs. METHODS: Ten patients were imaged simultaneously with (131)I-MIBG and (111)In-pentetreotide (as a surrogate for (90)Y-DOTATOC) on days 1, 2, and 3 post-administration. Blood samples were obtained at the same time points. Using dosimetry measures from this data and our previously published methodology for calculating optimal combined administered activity levels for therapy, we determined the amount of (131)I-MIBG that could be added to (90)Y-DOTATOC without exceeding normal organ dose limits (marrow and kidneys) along with the expected increase in associated tumor dose, if any. RESULTS: We found that a median value of 34.6 GBq of (131)I-MIBG could be safely added to (90)Y-DOTATOC (delivered over multiple cycles) by reducing the maximum total deliverable (90)Y-DOTATOC by a median value of 24.5%. Taking this treatment approach, we found that there would be a median increase in deliverable tumor dose of 4,046 cGy in six of the ten subjects. Of note, there were a small number of metastases that were positive for only one or the other of these radiopharmaceuticals within the same subject. CONCLUSIONS: We conclude that approximately half of the patients with midgut NETs that are eligible for PRRT could reasonably be expected to benefit from the addition of (131)I-MIBG to (90)Y DOTATOC. PMID- 26116110 TI - Multiparametric magnetic resonance in the assessment of the gender differences in a high-grade glioma rat model. AB - BACKGROUND: Glioblastoma, the most frequent and aggressive of all astrocytomas, presents a clear predominance in male humans, but the assessment of sexual differences in its tumourigenesis and growth has received little attention so far. In this study, we aim to identify gender-dependent surrogate markers in an animal model of this cancer by means of magnetic resonance (MR) imaging and biochemical and behavioural studies. METHODS: A high-grade glioma model developed in male and female rats was used. Multiparametric magnetic resonance images and localized spectra were acquired. The MR parameters linked to tumoural features were quantified. Motor and metabolic activity was also assessed. Postmortem analyses were carried out to measure indicators of malignancy, tumoural metabolism and viability of the blood-brain barrier (BBB). RESULTS: Statistically significant differences dependent on the animal sex were found in the study of pathological indicators like oedema, inflammation, cellularity and microvasculature. Results suggest higher cell proliferative rate, inflammation and vasogenic oedema and or necrosis in glioma-bearing male rats. Haemodynamic parameters measured indicated a major disruption of the BBB, postmortem confirmed, in this sex. Metabolomic and energetic metabolism activity data are in agreement with a major malignancy and aggressiveness of this cancer model on males. CONCLUSIONS: Gender differences should be taken into account in preclinical studies of glioblastoma models, in the characterization of the tumoural behaviour and consequently in the development and validation of new therapeutic approaches. MR imaging and spectroscopy allow to non-invasively monitor this sexual dimorphism in the diagnosis and prognosis of brain cancer. PMID- 26116111 TI - Therapeutic application of CCK2R-targeting PP-F11: influence of particle range, activity and peptide amount. AB - BACKGROUND: Targeted radionuclide therapy with high-energy beta-emitters is generally considered suboptimal to cure small tumours (<300 mg). Tumour targeting of the CCK2 receptor-binding minigastrin analogue PP-F11 was determined in a tumour-bearing mouse model at increasing peptide amounts. The optimal therapy was analysed for PP-F11 labelled with (90)Y, (177)Lu or (213)Bi, accounting for the radionuclide specific activities (SAs), the tumour absorbed doses and tumour (radio) biology. METHODS: Tumour uptake of (111)In-PP-F11 was determined in nude mice bearing CCK2 receptor-transfected A431 xenografts at 1 and 4 h post injection for escalating peptide masses of 0.03 to 15 nmol/mouse. The absorbed tumour dose was estimated, assuming comparable biodistributions of the (90)Y, (177)Lu or (213)Bi radiolabelled peptides. The linear-quadratic (LQ) model was used to calculate the tumour control probabilities (TCP) as a function of tumour mass and growth. RESULTS: Practically achievable maximum SAs for PP-F11 labelled with (90)Y and (177)Lu were 400 MBq (90)Y/nmol and 120 MBq(177)Lu/nmol. Both the large elution volume from the 220 MBq (225)Ac generator used and reaction kinetics diminished the maximum achieved (213)Bi SA in practice: 40 MBq (213)Bi/nmol. Tumour uptakes decreased rapidly with increasing peptide amounts, following a logarithmic curve with ED50 = 0.5 nmol. At 0.03 nmol peptide, the (300 mg) tumour dose was 9 Gy after 12 MBq (90)Y-PP-F11, and for (111)In and (177)Lu, this was 1 Gy. A curative dose of 60 Gy could be achieved with a single administration of 111 MBq (90)Y labelled to 0.28 nmol PP-F11 or with 4 * 17 MBq (213)Bi (0.41 nmol) when its alpha-radiation relative biological effectiveness (RBE) was assumed to be 3.4. Repeated dosing is preferable to avoid complete tumour receptor saturation. Tumours larger than 200 mg are curable with (90)Y-PP F11; the other radionuclides perform better in smaller tumours. Furthermore, (177)Lu is not optimal for curing fast-growing tumours. CONCLUSIONS: Receptor saturation, specific radiopharmaceutical activities and absorbed doses in the tumour together favour therapy with the CCK2 receptor-binding peptide PP-F11 labelled with (90)Y, despite its longer beta-particle range in tissue, certainly for tumours larger than 300 mg. The predicted TCPs are of theoretical nature and need to be compared with the outcome of targeted radionuclide experiments. PMID- 26116112 TI - Heterogeneity of microsphere distribution in resected liver and tumour tissue following selective intrahepatic radiotherapy. AB - BACKGROUND: Selective arterial radioembolisation of liver tumours has increased, because of encouraging efficacy reports; however, therapeutic parameters used in external beam therapy are not applicable for understanding and predicting potential toxicity and efficacy, necessitating further studies of the physical and biological characteristics of radioembolisation. The aim was to characterise heterogeneity in the distribution of microspheres on a therapeutically relevant geometric scale considering the range of yttrium-90 ((90)Y) beta-particles. METHODS: Two patients with intrahepatic cholangiocarcinoma, marginally resectable, were treated by selective arterial embolisation with (90)Y resin microspheres (SIRTEX(r)), followed 9 days post-infusion by resection, including macroscopic tumour tissue and surrounding normal liver parenchyma. Formalin fixed, sectioned resected tissues were exposed to autoradiographic films, or tissue biopsies of various dimensions were punched out for activity measurements and microscopy. RESULTS: Autoradiography and activity measurements revealed a higher activity in tumour tissue compared to normal liver parenchyma. Heterogeneity in activity distribution was evident in both normal liver and tumour tissue. Activity measurements were analysed in relation to the sample mass (5 to 422 mg), and heterogeneities were detected by statistical means; the larger the tissue biopsies, the smaller was the coefficient of variation. The skewness of the activity distributions increased with decreasing biopsy mass. CONCLUSIONS: The tissue activity distributions in normal tissue were heterogeneous on a relevant geometric scale considering the range of the ionising electrons. Given the similar and repetitive structure of the liver parenchyma, this finding could partly explain the tolerance of a relatively high mean absorbed dose to the liver parenchyma from beta-particles. PMID- 26116113 TI - The effect of volume of interest definition on quantification of lymph node immune response to a monkeypox virus infection assessed by (18)F-FDG-PET. AB - BACKGROUND: 2-deoxy-2-[(18)F]fluoro-D-glucose-positron emission tomography ((18)F FDG-PET) is applied in the clinic for infection assessment and is under consideration for investigating the inflammatory/immune response in lymphoid tissue in animal models of viral infection. Assessing changes in (18)F-FDG uptake of lymph nodes (LNs), primary lymphoid tissues targeted during viral infection, requires suitable methods for image analysis. Similar to tumor evaluation, reliable quantitation of the LN function via multiple (18)F-FDG-PET sessions will depend how the volume of interest is defined. Volume of interest definition has a direct effect on statistical outcome. The current study objective is to compare for the first time agreement between conventional and modified VOI metrics to determine which method(s) provide(s) reproducible standardized uptake values (SUVs) for (18)F-FDG uptake in the LN of rhesus macaques. METHODS: Multiple (18)F FDG-PET images of LNs in macaques were acquired prior to and after monkeypox virus intravenous inoculation. We compared five image analysis approaches, SUVmax, SUVmean, SUVthreshold, modified SUVthreshold, and SUVfixed volume, to investigate the impact of these approaches on quantification of the changes in LN metabolic activity denoting the immune response during viral infection progression. RESULTS: The lowest data repeatability was observed with SUVmax. The best correspondence was between SUVfixed volume and conventional and modified SUVthreshold. A statistically significant difference in the LN (18)F-FDG uptake between surviving and moribund animals was shown using modified SUVthreshold and SUVfixed volume (adjusted p = 0.0037 and p = 0.0001, respectively). CONCLUSIONS: Quantification of the LN (18)F-FDG uptake is highly sensitive to the method applied for PET image analysis. SUVfixed volume and modified SUVthreshold demonstrate better reproducibility for SUV estimates than SUVmax, SUVmean, and SUVthreshold. SUVfixed volume and modified SUVthreshold are capable of distinguishing between groups with different disease outcomes. Therefore, these methods are the preferred approaches for evaluating the LN function during viral infection by (18)F-FDG-PET. Validation of multiple approaches is necessary to choose a suitable method to monitor changes in LN metabolic activity during progression of viral infection. PMID- 26116114 TI - Identification of positron emission tomography (PET) tracer candidates by prediction of the target-bound fraction in the brain. AB - BACKGROUND: Development of tracers for imaging with positron emission tomography (PET) is often a time-consuming process associated with considerable attrition. In an effort to simplify this process, we herein propose a mechanistically integrated approach for the selection of tracer candidates based on in vitro measurements of ligand affinity (Kd), non-specific binding in brain tissue (Vu,brain), and target protein expression (Bmax). METHODS: A dataset of 35 functional and 12 non-functional central nervous system (CNS) PET tracers was compiled. Data was identified in literature for Kd and Bmax, whereas a brain slice methodology was used to determine values for Vu,brain. A mathematical prediction model for the target-bound fraction of tracer in the brain (ftb) was derived and evaluated with respect to how well it predicts tracer functionality compared to traditional PET tracer candidate selection criteria. RESULTS: The methodology correctly classified 31/35 functioning and 12/12 non-functioning tracers. This predictivity was superior to traditional classification criteria or combinations thereof. CONCLUSIONS: The presented CNS PET tracer identification approach is rapid and accurate and is expected to facilitate the development of novel PET tracers for the molecular imaging community. PMID- 26116115 TI - Preclinical imaging of kallikrein-related peptidase 2 (hK2) in prostate cancer with a (111)In-radiolabelled monoclonal antibody, 11B6. AB - BACKGROUND: Prostate cancer is a leading cause of death in the male population of the western world. Human kallikrein-related peptidase 2 (hK2) is abundantly expressed in malignant prostatic tissue, and its gene, KLK2, is regulated by the androgen receptor. 11B6 is a murine IgG1 monoclonal antibody directed against free human hK2. In this study, we performed a preclinical evaluation of (111)In labelled 11B6 in mouse xenografts to investigate its potential in the clinical staging and assessment of metastatic prostate cancer. METHODS: 11B6 was radiolabelled with (111)In through CHX-A"-DTPA chelation. In vivo biodistribution and uptake of (111)In-DTPA-11B6 were measured until 168 h post-injection in NMRI nude mice bearing subcutaneous LNCaP xenografts. The binding specificity to hK2 was evaluated by both in vivo competitive binding assays with excess non-labelled 11B6 and hK2-negative DU145 xenografts. SPECT/CT imaging of subcutaneous and intra-tibial LNCaP xenografts was used to visualize the tumours. RESULTS: Tumour uptake of (111)In-DTPA-11B6 in LNCaP xenografts was 19% +/- 0.78%IA/g at 48 h, giving a tumour-to-blood ratio of 1.6, which increases to 2.4 at 1 week post injection. Accumulation was low in other organs except for the salivary glands, which is probably the result of cross-reactivity with mouse kallikreins. Significantly lower tumour accumulation was observed in competitive assays and DU145 xenografts. SPECT/CT imaging could clearly visualize the subcutaneous and intra-tibial LNCaP xenografts. CONCLUSIONS: Our study demonstrates the potential of (111)In-DTPA-11B6 for the detection of metastatic prostate cancer and monitoring anti-androgen therapy, as it exhibits an increased uptake and accumulation in viable tumour when compared to normal tissue. A humanised version of the 11B6 monoclonal antibody is currently under evaluation. PMID- 26116116 TI - Quantification of [(11)C]-meta-hydroxyephedrine uptake in human myocardium. AB - BACKGROUND: The aims of this study were to determine the optimal tracer kinetic model for [(11)C]-meta-hydroxyephedrine ([(11)C]HED) and to evaluate the performance of several simplified methods. METHODS: Thirty patients underwent dynamic 60-min [(11)C]HED scans with online arterial blood sampling. Single tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (V T) data. RESULTS: The reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, V T derived using the single-tissue model correlated highly with that of the two-tissue model (r (2) = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in V T. RI and SUV can provide misleading results because of non-linear relationships with V T. CONCLUSIONS: Although the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with V T, and therefore, care has to be taken when using RI as a quantitative measure. PMID- 26116117 TI - Paclitaxel improved anti-L1CAM lutetium-177 radioimmunotherapy in an ovarian cancer xenograft model. AB - BACKGROUND: Today's standard treatment of advanced-stage ovarian cancer, including surgery followed by a paclitaxel-platinum-based chemotherapy, is limited in efficacy. Recently, we could show that radioimmunotherapy (RIT) with (177)Lu-labelled anti-L1 cell adhesion molecule (L1CAM) monoclonal antibody chCE7 is effective in ovarian cancer therapy. We investigated if the efficacy of anti L1CAM RIT can be further improved by its combination with paclitaxel (PTX). METHODS: In vitro cell viability and cell cycle arrest of human ovarian cancer cells were assessed upon different treatment conditions. For therapy studies, nude mice (n = 8) were injected subcutaneously with IGROV1 human ovarian carcinoma cells and received a single dose of 6 MBq (177)Lu-DOTA-chCE7 alone or in combination with 600 MUg PTX (31.6 mg/kg). Tumour growth delay and survival were determined. To investigate whether PTX can influence the tumour uptake of the radioimmunoconjugates (RICs), a biodistribution study (n = 4) and SPECT/CT images were acquired 120 h post injections of 2 MBq (177)Lu-DOTA-chCE7 alone or in combination with 600 MUg PTX. RESULTS: Lu-DOTA-chCE7 in combination with PTX revealed a significantly decreased cell viability of ovarian carcinoma cells in vitro and was effective in a synergistic manner (combination index < 1). PTX increased the RIT efficacy by arresting cells in the radiosensitive G2/M phase of the cell cycle 24 h post treatment start. In vivo combination therapy including (177)Lu-DOTA-chCE7 and PTX resulted in a significantly prolonged overall survival (55 days vs. 18 days/PTX and 29 days/RIT), without weight loss and/or signs of toxicity. Biodistribution studies revealed no significant difference in tumour uptakes of (177)Lu-DOTA-chCE7 72 h post injection regardless of an additional PTX administration. CONCLUSIONS: Combination of anti-L1CAM (177)Lu-RIT with PTX is a more effective therapy resulting in a prolonged overall survival of human ovarian carcinoma-bearing nude mice compared with either monotherapy. The combination is promising for future clinical applications. PMID- 26116118 TI - (11)C-acetate PET/CT in pre-therapeutic lymph node staging in high-risk prostate cancer patients and its influence on disease management - a retrospective study. AB - BACKGROUND: Radiation treatment with simultaneous integrated boost against suspected lymph node metastases may be a curative therapeutic option in patients with high-risk prostate cancer (>15% estimated risk of pelvic lymph node metastases according to the Cagiannos nomogram). (11)C-acetate positron emission tomography/computed tomography (PET/CT) can be used for primary staging as well as for detection of suspected relapse of prostate cancer. The aims of this study were to evaluate the association between positive (11)C-acetate PET/CT findings and the estimated risk of pelvic lymph node metastases and to assess the impact of (11)C-acetate PET/CT on patient management in high-risk prostate cancer patients. METHODS: Fifty consecutive prostate cancer patients referred for primary staging with (11)C-acetate PET/CT prior to radiotherapy with curative intention were enrolled in this retrospective study. RESULTS: All patients showed increased (11)C-acetate uptake in the prostate. Pelvic lymph node uptake was seen in 42% (21/50) of the patients, with positive external iliac lymph nodes in 71% (15/21) of these. The overall observed proportion of PET/CT-positive pelvic lymph nodes at patient level was higher than the average estimated risk, especially in low-risk groups (<15%). There was a significant association between observed proportion and estimated risk of pelvic lymph node metastases in groups with <=45 and >45% estimated risk. Treatment strategy was altered due to (11)C-acetate PET/CT findings in 43% (20/47) of the patients. CONCLUSIONS: The observed proportion of (11)C-acetate PET/CT findings suggestive of locoregional metastases was higher than the estimated risk, suggesting that the Cagiannos nomogram underestimates the risk for metastases. The imaging results with (11)C-acetate PET/CT have a considerable impact on patient management. PMID- 26116119 TI - Potential of (99m)Tc-MIBI SPECT imaging for evaluating non-alcoholic steatohepatitis induced by methionine-choline-deficient diet in mice. AB - BACKGROUND: Hepatic mitochondrial dysfunction has been implicated in pathological conditions leading to non-alcoholic steatohepatitis (NASH). Technetium-99 m-2 methoxyisobutyl-isonitrile ((99m)Tc-MIBI), a lipophilic cationic myocardial perfusion agent, is retained in the mitochondria depending on membrane potential. The aim of this study was to investigate the feasibility of (99m)Tc-MIBI for evaluating the hepatic mitochondrial dysfunction induced by methionine-choline deficient (MCD) diet in mice. METHODS: Male C57Black6J/jcl mice were fed a MCD diet for up to 4 weeks. SPECT scan (N =6) with (99m)Tc-MIBI was performed at 2 and 4 weeks after MCD diet. Mice were imaged with small-animal SPECT/CT under isoflurane anesthesia. Radioactivity concentrations of the liver were measured, and the time of maximum (T max) and the elimination half-life (T 1/2) were evaluated. After SPECT scan, liver histopathology was analyzed to evaluate steatosis and inflammation. Non-alcoholic fatty liver disease (NAFLD) activity score was obtained from the histological score of hepatic steatosis and inflammation. Blood biochemistry and hepatic ATP content were also measured (N =5 to 6). RESULTS: Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly elevated at 2 and 4 weeks after MCD diet. A decrease in hepatic ATP content was also observed in MCD-fed mice. (99m)Tc-MIBI SPECT imaging clearly showed the decrease of hepatic (99m)Tc-MIBI retention in MCD-fed mice compared to control mice. T 1/2 after (99m)Tc-MIBI injection was significantly decreased in the liver of MCD-fed mice (control, MCD 2 weeks, and MCD 4 weeks, T 1/2 = 57.6, 37.6, and 19.8 min, respectively), although no change in T max was observed in MCD-fed mice. SPECT data and histological score showed that the negative correlation (r = -0.74, p <0.05) between T 1/2 and NAFLD activity score was significant. CONCLUSIONS: Hepatic (99m)Tc-MIBI elimination was increased with increase in NAFLD activity score (NAS) in mice fed MCD diet for 2 and 4 weeks. These results suggest that (99m)Tc MIBI SPECT imaging might be useful for detecting hepatic mitochondrial dysfunction induced by steatosis and inflammation such as NAFLD or NASH. PMID- 26116120 TI - Evaluation of retinol binding protein 4 and carbamoylated haemoglobin as potential renal toxicity biomarkers in adult mice treated with (177)Lu octreotate. AB - BACKGROUND: The kidneys are regarded as one of the main dose-limiting organs in the treatment of neuroendocrine tumours with (177)Lu-[DOTA(0), Tyr(3)]-octreotate ((177)Lu-octreotate), despite the successful use of kidney uptake blocking agents such as lysine and arginine. To avoid renal toxicity but still give each patient as high amount of (177)Lu-octreotate as possible, there is a need for methods/biomarkers that indicate renal injury in an early stage of the treatment. The aim of this study was to investigate the potential of using urinary retinol binding protein 4 (RBP4) and carbamoylated haemoglobin (Hb) in blood as biomarkers of nephrotoxic effects on adult mice after (177)Lu-octreotate treatment. METHODS: Adult BALB/c nude mice were injected with 60 MBq or 120 MBq of (177)Lu-octreotate or with saline (control). Urine was collected before injection and concentrations of urinary RBP4 and creatinine were determined 14 to 90 days after injection Blood samples were collected after 90 days, and carbamoylated N-terminal valine in Hb, formed from urea, was measured as valine hydantoin (VH) after detachment from Hb. RESULTS: The RBP4 values increased with administered activity and time. For the 60 and 120 MBq groups, statistically significantly higher RBP4 levels (p <0.05) were found at day 60 and 90 compared to baseline, also at day 30 for 120 MBq group. For VH, the mean values were similar for the 60 MBq and control groups, while a small increase was observed for the 120 MBq group; but there were no statistically significant differences between any of the groups (p >0.05). No morphological changes in the kidney tissue were found. CONCLUSIONS: Urinary RBP4 is a promising new biomarker for radiation-induced renal toxicity. For the conditions used in this experiment, carbamoylated Hb (from urea) measured as VH may not be a sufficiently sensitive biomarker to be used for renal toxicity. TRIAL REGISTRATION: ID 326-2008. PMID- 26116121 TI - Immuno-PET of epithelial ovarian cancer: harnessing the potential of CA125 for non-invasive imaging. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is characterized by the overexpression of cancer antigen 125 (CA125), a mucinous glycoprotein that serves as a tumor biomarker. Early diagnosis of EOC is plagued by its asymptomatic nature of progression and the limitations of currently used immunoassay techniques that detect CA125 as a shed antigen in serum samples. Presently, there is no technique available for the in vivo evaluation of CA125 expression in malignant tissues. Moreover, there could be an unexplored pathophysiological time window for the detection of CA125 in EOC, during which it is expressed on tumor cells prior to being shed into the bloodstream. A method for the in vivo evaluation of CA125 expression on ovarian neoplasms earlier along disease progression and/or recurrence can potentially contribute to better disease management. To this end, the present work utilizes an anti-CA125 monoclonal antibody (MAb) and a single-chain variable fragment (scFv) labeled with the positron-emitting radionuclide (64)Cu for preclinical molecular imaging of CA125 expression in vivo. METHODS: Anti-CA125 MAb and scFv were prepared and functionally characterized for target binding prior to being tested as radiotracers in a preclinical setting. RESULTS: Immunoblotting, immunofluorescence, and flow cytometry revealed specific binding of CA125 targeting vectors to NIH:OVCAR-3 cells and no binding to antigen-negative SKOV3 cells. (64)Cu-labeled anti-CA125 MAb and scFv were obtained in specific activities of 296 and 122 MBq/mg, respectively. Both radioimmunoconjugate vectors demonstrated highly selective binding to NIH:OVCAR-3 cells and virtually no binding to SKOV3 cells. In vivo radiopharmacological evaluation using xenograft mouse models injected with (64)Cu-labeled anti-CA125 MAb provided a standardized uptake value (SUV) of 5.76 (29.70 %ID/g) in OVCAR3 tumors 24 h post-injection (p.i.) versus 1.80 (5.91 %ID/g) in SKOV3 tumors. (64)Cu-labeled anti-CA125 scFv provided an SUV of 0.64 (3.21 %ID/g) in OVCAR3 tumors 24 h p.i. versus 0.25 (1.49 %ID/g) in SKOV3 tumors. Results from small-animal PET imaging were confirmed by ex vivo autoradiography and immunohistochemistry. CONCLUSIONS: Radiolabeling of anti-CA125 MAb and scFv with (64)Cu did not compromise their immunoreactivity. Both radioimmunoconjugates presented specific tumor uptake and expected biological clearance profiles. This renders them as potential immuno-PET probes for targeted in vivo molecular imaging of CA125 in EOC. PMID- 26116122 TI - In vivo bioluminescence imaging for viable human neural stem cells incorporated within in situ gelatin hydrogels. AB - BACKGROUND: Three-dimensional (3D) hydrogel-based stem cell therapies contribute to enhanced therapeutic efficacy in treating diseases, and determining the optimal mechanical strength of the hydrogel in vivo is important for therapeutic success. We evaluated the proliferation of human neural stem cells incorporated within in situ-forming hydrogels and compared the effect of hydrogels with different elastic properties in cell/hydrogel-xenografted mice. METHODS: The gelatin-polyethylene glycol-tyramine (GPT) hydrogel was fabricated through enzyme mediated cross-linking reaction using horseradish peroxidase (HRP) and hydrogen peroxide (H2O2). RESULTS: The F3-effluc encapsulated within a soft 1,800 pascal (Pa) hydrogel and stiff 5,800 Pa hydrogel proliferated vigorously in a 24-well plate until day 8. In vitro and in vivo kinetics of luciferase activity showed a slow time-to-peak after D-luciferin administration in the stiff hydrogel. When in vivo proliferation of F3-effluc was observed up to day 21 in both the hydrogel group and cell-only group, F3-effluc within the soft hydrogel proliferated more vigorously, compared to the cells within the stiff hydrogel. Ki-67-specific immunostaining revealed highly proliferative F3-effluc with compactly distributed cell population inside the 1,800 Pa or 5,800 Pa hydrogel. CONCLUSIONS: We examined the in vivo effectiveness of different elastic types of hydrogels encapsulating viable neural stem cells by successfully monitoring the proliferation of implanted stem cells incorporated within a 3D hydrogel scaffold. PMID- 26116123 TI - Strategy to develop a MAO-A-resistant 5-hydroxy-L-[beta-(11)C]tryptophan isotopologue based on deuterium kinetic isotope effects. AB - BACKGROUND: The serotonin precursor 5-hydroxy-L-[beta-(11)C]tryptophan ([(11)C]HTP) is in clinical use for localization of neuroendocrine tumors and has been suggested as a proxy marker for pancreatic islet cells. However, degradation by monoamine oxidase-A (MAO-A) reduces retention and the contrast to non endocrine tissue. METHODS: A synthesis method was developed for 5-hydroxy-L-[beta (11)C(2)H]tryptophan ([(11)C]DHTP), an isotopologue of [(11)C]HTP, labeled with (11)C and (2)H at the beta-position adjacent to the carbon involved in MAO-A decarboxylation. MAO-A-mediated degradation of [(11)C]DHTP was evaluated and compared to non-deuterated [(11)C]HTP. RESULTS: [(11)C]DHTP was synthesized with a radiochemical purity of >98%, radioactivity of 620 +/- 190 MBq, and deuterium ((2)H or (2)H2) incorporation at the beta-position of 22% +/-5%. Retention and resistance to MAO-A-mediated degradation of [(11)C]DHTP were increased in cells but not in non-human primate pancreas. CONCLUSIONS: Partial deuteration of the beta-position yields improved resistance to MAO-A-mediated degradation in vitro but not in vivo. PMID- 26116124 TI - Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. AB - BACKGROUND: Due to its high expression in prostate cancer, PSMA (prostate specific membrane antigen) represents an ideal target for both diagnostic imaging and endoradiotherapeutic approaches. Based on a previously published highly specific PSMA ligand ([(68)Ga]DOTA-FFK(Sub-KuE)), we developed a corresponding metabolically stable 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10 triacetic acid (DOTAGA) construct for theranostic treatment of prostate cancer. METHODS: All ligands were synthesized by a combined solid phase and solution phase synthesis strategy. The affinity of the (nat)gallium and lutetium complexes to PSMA and the internalization efficiency of the radiotracers were determined on PSMA-expressing LNCaP cells. The (68)Ga- and (177)Lu-labelled ligands were further investigated for lipophilicity, binding specificity, metabolic stability, as well as biodistribution and MUPET in LNCaP-tumour-bearing mice. RESULTS: Radiochemical yields for (68)Ga (3 nmol, 5.0 M NaCl/2.7 M HEPES (approximately 5/1), pH 3.5 to 4.5, 5 min, 95 degrees C) and (177)Lu labelling (0.7 nmol, 0.1 M NH4OAc, pH 5.5, 30 min, 95 degrees C) were almost quantitative, resulting in specific activities of 250 to 300 GBq/MUmol for the (68)Ga analogues and 38 GBq/MUmol for (177)Lu complexes. Due to metabolic instability of L-amino acid spacers, D-amino acids were implemented resulting in a metabolically stable DOTAGA ligand. Compared to the DOTA ligand, the DOTAGA derivatives showed higher hydrophilicity (logP = -3.6 +/- 0.1 and -3.9 +/- 0.1 for (68)Ga and (177)Lu, respectively) and improved affinity to PSMA resulting in an about twofold increased specific internalization of the (68)Ga- and (177)Lu-labelled DOTAGA analogue. Especially, [(68)Ga]DOTAGA-ffk(Sub-KuE) exhibits favourable pharmacokinetics, low unspecific uptake and high tumour accumulation in LNCaP tumour-bearing mice. CONCLUSIONS: The pair of diagnostic/therapeutic PSMA-ligands [(68)Ga/(177)Lu]DOTAGA-ffk(Sub-KuE) possess remarkable potential for the management of prostate cancer. PMID- 26116125 TI - ABC transporter-dependent brain uptake of the 5-HT1B receptor radioligand [ (11)C]AZ10419369: a comparative PET study in mouse, rat, and guinea pig. AB - BACKGROUND: We have explored the possibility that the serotonin 1B receptor radioligand [(11)C]AZ10419369 is a substrate for adenosine triphosphate (ATP) binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), Mrp4, and Bcrp, in rodents and whether there is a species difference regarding its blood brain barrier (BBB) penetration. METHODS: In a series of preclinical positron emission tomography measurements, we have administered [(11)C]AZ10419369 to mice, rats, and guinea pigs under baseline conditions and, on separate experimental days, after administration of the ABC transporter inhibitor, cyclosporin A (CsA). RESULTS: During baseline conditions, the brain uptake was low in mice and rats, but not in guinea pigs. After CsA pretreatment, the peak whole brain uptake values of [(11)C]AZ10419369 increased by 207% in mice, 94% in rats, and 157% in guinea pigs. Binding potentials (BPND) could not be estimated during baseline conditions in mice and rats. After CsA pretreatment, the highest BPND values were obtained in the striatum and thalamus (BPND ~ 0.4) in mice, while in rats, the highest binding areas were the striatum, thalamus, hypothalamus, and periaqueductal gray (BPND ~ 0.5). In guinea pigs, we did not find any significant changes in BPND between baseline and CsA pretreatment, except in the striatum. CONCLUSIONS: The results indicate that BBB penetration of [(11)C]AZ10419369 was hindered by ABC transporter activity in mouse, rat, and guinea pig. This study highlights the importance of ABC transporters in the design of preclinical positron emission tomography (PET) studies. PMID- 26116126 TI - An evaluation of the brain distribution of [(11)C]GSK1034702, a muscarinic-1 (M 1) positive allosteric modulator in the living human brain using positron emission tomography. AB - BACKGROUND: The ability to quantify the capacity of a central nervous system (CNS) drug to cross the human blood-brain barrier (BBB) provides valuable information for de-risking drug development of new molecules. Here, we present a study, where a suitable positron emission tomography (PET) ligand was not available for the evaluation of a potent muscarinic acetylcholine receptor type-1 (M1) allosteric agonist (GSK1034702) in the primate and human brain. Hence, direct radiolabelling of the novel molecule was performed and PET measurements were obtained and combined with in vitro equilibrium dialysis assays to enable assessment of BBB transport and estimation of the free brain concentration of GSK1034702 in vivo. METHODS: GSK1034702 was radiolabelled with (11)C, and the brain distribution of [(11)C]GSK1034702 was investigated in two anaesthetised baboons and four healthy male humans. In humans, PET scans were performed (following intravenous injection of [(11)C]GSK1034702) at baseline and after a single oral 5-mg dose of GSK1034702. The in vitro brain and plasma protein binding of GSK1034702 was determined across a range of species using equilibrium dialysis. RESULTS: The distribution of [(11)C]GSK1034702 in the primate brain was homogenous and the whole brain partition coefficient (V T) was 3.97. In contrast, there was mild regional heterogeneity for GSK1034702 in the human brain. Human whole brain V T estimates (4.9) were in broad agreement with primate V T and the f P/f ND ratio (3.97 and 2.63, respectively), consistent with transport by passive diffusion across the BBB. CONCLUSION: In primate and human PET studies designed to evaluate the transport of a novel M1 allosteric agonist (GSK1034702) across the BBB, we have demonstrated good brain uptake and BBB passage consistent with passive diffusion or active influx. These studies discharged some of the perceived development risks for GSK1034702 and provided information to progress the molecule into the next stage of clinical development. TRIAL REGISTRATION: Clinical trial details: 'Brain Uptake of GSK1034702: a Positron Emission Tomography (PET) Scan Study.'; clinicaltrial.gov identifier: NCT00937846 . PMID- 26116127 TI - Factors affecting the stability and repeatability of gamma camera calibration for quantitative imaging applications based on a retrospective review of clinical data. AB - BACKGROUND: Absolute quantitative single-photon emission computed tomography (SPECT) has several important applications including monitoring tumor response after treatment and dose estimation for targeted radionuclide therapy treatment planning. Obtaining quantitative SPECT images in absolute activity units requires the use of a calibration factor, and the repeatability of this directly affects the repeatability of image quantification. This study focused on evaluating the factors affecting the repeatability of a calibration factor measured using a planar image of an in-air calibration source. METHODS: The calibration factors calculated as part of (131)I-tositumomab patient dosimetry scans used in treatment planning performed over a 4-year period were retrospectively analyzed. Raw data included total counts in whole-body images of a radioactive calibration source, the activity of the source measured in a radionuclide activity meter (often referred to as a dose calibrator), and the background count rate obtained at three time points for each patient. The count rate from extrinsic flood source acquisitions and radionuclide activity meter constancy obtained on the same day as each image were also used. The data were analyzed statistically using a mixed effects model to determine the factors affecting variations in the measured calibration factors. RESULTS: The global variability in the calibration factor was equal to 2.3% and was decreased by 20% to 1.8%, when the decay-corrected measurements of calibration source activity were averaged over the three time points for each patient. Camera sensitivity variation measured using a (57)Co sheet source was small and had a weak relationship to calibration factor variations. When the averaged source activity was used, the main source of variance was related to preparation and measurement of the source (77%). Radionuclide activity meter constancy had a smaller but statistically significant impact on the calibration factor. CONCLUSIONS: This study indicates that calibration factors based on planar measurements have good reproducibility. The findings of this study indicate (1) the importance of accurate and precise preparation and measurement of the calibration source activity, (2) the need to carefully control background activity during calibration factor assessment and patient data acquisition, and (3) that the calibration factor and camera sensitivity were stable over time, indicating that careful but less frequent calibration is needed. PMID- 26116128 TI - Toxicity and radiation dosimetry studies of the serotonin transporter radioligand [(18) F]AFM in rats and monkeys. AB - BACKGROUND: [(18) F]AFM is a potent and promising PET imaging agent for the serotonin transporter. We carried out an acute toxicity study in rats and radiation dosimetry in monkeys before the translation of the tracer to humans. METHODS: Single- and multiple-dose toxicity studies were conducted in Sprague Dawley rats. Male and female rats were injected intravenously with AFM tartrate as a single dose of 98.7 or 987 MUg/kg (592 or 5,920 MUg/m(2), 100* or 1,000* the proposed human dose of 8 MUg, respectively) on day 1 or as five consecutive daily doses of 98.7 MUg/kg/day (592 MUg /m(2)/day, 100* human dose, total dose 493.5 MUg/kg). PET/CT scans were performed in four Formosan rock monkeys (two males and two females, each monkey scanned twice) using a Siemens BIOGRAPH scanner. After injection of [(18) F]AFM (88.5 +/- 20.3 MBq), a low-dose CT scan and a series of eight whole-body PET scans in 3-D mode were performed. Time-activity data of source organs were used to calculate the residence times and estimate the absorbed radiation dose using the OLINDA/EXM software. RESULTS: In the rats, neither the single dose nor the five daily doses of AFM tartrate produced overt adverse effects clinically. In the monkeys, the radiation doses received by most organs ranged between 8.3 and 39.1 MUGy/MBq. The osteogenic cells, red marrow, and lungs received the highest doses of 39.1, 35.4, and 35.1 MUGy/MBq, respectively. The effective doses extrapolated to male and female adult humans were 18.0 and 18.3 MUSv/MBq, respectively. CONCLUSIONS: Toxicity studies in Sprague-Dawley rats and radiation dosimetry studies in Formosa rock monkeys suggest that [(18) F]AFM is safe for use in human PET imaging studies. TRIAL REGISTRATION: IACUC-12-200. PMID- 26116129 TI - Effects on the FDG distribution by a high uptake of brown adipose tissue at PET examination. AB - BACKGROUND: At fluorodeoxyglucose/positron emission tomography (FDG/PET) examinations, a generally increased uptake of the skeletal muscles is sometimes encountered. As the tracer distribution constitutes a 'zero-sum-game', the uptake of lesions as well as of normal tissues is reduced in these patients. This has to be considered at calculation of standardised uptake values (SUVs), especially at longitudinal examinations in the same patient. In the current study, a possible similar influence on the FDG distribution by a high uptake of brown adipose tissue (BAT) was studied. METHODS: Twelve patients with strongly increased BAT uptake were examined twice with a mean of 5 days (study group). In six of these patients, there was at least one pathological lesion with increased uptake. The BAT uptake was normalised at the second examination after pretreatment with propranolol. SUVs of the pathological lesions and of the liver, spleen, lung, blood, skeletal muscles, bone marrow, gluteal fat, abdomen and heart were assessed. In order to control the effects of propranolol on normal organs/tissues, which could interfere with the findings, 25 age and gender matched normal controls were also studied (control subjects). RESULTS: In the study group, there was only a lower bone marrow uptake after propranolol administration. Comparing the study group with the control subjects, the bone marrow activity was higher at examination before propranolol treatment compared to the control subjects. There was also a higher uptake of the spleen in the study group before propranolol treatment compared to the control subjects. There were no differences between the study group after propranolol administration and the control subjects. CONCLUSIONS: The differences found are small and cannot be explained, why they could be random phenomena. Together with, there were no differences between the study group after propranolol administration and the control subjects; it is concluded that an effect on the FDG distribution in patients with a strong BAT uptake by can be disregarded in clinical praxis. This is important at longitudinal examinations of patients undergoing tailored tumour therapy and in contrast to examinations in patients with a generally increased uptake of the skeletal muscles which significantly affects the distribution of the radiopharmaceutical. PMID- 26116130 TI - Cyclosporin A, but not tacrolimus, negatively affects the hepatic extraction fraction of hepatobiliary scintigraphy in liver transplant recipients. AB - BACKGROUND: Hepatobiliary scintigraphy using (99m)Tc-mebrofenin has been used as an investigation to study liver function after liver transplantation (LTx). Hepatic extraction fraction (HEF) is a measurement of the hepatic extraction efficiency and hepatic extraction rate. With the purpose of evaluating a possible diverging effect of cyclosporin A (CSA) and tacrolimus (TAC) on the HEF, we compared the HEF with biochemical and histological parameters in LTx patients receiving either CSA or TAC. METHODS: Thirty-nine adult patients who underwent LTx due to hepatitis C virus (HCV) cirrhosis were evaluated. All patients underwent a 3-month and 1-year follow-up that included hepatobiliary scintigraphy and biochemistry tests. Liver biopsy was performed at 1 year. These clinical parameters were compared between the two groups, TAC (n = 15) and CSA (n = 24). RESULTS: The average HEF was significantly lower in the CSA group compared to the TAC group both at 3 months and 1 year after LTx. The liver biochemistry tests, average donor and recipient age, average cold ischemia time (CIT), and a clearance were comparable in the two groups. The TAC group had more inflammation than the CSA group. Moreover, three patients who converted from CSA to TAC increased their HEF values. CONCLUSIONS: CSA-treated patients presented a lower HEF value on hepatobiliary scintigraphy in spite of comparable liver function by traditional measurements indicating a decrease on HEF values by CSA. PMID- 26116131 TI - Labeling galectin-3 for the assessment of myocardial infarction in rats. AB - BACKGROUND: Galectin-3 is a beta-galactoside-binding lectin expressed in most of tissues in normal conditions and overexpressed in myocardium from early stages of heart failure (HF). It is an established biomarker associated with extracellular matrix (ECM) turnover during myocardial remodeling. The aim of this study is to test the ability of (123)I-galectin-3 (IG3) to assess cardiac remodeling in a model of myocardial infarction (MI) using imaging techniques. METHODS: Recombinant galectin-3 was labeled with iodine-123 and in vitro binding assays were conducted to test (123)I-galectin-3 ability to bind to ECM targets. For in vivo studies, a rat model of induced-MI was used. Animals were subjected to magnetic resonance and micro-SPETC/micro-CT imaging two (2 W-MI) or four (4 W-MI) weeks after MI. Sham rats were used as controls. Pharmacokinetic, biodistribution, and histological studies were also performed after intravenous administration of IG3. RESULTS: In vitro studies revealed that IG3 shows higher binding affinity (measured as counts per minute, cpm) (p < 0.05) to laminin (2.45 +/- 1.67 cpm), fibronectin (4.72 +/- 1.95 cpm), and collagen type I (1.88 +/- 0.53 cpm) compared to bovine serum albumin (BSA) (0.88 +/- 0.31 cpm). Myocardial quantitative IG3 uptake (%ID/g) was higher (p < 0.01) in the infarct of 2 W-MI rats (0.15 +/- 0.04%) compared to control (0.05 +/- 0.03%). IG3 infarct uptake correlates with the extent of scar (r s = 1, p = 0.017). Total collagen deposition in the infarct (percentage area) was higher (p < 0.0001) at 2 W-MI (24.2 +/- 5.1%) and 4 W-MI (30.4 +/- 7.5%) compared to control (1.9 +/- 1.1%). However, thick collagen content in the infarct (square micrometer stained) was higher at 4 W-MI (20.5 +/- 11.2 MUm(2)) compared to control (4.7 +/- 2.0 MUm(2), p < 0.001) and 2 W-MI (10.6 +/- 5.1 MUm(2), p < 0.05). CONCLUSIONS: This study shows, although preliminary, enough data to consider IG3 as a potential contrast agent for imaging of myocardial interstitial changes in rats after MI. Labeling strategies need to be sought to improve in vivo IG3 imaging, and if proven, galectin-3 might be used as an imaging tool for the assessment and treatment of MI patients. PMID- 26116132 TI - An elusive low-hanging fruit for public health: gun violence prevention. PMID- 26116134 TI - What is significance? PMID- 26116133 TI - Firearm injuries in the United States. AB - OBJECTIVE: This paper examines the epidemiology of fatal and nonfatal firearm violence in the United States. Trends over two decades in homicide, assault, self directed and unintentional firearm injuries are described along with current demographic characteristics of victimization and health impact. METHOD: Fatal firearm injury data were obtained from the National Vital Statistics System (NVSS). Nonfatal firearm injury data were obtained from the National Electronic Injury Surveillance System (NEISS). Trends were tested using Joinpoint regression analyses. CDC Cost of Injury modules were used to estimate costs associated with firearm deaths and injuries. RESULTS: More than 32,000 persons die and over 67,000 persons are injured by firearms each year. Case fatality rates are highest for self-harm related firearm injuries, followed by assault-related injuries. Males, racial/ethnic minority populations, and young Americans (with the exception of firearm suicide) are disproportionately affected. The severity of such injuries is distributed relatively evenly across outcomes from outpatient treatment to hospitalization to death. Firearm injuries result in over $48 billion in medical and work loss costs annually, particularly fatal firearm injuries. From 1993 to 1999, rates of firearm violence declined significantly. Declines were seen in both fatal and nonfatal firearm violence and across all types of intent. While unintentional firearm deaths continued to decline from 2000 to 2012, firearm suicides increased and nonfatal firearm assaults increased to their highest level since 1995. CONCLUSION: Firearm injuries are an important public health problem in the United States, contributing substantially each year to premature death, illness, and disability. Understanding the nature and impact of the problem is only a first step toward preventing firearm violence. A science driven approach to understand risk and protective factors and identify effective solutions is key to achieving measurable reductions in firearm violence. PMID- 26116135 TI - Structure and sequence analysis-based engineering of pullulanase from Anoxybacillus sp. LM18-11 for improved thermostability. AB - Pullulanase (EC 3.2.1.41) is a well-known starch-debranching enzyme. Enhancing the thermostability of Pullulanase is required for industrial application. In this study, we used two methods to improve the thermostability of the pullulanase from Anoxybacillus sp. LM18-11; these methods were the modified amino acid consensus method combined with the analyses of the residue water-exposed surface (ACC) and the deletion of flexible domains. Four mutants (Y477A, Y175C, L215C and R473E) were obtained via the modified consensus method exhibited varying degrees of improvements in terms of thermostability. One deletion mutant termed D3 (residues(686-688)) was obtained and exhibited enhanced thermostability due to deletion of the flexible region at the C-terminus. The combination of the two strategies yielded the mutant M18 (Y477A/D3/Y175C/L215P/R473E). It retained 66% of its initial activity after incubation at 60 degrees C for 72 hrs, whereas that of the wild-type enzyme was only 35%. After incubation at 65 degrees C for 4 h, M18 retained 50.6% of its initial activity, whereas that of the wild-type was only 16.8%, respectively. Additionally, kinetic studies revealed that the Km of M17 (Y477A/D3/Y175C/L215P) was decreased by 33.9% and that the Kcat/Km value of M17 increased by 50%, while M18 exhibited Km and Kcat/Km values that were similar to those of the wild-type enzyme. The attractive improved thermostability and the high catalytic efficiency made M17 and M18 more suitable for industrial application. PMID- 26116136 TI - Genetic profiling of yeast industrial strains using in situ comparative genomic hybridization (CGH). AB - The genetic differences and changes in genomic stability may affect fermentation processes involving baker's, brewer's and wine yeast strains. Thus, it seems worthwhile to monitor the changes in genomic DNA copy number of industrial strains. In the present study, we developed an in situ comparative genomic hybridization (CGH) to investigate the ploidy and genetic differences between selected industrial yeast strains. The CGH-based system was validated using the laboratory Saccharomyces cerevisiae yeast strains (haploid BY4741 and diploid BY4743). DNA isolated from BY4743 cells was considered a reference DNA. The ploidy and DNA gains and losses of baker's, brewer's and wine strains were revealed. Taken together, the in situ CGH was shown a helpful molecular tool to identify genomic differences between yeast industrial strains. Moreover, the in situ CGH-based system may be used at the single-cell level of analysis to supplement array-based techniques and high-throughput analyses at the population scale. PMID- 26116137 TI - A novel milliliter-scale chemostat system for parallel cultivation of microorganisms in stirred-tank bioreactors. AB - A pH-controlled parallel stirred-tank bioreactor system was modified for parallel continuous cultivation on a 10 mL-scale by connecting multichannel peristaltic pumps for feeding and medium removal with micro-pipes (250 MUm inner diameter). Parallel chemostat processes with Escherichia coli as an example showed high reproducibility with regard to culture volume and flow rates as well as dry cell weight, dissolved oxygen concentration and pH control at steady states (n=8, coefficient of variation <5%). Reliable estimation of kinetic growth parameters of E. coli was easily achieved within one parallel experiment by preselecting ten different steady states. Scalability of milliliter-scale steady state results was demonstrated by chemostat studies with a stirred-tank bioreactor on a liter scale. Thus, parallel and continuously operated stirred-tank bioreactors on a milliliter-scale facilitate timesaving and cost reducing steady state studies with microorganisms. The applied continuous bioreactor system overcomes the drawbacks of existing miniaturized bioreactors, like poor mass transfer and insufficient process control. PMID- 26116139 TI - A retrospective cohort study of age-based differences in the care of hospitalized patients with sudden clinical deterioration. AB - PURPOSE: The proportion of elderly patients is increasing, but it is unknown if there are age-based differences in care of hospitalized patients with sudden clinical deterioration. We sought to examine the relation between patient age and care for hospitalized patients experiencing sudden clinical deterioration. METHODS: We identified hospitalized adults (n = 5103) in 4 hospitals with sudden clinical deteriorations triggering medical emergency team (MET) activation between January 1, 2007, and December 31, 2009. We compared intensive care unit (ICU) admission rates (within 2 hours of MET activation), goals of care (resuscitative vs nonresuscitative), and hospital mortality according to age (<50, 50-64, 65-79, and 80+ years), adjusting for patient, physician, and hospital characteristics. RESULTS: Age was associated with decreased likelihood of admission to ICU (P < .0001) and increased likelihood of change in goals of care (P < .0001). Compared to patients younger than 50 years, patients 80 years or older had 67% lower odds of ICU admission (odds ratio, 0.33; 95% confidence interval, 0.26-0.41) and 587% higher odds (odds ratio, 6.87; 95% confidence interval, 4.20-11.26) of having their goals of care changed to exclude resuscitation. Hospital mortality was associated with patient age, ranging from 15% to 46% (P < .0001). CONCLUSIONS: Patient age is associated with care for hospitalized patients with sudden clinical deterioration, suggesting that strategies to guide care of elderly patients during MET activation may be beneficial. PMID- 26116138 TI - Control of cerebrovascular patterning by neural activity during postnatal development. AB - The brain represents only a small portion of the body mass and yet consumes almost a quarter of the available energy, and has a limited ability to store energy. The brain is therefore highly dependent on oxygen and nutrient supply from the blood circulation, which makes it vulnerable to vascular pathologies. Key vascular determinants will ensure proper brain maturation and function: the establishment of vascular networks, the formation of the blood-brain barrier, and the regulation of blood flow. Recent evidence suggests that the phenomenon of neurovascular coupling, during which increased neural activity normally leads to increased blood flow, is not functional until few weeks after birth, implying that the developing brain must rely on alternative mechanisms to adequately couple blood supply to increasing energy demands. This review will focus on these alternative mechanisms, which have been partly elucidated recently via the demonstration that neural activity influences the maturation of cerebrovascular networks. We also propose possible mechanisms underlying activity-induced vascular plasticity. PMID- 26116140 TI - Mutual relationship between anxiety and pain in the intensive care unit and its effect on medications. AB - PURPOSE: Little is known about the relationship between anxiety and pain in intensive care unit (ICU) patients despite its importance. The aims of the present study are to examine the correlation between pain and anxiety during ICU care and to investigate its effects on the dose of opioids and anxiolytics administered. METHODS: The study subjects were awake critically ill patients admitted to an ICU over a 2-month period. Trained psychiatrists evaluated the nondelirious, noncomatose patients daily for anxiety and pain using the Numeric Rating Scale for Pain (NRS-Pain), Faces Anxiety Scale (FAS), and Hamilton Anxiety Rating Scale. RESULTS: Daily alterations of anxiety and pain were significantly correlated with one another among 123 patients. Both the FAS and the Hamilton Anxiety Rating Scale were positively correlated with the NRS-Pain (P < .001 for both). The NRS-Pain score (P = .016) and the FAS score (P = .007) both significantly correlated with the dose of anxiolytics. The dose of opioids was unaffected by the severity of pain or anxiety. CONCLUSIONS: Pain and anxiety among critically ill patients in the ICU were closely correlated. Pain and anxiety influenced the dose of anxiolytics administered. Therefore, a precise evaluation and comprehensive approach to the management of pain and anxiety are important for treating ICU patients. PMID- 26116141 TI - Errors and malpractice lawsuits in radiology: what the radiologist needs to know. AB - All medical specialties dealing with patients include an intrinsic risk in exposing them to issues resulting from human errors. Radiology is not spared from this risk since it includes "decision-making under conditions of uncertainty." In medical imaging, the line between the word "error" and misdiagnosis or discrepancy is very difficult to demarcate, mainly because the diagnostic process is not a binary relation and it is not always possible to establish if a pathological condition is present or not. The error in radiology is strongly related to the diagnostic process; hence, it can be defined as a "diagnostic error" which represents the most common cause of medical malpractice suits against radiologists. In this paper, the authors described the features of errors occurring in radiology, trying to establish their impact and prevalence. Secondly, some data coming from different countries were compared in order to highlight the most frequent causes leading to malpractice lawsuits in radiology and how the phenomenon of malpractice in this field is represented worldwide. PMID- 26116142 TI - Early urinary angiotensinogen excretion in critically ill neonates. AB - INTRODUCTION: Urinary angiotensinogen is considered a reliable biomarker for intrarenal renin-angiotensin system activity. The aims of this study were to assess the urinary angiotensinogen level during the first day of life and to evaluate its correlation with renal function in critically ill neonates. METHODS: Urinary angiotensinogen concentration during the first 24 hours of life was measured in 98 critically ill neonates. Neonatal renal function was assessed by urinary levels of cystatin-C, albumin and alpha1-microglobulin and urinary electrolyte excretion. RESULTS: Urinary angiotensinogen level decreased with increasing gestational age and body weight in critically ill neonates (P<0.001). After adjustment for gestational age, urinary angiotensinogen level correlated with urinary fractional excretion of sodium and urinary levels of cystatin-C and alpha1-microglobulin. Multivariate linear regression identified a significant impact of urinary cystatin-C on urinary angiotensinogen level (P<0.001). Furthermore, urinary angiotensinogen was significantly increased in neonates with a urinary cystatin-C-to-creatinine ratio ?2500 ng/mg, which was the optimal cut off value to predict acute kidney injury in our previous study. CONCLUSIONS: The urinary angiotensinogen level correlates with the overall maturity of renal function during the early postnatal period in critically ill neonates and an increased urinary angiotensinogen level might reflect renal injury in immature neonates. PMID- 26116143 TI - A Swedish version of the SCREEN II for malnutrition assessment among community dwelling elderly. AB - BACKGROUND: The Seniors in the Community: Risk Evaluation for Eating and Nutrition II (SCREEN II) Questionnaire assesses nutritional risk among elderly people living at home. Our aim was to produce a Swedish language version of the SCREEN II and to examine response patterns, data completeness and the relationship between malnutrition and general health. METHODS: The SCREEN II was translated into Swedish using dual panel methodology, and then followed up with field test interviews of 24 seniors (median age, 83 years). We used the survey data (n = 565) to assess item and score distribution, missing responses, and the relationship to the subject's general and nutritional health. RESULTS: The Swedish SCREEN II was considered easy to understand, respond to, and relevant (n = 21; 88% of subjects found it so in all three respects) and its median completion time was 5 minutes. The level of survey item data completeness was 94 99%, and 82% of surveys had computable total scores. Of those subjects with completed forms, 35% had no nutritional risk; 35% had moderate risk; and 30% were at high risk. The malnutrition risk increased with poorer perceived health. CONCLUSIONS: Our study results are similar to those using previous screen ii versions, indicating that the scale adaptation was successful and providing initial support for use of the Swedish SCREEN II questionnaire. PMID- 26116144 TI - Pertuzumab, trastuzumab and docetaxel reduced the recurrence of brain metastasis from breast cancer: a case report. AB - The CLEOPATRA trial reported the survival benefit of pertuzumab with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients. However, there are a few case reports concerning the effects of a pertuzumab-containing regimen on brain metastases. A 55-year-old woman, who underwent curative surgery for breast cancer after neoadjuvant chemotherapy 5 years previously, developed repeated solitary brain metastasis in her right occipital lobe. Whole brain radiation therapy, stereotactic radiosurgery and 3 times of surgical resection were performed. Lapatinib and capecitabine plus tamoxifen were administered. The metastasis recurred in the stump of the previous surgery. Pertuzumab with trastuzumab plus docetaxel was initiated as second-line chemotherapy. A complete response of the brain metastasis was achieved, which persisted for 5 months. Pertuzumab with trastuzumab plus docetaxel was effective in reducing the brain metastases from breast cancer. Further studies are warranted to confirm the effect of this regimen on brain metastases. PMID- 26116145 TI - Structural and biochemical insights into nucleotide-rhamnose synthase/epimerase reductase from Arabidopsis thaliana. AB - L-Rhamnose (Rha) is synthesized via a similar enzymatic pathway in bacteria, plants and fungi. In plants, nucleotide-rhamnose synthase/epimerase-reductase (NRS/ER) catalyzes the final step in the conversion of dTDP/UDP-alpha-D-Glc to dTDP/UDP-beta-L-Rha in an NAD(P)H dependent manner. Currently, only biochemical evidence for the function of NRS/ER has been described. In this study, a crystal structure for Arabidopsis thaliana NRS/ER was determined, which is the first report of a eukaryotic rhamnose synthase with both epimerase and reductase activities. NRS/ER functions as a metal ion independent homodimer that forms through hydrophobic interactions via a four-helix bundle. Each monomer exhibits alpha/beta folding that can be divided into two regions, nucleotide cofactor binding domain and sugar substrate binding domain. The affinities of ligands with NRS/ER were measured using isothermal titration calorimetry, which showed that NRS/ER has a preference for dTDP over UDP, while the cofactor binding site has a similar affinity for NADH and NADPH. Structural analysis coupled to site-directed mutagenesis suggested C115 and K183 as the acid/base pair responsible for epimerization, while T113, Y144 and K148 are the conserved residues in reduction. These findings shed light on the molecular mechanism of NRS/ER and were helpful to explore other eukaryotic enzymes involved in L-Rha synthesis. PMID- 26116146 TI - The effect of the carbohydrate binding module on substrate degradation by the human chitotriosidase. AB - Human chitotriosidase (HCHT) is one of two active glycoside hydrolase family 18 chitinases produced by humans. The enzyme is associated with several diseases and is thought to play a role in the anti-parasite responses of the innate immune system. HCHT occurs in two isoforms, one 50 kDa (HCHT50) and one 39 kDa variant (HCHT39). Common for both isoforms is a catalytic domain with the (beta/alpha)8 TIM barrel fold. HCHT50 has an additional linker-region, followed by a C-terminal carbohydrate-binding module (CBM) classified as CBM family 14 in the CAZy database. To gain further insight into enzyme functionality and especially the effect of the CBM, we expressed both isoforms and compared their catalytic properties on chitin and high molecular weight chitosans. HCHT50 degrades chitin faster than HCHT39 and much more efficiently. Interestingly, both HCHT50 and HCHT39 show biphasic kinetics on chitosan degradation where HCHT50 is faster initially and HCHT39 is faster in the second phase. Moreover, HCHT50 produces distinctly different oligomer distributions than HCHT39. This is likely due to increased transglycosylation activity for HCHT50 due the CBM extending the positive subsites binding surface and therefore promoting transglycosylation. Finally, studies with both chitin and chitosan showed that both isoforms have a similarly low degree of processivity. Combining functional and structural features of the two isoforms, it seems that HCHT combines features of exo processive and endo-nonprocessive chitinases with the somewhat unusual CBM14 to reach a high degree of efficiency, in line with its alleged physiological task of being a "complete" chitinolytic machinery by itself. PMID- 26116147 TI - Multiple disulfide bridges modulate conformational stability and flexibility in hyperthermophilic archaeal purine nucleoside phosphorylase. AB - 5'-Deoxy-5'-methylthioadenosine phosphorylase from Sulfolobus solfataricus is a hexameric hyperthermophilic protein containing in each subunit two pairs of disulfide bridges, a CXC motif, and one free cysteine. The contribution of each disulfide bridge to the protein conformational stability and flexibility has been assessed by comparing the thermal unfolding and the limited proteolysis of the wild-type enzyme and its variants obtained by site-directed mutagenesis of the seven cysteine residues. All variants catalyzed efficiently MTA cleavage with specific activity similar to the wild-type enzyme. The elimination of all cysteine residues caused a substantial decrease of DeltaHcal (850 kcal/mol) and Tmax (39 degrees C) with respect to the wild-type indicating that all cysteine pairs and especially the CXC motif significantly contribute to the enzyme thermal stability. Disulfide bond Cys200-Cys262 and the CXC motif weakly affected protein flexibility while the elimination of the disulfide bond Cys138-Cys205 lead to an increased protease susceptibility. Experimental evidence from limited proteolysis, differential scanning calorimetry, and sodium dodecyl sulfate polyacrylamide gel electrophoresis under reducing and nonreducing conditions also allowed to propose a stabilizing role for the free Cys164. PMID- 26116148 TI - The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives. AB - This review analyzes how interplay between folate binding and changes in folate binding protein (FBP) conformation/self-association affects the biological function of FBP. Concentration-dependent, reversible self-association of hydrophobic apo-FBP at pI=7.4 is associated with decreased affinity for folate, probably due to shielding of binding sites between interacting hydrophobic patches. Titration with folate removes apo-monomers, favoring dissociation of self-associated apo-FBP into apo-monomers. Folate anchors to FBP through a network of hydrogen bonds and hydrophobic interactions, and the binding induces a conformational change with formation of hydrophilic and stable holo-FBP. Holo-FBP exhibits a ligand-mediated concentration-dependent self-association into multimers of great thermal and chemical stability due to strong intermolecular forces. Both ligand and FBP are thus protected against biological/physicochemical decomposition. In biological fluids with low FBP concentrations, e.g., saliva, semen and plasma, hydrophobic apo-monomers and hydrophilic holo-monomers associate into stable asymmetrical complexes with aberrant binding kinetics unless detergents, e.g., cholesterol or phospholipids are present. PMID- 26116149 TI - Outcomes following renal transplantation in older renal transplant recipients: a single-center experience and "Croatian senior program". AB - BACKGROUND/OBJECTIVE: Outcomes of kidney transplantation in older patients have not, however, been fully defined. The aims of this study were to analyze the number of new end-stage renal disease (ESRD) patients >=65 years of age who were managed with kidney transplantation and their survival through the study period. In addition, we have analyzed post-transplantation outcomes in younger and older renal transplant recipients (RTRs). METHODS: We have analyzed the mean age of 505 RTRs transplanted between January 1990 and December 2013. Older people were defined as aging 65 years or older. Of 505 RTRs, there were 73 (14.5 %) patients who were >=65 years of age. Therefore, in further analysis, patients were divided into two subgroups: younger recipients (younger than 65 years) and older recipients (aging 65 years or older). RESULTS: In the period from 1990 to 2001, patients who were 65 years of age and older were only sporadically treated with kidney transplantation in Croatia. Since 2002, the number of patients older than 65 years undergoing renal transplantation has been increasing. The older recipients were more likely to receive organs from older donors (52.6 +/- 16.8 vs. 45.8 +/- 13.2; p = 0.0001). There were no significant differences due to HLA mismatch between the two groups of analyzed patients. There was no difference in the rates of DGF between the older and younger recipients. Older recipients were less likely than younger recipients to have acute rejection crisis during the first-ear after transplantation (16.4 vs. 34.7 %; p = 0.03). There were no significant differences due to readmission rates in the first-year post transplantation between the two groups. There was no significant difference due to graft function and 1-year graft and patient's survival between young and older recipients. Serum creatinine values at 1 year were higher in older recipients who received kidneys from elderly donor. CONCLUSION: Our experience supports the use of kidney transplantation in the population of older ESRD patients. We can increase patients and graft survivals in elderly individuals with careful pre transplant evaluation and HLA matching. "Croatian senior program" that includes HLA matching represents a good approach for kidney transplantation in older ESRD patients. PMID- 26116150 TI - Dosimetric comparison of hybrid volumetric-modulated arc therapy, volumetric modulated arc therapy, and intensity-modulated radiation therapy for left-sided early breast cancer. AB - To compare the dosimetric performance of 3 different treatment techniques: hybrid volumetric-modulated arc therapy (hybrid-VMAT), pure-VMAT, and fixed-field intensity-modulated radiation therapy (F-IMRT) for whole-breast irradiation of left-sided early breast cancer. The hybrid-VMAT treatment technique and 2 other treatment techniques-pure-VMAT and F-IMRT-were compared retrospectively in 10 patients with left-sided early breast cancer. The treatment plans of these patients were replanned using the same contours based on the original computed tomography (CT) data sets. Dosimetric parameters were calculated to evaluate plan quality. Total monitor units (MUs) and delivery time were also recorded and evaluated. The hybrid-VMAT plan generated the best results in dose coverage of the target and the dose uniformity inside the target (p < 0.0001 for conformal index [CI]; p = 0.0002 for homogeneity index [HI] of planning target volume [PTV](50.4 Gy) and p < 0.0001 for HI of PTV(62 Gy)). Volumes of ipsilateral lung irradiated to doses of 20 Gy (V(20 Gy)) and 5 Gy (V(5 Gy)) by the hybrid-VMAT plan were significantly less than those of the F-IMRT and the pure-VMAT plans. The volume of ipsilateral lung irradiated to a dose of 5 Gy was significantly less using the hybrid-VMAT plan than that using the F-IMRT or the pure-VMAT plan. The total mean MUs for the hybrid-VMAT plan were significantly less than those for the F-IMRT or the pure-VMAT plan. The mean machine delivery time was 3.23 +/- 0.29 minutes for the hybrid-VMAT plans, which is longer than that for the pure VMAT plans but shorter than that for the F-IMRT plans. The hybrid-VMAT plan is feasible for whole-breast irradiation of left-sided early breast cancer. PMID- 26116151 TI - Thrombopoietin Signaling Pathway Regulates Hepatocyte Activation in Rat Liver Regeneration. AB - Thrombopoietin (THPO) signaling pathway regulates cell activation and many other physiological activities. To study its role in liver regeneration (LR), hepatocytes were isolated from rat regenerating livers and gene expression profile was detected using the Rat Genome 230 2.0 Array. Spectral function (E t ) and information correlation coefficient (ICC) were used to analyze gene synergy based on gene expression changes. The results showed that 35 genes related to THPO signaling pathway were significantly changed during rat LR. Functional analysis with ICC showed that five genes, STAT3, PLSCR1, CTGF, PRLR, and LCP1, played a key role in hepatocyte activation. Fourteen channels of THPO signaling pathway participated in regulating hepatocyte activation during rat LR. PMID- 26116153 TI - A Male-Specific Genetic Map of the Microcrustacean Daphnia pulex Based on Single Sperm Whole-Genome Sequencing. AB - Genetic linkage maps are critical for assembling draft genomes to a meaningful chromosome level and for deciphering the genomic underpinnings of biological traits. The estimates of recombination rates derived from genetic maps also play an important role in understanding multiple aspects of genomic evolution such as nucleotide substitution patterns and accumulation of deleterious mutations. In this study, we developed a high-throughput experimental approach that combines fluorescence-activated cell sorting, whole-genome amplification, and short-read sequencing to construct a genetic map using single-sperm cells. Furthermore, a computational algorithm was developed to analyze single-sperm whole-genome sequencing data for map construction. These methods allowed us to rapidly build a male-specific genetic map for the freshwater microcrustacean Daphnia pulex, which shows significant improvements compared to a previous map. With a total of mapped 1672 haplotype blocks and an average intermarker distance of 0.87 cM, this map spans a total genetic distance of 1451 Kosambi cM and comprises 90% of the resolved regions in the current Daphnia reference assembly. The map also reveals the mistaken mapping of seven scaffolds in the reference assembly onto chromosome II by a previous microsatellite map based on F2 crosses. Our approach can be easily applied to many other organisms and holds great promise for unveiling the intragenomic and intraspecific variation in the recombination rates. PMID- 26116152 TI - Glycogen Fuels Survival During Hyposmotic-Anoxic Stress in Caenorhabditis elegans. AB - Oxygen is an absolute requirement for multicellular life. Animals that are deprived of oxygen for sufficient periods of time eventually become injured and die. This is largely due to the fact that, without oxygen, animals are unable to generate sufficient quantities of energy. In human diseases triggered by oxygen deprivation, such as heart attack and stroke, hyposmotic stress and cell swelling (edema) arise in affected tissues as a direct result of energetic failure. Edema independently enhances tissue injury in these diseases by incompletely understood mechanisms, resulting in poor clinical outcomes. Here, we present investigations into the effects of osmotic stress during complete oxygen deprivation (anoxia) in the genetically tractable nematode Caenorhabditis elegans. Our findings demonstrate that nematode survival of a hyposmotic environment during anoxia (hyposmotic anoxia) depends on the nematode's ability to engage in glycogen metabolism. We also present results of a genome-wide screen for genes affecting glycogen content and localization in the nematode, showing that nematode survival of hyposmotic anoxia depends on a large number of these genes. Finally, we show that an inability to engage in glycogen synthesis results in suppression of the enhanced survival phenotype observed in daf-2 insulin-like pathway mutants, suggesting that alterations in glycogen metabolism may serve as a basis for these mutants' resistance to hyposmotic anoxia. PMID- 26116154 TI - Human papillomavirus E7 serology and association with p16 immunohistochemistry in squamous cell carcinoma of the head and neck. AB - BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal cancer is associated with improved survival and treatment response as compared to HPV negative cancers. P16 overexpression is widely accepted as a surrogate marker for HPV positivity. METHODS: A total of 92 serum samples from 75 head and neck squamous cell carcinoma (HNSCC) patients were examined for HPV16 and 18 E7 antibodies by ELISA. Available tissue was tested for HPV-DNA by PCR, and p16 immunohistochemistry was obtained from a deidentified database. RESULTS: Of 75 HNSCC patients, 25 were HPV E7 seropositive. Seropositivity was strongly associated with cancers of the oropharynx, and correlated with positive p16 immunohistochemistry (IHC) and HPV-DNA. Post-treatment serum was available in a limited subset of patients, revealing a decrease in antibody titers following response to treatment. CONCLUSIONS: HPV E7 seropositivity correlated with positive tumor HPV-DNA and p16 expression, and was strongly associated with cancers of the oropharynx. E7 serology warrants further study as a potential biomarker in HPV-positive HNSCC. PMID- 26116155 TI - Maintaining Gains Following Pulmonary Rehabilitation. AB - PURPOSE: Pulmonary rehabilitation (PR) is an accepted intervention for individuals with chronic obstructive pulmonary disease. Despite initial improvements following PR, many patients eventually return to baseline function or decline even further. The aim of this study is to look at long-term (>1 year) outcomes following PR. METHODS: This was a prospective cohort study of patients who had completed PR. Participants were invited for an assessment consisting of participant interviews and clinical assessments using standardised instruments. RESULTS: 129 patients between 2003 and 2012 completed rehabilitation and were eligible. 88 patients were included in the analysis. The mean time of the long term assessment was 22 months following PR. The mean age was 71 years. Mean FEV1 was 46%. There was a statistically significant (p < 0.001) increase in the incremental shuttle walk test distance of 29.0 m following PR but this gain was lost at the long-term reassessment. Chronic Respiratory Questionnaire (CRQ) scores showed a statistically significant (p < 0.001) increase in all four domains but only the domains of dyspnoea and fatigue remained statistically significant (p < 0.001, p < 0.01, respectively) at the long-term reassessment. Hospital Anxiety and Depression Scale scores reduced following rehabilitation but only the anxiety component was statistically significant (p < 0.01). These improvements persisted at the long-term reassessment but were not statically significant. CONCLUSIONS: This study confirms that many of the functional gains achieved in PR are lost in the longer term. Regular surveillance or monitoring of these patients post-PR is important to identify those requiring further intervention. PMID- 26116156 TI - Consensus best practice pathway of the UK Scleroderma Study Group: digital vasculopathy in systemic sclerosis. AB - OBJECTIVE: Digital vasculopathy (comprising RP, digital ulceration and critical digital ischaemia) is responsible for much of the pain and disability experienced by patients with SSc. However, there is a limited evidence base to guide clinicians in the management of SSc-related digital vasculopathy. Our aim was to produce recommendations that would be helpful for clinicians, especially for those managing patients outside specialist centres. METHODS: The UK Scleroderma Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including digital vasculopathy. RESULTS: This overview presents the background and best practice consensus pathways for SSc-related RP, digital ulceration and critical ischaemia. Examples of drug therapies, including doses, are suggested in order to inform prescribing practice. CONCLUSION: A number of treatment algorithms are provided that are intended to provide the clinician with accessible reference tools for use in daily management. PMID- 26116157 TI - Varenicline can help smokers to stop smoking by gradual reduction. PMID- 26116158 TI - Type 2 diabetes mellitus screening has no effect on mortality. PMID- 26116159 TI - Ultrasound imaging of breast tumor perfusion and neovascular morphology. AB - A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time-intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time-intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic monitoring is currently undergoing profound changes. Novel imaging techniques that are sensitive to the unique biological conditions of each individual tumor represent valuable tools in the pursuit of personalized medicine. PMID- 26116160 TI - The Effect of Short Duration Ultrasound Pulses on the Interaction Between Individual Microbubbles and Fibrin Clots. AB - In previous work, we examined microscale interactions between microbubbles and fibrin clots under exposure to 1 ms ultrasound pulses. This provided direct evidence that microbubbles were capable of deforming clot boundaries and penetrating into clots, while also affecting fluid uptake and inducing fibrin network damage. Here, we investigate the effect of short duration (15 MUs) pulses on microscale bubble-clot interactions as function of bubble diameter (3-9 MUm) and pressure. Individual microbubbles (n = 45) were placed at the clot boundary with optical tweezers and exposed to 1 MHz ultrasound. High-speed (10 kfps) imaging and 2-photon microscopy were performed during and after exposure, respectively. While broadly similar phenomena were observed as in the 1 ms pulse case (i.e., bubble penetration, network damage and fluid uptake), substantial quantitative differences were present. The pressure threshold for bubble penetration was increased from 0.39 MPa to 0.6 MPa, and those bubbles that did enter clots had reduced penetration depths and were associated with less fibrin network damage and nanobead uptake. This appeared to be due in large part to increased bubble shrinkage relative to the 1 ms pulse case. Stroboscopic imaging was performed on a subset of bubbles (n = 11) and indicated that complex bubble oscillations can occur during this process. PMID- 26116161 TI - Assessment of liver fibrosis with 2-D shear wave elastography in comparison to transient elastography and acoustic radiation force impulse imaging in patients with chronic liver disease. AB - Two-dimensional shear wave elastography (2-D SWE) is an ultrasound-based elastography method integrated into a conventional ultrasound machine. It can evaluate larger regions of interest and, therefore, might be better at determining the overall fibrosis distribution. The aim of this prospective study was to compare 2-D SWE with the two best evaluated liver elastography methods, transient elastography and acoustic radiation force impulse (point SWE using acoustic radiation force impulse) imaging, in the same population group. The study included 132 patients with chronic hepatopathies, in which liver stiffness was evaluated using transient elastography, acoustic radiation force impulse imaging and 2-D SWE. The reference methods were liver biopsy for the assessment of liver fibrosis (n = 101) and magnetic resonance imaging/computed tomography for the diagnosis of liver cirrhosis (n = 31). No significant difference in diagnostic accuracy, assessed as the area under the receiver operating characteristic curve (AUROC), was found between the three elastography methods (2 D SWE, transient elastography, acoustic radiation force impulse imaging) for the diagnosis of significant and advanced fibrosis and liver cirrhosis in the "per protocol" (AUROCs for fibrosis stages >=2: 0.90, 0.95 and 0.91; for fibrosis stage [F] >=3: 0.93, 0.95 and 0.94; for F = 4: 0.92, 0.96 and 0.92) and "intention to diagnose" cohort (AUROCs for F >=2: 0.87, 0.92 and 0.91; for F >=3: 0.91, 0.93 and 0.94; for F = 4: 0.88, 0.90 and 0.89). Therefore, 2-D SWE, ARFI imaging and transient elastography seem to be comparably good methods for non invasive assessment of liver fibrosis. PMID- 26116162 TI - Celastrol blocks binding of lipopolysaccharides to a Toll-like receptor4/myeloid differentiation factor2 complex in a thiol-dependent manner. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii (lei gong teng; Thunder of God Vine), which belongs to the Celastraceae family, has long been used in traditional Chinese medicine to treat inflammation and rheumatoid arthritis. Celastrol is a bioactive compound isolated from T. wilfordii. AIM OF THE STUDY: We investigated whether celastrol suppressed binding of lipopolysaccharides (LPS) to myeloid differentiation factor 2 (MD2), thereby downregulating Toll-like receptor4 (TLR4) activation in mouse primary macrophages. MATERIALS AND METHODS: Cytokine expression was determined by polymerase chain reaction analysis and enzyme-linked immunosorbent assay in bone marrow-derived primary macrophages (BMDMs). The kinase activity of tank-binding kinase 1 (TBK1) was examined by a luciferase reporter assay and an in vitro kinase assay. LPS binding to MD2 was examined by an in vitro binding assay and confocal microscopy analysis. RESULTS: Celastrol reduced LPS-induced expression of inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-12, and IL-1beta, at both the mRNA and protein levels in BMDMs. Celastrol suppressed LPS binding to MD2, as shown by the in vitro binding assay, whereas it did not inhibit TBK1. In addition, co-localization of LPS with MD2 in BMDMs was blocked by celastrol. The inhibitory effects of celastrol on LPS binding to MD2 were reversed by thiol donors (N-acetyl-L-cysteine and dithiothreitol), suggesting that the thiol reactivity of celastrol contributes to its inhibitory effects on TLR4 activation in macrophages. CONCLUSION: Our results demonstrate that celastrol suppresses TLR4 activation through the inhibition of LPS binding to the TLR4/MD2 complex. These results provide a novel mechanism of action by which celastrol contributes to the anti-inflammatory activity of T. wilfordii. PMID- 26116163 TI - Acupuncture reduced apoptosis and up-regulated BDNF and GDNF expression in hippocampus following hypoxia-ischemia in neonatal rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acupuncture attenuates neuronal damages following ischemia. AIM OF THE STUDY: The purpose of the present study was to investigate the beneficial effects of acupuncture on hypoxia-ischemia induced brain damages in neonatal rats. MATERIALS AND METHODS: Male postnatal 7 days rats were randomly divided into 3 groups: sham control (sham), hypoxia-ischemia (HI), and HI plus acupuncture treatment (HI+Acu). The rats in HI and HI+Acu groups were submitted to model of neonatal HI, established by occluding the left common carotid artery followed by a 3.5h period of hypoxia (8% O2-92% N2). At 24h after HI, animals were stimulated by acupuncture treatment once a day and the treatment continued during 4 weeks, 5days/week. Behavioral functions, learning and memory ability, and body weight were observed at different time-points after HI. DNA fragmentation assay were performed with TUNEL staining to evaluate apoptosis and expression levels of mitochondrial Bcl-2, mitochondrial Bax, Cleaved caspase 3, Cleaved caspase 9 in the damaged hippocampus were detected by western blotting 28 days following HI. GDNF, BDNF levels in hippocampus were also determined. RESULTS: The results showed that acupuncture significantly promoted growth and development, improved neurobehavioral function, learning and memory ability after 20 days' treatment. Furthermore, we obtained one interesting finding that acupuncture attenuated cellular apoptosis and up-regulated GDNF and BDNF levels in hippocampus. CONCLUSIONS: All of these results suggest that acupuncture as a potential treatment may exert neuroprotective effects via inhibiting cellular apoptosis, increased GDNF and BDNF expression levels in rat hippocampus experiencing HI. PMID- 26116164 TI - Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, Gentiana macrophylla Pall have been prescribed for the treatment of pain and inflammatory conditions. In addition, it is a common Tibetan medicinal herb used for the treatment of tonsillitis, urticaria, and rheumatoid arthritis (RA), while the flowers of G. macrophylla Pall have been traditionally treated as an anti inflammatory agent to clear heat in Mongolian medicine. The secoiridoid glycosides and their derivatives are the primary active components of G. macrophylla and have been demonstrated to be effective as anti-inflammatory agents. MATERIALS AND METHODS: Solvent extraction and D101 macroporous resin columns were employed to concentratethe gentiopicroside. Gentiopicroside cytotoxicity was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; the toxicity of gentiopicroside in chondrocytes was reconfirmed using Hoechst staining. Western blotting, reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry were utilized to explore the protective effects and mechanisms of gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte. RESULTS: The MTT assay demonstrated that 50, 500, and 1,500 MUg/mL of gentiopicroside exhibited no significant toxicity to chondrocytes (P>0.05) after 24h. Using immunohistochemistry, ELISA, RT-PCR, Western blot method to explore the protective effect and mechanism of gentiopicroside on chondrocytes induced by IL-1beta. The results showed some pathways of IL-1beta signal transduction were inhibited by gentiopicroside in rat chondrocytes: p38, ERK and JNK. Meanwhile, gentiopicroside showed inhibition in the IL-1beta-induced release of MMPs while increasing Collagen type II expression. CONCLUSIONS: The current study demonstrated that gentiopicroside exhibited a potent protective effect on IL 1beta induced inflammation response in rat articular chondrocyte. Thus, gentiopicroside could be a potential therapeutic strategy for treatment of OA. PMID- 26116165 TI - The antioxidant effect of astaxanthin is higher in young mice than aged: a region specific study on brain. AB - Astaxanthin is a potential antioxidant which shows neuroprotective property. We aimed to investigate the age-dependent and region-specific antioxidant effects of astaxanthin in mice brain. Animals were divided into 4 groups; treatment young (3 months, n = 6) (AY), treatment old (16 months, n = 6) (AO), placebo young (3 months, n = 6) (PY) and placebo old (16 months, n = 6) (PO) groups. Treatment group was given astaxanthin (2 mg/kg/day, body weight), and placebo group was given 100 MUl of 0.9% normal saline orally to the healthy Swiss albino mice for 4 weeks. The level of non-enzymatic oxidative markers namely malondialdehyde (MDA); nitric oxide (NO); advanced protein oxidation product (APOP); glutathione (GSH) and the activity of enzymatic antioxidants i.e.; catalase (CAT) and superoxide dismutase (SOD) were determined from the isolated brain regions. Treatment with astaxanthin significantly (p < 0.05) reduces the level of MDA, APOP, NO in the cortex, striatum, hypothalamus, hippocampus and cerebellum in both age groups. Astaxanthin markedly (p < 0.05) enhances the activity of CAT and SOD enzymes while improves the level of GSH in the brain. Overall, improvement of oxidative markers was significantly greater in the young group than the aged animal. In conclusion, we report that the activity of astaxanthin is age-dependent, higher in young in compared to the aged brain. PMID- 26116166 TI - Thalamic resting-state functional connectivity: disruption in patients with type 2 diabetes. AB - To explore the disrupted thalamic functional connectivity and its relationships with cognitive dysfunction in type 2 diabetes mellitus (T2DM) by using resting state functional magnetic resonance imaging (fMRI). A total of 38 T2DM patients and 39 well-matched healthy controls participated in the resting-state fMRI and T1-weighted imaging scans. The thalamic functional connectivity was characterized by using a seed-based whole-brain correlation method and compared T2DM patients with healthy controls. Pearson correlation analysis was performed between thalamic functional connectivity and clinical data. When compared with healthy controls, T2DM showed significantly decreased functional connectivity of the thalamus mainly in the right middle temporal gyrus (MTG), right precentral gyrus and bilateral occipital cortex; Increased functional connectivity of the thalamus was detected in the left cerebellum, bilateral middle frontal gyrus and middle cingulate gyrus (p < 0.05, corrected for AlphaSim). In T2DM patients, the decreased thalamic functional connectivity of the right MTG was positively associated with the Verbal Fluency Test score (r = 0.438, p = 0.006). Meanwhile, the decreased thalamic functional connectivity of the right cuneus was positively correlated with the Complex Figure Test-delayed score and negatively correlated with the Trail Making Test-B score, respectively (r = 0.492, p = 0.002; r = 0.504, p = 0.001). Moreover, there was no structural damage in the thalamus of T2DM patients. T2DM patients develop disrupted thalamocortical functional connectivity, which is associated with cognitive impairment in selected brain regions. Resting-state thalamocortical connectivity disturbance may play a central role in the underlying neuropathological process of T2DM-related cognitive dysfunction. PMID- 26116167 TI - Taking Aim at Asthma Around the World: Global Results of the Asthma Insight and Management Survey in the Asia-Pacific Region, Latin America, Europe, Canada, and the United States. AB - BACKGROUND: Asthma, a worldwide health problem, can be controlled if properly diagnosed and managed. Multinational surveys conducted in patients with asthma from 1998 to 2003 indicated that asthma was inadequately controlled. The Asthma Insight and Management (AIM) study represents the largest survey conducted on patients with asthma since 2003. OBJECTIVE: The objective of this study was to assess findings from the United States (US), Europe and Canada (EUCAN), Latin America (LA), and the Asia-Pacific (AP) region surveys to identify differences and similarities with earlier surveys on patients with asthma. METHODS: The US, EUCAN, LA, and AP AIM surveys conducted from 2009 to 2011 all used a common set of questions. Responses to these are reported as proportions of patients with asthma for each country individually, and as totals for all regions. Results are presented as mean/median proportions for US, EUCAN, LA, and AP survey populations individually. Global medians and the range of regional response values are also described. RESULTS: A total of 10,302 patients or parents of adolescents with asthma were interviewed. Approximately one-quarter reported daytime symptoms daily or on most days over the previous 4 weeks. Globally, a median of 67% (range, 27%-88%) of patients perceived their asthma as completely and/or well controlled, but a median of only 9% (range, 0%-29%) of patients had well controlled asthma using criteria from asthma guidelines. A majority (>=60%) of patients felt that quick-relief medication could be used daily if needed, contrary to guideline recommendations. CONCLUSIONS: Patients exhibited a lack of knowledge and conviction for treatment recommendations and guidelines that was relatively uniform across the regions, similar to earlier survey findings. These results reveal an ongoing need for improvement in asthma care and education in most populations. PMID- 26116169 TI - Approaches that use software to support the prevention of pressure ulcer: A systematic review. AB - CONTEXT: The incidence and costs for pressure ulcer (PU) treatment remain high even though preventive methods are applied. Approaches that use software to support the prevention of PU are presented in the literature to make it more effective. OBJECTIVES: Identify the state of art of the approaches that use software to support the prevention of PUs. METHODS: A systematic literature review was performed to analyze approaches that use software to support the prevention of PU. ACM, IEEE, PubMed, Scopus, CINAHL and Embase databases have been searched with a predetermined search string to identify primary studies. We selected the ones that met the established inclusion criteria. RESULTS: Thirty six articles met the inclusion criteria. To support prevention, most approaches monitor the patient to provide information about exposure to pressure, temperature level, humidity level and estimated body position in bed providing risk factor intensity charts and intensity maps. The main method to perform patient's monitoring is using sensors installed on the mattress, but recently, alternative methods have been proposed such as electronic sensors and tactile sensory coils. Part of the approaches performs automated management of the risk factors using ventilation tubes and mattresses with porous cells to decrease body's temperature and movable cells to automatically redistribute the pressure over the body. Matters as cost of the approach, patient comfort and hygiene of the monitoring equipment is only briefly discussed in the selected articles. No experiments have been conducted to evidence the approached may reduce PU incidence. DISCUSSION AND CONCLUSION: Currently, approaches that use software to support the prevention of PU provide relevant information to health professionals such as risk factor intensity charts and intensity maps. Some of them can even automatically manage risk factors in a limited way. Yet, the approaches are based on risk factor monitoring methods that require patient's contact with the monitoring equipment. Therefore, some matters need to be considered such as patient's comfort and the hygiene or replacement of the equipment due to the risk of infection. With the emergence of new alternative methods of monitoring, new technologies that do not require contact could be explored by new researches. Randomized Control Trials could also be conducted to verify which approaches are really effective to reduce PU incidence. PMID- 26116168 TI - Autologous hematopoietic stem cell transplantation in elderly patients (>= 70 years) with non-Hodgkin's lymphoma: A French Society of Bone Marrow Transplantation and Cellular Therapy retrospective study. AB - INTRODUCTION: Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70 years of age with non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: In the setting of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70 years of age who received AHSCT. RESULTS: The median age at AHSCT was 72.3 years [70-80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5*109/L neutrophils and 20 * 10(9)/L platelets were of 12 [9-76] days and 12 [0-143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. CONCLUSION: In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70 years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate. PMID- 26116170 TI - Corrigendum. PMID- 26116171 TI - Integration of Downstream Signals of Insulin-like Growth Factor-1 Receptor by Endoplasmic Reticulum Stress for Estrogen-Induced Growth or Apoptosis in Breast Cancer Cells. AB - Estrogen (E2) exerts a dual function on E2-deprived breast cancer cells, with both initial proliferation and subsequent induction of stress responses to cause apoptosis. However, the mechanism by which E2 integrally regulates cell growth or apoptosis-associated pathways remains to be elucidated. Here, E2 deprivation results in many alterations in stress-responsive pathways. For instance, E2 deprived breast cancer cells had higher basal levels of stress-activated protein kinase, c-Jun N-terminal kinase (JNK), compared with wild-type MCF-7 cells. E2 treatment further constitutively activated JNK after 24 hours. However, inhibition of JNK (SP600125) was unable to abolish E2- induced apoptosis, whereas SP600125 alone arrested cells at the G2 phase of the cell cycle and increased apoptosis. Further examination showed that inhibition of JNK increased gene expression of TNFalpha and did not effectively attenuate expression of apoptosis related genes induced by E2. A notable finding was that E2 regulated both JNK and Akt as the downstream signals of insulin-like growth factor-1 receptor (IGFIR)/PI3K, but with distinctive modulation patterns: JNK was constitutively activated, whereas Akt and Akt-associated proteins, such as PTEN and mTOR, were selectively degraded. Endoplasmic reticulum-associated degradation (ERAD) was involved in the selective protein degradation. These findings highlight a novel IGFIR/PI3K/JNK axis that plays a proliferative role during the prelude to E2 induced apoptosis and that the endoplasmic reticulum is a key regulatory site to decide cell fate after E2 treatment. IMPLICATIONS: This study provides a new rationale for further exploration of E2-induced apoptosis to improve clinical benefit. PMID- 26116172 TI - YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors. AB - Radiotherapy and DNA-damaging chemotherapy are frequently utilized in the treatment of solid tumors. Innate or acquired resistance to these therapies remains a major clinical challenge in oncology. The development of small molecules that sensitize cancers to established therapies represents an attractive approach to extending survival and quality of life in patients. Here, we demonstrate that YU238259, a member of a novel class of DNA double-strand break repair inhibitors, exhibits potent synthetic lethality in the setting of DNA damage response and DNA repair defects. YU238259 specifically inhibits homology-dependent DNA repair, but not non-homologous end-joining, in cell-based GFP reporter assays. Treatment with YU238259 is not only synergistic with ionizing radiation, etoposide, and PARP inhibition, but this synergism is heightened by BRCA2 deficiency. Further, growth of BRCA2-deficient human tumor xenografts in nude mice is significantly delayed by YU238259 treatment even in the absence of concomitant DNA-damaging therapy. The cytotoxicity of these small molecules in repair-deficient cells results from an accumulation of unresolved DNA double-strand breaks. These findings suggest that YU238259 or related small molecules may have clinical benefit to patients with advanced BRCA2-negative tumors, either as a monotherapy or as an adjuvant to radiotherapy and certain chemotherapies. IMPLICATIONS: We have identified a novel series of compounds that demonstrate synthetic lethality in DNA repair-deficient cell and animal models and have strong potential for clinical translation. PMID- 26116173 TI - Distinct requirements for Wntless in habenular development. AB - Secreted Wnt proteins play pivotal roles in development, including regulation of cell proliferation, differentiation, progenitor maintenance and tissue patterning. The transmembrane protein Wntless (Wls) is necessary for secretion of most Wnts and essential for effective Wnt signaling. During a mutagenesis screen to identify genes important for development of the habenular nuclei in the dorsal forebrain, we isolated a mutation in the sole wls gene of zebrafish and confirmed its identity with a second, independent allele. Early embryonic development appears normal in homozygous wls mutants, but they later lack the ventral habenular nuclei, form smaller dorsal habenulae and otic vesicles, have truncated jaw and fin cartilages and lack swim bladders. Activation of a reporter for beta catenin-dependent transcription is decreased in wls mutants, indicative of impaired signaling by the canonical Wnt pathway, and expression of Wnt-responsive genes is reduced in the dorsal diencephalon. Wnt signaling was previously implicated in patterning of the zebrafish brain and in the generation of left right (L-R) differences between the bilaterally paired dorsal habenular nuclei. Outside of the epithalamic region, development of the brain is largely normal in wls mutants and, despite their reduced size, the dorsal habenulae retain L-R asymmetry. We find that homozygous wls mutants show a reduction in two cell populations that contribute to the presumptive dorsal habenulae. The results support distinct temporal requirements for Wls in habenular development and reveal a new role for Wnt signaling in the regulation of dorsal habenular progenitors. PMID- 26116176 TI - ROBO2 restricts the nephrogenic field and regulates Wolffian duct-nephrogenic cord separation. AB - ROBO2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations in humans and mice leading to supernumerary kidneys. Previous studies have established that the number and position of UB outgrowths is determined by the domain of metanephric mesenchymal Gdnf expression, which is expanded anteriorly in Robo2 mouse mutants. To clarify how this phenotype arises, we used high-resolution 3D imaging to reveal an increase in the number of nephrogenic cord cells, leading to extension of the metanephric mesenchyme field in Robo2-null mouse embryos. Ex vivo experiments suggested a dependence of this effect on proliferative signals from the Wolffian duct. Loss of Robo2 resulted in a failure of the normal separation of the mesenchyme from the Wolffian duct/ureteric epithelium, suggesting that aberrant juxtaposition of these two compartments in Robo2-null mice exposes the mesenchyme to abnormally high levels of proliferative stimuli. Our data suggest a new model in which SLIT-ROBO signalling acts not by attenuating Gdnf expression or activity, but instead by limiting epithelial/mesenchymal interactions in the nascent metanephros and restricting the extent of the nephrogenic field. These insights illuminate the aetiology of multiplex kidney formation in human individuals with ROBO2 mutations. PMID- 26116174 TI - Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice. AB - Cleft palate is among the most common human birth defects. Submucous cleft palate (SMCP) is a subgroup of cleft palate, which may be as common as overt cleft palate. Despite the high frequency of SMCP in humans, only recently have several animal models of SMCP begun to provide insight into the mechanisms by which SMCP develops. In this study, we show that enhanced BMP signaling through constitutively active ACVR1 in palatal epithelium causes submucous cleft palate in mice. In these mutant mice, the fusion of both palatal mesenchyme in hard palate, and muscles in soft palate were hampered by epithelial tissue. During palatal fusion, enhanced SMAD-dependent BMP signaling impaired cell death and altered cell proliferation rate in medial edge epithelium (MEE), and resulted in MEE persistence. At the molecular level, downregulation of DeltaNp63, which is crucial for normal palatal fusion, in MEE cells was impaired, leading to a reduction in caspase-3 activation. Our study provides a new insight into the etiology of SMCP caused by augmented BMP signaling. PMID- 26116177 TI - Pyrroloaryls and pyrroloheteroaryls: Inhibitors of the HIV fusion/attachment, reverse transcriptase and integrase. AB - Heterocyclic compounds execute a very important role in drug design and discovery. This article provides the basic milestones of the research for pyrroloaryl and pyrroloheteroaryl based components targeting HIV viral replication cycle. Anti-HIV activity is elaborated for several classes of pyrrolo compounds as pyrrolopyridines, pyrrolopyrimidines, pyrrolopyridazines, pyrrolobenzodiazepinones, pyrrolobenzothiazepines, pyrrolobenzoxazepinones, pyrrolophenanthridines, pyrroloquinoxalines, pyrrolotriazines, pyrroloquinolines, pyrrolopyrazinones, pyrrolothiatriazines, arylthiopyrroles and pyrrolopyrazolones targeting two essential HIV enzymes, reverse transcriptase and integrase as well as attachment/fusion of HIV virons to the host CD-4 cell. Such attempts were resulted in a discovery of highly potent anti-HIV agents suitable for clinical trials, for example, BMS-378806, BMS-585248, BMS-626529, BMS-663068, BMS-488043 and BMS-663749, etc. as anti-HIV attachment agents, triciribine, QX432, BI-1 and BI-2 as HIV RT inhibitors which are in preclinical or clinical development. Mechanism of action of compounds presented in this article towards the suppression of HIV attachment/fusion as well as against the activities of HIV enzymes reverse transcriptase and integrase has been discussed. Relationships of new compounds' molecular framework and HIV viral target has been overviewed in order to facilitate further construction of promising anti-HIV agents in future drug discovery process. PMID- 26116175 TI - Excessive feedback of Cyp26a1 promotes cell non-autonomous loss of retinoic acid signaling. AB - Teratogenic levels of retinoic acid (RA) signaling can cause seemingly contradictory phenotypes indicative of both increases and decreases of RA signaling. However, the mechanisms underlying these contradictory phenotypes are not completely understood. Here, we report that using a hyperactive RA receptor to enhance RA signaling in zebrafish embryos leads to defects associated with gain and loss of RA signaling. While the gain-of-function phenotypes arise from an initial increase in RA signaling, using genetic epistasis analysis we found that the loss-of-function phenotypes result from a clearing of embryonic RA that requires a rapid and dramatic increase in cyp26a1 expression. Thus, the sensitivity of cyp26a1 expression to increased RA signaling causes an overcompensation of negative feedback and loss of embryonic RA signaling. Additionally, we used blastula transplantation experiments to test if Cyp26a1, despite its cellular localization, can limit RA exposure to neighboring cells. We find that enhanced Cyp26a1 expression limits RA signaling in the local environment, thus providing the first direct evidence that Cyp26 enzymes can have cell non-autonomous consequences on RA levels within tissues. Therefore, our results provide novel insights into the teratogenic mechanisms of RA signaling and the cellular mechanisms by which Cyp26a1 expression can shape a RA gradient. PMID- 26116178 TI - Synthesis and evaluation of the anti-nociceptive and anti-inflammatory activity of 4-aminoquinoline derivatives. AB - In this paper, we describe the synthesis and pharmacological evaluation of a series of 4-aminoquinolines. The compounds were characterised and tested in models of pain and inflammation, using the writhing test with acetic acid, formalin test, peritonitis test by zymosan and arthritis test with Freund's adjuvant complete assay. The results revealed that all of the 4-aminoquinolines that were prepared promoted anti-nociceptive activity as well as acute and chronic anti-inflammatory effects, with marked activity in the derivates labelled with BAQ and 7-CF3-MAQ. After 7 days of treatment, 7-CF3-MAQ did not induce significant hepatotoxicity, gastrotoxicity or nephrotoxicity. PMID- 26116179 TI - Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents. AB - Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease. Here, we report on the synthesis and biological evaluation of a series of nitroxoline-based analogs that were designed by merging the scaffold of 8-hydroxyquinoline with that of a known selective butyrylcholinesterase inhibitor that has promising anti-Alzheimer properties. Most strikingly, compound 8g inhibits self-induced aggregation of the amyloid beta peptide (Abeta1-42), inhibits with sub-micromolar potency butyrylcholinesterase (IC50=215 nM), and also selectively complexes Cu(2+). Our study thus designates this compound as a promising multifunctional agent for therapeutic treatment of Alzheimer's disease. The crystal structure of human butyrylcholinesterase in complex with compound 8g is also solved, which suggests ways to further optimize compounds featuring the 8-hydroxyquinoline scaffold. PMID- 26116180 TI - Identification of 5-nitrofuran-2-amide derivatives that induce apoptosis in triple negative breast cancer cells by activating C/EBP-homologous protein expression. AB - The transcription factor C/EBP-homologous protein (CHOP) is a key component of the terminal unfolded protein response (UPR) that mediates unresolvable endoplasmic reticulum stress-induced apoptosis. CHOP induction is known to cause cancer cell death. Chemicals that induce CHOP expression would thus be valuable as potential cancer therapeutics and as research tools. Here, we identified 5 nitrofuran-2-amide derivatives as small molecule activators of CHOP expression that induced apoptosis in triple negative breast cancer (TNBC) cells. Our preliminary structure-activity relationship studies indicated that compounds with an N-phenyl-5-nitrofuran-2-carboxamide skeleton were particularly potent inducers of TNBC cell apoptosis. The compounds activate CHOP expression via the PERK eIF2alpha-ATF4 branch of the UPR. These results indicate that small molecule activators of CHOP expression may have therapeutic potential for TNBC. PMID- 26116182 TI - Factor XIII deficiency and head trauma: management and therapy. PMID- 26116181 TI - Atypical Femoral Fractures-Ongoing and History of Bone-Specific Therapy, Concomitant Diseases, Medications, and Survival. AB - Although atypical femoral fractures (AFFs) are generally rare events; several studies have indicated a potential link between AFF and long-term bone-specific therapies (BSTs). The aim of this study was to analyze the frequency of AFF and potential associations with prior or ongoing BST. A total of 8851 Caucasian female and male patients with de novo hip fractures treated in the largest Austrian level 1 trauma center from 2000 to 2013 were selected. Of the total, 194 patients with a de novo low-traumatic subtrochanteric or shaft fractures were identified: 35 atypical and 159 typical fractures. Of these patients, concomitant diseases, medication, previous fractures, and survival data were retrieved and analyzed. Female patients in both groups were significantly older. The median survival was significantly shorter in patients with AFF (9 vs 18 months; p < 0.0001). Cardiovascular disease, sarcopenia, chronic kidney disease, type 2 diabetes, smoking (past or current history), and prevalent fragility fractures were more frequent in AFF patients, as well as the concomitant use of phenprocoumon, furosemide, and sulfonylurea. Although the number of patients with current BST was less in (14.5%) both groups, more patients in the AFF group were previously treated with BST (71% vs 49%; p = 0.016), and they received these therapies for a longer time period. A combination of severe comorbidities, long term pharmaceutical therapies, and a history of previous or ongoing BST was associated with an increased individual risk for AFF. PMID- 26116184 TI - Towards genomic prediction of drug resistance in tuberculosis. PMID- 26116183 TI - Effect of the Ebola-virus-disease epidemic on malaria case management in Guinea, 2014: a cross-sectional survey of health facilities. AB - BACKGROUND: The ongoing west Africa Ebola-virus-disease epidemic has disrupted the entire health-care system in affected countries. Because of the overlap of symptoms of Ebola virus disease and malaria, the care delivery of malaria is particularly sensitive to the indirect effects of the current Ebola-virus-disease epidemic. We therefore characterise malaria case management in the context of the Ebola-virus-disease epidemic and document the effect of the Ebola-virus-disease epidemic on malaria case management. METHODS: We did a cross-sectional survey of public health facilities in Guinea in December, 2014. We selected the four prefectures most affected by Ebola virus disease and selected four randomly from prefectures without any reported cases of the disease. 60 health facilities were sampled in Ebola-affected and 60 in Ebola-unaffected prefectures. Study teams abstracted malaria case management indicators from registers for January to November for 2013 and 2014 and interviewed health-care workers. Nationwide weekly surveillance data for suspect malaria cases reported between 2011 and 2014 were analysed independently. Data for malaria indicators in 2014 were compared with previous years. FINDINGS: We noted substantial reductions in all-cause outpatient visits (by 23 103 [11%] of 214 899), cases of fever (by 20249 [15%] of 131 330), and patients treated with oral (by 22 655 [24%] of 94 785) and injectable (by 5219 [30%] of 17 684) antimalarial drugs in surveyed health facilities. In Ebola affected prefectures, 73 of 98 interviewed community health workers were operational (74%, 95% CI 65-83) and 35 of 73 were actively treating malaria cases (48%, 36-60) compared with 106 of 112 (95%, 89-98) and 102 of 106 (96%, 91-99), respectively, in Ebola-unaffected prefectures. Nationwide, the Ebola-virus disease epidemic was estimated to have resulted in 74 000 (71 000-77 000) fewer malaria cases seen at health facilities in 2014. INTERPRETATION: The reduction in the delivery of malaria care because of the Ebola-virus-disease epidemic threatens malaria control in Guinea. Untreated and inappropriately treated malaria cases lead to excess malaria mortality and more fever cases in the community, impeding the Ebola-virus-disease response. FUNDING: Global Fund to Fight AIDS, Tuberculosis and Malaria, and President's Malaria Initiative. PMID- 26116185 TI - Malaria kills more than Ebola virus disease. PMID- 26116187 TI - Use of isopycnic plots to understand the role of density in SFC - I. Effect of pressure variation on retention factors. AB - This paper aims to demonstrate the effect of pressure variations in modifying analyte retention behavior in SFC. There is a general understanding that in SFC increasing pressure decreases the retention factor (k'), and vice versa. What is not clearly discussed or explained in any recent literature is that these variations can be very different at different operating pressures, temperatures and modifier concentrations. It is important to have a clearer understanding on these variabilities during method development and results analysis. In this paper the nature of k' variation with pressure, at different temperatures and modifier concentrations, will be explained with the help of isopycnic plots of CO2 and CO2+methanol mixtures. PMID- 26116186 TI - Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study. AB - BACKGROUND: Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drug-susceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistance-determining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all first line and second-line drugs for tuberculosis. METHODS: Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identified from the drug-resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. FINDINGS: We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89.2% of the validation-set phenotypes with a mean 92.3% sensitivity (95% CI 90.7 93.7) and 98.4% specificity (98.1-98.7). 10.8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85.1% vs 81.6%). No additional resistance determinants were identified among mutations under selection pressure in non-candidate genes. INTERPRETATION: A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically predicted. This approach could be integrated into routine diagnostic workflows, phasing out phenotypic drug-susceptibility testing while reporting drug resistance early. FUNDING: Wellcome Trust, National Institute of Health Research, Medical Research Council, and the European Union. PMID- 26116188 TI - Rapid activity-directed screening of estrogens by parallel coupling of liquid chromatography with a functional gene reporter assay and mass spectrometry. AB - In this study we developed a new LC nanofractionation platform that combines a human cell (BG1.Luc) gene reporter assay with a high resolution mass spectrometer for the detection and identification of estrogenic and anti-estrogenic compounds in environmental waters. The selection of this assay was based on its high sensitivity and selectivity, which is required for environmental trace level detection. We modified an autosampler and controlled it with in-house developed software to collect fractions in the low second range in microtiter plates. This ensured that chromatographic separation was maintained and allowed straightforward hyphenation with the bioassay. After bioassay testing, bioassay chromatograms were reconstructed and directly correlated with MS chromatograms that were obtained in parallel. This enabled to pinpoint bioactives in the MS chromatogram within a single fractionation cycle and results in a significant increase in throughput compared to traditional EDA studies. The sensitivity of the platform was low enough for environmental waters (80nM for bisphenol A and 320pM and 3.2nM for estradiol and estriol, respectively). In addition, the ability of the platform to detect anti-estrogens was successfully demonstrated as well. Finally, real samples were analysed. PMID- 26116189 TI - Establishment of a 'natural' origin for phytochemicals. PMID- 26116190 TI - Modeling of closed-loop recycling liquid-liquid chromatography: Analytical solutions and model analysis. AB - In closed-loop recycling (CLR) chromatography, the effluent from the outlet of a column is directly returned into the column through the sample feed line and continuously recycled until the required separation is reached. To select optimal operating conditions for the separation of a given feed mixture, an appropriate mathematical description of the process is required. This work is concerned with the analysis of models for the CLR separations. Due to the effect of counteracting mechanisms on separation of solutes, analytical solutions of the models could be helpful to understand and optimize chromatographic processes. The objective of this work was to develop analytical expressions to describe the CLR counter-current (liquid-liquid) chromatography (CCC). The equilibrium dispersion and cell models were used to describe the transport and separation of solutes inside a CLR CCC column. The Laplace transformation is applied to solve the model equations. Several possible CLR chromatography methods for the binary and complex mixture separations are simulated. PMID- 26116191 TI - Sulfonated nanocellulose for the efficient dispersive micro solid-phase extraction and determination of silver nanoparticles in food products. AB - This paper reports a simple approach to Analytical Nanoscience and Nanotechnology (AN&N) that integrates the nanotool, sulfonated nanocellulose (s-NC), and nanoanalyte, silver nanoparticles (AgNPs), in the same analytical process by using an efficient, environmentally friendly dispersive micro solid-phase extraction (D-MUSPE) capillary electrophoresis (CE) method with s-NC as sorbent material. Introducing negatively charged sulfate groups onto the surface of cellulose enhances its surface chemistry and enables the extraction and preconcentration of AgNPs of variable diameter (10, 20 and 60nm) and shell composition (citrate and polyvinylpyrrolidone coatings) from complex matrices into a cationic surfactant. In this way, AgNPs of diverse nature were successfully extracted onto the s-NC sorbent and then desorbed into an aqueous solution containing thiotic acid (TA) prior to CE without the need for any labor intensive cleanup. The ensuing eco-friendly D-MUSPE method exhibited a linear response to AgNPs with a limit of detection (LOD) of 20MUg/L. Its ability to specifically recognize AgNPs of different sizes was checked in orange juice and mussels, which afforded recoveries of 70.9-108.4%. The repeatability of the method at the limit of quantitation (LOQ) level was 5.6%. Based on the results, sulfonated nanocellulose provides an efficient, cost-effective analytical nanotool for the extraction of AgNPs from food products. PMID- 26116192 TI - Identification of Chemical Compounds That Inhibit the Function of Glutamyl-tRNA Synthetase from Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa glutamyl-tRNA synthetase (GluRS) was overexpressed in Escherichia coli. Sequence analysis indicated that P. aeruginosa GluRS is a discriminating GluRS and, similar to other GluRS proteins, requires the presence of tRNA(Glu) to produce a glutamyl-AMP intermediate. Kinetic parameters for interaction with tRNA were determined and the k(cat) and KM were 0.8 s(-1) and 0.68 uM, respectively, resulting in a k(cat)/KM of 1.18 s(-1) uM(-1). A robust aminoacylation-based scintillation proximity assay (SPA) assay was developed and 800 natural products and 890 synthetic compounds were screened for inhibitory activity against P. aeruginosa GluRS. Fourteen compounds with inhibitory activity were identified. IC50s were in the low micromolar range. The minimum inhibitory concentration (MIC) was determined for each of the compounds against a panel of pathogenic bacteria. Two compounds, BT_03F04 and BT_04B09, inhibited GluRS with IC50s of 21.9 and 24.9 uM, respectively, and both exhibited promising MICs against Gram-positive bacteria. Time-kill studies indicated that one compound was bactericidal and one was bacteriostatic against Gram-positive bacteria. BT_03F04 was found to be noncompetitive with both ATP and glutamic acid, and BT_04B09 was competitive with glutamic acid but noncompetitive with ATP. The compounds were not observed to be toxic to mammalian cells in MTT assays. PMID- 26116193 TI - Early insertion of a malleable penile prosthesis in ischaemic priapism allows later upsizing of the cylinders. AB - OBJECTIVE: Early insertion of a penile prosthesis in prolonged ischaemic priapism is easier to perform than late prosthesis placement, and preserves the penile length. The aim of this study was to assess whether a delayed exchange to an inflatable implant allows upsizing of the cylinders in patients who have undergone early insertion for refractory ischaemic priapism. MATERIALS AND METHODS: Over a 30 month period, 10 patients with ischaemic priapism underwent an early insertion of a malleable penile prosthesis. The mean age was 41.3 years and the mean duration of priapism was 188 h. Following a median period of 130.5 days, all of these patients underwent exchange of the malleable to an inflatable prosthesis. RESULTS: At the time of penile implant exchange, a median upsize in the length of the cylinders of 1 cm in either one or both corporal bodies (range 0-3 cm) was recorded. Five patients had deliberate downsizing at the initial operation owing to a previous shunt. The mean score on the five-item International Index of Erectile Function (IIEF-5) before insertion of the malleable prosthesis was 24 (range 20-25). Three months after the initial insertion of a malleable penile implant the satisfaction rate according to the IIEF-5 score was 80%. Three months after the exchange, the patient satisfaction rate increased to 90%. CONCLUSION: Insertion of a malleable penile prosthesis is an acceptable option for patients with refractory ischaemic priapism. Although some patients deliberately have a shorter implant inserted initially owing to a previous distal shunt procedure, following a period of resolution the cylinders can be upsized at a later operation. PMID- 26116194 TI - The association between glaucoma and immunoglobulin e antibody response to indoor allergens. PMID- 26116195 TI - Incidence of late-onset ocular hypertension following uncomplicated pars plana vitrectomy in pseudophakic eyes. PMID- 26116196 TI - Bimonthly variability of persistent organochlorines in plastic pellets from four beaches in Mumbai coast, India. AB - Organochlorines (OCs) such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) were analysed in plastic pellets collected from four beaches of Mumbai coast bimonthly from May 2011 to March 2012. A total of 72 pools of pellets were extracted and analysed by gas chromatograph equipped with a Ni(63) electron capture detector (ECD). The median concentrations of seven SigmaPCBs and 16 SigmaOCPs were 37.08 and 104.90 ng g(-1) (n = 72), respectively. PCB-28 was recorded at the highest concentration with a mean of 17.58 +/- 2.77 ng g(-1) among the seven PCBs studied, followed by PCB-52 and PCB-101. Bimonthly variation was significant for SigmaPCBs. The SigmaPCB concentration in November was at par with that of September and was significantly higher than those of the other months (p < 0.05) with an increasing trend during the monsoon period. Among the OCPs, gamma-HCH recorded the highest concentration with a mean of 33.88 +/- 5.97 ng g(-1) followed by heptachlor and alpha-HCH. The SigmaOCPs and SigmaHCHs are not significantly varied among the months and sites. However, significant variation was observed for SigmaDDTs among the months and sites (p < 0.05). The significantly higher concentration of SigmaDDT (46.55 +/- 12.23 ng g(-1)) was found in January than in the other months while it was intermediate in November. The study confirmed that plastic pellets are a trap for various cyclodine compounds in addition to PCB, HCH and DDT. Further, pellets can be used to study the temporal variability for a range of organic micropollutants. PMID- 26116197 TI - Fractionation and risk assessment of Fe and Mn in surface sediments from coastal sites of Sonora, Mexico (Gulf of California). AB - The aim of this study was to evaluate Fe and Mn distribution in geochemical fractions of the surface sediment of four oyster culture sites in the Sonora coast, Mexico. A selective fractionation scheme to obtain five fractions was adapted for the microwave system. Surface sediments were analyzed for carbonates, organic matter contents, and Fe and Mn in geochemical fractions. The bulk concentrations of Fe ranged from 10,506 to 21,918 mg/kg (dry weight, dry wt), and the bulk concentrations of Mn ranged from 185.1 to 315.9 mg/kg (dry wt) in sediments, which was low and considered as non-polluted in all of the sites. The fractionation study indicated that the major geochemical phases for the metals were the residual, as well as the Fe and Mn oxide fractions. The concentrations of metals in the geochemical fractions had the following order: residual >> Fe and Mn oxides > organic matter > carbonates > interchangeable. Most of the Fe and Mn were linked to the residual fraction. Among non-residual fractions, high percentages of Fe and Mn were linked to Fe and Mn oxides. The enrichment factors (EFs) for the two metals were similar in the four studied coasts, and the levels of Fe and Mn are interpreted as non-enrichment (EF < 1) because the metals concentrations were within the baseline concentrations. According to the environmental risk assessment codes, Fe and Mn posed no risk and low risk, respectively. Although the concentrations of Fe and Mn were linked to the residual fraction, the levels in non-residual fractions may significantly result in the transference of other metals, depending on several physico-chemical and biological factors. PMID- 26116198 TI - Kinetics of cadmium, chromium, and lead sorption onto chemically modified sugarcane bagasse and wheat straw. AB - In this study, cadmium (Cd), chromium (Cr), and lead (Pb) adsorption potential of unmodified and modified sugarcane bagasse and ground wheat straw was explored from aqueous solution through batch equilibrium technique. Both the materials were chemically modified by treating with sodium hydroxide (NaOH) alone and in combination with nitric acid (HNO3) and sulfuric acid (H2SO4). Two kinetic models, pseudo-first order and pseudo-second order were used to follow the adsorption process and reaction fallowed the later model. The Pb removal by both the materials was highest and followed by Cr and Cd. The chemical treatment invariably increased the adsorption capacity and NaOH treatment proved more effective than others. Langmuir maximum sorption capacity (q m) of Pb was utmost (12.8-23.3 mg/g of sugarcane bagasse, 14.5-22.4 mg/g of wheat straw) and of Cd was least (1.5-2.2 mg/g of sugarcane bagasse, 2.5-3.8 mg/g of wheat straw). The q m was in the order of Pb > Cr > Cd for all the three adsorbents. Results demonstrate that agricultural waste materials used in this study could be used to remediate the heavy metal-polluted water. PMID- 26116200 TI - Vaccine Errors: Understanding the Risks and the Responsibilities for Public Safety. PMID- 26116199 TI - Inverse correlation among organochlorine pesticide levels to total lipid serum contents: a preliminary study in Veracruz, Mexico. AB - Organochlorine pesticides, due to their hydrophobic nature and persistence, accumulate in tissues rich in lipids, which had been used as a biomarker for environmental pollution. In humans, organochlorine pesticides are continuously circulating and equilibrating among body compartments. The objective of the study was to evaluate the concentrations of organochlorine pesticides in blood serum and compare their levels to the total lipid contents in Veracruz, Mexico inhabitants. Our hypothesis is that concentrations of organochlorine pesticides will increase just as lipid concentrations. Levels of organochlorine pesticides were divided in ascending tertils according to their total lipid content. The linear trend model applied surprisingly reveals that the average level of all organochlorine pesticides decreases as the lipid concentration increases. From one tertil to the next beta-HCH, it shows a decrease of -3.19 mg kg(-1) on lipid basis, pp.'DDE levels decrease by -3.70 mg kg(-1) on lipid basis and pp.'DDT levels decrease -1.13 mg kg(-1) on lipid basis. We conclude that the levels and the orderly sequence of organochlorine pesticide distributions in the blood serum maintain an inverse relationship to total lipid blood serum concentrations. PMID- 26116201 TI - Eastern Bluebirds Alter their Song in Response to Anthropogenic Changes in the Acoustic Environment. AB - Vocal responses to anthropogenic noise have been documented in several species of songbird. However, only a few studies have investigated whether these adjustments are made in "real time" or are longer-term responses to particular soundscapes. Furthermore, increased ambient noise often is accompanied by structural changes to the habitat, including the introduction of noisy roadways and the removal of native vegetation. To date, no studies have simultaneously investigated the impact of both acoustic and structural disturbance on the same species. The relevance of each of these variables must be quantified if we wish to refine our understanding of the ways in which human activities influence avian communication. In this study, we quantified both among-male and within-male adjustments of song in response to ambient noise, and also investigated whether anthropogenic modifications of the habitat explained variations in songs' parameters. Recordings of songs were collected from male, breeding eastern bluebirds (Sialia sialis) residing in a network of nestboxes distributed across a gradient of anthropogenic disturbance. Levels of ambient noise were associated both with the average song-parameters of each male and with the change in a male's song-parameters between the loudest and quietest periods at his nest box. Males' song parameters were also related to habitat structure, as assessed using geographic information systems techniques. Males in noisier sites produced both higher-pitched and louder songs than did birds in quieter areas. Likewise, individual males demonstrated immediate adjustments to disturbance by noise, increasing the amplitude of their song between periods of quiet and loud ambient noise. Both spectral and temporal aspects of a male's song were related to whether his habitat was more "natural" or "anthropogenic." Our results indicate that males' adjustments of song may represent simultaneous responses to multiple modifications of the habitat by humans. However, we also conclude that biotic noise remains an important influence on avian signals even in anthropogenic areas. We suggest that human habitats provide an ideal setting in which to perform experiments on communication strategies, with resulting data poised to reveal underlying evolutionary processes while also informing conservation and management. PMID- 26116202 TI - Additional Navigational Strategies Can Augment Odor-Gated Rheotaxis for Navigation under Conditions of Variable Flow. AB - The navigation strategies animals use to find sources of odor depend on the olfactory stimuli, the properties of flowing fluids, and the locomotory capabilities of the animal. In high Reynolds number environments, animals typically use odor-gated rheotaxis to find the source of turbulent odor plumes. This strategy succeeds because, although turbulence creates an intermittent chemical cue, the animal follows the (continuous) directional cue created by the flow that is transporting the chemical. However, in nature, animals may lose all contact with an odor plume as variations in the direction of bulk flow cause the plume to be rotated away before the animal reaches the source of the odor. Our goal was to use a mathematical model to test the hypothesis that strategies that augment odor-gated rheotaxis would be beneficial for finding the source of an odor plume in such variable flow. The model links a stochastic variable-direction odor plume with a turbulence-based intermittent chemical signal and four different movement strategies, including: odor-gated rheotaxis alone (as a control), odor-gated rheotaxis augmented by further rheotaxis in the absence of odor, odor-gated rheotaxis augmented by a random walk, and odor-gated rheotaxis augmented by movement actively guided by the heading of the flow when the odor was still present. We found that any of the three augmented strategies could improve on strict odor-gated rheotaxis. Moreover, variations in performance caused the best strategy to depend on the speed of movement of the animal and the magnitude of the variation in flow, and more subtly on the duration over which the augmented strategy was performed. For most combinations of parameters in the model, either augmenting with a random walk or following the last-known heading were the best-performing strategies. Overall, our results suggest that marine animals that rely on odor cues to navigate in turbulent environments may augment odor-gated rheotaxis with additional movements that will increase the probability of finding the sources of odors. Moreover, we believe our approach to modeling odor plumes in variable flows is a valuable step toward mathematically capturing the key conditions experienced by animals navigating on the basis of odors carried by flows. PMID- 26116203 TI - Conservation Physiology of an Uncatchable Animal: The North Atlantic Right Whale (Eubalaena glacialis). AB - The North Atlantic right whale, Eubalaena glacialis (NARW), a critically endangered species that has been under intensive study for nearly four decades, provides an excellent case study for applying modern methods of conservation physiology to large whales. By combining long-term sighting histories of known individuals with physiological data from newer techniques (e.g., body condition estimated from photographs; endocrine status derived from fecal samples), physiological state and levels of stress can be estimated despite the lack of any method for nonlethal capture of large whales. Since traditional techniques for validating blood assays cannot be used in large whales, assays of fecal hormones have been validated using information on age, sex, and reproductive state derived from an extensive NARW photo-identification catalog. Using this approach, fecal glucocorticoids have been found to vary dramatically with reproductive state. It is therefore essential that glucocorticoid data be interpreted in conjunction with reproductive data. A case study correlating glucocorticoids with chronic noise is presented as an example. Keys to a successful research program for this uncatchable species have included: consistent population monitoring over decades, data-sharing across institutions, an extensive photo-identification catalog that documents individual histories, and consistent efforts at noninvasive collection of samples over years. Future research will require flexibility to adjust to changing distributions of populations. PMID- 26116204 TI - Acute severe valgus instability without elbow dislocation. AB - BACKGROUND: The purpose of this study was to investigate the pathoanatomy of acute valgus instability without elbow dislocation and to evaluate clinical outcomes after operative treatment. METHODS: Seven patients presented with acute severe valgus instability without elbow dislocation or fracture after a single traumatic episode. Five patients had primary repair of the medial collateral ligament (MCL) and flexor-pronator tendon (FPT) with suture anchor. Two patients with highly unstable elbow had primary repair of both the medial and lateral structures. On the basis of magnetic resonance imaging and intraoperative findings, the injury patterns of the ligament, capsule, tendon, and bone structures were evaluated. Clinical outcomes were assessed with the Mayo Elbow Performance Score and the shortened Disabilities of the Arm, Shoulder, and Hand score. RESULTS: A complete tear of the MCL from its humeral origin and FPT was found in all patients. The anterior capsule was also damaged. A stripping-type complete tear of the lateral collateral ligament complex with significant instability was observed in 2 patients. Bone contusion at the capitellum or radial head was found in 6 patients. The mean Mayo Elbow Performance Score and shortened Disabilities of the Arm, Shoulder, and Hand score at final follow-up were 95.7 and 12.0. All patients returned to previous work levels within 4 months after operation. CONCLUSION: These results indicate that complete tears of both the MCL and FPT occur with severe valgus instability. Primary repair of medial structures with suture anchor in acute severe valgus instability can restore stability. PMID- 26116205 TI - The use of 3D printing technology in reconstruction of a severe glenoid defect: a case report with 2.5 years of follow-up. PMID- 26116206 TI - Does microvascularization of the footprint play a role in rotator cuff healing of the shoulder? AB - BACKGROUND: The aim of the study was to evaluate the relationship between bone microvascularization of the footprint and tendon integrity after rotator cuff repair of the shoulder. METHODS: Forty-eight patients (mean age, 59 years; +/ 7.9) with a chronic rotator cuff tear underwent a tendon repair with a single-row technique and were studied prospectively. A core obtained from the footprint during the procedure allowed determination of the bone's microvascularization with an immunohistochemistry technique using anti-CD34 antibodies. Clinical evaluation was performed at a minimum of 12-month follow-up, and rotator cuff integrity was assessed with ultrasound according to Sugaya's classification. RESULTS: At a mean follow-up of 13 months, the Constant score improved from 40 to 75 points; American Shoulder and Elbow Surgeons score, from 59 to 89 points; and subjective shoulder value, from 38% to 83% (P < .001). Ultrasound identified 18 patients with Sugaya type I healing, 27 patients with type II, and 3 patients with type IV. No patients showed Sugaya type III or V repairs. The rate of microvascularization of the footprint was 15.6%, 13.9%, and 4.2% for type I, II, and IV tendon integrity, respectively (I vs. II, P = .22; II vs. IV, P = .02; I vs. IV, P = .0022). Patients with a history of corticosteroid injection had a lower rate of microvascularization than the others (10.3% vs. 16.2%; P = .03). CONCLUSIONS: Even if overall satisfactory clinical outcomes are achieved after a rotator cuff repair, bone microvascularization of the footprint plays a role in rotator cuff healing. A lower rate of microvessels decreases the tendon integrity and healing potential after repair. PMID- 26116207 TI - Dietary habits and leisure-time physical activity in relation to adiposity, dyslipidemia, and incident dysglycemia in the pathobiology of prediabetes in a biracial cohort study. AB - BACKGROUND: Dietary and exercise data are frequently recorded in clinical research, but their correlation with metabolic measures needs further evaluation. OBJECTIVE: We examined the association of food and exercise habits with body size, lipid profile, and glycemia in a prospective biracial cohort. METHODS: The Pathobiology of Prediabetes in A Biracial Cohort study followed initially normoglycemic offspring of parents with type 2 diabetes (T2DM) for the occurrence of incident prediabetes, defined as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). At enrollment, participants underwent a 75-gram OGTT, anthropometry, measurement of fasting lipids, insulin, and body fat (DEXA), and completed the Food Habits Questionnaire (FHQ), and Modifiable Activity Questionnaire (MAQ). We assessed the relationship between FHQ and MAQ scores and adiposity, cardiometabolic measures, and incident dysglycemia. RESULTS: Among our cohort of 338 subjects (188 black, 150 white; mean age {+/-SD} 45.2+/-10.2 years, BMI 30.3+/-7.2 kg/m(2)), FHQ and MAQ scores were individually correlated with BMI (r=0.14, -0.12; P=0.01, 0.03) and waist circumference (r=0.19, -0.11; P=0.004, 0.05). Diet-adjusted leisure activity (MAQ/FHQ) was significantly correlated with total body fat (r=-0.20, P=0.0007), trunk fat (r=-0.20, P=0.0006), and serum triglycerides (r=-0.17, P=0.003) and HDL cholesterol (r=0.11, P=0.04) levels. During 5.5 years of follow-up, 111 subjects (Progressors) developed prediabetes (n=101) or diabetes (n=10) and 227 remained normoglycemic (Non-progressors). Age, BMI, MAQ and MAQ/FHQ values were significant predictors of incident prediabetes/diabetes. Progressors reported similar dietary habits (FHQ score 2.57+/-0.49 vs. 2.57+/-0.53) but 30% lower physical activity (MAQ score 15.2+/ 20.5 vs. 22.3+/-30.5 MET-hr/wk, P=0.015) compared with non-progressors. CONCLUSIONS: Among African-American and Caucasian offspring of parents with T2DM, self-reported dietary and exercise habits correlated with measures of adiposity and dyslipidemia; however, physical activity, but not dietary recall, significantly predicted incident dysglycemia during 5.5 years of follow-up. PMID- 26116208 TI - Abdominal admittance helps to predict the amount of fluid accumulation in patients with acute heart failure syndromes. AB - BACKGROUND: Predicting fluid volume that needs to be removed in acute heart failure syndromes (AHFS) patients remains challenging. Thoracic admittance (TA), the reciprocal of thoracic impedance measured by bioelectrical impedance, reflects the amount of fluid in the thorax. Abdominal organs play an important role in AHFS as systemic fluid reservoirs. We investigated the relationship between abdominal admittance (AA) at the time of admission for AHFS and net fluid loss (NFL) during hospitalization. METHODS: Sixty-two consecutive patients hospitalized for AHFS [age 71+/-10 years, left ventricular ejection fraction (LVEF) 39+/-17%] were studied. The admittance values, i.e. the reciprocals of the impedance values, were derived using a BioZ((r)) (CardioDynamics, San Diego, CA, USA). The change in weight from admission to discharge was used as a surrogate of amount of NFL. RESULTS: At the time of admission, a significant correlation was detected between TA and AA (r=0.46, p=0.0001). TA at admission was significantly correlated with the LV structural variables (end-diastolic dimension and end systolic dimension), and serum sodium level. AA at admission was significantly correlated with New York Heart Association (NYHA) class and plasma BNP, and also correlated with LVEF and variables related to systemic congestion [minimal inferior vena cava (IVC) diameter and tricuspid regurgitation grade]. Neither TA nor AA values were significantly correlated with weight at admission. During hospitalization, TA and AA declined from 44+/-8kOmega(-1) to 36+/-6kOmega(-1) (p<0.0001) and from 74+/-25kOmega(-1) to 56+/-17kOmega(-1) (p<0.0001), respectively. Weight fell from 60.1+/-10.8kg to 54.5+/-9.4kg (p<0.0001), while NFL was 5.8kg (range, 0.1-17.5kg). In univariate analyses, the admission NYHA class, TA, AA, weight, and IVC diameter correlated with NFL. Multivariate analysis demonstrated that only admission weight [standardized partial regression coefficient (SPRC)=0.596], AA (SPRC=0.529), and NYHA class (SPRC=0.277) were independent predictors of NFL. CONCLUSION: Abdominal admittance measurement helps to predict the amount of fluid volume to be removed in patients with AHFS. PMID- 26116209 TI - Noninvasive estimation of pulmonary capillary wedge pressure in patients with mitral regurgitation: A speckle tracking echocardiography study. AB - BACKGROUND: Echocardiographic parameters to predict pulmonary capillary wedge pressure (PCWP) in mitral regurgitation (MR) are not yet elucidated. We reported that PCWP could be accurately estimated by novel KT index which is defined as log10[left atrial (LA) emptying function (EF)/LA volume]. We examined the usefulness of the KT index as a predictor of PCWP in primary and secondary MR with sinus rhythm and also MR with atrial fibrillation. METHODS: LA dimension, strain, volume, EF, and E/e' were measured in moderate to severe MR with sinus rhythm (n=58, age: 67+/-8 years) and MR with atrial fibrillation (n=24, age: 69+/ 11 years) just before catheterization and in normal subjects (n=26, age: 67+/-11 years) using speckle tracking echocardiography. MR with sinus rhythm was divided into primary MR (n=27) and secondary MR (n=31). The estimated PCWP (ePCWP) was calculated as 10.8-12.4*KT index. RESULTS: There was a correlation between PCWP and LA dimension, E/e', minimum LA volume index, active LAEF, total LAEF, or LA strain (r=0.32, r=0.31, r=0.55, r=-0.61, r=-0.51, and r=-0.50, respectively, p<0.05). The better correlation was found between PCWP and ePCWP in MR including both primary and secondary MR and also MR with atrial fibrillation (r=0.70, r=0.67, and r=0.58, respectively, p<0.01). Multiple regression analysis revealed that ePCWP was an independent predictor of PCWP in MR. The ePCWP demonstrated good diagnostic accuracy (area under the curve of 0.86) and sensitivity (81%) and specificity (71%) to predict elevated PCWP >15mmHg using a cut-off of 16mmHg. CONCLUSION: The ePCWP was the reliable echocardiographic parameter to predict PCWP in primary and secondary MR and might also be useful in MR with atrial fibrillation. The ePCWP may have an incremental value in a clinical setting. PMID- 26116211 TI - Comparative Analysis of Transmembrane Regulators of the Filamentous Growth Mitogen-Activated Protein Kinase Pathway Uncovers Functional and Regulatory Differences. AB - Filamentous growth is a microbial differentiation response that involves the concerted action of multiple signaling pathways. In budding yeast, one pathway that regulates filamentous growth is a Cdc42p-dependent mitogen-activated protein kinase (MAPK) pathway. Several transmembrane (TM) proteins regulate the filamentous growth pathway, including the signaling mucin Msb2p, the tetraspan osmosensor Sho1p, and an adaptor Opy2p. The TM proteins were compared to identify common and unique features. Msb2p, Sho1p, and Opy2p associated by coimmunoprecipitation analysis but showed predominantly different localization patterns. The different localization patterns of the proteins resulted in part from different rates of turnover from the plasma membrane (PM). In particular, Msb2p (and Opy2p) were turned over rapidly compared to Sho1p. Msb2p signaled from the PM, and its turnover was a rate-limiting step in MAPK signaling. Genetic analysis identified unique phenotypes of cells overexpressing the TM proteins. Therefore, each TM regulator of the filamentous growth pathway has its own regulatory pattern and specific function in regulating filamentous growth. This specialization may be important for fine-tuning and potentially diversifying the filamentation response. PMID- 26116212 TI - Auxotrophic Mutations Reduce Tolerance of Saccharomyces cerevisiae to Very High Levels of Ethanol Stress. AB - Very high ethanol tolerance is a distinctive trait of the yeast Saccharomyces cerevisiae with notable ecological and industrial importance. Although many genes have been shown to be required for moderate ethanol tolerance (i.e., 6 to 12%) in laboratory strains, little is known of the much higher ethanol tolerance (i.e., 16 to 20%) in natural and industrial strains. We have analyzed the genetic basis of very high ethanol tolerance in a Brazilian bioethanol production strain by genetic mapping with laboratory strains containing artificially inserted oligonucleotide markers. The first locus contained the ura3Delta0 mutation of the laboratory strain as the causative mutation. Analysis of other auxotrophies also revealed significant linkage for LYS2, LEU2, HIS3, and MET15. Tolerance to only very high ethanol concentrations was reduced by auxotrophies, while the effect was reversed at lower concentrations. Evaluation of other stress conditions showed that the link with auxotrophy is dependent on the type of stress and the type of auxotrophy. When the concentration of the auxotrophic nutrient is close to that limiting growth, more stress factors can inhibit growth of an auxotrophic strain. We show that very high ethanol concentrations inhibit the uptake of leucine more than that of uracil, but the 500-fold-lower uracil uptake activity may explain the strong linkage between uracil auxotrophy and ethanol sensitivity compared to leucine auxotrophy. Since very high concentrations of ethanol inhibit the uptake of auxotrophic nutrients, the active uptake of scarce nutrients may be a major limiting factor for growth under conditions of ethanol stress. PMID- 26116213 TI - Functional Analysis of Sterol Transporter Orthologues in the Filamentous Fungus Aspergillus nidulans. AB - Polarized growth in filamentous fungi needs a continuous supply of proteins and lipids to the growing hyphal tip. One of the important membrane compounds in fungi is ergosterol. At the apical plasma membrane ergosterol accumulations, which are called sterol-rich plasma membrane domains (SRDs). The exact roles and formation mechanism of the SRDs remained unclear, although the importance has been recognized for hyphal growth. Transport of ergosterol to hyphal tips is thought to be important for the organization of the SRDs. Oxysterol binding proteins, which are conserved from yeast to human, are involved in nonvesicular sterol transport. In Saccharomyces cerevisiae seven oxysterol-binding protein homologues (OSH1 to -7) play a role in ergosterol distribution between closely located membranes independent of vesicle transport. We found five homologous genes (oshA to oshE) in the filamentous fungi Aspergillus nidulans. The functions of OshA-E were characterized by gene deletion and subcellular localization. Each gene-deletion strain showed characteristic phenotypes and different sensitivities to ergosterol-associated drugs. Green fluorescent protein-tagged Osh proteins showed specific localization in the late Golgi compartments, puncta associated with the endoplasmic reticulum, or diffusely in the cytoplasm. The genes expression and regulation were investigated in a medically important species Aspergillus fumigatus, as well as A. nidulans. Our results suggest that each Osh protein plays a role in ergosterol distribution at distinct sites and contributes to proper fungal growth. PMID- 26116214 TI - The Centriole Cartwheel Protein SAS-6 in Trypanosoma brucei Is Required for Probasal Body Biogenesis and Flagellum Assembly. AB - The centriole in eukaryotes functions as the cell's microtubule-organizing center (MTOC) to nucleate spindle assembly, and its biogenesis requires an evolutionarily conserved protein, SAS-6, which assembles the centriole cartwheel. Trypanosoma brucei, an early branching protozoan, possesses the basal body as its MTOC to nucleate flagellum biogenesis. However, little is known about the components of the basal body and their roles in basal body biogenesis and flagellum assembly. Here, we report that the T. brucei SAS-6 homolog, TbSAS-6, is localized to the mature basal body and the probasal body throughout the cell cycle. RNA interference (RNAi) of TbSAS-6 inhibited probasal body biogenesis, compromised flagellum assembly, and caused cytokinesis arrest. Surprisingly, overexpression of TbSAS-6 in T. brucei also impaired probasal body duplication and flagellum assembly, contrary to SAS-6 overexpression in humans, which produces supernumerary centrioles. Furthermore, we showed that depletion of T. brucei Polo-like kinase, TbPLK, or inhibition of TbPLK activity did not abolish TbSAS-6 localization to the basal body, in contrast to the essential role of Polo like kinase in recruiting SAS-6 to centrioles in animals. Altogether, these results identified the essential role of TbSAS-6 in probasal body biogenesis and flagellum assembly and suggest the presence of a TbPLK-independent pathway governing basal body duplication in T. brucei. PMID- 26116215 TI - A Meta-Regression Method for Studying Etiological Heterogeneity Across Disease Subtypes Classified by Multiple Biomarkers. AB - In interdisciplinary biomedical, epidemiologic, and population research, it is increasingly necessary to consider pathogenesis and inherent heterogeneity of any given health condition and outcome. As the unique disease principle implies, no single biomarker can perfectly define disease subtypes. The complex nature of molecular pathology and biology necessitates biostatistical methodologies to simultaneously analyze multiple biomarkers and subtypes. To analyze and test for heterogeneity hypotheses across subtypes defined by multiple categorical and/or ordinal markers, we developed a meta-regression method that can utilize existing statistical software for mixed-model analysis. This method can be used to assess whether the exposure-subtype associations are different across subtypes defined by 1 marker while controlling for other markers and to evaluate whether the difference in exposure-subtype association across subtypes defined by 1 marker depends on any other markers. To illustrate this method in molecular pathological epidemiology research, we examined the associations between smoking status and colorectal cancer subtypes defined by 3 correlated tumor molecular characteristics (CpG island methylator phenotype, microsatellite instability, and the B-Raf protooncogene, serine/threonine kinase (BRAF), mutation) in the Nurses' Health Study (1980-2010) and the Health Professionals Follow-up Study (1986 2010). This method can be widely useful as molecular diagnostics and genomic technologies become routine in clinical medicine and public health. PMID- 26116216 TI - The Safety of Yoga: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - As yoga has gained popularity as a therapeutic intervention, its safety has been questioned in the lay press. Thus, this review aimed to systematically assess and meta-analyze the frequency of adverse events in randomized controlled trials of yoga. MEDLINE/PubMed, Scopus, the Cochrane Library, and IndMED were screened through February 2014. Of 301 identified randomized controlled trials of yoga, 94 (1975-2014; total of 8,430 participants) reported on adverse events. Life threatening, disabling adverse events or those requiring intensive treatment were defined as serious and all other events as nonserious. No differences in the frequency of intervention-related, nonserious, or serious adverse events and of dropouts due to adverse events were found when comparing yoga with usual care or exercise. Compared with psychological or educational interventions (e.g., health education), more intervention-related adverse events (odds ratio = 4.21, 95% confidence interval: 1.01, 17.67; P = 0.05) and more nonserious adverse events (odds ratio = 7.30, 95% confidence interval: 1.91, 27.92; P < 0.01) occurred in the yoga group; serious adverse events and dropouts due to adverse events were comparable between groups. Findings from this review indicate that yoga appears as safe as usual care and exercise. The adequate reporting of safety data in future randomized trials of yoga is crucial to conclusively judge its safety. PMID- 26116217 TI - Re: "fragmentation and stability of circadian activity rhythms predict mortality: the Rotterdam study". PMID- 26116218 TI - An expected fusion. PMID- 26116219 TI - Transcriptome sequencing reveals the roles of transcription factors in modulating genotype by nitrogen interaction in maize. AB - KEY MESSAGE: Global transcriptome analysis in maize revealed differential nitrogen response between genotypes and implicate a crucial role of transcription factors in driving genotype by nitrogen interactions at gene expression level. Developing nitrogen-efficient cultivars are essential for sustainable and productive agriculture. Nitrogen use efficiency of plants is highly dependent on the interaction of environmental and genetic variation and results in adaptive phenotypes. This study used transcriptome sequencing to perform a comprehensive genotype by nitrogen (G * N) interaction analysis for two elite Chinese maize inbreds grown at normal and low nitrogen levels in field conditions. We demonstrated that the two maize inbreds showed contrasting agronomic and transcriptomic responses to changes in nitrogen availability. A total of 96 genes with a significant G * N interaction were detected. After characterizing the expression patterns of G * N interaction genes, we found that the G * N interaction genes tended to show condition-specific differential expression. The functional annotations of G * N interaction genes revealed that many different kinds of genes were involved in G * N interactions, but a significant enrichment for transcription factors was detected, particularly the AP2/EREBP and WRKY family, suggesting that transcription factors might play important roles in driving G * N interaction at gene expression level for nitrogen response in maize. Taken together, these results not only provide novel insights into the mechanism of nitrogen response in maize and set important basis for further characterization but also have important implications for other genotype by stress interaction. PMID- 26116220 TI - Risk-Adjusted Variation of Publicly Reported Emergency Department Timeliness Measures. AB - STUDY OBJECTIVE: The Centers for Medicare & Medicaid Services (CMS) recently published emergency department (ED) timeliness measures. These data show substantial variation in hospital performance and suggest the need for process improvement initiatives. However, the CMS measures are not risk adjusted and may provide misleading information about hospital performance and variation. We hypothesize that substantial hospital-level variation will persist after risk adjustment. METHODS: This cross-sectional study included hospitals that participated in the Emergency Department Benchmarking Alliance and CMS ED measure reporting in 2012. Outcomes included the CMS measures corresponding to median annual boarding time, length of stay of admitted patients, length of stay of discharged patients, and waiting time of discharged patients. Covariates included hospital structural characteristics and case-mix information from the American Hospital Association Survey, CMS cost reports, and the Emergency Department Benchmarking Alliance. We used a gamma regression with a log link to model the skewed outcomes. We used indirect standardization to create risk-adjusted measures. We defined "substantial" variation as coefficient of variation greater than 0.15. RESULTS: The study cohort included 723 hospitals. Risk-adjusted performance on the CMS measures varied substantially across hospitals, with coefficient of variation greater than 0.15 for all measures. Ratios between the 10th and 90th percentiles of performance ranged from 1.5-fold for length of stay of discharged patients to 3-fold for waiting time of discharged patients. CONCLUSION: Policy-relevant variations in publicly reported CMS ED timeliness measures persist after risk adjustment for nonmodifiable hospital and case-mix characteristics. Future "positive deviance" studies should identify modifiable process measures associated with high performance. PMID- 26116221 TI - Training the Mind, and the Food and Drug Administration, on Droperidol. PMID- 26116222 TI - Do alpha-Blockers Expedite Ureteral Stone Passage? PMID- 26116223 TI - Comparison of Early Goal-Directed Therapy With Usual Care for Severe Sepsis and Septic Shock. PMID- 26116224 TI - The Numeric Scoring of Pain: This Practice Rates a Zero Out of Ten. PMID- 26116225 TI - A national survey of the molecular epidemiology of Clostridium difficile in Israel: the dissemination of the ribotype 027 strain with reduced susceptibility to vancomycin and metronidazole. AB - Our goals were to study the molecular epidemiology and antimicrobial susceptibilities of C. difficile strains in Israel. Microbiology laboratories serving 6 general hospitals (GH) and 10 long-term care facilities (LTCF) were asked to submit all stool samples in January-February 2014 that tested positive for C. difficile. Toxigenic C. difficile isolates were recovered in 208 out of 217 samples (95.8%), of which 50 (23.6%) were from LTCFs. Ribotype 027 was the most common type overall, identified in 65 samples (31.8%), and was the predominant strain in the 3 GHs with the highest incidence of C. difficile infections. Other common strains were slpA types cr-02 (n = 45) and hr-02 (n = 18). The proportions of vancomycin and metronidazole MIC values >2mg/L were high in ribotype 027 (87.7% and 44.6%, respectively) and slpA-cr-02 strains (88.8% and 17.8%, respectively). This study demonstrates that the ribotype 027 strain has disseminated across Israel and is now the most common strain. PMID- 26116226 TI - Diverse cellular and organismal functions of the lysosomal thiol reductase GILT. AB - Gamma-interferon-inducible lysosomal thiol reductase (GILT) is the only enzyme known to catalyze disulfide bond reduction in the endocytic pathway. GILT facilitates the presentation of a subset of epitopes from disulfide bond containing antigens. Enhanced presentation of MHC class II-restricted epitopes alters central tolerance and modulates CD4+ T cell-mediated autoimmunity. Improved cross-presentation of viral epitopes results in improved cross-priming of viral-specific CD8+ T cells. GILT regulates the cellular redox state. In GILT /- cells, there is a shift from the reduced to the oxidized form of glutathione, resulting in mitochondrial autophagy, decreased superoxide dismutase 2, and elevated superoxide levels. GILT expression diminishes cellular activation, including decreased phosphorylated ERK1/2, and decreases cellular proliferation. GILT enhances the activity of bacterial hemolysins, such as listeriolysin O, and increases bacterial replication and infection. GILT expression in cancer cells is associated with improved patient survival. These diverse roles of GILT are discussed. PMID- 26116227 TI - Electroporation-based applications in biotechnology. AB - Electroporation is already an established technique in several areas of medicine, but many of its biotechnological applications have only started to emerge; we review here some of the most promising. We outline electroporation as a phenomenon and then proceed to applications, first outlining the best established - the use of reversible electroporation for heritable genetic modification of microorganisms (electrotransformation), and then explore recent advances in applying electroporation for inactivation of microorganisms, extraction of biomolecules, and fast drying of biomass. Although these applications often aim to upscale to the industrial and/or clinical level, we also outline some important chip-scale applications of electroporation. We conclude our review with a discussion of the main challenges and future perspectives. PMID- 26116229 TI - Rosiglitazone inhibition of calvaria-derived osteoblast differentiation is through both of PPARgamma and GPR40 and GSK3beta-dependent pathway. AB - Rosiglitazone (RSG) can cause bone loss, however the mechanisms remain largely unknown. This study aims to investigate the effects of RSG on differentiation and mineralization of osteoblasts using primary cultured mouse fetal calvaria-derived osteoblasts as a model, and elucidate the receptor and signaling pathways responsible for these effects. We found that RSG suppressed the differentiation and mineralization of calvaria-derived osteoblasts. Peroxisome proliferators activated receptor gamma (PPARgamma) siRNA significantly reversed the inhibitory effect of RSG on osteogenic differentiation. The expression of G protein-coupled receptor (GPR) 40 was suppressed during differentiation, but was increased by RSG treatment. GPR40 siRNA significantly reversed the inhibitory effect of RSG on osteogenesis. RSG activated glycogen synthase kinase (GSK)-3beta, which in turn decreased beta-catenin expression. RSG-induced GSK3beta activation was mediated through both PPARgamma and GPR40. These results suggest that both PPARgamma and GRP40 are required for RSG-induced inhibition of mouse calvaria osteoblast differentiation, which is mediated through GSK3beta-dependent pathway. PMID- 26116228 TI - Multiple roles of timing in somite formation. AB - During development, vertebrate embryos produce serially repeated elements, the somites, on each side of the midline. These generate the vertebral column, skeletal musculature and dermis. They form sequentially, one pair at a time, from mesenchymal tissue near the tail. Somite development is a complex process. The embryo must control the number, size, and timing of somite formation, their subdivision into functional regions along three axes, regional identity such that somites develop in a region-specific way, and interactions with neighbouring tissues that coordinate them with nearby structures. Here we discuss many timing related mechanisms that contribute to set up the spatial pattern. PMID- 26116230 TI - Metformin regulates stromal-epithelial cells communication via Wnt2/beta-catenin signaling in endometriosis. AB - In previous studies, we found that endometriotic stromal cells lose the ability to regulate cell survival signaling in endometriotic epithelial cells. Here, we invested the effect of Metformin on the stromal-epithelial cells crosstalk in endometriosis and explored the pathway that might be involved. We found that ectopic endometriotic stromal cells (ESC) expressed and secreted higher Wnt2 protein compared with normal endometrial stromal cells (NSC). Conditioned medium (CM) from ESC supplemented with Wnt2 antibody significantly inhibited the growth of normal endometrial epithelial cells (NEC), while CM from ESC per se showed no significant effect on the growth of NEC. Metformin decreased the expression and secretion of Wnt2 in ESC. CM from Metformin-pretreated ESC significantly inhibited the growth of NEC. In conclusion, Wnt2/beta-catenin signaling was involved in stromal-epithelial cells interaction in endometriosis. Metformin might regulate the stroma-epithelium communication via Wnt2-mediated signaling in endometriosis. PMID- 26116231 TI - Insulin resistance by TNF-alpha is associated with mitochondrial dysfunction in 3T3-L1 adipocytes and is ameliorated by punicic acid, a PPARgamma agonist. AB - Punicic acid (PA), a poly unsaturated fatty acid found abundantly in pomegranate seed oil is reported to have PPARgamma agonist property. TNF-alpha mediated insulin resistance plays an important role in the pathogenesis of diabetes and is associated with severe mitochondrial impairment. In this study, PA was evaluated for its ability to ameliorate TNF-alpha induced mitochondrial dysfunctions in 3T3 L1 adipocytes. For this, we examined the alterations in mitochondrial energetics, biogenesis, transmembrane potential and dynamics in TNF-alpha induced insulin resistant model of 3T3-L1 adipocytes. PA improved glucose uptake, ROS accumulation, mitochondrial biogenesis and energetics in TNF-alpha treated cells. In addition, treatment with PA was found to ameliorate TNF-alpha induced alterations in proteins associated with mitochondrial dynamics like FIS1 and OPA1. These findings suggest that PA can be considered as an active lead for the management of insulin resistance and associated mitochondrial dysfunctions. PMID- 26116232 TI - Hypusination of eukaryotic initiation factor 5A via cAMP-PKA-ERK1/2 pathway is required for ligand-induced downregulation of LH receptor mRNA expression in the ovary. AB - Luteinizing hormone receptor (LHR) mRNA expression in the ovary is regulated post transcriptionally by an LH receptor mRNA binding protein (LRBP). Eukaryotic initiation factor 5A (EIF5A), identified as an LRBP-interacting protein plays a crucial role in LHR mRNA expression. In this study, we have demonstrated that during hCG-induced LHR downregulation, a significant upregulation of eIF5A mRNA expression and hypusination of eIF5A protein occurs in a time dependent manner. Pretreatment with H89, a specific inhibitor of PKA, and U0126, a specific inhibitor of ERK1/2 significantly inhibited both hCG-induced eIF5A mRNA expression and hypusination of eIF5A protein. Pretreatment with GC7, a specific inhibitor of eIF5A hypusination significantly abolished hCG-induced LRBP mRNA and protein expression. Furthermore, GC7 pretreatment significantly inhibited hCG induced interaction of LRBP with LHR mRNA as assessed by RNA electrophoretic mobility gel shift assay (REMSA). GC7 treatment also reversed LHR mRNA downregulation. Taken together, these results suggest that hCG-induced LHR mRNA downregulation is mediated by cAMP-PKA-ERK1/2 signaling leading to activation of eIF5A hypusination. PMID- 26116233 TI - Histone hypoacetylation and increased histone deacetylases in peripheral blood mononuclear cells from patients with Graves' disease. AB - The objective of this study was to investigate histone modification patterns in peripheral blood mononuclear cells (PBMCs) of patients with Graves' disease (GD). Thirty GD patients and 20 healthy controls were enrolled in this study. Global histone H3/H4 acetylation levels of PBMCs in all subjects were detected by enzyme linked immunosorbent assay. mRNA levels of histone-related chromatin modifier genes were measured by real-time quantitative reverse transcription-polymerase chain reaction. Global histone H4 acetylation level in PBMCs of GD patients was significantly decreased compared with controls (p=0.005). The mRNA expression of histone deacetylases HDAC1 and HDAC2 were significantly increased in PBMCs of GD patients compared with controls (p=0.004 and 0.018; respectively). No significant difference was observed either in SIRT1 or in HATs mRNA including p300, CREBBP between GD patients and controls (p>0.05). Our findings firstly suggested that histone acetylation modifications are aberrant in PBMCs of GD patients, possibly due to the deregulation of epigenetic modifier genes. PMID- 26116235 TI - Distinct regions in the C-Terminus required for GLP-1R cell surface expression, activity and internalisation. AB - The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R), an important drug target in the treatment of type 2 diabetes, is a G-protein coupled receptor (GPCR) that mediates insulin secretion by GLP-1. The N-terminus controls GLP-1R biosynthetic trafficking to the cell surface but the C-terminus involvement in that trafficking is unknown. The aim of this study was to identify distinct regions within the C-terminal domain required for human GLP-1R (hGLP-1R) cell surface expression, activity and internalisation using a number of C-terminal deletions and site-directed mutations. The results of this study revealed that the residues 411-418 within the C-terminal domain of the hGLP-1R are critical in targeting the newly synthesised receptor to the plasma membrane. The residues 419-430 are important for cAMP producing activity of the receptor, most likely by coupling to Galphas. However, the residues 431-450 within the C-terminus are essential for agonist-induced hGLP-1R internalisation. In conclusion, these findings demonstrate the hGLP-1R has distinct regions within the C-terminal domain required for its cell surface expression, activity and agonist-induced internalisation. PMID- 26116234 TI - Trichostatin A reduces GnRH mRNA expression with a concomitant increase in retinaldehyde dehydrogenase in GnRH-producing neurons. AB - Trichostatin A (TSA) is a selective inhibitor of mammalian histone deacetylase and is widely used to modify the ability of DNA transcription factors to bind DNA within chromatin by interfering with histone deacetylation. In the GnRH-producing neuronal cell line GT1-7, TSA significantly reduced expression of GnRH mRNA. Kisspeptin, a known regulator of GnRH release, failed to increase GnRH mRNA expression and did not modify TSA-induced reduction of GnRH expression. TSA, but not kisspeptin, increased histone acetylation in whole-cell lysates and significantly stimulated the expression of retinaldehyde dehydrogenase (RALDH), a retinoic acid (RA)-synthesizing enzyme that is known to be involved in cell differentiation. In addition, treatment of the GT1-7 cells with RA dose dependently inhibited the expression of GnRH mRNA. Whereas, TSA-induced reduction of GnRH mRNA was not modulated by treatment with the pan-RA receptor inverse agonist BMS493 or the RA metabolism inhibitor liarozole. Our current results suggest that the RALDH and RA might not be directly involved in the reduction of GnRH expression induced by TSA, however these substances could be a novel regulator of GnRH. PMID- 26116236 TI - Rat Humanin is encoded and translated in mitochondria and is localized to the mitochondrial compartment where it regulates ROS production. AB - Evidence for the putative mitochondrial origin of the Humanin (HN) peptide has been lacking, although its cytoprotective activity has been demonstrated in a variety of organismal and cellular systems. We sought to establish proof-of principle for a mitochondria-derived peptide (MDP) in a rat-derived cellular system as the rat HN sequence is predicted to lack nuclear insertions of mitochondrial origin (NUMT). We found that the rat HN (Rattin; rHN) homologue is derived from the mitochondrial genome as evidenced by decreased production in Rho 0 cells, and that peptide translation occurs in the mitochondria as it is unaffected by cycloheximide. Rat HN localizes to the mitochondria in cellular subfractionation and immunohistochemical studies. Addition of a HN analogue to isolated mitochondria from rat INS-1 beta cells reduced hydrogen peroxide production by 55%. In summary, a locally bioactive peptide is derived and translated from an open reading frame (ORF) within rat mitochondrial DNA encoding 16S rRNA. PMID- 26116237 TI - GrOup based physical Activity for oLder adults (GOAL) randomized controlled trial: study protocol. AB - BACKGROUND: Physical activity has health benefits across the lifespan, yet only 13 % of Canadian older adults are sufficiently active. Results from a number of observational studies indicate that adults display positive preferences for exercising with others of a similar age and same gender, and that intra-group age and gender-similarity are associated with elevated exercise adherence. However, research has yet to experimentally examine the extent to which intra-group age- and gender-related similarity affect exercise adherence behaviors. METHODS/DESIGN: The GrOup-based physical Activity for oLder adults (GOAL) trial is a three-arm randomized control trial that will examine the efficacy of two different group-based exercise programs for older adults (informed by the tenets of self-categorization theory) in relation to a standard group-based exercise program. Within this manuscript we outline the design and proposed evaluation of the GOAL trial. The first arm is comprised of exercise groups made up of participants of a similar-age and of the same gender; the second arm consists of groups with similar-aged mixed gender participants; the control arm is comprised of mixed-aged mixed gender participants. We aim to compare the adherence rates of participants across conditions, as well as potential moderation effects and mediating mechanisms. DISCUSSION: Results from this trial will inform intervention designs to improve the exercise adherence behaviors of older adult. At a systems-level, should support be derived for the efficacy of the interventions tested in this trial, changing group composition (i.e., age, gender) represents a feasible program adaptation for physical activity centers. TRIAL REGISTRATION: ClinicalTrials.gov # NCT02023632 . Registered December 13, 2013. PMID- 26116238 TI - Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2 positive breast cancer patients undergoing neoadjuvant chemotherapy. AB - BACKGROUND: Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction. METHODS: The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8(+) T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-gamma ELISPOT and IFN-gamma/IL-2 DualSpot assays. RESULTS: After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti tumor T cell responses highlighted sustained levels of CD8(+) T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response. CONCLUSIONS: These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients. Trail registration: TRIAL REGISTRATION NUMBER: NCT02307227, registered on ClinicalTrials.gov ( http://www.clinicaltrials.gov , November 26, 2014). PMID- 26116240 TI - The home-made in situ passive flux sampler for the measurement of monoterpene emission flux: preliminary studies. AB - The paper presents the construction and metrological characteristics of the home made in situ passive flux sampler, an analytical tool representing small-scale emission chambers working in situ and passively sampling analytes from the gaseous phase. The sorption element was a cylindrical container made of stainless steel net, packed with a carbon sorbent bed-graphitized charcoal, Carbograph 4 (35/50 mesh). The recommended working/exposure time of the constructed passive device was determined by carrying out model tests in the laboratory. In addition, a preliminary study was conducted to determine the rate of the emission flux of selected monoterpenes released from the surface of wood-based indoor materials (laminated chipboard) used in residential areas. PMID- 26116239 TI - Evaluation of a protocol for vancomycin administration in critically patients with and without kidney dysfunction. AB - BACKGROUND: Administration of vancomycin in critically ill patients needs close regulation. While subtherapeutical vancomycin serum concentration (VSC) is associated with increased mortality, accumulation is responsible for nephrotoxicity. Our study aimed to estimate the efficacy of a vancomycin-dosing protocol in reaching appropriate serum concentration in patients with and without kidney dysfunction. METHODS: This was a retrospective study in critically ill patients treated with continuous infusion of vancomycin. Patients with creatinine clearance > 50 ml/min (Group A) were compared to those with creatinine clearance <= 50 ml/min (Group B). RESULTS: 348 patients were enrolled (210 in Group A, 138 in Group B). At first determination, patients with kidney dysfunction (Group B) had a statistically higher percentage of vancomycin in target range, while the percentage of patients with a VSC under the range was almost equal. These percentages differed at the subsequent measurements. The number of patients with low vancomycin concentration progressively decreased, except in those with augmented renal clearance; the percentage of patients with VSC over 30 mg/L was about 28 %, irrespective of the presence or absence of kidney dysfunction. Patients who reached a subtherapeutic level at the first VSC measurement had a significant correlation with in-hospital mortality. CONCLUSIONS: Our protocol seems to allow a rapid achievement of a target VSC particularly in patients with kidney dysfunction. In order to avoid subtherapeutical VSC, our algorithm should be implemented by the estimation of the presence of an augmented renal clearance. PMID- 26116241 TI - Characterization of ankle dorsiflexors performance in healthy subjects following maximal-intensity isokinetic resistance training. AB - The purpose of this randomized trial was to examine, in healthy subjects, the effect of unilateral isokinetic-concentric training of the dominant ankle dorsiflexors (DF) on the peak moment (PM), mean PM (MPM), maximal work and mean work (meanW). Thirty volunteers (26.7+/-4.6years old) underwent bilateral isokinetic testing of ankle DF at 45 and 90 degrees /s. Participants were randomly assigned to a control or a training group. The training lasted 4weeks (4 day/week). All dynamometric parameters increased significantly only in the training group for the trained leg (p<0.05), with greater gains in work (32-47% at 45 degrees /s and 31-41% at 90 degrees /s) than moment variables (14-18% at 45 degrees /s and 14-28% at 90 degrees /s). Similar increases in strength were also noted at both angular velocities in the untrained leg (p<0.01) for both work and moment parameters, depicting a cross-training effect. Correlations between 'moments' and 'works' increased in both legs after training from 0.59-0.77 to 0.79-0.95. Principal component analysis indicated that, at baseline, PM showed the highest weight on DF performance; after training, meanW at 90 degrees /s and MPM at 45 degrees /s exhibited the highest loadings. High-intensity training of ankle DF increase the ability in generating energy throughout the entire range of motion rather than maximizing the PM. PMID- 26116242 TI - Mitochondrial DNA polymorphisms, its copy number change and outcome in colorectal cancer. AB - BACKGROUND: Mitochondrion is a small organelle inside the eukaryotic cells. It has its own genome (mtDNA) and encodes for proteins that are critical for energy production and cellular metabolism. Mitochondrial dysfunctions have been implicated in cancer progression and may be related to poor prognosis in cancer patients. In this study we hypothesized that genetic variations in mtDNA are associated with clinical outcome in colorectal cancer patients. METHODS: We tested the associations of six mtDNA polymorphisms [MitoT479C, MitoT491C, MitoT10035C, MitoA13781G, 10398 (A/G), and 16189 (T/C)] and the mtDNA copy number change with overall survival (OS) and disease-free survival (DFS) times. Two mtDNA polymorphisms were genotyped using the TaqMan((r)) SNP genotyping technique and the genotypes for the remaining four mtDNA polymorphisms were obtained by the Illumina((r)) HumanOmni1-Quad genome wide SNP genotyping platform in 536 patients. The mtDNA copy number change (in tumor tissues with respect to non tumor tissues) was estimated using the quantitative real time polymerase chain reaction for 274 patients. Associations of these mtDNA variations with OS and DFS were tested using the Cox regression method. RESULTS: In both univariate and multivariable analyses, none of the six mtDNA polymorphisms were associated with OS or DFS. 39.6 and 60.4% of the patients had increased and decreased mtDNA copy number in their tumor tissues when compared to their non-tumor rectum or colon tissues, respectively. However, in contrast to previous findings, the change in the mtDNA copy number was associated with neither OS nor DFS in our patient cohort. CONCLUSIONS: Our results suggest that the mitochondrial genetic markers investigated in this study are not associated with outcome in colorectal cancer. PMID- 26116243 TI - Exposed: The Many and Varied Roles of Phospholipase C gamma SH2 Domains. PMID- 26116244 TI - A tower of paper spanning eighty years. PMID- 26116245 TI - Molecular and karyological identification and morphological description of cystocercous cercariae of Phyllodistomum umblae and Phyllodistomum folium (Digenea, Gorgoderidae) developing in European sphaeriid bivalves. AB - Two cystocercous gorgoderid cercariae of the genus Phyllodistomum Braun, 1899, Phyllodistomum umblae (Fabricius, 1780) and Phyllodistomum folium (Olfers, 1816), developing in sphaeriid bivalves from Norway and Lithuania, were studied and compared. Our previous molecular studies revealed very close phylogenetic relation of these two species and proved that cystocercous cercariae of P. folium develop in sporocysts in the gills of sphaeriid bivalves. In the present study morphological descriptions are given for the two cercariae, together with karyological and molecular characteristics. Comparative karyological and sequence analysis using ITS2 and 28S rDNA revealed the conspecificity of cercariae emitted from Pisidium hibernicum and Sphaerium corneum with adult P. umblae from Thymallus thymallus and Coregonus albula. The cercariae of P. folium and P. umblae are very similar morphologically with main differences in the structure of the tail. The two species clearly differ in karyotype structure. The diploid set of P. folium is composed of 18 chromosomes, but 16 chromosomes with one pair of large metacentrics were found in mitotic cells of P. umblae. Interspecific karyotypic difference presumably arose from Robertsonian fusion of two uni-armed chromosomes. PMID- 26116246 TI - Phylogenetic relationships of Paradiclybothrium pacificum and Diclybothrium armatum (Monogenoidea: Diclybothriidae) inferred from 18S rDNA sequence data. AB - The Diclybothriidae (Monogenoidea: Oligonchoinea) includes specific parasites of fishes assigned to the ancient order Acipenseriformes. Phylogeny of the Diclybothriidae is still unclear despite several systematic studies based on morphological characters. Together with the closely related Hexabothriidae represented by parasites of sharks and ray-fishes, the position of Diclybothriidae in different taxonomical systems has been matter of discussion. Here, we present the first molecular data on Diclybothriidae. The SSU rRNA gene was used to investigate the phylogenetic position of Paradiclybothrium pacificum and Diclybothrium armatum among the other Oligonchoinea. Complete nucleotide sequences of P. pacificum and D. armatum demonstrated high identity (98.53%) with no intraspecific sequence variability. Specimens of D. armatum were obtained from different hosts (Acipenser schrenckii and Huso dauricus); however, variation by host was not detected. The sequence divergence and phylogenetic trees data show that Diclybothriidae and Hexabothriidae are more closely related to each other than with other representatives of Oligonchoinea. PMID- 26116247 TI - Effect of rotavirus vaccine on childhood diarrhea mortality in five Latin American countries. AB - BACKGROUND: The aim of this study was to estimate the association between rotavirus vaccine (RV) introduction and reduction of all-cause diarrhea death rates among children in five Latin American countries that introduced RV in 2006. METHODS: Diarrhea mortality data was gathered from 2002 until 2009 from the Pan American Health Organization Mortality Database for five "vaccine adopter" countries (Brazil, El Salvador, Mexico, Nicaragua, and Panama) that introduced RV in 2006 and four "control" countries (Argentina, Chile, Costa Rica, and Paraguay) that did not introduce RV by 2009. Time trend analyses were carried out, and effects and 95% confidence intervals (CI) were estimated. RESULTS: Each of the five vaccine adopter countries, except Panama, showed a significant trend in declining mortality rates during the post-vaccine period from 2006 to 2009, whereas no decline was seen in control countries during these years. Furthermore, trends of reduction of all-cause diarrhea mortality in both children <1 year of age and <5 years of age were greater in the post-vaccination period compared with the pre-vaccine period in all vaccine adopter countries (except for Nicaragua), whereas in control countries, a reverse pattern was seen with greater reduction in the early years from 2002 to 2005 versus 2006-2009. An estimatedtotal of 1777 of annual under-5 deaths were avoided in Brazil, El Salvador, Mexico, and Nicaragua during the post-vaccination period. CONCLUSION: All vaccine adopter countries, except Panama, showed a significant decrease in all-cause diarrhea related deaths after RV implementation, even after adjusting for declining trends over time in diarrhea mortality. These data strongly support continuous efforts to increase vaccination coverage of RV vaccines, particularly in countries with high levels of child mortality from diarrhea. PMID- 26116248 TI - Avidity of maternal pertussis antibodies after vaccination during pregnancy. PMID- 26116249 TI - Risk perceptions, sexual attitudes, and sexual behavior after HPV vaccination in 11-12 year-old girls. AB - OBJECTIVES: Among 11-12 year-old girls who received the human papillomavirus (HPV) vaccine, we explored, over the subsequent 30 months: (1) trajectories of knowledge about HPV/HPV vaccines and vaccine-related risk perceptions; (2) whether knowledge and risk perceptions impacted sexual attitudes and sexual experience; (3) whether mothers, clinicians, and media influenced girls' risk perceptions, attitudes, and behavior. METHODS: Girls and mothers (n=25dyads) completed separate, semi-structured interviews within 2 days of, and 6, 18, and 30 months after, their first HPV vaccine dose. Knowledge, risk perceptions related to HPV and other sexually transmitted infections (STIs), and attitudes about sexual behaviors were assessed. Sexual experience was assessed at girls' 30 month interviews. Clinicians completed interviews at baseline. Transcribed interviews were analyzed using framework analysis. RESULTS: Girls' baseline knowledge was poor but often improved with time. Most girls (n=18) developed accurate risk perceptions about HPV but only half (n=12) developed accurate risk perceptions about other STIs by 30 months. The vast majority of girls thought that safer sex was still important, regardless of knowledge, risk perceptions, or sexual experience. Girls whose HPV knowledge was high at baseline or increased over time tended to articulate accurate risk perceptions; those who were able to articulate accurate risk perceptions tended to report not having initiated sexual activity. Girls whose mothers demonstrated higher knowledge and/or communication about HPV vaccination tended to articulate accurate risk perceptions, whereas clinicians and media exposure did not appear to influence risk perceptions. CONCLUSIONS: Higher knowledge about HPV vaccines among mothers and girls was linked with more accurate risk perceptions among girls. Clinicians may play an important role in providing education about HPV vaccines to mothers and girls. PMID- 26116250 TI - Estimating the herd immunity effect of rotavirus vaccine. AB - INTRODUCTION: Diarrhea is one of the leading causes of death in children under 5, and an estimated 39% of these deaths are attributable to rotavirus. Currently two live, oral rotavirus vaccines have been introduced on the market; however, the herd immunity effect associated with rotavirus vaccine has not yet been quantified. The purpose of this meta-analysis was to estimate the herd immunity effects associated with rotavirus vaccines. METHODS: We performed a systematic literature review of articles published between 2008 and 2014 that measured the impact of rotavirus vaccine on severe gastroenteritis (GE) morbidity or mortality. We assessed the quality of published studies using a standard protocol and conducted meta-analyses to estimate the herd immunity effect in children less than one year of age across all years presented in the studies. We conducted these analyses separately for studies reporting a rotavirus-specific GE outcome and those reporting an all-cause GE outcome. RESULTS: In studies reporting a rotavirus-specific GE outcome, four of five of which were conducted in the United States, the median herd effect across all study years was 22% [19-25%]. In studies reporting an all-cause GE outcome, all of which were conducted in Latin America, the median herd effect was 24.9% [11-30%]. CONCLUSIONS: There is evidence that rotavirus vaccination confers a herd immunity effect in children under one year of age in the United States and Latin American countries. Given the high variability in vaccine efficacy across regions, more studies are needed to better examine herd immunity effects in high mortality regions. PMID- 26116251 TI - Impact of PCV7/PCV13 introduction on community-acquired alveolar pneumonia in children <5 years. AB - BACKGROUND: Alveolar community-acquired pneumonia (A-CAP) is mostly considered a bacterial disease, mainly pneumococcal. This study was conducted to document the impact of sequential 7-valent and the 13-valent pneumococcal conjugate vaccines (PCV7; PCV13) on emergency room and hospitalization for A-CAP among children <5 years of age. METHODS: This is an ongoing prospective population-based study in southern Israel. The current analysis spans over the period July 2002 through June 2013. A-CAP was defined using the World Health Organization (WHO)'s criteria for radiologically-confirmed pneumonia. PCV7 was introduced in Israel in July 2009 and gradually replaced by PCV13 in November 2010. Pneumococcal conjugate vaccine (PCV) impact was calculated by comparing incidences during 3 pre-defined periods: pre-PCV (2002-2008), PCV7 (2010-2011) and PCV13 (2012-2013). RESULTS: Overall, 10,142 A-CAP episodes occurred. The annual incidences (per 1,000 inhabitants) in children <5 years old declined from a mean (+/-standard deviation) of 13.8 +/- 0.9 in the pre-PCV period to 11.2 +/- 2.7 in the PCV7 period and 7.4 in the PCV13 period, representing a reduction of 13% and 47%, respectively. The overall decrease was significantly faster among outpatients than among hospitalized children (42% and -8%, respectively in the PCV7 period; 68% vs. 32% in hospitalized children in the PCV13 period). While in children 12 23 months a significant decline was observed during the PCV7 and PCV13 periods, significant declines in A-CAP rates were observed only during the PCV13 period in the <12 months and 24-59 months age groups (44% and 46%, respectively). CONCLUSIONS: A moderate decline in hospital A-CAP visits in children <5 years old was observed after PCV7 introduction. In contrast, after PCV13 introduction a substantial reduction in all visits was evident. PMID- 26116252 TI - Self-reported hepatitis A vaccination as a predictor of hepatitis A virus antibody protection in U.S. adults: National Health and Nutrition Examination Survey 2007-2012. AB - OBJECTIVES: To estimate the predictive value of self-reported hepatitis A vaccine (HepA) receipt for the presence of hepatitis A virus (HAV) antibody (anti-HAV) from either past infection or vaccination, as an indicator of HAV protection. METHODS: Using 2007-2012 National Health and Nutrition Examination Survey data, we assigned participants to 4 groups based on self-reported HepA receipt and anti HAV results. We compared characteristics across groups and calculated three measures of agreement between self-report and serologic status (anti-HAV): percentage concordance, and positive (PPV) and negative (NPV) predictive values. Using logistic regression we investigated factors associated with agreement between self-reported vaccination status and serological results. RESULTS: Demographic and other characteristics varied significantly across the 4 groups. Overall agreement between self-reported HepA receipt and serological results was 63.6% (95% confidence interval [CI] 61.9-65.2); PPV and NPV of self-reported vaccination status for serological result were 47.0% (95% CI 44.2-49.8) and 69.4% (95% CI 67.0-71.8), respectively. Mexican American and foreign-born adults had the highest PPVs (71.5% [95% CI 65.9-76.5], and 75.8% [95% CI 71.4-79.7]) and the lowest NPVs (21.8% [95% CI 18.5-25.4], and 20.0% [95% CI 17.2-23.1]), respectively. Young (ages 20-29 years), US-born, and non-Hispanic White adults had the lowest PPVs (37.9% [95% CI 34.5-41.5], 39.1% [95% CI, 36.0-42.3], and 39.8% [36.1-43.7]), and the highest NPVs (76.9% [95% CI 72.2-81.0, 78.5% [95% CI 76.5-80.4)], and 80.6% [95% CI 78.2-82.8), respectively. Multivariate logistic analyses found age, race/ethnicity, education, place of birth and income to be significantly associated with agreement between self-reported vaccination status and serological results. CONCLUSIONS: When assessing hepatitis A protection, self report of not having received HepA was most likely to identify persons at risk for hepatitis A infection (no anti-HAV) among young, US-born and non-Hispanic White adults, and self-report of HepA receipt was least likely to be reliable among adults with the same characteristics. PMID- 26116253 TI - A recombinant varicella vaccine harboring a respiratory syncytial virus gene induces humoral immunity. AB - The varicella-zoster virus (VZV) Oka vaccine strain (vOka) is highly efficient and causes few adverse events; therefore, it is used worldwide. We previously constructed recombinant vOka (rvOka) harboring the mumps virus gene. Immunizing guinea pigs with rvOka induced the production of neutralizing antibodies against the mumps virus and VZV. Here, we constructed recombinant vOka viruses containing either the respiratory syncytial virus (RSV) subgroup A fusion glycoprotein (RSV A-F) gene or RSV subgroup B fusion glycoprotein (RSV B-F) gene (rvOka-RSV A-F or rvOka-RSV B-F). Indirect immunofluorescence and Western blot analyses confirmed the expression of each recombinant RSV protein in virus-infected cells. Immunizing guinea pigs with rvOka-RSV A-F or rvOka-RSV B-F led to the induction of antibodies against RSV proteins. These results suggest that the current varicella vaccine genome can be used to generate custom-made vaccine vectors to develop the next generation of live vaccines. PMID- 26116254 TI - Efficacy and immunogenicity of recombinant swinepox virus expressing the A epitope of the TGEV S protein. AB - To explore the possibility of developing a vaccine against transmissible gastroenteritis virus (TGEV) infection, a recombinant swinepox virus (rSPV-SA) expressing a TGEV protective antigen has been constructed. Immune responses and protection efficacy of the vaccination vector were assessed in both mice and pig models. An indirect ELISA assay suggested that when mice were vaccinated with rSPV-SA, the level of IgG against TGEV was enhanced dramatically. The cytokine assays were employed and the results indicated that both the Th1-type and Th2 type cytokine levels raised after vaccination with rSPV-SA in mice models. Results from the passive immunity protection test of new born piglets demonstrated that the recombinant live-vector vaccine, rSPV-SA, could 100% protect piglets from the SPV infection, and there was no significant clinical symptom in the rSPV-SA treatment group during this experiment. The data suggest that the novel recombinant swinepox virus is a potential vaccine against TGEV infection. PMID- 26116255 TI - Vaccines for prevention of group B meningococcal disease: Not your father's vaccines. AB - For decades, there was no licensed vaccine for prevention of endemic capsular group B meningococcal disease, despite the availability of vaccines for prevention of the other most common meningococcal capsular groups. Recently, however, two new vaccines have been licensed for prevention of group B disease. Although immunogenic and considered to have an acceptable safety profile, there are many scientific unknowns about these vaccines, including effectiveness against antigenically diverse endemic meningococcal strains; duration of protection; whether they provide any herd protection; and whether there will be meningococcal antigenic changes that will diminish effectiveness over time. In addition, these vaccines present societal dilemmas that could influence how they are used in the U.S., including high vaccine cost in the face of a historically low incidence of meningococcal disease. These issues are discussed in this review. PMID- 26116256 TI - Influenza vaccine: Delayed vaccination schedules and missed opportunities in children under 2 years old. AB - INTRODUCTION: In Argentina respiratory disease is the third leading cause of death in children under 5 years. In 2011 influenza vaccination was included in the National Calendar for children between 6 and 24 months (two doses schedule). Influenza vaccine coverage for second dose was 46.1% in 2013. The aim was to determine the proportion of delayed schedules and missed opportunities, to assess the characteristics of missed opportunities for vaccination and to explore the perception of influenza disease and vaccination from the parents of children between 6 and 24 months in different regions of Argentina in 2013. METHODS: Analytical observational multicenter cross-sectional study. Structured surveys were carried out to the children's parents who were between 6 and 24 months of age during the influenza virus vaccination season (April-October 2013). Chi Square test was used to assess association and differences between proportions and categorical variables. A logistic regression model was built to identify delay predictor variables in the vaccination schedules. Missed opportunities for vaccination were characterized through the estimation of proportions. RESULTS: 1350 surveys were conducted in the three centers. We detected 65% (884/1340) of delayed influenza vaccination schedules, 97% of them associated with missed opportunities of vaccination. The independent protective factors associated with a decreases risk of delayed schedules were: (a) perception of the importance of influenza vaccination (OR=0.42(0.18-0.94); p=0.035), (b) having less than one year of age (OR=0.75(0.59-0.96); p=0.022), (c) to have received information in pediatric visits or in any media (OR=0.71(0.56-0.90); p=0.004). There was 38% of MOIV in 1st dose and 63.4% in 2nd dose. The main cause of MOIV in 1st dose was not detecting the need for vaccination (39%) and in 2nd dose the unknowledge of the vaccination schedule (35.3%). No cultural reasons were detected. CONCLUSIONS: High frequency of delayed vaccination schedules and missed opportunities were detected. Parents had little concern about the safety of influenza vaccine. PMID- 26116257 TI - Pneumococcal disease prevention among adults: Strategies for the use of pneumococcal vaccines. AB - Use of the pneumococcal conjugate vaccines among children in the US since 2000 has dramatically reduced pneumococcal disease burden among adults. Significant vaccine-preventable morbidity and mortality from pneumococcal infections still remains, especially among older adults. The US Advisory Committee on Immunization Practices (ACIP) has recently recommended the routine use of both pneumococcal conjugate (PCV13) and polysaccharide vaccines (PPSV23) for adults >=65 years. These recommendations were based on the remaining burden of illness among adults and the importance of non-bacteremic pneumonia prevention in light of new evidence confirming the efficacy of PCV13 to prevent pneumococcal pneumonia among older adults. This paper reviews the evidence that led the ACIP to make recommendations for PCV13 and PPSV23 use among adults, and highlights potential gaps to be addressed by future studies to inform adult vaccination policy. The changing epidemiology of invasive pneumococcal disease and pneumonia should be closely monitored to evaluate the effectiveness and continued utility of the current vaccination strategy, and to identify future directions for pneumococcal disease prevention among older adults. PMID- 26116258 TI - Reduced Dose Intensity of Chemotherapy may not Lead to Inferior Palliation in Locally Advanced Carcinoma of the Gall Bladder: An Experience from a Regional Cancer Centre in Eastern India. AB - PURPOSE: To assess impact of relative total dose intensity (RTDI) on clinical benefit among patients with locally advanced carcinoma gall bladder receiving gemcitabine-cisplatin (GemCis). Comparison of clinical benefit among patients receiving variable RTDI was the primary objective. The secondary objective was an impact of RTDI on chemotherapy toxicity. METHODS: One-hundred twenty-one patients with locally advanced inoperable carcinoma gall bladder undergoing chemotherapy with three weekly gemcitabine-cisplatin chemotherapies (gemcitabine 1000 mg/m(2) on day 1 and 8, cisplatin 70 mg/m(2) on day 1) were studied. Clinical benefit and treatment toxicity was assessed. Total dose of chemotherapy and relative total dose intensity, the proportion of planned dose actually received was calculated. RESULTS: RTDI of at least 50 % conferred substantial clinical benefit compared to lower RTDI (75.49 vs. 21.05 %). RTDI above 50-59 % did not improve clinical benefit; two-tailed p values of RTDI >60 % vs. RTDI >50 % and RTDI >70 % vs. RTDI >50 % were 1.000 and 0.4266, respectively. Subsequent extended cholecystectomy rates did not significantly improve among patients who received RTDI greater than 50-59 %; two-tailed p values of RTDI >60 % vs. RTDI >50 % and RTDI >70 % vs. >50 % were 0.0920 and 0.5648, respectively. Significantly higher neutropenia and anemia of at least grade 2 occurred with RTDI >70 % vs. RTDI 50-59 %; two-tailed p values 0.0019 and 0.0048, respectively. CONCLUSIONS: Relative total dose intensity of chemotherapy higher than 60 % among patients with inoperable locally advanced carcinoma gall bladder conferred no significant improvement in clinical benefit and subsequent rates of extended cholecystectomy. Higher RTDI however led to significantly increased toxicity among these patients. PMID- 26116259 TI - Primary Gastric Diffuse Large B Cell Lymphoma Presenting as Gastric Outlet Obstruction: a Call for High Clinical Suspicion. PMID- 26116260 TI - Hydroxychloroquine screening practice patterns within a large multispecialty ophthalmic practice. AB - PURPOSE: To determine provider compliance with hydroxychloroquine screening following the revised recommendations published in 2011 by the American Academy of Ophthalmology. DESIGN: Evaluation of adherence to a screening protocol. METHODS: Subjects were identified with hydroxychloroquine as a medication by electronic query at a large multispecialty ophthalmic practice. Patients were excluded if patients: (1) were screened by an outside physician; (2) lacked recorded height, weight, start date, or dosing; or (3) took hydroxychloroquine for malaria prophylaxis. Screening tests were stratified by ophthalmic subspecialty. Guidelines define proper screening as 1 subjective test-Humphrey visual field (HVF), and 1 objective test-spectral-domain optical coherence tomography (SD OCT), fundus autofluorescence (FAF), or multifocal electroretinography (mfERG). Adherence to guidelines was determined by categorizing practices as: (1) "appropriate"-consistent with guidelines; (2) "underscreened"-insufficient testing; or (3) "inappropriate"-no testing. RESULTS: The study comprised 756 patients with a mean age of 56 years undergoing 1294 screening visits. Twenty-one patients received initial screenings outside the institution. Most common screening tests employed included SD OCT (56.6%), 10-2 HVF (55.0%), and Amsler grid (40.0%). Of the 735 initial screenings, 341 (46.4%) were appropriately screened, 204 (27.8%) underscreened, and 190 (25.9%) inappropriately screened. Of those who presented solely for screening (560), 307 (54.8%) were appropriately screened, 144 (25.7%) underscreened, and 109 (19.5%) inappropriately screened. CONCLUSIONS: Of patients presenting for hydroxychloroquine screening, 54.8% of patients received appropriate evaluation, indicating lack of adherence to guidelines. Overall, SD OCT and 10-2 HVF were the preferred screening modalities, with FAF and mfERG less frequently ordered. PMID- 26116261 TI - Comparison of clinical outcomes of iris fixation and scleral fixation as treatment for intraocular lens dislocation. AB - PURPOSE: To compare the efficacy and safety of iris fixation with scleral fixation in surgical repositioning of dislocated intraocular lenses (IOLs). DESIGN: Retrospective, consecutive, comparative interventional case series. METHODS: setting: Referral hospital. STUDY POPULATION: Seventy-eight consecutive patients who underwent surgical repositioning of dislocated intraocular lenses using suturing to the sclera or iris. INTERVENTION: Forty-four eyes of 44 patients underwent scleral fixation and 35 eyes of 34 patients underwent iris fixation of dislocated intraocular lenses. MAIN OUTCOME MEASURES: Visual acuity, refractive stability, operation time, and perioperative complications, including recurrence of IOL dislocation. RESULTS: Corrected distance visual acuity (CDVA) improved significantly 1 month postoperatively in both groups (P < .01 each), and remained stable for 12 months. One week postoperatively, however, CDVA improved significantly in the scleral fixation (P = .040) but not in the iris fixation (P = .058) group. The amount of refractive error significantly diminished 1 day after surgery (P = .028 in the scleral fixation and P = .046 in the iris fixation group). For the astigmatic components, Jackson crossed cylinders equivalent to conventional cylinders of positive power at axes of 0 degrees (J0) and 45 degrees (J45), J45 differed significantly in the scleral fixation and iris fixation groups (P = .009), whereas J0 was similar (P > .05). Operation time was significantly shorter (P = .0007), while immediate postoperative inflammation was significantly more severe (P = .001), in the iris fixation than in the scleral fixation group. Recurrence rates were similar (P > .05), but the mean time to recurrence was significantly shorter in the iris fixation than in the scleral fixation group (P = .031). CONCLUSIONS: Iris fixation and scleral fixation techniques had similar efficacy in the repositioning of dislocated intraocular lenses. Although operation time was shorter for iris fixation, it had several disadvantages, including induced astigmatism, immediate postoperative inflammation, earlier recurrence, and less stable refraction. PMID- 26116262 TI - Transplant rejection following endothelial keratoplasty and penetrating keratoplasty in the United Kingdom: incidence and survival. AB - PURPOSE: To investigate the incidence and outcome of cornea transplant rejection following endothelial keratoplasty (EK) and penetrating keratoplasty (PK) for Fuchs endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK). DESIGN: Multicenter cohort study. METHODS: Patients registered on the United Kingdom Transplant Registry (UKTR) who had an EK or PK for FED or PBK between April 1, 2005 and March 31, 2011 were included. Data were collected from UKTR forms at 1 and 2 years. Postoperative steroid use varies between surgeons and cannot be captured in this reporting system. Rejection events were identified as those recorded as endothelial rejection. RESULTS: A total of 3486 corneal transplants were undertaken: 1973 for FED, 1513 for PBK. For FED, 2-year rejection-free survival was 93% (95% confidence interval [CI] 90%-94%) for PK and 94% (95% CI 92%-96%) for EK (P = .3). In transplants that had a rejection episode, 50% of PKs (17) and 60% of EKs (15) subsequently failed. For PBK, 2-year rejection-free survival for PK was 88% (95% CI 86%-90%) and 90% (95% CI 86%-92%) for EK (P = .6). In transplants that had a rejection episode, 85% of PKs (41) and 76% of EKs (22) subsequently failed. Inflammation (ie, conjunctival injection, presence of keratic precipitates and intraocular signs) at the time of surgery for patients with FED was significant for developing rejection: 3.5 times greater compared with those with no inflammation (P = .02). CONCLUSIONS: There is no significant difference in rejection-free survival between EK and PK for FED or PBK. The presence of inflammation is an important risk factor, and attention to its control before and following surgery is important. PMID- 26116263 TI - Clinical color vision testing and correlation with visual function. AB - PURPOSE: To determine if Hardy-Rand-Rittler (H-R-R) and Ishihara testing are accurate estimates of color vision in subjects with acquired visual dysfunction. DESIGN: Assessment of diagnostic tools. METHODS: Twenty-two subjects with optic neuropathy (aged 18-65) and 18 control subjects were recruited prospectively from an outpatient clinic. Individuals with visual acuity (VA) <20/200 or with congenital color blindness were excluded. All subjects underwent a comprehensive eye examination including VA, color vision, and contrast sensitivity testing. Color vision was assessed using H-R-R and Ishihara plates and Farnsworth D-15 (D 15) discs. D-15 is the accepted standard for detecting and classifying color vision deficits. Contrast sensitivity was measured using Pelli-Robson contrast sensitivity charts. RESULTS: No relationship was found between H-R-R and D-15 scores (P = .477). H-R-R score and contrast sensitivity were positively correlated (P = .003). On multivariate analysis, contrast sensitivity (beta = 8.61, P < .001) and VA (beta = 2.01, P = .022) both showed association with H-R-R scores. Similar to H-R-R, Ishihara score did not correlate with D-15 score (P = .973), but on multivariate analysis was related to contrast sensitivity (beta = 8.69, P < .001). H-R-R and Ishihara scores had an equivalent relationship with contrast sensitivity (P = .069). CONCLUSION: Neither H-R-R nor Ishihara testing appears to assess color identification in patients with optic neuropathy. Both H R-R and Ishihara testing are correlated with contrast sensitivity, and these tests may be useful clinical surrogates for contrast sensitivity testing. PMID- 26116264 TI - Intravitreal anti-vascular endothelial growth factor treatment and the risk of thromboembolism. AB - PURPOSE: To evaluate the subsequent risk of thromboembolic events in patients receiving intravitreal ranibizumab and bevacizumab for age-related macular degeneration or macular edema. DESIGN: Population-based crossover analysis with self-matched historical control data. METHODS: setting: Ontario, Canada, between April 1, 2006, and March 31, 2013. STUDY POPULATION: Consecutive patients 65 and older who initiated intravitreal treatment (N = 57 919). INTERVENTION: Intravitreal injection of ranibizumab or bevacizumab. MAIN OUTCOME MEASURES: Emergency visits for thromboembolic events spanning 1-4 years before treatment were compared to 1 year after treatment. Also examined were other secondary events including hip fractures, congestive heart failure, angina, falls, depression, cholecystitis, and total emergencies, as well as a control group following cataract surgery. RESULTS: A total of 57 919 patients were included who accounted for 1858 thromboembolic emergencies (48 per month) during the 3-year Baseline interval and 1077 thromboembolic emergencies (83 per month) during the 1 year Subsequent interval after initiating treatment. The absolute change in risk equaled an increase from 10.7 to 18.6 per 1000 patients annually after initiation of treatment (rate ratio 1.74; 95% confidence interval 1.58-1.92; P < .0001). The relative increase was particularly pronounced for ischemic stroke (rate ratio 2.18; 95% confidence interval 1.94-2.46; P < .0001). The observed increase exceeded trends due to aging, applied across patients with diverse characteristics, occurred with each medication (ranibizumab and bevacizumab), was not apparent for emergencies unrelated to thromboembolic events, and did not occur in a control group following cataract surgery. CONCLUSIONS: Intravitreal anti-vascular endothelial growth factor medications ranibizumab and bevacizumab may contribute to systemic thromboembolic events in patients aged 65 years or older. PMID- 26116265 TI - Work patterns, sleeping hours and excess weight in commercial drivers. AB - BACKGROUND: Work and sleep patterns for commercial motor vehicle (CMV) drivers often include long working hours, shift work and diminished sleep duration and quality, which have been linked to overweight, obesity and other problems. AIMS: To explore possible connections between work, sleep and obesity among CMV drivers. METHODS: Survey and anthropometric data were collected from male long haul CMV drivers in central North Carolina, USA, over a period of 6 months. Drivers' body mass index (BMI) was used as a measure of total body obesity and sagittal abdominal diameter (SAD) as a measure of central adiposity. RESULTS: Among the 260 study subjects, mean BMI was 33.1 (64% were obese or morbidly obese) and mean SAD was 32.3cm, classifying 89% of drivers as being at high or very high cardiometabolic risk. About 83% of drivers worked an irregular daily schedule, 64% worked irregular total daily hours, 32% worked irregular days of the week and 46% reported getting <7h of sleep during work nights. Significant predictors of BMI included the number of hours worked daily (P < 0.05) and the age (P < 0.01) of the driver, while age was also a significant predictor for SAD (P < 0.05). Significant predictors of sleep quality included the extent of shift work (P < 0.05) and sleep duration (P < 0.001). CONCLUSIONS: Work and sleep configurations appear to affect the weight status of CMV drivers. Shift work and sleep duration are both associated with the weight status of CMV drivers, and both appear to function as indicators of their sleep quality. PMID- 26116266 TI - Density-dependent prey mortality is determined by the spatial scale of predator foraging. AB - Foraging theory predicts which prey patches predators should target. However, in most habitats, what constitutes a 'patch' and how prey density is calculated are subjective concepts and depend on the spatial scale at which the predator (or scientist) is observing. Moreover, the predator's 'foraging scale' affects prey population dynamics: predators should produce directly density-dependent (DDD) prey mortality at the foraging scale, but inversely density-dependent (IDD) mortality (safety-in-numbers) at smaller scales. We performed the first experimental test of these predictions using behavioral assays with guppies (Poecilia reticulata) feeding on bloodworm 'prey' patches. The guppy's foraging scale had already been estimated in a prior study. Our experimental results confirmed theoretical predictions: predation was IDD when prey were aggregated at a scale smaller than the foraging scale, but not when prey were aggregated at larger scales. These results could be used to predict outcomes of predator-prey interactions in continuous, non-discrete habitats in the field. PMID- 26116267 TI - Uterine torsion in Brown Swiss cattle: retrospective analysis from an alpine practice in Switzerland. PMID- 26116268 TI - Effect of early lactation foot trimming in lame and non-lame dairy heifers: a randomised controlled trial. AB - Foot trimming is a common management intervention in prevention of lameness in dairy cattle. Despite this, there is surprisingly limited experimental evidence on its efficacy, especially in regard to primiparous heifers. A randomised, negatively controlled trial was conducted to investigate the association between an early lactation foot trim on primiparous animals and production outcomes. 282 heifers were enrolled from eight farms in the UK, and randomly assigned to treatment or control groups. Milk yield (305-day-adjusted whole-milk yield) was not significantly different between groups (trimmed 7727 litres, untrimmed 7646 litres). However, multivariate regression analysis demonstrated that this relationship was confounded by lameness state. Animals that were lame at the time of trimming gave significantly more milk (734 litres, P=0.02) than those that were non-lame and untrimmed. The present results suggest that, based on milk production alone, it would not have been cost beneficial to trim all heifers; however, a targeted intervention aimed at lame animals would have delivered a substantial return on investment. As a very minimum, the authors recommend heifers should be regularly assessed in early lactation, and treated as soon as they are identifiably lame. The high prevalence of lesions identified suggests routine trimming for all heifers may be justifiable on welfare grounds even if the milk-yield benefits are marginal. PMID- 26116269 TI - Husbandry, health and biosecurity of the smallholder and pet pig population in England. AB - Three hundred and thirteen pet and smallholder pig owners in England responded to an online questionnaire regarding husbandry and healthcare of their pigs. There was a lack of knowledge of the legislation regarding Department for Environment, Food and Rural Affairs (DEFRA) registration, animal movements and feeding of domestic food waste. Only 83.8 per cent of respondents had registered their pigs with DEFRA, while 17.7 per cent were not familiar with the movement regulations, and 23.9 per cent were feeding their pigs with household scraps. Contact with veterinary surgeons may be positively associated with DEFRA registration, legal feeding practices and knowledge of vaccination. Furthermore, the veterinary surgeon was considered to be the primary source of husbandry and healthcare knowledge. This paper identifies the pet and smallholder pig population as a potential risk for the incursion and spread of infectious disease, while highlighting the need for improved owner education. PMID- 26116272 TI - ["Navratil's Artist Guest Book!" in the Gugging Museum]. PMID- 26116270 TI - Dual Targeting of Protein Degradation Pathways with the Selective HDAC6 Inhibitor ACY-1215 and Bortezomib Is Synergistic in Lymphoma. AB - PURPOSE: Pan-class histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. HDAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the aggresome for degradation. We investigated the mechanism and therapeutic impact of the selective HDAC6 inhibitor ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma. EXPERIMENTAL DESIGN: Concentration-effect relationships were defined for ACY-1215 across 16 lymphoma cell lines and for synergy with bortezomib. Mechanism was interrogated by immunoblot and flow cytometry. An in vivo xenograft model of DLBCL was used to confirm in vitro findings. A collection of primary lymphoma samples were surveyed for markers of the unfolded protein response (UPR). RESULTS: Concentration-effect relationships defined maximal cytotoxicity at 48 hours with IC50 values ranging from 0.9 to 4.7 MUmol/L. Strong synergy was observed in combination with bortezomib. Treatment with ACY-1215 led to inhibition of the aggresome evidenced by acetylated alpha-tubulin and accumulated polyubiquitinated proteins and upregulation of the UPR. All pharmacodynamic effects were enhanced with the addition of bortezomib. Findings were validated in vivo where mice treated with the combination demonstrated significant tumor growth delay and prolonged overall survival. Evaluation of a collection of primary lymphoma samples for markers of the UPR revealed increased HDAC6, GRP78, and XBP-1 expression as compared with reactive lymphoid tissue. CONCLUSIONS: These data are the first results to demonstrate that dual targeting of protein degradation pathways represents an innovative and rational approach for the treatment of lymphoma. PMID- 26116271 TI - Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 "Don't Eat Me" Signals. AB - Recent advances with immunotherapy agents for the treatment of cancer have provided remarkable, and in some cases, curative results. Our laboratory has identified CD47 as an important "don't eat me" signal expressed on malignant cells. Blockade of the CD47:SIRP-alpha axis between tumor cells and innate immune cells (monocytes, macrophages, and dendritic cells) increases tumor cell phagocytosis in both solid tumors (including, but not limited to, bladder, breast, colon, lung, and pancreatic) and hematologic malignancies. These phagocytic innate cells are also professional antigen-presenting cells (APC), providing a link from innate to adaptive antitumor immunity. Preliminary studies have demonstrated that APCs present antigens from phagocytosed tumor cells, causing T-cell activation. Therefore, agents that block the CD47:SIRP-alpha engagement are attractive therapeutic targets as a monotherapy or in combination with additional immune-modulating agents for activating antitumor T cells in vivo. PMID- 26116274 TI - Quantification of southern rice black streaked dwarf virus and rice black streaked dwarf virus in the organs of their vector and nonvector insect over time. AB - Southern rice black streaked dwarf virus (SRBSDV) and rice black streaked dwarf virus (RBSDV) are serious rice-infecting reoviruses, which are transmitted by different planthoppers in a persistent propagative manner. In this study, we quantitatively compared the spatial distribution of SRBSDV and RBSDV contents over time in their vector and nonvector insects using real time-PCR. Genome equivalent copies (GEC) were assessed every 2 days from 0 to 14 days after a 3 days acquisition access period (AAP) on infected plants. Results revealed 293.2+/ 21.6 to 404.1+/-46.4 SRBSDV GEC/ng total RNA in whole body of white-backed planthopper (WBPH, Sogatella furcifera) at day 0 and 12 and 513.5+/-88.4 to 816.8+/-110.7 RBSDV GEC/ng total RNA in the whole body of small brown planthopper (SBPH, Laodelphax striatellus) at day 0 and 14, respectively, after 3-days AAP. Highest GEC of both viruses were found in the gut of their respective vectors. Although SRBSDV was detected in the gut of SBPH, it did not spread into the hemolymph or other organs. After an 8-day latent period, the transmission efficiency of SRBSDV and RBSDV by their respective vectors was significantly positively correlated with GEC in the salivary gland (r(2)=0.7808, P=0.0036 and r(2)=0.9351, P<0.0001, respectively, at alpha=0.05). Together, these results confirm that accumulation of >200 SRBSDV or RBSDV GEC/ng total RNA in the gut of vector, indicated threshold for further spread and the virus content in the salivary gland was significantly correlated with transmission efficiency by their respective vectors. PMID- 26116273 TI - Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes. AB - Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer's disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS meta-analysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and co expression networks. We found 927 SNPs associated with both AD and T2D with p value <=0.01, an overlap significantly larger than random chance (overlapping p value of 6.93E-28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa. Collectively, our GWAS studies tentatively support the epidemiological observation of disease concordance between T2D and AD. Moreover, the studies provide the much needed information for the design of future novel therapeutic approaches, for a subpopulation of T2D subjects with genetic disposition to AD, that could benefit T2D and reduce the risk for subsequent development of AD. PMID- 26116275 TI - Mild and severe cereal yellow dwarf viruses differ in silencing suppressor efficiency of the P0 protein. AB - Viral pathogenicity has often been correlated to the expression of the viral encoded-RNA silencing suppressor protein (SSP). The silencing suppressor activity of the P0 protein encoded by cereal yellow dwarf virus-RPV (CYDV-RPV) and -RPS (CYDV-RPS), two poleroviruses differing in their symptomatology was investigated. CYDV-RPV displays milder symptoms in oat and wheat whereas CYDV-RPS is responsible for more severe disease. We showed that both P0 proteins (P0(CY-RPV) and P0(CY-RPS)) were able to suppress local RNA silencing induced by either sense or inverted repeat transgenes in an Agrobacterium tumefaciens-mediated expression assay in Nicotiana benthamiana. P0(CY-RPS) displayed slightly higher activity. Systemic spread of the silencing signal was not impaired. Analysis of short interfering RNA (siRNA) abundance revealed that accumulation of primary siRNA was not affected, but secondary siRNA levels were reduced by both CYDV P0 proteins, suggesting that they act downstream of siRNA production. Correlated with this finding we showed that both P0 proteins partially destabilized ARGONAUTE1. Finally both P0(CY-RPV) and P0(CY-RPS) interacted in yeast cells with ASK2, a component of an E3-ubiquitin ligase, with distinct affinities. PMID- 26116276 TI - Novel nanosized formulations of two diclofenac acid polymorphs to improve topical bioavailability. AB - In this work, nanocrystal formulations, containing two different diclofenac acid crystal forms, were developed with the aim to improve dermal drug bioavailability. Nanosuspensions were obtaining using wet media milling technique and were characterized in terms of size distribution, morphology, zeta potential, differential scanning calorimetry and X-ray powder diffractometry. The ability of the nanocrystals to improve dermal drug bioavailability was investigated in vitro using Franz diffusion vertical cells and newborn pig skin, in comparison with diclofenac acid coarse suspensions and a commercial topical formulation containing diclofenac sodium. Nanocrystals exhibited a mean diameter ranging between 279 and 315 nm and a PI lower than 0.25, as shown by PCS measurements. The XRDP and DSC analysis clearly indicated that the preparation process did not modify the diclofenac polymorphic forms. In vitro transdermal delivery experiments showed an improved skin deposition and permeation of the nanocrystals compared to coarse suspensions and diclofenac sodium commercial topical formulation. These results highlight the fundamental role of the crystal size on drug solubility and, thus, on the ability of a poorly soluble drug to cross the skin and accumulate in the deeper skin layers. PMID- 26116277 TI - Proliposomes containing a bile salt for oral delivery of Ginkgo biloba extract: Formulation optimization, characterization, oral bioavailability and tissue distribution in rats. AB - Proliposomes containing a bile salt were developed to improve the oral bioavailability of Ginkgo biloba extract (GbE). GbE loaded proliposomes (P-GbE) were successfully prepared by spray drying method. The formulation was optimized using the response surface methodology. FE-SEM, DSC, and FT-IR were used to study the surface morphology and molecular state of proliposomes, and demonstrated key interactions between the formulation ingredients. In vitro studies showed delayed release and enhanced dissolution of Ginkgo flavonoids and terpene lactones from GbE proliposomes. Proliposomes significantly enhanced GbE absorption in the gastrointestinal tract and decreased its elimination. The bioavailabilities of quercetin, kaempferol, isorhmnetin, ginkgolide A, ginkgolide B and ginkgolide C from proliposomes relative to the control were 245%, 211%, 264%, 203%, 333%, and 294%, respectively. Proliposomes were shown to selectively deliver GbE to critical target tissues. In conclusion, development of proliposomes formulation for GbE solved the problem of its poor oral bioavailability, prolonged its duration of action, and increased drug distribution in critical tissues, especially in the brain, therefore, warrant further investigation. PMID- 26116278 TI - Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites. AB - Atorvastatin is the most commonly used of all statins to lower cholesterol. Atorvastatin is extensively metabolized in both gut and liver to produce several active metabolites. The purpose of the present study is to develop a physiologically based pharmacokinetic (PBPK) model for atorvastatin and its two primary metabolites, 2-hydroxy-atorvastatin acid and atorvastatin lactone, using in vitro and in vivo data. The model was used to predict the pharmacokinetic profiles and drug-drug interaction (DDI) effect for atorvastatin and its metabolites in different DDI scenarios. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministration of atorvastatin with different medications such as itraconazole, clarithromycin, cimetidine, rifampin and phenytoin. This population based PBPK model was able to describe the concentration-time profiles of atorvastatin and its two metabolites reasonably well in the absence or presence of those drugs at different dose regimens. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC) values and between-phase ratios were in good agreement with clinically observed data. The model has also revealed the importance of different metabolic pathways on the disposition of atorvastatin metabolites. This PBPK model can be utilized to assess the safety and efficacy of atorvastatin in the clinic. This study demonstrated the feasibility of applying PBPK approach to predict the DDI potential of drugs undergoing complex metabolism. PMID- 26116279 TI - Application of physiologically based pharmacokinetic modeling in the prediction of pharmacokinetics of bicyclol controlled-release formulation in human. AB - Physiologically based pharmacokinetic (PBPK) modeling can assist in formulation development. Bicyclol is a novel anti-hepatitis drug. A bilayer osmotic pump table of bicyclol is being developed. PBPK models for bicyclol immediate-release (IR) and controlled-release (CR) tablets in beagle dog, as well as PBPK model for IR tablets in human were constructed. These models incorporated physicochemical properties and in vitro preclinical data. Parameter sensitivity analysis was performed for the effects of solubility and dissolution on pharmacokinetic (PK) parameters. Models were refined by comparing simulated results to experimental measurements. Furthermore, the clinical PK for bicyclol CR tablets was predicted using the in vivo dissolution profile by deconvolution of the mean PK profile of CR tablets in dogs. In summary, the present study described a strategy employing PBPK models to evaluate the effects of formulation factors on PK profiles and predict the performance of bicyclol CR tablets in human. PMID- 26116281 TI - The secret realm of phase I trials in healthy volunteers. PMID- 26116280 TI - Recognition of faces and names: multimodal physiological correlates of memory and executive function. AB - We sought to characterize electrophysiological, eye-tracking and behavioral correlates of face-name recognition memory in healthy younger adults using high density electroencephalography (EEG), infrared eye-tracking (ET), and neuropsychological measures. Twenty-one participants first studied 40 face-name (FN) pairs; 20 were presented four times (4R) and 20 were shown once (1R). Recognition memory was assessed by asking participants to make old/new judgments for 80 FN pairs, of which half were previously studied items and half were novel FN pairs (N). Simultaneous EEG and ET recording were collected during recognition trials. Comparisons of event-related potentials (ERPs) for correctly identified FN pairs were compared across the three item types revealing classic ERP old/new effects including 1) relative positivity (1R > N) bi-frontally from 300 to 500 ms, reflecting enhanced familiarity, 2) relative positivity (4R > 1R and 4R > N) in parietal areas from 500 to 800 ms, reflecting enhanced recollection, and 3) late frontal effects (1R > N) from 1000 to 1800 ms in right frontal areas, reflecting post-retrieval monitoring. ET analysis also revealed significant differences in eye movements across conditions. Exploration of cross-modality relationships suggested associations between memory and executive function measures and the three ERP effects. Executive function measures were associated with several indicators of saccadic eye movements and fixations, which were also associated with all three ERP effects. This novel characterization of face-name recognition memory performance using simultaneous EEG and ET reproduced classic ERP and ET effects, supports the construct validity of the multimodal FN paradigm, and holds promise as an integrative tool to probe brain networks supporting memory and executive functioning. PMID- 26116282 TI - Comparison of myocardial cell survival 2 h and 24 h after extracellular talaporfin sodium-induced photodynamic reaction. AB - BACKGROUND: We have proposed an application of photodynamic reaction for less heated myocardial ablation which employs talaporfin sodium. Intracellular photodynamic reactions with ongoing uptake have the ability to induce apoptosis over time, raising the possibility of extending the lesion depth. The objective of this study was to understand how, in myocardial cells, the late cell survival levels change by incubation time with talaporfin sodium, and what dependence talaporfin sodium uptake has on the duration of incubation with talaporfin sodium in vitro. METHODS: Rat myocardial cells were incubated with talaporfin sodium for 5-360 min and intracellular concentrations measured using a fluorescence micro plate reader after wash. Cell survival was measured using a water-soluble tetrazolium assay at 2 and 24 h after a photodynamic reaction using a red diode laser of 660 nm, following 15-180 min of incubation with talaporfin sodium. Cells were stained with Hoechst 33342 to observe nuclear changes. RESULTS: Intracellular talaporfin sodium concentration increased with incubation time, with a marked increase between 0 and 60 min. Cell survival at 24 h decreased by 20% when the duration of incubation with talaporfin sodium was extended from 15 to 30 min. Following incubation time of 30-180 min with talaporfin sodium, cell survival was decreased by approximately 30% between measurements at 2 and 24 h. The intracellular talaporfin sodium concentration that induced higher levels of late cell death with cell nuclei fragmentation in these cells was approximately 0.2 MUg/mL. CONCLUSION: We obtained the characteristics of late cell death occurrence and talaporfin sodium uptake to myocardial cell with various incubation times with talaporfin sodium. PMID- 26116283 TI - A new LED device used for photodynamic therapy in treatment of moderate to severe acne vulgaris. AB - OBJECTIVE: This study investigated the efficacy and safety of a newly designed LED device used in photodiagnosis and photodynamic therapy of moderate to severe acne vulgaris in Chinese patients. METHODS: Forty-six patients with moderate to severe facial acne showing high degrees of fluorescence by ultraviolet light examination were illuminated during ALA-PDT with two wavelengths of light (543 548 nm, and 630+/-6 nm, respectively) after 2 h of incubation with ALA. Each patient received treatment once every 30 days for two or three sessions. Two independent investigators assigned an acne severity score at baseline, one week after each treatment, as well as 4, 8, and 12 weeks after the completion of treatment. Adverse effects were recorded during and after each treatment. All patients rated their satisfaction with the results of treatment at a 12-week follow up visit. RESULTS: The ALA-PDL treatment regimen showed an overall effectiveness rate of 89.13% (41/46 patients). Some degree of clinical efficacy was seen in 71.42%, 86.67%, and 95.83% of patients with grades IV, V, and VI acne, respectively, and the rate of clinical effectiveness increased with increasing acne severity. When compared with baseline scores, significant reductions in acne scores were obtained at 8, and 12 weeks after completion of treatment. Maximum efficacy was shown at the 12 week follow up. No severe adverse events were observed. CONCLUSION: ALA-PDT administered with the newly designed LED device was an effective treatment for moderate to severe acne vulgaris, and side effects were mild and reversible. PMID- 26116284 TI - Spinal subdural haematoma after an epidural blood patch. PMID- 26116285 TI - Pocket warming of epidural medications. PMID- 26116286 TI - Genome sequence of a novel mycovirus of Rhizoctonia solani, a plant pathogenic fungus. AB - Here we present the genome sequence of a novel dsRNA virus we designed as Rhizoctonia solani RNA virus HN008 (RsRV-HN008) from a filamentous fungus R. solani. Its genome (7596 nucleotides) contains two non-overlapping open reading frames (ORF1 and ORF2). ORF1 encoded a 128 kDa protein that showed no significant identity to any other virus sequence in the NCBI database. ORF2 encoded a protein with a molecular weight of 140 kDa and shared a low percentage of sequence identity to the RdRps of unclassified dsRNA viruses. Sequence analysis revealed that RsRV-HN008 may be a member of a novel unclassified family of mycoviruses. PMID- 26116287 TI - Genetic characterization of Amazonian bovine papillomavirus reveals the existence of four new putative types. AB - Papillomaviruses are small and complex viruses that belong to the Papillomaviridae family, which comprises 39 genera. The bovine papillomavirus (BPV) causes an infectious disease that is characterized by chronic and proliferative benign tumors that affect cattle worldwide. Different genotypes of BPVs can cause distinct skin and mucosal lesions and the immunity they raise has low cross-protection. This report aimed to genotype BPVs in cattle from Northern Brazil based on nucleotide partial sequences of the L1 ORF. Skin wart samples from 39 bovines clinically and histopathologically diagnosed as cutaneous papillomatosis from Acre and Rondonia States were analyzed. The results revealed four already reported BPV types (BPVs 1, 2, 11, and 13), nine putative new BPV subtypes and four putative new BPV types as well as two putative new BPV types that were already reported. To our knowledge, this is the first record of BPVs from the Brazilian Amazon region that identified new possible BPV types and subtypes circulating in this population. These findings point to the great genetic diversity of BPVs that are present in this region and highlight the importance of this knowledge before further studies about vaccination are attempted. PMID- 26116288 TI - Low levels of ficolin-3 are associated with diabetic peripheral neuropathy. AB - AIMS: Ficolin-3, a soluble molecule of the innate immune system, has a primary role in the activation of the lectin pathway in the complement system. Considering that inflammatory mechanisms are involved in complement activation and take part in the pathophysiology of diabetic peripheral neuropathy (DPN), we conducted this study to explore the link between serum ficolin-3 and DPN in diabetic patients. METHODS: A total of 466 diabetic patients were enrolled in this cross-sectional study. DPN was evaluated by neurological symptoms, neurological signs, neurothesiometer and electromyogram. The concentration of serum ficolin-3 was determined by enzyme-linked immunosorbent assay. RESULTS: The concentration of serum ficolin-3 was lower in DPN patients compared with non-DPN patients (18.73 +/- 4.75 vs. 26.69 +/- 5.68 ng/mL, P < 0.001). In addition, it was found negatively correlated to the vibration perception threshold (r = 0.158; P = 0.025). The results of multiple regression analysis of DPN indicated that age, diabetes duration, serum ficolin-3 were all independent impact factors for DPN (P < 0.05). Patients were then assigned into quartiles according to the serum ficolin-3 levels, and the prevalence of DPN ascended as the concentration of ficolin-3 descended (Trend analysis, P < 0.001). Compared with ficolin-3 Quartile 1 (referent), the risk of DPN was significantly greater in Quartile 2 (OR 2.76; 95 % CI 1.56-4.88; P < 0.001), Quartile 3 (OR 3.02; 95 % CI 1.69-5.40; P < 0.001) and Quartile 4 (OR 6.84; 95 % CI 3.39-13.80; P < 0.001). CONCLUSIONS: Lower ficolin-3 level is independently associated with DPN, and it may be a potential biomarker for DPN. PMID- 26116289 TI - Genetic determinants of swallowing impairments among community dwelling older population. AB - BACKGROUND: Swallowing difficulties (dysphagia) affect a significant proportion of community dwelling older individuals, being more prevalent in age-associated neurological conditions such as stroke and Parkinson's disease. The genetic determinants of dysphagia are still being explored and have largely been studied through candidate gene analysis approaches. The aim of the study was to perform a genome-wide association study (GWAS) of common genetic single nucleotide polymorphisms (SNP) and self-reported swallowing impairments in a longitudinal cohort of community dwelling older adults. MATERIALS AND METHODS: We performed a case-control genome-wide association study of self-reported swallowing symptoms using the Sydney Swallow Questionnaire. The analysis included 555 community dwelling, unrelated, older adults (mean years of age=81.4; SD=5.349) with known phenotype and genetic information consisting of 512,806 single nucleotide polymorphisms. Gene-based association analysis of these traits was also conducted. RESULTS: Analysis of the cohort confirmed European ancestry with no major population stratification. Further analysis for association with swallowing impairment identified one SNP rs17601696 which achieved genome-wide significance (P-value=5*10(-8)) within a non-coding region of chromosome 10. Gene-based analysis did not result in any genome-wide significant association. CONCLUSION: SNP rs17601696 may have an impact on swallowing impairment among elderly individuals. The results require replication in an independent cohort with appropriate phenotype/genotype data. PMID- 26116290 TI - New genomic profiling tool to detect TB drug resistance. PMID- 26116291 TI - E-cigarettes: a harm-reduction strategy for socioeconomically disadvantaged smokers? PMID- 26116292 TI - Sweet syndrome. PMID- 26116293 TI - Comparative Transcriptome Analysis of the Cosmopolitan Marine Fungus Corollospora maritima Under Two Physiological Conditions. AB - Marine sandy beaches represent dynamic environments often subject to harsh conditions and climate fluctuations, where natural and anthropogenic inputs of freshwater from fluvial and pluvial sources alter salinity, which has been recognized as a key variable affecting the distribution of aquatic organisms and influencing critical physiological processes. The marine arenicolous fungus Corollospora maritima is a worldwide-distributed saprobe that has been reported to present tolerance to freshwater. Here, we present a transcriptome analysis that will provide the first insight of the genomic content for this fungus and a gene expression comparison between two different salinity conditions. We also identified genes that are candidates for being differentially expressed in response to environmental variations on salinity during the fungal growth. The de novo reconstruction of C. maritima transcriptome Illumina sequencing provided a total of 14,530 transcripts (16 megabases). The comparison between the two growth conditions rendered 103 genes specifically overexpressed in seawater, and 132 genes specifically up-regulated under freshwater. Using fungal isolates collected from different beaches, the specific environmental regulation of particular transcript differential expression was confirmed by RT-qPCR. To our knowledge, this is the first analysis that explores the marine fungus C. maritima molecular responses to overcome freshwater stress, and these data could shed light to understand the fungal adaptation and plasticity mechanisms to the marine habitat. PMID- 26116294 TI - Prospective randomized trial comparing magnetic resonance imaging (MRI)-guided in bore biopsy to MRI-ultrasound fusion and transrectal ultrasound-guided prostate biopsy in patients with prior negative biopsies. AB - BACKGROUND: A significant proportion of prostate cancers (PCas) are missed by conventional transrectal ultrasound-guided biopsy (TRUS-GB). It remains unclear whether the combined approach using targeted magnetic resonance imaging (MRI) ultrasound fusion-guided biopsy (FUS-GB) and systematic TRUS-GB is superior to targeted MRI-guided in-bore biopsy (IB-GB) for PCa detection. OBJECTIVE: To compare PCa detection between IB-GB alone and FUS-GB + TRUS-GB in patients with at least one negative TRUS-GB and prostate-specific antigen >=4 ng/ml. DESIGN, SETTING, AND PARTICIPANTS: Patients were prospectively randomized after multiparametric prostate MRI to IB-GB (arm A) or FUS-GB + TRUS-GB (arm B) from November 2011 to July 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The study was powered at 80% to demonstrate an overall PCa detection rate of >=60% in arm B compared to 40% in arm A. Secondary endpoints were the distribution of highest Gleason scores, the rate of detection of significant PCa (Gleason >=7), the number of biopsy cores to detect one (significant) PCa, the positivity rate for biopsy cores, and tumor involvement per biopsy core. RESULTS AND LIMITATIONS: The study was halted after interim analysis because the primary endpoint was not met. The trial enrolled 267 patients, of whom 210 were analyzed (106 randomized to arm A and 104 to arm B). PCa detection was 37% in arm A and 39% in arm B (95% confidence interval for difference, -16% to 11%; p=0.7). Detection rates for significant PCa (29% vs 32%; p=0.7) and the highest percentage tumor involvement per biopsy core (48% vs 42%; p=0.4) were similar between the arms. The mean number of cores was 5.6 versus 17 (p<0.001). A limitation is the limited number of patients because of early cessation of accrual. CONCLUSIONS: This trial failed to identify an important improvement in detection rate for the combined biopsy approach over MRI-targeted biopsy alone. A prospective comparison between MRI targeted biopsy alone and systematic TRUS-GB is justified. PATIENT SUMMARY: Our randomized study showed similar prostate cancer detection rates between targeted prostate biopsy guided by magnetic resonance imaging and the combination of targeted biopsy and systematic transrectal ultrasound-guided prostate biopsy. An important improvement in detection rates using the combined biopsy approach can be excluded. PMID- 26116295 TI - Osteoclast inhibitors in advanced prostate cancer: does the benefit extend beyond skeletal-related events? PMID- 26116296 TI - Notch filter artefact mimicking high frequency oscillation in epilepsy. PMID- 26116297 TI - Improvement of baroreflex sensitivity in patients with obstructive sleep apnea following surgical treatment. AB - OBJECTIVE: Depressed baroreflex sensitivity (BRS) have been reported in patients with obstructive sleep apnea (OSA). This study aimed to determine if surgery can improve the clinical outcomes by investigating changes in BRS and in other cardiovascular autonomic parameters. METHODS: Eighty-one OSA patients were enrolled. They were classified as mild OSA if their apnea-hypopnea index (AHI) was 5-15, moderate OSA if their AHI was 15-30, and sever OSA if their AHI was >30. Twenty-three subjects with AHI<5 were recruited as controls. For patients who received surgery, polysomnography (PSG) and autonomic tests were evaluated upon enrollment and six-months after surgery. RESULTS: The patient number for mild, moderate, and severe OSA was 22, 22, and 37, respectively. BRS on enrollment showed significant difference among the four groups, with the highest BRS in the control group, follow by the mild, moderate, and severe OSA groups. There were significant correlations between BRS and all PSG parameters. The depressed BRS significantly improved after surgery. CONCLUSIONS: Surgical modifications of the upper airways can improve the depressed BRS in OSA patients. SIGNIFICANCE: The study offers the promise that surgical treatment for OSA not only improves the index of PSG, but also reduces the possibility of cardiovascular risk. PMID- 26116298 TI - Two subtypes of positional obstructive sleep apnea: Supine-predominant and supine isolated. AB - OBJECTIVES: The body position has a strong influence on obstructive sleep apnea (OSA). The purpose of this study is to compare the clinical features of two subtypes of positional OSA (POSA), namely supine-predominant OSA (spOSA) and supine-isolated OSA (siOSA), so as to discuss whether the two groups can be classified separately. METHODS: A total of 279 consecutive patients with OSA were enrolled. The POSA was defined as having an overall apnea-hypopnea index (AHI) ? 5 with supine AHI > 2 times the non-supine AHI. Only those with ? 30 min spent in the supine and non-supine sleeping positions were included, and split night studies were excluded from the study. Patients were considered spOSA unless their non-supine AHI was negligible (<5) (siOSA). The clinical and polysomnographic characteristics of both groups were compared. RESULTS: Two hundred and sixteen subjects (77.4%) met the criteria for POSA, with 158 (73.1%) of them classified as spOSA, and 58 (26.9%) as siOSA. The siOSA patients had lower arousal indices, but poorer quality of sleep, and were more depressed and anxious compared with the spOSA subjects. CONCLUSIONS: Those with siOSA and spOSA show different clinical features. SIGNIFICANCE: These findings suggest that a more detailed sub classification of POSA is needed. PMID- 26116299 TI - Modulation of stimulus-induced 20-Hz activity for the tongue and hard palate during tongue movement in humans. AB - OBJECTIVE: Modulation of 20-Hz activity in the primary sensorimotor cortex (SM1) may be important for oral functions. Here, we show that 20-Hz event-related desynchronization/synchronization (20-Hz ERD/ERS) is modulated by sensory input and motor output in the oral region. METHODS: Magnetic 20-Hz activity was recorded following right-sided tongue stimulation during rest (Rest) and self paced repetitive tongue movement (Move). To exclude proprioception effects, 20-Hz activity induced by right-sided hard palate stimulation was also recorded. The 20 Hz activity in the two conditions was compared via temporal spectral evolution analyses. RESULTS: 20-Hz ERD/ERS was detected over bilateral temporoparietal areas in the Rest condition for both regions. Moreover, 20-Hz ERS was significantly suppressed in the Move condition for both regions. CONCLUSIONS: Detection of 20-Hz ERD/ERS during the Rest condition for both regions suggests that the SM1 functional state may be modulated by oral stimulation, with or without proprioceptive effects. Moreover, the suppression of 20-Hz ERS for the hard palate during the Move condition suggests that the stimulation-induced functional state of SM1 may have been modulated by the movement, even though the movement and stimulation areas were different. SIGNIFICANCE: Sensorimotor function of the general oral region may be finely coordinated through 20-Hz cortical oscillation. PMID- 26116300 TI - How to prepare head tissue-equivalent liquids for SAR calculations, dosimetry and hyperthermia researches at 900 and 1800 MHz GSM frequencies. AB - The potential harmful effect of electromagnetic fields on human health is an important issue that has been widely discussed in the scientific community. The investigation of temperature rise in human body following exposure to electromagnetic fields has been found impractical in many aspects. Therefore, fabrication of the tissue-equivalent liquids (TELs) is required. TELs have been widely employed in specific absorption rate calculations, dosimetry and hyperthermia researches. In this study, two separate head tissue-equivalent liquids (HELs) were prepared for 900 and 1800 MHz frequencies. The conductivity and relative permittivity of the HEL prepared for 900 MHz frequency were found to deviate from The Institute of Electrical and Electronics Engineers (IEEE) standards at the rates of 6.20 and 2.70 %, whereas the HEL prepared for 1800 MHz applications exhibited 1.83 and 3.22 % deviations from IEEE standards, respectively. This study provides a method for researchers to prepare their own HELs in a practical way. PMID- 26116301 TI - Prognostic value of late gadolinium enhancement in dilated cardiomyopathy patients: a meta-analysis. AB - AIM: To evaluate the association between late gadolinium enhancement (LGE) at cardiac magnetic resonance (CMR) and major adverse events in dilated cardiomyopathy (DCM) patients. MATERIALS AND METHODS: Databases, including PubMed, Ovid, and EMBASE, were searched for studies evaluating LGE at CMR in DCM patient prognostication. Clinical outcomes were analysed using fixed-effects models or, in cases of significant heterogeneity, random-effects models. RESULTS: In the meta-analysis of 13 studies on 1675 DCM patients with a mean follow-up of 3 years, LGE is associated with all-cause mortality (pooled odds ratio, 3.43 [95% confidence interval, 2.26-5.22], p<0.00001), cardiac death/transplantation (3.65 [1.80-7.40], p=0.0003), hospitalisation for heart failure (2.87 [1.53-5.39], p=0.001), major arrhythmia events (sudden cardiac death, sustained ventricular tachycardia or fibrillation, appropriate implantable cardioverter-defibrillator (ICD) discharge/pacing, and syncope: 4.24 [2.95-6.08], p<0.00001), and sudden cardiac death (3.33 [1.80-6.17], p=0.0001). CONCLUSION: LGE in DCM patients appears to be associated with mortality and major cardiac events, underscoring its potential as an independent index for risk stratification and treatment guidance. PMID- 26116302 TI - The Penrose hypothesis in the 21st century: revisiting the asylum. PMID- 26116303 TI - Do altitude and climate affect paranasal sinus volume? AB - OBJECTIVE: The aim of this study was to evaluate the effect of climate and altitude differences on the volume of paranasal sinuses and on the frequency of anatomic variations by comparing the paranasal sinus tomograms (PNSCT) of patients who were born and living in a cold, dry climate at high altitude with those of patients who were born and living on the coast at sea level in a temperate climate. We also aimed to determine differences relating to gender. MATERIAL AND METHODS: A total of 55 PNSCTs of 55 patients from the city center of Antalya and 60 PNSCTs of 60 patients from the city center of Agri were evaluated and compared prospectively. The study included a total of 115 patients with a mean age of 44.75 +/- 9.64 years (range, 27-63 years). Group 1 (Antalya) comprised 26 females (47.3%) and 29 males (52.7%) with a mean age of 36.7 +/- 12.4 years. Group 2 (Agri) comprised 25 females (41.7%) and 35 males (58.3%) with a mean age of 35.1 +/- 13.4 years. Maxillary sinus volumes were 18.27 cm(3) (range, 5.04-37.62) and 15.06 cm(3) (4.11-41.40); sphenoid sinus volumes were 7.81 cm(3) (1.80-20.63) and 6.35 cm(3) (0.54-16.50); frontal sinus volumes were 5.51 cm(3) (0.50-29.25) and 3.76 cm(3) (0.68-22.81) respectively. RESULTS: There was no statistically significant difference between the groups in term of volumes (p > 0.025). Both maxillary and frontal sinus volumes were greater in males compared to females (p < 0.025). The mean value of the maxillary sinus volume was 15.7 +/- 5.3 cm(3) and was significantly larger in males than in females (p = 0.004). There was no statistically significant correlation between the volume of maxillary sinuses with age or side. There was no statistically significant difference between the groups in terms of septum deviation and concha bullosa rates (p = 0.469 and p = 0.388). CONCLUSION: There have been many studies of nasal cavity changes due to climatic conditions but this is the first study to measure the difference of paranasal sinus volumes. No difference was determined in the anatomic variations and volumes of the maxillary, frontal, sphenoid sinuses on PNSCT of patients from different climates and altitudes. PMID- 26116304 TI - Update on orbital decompression as emergency treatment of traumatic blindness. AB - INTRODUCTION: Blindness is a rare and severe complication of craniofacial trauma. The management of acute orbital compartment syndrome (AOCS) is not well defined and there is no standard treatment. Our objective was to find indications for orbital decompression, the best time for treatment, and the appropriate techniques. MATERIALS AND METHODS: A literature review was made from articles published between 1994 and 2014 in the PubMed database, on the emergency treatment of AOCS. RESULTS: 59 of the 89 patients treated surgically for AOCS presented with significant improvement of visual acuity (VA) after orbital decompression. The delay between trauma and surgery was short. A lateral canthotomy with inferior cantholysis (LCIC) was the most frequently used technique. DISCUSSION: AOCS with a risk of visual impairment must be decompressed in emergency, at best in the 2 hours following trauma, most often by LCIC to have the best chance of recovering VA. Adjuvant medical treatment (acetazolamide, mannitol, corticosteroids) should not delay surgery. Postoperative corticosteroid therapy is not indicated, especially in patients with severe head trauma. PMID- 26116305 TI - Mandibular lingual release versus mandibular lip-split approach for expanded resection of middle-late tongue cancer: A case-control study. AB - OBJECTIVE: The mandibular lingual release (MLR) and mandibular lip-split (MS) approaches are the two common access approaches for resection of malignant tongue tumors. This case-control study aimed to evaluate the effectiveness and safety of these two approaches for the expanded resection of middle-late tongue cancer. MATERIAL AND METHODS: A total of 56 matched patients with resectable middle-late squamous cell carcinoma of the tongue body were consecutively hospitalized for expanded resection using the MLR (n = 26) or MS approach (n = 30) between March 2004 and November 2012. Main outcome measures consisted of tumor exposure, surgical morbidity, maxillofacial motor-sensory return, and head/neck-specific quality of life. RESULTS: The two approaches achieved similar en bloc R0 resection with similar tumor exposure. The MLR approach was associated with a significantly lower frequency of maxillofacial pain (P < 0.05) and no incidence of mandible nonunion. The MLR approach was also associated with a significantly better quality of life with respect to local pain, facial appearance, and mood. CONCLUSION: Compared to the MS approach, the MLR approach was associated with significantly less surgical morbidity and a significantly better quality of life for middle-late tongue cancer patients undergoing expanded resection. PMID- 26116306 TI - Value of nonsurgical therapeutic management of stage I bisphosphonate-related osteonecrosis of the jaw. AB - There is still controversy about the best treatment strategy for patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ) stage I. Therefore, the aim of the present study was to analyse the effect of a nonsurgical treatment protocol in patients with BRONJ stage I. During the study period we included 17 patients (11 male; 6 female) who presented with a total of 24 separate areas of BRONJ, stage I. All patients were exclusively treated with a monthly intravenous regime of zoledronic acid due to an underlying malignant disease. All patients were treated using a standardized nonsurgical protocol consisting of antimicrobial mouth rinsing with chlorhexidine (CHX) (0.12%) three times a day, and daily CHX gel application. In 11 patients (45.8%) the surface area of the exposed jawbone was completely healed by nonsurgical treatment. In seven patients (29.2%), nonsurgical treatment reduced the size of the exposed bone area by a mean of 64.7% (range 20.0-96.8%). None of the patients showed an increase in size of the area of exposed jawbone, or a worsening of the BRONJ from stage I to stages II or III. However, the duration of nonsurgical treatment or the duration of intravenous bisphosphonate therapy did not significantly influence the treatment outcome (p = 0.6628, p = 0.6077, respectively). The results of the present study support the beneficial role of nonsurgical treatment in patients presenting with BRONJ stage I. Surgical therapy of BRONJ should be restricted to patients with advanced stages with clinical symptoms and local signs of infection. PMID- 26116307 TI - Large maxillomandibular advancements for obstructive sleep apnea: An operative technique evolved over 30 years. AB - OBJECTIVE: Obstructive sleep apnea (OSA) can be a challenging disorder to treat. Maxillomandibular advancements (MMAs) generally have high success rates; however, larger advancements have higher success and cure rates. Our aim is to present and to describe the current technique used by the senior authors, which has been successful for performing large advancements, thereby improving post-operative outcomes. METHODS: The senior authors have developed and modified their maxillomandibular advancement operative techniques significantly over the past 30 years. The current version of the Riley-Powell MMA technique is described in a step-by-step fashion in this article. RESULTS: Initially, as part of the MMAs, patients underwent maxillomandibular fixation with wires, lag screws and harvested split calvarial bone grafts. The current technique utilizes plates, screws, Erich Arch Bars, and suspension wires which are left in place for 5-6 weeks. Guiding elastics are worn for the first week. The MMA technique described in this article has yielded a success rate over 90% for patients with a body mass index (BMI) <40 kg/m(2) and 81% for patients with a BMI >=40 kg/m(2). CONCLUSION: Large advancements during maxillomandibular advancement surgeries can help improve post-operative obstructive sleep apnea outcomes. PMID- 26116308 TI - Anthropometric analysis of the nose in young Turkish men and women. AB - PURPOSE: The aim of the study was to describe and compare values for nasal anthropometric measurements using the landmark-based geometric morphometric technique in young healthy Turkish men and women. MATERIALS AND METHODS: A total of 115 young adults (56 men and 59 women) whose ages ranged from 18 to 30 years (mean age 21.22 years) were included in the analysis. RESULTS: For men the mean nasal bridge length, total length, width and root width were 52.95, 54.38; 35.24 and 17.83 mm, respectively, and in women they were 47.81 and 50.90; 31.59 and 17.36 mm, respectively. The columella length and width were 12.76 and 5.77 mm, respectively, for men, and for women they were 11.88 and 5.60 mm, respectively. CONCLUSION: Data collected in the present research could serve as a database for the quantitative description of nasal morphology in young Turkish adults. It may also be used in sex based data banks for the Turkish population. PMID- 26116309 TI - IMF-screws or arch bars as conservative treatment for mandibular condyle fractures: Quality of life aspects. AB - OBJECTIVE: Arch bars as treatment for a fractured mandibular condyle are inconvenient to patients and lead to lowered quality of life (QOL). To overcome these inconveniences, IMF-screws (IMFS) to facilitate intermaxillary fixation during surgery have been developed. The purpose of the present study is to investigate and compare QOL for patients treated for a fractured mandibular condyle with either IMFS or arch bars. MATERIAL AND METHODS: This research trial was conducted from 2010 to 2014 as part of an earlier prospective, multicenter, randomized clinical trial in which the use of IMFS was compared to the use of arch bars in the treatment of mandibular condylar fractures. RESULTS: In total, 50 patients were included: 30 (60%) male patients and 20 (40%) female patients (mean age: 31.8 years, standard deviation [SD] = 13.9 years, range = 18-64 years). A total of 24 (48%) patients were allocated in the IMFS group, and 26 (52%) patients were assigned to the arch-bars control group. Significant results were observed in the subscales social isolation, possibility to eat and vary diet, influence on sleep, and satisfaction with the given treatment, all in favour of IMFS. CONCLUSION: In conclusion, using IMFS as a method for conservative treatment of condylar fractures led to a higher QOL during the 6 week period of fracture healing. In comparison to arch bars, patients treated with IMFS experienced less social isolation, had fewer problems with eating, and express the feeling they are able to continue their normal diet. Furthermore it seems that the use of IMFS has a lower negative impact on social and financial aspects of the patient. PMID- 26116310 TI - Intraosseous heat generation during sonic, ultrasonic and conventional osteotomy. AB - OBJECTIVES: To assess heat generation in osteotomies during application of sonic and ultrasonic saws compared to conventional bur. METHODS: Two glass-fiber isolated nickel-chromium thermocouples, connected to a recording device, were inserted into fresh bovine rib bone blocks and kept in 20 +/- 0.5 degrees C water at determined depths of 1.5 mm (cortical layer) and 7 mm (cancellous layer) and 1.0 mm away from the planned osteotomy site. Handpieces, angulated 24-32 degrees , were mounted in a vertical drill stand, and standardized weights were attached to their tops to exert loads of 5, 8, 15 and 20 N. Irrigation volumes of 20, 50 and 80 ml/min were used for each load. Ten repetitions were conducted using new tips each time for each test condition. The Mann-Whitney-U test was used for statistical analysis (p < 0.05). RESULTS: Both ultrasonic and sonic osteotomies were associated with significantly lower heat generation than conventional osteotomy (p < 0.01). Sonic osteotomy showed non-significantly lower heat generation than ultrasonic osteotomy. Generated heat never exceeded the critical limit of 47 degrees C in any system. Variation of load had no effect on heat generation in both bone layers for all tested systems. An increased irrigation volume resulted in lower temperatures in both cortical and cancellous bone layers during all tested osteotomies. CONCLUSION: Although none of the systems under the conditions of the present study resulted in critical heat generation, the application of ultrasonic and sonic osteotomy systems was associated with lower heat generation compared to the conventional saw osteotomy. Copious irrigation seems to play a critical role in preventing heat generation in the osteotomy site. PMID- 26116311 TI - Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders before and after transition to triheptanoin treatment--A retrospective chart review. AB - BACKGROUND: Long chain fatty acid oxidation disorders (LC-FAODs) are caused by defects in the metabolic pathway that converts stored long-chain fatty acids into energy, leading to a deficiency in mitochondrial energy production during times of physiologic stress and fasting. Severe and potentially life threatening clinical manifestations include rhabdomyolysis, hypoglycemia, hypotonia/weakness, cardiomyopathy and sudden death. We present the largest cohort of patients to date treated with triheptanoin, a specialized medium odd chain (C7) triglyceride, as a novel energy source for the treatment of LC-FAOD. METHODS: This was a retrospective, comprehensive medical record review study of data from 20 of a total 24 patients with LC-FAOD who were treated for up to 12.5 years with triheptanoin, as part of a compassionate use protocol. Clinical outcomes including hospitalization event rates, number of hospitalization days/year, and abnormal laboratory values were determined for the total period of the study before and after triheptanoin treatment, as well as for specified periods before and after initiation of triheptanoin treatment. Other events of interest were documented including rhabdomyolysis, hypoglycemia, and cardiomyopathy. RESULTS: LC-FAOD in these 20 subjects was associated with 320 hospitalizations from birth to the end date of study. The mean hospitalization days/year decreased significantly by 67% during the period after triheptanoin initiation (n=15; 5.76 vs 17.55 vs; P=0.0242) and a trend toward a 35% lower hospitalization event rate was observed in the period after triheptanoin initiation compared with the before treatment period (n=16 subjects >6 months of age; 1.26 vs 1.94; P=0.1126). The hypoglycemia event rate per year in 9 subjects with hypoglycemia problems declined significantly by 96% (0.04 vs 0.92; P=0.0091) and related hospitalization days/year were also significantly reduced (n=9; 0.18 vs 8.42; P=0.0257). The rhabdomyolysis hospital event rate in 11 affected subjects was similar before and after treatment but the number of hospitalization days/year trended lower in the period after triheptanoin initiation (n=9; 2.36 vs 5.94; P=0.1224) and peak CK levels trended toward a 68% decrease from 85,855 to 27,597 units in 7 subjects with reported peak CK values before and after treatment (P=0.1279). Triheptanoin was generally well tolerated. Gastrointestinal symptoms were the most commonly reported side effects. CONCLUSIONS: This retrospective study represents the largest analysis reported to date of treatment of LC-FAOD with triheptanoin. The data suggest that triheptanoin improves the course of disease by decreasing the incidence and duration of major clinical manifestations and should be the focus of prospective investigations. Significant heterogeneity in the routine clinical care provided to subjects during the periods studied and the natural variation of clinical course of LC-FAODs with time emphasize the need of additional study of the use of triheptanoin. PMID- 26116313 TI - alpha-Synuclein in Parkinson's disease: getting to the core of the matter. PMID- 26116312 TI - Electrocardiographic evolution in patients with hypertrophic cardiomyopathy who develop a left ventricular apical aneurysm. AB - INTRODUCTION: Hypertrophic cardiomyopathy (HCM) patients with apical aneurysm have a largely unfavourable clinical course, and are often unrecognised because echocardiography is limited in the assessment of the left ventricular (LV) apex. The aim of this study is the identification of electrocardiographic (ECG) abnormalities associated with the development of apical aneurysm in HCM patients. MATERIALS AND METHODS: Electrocardiographic features were assessed in 14 HCM patients who had a good-quality baseline ECG recorded before and after the diagnosis of apical aneurysm. RESULTS: During follow-up (8.8+/-7.5years), the following ECG changes were observed: increase in QRS-complex duration (87+/-12ms to 118+/-34ms, p=0.006), QRS-complex fragmentation, decrease in QRS-complex amplitude (SV1+RV5-6, from 41+/-18mm to 26+/-11mm, p=0.015), ST-segment elevation in V4-V6 (J-point in V5, from -0.9+/-1.3mm to +0.7+/-1.3, p=0.003), positivisation of negative T waves in V3-V6 (T-wave depth in V5, from -3.4+/-6.6 to +3.1+/-4.1, p=0.005). CONCLUSIONS: HCM patients who develop LV apical aneurysm exhibit distinctive ECG changes along with apical remodelling. Suggestive ECGs should lead the physician to study LV apex by nonstandard echocardiographic views, and perform MRI. PMID- 26116314 TI - Neuroprotection in Parkinson's disease: a difficult challenge. PMID- 26116316 TI - The SWENOTECA group: A good example of continuous binational and multidisciplinary collaboration for patients with testicular cancer in Sweden and Norway. AB - OBJECTIVE: The aim of this article is to present the Swedish and Norwegian Testicular Cancer Group (SWENOTECA), with an emphasis on the history of SWENOTECA, organization, results and current status. MATERIALS AND METHODS: SWENOTECA was founded in 1981 as a binational organization open to hospitals in Sweden and Norway treating testicular cancer. It has since published treatment protocols for testicular cancer and prospectively registered patients with testicular cancer. Today, all hospitals in Norway and Sweden involved in the care of testicular cancer participate in SWENOTECA, and all patients with testicular cancer are prospectively registered in a population-based database. RESULTS: Nine protocols with standardized guidelines on the diagnosis, treatment and follow-up of testicular cancer have been published. In addition to the guidelines, several studies have been performed or initiated within the scope of SWENOTECA. The details are presented in this article. CONCLUSIONS: SWENOTECA has been a very fruitful binational collaboration and has thoughtfully evolved over time. The group's continuous work and dedication have provided an example for other national and international cancer networks. The binational implementation of standardized guidelines has resulted in excellent patient outcomes, regardless of place of residence. Although testicular cancer is a relatively rare disease, the population-based binational organization of SWENOTECA has made it possible to publish some of the largest studies in the field of testicular cancer. PMID- 26116315 TI - Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial. AB - BACKGROUND: A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo controlled, futility clinical trial. METHODS: Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0.10. The study is registered at ClinicalTrials.gov, number NCT01280123. FINDINGS: 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4.42 (95% CI 2.55-6.28) for 15 mg pioglitazone, 5.13 (95% CI 3.17-7.08) for 45 mg pioglitazone, and 6.25 (95% CI 4.35-8.15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was -1.83 (80% CI -3.56 to -0.10) and the null hypothesis could not be rejected (p=0.19). The mean difference between the 45 mg and placebo groups was -1.12 (80% CI -2.93 to 0.69) and the null hypothesis was rejected in favour of futility (p=0.09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0.09 for LVCF, p=0.09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0.12 for LVCF, p=0.19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. INTERPRETATION: These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. FUNDING: National Institute of Neurological Disorders and Stroke. PMID- 26116317 TI - Ameliorating soil chemical properties of a hard setting subsoil layer in Coastal Plain USA with different designer biochars. AB - Biochar application is an emerging management option to increase soil fertility. Biochars could improve chemical properties of soils with hard setting subsoil layer. However, biochar effect can be inconsistent because different biochars react differently in soils. We hypothesized that addition of designer biochars will have variable effects on improving the chemical properties of hard setting layers. The objective of this study was to investigate the effects of biochars on soil properties in Norfolk's soil with a hard setting subsoil layer grown with winter wheat (Triticum aestivum L.). All designer biochars were added at the rate of 40 Mg ha(-1). Feedstocks used for biochars production were: plant-based (pine chips, 100% PC); animal-based (poultry litter, 100% PL); 50:50 blend (50% PC:50% PL); 80:20 blend (80% PC:20% PL); and hardwood (100% HW). Higher nutrient availability was found after additions of biochars especially additions of 100% PL and 50:50 blend of PC and PL. On the average, applications of 100% PL and 50:50 blend of PC:PL had the greatest amount of soil total nitrogen with means of 1.94+/-0.3% and 1.44+/-0.3%, respectively. When compared with the control and other biochars, 50:50 blend of PC:PL additions resulted in increase of 669% for P, 830% for K, 307% for Ca, 687% for Mg and 2315% for Na while application of 100% PL increased the concentration of extractable P, K, Ca, Mg, and Na by 363%, 1349%, 152%, 363%, and 3152%, respectively. Overall, our results showed promising significance since biochars did improve chemical properties of a Norfolk's soil. PMID- 26116318 TI - A new approach to carcinoma of the stomach? PMID- 26116319 TI - A comparison of outcomes of emergent, urgent, and elective surgical treatment of diverticulitis. AB - BACKGROUND: There is a controversy regarding the best urgent surgical treatment of colonic diverticulitis. We sought to compare outcomes of patients who underwent surgery for diverticulitis by the type of admission. METHODS: The National Surgical Quality Improvement Program databases were used to examine the clinical data of patients who underwent colorectal resection for diverticulitis during 2012 to 2013. Multivariate regression analysis was performed to identify outcomes of patients. RESULTS: We sampled a total of 13,510 patients admitted for diverticulitis who underwent colorectal resection, of which 7.8% had emergent and 19.7% had urgent operation. Patients with perforation (adjusted odds ratio [AOR] 188.56, P < .01) and preoperative sepsis (AOR 28.17, P < .01) had significantly higher rates of emergent surgery. Patients who underwent emergent operation had higher mortality (AOR 4.08, P = .04) and morbidity (AOR 2.14, P < .01). Emergent operations had a significantly higher risk of anastomosis leakage compared with elective operation (AOR 3.92, P = .02). CONCLUSIONS: Emergent treatment of diverticulitis is associated with a high morbidity and mortality. In the setting of emergent treatment of diverticulitis, colonic anastomosis without a stoma has a high risk of anastomosis leakage. PMID- 26116320 TI - In response to: Preston JF, Diggs BS, Dolan JP, Gilbert EW, Schein M, Hunter JG. Biliary dyskinesia: a surgical disease rarely found outside the United States. Am J Surg. 2015;209:799-803. PMID- 26116321 TI - Repeat laparotomy in a developing world tertiary level surgical service. AB - BACKGROUND: Repeat laparotomy is associated with significant morbidity and mortality; however, developing world data are scarce. This study reviews the spectrum and outcomes of relaparotomy in a developing world setting. METHODS: Prospectively collected data from adult patients needing repeat laparotomy over an 18-month period were analyzed. RESULTS: Relaparotomy rate was 24% and average age was 38 years with a male predominance (70%). Appendicitis and trauma were the most common diagnoses. Planned relaparotomy rate was high (41%); however, negative relaparotomy rate was only 9%. Need for intensive care unit admission (51%) and morbidity rate (64%) were both high, but overall mortality rate was 14%. Patients requiring multiple relaparotomies had further worsened outcomes. CONCLUSIONS: The need for repeat laparotomy in the developing world is high and it is associated with significant morbidity and need for intensive care unit admission. However, mortality rates and negative repeat laparotomy rates were low. PMID- 26116322 TI - Does comprehensive geriatric assessment improve the estimate of surgical risk in elderly patients? An Italian multicenter observational study. AB - BACKGROUND: The evaluation of surgical risk is crucial in elderly patients. At present, there is little evidence of the usefulness of comprehensive geriatric assessment (CGA) as a part of the overall assessment of surgical elderly patients. METHODS: We verified whether CGA associated with established surgical risk assessment tools is able to improve the prediction of postoperative morbidity and mortality in 377 elderly patients undergoing elective surgery. RESULTS: Overall mortality and morbidity were 2.4% and 19.9%, respectively. Multivariate analysis showed that impaired cognitive function (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.15 to 4.22; P < .02) and higher Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (OR, 1.11; 95% CI, 1.00 to 1.23; P < .04) are predictive of mortality. Higher comorbidity is predictive of morbidity (OR, 2.12; 95% CI, 1.06 to 4.22; P < .03) and higher American Society of Anesthesiologists (OR, 2.18; 95% CI, 1.31 to 3.63; P < .001) and National Confidential Enquiry into Patient Outcome of Death score (OR, 2.03; 95% CI, 1.03 to 4.00; P < .04). CONCLUSIONS: In elective surgical elderly patients, the morbidity and mortality are low. The use of CGA improves the identification of elderly patients at higher risk of adverse events, independent of the surgical prognostic indices. PMID- 26116323 TI - Horizontal tumor diameter as a prognostic factor. PMID- 26116324 TI - Preadmission Do Not Resuscitate advanced directive is associated with adverse outcomes following acute traumatic injury. AB - BACKGROUND: Do Not Resuscitate (DNR) orders have been associated with poor outcomes in surgical patients. There is limited literature on admitted trauma patients with advanced directives indicating DNR status before admission (preadmission DNR [PADNR]). METHODS: A retrospective review of the trauma registry of a suburban county was carried out for admitted trauma patients with age >=41 years, who were admitted between 2008 and 2013. RESULTS: Of 7,937 admitted patients, 327 had a preadmission advanced directive indicating DNR. PADNR patients were significantly older (87 vs 69 years), with more frequent comorbidities, and were more often admitted after a fall (94.2% vs 65.8%). PADNR patients had a higher Injury Severity Score (14 vs 11). They also had significantly increased rates of pneumonia, sepsis, myocardial infarction, and death (33.6% vs 5.9%). On multivariate logistic regression, the presence of a preadmission advanced directive indicating DNR status was independently associated with a 5.2-fold increased odds of mortality. CONCLUSION: An advanced directive indicating DNR is associated with adverse outcomes following trauma. PMID- 26116325 TI - [Heparin for clearance of peripherally inserted central venous catheter in newborns: an in vitro study]. AB - OBJECTIVE: To compare the efficacy of two concentrations of heparin to clear the lumen of in vitro clotted neonatal peripherally inserted central catheters (PICCs). METHODS: This is an in vitro, experimental quantitative study of 76 neonatal 2.0Fr PICCs coagulated in vitro. The catheters were divided into two groups of 38 PICCs each. In both groups an infusion of low molecular weight heparin was administered with a dose of 25IU/mL for Group 1 and 50IU/mL for Group 2. The negative pressure technique was applied to the catheters of both groups at 5, 15 and 30minutes and at 4hours to test their permeability. Kaplan-Meier survival analysis was used to verify the outcome of the groups according to time intervals. RESULTS: The comparison between both groups in the first five minutes showed that more catheters from Group 2 were cleared compared to Group 1 (57.9 vs. 21.1%, respectively). Kaplan-Meier survival analysis showed that less time was needed to clear catheters treated with 50IU/mL of heparin (p<0.001). CONCLUSIONS: The use of low-molecular weight heparin at a concentration of 50IU/mL was more effective in restoring the permeability of neonatal PICCs occluded in vitro by a clot, and the use of this concentration is within the safety margin indicated by scientific literature. PMID- 26116326 TI - [Influence of body position on the displacement of nasal prongs in preterm newborns receiving continuous positive airway pressure]. AB - OBJECTIVE: To evaluate the influence of body position on the displacement of nasal prongs in preterm infants. METHODS: This prospective, randomized, crossover study enrolled infants born at a mean gestational age of 29.7+/-2 weeks, birth weight of 1.353+/-280g and 2.9+/-2.2 days of life, submitted to continuous positive airway pressure by nasal prongs. The main outcome was the number of times that the nasal prongs were displaced following infant positioning in the following body positions: prone, right lateral, left lateral, and supine, according to a pre-established random order. Moreover, cardiorespiratory variables (respiratory rate, heart rate, and oxygen saturation) were evaluated for each body position. Data for each position were collected every 10 minutes, over a period of 60minutes. An occurrence was defined when the nasal prongs were displaced from the nostrils after 3 minutes in the desired position, requiring intervention of the examiner. RESULTS: Among the 16 studied infants, the occurrence of nasal prong displacement was only observed in the prone position (9 infants-56.2%) and in the left lateral position (2 infants-12.5%). The number of times that the prongs were displaced was 11 in the prone position (seven within the first 10minutes) and two in the left lateral position (one within the first 10minutes). No clinically significant changes were observed in the cardiorespiratory variables. CONCLUSIONS: Maintenance of the nasal prongs to provide adequate noninvasive respiratory support was harder in the prone position. PMID- 26116327 TI - Metacognitive profiles in individuals with a first episode of psychosis and their relation to social functioning and perceived social support. AB - Poorer metacognitive abilities are recognized as strong predictors of social functioning deficits in individuals with schizophrenia, but have not been studied in relation to perceived social support. Furthermore, traditional measures of metacognition fail to consider ecological aspects such as the interaction between thinking of one's own or other's mind, and mastery. As a constellation, these abilities may influence domains of social functioning and perceived social support differently. Therefore, this study aimed to establish whether distinct metacognitive profiles exist within a population of individuals with a first psychotic episode, and to determine how such profiles influence individual domains of social functioning and perceived social support. Participants (n=50) were recruited from two early psychosis outpatient clinics in Montreal, Canada. Demographic information, social functioning and perceived social support were measured using self-reported questionnaires, and metacognition was scored from the transcripts of a semi-structured interview designed to avoid leading responses. Cluster analysis revealed three distinct metacognitive profiles: (1) overall better abilities; (2) poor abilities on thinking of one's own and other's mind, but better mastery; and (3) overall poorer abilities. Analyses showed significant differences between profiles only for self-reported intimacy and independent living abilities, with the second profile showing better abilities than the third. Profiles did not simply represent consistently higher or lower functioning across subscales. Although mastery was predictive of social functioning, the ability to think in an increasingly complex manner of one's self and others did not seem to improve functioning in individuals with a first episode of psychosis. PMID- 26116328 TI - Validation of the Spanish version of the Clinical Assessment for Negative Symptoms (CAINS). AB - Negative symptoms are a core feature of schizophrenia and their reliable and valid assessment is a prerequisite for developing effective therapeutic interventions. This study examined the psychometric properties and validity of the Spanish version of a new rating instrument, the Clinical Assessment Interview for Negative Symptoms (CAINS). Outpatients and inpatients (N=100) with DSM-IV schizophrenia were administered the translated CAINS, the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), and the Calgary Depression Scale for Schizophrenia (CDSS). A subsample (N=46) was rated for Parkinsonism using the Extrapyramidal Symptoms Rating Scale (ESRS). The scale showed good inter-rater and intra-rater reliability. Both the CAINS overall and the subscales for motivation/pleasure (CAINS-Map) and expression (CAINS-Exp) scores correlated significantly with the SANS and PANSS negative symptom scale. Significant correlations with positive symptoms and general psychopathology were also found, but these reduced and mostly became insignificant when overall severity of illness was controlled for. Significant correlations with depression also disappeared when severity was controlled for. There was a trend-level correlation between the CAINS total score and Parkinsonism, which reflected an association with the CAINS-Exp subscale only. Factor analysis revealed a two dimensional structure that explained the 67.44% of the variance. Overall, the Spanish version of the CAINS appears to be a valid tool for measuring negative symptoms in schizophrenia. PMID- 26116329 TI - Malignant Mesothelioma of the Tunica Vaginalis: A Rare Neoplasm--Case Report and Literature Review. PMID- 26116330 TI - Acquired Hemophilia Caused by Ureteral Tumor. PMID- 26116331 TI - Knowledge, attitudes, and practices of health care personnel concerning hand hygiene in Shiraz University of Medical Sciences hospitals, 2013-2014. AB - This study evaluated knowledge and self-reported attitudes and practices concerning hand hygiene among hospital workers in Shiraz, Iran, using a 68 question survey divided into 4 sections: demographics, knowledge, attitudes, and practices. Work experience had a correlation with practices and knowledge (P < .05), and knowledge and practices scores were positively correlated (P < .05). Participants appear to have sufficient knowledge and proper attitudes regarding hand hygiene; however, compliance practices were suboptimal. PMID- 26116332 TI - Infection control: Public reporting, disincentives, and bad behavior. PMID- 26116333 TI - Development and implementation of a cleaning standard algorithm to monitor the efficiency of terminal cleaning in removing adenovirus within a pediatric hematopoietic stem cell transplantation unit. AB - Adenovirus infections within the hematopoietic stem cell transplantation setting can lead to high rates of mortality and hospital-acquired cases have been associated with environmental reservoirs. To establish both location and levels of environmental adenovirus contamination, 48 cubicles containing 794 surfaces were screened postterminal clean over a 4-year period. After initial cleaning 23% of these sites had detectable adenovirus. These data were then used to develop and implement a cleaning standard algorithm for terminal cleaning that was implemented to ensure cubicles were adenovirus-free before the next patient admission. PMID- 26116334 TI - Carbapenem-resistant Enterobacteriaceae carriers in acute care hospitals and postacute-care facilities: The effect of organizational culture on staff attitudes, knowledge, practices, and infection acquisition rates. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) carriers are frequently transferred between acute care hospitals (ACHs) and postacute-care facilities (PACFs). Compliance of health care workers with infection prevention guidelines in both care settings may be influenced by the institution's organizational culture. OBJECTIVES: To assess the association between organizational culture and health care workers' attitudes, knowledge, practices, and CRE acquisition rate and to identify differences between different care settings and health care workers' sectors. METHODS: Cross-sectional descriptive design. Self-administered questionnaires were distributed to a sample of 420 health care workers from 1 ACH and 1 PACF belonging to the same health maintenance organization located in central Israel. RESULTS: The organizational culture factor known as staff engagement was positively correlated with infection prevention attitudes and compliance with contact precaution protocols and negatively correlated with CRE acquisition rate. In the 2 care settings, health care workers' attitudes, knowledge, and practices were found to be similar, but CRE acquisition rate was lower in PACFs. Compliance with contact precaution protocols by physicians was lower than compliance reported by other health care workers. Auxiliary staff reported lower knowledge. CONCLUSIONS: In a setting of endemic CRE where a multifaceted intervention is already being implemented, organizational culture variables can predict health care workers' attitudes, knowledge, and practices and in turn can affect CRE acquisition rates. PMID- 26116335 TI - Ebola virus disease: What clinicians in the United States need to know. AB - In March 2014 the World Health Organization was notified of an outbreak of Ebola virus disease (EVD) in the forest region of Guinea. As of May 2015, the outbreak had become the most devastating EVD epidemic in history with more than 27,000 cases and more than 11,000 deaths. The introduction of EVD into noncontiguous countries, including the United States, from infected travelers highlights the importance of preparedness of all health care providers. Early identification and rapid isolation of patients suspected with EVD is critical to limiting the spread of Ebola virus. Additionally, enhanced understanding of EVD case definitions, clinical presentation, treatment procedures, and infection control strategies will improve the ability of health care workers to provide safe care for patients with EVD. PMID- 26116337 TI - Emergency Medicine: An Integral Component of the Continuum of Critical Care That is Devalued by Fellowship Programs. PMID- 26116336 TI - Subdural Hematoma Presenting as Recurrent Syncope. AB - BACKGROUND: Syncope is a common emergency department (ED) complaint. Recurrent syncope is less common, but may be concerning for serious underlying pathology. It often requires a broad diagnostic evaluation that may include neurologic imaging. CASE PRESENTATION: We present the case of a 75-year-old man with non small-cell carcinoma who presented to the ED for recurrent syncope after coughing spells over the 2 weeks preceding his arrival at the ED. He had a normal cardiac evaluation, however, he had some subacute neurologic changes that prompted obtaining a computed tomography (CT) scan of the head. This led to the diagnosis of atraumatic subdural hematoma that was causing transient transtentorial herniation leading to the recurrent syncope. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware that recurrent syncope is a possible presentation of increased intracranial pressure that may be due to a mass lesion, particularly if the patient has any acute or subacute neurologic changes. Although this association with a subdual hematoma is rare, other cases of mass lesions leading to syncope after coughing spells have been reported in the literature. PMID- 26116338 TI - An Unusual Case of Dysphagia. PMID- 26116339 TI - Impact of 4D-(18)FDG-PET/CT imaging on target volume delineation in SBRT patients with central versus peripheral lung tumors. Multi-reader comparative study. AB - PURPOSE: Evaluation of the effect of co-registered 4D-(18)FDG-PET/CT for SBRT target delineation in patients with central versus peripheral lung tumors. METHODS: Analysis of internal target volume (ITV) delineation of central and peripheral lung lesions in 21 SBRT-patients. Manual delineation was performed by 4 observers in 2 contouring phases: on respiratory gated 4DCT with diagnostic 3DPET available aside (CT-ITV) and on co-registered 4DPET/CT (PET/CT-ITV). Comparative analysis of volumes and inter-reader agreement. RESULTS: 11 cases of peripheral and 10 central lesions were evaluated. In peripheral lesions, average CT-ITV was 6.2 cm(3) and PET/CT-ITV 8.6 cm(3), resembling a mean change in hypothetical radius of 2 mm. For both CT-ITVs and PET/CT-ITVs inter reader agreement was good and unchanged (0.733 and 0.716; p=0.58). All PET/CT-ITVs stayed within the PTVs derived from CT-ITVs. In central lesions, average CT-ITVs were 42.1 cm(3), PET/CT-ITVs 44.2 cm(3), without significant overall volume changes. Inter-reader agreement improved significantly (0.665 and 0.750; p<0.05). 2/10 PET/CT-ITVs exceeded the PTVs derived from CT-ITVs by >1 ml in average for all observers. CONCLUSION: The addition of co-registered 4DPET data to 4DCT based target volume delineation for SBRT of centrally located lung tumors increases the inter-observer agreement and may help to avoid geographic misses. PMID- 26116340 TI - Nomogram for predicting pathologically complete response after neoadjuvant chemoradiotherapy for oesophageal cancer. AB - BACKGROUND: A pathologically complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) is seen in 30% of the patients with oesophageal cancer. The aim is to identify patient and tumour characteristics associated with a pCR and to develop a nomogram for the prediction of pCR. PATIENTS AND METHODS: Patients who underwent nCRT followed by surgery were identified and response to nCRT was assessed according to a modified Mandard classification in the resection specimen. A model was developed with age, gender, histology and location of the tumour, differentiation grade, alcohol use, smoking, percentage weight loss, Charlson Comorbidity Index (CCI), cT-stage and cN-stage as potential predictors for pCR. Probability of pCR was studied via logistic regression. Performance of the prediction nomogram was quantified using the concordance statistic (c statistic) and corrected for optimism. RESULTS: A total of 381 patients were included. After surgery, 27.6% of the tumours showed a pCR. Female sex, squamous cell histology, poor differentiation grade, and low cT-stage were predictive for a pCR with a c-statistic of 0.64 (corrected for optimism). CONCLUSION: A nomogram for the prediction of pathologically complete response after neoadjuvant chemoradiotherapy was developed, with a reasonable predictive power. This nomogram needs external validation before it can be used for individualised clinical decision-making. PMID- 26116341 TI - Verteporfin Photodynamic Therapy for the Treatment of Retinal Vasoproliferative Tumors. PMID- 26116342 TI - Tissue Interleukin-17 and Interleukin-23 as Biomarkers for Orbital Granulomatosis with Polyangiitis. PMID- 26116343 TI - From taxonomy and industry to genetics: Fungal Biology in China. PMID- 26116345 TI - Torticollis in Children: A Challenging Diagnosis of C1-C2 Septic Arthritis. PMID- 26116344 TI - Anti-tumor activity of the proteasome inhibitor BSc2118 against human multiple myeloma. AB - Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo. Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib. Together, these findings indicate the in vitro and in vivo anti-MM activities of BSc2118 through induction of cell cycle arrest and apoptosis, as well as inhibition of tumor angiogenesis. They also suggest that BSc2118 might, at least in vitro, partially overcome acquired bortezomib resistance, likely associated with inhibition of autophagy. PMID- 26116346 TI - Where Children Die: Obstacles to Quality End-of-Life Care. PMID- 26116347 TI - FluMist: Reconsidering the Contraindications. PMID- 26116348 TI - Thirteen-Year-Old Male Presenting With Fever, Cough, Weakness, and Somnolence. PMID- 26116349 TI - Developmental Screening With Spanish-Speaking Families in a Primary Care Setting. AB - Cultural beliefs may influence parents' willingness to raise concerns on a developmental screener. Our study evaluated the performance of the Parents' Evaluation of Developmental Status (PEDS) in an urban community health center where 75% of families are Spanish speaking. Our primary outcome was the presence of parent-reported concerns either in the medical record or on the PEDS before the PEDS was introduced compared with after it became routine care (post-PEDS). Covariates included family language and child age, gender, and risk status. The adjusted odds of a concern being identified was 1.5 times greater in the post PEDS period for Developmental concerns and 2.1 times greater for Behavioral concerns. There was no association with family language indicating that the PEDS performs equally well for English- and Spanish-speaking families. The systematic inclusion of developmental screening as part of culturally competent primary care may aid in reducing current disparities in the identification of developmental concerns. PMID- 26116350 TI - A Child With a Painless Lump on the Anterior Chest Wall. PMID- 26116352 TI - Pediatric Obesity in Early Childhood: A Physician Screening Tool. AB - Obesity is a public health crisis and continues to affect youth of increasingly younger ages. With significant medical and psychosocial comorbidities, it is critical that front-line providers feel confident in their abilities to assess, and appropriately refer, children and families to subspecialties to aid in weight management treatment. This article describes the development and utility of a 1 page screening tool for pediatricians and other providers. Utilizing research, clinical experience, and consensus opinion, a brief tool was developed that could be incorporated into medical visits to facilitate medical care decisions and management of pediatric obesity. PMID- 26116351 TI - A Narrative Synthesis of the Components of and Evidence for Patient- and Family Centered Care. AB - A narrative synthesis was conducted to determine typical patient- and family centered care (PFCC) components and their link to outcomes in pediatric populations. 68 studies with PFCC interventions and experimental designs were included. Study features were synthesized based on 5 core PFCC components (i.e., education from the provider to the patient and/or family, information sharing from the family to the provider, social-emotional support, adapting care to match family background, and/or s decision-making) and 4 outcome categories (health status; the experience, knowledge, and attitudes of the patient/family; patient/family behavior; or provider behavior). The most common PFCC component was education; the least common was adapting care to family background. The presence of social-emotional support alone, as well as educational interventions augmented with shared decision-making, social-emotional support, or adaptations of care based on family background, predicted improvements in families' knowledge, attitudes, and experience. Interventions that targeted the family were associated with positive outcomes. PMID- 26116353 TI - Post-childhood Presentation and Diagnosis of DiGeorge Syndrome. AB - BACKGROUND AND OBJECTIVES: The diversity of clinical presentations makes the diagnosis of DiGeorge syndrome (DGS) a diagnostic challenge. The objective of our study was to report the clinical presentation of DGS in the post-childhood period. METHODS: A retrospective study, investigating patients diagnosed clinically and genetically with DGS at Sheba Medical Center during the period of 2010-2013. Post-childhood period was defined as age >10 years. RESULTS: During the study period, 29 patients were diagnosed with DGS. Nine (31%) patients with DGS were diagnosed in their post-childhood period. The basis for clinical suspicion was diverse. However, once the suspicion was brought to attention, additional symptoms consistent with DGS were noted at up to 88% of patients who presented characteristic of facial features and developmental delay. CONCLUSION: Our research shows that diagnosing DGS patients in the post-childhood period is not uncommon. Characteristic facial features and developmental delay, although not leading presenting symptoms, are found very frequently in patients with DGS. PMID- 26116354 TI - Letter to the Editor: Multiple Infantile Hemangiomas or Multifocal Venous Malformations? PMID- 26116355 TI - Immobilization in External Rotation Versus Internal Rotation After Primary Anterior Shoulder Dislocation: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: The recurrence rate after primary anterior shoulder dislocation is high, especially in young, active individuals. Recent studies have suggested external rotation immobilization as a method to reduce the rate of recurrent shoulder dislocation in comparison to traditional sling immobilization. PURPOSE: To assess and summarize evidence from randomized controlled trials on the effect of internal rotation versus external rotation immobilization on the rate of recurrence after primary anterior shoulder dislocation. STUDY DESIGN: Meta analysis. METHODS: PubMed, MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and abstracts from recent proceedings were searched for eligible studies. Two reviewers selected studies for inclusion, assessed methodological quality, and extracted data. RESULTS: Six randomized controlled trials (632 patients) were included in this review. Demographic and prognostic variables measured at baseline were similar in the pooled groups. The average age was 30.1 years in the pooled external rotation group and 30.3 years in the pooled internal rotation group. Two studies found that external rotation immobilization reduced the rate of recurrence after initial anterior shoulder dislocation compared with conventional internal rotation immobilization, whereas 4 studies failed to find a significant difference between the 2 groups. This meta-analysis suggested no overall significant difference in the rate of recurrence among patients treated with internal rotation versus external rotation immobilization (risk ratio, 0.69; 95% CI, 0.42-1.14; P = .15). There was no significant difference in the rate of compliance between internal and external rotation immobilization (P = .43). The Western Ontario Shoulder Instability Index scores were pooled across 3 studies, and there was no significant difference between the 2 groups (P = .54). CONCLUSION: Immobilization in external rotation is not significantly more effective in reducing the recurrence rate after primary anterior shoulder dislocation than immobilization in internal rotation. Additionally, this review suggests that there is minimal difference in patients' perceptions of their health-related quality of life after immobilization in internal versus external rotation. PMID- 26116356 TI - Endogenous Toll-Like Receptor 9 Regulates AKI by Promoting Regulatory T Cell Recruitment. AB - Toll-like receptor 9 (TLR9) enhances proinflammatory responses, but whether it can act in a regulatory capacity remains to be established. In experimental murine AKI induced by cisplatin, Tlr9(-/-) mice developed enhanced renal injury and exhibited fewer intrarenal regulatory T cells (Tregs) compared with genetically intact mice. A series of reconstitution and depletion studies defined a role for TLR9 in maintaining Treg-mediated homeostasis in cisplatin-induced AKI. When Rag1(-/-) mice were reconstituted with nonregulatory CD25(-) splenocytes from wild-type (WT) or Tlr9(-/-) mice, AKI was similarly enhanced. However, when Rag1(-/-) mice were reconstituted with CD4(+)CD25(+) regulatory cells, WT CD4(+)CD25(+) cells were more renoprotective and localized to the kidney more efficiently than Tlr9(-/-) CD4(+)CD25(+) cells. In Treg-depleted Foxp3(DTR) mice, reconstitution with naive WT CD4(+)CD25(+) cells resulted in less severe AKI than did reconstitution with Tlr9(-/-) Tregs. Tlr9(-/-) mice were not deficient in CD4(+)CD25(+) cells, and WT and TLR9-deficient Tregs had similar suppressive function ex vivo. However, expression of adhesion molecules important in Treg trafficking was reduced on peripheral CD4(+)CD25(+) cells from Tlr9(-/-) mice. In conclusion, we identified a pathway by which TLR9 promotes renal Treg accumulation in AKI. PMID- 26116357 TI - Intravital Imaging Reveals Angiotensin II-Induced Transcytosis of Albumin by Podocytes. AB - Albuminuria is a hallmark of kidney disease of various etiologies and usually caused by deterioration of glomerular filtration barrier integrity. We recently showed that angiotensin II (Ang II) acutely increases albumin filtration in the healthy kidney. Here, we used intravital microscopy to assess the effects of Ang II on podocyte function in rats. Acute infusion of 30, 60, or 80 ng/kg per minute Ang II enhanced the endocytosis of albumin by activation of the type 1 Ang II receptor and resulted in an average (+/-SEM) of 3.7+/-2.2, 72.3+/-18.6 (P<0.001), and 239.4+/-34.6 um(3) (P<0.001) albumin-containing vesicles per glomerulus, respectively, compared with none at baseline or 10 ng/kg per minute Ang II. Immunostaining of Ang II-infused kidneys confirmed the presence of albumin containing vesicles, which colocalized with megalin, in podocin-positive cells. Furthermore, podocyte endocytosis of albumin was markedly reduced in the presence of gentamicin, a competitive inhibitor of megalin-dependent endocytosis. Ang II infusion increased the concentration of albumin in the subpodocyte space, a potential source for endocytic protein uptake, and gentamicin further increased this concentration. Some endocytic vesicles were acidified and colocalized with LysoTracker. Most vesicles migrated from the capillary to the apical aspect of the podocyte and were eventually released into the urinary space. This transcytosis accounted for approximately 10% of total albumin filtration. In summary, the transcellular transport of proteins across the podocyte constitutes a new pathway of glomerular protein filtration. Ang II enhances the endocytosis and transcytosis of plasma albumin by podocytes, which may eventually impair podocyte function. PMID- 26116359 TI - Ingenol Mebutate Signals via PKC/MEK/ERK in Keratinocytes and Induces Interleukin Decoy Receptors IL1R2 and IL13RA2. AB - Squamous cell carcinoma (SCC) is the second most common human skin cancer and the second leading cause of skin cancer-related death. Recently, a new compound, ingenol mebutate, was approved for treatment of actinic keratosis, a precursor of SCC. As the mechanism of action is poorly understood, we have further investigated the mechanism of ingenol mebutate-induced cell death. We elucidate direct effects of ingenol mebutate on primary keratinocytes, patient-derived SCC cells, and a SCC cell line. Transcriptional profiling followed by pathway analysis was performed on ingenol mebutate-treated primary keratinocytes and patient-derived SCC cells to find key mediators and identify the mechanism of action. Activation of the resulting pathways was confirmed in cells and human skin explants and supported by a phosphorylation screen of treated primary cells. The necessity of these pathways was demonstrated by inhibition of certain pathway components. Ingenol mebutate inhibited viability and proliferation of all keratinocyte-derived cells in a biphasic manner. Transcriptional profiling identified the involvement of PKC/MEK/ERK signaling in the mechanism of action and inhibition of this signaling pathway rescued ingenol mebutate-induced cell death after treatment with 100 nmol/L ingenol mebutate, the optimal concentration for the first peak of response. We found the interleukin decoy receptors IL1R2 and IL13RA2 induced by ingenol mebutate in a PKC/MEK/ERK-dependent manner. Furthermore, siRNA knockdown of IL1R2 and IL13RA2 partially rescued ingenol mebutate-treated cells. In conclusion, we have shown that ingenol mebutate induced cell death is mediated through the PKCdelta/MEK/ERK pathway, and we have functionally linked the downstream induction of IL1R2 and IL13RA2 expression to the reduced viability of ingenol mebutate-treated cells. PMID- 26116358 TI - Regression of Renal Disease by Angiotensin II Antagonism Is Caused by Regeneration of Kidney Vasculature. AB - Chronic renal insufficiency inexorably progresses in patients, such as it does after partial renal ablation in rats. However, the progression of renal diseases can be delayed by angiotensin II blockers that stabilize renal function or increase GFR, even in advanced phases of the disease. Regression of glomerulosclerosis can be induced by angiotensin II antagonism, but the effect of these treatments on the entire vascular tree is unclear. Here, using microcomputed tomography and scanning electron microscopy, we compared the size and extension of kidney blood vessels in untreated Wistar rats with those in untreated and angiotensin II antagonist-treated Munich Wistar Fromter (MWF) rats that spontaneously develop kidney disease with age. The kidney vasculature underwent progressive rarefaction in untreated MWF rats, substantially affecting intermediate and small vessels. Microarray analysis showed increased Tgf-beta and endothelin-1 gene expression with age. Notably, 10-week inhibition of the renin angiotensin system regenerated kidney vasculature and normalized Tgf-beta and endothelin-1 gene expression in aged MWF rats. These changes were associated with reduced apoptosis, increased endothelial cell proliferation, and restoration of Nrf2 expression, suggesting mechanisms by which angiotensin II antagonism mediates regeneration of capillary segments. These results have important implications in the clinical setting of chronic renal insufficiency. PMID- 26116360 TI - Heregulin-ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells. AB - PI3K is frequently mutated in cancer and plays an important role in cell growth and survival. Heregulin (HRG)-mediated autocrine or paracrine signaling through the receptor tyrosine kinase ErbB3 potently activates the PI3K/AKT pathway and has been shown to mediate resistance to a wide variety of anticancer agents. Although PI3K functions downstream of HRG-ErbB3, it is unknown whether activating mutations in PI3K render HRG ineffective. If so, patients with PI3K mutations would not be expected to benefit from ErbB3-directed therapies. Here, we find that a subset of cell lines harboring activating PI3K mutations can be further growth-stimulated by HRG, and this effect is blocked by incubation with seribantumab (MM-121), a monoclonal anti-ErbB3 antibody. Although expression of mutant PI3K in wild-type PI3K cells frequently results in loss of HRG-stimulated growth, some cell lines continue to respond to HRG. In cell lines where HRG stimulated growth is lost, this loss is invariably accompanied by a reduction in ErbB3 levels, a corresponding increase in basal phosphorylation levels of FOXO family transcription factors, and a reduction in HRG-induced downstream signaling. Importantly, HRG-stimulated growth is partially rescued by re expressing ErbB3. This response is blocked by seribantumab, indicating that ErbB3 levels rather than downstream signaling proteins limit HRG-stimulated growth in PI3K mutant cells. Overall, these results suggest that activating mutations in PI3K do not preclude potential benefit from ErbB3-directed therapy, but that it may be important to measure ErbB3 levels in patients with PI3K mutant cancers to determine if they would benefit. PMID- 26116361 TI - AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo. AB - PI3K/AKT/mTOR signaling plays an important role in breast cancer. Its interaction with estrogen receptor (ER) signaling becomes more complex and interdependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility; however, a negative feedback loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve breast cancer treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER(+) breast cancer cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term estrogen deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50 < 500 nmol/L) except HCC1428 and HCC1428-LTED. T47D LTED and ZR75-LTED were the most sensitive of the lines (GI50 ~ 100 nmol/L). AZD5363 resensitized TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERalpha-mediated transcription in a context-specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen response elements located on the TFF1, PGR, and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5, and IGFI signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER(+) patient-derived xenograft and delayed tumor progression after cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for breast cancer that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. PMID- 26116362 TI - Percutaneous Radiofrequency Ablation of Hepatic Metastases from Gastric Adenocarcinoma after Gastrectomy. AB - PURPOSE: To evaluate the efficacy of percutaneous radiofrequency (RF) ablation for treatment of hepatic metastases from gastric adenocarcinoma. MATERIALS AND METHODS: Of 24 patients who underwent percutaneous RF ablation after gastrectomy for a hepatic metastasis from a gastric cancer during the period 2000-2013, 19 were enrolled (median age, 63 y) with 21 metastatic tumors (mean diameter, 2.3 cm). Patient overall survival (OS) and local tumor progression-free survival (PFS) outcomes were assessed and compared according to patient and tumor characteristics, including tumor size and lobar distribution. The difference in diameter between tumor and ablation zone was compared according to lobar distribution. RESULTS: The median OS after RF ablation was 20.3 months, and the median local tumor PFS was 10.4 months. The OS rate was not significantly influenced by any patient or tumor characteristics. In multivariate analysis, independent negative prognostic factors for local tumor PFS were a tumor >= 3 cm in diameter (hazard ratio, 10.5; 95% confidence interval, 1.8-62.5; P = .009) and a tumor located in the left lobe (hazard ratio, 9.1; 95% confidence interval, 1.3 63.5; P = .026). The difference in diameter between the tumor and ablation zone was significantly different between the right and left lobes (right 1.8 cm +/- 0.6 vs left 1.1 cm +/- 0.70, P = .028). CONCLUSIONS: With the appropriate selection of patients with tumors <= 3 cm in diameter and with the possibility of sufficient safety margins, RF ablation is a safe and feasible treatment option for hepatic metastases from gastric adenocarcinoma. PMID- 26116363 TI - PGlcS: Prediction of protein O-GlcNAcylation sites with multiple features and analysis. AB - As a widespread type of protein post-translational modification, O-GlcNAcylation plays crucial regulatory roles in almost all cellular processes and is related to some diseases. To deeply understand O-GlcNAcylated mechanisms, identification of substrates and specific O-GlcNAcylated sites is crucial. Experimental identification is expensive and time-consuming, so computational prediction of O GlcNAcylated sites has considerable value. In this work, we developed a novel O GlcNAcylated sites predictor called PGlcS (Prediction of O-GlcNAcylated Sites) by using k-means cluster to obtain informative and reliable negative samples, and support vector machines classifier combined with a two-step feature selection. The performance of PGlcS was evaluated using an independent testing dataset resulting in a sensitivity of 64.62%, a specificity of 68.4%, an accuracy of 68.37%, and a Matthew's correlation coefficient of 0.0697, which demonstrated PGlcS was very promising for predicting O-GlcNAcylated sites. The datasets and source code were available in Supplementary information. PMID- 26116364 TI - Transmission dynamics of vivax malaria in the republic of Korea: Effectiveness of anti-malarial mass chemoprophylaxis. AB - BACKGROUND: Vivax malaria with two distinct (short- and long-term) incubation periods has been prevalent in the Republic of Korea since its re-emergence in 1993. As part of countermeasures, mass chemoprophylaxis has been conducted since 1997 among military personnel, a high risk group. To assess the population effectiveness of chemoprophylaxis, the time-dependent reproduction number was estimated in the present study. METHODS: A renewal process has been employed, estimating the yearly effective reproduction number (Ry) from 1993 to 2012 using a maximum likelihood estimation method. Akaike Information Criterion (AIC) was computed to identify the best-fit model with a time-dependent trend that coincides with the timing of mass chemoprophylaxis. RESULTS: The estimates of Ry revealed an overall declining trend from 1997 to 2012. Despite small fluctuations in 2005 and 2009, Ry was brought to be close to unity since 2000. An extrapolated model of the time-dependent reproduction number with the smallest AIC indicated that there was an abrupt decline in secondary transmission from 1997 to 1998. CONCLUSION: The epidemic of vivax malaria in the Republic of Korea has been on the whole brought under control in the last decades. Mass chemoprophylaxis assisted the decline in secondary transmissions from its second year, which presumed to have reflected the effect of long incubation period and expansion of the coverage. PMID- 26116365 TI - Chromosome replication status and DNA content at any cell age in a bacterial cell cycle. AB - An algorithm is presented to determine the chromosome replication status, the rate of DNA synthesis per fork, and the amount of DNA in chromosome equivalents (G) per chromosome, per cell and per age throughout a bacterial cell cycle. This algorithm is the only attempt to study replication and the G value at any cell age since the general model of the bacterial cell cycle by Cooper and Helmstetter (1968, J. Mol. Biol. 31, 619-644). To help using it, two implementations are provided. PMID- 26116366 TI - Cancer immunoediting: A process driven by metabolic competition as a predator prey-shared resource type model. AB - It is a well-established fact that tumors up-regulate glucose consumption to meet increasing demands for rapidly available energy by upregulating a purely glycolytic mode of glucose metabolism. What is often neglected is that activated cytotoxic cells of the immune system, integral players in the carcinogenesis process, also come to rely on glycolysis as a primary mode of glucose metabolism. Moreover, while cancer cells can revert back to aerobic metabolism, rapidly proliferating cytotoxic lymphocytes are incapable of performing their function when adequate resources are lacking. Consequently, it is likely that in the tumor microenvironment there may exist competition for shared resources between cancer cells and the cells of the immune system, which may underlie much of tumor-immune dynamics. Proposed here is a model of tumor-immune-glucose interactions, formulated as a predator-prey-common resource type system. The outcome of these interactions ranges from tumor elimination, to tumor dormancy, to unrestrained tumor growth. It is also predicted that the process of tumor escape can be preceded by periods of oscillatory tumor growth. A detailed bifurcation analysis of three subsystems of the model suggest that oscillatory regimes are a result of competition for shared resource (glucose) between the predator (immune cells) and the prey (cancer cells). Existence of competition for nutrients between cancer and immune cells may provide additional mechanistic insight as to why the efficacy of many immunotherapies may be limited. PMID- 26116367 TI - A stochastic microscopic model for the dynamics of antigenic variation. AB - We present a novel model that describes the within-host evolutionary dynamics of parasites undergoing antigenic variation. The approach uses a multi-type branching process with two types of entities defined according to their relationship with the immune system: clans of resistant parasitic cells (i.e. groups of cells sharing the same antigen not yet recognized by the immune system) that may become sensitive, and individual sensitive cells that can acquire a new resistance thus giving rise to the emergence of a new clan. The simplicity of the model allows analytical treatment to determine the subcritical and supercritical regimes in the space of parameters. By incorporating a density-dependent mechanism the model is able to capture additional relevant features observed in experimental data, such as the characteristic parasitemia waves. In summary our approach provides a new general framework to address the dynamics of antigenic variation which can be easily adapted to cope with broader and more complex situations. PMID- 26116368 TI - The effects of continuing care on emerging adult outcomes following residential addiction treatment. AB - BACKGROUND: Professional continuing care services enhance recovery rates among adults and adolescents, though less is known about emerging adults (18-25 years old). Despite benefit shown from emerging adults' participation in 12-step mutual help organizations (MHOs), it is unclear whether participation offers benefit independent of professional continuing care services. Greater knowledge in this area would inform clinical referral and linkage efforts. METHODS: Emerging adults (N=284; 74% male; 95% Caucasian) were assessed during the year after residential treatment on outpatient sessions per week, percent days in residential treatment and residing in a sober living environment, substance use disorder (SUD) medication use, active 12-step MHO involvement (e.g., having a sponsor, completing step work, contact with members outside meetings), and continuous abstinence (dichotomized yes/no). One generalized estimating equation (GEE) model tested the unique effect of each professional service on abstinence, and, in a separate GEE model, the unique effect of 12-step MHO involvement on abstinence over and above professional services, independent of individual covariates. RESULTS: Apart from SUD medication, all professional continuing care services were significantly associated with abstinence over and above individual factors. In the more comprehensive model, relative to zero 12-step MHO activities, odds of abstinence were 1.3 times greater if patients were involved in one activity, and 3.2 times greater if involved in five activities (lowest mean number of activities in the sample across all follow-ups). CONCLUSIONS: Both active involvement in 12-step MHOs and recovery-supportive, professional services that link patients with these community-based resources may enhance outcomes for emerging adults after residential treatment. PMID- 26116370 TI - Inhibition of monoamine oxidase A increases recovery after experimental cardiac arrest. AB - OBJECTIVES: Perioperative myocardial infarction (MI) with ischaemia-reperfusion injury (IRI) is a devastating entity occurring in 1-2% of patients after cardiac surgery. The molecular pathway leading to myocardial cellular destruction after MI may include monoamine oxidases. We experimentally investigated whether moclobemide, a monoamine oxidase inhibitor, enhances myocardial recovery after cardiac arrest and MI. METHODS: Fifty-six syngeneic Fischer rats underwent heterotopic cardiac transplantation to induce reversible IRI after cardiac arrest. Twenty-eight rats also underwent permanent ligation of the left anterior descending coronary artery to induce MI after cardiac arrest. Twenty-eight rats with or without MI were treated with subcutaneous moclobemide 10 mg/kg/day. Methods used to study myocardial recovery were microdialysis for intramyocardial metabolism, histology and quantitative reverse-transcription polymerase chain reaction for high-mobility group box-1 (HMGB1), haeme oxygenase-1 (HO-1), interleukin-6, hypoxia-inducible factor 1alpha and macrophages (CD68). RESULTS: Pyruvate increased in MI treated with moclobemide versus IRI with moclobemide (29.19 +/- 7.64 vs 13.86 +/- 8.49 uM, P = 0.028), reflecting metabolic activity after cardiac arrest and reperfusion. Myocardial inflammation increased in MI compared with IRI after 1 h (0.80 +/- 0.56 vs 0, point score units [PSUs], P = 0.003), but decreased after 5 days in MI treated with moclobemide versus MI alone (0.80 +/- 0.83 vs 2.00 +/- 0.70, PSU, P = 0.033). Expressions of HMGB1, CD68 and HO-1 decreased in MI treated with moclobemide versus MI alone (1.33 +/- 0.20 vs 1.75 +/- 0.24, fold changes [FCs], P = 0.028; 5.15 +/- 1.10 vs 9.59 +/- 2.75, FC, P = 0.050; 10.41 +/- 4.17 vs 21.28 +/- 10.01, FC, P = 0.047), indicating myocardial recovery and increased cellularity of remote intramyocardial arteries. CONCLUSIONS: Moclobemide enhances myocardial recovery after cardiac arrest and MI; inhibition of remote myocardial changes may be achieved by targeting treatment against monoamine oxidase. PMID- 26116369 TI - Spontaneous Chronic Pain After Experimental Thoracotomy Revealed by Conditioned Place Preference: Morphine Differentiates Tactile Evoked Pain From Spontaneous Pain. AB - Chronic pain after surgery limits social activity, interferes with work, and causes emotional suffering. A major component of such pain is reported as resting or spontaneous pain with no apparent external stimulus. Although experimental animal models can simulate the stimulus-evoked chronic pain that occurs after surgery, there have been no studies of spontaneous chronic pain in such models. Here the conditioned place preference (CPP) paradigm was used to reveal resting pain after experimental thoracotomy. Male Sprague Dawley rats received a thoracotomy with 1-hour rib retraction, resulting in evoked tactile hypersensitivity, previously shown to last for at least 9 weeks. Intraperitoneal injections of morphine (2.5 mg/kg) or gabapentin (40 mg/kg) gave equivalent 2- to 3-hour-long relief of tactile hypersensitivity when tested 12 to 14 days postoperatively. In separate experiments, single trial CPP was conducted 1 week before thoracotomy and then 12 days (gabapentin) or 14 days (morphine) after surgery, followed the next day by 1 conditioning session with morphine or gabapentin, both versus saline. The gabapentin-conditioned but not the morphine conditioned rats showed a significant preference for the analgesia-paired chamber, despite the equivalent effect of the 2 agents in relieving tactile allodynia. These results show that experimental thoracotomy in rats causes spontaneous pain and that some analgesics, such as morphine, that reduce evoked pain do not also relieve resting pain, suggesting that pathophysiological mechanisms differ between these 2 aspects of long-term postoperative pain. Perspective: Spontaneous pain, a hallmark of chronic postoperative pain, is demonstrated here in a rat model of experimental postthoracotomy pain, further validating the use of this model for the development of analgesics to treat such symptoms. Although stimulus-evoked pain was sensitive to systemic morphine, spontaneous pain was not, suggesting different mechanistic underpinnings. PMID- 26116371 TI - Uniportal video-assisted thoracic lobectomy in a semiprone position for the treatment of a large intralobar pulmonary sequestration. AB - Intralobar pulmonary sequestration (IPS) is a rare developmental abnormality of the lower respiratory system. Lobectomy by video-assisted thoracic surgery using a three-port or four-port technique is the generally accepted operative approach. However, lobectomy can also be accomplished with a single incision even if the IPS is large. This report describes the first case of a patient with a large IPS undergoing uniportal video-assisted thoracic lobectomy in a semiprone position. PMID- 26116373 TI - Population awareness of risks related to medicinal product use in Vientiane Capital, Lao PDR: a cross-sectional study for public health improvement in low and middle income countries. AB - BACKGROUND: While essential medicines have been made more available in all but the most remote areas in low and middle income countries (L/MICs) over the past years, inappropriate and incorrect use of good quality medicines remains a key impediment for public health. In addition, as medicines have a potential to cause harm (medicine risks), adequate awareness by medicine users of the risks of adverse reactions is essential, especially as self-medication is common in L/MICs. This study aimed to investigate the awareness of Lao residents regarding medicine risks in Vientiane Capital, Lao People's Democratic Republic. METHODS: Face-to-face interviews using structured questionnaires of 144 residents older than 16 years were carried out in 12 randomly selected villages out of the 146 villages of Vientiane Capital with at least one health facility. RESULTS: The respondents were mainly (85.0 %) the heads of households or their husband/spouse . The majority of the respondents were unaware (61.8 %) of medicine risks. Compared to residents living in the urban district of Xaysetha, living in peri urban and even more in rural areas were identified as factors associated with being unaware of medicine risks [adjusted odds ratio (aOR) =3.3, 95 % Confidence Interval (CI) = 1.1-9.4]) and aOR =7.5 (95 % CI = 2.3-24.2), respectively]. In addition, more than half of the respondents had never heard of poor quality medicines, with a higher rate in rural/peri-urban compared to urban districts (55.6 % vs 38.9 %, respectively, p = 0.02). Finally, approximately one third of all respondents thought that traditional medicines could not cause harm. CONCLUSIONS: Overall, these results suggest a lack of awareness about medicinal product risks. Differences according to the place of residence are apparent and could be partly explained by a lower level of training of healthcare providers in contact with the population in the rural districts in particular. Communication on medicinal product risks to patients through well-trained healthcare providers could probably make a valuable contribution towards the appropriate use of medicines in L/MICs. PMID- 26116374 TI - Treatment of hip/knee osteoarthritis in Dutch general practice and physical therapy practice: an observational study. AB - BACKGROUND: A multidisciplinary, guideline-based Stepped-Care-Strategy (SCS), has recently been developed to improve the management of hip and knee osteoarthritis (OA). To date, it is unknown to what extent current Dutch OA care is consistent with the SCS, both with respect to the content of care as well as the sequence of care. Furthermore, there is a lack of clarity regarding the role of different health care providers in the performance of OA care according to the SCS. Therefore, the main purpose of this study is to describe the content of primary care in patients with hip/knee OA, including the compliance to the SCS and taking into account the introduction of patient self-referral to physical therapy. METHODS: Data were used from NIVEL Primary Care Database. In total, 12.118 patients with hip/knee OA who visited their GP or physical therapist were selected. Descriptive statistics were used to compare the content of care in GP referred and self-referred patients to physical therapy. RESULTS: Content of care performed by GPs mostly concerned consultations, followed by NSAID prescriptions and referrals to secondary care. Both prescriptions of acetaminophen and referrals to physical therapy respectively dietary therapy were rarely mentioned. Nevertheless, still 65% of the patients in physical therapy practice were referred by their GP. Compared to GP-referred patients, self-referred patients more often presented recurrent complaints and were treated less often by activity related exercise therapy. Education was rarely registered as singular intervention, neither in GP-referred nor in self-referred patients. CONCLUSION: In accordance with the SCS, less advanced interventions are more often applied than more advanced interventions. To optimize the adherence to the SCS, GPs could reconsider the frequent use of NSAIDs instead of analgesics and the low referral rate to allied health care. Self-referral to physical therapy partially distorts both the low referral rate in general practice and the low application rate of education as singular intervention in physical therapy practice. Further research is recommended to evaluate the effects of task-shifting in OA care, taking into account the content of the SCS. PMID- 26116375 TI - Healthy n-6/n-3 fatty acid composition from five European game meat species remains after cooking. AB - BACKGROUND: Intensive farming of livestock along with recent food scandals and consumer deception have increased awareness about risks for human nutrition. In parallel, the demand for meat obtained under more natural conditions from animals that can freely forage has largely increased. Interestingly, the consumption of game meat has not become more common despite its excellent quality and content of polyunsaturated fatty acids (PUFAs). CONTEXT AND PURPOSE: We addressed the question if game meat fatty acid composition is modified through kitchen preparation. By analysing muscle fatty acid (FA) composition (polar and total lipids) of five European game species in a raw and a processed state, we aimed to quantify the proportion of PUFA that are oxidised and hydrogenated during processing. All game meat species originated from local hunters and free-living individuals. To mimic a realistic situation a professional chef prepared the meat samples with gentle use of heat in a standardised way. RESULTS: Expectedly, the overall content of polyunsaturated fatty acids declined during the cooking process but the decrease size was <5% and the nutritiously most important n-3/n-6 ratio was not affected by processing (F1,54 = 0.46; p = 0.5). Generally, our samples contained species-specific high PUFA and n-3 FA contents but we point out that differentiating between species is necessary. CONCLUSION: Game meat thus provides a healthy meat source, as cooking does not substantially alter its favourable fatty acid composition. Further research is needed to elucidate species-specific differences and the role of habitat quality and locomotion for tissue composition. PMID- 26116372 TI - MiR-21: an environmental driver of malignant melanoma? AB - Since the mid-1950's, melanoma incidence has been rising steadily in industrialized Caucasian populations, thereby pointing to the pivotal involvement of environmental factors in melanomagenesis. Recent evidence underlines the crucial role of microRNA (miR) signaling in cancer initiation and progression. Increased miR-21 expression has been observed during the transition from a benign melanocytic lesion to malignant melanoma, exhibiting highest expression of miR 21. Notably, common BRAF and NRAS mutations in cutaneous melanoma are associated with increased miR-21 expression. MiR-21 is an oncomiR that affects critical target genes of malignant melanoma, resulting in sustained proliferation (PTEN, PI3K, Sprouty, PDCD4, FOXO1, TIPE2, p53, cyclin D1), evasion from apoptosis (FOXO1, FBXO11, APAF1, TIMP3, TIPE2), genetic instability (MSH2, FBXO11, hTERT), increased oxidative stress (FOXO1), angiogenesis (PTEN, HIF1alpha, TIMP3), invasion and metastasis (APAF1, PTEN, PDCD4, TIMP3). The purpose of this review is to provide translational evidence for major environmental and individual factors that increase the risk of melanoma, such as UV irradiation, chemical noxes, air pollution, smoking, chronic inflammation, Western nutrition, obesity, sedentary lifestyle and higher age, which are associated with increased miR-21 signaling. Exosomal miR-21 induced by extrinsic and intrinsic stimuli may be superimposed on mutation-induced miR-21 pathways of melanoma cells. Thus, oncogenic miR-21 signaling may be the converging point of intrinsic and extrinsic stimuli driving melanomagenesis. Future strategies of melanoma treatment and prevention should thus aim at reducing the burden of miR-21 signal transduction. PMID- 26116376 TI - Progress and challenges in simulating and understanding electron transfer in proteins. AB - This Review presents an overview of the most common numerical simulation approaches for the investigation of electron transfer (ET) in proteins. We try to highlight the merits of the different approaches but also the current limitations and challenges. The article is organized into three sections. Section 2 deals with direct simulation algorithms of charge migration in proteins. Section 3 summarizes the methods for testing the applicability of the Marcus theory for ET in proteins and for evaluating key thermodynamic quantities entering the reaction rates (reorganization energies and driving force). Recent studies interrogating the validity of the theory due to the presence of non-ergodic effects or of non linear responses are also described. Section 4 focuses on the tunneling aspects of electron transfer. How can the electronic coupling between charge transfer states be evaluated by quantum chemistry approaches and rationalized? What interesting physics regarding the impact of protein dynamics on tunneling can be addressed? We will illustrate the different sections with examples taken from the literature to show what types of system are currently manageable with current methodologies. We also take care to recall what has been learned on the biophysics of ET within proteins thanks to the advent of atomistic simulations. PMID- 26116378 TI - Electron spin resonance of spin-labeled lipid assemblies and proteins. AB - Spin-label electron spin resonance (ESR) spectroscopy is a valuable means to study molecular mobility and interactions in biological systems. This paper deals with conventional, continuous wave ESR of nitroxide spin-labels at 9-GHz providing an introduction to the basic principles of the technique and applications to self-assembled lipid aggregates and proteins. Emphasis is given to segmental lipid chain order and rotational dynamics of lipid structures, environmental polarity of membranes and proteins, structure and conformational dynamics of proteins. PMID- 26116377 TI - Loss of L-FABP, SCP-2/SCP-x, or both induces hepatic lipid accumulation in female mice. AB - Although roles for both sterol carrier protein-2/sterol carrier protein-x (SCP 2/SCP-x) and liver fatty acid binding protein (L-FABP) have been proposed in hepatic lipid accumulation, individually ablating these genes has been complicated by concomitant alterations in the other gene product(s). For example, ablating SCP2/SCP-x induces upregulation of L-FABP in female mice. Therefore, the impact of ablating SCP-2/SCP-x (DKO) or L-FABP (LKO) individually or both together (TKO) was examined in female mice. Loss of SCP-2/SCP-x (DKO, TKO) more so than loss of L-FABP alone (LKO) increased hepatic total lipid and total cholesterol content, especially cholesteryl ester. Hepatic accumulation of nonesterified long chain fatty acids (LCFA) and phospholipids occurred only in DKO and TKO mice. Loss of SCP-2/SCP-x (DKO, TKO) increased serum total lipid primarily by increasing triglycerides. Altered hepatic level of proteins involved in cholesterol uptake, efflux, and/or secretion was observed, but did not compensate for the loss of L-FABP, SCP-2/SCP-x or both. However, synergistic responses were not seen with the combinatorial knock out animals-suggesting that inhibiting SCP-2/SCP-x is more correlative with hepatic dysfunction than L-FABP. The DKO- and TKO-induced hepatic accumulation of cholesterol and long chain fatty acids shared significant phenotypic similarities with non-alcoholic fatty liver disease (NAFLD). PMID- 26116379 TI - Nanometric features of myosin filaments extracted from a single muscle fiber to uncover the mechanisms underlying organized motility. AB - The single muscle fiber in vitro motility assay (SF-IVMA) is characterized by organized linear motility of actin filaments, i.e., actin filaments motility showing a parallel or anti-parallel direction with similar speed independent of direction in the central part of the flow-cell where density of myosin is high. In contrast, the low myosin density region in the flow-cell exhibits random filament movements, but the mechanisms underlying the organized motility remain unknown. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) imaging techniques have been combined to investigate the morphological features of myosin extracted from single muscle fiber segments in the flow cell. Nanometric scale imaging of myosin filaments in the SF-IVMA showed intact spatial distances between myosin heads being essential for myosin filament function. However, angular spectrum analyses of myosin filaments in the high myosin density region showed organized myosin filament orientation only in small areas, while unorganized filament orientation were dominantly presented when larger areas were analyzed. Thus, parallel myosin filament organization is a less likely mechanism underlying the organized motility of actin filaments and the high myosin density per se is therefore forwarded as the primary "driver" that promotes organized linear motility. PMID- 26116380 TI - mRNA expression of genes involved in inflammation and haemostasis in equine fibroblast-like synoviocytes following exposure to lipopolysaccharide, fibrinogen and thrombin. AB - BACKGROUND: Studies in humans have shown that haemostatic and inflammatory pathways both play important roles in the pathogenesis of joint disease. The aim of this study was to assess mRNA expression of haemostatic and inflammatory factors in cultured equine fibroblast-like synoviocytes exposed to lipopolysaccharide (LPS), fibrinogen and thrombin. Synovial membranes were collected from metacarpo-phalangeal joints of 6 skeletally mature horses euthanized for non-orthopaedic reasons. Passage 4 fibroblast-like synoviocytes were left non-treated or treated with either 0.1 MUg/ml LPS, 5 mg/ml fibrinogen or 5 U/ml thrombin and harvested at time points 0, 6, 24 and 48 h. mRNA expression of serum amyloid A (SAA), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), tissue factor (TF), plasminogen activator inhibitor 1 (PAI-1), urokinase plasminogen activator (uPA), vascular endothelial growth factor (VEGF) and protease activator receptor 1 (PAR-1) was assessed using quantitative real time reverse transcriptase PCR. RESULTS: LPS caused a significant increase in mRNA expression of SAA, IL-6, MCP-1 and uPA, and a decrease in TF, PAI-1 and PAR 1 when compared to non-treated cells. Treatment with thrombin resulted in increased mRNA expression of SAA, IL-6, MCP-1 and PAI-1, and a decreased PAR-1 expression compared to non-treated cells. The fibrinogen-treated synoviocytes showed significantly increased mRNA expression of IL-6, MCP-1, TF and PAI-1, and decreased PAR-1 expression compared to non-treated cells. CONCLUSION: LPS, fibrinogen and thrombin induced an increased gene expression of inflammatory markers in isolated equine fibroblast-like synoviocytes. LPS caused changes in gene expression promoting increased fibrinolysis, while fibrinogen and thrombin changed the gene expression resulting potentially in reduced fibrinolysis. Overall, it appeared that both inflammatory and haemostatic stimuli affected expression of genes involved in inflammatory and haemostatic pathways, supporting their importance in equine joint diseases. PMID- 26116382 TI - DNA Repair Dysfunction and Neurodegeneration: Lessons From Rare Pediatric Disorders. AB - Nucleotide excision repair disorders display a wide range of clinical syndromes and presentations, all associated at the molecular level by dysfunction of genes participating in the nucleotide excision repair pathway. Genotype-phenotype relationships are remarkably complex and not well understood. This article outlines neurodegenerative symptoms seen in nucleotide excision repair disorders and explores the role that nucleotide excision repair dysfunction can play in the pathogenesis of chronic neurodegenerative diseases. PMID- 26116383 TI - Survey of the Child Neurology Program Coordinator Association: Workforce Issues and Readiness for the Next Accreditation System. AB - In preparation for the implementation of the Next Accreditation System in Child Neurology, the authors organized the first meeting of child neurology program coordinators in October 2014. A workforce and program-readiness survey was conducted initially. Coordinator job titles varied widely. Most respondents (65%) managed 1 or more fellowships plus child neurology residency. Most had worked in graduate medical education less than 5 years (53%), with no career path (88%), supervised by someone without graduate medical education experience (85%), in divisions where faculty knowledge was judged inadequate (72%). A small proportion of programs had established clinical competency committee policies (28%) and was ready to implement milestone-based evaluations (56%). A post-conference survey demonstrated substantial improvements in relevant skills. The complexity of residency program management in the Next Accreditation System era supports substantive modifications to the program coordinator role. Such changes should include defined career pathway, managerial classification, administrative support, and continuing education. PMID- 26116381 TI - Case Series: Fractional Anisotropy Profiles of the Cerebellar Peduncles in Adolescents Born Preterm With Ventricular Dilation. AB - This case series assesses white matter microstructure of the cerebellar peduncles in 4 adolescents born preterm with enlarged ventricles and reduced white matter volume in the cerebrum but no apparent injury to the cerebellum. Subjects (ages 12-17 years, gestational age 26-32 weeks, birth weight 825-2211 g) were compared to a normative sample of 19 full-term controls (9-17 years, mean gestational age 39 weeks, mean birth weight 3154 g). Tract profiles for each of the cerebellar peduncles were generated by calculating fractional anisotropy at 30 points along the central portion of each tract. One or more case subjects exhibited higher fractional anisotropy beyond the 90th percentile in the inferior, middle, and superior cerebellar peduncles. Findings demonstrate that differences in cerebellar white matter microstructure can be detected in the absence of macrostructural cerebellar abnormalities. PMID- 26116384 TI - Improving agar electrospinnability with choline-based deep eutectic solvents. AB - Very recently our group has produced novel agar-based fibers by an electrospinning technique using water as solvent and polyvinyl alcohol (PVA) as co-blending polymer. Here, we tested the deep eutectic solvent (DES), (2 hydroxyethyl)trimethylammonium chloride/urea prepared at 1:2 molar ratio, as an alternative solvent medium for agar electrospinning. The electrospun materials were collected with an ethanol bath adapted to a previous electrospinning set-up. One weight percent agar-in-DES showed improved viscoelasticity and hence, spinnability, when compared to 1 wt% agar-in-water and pure agar nanofibers were successfully electrospun if working above the temperature of sol-gel transition (~80 degrees C). By changing the solvent medium we decreased the PVA concentration (5 wt% starting solution) and successfully produced composite fibers with high agar contents (50/50 agar/PVA). Best composite fibers were formed with the 50/50 and 30/70 agar/PVA solutions. These fibers were mechanically resistant, showed tailorable surface roughness and diverse size distributions, with most of the diameters falling in the sub-micron range. Both nano and micro forms of agar fibers (used separately or combined) may have potential for the design of new and highly functional agar-based materials. PMID- 26116385 TI - Synthesis, characterization and applications of N-quaternized chitosan/poly(vinyl alcohol) hydrogels. AB - Hydrogels composed of N-quaternized chitosan (NQC) and poly(vinyl alcohol) (PVA) in different weight ratios (1:3), (1:1) and (3:1) chemically crosslinked by glutaraldehyde in different weight ratios - 1.0 and 5.0% - have been prepared. The prepared hydrogels were characterized via several analysis tools such as: Fourier transform IR (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) and thermogravimetric analysis (TGA). Different applications have been done on NQC/PVA hydrogels including; metal ions uptake, swellability in different buffer solutions (pH: 4, 7 and 9), swellability and degradation studies in simulated body fluid (SBF) solutions and antimicrobial activity towards bacteria and fungi. The results indicated that crosslinked NQC/PVA hydrogels with glutaraldehyde (GA) are more thermallystable than non crosslinked hydrogels, NQC/PVA hydrogels swell highly in different buffer solutions as PVA content increases and the antimicrobial activity of NQC/PVA hydrogels is higher than NQC itself. PMID- 26116386 TI - Preparation, characterization and molecular modeling of PEGylated human growth hormone with agonist activity. AB - In this study, site-specific PEGylated human growth hormone (hGH) was prepared by microbial transglutaminase, modeled and characterized. To this end, the effects of different reaction parameters including reaction media, PEG:protein ratios, reaction time and pH value were investigated. PEG-hGH was purified by size exclusion chromatography method and analyzed by SDS-PAGE, BCA, peptide mapping, ESI and MALDI-TOF-TOF mass spectroscopy methods. Biophysical and biological properties of PEG-hGH were evaluated. Molecular simulation was utilized to provide molecular insight into the protein-receptor interaction. The optimum conditions that were obtained for PEGylation were phosphate buffer with pH of 7.4, 48 h of stirring and PEG:protein ratio of 40:1. By this method, mono-PEG-hGH with high reaction yield was obtained and PEGylation site was at Gln-40 residue. The circular dichroism and fluorescence spectrum indicated that PEGylation did not change the secondary structure while tertiary structure was altered. Upon enzymatic PEGylation, agonistic activity of hGH was preserved; however, Somavert((r)), which is prepared by chemical PEGylation, is an antagonist form of protein. These data were confirmed by the total energy of affinity obtained by computational protein-receptor interaction. In conclusion, PEGylation of hGH was led to prepare a novel form of hormone with an agonist activity which merits further investigations. PMID- 26116387 TI - Do pH and flavonoids influence hypochlorous acid-induced catalase inhibition and heme modification? AB - Hypochlorous acid (HOCl), highly reactive oxidizing and chlorinating species, is formed in the immune response to invading pathogens by the reaction of hydrogen peroxide with chloride catalyzed by the enzyme myeloperoxidase. Catalase, an important antioxidant enzyme, catalyzing decomposition of hydrogen peroxide to water and molecular oxygen, hampers in vitro HOCl formation, but is also one of the main targets for HOCl. In this work we have investigated HOCl-induced catalase inhibition at different pH, and the influence of flavonoids (catechin, epigallocatechin gallate and quercetin) on this process. It has been shown that HOCl-induced catalase inhibition is independent on pH in the range 6.0-7.4. Preincubation of catalase with epigallocatechin gallate and quercetin before HOCl treatment enhances the degree of catalase inhibition, whereas catechin does not affect this process. Our rapid kinetic measurements of absorption changes around the heme group have revealed that heme modification by HOCl is mainly due to secondary, intramolecular processes. The presence of flavonoids, which reduce active catalase intermediate, Compound I to inactive Compound II have not influenced the kinetics of HOCl-induced heme modification. Possible mechanisms of the reaction of hypochlorous acid with catalase are proposed and the biological consequences are discussed. PMID- 26116388 TI - Molecular docking study, synthesis and biological evaluation of Mannich bases as Hsp90 inhibitors. AB - The ubiquitously expressed heat shock protein 90 is an encouraging target for the development of novel anticancer agents. In a program directed towards uncovering novel chemical scaffolds against Hsp90, we performed molecular docking studies using Tripos-Sybyl drug designing software by including the required conserved water molecules. The results of the docking studies predicted Mannich bases derived from 2,4-dihydroxy acetophenone/5-chloro 2,4-dihydroxy acetophenone as potential Hsp90 inhibitors. Subsequently, a few of them were synthesized (1-6) and characterized by IR, (1)H NMR, (13)C NMR and mass spectral analysis. The synthesized Mannich compounds were evaluated for their potential to suppress Hsp90 ATPase activity by the colorimetric Malachite green assay. Subsequently, the molecules were screened for their antiproilferative effect against PC3 pancreatic carcinoma cells by adopting the 3-(4,5-dimethythiazol- 2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay method. The activity profile of the identified derivatives correlated well with their docking results. PMID- 26116389 TI - Kinetic regime of dithiothreitol-induced aggregation of bovine serum albumin. AB - A search for agents, which are capable of effectively suppressing protein aggregation, and elaboration of the appropriate test systems, are among important problems of modern biochemistry and biotechnology. One such test system is based on dithiothreitol (DTT)-induced aggregation of bovine serum albumin (BSA). Study of the kinetics of DTT-induced aggregation of BSA by asymmetric flow field flow fractionation showed that a decrease in the portion of the non-aggregated protein in time followed the exponential law, the rate constant of the first order remaining unchanged at varying protein concentration (0.1M Na-phosphate buffer, pH 7.0; 45 degrees C). The obtained results indicate that the rate-limiting stage of the general aggregation process is that of unfolding of the protein molecule. When studying the kinetics of DTT-induced aggregation of BSA by dynamic light scattering, we proposed to use parameter K(LS) as a measure of the initial rate of aggregation. Parameter K(LS) corresponds to the initial slope of the dependence of (I-I0)(0.5) on time (I0 and I are the initial and current values of the light scattering intensity, respectively). The K(LS) value has been applied to estimate anti-aggregation activity of chemical chaperones (arginine, its derivatives and proline). PMID- 26116390 TI - Distinction of fungal polysaccharides by N/C ratio and mid infrared spectroscopy. AB - A set of fungal polysaccharide samples was characterised by elemental analysis and FTIR spectroscopy and compared with reference chitins, chitosans and beta-D glucans. The nitrogen to carbon (N/C) values and FTIR spectra were used to compare the samples based on their composition. It was found that the N/C ratio correlates well with deacetylation degree (DD) of chitosans and chitin/glucan ratio R(chit) of fungal chitin - beta-D-glucan complexes with the exception of some samples having significant nitrogen and/or carbon admixtures. FTIR spectroscopy was indicative for the N-acetylation of chitins (chitosans) as well as for the chitin (chitosan) contribution to fungal polysaccharide preparations. Multivariate analyses of the FTIR data (HCA, PCA) discriminated samples and reference materials into several clusters depending on their similarity. Chitosan lactates, chitosan - beta-D-glucans and chitin - beta-D-glucans of high and low amounts of chitin were successfully discriminated from the reference polysaccharides and from each other. The proposed procedures based on the N/C ratio and multivariate analyses of FTIR spectra may be used in screening fungal polysaccharide preparations. PMID- 26116391 TI - Combined effects of eating alone and living alone on unhealthy dietary behaviors, obesity and underweight in older Japanese adults: Results of the JAGES. AB - We examined whether eating alone is associated with dietary behaviors and body weight status, and assessed the modifying effects of cohabitation status in older Japanese people. Data from the 2010 Japan Gerontological Evaluation Study, with a self-reported questionnaire for 38,690 men and 43,674 women aged >=65 years, were used. Eating status was classified as eating with others, sometimes eating alone, or exclusively eating alone. We calculated adjusted prevalence ratios (APRs) of unhealthy dietary behaviors, obesity, and underweight, adjusting for age, education, income, disease, and dental status using Poisson regression. Overall, 16% of men and 28% of women sometimes or exclusively ate alone. Among those who exclusively ate alone, 56% of men and 68% of women lived alone. Men who exclusively ate alone were 3.74 times more likely to skip meals than men who ate with others. Among men who exclusively ate alone, those who lived alone had a higher APR than men who lived with others. Compared with subjects who ate and lived with others, the APRs of being obese (BMI >= 30.0 kg/m(2)) among men who exclusively ate alone were 1.34 (1.01-1.78) in those who lived alone and 1.17 (0.84-1.64) in those who lived with others. These combined effects of eating and living alone were weaker in women, with a potential increase in the APRs among those who ate alone despite living with others. Men who exclusively ate alone were more likely to be underweight (BMI < 18.5 kg/m(2)) than men who ate with others in both cohabitation statuses. Eating alone and living alone may be jointly associated with higher prevalence of obesity, underweight and unhealthy eating behaviors in men. PMID- 26116392 TI - Altered heparan sulfate structure in Glce(-/-) mice leads to increased Hedgehog signaling in endochondral bones. AB - One of the key regulators of endochondral ossification is Indian hedgehog (Ihh), which acts as a long-range morphogen in the developing skeletal elements. Previous studies have shown that the distribution and signaling activity of Ihh is regulated by the concentration of the extracellular glycosaminoglycan heparan sulfate (HS). An essential step during biosynthesis of HS is the epimerization of D-glucuronic to L-iduronic acid by the enzyme glucuronyl C5-epimerase (Hsepi or Glce). Here we have investigated chondrocyte differentiation in Glce deficient mice and found increased regions of proliferating chondrocytes accompanied by a delayed onset of hypertrophic differentiation. In addition, we observed increased expression levels of the Ihh target genes Patched1 (Ptch1) and Parathyroid hormone related peptide (Pthrp; Parathyroid hormone like hormone (Pthlh)) indicating elevated Ihh signaling. We further show that Ihh binds with reduced affinity to HS isolated from Glce(-/-) mice. Together our results strongly indicate that not only the level, but also the structure of HS is critical in regulating the distribution and signaling activity of Ihh in chondrocytes. PMID- 26116393 TI - Pacing the Heart with Genes: Recent Progress in Biological Pacing. AB - The heartbeat originates within the sinoatrial node (SA node or SAN), a small highly specialized structure containing <10,000 genuine pacemaker cells. The ~5 billion working cardiomyocytes downstream of the SAN remain quiescent when it fails, leading to circulatory collapse and fueling a $6B/year electronic pacemaker industry. The electronic pacemaker devices work quite well. But, device related problems persist. These include lead failure/repositioning, finite battery life, and infection. For pediatric patients, the children outgrow the length of the leads, necessitating replacement with longer leads. These pitfalls have motivated creation of biological pacing. that are free from all hardware. Toward this goal, we and others have tested the concept of biological pacemakers. Combined with efforts to create clinically relevant, large animal models of biological pacing, the field is moving beyond a conceptual novelty toward a future with clinical reality. PMID- 26116394 TI - Cryptic Role of the ETHYLENE INSENSITIVE2 Nuclear Localization Signal in Ethylene Signaling. PMID- 26116395 TI - Anastomotic reinforcement with omentoplasty following gastrointestinal anastomosis: A systematic review and meta-analysis. AB - Anastomotic leak is a potentially devastating complication following gastrointestinal anastomosis. Some surgeons believe that reinforcing the anastomosis with omentum reduces the incidence and severity of anastomotic leak. A comprehensive electronic search of EMBASE, Medline, Web of Science and Cochrane databases was performed. Pooled odds ratios (POR) were calculated for discrete variables. There were six studies investigating esophageal anastomosis and 3 studies investigating colorectal anastomosis identified by the literature search. A total of 2296 patients were included, 1073 with omentoplasty and 1223 without. In esophageal surgery omentoplasty significantly reduced the rate of anastomotic leak (2.9% vs 10.5% (POR = 0.28; 95% CI = 0.17 to 0.47; P < 0.0001), but there was no significant effect upon in-hospital mortality (2.3% vs. 2.5%; POR = 0.911 [95% CI 0.439-1.887]; P = 0.802) or anastomotic stricture between the two groups (6.6% vs 9.1%; POR = 0.842 [95% CI 0.331 to 2.145]; P = 0.720). In colorectal surgery there was no significant difference in anastomotic leak rate (5.0% vs 8.4%; POR: 0.50; 95% CI 0.21 to 1.17) or in-hospital mortality (4.2% vs 4.1%; POR: 0.90; 95% CI 0.34 to 2.41). The results of this analysis show that omentoplasty significantly reduced the rate of anastomotic leak following esophageal anastomosis but these results were not observed in colorectal anastomosis. Omentoplasty could be used as an adjunct technique to reduce the incidence of anastomotic leak in oesophageal anastomosis. PMID- 26116396 TI - Lymphatic ascites after retroperitoneal lymphadenectomy in gynecologic cancer. AB - OBJECTIVES: The incidence, diagnosis, treatment and outcome of lymphatic ascites (LA) are studied on 85 consecutive patients with gynecologic cancer who had undergone pelvic and/or paraaortic lymphadenectomy by means of laparotomy or laparoscopy. METHODS: Patients were distributed in two groups depending in the access: Laparoscopy (study group: 44 patients) and laparotomy (control group: 41 patients). All surgical parameters were collected and patients underwent ultrasound examination on postoperative days 7, 14, and 28. The main outcome measure was the development of symptomatic or asymptomatic LA. DESIGN: Prospective cohort study. RESULTS: LA developed in 3 patients (6.8%) in the study group and 9 in the control group (22%), with statistical difference (p < 0.05). The relative risk to develop lymphatic ascites after surgery performed by laparotomy was 3.2 (95% CI 1.05-11.07). Mean nodes harvested during the surgery was 18.6 (SD 6.6) in the LA group and 20.4 (SD 9.1) in the group with no LA (p = 0.527). CONCLUSIONS: The incidence of LA after retroperitoneal lymphadenectomy in gynecologic cancer patients is lower in the patients treated by laparoscopy. PMID- 26116397 TI - Systematic review and meta-analysis comparing hypofractionated with conventional fraction radiotherapy in treatment of early breast cancer. AB - BACKGROUND: The purpose of this meta-analysis is to evaluate the efficacy and safety of altered radiation fraction size on outcomes for early breast cancer patients. METHODS: A search of MEDLINE, EMBASE, WEB OF SCIENCE, Cochrane Library and ClinicalTrials.gov was conducted. Quality of the randomized controlled trials (RCTs) or non-RCTs were evaluated according to Cochrane's risk of bias tool or Methodological Index for non-Randomized Studies (MINORS). Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated. Subgroup analysis was applied according to different fraction dose and sensitivity analysis was performed according to RCTs or non-RCTs. RESULTS: 23 studies were included in this systematic review. Meta-analysis demonstrated hypofractionation radiotherapy (HFRT) was associated with decreased grade 2/3 acute skin reactions compared with conventional fraction RT (CFRT), either 2.5-3.0 Gy per fraction or 5.0-6.5 Gy per fraction. HFRT with 2.5-3.0 Gy per fraction significantly decreased moderate/marked photographic changes in breast appearance compared with CFRT [RR = 0.80, 95% CI (0.70, 0.91), P = 0.001], while HFRT with more than 3.0 Gy per fraction significantly increased moderate/marked photographic changes [RR = 1.21, 95% CI (1.06, 1.38), P = 0.004]. In addition HFRT cost one-third lower than CFRT. Regarding to local regional recurrence, distant metastasis, overall survival, disease free survival, excellent/good cosmetic comes, symptomatic radiation pneumonitis, ischemic heart disease and symptomatic rib fracture, there was no significant difference between two arms. CONCLUSIONS: Based on available evidence, HFRT with 2.5-3.0 Gy per fraction should be the better choice for treatment of early breast cancer patients. PMID- 26116398 TI - Hazard effects of nanoparticles in central nervous system: Searching for biocompatible nanomaterials for drug delivery. AB - Nanostructured materials are widely used in many applications of industry and biomedical fields. Nanoparticles emerges as potential pharmacological carriers that can be applied in the regenerative medicine, diagnosis and drug delivery. Different types of nanoparticles exhibit ability to cross the brain blood barrier (BBB) and accumulate in several brain areas. Then, efforts have been done to develop safer nanocarrier systems to treat disorders of central nervous system (CNS). However, several in vitro and in vivo studies demonstrated that nanoparticles of different materials exhibit a wide range of neurotoxic effects inducing neuroinflammation and cognitive impairment. For this reason, polymeric nanoparticles arise as a promisor alternative due to their biocompatible and biodegradable properties. After an overview of CNS location and neurotoxic effects of translocated nanoparticles, this review addresses the use of polymeric nanoparticles to the treatment of neuroinfectious diseases, as acquired immunodeficiency syndrome (AIDS) and meningitis. PMID- 26116399 TI - Case Series of Three Infants with Erythema Multiforme Following Hepatitis B Vaccination. PMID- 26116400 TI - Critical Variables Affecting Cord Blood MPV and IMA Levels in Gestational Diabetic Mothers. PMID- 26116401 TI - Factors associated with family resilience during pregnancy among inner-city women. AB - OBJECTIVE: family resilience refers to the ability of a family group to adapt to challenging circumstances. For families residing in the inner-city, the concept of resilience is of particular salience as these families often encounter multiple stressors. The purpose of this study was to determine the factors associated with low family resilience during pregnancy among inner-city women. DESIGN: secondary analysis of data from a case-control study of factors related to inadequate antenatal care. SETTING/PARTICIPANTS: participants consisted of 603 postpartum women who gave birth to a live infant and resided in one of eight inner-city neighbourhoods in Winnipeg, Manitoba. METHODS: participants were designated as having low family resilience (n=155) or moderate to high family resilience (n=448) based on scores on the Family Hardiness Index. Univariate analyses were conducted to explore the association between a variety of factors during pregnancy and family resilience, and crude odds ratios (OR) and 95% confidence intervals (CI) were calculated. Factors significant at p<.10 were then entered into a multivariate logistic regression model, yielding adjusted ORs and 95% CI. RESULTS: the following factors were significantly associated with low family resilience among pregnant inner-city women in the final model: maternal age <25 years (AOR 1.69), low self-esteem (AOR 2.82), high perceived stress (AOR 3.01), alcohol use during pregnancy (AOR 3.20), and low interpersonal support (AOR 6.24). KEY CONCLUSIONS: inner-city women who are young or have low self esteem, high perceived stress, low interpersonal support, or who use alcohol during pregnancy are more likely to report lower levels of family resilience. IMPLICATIONS FOR PRACTICE: midwives have the opportunity to develop ongoing relationships with their clients and families. As such, they are in an excellent position to understand the specific needs and strengths of individual families and foster the abilities of these families to strengthen and support resilience. PMID- 26116402 TI - Low-Fidelity Simulation of Mitral Valve Surgery: Simple and Effective Trainer. AB - OBJECTIVES: Training in mitral valve (MV) surgery is difficult because of its complex 3-dimentional anatomy and sophisticated surgical techniques. The goal of this study was to create an effective and simple simulator to enable the trainee in performing MV repair and replacement techniques in a low-fidelity environment. METHODS: The MV surgery simulator is a self-shaped sponge integrated into a portable box that can be used for an unrestricted number of procedures. The building process is detailed in this study. MV procedures were performed in which the surgical handling was tested. The total cost was calculated in euros. RESULTS: The building of the MV simulator resulted in the development of a new low-cost tool for training in MV surgery. The usage of the sponge led to building the MV components with flexible properties and allowing the surgical procedures to be performed in unrestricted numbers. This involved MV replacement in both intra- and supra-annular fashion and MV repair according to the Carpentier classification. CONCLUSION: Surgical skills in mitral surgery could be improved by usage of the low-fidelity simulator. The high cost of the training for residents and junior surgeons could be effectively reduced by using this low cost, portable, reusable simulator and its accessories (ring and band). PMID- 26116403 TI - Quantification of pollen tube attraction in response to guidance by female gametophyte tissue using artificial microscale pathway. AB - We developed two types of artificial platforms, T-junction and crossroad microchannel devices, and obtained guidance response ratio of pollen tubes to the female tissue as 56-57%. The crossroad device was also able to collect the attracted pollen tubes with high purity, which is useful for future omics analysis. PMID- 26116404 TI - Anesthetist is sued after sedated patient recorded insults on phone. PMID- 26116405 TI - Cholecystitis after yttrium-90 resin microsphere radioembolization treatment: Clinical and pathologic findings. AB - BACKGROUND: Radioembolization with yttrium microspheres is an established therapeutic modality for primary and secondary hepatic malignancies, with studies demonstrating improved overall survival. There remains a paucity of data on cholecystitis as a complication of radioembolization. We describe a small series of patients who developed cholecystitis as a result of radioembolization. METHODS: Patients who had developed cholecystitis as a complication of radioembolization in our institution between 2001 and 2012 were retrospectively reviewed. Patient demographics, cancer details including treatment history, and procedural details of radioembolization and complications of cholecystitis were collected. RESULTS: Of 74 patients who underwent radioembolization using yttrium 90emitting microspheres, four (5.4%) presented with acute cholecystitis as a result of their treatment. All patients presented over 4 weeks following radioembolization and did not settle with conservative treatment. At surgery, the gallbladder was fibrotic and contracted in all cases making surgery difficult. CONCLUSION: The incidence of symptomatic radiation cholecystitis after radioembolization is low, and prophylactic cholecystectomy is not routinely recommended for patients undergoing radioembolization. Radiation cholecystitis should be suspected in patients presenting with symptoms of biliary colic or cholecystitis following radioembolization. Early cholecystectomy can be considered in patients undergoing surgery for other indications, especially in high-risk surgical patients in whom there is a high likelihood of radioembolization in the future as they do not respond to conservative treatment. PMID- 26116407 TI - [Preliminary study: Lower urinary tract dysfunction and anorectal disorders in children with cerebral palsy]. AB - GOAL: Describe lower urinary tract dysfunction and anorectal disorders to children with cerebral palsy (CP), indicating their impact on quality of life. MATERIALS: This was a prospective single-center study. A data collection was: type of PC, Gross Motor Function-Classification System (GMF-CS), mainstream education or not, Functional Independence Measure in children (MIF-kid), standardized vesicosphincteric symptoms and quality of life questionnaires (specific issue of impact sphincter dysfunction and generic scale Kidscreen-52). RESULTS: Between January and March 2013, 19 children aged 5-17 years were included, including 16 into mainstream schooling. Of the 19, 16 had bladder and sphincter disorders: 14 urinary incontinence, 3 nycturies, 6 dysuria, 12 urgenturies, no urinary infection. Of the 14 urinary incontinence, 13 were in school. Of the 16 children enrolled, 5 were daytime fecal incontinence and 2 nocturnal fecal incontinence. Functional scores (GMF-CS and MIF-kid) children urinary incontinence were lower than those of children urinary continents (P=0.04 and 0.0007). Ten children had an impact of these disorders on quality of life. All were enrolled, eight (80%) in the mainstream. CONCLUSION: The bladder and sphincter disorders were common in children with CP. They led to an impact on quality of life in more than half of the children studied, mostly educated in mainstream schools. PMID- 26116406 TI - Chemopreventive Effects of Korean Angelica versus Its Major Pyranocoumarins on Two Lineages of Transgenic Adenocarcinoma of Mouse Prostate Carcinogenesis. AB - We showed previously that daily gavage of Angelica gigas Nakai (AGN) root ethanolic extract starting 8 weeks of age inhibited growth of prostate epithelium and neuroendocrine carcinomas (NE-Ca) in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Because decursin (D) and its isomer decursinol angelate (DA) are major pyranocoumarins in AGN extract, we tested the hypothesis that D/DA represented active/prodrug compounds against TRAMP carcinogenesis. Three groups of male C57BL/6 TRAMP mice were gavage treated daily with excipient vehicle, AGN (5 mg per mouse), or equimolar D/DA (3 mg per mouse) from 8 weeks to 16 or 28 weeks of age. Measurement of plasma and NE-Ca D, DA, and their common metabolite decursinol indicated similar retention from AGN versus D/DA dosing. The growth of TRAMP dorsolateral prostate (DLP) in AGN- and D/DA-treated mice was inhibited by 66% and 61% at 16 weeks and by 67% and 72% at 28 weeks, respectively. Survival of mice bearing NE-Ca to 28 weeks was improved by AGN, but not by D/DA. Nevertheless, AGN- and D/DA-treated mice had lower NE-Ca burden. Immunohistochemical and mRNA analyses of DLP showed that AGN and D/DA exerted similar inhibition of TRAMP epithelial lesion progression and key cell-cycle genes. Profiling of NE-Ca mRNA showed a greater scope of modulating angiogenesis, epithelial-mesenchymal transition, invasion-metastasis, and inflammation genes by AGN than D/DA. The data therefore support D/DA as probable active/prodrug compounds against TRAMP epithelial lesions, and they cooperate with non pyranocoumarin compounds to fully express AGN efficacy against NE-Ca. PMID- 26116408 TI - Ergosteryl-beta-glucosidase (Egh1) involved in sterylglucoside catabolism and vacuole formation in Saccharomyces cerevisiae. AB - Sterylglucosides (SGs) are composed of a glucose and sterol derivatives, and are distributed in fungi, plants and mammals. We recently identified EGCrP1 and EGCrP2 (endoglycoceramidase-related proteins 1 and 2) as a beta glucocerebrosidase and steryl-beta-glucosidase, respectively, in Cryptococcus neoformans. We herein describe an EGCrP2 homologue (Egh1; ORF name, Yir007w) involved in SG catabolism in Saccharomyces cerevisiae. The purified recombinant Egh1 hydrolyzed various beta-glucosides including ergosteryl beta-glucoside (EG), cholesteryl beta-glucoside, sitosteryl beta-glucoside, para-nitrophenyl beta glucoside, 4-methylumberifellyl beta-glucoside and glucosylceramide. The disruption of EGH1 in S. cerevisiae BY4741 (egh1Delta) resulted in the accumulation of EG and fragmentation of vacuoles. The expression of EGH1 in egh1Delta (revertant) reduced the accumulation of EG, and restored the morphology of vacuoles. The accumulation of EG was not detected in EGH1 and UGT51(ATG26) double-disrupted mutants (ugt51Deltaegh1Delta), indicating that EG was synthesized by Ugt51(Atg26) and degraded by Egh1 in vivo. These results clearly demonstrated that Egh1 is an ergosteryl-beta-glucosidase that is functionally involved in the EG catabolic pathway and vacuole formation in S. cerevisiae. PMID- 26116409 TI - Adenotonsillectomy improves quality of life in children with sleep-disordered breathing regardless of nocturnal enuresis outcome. AB - BACKGROUND: Nocturnal enuresis (NE) and sleep-disordered breathing (SDB) have both been associated with impaired health-related quality of life (HRQoL). The following were investigated: (1) whether tonsillectomy and/or adenoidectomy (T&A) significantly affect the HRQoL in children with NE and SDB, and 2) differences in HRQoL between children with NE persistence versus resolution post-T&A. METHODS: This was a prospective study comparing the HRQoL of children with SDB and NE (study group) pre- and 4 weeks post-T&A, and the HRQoL of children with SDB without NE (control group) (independent t-tests). HRQol was assessed using the Obstructive Sleep Apnea Quality of Life 18 questionnaire (OSAS-18), a validated measure containing five subscales that combine to create a total score. Individual items were scored on a Likert-type scale ranging from 1 (none of the time) to 7 (all of the time). Symptoms of SDB were evaluated using the validated Pediatric Sleep Questionnaire (PSQ). Mixed ANOVA was conducted to evaluate changes in the measures between the wet and dry children post-T&A. Pre- and post T&A change scores were calculated for both the PSQ and the OSAS-18. RESULTS: There were 30 children in the study group (18 male, mean age 9.07 years, SD 2.19), and 30 age-matched controls (16 male). There were no statistically significant differences between the two groups in regards to OSAS-18 total, PSQ total, BMI, diagnosis of snoring or OSAS on sleep study, or race. Overall, OSAS 18 and PSQ scores significantly improved in all children post-surgery (p < 0.001; p < 0.001, respectively), with no significant differences between dry and wet children post-T&A. The correlation between the pre- and post-T&A change scores on the OSAS-18 and PSQ was significant (r(29) = 0.58, p = 0.001), suggesting that a reduction in SDB symptoms post T&A is related to improved HRQoL. CONCLUSIONS: T&A significantly improved HRQoL in all children with SDB and NE, regardless of NE outcomes. These findings support recommendations for T&A in children with SDB with or without NE. PMID- 26116410 TI - In vitro bioaccessibility and in vivo relative bioavailability in 12 contaminated soils: Method comparison and method development. AB - Previous studies have established in vivo-in vitro correlations (IVIVC) between arsenic (As) relative bioavailability (RBA) and bioaccessibility in contaminated soils. However, their ability to predict As-RBA in soils outside the models is unclear. In this study, As bioaccessibility and As-RBA in 12 As-contaminated soils (22.2-4172 mg kg(-1) As) were measured using five assays (SBRC, IVG, DIN, PBET, and UBM) and a mouse blood model. Arsenic RBA in the soils ranged from 6.38 +/- 2.80% to 73.1 +/- 17.7% with soils containing higher extractable Fe showing lower values. Arsenic bioaccessibility varied within and between assays. Arsenic bioaccessibility was used as input values into established IVIVC to predict As RBA in soils. There were significant differences between predicted and measured As-RBA for the 12 soils, illustrating the inability of established IVIVC to predict As-RBA in those contaminated soils. Therefore, a new IVIVC was established by correlating measured As-RBA and As bioaccessibility for the 12 soils. The strength of the predictive models varied from r(2) = 0.50 for PBET to r(2) = 0.83 for IVG, with IVG assay providing the best prediction of As-RBA. When IVIVC were compared to those of Juhasz et al. (2014a), slopes of the relationships were significantly higher possibly due to different As-RBA measurements. Our research showed that IVG has potential to measure As bioavailability in contaminated soils from China though UBM and SBRC assays were also suitable. More research is needed to verify their suitability to predict As RBA in soils for refining health risk assessment. PMID- 26116411 TI - Quantified biotic and abiotic responses to multiple stress in freshwater, marine and ground waters. AB - We reviewed 219 papers and built an inventory of 532 items of ecological evidence on multiple stressor impacts in rivers, lakes, transitional and coastal waters, as well as groundwaters. Our review revealed that, despite the existence of a huge conceptual knowledge base in aquatic ecology, few studies actually provide quantitative evidence on multi-stress effects. Nutrient stress was involved in 71% to 98% of multi-stress situations in the three types of surface water environments, and in 42% of those in groundwaters. However, their impact manifested differently along the groundwater-river-lake-transitional-coastal continuum, mainly determined by the different hydro-morphological features of these ecosystems. The reviewed papers addressed two-stressor combinations most frequently (42%), corresponding with the actual status-quo of pressures acting on European surface waters as reported by the Member States in the WISE WFD Database (EEA, 2015). Across all biological groups analysed, higher explanatory power of the stress-effect models was discernible for lakes under multi-stressor compared to single stressor conditions, but generally lower for coastal and transitional waters. Across all aquatic environments, the explanatory power of stress-effect models for fish increased when multi-stressor conditions were taken into account in the analysis, qualifying this organism group as a useful indicator of multi stress effects. In contrast, the explanatory power of models using benthic flora decreased under conditions of multiple stress. PMID- 26116412 TI - Post-surgical management of non-functioning pituitary adenoma. AB - Post-surgical surveillance of non-functioning pituitary adenoma (NFPA) is based on magnetic resonance imaging (MRI) at 3 or 6 months then 1 year. When there is no adenomatous residue, annual surveillance is recommended for 5 years and then at 7, 10 and 15 years. In case of residue or doubtful MRI, prolonged annual surveillance monitors any progression. Reintervention is indicated if complete residue resection is feasible, or for symptomatic optic pathway compression, to create a safety margin between the tumor and the optic pathways ahead of complementary radiation therapy (RT), or in case of post-RT progression. In case of residue, unless the tumor displays elevated growth potential, it is usually recommended to postpone RT until progression is manifest, as efficacy is comparable whether treatment is immediate or postponed. The efficacy of the various RT techniques in terms of tumor volume control is likewise comparable. RT induced hypopituitarism is frequent, whatever the technique. The choice thus depends basically on residue characteristics: size, delineation, and proximity to neighboring radiation-sensitive structures. Reduced rates of vascular complications and secondary brain tumor can be hoped for with one-dose or hypofractionated stereotactic RT, but there has been insufficient follow-up to provide evidence. Somatostatin analogs and dopaminergic agonists have yet to demonstrate sufficient efficacy. Temozolomide is an option in aggressive NFPA resistant to surgery and RT. PMID- 26116413 TI - Prognostic accuracy of prostate health index and urinary prostate cancer antigen 3 in predicting pathologic features after radical prostatectomy. PMID- 26116415 TI - Effect of plasmids harbouring blaCTX-M on the virulence and fitness of Escherichia coli ST131 isolates. AB - The effect of plasmids harbouring blaCTX-M on the virulence and fitness on Escherichia coli sequence type 131 (ST131) isolates was investigated. Plasmids harbouring blaCTX-M-14 or blaCTX-M-15 were transferred by transconjugation into five non-extended-spectrum beta-lactamase (ESBL)-producing ST131 isolates. Clinical non-ESBL-producing ST131 isolates demonstrated a higher degree of biofilm formation and serum resistance compared with CTX-M-producing ST131 isolates. In addition, non-ESBL-producing isolates were more competitive than CTX M-producing isolates. Transconjugants showed no significant defect in growth rate and competitiveness compared with their hosts. However, serum resistance and biofilm formation were diminished in the transconjugants. In conclusion, non-ESBL producing E. coli ST131 isolates were more competitive and virulent than CTX-M producing E. coli ST131 isolates. However, transconjugants harbouring blaCTX-M were no less competitive than their susceptible hosts, which may partially explain the global dissemination of CTX-M-14- and CTX-M-15-producing E. coli ST131 isolates, in addition to their increased antimicrobial resistance. PMID- 26116414 TI - Development and characterization of novel ZnO-loaded electrospun membranes for periodontal regeneration. AB - OBJECTIVES: This study reports on the synthesis, materials characterization, antimicrobial capacity, and cytocompatibility of novel ZnO-loaded membranes for guided tissue/bone regeneration (GTR/GBR). METHODS: Poly(E-caprolactone) (PCL) and PCL/gelatin (PCL/GEL) were dissolved in hexafluoropropanol and loaded with ZnO at distinct concentrations: 0 (control), 5, 15, and 30wt.%. Electrospinning was performed using optimized parameters and the fibers were characterized via scanning and transmission electron microscopies (SEM/TEM), energy dispersive X ray spectroscopy (EDS), Fourier transform infrared spectroscopy (FTIR), contact angle (CA), mechanical testing, antimicrobial activity against periodontopathogens, and cytotoxicity test using human dental pulp stem cells (hDPSCs). Data were analyzed using ANOVA and Tukey (alpha=5%). RESULTS: ZnO nanoparticles were successfully incorporated into the overall submicron fibers, which showed fairly good morphology and microstructure. Upon ZnO nanoparticles' incorporation, the PCL and PCL/GEL fibers became thicker and thinner, respectively. All GEL-containing membranes showed lower CA than the PCL-based membranes, which were highly hydrophobic. Overall, the mechanical properties of the membranes were reduced upon ZnO incorporation, except for PCL-based membranes containing ZnO at the 30wt.% concentration. The presence of GEL enhanced the stretching ability of membranes under wet conditions. All ZnO-containing membranes displayed antibacterial activity against the bacteria tested, which was generally more pronounced with increased ZnO content. All membranes synthesized in this study demonstrated satisfactory cytocompatibility, although the presence of 30wt.% ZnO led to decreased viability. SIGNIFICANCE: Collectively, this study suggests that PCL- and PCL/GEL-based membranes containing a low content of ZnO nanoparticles can potentially function as a biologically safe antimicrobial GTR/GBR membrane. PMID- 26116416 TI - A glucose anode for enzymatic fuel cells optimized for current production under physiological conditions using a design of experiment approach. AB - This study reports a design of experiment methodology to investigate and improve the performance of glucose oxidizing enzyme electrodes. Enzyme electrodes were constructed by co-immobilization of amine-containing osmium redox complexes, multiwalled carbon nanotubes and glucose oxidase in a carboxymethyldextran matrix at graphite electrode surfaces to provide a 3-dimensional matrix for electrocatalytic oxidation of glucose. Optimization of the amount of the enzyme electrode components to produce the highest current density under pseudo physiological conditions of 5 mM glucose in saline buffer at 37 degrees C was performed using response surface methodology. A statistical analysis showed that the proposed model had a good fit with the experimental results. From the validated model, the addition of multiwalled carbon nanotubes and carboxymethyldextran components was identified as major contributing factors to the improved performance. Based on the optimized amount of components, enzyme electrodes display current densities of 1.2+/-0.1 mA cm(-2) and 5.2+/-0.2 mA cm( 2) at 0.2 V vs. Ag/AgCl in buffer containing 5 mM and 100 mM glucose, respectively, largely consistent with the predicted values. This demonstrates that use of a design of experiment approach can be applied effectively and efficiently to improve the performance of enzyme electrodes as anodes for biofuel cell device development. PMID- 26116417 TI - Non-thermal plasma treatment altered gene expression profiling in non-small-cell lung cancer A549 cells. AB - BACKGROUND: Recent technological advances in atmospheric plasmas have made the creation of non-thermal atmospheric pressure plasma (NTP) possible for utilization in the medical field. Although accumulated evidence suggests that NTP induces cell death in various cancer cell types thus offering a promising alternative treatment strategy, the mechanism underlying its therapeutic effect is not fully understood. RESULTS: We analyzed relevant signaling cascades associated with the tumor protein p53, in particular the cell cycle arrest, DNA damage as well as the underlying apoptosis pathways. Based on our results, the major effect from plasma exposure was found to be the activation of MAPK and p53 signaling pathways, resulting in changes in gene expression of MEKK, GADD, FOS and JUN. Finally, a significant modulation in expression of genes related to cellular proliferation and differentiation was observed. CONCLUSION: Overall, the presented data of the tumor transcriptome helped identify the key players in modulated gene expression following exposure to plasma at the molecular level, and also helped interpret the downstream processes. The present work laid the foundation for further studies to clarify the roles of multiple pathways in plasma-induced biological processes. Further investigation of these genes in other cell lines may reveal comprehensive mechanisms of plasma induced effects. PMID- 26116418 TI - Towards diagnostic conversational profiles of patients presenting with dementia or functional memory disorders to memory clinics. AB - OBJECTIVE: This study explores whether the profile of patients' interactional behaviour in memory clinic conversations with a doctor can contribute to the clinical differentiation between functional memory disorders (FMD) and memory problems related to neurodegenerative diseases. METHODS: Conversation Analysis of video recordings of neurologists' interactions with patients attending a specialist memory clinic. "Gold standard" diagnoses were made independently of CA findings by a multi-disciplinary team based on clinical assessment, neuropsychological testing and brain imaging. RESULTS: Two discrete conversational profiles for patients with memory complaints emerged, including (i) who attends the clinic (i.e., whether or not patients are accompanied), and (ii) patients' responses to neurologists' questions about memory problems, such as difficulties with compound questions and providing specific and elaborated examples and frequent "I don't know" responses. CONCLUSION: Specific communicative difficulties are characteristic of the interaction patterns of patients with a neurodegenerative pathology. Those difficulties are manifest in memory clinic interactions with neurologists, thereby helping to differentiate patients with dementia from those with FMD. PRACTICAL IMPLICATIONS: Our findings demonstrate that conversational profiles based on patients' contributions to memory clinic encounters have diagnostic potential to assist the screening and referral process from primary care, and the diagnostic service in secondary care. PMID- 26116419 TI - The adaptive response of bacterial food-borne pathogens in the environment, host and food: Implications for food safety. AB - Bacteria are constantly faced to stress situations in their ecological niches, the food and the host gastrointestinal tract. The capacity to detect and respond to surrounding changes is crucial for bacterial pathogens to survive or grow in changing environments. To this purpose, cells have evolved various sophisticated networks designed to protect against stressors or repair damage caused by them. Challenges can occur during production of foods when subjected to processing, and after food ingestion when confronted with host defensive barriers. Some pathogenic bacteria have shown the capacity to develop stable resistance against extreme conditions within a defined genomic context and a limited number of generations. On the other hand, bacteria can also respond to adverse conditions in a transient manner, through the so-called stress tolerance responses. Bacterial stress tolerance responses include both structural and physiological modifications in the cell and are mediated by complex genetic regulatory machinery. Major aspects in the adaptive response are the sensing mechanisms, the characterization of cell defensive systems, such as the operation of regulatory proteins (e.g. RpoS), the induction of homeostatic and repair systems, the synthesis of shock response proteins, and the modifications of cell membranes, particularly in their fatty acid composition and physical properties. This article reviews certain strategies used by food-borne bacteria to respond to particular stresses (acid, cold stress, extreme pressure) in a permanent or transient manner and discusses the implications that such adaptive responses pose for food safety. PMID- 26116420 TI - A peptidomic approach to study the contribution of added casein proteins to the peptide profile in Spanish dry-fermented sausages. AB - Peptidomics is a necessary alternative in the analysis of naturally generated peptides in dry-fermented processing. The intense proteolysis occurred during the processing of dry-fermented sausages is due to the action of endopeptidases and exopeptidases from both, endogenous muscle origin and lactic acid bacteria (LAB) added in the starter. Sodium caseinate is frequently used as an additive in this type of products because of its emulsifying properties, and consequently influences the protein profile available during the proteolysis. In this study, a mass spectrometry approach has been used to determine the impact of added sodium caseinate in the final peptide profile as well as to analyse its possible influence in the presence of certain previously described casein-derived bioactive peptides. PMID- 26116421 TI - Molecular Genetic Tools and Techniques for Marchantia polymorpha Research. AB - Liverworts occupy a basal position in the evolution of land plants, and are a key group to address a wide variety of questions in plant biology. Marchantia polymorpha is a common, easily cultivated, dioecious liverwort species, and is emerging as an experimental model organism. The haploid gametophytic generation dominates the diploid sporophytic generation in its life cycle. Genetically homogeneous lines in the gametophyte generation can be established easily and propagated through asexual reproduction, which aids genetic and biochemical experiments. Owing to its dioecy, male and female sexual organs are formed in separate individuals, which enables crossing in a fully controlled manner. Reproductive growth can be induced at the desired times under laboratory conditions, which helps genetic analysis. The developmental process from a single celled spore to a multicellular body can be observed directly in detail. As a model organism, molecular techniques for M. polymorpha are well developed; for example, simple and efficient protocols of Agrobacterium-mediated transformation have been established. Based on them, various strategies for molecular genetics, such as introduction of reporter constructs, overexpression, gene silencing and targeted gene modification, are available. Herein, we describe the technologies and resources for reverse and forward genetics in M. polymorpha, which offer an excellent experimental platform to study the evolution and diversity of regulatory systems in land plants. PMID- 26116422 TI - Dual Targeting of the Protein Methyltransferase PrmA Contributes to Both Chloroplastic and Mitochondrial Ribosomal Protein L11 Methylation in Arabidopsis. AB - Methylation of ribosomal proteins has long been described in prokaryotes and eukaryotes, but our knowledge about the enzymes responsible for these modifications in plants is scarce. The bacterial protein methyltransferase PrmA catalyzes the trimethylation of ribosomal protein L11 (RPL11) at three distinct sites. The role of these modifications is still unknown. Here, we show that PrmA from Arabidopsis thaliana (AtPrmA) is dually targeted to chloroplasts and mitochondria. Mass spectrometry and enzymatic assays indicated that the enzyme methylates RPL11 in plasto- and mitoribosomes in vivo. We determined that the Arabidopsis and Escherichia coli PrmA enzymes share similar product specificity, making trimethylated residues, but, despite an evolutionary relationship, display a difference in substrate site specificity. In contrast to the bacterial enzyme that trimethylates the epsilon-amino group of two lysine residues and the N terminal alpha-amino group, AtPrmA methylates only one lysine in the MAFCK(D/E)(F/Y)NA motif of plastidial and mitochondrial RPL11. The plant enzyme possibly methylates the N-terminus of plastidial RPL11, whereas mitochondrial RPL11 is N-alpha-acetylated by an unknown acetyltransferase. Lastly, we found that an Arabidopsis prma-null mutant is viable in standard environmental conditions and no molecular defect could be associated with a lack of RPL11 methylation in leaf chloroplasts or mitochondria. However, the conservation of PrmA during the evolution of photosynthetic eukaryotes together with the location of methylated residues at the binding site of translation factors to ribosomes suggests that RPL11 methylation in plant organelles could be involved, in combination with other post-translational modifications, in optimizing ribosome function. PMID- 26116423 TI - Copper(II) complexes with new fluoroquinolones: Synthesis, structure, spectroscopic and theoretical study, DNA damage, cytotoxicity and antiviral activity. AB - Copper(II) complexes with fluoroquinolones in the presence of the nitrogen donor heterocyclic ligands 1,10-phenanthroline have been considered in detail. The phenanthroline moiety was introduced into the ligand environment with the aim to determine whether the nuclease activity is feasible. All suitable X-ray structures of the complexes under study reveal a distorted square pyramidal coordination geometry for Cu(II) atom. The conformational and spectroscopic (FT IR and UV-visible) behavior has been analyzed and has been interpreted with respect to B3LYP/6-311G* calculations including molecular dynamics. The ability of the complexes to cleave DNA was studied by agarose gel electrophoresis with plasmid DNA pBSK+. The results have confirmed that the complexes under study behave as the chemical nucleases. Nuclease like activity in the absence of hydrogen peroxide allows us to deduce an interaction of the complexes with the DNA resulting in the conversion of supercoiled circular DNA to the nicked form. The DNA cleavage activity enhanced by the presence of hydrogen peroxide demonstrates the participation of reactive oxygen species, such as superoxide radical anions and hydroxyl radicals which presence was confirmed independently using the standard radical scavenging agents. It has been suggested that the radical formation through the Fenton/Haber-Weiss reaction is mediated by the redox cycling mechanisms with the participation of cupric/cuprous ions. Cytotoxic activity was evaluated as the 50% cytotoxic concentration (CC50). The potential effects of tested compounds on replication of murine gammaherpesvirus 68 (MHV-68) under in vitro conditions were also evaluated. However, no antiviral activity against MHV-68 was observed. PMID- 26116424 TI - Conformational and structural studies of N-methylacetohydroxamic acid and of its mono- and bis-chelated uranium(VI) complexes. AB - The thermodynamics and kinetics of the cis/trans isomerism of N methylacetohydroxamic acid (NMAH) and its conjugated base (NMA(-)) have been reinvestigated in aqueous media by (1)H NMR spectroscopy. Hindered rotation around the central C-N bond due to electronic delocalization becomes slow enough on the NMR time scale to observe both rotamers in equilibrium in D2O at room temperature. By properly assigning the methyl group resonances, evidence for the prevalence of the E over the Z form is unambiguously provided [K300=[E]/[Z]=2.86(2) and 9.63(5) for NMAH and NMA(-), respectively], closing thereby a long-lasting dispute about the most stable conformer. To that end, calculations of the chemical shifts by density functional theory (DFT), which accurately reproduced the experimental data, turned out to be a much more reliable method than the direct computation of the relative energy for each conformer. The Z ? E interconversion dynamics was probed at 300 K in D2O by 2D exchange-correlated spectroscopy (EXSY), affording the associated rate constants [kZE=9.0(2) s(-1) and kEZ=3.14(5) s(-1) for NMAH, kZE=0.96(3) s(-1) and kEZ=0.10(2) s(-1) for NMA(-)] and activation barriers at 300 K [DeltaG(?)ZE=68.0 kJ mol(-1) and DeltaG(?)EZ=70.6 kJ mol(-1) for NMAH, DeltaG(?)ZE=73.6 kJ mol(-1) and DeltaG(?)EZ=79.2 kJ mol(-1) for NMA(-)]. For the first time, mono- and bis chelated uranium(VI) complexes of NMA(-) have been isolated. Crystals of [UO2(NMA)(NO3)(H2O)2] and [UO2(NMA)2(H2O)] have been characterized by X-ray diffractometry, infrared and Raman spectroscopies. PMID- 26116425 TI - Efficacy of erdosteine 900 versus 600 mg/day in reducing oxidative stress in patients with COPD exacerbations: Results of a double blind, placebo-controlled trial. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased airway and systemic inflammation. There is evidence that erdosteine accelerates recovery from AECOPD by reducing airway inflammation. AIM: To investigate the dose-dependent antioxidant/anti-inflammatory activity of erdosteine in COPD patients. METHODS: In this single-centre, double blind, double dummy study, patients with mild-to-moderate COPD (GOLD stage II-III), were randomised to receive either placebo or two dosages of oral erdosteine (300 mg tid or 300 mg bid + 1 capsule of indistinguishable placebo) for 28 days in addition to their standard treatment. Primary variables were plasma reactive oxygen species (ROS) and 8-isoprostane levels, while secondary variable was lung function (FEV1; FEV1/FVC; FEV1 short-term reversibility), all assessed in baseline; every two weeks during the study, and one week after the end of the study. RESULTS: Baseline demographic characteristics, plasma ROS and 8 isoprostane levels and lung function were not significantly different in the 24 eligible patients (14 males, aged 38-75 years). At 2 weeks, there was a dose dependent decrease in ROS in the erdosteine groups. By week 4 there were significant differences in ROS levels compared to baseline between patients receiving 900 mg/day (p < 0.003) and those receiving 600 mg/day (p < 0.04). This effect continued in the follow-up week (p < 0.021). Erdosteine also lowered 8 isoprostane plasma levels after 4 weeks (p < 0.01), and this effect lasted over the post-treatment week. Moreover, % FEV1 reversibility after salbutamol 400 mcg obtained after a 4 -week treatment of erdosteine 900 mg/day was significantly higher than that obtained after 600 mg/day (p < 0.01). Erdosteine was well tolerated and no treatment-related adverse event was reported. CONCLUSIONS: Results confirm the antioxidant dose- and time-dependent activity of erdosteine, and support the utility of including erdosteine it in the therapeutic strategy for the prevention and treatment of oxidative stress-induced inflammation, which frequently leads to AECOPD occurrence. PMID- 26116426 TI - Renal Dietitians' Perceptions of Roles and Responsibilities in Outpatient Dialysis Facilities. AB - OBJECTIVE: This study was designed to determine what job responsibilities renal dietitians working in outpatient dialysis facilities consider as most important and most time-consuming. We hypothesized that more time-consuming activities would not always be considered most important. DESIGN AND PARTICIPANTS: An online survey was sent to 3,382 renal dietitians via professional organization e-mail lists. The survey included 30 activities that renal dietitians perform, grouped into 3 categories (general responsibilities, assessments, and interventions) and based on the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative nutrition guidelines. For each category of activities, respondents were asked to rank the 10 activities from 1 (most important or time-consuming) to 10 (least important or time-consuming). For analysis, the rankings were combined into 3 groups: 1 to 3 = most; 4 to 6 = mid; and 7 to 10 = least important or time consuming. Demographic and professional questions were also included. RESULTS: Four hundred sixty six renal dietitians responded, and represented a broad range of experience in renal dietetics and type of dialysis facility. The mean number of patients per 40 hours full-time equivalent dietitian was 115.5 +/- 38.4. There was good agreement between the respondents' ranking of importance and time consumed. Those activities identified as most important were traditional dietitian roles such as diet assessment and nutrition education. Many respondents provided write-in response of other activities they considered important and time consuming such as communicating with family members or caregivers, enrolling and managing patients in the in-house pharmacy program, and serving as a care coordinator. CONCLUSIONS: It appears that the renal dietitian's role of providing nutrition assessments and counseling in outpatient dialysis facilities is being expanded to include administrative and coordination responsibilities. The impact of these changes on patient outcomes is unclear; however, previous research has indicated that administrative responsibilities take away from patient care time and decrease dietitian job satisfaction. PMID- 26116427 TI - Mathematical analysis of a multiple strain, multi-locus-allele system for antigenically variable infectious diseases revisited. AB - Many important pathogens such as HIV/AIDS, influenza, malaria, dengue and meningitis generally exist in phenotypically distinct serotypes that compete for hosts. Models used to study these diseases appear as meta-population systems. Herein, we revisit one of the multiple strain models that have been used to investigate the dynamics of infectious diseases with co-circulating serotypes or strains, and provide analytical results underlying the numerical investigations. In particular, we establish the necessary conditions for the local asymptotic stability of the steady states and for the existence of oscillatory behaviors via Hopf bifurcation. In addition, we show that the existence of discrete antigenic forms among pathogens can either fully or partially self-organize, where (i) strains exhibit no strain structures and coexist or (ii) antigenic variants sort into non-overlapping or minimally overlapping clusters that either undergo the principle of competitive exclusion exhibiting discrete strain structures, or co exist cyclically. PMID- 26116428 TI - A mathematical model of leptin resistance. AB - Obesity is often associated with leptin resistance, which leads to a physiological system with high leptin concentration but unable to respond to leptin signals and to regulate food intake. We propose a mathematical model of the leptin-leptin receptors system, based on the assumption that leptin is a regulator of its own receptor activity, and investigate its qualitative behavior. Based on current knowledge and previous models developed for body weight dynamics in rodents, the model includes the dynamics of leptin, leptin receptors and the regulation of food intake and body weight. It displays two stable equilibria, one representing a healthy state and the other one an obese and leptin resistant state. We show that a constant leptin injection can lead to leptin resistance and that a temporal variation in some parameter values influencing food intake can induce a change of equilibrium and a pathway to leptin resistance and obesity. PMID- 26116429 TI - A supervised adverse drug reaction signalling framework imitating Bradford Hill's causality considerations. AB - Big longitudinal observational medical data potentially hold a wealth of information and have been recognised as potential sources for gaining new drug safety knowledge. Unfortunately there are many complexities and underlying issues when analysing longitudinal observational data. Due to these complexities, existing methods for large-scale detection of negative side effects using observational data all tend to have issues distinguishing between association and causality. New methods that can better discriminate causal and non-causal relationships need to be developed to fully utilise the data. In this paper we propose using a set of causality considerations developed by the epidemiologist Bradford Hill as a basis for engineering features that enable the application of supervised learning for the problem of detecting negative side effects. The Bradford Hill considerations look at various perspectives of a drug and outcome relationship to determine whether it shows causal traits. We taught a classifier to find patterns within these perspectives and it learned to discriminate between association and causality. The novelty of this research is the combination of supervised learning and Bradford Hill's causality considerations to automate the Bradford Hill's causality assessment. We evaluated the framework on a drug safety gold standard known as the observational medical outcomes partnership's non specified association reference set. The methodology obtained excellent discrimination ability with area under the curves ranging between 0.792 and 0.940 (existing method optimal: 0.73) and a mean average precision of 0.640 (existing method optimal: 0.141). The proposed features can be calculated efficiently and be readily updated, making the framework suitable for big observational data. PMID- 26116430 TI - Association between information provision and decisional conflict in cancer patients. AB - BACKGROUND: In this study, we aimed to identify demographic and clinical variables that correlate with perceived information provision among cancer patients and determine the association of information provision with decisional conflict (DC). PATIENTS AND METHODS: We enrolled a total of 625 patients with cancer from two Korean hospitals in 2012. We used the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ INFO26) to assess patients' perception of the information received from their doctors and the Decisional Conflict Scale (DCS) to assess DC. To identify predictive sociodemographic and clinical variables for adequate information provision, backward selective logistic regression analyses were conducted. In addition, adjusted multivariate logistic regression analyses were carried out to identify clinically meaningful differences of perceived level of information subscales associated with high DC. RESULTS: More than half of patients with cancer showed insufficient satisfaction with medical information about disease (56%), treatment (73%), other services (83%), and global score (80%). In multiple logistic regression analyses, lower income and education, female, unmarried status, type of cancer with good prognosis, and early stage of treatment process were associated with patients' perception of inadequate information provision. In addition, Information about the medical tests with high DCS values clarity [adjusted odds ratio (aOR), 0.54; 95% confidence interval (CI) 0.30-0.97] and support (aOR, 0.53; 95% CI 0.33-0.85) showed negative significance. For inadequate information perception about treatments and other services, all 5 DCS scales (uncertainty, informed, values clarity, support, and effective decision) were negatively related. Global score of inadequate information provision also showed negative association with high DCS effective decision (aOR, 0.43; 95% CI 0.26-0.71) and DCS uncertainty (aOR, 0.46; 95% CI 0.27-0.77). CONCLUSION: This study found that inadequate levels of perceived information correlated with several demographic and clinical characteristics. In addition, sufficient perceived information levels may be related to low levels of DC. PMID- 26116431 TI - Influence of Ankle Position and Radiographic Projection Angle on Measurement of Supramalleolar Alignment on the Anteroposterior and Hindfoot Alignment Views. AB - BACKGROUND: Using digitally reconstructed radiographs (DRRs), we determined how changes in the x-ray beam projection angle from the horizon, tibiotalar joint angle, and axial rotation of the foot influenced measurements of the medial distal tibial angle (MDTA) on the anteroposterior (AP) and hindfoot alignment views (HAV). METHODS: Seven cadaver foot-ankle specimens were scanned by computed tomography (CT) at fixed tibiotalar joint positions, ranging from 15 degrees of dorsiflexion to 25 degrees of plantarflexion. DRRs were created from each CT scan to simulate alterations in the horizontal projection angle (0 to 25 degrees) and foot axial rotation (-30 to 30 degrees). The MDTA was measured on each DRR and compared with that quantified on the baseline HAV and AP view. RESULTS: Altering the horizontal projection angle by >=5 degrees and >10 degrees significantly altered the MDTA for the AP view and the HAV, respectively. Shifting dorsiflexion and plantarflexion caused minor changes in the MDTA that were only statistically significant for the HAV. Axial rotation significantly changed the MDTA on both views, but deviations were more pronounced for the HAV. CONCLUSIONS: Compared with the HAV, the MDTA on the AP view was less sensitive to changes in foot-ankle position. However, increasing the tilt of the x-ray beam from the horizon altered the MDTA on the AP view substantially. CLINICAL RELEVANCE: To avoid misinterpretation of the MDTA, we recommend using the AP view to quantify supramalleolar alignment as it is less sensitive to changes in positioning of the foot-ankle. When acquiring an AP film, the x-ray beam should be directed along the horizon to ensure consistent assessment of the MDTA across patients. PMID- 26116432 TI - Healthcare service providers' and facility administrators' perspectives of the free maternal healthcare services policy in Malindi District, Kenya: a qualitative study. AB - BACKGROUND: Globally, there are increasing efforts to improve maternal health outcomes including the reduction in maternal mortality rates. Improved access to skilled care utilisation during pregnancy and delivery has been one of the strategies employed to improve maternal health outcomes. In Kenya, more than half of the women deliver without the assistance of a skilled attendant and this has contributed to high maternal mortality rates. The free maternal healthcare services policy in all public facilities was initiated as a strategy to improve access to skilled care and reduce poor maternal health outcomes. This study aimed to explore the perspectives of the service providers and facility administrators of the free maternal health care service policy that was introduced in Kenya in 2013. METHODS: A qualitative inquiry using semi-structured one-on-one interviews was conducted in Malindi District, Kenya. The participants included maternal health service providers and facility administrators recruited from five different healthcare facilities. Data were analysed using a thematic framework analysis. RESULTS: Free maternal healthcare service provision was perceived to boost skilled care utilisation during pregnancy and delivery. However, challenges including; delays in the reimbursement of funds by the government to the facilities, stock outs of essential commodities in the facilities to facilitate service provision, increased workload amidst staff shortage and lack of consultation and sensitisation of key stakeholders were perceived as barriers to effective implementation of this policy. CONCLUSION: Free maternal healthcare services can be one of the strategies to improve a range of maternal health outcomes. However, the implementation of this policy would be more effective if; the healthcare facilities were upgraded, equipped with adequate supplies, funds and staff; the community are continually sensitized on the importance of seeking skilled care during pregnancy and delivery; and inclusivity and collaboration with other key stakeholders be fostered in addressing poor maternal health outcomes in the country. PMID- 26116433 TI - Formation of an ordered phase by ceramides and diacylglycerols in a fluid phosphatidylcholine bilayer--Correlation with structure and hydrogen bonding capacity. AB - Ceramides and diacylglycerols are lipids with a large hydrophobic part (acyl chains and long-chain base) whereas their polar function (hydroxyl group) is small. They need colipids with large head groups to coexist in bilayer membranes. In this study, we have determined how saturated and unsaturated ceramides and acyl-chain matched diacylglycerols form ordered domains in 1-palmitoyl-2-oleoyl sn-glycero-3-phosphocholine bilayers as a function of bilayer concentration. The formation of ordered domains was determined from lifetime analysis of trans parinaric acid. Ceramides formed ordered domains with equal average tPA lifetime at lower bilayer concentration when compared to acyl-chain matched diacylglycerols. This was true for both saturated (16:0) and mono-unsaturated (18:1) species. This finding suggested that hydrogen bonding among ceramides contributed to their more efficient ordered phase formation, since diacylglycerols do not form similar hydrogen bonding networks. The role of hydrogen bonding in ordered domain formation was further verified by using palmitoyl ceramide analogs with 2N and 3OH methylated long-chain bases. These analogs do not form hydrogen bonds from the 2NH or the 3OH, respectively. While methylation of the 3OH did not affect ordered phase formation compared to native palmitoyl ceramide, 2NH methylation markedly attenuated ceramide ordered phase formation. We conclude that in addition to acyl chain length, saturation, molecular order, and lack of large head group, also hydrogen bonding involving the 2NH is crucial for efficient formation of ceramide-rich domains in fluid phosphatidylcholine bilayers. PMID- 26116434 TI - Diabetes, hypertension and mobility among Brazilian older adults: findings from the Brazilian National Household Sample Survey (1998, 2003 and 2008). AB - BACKGROUND: The rapid population ageing has been accompanied by a growing number of older adults experiencing chronic conditions, especially diabetes and hypertension, which are conditions associated to the decline in physical functioning. The aim of this study was to investigate changes in the strength of the association between mobility and two chronic conditions (hypertension and diabetes) in a large representative sample of Brazilian older adults over a ten year period. METHODS: The data came from the Brazilian National Household Sample Survey (PNAD) of 1998, 2003 and 2008. The sample comprised 28,943 participants aged 60 years and older investigated in 1998, 35,042 in 2003 and 41,269 in 2008, totalling 105,254 older adults. The dependent variable was the physical mobility index (PMI) constructed based on the Item Response Theory (IRT) using five physical mobility indicators. The chronic conditions were self-reported and the confounders included: age, sex, schooling, ethnicity, family income, household composition, other co-morbidities and use of health services. The association between physical mobility (three different groups) and chronic conditions (hypertension and diabetes) was performed using multinomial logistic regression. RESULTS: Over the ten year period the prevalence of hypertension increased from 44 % (1998), 49 % (2003) to 53 % (2008) (p < 0.001). Similar pattern was observed for the prevalence of diabetes: 10 % in 1998, 13 % in 2003 and 16 % in 2008 (p < 0.001). Overall, physical mobility showed a statistical significant association with both chronic diseases studied even after adjusting for potential confounders. The time-disease interaction term was significant (p < 0.05) for the two chronic conditions studied, and the strength of the associations decreased over the first five years, but it was not sustained between 2003 and 2008. CONCLUSIONS: Despite the increases observed in the prevalence of the hypertension and diabetes over the ten year period, the decrease in strength of the association with physical mobility during the first period could be explained by improvements in health services and treatment of older adults. Special attention should be given to the treatment and management of diabetes in order to avoid declines in physical mobility levels. PMID- 26116435 TI - Therapeutic implications of the choroid plexus-cerebrospinal fluid interface in neuropsychiatric disorders. AB - The choroid plexus (CP) comprises an epithelial monolayer that forms an important physical, enzymatic and immunologic barrier, called the blood-cerebrospinal fluid barrier (BCSFB). It is a highly vascularized organ located in the brain ventricles that is key in maintaining brain homeostasis as it produces cerebrospinal fluid (CSF) and has other important secretory functions. Furthermore, the CP-CSF interface plays a putative role in neurogenesis and has been implicated in neuropsychiatric diseases such as the neurodevelopmental disorders schizophrenia and autism. A role for this CNS border was also implicated in sleep disturbances and chronic and/or severe stress, which are risk factors for the development of neuropsychiatric conditions. Understanding the mechanisms by which disturbance of the homeostasis at the CP-CSF interface is involved in these different chronic low-grade inflammatory diseases can give new insights into therapeutic strategies. Hence, this review discusses the different roles that have been suggested so far for the CP in these neuropsychiatric disorders, with special attention to potential therapeutic applications. PMID- 26116436 TI - Mind-body therapies and control of inflammatory biology: A descriptive review. AB - The use of mind-body therapies, including Tai Chi, Qigong, yoga, and meditation, has grown steadily in recent years. These approaches have been shown to be effective in reducing symptoms and improving quality of life, and research has begun to examine the impact of these therapies on biological processes, including inflammation. A review of 26 randomized controlled trials was conducted to describe the effects of mind-body therapies (MBTs) on circulating, cellular, and genomic markers of inflammation. This qualitative evaluation showed mixed effects of MBTs on circulating inflammatory markers, including CRP and IL-6, and on measures of stimulated cytokine production. More consistent findings were seen for genomic markers, with trials showing decreased expression of inflammation related genes and reduced signaling through the proinflammatory transcription factor NF-kappaB. Potential mechanisms for these effects are discussed, including alterations in neuroendocrine, neural, and psychological and behavioral processes. PMID- 26116437 TI - Rubella outbreak in a Rural Kenyan District, 2014: documenting the need for routine rubella immunization in Kenya. AB - BACKGROUND: Rubella infection has been identified as a leading cause of birth defects commonly known as Congenital Rubella Syndrome (CRS). Kenya does not currently have a rubella immunization program nor a CRS surveillance system. In 2014, a rubella outbreak was reported in a rural district in Kenya. We investigated the outbreak to determine its magnitude and describe the outbreak in time, place and person. We also analyzed the laboratory-confirmed rubella cases from 2010 to 2014 to understand the burden of the disease in the country. METHODS: The Rubella outbreak was detected using the case-based measles surveillance system. A suspected case was a person with generalized rash and fever while a confirmed case was a person who tested positive for rubella IgM. All laboratory-confirmed and epidemiologically linked cases were line listed. The measles case-based surveillance database was used to identify rubella cases from 2010 to 2014. RESULTS: A total of 125 rubella cases were line listed. Fifty four percent of cases were female. Case age ranged from 3 months to 32 years with a median of 4 years. Fifty-one percent were aged less than 5 years, while 82 % were aged less than 10 years. Six percent of the cases were women of reproductive age. All cases were treated as outpatients and there were no deaths. The number of confirmed rubella cases was 473 in 2010, 604 in 2011, 300 in 2012, 336 in 2013 and 646 in 2014. CONCLUSIONS: Analysis of Kenya rubella data shows that rubella is endemic throughout the country, and many outbreaks may be underestimated or undocumented. Six percent of all the cases in this outbreak were women of reproductive age indicating that the threat of CRS is real. The country should consider initiating a CRS surveillance system to quantify the burden with the goal of introducing rubella vaccine in the future. PMID- 26116438 TI - Evaluation of the Effect of Modafinil on Cognitive Functions in Patients with Idiopathic Hypersomnia with P300. AB - BACKGROUND: Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy and other excessive sleepiness. Whereas favorable effects of modafinil on cognitive functions have been shown in a large number of studies, there are very few reports presenting the effects of modafinil electrophysiologically. The aim of this study was to investigate the effects of modafinil on auditory P300 latency and amplitude electrophysiologically. MATERIAL AND METHODS: Eighteen patients (age range: 16-48 years) with a diagnosis of idiopathic hypersomnia (IH) were included in the present study. As a standard treatment, 200 mg/day modafinil was administered to each patient. The P300 auditory test was performed for each patient before and at the end of 1 week of modafinil treatment. RESULTS: After 1 week of modafinil treatment, mean P300 latencies (at all electrode sites) were significantly lower than the latencies before the treatment (P values for Fz, Cz and Pz recording sites were 0.039, 0.002, and 0.004, respectively). An increase in the P300 amplitudes was detected only at the Fz recording site, but not at Cz or Pz recording sites (P values for Fz, Cz, and Pz recording sites were 0.014, 0.100, and 0.05, respectively). CONCLUSIONS: One week of modafinil treatment improved the cognitive performance, alertness, and executive functions in IH patients. Our electrophysiologically obtained findings provide further confirmation for previous reports in which modafinil has been shown to exert favorable effects on cognitive performance, alertness, and executive functions. PMID- 26116439 TI - The antidepressant-like activity of nicotine, but not of 3-furan-2-yl-N-p-tolyl acrylamide, is regulated by the nicotinic receptor beta4 subunit. AB - The current study compares the antidepressant-like effect elicited by nicotine between wild-type (beta4+/+) and knockout (beta4-/-) mice, and subsequently, the effect of 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a positive allosteric modulator of alpha7 nicotinic receptors, on the previously determined activity of nicotine. Mice from each sex were injected daily with nicotine base (0.2 mg/kg; s.c.) or co-administered with PAM-2 (1.0 mg/kg; i.p.) for 3 weeks. Forced swim tests were performed to determine the acute (day 1), subchronic (day 7), and chronic (days 14 and 21) effects of the drugs, as well as their residual effects after treatment cessation (days 28 and 35). Our results indicate that nicotine mediates antidepressant-like activity after acute, subchronic, and chronic treatments in beta4+/+, but not beta4-/-, mice, and that these effects are not mediated by unspecific locomotor stimulation. Nicotine co-administered with PAM-2 produces antidepressant-like activity in both beta4+/+ and beta4-/- mice, except after the acute treatment of beta4-/- mice, and decreases locomotor activity. This suggests that although the beta4 subunit regulates the antidepressant-like activity of nicotine it does not affect the activity elicited by PAM-2 when is co administered with nicotine. The residual antidepressant-like activity of PAM-2 + nicotine was observed only in female mice, suggesting gender-specific differences. Our findings clearly indicate that beta4-containing nAChRs play an important role in the antidepressant-like activity elicited by nicotine but they are not essential for the modulatory activity of PAM-2. In fact, PAM-2 inhibits alpha4beta4 and alpha3beta4 AChRs at higher concentration ranges compared to that for the PAM activity previously found at the alpha7 AChR. PMID- 26116440 TI - Suppression of mitochondrial fission in experimental cerebral ischemia: The potential neuroprotective target of p38 MAPK inhibition. AB - In the present study, we investigated the neuroprotective role of p38 inhibition on experimental stroke in rats. p38 inhibition treatment alleviated the brain infarction volume and neurological deficits following ischemia, promoted the activation of Extracellular signal-regulated kinases (ERK1/2), suppressed the activation of Glycogen synthase kinase 3 beta (GSK3b). Application of two p38 inhibitors, both SB239063 and Losmapimod could down-regulate DLP1 and MFF, which were involved in mitochondrial fission and fragmentation. Losmapimod application progressively suppressed DLP1/MFF from 6 h to 24 h after ischemia-reperfusion injury. SB239063 pretreatment further showed the suppression of DLP1/MFF, and up regulated the protein levels of p62 and Mitochondrial Complex I at 5 mg/kg dose. Our results suggested that inhibition of p38 MAPK attenuated mitochondrial fragmentation/mitophagy after ischemic attack. In conclusion, p38 inhibition treatment might promote cellular survival signaling pathways, attenuate mitochondrial autophagy to maintain mitochondrial contents. This study suggests a potential neuroprotective target of p38 inhibition via suppressing mitochondrial fragmentation/mitophagy in cerebral ischemic injury. PMID- 26116441 TI - Identification of key residues involved in the activation and signaling properties of dopamine D3 receptor. AB - The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function. Our results show that trans-8-OH-PBZI, but not cis-8-OH-PBZI, elicit the D3 receptor tolerance and SRT properties. We show that while both agonists require a subset of residues in the orthosteric binding site of D3 receptors for activation of the receptor, the ability of the two isomers to differentially induce tolerance and SRT is mediated by interactions with specific residues in the sixth transmembrane helix and third extracellular loop of the D3 receptor. We also show that unlike cis-8-OH-PBZI, which is a partial agonist at the dopamine D2S receptor and full agonist at dopamine D2L receptor, trans-8-OH PBZI is a full agonist at both D2S and D2L receptors. The different effect of the two isomers on D3 receptor signaling properties and D2S receptor activation correlated with differential effects of the isomers on agonist-induced mouse locomotor activity. The two isomers of 8-OH-PBZI represent novel pharmacological tools for in silico D3 and D2 receptor homology modeling and for determining the role of D3 receptor tolerance and SRT properties in signaling and behavior. PMID- 26116442 TI - Genome-wide identification and transcript profile of the whole cathepsin superfamily in the intertidal copepod Tigriopus japonicus. AB - Modulation of expression of cathepsins in innate immune response has previously been reported in mollusks and large crustaceans including crabs, lobsters, and shrimps in response to immune challenges. However, similar responses in copepods and the related cathepsin members remain under-investigated. To understand molecular and innate immune responses in the intertidal copepod Tigriopus japonicus, we identified the full spectra of cathepsin members (2 aspartyl proteases, 18 cysteine proteases, and 4 serine proteases) and also analyzed transcriptional expression of cathepsin (Tj-cathepsin) genes in developmental stages, lipopolysaccharide (LPS)- and two Vibrio species-exposed T. japonicus. The transcriptional levels of most Tj-cathepsin genes were highly increased during the molting transition from the nauplius to the copepodid stages. LPS treatment induced innate immune response via significant transcriptional increase of serine cathepsin (e.g., cathepsin As) members with induction of several cysteine cathepsin genes. However, Tj-aspartyl cathepsin E-like and a novel cysteine cathepsin were slightly reduced in response to LPS exposure. Interestingly, Vibrio species showed very low transcriptional sensitivity in the expression of entire cathepsins, while LPS induced several cathepsin gene involved primitive immune responses in T. japonicus. In this paper, we discuss how whole cathepsin expression profiling can be linked to host defense mechanism to better understand and uncover the underlying mechanism of copepods' innate immunity. PMID- 26116443 TI - The analysis of the acute phase response during the course of Trypanosoma carassii infection in the goldfish (Carassius auratus L.). AB - The expression of genes encoding the acute phase proteins (APP) during the course of Trypanasoma carassii infection in the goldfish was determined using quantitative PCR. Significant changes in the mRNA levels of ceruloplasmin (Cp), C reactive protein (CRP), transferrin (Tf), hemopexin (Hx) and serum amyloid A (SAA) were observed in the kidney, liver and spleen at various days post infection (dpi). Of the five acute phase protein genes examined, CRP and SAA exhibited the highest expression in the tissues during the acute infection. Cp and Tf were up-regulated throughout the acute course of infection in the liver. During the chronic phase of the infection, APP expression in the liver was similar to that in the non-infected control fish. At 7 dpi, Cp, Tf and Hx were down-regulated in the spleen, and Cp and Tf kidney, but their mRNA levels gradually returned to those of control non-infected fish. In contrast, during the chronic phase of the infection, there was an up-regulation of Cp, Hx and Tf in the spleen, and Tf and SAA in the kidney. The goldfish CRP was cloned and functionally characterized. CRP was differentially expressed in normal goldfish immune cells, with highest expression in monocytes and lowest expression in mature macrophages. A recombinant goldfish CRP (rgfCRP) was generated using prokaryotic expression. rgfCRP enhanced complement-mediated killing of trypanosomes in vitro, and the lysis increased after addition of immune serum. rgfCRP did not affect the production of reactive oxygen and nitrogen intermediates by monocytes and macrophages, respectively. PMID- 26116444 TI - Impact of an interprofessional shared decision-making and goal-setting decision aid for patients with diabetes on decisional conflict--study protocol for a randomized controlled trial. AB - BACKGROUND: Competing health concerns present real obstacles to people living with diabetes and other chronic diseases as well as to their primary care providers. Guideline implementation interventions rarely acknowledge this, leaving both patients and providers feeling overwhelmed by the volume of recommended actions. Interprofessional (IP) shared decision-making (SDM) with the use of decision aids may help to set treatment priorities. We developed an evidence-based SDM intervention for patients with diabetes and other conditions that was framed by the IP-SDM model and followed a user-centered approach. Our objective in the present study is to pilot an IP-SDM and goal-setting toolkit following the Knowledge-to-Action Framework to assess (1) intervention fidelity and the feasibility of conducting a larger trial and (2) impact on decisional conflict, diabetes distress, health-related quality of life and patient assessment of chronic illness care. METHODS/DESIGN: A two-step, parallel-group, clustered randomized controlled trial (RCT) will be conducted, with the primary goal being to assess intervention fidelity and the feasibility of conducting a larger RCT. The first step is a provider-directed implementation only; the second (after a 6-month delay) involves both provider- and patient-directed implementation. Half of the clusters will be assigned to receive the IP-SDM toolkit, and the other will be assigned to be mailed a diabetes guidelines summary. Individual interviews with patients, their family members and health care providers will be conducted upon trial completion to explore toolkit use. A secondary purpose of this trial is to gather estimates of the toolkit's impact on decisional conflict. Secondary outcomes include diabetes distress, quality of life and chronic illness care, which will be assessed on the basis of patient completed questionnaires of validated scales at baseline and at 6 and 12 months. Multilevel hierarchical regression models will be used to account for the clustered nature of the data. DISCUSSION: An individualized approach to patients with multiple chronic conditions using SDM and goal setting is a desirable strategy for achieving guideline-concordant treatment in a patient-centered fashion. Our pilot trial will provide insights regarding strategies for the routine implementation of such interventions in clinical practice, and it will offer an assessment of the impact of this approach. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02379078. Date of Registration: 11 February 2015. PMID- 26116445 TI - Integrated hollow fiber membranes for gas delivery into optical waveguide based photobioreactors. AB - Compact algal reactors are presented with: (1) closely stacked layers of waveguides to decrease light-path to enable larger optimal light-zones; (2) waveguides containing scatterers to uniformly distribute light; and (3) hollow fiber membranes to reduce energy required for gas transfer. The reactors are optimized by characterizing the aeration of different gases through hollow fiber membranes and characterizing light intensities at different culture densities. Close to 65% improvement in plateau peak productivities was achieved under low light-intensity growth experiments while maintaining 90% average/peak productivity output during 7-h light cycles. With associated mixing costs of ~ 1 mW/L, several magnitudes smaller than closed photobioreactors, a twofold increase is realized in growth ramp rates with carbonated gas streams under high light intensities, and close to 20% output improvement across light intensities in reactors loaded with high density cultures. PMID- 26116446 TI - Metals removal and recovery in bioelectrochemical systems: A review. AB - Metal laden wastes and contamination pose a threat to ecosystem well being and human health. Metal containing waste streams are also a valuable resource for recovery of precious and scarce elements. Although biological methods are inexpensive and effective for treating metal wastewaters and in situ bioremediation of metal(loid) contamination, little progress has been made towards metal(loid) recovery. Bioelectrochemical systems are emerging as a new technology platform for removal and recovery of metal ions from metallurgical wastes, process streams and wastewaters. Biodegradation of organic matter by electroactive biofilms at the anode has been successfully coupled to cathodic reduction of metal ions. Until now, leaching of Co(II) from LiCoO2 particles, and removal of metal ions i.e. Co(III/II), Cr(VI), Cu(II), Hg(II), Ag(I), Se(IV), and Cd(II) from aqueous solutions has been demonstrated. This article reviews the state of art research of bioelectrochemical systems for removal and recovery of metal(loid) ions and pertaining removal mechanisms. PMID- 26116447 TI - The development of catalytic performance by coating Pt-Ni on CMI7000 membrane as a cathode of a microbial fuel cell. AB - Performance of cathode materials in microbial fuel cell (MFC) from dairy wastewater has been investigated in laboratory tests. Both cyclic voltammogram experiments and MFC tests showed that Pt-Ni cathode much better than pure Pt cathode. MFC with platinum cathode had the maximum power density of 0.180 W m(-2) while MFC with Pt:Ni (1:1) cathode produced the maximum power density of 0.637 W m(-2), even if the mass mixing ratio of Pt is lower in the alloy were used. The highest chemical oxygen demand (COD) removal efficiency was around 82-86% in both systems. The cyclic voltammogram (CV) analyses show that Pt:Ni (1:1) offers higher specific surface area than Pt alone does. X-ray diffraction (XRD) and Scanning Electron Microscopy (SEM) results showed that entire Pt:Ni (1:1) alloys can reduce the oxygen easily than pure platinum, even though less precious metal amount. The main outcome of this study is that Pt-Ni, may serve as a alternative catalyst in MFC applications. PMID- 26116448 TI - Riboflavin crosslinked high-density collagen gel for the repair of annular defects in intervertebral discs: An in vivo study. AB - Open annular defects compromise the ability of the annulus fibrosus to contain nuclear tissue in the disc space, and therefore lead to disc herniation with subsequent degenerative changes to the entire intervertebral disc. This study reports the use of riboflavin crosslinked high-density collagen gel for the repair of annular defects in a needle-punctured rat-tail model. High-density collagen has increased stiffness and greater hydraulic permeability than conventional low-density gels; riboflavin crosslinking further increases these properties. This study found that treating annular defects with crosslinked high density collagen inhibited the progression of disc degeneration over 18 weeks compared to untreated control discs. Histological sections of FITC-labeled collagen gel revealed an early tight attachment to host annular tissue. The gel was subsequently infiltrated by host fibroblasts which remodeled it into a fibrous cap that bridged the outer disrupted annular fibers and partially repaired the defect. This repair tissue enhanced retention of nucleus pulposus tissue, maintained physiological disc hydration, and preserved hydraulic permeability, according to MRI, histological, and mechanical assessments. Degenerative changes were partially reversed in treated discs, as indicated by an increase in nucleus pulposus size and hydration between weeks 5 and 18. The collagen gel appeared to work as an instant sealant and by enhancing the intrinsic healing capabilities of the host tissue. PMID- 26116449 TI - Tumor necrosis factor-mediated downregulation of spinal astrocytic connexin43 leads to increased glutamatergic neurotransmission and neuropathic pain in mice. AB - Spinal cord astrocytes are critical in the maintenance of neuropathic pain. Connexin 43 (Cx43) expressed on spinal dorsal horn astrocytes modulates synaptic neurotransmission, but its role in nociceptive transduction has yet to be fully elaborated. In mice, Cx43 is mainly expressed in astrocytes, not neurons or microglia, in the spinal dorsal horn. Hind paw mechanical hypersensitivity was observed beginning 3days after partial sciatic nerve ligation (PSNL), but a persistent downregulation of astrocytic Cx43 in ipsilateral lumbar spinal dorsal horn was not observed until 7days post-PSNL, suggesting that Cx43 downregulation mediates the maintenance and not the initiation of nerve injury-induced hypersensitivity. Downregulation of Cx43 expression by intrathecal treatment with Cx43 siRNA also induced mechanical hypersensitivity. Conversely, restoring Cx43 by an adenovirus vector expressing Cx43 (Ad-Cx43) ameliorated PSNL-induced mechanical hypersensitivity. The sensitized state following PSNL is likely maintained by dysfunctional glutamatergic neurotransmission, as Cx43 siRNA induced mechanical hypersensitivity was attenuated with intrathecal treatment of glutamate receptor antagonists MK801 and CNQX, but not neurokinin-1 receptor antagonist CP96345 or the Ca(2+) channel subunit alpha2delta1 blocker gabapentin. The source of this dysfunctional glutamatergic neurotransmission is likely decreased clearance of glutamate from the synapse rather than increased glutamate release into the synapse. Astrocytic expression of glutamate transporter GLT-1, but not GLAST, and activity of glutamate transport were markedly decreased in mice intrathecally injected with Cx43-targeting siRNA but not non-targeting siRNA. Glutamate release from spinal synaptosomes prepared from mice treated with either Cx43-targeting siRNA or non-targeting siRNA was unchanged. Intrathecal injection of Ad-Cx43 in PSNL mice restored astrocytic GLT-1 expression. The cytokine tumor necrosis factor (TNF) has been implicated in the induction of central sensitization, particularly through its actions on astrocytes, in the spinal cord following peripheral injury. Intrathecal injection of TNF in naive mice induced the downregulation of both Cx43 and GLT-1 in spinal dorsal horn, as well as hind paw mechanical hypersensitivity, as observed in PSNL mice. Conversely, intrathecal treatment of PSNL mice with the TNF inhibitor etanercept prevented not only mechanical hypersensitivity but also the downregulation of Cx43 and GLT-1 expression in astrocytes. The current findings indicate that spinal astrocytic Cx43 are essential for the maintenance of neuropathic pain following peripheral nerve injury and suggest modulation of Cx43 as a novel target for developing analgesics for neuropathic pain. PMID- 26116450 TI - Hypermethylation of the HLA-G promoter is associated with preeclampsia. AB - Preeclampsia (PE) is a severe pregnancy-induced disorder characterized by hypertension and proteinuria and a leading cause of perinatal maternal-fetal mortality and morbidity in developing countries. Dysregulated human leukocyte antigen (HLA)-G was found in placentas as well as in maternal sera from PE patients; however, the reason for this difference is unknown. As accumulating evidence has confirmed that DNA methylation is an important mechanism for regulating gene expression, we sought to test the hypothesis that alteration in the DNA methylation of the HLA-G promoter region is responsible for decreased expression of HLA-G in PE. Bisulfite pyrosequencing showed that a series of CpG sites in the HLA-G promoter region were significantly more highly methylated in PE than in normal pregnancy (NP). Interestingly, the hypermethylated CpG sites were mostly reported to be binding sites of active transcription factors. To further investigate the regulation of HLA-G methylation, we also defined the expression patterns of DNA methyltransferases (DNMTs) in placental tissue using immunohistochemistry and quantitative polymerase chain reaction analyses. Here, we demonstrate that DNMT-1 is overexpressed and HLA-G expression is reduced in PE women when compared with NP. Furthermore, both treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine and specific knockdown of DNMT-1 using siRNAs can significantly increase the expression level of HLA-G in a trophoblastic cell line, indicating the potential mechanism of DNMT-1-mediated DNA methylation in HLA-G regulation. Taken together, our research confirms that DNMT-1-mediated promoter hypermethylation of HLA-G is associated with PE. These findings provide new insights into the diagnosis and treatment of PE. PMID- 26116451 TI - Functional disparity between human PAWP and PLCzeta in the generation of Ca2+ oscillations for oocyte activation. AB - Mammalian oocyte activation is mediated by cytosolic calcium (Ca(2+)) oscillations initiated upon delivery of a putative 'sperm factor' by the fertilizing sperm. Previous studies suggest the identity of this sperm factor as the testis-specific phospholipase C-zeta (PLCzeta). Recently, a post-acrosomal sheath WW domain-binding protein (PAWP) has been proposed as an alternative sperm factor candidate, following a report that human PAWP protein and cRNA elicited Ca(2+) oscillations in mouse and human oocytes. Those Ca(2+) oscillations were inhibited by a PAWP-derived peptide corresponding to a functional PPGY binding motif. Herein, using a series of human PAWP expression constructs, we demonstrate that both human PAWP protein and cRNA are, in our experiments, unable to elicit Ca(2+) release following microinjection into mouse oocytes. Parallel experiments performed with human PLCzeta elicited the characteristic Ca(2+) oscillations present at mammalian fertilization, which produced oocyte activation and embryo development. Furthermore, sperm-induced Ca(2+) oscillations were not inhibited by the PAWP-derived PPGY peptide following in vitro fertilization or intracytoplasmic sperm injection. Thus, the functional disparity with PLCzeta leads us to conclude that human PAWP is neither sufficient nor necessary for the Ca(2+) oscillations that initiate mammalian oocyte activation at fertilization. PMID- 26116452 TI - Establishing molecular microbiology facilities in developing countries. AB - Microbiology laboratories play an important role in epidemiology and infection control programs. Within microbiology laboratories, molecular microbiology techniques have revolutionized the identification and surveillance of infectious diseases. The combination of excellent sensitivity, specificity, low contamination levels and speed has made molecular techniques appealing methods for the diagnosis of many infectious diseases. In a well-equipped microbiology laboratory, the facility designated for molecular techniques remains indiscrete. However, in most developing countries, poor infrastructure and laboratory mismanagement have precipitated hazardous consequences. The establishment of a molecular microbiology facility within a microbiology laboratory remains fragmented. A high-quality laboratory should include both conventional microbiology methods and molecular microbiology techniques for exceptional performance. Furthermore, it should include appropriate laboratory administration, a well-designed facility, laboratory procedure standardization, a waste management system, a code of practice, equipment installation and laboratory personnel training. This manuscript lays out fundamental issues that need to be addressed when establishing a molecular microbiology facility in developing countries. PMID- 26116453 TI - Diffusion and transmission of carbapenem-resistant Klebsiella pneumoniae in the medical and surgical wards of a university hospital in Milan, Italy. AB - Carbapenem-resistant Klebsiella pneumoniae (CRKP) is emerging as a public health problem worldwide. In Italy, a remarkable increase in CRKP cases has been reported since 2010. In this study, CRKP diffusion, distribution and in-hospital transmission trends were evaluated in a university hospital in Milan, Italy, from January 2012 to December 2013. Isolates from 63 newly detected CRKP-positive patients were genotyped, and possible transmission was determined by combining the molecular results with data concerning the patients' admission and in hospital transfers. Most of the cases (90.4%) were from general medical and surgery wards, and the remaining 9.6% were from the intensive care unit. Fifteen of the 46 hospital-associated cases (32.6%) were attributable to in-hospital transmission. After the introduction of targeted and hospital-wide control measures, the transmission index significantly decreased from 0.65 to 0.13 (p=0.01). There was also a decrease in the overall nosocomial case incidence, from 0.37 to 0.17 per 1000 person-days (p=0.07). Our findings indicate that the spread of CRKP in Northern Italy hospitals may go far beyond high-risk settings (i.e., intensive care units) and that strict surveillance should be extended to general areas of care. PMID- 26116454 TI - In vitro antimicrobial synergy studies of carbapenem-resistant Acinetobacter baumannii isolated from intensive care units of a tertiary care hospital in Egypt. AB - The increasing prevalence of multidrug-resistant and pan drug-resistant Acinetobacter baumannii as a cause of nosocomial infections has led to the need for the reassessment of novel combinations of antibiotics as our only current viable option for handling such infections until a new therapeutic option becomes available. Two of the most commonly used methods for testing antimicrobial synergy are the Time-kill assay method and the E-test method, and these were the methods used in this study. Antibiotic combinations tested in this study were azithromycin and polymyxin, tobramycin and polymyxin, polymyxin and rifampicin, and tobramycin and rifampicin. The azithromycin and polymyxin combination showed synergy, while the rifampicin and polymyxin combination showed antagonism. The synergy was achieved at lower MIC values than using each of the single agents alone against the same isolates. Synergy testing results varied according to the method used, and it is difficult to establish which method is more accurate. The use of these lower MIC values as a guide to determine effective therapeutic doses used in combination therapy can help to decrease the emergence of resistance and can also minimize the side effects associated with using a single agent at a higher dose. Further research is still required to predict in vivo efficacy of such combinations. PMID- 26116455 TI - Experimental cerebral and non-cerebral coenurosis in goats: A comparative study on the morphological and molecular characteristics of the parasite. AB - This experimental study was conducted to test whether cerebral and non-cerebral forms of Coenurus cerebralis belong to one origin or they are originated from two different tape worms. In the first step of the study, two groups of dogs were orally infected with the protoscoleces of cerebral and non-cerebral cysts and four months after infection, the adult worms were collected and morphologically characterized. Then the obtained eggs from two groups of adult worms were orally inoculated to two groups of goats to trace the predilection sites and also to compare the morphological and molecular characteristics of the larval stage of the parasites. The results showed that, both cerebral and non-cerebral coenuri, produced morphologically similar worms in the experimentally infected dogs. We observed only non-cerebral coenurus cysts in two groups of experimentally infected goats and the morphological characteristics of the cysts of two different groups were also similar. The molecular findings also showed that the cysts of two groups were 100% identical to each other based on the CO1 and nad1 sequences. In conclusion, our morphological and molecular findings reinforce the evidence that Taenia multiceps is the single origin of both cerebral and non cerebral form of C. cerebralis but in goats, the cysts show more tendency to non cerebral organs. PMID- 26116456 TI - Serological cross-reactivity of three commercial in-house immunoassays for detection of Dirofilaria immitis antigens with Spirocerca lupi in dogs with benign esophageal spirocercosis. AB - The nematode Spirocerca lupi infects dogs and is endemic in Israel. It leads to formation of esophageal nodules and neoplasia. Infection is diagnosed by coproscopy, endoscopy and radiography. Dirofilaria immitis causes heartworm disease in dogs, and has a world-wide distribution, but autochthonous infection has never been detected in Israel. Infection is confirmed based on identifying D. immitis microfilariae, in concentrated blood specimens by microscopy (Knott's test or other tests) and serological tests specifically detecting circulating adult worm antigens. In the first part of this study, sera from dogs definitively diagnosed with esophageal spirocercosis by endoscopy were examined using three in house immunoassays for detecting D. immitis antigen, and were positive in 2/19 (10.5%), 5/35 (14.3%) and 14/48 (29.2%) dogs, in assays 1 to 3, respectively, with no statistical difference between assays (P=0.08). Next, sera from 32 additional dogs with confirmed esophageal spirocercosis, which were confirmed to be negative for D. immitis and Dirofilaria repens DNA using a sensitive high resolution melt PCR were tested using assay 3 and 8/32 (25%) were positive. These results demonstrate serological cross-reactivity between D. immitis and S. lupi in blood samples of dogs. In areas where the distributions of both nematodes overlap, this cross-reactivity should be considered when dog are screened for heartworm disease. PMID- 26116457 TI - Abattoir based surveillance of cystic echinococcosis (CE) in the Sultanate of Oman during 2010-2013. AB - A passive surveillance was conducted in 8 selected abattoirs belonging to 8 governorates of Oman. Routine slaughtering of 282.020 animals was observed during 2010-2013 by duty veterinarians and suspected samples (n=1440) for cystic echinococcosis (CE) from camels (n=292), cattle (n=303), goats (n=682) and sheep (n=163) were collected. In total, 587 (40.8%) samples were found positive for CE and the highest percentage (64.2%) of positive samples belonged to Dhofar (Salalah) as compared to other governorates, p<0.01. The infection rate of CE was calculated as 5.3, 0.6, 0.07 and 0.03 in camel, cattle, sheep and goats respectively. Fertile cysts were found in 30.7% of positive samples and camels (52%) were found as major source of these followed by cattle (14.1%) and goats (9.7%). Percentage of positive to submitted samples was higher in females (67.9%) than males (29.8%). The fertility of cyst increased with age and the highest percentage of fertile cysts were collected from animals above 5 years of age (54.4%) followed by between 3 and 5 years (36.7%) and below 3 years of age (8.9%). For different breeds, 478 (62.7%) samples from local breeds of livestock were positive for CE as compared to 108 (15.9%) from imported animals (OR 8.92), p<0.01. The highest percent of positive samples was observed in cysts from lungs (54.4%) followed by those from liver (25.7%), liver and lungs (14.1%) and others (3.8%). Molecular investigations indicated that G1 and G6/7 were the two strains of CE circulating in camels and cattle while G1 was the only strain found in samples from small ruminants. Results indicated that CE is endemic in the livestock of Oman and further molecular epidemiological work in different host species is required for the conceptualization of a comprehensive control program. PMID- 26116458 TI - Association between plasma adiponectin and arteriolar vessel caliber among elderly hypertensive subjects. AB - Circulating adiponectin has been related to vascular diseases, but few studies examined the relationship between plasma adiponectin and microvascular abnormalities among hypertensive individuals. We tested the association between plasma adiponectin level and retinal vessel calibers in patients with hypertension.This study included 172 patients with confirmed hypertension, aged 18-80 years. Subjects with recent cardiovascular events, advanced heart failure and end-stage renal disease were excluded. Arteriolar and venular calibers were measured in retinographies using a microdensitometric image-processing method. Blood pressure was measured using a validated oscillometric device. We observed a statistically significant inverse association between plasma adiponectin and arteriolar caliber among participants aged 60 years or older after controlling for confounders (Adjusted beta = -0.42; P = .001). In the final model, HbA1C and low-density lipoprotein also remained independently associated with arteriolar caliber. There was no association of adiponectin with venular caliber and retinal vessel calibers in participants <60 years old.Adiponectin is inversely associated with retinal arteriolar caliber in elderly hypertensive participants, suggesting that plasma adiponectin may be a marker of microvascular damage and of higher cardiovascular risk in this age stratum. PMID- 26116459 TI - Ambulatory 24-hour cardiac oxygen consumption and blood pressure-heart rate variability: effects of nebivolol and valsartan alone and in combination. AB - We compared an angiotensin receptor blocker (valsartan; VAL), a beta-blocker (nebivolol; NEB) and the combination of NEB/VAL with respect to 24-hour myocardial oxygen consumption (determined by 24-hour ambulatory heart rate central systolic pressure product [ACRPP]) and its components. Subjects with hypertension (systolic blood pressure >140 or diastolic blood pressure >90; n = 26) were studied in a double-blinded, double-dummy, forced-titration, crossover design with 3 random-order experimental periods: VAL 320 mg, NEB 40 mg, and NEB/VAL 320/40 mg daily. After 4 weeks of each drug, ambulatory pulse wave analysis (MobilOGraph) was performed every 20 minutes for 24 hours. All three treatments resulted in nearly identical brachial and central systolic blood pressures. NEB alone or in combination with VAL resulted in lower ACRPP (by 11% 14%; P < .001 each) and heart rate (by 18%-20%; P < .001 each) compared with VAL, but stroke work (ACRPP per beat) was lower with VAL. Relative and adjusted variability (standard deviation and coefficient of variation) of heart rate were also lower with NEB and NEB/VAL than VAL. Results in African Americans, the majority subpopulation, were similar to those of the entire treatment group. We conclude that the rate-slowing effects of NEB cause ambulatory cardiac myocardial oxygen consumption to be lower with NEB monotherapy or NEB/VAL combination therapy than with VAL monotherapy. NEB/VAL is not superior to NEB alone in controlling heart rate, blood pressure, or ACRPP. Heart rate variability but not ACRPP variability is reduced by NEB or the combination NEB/VAL. There is no attenuation of beta-blocker-induced rate-slowing effects of in African Americans. PMID- 26116460 TI - U-shaped relationships between sleep duration and metabolic syndrome and metabolic syndrome components in males: a prospective cohort study. AB - OBJECTIVE: Based on cross-sectional studies, sleep duration has been shown to have a relationship with the prevalence of metabolic syndrome (MS); however, no prospective studies have verified a correlation between the incidence of MS and the gender difference. Herein we prospectively determined the association between MS and gender using a large sample. METHODS: A total of 4774 subjects without MS, 30-65 years of age, participated in this study. One-way ANOVA and Chi-square test were used to analyze the baseline variables. Cox regression models were performed separately in a mixed-gender population, males and females, while controlling for lifestyle and sleep-related factors. RESULTS: During an average of 4.4-year follow-up, 1506 subjects developed MS. Both short (<6 h) and long sleep durations (8-9 and >=9 h) increased the incidence of MS and elevated the fasting blood glucose (FBG) level in the mixed-gender population (MS: HR = 1.43, 1.25, and 1.45, respectively; elevated FBG: HR = 1.61, 1.65, and 1.98, respectively) and males (MS: HR = 1.87, 1.73, and 1.96, respectively; elevated FBG: HR = 2.27, 2.28, and 3.16, respectively). The HR(8-9 and >=9 h) for hypertriglyceridemia in males was 1.48 and 19.4, and the HR(<6, 6-7, and >=9 h) for hypertension in females was 1.25, 1.46, and 1.72, respectively. CONCLUSION: Both short and long sleep durations were associated with a greater incidence of MS and elevated FBG in a mixed-gender population and in males, and hypertension in females. Males who sleep longer were also at a higher risk for hypertriglyceridemia. PMID- 26116461 TI - Sleep-onset central apneas as triggers of severe nocturnal seizures. PMID- 26116462 TI - Epileptic hypnagogic jerks mimicking repetitive sleep starts. PMID- 26116463 TI - Obstructive sleep apnea is associated with liver disease: a population-based cohort study. AB - BACKGROUND: The association between obstructive sleep apnea (OSA) and the risk of liver disease is unclear. Moreover, population-based studies on the risk of liver disease among people with OSA have not yet been conducted. This study aimed to investigate the risk of subsequent development of liver disease among people with OSA. METHODS: Using Taiwan National Health Insurance claims data, this study collected subjects from a cohort of 17,374 people with OSA who were diagnosed between 2000 and 2008. A control group of 69,496 people was selected from the same database and matched by age, gender, urbanization, income, and date of initial admission. All subjects were followed up until 2010. Liver disease incidence and risk were calculated. RESULTS: The overall risk of liver disease among people with OSA was significantly higher than in the control group (aHR = 5.52, p <0.001). Non-alcoholic fatty liver disease, cirrhosis, and hepatitis C had significant aHRs of 5.29, 7.50, and 7.19 (all at p <0.001), respectively. In contrast, hepatitis B had the smallest aHR of 3.71. CONCLUSIONS: The risk of liver disease was more than five times higher among people with OSA compared with the control group; this was particularly for cirrhosis and hepatitis C. Liver disease is thus a very important health issue among people with OSA. PMID- 26116464 TI - Restless legs syndrome in stroke patients. AB - BACKGROUND: Restless legs syndrome (RLS) is associated with cerebrovascular risk factors, but its possible association with cerebrovascular disease has yielded conflicting results. OBJECTIVE: This was a case-control, in-hospital study to evaluate the association between RLS and acute stroke or transient ischemic attack (TIA). METHODS: We evaluated patients hospitalized with acute stroke/TIA and an age and gender 2:1 frequency-matched control group, for the presence of RLS. RESULTS: Twenty-two of 149 patients (15%) and 10 of 298 controls (3%) suffered from RLS (p <0.0001). A multivariate logistic regression model employing cerebrovascular risk factors as predictors, that is, hypertension, hyperlipidemia, diabetes, and body mass index (BMI), determined that stroke/TIA was significantly associated with RLS with odds ratio for RLS among patients with stroke/TIA versus controls of 7.60 (95% confidence interval (CI): 2.07-27.87; p = 0.002). Another multivariate logistic regression model adjusting for possible RLS risk factors, that is, hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function, determined that stroke/TIA was significantly associated with RLS with odds ratio of 6.85 (95% CI: 6.85-1.79; p = 0.005). Stepwise logistic regression with hypertension, hyperlipidemia, diabetes, BMI, anemia, and reduced renal function as potential predictors revealed that only stroke/TIA predicted RLS with similar odds ratio to the RLS-based multivariate model of 6.54 (95% CI: 2.63-16.27; p <0.0001). CONCLUSIONS: Examining stroke patients while in hospital allowed us to conclude that RLS and acute stroke/TIA are significantly associated. However, the cross-sectional design did not allow for the determination of a causative relationship between the two. PMID- 26116465 TI - Serum cytokine levels in Kleine-Levin syndrome. AB - OBJECTIVE: Kleine-Levin Syndrome (KLS) is a rare sleep disorder causing recurrent symptomatic episodes of severe hypersomnia, cognitive impairment, apathy, and derealization. These episodes are interspersed with long periods of normal sleep, cognition, and behavior. The pathogenesis of KLS is still unknown. The objective of this study was to determine serum cytokine levels in patients with KLS during and between episodes. PATIENTS/METHODS: Fifty-two typical KLS patients were included in the study of whom 17 patients donated blood samples both during and between episodes. Blood samples were collected in USA, France, and Taiwan in a clinical setting. Processing of the samples was performed at the Stanford Center for Sleep Sciences and Medicine. RESULTS: We did not observe any changes in serum cytokine levels during KLS episodes compared to between episodes. In a small cohort of asymptomatic KLS patients and age- and gender matched healthy controls (n = 8/group) whose blood samples were all collected and processed at the same day; asymptomatic KLS patients had significantly higher levels of serum sVCAM1 cytokine compared to healthy controls. CONCLUSION: These data suggest that KLS episodes are not accompanied by an abnormal systemic immune reaction. PMID- 26116466 TI - Use of sleep medications and risk of cancer: a matched case-control study. AB - BACKGROUND: Previous research suggests a possible link between sleep-medication use and mortality, especially cancer deaths, but findings are mixed, and large population-based studies are lacking. METHODS: Data from the Finnish Public Sector study were linked to the Finnish Cancer Register and the Drug Prescription Register of Finland. A total of 5053 cancer cases (mean age of 57.4 years) diagnosed in 2002-2011, and their 24,388 controls free of cancer and matched for sex, age, socioeconomic status, employer, and geographical area, were identified. The use of sleep medications was defined as purchases of prescribed sleep medications. RESULTS: Both quantity and duration of prior sleep-medication use during the seven years studied were associated with increased odds of having cancer. Compared with participants not using sleep medications, the odds ratio was 1.18-fold (95% confidence interval (CI): 1.01-1.39) for those who used >100 defined daily doses per year and 1.16-fold (95% CI: 1.01-1.34) for those who had such a medication for >3 years. Site-specific analyses showed a more pronounced association of quantity and duration of sleep-medication use with subsequent cancer of the respiratory system (odds ratio for >100 defined daily doses per year vs. no use: 3.47; 95% CI: 1.97-6.11). No associations were found with other cancer sites. CONCLUSION: In this register-based study, sleep-medication use was associated with an increased cancer incidence of the respiratory system. Further studies are needed to examine potential carcinogenic mechanisms associated with hypnotic medications. PMID- 26116467 TI - A new cell-based assay to evaluate myogenesis in mouse myoblast C2C12 cells. AB - The development of the efficient screening system of detecting compounds that promote myogenesis and prevent muscle atrophy is important. Mouse C2C12 cells are widely used to evaluate myogenesis but the procedures of the assay are not simple and the quantification is not easy. We established C2C12 cells expressing the N terminal green fluorescence protein (GFP) and the C-terminal GFP (GFP1-10 and GFP11 cells). GFP1-10 and GFP11 cells do not exhibit GFP signals until they are fused. The signal intensity correlates with the expression of myogenic markers and myofusion. Myogenesis-promoting reagents, such as insulin-like growth factor 1 (IGF1) and beta-guanidinopropionic acid (GPA), enhance the signals, whereas the poly-caspase inhibitor, z-VAD-FMK, suppresses it. GFP signals are observed when myotubes formed by GFP1-10 cells are fused with single nuclear GFP11 cells, and enhanced by IGF1, GPA, and IBS008738, a recently-reported myogenesis-promoting reagent. Fusion between myotubes formed by GFP1-10 and GFP11 cells is associated with the appearance of GFP signals. IGF1 and GPA augment these signals, whereas NSC23766, Rac inhibitor, decreases them. The conditioned medium of cancer cells suppresses GFP signals during myogenesis and reduces the width of GFP-positive myotubes after differentiation. Thus the novel split GFP-based assay will provide the useful method for the study of myogenesis, myofusion, and atrophy. PMID- 26116468 TI - The cooperative role of S1P3 with LYVE-1 in LMW-HA-induced lymphangiogenesis. AB - Lymphangiogenesis, the formation of new lymph vessels, plays a significant role in the development and metastasis of various cancers. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA) promotes lymphangiogenesis. However, the underlying mechanisms are poorly defined. In this study, using immunofluorescence and co-immunoprecipitation, we found that LMW-HA increased the colocalization of lymphatic vessel endothelial HA receptor (LYVE-1) and sphingosine 1-phosphate receptor (S1P3) at the cell surface. Silencing of either LYVE-1 or S1P3 decreased LMW-HA-mediated tube formation in lymphatic endothelial cells (LECs). Furthermore, silencing of either LYVE-1 or S1P3 significantly inhibited LMW-HA-induced tyrosine phosphorylation of Src kinase and extracellular signal-regulated kinase (ERK1/2). In summary, these results suggest that S1P3 and LYVE-1 may cooperate to play a role in LMW-HA-mediated lymphangiogenesis. This interaction may provide a useful target for the intervention of lymphangiogenesis-associated tumor progression. PMID- 26116469 TI - A prospective study of the risk of bacteremia in directed cholangioscopic examination of the common bile duct. AB - BACKGROUND AND AIMS: The frequency of bacteremia during ERCP with cholangioscopy has not been well studied. There are no formal guidelines regarding antibiotic prophylaxis before ERCP with cholangioscopy. The aim was to estimate the frequency of bacteremia and subsequent infectious adverse events after ERCP with cholangioscopy. METHODS: This prospective nonrandomized study performed in a single tertiary referral center included adult patients who were undergoing ERCP with cholangioscopic examination of the common bile duct. Blood cultures were drawn from patients before the procedure and 5 and 30 minutes after the procedure. Antibiotics were not given before or after the procedure. Patients were followed up after 24 hours and 1 week after the procedure for infectious adverse events. The primary outcome was bacteremia rate, and secondary outcomes were cholangitis rate and adverse events. RESULTS: Fifty-seven patients were enrolled in the study with 60 procedures performed. The first procedure from each patient was considered in the analysis, and thus we included 57 patients with 57 procedures in this study analysis. Postprocedure bacteremia was seen in 5 of 57 procedures (8.8%; 95% confidence interval, 2.9%-19.3%). Four patients were readmitted with cholangitis (7.0%). Bacteremia was more common in patients who had cholangioscopy with biopsy sampling compared with patients who had cholangioscopy without biopsy sampling (P = .011). Cholangitis was significantly more common in patients with bacteremia than in those patients with a negative blood culture (P = .035). CONCLUSION: ERCP with cholangioscopy is associated with a bacteremia rate of 8.8% and a cholangitis rate of 7.0%. Preprocedural antibiotics may be considered before cholangioscopy, especially if tissue acquisition with biopsy sampling is expected. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01673269.). PMID- 26116470 TI - Randomized, Placebo-Controlled Trial of Dobutamine for Low Superior Vena Cava Flow in Infants. AB - OBJECTIVE: To gather information for a future confirmatory trial of dobutamine (DB) for circulatory impairment (ie, low superior vena cava [SVC] flow). STUDY DESIGN: A total of 127 infants born at < 31 weeks gestational age were serially scanned from birth to 96 hours after birth. The infants were randomly assigned to 2 groups and were treated with DB (stepwise dose increase, 5-10-15-20 MUg/kg/min) or placebo if they had an SVC flow < 41 mL/kg/min within the first 24 hours after birth. The primary outcome measures were the achievement and maintenance of an SVC flow >= 41 mL/kg/min. Secondary outcome measures were the short-term evolution of clinical and biochemical variables, near-infrared spectroscopy, cranial Doppler ultrasound, and clinical outcomes. RESULTS: SVC flow increased throughout the first 96 hours for the entire cohort. All of the randomized infants (n = 28) except 2 achieved and maintained an SVC flow >= 41 mL/kg/min after intervention; however, the infants treated with DB (n = 16) showed a higher heart rate and improved base excess compared with those treated with placebo (n = 12). Low SVC flow was associated with low gestational age (P = .02) and poor condition at birth (P = .02). Low SVC flow significantly increased the risk of severe ischemic events (OR, 13; 95% CI, 2.4-69.2; P < .01). CONCLUSION: This exploratory trial demonstrates a tendency toward improved short-term clinical and biochemical perfusion variable outcomes in infants with low SVC flow treated with DB. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01605279) and the European Clinical Trials Database (EurodraCT 2009-010901-35). PMID- 26116471 TI - Trends in Ambulatory Care for Children with Concussion and Minor Head Injury from Eastern Massachusetts between 2007 and 2013. AB - OBJECTIVE: To characterize trends in health care utilization and costs for children diagnosed with concussion or minor head injury within a large pediatric primary-care association. STUDY DESIGN: We conducted a retrospective cohort analysis from 2007 through 2013 examining all outpatient medical claims related to concussion and minor head injury from 4 commercial insurance companies for children 6-21 years of age who were patients within a large pediatric independent practice association located throughout eastern Massachusetts. RESULTS: Health care visits for concussion and minor head injury increased more than 4-fold during the study period, with primary-care and specialty clinics experiencing the greatest increases in the rate of visits while emergency department visits increased comparatively less. These increases were accounted for by both the proportion of children diagnosed with concussion or minor head injury (1.3% of all children in 2007 vs 3.3% in 2013) and the number of encounters per diagnosed patient (1.0 encounters per patient in 2007 vs 1.7 in 2013). Although the overall population costs devoted to care for concussion or minor head injury increased 34%, the cost per individual diagnosed child decreased 31%. CONCLUSIONS: Over the past 7 years, health care encounters for children diagnosed with concussion or minor head injury increased substantially in eastern Massachusetts. Care for these injuries increasingly shifted from the emergency department to primary-care and specialty providers. PMID- 26116472 TI - Addressing Conflict of Interest and Bias in Research, Education and Clinical Practice. PMID- 26116473 TI - Supreme Court rejects challenge to Affordable Care Act. PMID- 26116474 TI - Molecular and functional characterization of BAFF from the Yangtze alligator (Alligator sinensis, Alligatoridae). AB - B-cell activating factor (BAFF) from the TNF family is critical for B-cell survival and maturation. In this study, we identified a Yangtze alligator (Alligator sinensis, Alligatoridae) BAFF cDNA, designated as asBAFF, using reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The open reading frame of this cDNA encodes a 287-amino acid protein containing a predicted transmembrane domain and a furin protease cleavage site, similar to mammalian and avian BAFF. The amino acid identity between biologically soluble asBAFF (assBAFF) and csBAFF, hsBAFF, and msBAFF is 94, 76, and 71%, respectively. Real-time quantitative PCR analysis showed that the asBAFF gene is strongly expressed in the spleen. Since BAFF is always expressed as inclusion bodies in bacteria, it is difficult to purify. To enhance the soluble expression of assBAFF in Escherichia coli, we fused the extracellular region of the asBAFF gene to a small ubiquitin-related modifier gene (SUMO). Purified assBAFF was able to promote the survival of splenic lymphocytes and co-stimulate the proliferation of mouse B cells with anti-mouse IgM. These findings suggest that asBAFF plays an important role in the survival and proliferation of Yangtze alligator B cells, and because it is evolutionarily highly conserved, functional cross-reactivity exists between mammalian and Yangtze alligator BAFF. PMID- 26116475 TI - Training Assistants Improves the Process of Adoption of Video-Assisted Thoracic Surgery Lobectomy. AB - BACKGROUND: Despite overwhelming evidence of decreased pain, fewer complications, and shorter length of stay with equivalent oncologic outcomes, video-assisted thoracic surgery (VATS) lobectomy has been slow to be adopted in the community. This study evaluates the role of training surgical assistants to ease the transition to VATS lobectomy. METHODS: A half-day training course for physician assistants in the specific skills needed to assist with VATS lobectomy was developed to be offered annually in conjunction with a national meeting. Each participant completed a needs assessment before the course and a course assessment afterward. One-year follow-up data were obtained from the first cohort to determine the effects of the course on their practice. RESULTS: Forty-four physician assistants participated in the course in either 2013 or 2014. Participant-identified educational needs included enhanced camera navigation skills, use of specialized instruments, and knowledge of the steps of the operation to provide proactive assistance. After completing the course, 90% (n = 39) felt more confident in their ability to provide optimal visualization for the operating surgeon, and 93% (n = 40) felt more confident in their ability to recognize and anticipate the steps of a VATS lobectomy. These changes persisted at 1 year. CONCLUSIONS: Specific training directed at surgical assistants may improve the adoption of new technology by mechanisms including improved visualization and better understanding of methods to facilitate the operation and avoid frustration. This type of training should be made available to assistants of surgeons learning new operations. PMID- 26116476 TI - Long-Term Outcomes of the Maze Procedure Combined With Mitral Valve Repair: Risk of Thromboembolism Without Anticoagulation Therapy. AB - BACKGROUND: Although the strongest benefit of a concomitant Maze procedure during mitral valve repair is the obviation of the need for anticoagulation therapy, the risk of thromboembolism without anticoagulation therapy has not been evaluated. METHODS: A total of 362 consecutive patients (aged 52.2 +/- 13.8 years, 180 females) who underwent the Maze procedure combined with mitral valve repair between 1997 and 2012 were evaluated. Anticoagulation therapy was discontinued after 6 months if synchronous atrial contraction was maintained in the absence of further risks of thromboembolism. RESULTS: The median follow-up period was 5.4 years (interquartile range, 2.9 to 9.6 years). Late atrial fibrillation (AF) occurred in 62 patients (17.1%). The 5-year freedom from AF off anti-arrhythmic drugs was 82.6% +/- 2.3%. In 96 patients (26.5%), warfarin was administered in the late period (>6 months), and of them, 54 patients (14.9%) were maintained with warfarin therapy until the end of the follow-up. Patients receiving warfarin therapy were older (p = 0.030), had longer AF duration (p = 0.012), and had rheumatic valvulopathy more frequently (p = 0.003) compared with those not receiving warfarin. Overall, patients were followed up off the warfarin therapy for 1,577 patient-years, during which there were 4 cases of stroke or transient ischemic accident and 21 late deaths. The linearized rates of thromboembolic event and death without warfarin therapy were 0.06% and 0.12% per patient-year, respectively, and these rates were not significantly different from those receiving warfarin therapy. CONCLUSIONS: Adopting appropriate selection criteria for discontinuing anticoagulation therapy, the majority of patients receiving concomitant mitral repair and the Maze procedure can discontinue warfarin with excellent long-term safety profiles. PMID- 26116477 TI - Pulmonary Resection for Lung Cancer in Patients With Idiopathic Interstitial Pneumonia. AB - BACKGROUND: After pulmonary resection, patients with lung cancer who have idiopathic pulmonary fibrosis (IPF) have been reported to have higher pulmonary morbidity and mortality and poorer outcomes than patients without IPF. However, whether morbidity, mortality, and outcomes differ according to the subtype of idiopathic interstitial pneumonia (IIP) remains unclear. METHODS: The clinical records of 678 patients with non-small cell lung cancer who underwent pulmonary resection were reviewed retrospectively. A total of 103 patients had IIP and were classified into an IPF group and a non-IPF group in accordance with the 2011 statement. RESULTS: The IPF group comprised 46 patients, and the non-IPF group comprised 57. The 5-year survival rate was significantly higher in the non-IPF group (53.2%) than in the IPF group (22.1%; p = 0.0093). Cause of death was IIP related respiratory failure in 26.1% (12 of 46) of the patients in the IPF group as compared with 7.0% (4 of 57) of patients in the non-IPF group (p = 0.008). Multivariate Cox analysis indicated that IPF was a significant predictor of long term survival (hazard ratio 1.910, 95% confidence interval: 1.102 to 3.313; p = 0.021). CONCLUSIONS: Idiopathic pulmonary fibrosis is independently associated with poorer overall survival in patients with lung cancer who undergo pulmonary resection. The decision whether to perform surgery in patients who have lung cancer with IIP should therefore take into account the subtype of IIP and the poorer outcomes associated with IPF. PMID- 26116478 TI - Hemiarch and Total Arch Surgery in Patients With Previous Repair of Acute Type I Aortic Dissection. AB - BACKGROUND: We examined our contemporary experience with hemiarch and total arch replacement in patients with previous acute type I aortic dissection. METHODS: Over an 8.5-year period, 137 consecutive patients (median age 58 years, interquartile range, 50 to 67) underwent hemiarch or total transverse aortic arch replacement a median of 7.7 years (range, 67 days to 32 years; interquartile range, 2.8 to 12.3 years) after previous acute type I aortic dissection repair. Interventions involving only the aortic root, aortic valve, descending aorta, or thoracoabdominal aorta were excluded. Multivariate analysis of 20 potential preoperative and intraoperative risk factors was performed to examine early death, neurologic deficit, composite endpoint (operative death, permanent neurologic deficit, or hemodialysis at discharge), and long-term mortality. RESULTS: Total arch replacement was performed in 103 patients (75.2%), hemiarch replacement in 34 (24.8%), and elephant trunk procedures in 77 (56.2%). Thirty one repairs (22.6%) were emergent or urgent. There were 16 operative deaths (11.7%), 4 permanent strokes (3.6%), and 21 (15.3%) instances of the composite endpoint. In the multivariate analysis, congestive heart failure and cardiopulmonary bypass time independently predicted operative mortality (p = 0.0027, p = 0.018). Emergency operation approached significance for stroke (p = 0.088). Predictors of long-term mortality (during a median follow-up period of 5.1 years, 95% confidence interval: 4.4 to 5.8) were female sex (p = 0.0036), congestive heart failure (p = 0.0045), and circulatory arrest time (p = 0.0013); preoperative pulmonary disease approached significance (p = 0.074). Five-year survival was 73.2%. CONCLUSIONS: In patients with previous acute type I aortic dissection repair, hemiarch and total arch operations have respectable morbidity and survival rates. Congestive heart failure predicts operative death, long-term mortality, and our adverse event endpoint. Cardiopulmonary bypass time predicts operative mortality, and female sex and circulatory arrest time predict long-term mortality. PMID- 26116479 TI - Multi Versus Single Arterial Coronary Bypass Graft Surgery Across the Ejection Fraction Spectrum. AB - BACKGROUND: Left internal thoracic artery (LITA) and radial artery (RA) multi arterial CABG (MABG) is generally associated with improved long-term survival compared with traditional LITA and saphenous vein single arterial CABG (SABG). We examined the hypothesis that this multi-arterial survival advantage persists irrespective of left ventricular ejection fraction (LVEF). METHODS: We retrospectively analyzed the primary, non-salvage multi-graft CABG experience (n = 11,261; 64.4 +/- 10.4 years, 70.4% men) from 2 institutions (1995 to 2011). Risk-adjusted 15-year survival was pairwise compared for the MABG versus SABG grafting approaches within 3 LVEF subcohorts (>0.50, n = 4,833 [44% MABG]; 0.36 to 0.50, n = 4,465 [39% MABG]; and <= 0.35, n = 1,963 [35% MABG]) using propensity-matched and covariate adjusted Cox regression (all patients) comparisons. RESULTS: Propensity matching yielded 1,317 (LVEF > 0.50), 1,179 (LVEF, 0.36 to 0.50), and 470 (LVEF <= 0.35) well-matched grafting method pairs. Acute perioperative mortality was equivalent between MABG and SABG within each LVEF group, but increased with decreasing LVEF. MABG was uniformly associated with better 15-year survival compared with SABG for all LVEF categories. The associated matched-adjusted hazard ratios (95% confidence intervals) were consistent across EF groups at 0.79 (0.68 to 0.93), 0.80 (0.69 to 0.93), and 0.82 (0.66 to 1.0), respectively. Covariate adjusted HR in all patients concurred with matched results. CONCLUSIONS: MABG results in significantly enhanced long-term survival compared with LITA/SVG SABG regardless of the degree of LV dysfunction. These results favor MABG as the therapy of choice in patients with LV dysfunction. PMID- 26116480 TI - Outcomes and Costs for Major Lung Resection in the United States: Which Patients Benefit Most From High-Volume Referral? AB - BACKGROUND: Accountable care organizations are designed to improve value by decreasing costs and maintaining quality. Strategies to maximize value are needed for high-risk surgery. We wanted to understand whether certain patient groups were differentially associated with better outcomes at high-volume hospitals in terms of quality and cost. METHODS: In all, 37,746 patients underwent elective major lung resection in 1,273 hospitals in the Nationwide Inpatient Sample from 2007 to 2011. Patients were stratified by hospital volume quartile and substratified by preoperative mortality risk, age, and chronic obstructive pulmonary disease status. Mortality was evaluated using clustered multivariable hierarchical logistic regression controlling for patient comorbidity, demographics, and procedure. Adjusted cost was evaluated using generalized linear models fit to a gamma distribution. RESULTS: Patients were grouped into volume quartiles based on cases per year (less than 21, 21 to 40, 40 to 78, and more than 78). Patient characteristics and procedure mix differed across quartiles. Overall, mortality decreased across volume quartiles (lowest 1.9% versus highest 1.1%, p < 0.0001). Patients aged more than 80 years were associated with greater absolute and relative mortality rates than patients less than 60 years old in highest volume versus lowest volume hospitals (age more than 80 years, 4.2% versus 1.3%, p < 0.0001, odds ratio 3.31, 95% confidence interval: 1.89 to 5.80; age less than 60 years, 1.0% versus 0.8%, p = 0.19, odds ratio 1.38, 95% confidence interval: 0.74 to 2.56). Patients with high preoperative risk (more than 75th percentile) were also associated with lower absolute mortality in high volume hospitals. Adjusted costs were not significantly different across quartiles or patient strata. CONCLUSIONS: Older patients show a significantly stronger volume-outcome relationship than patients less than 60 years of age. Costs were equivalent across volume quartile and patient strata. Selective patient referral may be a strategy to improve outcomes for elderly patients undergoing lung resection. PMID- 26116481 TI - Acute Respiratory Distress Syndrome With and Without Extracorporeal Membrane Oxygenation: A Score Matched Study. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening medical condition. Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for patients with ARDS and refractory hypoxia. This study compared the characteristics and outcomes of ARDS patients who did or did not receive ECMO matched with Acute Physiology and Chronic Health Evaluation II (APACHE II) score and age. METHODS: This retrospective, case-control study enrolled patients with ARDS admitted to the intensive care unit of a tertiary referral hospital between January 2007 and December 2012. Overall, 216 patients with ARDS-81 receiving ECMO (ECMO group) and 135 not receiving ECMO (non-ECMO group)-were enrolled in this study. Patients were paired when the difference in their APACHE II scores was within 3 points and their age difference was 3 years. In total, 126 patients could not be matched and were thus excluded. Eventually, of the 90 patients with ARDS enrolled in this study, 45 ECMO group patients were matched with 45 non-ECMO group patients. The demographic data, reasons for intensive care unit admission, and laboratory variables were evaluated. RESULTS: The primary etiology of ARDS was infection (72.2%). The APACHE II score and age-matched group receiving ECMO therapy had higher inhospital survival rates. Moreover, the patients receiving ECMO therapy had significantly lower 6-month mortality rates than did the non ECMO group. CONCLUSIONS: Patients with ARDS who received ECMO treatment had higher inhospital survival rates than did those with a similar disease severity and at a similar age who did not receive ECMO. PMID- 26116482 TI - An Assessment of the Optimal Time for Removal of Esophageal Stents Used in the Treatment of an Esophageal Anastomotic Leak or Perforation. AB - BACKGROUND: Esophageal stent for the treatment of a perforation or anastomotic leak has been shown to be effective and safe. However, the optimal timing for stent removal is in question. This purpose of this investigation was to identify a time for stent removal in patients treated for an acute perforation or anastomotic leak that resulted in sealing of the leak while minimizing the incidence of stent-related complications. METHODS: Patients undergoing esophageal stent placement for the treatment of an acute perforation or intrathoracic anastomotic leak were identified from a single institution's prospectively collected database. Patient outcomes were recorded and analyzed. Complications were segregated by stent dwell time. RESULTS: During the study period, 162 patients underwent esophageal stent placement for an acute perforation (n = 117) or anastomotic leak (n = 45). Patients whose stent was removed in less than 28 days after placement for an acute perforation realized a stent complication rate that was independently reduced by 39% (odds ratio, 0.61; 95% confidence interval, 0.54 to 0.78; p < 0.01), whereas patients whose stent was removed in less than 14 days after placement for an acute perforation realized a stent complication rate that was independently reduced by 56% (odds ratio, 0.44; 95% confidence interval, 0.38 to 0.69; p < 0.001). CONCLUSIONS: Endoluminal esophageal stent placement is a safe and effective treatment for patients with an acute esophageal perforation or intrathoracic anastomotic leak after esophagectomy. Removal of stents at 2 weeks for anastomotic leak or 4 weeks for perforation has the potential to significantly decrease the incidence of complications associated with stent use. PMID- 26116483 TI - Early Operation for Endocarditis Complicated by Preoperative Cerebral Emboli Is Not Associated With Worsened Outcomes. AB - BACKGROUND: Valve operations for patients presenting with infective endocarditis (IE) complicated by stroke are thought to carry elevated risk of postoperative complications. Our aim was to compare outcomes of IE patients who undergo surgical intervention early after diagnosis of septic cerebral emboli with outcomes of patients without preoperative emboli. METHODS: All patients undergoing operations for left-sided IE between 1996 and 2013 at our institution were reviewed. Patients undergoing operations more than 14 days after embolic stroke diagnosis (n = 11) and those with purely hemorrhagic lesions (n = 7) were excluded from the analysis. The study included 308 patients who were stratified according to the presence (STR, n = 54) or absence of a preoperative septic cerebral embolus (NoSTR, n = 254). Primary outcomes of interest were the development of a new postoperative stroke and 30-day mortality. RESULTS: Mean time to surgical intervention from stroke onset was 6.0 +/- 4.1 days. Staphylococcus aureus (39% STR vs 21% NoSTR, p = 0.004) infection and annular abscess at operation (52% STR vs 27% NoSTR, p < 0.001) were more prevalent in STR patients. There was no significant difference in 30-day mortality (9.3% STR vs 7.1% NoSTR, p = 0.57) or in the rate of new postoperative stroke (5 [9.4%] STR vs 12 [4.7%] NoSTR, p = 0.19) between groups. In addition, there was no difference in 10-year survival between groups (log-rank p = 0.74). CONCLUSIONS: Early surgical intervention in patients with IE complicated by preoperative septic cerebral emboli does not lead to significantly worse postoperative outcomes. Early surgical intervention for IE after embolic stroke warrants consideration, particularly in patients with high-risk features such as S aureus or annular abscess, or both. PMID- 26116484 TI - Robot-Assisted Minimally Invasive Ivor Lewis Esophagectomy With Real-Time Perfusion Assessment. AB - BACKGROUND: Surgical resection is viewed as the most effective way to ensure both locoregional control and long-term survival in esophageal cancer. Although minimally invasive esophagectomy has been widely accepted as an alternative to open surgery, the role of robotic assistance has yet to be elucidated. We report our institutional experience with robotic-assisted Ivor Lewis esophagectomy using real-time perfusion assessment and demonstrate this as a safe and technically feasible alternative to traditional open Ivor Lewis esophagectomy. METHODS: A retrospective chart review of all patients undergoing robotic-assisted Ivor Lewis esophagectomy at a single institution from 2011 to 2014 was performed. Operative and postoperative outcomes were recorded. RESULTS: Fifty-four patients underwent robotic-assisted Ivor Lewis esophagectomy during the study period. Indication for surgery was cancer in 49 patients, 38 of whom underwent neoadjuvant chemoradiation therapy. The average operative time was 6 hours 2 minutes, and the average blood loss was 74 mL. There was 1 postoperative mortality (1.9%). Three (5.5%) patients experienced an anastomotic leak. The average number of lymph nodes harvested in cancer patients was 16.2 (range, 3 to 35). The average length of stay was 12.9 days. CONCLUSIONS: Our study demonstrates that robotic-assisted Ivor Lewis esophagectomy using real-time perfusion assessment is a safe and technically feasible alternative to traditional open Ivor Lewis esophagectomy. It allows for R0 resection with adequate lymph node harvesting and a short hospital stay. PMID- 26116485 TI - Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-HIFi study): a randomised controlled trial. AB - BACKGROUND: Lung volume reduction surgery improves survival in selected patients with emphysema, and has generated interest in bronchoscopic approaches that might achieve the same effect with less morbidity and mortality. Previous trials with endobronchial valves have yielded modest group benefits because when collateral ventilation is present it prevents lobar atelectasis. METHODS: We did a single centre, double-blind sham-controlled trial in patients with both heterogeneous emphysema and a target lobe with intact interlobar fissures on CT of the thorax. We enrolled stable outpatients with chronic obstructive pulmonary disease who had a forced expiratory volume in 1 s (FEV1) of less than 50% predicted, significant hyperinflation (total lung capacity >100% and residual volume >150%), a restricted exercise capacity (6 min walking distance <450 m), and substantial breathlessness (MRC dyspnoea score >=3). Participants were randomised (1:1) by computer-generated sequence to receive either valves placed to achieve unilateral lobar occlusion (bronchoscopic lung volume reduction) or a bronchoscopy with sham valve placement (control). Patients and researchers were masked to treatment allocation. The study was powered to detect a 15% improvement in the primary endpoint, the FEV1 3 months after the procedure. Analysis was on an intention-to treat basis. The trial is registered at controlled-trials.com, ISRCTN04761234. FINDINGS: 50 patients (62% male, FEV1 [% predicted] mean 31.7% [SD 10.2]) were enrolled to receive valves (n=25) or sham valve placement (control, n=25) between March 1, 2012, and Sept 30, 2013. In the bronchoscopic lung volume reduction group, FEV1 increased by a median 8.77% (IQR 2.27-35.85) versus 2.88% (0-8.51) in the control group (Mann-Whitney p=0.0326). There were two deaths in the bronchoscopic lung volume reduction group and one control patient was unable to attend for follow-up assessment because of a prolonged pneumothorax. INTERPRETATION: Unilateral lobar occlusion with endobronchial valves in patients with heterogeneous emphysema and intact interlobar fissures produces significant improvements in lung function. There is a risk of significant complications and further trials are needed that compare valve placement with lung volume reduction surgery. FUNDING: Efficacy and Mechanism Evaluation Programme, funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership. PMID- 26116486 TI - Endobronchial valves in a highly parsed emphysema population. PMID- 26116487 TI - Physiotherapy management of joint hypermobility syndrome--a focus group study of patient and health professional perspectives. AB - OBJECTIVE: To develop an understanding of patient and health professional views and experiences of physiotherapy to manage joint hypermobility syndrome (JHS). DESIGN: An explorative qualitative design. Seven focus groups were convened, audio recorded, fully transcribed and analysed using a constant comparative method to inductively derive a thematic account of the data. SETTING: Four geographical areas of the U.K. PARTICIPANTS: 25 people with JHS and 16 health professionals (14 physiotherapists and two podiatrists). RESULTS: Both patients and health professionals recognised the chronic heterogeneous nature of JHS and reported a lack of awareness of the condition amongst health professionals, patients and wider society. Diagnosis and subsequent referral to physiotherapy services for JHS was often difficult and convoluted. Referral was often for acute single joint injury, failing to recognise the long-term multi-joint nature of the condition. Health professionals and patients felt that if left undiagnosed, JHS was more difficult to treat because of its chronic nature. When JHS was treated by health professionals with knowledge of the condition patients reported satisfactory outcomes. There was considerable agreement between health professionals and patients regarding an 'ideal' physiotherapy service. Education was reported as an overarching requirement for patients and health care professionals. CONCLUSIONS: Physiotherapy should be applied holistically to manage JHS as a long-term condition and should address injury prevention and symptom amelioration rather than cure. Education for health professionals and patients is needed to optimise physiotherapy provision. Further research is required to explore the specific therapeutic actions of physiotherapy for managing JHS. PMID- 26116488 TI - Management of extracranial carotid artery aneurysm. AB - INTRODUCTION: Aneurysms of the extracranial carotid artery (ECAA) are rare. Several treatments have been developed over the last 20 years, yet the preferred method to treat ECAA remains unknown. This paper is a review of all available literature on the risk of complications and long-term outcome after conservative or invasive treatment of patients with ECAA. METHODS: Reports on ECAA treatment until July 2014 were searched in PubMed and Embase using the key words aneurysm, carotid, extracranial, and therapy. RESULTS: A total of 281 articles were identified. Selected articles were case reports (n = 179) or case series (n = 102). Papers with fewer than 10 patients were excluded, resulting in the final selection of 39 articles covering a total of 1,239 patients. Treatment consisted of either conservative treatment in 11% of the cases or invasive treatment in 89% of the cases. Invasive treatment comprised surgery in 94%, endovascular approach in 5%, and a hybrid approach in 1% of the patients. The most common complication described after invasive therapy was cranial nerve damage, which occurred in 11.8% of patients after surgery. The 30 day mortality rate and stroke rate in conservatively treated patients was 4.67% and 6.67%, after surgery 1.91% and 5.16%. Information on confounders in the present study was incomplete. Therefore, adjustments to correct for confounding by indication could not be done. CONCLUSIONS: This review summarizes the largest available series in the literature on ECAA management. The number of ECAAs reported in current literature is scarce. The early and long-term outcome of invasive treatment in ECAA is favorable; however, cranial nerve damage after surgery occurs frequently. Unfortunately, due to limitations in reporting of results and confounding by indication in the available literature, it was not possible to determine the optimal treatment strategy. There is a need for a multicenter international registry to reveal the optimal treatment for ECAA. PMID- 26116490 TI - Cilostazol inhibits HMGB1 release in LPS-activated RAW 264.7 cells and increases the survival of septic mice. AB - INTRODUCTION: Inflammation and coagulation play important roles in the pathogenesis of sepsis. Anticoagulants with anti-inflammatory action draw attention as therapeutic agent in sepsis. OBJECTIVE: Whether cilostazol (6-[4-(1 cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2-(1H)-quinolinone), anticoagulant, protects mice against sepsis and underlying mechanism(s) were investigated. METHODS: Induction of heme oxygenase (HO)-1 protein, phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) luciferase activity, and release of high mobility group box 1 (HMGB1) were analyzed using signal inhibitors and transfection techniques. Survival and organ damage were compared in septic mice with and without cilostazol. RESULTS: In RAW264.7 cells, cilostazol increased phosphorylation of AMPK which was followed by HO-1 induction. Lipopolysaccharide (LPS)-activated HMGB1 release was reduced by cilostazol which was reversed by both SB203580 and silencing of HO-1 or AMPK RNA. Interestingly, silencing AMPK reduced HO-1 expression, whereas silencing HO 1 did not affect p-AMPK by cilostazol. Both compound C and zinc protoporphyrin IX (ZnPPIX) antagonized inhibitory effect of HMGB1 by cilostazol. Cilostazol inhibited NF-kappaB luciferase activity which was antagonized by SB203580. Finally, the administration of cilostazol increased the survival of endotoxemic mice but failed to do so when co-treated with rHMGB1. Cilostazol reduced circulating HMGB1, plasminogen activator inhibitor-1 (PAI-1) levels, organ damages and protein expression of PAI-1 in lung tissues of CLP-septic mice, which were antagonized by ZnPPIX. CONCLUSION: These findings suggest that HMGB1 can be a target molecule of cilostazol by 1) AMPK activation, and 2) induction of HO-1 by p38 MAPK and AMPK. Therefore, cilostazol may be useful for treatment of sepsis. PMID- 26116489 TI - Systematic Review and Meta-analysis of Long-term survival After Elective Infrarenal Abdominal Aortic Aneurysm Repair 1969-2011: 5 Year Survival Remains Poor Despite Advances in Medical Care and Treatment Strategies. AB - BACKGROUND: Improved critical care, pre-operative optimization, and the advent of endovascular surgery (EVAR) have improved 30 day mortality for elective abdominal aortic aneurysm (AAA) repair. It remains unknown whether this has translated into improvements in long-term survival, particularly because these factors have also encouraged the treatment of older patients with greater comorbidity. The aim of this study was to quantify how 5 year survival after elective AAA repair has changed over time. METHODS: A systematic review was performed identifying studies reporting 5 year survival after elective infrarenal AAA repair. An electronic search of the Embase and Medline databases was conducted to January 2014. Thirty six studies, 60 study arms, and 107,814 patients were identified. Meta-analyses were conducted to determine 5 year survival and to report whether 5 year survival changed over time. RESULTS: Five-year survival was 69% (95% CI 67 to 71%, I(2) = 87%). Meta-regression on study midpoint showed no improvement in 5 year survival over the period 1969-2011 (log OR -0.001, 95% CI -0.014-0.012). Larger average aneurysm diameter was associated with poorer 5 year survival (adjusted log OR 0.058, 95% CI -0.095 to -0.021, I(2) = 85%). Older average patient age at surgery was associated with poorer 5 year survival (adjusted log OR -0.118, 95% CI -0.142 to -0.094, I(2) = 70%). After adjusting for average patient age, an improvement in 5 year survival over the period that these data spanned was obtained (adjusted log OR 0.027, 95% CI 0.012 to 0.042). CONCLUSION: Five-year survival remains poor after elective AAA repair despite advances in short-term outcomes and is associated with AAA diameter and patient age at the time of surgery. Age-adjusted survival appears to have improved; however, this cohort as a whole continues to have poor long-term survival. Research in this field should attempt to improve the life expectancy of patients with repaired AAA and to optimise patient selection. PMID- 26116491 TI - Caries-preventive Effect of Supervised Toothbrushing and Sealants. AB - To investigate the effectiveness of 3 caries-preventive measures on high- and low caries risk occlusal surfaces of first permanent molars over 3 y. This cluster randomized controlled clinical trial covered 242 schoolchildren, 6 to 7 y old, from low socioeconomic areas. At baseline, caries risk was assessed at the tooth surface level, through a combination of ICDAS II (International Caries Detection and Assessment System) and fissure depth codes. High-caries risk occlusal surfaces were treated according to daily supervised toothbrushing (STB) at school and 2 sealants: composite resin (CR) and atraumatic restorative treatment-high viscosity glass-ionomer cement (ART-GIC). Low-caries risk occlusal surfaces received STB or no intervention. Evaluations were performed after 0.5, 1, 2, and 3 y. A cavitated dentine carious lesion was considered a failure. Data were analyzed according to the proportional hazard rate regression model with frailty correction, Wald test, analysis of variance, and t test, according to the jackknife procedure for calculating standard errors. The cumulative survival rates of cavitated dentine carious lesion-free, high-caries risk occlusal surfaces were 95.6%, 91.4%, and 90.2% for STB, CR, and ART-GIC, respectively, over 3 y, which were not statistically significantly different. For low-caries risk occlusal surfaces, no statistically significant difference was observed between the cumulative survival rate of the STB group (94.8%) and the no intervention group (92.1%) over 3 y. There was neither a difference among STB, CR, and ART-GIC on school premises in preventing cavitated dentine carious lesions in high-caries risk occlusal surfaces of first permanent molars nor a difference between STB and no intervention for low-caries risk occlusal surfaces of first permanent molars over 3 y. PMID- 26116492 TI - Hydroxyapatite Growth Inhibition Effect of Pellicle Statherin Peptides. AB - In our recent studies, we have shown that in vivo-acquired enamel pellicle is a sophisticated biological structure containing a significant portion of naturally occurring salivary peptides. From a functional aspect, the identification of peptides in the acquired enamel pellicle is of interest because many salivary proteins exhibit functional domains that maintain the activities of the native protein. Among the in vivo-acquired enamel pellicle peptides that have been newly identified, 5 peptides are derived from statherin. Here, we assessed the ability of these statherin pellicle peptides to inhibit hydroxyapatite crystal growth. In addition, atomistic molecular dynamics (MD) simulations were performed to better understand the underlying physical mechanisms of hydroxyapatite growth inhibition. A microplate colorimetric assay was used to quantify hydroxyapatite growth. Statherin protein, 5 statherin-derived peptides, and a peptide lacking phosphate at residues 2 and 3 were analyzed. Statherin peptide phosphorylated on residues 2 and 3 indicated a significant inhibitory effect when compared with the 5 other peptides (P < 0.05). MD simulations showed a strong affinity and fast adsorption to hydroxyapatite for phosphopeptides, whereas unphosphorylated peptides interacted weakly with the hydroxyapatite. Our data suggest that the presence of a covalently linked phosphate group (at residues 2 and 3) in statherin peptides modulates the effect of hydroxyapatite growth inhibition. This study provides a mechanism to account for the composition and function of acquired enamel pellicle statherin peptides that will contribute as a base for the development of biologically stable and functional synthetic peptides for therapeutic use against dental caries and/or periodontal disease. PMID- 26116495 TI - Observation for mildly symptomatic normal-flow, low-gradient severe aortic stenosis: caution advised. PMID- 26116494 TI - Relating Spontaneously Reported Extrapyramidal Adverse Events to Movement Disorder Rating Scales. AB - BACKGROUND: While antipsychotic-induced extrapyramidal symptoms (EPS) and akathisia remain important concerns in the treatment of patients with schizophrenia, the relationship between movement disorder rating scales and spontaneously reported EPS-related adverse events (EPS-AEs) remains unexplored. METHODS: Data from four randomized, placebo- and haloperidol-controlled ziprasidone trials were analyzed to examine the relationship between spontaneously reported EPS-AEs with the Simpson Angus Scale (SAS) and Barnes Akathisia Rating Scale (BARS). Categorical summaries were created for each treatment group to show the frequencies of subjects with EPS-AEs in each of the SAS and BARS categories at weeks 1, 3, and 6, and agreement between ratings was quantified by means of weighted kappa (kappa). RESULTS: In general, we found greater frequencies of EPS-AEs with increasing severity of the SAS and BARS scores. The EPS-AEs reported with a "none" SAS score ranged from 0 to 22.2%, with a "mild" SAS score from 3.3 to 29.0%, and with a "moderate" SAS score from 0 to 100%. No subjects in any treatment group reported "severe" SAS scores or corresponding EPS-AEs. Agreement between SAS scores and EPS-AEs was poor for ziprasidone and placebo (kappa < 0.2) and only slightly better for haloperidol. The EPS-AEs reported with "non questionable" BARS scores ranged from 1.9 to 9.8%, with "mild moderate" BARS scores from 12.8 to 54.6%, and with "marked severe" scores from 0 to 100%. Agreement was modest for ziprasidone and placebo (kappa < 0.4) and moderate for haloperidol (kappa < 0.6). CONCLUSIONS: These findings may reflect either underreporting of AEs by investigators and subjects or erroneous rating scale evaluations. PMID- 26116493 TI - Candidate Risks Indicators for Bipolar Disorder: Early Intervention Opportunities in High-Risk Youth. AB - BACKGROUND: Psychiatric illnesses like bipolar disorder are increasingly understood to be neurodevelopmental disorders with clinical, psychological, and biological indicators recognizable long before the emergence of the full-blown syndromes. METHODS: This paper is a selective review of findings from studies of high-risk children of affected parents that inform the knowledge of illness risk and development markers of bipolar disorder. We specifically focus on candidate clinical, biological, and psychological risk indicators that could serve as targets for future early intervention and prevention studies. RESULTS: There is convergent evidence from prospective studies that bipolar disorder typically debuts as depressive episodes after puberty. In some high-risk children, sleep and anxiety disorders precede mood disorders by several years and reflect an increased vulnerability. An association between early exposure to adversity (eg, exposure to parental illness, neglect from mother) and increased risk of psychopathology may be mediated through increased stress reactivity evident at both behavioral and biological levels. Inter-related psychological processes including reward sensitivity, unstable self-esteem, rumination, and positive self appraisal are risk factors for mood disorders. Disturbances in circadian rhythm and immune dysfunction are associated with mood disorders and may be vulnerability markers influenced by these other risk factors. CONCLUSIONS: There is accruing evidence of a number of measurable and potentially modifiable markers of vulnerability and developing illness in youth at familial risk for bipolar disorder. Longitudinal studies of multiple biological and psychological risk processes in high-risk offspring, both individually and together, will improve our understanding of illness onset and lead to the development of specific early interventions. PMID- 26116496 TI - Novel Cell-Penetrating Peptide-Based Vaccine Induces Robust CD4+ and CD8+ T Cell Mediated Antitumor Immunity. AB - Vaccines that can coordinately induce multi-epitope T cell-mediated immunity, T helper functions, and immunologic memory may offer effective tools for cancer immunotherapy. Here, we report the development of a new class of recombinant protein cancer vaccines that deliver different CD8(+) and CD4(+) T-cell epitopes presented by MHC class I and class II alleles, respectively. In these vaccines, the recombinant protein is fused with Z12, a novel cell-penetrating peptide that promotes efficient protein loading into the antigen-processing machinery of dendritic cells. Z12 elicited an integrated and multi-epitopic immune response with persistent effector T cells. Therapy with Z12-formulated vaccines prolonged survival in three robust tumor models, with the longest survival in an orthotopic model of aggressive brain cancer. Analysis of the tumor sites showed antigen specific T-cell accumulation with favorable modulation of the balance of the immune infiltrate. Taken together, the results offered a preclinical proof of concept for the use of Z12-formulated vaccines as a versatile platform for the development of effective cancer vaccines. PMID- 26116497 TI - Lateral Extra-articular Tenodesis Reduces Rotational Laxity When Combined With Anterior Cruciate Ligament Reconstruction: A Systematic Review of the Literature. AB - PURPOSE: To determine whether the addition of lateral extra-articular tenodesis (LET) to anterior cruciate ligament (ACL) reconstruction would provide greater control of rotational laxity and improved clinical outcomes compared with ACL reconstruction alone. METHODS: Two independent reviewers searched 9 databases for randomized and nonrandomized clinical studies comparing ACL reconstruction plus LET versus ACL reconstruction alone in a human adult population. All years and 5 languages were included. Animal and cadaveric studies, revision or repair surgical techniques, and studies focused on biomechanical outcomes were excluded. Quality assessment of the included studies was performed with the Cochrane Collaboration tool. Outcomes of interest included the pivot-shift test, KT-1000/ 2000 measurements (MEDmetric, San Diego, CA), and International Knee Documentation Committee scores. RESULTS: The literature search yielded 3,612 articles. After titles and abstracts were reviewed, 106 articles were selected for full-text review, of which 29 studies met the inclusion criteria (8 randomized and 21 nonrandomized studies). Of the 8 randomized studies, 3 concluded that the results were nonsignificant between treatment groups, 4 were in favor of the extra-articular tenodesis, and 1 was in favor of the ACL reconstruction alone. The Cochrane Collaboration tool showed an unclear to high risk of bias for most articles. A meta-analysis showed a statistically significant difference for the pivot-shift test (P = .002, I2 = 34%) in favor of ACL reconstruction with LET. No difference was found between the groups for International Knee Documentation Committee scores (P = .75, I2 = 19%) and KT 1000/-2000 measurements (P = .84, I2 = 34%). CONCLUSIONS: Meta-analysis showed a statistically significant reduction in pivot shift in favor of the combined procedure. Studies lacked sufficient internal validity, sample size, methodologic consistency, and standardization of protocols and outcomes. LEVEL OF EVIDENCE: Level III, systematic review of Level I, II, and III studies. PMID- 26116498 TI - The end of the sustainable growth rate: What was it and what happens next? PMID- 26116499 TI - CD4 T Cell Depletion Substantially Augments the Rescue Potential of PD-L1 Blockade for Deeply Exhausted CD8 T Cells. AB - In various models of chronic infections and cancers, blockade of the inhibitory programmed cell death-1 (PD-1) pathway has been shown to be promising at restoring immune function. However, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (PD-L1) blockade. In particular, it is currently unclear whether the efficacy of PD-L1 blockade is dependent on the stage of disease. In a model of chronic lymphocytic choriomeningitis virus infection in mice, we show that exhausted CD8 T cells during the late stage of infection are refractory to rescue by PD-L1 blockade. Interestingly, PD-L1 blockade during the late stage of infection resulted in a biased expansion of PD-1(+) CTLA-4(+) regulatory T cells (Tregs) over antiviral CD8 T cells. Although previous studies have shown that Treg ablation can enhance the immune rescue by PD-L1 blockade, this regimen may induce lethal autoimmunity. In this report, we show that PD-L1 blockade together with CD4 T cell depletion effectively rescued deeply exhausted CD8 T cells and enhanced antiviral control during the late stage of chronic infection without any associated mortality. These data demonstrate the pleiotropic effects of anti-PD-L1 therapy on both virus-specific CD8 T cells and Tregs, and suggest a novel strategy for effectively rescuing deeply exhausted CD8 T cells. PMID- 26116500 TI - Dissecting CD8+ NKT Cell Responses to Listeria Infection Reveals a Component of Innate Resistance. AB - A small pool of NK1.1(+) CD8(+) T cells is harbored among the conventional CD8(+) T cell compartment. Conclusions drawn from the analysis of immune responses mediated by cytotoxic CD8(+) T cells are often based on the total population, which includes these contaminating NK1.1(+) CD8(+) T cells. An unresolved question is whether NK1.1(+) CD8(+) cells are conventional T cells that acquire NK1.1 expression upon activation or delineation into memory phenotype or whether they are a distinct cell population that induces immune responses in a different manner than conventional T cells. To address this question, we used the Listeria monocytogenes model of infection and followed CD8(+) NK1.1(+) T cells and NK1.1( ) CD8(+) T cells during each phase of the immune response: innate, effector, and memory. Our central finding is that CD8(+) NK1.1(+) cells and conventional NK1.1( ) CD8(+) T cells both contribute to the adaptive immune response to Listeria, but only CD8(+) NK1.1(+) cells were equipped with the ability to provide a rapid innate immune response, as demonstrated by early and Ag-independent IFN-gamma production, granzyme B expression, and degranulation. More importantly, purified conventional CD8(+) T cells alone, in the absence of any contaminating CD8(+) NK1.1(+) cells, were not sufficient to provide early protection to lethally infected mice. These results highlight the role of CD8(+) NK1.1(+) T cells in mounting early innate responses that are important for host defense and support the therapeutic potential of this subset to improve the effectiveness of protective immunity. PMID- 26116501 TI - The Mammalian Sterile 20-like 1 Kinase Controls Selective CCR7-Dependent Functions in Human Dendritic Cells. AB - The chemokine receptor CCR7 directs mature dendritic cells (mDCs) to the lymph nodes where these cells control the initiation of the immune response. CCR7 regulates chemotaxis, endocytosis, survival, migratory speed, and cytoarchitecture in mDCs. The molecular mechanisms used by CCR7 to regulate these functions in mDCs are not completely understood. The mammalian sterile 20-like 1 kinase (Mst1) plays a proapoptotic role under stress conditions; however, recently, it has been shown that Mst1 can also control homeostatic cell functions under normal conditions. In this study, we show that stimulation of CCR7 in mDCs induces Galphai-dependent activation of Mst1, suggesting the involvement of this kinase in the control of CCR7-dependent functions. Analysis of the mDCs in which Mst1 expression levels were reduced with small interfering RNA shows that this kinase mediates CCR7-dependent effects on cytoarchitecture, endocytosis and migratory speed but not on chemotaxis or survival. In line with these results, biochemical analysis indicates that Mst1 does not control key signaling regulators of CCR7-dependent chemotaxis or survival. In contrast, Mst1 regulates downstream of CCR7 and, of note, independently of Galpha13, the RhoA pathway. Reduction of Mst1 inhibits CCR7-dependent phosphorylation of downstream targets of RhoA, including cofilin, myosin L chain, and myosin L chain phosphatase. Consistent with the role of the latter molecules as modulators of the actin cytoskeleton, mDCs with reduced Mst1 also displayed a dramatic reduction in actin barbed-end formation that could not be recovered by stimulating CCR7. The results indicate that the kinase Mst1 controls selective CCR7-dependent functions in human mDCs. PMID- 26116502 TI - Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR5- CD4 T Cell Responses in Rhesus Macaques. AB - The goal of an HIV vaccine is to generate robust and durable protective Ab. Vital to this goal is the induction of CD4(+) T follicular helper (TFH) cells. However, very little is known about the TFH response to HIV vaccination and its relative contribution to magnitude and quality of vaccine-elicited Ab titers. In this study, we investigated these questions in the context of a DNA/modified vaccinia virus Ankara SIV vaccine with and without gp140 boost in aluminum hydroxide in rhesus macaques. In addition, we determined the frequency of vaccine-induced CD4(+) T cells coexpressing chemokine receptor, CXCR5 (facilitates migration to B cell follicles) in blood and whether these responses were representative of lymph node TFH responses. We show that booster modified vaccinia virus Ankara immunization induced a distinct and transient accumulation of proliferating CXCR5(+) and CXCR5(-) CD4 T cells in blood at day 7 postimmunization, and the frequency of the former but not the latter correlated with TFH and B cell responses in germinal centers of the lymph node. Interestingly, gp140 boost induced a skewing toward CXCR3 expression on germinal center TFH cells, which was strongly associated with longevity, avidity, and neutralization potential of vaccine-elicited Ab response. However, CXCR3(+) cells preferentially expressed the HIV coreceptor CCR5, and vaccine-induced CXCR3(+)CXCR5(+) cells showed a moderate positive association with peak viremia following SIV251 infection. Taken together, our findings demonstrate that vaccine regimens that elicit CXCR3-biased TFH cell responses favor Ab persistence and avidity but may predispose to higher acute viremia in the event of breakthrough infections. PMID- 26116503 TI - IL-10 Production in Macrophages Is Regulated by a TLR-Driven CREB-Mediated Mechanism That Is Linked to Genes Involved in Cell Metabolism. AB - IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections, macrophages are an important source of IL-10; however, the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. In this study, bone marrow-derived macrophages exposed to excretory/secretory products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Moreover, skin-resident tissue macrophages, which encounter S. mansoni excretory/secretory products during infection, are the first monocytes to produce IL-10 in vivo early postinfection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site, and we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state. PMID- 26116505 TI - Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice. AB - Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1beta and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1beta output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1beta in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies. PMID- 26116504 TI - The Thermodynamic Mechanism of Peptide-MHC Class II Complex Formation Is a Determinant of Susceptibility to HLA-DM. AB - Peptides bind MHC class II molecules through a thermodynamically nonadditive process consequent to the flexibility of the reactants. Currently, how the specific outcome of this binding process affects the ensuing epitope selection needs resolution. Calorimetric assessment of binding thermodynamics for hemagglutinin 306-319 peptide variants to the human MHC class II HLA-DR1 (DR1) and a mutant DR1 reveals that peptide/DR1 complexes can be formed with different enthalpic and entropic contributions. Complexes formed with a smaller entropic penalty feature circular dichroism spectra consistent with a non-compact form, and molecular dynamics simulation shows a more flexible structure. The opposite binding mode, compact and less flexible, is associated with greater entropic penalty. These structural variations are associated with rearrangements of residues known to be involved in HLA-DR (DM) binding, affinity of DM for the complex, and complex susceptibility to DM-mediated peptide exchange. Thus, the thermodynamic mechanism of peptide binding to DR1 correlates with the structural rigidity of the complex, and DM mediates peptide exchange by "sensing" flexible complexes in which the aforementioned residues are rearranged at a higher frequency than in more rigid ones. PMID- 26116507 TI - Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4. AB - Previous studies demonstrated that bone marrow-derived mesenchymal stem (stromal) cells (MSCs) reduce the severity of acute lung injury in animal models and in an ex vivo perfused human lung model. However, the mechanisms by which MSCs reduce lung injury are not well understood. In the present study, we tested the hypothesis that human MSCs promote the resolution of acute lung injury in part through the effects of a specialized proresolving mediator lipoxin A4 (LXA4). Human alveolar epithelial type II cells and MSCs expressed biosynthetic enzymes and receptors for LXA4. Coculture of human MSCs with alveolar epithelial type II cells in the presence of cytomix significantly increased the production of LXA4 by 117%. The adoptive transfer of MSCs after the onset of LPS-induced acute lung injury (ALI) in mice led to improved survival (48 h), and blocking the LXA4 receptor with WRW4, a LXA4 receptor antagonist, significantly reversed the protective effect of MSCs on both survival and the accumulation of pulmonary edema. LXA4 alone improved survival in mice, and it also significantly decreased the production of TNF-alpha and MIP-2 in bronchoalveolar lavage fluid. In summary, these experiments demonstrated two novel findings: human MSCs promote the resolution of lung injury in mice in part through the proresolving lipid mediator LXA4, and LXA4 itself should be considered as a therapeutic for acute respiratory distress syndrome. PMID- 26116506 TI - Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation. AB - Complement is implicated in asthma pathogenesis, but its mechanism of action in this disease remains incompletely understood. In this study, we investigated the role of properdin (P), a positive alternative pathway complement regulator, in allergen-induced airway inflammation. Allergen challenge stimulated P release into the airways of asthmatic patients, and P levels positively correlated with proinflammatory cytokines in human bronchoalveolar lavage (BAL). High levels of P were also detected in the BAL of OVA-sensitized and challenged but not naive mice. Compared with wild-type (WT) mice, P-deficient (P(-/-)) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab blocking of P at both sensitization and challenge phases or at challenge phase alone, but not at sensitization phase alone, reduced airway inflammation. Conversely, intranasal reconstitution of P to P(-/-) mice at the challenge phase restored airway inflammation to wild-type levels. Notably, C3a levels in the BAL of OVA challenged P(-/-) mice were significantly lower than in wild-type mice, and intranasal coadministration of an anti-C3a mAb with P to P(-/-) mice prevented restoration of airway inflammation. These results show that P plays a key role in allergen-induced airway inflammation and represents a potential therapeutic target for human asthma. PMID- 26116508 TI - Conditional Deletion of NF-kappaB-Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation. AB - NF-kappaB-inducing kinase (NIK) is a primary regulator of the noncanonical NF kappaB signaling pathway, which plays a vital role downstream of BAFF, CD40L, lymphotoxin, and other inflammatory mediators. Germline deletion or inactivation of NIK in mice results in the defective development of B cells and secondary lymphoid organs, but the role of NIK in adult animals has not been studied. To address this, we generated mice containing a conditional allele of NIK. Deletion of NIK in adult mice results in decreases in B cell populations in lymph nodes and spleen, similar to what is observed upon blockade of BAFF. Consistent with this, B cells from mice in which NIK is acutely deleted fail to respond to BAFF stimulation in vitro and in vivo. In addition, mice with induced NIK deletion exhibit a significant decrease in germinal center B cells and serum IgA, which is indicative of roles for NIK in additional pathways beyond BAFF signaling. Our conditional NIK-knockout mice may be broadly useful for assessing the postdevelopmental and cell-specific roles of NIK and the noncanonical NF-kappaB pathway in mice. PMID- 26116509 TI - P2X7 Receptor Regulates Internalization of Antimicrobial Peptide LL-37 by Human Macrophages That Promotes Intracellular Pathogen Clearance. AB - Bioactive peptide LL-37/hCAP18, the only human member of the cathelicidin family, plays important roles in killing various pathogens, as well as in immune modulation. We demonstrate that LL-37 is internalized by human macrophages in a time-, dose-, temperature-, and peptide sequence-dependent endocytotic process. Both clathrin- and caveolae/lipid raft-mediated endocytosis pathways are involved in LL-37 internalization. We find that the P2X7 receptor (P2X7R) plays an important role in LL-37 internalization by human macrophages because significantly less internalized LL-37 was detected in macrophages pretreated with P2X7R antagonists or, more specifically, in differentiated THP-1 cells in which the P2X7R gene had been silenced. Furthermore, this P2X7R-mediated LL-37 internalization is primarily connected to the clathrin-mediated endocytosis pathway. In addition, our results demonstrate that internalized LL-37 traffics to endosomes and lysosomes and contributes to intracellular clearance of bacteria by human macrophages, coinciding with increased reactive oxygen species and lysosome formation. Finally, we show that human macrophages have the potential to import LL-37 released from activated human neutrophils. In conclusion, our study unveils a novel mechanism by which human macrophages internalize antimicrobial peptides to improve their intracellular pathogen clearance. PMID- 26116510 TI - Spred1, a Suppressor of the Ras-ERK Pathway, Negatively Regulates Expansion and Function of Group 2 Innate Lymphoid Cells. AB - Cytokines from group 2 innate lymphoid cells (ILC2s) have been implicated in acute allergic responses, such as papain-induced lung inflammation. However, the means of homeostatic regulation of ILC2s have not been established. In this study, we demonstrated that Spred1, a negative regulator of the Ras-ERK pathway, plays an important role in the proliferation and apoptosis of ILC2s and in cytokine secretion from ILC2s. Intranasal administration of papain stimulated IL 5 and IL-13 production in the lung, which was enhanced when Spred1 was deleted. In vitro, Spred1(-/-) ILC2s proliferated faster than wild type ILC2s did and produced higher levels of cytokines in response to IL-33. On the contrary, a MEK inhibitor suppressed ILC2 proliferation and cytokine production. Spred1 deficiency resulted in stabilization of GATA3, which has been shown to play essential roles in the maintenance and cytokine production of ILC2. These data suggest that Spred1 negatively regulates ILC2 development and functions through the suppression of the Ras-ERK pathway. PMID- 26116511 TI - Control of Viremia Enables Acquisition of Resting Memory B Cells with Age and Normalization of Activated B Cell Phenotypes in HIV-Infected Children. AB - HIV affects the function of all lymphocyte populations, including B cells. Phenotypic and functional defects of B cells in HIV-infected adults have been well characterized, but defects in children have not been studied to the same extent. We determined the proportion of B cell subsets and frequencies of Ag specific memory B cells in peripheral blood from HIV-infected children and healthy controls, using flow cytometry and B cell ELISPOT, respectively. In addition, we measured the quantities and avidities of plasma Abs against various Ags by ELISA. We also determined plasma levels of BAFF and expression of BAFF receptors on B cells. Children with high HIV viremia had increased proportions of activated mature B cells, tissue-like memory B cells and plasmablasts, and low proportions of naive B cells when compared with community controls and children with low HIV viremia, similar to adults infected with HIV. HIV-infected groups had lower proportions of resting memory B cells than did community controls. Notably, high HIV viremia prevented the age-dependent accumulation of class switched resting memory B cells. HIV-infected children, regardless of the level of viremia, showed lower quantities and avidities of IgG and lower frequencies of memory B cells against Expanded Program on Immunization vaccines. The HIV infected children had an altered BAFF profile that could have affected their B cell compartment. Therefore, B cell defects in HIV-infected children are similar to those seen in HIV-infected adults. However, control of HIV viremia is associated with normalization of activated B cell subsets and allows age dependent accumulation of resting memory B cells. PMID- 26116512 TI - Primary Central Nervous System (CNS) Lymphoma B Cell Receptors Recognize CNS Proteins. AB - Primary lymphoma of the CNS (PCNSL) is a diffuse large B cell lymphoma confined to the CNS. To elucidate its peculiar organ tropism, we generated recombinant Abs (recAbs) identical to the BCR of 23 PCNSLs from immunocompetent patients. Although none of the recAbs showed self-reactivity upon testing with common autoantigens, they recognized 1547 proteins present on a large-scale protein microarray, indicating polyreactivity. Interestingly, proteins (GRINL1A, centaurin-alpha, BAIAP2) recognized by the recAbs are physiologically expressed by CNS neurons. Furthermore, 87% (20/23) of the recAbs, including all Abs derived from IGHV4-34 using PCNSL, recognized galectin-3, which was upregulated on microglia/macrophages, astrocytes, and cerebral endothelial cells upon CNS invasion by PCNSL. Thus, PCNSL Ig may recognize CNS proteins as self-Ags. Their interaction may contribute to BCR signaling with sustained NF-kappaB activation and, ultimately, may foster tumor cell proliferation and survival. These data may also explain, at least in part, the affinity of PCNSL cells for the CNS. PMID- 26116513 TI - mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells. AB - Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4(+) T cell responses, the involvement of mTOR in CD8(+) T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8(+) T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A(-/-) CD8(+) T cells exhibited impairments in production of IFN gamma and TNF-alpha and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen specific effector CD8(+) T cell responses were significantly impaired in SEMA4A( /-) mice. Furthermore, SEMA4A(-/-) CD8(+) T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8(+) T cells. IFN-gamma production and mTORC1 activity in SEMA4A(-/-) CD8(+) T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8(+) T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8(+) T cells, but also reveal a novel link between a semaphorin and mTOR signaling. PMID- 26116515 TI - Multi-scale exploration of the technical, economic, and environmental dimensions of bio-based chemical production. AB - In recent years, bio-based chemicals have gained traction as a sustainable alternative to petrochemicals. However, despite rapid advances in metabolic engineering and synthetic biology, there remain significant economic and environmental challenges. In order to maximize the impact of research investment in a new bio-based chemical industry, there is a need for assessing the technological, economic, and environmental potentials of combinations of biomass feedstocks, biochemical products, bioprocess technologies, and metabolic engineering approaches in the early phase of development of cell factories. To address this issue, we have developed a comprehensive Multi-scale framework for modeling Sustainable Industrial Chemicals production (MuSIC), which integrates modeling approaches for cellular metabolism, bioreactor design, upstream/downstream processes and economic impact assessment. We demonstrate the use of the MuSIC framework in a case study where two major polymer precursors (1,3-propanediol and 3-hydroxypropionic acid) are produced from two biomass feedstocks (corn-based glucose and soy-based glycerol) through 66 proposed biosynthetic pathways in two host organisms (Escherichia coli and Saccharomyces cerevisiae). The MuSIC framework allows exploration of tradeoffs and interactions between economy-scale objectives (e.g. profit maximization, emission minimization), constraints (e.g. land-use constraints) and process- and cell scale technology choices (e.g. strain design or oxygenation conditions). We demonstrate that economy-scale assessment can be used to guide specific strain design decisions in metabolic engineering, and that these design decisions can be affected by non-intuitive dependencies across multiple scales. PMID- 26116514 TI - HIV-1 gp120 influences the expression of microRNAs in human monocyte-derived dendritic cells via STAT3 activation. AB - BACKGROUND: MicroRNAs (miRs) are an abundant class of small non-coding RNAs (~22 nt) that reprogram gene expression by targeting mRNA degradation and translational disruption. An emerging concept implicates miR coupling with transcription factors in myeloid cell development and function, thus contributing to host defense and inflammation. The important role that these molecules play in the pathogenesis of HIV-1 is only now emerging. RESULTS: We provide evidence that exposure of monocyte-derived dendritic cells (MDDCs) to recombinant HIV-1 R5 gp120, but not to CCR5 natural ligand CCL4, influences the expression of a panel of miRs (i.e., miR-21, miR-155 and miR-181b) regulated by STAT3 and potentially targeting genes belonging to the STAT3 signaling pathway. The blockage of gp120 induced STAT3 activation impairs gp120 capacity to modulate the expression level of above mentioned miRs. Predictive analysis of miR putative targets emphasizes that these miRs share common target genes. Furthermore, gene ontology and pathway enrichment analysis outline that these genes mainly belong to biological processes related to regulation of transcription, in a complex network of interactions involving pathways relevant to HIV-DC interaction. CONCLUSIONS: Overall, these results point to gp120-triggered modulation of miR expression via STAT3 activation as a novel molecular mechanism exploited by HIV-1 to affect DC biology and thus modulate the immune response through complex regulatory loops involving, at the same time, miRs and transcription factors. PMID- 26116516 TI - ABO-incompatible cardiac transplantation in pediatric patients with high isohemagglutinin titers. AB - BACKGROUND: ABO-incompatible (ABOi) cardiac transplantation is now used widely in infants with isohemagglutinin titers <1:4, but there is increasing evidence that ABOi transplantation can also be used in children with significantly higher titers. We reviewed our high-titer ABOi transplants and report our results here. METHODS: Patients who underwent ABOi cardiac transplantation from 2000 to 2013 with pre-existing isohemagglutinin titers of >=1:16 were identified from departmental databases. Outcomes were reviewed using medical and laboratory records. RESULTS: Thirty patients underwent ABOi cardiac transplantation between 2000 and 2013. Twelve (40%) had pre-transplant isohemagglutinin titers of >=1:16 and were included for further study. Median age was 14.9 (range 9.8 to 107.3) months and median weight was 9.6 (range 7.6 to 25) kg. Five (42%) were male. Pre transplant diagnosis was cardiomyopathy in 8 of 12 (67%) and congenital heart disease in 4 of 12 (33%). Highest pre-transplant isohemagglutinin titer was 1:256 in 2 patients. Four patients (33%) had early antibody-mediated rejection (AMR), all within 15 days post-transplant. Management included use of rituximab, bortezomib, immunoadsorption and eculizumab. Three patients died but no deaths were associated with high isohemagglutinin titers. CONCLUSIONS: ABOi cardiac transplantation in patients with isohemagglutinin titers >=1:16 is possible. AMR may occur early and immunoadsorption has proven effective at decreasing antibody titers. PMID- 26116517 TI - Striking differences in synaptic facilitation along the dorsoventral axis of the hippocampus. AB - Hippocampus displays functional heterogeneity along its long axis which has been interpreted in terms of segregation of inputs. Recent evidence has shown that there are also important differences in the organization of the local neuronal circuitry between the dorsal (DH) and the ventral hippocampus (VH). Synaptic plasticity is a crucial factor for the function of the hippocampal circuit. In this study I compared the synaptic facilitation of the CA1 excitatory postsynaptic potential (EPSP) between dorsal and ventral rat hippocampal slices using field recordings and paired-pulse stimulation delivered at varying inter pulse intervals (IPIs). The facilitation of the EPSP-slope displayed an exponential decline with increasing stimulation strength or IPI. Furthermore, the facilitation of threshold EPSP-slope was significantly higher in DH than in VH at all IPIs. Most remarkably, the facilitation of the area of EPSP displayed a prominent peak at around 200ms in DH but not VH. This optimal facilitation declined abruptly at a position located two thirds of the way along the dorsoventral axis. N-methyl-d-aspartic acid receptors (NMDARs) contributed to the facilitation of EPSP-area in an IPI-selective manner in DH but not VH. Furthermore, NMDARs participated to the single-pulse-evoked EPSP-area more in VH than in DH. Blockade of GABAB receptors (GABABRs) eliminated the prominent facilitation at around 200ms and abolished the large dorsoventral difference in the facilitation of EPSP-area. Blockade of GABAA receptors (GABAARs) increased the maximum area of EPSP more in VH than in DH and reversed facilitation into GABABR-dependent depression that was more robust in DH than in VH. I conclude that interactions between the synaptic actions of GABABR, GABAAR, and NMDAR contribute to diversifying short-term synaptic plasticity along the dorsoventral axis of the hippocampus. It is hypothesized that this diversification has important implications for the information processing performed by the local circuitries of the two hippocampal segments. PMID- 26116519 TI - Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers. AB - We here investigate the effects of two exercise modalities (endurance treadmill training-TM and voluntary free-wheel activity-FW) on the brain cortex and cerebellum mitochondrial bioenergetics, permeability transition pore (mPTP), oxidative stress, as well as on proteins involved in mitochondrial biogenesis, apoptosis, and quality control. Eighteen male rats were assigned to sedentary SED, TM and FW groups. Behavioral alterations and ex vivo brain mitochondrial function endpoints were assessed. Proteins involved in oxidative phosphorylation (OXPHOS, including the adenine nucleotide translocator), oxidative stress markers and regulatory proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn SOD), as well as proteins involved in mitochondrial biogenesis (PGC1alpha, TFAM) were evaluated. Apoptotic signaling was measured through quantifying caspase 3, 8 and 9-like activities, Bax, Bcl2, CypD, and cofilin expression. Mitochondrial dynamics (Mfn1/2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin, p62)-related proteins were also measured by Western blotting. Only the TM exercise group showed increased spontaneous alternation and exploratory activity. Both exercise regimens improved mitochondrial respiratory activity, increased OXPHOS complexes I, III and V subunits in both brain subareas and decreased oxidative stress markers. Increased resistance to mPTP and decreased apoptotic signaling were observed in the brain cortex from TM and in the cerebellum from TM and FW groups. Also, exercise increased the expression of proteins involved in mitochondrial biogenesis, autophagy and fusion, simultaneous with decreased expression of mitochondrial fission-related protein DRP1. In conclusion, physical exercise improves brain cortex and cerebellum mitochondrial function, decreasing oxidative stress and apoptotic related markers. It is also possible that favorable alterations in mitochondrial biogenesis, dynamics and autophagy signaling induced by exercise contributed to increased mitochondrial plasticity leading to a more robust phenotype. PMID- 26116520 TI - Brain diffusivity pattern is individual-specific information. AB - The human brain is composed of complex networks of 100 billion neurons that underlie its higher functions. The set of neural connections in the brain has recently attracted growing interest from the scientific community. It is important to identify individual differences in these neural connections to study the background of individual differences in brain function and performance. In the present study, we investigated whether the pattern of brain diffusion, reflecting neural connections, is discernibly different among individuals; i.e., whether brain diffusivity is personally identifiable information. Using diffusion tensor imaging data from 224 healthy subjects scanned twice at an interval of about 1year, we performed brain recognition by spatial normalization of fractional anisotropy maps, feature extraction based on Principal Component Analysis, and calculation of the Euclidean distances between image pairs projected into the subspace. Even with only 16 dimensions used for projection, the rank-one identification rate was 99.1%. The rank-one identification rate was 100% with ?32 dimensions used for projection. The genuine accept rates were 95.1% and 100% at a false accept rate of 0.001%, with 16 and ?32 dimensions used for projection, respectively. There were no large differences in the Euclidean distance among different combinations of scanners used or between image pairs with and without scanner upgrade. The results indicate that brain diffusivity can identify a specific individual; i.e., the pattern of brain diffusion is personally identifiable information. Individual differences in brain diffusivity will form the basis of individual differences in personality and brain function. PMID- 26116518 TI - The ins and outs of the striatum: role in drug addiction. AB - Addiction is a chronic relapsing disorder characterized by the loss of control over drug intake, high motivation to obtain the drug, and a persistent craving for the drug. Accumulating evidence implicates cellular and molecular alterations within cortico-basal ganglia-thalamic circuitry in the development and persistence of this disease. The striatum is a heterogeneous structure that sits at the interface of this circuit, receiving input from a variety of brain regions (e.g., prefrontal cortex, ventral tegmental area) to guide behavioral output, including motor planning, decision-making, motivation and reward. However, the vast interconnectivity of this circuit has made it difficult to isolate how individual projections and cellular subtypes within this circuit modulate each of the facets of addiction. Here, we review the use of new technologies, including optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), in unraveling the role of the striatum in addiction. In particular, we focus on the role of striatal cell populations (i.e., direct and indirect pathway medium spiny neurons) and striatal dopaminergic and glutamatergic afferents in addiction-related plasticity and behaviors. PMID- 26116521 TI - Simultaneous changes in gray matter volume and white matter fractional anisotropy in Alzheimer's disease revealed by multimodal CCA and joint ICA. AB - The prominent morphometric alterations of Alzheimer's disease (AD) occur both in gray matter and in white matter. Multimodal fusion can examine joint information by combining multiple neuroimaging datasets to identify the covariant morphometric alterations in AD in greater detail. In the current study, we conducted a multimodal canonical correlation analysis and joint independent component analysis to identify the covariance patterns of the gray and white matter by fusing structural magnetic resonance imaging and diffusion tensor imaging data of 39 AD patients (23 males and 16 females, mean age: 74.91+/ 8.13years) and 41 normal controls (NCs) (20 males and 21 females, mean age: 73.97+/-6.34years) derived from the Alzheimer's Disease Neuroimaging Initiative database. The results revealed 25 joint independent components (ICs), of which three joint ICs exhibited strong links between the gray matter volume and the white matter fractional anisotropy (FA) and significant differences between the AD and NC group. The joint IC maps revealed that the simultaneous changes in the gray matter and FA values primarily involved the following areas: (1) the temporal lobe/hippocampus-cingulum, (2) the frontal/cingulate gyrus-corpus callosum, and (3) the temporal/occipital/parietal lobe-corpus callosum/corona radiata. Our findings suggest that gray matter atrophy is associated with reduced white matter fiber integrity in AD and possibly expand the understanding of the neuropathological mechanisms in AD. PMID- 26116522 TI - Tanshinone IIA protects dopaminergic neurons against 6-hydroxydopamine-induced neurotoxicity through miR-153/NF-E2-related factor 2/antioxidant response element signaling pathway. AB - Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder with increased oxidative stress, the underlying vital process contributing to cell death. Tanshinone IIA (Tan IIA), a major bioactive diterpene quinone of Salva miltiorrhiza, had been proved effective in the MPTP model through its anti-inflammatory activity. Here in this research, we found that Tan IIA prevented the loss of nigrostriatal dopaminergic neurons by activating the NF E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was attenuated by the treatment of Tan IIA in SH-SY5Y cells, which significantly reduced 6-OHDA-induced lactic dehydrogenase release and reactive oxygen species production. Further study indicated that Tan IIA contributed to the nuclear accumulation of Nrf2, which bound to the ARE sequence, and activated ARE-regulated genes, including heme oxygenase-1, glutamate cysteine ligase catalytic subunit (GCLC) and glutamate cysteine ligase modifier subunit (GCLM). Tan IIA also protected against damage to mitochondrial membrane potential, reduced the translocation of cytochrome c from the mitochondria to the cytoplasm and the activation of Caspase-9 and Caspase-3. Moreover, we demonstrated the above effects were performed in Nrf2-dependent manner. Further studies revealed that Tan IIA reduced the enhancement of miR-153 by 6-OHDA, which targeted the 3'-UTR of Nrf2, and suppressed its expression and activation. Additionally, neurodegeneration caused by in vivo stereotaxic injection of 6-OHDA could also be ameliorated by the administration of Tan IIA. Taken together, our results strongly suggest that Tan IIA may be beneficial for the treatment of PD, and also confirm that targeting the Nrf2/ARE pathway is a promising strategy for therapeutic intervention in PD. PMID- 26116523 TI - The neuropathology of schizophrenia: A selective review of past studies and emerging themes in brain structure and cytoarchitecture. AB - Schizophrenia is a devastating mental illness. Although its etiology is still largely unknown, strides have been taken throughout the last several decades to elucidate the nature of the neuropathology behind this disorder. The advent of neuroimaging technologies such as computerized axial tomography and magnetic resonance imaging have progressed knowledge about the macroscopic brain changes that occur in schizophrenia, including the characteristic enlarged ventricle size and reductions in gray matter volume, whole-brain volume, and white matter anisotropy. Although this review presents a broad outline of current and historical neuropathological research, the focus is primarily on the quantitative neuropathology of the cerebral cortex in schizophrenia, which may underlie many of the larger scale changes observed. The reduced neuropil hypothesis has been suggested as a microanatomical explanation to account for these macroscopic changes, although the present review finds that evidence does not always support this. A quantitative meta-analytic summary of these studies, focused on neuron density, provides support for the finding of increased neuron density in schizophrenia, with variation dependent on age. This is consistent with neuroimaging data and implicates an altered aging trajectory as a factor in the pathogenesis of schizophrenia. Combined with evidence from other neuroanatomical studies reviewed here, as well as studies in childhood-onset schizophrenia, the evidence converges on a progressive neurodevelopmental model of schizophrenia related to altered neuroplasticity. The evidence also supports a particular vulnerability of inhibitory cortical circuits with markers of interneurons showing some of the more consistent reductions in schizophrenia. PMID- 26116525 TI - Right-Sided Colon Ischemia and Acute Mesenteric Insufficiency: Are They Separate Entities? PMID- 26116524 TI - Isolation and characterization of a novel Rhabdovirus from a wild boar (Sus scrofa) in Japan. AB - A novel rhabdovirus was isolated from the serum of a healthy Japanese wild boar (Sus scrofa leucomystax) and identified using the rapid determination system for viral nucleic acid sequences (RDV), next-generation sequencing, and electron microscopy. The virus was tentatively named wild boar rhabdovirus 1 (WBRV1). Phylogenetic analysis of the entire genome sequence indicated that WBRV1 is closely related to Tupaia rhabdovirus (TRV), which was isolated from cultured cells of hepatocellular carcinoma tissue of tree shrew. TRV has not been assigned to any genus of Rhabdoviridae till date. Analysis of the L gene indicated that WBRV1 belongs to the genus Vesiculovirus. These observations suggest that both TRV and WBRV1 belong to a new genus of Rhabdoviridae. Next-generation genome sequencing of WBRV1 revealed 5 open reading frames of 1329, 765, 627, 1629, and 6336 bases in length. The WBRV1 gene sequences are similar to those of other rhabdoviruses. Epizootiological analysis of a population of wild boars in Wakayama prefecture in Japan indicated that 6.5% were positive for the WBRV1 gene and 52% were positive for WBRV1-neutralizing antibodies. Furthermore, such viral neutralizing antibodies were found in domestic pigs in another prefecture. WBRV1 was inoculated intranasally and intraperitoneally into SCID and BALB/c mice and viral RNA was detected in SCID mice, suggesting that WBRV1 can replicate in immunocompromised mice. These results indicate this novel virus is endemic in wild animals and livestock in Japan. PMID- 26116526 TI - Unusual Cause of Fever and Abdominal Pain: Acute Suppuration of the Pancreas Duct and Endoscopic Management. PMID- 26116527 TI - The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond. AB - Drug-induced liver injury (DILI) remains a leading reason why new compounds are dropped from further study or are the subject of product warnings and regulatory actions. Hy's Law of drug-induced hepatocellular jaundice causing a case-fatality rate or need for transplant of 10% or higher has been validated in several large national registries, including the ongoing, prospective U.S. Drug-Induced Liver Injury Network. It serves as the basis for stopping rules in clinical trials and in clinical practice. Because DILI can mimic all known causes of acute and chronic liver disease, establishing causality can be difficult. Histopathologic findings are often nonspecific and rarely, if ever, considered pathognomonic. A daily drug dose >50-100 mg is more likely to be hepatotoxic than does <10 mg, especially if the compound is highly lipophilic or undergoes extensive hepatic metabolism. The quest for a predictive biomarker to replace alanine aminotransferase is ongoing. Markers of necrosis and apoptosis such as microRNA 122 and keratin 18 may prove useful in identifying patients at risk for severe injury when they initially present with a suspected acetaminophen overdose. Although a number of drugs causing idiosyncratic DILI have HLA associations that may allow for pre-prescription testing to prevent hepatotoxicity, the cost and relatively low frequency of injury among affected patients limit the current usefulness of such genome-wide association studies. Alanine aminotransferase monitoring is often recommended but has rarely been shown to be an effective method to prevent serious DILI. Guidelines on the diagnosis and management of DILI have recently been published, although specific therapies remain limited. The LiverTox Web site has been introduced as an interactive online virtual textbook that makes the latest information on more than 650 agents available to clinicians, regulators, and drug developers alike. PMID- 26116528 TI - Systemic administration of riluzole enhances recognition memory and facilitates extinction of fear memory in rats. AB - Strategies to enhance recognition memory and facilitate extinction of fear memory have attracted increasing attention for enhancing the effectiveness of exposure therapy for anxiety disorders. Previously, we demonstrated that systemic administration of riluzole has clear anxiolytic-like effects, without impairing memory, in rats. In the present study, we examined whether riluzole could have therapeutic potential for anxiety disorders when combined with exposure therapy. Both riluzole and D-cycloserine enhanced recognition memory in the novel object recognition test and facilitated extinction learning in the contextual fear conditioning in rats. Interestingly, the facilitatory effect of riluzole on extinction learning was clearly observed even after a short re-exposure to the context, while D-cycloserine was ineffective at facilitating extinction when a short duration exposure session was given. In contrast, diazepam impaired both recognition memory and the extinction of fear memory. Our findings strongly suggest that systemic administration of riluzole may have therapeutic efficacy when combined with exposure therapy for treating a range of anxiety disorders. Clinical trials to examine the efficacy of riluzole in combination with exposure therapy in these patients are warranted. PMID- 26116529 TI - RGS19 converts iron deprivation stress into a growth-inhibitory signal. AB - Iron chelation is a promising therapeutic strategy for cancer that works, in part, by inducing overexpression of N-myc downstream-regulated gene 1 protein (NDRG1), a known growth inhibitor and metastasis suppressor. However, details of the signaling cascades that convert physical stress into a biological response remain elusive. We investigated the role of RGS19, a regulator of G-protein signaling, in iron chelator-induced NDRG1 overexpression in HeLa cells. Knockdown of RGS19 diminished the expression of genes involved in desferrioxamine (DFO) induced growth inhibition. Conversely, overexpression of RGS19 enhanced the expression of these genes. Moreover, overexpression of RGS19 reduced cell viability. Overexpression of G-protein alpha subunit i3 (Galphai3) repressed the induction of NDRG1 expression. Selective inhibition of downstream targets of Galphai3 abrogated DFO-induced overexpression of NDRG1. DFO protected RGS19 from proteolysis induced by GAIP interacting protein N terminus (GIPN); moreover, an iron-deficient RGS19 mutant was stable in the presence of GIPN and retained GTPase-activating protein activity. RGS19 was co-purified with iron and showed unique UV-absorption characteristics frequently observed in iron-binding proteins. This study demonstrates that RGS19 senses cellular iron availability and is stabilized under iron-depleted conditions, resulting in the induction of a growth-inhibitory signal. PMID- 26116530 TI - An integrated RNA-Seq and network study reveals a complex regulation process of rice embryo during seed germination. AB - Seed germination is a crucial stage for plant development and agricultural production. To investigate its complex regulation process, the RNA-Seq study of rice embryo was conducted at three time points of 0, 12 and 48 h post imbibition (HPI). Dynamic transcriptional alterations were observed, especially in the early stage (0-12 HPI). Seed related genes, especially those encoding desiccation inducible proteins and storage reserves in embryo, decreased drastically after imbibition. The expression profiles of phytohormone related genes indicated distinct roles of abscisic acid (ABA), gibberellin (GA) and brassinosteroid (BR) in germination. Moreover, network analysis revealed the importance of protein phosphorylation in phytohormone interactions. Network and gene ontology (GO) analyses suggested that transcription factors (TFs) played a regulatory role in functional transitions during germination, and the enriched TF families at 0 HPI implied a regulation of epigenetic modification in dry seeds. In addition, 35 germination-specific TF genes in embryo were identified and seven genes were verified by qRT-PCR. Besides, enriched TF binding sites (TFBSs) supported physiological changes in germination. Overall, this study expands our comprehensive knowledge of multiple regulation factors underlying rice seed germination. PMID- 26116532 TI - The RNA-binding protein PCBP2 inhibits Ang II-induced hypertrophy of cardiomyocytes though promoting GPR56 mRNA degeneration. AB - Poly(C)-binding proteins (PCBPs) are known as RNA-binding proteins that interact in a sequence-specific fashion with single-stranded poly(C). This family can be divided into two groups: hnRNP K and PCBP1-4. PCBPs are expressed broadly in human and mouse tissues and all members of the PCBP family are related evolutionarily. However, their physiological or pathological functions in the hearts remain unknown. Here we reported that PCBP2 is an anti-hypertrophic factor by inhibiting GPR56 mRNA stability. We found the downregulation of PCBP2 in human failing hearts and mouse hypertrophic hearts. PCBP2 knockdown promoted angiotensin II (Ang II)-induced hypertrophy (increase in cell size, protein synthesis and activation of fetal genes) of neonatal cardiomyocytes and H9C2 cells, while PCBP2 overexpression obtained oppose effects. Furthermore, PCBP2 was shown to inhibit GPR56 expression by promoting its mRNA degeneration in cardiomyocytes. Finally, we knocked down GPR56 in cardiomyocytes and found that GPR56 promoted Ang II-induced cardiomyocyte hypertrophy and it contributed to PCBP2 effects on cardiomyocyte hypertrophy. PMID- 26116531 TI - Niclosamide, an anti-helminthic molecule, downregulates the retroviral oncoprotein Tax and pro-survival Bcl-2 proteins in HTLV-1-transformed T lymphocytes. AB - Adult T cell leukemia and lymphoma (ATL) is a highly aggressive form of hematological malignancy and is caused by chronic infection of human T cell leukemia virus type 1 (HTLV-1). The viral genome encodes an oncogenic protein, Tax, which plays a key role in transactivating viral gene transcription and in deregulating cellular oncogenic signaling to promote survival, proliferation and transformation of virally infected T cells. Hence, Tax is a desirable therapeutic target, particularly at early stage of HTLV-1-mediated oncogenesis. We here show that niclosamide, an anti-helminthic molecule, induced apoptosis of HTLV-1 transformed T cells. Niclosamide facilitated degradation of the Tax protein in proteasome. Consistent with niclosamide-mediated Tax degradation, this compound inhibited activities of MAPK/ERK1/2 and IkappaB kinases. In addition, niclosamide downregulated Stat3 and pro-survival Bcl-2 family members such as Mcl-1 and repressed the viral gene transcription of HTLV-1 through induction of Tax degradation. Since Tax, Stat3 and Mcl-1 are crucial molecules for promoting survival and growth of HTLV-1-transformed T cells, our findings demonstrate a novel mechanism of niclosamide in inducing Tax degradation and downregulating various cellular pro-survival molecules, thereby promoting apoptosis of HTLV-1 associated leukemia cells. PMID- 26116533 TI - Distinct functional modes of SUMOylation for retinoid X receptor alpha. AB - The present study investigated human retinoid X receptor alpha (hRXRalpha) as a substrate for modification with small ubiquitin like modifier (SUMO) and how members of the protein inhibitor of activated STAT (PIAS) family may impact upon this process. In agreement with a previous study, we validate Ubc9 to facilitate SUMOylation of hRXRalpha at lysine 108 but note this modification to occur for all isoforms rather than specifically with SUMO1 and to preferentially occur with the unliganded form of hRXRalpha. SUMOylation of hRXRalpha is significantly enhanced through PIAS4-mediated activity with lysine 245 identified as a specific SUMO2 acceptor site modified in a PIAS4-dependent fashion. While individual mutations at lysine 108 or 245 modestly increase receptor activity, the combined loss of SUMOylation at both sites significantly potentiates the transcriptional responsiveness of hRXRalpha suggesting both sites may cooperate in a DNA element dependent context. Our findings highlight combinatorial effects of SUMOylation may regulate RXRalpha-directed signalling in a gene-specific fashion. PMID- 26116534 TI - Netrin-1 induces the migration of Schwann cells via p38 MAPK and PI3K-Akt signaling pathway mediated by the UNC5B receptor. AB - Schwann cells (SCs) play an essentially supportive role in the regeneration of injured peripheral nerve system (PNS). As Netrin-1 is crucial for the normal development of nervous system (NS) and can direct the process of damaged PNS regeneration, our study was designed to determine the role of Netrin-1 in RSC96 Schwann cells (an immortalized rat Schwann cell line) proliferation and migration. Our studies demonstrated that Netrin-1 had no effect on RSC96 cells proliferation, while significantly promoted RSC96 cells migration. The Netrin-1 induced RSC96 cells migration was significantly attenuated by inhibition of p38 and PI3K through pretreatment with SB203580 and LY294002 respectively, but not inhibition of MEK1/2 and JNK by U0126-EtOH and SP600125 individually. Treatment with Netrin-1 enhanced the phosphorylation of p38 and Akt. QRT-PCR indicated that Netrin-1 and only its receptors Unc5a, Unc5b and Neogenin were expressed in RSC96 cells, among which Unc5b expressed the most. And UNC5B protein was significantly increased after stimulated by Netrin-1. In conclusion, we show here that Netrin-1 enhanced SCs migration is mediated by activating p38 MAPK and PI3K-Akt signal cascades via receptor UNC5B, which suggests that Netrin-1 could serve as a new therapeutic strategy and has potential application value for PNS regeneration. PMID- 26116536 TI - Sox2 promotes survival of satellite glial cells in vitro. AB - Sox2 is a transcriptional factor expressed in neural stem cells. It is known that Sox2 regulates cell differentiation, proliferation and survival of the neural stem cells. Our previous study showed that Sox2 is expressed in all satellite glial cells of the adult rat dorsal root ganglion. In this study, to examine the role of Sox2 in satellite glial cells, we establish a satellite glial cell enriched culture system. Our culture method succeeded in harvesting satellite glial cells with the somata of neurons in the dorsal root ganglion. Using this culture system, Sox2 was downregulated by siRNA against Sox2. The knockdown of Sox2 downregulated ErbB2 and ErbB3 mRNA at 2 and 4 days after siRNA treatment. MAPK phosphorylation, downstream of ErbB, was also inhibited by Sox2 knockdown. Because ErbB2 and ErbB3 are receptors that support the survival of glial cells in the peripheral nervous system, apoptotic cells were also counted. TUNEL-positive cells increased at 5 days after siRNA treatment. These results suggest that Sox2 promotes satellite glial cell survival through the MAPK pathway via ErbB receptors. PMID- 26116535 TI - Oxidative stress triggers lipid droplet accumulation in primary cultured hepatocytes by activating fatty acid synthesis. AB - Despite the impaired intestinal lipid absorption and low level of visceral fat, the Sod1-deficient mouse is susceptible to developing liver steatosis. To gain insights into the mechanism responsible for this abnormal lipid metabolism, we analyzed primary cultured hepatocytes obtained from Sod1-deficient and wild-type mice. Lipid droplets began to accumulate in the cultured hepatocytes and was further increased by a Sod1 deficiency. Levels of enzymes involved in lipogenesis were elevated. It thus appears that lipogenesis is activated by oxidative stress, which is more prominent in the case of Sod1 deficiency, and appears to participate in liver steatosis. PMID- 26116537 TI - Lactobionic acid reduces body weight gain in diet-induced obese rats by targeted inhibition of galectin-1. AB - Galectin-1 (GAL1), an animal lectin with a carbohydrate recognition domain, is known for its roles in cancer, tumor progression, as well as obesity and related complications. Here, we investigated the anti-obesity effect of lactobionic acid (LBA), a GAL1 inhibitor, both in vitro and in vivo. LBA treatment significantly reduced lipogenic capacity of both 3T3-L1 and HIB1B adipocytes through down regulation of major adipogenic transcription factors at both mRNA and protein levels. Moreover, oral administration and intraperitoneal injection of LBA in Sprague-Dawley male rats fed a high fat diet caused marked reduction of body weight gain as well as improvement of related metabolic parameters. Important lipogenic transcription factors were also down-regulated in LBA-treated rats, resulting in attenuated lipogenesis and fat accumulation. Collectively, pharmaceutical targeting of GAL1 using LBA would be a novel therapeutic approach for the treatment of obesity. PMID- 26116538 TI - miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma. AB - Emerging evidence suggests that microRNAs (miRNAs) play important roles in regulating HCC development and progression; however, the mechanisms by which their specific functions and mechanisms remained to be further explored. miR-129 has been reported in gastric cancers, lung cancer and colon cancer. In this study, we disclosed a new tumor suppresser function of miR-129 in HCC. We also found the downregulation of miR-129 occurred in nearly 3/4 of the tumors examined (56/76) compared with adjacent nontumorous tissues, which was more importantly, correlated to the advanced stage and vascular invasion. We then demonstrated that miR-129 overexpression attenuated HCC cells proliferation and invasion, inducing apoptosis in vitro. Moreover, we used miR-129 antagonist and found that anti-miR 129 promoted HCC cells malignant phenotypes. Mechanistically, our further investigations revealed that miR-129 suppressed cell proliferation and invasion by targeting the 3'-untranslated region of PAK5, as well as miR-129 silencing up regulated PAK5 expression. Moreover, miR-129 expression was inversely correlated with PAK5 expression in 76 cases of HCC samples. RNA interference of PAK5 attenuated anti-miR-129 mediated cell proliferation and invasion in HCC cells. Taken together, these results demonstrated that miR-129 suppressed tumorigenesis and progression by directly targeting PAK5, defining miR-129 as a potential treatment target for HCC. PMID- 26116539 TI - Selective upregulation of the expression of plasma membrane calcium ATPase isoforms upon differentiation and 1,25(OH)2D3-vitamin treatment of colon cancer cells. AB - We have previously presented co-expression of the plasma membrane calcium ATPase isoforms 4b (PMCA4b) and 1b (PMCA1b) in colon carcinoma cells, and selective upregulation of PMCA4b during differentiation initiated by short chain fatty acids or post-confluent growth. Here we show that the induction of PMCA4b expression is a characteristic feature of the post-confluency-induced differentiation of both enterocyte-type and goblet cell-type colon cancer cells. Vitamin D3 (1,25(OH)2D3) is a well-known regulator of intestinal Ca(2+) absorption and of basic cell functions such as growth and differentiation in various cell types. As PMCA proteins are involved both in intestinal Ca(2+) absorption and adenocarcinoma cell differentiation, we investigated the effect of 1,25(OH)2D3 on PMCA expression in enterocyte-like colon carcinoma cells, and monitored its effect on the expression of various differentiation markers. 1,25(OH)2D3 stimulated PMCA1b, but not PMCA4b expression without modulating the expression of the majority of the differentiation markers examined. Caco-2 cells differentiated in post-confluent cultures present normal enterocyte-like intestinal epithelial phenotype. To better understand the role of PMCA proteins in vectorial Ca(2+) transport by enterocytes, we also studied their subcellular localization in mature polarized Caco-2 cells. Both PMCA isoforms were located to the basolateral membrane, and the PMCA-specific immunofluorescent signal was significantly higher in vitamin D3-treated cells, underlining the 1,25(OH)2D3 induced upregulation of PMCA (presumably 1b isoform) expression in differentiated Caco-2 cells. We suggest that while PMCA1b has a housekeeping function in colon cancer cells, PMCA4b participates in the reorganization of the Ca(2+) signalling machinery during cell differentiation. The subcellular localization of PMCA1b and its selective 1,25(OH)2D3-dependent upregulation indicate that this isoform may have a specific role in 1,25(OH)2D3-stimulated intestinal Ca(2+) absorption. PMID- 26116540 TI - TGF-beta1-induced regulatory T cells. AB - Besides central tolerance peripheral tolerance is an important mechanism to avoid development of autoimmunity. Naturally occurring thymic-derived regulatory T cells (nTreg) mediate peripheral tolerance by suppressing autoreactive T cells clones having escaped thymic deletional control. This implies that nTreg have therapeutic potential to dampen autoimmune disease. However, one of the main challenges for the therapeutic application of nTreg still remains the scarce amount of nTreg available. Transforming growth factor beta (TGF-beta1) plays a critical role in the generation and immunosuppressive function of nTreg thereby contributing to immune homeostasis. TGF-beta1 is thought to be essential for the generation and function of nTreg and regulatory T cells with suppressive properties can be induced in vitro by TGF-beta1. These so-called TGF-beta1 induced regulatory T cells (iTreg) can be induced in vitro from conventional CD4(+) T cells by addition of TGF-beta1 and this discovery has added new options to use regulatory T cells therapeutically. Here we discuss the generation and in vitro and in vivo functions of murine and human TGF-beta1-induced regulatory T cells in light of potential application as treatment for autoimmune diseases including current problems and drawbacks in their therapeutic use. PMID- 26116541 TI - In silico discovery and modeling of non-coding RNA structure in viruses. AB - This review covers several computational methods for discovering structured non coding RNAs in viruses and modeling their putative secondary structures. Here we will use examples from two target viruses to highlight these approaches: influenza A virus-a relatively small, segmented RNA virus; and Epstein-Barr virus a relatively large DNA virus with a complex transcriptome. Each system has unique challenges to overcome and unique characteristics to exploit. From these particular cases, generically useful approaches can be derived for the study of additional viral targets. PMID- 26116542 TI - A proposed resolution to the paradox of drug reward: Dopamine's evolution from an aversive signal to a facilitator of drug reward via negative reinforcement. AB - The mystery surrounding how plant neurotoxins came to possess reinforcing properties is termed the paradox of drug reward. Here we propose a resolution to this paradox whereby dopamine - which has traditionally been viewed as a signal of reward - initially signaled aversion and encouraged escape. We suggest that after being consumed, plant neurotoxins such as nicotine activated an aversive dopaminergic pathway, thereby deterring predatory herbivores. Later evolutionary events - including the development of a GABAergic system capable of modulating dopaminergic activity - led to the ability to down-regulate and 'control' this dopamine-based aversion. We speculate that this negative reinforcement system evolved so that animals could suppress aversive states such as hunger in order to attend to other internal drives (such as mating and shelter) that would result in improved organismal fitness. PMID- 26116543 TI - How fast and how often: The pharmacokinetics of drug use are decisive in addiction. AB - How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, 'spiking' brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder. PMID- 26116546 TI - Corrigendum. AB - Corrigendum to ESLAV/ECLAM/LAVA/EVERI recommendations for the roles, responsibilities and training of the laboratory animal veterinarian and the designated veterinarian under Directive 2010/63/EU, by GM Poirier, C Bergmann, DG Denais-Lalieve, IA Dontas, N Dudoignon, H Ehall, JM Fentener van Vlissingen, M Fornasier, R Kalman, A Hansen, S Schueller, P Vergara, R Weilenmann, J Wilson, AD Degryse.Published in Laboratory Animals 2015, Vol. 49(2) 89-99. DOI: 10.1177/0023677214557717. PMID- 26116545 TI - Specific proactive and generic reactive inhibition. AB - Inhibition concerns the capacity to suppress on-going response tendencies. Patient data and results from neuro-imaging and magnetic-stimulation studies point to a proactive mechanism involving top-down control signals that potentiate inhibitory sensory-motor connections, depending on whether possibly necessary inhibition is anticipated or not. The proactive mechanism is manifest in stronger sensory-cortex responses to stop signals yielding successful inhibition, observed as a modulation of short-latency human evoked potentials (N1) which may overlap with generic mechanisms for infrequent-event detection. A second, reactive, mechanism would be much more independent of the specific inhibition context, and generalize to situations in which behavioral interrupt is not dictated by task demands but invoked by the salience of task-irrelevant but potentially distracting events. The reactive mechanism is visible in a longer-latency human event-related potential termed frontal P3 (fP3) which is elicited by (successful) stop stimuli and most likely originates from dorsal-medial prefrontal cortex (preSMA), and is dissociated from the proactive mechanism pharmacologically and by individual differences. Implications may arise for more personalized treatments of disorders such as ADHD. PMID- 26116547 TI - Teaching child psychiatric assessment skills: Using pediatric mental health screening tools. AB - This article describes the workshop "Teaching Child Psychiatric Assessment Skills: Using Mental Health Screening Instruments," presented at the 35th Forum for Behavioral Sciences in Family Medicine on 20 September 2014. The goals of the presentation were (1) to teach family medicine behavioral health educators to use both general and problem-specific mental health screening tools (MHSTs) in their work with trainees to help satisfy the Accreditation Council for Graduate Medical Education (ACGME) mandate for behavioral and mental health experience during family medicine residency, (2) to reflect on how MHSTs might be integrated into the flow of family medicine teaching practices, and (3) to exemplify how evidence based methods of adult education might be used in teaching such content. One general MHST, the Pediatric Symptom Checklist-17 and one problem-specific MHST for each of the four commonest pediatric mental health issues: for attention deficit hyperactivity disorder, the Vanderbilt; for Anxiety, the Screen for Childhood Anxiety-Related Emotional Disorders; for Depression, the Patient Health Questionnaire-9 for teens; and for Aggression, the Retrospective-Modified Overt Aggression Scale, were practiced at least twice in the context of a clinical vignette. All of the selected MHSTs are free in the public domain and available for download from the website: www.CAPPCNY.org. Participants were asked to reflect on their own office practice characteristics and consider how MHSTs might be integrated into their systems of care. This workshop could be replicated by others wishing to teach the use of MHSTs in primary care settings or teaching programs. PMID- 26116548 TI - Synovial tissue volume: a treatment target in knee osteoarthritis (OA). AB - BACKGROUND: Synovitis occurring frequently in osteoarthritis (OA) may be a targeted outcome. There are no data examining whether synovitis changes following intra-articular intervention. METHODS: Persons aged 40 years and older with painful knee OA participated in an open label trial of intra-articular steroid therapy. At all time points they completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. They had a contrast-enhanced (CE) MRI immediately prior to an intra-articular steroid injection with a repeat scan within 20 days. Response status was assessed using the Osteoarthritis Research Society International (OARSI) response criteria. OARSI responders were followed until their pain relapsed either within 20% of baseline or 6 months, shortly after which a third MRI was performed. Synovial tissue volume (STV) was measured on postcontrast knee images. We looked at changes in the STV and in pain, and their association. RESULTS: 120 subjects with preinjection and postinjection CE MRI were followed. Their mean age was 62.3 years (SD=10.3) and 62 (52%) were women. The median time between injection and follow-up scan was 8 days (IQR 7-14 days). 85/120 (71%) were OARSI responders. Pain decreased (mean change in KOOS=+23.9; 95% CI 20.1 to 27.8, p<0.001) following steroid injection, as did mean STV (mean change=-1071 mm(3); 95% CI -1839 mm(3) to -303 mm(3), p=0.01). Of the 80 who returned for a third MRI, pain relapsed in 57, and in the 48 of those with MRI data, STV increased between follow-up and final visit (+1220 mm(3); 95% CI 25 mm(3) to 2414 mm(3), p=0.05). 23 were persistent responders at 6 months and, in these, STV did not increase (mean change=-202 mm(3); 95% CI -2008 mm(3) to 1604 mm(3), p=0.83). Controlling for variation over time, there was a significant association between synovitis volume and KOOS pain (b coefficient change in KOOS pain score per 1000 mm(3) change in STV=-1.13; 95% CI -1.87 to 0.39, p=0.003), although STV accounted for only a small proportion of the variance in change in pain. CONCLUSIONS: Synovial tissue volume in knee OA shrinks following steroid therapy, and rebounds in those whose pain relapses. It can be considered a treatment target in symptomatic knee OA. TRIAL REGISTRATION NUMBER: ISRCTN07329370. PMID- 26116549 TI - Translocation of gold nanoparticles across the lung epithelial tissue barrier: Combining in vitro and in silico methods to substitute in vivo experiments. AB - BACKGROUND: The lung epithelial tissue barrier represents the main portal for entry of inhaled nanoparticles (NPs) into the systemic circulation. Thus great efforts are currently being made to determine adverse health effects associated with inhalation of NPs. However, to date very little is known about factors that determine the pulmonary translocation of NPs and their subsequent distribution to secondary organs. METHODS: A novel two-step approach to assess the biokinetics of inhaled NPs is presented. In a first step, alveolar epithelial cellular monolayers (CMLs) at the air-liquid interface (ALI) were exposed to aerosolized NPs to determine their translocation kinetics across the epithelial tissue barrier. Then, in a second step, the distribution to secondary organs was predicted with a physiologically based pharmacokinetic (PBPK) model. Monodisperse, spherical, well-characterized, negatively charged gold nanoparticles (AuNP) were used as model NPs. Furthermore, to obtain a comprehensive picture of the translocation kinetics in different species, human (A549) and mouse (MLE-12) alveolar epithelial CMLs were exposed to ionic gold and to various doses (i.e., 25, 50, 100, 150, 200 ng/cm(2)) and sizes (i.e., 2, 7, 18, 46, 80 nm) of AuNP, and incubated post-exposure for different time periods (i.e., 0, 2, 8, 24, 48, 72 h). RESULTS: The translocation kinetics of the AuNP across A549 and MLE-12 CMLs was similar. The translocated fraction was (1) inversely proportional to the particle size, and (2) independent of the applied dose (up to 100 ng/cm(2)). Furthermore, supplementing the A549 CML with two immune cells, i.e., macrophages and dendritic cells, did not significantly change the amount of translocated AuNP. Comparison of the measured translocation kinetics and modeled biodistribution with in vivo data from literature showed that the combination of in vitro and in silico methods can accurately predict the in vivo biokinetics of inhaled/instilled AuNP. CONCLUSION: Our approach to combine in vitro and in silico methods for assessing the pulmonary translocation and biodistribution of NPs has the potential to replace short-term animal studies which aim to assess the pulmonary absorption and biodistribution of NPs, and to serve as a screening tool to identify NPs of special concern. PMID- 26116550 TI - The cytohesin guanosine exchange factors (GEFs) are required to promote HGF mediated renal recovery after acute kidney injury (AKI) in mice. AB - The lack of current treatment and preventable measures for acute kidney injury (AKI) in hospitalized patients results in an increased mortality rate of up to 80% and elevated health costs. Additionally, if not properly repaired, those who survive AKI may develop fibrosis and long-term kidney damage. The molecular aspects of kidney injury and repair are still uncertain. Hepatocyte growth factor (HGF) promotes recovery of the injured kidney by inducing survival and migration of tubular epithelial cells to repopulate bare tubule areas. HGF-stimulated kidney epithelial cell migration requires the activation of ADP-ribosylation factor 6 (Arf6) and Rac1 via the cytohesin family of Arf-guanine-nucleotide exchange factors (GEFs), in vitro. We used an ischemia and reperfusion injury (IRI) mouse model to analyze the effects of modulating this signaling pathway on kidney recovery. We treated IRI mice with either HGF, the cytohesin inhibitor SecinH3, or a combination of both. As previously reported, HGF treatment promoted rapid improvement of kidney function as evidenced by creatinine (Cre) and blood urea nitrogen (BUN) levels. In contrast, simultaneous treatment with SecinH3 and HGF blocks the ability of HGF to promote kidney recovery. Immunohistochemistry showed that HGF treatment promoted recovery of tubule structure, and had enhanced levels of active, GTP-bound Arf6 and GTP-Rac1. SecinH3 treatment, however, caused a dramatic decrease in GTP-Arf6 and GTP-Rac1 levels when compared to kidney sections from HGF-treated IRI mice. Additionally, SecinH3 counteracted the renal reparative effects of HGF. Our results support the conclusion that cytohesin function is required for HGF-stimulated renal IRI repair. PMID- 26116544 TI - Chronic stress and brain plasticity: Mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. AB - Stress responses entail neuroendocrine, autonomic, and behavioral changes to promote effective coping with real or perceived threats to one's safety. While these responses are critical for the survival of the individual, adverse effects of repeated exposure to stress are widely known to have deleterious effects on health. Thus, a considerable effort in the search for treatments to stress related CNS disorders necessitates unraveling the brain mechanisms responsible for adaptation under acute conditions and their perturbations following chronic stress exposure. This paper is based upon a symposium from the 2014 International Behavioral Neuroscience Meeting, summarizing some recent advances in understanding the effects of stress on adaptive and maladaptive responses subserved by limbic forebrain networks. An important theme highlighted in this review is that the same networks mediating neuroendocrine, autonomic, and behavioral processes during adaptive coping also comprise targets of the effects of repeated stress exposure in the development of maladaptive states. Where possible, reference is made to the similarity of neurobiological substrates and effects observed following repeated exposure to stress in laboratory animals and the clinical features of stress-related disorders in humans. PMID- 26116551 TI - Myocyte contractility can be maintained by storing cells with the myosin ATPase inhibitor 2,3 butanedione monoxime. AB - Isolated intact myocytes can be used to investigate contractile mechanisms and to screen new therapeutic compounds. These experiments typically require euthanizing an animal and isolating fresh cells each day or analyzing cultured myocytes, which quickly lose their rod-shaped morphology. Recent data suggest that the viability of canine myocytes can be prolonged using low temperature and N-benzyl p-toluene sulfonamide (an inhibitor of skeletal myosin ATPase). We performed similar studies in rat myocytes in order to test whether the cardiac myosin ATPase inhibitors 2,3-Butanedione monoxime (BDM) and blebbistatin help to maintain cell-level function over multiple days. Myocytes were isolated from rats and separated into batches that were stored at 4 degrees C in a HEPES-buffered solution that contained 0.5 mmol L(-1) Ca(2+) and (1) no myosin ATPase inhibitors; (2) 10 mmol L(-1) BDM; or (3) 3 MUmol L(-1) blebbistatin. Functional viability of myocytes was assessed up to 3 days after the isolation by measuring calcium transients and unloaded shortening profiles induced by electrical stimuli in inhibitor-free Tyrode's solution. Cells stored without myosin ATPase inhibitors had altered morphology (fewer rod-shaped cells, shorter diastolic sarcomere lengths, and membrane blebbing) and were not viable for contractile assays after 24 h. Cells stored in BDM maintained morphology and contractile function for 48 h. Storage in blebbistatin maintained cell morphology for 72 h but inhibited contractility. These data show that storing cells with myosin ATPase inhibitors can extend the viability of myocytes that will be used for functional assays. This may help to refine and reduce the use of animals in experiments. PMID- 26116552 TI - Consecutive assessment of FA and ADC values of normal lumbar nerve roots from the junction of the dura mater. AB - BACKGROUND: Diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI) are widely used in the evaluation of the central nervous system and recently have been reported as a potential tool for diagnosis of the peripheral nerve or the lumbar nerve entrapment. The purpose of this study was to evaluate consecutive changes in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of normal lumbar nerve roots from the junction of the dura mater. METHODS: The lumbar spinal nerves were examined in 6 male healthy volunteers (mean age, 35 years) with no experiences of sciatica, with a 3.0-T MR unit using a five-element phased-array surface coil. DTI was performed with the following imaging parameters: 11084.6/73.7 ms for TR/TE; b-value, 800 s/mm2; MPG, 33 directions; slice thickness, 1.5 mm; and total scan time, 7 min 35 s. ADC and FA values at all consecutive points along the L4, L5 and S1 nerves were quantified on every 1.5 mm slice from the junction of the dura mater using short fiber tracking. RESULTS: ADC values of all L4, 5, and S1 nerve roots decreased linearly up to 15 mm from the dura junction and was constant distally afterward. ADC values in the proximal portion demonstrated S1 > L5 > L4 (p < 0.05). On the other hand, FA values increased linearly up to 15 mm from the dura junction, and was constant distally afterward. FA values in the proximal portion showed L4 > L5 > S1 (p < 0.05). CONCLUSION: Our study demonstrated that ADC and FA values of each L4, 5, and S1 at the proximal portion from the junction of the dura matter changed linearly. It would be useful to know the normal profile of DTI values by location of each nerve root so that we can detect subtle abnormalities in each nerve root. PMID- 26116553 TI - Systematic Review with Meta-analysis of Prospective Studies: Anti-tumour Necrosis Factor for Prevention of Postoperative Crohn's Disease Recurrence. AB - BACKGROUND AND AIM: Although promising, the evidence supporting the use of anti tumour necrosis factor agents [anti-TNFs] in postoperative Crohn's disease [CD] is still based on limited experience. We aimed to conduct a meta-analysis of prospective studies evaluating the efficacy and safety of anti-TNFs for prevention of postoperative recurrence [POR] in CD. METHODS: MEDLINE, EMBASE, Web of Science, the Cochrane database and conference proceeding abstracts were searched. The primary outcome measure was the number of patients who developed POR as defined by the primary studies. RESULTS: Six prospective studies were included. The rate of endoscopic recurrence [ER] was significantly lower using anti-TNFs [9.2%, 7/76] compared with the non-biologicals group [61.5%, 83/135] (odds ratio [OR] 0.05, 95% confidence interval [CI] 0.02-0.13; p < 0.001]. The rate of severe ER was also lower in the anti-TNFs group [1.6%, 1/64] than that in the non-biologicals group [32.7%, 18/55, OR 0.10; p = 0.04]. A significantly lower proportion of patients in the anti-TNFs group developed clinical recurrence [3.4%, 2/59] compared with the non-biologicals arm [41.1%, 49/119, OR 0.1; p < 0.001]. More anti-TNFs-treated patients [86.5%, 45/52] were maintained in clinical remission compared with the non-biologicals group [58.1%, 43/74, OR 4.05, 95% CI 1.60-10.29; p < 0.01]. The adverse events were similar between the two groups [anti-TNFs 44.9% [22/49] vs control 52.5% [42/80]; p = 0.69]. CONCLUSIONS: Anti-TNFs are superior to non-biological agents in preventing endoscopic and clinical recurrence of CD without causing more adverse events. PMID- 26116554 TI - High Rates of Smoking Especially in Female Crohn's Disease Patients and Low Use of Supportive Measures to Achieve Smoking Cessation--Data from the Swiss IBD Cohort Study. AB - BACKGROUND AND AIMS: Smoking is a crucial environmental factor in inflammatory bowel disease [IBD]. However, knowledge on patient characteristics associated with smoking, time trends of smoking rates, gender differences and supportive measures to cease smoking provided by physicians is scarce. We aimed to address these questions in Swiss IBD patients. METHODS: Prospectively obtained data from patients participating in the Swiss IBD Cohort Study was analysed and compared with the general Swiss population [GSP] matched by age, sex and year. RESULTS: Among a total of 1770 IBD patients analysed [49.1% male], 29% are current smokers. More than twice as many patients with Crohn's disease [CD] are active smokers compared with ulcerative colitis [UC] [UC, 39.6% vs CD 15.3%, p < 0.001]. In striking contrast to the GSP, significantly more women than men with CD smoke [42.8% vs 35.8%, p = 0.025], with also an overall significantly increased smoking rate compared with the GSP in women but not men. The vast majority of smoking IBD patients [90.5%] claim to never have received any support to achieve smoking cessation, significantly more in UC compared with CD. We identify a significantly negative association of smoking and primary sclerosing cholangitis, indicative of a protective effect. Psychological distress in CD is significantly higher in smokers compared with non-smokers, but does not differ in UC. CONCLUSIONS: Despite well-established detrimental effects, smoking rates in CD are alarmingly high with persistent and stagnating elevations compared with the GSP, especially in female patients. Importantly, there appears to be an unacceptable underuse of supportive measures to achieve smoking cessation. PMID- 26116555 TI - The Syk Inhibitor Fostamatinib Decreases the Severity of Colonic Mucosal Damage in a Rodent Model of Colitis. AB - BACKGROUND AND AIMS: Inflammatory bowel disease is a chronic inflammatory disease of the gastrointestinal system. In some cases, current medications used for inflammatory bowel disease may not be enough for remission, creating a need for more potent and reliable medications. There is no study showing the efficacy of fostamatinib, with proven effects on some inflammatory diseases, on ulcerative colitis. In our study we planned to research the efficacy of fostamatinib, a spleen tyrosine kinase inhibitor, on acetic acid-induced colitis. METHODS: The study included 28 male Sprague-Dawley rats, randomly divided into control group, fostamatinib group, colitis group and fostamatinib + colitis group, each containing seven rats. Colitis induction was performed with 4% acetic acid. Colonic inflammation was assessed with disease activity index, macroscopic and histological damage scores, colonic myeloperoxidase, malondialdehyde and superoxide dismutase activity, and tumour necrosis factor alpha [TNFalpha], CD3, Syk, and phospho-Syk expression. RESULTS: There was a significant difference between the colitis and control groups in terms of all parameters. The disease activity index, macroscopic and microscopic damage scores, immunohistochemical TNFalpha, CD3, Syk, and phospho-Syk expression, and tissue myeloperoxidase activity were found to be significantly lower in the colitis + fostamatinib group compared with the colitis group. There was no significant difference between the two groups in terms of myeloperoxidase and malondialdehyde activity. CONCLUSIONS: Fostamatinib reduced the inflammatory damage in the experimental colitis. This effect may be due to suppression of TNFalpha, T-lymphocytes, and neutrophils in colonic mucosa via suppression of Syk. Fostamatinib may be an appropriate treatment alternative for ulcerative colitis. Further clinical studies are required to support this. PMID- 26116556 TI - Higher Rates of Dose Optimisation for Infliximab Responders in Ulcerative Colitis than in Crohn's disease. AB - BACKGROUND: Studies have demonstrated the benefit of dose optimisation in the setting of secondary loss of response to infliximab in inflammatory bowel disease. AIM: The aim of our study was to retrospectively investigate the rates of dose optimisation in an inflammatory bowel disease cohort receiving maintenance infliximab therapy to determine if there are different rates of dose optimisation between CD and UC cases and what impact this has on the durability of treatment effect. METHODS: Cases receiving infliximab for treatment of IBD between January 2008 and February 2014 were identified from an infusion centre database. Cases receiving >= 4 infusions were included in the study. Details of infusion dosing and timing were obtained. A dose increase from 5mg/kg to 10mg/kg or a reduction in the dosing interval was considered a dose optimisation. RESULTS: A total of 412 cases were included in the study; 52.7% required at least one dose optimisation. Dose optimisation was more common in UC than in CD cases [67.2% vs 46.3%, p = 0.00006]. The median time to dose optimisation was 7 months (95% confidence interval [CI] 4.8-9.2) for UC cases and 27 months [95% CI 7.3 46.7] for CD cases, p = 0.00003. CONCLUSIONS: Here we have shown that dose optimisation is required more frequently in UC than in CD, with a significantly shorter time to dose optimisation for UC cases than CD cases. The majority of cases responding to induction therapy with infliximab will have a sustained response to therapy, but over 50% will require a dose optimisation during their treatment. PMID- 26116557 TI - Serum Concentration of Anti-TNF Antibodies, Adverse Effects and Quality of Life in Patients with Inflammatory Bowel Disease in Remission on Maintenance Treatment. AB - BACKGROUND AND AIMS: High serum concentrations of infliximab [IFX] and adalimumab [ADA] may be associated with adverse effects in patients with inflammatory bowel disease [IBD]. We aimed to investigate whether high anti-tumour necrosis factor [TNF] trough levels [TLs] were associated with toxicity and impaired quality of life [QoL]. METHODS: We conducted a prospective cohort study in IBD patients in clinical and biochemical remission on IFX or ADA maintenance therapy. Trough serum concentrations and antidrug antibodies were measured in addition to biochemical markers of inflammation in serum and stool to confirm quiescent disease. QoL was assessed using the Inflammatory Bowel Disease Questionnaire and 36-item short form]. Side effects such as fatigue and arthralgia were measured with a visual analogue score [VAS]. Skin toxicity was reported with a European Organization for Research and Treatment of Cancer-derived score. RESULTS: In all, 252 IBD patients on maintenance anti-TNF therapy were screened, of whom 95 [73 with Crohn's disease, 22 with ulcerative colitis; 72 on IFX, 23 on ADA] were in clinical and biochemical remission and were included. Median TLs were 5.5 ug/ml and 6.6 ug/ml for IFX and ADA, respectively. Patients with anti-TNF TLs above median had lower IBDQ scores than patients with lower TLs [IBDQ 176 vs 187, p = 0.02], particularly regarding systemic symptoms and emotional status. A trend towards lower SF-36 and higher fatigue scores was observed in the higher anti-TNF TL group. Skin and arthralgia scores were not significantly different between the groups. CONCLUSIONS: IBD patients with higher anti-TNF serum concentrations had significantly lower disease-specific QoL. Fatigue, arthralgia, and skin lesions do not occur more often in these patients. These data are reassuring that high serum concentrations of anti-TNF antibodies are not toxic. PMID- 26116558 TI - The Modified Mayo Endoscopic Score (MMES): A New Index for the Assessment of Extension and Severity of Endoscopic Activity in Ulcerative Colitis Patients. AB - BACKGROUND AND AIMS: Current endoscopic activity scores for ulcerative colitis (UC) do not take into account the extent of mucosal inflammation. We have developed a simple endoscopic index for UC that takes into account the severity and distribution of mucosal inflammation. METHODS: In this multicentre trial, UC patients undergoing colonoscopy were prospectively enrolled. For the Modified Score (MS), the sum of Mayo Endoscopic Subscores (MESs) for five colon segments (ascending, transverse, descending, sigmoid and rectum) was calculated. The Extended Modified Score (EMS) was obtained by multiplying the MS by the maximal extent of inflammation. The Modified Mayo Endoscopic Score (MMES) was obtained by dividing the EMS by the number of segments with active inflammation. Colon biopsies were obtained from the rectum and sigmoid, as well as from all inflamed segments, by standard methods. Clinical activity was scored according to the Partial Mayo Score (PMS). Biological activity was scored according to C-reactive protein (CRP) and faecal calprotectin (FC) levels. Histological activity was scored according to the Geboes Score (GS). RESULTS: One hundred and seventy-one UC patients (38% female, median age 47 years, median disease duration 13 years) were included. The MMES correlated significantly with the PMS (r = 0.535), CRP (r = 0.238), FC (r = 0.730) and GS (r = 0.615) (all p < 0.001). Median MMES scores were significantly higher in patients with clinical, biological or histological activity (all p <= 0.001) CONCLUSIONS: The MMES is an easy to use endoscopic index for UC that combines the severity analysis of the MES with disease extent, and correlates very well with clinical, biological and histological disease activity. PMID- 26116559 TI - A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation. AB - We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Recent exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2. PMID- 26116560 TI - Prevalence of Klebsiella pneumoniae strains producing carbapenemases and increase of resistance to colistin in an Italian teaching hospital from January 2012 To December 2014. AB - BACKGROUND: The aim of this study was to characterize the spread of carbapenemase producing Klebsiella pneumoniae (CPKP) in a tertiary level hospital using ongoing active surveillance with rectal swab cultures. Furthermore, this study analyzed the presence of CPKP in the clinical samples (CS) of a single patient as well as the evolution of Colistin-sensitive strains (CoS) to Colistin-resistant strains (CoR). METHODS: This study was performed from January 1, 2012 to December 31, 2014. In 2012, a survey was conducted in the Intensive Care Department. In autumn 2013, active monitoring was extended to the Surgery Department, and since mid 2014, the surveillance has included the Medical Department as well. Only the first isolated strain from each patient was included. Antimicrobial susceptibility testing was performed on CPKP isolates: Klebsiella pneumoniae carbapenemase, oxacillinase-48, Verona integron-encoded metallo-beta-lactamase and New Delhi metallo-beta-lactamase were detected using a validated in-house PCR method, and multilocus sequence typing (MLST) was used to investigate the clonal transmission of strains. RESULTS: A total of 15,104 patients were included in the study, and 496 consecutive non-replicated strains of CPKP were collected: 149 strains were collected in 2012 (39 [26.2 %] from surveillance rectal swabs [SRS]), 133 strains were collected in 2013 (70 [52.6 %] from SRS) and 214 strains were collected in 2014 (164 [76.6 %] from SRS). We observed a significant increase in the percentage of positive SRS cases in 2014 relative to 2013 and 2012 (p = 0.0001 and p = 0.0172, respectively) and in the proportion of CPKP first isolated by SRS relative to those identified by CS (p < 0.0001). Among all available samples, the number of CoR isolated from SRS was higher in 2013 and 2014 compared with 2012 (p = 0.0019 and p = 0.008, respectively). ST-258 and ST 512 were more prevalent in the tested specimens, and a new single locus variant (SLV) of ST-512 (ST-745) was isolated. CONCLUSIONS: The results of this 3-year study of 15,104 patients highlight the clinical relevance of antimicrobial resistance as well as the drug-selection pressure of colistin therapy. The active surveillance in the three different departments increased the level of CPKP cases isolated by SRS. PMID- 26116561 TI - Immediate help through group therapy for patients with somatic diseases and depressive or adjustment disorders in outpatient care: study protocol for a randomized controlled trial. AB - BACKGROUND: One in three people with a chronic somatic disease suffer from a comorbid mental disorder. Most common comorbidities are depressive, anxiety and adjustment disorders. These lead to an increase in morbidity and mortality, and a deterioration of quality of life and healthcare costs. Treatment of mental disorders is of great importance, but the waiting time for outpatient individual psychotherapy can be up to six months in Germany. Group therapy has comparable treatment effects and is considerably more economic than individual therapy; however, it is still almost unused in the outpatient care system. The introduction of a stepped care approach, such as attending a group program before individual therapy, could improve this issue. For this purpose we developed a group program (STEpS), and its efficacy will be evaluated in this study. METHODS/DESIGN: A randomized controlled trial will be conducted to evaluate the efficacy of a cognitive behavioral therapy (CBT) group program for patients with somatic diseases and depressive or adjustment disorders, compared to a wait-list control group. A total of 128 adults with any chronic somatic disease and comorbid depression or adjustment disorder will be recruited in our outpatient clinic, and will be randomly assigned to participate in the group program immediately after contacting the clinic (intervention group) or after a waiting period of four months (wait-list control group). Primary outcomes will be self reported depressive and anxiety symptoms. Secondary outcomes will be self reported psychological distress, changes in experience and behavior, health related quality of life, state of self-esteem and subjective need for therapy. Assessments will take place at baseline, 10 weeks (post-treatment) and 18 weeks (follow-up) after randomization. Additionally, treatment acceptance and psychotherapeutic process will be assessed after each session. DISCUSSION: This study investigates whether the CBT group program is an effective treatment to reduce depressive and anxiety symptoms and psychological distress in these patients. If the group program is effective, it could be implemented as a treatment option prior to individual outpatient therapy. These results will contribute to improving outpatient care for mental disorders in patients with somatic diseases. TRIAL REGISTRATION: German Clinical Trials Register DRKS00005140 (27 August 2013). PMID- 26116563 TI - Corrigenda. PMID- 26116562 TI - Radiological Protection in Cone Beam Computed Tomography (CBCT). ICRP Publication 129. AB - The objective of this publication is to provide guidance on radiological protection in the new technology of cone beam computed tomography (CBCT). Publications 87 and 102 dealt with patient dose management in computed tomography (CT) and multi-detector CT. The new applications of CBCT and the associated radiological protection issues are substantially different from those of conventional CT. The perception that CBCT involves lower doses was only true in initial applications. CBCT is now used widely by specialists who have little or no training in radiological protection. This publication provides recommendations on radiation dose management directed at different stakeholders, and covers principles of radiological protection, training, and quality assurance aspects. Advice on appropriate use of CBCT needs to be made widely available. Advice on optimisation of protection when using CBCT equipment needs to be strengthened, particularly with respect to the use of newer features of the equipment. Manufacturers should standardise radiation dose displays on CBCT equipment to assist users in optimisation of protection and comparisons of performance. Additional challenges to radiological protection are introduced when CBCT-capable equipment is used for both fluoroscopy and tomography during the same procedure. Standardised methods need to be established for tracking and reporting of patient radiation doses from these procedures. The recommendations provided in this publication may evolve in the future as CBCT equipment and applications evolve. As with previous ICRP publications, the Commission hopes that imaging professionals, medical physicists, and manufacturers will use the guidelines and recommendations provided in this publication for implementation of the Commission's principle of optimisation of protection of patients and medical workers, with the objective of keeping exposures as low as reasonably achievable, taking into account economic and societal factors, and consistent with achieving the necessary medical outcomes. PMID- 26116564 TI - NOX1 to NOX2 switch deactivates AMPK and induces invasive phenotype in colon cancer cells through overexpression of MMP-7. AB - BACKGROUND: Although matrix metalloproteinase (MMP)-7 expression is correlated with increased metastatic potential in human colon cancer cells, the underlying molecular mechanism of invasive phenotype remains unknown. In the current study, we investigated the regulatory effects of membrane NADPH oxidase (NOX) and AMP activated protein kinase (AMPK) on MMP-7 expression and invasive phenotype change in colon cancer cells. METHODS: Production of superoxide anion was measured by lucigenin chemiluminescence assay using whole cells and protein extracts (NADPH oxidase activity), and intracellular reactive oxygen species (ROS) by fluorescence microscopy using 2',7'-dichlorofluorescein diacetate (DCF-DA). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Luciferase reporter assay was performed to identify transcription factors linked to gene expression. RESULTS: Under basal conditions, less invasive human colon cancer cells (HT29 and Caco-2) showed low MMP-7 expression but high NOX1 expression and AMPK phosphorylation. Treatment of HT29 and Caco-2 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced an invasive phenotype response along with corresponding increases in ROS production and NOX2 and MMP-7 expression as well as reduced AMPK phosphorylation, which resemble basal conditions of highly invasive human colon cancer cells (SW620 and HCT116). In addition, inverse regulation between AMPK phosphorylation and NOX2 and MMP-7 expression was observed in HT29 cells treated with different concentrations of exogenous hydrogen peroxide. TPA-induced invasive phenotype in HT29 cells was abolished by treatment with Vit. E, DPI, apocynin, and NOX2 siRNA but not NOX1 siRNA, indicating NOX2-derived ROS production induced an invasive phenotype. TPA-induced induction of MMP-7 expression was suppressed by AP-1, NF kappaB, and MAPK (ERK, p38, and JNK) inhibitors, whereas TPA-induced expression of NOX2 and its regulators, p47phox and p67phox, was blocked by p38 and NF-kappaB inhibitors. CONCLUSIONS: Molecular switch from NOX1 to NOX2 in colon cancer cells induces ROS production and subsequently enhances MMP-7 expression by deactivating AMPK, which otherwise inhibits stimulus-induced autoregulation of ROS and NOX2 gene expression. PMID- 26116565 TI - Varying levels of complexity in transcription factor binding motifs. AB - Binding of transcription factors to DNA is one of the keystones of gene regulation. The existence of statistical dependencies between binding site positions is widely accepted, while their relevance for computational predictions has been debated. Building probabilistic models of binding sites that may capture dependencies is still challenging, since the most successful motif discovery approaches require numerical optimization techniques, which are not suited for selecting dependency structures. To overcome this issue, we propose sparse local inhomogeneous mixture (Slim) models that combine putative dependency structures in a weighted manner allowing for numerical optimization of dependency structure and model parameters simultaneously. We find that Slim models yield a substantially better prediction performance than previous models on genomic context protein binding microarray data sets and on ChIP-seq data sets. To elucidate the reasons for the improved performance, we develop dependency logos, which allow for visual inspection of dependency structures within binding sites. We find that the dependency structures discovered by Slim models are highly diverse and highly transcription factor-specific, which emphasizes the need for flexible dependency models. The observed dependency structures range from broad heterogeneities to sparse dependencies between neighboring and non-neighboring binding site positions. PMID- 26116567 TI - Experimental research in public health. PMID- 26116566 TI - US Supreme Court's exoneration of the Affordable Care Act. PMID- 26116570 TI - The role of mechanical stimuli in the vascular differentiation of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are among the most promising and suitable stem cell types for vascular tissue engineering. Substantial effort has been made to differentiate MSCs towards vascular cell phenotypes, including endothelial cells and smooth muscle cells (SMCs). The microenvironment of vascular cells not only contains biochemical factors that influence differentiation, but also exerts hemodynamic forces, such as shear stress and cyclic strain. Recent evidence has shown that these forces can influence the differentiation of MSCs into endothelial cells or SMCs. In this Commentary, we present the main findings in the area with the aim of summarizing the mechanisms by which shear stress and cyclic strain induce MSC differentiation. We will also discuss the interactions between these mechanical cues and other components of the microenvironment, and highlight how these insights could be used to maintain differentiation. PMID- 26116569 TI - Paxillin-dependent regulation of IGF2 and H19 gene cluster expression. AB - Paxillin (PXN) is a focal adhesion protein that has been implicated in signal transduction from the extracellular matrix. Recently, it has been shown to shuttle between the cytoplasm and the nucleus. When inside the nucleus, paxillin promotes cell proliferation. Here, we introduce paxillin as a transcriptional regulator of IGF2 and H19 genes. It does not affect the allelic expression of the two genes; rather, it regulates long-range chromosomal interactions between the IGF2 or H19 promoter and a shared distal enhancer on an active allele. Specifically, paxillin stimulates the interaction between the enhancer and the IGF2 promoter, thus activating IGF2 gene transcription, whereas it restrains the interaction between the enhancer and the H19 promoter, downregulating the H19 gene. We found that paxillin interacts with cohesin and the mediator complex, which have been shown to mediate long-range chromosomal looping. We propose that these interactions occur at the IGF2 and H19 gene cluster and are involved in the formation of loops between the IGF2 and H19 promoters and the enhancer, and thus the expression of the corresponding genes. These observations contribute to a mechanistic explanation of the role of paxillin in proliferation and fetal development. PMID- 26116571 TI - Endothelial MMP14 is required for endothelial-dependent growth support of human airway basal cells. AB - Human airway basal cells are the stem (or progenitor) population of the airway epithelium, and play a central role in anchoring the epithelium to the basement membrane. The anatomic position of basal cells allows for potential paracrine signaling between them and the underlying non-epithelial stromal cells. In support of this, we have previously demonstrated that endothelial cells support growth of basal cells during co-culture through vascular endothelial growth factor A (VEGFA)-mediated signaling. Building on these findings, we found, by RNA sequencing analysis, that basal cells expressed multiple fibroblast growth factor (FGF) ligands (FGF2, FGF5, FGF11 and FGF13) and that only FGF2 and FGF5 were capable of functioning in a paracrine manner to activate classical FGF receptor (FGFR) signaling. Antibody-mediated blocking of FGFR1 during basal-cell endothelial-cell co-culture significantly reduced the endothelial-cell-dependent basal cell growth. Stimulation of endothelial cells with basal-cell-derived growth factors induced endothelial cell expression of matrix metallopeptidase 14 (MMP14), and short hairpin RNA (shRNA)-mediated knockdown of endothelial cell MMP14 significantly reduced the endothelial-cell-dependent growth of basal cells. Overall, these data characterize a new growth-factor-mediated reciprocal 'crosstalk' between human airway basal cells and endothelial cells that regulates proliferation of basal cells. PMID- 26116572 TI - A local VE-cadherin and Trio-based signaling complex stabilizes endothelial junctions through Rac1. AB - Endothelial cell-cell junctions maintain a restrictive barrier that is tightly regulated to allow dynamic responses to permeability-inducing angiogenic factors, as well as to inflammatory agents and adherent leukocytes. The ability of these stimuli to transiently remodel adherens junctions depends on Rho-GTPase controlled cytoskeletal rearrangements. How the activity of Rho-GTPases is spatio temporally controlled at endothelial adherens junctions by guanine-nucleotide exchange factors (GEFs) is incompletely understood. Here, we identify a crucial role for the Rho-GEF Trio in stabilizing junctions based around vascular endothelial (VE)-cadherin (also known as CDH5). Trio interacts with VE-cadherin and locally activates Rac1 at adherens junctions during the formation of nascent contacts, as assessed using a novel FRET-based Rac1 biosensor and biochemical assays. The Rac-GEF domain of Trio is responsible for the remodeling of junctional actin from radial into cortical actin bundles, a crucial step for junction stabilization. This promotes the formation of linear adherens junctions and increases endothelial monolayer resistance. Collectively, our data show the importance of spatio-temporal regulation of the actin cytoskeleton through Trio and Rac1 at VE-cadherin-based cell-cell junctions in the maintenance of the endothelial barrier. PMID- 26116573 TI - RNA splicing regulated by RBFOX1 is essential for cardiac function in zebrafish. AB - Alternative splicing is one of the major mechanisms through which the proteomic and functional diversity of eukaryotes is achieved. However, the complex nature of the splicing machinery, its associated splicing regulators and the functional implications of alternatively spliced transcripts are only poorly understood. Here, we investigated the functional role of the splicing regulator rbfox1 in vivo using the zebrafish as a model system. We found that loss of rbfox1 led to progressive cardiac contractile dysfunction and heart failure. By using deep transcriptome sequencing and quantitative real-time PCR, we show that depletion of rbfox1 in zebrafish results in an altered isoform expression of several crucial target genes, such as actn3a and hug. This study underlines that tightly regulated splicing is necessary for unconstrained cardiac function and renders the splicing regulator rbfox1 an interesting target for investigation in human heart failure and cardiomyopathy. PMID- 26116575 TI - A STIM1-dependent 'trafficking trap' mechanism regulates Orai1 plasma membrane residence and Ca2+ influx levels. AB - The key proteins mediating store-operated Ca(2+) entry (SOCE) are the endoplasmic reticulum (ER) Ca(2+) sensor STIM1 and the plasma membrane Ca(2+)-selective channel Orai1. Here, we quantitatively dissect Orai1 trafficking dynamics and show that Orai1 recycles rapidly at the plasma membrane (Kex?0.1 min(-1)), with ~40% of the total Orai1 pool localizing to the plasma membrane at steady state. A subset of intracellular Orai1 localizes to a sub-plasmalemal compartment. Store depletion is coupled to Orai1 plasma membrane enrichment in a STIM1-dependent fashion. This is due to trapping of Orai1 into cortical ER STIM1 clusters, leading to its removal from the recycling pool and enrichment at the plasma membrane. Interestingly, upon high STIM1 expression, Orai1 is trapped into STIM1 clusters intracellularly, thus preventing its plasma membrane enrichment following store depletion. Consistent with this, STIM1 knockdown prevents trapping of excess Orai1 into limiting STIM1 clusters in the cortical ER. SOCE dependent Ca(2+) influx shows a similar biphasic dependence on the Orai1:STIM1 ratio. Therefore, a STIM1-dependent Orai1 'trafficking trap' mechanism controls Orai1 plasma membrane enrichment and SOCE levels, thus modulating the SOCE 'bandwidth' for downstream signaling. PMID- 26116574 TI - Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury. AB - Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema and respiratory failure. Here, we examined the efficacy the DNA methyl transferase (DNMT) inhibitor 5-Aza 2-deoxycytidine (Aza), the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), as well as the combination therapy of Aza and TSA (Aza+TSA) provides in the protection of ALI. In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed substantial attenuation of adverse lung histopathological changes and inflammation. Importantly, these protective effects were due to substantial macrophage phenotypic changes observed in LPS-stimulated macrophages treated with Aza+TSA as compared with untreated LPS-induced macrophages or LPS-stimulated macrophages treated with either drug alone. Further, we observed significantly lower levels of pro-inflammatory molecules and higher levels of anti-inflammatory molecules in LPS-induced macrophages treated with Aza+TSA than in LPS-induced macrophages treated with either drug alone. The protection was ascribed to dual effects by an inhibition of MAPK-HuR-TNF and activation of STAT3-Bcl2 pathways. Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti inflammatory M2 macrophage phenotype in ALI, and has a therapeutic potential for patients with sepsis. PMID- 26116576 TI - Attractive and repulsive factors act through multi-subunit receptor complexes to regulate nerve fiber growth. AB - In the nervous system, attractive and repulsive factors guide neuronal growth, pathfinding and target innervation during development, learning and regeneration after injury. Repulsive and growth-inhibitory factors, such as some ephrins, semaphorins, netrins and myelin-associated growth inhibitors, restrict nerve fiber growth, whereas neurotrophins, and other ephrins, semaphorins and netrins attract fibers and promote neurite growth. Several of these guidance molecules also play crucial roles in vasculogenesis, and regulate cell migration and tissue formation in different organs. Precise and highly specific signal transduction in space and time is required in all these cases, which primarily depends on the presence and function of specific receptors. Interestingly, many of these ligands act through multi-subunit receptor complexes. In this Commentary, we review the current knowledge of how complexes of the receptors for attractive and repulsive neurite growth regulatory factors are reorganized in a spatial and temporal manner, and reveal the implications that such dynamics have on the signaling events that coordinate neurite fiber growth. PMID- 26116577 TI - Profile of people with hypertension in Nairobi's slums: a descriptive study. AB - BACKGROUND: Cardiovascular disease (CVD) is a rising health burden among the world's poor with hypertension as the main risk factor. In sub-Saharan Africa, hypertension is increasingly affecting the urban population of which a substantial part lives in slums. This study aims to give insight into the profile of patients with hypertension living in slums of Nairobi, Kenya. METHODS: Sociodemographic and anthropometric data as well as clinical measurements including BP from 440 adults with hypertension aged 35 years and above living in Korogocho, a slum on the eastern side of Nairobi, Kenya, will be collected at baseline and at the first clinic visit. CONCLUSION: The study population showed high prevalence of overweight and abdominal obesity as well as behavioral risk factors such as smoking, alcohol and a low vegetable and fruit intake. Furthermore, the majority of hypertensive patients do not take anti-hypertensive medication and the ones who do show little adherence. TRIAL REGISTRATION: Current controlled trials ISRCTN84424579 . PMID- 26116578 TI - Symptoms of attention deficit hyperactivity disorder in patients with systemic lupus erythematosus. AB - OBJECTIVES: Cognitive function and mood disturbance are common in patients with systemic lupus erythematosus (SLE). This study aims to examine whether SLE patients have more features of adult attention deficit hyperactivity disorder (ADHD) and their relation to anxiety and depressive symptoms. METHODS: Symptoms and clinically significant items of the inattention and hyperactivity/impulsivity domains of ADHD were examined in Part A and Part B by the screening instrument of the ADHD Self-Reported Scale (ASRS), respectively. Anxiety and depressive symptoms were measured by HADS-A and HADS-D, respectively. RESULTS: There were no differences in symptom scores of inattention and hyperactivity/impulsivity between inactive SLE patients (n = 117) and age- and sex-matched controls (n = 64). However, SLE patients had more clinically significant items in the inattention domain compared with controls (p = 0.006), particularly among those who had previous cerebral involvement (p = 0.004). Patients who had psychiatric diseases had more clinically significant items in the hyperactivity/impulsivity domain (p = 0.006). Possible ADHD was found in 7.7% of SLE and 6.3% of healthy individuals (p = 1.00) by the screening tool. Patients with higher inattention symptom scores were more likely to be unemployed but not for duration of education and smoking habit. Anxiety and depressive symptoms correlated with ADHD symptoms. HADS-A was an independent predictive factor for clinically significant symptoms of inattention (p < 0.001) and hyperactivity/impulsivity (p = 0.04) by logistic regression. CONCLUSION: Inactive SLE patients, particularly those who had previous cerebral lupus, had more clinically significant symptoms of inattention but not hyperactivity/impulsivity reflecting underlying cognitive impairment. Anxiety and depressive symptoms were common confounders for ADHD-like symptoms. PMID- 26116579 TI - Molecular Confirmation of Ewing Sarcoma in an 85-Year-Old Woman. AB - We report a case of a Ewing sarcoma/primitive neuroectodermal tumor in an 85-year old woman who presented with an enlarging circumscribed left flank mass. Magnetic resonance imaging revealed a 3 * 5 * 10 cm heterogeneous mass arising from the 10th rib. Computed tomography demonstrated a small nodule in the right middle lobe and bilateral pleural effusions. The patient underwent computed tomography guided biopsy followed by open biopsy. The tumor cells were characterized by loosely cohesive sheets of tumor cells with uniform nuclei, and scant, granular, eosinophilic cytoplasm with indistinct cell membranes. Frequent mitoses, apoptosis, and necrosis were present. The cells were positive for CD99 with a strong concentric staining pattern. Epithelial, hematopoietic, and neural markers were all negative. Fluorescence in situ hybridization was performed and demonstrated EWSR1 (22q12) gene rearrangement. Sanger sequencing of the reverse transcriptase polymerase chain reaction product from the patient's tumor demonstrated the EWSR1-FLI1 type 1 fusion. Following diagnosis the patient elected to proceed with localized radiation and declined chemotherapy. She developed progressive lung disease and subsequently died of her disease a year after her initial diagnosis. Ewing sarcoma is predominantly a pediatric disease and uncommon in patients older than 40 years of age. To the best of our knowledge, this is the oldest documented case of Ewing sarcoma, diagnosed using modern molecular techniques. PMID- 26116580 TI - Secretion of Fc-amidated peptide fusion proteins by Chinese hamster ovary cells. AB - BACKGROUND: The therapeutic use of alpha-amidated peptides (e.g. calcitonin, glucagon-like peptide) has increased dramatically, but there are major impediments to wider use of such peptides. Larger peptides are expensive to synthesize, and short plasma half-lives frequently limit the clinical circumstances in which the peptides would be useful. Both problems are potentially solved by producing peptides as fusions with the Fc region of human immunoglobulin. METHODS: Glucagon-like peptide 1 (GLP1), peptide YY (PYY) and neuromedin U (NMU) were expressed and purified from stable CHO lines; since the alpha-amide group is essential for full biological potency of many peptides, Fc fusion peptides were expressed in CHO lines stably expressing the alpha-amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM: EC 1.14.17.3). Purified fusion proteins were analyzed intact and after HRV3C rhinovirus protease cleavage, at a site in the linker separating the Fc region from the peptide, by mass spectrometry and amide-specific immunoassays. RESULTS: The Fc fusions were expressed at 1-2.5 MUg/mg cell protein and secreted at 5-20% of cell content per hour, in a peptide-specific manner. CHO cells express measurable endogenous PAM activity, amidating 25% of Fc-PYY and almost 90% of Fc-GLP1. Expression of exogenous PAM increased the level of peptide amidation to 50% of Fc-PYY and 95 % of Fc-NMU. The Fc-GLP1 fusions were 10,000-fold less active than synthetic GLP1 in a cell-receptor cyclic AMP-based assay, as expected since the amino terminal of GLP1 is essential for full biological activity. The Fc-PYY fusions were 100 fold less active than PYY-NH2 but 10-fold more active than non-amidated PYY-Gly. CONCLUSIONS: This type of approach can be used for the production of stabilized alpha-amidated peptides aimed at clinical trials. PMID- 26116582 TI - Equitable Distribution of Public Hospitals According to Health Needs in Malaysia: Does It Exist or Not? AB - The goal of ensuring geographic equity of health care can be achieved if the geographic distribution of health care services is according to the health needs. This study aims to examine whether acute Ministry of Health hospital beds are distributed according to population health needs in various states within Peninsular Malaysia. The health needs of each state are indicated by the crude death rate. Comparisons of the share of hospital beds to that of population with differential health needs were assessed using concentration curve and index. In most years between 1995 and 2010, the distribution of hospital beds in Peninsular Malaysia were concentrated among states with higher health needs. This is in line with the principle of vertical equity and could be one advantage of a central federal government that can allocate health care resources to prioritize states with higher health care needs. PMID- 26116581 TI - The Omega-3 fatty acids (Fish Oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) study: the updated final trial protocol and rationale of post-initiation trial modifications. AB - BACKGROUND: The FAVOURED study is an international multicentre, double-blind, placebo-controlled trial which commenced recruitment in 2008 and examines whether omega-3 polyunsaturated fatty acids (omega-3 PUFAs) either alone or in combination with aspirin will effectively reduce primary access failure of de novo arteriovenous fistulae (AVF) in patients with stage 4 and 5 chronic kidney disease. Publication of new evidence derived from additional studies of clopidogrel and a high screen failure rate due to prevalent aspirin usage prompted an updated trial design. METHODS/DESIGN: The original trial protocol published in 2009 has undergone two major amendments, which were implemented in 2011. Firstly, the primary outcome 'early thrombosis' at 3 months following AVF creation was broadened to a more clinically relevant outcome of 'AVF access failure'; a composite of thrombosis, AVF abandonment and cannulation failure at 12 months. Secondly, participants unable to cease using aspirin were allowed to be enrolled and randomised to omega-3 PUFAs or placebo. The revised primary aim of the FAVOURED study is to test the hypothesis that omega-3 PUFAs will reduce rates of AVF access failure within 12 months following AVF surgery. The secondary aims are to examine the effect of omega-3 PUFAs and aspirin on the individual components of the primary end-point, to examine the safety of study interventions and assess central venous catheter requirement as a result of access failure. DISCUSSION: This multicentre international clinical trial was amended to address the clinically relevant question of whether the usability of de novo AVF at 12 months can be improved by the early use of omega-3 PUFAs and to a lesser extent aspirin. This study protocol amendment was made in response to a large trial demonstrating that clopidogrel is effective in safely preventing primary AVF thrombosis, but ineffective at increasing functional patency. Secondly, including patients taking aspirin will enroll a more representative cohort of haemodialysis patients, who are significantly older with a higher prevalence of cardiovascular disease and diabetes which may increase event rates and the power of the study. TRIAL REGISTRATION: Australia & New Zealand Clinical Trial Register (ACTRN12607000569404). PMID- 26116583 TI - 'Cigarettes are priority': a qualitative study of how Australian socioeconomically disadvantaged smokers respond to rising cigarette prices. AB - Despite substantial modelling research assessing the impact of cigarette taxes on smoking rates across income groups, few studies have examined the broader financial effects and unintended consequences on very low-income smokers. This study explored how socioeconomically disadvantaged smokers in a high-income country manage smoking costs on limited budgets. Semi-structured face-to-face interviews were conducted with 20 smokers recruited from a welfare organization in NSW, Australia. Participants discussed perceived impact of tobacco costs on their essential household expenditure, smoking behaviour and quit cognitions. Interviews were audio-taped, transcribed verbatim and analysed using thematic framework analysis. Instances of smoking-induced deprivation and financial stress, such as going without meals, substituting food choices and paying bills late in order to purchase cigarettes were reported as routine experiences. Price minimization strategies and sharing tobacco resources within social networks helped to maintain smoking. Participants reported tobacco price increases were good for preventing uptake, and that larger price rises and subsidized cessation aids were needed to help them quit. Socioeconomically disadvantaged smokers engage in behaviours that exacerbate deprivation to maintain smoking, despite the consequences. These data do not suggest a need to avoid tobacco taxation, rather a need to consider how better to assist socioeconomically disadvantaged smokers who struggle to quit. PMID- 26116584 TI - A block randomized controlled trial of a brief smoking cessation counselling and advice through short message service on participants who joined the Quit to Win Contest in Hong Kong. AB - The present trial examined the effectiveness of brief interventions for smokers who joined the Hong Kong Quit to Win Contest to quit smoking. A block randomized controlled trial allocated 1003 adult daily smokers to three groups: (i) The TEL group (n = 338) received a 5-min nurse-led telephone counselling; (ii) The SMS group (n = 335) received eight text messages through mobile phone and (iii) The CONTROL group (n = 330) did not receive the above interventions. Participants with biochemically verified abstinence at 6-month follow-up could receive cash incentive. The primary outcome was the self-reported 7-day point prevalence (PP) of tobacco abstinence at 6-month follow-up. The abstinence rate in the TEL, SMS and CONTROL group was 22.2, 20.6 and 20.3%, respectively (P for TEL versus CONTROL = 0.32; P for SMS versus CONTROL = 0.40). When abstinence at 2-, 6- and 12-month follow-up was modelled simultaneously, the TEL group had a higher abstinence than the CONTROL group (Adjusted OR = 1.38, 95% CI = 1.01-1.88, P = 0 .04). In the Quit to Win Contest, the brief telephone counselling might have increased abstinence, but the text messages had no significant effect. Further studies on intensive intervention and interactive messaging services are warranted. PMID- 26116585 TI - Visual portrayals of obesity in health media: promoting exercise without perpetuating weight bias. AB - Health education campaigns for preventing and reducing obesity often contain weight-stigmatizing visual content, which may have unintended negative health consequences. The goal of the present research was to identify non-stigmatizing visual content for health education materials that can promote exercise among people of diverse weight statuses. An online sample of 483 US women viewed: (i) a woman with obesity portrayed stereotypically; (ii) a woman with obesity exercising; (iii) a woman with obesity portrayed neutrally; or (iv) a lean woman exercising. Race of the models pictured was randomized (White or Black). Participants completed measures of weight bias and exercise behavior and attitudes, and provided information about their weight status. Analysis of covariance revealed that responses to stereotypical and exercise images varied by participant weight status. Across participants, neutral obesity portrayals elicited lower expressions of weight-biased attitudes and higher reports of exercise liking/comfort. Among non-overweight participants, images portraying women with obesity stereotypically or counter-stereotypically produced greater endorsement of negative stereotypes than control, lean images. No effects of model race were found. These findings suggest that the public responds differently to visual portrayals of obesity depending on weight status, and neutral portrayals may be an effective route toward promoting exercise without perpetuating stigma. PMID- 26116586 TI - Exploring New Ways to Deliver Value to Healthcare Organizations: Algorithmic Testing, Data Integration, and Diagnostic E-consult Service. AB - As the USA Health Care System undergoes transformation and transitions to value based models it is critical for laboratory medicine/clinical pathology physicians to explore opportunities and find new ways to deliver value, become an integral part of the healthcare team. This is also essential for ensuring financial health and stability of the profession when the payment paradigm changes from fee-for service to fee-for-performance. About 5 years ago we started searching for ways to achieve this goal. Among other approaches, the search included addressing the laboratory work-ups for specialists' referrals in the HarrisHealth System, a major safety net health care organization serving mostly indigent and underserved population of Harris County, TX. We present here our experience in improving the efficiency of laboratory testing for the referral process and in building a prototype of a diagnostic e-consult service using rheumatologic diseases as a starting point. The service incorporates algorithmic testing, integration of clinical, laboratory and imaging data, issuing structured comprehensive consultation reports, incorporating all the relevant information, and maintaining personal contacts and an e-line of communications with the primary providers and referral center personnel. Ongoing survey of providers affords testimony of service value in terms of facilitating their work and increasing productivity. Analysis of the cost effectiveness and of other value indicators is currently underway. We also discuss our pioneering experience in building pathology residents and fellows training in integrated diagnostic consulting service. PMID- 26116587 TI - Corrected Neutrophil Gelatinase-Associated Lipocalin (NGAL) Level Adjusted by the Scoring System of an Inflammation Index for Screening Renal Dysfunction in Patients with Systemic Inflammation. AB - This study investigated the use of corrected neutrophil gelatinase-associated lipocalin (cNGAL) values to screen renal dysfunction in patients with systemic inflammation. Plasma NGAL concentrations were measured using a fluorescent immunoassay in 259 patients with inflammatory diseases. An inflammation index was calculated using a scoring system based on high-sensitivity C-reactive protein (hsCRP) and corrected erythrocyte sedimentation rates. The uncorrected NGAL (uNGAL) concentration increased with the inflammation index, but cNGAL increased in parallel with serum creatinine (sCr) levels. After adjustment with the inflammation index, increased uNGAL concentrations returned to a level not significantly different from the control value. In a multivariate regression analysis, hsCRP was more closely associated with uNGAL than cNGAL [r=0.513 (p<0.001) vs. r=0.201 (p=0.017)], but the sCr level was more strongly linked to cNGAL than uNGAL (r=0.692 vs. r=0.583, respectively, p<0.001). In a receiver operating characteristics (ROC) curve analysis, the diagnostic accuracy of cNGAL, which identifies an increase of sCr >=0.3 mg/dL within 48 hours, was found to be superior to that of uNGAL [0.72 (95% CI, 0.61-0.84) vs. 0.67 (95% CI, 0.56-0.81), p=0.038]. In conclusion, cNGAL more accurately reflects renal dysfunction than uNGAL under inflammatory conditions. A measurement of cNGAL may provide helpful information for assessing patients with renal impairment, particularly in association with systemic inflammation. PMID- 26116588 TI - Serum Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy. AB - BACKGROUND: Diabetes is the leading cause of end stage renal disease (ESRD) in the United States, representing 44% of incident cases [1]. In this study, serum and peripheral blood collected from diabetic patients in five stages of chronic kidney disease (CKD), as defined by glomerular filtration rate (GFR), were compared to healthy (non-CKD) subjects. METHODS: Serum samples were analyzed for 39 inflammatory or immune mediator protein levels and peripheral blood samples were analyzed for expression of 35 gene transcripts. RESULTS: In serum, MCP-1, FGF-2, VEGF, and EGF levels were elevated above controls at all stages of DN. Five mediator levels, GM-CSF, IL-1alpha, IL-1RA, IL-6, and MIP1beta increased with disease progression until stage 4-5, at which point a decrease was observed paralleling a loss of functional renal mass that occurs in late stage CKD. Five mediator levels: GRO, IFNgamma, MDC, Eotaxin, and G-CSF significantly differed from controls at one or more stages without apparent correlation with disease stage. Only a single mediator, sIL2RA, exhibited a linear increase with disease severity consistent with declining GFR. In peripheral blood, the transcript level of seven mediators, ICAM1, TNF-alpha, TGF-beta, IL-8, IL17RA, IFNgamma, and MYD88 were significantly elevated at all disease stages as compared to control. CONCLUSION: Statistically significant differences in protein and transcripts levels between diseased and control can be detected in serum and peripheral blood utilizing high content profiling. These changes occur as early as stage 1-2 before a significant decline in renal function. PMID- 26116589 TI - Screening High Abundance of Peptide for Making Examination Possible in Human Urine. AB - OBJECTIVE: We aim to explore and identify the high abundance of peptides in urine. METHODS: Random urine samples from 30 healthy individuals were purified by weak cationic-exchange magnetic beads (MB-WCX) and then analyzed by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Then the generated mass spectra of peptides were handled by ClinPro-Tools2.1 bioinformatics software and the high abundance of urinary peptide was filtered. Subsequently, the amino acid sequences of highly expressed peptides were identified by a nano-liquid chromatography-tandem mass spectrometry and the corresponding protein names were found by Sequest search. RESULTS: There were 159 urinary peptides of which mass to charge ratios (m/z) varied between 1,000 and 10,000 in the 30 healthy samples. Only peaks with average intensity >600 and the frequency >50% in the whole group were filtered. There were 15 peptides passed though the threshold and they were identified as fragments of fibrinogen alpha chain precursor, vitronectin precursor, inter-alpha-trypsin inhibitor heavy chain H4, complement component 3, prothrombin, apolipoprotein C-II, and alpha fetoprotein. CONCLUSION: These urinary peptides could be used for further research on urine. PMID- 26116590 TI - Target-antigen Detection and Localization of Human Amniotic-derived Cells after in Utero Transplantation in Rats. AB - Human amniotic-derived cells (hAMCs) have recently raised interest for their differentiation capability and immunomodulatory properties. To assess the feasibility of hAMCs therapeutic treatment during fetal development, we explored the localization of cells derived from the human amniotic membrane in rat organs after in utero transplantation. Rats were sacrificed at different time points and their organs were analyzed for the distribution of hAMCs by immunohistochemistry using an antibody against Human Cytoplasm and through detection of human DNA. Immunohistochemical and PCR analysis showed that most of the rat tissues presented human cells/DNA suggesting a widespread migration of hAMCs after transplantation. We developed an efficient target-antigen detection method based on an immunohistochemical technique that resulted to be highly specific and sensitive to identify the hAMCs into rat tissues. PMID- 26116591 TI - Neutrophil-Lymphocyte Ratio (NLR) Could Be Better Predictor than C-reactive Protein (CRP) for Liver Fibrosis in Non-alcoholic Steatohepatitis(NASH). AB - BACKGROUND-AIM: Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease worldwide. The aims of this study were to assess Neutrophil Lymphocyte Ratio (NLR) and C-reactive protein (CRP), and their association with liver histology in patients with non-alcoholic steatohepatitis (NASH), chronic hepatitis B (HBV), and hepatitis C (HCV). MATERIAL-METHODS: We studied 38 consecutive patients with biopsy-proven NASH, 19 patients with HCV, 45 patients with HBV, and 35 healthy controls who were similar for age and gender. The stage of fibrosis was measured using a 6-point scale. RESULTS: NLR was significantly higher in NASH patients compared to controls, HBV, and HCV patients (p<0.001, p<0.001, and p<0.001, respectively). NLR was positively associated with NAFLD activity scores (r=0.861, p<0.001). NLR was associated with hepatocyte ballooning degeneration (r=0.426, p=0.024), lobular inflammation(r=0.694, p<0.001), steatosis(r=0.498, p=0.007), and fibrosis stage(r=0.892, p<0.001) in NASH patients. Univariate and multivariate analyses showed that NLR was significantly associated with liver fibrosis and NAS (beta=0.631, p<0.001 for liver fibrosis; beta=0.753, p<0.001 for NAS in the multivariate model); however, CRP had no association with liver fibrosis and NAS CONCLUSION: NLR is a promising and inexpensive inflammation marker that correlates with histological grade and fibrosis stage in NASH patients. PMID- 26116592 TI - Plasma Adiponectin Levels Inversely Correlate to Clinical Parameters in Type 2 Diabetes Mellitus Patients with Macrovascular Diseases. AB - It has been shown that adiponectin (APN) and plasminogen activator inhibitor type 1 (PAI-1) are inversely involved in the regulation of atherosclerosis formation. However, the clinical impact of APN and PAI-1 in type 2 diabetes mellitus (T2DM) with macrovascular diseases (MVD) has not been investigated. In the present study, we found that plasma APN levels were significantly lower in T2DM patients than healthy donors, with a further decrease in T2DM patients with MVD. In contrast, plasma PAI-1 levels were significantly higher in T2DM patients than healthy donors, with a further increase in T2DM patients with MVD. We observed that plasma APN levels negatively correlated to values of BMI, FBG, FINS, TG, and PAI-1 in T2DM patients. In patients with MVD, plasma APN levels were negatively associated with values of BMI, SBP, FBG, FINS, TG, and PAI-1. By multiple stepwise regression analysis, we found that values of BMI, FCP, PAI-1, and FBG independently related to plasma levels of APN in T2DM patients with MVD. Taken together, our results indicate that APN might be a promising biomarker in patients with T2DM, especially in those with MVD. PMID- 26116593 TI - Cyclophosphamide Combined with Bone Marrow Mesenchymal Stromal Cells Protects against Bleomycin-induced Lung Fibrosis in Mice. AB - INTRODUCTION: To examine the effects and possible mechanism of the immunosuppressant agent cyclophosphamide (CP) combined with bone marrow mesenchymal stromal cells (BM-MSCs) on bleomycin induced lung fibrosis in mice. METHODS: BM-MSCs labeled with red fluorescence protein (RFP) from male Friend virus B-type(FVB) mice were cultured in vitro. Pulmonary fibrosis(PF) was induced in female wild type FVB mice and mice were randomly divided into five groups: control, model, CP, BM-MSCs, and BM-MSCs+CP. Pathological changes and distribution of RFP (+) BMSC in lung tissue were observed and hydroxyproline (Hyp) content in the lungs was measured. Changes in TGF-beta mRNA, PDGF mRNA, and SDF-1mRNA expression in lung tissue were measured. RESULTS: PF and Hyp levels in the BM-MSCs and BM-MSCs+CP groups were significantly alleviated (p<0.01) compared to the model group. The RFP (+) cells were distributed in the periphery of the alveolar space and endomembrane of bronchus. Hyp levels were reduced in the BM MSCs+CP group compared to the BM-MSCs group (p<0.05). TGF-beta and PDGF levels in the BM-MSCs and BM-MSCs+CP groups were higher than in the control or model group (p<0.05). SDF-1 level in the CP group showed no significant differences compared to the control group, in the other groups were higher than in the control group (p<0.05) and in the BM-MSCs+CP group was lower than in the BM-MSCs group (p<0.05). CONCLUSION: It was concluded that CP alone does not improve PF and may be harmful. In contrast, combined application of BM-MSCs with CP provided better protection against PF and may serve as an effective therapy. PMID- 26116594 TI - Clot Strength as Measured by Thrombelastography Correlates with Platelet Reactivity in Stroke Patients. AB - OBJECTIVE: Platelet reactivity may be important in the management of patients with stroke. However, degree of platelet reactivity has not been correlated with Thrombelastography (TEG((r))) parameters in stroke. We sought to detect a correlation between TEG((r)) values and clot platelet reactivity in ex vivo clots of stroke patients. METHODS: We collected venous blood from 40 patients with stroke. TEG((r)) measurements were carried out and residual clots were fixed in 10% formalin immediately following completion of TEG((r)). The formalin specimens were embedded in paraffin blocks, cut at 4 micrometers, and stained with CD 61 (immunohistochemical stain used to detect platelets) with appropriate controls. Under light microscopy, three pathologists blinded to TEG((r)) results independently graded CD61 intensity (how aggregated/intense the CD61 stained) into a low and high group, as a proposed measurement representing the platelet reactivity of the clot. We compared pre-tPA-TEG((r)) values among groups with different CD 61 intensities. RESULTS: After adjusting for confounding factors, we found statistically significant correlation between CD61 staining and several TEG((r)) parameters (Delta and CD61 staining intensity (p=0.047); Angle and CD61 staining intensity grade (p=0.04); and G and CD61 staining intensity grade (p=0.04)). CONCLUSIONS: Clot strength on TEG((r)) as measured by Delta, Angle, and G correlates with a clot with greater platelet reactivity. PMID- 26116595 TI - Up-regulation of MicroRNA 146b is Associated with Myelofibrosis in Myeloproliferative Neoplasms. AB - In this study, our goal was to evaluate whether the expressions of microRNA (miR) 150, miR-146b, miR-31 and miR-95 demonstrate primary myelofibrosis (PMF) specificity, associations with fibrosis grade, hematologic phenotypes, or myeloproliferative neoplasm (MPN)-associated mutations. A total of 51 formalin fixed and paraffin-embedded bone marrow MPN samples, including 15 polycythemia vera (PV), 26 essential thrombocythemia (ET), and 10 PMF, and 24 normal controls were included. The expression of microRNA (miRNA) was detected by quantitative real-time polymerase chain reaction using miRNA specific primers. RNU6-2 was analyzed for all samples as endogenous control for relative quantification. Information for fibrosis, hematologic parameters, Janus kinase 2 (JAK2) V617F, and calreticulin (CALR) mutations was obtained from medical records. Significant increment of miR-146b was detected in PMF compared to normal controls (P=0.008). Moreover, expression of miR-146b tended to increase according to increment of fibrosis grade, and patients with myelofibrosis (MF) grade 3 showed significantly higher expression than patients with MF 0 to 2 (P=0.022, 0.001 and 0.013, respectively) or normal controls (P<0.001). The expression of miR-31 also showed tendency to increase following fibrosis and miR-150 showed up-regulated expression in ET (P=0.015) compared to normal control. There was no relationship between miRNA expression and hematologic indices except miR-95 showed negative correlation with platelet count (P=0.024). There was no significant correlation between miRNA expression and JAK2 V617F or CALR mutation. Up-regulation of miR 146b could be used as a fibrosis-indicating marker and might be helpful in the study of fibrotic mechanism in MPN, as well as other fibrotic diseases. PMID- 26116596 TI - GPR109A Expression in the Murine Min6 Pancreatic Beta Cell Line, and Its Relation with Glucose Metabolism and Inflammation. AB - BACKGROUND: Nicotinic acid has been used clinically to manage dyslipidemia for many years, and its receptor, GPR109A, is expressed in various tissues or cells. It is not known if GPR109A is also expressed in pancreatic beta cells or if it takes part in maintaining homeostasis of glucose metabolism. AIMS: In this study, the expression of GPR109A was investigated in the murine Min6 pancreatic beta cell line. The anti-inflammatory role of GPR109A in MIN6 cells was also explored. METHODS: RT-PCR, western blotting, and immunocytochemical staining were used to detect the expression of GPR109A in MIN6 cells. Real-Time RT-PCR was used to investigate GPR109A mRNA levels influenced by IFN-gamma and glucose. Cell viability and cytoplasmic nitrite levels were measured colorimetrically. RESULTS: We have identified that MIN6 cell, a mouse pancreatic beta cell line, expresses GPR109A transcripts and protein. GPR109A protein is mainly located in the cell membrane and cytoplasm. GPR109A mRNA increased more than 9-fold in MIN6 cells incubated with IFN-gamma. High glucose inhibited GPR109A mRNA expression. Nitric oxide accumulation, induced by IFN-gamma/TNF-alpha, was inhibited by nicotinic acid and 3-hydroxy-butyrate. CONCLUSIONS: Our results suggest that the expression of GPR109A in pancreatic beta cells is not only influenced by inflammation and glucose, but also plays a protective role under inflammatory conditions. Moreover, the MIN6 cell line may serve as a cellular model for further investigation of GPR109A-mediated signal transduction in modulating metabolism and diabetes. PMID- 26116597 TI - The iDigoxin Assay is More Sensitive than LOCI Digoxin Assay for Rapid Detection of Convallatoxin, the Active Cardiac Glycoside of Lily of The Valley. AB - OBJECTIVE: Lily of the valley is a poisonous plant due to the presence of the cardiac glycoside convallatoxin. We compared two immunoassays (LOCI digoxin assay and iDigoxin assay) for rapid detection of convallatoxin if present in human serum. MATERIALS AND METHODS: Aliquots of a drug free serum pool and a digoxin serum pool were supplemented with microliter amounts of lily of the valley extract or nanogram to microgram quantities of convallatoxin, followed by measurement of apparent digoxin concentrations using the LOCI and iDigxoin assays. RESULTS: Apparent digoxin concentrations were observed when aliquots of a drug free serum pool were supplemented with convallatoxin or lily of the valley extract using both assays but apparent digoxin concentrations were significantly higher using the iDigoxin assay. In addition, the interference of convallatoxin in serum digoxin measurement was also significantly higher using iDigxoin assay compared to the LOCI digoxin assay. CONCLUSIONS: The iDigxoin assay is more sensitive in detecting convallatoxin in human serum. PMID- 26116598 TI - Comparison of the Xpert MTB/RIF Assay and Real-time PCR for the Detection of Mycobacterium tuberculosis. AB - INTRODUCTION: We compared the Xpert MTB/RIF assay with a real-time PCR assay using samples from culture-positive patients with TB. In addition, drug susceptibility test results were compared to evaluate the usefulness of these methods. MATERIALS AND METHODS: Fifty-two clinical specimens were analyzed by standard smear-microscopy, mycobacterial growth indicator tube (MGIT) culture, solid culture, MGIT drug-susceptibility testing, TB real-time PCR, and the Xpert MTB/RIF assay. RESULTS: Diagnostic sensitivity of AdvanSure TB/NTM real-time PCR was 80.0%. As shown from smear positive and negative specimens, sensitivities were 87.5% and 75.9%, respectively. The diagnostic sensitivity of Xpert MTB/RIF assay was 75.5%, and from smear positive and negative specimens, sensitivities were 93.8% and 65.5%, respectively. There were 10 cases with discrepant results between two methods. 2 cases were found resistant to rifampin, although Xpert MTB/RIF assay was able to detect rifampin resistance in only one specimen. DISCUSSION: Xpert MTB/RIF assay is an easier method to conduct and while its ability to detect rifampin resistance simultaneously is a benefit, its sensitivity from smear negative-culture positive specimens was lower than Advansure TB/NTM real-time PCR. Further investigation to increase the sensitivity and detect other drug resistances by kit-based assays is required for the rapid and accurate diagnosis of tuberculosis. PMID- 26116599 TI - Laboratory and Clinical features of EIA Toxin-positive and EIA Toxin-negative Community-acquired Clostridium difficile Infection. AB - Studies have described the clinical course of patients with Clostridium difficile infection (CDI) with positive enzyme immunoassay (EIA) for toxins A and B. Limited information is available for the patients with negative EIA but positive for the toxin B gene (TcdB) by the PCR. The aim of our study is to determine if there are any differences that exist among the clinical and laboratory parameters in the patients tested to be positive by EIA for toxin and those who were negative. This is a retrospective cohort study conducted in a 700-bed teaching hospital. We reviewed charts of the patients with presumptive CDI between January 2006 and July 2013. We divided these patients into two groups, EIA-positive and EIA-negative, based on result of EIA for toxins A and B and the requirement for a positive PCR analysis of the TcdB gene. The EIA-positive group had significantly higher white blood cell counts (p<0.001), with a significantly greater percentage of bands (p<0.0001). Albumin and total protein both exhibit significantly (p<0.0001, both comparisons) lower values in the EIA-positive group. Among clinical findings, the EIA-positive group had significantly longer length of hospital stay (p=0.010). These data suggest that an infection with an EIA negative strain of C. difficile presents laboratory markers closer to those of healthy subjects and clinical features suggesting considerably less severe than infection with EIA-positive C. difficile. PMID- 26116600 TI - Plasma Cell Granuloma: An Entity within the Spectrum of IgG4-Related Disease. AB - Plasma cell granuloma (PCG) is a relatively rare, mass-forming lesion comprised of polyclonal plasma cells set in a background of storiform fibrosis and spindle cell proliferation. While uncommon, this lesion may occur within any site and should be included in the list of differential diagnoses for plasma cell neoplasms. As this entity can be mistaken for a plasma cell neoplasm, surgical pathologists should consider ancillary studies to assess clonality of plasma cell proliferations, especially during intraoperative consultation.Although the etiology of these lesions is unclear, recent literature and immunohistochemical stains performed on our own cases suggest that PCG falls within the spectrum of IgG4 related diseases, which would have significant clinical significance impacting treatment and the potential for associated disease at distant body sites. We present two cases of head and neck PCG encountered at a tertiary academic medical center with immunohistochemical staining demonstrating increased IgG4-secreting plasma cells. PMID- 26116601 TI - Spinal Stenosis with Paraparesis in a Korean Boy with Albright's Hereditary Osteodystrophy: Identification of a Novel Nonsense Mutation in the GNAS. AB - Children with Albright's hereditary osteodystrophy (AHO) suffering from spinal cord compression are rarely reported worldwide. The association of compressive myelopathy with AHO is not still well known. AHO is a rare heterogeneous group of inherited disorders and results from the GNAS mutation. AHO manifests in two different phenotypes, pseudohypoparathyroidism type Ia (PHP-Ia) and pseudopsedohypoparthyroidim (PPHP), which may happen in the same family members. We present the case of a 15-year-old boy with AHO features, who was later diagnosed with PHP-Ia. He suffered from cervical myelopathy with paraparesis due to spinal stenosis. His mother with AHO phenotype was diagnosed with PPHP without spinal stenosis. Genetic analysis revealed a novel heterozygous nonsense mutation within exon 1 of GNAS(c.49A>T; p.Lys17*) in both of them. This is the first clinically, biochemically, and genetically identified child case of spinal stenosis and paraparesis associated with PHP-Ia, having a novel GNAS mutation in Korea. PMID- 26116602 TI - Ovarian Sertoli-Leydig Cell Tumor with Predominant Heterologous Mucinous Differentiation and Foci of Hepatocytic Differentiation: Case Report and Review of The Literature. AB - Sertoli-Leydig cell tumor is a rare ovarian neoplasm and belongs to the group of sex cord stromal tumors. We present a case of a 15-year old girl diagnosed with Sertoli-Leydig cell tumor with heterologous elements consisting predominantly of mucinous epithelium and a sparse Sertoli-Leydig cell component, mimicking mucinous neoplasm. Furthermore, foci of hepatocytic differentiation were also identified. Immunohistochemical stains showed the component of Sertoli cell differentiation was positive for cytokeratin 18 and inhibin. The component of Leydig cell differentiation was strongly positive for inhibin. The component of hepatocytic differentiation was positive for low molecular weight keratin, HepPar1, alpha-fetoprotein and weakly positive for inhibin. Thus, this was a very rare case which created a challenge for pathologists, especially on frozen sections. PMID- 26116603 TI - A Case Report of a Child with a Marker Chromosome Presenting as Isodicentric Yp and Literature Review. PMID- 26116604 TI - Rifampicin Interference in the Measurement of Urinary Catecholamines by High Performance Liquid Chromatography. AB - Measurement of urine and plasma catecholamines and their metabolites are essential for the diagnosis of pheochromocytoma. Here, we report our experience of rifampicin interference in the measurement of urinary catecholamines using high-performance liquid chromatography. During a 1-year period, four patients taking rifampicin showed unusual chromatograms with markedly larger norepinephrine spikes, translating to highly elevated norepinephrine concentrations: 290.2, 720.1, 312.0, and 812.7 MUg/L. This interference effect did not occur when samples were prepared using the alumina method, with norepinephrine values decreasing to 26.4, 31.5, 21.9, and 17.2 MUg/L. Interference was also absent in data using LC-MS/MS. Clinical laboratories should verify whether rifampicin interferes with test results in their assays, and physicians should be informed that urinary norepinephrine levels can be falsely elevated in patients taking rifampicin. PMID- 26116605 TI - Primary Epithelioid Angiosarcoma of Bone with Robust Cell Cycle Progression and High Expression of SPARC: A Case Report and Review of the Literature. AB - Epithelioid angiosarcoma of bone is a rare entity. Secreted protein acidic and rich in cysteine (SPARC), or osteonectin, is a secreted glycoprotein that has been implicated in tumorigenesis. We report a case of epithelioid angiosarcoma involving the long bones of the lower extremity showing diffuse and strong expression for SPARC immunohistochemistry in tumor cells. Ki-67 was positive in ~50% of tumor cell nuclei and the accompanying mitotic index was 19 mitotic figures/10 high power fields.Expression of SPARC in tumors has been correlated with sensitivity to nanoparticle albumin-bound paclitaxel (Nab-paclitaxel), particularly in the context of robust cell cycle progression into the mitotic phase. This finding could suggest new therapeutic options for further consideration. PMID- 26116606 TI - Clinical Course of Unilateral Acanthamoeba Keratitis in a Cosmetic Contact Lens Wearer. AB - PURPOSE: To report the features and clinical course of Acanthamoeba keratitis in a cosmetic contact lens wearer. CASE REPORT: A 29-year-old man sought medical attention for severe ocular pain, blurry vision, photophobia, and a foreign body sensation in the left eye for the past 3-4 days. He had been wearing a single sapphire cosmetic soft contact lens for 1-2 months. The left upper eyelid was edematous and the conjunctiva was hyperemic; the best corrected distance visual acuity was 20/400. A slit lamp examination revealed circular and perineural linear stromal opacities and diffuse keratic precipitates. A clinical diagnosis of herpes simplex keratitis was made and the patient was started on antiviral therapy. After initial improvement, the patient returned with worsening pain and vision; the corneal lesions had exacerbated. Unresponsiveness to antiviral therapy prompted examination of corneal scrapings, which revealed Acanthamoeba developmental forms. Antimicrobial therapy was prescribed resulting in relief of symptoms despite corneal opacities and poor vision. CONCLUSION: This case illustrates the importance of considering Acanthamoeba keratitis in contact lens wearers at presentation, particularly in those with symptomatic keratitis unresponsive to antiviral and antifungal therapy. PMID- 26116607 TI - Nicotinate O-Glucosylation Is an Evolutionarily Metabolic Trait Important for Seed Germination under Stress Conditions in Arabidopsis thaliana. AB - The glycosylation of nicotinate (NA), a key intermediate of the NAD salvage pathway, occurs widely in land plants. However, the physiological function of NA glycosylation is not well understood in planta, and no gene encoding NA glycosyltransferase has been reported to date. NA glycosylation in Arabidopsis thaliana occurs at either the N- or the O-position of the NA molecule, and O glucosylation appears to be unique to the Brassicaceae. Using gene-enzyme correlations focused on Family 1 glycosyltransferases (GTs; EC 2.4), we identified and characterized three Arabidopsis GTs, which are likely involved in NA glycosylation. These include one NAOGT (UGT74F2; previously identified as a salicylic acid glycosyltransferases) and two NANGTs (UGT76C4 and UGT76C5). Arabidopsis mutants of UGT74F2 accumulate higher levels of free NA, but not salicylic acid, than that of the wild type, and this inversely correlated with seed germination rates under various abiotic stresses. The germination defect of the ugt74f2-1 mutant could be fully complemented by overexpression of UGT74F2. These observations, together with comprehensive chemical analysis, suggest that NA glycosylation may function to protect plant cells from the toxicity of NA overaccumulation during seed germination. Combined with phylogenetic analysis, our results suggest that NAOGTs arose recently in the Brassicaceae family and may provide a fitness benefit. The multifunctionality of UGT74F2 in Arabidopsis is also investigated and discussed. PMID- 26116609 TI - Changes in cuff pressure and position of cylindrical-cuff and tapered-cuff tracheal tubes during laparoscopic abdominal surgery. AB - OBJECTIVES: To evaluate changes in cuff pressure and position of tapered-cuff and cylindrical-cuff tracheal tubes (TTs) during laparoscopic cholecystectomy; to compare the frequency of endobronchial intubation and airway complaints with the two types of TT. METHODS: Patients were randomly assigned to intubation with a TT with a cylindrical cuff (group C) or a tapered cuff (group T). Anaesthesia was maintained with sevoflurane, O(2) and N(2)O after intubation. TT cuffs were inflated to 20 cm H(2)O; changes in cuff pressure and volume were measured up to 30 min after the start of N(2)O use. Distance between the TT tip and the carina was measured before and after pneumoperitoneum and position change. Frequency of sore throat, dysphagia and hoarseness in the two groups was recorded. RESULTS: Cuff volume and pressure were significantly lower in group T than in group C (n = 32 per group). Cuff pressure and volume significantly increased 30 min after start of N(2)O use in both groups. Distance from the TT tip to the carina decreased during surgery in both groups. There were no cases of endobronchial intubation, and there were no between-group differences in the frequency of airway complaints. CONCLUSIONS: The tapered cuff was associated with a smaller change in cuff pressure during laparoscopic cholecystectomy than the cylindrical cuff, and therefore may be associated with increased preservation of tracheal mucosal perfusion. PMID- 26116608 TI - Mitochondrial Dihydrolipoyl Dehydrogenase Activity Shapes Photosynthesis and Photorespiration of Arabidopsis thaliana. AB - Mitochondrial dihydrolipoyl dehydrogenase (mtLPD; L-protein) is an integral component of several multienzyme systems involved in the tricarboxylic acid (TCA) cycle, photorespiration, and the degradation of branched-chain alpha-ketoacids. The majority of the mtLPD present in photosynthesizing tissue is used for glycine decarboxylase (GDC), necessary for the high-flux photorespiratory glycine-into serine conversion. We previously suggested that GDC activity could be a signal in a regulatory network that adjusts carbon flux through the Calvin-Benson cycle in response to photorespiration. Here, we show that elevated GDC L-protein activity significantly alters several diagnostic parameters of cellular metabolism and leaf gas exchange in Arabidopsis thaliana. Overexpressor lines displayed markedly decreased steady state contents of TCA cycle and photorespiratory intermediates as well as elevated NAD(P)(+)-to-NAD(P)H ratios. Additionally, increased rates of CO2 assimilation, photorespiration, and plant growth were observed. Intriguingly, however, day respiration rates remained unaffected. By contrast, respiration was enhanced in the first half of the dark phase but depressed in the second. We also observed enhanced sucrose biosynthesis in the light in combination with a lower diel magnitude of starch accumulation and breakdown. These data thus substantiate our prior hypothesis that facilitating flux through the photorespiratory pathway stimulates photosynthetic CO2 assimilation in the Calvin-Benson cycle. They furthermore suggest that this regulation is, at least in part, dependent on increased light-capture/use efficiency. PMID- 26116610 TI - Iron overload increases osteoclastogenesis and aggravates the effects of ovariectomy on bone mass. AB - Postmenopausal osteoporosis is a metabolic disease associated with estrogen deficiency. The results of numerous studies have revealed the positive correlation between iron accumulation and postmenopausal osteoporotic status. Although the results of previous studies have indicated that estrogen or iron alone have an effect on bone metabolism, their combined effects are not well defined. Using an in vivo mouse model, we found that bone mass was minimally affected by an excess of iron in the presence of estrogen. Once the source of estrogen was removed (ovariectomy), iron accumulation significantly decreased bone mass. These effects were accompanied by fluctuations in the level of oxidative stress. To determine whether these effects were related to bone formation or bone resorption, primary osteoblasts (OBs), RAW264.7 cells, and bone marrow-derived macrophages were used for in vitro experiments. We found that iron accumulation did inhibit the activity of OBs. However, estrogen had little effect on this inhibition. In contrast, iron promoted osteoclast differentiation through the production of reactive oxygen species. Estrogen, a powerful reactive oxygen scavenger, suppressed this effect in osteoclasts. Our data provided direct evidence that iron affected the bone mass only in the absence of estrogen. The inhibitory effect of estrogen on iron-induced osteopenia was particularly relevant to bone resorption rather than bone formation. PMID- 26116611 TI - Implementing Role-Changing Versus Time-Changing Innovations in Health Care: Differences in Helpfulness of Staff Improvement Teams, Management, and Network for Learning. AB - Health care organizations often fail in their effort to implement care-improving innovations. This article differentiates role-changing innovations, altering what workers do, from time-changing innovations, altering when tasks are performed or for how long. We examine our hypothesis that the degree to which access to groups that can alter organizational learning--staff, management, and external network- facilitates implementation depends on innovation type. Our longitudinal study using ordinal logistic regression and survey data on 517 hospitals' implementation of evidence-based practices for treating heart attack confirmed our thesis for factors granting access to each group: improvement team's representativeness (of affected staff), senior management engagement, and network membership. Although team representativeness and network membership were positively associated with implementing role-changing practices, senior management engagement was not. In contrast, senior management engagement was positively associated with implementing time-changing practices, whereas team representativeness was not, and network membership was not unless there was limited management engagement. These findings advance implementation science by explaining mixed results across past studies: Nature of change for workers alters potential facilitators' effects on implementation. PMID- 26116612 TI - Fatty acid synthase is a metabolic oncogene targetable in malignant peripheral nerve sheath tumors. AB - BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target. METHODS: Based on preliminary findings that MPNSTs accumulate LDs, we hypothesized that a deregulated lipid metabolism supports MPNST cell survival/proliferation rate. To test this, we examined respiration, role of fatty acid oxidation (FAO), and the enzyme fatty acid synthase involved in de novo fatty acid synthesis in MPNSTs using both genetic and pharmacological tools. RESULTS: We demonstrate that LDs accumulate in MPNST cell lines, primary human and mouse MPNST tumors, and neural crest cells. LDs from MPNST cells disappear on lipid deprivation, indicating that LDs can be oxidized as a source of energy. Inhibition of FAO decreased oxygen consumption and reduced MPNST survival, indicating that MPNST cells likely metabolize LDs through active FAO. FAO inhibition reduced oxygen consumption and survival even in the absence of exogenous lipids, indicating that lipids synthesized de novo can also be oxidized. Consequently, inhibition of de novo fatty acid synthesis, which is overexpressed in human MPNST cell lines, effectively reduced MPNST survival and delayed induction of tumor growth in vivo. CONCLUSION: Our results show that MPNSTs depend on lipid metabolic pathways and suggest that disrupting lipid metabolism could be a potential new strategy for the development of MPNST therapeutics. PMID- 26116613 TI - Effect of self-reported home smoking restriction on smoking initiation among adolescents in Taiwan: a prospective cohort study. AB - OBJECTIVE: The aims of this study were to investigate the influence of home smoking restriction (HSR) and the modified effect of parental smoking on smoking initiation among adolescents. DESIGN: Prospective Cohort Study. SETTING: Junior high school in Keelung City, Taiwan. PARTICIPANTS: This study collected and evaluated primary data from the Adolescent Smoking and Other Health-Related Behaviour Survey conducted in Keelung City, which aimed to investigate smoking and health-related behaviours in junior high school students (2008-2009). Data on students free of smoking in 2008 and following them until 2009 (n=901) to ascertain whether they had started smoking were analysed with logistic regression mode to examine the proposed postulates. MAIN OUTCOME MEASURE: The outcome variable was smoking initiation, which was defined as smoking status (yes/no) in the 2009 follow-up questionnaire. The main independent variable was HSR obtained from an adolescent self-reported questionnaire. Information on parental smoking was measured by adolescents self-reporting the smoking behaviour of their father and mother. RESULTS: The rate of HSR was 29.79% among 7th grade adolescents. The effect of HSR on smoking initiation in adolescents was statistically significantly modified by paternal smoking (p=0.04) but not by maternal smoking (p=0.54). The effect of HSR on smoking initiation was small for fathers with the habit of smoking (OR=0.89, 95% CI (0.42 to 1.88)), but the corresponding effect size was 3.2-fold (OR=2.84, 95% CI 1.19 to 6.81) for fathers without the habit of smoking. CONCLUSIONS: Paternal smoking behaviour may play an interactive role with HSR in preventing smoking initiation among Taiwanese adolescents. PMID- 26116615 TI - The transition model test for serial dependence in mixed-effects models for binary data. AB - Generalized linear mixed models for longitudinal data assume that responses at different occasions are conditionally independent, given the random effects and covariates. Although this assumption is pivotal for consistent estimation, violation due to serial dependence is hard to assess by model elaboration. We therefore propose a targeted diagnostic test for serial dependence, called the transition model test (TMT), that is straightforward and computationally efficient to implement in standard software. The TMT is shown to have larger power than general misspecification tests. We also propose the targeted root mean squared error of approximation (TRSMEA) as a measure of the population misfit due to serial dependence. PMID- 26116614 TI - FAST CP: protocol of a randomised controlled trial of the efficacy of a 12-week combined Functional Anaerobic and Strength Training programme on muscle properties and mechanical gait deficiencies in adolescents and young adults with spastic-type cerebral palsy. AB - INTRODUCTION: Individuals with cerebral palsy (CP) have muscles that are smaller, weaker and more resistant to stretch compared to typically developing people. Progressive resistance training leads to increases in muscle size and strength. In CP, the benefits of resistance training alone may not transfer to improve other activities such as walking; however, the transfer of strength improvements to improved mobility may be enhanced by performing training that involves specific functional tasks or motor skills. This study aims to determine the efficacy of combined functional anaerobic and strength training in (1) influencing muscle strength, structure and function and (2) to determine if any changes in muscle strength and structure following training impact on walking ability and gross motor functional capacity and performance in the short (following 3 months of training) and medium terms (a further 3 months post training). METHODS AND ANALYSIS: 40 adolescents and young adults with CP will be recruited to undertake a 12-week training programme. The training programme will consist of 3 * 75 min sessions per week, made up of 5 lower limb resistance exercises and 2-3 functional anaerobic exercises per session. The calf muscles will be specifically targeted, as they are the most commonly impacted muscles in CP and are a key muscle group involved in walking. If, as we believe, muscle properties change following combined strength and functional training, there may be long-term benefits of this type of training in slowing the deterioration of muscle function in people with spastic-type CP. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the ethics committees at The University of Queensland (2014000066) and Children's Health Queensland (HREC/15/QRCH/30). The findings will be disseminated by publications in peer-reviewed journals, conferences and local research organisations' media. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12614001217695). PMID- 26116616 TI - Performance of methods for meta-analysis of diagnostic test accuracy with few studies or sparse data. AB - Hierarchical models such as the bivariate and hierarchical summary receiver operating characteristic (HSROC) models are recommended for meta-analysis of test accuracy studies. These models are challenging to fit when there are few studies and/or sparse data (for example zero cells in contingency tables due to studies reporting 100% sensitivity or specificity); the models may not converge, or give unreliable parameter estimates. Using simulation, we investigated the performance of seven hierarchical models incorporating increasing simplifications in scenarios designed to replicate realistic situations for meta-analysis of test accuracy studies. Performance of the models was assessed in terms of estimability (percentage of meta-analyses that successfully converged and percentage where the between study correlation was estimable), bias, mean square error and coverage of the 95% confidence intervals. Our results indicate that simpler hierarchical models are valid in situations with few studies or sparse data. For synthesis of sensitivity and specificity, univariate random effects logistic regression models are appropriate when a bivariate model cannot be fitted. Alternatively, an HSROC model that assumes a symmetric SROC curve (by excluding the shape parameter) can be used if the HSROC model is the chosen meta-analytic approach. In the absence of heterogeneity, fixed effect equivalent of the models can be applied. PMID- 26116617 TI - CUSUM control charts to monitor series of Negative Binomial count data. AB - To detect outbreaks of diseases in public health, several control charts have been proposed in the literature. In this context, the usual generalized linear model may be fitted for counts under a Negative Binomial distribution with a logarithm link function and the population size included as offset to model hospitalization rates. Different statistics are used to build CUSUM control charts to monitor daily hospitalizations and their performances are compared in simulation studies. The main contribution of the current paper is to consider different statistics based on transformations and the deviance residual to build control charts to monitor counts with seasonality effects and evaluate all the assumptions of the monitored statistics. The monitoring of daily number of hospital admissions due to respiratory diseases for people aged over 65 years in the city Sao Paulo-Brazil is considered as an illustration of the current proposal. PMID- 26116618 TI - Efficacy of intravesical pentosan polysulfate sodium in cats with obstructive feline idiopathic cystitis. AB - OBJECTIVES: Obstructive feline idiopathic cystitis is a common emergency in small animal practice. There is evidence for a defective glycosaminoglycan layer in the urinary bladder of affected cats. The aim of this study was to investigate the effect of intravesical pentosan polysulfate sodium (PPS) in cats with obstructive feline idiopathic cystitis in a randomised, placebo-controlled, blinded clinical study. METHODS: Thirty-five cats with obstructive feline idiopathic cystitis were enrolled into the study. On day 0, cats were randomised to receive either 30 mg PPS in saline (18 cats) or saline alone as placebo (17 cats) at the time of indwelling urinary catheter placement and then after 24 and 48 h. The catheter was clamped for 30 mins after administration before connecting it to a sterile urine collection system. The procedure was repeated after 24 and 48 h, and then the indwelling catheter was removed. Treatment success was assessed via the incidence of recurrent urethral obstruction, results of a scoring system for physical examination and daily urinalysis from day 0 to 5. RESULTS: Recurrent urethral obstruction occurred in 3/18 cats of the verum group and 3/17 of the placebo group (P = 1.000). The verum group showed a significantly lower degree of microscopic haematuria between day 5 and day 0 (P ?0.05). The placebo group showed a significantly lower degree of dipstick haematuria between day 5 and day 0 (P ?0.05). There was no difference in the clinical score between the groups in the investigated time period. CONCLUSIONS AND RELEVANCE: Intravesical instillation of PPS three times within 48 h in the chosen dose had no influence on the incidence of recurrent urethral obstruction and clinical signs in cats with obstructive feline idiopathic cystitis. PMID- 26116619 TI - Diagnostic value of Light's criteria and albumin gradient in classifying the pathophysiology of pleural effusion formation in cats. AB - The primary aim of this study was to assess whether human Light's criteria with the cut-off values previously published for cats are useful and superior to the traditional veterinary classification in diagnosing pathophysiology of fluid formation in cats with pleural effusion. The secondary aim was to assess if the albumin gradient (ALBg) is a reliable criterion for differentiating exudates from transudates in patients with pleural effusion thought to be transudative by clinical criteria but identified as exudative by Light's criteria. Nineteen client-owned cats with pleural effusion were studied. The aetiology of the pleural effusion was used to establish the pathophysiology of its formation. Parameters measured or calculated undergoing statistical analysis included Light's criteria, total protein and total nucleated cell count in the pleural effusions, and the ALBg. Based on the pathophysiology of fluid formation there were seven transudates caused by increased hydrostatic pressure and 12 exudates. There was a significant difference in the accuracy of the Light's criteria in correctly classifying origin of the pleural fluid formation compared with the traditional veterinary classification (84% vs 53%). ALBg values were significantly different between transudates and exudates. One of the three transudates misclassified as exudates by Light's criteria was correctly identified as a transudate by the ALBg. In conclusion, pleural effusion should be classified as either a transudate or an exudate using Light's criteria. In cats with pleural effusion thought to be transudative by clinical criteria, but identified as exudative by Light's criteria, the ALBg may further help in correctly differentiating exudates from transudates. PMID- 26116620 TI - What do we know about feline leishmaniosis? AB - According to the World Health Organization (WHO), endemic areas of leishmaniosis have spread and the number of reported cases has increased. Europe is one of the continents with greatest risk of the re-emergence of this zoonosis. The significance of the cat as a reservoir of Leishmania species and not simply an accidental host seems to be gaining ground, mainly because: (i) cats can present increased seropositivity between serological analyses, but the pattern of seropositivity is not consistent between cats; (ii) cats can be infected for some months and thus are available for sandflies; and (iii) cats transmit the Leishmania species agent in a competent form. Furthermore, cats have behavioural characteristics that contribute to infection by Leishmania infantum and, as such, feline leishmaniosis (FeL) has been reported worldwide. When clinical signs of FeL are present, they are non-specific and frequently occur in other feline diseases. If they go undiagnosed, they can contribute to an underestimation of the actual occurrence of the disease in cats. The low seroprevalence titres, along with the commonly asymptomatic infection in cats, can further contribute to the underestimation of FeL occurrence. This work aims to raise awareness about FeL among veterinarians by providing a review of the current status of FeL infection caused by L infantum worldwide, the major clinicopathological features of infection, along with recent developments on FeL diagnosis, treatment and prevention. PMID- 26116621 TI - Feline non-regenerative immune-mediated anaemia: features and outcome in 15 cases. AB - OBJECTIVES: Pure red cell aplasia (PRCA) and non-regenerative immune-mediated haemolytic anaemia (NRIMHA) are uncommon causes of non-regenerative anaemia affecting the bone marrow in the cat. This retrospective study aimed to describe the clinical features, treatment and outcome (remission and survival) of cats with these disorders. METHODS: Cases of PRCA and NRIMHA presenting between 2009 and 2013 were retrieved. Clinical features including signalment, history, clinical signs and diagnostic investigations were recorded, as well as treatment(s) used and outcome (remission and survival). Outcome was compared for PRCA and NRIMHA. RESULTS: Fifteen cats met inclusion criteria: seven with PRCA and eight with NRIMHA. The majority (12/15) were younger than 3 years of age. Volume overload was common (8/11). Treatment with whole blood transfusions with or without Oxyglobin was necessary in most cats (14/15) and resulted in congestive heart failure in one cat. Most cats (11/15) achieved remission 12-42 days after starting immunosuppressive treatment. Treatment protocols associated with remission were glucocorticoids alone (remission in 6/7 cats), glucocorticoids and chlorambucil (remission in 3/6 treated cats), glucocorticoids and ciclosporin (one cat only) and ciclosporin alone (one cat only). Relapse was observed in 3/11 cats, and 8/11 cats were still receiving treatment at the time of follow-up. Outcome (remission and survival) did not differ between PRCA and NRIMHA. CONCLUSIONS AND RELEVANCE: PRCA and NRIMHA are uncommon causes of anaemia in predominantly young cats. The prognosis is reasonable, with a mortality rate of 27%, and it can take at least 6 weeks before remission is observed. Following clinical remission, gradual withdrawal of immunosuppressive treatments should be attempted, with close monitoring for relapse; some cats may require long-term treatment. This study is the first to report the use of chlorambucil as an adjunctive immunosuppressant in these cases. Outcome did not differ for PRCA and NRIMHA. PMID- 26116622 TI - FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs. AB - Most hormones secreted from specific organs of the body in response to diverse stimuli contribute to the homeostasis of the whole organism. Fibroblast growth factor 21 (FGF21), a hormone induced by a variety of environmental or metabolic stimuli, plays a crucial role in the adaptive response to these stressful conditions. In addition to its role as a stress hormone, FGF21 appears to function as a mediator of the therapeutic effects of currently available drugs and those under development for treatment of metabolic diseases. In this review, we highlight molecular mechanisms and the functional importance of FGF21 induction in response to diverse stress conditions such as changes of nutritional status, cold exposure, and exercise. In addition, we describe recent findings regarding the role of FGF21 in the pathogenesis and treatment of diabetes associated with obesity, liver diseases, pancreatitis, muscle atrophy, atherosclerosis, cardiac hypertrophy, and diabetic nephropathy. Finally, we discuss the current understanding of the actions of FGF21 as a crucial regulator mediating beneficial metabolic effects of therapeutic agents such as metformin, glucagon/glucagon-like peptide 1 analogues, thiazolidinedione, sirtuin 1 activators, and lipoic acid. PMID- 26116623 TI - C6 ceramide dramatically increases vincristine sensitivity both in vivo and in vitro, involving AMP-activated protein kinase-p53 signaling. AB - Use of the conventional cancer chemotherapy (i.e. vincristine) is limited in tumor cells exhibiting pre-existing or acquired resistance. Here, we found that C6 ceramide (C6) dramatically sensitized vincristine's activity. In vitro, C6 and vincristine coadministration induced substantial necrosis and apoptosis in multiple human cancer cell lines, which were accompanied by a profound AMP activated protein kinase (AMPK) activation, subsequent p53 activation, mTORC1 inactivation and Bcl-2/HIF-1alpha downregulation. Such synergistic effects were attenuated by AMPK inactivation through genetic mutation or short hairpin RNA silencing. Coadministration-activated p53 translocated to mitochondria, and formed a complex with cyclophilin-D, leading to mitochondrial permeability transition pore opening and cell necrosis. Disrupting p53-Cyp-D complexation through pharmacological or genetic means reduced costimulation-induced cytotoxicity. In vivo, a liposomal C6 was synthesized, which dramatically enhanced the antiproliferative activity of vincristine on HCT-116 or A2780 xenografts. Together, C6 sensitizes vincristine-induced anticancer activity in vivo and in vitro, involving activating AMPK-p53 signaling. PMID- 26116624 TI - The cancer cells-of-origin in the gastrointestinal tract: progenitors revisited. AB - A prominent model of tumor progression posits that normal self-renewing and multipotent stem cells(SCs) are the initial target of transformation. This view has been robustly challenged by the recurring observation that transit-amplifying cells and differentiated progenitors can initiate neoplasia outside the SC zone thus qualifying as cancer cells-of-origin. The emerging concept is that a cancer SC and a cancer cell-of-origin are not necessarily the same cell. Importantly, progenitor cells were shown to possess remarkable plasticity and to revert, on demand, to a SC-like state. The present review revisits our early hypothesis that colonic progenitors acquiring a mutant adenomatous polyposis coli gene after exiting the stem zone may serve as genuine cancer cells-of-origin. New findings consonant with this view are examined, and tenable molecular and cellular mechanisms underpinning the plasticity of progenitor cells in the gastrointestinal tract and in other tissues are discussed. The translational impact of cell plasticity is addressed, and recommendations for future research are advanced. PMID- 26116625 TI - Light-driven generation of hydrogen: New chromophore dyads for increased activity based on Bodipy dye and Pt(diimine)(dithiolate) complexes. AB - New dyads consisting of a strongly absorbing Bodipy (dipyrromethene-BF2) dye and a platinum diimine dithiolate (PtN2S2) charge transfer (CT) chromophore have been synthesized and studied in the context of the light-driven generation of H2 from aqueous protons. In these dyads, the Bodipy dye is bonded directly to the benzenedithiolate ligand of the PtN2S2 CT chromophore. Each of the new dyads contains either a bipyridine (bpy) or phenanthroline (phen) diimine with an attached functional group that is used for binding directly to TiO2 nanoparticles, allowing rapid electron photoinjection into the semiconductor. The absorption spectra and cyclic voltammograms of the dyads show that the spectroscopic and electrochemical properties of the dyads are the sum of the individual chromophores (Bodipy and the PtN2S2 moieties), indicating little electronic coupling between them. Connection to TiO2 nanoparticles is carried out by sonication leading to in situ attachment to TiO2 without prior hydrolysis of the ester linking groups to acids. For H2 generation studies, the TiO2 particles are platinized (Pt-TiO2) so that the light absorber (the dyad), the electron conduit (TiO2), and the catalyst (attached colloidal Pt) are fully integrated. It is found that upon 530 nm irradiation in a H2O solution (pH 4) with ascorbic acid as an electron donor, the dyad linked to Pt-TiO2 via a phosphonate or carboxylate attachment shows excellent light-driven H2 production with substantial longevity, in which one particular dyad [4(bpyP)] exhibits the highest activity, generating ~ 40,000 turnover numbers of H2 over 12 d (with respect to dye). PMID- 26116626 TI - The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias. AB - Without an active regulatory feedback loop, increased blood viscosity could lead to a vicious cycle of ischemia, increased erythropoiesis, further increases of blood viscosity, decreased tissue perfusion with worsened ischemia, further increases in red cell mass, etc. We suggest that an increase in blood viscosity is detected by mechanoreceptors in the left ventricle which upregulate expression of cardiac natriuretic peptides and soluble erythropoietin receptor. This response normalizes systemic vascular resistance and blood viscosity at the cost of producing 'anemia of chronic disease or inflammation' or 'hemolytic anemia' both of which are better described as states of compensated hyperviscosity. Besides its role in disease, this response is also active in the physiologic adaptation to chronic exercise. Malfunction of this response may cause primary hypertension. PMID- 26116627 TI - Spironolactone is secure and reduces left ventricular hypertrophy in hemodialysis patients. AB - OBJECTIVES: There is recent evidence that aldosterone play a role in the pathogenesis of cardiovascular disease in dialysis patients, which leads to the opportunity to block its actions for the benefit of these patients. In nondialytic chronic kidney disease, spironolactone was safe and effective in reducing left ventricular hypertrophy. However, routine use has been precluded in hemodialysis patients due to the risk of hyperkalemia. The aim of this study is to verify the safety and efficacy in regression of left ventricular hypertrophy with spironolactone in hemodialysis patients undergoing pharmacotherapeutic monitoring. METHODS: We performed a controlled, randomized, double blind study evaluating 17 hemodialysis patients who received spironolactone at a dose of 12.5 mg titrated, in the second week, to 25 mg of spironolactone or placebo. The patients were treated for 6 months. RESULTS: The groups were composed of eight patients (intervention) and nine patients (control). These groups did not differ in their baseline characteristics. The group receiving spironolactone had a left ventricular mass index reduction from 77 +/- 14.6 g/m(2.7) to 69 +/- 10.5 g/m(2.7), p < 0.04, whereas in placebo group there was an increase from 71 +/- 14.2 g/m(2.7) to 74 +/- 17.4 g/m(2.7). Systolic or diastolic blood pressure did not change during the study. Potassium did not differ statistically between groups in all instances. CONCLUSION: Spironolactone treatment in hemodialysis patients was secure and effective in regression of left ventricular hypertrophy, a major risk factor for cardiovascular events in these patients. This effect occurred in spite of blood pressure stability. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01128101. PMID- 26116628 TI - Alternative splicing, expression and cellular localization of Calneuron-1 in the rat and human brain. AB - Calneuron-1 and -2 are members of the neuronal calcium-binding protein family (nCaBP). They are transmembrane Calmodulin-like EF-hand Ca(2+)-sensors, and a function in the control of Golgi-to-plasma membrane vesicle trafficking has been assigned to both proteins. In this paper, we describe the distribution of Calneuron-1 in rat and human brains. We show that Calneuron-1 is ubiquitously expressed in all brain regions examined. The protein is most abundant in Purkinje cells of the cerebellum and principal neurons of the cortex and limbic brain whereas no expression in glial cells is apparent. In addition, we identify two novel splice isoforms of Calneuron-1 with extended N-termini. These isoforms are particular abundant in the cerebellum. Taken together, these data set grounds for a better understanding of the cellular function of Calneurons. PMID- 26116629 TI - The natural history of idiopathic neuroretinitis. PMID- 26116630 TI - Translational Pharmacodynamics of Calcitonin Gene-Related Peptide Monoclonal Antibody LY2951742 in a Capsaicin-Induced Dermal Blood Flow Model. AB - LY2951742, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), is being developed for migraine prevention and osteoarthritis pain. To support the clinical development of LY2951742, capsaicin-induced dermal blood flow (DBF) was used as a target engagement biomarker to assess CGRP activity in nonhuman primates and healthy volunteers. Inhibition of capsaicin-induced DBF in nonhuman primates, measured with laser Doppler imaging, was dose dependent and sustained for at least 29 days after a single intravenous injection of the CGRP antibody. This information was used to generate a pharmacokinetic/pharmacodynamic model, which correctly predicted inhibition of capsaicin-induced DBF in humans starting at a single subcutaneous 5-mg dose. As expected, the degree of inhibition in capsaicin-induced DBF increased with higher LY2951742 plasma concentrations. Utilization of this pharmacodynamic biomarker with pharmacokinetic data collected in phase I studies provided the dose-response relationship that assisted in dose selection for the phase II clinical development of LY2951742. PMID- 26116631 TI - Complaints filed against nursing professionals. AB - BACKGROUND: In their daily practice, Brazilian nurses have been met with complaints from co-workers and patients, as well as bioethical dilemmas intrinsic to the profession, particularly in the context of care delivery. Complaints against nursing professionals have been in the media spotlight. OBJECTIVE: To examine complaints filed with the Regional Board of Nursing of Mato Grosso do Sul (COREN-MS) in Midwest Brazil. METHOD: Retrospective, analytical desk research of 111 complaints received by COREN-MS in 2003-2013 was carried out. Characterizations of complainant, professionals investigated, and complaints were the variables investigated. Ethical consideration: The project was approved by the Research Ethics Committee of the Federal University of Mato Grosso do Sul. To ensure confidentiality and anonymity, all documents retrieved were examined in situ and subjects were assigned numbered codes. RESULTS: Most complainants were nursing professionals (40). Most causes of complaint originated in the hospital setting (65). Most allegations were made against nursing technicians and licensed practical nurses (82). Complaints involving interprofessional relationships (85), iatrogenic events (36), and professional liability (20) predominated. DISCUSSION: Bioethical principles were breached, translating to poor-quality nursing care, detrimental to the professional image of nurses among users and nursing professionals alike. CONCLUSION: The findings can serve as input to guide nursing schools and boards of nursing in developing policies to raise awareness among nursing professionals, sensitizing them to the responsible provision of care in the light of bioethical and legal principles. PMID- 26116632 TI - Healthcare professionals' perceptions of the ethical climate in paediatric cancer care. AB - BACKGROUND: How well ethical concerns are handled in healthcare is influenced by the ethical climate of the workplace, which in this study is described as workplace factors that contribute to healthcare professionals' ability to identify and deal with ethical issues in order to provide the patient with ethically good care. OBJECTIVES: The overall aim of the study was to describe perceptions of the paediatric hospital ethical climate among healthcare professionals who treat/care for children with cancer. RESEARCH DESIGN: Data were collected using the Hospital Ethical Climate Survey developed by Olsson as a separate section in a questionnaire. Descriptive statistics were used to analyse perceptions of the ethical climate. Participants and research context: Physicians, nurses and nurse-aides (n = 89) from three paediatric units participated in this study: haematology/oncology, chronic diseases and neurology. Ethical considerations: The study was approved by the regional ethical review board. FINDINGS: Different perceptions of the ethical climate were rated as positive or negative/neutral. Nurses' ratings were less positive than physicians on all items. One-third of the participants perceived that they were able to practice ethically good care as they believed it should be practised. DISCUSSION: Differences in professional roles, involving more or less power and influence, might explain why physicians and nurses rated items differently. A positive perception of the possibility to practice ethically good care seems to be related to inter-professional trust and listening to guardians/parents. A negative/neutral perception of the possibility to practice ethically good care appears to be influenced by experiences of ethical conflicts as well as a lack of ethical support, for example, time for reflection and discussion. CONCLUSION: The two-thirds of participants who had a negative/neutral perception of the possibility to practice ethically good care are at risk of developing moral stress. Clinical ethics support needs to be implemented in care where important values are at stake. PMID- 26116633 TI - Membrane-bound Klotho is not expressed endogenously in healthy or uraemic human vascular tissue. AB - AIMS: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD), a disease state that is strongly associated with loss of renal and systemic (alpha-)Klotho. Reversely, murine Klotho deficiency causes marked medial calcification. It is therefore thought that Klotho conveys a vasculoprotective effect. Klotho expression in the vessel wall, however, is disputed. METHODS AND RESULTS: We assessed Klotho expression in healthy human renal donor arteries (n = 9), CKD (renal graft recipient) arteries (n = 10), carotid endarterectomy specimens (n = 8), other elastic arteries (three groups of n = 3), and cultured human aortic smooth muscle cells (HASMCs) (three primary cell lines), using immunohistochemistry (IHC), immunofluorescence, quantitative reverse transcriptase-polymerase chain reaction, and western blotting (WB). We have extensively validated anti-Klotho antibody KM2076 by comparing staining patterns with other anti-Klotho antibodies (SC-22220, SC-22218, and AF1819), competition assays with recombinant Klotho, IHC on Klotho-deficient kl/kl mouse kidney, and WB with recombinant Klotho. Using KM2076, we could not detect full length Klotho in vascular tissues or HASMCs. On the mRNA level, using primers against all four exon junctions, klotho expression could not be detected either. Fibroblast growth factor 23 (FGF23) injections in mice induced FGF23 signalling in kidneys but not in the aorta, indicating the absence of Klotho-dependent FGF23 signalling in the aorta. CONCLUSION: Using several independent and validated methods, we conclude that full-length, membrane-bound Klotho is not expressed in healthy or uraemic human vascular tissue. PMID- 26116634 TI - Games in the Brain: Neural Substrates of Gambling Addiction. AB - As a popular form of recreational risk taking, gambling games offer a paradigm for decision neuroscience research. As an individual behavior, gambling becomes dysfunctional in a subset of the population, with debilitating consequences. Gambling disorder has been recently reconceptualized as a "behavioral addiction" in the DSM-5, based on emerging parallels with substance use disorders. Why do some individuals undergo this transition from recreational to disordered gambling? The biomedical model of problem gambling is a "brain disorder" account that posits an underlying neurobiological abnormality. This article first delineates the neural circuitry that underpins gambling-related decision making, comprising ventral striatum, ventromedial prefrontal cortex, dopaminergic midbrain, and insula, and presents evidence for pathophysiology in this circuitry in gambling disorder. These biological dispositions become translated into clinical disorder through the effects of gambling games. This influence is better articulated in a public health approach that describes the interplay between the player and the (gambling) product. Certain forms of gambling, including electronic gambling machines, appear to be overrepresented in problem gamblers. These games harness psychological features, including variable ratio schedules, near-misses, "losses disguised as wins," and the illusion of control, which modulate the core decision-making circuitry that is perturbed in gambling disorder. PMID- 26116635 TI - The role of kinesitherapy and electrotherapeutic procedures in non-operative management of patients with intermittent claudications. AB - PURPOSE: To examine the effects of physical therapy (kinesitherapy and electrotherapeutic procedures) on the course of peripheral arterial occlusive disease by monitoring the changes in values of claudication distance and ankle brachial indexes. METHODS: Prospective randomized study included 47 patients with peripheral arterial occlusive disease manifested by intermittent claudications associated with ankle-brachial indexes values ranging from 0.5 to 0.9. Patients from the first group (25 pts) were treated with medicamentous therapy, walking exercises beyond the pain threshold, dynamic low-burden kinesi exercises and electrotherapeutic ageneses (interference therapy, diadynamic therapy, and electromagnetic field), while the second group of patients (22 pts) was treated with "conventional" non-operative treatment - medicamentous therapy and walking exercises. The values of newly established absolute claudication distance and ankle-brachial indexes were measured. FINDINGS: Significant increase of absolute claudication distance in both groups of patients was registered, independently of therapeutic protocol applied (p < 0.001), as well as the increase in the claudication distance interval in the physical therapy group. There was no significant increase in ankle-brachial indexes values in both groups of patients. CONCLUSION: Methods of physical therapy presented valuable supplement in non operative treatment of peripheral arterial occlusive disease patients, improving their functional ability and thus postponing surgical treatment. However, further investigations including larger number of patients are needed. PMID- 26116636 TI - Determination of Acidity in Donor Milk. AB - BACKGROUND: There is no uniformity among milk banks on milk acceptance criteria. The acidity obtained by the Dornic titration technique is a widely used quality control in donor milk. However, there are no comparative data with other acidity measuring techniques, such as the pH meter. OBJECTIVE: The objective of this study was to assess the correlation between the Dornic technique and the pH measure to determine the pH cutoff corresponding to the Dornic degree limit value used as a reference for donor milk quality control. METHODS: Fifty-two human milk samples were obtained from 48 donors. Acidity was measured using the Dornic method and pH meter in triplicate. Statistical data analysis to estimate significant correlations between variables was carried out. The Dornic acidity value that led to rejecting donor milk was >= 8 Dornic degrees ( degrees D). RESULTS: In the evaluated sample size, Dornic acidity measure and pH values showed a statistically significant negative correlation (tau = -0.780; P = .000). A pH value of 6.57 corresponds to 8 degrees D and of 7.12 to 4 degrees D. CONCLUSION: Donor milk with a pH over 6.57 may be accepted for subsequent processing in the milk bank. Moreover, the pH measurement seems to be more useful due to certain advantages over the Dornic method, such as objectivity, accuracy, standardization, the lack of chemical reagents required, and the fact that it does not destroy the milk sample. PMID- 26116637 TI - Host Defense Proteins in Breast Milk and Neonatal Yeast Colonization. AB - BACKGROUND: Colonization increases risk for invasive candidiasis in neonates. Breast milk host defense proteins may affect yeast colonization of infants. OBJECTIVE: This study aimed to evaluate breast milk host defense proteins relative to yeast colonization in infants. METHODS: Infants admitted for longer than 72 hours to the neonatal intensive care unit at Women & Infants Hospital in Providence, Rhode Island, were eligible. After consent, expressed breast milk and swabs from oral, rectal, and inguinal sites from infants were cultured weekly for 12 weeks, or until discharge, transfer, or death. Breast milk was tested for levels of human lactoferrin, lysozyme, apolipoprotein J, mucin-1, dermcidin, and soluble CD14 using commercial ELISA. Concentrations of these components were compared in breast milk received by infants who were colonized or not colonized with yeast. RESULTS: From an original cohort of 130, 61 infants had samples available for this subanalysis. A convenience sample of stored breast milk was analyzed. Median lactoferrin, apolipoprotein J, and mucin-1 did not differ between colonized and uncolonized groups. Soluble CD14 was higher in the surface colonized group (1.8 MUg/mL, n = 12) compared with the surface-uncolonized group (1.6 MUg/mL, n = 12, P = .02). Median lysozyme levels were higher in the surface uncolonized group (483.0 ng/mL, n = 12) versus the surface-colonized group (298.3 ng/mL, n = 12, P = .04). Median dermcidin levels were higher in the surface uncolonized group (19.4 ng/mL, n = 12) versus the surface-colonized group (8.7 ng/mL, n = 12, P = .04). CONCLUSION: This study shows an association between colonization with Candida in neonates and lower levels of lysozyme and dermcidin in received breast milk. Further study is needed to confirm these findings. PMID- 26116638 TI - Elderly female with a personal and family history of a bleeding disorder. PMID- 26116639 TI - Commentary. PMID- 26116640 TI - Commentary. PMID- 26116641 TI - A dark-brown serum sample. PMID- 26116643 TI - A think tank or a template for university campus: Plato's academy. PMID- 26116645 TI - Production of biosolid fuels from municipal sewage sludge: Technical and economic optimisation. AB - The article presents the technical and economic analysis of the production of fuels from municipal sewage sludge. The analysis involved the production of two types of fuel compositions: sewage sludge with sawdust (PBT fuel) and sewage sludge with meat and bone meal (PBM fuel). The technology of the production line of these sewage fuels was proposed and analysed. The main objective of the study is to find the optimal production capacity. The optimisation analysis was performed for the adopted technical and economic parameters under Polish conditions. The objective function was set as a maximum of the net present value index and the optimisation procedure was carried out for the fuel production line input capacity from 0.5 to 3 t h(-1), using the search step 0.5 t h(-1). On the basis of technical and economic assumptions, economic efficiency indexes of the investment were determined for the case of optimal line productivity. The results of the optimisation analysis show that under appropriate conditions, such as prices of components and prices of produced fuels, the production of fuels from sewage sludge can be profitable. In the case of PBT fuel, calculated economic indexes show the best profitability for the capacity of a plant over 1.5 t h(-1) output, while production of PBM fuel is beneficial for a plant with the maximum of searched capacities: 3.0 t h(-1). Sensitivity analyses carried out during the investigation show that influence of both technical and economic assessments on the location of maximum of objective function (net present value) is significant. PMID- 26116646 TI - The safety and efficacy of preoperative embolization of meningioma with N-butyl cyanoacrylate. AB - OBJECTIVE: Preoperative embolization of meningioma is commonly performed; however, there is no consensus on the best embolic material to reduce intraoperative blood loss and surgery time. METHOD: We retrospectively assessed the safety and efficacy of 56 cases of preoperative embolization of the middle meningeal artery with N-butyl cyanoacrylate (NBCA) in 105 cases of surgery for meningioma. We also defined a blood loss to tumor volume ratio to compensate for bias caused by tumor volume, and analyzed limited cases (the embolized group n = 52, the non-embolized group n = 21) of the convexity, the parasagittal region, the falx, and the sphenoidal ridge. RESULT: The blood loss to tumor volume ratio was significantly less in the embolized group (p < 0.007). Preoperative embolization could be useful for cases with the external carotid artery as the dominant feeder vessel (p < 0.02); however, the efficacy decreased for cases with an internal carotid artery feeder. Transient complications occurred in four cases (hemiparesis secondary to edema: two cases; intratumoral bleeding: one case; trigeminal nerve disorder: one case). The cases that showed a postoperative increase in edema or intratumoral bleeding were large tumors with the early filling of veins. For such cases, surgeons should pay close attention to slow injection speed and higher NBCA viscosity, not to cause the occlusion of draining vessels. CONCLUSION: Tumor embolization with NBCA can be safely performed, and the procedure significantly reduces intraoperative blood loss. PMID- 26116647 TI - Serious myelopathy due to magnetic resonance imaging-occult arteriovenous fistula: Case report of petrous ridge dural arteriovenous fistula. AB - BACKGROUND AND PURPOSE: We present a case of magnetic resonance imaging (MRI) occult intracranial dural arteriovenous fistula (DAVF) with serious cervical myelopathy and review the pathophysiological background. SUMMARY OF CASE: A 61 year-old man had suffered from progressive neurological deterioration. He had demonstrated swollen spinal cord with diffuse enhancement and no dilated vascularity on MRI. Finally, digital subtraction angiography revealed DAVF at the petrous ridge and it was successfully treated by embolization. CONCLUSION: A slow flow DAVF is not readily recognizable on MRI. Whenever a patient presents with unexplainable progressive myelopathy, a possibility of vascular origin has to be considered. PMID- 26116648 TI - Resolution of brainstem edema after treatment of a dural tentorial arteriovenous fistula. AB - We report a patient with a petrosal arterio-venous dural fistula draining into the ponto-mesencephalic and medullary venous systems presenting with edema of the brain stem and complete reversal of magnetic resonance imaging (MRI) abnormalities after combined endovascular and surgical treatments. The venous anatomy of the posterior fossa and the significance of the venous involvement as the cause of clinical symptoms and imaging abnormalities in cerebro-medullary vascular lesions are discussed. PMID- 26116649 TI - Vertebral artery dissecting aneurysm treated by internal trapping via the contralateral vertebral artery: A case report. AB - A 42-year-old man with a history of sudden onset of severe headache followed by consciousness disturbance was brought to our hospital. Radiological examinations revealed subarachnoid hemorrhage, associated with rupture of a left vertebral artery dissecting aneurysm. Initially, internal trapping was attempted via the ipsilateral vertebral artery. However, the microcatheter could not be navigated through the true lumen to the distal side of the vertebral artery. Subsequently, therefore, the guiding catheter was placed in the right vertebral artery, and the microcatheter was retrogradely navigated successfully through the lesion to the proximal side of the left vertebral artery. Finally, the lesion was completely embolized with electrodetachable coils without complications. However, the patient died after the operation because of deterioration of the general condition. The postmortem examination revealed how an intimal flap had interfered with the antegrade navigation of the microcatheter in the lesion. The present case showed that endovascular treatment for a vertebral artery dissecting aneurysm via the contralateral vertebral artery may be a useful option in cases where antegrade navigation of the microcatheter via the ipsilateral vertebral artery is found to be difficult. PMID- 26116650 TI - Assisted coiling using LEO Baby or LVIS Jr stents: Report of six cases. AB - BACKGROUND AND PURPOSE: Endovascular treatment of broad-neck, complex cerebral aneurysms is a challenging issue. Placement of a stent over the aneurysm neck and secondary coil embolization prevents coil migration and allows dense packing of the coils. Another challenge is represented by distal aneurysms situated in small vessels. In these cases, the use of little stents, which we are going call ministents, could be a good decision. These low-profile intracranial ministents can be deployed into arteries with diameters between 1.5 and 3.10 mm and delivered through microcatheters with an internal diameter of 0.0165 inches, which allows easier navigation in small-sized, delicate vessels. We present six cases of wide-neck aneurysms, with small parental arteries less than 2.5 mm using a low-profile ministent system (LEO Baby and LVIS Jr) plus coil embolization. MATERIALS AND METHODS: We retrospectively reviewed patients in whom LEO Baby or LVIS Jr stent was used for the treatment of intracranial aneurysms. Five aneurysms were treated during 2013-2014 in our service using the LEO Baby stent and one aneurysm using LVIS Jr. Stent-assisted coil embolization was performed using the jailing technique in all cases. Clinical and angiographic findings, procedural data, and follow-up are reported. RESULTS: Six consecutive patients were included in this study. Four patients presented with subarachnoid hemorrhage in the subacute-chronic phase and two patients had unruptured aneurysms. Two of the six aneurysms were located at branches of the sylvian artery, one at the basilar artery, two at the anterior communicating artery, and one at the P1-P2 artery. The procedures were successful. Six-month control digital subtraction angiograms were obtained in all cases; they demonstrated complete occlusion of the aneurysms in all instances. All patients had good clinical outcomes on follow up, as measured with the Glasgow Outcome Scale and Modified Rankin Scale. CONCLUSIONS: The results of this small study show that the LEO Baby and LVIS Jr ministents could be safe and efficient for endovascular treatment of intracranial broad-neck aneurysms situated in small arteries. PMID- 26116652 TI - Nepal Disaster: A Public Health Response Needed. PMID- 26116651 TI - Living Donor Kidney Transplantation: Improving Education Outside of Transplant Centers about Live Donor Transplantation--Recommendations from a Consensus Conference. AB - Living donor kidney transplantation (LDKT) offers better quality of life and clinical outcomes, including patient survival, compared with remaining on dialysis or receiving a deceased donor kidney transplant. Although LDKT education within transplant centers for both potential recipients and living donors is very important, outreach and education to kidney patients in settings other than transplant centers and to the general public is also critical to increase access to this highly beneficial treatment. In June 2014, the American Society of Transplantation's Live Donor Community of Practice, with the support of 10 additional sponsors, convened a consensus conference to determine best practices in LDKT, including a workgroup focused on developing a set of recommendations for optimizing outreach and LDKT education outside of transplant centers. Members of this workgroup performed a structured literature review, conducted teleconference meetings, and met in person at the 2-day conference. Their efforts resulted in consensus around the following recommendations. First, preemptive transplantation should be promoted through increased LDKT education by primary care physicians and community nephrologists. Second, dialysis providers should be trained to educate their own patients about LDKT and deceased donor kidney transplantation. Third, partnerships between community organizations, organ procurement organizations, religious organizations, and transplant centers should be fostered to support transplantation. Fourth, use of technology should be improved or expanded to better educate kidney patients and their support networks. Fifth, LDKT education and outreach should be improved for kidney patients in rural areas. Finally, a consensus-driven, evidence-based public message about LDKT should be developed. Discussion of the effect and potential for implementation around each recommendation is featured, particularly regarding reducing racial and socioeconomic disparities in access to LDKT. To accomplish these recommendations, the entire community of professionals and organizations serving kidney patients must work collaboratively toward ensuring accurate, comprehensive, and up-to-date LDKT education for all patients, thereby reducing barriers to LDKT access and increasing LDKT rates. PMID- 26116653 TI - Vitamin D Deficiency May Explain Comorbidity as an Independent Risk Factor for Death Associated with Cancer in Taiwan. PMID- 26116654 TI - Retraction notice for P635 in abstract supplement 2015. PMID- 26116655 TI - The guanine exchange factor Gartenzwerg and the small GTPase Arl1 function in the same pathway with Arfaptin during synapse growth. AB - The generation of neuronal morphology requires transport vesicles originating from the Golgi apparatus (GA) to deliver specialized components to the axon and dendrites. Drosophila Arfaptin is a membrane-binding protein localized to the GA that is required for the growth of the presynaptic nerve terminal. Here we provide biochemical, cellular and genetic evidence that the small GTPase Arl1 and the guanine-nucleotide exchange factor (GEF) Gartenzwerg are required for Arfaptin function at the Golgi during synapse growth. Our data define a new signaling pathway composed of Arfaptin, Arl1, and Garz, required for the generation of normal synapse morphology. PMID- 26116656 TI - Neurl4 contributes to germ cell formation and integrity in Drosophila. AB - Primordial germ cells (PGCs) form at the posterior pole of the Drosophila embryo, and then migrate to their final destination in the gonad where they will produce eggs or sperm. Studies of the different stages in this process, including assembly of germ plasm in the oocyte during oogenesis, specification of a subset of syncytial embryonic nuclei as PGCs, and migration, have been informed by genetic analyses. Mutants have defined steps in the process, and the identities of the affected genes have suggested biochemical mechanisms. Here we describe a novel PGC phenotype. When Neurl4 activity is reduced, newly formed PGCs frequently adopt irregular shapes and appear to bud off vesicles. PGC number is also reduced, an effect exacerbated by a separate role for Neurl4 in germ plasm formation during oogenesis. Like its mammalian homolog, Drosophila Neurl4 protein is concentrated in centrosomes and downregulates centrosomal protein CP110. Reducing CP110 activity suppresses the abnormal PGC morphology of Neurl4 mutants. These results extend prior analyses of Neurl4 in cultured cells, revealing a heightened requirement for Neurl4 in germ-line cells in Drosophila. PMID- 26116657 TI - The homeodomain transcription factor Phox2 in the stellate ganglion of the squid Loligo pealei. AB - Homeodomain transcription factors regulate development of embryos and cellular physiology in adult systems. Paired-type homeodomain genes constitute a subclass that has been particularly implicated in establishment of neuronal identity in the mammalian nervous system. We isolated fragments of eight homeodomain genes of this subclass expressed in the stellate ganglion of the North Atlantic long finned squid Loligo pealei (lp) [Note: Loligo pealei has been officially renamed Doryteuthis pealei. For reasons of uniformity and clarity Loligo pealei (lp) is used here]. Of the most abundant ones, we cloned a full length cDNA which encoded the squid ortholog of the paired-type homeodomain proteins Phox2a/b. The homology of lpPhox2 to invertebrate and mammalian Phox2 was limited to the homeodomain. In contrast to mouse Phox2b, lpPhox2 was unable to transactivate the dopamine beta hydroxylase (DBH) promoter in a heterologous mammalian transfection system. In vivo, lpPhox2 was expressed in the developing stellate ganglion of stage 27 squid embryos and continued to be expressed in the adult stellate neurons where expression was confined to the giant fiber lobe containing the neurons that form the giant axons. The expression of lpPhox was similarly timed and distributed as the Fmrf gene. Furthermore, the Fmrf upstream region contained putative Phox2a/b binding sites. These results suggest a role of lpPhox2 in the developmental specification of neuronal identity and regulation of neurons of the squid giant axon. PMID- 26116658 TI - Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. AB - Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed >=2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749. PMID- 26116659 TI - AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. AB - PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. In a panel of 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 showed significantly greater efficacy against T-lineage ALL (T-ALL) than B-cell precursor ALL (BCP-ALL) xenografts. Single-agent PR-104 was more efficacious against T-ALL xenografts compared with a combination regimen of vincristine, dexamethasone, and l-asparaginase. Expression of AKR1C3 was significantly higher in T-ALL xenografts compared with BCP-ALL, and correlated with PR-104/PR-104A sensitivity in vivo and in vitro. Overexpression of AKR1C3 in a resistant BCP-ALL xenograft resulted in dramatic sensitization to PR-104 in vivo. Testing leukemic blasts from 11 patients confirmed that T-ALL cells were more sensitive than BCP ALL to PR-104A in vitro, and that sensitivity correlated with AKR1C3 expression. Collectively, these results indicate that PR-104 shows promise as a novel therapy for relapsed/refractory T-ALL, and that AKR1C3 expression could be used as a biomarker to select patients most likely to benefit from such treatment in prospective clinical trials. PMID- 26116660 TI - Bi-directional gap junction-mediated soma-germline communication is essential for spermatogenesis. AB - Soma-germline interactions play conserved essential roles in regulating cell proliferation, differentiation, patterning and homeostasis in the gonad. In the Drosophila testis, secreted signalling molecules of the JAK-STAT, Hedgehog, BMP and EGF pathways are used to mediate soma-germline communication. Here, we demonstrate that gap junctions may also mediate direct, bi-directional signalling between the soma and germ line. When gap junctions between the soma and germ line are disrupted, germline differentiation is blocked and germline stem cells are not maintained. In the soma, gap junctions are required to regulate proliferation and differentiation. Localization and RNAi-mediated knockdown studies reveal that gap junctions in the fly testis are heterotypic channels containing Zpg (Inx4) and Inx2 on the germ line and the soma side, respectively. Overall, our results show that bi-directional gap junction-mediated signalling is essential to coordinate the soma and germ line to ensure proper spermatogenesis in Drosophila. Moreover, we show that stem cell maintenance and differentiation in the testis are directed by gap junction-derived cues. PMID- 26116661 TI - Stromal Fat4 acts non-autonomously with Dchs1/2 to restrict the nephron progenitor pool. AB - Regulation of the balance between progenitor self-renewal and differentiation is crucial to development. In the mammalian kidney, reciprocal signalling between three lineages (stromal, mesenchymal and ureteric) ensures correct nephron progenitor self-renewal and differentiation. Loss of either the atypical cadherin FAT4 or its ligand Dachsous 1 (DCHS1) results in expansion of the mesenchymal nephron progenitor pool, called the condensing mesenchyme (CM). This has been proposed to be due to misregulation of the Hippo kinase pathway transcriptional co-activator YAP. Here, we use tissue-specific deletions to prove that FAT4 acts non-autonomously in the renal stroma to control nephron progenitors. We show that loss of Yap from the CM in Fat4-null mice does not reduce the expanded CM, indicating that FAT4 regulates the CM independently of YAP. Analysis of Six2(-/ );Fat4(-/-) double mutants demonstrates that excess progenitors in Fat4 mutants are dependent on Six2, a crucial regulator of nephron progenitor self-renewal. Electron microscopy reveals that cell organisation is disrupted in Fat4 mutants. Gene expression analysis demonstrates that the expression of Notch and FGF pathway components are altered in Fat4 mutants. Finally, we show that Dchs1, and its paralogue Dchs2, function in a partially redundant fashion to regulate the number of nephron progenitors. Our data support a model in which FAT4 in the stroma binds to DCHS1/2 in the mouse CM to restrict progenitor self-renewal. PMID- 26116662 TI - Inhibitory neuron migration and IPL formation in the developing zebrafish retina. AB - The mature vertebrate retina is a highly ordered neuronal network of cell bodies and synaptic neuropils arranged in distinct layers. Little, however, is known about the emergence of this spatial arrangement. Here, we investigate how the three main types of retinal inhibitory neuron (RIN)--horizontal cells (HCs), inner nuclear layer amacrine cells (iACs) and displaced amacrine cells (dACs)- reach their specific laminar positions during development. Using in vivo time lapse imaging of zebrafish retinas, we show that RINs undergo distinct phases of migration. The first phase, common to all RINs, is bipolar migration directed towards the apicobasal centre of the retina. All RINs then transition to a less directionally persistent multipolar phase of migration. Finally, HCs, iACs and dACs each undergo cell type-specific migration. In contrast to current hypotheses, we find that most dACs send processes into the forming inner plexiform layer (IPL) before migrating through it and inverting their polarity. By imaging and quantifying the dynamics of HCs, iACs and dACs from birth to final position, this study thus provides evidence for distinct and new migration patterns during retinal lamination and insights into the initiation of IPL formation. PMID- 26116663 TI - Constraint of gene expression by the chromatin remodelling protein CHD4 facilitates lineage specification. AB - Chromatin remodelling proteins are essential for different aspects of metazoan biology, yet functional details of why these proteins are important are lacking. Although it is possible to describe the biochemistry of how they remodel chromatin, their chromatin-binding profiles in cell lines, and gene expression changes upon loss of a given protein, in very few cases can this easily translate into an understanding of how the function of that protein actually influences a developmental process. Here, we investigate how the chromatin remodelling protein CHD4 facilitates the first lineage decision in mammalian embryogenesis. Embryos lacking CHD4 can form a morphologically normal early blastocyst, but are unable to successfully complete the first lineage decision and form functional trophectoderm (TE). In the absence of a functional TE, Chd4 mutant blastocysts do not implant and are hence not viable. By measuring transcript levels in single cells from early embryos, we show that CHD4 influences the frequency at which unspecified cells in preimplantation stage embryos express lineage markers prior to the execution of this first lineage decision. In the absence of CHD4, this frequency is increased in 16-cell embryos, and by the blastocyst stage cells fail to properly adopt a TE gene expression programme. We propose that CHD4 allows cells to undertake lineage commitment in vivo by modulating the frequency with which lineage-specification genes are expressed. This provides novel insight into both how lineage decisions are made in mammalian cells, and how a chromatin remodelling protein functions to facilitate lineage commitment. PMID- 26116664 TI - Coco is a dual activity modulator of TGFbeta signaling. AB - The TGFbeta signaling pathway is a crucial regulator of developmental processes and disease. The activity of TGFbeta ligands is modulated by various families of soluble inhibitors that interfere with the interactions between ligands and receptors. In an unbiased, genome-wide RNAi screen to identify genes involved in ligand-dependent signaling, we unexpectedly identified the BMP/Activin/Nodal inhibitor Coco as an enhancer of TGFbeta1 signaling. Coco synergizes with TGFbeta1 in both cell culture and Xenopus explants. Molecularly, Coco binds to TGFbeta1 and enhances TGFbeta1 binding to its receptor Alk5. Thus, Coco acts as both an inhibitor and an enhancer of signaling depending on the ligand it binds. This finding raises the need for a global reconsideration of the molecular mechanisms regulating TGFbeta signaling. PMID- 26116665 TI - Wnt signaling orients the proximal-distal axis of chick kidney nephrons. AB - The nephron is the fundamental structural and functional unit of the kidney. Each mature nephron is patterned along a proximal-distal axis, with blood filtered at the proximal end and urine emerging from the distal end. In order to filter the blood and produce urine, specialized structures are formed at specific proximal distal locations along the nephron, including the glomerulus at the proximal end, the tubule in the middle and the collecting duct at the distal end. The developmental processes that specify these different nephron segments are not fully understood. Wnt ligands, which are expressed in the nephric duct and later in the nascent nephron itself, are well-characterized inducers of nephrons, and are both required and sufficient for initiation of nephron formation from nephrogenic mesenchyme. Here, we present evidence that Wnt signaling also patterns the proximal-distal nephron axis. Using the chick mesonephros as a model system, a Wnt ligand was ectopically expressed in the coelomic lining, thereby introducing a source of Wnt signaling that is at right angles to the endogenous Wnt signal of the nephric duct. Under these conditions, the nephron axis was re oriented, such that the glomerulus was always located at a position farthest from the Wnt sources. This re-orientation occurred within hours of exposure to ectopic Wnt signaling, and was accompanied initially by a repression of the early glomerular podocyte markers Wt1 and Pod1, followed by their re-emergence at a position distant from the Wnt signals. Activation of the Wnt signaling pathway in mesonephric explant cultures resulted in strong and specific repression of early and late glomerular markers. Finally, cytoplasmic beta-catenin, indicative of active canonical Wnt signaling, was found to be enriched in the distal as compared with the proximal region of the forming nephron. Together, these data indicate that Wnt signaling patterns the proximal-distal axis of the nephron, with glomeruli differentiating in regions of lowest Wnt signaling. PMID- 26116666 TI - Fat4/Dchs1 signaling between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching. AB - Formation of the kidney requires reciprocal signaling among the ureteric tubules, cap mesenchyme and surrounding stromal mesenchyme to orchestrate complex morphogenetic events. The protocadherin Fat4 influences signaling from stromal to cap mesenchyme cells to regulate their differentiation into nephrons. Here, we characterize the role of a putative binding partner of Fat4, the protocadherin Dchs1. Mutation of Dchs1 in mice leads to increased numbers of cap mesenchyme cells, which are abnormally arranged around the ureteric bud tips, and impairment of nephron morphogenesis. Mutation of Dchs1 also reduces branching of the ureteric bud and impairs differentiation of ureteric bud tip cells into trunk cells. Genetically, Dchs1 is required specifically within cap mesenchyme cells. The similarity of Dchs1 phenotypes to stromal-less kidneys and to those of Fat4 mutants implicates Dchs1 in Fat4-dependent stroma-to-cap mesenchyme signaling. Antibody staining of genetic mosaics reveals that Dchs1 protein localization is polarized within cap mesenchyme cells, where it accumulates at the interface with stromal cells, implying that it interacts directly with a stromal protein. Our observations identify a role for Fat4 and Dchs1 in signaling between cell layers, implicate Dchs1 as a Fat4 receptor for stromal signaling that is essential for kidney development, and establish that vertebrate Dchs1 can be molecularly polarized in vivo. PMID- 26116667 TI - Hedgehog signaling stimulates the formation of proliferating Muller glia-derived progenitor cells in the chick retina. AB - Muller glia can be stimulated to de-differentiate and become proliferating progenitor cells that regenerate neurons in the retina. The signaling pathways that regulate the formation of proliferating Muller glia-derived progenitor cells (MGPCs) are beginning to be revealed. The purpose of this study was to investigate whether Hedgehog (Hh) signaling influences the formation of MGPCs in the chick retina. We find that Hh signaling is increased in damaged retinas where MGPCs are known to form. Sonic Hedgehog (Shh) is normally present in the axons of ganglion cells, but becomes associated with Muller glia and MGPCs following retinal damage. Activation of Hh signaling with recombinant human SHH (rhShh) or smoothened agonist (SAG) increased levels of Ptch1, Gli1, Gli2, Gli3, Hes1 and Hes5, and stimulated the formation of proliferating MGPCs in damaged retinas. In undamaged retinas, SAG or rhShh had no apparent effect upon the Muller glia. However, SAG combined with FGF2 potentiated the formation of MGPCs, whereas SAG combined with IGF1 stimulated the nuclear migration of Muller glia, but not the formation of MGPCs. Conversely, inhibition of Hh signaling with KAAD-cyclopamine, Gli antagonists or antibody to Shh reduced numbers of proliferating MGPCs in damaged and FGF2-treated retinas. Hh signaling potentiates Pax6, Klf4 and cFos expression in Muller glia during the formation of MGPCs. We find that FGF2/MAPK signaling recruits Hh signaling into the signaling network that drives the formation of proliferating MGPCs. Our findings implicate Hh signaling as a key component of the network of signaling pathways that promote the de differentiation of Muller glia and proliferation of MGPCs. PMID- 26116668 TI - Spatial and Temporal Factors Associated with an Increased Prevalence of Listeria monocytogenes in Spinach Fields in New York State. AB - While rain and irrigation events have been associated with an increased prevalence of foodborne pathogens in produce production environments, quantitative data are needed to determine the effects of various spatial and temporal factors on the risk of produce contamination following these events. This study was performed to quantify these effects and to determine the impact of rain and irrigation events on the detection frequency and diversity of Listeria species (including L. monocytogenes) and L. monocytogenes in produce fields. Two spinach fields, with high and low predicted risks of L. monocytogenes isolation, were sampled 24, 48, 72, and 144 to 192 h following irrigation and rain events. Predicted risk was a function of the field's proximity to water and roads. Factors were evaluated for their association with Listeria species and L. monocytogenes isolation by using generalized linear mixed models (GLMMs). In total, 1,492 (1,092 soil, 334 leaf, 14 fecal, and 52 water) samples were collected. According to the GLMM, the likelihood of Listeria species and L. monocytogenes isolation from soil samples was highest during the 24 h immediately following an event (odds ratios [ORs] of 7.7 and 25, respectively). Additionally, Listeria species and L. monocytogenes isolates associated with irrigation events showed significantly lower sigB allele type diversity than did isolates associated with precipitation events (P = <0.001), suggesting that irrigation water may be a point source of L. monocytogenes contamination. Small changes in management practices (e.g., not irrigating fields before harvest) may therefore reduce the risk of L. monocytogenes contamination of fresh produce. PMID- 26116669 TI - Type III Secretion System Translocon Component EseB Forms Filaments on and Mediates Autoaggregation of and Biofilm Formation by Edwardsiella tarda. AB - The type III secretion system (T3SS) of Edwardsiella tarda plays an important role in infection by translocating effector proteins into host cells. EseB, a component required for effector translocation, is reported to mediate autoaggregation of E. tarda. In this study, we demonstrate that EseB forms filamentous appendages on the surface of E. tarda and is required for biofilm formation by E. tarda in Dulbecco's modified Eagle's medium (DMEM). Biofilm formation by E. tarda in DMEM does not require FlhB, an essential component for assembling flagella. Dynamic analysis of EseB filament formation, autoaggregation, and biofilm formation shows that the formation of EseB filaments occurs prior to autoaggregation and biofilm formation. The addition of an EseB antibody to E. tarda cultures before bacterial autoaggregation prevents autoaggregation and biofilm formation in a dose-dependent manner, whereas the addition of the EseB antibody to E. tarda cultures in which biofilm is already formed does not destroy the biofilm. Therefore, EseB filament-mediated bacterial cell-cell interaction is a prerequisite for autoaggregation and biofilm formation. PMID- 26116670 TI - Molecular and Physical Factors That Influence Attachment of Vibrio vulnificus to Chitin. AB - The human pathogen Vibrio vulnificus is the leading cause of seafood-related deaths in the United States. Strains are genotyped on the basis of alleles that correlate with isolation source, with clinical (C)-genotype strains being more often implicated in disease and environmental (E)-genotype strains being more frequently isolated from oysters and estuarine waters. Previously, we have shown that the ecologically distinct C- and E-genotype strains of V. vulnificus display different degrees of chitin attachment, with C-genotype strains exhibiting reduced attachment relative to their E-genotype strain counterparts. We identified type IV pili to be part of the molecular basis for this observed genotypic variance, as E-genotype strains exhibit higher levels of expression of these genes than C-genotype strains. Here, we used a C-genotype quorum-sensing (QS) mutant to demonstrate that quorum sensing is a negative regulator of type IV pilus expression, which results in decreased chitin attachment. Furthermore, calcium depletion reduced E-genotype strain attachment to chitin, which suggests that calcium is necessary for proper functioning of the type IV pili in E genotype strains. We also found that starvation or dormancy can alter the efficiency of chitin attachment, which has significant implications for the environmental persistence of V. vulnificus. With the increasing incidence of wound infections caused by V. vulnificus, we investigated a subset of E-genotype strains isolated from human wound infections and discovered that they attached to chitin in a manner more similar to that of C-genotype strains. This study enhances our understanding of the molecular and physical factors that mediate chitin attachment in V. vulnificus, providing insight into the mechanisms that facilitate the persistence of this pathogen in its native environment. PMID- 26116671 TI - AguR, a Transmembrane Transcription Activator of the Putrescine Biosynthesis Operon in Lactococcus lactis, Acts in Response to the Agmatine Concentration. AB - Dairy industry fermentative processes mostly use Lactococcus lactis as a starter. However, some dairy L. lactis strains produce putrescine, a biogenic amine that raises food safety and spoilage concerns, via the agmatine deiminase (AGDI) pathway. The enzymatic activities responsible for putrescine biosynthesis in this bacterium are encoded by the AGDI gene cluster. The role of the catabolic genes aguB, aguD, aguA, and aguC has been studied, but knowledge regarding the role of aguR (the first gene in the cluster) remains limited. In the present work, aguR was found to be a very low level constitutively expressed gene that is essential for putrescine biosynthesis and is transcribed independently of the polycistronic mRNA encoding the catabolic genes (aguBDAC). In response to agmatine, AguR acts as a transcriptional activator of the aguB promoter (PaguB), which drives the transcription of the aguBDAC operon. Inverted sequences required for PaguB activity were identified by deletion analysis. Further work indicated that AguR is a transmembrane protein which might function as a one-component signal transduction system that senses the agmatine concentration of the medium and, accordingly, regulates the transcription of the aguBDAC operon through a C terminal cytoplasmic DNA-binding domain typically found in LuxR-like proteins. PMID- 26116672 TI - A Caleosin-Like Protein with Peroxygenase Activity Mediates Aspergillus flavus Development, Aflatoxin Accumulation, and Seed Infection. AB - Caleosins are a small family of calcium-binding proteins endowed with peroxygenase activity in plants. Caleosin-like genes are present in fungi; however, their functions have not been reported yet. In this work, we identify a plant caleosin-like protein in Aspergillus flavus that is highly expressed during the early stages of spore germination. A recombinant purified 32-kDa caleosin like protein supported peroxygenase activities, including co-oxidation reactions and reduction of polyunsaturated fatty acid hydroperoxides. Deletion of the caleosin gene prevented fungal development. Alternatively, silencing of the gene led to the increased accumulation of endogenous polyunsaturated fatty acid hydroperoxides and antioxidant activities but to a reduction of fungal growth and conidium formation. Two key genes of the aflatoxin biosynthesis pathway, aflR and aflD, were downregulated in the strains in which A. flavus PXG (AfPXG) was silenced, leading to reduced aflatoxin B1 production in vitro. Application of caleosin/peroxygenase-derived oxylipins restored the wild-type phenotype in the strains in which AfPXG was silenced. PXG-deficient A. flavus strains were severely compromised in their capacity to infect maize seeds and to produce aflatoxin. Our results uncover a new branch of the fungal oxylipin pathway and may lead to the development of novel targets for controlling fungal disease. PMID- 26116673 TI - Clostridium botulinum Group II Isolate Phylogenomic Profiling Using Whole-Genome Sequence Data. AB - Clostridium botulinum group II isolates (n = 163) from different geographic regions, outbreaks, and neurotoxin types and subtypes were characterized in silico using whole-genome sequence data. Two clusters representing a variety of botulinum neurotoxin (BoNT) types and subtypes were identified by multilocus sequence typing (MLST) and core single nucleotide polymorphism (SNP) analysis. While one cluster included BoNT/B4/F6/E9 and nontoxigenic members, the other comprised a wide variety of different BoNT/E subtype isolates and a nontoxigenic strain. In silico MLST and core SNP methods were consistent in terms of clade level isolate classification; however, core SNP analysis showed higher resolution capability. Furthermore, core SNP analysis correctly distinguished isolates by outbreak and location. This study illustrated the utility of next-generation sequence-based typing approaches for isolate characterization and source attribution and identified discrete SNP loci and MLST alleles for isolate comparison. PMID- 26116674 TI - Development of Spatial Distribution Patterns by Biofilm Cells. AB - Confined spatial patterns of microbial distribution are prevalent in nature, such as in microbial mats, soil communities, and water stream biofilms. The symbiotic two-species consortium of Pseudomonas putida and Acinetobacter sp. strain C6, originally isolated from a creosote-polluted aquifer, has evolved a distinct spatial organization in the laboratory that is characterized by an increased fitness and productivity. In this consortium, P. putida is reliant on microcolonies formed by Acinetobacter sp. C6, to which it attaches. Here we describe the processes that lead to the microcolony pattern by Acinetobacter sp. C6. Ecological spatial pattern analyses revealed that the microcolonies were not entirely randomly distributed and instead were arranged in a uniform pattern. Detailed time-lapse confocal microscopy at the single-cell level demonstrated that the spatial pattern was the result of an intriguing self-organization: small multicellular clusters moved along the surface to fuse with one another to form microcolonies. This active distribution capability was dependent on environmental factors (carbon source and oxygen) and historical contingency (formation of phenotypic variants). The findings of this study are discussed in the context of species distribution patterns observed in macroecology, and we summarize observations about the processes involved in coadaptation between P. putida and Acinetobacter sp. C6. Our results contribute to an understanding of spatial species distribution patterns as they are observed in nature, as well as the ecology of engineered communities that have the potential for enhanced and sustainable bioprocessing capacity. PMID- 26116675 TI - Evaluation of a New Environmental Sampling Protocol for Detection of Human Norovirus on Inanimate Surfaces. AB - Inanimate surfaces are regarded as key vehicles for the spread of human norovirus during outbreaks. ISO method 15216 involves the use of cotton swabs for environmental sampling from food surfaces and fomites for the detection of norovirus genogroup I (GI) and GII. We evaluated the effects of the virus drying time (1, 8, 24, or 48 h), swab material (cotton, polyester, rayon, macrofoam, or an antistatic wipe), surface (stainless steel or a toilet seat), and area of the swabbed surface (25.8 cm(2) to 645.0 cm(2)) on the recovery of human norovirus. Macrofoam swabs produced the highest rate of recovery of norovirus from surfaces as large as 645 cm(2). The rates of recovery ranged from 2.2 to 36.0% for virus seeded on stainless-steel coupons (645.0 cm(2)) to 1.2 to 33.6% for toilet seat surfaces (700 cm(2)), with detection limits of 3.5 log10 and 4.0 log10 RNA copies. We used macrofoam swabs to collect environmental samples from several case cabins and common areas of a cruise ship where passengers had reported viral gastroenteritis symptoms. Seventeen (18.5%) of 92 samples tested positive for norovirus GII, and 4 samples could be sequenced and had identical GII.1 sequences. The viral loads of the swab samples from the cabins of the sick passengers ranged from 80 to 31,217 RNA copies, compared with 16 to 113 RNA copies for swab samples from public spaces. In conclusion, our swab protocol for norovirus may be a useful tool for outbreak investigations when no clinical samples are available to confirm the etiology. PMID- 26116676 TI - In-Frame Deletions Allow Functional Characterization of Complex Cellulose Degradation Phenotypes in Cellvibrio japonicus. AB - The depolymerization of the recalcitrant polysaccharides found in lignocellulose has become an area of intense interest due to the role of this process in global carbon cycling, human gut microbiome nutritional contributions, and bioenergy production. However, underdeveloped genetic tools have hampered study of bacterial lignocellulose degradation, especially outside model organisms. In this report, we describe an in-frame deletion strategy for the Gram-negative lignocellulose-degrading bacterium Cellvibrio japonicus. This method leverages optimized growth conditions for conjugation and sacB counterselection for the generation of markerless in-frame deletions. This method produces mutants in as few as 8 days and allows for the ability to make multiple gene deletions per strain. It is also possible to remove large sections of the genome, as shown in this report with the deletion of the nine-gene (9.4-kb) gsp operon in C. japonicus. We applied this system to study the complex phenotypes of cellulose degradation in C. japonicus. Our data indicated that a Deltacel5B Deltacel6A double mutant is crippled for cellulose utilization, more so than by either single mutation alone. Additionally, we deleted individual genes in the two-gene cbp2ED operon and showed that both genes contribute to cellulose degradation in C. japonicus. Overall, these described techniques substantially enhance the utility of C. japonicus as a model system to study lignocellulose degradation. PMID- 26116677 TI - Polar Fixation of Plasmids during Recombinant Protein Production in Bacillus megaterium Results in Population Heterogeneity. AB - During the past 2 decades, Bacillus megaterium has been systematically developed for the gram-per-liter scale production of recombinant proteins. The plasmid based expression systems employed use a xylose-controlled promoter. Protein production analyses at the single-cell level using green fluorescent protein as a model product revealed cell culture heterogeneity characterized by a significant proportion of less productive bacteria. Due to the enormous size of B. megaterium, such bistable behavior seen in subpopulations was readily analyzed by time lapse microscopy and flow cytometry. Cell culture heterogeneity was not caused simply by plasmid loss: instead, an asymmetric distribution of plasmids during cell division was detected during the exponential-growth phase. Multicopy plasmids are generally randomly distributed between daughter cells. However, in vivo and in vitro experiments demonstrated that under conditions of strong protein production, plasmids are retained at one of the cell poles. Furthermore, it was found that cells with accumulated plasmids and high protein production ceased cell division. As a consequence, the overall protein production of the culture was achieved mainly by the subpopulation with a sufficient plasmid copy number. Based on our experimental data, we propose a model whereby the distribution of multicopy plasmids is controlled by polar fixation under protein production conditions. Thereby, cell lines with fluctuating plasmid abundance arise, which results in population heterogeneity. Our results provide initial insights into the mechanism of cellular heterogeneity during plasmid-based recombinant protein production in a Bacillus species. PMID- 26116678 TI - Cable Bacteria in Freshwater Sediments. AB - In marine sediments cathodic oxygen reduction at the sediment surface can be coupled to anodic sulfide oxidation in deeper anoxic layers through electrical currents mediated by filamentous, multicellular bacteria of the Desulfobulbaceae family, the so-called cable bacteria. Until now, cable bacteria have only been reported from marine environments. In this study, we demonstrate that cable bacteria also occur in freshwater sediments. In a first step, homogenized sediment collected from the freshwater stream Giber A, Denmark, was incubated in the laboratory. After 2 weeks, pH signatures and electric fields indicated electron transfer between vertically separated anodic and cathodic half reactions. Fluorescence in situ hybridization revealed the presence of Desulfobulbaceae filaments. In addition, in situ measurements of oxygen, pH, and electric potential distributions in the waterlogged banks of Giber A demonstrated the presence of distant electric redox coupling in naturally occurring freshwater sediment. At the same site, filamentous Desulfobulbaceae with cable bacterium morphology were found to be present. Their 16S rRNA gene sequence placed them as a distinct sister group to the known marine cable bacteria, with the genus Desulfobulbus as the closest cultured lineage. The results of the present study indicate that electric currents mediated by cable bacteria could be important for the biogeochemistry in many more environments than anticipated thus far and suggest a common evolutionary origin of the cable phenotype within Desulfobulbaceae with subsequent diversification into a freshwater and a marine lineage. PMID- 26116680 TI - Composition of Bacterial Communities Associated with Aurelia aurita Changes with Compartment, Life Stage, and Population. AB - The scyphozoan Aurelia aurita is recognized as a key player in marine ecosystems and a driver of ecosystem change. It is thus intensely studied to address ecological questions, although its associations with microorganisms remain so far undescribed. In the present study, the microbiota associated with A. aurita was visualized with fluorescence in situ hybridization (FISH) analysis, and community structure was analyzed with respect to different life stages, compartments, and populations of A. aurita by 16S rRNA gene amplicon sequencing. We demonstrate that the composition of the A. aurita microbiota is generally highly distinct from the composition of communities present in ambient water. Comparison of microbial communities from different developmental stages reveals evidence for life stage-specific community patterns. Significant restructuring of the microbiota during strobilation from benthic polyp to planktonic life stages is present, arguing for a restructuring during the course of metamorphosis. Furthermore, the microbiota present in different compartments of the adult medusa (exumbrella mucus and gastric cavity) display significant differences, indicating body part-specific colonization. A novel Mycoplasma strain was identified in both compartment-specific microbiota and is most likely present inside the epithelium as indicated by FISH analysis of polyps, indicating potential endosymbiosis. Finally, comparison of polyps of different populations kept under the same controlled laboratory conditions in the same ambient water showed population specific community patterns, most likely due the genetic background of the host. In conclusion, the presented data indicate that the associated microbiota of A. aurita may play important functional roles, e.g., during the life cycle. PMID- 26116679 TI - Phenotypic and Phylogenetic Identification of Coliform Bacteria Obtained Using 12 Coliform Methods Approved by the U.S. Environmental Protection Agency. AB - The current definition of coliform bacteria is method dependent, and when different culture-based methods are used, discrepancies in results can occur and affect the accuracy of identification of true coliforms. This study used an alternative approach to the identification of true coliforms by combining the phenotypic traits of the coliform isolates and the phylogenetic affiliation of 16S rRNA gene sequences with the use of lacZ and uidA genes. A collection of 1,404 isolates detected by 12 U.S. Environmental Protection Agency-approved coliform-testing methods were characterized based on their phylogenetic affiliations and responses to their original isolation media and lauryl tryptose broth, m-Endo, and MI agar media. Isolates were phylogenetically classified into 32 true-coliform, or targeted Enterobacteriaceae (TE), groups and 14 noncoliform, or nontargeted Enterobacteriaceae (NTE), groups. It was shown statistically that detecting true-positive (TP) events is more challenging than detecting true negative (TN) events. Furthermore, most false-negative (FN) events were associated with four TE groups (i.e., Serratia group I and the Providencia, Proteus, and Morganella groups) and most false-positive (FP) events with two NTE groups, the Aeromonas and Plesiomonas groups. In Escherichia coli testing, 18 out of 145 E. coli isolates identified by enzymatic methods were validated as FN. The reasons behind the FP and FN reactions could be explained through analysis of the lacZ and uidA genes. Overall, combining the analyses of the 16S rRNA, lacZ, and uidA genes with the growth responses of TE and NTE on culture-based media is an effective way to evaluate the performance of coliform detection methods. PMID- 26116681 TI - Use of the mCherry Fluorescent Protein To Study Intestinal Colonization by Enterococcus mundtii ST4SA and Lactobacillus plantarum 423 in Mice. AB - Lactic acid bacteria (LAB) are natural inhabitants of the gastrointestinal tract (GIT) of humans and animals, and some LAB species receive considerable attention due to their health benefits. Although many papers have been published on probiotic LAB, only a few reports have been published on the migration and colonization of the cells in the GIT. This is due mostly to the lack of efficient reporter systems. In this study, we report on the application of the fluorescent mCherry protein in the in vivo tagging of the probiotic strains Enterococcus mundtii ST4SA and Lactobacillus plantarum 423. The mCherry gene, encoding a red fluorescent protein (RFP), was integrated into a nonfunctional region on the genome of L. plantarum 423 by homologous recombination. In the case of E. mundtii ST4SA, the mCherry gene was cloned into the pGKV223D LAB/Escherichia coli expression vector. Expression of the mCherry gene did not alter the growth rate of the two strains and had no effect on bacteriocin production. Both strains colonized the cecum and colon of mice. PMID- 26116682 TI - Responses of Bacterial Communities to Simulated Climate Changes in Alpine Meadow Soil of the Qinghai-Tibet Plateau. AB - The soil microbial community plays an important role in terrestrial carbon and nitrogen cycling. However, microbial responses to climate warming or cooling remain poorly understood, limiting our ability to predict the consequences of future climate changes. To address this issue, it is critical to identify microbes sensitive to climate change and key driving factors shifting microbial communities. In this study, alpine soil transplant experiments were conducted downward or upward along an elevation gradient between 3,200 and 3,800 m in the Qinghai-Tibet plateau to simulate climate warming or cooling. After a 2-year soil transplant experiment, soil bacterial communities were analyzed by pyrosequencing of 16S rRNA gene amplicons. The results showed that the transplanted soil bacterial communities became more similar to those in their destination sites and more different from those in their "home" sites. Warming led to increases in the relative abundances in Alphaproteobacteria, Gammaproteobacteria, and Actinobacteria and decreases in Acidobacteria, Betaproteobacteria, and Deltaproteobacteria, while cooling had opposite effects on bacterial communities (symmetric response). Soil temperature and plant biomass contributed significantly to shaping the bacterial community structure. Overall, climate warming or cooling shifted the soil bacterial community structure mainly through species sorting, and such a shift might correlate to important biogeochemical processes such as greenhouse gas emissions. This study provides new insights into our understanding of soil bacterial community responses to climate warming and cooling. PMID- 26116683 TI - Whole-Genome Sequencing Allows for Improved Identification of Persistent Listeria monocytogenes in Food-Associated Environments. AB - While the food-borne pathogen Listeria monocytogenes can persist in food associated environments, there are no whole-genome sequence (WGS) based methods to differentiate persistent from sporadic strains. Whole-genome sequencing of 188 isolates from a longitudinal study of L. monocytogenes in retail delis was used to (i) apply single-nucleotide polymorphism (SNP)-based phylogenetics for subtyping of L. monocytogenes, (ii) use SNP counts to differentiate persistent from repeatedly reintroduced strains, and (iii) identify genetic determinants of L. monocytogenes persistence. WGS analysis revealed three prophage regions that explained differences between three pairs of phylogenetically similar populations with pulsed-field gel electrophoresis types that differed by <=3 bands. WGS-SNP based phylogenetics found that putatively persistent L. monocytogenes represent SNP patterns (i) unique to a single retail deli, supporting persistence within the deli (11 clades), (ii) unique to a single state, supporting clonal spread within a state (7 clades), or (iii) spanning multiple states (5 clades). Isolates that formed one of 11 deli-specific clades differed by a median of 10 SNPs or fewer. Isolates from 12 putative persistence events had significantly fewer SNPs (median, 2 to 22 SNPs) than between isolates of the same subtype from other delis (median up to 77 SNPs), supporting persistence of the strain. In 13 events, nearly indistinguishable isolates (0 to 1 SNP) were found across multiple delis. No individual genes were enriched among persistent isolates compared to sporadic isolates. Our data show that WGS analysis improves food-borne pathogen subtyping and identification of persistent bacterial pathogens in food associated environments. PMID- 26116684 TI - Environmental Factors Associated with High Fly Densities and Diarrhea in Vellore, India. AB - Diarrhea causes significant morbidity and mortality in Indian children under 5 years of age. Flies carry enteric pathogens and may mediate foodborne infections. In this study, we characterized fly densities as a determinant of infectious diarrhea in a longitudinal cohort of 160 urban and 80 rural households with 1,274 individuals (27% under 5 years of age) in Vellore, India. Household questionnaires on living conditions were completed at enrollment. Fly abundance was measured during the wet and dry seasons using fly ribbons placed in kitchens. PCRs for enteric bacteria, viruses, and protozoa were performed on 60 fly samples. Forty-three (72%) fly samples were positive for the following pathogens: norovirus (50%), Salmonella spp. (46.7%), rotavirus (6.7%), and Escherichia coli (6.7%). Ninety-one episodes of diarrhea occurred (89% in children under 5 years of age). Stool pathogens isolated in 24 of 77 (31%) samples included E. coli, Shigella spp., Vibrio spp., Giardia, Cryptosporidium, and rotavirus. Multivariate log-linear models were used to explore the relationships between diarrhea and fly densities, controlling for demographics, hygiene, and human-animal interactions. Fly abundance was 6 times higher in rural than urban sites (P < 0.0001). Disposal of garbage close to homes and rural living were significant risk factors for high fly densities. The presence of latrines was protective against high fly densities and diarrhea. The adjusted relative risks of diarrheal episodes and duration of diarrhea, associated with fly density at the 75th percentile, were 1.18 (95% confidence interval [CI], 1.03 to 1.34) and 1.15 (95% CI, 1.02 to 1.29), respectively. Flies harbored enteric pathogens, including norovirus, a poorly documented pathogen on flies. PMID- 26116686 TI - Unusual cause of transient atrioventricular block during cavotricuspid isthmus ablation for typical right atrial flutter. PMID- 26116687 TI - Use of fluoroscopy in clinical electrophysiology in Europe: results of the European Heart Rhythm Association Survey. AB - Despite the advent of non-fluoroscopic technologies, fluoroscopy remains the cornerstone of imaging in most interventional electrophysiological procedures, from diagnostic studies to ablation interventions and device implantation. The purpose of the European Heart Rhythm Association survey was to provide an insight into regulatory policies and physicians' clinical practice when using fluoroscopy during ablation procedures and device implantation. The survey has shown that only 50% of the participating centres worked with low frame rates (3-6 frames per second) and that the left anterior oblique projection, with higher radiation exposure for the physician, is used for nearly every ablation target. Although three-dimensional imaging systems may reduce the radiation exposure, most centres never used these systems for standard ablation procedures and a trend is that non fluoroscopy technologies are even less frequently used than in 2012, when the use of robotic systems was still rare. Even less costly equipment such as lead gloves, lead glass cabins, or radiation absorbing pads are still not routinely used. PMID- 26116688 TI - Syphilis and gonorrhoea increase sharply in England. PMID- 26116685 TI - Non-vitamin K antagonist oral anticoagulants and atrial fibrillation guidelines in practice: barriers to and strategies for optimal implementation. AB - Stroke is a leading cause of morbidity and mortality worldwide. Atrial fibrillation (AF) is an independent risk factor for stroke, increasing the risk five-fold. Strokes in patients with AF are more likely than other embolic strokes to be fatal or cause severe disability and are associated with higher healthcare costs, but they are also preventable. Current guidelines recommend that all patients with AF who are at risk of stroke should receive anticoagulation. However, despite this guidance, registry data indicate that anticoagulation is still widely underused. With a focus on the 2012 update of the European Society of Cardiology (ESC) guidelines for the management of AF, the Action for Stroke Prevention alliance writing group have identified key reasons for the suboptimal implementation of the guidelines at a global, regional, and local level, with an emphasis on access restrictions to guideline-recommended therapies. Following identification of these barriers, the group has developed an expert consensus on strategies to augment the implementation of current guidelines, including practical, educational, and access-related measures. The potential impact of healthcare quality measures for stroke prevention on guideline implementation is also explored. By providing practical guidance on how to improve implementation of the ESC guidelines, or region-specific modifications of these guidelines, the aim is to reduce the potentially devastating impact that stroke can have on patients, their families and their carers. PMID- 26116689 TI - Prenatal stress and childhood asthma in the offspring: role of age at onset. AB - BACKGROUND: Asthma is a heterogeneous disorder with different phenotypes, and age at onset may define part of them. Little is known about possible association between prenatal stress and asthma phenotypes according to age at onset. We aim to investigate whether there is an association between prenatal stress and asthma, and if so, whether such an association differs according to age at asthma onset. METHODS: We carried out a cohort study based on several national registers in Denmark, including all live singletons born during 1996-2007 in Denmark (N = 750,058). We identified children born to mothers who lost a close relative (a child, partner/spouse, a parent or a sibling) 1 year prior to or during pregnancy as the bereaved group. Using Cox proportional hazards regression model, we evaluated the hazard ratios (HRs) for asthma in children of bereaved mothers, compared with children of non-bereaved mothers. RESULTS: Prenatal stress following maternal bereavement was associated with a marginally increased risk of asthma events in children aged 0-3 years [HR = 1.04, 95% confidence interval (CI): 1.00-1.07], while unexpected bereavement was associated with a higher risk (HR = 1.13, 95% CI: 1.02-1.24). There was no association between prenatal bereavement and asthma in children aged 4-15 years (HR = 1.02, 95% CI: 0.96 1.09). CONCLUSIONS: Prenatal stress is possibly associated with asthma events in children aged 0-3 years, but not with asthma in children aged 4-15 years irrespective of age at asthma onset. PMID- 26116690 TI - Angioplasty with paclitaxel coated balloon reduces restenosis in peripheral artery disease. PMID- 26116692 TI - Rapid Surface Cooling by ThermoSuit System Dramatically Reduces Scar Size, Prevents Post-Infarction Adverse Left Ventricular Remodeling, and Improves Cardiac Function in Rats. AB - BACKGROUND: The long-term effects of transient hypothermia by the non-invasive ThermoSuit apparatus on myocardial infarct (MI) scar size, left ventricular (LV) remodeling, and LV function were assessed in rat MI model. METHODS AND RESULTS: Rats were randomized to normothermic or hypothermic groups (n=14 in each group) and subjected to 30 minutes coronary artery occlusion and 6 weeks of reperfusion. For hypothermia therapy, rats were placed into the ThermoSuit apparatus at 2 minutes after the onset of coronary artery occlusion, were taken out of the apparatus when the core body temperature reached 32 degrees C (in ~8 minutes), and were then allowed to rewarm. After 6 weeks of recovery, rats treated with hypothermia demonstrated markedly reduced scar size (expressed as % of left ventricular area: hypothermia, 6.5+/-1.1%; normothermia, 19.4+/-1.7%; P=1.3*10( 6)); and thicker anterior LV wall (hypothermia, 1.57+/-0.09 mm; normothermia, 1.07+/-0.05 mm; P=3.4*10(-5)); decreased postmortem left ventricular volume (hypothermia, 0.45+/-0.04 mL; normothermia, 0.6+/-0.03 mL; P=0.028); and better LV fractional shortening by echocardiography (hypothermia, 37.2+/-2.8%; normothermia, 18.9+/-2.3%; P=0.0002) and LV ejection fraction by LV contrast ventriculography (hypothermia, 66.8+/-2.3%; normothermia, 56.0+/-2.0%; P=0.0014). CONCLUSIONS: Rapid, transient non-invasive surface cooling with the ThermoSuit apparatus in the acute phase of MI decreased scar size by 66.5%, attenuated adverse post-infarct left ventricular dilation and remodeling, and improved cardiac function in the chronic phase of experimental MI. PMID- 26116693 TI - Without proper research funding, how can medical education be evidence based? PMID- 26116694 TI - Maiga et al (J Infect Dis 2012; 205:1705-8). PMID- 26116691 TI - Effects of Exercise Training on Cardiorespiratory Fitness and Biomarkers of Cardiometabolic Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Guidelines recommend exercise for cardiovascular health, although evidence from trials linking exercise to cardiovascular health through intermediate biomarkers remains inconsistent. We performed a meta-analysis of randomized controlled trials to quantify the impact of exercise on cardiorespiratory fitness and a variety of conventional and novel cardiometabolic biomarkers in adults without cardiovascular disease. METHODS AND RESULTS: Two researchers selected 160 randomized controlled trials (7487 participants) based on literature searches of Medline, Embase, and Cochrane Central (January 1965 to March 2014). Data were extracted using a standardized protocol. A random-effects meta-analysis and systematic review was conducted to evaluate the effects of exercise interventions on cardiorespiratory fitness and circulating biomarkers. Exercise significantly raised absolute and relative cardiorespiratory fitness. Lipid profiles were improved in exercise groups, with lower levels of triglycerides and higher levels of high-density lipoprotein cholesterol and apolipoprotein A1. Lower levels of fasting insulin, homeostatic model assessment insulin resistance, and glycosylated hemoglobin A1c were found in exercise groups. Compared with controls, exercise groups had higher levels of interleukin 18 and lower levels of leptin, fibrinogen, and angiotensin II. In addition, we found that the exercise effects were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, dyslipidemia, or metabolic syndrome appeared to benefit more. CONCLUSIONS: This meta-analysis showed that exercise significantly improved cardiorespiratory fitness and some cardiometabolic biomarkers. The effects of exercise were modified by age, sex, and health status. Findings from this study have significant implications for future design of targeted lifestyle interventions. PMID- 26116695 TI - Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System. AB - Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 +/- 0.1%, fasting glucose of 114 +/- 3 mg/dL, and 2-h glucose of 177 +/- 11 mg/dL, exenatide (5 MUg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 +/- 1.4 vs. 13.1 +/- 1.7 MUmol/min ? kg) and decreased the rise in mean glucose0-60 min (107 +/- 6 vs. 138 +/- 8 mg/dL) and insulin0-60 min (17.3 +/- 3.1 vs. 24.7 +/- 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state. PMID- 26116696 TI - Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro. AB - Insulinomas are beta-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of 10 human insulinomas permitted their subdivision into three functional groups with similar insulin content. Group A (four patients with fasting and/or postprandial hypoglycemic episodes) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide, and extracellular CaCl2 omission or excess. The effect of glucose was concentration dependent, but, compared with normal islets, insulin secretion was excessive in both low- and high-glucose conditions. Group B (three patients with fasting hypoglycemic episodes) was mainly characterized by large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide but were not further augmented by other agents except for high levels of CaCl2. Group C (three patients with fasting hypoglycemic episodes) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2 concentration) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma beta-cells (not in adjacent islets) was revealed by immunohistochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to the undue expression of hexokinase-I in 3 of 10 patients. PMID- 26116697 TI - Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-kappaB and STAT Signaling Pathways in Diabetic Mice. AB - Heat shock proteins (HSPs) are induced by cellular stress and function as molecular chaperones that regulate protein folding. Diabetes impairs the function/expression of many HSPs, including HSP70 and HSP90, key regulators of pathological mechanisms involved in diabetes complications. Therefore, we investigated whether pharmacological HSP90 inhibition ameliorates diabetes associated renal damage and atheroprogression in a mouse model of combined hyperglycemia and hyperlipidemia (streptozotocin-induced diabetic apolipoprotein E-deficient mouse). Treatment of diabetic mice with 17-dimethylaminoethylamino-17 demethoxygeldanamycin (DMAG, 2 and 4 mg/kg, 10 weeks) improved renal function, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leukocyte infiltration, and fibrosis), and expression of proinflammatory and profibrotic genes. Furthermore, DMAG significantly reduced atherosclerotic lesions and induced a more stable plaque phenotype, characterized by lower content of lipids, leukocytes, and inflammatory markers, and increased collagen and smooth muscle cell content. Mechanistically, the renoprotective and antiatherosclerotic effects of DMAG are mediated by the induction of protective HSP70 along with inactivation of nuclear factor-kappaB (NF-kappaB) and signal transducers and activators of transcription (STAT) and target gene expression, both in diabetic mice and in cultured cells under hyperglycemic and proinflammatory conditions. In conclusion, HSP90 inhibition by DMAG restrains the progression of renal and vascular damage in experimental diabetes, with potential implications for the prevention of diabetes complications. PMID- 26116699 TI - Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis. AB - Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)-derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by ~84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds. PMID- 26116698 TI - Leptin Suppresses Mouse Taste Cell Responses to Sweet Compounds. AB - Leptin is known to selectively suppress neural and behavioral responses to sweet tasting compounds. However, the molecular basis for the effect of leptin on sweet taste is not known. Here, we report that leptin suppresses sweet taste via leptin receptors (Ob-Rb) and KATP channels expressed selectively in sweet-sensitive taste cells. Ob-Rb was more often expressed in taste cells that expressed T1R3 (a sweet receptor component) than in those that expressed glutamate-aspartate transporter (a marker for Type I taste cells) or GAD67 (a marker for Type III taste cells). Systemically administered leptin suppressed taste cell responses to sweet but not to bitter or sour compounds. This effect was blocked by a leptin antagonist and was absent in leptin receptor-deficient db/db mice and mice with diet-induced obesity. Blocking the KATP channel subunit sulfonylurea receptor 1, which was frequently coexpressed with Ob-Rb in T1R3-expressing taste cells, eliminated the effect of leptin on sweet taste. In contrast, activating the KATP channel with diazoxide mimicked the sweet-suppressing effect of leptin. These results indicate that leptin acts via Ob-Rb and KATP channels that are present in T1R3-expressing taste cells to selectively suppress their responses to sweet compounds. PMID- 26116700 TI - Unidirectional incorporation of a bacterial mechanosensitive channel into liposomal membranes. AB - The bacterial mechanosensitive channel of small conductance (MscS) plays a crucial role in the protection of bacterial cells against hypo-osmotic shock. The functional characteristics of MscS have been extensively studied using liposomal reconstitution. This is a widely used experimental paradigm and is particularly important for mechanosensitive channels as channel activity can be probed free from cytoskeletal influence. A perpetual issue encountered using this paradigm is unknown channel orientation. Here we examine the orientation of MscS in liposomes formed using 2 ion channel reconstitution methods employing the powerful combination of patch clamp electrophysiology, confocal microscopy, and continuum mechanics simulation. Using the previously determined electrophysiological and pharmacological properties of MscS, we were able to determine that in liposomes, independent of lipid composition, MscS adopts the same orientation seen in native membranes. These results strongly support the idea that these specific methods result in uniform incorporation of membrane ion channels and caution against making assumptions about mechanosensitive channel orientation using the stimulus type alone. PMID- 26116701 TI - Elevated ergosterol protects Leishmania parasites against antimony-generated stress. AB - Parasite lipids can serve as signaling molecules, important membrane components, energy suppliers, and pathogenesis factors critical for survival. Functional roles of lipid changes in response to drug-generated stress in parasite survival remains unclear. To investigate this, Leishmania donovani parasites, the causative agents of kala-azar, were exposed to the antileishmanial agent potassium antimony tartrate (PAT) (half-maximal inhibitory concentration ~ 284 ug/ml). Analysis of cell extracts using gas chromatography-mass spectrometry showed significant increases in very long-chain fatty acids (VLCFAs) prior to an increase in ergosterol in PAT-treated parasites as compared with vehicle-treated controls. Ergosterol biosynthesis inhibition during PAT treatment decreased cell viability. VLCFA inhibition with specific inhibitors completely abrogated ergosterol upsurge followed by a reduction in cell viability. Following PAT induced VLCFA increase, an upsurge in reactive oxygen species (ROS) occurred and inhibition of this ROS with antioxidants abrogated ergosterol increase. Genetically engineered parasites expressing low constitutive ergosterol levels showed more susceptibility to PAT as compared with wild-type control cells but ergosterol supplementation during PAT treatment increased cell viability. In conclusion, we propose that during antimony treatment, the susceptibility of parasites is determined by the levels of cellular ergosterol that are regulated by oxidative stress generated by VLCFAs. PMID- 26116702 TI - Allosteric modulation of metabotropic glutamate receptors by chloride ions. AB - Metabotropic glutamate receptors (mGluRs) play key roles in the modulation of many synapses. Chloride (Cl(-)) is known to directly bind and regulate the function of different actors of neuronal activity, and several studies have pointed to the possible modulation of mGluRs by Cl(-). Herein, we demonstrate that Cl(-) behaves as a positive allosteric modulator of mGluRs. For example, whereas glutamate potency was 3.08 +/- 0.33 MUM on metabotropic glutamate (mGlu) 4 receptors in high-Cl(-) buffer, signaling activity was almost abolished in low Cl(-) in cell-based assays. Cl(-) potency was 78.6 +/- 3.5 mM. Cl(-) possesses a high positive cooperativity with glutamate (Hill slope ~6 on mGlu4), meaning that small variations in [Cl(-)] lead to large variations in glutamate action. Using molecular modeling and mutagenesis, we have identified 2 well-conserved Cl(-) binding pockets in the extracellular domain of mGluRs. Moreover, modeling of activity-dependent Cl(-) variations at GABAergic synapses suggests that these variations may be compatible with a dynamic modulation of the most sensitive mGluRs present in these synapses. Taken together, these data reveal a necessary role of Cl(-) for the glutamate activation of many mGluRs. Exploiting Cl(-) binding pockets may yield to the development of innovative regulators of mGluR activity. PMID- 26116703 TI - An intramolecular bond at cluster of differentiation 81 ectodomain is important for hepatitis C virus entry. AB - Hepatitis C virus (HCV) infection is one of the leading causes of chronic liver diseases; however, HCV vaccine remains unavailable to date. One main obstacle is the lack of an efficient small animal model. Cluster of differentiation 81 (CD81) is an essential entry coreceptor for HCV species specificity to humans, though the underlying mechanisms are yet to be fully elucidated. We performed structural, biophysical, and virologic studies on HCV nonpermissive CD81s from mice and African green monkeys [mouse cluster of differentiation 81 (mCD81) and African green monkey cluster of differentiation 81 (agmCD81)] and compared with human cluster of differentiation 81 (hCD81). We discovered an intramolecular hydrogen bond (Gln188-Nepsilon2-H: Glu196-Oepsilon2, 2 A, 124 degrees ) within the large extracellular loop (LEL) of mCD81 and a salt bridge (Lys188-Nzeta: Asp196-Odelta2, 2.4 A) within agmCD81-LEL between residues 188 and 196. This structural feature is missing in hCD81. We demonstrated that the introduction of a single 188-196 bond to hCD81 impaired its binding affinity to HCV envelope glycoprotein 2 (HCV E2) and significantly decreased HCV pseudoviral particle (HCVpp) entry efficiency (4.92- to 8.42-fold) and cell culture-grown HCV (HCVcc) infectivity (4.55-fold), despite the availability of Phe186. For HCV nonpermissive CD81s, the introduction of Phe186 by Leu186F substitution alone was insufficient to confer HCV permissiveness. The disruption of the original 188-196 bond and Leu186F substitution were both required for potent binding to HCV E2 HCVpp entry efficiency and HCVcc infectivity. Our structural and biophysical analyses suggest that the intramolecular 188-196 bond restricts the intrinsic conformational dynamics of D-helix of CD81-LEL, which is essential for HCV entry, thus impairs HCV permissiveness. Our findings reveal a novel molecular determinant for HCV entry in addition to the well-characterized Phe186 and provide further guideline for selecting an HCV small animal model. PMID- 26116704 TI - IL-1beta production is dependent on the activation of purinergic receptors and NLRP3 pathway in human macrophages. AB - The Nod-like receptor family protein 3 (NLRP3)-inflammasome pathway is known to be activated by danger signals such as monosodium urate (MSU). We investigated the role of P2 purinergic receptors in the activation of NLRP3-inflammasome pathway after MSU treatment of primary human monocyte-derived macrophages (MDMs). After initial stimulation with a low concentration of LPS (0.1 ug/ml), a 6 h treatment with MSU crystals (250, 500, and 1000 ug/ml) induced the MDMs to release IL-1beta, IL-1alpha, and IL-6 in a dose-dependent manner. Moreover, the caspase 1 inhibitor Z-YVAD-FMK and the cathepsin B inhibitor CA-074Me reduced production of IL-1beta in a dose-dependent manner after LPS + MSU treatment. We used real-time reverse transcription-quantitative PCR to show that treatment with LPS and MSU (500 ug/ml) induced significantly greater expression of NLRP3 and IL 1beta than after treatment with LPS. We also found that MSU treatment induced P2X purinergic receptor 7 (P2X7R) mRNA and protein expression. Furthermore, addition of the P2X7 purinergic receptor antagonist A-740003 significantly impeded IL 1beta production and pro-IL-1beta cleavage after treatment with LPS + MSU. Remarkably, RNA silencing of P2X7R (but not P2X4R) inhibited the release of IL 1beta and other M1 macrophage cytokines (such as IL-1alpha, IL-6, and TNF-alpha) from MDMs stimulated with LPS + MSU. Taken as a whole, our results show that P2 purinergic receptors and the NLRP3 inflammasome pathway are involved in the secretion of IL-1beta from MSU-stimulated human macrophages. This pathway may constitute a novel therapeutic target for controlling the inflammatory process in several associated pathologies. PMID- 26116705 TI - SET7/9 regulates cancer cell proliferation by influencing beta-catenin stability. AB - beta-Catenin, which is a key mediator of the wingless-integration site (Wnt)/beta catenin signaling pathway, plays an important role in cell proliferation, cell fate determination, and tumorigenesis, by regulating the expression of a wide range of target genes. Although a variety of posttranslational modifications are involved in beta-catenin activity, the role of lysine methylation in beta-catenin activity is largely unknown. In this study, su(var)3-9, enhancer-of-zeste, trithorax (SET) domain-containing protein 7 (SET7/9), a lysine methyltransferase, interacted with and methylated beta-catenin, as demonstrated both in vitro and in vivo. The interaction and methylation were significantly enhanced in response to H2O2 stimulation. A mutagenesis assay and mass spectrometric analyses revealed that beta-catenin was monomethylated by SET7/9 at lysine residue 180. Methylated beta-catenin was easily recognized by phosphokinase glycogen synthase kinase (GSK)-3beta for degradation. Consistent with this finding, the mutated beta catenin (K180R) that cannot be methylated exhibited a longer half-life than did the methylated beta-catenin. The consequent depletion of SET7/9 by shRNA or the mutation of the beta-catenin (K180R) significantly enhanced the expression of Wnt/beta-catenin target genes such as c-myc and cyclin D1 and promoted the growth of cancer cells. Together, these results provide a novel mechanism by which Wnt/beta-catenin signaling is regulated in response to oxidative stress. PMID- 26116706 TI - Genetic profiling reveals an alarming rate of cross-contamination among human cell lines used in China. AB - Cell lines are widely used as in vitro model systems in biologic and medical research. However, much of the research has been invalidated by the unwitting use of false cell lines. A significant proportion of the research involving human cell lines was initiated in China. Paradoxically, the cell lines used in China have never been authenticated. Here, we present a comprehensive survey of cross contamination in 380 samples from 113 independent sources in China using short tandem repeat profiling methods. High levels of cross-contamination were uncovered (95 of 380, 25%). Notable false cell lines (e.g., KB and WISH) are still actively used under their false identity and tissue attributions. Most strikingly, 85.51% of lines established in China were misidentified (59 of 69) and accounted for over half of the misidentifications (59 of 95, 62.11%). Further, 93.22% of the contaminants in cell lines established in laboratories of China were HeLa cells or a possible hybrid of HeLa with an unknown cell line. Results from these misidentified lines have been published in thousands of potentially erroneous articles and may have distorted the findings visible to the scientific community. False lines have been used in drug screening, potentially leading to unusable or even harmful therapeutic strategies. We also noted the causes of contamination and provided suggestions for remediation. PMID- 26116707 TI - Tailoring informatics interventions to patients and healthcare providers. PMID- 26116708 TI - Patients as first-order participants in health, health care, and research. PMID- 26116709 TI - The alpha1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. AB - Dysfunction of the right ventricle (RV) is closely related to prognosis for patients with RV failure. Therefore, strategies to improve failing RV function are significant. In a mouse RV failure model, we previously reported that alpha1 adrenergic receptor (alpha1-AR) inotropic responses are increased. The present study determined the roles of both predominant cardiac alpha1-AR subtypes (alpha1A and alpha1B) in upregulated inotropy in failing RV. We used the mouse model of bleomycin-induced pulmonary fibrosis, pulmonary hypertension, and RV failure. We assessed the myocardial contractile response in vitro to stimulation of the alpha1A-subtype (using alpha1A-subtype-selective agonist A61603) and alpha1B-subtype [using alpha1A-subtype knockout mice and nonsubtype selective alpha1-AR agonist phenylephrine (PE)]. In wild-type nonfailing RV, a negative inotropic effect of alpha1-AR stimulation with PE (force decreased ~50%) was switched to a positive inotropic effect (PIE) with bleomycin-induced RV injury. Upregulated inotropy in failing RV occurred with alpha1A-subtype stimulation (force increased ~200%), but not with alpha1B-subtype stimulation (force decreased ~50%). Upregulated inotropy mediated by the alpha1A-subtype involved increased activator Ca(2+) transients and increased phosphorylation of myosin regulatory light chain (a mediator of increased myofilament Ca(2+) sensitivity). In failing RV, the PIE elicited by the alpha1A-subtype was appreciably less when the alpha1A-subtype was stimulated in combination with the alpha1B-subtype, suggesting functional antagonism between alpha1A- and alpha1B-subtypes. In conclusion, upregulation of alpha1-AR inotropy in failing RV myocardium requires the alpha1A-subtype and is opposed by the alpha1B-subtype. The alpha1A subtype might be a therapeutic target to improve the function of the failing RV. PMID- 26116710 TI - Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats. AB - Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 +/- 15%, n = 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 +/- 5% vs. control, n = 6; tiron: 8 +/- 10% vs. control, n = 5; P < 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway. PMID- 26116711 TI - Effects of oral N-acetylcysteine on walking capacity, leg reactive hyperemia, and inflammatory and angiogenic mediators in patients with intermittent claudication. AB - Increased oxidative stress and inflammation contribute to impaired walking capacity and endothelial dysfunction in patients with intermittent claudication (IC). The goal of the study was to determine the effects of oral treatment with the antioxidant N-acetylcysteine (NAC) on walking capacity, leg postocclusive reactive hyperemia, circulating levels of inflammatory mediators, and whole blood expression of angiogenic mediators in patients with IC. Following a double blinded randomized crossover design, 10 patients with IC received NAC (1,800 mg/day for 4 days plus 2,700 mg before the experimental session) and placebo (PLA) before undergoing a graded treadmill exercise test. Leg postocclusive reactive hyperemia was assessed before and after the test. Blood samples were taken before and after NAC or PLA ingestions and 5 and 30 min after the exercise test for the analysis of circulating inflammatory and angiogenic markers. Although NAC increased the plasma ratio of reduced to oxidized glutathione, there were no differences between experimental sessions for walking tolerance and postocclusive reactive hyperemia. Plasma concentrations of soluble vascular cell adhesion protein-1, monocyte chemotactic protein-1, and endothelin-1 increased similarly following maximal exercise after PLA and NAC (P < 0.001). Whole blood expression of pro-angiogenic microRNA-126 increased after maximal exercise in the PLA session, but treatment with NAC prevented this response. Similarly, exercise induced changes in whole blood expression of VEGF, endothelial nitric oxide synthase and phosphatidylinositol 3-kinase R2 were blunted after NAC. In conclusion, oral NAC does not increase walking tolerance or leg blood flow in patients with IC. In addition, oral NAC prevents maximal exercise-induced increase in the expression of circulating microRNA-126 and other angiogenic mediators in patients with IC. PMID- 26116712 TI - Exploring autoimmunity in the pathogenesis of abdominal aortic aneurysms. AB - The abdominal aortic aneurysm (AAA) is a disease process that carries significant morbidity and mortality in the absence of early identification and treatment. While current management includes surveillance and surgical treatment of low- and high-risk aneurysms, respectively, our narrow understanding of the pathophysiology of AAAs limits our ability to more effectively manage and perhaps even prevent the occurrence of this highly morbid disease. Over the past couple of decades, there has been considerable interest in exploring the role of autoimmunity as an etiological component of AAA. This review covers the current literature pertaining to this immunological process, focusing on research that highlights the local and systemic immune components found in both human patients and murine models. A better understanding of the autoimmune mechanisms in the pathogenesis of AAAs can pave the way to novel and improved treatment strategies in this patient population. PMID- 26116714 TI - Spontaneous ventricular tachyarrhythmias in beta2-adrenoceptor transgenic mice in relation to cardiac interstitial fibrosis. AB - Myocardial fibrosis is regarded as a pivotal proarrhythmic substrate, but there have been no comprehensive studies showing a correlation between the severity of fibrosis and ventricular tachyarrhythmias (VTAs). Our purpose was to document this relationship in a transgenic (TG) strain of mice with fibrotic cardiomyopathy. TG mice with cardiac overexpression of beta2-adrenoceptors (beta2 AR mice) and non-TG (NTG) littermates were studied at 4-12 mo of age. VTA was quantified by ECG telemetry. The effect of pharmacological blockade of beta2-ARs on VTA was examined. Myocardial collagen content was determined by hydroxyproline assay. NTG and TG mice displayed circadian variation in heart rate, which was higher in TG mice than in NTG mice (P <0.05). Frequent spontaneous ventricular ectopic beats (VEBs) and ventricular tachycardia (VT) were prominent in TG mice but not present in NTG mice. The frequency of VEB and VT episodes in TG mice increased with age (P < 0.01). Ventricular collagen content was greater in TG mice than in NTG mice (P <0.001) and correlated with age (r = 0.71, P < 0.01). The number of VEBs or VT episodes correlated with age (r = 0.83 and r = 0.73) and the content of total or cross-linked collagen (r = 0.62~0.66, all P <0.01). While having no effect in younger beta2-TG mice, beta2-AR blockade reduced the frequency of VTA in old beta2-TG mice with more severe fibrosis. In conclusion, beta2-TG mice exhibit interstitial fibrosis and spontaneous onset of VTA, becoming more severe with aging. The extent of cardiac fibrosis is a major determinant for both the frequency of VTA and proarrhythmic action of beta2-AR activation. PMID- 26116713 TI - Analysis of erectile responses to H2S donors in the anesthetized rat. AB - Hydrogen sulfide (H2S) is a biologically active endogenous gasotransmitter formed in penile tissue that has been shown to relax isolated cavernosal smooth muscle. In the present study, erectile responses to the H2S donors sodium sulfide (Na2S) and sodium hydrosulfide (NaHS) were investigated in the anesthetized rat. Intracavernosal injections of Na2S in doses of 0.03-1 mg/kg increased intracavernosal pressure and transiently decreased mean arterial pressure in a dose-dependent manner. Blood pressure responses to Na2S were rapid in onset and short in duration. Responses to Na2S and NaHS were similar at doses up to 0.3 mg/kg, after which a plateau in the erectile response to NaHS was reached. Increases in intracavernosal pressure in response to Na2S were attenuated by tetraethylammonium (K(+) channel inhibitor) and iberiotoxin (large-conductance Ca(2+)-activated K(+) channel inhibitor), whereas glybenclamide [ATP-sensitive K(+) (KATP) channel inhibitor] and inhibitors of nitric oxide (NO) synthase, cyclooxygenase, and cytochrome P-450 epoxygenase had no effect. These data indicate that erectile responses to Na2S are mediated by a tetraethylammonium- and iberiotoxin-sensitive mechanism and that KATP channels, NO, or arachidonic acid metabolites are not involved. Na2S did not alter erectile responses to sodium nitroprusside (NO donor) or cavernosal nerve stimulation, indicating that neither NO nor cGMP metabolism are altered. Thus, Na2S has erectile activity mediated by large-conductance Ca(2+)-activated K(+) channels. It is suggested that strategies that increase H2S formation in penile tissue may be useful in the treatment of erectile dysfunction when NO bioavailability, KATP channel function, or poor responses to PGE1 are present. PMID- 26116715 TI - Demystifying the publishing process: a primer for early career investigators. PMID- 26116716 TI - Insect Gut Symbiont Susceptibility to Host Antimicrobial Peptides Caused by Alteration of the Bacterial Cell Envelope. AB - The molecular characterization of symbionts is pivotal for understanding the cross-talk between symbionts and hosts. In addition to valuable knowledge obtained from symbiont genomic studies, the biochemical characterization of symbionts is important to fully understand symbiotic interactions. The bean bug (Riptortus pedestris) has been recognized as a useful experimental insect gut symbiosis model system because of its cultivatable Burkholderia symbionts. This system is greatly advantageous because it allows the acquisition of a large quantity of homogeneous symbionts from the host midgut. Using these naive gut symbionts, it is possible to directly compare in vivo symbiotic cells with in vitro cultured cells using biochemical approaches. With the goal of understanding molecular changes that occur in Burkholderia cells as they adapt to the Riptortus gut environment, we first elucidated that symbiotic Burkholderia cells are highly susceptible to purified Riptortus antimicrobial peptides. In search of the mechanisms of the increased immunosusceptibility of symbionts, we found striking differences in cell envelope structures between cultured and symbiotic Burkholderia cells. The bacterial lipopolysaccharide O antigen was absent from symbiotic cells examined by gel electrophoretic and mass spectrometric analyses, and their membranes were more sensitive to detergent lysis. These changes in the cell envelope were responsible for the increased susceptibility of the Burkholderia symbionts to host innate immunity. Our results suggest that the symbiotic interactions between the Riptortus host and Burkholderia gut symbionts induce bacterial cell envelope changes to achieve successful gut symbiosis. PMID- 26116717 TI - A Randomized Controlled Trial Comparing Telemedical and Standard Outpatient Monitoring of Diabetic Foot Ulcers. AB - OBJECTIVE: The role of telemedical monitoring in diabetic foot ulcer care is still uncertain. Our aim was to compare telemedical and standard outpatient monitoring in the care of patients with diabetic foot ulcers in a randomized controlled trial. RESEARCH DESIGN AND METHODS: Of the 736 screened individuals with diabetic foot ulcers, 401 met the eligibility criteria and were randomized between October 2010 and November 2014. The per-protocol telemedical monitoring consisted of two consultations in the patient's own home and one consultation at the outpatient clinic. Standard practice consisted of three outpatient clinic visits. The three-visit cycle was repeated until study end point. The study end points were defined as complete ulcer healing, amputation, or death. RESULTS: One hundred ninety-three individuals were randomized to telemedical monitoring and 181 to standard care. Demographics were similar in both groups. A cause-specific Cox proportional hazards model showed no difference in individuals monitored through telemedicine regarding wound healing (hazard ratio 1.11 [95% CI 0.87, 1.42], P = 0.42) or amputation (0.87 [0.54, 1.42], P = 0.59). We found a higher mortality incidence in the telemedical monitoring group compared with the standard outpatient monitoring group (8.68 [6.93, 10.88], P = 0.0001). CONCLUSIONS: The findings of no significant difference regarding amputation and healing between telemedical and standard outpatient monitoring seem promising; however, for telemedical monitoring, a higher mortality throws into question the role of telemedicine in monitoring diabetic foot ulcers. Further studies are needed to investigate effects of telemedicine on mortality and other clinical outcomes and to identify patient subgroups that may have a poorer outcome through telemedical monitoring. PMID- 26116718 TI - Effects of Age, Diabetes, and Vascular Disease on Growth Differentiation Factor 11: First-in-Human Study. PMID- 26116719 TI - Gestational Diabetes Mellitus in Mothers as a Diabetes Predictor in Fathers: A Retrospective Cohort Analysis. PMID- 26116720 TI - Anti-PD-1 and Anti-PDL-1 Monoclonal Antibodies Causing Type 1 Diabetes. PMID- 26116721 TI - Pancreatic Inflammation Captured by Imaging Technology at the Onset of Fulminant Type 1 Diabetes. PMID- 26116722 TI - Sustained Treatment Effect of Spinal Cord Stimulation in Painful Diabetic Peripheral Neuropathy: 24-Month Follow-up of a Prospective Two-Center Randomized Controlled Trial. PMID- 26116723 TI - Symposium in Honor of Hilary Koprowski's Scientific Achievements. PMID- 26116724 TI - Increasing Complexity of Vaccine Development. AB - Vaccines already developed have been enormously successful. However, the development of future vaccines requires solution of a number of immunologic problems, including pathogen variability, short effector memory, evoking functional responses, and identification of antigens that generate protective responses. In addition, different populations may respond differently to the same vaccine because of genetic, age, or environmental factors. PMID- 26116726 TI - Hilary Koprowski, MD, 5 December 1916-11 April 2013. PMID- 26116725 TI - Use of a 2-aminothiazole to Treat Chronic Wasting Disease in Transgenic Mice. AB - Treatment with the 2-aminothiazole IND24 extended the survival of mice infected with mouse-adapted scrapie but also resulted in the emergence of a drug-resistant prion strain. Here, we determined whether IND24 extended the survival of transgenic mice infected with prions that caused scrapie in sheep or prions that caused chronic wasting disease (CWD; hereafter "CWD prions") in deer, using 2 isolates for each disease. IND24 doubled the incubation times for mice infected with CWD prions but had no effect on the survival of those infected with scrapie prions. Biochemical, neuropathologic, and cell culture analyses were used to characterize prion strain properties following treatment, and results indicated that the CWD prions were not altered by IND24, regardless of survival extension. These results suggest that IND24 may be a viable candidate for treating CWD in infected captive cervid populations and raise questions about why some prion strains develop drug resistance whereas others do not. PMID- 26116727 TI - A Vision for Investigating the Microbiology of Health and Disease. AB - The fields of microbial surveillance, discovery, and pathogenesis are evolving rapidly with introduction of cultivation-independent molecular diagnostic assays and highly multiplexed serologic analyses, as well as the development of animal models and prospective birth cohorts that can provide insights into host and microbial determinants of health and disease. Here, past, present, and future perspectives on these fields are provided. PMID- 26116728 TI - A Jekyll and Hyde Profile: Type 1 Interferon Signaling Plays a Prominent Role in the Initiation and Maintenance of a Persistent Virus Infection. AB - The hallmarks of persistent viral infections are exhaustion of virus-specific T cells, elevated production of interleukin 10 (IL-10) and programmed death-1 (PD 1) the dominant negative regulators of the immune system and disruption of secondary lymphoid tissues. Within the first 12-24 hours after mice are infected with lymphocytic choriomeningitis virus (LCMV) clone 13, which is used as a model of persistent virus infection, we note generation of high titers of type 1 interferon. Blockade of type 1 interferon significantly lessens IL-10 and PD-1/PD L1, allows normal secondary lymphoid architecture and re-establishes antiviral T cell function, thus eradicating the virus and clearing the infection. Hence, type 1 interferon is a master reostat for establishing persistent viral infection. PMID- 26116729 TI - Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis. AB - Giant cell arteritis (GCA) is an immune-mediated disease of unknown etiology. Varicella zoster virus (VZV) antigen was found in all of 4 GCA-positive temporal arteries (TAs) but was not present in any of 13 normal TAs. All 4 GCA-positive TAs contained viral antigen in skip areas, mostly in the adventitia and media and least in the intima. Despite formalin fixation, VZV DNA was detected in 2 of 4 GCA-positive, VZV antigen-positive TAs. Skeletal muscle was attached to 3 of 4 TAs, and VZV antigen was found in 2 and VZV DNA in 1. VZV may cause GCA. PMID- 26116730 TI - Developing a Successful HIV Vaccine. AB - Human immunodeficiency virus (HIV) genome integration indicates that persistent sterilizing immunity will be needed for a successful vaccine candidate. This suggests a need for broad antibodies targeting the Env protein. Immunogens targeting gp120 have been developed that block infection in monkeys and mimic the modest success of the RV144 clinical trial in that protection is short-lived following a decline in antibody-depending cell-mediated cytotoxicity-like antibodies. Attempts to induce antibody persistence have been complicated by a loss of efficacy, presumably by increasing the number of HIV-target cells. The key seems to be achieving an immune balance. PMID- 26116731 TI - Polyreactive Antibodies: Function and Quantification. AB - Polyreactive antibodies, a major component of the natural antibody repertoire, bind with low affinity to a variety of structurally unrelated antigens. Many of these antibodies are germline or near germline in sequence. Little is known, however, about the function of these antibodies. In the present mini-review we show: (1) that the broad antibacterial activity of the natural antibody repertoire is largely due to polyreactive antibodies, which in the presence of complement lyse bacteria and enhance phagocytosis; (2) that polyreactive antibodies bind to UV- or human immunodeficiency virus-induced apoptotic cells and with complement enhance the phagocytosis of these cells by macrophages; and (3) that dinitrophenol can be used as a surrogate for quantitating the level of polyreactive antibodies in serum. We conclude that polyreactive antibodies protect the host against both foreign invaders and its own damaged/apoptotic cells. PMID- 26116732 TI - Controlling Endogenous Retroviruses and Their Chimeric Transcripts During Natural Reprogramming in the Oocyte. AB - Complete genomic reprogramming happens twice during the life of a genome, once during the formation of gametes in their parents and once after their union at fertilization. For that matter complete genomic reprogramming happens twice in the same parental cell, the oocyte, when it is forming and after it matures and receives the paternal gamete. Control of these processes in this unique single cell is epigenetic, and our understanding of it is based on information gleaned from imprinting, X chromosome inactivation, and activation and silencing of endogenous retroviruses (ERV). Activation of ERVs is attributed to demethylation of chromatin and DNA, whereas silencing requires methylation, attributed to the nuage proteins, which engage the Piwi-interacting RNA pathway and other posttranscriptional mechanisms. This reprogramming process has evolved throughout speciation because in mammals, but not fish, flies and worms, nuage-component muations affect male and female gametogenesis differentially. Transcription of ERVs is derepressed in both sexes in nuage-mutant mice, but whereas males are sterile, females are fertile. Using a proteomic approach we now report molecular interactions between nuage proteins and components of the oocyte cytoplasmic lattice and speculate how this interaction could preserve ERV/host chimeric gene products affecting female fertility. PMID- 26116733 TI - Memories and Vignettes From Friends of Hilary Koprowski. PMID- 26116734 TI - From Immunity and Vaccines to Mammalian Regeneration. AB - Our current understanding of major histocompatibility complex (MHC)-mediated antigen presentation in self and nonself immune recognition was derived from immunological studies of autoimmunity and virus-host interactions, respectively. The trimolecular complex of the MHC molecule, antigen, and T-cell receptor accounts for the phenomena of immunodominance and MHC degeneracy in both types of responses and constrains vaccine development. Out of such considerations, we developed a simple peptide vaccine construct that obviates immunodominance, resulting in a broadly protective T-cell response in the absence of antibody. In the course of autoimmunity studies, we identified the MRL mouse strain as a mammalian model of amphibian-like regeneration. A significant level of DNA damage in the cells from this mouse pointed to the role of the cell cycle checkpoint gene CDKN1a, or p21(cip1/waf1). The MRL mouse has highly reduced levels of this molecule, and a genetic knockout of this single gene in otherwise nonregenerating strains led to an MRL-type regenerative response, indicating that the ability to regenerate has not been lost during evolution. PMID- 26116735 TI - Antibodies: At The Nexus of Antigens and Cancer Vaccines. AB - This review describes the development of monoclonal antibodies and the inception of their use in cancer therapy, their impact on defining cancer biomarkers, and their structural utility in new cancer vaccine development. PMID- 26116736 TI - Cancer Immunity: Lessons From Infectious Diseases. AB - Innate and adaptive immunity are activated by both infections and tumors. The immune cells infiltrating infected tissues are similar to those infiltrating neoplastic tissues, but their function in the first setting is quite different from that in the latter. Infected tissues are usually characterized by an acute inflammatory environment that favors the generation of protective immunity, whereas tumors are characterized by chronic inflammation that suppresses antitumor immune responses and promotes tumor growth and escape from the immune system. During resolution of the immune response to infection or in chronic infections, immunosuppressive mechanisms that are typical of the tumor microenvironment are observed in infected tissues. Conversely, immunotherapy and chemotherapy may redirect the tumor microenvironment and allow the activation of effective anticancer immune responses. The transformation of neoplastic cells is determined by intrinsic genetic alteration but tumor progression is controlled by the tumor microenvironment and by the inflammatory and immune response to the tumors. Commensal microorganisms live in great numbers in all our barrier epithelia and control inflammation and immunity both locally and systemically. The commensal microbiota is essential for optimal immune response to pathogens and for the establishment of autoimmunity. It also modulates inflammation and immune responses that affect tumor growth and it is required for the effectiveness of anticancer immunotherapy and chemotherapy. PMID- 26116738 TI - Tracheal obstruction caused by cervical malignant peripheral nerve sheath tumor. PMID- 26116737 TI - MicroRNA in Cancer and Cachexia--A Mini-Review. AB - MicroRNAs (miRNAs) are short noncoding RNAs with a length of approximately 22 nucleotides that are involved in posttranscriptional regulation of gene expression. miRNAs cover an important role in all biological processes, and aberrant miRNA expression is commonly associated with cancer. Recent discoveries have associated the involvement of miRNA in an increasingly large number of biological processes, including cachexia. The cachexia syndrome is a debilitating state of cancer that is, at least in part, associated with apoptosis. The mechanism through which tumors promote the characteristic distal loss of muscle and fat mass during the cachectic process is still not deeply investigated. In this review, we briefly describe the role of miRNAs in cancer development and cachexia. PMID- 26116739 TI - Analysis of lipid-composition changes in plasma membrane microdomains. AB - Sphingolipids accumulate in plasma membrane microdomain sites, such as caveolae or lipid rafts. Such microdomains are considered to be important nexuses for signal transduction, although changes in the microdomain lipid components brought about by signaling are poorly understood. Here, we applied a cationic colloidal silica bead method to analyze plasma membrane lipids from monolayer cells cultured in a 10 cm dish. The detergent-resistant fraction from the silica bead coated membrane was analyzed by LC-MS/MS to evaluate the microdomain lipids. This method revealed that glycosphingolipids composed the microdomains as a substitute for sphingomyelin (SM) in mouse embryonic fibroblasts (tMEFs) from an SM synthase 1/2 double KO (DKO) mouse. The rate of formation of the detergent-resistant region was unchanged compared with that of WT-tMEFs. C2-ceramide (Cer) stimulation caused greater elevations in diacylglycerol and phosphatidic acid levels than in Cer levels within the microdomains of WT-tMEFs. We also found that lipid changes in the microdomains of SM-deficient DKO-tMEFs caused by serum stimulation occurred in the same manner as that of WT-tMEFs. This practical method for analyzing membrane lipids will facilitate future comprehensive analyses of membrane microdomain-associated responses. PMID- 26116740 TI - Commentary on: Superficial Enhanced Fluid Fat Injection (SEFFI) to Correct Volume Defects and Skin Aging of the Face and Periocular Region. PMID- 26116741 TI - Lymphomas Associated with Breast Implants: A Review of the Literature. AB - BACKGROUND: Recently there have been concerns raised about anaplastic large cell lymphoma (ALCL) associated with breast implants. OBJECTIVES: The main aim of this article was to review and analyze the published literature specifically for hematopoietic malignancies associated with breast implants and postulate a hypothesis for their etiology and pathogenesis. METHODS: The PubMed database was searched using key words "lymphoma" and "breast implants" for published papers and abstracts on implant-associated hematopoietic malignancies. RESULTS: The authors found 83 published cases reported of lymphomas associated with breast implants in the medical literature. The reported cases involved various subtypes of lymphomas and the majority were ALCL, of which 66 were confirmed as ALK negative; however there was no association with any particular type of implant. The more aggressive cases and reported low death rate appeared to be related to the presence of breast masses at the time of presentation rather than effusion. The remaining reports were occasional case reports of T-cell lymphoma, follicular lymphoma, marginal zone B-cell lymphoma, primary effusion lymphoma and lymphoplasmacytic lymphoma. CONCLUSIONS: Considering the many thousands of women that have breast implants every year; the compiled data show that there is a very small risk of developing lymphoma. Increased awareness of association between implants and ALCL is needed globally and prospective patients considering breast implants should be fully informed of the risk. As the behavior of ALCL in these cases was indolent as compared with other primary breast lymphomas, it could suggest an abnormal reactive process. LEVEL OF EVIDENCE: 3 PMID- 26116742 TI - Commentary on: Lymphomas Associated With Breast Implants: A Review of the Literature. PMID- 26116743 TI - Commentary on: Nipple-Sparing Mastectomy Through an Inframammary Fold Incision with Implant-Based Reconstruction in Patients with Prior Cosmetic Breast Surgery. PMID- 26116744 TI - Some Random(ized) Thoughts. PMID- 26116745 TI - Erratum on: Absence of Bacterial or Fungal Growth in Vials of Reconstituted Botulinum Toxin Type A After Storage. PMID- 26116746 TI - Retraction of: T-shaped excision of the orbicularis oris muscle: an innovative technique for upper lip lift procedures. PMID- 26116747 TI - Comments on "The Lateral Crural Rein Flap: A Novel Technique for Management of Tip Rotation in Primary Rhinoplasty". PMID- 26116748 TI - Response to "Comments on 'The Lateral Crural Rein Flap: A Novel Technique for Management of Tip Rotation in Primary Rhinoplasty'". PMID- 26116749 TI - Shedding Some Light on the Sunshine Act. PMID- 26116750 TI - Response to "Shedding Some Light on the Sunshine Act". PMID- 26116751 TI - The Value of 2-Dimensional Analysis of Changes in Breast Shape. PMID- 26116752 TI - Response to "The Value of Two-Dimensional Analysis of Changes in Breast Shape". PMID- 26116753 TI - Surgery of the thymus in 2015: more quality from the available data. PMID- 26116754 TI - PARD3 induces TAZ activation and cell growth by promoting LATS1 and PP1 interaction. AB - The Hippo pathway plays a major role in organ size control, and its dysregulation contributes to tumorigenesis. The major downstream effectors of the Hippo pathway are the YAP/TAZ transcription co-activators, which are phosphorylated and inhibited by the Hippo pathway kinase LATS1/2. Here, we report a novel mechanism of TAZ regulation by the tight junction protein PARD3. PARD3 promotes the interaction between PP1A and LATS1 to induce LATS1 dephosphorylation and inactivation, therefore leading to dephosphorylation and activation of TAZ. The cytoplasmic, but not the tight junction complex associated, PARD3 is responsible for TAZ regulation. Our study indicates a potential molecular basis for cell growth-promoting function of PARD3 by modulating the Hippo pathway signaling in response to cell contact and cell polarity signals. PMID- 26116755 TI - Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1 dependent phosphorylation and activation. AB - Mutations in the mitochondrial protein kinase PINK1 are associated with autosomal recessive Parkinson disease (PD). We and other groups have reported that PINK1 activates Parkin E3 ligase activity both directly via phosphorylation of Parkin serine 65 (Ser(65))--which lies within its ubiquitin-like domain (Ubl)--and indirectly through phosphorylation of ubiquitin at Ser(65). How Ser(65) phosphorylated ubiquitin (ubiquitin(Phospho-Ser65)) contributes to Parkin activation is currently unknown. Here, we demonstrate that ubiquitin(Phospho Ser65) binding to Parkin dramatically increases the rate and stoichiometry of Parkin phosphorylation at Ser(65) by PINK1 in vitro. Analysis of the Parkin structure, corroborated by site-directed mutagenesis, shows that the conserved His302 and Lys151 residues play a critical role in binding of ubiquitin(Phospho Ser65), thereby promoting Parkin Ser(65) phosphorylation and activation of its E3 ligase activity in vitro. Mutation of His302 markedly inhibits Parkin Ser(65) phosphorylation at the mitochondria, which is associated with a marked reduction in its E3 ligase activity following mitochondrial depolarisation. We show that the binding of ubiquitin(Phospho-Ser65) to Parkin disrupts the interaction between the Ubl domain and C-terminal region, thereby increasing the accessibility of Parkin Ser(65). Finally, purified Parkin maximally phosphorylated at Ser(65) in vitro cannot be further activated by the addition of ubiquitin(Phospho-Ser65). Our results thus suggest that a major role of ubiquitin(Phospho-Ser65) is to promote PINK1-mediated phosphorylation of Parkin at Ser(65), leading to maximal activation of Parkin E3 ligase activity. His302 and Lys151 are likely to line a phospho-Ser(65)-binding pocket on the surface of Parkin that is critical for the ubiquitin(Phospho-Ser65) interaction. This study provides new mechanistic insights into Parkin activation by ubiquitin(Phospho Ser65), which could aid in the development of Parkin activators that mimic the effect of ubiquitin(Phospho-Ser65). PMID- 26116756 TI - Benzimidazole analogs inhibit respiratory syncytial virus G protein function. AB - Human respiratory syncytial virus (hRSV) is a highly contagious Paramyxovirus that infects most children by age two, generating an estimated 75,000-125,000 hospitalizations in the U.S. annually. hRSV is the most common cause of bronchiolitis and pneumonia among infants and children under 1year of age, with significant mortality among high-risk groups. A regulatory agency-approved vaccine is not available, and existing prophylaxis and therapies are limited to use in high-risk pediatric patients; thus additional therapies are sorely needed. Here, we identify a series of benzimidazole analogs that inhibit hRSV infection in vitro with high potency, using a previously-reported high-throughput screening assay. The lead compound, SRI 29365 (1-[6-(2-furyl)[1,2,4]triazolo[3,4 b][1,3,4]thiadiazol-3-yl]methyl-1H-benzimidazole), has an EC50 of 66MUM and a selectivity >50. We identified additional compounds with varying potencies by testing commercially-available chemical analogs. Time-of-addition experiments indicated that SRI 29365 effectively inhibits viral replication only if present during the early stages of viral infection. We isolated a virus with resistance to SRI 29365 and identified mutations in the transmembrane domain of the viral G protein genomic sequence that suggested that the compound inhibits G-protein mediated attachment of hRSV to cells. Additional experiments with multiple cell types indicated that SRI 29365 antiviral activity correlates with the binding of cell surface heparin by full-length G protein. Lastly, SRI 29365 did not reduce hRSV titers or morbidity/mortality in efficacy studies using a cotton rat model. Although SRI 29365 and analogs inhibit hRSV replication in vitro, this work suggests that the G-protein may not be a valid drug target in vivo. PMID- 26116757 TI - Molecular functions of NEDD4 E3 ubiquitin ligases in cancer. AB - The initiation, progression and cure of cancer rely heavily on altered gene expression and posttranslational functions. Protein ubiquitination is a major mechanism for posttranslational reorganization of the genome. This evolutionary conserved cascade, through regulation of protein stability, distribution, and function, governs nearly every biological process in the cell. E3 ubiquitin ligases are pivotal components of the ubiquitination pathway. Genetic alterations, abnormal expression, and dysfunctions of E3s have been implicated in the pathogenesis of a wide spectrum of human malignancies. In this review, we summarize and discuss recent discoveries on the roles of NEDD4 E3s in cancer. Over the past decade, members of this family have increasingly surfaced as fundamental components and critical regulators of molecular pathways central to the pathogenesis and cure of the disease. PMID- 26116758 TI - The emerging role of the transcriptional coregulator RIP140 in solid tumors. AB - RIP140 is a transcriptional coregulator (also known as NRIP1) which plays very important physiological roles by finely tuning the activity of a large number of transcription factors. Noticeably, the RIP140 gene has been shown to be involved in the regulation of energy expenditure, in mammary gland development and intestinal homeostasis as well as in behavior and cognition. RIP140 is also involved in the regulation of various oncogenic signaling pathways and participates in the development and progression of solid tumors. This short review aims to summarize the role of this transcription factor on nuclear estrogen receptors, E2F and Wnt signaling pathways based on recent observations focusing on breast, ovary, liver and colon tumors. PMID- 26116760 TI - Central serotonin(2B) receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow. AB - The central serotonin2B receptor (5-HT2BR) is currently considered as an interesting pharmacological target for improved treatment of drug addiction. In the present study, we assessed the effect of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on cocaine-induced hyperlocomotion and dopamine (DA) outflow in the nucleus accumbens (NAc) and the dorsal striatum of freely moving rats. The peripheral administration of RS 127445 (0.16 mg/kg, i.p.) or LY 266097 (0.63 mg/kg, i.p.) significantly reduced basal DA outflow in the NAc shell, but had no effect on cocaine (10 mg/kg, i.p.)-induced DA outflow in this brain region. Also, RS 127445 failed to modify both basal and cocaine-induced DA outflow in the NAc core and the dorsal striatum. Conversely, both 5-HT2BR antagonists reduced cocaine-induced hyperlocomotion. Furthermore, RS 127445 as well as the DA-R antagonist haloperidol (0.1 mg/kg, i.p.) reduced significantly the late-onset hyperlocomotion induced by the DA-R agonist quinpirole (0.5 mg/kg, s.c.). Altogether, these results demonstrate that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical DA outflow. This interaction takes place downstream to DA neurons and could involve an action at the level of dorsostriatal and/or NAc DA transmission, in keeping with the importance of these brain regions in the behavioural responses of cocaine. Overall, this study affords additional knowledge into the regulatory control exerted by the 5-HT2BR on ascending DA pathways, and provides additional support to the proposed role of 5-HT2BRs as a new pharmacological target in drug addiction. PMID- 26116761 TI - Endomorphin-1 analogues (MELs) penetrate the blood-brain barrier and exhibit good analgesic effects with minimal side effects. AB - Endomorphins are endogenous opioid peptides in mammals and display a strong antinociceptive effect after central administration. However, the clinical usage of these peptides is limited because of their diminished analgesic effect following systemic injection and their inability to cross the blood-brain barrier. In this study, we characterized the in vivo effects of four novel endomorphin-1 analogues (termed MELs), which previously showed potential as highly potent analgesics with a good pharmacological profile in vitro. The analogues were administered intravenously to several rodent pain models to examine their antinociception and blood-brain barrier permeability. The tested peptides, especially MEL1214, showed good analgesic activity and blood-brain barrier permeability. Behavioral studies showed dose-dependent analgesic effect after systematic administration of MEL1214 in the tested pain models. Pre treatment of subcutaneous administration of naloxone methiodide did not affect the antinociception of these peptides. As compared to morphine, MEL1214 was less prone to induce tolerance after consecutive intravenous administration for 5 days. Gastrointestinal transit was evaluated by the isolated colon response and bead expulsion to determine the potential constipation effect. In contrast to morphine, MEL1214 produced no significant constipation effect at an equivalent dose. MEL1214 shows promise as a suitable compound to treat pain with reduced side effects, and exhibits good potential to be further developed as a novel opioid analgesic in pain treatment. PMID- 26116762 TI - ClickSeq: Fragmentation-Free Next-Generation Sequencing via Click Ligation of Adaptors to Stochastically Terminated 3'-Azido cDNAs. AB - We present a simple method called "ClickSeq" for NGS (next-generation sequencing) library synthesis that uses click chemistry rather than enzymatic reactions for the ligation of Illumina sequencing adaptors. In ClickSeq, randomly primed reverse transcription reactions are supplemented with azido-2',3' dideoxynucleotides that randomly terminate DNA synthesis and release 3'-azido blocked cDNA fragments in a process akin to dideoxy-Sanger sequencing. Purified fragments are "click ligated" via copper-catalyzed alkyne-azide cycloaddition to DNA oligos modified with a 5'-alkyne group. This generates ssDNA molecules containing an unnatural triazole-linked DNA backbone that is sufficiently biocompatible for PCR amplification to generate a cDNA library for RNAseq. Here, we analyze viral RNAs and mRNA to demonstrate that ClickSeq produces unbiased NGS libraries with low error rates comparable to standard methods. Importantly, ClickSeq is robust against common artifacts of NGS such as chimera formation and artifactual recombination with fewer than 3 aberrant events detected per million reads. PMID- 26116763 TI - Sclerosed Hemangioma Accompanied by Multiple Cavernous Hemangiomas of the Liver. AB - BACKGROUND: A sclerosed hemangioma of the liver, an extremely rare type of benign hepatic tumor, was found at autopsy. CASE REPORT: An 81-year-old Japanese man was admitted to our hospital for surgical resection of squamous cell carcinoma of the skin in his left forearm. At admission, serological tests for hepatitis B surface antigen and hepatitis C antibody were negative with no evidence of cirrhosis. At 2, 3, and 5 months after the removal of the forearm tumor, skin grafting was performed because of unhealed skin ulceration. Although anti-bacterial drugs were prescribed, the patient died after the 3rd skin graft (5 months after the surgery) because of pneumonia. During the treatment course, the patient was diagnosed as having multiple liver masses suspected to be cysts of the liver based on non-contrasted computed tomography results. Autopsy revealed a sclerosed hemangioma occupying the entire left lobe accompanied by multiple small cavernous hemangiomas in the right lobe of the liver. CONCLUSIONS: Sclerosed hemangioma, a rare benign disease, occurred in association with degeneration and sclerosis of cavernous hemangiomas of the liver. The VEGF pathway may be involved in the genesis of cavernous and sclerosed hemangioma of the liver. PMID- 26116764 TI - Elevation of cardiac troponins measured after recreational resistance training. AB - BACKGROUND: Whereas elevated cardiac troponin (cTn) concentrations i.e. above the 99th percentile of healthy reference population (recommended cutoff for the diagnosis of myocardial infarction) are well-documented in healthy individuals after prolonged and/or intensive exercises such as marathons, data on less strenuous sports are scarce. Therefore, our aim was to investigate cTnI and cTnT release in response to recreational resistance training, here a single-bout of 1 h kettlebell workout. METHODS: Serum samples were collected from 11 apparently healthy volunteers the previous day (pre-exercise), three hours after the kettlebell class (post-exercise), the next day and three days later. The aliquoted samples were analyzed with Abbott Laboratories' Architect high sensitivity (hs)-cTnI assay (limit of detection, LoD = 2 ng/L), our 3+1-type cTnI assay free from cTn-specific autoantibody interference (LoD = 3 ng/L) and Roche Diagnostics' hs-cTnT assay (LoD = 5 ng/L). RESULTS: The post-exercise cTn concentrations were significantly higher than the pre-exercise values (median 5.5 9.6 ng/L vs. 26 ng/L, n = 2) and/or hs-cTnT (>14 ng/L, n = 4). The cTn concentrations returned to baseline during the three days of follow-up. CONCLUSIONS: Our study demonstrates abnormally elevated cTns with well-validated sensitive cTn assays after resistance training. This confirms that different kinds of recreational physical activity are yet another confounder that may affect the determination and use of 99th percentile reference values. Therefore, exercise-associated changes should be carefully addressed as part of the evaluation what is "normal cTn". PMID- 26116765 TI - Multigenerational maternal inhibition of prepupal diapause in two Trichogramma species (Hymenoptera: Trichogrammatidae). AB - It is known that in some insect species the incidence of diapause among the progeny of females that had undergone diapause is relatively low or zero even under strong diapause-inducing conditions. Moreover, the maternal inhibition, preventing the induction of a maladaptive diapause in spring, can persist over several generations. This multigenerational effect based on hypothetical 'interval timer' was thoroughly studied in Aphididae. We first described a similar phenomenon in Hymenoptera: laboratory experiments demonstrated that the proportion of diapausing progeny of Trichogramma females that had undergone diapause was practically zero independently of photoperiodic and temperature conditions used (day lengths of 12 and 18h and temperatures of 12-15 degrees C). Then the ability to enter diapause recovered gradually and returned to the normal level over two (in Trichogramma telengai) or even five (in Trichogramma principium) generations. We conclude that the observed effect may be based on an interval timer similar to that in aphids. PMID- 26116766 TI - Influences of multiple firings and aging on surface roughness, strength and hardness of veneering ceramics for zirconia frameworks. AB - OBJECTIVES: To evaluate the effects of multiple firings and aging on surface roughness, strength, and hardness of veneering ceramics for zirconia frameworks. METHODS: Five different veneering ceramics for zirconia frameworks were used: Vintage ZR (ZR), Cerabien ZR (CZR), VitaVM9 (VM9), Cercon ceram KISS (KISS), and IPS e.max ceram (e.max). Specimens were fired 2 or 10 times in order to accelerate aging. Surface roughness was evaluated using laser profilometry. Flexural strength and Vickers hardness were also measured. Surface topography was observed using scanning electron microscopy. RESULTS: After accelerated aging, the surface roughness of all specimens fired 10 times was significantly lower than that of the same specimens fired 2 times (P=0.000). Except for VM9, the flexural strength of all specimens fired 10 times was greater than that of the same specimens fired 2 times, and the differences were significant for ZR and CZR (P<0.01). The flexural strength of VM9 fired 10 times was significantly lower than that of VM9 fired 2 times (P=0.034). The Vickers hardness of ZR and VM9 fired 10 times was significantly higher than that of the same specimens fired 2 times (P<0.05), but that of KISS fired 10 times was significantly lower than that of KISS fired 2 times (P=0.000). CONCLUSIONS: Multiple firings had a positive effect on the surface roughness of all aged veneering ceramics used for zirconia restorations and on the strength and hardness of many aged veneering ceramics used for zirconia restorations. PMID- 26116759 TI - Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology. AB - White matter disease afflicts both developing and mature central nervous systems. Both cell intrinsic and extrinsic dysregulation result in profound changes in cell survival, axonal metabolism and functional performance. Experimental models of developmental white matter (WM) injury and demyelination have not only delineated mechanisms of signaling and inflammation, but have also paved the way for the discovery of pharmacological approaches to intervention. These reagents have been shown to enhance protection of the mature oligodendrocyte cell, accelerate progenitor cell recruitment and/or differentiation, or attenuate pathological stimuli arising from the inflammatory response to injury. Here we highlight reports of studies in the CNS in which compounds, namely peptides, hormones, and small molecule agonists/antagonists, have been used in experimental animal models of demyelination and neonatal brain injury that affect aspects of excitotoxicity, oligodendrocyte development and survival, and progenitor cell function, and which have been demonstrated to attenuate damage and improve WM protection in experimental models of injury. The molecular targets of these agents include growth factor and neurotransmitter receptors, morphogens and their signaling components, nuclear receptors, as well as the processes of iron transport and actin binding. By surveying the current evidence in non-immune targets of both the immature and mature WM, we aim to better understand pharmacological approaches modulating endogenous oligodendroglia that show potential for success in the contexts of developmental and adult WM pathology. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. PMID- 26116767 TI - Amalgam and resin composite longevity of posterior restorations: A systematic review and meta-analysis. AB - OBJECTIVES: The aim of the present review was to evaluate by means of a systematic review and meta-analysis the hypothesis of no difference in failure rates between amalgam and composite resin posterior restorations. DATA: Randomized controlled trials, controlled clinical trials and prospective and retrospective cohort studies were included in this review. The eligibility criteria included clinical trials in humans with at least 12 months of follow-up comparing the failures rates between occlusal and occlusoproximal amalgam and composite resin restorations. Clinical questions were formulated and organized according to the PICOS strategy. SOURCE: An electronic search without restriction on the dates or languages was performed in PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science up until March 2015. STUDY SELECTION: The initial search resulted in 938 articles from PubMed/MEDLINE, 89 titles from the Cochrane Central Register of Controlled Trials, and 172 from the Web of Science. After an initial assessment and careful reading, 8 studies published between 1992 and 2013 were included in this review. According to the risk of bias evaluation, all studies were classified as high quality. CONCLUSIONS: The results of this review suggest that composite resin restorations in posterior teeth still have less longevity and a higher number of secondary caries when compared to amalgam restorations. In relation to fractures, there was no statistically significant difference between the two restorative materials regarding the time of follow-up. CLINICAL SIGNIFICANCE: There is currently a worldwide trend towards replacing amalgam restorations with mercury-free materials, which are adhesive and promote aesthetics. It is important to perform an updated periodic review to synthesize the clinical performance of restorations in the long-term. PMID- 26116768 TI - PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma. AB - Accumulating evidence has shown that PI3K/Akt pathway is frequently hyperactivated in osteosarcoma (OS) and contributes to tumor initiation and progression. Altered phenotype of glucose metabolism is a key hallmark of cancer cells including OS. However, the relationship between PI3K/Akt pathway and glucose metabolism in OS remains largely unexplored. In this study, we showed that elevated Hexokinase-2 (HK2) expression, which catalyzes the first essential step of glucose metabolism by conversion of glucose into glucose-6-phosphate, was induced by activated PI3K/Akt signaling. Immunohistochemical analysis showed that HK2 was overexpressed in 83.3% (25/30) specimens detected and was closely correlated with Ki67, a cell proliferation index. Silencing of endogenous HK2 resulted in decreased aerobic glycolysis as demonstrated by reduced glucose consumption and lactate production. Inhibition of PI3K/Akt signaling also suppressed aerobic glycolysis and this effect can be reversed by reintroduction of HK2. Furthermore, knockdown of HK2 led to increased cell apoptosis and reduced ability of colony formation; meanwhile, these effects were blocked by 2-Deoxy-d glucose (2-DG), a glycolysis inhibitor through its actions on hexokinase, indicating that HK2 functions in cell apoptosis and growth were mediated by altered aerobic glycolysis. Taken together, our study reveals a novel relationship between PI3K/Akt signaling and aerobic glycolysis and indicates that PI3K/Akt/HK2 might be potential therapeutic approaches for OS. PMID- 26116769 TI - The STAT3 inhibitor WP1066 synergizes with vorinostat to induce apoptosis of mantle cell lymphoma cells. AB - Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t (11; 14) (q13; q32). Drug resistance remains a formidable obstacle to treatment and the median survival for MCL patients is between 3 and 5 years. Thus, there is an urgent need to discover novel approaches to MCL therapy. The signal transducer and activation of transcription 3 (STAT3) has been found to be constitutively activated in several subtypes of MCL cell lines and MCL tumors. WP1066, a small-molecule inhibitor of STAT3, exerted antitumor activity in hematological and solid malignancies by inhibiting key survival and growth signaling pathways. In the present study, we evaluated the antiproliferative and proapoptotic activity of WP1066 combined with pan-histone deacetylase (HDAC) inhibitor vorinostat (SAHA) in a panel of MCL cell lines. In addition, potential mechanisms involved were also explored. The outcome showed that combination of WP1066 with SAHA resulted in synergistic growth inhibition and apoptosis induction in MCL cell lines in vitro. Furthermore, combination of WP1066 with SAHA inhibited the constitutive STAT3 activation and modulated mRNA expressions of anti- and pro-apoptotic genes. Our findings suggest that agents targeting the STAT3 pathway such as WP1066 may be useful therapeutic drugs for MCL when combined with SAHA. PMID- 26116770 TI - Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine. AB - Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood-brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. PMID- 26116771 TI - Inhibition of invasion by glycogen synthase kinase-3 beta inhibitors through dysregulation of actin re-organisation via down-regulation of WAVE2. AB - Cancer cell invasion is a critical phenomenon in cancer pathogenesis. Glycogen synthase kinase-3beta (GSK-3beta) has been reported to regulate cancer cell invasion both negatively and positively. Thus, the net effect of GSK-3beta on invasion is unclear. In this report, we showed that GSK-3beta inhibitors induced dysregulation of the actin cytoskeleton and functional insufficiency of focal adhesion, which resulted in suppressed invasion. In addition, WAVE2, an essential molecule for actin fibre branching, was down-regulated after GSK-3beta inhibition. Collectively, we propose that the WAVE2-actin cytoskeleton axis is an important target of GSK-3beta inhibitors in cancer cell invasion. PMID- 26116772 TI - Trophic factors from adipose tissue-derived multi-lineage progenitor cells promote cytodifferentiation of periodontal ligament cells. AB - Stem and progenitor cells are currently being investigated for their applicability in cell-based therapy for periodontal tissue regeneration. We recently demonstrated that the transplantation of adipose tissue-derived multi lineage progenitor cells (ADMPCs) enhances periodontal tissue regeneration in beagle dogs. However, the molecular mechanisms by which transplanted ADMPCs induce periodontal tissue regeneration remain to be elucidated. In this study, trophic factors released by ADMPCs were examined for their paracrine effects on human periodontal ligament cell (HPDL) function. ADMPC conditioned medium (ADMPC CM) up-regulated osteoblastic gene expression, alkaline phosphatase activity and calcified nodule formation in HPDLs, but did not significantly affect their proliferative response. ADMPCs secreted a number of growth factors, including insulin-like growth factor binding protein 6 (IGFBP6), hepatocyte growth factor and vascular endothelial growth factor. Among these, IGFBP6 was most highly expressed. Interestingly, the positive effects of ADMPC-CM on HPDL differentiation were significantly suppressed by transfecting ADMPCs with IGFBP6 siRNA. Our results suggest that ADMPCs transplanted into a defect in periodontal tissue release trophic factors that can stimulate the differentiation of HPDLs to mineralized tissue-forming cells, such as osteoblasts and cementoblasts. IGFBP6 may play crucial roles in ADMPC-induced periodontal regeneration. PMID- 26116773 TI - Molecular dynamics simulations of Na(+) and leucine transport by LeuT. AB - Molecular dynamics simulations are used to gain insight into the binding of Na(+) and leucine substrate to the bacterial amino acid transporter LeuT, focusing on the crystal structures of LeuT in the outward-open and inward-open states. For both conformations of LeuT, a third Na(+) binding site involving Glu290 in addition to the two sites identified from the crystal structures is observed. Once the negative charge from Glu290 in the inward-open LeuT is removed, the ion bound to the third site is ejected from LeuT rapidly, suggesting that the protonation state of Glu290 regulates Na(+) binding and release. In Cl(-) dependent transporters where Glu290 is replaced by a neutral serine, a Cl(-) ion would be required to replace the role of Glu290. Thus, the simulations provide insights into understanding Na(+) and substrate transport as well as Cl(-) independence of LeuT. PMID- 26116774 TI - VEGF inhibits the inflammation in spinal cord injury through activation of autophagy. AB - Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis and re-vascularization of spinal cord injury (SCI). VEGF has long been thought to be a potent neurotrophic factor for the survival of spinal cord neuron. However, the neuroprotective mechanism of VEGF is still unclear. The aim of this study was to investigate the effect of VEGF on spinal cord injury and its mechanisms. Young male Wistar rats were subjected to SCI and then VEGF165 were injected directly into the lesion epicenter 24 h post injury. We detected Basso, Beattie and Bresnahan (BBB) scores and numbers of motor neuron via Nissl staining. The expressions of autophagy related protein Beclin1 and LC3B were determined by Western blot and RT-PCR. We also detected the contents of inflammation factors interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-10(IL-10) in LPS (Lipopolysaccharide) treated spinal neuron-glia co-culture by ELISA. We found that VEGF165 administration increased the BBB score and reduced the loss of motor neuron of rats induced by SCI. VEGF decreased the protein expressions of IL-1beta, TNF-alpha and IL-10 and up regulated the expressions of Beclin1 and LC3B of rats. In the in vitro study, VEGF165 decreased the levels of IL-1beta, IL-10 and TNF-a in the medium of LPS treated spinal neuron-glia co-culture, which was partially blocked by 3-MA, the inhibitor of autophagy. In addition, VEGF165 up-regulate the expressions of Beclin1 and LC3B in co-culture cells. The results suggested that VEGF165 attenuated the spinal cord injury by inhibiting the inflammation and increasing the autophagy function. PMID- 26116775 TI - The intravenous injection of oxidized LDL- or Apolipoprotein B100--Coupled splenocytes promotes Th1 polarization in wildtype and Apolipoprotein E--Deficient mice. AB - BACKGROUND: Th1 responses in atherosclerosis are mainly associated with the aggravation of atherosclerotic plaques, whereas Th2 responses lead to a less pronounced disease in mouse models. The fixation of antigens on cells by means of ethylene carbodiimide (ECDI), and subsequent injection of these antigen-coupled splenocytes (Ag-SP) to induce tolerance against the attached antigens, has been successfully used to treat murine type 1 diabetes or encephalomyelitis in. We analyzed this approach in a mouse model for atherosclerosis. METHODS AND RESULTS: OTII-transgenic mice that were treated with a single dose of 5 * 10(7) OVA coupled splenocytes (OVA-SP), had decreased splenocyte proliferation, and lower IFNgamma production in vitro upon antigen recall. However, in vivo CD4 cell activation was increased. To try lipoprotein-derived, "atherosclerosis associated" antigens, we first tested human oxidized LDL. In wild type mice, an increase of IFNgamma production upon in vitro recall was detected in the oxLDL-SP group. In Apolipoprotein E - deficient (ApoE-/-) mice that received oxLDL-SP every 5 weeks for 20 weeks, we did not find any difference of atherosclerotic plaque burden, but again increased IFNgamma production. To overcome xenogenous limitations, we then examined the effects of mouse Apolipoprotein B100 peptides P3 and P6. ApoB100-SP treatment again promoted a more IFNgamma pronounced response upon in vitro recall. Flow cytometry analysis of cytokine secreting spleen cells revealed CD4 positive T cells to be mainly the source for IFNgamma. In ApoE-/- mice that were administered ApoB100-SP during 20 weeks, the atherosclerotic plaque burden in aortic roots as well as total aorta was unchanged compared to PBS treated controls. Splenocyte proliferation upon antigen recall was not significantly altered in ApoB100-SP treated ApoE-/- mice. CONCLUSION: Although we did not observe a relevant anti-atherosclerotic benefit, the treatment with antigen-coupled splenocytes in its present form already impacts the immune responses and deserves further exploration. PMID- 26116776 TI - ABT-737 sensitizes curcumin-induced anti-melanoma cell activity through facilitating mPTP death pathway. AB - In the current study, we studied the potential role of ABT-737, a novel Bcl-2 inhibitor, on curcumin-induced anti-melanoma cell activity in vitro. The associated mechanisms were also investigated. We demonstrated that ABT-737 significantly sensitized curcumin-induced activity against melanoma cells (WM-115 and B16 lines), resulting in substantial cell death and apoptosis with co administration. At the molecular level, curcumin and ABT-737 synergistically induced mitochondrial permeability transition pore (mPTP) opening in melanoma cells, the latter was evidenced by mitochondrial membrane potential (MPP) reduction and mitochondrial complexation between cyclophilin-D (CyPD) and adenine nucleotide translocator 1 (ANT-1). Significantly, mPTP blockers, including cyclosporin A and sanglifehrin A, remarkably inhibited curcumin and ABT-737 co administration-induced cytotoxicity against melanoma cells. Meanwhile, siRNA mediated knockdown of CyPD or ANT-1, the two key components of mPTP, alleviated WM-116 cell death by the co-treatment. Collectively, we show that ABT-737 sensitizes curcumin-induced anti-melanoma cell activity probably through facilitating mPTP death pathway. ABT-737 could be further investigated as a potential curcumin adjuvant in melanoma and other cancer treatment. PMID- 26116777 TI - Respiratory metabolism of salivary glands during the late larval and prepupal development of Drosophila melanogaster. AB - During the late larval period, the salivary glands (SG) of Drosophila show a cascade of cytological changes associated with exocytosis and the expectoration of the proteinaceous glue that is used to affix the pupariating larva to a substrate. After puparium formation (APF), SG undergo extensive cytoplasmic vacuolation due to endocytosis, vacuole consolidation and massive apocrine secretion. Here we investigated possible correlations between cytological changes, the puffing pattern in polytene chromosomes and respiratory metabolism of the SG. The carefully staged SG were explanted into small amounts (1 or 2MUl) of tissue culture medium. The respiratory metabolism of single or up to 3 pairs of glands was evaluated by recording the rate of O2 consumption using a scanning microrespirographic technique sensitive to subnanoliter volumes of the respiratory O2 or CO2. The recordings were carried out at times between 8h before pupariation (BPF), until 16h APF, at which point the SG completely disintegrate. At the early wandering larval stage (8h BPF), the glands consume 2nl of O2/gland/min (=2500MUl O2/g/h). This relatively high metabolic rate decreases down to 1.2-1.3nl of O2 during the endogenous peak in ecdysteroid concentration that culminates around pupariation. The metabolic decline coincides with the exocytosis of the proteinaceous glue. During and shortly after puparium formation, which is accompanied cytologically by intense vacuolation, O2 consumption in the SG temporarily increases to 1.6nl O2/gland/min. After this time, the metabolic rate of the SG decreases downward steadily until 16h APF, when the glands disintegrate and cease to consume oxygen. The SG we analyzed from Drosophila larvae were composed of 134 intrinsic cells, with the average volume of one lobe being 37nl. Therefore, a single SG cell of the wandering larva (with O2 consumption of 2nl/gland/min), consumes each about 16pl of O2/cell/min. A simultaneous analysis of the rate of protein and RNA synthesis in the SG shows a course similar to that found in respiratory metabolism. PMID- 26116778 TI - Heart rate variability is enhanced in controls but not maladaptive perfectionists during brief mindfulness meditation following stress-induction: A stratified randomized trial. AB - Heart rate variability (HRV) is a vagal nerve-mediated biomarker of cardiac function used to investigate chronic illness, psychopathology, stress and, more recently, attention-regulation processes such as meditation. This study investigated HRV in relation to maladaptive perfectionism, a stress-related personality factor, and mindfulness meditation, a stress coping practice expected to elevate HRV, and thereby promote relaxation. Maladaptive perfectionists (n=21) and Controls (n=39) were exposed to a lab-based assessment in which HRV was measured during (1) a 5-minute baseline resting phase, (2) a 5-minute cognitive stress-induction phase, and (3) a post-stress phase. In the post-stress phase, participants were randomly assigned to a 10-minute audio-instructed mindfulness meditation condition or a 10-minute rest condition with audio-description of mindfulness meditation. Analyses revealed a significant elevation in HRV during meditation for Controls but not for Perfectionists. These results suggest that mindfulness meditation promotes relaxation following cognitive stress and that the perfectionist personality hinders relaxation possibly because of decreased cardiac vagal tone. The results are discussed in the context of developing psychophysiological models to advance therapeutic interventions for distressed populations. PMID- 26116779 TI - Nano-hydroxyapatite/chitosan-starch nanocomposite as a novel bone construct: Synthesis and in vitro studies. AB - A novel ternary nanocomposite system incorporating hydroxyapatite, chitosan and starch (n-HA/CS-ST) has been synthesized by co-precipitation method at room temperature, addressing the issues of biocompatibility, mechanical strength and cytotoxicity required for bone tissue engineering. The interactions, crystallite size, surface morphology and thermal stability against n-HA/CS nanocomposite have been obtained by comparing the results of FTIR, SEM, TEM, DLS, XRD and TGA/DTA. A comparative study of bioactivity and thermal stability of n-HA/CS and n-HA/CS-ST nanocomposites revealed that the incorporation of starch as templating agent enhanced these properties in n-HA/CS-ST nanocomposite. A lower swelling rate of n HA/CS-ST relative to n-HA/CS indicates a higher mechanical strength supportive of bone tissue ingrowths. The MTT assay on murine fibroblast L929 and human osteoblasts-like MG-63 cells and in vitro bioactivity of n-HA/CS-ST matrix referred superior non-toxic nature of n-HA/CS-ST nanocomposite and greater possibility of osteointegration in vivo respectively. Furthermore n-HA/CS-ST exhibited improved antibacterial property against both Gram-positive and Gram negative bacteria relative to n-HA/CS. PMID- 26116780 TI - Comorbidity and favorable neurologic outcome after out-of-hospital cardiac arrest in patients of 70 years and older. AB - INTRODUCTION: Advanced age is reported to be associated with lower survival after out-of-hospital cardiac arrest (OHCA). We aimed to establish survival rate and neurological outcome at hospital discharge after OHCA in older patients and evaluated whether pre-OHCA comorbidity was associated with favorable neurologic outcome. METHODS: From a prospective registry of all cardiopulmonary resuscitation (CPR) attempts after OHCA, we established survival in 1332 patients aged >= 70 years in whom resuscitation with non-traumatic etiology was attempted in 2009-2011. Pre-OHCA factors (age, gender, residing in long-term care institution, Charlson Comorbidity Index [CCI] score) and resuscitation parameters (initial rhythm, bystander witnessed, bystander CPR and time to defibrillator connection) with survival at hospital discharge with favorable neurologic outcome were regressed in the 851 patients of whom CCI was known. RESULTS: We found a 12% survival to discharge rate in patients aged >= 70 years (70-79 years: 16%; >= 80 years: 8%, p=0.001). Among surviving patients, 90% survived with favorable neurologic outcome. In a model with only pre-OHCA factors age was significantly associated with outcome (age OR 0.94, 95%CI 0.91-0.98), p = 0.003). High CCI score (>= 4) was not statistically significant when associated with survival (7% vs. 12%, OR 0.53, 95%CI (0.25-1.13), p = 0.10). When adjusted for resuscitation parameters, OR for high CCI was 0.71 (95% CI 0.28-1.80, p = 0.47), also none of the other pre-OHCA factors remained statistically significant. CONCLUSION: In the Netherlands, the survival rate in older patients was 12%; the great majority survived with favorable neurologic outcome. Resuscitation-related factors and not comorbidity determine outcome after OHCA in older patients. PMID- 26116781 TI - In vitro ACE-inhibitory peptide KGYGGVSLPEW facilitates noradrenaline release from sympathetic nerve terminals: Relationship with the lack of antihypertensive effect on spontaneous hypertensive rats. AB - This study aimed to validate the antihypertensive activity of the angiotensin converting enzyme (ACE)-inhibitor whey protein hydrolysate (WPH) obtained through the action of proteolytic enzymes from Cynara Cardunculus. The antihypertensive activity of WPH fractions containing peptides with molecular weight below 3kDa (Whey<3kDa) and 1kDa (Whey<1kDa) along with the antihypertensive activity of three potent ACE-inhibitory peptide sequences (DKVGINYW, DAQSAPLRVY and KGYGGVSLPEW), previously identified in WPH, were also investigated. In parallel, the influence of KGYGGVSLPEW (the most potent ACE-inhibitory peptide sequence) on AT1 receptors (a common pharmacological target of antihypertensive therapies beyond ACE), was evaluated. The effect of WPH and fractions (300mg/kg) and peptide sequences (5mg/kg) on systolic, diastolic and mean blood pressure was evaluated by telemetry on spontaneously hypertensive rats (SHR), after single oral administration. Despite their ACE-inhibitory effect in vitro, neither WPH, Whey <3kDa, Whey <1kDa or peptide sequences exhibited antihypertensive activity. In addition, KGYGGVSLPEW was not only devoid of AT1 receptor antagonism but, on the contrary, had a similar effect to that of Ang II by facilitating the noradrenaline release from sympathetic nerve terminals. In vitro ACE blockade does not always correlate with antihypertensive activity and food-derived peptides cannot be classified as antihypertensive agents based exclusively on in vitro assays. The absence of an antihypertensive effect may also be a result of the interaction of these compounds with other components of the systems involved in the blood pressure control. PMID- 26116782 TI - Isolation and characterization of Ts19 Fragment II, a new long-chain potassium channel toxin from Tityus serrulatus venom. AB - Ts19 Fragment II (Ts19 Frag-II) was first isolated from the venom of the scorpion Tityus serrulatus (Ts). It is a protein presenting 49 amino acid residues, three disulfide bridges, Mr 5534Da and was classified as a new member of class (subfamily) 2 of the beta-KTxs, the second one described for Ts scorpion. The beta-KTx family is composed by two-domain peptides: N-terminal helical domain (NHD), with cytolytic activity, and a C-terminal CSalphabeta domain (CCD), with Kv blocking activity. The extensive electrophysiological screening (16 Kv channels and 5 Nav channels) showed that Ts19 Frag-II presents a specific and significant blocking effect on Kv1.2 (IC50 value of 544+/-32nM). However, no cytolytic activity was observed with this toxin. We conclude that the absence of 9 amino acid residues from the N-terminal sequence (compared to Ts19 Frag-I) is responsible for the absence of cytolytic activity. In order to prove this hypothesis, we synthesized the peptide with these 9 amino acid residues, called Ts19 Frag-III. As expected, Ts19 Frag-III showed to be cytolytic and did not block the Kv1.2 channel. The post-translational modifications of Ts19 and its fragments (I-III) are also discussed here. A mechanism of post-translational processing (post-splitting) is suggested to explain Ts19 fragments production. In addition to the discovery of this new toxin, this report provides further evidence for the existence of several compounds in the scorpion venom contributing to the diversity of the venom arsenal. PMID- 26116783 TI - Nesfatin-1 - More than a food intake regulatory peptide. AB - Nesfatin-1 was discovered a decade ago and despite the fact that it represents just one of a multitude of food intake-inhibiting factors it received increasing attention. This led to a detailed characterization of NUCB2/nesfatin-1's physiological property to reduce food intake and also gave rise to an involvement in the long term regulation of body weight, especially under conditions of obesity. In addition, studies indicated the involvement of NUCB2/nesfatin-1 in other homeostatic functions as well: glucose homeostasis, water intake, gastrointestinal functions, temperature regulation, cardiovascular functions, puberty onset and sleep. These pleiotropic actions underline the physiological relevance of this peptide. Recently, the involvement of NUCB2/nesfatin-1 in psychiatric disorders such as anxiety has been investigated giving rise to the speculation that NUCB2/nesfatin-1 represents a peptidergic link between eating and anxiety/depression disorders. PMID- 26116784 TI - Prospects for T. cruzi lineage-specific serological surveillance of wild mammals. AB - Sequence diversity in the Trypanosoma cruzi small surface molecule TSSA has yielded antigens for serology to investigate the T. cruzi lineage-specific infection history of patients with Chagas disease. Synthetic peptides can be used as the lineage-specific antigens. Here we consider the rationale, feasibility and potential of applying peptide-based lineage-specific serology to naturally infected wild mammals. The commercial availability of appropriate secondary antibodies encourages this further development, for discovery of new reservoir host species and to reveal the wider ecological distribution of T. cruzi lineages, currently hindered by the need to recover live isolates or to attempt genotyping of DNA extracted from blood samples. PMID- 26116785 TI - Vaccine potential of recombinant pro- and mature cathepsinL1 against fasciolosis gigantica in mice. AB - In Fasciola gigantica cathepsin L1 (CatL1) is a family of predominant proteases that is expressed in caecal epithelial cells and secreted into the excretory secretory products (ES). CatL1 isotypes are expressed in both early and late stages of the life cycle and the parasites use them for migration and digestion. Therefore, CatL1 is a plausible target for vaccination against this parasite. Recombinant pro-F.gigantica CatL1 (rproFgCatL1) and recombinant mature F.gigantica CatL1 (rmatFgCatL1) were expressed in Escherichia coli BL21. The vaccination was performed in Imprinting Control Region (ICR) mice (n=10) by subcutaneous injection with 50MUg of rproFgCatL1 and rmatFgCatL1 combined with Freund's adjuvant. Two weeks after the second boost, mice were infected with 15 metacercariae by the oral route. The level of protection of rproFgCatL1 and rmatFgCatL1 vaccines was estimated to be 39.1, 41.7% and 44.9, 47.2% when compared with non vaccinated-infected and adjuvant-infected controls, respectively. Antibodies in the immune sera of vaccinated mice were shown by immuno-blotting to react with the native FgCatL1 in the extract of newly excysted juveniles (NEJ), 4-week-old juveniles and the ES products of 4 week-old juveniles. By determining the levels of IgG1 and IgG2a in the immune sera, which are indicative of Th2 and Th1 immune response, respectively, it was found that both Th1 and Th2 responses were significantly increased in rproFgCatL1- and rmatFgCatL1-immunized groups compared with the control groups, with higher levels of Th2 (IgG1) than Th1 (IgG2a). The levels of serum aspartate aminotransferase (AST) and alanine transaminase (ALT) in rmatFgCatL1-immunized group showed a significant decrease when compared to rproFgCatL1-immunized group, indicating that rmatFgCatL1-vaccinated mice had reduced liver parenchyma damage. The pathological lesions of liver in vaccinated groups were significantly decreased when compared with control groups. This study indicates that rFgCatL1 has a potential as a vaccine candidate against F. gigantica in mice, and this potential will be tested in ruminants. PMID- 26116786 TI - Manganese ions induce H2O2 generation at the ubiquinone binding site of mitochondrial complex II. AB - Manganese-induced toxicity has been recently associated with an increased ROS generation from mitochondrial complex II (succinate:ubiquinone oxidoreductase). To achieve a deeper mechanistic understanding how divalent manganese ions (Mn(2+)) could stimulate mitochondrial ROS production we performed investigations with bovine heart submitochondrial particles (SMP). In succinate fueled SMP, the Mn(2+) induced hydrogen peroxide (H2O2) production was blocked by the specific complex II ubiquinone binding site (IIQ) inhibitor atpenin A5 while a further downstream block at complex III increased the rate markedly. This suggests that site IIQ was the source of the reactive oxygen species. Moreover, Mn(2+) ions also accelerated the rate of superoxide dismutation, explaining the general increase in the measured rates of H2O2 production and an attenuation of direct superoxide detection. PMID- 26116787 TI - Validation methods for low-resolution fitting of atomic structures to electron microscopy data. AB - Fitting of atomic-resolution structures into reconstructions from electron cryo microscopy is routinely used to understand the structure and function of macromolecular machines. Despite the fact that a plethora of fitting methods has been developed over recent years, standard protocols for quality assessment and validation of these fits have not been established. Here, we present the general concepts underlying current validation ideas as they relate to fitting of atomic resolution models into electron cryo-microscopy reconstructions, with an emphasis on reconstructions with resolutions below the sub-nanometer range. PMID- 26116788 TI - Beta glucosidase from Bacillus polymyxa is activated by glucose-6-phosphate. AB - Optimization of cellulose enzymatic hydrolysis is crucial for cost effective bioethanol production from lignocellulosic biomass. Enzymes involved in cellulose hydrolysis are often inhibited by their end-products, cellobiose and glucose. Efforts have been made to produce more efficient enzyme variants that are highly tolerant to product accumulation; however, further improvements are still necessary. Based on an alternative approach we initially investigated whether recently formed glucose could be phosphorylated into glucose-6-phosphate to circumvent glucose accumulation and avoid inhibition of beta-glucosidase from Bacillus polymyxa (BGLA). The kinetic properties and structural analysis of BGLA in the presence of glucose-6-phosphate (G6P) were investigated. Kinetic studies demonstrated that enzyme was not inhibited by G6P. In contrast, the presence of G6P activated the enzyme, prevented beta glucosidase feedback inhibition by glucose accumulation and improved protein stability. G6P binding was investigated by fluorescence quenching experiments and the respective association constant indicated high affinity binding of G6P to BGLA. Data reported here are of great impact for future design strategies for second-generation bioethanol production. PMID- 26116789 TI - Myosin regulatory light chain phosphorylation enhances cardiac beta-myosin in vitro motility under load. AB - Familial hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and myofibrillar disarray, and often results in sudden cardiac death. Two HCM mutations, N47K and R58Q, are located in the myosin regulatory light chain (RLC). The RLC mechanically stabilizes the myosin lever arm, which is crucial to myosin's ability to transmit contractile force. The N47K and R58Q mutations have previously been shown to reduce actin filament velocity under load, stemming from a more compliant lever arm (Greenberg, 2010). In contrast, RLC phosphorylation was shown to impart stiffness to the myosin lever arm (Greenberg, 2009). We hypothesized that phosphorylation of the mutant HCM-RLC may mitigate distinct mutation-induced structural and functional abnormalities. In vitro motility assays were utilized to investigate the effects of RLC phosphorylation on the HCM-RLC mutant phenotype in the presence of an alpha actinin frictional load. Porcine cardiac beta-myosin was depleted of its native RLC and reconstituted with mutant or wild-type human RLC in phosphorylated or non phosphorylated form. Consistent with previous findings, in the presence of load, myosin bearing the HCM mutations reduced actin sliding velocity compared to WT resulting in 31-41% reductions in force production. Myosin containing phosphorylated RLC (WT or mutant) increased sliding velocity and also restored mutant myosin force production to near WT unphosphorylated values. These results point to RLC phosphorylation as a general mechanism to increase force production of the individual myosin motor and as a potential target to ameliorate the HCM induced phenotype at the molecular level. PMID- 26116790 TI - Metabolomics applied to the pancreatic islet. AB - Metabolomics, the characterization of the set of small molecules in a biological system, is advancing research in multiple areas of islet biology. Measuring a breadth of metabolites simultaneously provides a broad perspective on metabolic changes as the islets respond dynamically to metabolic fuels, hormones, or environmental stressors. As a result, metabolomics has the potential to provide new mechanistic insights into islet physiology and pathophysiology. Here we summarize advances in our understanding of islet physiology and the etiologies of type-1 and type-2 diabetes gained from metabolomics studies. PMID- 26116791 TI - Poor efficacy of nucleic acid testing in identifying occult HBV infection and consequences for safety of blood supply in Italy. AB - BACKGROUND & AIMS: In Italy, DNA screening of blood donations for hepatitis B virus (HBV) was introduced to prevent the transmission of window period and occult HBV infection. Anti-HBc screening is not recommended in order to avoid shortage of the blood supply. To contain costs, donor samples are generally pooled before testing. We evaluated the safety of this national policy using a prospective repository of donors/recipient pairs. METHODS: We used highly sensitive nucleic acid testing (NAT) assays to test repository and follow-up samples from donors who were initially classified as negative by minipool NAT assays (6-MP), but were later found to carry occult HBV DNA. When available, we also analysed recipients' pre- and post-transfusion samples, collected in the context of a repository financed by the European Commission (the BOTIA project). RESULTS: Between 2008 and 2011 6-MP NAT assays identified 18 carriers of occult HBV infection among 12,695 donors; 28 samples from previous donations were available from 13 of these carriers. Highly sensitive HBV DNA detection methods showed that 6-MP HBV DNA screening failed to identify 14/28 (50%) viraemic donations, that were released for transfusion. HBV marker testing of such blood product recipients revealed two cases of transfusion transmitted HBV infection, documented by donor-recipient sequence identity. CONCLUSIONS: Viraemic blood donations from occult HBV infection carriers remain undetected by current minipool HBV DNA screening, and transfusion transmission of HBV continues to occur in susceptible patients. More effective individual HBV DNA screening and/or tests for antibodies to HBV core antigen should be considered to improve blood safety. PMID- 26116793 TI - Antiviral activity of cuprous oxide nanoparticles against Hepatitis C Virus in vitro. AB - Small molecular inhibitors in combination with or without interferon have improved sustained antiviral responses against Hepatitis C Virus (HCV) infection. Nonetheless, resistance to these inhibitors is expected to emerge rapidly due to the high mutation rate of the virus. Thus, new antiviral drugs, in combination with currently available therapies, are urgently needed to treat HCV infection. In the present study, we evaluated the antiviral efficacy of cuprous oxide nanoparticles (CO-NPs) against HCV in the HCVcc/Huh7.5.1 cell culture system. CO NPs were able to significantly inhibit the infectivity of HCVcc at a non cytotoxic concentration. In addition, CO-NPs inhibited the entry of HCV pseudoparticle (HCVpp), including genotypes 1a, 1b, and 2a, while no effect on HCV replication was observed. Further time-of-addition experiment indicated that CO-NPs blocked HCV infection both at the attachment and entry stages. In conclusion, we report that CO-NPs can act as an anti-HCV agent by targeting the binding of infectious HCV particles to hepatic cells and the virus entry into the cells. These findings suggest that CO-NPs may have novel roles in the treatment of patients with chronic hepatitis C. PMID- 26116794 TI - Association of GABAA receptor alpha2 subunit gene (GABRA2) with alcohol dependence-related aggressive behavior. AB - Alcohol dependence is a common chronic disorder precipitated by the complex interaction between biological, genetic and environmental risk factors. Recent studies have demonstrated that polymorphisms of the gene encoding the GABAA receptor alpha2 subunit (GABRA2) are associated with alcohol dependence in different populations of European ancestry. As aggression often occurs in the context of alcohol dependence, the aim of this study was to examine the allelic and haplotypic association of GABRA2 gene with alcohol dependence and related aggressive behavior in subjects of Eastern European (Croatian) origin. Genotyping of the 3 single nucleotide polymorphisms (SNPs) across the GABRA2 gene (rs567926, rs279858 and rs9291283) was performed in patients with alcohol dependence (N=654) and healthy control subjects (N=574). Alcohol-dependent participants were additionally subdivided according to the presence/absence of aggressive behavior and type of alcohol dependence according to the Cloninger's classification. The association of rs279858 with alcohol dependence yielded nominal significance level. Haplotype analysis revealed a high degree of linkage disequilibrium (LD) for rs567926 and rs279858, but not for rs9291283 polymorphism in the GABRA2 gene. In patients with alcohol dependence, the A-C (rs567926 and rs279858) haplotype carriers were more likely to demonstrate aggressive behavior. The same haplotype (present only in 1.6% of all subjects) was significantly more often present in patients with a combination of early onset alcohol abuse and aggression, corresponding to the Cloninger's type II alcoholism subgroup. These findings support the involvement of GABRA2 gene in alcohol dependence-related aggressive behavior. PMID- 26116792 TI - Structural and functional hepatocyte polarity and liver disease. AB - Hepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease. A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases. PMID- 26116795 TI - Neural Correlates of Response to Pharmacotherapy in Obsessive-Compulsive Disorder: Individualized Cortical Morphology-Based Structural Covariance. AB - BACKGROUND: Primary pharmacotherapy regimen for obsessive-compulsive disorder (OCD) named Serotonin reuptake inhibitors (SRIs) does not attain sufficient symptom improvement in 40-60% of OCD. We aimed to decode the differential profile of OCD-related brain pathology per subject in the context of cortical surface area (CSA) or thickness (CT)-based individualized structural covariance (ISC) and to demonstrate the potential of which as a biomarker of treatment response to SRI based pharmacotherapy in OCD using the support vector machine (SVM). METHODS: T1 weighted magnetic resonance imaging was obtained at 3T from 56 unmedicated OCD subjects and 75 healthy controls (HCs) at baseline. After 4months of SRI-based pharmacotherapy, the OCD subjects were classified as responders (OCD-R,N=25; >=35% improvement) or nonresponders (OCD-NR,N=31; <35% improvement) according to the percentage change in the Yale-Brown Obsessive Compulsive Scale total score. Cortical ISCs sustaining between-group difference (p<.001) for every run of leave one-out group-comparison were packaged as feature set for group classification using the SVM. RESULTS: An optimal feature set of the top 12 ISCs including a CT ISC between the dorsolateral prefrontal cortex versus precuneus, a CSA-ISC between the anterior insula versus intraparietal sulcus, as well as perisylvian area-related ISCs predicted the initial prognosis of OCD as OCD-R or OCD-NR with an accuracy of 89.0% (sensitivity 88.4%, specificity 90.1%). Extended sets of ISCs distinguished the OCD subjects from the HCs with 90.7-95.6% accuracy (sensitivity 90.8-96.2%, specificity 91.1-95.0%). CONCLUSION: We showed the potential of cortical morphology-based ISCs, which reflect dysfunctional cortical maturation process, as a possible biomarker that predicts the clinical treatment response to SRI-based pharmacotherapy in OCD. PMID- 26116796 TI - Symptom Generation by Mucosal Inflammation in Irritable Bowel Syndrome. PMID- 26116797 TI - Amitriptyline for Functional Dyspepsia: Importance of Symptom Profile and Making a Case for Gastric Emptying Testing. PMID- 26116799 TI - New Molecular Tools to Investigate the Development and Functions of Interstitial Cells of Cajal in the GI Tract. PMID- 26116800 TI - The Hierarchical Model of NAFLD: Prognostic Significance of Histologic Features in NASH. PMID- 26116798 TI - Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. AB - BACKGROUND & AIMS: Patients with bi-allelic germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrome called constitutional MMR deficiency (CMMRD). This syndrome is characterized by early-onset colorectal cancers, lymphomas or leukemias, and brain tumors. There is no satisfactory method for diagnosis of CMMRD because screens for mutations in MMR genes are noninformative for 30% of patients. MMR deficient cancer cells are resistant to genotoxic agents and have microsatellite instability (MSI), due to accumulation of errors in repetitive DNA sequences. We investigated whether these features could be used to identify patients with CMMRD. METHODS: We examined MSI by PCR analysis and tolerance to methylating or thiopurine agents (functional characteristics of MMR-deficient tumor cells) in lymphoblastoid cells (LCs) from 3 patients with CMMRD and 5 individuals with MMR proficient LCs (controls). Using these assays, we defined experimental parameters that allowed discrimination of a series of 14 patients with CMMRD from 52 controls (training set). We then used the same parameters to assess 23 patients with clinical but not genetic features of CMMRD. RESULTS: In the training set, we identified parameters, based on MSI and LC tolerance to methylation, that detected patients with CMMRD vs controls with 100% sensitivity and 100% specificity. Among 23 patients suspected of having CMMRD, 6 had MSI and LC tolerance to methylation (CMMRD highly probable), 15 had neither MSI nor LC tolerance to methylation (unlikely to have CMMRD), and 2 were considered doubtful for CMMRD based on having only 1 of the 2 features. CONCLUSION: The presence of MSI and tolerance to methylation in LCs identified patients with CMMRD with 100% sensitivity and specificity. These features could be used in diagnosis of patients. PMID- 26116801 TI - Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn's Disease. AB - BACKGROUND & AIMS: Patients with perianal fistulizing Crohn's disease have a poor prognosis because these lesions do not heal well. We evaluated the effects of local administration of bone marrow-derived mesenchymal stromal cells (MSCs) to these patients from healthy donors in a double-blind, placebo-controlled study. METHODS: Twenty-one patients with refractory perianal fistulizing Crohn's disease were randomly assigned to groups given injections of 1 * 10(7) (n = 5, group 1), 3 * 10(7) (n = 5, group 2), or 9 * 10(7) (n = 5, group 3) MSCs, or placebo (solution with no cells, n = 6), into the wall of curettaged fistula, around the trimmed and closed internal opening. The primary outcome, fistula healing, was determined by physical examination 6, 12, and 24 weeks later; healing was defined as absence of discharge and <2 cm of fluid collection-the latter determined by magnetic resonance imaging at week 12. All procedures were performed at Leiden University Medical Center, The Netherlands, from June 2012 through July 2014. RESULTS: No adverse events were associated with local injection of any dose of MSCs. Healing at week 6 was observed in 3 patients in group 1 (60.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 1 patient in the placebo group (16.7%) (P = .08 for group 2 vs placebo). At week 12, healing was observed in 2 patients in group 1 (40.0%), 4 patients in group 2 (80.0%), and 1 patient in group 3 (20.0%), vs 2 patients in the placebo group (33.3%); these effects were maintained until week 24 and even increased to 4 (80.0%) in group 1. At week six, 4 of 9 individual fistulas had healed in group 1 (44.4%), 6 of 7 had healed in group 2 (85.7%), and 2 of 7 had healed in group 3 (28.6%) vs 2 of 9 (22.2%) in the placebo group (P = .04 for group 2 vs placebo). At week twelve, 3 of 9 individual fistulas had healed in group 1 (33.3%), 6 of 7 had healed in group 2 (85.7%), 2 of 7 had healed in group 3 (28.6%), and 3 of 9 had healed in the placebo group (33.3%). These effects were stable through week 24 and even increased to 6 of 9 (66.7%) in group 1 (P = .06 group 2 vs placebo, weeks 12 and 24). CONCLUSIONS: Local administration of allogeneic MSCs was not associated with severe adverse events in patients with perianal fistulizing Crohn's disease. Injection of 3 * 10(7) MSCs appeared to promote healing of perianal fistulas. ClinicalTrials.gov ID NCT01144962. PMID- 26116802 TI - Helping Authors Organize Their Research: ORCID in the AGA Journals. PMID- 26116803 TI - Weight Loss for a Healthy Liver. PMID- 26116804 TI - Adenoma Detection Race at Colonoscopy: The Good and the Bad. PMID- 26116805 TI - MELDing the Lille Score to More Accurately Predict Mortality in Alcoholic Hepatitis. PMID- 26116807 TI - Practical Teaching Cases: A New Section for Trainees and Young GIs. PMID- 26116806 TI - Effects of the Learning Curve on Efficacy of Radiofrequency Ablation for Barrett's Esophagus. AB - BACKGROUND & AIMS: Complete eradication of Barrett's esophagus (BE) often requires multiple sessions of radiofrequency ablation (RFA). Little is known about the effects of case volume on the safety and efficacy of RFA or about the presence or contour of learning curves for this procedure. METHODS: We collected data from the US RFA Patient Registry (from 148 institutions) for patients who underwent RFA for BE from July 2007 to July 2011. We analyzed the effects of the number of patients treated by individual endoscopists and individual centers on safety and efficacy outcomes of RFA. Outcomes, including stricture, bleeding, hospitalization, and complete eradication of intestinal metaplasia (CEIM), were assessed using logistic regression. The effects of center and investigator experience on numbers of treatment sessions to achieve CEIM were examined using linear regression. RESULTS: After we controlled for potential confounders, we found that as the experience of endoscopists and centers increased with cases, the numbers of treatment sessions required to achieve CEIM decreased. This relationship persisted after adjusting for patient age, sex, race, length of BE, and presence of pretreatment dysplasia (P < .01). Center experience was not significantly associated with overall rates of CEIM or complete eradication of dysplasia. We did not observe any learning curve with regard to risks of stricture, gastrointestinal bleeding, perforation, or hospitalization (P > .05). CONCLUSIONS: Based on analysis of a large multicenter registry, efficiency of the treatment, as measured by number of sessions needed to achieve CEIM, increased with case volume, indicating a learning curve effect. This trend began to disappear after treatment of approximately 30 patients by the center or individual endoscopist. However, there was no significant association between safety or efficacy outcomes and previous case volume. PMID- 26116808 TI - Modeling ephemeral mating encounters in insects: The emergence of mate-finding Allee effects and applications to theoretical models of sterile release. AB - Lack of successful mating encounters in two-sex insect populations is a mechanism that might trigger reproductive Allee effects. In this paper I examine a function that models ephemeral mating encounters through the expected density of pairs formed by individuals of both sexes at any time. When this function is incorporated in a general system of differential equations for a two-sex population the solutions exhibit the emergence of an Allee effect for low population densities. Compared with current conceptual models for mate-finding Allee effects, the proposed pairing function does not include a parameter that quantifies the Allee effect strength, a feature that might be useful when information to parameterize Allee effects is unavailable. The mating function is then used to numerically explore how mate-finding Allee effects are enhanced by the release of sterile males in theoretical models where (i) the initial sex ratio is skewed, (ii) sterile males are released in pulses and (iii) partial female remating is allowed. PMID- 26116809 TI - Clinical management of negative symptoms of schizophrenia: An update. AB - Overwhelming research evidence suggests that the negative symptoms of schizophrenia (NSS) contribute more to impaired quality of life and poor functioning than positive symptoms, and that NSS, including affective flattening, alogia and avolition are present in at least one-fifth of patients diagnosed with schizophrenia. Despite this, management of NSS continues to be a major clinical unmet need as treatment with current antipsychotic medication seems to reach at best modest efficacy. A critical review of the current pharmacological, non pharmacological and psychosocial treatments available for NSS is presented here, using data retrieved from the MEDLINE/PUBMED, the Cochrane Database of Systematic Reviews and the ClinicalTrials.gov databases. An early and accurate diagnosis using selective scales is essential for documentation and monitoring of change in NSS according to treatment response. Typical and atypical antipsychotic drugs, showed modest efficacy in managing NSS. Conflicting results were obtained with the use of glycinergic neuromodulators, anticholinergics, antidepressants, anticonvulsants, psychostimulants, modafinil and 5-HT3 receptor antagonists. Moreover, non-pharmacological therapies including psychological therapies have failed to address NSS effectively. At present, it appears that the best effective approach for clinical management of NSS is achieved by complementing drug therapy with psychosocial therapies. Continuing basic and clinical research for the understanding of the genetic, behavioral and neural basis of NSS should yield novel pharmacotherapies with superior efficacy, tolerability and long-term maintenance for improved treatment of NSS. PMID- 26116810 TI - Inflammation, oxidative stress and postoperative atrial fibrillation in cardiac surgery. AB - Postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery that occurs in up to 60% of patients. POAF is associated with increased risk of cardiovascular mortality, stroke and other arrhythmias that can impact on early and long term clinical outcomes and health economics. Many factors such as disease-induced cardiac remodelling, operative trauma, changes in atrial pressure and chemical stimulation and reflex sympathetic/parasympathetic activation have been implicated in the development of POAF. There is mounting evidence to support a major role for inflammation and oxidative stress in the pathogenesis of POAF. Both are consequences of using cardiopulmonary bypass and reperfusion following ischaemic cardioplegic arrest. Subsequently, several anti-inflammatory and antioxidant drugs have been tested in an attempt to reduce the incidence of POAF. However, prevention remains suboptimal and thus far none of the tested drugs has provided sufficient efficacy to be widely introduced in clinical practice. A better understanding of the cellular and molecular mechanisms responsible for the onset and persistence of POAF is needed to develop more effective prediction and interventions. PMID- 26116811 TI - Abnormal intrinsic brain activity patterns in leukoaraiosis with and without cognitive impairment. AB - The amplitude of low frequency fluctuations (ALFF) from resting-state functional MRI (rs-fMRI) signals can be used to detect intrinsic spontaneous brain activity and provide valuable insights into the pathomechanism of neural disease. In this study, we recruited 56 patients who had been diagnosed as having mild to severe leukoaraiosis. According to the neuropsychological tests, they were subdivided into a leukoaraiosis with cognitive impairment group (n = 28) and a leukoaraiosis without cognitive impairment group (n = 28). 28 volunteers were included as normal controls. We found that the three groups showed significant differences in ALFF in the brain regions of the right inferior occipital gyrus (IOG_R), left middle temporal gyrus (MTG_L), left precuneus (Pcu_L), right superior frontal gyrus (SFG_R) and right superior occipital gyrus (SOG_R). Compared with normal controls, the leukoaraiosis without cognitive impairment group exhibited significantly increased ALFF in the IOG_R, Pcu_L, SFG_R and SOG_R. While compared with leukoaraiosis without cognitive impairment group, the leukoaraiosis with cognitive impairment group showed significantly decreased ALFF in IOG_R, MTG_L, Pcu_L and SOG_R. A close negative correlation was found between the ALFF values of the MTG_L and the Montreal Cognitive Assessment (MoCA) scores. Our data demonstrate that white matter integrity and cognitive impairment are associated with different amplitude fluctuations of rs-fMRI signals. Leukoaraiosis is related to ALFF increases in IOG_R, Pcu_L, SFG_Orb_R and SOG_R. Decreased ALFF in MTG_L is characteristic of cognitive impairment and may aid in its early detection. PMID- 26116812 TI - The mediating role of LPFC-vmPFC functional connectivity in the relation between regulatory mode and delay discounting. AB - Previous studies have shown that regulatory mode orientation can affect many human behaviors, such as risk-taking, counterfactual thinking and economic decision making. However, little is known about how regulatory mode affects delay discounting. To address this question, we used resting-state functional magnetic resonance imaging (rs-fMRI) to investigate whether regulatory mode orientations can be represented by functional connectivity and the influence of two regulatory modes (assessment and locomotion) on delay discounting. The behavioral results showed that delay discounting was negatively correlated with assessment scores but positively correlated with locomotion scores. Neuroimaging results indicated that the functional connectivity between lateral prefrontal cortex (LPFC) and ventromedial prefrontal cortex (vmPFC) was negatively correlated with assessment scores but positively correlated with locomotion scores. Furthermore, mediation analysis showed that the effect of regulatory mode on delay discounting is mediated by LPFC-vmPFC functional connectivity. These results suggested that people's regulatory mode orientation could predict delay discounting, which is mediated by LPFC-vmPFC functional connectivity. Therefore, the present study extends our perspective on regulatory mode and provides neural mechanism for understanding the link between regulatory mode and delay discounting. PMID- 26116813 TI - Genome sequence of Bacillus anthracis attenuated vaccine strain A16R used for human in China. AB - An attenuated Bacillus anthracis vaccine strain for human use, A16R, was obtained in China after ultraviolet radiation treatment and continuous subculture of the wild-type strain A16. A16R can synthesize the exotoxin, but without a capsule. We sequenced and annotated the A16R genome to encourage the use of this strain. The genome sequencing of the wild-type strain A16 is underway and the genomic comparison between the two strains will help to illustrate the attenuating mechanism of the A16R vaccine strain. PMID- 26116814 TI - Melatonin or ramelteon therapy differentially affects hepatic gene expression profiles after haemorrhagic shock in rat--A microarray analysis. AB - BACKGROUND & AIMS: Melatonin has been demonstrated to reduce liver damage in different models of stress. However, there is only limited information on the impact of this hormone on hepatic gene expression. The aim of this study was, to investigate the influence of melatonin or the melatonergic agonist ramelteon on hepatic gene expression profiles after haemorrhagic shock using a whole genome microarray analysis. METHODS: Male Sprague-Dawley rats (200-300 g, n=4/group) underwent haemorrhagic shock (mean arterial pressure 35+/-5 mmHg). After 90 min of shock, animals were resuscitated with shed blood and Ringer's and treated with vehicle (5% dimethyl sulfoxide), melatonin or ramelteon (each 1.0 mg/kg intravenously). Sham-operated animals were treated likewise but did not undergo haemorrhage. After 2 h of reperfusion, the liver was harvested, and a whole genome microarray analysis was performed. Functional gene expression profiles were determined using the Panther(r) classification system; promising candidate genes were evaluated by quantitative polymerase chain reaction (PCR). RESULTS: Microarray and PCR data showed a good correlation (r(2)=0.84). A strong influence of melatonin on receptor mediated signal transduction was revealed using the functional gene expression profile analysis, whereas ramelteon mainly influenced transcription factors. Shock-induced upregulation of three candidate genes with relevant functions for hepatocytes (ppp1r15a, dusp5, rhoB) was significantly reduced by melatonin (p<0.05 vs. shock/vehicle), but not by ramelteon. Two genes previously known as haemorrhage-induced (il1b, s100a8) were transcriptionally repressed by both drugs. CONCLUSIONS: Melatonin and ramelteon appear to induce specific hepatic gene expression profiles after haemorrhagic shock in rats. The observed differences between both substances are likely to be attributable to a distinct mechanism of action in these agents. PMID- 26116815 TI - An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling. AB - Many neurodegenerative diseases present the loss of synapses as a common pathological feature. Here we have employed an in vitro model for synaptic loss to investigate the molecular mechanism of a therapeutic treatment, valproic acid (VPA). We show that amyloid-beta (Abeta), isolated from patient tissue and thought to be the causative agent of Alzheimer's disease, caused the loss of synaptic proteins including synaptophysin, synapsin-1 and cysteine-string protein from cultured mouse neurons. Abeta-induced synapse damage was reduced by pre treatment with physiologically relevant concentrations of VPA (10 MUM) and a structural variant propylisopropylacetic acid (PIA). These drugs also reduced synaptic damage induced by other neurodegenerative-associated proteins alpha synuclein, linked to Lewy body dementia and Parkinson's disease, and the prion derived peptide PrP82-146. Consistent with these effects, synaptic vesicle recycling was also inhibited by these proteins and protected by VPA and PIA. We show a mechanism for this damage through aberrant activation of cytoplasmic phospholipase A2 (cPLA2) that is reduced by both drugs. Furthermore, Abeta dependent cPLA2 activation correlates with its accumulation in lipid rafts, and is likely to be caused by elevated cholesterol (stabilising rafts) and decreased cholesterol ester levels, and this mechanism is reduced by VPA and PIA. Such observations suggest that VPA and PIA may provide protection against synaptic damage that occurs during Alzheimer's and Parkinson's and prion diseases. PMID- 26116817 TI - Interferon-beta1a modulates glutamate neurotransmission in the CNS through CaMKII and GluN2A-containing NMDA receptors. AB - Interferons (IFNs) are widely expressed cytokines with antiviral and immune modulating effects and have been utilised for the treatment of several human pathological conditions. In particular, the immune-modulatory drug IFN-beta is utilized in the treatment of multiple sclerosis (MS), a chronic autoimmune and neurodegenerative disorder of the central nervous system (CNS). Although the effects of IFN-beta on immune cells functions have been widely investigated, information about the ability of the drug to modulate neuronal transmission in the CNS is still largely lacking. The aim of this study was to investigate the ability of IFN-beta1a to modulate excitatory synaptic transmission in the CNS. Whole cell patch-clamp electrophysiological recordings were performed in the nucleus striatum, one of the CNS grey matter structures that is prone to degenerate during the course of MS. We demonstrate that the drug IFN-beta1a, independently from its known peripheral immune-modulating action, is able to directly modulate synaptic transmission. In particular, we demonstrated that IFN beta1a reduces the amplitude of striatal excitatory post-synaptic currents, indicating an inhibitory effect on glutamate neurotransmission, and in particular on its NMDA component. The inhibitory effect of IFN-beta1a on striatal glutamate neurotransmission was found to be mediated by a novel post-synaptic mechanism requiring Ca(2+), CaMKII and the GluN2A subunit of the NMDA receptor, without the involvement of the classic STAT1 pathway. The evidence of a novel neuro modulating effect of IFN-beta shed light on the mechanisms of action of the drug and on the complex bidirectional interaction occurring between the immune and the nervous system. This article is part of the Special Issue entitled 'Synaptopathy- from Biology to Therapy'. PMID- 26116816 TI - Long term sertraline effects on neural structures in depressed and nondepressed adult female nonhuman primates. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for mood and other disorders. However, their neural effects are difficult to study due to patient compliance and drug history variability, and rarely studied in those prescribed SSRIs for non-mood disorders. Here we evaluated SSRI effects on neural volumetrics in depressed and nondepressed monkeys. METHODS: 42 socially housed cynomolgus monkeys were randomized to treatment balanced on pretreatment depressive behavior and body weight. Monkeys were trained for oral administration of placebo or 20 mg/kg sertraline HCl daily for 18 months and depressive and anxious behavior recorded. Volumes of neural regions of interest in depression were measured in magnetic resonance images and analyzed by 2 (depressed, nondepressed)*2 (placebo, sertraline) ANOVA. RESULTS: Sertraline reduced anxiety (p=0.04) but not depressive behavior (p=0.43). Left Brodmann's Area (BA) 32 was smaller in depressed than nondepressed monkeys (main effect of depression: p<0.05). Sertraline and depression status interacted to affect volumes of left Anterior Cingulate Cortex (ACC), left BA24, right hippocampus (HC), and right anterior HC (sertraline*depression interactions: all p's<0.05). In the Placebo group, depressed monkeys had smaller right anterior HC and left ACC than nondepressed monkeys. In nondepressed monkeys, sertraline reduced right HC volume, especially right anterior HC volume. In depressed monkeys sertraline increased left ACC volume. In nondepressed monkeys, sertraline reduced left BA24 volumes resulting in smaller BA24 volumes in nondepressed than sertraline-treated depressed monkeys. CONCLUSIONS: These observations suggest that SSRIs may differentially affect neural structures in depressed and nondepressed individuals. PMID- 26116818 TI - Cigarette smoke exposure during adolescence enhances sensitivity to the rewarding effects of nicotine in adulthood, even after a long period of abstinence. AB - Adolescence is a period of enhanced vulnerability to the motivational properties of tobacco/cigarette smoking. Several studies have suggested that smoking initiation during this period will more likely lead to long-lasting cigarette or nicotine addiction. In the present study, we investigated the influences of adolescent cigarette smoke or nicotine exposure on the rewarding effects of nicotine, particularly whether these influences persist even after a long period of abstinence. Towards this, adolescent and adult Sprague-Dawley rats were repeatedly exposed to cigarette smoke or nicotine, for 14 days, and then were subjected to a 1-month abstinence period. Thereafter, the rewarding effects of nicotine were evaluated through the conditioned place preference (CPP) and self administration (SA) tests. Even after a 1-month abstinence period, rats pre exposed to either nicotine or cigarette smoke demonstrated enhanced CPP for the higher dose (0.6 mg/kg) of nicotine. Notably, cigarette smoke-preexposed adolescent rats, now adults, showed CPP for both 0.2 and 0.6 mg/kg dose of nicotine. Moreover, only these rats (pre-exposed to cigarette smoke during adolescence) showed significant acquisition and maintenance of nicotine (0.03 mg/kg/infusion) SA. These results suggest that cigarette smoke exposure during adolescence enhances sensitivity to the rewarding effects of nicotine in adulthood, even after a long period of abstinence. This may be a factor in the high rates of nicotine addiction and dependence observed in smokers who started during adolescence. More importantly, our findings highlight the enduring consequences of adolescent-onset cigarette smoking and the need to protect this vulnerable population. PMID- 26116819 TI - H2A histone-fold and DNA elements in nucleosome activate SWR1-mediated H2A.Z replacement in budding yeast. AB - The histone variant H2A.Z is a universal mark of gene promoters, enhancers, and regulatory elements in eukaryotic chromatin. The chromatin remodeler SWR1 mediates site-specific incorporation of H2A.Z by a multi-step histone replacement reaction, evicting histone H2A-H2B from the canonical nucleosome and depositing the H2A.Z-H2B dimer. Binding of both substrates, the canonical nucleosome and the H2A.Z-H2B dimer, is essential for activation of SWR1. We found that SWR1 primarily recognizes key residues within the alpha2 helix in the histone-fold of nucleosomal histone H2A, a region not previously known to influence remodeler activity. Moreover, SWR1 interacts preferentially with nucleosomal DNA at superhelix location 2 on the nucleosome face distal to its linker-binding site. Our findings provide new molecular insights on recognition of the canonical nucleosome by a chromatin remodeler and have implications for ATP-driven mechanisms of histone eviction and deposition. PMID- 26116820 TI - Cortico-muscular coherence parallels coherence of postural tremor and MEG during static muscle contraction. AB - Corticokinematic coherence (CKC), i.e., coherence calculated between MEG and an accelerometer signal, recording movement kinematics, can be used for functional mapping of the sensorimotor cortex. Cortical sources of CKC, induced by both voluntary and passive movements, localize at the proximity of sensorimotor cortex. We tested the CKC during a static muscle contraction to compare it with simultaneously measured cortico-muscular coherence (CMC) estimated between MEG and surface EMG to study the role of postural tremor in CMC in ten healthy volunteers. CKC was detectable also during this static task. CKC and CMC spectra had similar power distributions, and sources of CMC and CKC colocalized at the cortex in close proximity of the central sulcus. During the static hold task, the accelerometer signal originates from the postural tremor. The similarities between CMC and CKC indicate that postural tremor is related to CMC in healthy subjects. PMID- 26116821 TI - Hypothalamic dopaminergic neurons in an animal model of seasonal affective disorder. AB - Light has profound effects on mood regulation as exemplified in seasonal affective disorder (SAD) and the therapeutic benefits of light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD. Following housing conditions of either 12:12 h dim light:dark (DLD) or 8:16 h short photoperiod (SP), which mimic the lower light intensity or short day-length of winter, respectively, grass rats exhibit an increase in depression-like behavior compared to those housed in a 12:12 h bright light:dark (BLD) condition. Furthermore, we have shown that the orexinergic system is involved in mediating the effects of light on mood and anxiety. To explore other potential neural substrates involved in the depressive phenotype, the present study examined hypothalamic dopaminergic (DA) and somatostatin (SST) neurons in the brains of grass rats housed in DLD, SP and BLD. Using immunostaining for tyrosine hydroxylase (TH) and SST, we found that the number of TH- and SST-ir cells in the hypothalamus was significantly lower in the DLD and SP groups compared to the BLD group. We also found that treating BLD animals with a selective orexin receptor 1 (OX1R) antagonist SB-334867 significantly reduced the number of hypothalamic TH-ir cells. The present study suggests that the hypothalamic DA neurons are sensitive to daytime light deficiency and are regulated by an orexinergic pathway. The results support the hypothesis that the orexinergic pathways mediate the effects of light on other neuronal systems that collectively contribute to light-dependent changes in the affective state. PMID- 26116822 TI - Tumour modelling using viral vectors. PMID- 26116823 TI - Long tails, short telomeres: Dyskeratosis congenita. PMID- 26116824 TI - Erratum: Clinical and biological significance of de novo CD5+ diffuse large B cell lymphoma in Western countries. PMID- 26116826 TI - Combination of DPP-4 inhibitor and PPARgamma agonist exerts protective effects on pancreatic beta-cells in diabetic db/db mice through the augmentation of IRS-2 expression. AB - We investigated the effects of long- and short-term treatment with pioglitazone (Pio) and/or alogliptin (Alo) on beta-cells in diabetic db/db mice. Six-week-old male db/db mice received Pio (25 mg/kg, oral) and/or Alo (30 mg/kg, oral) for 4 weeks and for 2 days. Blood glucose levels were decreased after 4-week intervention, but not after 2-day intervention. Pio increased adiponectin levels, and Alo decreased glucagon levels and increased active GlP-1 levels. Insulin sensitivity was restored by Pio. After 4-week treatment, beta-cell mass was increased (over 2-fold increase) and expression levels of various beta-cell related factors were restored. Expression levels of IRS-2 and various downstream factors were up-regulated by Pio and Alo after 2-day and 4-week intervention. In addition, mRNA and protein levels of IRS-2 and various downstream factors were up regulated in MIN6 cells after 24-h exposure to Pio and exendin-4. These results suggest that Pio and Alo additively up-regulate IRS-2 expression independently of the alteration of glycemic control. Taken together, combination of Pio and Alo exerts protective effects on beta-cells in diabetic db/db mice, at least in part, through the augmentation of IRS-2 expression. PMID- 26116827 TI - Melatonin replacement restores the circadian behavior in adult rat Leydig cells after pinealectomy. AB - Melatonin actions on oscillators in reproductive organs are poorly understood. Here we analyzed melatonin effects on rhythmic expression of clock and steroidogenesis-related genes in adult rat Leydig cells (LCs). The effect of melatonin was tested both in vivo using pinealectomized and melatonin-substituted rats and in vitro on isolated LCs. Data revealed 24-h-rhythmic expression of clock genes (Bmal1, Per1,2,3, Rev-erba,b, Rorb), steroidogenic genes (Star, Cyp11a1, Cyp17a1), and genes of steroidogenic regulators (positive-Nur77, negative-Arr19). Pinealectomy increased 24-h-oscillations of serum testosterone and LC's cAMP levels, expression of Insl3, Per1, Star/StAR, Hsd3b1/2, Nur77, decreased Arr19 and canceled Per2 oscillatory expression pattern. At hypothalamic pituitary level, pinealectomy increased mesor of Gnrh, Lhb and rhythm robustness of Mntr1a expression. All parameters disturbed were restored by melatonin replacement. In vitro studies did not confirm direct melatonin effects on neither clock nor steroidogenic genes. Accordingly, melatonin influence 24-h-rhythmic LC function likely through hypothalamic-pituitary axis and consequently cAMP signaling in LCs. PMID- 26116825 TI - The ubiquitin ligase MuRF1 regulates PPARalpha activity in the heart by enhancing nuclear export via monoubiquitination. AB - The transcriptional regulation of peroxisome proliferator-activated receptor (PPAR) alpha by post-translational modification, such as ubiquitin, has not been described. We report here for the first time an ubiquitin ligase (muscle ring finger-1/MuRF1) that inhibits fatty acid oxidation by inhibiting PPARalpha, but not PPARbeta/delta or PPARgamma in cardiomyocytes in vitro. Similarly, MuRF1 Tg+ hearts showed significant decreases in nuclear PPARalpha activity and acyl carnitine intermediates, while MuRF1-/- hearts exhibited increased PPARalpha activity and acyl-carnitine intermediates. MuRF1 directly interacts with PPARalpha, mono-ubiquitinates it, and targets it for nuclear export to inhibit fatty acid oxidation in a proteasome independent manner. We then identified a previously undescribed nuclear export sequence in PPARalpha, along with three specific lysines (292, 310, 388) required for MuRF1's targeting of nuclear export. These studies identify the role of ubiquitination in regulating cardiac PPARalpha, including the ubiquitin ligase that may be responsible for this critical regulation of cardiac metabolism in heart failure. PMID- 26116828 TI - Physical exercise training for cystic fibrosis. AB - BACKGROUND: Physical exercise training may form an important part of regular care for people with cystic fibrosis. This is an update of previously published reviews. OBJECTIVES: To determine the effects of physical exercise training compared to no training on aerobic exercise capacity, forced expiratory volume in one second, health-related quality of life and other patient-relevant (secondary) outcomes in cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 10 March 2015. SELECTION CRITERIA: All randomised and quasi randomised controlled clinical trials comparing exercise training of any type and duration with conventional care in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion, assessed methodological quality and extracted data. MAIN RESULTS: Of the 48 studies identified, 13 studies which included 402 participants, met the inclusion criteria. The numbers in each study ranged from nine up to 72 participants; one study was in adults, six were in children and adolescents and six studies included all age ranges. Four studies of hospitalised participants lasted less than one month and nine studies were outpatient-based, lasting between two months and three years. The studies included participants with a wide range of disease severity and employed differing levels of supervision with a mixture of types of training. There was also wide variation in the quality of the included studies.This systematic review shows limited evidence from both short- and long term studies that in people with cystic fibrosis aerobic or anaerobic physical exercise training or a combination of both has a positive effect on aerobic exercise capacity, pulmonary function and health-related quality of life. Although improvements are not consistent between studies and ranged from no effects to clearly positive effects, the most consistent effects of the heterogeneous exercise training modalities and durations were found for maximal aerobic exercise capacity (in four out of six studies) with unclear effects on FEV1 (in two out of 10 studies) and health-related quality of life (in two out of five studies). AUTHORS' CONCLUSIONS: Evidence about the efficacy of physical exercise training in cystic fibrosis from 13 small studies with low to moderate methodological quality is limited. Exercise training is already part of regular outpatient care offered to most people with cystic fibrosis, and since there is some evidence for beneficial effects on aerobic fitness and no negative side effects exist, there is no reason to actively discourage this. The benefits from including physical exercise training in an individual's regular care may be influenced by the type and duration of the training programme. High quality randomised controlled trials are needed to comprehensively assess the benefits of exercise programmes in people with cystic fibrosis and the relative benefits of the addition of aerobic versus anaerobic versus a combination of both types of physical exercise training to the care of people with cystic fibrosis. PMID- 26116829 TI - Mothers 'don't like it; never tried it': Blind Sensory Test of a Homemade Chicken Liver Baby Food, a Source of Iron, by Infants and their Mothers. AB - A homemade chicken liver baby food (CLBF) that meets infants' nutritional requirements was developed and its acceptance by children and their mothers determined. CLBF's nutritional content was determined by chemical analyses. A blind sensory test (ST) by 50 infants 7-12 months old and their mothers of CLBF and ground beef baby food (GBBF) was applied. Mothers' preferences for liver and beef, answers of an hedonic scale and infants' acceptance were investigated. CLBF met the nutritional requirements for infants. There were no significant differences in the ST between the CLBF and GBBF, either for infants or for their mothers. There was no correlation between mothers' like or dislike of liver and the ST scores. Infants tried and liked the CLBF that match dietary recommendations and could help prevent iron deficiency. Mothers, on the other hand, demonstrated an 'I don't like it; I never tried it' attitude. PMID- 26116831 TI - Untangling the complexity of blood coagulation network: use of computational modelling in pharmacology and diagnostics. AB - Blood coagulation is a complex biochemical network that plays critical roles in haemostasis (a physiological process that stops bleeding on injury) and thrombosis (pathological vessel occlusion). Both up- and down-regulation of coagulation remain a major challenge for modern medicine, with the ultimate goal to correct haemostasis without causing thrombosis and vice versa. Mathematical/computational modelling is potentially an important tool for understanding blood coagulation disorders and their treatment. It can save a huge amount of time and resources, and provide a valuable alternative or supplement when clinical studies are limited, or not ethical, or technically impossible. This article reviews contemporary state of the art in the modelling of blood coagulation for practical purposes: to reveal the molecular basis of a disease, to understand mechanisms of drug action, to predict pharmacodynamics and drug drug interactions, to suggest potential drug targets or to improve quality of diagnostics. Different model types and designs used for this are discussed. Functional mechanisms of procoagulant bypassing agents and investigations of coagulation inhibitors were the two particularly popular applications of computational modelling that gave non-trivial results. Yet, like any other tool, modelling has its limitations, mainly determined by insufficient knowledge of the system, uncertainty and unreliability of complex models. We show how to some extent this can be overcome and discuss what can be expected from the mathematical modelling of coagulation in not-so-far future. PMID- 26116830 TI - Longer right to left ventricular activation delay at cardiac resynchronization therapy implantation is associated with improved clinical outcome in left bundle branch block patients. AB - AIMS: Data on longer right to left ventricular activation delay (RV-LV AD) predicting clinical outcome after cardiac resynchronization therapy (CRT) by left bundle branch block (LBBB) are limited. We aimed to evaluate the impact of RV-LV AD on N-terminal pro-B-type natriuretic peptide (NT-proBNP), ejection fraction (EF), and clinical outcome in patients implanted with CRT, stratified by LBBB at baseline. METHODS AND RESULTS: Heart failure (HF) patients undergoing CRT implantation with EF <= 35% and QRS >= 120 ms were evaluated based on their RV-LV AD at implantation. Baseline and 6-month clinical parameters, EF, and NT-proBNP values were assessed. The primary endpoint was HF or death, the secondary endpoint was all-cause mortality. A total of 125 patients with CRT were studied, 62% had LBBB. During the median follow-up of 2.2 years, 44 (35%) patients had HF/death, 36 (29%) patients died. Patients with RV-LV AD >= 86 ms (lower quartile) had significantly lower risk of HF/death [hazard ratio (HR): 0.44; 95% confidence interval (95% CI): 0.23-0.82; P = 0.001] and all-cause mortality (HR: 0.48; 95% CI: 0.23-1.00; P = 0.05), compared with those with RV-LV AD < 86 ms. Patients with RV-LV AD >= 86 ms and LBBB showed the greatest improvement in EF (28-36%; P<0.001), NT-proBNP (2771-1216 ng/mL; P < 0.001), and they had better HF free survival (HR: 0.23, 95% CI: 0.11-0.49, P < 0.001) and overall survival (HR: 0.35, 95% CI: 0.16-0.75; P = 0.007). There was no difference in outcome by RV-LV AD in non-LBBB patients. CONCLUSION: Left bundle branch block patients with longer RV-LV activation delay at CRT implantation had greater improvement in NT proBNP, EF, and significantly better clinical outcome. PMID- 26116832 TI - Quantification of nardosinone in rat plasma using liquid chromatography-tandem mass spectrometry and its pharmacokinetics application. AB - A rapid, sensitive and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was established and validated to assay the concentration of nardosinone, a main active compound isolated from Nardostachys chinensis, in rat plasma. Plasma samples were processed by protein precipitation with acetonitrile and separated on a Venusil MP-C18 column (50 * 2.1 mm, 5 um) at an isocratic flow rate of 0.6 mL/min using methanol-0.1% formic acid in water (55 : 45, v/v) as mobile phase, and total run time was 2.5 min. MS-MS detection was accomplished in selected reaction monitoring mode with positive electrospray ionization. The calibration curve was linear over the concentration range of 9.60 320 ng/mL with lower limit of quantification of 9.60 ng/mL. The intra- and inter day precisions were below 12.3% in terms of relative standard deviation, and the accuracy was within +/-9.0% in terms of relative error. Extraction recovery, matrix effect and stability were also satisfactory in rat plasma. The developed method was successfully applied to a pharmacokinetic study of nardosinone following an intravenous injection at a dose of 1.04 mg/kg to Sprague-Dawley rats. PMID- 26116833 TI - Simultaneous determination of alkaloids and their related tobacco-specific nitrosamines in tobacco leaves using LC-MS-MS. AB - Tobacco alkaloids (e.g., nicotine) and their metabolized tobacco-specific nitrosamines (TSNAs) are very important compounds for tobacco quality and safety. A simple and specific liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of eight tobacco alkaloids and their related four TSNAs in tobacco leaves. The milled tobacco was extracted using 0.1 mol/L ammonium acetate solution and purified using methanol. Mass spectrometry parameters including declustering potential and collision energy were optimized to ensure that both the TSNAs and the tobacco alkaloids have suitable responses. Recoveries for accuracy were in the range of 80.2-105.2%. Intra-day and inter-day repeatability were in the range of 1.7-12.1% and 6.4-18.7%, respectively. Limit of detection and limit of quantitation were estimated in the range of 6 ng/g-45 MUg/g and 24 ng/g-90 MUg/g, respectively. The established method was applied to investigate the distribution of tobacco alkaloids and TSNAs in four kinds of tobacco. The result showed that the burley and the flue-cured have the highest (0.00047%) and the lowest (0.000024%) percentage of transformation from alkaloids to TSNAs, respectively. Thus, this method can be used for a wide range of samples. PMID- 26116834 TI - Curcumin inhibits in vitro and in vivo chronic myelogenous leukemia cells growth: a possible role for exosomal disposal of miR-21. AB - Exosomes are nanosize vesicles released from cancer cells containing microRNAs that can influence gene expression in target cells. Curcumin has been shown to exhibit antitumor activities in a wide spectrum of human cancer. The addition of Curcumin, to Chronic Myelogenous Leukemia (CML) cells, caused a dose-dependent increase of PTEN, target of miR-21. Curcumin treatment also decreased AKT phosphorylation and VEGF expression and release. Colony formation assays indicated that Curcumin affects the survival of CML cells. Some observation suggest a possible cellular disposal of miRNAs by exosomes. To elucidate if Curcumin caused a decrease of miR-21 in CML cells and its packaging in exosomes, we analyzed miR-21 content in K562 and LAMA84 cells and exosomes, after treatment with Curcumin. Furthermore, we showed that addition of Curcumin to CML cells caused a downregulation of Bcr-Abl expression through the cellular increase of miR-196b.The effects of Curcumin was then investigated on a CML xenograft in SCID mice. We observed that animals treated with Curcumin, developed smaller tumors compared to mice control. Real time PCR analysis showed that exosomes, released in the plasma of the Curcumin-treated mice, were enriched in miR-21 with respect control. Taken together, our results suggested that a selective packaging of miR 21 in exosomes may contribute to the antileukemic effect of Curcumin in CML. PMID- 26116835 TI - Yin-and-Yang of mTORC1/C2 in Angelman syndrome mice. PMID- 26116836 TI - A nutritional perspective on cellular rejuvenation. PMID- 26116837 TI - Digesting dietary miRNA therapeutics. PMID- 26116838 TI - Delta113p53/Delta133p53: survival and integrity. PMID- 26116839 TI - Plant and animal organelles in cell death. PMID- 26116840 TI - Relevance of level IIb neck dissection in oral squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to determine the prevalence of level IIb metastasis in patients with oral squamous cell carcinomas (OSCCs). MATERIAL AND METHODS: A prospective analysis of 56 patients with OSCC who underwent surgical treatment of the primary lesion with simultaneous neck dissection was performed. During neck dissection, level IIb lymph nodes were separately removed and processed. Neck dissection was bilateral in 26 patients (46%) and unilateral in 30 patients (54%). RESULTS: The mean number of nodes found in the level IIb specimens was 4.7 (range: 0-8 nodes). The prevalence of metastasis at level IIb was 0% in pN0 necks and 3.4% in pN+ necks, with an overall prevalence of 1.8%. A significant association between metastasis to level IIb and type of neck dissection was observed. There were no isolated metastases to level IIb without the involvement of other nodes in the remaining neck specimen. Four regional recurrences were observed during follow-up. CONCLUSIONS: Based on our findings, we suggest that dissection of the level IIb region in patients with OSCC may be required only in patients with multilevel neck metastasis or if level IIa metastasis is found intraoperatively. PMID- 26116841 TI - Pseudoepitheliomatous hyperplasia after diode laser oral surgery. An experimental study. AB - BACKGROUND: to examine the process of epithelial reparation in a surgical wound caused by diode laser. MATERIAL AND METHODS: An experimental study with 27 Sprage Dawley rats was undertaken. The animals were randomly allocated to two experimental groups, whose individuals underwent glossectomy by means of a diode laser at different wattages, and a control group treated using a number 15 scalpel blade. The animals were slaughtered at the 2nd, 7th, and 14th day after glossectomy. The specimens were independently studied by two pathologists (blinded for the specimens' group). RESULTS: at the 7th day, re-epithelisation was slightly faster for the control group (conventional scalpel) (p=0.011). At the 14th day, complete re-epithelization was observed for all groups. The experimental groups displayed a pseudoepitheliomatous hyperplasia. CONCLUSIONS: it is concluded that, considering the limitations of this kind of experimental studies, early re-epithelisation occurs slightly faster when a conventional scalpel is used for incision, although re-epithelisation is completed in two weeks no matter the instrument used. In addition, pseudoepitheliomatous hyperplasia is a potential event after oral mucosa surgery with diode laser. Knowledge about this phenomenon (not previously described) may prevent diagnostic mistakes and inadequate treatment approaches, particularly when dealing with potentially malignant oral lesions. PMID- 26116842 TI - Efficacy of different methods used for dry socket management: A systematic review. AB - BACKGROUND: Dry socket is one of the most common complications occurring after the extraction of a permanent tooth, but in spite of its high incidence there is not an established treatment for this condition. OBJECTIVES: Analyze the efficacy of different methods used in the management of dry socket regarding results of pain's relief and alveolar mucosa healing compared to conventional surgical treatment of curettage and saline irrigation. MATERIAL AND METHODS: A Cochrane and PubMed-MEDLINE database search was conducted with the search terms "dry socket", "post-extraction complications", "alvogyl", "alveolar osteitis" and "fibrynolitic alveolitis", individually and next, using the Boolean operator "AND". The inclusion criteria were: clinical studies including at least 10 patients, articles published from 2004 to 2014 written in English. The exclusion criteria were case reports and nonhuman studies. RESULTS: 11 publications were selected from a total of 627. Three of the 11 were excluded after reading the full text. The final review included 8 articles: 3 prospective studies, 2 retrospective studies and 3 clinical trials. They were stratified according to their level of scientific evidence using the SORT criteria (Strenght of Recommendation Taxonomy). CONCLUSIONS: All treatments included in the review have the aim to relief patient's pain and promote alveolar mucosa healing in dry socket. Given the heterogeneity of interventions and the type of measurement scale, the results are difficult to compare. Curettage and irrigation should be carried out in dry socket, as well as another therapy such as LLLT, zinc oxide eugenol or plasma rich in growth factors, which are the ones that show better results in pain remission and alveolar mucosa healing. Assessment alveolar bone esposure must be a factor to consider in future research. Taking into account the scientific quality of the articles evaluated, a level B recommendation is given for therapeutic interventions proposed for the treatment of dry socket. PMID- 26116843 TI - Influence of two different surgical techniques on the difficulty of impacted lower third molar extraction and their post-operative complications. AB - BACKGROUND: Post-operative complications of various degrees of severity are commonly observed in third molar impaction surgery. For this reason, a surgical procedure that decreases the trauma of bone and soft tissues should be a priority for surgeons. In the present study, we compare the efficacy and the post operative complications of patients to whom two different surgical techniques were applied for impacted lower third molar extraction. MATERIAL AND METHODS: Patients of the first group underwent the classical bur technique, while patients of the second group underwent another technique, in which an elevator was placed on the buccal surface of the impacted molar in order to luxate the alveolar socket more easily. RESULTS: Comparing the two techniques, we observed a statistically significant decrease in the duration of the procedure and in the need for tooth sectioning when applying the second surgical technique, while the post-operative complications were similar in the two groups. We also found a statistically significant lower incidence of lingual nerve lesions and only a slightly higher frequency of sharp mandibular bone irregularities in the second group, which however was not statistically significant. CONCLUSIONS: The results of our study indicate that the surgical technique using an elevator on the buccal surface of the tooth seems to be a reliable method to extract impacted third molars safely, easily, quickly and with the minimum trauma to the surrounding tissues. PMID- 26116844 TI - Evaluation of volumetric measurements on CBCT images using stafne bone cavities as an example. AB - BACKGROUND: The aim of the present study is to evaluate the efficacy of CBCT in volume measuring using Stafne Bone Cavities (SBC) as an example. MATERIAL AND METHODS: The study was conducted with 14 subjects with SBC detected on panoramic radiographs. In order to evaluate lesions volumetric dimensions, CBCT images for each patient were captured. Files in Digital Imaging and Communications in Medicine (DICOM) format were transferred into a medical image processing program (ITK-SNAP 2.4.0) and volume in mm3 of the cavities were measured using semi automatic segmentation procedure by 2 observers blinded to each other over a one month period. Inter-reliability of volumetric measurements between observers was compared. SBCs relation to mandibular canal was also examined and three types of relation were observed; type 1: mandibular canal is separated from the SBC, type 2: mandibular canal is in contact with SBC, type 3: mandibular canal goes through the SBC. RESULTS: There were 12 males and 2 females who had SBC in this study (age range: 37-73, mean age: 55.3 years). The total volume of SBC in patients ranged from 160 mm3 to 520 mm3 (mean: 361.7 mm3). There was no significant difference between observers for volume measurements (p>0.05). According to relationship of SBC with mandibular canal, most SBCs were Type 1 (64.3 %) followed by type 3 (21.4 %) and type 2 (14.3 %). Pearson correlation coefficient shows a positive correlation between lesions volumetric size and relation with mandibular canal (pearson correlation = 0.54, sig < 0.05). CONCLUSIONS: Based on the results of this preliminary study, CBCT was considered to be an effective radiographic technic for measuring volumetric sizes of SBCs. However further studies with larger sample sizes are needed to prove the usefulness of CBCT in volume measurements. PMID- 26116845 TI - Retrospective study maxillofacial fractures epidemiology and treatment plans in Southeast of Iran. AB - BACKGROUND: The epidemiology of facial injuries varies in different countries and geographic zones. Population concentration, lifestyle, cultural background, and socioeconomic status can affect the prevalence of maxillofacial injuries. Therefore, in this study, we evaluated the maxillofacial fractures epidemiology and treatment plans in hospitalized patients (2012-2014) which would be useful for better policy making strategies. MATERIAL AND METHODS: In this retrospective study, the medical records of 386 hospitalized patients were evaluated from the department of maxillofacial surgery at Bahonar Hospital of Kerman, Iran. The type and cause of fractures and treatment plans were recorded in a checklist. For data analysis, ANOVA, t-test, Chi-square, and Fisher's exact test were performed, using SPSS version 21. RESULTS: The majority of patients were male (76.5%). Most subjects were within the age range of 20-30 years. Fractures were mostly caused by accidents, particularly motorcycle accidents (MCAs), and the most common site of involvement was the mandible (parasymphysis). There was a significant association between the type of treatment and age. In fact, the age group of 16 59 years under went open reduction internal fixation (ORIF) more than other age groups (P=0.02). Also, a significant association was observed between gender and the occurrence of fractures (P=0.01). CONCLUSIONS: Considering the geographic and cultural indices of the evaluated population, it can be concluded that patients age and gender and trauma causes significantly affect the prevalence of maxillofacial traumas and fracture kinds and treatment plans. PMID- 26116846 TI - Incidence and types of complications after ablative oral cancer surgery with primary microvascular free flap reconstruction. AB - BACKGROUND: The aims of the study were 1) to evaluate the incidence and types of postoperative complications after ablative oral cancer surgery with primary free flap reconstruction and 2) identify prognostic variables for postoperative complications. MATERIAL AND METHODS: Desired data was retrieved from a computer database at the department of Oral and Maxillofacial Department, Queen Elisabeth hospital Birmingham, United Kingdom, between June 2007 and October 2012. Logistic regression was used to study relationships between preoperative variables and postoperative outcomes. RESULTS: The study population consisted 184 patients, comprising 189 composite resections with reconstruction. Complications developed in 40.2% of the patients. Three patients (1.6%) died, 11.1% returned to the operating room, 5.3% developed donor site complications and 6.9% flap complications of which 3.2% total flap failure. In the multivariable analysis systemic complications were associated with anaesthesia time and hospital stay with red cell transfusion. CONCLUSIONS: A significant proportion of the patients with primary free flap reconstructions after oral cancer surgery develops postoperative complications. Prolonged anaesthesia time and red cell transfusion are possible predictors for systemic complications and hospital stay respectively. Preoperative screening for risk factors is advocated for patient selection and to have realistic information and expectations. PMID- 26116847 TI - Satisfaction and quality of life with palatal positioned implants in severely atrophic maxillae versus conventional implants supporting fixed full-arch prostheses. AB - BACKGROUND: To evaluate satisfaction and quality of life in patients with palatal positioned implants supporting fixed full-arch prostheses to rehabilitate edentulous maxillae with horizontal atrophy and compare them with conventional well-centered implants placed in non-atrophic supporting fixed full-arch prostheses. MATERIAL AND METHOD: A clinical retrospective study was performed of patients that were rehabilitated with full-arch fixed implant-supported maxillary prostheses and had a minimum follow-up of 5 years after implant loading. Patients were divided into 2 groups: patients with class IV maxilla according to Cawood and Howell and treated with palatal positioned implants (test) and with class III maxilla and treated with implants well-centered in the alveolar ridge and completely surrounded by bone (control). Ten-cm visual analogue scales (VAS) (range 1-10) and the OHIP-14 (Oral Health Impact Profile) questionnaire were used respectively to estimate patient satisfaction and quality of life after implant therapy. Statistical analysis was performed applying Mann-Whitney Test using alpha set at 0.05. RESULTS: Mean global and specific satisfaction--except for self-esteem--were superior for the test group than the control group, although differences were not statistically significant. Regarding quality of life, the reported incidence of problems was lower in the test group for all the studied items except for 'problems at work'. However, differences were not statistically significant in any case. CONCLUSION: Despite the limitations of the study (retrospective and nonrandomized design) the results suggest that the prosthesis design needed to rehabilitate palatally positioned implants (more coverage of palate) does not lead to lower satisfaction and quality of life of patients, compared to patients treated with implants placed centered and conventional design prostheses that do not cover the palate. PMID- 26116848 TI - Pediatric Posterior Sternoclavicular Joint Injuries. AB - Posterior sternoclavicular joint injuries are increasingly diagnosed in children and young adults. Most of these injuries are the result of indirect mechanisms, typically lateral compression, with a posterior-to-anterior force applied to the shoulder during sports. Less frequently, these injuries are caused by direct impact on the medial clavicle, which can occur in rollover motor vehicle accidents, or may represent atraumatic instability. In patients younger than 25 years, physeal separation is more common than true dislocation. Theoretically, these patients have increased remodeling potential. Reduction is recommended to prevent and/or manage the compression of mediastinal structures, which can lead to life-threatening injury. Open surgical stabilization is the preferred treatment for acute and chronic retrosternal injuries. A thoracic or trauma surgeon should be available during stabilization in the rare event of potentially life-threatening hemorrhage after reduction. Outcomes have been largely successful, with pain-free, unrestricted range of motion and return to activity. PMID- 26116849 TI - Extremity War Injuries IX: Reducing Disability Within the Military. AB - Extremity War Injury Symposium IX focused on reducing disability within the military, centering on cartilage defects, amputations, and spinal cord injury. Many areas of upper and lower extremity trauma and disability were discussed, including segmental nerve injuries, upper extremity allotransplantation, and the importance of patient-reported functional outcomes compared with the traditionally reported measures. Strategic planning addressed progression toward clinical solutions by setting clear objectives and goals and outlining pathways to address the "translation gap" that often prevents bridging of basic science to clinical application. PMID- 26116850 TI - Considerations in the Radiologic Evaluation of the Pregnant Orthopaedic Patient. AB - Radiographic imaging of the pregnant patient represents a diagnostic and management dilemma for the orthopaedic surgeon. Imaging is often necessary in the setting of trauma; however, in utero radiation exposure can result in deleterious developmental effects in the embryo and fetus. The likelihood of a negative effect is proportional to the radiation dose and the gestational age of the embryo or fetus at the time of exposure. Ionizing radiation doses >100 mGy in the first trimester of pregnancy may lead to spontaneous abortion, malformation, and mental retardation. Whereas plain radiographs of the extremities and cervical spine expose the fetus to minimal doses of radiation of <10 mGy, other commonly performed orthopaedic diagnostic studies, such as CT of the pelvis, emit significantly higher exposure doses of approximately 35 mGy. Non-emitting modalities, such as ultrasonography and MRI, are alternatives for evaluation in the clinical setting. PMID- 26116851 TI - Clinical Differentiation of Upper Extremity Pain Etiologies. AB - Upper extremity pain can result from many overlapping etiologies. These can be categorized into anatomic regions and specific organ systems. Anatomically, pain etiologies are classified into four major groups: neurologic, musculoskeletal, vascular, and other (eg, tumor, infection). Knowledge of the characteristic clinical presentation and physical examination findings of each group can help distinguish the source of the patient's complaints quickly so that an accurate clinical diagnosis can facilitate appropriate diagnostic measures and treatment. A focus on the neurologic causes of upper extremity pain (ie, cervical spine pathology, peripheral nerve compression, neuropathy) and musculoskeletal causes of shoulder and elbow pain (eg, adhesive capsulitis, calcific tendinitis, biceps tendinitis, synovitis) and the distinguishing characteristics (eg, periscapular pain, two-point discrimination, signal intensity on T2-weighted MRI) helps determine the appropriate diagnosis. PMID- 26116852 TI - Compliance with dental treatment recommendations by rural paediatric patients after a live-video teledentistry consultation: A preliminary report. AB - OBJECTIVE: The purpose of this research was to assess the compliance rate with recommended dental treatment by rural paediatric dental patients after a live video teledentistry consultation. METHODS: A retrospective dental chart review was completed for 251 rural paediatric patients from the Finger Lakes region of New York State who had an initial teledentistry appointment with a paediatric dentist located remotely at the Eastman Institute for Oral Health in Rochester, NY. The recommended treatment modalities were tabulated and comprehensive dental treatment completion rates were obtained. RESULTS: The recommended treatment modality options of: treatment in the paediatric dental clinic; treatment using nitrous oxide anxiolysis; treatment with oral sedation; treatment in the operating room with general anaesthesia; or teleconsultation were identified for the 251 patients. Compliance rates for completed dental treatment based on initial teleconsultation recommendations were: 100% for treatment in the paediatric dental clinic; 56% for nitrous oxide patients; 87% for oral sedation; 93% for operating room; and 90% for teleconsultations. The differences in the compliance rates for all treatment modalities were not statistically significant (Fisher's exact test, p > 0.05). CONCLUSIONS: Compliance rates for completed comprehensive dental treatment for this rural population of paediatric dental patients were quite high, ranging from 56% to 100%, and tended to be higher when treatment was completed in fewer visits. Live-video teledentistry consultations conducted among rural paediatric patients and a paediatric dentist in the specialty clinic were feasible options for increasing dental treatment compliance rates when treating complex paediatric dental cases. PMID- 26116853 TI - Research funding for telemedicine: an Australian perspective. AB - Winning research funding is one of the most difficult challenges faced by researchers, especially with falling success rates and shrinking budgets. Telemedicine researchers can find it especially hard to win funding as they are often researching small changes to the health system that whilst important for patient care are often not as competitive as proposals that promise to cure diseases. In a climate of both tight health funding and tight research funding, telemedicine researchers should emphasise the potential for their research to add value and lower costs in order to increase their chances of winning funding. PMID- 26116855 TI - "Tele-rounding" with a remotely controlled mobile robot in the neonatal intensive care unit. AB - OBJECTIVE: To investigate the feasibility of 'tele-rounding' in the neonatal intensive care. METHODS: In this prospective study utilizing telemedicine technology in the NICU for daily patient bedside rounds ('tele-rounds'), twenty pairs of neonates were matched according to gestational age, diagnoses, and disease severity. One patient was cared for by the on-site NICU team lead by an on-site neonatologist. The other patient was cared for by the on-site team but led by an off-site neonatologist using a remote-controlled robot. Patient rounding data, clinical outcomes, length of stay, and hospital costs were compared between the two groups. Parents and staff were also surveyed about their satisfaction with telemedicine. RESULTS: Except for one parameter, no significant differences in care or outcomes were found between patients cared for by either neonatologist. The exception was the time the off-site neonatologist spent on the patient encounter compared to the on-site neonatologist (median [interquartile range]), (5 minutes [5, 6] vs. 8 minutes [7, 10.5], p = 0.002). This difference was due primarily to time needed to operate and maneuver the robot or occasionally to slower or dropped connection to the Internet. There were positive perceptions of telemedicine among both parents and NICU staff. CONCLUSION: As long as direct bedside care providers are available, remote-controlled, robotic telemedicine technology can be utilized by neonatologists to perform daily patient rounds in the neonatal intensive care unit. PMID- 26116854 TI - The effects of telemedicine on racial and ethnic disparities in access to acute stroke care. AB - Racial and ethnic disparities have been previously reported in acute stroke care. We sought to determine the effect of telemedicine (TM) on access to acute stroke care for racial and ethnic minorities in the state of Texas. Data were collected from the US Census Bureau, The Joint Commission and the American Hospital Association. Access for racial and ethnic minorities was determined by summing the population that could reach a primary stroke centre (PSC) or telemedicine spoke within specified time intervals using validated models. TM extended access to stroke expertise by 1.5 million residents. The odds of providing 60-minute access via TM were similar in Blacks and Whites (prevalence odds ratios (POR) 1.000, 95% CI 1.000-1.000), even after adjustment for urbanization (POR 1.000, 95% CI 1.000-1.001). The odds of providing access via TM were also similar for Hispanics and non-Hispanics (POR 1.000, 95% CI 1.000-1.000), even after adjustment for urbanization (POR 1.000, 95% CI 1.000-1.000). We found that telemedicine increased access to acute stroke care for 1.5 million Texans. While racial and ethnic disparities exist in other components of stroke care, we did not find evidence of disparities in access to the acute stroke expertise afforded by telemedicine. PMID- 26116856 TI - Teledermatology-directed surgical care is safe and reduces travel. AB - METHODS: We conducted a retrospective chart review and identified 186 Veterans in the VA Corporate Data Warehouse as having malignant melanomas or severely dysplastic nevi during the four-year period of observation from 1 July 2009 to 30 June 2013 and met inclusion and exclusion criteria for analysis. RESULTS: Three hundred and sixty-six surgical procedures were performed for diagnosis and treatment of these conditions including biopsy and wide-local excision, of which 189 carefully selected cases were performed by primary care clinicians with 2.0% biopsy complication rate and a 7.7% wide-local excision complication rate. Cases not performed by primary care providers were referred to specialists (e.g. dermatologists, general surgeons or specialty surgeons) who had a 2.5% complication rate in biopsies and wide-local excision complication rate of 13.5% in severely dysplastic nevi and pTis and pT1a lesions and a 10.7% complication rate for lesions pT1b and greater. DISCUSSION: These results show that a significant fraction of surgical procedures for diagnosis and treatment of malignant melanoma and severely dysplastic nevi can be safely performed in rural clinics by trained primary care providers. PMID- 26116857 TI - Kissing Cousins, Arranged Marriages, and Genetic Diversity. PMID- 26116858 TI - Fitness Trade-Offs Determine the Role of the Molecular Chaperonin GroEL in Buffering Mutations. AB - Molecular chaperones fold many proteins and their mutated versions in a cell and can sometimes buffer the phenotypic effect of mutations that affect protein folding. Unanswered questions about this buffering include the nature of its mechanism, its influence on the genetic variation of a population, the fitness trade-offs constraining this mechanism, and its role in expediting evolution. Answering these questions is fundamental to understand the contribution of buffering to increase genetic variation and ecological diversification. Here, we performed experimental evolution, genome resequencing, and computational analyses to determine the trade-offs and evolutionary trajectories of Escherichia coli expressing high levels of the essential chaperonin GroEL. GroEL is abundantly present in bacteria, particularly in bacteria with large loads of deleterious mutations, suggesting its role in mutational buffering. We show that groEL overexpression is costly to large populations evolving in the laboratory, leading to groE expression decline within 66 generations. In contrast, populations evolving under the strong genetic drift characteristic of endosymbiotic bacteria avoid extinction or can be rescued in the presence of abundant GroEL. Genomes resequenced from cells evolved under strong genetic drift exhibited significantly higher tolerance to deleterious mutations at high GroEL levels than at native levels, revealing that GroEL is buffering mutations in these cells. GroEL buffered mutations in a highly diverse set of proteins that interact with the environment, including substrate and ion membrane transporters, hinting at its role in ecological diversification. Our results reveal the fitness trade-offs of mutational buffering and how genetic variation is maintained in populations. PMID- 26116859 TI - Selection Maintains Low Genomic GC Content in Marine SAR11 Lineages. AB - The genomic G+C content of ocean bacteria varies from below 30% to over 60%. This broad range of base composition is likely shaped by distinct mutational processes, recombination, effective population size, and selection driven by environmental factors. A number of studies have hypothesized that depletion of G/C in genomes of marine bacterioplankton cells is an adaptation to the nitrogen poor pelagic oceans, but they failed to disentangle environmental factors from mutational biases and population history. Here, we reconstructed the evolutionary changes of bases at synonymous sites in genomes of two marine SAR11 populations and a freshwater counterpart with its evolutionary origin rooted in the marine lineage. Although they all have similar genome sizes, DNA repair gene repertoire, and base compositions, there is a stronger bias toward A/T changes, a reduced frequency of nitrogenous amino acids, and an exclusive occurrence of polyamine, opine, and taurine transport systems in the ocean populations, consistent with a greater nitrogen stress in surface oceans compared with freshwater lakes. Furthermore, the ratio of nonsynoymous to synonymous nucleotide diversity is not statistically distinguishable among these populations, suggesting that population history has a limited effect. Taken together, the ecological transition of SAR11 from ocean to freshwater habitats makes nitrogen more available to these organisms, and thus relaxation of purifying selection drove a genome-wide reduction in the frequency of G/C to A/T changes in the freshwater population. PMID- 26116860 TI - Parallel Domestication of the Heading Date 1 Gene in Cereals. AB - Flowering time is one of the key determinants of crop adaptation to local environments during domestication. However, the genetic basis underlying flowering time is yet to be elucidated in most cereals. Although staple cereals, such as rice, maize, wheat, barley, and sorghum, have spread and adapted to a wide range of ecological environments during domestication, it is yet to be determined whether they have a common genetic basis for flowering time. In this study, we show, through map-based cloning, that flowering time in sorghum is controlled by a major quantitative trait locus (QTL) Heading Date 1 (HD1), located on chromosome 10. The causal gene encodes the CONSTANS gene family which contains a CCT domain. A 5-bp deletion of a minor allele present in the coding sequence leads to a gene frameshift that delays flowering in sorghum. In contrast, in foxtail millet, association mapping of HD1 showed a common causal site with a splicing variant from "GT" to "AT" that was highly correlated with flowering time. In addition, the rice HD1 gene is known to harbor several causal variants controlling flowering time. These data indicate that the major flowering time QTL HD1 was under parallel domestication in sorghum, foxtail millet, and rice. The pattern of common mixed minor, or even rare, causal alleles in HD1 across different species may be representative of the genetic basis of the domestication syndrome. Furthermore, large DNA sequence analysis of HD1 revealed multiple origins for domesticated sorghum and a single origin for domesticated foxtail millet. PMID- 26116861 TI - Combined peri-ischemic administration of Bbeta15-42 in treating ischemia reperfusion injury of the mouse kidney. AB - The disruption of endothelial integrity is a crucial step for the development of vascular leakage and consequently ischemia-reperfusion injury (IRI). Regarding the molecular cell-cell interaction, the fibrinopeptide Bbeta15-42 prevents vascular leakage by stabilizing the inter-endothelial junctions via association with the vascular endothelial-cadherin. In a previous study we showed that a renoprotective effect in early IRI may be achieved by intravenous administration of Bbeta15-42 at the time of reperfusion. We now aimed to investigate whether additional pre-ischemic application of Bbeta15-42 could enhance this effect. Therefore C57BL/6 mice were subjected to 0.5h bilateral renal ischemia followed by reperfusion. The animals were randomized into 6 groups (n=6): two control groups treated with i.v. administration of NaCl at reperfusion for 0.5h (NaCl 1h) and 2.5h (NaCl 3h), two groups with Bbeta15-42 at reperfusion for 0.5h (Bbeta(rep) 1h) and 2.5h (Bbeta(rep) 3h), and two groups with administration of Bbeta15-42 immediately pre-ischemic as well as at reperfusion for 0.5h (Bbeta(peri) 1h) and 2.5h (Bbeta(peri) 3h). We found that both Bbeta(rep) and Bbeta(peri) mice displayed reduced early renal damage compared with NaCl treated mice. However, there was no further reduction of the IR damage through added pre ischemic application of Bbeta15-42. Overall, we detected significantly reduced endothelial activation, lower tissue infiltration of neutrophils as well as lower tissue levels of neutrophil gelatinase-associated lipocalin (NGAL) in all mice treated with Bbeta15-42 compared to mice treated with NaCl. Our data confirm the renoprotective effect of Bbeta15-42 in the early therapeutic treatment of acute kidney injury due to ischemia and reperfusion. However, a combined pre-and post ischemic administration of Bbeta15-42 appears to provide no additional benefit compared with a sole administration at reperfusion. PMID- 26116862 TI - Experimental TLR4 inhibition improves intestinal microcirculation in endotoxemic rats. AB - INTRODUCTION: Toll like receptor 4 (TLR4) represents a critical cellular link for endotoxin-induced pathology. The aim of this study was to evaluate the potential role of TLR4 inhibition on the intestinal microcirculation during experimental endotoxemia. MATERIALS AND METHODS: The intestinal microcirculation was studied by intravital microscopy in four groups of Lewis rats (n=10 per group): healthy controls (CON group), endotoxemic animals (15mg/kg lipopolysaccharide, LPS group), endotoxemic animals treated with a TLR4 antagonist (1mg/kg CRX-526, LPS+CRX526 group), and controls treated with CRX-526 (C-CRX526 group). Plasma samples were obtained for cytokine measurements at the end of the experiments. RESULTS: Endotoxemia significantly increased leukocyte adhesion in intestinal submucosal venules (e.g., V1 venules: CON 20.4+/-6.5n/mm(2), LPS 237.5+/ 36.2n/mm(2), p<0.05) and reduced capillary perfusion of the intestinal wall (e.g., longitudinal muscular layer: CON 112.5+/-5.9cm/cm(2), LPS 71.3+/ 11.0cm/cm(2), p<0.05) at 2h. TLR4 inhibition significantly reduced endotoxemia associated leukocyte adhesion (V1 venules: 104.3+/-7.8n/mm(2)) and improved capillary perfusion (longitudinal muscular layer: 111.0+/-12.3cm/cm(2)). Cytokine release was not significantly affected. CONCLUSIONS: The TLR4 pathway may be a target in clinical Gram-negative sepsis since administration of the TLR4 antagonist CRX-526 improved intestinal microcirculation parameters in experimental endotoxemia. PMID- 26116863 TI - The helminth parasite proteome at the host-parasite interface - Informing diagnosis and control. AB - Helminth parasites are a significant health burden for humans in the developing world and also cause substantial economic losses in livestock production across the world. The combined lack of vaccines for the major human and veterinary helminth parasites in addition to the development of drug resistance to anthelmintics in sheep and cattle mean that controlling helminth infection and pathology remains a challenge. However, recent high throughput technological advances mean that screening for potential drug and vaccine candidates is now easier than in previous decades. A better understanding of the host-parasite interactions occurring during infection and pathology and identifying pathways that can be therapeutically targeted for more effective and 'evolution proof' interventions is now required. This review highlights some of the advances that have been made in understanding the host-parasite interface in helminth infections using studies of the temporal expression of parasite proteins, i.e. the parasite proteome, and discuss areas for potential future research and translation. PMID- 26116864 TI - Antileishmanial activity of essential oil and 6,7-dehydroroyleanone isolated from Tetradenia riparia. AB - Tetradenia riparia plant is used as a traditional medicine in Africa for the treatment of inflammatory and infectious diseases as like parasitic. Therapy for leishmaniasis caused by Leishmania (Leishmania) amazonensis specie often fails, and the conventional drugs are toxic, expensive, require a long period of treatment, and adverse effects are common. The alternative therapies using natural products are inexpensive and have few or any adverse reaction. These reasons are sufficient to investigate the new natural therapeutic for leishmaniasis. We evaluated the potential of the essential oil (TrEO) and 6,7 dehydroroyleanone (TrROY) isolated from T. riparia on L. (L.) amazonensis promastigote and amastigote forms, cytotoxicity on human erythrocytes and murine macrophages, nitric production and inducible nitric oxide synthase (iNOS) mRNA expression. TrEO was the most effective to promote the Leishmania promastigote death. After 72 h incubation, the lethal dose of TrEO and TrROY that promoted 50% Leishmania death (LD50) were 0.8 MUg/mL and 3 MUg/mL, respectively. TrEO and TrROY were not cytotoxic to human erythrocytes, but TrROY was toxic to murine macrophages resulting in a low selectivity index. The transmission electronic microscopy showed that TrEO (0.03 MUg/mL) was able to modify the promastigote ultrastructures suggesting autophagy as chromatin condensation, blebbing, membranous profiles and nuclear fragmentation. Infected-macrophages treated with TrEO (0.03 MUg/mL) or TrROY (10 MUg/mL) had an infection index decreased in 65 and 48%. TrEO did not induce iNOS mRNA expression or nitrite production in macrophages infected with Leishmania. TrROY and mainly TrEO promoted the Leishmania death, and TrROY showed loss toxicity to erythrocytes cells. Other compounds derived from T. riparia and the essential oil could be explored to develop a new alternative treatment for leishmaniasis. PMID- 26116865 TI - Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension. AB - Our objective was to investigate the role of creatine kinase in the contractile dysfunction of right ventricular failure caused by pulmonary artery hypertension. Pulmonary artery hypertension and right ventricular failure were induced in rats by monocrotaline and compared to saline-injected control animals. In vivo right ventricular diastolic pressure-volume relationships were measured in anesthetized animals; diastolic force-length relationships in single enzymatically dissociated myocytes and myocardial creatine kinase levels by Western blot. We observed diastolic dysfunction in right ventricular failure indicated by significantly steeper diastolic pressure-volume relationships in vivo and diastolic force length relationships in single myocytes. There was a significant reduction in creatine kinase protein expression in failing right ventricle. Dysfunction also manifested as a shorter diastolic sarcomere length in failing myocytes. This was associated with a Ca(2+)-independent mechanism that was sensitive to cross-bridge cycling inhibition. In saponin-skinned failing myocytes, addition of exogenous creatine kinase significantly lengthened sarcomeres, while in intact healthy myocytes, inhibition of creatine kinase significantly shortened sarcomeres. Creatine kinase inhibition also changed the relatively flat contraction amplitude stimulation frequency relationship of healthy myocytes into a steeply negative, failing phenotype. Decreased creatine kinase expression leads to diastolic dysfunction. We propose that this is via local reduction in ATP:ADP ratio and thus to Ca(2+)-independent force production and diastolic sarcomere shortening. Creatine kinase inhibition also mimics a definitive characteristic of heart failure, the inability to respond to increased demand. Novel therapies for pulmonary artery hypertension are needed. Our data suggest that cardiac energetics would be a potential ventricular therapeutic target. PMID- 26116867 TI - Marfan syndrome and aortic aneurysm: Lysyl oxidases to the rescue? PMID- 26116866 TI - Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. AB - Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase (NOS), and reduced BH4 availability leads to endothelial NOS (eNOS) uncoupling and increased reactive oxygen species (ROS) generation. Questions remain regarding the functional state of eNOS and role of BH4 availability in the process of in vivo myocardial ischemia-reperfusion (I/R) injury. Rats were subjected to 60min of in vivo left coronary artery occlusion and varying periods of reperfusion with or without pre-ischemic liposomal BH4 supplementation (1mg/kg, iv). Myocardial infarction was correlated with cardiac BH4 content, eNOS protein level, NOS enzyme activity, and ROS generation. In the vehicle group, 60 min ischemia drastically reduced myocardial BH4 content in the area at risk (AAR) compared to non-ischemic (NI) area and the level remained lower during early reperfusion followed by recovery after 24-h reperfusion. Total eNOS, activated eNOS protein level (eNOS Ser1177 phosphorylation) and NOS activity were also significantly reduced during ischemia and/or early reperfusion, but recovered after 24-h reperfusion. With liposomal BH4 treatment, BH4 levels were identical in the AAR and NI area during ischemia and/or early reperfusion, and were significantly higher than with vehicle. BH4 pre-treatment preserved eNOS Ser1177 phosphorylation and NOS activity in the AAR, and significantly reduced myocardial ROS generation and infarction compared to vehicle. These findings provide direct evidence that in vivo I/R induces eNOS dysfunction secondary to BH4 depletion, and that pre-ischemic liposomal BH4 administration preserves eNOS function conferring cardioprotection with reduced oxidative stress. PMID- 26116868 TI - Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload. AB - The in vivo function status of the ubiquitin-proteasome system (UPS) in pressure overloaded hearts remains undefined. Cardiotoxicity was observed during proteasome inhibitor chemotherapy, especially in those with preexisting cardiovascular conditions; however, proteasome inhibition (PsmI) was also suggested by some experimental studies as a potential therapeutic strategy to curtail cardiac hypertrophy. Here we used genetic approaches to probe cardiac UPS performance and determine the impact of cardiomyocyte-restricted PsmI (CR-PsmI) on cardiac responses to systolic overload. Transgenic mice expressing an inverse reporter of the UPS (GFPdgn) were subject to transverse aortic constriction (TAC) to probe myocardial UPS performance during systolic overload. Mice with or without moderate CR-PsmI were subject to TAC and temporally characterized for cardiac responses to moderate and severe systolic overload. After moderate TAC (pressure gradient: ~40mmHg), cardiac UPS function was upregulated during the first two weeks but turned to functional insufficiency between 6 and 12weeks as evidenced by the dynamic changes in GFPdgn protein levels, proteasome peptidase activities, and total ubiquitin conjugates. Severe TAC (pressure gradients >60mmHg) led to UPS functional insufficiency within a week. Moderate TAC elicited comparable hypertrophic responses between mice with and without genetic CR-PsmI but caused cardiac malfunction in CR-PsmI mice significantly earlier than those without CR-PsmI. In mice subject to severe TAC, CR-PsmI inhibited cardiac hypertrophy but led to rapidly progressed heart failure and premature death, associated with a pronounced increase in cardiomyocyte death. It is concluded that cardiac UPS function is dynamically altered, with the initial brief upregulation of proteasome function being adaptive; and CR-PsmI facilitates cardiac malfunction during systolic overload. PMID- 26116869 TI - Mode of delivery at periviability and early childhood neurodevelopment. AB - OBJECTIVE: Little is known regarding the impact of mode of delivery in the periviable period. Even less is understood regarding the effect of mode of delivery on neurodevelopment. Our objective is to determine if the mode of delivery at time of periviability impacts Bayley II scores at 2 years of age. STUDY DESIGN: This is a secondary analysis of a randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy, a multicenter trial where women at imminent risk for delivery were assigned to receive magnesium sulfate or placebo. For this secondary analysis we included nonanomalous singleton gestations delivered between 23 4/7 and 25 6/7 weeks. We excluded women with missing exposure or outcome data. The primary exposure of interest was mode of delivery. The primary outcome was Bayley II scores <70 (mental and motor) at 2 years of age. Log binomial regression was used to control for possible confounders including gestational age at delivery, presentation at time of delivery, chorioamnionitis, years of maternal education, maternal body mass index, and original study treatment group. RESULTS: A total of 158 women met inclusion criteria. In all, 91 had a vaginal delivery and 67 had a cesarean delivery. Exposure to magnesium sulfate, maternal education, chorioamnionitis, years of maternal education, and maternal body mass index were similar in both groups. There was no difference in either mental or motor Bayley II scores <70 or <85 by mode of delivery in either univariable or multivariable analysis. CONCLUSION: There is no detectable difference in Bayley II scores between mode of delivery at time of periviability. This adds to the literature supporting obstetric indications dictating mode of delivery at this gestational age. PMID- 26116870 TI - Circulating endothelial cell number and markers of endothelial dysfunction in previously preeclamptic women. AB - OBJECTIVE: Patients with preeclampsia (PE) have endothelial dysfunction and an increased future risk of cardiovascular (CV) mortality. The number of circulating endothelial cells (CECs) is markedly increased in conditions associated with a high degree of endothelial cell activation/injury including PE. We hypothesized that the number of CECs continues to be increased in women with a history of PE, reflecting ongoing endothelial cell activation/injury. STUDY DESIGN: CECs, flow mediated vasodilation, levels of adhesion molecules and soluble vascular endothelial growth factor receptor-1 (sVEGFR1), and urine albumin/creatinine ratio were determined in 21 healthy women with ongoing normal pregnancy, 24 healthy currently nonpregnant women with a history of normal pregnancy, a total of 17 women with currently active mild (n = 11) or severe (n = 6) PE without hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and 16 currently nonpregnant women with a history of mild (n = 10) or severe (n = 6) PE. RESULTS: Blood samples from women with active preeclampsia had higher CECs (9.9 +/- 7.9 cells/mL) than healthy pregnant women (3.0 +/- 4.1 cells/mL; P < .001), healthy nonpregnant women with a history of normal pregnancy (3.4 +/- 4.0 cells/mL; P < .001), or women with a history of preeclampsia (2.4 +/- 2.0 cells/mL; P < .001). The number of CECs were similar between women with a history of preeclampsia and healthy nonpregnant women with a history of normal pregnancy. Patients with active preeclampsia had significantly higher soluble vascular cell adhesion molecule-1, soluble E-selectin, sVEGFR1, and urinary albumin/creatinine ratio than healthy pregnant women. However, soluble vascular cell adhesion molecule-1, soluble E-selectin, urinary albumin/creatinine ratio were similar in women with a history of preeclampsia and healthy nonpregnant women with a history of normal pregnancy. However, women with a history of preeclampsia had higher sVEGFR1 levels than women with a history of normal pregnancy (P < .05). CONCLUSION: Markers of endothelial activation, dysfunction, and damage were increased in patients with PE. After the delivery, this activation status is similar to the age-matched nonpregnant women with a history of normal pregnancy. However, sVEGFR-1 levels remain higher in women with a history of preeclampsia compared with women without a history of preeclampsia. PMID- 26116871 TI - Elevated amniotic fluid lactate predicts labor disorders and cesarean delivery in nulliparous women at term. AB - OBJECTIVE: We sought to assess amniotic fluid lactate (AFL) at diagnosis of spontaneous labor at term (>=37 weeks) as a predictor of labor disorders (dystocia) and cesarean delivery (CD). STUDY DESIGN: This was a single institution, prospective cohort study of 905 singleton, cephalic, term (>=37 weeks) nulliparous women in spontaneous labor. A standard management of labor (active management of labor) including a standard oxytocin regimen up to a maximum dose of 30 mU/min was applied. AFL was measured using a point-of-care device (LMU061; ObsteCare, Stockholm, Sweden). Labor arrest in the first stage of labor was defined as the need for oxytocin when cervical dilatation was <1 cm/h over 2 hours and in the second stage of labor by poor descent and rotation over 1 hour. Standard statistical analysis included analysis of variance, Pearson correlations, and binary logistic regression. Unsupervised decision tree analysis with 10-fold cross-validation was used to identify AFL thresholds. RESULTS: AFL was normally distributed and did not correlate with age, body mass index, or gestation. Unsupervised decision tree analysis demonstrated that AFL could be divided into 3 groups: 0-4.9 mmol/L (n = 118), 5.0-9.9 mmol/L (n = 707), and >=10.0 mmol/L (n = 80). Increasing AFL was associated with higher total oxytocin dose (P = .001), labor disorders (P = .005), and CD (P <= .001). Multivariable regression analysis demonstrated that women with AFL >=5.0-9.9 mmol/L (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.06-2.39) and AFL >=10.0 mmol/L (OR, 1.72; 95% CI, 1.01-2.93) were independent predictors of a labor disorder. AFL >=5.0-9.9 mmol/L did not predict CD but multivariable analysis confirmed that AFL >=10.0 mmol/L was an independent predictor of CD (OR, 3.35; 95% CI, 1.73-6.46). AFL >=5.0-9.9 mmol/L had a sensitivity of 89% in predicting a labor disorder and a sensitivity of 93% in predicting CD with a 97% negative predictive value. AFL >=10.0 mmol/L was highly specific but lacked sensitivity for CD. There was no difference in birthweight of infants according to labor disorder and delivery method. CONCLUSION: AFL at diagnosis of labor in spontaneously laboring single cephalic nulliparous term women is an independent predictor of a labor disorder and CD. These data suggest that women with AFL between 5.0-9.9 mmol/L with a labor disorder may be amenable to correction using the active management of labor protocol. PMID- 26116872 TI - Delivery planning for pregnancies with gastroschisis: findings from a prospective national registry. AB - OBJECTIVE: The purpose of this study was to determine the influence of planned mode and planned timing of delivery on neonatal outcomes in infants with gastroschisis. STUDY DESIGN: Data from the Canadian Pediatric Surgery Network cohort were used to identify 519 fetuses with isolated gastroschisis who were delivered at all tertiary-level perinatal centers in Canada from 2005-2013 (n = 16). Neonatal outcomes (including length of stay, duration of total parenteral nutrition, and a composite of perinatal death or prolonged exclusive total parenteral nutrition) were compared according to the 32-week gestation planned mode and timing of delivery with the use of the multivariable quantile and logistic regression. RESULTS: Planned induction of labor was not associated with decreased length of stay (adjusted median difference, -2.6 days; 95% confidence interval [CI], -9.9 to 4.8), total parenteral nutrition duration (adjusted median difference, -0.2 days; 95% CI, -6.4 to 6.0), or risk of the composite adverse outcome (relative risk, 1.7; 95% CI, 0.1-3.2) compared with planned vaginal delivery after spontaneous onset of labor. Planned delivery at 36-37 weeks' gestation was not associated with decreased length of stay (adjusted median difference, 5.9 days; 95% CI, -5.7 to 17.5), total parenteral nutrition duration (adjusted median difference, 3.2 days; 95% CI, -7.9 to 14.3), or risk of composite outcome (relative risk, 2.3; 95% CI, 0.8-5.4) compared with planned delivery at >=38 weeks' gestation. CONCLUSION: Infants with gastroschisis who were delivered after planned induction or planned delivery at 36-37 weeks' gestation did not have significantly better neonatal outcomes than planned vaginal delivery after spontaneous onset of labor and planned delivery at >=38 weeks' gestation. PMID- 26116873 TI - Insertion characteristics of intrauterine devices in adolescents and young women: success, ancillary measures, and complications. AB - OBJECTIVE: The objective of the study was to evaluate success and safety of intrauterine device (IUD) placement in a large cohort of adolescents. STUDY DESIGN: We examined the medical records of patients aged 13-24 years at the Children's Hospital Colorado Adolescent Family Planning Clinic with at least 1 attempt at IUD placement. We abstracted demographic, reproductive, and procedural variables. The primary outcome was successful placement at first IUD insertion visit. We compared nulliparous with parous adolescents and patients younger than 18 years with those 18 years of age and older. RESULTS: Between April 2009 and December 2011, 1177 adolescent women aged 13-24 years (mean age 20.8 +/- 2.5 years) had an attempted IUD placement, 1012 (86%) of which were with an advanced practice clinician. The first attempt was successful for 1132 women (96.2%). The first-attempt success rate was 95.8% for nulliparous women and 96.7% for parous women (P = .45). The first-attempt success rate was 95.5% (n = 169) for women aged 13-17 years compared with 96.3% (n = 963) for women aged 18-24 years (P = .6). Only 1.8% (n = 21) of all first-attempt successful insertions required ancillary measures. Of the 45 patients with a failed first insertion attempt, 40% (n = 18) had a second attempt with a physician, of which 78% (n = 14) were successful. Within the first 6 months of IUD placement, no perforations were identified and 24 patients (3.0%) expelled the IUD. Insertion failures and IUD expulsions were not related to IUD type, age, or parity. CONCLUSION: Intrauterine devices can be inserted in nulliparous adolescents of any age with similar success to parous adolescents, by both physicians and advanced practice clinicians. Inability to provide ancillary measures such as paracervical block or cervical dilation should not limit access to this first-line contraceptive method. PMID- 26116874 TI - Maternal obesity and neuroprotective magnesium sulfate. AB - OBJECTIVE: Given the association between risk of cerebral palsy and children born to obese women, the study aim was to estimate whether maternal obesity is associated with reduced effectiveness of conventional antenatal magnesium sulfate dosing for the prevention of cerebral palsy and death. STUDY DESIGN: This is a secondary cohort analysis of a multicenter randomized clinical trial completed by the Maternal-Fetal Medicine Units Network. Women were included in the original trial if deemed high risk for preterm delivery in the subsequent 24 hours. The present study included singleton, nonanomalous fetuses that were randomized to and received magnesium sulfate with complete data available. Outcomes between obese (body mass index >=30 kg/m(2)) and nonobese women were compared. A secondary analysis of outcomes between morbidly obese (body mass index >=40 kg/m(2)) and nonmorbidly obese women was performed. The primary outcome was a composite of cerebral palsy or perinatal death before 15 months corrected age. Secondary outcomes included moderate to severe cerebral palsy or death, any cerebral palsy, moderate to severe cerebral palsy, and death. A logistic regression analysis was used to estimate the odds ratio of each outcome. Based on sample size, exposure rate (obesity) and an outcome rate of 10%, assuming an 80% power and a 0.05 alpha error, this study had sufficient power to detect a 2-fold increase in the primary outcome. RESULTS: Of 1188 women randomized to receive magnesium sulfate, 806 were included in this analysis. After adjusting for gestational age at delivery, maternal obesity was not associated with an increased risk of cerebral palsy or death in children born to women who received magnesium sulfate. Women with morbid obesity had higher rates of the primary outcome and cerebral palsy in an unadjusted analysis but did not have increased risks after adjusting for gestational age at delivery. In analyses stratified on gestational age, morbidly obese women who delivered after 28 weeks had increased risks of children with cerebral palsy or death and cerebral palsy, although case numbers were small. CONCLUSION: Among women receiving antenatal neuroprotective magnesium sulfate, maternal obesity is not associated with an increased risk of having a child with cerebral palsy or death. PMID- 26116875 TI - The antidepressant mechanism of action of vagus nerve stimulation: Evidence from preclinical studies. AB - Vagus nerve stimulation (VNS) is a proposed neuromodulatory treatment for medically refractory major depression. Although VNS is already used in clinical practice, the underlying mechanism of action remains unknown. The present review provides an overview of the preclinical VNS studies in view of two major hypotheses in depression research: the monoaminergic and the neural plasticity hypothesis of depression. PMID- 26116876 TI - Regulation of the mesocorticolimbic and mesostriatal dopamine systems by alpha melanocyte stimulating hormone and agouti-related protein. AB - The melanocortin system of the hypothalamus, including the neuropeptides alpha melanocyte stimulating hormone (alphaMSH) and agouti-related protein (AgRP), and their receptors, the melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R), have been well-studied for their roles in the central control of feeding and body weight. In this review, we discuss the evidence demonstrating that alphaMSH and AgRP also act on the mesocorticolimbic and mesostriatal dopamine systems to regulate a wide variety of behaviors. In addition to the well described ability of alphaMSH to increase dopamine transmission and to increase grooming and rearing when injected directly into the ventral tegmental area, a growing body of evidence indicates that alphaMSH and AgRP can also act on dopamine pathways to regulate feeding and drug abuse, including reward-related behaviors toward food and drugs. Increasing our understanding of how alphaMSH and AgRP act on dopamine pathways to affect behavior may allow for identification of new strategies to combat disorders involving dysfunction of dopamine pathways, such as obesity and drug abuse. PMID- 26116877 TI - Building exploration with leeches Hirudo verbana. AB - Safe evacuation of people from building and outdoor environments, and search and rescue operations, always will remain actual in course of all socio-technological developments. Modern facilities offer a range of automated systems to guide residents towards emergency exists. The systems are assumed to be infallible. But what if they fail? How occupants not familiar with a building layout will be looking for exits in case of very limited visibility where tactile sensing is the only way to assess the environment? Analogous models of human behaviour, and socio-dynamics in general, are provided to be fruitful ways to explore alternative, or would-be scenarios. Crowd, or a single person, dynamics could be imitated using particle systems, reaction-diffusion chemical medium, electro magnetic fields, or social insects. Each type of analogous model offer unique insights on behavioural patterns of natural systems in constrained geometries. In this particular paper we have chosen leeches to analyse patterns of exploration. Reasons are two-fold. First, when deprived from other stimuli leeches change their behavioural modes in an automated regime in response to mechanical stimulation. Therefore leeches can give us invaluable information on how human beings might behave under stress and limited visibility. Second, leeches are ideal blueprints of future soft-bodied rescue robots. Leeches have modular nervous circuitry with a rich behavioral spectrum. Leeches are multi-functional, fault-tolerant with autonomous inter-segment coordination and adaptive decision making. We aim to answer the question: how efficiently a real building can be explored and whether there any dependencies on the pathways of exploration and geometrical complexity of the building. In our case studies we use templates made on the floor plan of real building. PMID- 26116878 TI - A systemic approach for modeling biological evolution using Parallel DEVS. AB - A new model for studying the evolution of living organisms is proposed in this manuscript. The proposed model is based on a non-neodarwinian systemic approach. The model is focused on considering several controversies and open discussions about modern evolutionary biology. Additionally, a simplification of the proposed model, named EvoDEVS, has been mathematically described using the Parallel DEVS formalism and implemented as a computer program using the DEVSLib Modelica library. EvoDEVS serves as an experimental platform to study different conditions and scenarios by means of computer simulations. Two preliminary case studies are presented to illustrate the behavior of the model and validate its results. EvoDEVS is freely available at http://www.euclides.dia.uned.es. PMID- 26116879 TI - A thioredoxin fold protein Sh3bgr regulates Enah and is necessary for proper sarcomere formation. AB - The sh3bgr (SH3 domain binding glutamate-rich) gene encodes a small protein containing a thioredoxin-like fold, SH3 binding domain, and glutamate-rich domain. Originally, it was suggested that increased expression of Sh3bgr may cause the cardiac phenotypes in Down's syndrome. However, it was recently reported that the overexpression of Sh3bgr did not cause any disease phenotypes in mice. In this study, we have discovered that Sh3bgr is critical for sarcomere formation in striated muscle tissues and also for heart development. Sh3bgr is strongly expressed in the developing somites and heart in Xenopus. Morpholino mediated-knockdown of sh3bgr caused severe malformation of heart tissue and disrupted segmentation of the somites. Further analysis revealed that Sh3bgr specifically localized to the Z-line in mature sarcomeres and that knockdown of Sh3bgr completely disrupted sarcomere formation in the somites. Moreover, overexpression of Sh3bgr resulted in abnormally discontinues thick firmaments in the somitic sarcomeres. We suggest that Sh3bgr does its function at least partly by regulating localization of Enah for the sarcomere formation. In addition, we provide the data supporting Sh3bgr is also necessary for proper heart development in part by affecting the Enah protein level. PMID- 26116880 TI - MicroRNAs in liver tissue engineering - New promises for failing organs. AB - miRNA-based technologies provide attractive tools for several liver tissue engineering approaches. Herein, we review the current state of miRNA applications in liver tissue engineering. Several miRNAs have been implicated in hepatic disease and proper hepatocyte function. However, the clinical translation of these findings into tissue engineering has just begun. miRNAs have been successfully used to induce proliferation of mature hepatocytes and improve the differentiation of hepatic precursor cells. Nonetheless, miRNA-based approaches beyond cell generation have not yet entered preclinical or clinical investigations. Moreover, miRNA-based concepts for the biliary tree have yet to be developed. Further research on miRNA based modifications, however, holds the promise of enabling significant improvements to liver tissue engineering approaches due to their ability to regulate and fine-tune all biological processes relevant to hepatic tissue engineering, such as proliferation, differentiation, growth, and cell function. PMID- 26116881 TI - The two transmembrane helices of CcoP are sufficient for assembly of the cbb3 type heme-copper oxygen reductase from Vibrio cholerae. AB - The C-family (cbb3) of heme-copper oxygen reductases are proton-pumping enzymes terminating the aerobic respiratory chains of many bacteria, including a number of human pathogens. The most common form of these enzymes contains one copy each of 4 subunits encoded by the ccoNOQP operon. In the cbb3 from Rhodobacter capsulatus, the enzyme is assembled in a stepwise manner, with an essential role played by an assembly protein CcoH. Importantly, it has been proposed that a transient interaction between the transmembrane domains of CcoP and CcoH is essential for assembly. Here, we test this proposal by showing that a genetically engineered form of cbb3 from Vibrio cholerae (CcoNOQP(X)) that lacks the hydrophilic domain of CcoP, where the two heme c moieties are present, is fully assembled and stable. Single-turnover kinetics of the reaction between the fully reduced CcoNOQP(X) and O2 are essentially the same as the wild type enzyme in oxidizing the 4 remaining redox-active sites. The enzyme retains approximately 10% of the steady state oxidase activity using the artificial electron donor TMPD, but has no activity using the physiological electron donor cytochrome c4, since the docking site for this cytochrome is presumably located on the absent domain of CcoP. Residue E49 in the hydrophobic domain of CcoP is the entrance of the K(C)-channel for proton input, and the E49A mutation in the truncated enzyme further reduces the steady state activity to less than 3%. Hence, the same proton channel is used by both the wild type and truncated enzymes. PMID- 26116882 TI - The total margin of exposure of ethanol and acetaldehyde for heavy drinkers consuming cider or vodka. AB - Heavy drinkers in Scotland may consume 1600 g ethanol per week. Due to its low price, cider may be preferred over other beverages. Anecdotal evidence has linked cider to specific health hazards beyond other alcoholic beverages. To examine this hypothesis, nine apple and pear cider samples were chemically analysed for constituents and contaminants. None of the products exceeded regulatory or toxicological thresholds, but the regular occurrence of acetaldehyde in cider was detected. To provide a quantitative risk assessment, two collectives of exclusive drinkers of cider and vodka were compared and the intake of acetaldehyde was estimated using probabilistic Monte-Carlo type analysis. The cider consumers were found to ingest more than 200-times the amount of acetaldehyde consumed by vodka consumers. The margins of exposure (MOE) of acetaldehyde were 224 for the cider and over 220,000 for vodka consumers. However, if the effects of ethanol were considered in a cumulative assessment of the combined MOE, the effect of acetaldehyde was minor and the combined MOE for both groups was 0.3. We suggest that alcohol policy priority should be given on reducing ethanol intake by measures such as minimum pricing, rather than to focus on acetaldehyde. PMID- 26116883 TI - RIFM fragrance ingredient safety assessment, isophytol, CAS Registry Number 505 32-8. PMID- 26116884 TI - Saururus chinensis Baill induces apoptosis through endoplasmic reticulum stress in HepG2 hepatocellular carcinoma cells. AB - In this study, we examined the mechanism underlying the effect of Saururus chinensis Baill (saururaceae) on hepatocellular carcinoma HepG2 cells. HepG2 cells and Chang cells were exposed to various concentrations of S. chinensis Baill extract (SC-E) for 24 h. SC-E affected more significantly HepG2 cells than Chang cells in terms of cell viability and ATP production. Therefore, current study examined detailed mechanism how SC-E affected HepG2 cell survival. We found that SC-E (75 and 150 MUg/ml) induced apoptosis via oxidative stress. SC-E also caused CCAAT-enhancer-binding protein homologous protein (CHOP) activation by dissociating the binding immunoglobulin protein (BiP) from inositol-requiring 1alpha (IRE1alpha) in the endoplasmic reticulum (ER) and induced Bax, cytochrome c release to cytosol, caspase-3 activation, and poly ADP ribose polymerase (PARP) cleavage, resulting in HepG2 cell apoptosis. Furthermore, SC-E caused ER Ca(2+) leakage into the cytosol; ER dilation and mitochondrial membrane damage were observed in transmission electron microscopy (TEM). Taken together, our results demonstrated that SC-E induced cancer cell apoptosis specifically through ER stress. PMID- 26116885 TI - Redox state influence on human galectin-1 function. AB - Intracellular and extracellular functions of human galectin-1 are influenced by its redox surroundings due to the presence of six cysteines within its amino acid sequence. Galectin-1 recognises intracellular-membrane-anchored Ras proteins that act as molecular switches regulating multiple signal transduction pathways. Human tumours frequently express Ras proteins that have become continuously activated due to point mutations, and this typically leads to deregulation of tumour cell growth, angiogenesis and invasion of metastatic cancer cells. Of significance is that galectin-1 preferably recognises H-Ras, one of the human Ras isoforms, and in particular galectin-1 recognition of the H-Ras farnesyl moiety is paramount to H-Ras membrane anchorage, a prerequisite step for H-Ras-mediated signal transduction regulating normal cell growth and malignant transformation. Herein the impact of the redox state on galectin-1's ability to interact with farnesyl analogues is explored. We demonstrate for the first time that reduced galectin-1 directly binds farnesyl and does so in a carbohydrate-independent manner. A K28T mutation abolishes farnesyl recognition by reduced dimeric galectin-1 whilst its carbohydrate-binding activity is retained, thus demonstrating the presence of an independent region on galectin-1 pertaining to growth inhibitory activity. Intriguingly, oxidised galectin-1 also recognises farnesyl, the biological implication of this novel finding is yet to be elucidated. Further, the redox effect on galectin-1 extracellular function was investigated and we discover that oxidised galectin-1 demonstrates a protective effect upon acute lymphoblastic leukaemia cells challenged by oxidative stress. PMID- 26116886 TI - Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis. AB - Liver fibrosis is an important pathological repair process in reaction to liver injury characterized by progressive accumulation of extracellular matrix (ECM) components. Mechanism that orchestrates this fibrotic disorder is the activation of hepatic stellate cell (HSC) that requires extensive alterations in gene expression. Reversible deacetylation of histone proteins is one of the most abundant epigenetic modifications and is crucial in modulating gene expression. Recent evidence has highlighted a pathological imbalance between the acetylation and deacetylation of histone proteins regulated by histone deacetylases (HDACs). In the past several years, the role of HDACs in liver fibrosis initiation and progression, as well as the therapeutic effects of HDAC inhibitors, has been well studied. Here, the innovative aspects of histone deacetylation will be presented, with respect to the roles of HDACs in liver fibrosis, the affected genes and signal pathways involved in HSCs activation, as well as significant data emerging from the field in support of HDAC inhibitors as potential therapeutic targets for the treatment of liver fibrosis. PMID- 26116887 TI - A specific proteomic response of Sulfolobus solfataricus P2 to gamma radiations. AB - Sulfolobus solfataricus is an acidophilic hyperthermophilic crenarchaeon living at 80 degrees C in aerobic conditions. As other thermophilic organisms, S. solfataricus is resistant to gamma irradiation and we studied the response of this microorganism to this ionizing irradiation by monitoring cell growth, DNA integrity and proteome variations. In aerobic conditions, the S. solfataricus genome was fragmented due to the multiple DNA double strand breakages induced by gamma-rays and was fully restored within a couple of hours. Comparison of irradiated and unirradiated cell proteomes indicated that only few proteins changed. The proteins identified by mass spectrometry are involved in different cellular pathways including DNA replication, recombination and repair. Interestingly, we observed that some proteins are irradiation dose-specific while others are common to the cell response regardless of the irradiation dose. Most of the proteins highlighted in these conditions seem to act together to allow an efficient cell response to gamma-irradiation. PMID- 26116888 TI - EndoQ and EndoV work individually for damaged DNA base repair in Pyrococcus furiosus. AB - Base deamination is a typical form of DNA damage, and it must be repaired quickly to maintain the genome integrity of living organisms. Endonuclease Q (EndoQ), recently found in the hyperthermophilic archaea, is an enzyme that cleaves the phosphodiester bond 5' from the damaged nucleotide in the DNA strand, and may primarily function to start the repair process for the damaged bases. Endonuclease V (EndoV) also hydrolyzes the second phosphodiester bond 3' from the damaged nucleotide, although the hyperthermophilic archaeal EndoV is a strictly hypoxanthine-specific endonuclease. To understand the relationships of the EndoQ and EndoV functions in hyperthermophilic archaea, we analyzed their interactions in hypoxanthine repair. EndoQ and EndoV do not directly interact with each other in either the presence or absence of DNA. However, EndoQ and EndoV individually worked on deoxyinosine (dI)-containing DNA at each cleavage site. EndoQ has higher affinity to dI-containing DNA than EndoV, and cells produce higher amounts of EndoQ, as compared to EndoV. These data support the proposal that EndoQ primarily functions for, at least, dI-containing DNA. PMID- 26116890 TI - Re-examining the effectiveness of monogamy as an STI-preventive strategy. AB - The utility of monogamy (in practice) as a strategy for preventing sexually transmitted infections (STIs) was investigated. By reviewing recent literature surrounding monogamous relationships and sexual behaviors, the authors determined that monogamy might not prevent against STIs as expected. First, the authors elucidate the ways in which public health officials and the general public define and interpret monogamy and discuss how this contributes to monogamy as an ineffectual STI prevention strategy. Second, the authors provide evidence that individuals' compliance with monogamy is likely to be low, similar to rates of compliance with other medical advice. Lastly, the authors draw upon recent research findings suggesting that people who label themselves as monogamous are less likely to engage in safer sex behaviors than people who have an explicit agreement with their partner to be non-monogamous. Future research and clinical directions to promote sexual health and destigmatize sexual behaviors are considered. PMID- 26116889 TI - Perceived effectiveness of HPV test as a primary screening modality among US providers. AB - BACKGROUND: The human papillomavirus (HPV) test, administered alone without the Papanicolaou (Pap) test, was recently recognized as a cervical cancer screening option in the United States by the Society of Gynecologic Oncology and the American Society for Colposcopy and Cervical Pathology, and the Food and Drug Administration has approved an HPV test for primary screening. METHODS: Surveys of US internists, family practitioners, nurse practitioners, and obstetrician gynecologists were conducted in 2009 and 2012 to investigate providers' perceptions of the effectiveness of the HPV test administered alone as a population-based screening modality (2009: N=1040, 141-494 per provider group; 2012: N=1039, 155-435 per provider group). RESULTS: The majority in each provider group agreed that the HPV test administered alone is an effective screening modality in 2009 (75.3%-86.1%) and 2012 (79.5%-91.8%), and agreement rose significantly during this time period among family practitioners (chi(2)=15.26, df=1, p<0.001) and nurse practitioners (chi(2)=4.53, df=1, p=0.033). CONCLUSIONS: Agreement that the HPV test administered alone is an effective cervical cancer screening modality was widespread among providers in both 2009 and 2012, however implementation of guidelines for screening with the HPV test may be influenced by many other factors including reimbursement and patient preferences. PMID- 26116891 TI - Microglia in the pathogenesis of autism spectrum disorders. AB - Proper synaptic pruning is essential for the development of functional neural circuits. Impairments in synaptic pruning disrupt the excitatory versus inhibitory balance (E/I balance) of synapses, which may cause neurodevelopmental disorders such as autism spectrum disorder (ASD). Recent studies have determined molecular mechanisms by which microglia, the brain's resident immune cells, engulf inappropriate and less active synapses. Thus, microglial dysfunction may be involved in the pathogenesis of ASD through attenuated or excess synaptic pruning. In this review, we discuss recent animal and human studies that report an E/I imbalance and the characteristics of microglia in ASD. We will further discuss whether and how synaptic pruning by microglia is involved in the pathogenesis of ASD. PMID- 26116892 TI - Application of failure mode and effects analysis in a clinical chemistry laboratory. AB - BACKGROUND: Timely delivery of correct results has long been considered as the goal of quality management in clinical laboratory. With increasing workload as well as complexities of laboratory testing and patient care, the traditional technical adopted like internal quality control (IQC) and external quality assessment (EQA) may not enough to cope with quality management problems for clinical laboratories. We applied failure mode and effects analysis (FMEA), a proactive tool, to reduce errors associated with the process beginning with sample collection and ending with a test report in a clinical chemistry laboratory. Our main objection was to investigate the feasibility of FMEA in a real-world situation, namely the working environment of hospital. METHODS: A team of 8 people (3 laboratory workers, 2 couriers, 2 nurses, and 1 physician) from different departments who were involved in the testing process were recruited and trained. Their main responsibility was to analyze and score all possible clinical chemistry laboratory failures based on three aspects: the severity of the outcome (S), the likeliness of occurrence (O), and the probability of being detected (D). These three parameters were multiplied to calculate risk priority numbers (RPNs), which were used to prioritize remedial measures. Failure modes with RPN>=200 were deemed as high risk, meaning that they needed immediate corrective action. After modifications that were put, we compared the resulting RPN with the previous one. RESULTS: A total of 33 failure modes were identified. Many of the failure modes, including the one with the highest RPN (specimen hemolysis) appeared in the pre analytic phase, whereas no high-risk failure modes (RPN>=200) were found during the analytic phase. High-priority risks were "sample hemolysis" (RPN, 336), "sample delivery delay" (RPN, 225), "sample volume error" (RPN, 210), "failure to release results in a timely manner" (RPN, 210), and "failure to identify or report critical results" (RPN, 200). The corrective measures that we took allowed a decrease in the RPN, especially for the high-priority risks. The maximum reduction was approximately 70%, as observed for the failure mode "sample hemolysis". CONCLUSIONS: FMEA can effectively reduce errors in clinical chemistry laboratories. PMID- 26116893 TI - MicroRNAs: Key regulators of endothelial progenitor cell functions. AB - Development of cardiovascular diseases mobilises endothelial progenitor cells (EPCs) from the bone marrow to participate in vascular repair and formation of new blood vessels under both pathological and physiological conditions. Therefore, EPCs show great potential for therapeutic applications; however, the phenotypic and functional characterisation of EPCs is still difficult because controversies exist regarding their accurate definition. Growing studies have shown modest clinical benefits of EPCs; however, it is necessary to better understand the regulation of EPC functions. MicroRNAs are small, non-coding, single-stranded RNAs with regulatory activities. Results of some recent studies have found that microRNAs play an important role in regulating EPC functions. In this review, we will summarise the results of some recent studies to provide an integral picture of the role of microRNAs in the regulation of EPC functions and will discuss the therapeutic applications and the new research direction. PMID- 26116894 TI - Stability of vitamin B12 - A preanalytical view. PMID- 26116895 TI - Interleukin-18 promoter -607 C/A and -137 G/C polymorphisms and susceptibility to type 1 diabetes: A meta-analysis. AB - OBJECTIVE: The aim of this study was to determine whether the functional interleukin-18 (IL-18) promoter -607 C/A (rs1946518) and -137 G/C (rs187238) polymorphisms are associated with susceptibility to type 1 diabetes (TID). METHODS: A meta-analysis was conducted to assess the associations between the IL 18 -607 C/A and -137 G/C polymorphisms and T1D in overall and by ethnic group. RESULTS: A total of 6075 cases and 5744 controls from ten studies were considered in this meta-analysis. In all study subjects, the meta-analysis showed no association between T1D and the IL-18 -607 C allele (OR=1.083, 95% CI=0.930 1.260, p=0.307). However, stratification by ethnicity indicated an association between the IL-18 -607 C allele and T1D in Asians (OR=1.506, 95% CI=1.172-1.936, p=0.001), but not in Europeans (OR=0.988, 95% CI=0.808-1.209, p=0.907). Analysis using recessive and dominant models and homozygote contrast showed the same -607 C allele pattern in Asians and Europeans. Meta-analysis of the IL-18 -137 G/C polymorphism showed no association between T1D and the IL-18 -137 G allele in all study subjects (OR=1.066, 95% CI=0.926-1.2289, p=0.375). Stratification by ethnicity indicated no association between the IL-18 -137 G allele and T1D in Europeans and Asians (OR=1.021, 95% CI=0.961-1.085, p=0.504; OR=0.851, 95% CI=0.5821-1.245, p=0.406). CONCLUSIONS: Our meta-analysis demonstrates that the IL-18 -607 C/A polymorphism may be associated with susceptibility to T1D in Asians, but not in Europeans. PMID- 26116896 TI - Pregnancy-induced HLA antibodies respond more vigorously after renal transplantation than antibodies induced by prior transplantation. AB - Acute antibody mediated rejection after HLA-specific antibody incompatible renal transplantation is related to donor specific HLA antibody (DSA) levels. DSA levels may rise sharply after transplant, and aim of this study was to examine changes in DSA levels, particularly according to the primary sensitising event. Changes in 220 HLA specificities in 64 patients over the first 30days after transplantation were evaluated using microbead assays. The greatest increase from pre-treatment to peak DSA levels was seen in pregnancy-stimulated specificities, median (IQR) increase in MFI of 1981 (94-5870). The next highest increase was for those sensitised by transplant with repeat HLA epitope mismatch, at 546 (-308 2698) (p<0.01). The difference was especially marked when the pre-treatment antibody level was low; with pre-treatment MFI <1000, peak level was >1000 in 19/26 (73%) of pregnancy stimulated specificities, compared with 9/29 (31%) for all others (p<0.001). DSA production to specificities stimulated by previous pregnancy was marked, even from very low pre-transplant levels. By contrast, there was a lower rate of antibody resynthesis to specificities repeated from previous transplants, both at antigen and epitope levels. PMID- 26116897 TI - Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. AB - Recent evidence suggests immune and inflammatory alterations are important in chronic fatigue syndrome (CFS). This study was done to explore the association of functionally important genetic variants in inflammation and immune pathways with CFS. Peripheral blood DNA was isolated from 50 CFS and 121 non-fatigued (NF) control participants in a population-based study. Genotyping was performed with the Affymetrix Immune and Inflammation Chip that covers 11K single nucleotide polymorphisms (SNPs) following the manufacturer's protocol. Genotyping accuracy for specific genes was validated by pyrosequencing. Golden Helix SVS software was used for genetic analysis. SNP functional annotation was done using SPOT and GenomePipe programs. CFS was associated with 32 functionally important SNPs: 11 missense variants, 4 synonymous variants, 11 untranslated regulatory region (UTR) variants and 6 intronic variants. Some of these SNPs were in genes within pathways related to complement cascade (SERPINA5, CFB, CFH, MASP1 and C6), chemokines (CXCL16, CCR4, CCL27), cytokine signaling (IL18, IL17B, IL2RB), and toll-like receptor signaling (TIRAP, IRAK4). Of particular interest is association of CFS with two missense variants in genes of complement activation, rs4151667 (L9H) in CFB and rs1061170 (Y402H) in CFH. A 5' UTR polymorphism (rs11214105) in IL18 also associated with physical fatigue, body pain and score for CFS case defining symptoms. This study identified new associations of CFS with genetic variants in pathways including complement activation providing additional support for altered innate immune response in CFS. Additional studies are needed to validate the findings of this exploratory study. PMID- 26116898 TI - Adenovirus VA RNA: An essential pro-viral non-coding RNA. AB - Adenovirus (AdV) 'virus-associated' RNAs (VA RNAs) are exceptionally abundant (up to 10(8)copies/cell), heterogeneous, non-coding RNA transcripts (~ 150-200 nucleotides). The predominant species, VA RNAI, is best recognized for its essential function in relieving the cellular anti-viral blockade of protein synthesis through inhibition of the double-stranded RNA-activated protein kinase (PKR). More recent evidence has revealed that VA RNAs also interfere with several other host cell processes, in part by virtue of the high level to which they accumulate. Following transcription by cellular RNA polymerase III, VA RNAs saturate the nuclear export protein Exportin 5 (Exp5) and the cellular endoribonculease Dicer, interfering with pre-micro (mi)RNA export and miRNA biogenesis, respectively. Dicer-processed VA RNA fragments are incorporated into the RNA-induced silencing complex (RISC) as 'mivaRNAs', where they may specifically target cellular genes. VA RNAI also interacts with other innate immune proteins, including OAS1. While intact VA RNAI has the paradoxical effect of activating OAS1, a non-natural VA RNAI construct lacking the entire Terminal Stem has been reported to be a pseudoinhibitor of OAS1. Here, we show that a VA RNAI construct corresponding to an authentic product of Dicer processing similarly fails to activate OAS1 but also retains only a modest level of inhibitory activity against PKR in contrast to the non-natural deletion construct. These findings underscore the complexity of the arms race between virus and host, and highlight the need for further exploration of the impact of VA RNAI interactions with host defenses on the outcome of AdV infection beyond that of well-established PKR inhibition. Additional contributions of VA RNAI heterogeneity resulting from variations in transcription initiation and termination to each of these functions remain open questions that are discussed here. PMID- 26116899 TI - Genome-wide transcriptional profiling reveals that HIV-1 Vpr differentially regulates interferon-stimulated genes in human monocyte-derived dendritic cells. AB - Dendritic cells (DCs) are potent antigen-presenting cells (APCs) that directly link the innate and adaptive immune responses. HIV-1 infection of DCs leads to a diverse array of changes in gene expression and play a major role in dissemination of the virus into T-cells. Although HIV-1 Vpr is a pleiotropic protein involved in HIV-1 replication and pathogenesis, its exact role in APCs such as DCs remains elusive. In this study, utilizing a microarray-based systemic biology approach, we found that HIV-1 Vpr differentially regulates (fold change >2.0) more than 200 genes, primarily those involved in the immune response and innate immune response including type I interferon signaling pathway. The differential expression profiles of select genes involved in innate immune responses (interferon-stimulated genes [ISGs]), including MX1, MX2, ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI27, IFI44L, and TNFSF10, were validated by real-time quantitative PCR; the results were consistent with the microarray data. Taken together, our findings are the first to demonstrate that HIV-1 Vpr induces ISGs and activates the type I IFN signaling pathway in human DCs, and provide insights into the role of Vpr in HIV-1 pathogenesis. PMID- 26116900 TI - Plant subviral RNAs as a long noncoding RNA (lncRNA): Analogy with animal lncRNAs in host-virus interactions. AB - Satellite RNAs (satRNAs) and viroids belong to the group called subviral agents and are the smallest pathogens of plants. In general, small satRNAs and viroids are 300-400 nt in size and do not encode any functional proteins; they are thus regarded as so-called long noncoding RNAs (lncRNAs). These lncRNAs are receiving great attention as a new RNA class involved in gene regulation to control important biological processes such as gene transcription and epigenetic regulation. A substantial number of lncRNAs in animal cells have been found to play important roles in the interactions between a virus and its host. We here discuss the pathogenicity of subviral RNAs (especially satRNAs) in plant cells and their functions as lncRNAs associated with viral diseases, using animal lncRNAs as an analogy. Because, unlike animal lncRNAs, plant subviral RNAs can replicate and accumulate at very high levels in infected cells, we here considered the unique possibility that the RNA silencing machinery of plants, an important defense mechanism against virus infection, may have brought about the replication ability of subviral molecules. In addition, we also discuss the possibility that satRNAs may have arisen from plant-virus interactions in virus infected cells. Understanding the molecular functions of these unique lncRNAs in plants will enable us to reveal the most plausible origins of these subviral RNAs. PMID- 26116901 TI - High-dose cyclophosphamide induces specific tumor immunity with concomitant recruitment of LAMP1/CD107a-expressing CD4-positive T cells into tumor sites. AB - Cancer chemotherapy regimens, particularly those employing high-dose cytotoxic drugs such as cyclophosphamide (CTX), have been considered to be immune suppressive. However, we observed that a single administration of high-dose CTX abolished tumors arising from subcutaneous injection of a mouse hepatoma cell line and subsequently induced specific tumor immunity. Depletion of T cells, specifically CD4(+) T cells, abrogated the CTX-mediated tumor regression. CTX treatment induced the rapid recruitment of CD4(+) T cells into the tumors, and these recruited cells initiated expression of LAMP1/CD107a, a cytotoxic granule molecule, and granzyme B in the absence of antigen presentation at draining lymph nodes and proliferation in the tumor tissues. Moreover, CTX enhanced the expression of a CC chemokine, CCL3, in tumor tissues, and CTX-mediated tumor regression was attenuated in mice deficient in CCR5, the receptor for this chemokine. Consistently, less CTX-induced accumulation of intratumoral LAMP1/CD107a-expressing CD4(+) T cells was observed in mice receiving splenocytes derived from CCR5-deficient mice than in those receiving splenocytes derived from WT mice. Thus, CTX induces the expression of CCL3, which induces the intratumoral migration of CD4(+) T cells expressing cytotoxic molecules, leading to tumor eradication and subsequent specific tumor immunity. PMID- 26116902 TI - Hypoxia inducible factor-1alpha: Its role in colorectal carcinogenesis and metastasis. AB - Tumor growth creates a hypoxic microenvironment, which promotes angiogenesis and aggressive tumor growth and invasion. HIF1alpha is a central molecule involved in mediating these effects of hypoxia. In colorectal cancer (CRC), hypoxia stabilizes the transcription factor HIF1alpha, leading to the expression of genes that are involved in tumor vascularization, metastasis/migration, cell survival and chemo-resistance. Therefore, HIF1alpha is a rational target for the development of new therapeutics for CRC. This article reviews the central role of HIF1alpha in CRC angiogenesis, metastasis, and progression as well as the strategies to target HIF1alpha stabilization. PMID- 26116904 TI - Microbead models in glaucoma. AB - The sustained and moderate elevation of intraocular pressure, which can be initiated at precise time points, remains the cornerstone of research into the mechanisms of glaucomatous retinal damage. We focus on the use of microbeads to block the outflow of aqueous following anterior chamber injection in a range of animals (mouse, rat and primate). We describe some of the most commonly used parameters and present guidance on injection technique and bead manipulation to facilitate the successful generation of experimental glaucoma. PMID- 26116905 TI - Expression profile of IL-1 family cytokines in aqueous humor and sera of patients with HLA-B27 associated anterior uveitis and idiopathic anterior uveitis. AB - The purpose of this study was to evaluate the cytokine expression profile of specific IL-1 family members in the aqueous humor and sera of patients with HLA B27 associated acute anterior uveitis (AAU) and idiopathic AAU. Following informed consent, a total of 13 patients with HLA-B27 associated AAU, 12 patients with idiopathic AAU and 9 controls were recruited to this study from May 2013 to July 2014. Each individual received a complete ophthalmologic examination. Aqueous humor and sera samples were collected and 11 inflammation-related cytokines of the IL-1 family (IL-1alpha, IL-1beta, IL-1 receptor antagonist [IL 1Ra], IL-18, IL-36 receptor antagonist [IL-36Ra], IL-33, IL-36alpha, IL-36beta, IL-36gamma, IL-37, IL-38) were quantitatively measured and analyzed for statistical significance between groups. The degree of inflammation, anterior chamber cell or flare, correlated with expression of IL-1beta, IL-1Ra, and IL-18. The highest levels of IL-1beta, IL-1Ra, IL-18, and IL-36Ra were seen in the aqueous of patients with HLA-B27 associated AAU and this was statically significant when compared to the controls, but not to idiopathic AAU. Expression of IL-18 was statistically higher in the aqueous of patients with HLA-B27 associated AAU in comparison to either idiopathic AAU or controls, but this may reflect greater inflammation in this patient group. In the sera only IL-1alpha was statistically higher in the HLA-B27 associated AAU in comparison to the control. Cytokine analysis reveals elevation of multiple IL-1 family members in the aqueous humor of patients with AAU as compared to controls. The specific signature of inflammation may potentially be useful in developing new future therapies for AAU. PMID- 26116906 TI - Alpha particles induce pan-nuclear phosphorylation of H2AX in primary human lymphocytes mediated through ATM. AB - The use of high linear energy transfer radiations in the form of carbon ions in heavy ion beam lines or alpha particles in new radionuclide treatments has increased substantially over the past decade and will continue to do so due to the favourable dose distributions they can offer versus conventional therapies. Previously it has been shown that exposure to heavy ions induces pan-nuclear phosphorylation of several DNA repair proteins such as H2AX and ATM in vitro. Here we describe similar effects of alpha particles on ex vivo irradiated primary human peripheral blood lymphocytes. Following alpha particle irradiation pan nuclear phosphorylation of H2AX and ATM, but not DNA-PK and 53BP1, was observed throughout the nucleus. Inhibition of ATM, but not DNA-PK, resulted in the loss of pan-nuclear phosphorylation of H2AX in alpha particle irradiated lymphocytes. Pan-nuclear gamma-H2AX signal was rapidly lost over 24h at a much greater rate than foci loss. Surprisingly, pan-nuclear gamma-H2AX intensity was not dependent on the number of alpha particle induced double strand breaks, rather the number of alpha particles which had traversed the cell nucleus. This distinct fluence dependent damage signature of particle radiation is important in both the fields of radioprotection and clinical oncology in determining radionuclide biological dosimetry and may be indicative of patient response to new radionuclide cancer therapies. PMID- 26116907 TI - Using the local immune response from the natural buffalo host to generate an antibody fragment library that binds the early larval stages of Schistosoma japonicum. AB - Antibodies isolated from the local draining inguinal lymph node of field exposed water buffaloes following challenge with Schistosoma japonicum cercariae showed high reactivity towards S. japonicum antigen preparations and bound specifically to formaldehyde-fixed S. japonicum schistosomules. Using this specific local immune response we produced a series of single-chain antibody Fv domain libraries from the same lymph nodes. Removal of phage that cross reacted with epitopes on adult parasites yielded a single-chain antibody Fv domain-phage library that specifically bound to whole formaldehyde-fixed and live S. japonicum schistosomules. DNA sequencing indicated clear enrichment of the single-chain antibody Fv domain library for buffalo B-cell complementarity determining regions post-selection for schistosomule binding. This study also revealed that long heavy chain complementarity determining regions appear to be an important factor when selecting for antibody binding fragments against schistosomule proteins. The selected single-chain antibody Fv domain-phage were used to probe a schistosome specific protein microarray, which resulted in the recognition of many proteins expressed across all schistosome life-cycle stages. Following absorption to adult worms, the single-chain antibody Fv domain-phage library showed significantly reduced binding to most proteins, whilst two proteins (NCBI GenBank accession numbers AY915878 and AY815196) showed increased binding. We have thus developed a unique set of host derived single-chain antibody Fv domains comprising buffalo B cell variable regions that specifically bind to early S. japonicum life-stages. PMID- 26116903 TI - Using genetic mouse models to gain insight into glaucoma: Past results and future possibilities. AB - While all forms of glaucoma are characterized by a specific pattern of retinal ganglion cell death, they are clinically divided into several distinct subclasses, including normal tension glaucoma, primary open angle glaucoma, congenital glaucoma, and secondary glaucoma. For each type of glaucoma there are likely numerous molecular pathways that control susceptibility to the disease. Given this complexity, a single animal model will never precisely model all aspects of all the different types of human glaucoma. Therefore, multiple animal models have been utilized to study glaucoma but more are needed. Because of the powerful genetic tools available to use in the laboratory mouse, it has proven to be a highly useful mammalian system for studying the pathophysiology of human disease. The similarity between human and mouse eyes coupled with the ability to use a combination of advanced cell biological and genetic tools in mice have led to a large increase in the number of studies using mice to model specific glaucoma phenotypes. Over the last decade, numerous new mouse models and genetic tools have emerged, providing important insight into the cell biology and genetics of glaucoma. In this review, we describe available mouse genetic models that can be used to study glaucoma-relevant disease/pathobiology. Furthermore, we discuss how these models have been used to gain insights into ocular hypertension (a major risk factor for glaucoma) and glaucomatous retinal ganglion cell death. Finally, the potential for developing new mouse models and using advanced genetic tools and resources for studying glaucoma are discussed. PMID- 26116908 TI - Separating stages of arithmetic verification: An ERP study with a novel paradigm. AB - In studies of arithmetic verification, participants typically encounter two operands and they carry out an operation on these (e.g. adding them). Operands are followed by a proposed answer and participants decide whether this answer is correct or incorrect. However, interpretation of results is difficult because multiple parallel, temporally overlapping numerical and non-numerical processes of the human brain may contribute to task execution. In order to overcome this problem here we used a novel paradigm specifically designed to tease apart the overlapping cognitive processes active during arithmetic verification. Specifically, we aimed to separate effects related to detection of arithmetic correctness, detection of the violation of strategic expectations, detection of physical stimulus properties mismatch and numerical magnitude comparison (numerical distance effects). Arithmetic correctness, physical stimulus properties and magnitude information were not task-relevant properties of the stimuli. We distinguished between a series of temporally highly overlapping cognitive processes which in turn elicited overlapping ERP effects with distinct scalp topographies. We suggest that arithmetic verification relies on two major temporal phases which include parallel running processes. Our paradigm offers a new method for investigating specific arithmetic verification processes in detail. PMID- 26116909 TI - Excitability of the motor system: A transcranial magnetic stimulation study on singing and speaking. AB - The perception of movements is associated with increased activity in the human motor cortex, which in turn may underlie our ability to understand actions, as it may be implicated in the recognition, understanding and imitation of actions. Here, we investigated the involvement and lateralization of the primary motor cortex (M1) in the perception of singing and speech. Transcranial magnetic stimulation (TMS) was applied independently for both hemispheres over the mouth representation of the motor cortex in healthy participants while they watched 4-s audiovisual excerpts of singers producing a 2-note ascending interval (singing condition) or 4-s audiovisual excerpts of a person explaining a proverb (speech condition). Subjects were instructed to determine whether a sung interval/written proverb, matched a written interval/proverb. During both tasks, motor evoked potentials (MEPs) were recorded from the contralateral mouth muscle (orbicularis oris) of the stimulated motor cortex compared to a control task. Moreover, to investigate the time course of motor activation, TMS pulses were randomly delivered at 7 different time points (ranging from 500 to 3500 ms after stimulus onset). Results show that stimulation of the right hemisphere had a similar effect on the MEPs for both the singing and speech perception tasks, whereas stimulation of the left hemisphere significantly differed in the speech perception task compared to the singing perception task. Furthermore, analysis of the MEPs in the singing task revealed that they decreased for small musical intervals, but increased for large musical intervals, regardless of which hemisphere was stimulated. Overall, these results suggest a dissociation between the lateralization of M1 activity for speech perception and for singing perception, and that in the latter case its activity can be modulated by musical parameters such as the size of a musical interval. PMID- 26116910 TI - Voluntary control of a phantom limb. AB - Voluntary actions are often accompanied by a conscious experience of intention. The content of this experience, and its neural basis, remain controversial. On one view, the mind just retrospectively ascribes intentions to explain the occurrence of actions that lack obvious triggering stimuli. Here, we use EEG frequency analysis of sensorimotor rhythms to investigate brain activity when a participant (CL, co-author of this paper) with congenital absence of the left hand and arm, prepared and made a voluntary action with the right or the phantom "left hand". CL reported the moment she experienced the intention to press a key. This timepoint was then used as a marker for aligning and averaging EEG. In a second condition, CL was asked to prepare the action on all trials, but then, on some trials, to cancel the action at the last moment. For the right hand, we observed a typical reduction in beta-band spectral power prior to movement, followed by beta rebound after movement. When CL prepared but then cancelled a movement, we found a characteristic EEG pattern reported previously, namely a left frontal increase in spectral power close to the time of the perceived intention to move. Interestingly, the same neural signatures of positive and inhibitory volition were also present when CL prepared and inhibited movements with her phantom left hand. These EEG signals were all similar to those reported previously in a group of 14 healthy volunteers. Our results suggest that conscious intention may depend on preparatory brain activity, and not on making, or ever having made, the corresponding physical body movement. Accounts that reduce conscious volition to mere retrospective confabulation cannot easily explain our participant's neurophenomenology of action and inhibition. In contrast, the results are consistent with the view that specific neural events prior to movement may generate conscious experiences of positive and negative volition. PMID- 26116911 TI - Mesenchymal stromal cells and hematopoietic stem cell transplantation. AB - Mesenchymal stromal cells (MSCs) comprise a heterogeneous population of multipotent cells that can be isolated from various human tissues and culture expanded ex vivo for clinical use. Due to their immunoregulatory properties and their ability to secrete growth factors, MSCs play a key role in the regulation of hematopoiesis and in the modulation of immune responses against allo- and autoantigens. In light of these properties, MSCs have been employed in clinical trials in the context of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs) and to prevent graft failure, as well as to treat steroid-resistant acute graft-versus-host disease (GvHD). The available clinical evidence derived from these studies indicates that MSC administration is safe. Moreover, promising preliminary results in terms of efficacy have been reported in some clinical trials, especially in the treatment of acute GvHD. In this review we critically discuss recent advances in MSC therapy by reporting on the most relevant studies in the field of HSCT. PMID- 26116912 TI - Structure and function of alpha-crystallins: Traversing from in vitro to in vivo. AB - BACKGROUND: The two alpha-crystallins (alphaA- and alphaB-crystallin) are major components of our eye lenses. Their key function there is to preserve lens transparency which is a challenging task as the protein turnover in the lens is low necessitating the stability and longevity of the constituent proteins. alpha Crystallins are members of the small heat shock protein family. alphaB-crystallin is also expressed in other cell types. SCOPE OF THE REVIEW: The review summarizes the current concepts on the polydisperse structure of the alpha-crystallin oligomer and its chaperone function with a focus on the inherent complexity and highlighting gaps between in vitro and in vivo studies. MAJOR CONCLUSIONS: Both alpha-crystallins protect proteins from irreversible aggregation in a promiscuous manner. In maintaining eye lens transparency, they reduce the formation of light scattering particles and balance the interactions between lens crystallins. Important for these functions is their structural dynamics and heterogeneity as well as the regulation of these processes which we are beginning to understand. However, currently, it still remains elusive to which extent the in vitro observed properties of alpha-crystallins reflect the highly crowded situation in the lens. GENERAL SIGNIFICANCE: Since alpha-crystallins play an important role in preventing cataract in the eye lens and in the development of diverse diseases, understanding their mechanism and substrate spectra is of importance. To bridge the gap between the concepts established in vitro and the in vivo function of alpha-crystallins, the joining of forces between different scientific disciplines and the combination of diverse techniques in hybrid approaches are necessary. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID- 26116913 TI - Gamma crystallins of the human eye lens. AB - BACKGROUND: Protein crystallins co me in three types (alpha, beta and gamma) and are found predominantly in the eye, and particularly in the lens, where they are packed into a compact, plastic, elastic, and transparent globule of proper refractive power range that aids in focusing incoming light on to the retina. Of these, the gamma-crystallins are found largely in the nuclear region of the lens at very high concentrations (>400 mg/ml). The connection between their structure and inter-molecular interactions and lens transparency is an issue of particular interest. SCOPE OF REVIEW: We review the origin and phylogeny of the gamma crystallins, their special structure involving the use of Greek key supersecondary structural motif, and how they aid in offering the appropriate refractive index gradient, intermolecular short range attractive interactions (aiding in packing them into a transparent ball), the role that several of the constituent amino acid residues play in this process, the thermodynamic and kinetic stability and how even single point mutations can upset this delicate balance and lead to intermolecular aggregation, forming light-scattering particles which compromise transparency. We cite several examples of this, and illustrate this by cloning, expressing, isolating and comparing the properties of the mutant protein S39C of human gammaS-crystallin (associated with congenital cataract-microcornea), with those of the wild type molecule. In addition, we note that human gamma-crystallins are also present in other parts of the eye (e.g., retina), where their functions are yet to be understood. MAJOR CONCLUSIONS: There are several 'crucial' residues in and around the Greek key motifs which are essential to maintain the compact architecture of the crystallin molecules. We find that a mutation that replaces even one of these residues can lead to reduction in solubility, formation of light-scattering particles and loss of transparency in the molecular assembly. GENERAL SIGNIFICANCE: Such a molecular understanding of the process helps us construct the continuum of genotype molecular structural phenotype-clinical (pathological) phenotype. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID- 26116914 TI - Raf kinase inhibitor protein mediated signaling inhibits invasion and metastasis of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality and poor prognosis. Mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB) signaling pathways have been implicated in promoting tumor cell proliferation and invasion of HCC cells. METHODS: As a potential inhibitor of tumor metastasis, the role of Raf kinase inhibitor protein (RKIP) in HCC development and the functional relevance with MAPK and NF-kappaB signaling pathways were investigated. The levels of RKIP expression were examined in human HCC tissues and correlated with tumor stages and metastatic status. Function of RKIP in cellular proliferation, migration, invasion and apoptosis was investigated in HCC cell lines by either overexpressing or knocking down RKIP expression. Mouse xenograft model was established to assess the effect of RKIP expression on tumor growth. RESULTS: Our results demonstrated decreased RKIP expression in HCC tissues and a strong correlation with tumor grade and distant metastasis. Manipulation of RKIP expression in HCCLM3 and HepG2 cells indicated that RKIP functioned to inhibit HCC cell motility and invasiveness, and contributed to tumor growth inhibition in vivo. Mechanistic studies showed that the function of RKIP was mediated through MAPK and NF-kappaB signaling pathways. However, cell type-dependent RKIP regulation on these two pathways was also suggested, indicating the complex nature of signaling network. CONCLUSION: Our study provides a better understanding on the molecular mechanisms of HCC metastasis and sets the foundation for the development of targeted therapeutics for HCC. PMID- 26116915 TI - Auxin-driven patterning with unidirectional fluxes. AB - The plant hormone auxin plays an essential role in the patterning of plant structures. Biological hypotheses supported by computational models suggest that auxin may fulfil this role by regulating its own transport, but the plausibility of previously proposed models has been questioned. We applied the notion of unidirectional fluxes and the formalism of Petri nets to show that the key modes of auxin-driven patterning-the formation of convergence points and the formation of canals-can be implemented by biochemically plausible networks, with the fluxes measured by dedicated tally molecules or by efflux and influx carriers themselves. Common elements of these networks include a positive feedback of auxin efflux on the allocation of membrane-bound auxin efflux carriers (PIN proteins), and a modulation of this allocation by auxin in the extracellular space. Auxin concentration in the extracellular space is the only information exchanged by the cells. Canalization patterns are produced when auxin efflux and influx act antagonistically: an increase in auxin influx or concentration in the extracellular space decreases the abundance of efflux carriers in the adjacent segment of the membrane. In contrast, convergence points emerge in networks in which auxin efflux and influx act synergistically. A change in a single reaction rate may result in a dynamic switch between these modes, suggesting plausible molecular implementations of coordinated patterning of organ initials and vascular strands predicted by the dual polarization theory. PMID- 26116916 TI - The enigmatic nodding syndrome outbreak in northern Uganda: an analysis of the disease burden and national response strategies. AB - To date, the cause of nodding syndrome (NS) remains unknown; however, efforts continue to establish risk factors and optimal symptomatic treatments. We documented the burden and national response strategies including involvement of key stakeholders in the management of the NS epidemic in order to inform future interventions against epidemics of undetermined aetiology. Data were collected through semi-structured interviews with selected leaders in the affected districts and at the Ministry of Health, and through review of documents. We participated in and analysed the proceedings of the first international scientific conference on NS held in Kampala in August 2012. We then analysed the chronology of the NS notification and the steps undertaken in the response plan. Over 3000 children have been affected by NS in northern Uganda; with an estimated case fatality of 6.7%. The first cases of NS were reported in 1997 in internally displaced people's camps in Kitgum district; however, response efforts by the Ministry of Health and partners towards understanding the disorder and establish management only commenced in 2009. Key strategies in response to the NS epidemic have included formation of a national and district task forces, development of training manual on NS and training of primary healthcare professionals on case diagnosis and clinical management, establishment of treatment and rehabilitation centres, surveillance and promotion of researches to further inform management of the syndrome. PMID- 26116917 TI - Return-to-work outcomes and usefulness of actual fit notes received by employers. AB - BACKGROUND: GPs can use the fit note to advise that a patient 'may be fit' or is 'not fit' for work. Previous employer-based research on the fit note is largely qualitative and based on general perceptions and past experience. Knowledge of the return-to-work outcomes and usefulness of actual fit notes is needed to strengthen the evidence-base and inform practice. OBJECTIVE: To investigate the return-to-work outcomes of fit notes issued to employed patients, and their employers' opinions as to the usefulness of each note. METHODS: Participating organizations collecting fit notes were asked to rate the outcome and usefulness of each fit note via postal questionnaires. Quantitative data were analysed descriptively; qualitative data were analysed using thematic content analysis. RESULTS: Five hundred and sixteen questionnaires were posted, with a 97% return rate (n=498). More than 80% of employees (n=44) returned to work after the expiry date of a 'may be fit' note compared with 43% (n=167) of those issued with a 'not fit' note. Fit notes were considered more useful if they provided information on the condition and its effect on the employee's ability to work, if they stated whether or not the employee needed reassessment and if clear advice regarding return-to-work had been provided. CONCLUSIONS: 'May be fit' notes are useful in helping employees return to work. However, this option is infrequently used, and the completion and content of many fit notes does not meet employers' needs. These factors need to be urgently addressed if the fit note is to reach its full potential. PMID- 26116918 TI - Cytonuclear Interactions in the Evolution of Animal Mitochondrial tRNA Metabolism. AB - The evolution of mitochondrial information processing pathways, including replication, transcription and translation, is characterized by the gradual replacement of mitochondrial-encoded proteins with nuclear-encoded counterparts of diverse evolutionary origins. Although the ancestral enzymes involved in mitochondrial transcription and replication have been replaced early in eukaryotic evolution, mitochondrial translation is still carried out by an apparatus largely inherited from the alpha-proteobacterial ancestor. However, variation in the complement of mitochondrial-encoded molecules involved in translation, including transfer RNAs (tRNAs), provides evidence for the ongoing evolution of mitochondrial protein synthesis. Here, we investigate the evolution of the mitochondrial translational machinery using recent genomic and transcriptomic data from animals that have experienced the loss of mt-tRNAs, including phyla Cnidaria and Ctenophora, as well as some representatives of all four classes of Porifera. We focus on four sets of mitochondrial enzymes that directly interact with tRNAs: Aminoacyl-tRNA synthetases, glutamyl-tRNA amidotransferase, tRNA(Ile) lysidine synthetase, and RNase P. Our results support the observation that the fate of nuclear-encoded mitochondrial proteins is influenced by the evolution of molecules encoded in mitochondrial DNA, but in a more complex manner than appreciated previously. The data also suggest that relaxed selection on mitochondrial translation rather than coevolution between mitochondrial and nuclear subunits is responsible for elevated rates of evolution in mitochondrial translational proteins. PMID- 26116919 TI - Evolutionary Stasis in Cycad Plastomes and the First Case of Plastome GC-Biased Gene Conversion. AB - In angiosperms, gene conversion has been known to reduce the mutational load of plastid genomes (the plastomes). Particularly, more frequent gene conversions in inverted repeat (IR) than in single copy (SC) regions result in contrasting substitution rates between these two regions. However, little has been known about the effect of gene conversion in the evolution of gymnosperm plastomes. Cycads (Cycadophyta) are the second largest gymnosperm group. Evolutionary study of their plastomes is limited to the basal cycad genus, Cycas. In this study, we addressed three questions. 1) Do the plastomes of other cycad genera evolve slowly as previously observed in the plastome of Cycas taitungensis? 2) Do substitution rates differ between their SC and IR regions? And 3) Does gene conversion occur in the cycad plastomes? If yes, is it AT-biased or GC-biased? Plastomes of eight species from other eight genera of cycads were sequenced. These plastomes are highly conserved in genome organization. Excluding ginkgo, cycad plastomes have significantly lower synonymous and nonsynonymous substitution rates than other gymnosperms, reflecting their evolutionary stasis in nucleotide mutations. In the IRs of cycad plastomes, the reduced substitution rates and GC-biased mutations are associated with a GC-biased gene conversion (gBGC) mechanism. Further investigations suggest that in cycads, gBGC is able to rectify plastome-wide mutations. Therefore, this study is the first to uncover the plastomic gBGC in seed plants. We also propose a gBGC model to interpret the dissimilar evolutionary patterns as well as the compositionally biased mutations in the SC and IR regions of cycad plastomes. PMID- 26116920 TI - Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study. AB - OBJECTIVES: Thymic carcinoma is a rare thymic malignancy. The purpose of this study was to evaluate the prognostic impact of clinicopathological variables and perioperative therapy for surgically treated thymic carcinoma using a nationwide database. METHODS: Of 2835 patients with surgically treated thymic epithelial tumours collected from 32 Japanese institutions, a total of 306 patients with thymic carcinomas, excluding neuroendocrine tumours, were enrolled in this retrospective study. Multivariable Cox regression analyses were performed for overall (OS) and recurrence-free survival (RFS) after R0 resection. RESULTS: Of 306 patients, 228 (75%) patients presented with Masaoka stage III-IV. Squamous cell carcinoma was the most common histological type (n = 216, 71%). R0 resection was performed in 181 (61%) patients, R1 in 46 (16%), R2 sub-total (>=80% tumour resection) in 43 (14%) and R2 non-resection in 27 (9%). The 5-year OS rate was 61%. Prognostic factors for OS were Masaoka stage and resection status. R0 resection was associated with most improved OS; however, both R1 and R2 sub-total resection resulted in superior OS compared with R2 non-resection [hazard ratio (95% confidence interval) for R0, R1 and R2 sub-total, 0.27 (0.15-0.48), 0.40 (0.22-0.74) and 0.38 (0.20-0.72), respectively]. Histological type and perioperative therapy did not affect OS, whereas tumour size and postoperative radiotherapy were associated with improved RFS after R0 resection. CONCLUSIONS: R0 resection is essential for prolonged OS for surgically treated thymic carcinoma, but maximal debulking surgery might be beneficial and worth evaluating for advanced disease deemed difficult for R0 resection. The benefit of postoperative radiotherapy after R0 resection should also be evaluated prospectively. PMID- 26116921 TI - EuroSCORE II underestimates mortality after cardiac surgery for infective endocarditis. AB - OBJECTIVES: To better select for patients who most likely will benefit from cardiac surgery among those with infective endocarditis (IE), we aimed to identify preoperative markers associated with poor outcome after cardiac surgery for IE, and to evaluate the accuracy of European System for Cardiac Operative Risk Evaluation (EuroSCORE) II to predict mortality. METHODS: We enrolled all adult patients who underwent cardiac surgery during the acute phase of definite IE (Duke Criteria) in two referral centres for cardiac surgery. Patients were identified through intensive care unit (ICU) electronic databases, and data were collected from medical charts on standardized questionnaire. RESULTS: Between 2002 and 2013, 149 patients (117 males), with a median age of 64 years [interquartile range 52-73], fulfilled the inclusion criteria. Main complications before surgery were left ventricular dysfunction (23%), central nervous system symptomatic events (34%) and septic shock (24%). Most patients (95%) presented with valve regurgitation, and 49% had perivalvular abscess. Surgery was performed with a median delay of 12 days [5-24] after IE diagnosis, and mean EuroSCORE II was 15.8 (13.4-18.1). In-hospital mortality was 21%. Preoperative variables associated with mortality in multivariate analysis were obesity [odds ratio (OR) 3.67 [1.10-12.19], P = 0.03], vegetation >15 mm (OR 6.72 [1.46-30.98], P = 0.01), septic shock (OR 4.87 [1.67-14.28], P = 0.004) and mechanical prosthetic valve IE (OR 4.99 [1.72-28.57], P = 0.007). EuroSCORE II underestimated mortality in patients with predicted mortality over 10%. CONCLUSION: Factors independently predictive of mortality after cardiac surgery for IE are obesity, septic shock, large vegetation and a mechanical prosthetic valve IE. EuroSCORE II underestimates post-cardiac surgery mortality in patients with IE. PMID- 26116922 TI - Are we ready to go directly to videothoracoscopic surgery at a first presentation of primary spontaneous pneumothorax? PMID- 26116923 TI - Fine-scale geographic variation in photosynthetic-related traits of Picea glauca seedlings indicates local adaptation to climate. AB - Climate-related variations in functional traits of boreal tree species can result both from physiological acclimation and genetic adaptation of local populations to their biophysical environment. To improve our understanding and prediction of the physiological and growth responses of populations to climate change, we studied the role of climate of seed origin in determining variations in functional traits and its implications for tree improvement programs for a commonly reforested boreal conifer, white spruce (Picea glauca (Moench) Voss). We evaluated growth, root-to-shoot ratio (R/S), specific leaf area (SLA), needle nitrogen (N(mass)), total non-structural carbohydrates (NSC) and photosynthetic traits of 3-year-old seedlings in a greenhouse experiment using seed from six seed orchards (SO) representing the different regions where white spruce is reforested in Quebec. Height and total dry mass (TDM) were positively correlated with photosynthetic capacity (A(max)), stomatal conductance (g(s)) and mesophyll conductance (g(m)). Total dry mass, but not height growth, was strongly correlated with latitude of seed origin (SO) and associated climate variables. A(max), g(s), g(m) and more marginally, photosynthetic nitrogen-use efficiency (PNUE) were positively associated with the mean July temperature of the SO, while water use efficiency (WUE) was negatively associated. Maximum rates of carboxylation (V(cmax)), maximum rates of electron transport (J(max)), SLA, N(mass), NSC and R/S showed no pattern. Our results did not demonstrate a higher Amax for northern seed orchards, although this has been previously hypothesized as an adaptation mechanism for maintaining carbon uptake in northern regions. We suggest that gs, gm, WUE and PNUE are the functional traits most associated with fine-scale geographic clines and with the degree of local adaptation of white spruce populations to their biophysical environments. These geographic patterns may reflect in situ adaptive genetic differences in photosynthetic efficiency along the cline. PMID- 26116924 TI - Seedling growth and biomass allocation in relation to leaf habit and shade tolerance among 10 temperate tree species. AB - Initial growth of germinated seeds is an important life history stage, critical for establishment and succession in forests. Important questions remain regarding the differences among species in early growth potential arising from shade tolerance. In addition, the role of leaf habit in shaping relationships underlying shade tolerance-related differences in seedling growth remains unresolved. In this study we examined variation in morphological and physiological traits among seedlings of 10 forest tree species of the European temperate zone varying in shade tolerance and leaf habit (broadleaved winter deciduous species vs needle-leaved conifers) during a 10-week period. Seeds were germinated and grown in a controlled environment simulating an intermediate forest understory light environment to resolve species differences in initial growth and biomass allocation. In the high-resource experimental conditions during the study, seedlings increased biomass allocation to roots at the cost of leaf biomass independent of shade tolerance and leaf habit. Strong correlations between relative growth rate (RGR), net assimilation rate (NAR), leaf area ratio (LAR), specific leaf area (SLA) and leaf mass fraction (LMF) indicate that physiology and biomass allocation were equally important determinants of RGR as plant structure and leaf morphology among these species. Our findings highlight the importance of seed mass- and seed size-related root morphology (specific root length-SRL) for shade tolerance during early ontogeny. Leaf and plant morphology (SLA, LAR) were more successful in explaining variation among species due to leaf habit than shade tolerance. In both broadleaves and conifers, shade-tolerant species had lower SRL and greater allocation of biomass to stems (stem mass fraction). Light-seeded shade-intolerant species with greater SRL had greater RGR in both leaf habit groups. However, the greatest plant mass was accumulated in the group of heavy-seeded shade-tolerant broadleaves. The results of our study suggest that the combinations of plant attributes enhancing growth under high light vary with shade tolerance, but differ between leaf habit groups. PMID- 26116925 TI - Linking carbon and water relations to drought-induced mortality in Pinus flexilis seedlings. AB - Survival of tree seedlings at high elevations has been shown to be limited by thermal constraints on carbon balance, but it is unknown if carbon relations also limit seedling survival at lower elevations, where water relations may be more important. We measured and modeled carbon fluxes and water relations in first year Pinus flexilis seedlings in garden plots just beyond the warm edge of their natural range, and compared these with dry-mass gain and survival across two summers. We hypothesized that mortality in these seedlings would be associated with declines in water relations, more so than with carbon-balance limitations. Rather than gradual declines in survivorship across growing seasons, we observed sharp, large-scale mortality episodes that occurred once volumetric soil-moisture content dropped below 10%. By this point, seedling water potentials had decreased below -5 MPa, seedling hydraulic conductivity had decreased by 90% and seedling hydraulic resistance had increased by >900%. Additionally, non-structural carbohydrates accumulated in aboveground tissues at the end of both summers, suggesting impairments in phloem-transport from needles to roots. This resulted in low carbohydrate concentrations in roots, which likely impaired root growth and water uptake at the time of critically low soil moisture. While photosynthesis and respiration on a leaf area basis remained high until critical hydraulic thresholds were exceeded, modeled seedling gross primary productivity declined steadily throughout the summers. At the time of mortality, modeled productivity was insufficient to support seedling biomass-gain rates, metabolism and secondary costs. Thus the large-scale mortality events that we observed near the end of each summer were most directly linked with acute, episodic declines in plant hydraulic function that were linked with important changes in whole seedling carbon relations. PMID- 26116926 TI - Diurnal changes in embolism rate in nine dry forest trees: relationships with species-specific xylem vulnerability, hydraulic strategy and wood traits. AB - Recent studies have reported correlations between stem sapwood capacitance (C(wood)) and xylem vulnerability to embolism, but it is unclear how C(wood) relates to the eventual ability of plants to reverse embolism. We investigated possible functional links between embolism reversal efficiency, C(wood), wood density (WD), vulnerability to xylem embolism and hydraulic safety margins in nine woody species native to dry sclerophyllous forests with different degrees of iso versus anisohydry. Substantial inter-specific differences in terms of seasonal/diurnal changes of xylem and leaf water potential, maximum diurnal values of transpiration rate and xylem vulnerability to embolism formation were recorded. Significant diurnal changes in percentage loss of hydraulic conductivity (PLC) were recorded for five species. Significant correlations were recorded between diurnal PLC changes and P50 and P88 values (i.e., xylem pressure inducing 50 and 88% PLC, respectively) as well as between diurnal PLC changes and safety margins referenced to P50 and P88. WD was linearly correlated with minimum diurnal leaf water potential, diurnal PLC changes and wood capacitance across all species. In contrast, significant relationships between P50, safety margin values referenced to P50 and WD were recorded only for the isohydric species. Functional links between diurnal changes in PLC, hydraulic strategies and WD and C(wood) are discussed. PMID- 26116927 TI - Long-term trends of changes in pine and oak foliar nitrogen metabolism in response to chronic nitrogen amendments at Harvard Forest, MA. AB - We evaluated the long-term (1995-2008) trends in foliar and sapwood metabolism, soil solution chemistry and tree mortality rates in response to chronic nitrogen (N) additions to pine and hardwood stands at the Harvard Forest Long Term Ecological Research (LTER) site. Common stress-related metabolites like polyamines (PAs), free amino acids (AAs) and inorganic elements were analyzed for control, low N (LN, 50 kg NH4NO3 ha(-1) year(-1)) and high N (HN, 150 kg NH4NO3 ha(-1) year(-1)) treatments. In the pine stands, partitioning of excess N into foliar PAs and AAs increased with both N treatments until 2002. By 2005, several of these effects on N metabolites disappeared for HN, and by 2008 they were mostly observed for LN plot. A significant decline in foliar Ca and P was observed mostly with HN for a few years until 2005. However, sapwood data actually showed an increase in Ca, Mg and Mn and no change in PAs in the HN plot for 2008, while AAs data revealed trends that were generally similar to foliage for 2008. Concomitant with these changes, mortality data revealed a large number of dead trees in HN pine plots by 2002; the mortality rate started to decline by 2005. Oak trees in the hardwood plot did not exhibit any major changes in PAs, AAs, nutrients and mortality rate with LN treatment, indicating that oak trees were able to tolerate the yearly doses of 50 kg NH4NO3 ha(-1) year(-1). However, HN trees suffered from physiological and nutritional stress along with increased mortality in 2008. In this case also, foliar data were supported by the sapwood data. Overall, both low and high N applications resulted in greater physiological stress to the pine trees than the oaks. In general, the time course of changes in metabolic data are in agreement with the published reports on changes in soil chemistry and microbial community structure, rates of soil carbon sequestration and production of woody biomass for this chronic N study. This correspondence of selected metabolites with other measures of forest functions suggests that the metabolite analyses are useful for long-term monitoring of the health of forest trees. PMID- 26116928 TI - Proteny: discovering and visualizing statistically significant syntenic clusters at the proteome level. AB - BACKGROUND: With more and more genomes being sequenced, detecting synteny between genomes becomes more and more important. However, for microorganisms the genomic divergence quickly becomes large, resulting in different codon usage and shuffling of gene order and gene elements such as exons. RESULTS: We present Proteny, a methodology to detect synteny between diverged genomes. It operates on the amino acid sequence level to be insensitive to codon usage adaptations and clusters groups of exons disregarding order to handle diversity in genomic ordering between genomes. Furthermore, Proteny assigns significance levels to the syntenic clusters such that they can be selected on statistical grounds. Finally, Proteny provides novel ways to visualize results at different scales, facilitating the exploration and interpretation of syntenic regions. We test the performance of Proteny on a standard ground truth dataset, and we illustrate the use of Proteny on two closely related genomes (two different strains of Aspergillus niger) and on two distant genomes (two species of Basidiomycota). In comparison to other tools, we find that Proteny finds clusters with more true homologies in fewer clusters that contain more genes, i.e. Proteny is able to identify a more consistent synteny. Further, we show how genome rearrangements, assembly errors, gene duplications and the conservation of specific genes can be easily studied with Proteny. AVAILABILITY AND IMPLEMENTATION: Proteny is freely available at the Delft Bioinformatics Lab website http://bioinformatics.tudelft.nl/dbl/software. CONTACT: t.gehrmann@tudelft.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26116929 TI - ISQuest: finding insertion sequences in prokaryotic sequence fragment data. AB - MOTIVATION: Insertion sequences (ISs) are transposable elements present in most bacterial and archaeal genomes that play an important role in genomic evolution. The increasing availability of sequenced prokaryotic genomes offers the opportunity to study ISs comprehensively, but development of efficient and accurate tools is required for discovery and annotation. Additionally, prokaryotic genomes are frequently deposited as incomplete, or draft stage because of the substantial cost and effort required to finish genome assembly projects. Development of methods to identify IS directly from raw sequence reads or draft genomes are therefore desirable. Software tools such as Optimized Annotation System for Insertion Sequences and IScan currently identify IS elements in completely assembled and annotated genomes; however, to our knowledge no methods have been developed to identify ISs from raw fragment data or partially assembled genomes. We have developed novel methods to solve this computationally challenging problem, and implemented these methods in the software package ISQuest. This software identifies bacterial ISs and their sequence elements-inverted and direct repeats-in raw read data or contigs using flexible search parameters. ISQuest is capable of finding ISs in hundreds of partially assembled genomes within hours, making it a valuable high-throughput tool for a global search of IS elements. We tested ISQuest on simulated read libraries of 3810 complete bacterial genomes and plasmids in GenBank and were capable of detecting 82% of the ISs and transposases annotated in GenBank with 80% sequence identity. CONTACT: abiswas@cs.odu.edu. PMID- 26116931 TI - Bringing (domestic) politics back in: global and local influences on health equity. AB - The Lancet-University of Oslo Commission on Global Governance for health correctly concluded that: 'with globalization, health inequity increasingly results from transnational activities that involve actors with different interests and degrees of power'. At the same time, taking up that Commission's focus on political determinants of health and 'power asymmetries' requires recognizing the interplay of globalization with domestic politics, and the limits of global influences as explanations for policies that affect health inequalities. I make this case using three examples - trade policy, climate change policy, and the domestic politics of poverty reduction and social policy - and a concluding observation about the 2015 UK election. PMID- 26116930 TI - Pilot study of the effects of lisdexamfetamine on cocaine use: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Amphetamine analogs have been demonstrated to have some efficacy in reducing use in cocaine dependent individuals. However, these agents also have potential for abuse. Lisdexamfetamine (LDX), a lysine+dextroamphetamine formulation, has been approved for the treatment of Attention Deficit/Hyperactivity Disorder (ADHD) and as a prodrug, has less abuse potential. OBJECTIVE: This pilot study sought to evaluate the safety, tolerability, and efficacy of LDX as a candidate treatment for cocaine dependence. METHODS: A randomized, double-blind, placebo-controlled parallel group study served to evaluate LDX in 43 cocaine-dependent individuals: (1) placebo (PBO; 0mg, n=21), (2) LDX (70mg, n=22). Participants received medication for 14 weeks. Cocaine use was determined based on urine analysis for benzoylecgonine (BE; a cocaine metabolite). RESULTS: Retention rates were higher though not significantly different in the PBO (71.4%) than the LDX condition (57.1%). Compared to those in the PBO condition, those receiving LDX were more likely to report experiencing (ps<0.05) diarrhea (45.5% vs. 14.3%), headaches (45.5% vs. 9.5%), and anxiety (31.8% vs. 4.8%). No differences in medication conditions were observed for blood pressure, heart rate, or body weight. In the randomized sample, no differences in cocaine use were seen. Those receiving LDX reported significantly less craving for cocaine than participants receiving PBO. CONCLUSIONS: LDX did not significantly reduce cocaine use compared to PBO in the randomized sample. PMID- 26116932 TI - The impact of multipolicy tobacco control legislation on smoking behavior. PMID- 26116934 TI - Fat Grafting for Facial Filling and Regeneration. AB - Plastic surgeons have come to realize that fat grafting can rejuvenate an aging face by restoring or creating fullness. However, fat grafting does much more than simply add volume. Grafted fat can transform or repair the tissues into which it is placed. Historically, surgeons have hesitated to embrace the rejuvenating potential of fat grafting because of poor graft take, fat necrosis, and inconsistent outcomes. This article describes fat grafting techniques and practices to assist readers in successful harvesting, processing, and placement of fat for optimal graft retention and facial esthetic outcomes. PMID- 26116935 TI - Primary Breast Augmentation with Fat Grafting. AB - The controversy over fat grafting to the breasts has now been settled. In 2009, the American Society of Plastic Surgeons Fat Graft Task Force stated that "Fat grafting may be considered for breast augmentation and correction of defects associated with medical conditions and previous breast surgeries; however, results are dependent on technique and surgeon expertise." This article discusses the history, indications, planning, complications, and present technique of fat grafting to the breast using the Coleman technique. PMID- 26116933 TI - Memory improvement via slow-oscillatory stimulation during sleep in older adults. AB - We examined the intriguing but controversial idea that disrupted sleep-dependent consolidation contributes to age-related memory decline. Slow-wave activity during sleep may help strengthen neural connections and provide memories with long-term stability, in which case decreased slow-wave activity in older adults could contribute to their weaker memories. One prediction from this account is that age-related memory deficits should be reduced by artificially enhancing slow wave activity. In young adults, applying transcranial current oscillating at a slow frequency (0.75 Hz) during sleep improves memory. Here, we tested whether this procedure can improve memory in older adults. In 2 sessions separated by 1 week, we applied either slow-oscillatory stimulation or sham stimulation during an afternoon nap in a double-blind, crossover design. Memory tests were administered before and after sleep. A larger improvement in word-pair recall and higher slow-wave activity was observed with slow-oscillatory stimulation than with sham stimulation. This is the first demonstration that this procedure can improve memory in older adults, suggesting that declarative memory performance in older adults is partly dependent on slow-wave activity during sleep. PMID- 26116936 TI - Combined Use of Implant and Fat Grafting for Breast Augmentation. AB - Composite breast augmentation is a simple procedure combining the ability of an implant to provide increased volume with the reshaping possibilities offered by fat grafting. The ability to camouflage the implant allows use of a premuscular, retrofascial pocket, avoiding the disadvantages and morbidity associated with retromuscular positioning. PMID- 26116937 TI - The Role of Fat Grafting in Breast Reconstruction. AB - Breast lipomodeling, or breast fat grafting, is a major development in breast plastic surgery. This technique has a low complication rate, excellent results, and patient acceptance. Radiologic evaluation mostly shows a normal-appearing breast. During breast reconstruction, fat grafting is the ideal complement of the latissimus dorsi flap. Fat grafting for Poland syndrome seems to be a great step and will most likely drastically change the surgical treatment of severe cases. Finally, lipomodeling is a new alternative in the treatment of pectus excavatum, tuberous breasts, and breast asymmetries. PMID- 26116938 TI - Tissue-Engineered Autologous Breast Regeneration with Brava(r)-Assisted Fat Grafting. AB - A technique of whole and partial breast reconstruction is described based on tissue-engineering principles. Brava-assisted external tissue expansion generates an in situ biological recipient scaffold that favors the survival of large volumes of autologous fat graft required for breast reconstruction. Also presented are the results of the authors' multicenter experience with this regenerative alternative in 488 patients over a 7-year period tracking surgical complications, patient satisfaction, efficacy, and costs. PMID- 26116939 TI - Safety of Lipofilling in Patients with Breast Cancer. AB - Lipotransfer represents a technical revolution in plastic surgery and is increasingly used worldwide. Although known for several decades, lipofilling has only recently found widespread use in patients with breast cancer to improve the results of breast reconstructions and to correct deformities after conservative treatment. The plastic surgery literature underlines the technique's versatility and the quality of the results, showing lipofilling as an effective cosmetic procedure and proposing it as a safe, neutral biological material that is able to restore the body contour. Several studies underline the power of transferred fat to regenerate blood supply in skin disorders following radiotherapy. PMID- 26116940 TI - Regenerative Approach to Scars, Ulcers and Related Problems with Fat Grafting. AB - The article focuses on the authors' autologous fat grafting technique and its application in regenerative treatment of different scars and ulcers. Although easy to perform, this surgical approach requires some technical procedures and specific management to maximize its effectiveness which are highlighted in the article. In the authors' experience, autologous fat graft has proved to be an efficient and safe procedure to treat scars of different origin demonstrating the capability of lipostructure to achieve an architectural remodeling and loose connective regeneration. PMID- 26116941 TI - Regenerative Approach to Scleroderma with Fat Grafting. AB - Grafted fat has many qualities of ideal filler; it is autologous, easily available, and naturally integrated into the host tissues. From a lipoaspirate, the adipose-tissue-derived stromal vascular fraction can be isolated, which is an excellent source of stem/stromal cells, endothelial progenitors, and immune cells. Fat grafting is being increasingly applied in autoimmune diseases, and this article focuses on systemic sclerosis, a rare autoimmune disease characterized by skin fibrosis and microvascular damage. The authors' approach of using fat graft in the face and adipose-tissue-derived stromal vascular fraction for hands is presented as innovative and promising therapy for patients with systemic sclerosis. PMID- 26116942 TI - Regenerative Approach to Velopharyngeal Incompetence with Fat Grafting. AB - Surgical management of velopharyngeal incompetence (VPI) aims at improving voice resonance and correcting nasal air escape by restoring a competent velopharyngeal sphincter. Assessment of VPI requires the examination of multiple variables. The dynamic study of movements of the velopharyngeal port during speech and the quantification of the closure gap, using flexible videonasoendoscopy and/or videofluoroscopy, is essential. Autologous fat injection represents a minimally invasive alternative to major surgery in the management of mild to moderate VPI that minimizes the risk of complications and sequelae, and can be performed without modifying the anatomy of the velopharyngeal port. PMID- 26116943 TI - Percutaneous Aponeurotomy and Lipofilling (PALF): A Regenerative Approach to Dupuytren Contracture. AB - Dupuytren disease is a progressive fibroproliferative disorder, which leads to flexion contractures of the digits. A minimally invasive technique consisting of an extensive percutaneous aponeurotomy of the cord with a needle combined with lipofilling is presented. The selective cutting of the cords under continuous tension disintegrates the cords while sparing the looser neurovascular bundles. Subsequently, lipoaspirate is injected subcutaneously. The authors' prospective results show a significantly shorter recovery time and less overall complications in this technique when compared with open surgery, while no significant difference was observed in the extent of immediate contracture correction and in the recurrence rate at 1 year follow-up. PMID- 26116944 TI - Complications of Fat Grafting: How They Occur and How to Find, Avoid, and Treat Them. AB - Recent technical and scientific advances in fat grafting procedures and concepts have improved predictability of fat grafting. Large-volume fat injection is gaining much attention as an attracting procedure for body contouring and reconstruction, but an increasing number of complications also has been recognized over the world. In this article, typical complications after fat grafting are described, as well as an explanation of how and why they occur, and how surgeons can avoid and treat complications. PMID- 26116945 TI - Future Perspectives of Fat Grafting. AB - Autologous fat grafting is an exciting part of plastic and reconstructive surgery. Fat serves as a filler and its role in tissue regeneration will likely play a more important role in our specialty. As we learn more about the basic science of fat grafting and the standardized techniques and instruments used for fat grafting, this procedure alone or in conjunction with invasive procedures may be able to replace many operations that we perform currently. Its minimally invasive nature will benefit greatly our cosmetic and reconstructive patients, and may even achieve better clinical outcomes. PMID- 26116946 TI - Fat Grafting: Current Concept, Clinical Application, and Regenerative Potential, Part 2. Preface. PMID- 26116947 TI - Boosting drug named entity recognition using an aggregate classifier. AB - OBJECTIVE: Drug named entity recognition (NER) is a critical step for complex biomedical NLP tasks such as the extraction of pharmacogenomic, pharmacodynamic and pharmacokinetic parameters. Large quantities of high quality training data are almost always a prerequisite for employing supervised machine-learning techniques to achieve high classification performance. However, the human labour needed to produce and maintain such resources is a significant limitation. In this study, we improve the performance of drug NER without relying exclusively on manual annotations. METHODS: We perform drug NER using either a small gold standard corpus (120 abstracts) or no corpus at all. In our approach, we develop a voting system to combine a number of heterogeneous models, based on dictionary knowledge, gold-standard corpora and silver annotations, to enhance performance. To improve recall, we employed genetic programming to evolve 11 regular expression patterns that capture common drug suffixes and used them as an extra means for recognition. MATERIALS: Our approach uses a dictionary of drug names, i.e. DrugBank, a small manually annotated corpus, i.e. the pharmacokinetic corpus, and a part of the UKPMC database, as raw biomedical text. Gold-standard and silver annotated data are used to train maximum entropy and multinomial logistic regression classifiers. RESULTS: Aggregating drug NER methods, based on gold-standard annotations, dictionary knowledge and patterns, improved the performance on models trained on gold-standard annotations, only, achieving a maximum F-score of 95%. In addition, combining models trained on silver annotations, dictionary knowledge and patterns are shown to achieve comparable performance to models trained exclusively on gold-standard data. The main reason appears to be the morphological similarities shared among drug names. CONCLUSION: We conclude that gold-standard data are not a hard requirement for drug NER. Combining heterogeneous models build on dictionary knowledge can achieve similar or comparable classification performance with that of the best performing model trained on gold-standard annotations. PMID- 26116948 TI - Response to the letter "New avenues to prevent sudden unexpected death in nocturnal frontal lobe epilepsy: follow the route established by omega-3 polyunsaturated fatty acids". PMID- 26116949 TI - Effects of sleep timing, sleep quality and sleep duration on school achievement in adolescents. AB - OBJECTIVE: The aim of this study was to examine the effects of sleep timing, quality and duration on school achievement in adolescents. METHODS: Thirty-six Italian students (mean age: 18.14 +/- 0.49 years) attending their last year of high school participated in the study. They completed the Morningness-Eveningness Questionnaire for Children and Adolescents (MEQ-CA). This was used to determine their ideal sleep timing by computing the total score, with higher scores corresponding to a greater tendency toward morningness. In addition, students underwent two non-consecutive weeks of actigraphy in one-month period to objectively assess: habitual sleep timing through the midpoint of sleep (MS); habitual sleep quality through the parameter of sleep efficiency (SE); and habitual sleep duration through the parameter of total sleep time (TST). Participants also completed the Mini Sleep Questionnaire, which allowed us to assess perceived sleep quality, at the end of each actigraphic-recording week. School performance was assessed using the grades obtained by students in their school leaving exams taken at the end of the school year. RESULTS: A significant positive correlation was observed between SE and exam grades, as well as MEQ-CA scores and grades. Multiple regression analysis showed that only SE was significantly and positively related to the final grade. CONCLUSIONS: Examining objective and ecological measures, SE (indicator of sleep quality) had the strongest effect on school achievement in adolescents. PMID- 26116950 TI - Occupational asthma to "the miracle tree" (Moringa oleifera): first description. PMID- 26116951 TI - Safety of Fluticasone Propionate Prescribed for Asthma During Pregnancy: A UK Population-Based Cohort Study. AB - BACKGROUND: Asthma is commonly treated during pregnancy, yet data on the safety of asthma medicines used during pregnancy are sparse. OBJECTIVE: The objective of this study was to evaluate the safety of the inhaled corticosteroid (ICS) fluticasone propionate (FP), alone and in fixed-dose combination with salmeterol (FSC) in terms of the risk of all major congenital malformations (MCMs), compared with all other non-FP ICS. METHODS: Women with asthma who had a pregnancy between January 1, 2000, and December 31, 2010, were identified in the United Kingdom's Clinical Practice Research Datalink. Exposure to asthma medicines during the first trimester of pregnancy was based on issued prescriptions. The mothers' and infants' medical records were linked where possible, and pregnancy outcomes with an MCM diagnosed by age 1 year were identified based on medical codes in the mother's and infant's medical records, including those MCMs prenatally diagnosed that ended in an induced pregnancy termination. The absolute and relative risks of an MCM after different ICS exposures, stratified by the asthma treatment intensity level, were calculated. RESULTS: A total of 14,654 mother-infant pairs were identified, of which 6,174 received an ICS prescription during the first trimester, in addition to 13 first trimester ICS exposed pregnancies that ended in an induced termination after a prenatal MCM diagnosis. In total, 5,362 pregnancies were eligible for the primary analysis at age 1 year. The absolute risk of an MCM after any first trimester FP exposure was 2.4% (CI95 0.8-4.1) and 2.7% (CI95 1.8-3.6) for the "moderate" and "considerable/severe" asthma treatment intensity levels, respectively. The adjusted odds ratios when compared with non FP ICS were 1.1 (CI95 0.5-2.3) and 1.2 (CI95 0.7-2.0) for the "moderate" and "considerable/severe" intensity levels; risks for any FP and for FSC did not differ substantially. CONCLUSION: No increase in the overall risk of MCMs was identified after first trimester FP exposure compared with non-FP ICS. PMID- 26116952 TI - Exuberant Positive Patch Test to Abacavir in a Patient with the HLA-B*5701 Haplotype. PMID- 26116953 TI - Treatment of adult hyper-IgD syndrome with canakinumab. PMID- 26116954 TI - Non-invasive pulmonary function test on Morquio patients. AB - In clinical practice, respiratory function tests are difficult to perform in Morquio syndrome patients due to their characteristic skeletal dysplasia, small body size and lack of cooperation of young patients, where in some cases, conventional spirometry for pulmonary function is too challenging. To establish feasible clinical pulmonary endpoints and determine whether age impacts lung function in Morquio patients non-invasive pulmonary tests and conventional spirometry were evaluated. The non-invasive pulmonary tests: impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography in conjunction with conventional spirometry were evaluated in twenty-two Morquio patients (18 Morquio A and 4 Morquio B) (7 males), ranging from 3 to 40 years of age. Twenty-two patients were compliant with non-invasive tests (100%) with the exception of IOS (81.8%-18 patients). Seventeen patients (77.3%) were compliant with spirometry testing. All subjects had normal vital signs at rest including >95% oxygen saturation, end tidal CO2 (38-44 mmHg), and age-appropriate heart rate (mean=98.3, standard deviation=19) (two patients were deviated). All patients preserved normal values in the impulse oscillometry system, pneumotachography, and respiratory inductance plethysmography, although predicted forced expiratory total (72.8+/-6.9 SE%) decreased with age and was below normal; phase angle (35.5+/-16.5 degrees ), %rib cage (41.6+/-12.7%), resonant frequency, and forced expiratory volume in 1 s/forced expiratory volume total (110.0+/-3.2 SE%) were normal and not significantly impacted by age. The proposed non-invasive pulmonary function tests are able to cover a greater number of patients (young patients and/or wheel-chair bound), thus providing a new diagnostic approach for the assessment of lung function in Morquio syndrome which in many cases may be difficult to evaluate. Morquio patients studied herein demonstrated no clinical or functional signs of restrictive and/or obstructive lung disease. PMID- 26116955 TI - Fabrication and characterization of novel microneedles made of a polystyrene solution. AB - Nowadays, microneedles are attracting a lot of attention because microneedles can deliver drugs, vaccines and hormones into the body without pain unlike conventional hypodermic needles. Furthermore, microneedles are safe for self injection and disposal. This work aims to develop novel microneedles made of a solution of polystyrene (PS) in toluene. The mechanical properties of the fabricated PS microneedles were characterized in failure strength test and skin penetration test. According to the experimental results, a PS microneedle could withstand a large force up to 1.0 N without fracturing. Owing to the superior mechanical strength, the PS microneedles could penetrate the skin without any deterioration making them a promising alternative for commercial applications. PMID- 26116957 TI - Clinical and laboratory surface finishing procedures for zirconia on opposing human enamel wear: A laboratory study. AB - AIM: To investigate the effect of laboratory and clinical finishing procedures for zirconia on antagonistic enamel wear. MATERIALS AND METHODS: Forty-eight yttria-tetragonal partially stabilised zirconia (Y-TZP) specimens were prepared and divided into four groups according to their surface preparation: laboratory polished (LP); laboratory polished and glazed (G); clinically adjusted (CA); and clinically adjusted and repolished (CAR). Enamel opposing enamel was used as a control. Pre-testing surface roughness for each group was determined using contact profilometry. Two-body wear resistance tests were conducted using a masticatory simulator. Enamel specimens were subjected to 120,000 cycles in distilled water (frequency 1.6 Hz, loading force of 49 N). Volumetric and vertical enamel losses were measured by superimposition of pre- and post-testing images using a three-dimensional laser scanner and software analysis. Scanning electron microscopy was used for qualitative surface analysis of pre- and post testing zirconia and enamel surfaces. One-way ANOVA and multiple comparisons with Bonferroni corrections were used for statistical analysis at a significance level of alpha=0.05. RESULTS: There was no statistical difference in volumetric and vertical enamel loss between CAR, G and LP. CAR produced statistically significantly less volumetric enamel loss compared with CA and control, and statistically significantly less vertical enamel loss compared with CA. Volumetric and vertical enamel loss were highly correlated in all groups. CONCLUSIONS: Enamel wear by clinically ground zirconia is comparable to that of opposing enamel surfaces and greater than clinically repolished zirconia. Repolishing of zirconia restorations following clinical adjustment with diamond burs is effective in reducing antagonistic enamel wear. PMID- 26116958 TI - Initial Experience of (68)Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. AB - Prostate-specific membrane antigen (PSMA) overexpression theoretically enables targeting of prostate cancer (PCa) metastases using gallium Ga 68 ((68)Ga) labeled PSMA ligands for positron emission tomography/computed tomography (PET/CT) imaging. Promising detection rates have been reported when using this approach for functional imaging of recurrent PCa; however, until now, the diagnostic accuracy of (68)Ga-PSMA PET/CT for preoperatively identifying lymph node metastases (LNMs) had not been assessed. We retrospectively compared preoperative (68)Ga-PSMA PET/CT lymph node (LN) findings with histologic work-up after radical prostatectomy (RP). Overall, 608 LNs containing 53 LNMs were detected during RP. LNMs were present in 12 of 30 patients (40%). The (68)Ga-PSMA PET/CT scans identified 4 patients (33.3%) as LN true positive and 8 patients (66.7%) as false negative. Median size of (68)Ga-PSMA-PET/CT-detected versus undetected LNMs was 13.6 versus 4.3 mm (p<0.05). Overall sensitivity, specificity, positive predictive value, and negative predictive value of (68)Ga PSMA PET/CT for LNM detection were 33.3%, 100%, 100%, and 69.2%, respectively. Per-side analyses revealed corresponding values of 27.3%, 100%, 100%, and 52.9%. Conversely, (68)Ga-PSMA PET/CT enabled tumor visualization in the prostate. In 92.9% of patients, the intraprostatic tumor foci were correctly predicted. Overall, (68)Ga-PSMA PET/CT is a promising tool for functional imaging; however, our initial experience revealed substantial influence of LNM size on the diagnostic accuracy of (68)Ga-PSMA PET/CT. PATIENT SUMMARY: We assessed the diagnostic accuracy of (68)Ga-PSMA PET/CT in high-risk prostate cancer patients prior to radical prostatectomy. We found that lymph node metastasis detection rates were substantially influenced by lymph node metastasis size. PMID- 26116959 TI - The cortisol awakening response (CAR) in toddlers: Nap-dependent effects on the diurnal secretory pattern. AB - INTRODUCTION: Cortisol levels in adults show a sharp decrease from mid-morning to mid-afternoon. Most toddlers take afternoon naps, which is associated with a less mature diurnal pattern characterized by a midday plateau in cortisol secretion. Napping in preschoolers produces a robust cortisol awakening response (CAR), which may account for such maturational differences. This experimental study extends prior work by examining whether the presence and timing of the nap dependent CAR influences the diurnal cortisol pattern in toddlers. METHODS: Toddlers (n = 28; 13 females; 30-36 months) followed a strict biphasic sleep schedule (>= 12.5h time in bed; >= 90 min nap) for >= 3 days before each of four randomly ordered, in-home cortisol assessments. For each assessment, saliva samples were obtained at morning awakening, ~ 09:30, pre-nap, 0, 15, 30, 45, 90, and 135 min post-nap awakening (verified with actigraphy), and ~ 19:30. On one day, children napped at their scheduled time, and parents collected saliva samples. On another day, children missed their nap, and parents collected saliva samples at matched times. On two other days, children napped 4h (morning) and 7h (afternoon) after awakening in the morning, during which time researchers collected pre- and post-nap saliva samples. Saliva was assayed for cortisol (MUg/dl). RESULTS: Three-level multilevel models were used to estimate the CAR and diurnal cortisol patterns in all four conditions. Compared to the no-nap condition (no observed CAR; b = -0.78, p = 0.65), we found a pronounced cortisol rise following the morning nap (b = 11.00, p < 0.001) and both afternoon naps whether samples were collected by parents (b = 5.19, p < 0.01) or experimenters (b = 4.97, p < 0.01). Napping in the morning resulted in the most robust post-nap cortisol rise (b = 10.21, p < 0.001). Diurnal patterns were analyzed using piecewise growth modeling that estimated linear coefficients for five separate periods throughout the day (corresponding to morning decline, noon decline, post nap rise, post-nap decline, and evening decline). We observed a significant post nap rise in cortisol values on the parent-collected afternoon nap (b = 3.41, p < 0.01) and the experimenter-collected morning nap (b = 7.50, p < 0.01) days as compared to the no-nap day (b = -0.17, p = 0.82). No other differences in diurnal profiles were observed between the parent-collected nap and no-nap conditions; however, toddlers had a steeper evening decline on the day of the morning nap compared to the parent-collected afternoon nap (b = 0.30, p < 0.05) and no-nap conditions (b = 0.27, p < 0.05). DISCUSSION: These well-controlled findings suggest that the presence and timing of daytime naps influence the pattern of diurnal cortisol secretion in toddlers. They also provide support for the hypothesis that napping is the primary state driving the immature midday plateau in cortisol secretion, which becomes more adult-like across childhood. Prior studies of the diurnal cortisol pattern have employed a cubic model, and therefore, have not detected all possible variations due to napping. Our experimental data have important methodological implications for researchers examining associations between the slope of the diurnal cortisol pattern and developmental outcomes, as well as those utilizing afternoon cortisol reactivity protocols in napping children. PMID- 26116960 TI - Changes in endometrial ezrin and cytokeratin 18 expression during bovine implantation and in caruncular endometrial spheroids in vitro. AB - INTRODUCTION: The feto-maternal interface during bovine implantation was studied in vivo and using three-dimensional bovine endometrial (BCECph) and trophoblast spheroids (CCS), each with underlying fibroblasts. METHODS: The expression of ezrin and cytokeratin 18 (CK18) was analyzed via immunohistochemistry (IHC), RT PCR and western blotting in bovine endometrium (GD 18-44) with in vivo (VIVO) and in vitro-produced embryos (VITRO). BCECph were stimulated with cotyledon conditioned media (CCM) and analyzed by TEM/SEM and IHC. CCS were stained (IHC) for TGC markers, to test if spheroidal trophoblast cells had differentiated into TGC. RESULTS: At GD 20, caruncular epithelium (CE) and uterine glands (UG) showed a loss of cytosolic ezrin and CK18 followed by a complete loss of both proteins. At GD 35 both reappeared in CE and UG. The endometrial expression pattern did not differ between VIVO and VITRO. RT-PCR and western blotting confirmed the presence of ezrin and CK18. All spheroids had an outer polarized, cytokeratin and ezrin positive epithelium (CE or trophoblast) with apical microvilli. Stimulation of BCECph with CCM induced similar changes in ezrin expression as observed in endometrial tissue. However, no ultrastructural alterations were found by transmission electron microscopy. Absence of TGC-specific glycoproteins in CCS indicated that TGC differentiation was not induced by three-dimensional culture conditions. DISCUSSION: Ezrin and CK18 are downregulated during implantation in cattle. The expression changes represent a temporal depolarization, which could be important for an establishment of bovine pregnancy. Our in vitro experiments demonstrate that the trophoblast could contribute to this change in vivo. PMID- 26116961 TI - Pericardial fat is associated with ventricular tachyarrhythmia and mortality in patients with systolic heart failure. AB - OBJECTIVE: Pericardial fat (PF) has been hypothesized to exert local pathogenic effects on nearby cardiac structures above and beyond that of systemic adiposity which might be associated with the presence of arrhythmia or even worse outcomes. The aims of this study was to characterize the relationship between PF and the prognosis in patients with systolic heart failure (HF). METHODS: This is a retrospective cohort study of a cardiac magnetic resonance imaging (CMRI) database from 2004 to 2011. Fifty patients with systolic HF underwent CMRI examinations were included. We also enrolled twenty patients with HF as the control group. The cine imaging was analyzed to derive total PF volumes, left ventricular volumes and mass and left ventricular ejection fraction by using a previously validated technique. The outcomes, including ventricular tachycardia (VT), ventricular fibrillation (VF) and total mortality were obtained by reviewing medical records. RESULTS: After a median follow-up of 694 days, patients with VT/VF had significant larger indexed PF volumes than those without [36.3 (32.8-43.1) ml/m(2) vs. 24.1 (20.2-27.6) ml/m(2), p = 0.001]. The mortality group also had significant larger indexed PF volumes (PF/body surface area) than those without [31.3 (22.8-38.4) ml/m(2) vs. 23.9 (19.8-27.3) ml/m(2), p = 0.010]. Indexed PF volumes were associated with the development of VT/VF (Hazard ratio, 7.510; 95% C.I, 0.901-62.582, p = 0.062) and mortality (Hazard ratio, 3.998; 95% C.I, 1.077-14.845, p = 0.038) by Cox's regression analyses. CONCLUSION: PF is associated with the development of VT/VF and long-term overall mortality in patients with systolic HF. PMID- 26116962 TI - Retinoic acid inhibits tissue factor and HMGB1 via modulation of AMPK activity in TNF-alpha activated endothelial cells and LPS-injected mice. AB - OBJECTIVE: Retinoic acid (RA) is the active vitamin A derivative and has diverse immunomodulatory actions. We hypothesized that RA reduces prothrombotic mediators such as tissue factor (TF) in endothelial cells during inflammatory conditions via an AMPK-dependent pathway, which attenuates cardiovascular complications. RESULTS: RA significantly increased AMPK and Akt phosphorylation in a time- and concentration-dependent manner in endothelial cells (EC). RA downregulated TF expression at the transcriptional and translational levels in TNF-alpha activated ECs, which was reversed by the silencing of AMPK and transfection of DN-AMPK. Interestingly, the PI3-kinase inhibitor LY294002 reversed the RA effect on TF expression. Increased AMPK phosphorylation by RA was inhibited by LY294002. However, increased Akt phosphorylation was not reduced by compound C, indicating that PI3K/Akt signaling modulates AMPK activity. In addition, RA reduced HMGB1 release in TNF-alpha activated ECs, which was reversed by both LY294001 and siAMPK. Importantly, administration of RA (1 mg/kg) significantly reduced blood TF activity, circulating HMGB1 and PAI-1 levels and expression of hepatic TF mRNA as well as fibrin deposition in LPS (5 mg/kg)-injected mice. CONCLUSIONS: Taken together, the activation of PI3K/Akt by RA modulates AMPK activity in ECs and plays a crucial role in the inhibition of coagulatory factors such as TF, PAI-1, and HMGB1 in inflammatory conditions. PMID- 26116963 TI - Model-based estimation of intra-cortical connectivity using electrophysiological data. AB - This paper provides a new method for model-based estimation of intra-cortical connectivity from electrophysiological measurements. A novel closed-form solution for the connectivity function of the Amari neural field equations is derived as a function of electrophysiological observations. The resultant intra-cortical connectivity estimate is driven from experimental data, but constrained by the mesoscopic neurodynamics that are encoded in the computational model. A demonstration is provided to show how the method can be used to image physiological mechanisms that govern cortical dynamics, which are normally hidden in clinical data from epilepsy patients. Accurate estimation performance is demonstrated using synthetic data. Following the computational testing, results from patient data are obtained that indicate a dominant increase in surround inhibition prior to seizure onset that subsides in the cases when the seizures spread. PMID- 26116965 TI - Stuttering priapism associated with topiramate. AB - OBJECTIVES: Priapism, or prolonged penile erection in the absence of sexual stimulation, may be a medical emergency. Many medications including antianxiety, antidepressants and antipsychotics have been implicated. This paper presents a case of priapism associated with topiramate use. METHODS: This is a description of case report where topiramate was prescribed as anticraving medication in a patient with alcohol dependence. Episodic priapism developed soon after topiramate was prescribed. The severity of priapism reduced with reduction of dosage and disappeared with its discontinuation. RESULTS: Reversible priapism (stuttering subtype) is associated with topiramate. CONCLUSIONS: This is the first report of priapism associated with topiramate in the scientific literature. PMID- 26116964 TI - The human voice areas: Spatial organization and inter-individual variability in temporal and extra-temporal cortices. AB - fMRI studies increasingly examine functions and properties of non-primary areas of human auditory cortex. However there is currently no standardized localization procedure to reliably identify specific areas across individuals such as the standard 'localizers' available in the visual domain. Here we present an fMRI 'voice localizer' scan allowing rapid and reliable localization of the voice sensitive 'temporal voice areas' (TVA) of human auditory cortex. We describe results obtained using this standardized localizer scan in a large cohort of normal adult subjects. Most participants (94%) showed bilateral patches of significantly greater response to vocal than non-vocal sounds along the superior temporal sulcus/gyrus (STS/STG). Individual activation patterns, although reproducible, showed high inter-individual variability in precise anatomical location. Cluster analysis of individual peaks from the large cohort highlighted three bilateral clusters of voice-sensitivity, or "voice patches" along posterior (TVAp), mid (TVAm) and anterior (TVAa) STS/STG, respectively. A series of extra temporal areas including bilateral inferior prefrontal cortex and amygdalae showed small, but reliable voice-sensitivity as part of a large-scale cerebral voice network. Stimuli for the voice localizer scan and probabilistic maps in MNI space are available for download. PMID- 26116967 TI - Bone health of patients with juvenile idiopathic arthritis: a comparison between dual-energy X-ray absorptiometry and digital X-ray radiogrammetry. AB - OBJECTIVES: Juvenile idiopathic arthritis (JIA) affects bone mineral density (BMD). Dual-energy X-ray absorptiometry (DXA) is the most widely used technique to determine BMD. Digital X-ray radiogrammetry (DXR) is a feasible method for determination of cortical BMD on hand radiographs. This study aimed to compare DXR and DXA in the assessment of BMD in JIA patients. METHODS: Thirty-five JIA patients with available DXA and hand radiograph within the same time period were included from the Dutch Arthritis and Biologicals in Children register. Outcome measures for BMD were Bone Health Index from DXR and BMD total body, BMD lumbar spine and Bone Mineral Apparent Density from DXA. All measures were transformed to Z-scores. Correlations were assessed with Pearson correlation coefficients. RESULTS: Median age of the patients (60% female) was 11.7 years. Pearson correlation coefficient was significant for the absolute scores: 0.568-0.770 (p<0.001). No significant correlation was found between the Z-scores of DXA and DXR. CONCLUSIONS: The BMD assessment from the DXR was correlated to DXA measures in a cohort of JIA patients, although only in absolute scores. Future steps for implementation of DXR in clinical practice include evaluation of responsiveness to change, predictive value and comparison with other imaging techniques. PMID- 26116966 TI - Functional characterization and expression analysis of myoglobin in high-altitude lizard Phrynocephalus erythrurus. AB - Myoglobin (Mb) is a monomeric hemoprotein which plays an important role in oxygen storage and transport in cardiac and skeletal muscle under hypoxia. The red tail toad-headed lizard Phrynocephalus erythrurus (Lacertilia: Agamidae), which inhabits at an elevation of 4500-5300 m on the Qinghai-Tibetan plateau, is known to be the highest living lizard in the world. To investigate the characters of myoglobin of this unique species, another low altitude lizard Phrynocephalus przewalskii (Lacertilia: Agamidae) was selected as a reference. The open reading frame (ORF) of myoglobin in two lizards was 465 bp which encodes a polypeptide of 154 amino acids with different theoretical molecular weight and isoelectric point. The amino acid substitutions of myoglobin between two species were found at Thr13Ile, Lys87Thr and His118Asn. Homology modeling results indicated that P. erythrurus myoglobin has a greater heme pocket, which may be more favorable to oxygen binding and unloading. On the other hand, the mRNA levels of myoglobin in both cardiac and skeletal muscle in P. erythrurus were significantly larger than those in low altitude P. przewalskii. At protein level, myoglobin concentration in skeletal muscle in P. erythrurus was notably increased, but no significant difference was observed in cardiac muscle. PMID- 26116968 TI - Techniques used by United Kingdom consultant plastic surgeons to select implant size for primary breast augmentation. AB - BACKGROUND: Techniques used to estimate implant size for primary breast augmentation have evolved since the 1970s. Currently no consensus exists on the optimal method to select implant size for primary breast augmentation. METHODS: In 2013 we asked United Kingdom consultant plastic surgeons who were full members of BAPRAS or BAAPS what was their technique for implant size selection for primary aesthetic breast augmentation. We also asked what was the range of implant sizes they commonly used. The answers to question one were grouped into four categories: experience, measurements, pre-operative external sizers and intra-operative sizers. RESULTS: The response rate was 46% (164/358). Overall, 95% (153/159) of all respondents performed some form of pre-operative assessment, the others relied on "experience" only. The most common technique for pre operative assessment was by external sizers (74%). Measurements were used by 57% of respondents and 3% used intra-operative sizers only. A combination of measurements and sizers was used by 34% of respondents. The most common measurements were breast base (68%), breast tissue compliance (19%), breast height (15%), and chest diameter (9%). The median implant size commonly used in primary breast augmentation was 300cc. SUMMARY: Pre-operative external sizers are the most common technique used by UK consultant plastic surgeons to select implant size for primary breast augmentation. We discuss the above findings in relation to the evolution of pre-operative planning techniques for breast augmentation. PMID- 26116969 TI - Early surgical treatment by free flap reconstruction of hydrofluoric acid burn injury. PMID- 26116970 TI - Recurrence rate and shift in histopathological differentiation of oral squamous cell carcinoma - A long-term retrospective study over a period of 13.5 years. AB - OBJECTIVE: Little information is available as to whether recurrences of oral squamous cell carcinoma (OSCC) show different histopathological grades than the primary tumor and whether postoperative radiotherapy (PORT) influences the grade of differentiation in the case of recurrence. The objective of this study was the evaluation of recurrence rates and change in differentiation. MATERIAL AND METHODS: This retrospective, single-institution cohort study included surgically treated OSCC patients over a 13-year period (2000-2013). The relationship among tumor size, lymph node metastases, and recurrence rate of OSCC was investigated. Primary tumor differentiation was compared with differentiation of recurrence. RESULTS: A total of 429 patients (277 men and 152 women) were included in this study. Of these, 124 (28.9%) received PORT. The incidence of primary cervical metastases increased significantly with tumor size (p < 0.001). Recurrence developed in 82 patients (19.1%). Stage T1/T2 showed a significantly lower recurrence rate than stage T3/T4 (16.3% vs. 30.2%) (p < 0.01). A total of 23 (30.7%) patients with recurrence showed a change in differentiation. CONCLUSION: Increasing primary tumor size correlates with incidence of cervical metastases and recurrence rate. Initial cervical metastases show no effect on recurrence rates. Differentiation of primary tumor does not correlate with the recurrence rate. The majority of recurrences show consistent histopathological grading. PMID- 26116971 TI - Sensitivity and specificity of cone beam computed tomography in thin bony structures in maxillofacial surgery - A clinical trial. AB - INTRODUCTION: Cone-Beam Computed Tomography (CBCT) has become widely used in dentistry and maxillofacial surgery. Accuracy, sensitivity and specificity of thin bony structures below 0.5 mm have been subject of some in vitro studies. This prospective in vivo study investigates the correlation between preoperative CBCT-imaging and intraoperative clinical examination of thin bony structures. We hereby present results from daily clinical routine. METHODS: A total number of 80 sites in 64 patients has been examined to differentiate between preoperative 3D imaging and clinical measurements on cystic lesions in maxilla and mandible. Different CBCT-devices with a voxel size ranging from 0.08 mm to 0.4 mm were used. RESULTS: Overall-specificity found for detecting thin bony structures of the human jaw is 13.89%, overall sensitivity is 100%, positive predictive value (PPV) is 58.67% and negative predictive value (NPV) is 100%. DISCUSSION: Image quality is the key to make use of additional information CBCT provides and depends on spatial, temporal and contrast resolution. CBCT does not depict reliably thin bony structures of the jaw, even if high voxel resolution is used. CONCLUSION: In selected cases using high resolution protocols should be considered despite affecting the patient with higher doses of radiation. PMID- 26116972 TI - The value of tranexamic acid during fronto-orbital advancement in isolated metopic craniosynostosis. AB - Craniofacial surgery in infants still harbors the risk of significant blood loss and the need for red blood cell (RBC) transfusion. Hence, the aim of the present study was to investigate the antifibrinolytic effect of tranexamic acid (TXA) on intraoperative blood loss and RBC transfusion rates during fronto-orbital advancement (FOA) in isolated metopic synostosis. A total of 33 children with metopic synostosis were operated on using standardized FOA, of which 16 patients (48.5%) were treated without intraoperative TXA (non-TXA group) and 17 patients (51.5%) received TXA intraoperatively (TXA group). To accurately evaluate the calculated blood loss (CBL) we analyzed the values for pre- and postoperative hematocrit and the volume of the RBC transfusion. The mean CBL and the mean weight-adjusted CBL was significantly lower for patients receiving TXA compared with the non-TXA group (158.8 ml vs. 198.5 ml, p = 0.0001; and 19.1 ml/kg vs. 22.3 ml/kg, p = 0.0293, respectively). In addition, the mean RBC transfusion and the mean weight-adjusted RBC transfusion was significantly lower for the TXA group (252.2 ml vs. 280.0 ml, p = 0.0001; and 27.9 ml/kg vs. 31.3 ml/kg, p = 0.0345, respectively). The mean duration of the surgical procedure did not differ statistically between the groups (132 min vs. 136 min, p = 0.4081), hence the lower CBL in the TXA-group was not related to a shorter cutting-suture time. As the use of intraoperative TXA minimizes blood transfusion volumes in children who undergo FOA, antifibrinolytics, such as TXA, should be considered for routine use in pediatric craniofacial surgery. PMID- 26116973 TI - Exercising influence: distinct biotic interactions shape root microbiomes. AB - Root microbiomes are formed from diverse microbial soil settings with extraordinary consistency, suggesting both defined mechanisms of assembly and specific microbial activity. Recent improvements in sequencing technologies, data analysis techniques, and study design, allow definition of the microbiota within these intimate and important relationships with increasing accuracy. Comparing datasets provides powerful insights into the overlap of plant microbiomes, as well as the impacts of surrounding plants and microbes on root microbiomes and long-term soil conditioning. Here we address how recent studies tease apart the impact of various biotic interactions, including: plant-plant, plant-microbe, and microbe-microbe on root microbiome composition. PMID- 26116974 TI - Phylogenomics and evolution of secondary metabolism in plant-associated fungi. AB - Fungi produce a myriad of secondary metabolites, compounds that are not required for basic cellular processes, but are thought to be central to ecological functions. Genomic sequencing of fungi has revealed a greater diversity of secondary metabolism than previously realized, including novel taxonomic distributions of known compounds and uncharacterized gene clusters in well studied organisms. Here we provide an overview of the major groups of metabolites, their ecological functions, the genetic systems that produce them, and the patterns and processes associated with evolutionary diversification of secondary metabolism in plant-associated filamentous ascomycetes. PMID- 26116975 TI - Reconsidering mutualistic plant-fungal interactions through the lens of effector biology. AB - Mutualistic mycorrhizal plant-fungal interactions have shaped the evolution of plant life on land. In these intimate associations, fungal hyphae grow invasively within plant tissues. Despite this invasion, these mycorrhizal fungi are not repulsed leading to a great deal of research focused on the signals exchanged between mutualistic fungi and their host plants in an effort to understand how these relationships are established. In this review, we focus on one type of signal used by mutualistic fungi during symbiosis: effector proteins. These small secreted proteins have recently been found to be used by a range of beneficial fungi to alter the physiological status of the plant host such that symbiosis is favoured. We discuss how the role of these novel proteins has altered our vision of how the 'mutualistic' lifestyle evolved in fungi: rather than being perceived as beneficial by their plant hosts, these microbes currently viewed as 'beneficial' may actually be overcoming the defences of their plant hosts in a mechanism originally thought to be unique to pathogenic microbes. PMID- 26116976 TI - Chromatin-based control of effector gene expression in plant-associated fungi. AB - Plant-associated fungi often present in their genome areas enriched in repeat sequences and effector genes, the latter being specifically induced in planta. The location of effector genes in regions enriched in repeats has been shown to have an impact on adaptability of fungi but could also provide for tight control of effector gene expression through chromatin-based regulation. The distribution of two repressive histone marks was shown to be an important regulatory layer in two fungal species with different lifestyles. Chromatin-based control of effector gene expression is likely to provide an evolutionary advantage by preventing the expression of genes not needed during vegetative growth and allow for a massive concerted expression at particular time-points of plant infection. PMID- 26116977 TI - Plant cysteine-rich peptides that inhibit pathogen growth and control rhizobial differentiation in legume nodules. AB - Plants must co-exist with both pathogenic and beneficial microbes. Antimicrobial peptides with broad antimicrobial activities represent one of the first lines of defense against pathogens. Many plant cysteine-rich peptides with potential antimicrobial properties have been predicted. Amongst them, defensins and defensin-like peptides are the most abundant and plants can express several hundreds of them. In some rhizobial-legume symbioses special defensin-like peptides, the nodule-specific cysteine-rich (NCR) peptides have evolved in those legumes whose symbiotic partner terminally differentiates. In Medicago truncatula, >700 NCRs exist and collectively act as plant effectors inducing irreversible differentiation of rhizobia to nitrogen-fixing bacteroids. Cationic NCR peptides have a broad range of potent antimicrobial activities but do not kill the endosymbionts. PMID- 26116978 TI - Chitin-mediated plant-fungal interactions: catching, hiding and handshaking. AB - Plants can detect infecting fungi through the perception of chitin oligosaccharides by lysin motif receptors such as CEBiP and CERK1. A major function of CERK1 seems to be as a signaling molecule in the receptor complex formed with ligand-binding molecules and to activate downstream defense signaling. Fungal pathogens, however, have developed counter strategies to escape from the chitin-mediated detection by using effectors and/or changing their cell walls. Common structural features between chitin and Nod-/Myc-factors and corresponding receptors have suggested the close relationships between the chitin mediated immunity and rhizobial/arbuscular mycorrhizal symbiosis. The recent discovery of the dual function of OsCERK1 in both plant immunity and mycorrhizal symbiosis sheds new light on the evolutionary relationships between defense and symbiotic systems in plants. PMID- 26116979 TI - How can an understanding of plant-pollinator interactions contribute to global food security? AB - Pollination of crops by animals is an essential part of global food production, but evidence suggests that wild pollinator populations may be declining while a number of problems are besetting managed honey bee colonies. Animal-pollinated crops grown today, bred in an environment where pollination was less likely to limit fruit set, are often suboptimal in attracting and sustaining their pollinator populations. Research into plant-pollinator interactions is often conducted in a curiosity-driven, ecological framework, but may inform breeding and biotechnological approaches to enhance pollinator attraction and crop yield. In this article we review key topics in current plant-pollinator research that have potential roles in future crop breeding for enhanced global food security. PMID- 26116980 TI - Impact of chronic use of cibenzoline on left ventricular pressure gradient and left ventricular remodeling in patients with hypertrophic obstructive cardiomyopathy. AB - BACKGROUND: Cibenzoline, a class Ia antiarrhythmic drug, is useful for reducing the left ventricular pressure gradient (LVPG) in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, chronic effects of cibenzoline on LVPG and left ventricular (LV) remodeling are unknown. METHODS: Forty-one patients with HOCM participated in this study. Echocardiographic, electrocardiographic, and brain natriuretic peptide (BNP) data collected before and after cibenzoline treatment were compared. From the relation between LVPG and plasma concentration of cibenzoline, an efficacious plasma concentration of cibenzoline was estimated. RESULTS: The mean follow-up period was 74.2+/-47.1 months. The LVPG decreased from 104.8+/-62.6mmHg to 27.6+/-30.5mmHg (p<0.0001). The LV end-diastolic dimension increased from 42.8+/-5.8mm to 46.2+/-5.4mm (p<0.0001), but neither LV end-systolic dimension nor LV fractional shortening changed significantly. The left atrial dimension decreased from 40.0+/-4.7mm to 36.2+/-5.1mm (p<0.0001). The E-wave velocity/A-wave velocity ratio increased, early diastolic annular velocity (Ea) increased, and E/Ea ratio decreased. The interventricular septal wall thickness, LV posterior wall thickness, the Sokolow Lyon index, and the depth of negative T wave decreased. The heart rate-corrected QT interval was shortened. Plasma BNP level decreased from 418.8+/-423.7pg/ml to 213.7+/-154.1pg/ml (p<0.02). The safe and efficacious plasma concentration of cibenzoline was between 300ng/mL and 1500ng/mL. CONCLUSIONS: Long-term treatment with cibenzoline attenuated LVPG, improved LV diastolic dysfunction, and induced LV hypertrophy regression in patients with HOCM without causing serious complications. PMID- 26116981 TI - Pre-PCI angiographic TIMI flow in the culprit coronary artery influences infarct size and microvascular obstruction in STEMI patients. AB - OBJECTIVE: The influence of initial-thrombolysis in myocardial infarction (i TIMI) coronary flow in the culprit coronary artery on myocardial infarct and microvascular obstruction (MVO) size is unclear. We assessed the impact on infarct size of i-TIMI flow in the culprit coronary artery, as well as on MVO incidence and size, by contrast-enhanced cardiac magnetic resonance (ce-CMR). METHODS: In a prospective, multicenter study, pre-percutaneous coronary intervention (PCI) coronary occlusion was defined by an i-TIMI flow <=1, and patency was defined by an i-TIMI flow >=2. Infarct size, as well as MVO presence and size, were measured on ce-CMR 72h after admission. RESULTS: A total of 140 patients presenting with ST-elevated myocardial infarction referred for primary PCI were included. There was no significant difference in final post-PCI TIMI flow between the groups (2.95+/-0.02 vs. 2.97+/-0.02, respectively; p=0.44). In the i-TIMI flow <=1 group, infarct size was significantly larger (32+/-17g vs. 21+/-17g, respectively; p=0.002), MVO was significantly more frequent (74% vs. 53%, respectively; p=0.012), and MVO size was significantly larger [1.3 IQR (0; 7.1) vs. 0 IQR (0; 1.6)], compared to in the i-TIMI >=2 patient group. CONCLUSION: Initial angiographic TIMI flow in the culprit coronary artery prior to any PCI predicted final infarct size and MVO size: the better was the i-TIMI flow, the smaller were the infarct and MVO size. PMID- 26116983 TI - Long lasting cerebellar alterations after perinatal asphyxia in rats. AB - The developing brain may be particularly vulnerable to injury before, at and after birth. Among possible insults, hypoxia suffered as a consequence of perinatal asphyxia (PA) exhibits the highest incidence levels and the cerebellar circuitry appears to be particularly susceptible, as the cellular makeup and the quantity of inputs change quickly during days and weeks following birth. In this work, we have used a murine model to induce severe global PA in rats at the time of birth. Short-term cerebellar alterations within this PA model have been previously reported but whether such alterations remain in adulthood has not been conclusively determined yet. For this reason, and given the crucial cerebellar role in determining connectivity patterns in the brain, the aim of our work is to unveil long-term cerebellum histomorphology following a PA insult. Morphological and cytological neuronal changes and glial reaction in the cerebellar cortex were analyzed at postnatal 120 (P120) following injury performed at birth. As compared to control, PA animals exhibited: (1) an increase in molecular and granular thickness, both presenting lower cellular density; (2) a disarrayed Purkinje cell layer presenting a higher number of anomalous calbindin-stained cells. (3) focal swelling and marked fragmentation of microtubule-associated protein 2 (MAP-2) in Purkinje cell dendrites and, (4) an increase in glial fibrillary acidic protein (GFAP) expression in Bergmann cells and the granular layer. In conclusion, we demonstrate that PA produces long-term damage in cellular histomorphology in rat cerebellar cortex which could be involved in the pathogenesis of cognitive deficits observed in both animals and humans. PMID- 26116982 TI - Hyperbaric hyperoxia alters innate immune functional properties during NASA Extreme Environment Mission Operation (NEEMO). AB - BACKGROUND: Spaceflight is associated with immune dysregulation which is considered as risk factor for the performance of exploration-class missions. Among the consequences of confinement and other environmental factors of living in hostile environments, the role of different oxygen concentrations is of importance as either low (e.g. as considered for lunar or Martian habitats) or high (e.g. during extravehicular activities) can trigger immune dysfunction. The aim of this study was to investigate the impact of increased oxygen availability- generated through hyperbaricity--on innate immune functions in the course of a 14 days NEEMO mission. METHODS: 6 male subjects were included into a 14 days undersea deployment at the Aquarius station (Key Largo, FL, USA). The underwater habitat is located at an operating depth of 47 ft. The 2.5 times higher atmospheric pressure in the habitat leads to hyperoxia. The collection of biological samples occurred 6 days before (L-6), at day 7 (MD7) and 11/13 (MD11/13) during the mission, and 90 days thereafter (R). Blood analyses included differential blood cell count, ex vivo innate immune activation status and inhibitory competences of granulocytes. RESULTS: The absolute leukocyte count showed an increase during deployment as well as the granulocyte and monocyte count. Lymphocyte count was decreased on MD7. The assessments of native adhesion molecules on granulocytes (CD11b, CD62L) indicated a highly significant cellular activation (L-6 vs. MD7/MD13) during mission. In contrast, granulocytes were more sensitive towards anti-inflammatory stimuli (adenosine) on MD13. CONCLUSION: Living in the NEEMO habitat for 14 days induced significant immune alterations as seen by an activation of adhesion molecules and vice versa higher sensitivity towards inhibition. This investigation under hyperbaric hyperoxia is important especially for Astronauts' immune competence during extravehicular activities when exposed to similar conditions. PMID- 26116984 TI - Low processivity for DNA translocation by the ISWI molecular motor. AB - The motor protein ISWI (Imitation SWItch) is the conserved catalytic ATPase domain of the ISWI family of chromatin remodelers. Members of the ISWI family are involved in regulating the structure of cellular chromatin during times of transcription, translation, and repair. Current models for the nucleosome repositioning activity of ISWI and other chromatin remodelers require the translocation of the remodeling protein along double-stranded DNA through an ATP dependent mechanism. Here we report results from spectrofluorometric stopped-flow experiments which demonstrate that ISWI displays very low processivity for free DNA translocation. By combining these results with those from experiments monitoring the DNA stimulated ATPase activity of ISWI we further demonstrate that the DNA translocation by ISWI is tightly coupled to ATP hydrolysis. The calculated coupling efficiency of 0.067+/-0.018 ATP/ISWI/bp is seemingly quite low in comparison to similar DNA translocases and we present potential models to account for this. Nevertheless, the tight coupling of ATP hydrolysis to DNA translocation suggests that DNA translocation is not energetically rate limiting for nucleosome repositioning by ISWI. PMID- 26116985 TI - Comparison of Distal Limb Warming With Fluidotherapy and Warm Water Immersion for Mild Hypothermia Rewarming. AB - OBJECTIVE: The purpose of the study was to determine the effectiveness of Fluidotherapy rewarming through the distal extremities for mildly hypothermic, vigorously shivering subjects. Fluidotherapy is a dry heat modality in which cellulose particles are suspended by warm air circulation. METHODS: Seven subjects (2 female) were cooled on 3 occasions in 8C water for 60 minutes, or to a core temperature of 35 degrees C. They were then dried and rewarmed in a seated position by 1) shivering only; 2) Fluidotherapy applied to the distal extremities (46 +/- 1 degrees C, mean +/- SD); or 3) water immersion of the distal extremities (44 +/- 1 degrees C). The order of rewarming followed a balanced design. Esophageal temperature, skin temperature, heart rate, oxygen consumption, and heat flux were measured. RESULTS: The warm water produced the highest rewarming rate, 6.1 degrees C.h(-1), 95% CI: 5.3-6.9, compared with Fluidotherapy, 2.2 degrees C.h(-1), 95% CI: 1.4-3.0, and shivering only, 2.0 degrees C.h(-1), 95% CI: 1.2-2.8. The Fluidotherapy and warm water conditions increased skin temperature and inhibited shivering heat production, thus reducing metabolic heat production (166 +/- 42 W and 181 +/- 45 W, respectively), compared with shivering only (322 +/- 142 W). Warm water provided a significantly higher net heat gain (398.0 +/- 52 W) than shivering only (288.4 +/- 115 W). CONCLUSIONS: Fluidotherapy was not as effective as warm water for rewarming mildly hypothermic subjects. Although Fluidotherapy is more portable and technically simpler, it provides a lower rate of rewarming that is similar to shivering only. It does help decrease shivering heat production, lowering energy expenditure and cardiac work, and could be considered in a hospital setting, if convenient. PMID- 26116986 TI - Surface engineered polymeric nanocarriers mediate the delivery of transferrin methotrexate conjugates for an improved understanding of brain cancer. AB - The objective of present study was to enhance permeation of bioactive molecules across blood brain barrier (BBB) through polysorbate 80 coated poly-lactic-co glycolic acid (PLGA) nanoparticles (NPs) loaded with methotrexate-transferrin (Tw Mtx-Tf-NP) conjugates (Mtx-Tf). The easy trans-BBB migration of developed formulations through endocytosis, and inhibition of P-gp efflux pump present in brain were established by Pluronic F-68 and/or polysorbate 80 (Tween 80/Tw). The over-expression of transferrin (Tf) receptors on cancer cell surface allowed targeted and sustained delivery of Mtx-Tf conjugated to brain cancer cells by receptor mediated endocytosis. The developed formulations showed improved penetration in comparison to non-targeting experimental NP controls. The transportation potential and bio-distribution studies of such nanosized polymeric carriers showing successful migration and trans-BBB passage was carried out by administering FITC labeled drug loaded NPs to albino rats through intravenous route. We have validated anti-tumor efficiency of newly formulated and drug loaded NPs compared to controls in experimentally induced tumor-harboring rat model. The present study suggests greater compatibility, less organ toxicity and higher anti-tumor activity of developed formulations due to their targeting and sustained delivery potential in cancer therapeutic interventions. In conclusion, our findings of targeted and sustained drug delivery potential of NPs for are corroborated with in vitro and in vivo evidence, and formulated novel delivery vehicle shows its value in developing new tools for treating brain cancer. PMID- 26116987 TI - Where Did She Go? The Transformation of Self-Esteem, Self-Identity, and Mental Well-Being among Women Who Have Experienced Intimate Partner Violence. AB - BACKGROUND: Discussions on intimate partner violence (IPV) often focus on physical abuse, ignoring psychological and sexual abuse and controlling behaviors. The damage of varied forms of IPV on mental well-being in its broader form have been far less explored, especially among low-income women. Our aim was to improve our understanding of self-perceptions of mental well-being among low income women who have experienced IPV by considering a broader definition of mental well-being that includes self-esteem and self-identity as core components. METHODS: Using qualitative methods, we present findings from in-depth interviews with 41 low-income women currently or recently experiencing abuse and housing instability. RESULTS: Women experienced varied types of violence (physical, sexual, emotional, psychological, social isolation, and controlling behaviors). Injuries resulting from physical abuse were viewed differently from those arising from emotional and psychological control. Physical injuries healed faster, whereas damage to self-esteem and identity lingered. The journey through and out of IPV is often marked by an initial erosion of sense of self (identity deconstruction) followed by the identity reconstruction through an extended process of change aimed at rebuilding self-esteem, mental well-being, self efficacy, and ultimately self-identity. CONCLUSIONS: IPV-related training for physicians and allied health professionals should emphasize the varied nature of IPV and its impact on identity, self-esteem, and self-efficacy. Treatment should be holistic to address comorbid needs, including physical injury, mental health, and addiction problems. Consider supportive programs that integrate those living with or leaving IPV with women with past lived experience who can help women to understand the process of change and support this change in a nurturing setting. PMID- 26116988 TI - Attention: the claustrum. AB - The claustrum is a mysterious thin sheet of neurons lying between the insular cortex and the striatum. It is reciprocally connected with almost all cortical areas, including motor, somatosensory, visual, auditory, limbic, associative, and prefrontal cortices. In addition, it receives neuromodulatory input from subcortical structures. A decade ago, Sir Francis Crick and Christof Koch published an influential review proposing the claustrum as the 'seat of consciousness', spurring a revival of interest in the claustrum. We review the literature on the claustrum, emphasizing recent discoveries, and develop a detailed hypothesis describing a role for the claustrum in the segregation of attention. PMID- 26116989 TI - The truth about the lower plasma concentration of the (-)-isomer after racemic doxazosin administration in rats: Stereoselective inhibition of the (-)-isomer by the (+)-isomer at CYP3A. AB - Doxazosin (DOX), a long-lasting alpha1-adrenoceptor antagonist, is used clinically as a racemate that consists of two optical isomers. In humans and rats, following oral administration of racemic DOX [(+/-)-DOX], the plasma concentration of the (-)-isomer is lower than that of the (+)-isomer, but the mechanism for this interaction is not known. In this study, a chiral HPLC with fluorescence detection was used to measure the drug concentrations for analysis of the stereoselective metabolism of DOX in in vivo and in vitro experiments. We found that the plasma levels of the (-)-isomer were significantly lower than those of the (+)-enantiomer following i.v. administration of (+/-)-DOX to the rats and that the depletion rate constant (kdep) of (-)-DOX (0.0107+/ 0.0007L/min) was significantly larger than that of (+)-DOX (kdep 0.0088+/ 0.0005L/min) (p<0.05) when (+/-)-DOX was incubated with rat liver microsomes (RLMs). However, (-)-DOX was not depleted faster than (+)-DOX following their separate incubation with RLMs. The metabolism of (-)- or (+)-isomer in RLMs was catalysed by CYP3A because the depletion of the compounds was inhibited by ketoconazole (a potent CYP3A-selective inhibitor) similarly. More importantly, the kdep of (+)-DOX in the 1.0/2.0 and 0.5/2.5 (+)-DOX/(-)-DOX mixtures was significantly lower than that of (-)-DOX in the 1.0/2.0 and 0.5/2.5 (-)-DOX/(+) DOX mixtures (p<0.05). In conclusion, although (-)-DOX is not depleted faster than (+)-DOX when only a single isomer of DOX is incubated with rat liver microsomes, it is depleted much faster than (+)-DOX when a mixture of the two isomers was used, suggesting a prominent and stereoselective inhibition of the ( )-isomer over the (+)-isomer at the CYP3A enzyme. PMID- 26116990 TI - Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlusTM. AB - DZNep is a potential epigenetic drug, and exerts potent anti-proliferative and pro-apoptotic effects on broad-spectrum carcinomas via disruption of the EZH2 pathway. Antitumor studies on DZNep have been stuck in the preclinical phase because of the lack of information about its integral pharmacokinetic (PK) properties. To circumvent this problem, we extensively investigated the disposition characteristics of the DZNep in rats. By incorporating the disposition data across species into a whole-body physiologically based pharmacokinetic (PBPK) models using the GastroPlus(TM) software, we simulated human PK properties of DZNep and determined whether DZNep could be developed for human cancer therapy. Firstly, DZNep was found to cause nephrotoxicity in a dose dependent manner in rats and its safe dose was determined to be 10mg/kg. DZNep showed a short plasma elimination half-life (1.1h) in rats, a low protein binding in plasma (18.5%), a low partitioning to erythrocyte (0.78), and a low intrinsic hepatic clearance in rats and humans. There was extensive tissue distribution and predominant renal excretion (80.3%). The simulated rat PBPK model of DZNep was well-verified with satisfactory coefficients of determination for all the tested tissues (R(2)>0.781). The simulated human PBPK model successfully identified that intravenous administration of DZNep at appropriate dosing regimen could be further developed for human non-small cell lung carcinoma treatments. The present findings provide valuable information regarding experimental or in silico PK characteristics of DZNep in rats and humans, which is helpful to guide future studies of DZNep in both preclinical and clinical phases. PMID- 26116991 TI - Meta-Analysis of Non-O Blood Group as an Independent Risk Factor for Coronary Artery Disease. AB - To determine whether non-O blood group is an independent risk factor for coronary artery disease (CAD), we performed a meta-analysis of contemporary studies reporting adjusted relative risk estimates using multivariable logistic regression and multivariable Cox proportional hazards regression. MEDLINE and EMBASE were searched from January 2001 to March 2015 using Web-based search engines (PubMed and OVID). Search terms included blood group/type and coronary (artery/heart) disease, ischemic/ischaemic heart disease, acute coronary syndrome, myocardial infarction, or angina. Eligible were case-control, cross sectional, or cohort studies reporting adjusted odds ratios (ORs) and hazard ratios (HRs) for CAD in subjects with non-O versus O blood group using multivariable logistic regression/multivariable Cox proportional hazards regression. Study-specific estimates were combined using inverse variance weighted averages of logarithmic ORs/HRs in the random-effects model. Of 117 potentially relevant articles screened initially, 12 relative risk estimates in 10 eligible studies were identified and included. Pooled analysis of all the 12 ORs/HRs demonstrated that non-O blood group was associated with a statistically significant 14% increase in CAD incidence relative to O blood group (OR/HR 1.14, 95% confidence interval 1.04 to 1.25, p = 0.006). There was no evidence of significant publication bias. Combining 8 studies reporting data regarding (acute) myocardial infarction also generated a statistically significant result unfavoring non-O blood group (OR/HR 1.16, 95% confidence interval 1.02 to 1.31, p = 0.02). In conclusion, we found that based on a meta-analysis of 10 studies enrolling a total of 174,945 participants, non-O blood group appears to be an independent risk factor for CAD and myocardial infarction. PMID- 26116992 TI - Predictive Value of Gamma-Glutamyl Transferase Levels for Contrast-Induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction Who Underwent Primary Percutaneous Coronary Intervention. AB - Contrast-induced nephropathy (CIN) after primary percutaneous coronary intervention (PPCI) is associated with adverse short- and long-term outcomes. The aim of this study was to evaluate the predictive value of gamma-glutamyl transferase (GGT) for risk of CIN in patients with ST-segment elevation myocardial infarction who underwent PPCI. A total of 473 patients were enrolled in the study. A relative increase in serum creatinine >=25%, or an absolute increase >=0.5 mg/dl, from the baseline within 72 hours of contrast exposure was defined as CIN. Patients were divided into 3 groups according to GGT tertiles (tertile 1, GGT <19 U/L; tertile 2, GGT 19 to 33 U/L; and tertile 3, GGT >33 U/L) on admission. Demographics, clinical risk factors, laboratory parameters, CIN incidence, and other inhospital clinical outcomes were compared among GGT tertiles. CIN incidence was significantly higher in tertile 3 (29%) compared with tertiles 1 (11%) and 2 (11%, p <0.001). Inhospital death incidence was significantly increased across tertiles (from tertile 1 to tertiles 2 and 3, 1%, 4%, and 5%, respectively, p <0.05). In receiver operating characteristic analysis, a threshold value of GGT >26.5 U/L had 70% sensitivity and 60% specificity for CIN. After including variables found significant in univariate analysis, the presence of diabetes mellitus (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.22 to 2.31, p <0.001), C-reactive protein (for each 1 mg/L increase; OR 1.01, 95% CI 1.00 to 1.02, p = 0.007), contrast volume (for each 1 ml increase; OR 1.01, 95% CI 1.00 to 1.02, p = 0.012), and GGT >26.5 U/L (OR 2.59, 95% CI 1.48 to 4.53, p <0.001) were found as independent associates of CIN in multivariate regression analysis. Each 1 U/L increase in GGT was also associated with CIN risk (OR 1.04, 95% CI 1.03 to 1.06, p <0.001). In conclusion, GGT on admission was a significant and independent predictor of CIN after PPCI in patients with ST-segment elevation myocardial infarction. PMID- 26116993 TI - Approaches for identifying multiple-SNP haplotype blocks for use in human identification. AB - Single nucleotide polymorphism (SNP) discrimination effectiveness is low due to the bi-allelic nature of SNPs, and large numbers of loci must be analyzed for human identification in forensic casework. To resolve these issues, the authors support the use of multiple SNP haplotypes that will generate many haplotypes based on the combination of SNP alleles. First, 27 regions were selected from the JSNP database (http://snp.ims.u-tokyo.ac.jp) according to the following criteria: (1) 3 or more SNP loci within 100bp; (2) on-intron or out-of-gene location; and (3) frequency of more than 40% for each SNP allele. PCR amplification and high resolution melting curve (HRM) analysis were then carried out for all selected regions to determine variation in the haplotypes of each. HRM analysis indicated that 7 regions (1q25, 1q42.2, 3p24, 10p13, 11p15.1, 14q12-q13, and 20q12) containing 3 SNP loci had more than 2 haplotypes. The frequencies of the haplotypes for each region were observed via direct sequencing of more than 100 individuals. Not only haplotyping increases the effectiveness of individual identification but also the analysis region is shorter than in common short tandem repeat analysis, representing a further advantage for fragmented DNA samples in SNP typing. PMID- 26116994 TI - European Code against Cancer 4th Edition: Breastfeeding and cancer. AB - Breast cancer is the most frequent cancer in women, and incidence rates have been rising in European Union (EU) countries over recent decades due in part to a sharp decline in breastfeeding practices. Evidence for a protective association between breastfeeding and the risk of breast cancer at all ages is convincing, and modest protective relationships between breastfeeding and the risk of endometrial and ovarian cancers have been suggested. The reduction in breast cancer risk is estimated at 2% for an increase of 5 months of lifetime breastfeeding. The longer women breastfeed, the more they are protected against breast cancer. In addition, breastfeeding is associated with several health benefits for both the mother and the breastfed child. Taking all this evidence into account, the 4th edition of the European Code against Cancer recommends: "Breastfeeding reduces the mother's cancer risk. If you can, breastfeed your baby". PMID- 26116995 TI - A polyoxometalate-based inorganic-organic hybrid polymer constructed from silver Schiff base building block and Keggin-type cluster: Synthesis, crystal structure and photocatalytic performance for the degradation of rhodamine B. AB - One polyoxometalate-based inorganic-organic hybrid polymer [Ag3L4(PMo12O40)(CH3OH)].CH3OH (1), where L is N,N'-bis(furan-2 ylmethylene)hydrazine, has been synthesized at room temperature and structurally characterized by infrared spectroscopy, ultraviolet-visible spectroscopy, elemental analysis, X-ray powder diffraction and X-ray single-crystal crystallography. The structure of 1 exhibits a crystalline one-dimensional polymer constructed by the connections of Keggin-type [PMo12O40](3-) anions and [Ag3L4](3+) units, in which each Ag(I) center adopted a distorted square pyramidal environment. The spectroscopic experiments show that polymer 1 not only is potential semiconductor materials but also displays the obvious photocatalytic performance for the degradation of rhodamine B. PMID- 26116996 TI - The electronic structure engineering of organic dye sensitizers for solar cells: The case of JK derivatives. AB - The design and development of novel dye sensitizers are effective method to improve the performance of dye-sensitized solar cells (DSSCs) because dye sensitizers have significant influence on photo-to-current conversion efficiency. In the procedure of dye sensitizer design, it is very important to understand how to tune their electronic structures and related properties through the substitution of electronic donors, acceptors, and conjugated bridges in dye sensitizers. Here, the electronic structures and excited-state properties of organic JK dye sensitizers are calculated by using density functional theory (DFT) and time dependent DFT methods. Based upon the calculated results, we investigated the role of different electronic donors, acceptors, and pi conjugated bridges in the modification of electronic structures, absorption properties, as well as the free energy variations for electron injection and dye regeneration. In terms of the analysis of transition configurations and molecular orbitals, the effective chromophores which are favorable for electron injection in DSSCs are addressed. Meanwhile, considering the absorption spectra and free energy variation, the promising electronic donors, pi-conjugated bridges, and acceptors are presented to design dye sensitizers. PMID- 26116997 TI - Cobalt ferrite nano-composite coated on glass by Doctor Blade method for photo catalytic degradation of an azo textile dye Reactive Red 4: XRD, FESEM and DRS investigations. AB - Cobalt ferrite nano-composite was prepared by hydrothermal route using cobalt nitrate, iron nitrate and ethylene glycol as chelating agent. The nano-composite was coated on glass by Doctor Blade method and annealed at 300 degrees C. The structural, optical, and photocatalytic properties have been studied by powder X ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and UV visible spectroscopy (UV-Vis DRS). Powder XRD analysis confirmed formation of CoFe2O4 spinel phase. The estimated particle size from FESEM data was 50 nm. The calculated energy band gaps, obtained by Tauc relation from UV-Vis absorption spectra was 1.3 eV. Photocatalytic degradation of Reactive Red 4 as an azo textile was investigated in aqueous solution under irradiation showed 68.0% degradation of the dye within 100 min. The experimental enhanced activity compare to pure Fe2O3 can be ascribed to the formation of composite, which was mainly attributable to the transfer of electron and hole to the surface of composite and hinder the electron hole recombination. PMID- 26116998 TI - Phenanthrimidazole as a fluorescent sensor with logic gate operations. AB - A novel sensor namely, 1-(1-(p-tolyl)-1H-phenanthro[9,10-d]imidazol-2 yl)naphthalen-2-ol was synthesised for the detection of anion as well as cation through intramolecular charge transfer mechanism. This compound was used for the selective detection of Zn(2+) ion as compared to other metal ions and the binding was evidenced from the new absorption band at 356 nm and switch on fluorescence at 453 nm. The switch on fluorescence can be explained on the basis of photoinduced electron transfer (PET) mechanism and it was demonstrated by logic gate functions. PMID- 26116999 TI - Accumulating exercise and postprandial health in adolescents. AB - PURPOSE: To examine the influence of exercise intensity on postprandial health outcomes in adolescents when exercise is accumulated throughout the day. METHODS: 19 adolescents (9 male, 13.7+/-0.4 years old) completed three 1-day trials in a randomised order: (1) rest (CON); or four bouts of (2) 2*1 min cycling at 90% peak power with 75 s recovery (high-intensity interval exercise; HIIE); or (3) cycling at 90% of the gas exchange threshold (moderate-intensity exercise; MIE), which was work-matched to HIIE. Each bout was separated by 2 hours. Participants consumed a high fat milkshake for breakfast and lunch. Postprandial triacylglycerol (TAG), glucose, systolic blood pressure (SBP) and fat oxidation were assessed throughout the day. RESULTS: There was no effect of trial on total area under the curve (TAUC) for TAG (P=0.87). TAUC-glucose was lower in HIIE compared to CON (P=0.03, ES=0.42) and MIE (P=0.04, ES=0.41), with no difference between MIE and CON (P=0.89, ES=0.04). Postprandial SBP was lower in HIIE compared to CON (P=0.04, ES=0.50) and MIE (P=0.04, ES=0.40), but not different between MIE and CON (P=0.52, ES=0.11). Resting fat oxidation was increased in HIIE compared to CON (P=0.01, ES=0.74) and MIE (P=0.05, ES=0.51), with no difference between MIE and CON (P=0.37, ES=0.24). CONCLUSION: Neither exercise trial attenuated postprandial lipaemia. However, accumulating brief bouts of HIIE, but not MIE, reduced postprandial plasma glucose and SBP, and increased resting fat oxidation in adolescent boys and girls. The intensity of accumulated exercise may therefore have important implications for health outcomes in youth. PMID- 26117000 TI - In adult twins, visceral fat accumulation depends more on exceeding sex-specific adiposity thresholds than on genetics. AB - OBJECTIVE: We recently reported sex-specific percent body fat (%BF) thresholds (males=23%, females=38%) above which, visceral adipose tissue (VAT) significantly increases. Using monozygotic (MZ) and dizygotic (DZ) twins, we examined the influence of genetics on regional fat distribution measured by dual-energy X-ray absorptiometry, above and below these sex-specific thresholds for VAT accumulation. METHODS: Fifty-eight twin pairs (44 MZ, 14 DZ) were recruited from the University of Washington Twin Registry. Segmented linear regression was used to assess the threshold between VAT mass and %BF by sex and by zygosity. To assess the effect of genetics on VAT accumulation, Dunnett's T3 compared MZ and DZ pairs whether the twin pairs were both above the adiposity threshold or not. RESULTS: %BF thresholds for VAT accumulation were identified (%BF: M=20.6%, F=39.4%). Zygosity-specific thresholds were not significantly different (p>0.05). If at least one twin was below threshold, DZ twins still exhibited greater within pair differences than MZ pairs in %BF (p=0.023) but not VAT (p=0.121). CONCLUSIONS: Using a twin study approach, we observed no difference by zygosity for the threshold as which VAT accumulates. Additionally, for the first time we observed that while total BF is influenced by genetics, VAT accumulation may depend more on whether a person's %BF is above their sex-specific adiposity threshold. These results suggest that there may not be a genetic predisposition for VAT accumulation but rather it is a result of a predisposition for total fat accumulation. PMID- 26117001 TI - Pharmacist-led screening program for an inner-city pediatric population. AB - OBJECTIVES: To identify the prevalence of asthma, obesity, hypertension, and environmental tobacco smoke (ETS) exposure among youth and provide recommendations for follow-up care. METHODS: This cross-sectional study consisted of 12 health screenings for children between 5 and 17 years of age in various inner city, lower socioeconomic, and predominantly black communities throughout the city of Pittsburgh, PA. The screenings were conducted by pharmacists and student pharmacists from April 2010 to April 2012. Asthma, obesity, hypertension, and ETS screenings were offered at each event. RESULTS: A total of 144 children (50% girls, 89% black, non-Hispanic) were enrolled. Sixteen percent of the study population had a previous diagnosis of asthma; 4% were poorly controlled, and 18% were identified as having potential, undiagnosed asthma. Fifty-three percent were at an unhealthy weight (0.7% underweight, 24.3% overweight, 28.5% obese), 24% had abnormal blood pressure (12.8% prehypertension, 8.5% stage 1 hypertension, 2.8% stage 2 hypertension), and 26% had ETS exposure equivalent to that of smokers (0.7% light smokers, 17.5% smokers, and 7.7% heavy smokers). Overall, 177 specific referrals were made. The incidence of hypertension (P <0.001) and the proportion of ETS equivalent to heavy smokers increased (P = 0.019) with increased weight classification. CONCLUSION: Within this self-selected inner city, predominantly black pediatric population, there were high rates of positive screens for potential asthma, obesity, hypertension, and smoking. Additionally, the risk for high ETS exposure and hypertension increased with increasing weight. This study highlights the importance of pharmacists in disease screening and the need for alternative prevention and management strategies in disparate pediatric populations. PMID- 26117002 TI - [Relationship between RAD51-G135C and XRCC3-C241T Single Nucleotide Polymorphisms and Onset of Acute Myeloid Leukemia]. AB - OBJECTIVE: To investigate the relationship between RAD51-G135C and XRCC3-C241T single nucleotide polymorphisms and onset of acute myeloid leukemia (AML). METHODS: The study was performed in 2 groups: AML patient group and normal person group as control group. Genomic DNA was extracted from peripheral blood cells of 545 AML patients and 1 034 normal persons. Genotypes of RAD51-G135C and XRCC3 C241T were analyzed by TaqMan probe technology and the ralatienship between RAD51 G135C/XRCC3-C241T polymorphisms and onset of acute myeloid leukemia was investigated. RESULTS: Compared with the control group, RAD51-G135C homozygous mutant (CC) could significantly increase the risk of AML patients (OR=3.07), and there was no statistical relationship between heterozygous mutant (GC) of RAD51 G135C and onset of AML. There was no statistical relationship between homozygous mutant (TT) of XRCC3-C241T and onset of AML, and the XRCC3-C241T heterozygous mutation type (CT) increased the risk of AML patients (OR=0.66). CONCLUSION: RAD51-G135C homozygous mutant and XRCC3-C241T heterozygous mutation significantly increase the risk of the AML onset, which can provide more predictive value for incidence of AML. PMID- 26117003 TI - [Mutations of FBXW7 in Adult T-Cell Acute Lymphocytic Leukemia]. AB - BACKGROUD: F-Box and WD40 domain containing protein 7 gene (FBXW7) is part of the E3 ubiquitin ligase complex that controls the turnover of various proteins including NOTCH1, c-MYC and Cyclin E. OBJECTIVE: To investigate the mutations of FBXW7 gene in adult T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Exon 5 12 of FBXW7 were amplified, cloned and sequenced in 54 adult T-ALL patients; the frequency, position and types of FBXW7 mutation were analyzed; the co-existing of mutations with NOTCH1 and their relevant prognostic significance were explored as well. RESULTS: FBXW7 mutations were identified in 11.1% of adult T-ALL patients. A total of 4 types of point mutations (R465H, R465L, R479P and R505C) and 1 deletion/insertion mutation were observed, and all of them located in WD40 domain of FBXW7. In addition, co-existing mutations with NOTCH1 were identified in 83.3% of patients with FBXW7 mutation. Notably, the co-existed NOTCH1 mutations, including 3 point mutations (L1574P, L1596H and L1600P) and 2 deletion/insertion mutations located in HD domain. Furthermore, patients with FBXW7 mutation only had significantly longer overall survival compared with those without mutation (P=0.049). CONCLUSION: FBXW7 mutations may play an important role in NOTCH1 mediated pathogenesis in T-ALL. PMID- 26117004 TI - [CD20 Expression in Adult Patients with B-lineage Acute Lymphoblastic Leukemia and Its Prognostic Significance]. AB - OBJECTIVE: To explore the relationship between the expression of CD20 antigen and clinical characteristics in adult patients with B-acute lymphoblastic leukemia(B ALL). METHODS: The CD20 expression of 126 acute lympho-blastic leukemia patients in our hospital from July 2009 to July 2012 were determined by flow cytometry. The characteristics, examination results and outcome were analyzed retrospectively. The complete remission rate (CR rate), relape rate, 2-year survival rate and 2-year event-free survival (EFS) of patients with CD20 positive and negative after the first cycle of chemstherapy were compared. RESULTS: Positive rate of CD20 antigen expression in 126 patients was 24.4% (31 cases), negative rate of CD20 antigen expression in 126 patients was 75.6% (95 cases). No significant relationship was found between CD20 antigen expression and sex, age, peripheral blood leucocytes count and chromosomal changes. The relapse rate, 2 year survival rate (OS) and 2-year event-free survival (EFS) of adult patients with B-ALL in CD20 positive and negative groups were 53.3% and 38.0%, 52.1% and 92.3%, 33.7% and 70.8% respectively. CONCLUSION: Expression of CD20 in adult patients with B-ALL did not related with clinical features, but related with poor prognosis. PMID- 26117005 TI - [Establishment of Human Acute B-Lymphoblastic Leukemia--NOD/SCID Xenotransplant Mouse Model]. AB - OBJECTIVE: To establish human B-acute lymphoblastic leukemia NOD/SCID mouse model. METHODS: The unirradiated mice aged 4-5 weeks were injected with Nalm-6 cells via the tail vein. Successful transplantation was assessed by the general state, bone marrow smear and histopathologic examination. RESULTS: After 15 days of injection with Nalm-6 cells, the NOD/SCID mice displayed the morbidily with lethargy, hind limb paralysis, hunched back and lossing weight. The infiltration of leukemia cells could be observed in bone marrow and spleen sections. CONCLUSION: Systemic B lineage acute leukemia animal mode1 has been successfully established in the NOD/SCID mice, which is a useful tool for studying pathogenesis of leukemia and guiding clinical chemotherapy regimens. PMID- 26117006 TI - [Inducing Effect of Akt Kinase Inhibitor MK2206 on Apoptosis in U937 Cells and RS4;11 Cells, and Its Mechanism]. AB - OBJECTIVE: This study was purposed to investigate the effect of Akt kinase inhibitor MK2206 on proliferation and apoptosis of U937 cells and RS4;11 cells, and to explore its possible mechanism. METHODS: U937 and RS4;11 cells were cultured with different concentrations of MK2206 for 24 h and 48 h, and cell growth curve was analyzed by CCK-8; cell apoptosis was analyzed by Annexin V/7 AAD double labeling; cell cycle changes were analyzed by flow cytometry. The BAX, BCL-2, XIAP, CDK1, caspase-3 mRNA expressions were determined by real time PCR. RESULTS: MK2206 significantly inhibited the growth of U937 and RS4;11 cells in a time-and dose-dependent manner, and the IC50 values of U937 cells for 24 h and 48 h were (0.48+/-0.15) umol/L and (0.09+/-0.01) umol/L respectively, while IC50 values of RS4;11 cells for 24 h and 48 h were (0.91+/-0.02) umol/L and (0.68+/ 0.11) umol/L respectively. U937 were cultured with 0.5 umol/L MK2206 and RS4;11 cells were cultured with 1.0 umol/L MK2206 for 24 h and 48 h, and the both apoptosis rates were higher for 24 h or 48 h than that in control group (P<0.05), meanwhile the apoptosis rates for 48 h were higher than 24 h. The results of cell cycle detection showed that the both cells were arrested in G2/M phase compared with control group. The real time PCR assay revealed that the expressions of BAX, caspase-3 mRNA in cells treated with MK2206 were increased, while BCL-2, XIAP, CDK1 were reduced compared with control group. CONCLUSION: MK2206 can inhibit proliferation and induce apoptosis of U937 and RS4;11 cells, and the both cells are arrested in G2/M phase. The mechanism of promoting apoptosis may be related with up-regulating BAX, caspase-3 and down-regulating BCL-2, XIAP, meanwhile the cell cycle arrested in G2/M phase may be associated with down-regulating CDK1. PMID- 26117007 TI - [Effect of Metformin on Proliferation, Differentiation and Apoptosis of THP-1 Cells]. AB - OBJECTIVE: To investigate the effect of metformin on proliferation, differentiation and apoptosis of THP-1 cells and explore its possible mechanism. MEHODS: THP-1 cells were cultured with different concentrations of metformin for 24 h and 48 h. The cell proliferation was evaluated by CCK-8, the cell apoptosis was analyzed by Annexin V/7-AAD double labeling, the expression of CD14 and CD11b (surface differentiation antigens on THP-1 cells) was evaluated by flow cytometry, the BCL-XL, BAX, BIM and caspase-3 mRNA expressions of THP-1 cells were detected by real time quantitative PCR. RESULTS: Metformin could significantly inhibit the growth of THP-1 cells in a time- and dose- dependent manner. After treated with 20 mmol/L metformin for 24 h, the expressions of CD14 and CD11b in THP-1 cells didn't change much (P>0.05), the early apoptosis rates in exprimental and control groups were (2.02+/-0.85)% and (4.46+/-1.33)% respectively, the late apoptosis rates in experimental and control groups were (1.43+/-0.83)% and (3.31+/-0.59)% respectively. In process of inducing effect of 20 mmol/L metformin on THP-1 cells, the expressions of BCL-XL and BIM did not significantly changed, while the expressions of BAX and caspase-3 significantly increased (P<0.01). CONCLUSION: Metformin can effectively inhibit proliferation and induce apoptosis of THP-1 cells. However, it has no significant effect on differentiation of THP-1 cells, its mechanism inducing apoptosis maybe related with up-regulating BAX and caspase-3. PMID- 26117008 TI - [Biological Effects of the SARI Over-expression on K562 Cell Line]. AB - OBJECTIVE: To construct a lentivirus vector carrying SARI gene and to investigate its biological effects on K562 cells. METHODS: SARI was amplified from the plasmid containing SARI cDNA and subcloned into pLOV.CMV.eGFP virus vector. After sequencing, lentivirus packaging, titering, the viruses of SARI-pLOV.CMV.eGFP were harvested and tansfected into the K562 cells. Real-time quantitive PCR and Western blot were performed to validate the SARI expression at the level of mRNA and protein respectively. Simultaneously, the proliferation, apoptosis and cell cycle of K562 cells were detected by CCK-8 and flow cytometry respectively. RESULTS: The SARI overexpressed lentivirus vector was successfully constructed. The mRNA and protein levels of SARI increased significantly in the pLOV.CMV.eGFP SARI group, which was confirmed by Q-PCR and Western blot; as compared with blank and mock groups, SARI over-expression leaded to significant proliferation inhibition and increased apoptosis of K562 cells, without visible effects on cell cycle. CONCLUSION: the over-expression of SARI gene obviously suppresses the cell proliferation of the K562 cells as well as promotes the apoptosis. The results implied that the induction of the SARI gene expression may be an important candidate therapeutic method for the CML. PMID- 26117009 TI - [Prognostic Value of Prednisone Response in CCLG-ALL 2008]. AB - OBJECTIVE: To ovaluate the prognostic value of prednisone response in treatment regimes of children with acute lymphoblastic leukemia. METHODS: A total of 598 newly diagnosed ALL patients were enrolled and received prednisone pre-treatment. Based on the peripheral lymphoblast count on day 8, these patients were divided into 2 groups: prednisone good response (PGR) and prednisone poor response (PPR). PPR patients were classified into high risk group immediately and then received intensed chemotherapy. The all enrolled patients were followed up and the clinical features and treatment outcomes of the two groups were analyzed. RESULTS: Compared with PGR group, PPR group had different characteristics. They were older in age and had higher initial white blood cell count (P<0.05). T-cell ALL (T-ALL) and Philadelphia chromosome positive ALL (Ph+ ALL) were frequent in PPR group (P<0.05). Event-free survival (EFS) rate of PPR group was significantly lower than that of PGR group (P<0.05). 2 year event-free survival(EFS) rate of PGR group was (88.3+/-1.5)%, while the 2-year EFS rate of PPR group was (58.4+/ 5.3)%. 5 year EFS rates of PGR and PPR were (80.8+/-2.1)% and (53.4+/-6.0)%, respectively. The EFS rate of PPR group was falling rapidly within 2 years. PPR group had higher relapse rate, and most relapses occurred within 18 months (P<0.05). PPR group had more high incidence of minimal residual disease (MRD) both on day 33 and on week 12 (P<0.05). No significant difference of EFS and relapse time was found between PPR and high risk PGR patients (P>0.05). In multi variate regression analysis, the PPR, the presence of BCR-ABL1 and MLL were significantly unfavorable factors (P<0.05). CONCLUSION: Prednisone response has been confirmed to be still great prognostic value and PPR children patients have poor outcomes generally. It is likely that the response to prednisone does not make much sense to high risk ALL patients. PMID- 26117010 TI - [Effects of As2O3 on the Proliferation, Differentiation and Apoptosis of HL-60 Cells and Its Related Mechanisms]. AB - OBJECTIVE: To investigate the effects of arsenic trioxide (As2O3) on the proliferation, differentiation and apoptosis of HL-60 cells in vitro and explore the underlying mechanisms. METHODS: After HL-60 cells were treated with different concentration of As2O3, the cell proliferation was determined by MTS/PES method, the differentiation state was detected by the nitroblue tetrazolium (NBT) reduction test; flow cytometry was used to analyze the apoptosis and expression of CD11b. In addition, SYBR Green real-time RT-PCR was used to measure the mRNA levels of C-FES, BCL-2, BAX, survivin , P21 and P27. RESULTS: As2O3 could obviously inhibit the proliferation of HL-60 cells, and the effect was in dose- and time-dependent manners (r=-0.967; r=-0.954). Low concentration (0.1, 0.5 and 1.0 umol/L) of As2O3 could significantly promote the differentiation of HL-60 cells, the cells exhibited a higher NBT-reducing ability and expressed far more CD11b antigens. High concentration (2.5 and 5.0 umol/L) of As2O3 induced HL-60 cell apoptosis, but the ability of promoting differentiation decreased. The expression of C-FES mRNA significantly increased after being treated with As2O3 at the concentrations 1.0 and 5.0 umol/L, and the former is more obvious, which confirmed that C-FES mRNA level paralleled the cell differentiation degree. Also, the expression of BCL-2 and survivin significantly decreased, while the expression of BAX, P21 and P27 was significantly upregulated in HL-60 cells after being treated with 5.0 umol/L As2O3. CONCLUSION: As2O3 can significantly suppress cell proliferation, promote the differentiation and induce the apoptosis in HL-60 cells, and the mechanism of As2O3 anti-tumor activity may be involved in the regulation of C-FES, cell cycle and apoptosis-related genes. PMID- 26117011 TI - [Salinomycin Enhances the Apoptosis of T-cell Acute Lymphoblastic Leukemia Cell Line Jurkat Cells Induced by Vincristine]. AB - OBJECTIVE: This study was aimed to investigate the effect of salinomycin combined with vincristine on the proliferation and apoptosis of Jurkat cells and its possible mechanisms. METHODS: The proliferation of Jurkat cells was examined by CKK-8 assay. Flow cytometry was used to assess cellular apoptosis. Levels of BCL 2, caspase-3, and caspase- 8 were measured by Western blot. RESULTS: The salinomycin or vincristine, either alone or in combination, inhibited the proliferation of Jurkat cells in a dose-dependent manner. Salinomycin combined with vincristine produced more obveous inhibition of cell proliferation than either compound used alone (P<0.05). Western blot analysis showed that the combined use of Sal and VCR reduced the expression of BCL-2 protein, and increased expression of caspase 3 and caspase 8 protein, more significantly. Furthermore, combination of Sal and VCR synergistally promoted apoptosis of the Jurkat cells (P<0.05). CONCLUSION: The combination of salinomycin and vincristine synergistically inhibits proliferation and promotes apoptosis of T-cell acute lymphoblastic leukemia Jurkat cells. PMID- 26117012 TI - [Role of Dynamic Monitoring Chromosome Karyotypes for Evaluation of Chemotherapy Efficacy in Patients with Acute Leukemia]. AB - OBJECTIVE: To explore the role of dynamic monitoring the karyotype changes for evaluation of chemotherapy efficacy in patients with acute leukemia. METHODS: A total of 80 patients with acute leukemia were collected and according to FAB classification standards they were divided into 65 cases of acute myeloid leukemia (AML) and 15 cases of acute lymphoblastic leukemia (ALL); R banding technique was used taken to detect their chromosome and to analyze the relationship between chromosome and efficacy of chemotherapy. RESULTS: Out of 65 cases of AML, 31 cases showed abnormal karyotypes and their aberration rate was 47.7%; among 31 cases of AML with chromosome abnormalities, the t (15; 17) was found in 9 cases and they accounted for 29%; t (8; 21) was found in 7 cases and they accounted for 22.6%; other karyotype and complex karyotypes were found in 15 cases and they accounted for 48.4%; the remission rate of t (15; 17) group was 88.9%, remission rate of t (8; 21) group was 71.4%, remission rate of other karyotype group was 66.7%. The comparison of between different groups showed that remission rate of t (15; 17) group was significantly higher than that in T (8; 21) group, other karyotype group and normal karyotype group (chi2=9.625,14.267,7.768, P<0.05); the remission rate between t (8; 21) group, other karyotype group and normal karyotype group was no significant different (chi2=0.517, 0.111, P>0.05). In 15 cases of ALL, 8 cases with normal karyotype accounted for 53.3%, 7 cases with abnormal karyotype accounted for 46.7% of ALL; as compared with AML, no significant difference was shown (chi2=0.020, P>0.05); the remission rates of patients with normal karyotype and abnormal karyotype were 87.5% and 42.9% respectively, the difference between the two groups had statistical significance (chi2=43.834, P<0.01). CONCLUSION: For patients with AML, patients with t (15; 17) chromosomal abnormality can obtain better effect from chemotherapy, the clinical remission rate of ALL patients with normal karyotype is higher; the karyotype analysis has the important reference value for evaluating efficacy of chemotherapy in patients with leukemia. PMID- 26117013 TI - [Expression and Clinical Pathological Significance of EBER, PTEN and VEGF in Angioimmunoblastic T-Cell Lymphoma]. AB - OBJECTIVE: To investigate the expression and clinical pathological significance of EB virus (Epstein-Barr virus, EBV), PTEN and VEGF in angioimmunoblastic T cell lymphoma (AITL). METHODS: The EBV -encoded small RNA (EBER) expression in 21 cases of AITL was detected by in situ hybridization. The expressions of PTEN and VEGF were detected in 21 cases of AITL and 20 cases of lymph node reactive hyperplasia by immunohistochemical EnVision two-steps method. The expression and clinicopathological significance of EBV, PTEN and VEGF in AITL were analyzed. RESULTS: The positive expression rate of EBER in 21 cases of AITL was 61.9%; the expressions of PTEN and VEGF in AITL and lymph node reactive hyperplasia were significantly different (P<0.05). The expressions of EBER and PTEN negatively correlated (P<0.05). The EBER positive expression rates of male patients in AITL group and the progressed group was 80% and 78.6% respectively, which were significantly higher than that in female patients and patients in non- advanced group (P<0.05); the PTEN expression rates in the AITL group accompanying B symptoms and progressed group were 31.3% and 21.4%, respectively, which were significantly lower than those in patients without B symptoms and non-progressed group (P<0.05). Survival analysis showed that the PTEN expression negatively correlated with the overall survival rate of patients (P<0.05). CONCLUSION: EBV infection and low expression of PTEN may indicate the deterioration of angioimmunoblastic T-cell lymphoma. Whether the EBV involved in the ocurring of T cell angioimmunoblastic lymphoma by down-regulating PTEN expression is unclear, further research is needed. PMID- 26117014 TI - [Long Term Curative Effects and Prognostic Analysis of Stem Cell Transplantation for Treating Patients with Peripheral T Cell Lymphoma]. AB - OBJECTIVE: To explore the efficacy and prognostic factors of hematopoietic stem cell transplantation in the treatment of patients with peripheral T cell lymphoma (PTCL). METHODS: The clinical records of 53 patients with PTCL were collected and analyzed retrospectively. The prognostic value of prognostic index PIT were evaluated. RESULTS: Among 53 cases of PTCL, 31 patients underwent hematopoietic autologous stem cell transplantation (auto-HSCT), 22 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), their median follow-up time was 62 (1-174) months, from them 1 patients was not engrafted in each group, 4 patients underwent allo-HSCT died within 1 month after transplantation. The 3 year overall survival rates in auto- and allo-HSCT groups were 42.3% (95% CI 24.1 60.5%) and 42.9% (95% CI 21.7-64.1%) respectively, 11 and 3 patients died of relapse after auto-HSCT and allo-HSCT, respectively, the treatment-related mortality (TRM) was 22.6% (95% CI 6.1%-39.0%) and 48.7% (95% CI 26.8%-70.7%), respectively. Univariate analysis showed that bone marrow involvement at diagnosis was associated with poor prognosis. In allo-HSCT group, PIT showed statistically significant difference in both OS and PFS between the patients without or with one risk factor and the patients with 3-4 risk factors. CONCLUSION: The relapse rate of relapse/refractory patients is high after auto HSCT. The TRM is high after allo-HSCT, but long term survival is promising. The prognostic index for PTCL can reliably assess the prognosis of PTCL. PMID- 26117015 TI - [Pathological Characteristics of Bone Marrow in Non-Hodgkin's Lymphoma Patients with Secondary Myelofibrosis and Their Relationship with Prognosis]. AB - OBJECTIVE: To investigate the pathological characteristics of bone marrow in non Hodgkin's lymphoma(NHL) patients with secondary myelofibrosis and their relationship with disease prognosis. METHODS: The pathological characteristics of bone marrow in 14 NHL patients with secondary myelofibrosis and 30 NHL patients without secondary myelofibrosis received from January 2012 to December 2013 in Department of Hematology, the First Affiliated Hospital Xi'an Jiaotong University Medical School were analysed, and overall survival and progress-free survival rates of NHL patients with and without secondary myelofibrosis were analyzed and compared. RESULTS: 14 cases of NHL with secondary myelofibrosis including 9 cases of lymphoma cell leukemia were all at stage IV and had hyperplasia of bone marrow fibrous tissue, the Gomori staining were all positive. When the lymphoma cells in bone marrow decreased or negative, their Gomori staining were negative. If the disease relapsed, the Gomori staining became positive again. There were 30 cases of NHL at stage IV wihtout secondary myelofibrosis. The overall survival rates and progression-free survival rates at 1,3,5 years in these patients were 100%, 93.1%, 57.6% and 100%, 92.6%,52.6% respectively. The overall survival rates and progression-free survival rates at 1,3,5 years in 14 NHL patients with secondary myelofibrosis were 92.9%,81.3%, 48.8% and was 71.8%, 62.3%, 47.9%, respectively. CONCLUSION: NHL patients with secondary myelofibrosis are almost at stage IV, especially in the patients with lymphoma cell leukemia. They had different degree of hyperplasia of bone marrow fibrous tissue, and the myelofibrosis would be reduced or disappeared when the disease in remission. The overall and progression -free survival rates decrease in NHL patients with secondary myelofibrosis, compared with patients without secondary myelofibrosis. Secondary myelofibrosis is one of the indicators of poor prognosis. PMID- 26117016 TI - [Effects of Silencing AKT Gene by shRNA on Proliferation, Apoptosis and Notch1 Signal Pathway in Jeko-1 Cells]. AB - OBJECTIVE: To investigate the effects of silencing AKT gene by RNA interference on the proliferation, apoptosis and the expression of Notch1 signal pathway related proteins in mantle cell lymphoma Jeko-1 cell line. METHODS: The hairpin like oligonucleotide sequences targeting AKT gene were designed and transfected into Jeko-1 cells by lipofectamine(TM) 2000. The AKT mRNA and protein were detected by RQ-PCR and Western blot respectively. Cell growth was determined by MTT. Cell apoptosis was analyzed by flow cytometry. The expression of BCL-2, BAX, caspase-3, caspase-9, p-AKT, Notch1, HES1 was detected by Western blot. RESULTS: AKT mRNA was markedly suppressed by the shRNA targeting AKT. AKT shRNA suppressed the proliferation of Jeko-1 cells and induced apoptosis of these cells. The cell apoptotic rates were (37.72+/-4.39)%, (2.62+/-1.53)%, (1.57+/-0.42)% in AKT shRNA, Neg-shRNA and Control, respectively, The difference between them was statistically significant (P<0.01). AKT shRNA down-regulated the expression of Bcl-2, AKT p-AKT , Notch1, and HES1, up-regulated the expression of BAX, caspase 3, caspase-9. CONCLUSION: Silencing AKT gene can inhibit the proliferation of Jeko-1 cells line, induc cell apoptosis, its mechanism may be associated with specially inhibiting PI3K/AKT signaling pathway and down-regulating the activity of Notch1 signaling pathway. PMID- 26117017 TI - [Clinical Efficacy of Radiotherapy Combined with Chemotherapy for Primary Mediastinal Large B-cell Lymphoma]. AB - OBJECTIVE: To explore the clinical efficacy of radiotherapy combined with chemotherapy for patients with primary mediastinal large B-cell lymphoma(PMLBCL). METHODS: A total of 34 cases of PMLBCL were treated by radiotherapy combined with chemotherapy(radio-chemotherapy group), 28 cases of PMLBCL were treated by chemotherapy alone (single chemotherapy group as control). The clinical efficacy, side effects, long-term survival of the two group patients were compared. RESULTS: The overall remission(OR) in the radio-chemotherapy group were higher than that in single chemotherapy group (P<0.05); the blood toxicity reaction, mucositis, radiation dermatitis in radio-chemotherapy group were higher than those in single chemotherapy group (P<0.05); the progress free survival(PFS) for 1 year in radio-chemotherapy group was higher than that in the single chemotherapy group (P<0.05), the local control (LC), PFS for 3 years in the radio chemotherapy group were higher than those in the single chemotherapy group (P<0.05), the LC, OS, PFS for 5 years in the radio-chemotherapy group were higher than those in the single chemotherapy group (P<0.05). CONCLUSION: The radiotherapy combined with chemotherapy has good clinical efficacy for patients with primary mediastinal large B-cell lymphoma, it has high rate of progression free survival, it can be used as optimed scheme for treating PMLBCL, but the complications resulting from radio-chemotherapy should be prevented. PMID- 26117018 TI - [Molecular Pathological Diagnosis of Mucosa-associated Lymphoid Tissue Lymphoma]. AB - OBJECTIVE: To explore the molecular pathological diagnosis of mucosa-associated lymphoid tissue lymphoma(MALTL). METHODS: Sixty MALTL paraffin embedding specimens were analyzed retrospectively. The distribution of the primary lesion, morphology, immunophenotype, IgH gene cloning rearrangement were evaluated. RESULTS: The main risk area for the patients with MALTL was gastric area(37%), in the second place was salivary gland(20%), in the third place was intestine (12%), orbit and ocular adnexa(12%); at low magnification, MALTL specimens manifasted diffuse growth majority, a few of nodular structure, lymphoma cell forms were diversified; The results of immunohistochemical detection showed that the CD20 and the BCL-2 were positive, the CD3, CD5, CD10, CD23, cyclin D1 and CD21 were negative, 17 specimen kappa or lambda express more obviously, their sensibility was 28.33%(17/60); 61.67%(37/60) developed IgH gene rearrangement, 19 specimen IgH gene rearrangement monoclonal and kappa or lambda were negative, the positive rate of both combined detections was 68.33%. CONCLUSION: The tissue morphologic characteristics and immuno-histochemistry detection are the basic means for MALTL diagnosis, the detection of IgH gene reasragement and Kappa or lamda restrictive expression has the practical importance for MALTL diagnosis, both combination can show higher positive rate for MALTL diagnosis. PMID- 26117019 TI - [Clinical Efficacy of Bleomycin, Cyclophosphamide, Vindesine, Ara-C and Dexamethasone for Treatment of Patients with Relapsed Refractory Diffuse Large B Cell Lymphoma]. AB - OBJECTIVE: To investigate the clinical efficacy of bleomycin, cyclophosphamide, vindesine, Ara-C and dexamethasone(BACOD) for treatment of patients with relapsed/refractory diffuse large B cell lymphoma. METHODS: A total of 56 patients with relapsed/refractory diffuse large B cell lymphoma were divided into control group and treatment group. The control group were received the conventional BACOD treatment, and the treatment group received continuous venoclysis with BACOD. Clinical efficacy was observed and compared. RESULTS: In control group, 6 patients achieved CR, 9 patients achieved PR, and their overall remission rate was 53.6%. In treatment group, 10 patients achieved CR, 12 patients achieved PR, and their overall remission rate was 78.6%. The overall remission rate of treatment group was significantly higher than that of control group (chi2=3.903, P<0.05). The incidence rates of nausea and vomiting, thrombocytopenia, abnormal liver function, fever and granulocytopenia were not significant difference (P>0.05) between the two groups. CONCLUSION: The clinical efficacy of cyclophosphamide, vindesine and dexamethasone for treatment of patients with relapsed/refractory/diffuse large B cell lymphoma has been confirmed to be satisfactory, suggesting that the continuous venoclysis with BACOD can be apptied to the in clinical treatment. PMID- 26117020 TI - [Clinical Analysis of Anemia in Castleman Disease]. AB - OBJECTIVE: This study was to explore the characteristics of anemia in Castleman disease (CD). METHODS: Clinical data were collected retrospectively to analyze the prevalence and characteristics of CD with anemia were analysed retrospectively, and different types of anemia and their therapeutic effects were evaluated. RESULTS: Anemia was observed in 13/33(39%) newly diagnosed CD patients, most of them was mild and normocytic. Incidence of anemia in multicentric CD (MCD) was higher than that in unicentric CD (UCD) (85% vs 10%, P<0.001). Most of CD patients with anemia presented systematic manifestations; moreover, they had higher levels of erythrocyte sedimentation and inflammatory indices, higher incidence of polyclonal hyperimmunoglobulinemia, and higher positive rate of autoantibodies than those without anemia (P<0.05). Except for 2 cases of autoimmune hemolytic anemia (AIHA) and 1 case of anemia secondary to hypersplenism, the anemia in the other 10 patients exhibited features similar to anemia of chronic disease (ACD), whose hemoglobin levels were negatively correlated with the serum levels of C reactive protein and fibrinogen (r -0.917 and -0.717, respectively, P<0.001). Anemia in UCD was cured by the removal of tumor. Yet, anemia in MCD was improved after systemic treatment with immunotherapy and/or chemotherapy. CONCLUSIONS: anemia with an inflammatory and immunologic mechanism presents as a common symptom in MCD, but also can be observed in UCD. In addition to occasional AIHA, anemia associated with CD mainly presents characteristics of ACD. Treatment for anemia in CD is mainly based on the control of primary disease. PMID- 26117021 TI - [Analysis of the Detection for the LPD Patients with EB Infection]. AB - OBJECTIVE: To analyze the detection results for the patients with lymphoproliferative disease(LPD) accompanied with the infection of EB. METHODS: The EBV specific antibody, serum cytokine, EBV DNA copy number in peripheral blood mononuclear cells (PBMNC) of 70 LPD patients and 70 healthy volunteers were analyzed and compared. RESULTS: The positive rates of VCA-IgG and VCA-IgM were not significantly different in two groups (P>0.05); The positive rate of EA-IgG in the PLD patient group was higher than that in the control group (P<0.05); the levels of IL-18 and IFN-gamma were not significantly different between the 2 group (P>0.05); the EBV DNA copy number in PBMNC of the PLD patient group was higher than that in the control group (P<0.05). CONCLUSION: The patients with LPD show the active infection of EBV, that is the main reason for the abnormal function of lymphatic system in the patients with LPD. The active infection of EBV maybe involve in PLD pathogenesis. PMID- 26117022 TI - [Growth Inhibition of Multiple Myeloma Cells Caused by MicroRNA-15a and Its Mechanisms]. AB - OBJECTIVE: To explore the effect and possible mechanisms of miR-15a on growth of multiple myeloma(MM) cells. METHODS: MM cell lines (U266 and RPMI8226) were transfected by lentiviral particles. MM stable cell lines were selected and collected by flow cytometry (FCM). Proliferation of MM cells before and after miR 15a high expression was detected by CCK-8 method. Apoptosis of MM cells before and after miR-15a high expression was detected by AO/EB dying, Hoechst 33258 dying and FCM, respectively. Cell cycle of MM cells before and after miR-15a high expression was detected by FCM. The expressions of miR-15a, BMI-1 and BCL-2 mRNA of MM cells before and after miR-15a high expression were detected by real-time PCR. The expressions of BMI-1 protein of MM cells before and after miR-15a high expression were detected by Western blot. RESULTS: MM stable cell lines with miR 15a high expression was acquired. CCK-8 result showed that high expression of miR 15a could inhibit growth of MM cells (U266 and RPMI8226). AO/EB dying, Hoechst 33258 dying and FCM testing results showed that high expression of miR-15a could significantly induce apoptosis of MM cells (U266 and RPMI8226). The apoptosis rates of U266 and RPMI8226 cells in high expression group and control group were 90.52% vs 37.08% and 59.40% vs 44.17%, respectively. Meanwhile, FCM testing results showed that high expression of miR-15a could induce G1 arrest of MM cells (U266 and RPMI8226), which proportion of G1 phase were 41.50%+/-0.64%, 45.31%+/ 0.77%, respectively. Real-time PCR results showed that during the growth inhibition process of MM cells caused by miR-15a high expression, the expression of BCL-2 mRNA decreased, but there was no significant changes in the expression of BMI-1 mRNA, while the expression of BMI-1 protein decreased significantly. CONCLUSION: High expression of miR-15a can induce cell cycle arrest and apoptosis of MM cells, then inhibit their growth. The mechanisms may be related with the negative regulation of BMI-1 and BCL-2 genes in post-transcription level caused by miR-15a. PMID- 26117023 TI - [Effects of DNMT1 Gene Silencing on Methylation of SOCS-1 Gene in Myeloma Cells]. AB - OBJECTIVE: To investigate the effect of DNA methyhransferase l (DNMT1) gene silencing on methylation of suppressor of cytokine signaling (SOCS-1) in multiple myeloma RPMI 8226 cells. METHODS: Recombinant plasmid pshRNA-DNMTl was transfected into multiple myeloma RPMI 8226 cells by lipofectamine 2000. RT-PCR and Western blot were used to detect the mRNA and protein expression of DNMTl in RPMI 8226 cells respectively before and after transfection. Methylation-specific polymerase chain reaction was used to detect the methylation level change of SOCS 1 gene in RPMI8226 cells transfected. RESULTS: DNMTl targeted short hairpin RNA(shRNA) was successfully inserted into the plasmid vector pshRNA. RT-PCR results showed that the relative mRNA expression level of DNMTI gene in RPMI 8226 cells transfected with pshRNA was 0.176+/-0.004 which was significantly lower than that in cells transfected by empty vector (0.956+/-0.033, P<0.01). Western blot analysis showed that the relative expression level of DNMT1 protein of RPMI 8226 cells transfected by pshRNA was 0.065+/-0.014, which was significantly lower than that in transfected cells by empty vector(0.415+/-0.027) (P<0.05). These results indicated that the recombinant plasmid pshRNA could effectively knock down the expression of DNMT1 gene in RPMI 8226 cells. Methylation analysis showed that the methylation level of SOCS-1 gene was obviously reduced after transfection. CONCLUSION: DNMT1 gene in RPMI 8226 cell can be silenced by shRNA. DNMT1 gene silencing can significantly induce SOCS-1 gene hypomethylation, which indicates that DNMT1 may play an important role in the process of SOCS-1 hypermethylation. PMID- 26117024 TI - [Valproic Acid Represses Autophagy and Enhances the Anti-myeloma Activity of DNA damaging Drugs]. AB - OBJECTIVE: To explore the effect of valproic acid(VPA) on anti-myeloma activity of Doxorubicin(DOX) or Melphalan(MEL) and its related mechanism. METHODS: Human multiple myeloma(MM) cells were treated with VPA of non-toxic dose in absence and presence of DOX or MEL at different concentrations (ie. IC10, IC20, IC40). The cell proliferation was detected by MTT method. Western blot was used to detect the expression levels of autophagy-related proteins (LC3, ATG5, ATG7) and acetylated histone H4K16ac. RESULTS: Cell proliferation inhibition markedly increased in VPA plus DOX or MEL as compared with DOX or MEL alone (P<0.05). Both LC3 and H4K16ac expression levels in co-treatment were between VPA and DOX or MEL treated alone. Importantly, VPA of non-toxic dose not only augmented the anti myeloma activity of DOX or MEL, but also down-regulated the autophagy-related protein expression and increases H4K16ac protein levels. CONCLUSION: H4K16ac can inhibit the transcription of autophagy-related genes, The VPA enhance the anti myeloma activity of DNA-damaging drugs, at least in part, via H4K16ac-mediated suppression of cytoprotective autophagy. PMID- 26117025 TI - [Clinical Research about Risk Factors and Reversible Predictors in Renal Impairment due to Multiple Myeloma]. AB - OBJECTIVE: This study was aimed to investigate the risk factors of renal impairment and the predictive factors of renal function recovery so as to provide basis for its prevention and treatment. METHODS: Medical records of 161 patients with MM firstly diagnosed from January 2007 to April 2013 were analyzed retrospectively. Among them 58 cases accompanied with renal insufficiency (group A, others belong to group B) and 39 of them regain normal renal function after some treatment. The possible related renal impairment risk factors and reversible predictors were analyzed with chi-square test for significance firstly, then factors that have significant difference were entered into multivariate logistic regression analysis. RESULTS: Systolic blood pressure (SBP), hemoglobin, uric acid, blood calcium, phosphorus, serum beta2-microglobulin, urine beta2 microglobulin levels, M-component type, light chain type, nephrotoxic drug use, infection in group A had significant difference (P<0.05) compared with those in group B; the systolic blood pressure, diastolic blood pressure, platelet, globulin, blood calcium, and urine beta2-microglobulin levels, the chemotherapy applied and the response to chemotherapy in reversed group were significantly different from no-reversed group (P<0.05). Multivariate logistic regression showed that light chain type, Hb, uric acid, Ca were the independent risk factors for the development of renal failure in MM, and Ca, chemotherapy and the response to chemotherapy were the predictors of renal function recovery. CONCLUSION: High blood calcium, severe anemia, lambda light chain, high uric acid are the independent risk factors of renal impairment in MM patients. Patients with high blood calcium before treatment easily regain normal renal function after effective chemotherapy. Bortezomib-based chemotherapy has higher response rate and higher reversal rate, and it may be related with its unique mechanism. PMID- 26117026 TI - [Relationship of GSTT1 and GSTM1 Gene Polymorphisms and PAH-DNA Adducts with Pathogenesis of Multiple Myeloma]. AB - OBJECTIVE: To explore the relationship of GSTT1, GSTM1 gene polymorphisms and PAH DNA adduct with pathogenesis of multiple myeloma. METHODS: The bone marrow samples from 37 newly-diagnosed MM patients and 52 healthy peoples as controls were collected; the PCR-based restriction fragment length polymorphism (PCR-RFLP) method was used to detecte the polymorphism of GSTT1 and GSTM1, and to analysis their relationship with clinical characters of MM patients; the engyme linked immunosorbent assay (ELISA) was performed to detect the concentration of PAH-DNA adducts. RESULTS: GSTT1 null and GSTM1 null genotypes increased the risk of multiple myeloma with OR 2.57 (P=0.035) and 1.37 (P>0.05) respectively. In MM patients group, GSTT1 null genotype in stage III was significantly higher than that in stages I, II (P=0.038). However, no statistically significant association was found between GSTT1 gene polymorphism and clinical characters, such as age, type, hemoglobin, beta2-MG, albumin. Compared with Hb>=85 g/L of the newly diagnosed MM patients, MM patients with Hb<85 g/L had significantly higher incidence of GSTM1 null genetype (P<0.05). The level of PAH-DNA adducts in MM patients was higher than that in controls (2358+/-1182 pg/ml vs 1853+/-996 pg/ml) (P<0.05). GSTT1 null genotype with PAH-DNA level>=2100 pg/ml showed a risk index of MM (OR=4.500, P<0.05). CONCLUSION: GSTT1 gene may have a critical function in the development of MM, and correlates with staging of MM. GSTM1 gene polymorphism correlates with hemoglobin levels of patients with MM. The content of PAH-DNA adducts may play an important role in the pathogenesis of multiple myeloma. PMID- 26117027 TI - [Correlation of WT1 and VEGF Expression with Angiogenesis in Bone Marrow Biopsies of Multiple Myeloma Patients]. AB - OBJECTIVE: To investigate the relationship of WT1 and VEGF expression with angiogenesis in bone marrow biopsies of multiple myeloma patients. METHODS: VEGF, WT1 expression and microvessel density (MVD) of 62 cases of multiple myeloma and 10 normal bone marrow tissue were detected by in situ hybridization and immunohistochemistry SP method. RESULTS: Microvessel density (MVD) of the control group was (45+/-6)/visual field, and while MVD of the multiple myeloma group was (84+/-26)/sight, and statistical analysis showed that MVD in multiple myeloma group was significantly higher than that in control group (P<0.05); in 62 cases of multiple myeloma the VEGF positive rate was 51.6% (32/62), and MVD in VEGF positive group was significantly higher than that in the negative group (P<0.05). WT1 positive rate was 30.6% (19/62), and MVD in WT1-positive group was significantly higher than that in the negative group (P<0.05). And statistical analysis showed that WT1 expression significantly correlated with VEGF expression (P<0.05). CONCLUSION: WT1 high expression of multiple myeloma bone tissue can up regulate VEGF expression and promote angiogenesis. PMID- 26117028 TI - [Clinical Efficacy of DC and CIK Immunotherapy Combined with Chemotherapy and Its Impact on Treg Cells in Newly Diagnosed Multiple Myeloma]. AB - OBJECTIVE: To investigate the clinical efficacy and immune mechanism of immunotherapy of dendritic cells (DC) and cytokine-induced killer cell (CIK) combined with chemotherapy in patients with newly diagnosed multiple myeloma (MM). METHODS: twenty-two newly diagnosed MM patients were chosen and divided into two groups, out of them,12 patients in single chemotherapy group were treated by chemotherapy only, 10 patients in combined group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy. Using flow cytometry, the CD4 Treg cells in the peripheral blood of 22 MM patients were detected before and after treatment. And the clinical outcomes between two groups were also compared. RESULTS: After treatment the overall response rate(ORR) of patients in the single chemotherapy group was 50% (6/12), among them 2 cases were in complete remission (CR) (16.67%), 2 cases very good partial remission (VGPR) (16.67%), 2 cases were in partial remission (PR) (16.67%). However, the ORR of patients in immunotherapy combined with chemotherapy group was 70.% (7/10), including in 3 cases of CR (30%), 2 cases of VGPR (20%), 2 cases of PR (20%). Compared to healthy volunteers, the proportion of Treg cells in peripheral blood of two groups before treatment was significantly higher (P<0.05). In contrast, the proportion of Treg cells in the peripheral blood of above-mentioned 2 groups after treatment was reduced significantly (P<0.05). In addition, compared to chemotherapy group, the proportion of Treg cells in the combined group decreased significantly (P<0.05). The further analysis found that the proportion of Treg cells in the peripheral blood of the 2 groups was not significant changed (P>0.05) in the patients with ineffictive clinical treatment, but the proportion of Treg cells significantly decreased (P<0.05) in the patients with effective clinical treatment. CONCLUSION: DC-CIK immunotherapy can synergize or enhance the effect of chemotherapeutics, alleviate the immune dysfunction in MM; and DC-CIK immunotherapy combined with chemotherapy can elevate the clinical efficacy in patients with newly diagnosed multiple myeloma. PMID- 26117029 TI - [One Case of Multiple Myeloma with Central Never System Infiltration]. AB - OBJECTIVE: To analyses and summarize a case of multiple myeloma with disseminated infiltration in central nervous system. METHODS: The results of laboratorial examination and clinical data were analyzed and compared in the light of published literatures. RESULTS: The headache and diplopia were caused by infiltration of multiple myeloma cells to the central nervous system. Unlike those reported in the literatures, this case was a rare case of disseminated infiltration inside the brain, and plasma cells were CD56+, this patient has not yet accepted any multiple myeloma-associated treatment as like that reported in the literatures. And different from cases reported, this patient showed a good response to the intrathecal chemotherapy. CONCLUSION: Whether this good response is due to a heterogeneity of MM or effect of treatment-associated drug is still to be decided. PMID- 26117030 TI - [Clinical Implications on ZO-1 Gene Methylation in Myelodysplastic Syndrome Progression]. AB - OBJECTIVE: To investigate the clinical significance of ZO-1 gene methylation level in MDS progression in order to provide a theoretical basis for evaluating progrosis of MDS patients. METHODS: The methylation specific PCR (MS-PCR) was performed to evaluate the ZO-1 gene methylation status in bone marrow samples of normal persons as control (NC). MDS and AML patients, the bisulfite sequencing PCR (BSP) was applied to detect the ZO-1 gene methylation status in serial bone marrow samples of MDS-RA, MDS-RAEB and AML stages of a MDS patients. RESULTS: The possitive rate of ZO-1 gene methylation in samples of NC, MDS and AML patients displayed significant difference; in sample of NC group the positive of ZO-1 gene methylation was not observed, but the positive rate of ZO-1 gene methylation in samples of AML patients was highest (65.0%), the proportion of ZO-1 gene methylation in myeloid blast count of MDS/AML patients was higher (P=0.000). The serial samples in one MDS patient showed that along with progress of disease, the positive rate of ZO-1 gene methylation in MDS-RA, MDS-RAEB and AML stages was found to be obvious different (P=0.000), the positive rate of ZO-1 gene methylation in AML stage was highest (64.65%). CONCLUSION: The high methylation in promoter region of ZO-1 gene has been found in MDS/AML patients, and along with clonal proliferation, the positive rate of ZO-1 methylation and positive froguency of methylation sites increase graduatly which suggests that the MDS progresses in a certain degree, and the ZO-1 gene methylation level may be used as an new indicator for monitoring desease progression from MDS to AML. PMID- 26117031 TI - [Osteogenic Differentiation Potential of Bone Marrow Mesenchymal Stem Cells in Patients with Myelodysplastic Syndromes]. AB - OBJECTIVE: To investigate the osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMMSC) in patients with myelodysplastic syndromes (MDS) and to explore the role of BMMSC osteogenic differentiation in the pathogenesis of MDS. METHODS: BMMSC were isolated from bone marrow of patients with MDS and healthy donors, then expanded in vitro. The expression of transcription factor gene RUNX2, Osterix and osteogenic differentiation markers (ALP, BSP, OPN, OCN) were measured by real-time PCR, the alkaline phosphatase(ALP) activity was assessed at 3, 7, 10 days after osteogenic differentiation. Mineralization analysis was performed at day 21 of osteogenic induction. RESULTS: The expression level of RUNX2 and Osterix were significantly decreased in BMMSC from lower-risk MDS patients compared with normal controls (P<0.05). After osteogenic induction, low-risk MDS showed lower alkaline phosphatase activity at day 3 (P<0.05), less intense alizarin red S staining at day 21 (P<0.05), and lower gene expression of osteogenic differentiation markers (P<0.05), however, these expressions in higher risk MDS were normal. CONCLUTION: BMMSC from low-risk MDS have abnormalities in osteogenic differentiation, it may contribute to the ineffective hamatopoiesis of MDS. PMID- 26117032 TI - [Follicular Helper T Cells and Expression of PD-1 in Mice with Myelodysplastic Syndrome]. AB - OBJECTIVE: To investigate the complete blood count, morphological changes, follicular T helper (Tfh) cells and expression of PD-1 in bone marrow and spleen of mice with myelodysplastic syndrome(MDS) and to explore their significance in pathogenesis of MDS. METHODS: The 10 male NUP98-HOXD13 transgenic mice and 10 male homologous wild-type C57BL/6J mice were used for experments. The complete blood count, morphological change of NUP98-HOXD13 transgenic mice and wild-type C57BL/6J were detected by routine methods. The level of Tfh cells and expression of PD-1 in bone marrow and spleen were measured by flow cytometry. The PD-1 mRNA of bone marrow mononuclear cells and spleen cells were analyzed by real-time PCR method. RESULTS: The counts of RBC, neutrophile and platelet in above- mentioned transgenic mice were less than that in wild type C57BL/6J mice. As compared with wild type C57BL/6J mice, the morphology of RBC and platelet in transgenic mice was some abnormal, including bi-nucleated erythrocytes, ringed mucleated neutrophil and erythroblastic islands. The count of Tfh cells in transgenic mice was less than that in wild type mice, but the expression of PD-1 was higher. The expression of BMMNC PD-1 mRNA was obviously higher than that in wild type mice. CONCLUSION: The pancytopenia and dysplasia, decrease of Tfh cells and increase of PD-1 expression have been observed in NUP98-HOXD13 transgenic mice, which may be one of important reasons for promoting malignant clone and leading to impair anti immune respones. PMID- 26117033 TI - [Myr-RKEFAK Peptide Selectively Regulates Outside-in Signaling Transduction related Functions in Human Platelets]. AB - OBJECTIVE: To study the effect of interaction of the talin rod domain integrin binding site 2 with integrin beta3 on platelet signal transduction. METHODS: A peptide that mimics the membrane proximal alpha helix 6 residues R724 KEFAK729 of the integrin beta3 cytoplasmic tails was designed and synthesized, to which the myristoylation was covalently linked to the N-terminal of the peptide enabling membrane penetration. The effects of myr-RKEFAK peptide on the typical platelet outside-in signaling ovent (stable adhesion and spreading on immobilized fibrinogen, aggregation, fibrin clot retraction) and inside-out signaling events (soluble fibrinogen binding) were tested. RESULTS: myr-RKEFAK peptide dose dependently inhibited platelet stable adhesion and spreading on immobilized fibrinogen, irreversible aggregation, as well as fibrin clot retraction, but not soluble fibrinogen binding and reversible phase of platelet aggregation. CONCLUSION: The cell-penetrating peptide myr-RKEFAK causes an inhibitory effect on integrin beta3 outside-in signaling-regulated platelets functions, but did not affect inside-out signaling-regulated platelets functions. PMID- 26117034 TI - [Effect of the Integrin beta3 Cytoplasmic NITY Motif on alpha II bbeta3-Mediated Cell Functions in CHO Cell Model]. AB - OBJLECTIVE: To investigate the effect of integrin beta3 cytoplasmic NITY motif on alphaIIbbeta3-mediated cell functions. METHODS: Stable Chinese hamster ovary (CHO) cell lines that co-express human wild type integrin alphaIIb and wild type beta3 or mutant beta3DeltaNITY (beta3 deleting cytoplasmic NITY motif) were established. Expression of alphaIIb and beta3 were tested by Western blot and flow cytometry in CHO cell lines. Spreading and adhesion of stable cell lines on immobilized fibrinogen were examined. The co-immunoprecipitation was used to detect protein interactions. RESULTS: CHO-alphaIIbbeta3, CHO alphaIIbbeta3DeltaNITY cells were successfully established. The CHO cells transfected with wild type alphaIIbbeta3 had the ability of adhesion and spreading. Compared with CHO-alphaIIbbeta3 cells, CHO-alphaIIbbeta3DeltaNITY cells showed an impaired capacity of adhesion but no significant difference was observed in spreading of adhered cells. The co-immunoprecipitation showed that kindlin-2 associated with wild type integrin alphaIIbbeta3. The beta3DeltaNITY mutation substantially reduced kindlin-2 association. CONCLUSION: Deletion of NITY motif causes an impaired ability of adhesion. The deletion mutation can suppress kindlin-2 binding to integrin beta3, thereby partially inhibit the integrin beta3 signaling. PMID- 26117035 TI - Clinical Analysis of 70 Adult Patients with Paroxysmal Nocturnal Hemoglobinuria. AB - OBJECTIVE: To investigate the clinical characteristics of Chinese patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: The clinical data of 70 adult PNH cases in our hospital from January 2000 to December 2009 were analyzed retrospectively, and the clinical manifestation, laboratory examination, treatment, complications and prognostic factors influencing survival rate were assessed. RESULTS: The nosopoietic median age of 70 cases(41 male cases and 29 female cases) was 37 (18-73) years old. The clinical manifestation included fatigue (87.1%), hemogolobinuria (44.3%), infection (22.9%), bleeding (37.1%), and abdominal pain (2.9%). FHb (free hemoglobin) in 56 patients (80%) was <50 mg/L. Hp (haptoglobin) in 54 patients (77.1%) was <0.5 g/L, and LDH in 49 patients (70.0%) was <220 U/L. The overall 10 year-survival rate after diagnosis was 72.2% estimated by Kaplan-Meier. The complications in this study were as follow: recurrent abdominal pain crisis (2.9%), infections (30.0%), thrombotic events (8.6%), evolution to MDS/AML (5.7%), calculus (11.4%) and death (17.1%). Both univariate and multivariate analyses identified risk factors affecting survival, including development of thrombotic events, progression to myelodysplastic syndrome or acute myelogenous leukemia (MDS/AML) and recurrent infections. CONCLUSION: This larger number of cases for the first time allowed us to carry out a detailed analysis of prognostic factors for this rare disease. Evaluation of PNH prognostic factors may provide a basis to assess the current and future therapies of this disease. PMID- 26117036 TI - [Effect of Bear Bile Powder and Its Succedaneum on Peripheral Blood and Bone Marrow Megakaryocytes in Mouse Model with Thrombocytopenia Induced by Cytosine Arabinoside]. AB - OBJECTIVE: To investigate the effect of bear bile powder and ursodesxy cholic acid (UDCA) on peripheral blood, bone marrow megakaryocyte and immune organs in mouse model with thrombocytopenia, so as to provide a reference for studying the curative effects of bear bile powder and its succedaneum on thrombocytopenic purpura (TP). METHODS: The mouse model with thrombocytopenia indued by cytosine arabinoside (Ara-C) was established, a total of 70 mice were randomly divided into normal group, model group, prednisone group, bear bile (middle and high dose) powder group and UDCA (middle and high dose) group. From the first day of making model mice in the each group, 0.4 ml/(20 g.d) corresponding drug was administered by infusion. At day 10 after treatment the peripheral blood, spleen and thymus organ index, the number of bone marrow megakaryocyte in each group were compared. RESULTS: compared with the normal group, the Plt, WBC and megakaryocyte counts in model group decreased, the spleen index increased obviously (P<0.05), but the WBC count returned to normal by 10 days; after treatment, compared with model group, the Plt, WBC and megakaryocyte counts of treated groups increased, spleen index decreased significantly (P<0.05), but the WBC count in prednisone group decreased, which in bear bile powder (high) group and UDCA (high) group were particularly significant. CONCLUSION: The bear bile powder and UDCA have been confirmed to have therapeutical effect on thrombocytopenia models induced by Ara-C, UDCA can substitute bear bile powder as a treatment drug for thrombocytopenic purpura. PMID- 26117037 TI - [Analysis of TERT and TIN2 Gene Expression in Patients with Acquired Aplastic Anemia and Their Correlation with Pathogenesis]. AB - OBJECTIVE: To detect the mRNA expression levels of TERT and TIN2 in peripheral blood mononuclear cells of acquired aplastic anemia(AAA) patients, and to explore their correlation with pathogenesis of acquired aplastic anemia. METHODS: Peripheral blood mononuclear cells of 40 cases of AAA including 33 cases of non severe aplastic anemia(NSAA), 7 cases of severe aplastic anemia (SAA) and 20 subjects as control group were collected to detect mRNA expression of TERT and TIN2 by using real-time quantitative polymerase chain reaction(RT-qPCR), the correlation of TERT and TIN2 mRNA expression levels with classification of peripheral blood cells were analyzed. RESULTS: The expression levels of TERT and TIN2 mRNA in patients with AAA were lower significantly than those in control group (P<0.05), and the SAA (P<0.01). The expression levels of TERT and TIN2 mRNA in patients with SAA were all lower significantly than those in patients with NSAA (P<0.05). The expression levels of TIN2 mRNA in patients with NSAA were lower significantly than those in control group (P<0.01). There were no significant difference in the expression level of TERT mRNA between patients with NSAA and control group (P=0.082). There was significant correlation between the expression level of TERT mRNA and red blood cells count (r=0.437, P=0.029), and hemoglobin level (r=0.522, P=0.007). There was significant correlation between the expression levels of TIN2 mRNA and the lymphocyte percentage (r=-0.404, P=0.045). CONCLUSION: The expression level of TERT mRNA may be associated with the red blood cells and hemoglobin level. The expression level of TIN2 mRNA may be associated with the lymphocyte percentage. PMID- 26117038 TI - [Effect of Vascular Cell Adhesion Molecule -1 Overexpression on Adipogenic Differentiation of Murine Mesenchymal Stem Cells and Its Mechanism]. AB - OBJECTIVE: To investigate the effect of vascular cell adhesion molecule-1 (VCAM 1) gene overexpression on adipogenic differentiation of mouse mesenchymal stem cells(MSC) and explore its molecular mechanism. METHODS: VCAM-1 overexpression MSC (MIGR1-VCAM-1/MSC) and the empty plasmid transfection MSC (MIGR1/MSC) were induced to adipogenic differentiation, oil-red-O staining and real-time PCR were used to detect the adipogenic differentiation ability and the mRNA expression level of key transcription factors C/EBP alpha and PPAR gamma. The activation of P38, ERK and JNK pathways were analyzed by Western blot. Furthermore, the specific chemical inhibitors of MAPK pathway (SB203580, PD98059 and JNK inhibitor II) were added to the induced culture system and the alteration of the MSC adipogenic differentiation ability were evaluated. RESULTS: no matter in self or induced differentiation groups, the lipid droplets in MIGR1-VCAM-1/MSC became larger, the amount of adipocyte increased than that in MIGR1/MSC (P<0.01), the mRNA expression level of C/EBPalpha and PPARgamma were upregulated, and JNK pathway were down-regulated while the P38 and ERK pathway were significantly up regulated. The inhibition of JNK pathway of MIGR1-VCAM-1/MSC could lead to increased mRNA expression level of C/EBP alpha and PPAR gamma, the amount of adipocytes increased (P<0.01), however, the inhibition of the P38 and ERK pathway of MIGR1-VCAM-1/MSC could lead to decreased mRNA expression level of C/EBP alpha and PPAR gamma, and the lipid droplets and the number of adipocytes became smaller and less. CONCLUSION: The overexpression of VCAM-1 may promote MSC to differentiate into adipocytes through inhibiting JNK signaling pathway, activating P38 and ERK pathways. PMID- 26117039 TI - [Effect of Knockdown of Vascular Cell Adhesion Molecule-1 on the Immunologic Regulation Capacity of Murine Mesenchymal Stem Cells]. AB - OBJECTIVE: To establish the stably lower expression of vascular cell adhesion molecule-1 (VCAM-1) in MSC cell line (C3H10T1/2) by siRNA technology, and explore the effect of knockdown of VCAM-1 on the immunologic regulation capacity of murine MSC. METHODS: The mouse GV118-VCAM-1-RNAi retrovirus vector was constructed by gene recombination technology. The recombinant plasmid was identified by restriction analysis and sequencing, and then the recombinant plasmid GV118-VCAM-1-RNAi was transfected into 293 cells by Lipofectamine, and the supernatant was collected to transfect C3H10T1/2. Moreover, the VCAM-1 lower expression on MSC was evaluated by flow cytometry and fluorescent microscopy. The knockdown VCAM-1 MSC was sorted by flow cytometry. Furthermore, the inhibitory effect of the knockdown VCAM-1 MSC on lymphocyte proliferation was tested by lymphoblast transformation assay (LTT) and mixed lymphocyte reaction assay(MLR). RESULTS: The recombinant retroviral vector of knockdown VCAM-1 (GV118-VCAM-1 RNAi) was successfully constructed and transfected into mouse MSC cell line C3H10T1/2. The knockdown VCAM-1/MSC was obtained by flow cytometric sorting. The LTT and MLR assay showed that the immunosuppressive effect of MSC lower expressing VCAM-1 dramatically decreased (P<0.05). CONCLUSION: Knockdown VCAM-1 in MSC can significantly down-regulate the inhibitory capability of MSC on the proliferation of T-cells. The data of this study laid an experimental foundation for studying effect of VCAM-1 transfecting into MSC on immune function. PMID- 26117040 TI - Supporting Effect of Umbilical Cord Blood-Derived Mesenchymal Stem Cells on CD34+ Cell Proliferation and Its Mechanism. AB - OBJECTIVE: To investigate the ability of UCB-derived MSCs to support the expansion of HSCs ex vivo and the possible mechanisms involved in this process. METHODS: HSCs from UCB were co-cultured with UCB-derived MSCs for 14 days, and then the total number of HSCs and colony-forming units (CFU) were detected. Cytokines levels of MSCs supernatant were analyzed using ELISA. RESULTS: The proliferation rate of HSCs co-cultured with MSCs was significantly higher than that of cultured HSCs alone (P<0.05). Furthermore, the addition of exogenous cytokines to the culture system significantly increased the proliferation rate of HSCs (P<0.05). MSCs had secretion of many cytokines, including GM-CSF, IL-7, IL 8, IL-11, SCF and SDF-1alpha. CONCLUSION: UCB-derived MSCs as a feeder layer can be an alternative approach for ex vivo expansion of HSCs, and the cytokines by secreted UCB-MSCs may mediate the supportive role of MSC to HSC proliferation. PMID- 26117041 TI - [Putrescine Promotes Human Marrow Mesenchymal Stem Cells to Differentiate along Osteogenic Pathway]. AB - OBJECTIVE: To investigate the effects of putrescine on the growth and differentiation of human bone marrow mesenchymal stem cells (MSC) to develop a new inductive medium mixture for their osteogenic differentiation. METHODS: Human bone marrow MSC were collected from three healthy donors and were used to observe the growth-promoting activity of putrescine with MTT test. Experiments were divided into 3 groups: (1) putrescine group, (2) positive control group (presence of dexamethasone, ascorbate, and glycerol phosphate) and negative group (d-alpha with 5% FCS). The cellular expression level of Runx-2 was detected by PCR assay after the culture was maintained for 1 week. After 2 weeks, the intracellular activity of alkaline phosphatase was revealed by histochemistry staining, the phosphatase activity, and the protein concentration in the cell lysates were also detected. Furthermore, MSC were cultured in the presence of putrescine for 2 weeks and Oil-red O staining was performed to reveal the differentiated adipocytes; the cells induced by the standard agent cocktail were used as the positive control. RESULTS: Putrescine promoted the proliferation of human marrow MSC in a dose-dependent manner. MSC exposed to putrescine at a concentration of 100 umol/L for 1 week expressed greatly higher level of Runx-2, compared with the negative control. Alkaline phosphatase activity was evidently observed after MSC were maintained in the presence of putrescine for 2 weeks. The phosphatase activity contrasted to the protein content in putrescine-treated MSC was significantly higher than that of the control cells (0.87+/-0.012 vs 0.52+/ 0.010) (P<0.01), and also greatly higher than that of the positive control (0.83+/-0.029) (P=0.02). Oil red O staining showed that MSC treated by putrescine did not differentiate into adipoblasts. CONCLUSION: Putrescine can promote the proliferation and osteogenic differentiation of MSC, suggesting the potential application of putrescine as a novel inductive agent for in vitro osteogenesis of MSC. PMID- 26117042 TI - [Amplification Ex Vivo and Cytocidal Activity of Leukemia Tumor-Associated Antigen-Specific Cytotoxic T Lymphocytes]. AB - OBJECTIVE: To explore the feasibility of amplifying the leukemia tumor associated antigens-specific cytotoxic T lymphocytes (TAA-CTL) ex vivo and to evaluate the cytotoxicity of TAA-CTL. METHODS: The peripheral blood mononuclear cells were enriched by density gradient centrifugtion; TAA-CTL were generated by stimulation of PBMNC with peptide-pulsed DC at an effector-to-target ratio of 10:1; immunophenotype of TAA-CTL was analyzed by flow cytometry; cytotoxicity assay was used to evaluate the cytotoxic activity of TAA-CTL against peptide-pulsed autologous target cells (PHA-Blasts). RESULTS: TAA-CTL expanded from volunteer showed a mean expansion of 3.81+/-1.61, the phenotyping of the TAA-CTL was predominantly CD3+ (97.22+/-0.71)% with varying content of CD4+ (41.47+/-27.08)% and CD8+ (56.40+/-11.15)% T cells, it also contained few nature killer cells (0.50+/-0.31)% and rare residual B cells (0.14+/-0.20)%; the subpopulations of TAA-CTL and CTL were not statisticaly significantly different in the proportion (P>0.05); the detection of intracellular cytokines after stimulation with peptide showed that the secretion rates of IFN-gamma and TNF-alpha in CD8+ TAA-CTL were (27.67+/-2.21)% and (34.2+/-0.71)%, while the secretion rates were (21.6+/-2.55)% and (9.97+/-3.44)% in CD4+ TAA-CTL. Compared with the CD8+ TAA-CTL group, the secretion rates of IFN-gamma and TNF-alpha were (1.36+/-0.04)% and (5.58+/-0.03)% in CD8+ CTL, the rates of IFN-gamma and TNF-alpha were (0.91+/-0.06)% and (1.60+/ 0.07)% in CD4+ CTL. The secretions of IFN-gamma and TNF-alpha in CTL were both significantly lower than those in TAA-CTL (P<0.01); the specific killing efficiency of the TAA-CTL against TAA-pulesd target cells were (77.00+/-1.00)%, (67.40+/-3.60)%, (60.55+/-2.45)% and (26.85+/-5.25)%, when the effecto-target ratios were 40:1, 20:1, 10:1 and 5:1, and there was negligible lysis of TAA-CTL for PHA-blast (P<0.01). CONCLUSION: TAA-CTL can be successfully induced and generated ex vivo from the healthy volunteer peripheral blood, and the TAA-CTL possess a specific killing activity. PMID- 26117043 TI - [Effect of SAHA on Maturation of Dendritic Cells and Its Mechanism]. AB - OBJECTIVE: To investigate the effect of SAHA on the maturation of human dendritic cells (DC) and to explore its underlying mechanism. METHODS: Peripheral blood mononuclear cells (PBMNC) were isolated from human peripheral blood and cultured in RPMI 1640 medium with 100 ng/ml rhGM-CSF and 500 U/ml rhIL-4. In the LPS induced maturation process, dendritic cells treated with or without SAHA were used as test group, and dendritic cells treated without LPS or SAHA were used as control group. DC was observed under inverted microscope. Flow cytometer was used to detect the surface antigen molecules expressed by DC. The mixed lymphocyte culture (MLC) was used to observe the allogeneic lymphocyte stimulation. The NF kappaB signaling pathway was detected by electrophoretic mobility shift assay (EMSA). RESULTS: The SAHA could effectively suppress the maturation of DC induced by LPS, the DC treated with SAHA+LPS had immature morphological characteristics; the expression of CD80, CD83 and HLA-DR in SAHA+LPS group and control group were significantly down-regulated as compared with single LPS group (P<0.01); the ability of DC to stimulate the proliferation of allogeneic T lymphocytes in SAHA+LPS group and control group was significantly weaker than that in single LPS group (P<0.01); EMSA results showed that NF-kappaB activity decreased after SAHA and LPS treatment and was significantly lower than that of single LPS group. CONCLUSION: SAHA can effectively suppress DC maturation induced by LPS and also weaken the ability to stimulate allogeneic T lymphocyte. NF-kappaB signaling pathway is involved in regulating DC maturation. PMID- 26117044 TI - [Effect of Norcantharidin on Hematopoietic Function in Leucopenia Model Rat Induced by Cyclophosphamide]. AB - OBJECTIVE: To explore the effect and mechanism of norcantharidin (NCTD) on hematopoiesis function in leucopenia model rat induced by cyclophosphamide (CTX). METHODS: Leucopenia model was replicated in SD rat with cyclophosphamide(CTX) and model animal was treated with NCTD. Peripheral blood and bone marrow tissue samples were collected from the rats in each experimental group. Peripheral white blood cells (WBC) were counted and analyzed by automatic blood cell analyzer. Histopathologic changes of the biopsied bone marrow tissues were observed by histopathological techniques. The cell cycle and apoptosis rate of bone marrow cells were detected by flow cytometry. Immunohistochemical method was applied to observe the expression of apoptosis-related proteins BCL-2 and BAX in bone marrow. RESULTS: After NCTD treatment in model rats, the WBC count of peripheral blood obviously increased, the cell structure of bone tissue significantly recovered, NCTD could promote the cell proliferation and cycle changes of bone marrow cells, inhibit the bone marrow cell apoptosis and necrosis induced with CTX, up-regulate the expression of apoptosis-related protein BCL-2 and downregulated the BAX. CONCLUSION: NCTD can stimulate the bone marrow hematopoiesis and promote recovery of peripheral white blood cell level in the leukopenia model induced by CTX, and its mechanism may be related with NCTD regulating bone marrow cell cycle and with NCTD inhibiting cell apoptosis. PMID- 26117045 TI - [Applications of Microscopic Imaging and Analysis Technology in Studies of Neutrophil Movement and Phagocytosis]. AB - OBJECTIVE: To analyze and evaluate the application of spinning disk confocal microscopy and imaging analysis software in movement and phagocytosis of neutrophils. METHODS: Neutrophils were isolated from bone marrow by centrifugation on discontinuous Percoll gradient, and then were stained with PE Gr-1 antibody and mixed with FITC-labeled Zymosan A bioparticles. Multichannel time-lapse videos were captured by using the spinning disk confocal microscopy. The result was analyzed by using volocity and ImageJ software, the parameters associated with movement and phagocytosis of neutrophils were analyzed, including morphological changes, cell tracking, pseudopod dynamics, binding and phagocytosis index. RESULTS: Most neutrophils would be polarized in response to Zymosan particles during a short time. Binding and phagocytosis process occured in forty minutes. CONCLUSION: A method of precisely quantifying the movement and phagocytosis of neutrophils using microscopic imaging and imaging analysis technique has been set up successfully. Using this method, biological activity and function of neutrophils can be evaluated visually and rapidly. The physiologically rapid response to Zymosan particles can be applied to the neutrophils function research in the future. PMID- 26117046 TI - [Interactions between Hemoglobin and Other Proteins were Proved by the Electrophoresis Release Test and Co-immunoprecipitation]. AB - OBJECTIVE: To study the interactions between hemoglobin (Hb) and other proteins within human erythrocytes by using the electrophoresis release test (ERT) and co immunoprecipitation. METHODS: First, the fresh normal adult anti-coagulated whole blood was washed to prepare packed RBCs, which were further prepared to erythrocyte suspension and hemolysate.The erythrocyte suspension and hemolysate were analyzed by the electrophoresis release test (ERT) at the same time, and then the band of HbA of erythrocyte sample (RA) and the corresponding band of hemolysate sample (HA) were cut out from the gel and were enriched by freeze-thaw method. Then, the samples were bound with hemoglobin beta antibody (37-8) AC, the complexes were separated through 5%-12% SDS-PAGE followed by Q-TOF. RESULTS: Five bands were found in the gel, each of which was treated by hemoglobin beta antibody (37-8) AC, the protein bands of 16,20,22,28 and 50 kD were emerged in RA, HA and RBC lysis.The bands were identified by MS, and the results showed that these bands were hemoglobin, band 3, peroxiredoxin2 (Prx2), band 3 and beta actin, band 3 respectively. CONCLUSION: HbA may interact with Prx2, Band 3 and beta-actin, and then the complexes are formed with each other within erythrocytes. PMID- 26117047 TI - [alpha-GalCer reduces Acute Graft-versus-Host Disease by Altering Donor T Cells Migration]. AB - OBJECTIVE: This study was aimed to explore the new mechanism of alpha Galactosyleramide (alpha-GalCer), a synthetic glycolipid, and a well-known activator of natural killer T cells (NKT) for improving acute graft-versus-host disease(aGVHD). METHODS: Murine allogeneic bone marrow transplantation (allo-BMT) model was established. Recipient mice were injected intraperitoneally with alpha GalCer immediately after allo-BMT, whereas mice from the vehicle groups received the diluent (DMSO) only. The severity degree of aGVHD was estimated by survival, aGVHD clinical score and pathology. The mechanism of aGVHD reduced by alpha GalCer was explored by detecting T cells migration in vivo and in vitro. RESULTS: Mice in alpha-GalCer group survived longer than in control group, and their clinical and pathological status of aGVHD were lighter. alpha-GalCer reduced aGVHD by altering donors T cell migration. CONCLUSION: After allo-BMT alpha GalCer reduces aGVHD by altering donor T cells migration. PMID- 26117048 TI - [Expression Changes of Matrix Reconstitution-related Genes in Bone Marrow during 5-Fluorouracil-Induced Hemopoietic Injury and Their Significance]. AB - OBJECTIVE: To explore the expression change of the genes related with matrix reconstitution during the injury and reconstitution of murine bone marrow following treatment with 5-fluorouracil (5-FU). METHODS: C57BL/6 mice received intraperitoneal injection of 5-FU (200 mg/kg), and peripheral blood cell counts were monitored at 3, 6, 9, 15, 21, 27 days after treatment. Bone marrow cells were harvested at these times for total RNA extraction using TRIzol. Reverse transcriptions in combination with real-time PCR were performed for detecting expression of genes related with matrix reconstitution, including ECM-1, MMP-2, MMP-3, MMP-13 and TIMP-1. RESULTS: After injection of 5-FU, the numbers of three line cells in peripheral blood (i.e. RBC, WBC and platelets) decreased and then recovered with differential dynamics. Similarly, RT-qPCR revealed that all the 5 detected gene expressions were significantly up-regulated during the injury. The mRNA expression of MMP-2 reached to peak at day 3 while the other genes reached to peak at day 6. MMP-3 has a low expression when compared with others, but its expression increased significantly after injury. CONCLUSION: In 5-FU induced hematopoietic injury and reconstitution model, matrix reconstitution-related genes may play an important role in hematopoietic reconstitution, but different genes play different roles at various time, and cooperate with each other for hematopoietic reconstitution. PMID- 26117049 TI - [Diagnostic Value of Neutrophil CD64 for Bacterial Infection in Patients with Hematologic Malignancies after Chemotherapy]. AB - OBJECTIVE: To investigate the value of CD64 mean fluorescence intensity of the peripheral blood neutrophils as a diagnostic marker of bacterial infection in patients with hematologic malignancies after chemotherapy. METHODS: The neutrophil CD64 mean fluorescence intensity of all patients was detected by flow cytometry, and compared with procalcitonin (PCT) and C reactive protein (CRP) detected in part of patients; the relationship between nCD64 and bacterial infection were analyzed through continuous dynamic monitoring nCD64 mean fluorescence intensity in part of patients. RESULTS: The expression of nCD64 was not affected by neutrophils counts (P>0.01); the nCD64 mean fluorescence intensity, PCT and CRP levels in infection group and dynamic monitoring group were significantly higher than those in non-infected group (P<0.01); the sensitivity and specificity of nCD64 mean fluorescence intensity were much higher, as compared with PCT and CRP in diagnosis of bacterial infection. CONCLUSION: nCD64 mean fluorescence intensity can be used as an effective diagnostic marker for bacterial infection in patients with hematologic malignancies after chemotherapy, and may be used to forecast bacterial infection to a certain extent. PMID- 26117050 TI - [Analysis of the Physiological Activities and Functions in Vitro of Apheresis Platelets during Storage]. AB - OBJECTIVE: To investigate the changes of physiological activities and functions in vitro of apheresis platelets during storage. METHOD: 17 units of apheresis platelets were randomly chosen and stored at 20 degrees C to 24 degrees C with agitation. Platelet counting (Plt), mean platelet volume (MPV), blood gases, pH value, glucose (Glu) concentration, lactate (LA) concentration, LDH concentration, thromboelastogram (TEG), hypotonic shock response (HSR), CD62p expression rate and anew expression rate were measured on days 0, 1, 3, 5 after platelet storage. Changes of physiological activities and functions in vitro were systematically evaluated by above-mentioned indexes. RESULTS: During storage, Plt, MPV and HSR were not significantly changed; but pH value, blood gases, Glu, LA, LDH, HSR, expression rate of CD62p and anew expression rate were significant differenty. Among thromboelastogram indexes, R value increased obviously with prolongation of storage time; K value and alphaAngle were not significantly changed; MA was not significantly changed on day 1 and 3, but was slightly increase on day 5. CONCLUSION: The physiological activities and functions in vitro of apheresis platelets are kept well during storage. For clinical transfusion of apheresis platelet during storage, clinical effect of transfusione is not influenced. PMID- 26117051 TI - [Analysis of Patients' Irregular Antibody Screening and Identification Results before Blood Transfusion]. AB - OBJECTIVE: To analyze the results of irregular antibody screening and identification among patients before blood transfusion, and to investigate the specific distribution of irregular antibodies and the distribution regularity in different diseases. METHODS: Choosing the patients intended to be transfused in our hospital from January 1, 2009 to December 31, 2013 years, micro-column gel technique was used to screen the irregular antibodies of those receptors and to identify the antibody specificity of the positive specimens. RESULTS: Among 44194 patients, 137 patients were with irregular antibody positive and their positive rate was 0.31%, among them 33 cases were male and accounted for 0.18% in the studied males; the 104 cases were females and accounted for 0.40% in all the studied females. The difference of sex distribution was statistically significant (X2=15.38, P<0.05). In the irregular antibody screening positive patients, patients with transfusion or pregnancy history were 129 cases, and the patients without transfusion or pregnancy history were 8 cases. In the irregular antibody screening positive patients, the main antibody of 54 cases belongs to Rh blood type system, accounting for 39.42%; The main antibody of 37 cases belongs to MNS blood type system, accounting for 27.01%; while the 30 cases belong to Lewis blood type system, accounting for 21.90%. According to the classification of diseases, the irregular antibody screening-positive patients with tumors were ranked in the highest rate at 5.960/00, the secondary hemorrhage of digestive tract and chronic renal failure were ranked at the rate of 3.280/00 and 3.190/00. The difference of positive rates between diseases was statistically significant (chi2=19.33, P<0.05). CONCLUSION: Irregular antibody screening before blood transfusion is necessary, which can discover the irregular antibodies of clinical significance, especially for patients with tumors and the other patients with the history of frequent blood transfusions or multiple pregnancies. Antibody screening is a useful warning signal, as it ensures the safety of blood transfusions. PMID- 26117052 TI - [Origin of Hematopoietic Stem Cells in Bone Marrow--Endothelial to Hematopoietic Transition (EHT)?]. AB - In contrast to primitive hematopoiesis, during embryonic definitive hematopoiesis, it has been demonstrated that multilineage hematopoietic stem/progenitor cells (HSPCs) arise from hemogenic endothelium, and the endothelial to hematopoietic transition (EHT) exists within the yolk sac, placenta, AGM, mouse head vascular and extraembryonic vessels. However, whether hemogenic endothelial cells contribute to blood cell development at other sites of definitive hematopoiesis, including fetal liver and bone marrow, remains largely unknown. Recently, more and more researches showed that hematopoiesis within bone marrow had a close relationship with vascular endothelium development, too. This review summarizes the mechanism of EHT during embryo development, and discuss whether EHT exists in adult hematopoiesis. PMID- 26117053 TI - [G-CSF and Its Receptor in Hematonosis]. AB - The granulocyte colony-stimulating factor (G-CSF), now referred to as CSF3, is a very important cell growth factor that supports the proliferation, survival, and differentiation of neutrophilic progenitor cells, and also is a strong immune regulator of T cells and a promising therapeutic tool in acute graft versus host disease (GVHD). G-CSF acts by binding to its receptor G-CSFR (also called CSF3R), a member of the cytokine receptor type I superfamily, which after binding with G CSF activates the canonical Janus kinase (Jak)/signal transducer, activator of transcription (STAT)and Ras/Raf/MAP kinase pathways. G-CSF has been applied to the clinic to treat congenital and acquired neutropenia before or during courses of intensive chemotherapy. It has also been applied to mobilize hematopoietic stem cells into the peripheral blood for Auto-or allogeneic transplantation, and the priming strategies designed to enhance the sensitivity of leukemia stem cells to cytotoxic agents in protocols aimed to induce their differentiation, accompanying growth arrest, and cell death. With the rapid development of molecular genetics and clinical research, CSF3R mutations have been implicated in the progression of severe congenital neutropenia (SCN) to leukemia. Recently, CSF3R mutations have been discovered frequently in chronic neutrophilic leukemia (CNL). Such findings might provide the theoretical basis for the targeted therapy. In this review, the clinical application of G-CSF receptor in hematonosis is briefhy summarized. PMID- 26117054 TI - [Progress of Study on Cytokines in Myeloproliferative Neoplasms]. AB - The clonal blood disorder, such as polycythemia vera, essential thrombocythemia and primary myelofibrosis belong to the BCR-ABL1-negative myeloproliferative neoplasms(MPN) and are specified by increased production of terminally differentiated myeloid cells. Abnormal expression and activities of a number of proinflammatory cytokines are associated with MPN, in which immune dysregulation is pronounced as evidenced by the dysregulation of several immune and inflammation genes. It is becoming increasingly clear that the dysregulation of cytokine levels contributes to the pathophysiology of MPN and they are prognostic indicators. In this review, the role of cytokines in the pathogenesis of MPN, the clinical relevance of cytokines with MPN, current therapies and the combination with the new treatments targeting cytokines are summarized. PMID- 26117055 TI - [Chemokine Receptor-5 and Graft-versus-Host Disease]. AB - Chemokine receptor-5 (CCR5) belongs to a G-protein coupled receptors superfamily. It is mainly expressed on a wide variety of immune cells. CCR5 can bind with its specific ligands, which plays very important roles in inflammatory cell growth, differentiation, activation, adhesion and migration. CCR5 was identified as a co receptor for human immunodeficiency virus type-1 (HIV-1) to infect CD4+ T cells. In addition, CCR5 not only participates in the pathogenic mechanisms of many inflammation disease such as AIDS, auto-immune disease, and atherosclerosis, but also plays important roles in the development of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Recent studies using murine models have demonstrated the critical role of CCR5 and its ligands which direct T-cell infiltration and recruitment into target tissues during acute GVHD. CCR5 has become the focus of intense interest and discussion, and this review will attempt to describe what is understood about the structure and function, internalization, signal transduction of CCR5, in order to investigate the relationship between CCR5 and acute GVHD. PMID- 26117056 TI - [Expression and Clinical Significance of Lymphoid Enhancer-Binding Factor 1 in Acute Leukemias]. AB - Lymphoid enhancer-binding factor 1 (LEF1), a key downstream effector of Wnt/beta catenin signal transduction pathway, plays a crucial role in the maintenance, proliferation and differentiation of normal hematopoietic stem/progenitor cells through regulating the transcription of its target genes. Aberrant LEF1 expression has been documented in a variety of leukemias, and implicated in the prediction of prognosis. Nevertheless, discrepancies exist regarding the expression level and clinical implication of LEF1 in different types of leukemias, suggesting LEF1 might exert distinct roles in different types of leukemia. In the present article, recent research advances of the relationship of LEF1 and regulation of hematopoiesis and leukemogenesis are reviewed. PMID- 26117057 TI - [Association of CRBN Gene with Immunomodulatory Drug Resis- tance in Multiple Myeloma]. AB - Human CRBN (cereblon) gene is located on chromosome 3 at 3p26 and its encoding protein is a member of E3 ubiquitin ligase complex (composed of CRBN, DDB1, CUL4A and ROC1). The E3 ubiquitin ligase complex functions in the ubiquitin-proteasome protein degradation pathway and attaches polyubiquitin chains to substrate proteins for degradation via the protease complex. Currently, there are no standardized assays for CRBN gene and protein measurement although quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry and Western blot are widely used. CRBN has been identified as a direct target for immunomodulatory drugs (IMiD) and plays a significant role in anti-proliferation, pro-apoptotic effects, anti-angiogenic activities, immunomodulatory activities and intervention of cell surface adhesion molecules between myeloma cells and bone marrow stromal cells. Recently, clinical data show that majority of the multiple myeloma patients treated with IMiD develop drug-resistance over time by unknown mechanisms. Fortunately, various in vivo and in vitro studies have revealed that the decreased CRBN expression or CRBN deletion is associated with resistance to IMiD in treating multiple myeloma, and CRBN expression levels may have a prognostic significance. Furthermore, the most recently discovered protein IKZF1, IKZF3, IRF4, C/EBPbeta and Wnt/catenin signaling pathways may also be closely related to IMiD resistance in myeloma. PMID- 26117058 TI - [Recent Research Advances on Pediatric Myelodysplastic Syndrome]. AB - Myelodysplastic syndrome (MDS) is a group of highly heterogeneous, acquired hematopoietic stem/clonal disease, which is characterized by bone marrow dysplasia and high-risk conversion to acute leukemia, and is manifested by single or multi-lineage of cytopenia.The pathogenesis of MDS is complex, and has not yet been fully elucidated. Studies have shown that there are many differences between children and adults MDS.In this article the advances of studies on pediatric myelodysplastic syndrome are summaried. PMID- 26117059 TI - [Application of Self-assembling Peptides to Hemostasis]. AB - As a widespread phenomenon in living system, molecular self-assembly has become the meeting point of multidisciplinary research including chemistry, biology, materials science and medicine. In recent years, the rapid development in molecular self-assembly of peptide technology is showing a great potential in the application of tissue engineering, drug delivery, bionic medicine, cosmetology field, optical and electronic product development, etc. Especially, the remarkable hemostatic effect of self-assembling peptides (SAP) on organs, nerves and brain wounds successfully promoted its application to the material science and clinical medicine. This review focuses on the hemostatic effects and characteristics of SAP on different bleeding wound models, action mechanism, its benefits and limitations as well as its adrancing trends. PMID- 26117060 TI - [Light Chain Amyloidosis: an Update for Treatment]. AB - Systemic light chain amyloidosis (AL amyloidosis) is the most common type of amyloidosis, in which deposition of misfolded monoclonal light chain secreted by underlying clonal plasma cells leads to organ dysfunction. Tissue biopsy of involved organ is needed to confirm the type of amyloid deposits, thus proper treatment could be applied. Laser microdissection followed by mass spectrometry, performed on formalin-fixed paraffin-embedded specimens, has been proven superior to traditional methods on accurate diagnosis of amyloidosis. Prognosis depends on the extent of cardiac involvement. The Mayo staging system using NT-ProBNP, cardiac troponin-T and free light chain, is the most robust method for risk stratification and treatment guidance. The introduction of autologous stem cell transplantation (auto-ASCT) resulted in long-term survival in responders, while treatment-related toxicity substantially limited the number of eligible candidates. Novel agents, especially bortezomib, thalidomide and lenalidomide hold promise to achieve comparable hematological responses with auto-ASCT, which might play significant role in treatment of recurrent or refractory AL amyloidosis. PMID- 26117061 TI - The relationship between dissociation and voices: A systematic literature review and meta-analysis. AB - There are an increasing number of studies exploring the association between voice hearing (auditory verbal hallucinations) and dissociative experiences. The current study provides a systematic literature review and meta-analytic synthesis of quantitative studies investigating the relationship between voice-hearing and dissociation. A systematic search identified and included 19 clinical studies, comprising 1620 participants, and 12 non-clinical studies, comprising 2137 participants, published between 1986 and 2014. Nineteen of these studies provided sufficient data to be included within the meta-analysis. The narrative review findings suggested that dissociative experiences may be implicated in voice hearing, and may potentially be a mediating factor within the well-established trauma and voice-hearing relationship. Similarly, the meta-analytic findings suggested that the majority of the identified studies showed a significant positive relationship between dissociative experiences and voice-hearing. The magnitude of the summary effect was large and significant (r=.52), indicating a robust relationship between these two phenomena. However, considerable heterogeneity within the meta-analytic results and methodological limitations of the identified studies were evident, highlighting areas for future investigation. As the majority of the studies were cross-sectional by design, we recommended future research to include longitudinal designs with a view to exploring directional effects. Additionally, future studies should control for potential confounding factors. Clinical implications of the findings were also considered. PMID- 26117062 TI - Cognitive behavioral treatments of obsessive-compulsive disorder. A systematic review and meta-analysis of studies published 1993-2014. AB - Obsessive-compulsive disorder is ranked by the WHO as among the 10 most debilitating disorders and tends to be chronic without adequate treatment. The only psychological treatment that has been found effective is cognitive behavior therapy (CBT). This meta-analysis includes all RCTs (N=37) of CBT for OCD using the interview-based Yale-Brown Obsessive Compulsive Scale, published 1993 to 2014. The effect sizes for comparisons of CBT with waiting-list (1.31), and placebo conditions (1.33) were very large, whereas those for comparisons between individual and group treatment (0.17), and exposure and response prevention vs. cognitive therapy (0.07) were small and non-significant. CBT was significantly better than antidepressant medication (0.55), but the combination of CBT and medication was not significantly better than CBT plus placebo (0.25). The RCTs have a number of methodological problems and recommendations for improving the methodological rigor are discussed as well as clinical implications of the findings. PMID- 26117064 TI - Responses of growth inhibition and antioxidant gene expression in earthworms (Eisenia fetida) exposed to tetrabromobisphenol A, hexabromocyclododecane and decabromodiphenyl ether. AB - Tetrabromobisphenol A (TBBPA), hexabromocyclododecane (HBCD) and decabromodiphenyl ether (BDE 209), suspected ubiquitous contaminants, account for the largest volume of brominated flame retardants (BFRs) since penta-BDE and octa BDE have been phased out globally. In this paper, the growth inhibition and gene transcript levels of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT)) and the stress-response gene involved in the prevention of oxidative stress (Hsp70) of earthworms (Eisenia fetida) exposed to TBBPA, HBCD and BDE 209 were measured to identify the toxicity effects of selected BFRs on earthworms. The growth of earthworms treated by TBBPA at 200 and 400 mg/kg dw were inhibited at rate of 13.7% and 22.0% respectively, while there was no significant growth inhibition by HBCD and BDE 209. A significant (P<0.01) up-regulation of SOD expression level was observed in earthworms exposed to TBBPA at 50 mg/kg dw (1.77 fold) and to HBCD at 400 mg/kg dw (2.06-fold). The transcript level of Hsp70 gene was significantly up-regulated (P<0.01) when earthworms exposed to TBBPA at concentration of 50-200 mg/kg (2.16-2.19-fold) and HBCD at 400 mg/kg (2.61-fold). No significant variation of CAT gene expression in all the BFRs treatments was observed, neither does all the target gene expression level exposed to BDE 209. Assessed by growth inhibition and the changes at mRNA levels of encoding genes in earthworms, TBBPA showed the greatest toxicity, followed by HBCD and BDE 209, consistent with trends in molecular properties. The results help to understand the molecular mechanism of antioxidant defense. PMID- 26117065 TI - Bisphenol A alters the cardiovascular response to hypoxia in Danio rerio embryos. AB - The purpose of this study was to determine if the cardiovascular response to hypoxia was altered by the presence of bisphenol A (BPA) in Danio rerio embryos. It was expected that BPA exposure would affect cardiovascular parameters during hypoxia more than normoxia due to an interaction between BPA and the hypoxia inducible factor (HIF-1alpha) pathway. We demonstrate that BPA exposure has a minimal effect during normoxia but can severely affect the cardiovascular system during a hypoxic event. Cardiovascular response was measured in vivo using video microscopy and digital motion analysis. RBC density increased 35% in hypoxia alone but decreased 48% with addition of 0.25mg/L BPA. Tissue vascularization (% coverage) was unaffected by hypoxia alone but decreased 37% with addition of 0.25mg/L BPA. The diameter and RBC velocity of arteries were more sensitive than veins to BPA exposure during both normoxia and hypoxia. Arterial RBC velocity decreased 42% during normoxia and 52% during hypoxia with 1mg/L BPA. This decrease in velocity may in part be due to the 86% decrease in heart rate (fH) observed during co-exposure to hypoxia and 5mg/L BPA. While stroke volume (SV) was unaffected by treatment, cardiac output (Q) decreased by 69% with co exposure. fH and Q were not affected by BPA exposure during normoxia. Development ultimately slowed by 146% and mortality rates were 95% during hypoxia when exposed to 5mg/L BPA. Our results show for the first time that BPA exposure alters the cardiovascular system during hypoxia more so than normoxia. PMID- 26117063 TI - Using Xenopus to discover new genes involved in branchiootorenal spectrum disorders. AB - Congenital hearing loss is an important clinical problem because, without early intervention, affected children do not properly acquire language and consequently have difficulties developing social skills. Although most newborns in the US are screened for hearing deficits, even earlier diagnosis can be made with prenatal genetic screening. Genetic screening that identifies the relevant mutated gene can also warn about potential congenital defects in organs not related to hearing. We will discuss efforts to identify new candidate genes that underlie the Branchiootorenal spectrum disorders in which affected children have hearing deficits and are also at risk for kidney defects. Mutations in two genes, SIX1 and EYA1, have been identified in about half of the patients tested. To uncover new candidate genes, we have used the aquatic animal model, Xenopus laevis, to identify genes that are part of the developmental genetic pathway of Six1 during otic and kidney development. We have already identified a large number of potential Six1 transcriptional targets and candidate co-factor proteins that are expressed at the right time and in the correct tissues to interact with Six1 during development. We discuss the advantages of using this system for gene discovery in a human congenital hearing loss syndrome. PMID- 26117066 TI - Methionine sulfoxide reductase A (MsrA) associated with bipolar I disorder and executive functions in A Han Chinese population. AB - BACKGROUND: The oxidative stress hypothesis proposed to explain bipolar I disorder (BD I) pathogenesis has gained growing attention based on its association with cognitive impairment. The aim of the present study was to explore the association of the methionine sulfoxide reductase A (MsrA) gene with BD I as well as executive functions of BD I patients. METHODS: A total of 44 tagging single-nucleotide polymorphisms within the MsrA gene were selected to analyze gene association with BD I in 375 BD I patients and 475 controls in a Han Chinese population. The association of MsrA haplotypes with executive functions was analyzed in 157 clinically stable BD I patients and 210 controls. RESULTS: Allele frequencies of the rs4840463 polymorphism were significantly different between BD I patients and controls, and between patients with psychotic symptoms and controls. BD I patients performed more poorly in 11 of the 13 neurocognitive measurements compared with controls. Three MsrA haplotypes showed significant associations with different executive functions. LIMITATIONS: The limited sample size requires a cautious conclusion, and further comprehensive approaches are needed to explore the mechanism of MsrA's effect on BD I. CONCLUSIONS: The rs4840463 polymorphism in the MsrA gene may be associated with the increased risk of BD I in a Chinese population. The association of MsrA haplotypes with executive functions indicated that MsrA is associated with executive function defects in BD I patients. PMID- 26117067 TI - BDNF Val66Met polymorphism in patterns of neural activation in individuals with MDD and healthy controls. AB - BACKGROUND: Rs6265 single nucleotide polymorphism, which influences brain-derived neurotrophic factor (BDNF) levels in the cortical and subcortical brain structures, may result in distinguished patterns of neural activation during a major depressive disorder (MDD) episode. Valine homozygotes with high levels of BDNF and methionine carriers with lower levels of BDNF may present specific neural correlates of MDD. In our study we have tested differences in blood oxygen level dependant (BOLD) signal between individuals with MDD and healthy controls for both allelic variants. METHODS: Individuals with MDD (N = 37) and healthy controls (N = 39) were genotyped for rs6265 and compared separately in each allelic variant for BOLD response in a functional magnetic resonance imaging experiment examining appraisal of emotional scenes. The two allelic variants were also compared separately for both individuals with MDD and healthy controls. RESULTS: In the homozygous valine group MDD was associated with decreased neural activation in areas responsible for cognitive appraisal of emotional scenes. In the methionine group MDD was related to increased activation in subcortical regions responsible for visceral reaction to emotional stimuli. During an MDD episode methionine carriers showed more activation in areas associated with cognitive appraisal of emotional information in comparison to valine homozygotes. LIMITATIONS: Small sample size of healthy controls carrying methionine (N=8). CONCLUSION: Our results suggest that allelic variations in the rs6265 gene lead to specific neural correlates of MDD which may be associated with different mechanisms of MDD in the two allelic groups. This may have potential importance for screening and treatment of patients. PMID- 26117068 TI - Sit-To-Stand Biomechanics Before and After Total Hip Arthroplasty. AB - The purpose of this study was to evaluate changes in movement patterns during a sit-to-stand (STS) task before and after total hip arthroplasty (THA), and to compare biomechanical outcomes after THA to a control group. Forty-five subjects who underwent THA and twenty-three healthy control subjects participated in three dimensional motion analysis. Pre-operatively, subjects exhibited inter-limb movement asymmetries with lower vertical ground reaction force (VGRF) and smaller moments on the operated limb. Although there were significant improvements in movement symmetry 3 months after THA, patients continued to demonstrate lower VGRF and smaller moments on the operated limb compared to non-operated and to control limbs. Future studies should identify the contributions of physical impairments and the influence of surgical approach on STS biomechanics. PMID- 26117069 TI - Measuring the Femoral Head Size--An Additional Real-Time Intraoperative Monitoring Tool for the Accuracy of the Preoperative Process and Implant Selection. AB - The purpose of this study was to examine the correlation between the implanted cup's outer diameter and the actual femoral head diameter removed during surgery. Seventy-five patients with primary total hip arthroplasty were evaluated. The difference between the implanted cup diameter and the femoral head diameter was calculated for each patient. The mean+/-SD actual femoral head diameter that was removed and measured during surgery was 48.5+/-3.7 mm. The mean+/-SD cementless implanted cup outer diameter was 51.8+/-3.5 mm. A high correlation was found between the implanted cup diameter and the actual femoral head diameter (r=0.923). A cut-off point of 4mm of the measured femoral head diameter should be considered as an additional monitoring indicator. PMID- 26117070 TI - Complications of Morbid Obesity in Total Joint Arthroplasty: Risk Stratification Based on BMI. AB - This study stratifies complication risk in primary total joint arthroplasty (TJA) based on body mass index (BMI). Demographics, co-morbidities, perioperative variables, and complications were reviewed for 22,808 patients. Chi-squared, one way ANOVA, univariate and multivariable regression analysis were performed. Increasing BMI led to an increase (P<0.05) in combined complications, acute kidney injury (AKI), cardiac arrest (CA), reintubation, reoperation, and superficial infection (SI). Univariate analysis for BMI>40 revealed an increase in combined complications (15.21-vs-17.40%), AKI (1.93-vs-3.87%), CA (0.22-vs 0.57%), reintubation (0.47-vs-0.95%), reoperation (2.36-vs-3.37%), and SI (0.82 vs-1.65%). Multivariable regression showed BMI>40 as an independent predictor for combined complications (OR=1.18), AKI (OR=1.79), CA (OR=3.94), reintubation (OR=2.56), reoperation (OR=1.44), and SI (OR=2.11). Morbid obesity confers increased risk for complications in TJA. PMID- 26117071 TI - The Impact of Wear and Lift-Off on Coronal Plane Alignment in TKA and Implications to Future Constrained Revision: A Retrieval Study. AB - Current discussion exists whether to position a total knee arthroplasty (TKA) in slight undercorrection in varus osteoarthritis. The goal of this study was to analyse the effect of wear and lateral lift-off in primary TKA on coronal plane alignment and the implication to future constrained revision TKA. Seventy-six retrieved tibial inserts were analysed for the ratio of wear (RW), lateral lift off and implications for future constrained revision surgery according to the coronal plane alignment. The RW significantly affects the coronal plane alignment in TKA. Progressive wear and lateral lift-off were seen with progressive varus alignment. However, there was no difference in constrained revision between mild varus and moderate varus aligned TKAs. PMID- 26117072 TI - Does Extended-Release Liposomal Bupivacaine Better Control Pain Than Bupivacaine After Total Knee Arthroplasty (TKA)? A Prospective, Randomized Clinical Trial. AB - Liposomal bupivacaine periarticular injection (PAI) offers sustained bupivacaine release after TKA, but few prospective independent studies exist. In this prospective, blinded study, liposomal bupivacaine was randomized against bupivacaine and incorporated into a comprehensive multimodal pain management protocol. 111 primary TKAs were randomized to receive PAI: 58 patients received 266 mg (20cc) liposomal bupivacaine mixed with 75 mg (30cc) 0.25% bupivacaine, and 53 patients received 150 mg (60cc) 0.25% bupivacaine. Visual analog pain scores and narcotic use were determined. No pain score differences occurred between study and control patients: Day 1: 4.5/4.6 (P=0.73); Day 2: 4.4/4.8 (P=0.27); or Day 3: 3.5/3.7 (P=0.58). Narcotic use was similar during hospitalization, 51.8/54.2 (P=0.34). The study medication costs $285, and the control medication costs $2.80. This finding does not justify the routine use of liposomal bupivacaine. PMID- 26117073 TI - The Anatomische Gesellschaft and National Socialism: an analysis based on newly available archival material. AB - The newly available scientific estate of Heinrich von Eggeling (1869-1954), long time secretary of the Anatomische Gesellschaft (AG), allows a more profound analysis of how this scientific association went through the period of the "Third Reich". At the first meeting under the new rulers in 1934, von Eggeling and Siegfried Mollier prevented their board colleague Martin Heidenhain from giving an introductory talk because they (not unjustly) feared anti-Jewish protests, but also because many anatomy professors, like other German scholars, were fervent nationalists who welcomed Hitler and largely accepted the expulsion of Jewish and other colleagues as 'inevitable' for national renewal. Many persecuted members nevertheless remained on the membership lists and the AG never officially introduced anti-Jewish bylaws. Eggeling and his like-minded colleagues successfully defended the international status of the AG, though not so much against the Nazi authorities but against a younger generation of anatomists who were willing to benefit from the new political situation and strived for their own German anatomical association. The available archival material suggests that the motivation of the established leading members of the AG to take this specific path was not rooted in opposition to the new rulers but rather in defence of their traditional status of reputed professors running a time-honoured, world leading society. This made international reputation an important guideline for many decisions. While they did ward off attempts by the younger generation to politicise the AG, their post-war calls for an apolitical science remain ambivalent, as their own stance had not always been apolitical. PMID- 26117074 TI - The influence of cycle time on shoulder fatigue responses for a fixed total overhead workload. AB - The relationship between overhead work and musculoskeletal health depends on multiple task and individual factors. Knowledge gaps persist, despite examination of many of these factors individually and in combination. This investigation targeted task variation, as parameterized by cycle time within a fixed overall workload. Participants performed an intermittent overhead pressing task with four different cycle time conditions while overall workload and duty cycle was held constant. Several manifestations of fatigue were monitored during task performance. Endurance time was influenced by cycle time with shorter cycle times having endurance times up to 25% higher than longer cycle times. Surface electromyography (sEMG) results were mixed, with two muscles demonstrating amplitude increases (middle deltoid and upper trapezius) that varied with cycle time. sEMG frequency was not influenced by cycle time for any muscle monitored, despite decreases for several cycle times. Trends existed for the influence of cycle time on time-varying reported discomfort (p=0.056) and static strength (p=0.055); large effect sizes were present (etap(2)=0.31 and 0.27, respectively). The equivocal association of fatigue indicators and cycle time is analogous to the influence of other factors implicated in overhead work musculoskeletal risk, and probabilistic modeling offers a compelling avenue for integration of the known variation in the many factors that combine to inform this risk. PMID- 26117075 TI - Evaluation of a laboratory model of human head impact biomechanics. AB - This work describes methodology for evaluating laboratory models of head impact biomechanics. Using this methodology, we investigated: how closely does twin-wire drop testing model head rotation in American football impacts? Head rotation is believed to cause mild traumatic brain injury (mTBI) but helmet safety standards only model head translations believed to cause severe TBI. It is unknown whether laboratory head impact models in safety standards, like twin-wire drop testing, reproduce six degree-of-freedom (6DOF) head impact biomechanics that may cause mTBI. We compared 6DOF measurements of 421 American football head impacts to twin wire drop tests at impact sites and velocities weighted to represent typical field exposure. The highest rotational velocities produced by drop testing were the 74th percentile of non-injury field impacts. For a given translational acceleration level, drop testing underestimated field rotational acceleration by 46% and rotational velocity by 72%. Primary rotational acceleration frequencies were much larger in drop tests (~100 Hz) than field impacts (~10 Hz). Drop testing was physically unable to produce acceleration directions common in field impacts. Initial conditions of a single field impact were highly resolved in stereo high-speed video and reconstructed in a drop test. Reconstruction results reflected aggregate trends of lower amplitude rotational velocity and higher frequency rotational acceleration in drop testing, apparently due to twin-wire constraints and the absence of a neck. These results suggest twin-wire drop testing is limited in modeling head rotation during impact, and motivate continued evaluation of head impact models to ensure helmets are tested under conditions that may cause mTBI. PMID- 26117076 TI - The distribution of superficial zone protein (SZP)/lubricin/PRG4 and boundary mode frictional properties of the bovine diarthrodial joint. AB - The diarthrodial, knee joint is a remarkably efficient bearing system; articulating cartilage surfaces provide nearly frictionless performance with minimal wear. The low friction properties of the cartilage surfaces are due in part to the boundary lubricant, superficial zone protein (SZP); also known as lubricin or proteoglycan 4 (PRG4). In previous work, SZP localization and cartilage friction were examined across the femoral condyles. Studies in the literature have also individually investigated the other tissues that comprise the human knee and four-legged animal stifle joint, such as the meniscus or patella. However, comparisons between individual studies are limited due to the variable testing conditions employed. Friction is a system property that is dependent on the opposing articulating surface, entraining speed, and loading. A cross-comparison of the frictional properties and SZP localization across the knee/stifle joint tissues utilizing a common testing configuration is therefore needed. The objective of this investigation was to determine the friction coefficient and SZP localization of the tissues comprising the three compartments of the bovine stifle joint: patella, patellofemoral groove, femoral condyles, meniscus, tibial plateau, and anterior cruciate ligament. The boundary mode coefficient of friction was greater in tissues of the patellofemoral compartment than the lateral and medial tibiofemoral compartments. SZP immunolocalization followed this trend with reduced depth of staining and intensity in the patella and patellofemoral groove compared to the femoral condyles and tibial plateau. These results illustrate the important role of SZP in reducing friction in the tissues and compartments of the knee/stifle joint. PMID- 26117077 TI - Evaluation of the Plastic Surgery In-Service Training Exam: Lower Extremity Questions. AB - OBJECTIVE: To facilitate the training of plastic surgery residents, we analyzed a knowledge-based curriculum for plastic and reconstructive surgery of the lower extremity. DESIGN: The Plastic Surgery In-Service Training Exam (PSITE) is a commonly used tool to assess medical knowledge in plastic surgery. We reviewed the lower extremity content on 6 consecutive score keys (2008-2013). Questions were classified by taxonomy, anatomy, and subject. Answer references were quantified by source and relative year of publication. RESULTS: Totally, 107 questions related to the lower extremity (9.1% of all questions) and 14 questions had an associated image (13.1%). Questions required decision making (49%) over interpretation (36%) and direct recall (15%) skills (p < 0.001). Conditions of the leg (42.1%) and thigh (24.3%) constituted most of the questions. Subject matter focused on flap reconstruction (38.3%), nerve injury (8.4%), and congenital deformity (6.5%). Analysis of 263 citations to 66 unique journals showed that Plastic and Reconstructive Surgery (54.9%) was the highest yield primary source. The median year of publication relative to PSITE administration was 6 (range: 1-58) with a mode of 2 years. Plastic Surgery by Mathes et al. was the most referenced textbook (21.9%). CONCLUSIONS: These data establish a benchmark for lower extremity training during plastic surgery residency. Study efforts focused on the most common topics and references will enhance trainee preparation for lower extremity PSITE questions. PMID- 26117078 TI - Patient Safety Risks of Basic Urological Procedures Performed by Junior and Senior Residents. AB - OBJECTIVE: To investigate the current performance of urological residents regarding basic urological procedures in relation to patient safety issues and the identification of specific training needs. DESIGN: Observational data of 146 urethrocystoscopies (UCSs), 27 transrectal ultrasounds of the prostate (TRUSs), 38 transrectal ultrasound-guided prostatic biopsies (TRUSPs), and 30 transurethral resections of bladder tumor (TURBTs) were collected. Performance was evaluated using scoring lists including details on completeness of procedural steps, level of independence, time, and the incidence of unintended events. The causal factors contributing to the unintended events were identified by 2 expert urologists and classified according to the recognized PRISMA method. SETTING: This study was performed in 5 teaching hospitals in the Netherlands. PARTICIPANTS: We included 11 junior residents and 5 senior residents in urology in the final study cohort. RESULTS: Senior residents showed a lower degree of completeness in material usage than junior residents did during UCS (p < 0.01) and in preparation, material usage, and procedure during TRUSP (all p < 0.05). In UCS and TURBT, senior residents received significantly less feedback than junior residents did (both p < 0.01). Incidence of unintended events for junior vs senior residents was 11% and 4% in UCS, 0% and 7% in transrectal ultrasound of the prostate, 36% and 62% in TRUSP, and 41% and 23% in TURBT, respectively. Overall, unintended events were mainly caused by human factors, in particular, verification and skills-based issues. CONCLUSION: Present performance of basic urological procedures involves a high percentage of unintended events, especially in TRUSP and TURBT, which are mainly caused by human factors and are a potential threat for patient safety. Junior residents are less independent but more thorough in the performance of UCS and TRUSP than senior residents are. Targeted skills training including assessment should be implemented before privileges for independent practice are granted to reduce the incidence of unintended events and optimize patient safety. PMID- 26117079 TI - Reliable Assessment of Performance in Surgery: A Practical Approach to Generalizability Theory. PMID- 26117080 TI - The Potential Reach of Opioid Substitution Settings to Deliver HCV Care to People Who Inject Drugs in Australia. AB - BACKGROUND: Recent efforts in Australia to engage people who inject drugs (PWID) in hepatitis C (HCV) care have focussed on opioid substitution treatment (OST) services as a delivery site. This approach potentially excludes non-opioid using PWID. This study aimed to determine differences between those currently receiving OST and those not among a sample of PWID. METHODS: Additional questions on HCV testing were included in the 2013 Illicit Drug Reporting System (IDRS), an annual sentinel surveillance system. The IDRS recruits PWID in all Australian capital cities from a range of sources, predominantly needle and syringe programs. All participants are reimbursed AUD$40 for a ~45 minute interview-administered survey. RESULTS: Current OST was reported by 44% of the total sample, and two thirds reported an opioid as their drug of choice. Those participants who reported current OST were significantly more likely than those not in OST to report heroin as their drug of choice (65% vs. 43%, p<0.0.001) and the drug injected most often (53% vs. 30%, p<0.001). Compared to those in OST, those not in OST were more likely to report methamphetamine as their drug of choice (29% vs. 14%, p<0.001) or drug injected most often (33% vs. 17%, p<0.001). Current OST clients were more likely to have been tested for HCV antibodies (anti-HCV) than those not in OST (96% vs. 93%, p<0.05) and to report an anti-HCV positive result (75% vs. 64%, p<0.001). Those receiving OST were no more likely than those not to undergo further HCV-related testing (e.g. RNA) (62% vs. 56%, p=0.136). Both groups reported further HCV-related testing was undertaken primarily at a community general practice. DISCUSSION: Despite a large proportion of current PWID receiving OST, there remains a substantial minority who are neither seeking nor eligible for treatment. Efforts to improve access to HCV care for PWID in Australia therefore need to be expanded beyond OST, especially given the large proportion of participants who reported inadequate HCV testing. PMID- 26117081 TI - A Randomized Evaluation of Motivational Interviewing Training for Mandated Implementation of Alcohol Screening and Brief Intervention in Trauma Centers. AB - The American College of Surgeons has mandated that level I and level II trauma centers implement universal alcohol screening and brief intervention (SBI) for injured patients. This study was a secondary analysis of a national, 20-hospital, cluster-randomized implementation trial focusing on practical issues of training and supervising alcohol SBI providers in motivational interviewing (MI). The purpose of this study was to examine whether real-world trauma center providers can be trained to provide higher quality counseling using MI as part of brief interventions for alcohol and whether MI skills can be maintained over time. Sites were randomly assigned to receive a 1day workshop training in MI for alcohol SBI or not, and all providers regardless of training completed up to seven standardized patient assessments of MI fidelity over 27months. Six domains on the Motivational Interviewing Treatment Integrity (MITI) coding system were assessed and compared to proficiency criteria. Providers in the intervention training group showed substantially improved MITI scores over the course of the 27-month time period. Domains that had particularly strong improvement were MI spirit and empathy; however, despite the overall improvement in the intervention group scores, expert-derived proficiency criteria were attained only for the global scores. Routine trauma center providers who receive MI training can deliver higher quality counseling in alcohol brief interventions, but may not, however, attain previously derived proficiency standards. Future implementation efforts in real-world acute care medical settings could further elucidate provider characteristics that predict training response and also strive to demonstrate that higher quality alcohol SBI implementation is associated with improved patient-level outcomes. PMID- 26117082 TI - Rate of repeat diagnoses in men who have sex with men for Chlamydia trachomatis and Neisseria gonorrhoeae: a retrospective cohort study. AB - Background Sexually transmissible infections (STIs) have increased rapidly among men who have sex with men (MSM). One of the most effective strategies to control STIs is partner notification. Inadequate partner notification may be associated with high rates of repeat diagnoses with STIs. The aim of this study is to estimate and compare the rate of chlamydia and gonorrhoea infection following primary infection to the overall clinic rate. METHODS: A retrospective cohort analysis of MSM attending the Melbourne Sexual Health Clinic was conducted. For both infections, the overall incidence and that following diagnosis and treatment was calculated. RESULTS: Of the 13053 MSM, the incidence of diagnoses for chlamydia and gonorrhoea was 8.5 (95% CI: 8.2-8.9) and 6.2 (95% CI: 5.9-6.5) per 100 person-years, respectively. Seventy per cent of chlamydia and 64% of gonorrhoea cases were retested at 10-365 days after diagnosis and treatment. Following diagnosis and treatment of chlamydia, the rate ratio in these individuals in the first quarter was 16- and 8-fold higher for chlamydia and gonorrhoea, respectively, compared with the background incidence of diagnoses. Similarly, following diagnosis and treatment of gonorrhoea, the rate ratio in these individuals in the first quarter was 18- and 10-fold higher for gonorrhoea and chlamydia, respectively. CONCLUSIONS: These data suggest that approximately half of MSM who test positive for chlamydia or gonorrhoea within 90 days after an initial infection represent contact with either a previous sexual partner or member of the same sexual network, the remainder representing the particularly high STI risk for these MSM. PMID- 26117083 TI - Vessel Wall Magnetic Resonance Imaging, Inflammatory Cascade, Aspirin, and Aneurysm Rupture: Future Paradigms? PMID- 26117084 TI - Endoscopic Endonasal Clipping of Intracranial Aneurysms: Surgical Technique and Results. AB - OBJECTIVE: Microsurgical clipping of intracranial aneurysms requires meticulous technique and is usually performed through open approaches. Endoscopic endonasal clipping of intracranial aneurysms may use the same techniques through an alternative corridor. The aim of this article is to report a series of patients who underwent an endoscopic endonasal approach (EEA) for microsurgical clipping of intracranial aneurysms. METHODS: We conducted a retrospective chart review. Surgical outcome and complications were noted. The conceptual application and the technical nuances of these procedures are discussed. RESULTS: Ten patients underwent EEA for clipping of 11 intracranial aneurysms arising from the paraclinoidal internal carotid artery (n = 9) and vertebrobasilar system (n = 2). The internal carotid artery aneurysms projected medially, whereas the vertebrobasilar artery aneurysms were directly ventral to the brainstem with low lying basilar apices. One patient required craniotomy for distal control given the size and thrombosed nature of the aneurysm. Proximal and distal vascular control with direct visualization of the aneurysm was obtained in all patients. In all cases, aneurysms were completely occluded. Among complications, 3 patients had postoperative cerebrospinal fluid leakage and 2 other patients had meningitis. Two patients suffered lacunar strokes. One recovered completely and the other remains with mild disabling symptoms. CONCLUSIONS: EEAs can provide direct access for microsurgical clipping of rare and carefully selected intracranial aneurysms. The basic principles of cerebrovascular surgery have to be followed throughout the procedure. These surgeries require a skull base team with a neurosurgeon well versed in both endoscopic endonasal and cerebrovascular surgery, working in concert with an otolaryngologist experienced in skull base endoscopy and reconstruction. PMID- 26117085 TI - Analysis of Venous Thromboembolism Risk in Patients Undergoing Craniotomy. AB - OBJECTIVES: Craniotomy poses a risk for postoperative venous thromboembolism (VTE), but the utility of anticoagulation in this patient population is unclear. We sought to identify risk factors predictive of VTE in patients undergoing craniotomy. METHODS: The American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database was reviewed for patients undergoing craniotomy. Clinical factors provided by the database were analyzed for association with VTE. RESULTS: A total of 10,477 adult patients who underwent craniotomy from 2011-2012 were identified. The rate of VTE was 3.2% (pulmonary embolism [PE] was 1.3%; deep vein thrombosis [DVT] was 2.4%). Several factors were significant in univariate analysis, and a subset persisted after multivariate analysis. Patients were assigned a risk score on the basis of the presence of those variables. Higher risk scores were predictive of VTE risk, as well as increasing time from surgery to discharge and mortality. A receiver operating characteristics curve revealed a significant area under the curve (0.719) for scores being predictive of VTE risk. The model was validated against our similar analysis of 2006-2010 NSQIP data and demonstrated comparable findings. CONCLUSIONS: The risk of postoperative VTE after craniotomy can be quantified by a simple risk score, with increasing risk factors conferring increased risk of VTE. On the basis of risk scoring, a subset of patients who would benefit from anticoagulation post craniotomy may be identified. PMID- 26117086 TI - A Neurosurgical Call to Arms: Lessons from ARUBA, Mr. Clean, and the Hydrocephalus Clinical Research Network. PMID- 26117087 TI - Intrasaccular Flow Diversion for Wide-Neck Bifurcation Aneurysms: Should the Bar Be Set Higher? PMID- 26117088 TI - From Delivering the Patient to the Hospital to Delivering the Hospital to the Patient: Acute Stroke Therapy in an Ambulance. PMID- 26117089 TI - Search for Biomarkers of Intracranial Aneurysms: A Systematic Review. AB - INTRODUCTION: Intracranial aneurysms (IAs) remain a devastating clinical challenge, and the pathogenesis of IA formation and progression continues to be unclear. Biomarker analysis can help us understand IA development. The authors performed a systematic review of current literature on genetic and serum biomarkers for IAs in an attempt to identify diagnostic/prognostic factors for ruptured and unruptured aneurysms. METHODS: All relevant studies on PubMed that reported blood/cerebrospinal fluid (CSF) biomarkers and genes that regulate biomarker levels for IAs were assessed for whether the biomarkers/genes studied correlated with IA formation and rupture. RESULTS: Thirty-three studies were reviewed. IAs are associated with an increase in levels of immunologic markers, particularly complement C3 and C9, immunoglobulins IgG and IgM, M1/M2 macrophages, monocytes, and B and T lymphocytes; increase in blood and CSF levels of adhesion molecules; selectins found on vascular endothelium, platelets, and leukocytes; doubled ratios of elastase-to-alpha-1-antitrypsin as controls; elevated levels of neurofilament heavy chain SM135 and S-100 post rupture; and locus 19q13 with many candidate genes. CONCLUSION: Though the pathophysiology of the disease remains unclear, the current literature supports the role of inflammatory and cell adhesion molecules, enzymes and hormones that effect cerebral vasculature, and other cerebral proteins related to brain and vascular damage in both the formation and progression to rupture of IAs. Future investigations are needed to validate results from previous studies and identify new diagnostic/prognostic biomarkers of IAs. PMID- 26117090 TI - Synovial TRPV1 is upregulated by 17-beta-estradiol and involved in allodynia of inflamed temporomandibular joints in female rats. AB - Women with reproductive capability are more likely to suffer from temporomandibular disorders (TMD), with orofacial pain as the most common complaint. In the past, we focused on the role of estradiol in TMD pain through the nervous system. In this study, we explored estradiol's influence on synoviocyte gene expressions involved in the allodynia of the inflamed TMJ. The influence of 17-beta-estradiol on NGF and TRPV1 expression in TMJ synovium was determined in vivo and in vitro and analyzed by Western blot and real-time PCR. Complete Freund's adjuvant (CFA) injection into the TMJ was used to induce TMJ arthritis. Capsazepine served as a TRPV1 antagonist. Head withdrawal threshold was examined using a von Frey Anesthesiometer. We observed that estradiol upregulated the expressions of TRPV1 and NGF in a dose-dependent manner. In the primary cultured synoviocytes, TRPV1 was upregulated by lipopolysaccharide (LPS), estradiol, and NGF, while NGF antibodies fully blocked LPS and estradiol-induced upregulation of TRPV1. Activation of TRPV1 in the primary synoviocytes with capsaicin, a TRPV1 agonist, dose-dependently enhanced COX-2 transcription. Moreover, intra-TMJ injection of TRPV1 antagonist, capsazepine, significantly attenuated allodynia of the inflamed TMJ induced by intra-TMJ injection of CFA in female rats. This article presents a possible local mechanism for estradiol that may be involved in TMJ inflammation or pain in the synovial membrane through the pain-related gene TRPV1. This finding could potentially help clinicians understand the sexual dimorphism of TMD pain. PMID- 26117091 TI - Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: Prospective study of a chronic hepatitis C cohort. AB - BACKGROUND: Major depressive disorder (MDD) is a common consequence of interferon alpha (IFNalpha) treatment and important supporting evidence of a role of inflammation in the aetiology of depression. OBJECTIVE: This study aimed to expand the knowledge of baseline clinical vulnerability characteristics to IFNalpha induced MDD, particularly exploring sub-threshold depressive symptoms. METHODS: A prospective cohort of chronic HCV patients undergoing treatment with pegylated-IFNalpha and ribavirin was studied. MDD was assessed using the Structured Clinical Interview for DSM-IV (SCID-I). Depressive symptoms and severity were assessed at baseline and monthly with the Hamilton Depression Rating Scale (HAMD). Subjects with MDD or taking antidepressant treatment at baseline were excluded. RESULTS: 278 patients were assessed for this cohort with a final study sample of 190. 94.2% had contracted HCV through intravenous drug use. During six months IFNalpha treatment, 53.2% of patients transitioned to DSM IV threshold MDD. In the multivariate logistic analysis, independent factors significantly associated with development of MDD were younger age (OR 0.96, 95% CI 0.93-1.00, p=0.028), past history of MDD (OR 3.82, 95% CI 1.63-8.92, p=0.002), baseline HAMD items psychomotor retardation (OR 15.21, 95% CI 1.33-173.41, p=0.032) and somatic symptoms (general) (OR 2.96, 95% CI 1.44-6.08, p=0.003), and HCV genotype 2 (OR 2.27, 95% CI 1.07-4.78, p=0.032). CONCLUSIONS: During IFNalpha treatment, the rate of transition to MDD was high in this cohort. Psychomotor retardation and somatic symptoms may represent a greater inflamed state pre treatment. This iatrogenic model of MDD may offer important insights into wider depression aetiology. PMID- 26117092 TI - Synthesis of fused tricyclic peptides using a reprogrammed translation system and chemical modification. AB - Here we report a unique method of ribosomally synthesizing fused tricyclic peptides. Flexizyme-assisted in vitro translation of a linear peptide with the N terminal chloroacetyl group and four downstream cysteines followed by the addition of 1,3,5-tris(bromomethyl)benzene results in selective production of the fused tricyclic peptide. This technology can be used for the ribosomal synthesis of fused tricyclic peptide libraries for the in vitro selection of bioactive peptides with tricyclic topology. PMID- 26117093 TI - Considering long-term care insurance for middle-income countries: comparing South Korea with Japan and Germany. AB - Financing and provision of long-term care is an increasingly important concern for many middle-income countries experiencing rapid population aging. We examine three countries (South Korea, Japan, and Germany) that use social insurance to finance medical care and have developed long-term care insurance (LTCI) systems. These countries have adopted different approaches to LTCI design within the social insurance framework. We contrast their financing systems and draw lessons regarding revenue generation, benefits design, and eligibility. Based on this review, it seems important for middle-income countries to start developing LTCI schemes early, before aging becomes a significant problem and substantial revenues are needed. Early financing also ensures that the service delivery system has time to adapt because most middle-income countries lack the infrastructure for providing long-term care services. One approach is to start with a limited benefit package and strict eligibility rules and expanded the program as the country develops sufficient experience and more providers became available. All three countries use some form of cost-sharing to discourage service overuse, combined with subsidies for poor populations to maintain appropriate access. A major policy choice is between cash benefits or direct provision of services and the approach will have a large impact on the workforce participation of women. PMID- 26117095 TI - Interplay between modulational instability and self-trapping of wavepackets in nonlinear discrete lattices. AB - We investigate the modulational instability of uniform wavepackets governed by the discrete nonlinear Schrodinger equation in finite linear chains and square lattices. We show that, while the critical nonlinear coupling chiMI above which modulational instability occurs remains finite in square lattices, it decays as 1/L in linear chains. In square lattices, there is a direct transition between the regime of stable uniform wavefunctions and the regime of asymptotically localized solutions with stationary probability distributions. On the other hand, there is an intermediate regime in linear chains for which the wavefunction dynamics develops complex breathing patterns. We analytically compute the critical nonlinear strengths for modulational instability in both lattices, as well as the characteristic time tau governing the exponential increase of perturbations in the vicinity of the transition. We unveil that the interplay between modulational instability and self-trapping phenomena is responsible for the distinct wavefunction dynamics in linear and square lattices. PMID- 26117094 TI - Acute effects of a prooxidant herbicide on the microalga Chlamydomonas reinhardtii: Screening cytotoxicity and genotoxicity endpoints. AB - Since recent evidence has demonstrated that many types of chemicals exhibit oxidative and/or genotoxic potential on living organisms, reactive oxygen species (ROS) formation and DNA damage are currently the best accepted paradigms to assess the potential hazardous biological effects of a wide range of contaminants. The goal of this study was to evaluate the sensitivity of different cytotoxicity and genotoxicity responses on the model microalga Chlamydomonas reinhardtii exposed to the prooxidant herbicide paraquat. In addition to the growth endpoint, cell viability, mitochondrial membrane potential and presence of reactive oxygen species (ROS) were assayed as potential markers of cytotoxicity using flow cytometry (FCM). To study the effects of paraquat on C. reinhardtii DNA, several genotoxicity approaches were implemented for the first time in an ecotoxicological study on microalgae. Oxidative DNA base damage was analysed by measuring the oxidative DNA lesion 8-OHdG by FCM. DNA fragmentation was analysed by different methods: comet assay, and cell cycle analysis by FCM, with a particular focus on the presence of subG1-nuclei. Finally, effects on morphology of nuclei were monitored through DAPI staining. The evaluation of these endpoints showed that several physiological and biochemical parameters reacted to oxidative stress disturbances with greater sensitivity than integrative parameters such as growth rates or cell viability. The experiments revealed concentration-dependent cytotoxicity (ROS formation, depolarization of mitochondrial membrane), genotoxicity (oxidative DNA damage, DNA strand breakage, alterations in nuclear morphology), and cell cycle disturbances (subG1-nuclei, decrease of 4N population) in paraquat-treated cells. Overall, the genotoxicity results indicate that the production of ROS caused by exposure to paraquat induces oxidative DNA damage followed by DNA single- and double-strand breaks and cell cycle alterations, possibly leading to apoptosis in C. reinhardtii cells. This is supported by the observation of typical hallmarks of apoptosis, such as mitochondrial membrane depolarization, alterations in nuclear morphology and subG1 nuclei in cells exposed to the highest assayed concentrations. To our knowledge, this is the first study that provides a comprehensive analysis of oxidative DNA base damage in unicellular algal cells exposed to a prooxidant pollutant, as well as of its possible relation with other physiological effects. These results reinforce the need for additional studies on the genotoxicity of environmental pollutants on ecologically relevant organisms such as microalgae that can provide a promising basis for the characterization of potential pollutant hazards in the aquatic environment. PMID- 26117096 TI - Generalized correlation integral vectors: A distance concept for chaotic dynamical systems. AB - Several concepts of fractal dimension have been developed to characterise properties of attractors of chaotic dynamical systems. Numerical approximations of them must be calculated by finite samples of simulated trajectories. In principle, the quantities should not depend on the choice of the trajectory, as long as it provides properly distributed samples of the underlying attractor. In practice, however, the trajectories are sensitive with respect to varying initial values, small changes of the model parameters, to the choice of a solver, numeric tolerances, etc. The purpose of this paper is to present a statistically sound approach to quantify this variability. We modify the concept of correlation integral to produce a vector that summarises the variability at all selected scales. The distribution of this stochastic vector can be estimated, and it provides a statistical distance concept between trajectories. Here, we demonstrate the use of the distance for the purpose of estimating model parameters of a chaotic dynamic model. The methodology is illustrated using computational examples for the Lorenz 63 and Lorenz 95 systems, together with a framework for Markov chain Monte Carlo sampling to produce posterior distributions of model parameters. PMID- 26117097 TI - True orbit simulation of piecewise linear and linear fractional maps of arbitrary dimension using algebraic numbers. AB - We introduce a true orbit generation method enabling exact simulations of dynamical systems defined by arbitrary-dimensional piecewise linear fractional maps, including piecewise linear maps, with rational coefficients. This method can generate sufficiently long true orbits which reproduce typical behaviors (inherent behaviors) of these systems, by properly selecting algebraic numbers in accordance with the dimension of the target system, and involving only integer arithmetic. By applying our method to three dynamical systems-that is, the baker's transformation, the map associated with a modified Jacobi-Perron algorithm, and an open flow system-we demonstrate that it can reproduce their typical behaviors that have been very difficult to reproduce with conventional simulation methods. In particular, for the first two maps, we show that we can generate true orbits displaying the same statistical properties as typical orbits, by estimating the marginal densities of their invariant measures. For the open flow system, we show that an obtained true orbit correctly converges to the stable period-1 orbit, which is inherently possessed by the system. PMID- 26117098 TI - Numerical identification of epidemic thresholds for susceptible-infected recovered model on finite-size networks. AB - Epidemic threshold has always been a very hot topic for studying epidemic dynamics on complex networks. The previous studies have provided different theoretical predictions of the epidemic threshold for the susceptible-infected recovered (SIR) model, but the numerical verification of these theoretical predictions is still lacking. Considering that the large fluctuation of the outbreak size occurs near the epidemic threshold, we propose a novel numerical identification method of SIR epidemic threshold by analyzing the peak of the epidemic variability. Extensive experiments on synthetic and real-world networks demonstrate that the variability measure can successfully give the numerical threshold for the SIR model. The heterogeneous mean-field prediction agrees very well with the numerical threshold, except the case that the networks are disassortative, in which the quenched mean-field prediction is relatively close to the numerical threshold. Moreover, the numerical method presented is also suitable for the susceptible-infected-susceptible model. This work helps to verify the theoretical analysis of epidemic threshold and would promote further studies on the phase transition of epidemic dynamics. PMID- 26117099 TI - Lagrangian coherent structures along atmospheric rivers. AB - We show that filamentous Atmospheric Rivers (ARs) over the Northern Atlantic Ocean are closely linked to attracting Lagrangian Coherent Structures (LCSs) in the large scale wind field. The detected LCSs represent lines of attraction in the evolving flow with a significant impact on all passive tracers. Using Finite Time Lyapunov Exponents, we extract LCSs from a two-dimensional flow derived from water vapor flux of atmospheric reanalysis data and compare them to the three dimensional LCS obtained from the wind flow. We correlate the typical filamentous water vapor patterns of ARs with LCSs and find that LCSs bound the filaments on the back side. Passive advective transport of water vapor in the AR from tropical latitudes is potentially possible. PMID- 26117100 TI - Non-Markovian character in human mobility: Online and offline. AB - The dynamics of human mobility characterizes the trajectories that humans follow during their daily activities and is the foundation of processes from epidemic spreading to traffic prediction and information recommendation. In this paper, we investigate a massive data set of human activity, including both online behavior of browsing websites and offline one of visiting towers based mobile terminations. The non-Markovian character observed from both online and offline cases is suggested by the scaling law in the distribution of dwelling time at individual and collective levels, respectively. Furthermore, we argue that the lower entropy and higher predictability in human mobility for both online and offline cases may originate from this non-Markovian character. However, the distributions of individual entropy and predictability show the different degrees of non-Markovian character between online and offline cases. To account for non Markovian character in human mobility, we apply a protype model with three basic ingredients, namely, preferential return, inertial effect, and exploration to reproduce the dynamic process of online and offline human mobilities. The simulations show that the model has an ability to obtain characters much closer to empirical observations. PMID- 26117101 TI - Tracking stochastic resonance curves using an assisted reference model. AB - The optimal noise amplitude for Stochastic Resonance (SR) is located employing an Artificial Neural Network (ANN) reference model with a nonlinear predictive capability. A modified Kalman Filter (KF) was coupled to this reference model in order to compensate for semi-quantitative forecast errors. Three manifestations of stochastic resonance, namely, Periodic Stochastic Resonance (PSR), Aperiodic Stochastic Resonance (ASR), and finally Coherence Resonance (CR) were considered. Using noise amplitude as the control parameter, for the case of PSR and ASR, the cross-correlation curve between the sub-threshold input signal and the system response is tracked. However, using the same parameter the Normalized Variance curve is tracked for the case of CR. The goal of the present work is to track these curves and converge to their respective extremal points. The ANN reference model strategy captures and subsequently predicts the nonlinear features of the model system while the KF compensates for the perturbations inherent to the superimposed noise. This technique, implemented in the FitzHugh-Nagumo model, enabled us to track the resonance curves and eventually locate their optimal (extremal) values. This would yield the optimal value of noise for the three manifestations of the SR phenomena. PMID- 26117102 TI - Homoclinic behaviors and chaotic motions of double layered viscoelastic nanoplates based on nonlocal theory and extended Melnikov method. AB - The nonlinear dynamical equations are established for the double layered viscoelastic nanoplates (DLNP) subjected to in-plane excitation based on the nonlocal theory and von Karman large deformation theory. The extended high dimensional homoclinic Melnikov method is employed to study the homoclinic phenomena and chaotic motions for the parametrically excited DLNP system. The criteria for the homoclinic transverse intersection for both the asynchronous and synchronous buckling cases are proposed. Lyapunov exponents and phase portraits are obtained to verify the Melnikov-type analysis. The influences of structural parameters on the transverse homoclinic orbits and homoclinic bifurcation sets are discussed for the two buckling cases. Some novel phenomena are observed in the investigation. It should be noticed that the nonlocal effect on the homoclinic behaviors and chaotic motions is quite remarkable. Hence, the small scale effect should be taken into account for homoclinic and chaotic analysis for nanostructures. It is significant that the nonlocal effect on the homoclinic phenomena for the asynchronous buckling case is quite different from that for the synchronous buckling case. Moreover, due to the van der Walls interaction between the layers, the nonlocal effect on the homoclinic behaviors and chaotic motions for high order mode is rather tiny under the asynchronous buckling condition. PMID- 26117103 TI - Entoptic perceptions of spiral waves and rare inward spirals. AB - This report concerns Entoptic Rotating Spiral Waves as observed and documented by the author over a period of 46 years (1962-2008). The manifestations of these state-dependent, elusive rotating spiral entities were brief, emerging only during sleep-to-waking arousal epochs (in limbo). The images were seen only with closed lids in favorable ambient lighting-here, termed the umbral view. The clusters of rotating spiral entities emerge briefly to conscious view; their angular subtenses are estimated to be between 1 degrees and 4 degrees , and the rotations at ten-turns per second. Epochs of these activities commonly continued for about 20 s, with longevity of each visible entity up to 4 s. 90% of all observed entities were circular and outwardly levorotary; 5% were elliptical, appearing only as horizontal (prolate) entities. Overlapping units were rare, and were chiefly elliptical. Observations of twin spirals were also rare, seen in counter rotations, each twin inwardly rotating. PMID- 26117104 TI - Minima of the fluctuations of the order parameter of global seismicity. AB - It has been recently shown [N. V. Sarlis, Phys. Rev. E 84, 022101 (2011) and N. V. Sarlis and S.-R. G. Christopoulos, Chaos 22, 023123 (2012)] that earthquakes of magnitude M greater or equal to 7 are globally correlated. Such correlations were identified by studying the variance kappa1 of natural time which has been proposed as an order parameter for seismicity. Here, we study the fluctuations of this order parameter using the Global Centroid Moment Tensor catalog for a magnitude threshold Mthres = 5.0 and focus on its behavior before major earthquakes. Natural time analysis reveals that distinct minima of the fluctuations of the order parameter of seismicity appear within almost five and a half months on average before all major earthquakes of magnitude larger than 8.4. This phenomenon corroborates the recent finding [N. V. Sarlis et al., Proc. Natl. Acad. Sci. U.S.A. 110, 13734 (2013)] that similar minima of the seismicity order parameter fluctuations had preceded all major shallow earthquakes in Japan. Moreover, on the basis of these minima a statistically significant binary prediction method for earthquakes of magnitude larger than 8.4 with hit rate 100% and false alarm rate 6.67% is suggested. PMID- 26117105 TI - Modulational instability, higher-order localized wave structures, and nonlinear wave interactions for a nonautonomous Lenells-Fokas equation in inhomogeneous fibers. AB - In this paper, the nonautonomous Lenells-Fokas (LF) model is investigated. The modulational instability analysis of the solutions with variable coefficients in the presence of a small perturbation is studied. Higher-order soliton, breather, earthwormon, and rogue wave solutions of the nonautonomous LF model are derived via the n-fold variable-coefficient Darboux transformation. The solitons and earthwormons display the elastic collisions. It is found that the nonautonomous LF model admits the higher-order periodic rogue waves, composite rogue waves (rogue wave pair), and oscillating rogue waves, whose dynamics can be controlled by the inhomogeneous nonlinear parameters. Based on the second-order rogue wave, a diamond structure consisting of four first-order rogue waves is observed. In addition, the semirational solutions (the mixed rational-exponential solutions) of the nonautonomous LF model are obtained, which can be used to describe the interactions between the rogue waves and breathers. Our results could be helpful for the design of experiments in the optical fiber communications. PMID- 26117106 TI - Some examples related to the method of Lagrangian descriptors. AB - We provide families of counter-examples, including Hamiltonian systems, to the method of Lagrangian descriptors developed by Mancho, Wiggins, and their co workers. A detailed mathematical discussion on why that methodology fails together with some pathological phenomena are given as well. PMID- 26117107 TI - Multifractal analysis of time series generated by discrete Ito equations. AB - In this study, we show that discrete Ito equations with short-tail Gaussian marginal distribution function generate multifractal time series. The multifractality is due to the nonlinear correlations, which are hidden in Markov processes and are generated by the interrelation between the drift and the multiplicative stochastic forces in the Ito equation. A link between the range of the generalized Hurst exponents and the mean of the squares of all averaged net forces is suggested. PMID- 26117108 TI - Improvements to local projective noise reduction through higher order and multiscale refinements. AB - The broad spectrum characteristic of signals from nonlinear systems obstructs noise reduction techniques developed for linear systems. Local projection was developed to reduce noise while preserving nonlinear deterministic structures, and a second order refinement to local projection which was proposed ten years ago does so particularly effectively. It involves adjusting the origin of the projection subspace to better accommodate the geometry of the attractor. This paper describes an analytic motivation for the enhancement from which follows further higher order and multiple scale refinements. However, the established enhancement is frequently as or more effective than the new filters arising from solely geometric considerations. Investigation of the way that measurement errors reinforce or cancel throughout the refined local projection procedure explains the special efficacy of the existing enhancement, and leads to a new second order refinement offering widespread gains. Different local projective filters are found to be best suited to different noise levels. At low noise levels, the optimal order increases as noise increases. At intermediate levels second order tends to be optimal, while at high noise levels prototypical local projection is most effective. The new higher order filters perform better relative to established filters for longer signals or signals corresponding to higher dimensional attractors. PMID- 26117109 TI - Energy transport in the three coupled alpha-polypeptide chains of collagen molecule with long-range interactions effect. AB - The dynamics of three coupled alpha-polypeptide chains of a collagen molecule is investigated with the influence of power-law long-range exciton-exciton interactions. The continuum limit of the discrete equations reveal that the collagen dynamics is governed by a set of three coupled nonlinear Schrodinger equations, whose dispersive coefficient depends on the LRI parameter r. We construct the analytic symmetric and asymmetric (antisymmetric) soliton solutions, which match with the structural features of collagen related with the acupuncture channels. These solutions are used as initial conditions for the numerical simulations of the discrete equations, which reveal a coherent transport of energy in the molecule for r > 3. The results also indicate that the width of the solitons is a decreasing function of r, which help to stabilize the solitons propagating in the molecule. To confirm further the efficiency of energy transport in the molecule, the modulational instability of the system is performed and the numerical simulations show that the energy can flow from one polypeptide chain to another in the form of nonlinear waves. PMID- 26117110 TI - Unstable spiral waves and local Euclidean symmetry in a model of cardiac tissue. AB - This paper investigates the properties of unstable single-spiral wave solutions arising in the Karma model of two-dimensional cardiac tissue. In particular, we discuss how such solutions can be computed numerically on domains of arbitrary shape and study how their stability, rotational frequency, and spatial drift depend on the size of the domain as well as the position of the spiral core with respect to the boundaries. We also discuss how the breaking of local Euclidean symmetry due to finite size effects as well as the spatial discretization of the model is reflected in the structure and dynamics of spiral waves. This analysis allows identification of a self-sustaining process responsible for maintaining the state of spiral chaos featuring multiple interacting spirals. PMID- 26117111 TI - Introduction to Focus Issue: Oscillations and Dynamic Instabilities in Chemical Systems: Dedicated to Irving R. Epstein on occasion of his 70th birthday. PMID- 26117112 TI - Standing wave-like patterns in the Gray-Scott model. AB - Standing wave-like patterns are obtained in the Gray-Scott model when the dynamics that correspond to defect-mediated turbulence for equal diffusivities interact with a Turing instability. The Turing instability can be caused by either differential or cross-diffusion. We compare results with the Oregonator model, for which standing wave-like patterns are also observed under similar conditions. PMID- 26117113 TI - Modeling the entrainment of self-oscillating gels to periodic mechanical deformation. AB - Polymer gels undergoing the oscillatory Belousov-Zhabotinsky (BZ) reaction are one of the few synthetic materials that exhibit biomimetic mechano-chemical transduction, converting mechanical input into chemical energy. Here, we consider self-oscillating BZ gels that are subjected to periodic mechanical forcing, and model the entrainment of the oscillatory gel dynamics to this external stimulus. The gel size is assumed to be sufficiently small that the chemo-mechanical oscillations are spatially uniform. The behavior of the system is captured by equations describing the kinetics of the oscillatory BZ reaction in the gel coupled to equations for the variations in gel size due to the inherent reaction and imposed force. We employ the phase dynamics approach for analyzing the entrainment of the BZ gel to force- and strain-controlled compressive deformations. The phase response curves are obtained using Malkin's method, and time-averaging is applied to extract the slow phase dynamics caused by the periodic forcing. We demonstrate that the entrainment of the self-oscillating BZ gel is sensitive to the chemo-mechanical coupling in gel, the mode of deformation, and the level of static compression. Kuramoto's model of phase oscillators is shown to be applicable if the external forcing is purely harmonic. PMID- 26117114 TI - Scroll wave drift along steps, troughs, and corners. AB - Three-dimensional excitable systems can create nonlinear scroll waves that rotate around one-dimensional phase singularities. Recent theoretical work predicts that these filaments drift along step-like height variations. Here, we test this prediction using experiments with thin layers of the Belousov-Zhabotinsky reaction. We observe that over short distances scroll waves are attracted towards the step and then rapidly commence a steady drift along the step line. The translating filaments always reside on the shallow side of the step near the edge. Accordingly, filaments in the deep domain initially collide with and shorten at the step wall. The drift speeds obey the predicted proportional dependence on the logarithm of the height ratio and the direction depends on the vortex chirality. We also observe drift along the perimeter of rectangular plateaus and find that the filaments perform sharp turns at the corners. In addition, we investigate rectangular troughs for which vortices of equal chirality can drift in different directions. The latter two effects are reproduced in numerical simulations with the Barkley model. The simulations show that narrow troughs instigate scroll wave encounters that induce repulsive interaction and symmetry breaking. Similar phenomena could exist in the geometrically complicated ventricles of the human heart where reentrant vortex waves cause tachycardia and fibrillation. PMID- 26117115 TI - Diffusion-driven instabilities by immobilizing the autocatalyst in ionic systems. AB - Spatiotemporal coupling of an autocatalytic chemical reaction between ions with diffusion yields various types of reaction-diffusion patterns. The driving force is short range activation and long range inhibition which can be achieved by selective binding of the autocatalyst even for ions with equal mobility. For Turing and lateral instability, we show that identical charge on the autocatalyst and its counterpart has a stabilizing effect on the base state, while opposite charge on them favors the formation of spatial patterns with reversible binding. PMID- 26117116 TI - Effects of the positive feedback loop in polymerization on the reaction-induced phase separation of polymer mixtures. AB - Phase separation of mixtures composed of a guest polymer dissolved in monomer of a host polymer was induced by photopolymerization. From the polymerization kinetics, it was found that for the host polymer with the glass transition temperature (Tg) higher than the experimental temperature, the Trommsdorff Norrish effect emerges, providing a method to terminate the phase separation at various intermediate stages of the process and thereby a variety of morphologies can be constructed. For the host polymers with (Tg) lower than the experimental temperature, the freezing process of morphology is not complete, leading to the secondary phase separation inside the domains already generated by the primary process. The kinetics of this secondary phase separation indicates that the peculiar morphology like "sunny-side-up egg"-like structures was generated via spinodal decomposition. The experimental results obtained in this study show that the competition between photopolymerization and phase separation can provide a useful method of materials design in the micro- and sub-micrometer scales. PMID- 26117117 TI - Three-dimensional modeling of propagating precipitation waves. AB - A general three-dimensional model for propagating precipitation waves is presented. Structural features identified in experimental studies of propagating waves in the AlCl3/NaOH and NaAl(OH)4/HCl systems are described by the 3D model. Two forms of precipitate with different physical properties play key mechanistic roles in the wave propagation. Experimentally observed circular and spiral waves are simulated by the 3D model, as well as wave annihilation on the collision of two waves. PMID- 26117118 TI - Non-monotonic resonance in a spatially forced Lengyel-Epstein model. AB - We study resonant spatially periodic solutions of the Lengyel-Epstein model modified to describe the chlorine dioxide-iodine-malonic acid reaction under spatially periodic illumination. Using multiple-scale analysis and numerical simulations, we obtain the stability ranges of 2:1 resonant solutions, i.e., solutions with wavenumbers that are exactly half of the forcing wavenumber. We show that the width of resonant wavenumber response is a non-monotonic function of the forcing strength, and diminishes to zero at sufficiently strong forcing. We further show that strong forcing may result in a pi/2 phase shift of the resonant solutions, and argue that the nonequilibrium Ising-Bloch front bifurcation can be reversed. We attribute these behaviors to an inherent property of forcing by periodic illumination, namely, the increase of the mean spatial illumination as the forcing amplitude is increased. PMID- 26117119 TI - Helical Turing patterns in the Lengyel-Epstein model in thin cylindrical layers. AB - The formation of Turing patterns was investigated in thin cylindrical layers using the Lengyel-Epstein model of the chlorine dioxide-iodine-malonic acid reaction. The influence of the width of the layer W and the diameter D of the inner cylinder on the pattern with intrinsic wavelength l were determined in simulations with initial random noise perturbations to the uniform state for W < l/2 and D ~ l or lower. We show that the geometric constraints of the reaction domain may result in the formation of helical Turing patterns with parameters that give stripes (b = 0.2) or spots (b = 0.37) in two dimensions. For b = 0.2, the helices were composed of lamellae and defects were likely as the diameter of the cylinder increased. With b = 0.37, the helices consisted of semi-cylinders and the orientation of stripes on the outer surface (and hence winding number) increased with increasing diameter until a new stripe appeared. PMID- 26117120 TI - Externally controlled anisotropy in pattern-forming reaction-diffusion systems. AB - The effect of centrifugal forces is analyzed in a pattern-forming reaction diffusion system. Numerical simulations conducted on the appropriate extension of the Oregonator model for the Belousov-Zhabotinsky reaction show a great variety of dynamical behaviors in such a system. In general, the system exhibits an anisotropy that results in new types of patterns or in a global displacement of the previous one. We consider the effect of both constant and periodically modulated centrifugal forces on the different types of patterns that the system may exhibit. A detailed analysis of the patterns and behaviors observed for the different parameter values considered is presented here. PMID- 26117121 TI - Spontaneous formation of complex structures made from elastic membranes in an aluminum-hydroxide-carbonate system. AB - A popular playground for studying chemo-hydrodynamic patterns and instabilities is chemical gardens, also known as silicate gardens. In these systems, complex structures spontaneously form, driven by buoyant forces and either osmotic or mechanical pumps. Here, we report on systems that differ somewhat from classical chemical gardens in that the membranes are much more deformable and soluble. These properties lead to structures that self-construct and evolve in new ways. For example, they exhibit the formation of chemical balloons, a new growth mechanism for tubes, and also the homologous shrinking of these tubes. The stretching mechanism for the membranes is probably different than for other systems by involving membrane "self-healing." Other unusual properties are osmosis that sometimes occurs out of the structure and also small plumes that flow away from the structure, sometimes upwards, and sometimes downwards. Mathematical models are given that explain some of the observed phenomena. PMID- 26117122 TI - Contribution to an effective design method for stationary reaction-diffusion patterns. AB - The British mathematician Alan Turing predicted, in his seminal 1952 publication, that stationary reaction-diffusion patterns could spontaneously develop in reacting chemical or biochemical solutions. The first two clear experimental demonstrations of such a phenomenon were not made before the early 1990s when the design of new chemical oscillatory reactions and appropriate open spatial chemical reactors had been invented. Yet, the number of pattern producing reactions had not grown until 2009 when we developed an operational design method, which takes into account the feeding conditions and other specificities of real open spatial reactors. Since then, on the basis of this method, five additional reactions were shown to produce stationary reaction-diffusion patterns. To gain a clearer view on where our methodical approach on the patterning capacity of a reaction stands, numerical studies in conditions that mimic true open spatial reactors were made. In these numerical experiments, we explored the patterning capacity of Rabai's model for pH driven Landolt type reactions as a function of experimentally attainable parameters that control the main time and length scales. Because of the straightforward reversible binding of protons to carboxylate carrying polymer chains, this class of reaction is at the base of the chemistry leading to most of the stationary reaction-diffusion patterns presently observed. We compare our model predictions with experimental observations and comment on agreements and differences. PMID- 26117123 TI - Chimeras in globally coupled oscillatory systems: From ensembles of oscillators to spatially continuous media. AB - We study an oscillatory medium with a nonlinear global coupling that gives rise to a harmonic mean-field oscillation with constant amplitude and frequency. Two types of cluster states are found, each undergoing a symmetry-breaking transition towards a related chimera state. We demonstrate that the diffusional coupling is non-essential for these complex dynamics. Furthermore, we investigate localized turbulence and discuss whether it can be categorized as a chimera state. PMID- 26117124 TI - Three-dimensional convection-driven fronts of the exothermic chlorite tetrathionate reaction. AB - Horizontally propagating autocatalytic reaction fronts in fluids are often accompanied by convective motion in the presence of gravity. We experimentally and numerically investigate the stable complex three-dimensional pattern arising in the exothermic chlorite-tetrathionate reaction as a result of the antagonistic thermal and solutal contribution to the density change. By particle image velocimetry measurements, we construct the flow field that stabilizes the front structure. The calculations applied for incompressible fluids using the empirical rate-law model reproduce the experimental observations with good agreement. PMID- 26117125 TI - Interfacial hydrodynamic instabilities driven by cross-diffusion in reverse microemulsions. AB - When two microemulsions are put in contact in the gravity field along a horizontal contact line, cross-diffusion can trigger the transport of one species in the presence of a gradient in concentration of another species. We show here theoretically that such cross-diffusion effects can induce buoyancy-driven convective instabilities at the interface between two solutions of different compositions even when initially the less dense solution lies on top of the denser one. Two different sources of convective modes are identified depending whether positive or negative cross-diffusion is involved. We evidence the two predicted cross-diffusion driven instabilities experimentally using a two-layer stratification of Aerosol-OT (AOT) water-in-oil microemulsions solutions with different water or AOT composition. PMID- 26117126 TI - Inhibitory and excitatory pulse coupling of two frequency-different chemical oscillators with time delay. AB - Dynamical regimes of two pulse coupled non-identical Belousov-Zhabotinsky oscillators have been studied experimentally as well as theoretically with the aid of ordinary differential equations and phase response curves both for pure inhibitory and pure excitatory coupling. Time delay tau between a spike in one oscillator and perturbing pulse in the other oscillator plays a significant role for the phase relations of synchronous regimes of the 1:1 and 1:2 resonances. Birhythmicity between anti-phase and in-phase oscillations for inhibitory pulse coupling as well as between 1:2 and 1:1 resonances for excitatory pulse coupling have also been found. Depending on the ratio of native periods of oscillations T2/T1, coupling strength, and time delay tau, such resonances as 1:1 (with different phase locking), 2:3, 1:2, 2:5, 1:3, 1:4, as well as complex oscillations and oscillatory death are observed. PMID- 26117127 TI - pH-oscillations in the bromate-sulfite reaction in semibatch and in gel-fed batch reactors. AB - The simplest bromate oxidation based pH-oscillator, the two component BrO3(-) SO3(2-) flow system was transformed to operate under semibatch and closed arrangements. The experimental preconditions of the pH-oscillations in semibatch configuration were predicted by model calculations. Using this information as guideline large amplitude (DeltapH~3), long lasting (11-24 h) pH-oscillations accompanied with only a 20% increase of the volume in the reactor were measured when a mixture of Na2SO3 and H2SO4 was pumped into the solution of BrO3(-) with a very low rate. Batch-like pH-oscillations, similar in amplitude and period time appeared when the sulfite supply was substituted by its dissolution from a gel layer prepared previously in the reactor in presence of high concentration of Na2SO3. The dissolution vs time curve and the pH-oscillations in the semibatch and closed systems were successfully simulated. Due to the simplicity in composition and in experimental technique, the semibatch and batch-like BrO3(-) SO3(2-) pH-oscillators may become superior to their CSTR (continuous flow stirred tank reactor) version in some present and future applications. PMID- 26117128 TI - Nested arithmetic progressions of oscillatory phases in Olsen's enzyme reaction model. AB - We report some regular organizations of stability phases discovered among self sustained oscillations of a biochemical oscillator. The signature of such organizations is a nested arithmetic progression in the number of spikes of consecutive windows of periodic oscillations. In one of them, there is a main progression of windows whose consecutive number of spikes differs by one unit. Such windows are separated by a secondary progression of smaller windows whose number of spikes differs by two units. Another more complex progression involves a fan-like nested alternation of stability phases whose number of spikes seems to grow indefinitely and to accumulate methodically in cycles. Arithmetic progressions exist abundantly in several control parameter planes and can be observed by tuning just one among several possible rate constants governing the enzyme reaction. PMID- 26117129 TI - Compatible mechanism to characterize three independent but cross-coupled reactions of chlorite ion. AB - Individually proposed kinetic models of the key subsystems of the chlorite thiosulfate reaction, such as the hypochlorous acid-chlorite, tetrathionate chlorite, and tetrathionate-chlorine dioxide reactions, have been unified to be able to describe all the main characteristics of these systems simultaneously. A complex 38-step kinetic model is composed in which the subsystems are coupled by the necessary short-lived intermediates and such species that is products or reactants in one system but transients in the other. Such a cross-coupling between the individual systems as well as the sound agreement between the measured and calculated absorbance-time profiles in 367 experimental curves strongly validates the proposed kinetic model. PMID- 26117130 TI - Self-oscillating AB diblock copolymer developed by post modification strategy. AB - We prepared AB diblock copolymer composed of hydrophilic poly(ethylene oxide) segment and self-oscillating polymer segment. In the latter segment, ruthenium tris(2,2'-bipyridine) (Ru(bpy)3), a catalyst of the Belousov-Zhabotinsky reaction, is introduced into the polymer architecture based on N isopropylacrylamide (NIPAAm). The Ru(bpy)3 was introduced into the polymer segment by two methods; (i) direct random copolymerization (DP) of NIPAAm and Ru(bpy)3 vinyl monomer and (ii) post modification (PM) of Ru(bpy)3 with random copolymer of NIPAAm and N-3-aminopropylmethacrylamide. For both the diblock copolymers, a bistable temperature region (the temperature range; DeltaTm), where the block copolymer self-assembles into micelle at reduced Ru(bpy)3(2+) state whereas it breaks-up into individual polymer chain at oxidized Ru(bpy)3(3+) state, monotonically extends as the composition of the Ru(bpy)3 increases. The DeltaTm of the block copolymer prepared by PM is larger than that by DP. The difference in DeltaTm is rationalized from the statistical analysis of the arrangement of the Ru(bpy)3 moiety along the self-oscillating segments. By using the PM method, the well-defined AB diblock copolymer having DeltaTm (ca. 25 degrees C) large enough to cause stable self-oscillation can be prepared. The periodic structural transition of the diblock copolymer in a dilute solution ([Polymer] = 0.1 wt. %) is closely investigated in terms of the time-resolved dynamic light scattering technique at constant temperature in the bistable region. A macroscopic viscosity oscillation of a concentrated polymer solution (15 wt. %) coupled with the periodic microphase separation is also demonstrated. PMID- 26117131 TI - Collective and individual glycolytic oscillations in yeast cells encapsulated in alginate microparticles. AB - Yeast cells were encapsulated into alginate microparticles of a few hundred micrometers diameter using a centrifuge-based droplet shooting device. We demonstrate the first experimental results of glycolytic oscillations in individual yeast cells immobilized in this way. We investigated both the individual and collective oscillatory behaviors at different cell densities. As the cell density increased, the amplitude of the individual oscillations increased while their period decreased, and the collective oscillations became more synchronized, with an order parameter close to 1 (indicating high synchrony). We also synthesized biphasic-Janus microparticles encapsulating yeast cells of different densities in each hemisphere. The cellular oscillations between the two hemispheres were entrained at both the individual and population levels. Such systems of cells encapsulated into microparticles are useful for investigating how cell-to-cell communication depends on the density and spatial distribution of cells. PMID- 26117132 TI - Experimental, numerical, and mechanistic analysis of the nonmonotonic relationship between oscillatory frequency and photointensity for the photosensitive Belousov-Zhabotinsky oscillator. AB - The oscillation frequency of a nonlinear reaction system acts as a key factor for interaction and superposition of spatiotemporal patterns. To control and design spatiotemporal patterns in oscillatory media, it is important to establish the dominant frequency-related mechanism and the effects of external forces and species concentrations on oscillatory frequency. In the Ru(bipy)3(2+)-catalyzed Belousov-Zhabotinsky oscillator, a nonmonotonic relationship exists between light intensity and oscillatory frequency (I-F relationship), which is composed of fast photopromotion and slow photoinhibition regions in the oscillation frequency curve. In this work, we identify the essential mechanistic step of the I-F relationship: the previously proposed photoreaction Ru(II)* + Ru(II) + BrO3(-) + 3H(+) -> HBrO2 + 2Ru(III) + H2O, which has both effects of frequency-shortening and frequency-lengthening. The concentrations of species can shift the light intensity that produces the maximum frequency, which we simulate and explain with a mechanistic model. This result will benefit studies of pattern formation and biomimetic movement of oscillating polymer gels. PMID- 26117133 TI - Delayed feedback induced multirhythmicity in the oscillatory electrodissolution of copper. AB - Occurrence of bi- and trirhythmicities (coexistence of two or three stable limit cycles, respectively, with distinctly different periods) has been studied experimentally by applying delayed feedback control to the copper-phosphoric acid electrochemical system oscillating close to a Hopf bifurcation point under potentiostatic condition. The oscillating electrode potential is delayed by tau and the difference between the present and delayed values is fed back to the circuit potential with a feedback gain K. The experiments were performed by determining the period of current oscillations T as a function of (both increasing and decreasing) tau at several fixed values of K. With small delay times, the period exhibits a sinusoidal type dependence on tau. However, with relatively large delays (typically tau ? T) for each feedback gain K, there exists a critical delay taucrit above which birhythmicity emerges. The experiments show that for weak feedback, Ktaucrit is approximately constant. At very large delays, the dynamics becomes even more complex, and trirhythmicity could be observed. Results of numerical simulations based on a general kinetic model for metal electrodissolution were consistent with the experimental observations. The experimental and numerical results are also interpreted by using a phase model; the model parameters can be obtained from experimental data measured at small delay times. Analytical solutions to the phase model quantitatively predict the parameter regions for the appearance of birhythmicity in the experiments, and explain the almost constant value of Ktaucrit for weak feedback. PMID- 26117134 TI - Kuramoto transition in an ensemble of mercury beating heart systems. AB - We have studied, experimentally, the collective behavior of the electrically coupled autonomous Mercury Beating Heart (MBH) systems exhibiting the breathing mode, by varying both the coupling strength and the population size (from N = 3 to N = 16). For a fixed N, the electrical and the mechanical activities of the MBH systems achieve complete synchronization at different coupling strengths. The electrical activity of each MBH system is measured by the corresponding electrode potential (Ei = Vi). Additionally, the mechanical activity of each MBH oscillator is visually observed (snapshots and video clips). Subsequently, this activity is quantified by calculating the temporal variation in the area (Ai) of the Hg drop. As a result, the synchronization of the electrical (Ei = Vi) and the mechanical (Ai) activities can be measured. The extent of synchronization was quantified by employing the order parameter (r). Our experimental results are found to be in agreement with the Kuramoto theory. PMID- 26117135 TI - Characteristic oscillatory motion of a camphor boat sensitive to physicochemical environment. AB - A self-propelled camphor boat on water was investigated from the viewpoint of characteristic features of motion and mode-bifurcation depending on the diffusion length of camphor molecules. When a camphor disk was connected to the bottom of a larger plastic plate and then was placed on water, either oscillatory motion (repetition between rest and motion) or continuous motion was observed. In this paper, we report the novel features of this motion and mode-bifurcation as a function of the diffusion length of camphor molecules, e.g., multiple accelerations during oscillation, period-2 or irregular oscillatory motion, and reciprocating oscillation. These characteristic motion and mode-bifurcation are discussed in relation to the diffusion length of camphor molecules under the camphor boat and the development of camphor molecules from the camphor boat on water. PMID- 26117136 TI - Creation and perturbation of planar networks of chemical oscillators. AB - Methods for creating custom planar networks of diffusively coupled chemical oscillators and perturbing individual oscillators within the network are presented. The oscillators consist of the Belousov-Zhabotinsky (BZ) reaction contained in an emulsion. Networks of drops of the BZ reaction are created with either Dirichlet (constant-concentration) or Neumann (no-flux) boundary conditions in a custom planar configuration using programmable illumination for the perturbations. The differences between the observed network dynamics for each boundary condition are described. Using light, we demonstrate the ability to control the initial conditions of the network and to cause individual oscillators within the network to undergo sustained period elongation or a one-time phase delay. PMID- 26117137 TI - Complex mixed-mode oscillatory patterns in a periodically forced excitable Belousov-Zhabotinsky reaction model. AB - The Oregonator is the simplest chemically plausible model for the Belousov Zhabotinsky reaction. We investigate the response of the Oregonator to sinusoidal inputs with amplitudes and frequencies within plausible ranges. We focus on a regime where the unforced Oregonator is excitable (with no sustained oscillations). We use numerical simulations and dynamical systems tools to both characterize the response patterns and explain the underlying dynamic mechanisms. PMID- 26117140 TI - Disentangling the Longitudinal Relations of Race, Sex, and Socioeconomic Status, for Childhood Body Mass Index Trajectories. AB - OBJECTIVE: Race, sex, and socioeconomic status (SES) are associated with childhood obesity. The present research longitudinally examines these factors with 12,674 White and Black children from kindergarten through 8th grade. METHODS: Body mass index (BMI) data were collected and standardized at six time points (zBMI). Using Latent Growth Curve Modeling, race and sex were evaluated as moderators for the relation between SES and initial zBMI and rate of zBMI change. RESULTS: Higher SES significantly predicted higher initial zBMI for Black males and lower initial zBMI and rate of change for White males. A nonlinear relation between SES and zBMI was found for White females. CONCLUSIONS: SES has a differential impact on adiposity for different demographic groups. The longitudinal nature of the study and the focus on younger school-aged children provide important information regarding the complex interplay of race, sex, and SES for the prediction of childhood adiposity. PMID- 26117139 TI - The past, present and future of mitochondrial genomics: have we sequenced enough mtDNAs? AB - The year 2014 saw more than a thousand new mitochondrial genome sequences deposited in GenBank-an almost 15% increase from the previous year. Hundreds of peer-reviewed articles accompanied these genomes, making mitochondrial DNAs (mtDNAs) the most sequenced and reported type of eukaryotic chromosome. These mtDNA data have advanced a wide range of scientific fields, from forensics to anthropology to medicine to molecular evolution. But for many biological lineages, mtDNAs are so well sampled that newly published genomes are arguably no longer contributing significantly to the progression of science, and in some cases they are tying up valuable resources, particularly journal editors and referees. Is it time to acknowledge that as a research community we have published enough mitochondrial genome papers? Here, I address this question, exploring the history, milestones and impacts of mitochondrial genomics, the benefits and drawbacks of continuing to publish mtDNAs at a high rate and what the future may hold for such an important and popular genetic marker. I highlight groups for which mtDNAs are still poorly sampled, thus meriting further investigation, and recommend that more energy be spent characterizing aspects of mitochondrial genomes apart from the DNA sequence, such as their chromosomal and transcriptional architectures. Ultimately, one should be mindful before writing a mitochondrial genome paper. Consider perhaps sending the sequence directly to GenBank instead, and be sure to annotate it correctly before submission. PMID- 26117141 TI - Pioneers in Pediatric Psychology: Assisting the Developmental Progress of Pediatric Psychology. PMID- 26117143 TI - An empirical analysis of the financial benefits of health information exchange in emergency departments. AB - OBJECTIVE: To examine the impact of health information exchange (HIE) on reducing laboratory tests and radiology examinations performed in an emergency department (ED). MATERIALS AND METHODS: The study was conducted in an ED setting in Western New York over a period of 2 months. The care of the patients in the treatment group included an HIE query for every encounter, while the care of other patients in the control group did not include such queries. A group of medical liaisons were hired to query the medical history of patients from an HIE and provide it to the ED clinicians. Negative binomial regression was used to analyze the effects of HIE queries on the number of performed laboratory tests and radiology examinations. The log files of the HIE system since 1 year before the ED admission were used to analyze the differences in outcome measures between the 2 groups of patients. RESULTS: Ceteris paribus, HIE usage is associated with, respectively, 52% and 36% reduction in the expected total number of laboratory tests and radiology examinations ordered per patient at the ED. CONCLUSIONS: The results indicate that access to additional clinical data through the HIE will significantly reduce the number of laboratory tests and radiology examinations performed in the ED settings and thus support the ongoing HIE efforts. PMID- 26117142 TI - Dynamic software design for clinical exome and genome analyses: insights from bioinformaticians, clinical geneticists, and genetic counselors. AB - BACKGROUND: The transition of whole-exome and whole-genome sequencing (WES/WGS) from the research setting to routine clinical practice remains challenging. OBJECTIVES: With almost no previous research specifically assessing interface designs and functionalities of WES and WGS software tools, the authors set out to ascertain perspectives from healthcare professionals in distinct domains on optimal clinical genomics user interfaces. METHODS: A series of semi-scripted focus groups, structured around professional challenges encountered in clinical WES and WGS, were conducted with bioinformaticians (n = 8), clinical geneticists (n = 9), genetic counselors (n = 5), and general physicians (n = 4). RESULTS: Contrary to popular existing system designs, bioinformaticians preferred command line over graphical user interfaces for better software compatibility and customization flexibility. Clinical geneticists and genetic counselors desired an overarching interactive graphical layout to prioritize candidate variants--a "tiered" system where only functionalities relevant to the user domain are made accessible. They favored a system capable of retrieving consistent representations of external genetic information from third-party sources. To streamline collaboration and patient exchanges, the authors identified user requirements toward an automated reporting system capable of summarizing key evidence-based clinical findings among the vast array of technical details. CONCLUSIONS: Successful adoption of a clinical WES/WGS system is heavily dependent on its ability to address the diverse necessities and predilections among specialists in distinct healthcare domains. Tailored software interfaces suitable for each group is likely more appropriate than the current popular "one size fits all" generic framework. This study provides interfaces for future intervention studies and software engineering opportunities. PMID- 26117144 TI - The 'cotton wool' sign in paget's disease of the skull. PMID- 26117145 TI - Ultrasonic transducers based on undoped lead-free (K0.5Na0.5)NbO3 ceramics. AB - Lead zirconate titanate (PZT) ceramics are the dominant piezoelectric elements for non-destructive evaluation (NDE) and ultrasonic transducers devices. However, the presence of lead content may impose the scientific community to develop lead free ceramics, concerning human health and environmental safety. During the past ten years, many contributions have highlighted the potential properties of complex compositions like LiNbO3, LiTaO3 and LiSbO3 in the lead-free (K0.5Na0.5)NbO3 KNN system. In this context, for the first time, the practical applications and the effectiveness of simply undoped (K0.5Na0.5)NbO3 (KNN) ceramics are investigated. KNN powder is prepared by conventional solid state mixed oxide route. Ceramics of this material are prepared using conventional sintering (CS) and spark plasma sintering (SPS). Thickness coupling factor kt of 44-46%, planar coupling factor kp of 29-45%, relative permittivity at constant strain epsilon33,r(S) of 125-243 and acoustic impedance Z of 23-30 MRay are obtained for these two kinds of undoped KNN ceramics. Both ceramics are used to build single-element ultrasonic transducers. Relative bandwidth of 49-78% and insertion loss of -27 and -51dB are obtained for SPS and CS transducers, respectively. These results are suitable for use in non-destructive evaluation. The effectiveness of undoped KNN is evaluated using the KLM model, and compared to standard PZT based probe. Finally, chemical aging test of undoped KNN has demonstrated its stability in water. PMID- 26117146 TI - Small cell carcinoma of the lung in a treated case of Myoepithelial carcinoma of the tongue--report of a rare case with illustrated review of the literature. AB - Myoepithelial carcinoma has rarely been reported in the oral cavity and oropharynx. We found only 6 cases of myoepithelioma of the tongue reported till date. Two cases had a benign myoepithelioma; four had epithelial-Myoepithelial carcinoma. The present case had malignant myoepithelioma, a distinct entity from other histologies. PMID- 26117147 TI - A hospital-associated measles outbreak among individuals not targeted for vaccination in eastern China, 2014. AB - BACKGROUND: An outbreak of measles occurred in early 2014 among individuals not targeted for vaccination-adults, and infants too young to vaccinate, in Xiangshan County, Zhejiang Province, in eastern China. OBJECTIVE: We conducted an investigation to identify risk factors responsible for this outbreak and to provide evidence-based recommendations for measles elimination strategies in China. METHODS: Measles was diagnosed using national standard case definitions. In a case-control study, 20 randomly selected measles patients were matched with controls selected from the same village or community as each case in a 1:2 case to-control ratio. Controls were matched on age, within 5 years, and gender. We compared exposure histories during the 7-21 days before rash onset of the case and the same time period for the matched controls. We also conducted a measles antibody seroprevalence survey of a convenient sample of residual serum obtained from healthy patients during routine care in a hospital. RESULTS: The outbreak consisted of 45 measles cases, with an attack rate of 8.9/100,000 total population. Among cases, 91.1% (41/45) were adults (ranged 23-51 years) who had unknown vaccination histories; the other cases were infants younger than 8 months of age. The case-control study showed major risk factors to be a visit to Hospital X (OR(MH)=7.3, 95% CI: 1.8-30.7) and treatment in an IV room in Hospital X (OR(MH)=11.0, 95% CI: 1.3-96.1). The seroprevalence survey showed that 88.8% of adults had measles IgG antibodies, and that 100% of children 2-19 years of age were seropositive. CONCLUSIONS: The outbreak was primarily among age groups not targeted for vaccination-primarily adults, but with some children too young to vaccinate. Visiting a hospital was the major risk factor for measles transmission. We conclude that in addition to maintaining high 2-dose coverage with measles vaccine, working with hospital infection control programs to implement evidence-based strategies to prevent or limit hospital transmission is an important action for eliminating measles in eastern China. PMID- 26117149 TI - Reply to Letter to the Editor. PMID- 26117148 TI - Immune response in infants after universal high-dose hepatitis B vaccination: A community-based study in Beijing, China. AB - BACKGROUND: Vaccination of infants beginning at birth is recommended to prevent Hepatitis B virus (HBV) infection in China. Compared to 5 MUg/dose vaccine administered in other regions in China, a three-dose HB recombinant yeast vaccine at 10 MUg/dose has been administered for infants within 24h after birth, 1 month and 6 months of age in Beijing since 2006. In a community-based retrospective cohort study, factors influencing immunologic vaccine response were evaluated. METHODS: A total of 3670 infants who completed a 3-dose 10 MUg recombinant HB vaccine regimen and born to hepatitis B antigen negative mothers were included. The effect on anti-HBs titers of maternal nutrient status, infants' birth condition, growth factors, timeliness of vaccination, dosing interval and the interval until post-vaccination serologic testing (PVST) were evaluated. RESULTS: A total of 3666 infants with no markers of HBV infection were included in analysis. The mean anti-HB titers were 1767.17 mIU/ml. Only 16.9% of the infants completed their PVST within 30-59 days after the final dose of vaccination. Multivariate linear regression analysis showed that delay in PVST (beta=-0.097, p<0.0001) and maternal folic acid supplementation (beta=0.067, p=0.002) were associated with log-transformed anti-HB titers. Also a trend toward significant association was observed between the calcium supplementation of infants and log transformed anti-HBs titers (beta=0.062, p=0.057). Longer interval between dose 2 and dose 3 was not observed to increase the anti-HB titers after cofactors adjustment. CONCLUSIONS: Our findings illustrate the importance of timing of PVST to avoid unnecessary revaccination. Multi-center large cohort studies should verify the effect and magnitude of folate and calcium supplementation on HB vaccine response. PMID- 26117150 TI - Self-administration of intranasal influenza vaccine: Immunogenicity and volunteer acceptance. AB - BACKGROUND: In outbreak settings, mass vaccination strategies could maximize health protection of military personnel. Self-administration of live attenuated influenza vaccine (LAIV) may be a means to vaccinate large numbers of people and achieve deployment readiness while sparing the use of human resources. METHODS: A phase IV, open-label, randomized controlled trial evaluating the immunogenicity and acceptance of self-administered (SA) LAIV was conducted from 2012 to 2014. SA subjects were randomized to either individual self-administration or self administration in a group setting. Control randomized subjects received healthcare worker-administered (HCWA) LAIV. Anti-hemagglutinin (HAI) antibody concentrations were measured pre- and post-vaccination. The primary endpoint was immunogenicity non-inferiority between SA and HCWA groups. Subjects were surveyed on preferred administration method. RESULTS: A total of 1077 subjects consented and were randomized (529 SA, 548 HCWA). Subject characteristics were very similar between groups, though SA subjects were younger, more likely to be white and on active duty. The per-protocol analysis included 1024 subjects (501 SA, 523 HCWA). Post-vaccination geometric mean titers by vaccine strain and by study group (HCWA vs. SA) were: A/H1N1 (45.8 vs. 48.7, respectively; p=0.43), A/H3N2 (45.5 vs. 46.4; p=0.80), B/Yamagata (17.2 vs. 17.8; p=0.55). Seroresponses to A components were high (~67%), while seroresponses to B components were lower (~25%). Seroresponse did not differ by administration method. Baseline preference for administration method was similar between groups, with the majority in each group expressing no preference. At follow-up, the majority (64%) of SA subjects preferred SA vaccine. CONCLUSIONS: LAIV immunogenicity was similar for HCWA and SA vaccines. SA was well-tolerated and preferred to HCWA among those who performed SA. PMID- 26117151 TI - Chinese border disease virus strain JSLS12-01 infects piglets and down-regulates the antibody responses of classical swine fever virus C strain vaccination. AB - During 2012 and 2013, several border disease virus (BDV) strains were identified from Chinese goat and sheep herds. At the same time, pigs from the same areas were found to be seropositive to BDV by ELISA, without showing clinical signs (unpublished data). To examine the susceptibility of pigs to the Chinese BDV strains, BDV isolate JSLS12-01, isolated from naturally infected sheep, was used to infect pigs. Antibody responses, viremia, clinical signs and pathological changes of the infected animals were examined. It confirmed that the current BDV strain could infect the domestic pigs, the animals showed viremia during 4 to 14 days post infection (dpi) and sero-conversion from 14dpi; no clinical and pathological changes were observed. In addition, CSFV maternal antibody did not influence BDV infection. Subsequently, pigs were infected with the BDV isolate and vaccinated with Hog cholera lapinized virus (HCLV) 21 days later to determine the effect of BDV infection on antibody induction of CSFV vaccination. The specific CSFV antibody and neutralizing antibody titers of the BDV infected group remained negative after the primary vaccination. Even after the boost vaccination, they were still significantly lower than those of the uninfected groups (p<0.05). These results indicated that BDV infection could down-regulate the antibody responses of CSFV C-strain vaccination. It should be paid attention that BDV prevalence in pig herds and in live vaccines might hamper the vaccination of CSF. PMID- 26117152 TI - Deoxynivalenol (DON) naturally contaminated feed impairs the immune response induced by porcine reproductive and respiratory syndrome virus (PRRSV) live attenuated vaccine. AB - Cereal commodities are frequently contaminated with mycotoxins produced by the secondary metabolism of fungal infection. Among these contaminants, deoxynivalenol (DON), also known as vomitoxin, is the most prevalent type B trichothecene mycotoxin worldwide. Pigs are very sensitive to the toxic effects of DON and are frequently exposed to naturally contaminated feed. Recently, DON naturally contaminated feed has been shown to decrease porcine reproductive and respiratory syndrome virus (PRRSV) specific antibody responses following experimental infection. The objective of this study was to determine the impact of DON naturally contaminated feed on the immune response generated following vaccination with PRRSV live attenuated vaccine. Eighteen pigs were randomly divided into three experimental groups of 6 animals based on DON content of the diets (0, 2.5 and 3.5mg DON/kg). They were fed these rations one week prior to the vaccination and for all the duration of the immune response evaluation. All pigs were vaccinated intra-muscularly with one dose of Ingelvac((r)) PRRSV modified live vaccine (MLV). Blood samples were collected at day -1, 6, 13, 20, 27 and 35 post vaccination (pv) and tested for PRRSV RNA by RT-qPCR and for virus specific antibodies by ELISA. Results showed that ingestion of DON-contaminated diets significantly decreased PRRSV viremia. All pigs fed control diet were viremic while only 1 (17%) and 3 (50%) out of 6 pigs were viremic in the groups receiving 3.5 and 2.5mg of DON/kg, respectively. Subsequently, all pigs fed control diet developed PRRSV specific antibodies while only viremic pigs that were fed contaminated diets have developed PRRSV specific antibodies. These results suggest that feeding pigs with DON-contaminated diet could inhibit vaccination efficiency of PRRSV MLV by severely impairing viral replication. PMID- 26117153 TI - Posture modulates implicit hand maps. AB - Several forms of somatosensation require that afferent signals be informed by stored representations of body size and shape. Recent results have revealed that position sense relies on a highly distorted body representation. Changes of internal hand posture produce plastic alterations of processing in somatosensory cortex. This study therefore investigated how such postural changes affect implicit body representations underlying position sense. Participants localised the knuckles and tips of each finger in external space in two postures: the fingers splayed (Apart posture) or pressed together (Together posture). Comparison of the relative locations of the judgments of each landmark were used to construct implicit maps of represented hand structure. Spreading the fingers apart produced increases in the implicit representation of hand size, with no apparent effect on hand shape. Thus, changes of internal hand posture produce rapid modulation of how the hand itself is represented, paralleling the known effects on somatosensory cortical processing. PMID- 26117154 TI - Mutual interferences between automatic ongoing spatial-updating with self-motion and source recall. AB - Recent models suggest that spatial updating of position with self-motion is a key component of remembering. In the first experiment, participants simultaneously performed a spatial task and a source recall. In the spatial task, blindfolded participants rotated to a new orientation and then pointed to an object's position. They pointed either from their new orientation (in the updating condition), or as if they were still in their starting orientation (in the ignoring condition). In the updating condition, participants had to accurately integrate their own movement whereas, in the ignoring condition, they had to ignore it. If spatial updating and episodic memory rely on the same network, only the updating condition should interfere with source recall. Results are in line with this prediction. A second experiment using a semantic memory task instead of source recall showed no interference effect. These results suggest that episodic memory and spatial updating are functionally linked. PMID- 26117155 TI - Towards continuous glucose monitoring in the ICU. PMID- 26117156 TI - Clarifying the role of pattern separation in schizophrenia: the role of recognition and visual discrimination deficits. AB - Patients with schizophrenia show marked memory deficits which have a negative impact on their functioning and life quality. Recent models suggest that such deficits might be attributable to defective pattern separation (PS), a hippocampal-based computation involved in the differentiation of overlapping stimuli and their mnemonic representations. One previous study on the topic concluded in favour of pattern separation impairments in the illness. However, this study did not clarify whether more elementary recognition and/or visual discrimination deficits could explain observed group differences. To address this limitation we investigated pattern separation in 22 schizophrenic patients and 24 healthy controls with the use of a task requiring individuals to classify stimuli as repetitions, novel or similar compared to a previous familiarisation phase. In addition, we employed a visual discrimination task involving perceptual similarity judgments on the same images. Results revealed impaired performance in the patient group; both on baseline measure of pattern separation as well as an index of pattern separation rigidity. However, further analyses demonstrated that such differences could be fully explained by recognition and visual discrimination deficits. Our findings suggest that pattern separation in schizophrenia is predicated on earlier recognition and visual discrimination problems. Furthermore, we demonstrate that future studies on pattern separation should include appropriate measures of recognition and visual discrimination performance for the correct interpretation of their findings. PMID- 26117157 TI - Effect of lurasidone dose on cognition in patients with schizophrenia: post-hoc analysis of a long-term, double-blind continuation study. AB - We previously reported that treatment with 160mg/d of lurasidone improved cognitive performance in a manner superior to placebo, quetiapine XR 600mg/d, and lurasidone 80mg/d, based on a 6-week randomized trial of patients with an acute exacerbation of schizophrenia. The objective of this post-hoc analysis was to explore the cognitive and functional performance of patients whose final doses of lurasidone were 40/80mg/d, 120mg/d, and 160mg/d compared to quetiapine XR 200 800mg/d (QXR) during a 6-month, double-blind continuation study that followed a short-term trial. Subjects who received final doses of lurasidone 120mg/d (n=77) and 160mg/d (n=49) showed significantly greater improvement in overall cognitive performance compared to QXR (n=85) at week 32 (month 6 of the extension study), while those on last doses of 40/80mg/d (n=25) showed a trend towards significance at week 32. Mean changes in neurocognitive composite z-score from pre-treatment baseline were significant for the 3 lurasidone final dose groups at both weeks 19 and 32, with composite change scores of z=1.53, z=1.43, and z=1.34 for the lurasidone 40/80mg/d, 120mg/d, and 160mg/d, respectively, at week 32. In contrast, the composite change score was not statistically significant in the overall quetiapine group (z=0.46), with none of the individual quetiapine doses showing any significant improvement. Functional capacity scores improved in all treatment groups. Our findings indicate improved cognitive performance in patients treated with each of the flexible doses of lurasidone 40-160mg/d, compared to quetiapine XR 200-800mg/d. All doses of lurasidone were superior to all doses of quetiapine for cognitive performance. PMID- 26117158 TI - A new chapter in therapy for cystic fibrosis. PMID- 26117159 TI - The effect of reduced ankle dorsiflexion on lower extremity mechanics during landing: A systematic review. AB - OBJECTIVES: To examine the evidence for effect of restricted ankle dorsiflexion range of motion on lower-extremity landing mechanics. DESIGN: Literature review. METHODS: Systematic search of the literature. Articles critiqued by two reviewers. RESULTS: Six studies were identified that investigated the effect of restricted DF ROM on landing mechanics. Overall, results suggest that landing mechanics are altered with restricted DF ROM, but studies disagree as to the particular mechanical variables affected. CONCLUSIONS: There is evidence that restricted dorsiflexion range of motion may alter lower-extremity landing mechanics in a manner, which predisposes athletes to injury. Interpretation of results was made difficult by the variation in landing tasks investigated and the lack studies investigating sport-specific landing tasks. The focus of studies on specific mechanical variables rather than mechanical patterns and the analysis of pooled data in the presence of different compensation strategies between participants also made interpretation difficult. These areas require further research. PMID- 26117160 TI - Factors affecting exercise intensity in professional rugby league match-play. AB - OBJECTIVES: To examine the effects of match-related and individual player characteristics on running performance in professional rugby league matches. DESIGN: Longitudinal observational study. METHODS: Global positioning system (GPS) and technical performance measures (attacking involvements and tackles made) were collected from 23 players competing in the National Rugby League (NRL) over 24 matches during a season. The GPS data were categorised into relative total distance (mmin(-1)) and relative high-speed running distance (HSR mmin(-1), >14.4kmh(-1)). Each match was classified according to season phase, location, recovery length, opposition strength and result. Individual player fitness status was obtained from a 1.2-km shuttle run test conducted prior to the start of the season. Two separate linear mixed models were constructed to examine the influence of match-related and individual player characteristics on relative total and HSR distances. RESULTS: Matches played away from home, early in the season and following short recovery cycles were associated with reduced relative total and HSR distances. Matches won contained less relative total and HSR distance; whereas only HSR distance was higher against weaker opposition. The total time the ball was out of play reduced relative total but not HSR distances. The number of defensive but not attacking involvements influenced both physical performance measures. Finally, player fitness was positively related to both relative total and HSR distances. CONCLUSIONS: There appears to be a complex interplay of factors affecting match-running performance in rugby league. The results underline the importance of considering contextual factors when analysing rugby league match-activity profiles. PMID- 26117161 TI - The effectiveness of massage based on the tensegrity principle compared with classical abdominal massage performed on patients with constipation. AB - PURPOSE OF THE RESEARCH: The purpose of the study was to compare the effectiveness of massage based on the tensegrity principle and classical abdominal massage performed on patients with constipation. MATERIALS AND METHODS: The study group consisted of 29 subjects with a pre-existing diagnosis of constipation based on the Rome III criteria. The patients were divided into two groups: the first group was made up of 15 patients who underwent tensegrity massage (average age: 59.8 years), and the second was made up of 14 patients who were given classical abdominal massage (average age: 55.7 years). The study consisted of six massage sessions in both groups, with two sessions per week performed over 21 days. The assessment was based on a patient questionnaire, the Rome III questionnaire and a diary of bowel movements. The results were analyzed before therapy, after one week of therapy and after the third (final) week of therapy. RESULTS: Changes in the number of defecations were compared between the two groups; the biggest changes occurred in the first and third week of therapy (P<0.01, calculated by the Mann-Whitey test). As a result of the therapy, tension during defecation dropped from 60% to 20% in Group I, and from 42.8% to 35.7% in Group II. The influence of the applied therapy was evaluated positively by 80% of the tensegrity massage group and 29% of the classical abdominal massage group. CONCLUSIONS: Massage based on the tensegrity principle may have a greater positive influence on the quality and quantity of bowel movements than classical abdominal massage. PMID- 26117162 TI - Biomechanical comparison of traditional anchors to all-suture anchors in a double row rotator cuff repair cadaver model. AB - BACKGROUND: To further reduce the invasiveness of arthroscopic rotator cuff repair surgery the all-suture anchor has been developed. The all-suture anchor requires less bone removal and reduces the potential of loose body complications. The all-suture anchor must also have adequate biomechanical strength for the repair to heal. The hypothesis is there is no significant difference in the biomechanical performance of supraspinatus repairs using an all-suture anchor when compared to traditional solid-body suture anchors. METHODS: Using nine shoulders per group, the supraspinatus tendon was dissected from the greater tuberosity. The four different double row repairs tested were (medial row/lateral row): A: ICONIX2/ICONIX2; B: ICONIX2/Stryker ReelX 3.9mm; C: ICONIX2/Stryker ReelX 4.5mm; D: Arthrex BioComposite CorkScrew FT 4.5mm/Arthrex BioComposite SwiveLock 4.75mm. The ICONIX2 was the only all-suture anchor tested. Tendons underwent cyclic loading from 10 to 100N for 500 cycles, followed by load-to failure. Data was collected at cycles 5, 100, 200, 300, 400, and 500. One-way ANOVA analysis was used to assess significance (P<=0.05). FINDINGS: The anchor combinations tested did not differ significantly in anterior (P>0.4) or posterior (P>0.3) gap formation, construct stiffness (P>0.7), ultimate load (P=0.06), or load to 5mm gap formation (P=0.84). INTERPRETATION: The all-suture anchor demonstrated comparable biomechanical performance in multiple double-row anchor combinations to a combination of traditional solid-body anchors. Thus it may be an attractive option to further reduce the invasiveness of rotator cuff repairs. PMID- 26117163 TI - Does component alignment affect gait symmetry in unilateral total hip arthroplasty patients? AB - BACKGROUND: Component malposition in total hip arthroplasty patients has been associated with adverse clinical outcomes. However, whether the component alignment influences hip dynamic performance following total hip arthroplasty remains unclear. The purpose of this study was to investigate the relationship between the component alignment and in vivo hip kinematics during gait. METHODS: Nineteen unilateral total hip arthroplasty patients received CT scan for creation of 3D hip models. The component alignment between the non-implanted and implanted hips were measured and compared. Three-dimensional hip kinematics for both hips of the total hip arthroplasty patients during gait was quantified using a dual fluoroscopic imaging technique. The differences between the implanted and non implanted hip kinematics during gait were calculated. A forward stepwise multiple linear regression was performed to evaluate the relationships between the changes in implanted hip kinematics and the differences in component alignment with respect to the non-implanted hips. FINDINGS: An average 5.1 degrees (SD 6.5 degrees ; range -11.1 degrees to 18.3 degrees ) increase in internal rotation was observed in the implanted hip than the contralateral non-implanted hip and significantly correlated with a linear combination of the increase of cup anteversion, cup medial translation and leg lengthening (R=0.81). INTERPRETATION: Results suggested that the total hip arthroplasty patients compensated the changes in hip geometry by altering the dynamic movement during gait. Restoration of the native hip geometry, including acetabular cup anteversion, position and leg length could be one of the factors that influence the hip kinematics symmetry in total hip arthroplasty patients during gait. PMID- 26117164 TI - Does implicit emotion regulation in binge eating disorder matter? AB - OBJECTIVE: To examine if implicit emotion regulation (occurring outside of awareness) is related to binge eating disorder (BED) symptomatology and explicit emotion regulation (occurring within awareness), and can be altered via intervention. METHODS: Implicit emotion regulation was assessed via the Emotion Conflict Task (ECT) among a group of adults with BED. Study 1 correlated BED symptomatology and explicit emotion regulation with ECT performance at baseline (BL) and after receiving BED treatment (PT). Study 2 generated effect sizes comparing ECT performance at BL and PT with healthy (non-eating disordered) controls (HC). RESULTS: Study 1 yielded significant correlations (p<.05) between both BED symptomatology and explicit emotion regulation with ECT performance. Study 2 found that compared to BL ECT performance, PT shifted (d=-.27), closer to HC. Preliminary results suggest a) BED symptomatology and explicit emotion regulation are associated with ECT performance, and b) PT ECT performance normalized after BED treatment. CONCLUSIONS: Implicit emotion regulation may be a BED treatment mechanism because psychotherapy, directly or indirectly, decreased sensitivity to implicit emotional conflict. Further understanding implicit emotion regulation may refine conceptualizations and effective BED treatments. PMID- 26117165 TI - Preeclampsia and future cardiovascular disease in women: How good are the data and how can we manage our patients? AB - Women with a history of preeclampsia have double the risk of future heart disease and stroke, and elevated risks of hypertension and diabetes. The American Heart Association (AHA) and the American College of Obstetrics and Gynecology now include preeclampsia as a risk factor for future cardiovascular disease (CVD) with the recommendation of obtaining a history of preeclampsia and improving lifestyle behaviors for women with such a history. Research has progressed from asking whether preeclampsia is associated with CVD to how preeclampsia is associated with CVD, and the implications for prevention of CVD among women with a history of preeclampsia. A history of preeclampsia "unmasks" future CVD risk; research is inconclusive whether it also causes vascular damage that leads to CVD. For women with prior preeclampsia, the AHA recommends CVD risk reduction actions similar to those for other "at risk" groups: cessation of cigarette smoking, physical activity, weight reduction if overweight or obese and counseling to follow a "DASH" like diet. The efficacy of these lifestyle modifications to lower risk of CVD in women with prior preeclampsia remains to be determined. Barriers exist to implementing lifestyle improvement measures in this population, including lack of awareness of both patients and clinicians of this link between preeclampsia and CVD. We review patient, provider, and systems level barriers and solutions to leverage this information to prevent CVD among women with a history of preeclampsia. PMID- 26117166 TI - Development of a sleeve gastrectomy risk calculator. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is rapidly gaining popularity. Estimating the risk of postoperative adverse events can improve surgical decision making and informed patient consent. The objective of this study was to develop and validate a risk prediction model for early postoperative morbidity and mortality after LSG. METHODS: Cases of primary LSG in the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) data set at year 2012 (n = 5871) and 2011 (n = 3130) were identified to develop and examine the validity of model. The composite primary outcome was defined as presence of any of 14 serious adverse events within the 30-days after LSG. Multiple logistic regression analysis was performed and a risk calculator was created to predict the primary outcome. RESULTS: Thirty-day postoperative mortality and composite adverse events rates of 5871 LSG cases were .05% and 2.4%, respectively. Of the 52 examined baseline variables, the final model contained history of congestive heart failure (odds ratio [OR] 6.23; 95% CI 1.25-31.07), chronic steroid use (OR 5.00; 95% CI 2.06-12.15), male sex (OR 1.68; 95% CI 1.03-2.72), diabetes (OR 1.62; 95% CI 1.07-2.48), preoperative serum total bilirubin level (OR 1.57; 95% CI 1.11-2.22), body mass index (OR 1.03; 95% CI 1.01-1.05), and preoperative hematocrit level (OR .95; 95% CI .89-1.00). The risk model was then validated with the 2011 data set and was used to create an online risk calculator with a relatively good accuracy (c-statistic .682). CONCLUSIONS: This risk assessment scoring system, which specifically estimates serious adverse events after LSG, can contribute to surgical decision-making, informed patient consent, and prediction of surgical risk for patients and referring physicians. PMID- 26117167 TI - Enhanced recovery protocols--time to trim and adopt a lean bariatric practice. PMID- 26117168 TI - Laparoscopic conversion of an omega loop gastric bypass to Roux-en-Y gastric bypass. PMID- 26117169 TI - Phylogenetic analysis of the complete mitogenome sequence of the raspberry weevil, Aegorhinus superciliosus (Coleoptera: Curculionidae), supports monophyly of the tribe Aterpini. AB - The superfamily Curculionoidea is one of the most diverse groups of insects in the world, including many species which are crop pests. Within this group, the native raspberry weevil, Aegorhinus superciliosus (Guerin, 1830), is an important pest in blueberry and raspberry fields in southern South America. Using a 454 sequencing approach, we sequenced and annotated the mitogenome of A. superciliosus, it, providing the first such information for any species in the tribe Aterpini, subfamily Cyclominae. The assembled mitogenome is a circular DNA molecule 15,121bp in length containing all 37 genes normally found in metazoans. Mitogenome organization and transcriptional orientation in A. superciliosus showed the same pattern that characterizes the suborder Polyphaga. Bayesian and Maximum Likelihood phylogenetic analyses supported the monophyly of the tribe Aterpini and the subfamily Cyclominae, recovering this clade in a sister group relationship with Entiminae and Hyperinae. The monophyly of these three subfamilies defines a critical transition to an ectophagous lifestyle in the larvae, from an ancestrally endophagous larval lifestyle in all other lineages. The sequenced mitogenome of A. superciliosus can provide basic data for future studies investigating population history, molecular systematics, stress ecophysiology and phylogeography. PMID- 26117170 TI - Identification of differentially expressed microRNA in the stems and leaves during sugar accumulation in sweet sorghum. AB - MicroRNAs (miRNAs) have been shown to play important roles in plant development, growth and stress response. Sweet sorghum [Sorghum bicolor (L.) Moench] is an important source of bioenergy due to the high sugar content in its stems. However, it is not clear how the miRNA is involved in sugar accumulation in sorghum stems. In order to identify the miRNAs in the stems and the leaves of sweet sorghum, we extracted RNAs of the stems and leaves of sweet sorghum (Rio) and grain sorghum (BTx623) at the heading and dough stages for high-throughput sequencing. A total of 179279048 reads were obtained from Illumina-based sequencing. Further analysis identified nine known miRNAs and twelve novel miRNAs that showed significantly and specifically differentially expressed in the stems of sweet sorghum. The target genes of the differentially expressed novel miRNAs include the transcription factor, glucosyltransferase, protein kinase, cytochrome P450, transporters etc. GO enrichment analysis showed that the predicted targets of these differentially expressed miRNAs participated in diverse physiological and metabolic processes. We performed RT-qRCR analysis on these miRNAs across eight different libraries to validate the miRNAs. Finally, we screened stem specifically expressed novel miRNA and a leaf-specifically expressed novel miRNA in sweet sorghum comparing with grain sorghum. Our results provide a basis for further investigation of the potential role of these individual miRNAs in sugar accumulation. PMID- 26117171 TI - Identifying genes related with rheumatoid arthritis via system biology analysis. AB - Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease that mainly attacks synovial joints. However, the underlying systematic relationship among different genes and biological processes involved in the pathogenesis are still unclear. By analyzing and comparing the transcriptional profiles from RA, OA (osteoarthritis) patients as well as ND (normal donors) with bioinformatics methods, we tend to uncover the potential molecular networks and critical genes which play important roles in RA and OA development. Initially, hierarchical clustering was performed to classify the overall transcriptional profiles. Differentially expressed genes (DEGs) between ND and RA and OA patients were identified. Furthermore, PPI networks were constructed, functional modules were extracted, and functional annotation was also applied. Our functional analysis identifies 22 biological processes and 2 KEGG pathways enriched in the commonly regulated gene set. However, we found that number of set of genes differentially expressed genes only between RA and ND reaches up to 244, indicating this gene set may specifically accounts for processing to disease of RA. Additionally, 142 biological processes and 19 KEGG pathways are over-represented by these 244 genes. Meanwhile, although another 21 genes were differentially expressed only in OA and ND, no biological process nor pathway is over-represented by them. PMID- 26117172 TI - The mitochondrial genome of a Texas outbreak strain of the cattle tick, Rhipicephalus (Boophilus) microplus, derived from whole genome sequencing Pacific Biosciences and Illumina reads. AB - The cattle fever tick, Rhipicephalus (Boophilus) microplus is one of the most significant medical veterinary pests in the world, vectoring several serious livestock diseases negatively impacting agricultural economies of tropical and subtropical countries around the world. In our study, we assembled the complete R. microplus mitochondrial genome from Illumina and Pac Bio sequencing reads obtained from the ongoing R. microplus (Deutsch strain from Texas, USA) genome sequencing project. We compared the Deutsch strain mitogenome to the mitogenome from a Brazilian R. microplus and from an Australian cattle tick that has recently been taxonomically designated as Rhipicephalus australis after previously being considered R. microplus. The sequence divergence of the Texas and Australia ticks is much higher than the divergence between the Texas and Brazil ticks. This is consistent with the idea that the Australian ticks are distinct from the R. microplus of the Americas. PMID- 26117173 TI - Distinct differences in global gene expression profiles in non-implanted blastocysts and blastocysts resulting in live birth. AB - Results from animal models points towards the existence of a gene expression profile that is distinguishably different in viable embryos compared with non viable embryos. Knowledge of human embryo transcripts is however limited, in particular with regard to how gene expression is related to clinical outcome. The purpose of the present study was therefore to determine the global gene expression profiles of human blastocysts. Next Generation Sequencing was used to identify genes that were differentially expressed in non-implanted embryos and embryos resulting in live birth. Three trophectoderm biopsies were obtained from morphologically high quality blastocysts resulting in live birth and three biopsies were obtained from non-implanting blastocysts of a comparable morphology. Total RNA was extracted from all samples followed by complete transcriptome sequencing. Using a set of filtering criteria, we obtained a list of 181 genes that were differentially expressed between trophectoderm biopsies from embryos resulting in either live birth or no implantation (negative hCG), respectively. We found that 37 of the 181 genes displayed significantly differential expression (p<0.05), e.g. EFNB1, CYTL1 and TEX26 and TESK1, MSL1 and EVI5 in trophectoderm biopsies associated with live birth and non-implanting, respectively. Out of the 181 genes, almost 80% (145 genes) were up-regulated in biopsies from un-implanted embryos, whereas only 20% (36 genes) showed an up regulation in the samples from embryos resulting in live birth. Our findings suggest the presence of molecular differences visually undetectable between implanted and non-implanted embryos, and represent a proof of principle study. PMID- 26117174 TI - Prevalence and screening for risk factors of type 2 diabetes in Rize, Nourtheast Turkey: findings from a population-based study. AB - AIMS: We aimed to determine the prevalence of diagnosed and undiagnosed diabetes, risk factors affecting the healthy population, and factors that increase diabetes risk in the adult northeast Turkish population. METHODS: Using population proportional cluster sampling, 930 adults were selected. After excluding people with diabetes, risk screening was conducted in the healthy population (n: 825) using the Information Form and FINDRISK questionnaire. Fasting venous blood and biochemical parameters were measured. RESULTS: Prevalence of diabetes was 13.6% (new % 2.3), translating to approximately 44 thousand adults. Among the healthy population, 37.5% had high risk. Prevalence of not exercising (78.2%), obesity (36.1%), and hypertension (24.5%) were high. Predictors of risk of diabetes were aging (OR 1.09), low education (OR 0.51), familial diabetes history (OR 15.27), not exercising (OR 0.41), obesity (OR 5.17), high waist circumference (OR 1.05), heart disease (OR 4.81), and hypertension (OR 2.60). CONCLUSIONS: This study can stimulate early screening for cardiovascular diseases and hypertension and initiating aggressive treatments in people with high diabetes risk. In primary health services, number of doctors and nurses trained in diabetes should be increased and dieticians should be involved. People with high risk should receive lifestyle regulations training. PMID- 26117176 TI - Thrombolysis in acute stroke: ongoing challenges based on a tertiary hospital audit and comparisons with other Australian studies. AB - OBJECTIVE: Intravenous thrombolysis with tissue plasminogen activator (tPA) improves patient outcomes in acute ischaemic stroke. Because its benefit is time dependant, treatment delays must be minimised. The aim of the present study was to review patient characteristics, timeliness of tPA delivery and clinical outcome in patients receiving t-PA in a tertiary hospital stroke unit in Queensland, and to compare the findings with those of other Australian studies. METHODS: The present study was a retrospective study conducted between 1 January 2010 and 31 December 2012. Information was collected regarding demographics, stroke characteristics, timeliness of tPA delivery, clinical outcome, safety outcome and protocol deviation. RESULTS: Of 490 patients admitted with ischaemic stroke, 57 (11.6%) received tPA. Compared with other studies, the patients in the present study had more severe stroke (median National Institutes of Health Stroke Scale (NIH SS) score), more cardioembolic strokes and more patients receiving tPA between 3 and 4.5 h of symptoms onset. Median symptom onset to treatment time was 175 min and median door to needle time was 97 min. At 3 months, 21.1% of patients had died and 41.5% had a favourable outcome (modified Rankin scale <= 2). Symptomatic intracerebral haemorrhage occurred in 5.3% of patients and protocol deviations occurred in 21.1%. Overall, delivery and outcomes of tPA at the Princess Alexandra Hospital were comparable to those reported in other Australian studies of usual care. Several challenges and strategies for optimal thrombolysis were identified, with supporting evidence from selected Australian sites. CONCLUSION: The proportion of eligible stroke patients who receive tPA in a timely manner remains less than ideal at our centre. More accurate patient selection and reductions in treatment delays serve as targets for quality improvement efforts that have broad applicability. PMID- 26117175 TI - Characterization of degenerative human facet joints and facet joint capsular tissues. AB - OBJECTIVE: Lumbar facet joint degeneration (FJD) may be an important cause of low back pain (LBP) and sciatica. The goal of this study was to characterize cellular alterations of inflammatory factor expression and neovascularization in human degenerative facet joint capsular (FJC) tissue. These alterations in FJC tissues in pain stimulation were also assessed. DESIGN: FJs were obtained from consented patients undergoing spinal reconstruction surgery and cadaveric donors with no history of back pain. Histological analyses of the FJs were performed. Cytokine antibody array and quantitative real-time polymerase chain reaction (qPCR) were used to determine the production of inflammatory cytokines, and western blotting analyses (WB) were used to assay for cartilage-degrading enzymes and pain mediators. Ex vivo rat dorsal root ganglion (DRG) co-culture with human FJC tissues was also performed. RESULTS: Increased neovascularization, inflammatory cell infiltration, and pain-related axonal-promoting factors were observed in degenerative FJCs surgically obtained from symptomatic subjects. Increased VEGF, (NGF/TrkA), and sensory neuronal distribution were also detected in degenerative FJC tissues from subjects with LBP. qPCR and WB results demonstrated highly upregulated inflammatory cytokines, pain mediators, and cartilage-degrading enzymes in degenerative FJCs. Results from ex vivo co-culture of the DRG and FJC tissue demonstrated that degenerative FJCs increased the expression of inflammatory pain molecules in the sensory neurons. CONCLUSION: Degenerative FJCs possess greatly increased inflammatory and angiogenic features, suggesting that these factors play an important role in the progression of FJD and serve as a link between joint degeneration and neurological stimulation of afferent pain fibers. PMID- 26117177 TI - Sire carcass breeding values affect body composition in lambs - 1. Effects on lean weight and its distribution within the carcass as measured by computed tomography. AB - Data are obtained from computed tomography scanning of 1665 lambs at locations around Australia. Lambs were progeny of Terminal, Maternal and Merino sires with known Australian Sheep Breeding Values for post weaning c-site eye muscle depth (mm; PEMD) and fat depth (mm; PFAT), and post weaning weight (kg; PWWT). Across the 7.8 unit range of sire PEMD, carcass lean weight increased by 7.7%. This lean was distributed to the saddle section (mid-section) where lean became 3.8% heavier, with fore section lean becoming 3.5% lighter. Reducing sire PFAT across its 5.1 unit range increased carcass lean weight by 9.5%, and distributed lean to the saddle section which was 3.7% heavier. Increasing sire PWWT increased lean at some sites in some years, and on average increased saddle lean by 4% across the 24.7 unit PWWT range. Changes in lean weight and distribution due to selection for carcass breeding values will increase carcass value, particularly through increased weight of high value loin cuts. PMID- 26117178 TI - High-risk metachronous polyps are more frequent in patients with traditional serrated adenomas than in patients with conventional adenomas: a multicenter prospective study. AB - BACKGROUND AND AIMS: Although the malignant progression of serrated polyps has been clearly documented, the malignant potential of the traditional serrated adenoma (TSA) subtype has not been established. We compared the prevalence of metachronous polyps in surveillance colonoscopies between patients with TSA and those with conventional adenomas (CAs). METHODS: Four hundred twenty patients were diagnosed with TSAs by current diagnostic criteria at 10 tertiary care university hospitals in Korea from January 2003 to December 2005; 186 patients who received surveillance colonoscopy after removal of initial polyps were enrolled. During the same time period, 372 age- and sex-matched patients diagnosed with CAs were used as a control group. RESULTS: TSA patients had a significantly higher recurrence rate of colorectal polyps compared with CA patients (66.1% vs 43.5%, respectively). TSA patients had a greater number (3 vs 2) and larger size (8.6 +/- 5.7 vs 6.3 +/- 5.2 mm) of recurrent polyps compared with CA patients. TSA patients also had a higher rate of CA (54.8% vs 37.9%), serrated adenoma (14.0% vs. 0.8%), and hyperplastic polyp (33.3% vs. 13.7%) recurrence compared with CA patients. TSA patients had significantly greater odds of having a recurrent high-risk polyp than CA patients (odds ratio, 2.37; 95% confidence interval, 1.55-3.63). CONCLUSIONS: In comparison with patients with CAs, patients with TSAs have a higher metachronous occurrence rate of all polyp subtypes including CAs, serrated adenomas, and hyperplastic polyps. Moreover, the presence of TSAs is an independent predictor of a high-risk polyp occurrence. PMID- 26117179 TI - Endoscopic management of a GI perforation. PMID- 26117180 TI - Digital cholangioscopy-directed removal of a surgical staple from a strictured bile duct. PMID- 26117181 TI - The upstream regulatory sequence of the light harvesting complex Lhcf2 gene of the marine diatom Phaeodactylum tricornutum enhances transcription in an orientation- and distance-independent fashion. AB - Diatoms are a key phytoplankton group in the contemporary ocean, showing extraordinary adaptation capacities to rapidly changing environments. The recent availability of whole genome sequences from representative species has revealed distinct features in their genomes, like novel combinations of genes encoding distinct metabolisms and a significant number of diatom-specific genes. However, the regulatory mechanisms driving diatom gene expression are still largely uncharacterized. Considering the wide variety of fields of study orbiting diatoms, ranging from ecology, evolutionary biology to biotechnology, it is thus essential to increase our understanding of fundamental gene regulatory processes such as transcriptional regulation. To this aim, we explored the functional properties of the 5'-flanking region of the Phaeodatylum tricornutum Lhcf2 gene, encoding a member of the Light Harvesting Complex superfamily and we showed that this region enhances transcription of a GUS reporter gene in an orientation- and distance-independent fashion. This represents the first example of a cis regulatory sequence with enhancer-like features discovered in diatoms and it is instrumental for the generation of novel genetic tools and diatom exploitation in different areas of study. PMID- 26117182 TI - Emirati Teachers' Perceptions of Voice Handicap. AB - OBJECTIVES: The purpose of the study was to explore Emirati teachers' perceptions of voice handicap and to analyze their acoustic characteristics to determine whether acoustic measures of teachers' voice would verify their perceptions of voice handicap. METHODS: Sixty-six Emirati school teachers (33 men and 33 women), with different years of teaching experience and age, and 100 control participants (50 men and 50 women) underwent vocal assessment that included the Voice Handicap Index (VHI-Arab) and acoustic measures (F0, jitter%, shimmer%, signal to noise ratio [SNR]). RESULTS: Significant differences between the teachers' group scores and the control group scores on the following subscales of VHI-Arab: physical (P = 0.006), emotional (P = 0.004), and total score of the test (P = 0.002). No significant differences were found among teachers in the three VHI subscales, and the total score regarding gender (functional P = 0.307; physical P = 0.341; emotional P = 0.126; and total P = 0.184), age (functional P = 0.972; physical P = 0.525; emotional P = 0.772; and total P = 0.848), and years of teaching experience (functional P = 0.319; physical P = 0.619; emotional P = 0.926; and total P = 0.638). The significant differences between the teacher's group and the control group in three acoustic measures: F0 (P = 0.000), shimmer% (P = 0.000), and SNR (P = 0.000) were further investigated. Significant differences were found among female and male teachers in F0 (P = 0.00) and SNR (P = 0.007). As for teachers' age, significant differences were found in SNR (P = 0.028). Teachers' years of experience did not show significant differences in any of the acoustic measures. CONCLUSIONS: Teachers have a higher perception of voice handicap. However, they were able to produce better voice quality than control participants were, as expressed in better SNRs. This might have been caused either by manipulation of vocal properties or abusive overloading the vocal system to produce a procedurally acceptable voice quality. PMID- 26117183 TI - Survey of acaricides resistance status of Rhipiciphalus (Boophilus) microplus collected from selected places of Bihar, an eastern state of India. AB - Monitoring acaricide resistance in field ticks and use of suitable managemental practices are essential for controlling tick populations infesting animals. In the present study, the acaricide resistance status in Rhipicephalus (Boophilus) microplus ticks infesting cattle and buffaloes of five districts located in the eastern Indian state, Bihar were characterized using three data sets (AIT, Biochemical assays and gene sequences). Adult immersion test (AIT) was adopted using seven field isolates and their resistance factor (RF) was determined. Six isolates (DNP, MUZ, BEG, VSH, DRB and SUL) were found resistant to both deltamethrin and diazinon and except VSH all were resistant to cypermethrin. One isolate (PTN) was susceptible with a RF below 1.5. To understand the possible mode of resistance development, targeted enzymes and gene sequences of the para sodium channel and achetylcholinesterase 2 (AChE2) were analyzed. The esterase, monooxygenase and glutathione-S-transferase (GST) activity of reference susceptible IVRI-I line was determined as 2.47 +/- 0.007 nmol/min/mg protein, 0.089 +/- 0.0016 nmol/mg of protein and 0.0439 +/- 0.0003 nmol/mg/min respectively, which increased significantly in the resistant field isolates. However, except esterases, the fold increase of monooxygenase (1.14-2.27 times) and GST (0.82-1.53 times) activities were not very high. A cytosine (C) to adenine (A) nucleotide substitution (CTC to ATC) at position 190 in domain II S4 5 linker region was detected only in one isolate (SUL) having RF of 34.9 and in the reference deltamethrin resistant line (IVRI-IV). However, the T2134A mutation was not detected in domain IIIS6 transmembrane segment of resistant isolates and also in reference IVRI-IV line despite of varying degree of resistance. The flumethrin specific G215T and the recently identified T170C mutations were also absent in domain II sequences under study. Four novel amino acid substitutions in AChE2 gene of field isolates and in organophosphate (OP) resistant reference IVRI III line were identified which can possibly have a role in resistance development. PMID- 26117184 TI - Renal targeted delivery of triptolide by conjugation to the fragment peptide of human serum albumin. AB - We have previously demonstrated that peptide fragments (PFs) of the human serum albumin could be developed as potential renal targeting carriers, in particular, the peptide fragment, PF-A299-585 (A299-585 representing the amino acid sequence of the human serum albumin). In this paper, we conjugated triptolide (TP), the anti-inflammatory Chinese traditional medicine, to PF-A299-585 via a succinic acid spacer to give TPS-PF-A299-585 (TP loading 2.2% w/w). Compared with the free TP, TPS-PF-A299-585 exhibited comparable anti-inflammatory activity in the lipopolysaccharide stimulated MDCK cells, but was significantly less cytotoxic than the free drug. Accumulation of TPS-PF-A299-585 in the MDCK cells in vitro and in rodent kidneys in vivo was demonstrated using FITC-labeled TPS-PF-A299 585. Renal targeting was confirmed in vivo in a membranous nephropathic (MN) rodent model, where optical imaging and analyses of biochemical markers were combined to show that TPS-PF-A299-585 was capable of alleviating the characteristic symptoms of MN. The collective data affirm PF-A299-585 to be a useful carrier for targeting TP to the kidney. PMID- 26117185 TI - Antibiotic delivery by liposomes from prokaryotic microorganisms: Similia cum similis works better. AB - To date the effectiveness of antibiotics is undermined by microbial resistance, threatening public health worldwide. Enhancing the efficacy of the current antibiotic arsenal is an alternative strategy. The administration of antimicrobials encapsulated in nanocarriers, such as liposomes, is considered a viable option, though with some drawbacks related to limited affinity between conventional liposomes and bacterial membranes. Here we propose a novel "top down" procedure to prepare unconventional liposomes from the membranes of prokaryotes (PD-liposomes). These vectors, being obtained from bacteria with limited growth requirements, also represent low-cost systems for scalable biotechnology production. In depth physico-chemical characterization, carried out with dynamic light scattering (DLS) and Small Angle X-ray Scattering (SAXS), indicated that PD-liposomes can be suitable for the employment as antibiotic vectors. Specifically, DLS showed that the mean diameter of loaded liposomes was ~200-300nm, while SAXS showed that the structure was similar to conventional liposomes, thus allowing a direct comparison with more standard liposomal formulations. Compared to free penicillin G, PD-liposomes loaded with penicillin G showed minimal inhibitory concentrations against E. coli that were up to 16 times lower. Noteworthy, the extent of the bacterial growth inhibition was found to depend on the microorganisms from which liposomes were derived. PMID- 26117186 TI - The in vivo fate of nanoparticles and nanoparticle-loaded microcapsules after oral administration in mice: Evaluation of their potential for colon-specific delivery. AB - Anti-cancer drug loaded-nanoparticles (NPs) or encapsulation of NPs in colon targeted delivery systems shows potential for increasing the local drug concentration in the colon leading to improved treatment of colorectal cancer. To investigate the potential of the NP-based strategies for colon-specific delivery, two formulations, free Eudragit(r) NPs and enteric-coated NP-loaded chitosan hypromellose microcapsules (MCs) were fluorescently-labelled and their tissue distribution in mice after oral administration was monitored by multispectral small animal imaging. The free NPs showed a shorter transit time throughout the mouse digestive tract than the MCs, with extensive excretion of NPs in faeces at 5h. Conversely, the MCs showed complete NP release in the lower region of the mouse small intestine at 8h post-administration. Overall, the encapsulation of NPs in MCs resulted in a higher colonic NP intensity from 8h to 24h post administration compared to the free NPs, due to a NP 'guarding' effect of MCs during their transit along mouse gastrointestinal tract which decreased NP excretion in faeces. These imaging data revealed that this widely-utilised colon targeting MC formulation lacked site-precision for releasing its NP load in the colon, but the increased residence time of the NPs in the lower gastrointestinal tract suggests that it is still useful for localised release of chemotherapeutics, compared to NP administration alone. In addition, both formulations resided in the stomach of mice at considerable concentrations over 24h. Thus, adhesion of NP- or MC-based oral delivery systems to gastric mucosa may be problematic for colon-specific delivery of the cargo to the colon and should be carefully investigated for a full evaluation of particulate delivery systems. PMID- 26117187 TI - Influence of humidity on the phase behavior of API/polymer formulations. AB - Amorphous formulations of APIs in polymers tend to absorb water from the atmosphere. This absorption of water can induce API recrystallization, leading to reduced long-term stability during storage. In this work, the phase behavior of different formulations was investigated as a function of relative humidity. Indomethacin and naproxen were chosen as model APIs and poly(vinyl pyrrolidone) (PVP) and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) as excipients. The formulations were prepared by spray drying. The water sorption in pure polymers and in formulations was measured at 25 degrees C and at different values of relative humidity (RH=25%, 50% and 75%). Most water was absorbed in PVP containing systems, and water sorption was decreasing with increasing API content. These trends could also be predicted in good agreement with the experimental data using the thermodynamic model PC-SAFT. Furthermore, the effect of absorbed water on API solubility in the polymer and on the glass-transition temperature of the formulations was predicted with PC-SAFT and the Gordon-Taylor equation, respectively. The absorbed water was found to significantly decrease the API solubility in the polymer as well as the glass-transition temperature of the formulation. Based on a quantitative modeling of the API/polymer phase diagrams as a function of relative humidity, appropriate API/polymer compositions can now be selected to ensure long-term stable amorphous formulations at given storage conditions. PMID- 26117188 TI - The STEP database through the end-users eyes--USABILITY STUDY. AB - OBJECTIVES: The user-designed database of Safety and Toxicity of Excipients for Paediatrics ("STEP") is created to address the shared need of drug development community to access the relevant information of excipients effortlessly. Usability testing was performed to validate if the database satisfies the need of the end-users. METHOD: Evaluation framework was developed to assess the usability. The participants performed scenario based tasks and provided feedback and post-session usability ratings. Failure Mode Effect Analysis (FMEA) was performed to prioritize the problems and improvements to the STEP database design and functionalities. RESULT: The study revealed several design vulnerabilities. Tasks such as limiting the results, running complex queries, location of data and registering to access the database were challenging. The three critical attributes identified to have impact on the usability of the STEP database included (1) content and presentation (2) the navigation and search features (3) potential end-users. CONCLUSION: Evaluation framework proved to be an effective method for evaluating database effectiveness and user satisfaction. This study provides strong initial support for the usability of the STEP database. Recommendations would be incorporated into the refinement of the database to improve its usability and increase user participation towards the advancement of the database. PMID- 26117189 TI - In vitro dissolution-permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using MUFluxTM. AB - Since it is a well-known fact that among the newly discovered active pharmaceutical ingredients the number of poorly water soluble candidates is continually increasing, dissolution enhancement of poorly water soluble drugs has become one of the central challenges of pharmaceutical studies. So far the preclinical studies have been mainly focused on formulation methods to enhance the dissolution of active compounds, in many cases disregarding the fact that the formulation matrix not only affects dissolution but also has an effect on the transport through biological membranes, changing permeation of the drug molecules. The aim of this study was to test an electrospun cyclodextrin-based formulation of aripiprazole with the novel MUFlux apparatus, which monitors permeation together with dissolution, and by this means better in vitro-in vivo correlation is achieved. It was evinced that a cyclodextrin-based electrospun formulation of aripiprazole has the potential to ensure fast drug delivery through the oral mucosa owing to the ultrafast dissolution of the drug from the formulation and the enhanced flux across membranes as shown by the result of the novel in vitro dissolution and permeation test. PMID- 26117190 TI - In vitro biological activity of resveratrol using a novel inhalable resveratrol spray-dried formulation. AB - The aim of the study was to prepare inhalable resveratrol by spray drying for the treatment of chronic obstructive pulmonary disease (COPD). Resveratrol, with a spherical morphology and particle diameter less than 5 MUm, was successfully manufactured. Fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of spray-dried resveratrol was 39.9 +/- 1.1% and 3.7 +/- 0.1 MUm, respectively, when assessed with an Andersen cascade impactor (ACI) at 60 l/min. The cytotoxicity results of resveratrol on Calu-3 revealed that the cells could tolerate high concentration of resveratrol (up to 160 MUM). In addition, in transport experiments using Snapwells, it was observed that more than 80% of the deposited dry powder was transported across the Calu-3 cells to the basal chamber within four hours. The expression of interleukin-8 (IL-8) from Calu-3 induced with tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta1) and lipopolysaccharide (LPS) were significantly reduced after treatment with spray-dried resveratrol. The antioxidant assay (radical scavenging activity and nitric oxide production) showed spray-dried resveratrol to possess an equivalent antioxidant property as compared to vitamin C. Results presented in this investigation suggested that resveratrol could potentially be developed as a dry powder for inhalation for the treatment of inflammatory lung diseases like COPD. PMID- 26117191 TI - Importance of a suitable working protocol for tape stripping experiments on porcine ear skin: Influence of lipophilic formulations and strip adhesion impairment. AB - The tape stripping method is a very important tool for dermopharmacokinetic experiments in vitro and the accurate measurement of the removed corneocytes is key for a reliable calculation of a drug's skin penetration behavior. Therefore, various methods to quantify the amount of corneocytes removed with each tape strip have been employed, ranging from gravimetric approaches to protein assays and recently near infrared densitometry (NIR) has become very widely used. As this method is based on a reduction of light intensity, interference of formulation components seems conceivable, as they could scatter light and change the results. In this study, NIR measurements were compared to a protein assay and in addition, the influence of highly lipophilic formulations on the results of tape stripping experiments was investigated as impairment of the adherence of strips has been reported. To this end, different tape stripping protocols were employed. The obtained results ensure suitability of the NIR method and moreover suggest a more pronounced influence on adherence with increasing lipophilicity in applied formulations. The results show that adaptation of the tape stripping protocol to the specifications of envisioned experiments is important for reliable results. Two protocols were found favorable and are presented in this work. PMID- 26117192 TI - Phosphorus dendrimers and photodynamic therapy. Spectroscopic studies on two dendrimer-photosensitizer complexes: Cationic phosphorus dendrimer with rose bengal and anionic phosphorus dendrimer with methylene blue. AB - Dendrimers due to their unique architecture may play an important role in drug delivery systems including chemotherapy, gene therapy and recently, photodynamic therapy as well. We investigated two dendrimer-photosensitizer systems in context of potential use of these systems in photodynamic therapy. The mixtures of an anionic phosphorus dendrimer of the second generation and methylene blue were studied by UV-vis spectroscopy while that of a cationic phosphorus dendrimer (third generation) and rose bengal were investigated by spectrofluorimetric methods. Spectroscopic analysis of these two systems revealed the formation of dendrimer-photosensitizer complexes via electrostatic interactions as well as pi stacking. The stoichiometry of the rose bengal-cationic dendrimer complex was estimated to be 7:1 and 9:1 for the methylene blue-anionic dendrimer complex. The results suggest that these polyanionic or polycationic phosphorus dendrimers can be promising candidates as carriers in photodynamic therapy. PMID- 26117194 TI - Vibrational spectroscopic study of vinyl substituted polycyclic aromatic hydrocarbons. AB - The mid infrared emission features observed in various astrophysical sources are attributed to polycyclic aromatic hydrocarbon (PAH) molecules. The models of emission spectra from a collection of PAHs show uncertainty in matching the 6.2 MUm feature. This indicates the need to consider a larger variety of PAHs and PAH derivatives. Chemical pathways towards formation of PAHs in the astrophysical environments involve vinyl substituted PAHs as intermediate products. Vibrational spectroscopic study of vinyl-PAHs is reported in the present work. The vinyl group is substituted at similar positions in eight different PAHs. The obtained optimized structures show that vinyl substitution at 2 position in acenes gives planar geometry, while all other vinyl-PAHs are non-planar. Infrared spectra is simulated for neutrals as well as for cations. The results are compared with the spectra of corresponding plain PAHs and analyzed for possible match with astrophysical observations. New features, due to vinyl group in the composite spectra, identified at 6.64, 6.92, 7.27, 8.77 and 10.35 MUm fall close to some sub features of the observed emission spectra. The paper provides data that may be used in the emission models particularly along proto planetary nebulae type cool objects. PMID- 26117193 TI - Agrobacterium arsenijevicii sp. nov., isolated from crown gall tumors on raspberry and cherry plum. AB - Two plant-tumorigenic strains KFB 330(T) and KFB 335 isolated from galls on raspberry (Rubus idaeus) in Serbia, and a non-pathogenic strain AL51.1 recovered from a cherry plum (Prunus cerasifera) tumor in Poland, were genotypically and phenotypically characterized. Phylogenetic reconstruction based on 16S rDNA placed them within the genus Agrobacterium, with A. nepotum as their closest relative. Multilocus sequence analysis (MLSA) based on the partial sequences of atpD, glnA, gyrB, recA and rpoB housekeeping genes suggested that these three strains represent a new Agrobacterium species, that clustered with type strains of A. nepotum, A. radiobacter, "A. fabrum" and A. pusense. This was further supported by average nucleotide identity values (<92%) between the whole genome sequences of strain KFB 330(T) and related Agrobacterium species. The major cellular fatty acids of the novel strains were 18:1 w7c (72.8-77.87%) and 16:0 (6.82-8.58%). Phenotypic features allowed their differentiation from closely related species. Polyphasic characterization showed that the three strains represent a novel species of the genus Agrobacterium, for which the name Agrobacterium arsenijevicii sp. nov. is proposed. The type strain of A. arsenijevicii is KFB 330(T) (= CFBP 8308(T) = LMG 28674(T)). PMID- 26117195 TI - Using IR and Raman spectra to explain the catalytic activity of the Fe(II)/Fe(III) pair toward the cleavage of peptide bonds. AB - IR and Raman experiments of formamide (FA) solutions containing variable amounts of Fe(II) and Fe(III) salts were carried out. The nuCO vibration is downshifted whereas the nuCN mode is upshifted in the presence of the divalent ion. As the trivalent ion is added to the solvent, upshifts of both nuCO and nuCN vibrations are observed. These spectral patterns are related to the distinct FA forms that are stabilized by each ion. Fe(II) is surrounded by 6 ionic FA species while neutral ones coordinate to the trivalent ion with formation of [Fe(FA)3Cl](2+) and [Fe(FA)2(Cl)2](+). In higher salt compositions [FeCl4](-) is also identified in the spectra. Our vibrational results are very well corroborated by biological studies on the catalytic activity of the Fe(II)/Fe(III) pair in oxidative cleavage processes of polypeptides and proteins. PMID- 26117196 TI - Raman microspectroscopic analysis of decorative pigments from the Roman villa of El Ruedo (Almedinilla, Spain). AB - In this work, we analysed the preparatory layer and paintings in the hypocaustum of the Roman villa of El Ruedo (Almedinilla, southern Spain). The specimens studied were from the III and IV centuries. Raman microscopy was for the first time used here to examine Roman pictures in the south of the Iberian peninsula. The results obtained allowed us to establish the chemical nature of the different pigments used by the Roman artists. All were applied over a preparatory layer consisting of limewash. The different colours used (black, white, red, yellow, green and blue) were obtained by using carbon, calcite, gypsum, hematite, goethite, green earth and Egyptian blue. Some exhibited various hues that were obtained by mixing the previous compounds. Worth special note is the incipient presence of blue pigments, which were rarely used in Roman Hispania owing to their scarcity and high price. PMID- 26117197 TI - Label-free fluorescence strategy for sensitive detection of exonuclease activity using SYBR Green I as probe. AB - A label-free and sensitive fluorescence assay for exonuclease activity is developed using commercially available SYBR Green I (SG) dye as signal probe. A proof-of-concept of this assay has been demonstrated by using exonuclease III (Exo III) as a model enzyme. In this assay, double-stranded DNA (dsDNA) can bind SG, resulting in a strong fluorescence signal of SG. Upon the addition of Exo III, dsDNA would be digested, and SG emits very weak fluorescence. Thus, Exo III activity can be facilely measured with a simple fluorescence reader. This method has a linear detection range from 1 U/mL to 200 U/mL with a detection limit of 0.7 U/mL. This label-free approach is selective, simple, convenient and cost efficient without any complex DNA sequence design or fluorescence dye label. The method not only provides a platform for monitoring activity and inhibition of exonuclease but also shows great potential in biological process researches, drug discovery, and clinic diagnostics. PMID- 26117198 TI - An in vitro comparison of quantitative light-induced fluorescence-digital and spectrophotometer on monitoring artificial white spot lesions. AB - PURPOSE: The aim of this study was to evaluate the efficacy of quantitative light induced fluorescence-digital (QLF-D) compared to a spectrophotometer in monitoring progression of enamel lesions. METHODS: To generate artificial caries with various severities of lesion depths, twenty bovine specimens were immersed in demineralizing solution for 40 days. During the production of the lesions, repeat measurements of fluorescence loss (DeltaF) and color change (DeltaE) were performed in six distinct stages after the demineralization of the specimens: after 3, 5, 10, 20, 30, and 40 days of exposure to the demineralizing solution. Changes in the DeltaF values in the lesions were analyzed using the QLF-D, and changes in the DeltaE values in lesions were analyzed using a spectrophotometer. The repeated measures ANOVA of DeltaF and DeltaE values were used to determine whether there are significant differences at different exposure times in the demineralizing solution. Spearman's rank correlation coefficient was analyzed between DeltaF and DeltaE. RESULTS AND CONCLUSION: The DeltaF values significantly decreased based on the demineralizing period (p<0.001). Relatively large changes in DeltaF values were observed during the first 10 days. There were significant changes in L(*), a(*), b(*), and DeltaE values in lesions with increasing demineralizing duration (p<0.001). A strong correlation was observed between DeltaF and DeltaE with p=-0.853 (p<0.001). The results support the efficacy of QLF-D in monitoring color changes. Our findings demonstrate that QLF D are a more efficient and stable tool for early caries detection. PMID- 26117199 TI - Virucidal efficacy of treatment with photodynamically activated curcumin on murine norovirus bio-accumulated in oysters. AB - Norovirus (NoV) is one of the most important seafood- and water-borne viruses, and is a major cause of acute gastroenteritis outbreaks. In the present study we investigated the effect of curcumin as a sensitizer to photodynamic treatment both in buffer and in oysters against murine norovirus 1 (MNV-1), a surrogate of NoV. MNV-1 cultured in buffer and MNV-1 bio-accumulated in oysters were irradiated with a novel LED light source with a wavelength of 470nm and an energy of 3.6J/cm(2). Inactivation of MNV-1 was investigated by plaque assays. After virus was extracted from the gut of oysters treated over a range of curcumin concentrations, the ultrastructural morphology of the virus was observed using electron microscopy, and the integrity of viral nucleic acids and stability of viral capsid proteins were also determined. Results showed that the infectivity of MNV-1 was significantly inhibited by 1-3logPFU/ml, with significant damage to viral nucleic acids in a curcumin dose-dependent manner after photodynamic activation. Virus morphology was altered after the photodynamic treatment with curcumin, presumably due to the change of the viral capsid protein structures. The data suggest that treatment of oysters with photodynamic activation of curcumin is a potentially efficacious and cost-effective method to inactivate food-borne NoV. Further studies are necessary to evaluate the toxicology of this approach in detail and perform sensory evaluation of the treated product. PMID- 26117200 TI - Does dexamethasone affect hepatic CYP450 system of fish? Semi-static in-vivo experiment on juvenile rainbow trout. AB - Effects of aquatic pollutants on fish are of increasing concern. Pharmaceutical based contaminants are prioritized for further study in environmental risk assessment using several approaches. Dexamethasone (DEX) was one such contaminant recognised for its effect on fish health status. Thus, we carried out an in vivo experiment to identify potential effects of DEX on rainbow trout. Fish were exposed to 3, 30, 300 and 3000ngL(-1) DEX in a semi-static system over a period of 42d. The concentrations of DEX that fish were exposed to was confirmed by LC LC-MS/MS. Using hepatic microsomes, we determined cytochrome P450 content, activities of ethoxyresorufin O-deethylase (EROD), p-nitrophenol hydroxylase (PNPH), 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase (BFCOD) and benzyloxyquinoline O-debenzylase (BQOD), as well as protein expression. Our results showed that fish do not change the catalytic activity of CYP450-mediated reactions after high DEX concentration exposure. These results disagree with mammalian studies, where DEX is a well-known inducer of CYP450. We showed a significant effect of DEX exposure on CYP450-mediated reactions (EROD, BCFOD, BQOD and PNPH) when expressed as amount of product formed per min per nmol total CYP450 at 3, 30 and 300ngL(-1) after 21d exposure. Moreover, BFCOD and BQ activities showed matching trends in all groups. Western blot analysis showed induction of CYP3A-like protein in the presence of the lowest environmentally relevant concentration of DEX. Based on these findings, continued investigation of the effect of DEX on fish using a battery of complementary biomarkers of exposure and effect is highly relevant. PMID- 26117201 TI - Exploring simple, transparent, interpretable and predictive QSAR models for classification and quantitative prediction of rat toxicity of ionic liquids using OECD recommended guidelines. AB - The present study explores the chemical attributes of diverse ionic liquids responsible for their cytotoxicity in a rat leukemia cell line (IPC-81) by developing predictive classification as well as regression-based mathematical models. Simple and interpretable descriptors derived from a two-dimensional representation of the chemical structures along with quantum topological molecular similarity indices have been used for model development, employing unambiguous modeling strategies that strictly obey the guidelines of the Organization for Economic Co-operation and Development (OECD) for quantitative structure-activity relationship (QSAR) analysis. The structure-toxicity relationships that emerged from both classification and regression-based models were in accordance with the findings of some previous studies. The models suggested that the cytotoxicity of ionic liquids is dependent on the cationic surfactant action, long alkyl side chains, cationic lipophilicity as well as aromaticity, the presence of a dialkylamino substituent at the 4-position of the pyridinium nucleus and a bulky anionic moiety. The models have been transparently presented in the form of equations, thus allowing their easy transferability in accordance with the OECD guidelines. The models have also been subjected to rigorous validation tests proving their predictive potential and can hence be used for designing novel and "greener" ionic liquids. The major strength of the present study lies in the use of a diverse and large dataset, use of simple reproducible descriptors and compliance with the OECD norms. PMID- 26117202 TI - Passive dosing versus solvent spiking for controlling and maintaining hydrophobic organic compound exposure in the Microtox(r) assay. AB - Microbial toxicity bioassays such as the Microtox(r) test are ubiquitously applied to measure the toxicity of chemicals and environmental samples. In many ways their operation is conducive to the testing of organic chemicals. They are of short duration, use glass cuvettes and take place at reduced temperatures in medium lacking sorbing components. All of these are expected to reduce sorptive and volatile losses, but particularly for hydrophobic organics the role of such losses in determining the bioassay response remains unclear. This study determined the response of the Microtox(r) test when using solvent spiking compared to passive dosing for introducing the model hydrophobic compounds acenaphthene, phenanthrene, fluoranthene and benzo(a)pyrene. Compared to solvent spiking, the apparent sensitivity of the Microtox(r) test with passive dosing was 3.4 and 12.4 times higher for acenaphthene and phenanthrene, respectively. Furthermore, fluoranthene only gave a consistent response with passive dosing. Benzo(a)pyrene did not result in a response with either spiking or passive dosing even at aqueous solubility. Such differences in the apparent sensitivity of the Microtox(r) test can be traced back to the precise definition of the dissolved exposure concentrations and the buffering of losses with passive dosing. This highlights the importance of exposure control even in simple and short-term microbial bioassays such as the Microtox(r) test. PMID- 26117203 TI - Prophylactic central lymph node dissection in cN0 patients with papillary thyroid carcinoma: A retrospective study in China. AB - OBJECTIVE: The objective of the study was to assess the patterns of central cervical lymph node metastasis (CLNM) and evaluate the prophylactic central lymph node dissection (CLND) in papillary thyroid carcinoma (PTC) patients without clinical positive lymph nodes. METHODS: We retrospectively reviewed 1555 patients with PTC between 2003 and 2008. Lymph node metastatic risk factors and the pattern of lymph node metastasis in PTC were studied using multivariate analysis. RESULTS: Male patients, aged <= 45 years, the presence of extrathyroidal extension, and a primary tumor size > 10 mm were identified as risk factors for CLNM with odds ratios of 2.089, 2.417, 1.534, and 3.079, respectively. Among 1555 patients, 97 cases (6.24%) had transient hypoparathyroidism, and only two patients (0.13%) had permanent hypoparathyroidism. Recurrent laryngeal nerve injury after thyroidectomy occurred in 14 patients (0.9%). In this group, nine cases were transient injury and the remaining five were permanent. During the period of follow-up, ranging from 5 years to 10 years, 18 patients (1.16%) were found with locoregional recurrence. CONCLUSION: Taken together, in terms of the high incidence rate of CLNM in cN0 PTC patients, we believe that routine prophylactic CLND is optimal for clinically negative PTC patients, during their first treatment, especially for those with risk factors for CLNM. PMID- 26117204 TI - Comparative outcomes of lateral transperitoneal adrenalectomy versus posterior retroperitoneoscopic adrenalectomy in consecutive patients: A single surgeon's experience. AB - BACKGROUND: Among several minimally invasive adrenalectomy techniques, lateral transperitoneal adrenalectomy (LTA) is the procedure of choice for benign adrenal tumors; however, posterior retroperitoneoscopic adrenalectomy (PRA) is an alternative that is increasing in popularity. This study compared the outcomes of these two approaches. METHODS: Since a single surgeon started adrenalectomy, LTA had been performed exclusively until PRA was adopted and became the standard treatment. Therefore, the consecutive patients were allocated into two groups according to the date of surgery: the first group received LTA and the second group received PRA. RESULTS: LTA was performed in 29 patients and PRA in 19 patients. There was no difference in sex, age, body mass index, clinical diagnosis, and tumor size between the LTA and the PRA group. The PRA group showed less blood loss (117.0 mL vs. 58.5 mL, p = 0.035) and tended to have a shorter operating time (92.2 minutes vs. 78.1 minutes, p = 0.054) and less pain score on postoperative Day 1 (3.8 vs. 3.0, p = 0.095) and Day 2 (3.2 vs. 2.5, p = 0.051). The mean operation time was significantly shorter for patients in the PRA group undergoing right adrenalectomy (109.2 minutes vs. 80.5 minutes, p = 0.009), but those undergoing left adrenalectomy had a similar operating time to the LTA group (83.2 minutes vs. 74.8 minutes, p = 0.380). CONCLUSION: PRA is a good alternative operative technique for an endocrine surgeon who is experienced in the transperitoneal approach. PMID- 26117205 TI - Is surgical plication necessary in diaphragm eventration? AB - BACKGROUND: Diaphragm plication surgery is conducted to remove dyspnea, which results from mediastinal shift, atelectasia, and ventilation/perfusion dyssynchrony in lungs that occur because of an eventrated diaphragm. This study aims to determine whether diaphragm plication has any effect on respiration by analyzing the patients' changing values in the respiratory function test (RFT) after plication surgery. METHODS: Sixteen patients who underwent diaphragm plication surgery in our clinic because of plication eventration or paralysis were examined prospectively. Diaphragm eventration values were assessed using a calculation method that uses posteroanterior pulmonary radiographies taken during patient admission and control; then, these data were recorded. The amount of changes in the eventration levels and in restrictive respiratory failure parameters-forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) of RFTs-conducted in pre- and postoperative control periods were compared using statistical analysis methods. The compatibility between the amounts of RFT changes was examined through a satisfaction survey-using a questionnaire that consisted of multiple choice questions with answer options such as "better," "the same," and "worse"-to understand preoperative and postoperative symptom levels in the 12(th) month of postoperative control. RESULTS: According to postoperative levels, a decrease between 19% and 23% was observed in eventration amounts within the 1(st) postoperative month, 6(th) postoperative month, and 12(th) postoperative month. In addition, the highest average increase in FEV1 liter (lt) values was 0.2 lt and 0.25 in FVC (lt) values. CONCLUSION: Researchers of this study believe that more distinctive decisions need to be taken while identifying patients for surgery in unilateral diaphragm eventrations, especially in the adult patient group; surgical option should be used for cases in which the eventrated diaphragm results in mediastinal shift and respiratory failure. PMID- 26117206 TI - Successful Management of an Infected Aortic Stent Graft in a Liver Transplanted Patient. AB - We report on a 57-year-old female liver transplanted patient who underwent endovascular aneurysm repair because of an infrarenal abdominal aortic aneurysm. Two months later, she developed an infection, and positron emission tomography computed tomography detected a paraprosthetic abscess. Explantation of the endoprosthesis and aortic reconstruction with a Y-shaped silver graft was made. The patient was discharged on the 12th postoperative day and shows up regularly in our outpatients department in a good clinical condition. After meticulous research of the current literature, this is the first published case of the successful management of an infected endovascular aortic stent in a liver transplanted patient. PMID- 26117207 TI - A Rare Case of Colonic Mucosal Dehiscence after Emergency Abdominal Aortic Aneurysm Repair. AB - We present the first-reported case of a complete colonic mucosal dehiscence after an emergency abdominal aortic aneurysm repair. PMID- 26117208 TI - Pseudostenosis of the External Iliac Artery after Common Iliac Artery Occlusion: 2 Case Reports. AB - We report 2 cases of pseudostenosis of the external iliac artery (EIA) combined with aortoiliac occlusive disease. Both cases were treated successfully by aortobi-iliac bypass surgery instead of aortobi-femoral bypass. Pseudostenoses of the EIA disappeared in the postoperative computed tomographic angiography. We are not aware of previous reports of similar findings. Pseudostenosis should be considered if the EIA shows diffuse narrowing without wall irregularity in combination with severe stenosis or occlusion of the common iliac artery. PMID- 26117209 TI - ERalpha down-regulation plays a key role in silibinin-induced autophagy and apoptosis in human breast cancer MCF-7 cells. AB - The estrogen receptor alpha (ERalpha) has been proven to be one of the most important therapeutic targets in breast cancer over the last 30 years. Previous studies pointed out that a natural flavonoid, silibinin, induced apoptosis in human breast cancer MCF-7 cells. In the present study we report that exposure of MCF-7 cells to silibinin led to cell death through the down-regulation of ERalpha expression. Silibinin-induced apoptosis of MCF-7 cells through up-regulation of caspase 6 due to ERalpha signalling repression was further boosted by ERalpha antagonist. Moreover, up-regulation of autophagy induced by silibinin accounted for apoptotic exacerbation, being further enhanced by ERalpha inhibition. Upon ERalpha activation, series of downstream signalling pathways can be activated. We found that silibinin reduced the expressions of Akt/mTOR and extracellular-signal related kinase (ERK), which respectively accounted for the induction of autophagy and apoptosis. These effects were further augmented by co-treatment with ERalpha inhibitor. We conclude that the treatment with silibinin of ERalpha-positive MCF 7 cells down-regulates the expression of ERalpha, and subsequently mTOR and ERK signaling pathways, ERalpha downstream, finally resulting in induction of autophagy and apoptosis. PMID- 26117210 TI - Decreased plasma endogenous soluble RAGE, and enhanced adipokine secretion, oxidative stress and platelet/coagulative activation identify non-alcoholic fatty liver disease among patients with familial combined hyperlipidemia and/or metabolic syndrome. AB - OBJECTIVE: In patients with familial combined hyperlipidemia (FCHL), without metabolic syndrome (MS), occurrence of non-alcoholic fatty liver disease (NAFLD) is related to a specific pro-inflammatory profile, influenced by genetic traits, involved in oxidative stress and adipokine secretion. Among FCHL or MS patients, hyperactivity of the ligand-receptor for advanced glycation-end-products (RAGE) pathway, as reflected by inadequate protective response by the endogenous secretory (es)RAGE, in concert with genetic predisposition, may identify those with NAFLD even before and regardless of MS. METHODS: We cross-sectionally compared 60 patients with vs. 50 without NAFLD. Each group included patients with FCHL alone, MS alone, and FCHL plus MS. RESULTS: NAFLD patients had significantly lower plasma esRAGE, IL-10 and adiponectin, and higher CD40 ligand, endogenous thrombin potential and oxidized LDL. The effects of MS plus FCHL were additive. The genotypic cluster including LOX-1 IVS4-14A plus ADIPO 45GG and 256 GT/GG plus IL-10 10-1082G, together with higher esRAGE levels highly discriminate FCHL and MS patients not developing NAFLD. CONCLUSIONS: Among FCHL or MS patients, noncarriers of the protective genotypic cluster, with lower esRAGE and higher degree of atherothrombotic abnormalities coincide with the diagnosis of NAFLD. This suggests an interplay between genotype, adipokine secretion, oxidative stress and platelet/coagulative activation, accelerating NAFLD occurrence as a proxy for cardiovascular disease. PMID- 26117211 TI - Detection and Predictors of Paroxysmal Atrial Fibrillation in Acute Ischemic Stroke and Transient Ischemic Attack Patients in Singapore. AB - BACKGROUND: Detection of paroxysmal atrial fibrillation (pAF) is important for optimal secondary stroke prevention. Data are limited from Asia regarding inpatient occurrence and predictors of pAF to optimize electrocardiographic (ECG) monitoring despite it having nearly two thirds of the world's population and different subtypes of stroke from the West. METHODS: We analyzed a prospective dataset comprising 370 acute ischemic stroke (AIS) and 25 transient ischemic attack (TIA) patients without known atrial fibrillation who underwent continuous ECG monitoring (CEM) in an acute stroke unit from July 2012 to February 2013. The median duration of monitoring was 61 hours. RESULTS: There were 31 cases of pAF. The detection rate was 8% for both AIS and TIA patients. It occurred less often in lacunar infarcts (3%) compared to nonlacunar infarcts (10%) (P = .047). The detection rates in cryptogenic infarcts (10%) and infarcts of known causes (7%) were not significantly different (P = .224). The predictors of pAF according to logistic regression were hemorrhagic conversion (P = .006), scattered infarcts (P = .007), radiological cardiomegaly (P = .007), occlusion of symptomatic artery (P = .023), and older age (P < .001). CONCLUSIONS: pAF occurred in 8% of AIS and TIA in a hospitalized cohort of Asian patients. All patients without known atrial fibrillation should undergo CEM for at least 3 days during hospitalization and priority given to patients with predictors of pAF in centers with resource constraints. PMID- 26117212 TI - The Effect of a Brief Intervention for Patients with Ischemic Stroke: A Randomized Controlled Trial. AB - BACKGROUND: Depression and anxiety are common after stroke. There is inconclusive evidence of the benefit of psychotherapy for poststroke depression and anxiety. Here, we used a brief intervention, Neuro-Linguistic Programming (NLP) brief therapy plus health education, to evaluate the changes in patients with ischemic stroke. METHODS: One hundred eighty patients were randomly allocated to receive 4 sessions of NLP plus health education (n = 90) or usual care (n = 90). A set of questionnaires was used preintervention and postintervention as well as at the 6 month follow-up. The primary outcomes were the prevalence of depression and anxiety, and the awareness of stroke knowledge. RESULTS: More patients in the intervention group achieved remission of depressive (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.41-5.59) and anxious symptoms (OR, 2.19; 95% CI, 1.15 4.18) after intervention. At the 6-month follow-up, we found no differences between groups in both the prevalence of depression and anxiety. After intervention, the intervention group had better awareness rates on most of the stroke knowledge items (P < .05). It also had better quality of life and physical function both after intervention and at the follow-up (P < .05). CONCLUSIONS: NLP plus health education could reduce depression and anxiety immediately after intervention, but not at the 6-month follow-up. The intervention could also improve the awareness of stroke knowledge and benefit patients on quality of life and physical function. PMID- 26117213 TI - Application of the ATLAS score for evaluating the severity of Clostridium difficile infection in teaching hospitals in Mexico. AB - BACKGROUND: For clinicians, a practical bedside tool for severity assessment and prognosis of patients with Clostridium difficile infection is a highly desirable unmet medical need. SETTING: Two general teaching hospitals in northeast Mexico. POPULATION: Adult patients with C. difficile infection. METHODS: Prospective observational study. RESULTS: Patients included had a median of 48 years of age, 54% of male gender and an average of 24.3 days length of hospital stay. Third generation cephalosporins were the antibiotics most commonly used prior to C. difficile infection diagnosis. Patients diagnosed with C. difficile infection had a median ATLAS score of 4 and 56.7% of the subjects had a score between 4 and 7 points. Patients with a score of 8 through 10 points had 100% mortality. CONCLUSION: The ATLAS score is a potentially useful tool for the routine evaluation of patients at the time of C. difficile infection diagnosis. At 30 days post-diagnosis, patients with a score of <=3 points had 100% survival while all of those with scores >=8 died. Patients with scores between 4 and 7 points had a greater probability of colectomy with an overall cure rate of 70.1%. PMID- 26117214 TI - Alcohol use, smoking and their co-occurrence during pregnancy among Canadian women, 2003 to 2011/12. AB - INTRODUCTION: The co-occurrence of alcohol use and smoking during pregnancy has been shown to have a negative synergistic effect on fetal and perinatal risks. The objectives were to: 1) obtain an estimate of the prevalence of smoking during pregnancy in Canada by province and territory from 2003 to 2011/12; 2) determine if the prevalence of smoking during pregnancy has increased or decreased over time; 3) investigate whether smoking status is differentially associated with alcohol use during pregnancy; and 4) examine the risk factors predictive of alcohol use only, smoking only, and the co-occurrence of alcohol use and smoking during pregnancy. METHODS: Secondary data analysis was conducted using five cycles of the Canadian Community Health Survey (CCHS; 2003, 2005, 2007/08, 2009/10 and 2011/12). The prevalence of smoking during pregnancy, and 95% confidence interval (CI) was calculated by province and territory and by year. The likelihood ratio test was used to determine if the prevalence of smoking during pregnancy has increased or decreased over time. The relationship between smoking status and alcohol use during pregnancy was explored using a quasi Poisson regression model. A multinomial logistic regression model was utilized to determine which factors were predictive of alcohol use only, smoking only, and the co-occurrence of alcohol use and smoking during pregnancy. RESULTS: In Canada, between 2003 and 2011/12, the weighted pooled prevalence of smoking during pregnancy was 14.3% (95% CI: 13.6%-15.0%). Women who smoked daily during pregnancy, occasionally during pregnancy, or had a lifetime history of smoking (but did not smoke while pregnant) were 2.54 (95% CI: 2.11-3.06, P < 0.0001), 2.71 (95% CI: 2.25-3.27, P < 0.0001), and 2.09 (95% CI: 1.85-2.37, P < 0.0001), respectively, times more likely to have consumed alcohol during pregnancy, compared to pregnant women who were lifetime non-smokers when controlling for age, household income, ethnicity and CCHS cycle. Risk factors that predicted alcohol use only, smoking only, and the co-occurrence of alcohol use and smoking during pregnancy differed. CONCLUSION: It is apparent that smoking in any capacity, whether during pregnancy or not, increases the likelihood that a woman consumed alcohol while pregnant. Ascertaining smoking status among pregnant women and women of childbearing age could be a useful screening method for identifying those at-risk of consuming alcohol during pregnancy, and vice versa. PMID- 26117215 TI - Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1 propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern. AB - Epoxides from polyunsaturated fatty acids (PUFAs) are potent lipid mediators. In vivo stabilization of these epoxides by blockade of the soluble epoxide hydrolase (sEH) leads to anti-inflammatory, analgesic and normotensive effects. Therefore, sEH inhibitors (sEHi) are a promising new class of drugs. Herein, we characterized pharmacokinetic (PK) and pharmacodynamic properties of a commercially available potent sEHi 1-(1-propanoylpiperidin-4-yl)-3-[4 (trifluoromethoxy)phenyl]urea (TPPU). Cell culture studies suggest its high absorption and metabolic stability. Following administration in drinking water to rats (0.2, 1, and 5mg TPPU/L with 0.2% PEG400), TPPU's blood concentration increased dose dependently within the treatment period to reach an almost steady state after 8 days. TPPU was found in all the tissues tested. The linoleic epoxide/diol ratios in most tissues were dose dependently increased, indicating significant sEH inhibition. Overall, administration of TPPU with the drinking water led to systemic distribution as well as high drug levels and thus makes chronic sEH inhibition studies possible. PMID- 26117216 TI - Adherence of the indication to European Association of Urology guideline recommended pelvic lymph node dissection at a high-volume center: Differences between open and robot-assisted radical prostatectomy. AB - PURPOSE: Contemporary adherence of the indication to European Association of Urology (EAU) guideline recommendation for pelvic lymph node dissection (PLND) at either open (ORP) or robot-assisted radical prostatectomy (RARP) at a high-volume center is unknown. To assess guideline recommended and observed PLND rates in a high-volume center cohort. METHODS: We relied on the Martini-Clinic database and focused on patients treated with either ORP or RARP, between 2010 and 2013. Actual performed PLND was compared to European Association of Urology (EAU) guideline recommendation defined by nomogram predicted risk of lymph node invasion >5%. Categorical and multivariable logistic regression analyses targeted two endpoints: 1) probability of guideline recommended PLND and 2) probability of no PLND, when not recommended by EAU guideline. RESULTS: Within 7868 PCa patients, adherence to EAU PLND guideline recommendation was 97.1% at ORP and 96.8% at RARP (p = 0.7). When PLND was not recommended, it was more frequently performed at RARP (71.6%) than at ORP (66.2%) (p = 0.002). Gleason score, PSA and number of positive biopsy cores were independent predictors for both either PLND when recommended, or no PLND when not recommended (all p < 0.05). Clinical tumor stage, age and surgical approach were also independent predictors for no PLND when not recommended (all p < 0.05). CONCLUSIONS: Adherence of the indication to EAU guideline recommended PLND is high at this high-volume center. Neither ORP nor RARP represent a barrier for PLND, when recommended. However, a high number of patients underwent PLND despite absence of guideline recommendation. Possible staging advantages and PLND related complications needs to be individually considered, especially, when LNI risk is low. PMID- 26117217 TI - Factors associated with interhospital transfer of children with respiratory failure from level II to level I pediatric intensive care units. AB - PURPOSE: Of all sources of admission to level I pediatric intensive care units (PICUs), interhospital transfer admissions from level II PICUs carry the highest mortality and resource use burden. We sought to investigate factors associated with transfer of children with respiratory failure from level II to level I PICUs. METHODS: A case-control study was conducted among children with respiratory failure admitted to 6 level II PICUs between January 1, 1997, and December 31, 2007, with frequency matching of 466 nontransferred children (controls) to 187 transferred children (cases). RESULTS: Among 653 children, transferred children were younger and had more comorbidities. After multivariable analysis, transferred children were more likely to have comorbidities (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.36-2.98) and receive escalated care including high-frequency ventilation (OR, 2.57; 95% CI, 1.04-6.37) and surfactant therapy (OR, 5.33; 95% CI, 1.35-21.0). CONCLUSIONS: The study identified patient level and process-of-care factors associated with transfer from level II to level I PICUs. These findings highlight the influence of escalated care on transfer decision making for critically ill children in respiratory failure. PMID- 26117218 TI - Subtle but serious: Pulmonary support after cardiac surgery. PMID- 26117219 TI - Letter to the Editor regarding "Sixty-Four-Slice Computed Tomographic Scanner to Clear Traumatic Cervical Spine Injury: Systematic Review of the Literature". PMID- 26117220 TI - Postintubation hypotension in intensive care unit patients: A multicenter cohort study. AB - PURPOSE: To determine the incidence of postintubation hypotension (PIH) and associated outcomes in critically ill patients requiring endotracheal intubation. MATERIALS AND METHODS: Medical records were reviewed for 479 consecutive critically ill adult patients who required intubation by an intensive care unit (ICU) service at 1 of 4 academic tertiary care hospitals. The primary outcome measure was the incidence of PIH. Secondary outcome measures included mortality, ICU length of stay, requirement for renal replacement therapy, and a composite end point consisting of overall mortality, ICU length of stay greater than 14 days, duration of mechanical ventilation longer than 7 days, and renal replacement therapy requirement. RESULTS: Overall, the incidence of PIH among ICU patients requiring intubation was 46% (218/479 patients). On univariate analysis, patients who developed PIH had increased ICU mortality (37% PIH vs 28% no PIH, P = .049) and overall mortality (39% PIH vs 30% no PIH, P = .045). After adjusting for important risk factors, development of PIH was associated with the composite end point of major morbidity and mortality (odds ratio, 2.00; 95% confidence interval, 1.30-3.07; P = .0017). CONCLUSIONS: The development of PIH is common in ICU patients requiring emergency airway control and is associated with poor patient outcomes. PMID- 26117221 TI - Fast and accurate numerical method for predicting gas chromatography retention time. AB - Predictive modeling for gas chromatography compound retention depends on the retention factor (ki) and on the flow of the mobile phase. Thus, different approaches for determining an analyte ki in column chromatography have been developed. The main one is based on the thermodynamic properties of the component and on the characteristics of the stationary phase. These models can be used to estimate the parameters and to optimize the programming of temperatures, in gas chromatography, for the separation of compounds. Different authors have proposed the use of numerical methods for solving these models, but these methods demand greater computational time. Hence, a new method for solving the predictive modeling of analyte retention time is presented. This algorithm is an alternative to traditional methods because it transforms its attainments into root determination problems within defined intervals. The proposed approach allows for tr calculation, with accuracy determined by the user of the methods, and significant reductions in computational time; it can also be used to evaluate the performance of other prediction methods. PMID- 26117222 TI - Influence of stigma and homophobia on mental health and on the uptake of HIV/sexually transmissible infection services for Cameroonian men who have sex with men. AB - Background Men who have sex with men (MSM) in Cameroon consistently face significant stigma and discrimination. The urban HIV prevalence in MSM is estimated at 35%. This study investigates the effect of stigma, discrimination and alienation on Cameroonian MSM's engagement of the HIV treatment cascade. METHODS: Qualitative interviews were semi-structured using a guide. Participants in Douala, Ngaoundere, Bamenda, Bertoua and Yaounde were asked to describe the MSM social and structural context, MSM knowledge of existing HIV-related services in public and MSM-focussed non-governmental organisation (NGO) clinics. Using a codebook, coded text was extracted from 40 transcripts with Microsoft Word Macros. These texts were analysed for recurring themes that were developed into results. RESULTS: There were three main themes that emerged. First, among those MSM participants seeking HIV services, many commonly reported experiences of discrimination and physical violence outside the healthcare setting. Second, a few respondents used services provided by the Ministry of Health and local NGOs. However, most participants observed limited clinical and cultural competency of public clinic staff. Third, MSM declared that lack of social support and healthcare access caused them much stress. Several individuals recounted their alienation greatly discouraged them from seeking HIV prevention, treatment and care services. CONCLUSIONS: Community-level and public healthcare-related stigma impacts the mental wellbeing of Cameroonian MSM. Alienation among MSM also represents a common obstacle to the uptake of MSM-oriented HIV/AIDS services. Improving provider cultural and clinical competency among Cameroonian health care workers combined with a broader stigma-reduction intervention for Cameroonian healthcare may increase the uptake of HIV prevention, treatment and care among MSM. PMID- 26117223 TI - Baseline adjustment increases accurate interpretation of posturographic sway scores. AB - Postural steadiness may be quantified using posturographic sway measures. These measures are commonly used to differentiate between a person's baseline balance and balance related to some physiological condition. However, the difference in sway scores between the two conditions may be difficult to detect due to large inter-subject variation. We compared detection accuracy provided by three models that linearly regress a sway measure (mean distance, velocity, or frequency) on the effect of eye closure on balance (eyes open (EO) vs. eyes closed (EC)). In Model 1 the dependent variable is a single sway score (EO or EC), whereas in Models 2 and 3 it is a change score (EO-EO or EC-EO). The independent variable is always the group (group=0: EO or group=1: EC). Model 3 also accounts for the regression to the mean effect (RTM), by considering the baseline value (EO) as a covariate. When differentiating between EO and EC conditions, 94% accuracy can be achieved when using mean velocity as sway measure and either Model 2 or 3. Thus by adjusting for baseline score one increases the accurate interpretation of posturographic sway scores. PMID- 26117224 TI - The effect of school trolley load on spatiotemporal gait parameters of children. AB - OBJECTIVE: The present study evaluated spatiotemporal gait parameters in children when they were carrying school trolleys of different weights. METHODS: We assessed four conditions: without trolley, 10%, 15% and 20% of the subject's body weight. Fourteen students from a primary school (aged 11.43+/-0.51 years) participated in this study. Velocity, cadence, stride length, stance phase, swing phase, single support phase and double support phase were analysed using an electronic walkway. RESULTS: Compared with normal walking, the three load conditions produced significant decreases in swing phase (p<0.001) and single support phase (p<0.001) and significant increases in cadence (p=0.019), stance phase (p<0.001) and double support phase (p<0.001). No statistically-significant differences were found between the three load conditions. CONCLUSION: Compared with normal walking, walking while carrying a trolley produced significant changes in most of the spatiotemporal gait parameters measured, perhaps due to the load-mediated changes in stability and balance. The spatiotemporal gait parameters were similar between the load conditions, indicating that the amount of load did not affect gait. PMID- 26117225 TI - Tibial stress reaction presenting as bilateral shin pain in a man taking denosumab for giant cell tumor of the bone. AB - Prolonged bisphosphonate use has been associated with increased risk of atypical femoral fractures. Very few cases of atypical femoral fractures have been reported with denosumab. We report a case of bilateral tibial stress reactions in a 60-year-old man with no history of osteoporosis who was on prolonged high-dose denosumab for the treatment of giant cell tumor of bone. He presented with a 3 month history of pain in his bilateral shins worsening with activity and improving with rest. Although initial radiographs were unremarkable, he was found to have changes consistent with a stress reaction on magnetic resonance imaging of the distal tibia. To our knowledge, bilateral tibial stress reactions have not been previously reported with anti-resorptive therapies (neither bisphosphonates nor denosumab). Our case is intriguing in terms of the development of stress reactions as a precursor to stress fractures which may also relate to atypical fractures. Our case suggests a possible association between denosumab use and stress reactions. Of note the indication for denosumab in our case was for the treatment of giant cell tumor of bone where the Food and Drug Administration (FDA) approved dose is substantially higher than the FDA approved dose for osteoporosis treatment. Although rare, clinicians should consider the possibility of stress fractures in patients on anti-resorptive medications such as denosumab, especially when a patient presents with new onset thigh pain, hip pain or pain over an area affecting the long bones. Evaluation by imaging of affected areas should be pursued to enable early detection and intervention, as well as prevention of morbidity and associated ongoing risk to the patient. PMID- 26117226 TI - Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: A cross-sectional study. AB - BACKGROUND: Bi-allelic CYP24A1 mutations can cause idiopathic infantile hypercalcemia (IIH), adult-onset nephrocalcinosis, and possibly bone metabolism disturbances. It is currently unclear if heterozygous carriers experience clinical problems or biochemical abnormalities. Our objective is to gain insight in the biochemical profile and health problems in CYP24A1 heterozygotes. STUDY DESIGN: Cross-sectional evaluation of participants. Data of previously reported carriers are reviewed. SETTING AND PARTICIPANTS: Outpatient clinic of a tertiary care hospital. Participants were eight family members of an infant with a well characterized homozygous CYP24A1 mutation c.1186C>T p.(Arg396Trp). OUTCOMES: Serum vitamin D metabolites. Symptoms or biochemical signs of hypercalcemia, hypercalciuria or nephrocalcinosis. Bone health in heterozygous as compared to wild type (WT) subjects. MEASUREMENTS: Genotyping by Sanger sequencing; vitamin D metabolites by liquid chromatography tandem mass spectrometry; renal, calcium and bone markers by biochemical analyses; presence of nephrocalcinosis by renal ultrasound; bone health by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: Six participants were heterozygous carriers of the mutation. None of the heterozygous subjects had experienced IIH. One had a documented history of nephrolithiasis, two others had complaints compatible with this diagnosis. No major differences between WT and heterozygous subjects were found regarding bone health, serum or urinary calcium or 25OHD/24,25(OH)2D ratio. Literature reports on three out of 33 heterozygous cases suffering from IIH. In all three, the 25OHD/24,25(OH)2D ratio was highly elevated. Nephrocalcinosis was frequently reported in family members of IIH cases. LIMITATIONS: Small sample size, lack of a large control group. CONCLUSIONS: Our and literature data suggest that most heterozygous CYP24A1 mutation carriers have a normal 25OHD/24,25(OH)2D ratio, are usually asymptomatic and have a normal skeletal status but may possibly be at increased risk of nephrocalcinosis. A review of the available literature suggests that an elevated 25OHD/24,25(OH)2D ratio may be associated with symptoms of IHH, irrespective of carrier status. PMID- 26117227 TI - Structural investigation of cell wall polysaccharides of Lactobacillus delbrueckii subsp. bulgaricus 17. AB - Lactobacilli are valuable strains for commercial (functional) food fermentations. Their cell surface-associated polysaccharides (sPSs) possess important functional properties, such as acting as receptors for bacteriophages (bacterial viruses), influencing autolytic characteristics and providing protection against antimicrobial peptides. The current report provides an elaborate molecular description of several surface carbohydrates of Lactobacillus delbrueckii subsp. bulgaricus strain 17. The cell surface of this strain was shown to contain short chain poly(glycerophosphate) teichoic acids and at least two different sPSs, designated here as sPS1 and sPS2, whose chemical structures were examined by 2D nuclear magnetic resonance spectroscopy and methylation analysis. Neutral branched sPS1, extracted with n-butanol, was shown to be composed of hexasaccharide repeating units (-[alpha-d-Glcp-(1-3)-]-4-beta-l-Rhap2OAc-4-beta-d Glcp-[alpha-d-Galp-(1-3)]-4-alpha-Rhap-3-alpha-d-Galp-), while the major component of the TCA-extracted sPS2 was demonstrated to be a linear d-galactan with the repeating unit structure being (-[Gro-3P-(1-6)-]-3-beta-Galf-3-alpha Galp-2-beta-Galf-6-beta-Galf-3-beta-Galp-). PMID- 26117228 TI - Structure of the O-specific polysaccharide from the deep-sea marine bacterium Idiomarina abyssalis KMM 227(T) containing a 2-O-sulfate-3-N-(4-hydroxybutanoyl) 3,6-dideoxy-d-glucose. AB - The O-specific polysaccharide was isolated from the lipopolysaccharide of type strain Idiomarina abyssalis KMM 227(T) and studied by sugar analysis, Smith degradation, and two-dimensional (1)H and (13)C NMR spectroscopy including (1)H,(1)H-TOCSY, (1)H,(1)H-COSY, (1)H,(1)H-ROESY, (1)H,(13)C-HSQC, (1)H,(13)C HMBC, (1)H,(13)C-H2BC and (1)H,(13)C-HSQC-TOCSY experiments. The new structure of the O-specific polysaccharide of I. abyssalis KMM 227(T) containing 2-O-sulfate-3 N-(4-hydroxybutanoyl)-3,6-dideoxy-d-glucose was established. PMID- 26117229 TI - Malpractice in colorectal surgery: a review of 122 medicolegal cases. AB - BACKGROUND: Medical malpractice has become a rising concern for physicians, affecting the cost and delivery of health care. Colorectal procedures account for 24% of all general surgery cases, a high-risk specialty, with 15% of its physicians facing malpractice suit annually. METHODS: The Westlaw legal database was used to identify colorectal malpractice cases. RESULTS: In all, 122 of 230 lawsuits were included in this study. A majority of 65.6% were physician verdicts, 19.7% plaintiff verdicts, and 14.8% reached a settlement. Plaintiff payments were found to be significantly higher than settlement awards. The most common cause of alleged malpractice was failure to recognize a complication in a timely manner (45.1%), followed by damage to surrounding tissues (36.1%). CONCLUSIONS: The most common cause of alleged malpractice was failure to recognize a complication in a timely manner, followed by damage to surrounding tissue. Plaintiff awards were significantly higher than settlement payments. It is important to understand the mechanism of malpractice allegations to better prevent litigation and improve patient care. PMID- 26117230 TI - Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model. AB - Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP 1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP 1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases. PMID- 26117231 TI - Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis. AB - OBJECTIVES: Development of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC)-patients is associated with a poor prognosis. It has been suggested that LM-patients with epidermal growth factor receptor mutated (EGFR+) NSCLC have a superior prognosis compared to EGFR-wild type NSCLC. Studies in EGFR+ NSCLC-patients with LM are scarce. We retrospectively evaluated a multi institutional cohort of EGFR+ NSCLC-patients for LM to assess clinical outcome in relation to patient characteristics and treatment modalities. MATERIAL AND METHODS: Medical records of advanced-stage EGFR+ NSCLC-patients (diagnosed between August 2000 and June 2014) from 11 Dutch hospitals were evaluated for LM as diagnosed by MRI and/or cytopathological liquor analysis. Data on patient characteristics, treatment and outcome were collected. RESULTS: Thirty-two of 356 (9.0%) advanced-stage EGFR+ NSCLC-patients (median follow-up 21.0 months), were diagnosed with LM between 2006 and 2014. LM was diagnosed by MRI (59.4%), liquor analysis (9.4%) or by both MRI and liquor analysis (31.3%). Median survival after LM-diagnosis was 3.1 months (95% CI: 0.0-7.3). Six- and 12-month survival rates were 43.8% and 18.8%, respectively. Patients with performance status (PS) 0-1 at time of diagnosis of LM had a significantly higher chance to be alive after 6 months and had a significantly longer survival after diagnosis of LM compared to patients with PS>=2. Age, treatment with high-dose EGFR-TKI, radiotherapy and whether LM was the only site of progressive disease did not influence survival after LM-diagnosis. CONCLUSION: Although median survival after LM-diagnosis in EGFR-mutated NSCLC-patients was poor, a substantial part of the patients had a prolonged survival of more than 6 months. PS of 0-1 at time of diagnosis of LM was associated with prolonged survival. No other patient- or treatment-related characteristics were identified. Further research is warranted to identify treatment strategies that improve survival in EGFR+ NSCLC-patients with LM. PMID- 26117232 TI - Performance of the BG1Luc ER TA method in a qHTS format. AB - In 2012, the BG1Luc4E2 estrogen receptor (ER) transactivation (TA) method (BG1Luc ER TA) was accepted by U.S. regulatory agencies and the Organisation for Economic Co-operation and Development to detect substances with ER agonist activity. The method is now part of the Tier 1 testing battery in the Environmental Protection Agency's Endocrine Disruptor Screening Program. The BG1Luc ER TA method uses the BG1 ovarian cell line that endogenously expresses full-length ER (alpha and beta) and is stably transfected with a plasmid containing four estrogen responsive elements upstream of a luciferase reporter gene. To allow increased throughput and testing efficiency, the BG1Luc ER TA ("BG1 manual") method was adapted for quantitative high-throughput screening (BG1 qHTS) in the U.S. Tox21 testing program. The BG1 qHTS test method was used to test approximately 10,000 chemicals three times each, and concentration-response data (n=15) were analyzed to evaluate test method performance. The balanced accuracy of the BG1 qHTS test method (97% [32/33]) was determined by comparing results to ER TA performance standards for the BG1 manual method. Concordance between the BG1 manual and qHTS methods was 92% (57/62) when calculated for a larger set of non-reference chemicals tested in both methods. These data demonstrate that the performance of the BG1 qHTS is similar to the currently accepted BG1 manual method, thereby establishing the utility of the BG1 qHTS method for identifying ER active environmental chemicals. PMID- 26117233 TI - Fed-batch cultivation of Arthrospira and Chlorella in ammonia-rich wastewater: Optimization of nutrient removal and biomass production. AB - In the present work the cyanobacterium Arthrospira platensis and the microalga Chlorella vulgaris were fed-batch cultivated in ammonia-rich wastewater derived from the anaerobic digestion of poultry litter. Aim of the study was to maximize the biomass production along with the nutrient removal aiming to wastewater treatment. Ammonia and phosphorus removals were very high (>95%) for all cultures investigated. Both microorganisms were able to remove volatile fatty acids to an extent of >90%, indicating that they were capable of mixotrophic growth. Chemical oxygen demand and proteins were also removed in various degrees. In contrast, in all cultures carbohydrate concentration was increased. The biochemical composition of the microorganisms varied greatly and was influenced by the indicate that the nutrient availability. A. platensis accumulated carbohydrates (~ 40%), while C. vulgaris accumulated lipids (~ 50%), rendering them interesting for biofuel production. PMID- 26117234 TI - Impact of the substrate loading regime and phosphoric acid supplementation on performance of biogas reactors and microbial community dynamics during anaerobic digestion of chicken wastes. AB - This study evaluates the effects of increasing organic loading rate (OLR) and decreasing hydraulic retention time (HRT) as well as phosphoric acid addition on mesophilic reactors' performance and biogas production from chicken wastes. Furthermore, microbial community composition in reactors was characterized by a 16S rRNA gene-based pyrosequencing analysis. Each step of increasing OLR impacted on the activity of microorganisms what caused a temporary decrease in biogas production. The addition of phosphoric acid resulted in the increased biogas production with values between 361 and 447 mL g(VS)(-1) from day 61 to day 74 compared to control reactor (309-350 mL g(VS)(-1)). With reactors' operation, Bacteroidetes phylotypes were noticeably replaced with Firmicutes representatives, and significant increase of Clostridium sp. was identified. Within Euryarchaeota, Methanosarcina sp. dominated in all analyzed samples, in which high ammonium levels were detected (3.4-4.9 NH4(+)-N g L(-1)). These results can help in better understanding the anaerobic digestion process of simultaneously ammonium/phosphate-rich substrates. PMID- 26117235 TI - Anaerobic treatment of rice winery wastewater in an upflow filter packed with steel slag under different hydraulic loading conditions. AB - Rice-washing drainage (RWD), a strong organic wastewater, was anaerobically treated using an upflow filter filled with blast-furnace slag. The continuous performance of the reactor was examined at varying hydraulic retention times (HRTs). The reactor achieved 91.7% chemical oxygen demand removal (CODr) for a 10 day HRT (0.6 g COD/Ld organic loading rate) and maintained fairly stable performance until the HRT was shortened to 2.2 days (CODr > 84%). Further decreases in HRT caused process deterioration (CODr < 50% and pH < 5.5 for a 0.7 day HRT). The methane production rate increased with decreasing HRT to reach the peak level for a 1.3-day HRT, whereas the yield was significantly greater for 3.4 day or longer HRTs. The substrate removal and methane production kinetics were successfully evaluated, and the generated kinetic models produced good performance predictions. The methanogenic activity of the reactor likely relies on the filter biofilm, with Methanosaeta being the main driver. PMID- 26117236 TI - Mass flow and energy balance plus economic analysis of a full-scale biogas plant in the rice-wine-pig system. AB - This paper presents mass flow and energy balance as well as an economic analysis for a biogas plant in a rice-wine-pig system at a practical rather than laboratory scale. Results showed feeding amount was 65.30 t d(-1) (total solid matter (TSM) 1.3%) for the normal temperature continuous stirred tank reactor (CSTR), and 16.20 t d(-1) (TSM 8.4%) for the mesophilic CSTR. The digestion produced 80.50 t d(-1) of mass, with 76.41 t d(-1) flowing into rice fields and 4.49 t d(-1) into composting. Energy consumption of this plant fluctuated with seasons, and surplus energy was 823, 221 kWh/year. Thus, biogas plant was critical for material recycling and energy transformation of this agro-ecosystem. The economic analysis showed that the payback time of the plant was 10.9 years. It also revealed application of biogas as a conventional energy replacement would be attractive for a crop-wine-livestock ecosystem with anaerobic digestion of manure. PMID- 26117237 TI - Saline wastewater treatment by Chlorella vulgaris with simultaneous algal lipid accumulation triggered by nitrate deficiency. AB - Chlorella vulgaris, a marine microalgae strain adaptable to 0-50 g L(-1) of salinity, was selected for studying the coupling system of saline wastewater treatment and lipid accumulation. The effect of total nitrogen (T N) concentration was investigated on algal growth, nutrients removal as well as lipid accumulation. The removal efficiencies of TN and total phosphorus (TP) were found to be 92.2-96.6% and over 99%, respectively, after a batch cultivation of 20 days. To illustrate the response of lipid accumulation to nutrients removal, C. vulgaris was further cultivated in the recycling experiment of tidal saline water within the photobioreactor. The lipid accumulation was triggered upon the almost depletion of nitrate (<5 mg L(-1)), till the final highest lipid content of 40%. The nitrogen conversion in the sequence of nitrate, nitrite, and then to ammonium in the effluents was finally integrated with previous discussions on metabolic pathways of algal cell under nitrogen deficiency. PMID- 26117238 TI - Grape marc as a source of carbohydrates for bioethanol: Chemical composition, pre treatment and saccharification. AB - Global grape production could generate up to 13 Mt/yr of wasted biomass. The compositions of Cabernet Sauvignon (red marc) and Sauvignon Blanc (white marc) were analyzed with a view to using marc as raw material for biofuel production. On a dry weight basis, 31-54% w/w of the grape marc consisted of carbohydrate, of which 47-80% was soluble in aqueous media. Ethanol insoluble residues consisted mainly of polyphenols, pectic polysaccharides, heteroxylans and cellulose. Acid and thermal pre-treatments were investigated for their effects on subsequent cellulose saccharification. A 0.5M sulfuric acid pre-treatment yielded a 10% increase in the amount of liberated glucose after enzymatic saccharification. The theoretical amount of bioethanol that could be produced by fermentation of grape marc was up to 400 L/t. However, bioethanol from only soluble carbohydrates could yield 270 L/t, leaving a polyphenol enriched fraction that may be used in animal feed or as fertilizer. PMID- 26117239 TI - One-step production of biodiesel from oils with high acid value by activated Mg Al hydrotalcite nanoparticles. AB - Activated Mg-Al hydrotalcite (HT-Ca) nanoparticles (<45 nm) were synthesized by co-precipitation and hydrothermal activation with aqueous Ca(OH)2 solution. They were characterized by various techniques including X-ray diffraction, inductively coupled plasma atomic-emission spectrometer, Brunauer-Emmett-Teller method, scanning electronic microscope-X-ray energy dispersive analysis and temperature programmed desorption method. HT-Ca presented both acidic and basic due to the formation of Mg4Al2(OH)14 . 3H2O, Mg2Al(OH)7 and AlO(OH) nanocrystals to esterify and transesterify oils with high acid value (AV). Under conditions of 5 wt% HT Ca, 160 degrees C, 30/1 methanol/oil molar ratio and 4h, 93.4% Jatropha biodiesel yield was obtained at AV of 6.3 mg KOH/g with 4 cycles (biodiesel yield>86%). It was further found that it can resist free fatty acids, and biodiesel yield reached 92.9% from soybean oil with high AV of 12.1. HT-Ca catalyst showed a potential practical application for direct production of biodiesel from oils with high AV without pretreatment. PMID- 26117240 TI - The role of co-solvents in improving the direct transesterification of wet microalgal biomass under supercritical condition. AB - In this research, direct conversion of wet algal biomass into biodiesel using supercritical methanol was studied. In this process, microalgal lipids simultaneously was extracted and converted to biodiesel under high pressure and temperature conditions without using any catalyst. Several experiments have been performed to optimize the methanol amount and it has been revealed that the best performance was achieved by using methanol/wet biomass ratio of 8:1. The effect of using various co-solvents in increasing the efficiency of the supercritical process was investigated. It has been shown that hexane was the most effective co solvent and its optimal ratio respect to wet biomass was 6:1. The results indicated that compare to conventional extraction plus transesterification reaction, fatty acid methyl esters (FAMEs) yield was slightly higher in the direct conversion process. Moreover, increasing the moisture content up to 80% has no significant effect on reducing the performance of this process. PMID- 26117241 TI - Effectiveness of activated carbon disk for the analysis of iodine in water samples using wavelength dispersive X-ray fluorescence spectrometry. AB - A novel approach using wavelength dispersive X-ray fluorescence (WDXRF) spectrometry combined with an activated carbon (AC) disk was developed for the determination of total iodine concentrations in water samples. Dissolved iodine species (i.e., I(-) and IO3(-)) in water samples were preconcentrated on the AC disk and directly analyzed by WDXRF spectrometry. The adsorption behavior of I(-) and IO3(-) on the AC disk was assessed at varying pH levels (4, 6, and 8). The AC disks completely retained the I(-) and IO3(-) for all the pH levels tested. The calibration curve obtained from the iodine concentrations (i.e., 0, 20, 200, and 400 MUg) of AC disks and the measured X-ray intensity from the WDXRF analysis showed a good linearity (R(2)=0.9960), with a relatively low limit of detection (0.575 MUg). The durability of the AC disk for repeatable measurements was also assessed to validate the sustainability of the proposed method and consequently the measured X-ray intensity for the AC disks was constant until 8d of analysis time. The accuracy of the proposed AC-WDXRF method was confirmed by measuring iodine concentration spiked in drinking water using inductively coupled plasma mass spectrometry (ICP-MS). The proposed method is simple, rapid, efficient, and environmental friendly for iodine analysis in water samples. As a precursor of disinfection by products (DBPs), it is important to determine the total iodine concentrations in raw water. PMID- 26117242 TI - A cost-effective technique for cardiac sparing with deep inspiration-breath hold (DIBH). AB - Deep inspiration breath hold (DIBH) is an effective technique to reduce cardiac and pulmonary dose during breast radiotherapy (RT). However, as a result of expense and the technical challenges of program implementation, DIBH has not been widely adopted in clinical practice. This report describes a program for DIBH this is relatively inexpensive to implement and has little impact on patient throughput. Multiple redundant mechanisms are incorporated to assure accurate and safe delivery of RT during DIBH. Laser alignment verifies that chest wall excursion is reliably reproduced and maintained during treatment. Chest wall excursion is also monitored independently using an infrared camera trained on a reflective marker on the chest wall. This system automatically triggers "beam off" in the event of movement of the target beyond pre-determined thresholds. Finally, physician review of cine imaging obtained during treatment provides an off-line verification of accurate RT delivery. The approach described herein lowers the investment necessary for implementation of DIBH and may facilitate broader adoption of this valuable technique. PMID- 26117244 TI - Commentary. Oligognostic mega-analysis. Is Archie turning in his grave? AB - The Cochrane Collaboration has developed guidelines for the conduct of meta analyses and systematic reviews. When applied to well-conducted short-duration randomized controlled trials, meta-analysis can be informative, but seldom in prolonged trials, because of "unblinding", non-adherence, losses to follow-up, and "crossovers". The meta-analysis of observational studies is beset by problems of bias, confounding, variable methodology, and lack of transparency, and is seldom valid. For the evaluation of partly quantitative or non-quantitative studies, systematic reviews using standardized methods have been developed. However, such reviews are inferior to well-conducted qualitative reviews tailored to the specific topics at issue. PMID- 26117245 TI - Association of Lecithin Cholesterol Acyltransferase rs5923 Polymorphism in Iranian Individuals with Extremely Low High-Density Lipoprotein Cholesterol: Tehran Lipid and Glucose Study. AB - BACKGROUND: The serum concentration of high-density lipoprotein cholesterol (HDL C) is one of the important heritable risk factors for cardiovascular disease and is a target for therapeutic intervention. In this study, we aimed to evaluate the effects of lecithin cholesterol acyltransferase (LCAT) gene polymorphism rs5923 on LCAT enzyme activity and serum HDL-C concentration. METHODS: The study population was selected from consecutive individuals with HDL-C <= 5th percentile (n = 73) and extremely high HDL-C >= 95th percentile (n = 57) who had participated in the Tehran Lipid and Glucose Study. The rs5923 polymorphism was genotyped using direct sequencing. LCAT activity was measured by fluorometric assay kit, and lipid concentrations were measured using the enzymatic colorimetric method. RESULTS: The genotype frequencies were significantly different between the high HDL-C group (CC 94.7%, CT 5.3%) and the low HDL-C group (CC 83.6%, CT 16.4%) (P = 0.048). The T-allele frequencies in subjects with low and high HDL-C were 0.082 and 0.026, respectively (P = 0.16). The association of the single-nucleotide polymorphism rs5923 with low HDL-C was not statistically significant after adjustment for age, sex, and BMI (odd ratio = 2.65, 95% confidence interval = 0.32-21.5, P = 0.36, regression logistic analysis). Also, the effects of LCAT enzyme activity did not depend on the HDL-C level (P = 0.24). CONCLUSION: rs5923 polymorphism is not associated with low HDL-C levels in Iranian population. PMID- 26117246 TI - Oxidative stress in bipolar and schizophrenia patients. AB - Oxidative stress has an important place in studies investigating the pathophysiology of psychiatric diseases. In spite of this fact, longitudinal studies are required to clarify the subject. Therefore, in this study, we examined lipid peroxidation, protein oxidation, total oxidized guanine species, superoxide dismutase (SOD) and total glutathione (GSH) levels in blood collected from adult bipolar patients (n=18) during manic and euthymic episodes, schizophrenic patients (n=18) during acute psychotic attack and remission phases and the control group (n=18). There was a significant increase in the level of lipid peroxidation in the bipolar disorder manic episode group (BD-ME) compared to control group. The level of protein oxidation was significantly higher in the schizophrenia acute psychotic attack group (SZ-APA) compared to the control group. The level of total oxidized guanine species was statistically higher in all psychiatric groups compared to the control group. There was no significant difference among the groups with regard to SOD and GSH. Consequently, we believe that lipid peroxidation may be effective in the pathogenesis of bipolar patients; that protein oxidation may be of importance in the pathogenesis of schizophrenia and that total oxidized guanine species may be crucial in the pathogeneses of both psychiatric disorders. PMID- 26117247 TI - Adjunctive psychosocial intervention following Hospital discharge for Patients with bipolar disorder and comorbid substance use: A pilot randomized controlled trial. AB - Bipolar disorder and substance use disorders are highly debilitating conditions, and especially when co-occurring, are associated with a variety of negative outcomes. Surprisingly, there is a relative lack of research on feasible and effective psychosocial treatments for individuals with comorbid bipolar and substance use disorder (BD-SUD), and a dearth of literature examining interventions designed specifically to improve outcomes such as symptoms, functioning, and treatment engagement/adherence following psychiatric hospitalization in this population. In the current paper, we report results of a pilot randomized controlled trial (n=30), comparing the recently developed Integrated Treatment Adherence Program, which includes individual and telephone sessions provided to patients and their significant others, versus Enhanced Assessment and Monitoring for those with BD-SUD. Participants who received the Integrated Treatment Adherence Program demonstrated significantly faster and greater improvements in depression, mania, functioning, and values-consistent living than participants randomized to Enhanced Assessment and Monitoring, and there was a trend for increased treatment adherence over time. Results are discussed in light of existing literature and study limitations, and suggestions for future research are proposed. PMID- 26117248 TI - Intact speed of processing in a community-based sample of adults with high schizotypy: A marker of reduced psychosis risk? AB - Speed of processing is impaired in schizophrenia but intact in schizotypal college students. In view of this disparity, we investigated whether deficient processing speed was associated with schizotypy in adults from the general community. Data were drawn from the Western Australian Family Study of Schizophrenia, including 216 (non-clinical) adults from the general community, and a reference group with schizophrenia spectrum disorder (N=224). Schizotypal traits were assessed with the Schizotypal Personality Questionnaire, whilst processing speed was assessed with a digit-symbol coding task. Community controls had significantly higher digit symbol coding scores than patients with psychosis. However, both correlational and hierarchical regression analysis indicated a lack of association between Cognitive-perceptual, Interpersonal or Disorganized schizotypy traits and digit symbol coding performance. Relative to Australian norms there was also no evidence of a non-linear decline in coding in high schizotypes in young, mature or senior age groups. The results show that speed of information processing is unimpaired in high schizotypes from the general community. The possibility that intact processing speed in at-risk groups confers protection to psychosis onset is discussed. Assessing the trajectory of processing speed throughout development may provide a useful clinical screening tool to distinguish those at heightened risk of developing psychosis. PMID- 26117249 TI - Factor structure of the autonomy preference index in people with severe mental illness. AB - People vary in the amount of control they want to exercise over decisions about their healthcare. Given the importance of patient-centered care, accurate measurement of these autonomy preferences is critical. This study aimed to assess the factor structure of the Autonomy Preference Index (API), used widely in general healthcare, in individuals with severe mental illness. Data came from two studies of people with severe mental illness (N=293) who were receiving mental health and/or primary care/integrated care services. Autonomy preferences were assessed with the API regarding both psychiatric and primary care services. Confirmatory factor analysis was used to evaluate fit of the hypothesized two factor structure of the API (decision-making autonomy and information-seeking autonomy). Results indicated the hypothesized structure for the API did not adequately fit the data for either psychiatric or primary care services. Three problematic items were dropped, resulting in adequate fit for both types of treatment. These results suggest that with relatively minor modifications the API has an acceptable factor structure when asking people with severe mental illness about their preferences to be involved in decision-making. The modified API has clinical and research utility for this population in the burgeoning field of autonomy in patient-centered healthcare. PMID- 26117250 TI - Emotional intelligence as a mediator between rumination and suicidal ideation among depressed inpatients: The moderating role of suicidal history. AB - Suicide is a substantial public health problem, and it remains a serious cause of death in the world. Therefore, this study was designed to examine the relationships between brooding, reflection, emotional intelligence (assessed by performance-based test), and suicidal ideation; the mediation role of emotional intelligence on the relationships between brooding and reflection with suicidal ideation; and the moderating role of suicidal history on the relationships between brooding, reflection, and emotional intelligence with suicidal ideation among Iranian depressed adolescents. The study consisted of a cross-sectional sample of 202 depressed adolescent inpatients from five public hospitals in Tehran, Iran completed measures of depression, rumination, emotional intelligence, and suicide attempt history as indices of suicidal ideation. Structural Equation Modelling estimated that depressed adolescent inpatients with high levels of brooding and reflective rumination, and low levels of emotional intelligence were more likely to report suicidal ideation. Moreover, emotional intelligence partially mediated the relationships between brooding and reflective rumination with suicidal ideation. Suicidal history moderated the relationships between brooding, reflection, and emotional intelligence with suicidal ideation. These findings reinforce the importance of emotional intelligence as an influencing factor against the deleterious effects of rumination styles and suicidal ideation. The results indicate that brooding and reflection have detrimental effects on suicidal ideation in depressed inpatients. PMID- 26117251 TI - Innate lymphoid cells open a new window on allergic diseases. PMID- 26117253 TI - Group 2 innate lymphoid cells and asthma. AB - Group 2 innate lymphoid cells (ILC2s) are recently identified cell populations that produce type 2 cytokines such as IL-5 and IL-13 in response to epithelial cell-derived cytokines. Although ILC2s were initially reported to play a key role in the anti-helminth innate immunity, we now have greater interest in their role in asthma and other allergic diseases. In various asthma mouse models, ILC2s provoke eosinophilic inflammation accompanied by airway hyperresponsiveness independent of acquired immunity. Moreover, recent mouse studies show that ILC2s also promote acquired immunity and Th2 polarization, and various cytokines and lipid mediators influence the functions of ILC2s. Although ILC2s have also been identified in humans, studies on the role of human ILC2s in asthma are very limited. Thus far, human studies have shown that there is a slight difference in responsiveness and production of cytokines between mouse and human ILC2s, and it has been suggested that ILC2s are involved in allergic-type asthma and the exacerbation of asthma. In this review, we focus on mouse and human ILC2s, and discuss their role in asthma. PMID- 26117252 TI - ILC2s and fungal allergy. AB - Innate lymphoid cells (ILCs) have emerged recently as an important component of the immune system and the cell type that regulates mucosal immune responses and tissue homeostasis. Group 2 ILCs (ILC2s), a subset of ILCs, reside in various tissues and are characterized by their capacity to produce type 2 cytokines and tissue growth factors. These ILC2s play an important role in allergic immune responses by linking signals in the atmospheric environment to the immune system. Fungi are one of the major allergens associated with human asthma, and animal and in vitro models using the fungal allergens have provided significant information toward our understanding of the mechanisms of allergic disease. In mouse models of fungus-induced allergic airway inflammation, IL-33, IL-25, and TSLP are released by airway epithelial cells. Lung ILC2s that respond to these cytokines quickly produce a large quantity of type 2 cytokines, resulting in airway eosinophilia, mucus production, and airway hyperreactivity even in the absence of adaptive immune cells. Evidence also suggests that ILC2s interact with conventional immune cells, such as CD4(+) T cells, and facilitate development of adaptive immune response and persistent airway inflammation. ILC2s are also present in respiratory mucosa in humans. Further investigations into the biology of ILC2s and their roles in the pathophysiology of allergic diseases will provide major conceptual advances in the field and may provide useful information toward development of new therapeutic strategies for patients. PMID- 26117254 TI - Proallergic cytokines and group 2 innate lymphoid cells in allergic nasal diseases. AB - Recent advances in our understanding of proallergic cytokines and group 2 innate lymphoid cells (ILC2s) indicate their critical roles in type 2 immunity-mediated disorders. Proallergic cytokines, interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin, are released from epithelial cells in inflamed tissues and drive type 2 inflammation by acting on innate and acquired immune systems. ILC2s are an innate immune population that responds to proallergic cytokines by producing type 2 cytokines. In line with allergic disorders in the lung, skin, and intestine, emerging evidence suggests the involvement of proallergic cytokines and ILC2s in allergic nasal diseases such as chronic rhinosinusitis with polyps (CRSwNP), allergic fungal rhinosinusitis, and allergic rhinitis (AR). In CRSwNP patients, both proallergic cytokine levels and ILC2s frequency are increased in the nasal mucosa. Increased proallergic cytokine levels correlate with poorer disease outcomes in CRSwNP. Levels of nasal proallergic cytokines are also elevated in AR patients. In addition, animal studies demonstrate that cytokines are essential for the development of AR. It is becoming clear that the proallergic cytokine/ILC2s axis participates in allergic diseases by multiple mechanisms dependent upon the inflammatory context. Thus, a thorough understanding of these cytokines and ILC2s including their tissue- and disease-specific roles is essential for targeting the pathways to achieve therapeutic applications. PMID- 26117255 TI - Involvement of PU.1 in NFATc1 promoter function in osteoclast development. AB - BACKGROUND: The transcription factors NFATc1 and PU.1 play important roles in osteoclast development. NFATc1 and PU.1 transactivate osteoclast-specific gene expression and a deficiency in NFATc1 or PU.1 genes causes osteopetrosis due to an insufficient development of osteoclasts. However, the existence of cross regulation between NFATc1 and PU.1 is largely unknown. In the present study, the role of PU.1 in NFATc1 expression was investigated. METHODS: Osteoclasts were generated from mouse bone marrow cells. PU.1 knockdown was performed with siRNA introduction. The mRNA levels in siRNA-introduced cells were determined by quantitative RT-PCR. The involvement of PU.1 in the NFATc1 promoter was analyzed by using a chromatin immunoprecipitation (ChIP) assay and a reporter assay. Retrovirus vector was used for enforced expression of PU.1. RESULTS: Introduction of PU.1 siRNA into bone marrow-derived osteoclasts resulted in a decrease in NFATc1 mRNA level. A ChIP assay showed that PU.1 bound to the NFATc1 promoter in osteoclasts. NFATc1 promoter activity was reduced in PU.1 knockdown cells as assessed by a reporter assay. PU.1 siRNA introduction also downregulated the expression of osteoclast-specific genes and tartrate resistant acid phosphatase (TRAP) activity. Enforced expression of PU.1 using a retrovirus vector increased NFATc1 expression and TRAP activity. When NFATc1 expression was knocked down by using siRNA, the induction of osteoclast-specific genes and TRAP-positive cells was suppressed without affecting the expression level of PU.1. CONCLUSIONS: These results indicate that PU.1 is involved in osteoclast development by transactivating NFATc1 expression via direct binding to the NFATc1 promoter. PMID- 26117256 TI - Improved sensitivity to venom specific-immunoglobulin E by spiking with the allergen component in Japanese patients suspected of Hymenoptera venom allergy. AB - BACKGROUND: Ves v 5 and Pol d 5, which constitute antigen 5, are recognized as the major, most potent allergens of family Vespidae. Several studies have reported the diagnostic sensitivity of the novel recombinant (r)Ves v 5 and rPol d 5 allergens in routine clinical laboratory settings by analyzing a group of Vespula and Polistes venom-allergic patients. In this study, we analyzed the sensitivity to venom specific (s)IgE by spiking with rVes v 5 and rPol d 5 in Japanese patients suspected of Hymenoptera venom allergy. METHODS: Subjects were 41 patients who had experienced systemic reactions to hornet and/or paper wasp stings. Levels of serum sIgE against hornet and paper wasp venom by spiking with rVes v 5 and rPold d 5, respectively, as improvement testing, compared with hornet and paper wasp venom, as conventional testing, were measured by ImmunoCAP. RESULTS: Of the 41 patients, 33 (80.5%) were positive (>=0.35 UA/ml) for hornet and/or paper wasp venom in conventional sIgE testing. sIgE levels correlated significantly (P < 0.01) between hornet (R = 0.92) or paper wasp venom (R = 0.78) in improvement testing and conventional testing. To determine specificity, 20 volunteers who had never experienced a Hymenoptera sting were all negative for sIgE against these venoms in both improvement and conventional testing. Improved sensitivity was seen in 8 patients negative for sIgE against both venoms in conventional testing, while improvement testing revealed sIgE against hornet or paper wasp venom in 5 (total 38 (92.7%)) patients. CONCLUSIONS: The measurement of sIgE following spiking of rVes v 5 and rPol d 5 by conventional testing in Japanese subjects with sIgE against hornet and paper wasp venom, respectively, improved the sensitivity for detecting Hymenoptera venom allergy. Improvement testing for measuring sIgE levels against hornet and paper wasp venom has potential for serologically elucidating Hymenoptera allergy in Japan. PMID- 26117257 TI - Racial differences in eosinophilic gastrointestinal disorders among Caucasian and Asian. AB - BACKGROUND: Although there is an increasing number of eosinophilic gastrointestinal disorders (EGID) cases including eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE), being reported globally, no systematic reviews have been conducted to elucidate the racial differences in these disorders. We aimed to show the racial differences, especially among Caucasians and Asians, in the risk of EoE and EGE. METHODS: We conducted a systematic review using PubMed in September 2012. All case reports and case series on EGID that involved human subjects and described race or ethnicity, as well as pathological findings, were included. For the comparison of reported cases between Caucasians and Asians, a chi-squared test was used. RESULTS: Among the 687 studies found in PubMed, 121 studies fulfilled the eligibility criteria. In total, 2621 patients were reviewed. Among Caucasian EGID patients, 94% had EoE; while among Asian EGID patients, 72% had EGE (p < 0.001). Among EoE, Asians were significantly less likely to have dysphagia and heartburn, but more likely to have vomit and abdominal pain, compared to Caucasians (p < 0.001). Further, among EGE, Asians were significantly more likely to have eosinophil-infiltrated colon than Caucasians (OR: 3.22, 95% confidence interval [CI]: 1.60-7.04), but were less likely to have eosinophil-infiltrated stomach (OR: 0.29, 95% CI: 0.17-0.49). CONCLUSIONS: We found that EoE occurs more frequently in Caucasian EGID patients than Asian EGID patients, while the reverse is true for EGE. Also, racial disparities in symptoms and eosinophil-infiltrated tissues were observed. Our findings suggest further genetic and environmental studies to elucidate the etiology of EGID. PMID- 26117258 TI - Comparison of gene expression profiles in eosinophilic esophagitis (EoE) between Japan and Western countries. AB - BACKGROUND: The prevalence rate of eosinophilic esophagitis (EoE) between Japan and Western countries is quite different. Although multiple factors, including the genetic background, lifestyle and dietary habits, may account for the difference, the pathogenic mechanism of EoE has not been fully clarified in Japanese. To elucidate whether EoE's pathogenic mechanisms differ between those populations, we performed transcriptome analysis of esophageal biopsy specimens from Japanese EoE patients and compared the identified gene signatures with published microarray data for EoE patients in the US. METHODS: We prospectively enrolled adult Japanese EoE patients (n = 4) according to the 2011 consensus guidelines for diagnosis of EoE. Age-matched healthy volunteer subjects (n = 4) were also enrolled as controls. We assessed the gene expression profiles of esophageal biopsies using microarray technology and then compared the identified gene signatures with earlier data generated in the US. RESULTS: Of 42,545 transcripts represented on the microarray, 385 were differentially expressed between the EoE and control samples (>=2 fold change and adjusted p-value of <0.05). Our microarray data showed strong overlapping with the data from US patients with EoE. An EoE-specific-transcript signature is typically composed of IL-13-inducible and eosinophil-related genes, including eotaxin-3/C-C chemokine ligand 26 (CCL26). CONCLUSIONS: This transcriptome study suggests that the pathogenetic mechanisms of EoE in Japan and Western countries are similar. Our findings may contribute to a better understanding of the pathogenesis of EoE and to more accurate diagnosis of this disease in Japanese individuals. PMID- 26117259 TI - Evaluation of recombinant MGL_1304 produced by Pichia pastoris for clinical application to sweat allergy. AB - BACKGROUND: We previously identified MGL_1304 secreted by Malassezia globosa as a sweat antigen for patients with atopic dermatitis (AD) and cholinergic urticaria (ChU). However, purifying native MGL_1304 from human sweat or culture supernatant of M. globosa (sup-MGL_1304) is costly and time-consuming. Moreover, recombinant MGL_1304 expressed by using Escherichia coli (TF-rMGL_1304) needs a large chaperon protein and lacks the original glycosylation of yeasts. Thus, we generated a recombinant MGL_1304 by Pichia pastoris (P-rMGL_1304) and investigated its characteristic features. METHODS: Recombinant MGL_1304 proteins expressed by E. coli and P. pastoris were generated. Properties of these recombinants and native antigens were compared by western blot analysis, histamine release tests (HRT) of patients with AD and ChU, and beta hexosaminidase release tests with RBL-48 cells. P-rMGL_1304-specific IgE in sera of patients with AD were measured by sandwich ELISA. RESULTS: Western blot analysis revealed that IgE of patients with AD bound to all MGL_1304 recombinants and native antigens. The histamine releasing ability of P-rMGL_1304 was 100 times higher than that of TF-rMGL_1304, and was comparable to that of sup-MGL_1304. Degranulation rates of RBL-48 cells, sensitized with sera of patients with AD in response to the stimulation of P-rMGL_1304, were comparable to those of sup MGL_1304, whereas those of TF-rMGL_1304 were relatively weak. The levels of P rMGL_1304-specific IgE in sera of patients with AD were correlated with their disease severities. CONCLUSIONS: P-rMGL_1304 has an antigenicity comparable to the native antigen, and is more useful than TF-rMGL_1304, especially in HRT and degranulation assay of RBL-48 cells. PMID- 26117260 TI - Better management of cow's milk allergy using a very low dose food challenge test: a retrospective study. AB - BACKGROUND: Low dose reactive cow's milk (CM) allergic children are at high risk of persistent CM allergy and a positive oral food challenge (OFC). The present study aimed to evaluate if the results of a very low dose (VL) OFC with these children contributes to better management of CM allergy. METHODS: We retrospectively reviewed subjects with CM allergy who underwent a VL OFC with 3 mL heated CM and had a previous allergic reaction to <25 mL heated CM in the 2 years before the OFC. Subjects who passed the OFC were defined as VL tolerant, and subjects who failed were defined as VL reactive. VL tolerant subjects increased the dose to 25 mL heated CM either during an OFC in our hospital or gradually at home. RESULTS: Of the 83 subjects (median age, 4.3 years; range, 1.0 12.9 years) who were included, 41 (49.4%) were VL tolerant, and 42 (51.6%) were VL reactive. Thirty-nine VL reactive subjects had skin and/or respiratory symptoms during the OFC. Most reactions could be treated with an antihistamine and/or a nebulized beta2 agonist. The VL tolerant subjects consumed 3 mL heated CM or 10 g butter. Within the year following the OFC, 18 VL tolerant subjects (45.0%), but none of the VL reactive subjects, were able to consume 25 mL heated CM (p < 0.001). CONCLUSIONS: A VL OFC allows the management of some low dose reactive CM allergic children to change from complete avoidance to partial intake of CM. PMID- 26117261 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis: the Food and Drug Administration adverse event reporting system, 2004-2013. PMID- 26117262 TI - Drug eruption to clavulanic acid with sparing of cellulitis-affecting site. PMID- 26117263 TI - Intrinsic atopic dermatitis shows high serum nickel concentration. PMID- 26117264 TI - Food-dependent exercise-induced anaphylaxis among junior high school students: a 14-year epidemiological comparison. PMID- 26117265 TI - Occupational food allergy due to parvalbumin and phaseolin induced by epicutaneous sensitization. PMID- 26117266 TI - No increase in the serum periostin level is detected in elementary school-age children with allergic diseases. PMID- 26117267 TI - [Prognostic value of preoperative carcinoembryogenic antigen: Is it useful in all stages of colorectal cancer?]. AB - INTRODUCTION: Recent reports have reopened discussion of the prognostic value of elevated pre-treatment carcinoembryonic antigen (CEA) levels in colorectal cancer. Due to the discrepancies in the published results, we aimed to analyze the possible predictive value of CEA, both overall and in different tumoral stages in our environment. PATIENTS AND METHODS: We retrospectively studied 303 consecutive patients with colorectal cancer resected with curative intent by analysing tumor-related mortality. The frequency of patients with increased CEA levels (> 5mg/l) was registered. Univariate and multivariate analyses of survival curves were performed, comparing patients with increased CEA levels and those with CEA levels within normal limits, both in the overall series and in the different pTNM tumoral stages. RESULTS: Frequency of patients with CEA>5mg/l was 31%. The median clinical follow-up was 83 months. A poor survival rate was registered in the multivariate analysis of the whole series in patients with high CEA levels: hazard ratio (HR)=1.81; 95% confidence interval (95% CI)=(1.15-3.10); P=.012. This predictive value was only maintained in stage II in the survival analysis of the distinct tumoral stages (n=104): HR=3.02; 95% CI=(1.22-7.45); P=.017. CONCLUSIONS: Before treatment, 31% of our patients with colorectal cancer resected with curative intent had pathological CEA values. In the overall series, a high pretreatment CEA level showed an independent prognostic value for poor survival. When pTNM tumoral stages were analyzed separately, CEA level had predictive value only in pTNM II tumors. PMID- 26117268 TI - HOTAIR Interacting with MAPK1 Regulates Ovarian Cancer skov3 Cell Proliferation, Migration, and Invasion. AB - BACKGROUND: The aim of this study was to evaluate the effect of when silencing HOTAIR in ovarian cancer skov3 cells on proliferation, migration, and invasion, and to elucidate the mechanism by which this occurs. MATERIAL AND METHODS: We detected the mRNA level of HOTAIR (HOX antisense intergenic RNA) and MAPK1 (mitogen-activated protein kinase 1) in ovarian cancer SKOV3, ES-2, OVCAR3, A2780, and COC1 cell lines. We detected the mRNA level of HOTAIR and MAPK1 in ovarian SKOV3 when transected with miR-1, miR-214-3p, or miR-330-5p. We detected the mRNA and protein level of MAPK1 when silencing HOTAIR. We detected the expression of HOTAIR when silencing MAPK1. Then we detected the proliferation, migration, and invasion in ovarian cancer skov3 after silencing HOTAIR or MAPK1. RESULTS: The expression of HOTAIR and MAPK1 in ovarian SKOV3, ES-2, and OVCAR3 increased compared with A2780 and COC1 cells (P<0.05). The mRNA level of HOTAIR and MAPK1 in ovarian SKOV3 decreased when transected with miR-1, miR-214-3p, or miR-330-5p compared to negative control (p<0.05). The mRNA and protein level of MAPK1 was decreased when silencing HOTAIR and the mRNA level of HOTAIR was decreased when silencing MAPK1 (p<0.05). The proliferation, migration, and invasion was inhibited in ovarian SKOV3 after silencing HOTAIR or MAPK1 (p<0.05). CONCLUSIONS: HOTAIR can promote proliferation, migration, and invasion in ovarian SKOV3 cells as a competing endogenous RNA. PMID- 26117269 TI - Mice overexpressing integrin alphav in fibroblasts exhibit dermal thinning of the skin. AB - BACKGROUND: Integrins, especially alphav integrin (ITGAV), are thought to play central roles in tissue fibrosis and the pathogenesis of scleroderma. So far, skin phenotype of tissue-specific transgenic mice of ITGAV have not been investigated. OBJECTIVE: To investigate the role of ITGAV in the skin fibrosis, we engineered transgenic mice that overexpress ITGAV in the fibroblasts under the control of the COL1A2 enhancer promoter. METHODS: Protein or RNA expression was evaluated by real-time PCR, immunohistochemistry, immunoblotting and immunoprecipitation. RESULTS: Dermal thickness and Masson's trichrome staining were decreased in ITGAV transgenic (Tg) mice compared with wild-type (WT) mice. Protein and mRNA levels of COL1A2, COL3A1, CTGF and integrin beta3 were down regulated in the skin of Tg mice. In addition, the cell proliferation of cultured dermal fibroblasts obtained from Tg mice skin was decreased compared to those of WT mice. FAK phosphorylation was reduced in fibroblasts cultured from Tg mice skin in comparison to WT mice fibroblasts. Integrin beta3 siRNA inhibited FAK phosphorylation levels, while FAK inhibitor reduced the expression of collagens and CTGF in mice dermal fibroblasts. CONCLUSIONS: The down-regulation of collagen or CTGF by decreased integrin beta3 and FAK phosphorylation may cause the dermal thinning in Tg mice. Lower CTGF may also result in reduced growth of Tg mice fibroblasts. Our hypothesis is that the balance between alpha and beta chain of integrins positively or negatively control collagen expression and dermal thickness. This study gave a new insight in the treatment of tissue fibrosis and scleroderma by balancing integrin expression. PMID- 26117270 TI - (18)F FDOPA uptake in brain metastasis of breast cancer. PMID- 26117271 TI - Pronounced alterations in T-wave morphology during dipyridamole-induced ischaemia. AB - The case describes a 77-year-old woman with multivessel coronary disease exhibiting marked changes of T-wave morphology induced by dipyridamole, an unusual finding in which the diagnostic accuracy in this clinical context is uncertain. Gated-SPECT imaging demonstrated severe ischaemia extending through inferior and posterolateral regions of the left ventricle with normal motility and contractile function in response to vasodilator stress. Possible underlying mechanisms and clinical implications of observed electrocardiographic changes are discussed. T-loop modifications during vasodilator stress SPECT and correlation of these changes with the amount of ischaemic injury need further evaluation. PMID- 26117272 TI - Level of energy restriction alters body condition score and morphometric profile in obese Shetland ponies. AB - Due to the high prevalence of obesity in some horses and ponies (especially in the leisure horse sector), effective and safe weight loss strategies are required. The present study evaluated the effect of two different energy restriction rates on physical, morphometric and welfare parameters in 18 obese (body condition score [BCS] 7-9/9) Shetland geldings. The trial was divided into three periods: (1) a 4 week adaptation period, during which the maintenance energy intakes to maintain a stable obese bodyweight were determined (100% MERob); (2) a 16.5-week weight loss period during which the ponies were randomly divided into three groups (n = 6/group) comprising a control group (CONTROL), moderate energy restricted (MOD), and severe energy restricted (SEV) groups that were respectively fed at 100%, 80% and 60% of their individual MERob; and (3) a 3 week follow up period in which the ponies were again fed at their outset individual 100% MERob. Between the start and end of the weight loss period, significant pairwise differences between the three treatment groups were seen for bodyweight, BCS, heart girth, belly girth, and relative ultrasound fat depth at the level of loin and ribs at several time points (P < 0.05). The higher energy restriction was associated with a faster decrease in BCS, tail head, and heart plus belly girth, but no gastric ulcers or stereotypic behaviours were seen. PMID- 26117273 TI - Stigmatization and social impacts of epilepsy in Turkey. AB - OBJECTIVE: Stigma associated with epilepsy has negative effects on psychosocial outcomes, affecting the lives of people with epilepsy (PWE). Obtaining basic social rights can be difficult compared to the general population. The aim of our study was to evaluate the perceived stigma among PWE and social attitude towards the disease and to compare the social measures with the general population in Turkey. METHOD: A self-completed questionnaire consisting of demographic details and items about attitudes and perceived stigmatization was developed. Participants consisted of patients with various types of seizures who were randomly chosen from the epilepsy outpatient clinic. They were requested to complete the questionnaire. RESULTS: Questionnaires were obtained from 330 PWE. One hundred forty individuals (43.3%) out of 323 reported feeling stigmatized. The marriage and total fertility rates were below the national rates of Turkey. Keeping their epilepsy as a secret from society was prevalent. Although the education rate was not below the national rate, unemployment rate was high, and the average monthly wage was significantly lower than that of the general population. The majority thought that their families were protective towards them. Only 2 of the 330 participants were living alone. CONCLUSION: The present study supports the perception of stigma associated with epilepsy and its negative impact on the lives of PWE in Turkey. Clearly, more research is needed to understand the reasons for stigma and how to decrease its impact. PMID- 26117274 TI - Mass chemical casualties: treatment of 41 patients with burns by anhydrous ammonia. AB - BACKGROUND: This article reports a chemical burn incident that occurred on 31 August 2013 in Shanghai. We describe situations at the scene, emergency management, triage, evacuation, and follow-up of the victims. METHOD: The scene of the incident and information on the 41 victims of this industrial chemical incident were investigated. The emergency management, triage, evacuation, and hospitalization data of the patients were summarized. RESULTS: At the time of the incident, 58 employees were working in a closed refrigerator workshop, 41 of whom sustained burns following the leakage of anhydrous ammonia. Ten victims died of severe inhalation injury at the scene, and another five victims died during the process of evacuation to the nearest hospital. After receiving information on the incident, a contingency plan for the burn disaster was launched immediately, and a first-aid group and an emergency and triage group were dispatched by the Changhai Hospital to the scene to aid the medical organization, emergency management, triage, and evacuation. All casualties were first rushed to the nearest hospital by ambulance. The six most serious patients with inhalation injuries were evacuated to the Changhai Hospital and admitted to the burn intensive care unit (BICU) for further treatment, one of whom died of respiratory failure and pulmonary infection. CONCLUSION: This mass casualty incident of anhydrous ammonia leakage caused potential devastating effects to the society, especially to the victims and their families. Early first-aid organization, emergency management, triage, and evacuation were of paramount importance, especially rapid evaluation of the severity of inhalation injury, and subsequent corresponding medical treatment. The prognosis of ammonia burns was poor and the sequelae were severe. Management and treatment lessons were drawn from this mass casualty chemical burn incident. PMID- 26117275 TI - Vasoconstrictor clysis in burn surgery and its impact on outcomes: systematic review and meta-analysis. AB - AIM: Clysis is the subcutaneous or subdermal injection of a vasopressor containing fluid, with or without local anaesthetic agent, and has been used to limit blood loss in patients undergoing surgical burn management. In this systematic review and meta-analysis we aimed to determine the impact of clysis of a vasoconstrictor on burn patient outcomes. METHODS: We conducted a systematic review to identify trials investigating clysis in burn patients undergoing debridement and/or skin grafting. For each eligible trial we aimed to extract the outcomes of perioperative blood loss, blood transfusion, duration of surgery, graft success and healing time, inflammatory response, sepsis, mortality, duration of hospital stay, catecholamine levels and cardiovascular effects in both the short (<72h) and long term (30 days) after surgery. RESULTS: From 443 citations, we selected 39 for full-text evaluation, and identified 10 eligible trials. Due to a lack of reporting on outcomes of interest, meta-analysis could only be conducted for the outcome of red blood cell (RBC) units transfused per patient. Patients receiving clysis (n=222) were transfused 1.89 less units (95% CI -2.12 to -1.66) as compared to those not receiving clysis, although this was associated with a high degree of heterogeneity (I(2)=88%). CONCLUSION: Few studies have adequately evaluated the impact of clysis in burn surgery on patient important outcomes such mortality, duration of surgery and graft success. These results suggest clysis may reduce the need for blood transfusion but additional high quality research is required. PMID- 26117276 TI - Probability and amounts of yogurt intake are differently affected by sociodemographic, economic, and lifestyle factors in adults and the elderly results from a population-based study. AB - The aim of this population-based cross-sectional health survey (N = 532) was to investigate the factors associated with the probability and amounts of yogurt intake in Brazilian adults and the elderly. A structured questionnaire was used to obtain data on demographics, socioeconomic information, presence of morbidities and lifestyle and anthropometric characteristics. Food intake was evaluated using two nonconsecutive 24-hour dietary recalls and a Food Frequency Questionnaire. Approximately 60% of the subjects were classified as yogurt consumers. In the logistic regression model, yogurt intake was associated with smoking (odds ratio [OR], 1.98), female sex (OR, 2.12), and age 20 to 39 years (OR, 3.11). Per capita family income and being a nonsmoker were factors positively associated with the amount of yogurt consumption (coefficients, 0.61 and 3.73, respectively), whereas the level of education of the head of household was inversely associated (coefficient, 0.61). In this study, probability and amounts of yogurt intake are differently affected by demographic, socioeconomic, and lifestyle factors in adults and the elderly. PMID- 26117277 TI - Real-World Vinflunine Outcomes in Bladder Cancer in a Single-Institution Study: Moving Beyond Clinical Trials. AB - PURPOSE: Intravenous vinflunine 320 mg/m(2) every 3 weeks plus best supportive care resulted in better overall survival in comparison with best supportive care alone for eligible patients with failure of prior therapy with locally advanced or metastatic transitional cell cancer of urothelial tract (TCCU). The objective of the present study was to describe our real-life experience of vinflunine for treatment of patients with TCCU. PATIENTS AND METHODS: We retrospectively investigated all patients with TCCU who received at least 1 cycle of vinflunine. RESULTS: Nineteen patients were treated between May 2010 and March 2014 in a compassionate-use program. Performance status was poor in our real-life cohort, with 6 patients (32%) with an Eastern Cooperative Oncology Group performance status of 2. Median duration of vinflunine treatment was 2.4 months (range, 0-4.3 months), and median number of cycles was 3 (range, 1-6). Total response rate was 32%, with partial responses only. Disease control rate was 53%, with a median duration of 7.7 months (range, 6.0-9.4 months). Median progression-free survival was 87 days, or 2.9 months (range, 0.7-11.7 months). After vinflunine treatment, 42% of patients received from 1 to 3 additional lines of chemotherapy. The most frequent grade 4 toxicities were constipation (26%), with 3 intestinal obstructions (16%) and 1 mechanical ileus (5%); and asthenia and fatigue (21%). CONCLUSION: Vinflunine, as a TCCU second-line chemotherapy, brings benefits, particularly in cases where there is no alternative treatment. PMID- 26117278 TI - Eggshell: A green adsorbent for heavy metal removal in an MBR system. AB - Presence of heavy metals as well as different metal ions in treated wastewater is a problem for the environment as well as human health. This paper aims to investigate the possibility to combine an MBR (membrane biological reactor) with an adsorption process onto powdered eggshell and eggshell membrane in order to improve metal removal from wastewater. The first step of the experimental analysis consists of the evaluation of the compatibility between the two processes. Then, a study about sorbent concentration and size effect on fouling was conducted, because the use of this kind of sorbent could affect membrane performance. The second step of the work concerns the check up of eggshell removal capacity as a function of sorbent size, achieved treating an aqueous solution containing Al(3+), Fe(2+) and Zn(2+) as water pollutants. Finally, synthetic wastewater, containing the metal species, was treated by two alternative process schemes: one of them performs the metal uptake in a dedicated adsorption unit, before the MBR. In the second, the two processes take place in the same unit. Results demonstrate that the optimization of the first option could be a solution to MBR upgrading. PMID- 26117279 TI - Roller compaction: Effect of morphology and amorphous content of lactose powder on product quality. AB - The effect of morphology and amorphous content, of three types of lactose, on the properties of ribbon produced using roller compaction was investigated. The three types of lactose powders were; anhydrous SuperTab21AN, alpha-lactose monohydrate 200 M, and spray dried lactose SuperTab11SD. The morphology of the primary particles was identified using scanning electron microscopy (SEM) and the powder amorphous content was quantified using NIR technique. SEM images showed that 21AN and SD are agglomerated type of lactose whereas the 200 M is a non-agglomerated type. During ribbon production, an online thermal imaging technique was used to monitor the surface temperature of the ribbon. It was found that the morphology and the amorphous content of lactose powders have significant effects on the roller compaction behaviour and on ribbon properties. The agglomerated types of lactose produced ribbon with higher surface temperature and tensile strength, larger fragment size, lower porosity and lesser fines percentages than the non agglomerated type of lactose. The lactose powder with the highest amorphous content showed to result in a better binding ability between the primary particles. This type of lactose produced ribbons with the highest temperature and tensile strength, and the lowest porosity and amount of fines in the product. It also produced ribbon with more smooth surfaces in comparison to the other two types of lactose. It was noticed that there is a relationship between the surface temperature of the ribbon during production and the tensile strength of the ribbon; the higher the temperature of the ribbon during production the higher the tensile strength of the ribbon. PMID- 26117280 TI - Estimation of EEC, unattached fraction and equilibrium factor for the assessment of radiological dose using pin-hole cup dosimeters and deposition based progeny sensors. AB - High concentration of radon ((222)Rn), thoron ((220)Rn) and their decay products in environment may increase the risk of radiological exposure to the mankind. The (222)Rn, (220)Rn concentration and their separate attached and unattached progeny concentration in units of EEC have been measured in the dwellings of Muktsar and Mansa districts of Punjab (India), using Pin-hole cup dosimeters and deposition based progeny sensors (DTPS/DRPS). The indoor (222)Rn and (220)Rn concentration was found to vary from 21 Bqm(-3) to 94 Bqm(-3) and 17 Bqm(-3) to 125 Bqm(-3). The average EEC (attached + unattached) of (222)Rn and (220)Rn was 25 Bqm(-3) and 1.8 Bqm(-3). The equilibrium factor for (222)Rn and (220)Rn in studied area was 0.47 +/- 0.13 and 0.05 +/- 0.03. The equilibrium factor and unattached fraction of (222)Rn and (220)Rn has been calculated separately. Dose conversion factors (DCFs) of different models have been calculated from unattached fraction for the estimation of annual effective dose in the studied area. From the experimental data a correlation relationship has been observed between unattached fraction (f(p)(Rn)) and equilibrium factor (F(Rn)). The present work also aims to evaluate an accurate expression among available expression in literature for the estimation of f(p)(Rn). PMID- 26117281 TI - Introduction and issue summary: New trends in forensic genetics. PMID- 26117282 TI - Left Ventricular Decompression During Speed Optimization Ramps in Patients Supported by Continuous-Flow Left Ventricular Assist Devices: Device-Specific Performance Characteristics and Impact on Diagnostic Algorithms. AB - BACKGROUND: Echocardiographic ramp tests have been widely used to help guide speed adjustments and for identification of potential device malfunctions in patients with axial continuous-flow left ventricular assist devices (LVADs) (Heartmate II LVAD [HMII]). Recently, the use of centrifugal-flow LVADs (Heartware LVAD [HVAD]) has been on the rise. The purpose of this study was to evaluate the utility of ramp tests for assessing ventricular decompression in HVAD patients. METHODS AND RESULTS: In this prospective study, ramp tests were performed before index hospitalization discharge or at the time of device malfunction. Vital signs, device parameters (including flow), and echocardiographic parameters (including left ventricular end-diastolic dimension [LVEDD], frequency of aortic valve [AV] opening, and valvular insufficiency) were recorded in increments of 100 rpm, from 2,300 rpm to 3,200 rpm. Twenty-six ramp tests were performed, 19 for speed optimization and 7 for device malfunction assessment. The average speed after the speed optimization ramp tests was 2,534.74 +/- 156.32 RPM, and the AV closed at a mean speed of 2,751.77 +/- 227.16 rpm, with 1 patient's valve remaining open at the maximum speed. The reduction in LVEDD for each speed increase was significantly different when the AV was open or closed, at -0.09 cm/increment and -0.15 cm/increment, respectively (P = .013), which is significantly different than previously established HMII LVEDD slopes. There were also significant changes in overall device flow (P = .001), upper flow (P = .031), and lower flow (P = .003) after AV closure. The power slope did not change significantly after the AV closed (P = .656). Five of the 19 tests were stopped before completion owing to suction events, but all tests reached >=3,000 rpm. CONCLUSIONS: The parameter slopes for the HMII cannot be directly applied to ramp studies in HVAD patients. Overall, the LVEDD slope is drastically smaller in magnitude than the previously reported HMII findings, and speed adjustments were not based on the degree of left ventricular unloading. Therefore, the slope of the LVEDD-rpm relationship is not likely to be helpful in evaluating HVAD function. PMID- 26117283 TI - Detecting change in patient outcomes in a rural ambulatory rehabilitation service: the responsiveness of Goal Attainment Scaling and the Lawton Scale. AB - OBJECTIVE: The Wagga Wagga Ambulatory Rehabilitation Service (WWARS) clinicians felt the Australian Modified Lawton's Instrumental Activities of Daily Living Scale (Lawton Scale) was unresponsive to changes detected in many patients following their individualised programs. This study examined the performance of the Goal Attainment Scaling (GAS) concomitantly with the Lawton Scale in ambulatory rehabilitation patients. METHODS: Consecutive patients (n = 83) of WWARS were evaluated pre and post treatment with the Lawton Scale and GAS. The statistical properties, particularly responsiveness, of the scales were compared. RESULTS: Statistically significant change (P < 0.001) was observed following treatment on both the Lawton Scale and GAS. Mean GAS scores changed by 38.7% compared with 8.3% for the Lawton Scale. GAS demonstrated a greater effect size (Cliff's delta) of 1.67 (95% confidence interval 1.51-1.91) than the Lawton Scale 0.83 (95% confidence interval 0.57-0.94). In 33.7% of patients, the Lawton Scale was invariant but improved with GAS. CONCLUSIONS: GAS was a more responsive measure than the Lawton Scale in rural ambulatory rehabilitation patients. Consequently, GAS is recommended as a performance outcome measure in the evaluation of ambulatory rehabilitation services to supplement standardised outcome measures such as the Lawton Scale. PMID- 26117284 TI - A novel auto-tuning PID control mechanism for nonlinear systems. AB - In this paper, a novel Runge-Kutta (RK) discretization-based model-predictive auto-tuning proportional-integral-derivative controller (RK-PID) is introduced for the control of continuous-time nonlinear systems. The parameters of the PID controller are tuned using RK model of the system through prediction error-square minimization where the predicted information of tracking error provides an enhanced tuning of the parameters. Based on the model-predictive control (MPC) approach, the proposed mechanism provides necessary PID parameter adaptations while generating additive correction terms to assist the initially inadequate PID controller. Efficiency of the proposed mechanism has been tested on two experimental real-time systems: an unstable single-input single-output (SISO) nonlinear magnetic-levitation system and a nonlinear multi-input multi-output (MIMO) liquid-level system. RK-PID has been compared to standard PID, standard nonlinear MPC (NMPC), RK-MPC and conventional sliding-mode control (SMC) methods in terms of control performance, robustness, computational complexity and design issue. The proposed mechanism exhibits acceptable tuning and control performance with very small steady-state tracking errors, and provides very short settling time for parameter convergence. PMID- 26117285 TI - On spacecraft maneuvers control subject to propellant engine modes. AB - The paper attempts to address a new control approach to spacecraft maneuvers based upon the modes of propellant engine. A realization of control strategy is now presented in engine on mode (high thrusts as well as further low thrusts), which is related to small angle maneuvers and engine off mode (specified low thrusts), which is also related to large angle maneuvers. There is currently a coarse-fine tuning in engine on mode. It is shown that the process of handling the angular velocities are finalized via rate feedback system in engine modes, where the angular rotations are controlled through quaternion based control (QBCL)strategy in engine off mode and these ones are also controlled through an optimum PID (OPIDH) strategy in engine on mode. PMID- 26117286 TI - Fast engineering optimization: A novel highly effective control parameterization approach for industrial dynamic processes. AB - Control vector parameterization (CVP) is an important approach of the engineering optimization for the industrial dynamic processes. However, its major defect, the low optimization efficiency caused by calculating the relevant differential equations in the generated nonlinear programming (NLP) problem repeatedly, limits its wide application in the engineering optimization for the industrial dynamic processes. A novel highly effective control parameterization approach, fast-CVP, is first proposed to improve the optimization efficiency for industrial dynamic processes, where the costate gradient formulae is employed and a fast approximate scheme is presented to solve the differential equations in dynamic process simulation. Three well-known engineering optimization benchmark problems of the industrial dynamic processes are demonstrated as illustration. The research results show that the proposed fast approach achieves a fine performance that at least 90% of the computation time can be saved in contrast to the traditional CVP method, which reveals the effectiveness of the proposed fast engineering optimization approach for the industrial dynamic processes. PMID- 26117287 TI - One day of contact with photostimulated bucks is sufficient to induce ovulation in seasonally anestrous goats. AB - In seasonally anovulatory goats, daily contact with photostimulated bucks for 15 days stimulates ovulations in most females. In this study, we determined whether ovulation could be induced in goats exposed to photostimulated bucks for less than 15 days. Bucks were rendered sexually active during the nonbreeding season by exposure to 2.5 months of long days from November 1. The control group of females was exposed to one photostimulated buck for 15 days (n = 12). Other three experimental groups were exposed to males (n = 1 per group) for 1, 5, or 10 days (n = 14 or 15 females per group). Ovulations were determined by measurement of daily plasma progesterone concentrations during 17 days. All females from the control and experimental groups ovulated at least once during the experiment (P > 0.05). Furthermore, the proportions of goats that displayed a short luteal phase followed by a new ovulation, or a normal luteal phase after being in contact with males, did not differ between groups depending on the duration of time of contact with the photostimulated males (P > 0.05). In contrast, the proportions of females that displayed a short luteal phase followed by anovulation were greater in goats in contact with males for 1 day than in those in contact with males for 10 and 15 days (P < 0.05), whereas they did not differ from females exposed to males for 5 days (P > 0.05). We conclude that 1 day of contact with sexually active males is long enough to stimulate the ovulatory activity in seasonally anovulatory goats. However, a significantly higher proportion of females exposed to males for 1 day did not ovulate again after showing a short luteal phase. PMID- 26117288 TI - Alteration of glycan structures by swainsonine affects steroidogenesis in bovine luteal cells. AB - The indolizidine alkaloid swainsonine (SW), a potent inhibitor of Golgi alpha mannosidase II, is considered the primary toxicant in locoweeds causing toxicity syndrome known as locoism in livestock. Locoweed consumption decreases serum progesterone concentration and causes serious disorders in reproductive functions of livestock. However, direct effects of SW on luteal steroidogenic cells (LSCs) remain unclear. In the present study, we investigated the effect of N-glycan processing inhibition by SW on progesterone production and viability in cultured bovine LSCs. Swainsonine (0.1 MUg/mL) fully inhibited glycosylation in the LSCs, but it had no effect on viability and progesterone production in the LSCs. Luteinizing hormone is known to promote progesterone production and expressions of steroidogenic acute regulatory protein and scavenger receptor type B class I. Pretreatment of LSCs with SW suppressed each of these effects, possibly by inhibiting LH receptor activity. These results suggest that SW inhibits N-glycan processing, which attenuates LH receptor activity, which, in turn, reduces progesterone production by CL. PMID- 26117289 TI - Marked protection against acute renal and hepatic injury after nitrited myoglobin + tin protoporphyrin administration. AB - The phenomenon known as renal "ischemic preconditioning," whereby an initial ischemic insult induces resistance against subsequent kidney damage, has been well established in the experimental literature. However, a clinically applicable way to safely recapitulate this state has not been defined. We hypothesized that a unique combination of agents (nitrited myoglobin [N-Mgb] + tin protoporphyrin [SnPP]) can achieve these ends safely and synergistically, increasing cytoprotective proteins (eg, heme oxygenase 1 [HO-1], interleukin 10 [IL-10], and haptoglobin) in kidney cells. To test this hypothesis, CD-1 mice received 1 mg of N-Mgb and 1 MUmol of SnPP, either alone or in combination. Renal cortical HO-1, haptoglobin, and IL-10 gene expressions (messenger RNA [mRNA], protein levels) were determined 4 and 18 hours later. Cytoresistance to 3 forms of acute kidney injury (AKI; glycerol-induced rhabdomyolysis, maleate nephrotoxicity, and postischemic AKI progression to chronic kidney disease [CKD]) was assessed. To ascertain whether cytoresistance might emerge in extrarenal organs, hepatic HO-1, IL-10, and haptoglobin levels were also measured, and resistance to 25 minutes of hepatic ischemia-reperfusion injury and hepatotoxicity (intraperitoneal glycerol injection) was sought. N-Mgb + SnPP induced additive or synergistic increases in renal HO-1, haptoglobin, and IL-10 mRNA and protein levels (up to 20-fold) without inducing any apparent renal or extrarenal damage. After 18 hours of post treatment, marked or complete protection against glycerol-induced AKI, maleate induced AKI, and postischemic AKI progression to CKD had emerged. Combined N-Mgb + SnPP was more protective than either agent alone (assessed in glycerol model). N-Mgb + SnPP also upregulated cytoprotective pathways in liver and induced marked protection against both hepatic ischemia-reperfusion and toxic liver damage. In conclusion, we posit that "preconditioning" with combined administration of N-Mgb + SnPP represents a promising approach for protecting against diverse forms of renal and nonrenal (hepatic) forms of tissue damage. PMID- 26117290 TI - Angiogenic factors and inflammation in steroid-refractory acute graft-vs-host disease. AB - Steroid-refractory acute graft-vs-host disease (aGVHD) remains a frequent and often fatal complication of allogeneic hematopoietic cell transplantation. Recent evidence suggests that angiogenic factors-growth factors that contribute to blood vessel development-may be involved in tissue healing and restitution after inflammatory insults such as aGVHD. However, some angiogenic factors may also be involved in inflammation and worsen clinical outcomes. In this review, we summarize the data relevant to angiogenic factors that may contribute to healing after aGVHD (epidermal growth factor and vascular endothelial growth factor A) and angiogenic factors that may promote inflammation after aGVHD (placental growth factor and follistatin). It is currently unknown whether changes in these factors are a cause or a consequence of aGVHD. Mechanistic studies in the coming years will clarify their roles and identify new pathways for improving outcomes in steroid-refractory aGVHD. PMID- 26117291 TI - Long term effect and allergic sensitization in newly employed workers in laboratory animal facilities. AB - OBJECTIVE: The aim of this study was to identify targets predicting allergic sensitization to laboratory animals using shift in skin prick test to laboratory animals as primary outcome variable. METHODS: In a prospective longitudinal study, personnel who were employed to work with laboratory animals at a medical university were investigated before and 6, 12 and 24 month after the start of employment. Lung function, bronchial challenges, exhaled NO and nasal lavage were performed and blood samples were drawn at all visits. RESULTS: Seventy subjects attended all four visits and 13 (19%) became sensitized to laboratory animals during the two years of follow up. Lung function (VC and FEV1) deteriorated and blood levels of eosinophils and IL-2 producing lymphocytes increased after 24 months. An increased risk of developing laboratory animal allergy was significantly associated with female sex, atopy, symptoms associated with exposure to laboratory animals, low proportion of blood CD4+ cells, specific IgE to rat and mouse and high total IgE when starting to work with laboratory animals. CONCLUSIONS: A sensitization rate of 19% in 2 years, were demonstrated in laboratory animal workers. Atopy, increased total and specific IgE levels (rat and mouse) were the strongest predictors for laboratory animal sensitization. The progressive lung function impairment over time, observed in the whole study population may indicate that exposure in animal facilities induces harmful effects, irrespective to allergic sensitization. PMID- 26117293 TI - Tunable synthesis of single-crystalline-like TiO2 mesocrystals and their application as effective scattering layer in dye-sensitized solar cells. AB - Single-crystalline-like TiO2 mesocrystals (TMCs) with spherical and spindle-like shapes were selectively prepared in acetic acid system using benzoic acid as structural directing regent. It was found that the intermediate butyl-benzoic acid could interval the oriented assembly of the primary nanoparticles as porogen and shape regulator, which results in spherical TMCs with greater pore size distribution compared with the spindle-like TMCs. When used as scattering layer in dye sensitized solar cells (DSSCs), the spherical TMCs with long-range ordered stacking pattern results in characteristic photonic reflection, which enhances the scattering effect of the photoanode and leads to a high short circuit current density of 16.6 mA cm(-2). Therefore, Cell-spherical TMCs demonstrated a high power conversion efficiencies of 8.10%, indicating substantial improvements compared with Cell-spindle-like TMCs (7.58%) and Cell-nanoparticle (6.59%). PMID- 26117292 TI - Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: Results of two randomized studies. AB - OBJECTIVE: The aim of these studies (NCT01957163; NCT02119286) was to evaluate the efficacy and safety of umeclidinium (UMEC 62.5 MUg and 125 MUg) added to fluticasone furoate/vilanterol (FF/VI, 100/25 MUg) in chronic obstructive pulmonary disease (COPD). METHODS: These were 12-week, double-blind, placebo controlled, parallel-group, multicenter studies. Eligible patients were randomized 1:1:1 to treatment with once-daily blinded UMEC 62.5 MUg (delivering 55 MUg), UMEC 125 MUg (delivering 113 MUg) or placebo (PBO) added to open-label FF/VI (delivering 92/22 MUg; N = 1238 [intent-to-treat population]). The primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 85; the secondary endpoint was 0-6 h post-dose weighted mean (WM) FEV1 at Day 84. Health related quality of life was reported using St George's respiratory questionnaire (SGRQ). Adverse events (AEs) were also assessed. RESULTS: In both studies, trough FEV1 was significantly improved with UMEC + FF/VI (62.5 MUg and 125 MUg) versus PBO + FF/VI (range: 0.111-0.128 L, all p < 0.001 [Day 85]), as was 0-6 h post dose WM FEV1 (range: 0.135-0.153 L, all p < 0.001 [Day 84]). SGRQ results were inconsistent, with statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI in one study only and with UMEC 62.5 MUg only (difference in SGRQ total score from baseline between treatments: -2.16, p < 0.05). Across all treatment groups, the overall incidences of AEs were similar (30-39%), as were cardiovascular AEs of special interest (<1-3%) and pneumonia AEs (0-1%). CONCLUSION: Overall, the addition of UMEC to FF/VI therapy resulted in significant improvements in lung function compared with PBO + FF/VI in patients with COPD, with similar safety profiles, though SGRQ results were inconsistent. CLINICAL RELEVANCE: The results from these two studies demonstrate that the addition of umeclidinium (62.5 MUg and 125 MUg) to FF/VI (100/25 MUg) provides statistically significant and clinically meaningful improvements in lung function compared with placebo + FF/VI in patients with COPD. Statistically significant improvements in quality of life with UMEC + FF/VI versus placebo + FF/VI were reported in one study only. Safety profiles were consistent across all treatment groups in both studies. These studies support the use of triple therapy in COPD, providing physicians with an alternative treatment option. PMID- 26117294 TI - Adsorption of nucleotides on biomimetic apatite: The case of cytidine 5' monophosphate (CMP). AB - The chemical interaction between DNA macromolecules and hard tissues in vertebrate is of foremost importance in paleogenetics, as bones and teeth represent a major substrate for the genetic material after cell death. Recently, the empirical hypothesis of DNA "protection" over time thanks to its adsorption on hard tissues was revisited from a physico-chemical viewpoint. In particular, the existence of a strong interaction between phosphate groups of DNA backbone and the surface of apatite nanocrystals (mimicking bone/dentin mineral) was evidenced on an experimental basis. In the field of nanomedicine, DNA or RNA can be used for gene transport into cells, and apatite nanocarriers then appear promising. In order to shed some more light on interactions between DNA molecules and apatite, the present study focuses on the adsorption of a "model" nucleotide, cytidine 5' monophosphate (CMP), on a carbonated biomimetic apatite sample. The follow-up of CMP kinetics of adsorption pointed out the rapidity of interaction with stabilization reached within few minutes. The adsorption isotherm could be realistically fitted to the Sips model (Langmuir-Freundlich) suggesting the influence of surface heterogeneities and adsorption cooperativity in the adsorption process. The desorption study pointed out the reversible character of CMP adsorption on biomimetic apatite. This contribution is intended to prove helpful in view of better apprehending the molecular interaction of DNA fragments and apatite compounds, independently of the application domain, such as bone diagenesis or nanomedicine. This study may also appear informative for researchers interested in the origins of life on Earth and the occurrence and behavior of primitive biomolecules. PMID- 26117296 TI - Avoiding Complications in Endoscopic Sinus Surgery. AB - Complications of endoscopic sinus surgery (ESS) can range from the mundane to the catastrophic, with nasal hemorrhage being the most common. Intraorbital and intracranial complications are much less common. Despite the rarity of complications, they are often avoidable. Certain identifiable risk factors can be appreciated during the preoperative, intraoperative, and postoperative evaluations of the sinus patient. With awareness of these risk factors the rhinologist can develop a strategic plan of risk factor mitigation. This article identifies areas of increased risk that are amenable to preventive strategies before complications become realized. PMID- 26117295 TI - Speckle-Tracking Echocardiographic Measures of Right Ventricular Function Correlate With Improvement in Exercise Function After Percutaneous Pulmonary Valve Implantation. AB - BACKGROUND: Speckle-tracking echocardiographic (STE) measures of right ventricular (RV) function appear to improve after transcatheter pulmonary valve implantation (TPVI). Measures of exercise function, such as ventilatory efficiency (the minute ventilation [VE]/carbon dioxide production [VCO2] slope), have been shown to be prognostic of mortality in patients who may require TPVI. The aim of this study was to evaluate the correlation between STE measures of RV function and changes in VE/VCO2 after TPVI. METHODS: Speckle-tracking echocardiography and cardiopulmonary exercise testing were performed at baseline and 6 months after TPVI in 24 patients from four centers. Conventional echocardiographic measures of RV function were also assessed. Echocardiographic and exercise stress test results were interpreted by single blinded observers at separate core laboratories. RESULTS: All patients demonstrated relief of pulmonary regurgitation and stenosis after TPVI. Improvements in RV longitudinal strain (-16.9 +/- 3.5% vs -19.7 +/- 4.3%, P < .01) and strain rate (-0.9 +/- 0.4 vs. -1.2 +/- 0.4 s(-1), P < .01) were noted. The VE/VCO2 slope improved (32.4 +/- 5.7 vs 31.5 +/- 8.8, P = .03). No other significant echocardiographic or exercise changes were found. On multivariate regression, the change in VE/VCO2 was independently associated with change in RV longitudinal early diastolic strain rate (P < .001) and tricuspid A velocity (P < .001). Preintervention RV longitudinal strain was found to be a predictor of change in VE/VCO2 after TPVI (r = -0.60, P < .001). CONCLUSIONS: STE measures of RV function appear to hold the potential for use as predictors of improved outcomes in patients requiring TPVI. Future studies should directly assess the prognostic significance of STE measures of RV function in this population. PMID- 26117297 TI - Medicolegal Implications of Common Rhinologic Medications. AB - As otolaryngologists, we prescribe many medications to our patients. The objective of this article is to review the potential side effects and medicolegal risks of the common medications used to treat chronic rhinosinusitis. The authors evaluate some of the common side effects as well as the published literature on the lawsuits associated with those medications. Finally, the authors review the informed consent discussion and opportunities to improve patient care and decrease the risk of litigation. PMID- 26117298 TI - Olfaction in Endoscopic Sinus and Skull Base Surgery. AB - Olfactory dysfunction is a common complaint for patients with chronic rhinosinusitis, because smell loss decreases a patient's quality of life. Smell loss is caused by obstruction from polyps, nasal discharge, and mucosal edema, as well as inflammatory changes within the olfactory epithelium. Addressing olfaction before endoscopic sinus and skull base surgery is important in order to set postoperative expectations, because an improvement in smell is difficult to predict. Several commercially available olfactory testing measures are available and can easily be administered in clinic. During surgery, careful dissection within the olfactory cleft is recommended in order to optimize postoperative olfactory function. PMID- 26117299 TI - Imaging of the Paranasal Sinuses: Mitigation, Identification, and Workup of Functional Endoscopic Surgery Complications. AB - The purpose of this article is to identify and define the appropriate imaging techniques in the evaluation of post-functional endoscopic surgery (FESS) complications. Although most complications encountered during FESS are identified readily during surgery, some are less conspicuous and require postoperative imaging. As illustrated in this article, these include cerebrospinal fluid leak, vascular injury, brain injury, orbital injury, and infectious complications of the brain and meninges. Some of the common anatomic variants of the paranasal sinuses are identified, and how these may predispose to surgical complications is discussed. PMID- 26117300 TI - Rare and Other Notable Complications in Endoscopic Sinus Surgery. AB - This article focuses on the rare and obscure complications of endoscopic sinus surgery. The majority of surgeons will not encounter these complications in their practice, but should be aware of their possibility. With knowledge of these rare complications, the surgeon can understand the possible avoidance as well as urgent management of these problems. PMID- 26117301 TI - Orbital Complications Associated with the Treatment of Chronic Rhinosinusitis. AB - Orbital injuries from endoscopic sinus surgery are rare but potentially catastrophic. The most feared complications from sinus surgery include blindness and diplopia. Recent publications note that the rate of orbital complications has decreased when compared with the past, reflecting the use of endoscopes, better technology, and improved training. The sinus surgeon must have mastery over the procedure she or he plans to undertake and be aware of the specific potential for orbital injury given the patient's anatomy and disease. The sinus surgeon must also have expert knowledge of the appropriate and immediate medical and surgical management of orbital complications. PMID- 26117302 TI - Pitfalls in Sinus Surgery: An Overview of Complications. AB - There is a potential for significant complications from the medical and surgical treatment of rhinosinusitis because of the intimate relationship between the paranasal sinuses and surrounding vital structures. Familiarity with the complex anatomic relationships between the skull base and other critical structures and knowledge of pharmacologic properties of commonly used medical therapies are essential for preventing serious and harmful seqsuelae. The authors hope that this review represents a valuable addition to the otolaryngologist-in-training's therapeutic armamentarium, and also serves as a reminder of the potential pitfalls for the experienced sinus surgeon. PMID- 26117303 TI - Outcome of pancreaticoduodenectomy in octogenarians: Single institution's experience and review of the literature. AB - INTRODUCTION: Pancreatic and perampullary neoplasms in patients aged 80 or older trouble the surgeons because of the risk of surgical treatment. We have reviewed our experience and literature's reports of pancreaticoduodenectomy in octogenarians, evaluating early results and long-term survival in pancreatic cancer group. METHODS: Three hundred eighty-five patients who underwent pancreaticoduodenectomy for neoplasms from 1998 to 2011 were included in the study, and were divided in two groups: group 1, patients younger than 80 years of age, and group 2, patients 80 years of age and older. Operative morbidity, mortality, disease-free and long-term survival were analysed. English literature was systematically searched for pancreatic resection's outcome in octogenarians. RESULTS: There were 385 pancreaticoduodenectomies: 362 patients were in group 1 and 23 patients in group 2. There was no significant difference regarding gender, and pathologic findings between the two groups. Complications' rate (40 vs. 43%), mortality rate (4% vs. 0%), and overall median survival for pancreatic cancer patients were not statistically different in the two groups (median 21 vs. 19 months). Literature's review showed 14 reports of pancreatic resection in octogenarians. Most of the studies (particularly in centres with high-volume pancreatic surgery) showed that outcome after pancreatectomy was not different in octogenarians or in younger patients. CONCLUSION: Pancreaticoduodenectomy is an acceptable option for elderly patients. Age alone should not be considered a contraindication to major pancreatic resection, but a careful preoperative evaluation and an accurate postoperative management are mandatory. PMID- 26117305 TI - Zinc affects the proteolytic stability of Apolipoprotein E in an isoform dependent way. AB - The pathological role of zinc in Alzheimer's disease (AD) is not yet fully elucidated, but there is strong evidence that zinc homeostasis is impaired in the AD brain and that this contributes to disease pathogenesis. In this study we examined the effects of zinc on the proteolysis of synthetic Apolipoprotein E (ApoE), a protein whose allelic variants differentially contribute to the onset/progression of disease. We have demonstrated that zinc promotes the proteolysis (using plasma kallikrein, thrombin and chymotrypsin) of synthetic ApoE in an isoform-specific way (E4>E2 and E3), resulting in more ApoE fragments, particularly for ApoE4. In the absence of exogenous proteases there was no effect of metal modulation on either lipidated or non-lipidated ApoE isoforms. Thus, increased zinc in the complex milieu of the ageing and AD brain could reduce the level of normal full-length ApoE and increase other forms that are involved in neurodegeneration. We further examined human plasma samples from people with different ApoE genotypes. Consistent with previous studies, plasma ApoE levels varied according to different genotypes, with ApoE2 carriers showing the highest total ApoE levels and ApoE4 carriers the lowest. The levels of plasma ApoE were not affected by either the addition of exogenous metals (copper, zinc or iron) or by chelation. Taken together, our study reveals that zinc may contribute to the pathogenesis of AD by affecting the proteolysis of ApoE, which to some extent explains why APOE4 carriers are more susceptible to AD. PMID- 26117304 TI - The impact of a parkinsonian lesion on dynamic striatal dopamine transmission depends on nicotinic receptor activation. AB - Dopamine function is disturbed in Parkinson's disease (PD), but whether and how release of dopamine from surviving neurons is altered has long been debated. Nicotinic acetylcholine receptors (nAChRs) on dopamine axons powerfully govern dopamine release and could be critical contributing factors. We revisited whether fundamental properties of dopamine transmission are changed in a parkinsonian brain and tested the potentially profound masking effects of nAChRs. Using real time detection of dopamine in mouse striatum after a partial 6-hydroxydopamine lesion and under nAChR inhibition, we reveal that dopamine signals show diminished sensitivity to presynaptic activity. This effect manifested as diminished contrast between DA release evoked by the lowest versus highest frequencies. This reduced activity-dependence was underpinned by loss of short term facilitation of dopamine release, consistent with an increase in release probability (Pr). With nAChRs active, the reduced activity-dependence of dopamine release after a parkinsonian lesion was masked. Consequently, moment-by-moment variation in activity of nAChRs may lead to dynamic co-variation in dopamine signal impairments in PD. PMID- 26117306 TI - An 11,000-isolate same plate/same day comparison of the 3 most widely used platforms for analyzing multidrug-resistant clinical pathogens. AB - Stewardship of the dwindling number of effective antibiotics relies on accurate phenotyping. We sought to conduct the first large-scale, same plate and day comparison of the 3 most widely used bacterial analyzers. A total of 11,020 multidrug-resistant clinical isolates corresponding to more than 485,000 data points were used to compare the 3 major identification and antibiotic susceptibility testing (AST) platforms. Bacterial suspensions, prepared from a single plate, were simultaneously tested on all platforms in the same laboratory. Discrepancies were derived from MIC values using 2014 interpretive guidelines. Molecular methods and manual microbroth dilution were reference standards. Most discrepancies were due to drug-organism-AST platform combination instead of individual factors. MicroScan misidentified Acinetobacter baumannii (P<0.001) and underestimated carbapenem susceptibility in Klebsiella pneumoniae. Vitek-2 and Phoenix had higher discrepancies for blaKPC-containing Enterobacteriaceae (P<0.05) and reported false susceptibilities more often. While all platforms performed according to standards, each had strengths and weaknesses for organism identification, assaying specific drug-organism combinations and inferring carbapenemase production. PMID- 26117307 TI - Differential expression of Marek's disease virus (MDV) late proteins during in vitro and in situ replication: role for pUL47 in regulation of the MDV UL46-UL49 gene locus. AB - Marek's disease virus (MDV) is a lymphotropic alphaherpesvirus that replicates in a highly cell-associated manner in vitro. Production of infectious cell-free virus only occurs in feather follicle epithelial (FFE) cells of infected chicken skins. Previously, we described differential expression for a core alphaherpesvirus protein, pUL47 that was found to be abundantly expressed in FFE cells of infected chickens, while barely detectable during in vitro propagation. Here, we further examined the dynamics of expression of four tegument proteins within the UL46-49 locus during in vitro and in situ replication. All four proteins examined were expressed abundantly in situ, whereas both pUL47 and pUL48 expression were barely detectable in vitro. Replacement of the putative UL47 and UL48 promoters with the minimal cytomegalovirus promoter enhanced mRNA and protein expression in vitro. Interestingly, enhanced expression of pUL47 resulted in increased UL46, UL48, and UL49 transcripts that resulted in increased pUL46 and pUL48 expression. PMID- 26117309 TI - Measurement of catecholamines in rat and mini-pig plasma and urine by liquid chromatography-tandem mass spectrometry coupled with solid phase extraction. AB - A tandem mass spectrometry method combined with an ion-pair chromatographic separation after weak cation exchange solid phase sample extraction for epinephrine (E), norepinephrine (NE) and dopamine (DA) has been developed. Two surrogate matrixes for plasma and urine as well as stable isotope labeled internal standards were utilized for quantitation. The observed dynamic range of E, NE and DA was 0.025-100ng/ml for plasma, and 0.25-1000ng/ml for urine with a r(2) regression coefficient >0.99. Extraction recoveries were greater than 60% and the lower limit of quantitation was 25pg/ml for all three analytes in plasma. This method provided excellent sensitivity and selectivity for use with small sample volumes (<=25uL), enabling high-throughput pharmacodynamic animal model development and screening of adverse effects. PMID- 26117308 TI - A Prospective 5-Year Re-examination of Alcohol Response in Heavy Drinkers Progressing in Alcohol Use Disorder. AB - BACKGROUND: The main neurobiological theories of the development of addiction, including tolerance, sensitization, incentive-sensitization, and allostasis, have not been tested in longitudinal human alcohol response research. To address this issue, we conducted the first controlled prospective investigation of subjective and neuroendocrine responses to alcohol measured over a 5-year interval in at risk young adult heavy drinkers (HD) and light drinker control subjects. METHODS: Participants were 156 individuals, 86 heavy drinkers and 70 light drinkers, undergoing an initial oral alcohol challenge testing (.8 g/kg alcohol vs. placebo) and an identical re-examination testing 5 to 6 years later. Alcohol use disorder (AUD) symptoms and drinking behaviors were assessed in the interim follow-up period. RESULTS: At re-examination, HD continued to exhibit higher sensitivity on alcohol's stimulating and rewarding effects with lower sensitivity to sedative effects and cortisol reactivity, relative to light drinkers. In HD with high AUD symptom trajectories over follow-up, heightened alcohol stimulation and reward persisted at re-examination. HD with low AUD symptoms showed reduced alcohol stimulation over time and lower reward throughout compared with the HD with high and intermediate AUD symptoms. CONCLUSIONS: Results support the early stage phase of the allostasis model, with persistently heightened reward sensitivity and stimulation in heavy drinkers exhibiting AUD progression in early mid-adulthood. While there are multiple pathways to development of a disorder as complex as AUD, maintenance of alcohol stimulatory and rewarding effects may play an important role in the continuation and progression of alcohol addiction. PMID- 26117310 TI - Pharmacokinetics and tissue distribution study of camellianin A and its major metabolite in rats by liquid chromatography with tandem mass spectrometry. AB - Camellianin A is a major active constituent of Adinandra nitida. A LC-MS/MS method for the determination of camellianin A and its metabolite (camellianin B) in rat plasma and tissues was developed and applied to a pharmacokinetics and tissue distribution study. Samples were separated on a Waters HSS T3 column with a mobile phase consisted of methanol and water (containing 0.1% formic acid). MS/MS detection was carried out on a triple-quadruple mass spectrometer under negative ESI mode. Pharmacokinetics study showed that camellianin A was rapidly eliminated with a t1/2 of 92.6+/-41.4h and CL of 3.19+/-0.471L/min/kg. Additionally, camellianin A showed a low oral bioavailability of 2.99% and a narrow tissue distribution; however, camellianin B was proved to have a wide tissue distribution with brain penetration. The data presented in this study provides useful information for the further applications of A. nitida and camellianin A. PMID- 26117311 TI - Protocols for studies of intraocular lens formula accuracy. PMID- 26117312 TI - Establishing correlations in the en-mass migration of dermal fibroblasts on oriented fibrillar scaffolds. AB - Wound healing proceeds via fibroblast migration along three dimensional fibrillar substrates with multiple angles between fibers. We have developed a technique for preparation of three dimensional fibrillar scaffolds with where the fiber diameters and the angles between adjacent fiber layers could be precisely controlled. Using the agarose droplet method we were able to make accurate determinations of the dependence of the migration speed, focal adhesion distribution, and nuclear deformation on the fiber diameter, fiber spacing, and angle between adjacent fiber layers. We found that on oriented single fiber layers, whose diameters exceeded 1 MUm, large focal adhesion complexes formed in a linear arrangement along the fiber axis and cell motion was highly correlated. On multi layered scaffolds most of the focal adhesion sites reformed at the junction points and the migration speed was determined by the angle between adjacent fiber layers, which followed a parabolic function with a minimum at 30 degrees . On these surfaces we observed a 25% increase in the number of focal adhesion points and a similar decrease in the degree of nuclear deformation, both phenomena associated with decreased mobility. These results underscore the importance of substrate morphology on the en-mass migration dynamics. STATEMENT OF SIGNIFICANCE: En-mass fibroblast migration is an essential component of the wound healing process which can determine rate and scar formation. Yet, most publications on this topic have focused on single cell functions. Here we describe a new apparatus where we designed three dimensional fibrillar scaffolds with well controlled angles between junction points and highly oriented fiber geometries. We show that the motion of fibroblasts undergoing en-mass migration on these scaffolds can be controlled by the substrate topography. Significant differences in cell morphology and focal adhesions was found to exist between cells migrating on flat versus fibrillar scaffolds where the migration speed was found to be a function of the angle between fibers, the fiber diameter, and the distance between fibers. PMID- 26117313 TI - Designing a fibrotic microenvironment to investigate changes in human liver sinusoidal endothelial cell function. AB - The deposition of extracellular matrix (ECM) proteins by hepatic cells during fibrosis leads to the stiffening of the organ and perturbed cellular functions. Changes in the elasticity of liver tissue are manifested by altered phenotype in hepatic cells. We have investigated changes in human liver sinusoidal endothelial cells (hLSECs) that occur as the elastic modulus of their matrix transitions from healthy (6kPa) to fibrotic (36kPa) conditions. We have also investigated the role played by Kupffer cells in the dedifferentiation of hLSECs. We report the complete loss of fenestrae and the expression of CD31 at the surface as a result of increasing elastic moduli. LSECs exhibited a greater number of actin stress fibers and vinculin focal adhesion on the stiffer substrate, as well. A novel finding is that these identical trends can be obtained on soft (6kPa) substrates by introducing an inflamed microenvironment through the addition of Kupffer cells. hLSEC monocultures on 6kPa gels exhibited fenestrae that were 140.7+/ 52.6nm in diameter as well as a lack of surface CD31 expression. Co-culturing hLSECs with rat Kupffer cells (rKCs) on 6kPa substrates, resulted in the complete loss of fenestrae, an increase in CD31 expression and in a well-organized cytoskeleton. These results demonstrate that the increasing stiffness of liver matrices does not solely result in changes in hLSEC phenotype. Even on soft substrates, culturing hLSECs in an inflamed microenvironment can result in their dedifferentiation. Our findings demonstrate the interplay between matrix elasticity and inflammation in the progression of hepatic fibrosis. PMID- 26117315 TI - Pretreatment body mass index and head and neck cancer outcome: A review of the literature. AB - BACKGROUND: The prevalence of overweight and obesity defined as BMI>=25kg/m(2) is increasing, also among head and neck cancer patients. It is unknown whether the presence of high BMI influences disease-related mortality, overall survival and recurrence in these patients. METHODS: We reviewed available literature using Pubmed and Web of Science. Human observational studies were included if they reported the impact of high BMI on mortality, recurrence or survival for head and neck cancer. RESULTS: Eleven full articles and two abstracts met the inclusion criteria: six prospective and seven retrospective cohort studies, which comprised 8.306 patients. Patients with higher BMI had increased overall survival and decreased disease-related mortality and recurrence rate compared with underweight and normal weight patients. Most studies were adjusted for potentially confounding variables, such as stage of disease and smoking habits. CONCLUSION: High BMI is associated with a better outcome in head and neck cancer. PMID- 26117314 TI - Language and affective facial expression in children with perinatal stroke. AB - Children with perinatal stroke (PS) provide a unique opportunity to understand developing brain-behavior relations. Previous research has noted distinctive differences in behavioral sequelae between children with PS and adults with acquired stroke: children fare better, presumably due to the plasticity of the developing brain for adaptive reorganization. Whereas we are beginning to understand language development, we know little about another communicative domain, emotional expression. The current study investigates the use and integration of language and facial expression during an interview. As anticipated, the language performance of the five and six year old PS group is comparable to their typically developing (TD) peers, however, their affective profiles are distinctive: those with right hemisphere injury are less expressive with respect to affective language and affective facial expression than either those with left hemisphere injury or TD group. The two distinctive profiles for language and emotional expression in these children suggest gradients of neuroplasticity in the developing brain. PMID- 26117317 TI - The antioxidant function of sestrins is mediated by promotion of autophagic degradation of Keap1 and Nrf2 activation and by inhibition of mTORC1. AB - Sestrins 1 to 3 constitute a family of proteins that are induced in mammalian cells in response to environmental stressors. Despite their apparent lack of intrinsic catalytic antioxidant activity, Sestrins protect cells from oxidative stress by lowering intracellular levels of H2O2. Here we review the mechanisms by which various types of cellular stress induce Sestrin gene transcription as well as those underlying the antioxidant function of these proteins. Several transcriptional factors, including p53, HIF-1, FoxO, C/EBP-beta, ATF4, Nrf2, and PGC-1alpha, contribute directly to the transcriptional activation of Sestrin genes in response to various types of stress. The antioxidant function of Sestrins is mediated by two main pathways. In one pathway, Sestrins promote the p62-dependent autophagic degradation of Keap1 and thereby upregulate Nrf2 signaling and the consequent expression of genes for antioxidant enzymes. In the second pathway, Sestrins block mTORC1 activation and thereby attenuate reactive oxygen species accumulation. This inhibition of mTORC1 activity is achieved either via the AMPK-dependent phosphorylation and activation of TSC2 and consequent inhibition of the GTPase Rheb or via inhibition of the GTPase Rag and consequent prevention of the lysosomal localization of mTORC1 triggered by amino acids. Elucidation of how these pathways operate individually or cooperatively under different stress conditions awaits further study. PMID- 26117316 TI - PEGylated ceria nanoparticles used for radioprotection on human liver cells under gamma-ray irradiation. AB - Ceria nanoparticles (CNPs) have recently been shown to protect cells and animals from radiation-induced damage. However, most of the CNPs used in previous studies were either naked or weakly protected by surfactants, which inevitably encounter many obstacles in biological applications. Here, alendronate was used as an ideal anchor to graft polyethylene glycol (PEG) onto CNPs, leading to enhanced stability, reduced cytotoxicity, and improved biological properties. Further investigation assessed the protective ability of the nanoparticles against radiation-induced effects for human normal liver cells (L-02), indicating that the PEGylated CNPs (CNPs-AL-PEG) were more efficient than naked CNPs. We determined that enhanced Ce(3+)/Ce(4+) ratios improved intracellular dispersion and that the ameliorated intracellular distribution of CNPs-AL-PEG contributes to the elevated expression of SOD2, which leads to increased protection of normal cells against ROS and reduces the oxidatively generated DNA damage. These studies hold tremendous promise for radioprotection and biological applications. PMID- 26117318 TI - Functional polymorphisms in Nrf2: implications for human disease. AB - Nuclear factor (erythroid derived)-2 like 2 (NFE2L2), also known as nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), is a ubiquitous transcription factor essential for protecting cells and tissues from oxidative stress-induced injury. Positional cloning and studies with Nrf2 knockout mice have identified important roles for this transcription factor in disease phenotypes for many organ systems. Studies have also characterized the means through which human Nrf2 is regulated and the mechanisms of interaction with antioxidant response elements (ARE) in promoters of effector genes. Moreover, single nucleotide polymorphisms (SNPs) in Nrf2 have been identified and evaluated for effects on gene expression and function, and translational investigations have sought to determine whether loss of function SNPs associate with disease progression. In this review, we present 1) an overview of the human Nrf2 gene and protein domain, 2) identification of genetic mutations in Nrf2 and associations of the mutations with multiple diseases, and 3) the role of somatic mutations in Nrf2 in diseases, primarily various cancers. PMID- 26117319 TI - Thioredoxin-1/peroxiredoxin-1 as sensors of oxidative stress mediated by NADPH oxidase activity in atherosclerosis. AB - To assess the potential association between TRX-1/PRX-1 and NADPH oxidase (Nox) activity in vivo and in vitro, TRX-1/PRX-1 levels were assessed by ELISA in 84 asymptomatic subjects with known phagocytic NADPH oxidase activity and carotid intima-media thickness (IMT). We found a positive correlation between TRX-1/PRX-1 and NADPH oxidase-dependent superoxide production (r=0.48 and 0.47; p<0.001 for both) and IMT (r=0.31 and 0.36; p<0.01 for both) adjusted by age and sex. Moreover, asymptomatic subjects with plaques have higher PRX-1 and TRX plasma levels (p<0.01 for both). These data were confirmed in a second study in which patients with carotid atherosclerosis showed higher PRX-1 and TRX plasma levels than healthy subjects (p<0.001 for both). In human atherosclerotic plaques, the NADPH oxidase subunit p22phox colocalized with TRX-1/PRX-1 in macrophages (immunohistochemistry). In monocytes and macrophages, phorbol 12-myristate 13 acetate (PMA) induced NADPH activation and TRX-1/PRX-1 release to the extracellular medium, with a concomitant decrease in their intracellular levels, which was reversed by the NADPH inhibitor apocynin (Western blot). In loss-of function experiments, genetic silencing of the NADPH oxidase subunit Nox2 blocked PMA-induced intracellular TRX-1/PRX-1 downregulation in macrophages. Furthermore, the PMA-induced release of TRX-1/PRX-1 involves the modulation of their redox status and exosome-like vesicles. TRX-1/PRX-1 levels are associated with NADPH oxidase-activity in vivo and in vitro. These data could suggest a coordinated antioxidant response to oxidative stress in atherothrombosis. PMID- 26117321 TI - Role of Nrf2 in the pathogenesis of atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease of the vascular arterial walls. A number of studies have revealed the biological and genetic bases of atherosclerosis, and over 100 genes influence atherosclerosis development. Nrf2 plays an important role in oxidative stress response and drug metabolism, but the Nrf2 signaling pathway is closely associated with atherosclerosis development. During atherosclerosis progression, Nrf2 signaling modulates many physiological and pathophysiological processes, such as lipid homeostasis regulation, foam cell formation, macrophage polarization, redox regulation and inflammation. Interestingly, Nrf2 exhibits both pro- and anti-atherogenic effects in experimental animal models. These observations make the Nrf2 pathway a promising target to prevent atherosclerosis. PMID- 26117320 TI - Epigenetic regulation of Keap1-Nrf2 signaling. AB - The kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) signaling axis serves as a "master regulator" in response to oxidative/electrophilic stresses and chemical insults through the coordinated induction of a wide array of cytoprotective genes. Therefore, activation of Nrf2 is considered to be an important approach for preventing chronic diseases triggered by stresses and toxins, including cancer. Despite extensive studies suggested that the Keap1-Nrf2 signaling pathway is subject to multiple layers of regulation at the transcriptional, translational, and post-translational levels, the potential epigenetic regulation of Nrf2 and Keap1 has begun to be recognized only in recent years. Epigenetic modifications, heritable alterations in gene expression that occur without changes in the primary DNA sequence, have been reported to be profoundly involved in oxidative stress responses. In this review, we discuss the latest findings regarding the epigenetic regulation of Keap1-Nrf2 signaling by DNA methylation, histone modification, and microRNAs. The crosstalk among these epigenetic modifications in the regulation of Keap1-Nrf2 signaling pathways is also discussed. Studies of the epigenetic modification of Nrf2 and Keap1 have not only enhanced our understanding of this complex cellular defense system but have also provided potential new therapeutic targets for the prevention of certain diseases. PMID- 26117323 TI - Molecular hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor-knockout mice. AB - Hydrogen (H(2)) attenuates the development of atherosclerosis in mouse models. We aimed to examine the effects of H(2) on atherosclerotic plaque stability. Low density lipoprotein receptor-knockout (LDLR(-/-)) mice fed an atherogenic diet were dosed daily with H(2) and/or simvastatin. In vitro studies were carried out in an oxidized-LDL (ox-LDL)-stimulated macrophage-derived foam cell model treated with or without H(2). H(2) or simvastatin significantly enhanced plaque stability by increasing levels of collagen, as well as reducing macrophage and lipid levels in plaques. The decreased numbers of dendritic cells and increased numbers of regulatory T cells in plaques further supported the stabilizing effect of H(2) or simvastatin. Moreover, H(2) treatment decreased serum ox-LDL level and apoptosis in plaques with concomitant inhibition of endoplasmic reticulum stress (ERS) and reduction of reactive oxygen species (ROS) accumulation in the aorta. In vitro, like the ERS inhibitor 4-phenylbutyric acid, H(2) inhibited ox-LDL- or tunicamycin (an ERS inducer)-induced ERS response and cell apoptosis. In addition, like the ROS scavenger N-acetylcysteine, H(2) inhibited ox-LDL- or Cu(2+) (an ROS inducer)-induced reduction in cell viability and increase in cellular ROS. Also, H(2) increased Nrf2 (NF-E2-related factor-2, an important factor in antioxidant signaling) activation and Nrf2 small interfering RNA abolished the protective effect of H(2) on ox-LDL-induced cellular ROS production. The inhibitory effects of H(2) on the apoptosis of macrophage-derived foam cells, which take effect by suppressing the activation of the ERS pathway and by activating the Nrf2 antioxidant pathway, might lead to an improvement in atherosclerotic plaque stability. PMID- 26117322 TI - Mechanisms and functions of Nrf2 signaling in Drosophila. AB - The Nrf2 transcription factor belongs to the Cap'n'collar family, named after the founding member of this group, the product of the Drosophila Cap'n'collar gene. The encoded protein, Cap'n'collar, abbreviated Cnc, offers a convenient and accessible model to study the structure, function, and biology of Nrf2 transcription factors at the organismic, tissular, cellular, and molecular levels, using the powerful genetic, genomic, and biochemical tools available in Drosophila. In this review we provide an account of the original identification of Cnc as a regulator of embryonic development. We then describe the discovery of Nrf2-like functions of Cnc and its role in acute stress signaling and aging. The establishment of Drosophila as a model organism in which the mechanisms and functions of Nrf2 signaling can be studied has led to several discoveries: the regulation of stem cell activity by an Nrf2-mediated redox mechanism, the interaction of Nrf2 with p62 and Myc in the control of tissue growth and the unfolded protein response, and more. Several of these more recent lines of investigation are highlighted. Model organisms such as the fly and the worm remain powerful experimental platforms that can help to unravel the many remaining puzzles regarding the role of Nrf2 and its relatives in controlling the physiology and maintaining the health of multicellular organisms. PMID- 26117326 TI - Bioinformatics analyses provide insight into distant homology of the Keap1-Nrf2 pathway. AB - An essential requirement for the evolution of early eukaryotic life was the development of effective means to protect against metabolic oxidative stress and exposure to environmental toxicants. In present-day mammals, the master transcription factor Nrf2 regulates basal level homeostasis and inducible expression of numerous detoxifying and antioxidant genes. To examine early evolution of the Keap1-Nrf2 pathway, we present bioinformatics analyses of distant homology of mammalian Keap1 and Nrf2 proteins across the Kingdoms of Life. Software written for this analysis is made freely available on-line. Furthermore, utilizing protein modeling and virtual screening methods, we demonstrate potential for Nrf2 activation by competitive inhibition of its binding to Keap1, specifically by UV-protective fungal mycosporines and marine mycosporine-like amino acids (MAAs). We contend that coevolution of Nrf2 activating secondary metabolites by fungi and other extant microbiota may provide prospective compound leads for the design of new therapeutics to target activation of the human Keap1-Nrf2 pathway for treating degenerative diseases of ageing. PMID- 26117325 TI - p62 links autophagy and Nrf2 signaling. AB - The Nrf2-Keap1-ARE pathway is a redox and xenobiotic sensitive signaling axis that functions to protect cells against oxidative stress, environmental toxicants, and harmful chemicals through the induction of cytoprotective genes. To enforce strict regulation, cells invest a great deal of energy into the maintenance of the Nrf2 pathway to ensure rapid induction upon cellular insult and rapid return to basal levels once the insult is mitigated. Because of the protective role of Nrf2 transcriptional programs, controlled activation of the pathway has been recognized as a means for chemoprevention. On the other hand, constitutive activation of Nrf2, due to somatic mutations of genes that control Nrf2 degradation, promotes carcinogenesis and imparts chemoresistance to cancer cells. Autophagy, a bulk protein degradation process, is another tightly regulated complex cellular process that functions as a cellular quality control system to remove damaged proteins or organelles. Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. Recently, these two cellular pathways were shown to intersect through the direct interaction between p62 (an autophagy adaptor protein) and Keap1 (the Nrf2 substrate adaptor for the Cul3 E3 ubiquitin ligase). Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. In this review, we will discuss the progress that has been made in dissecting the intersection of these two pathways and the potential tumor-promoting role of prolonged Nrf2 activation. PMID- 26117327 TI - Critical role of peroxiredoxin 6 in the repair of peroxidized cell membranes following oxidative stress. AB - Phospholipids are a major structural component of all cell membranes; their peroxidation represents a severe threat to cellular integrity and their repair is important to prevent cell death. Peroxiredoxin 6 (Prdx6), a protein with both GSH peroxidase and phospholipase A(2) (PLA(2)) activity, plays a critical role in antioxidant defense of the lung and other organs. We investigated the role of Prdx6 in the repair of peroxidized cell membranes in pulmonary microvascular endothelial cells (PMVEC) and isolated mouse lungs treated with tert-butyl hydroperoxide and lungs from mice exposed to hyperoxia (100% O(2)). Lipid peroxidation was evaluated by measurement of thiobarbituric acid reactive substances, oxidation of diphenyl-1-pyrenylphosphine, or ferrous xylenol orange assay. The exposure dose was varied to give a similar degree of lipid peroxidation at the end of exposure in the different models. Values for lipid peroxidation returned to control levels within 2 h after oxidant removal in wild type PMVEC and perfused lungs but were unchanged in Pxdx6 null preparations. An intermediate degree of repair was observed with PMVEC and lungs that expressed only C47S or D140A mutant Prdx6; the former mutant does not have peroxidase activity, while the latter loses its PLA(2) activity. Prdx6 null mice showed markedly delayed recovery from lipid peroxidation during 20 h observation following exposure to hyperoxia. Thus, Prdx6 plays a critical role in the repair of peroxidized phospholipids in cell membranes and the recovery of lung cells from peroxidative stress; the peroxidase and PLA(2) activity each contribute to the recovery process. PMID- 26117328 TI - A polyphenolic flavonoid glabridin: Oxidative stress response in multidrug resistant Staphylococcus aureus. AB - Glabridin a polyphenolic flavonoid from Glycyrrhiza glabra is known to possess several therapeutic properties. In the present study, we report for the first time the in vitro antibacterial activity (MIC values ranging from 3.12 to 25 MUg/mL) of glabridin against multidrug-resistant clinical isolates of S. aureus by inducing oxidative stress. Increased levels of H2O2 and NO were observed in a dose-dependent manner after treatment of glabridin that further affected macromolecules such as DNA, lipids, and proteins. Surprisingly, glabridin was found to possess antioxidant properties when used at lower concentrations using three different methods including DPPH, FRAP, and SOD assays. These observations were further validated through the expression analysis of oxidative stress responsive genes using qRT-PCR wherein glabridin was observed to up- and down regulate these genes at lower and higher concentrations, respectively. In in vitro combination experiments, glabridin was found to reduce the MIC of different antibiotics such as norfloxacin, oxacillin, and vancomycin by up to 4-fold, while the MIC of glabridin itself was found to be reduced by up to 8-fold in the presence of antibiotics. A synergistic interaction was observed between norfloxacin and glabridin when used in combination against multidrug-resistant clinical isolate SA 4627 of Staphylococcus aureus at much lower concentrations, indicating the suitability of glabridin in combination therapy. PMID- 26117329 TI - Systemic lupus erythematosus onset in lupus-prone B6.MRL/lpr mice Is influenced by weight gain and Is preceded by an increase in neutrophil oxidative burst activity. AB - In this study, we assessed whether weight gain influenced the systemic lupus erythematosus (SLE) onset and/or outcome, and examined the role that reactive oxygen species (ROS) production by neutrophils played in the SLE onset and/or outcome. Female control (C57BL/6) and lupus-prone B6.MRL/lpr mice (CM and LPM, respectively) at 4 weeks old were fed standard diet or standard diet plus cafeteria diet during 12 weeks. SLE diagnosis relied on the presence of both antinuclear antibodies (ANA) and renal abnormalities. We found that the percentage of weight gain in CM and LPM increased as a function of the length of cafeteria diet feeding period, but it was not associated with energy intake. Cafeteria diet-fed CM and LPM at 8 and 12 weeks old were overweight, while CM and LPM at 16 weeks old were obese. Compared with standard diet-fed CM and LPM, cafeteria diet-fed CM and LPM exhibited elevated glucose and total cholesterol levels, and diminished triglycerides levels. Standard diet-fed 16-week-old LPM and cafeteria diet-fed 12-week-old LPM had nephritis, characterized by the increased interstitial infiltration of leukocytes. Cafeteria diet-induced weight gain rose the frequency of homogeneous and speckled ANA staining patterns in the 12- and 16-week-old LPM groups. Together, these results indicated that weight gain anticipated the SLE onset. In addition, neutrophils from cafeteria diet-fed 8-week-old LPM exhibited augmented ROS production capacity; in standard diet-fed LPM, such rise occurred only in the 16-week-old group. Thus, the neutrophil ROS production capacity was increased before the SLE onset and during its outcome. Overweight and obese CM and LPM displayed elevated levels of kidney, liver, heart, and spleen lipid peroxidation. In conclusion, cafeteria diet-induced weight gain is associated with the increased production of ANA and neutrophil derived ROS, which may contribute to accelerate the SLE onset. PMID- 26117324 TI - Signaling and stress: The redox landscape in NOS2 biology. AB - Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. However, deleterious as well as beneficial roles of NO have been reported. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitrosative signaling and nitrosative stress-related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including processes that lead to interconversion of RNS and interactions with molecular targets. PMID- 26117330 TI - Regulation of catalase expression in healthy and cancerous cells. AB - Catalase is an important antioxidant enzyme that dismutates hydrogen peroxide into water and molecular oxygen. The catalase gene has all the characteristics of a housekeeping gene (no TATA box, no initiator element sequence, high GC content in promoter) and a core promoter that is highly conserved among species. We demonstrate in this review that within this core promoter, the presence of DNA binding sites for transcription factors, such as NF-Y and Sp1, plays an essential role in the positive regulation of catalase expression. Additional transcription factors, such as FoxO3a, are also involved in this regulatory process. There is strong evidence that the protein Akt/PKB in the PI3K signaling pathway plays a major role in the expression of catalase by modulating the activity of FoxO3a. Over the past decade, other transcription factors (PPARgamma, Oct-1, etc.), as well as genetic, epigenetic, and posttranscriptional processes, have emerged as crucial contributors to the regulation of catalase expression. Altered expression levels of catalase have been reported in cancer tissues compared to their normal counterparts. Deciphering the molecular mechanisms that regulate catalase expression could, therefore, be of crucial importance for the future development of pro-oxidant cancer chemotherapy. PMID- 26117331 TI - Molecular basis of the Keap1-Nrf2 system. AB - Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes, and Keap1 (Kelch-like ECH-associated protein 1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity. Keap1 also acts as a sensor for oxidative and electrophilic stresses. Keap1 retains multiple sensor cysteine residues that detect various stress stimuli. Increasing attention has been paid to the roles that Nrf2 plays in the protection of our bodies against drug toxicity and stress-induced diseases. On the other hand, Nrf2 is found to promote both oncogenesis and cancer cell resistance against chemotherapeutic drugs. Thus, although Nrf2 acts to protect our body from deleterious stresses, cancer cells hijack the Nrf2 activity to support their malignant growth. Nrf2 has emerged as a new therapeutic target, and both inducers and inhibitors of Nrf2 are awaited. Studies challenging the molecular basis of the Keap1-Nrf2 system functions are now critically important to improve translational studies of the system. Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1-Nrf2 system serves as a potent regulator of our health and disease. PMID- 26117332 TI - From mechanical stimulus to bone formation: A review. AB - Bone is a remarkable tissue that can respond to external stimuli. The importance of mechanical forces on the mass and structural development of bone has long been accepted. This adaptation behaviour is very complex and involves multidisciplinary concepts, and significant progress has recently been made in understanding this process. In this review, we describe the state of the art studies in this area and highlight current insights while simultaneously clarifying some basic yet essential topics related to the origin of mechanical stimulus in bone, the biomechanisms associated with mechanotransduction, the nature of physiological bone stimuli and the test systems most commonly used to study the mechanical stimulation of bone. PMID- 26117333 TI - Comparison of trunk muscle forces, spinal loads and stability estimated by one stability- and three EMG-assisted optimization approaches. AB - Various hybrid EMG-assisted optimization (EMGAO) approaches are commonly used to estimate muscle forces and joint loads of human musculoskeletal systems. Use of EMG data and optimization enables the EMGAO models to account for inter- and intra-individual variations in muscle recruitments while satisfying equilibrium requirements. Due to implications in ergonomics/prevention and rehabilitation/treatment managements of low-back disorders, there is a need to evaluate existing approaches. The present study aimed to compare predictions of three different EMGAO and one stability-based optimization (OPT) approaches for trunk muscle forces, spinal loads, and stability. Identical measured kinematics/EMG data and anatomical model were used in all approaches when simulating several sagittally symmetric static activities. Results indicated substantial inter-model differences in predicted muscle forces (up to 123% and 90% for total muscle forces in tasks with upright and flexed postures, respectively) and spinal loads (up to 74% and 78% for compression loads in upright and flexed postures, respectively). Results of EMGAO models markedly varied depending on the manner in which correction (gain) factors were introduced. Large range of gain values (from ~0.47 to 41) was estimated in each model. While EMGAO methods predicted an unstable spine for some tasks, OPT predicted, as intended, either a meta-stable or stable states in all simulated tasks. An unrealistic unstable state of the spine predicted by EMGAO methods for some of the simulated tasks (which are in reality stable) could be an indication of the shortcoming of these models in proper prediction of muscle forces. PMID- 26117334 TI - Trade-off between stress shielding and initial stability on an anatomical cementless stem shortening: in-vitro biomechanical study. AB - Shortened cementless femoral stems have become popular with the advent of minimally invasive total hip arthroplasty (THA). Successful THA requires initial stem stability and prevention of stress shielding-mediated bone loss, although the effect of stem shortening is controversial. Here we experimentally examined whether stem shortening affects stress shielding and initial stability. Anatomical stems (length, 120 mm) were cut to an 80 mm or 50 mm length. Ten tri axial strain gauges measured the cortical strain on each stem-implanted femur to evaluate stress shielding. Two transducers measured axial relative displacement and rotation under single-leg stance loading. The 50 mm stem increased the equivalent strains with respect to the original stem in the proximal calcar region (31.0% relative to intact strain), proximal medial region (63.1%), and proximal lateral region (53.9%). In contrast, axial displacement and rotation increased with a decreasing stem length. However, the axial displacement of the 50 mm stem was below a critical value of 150 um for bone ingrowth. Our findings indicate that, with regard to a reduction in stem length, there is a tradeoff between stress shielding and initial stability. Shortening the stem up to 50 mm can promote proximal load transfer, but bone loss would be inevitable, even with sufficient initial stability for long-term fixation. PMID- 26117335 TI - The alternative CD20 transcript variant is not a surrogate marker for resistance to rituximab in patients with rheumatoid arthritis. PMID- 26117337 TI - Chronic cutaneous leishmaniasis presenting as commissural cheilitis. PMID- 26117336 TI - Oncogenic miR-17/20a Forms a Positive Feed-forward Loop with the p53 Kinase DAPK3 to Promote Tumorigenesis. AB - MicroRNAs (miRs) are a class of small regulatory RNAs that have been implicated in diverse biological pathways, including cancer. miR-17/20a encoded by the c13orf25 locus is among the first miRs discovered to have oncogenic functions. The E2F family members have been established as the targets for these oncomiRs, which form a negative feedback loop to control cell cycle progression. However, this pathway does not seem to be sufficient to account for elevated expression of these oncomiRs in cancer cells to promote tumorigenesis. Here we report that miR 17/20a targets a p53 activating kinase DAPK3, leading to p53-dependent transcriptional de-repression of the oncomiRs. We demonstrate that DAPK3 plays a central role in preventing miR-17/20a depletion-induced genome instability and in miR-17/20a overexpression-triggered tumor formation. This newly identified tumorigenic pathway may thus contribute to miR-17/20a amplification and tumor growth in diverse human cancers. PMID- 26117338 TI - Leading-edge forensic DNA analyses and the necessity of including crime scene investigators, police officers and technicians in a DNA elimination database. AB - In recent years, sophisticated technology has significantly increased the sensitivity and analytical power of genetic analyses so that very little starting material may now produce viable genetic profiles. This sensitivity however, has also increased the risk of detecting unknown genetic profiles assumed to be that of the perpetrator, yet originate from extraneous sources such as from crime scene workers. These contaminants may mislead investigations, keeping criminal cases active and unresolved for long spans of time. Voluntary submission of DNA samples from crime scene workers is fairly low, therefore we have created a promotional method for our staff elimination database that has resulted in a significant increase in voluntary samples since 2011. Our database enforces privacy safeguards and allows for optional anonymity to all staff members. We also offer information sessions at various police precincts to advise crime scene workers of the importance and success of our staff elimination database. This study, a pioneer in its field, has obtained 327 voluntary submissions from crime scene workers to date, of which 46 individual profiles (14%) have been matched to 58 criminal cases. By implementing our methods and respect for individual privacy, forensic laboratories everywhere may see similar growth and success in explaining unidentified genetic profiles in stagnate criminal cases. PMID- 26117339 TI - Drainage of a Pancreatic Pseudocyst via a Spontaneous Cyst Duodenostomy. PMID- 26117340 TI - Near-Fatal Pneumopericardium During Tracheal Stent Exchange. PMID- 26117342 TI - Daptomycin-induced eosinophilic pneumonia. PMID- 26117341 TI - Secondhand Smoke Exposure and Stroke: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. AB - INTRODUCTION: Stroke is a major public health concern worldwide given the associated morbidity and mortality. Smoking is a risk factor for stroke, but the relationship between secondhand smoke (SHS) exposure and stroke has been inconsistent to date. The aim of the current study was to examine the association of SHS exposure and risk of stroke and its subtypes (ischemic and hemorrhagic stroke) among nonsmokers. METHODS: Demographic and clinical characteristics were compared by SHS exposure status for African American and white nonsmokers aged >=45 years in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study in 2014. Hazard ratios (HRs) and corresponding 95% CIs were calculated by Cox proportional hazards models to assess the relationship between SHS exposure and stroke risk. RESULTS: Of the 21,743 participants (38% African American, 45% male), SHS exposure in the past year was reported by 23%. Compared with those without SHS exposure, exposed participants were more likely to be female, white, younger, and reside with a smoker (all p<0.001). A total of 428 incident strokes were observed from April 2003 to March 2012 during a mean follow up of 5.6 years. The risk of overall stroke was increased 30% among those with SHS exposure after adjustment for other stroke risk factors (95% CI=2%, 67%). This relationship appeared to be driven by ischemic strokes. CONCLUSIONS: SHS exposure is independently associated with an increased risk of stroke. Future studies are needed to confirm these findings and examine the role of long-term effects of SHS exposure on stroke outcomes. PMID- 26117343 TI - Comparison of susceptibility of HIV-1 variants to antiretroviral drugs by genotypic and recombinant virus phenotypic analyses. AB - OBJECTIVE: This study utilized genotypic and in-house recombinant virus phenotypic assays to examine HIV-1 variant susceptibility to antiretroviral (ARV) drugs; comparisons were made between the analyses. METHODS: A nested PCR was employed to amplify the HIV-1 gag-pol gene, which comprised the entire PR gene (codons 1-99) and the former RT gene (codons 1-312). Genetic resistance was determined by submitting the sequences to the Stanford University Network HIV-1 Database. Phenotypic susceptibilities to six ARV drugs were measured using a high throughput, multi-cycle, recombinant virus phenotypic assay. Results were expressed in terms of the IC50 (half maximal inhibitory concentration) and fold change values. The relationship between phenotypic drug resistance and genetic polymorphisms was determined. RESULTS: Nineteen fragment sequences for which recombinant viruses were successfully constructed were translated and compared with the consensus B sequences in the Stanford University Network HIV-1 Database. No recognizable genotypic resistance-associated mutations were noted, except in one sample. Each homologous replication-competent recombinant viral fold-change in the presence of six ARV drugs used widely in China was measured. According to the clinical and statistical criteria, 16 of the 19 samples were susceptible to the six drugs tested. The majority of phenotypic and genotypic results obtained were in agreement, with a concordance rate of 97.4%. Both phenotypic and genotypic assays suggested that sample HN2009001 was resistant to all drugs tested. All phenotypic and genotypic results obtained regarding the susceptibility of the 19 recombinant viruses to nucleoside reverse transcriptase inhibitors (NRTIs) were in agreement. With regard to the genotypic results for the non-nucleoside reverse transcriptase inhibitors (NNRTIs), 7.9% (3/38) were inconsistent with the phenotypic results. CONCLUSIONS: The in-house recombinant virus phenotypic assay was able to provide a straightforward quantitative assessment of resistance. In most cases, the genotypic and novel phenotypic assays yielded similar results. The disparity in HIV-1 susceptibility indicates a need to further investigate the clinical outcomes of antiretroviral therapy in certain individuals. PMID- 26117344 TI - Short communication: localization and expression of monocyte chemoattractant protein-1 in different subcutaneous and visceral adipose tissues of early lactating dairy cows. AB - The present study aimed to examine the mRNA abundance of the monocyte chemoattractant protein-1 (MCP-1) and to localize the MCP-1 protein in different subcutaneous (s.c.) and visceral (v.c.) fat depots in high-yielding dairy cows. Early-lactating German Holstein cows (n=25) were divided into a control (CON) and a conjugated linoleic acids (CLA)-supplemented group to investigate potential effects of dietary CLA treatment on MCP-1. The MCP-1 was localized in different s.c. and v.c. adipose tissue (AT) by immunohistochemistry, whereas the mRNA abundance was investigated using quantitative PCR. Albeit the infiltration of immune cells into bovine AT has been demonstrated to be only marginal, both MCP-1 protein and mRNA could be detected in bovine AT depots. The MCP-1 protein was localized both in the cytoplasm of adipocytes and in the cytoplasm of cells from the stromal vascular fraction; however, the number of MCP-1-positive cells was low. The mRNA abundances of MCP-1 were higher in v.c. compared with s.c. AT. Moreover, neither mRNA abundance nor protein expression of MCP-1 was seriously influenced by CLA supplementation of early-lactating dairy cows. PMID- 26117345 TI - Effect of biotin and pantothenic acid on performance and concentrations of avidin binding substances in blood and milk of lactating dairy cows. AB - We hypothesized that pantothenic acid reduces the absorption of biotin in lactating dairy cows. Therefore, the objective of this study was to evaluate the plausible interaction between biotin and pantothenic acid on production performance and concentration of avidin-binding substances (ABS), an indicator of biotin concentration, in blood and milk of lactating dairy cows. Eight primiparous and 16 multiparous Holstein cows were assigned to 1 of 4 diet sequences in a replicated 4*4 Latin square design with 18-d periods. Cows were housed in a freestall barn and fed once daily (0730 h) by means of a Calan gate system (American Calan Inc., Northwood, NH). Treatments consisted of a control diet that contained no B-vitamins, a biotin diet that contained 0.87 mg of biotin per kilogram of dry matter (DM), a pantothenic acid diet that contained 21 mg of pantothenic acid per kilogram of DM, and a biotin plus pantothenic acid diet that contained 0.87 mg of biotin and 21 mg of calcium pantothenic acid per kilogram of DM. Four different concentrates were prepared in a commercial feed mill. These concentrates were mixed with corn silage and grass hay and delivered ad libitum as a total mixed ration. Biotin supplementation did not affect DM intake, milk yield, or milk fat, protein, lactose, and milk-urea-nitrogen concentrations. Fat, protein, and lactose yields were not affected by treatments. The fat-to-protein ratio was <1 and similar among all treatments. Biotin supplementation did not increase the concentration of ABS in plasma. The supplementation of pantothenic acid did not affect the concentration of ABS in plasma when either supplemented alone or in combination with biotin. Biotin supplementation increased the concentration of ABS in milk relative to control. Contrary to our hypothesis, the supplementation of pantothenic acid did not decrease the concentration of ABS in milk relative to the control. When cows were supplemented with both biotin and pantothenic acid, the concentration of ABS in milk was similar to that of cows supplemented with biotin alone. In conclusion, pantothenic acid did not affect the concentrations of ABS in plasma and milk, suggesting that increasing dietary supply of pantothenic acid did not inhibit biotin absorption. PMID- 26117346 TI - Short communication: artificial ultraviolet B light exposure increases vitamin D levels in cow plasma and milk. AB - The number of dairy cows without access to pasture or sunlight is increasing; therefore, the content of vitamin D in dairy products is decreasing. Ultimately, declining vitamin D levels in dairy products will mean that dairy products are a negligible source of natural vitamin D for humans. We tested the ability of a specially designed UVB lamp to enhance the vitamin D3 content in milk from dairy cows housed indoors. This study included 16 cows divided into 4 groups. Each group was exposed daily to artificial UVB light simulating 1, 2, 3, or 4 h of summer sun at 56 degrees N for 24 d, and the group with simulated exposure to 2 h of summer sun daily continued to be monitored for 73 d. We found a significant increase in 25-hydroxyvitamin D3 (25OHD3) levels in plasma as well as vitamin D3 and 25OHD3 levels in milk after daily exposure for 24 d in all treatment groups. Extending daily exposure to artificial UVB light to 73 d did not lead to an increase of vitamin D3 or 25OHD3 level in the milk. In conclusion, the change in production facilities for dairy cows providing cows with no access to pasture and sunlight causes a decrease of vitamin D levels in dairy products. This decrease may be prevented by exposing cows to artificial UVB light in the stable. PMID- 26117347 TI - Glucose supplementation has minimal effects on blood neutrophil function and gene expression in vitro. AB - During early lactation, glucose availability is low and the effect of glucose supply on bovine polymorphonuclear leukocyte (PMNL) function is poorly understood. The objective of this study was to determine the effect of glucose supplementation on the function and transcriptomic inflammatory response of PMNL from cows in early and mid-lactation in vitro. Twenty Holstein cows in early (n=10; days in milk=17+/-3.1) and mid-lactation (n=10; days in milk=168+/-14.8) were used for this study. Jugular blood was analyzed for serum concentrations of nonesterified fatty acids, beta-hydroxybutyrate, and glucose. Polymorphonuclear leukocytes were isolated and diluted using RPMI (basal glucose concentration was 7.2 mM) to different concentrations of PMNL/mL for phagocytosis, chemotaxis, gene expression, and medium analyses. Working solutions of glucose (0 or 4 mM of d glucose) and lipopolysaccharide (0 or 50MUg/mL) were added and tubes were incubated for 120 min at 37 degrees C. Media were analyzed for concentrations of glucose and tumor necrosis factor-alpha (TNF-alpha). Data were analyzed in a randomized block (stage of lactation) design. Challenge with lipopolysaccharide increased the expression of the genes encoding for nuclear factor kappa B (NFKB1), IL-10 (IL10), IL1B, IL6, IL8, TNF-alpha (TNFA), glucose transporter 3 (SLC2A3), and the concentration of TNF-alpha in medium (147.3 vs. 72.5 pg/mL for lipopolysaccharide and control, respectively). Main effect of stage of lactation was minimal where the expression of IL10 increased for cows in early compared with cows in mid-lactation. After lipopolysaccharide challenge, cows in early lactation experienced more marked increases in the expression of IL6, TNFA, and IL8 when compared with cows in mid-lactation. Glucose supplementation had minimal effects on gene expression where glucose supplementation increased the expression of lysozyme (LYZ). Glucose supplementation increased PMNL phagocytosis but did not alter chemotaxis, morphology, or concentration of TNF-alpha in the medium. Under the conditions of the experiment, stage of lactation had minimal effects on PMNL response to glucose supply where only the expression of NFKB1 and the production of TNF-alpha were greater for cows in mid-lactation when compared with early lactation. Metabolic profiles for cows in early lactation did not parallel those for cows during the early postpartum period and may partly explain results for this study. Future studies investigating the effect of glucose supply on bovine PMNL function in vivo and how this may be altered by stage of lactation are warranted. PMID- 26117348 TI - Cost-benefit analysis of vaccination against Mycobacterium avium ssp. paratuberculosis in dairy cattle, given its cross-reactivity with tuberculosis tests. AB - Johne's disease (JD), or paratuberculosis, is a chronic enteric disease of ruminants, caused by infection with Mycobacterium avium ssp. paratuberculosis (MAP). Johne's disease causes considerable economic losses to the US dairy industry, estimated to be over $200 million annually. Available control strategies include management measures to improve calf hygiene, test-and-cull strategies, and vaccination. Although the first 2 strategies have shown to reduce the prevalence of MAP, they require dedicated and long-term efforts from dairy producers, with often relatively slow progress. As a result, uptake of both strategies has not been as wide as expected given the economic benefits especially of improved hygiene. Vaccination has also been found to reduce the prevalence and economic losses of JD, but most economic estimates have been based on simulation of hypothetical vaccines. In addition, if an animal is vaccinated, cross-reactivity between MAP antibodies and bovine tuberculosis (BTB) antigens may occur, decreasing the specificity of BTB tests. Therefore, MAP vaccination would cause additional indirect costs to the BTB surveillance and control program. The objective of the present study was to use data from a MAP vaccine trial together with an epidemiologic and economic model to estimate the direct on farm benefits of MAP vaccination and to estimate the indirect costs of MAP vaccination due to the cross-reactivity with BTB tests. Direct economic benefits of MAP vaccination were estimated at $8.03 (90% predictive interval: -$25.97 to $41.36) per adult animal per year, all accruing to the dairy producers. This estimate is likely an underestimation of the true direct benefits of MAP vaccination. In addition, indirect economic costs due to cross-reactivity were $2.14 per adult animal per year, making MAP vaccination economically attractive. Only in regions or states with a high frequency of BTB testing (because of, for example, Mycobacterium bovis outbreaks in a wild deer population) and areas where typically small groups of animals are BTB tested would MAP vaccination not be economically attractive. PMID- 26117349 TI - Supplementing fresh bovine colostrum with gut-active carbohydrates reduces passive transfer of immunoglobulin G in Holstein dairy calves. AB - High concentrations of coliform bacteria in maternal colostrum (MC) have been associated with reduced IgG absorption in calves. Mannan-oligosaccharide, a gut active carbohydrate (GAC) derived from yeast cell wall, has been shown to adsorb pathogens expressing type-1-fimbriae, reducing their ability to colonize the gastrointestinal tract. The objective of this study was to investigate if addition of a GAC to colostrum would result in increased IgG absorption in newborn calves. Newborn Holstein heifer and bull calves were enrolled in summer 2012 at a commercial transition cow facility in western Wisconsin. Each day, 7.6 L pools of fresh, first milking MC were created, split into 3.8-L aliquots, and refrigerated until feeding. Eligible newborn calves were removed from the dam 30 to 60min after birth, weighed, and randomly assigned to be fed either 3.8 L of the MC pool (control) or 3.8 L of the MC pool with 30 g of GAC mixed in immediately before feeding. Duplicate 10-mL samples of colostrum were collected and frozen at -20 degrees C before feeding (and before addition of GAC) for bacterial culture and IgG determination. A 10-mL venous blood sample was collected from calves before feeding colostrum and 24 h after colostrum feeding, for laboratory determination of serum IgG using radial immunodiffusion analysis. Colostrum and calf characteristics, including colostrum IgG concentration (g/L), colostrum bacteria counts (log10, cfu/mL), calf dystocia scores (1 to 4), birth weights (kg), and age at first feeding (min) were not different between the group fed GAC (n=47) and the control group (n=48). Mixed linear regression analysis showed that calves fed colostrum supplemented with 30 g of GAC had lower mean (standard error) apparent efficiency of absorption of IgG and lower serum IgG concentrations at 24 h [23.9% (1.0); IgG=24.0 (1.1) g/L] than did control calves [30.4% (1.0); IgG=30.8 (1.0) g/L]. Given the negative effect observed in this study, it is not recommended that fresh colostrum be supplemented with 30 g of GAC. PMID- 26117350 TI - Consequences and economics of metritis in Iranian Holstein dairy farms. AB - The objectives of this study were (1) to describe the risk factors, incidence, and productive and reproductive consequences of metritis in dairy cows, and (2) to estimate the financial losses associated with metritis using data gathered from 4 Holstein dairy farms in Isfahan, Iran. Calving records from March 2008 to December 2013, comprising 43,488 calvings, were included in the data set. The effects of metritis on productive and reproductive performance were analyzed using a mixed linear model for primiparous and multiparous cows separately and in an overall data set (all cows combined), whereas risk factors on metritis incidence were examined using a multivariable logistical regression model for the overall data set. The incidence of metritis per cow per year was 13.2% on average and ranged from 9.0 to 15.8%. Results of logistic regression analysis demonstrated that calving year, parity number, calving season, twinning, dystocia, and retained placenta were significantly associated with the occurrence of metritis, whereas previous metritis incidence did not show an association. Greatest odds of metritis occurred in first-parity cows that calved in winter and had retained placenta, twinning, and dystocia in recent years. A case of metritis significantly reduced the 305-d milk yield in primiparous and multiparous cows and overall, but had no significant effects on 305-d fat and protein percentages in either primiparous or multiparous cows. Overall, a case of metritis reduced 305-d milk yield by 129.8+/-41.5kg/cow per lactation. The negative reproductive effects due to metritis were smaller and nonsignificant for primiparous cows compared with multiparous cows. Overall, a case of metritis increased days open and number of insemination per conception by 16.4+/-1.2 and 0.1+/-0.0 per cow per lactation, respectively. Among the individual farms, metritis costs ranged from $146.4 to $175.7 with a mean of $162.3/case. The model to calculate metritis costs proposed here could be used to estimate economic losses for metritis in other developing countries, where farm productive and economic data are generally scarce. PMID- 26117351 TI - Solubilization of rehydrated frozen highly concentrated micellar casein for use in liquid food applications. AB - Highly concentrated micellar casein concentrate (HC-MCC), a potential ingredient of protein-fortified food, is a gel at cold temperature. It contains ~17 to 21% casein, with most serum proteins and lactose removed by microfiltration and diafiltration, and it is then further concentrated using vacuum evaporation. The HC-MCC can be stored frozen, and our objective was to determine the conditions needed to obtain complete solubility of thawed HC-MCC in water and to understand its gelation upon cooling. Dispersibility (ability to pass through a 250-um mesh sieve), suspendability (percentage of protein not sedimented at 80 * g within 5min), and solubility (percentage of protein not sedimented at 20,000 * g within 5min) were measured at 4, 12, or 20 degrees C after various mixing conditions. Gelation upon cooling from 50 to 5 degrees C was monitored based on storage (G') and loss (G'') moduli. The gelled HC-MCC was also examined by transmission electron microscopy. Thawed HC-MCC was added to water to reach a protein concentration of 3% and mixed using high shear (7,500rpm) for 1min or low shear (800rpm) for 30min at 4, 12, 20, or 50 degrees C and at pH 6.4 to 7.2. The HC-MCC completely dispersed at 50 degrees C, or at <=20 degrees C followed by overnight storage at 4 degrees C. Suspendability at 50 degrees C was ~90% whereas mixing at <=20 degrees C followed by overnight storage resulted in only ~57% suspendability. Solubility followed a similar trend with ~83% at 50 degrees C and only ~29% at <=20 degrees C. Mixing HC-MCC with 60mM trisodium citrate increased dispersibility to 99% and suspendability and solubility to 81% at 20 degrees C. Cold-gelling temperature, defined as the temperature at which G'=G'' when cooling from 50 to 5 degrees C, was positively correlated with protein level in HC-MCC. Gelation occurred at 38, 28, and 7 degrees C with 23, 20, and 17% of protein, respectively. Gelation was reversible upon heating, although after a second cooling cycle the HC-MCC gel had lower G'. In micrographs of gelled HC-MCC, the casein micelles were observed to be within the normal size range but packed very closely together, with only ~20 to 50 nm of space between them. We proposed that cold-gelation of HC-MCC occurs when the kinetic energy of the casein micelles is sufficiently reduced to inhibit their mobility in relation to adjacent casein micelles. Understanding solubilization of rehydrated frozen HC-MCC and its rheological properties can help in designing process systems for using HC-MCC as a potential ingredient in liquid food. PMID- 26117352 TI - An investigation of the dynamics of intramammary infections acquired during the dry period on European dairy farms. AB - The dry period is acknowledged as playing a key role in mastitis epidemiology and yet surprisingly few studies have explored dry period infection dynamics in detail. The aim of this study was to investigate the dynamics of intramammary infection across a cohort of dairy herds in Europe. Five hundred and twenty-two cows were recruited from 12 farms in 6 European countries. All cows received antibiotic dry cow therapy but teat sealants were not used. All quarters of all cows were sampled for bacteriology at drying off and in the week immediately postcalving. Two ipsilateral quarters were also sampled for bacteriology in each cow 2 and 6wk after drying off. Cows were body condition scored and teats assessed for cleanliness at all sampling time points and for the presence of a keratin plug during the dry period. Other cow-level parameters such as historic somatic cell counts and milk yields before drying off were collated from farm records. Univariable and multivariable analyses were undertaken to investigate the etiology, prevalence, and dynamics of infection during the dry period and associated influential factors. In summary, environmental mastitis pathogens predominated. Although gram-positive major pathogens were typically well controlled and did not increase in prevalence across the dry period, gram negative pathogens generally increased in prevalence. There was an increase in the number of quarters that yielded no growth across the dry period, although this was driven by minor rather than major mastitis pathogen control. Other than the presence of a gram-positive or gram-negative pathogen 6wk after drying off, the measured parameters were not influential when considering their effect on the presence of pathogens postcalving. Analysis also suggested that the early and mid dry period may be more important with respect to the timing of acquisition of infection than previously thought. We observed substantial variation in the etiology and prevalence of different pathogens on different farms with, in all cases, at least one of the 12 herds experiencing the opposite of the others with respect to increases and decreases in pathogen prevalence. Overall, this study confirms the importance of the dry period in mastitis epidemiology but highlights the importance of assessing and understanding infection dynamics on individual units. The lack of influence of the cow and quarter factors measured in this study suggests that herd and management factors may be more influential. PMID- 26117353 TI - Estimation of risk management effects on revenue and purchased feed costs on US dairy farms. AB - Variations in milk and feed prices directly affect dairy farm risk management decisions. This research used data from the 2010 US Department of Agriculture Agricultural Resource Management Surveys phase III dairy survey to examine how risk management tools affected revenues and expenses across US dairy farms. The survey was sent to 26 states and collected information on costs and returns to individual dairy farms. This research used the information from milk sales, crops sales, feed expenses, and farm and operator characteristics, as well as the use of risk management tools. Matching methodology was used to evaluate the effect of 5 independent risk management tools on revenues and expenses: selling milk to a cooperative, using a commodity contract to sell grain, feeding homegrown forage at a basic and intensive level, and use of a nutritionist. Results showed that dairy farms located in the Midwest and East benefit from selling milk to a cooperative and using commodity contracts to sell grain. Across the United States, using a nutritionist increased total feed costs, whereas a feeding program that included more than 65% homegrown forages decreased total feed costs. Results point to benefits from educational programming on risk management tools that are region specific rather than a broad generalization to all US dairy farmers. PMID- 26117354 TI - Ketonemia in dairy goats: effect of dry period length and effect on lying behavior. AB - In dairy animals, a successful transition from one lactation to the next includes minimizing negative energy balance. Cows experiencing excessive negative energy balance typically develop metabolic complications following parturition (e.g., ketosis); does are also susceptible before kidding (e.g., pregnancy toxemia). It is not known to what extent the provision and the length of the dry period affect these conditions in does. Furthermore, whereas clinical symptoms of these conditions include lethargy, behavioral changes resulting from ketosis and pregnancy toxemia have not been quantified in small ruminants. The aims of this study were to (1) describe the relationship between the dry period and negative energy balance, and (2) determine if lying behavior changes are indicative of the metabolic status of dairy goats. A total of 420 does on 10 commercial dairy goat farms in southern Ontario, Canada, were enrolled in the study (mean +/- SD: 42+/ 18 does/farm). Each doe was affixed with a data logger to measure lying behavior from 12 d before to 12 d after kidding. Blood samples were collected at least once before and at least once following kidding to determine blood beta hydroxybutyrate (BHBA) concentration as an indicator of negative energy balance. Does were categorized as healthy (HLTH; both pre- and postkidding samples BHBA <0.9 mmol/L), PREGTOX (prekidding BHBA >=1.7 mmol/L), or KET (postkidding BHBA >=1.7 mmol/L). Behaviors were analyzed according to 5 periods: P-2 (d -12 to d -2 relative to kidding), P-1 (d -1 relative to kidding), P0 (d 0, kidding day), P1 (d 1 relative to kidding), and P2 (d 2 to 12 relative to kidding). Dry period length and milk production after kidding were recorded when available. Farms ranged from 0 to 15% and 0 to 50% in prekidding and postkidding ketonemia, respectively. The HLTH does had shorter dry periods compared with PREGTOX and KET does (43 vs. 55 d, SE of the differences of means=4 d). One farm kept some does milking, while drying off others; on this farm more PREGTOX and KET does (11/28) were found in the dry group versus the continuously milked group (1/16). Overall, does that had ketonemia before kidding (PREGTOX) spent more time lying down compared with healthy does (16.1 vs. 12.7 h/d, SE of the differences of means=0.9). Both PREGTOX and HLTH does had increased lying bouts in P-2 compared with the day before (P-1) kidding [(mean (95% CI): 16.8 (15.8-17.8) vs. 20.5 (19.4-21.8) bout/d]. Compared with HLTH does, animals that were ketonemic following kidding (KET) had higher mean lying times throughout the study (14.5 vs. 13.5 h/d, SE=0.4). Previous work has shown a relationship between shorter and skipped dry periods and improved energy balance in dairy cows; the current study is the first to indicate a similar relationship in dairy goats. Furthermore, goats that developed ketonemia, particularly before kidding, displayed decreased activity, including longer lying times and fewer lying bouts in the days around kidding. PMID- 26117355 TI - Macrophage infiltration in the omental and subcutaneous adipose tissues of dairy cows with displaced abomasum. AB - High concentrations of plasma nonesterified fatty acids (NEFA), a direct measure of lipolysis, are considered a risk factor for displaced abomasum (DA) and other clinical diseases. In nonruminants, uncontrolled lipolysis is commonly associated with adipose tissue macrophage (ATM) infiltration. In dairy cows, recent studies report ATM infiltration in specific adipose depots during the first week of lactation. Depending on their phenotype, ATM can be broadly classified as classically activated (M1) or alternatively activated (M2). The M1 ATM are considered pro-inflammatory, whereas M2 ATM enhance inflammation resolution. Currently, it is not known whether multiparous transition cows with DA have increased ATM infiltration, and the predominant phenotype of these mononuclear cells remains unclear. The objective of this study was to characterize ATM infiltration into different adipose tissue depots in transition cows with DA (days in milk=7.8+/-4.6 d; body condition score=2.95+/-0.10; n=6). Serum samples and biopsies from omental (OM) and subcutaneous (SC) fat depots were obtained during corrective surgery for DA. In an effort to compare ATM infiltration in DA cows with that of healthy cows in anabolic state (AS), adipose biopsies and blood samples were collected from nonlactating, nongestating dairy cows at the time of slaughter (body condition score=3.75+/-0.12; n=6). Adipose tissues were digested and cells from the stromal vascular fraction (SVF) were analyzed using flow cytometry to establish cell surface expression of specific macrophage markers including CD14, CD11c, CD163, and CD172a. Tissue sections were analyzed by immunohistochemistry to assess ATM localization. Cows with DA were ketotic and had plasma NEFA above 1.0 mEq/L. The same group of cows had significant infiltration of ATM in OM characterized by increased numbers of SVF cells expressing CD14 and CD172a. At the same time, expression of CD11c, and CD163 was significantly higher in SVF from OM and SC of DA cows compared with those from AS animals. Expression of M1 macrophage inflammatory phenotype-related genes CCL2, IL6, and TNFalpha in SVF from cows with DA was significantly higher than that in healthy cows (AS). Significant populations of ATM in OM and SC depots of cows with DA were localized in multiple cellular aggregates that included multinucleated cells. In contrast, ATM in AS cows were fewer and randomly localized in both SC and OM. Together, these results indicate that infiltration of classically activated ATM is a concurrent finding in DA cases and may be associated with metabolic stress around parturition contributing to the pro inflammatory status of transition dairy cows. Future studies are needed to establish whether ATM infiltration is more pronounced in cows with DA compared with healthy dairy cows at the same lactation stage and if this increased mononuclear immune cell trafficking has any pathophysiological significance. PMID- 26117356 TI - Cortical Anatomical Variations and Efficacy of rTMS in the Treatment of Auditory Hallucinations. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) shows high inter subject variability in its efficacy for treating resistant auditory verbal hallucinations in schizophrenia. Currently, the response of an individual patient to rTMS treatment cannot be predicted. It is possible that cortical anatomical characteristics could affect the therapeutic response. OBJECTIVE: We hypothesized that rTMS efficacy is related to anatomical variations underlying the stimulation target in the left temporal cortex. We investigated two regions of interest (ROIs) that have been implicated in rTMS: the left temporal cortex, where the stimulation is delivered, and the primary hand motor cortex, where the stimulation strength is determined by the resting motor threshold (rMT). METHODS: Fifteen patients with schizophrenia (DSM IV) underwent rTMS and magnetic resonance imaging. The scalp-to-cortex distance (SCD) and the grey matter density (GMD) were measured in both ROIs. Linear regression models were used to investigate the relationships between these measures and the clinical efficacy of rTMS. RESULTS: Treatment efficacy was highly predicted by the temporal SCD and the GMD in the temporal and primary hand motor cortex regions. In contrast, the rMT was not predicted by the primary hand motor cortex SCD or GMD. CONCLUSION: These results suggest that rTMS treatment efficacy could be related to the depth of the temporal target. The data raise the question of whether rMT is the best measure for assessing the stimulation intensity in treating patients with schizophrenia. PMID- 26117357 TI - Acceptance of and experiences utilising expedited partner therapy among African American juvenile girls. AB - Background The aim of this study was to describe acceptance of and experiences utilising expedited partner therapy (EPT) among African-American girls recruited from short-term juvenile detention centres. METHODS: Ninety-five detained African American girls (aged 13-17 years) completed audio computer-assisted self interviews (ACASI) and self-collected vaginal swab specimens assayed for chlamydia and gonorrhoea. EPT was offered to sexually transmissible infection (STI)-positive participants (n=51); follow-up phone interviews assessed medication delivery to partners. Summary statistics described EPT acceptance frequency. Generalised estimating equations assessed correlates of acceptance. Nine semi-structured interviews elicited EPT experiences. RESULTS: EPT was offered 69 times, accepted by 70% (n=37) girls and provided to 68% (n=36) of girls. Acceptance was significantly associated with sexual risk behaviours such as infrequent partner STI prevention discussion (OR=3.2, 95% CI: 1.0,-10.1, P=0.048) and>=4 lifetime sex partners (OR=3.3, 95% CI: 1.0-11.0, P=0.048). Discontinued relationships were the most common barrier to EPT acceptance. Emergent interview themes included sense of responsibility, which appeared to motivate acceptance and help overcome identified discomfort with partner disclosure conversations. CONCLUSIONS: Future research is needed to determine EPT efficacy among African-American juvenile populations and feasibility of its use outside of research settings. PMID- 26117358 TI - Management of glioblastoma in Victoria, Australia (2006-2008). AB - We describe the management of patients with newly diagnosed glioblastoma multiforme (GBM) in a population-based cohort and compare this to a previously studied cohort. We performed a retrospective cohort study of patients diagnosed with GBM from 2006-2008 in Victoria, Australia. Patients were identified from the population-based Victorian Cancer Registry and their treating doctors surveyed by questionnaire. Outcomes were then compared to a study of GBM patients who were diagnosed between 1998 and 2000 using an identical methodology. We reviewed 351 eligible patients. There were slightly more males (62%) and a minority had multifocal disease (13%). Total macroscopic resection, partial resection or biopsy only was performed in 32%, 37% and 24% of patients, respectively. The majority of patients were referred to a radiation oncologist and medical oncologist postoperatively. A total of 56% of patients were treated with postoperative radiotherapy with concurrent and sequential temozolomide and had a median survival of 14.4 months. This was significantly better than patients treated with postoperative radiotherapy alone in the current or earlier cohorts (2006-2008: median survival 6.2 months, p<0.0001 versus 1998-2000: 8.9 months, p<0.0001). This study demonstrates that postoperative chemoradiation has become the standard of care in this Victorian population with an associated improvement in median survival. PMID- 26117359 TI - Malignant peripheral nerve sheath tumor arising in the setting of cervical nerve root schwannomas. AB - We present a 23-year-old woman who was diagnosed with a malignant peripheral nerve sheath tumor (MPNST), 17 months following the resection of a schwannoma. MPNST is rare and is usually associated with neurofibromatosis. The typical treatment of resection and radiation is difficult to achieve in the spine. PMID- 26117360 TI - Disgust- and anxiety-based emotional reasoning in non-clinical fear of vomiting. AB - BACKGROUND AND OBJECTIVES: Emotional reasoning has been described as a dysfunctional tendency to use subjective responses to make erroneous inferences about threatening outcomes in objectively safe situations (e.g., "If I feel anxious/disgusted, there must be danger/risk of becoming ill"). Prior studies found evidence for anxiety-based emotional reasoning (ER) in several anxiety disorders as well as disgust-based ER in healthy individuals scoring above the clinical cut-off on a measure of contamination fear. The current study tested whether disgust- and anxiety-based ER might be involved in fear of vomiting, a phobic disorder in which both fear/anxiety and disgust are assumed to play an important role. METHODS: Non-clinical participants scoring high (>75%; n = 35) and low (<25%; n = 38) on a measure of fear of vomiting were presented with a series of scripts describing objectively safe everyday situations that systematically varied in the absence/presence of the actor's disgust/anxiety response. Following each script, participants rated their perceived danger and threat of contamination/illness. RESULTS: In line with hypotheses, specifically high vomit-fearful individuals used experienced disgust and anxiety to overestimate risk of becoming ill. Follow up analyses taking into account shared variance between both emotions revealed that more pronounced ER in the high vomit fearful group was mainly driven by the emotion of disgust. LIMITATIONS: Current study asked participants to imagine experienced emotions in scenarios instead of experimentally inducing real-life emotions. CONCLUSIONS: These findings are consistent with the view that disgust-based ER is involved in fear of vomiting. PMID- 26117361 TI - Event related potential and response time give evidence for a physiological reserve in cognitive functioning in relapsing-remitting multiple sclerosis. AB - Cognitive dysfunction is common in multiple sclerosis (MS). Different factors may moderate the degree of cognitive deficit. The aim of the present study was to distinguish different mechanisms for cognitive reserve in relapsing-remitting MS (RRMS). The effects of clinical variables (physical disability, depression), premorbid intelligence (years of education, vocabulary knowledge), visual event related potential measures (P300) and response time (RT) were studied in RRMS patients (n=71) and healthy subjects (n=89). Patients with high P300 amplitude and short RT had better cognitive performance. This effect was significantly weaker in controls. High P300 and short RT may be physiological markers of a cognitive reserve in RRMS. In contrast, the association between cognitive scores and premorbid intelligence was similar in patients and in control subjects. The effects of physiological reserve and clinical variables were studied in a hierarchical linear regression model of cognitive performance in RRMS. P300 amplitude and RT explained a considerable amount of variance in global cognitive performance (34%, p<0.001). The effects of P300 and RT were not moderated by premorbid intelligence. Physical disability and depression added significantly to explained variance, and the final model accounted for 44% (p<0.001) of the variation. We conclude that physiological reserve is the strongest moderator of cognitive impairment in RRMS. PMID- 26117362 TI - Overlap of autism spectrum disorder and glucose transporter 1 deficiency syndrome associated with a heterozygous deletion at the 1p34.2 region. PMID- 26117363 TI - Combined remediation of Cd-phenanthrene co-contaminated soil by Pleurotus cornucopiae and Bacillus thuringiensis FQ1 and the antioxidant responses in Pleurotus cornucopiae. AB - Remediation of soil co-contaminated with heavy metals and PAHs by mushroom and bacteria is a novel technique. In this study, the combined remediation effect of mushroom (Pleurotus cornucopiae) and bacteria (FQ1, Bacillus thuringiensis) on Cd and phenanthrene co-contaminated soil was investigated. The effect of bacteria (B. thuringiensis) on mushroom growth, Cd accumulation, phenanthrene degradation by P. cornucopiae and antioxidative responses of P. cornucopiae were studied. P. cornucopiae could adapt easily and grow well in Cd-phenanthrene co-contaminated soil. It was found that inoculation of FQ1 enhanced mushroom growth (biomass) and Cd accumulation with the increment of 26.68-43.58% and 14.29-97.67% respectively. Up to 100% and 95.07% of phenanthrene were removed in the bacteria-mushroom (B+M) treatment respectively spiked with 200mg/kg and 500mg/kg phenanthrene. In addition, bacterial inoculation alleviated oxidative stress caused by co contamination with relative decreases in lipid peroxidation and enzyme activity, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). This study demonstrated that the integrated remediation strategy of bacteria and mushroom is an effective and promising method for Cd phenanthrene co-contaminated soil bioremediation. PMID- 26117364 TI - Levels of polybrominated diphenyl ethers in indoor dust and human exposure estimates from Makurdi, Nigeria. AB - Information on polybrominated diphenyl ethers (PBDEs) in the indoor environment in developing countries is still relatively scarce. In this study, house (n=10) and office (n=11) dusts samples collected from Makurdi, Benue State Nigeria were extracted and analysed for most abundant PBDEs congeners in the environment. Soxhlet extraction followed by GC-EIMS was employed for the measurement of PBDEs (BDE-47, -100, -99, -154, -153, -183 and -209). The mean concentration of ?7 PBDEs ranged from 57ngg(-1) to 80ngg(-1) and a median value of 45ngg(-1)and 63ngg(-1) were obtained for house and office dust respectively. The daily exposure and ingestion dose estimates were calculated based on the assumption that 30mg and 60mgday(-1) dust represent the ingestion rate. In addition, the corresponding time spent indoors was assumed to be 87.5% (adult) and 69% (children) in homes and 22% in offices and day care. The average value exposure rate of ?7PBDEs for children and adults were 2ngday(-1) and 0.84ngday(-1) respectively. The results in the present study, showed higher exposure estimates for both children and adults' in house dust from Nigeria compared to South Africa. PMID- 26117365 TI - Behavioural impact of a double dopaminergic and serotonergic lesion in the non human primate. AB - Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms. PMID- 26117366 TI - Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. AB - Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 umol/l/h versus 7.88 umol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 umol/l/h versus 11.93 umol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 umol/l/h versus 11.85 umol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 umol/l/h, versus 12.11 umol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 umol/l/h versus 11.93 umol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target. PMID- 26117367 TI - Intrinsic functional connectivity differentiates minimally conscious from unresponsive patients. AB - Despite advances in resting state functional magnetic resonance imaging investigations, clinicians remain with the challenge of how to implement this paradigm on an individualized basis. Here, we assessed the clinical relevance of resting state functional magnetic resonance imaging acquisitions in patients with disorders of consciousness by means of a systems-level approach. Three clinical centres collected data from 73 patients in minimally conscious state, vegetative state/unresponsive wakefulness syndrome and coma. The main analysis was performed on the data set coming from one centre (Liege) including 51 patients (26 minimally conscious state, 19 vegetative state/unresponsive wakefulness syndrome, six coma; 15 females; mean age 49 +/- 18 years, range 11-87; 16 traumatic, 32 non traumatic of which 13 anoxic, three mixed; 35 patients assessed >1 month post insult) for whom the clinical diagnosis with the Coma Recovery Scale-Revised was congruent with positron emission tomography scanning. Group-level functional connectivity was investigated for the default mode, frontoparietal, salience, auditory, sensorimotor and visual networks using a multiple-seed correlation approach. Between-group inferential statistics and machine learning were used to identify each network's capacity to discriminate between patients in minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Data collected from 22 patients scanned in two other centres (Salzburg: 10 minimally conscious state, five vegetative state/unresponsive wakefulness syndrome; New York: five minimally conscious state, one vegetative state/unresponsive wakefulness syndrome, one emerged from minimally conscious state) were used to validate the classification with the selected features. Coma Recovery Scale Revised total scores correlated with key regions of each network reflecting their involvement in consciousness-related processes. All networks had a high discriminative capacity (>80%) for separating patients in a minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Among them, the auditory network was ranked the most highly. The regions of the auditory network which were more functionally connected in patients in minimally conscious state compared to vegetative state/unresponsive wakefulness syndrome encompassed bilateral auditory and visual cortices. Connectivity values in these three regions discriminated congruently 20 of 22 independently assessed patients. Our findings point to the significance of preserved abilities for multisensory integration and top-down processing in minimal consciousness seemingly supported by auditory-visual crossmodal connectivity, and promote the clinical utility of the resting paradigm for single-patient diagnostics. PMID- 26117369 TI - Early non-destructive biofouling detection and spatial distribution: Application of oxygen sensing optodes. AB - Biofouling is a serious problem in reverse osmosis/nanofiltration (RO/NF) applications, reducing membrane performance. Early detection of biofouling plays an essential role in an adequate anti-biofouling strategy. Presently, fouling of membrane filtration systems is mainly determined by measuring changes in pressure drop, which is not exclusively linked to biofouling. Non-destructive imaging of oxygen concentrations (i) is specific for biological activity of biofilms and (ii) may enable earlier detection of biofilm accumulation than pressure drop. The objective of this study was to test whether transparent luminescent planar O2 optodes, in combination with a simple imaging system, can be used for early non destructive biofouling detection. This biofouling detection is done by mapping the two-dimensional distribution of O2 concentrations and O2 decrease rates inside a membrane fouling simulator (MFS). Results show that at an early stage, biofouling development was detected by the oxygen sensing optodes while no significant increase in pressure drop was yet observed. Additionally, optodes could detect spatial heterogeneities in biofouling distribution at a micro scale. Biofilm development started mainly at the feed spacer crossings. The spatial and quantitative information on biological activity will lead to better understanding of the biofouling processes, contributing to the development of more effective biofouling control strategies. PMID- 26117368 TI - DEGRO practical guidelines for radiotherapy of non-malignant disorders: Part I: physical principles, radiobiological mechanisms, and radiogenic risk. AB - PURPOSE: Synopsis of the introductory paragraph of the DEGRO consensus S2e guideline recommendations for the radiotherapy of benign disorders, including physical principles, radiobiological mechanisms, and radiogenic risk. MATERIALS AND METHODS: This work is based on the S2e-guideline recommendations published November 14, 2013. The basic principles of radiation physics and treatment delivery, evaluation of putative underlying radiobiological mechanisms, and the assessment of genetic and cancer risk following low-dose irradiation will be presented. RESULTS: Radiation therapy of benign diseases is performed according to similar physical principles as those governing treatment of malignant diseases in radiation oncology, using the same techniques and workflows. These methods comprise usage of orthovoltage X-ray units, gamma irradiation facilities, linear accelerators (LINACs), and brachytherapy. Experimental in vitro and in vivo models recently confirmed the clinically observed anti-inflammatory effect of low dose X-irradiation, and implicated a multitude of radiobiological mechanisms. These include modulation of different immunological pathways, as well as the activities of endothelial cells, mono- and polymorphonuclear leukocytes, and macrophages. The use of effective dose for radiogenic risk assessment and the corresponding tumor incidence rate of 5.5%/Sv are currently controversially discussed. Some authors argue that the risk of radiation-induced cancers should be estimated on the basis of epidemiological data. However, such data are rarely available at present and associated with high variability. CONCLUSION: Current radiobiological studies clearly demonstrate a therapeutic effectiveness of radiation therapy used to treat benign diseases and implicate various molecular mechanisms. Radiogenic risks should be taken into account when applying radiation treatment for benign diseases. PMID- 26117370 TI - An integrated bioremediation process for petroleum hydrocarbons removal and odor mitigation from contaminated marine sediment. AB - This study developed a novel integrated bioremediation process for the removal of petroleum hydrocarbons and the mitigation of odor induced by reduced sulfur from contaminated marine sediment. The bioremediation process consisted of two phases. In Phase I, acetate was dosed into the sediment as co-substrate to facilitate the sulfate reduction process. Meanwhile, akaganeite (beta-FeOOH) was dosed in the surface layer of the sediment to prevent S(2-) release into the overlying seawater. In Phase II, NO3(-) was injected into the sediment as an electron acceptor to facilitate the denitrification process. After 20 weeks of treatment, the sequential integration of the sulfate reduction and denitrification processes led to effective biodegradation of total petroleum hydrocarbons (TPH), in which about 72% of TPH was removed. In Phase I, the release of S(2-) was effectively controlled by the addition of akaganeite. The oxidation of S(2-) by Fe(3+) and the precipitation of S(2-) by Fe(2+) were the main mechanisms for S(2-) removal. In Phase II, the injection of NO3(-) completely inhibited the sulfate reduction process. Most of residual AVS and S(0) were removed within 4 weeks after NO3(-) injection. The 16S rRNA clone library-based analysis revealed a distinct shift of bacterial community structure in the sediment over different treatment phases. The clones affiliated with Desulfobacterales and Desulfuromonadales were the most abundant in Phase I, while the clones related to Thioalkalivibrio sulfidophilus, Thiohalomonas nitratireducens and Sulfurimonas denitrificans predominated in Phase II. PMID- 26117371 TI - Electrochemical incineration of the antibiotic ciprofloxacin in sulfate medium and synthetic urine matrix. AB - The degradation of 100 mL of 0.245 mM of the antibiotic ciprofloxacin in 0.05 M Na2SO4 at pH 3.0 has been studied by electrochemical oxidation with electrogenerated H2O2 (EO-H2O2), electro-Fenton (EF), UVA photoelectro-Fenton (PEF) and solar PEF (SPEF). Electrolyses were performed with a stirred tank reactor using either a boron-doped diamond (BDD) or Pt anode and an air-diffusion cathode. In EF, PEF and SPEF, ciprofloxacin was rapidly removed due to its oxidation with (*)OH formed from Fenton's reaction between added Fe(2+) and H2O2 generated at the cathode. The larger electrochemical incineration of the antibiotic was achieved by SPEF with BDD with 95% mineralization thanks to the additional attack by hydroxyl radicals formed from water oxidation at the BDD anode surface and the photolysis of final Fe(III)-oxalate and Fe(III)-oxamate species from sunlight. Up to 10 primary intermediates and 11 hydroxylated derivatives were identified by LC-MS, allowing the proposal of a reaction sequence for ciprofloxacin mineralization. A different behavior was found when the same antibiotic concentration was oxidized in a synthetic urine matrix with high urea content and a mixture of PO4(3-), SO4(2-) and Cl(-) ions. Since Fenton's reaction was inhibited in this medium, only EO and EO-H2O2 processes were useful for mineralization, being the organics mainly degraded by HClO formed from Cl(-) oxidation. The EO process with a BDD/stainless steel cell was found to be the most powerful treatment for the urine solution, yielding 96% ciprofloxacin removal and 98% mineralization after 360 min of electrolysis at optimum values of pH 3.0 and current density of 66.6 mA cm(-2). The evolution of released inorganic ions was followed by ion chromatography. PMID- 26117373 TI - Lab-testing, predicting, and modeling multi-stage activated carbon adsorption of organic micro-pollutants from treated wastewater. AB - Multi-stage reuse of powdered activated carbon (PAC) is often applied in practice for a more efficient exploitation of the PAC capacity to remove organic micro pollutants (OMP). However, the adsorption mechanisms in multi-stage PAC reuse are rarely investigated, as large-scale experiments do not allow for systematic tests. In this study, a laboratory method for the separation of PAC/water suspensions and the subsequent reuse of the PAC and the water was developed. The method was tested on wastewater treatment plant (WWTP) effluent in a setup with up to 7 PAC reuse stages. The tests show that the overall OMP removal from WWTP effluent can be increased when reusing PAC. The reason is that a repeated adsorption in multi-stage PAC reuse results in similar equilibrium concentrations as a single-stage adsorption. Thus, a single relationship between solid and liquid phase OMP concentrations appears valid throughout all stages. This also means that the adsorption efficiency of multi-stage PAC reuse setups can be estimated from the data of a single-stage setup. Furthermore, the overall OMP removals in multi-stage setups coincide with the overall UV254 removals, and for each respective OMP one relationship to UV254 removal is valid throughout all stages. The results were modeled by a simple modification of the equivalent background compound model (EBCM) which was also used to simulate the additional OMP removals in multi-stage setups with up to 50 reuse stages. PMID- 26117372 TI - Urban wastewater treatment by seven species of microalgae and an algal bloom: Biomass production, N and P removal kinetics and harvestability. AB - This study evaluates the capacity of seven species and a Bloom of microalgae to grow in urban wastewater. Nutrient removal kinetics and biomass harvesting by means of centrifugation and coagulation-flocculation-sedimentation have been also tested. Results show that the best biomass productivities ranged from between 118 and 108 mgSS L(-1) d(-1) for the Bloom (Bl) and Scenedesmus obliquus (Sco). Regarding nutrient removal, microalgae were able to remove the total dissolved phosphorus and nitrogen concentrations by more than 80% and 87% respectively, depending on the species tested. The final total dissolved concentration of nitrogen and phosphorus in the culture media complies with the European Commission Directive 98/15/CE on urban wastewater treatment. Regarding harvesting, the results of coagulation-flocculation sedimentation using a 60 mg L(-1) dose of Ferric chloride were similar between species, exceeding the biomass removal efficiency by more than 90%. The results of centrifugation (time required to remove 90% of solids at 1000 rpm) were not similar between species, with the shortest time being 2.9 min for Sco, followed by the bloom (7.25 min). An overall analysis suggested that the natural bloom and Scenedesmus obliquus seem to be the best candidates to grow in pre-treated wastewater, according to their biomass production, nutrient removal capability and harvestability. PMID- 26117374 TI - The relative correspondence of cranial and genetic distances in papionin taxa and the impact of allometric adjustments. AB - The reconstruction of phylogenetic relationships in the primate fossil record is dependent upon a thorough understanding of the phylogenetic utility of craniodental characters. Here, we test three previously proposed hypotheses for the propensity of primate craniomandibular data to exhibit homoplasy, using a study design based on the relative congruence between cranial distance matrices and a consensus genetic distance matrix ("genetic congruence") for papionin taxa: 1) matrices based on cranial regions subjected to less masticatory strain are more genetically congruent than high-strain cranial matrices; 2) matrices based on cranial regions developing earlier in ontogeny are more genetically congruent than matrices based on regions that develop later; and 3) matrices based on cranial regions with greater anatomical/functional complexity are more genetically congruent than matrices based on anatomically simpler regions. Morphological distance matrices based on the shape of 15 different cranial regions, delineated on the basis of previous catarrhine studies, were statistically compared to a matrix of known genetic distances in papionins. Since sexual dimorphism and allometry are known to characterize this clade, several analytical iterations were conducted: 1) mixed-sex, male-only, and female-only analyses and 2) with and without an allometric scaling adjustment. Across all datasets, the chondrocranium matrix was the most consistently correlated with genetic distances, which is also consistent with previous studies of cercopithecoid taxa; however, there was no support for the internal predictions of the three hypotheses tested. Allometric scaling corrections had the largest impact on the genetic congruence of facial shape matrices, a result consistent with previous studies that have described facial homoplasy in papionin taxa. These findings differ from patterns described for hominoid taxa, suggesting that no single predictive criterion can explain phylogenetic utility of cranial datasets across catarrhine primate taxa. Many of the differences in morphological genetic matrix correlations could result from different levels of phenotypic integration and evolvability in cercopithecoids and hominoids, suggesting that further study of these phenomena in extant primates is warranted. PMID- 26117375 TI - Regulation of chicken immunity-related genes and host response profiles against Avibacterium paragallinarum pathogen challenge. AB - Infectious coryza (IC) is a well-recognised and commonly encountered upper respiratory tract disease in chickens. The aim of this study was to monitor aspects of the immune response of chickens infected with Avibacterium paragallinarum. Gene expression profiling of 30 genes was carried out for 11 chicken nasal area samples belonging to four groups, including one non-infected control group. For this purpose, 30 biomarker transcripts were selected for comparative gene expression analysis and were analysed by real-time PCR using TaqMan((r)) assays. The biomarkers included three reference genes. The reference genes were used to normalise the results in a relative quantification approach. The gene expression changes of the 27 biomarker transcripts (genes of interest) were quantified between all treated groups in six pair-wise comparisons. It was concluded from the data that immune response initiation is via TLR4, which leads to a Th2 dominant type response. Furthermore, TLR4 results in signalling via the MyD88-dependent pathway, resulting in early onset of NF-kbeta leading to the production of inflammatory cytokines. This work provides an informative outlay of immune response initiation upon infection with this pathogen. PMID- 26117376 TI - Functional analysis of 3'UTR polymorphisms in the caprine SLC11A1 gene and its association with the Mycobacterium avium subsp. paratuberculosis infection. AB - The study aimed to investigate whether the genetic polymorphisms in the 3'UTR of the caprine SLC11A1 gene are functional, and to assess the role of MAP as a regulatory parameter in gene expression. To this goal we constructed plasmids expressing the Luciferase reporter gene in transient transfections of a mouse (Balb/c) macrophage cell line (RAW264.7), incorporating those polymorphisms that our previous work indicated as more prominent in terms of SLC11A1 expression and responsiveness to MAP infection. Gene expression variation was recorded on the average of the respective measurements after exposure to Mycobacterium avium subsp. paratuberculosis (MAP) combined with microbial antigens and cytokines. In silico analysis of the region under study allowed identification of one cis acting RNA element, five putative transcriptional regulatory elements and 85 3'end microRNA binding sites. The two polymorphic regions (regions A and B) of the 3'UTR of the caprine SLC11A1 gene were recognized as regulators of its activity, at transcriptional and post-transcriptional level. The GT16 polymorphism at region A, combined with the GT8 polymorphism at region B, results in up-regulation of the SLC11A1 gene. The specific genotype was also found to be more responsive to MAP exposure at a statistically significant level. PMID- 26117377 TI - Does Intraoral Miniplate Fixation Have Good Postoperative Stability After Sagittal Splitting Ramus Osteotomy? Comparison With Intraoral Bicortical Screw Fixation. AB - PURPOSE: Bicortical screw fixation systems and miniplate with monocortical screw fixation systems have been reported mainly in bilateral sagittal split ramus osteotomy (BSSO). This study compared postoperative stability between these 2 fixation systems by an intraoral approach. MATERIALS AND METHODS: This was a retrospective cohort study. The study sample was composed of patients treated by BSSO at the authors' institute from January 2006 through December 2012. All cases had facial symmetry and were performed by setback surgery. The predictor variable was treatment group (intraoral screw fixation [SG] vs intraoral miniplate fixation [MG]), and the primary outcome variable was stability defined as the change in the position of point B. Other outcome variables were stability defined as the change in the position of the menton, blood loss, incidence of postoperative temporomandibular joint disorder, and nerve injury. Descriptive and bivariate statistics were computed and the P value was set at .05. RESULTS: Seventy-five patients (35 men and 40 women; mean age, 25.8 yr) were divided into 2 groups (39 SG cases and 36 MG cases). Postoperative changes at point B and the menton in the 2 fixation groups were not statistically different. Lingual nerve injury occurred only in SG cases. Moreover, total blood loss was greater in SG cases. CONCLUSION: An intraoral miniplate with monocortical screw fixation system is recommended over intraoral bicortical screw fixation for bone segments in setback BSSO in patients without facial asymmetry. PMID- 26117378 TI - Elevated Matrix Metalloproteinase-9 Expression Correlates With Advanced Stages of Oral Cancer and Is Linked to Poor Clinical Outcomes. AB - PURPOSE: Using a meta-analytic approach, the relation between increased matrix metalloproteinase-9 (MMP-9) expression, tumor stage, and clinical outcomes in oral cancers was investigated. MATERIALS AND METHODS: Multiple English- and Chinese-language electronic databases were searched to identify high-quality case and-control studies relevant to this meta-analysis. Methodologic quality of the included trials was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology statement to ensure consistency in reviewing and reporting the results. Statistical analyses were carried out with STATA 12.0 statistical software. RESULTS: Nine case-and-control studies containing a combined total of 419 patients with oral cancer were included in the present meta-analysis. Results showed that patients who were positive for MMP-9 expression had a significantly poorer overall survival compared with those negative for MMP-9 (effect size = 2.10; 95% confidence interval, 0.98 to 3.22; P < .001). MMP-9 expression also positively correlated with lymph node metastasis and advanced T-stage groups (P < .05 for all comparisons). Further, high MMP-9 expression level correlated with increased oral cancer risk in Asians (P < .05 for all comparisons) as shown by method-stratified subgroup analysis. CONCLUSION: The present results strongly suggest that MMP-9 expression level influences tumor invasion and metastasis in oral cancers. Based on these results, MMP-9 can be an excellent therapeutic target in patients with oral cancer. PMID- 26117379 TI - A Novel Surgical Technique for Augmented Corticotomy-Assisted Orthodontics: Bone Grafting With Periosteum. AB - PURPOSE: To introduce grafting fixed with the periosteum (dumpling technique) as an alternative surgical technique for augmented corticotomy-assisted orthodontics in the lower anterior region and evaluate the preliminary outcomes. MATERIALS AND METHODS: Eleven patients (9 women, 2 men; mean age, 21.4 yr) with a thin alveolus or alveolar defect in the lower anterior region by clinical and radiographic examination underwent an augmented corticotomy using the new dumpling technique. Cone-beam computerized tomography was used to evaluate morphologic changes of the lower anterior ridge before treatment (T0) and 1 week (T1) and 6 months (T2) after the bone-augmentation procedure. Repeated-measures analysis of variance with Bonferroni multiple-comparison test was used to compare variables at each time point. RESULTS: No severe postsurgical complications occurred in any patient. The mean alveolar bone thickness of the labial plate increased from T0 to T1 (P < .001) and decreased from T1 to T2 (P < .001). However, compared with T0, there was still a significant increase in horizontal bone thickness at T2 (P < .05). The vertical alveolar bone level increased from T0 to T1 (P < .001) and was maintained from T1 to T2 (P > .05). No significant differences were found in root length of the lower anterior teeth at these 3 time points (P > .05). CONCLUSIONS: In this preliminary study, the dumpling technique for augmented corticotomy-assisted surgical orthodontics showed alveolar bone augmentation by increasing the vertical alveolar height and the horizontal bone thickness in the labial aspect of the anterior mandibular area. However, long-term follow-up is necessary. PMID- 26117380 TI - Understanding healthcare practices in superdiverse neighbourhoods and developing the concept of welfare bricolage: Protocol of a cross-national mixed-methods study. AB - BACKGROUND: Diversity in Europe has both increased and become more complex posing challenges to both national and local welfare state regimes. Evidence indicates specific barriers for migrant, faith and minority ethnic groups when accessing healthcare. However, previous studies of health in diverse cities in European countries have mainly adopted an ethno-national focus. Taking into account the new complexity of diversity within cities, a deeper and multi-faceted understanding of everyday health practices in superdiverse contexts is needed to support appropriate healthcare provision. METHODS/DESIGN: This protocol describes a mixed method study investigating how residents in superdiverse neighbourhoods access healthcare. The study will include participant observation and qualitative interviewing as well as a standardised health survey and will be carried out in eight superdiverse neighbourhoods - with varying deprivations levels and trajectories of change - in four European countries (Germany, Portugal, Sweden and UK). In each neighbourhood, trained polylingual community researchers together with university researchers will map formal and informal provision and infrastructures supportive to health and healthcare. In-depth interviews with residents and healthcare providers in each country will investigate local health supportive practices. Thematic analysis will be used to identify different types of help-seeking behaviours and support structures across neighbourhoods and countries. Using categories identified from analyses of interview material, a health survey will be set up investigating determinants of access to healthcare. Complex models, such as structural equation modelling, will be applied to analyse commonalities and differences between population groups, neighbourhoods and countries. DISCUSSION: This study offers the potential to contribute to a deeper understanding of how residents in superdiverse neighbourhoods deal with health and healthcare in everyday practices. The findings will inform governmental authorities, formal and informal healthcare providers how to further refine health services and how to achieve equitable access in diverse population groups. PMID- 26117381 TI - Induced abortions and birth outcomes of women with a history of severe psychosocial problems in adolescence. AB - OBJECTIVE: To increase knowledge on the reproductive health of women who have been placed in a residential school, a child welfare facility for adolescents with severe psychosocial problems. METHODS: All women (n=291) who lived in the Finnish residential schools on the last day of the years 1991, 1996, 2001 and 2006 were included in this study and compared with matched general population controls. Register-based information on induced abortions and births was collected until the end of the year 2011. RESULTS: Compared to controls, women with a residential school history had more induced abortions. A higher proportion of their births took place when they were teenagers or even minors. They were more often single, smoked significantly more during pregnancy and had a higher risk of having a preterm birth or a baby with a low birth weight. CONCLUSIONS: The findings have implications for the planning of preventive and supportive interventions that aim to increase the well-being of women with a residential school history and their offspring. PMID- 26117382 TI - Construct development, description and initial validation of the Knowledge about Older Patients Quiz (KOP-Q) for nurses. AB - BACKGROUND: Literature shows that nurses have a negative attitude toward older patients. Increasing nurses' knowledge (part of attitudes) may affect hospital nurses' attitudes and improve the quality of care for older patients. A first step is understanding nurses' current knowledge. This can be achieved by using a measurement instrument with good validity and reliability. OBJECTIVES: This study explains the content development and initial validation of the 'Knowledge about Older Patients Quiz' (KOP-Q) for nurses, describing the first step in developing a valid and reliable instrument. DESIGN: Qualitative method followed by 2 pilot studies. METHODS: Open interviews were conducted with 7 scientific experts and 10 nurse specialists in gerontology, geriatrics, and/or nursing and 5 older patients, 70+ with hospital experience in the last two years. The data were analyzed using thematic analysis. Items were generated from literature on themes derived from interviews. A Delphi round with three nurse specialists and two researchers was organized for item reduction. Two pilot survey studies were conducted for measuring readability and face validity of the KOP-Q. Readability was examined by a Dutch language specialist and 7 nurses working on a cardiovascular ward. Face validity was tested in two hospitals with 22 nurses working on geriatric wards. RESULTS: Identified themes were: normal aging, geriatric conditions, signaling problems in old age, interventions, family interventions, vulnerable patients versus older patients and internal motivation for learning and reflection. 185 questions on these themes were developed. After conceptualization, generation and reduction of questions in the Delphi round 52 questions remained eligible for use. Readability and face validity of this initial version of the KOP-Q proved good. CONCLUSIONS: Content development of the KOP-Q is of good methodological rigor and each step is carefully described, therefore it can be of use for future diagnostic instrument developers, curriculum developers and educators. PMID- 26117383 TI - Liver pathology in severe multidrug resistant 3 protein deficiency: a series of 10 pediatric cases. AB - Multidrug resistance protein 3 (MDR3) is a hepatocyte canalicular membrane protein encoded by the ABCB4/MDR3 gene located on chromosome 7. Several liver diseases are known to be associated with MDR3 deficiency. The basic defect is reduced secretion of biliary phospholipid causing disturbance in the primary bile composition, leading to injury to biliary epithelium inducing cell death and inflammation. Severe MDR3 deficiency typically presents during the first year of life or early childhood, often progressing to chronic liver disease with cirrhosis and portal hypertension, requiring liver transplantation. Negative MDR3 immunostaining is suggestive of MDR3 deficiency. Herein, we report the clinical and histopathologic features of 10 cases (6 male/4 female) in infants and children with severe MDR3 deficiency (age range of 8 months to 7 years) diagnosed with negative MDR3 immunostaining in hepatic canaliculi. Three cases underwent liver transplantation. The cases showed periportal bridging fibrosis to micronodular cirrhosis, ductular proliferation with bile plugs, and lobular canalicular bile stasis with rosetting. All 3 explant livers demonstrated cystically dilated large ducts with crystallization of cholesterol. One case showed well-differentiated hepatocellular carcinoma. We conclude that MDR3 immunostaining on formalin-fixed and paraffin-embedded sections is a useful tool to diagnose severe MDR3 deficiency in pediatric liver cholestatic disease cases where genetic testing is not available. PMID- 26117384 TI - Leprosy in New Zealand. PMID- 26117385 TI - Leprosy in New Zealand: an epidemiological update. AB - AIM: To examine the current epidemiological trends of leprosy in New Zealand and raise awareness of this disease in the health professional community. METHOD: Epidemiological data of leprosy, a notifiable disease in New Zealand, was accessed for the 10 year time period 2004 to 2013. Using an illustrative case as an introduction, all 38 case reports from the study period are summarised. RESULTS: Most cases of leprosy in New Zealand notified during the study period are immigrants from countries with endemic leprosy, reflecting the origin of disease. Delay to diagnosis is common. CONCLUSION: Leprosy remains a clinical problem in New Zealand. Cases are more likely to arise in geographical areas with higher numbers of immigrants from endemic countries. PMID- 26117386 TI - Implementation of the 2013 Psychoactive Substances Act and mental health harms from synthetic cannabinoids. AB - AIMS: Use of synthetic cannabinoids is associated with a range of mental health harms. The 2013 Psychoactive Substances Act (PSA) was intended to limit retail availability of synthetic cannabinoids which had acceptable safety profiles. We evaluated numbers and clinical characteristics of patients presenting with mental health harms associated with use of synthetic cannabinoids for three months before and after implementation of the PSA on 18July 2013. METHODS: Retrospective audit of case notes of patients presenting to an emergency psychiatric service (EPS) in Dunedin. RESULTS: In the three months post-PSA, there was a 42% reduction in EPS contacts and 52% reduction in patient presentations, compared with the three months pre-PSA. Patient demographics (predominantly young males with prior contact with mental health services), presenting symptoms (mood and psychotic symptoms and suicidality), and management and disposition were identical in both periods. CONCLUSIONS: The decrease in mental health harms, as measured by frequency of EPS contacts, appeared to be due to reduced retail availability of synthetic cannabinoids rather that reduced toxicity of available products. PMID- 26117387 TI - GPs, community pharmacists and shifting professional boundaries. AB - AIMS: In the context of expectations regarding role evolution, including increased interprofessional working, this study aimed to gain insight into how GPs and pharmacists understood the professional role of the pharmacist and its expansion, extension and calls for increased collaboration. METHODS: Qualitative interviews with 16 GPs and 17 pharmacists were conducted in the Canterbury region. Data were analysed using descriptive thematic analysis. RESULTS: Both groups were generally supportive in principle of more collaborative forms of working. GPs seemed more comfortable with collaboration that involved pharmacists being under the umbrella of the general practice. Pharmacists welcomed greater meaningful collaboration with general practice. Pharmacists did not express any particular view about what types of collaboration they preferred. They did discus tensions resulting from the need to contact doctors over minor prescribing errors. Extension and/or expansion of pharmacist roles were met with caution by GPs, although there was greater acceptance of medicines management. Pharmacists had mixed views about role expansion. Most were keen on role extension, particularly in relation to medicines management. CONCLUSIONS: Attempts to encourage one professional group to expand or extend their practice may be perceived as a threat by those adjacent. Mitigation strategies involve clear communication and acknowledgment that interprofessional trust takes time to establish. PMID- 26117388 TI - Medical Students and informed consent: A consensus statement prepared by the Faculties of Medical and Health Science of the Universities of Auckland and Otago, Chief Medical Officers of District Health Boards, New Zealand Medical Students' Association and the Medical Council of New Zealand. AB - To develop a national consensus statement to promote a pragmatic, appropriate and unified approach to seeking consent for medical student involvement in patient care. A modified Delphi technique was used to develop the consensus statement involving stakeholders. Feedback from consultation and each stakeholder helped to shape the final consensus statement. The consensus statement is a nationally agreed statement concerning medical student involvement in patient care, which will be useful for medical students, health care professionals and patients. PMID- 26117389 TI - An ageing trauma population: The Auckland experience. AB - AIM: As the population ages, the number of elderly patients suffering injuries is increasing. Reports from North America have shown an increasing proportion of elderly admissions with a disproportionate number of deaths. However, this trend has not yet been examined in New Zealand. The aim of this study was to determine unique characteristics of geriatric patients as compared to the general trauma population. METHOD: The trauma database at Auckland City Hospital (ACH) was queried for patients age 65 years and above admitted between 2005-2012. Demographics, mechanism of injury, length of stay, and disposition were recorded. RESULTS: 1644 patients were included. The proportion of elderly patient admissions increased from 15% to 20% over the study period (p=<0.001). There were 93 deaths (6%); mortality increased with age-9% for patients 85+ compared to 5% for age 65-84 (p=0.004). Elderly trauma patients accounted for 38% of all trauma deaths. Average length of stay for survivors was 9 +/- 10 days, with 63% discharged home (n=1042), 19% to rehabilitation (n=316) and 7% to rest home (n=111). Falls were the most common mechanism (n=1261, 76%), however these patients had lower mortality compared to road traffic collision (4% vs. 12%, p<0.001) and pedestrians struck (4% vs. 11%, p<0.001). CONCLUSION: ACH has seen a significant increase in elderly trauma admissions without a change in catchment or referral pattern. These patients have a higher mortality than those under 65, longer length of stay, and are less likely to return home. Specific education on fall prevention should be increased to lessen the burden on the health system as a whole. Given the linear increase in mortality, specialised geriatric care should be considered starting at age 75. PMID- 26117390 TI - 7-year retrospective review of quad bike injuries admitted to Starship Children's Hospital. AB - AIMS: To ascertain morbidity and mortality of children who presented to Starship Children's Hospital with injuries from a quad bike incident from 2007 to 2014, and to review whether current guidelines are sufficient to prevent injury. METHODS: A retrospective case note review of all children under the age of 16 years who presented to Starship Hospital with an injury sustained whilst riding a quad bike between January 2007 and July 2014. RESULTS: Twenty-seven patients were identified through both the Starship Children's Hospital Trauma and Paediatric Intensive Care databases with injuries resulting from a quad bike incident. Fifteen patients (56%) had multisystem injuries. The average injury severity score (ISS) was 14 (range 1-75). ISS was higher in those of younger age (<5 years), lower body weight (<20kg), requiring PICU admission and those sustaining head injuries with no helmet. Seven (25.9%) patients required PICU admission, two patients died (7.4%) and three patients (12%) survived to discharge with disability. CONCLUSIONS: This study supports current published guidelines which recommend limiting the use of quad bikes by children. Current guidelines do not, however, prevent injury in the paediatric population. PMID- 26117391 TI - A new surgical site infection improvement programme for New Zealand: early progress. AB - Two to five percent of those who have an inpatient surgical procedure will experience a surgical site infection (SSI). The Health Quality & Safety Commission has instituted New Zealand's first national Surgical Site Infection Improvement Programme (the SSII Programme), delivered jointly by Auckland and Canterbury District Health Boards. Through a combined package of surveillance and improvement interventions the SSII Programme aims to reduce the incidence of SSIs in New Zealand hospitals, beginning initially with hip and knee arthroplasties. Within one year of the programme starting there has been a significant nationwide improvement in the timing of surgical antimicrobial prophylaxis (p<0.0001), and the administration of the correct dose (p<0.0001). National compliance with an alcohol-based skin preparation remains high at > 95 %. In this paper we describe the purpose, background, structure and rationale of the programme and provide results to date. PMID- 26117392 TI - An unusual cause of persistent dysphagia. PMID- 26117393 TI - Importance of blood cultures to aid the diagnosis of Lemierre's syndrome. AB - This is a case report of Lemierre's syndrome, a septic thrombophlebitis of the internal jugular vein (IJV) usually preceded by pharyngitis and bacteraemia with an anaerobic organism. Fusobacterium necrophorum is ananaerobic Gram-negative bacillus and is the most common organism reported to cause Lemierre's syndrome which usually occurs one to three weeks post pharyngitis or oropharyngeal surgery. A 21-year-old patient presented with signs of sepsis and a history of sore throat, fever, and tender cervical lymph nodes. Blood cultures grew F. necrophorum and Computed Tomography (CT) showed a filling defect in the left retromandibular vein and thrombosis in the left internal jugular vein (IJV) consistent with Lemierre's syndrome. This is an uncommon condition which normally occurs in young individuals and diagnosis is often delayed. PMID- 26117394 TI - Request from Cook Islands Secretary of Health. PMID- 26117395 TI - Time for the New Zealand health sector to divest all investment funds out of fossil fuels. PMID- 26117396 TI - World meat consumption patterns: An overview of the last fifty years (1961-2011). AB - Driven by economic development and urbanisation, protein consumption has surged worldwide over the last 50years, rising from 61g per person per day in 1961 to 80g per person per day in 2011 [Corrected]. This contribution analyses the apparent convergence of dietary models worldwide with respect to the proportion of ABP and especially meat in intake. By using FAO data for 183 countries over the period 1961-2011, the authors show the connection between annual per capita GDP and the level of ABP (R2=0.62) and meat consumption (R2=0.62). They emphasise the surge in ABP intake in emerging countries (China, Brazil) which has partly replaced plant protein. However, for similar degrees of economic development, the composition of ABPs and the position of meat within this category vary significantly among countries, suggesting that historical, geographical, cultural and religious factors may be involved. PMID- 26117397 TI - Environmental impacts of beef production: Review of challenges and perspectives for durability. AB - Beef makes a substantial contribution to food security, providing protein, energy and also essential micro-nutrients to human populations. Rumination allows cattle - and other ruminant species - to digest fibrous feeds that cannot be directly consumed by humans and thus to make a net positive contribution to food balances. This contribution is of particular importance in marginal areas, where agro ecological conditions and weak infrastructures do not offer much alternative. It is also valuable where cattle convert crop residues and by-products into edible products and where they contribute to soil fertility through their impact on nutrients and organic matter cycles. At the same time, environmental sustainability issues are acute. They chiefly relate to the low efficiency of beef cattle in converting natural resources into edible products. Water use, land use, biomass appropriation and greenhouse gas emissions are for example typically higher per unit of edible product in beef systems than in any other livestock systems, even when corrected for nutritional quality. This particularly causes environmental pressure when production systems are specialized towards the delivery of edible products, in large volumes. The paper discusses environmental challenges at global level, recognizing the large diversity of systems. Beef production is faced with a range of additional sustainability challenges, such as changing consumer perceptions, resilience to climate change, animal health and inequities in access to land and water resources. Entry-points for environmental sustainability improvement are discussed within this broader development context. PMID- 26117399 TI - The role of microRNAs in coronary artery disease: From pathophysiology to diagnosis and treatment. AB - MicroRNAs (miRNAs) are tiny non-coding RNA molecules that regulate gene expression predominantly at the post-transcriptional level. Far from being simple intracellular regulators, miRNAs have recently been involved in intercellular communication and have been shown to circulate in the bloodstream in stable forms. In the past years specific miRNA expression patterns have been linked to the development of atherosclerosis and coronary artery disease, two closely related conditions. The study of miRNAs has promoted our understanding of the processes involved in the pathogenesis of atherosclerosis and innovative diagnostic and therapeutic approaches have emerged. In this review, we present the role of miRNAs in the development of atherosclerosis, on coronary artery disease progression and we assess their role as diagnostic biomarkers. Finally we evaluate the therapeutic and preventive opportunities that arise from the study of miRNAs in coronary artery disease and especially in myocardial infarction. PMID- 26117398 TI - The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society. AB - While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required. PMID- 26117400 TI - Low cardiorespiratory fitness and coronary artery calcification: Complementary cardiovascular risk predictors in asymptomatic type 2 diabetics. AB - BACKGROUND: Despite its well-established prognostic value, cardiorespiratory fitness (CRF) is not incorporated routinely in risk assessment tools. Whether low CRF provides additional predictive information in asymptomatic type 2 diabetics beyond conventional risk scores and coronary artery calcification (CAC) is unclear. METHODS: We studied 600 type 2 diabetics aged 55-74 years without known coronary heart disease. CRF was quantified in metabolic equivalents (METs) by maximal treadmill testing and categorized as tertiles of percent predicted METs (ppMETs) achieved. CAC was calculated by non-enhanced computed tomography scans. The individual and joint association of both measures with an outcome event of all-cause mortality, myocardial infarction or stroke, was determined over a mean follow-up period of 80 +/- 16 months. RESULTS: There were 72 (12%) events during follow-up. Low CRF was independently associated with event risk after adjustment for traditional risk factors and CAC (HR 2.25, 95% CI 1.41-3.57, p = 0.001). CRF (unfit/fit) allowed further outcome discrimination both amongst diabetics with low CAC scores (9.5% versus 2.0% event rate), and amongst diabetics with high CAC scores (23.5% versus 12.4% event rate), p < 0.001. The addition of CRF to a model comprising UKPDS and CAC scores improved the area under the curve for event prediction from 0.66 to 0.71, p = 0.03, with a positive continuous net reclassification improvement (NRI) of 0.451, p = 0.002. CONCLUSIONS: CRF, quantified by ppMETs, provided independent prognostic information which was additive to CAC. Low CRF may identify asymptomatic diabetic subjects at higher risk for all-cause mortality, myocardial infarction or stroke, despite low CAC. PMID- 26117402 TI - Supplementation with two probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, reduces fasting triglycerides and enhances apolipoprotein A-V levels in non-diabetic subjects with hypertriglyceridemia. AB - OBJECTIVE: Previous studies have indicated that supplementation with probiotics might improve lipid metabolism. The objective of the study was to evaluate the effect of supplementation with probiotic strains Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on triglyceride (TG) and apolipoprotein A-V (apo A-V) levels. METHODS: A randomized, double-blinded, placebo-controlled study was conducted with 128 non-diabetic subjects with hypertriglyceridemia. Over a 12-week test period, the probiotic group consumed 2 g/day of a powdered supplement containing L. curvatus HY7601 and L. plantarum KY1032, whereas the placebo group consumed a powder lacking probiotics. RESULTS: After the treatment, the probiotic group showed an 18.3% (P < 0.001) reduction in TGs and increases of 21.1% (P = 0.001) and 15.6% (P < 0.001) in the apo A-V and LDL particle size, respectively. The probiotic group had a significant reduction in TGs (P = 0.040) and increases in the plasma apo A V (P = 0.003) and LDL particle size (P < 0.001) compared with the placebo group. In the probiotic group, the reduction in the TG levels was negatively correlated with changes in the apo A-V and baseline TGs, regardless of the APOA5 -1131T > C genotype. CONCLUSION: The consumption of two probiotic strains for 12 weeks reduced TGs and increased the apo A-V and LDL particle size in hypertriglyceridemic subjects. This effect was more pronounced in subjects with higher levels of fasting TGs regardless of their APOA5 -1131T > C genotype. PMID- 26117401 TI - Lipoprotein associated phospholipase A2 activity, apolipoprotein C3 loss-of function variants and cardiovascular disease: The Atherosclerosis Risk In Communities Study. AB - OBJECTIVE: Lipoprotein-associated phospholipase A2 (LpPLA2) activity was associated with higher CHD risk in a meta-analysis, which was partly dependent on circulating lipid levels. Apolipoprotein C3 loss-of-function (ApoC3 LOF) mutations were related with reduced postprandial lipemia and CHD risk. However, the association of LpPLA2 activity with ApoC3 LOF is not known. METHODS: We examined the association of LpPLA2 activity and ApoC3 LOF mutations and incident cardiovascular disease (CVD) (defined as coronary heart disease [CHD] plus ischemic stroke) and all-cause mortality in the biracial longitudinal Atherosclerosis Risk In Communities (ARIC) study. RESULTS: The mean LpPLA2 activity was 229.3 nmol/min/mL and was higher in men and whites. LpPLA2 activity correlated positively with atherogenic dyslipidemia. ApoC3 LOF carriers had lower LpPLA2 activity levels compared to non-carriers, and there was inverse association between LpPLA2 activity and ApoC3 LOF mutations in whites. In a fully adjusted model, greater LpPLA2 activity was independently associated with incident CVD (HR 1.35, 1.09-1.68 for highest vs. lowest quintile), which was mainly explained by its association with CHD, and was also associated with all cause mortality (HR 1.65, 1.38-1.98). CONCLUSIONS: Greater LpPLA2 activity was associated with increased CHD and all-cause mortality in both whites and African Americans in the ARIC study. The inverse relation between LpPLA2 activity and ApoC3 LOF mutations suggests that delayed lipoprotein clearance may at least in part explain the observed association of LpPLA2 activity with increased CVD risk. PMID- 26117403 TI - Association between levels of serum bisphenol A, a potentially harmful chemical in plastic containers, and carotid artery intima-media thickness in adolescents and young adults. AB - OBJECTIVE: Bisphenol A (BPA) is a chemical produced at high volumes and used widely in food and drink packaging. In adults, elevated BPA concentrations are associated with cardiovascular disease. BPA exposure is plausibly linked to atherosclerosis in adolescents and young adults, but evidence is lacking to date. METHODS: We recruited 886 subjects (12-30 years of age) from a population-based sample of adolescents and young adults based on a mass urine screening to determine the relationship between serum levels of BPA and carotid intima-media thickness (CIMT). RESULTS: The geometric mean (standard deviation) of concentrations of BPA were 1.72 (5.5) ng/mL After controlling for confounding factors, linear regression analyzes showed a 1-unit increase in natural log BPA was significantly associated with an increase in mean CIMT (mm) (beta = 0.005, 95% C.I. = 0.003-0.007, p < 0.001) and other measurement of CIMT (including right and left side of common carotid artery, carotid bulb and internal carotid artery). CONCLUSION: Higher serum concentrations of BPA were associated with increased CIMT in this cross-sectional study of adolescents and young adults. Studies to clarify the mechanisms of these associations are needed. PMID- 26117404 TI - Relationship of pericardial fat with lipoprotein distribution: The Multi-Ethnic study of atherosclerosis. AB - OBJECTIVE: Pericardial fat and lipoprotein abnormalities contribute to increased risk of cardiovascular disease (CVD). We investigated the relationship between pericardial fat volume and lipoprotein distribution, and whether the association of pericardial fat volume with subclinical atherosclerosis and incident CVD events differs according to lipoprotein distribution. METHODS: We analyzed data from 5407 participants from the Multi-Ethnic Study of Atherosclerosis who had measurements of pericardial fat volume, lipoprotein distribution, carotid intima media thickness (IMT), and coronary artery calcium (CAC). All participants were free of clinically apparent CVD at baseline. Incident CVD was defined as any adjudicated CVD event. RESULTS: After adjusting for demographic factors, traditional risk factors, and biomarkers of inflammation and hemostasis, a larger pericardial fat volume was associated with higher large VLDL particle (VLDL-P) concentration and small HDL particle (HDL-P) concentration, and smaller HDL-P size (regression coefficients = 0.585 nmol/L, 0.366 MUmol/L, and -0.025 nm per SD increase in pericardial fat volume respectively, all P < 0.05). The association of pericardial fat volume with large VLDL-P concentration and HDL-P size, but not small HDL-P concentration, remained significant after further adjusting for each other as well as LDL cholesterol, HDL cholesterol, and triglycerides. The relationship of pericardial fat volume with incident CVD events, carotid IMT, and prevalence and severity of CAC did not differ by quartiles of large VLDL-P concentration, small HDL-P concentration, or HDL-P size (P for interaction>0.05). CONCLUSION: Pericardial fat is associated with atherogenic lipoprotein abnormalities. However, its relationship with subclinical atherosclerosis and incident CVD events does not differ according to lipoprotein distribution. PMID- 26117405 TI - MicroRNA-19b/221/222 induces endothelial cell dysfunction via suppression of PGC 1alpha in the progression of atherosclerosis. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a master regulator of cellular energy metabolism that is associated with many cardiovascular diseases, including atherosclerosis. However, the role and underling regulatory mechanisms of PGC-1alpha in the pathogenesis of atherosclerosis are not completely understood. Here, we identified the microRNAs that post-transcriptionally regulate PGC-1alpha production and their roles in the pathogenesis of atherosclerosis. METHODS AND RESULTS: A significant down regulation of PGC-1alpha protein was observed in human atherosclerotic vessel samples. Using microarray and bioinformatics analyses, PGC-1alpha was identified as a common target gene of miR-19b-3p, miR-221-3p and miR-222-3p, which are mainly located in the intima of atherosclerotic vessels. In vitro induction of miR-19b-3p, miR-221-3p and miR-222-3p by the inflammatory cytokines TNFalpha and IFNgamma may affect PGC-1alpha protein production and consequently result in mitochondrial dysfunction in Human Aortic Endothelial Cells (HAECs). The overexpression of miR-19b-3p, miR-221-3p and miR-222-3p in HAECs caused intracellular ROS accumulation, which led to cellular apoptosis. CONCLUSION: Taken together, these results demonstrate that PGC-1alpha plays a protective role against the vascular complications of atherosclerosis. Moreover, the posttranscriptional regulation of PGC-1alpha by miR-19b/221/222 was unveiled, which provides a novel mechanism in which a panel of microRNAs can modulate endothelial cell apoptosis via the regulation mitochondrial function. PMID- 26117406 TI - Systematic Literature Review and Meta-analysis of Medication Adherence With Once weekly Versus Once-daily Therapy. AB - PURPOSE: To compare medication adherence rates for once-weekly (QW) versus once daily (QD) dosing regimens in patients with chronic disease. METHODS: A systematic literature review was conducted to identify articles published in English-language journals examining the rate of adherence to medications in patients with chronic disease. Relevant studies were identified from January 2002 through August 2013 using PubMed, EMBASE, and the Cochrane Library databases. Twenty-two published observational studies reporting adherence were identified by 2 independent reviewers, and 7 articles reported relevant measures for analysis. All studies were conducted in patients with osteoporosis. Meta-analyses estimated (1) mean difference (MD) in adherence (defined using the mean medication possession ratio [MPR]) between QW and QD dosing groups and (2) odds ratio (OR) for adherence (defined using an MPR cutoff of >=80%) for QW versus QD dosing. Heterogeneity was assessed using Cochran's Q and I(2) values, and meta-analyses used both fixed- and random-effects models. FINDINGS: The random-effects meta analysis revealed a significantly greater MPR with QW compared with QD dosing (pooled MD = 12.29%; 95% CI, 10.76%-13.82%; n = 9 [data reported in 7 publications]). Because of the high level of heterogeneity (I(2) = 83.4%), the fixed-effects model results were not appropriate to report for the pooled MD. When examining the OR for adherence, both fixed- and random-effects models provided similar results due to the low level of heterogeneity (I(2) = 7.9%; n = 5 [data reported in 3 publications]). Using either model, the pooled odds of being adherent (MPR >=80%) in the QW dosing group was approximately 1.9 times the odds in the QD dosing group (random-effects OR = 1.90; 95% CI, 1.81-2.00; fixed effects OR = 1.92; 95% CI, 1.84-1.99). IMPLICATIONS: In our meta-analysis, QW dosing was associated with better adherence levels and greater odds of being adherent compared with QD dosing in patients with osteoporosis. PMID- 26117407 TI - The effect of visual cues on top-down restoration of temporally interrupted speech, with and without further degradations. AB - In complex listening situations, cognitive restoration mechanisms are commonly used to enhance perception of degraded speech with inaudible segments. Profoundly hearing-impaired people with a cochlear implant (CI) show less benefit from such mechanisms. However, both normal hearing (NH) listeners and CI users do benefit from visual speech cues in these listening situations. In this study we investigated if an accompanying video of the speaker can enhance the intelligibility of interrupted sentences and the phonemic restoration benefit, measured by an increase in intelligibility when the silent intervals are filled with noise. Similar to previous studies, restoration benefit was observed with interrupted speech without spectral degradations (Experiment 1), but was absent in acoustic simulations of CIs (Experiment 2) and was present again in simulations of electric-acoustic stimulation (Experiment 3). In all experiments, the additional speech information provided by the complementary visual cues lead to overall higher intelligibility, however, these cues did not influence the occurrence or extent of the phonemic restoration benefit of filler noise. Results imply that visual cues do not show a synergistic effect with the filler noise, as adding them equally increased the intelligibility of interrupted sentences with or without the filler noise. PMID- 26117408 TI - The role of extended preoperative steroids in hearing preservation cochlear implantation. AB - INTRODUCTION: Steroids have been shown to reduce the hearing threshold shifts associated with cochlear implantation. Previous studies have examined only the administration of steroids just prior to surgery. The aim of this study is to examine the role of extended preoperative systemic steroids in hearing preservation cochlear implantation. METHODS: An animal model of cochlear implantation was used. 24 Hartley strain guinea pigs with a mean weight of 768 g and normal hearing were randomised into a control group, a second group receiving a single dose of systemic dexamethasone one day prior to surgery, and a third group receiving a daily dose of systemic dexamethasone for 5 days prior to surgery. A specially designed cochlear implant electrode by Med-EL (Innsbruck) was inserted through a dorsolateral approach to an insertion depth of 5 mm and left in-situ. Auditory brain stem responses at 8 kHz, 16 kHz and 32 kHz were measured preoperatively, and 1 week, 1 month and 2 months postoperatively. Cochlear histopathology was examined at the conclusion of the study. RESULTS: At 1-week post operative, both groups receiving dexamethasone prior to implantation had smaller threshold shifts across all frequencies and which was significant at 32 kHz (p < 0.05). There were no differences among the three groups in the area of electrode related fibrosis. Spiral ganglion neuron (SGN) density was significantly higher in the group receiving steroids for 5 days, but only in the basal cochlear turn. DISCUSSION: This is study demonstrates the benefits of extended preoperative systemic steroids on hearing outcomes and SGN density in an animal model of cochlear implantation surgery. PMID- 26117409 TI - Theta, beta and gamma rate modulations in the developing auditory system. AB - In the brain, the temporal analysis of many important auditory features relies on the synchronized firing of neurons to the auditory input rhythm. These so-called neural oscillations play a crucial role in sensory and cognitive processing and deviances in oscillatory activity have shown to be associated with neurodevelopmental disorders. Given the importance of neural auditory oscillations in normal and impaired sensory and cognitive functioning, there has been growing interest in their developmental trajectory from early childhood on. In the present study, neural auditory processing was investigated in typically developing young children (n = 40) and adults (n = 27). In all participants, auditory evoked theta, beta and gamma responses were recorded. The results of this study show maturational differences between children and adults in neural auditory processing at cortical as well as at brainstem level. Neural background noise at cortical level was shown to be higher in children compared to adults. In addition, higher theta response amplitudes were measured in children compared to adults. For beta and gamma rate modulations, different processing asymmetry patterns were observed between both age groups. The mean response phase was also shown to differ significantly between children and adults for all rates. Results suggest that cortical auditory processing of beta develops from a general processing pattern into a more specialized asymmetric processing preference over age. Moreover, the results indicate an enhancement of bilateral representation of monaural sound input at brainstem with age. A dissimilar efficiency of auditory signal transmission from brainstem to cortex along the auditory pathway between children and adults is suggested. These developmental differences might be due to both functional experience-dependent as well as anatomical changes. The findings of the present study offer important information about maturational differences between children and adults for responses to theta, beta and gamma rates. The current study can have important implications for the understanding of developmental disorders which are known to be associated with deviances in neural auditory processing. PMID- 26117410 TI - Hydrosalpinx in Postmenarchal Nonsexually Active Girls: A Review of 6 Cases in a Children's Hospital. AB - BACKGROUND: The objective of the study was to identify the presence of hydrosalpinx in postmenarchal nonsexually active girls in a children's hospital and to review the available literature on hydrosalpinx in this population. CASES: In a tertiary care children's hospital, we performed a retrospective review of charts from January 1, 2000 to December 31, 2014 and identified six cases of hydrosalpinx in postmenarchal nonsexually active female adolescents ranging in age from 12 to 19 years old. The diagnosis of hydrosalpinx was made using imaging studies. Four of six patients were symptomatic at presentation, and two patients were diagnosed when seen for unrelated reasons. Five of these six girls had previous abdominopelvic surgery. Four girls were given empiric antibiotic treatment for presumed pelvic inflammatory disease related to hydrosalpinx. Two patients required surgical intervention that resulted in complete resolution of the hydrosalpinx. The oldest patient in the series underwent ultrasound-guided drainage of the pyo- and/or hydrosalpinx with subsequent recurrence with tubal ovarian abscess five months later. SUMMARY AND CONCLUSIONS: The presence of hydrosalpinx might be discovered in the workup of pelvic pain in nonsexually active adolescents or on routine follow-up in patients with previous abdominal surgery, some of whom are asymptomatic. The underlying pathophysiology for hydrosalpinx in this population remains unclear. Among our cases, postsurgical adhesions appeared to be the most likely predisposing factor for tubular obstruction. Early detection and prompt diagnosis will allow for appropriate conservative or definitive treatment. PMID- 26117411 TI - Prevalence and associations of general practice nurses' involvement in consultations of general practitioner registrars: a cross-sectional analysis. AB - OBJECTIVE: To establish prevalence and associations of general practice nurses' (GPNs) involvement in general practitioner (GP) registrars' consultations. METHODS: A cross-sectional analysis from an ongoing cohort study of registrars' clinical consultations in five Australian states. Registrars recorded detailed data from 60 consecutive consultations per 6-month training term. Problems and diagnoses encountered, including chronic disease classification, were coded using the International Classification of Primary Care, second edition duplication system (ICPC-2plus) classification system. The outcome factor in our analysis was GPN involvement in management of individual problems and diagnoses. Independent variables were a range of patient, registrar, practice, consultation and educational factors. RESULTS: We analysed 108 759 consultations of 856 registrars including 169 307 problems or diagnoses. Of the problems/diagnoses, 5.1% (95% confidence interval (CI) 5.0-5.2) involved a GPN. Follow-up with a GPN was organised for 1.5% (95% CI 1.4-1.5) of all problems/diagnoses. Significant associations of GPN involvement included patient age, male sex, Aboriginal or Torres Strait Islander status, non-English-speaking background (NESB) and the patient being new to the practice. Larger practice size, the particular training organisation, and the problem/diagnosis being new and not a chronic disease were other associations. CONCLUSIONS: Associations with Aboriginal or Torres Strait Islander status and NESB status suggest GPNs are addressing healthcare needs of these under-serviced groups. But GPNs may be underutilised in chronic disease care. PMID- 26117412 TI - Precise placement of lag screws in operative treatment of trochanteric femoral fractures with a new guide system. AB - PURPOSE: We assessed the accuracy of a new guide system that we developed to place lag screws in the proper position with the minimum number of attempts for operative treatment of trochanteric femoral fractures. METHODS: A total of 55 consecutive trochanteric femoral fractures were treated with a cephalomedullary nail. The first 27 consecutive patients were treated with the standard operation (group A), while the new guide system was used in the last 28 consecutive patients (group B). The numbers of attempts to place K wires and the duration of surgery were noted. Accuracy of lag screw placement was evaluated by measuring the angle of deviation from the central axis of the femoral head. RESULTS: Deviation values ranged from -11 to +15 for the 27 cases in group A, with a median absolute deviation of 8+/-6. That in the 28 cases after the introduction of the new guide system (group B) ranged from -5 to +6, with a median absolute deviation of 0.5+/-3 (P<0.001). The total numbers of attempts to place lag screws and mean operation time decreased significantly after introduction of the new guide system (P<0.001). CONCLUSIONS: With this new guide system, we are able to insert lag screws successfully in the optimal position even in most unstable fractures. The present study indicated that this new guide system and nail facilitate accurate placement of lag screws in the appropriate position with the minimum number of attempts. PMID- 26117413 TI - Selective management of penetrating neck injuries using "no zone" approach. AB - INTRODUCTION: Selective management has been the standard management protocol in penetrating neck injuries (PNIs) since this approach has significantly reduced unnecessary neck exploration. The purpose of this study is to evaluate outcomes of selective management in PNIs using the "no zone" approach, in which the management is guided mainly by clinical signs and symptoms, not the location of the neck wounds. MATERIALS AND METHODS: A retrospective study was performed in patients treated for PNIs at King Chulalongkorn Memorial Hospital (KCMH) from January 2003 to December 2013. The patients with hard signs of neck injury (i.e., active bleeding, significant haematoma, massive subcutaneous emphysema, and air bubbling through the neck wound) underwent emergency neck exploration. The asymptomatic patients and the patients with soft signs (other symptoms) were considered to be candidates for selective management. Data collection included demographic data, emergency department parameters, details of neck injury, and outcomes in terms of mortality, negative exploration rate, and missed injury rate. RESULTS: Eighty-six PNI patients were treated at KCMH from 2003 to 2013, 64 of which sustained stab wounds, 12 gunshot wounds, 4 shotgun wounds, and 6 other causes. Thirty-six patients presenting with hard signs underwent immediate neck exploration and there were 2 negative explorations. Twenty-six patients with soft signs underwent selective investigations (including computed tomographic angiography in 21 patients), 5 patients required neck explorations due to positive results of the investigations with one negative exploration. All of the twenty-four asymptomatic patients were managed with close observation, none required subsequent neck exploration. There was no missed injury found in the present study. Successful non-operative management was carried out in 45 patients (52%). The overall negative exploration rate was 7% (3 in 41 patients undergoing neck exploration). Two patients with hard signs died from associated chest injuries (mortality rate 2%). CONCLUSION: Selective management of penetrating neck injuries based on physical examination and selective use of investigations (no zone approach) is safe and simple with low negative exploration rate and no missed injury. PMID- 26117414 TI - Comparison of screw fixation with elastic fixation methods in the treatment of syndesmosis injuries in ankle fractures. AB - 17 patients with ankle syndesmosic injury were treated with a 4.5mm single cortical screw fixation (passage of screw 4 cortices) and 15 patients were treated with single-level elastic fixation material. All patients were evaluated according to the AOFAS ankle and posterior foot scale at the third, sixth and twelfth months after the fixation. The ankle range of movement was recorded together with the healthy side. The Student's t test was used for statistical comparisons. No statistical significant difference was observed between the AOFAS scores (p>0.05). The range of dorsiflexion and plantar flexion motion of the elastic fixation group at the 6th and 12th months were significantly better compared to the screw fixation group (p<0.01). Elastic fixation is as functional as screw fixation in the treatment of ankle syndesmosis injuries. The unnecessary need of a second surgical intervention for removal of the fixation material is another advantageous aspect of this method of fixation. PMID- 26117415 TI - Injuries and outcomes associated with traumatic falls in the elderly population on oral anticoagulant therapy. AB - INTRODUCTION: Fall risk for older adults is a multi-factorial public health problem as 90% of geriatric injuries are caused by traumatic falls. The CDC estimated 33% of adults >65 years incurred a fall in 2011, with 30% resulting in moderate injury. While much has been written about overall risk to trauma patients on oral anticoagulant (OAC) therapy, less has been reported on outcomes in the elderly trauma population. We used data from the National Trauma Data Bank (NTDB) to identify the types of injury and complications incurred, length of stay, and mortality associated with OACs in elderly patients sustaining a fall. METHODS: Using standard NTDB practices, data were collected on elderly patients (>=65 years) on OACs with diagnosis of fall as the primary mechanism of injury from 2007 to 2010. Univariate analysis was used to determine patient variables influencing risk of fall on OACs. Odds ratios were calculated for types of injury sustained and post-trauma complications. Logistic regression was used to determine mortality associated with type of injury incurred. RESULTS: Of 118,467 elderly patients sampled, OAC use was observed in 444. Predisposing risk factors for fall on OACs were >1 comorbidity (p<0.0001). Patients on OACs were 188% and 370% more likely to develop 2 and >3 complications (p<0.0001); the most significant being ARDS and ARF (p<0.0001). The mortality rate on OACs was 16%. Injuries to the GI tract, liver, spleen, and kidney (p<0.0002) were more likely to occur. However, if patients suffered a mortality, the most significant injuries were skull fractures and intracranial haemorrhage (p<0.0001). CONCLUSIONS: Risks of anticoagulation in elderly trauma patients are complex. While OAC use is a predictor of 30-day mortality after fall, the injuries sustained are markedly different between the elderly who die and those who do not. As a result there is a greater need for healthcare providers to identify preventable and non-preventable risks factors indicative of falls in the anti coagulated elderly patient. PMID- 26117416 TI - The relationship between UV-irradiance, photoprotective compounds and DNA damage in two intertidal invertebrates with contrasting mobility characteristics. AB - The photoprotective role of mycosporine-like amino acids (MAA) against the generation of DNA cyclobutane pyrimidine dimers (CPD) was studied in the sessile intertidal anemone Actinia tenebrosa and the mobile intertidal gastropod Diloma aethiops through 27months at a mid-latitude New Zealand location. MAA were sequestered by A. tenebrosa and D. aethiops from their diet, although maximum total MAA levels in both species were not correlated with seasonal variation in maximum ambient UV-B levels recorded at the collection site. Temporal changes in total MAA in A. tenebrosa showed a six months lag-time in their concentration regarding to the environmental UV-B levels. This lag period corresponded to an observed increase in CPD production from spring to summer; suggesting that MAA do not completely protect the anemone from UV-B during summer. For D. aethiops, total MAA concentrations did not change significantly during the study, although qualitative changes in MAA were apparent. A month lag-time in MAA concentration in D. aethiops and possibly the physical barrier that the shell confers to the animal, can explain reduced CPD levels in comparative terms with A. tenebrosa. Although MAA are used by invertebrates for photoprotection, contrasting mobility characteristics and the presence of physical adaptations can confer them important protection levels during temporal changes of UV-B at mid-latitude places of the Southern Hemisphere. PMID- 26117417 TI - Relation of motor, linguistic and temperament factors in epidemiologic subtypes of persistent and recovered stuttering: Initial findings. AB - PURPOSE: The purpose of this study was to determine the presence of any patterns reflecting underlying subtypes of persistence and recovery across epidemiologic, motor, language, and temperament domains in the same group of children beginning to stutter and followed for several years. METHODS: Participants were 58 2-4-year old CWS and 40 age and gender matched NFC from four different sites in the Midwest. At the end of the multi-year study, stuttering children were classified as Persistent or Recovered. The same protocol obtaining data to measure stuttering, motor, language and temperament characteristics was used at each site. They have not been included in previous reports. RESULTS: The Persistent group performed consistently differently from the Recovered and Control groups. They performed lower on standardized language tests and in phonological accuracy, had greater kinematic variability, and were judged by their parents to be more negative in temperament. CONCLUSIONS: The present study provides data supporting the hypothesis that subtypes of stuttering can be identified along persistency/recovery lines, but results were not definitive. EDUCATIONAL OBJECTIVES: Readers will be able to (a) describe the current state of subtypes of stuttering research; (b) summarize possible contributions of epidemiologic, motoric, linguistic and temperament to such subtyping with regard to persistency and recovery. PMID- 26117418 TI - Solid phase bio-electrofermentation of food waste to harvest value-added products associated with waste remediation. AB - A novel solid state bio-electrofermentation system (SBES), which can function on the self-driven bioelectrogenic activity was designed and fabricated in the laboratory. SBES was operated with food waste as substrate and evaluated for simultaneous production of electrofuels viz., bioelectricity, biohydrogen (H2) and bioethanol. The system illustrated maximum open circuit voltage and power density of 443 mV and 162.4 mW/m(2), respectively on 9 th day of operation while higher H2 production rate (21.9 ml/h) was observed on 19th day of operation. SBES system also documented 4.85% w/v bioethanol production on 20th day of operation. The analysis of end products confirmed that H2 production could be generally attributed to a mixed acetate/butyrate-type of fermentation. Nevertheless, the presence of additional metabolites in SBES, including formate, lactate, propionate and ethanol, also suggested that other metabolic pathways were active during the process, lowering the conversion of substrate into H2. SBES also documented 72% substrate (COD) removal efficiency along with value added product generation. Continuous evolution of volatile fatty acids as intermediary metabolites resulted in pH drop and depicted its negative influence on SBES performance. Bio-electrocatalytic analysis was carried out to evaluate the redox catalytic capabilities of the biocatalyst. Experimental data illustrated that solid-state fermentation can be effectively integrated in SBES for the production of value added products with the possibility of simultaneous solid waste remediation. PMID- 26117419 TI - Mineralogical analysis of dust collected from typical recycling line of waste printed circuit boards. AB - As dust is one of the byproducts originating in the mechanical recycling process of waste printed circuit boards such as crushing and separating, from the viewpoints of resource reuse and environmental protection, an effective recycling method to recover valuable materials from this kind of dust is in urgent need. In this paper, detailed mineralogical analysis on the dust collected from a typical recycling line of waste printed circuit boards is investigated by coupling several analytical techniques. The results demonstrate that there are 73.1wt.% organic matters, 4.65wt.% Al, 4.55wt.% Fe, 2.67wt.% Cu and 1.06wt.% Pb in the dust, which reveals the dust is worthy of reuse and harmful to environment. The concentration ratios of Fe, Mn and Zn can reach 12.35, 12.33 and 6.67 respectively by magnetic separation. The yield of dust in each size fraction is nonuniform, while the yield of -0.75mm size fraction is up to 51.15wt.%; as the particle size decreases, the content of liberated metals and magnetic materials increase, and metals are mainly in elemental forms. The F, Cl and Br elements combing to C in the dust would make thermal treatment dangerous to the environment. Based on these results, a flowsheet to recycle the dust is proposed. PMID- 26117420 TI - Current limitations and challenges in nanowaste detection, characterisation and monitoring. AB - Engineered nanomaterials (ENMs) are already extensively used in diverse consumer products. Along the life cycle of a nano-enabled product, ENMs can be released and subsequently accumulate in the environment. Material flow models also indicate that a variety of ENMs may accumulate in waste streams. Therefore, a new type of waste, so-called nanowaste, is generated when end-of-life ENMs and nano enabled products are disposed of. In terms of the precautionary principle, environmental monitoring of end-of-life ENMs is crucial to allow assessment of the potential impact of nanowaste on our ecosystem. Trace analysis and quantification of nanoparticulate species is very challenging because of the variety of ENM types that are used in products and low concentrations of nanowaste expected in complex environmental media. In the framework of this paper, challenges in nanowaste characterisation and appropriate analytical techniques which can be applied to nanowaste analysis are summarised. Recent case studies focussing on the characterisation of ENMs in waste streams are discussed. Most studies aim to investigate the fate of nanowaste during incineration, particularly considering aerosol measurements; whereas, detailed studies focusing on the potential release of nanowaste during waste recycling processes are currently not available. In terms of suitable analytical methods, separation techniques coupled to spectrometry-based methods are promising tools to detect nanowaste and determine particle size distribution in liquid waste samples. Standardised leaching protocols can be applied to generate soluble fractions stemming from solid wastes, while micro- and ultrafiltration can be used to enrich nanoparticulate species. Imaging techniques combined with X-ray-based methods are powerful tools for determining particle size, morphology and screening elemental composition. However, quantification of nanowaste is currently hampered due to the problem to differentiate engineered from naturally occurring nanoparticles. A promising approach to face these challenges in nanowaste characterisation might be the application of nanotracers with unique optical properties, elemental or isotopic fingerprints. At present, there is also a need to develop and standardise analytical protocols regarding nanowaste sampling, separation and quantification. In general, more experimental studies are needed to examine the fate and transport of ENMs in waste streams and to deduce transfer coefficients, respectively to develop reliable material flow models. PMID- 26117421 TI - Extraction of medium chain fatty acids from organic municipal waste and subsequent production of bio-based fuels. AB - This paper provides an overview on investigations for a new technology to generate bio-based fuel additives from bio-waste. The investigations are taking place at the composting plant in Darmstadt-Kranichstein (Germany). The aim is to explore the potential of bio-waste as feedstock in producing different bio-based products (or bio-based fuels). For this investigation, a facultative anaerobic process is to be integrated into the normal aerobic waste treatment process for composting. The bio-waste is to be treated in four steps to produce biofuels. The first step is the facultative anaerobic treatment of the waste in a rotting box namely percolate to generate a fatty-acid rich liquid fraction. The Hydrolysis takes place in the rotting box during the waste treatment. The organic compounds are then dissolved and transferred into the waste liquid phase. Browne et al. (2013) describes the hydrolysis as an enzymatically degradation of high solid substrates to soluble products which are further degraded to volatile fatty acids (VFA). This is confirmed by analytical tests done on the liquid fraction. After the percolation, volatile and medium chain fatty acids are found in the liquid phase. Concentrations of fatty acids between 8.0 and 31.5 were detected depending on the nature of the input material. In the second step, a fermentation process will be initiated to produce additional fatty acids. Existing microorganism mass is activated to degrade the organic components that are still remaining in the percolate. After fermentation the quantity of fatty acids in four investigated reactors increased 3-5 times. While fermentation mainly non-polar fatty acids (pentanoic to octanoic acid) are build. Next to the fermentation process, a chain elongation step is arranged by adding ethanol to the fatty acid rich percolate. While these investigations a chain-elongation of mainly fatty acids with pair numbers of carbon atoms (acetate, butanoic and hexanoic acid) are demonstrated. After these three pre-treatments, the percolate is brought to a refinery to extract the non-polar fatty acids using bio-diesel, which was generated from used kitchen oil at the refinery. The extraction tests in the lab have proved that the efficiency of the liquid-liquid-extraction is directly linked with the chain length and polarity of the fatty acids. By using a non-polar bio-diesel mainly the non-polar fatty acids, like pentanoic to octanoic acid, are extracted. After extraction, the bio-diesel enriched with the fatty acids is esterified. As a result bio-diesel with a lower viscosity than usual is produced. The fatty acids remaining in the percolate after the extraction can be used in another fermentation process to generate biogas. PMID- 26117422 TI - A comparative study on the efficiency of ozonation and coagulation-flocculation as pretreatment to activated carbon adsorption of biologically stabilized landfill leachate. AB - The present work investigates the potential of coagulation-flocculation and ozonation to pretreat biologically stabilized landfill leachate before granular activated carbon (GAC) adsorption. Both iron (III) chloride (FeCl3) and polyaluminium chloride (PACl) are investigated as coagulants. Better organic matter removal is observed when leachate was treated with FeCl3. At a dose of 1mg FeCl3/mg CODo (CODo: initial COD content), the COD and alpha254 removal was 66% and 88%, respectively. Dosing 1mg PACl/mg CODo resulted in 44% COD and 72% alpha254 removal. The settle-ability of sludge generated by PACl leveled off at 252mL/g, while a better settle-ability of 154mL/g was obtained for FeCl3 after dosing 1mg coagulant/mg CODo. For ozonation, the percentage of COD and alpha254 removal increased as the initial COD concentration decreased. Respectively 44% COD and 77% alpha254 removal was observed at 112mg COD/L compared to 5% COD and 26% alpha254 removal at 1846mg COD/L. Subsequent activated carbon adsorption of ozonated, coagulated and untreated leachate resulted in 77%, 53% and 8% total COD removal after treatment of 6 bed volumes. Clearly showing the benefit of treating the leachate before GAC adsorption. Mathematical modeling of the experimental GAC adsorption data with Thomas and Yoon-Nelson models show that ozonation increases the adsorption capacity and breakthrough time of GAC by a factor of 2.5 compared to coagulation-flocculation. PMID- 26117423 TI - The BAH domain of BAF180 is required for PCNA ubiquitination. AB - Monoubiquitination of proliferating cell nuclear antigen (PCNA) is a critical regulator of post replication repair (PRR). The depletion of BAF180, a unique subunit of the PBAF chromatin remodeling complex in human cells results in reduced PCNA ubiquitination leading to less efficient fork progression following DNA damage, but little is known about the mechanism. Here, we report that the expression of exogenous BAF180 in cells promotes PCNA ubiquitination during S phase after UV irradiation and it persists for many hours. No correlation was observed between the protein level of ubiquitin-specific protease 1 (USP1) and ubiquitinated PCNA in BAF180 expressing cells. Analysis of cells expressing BAF180 deletion mutants showed that the bromo-adjacent homology (BAH) domains are responsible for this effect. Surprisingly, a deletion construct encoding only the BAH domain region is able to increase the level of ubiquitinated PCNA, even though it is unable to be assembled into the PBAF complex. These results suggest that the ATPase-dependent chromatin remodeling activity of PBAF is not necessary, but instead the BAH domains are sufficient to promote PCNA ubiquitination. PMID- 26117424 TI - Diabetes and Ramadan. PMID- 26117425 TI - Literature search methodology for systematic reviews: conventional and natural language processing enabled methods are complementary (Letter commenting on: J Clin Epidemiol. 2015;68:191-9). PMID- 26117426 TI - CB(2) and TRPV(1) receptors oppositely modulate in vitro human osteoblast activity. AB - In the current study, we have investigated the effect of CB2 and TRPV1 receptor ligands on in vitro osteoblasts from bone marrow of human healthy donors. A pivotal role for the endocannabinoid/endovanilloid system in bone metabolism has been highlighted. We have demonstrated a functional cross-talk between CB2 and TRPV1 in human osteoclasts, suggesting these receptors as new pharmacological target for the treatment of bone resorption disease as osteoporosis. Moreover, we have shown the presence of these receptors on human mesenchimal stem cells, hMSCs. Osteoblasts are mononucleated cells originated from hMSCs by the essential transcription factor runt-related transcription factor 2 and involved in bone formation via the synthesis and release of macrophage colony-stimulating factor, receptor activator of nuclear factor kappa-B ligand and osteoprotegerin. For the first time, we show that CB2 and TRPV1 receptors are both expressed on human osteoblasts together with enzymes synthesizing and degrading endocannabinoids/endovanilloids, and oppositely modulate human osteoblast activity in culture in a way that the CB2 receptor stimulation improves the osteogenesis whereas TRPV1 receptor stimulation inhibits it. PMID- 26117427 TI - PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction. AB - Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but also has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (8-[(6 iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy. PMID- 26117428 TI - Novel insight into drug repositioning: Methylthiouracil as a case in point. AB - Drug repositioning refers to the development of existing drugs for new indications. These drugs may have (I) failed to show efficacy in late stage clinical trials without safety issues; (II) stalled in the development for commercial reasons; (III) passed the point of patent expiry; or (IV) are being explored in new geographic markets. Over the past decade, pressure on the pharmaceutical industry caused by the 'innovation gap' owing to rising development costs and stagnant product output have become major reasons for the growing interest in drug repositioning. Companies that offer a variety of broad platforms for identifying new indications have emerged; some have been successful in building their own pipelines of candidates with reduced risks and timelines associated with further clinical development. The business models and platforms offered by these companies will be validated if they are able to generate positive proof-of-concept clinical data for their repositioned compounds. This review describes the strategy of biomarker-guided repositioning of chemotherapeutic drugs for inflammation therapy, considering the repositioning of methylthiouracil (MTU), an antithyroid drug, as a potential anti-inflammatory reagent. PMID- 26117429 TI - [Is a Mexican Flexner possible in this century?]. PMID- 26117430 TI - Immunomodulatory and anti-inflammatory action of Nigella sativa and thymoquinone: A comprehensive review. AB - Many herbal products are now used as remedies to treat various infectious and non infectious conditions. Even though the use of herbs and natural products is much more evident in the Eastern world, their use in Western cultures is continuously increasing. Although the immunomodulatory effects of some herbs have been extensively studied, research related to possible immunomodulatory effects of many herbs and various spices is relatively scarce. Here, we provide a comprehensive review of the immunomodulatory and anti-inflammatory properties of Nigella sativa, also known as black seed or black cumin, and its major active ingredient, thymoquinone (TQ). This review article focuses on analyzing in vitro and in vivo experimental findings that were reported with regard to the ability of N. sativa and TQ to modulate inflammation, cellular and humoral adaptive immune responses, and Th1/Th2 paradigm. The reported capability of N. sativa to augment the cytotoxic activity of natural killer (NK) cells against cancer cells is also emphasized. The molecular and cellular mechanisms underlying such immunomodulatory and anti-inflammatory effects of N. sativa and TQ are highlighted. Moreover, the signal transduction pathways implicated in the immunoregulatory functions of N. sativa and TQ are underscored. Experimental evidence suggests that N. sativa extracts and TQ can potentially be employed in the development of effective therapeutic agents towards the regulation of immune reactions implicated in various infectious and non-infectious conditions including different types of allergy, autoimmunity, and cancer. PMID- 26117431 TI - Treatment options for chylous ascites after major abdominal surgery: a systematic review. AB - BACKGROUND: Chylous leakage is a relevant clinical problem after major abdominal surgery leading to an increased length of stay. DATA SOURCES: A systematic search of MEDLINE/PubMed and the Cochrane Library was performed according to the PRISMA statement. The search for the MeSH terms "chylous ascites" and/or "lymphatic fistula" retrieved a total of 2,348 articles, of which 36 full-text articles were reviewed by 2 independent investigators. RESULTS: Chylous ascites is described with an incidence of up to 11%, especially after pancreatic surgery. The incidence is increasing with the number of lymph nodes harvested. In patients treated with total parenteral nutrition, conservative treatment is demonstrated to be effective in up to 100% of cases. CONCLUSIONS: The extent of abdominal surgery mainly predicts the risk of chylous ascites. Conservative treatment has been shown to be effective in almost all cases and is the treatment of choice. PMID- 26117432 TI - Postoperative diarrhea and high ostomy output impact postoperative outcomes after elective colon and rectal operations regardless of Clostridium difficile infection. AB - BACKGROUND: We aimed to review and compare outcomes of patients with and without Clostridium difficile infection (CDI) after elective colorectal operations. METHODS: Retrospective cohort study of patients with CDI after elective colon and rectal operations from 2007 to 2012 (Group A) was conducted. Outcomes were compared with patients with a negative C. difficile toxin assay performed for postoperative diarrhea or high stoma output (Group B) and matched controls (Group C). RESULTS: Forty-four patients (median age 53 years) developed CDI postoperatively (Group A). Fourteen patients (32%) had surgical site infections. Both Group A and Group B patients received ertapenem as preoperative antibiotic prophylaxis significantly more often than matched controls (P < .0001), and also had significantly more surgical site infections (P = .004), longer hospital stays (P = .003), and more readmissions (P = .02) compared with Group C patients. CONCLUSIONS: In this study, postoperative CDI was uncommon, of low morbidity, and no mortality. Postoperative diarrhea and high stoma output, whether in patients who are C. difficile positive or not, appear to impact postoperative outcomes. PMID- 26117433 TI - Can the measurement of amylase in drain after distal pancreatectomy predict post operative pancreatic fistula? AB - INTRODUCTION: The most frequent reason for performing a distal pancreatectomy is the presence of cystic or neuroendocrine tumors, in which the distal pancreatic stump is often soft and non fibrotic. This parenchymal consistence represents the main risk factor for post-operative pancreatic fistula. In order to identify the fistula and assessing its severity postoperative monitoring of amylase from intraperitoneal drains is important. METHODS: From a retrospective multicentric database analysis were included 33 patients who underwent distal pancreatectomy for pancreatic neoplastic disease. RESULTS: Postoperative pancreatic fistula occurred in four cases. One patient had a ductal adenocarcinoma, two presented with pancreatic endocrine neoplasms and the last one had an intraductal papillary mucinous neoplasia. Two patients underwent open, the other two laparoscopic distal pancreatectomy. DISCUSSION: Postoperative pancreatic fistulas after distal pancreatectomy worsen the quality of life, prolong the post-operative stay and delay further adjuvant therapy. In patients who underwent distal pancreatectomy literature exposed some advantages deriving from the placement of abdominal drainages only in selected cases and from their early removal. Patients presenting a high risk of pancreatic fistula had higher amylase levels of drainage fluid in the first postoperative day. CONCLUSION: POPF is the most frequently complication after pancreatectomy. In our analysis DFA1>5000 can be considered as a predictive factor for pancreatic fistula. For this reason, the systematic measurement of amylase in drain fluid in first-postoperative day can be considered a good clinical practice. PMID- 26117434 TI - New fabrication technique for highly sensitive qPlus sensor with well-defined spring constant. AB - A new technique for the fabrication of highly sensitive qPlus sensor for atomic force microscopy (AFM) is described. The focused ion beam was used to cut then weld onto a bare quartz tuning fork a sharp micro-tip from an electrochemically etched tungsten wire. The resulting qPlus sensor exhibits high resonance frequency and quality factor allowing increased force gradient sensitivity. Its spring constant can be determined precisely which allows accurate quantitative AFM measurements. The sensor is shown to be very stable and could undergo usual UHV tip cleaning including e-beam and field evaporation as well as in situ STM tip treatment. Preliminary results with STM and AFM atomic resolution imaging at 4.5 K of the silicon Si(111)-7*7 surface are presented. PMID- 26117435 TI - Caregiver report of apathy predicts dementia in Parkinson's disease. AB - INTRODUCTION: Apathy is a common, troublesome symptom in Parkinson's disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia. METHODS: Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson's Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score >=1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors. RESULTS: Of 132 PD patients 12.1% (N = 16) scored in the apathetic range at baseline. A total of 19.6% (N = 26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR = 3.56; 95% CI = 1.09-11.62; p = 0.04). CONCLUSIONS: A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia. PMID- 26117436 TI - A biological measure of stress levels in patients with functional movement disorders. AB - INTRODUCTION: While the presence of co-existing psychological stressors has historically been used as a supportive factor in the diagnosis of functional neurological disorders, many patients with functional neurological disorders deny the presence of these stressors. The stress response circuitry in these patients remains largely unexplored. METHODS: We performed an observational study examining biological stress levels in patients with functional movement disorders as compared with matched healthy controls. Specifically, we compared levels of circulating cortisol, the end-product of the hypothalamic-pituitary-adrenal axis. Salivary cortisol samples were collected from patients with "clinically definite" functional movement disorders (n = 33) and their age- and sex-matched controls (n = 33). Collections were performed at five standardized time points, reflecting participants' diurnal cortisol cycles. To rule out confounders, participants also underwent extensive psychological assessment including Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Hamilton Anxiety Rating Scale, and Hamilton Rating Scale for Depression. RESULTS: Patients with functional movement disorders did not differ from matched controls with respect to levels of circulating cortisol. CONCLUSION: We demonstrate that current stress levels are not altered in patients with functional movement disorders. Our results warrant careful review of current management of patients with functional neurological symptoms, and suggest that the insistence on heightened stress levels in these patients is unjustified. PMID- 26117437 TI - Effects of cerebellar continuous theta burst stimulation on resting tremor in Parkinson's disease. AB - INTRODUCTION: Recent studies have suggested that the cerebellum may be involved in the pathophysiology of resting tremor in patients with Parkinson's disease (PD). The aim of the study was to investigate the effects of cerebellar continuous theta burst stimulation (cTBS) on cerebello-thalamo-cortical connectivity and resting tremor in PD patients. METHODS: Thirteen PD patients and ten healthy subjects underwent two experimental sessions: (i) 'real' cTBS, delivered over the cerebellar hemisphere and (ii) 'sham' cerebellar cTBS, delivered over the neck muscles. The two sessions were performed at least one week apart. The effects of 'real' and 'sham' cerebellar cTBS were quantified as excitability changes in the contralateral primary motor cortex or as possible changes in resting tremor in the ipsilateral hand. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials from the contralateral first dorsal interosseous muscle. RESULTS: Resting tremor was rated clinically and objectively assessed by means of kinematic techniques. 'Real' cerebellar cTBS, though not 'sham' cerebellar cTBS, reduced the excitability in the contralateral primary motor cortex both in healthy subjects and in patients with PD. There was no significant change in rest tremor severity, as assessed by a clinical examination or kinematic techniques, after either 'real' or 'sham' cerebellar cTBS in patients. Lastly, there was no correlation between individual changes in M1 excitability and clinical or kinematic measures of resting tremor in patients. CONCLUSION: The cerebello thalamo-cortical connectivity, as tested by cTBS, is not predominantly involved in the generation of resting tremor in PD. PMID- 26117438 TI - Influence of depression in mild Parkinson's disease on longitudinal motor and cognitive function. AB - BACKGROUND: Studies have suggested a relationship between non-motor symptoms with motor fluctuations in patients with Parkinson's disease (PD). We studied the influence of depression on longitudinal motor and cognitive function among mild PD patients. METHODS: A 1.5 years longitudinal study of 102 patients with mild idiopathic PD. Patients were assessed with a standardized clinical assessment battery including motor and non-motor scales. Patients also underwent serial neurocognitive testing that assessed global cognition, memory, attention, language, visuospatial and executive function. RESULTS: 81 patients with mean age of 64.9(SD = 7.9) years and mean Hoehn & Yahr of 1.9(SD = 0.4) completed baseline and follow-up visits. 22 patients had clinically significant depression at baseline with mean Geriatric Depression Scale of 6.9(SD = 2.4). These patients presented with concomitant apathy and anxiety and were more likely to be females with longer duration of PD. At baseline, patients with depression had poorer performance on global cognition and all cognitive domains although not significantly different from patients without depression. At follow-up, there was no statistically significant difference on cognitive performance between those with and without baseline depression. Patients with baseline depression demonstrated worsening of motor function after 18 months (UPDRS Motor Score Change: +5.0[7.0]vs.+0.2[7.3]; p = 0.015). On multivariate analysis Baseline Motor Score (B = -0.229,CI = -0.445 to-0.013,p = 0.038), Baseline GDS (B = 0.622,CI = 0.078 to 1.166,p = 0.026) and PD duration (B = 0.520,CI = 0.105 to 0.935,p = 0.015) independently predicted increase in UPDRS Motor Score. CONCLUSIONS: The findings suggest a relationship between early depression with motor worsening and cognition decline in PD patients. Further biomarker-supported studies investigating the role of depression on motor and cognitive function are needed. PMID- 26117439 TI - Reporting and methodological qualities of published surgical meta-analyses. AB - OBJECTIVES: To assess the overall qualities of published surgical meta-analysis and predictive factors for high qualities. STUDY DESIGN AND SETTING: All meta analyses pertinent to surgical procedures published in year 2013 were selected from PubMed and EMBASE. The characteristics of the included meta-analyses were collected, and their reporting and methodologic qualities were assessed by the PRISMA (27 items) and AMSTAR (11 items) checklists, respectively. Independent predictive factors associated with these two qualities were evaluated by univariate and multivariate analyses. RESULTS: Hundred ninety-seven meta-analyses representing 10 surgical subspecialties were included. The mean PRISMA and AMSTAR adherences (by items) were 22.2 +/- 2.4 and 7.8 +/- 1.2, respectively, and a positive linear correlation was found between them with an R(2) of 0.793. Those meta-analyses conducted by the first authors having meta-analysis publication previously had significantly higher reporting and methodologic qualities than those who did not (P = 0.002 and P = 0.001). Meanwhile, there were also significant differences in these two qualities between studies published in Q1 ranked and (Q2 + Q3)-ranked journals as rated by the SCImago indicator (P < 0.001 and P < 0.001). On multivariate analyses, region of origin (non-Asia vs. Asia), publishing experience of first authors (ever vs. never), rank of publishing journals (Q1 vs. Q2 + Q3), and preregistration (presence vs. absence) were independently associated with superior reporting and methodologic qualities. CONCLUSIONS: The reporting and methodologic qualities of current surgical meta analyses remained suboptimal, and first authors' experience and ranking of publishing journals were independently associated with both qualities. Preregistration might be an effective measure to improve the quality of meta analyses, which deserves more attention from future study conductors. PMID- 26117440 TI - The association of skin-incision type at cesarean with maternal and neonatal morbidity for women with multiple prior cesarean deliveries. AB - OBJECTIVE: In women with multiple prior cesarean deliveries (CDs), vertical skin incisions are thought by some to result in better outcomes. The objective of this study was to compare maternal and neonatal outcomes according to the type of skin incisions among women with multiple prior CDs. STUDY DESIGN: This was a secondary analysis of MFMU Cesarean Registry data. Women undergoing repeat CD with a viable singleton gestation and history of >=2 prior CDs were included in this analysis. Women who had indications for urgent CD (e.g., cord prolapse) or suspected placenta accreta were excluded. Maternal and neonatal outcomes of women with 2, 3 and >=4 prior CDs were compared by skin-incision type (transverse vs. vertical) using univariable and multivariable analyses. RESULTS: 5007 women met the inclusion criteria. In univariable analysis, women with 2 prior CDs who had a vertical skin incision had shorter incision-to-delivery intervals (12.9 min vs. 14.1 min, p<0.001) but also higher rates of endometritis and composite adverse maternal outcomes (4.9% vs. 2.7%, p=0.001, 16.1% vs. 13.4%, p=0.026, respectively). Women with 3 prior CDs also had higher rates of composite adverse maternal outcomes (21.2% vs. 15.8%, p=0.042). In women with >=4 prior CDs, prolonged hospitalization, composite adverse maternal outcomes, NICU admission and composite adverse neonatal outcomes also were higher with vertical skin incision (23.2% vs. 9.3%, p=0.005, 32.9% vs. 13.7%, p=0.001, 32.1% vs.19.6%, p=0.045, 32.9% vs.19.4%, p=0.024, respectively). In multivariable analyses, vertical skin incision remained associated with prolonged hospitalization and composite adverse maternal outcome among women with >=4 prior CDs (aOR 3.40, CI 1.11-10.38, aOR=2.37, CI 1.02-5.55, respectively). CONCLUSION: Vertical skin incision at the time of multiple repeat CD was not associated with better obstetric or perinatal outcomes and was associated among women with >=4 prior CDs with a higher frequency of prolonged hospitalization and adverse maternal outcomes. PMID- 26117441 TI - Outcome following selective fetoscopic laser ablation for twin to twin transfusion syndrome: an 8 year national collaborative experience. AB - OBJECTIVE: With the recognition of the role of fetoscopic laser ablation for twin to twin transfusion syndrome (TTTS), there is a requirement for auditable standards for this technically challenging and specialized treatment. The purpose of this study is to report on the perinatal and medium-term neurodevelopmental outcomes following an 8-year national single center experience in the management of TTTS using the selective fetoscopic laser ablation technique. STUDY DESIGN: An audit of all cases of TTTS treated with selective laser ablation by a single national fetal medicine team was performed. Overall perinatal survival and medium term neurodevelopmental outcomes were reported and correlated with gestational age at diagnosis, placental location, volume of amnio-reduction, Quintero staging and percentage inter-twin growth discordance. Procedure-related complications were recorded. RESULTS: The overall fetal survival for the first 105 consecutive cases of TTTS was 61% (128/210 fetuses). Dual survival occurred in 47% (49/105) of cases, and with a single survival rate of 28% (30/105), perinatal survival of least one infant was achieved in 75% (79/105) of cases. No correlation was found between any clinical or sonographic marker and perinatal outcome, although dual survival was noted to be significantly decreased with increasing Quintero stage (p=0.041). Currently, 86% of survivors have been reported to have a normal medium term neurological outcome. CONCLUSION: Fetoscopic laser ablation is the established optimal treatment for severe twin to twin transfusion syndrome (TTTS). We report comparable short and medium-term outcomes following the selective fetoscopic technique comparing results from our national program with internationally published single-center outcomes, supporting the efficacy and safety of this treatment at our center. PMID- 26117442 TI - Literature review of outcomes and prevalence and case report of leiomyosarcomas and non-typical uterine smooth muscle leiomyoma tumors treated with uterine artery embolization. AB - OBJECTIVE: To describe the early and late outcomes of uterine smooth muscle tumors that are either malignant or have the potential for recurrence (MRUSMTs) after uterine artery embolization (UAE). DESIGN: Literature review of MRUSMTs in case reports and in studies on patient outcome after UAE and reports of one case of leiomyosarcoma (LMS) and 2 cases of bizarre leiomyoma (BL) after UAE. SETTING: University hospital. INTERVENTION(S): Main outcome measure(s) and clinical outcome of UAE and prevalence of MRUSMT. RESULT(S): In the review of clinical trials, six cases of sarcomas were reported after UAE treatment in 8084 procedures. One of the six sarcoma cases and one case of intravenous leiomyomatosis occurred more than two years after the UAE. Thirteen cases of LMS, two cases of BL and no cases of MRUSMTs after UAE were identified in the published case reports. Six of the thirteen patients with sarcomas exhibited a good initial clinical response, but their symptoms relapsed after six months. UAE had a failed outcome in the two BL cases. CONCLUSION(S): MRUSMTs are rarely treated using UAE; late malignant transformation is infrequent but may be underreported. UAE treatment of leiomyosarcomas does not seem to spread the disease, but this approach may impair prognosis by delaying diagnosis. Tumors with low malignant potential may initially exhibit volume reduction and a good clinical response, but these tumors may exhibit persistent enhancement with contrast-enhanced magnetic resonance imaging (MRI). Special attention is required in cases with or without a limited response to UAE. PMID- 26117443 TI - Clonal dissemination of a single Shigella sonnei strain among Iranian children during Fall 2012 in Tehran, I.R. Iran. AB - Shigella species are a common cause of bacterial diarrhea worldwide and the disease is characterized by seasonality. Shigella has been encountered by widespread resistance to commonly used antibiotics which is a serious concern. The aim of this study was to analyze the epidemiological relatedness of Shigella strains isolated from children during one year period by PFGE method and to investigate antimicrobial resistance determinants and cassettes among Shigella species. The occurrence of Shigella spp. in the present study was 1.32% during the study period and the majority of cases (56 (80%)) were occurred during autumn while Shigella sonnei was the most prevalent species identified. Multi-drug resistance phenotype was seen in 98.5% of total isolates with SXT(r)/TE(r)/TMP(r) resistance pattern. Among the 70 Shigella spp. analyzed in this study, 16 isolates were positive for class I integron (int1(+)) with two types of gene cassette arrays (dfrA17/aadA5 and dfrA7).The class 2 integron was more frequently detected among the isolates (85.71%) with dfrA1/sat1/aadA1 (10%) and dfrA1/sat1 (75.71%) gene cassettes. The tetA and tetB determinants were observed in 75.7% and 21.42% of Shigella isolates and tet(A) was the foremost in S. sonnei and Shigella flexneri population. In this study 5 tetracycline resistant isolates had no tetracycline resistance gene (A-D) and no association was recognized between the value of MIC against tetracycline and the tet genes content of isolates. Fifty three of total Shigella isolates (75.7%) showed an identical PFGE patterns. Seven PFGE clusters observed in our study were composed of members with one to three band variations, which is indicative of closely related isolates. The major cluster (cluster C) constituted 75.7% of total isolates, all of which (except eight isolates) consonantly showed identical class 2 integron of 1500 bp which strongly suggests the dissemination of a single S. sonnei clone among the pediatric population in 2012 autumn in Tehran, Iran, in comparison with the equal data from the comparable time period from recent years. PMID- 26117444 TI - First molecular survey and novel genetic variants' identification of Anaplasma marginale, A. centrale and A. bovis in cattle from Tunisia. AB - Few data are available about the presence and distribution of Anaplasma species in cattle in North African countries. In this study prevalence, co-infections, risk factors and genetic diversity of Anaplasma species were evaluated in bovines from Northern Tunisia. A total of 232 cattle from 36 randomly selected farms in three Tunisian localities were investigated for the presence of Anaplasma species in blood by Real-time PCR and/or nested PCR. Overall infection rates of Anaplasma spp., Anaplasma marginale, Anaplasma centrale and Anaplasma bovis were 34.9%, 25.4%, 15.1%, and 3.9%, respectively. Anaplasma phagocytophilum was not detected in cattle. The most common co-infection pattern was an association of A. marginale and A. centrale (11.2%). Five cattle (2.1%) all reared in the sub-humid bioclimatic area, were co-infected by the three Anaplasma species. Molecular prevalence of Anaplasma infection varied significantly according to locality, bioclimatic area, tick infestation and type of breeding. Animals of the Holstein breed were less infected by A. marginale and A. centrale than other breeds. Genetic analysis of A. marginale msp4 gene indicated a high sequence diversity of Tunisian strains, suggesting a multiple introduction of infected cattle from different origins. Phylogenetic studies based on the 16S rRNA gene showed that the most prevalent A. centrale strains were closely related to the A. centrale vaccine strain. Moreover, all A. bovis variants clustered with other A. bovis sequences obtained from domestic and wild ruminant strains. This is the first molecular investigation on Anaplasma species in Tunisian cattle providing pivotal background for designing epidemiological studies and to develop control strategies in the country. PMID- 26117445 TI - A giant cavernous hemangioma of the liver extending into the pelvis. AB - INTRODUCTION: Giant cavernous hemangiomas are the most common tumors of the liver, ocurring in up to 20% of the general population. Given their benign course, asymptomatic nature and slow growth rate, treatment is rarely indicated. The case presented herein is unique as it describes an uncommon presentation of this common tumor and the circumstances in which surgical treatment is beneficial. PRESENTATION OF CASE: We present a case of a 66 year-old patient with prostate cancer referred for evaluation of a massive 37cm giant liver hemangioma, extending into the pelvis and in the planned field of radiation for prostate cancer, exhibiting rapid growth, and associated with significant symptomatology. Given these clinical characteristics, the patient was offered surgery and underwent a left trisectionectomy with an uneventful recovery. The patient's symptoms resolved and he was able to complete radiation to the pelvis. DISCUSSION: In the context of an unusual presentation, this case presentation reviews the typical clinical and imaging characteristics of giant liver hemangiomas and expands on the current indications for treatment, emphasizing the role of enucleation and resection for patients meeting appropriate indications. CONCLUSION: Although liver hemangiomas are extremely common, surgical treatment is rarely required. With appropriate indications, and when enucleation is not feasible or ideal, major liver resection is a safe alternative approach with excellent outcomes when performed in the right setting. PMID- 26117446 TI - Successful surgical repair of an ilio-iliac arteriovenous fistula associated with a ruptured common iliac artery aneurysm. AB - INTRODUCTION: We describe the case of an 86-year-old man with an ilio-iliac arteriovenous fistula (AVF) resulting from a ruptured aneurysm. This condition rarely occurs, has a high mortality rate, and was successfully treated via surgery. PRESENTATION OF CASE: The patient presented with a temporary loss of consciousness and left leg edema. A pulsatile abdominal mass with vascular murmur and thrill was detected. Enhanced computed tomography showed abdominal aortic and iliac aneurysms with left common iliac vein occlusion, and the left external iliac vein was easily seen through the AVF. We directly sutured the AVF and performed aneurysmectomy and prosthetic graft replacement. During surgery, placement of occlusive balloon catheters through the AVF minimized intraoperative bleeding. The patient recovered uneventfully, and swelling of the left leg was immediately reduced after surgery. DISCUSSION: Although rare, AVFs can be life threatening, and urgent treatment and intensive care are occasionally needed. Surgical management of AVF requires a definitive preoperative diagnosis and control of venous bleeding during surgery. Fulfilling these major requirements can potentially reduce morbidity and mortality in patients with AVFs. Interestingly, there was no sign of high-output heart failure throughout the treatment course due to compression of the aneurysm and consequent blood flow failure to the left iliac vein. CONCLUSION: Using the balloon occlusion technique, we were able to minimize blood loss during open repair. Use of multiple imaging modalities facilitates correct preoperative diagnosis and consequently improves surgical outcome. PMID- 26117447 TI - Acute pancreatitis secondary to duodeno-duodenal intussusception caused by a duodenal membrane, in a patient with intestinal malrotation. AB - Duodeno-duodenal intussusception is often caused by an intraluminal tumour. The condition is rare owing to the retroperitoneal fixation of the duodenum, which is sometime absent in cases of intestinal malrotation. We describe the case of a 19 year old man admitted to hospital with abdominal pain and vomiting. A CT scan revealed a duodeno-duodenal intussusception including the head of the pancreas, which was confirmed by laparotomy. The cause was found to be a duodenal membrane with a pinhole passage combined with non-rotation of the duodenum. PMID- 26117448 TI - Strangulated internal hernia by giant Meckel diverticulum presented as acute appendicitis. AB - INTRODUCTION: Internal hernia due to a Meckel diverticulum is a common presentation of bowel obstruction mostly seen in pediatric population. However, it has been stated that among 5% of the patients had a giant Meckel diverticulum (defined as a Meckel diverticulum with increased dimensions than the ones commonly found), being this condition very unusual. PRESENTATION OF CASE: We presented a 19 year old male with acute abdominal pain suggestive of appendicitis. During appendectomy we discovered ischemic and necrotic signs in a bowel segment, leading us to perform a laparotomy that revealed a portion of ischemic and necrotic jejunum, and another bowel segment with a strong adherence to the mesentery root that created an internal hernia. The internal hernia was reduced and the injured bowel portions were resected. Necrotic bowel samples were sent to the pathology department who posteriorly reported a giant Meckel diverticulum. The patient had an excellent recovery after procedure. DISCUSSION: After searching in PubMed for a similar association between Meckel diverticulum and internal hernia, we found few cases that reported a giant Meckel diverticulum and a low occurrence with internal hernias making our case not so common to find. CONCLUSION: We concluded that a giant Meckel diverticulum in association with mesenteric defects producing internal hernias are not common pathologies to find together in a patient as our research and case suggest. PMID- 26117449 TI - A rare case of splenic pseudoaneurysm in pediatric splenic blunt trauma patient: Review of diagnosis and management. AB - INTRODUCTION: Splenic pseudoaneurysms (SPA) are a rare but serious sequela of blunt traumatic injury to the spleen. Management of adult blunt splenic trauma is well-studied, however, in children, the management is much less well-defined. PRESENTATION OF CASE: A 15 year-old male presented with severe abdominal pain of acute onset after sustaining injury to his left side while playing football. FAST was positive for free fluid in the abdomen. Initial abdomen CT demonstrated a grade III/IV left splenic laceration with moderate to large hemoperitoneum with no active extravasation or injury to the splenic vessels noted. A follow-up CT angiography of the abdomen demonstrated a splenic hypervascular structure suspicious for a small pseudoaneurysm. Splenic arteriogram which demonstrated multiple pseudoaneurysms arising from the second order splenic artery branches which was angioembolized and treated. DISCUSSION & CONCLUSION: Questions still remain regarding the timing of repeat imaging for diagnosis of SPA following non operative blunt splenic trauma, which patients should be imaged, and how to manage SPA upon diagnosis. More clinical study and basic science research is warranted to study the disease process of SPA in pediatric patient. We believe that our proposed management algorithm timely detect formation of delayed SPA formation and addresses the possible fatal disease course of pediatric SPA. PMID- 26117450 TI - Multiple nodal locoregional recurrence of pheochromocytoma. AB - INTRODUCTION: Malignancy is present in 10% of pheochromocytomas (PCC) and is defined as local/vascular infiltration of surrounding tissues or the presence of chromaffin cells deposits in distant organs. The presence of isolated nodal recurrence is very rare and only 7 cases have been reported in the medical literature. PRESENTATION OF THE CASE: The case of a 32-y male with a symptomatic recurrence of a previously operated (2-years ago) PCC is presented. Radiological and functional imaging studies confirmed the presence of multiple nodules in the surgical site. A radical left nephrectomy with extensive lymphatic clearance in order to get an R0 resection was performed. The pathologist confirmed the diagnosis of massive locoregional nodal invasion. DISCUSSION: A detailed histological report and a thorough genetic study must be considered in every operated PCC in order to identify mutations and profiles of risk for malignancy. When recurrence or metastastic disease is suspected, imaging and functional exams are done in order to obtain a proper staging. Radical surgery for the metastatic disease is the only treatment that may provide prolonged survival. If an R0 resection is not possible, then a debulking surgery is a good option when the benefit/risk ratio is acceptable. CONCLUSION: Isolated lymph nodal recurrence is very rare in malignant PCC, with only 7 cases previously published. The role of surgery is essential to get long-term survival because provides clinical and functional control of the disease. PMID- 26117451 TI - (18)F-Fluorocholine PET-CT enables minimal invasive parathyroidectomy in patients with negative sestamibi SPECT-CT and ultrasound: A case report. AB - INTRODUCTION: Primary hyperparathyroidism is a common endocrine disorder for which the primary treatment is surgery. For minimal invasive parathyroidectomy adequate pre-operative imaging is essential. Conventional imaging is often inconclusive. There are reports that (18)F-fluorocholine PET-CT might be a superior imaging modality, however evidence is still very scarce. This is the first report of a case with negative ultrasound and sestamibi SPECT-CT imaging that underwent successful minimal invasive surgery because of (18)F-fluorocholine PET-CT. PRESENTATION OF CASE: A 57 year-old man presented to us with complaints of fatigue. Laboratory results showed a biochemical primary hyperparathyroidism and an additional DEXA-scan revealed osteopenia of the lumbar spine. Conventional imaging consisting of neck ultrasound and Tc-99m-sestamibi SPECT-CT was however unable to localize the pathological gland. Subsequent (18)F-fluorocholine PET-CT did clearly localize an adenoma dorsally of the left thyroid lobe which was removed at that exact location using minimal invasive parathyroidectomy. Histological examination confirmed the diagnosis adenoma and calcium levels remained normal at follow-up. DISCUSSION: There is clinical need for a superior imaging modality to detect pathological parathyroid glands to enable minimal invasive surgery. (18)F-Fluorocholine is widely available. CONCLUSION: (18)F Fluorocholine PET-CT is a promising new imaging modality for localizing parathyroid adenomas and enabling minimal invasive parathyroidectomy when conventional imaging fails to do. Clinicians should consider its use as a second line modality for optimal patient care. PMID- 26117452 TI - On-cartridge derivatization coupled with solid-phase extraction for the ultra sensitive determination of minodronic acid in human plasma by LC-MS/MS method. AB - Minodronic acid (MA) is a third-generation bisphosphonate (BP). Its high potency allows lower doses to be administered in clinical settings compared with other BPs, which results in extremely low systemic exposure. Therefore, it is essential to develop an ultra-sensitive bioassay for pharmacokinetics studies of MA. In this work, we used on-cartridge derivatization of MA with trimethylsilyldiazomethane to extract MA from plasma samples and improve its LC MS/MS behavior. The reaction produced a known derivative, tetramethylated MA, and a novel derivative, pentamethylated MA (PMMA). PMMA exhibited a better signal-to noise ratio, and was monitored for the quantification of MA. However, the derivatization yield of d4-PMMA was much lower and more variable than that of PMMA, which decreased the effectiveness of its correction function as an internal standard. Therefore, a two-cycle derivatization approach was introduced to increase its yield and improve the reproducibility. The calibration curves of MA showed good linearity over the range of 10.0-1000 pg/mL. A lower limit of quantification of 10.0 pg/mL was achieved with acceptable precision (<10.5%) and accuracy (5.0%). The intra- and inter-batch precision of quality control samples was <9.5%, and the accuracy ranged from -2.8% to 0.6%. The stability results showed that MA was stable in human plasma for 6h at room temperature (25 degrees C), for 115 days at -20 degrees C, during three freeze/thaw cycles (from -20 degrees C to 25 degrees C), and in post-preparative samples for 24h at 4 degrees C. The method was successfully used to characterize the pharmacokinetic profile of MA following an oral dose of 1.0mg MA hydrate to healthy volunteers (n=12). The proposed derivatization procedure was also extended to measure other BPs (risedronic acid and zoledronic acid) in human plasma at low pg/mL. PMID- 26117453 TI - [Nasally delivered drugs (corticosteroids and vaccines), ultra long-acting bronchodilators and inhaled therapies in an animal model]. AB - Inhaled therapies are widely prescribed. Several aspects of these treatments were considered during the 4th meeting of the aerosol therapy workgroup (GAT) of the French-speaking respiratory society (Societe de pneumologie de langue francaise [SPLF]). In this report, will be detailed the medications delivered by the nasal route, particularly corticosteroids and vaccines as well as the ultra long-acting beta2-agonists, and inhaled therapies for asthma due to allergy to cat dander. PMID- 26117454 TI - Exposure to arginine analog canavanine induces aberrant mitochondrial translation products, mitoribosome stalling, and instability of the mitochondrial proteome. AB - Impairment of mitochondrial protein homeostasis disrupts mitochondrial function and causes human diseases and aging, but the molecular mechanisms of protein synthesis and quality control in mammalian mitochondria are not fully understood. Here we demonstrate in human cells that misincorporation of an arginine analog, canavanine, during mitochondrial protein synthesis, induced aberrant translation products and destabilized the mtDNA-encoded proteome, leading to loss of mitochondrial respiratory chain complexes. Furthermore, in the presence of a high concentration of canavanine, mitoribosome stalling could be demonstrated. The stalling did not, however, occur at arginine codons, but downstream of those codons. In particular, two adjacent arginines induced the most prominent downstream stalling effect, with the distance between the arginine codons and the stalling peak corresponding roughly to the length of the ribosomal exit tunnel. These results suggest that misincorporated canavanine disrupted the proper folding of the hydrophobic nascent polypeptides within the exit tunnel or while being inserted into the inner mitochondrial membrane. The canavanine treatment provides a model system for studying the consequences of mitoribosome stalling and the responses to misfolded proteins exiting the mitochondrial ribosome. PMID- 26117455 TI - Role of S-adenosylhomocysteine in cardiovascular disease and its potential epigenetic mechanism. AB - Transmethylation reactions utilize S-adenosylmethionine (SAM) as a methyl donor and are central to the regulation of many biological processes: more than fifty SAM-dependent methyltransferases methylate a broad spectrum of cellular compounds including DNA, histones, phospholipids and other small molecules. Common to all SAM-dependent transmethylation reactions is the release of the potent inhibitor S adenosylhomocysteine (SAH) as a by-product. SAH is reversibly hydrolyzed to adenosine and homocysteine by SAH hydrolase. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. However, a major unanswered question is if homocysteine is causally involved in disease pathogenesis or simply a passive and indirect indicator of a more complex mechanism. A chronic elevation in homocysteine levels results in a parallel increase in intracellular or plasma SAH, which is a more sensitive biomarker of cardiovascular disease than homocysteine and suggests that SAH is a critical pathological factor in homocysteine-associated disorders. Previous reports indicate that supplementation with folate and B vitamins efficiently lowers homocysteine levels but not plasma SAH levels, which possibly explains the failure of homocysteine-lowering vitamins to reduce vascular events in several recent clinical intervention studies. Furthermore, more studies are focusing on the role and mechanisms of SAH in different chronic diseases related to hyperhomocysteinemia, such as cardiovascular disease, kidney disease, diabetes, and obesity. This review summarizes the current role of SAH in cardiovascular disease and its effect on several related risk factors. It also explores possible the mechanisms, such as epigenetics and oxidative stress, of SAH. This article is part of a Directed Issue entitled: Epigenetic dynamics in development and disease. PMID- 26117456 TI - Keap1-Nrf2 signalling in pancreatic cancer. AB - Transcription factor NF-E2 p45-related factor 2 (Nrf2, also called Nfe2l2), a master regulator of redox homeostasis, and its dominant negative regulator, Kelch like ECH-associated protein 1 (Keap1), together tightly control the expression of numerous detoxifying and antioxidant genes. Nrf2 and the 'antioxidant response element' (ARE)-driven genes it controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Upregulation of Nrf2 is, at least in part, K-Ras oncogene-driven and contributes to pancreatic cancer proliferation and chemoresistance. In this review, we aim to provide an overview of Keap1-Nrf2 signalling as it relates to pancreatic cancer, discussing the effects of inhibiting Nrf2 or Nrf2/ARE effector proteins to increase chemosensitivity. PMID- 26117457 TI - ECG-based estimation of dispersion of APD restitution as a tool to stratify sotalol-induced arrhythmic risk. AB - BACKGROUND: Increased spatial dispersion of restitution properties has been associated to arrhythmic risk. An ECG-based index quantifying restitution dispersion, DRest, is evaluated in patients who experienced Torsades de Pointes (TdP) under sotalol challenge and compared with the response in healthy subjects. METHODS AND RESULTS: ECG recordings were analyzed for quantification of DRest and QTc, among others biomarkers. DRest provides improved discrimination following sotalol administration between TdP and healthy subjects ([min-max]: [0.18-0.22] vs [0.02-0.12]), compared to other biomarkers including QTc ([436-548ms] vs [376 467ms]). Results in healthy subjects are in agreement with simulations of sotalol effects on a human tissue electrophysiological model. CONCLUSIONS: This case study supports the potential of DRest for improved arrhythmia risk stratification even with QTc values below 450ms. PMID- 26117458 TI - 5-Year Outcomes After Transcatheter Aortic Valve Implantation With CoreValve Prosthesis. AB - OBJECTIVES: The purpose of this analysis was to assess 5-year outcomes of transcatheter aortic valve implantation (TAVI) using the current technology of the self-expanding CoreValve prosthesis (Medtronic Inc., Minneapolis, Minnesota). BACKGROUND: There is a paucity of evidence on long-term durability of currently available transcatheter heart valves. METHODS: Starting in June 2007, all consecutive patients with severe aortic stenosis undergoing TAVI with the third generation 18-F CoreValve device in 8 Italian centers were prospectively included in the ClinicalService Project. For the purposes of this study, we included only consecutive patients with 5-year follow-up data available (n = 353) treated from June 2007 to August 2009. All outcomes were reported according to VARC (Valve Academic Research Consortium)-1 criteria. RESULTS: All-cause mortality rates at 1, 2, 3, 4, and 5 years were 21%, 29%, 38%, 48%, and 55.0%, respectively. Cardiovascular mortality rates at 1, 2, 3, 4, and 5 years were 10%, 14%, 19%, 23%, and 28.0%, respectively. The overall neurological event rate at 5 years was 7.5%, of which more than two-thirds occurred early after the procedure. During follow-up, there were 241 rehospitalizations for cardiovascular reasons in 164 (46%) patients. Among all rehospitalizations, acute heart failure was the most frequently reported (42.7%), followed by requirement of permanent pacemaker implantation (17.4%). On echocardiography, mean transaortic gradients decreased from 55.6 +/- 16.8 mm Hg (pre-TAVI) to 12.8 +/- 10.9 mm Hg (5-year post-TAVI) (p < 0.001). Late prosthesis failure occurred in 5 cases (1.4%); among these, redo TAVI was successfully carried out in 2 patients (0.6%) presenting with symptomatic prosthesis restenosis. The remaining 3 cases of prosthesis failure did not undergo further invasive interventions. Ten patients (2.8%) showed late mild stenosis with a mean transaortic gradient ranging from 20 to 40 mm Hg. No other cases of structural or nonstructural valvular deterioration were observed. Valve thrombosis or late valve embolization were not reported. CONCLUSIONS: TAVI with the currently adopted CoreValve generation was associated with sustained clinical outcomes up to 5-year follow-up, with a low rate (1.4%) of significant prosthetic valve degeneration. The procedure appears to be an adequate and lasting resolution of aortic stenosis in selected high-risk patients. PMID- 26117459 TI - Percutaneous Transcatheter Closure for Aortic Puncture and Paravalvular Leak Closure With the New Amplatzer III Device. PMID- 26117460 TI - Iatrogenic Aortocoronary Arteriovenous Fistula: Percutaneous Management of a Surgical Complication. PMID- 26117461 TI - Treatment of Heart Failure With Associated Functional Mitral Regurgitation Using the ARTO System: Initial Results of the First-in-Human MAVERIC Trial (Mitral Valve Repair Clinical Trial). AB - OBJECTIVES: MAVERIC (Mitral Valve Repair Clinical Trial) reports the safety and efficacy of the ARTO system in patients with symptomatic heart failure and functional mitral regurgitation (FMR). BACKGROUND: The ARTO system percutaneously modifies the mitral annulus to improve leaflet coaptation in FMR. METHODS: The MAVERIC trial is a prospective, nonrandomized first-in-human study. Key inclusion criteria were systolic heart failure New York Heart Association functional classes II to IV, FMR grade >=2+, left ventricular (LV) ejection fraction <=40%, LV end-diastolic diameter >50 mm and <=75 mm. Exclusion criteria were clinical variables that precluded feasibility of the ARTO procedure. Primary outcomes were safety (30-day major adverse events) and efficacy (MR reduction, LV volumes, and functional status). RESULTS: Eleven patients received the ARTO system, and there were no procedural adverse events. From baseline to 30 days, there were meaningful improvements. Effective regurgitant orifice area decreased from 30.3 +/- 11.1 mm(2) to 13.5 +/- 7.1 mm(2) and regurgitant volumes from 45.4 +/- 15.0 ml to 19.5 +/- 10.2 ml. LV end-systolic volume index improved from 77.5 +/- 24.3 ml/m(2) to 68.5 +/- 21.4 ml/m(2), and LV end-diastolic volume index 118.7 +/- 28.6 ml/m(2) to 103.9 +/- 21.2 ml/m(2). Mitral annular anteroposterior diameter decreased from 45.0 +/- 3.3 mm to 38.7 +/- 3.0 mm. Functional status was 81.8% New York Heart Association functional class III/IV improving to 54.6% functional class I/II. At 30 days, there were 2 adverse events: 1 pericardial effusion requiring surgical drainage; and 1 asymptomatic device dislodgement. CONCLUSIONS: The ARTO system is a novel transcatheter device that can be used safely with meaningful efficacy in the treatment of FMR. (Mitral Valve Repair Clinical Trial [MAVERIC]; NCT02302872). PMID- 26117462 TI - Outcomes of Comatose Cardiac Arrest Survivors With and Without ST-Segment Elevation Myocardial Infarction: Importance of Coronary Angiography. AB - OBJECTIVES: The aim of this study was to compare outcomes and coronary angiographic findings in post-cardiac arrest patients with and without ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The 2013 STEMI guidelines recommend performing immediate angiography in resuscitated patients whose initial electrocardiogram shows STEMI. The optimal approach for those without STEMI post cardiac arrest is less clear. METHODS: A retrospective evaluation of a post cardiac arrest registry was performed. RESULTS: The database consisted of 746 comatose post-cardiac arrest patients including 198 with STEMI (26.5%) and 548 without STEMI (73.5%). Overall survival was greater in those with STEMI compared with those without (55.1% vs. 41.3%; p = 0.001), whereas in all patients who underwent immediate coronary angiography, survival was similar between those with and without STEMI (54.7% vs. 57.9%; p = 0.60). A culprit vessel was more frequently identified in those with STEMI, but also in one-third of patients without STEMI (80.2% vs. 33.2%; p = 0.001). The majority of culprit vessels were occluded (STEMI, 92.7%; no STEMI, 69.2%; p < 0.0001). An occluded culprit vessel was found in 74.3% of STEMI patients and in 22.9% of no STEMI patients. Among cardiac arrest survivors discharged from the hospital who had presented without STEMI, coronary angiography was associated with better functional outcome (93.3% vs. 78.7%; p < 0.003). CONCLUSIONS: Early coronary angiography is associated with improved functional outcome among resuscitated patients with and without STEMI. Resuscitated patients with a presumed cardiac etiology appear to benefit from immediate coronary angiography. PMID- 26117463 TI - 1-Year Results of the ZEPHYR Registry (Zilver PTX for the Femoral Artery and Proximal Popliteal Artery): Predictors of Restenosis. AB - OBJECTIVES: This study sought to assess the rate and predictors of 1-year restenosis after drug-eluting stent implantation for femoropopliteal (FP) lesions in patients with peripheral arterial disease. BACKGROUND: Zilver PTX, a paclitaxel-eluting stent for FP lesions, provides superior outcomes to angioplasty and bare-metal stents in clinical trials. However, its real-world outcomes and the associated features remain unclear. METHODS: This was a prospective multicenter study enrolling 831 FP lesions (797 limbs, 690 patients) treated by Zilver PTX implantation. The primary endpoint was 1-year restenosis. Secondary endpoints included major adverse limb event and stent thrombosis. RESULTS: Mean lesion length was 17 +/- 10 cm. One-year restenosis, major adverse limb event, and stent thrombosis rates were 37%, 22%, and 2%, respectively. The generalized linear mixed model showed that lesion length >=16 cm assessed by angiography and distal external elastic membrane area <=27 mm(2) and minimum stent area <=12 mm(2) assessed by intravascular ultrasound were independent risk factors for restenosis. One-year restenosis rates were 15% in cases with none of these risk factors and 50% in those with >=2 risk factors. CONCLUSIONS: The current study demonstrated 1-year real-world outcomes after drug-eluting stent treatment for FP lesions, including challenging ones in clinical practice. Lesion length, external elastic membrane area, and minimum stent area were independent predictors for restenosis. (Zilver PTX for the Femoral Artery and Proximal Popliteal Artery-Prospective Multicenter Registry [ZEPHYR]; UMIN000008433). PMID- 26117464 TI - A Combined Optical Coherence Tomography and Intravascular Ultrasound Study on Plaque Rupture, Plaque Erosion, and Calcified Nodule in Patients With ST-Segment Elevation Myocardial Infarction: Incidence, Morphologic Characteristics, and Outcomes After Percutaneous Coronary Intervention. AB - OBJECTIVES: This study sought to evaluate the incidence of plaque rupture (PR), plaque erosion (PE), and calcified nodule (CN) using optical coherence tomography (OCT) in patients with ST-segment elevation myocardial infarction (STEMI); to compare detailed morphologic plaque characteristics of PR, PE, and CN with optical coherence tomography and intravascular ultrasound; and to compare the post-procedure outcomes among PR, PE, and CN. BACKGROUND: The incidence and detailed morphologic characteristics of PR, PE, and CN in STEMI patients and their outcome after percutaneous coronary intervention (PCI) are unknown. METHODS: A total of 112 STEMI patients who underwent PCI within 24 h [corrected] from symptom onset were included. Both optical coherence tomography and intravascular ultrasound were performed following aspiration thrombectomy. RESULTS: The incidence of PR, PE, and CN was 64.3%, 26.8%, and 8.0%, respectively. PE and CN, compared with PR, had more fibrous plaque (p < 0.001 and p < 0.001) and less thin-cap fibroatheroma (p < 0.001 and p < 0.001) as well as smaller plaque burden (p = 0.003 and p = 0.001) and remodeling index (p = 0.003 and p < 0.001). PE had greater plaque eccentricity index than PR and CN (p < 0.001 and p < 0.001). CN had greater calcified arc and shallower calcium than PR (p < 0.001 and p < 0.001) or PE (p < 0.001 and p < 0.001). More than one-half of CN had negative remodeling. PE had a lower incidence of no-reflow phenomenon after PCI than PR (p = 0.011). CONCLUSIONS: PE was the underlying mechanism in one-fourth of STEMI. PE was characterized by eccentric fibrous plaque. CN was characterized by superficial large calcium and negative remodeling. PE was associated with less microvascular damage after PCI. PMID- 26117465 TI - Comparison of Neoatherosclerosis and Neovascularization Between Patients With and Without Diabetes: An Optical Coherence Tomography Study. AB - OBJECTIVES: This study aimed to investigate the characteristics of neoatherosclerosis (NA) in patients with diabetes mellitus (DM) after drug eluting stent (DES) implantation using optical coherence tomography. BACKGROUND: NA is an important substrate for stent failure. In vivo NA characteristics in DM patients have not been investigated. METHODS: A total of 397 patients with 452 DES who underwent follow-up optical coherence tomography examination after DES implantation were enrolled. Characteristics of NA were compared between DM and non-DM patients. Neovascularization was defined as signal-poor holes or tubular structures with a diameter of 50 to 300 MUm. RESULTS: A total of 123 DES with NA lesions in 115 patients were identified. The incidence of NA was similar between DM and non-DM patients (29.6% vs. 28.6%; p = 0.825). Compared with the non-DM group, neovascularization was more frequently observed in the DM group (55.1% vs. 32.4%; p = 0.012). The multivariate logistic model demonstrated that DM (odds ratio: 3.00; 95% confidence interval: 1.31 to 6.81; p = 0.009) and follow-up duration (odds ratio: 1.03; 95% confidence interval: 1.02 to 1.05; p < 0.001) were the independent predictors for neovascularization in NA lesions. DM patients with glycated hemoglobin >=7.0% had a higher prevalence of thin-cap fibroatheroma compared with those with glycated hemoglobin <7.0% (40.0% vs. 8.3%; p = 0.01). CONCLUSIONS: The incidence of NA was similar between patients with and without DM. Neovascularization in NA lesions was more frequent in those with DM. Poorly controlled DM patients had a higher incidence of thin-cap fibroatheroma, compared with those with well-controlled DM. PMID- 26117466 TI - Pharmacodynamic Effects of Ticagrelor Dosing Regimens in Patients on Maintenance Ticagrelor Therapy: Results From a Prospective, Randomized, Double-Blind Investigation. AB - OBJECTIVES: The aim of this study was to assess the impact of ticagrelor dosing regimens on pharmacodynamic (PD) profiles in patients on maintenance ticagrelor therapy. BACKGROUND: Many patients on maintenance P2Y12-inhibiting therapies may require coronary revascularization procedures, raising a common clinical question with regard to the dosing regimen of the P2Y12-inhibiting agent to be used. To date, investigations assessing dosing regimens of P2Y12 receptor inhibitors in patients on maintenance therapy have been only assessed with thienopyridines, but not with ticagrelor. METHODS: This was a prospective, randomized, double-blind, placebo-controlled study assessing the PD effects of 2 dosing regimens of ticagrelor in patients on standard aspirin and ticagrelor maintenance therapy. A total of 60 patients were randomized to either 90 mg (maintenance dose [MD] group) or 180 mg (loading dose [LD] group) dose of ticagrelor. PD assessments were conducted at 3 time points (baseline, 1 h and 4 h). PD assessments were defined according to the platelet reactivity index (PRI) (vasodilator-stimulated phosphoprotein phosphorylation assay), P2Y12 reaction unit (VerifyNow P2Y12 assay) and adenosine diphosphate-induced platelet aggregation by light transmittance aggregometry. RESULTS: There were no differences in baseline levels of platelet reactivity with all assays. Intergroup comparisons by means of repeated-measures analysis adjusted for baseline PRI values showed that the LD group had significantly lower PRI levels compared with the MD group during the overall study time course (p = 0.031). Consistent findings were found for P2Y12 reaction unit (p = 0.026) and light transmittance aggregometry (p = 0.004). Intragroup comparisons showed that a more prompt and sustained platelet inhibitory effect was achieved more consistently with an LD regimen compared with a MD regimen. CONCLUSIONS: In patients on maintenance ticagrelor therapy, a 180 mg LD regimen of ticagrelor is associated with more potent and prompt platelet inhibition compared with a 90-mg MD. (Impact of Ticagrelor Re-Load Pharmacodynamic Profiles; NCT01731041). PMID- 26117467 TI - Instant Stent-Accentuated 3-Dimensional Optical Coherence Tomography of Struts Pulled Up by Pulling Stuck Wire and Folded by Kissing Balloon Dilation. PMID- 26117468 TI - Tricuspid Valve Replacement: A Percutaneous Transfemoral Valve-in-Ring Approach. PMID- 26117469 TI - Drug-Eluting Stent Implantation on Calcified Nodule: Ex Vivo Intravascular Images and Histopathology. PMID- 26117470 TI - Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: A Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral In-Stent Restenosis. AB - OBJECTIVES: This study sought to compare the effect of paclitaxel-coated balloon (PCB) concentration on tissue levels and vascular healing using 3 different PCB technologies (In.Pact Pacific = 3 MUg/mm(2), Lutonix = 2 MUg/mm(2) and Ranger = 2 MUg/mm(2)) in the experimental setting. BACKGROUND: The optimal therapeutic dose for PCB use has not been determined yet. METHODS: Paclitaxel tissue levels were measured up to 60 days following PCB inflation (Ranger and In.Pact Pacific) in the superficial femoral artery of healthy swine (18 swine, 36 vessels). The familial hypercholesterolemic swine model of superficial femoral artery in-stent restenosis (6 swine, 24 vessels) was used in the efficacy study. Two weeks following bare-metal stent implantation, each in-stent restenosis site was randomly treated with a PCB or an uncoated control balloon (Sterling). Quantitative vascular analysis and histology evaluation was performed 28 days following PCB treatment. RESULTS: All PCB technologies displayed comparable paclitaxel tissue levels 4 h following balloon inflation. At 28 days, all PCB had achieved therapeutic tissue levels; however, the In.Pact PCB resulted in higher tissue concentrations than did the other PCB groups at all time points. Neointimal inhibition by histology was decreased in all PCB groups compared with the control group, with a greater decrease in the In.Pact group. However, the neointima was more mature and contained less peri-strut fibrin deposits in both 2 MUg/mm(2) PCB groups. CONCLUSIONS: Compared with the clinically established PCB dose, lower-dose PCB technologies achieve lower long-term tissue levels but comparable degrees of neointimal inhibition and fewer fibrin deposits. The impact of these findings in restenosis reduction and clinical outcomes needs to be further investigated. PMID- 26117472 TI - Implementing the End TB Strategy: Well begun will be half done. PMID- 26117471 TI - "Virtual" (Computed) Fractional Flow Reserve: Current Challenges and Limitations. AB - Fractional flow reserve (FFR) is the "gold standard" for assessing the physiological significance of coronary artery disease during invasive coronary angiography. FFR-guided percutaneous coronary intervention improves patient outcomes and reduces stent insertion and cost; yet, due to several practical and operator related factors, it is used in <10% of percutaneous coronary intervention procedures. Virtual fractional flow reserve (vFFR) is computed using coronary imaging and computational fluid dynamics modeling. vFFR has emerged as an attractive alternative to invasive FFR by delivering physiological assessment without the factors that limit the invasive technique. vFFR may offer further diagnostic and planning benefits, including virtual pullback and virtual stenting facilities. However, there are key challenges that need to be overcome before vFFR can be translated into routine clinical practice. These span a spectrum of scientific, logistic, commercial, and political areas. The method used to generate 3-dimensional geometric arterial models (segmentation) and selection of appropriate, patient-specific boundary conditions represent the primary scientific limitations. Many conflicting priorities and design features must be carefully considered for vFFR models to be sufficiently accurate, fast, and intuitive for physicians to use. Consistency is needed in how accuracy is defined and reported. Furthermore, appropriate regulatory and industry standards need to be in place, and cohesive approaches to intellectual property management, reimbursement, and clinician training are required. Assuming successful development continues in these key areas, vFFR is likely to become a desirable tool in the functional assessment of coronary artery disease. PMID- 26117473 TI - Viewpoint: Is it right time for undergraduate curriculum change based on our National Health Programmes--Tuberculosis Programme a perfect example? PMID- 26117474 TI - Ocular manifestations of tuberculosis. AB - Tuberculosis (TB) is a chronic debilitating infection which is caused by Mycobacteriumn tuberculosis and other mycobacteria. Mycobacterium tuberculosis affects predominantly the lungs although it can affect every organ of the body. Two billion people are affected by tuberculosis. Majority of tuberculosis cases and related deaths occur in Asia. Tuberculosis most commonly occurs in people belonging to the low socio-economic status. Crowding, poor healthcare, unemployment and poor knowledge about basic sanitation increase the risk of acquiring the infection. India is endemic for tuberculosis with 256/lakh population. TB can affect majority of the structures of the eye with marked variability of the lesions. This review will focus on the clinical presentation and management of ocular TB. PMID- 26117475 TI - A study of adherence to DOTS regimen among pulmonary tuberculosis patients in West Tripura District. AB - BACKGROUND: Noncompliance to the DOTS regimen leads to treatment failure, relapse, MDR tuberculosis, XDR tuberculosis etc. requiring more prolonged & expensive therapy. AIM: To assess the adherence rate among pulmonary tuberculosis patients in west Tripura district and to study the factors affecting adherence to DOTS regimen among pulmonary tuberculosis patients. MATERIAL AND METHODS: This community based cross-sectional study was conducted among 220 pulmonary tuberculosis patients registered for treatment with DOTS therapy; under six randomly selected DMC of West Tripura District. RESULTS: The study revealed that the adherence rate among the pulmonary TB patients was 84.50 percent. Male tuberculosis patients had 87.10 percent less chance of being adherent to the DOTS regimen in reference to females, and Cat I patients were 8.96 times (C.I. 2.689 29.857) more adherent to the therapy compared to the retreatment cases. Again, patients whose continuation phase was supervised as per the guidelines of DOTS were 12.07 times more adherent to the therapy. PTB patients who had the knowledge of supervised therapy in DOTS and curability of the disease, were 4.70 times (C.I. 1.39-15.79) and 9.39 times (C.I. 1.03-85.99) more adherent to the therapy, respectively. CONCLUSION: The study showed good adherence to the regimen among pulmonary tuberculosis patients in spite of being a difficult area. It may also help in planning and implementation of tuberculosis control measures by addressing and overcoming the barriers regarding treatment completion. PMID- 26117477 TI - Rapid identification of Mycobacterium tuberculosis complex in clinical isolates by combining presumptive cord formation and MPT64 Antigen Immunochromatographic Assay. AB - PURPOSE: Combining the results of presumptive cord formation in smear and MPT64 Antigen Immunochromatographic Assay has been suggested to reduce the false negative and positive rates for identification of Mycobacterium tuberculosis (MTB) complex in liquid culture. This study was done to evaluate the clinical utility of combining the results of the two tests for rapid identification MTB complex in mycobacterial isolates. METHODS: 484 isolates of mycobacteria obtained in MGIT culture were identified using presumptive cord formation in smear and further by MPT64 Antigen ICT assay. Result obtained were analyzed taking PNB inhibition test as the reference standard. RESULTS: Combining the results of the two tests, 464 (95.9%) isolates were correctly identified while discrepant results were obtained in 20 (4.1%) isolates. When the results of the two tests were intersected, the specificity and PPV was 100%, but the sensitivity decreased to 96.4% and the NPV to 68.6%. On the other hand, when the results of the two methods were combined, the sensitivity and NPV was 100%, but the specificity decreased to 88.6% and the PPV to 99.1%. CONCLUSION: Presumptive cord formation and MPT64 antigen ICT assay can be used in combination for identification of MTB complex. When both the test are positive, the culture can be reported to contain MTB complex. If both the tests are negative, the culture should be reported to contain NTM. Only when discrepant results are obtained by the two tests, further evaluation is necessary to ensure an accurate diagnosis. PMID- 26117476 TI - Blood levels of isoniazid in Indian children with tuberculosis. AB - BACKGROUND: Under the Revised National Tuberculosis Control Program (RNTCP) in India children are receiving antituberculosis treatment (ATT) as per a weight band system. In this children may be receiving antituberculosis drugs in doses which may be more or less than that recommended in mg/kg body weight doses. The recommended dose of isoniazid (INH) for intermittent therapy under the RNTCP is 8 12 mg/kg body weight and by the World Health Organization (WHO) for daily therapy is 10-15 mg/kg body weight. AIMS: To evaluate the blood levels and pharmacokinetics of INH, in children suffering from tuberculosis, at doses administered under the weight band system of the Revised National Tuberculosis Control Program (RNTCP) 2009 of India. DESIGN: Prospective, open label, non randomized single-dose study conducted in 20 children in the age group 5-12 years attending the outpatient, chest clinic of a tertiary care hospital. RESULTS: Group I (n = 8) included children who received INH in a dose of 10 mg/kg body weight or more and Group II (n = 12) included those who received INH in a dose less than 10 mg/kg body weight. The mean peak INH concentration (Cmax) was 6.03 +/- 1.4 MUg/mL and this was achieved in 2 hours (Tmax). The mean serum INH concentration was significantly higher in children who received INH in dose more than 10 mg/kg (Group I) as compared to those who received INH in doses lesser than 10 mg/kg body weight (Group II) at all-time points except at 2 hours (P < 0.05). The Cmax was also lower in Group II patients in comparison to Group I patients. Area under the concentration time curve (AUC) was significantly lower in Group II patients (P value 0.002). The elimination half-life of INH was 4.3 +/ 0.4 h, elimination rate constant 0.16 +/- 0.01/h, the volume of distribution 44.05 +/- 5.3 L and clearance 7.1 +/- 0.8 L/h. CONCLUSIONS: Lower blood levels and AUC of INH were achieved in children receiving doses of INH lesser than 10 mg/kg body weight. Long elimination half-life of INH is indicative of a slower rate of metabolism. Lower INH levels despite a slower rate of drug metabolism indicate caution with the INH doses being administered to children for intermittent therapy under the RNTCP. PMID- 26117478 TI - Home based care to multi-drug resistant tuberculosis patients: A pilot study. AB - BACKGROUND: India is a high tuberculosis burden and large population setting country. Multidrug-resistant tuberculosis patient has to undergo 24-27 months treatment and is expected to adhere to it. There is a need to increase compliance of MDR Regimen in MDR-TB cases, to prevent its further spread. The present study focuses on describing the role of home care support with counseling in the outcome of MDR-TB patients, in Delhi, India. MATERIAL AND METHODS: This is a prospective study carried out at a Community Health Centre, Delhi, involving 113 MDR-TB patients as and when they got registered with DOTS Plus centres, in two government hospitals of Delhi between August 2009 and March 2010. The study period was August 2009 to October 2012. These patients received daily MDR Regimen from their respective DOTS Providers. The patients' names and addresses were taken from the lists supplied by these hospitals. Final analysis was carried out for 101 MDR-TB cases. RESULTS: Out of 101 patients treatment outcomes were: 69.3% cured and 2.0% treatment completed (treatment success rate 71.3%). A low default rate of 6.9% was seen which is assumed to be due to the home based care. CONCLUSION: These results indicate that Home based care with counseling support is an important intervention in management of MDR-TB patients and it needs to be substantiated by further research. PMID- 26117479 TI - A study on assessment of symptoms and functionality in DOTS cured patients in two districts of Garhwal, Uttarakhand. AB - BACKGROUND: In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease. India has achieved the target of a case detection rate of 70% and a cure rate of 85% through the nationwide Directly Observed Treatment Short Course (DOTS) strategy. Tuberculosis may generate residual lesions in the course of its pathology, which impair the functionality of the patient even after achieving "cure" or "treatment completion". AIMS: To assess the presence of symptoms and functionality of tuberculosis patients who had completed the treatment or had been declared as cured under Revised National Tuberculosis Programme (RNTCP). METHODS: The present study was a cross sectional study. It was conducted in the two Tuberculosis Units (TUs) of Rudraprayag and Pauri in Garhwal region of Uttarakhand among the people who had completed treatment under DOTS or had been declared as cured under RNTCP in last one year. RESULTS: Even at the completion of the treatment about 37% had cough, 25% had expectoration, 6% had hemoptysis, more than 50% had chest pain and 65% had breathlessness. The mean distance walked by the participants in six minutes was 363.5 +/- 58.2 m with a range of 245-490 m. CONCLUSIONS: The persistence of symptoms indicate that the functionality of DOTS cured patients remains compromised even after days and months of treatment completion, thereby necessitating measures for the improvement of the overall health of the patients rather than just the microbiological cure. PMID- 26117480 TI - Leptin level correlates with obesity and health related quality of life in obstructive sleep apnea syndrome patients. AB - BACKGROUND: Leptin takes part in regulation of energy balance, neuronal functions, pain and mood. It may act as intermediary marker for various components of HRQOL in patients of obstructive sleep apnea syndrome. AIMS: To document the correlation among leptin levels, obesity and HRQoL in OSAS patients. METHODS: A tertiary care hospital based cross-sectional study was done in 224 subjects aged 18-65 years, after taking informed consent. Subjects with previous history of smoking, Liver disease, COPD, CHD, T2 DM, asthma, cancer, end stage renal disease, heart failure, any endocrine disorder including Cushing syndrome, thyroid, on systemic steroid or any continuous medication for last 6 months, on dieting or suffering from any disability condition (other than obesity and OSAS) affecting their HRQoL were excluded from the study. All subjects underwent Polysomnography. Leptin assay was done by ELISA method. Hindi version of HRQoL tool SF-36 was used to evaluate HRQoL. RESULTS: SPSS 20 was used to analyse data. Three groups (AHI <5, 5 to 15 and >15) were compared. Significant differences were observed in BMI, NC, WC, WHR and ESS. Differences were not significant in sleep architecture and Leptin level. SF-36 HRQoL, scores were observed decreased with increase in severity of disease. Leptin level was found significantly correlated with "Role limitations due to physical health problems", "Social functioning", Hypopnea and obesity indices. CONCLUSIONS: In these subjects Obesity indices are the most important correlates of Leptin level. Oxygen desaturation indices with exception of Hypopnea and HRQoL may not be exclusively correlated to leptin levels. PMID- 26117481 TI - Tubercular prostate abscess in an immunocompetent patient. AB - Prostate tuberculosis is an infrequent manifestation of genitourinary tuberculosis Complications like prostate abscess, perineal fistula, sinus can occur in immunocompromised individuals. Various predisposing factors like diabetes, bladder outlet obstruction, chronic renal failure can lead to prostate abscess. TRUS (Transrectal USG) is one of the tools useful for the diagnosis of prostatic abscess. We present our case, 57 year man, ethanolic with features of chronic liver disease and pulmonary tuberculosis which disseminated to prostate, developed abscess presenting as pyrexia of unknown origin. PMID- 26117482 TI - Iatrogenic Mycobacterium abscessus infection in a trigger finger. AB - An immunocompetent 63-year-old lady developed Mycobacterium abscessus soft tissue infection of the hand following local corticosteroid injection for trigger finger. The patient was successfully treated with repeated radical debridement and prolonged antimicrobial therapy. Atypical mycobacterial infections, including those caused by M. abscessus, albeit rare, should be considered in cases of late onset indolent infection following local injury surgical procedures, and injections. Clinical vigilance, timely diagnosis, combined directed antimicrobial treatment, coupled with adequate surgical debridement are key for successful management. PMID- 26117483 TI - Intrathoracic goitre associated with pulmonary tuberculosis. AB - Intrathoracic goitre is an uncommon condition which usually occurs in females in the fifth decade. It can cause compression of several mediastinal structures. A 42-year-old female with goitre since childhood was evaluated for dry cough, occasional wheezing and low grade fever. Imaging showed patchy airspace opacities with cavitation in left lung. Imaging of the neck revealed retrosternal extension of the goitre. Stains and cultures of bronchial aspirate were positive for Mycobacterium tuberculosis. A diagnosis of pulmonary tuberculosis with intrathoracic goitre was established, an unusual association. PMID- 26117484 TI - Yield of pulmonary tuberculosis cases by symptoms: Findings from a community survey in Madhya Pradesh, central India. AB - A cross-sectional tuberculosis prevalence survey was undertaken in Jabalpur district, Madhya Pradesh, central India. All individuals were questioned for chest symptoms. Sputum samples were collected and examined for microscopy and culture. Overall prevalence of sputum positive pulmonary tuberculosis was found to be 255.3 per 100,000 population. Cough, with or without other symptoms, was present in 75.5% individuals and yielded 88.2% of the detected pulmonary tuberculosis cases. Elicitation of a previous history of treatment yielded 5.9%, and chest pain 4.5% cases. History of fever alone yielded no cases. The findings suggest that a history of fever alone may be safely excluded from the list of symptoms to be elicited in future TB prevalence surveys in India. PMID- 26117485 TI - Profile of NGOs involved in management of MDR TB in Mumbai before rollout of DOTS Plus. PMID- 26117486 TI - Effects of an unloader knee brace on knee-related symptoms and function in people with post-traumatic knee osteoarthritis after anterior cruciate ligament reconstruction. AB - BACKGROUND AND PURPOSE: This pilot study evaluated the immediate and four-week effects of an unloader knee brace on knee-related symptoms and performance-based function in people with knee osteoarthritis (OA) after anterior cruciate ligament reconstruction (ACLR). METHODS: Individuals with knee OA, five to 20years post ACLR, were recruited for two within-subject randomized studies: immediate effects (n=18) and four-week effects (n=11). Patient-reported knee-related symptoms (knee pain, perceived task difficulty, confidence, stability) were assessed during hop for distance and step-down tests, while performance-based function was assessed with hopping distance under three conditions: i) no brace; ii) unadjusted brace (sagittal plane support); and iii) adjusted brace (sagittal plane support with varus/valgus readjustment). Participants in the four-week brace effect study were randomized to wear the unadjusted or adjusted brace for four weeks after baseline (no brace) testing, and repeated tests in their allocated brace at four-week follow-up. Friedman tests evaluated differences between the three brace conditions for each variable for the immediate brace effect study (p<0.05), and Wilcoxon signed-rank tests evaluated differences between no brace and allocated brace for the four-week study (p<0.05). RESULTS: The adjusted and unadjusted unloader braces produced immediate improvements in knee confidence during hop for distance, and knee pain during step-down. Following the four-week brace intervention, the allocated brace improved knee confidence, perceived task difficulty and stability during hop for distance; and knee pain, perceived task difficulty, confidence, and stability during step-down. CONCLUSIONS: The unloader knee brace, adjusted or unadjusted, has the potential to improve knee-related symptoms associated with knee OA after ACLR. PMID- 26117487 TI - Recent evolution of learnability in American English from 1800 to 2000. AB - Concreteness-the psycholinguistic property of referring to a perceptible entity enhances processing speed, comprehension, and memory. These represent selective filters for cognition likely to influence language evolution in competitive language environments. Taking a culturomics approach, we use multiple language corpora representing more than 350 billion words combined with concreteness norms for over 40,000 English words and demonstrate a systematic rise in concrete language in American English over the last 200years, both within and across word classes (nouns, verbs, and prepositions). Comparisons between new and old concreteness norms indicate this is not explained by semantic bleaching, but we find some evidence that the rise is related to changes in population demographics and may be associated with increasing numbers of second language learners or attention economics in response to crowding in the language market. We also examine the influence of gender and literacy. In sum, we demonstrate evolution in the psycholinguistic structure of American English, with a well-established impact on cognitive processing, which is likely to permeate modern language use. PMID- 26117488 TI - What makes words special? Words as unmotivated cues. AB - Verbal labels, such as the words "dog" and "guitar," activate conceptual knowledge more effectively than corresponding environmental sounds, such as a dog bark or a guitar strum, even though both are unambiguous cues to the categories of dogs and guitars (Lupyan & Thompson-Schill, 2012). We hypothesize that this advantage of labels emerges because word-forms, unlike other cues, do not vary in a motivated way with their referent. The sound of a guitar cannot help but inform a listener to the type of guitar making it (electric, acoustic, etc.). The word "guitar" on the other hand, can leave the type of guitar unspecified. We argue that as a result, labels gain the ability to cue a more abstract mental representation, promoting efficient processing of category members. In contrast, environmental sounds activate representations that are more tightly linked to the specific cause of the sound. Our results show that upon hearing environmental sounds such as a dog bark or guitar strum, people cannot help but activate a particular instance of a category, in a particular state, at a particular time, as measured by patterns of response times on cue-picture matching tasks (Exps. 1 2) and eye-movements in a task where the cues are task-irrelevant (Exp. 3). In comparison, labels activate concepts in a more abstract, decontextualized way-a difference that we argue can be explained by labels acting as "unmotivated cues". PMID- 26117489 TI - Providing optimal cardiovascular and thoracic critical care in the Great White North. PMID- 26117490 TI - Surgery for anomalous aortic origin of a coronary artery: More is better? PMID- 26117491 TI - A new outlet for pulmonary arterial hypertension. PMID- 26117492 TI - Omalizumab therapy for refractory allergic fungal rhinosinusitis patients with moderate or severe asthma. AB - PURPOSE: 1. To assess the efficacy of omalizumab therapy in improving sinonasal outcomes in refractory allergic fungal rhinosinusitis (AFRS) patients with moderate or severe asthma. 2. To determine if omalizumab therapy reduces the usage of corticosteroids or antifungal therapy in AFRS patients METHOD: DESIGN: The clinical charts of patients with AFRS with moderate or severe asthma who received at least three subcutaneous injections of omalizumab therapy between 1st January 2012 and 1st May 2014 were retrospectively reviewed. These patients had undergone bilateral functional endoscopic sinus surgery (FESS) and failed adjunct medical treatments (oral or topical corticosteroids and/or antifungal therapy) prior to omalizumab therapy. RESULTS: Seven patients met the inclusion criteria and were included in this study. The mean age of the patients was 48.14. The average number of subcutaneous omalizumab injections was 7.57 (range 6-11) with a mean dosage of 287mg (range 225-375mg). The mean pre-omalizumab treatment Sino Nasal Outcome Test-22 (SNOT-22) score was 52.14 while the mean post-omalizumab treatment SNOT-22 score was 35.86 (31% improvement). The mean pre-omalizumab therapy Phillpott-Javer endoscopic score (over the last one year before omalizumab therapy) was 36 while the mean post-omalizumab therapy endoscopic score (from the last clinic visit) was 14 (61% improvement). Omalizumab therapy reduced the dependence of AFRS patients on corticosteroid and antifungal treatments. CONCLUSION: Omalizumab therapy can be considered as a potential adjunct for the treatment for patients with refractory AFRS with moderate or severe asthma. However, larger prospective studies to confirm the findings of this study will be required. PMID- 26117493 TI - Development of infant leg coordination: Exploiting passive torques. AB - Leg joint coordination systematically changes over the first months of life, yet there is minimal data on the underlying change in muscle torques that might account for this change in coordination. The purpose of this study is to investigate the contribution of torque changes to early changes in leg joint coordination. Kicking actions were analyzed of 10 full-term infants between 6 and 15-weeks of age using three-dimensional kinematics and kinetics. We found 11 of 15 joint angle pairs demonstrated a change from more in-phase intralimb coordination at 6-weeks to less in-phase coordination at 15-weeks. Although the magnitude of joint torques normalized to the mass of the leg remained relatively consistent, we noted more complex patterns of torque component contribution across ages. By focusing on the change in torques associated with hip-knee joint coordination, we found that less in-phase hip-knee joint coordination at 15-weeks was associated with decreased influence of knee muscle torque and increased influence of knee gravitational and motion-dependent torques, supporting that infants coordinate hip muscle torque with passive knee gravitational and motion dependent torques to generate kicks with reduced active knee muscle torque. We propose that between 6 and 15-weeks of age less in-phase hip-knee coordination emerges as infants exploit passive dynamics in the coordination of hip and knee motions. PMID- 26117494 TI - Urologic cancers in Korea. AB - The incidence and prevalence of prostate and kidney cancers have been increasing in Korea during the last decade, and a marked improvement in survival rates has been noted. With a substantial proportion of the cancers diagnosed at an earlier stage of the disease, the landscape of urologic cancer treatment in Korea has been characterized by an exponential increase in the number of patients receiving surgical treatment. Throughout the last decade, an increasing proportion of surgeries have been performed using minimally invasive methods, with a notable increase in robot-assisted surgery.The evaluation and management strategies of urologic cancer in Korea are primarily based on an existing evidence-based framework provided by international guidelines. The adoption and clinical application of novel surgical techniques and systemic agents targeted at advanced stage cancer are promptly adopted; accordingly, multidisciplinary treatment options are often available for various cancers at different stages. At the same time, treatment decisions are greatly influenced by the availability of healthcare resources, which may be limited due to the National Health Insurance reimbursement policy.A racial disparity in cancer features appears to exist for certain urologic cancers among Korean patients, and the optimal management strategy specific for the Korean population has yet to be confirmed. A national comprehensive cancer database is needed for better insight into risk factors, selection of sequential strategies, tumor biology and survival outcome of Korean urologic cancer patients. PMID- 26117495 TI - Special AT-rich sequence-binding protein 1: a novel biomarker predicting cervical squamous cell carcinoma prognosis and lymph node metastasis. AB - OBJECTIVE: Special AT-rich sequence-binding protein 1 is aberrantly expressed in various malignant tumors. However, the expression and function of special AT-rich sequence-binding protein 1 in cervical squamous cell carcinoma have not been reported. The objective of this study was to investigate the clinical significance of special AT-rich sequence-binding protein 1 in cervical squamous cell carcinoma. METHODS: In this study, we investigated the expression of special AT-rich sequence-binding protein 1 through immunohistochemistry in 25 normal cervix specimens and 167 cervical squamous cell carcinomas and analyzed its association with various clinicopathologic parameters, including patient outcome. RESULTS: Special AT-rich sequence-binding protein 1 protein was detected in 58 (34.7%) out of 167 patients and was highly related to International Federation of Gynecology and Obstetrics stage, histologic grade, lymph node metastasis, vascular-lymphatic invasion and recurrence of cervical squamous cell carcinoma. Patients with positive special AT-rich sequence-binding protein 1 expression had significantly lower overall survival and disease-free survival compared with patients with negative expression of special AT-rich sequence-binding protein 1 (P = 0.001 and P < 0.001, respectively). A multivariate Cox regression analysis revealed that special AT-rich sequence-binding protein 1 was an independent prognostic marker for both disease-free survival and overall survival of cervical squamous cell carcinoma patients (P = 0.038 and P = 0.010, respectively). A multivariate logistic regression analysis showed that special AT-rich sequence binding protein 1 expression was strongly associated with lymph node metastasis (odds ratio = 2.497; P = 0.032). Sensitivity and specificity of special AT-rich sequence-binding protein 1 for lymph node metastasis were 61.0 and 73.8%, respectively. CONCLUSIONS: These results showed that special AT-rich sequence binding protein 1 expression was associated with tumor progression, metastasis and poor prognosis in cervical squamous cell carcinoma. It may serve as a new prognostic biomarker or a target for improving the treatment efficiency of patients with cervical squamous cell carcinoma. PMID- 26117496 TI - Comparing humans and nonhuman great apes in the broken cloth problem: Is their knowledge causal or perceptual? AB - When presented with the broken cloth problem, both human children and nonhuman great apes prefer to pull a continuous cloth over a discontinuous cloth in order to obtain a desired object resting on top. This has been interpreted as evidence that they preferentially attend to the functionally relevant cues of the task (e.g., presence or absence of a gap along the cloth). However, there is controversy regarding whether great apes' behavior is underpinned by causal knowledge, involving abstract concepts (e.g., support, connection), or by perceptual knowledge, based on percepts (e.g., contact, continuity). We presented chimpanzees, orangutans, and 2-, 3-, and 4-year-old children with two versions of the broken cloth problem. The Real condition, made with paper strips, could be solved based on either perceptual cues or causal knowledge. The Painted condition, which looked very similar, could be solved only by attending to perceptual cues. All groups mastered the Real condition, in line with previous results. Older children (3- and 4-year-olds) performed significantly better in this condition than all other groups, but the performance of apes and children did not differ sharply, with 2-year-olds and apes obtaining similar results. In contrast, only 4-year-olds solved the Painted condition. We propose causal knowledge to explain the general good performance of apes and humans in the Real condition compared with the Painted condition. In addition, we suggest that symbolic knowledge might account for 4-year-olds' performance in the Painted condition. Our findings add to the growing literature supporting the idea that learning from arbitrary cues is not a good explanation for the performance of apes and humans on some kinds of physical task. PMID- 26117497 TI - Whole-genome resequencing analyses of five pig breeds, including Korean wild and native, and three European origin breeds. AB - Pigs have been one of the most important sources of meat for humans, and their productivity has been substantially improved by recent strong selection. Here, we present whole-genome resequencing analyses of 55 pigs of five breeds representing Korean native pigs, wild boar and three European origin breeds. 1,673.1 Gb of sequence reads were mapped to the Swine reference assembly, covering ~99.2% of the reference genome, at an average of ~11.7-fold coverage. We detected 20,123,573 single-nucleotide polymorphisms (SNPs), of which 25.5% were novel. We extracted 35,458 of non-synonymous SNPs in 9,904 genes, which may contribute to traits of interest. The whole SNP sets were further used to access the population structures of the breeds, using multiple methodologies, including phylogenetic, similarity matrix, and population structure analysis. They showed clear population clusters with respect to each breed. Furthermore, we scanned the whole genomes to identify signatures of selection throughout the genome. The result revealed several promising loci that might underlie economically important traits in pigs, such as the CLDN1 and TWIST1 genes. These discoveries provide useful genomic information for further study of the discrete genetic mechanisms associated with economically important traits in pigs. PMID- 26117498 TI - Boiling significantly promotes photodegradation of perfluorooctane sulfonate. AB - The application of photochemical processes for perfluorooctane sulfonate (PFOS) degradation has been limited by a low treatment efficiency. This study reports a significant acceleration of PFOS photodegradation under boiling condition compared with the non-boiling control. The PFOS decomposition rate increased with the increasing boiling intensity, but declined at a higher hydronium level or under oxygenation. These results suggest that the boiling state of solution resulted in higher effective concentrations of reactants at the gas-liquid interface and enhanced the interfacial mass transfer, thereby accelerating the PFOS decomposition. This study broadens our knowledge of PFOS photodegradation process and may have implications for development of efficient photodegradation technologies. PMID- 26117499 TI - Assessment of the genotoxic potential along the Danube River by application of the comet assay on haemocytes of freshwater mussels: The Joint Danube Survey 3. AB - In this study we assessed the level of genotoxic pollution along the Danube River by measuring the level of DNA damage in the haemocytes of freshwater mussels of Unio sp. (Unio pictorum/Unio tumidus) and Sinanodonta woodiana. The comet assay was used for the assessment of DNA damage. The research was performed on 34 out of 68 sites analysed within the Joint Danube Survey 3 - the world's biggest river research expedition of its kind in 2013. During research, 2285 river kilometres were covered with an average distance of 68 km between the sites. The complex data set on concentrations of various substances present in water, suspended particulate matter and sediment on investigated sites gave the opportunity to identify the groups of xenobiotics which mostly affect the studied biomarker - DNA damage. The highest levels of DNA damage were recorded in the section VI (Panonnian Plain), which is under the impact of untreated wastewater discharges. Both positive and negative influences of the large tributaries on the level of genotoxicity in the Danube River were evident. Significant correlation in response was detected between the studied species of freshwater mussels. The level of DNA damage in mussels correlated with concentrations of compounds from the group of hazardous priority substances (polycyclic aromatic hydrocarbons), persistent organic pollutants (dioxins) and emerging pollutants (Oxazepam, Chloridazon-desphenyl). PMID- 26117500 TI - Nonlinear vegetation cover changes in the North Ethiopian Highlands: Evidence from the Lake Ashenge closed basin. AB - Vegetation cover changes in African drylands are often thought to result from population growth, social factors and aridification. Here we show that long-term vegetation proxy records can help disentangling these main driving factors. Taking the case of North Ethiopia, we performed an integrated investigation of land cover changes over the last four centuries around the endorheic Lake Ashenge, as derived from pollen analysis and repeat photography complemented with information from historical sources. Pollen and sediment analysis of radiocarbon dated lake deposits shows a phase of environmental destabilization during the 18th century, after a more stable previous period. This is evidenced by decreases of tree pollen (Juniperus, Olea, Celtis, Podocarpus<5%), increases in Poaceae (>40%) and deposition of coarser silt lake sediments (>70%). Quantitative analysis of 30 repeated landscape photographs around the lake indicates a gradual decline of the vegetation cover since a relative maximum during the mid-19th Century. Vegetation cover declined sharply between the 1950s and the 1980s, but has since begun to recover. Overall, the data from around Lake Ashenge reveal a nonlinear pattern of deforestation and forest regrowth with several periods of vegetation cover change over the past four centuries. While there is forcing of regional drought and the regional land tenure system, the cyclic changes do not support a simplified focus on aridification or population growth. PMID- 26117501 TI - Forensic application of microRNA-706 as a biomarker for drowning pattern identification. AB - Forensic research using microRNA has been used so far only for the identification of body fluids, but its use in understanding biological processes in post-mortem pathology has not been studied before. Therefore, we performed experiments in mice to compare between freshwater and saltwater drowning models, and miRNA expression was analyzed in the brain through a forward bioinformatics screening approach. In this study, we identified eight specific microRNAs whose expression increased in freshwater and decreased in saltwater. Among them, miR-706 - targeting HCN1 - was identified as a potent biomarker for the drowning pattern identification. A higher expression of miR-706 was detected in the freshwater drowning compared to the control and saltwater drowning group (p<0.05, and p<0.01, respectively). HCN1 mRNA expression, a suggested candidate target for miR 706, was lower in the freshwater (p<0.01) than in the saltwater drowning group, and showed statistical difference between freshwater and saltwater drowning (p<0.01). miR-706 was specifically expressed in the hippocampal neurons as detected by in situ hybridization. Our data suggest that a specific microRNA may provide clues to understanding some crime scene investigations and pathobiological processes in the dead body. PMID- 26117502 TI - Sex determination using discriminant analysis of upper and lower extremity bones: New approach using the volume and surface area of digital model. AB - This study used 110 CT images taken from donated Korean cadavers to create 3-D models of the following upper and lower limb bones: the clavicle, scapula, humerus, radius, ulna, hip bone (os coxa), femur, patella (knee cap), tibia, talus, and calcaneus. In addition, the bone volume and surface area were calculated to determine sex differences using discriminant analysis. Significant sex differences were found in all bones with respect to volume and surface area (p<0.01). The order of volume was the same in females and males (femur>hip bone>tibia>humerus>scapula), although the order of surface area was different. The largest surface area in men was the femur and in women was the hip bone (p<0.01). An interesting finding of this study was that the ulna is the bone with the highest accuracy for sex determination (94%). When using the surface area of multiple bones, the maximum accuracy (99.4%) was achieved. The equation was as follows: (discriminant equation of surface area; female<0 0.8). For genes ubiquitously expressed across all tissues, the two data sets showed high genome-wide correlation (91% agreement), with differences observed for a small number of individual genes indicating the need to update their gene models. Among the identified single tissue enriched genes, up to 75% showed consensus of 7-fold enrichment in the same tissue in both methods, while another 17% exhibited multiple tissue enrichment and/or high expression variety in the other data set, likely dependent on the cell type proportions included in each tissue sample. Our results show that RNA-Seq and CAGE tissue transcriptome data sets are highly complementary for improving gene model annotations and highlight biological complexities within tissue transcriptomes. Furthermore, integration with image-based protein expression data is highly advantageous for understanding expression specificities for many genes. PMID- 26117542 TI - The structure of Rpf2-Rrs1 explains its role in ribosome biogenesis. AB - The assembly of eukaryotic ribosomes is a hierarchical process involving about 200 biogenesis factors and a series of remodeling steps. The 5S RNP consisting of the 5S rRNA, RpL5 and RpL11 is recruited at an early stage, but has to rearrange during maturation of the pre-60S ribosomal subunit. Rpf2 and Rrs1 have been implicated in 5S RNP biogenesis, but their precise role was unclear. Here, we present the crystal structure of the Rpf2-Rrs1 complex from Aspergillus nidulans at 1.5 A resolution and describe it as Brix domain of Rpf2 completed by Rrs1 to form two anticodon-binding domains with functionally important tails. Fitting the X-ray structure into the cryo-EM density of a previously described pre-60S particle correlates with biochemical data. The heterodimer forms specific contacts with the 5S rRNA, RpL5 and the biogenesis factor Rsa4. The flexible protein tails of Rpf2-Rrs1 localize to the central protuberance. Two helices in the Rrs1 C-terminal tail occupy a strategic position to block the rotation of 25S rRNA and the 5S RNP. Our data provide a structural model for 5S RNP recruitment to the pre-60S particle and explain why removal of Rpf2-Rrs1 is necessary for rearrangements to drive 60S maturation. PMID- 26117541 TI - Integrative genomic analysis in K562 chronic myelogenous leukemia cells reveals that proximal NCOR1 binding positively regulates genes that govern erythroid differentiation and Imatinib sensitivity. AB - To define the functions of NCOR1 we developed an integrative analysis that combined ENCODE and NCI-60 data, followed by in vitro validation. NCOR1 and H3K9me3 ChIP-Seq, FAIRE-seq and DNA CpG methylation interactions were related to gene expression using bootstrapping approaches. Most NCOR1 combinations (24/44) were associated with significantly elevated level expression of protein coding genes and only very few combinations related to gene repression. DAVID's biological process annotation revealed that elevated gene expression was uniquely associated with acetylation and ETS binding. A matrix of gene and drug interactions built on NCI-60 data identified that Imatinib significantly targeted the NCOR1 governed transcriptome. Stable knockdown of NCOR1 in K562 cells slowed growth and significantly repressed genes associated with NCOR1 cistrome, again, with the GO terms acetylation and ETS binding, and significantly dampened sensitivity to Imatinib-induced erythroid differentiation. Mining public microarray data revealed that NCOR1-targeted genes were significantly enriched in Imatinib response gene signatures in cell lines and chronic myelogenous leukemia (CML) patients. These approaches integrated cistrome, transcriptome and drug sensitivity relationships to reveal that NCOR1 function is surprisingly most associated with elevated gene expression, and that these targets, both in CML cell lines and patients, associate with sensitivity to Imatinib. PMID- 26117543 TI - The ancestor of modern Holozoa acquired the CCA-adding enzyme from Alphaproteobacteria by horizontal gene transfer. AB - Transfer RNAs (tRNAs) require the absolutely conserved sequence motif CCA at their 3'-ends, representing the site of aminoacylation. In the majority of organisms, this trinucleotide sequence is not encoded in the genome and thus has to be added post-transcriptionally by the CCA-adding enzyme, a specialized nucleotidyltransferase. In eukaryotic genomes this ubiquitous and highly conserved enzyme family is usually represented by a single gene copy. Analysis of published sequence data allows us to pin down the unusual evolution of eukaryotic CCA-adding enzymes. We show that the CCA-adding enzymes of animals originated from a horizontal gene transfer event in the stem lineage of Holozoa, i.e. Metazoa (animals) and their unicellular relatives, the Choanozoa. The tRNA nucleotidyltransferase, acquired from an alpha-proteobacterium, replaced the ancestral enzyme in Metazoa. However, in Choanoflagellata, the group of Choanozoa that is closest to Metazoa, both the ancestral and the horizontally transferred CCA-adding enzymes have survived. Furthermore, our data refute a mitochondrial origin of the animal tRNA nucleotidyltransferases. PMID- 26117544 TI - Redefining the transcriptional regulatory dynamics of classically and alternatively activated macrophages by deepCAGE transcriptomics. AB - Classically or alternatively activated macrophages (M1 and M2, respectively) play distinct and important roles for microbiocidal activity, regulation of inflammation and tissue homeostasis. Despite this, their transcriptional regulatory dynamics are poorly understood. Using promoter-level expression profiling by non-biased deepCAGE we have studied the transcriptional dynamics of classically and alternatively activated macrophages. Transcription factor (TF) binding motif activity analysis revealed four motifs, NFKB1_REL_RELA, IRF1,2, IRF7 and TBP that are commonly activated but have distinct activity dynamics in M1 and M2 activation. We observe matching changes in the expression profiles of the corresponding TFs and show that only a restricted set of TFs change expression. There is an overall drastic and transient up-regulation in M1 and a weaker and more sustainable up-regulation in M2. Novel TFs, such as Thap6, Maff, (M1) and Hivep1, Nfil3, Prdm1, (M2) among others, were suggested to be involved in the activation processes. Additionally, 52 (M1) and 67 (M2) novel differentially expressed genes and, for the first time, several differentially expressed long non-coding RNA (lncRNA) transcriptome markers were identified. In conclusion, the finding of novel motifs, TFs and protein-coding and lncRNA genes is an important step forward to fully understand the transcriptional machinery of macrophage activation. PMID- 26117546 TI - A predictive biophysical model of translational coupling to coordinate and control protein expression in bacterial operons. AB - Natural and engineered genetic systems require the coordinated expression of proteins. In bacteria, translational coupling provides a genetically encoded mechanism to control expression level ratios within multi-cistronic operons. We have developed a sequence-to-function biophysical model of translational coupling to predict expression level ratios in natural operons and to design synthetic operons with desired expression level ratios. To quantitatively measure ribosome re-initiation rates, we designed and characterized 22 bi-cistronic operon variants with systematically modified intergenic distances and upstream translation rates. We then derived a thermodynamic free energy model to calculate de novo initiation rates as a result of ribosome-assisted unfolding of intergenic RNA structures. The complete biophysical model has only five free parameters, but was able to accurately predict downstream translation rates for 120 synthetic bi cistronic and tri-cistronic operons with rationally designed intergenic regions and systematically increased upstream translation rates. The biophysical model also accurately predicted the translation rates of the nine protein atp operon, compared to ribosome profiling measurements. Altogether, the biophysical model quantitatively predicts how translational coupling controls protein expression levels in synthetic and natural bacterial operons, providing a deeper understanding of an important post-transcriptional regulatory mechanism and offering the ability to rationally engineer operons with desired behaviors. PMID- 26117545 TI - An atlas of RNA base pairs involving modified nucleobases with optimal geometries and accurate energies. AB - Posttranscriptional modifications greatly enhance the chemical information of RNA molecules, contributing to explain the diversity of their structures and functions. A significant fraction of RNA experimental structures available to date present modified nucleobases, with half of them being involved in H-bonding interactions with other bases, i.e. 'modified base pairs'. Herein we present a systematic investigation of modified base pairs, in the context of experimental RNA structures. To this end, we first compiled an atlas of experimentally observed modified base pairs, for which we recorded occurrences and structural context. Then, for each base pair, we selected a representative for subsequent quantum mechanics calculations, to find out its optimal geometry and interaction energy. Our structural analyses show that most of the modified base pairs are non Watson-Crick like and are involved in RNA tertiary structure motifs. In addition, quantum mechanics calculations quantify and provide a rationale for the impact of the different modifications on the geometry and stability of the base pairs they participate in. PMID- 26117547 TI - Active promoters give rise to false positive 'Phantom Peaks' in ChIP-seq experiments. AB - Chromatin immunoprecipitation (ChIP) is widely used to identify chromosomal binding sites. Chromatin proteins are cross-linked to their target sequences in living cells. The purified chromatin is sheared and the relevant protein is enriched by immunoprecipitation with specific antibodies. The co-purifying genomic DNA is then determined by massive parallel sequencing (ChIP-seq).We applied ChIP-seq to map the chromosomal binding sites for two ISWI-containing nucleosome remodeling factors, ACF and RSF, in Drosophila embryos. Employing several polyclonal and monoclonal antibodies directed against their signature subunits, ACF1 and RSF-1, robust profiles were obtained indicating that both remodelers co-occupied a large set of active promoters.Further validation included controls using chromatin of mutant embryos that do not express ACF1 or RSF-1. Surprisingly, the ChIP-seq profiles were unchanged, suggesting that they were not due to specific immunoprecipitation. Conservative analysis lists about 3000 chromosomal loci, mostly active promoters that are prone to non-specific enrichment in ChIP and appear as 'Phantom Peaks'. These peaks are not obtained with pre-immune serum and are not prominent in input chromatin.Mining the modENCODE ChIP-seq profiles identifies potential Phantom Peaks in many profiles of epigenetic regulators. These profiles and other ChIP-seq data featuring prominent Phantom Peaks must be validated with chromatin from cells in which the protein of interest has been depleted. PMID- 26117548 TI - Structures of the T. brucei kRNA editing factor MRB1590 reveal unique RNA-binding pore motif contained within an ABC-ATPase fold. AB - Kinetoplastid RNA (kRNA) editing is a process that creates translatable mitochondrial mRNA transcripts from cryptogene encoded RNAs and is unique for kinetoplastids, such as Trypanosoma brucei. In addition to the catalytic 20S editosome, multiple accessory proteins are required for this conversion. Recently, the multiprotein mitochondrial RNA binding complex 1 (MRB1) has emerged as a key player in this process. MRB1 consists of six core proteins but makes dynamic interactions with additional accessory proteins. Here we describe the characterization of one such factor, the 72 kDa MRB1590 protein. In vivo experiments indicate a role for MRB1590 in editing mitochondrial mRNA transcripts, in particular the transcript encoding the ATP synthase subunit 6 (A6). Structural studies show that MRB1590 is dimeric and contains a central ABC ATPase fold embedded between novel N- and C-terminal regions. The N-terminal domains combine to create a basic pore and biochemical studies indicate residues in this region participate in RNA binding. Structures capturing distinct MRB1590 conformations reveal that the RNA binding pore adopts closed and open states, with the latter able to accommodate RNA. Based on these findings, implications for MRB1590 function are discussed. PMID- 26117549 TI - Neurometabolic Disorders-Related Early Childhood Epilepsy: A Single-Center Experience in Saudi Arabia. AB - BACKGROUND: Data on the pattern of epilepsy caused by metabolic disorders in the first 2 years of life are limited in developing countries. We aimed to identify the metabolic causes of epilepsy presented in the first 2 years of life and to describe their clinical, radiological, molecular, and electroencephalographic characteristics. METHODS: This retrospective study was conducted between January 2010 and December 2011 at Saad Specialist Hospital (Al Khobar, Saudi Arabia). All patients younger than 2 years at the onset of epilepsy caused by metabolic disorders were reviewed. The International League Against Epilepsy definition was used, and febrile convulsion was excluded. RESULTS: Of 221 children diagnosed with epilepsy in the first 2 years of life at our hospital, 24 had metabolic diseases. The characteristics of these 24 children included the following: consanguinity in 18 patients (75%), developmental delay in 13 (54%), generalized tonic-clonic seizures in 10 (42%), infantile spasms in four (17%), myoclonic in seven (29%), and focal seizures in three. The diagnosis was confirmed by DNA studies in 17 patients (71%) and enzyme assay in seven (29%). The main diagnoses were peroxisomal disorders (n = 3), nonketotic hyperglycinemia (n = 3), Menkes disease (n = 2), neuronal ceroid lipofuscinosis (n = 2), biotinidase deficiency (n = 2), and mitochondrial disorder (n = 2). The remaining patients had lysosomal storage disease, aminoacidopathy, fatty acid oxidation defects, and organic aciduria. Seizure freedom was achieved in one third of patients in this cohort. CONCLUSION: Different metabolic disorders were identified in this cohort, which caused different types of epilepsy, especially myoclonic seizures and infantile spasms. PMID- 26117551 TI - The effectiveness of combined abdominal myomectomy and uterine artery embolization. AB - OBJECTIVE: To evaluate the efficacy of abdominal myomectomy after uterine artery embolization (UAE-AM) among patients with myomas. METHODS: In a retrospective study, chart data were reviewed for patients attending a center in California, USA, who underwent UAE-AM between 1999 and 2012. Patients had been offered the combined procedure if the diameter of the myoma was at least 4cm, they wished to preserve fertility, or they were candidates for a traditional abdominal myomectomy. Estimated blood loss, fluoroscopy times, and hospital stay were recorded. Follow-up data on uterine volume and fibroid size had been collected via magnetic resonance imaging or ultrasonography approximately 3-6 months after UAE-AM. RESULT: Overall, 20 patients underwent UAE-AM. Approximately 6 months after the procedure, the mean decrease in uterine volume was 77.33%+/-14.25% and that in myoma diameter was 46.45%+/-25.61%. Six women subsequently became pregnant; one patient had two separate pregnancies. No patient required a conversion to hysterectomy or blood transfusion, and no recurrences were reported. CONCLUSION: UAE-AM was found to be an effective option available to women with large myomas who wished to preserve their uterus. With the combination procedure, patients had favorable outcomes with no fibroid recurrence. PMID- 26117550 TI - Human Metapneumovirus Infection is Associated with Severe Respiratory Disease in Preschool Children with History of Prematurity. AB - BACKGROUND: Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen of the family Paramyxoviridae, the same family as that of respiratory syncytial virus (RSV). Premature children are at high risk of severe RSV infections, however, it is unclear whether HMPV infection is more severe in hospitalized children with a history of severe prematurity. METHODS: We conducted a retrospective analysis of the clinical respiratory presentation of all polymerase chain reaction-confirmed HMPV infections in preschool-age children (<=5 years) with and without history of severe prematurity (<32 weeks gestation). Respiratory distress scores were developed to examine the clinical severity of HMPV infections. Demographic and clinical variables were obtained from reviewing electronic medical records. RESULTS: A total of 571 preschool children were identified using polymerase chain reaction-confirmed viral respiratory tract infection during the study period. HMPV was identified as a causative organism in 63 cases (11%). Fifty-eight (n = 58) preschool-age children with HMPV infection were included in this study after excluding those with significant comorbidities. Our data demonstrated that 32.7% of children admitted with HMPV had a history of severe prematurity. Preschool children with a history of prematurity had more severe HMPV disease as illustrated by longer hospitalizations, new or increased need for supplemental O2, and higher severity scores independently of age, ethnicity, and history of asthma. CONCLUSION: Our study suggests that HMPV infection causes significant disease burden among preschool children with a history of prematurity leading to severe respiratory infections and increasing health care resource utilization due to prolonged hospitalizations. PMID- 26117552 TI - Clinical characteristics and management experience of unexpected uterine sarcoma after myomectomy. AB - OBJECTIVE: To identify the prevalence of unexpected uterine sarcoma after myomectomy for presumed leiomyoma and compare clinical outcomes after primary myomectomy with and without power morcellation. METHODS: In a retrospective study, a review was undertaken of the medical records of patients who had unexpected uterine sarcoma after myomectomy with and without power morcellation at Peking Union Medical College Hospital, Beijing, China, between January 2009 and December 2013. RESULTS: Among 4248 patients who underwent myomectomy for presumed leiomyoma, 9 (0.2%) had unexpected uterine sarcoma (1 [<0.1%] had leiomyosarcoma; 8 [0.2%] endometrial stromal sarcoma). The malignancy was identified in 5 (0.2%) of 3068 women who were treated by laparoscopy with power morcellation and 4 (0.3%) of 1180 who underwent laparotomy (P=0.274). All nine patients were alive after a mean follow-up of 31.2 months in the laparoscopy group and 40.5 months in the laparotomy group. CONCLUSION: The overall incidence of unexpected uterine sarcoma after myomectomy was low. Incidental power morcellation of unexpected uterine sarcoma seemed to cause no increase in sarcoma dissemination. PMID- 26117553 TI - Third-trimester uterine artery Doppler measurement and maternal postpartum outcome among patients with severe pre-eclampsia. AB - OBJECTIVE: To evaluate the association between uterine artery Doppler measurements and maternal complications among women with severe pre-eclampsia. METHODS: As part of a cross-sectional study, women with a single intrauterine pregnancy of more than 28 weeks and a diagnosis of severe pre-eclampsia were enrolled at a unit in Cairo, Egypt, between December 2012 and September 2014. Uterine artery Doppler was evaluated and maternal complications were recorded. RESULTS: Among the 100 participants, 76 (76%) experienced maternal complications. There were significant differences in resistance index (RI) and pulsatility index (PI) between women who experienced no complications and those who had accidental hemorrhage, HELLP syndrome, and acute pulmonary edema (P<0.001 for all), and postpartum hemorrhage (P=0.004 and P<0.001, respectively). There was no significant difference in RI for women with postpartum fits (P=0.360). There was a statistically significant difference regarding RI (P<0.001) and PI (P=0.005) between cases presenting with complications and those without. There was a significant negative correlation between PI and gestational age (r=-0.988; P<0.001) and between RI and gestational age (r=-0. 854; P<0.001), but no significant correlation between PI or RI and age, systolic blood pressure, or diastolic blood pressure. CONCLUSION: Increased uterine artery resistance in the third trimester of pregnancy could be used to predict postpartum maternal complications. PMID- 26117554 TI - Translational networks in healthcare? Evidence on the design and initiation of organizational networks for knowledge mobilization. AB - International attention has focussed on the variations between research evidence and practice in healthcare. This prompted the creation of formalized translational networks consisting of academic-service partnerships. The English Collaborations for Leadership in Applied Health Research and Care (CLAHRCs) are one example of a translational network. Using longitudinal, archival case study data from one CLAHRC over a 3-year period (2008-11), this article explores the relationship between organizational form and the function(s) of a translational network. The article focuses on the research gaps on the effective structures and appropriate governance to support a translational network. Data analysis suggested that the policy of setting up translational networks is insufficient of itself to produce positive translational activity. The data indicate that to leverage the benefits of the whole network, attention must be paid to devising a structure which integrates research production and use and facilitates lateral cross-disciplinary and cross-organizational communication. Equally, appropriate governance arrangements are necessary, particularly in large, multi-stakeholder networks, where shared governance may be questionable. Inappropriate network structure and governance inhibits the potential of the translational network. Finally, the case provides insights into the movement of knowledge within and between network organizations. The data demonstrate that knowledge mobilization extends beyond knowledge translation; knowledge mobilization includes the negotiated utilization of knowledge - a balanced power form of collaboration. Whilst much translational effort is externally focused on the health system, our findings highlight the essential need for the internal negotiation and mobilization of knowledge within academia. PMID- 26117555 TI - Can you party your way to better health? A propensity score analysis of block parties and health. AB - While other indicators of social capital have been linked to health, the role of block parties on health in Black neighborhoods and on Black residents is understudied. Block parties exhibit several features of bonding social capital and are present in nearly 90% of Philadelphia's predominantly Black neighborhoods. This analysis investigated: (1) whether or not block parties are an indicator of bonding social capital in Black neighborhoods; (2) the degree to which block parties might be related to self-rated health in the ways that other bonding social indicators are related to health; and (3) whether or not block parties are associated with average self-rated health for Black residents particularly. Using census tract-level indicators of bonding social capital and records of block parties from 2003 to 2008 for 381 Philadelphia neighborhoods (defined by census tracts), an ecological-level propensity score was generated to assess the propensity for a block party, adjusting for population demographics, neighborhood characteristics, neighborhood resources and violent crime. Results indicate that in multivariable regression, block parties were associated with increased bonding social capital in Black neighborhoods; however, the calculation of the average effect of the treatment on the treated (ATT) within each propensity score strata showed no effect of block parties on average self-rated health for Black residents. Block parties may be an indicator of bonding social capital in Philadelphia's predominantly Black neighborhoods, but this analysis did not show a direct association between block parties and self-rated health for Black residents. Further research should consider what other health outcomes or behaviors block parties may be related to and how interventionists can leverage block parties for health promotion. PMID- 26117556 TI - Occurrence of the "applause sign" in patients with amyotrophic lateral sclerosis. AB - The applause sign was originally described as a quick bedside test to discriminate progressive supranuclear palsy (PSP) (positive applause sign, PAS) from Parkinson's disease (PD) and frontotemporal dementia (FTD) (negative applause sign). However, recent research demonstrated that the test is positive not only in a subset of patients with PD and FTD, but also in other neurodegenerative diseases. We tested 22 patients with amyotrophic lateral sclerosis (ALS) together with 22 healthy sex- and age-matched controls for the occurrence of PAS. Furthermore, we performed neuropsychological testing with the EXIT-25 battery to correlate PAS with neuropsychological deficits, especially frontal lobe dysfunction. Five ALS patients (23%) and none of the controls displayed PAS (p<=0.05). The occurrence of PAS in ALS patients was not correlated with pathologic EXIT-25 scores or subtests for aberrant motor behaviour. We describe for the first time the occurrence of the applause sign in ALS and provide additional evidence that PAS is not specific for Parkinsonian disorders. Although its occurrence has been related to aberrant motor behaviour due to frontal involvement, in our study PAS did not correlate with executive dysfunction as tested by the EXIT-25 test battery, or with subtests of aberrant motor behaviour. PMID- 26117557 TI - Early Guillain-Barre syndrome with normal peripheral conduction: which is the pathological hallmark? PMID- 26117558 TI - Significant Transplantation-Related Mortality from Respiratory Virus Infections within the First One Hundred Days in Children after Hematopoietic Stem Cell Transplantation. AB - Respiratory viral infections (RVI) are important in hematopoietic stem cell transplantations (HSCT) and knowledge regarding incidence, morbidity, mortality, and long-term pulmonary complications is limited. We report a study to evaluate incidence and outcomes, both short and long-term, of RVI in children receiving HSCT. Between January 2000 and December 2012, 844 patients underwent hematopoietic stem cell transplantation (HSCT) at the Hospital for Sick Children: 491 were allogeneic and 353 were autologous. When screening for causes of death in the first year after HSCT in the 844 patients, we found that RVI as a cause of death was only evident in the first 100 days after HSCT. Fifty-four (6.5%) patients were found to have an RVI within the first 100 days after HSCT (allogeneic = 32, autologous = 22). Upper and lower respiratory tract infections were documented in 31 (57%) and 23 (43%) patients, respectively. Viruses were parainfluenza (35%), respiratory syncytial virus (28%), influenza (22%), adenovirus (7%), human metapneumovirus (4%), coronavirus (2%), and rhinovirus (2%). Three patients relapsed with their primary disease before day 100 and were excluded. The overall mortality for the remaining 51 patients was 10% (allogeneic = 4, autologous = 1). All 5 deaths were directly attributable to RVI and all 5 deaths occurred in patients with a lower respiratory tract infection. The remaining patients were followed for a median of 4.3 years (range, 1.4 to 11.8) and no chronic pulmonary complications were observed. A clear seasonal pattern for contracting RVI was evident with 65% of total RVI occurring between October and March (35 of 427 versus 19 of 417, P = .03). Given the significant mortality from RVI and the challenges in preventing them, choosing the time to start HSCT, whenever possible, may help prevent RVI and improve outcomes. PMID- 26117559 TI - Successful linking of patient records between hospital services and general practice to facilitate integrated care in a hospital and health service in south east Queensland. AB - This brief paper describes a recent exercise undertaken within a hospital and health service in south-east Queensland to attempt to link patient records between general practice and hospital services. It describes the technical and governance processes undertaken to achieve this link and the challenges experienced to date in linking the two data sources. PMID- 26117560 TI - The effect of air-abrasion and heat treatment on the fracture behavior of Y-TZP. AB - OBJECTIVES: This study evaluated how the flexural strength and fracture behavior of a zirconia-based ceramic (Y-TZP) were affected by pre- and post-sintering mechanical and thermal treatments. METHODS: Treatments included sandblasting with different particle size and type (30MUm SiO2; 50 and 110MUm Al2O3) and thermal conditioning. Two hundred bar-shaped specimens of pre-sintered Y-TZP ceramic (Lava Frame, 3M) were prepared (specimen dimensions: 25mm length*4mm width*0.7mm thickness) and divided into three groups (before sintering, after sintering and after sintering with heating treatment). The before sintering group specimens were airborne-particle abraded prior to dense sintering. Specimens from the after sintering group were airborne-particle abraded after sintering. The after sintering with heating treatment group specimens were submitted to a heating procedure after airborne-particle abrasion. The controls were the specimens that were sintered and not treated with any conditioning procedures. The specimens from all experimental conditions were analyzed by SEM, CLSM and XRD. All specimens were tested in four-point bending. Data were statistically analyzed using one-way ANOVA and Post Hoc tests (alpha=0.05). A Weibull analysis was used to analyze the strength reliability. RESULTS: Sandblasting pre-sintered zirconia before sintering significantly decreased the flexural strength, except when the smallest blasting particles were used (30MUm SiO2). Phase transformation (t-m) was observed after sandblasting and reverse transformation (m-t) was observed after heating. SIGNIFICANCE: Sandblasting with 30MUm SiO2 and 50MUm Al2O3 allowed lower phase transformation. However, 30mm SiO2 presented better reliability. PMID- 26117561 TI - Generation and characterization of antibodies against arginine-derived advanced glycation endproducts. AB - Although antibodies reagents have been widely employed for studying advanced glycation end-products (AGEs), these materials have been produced using complex mixtures of immunogens. Consequently, their epitope specificity remains unknown. Here we have generated the first antibodies capable of recognizing each of the three isomers of the methylglyoxal hydroimidazolones (MG-Hs) by using chemical synthesis to create homogenous immunogens. Furthermore, we have thoroughly characterized the epitope specificity of both our antibodies and that of two existing monoclonals by implementing a direct ELISA protocol employing synthetic MG-H antigens. Finally, we employed the reported anti-MG-H antibodies to the detection of MG-Hs in cellular systems using immunofluorescence microscopy. These studies have demonstrated that anti-MG-H1 and anti-MG-H3 staining is concentrated within the nucleus, while anti-MG-H2 affords only minimal signal. These observations are consistent with reported formation preferences for MG-Hs, and may suggest novel nuclear targets for non-enzymatic posttranslational modification. The antibody reagents reported herein, as well as the strategy employed for their creation, are likely to prove useful for the immunochemical study of AGEs in biological systems. PMID- 26117562 TI - Biarylsulfonamide CCR9 inhibitors for inflammatory bowel disease. AB - Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve. PMID- 26117563 TI - Design, synthesis and evaluation of benzotriazole derivatives as novel antifungal agents. AB - Considering the need for discovery of new antifungal drugs with greater potency and broader spectrum of activity, a new series of 5-substituted benzotriazole derivatives were designed, through structure based design, as inhibitors of fungal cytochrome P450 lanosterol 14-alpha demethylase. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some benzotriazole derivatives were synthesized and characterized by IR, (1)H NMR and MS/MS. The molecules were evaluated for their antifungal action against Candida albicans by cup plate method and ergosterol quantification method by UV spectroscopy. Reasonably good correlation between docking scores and antifungal activity were observed. The computational predictions were in consensus with the experimental results. PMID- 26117564 TI - Postoperative complications after thoracic surgery for lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths in the United States. Several surgical techniques are currently used as part of the standard of care for early-stage lung cancer. Differentiating normal postoperative changes from complications is essential in the management of these patients. This article will review the various surgical approaches used, ranging from wedge resection to pneumonectomy, and will outline their expected postsurgical changes. Early and late postsurgical complications will be described, some of which are unique to the type of surgery performed. In addition, local tumor recurrence is a form of postoperative complication and must be distinguished from typical postoperative or postradiation change. Knowledge of both common and uncommon postoperative complications is crucial in the follow-up of lung cancer patients. SUMMARY STATEMENT: Familiarity with the appearance of postoperative complications in lung cancer patients is vital to distinguish it from the normal postoperative or postradiation appearance in follow-up imaging. PMID- 26117565 TI - (18)F-FDG PET/MRI for therapy response assessment in sarcoma: comparison of PET and MR imaging results. AB - BACKGROUND: (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) has proven to be of substantial benefit in imaging of sarcoma patients. We therefore investigated the feasibility and benefit of combined PET/magnetic resonance imaging (MRI). METHODS: Twelve patients with sarcoma who underwent FDG PET/MRI for staging and response assessment after chemotherapy were included. RESULTS: Based on contrast-enhanced MRI and application of Choi criteria, therapy response was classified as stable disease in 6/12 patients (50%) and as partial remission in 6/12 patients (50%). CONCLUSION: In sarcoma patients, response assessment using Choi criteria based on contrast-enhanced MRI in comparison to FDG PET imaging only demonstrates slight correlation. PMID- 26117566 TI - Social support contributes to resilience among physiotherapy students: a cross sectional survey and focus group study. AB - OBJECTIVE: The present study, taking a resource-oriented approach to mental health, aimed at investigating mental resilience and its determinants among undergraduate physiotherapy students using quantitative and qualitative tools. DESIGN: A questionnaire-based cross-sectional survey supplemented by 2 focus groups. SETTING: One university in Hungary. PARTICIPANTS: 130 physiotherapy students at years 1, 2, and 3. MAIN OUTCOME MEASURES: Sense of coherence, a measure of dynamic self-esteem, as well as social support from family and peers were used to assess mental well-being. A screening instrument for psychological morbidity and perceived stress were used as deficiency-oriented approaches. Student opinions were gathered on positive and negative determinants of mental health. RESULTS: Resilience was lower [mean difference 4.8 (95% CI -3.4; 13.1)], and the occurrence of psychological morbidity (32.5% vs. 0%) was higher among female compared to male students. However, the proportion of students fully supported by their peers was higher among females (63% vs. 37.5%). Female students, unlike their male counterparts, experienced higher stress compared to their peers in the general population. Social support declined as students progressed in their studies though this proved to be the most important protective factor for their mental well-being. CONCLUSIONS: Results were fed back to the course organizers recommending the implementation of an evidence-based method to improve social support as delineated by the Guide to Community Preventive Services of the US the outcomes of which are to be seen in the future. PMID- 26117567 TI - Exercise prescription for patients with non-specific chronic low back pain: a qualitative exploration of decision making in physiotherapy practice. AB - BACKGROUND: Providing an effective exercise prescription process for patients with non-specific chronic low back pain (NSCLBP) is a challenging task. Emerging research has indicated that partnership in care and shared decision making are important for people with NSCLBP and calls for further investigation into the approaches used to prescribe exercise. OBJECTIVE: To explore how shared decision making and patient partnership are addressed by physiotherapists in the process of exercise prescription for patients with NSCLBP. DESIGN: A qualitative study using a philosophical hermeneutic approach. METHODS: Eight physiotherapists were each observed on three occasions undertaking their usual clinical activities (total n=24 observations). They conducted brief interviews after each observation and a later in depth semi-structured interview. Iterative hermeneutic strategies were used to interpret the texts and identify the characteristics and processes of exercise prescription for patients with NSCLBP. FINDINGS: The findings revealed how physiotherapy practice often resulted in unequal possibilities for patient participation which were in turn linked to the physiotherapists' assumptions about the patients, clinical orientation, cognitive and decision making processes. Three linked themes emerged: (1) I want them to exercise, (2) which exercise? - the tension between evidence and everyday practice and (3) compliance-orientated more than concordance based. CONCLUSIONS: This research, by focusing on a patient-centred approach, makes an important contribution to the body of evidence relating to the management of NSCLBP. It challenges physiotherapists to critically appraise their approaches to the prescription of exercise therapy in order to improve outcomes for these patients. PMID- 26117568 TI - Comparison of radial forearm flap and thoracodorsal artery perforator flap donor site morbidity for reconstruction of oral and oropharyngeal defects in head and neck cancer. AB - INTRODUCTION: Reconstruction of the oral cavity and oropharynx after tumour resection often involves the use of free flaps, but donor site morbidity must be taken into account. The radial forearm flap, the flap most commonly used in this setting, leaves a readily visible scar on an exposed region of the body. The thoracodorsal artery perforator flap (TDAP), which possesses the same plastic qualities as the radial forearm flap, leaves a scar that is hidden in the axilla. The purpose of this study was to evaluate the cosmetic results of radial forearm and thoracodorsal artery perforator free flap donor sites. MATERIAL AND METHODS: The medical charts of all patients undergoing reconstruction by a radial forearm or thoracodorsal artery perforator free flap between January 2011 and December 2011 were retrospectively reviewed. The Patient and Observer Scar Assessment Scales and the Vancouver Scar Scale were used to evaluate the quality of the scars. RESULTS: Reconstruction was performed by radial forearm flap in 4 cases and TDAP flap in 7 cases. The PSAS score was significantly lower in the TDAP group than in the radial forearm group (P=0.03), and the OSAS score was higher in the radial forearm group (21.5 versus 14). The Vancouver Scar Scale was significantly higher for radial forearm flap scars than for TDAP scars (8 versus 2.7, P=0.005). CONCLUSION: This is the first study to compare radial forearm and thoracodorsal artery perforator free flap donor site scars. It demonstrates the minimal TDAP donor site morbidity and the high level of patient satisfaction. PMID- 26117569 TI - Lesser Metatarsal Osteotomy. AB - Central metatarsal osteotomy is an effective approach in alleviating pain oriented to the forefoot. The procedures individually are straightforward in the isolated scenario. A working knowledge of the specific and unique pathobiomechanics is imperative when considering surgical intervention for the given pathologic scenario. Treating only the pain focus generally underserves the pathology and does not address the high point of the deformity. The surgeon must be cognizant of the complication potpourri, prepare the patient expectations, and engage a level of proactivity against sequelae to ensure the best possible and most predictable outcome. PMID- 26117570 TI - Percutaneous Surgery of the Forefoot. AB - This article describes some of the common techniques used in percutaneous surgery of the forefoot. Techniques such as minimally invasive chevron Akin osteotomy for correction of hallux valgus, first metatarsophalangeal joint cheilectomy, distal minimally invasive metatarsal osteotomies, bunionette correction, and hammertoe correction are described. This article is an introduction to this rapidly developing area of foot and ankle surgery. Less invasive techniques are continually being developed across the whole spectrum of surgical specialties. The surgical ethos of minimizing soft-tissue disruption in the process of achieving surgical objectives remains at the center of this evolution. PMID- 26117571 TI - Fifth Metatarsal Osteotomies. AB - A tailor's bunion or bunionette deformity is a combination of osseous and soft tissue bursitis on the lateral aspect of the fifth metatarsal head. This article discusses 7 corrective measures: medial oblique sliding osteotomy with fixation, medial oblique slide osteotomy-minimal incision procedure without fixation, SERI (simple, effective, rapid, inexpensive) with fixation, chevron with or without fixation, closing, lateral wedge osteotomy at the metatarsal neck or proximal diaphysis, Weil osteotomy, and scarfette. These evidence-based techniques can be used by practitioners for medical management of their patients through evaluation, diagnosis, and prognosis. Complications are also addressed. PMID- 26117572 TI - Metatarsus Primus Varus Correction. AB - We present a discussion on the use of proximal first-ray osteotomies in the surgical treatment for hallux valgus as a valid option compared with first tarsometatarsal arthrodesis. Recent and historical literature tells us that stability of the first ray is a function of the alignment and reestablishment of retrograde stabilizing forces at the first tarsometatarsal joint. This realignment and stabilization may be accomplished with the use of distal soft tissue and proximal osteotomy procedures. PMID- 26117573 TI - Corrective Osteotomies Used in Cavus Reconstruction. AB - The authors dedicate this article to describing the clinical work-up and etiology for a cavus foot deformity as well as the surgical decision making for correction. Understanding and proper utilization of osteotomies is paramount in the improvement of cavus foot deformities. Also, the authors share their own experiences with preferred techniques for optimal outcomes. PMID- 26117574 TI - Osteotomies for the Flexible Adult Acquired Flatfoot Disorder. AB - Flexible adult acquired flatfoot disorder is commonly treated with the use of osteotomies in the calcaneus and medial column. The combination of these joint preserving osteotomies with additional soft-tissue procedures allows realignment of the hindfoot with the goal of preventing further deformity or degenerative joint disease. A thorough understanding of each patient's condition allows the surgeon to match the correct osteotomy to the clinical indication, while also successfully executing the planned surgery. PMID- 26117575 TI - Osteotomies for the Management of Charcot Neuroarthropathy of the Foot and Ankle. AB - Patients with diabetic neuropathy that develop unstable Charcot neuroarthropathy not only have an autoimmune disease that prolongs the healing process, they also often have an inability to maintain a non-weight bearing status. Charcot neuroarthopathy is often devastating to the structure and stability of the foot and ankle. This disease may require permanent bracing, reconstructive surgical stabilization, and in some cases lower leg amputation. Successful management of Charcot neuroarthopathy requires diligence and surveillance by physician and patient alike. PMID- 26117576 TI - Minimally Invasive Surgery Osteotomy of the Hindfoot. AB - A minimally invasive surgical approach has been developed for hindfoot as well as forefoot procedures. Percutaneous techniques have been evolving for more than 20 years. Many conventional surgical techniques can be performed percutaneously after training. Percutaneous surgical techniques require knowledge specific to each procedure (eg, percutaneous Zadek osteotomy or percutaneous medial heel shift). In the treatment and correction of the hindfoot pathology the surgeon now has percutaneous options including medial or lateral heel shift, Zadek osteotomy, and exostectomy with/without arthroscopy. PMID- 26117577 TI - Supramalleolar Osteotomies: An Algorithm for the Deformed Ankle. AB - Supramalleolar osteotomies are powerful osteotomies that realign the tibiotalar and optimize hindfoot position in the presence of varus, valgus, procurvatum, recurvatum, as well as internal and external rotation of the tibia. Although used in the pediatric and hemophilic population earlier, supramalleolar osteotomy is a relatively new reconstructive surgical technique that was introduced in 1995. Conducted primarily in cancellous bone, supramalleolar osteotomies offer rapid, reliable bony consolidation compared with dome osteotomies and complex arthrodesis. PMID- 26117578 TI - Supramalleolar Osteotomy: Indications and Surgical Techniques. AB - Supramalleolar osteotomies are a surgical treatment option for asymmetric varus or valgus ankle arthritis where at least 50% of the joint surface is spared. Procedure selection requires significant preoperative planning for appropriate execution. Thus, the surgeon must be familiar with the principles of deformity correction. With appropriate patient selection and proper preoperative planning, the procedure has been shown to yield excellent results, redistributing forces more evenly across the ankle joint by restoring the mechanical axis of the lower leg with minimal complications. PMID- 26117579 TI - Foot and Ankle Osteotomies. PMID- 26117580 TI - A Fresh Look at Foot and Ankle Osteotomies. PMID- 26117581 TI - Advanced methods for tissue engineering and regenerative medicine. PMID- 26117582 TI - Scombroid poisoning from tilapia. PMID- 26117583 TI - In vitro efficacy testing of a novel high-pressure wound irrigator. PMID- 26117584 TI - Mirror exposure to increase body satisfaction: Should we guide the focus of attention towards positively or negatively evaluated body parts? AB - BACKGROUND AND OBJECTIVES: Though there is some evidence that body exposure increases body satisfaction, it is still unclear why exposure works and how attention should be guided during exposure. This pilot study manipulates the focus of attention during body exposure. METHODS: Female participants high in body dissatisfaction were randomly assigned to an exposure intervention that exclusively focused on self-defined attractive (n = 11) or self-defined unattractive (n = 11) body parts. Both interventions consisted of five exposure sessions and homework. Outcome and process of change were studied. RESULTS: Both types of exposure were equally effective and led to significant improvements in body satisfaction, body checking, body concerns, body avoidance and mood at post test. Improvements for body satisfaction and mood were maintained at follow-up while body shape concerns and body checking still improved between post-test and follow-up. Body avoidance improvements were maintained for the positive exposure while the negative exposure tended to further decrease long-term body avoidance at follow-up.. The 'positive' exposure induced positive feelings during all exposure sessions while the 'negative' exposure initially induced a worsening of feelings but feelings started to improve after some sessions. The most unattractive body part was rated increasingly attractive in both conditions though this increase was significantly larger in the negative compared to the positive exposure condition. LIMITATIONS: The sample size was small and non clinical. CONCLUSIONS: Both types of exposure might be effective and clinically useful. Negative exposure is emotionally hard but might be significantly more effective in increasing the perceived attractiveness of loathed body parts and in decreasing avoidance behavior. PMID- 26117585 TI - Variable expressivity of a familial 1.9 Mb microdeletion in 3q28 leading to haploinsufficiency of TP63: Refinement of the critical region for a new microdeletion phenotype. AB - We report on a 3-year-old male with intellectual disability (ID), characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion of 1.9 Mb. The father, carrying the same deletion, presents with cleft palate, nail dystrophy and learning difficulties. The deleted region in this family is one of the smallest so far reported among genomic deletions affecting 3q27-3q28 for which some phenotypic descriptions are available. In particular, since the phenotype of our proband is strikingly similar to that previously described in a patient with a 9.3 Mb deletion, the deletion identified in this report contributes to the definition of the molecular boundaries of a genomic region responsible for a distinct clinical phenotype. Within the deleted interval there are 9 annotated genes, including TP63. Gain of function mutations of TP63 are known to be responsible for a group of conditions with distal limb and ectodermal involvement, such as ADULT, EEC, LMS, and SHFM4 syndromes. Interestingly, our cases demonstrate a milder phenotypic effect for loss of function of this gene. PMID- 26117586 TI - Lenz-Majewski syndrome: Report of a case with novel mutation in PTDSS1 gene. AB - Lenz-Majewski syndrome (LMS) is an extremely rare syndrome characterized by osteosclerosis, intellectual disability, characteristic facies and distinct craniofacial, dental, cutaneous and distal - limb anomalies. Recently, mutations in PTDSS1 gene have been identified as causative in six unrelated individuals. We report the seventh mutation proven case of LMS and provide a concise review of all known patients till date. PMID- 26117587 TI - Low Incidence of Paravalvular Leakage With the Balloon-Expandable Sapien 3 Transcatheter Heart Valve. AB - BACKGROUND: We evaluated the clinical and hemodynamic performance of the new balloon-expandable Sapien 3 (Edwards Lifesciences, Irvine, CA) transcatheter heart valve (S3 THV). METHODS: Between April 2013 and January 2015, 54 consecutive high-risk patients presenting with aortic stenosis were treated with the new S3 THV. Clinical and hemodynamic data as well as device and procedure variables were obtained at baseline, intraoperatively and at 30-days according to Valve Academic Research Consortium-2. RESULTS: The S3 THV was implanted in 41 patients (44% female) via transapical access and in 13 patients via transaortic access. Patients were a mean +/- standard deviation age of 80.3 +/- 6.0 years. The mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of all patients was 33.3% +/- 13.4%, the mean The Society of Thoracic Surgeons Score was 6.7% +/- 5.3%, and the mean EuroSCORE II was 7.0% +/- 5.5%. All patients underwent successful implantation (23 mm, n = 12; 26 mm, n = 22; 29 mm, n = 20), without any intraprocedural complications or repeat ballooning. At 30 days, 53 patients (97.8%) showed no or mild paravalvular aortic regurgitation, 1 patient (2.2%) showed moderate regurgitation, and no patients had more than moderate postprocedural aortic regurgitation. Stroke incidence was 3.7% (2 of 54), and all-cause mortality was 3.7% (2 of 54, sepsis and multiorgan failure). Two patients required a new pacemaker. At 30 days, all patients were in New York Heart Association Functional Class I or II, and the mean pressure gradients were 10.8 +/- 3.6 mm Hg. CONCLUSIONS: The present study shows excellent clinical and hemodynamic outcomes of high-risk transapical valve replacement patients treated with the new S3 THV. The S3 THV shows a low incidence of postoperative aortic regurgitation, with 98% presenting with less than mild aortic regurgitation. PMID- 26117588 TI - Low-dose dobutamine stress echo for reverse remodeling prediction after cardiac resynchronization. AB - PURPOSE: Cardiac resynchronization therapy (CRT) is a valuable option for patients with heart failure and wide QRS to reduce electromechanical dyssynchrony (DYS). High non-responders rate (30%) urges the need to improve selection of candidates for CRT. We hypothesized that low-dose dobutamine stress echocardiography (DSE) can help unmask dyssynchronous motion. The aim of this study is comparison between dyssynchrony index at rest and during low-dose dobutamine stress to predict left ventricular reverse remodeling after CRT. PATIENTS AND METHODS: Prospectively, 57 consecutive patients (37 male) aged 61.8+/-9 who qualified for CRT according to current guidelines were enrolled. Two dimensional echocardiography and tissue Doppler imaging (TDI) were performed before and 6 month after CRT to assess reverse remodeling (rLV). Additionally DSE was performed before CRT. DYS was assessed at rest (DYSr) and peak DSE (DYSd) separately, as a difference between time to peak systolic velocity (Ts) of septum and lateral wall. Ts was corrected for heart rate. RESULTS: rLV defined as decrease >=15% of LVESV at follow-up was found in 38 (67%) patients. DYSr and DYSd were independent predictors of rLV (OR=1.04, Cl +/-1.02-1.06, p<0.02 and OR=1.05, Cl+/-1.03-1.08, p<0.0002 respectively). ROC analysis found that DYSr>42ms and DYSd>59ms had sensitivity of 70% and 87%, specificity of 61% and 78%, and accuracy of 70% and 84% respectively for prediction of reverse remodeling LV. Area under Receiver Operating Characteristic Curve for DYSd was higher than for DYSr (0.89 vs 0.71, p<0.007). CONCLUSION: Exercise intraventricular dyssynchrony assessed by dobutamine stress echo is a strong independent predictor of cardiac resynchronization therapy response. PMID- 26117589 TI - Contribution of socioeconomic position over life to frailty differences in old age: comparison of life-course models in a French sample of 2350 old people. AB - PURPOSE: To assess the impact of socioeconomic position (SEP) over life on a measure of frailty in old age. METHODS: This is a cross-sectional population study of people aged 70 years and more in which 2350 respondents were interviewed in 2008 to 2010. The relationships between different indicators of SEP (childhood standard of living, level of education, occupational class, and current affluence) and quartiles of a frailty index including 43 variables were assessed in ordinal regression models adjusted for potential confounders. RESULTS: Mean age of the population was 83.3 +/- 7.5 years, with 59.4% of women. The mean value of the frailty index was 0.19 +/- 0.13, with values ranging between 0 and 0.65. All periods of social disadvantage were associated with increasing frailty in bivariate analysis. In multivariate analysis, a poor level financial security in the old age was the SEP indicator the most strongly associated with frailty (odds ratio [OR]: 2.81, 95% confidence interval [CI]: 2.20-3.59), followed by a low level of education (OR: 1.45, 95% CI: 1.17-1.80) and occupation during active life (OR: 1.38, 95% CI: 1.06-1.79). CONCLUSIONS: Socioeconomic inequalities over life affect health capital in old age. The most important risk factor identified in this study, contemporary financial difficulties, was also the most accessible to prevention. PMID- 26117590 TI - Reanalysis of the socioeconomic gradient in all cause mortality for women with breast cancer after detection of an inadvertent error. PMID- 26117591 TI - Predicting scleral GP lens entrapped tear layer oxygen tensions. PMID- 26117592 TI - Aspirin Response Test role in platelet transfusion following intracerebral hemorrhage. AB - OBJECTIVES: Spontaneous intracerebral hemorrhage (ICH) results in high morbidity and mortality. A target for therapy might be hematoma expansion, which occurs in a significant proportion of patients, and can be exacerbated by antiplatelet medications, such as aspirin. It is not clear whether platelet transfusion neutralizes aspirin. The Aspirin Response Test (ART) is commonly ordered in this patient population, but it is not clear whether the results of this test can help select patients for transfusion of platelets. The aim of our study is to investigate whether a selected group of ICH patients, those with reduced platelet activity ("aspirin responders"), will benefit from platelet transfusion. MATERIALS AND METHODS: This retrospective study included 63 patients who were taking aspirin but no other antithrombotic medication prior to the ICH. For each patient, we measured hematoma size by head CT on admission and compared with follow-up head CT 1 day later. RESULTS: In the general cohort, 41% of transfused patients and 29% of non-transfused patients had a hematoma expansion. In the "aspirin responders" group, 46% of transfused patients and 22% of non-transfused patients had an expansion. CONCLUSIONS: Our data suggest that platelet transfusion following an ICH in "aspirin responders" does not reduce hematoma expansion rates in those patients. A larger prospective study is needed. PMID- 26117593 TI - Association between renal dysfunction and 3-year mortality in patients with acute first-ever ischemic stroke. AB - OBJECTIVE: The influence of renal dysfunction on the clinical presentation and outcomes of patients with acute ischemic stroke is still controversial. We investigate the influence of renal dysfunction on the outcomes of patients with acute first-ever ischemic stroke. METHODS: Nine-hundred thirty-four patients with acute first-ever ischemic stroke were enrolled and followed for 3 years. Renal function was assessed using the equation of the Modification Diet for Renal Disease for estimated glomerular filtration rate (eGFR). Serum creatinine levels were obtained within 3 days of acute stroke onset. Reduced eGFR was defined as eGFR<60ml/min/1.73m(2). Clinical presentation, risk factors for stroke, laboratory data, co-morbidities, and outcomes were recorded. RESULTS: Total 264 patients (28.3%) had a reduced eGFR. The prevalence of older age, hypertension, and atrial fibrillation was significantly higher in patients with a reduced eGFR. Total anterior circulation syndrome occurred more frequently among patients with a reduced eGFR (P=0.010). Multivariate Cox regression revealed that a reduced eGFR is a significant predictor of 3-year mortality (HR=1.67, 95% CI=1.06-2.62, P=0.026). CONCLUSION: Reduced eGFR during the acute stroke stage is associated with increased risk of 3-year mortality. Furthermore, risk of acute complications and poor functional outcomes following discharge was significantly higher in patients with a reduced eGFR. PMID- 26117594 TI - Selectin-mediated leukocyte trafficking during the development of autoimmune disease. AB - Tissue inflammation is a finely regulated process that controls wound healing and allows the clearance of damaged cells, pathogens and irritants. However, excessive or uncontrolled inflammation is detrimental, causing tissue damage and leading to autoimmunity. The recruitment of circulating leukocytes to the target tissue is a key stage in the inflammatory process, and is controlled by a multistep cascade in which adhesive receptors known as selectins mediate initial leukocyte tethering and rolling along vascular surfaces, which is required for their subsequent adhesion and arrest. This review considers the role of selectins and their ligands in the recruitment of circulating leukocytes to peripheral tissues during inflammatory responses that lead to the development of autoimmunity, focusing on data from animal models and clinical trials suggesting that selectins may offer valuable therapeutic targets for the treatment of autoimmune diseases. PMID- 26117595 TI - Oral mucosal manifestations of autoimmune skin diseases. AB - A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by various methods including histological examination, direct and indirect immunofluorescence microscopy, immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practitioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatosis with oral involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity with a specific emphasis on their differential diagnosis and current management approaches. PMID- 26117596 TI - Prevention of cardiovascular disease in rheumatoid arthritis. AB - The increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA) has been recognized for many years. However, although the characteristics of CVD and its burden resemble those in diabetes, the focus on cardiovascular (CV) prevention in RA has lagged behind, both in the clinical and research settings. Similar to diabetes, the clinical picture of CVD in RA may be atypical, even asymptomatic. Therefore, a proactive screening for subclinical CVD in RA is warranted. Because of the lack of clinical trials, the ideal CVD prevention (CVP) in RA has not yet been defined. In this article, we focus on challenges and controversies in the CVP in RA (such as thresholds for statin therapy), and propose recommendations based on the current evidence. Due to the significant contribution of non-traditional, RA-related CV risk factors, the CV risk calculators developed for the general population underestimate the true risk in RA. Thus, there is an enormous need to develop adequate CV risk stratification tools and to identify the optimal CVP strategies in RA. While awaiting results from randomized controlled trials in RA, clinicians are largely dependent on the use of common sense, and extrapolation of data from studies on other patient populations. The CVP in RA should be based on an individualized evaluation of a broad spectrum of risk factors, and include: 1) reduction of inflammation, preferably with drugs decreasing CV risk, 2) management of factors associated with increased CV risk (e.g., smoking, hypertension, hyperglycemia, dyslipidemia, kidney disease, depression, periodontitis, hypothyroidism, vitamin D deficiency and sleep apnea), and promotion of healthy life style (smoking cessation, healthy diet, adjusted physical activity, stress management, weight control), 3) aspirin and influenza and pneumococcus vaccines according to current guidelines, and 4) limiting use of drugs that increase CV risk. Rheumatologists should take responsibility for the education of health care providers and RA patients regarding CVP in RA. It is immensely important to incorporate CV outcomes in testing of anti-rheumatic drugs. PMID- 26117597 TI - hfq regulates acid tolerance and virulence by responding to acid stress in Shigella flexneri. AB - Shigella flexneri is an important etiological agent of bacillary dysentery in developing countries. The Hfq protein is thought to play a major regulatory role in various cellular processes in this organism. However, the roles of Hfq in stress tolerance and virulence in S. flexneri in response to environmental stress have not been fully studied. In this study, hfq was highly expressed when S. flexneri was exposed to low pH. Growth retardation was observed in the hfq deletion mutant at pH values ranging from 5.0 to 7.0 and the survival rate of the mutant strain was reduced by 60% in acidic conditions (pH 3.0) compared with the wild-type strain. Additionally, competitive invasion assays in HeLa cells and lung invasion assays showed that the virulence of the hfq deletion mutant was significantly decreased. An evaluation of the mechanism revealed that, along with the expression of the Type III secretion system genes, acid resistance genes were also increased with acid stress. Interestingly, a statistically strong linear correlation was observed between the expression of hfq and Type III secretion system genes, as well as between hfq and acid resistance genes, under various pH conditions. In this study, we provide evidence that Hfq regulates genes related to acid resistance for survival under acid stress and controls virulence through the positive regulation of Type III secretion systems. Importantly, we propose that hfq is a key factor in maximal adaptation to host acid stress during infection, regulating acid stress tolerance and virulence in response to acid stress in S. flexneri. PMID- 26117598 TI - Comparative metagenomics reveals microbial community differentiation in a biological heap leaching system. AB - The microbial community in a biological heap leaching (BHL) system is crucial for the decomposition of ores. However, the microbial community structure and functional differentiation in different parts of a biological heap leaching system are still unknown. In this study, metagenomic sequencing was used to fully illuminate the microbial community differentiation in the pregnant leach solution (PLS) and leaching heap (LH) of a BHL system. Long-read sequences (1.3 million) were obtained for the two samples, and the MG_RAST server was used to perform further analysis. The taxa analysis results indicated that the dominant genera of PLS is autotrophic bacterium Acidithiobacillus, but heterotrophic bacterium Acidiphilium is predominant in LH. Furthermore, functional annotation and hierarchical comparison with different reference samples showed that the abundant presence of genes was involved in transposition, DNA repair and heavy metal transport. The sequences related to transposase, which is important for the survival of the organism in the hostile environment, were both mainly classified into Acidiphilium for PLS and LH. These results indicated that not only autotrophic bacteria such as Acidithiobacillus, but also heterotrophic bacteria such as Acidiphilium, were essential participants in the bioleaching process. This new meta-view research will further facilitate the effective application of bioleaching. PMID- 26117599 TI - Direct measurement of efflux in Pseudomonas aeruginosa using an environment sensitive fluorescent dye. AB - Resistance-Nodulation-Division (RND) family pumps AcrB and MexB are the major efflux routes in Escherichia coli and Pseudomonas aeruginosa respectively. Fluorescent environment-sensitive dyes provide a means to study efflux pump function in live bacterial cells in real-time. Recently, we demonstrated the utility of this approach using the dye Nile Red to quantify AcrB-mediated efflux and measured the ability of antibiotics and other efflux pump substrates to compete with efflux of Nile Red, independent of antibacterial activity. Here, we extend this method to P. aeruginosa and describe a novel application that permits the comparison and rank-ordering of bacterial strains by their inherent efflux potential. We show that glucose and l-malate re-energize Nile Red efflux in P. aeruginosa, and we highlight differences in the glucose dependence and kinetics of efflux between P. aeruginosa and E. coli. We quantify the differences in efflux among a set of P. aeruginosa laboratory strains, which include PAO1, the hyper-sensitive strain ATCC 35151 and its parent, ATCC 12055. Efflux of Nile Red in P. aeruginosa is mediated by MexAB-OprM and is slower than in E. coli. In conclusion, we describe an efflux measurement tool for use in antibacterial drug discovery and basic research on P. aeruginosa efflux pumps. PMID- 26117600 TI - Riemerella anatipestifer lacks luxS, but can uptake exogenous autoinducer-2 to regulate biofilm formation. AB - Riemerella anatipestifer (RA) causes major economic losses to the duck industry. Autoinducer-2 (AI-2) is a quorum-sensing signal that regulates bacterial physiology. The luxS and pfs genes are required for AI-2 synthesis in many bacterial species. pfs encodes Pfs, which functions upstream of LuxS in the biosynthesis of AI-2. In this study, we investigated the AI-2 activity of RA using an AI-2 bioassay, which showed that RA does not produce AI-2. Bioinformatic analysis indicated that the RA genome has a pfs, but not a luxS, homologue. To investigate the function of RA pfs, an avian pathogenic Escherichia coli (APEC) pfs mutant was constructed, which was subsequently transformed with a recombinant plasmid carrying RA pfs. An AI-2 bioassay demonstrated that RA pfs restored AI-2 production to the APEC pfs mutant, suggesting that RA pfs functions in AI-2 synthesis. Furthermore, we found that RA utilizes exogenous AI-2 to regulate biofilm formation. RA biofilm formation decreased significantly upon addition of exogenous AI-2. Real-time quantitative PCR results showed that expression of 13 genes related to RA biofilm formation decreased significantly when exogenous AI-2 was added to the RA culture media. These findings will benefit future studies on AI-2 regulation in RA. PMID- 26117602 TI - Uncommon RB1 somatic mutations in a unilateral retinoblastoma patient. AB - Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Somatic inactivation of both alleles of the RB1 tumor suppressor gene in a developing retina is a crucial event in the initiation of tumorigenesis in most cases of isolated unilateral retinoblastoma. We analyzed the DNA from tumor tissue and peripheral blood of a unilateral retinoblastoma patient to determine the RB1 mutation status and to provide an accurate genetic counseling. A comprehensive approach, based on our previous experience, was used to identify the causative RB1 mutations. Screening for RB1 mutations was performed by PCR direct sequencing, multiplex ligation-dependent probe amplification (MLPA) and Real Time-PCR analyses. Three different mutations were identified in the tumor DNA, which were absent in blood DNA. The somatic origin of these mutations was vital to rule out the heritable condition in this patient. PMID- 26117601 TI - Ovotoxicants 4-vinylcyclohexene 1,2-monoepoxide and 4-vinylcyclohexene diepoxide disrupt redox status and modify different electrophile sensitive target enzymes and genes in Drosophila melanogaster. AB - The compounds 4-vinylcyclohexene 1,2-monoepoxide (VCM) and 4-Vinylcyclohexene diepoxide (VCD) are the two downstream metabolites of 4-vinylcyclohexene (VCH), an ovotoxic agent in mammals. In addition, VCM and VCD may be found as by products of VCH oxidation in the environment. Recently, we reported the involvement of oxidative stress in the toxicity of VCH in Drosophila melanogaster. However, it was not possible to determine the individual contributions of VCM and VCD in VCH toxicity. Hence, we investigated the toxicity of VCM and VCD (10-1000 uM) in flies after 5 days of exposure via the diet. Our results indicated impairments in climbing behaviour and disruptions in antioxidant balance and redox status evidenced by an increase in DCFH oxidation, decreases in total thiol content and glutathione-S-transferase (GST) activity in the flies exposed to VCM and VCD (p<0.05). These effects were accompanied by disruptions in the transcription of the genes encoding the proteins superoxide dismutase (SOD1), kelch-like erythroid-derived cap-n-collar (CNC) homology (ECH) associated protein 1 (Keap-1), mitogen activated protein kinase 2 (MAPK-2), catalase, Cyp18a1, JAFRAC 1 (thioredoxin peroxidase 1) and thioredoxin reductase 1 (TrxR-1) (p<0.05). VCM and VCD inhibited acetylcholinesterase (AChE) and delta aminolevulinic acid dehydratase (delta-ALA D) activities in the flies (p<0.05). Indeed, here, we demonstrated that different target enzymes and genes were modified by the electrophiles VCM and VCD in the flies. Thus, D. melanogaster has provided further lessons on the toxicity of VCM and VCD which suggest that the reported toxicity of VCH may be mediated by its transformation to VCM and VCD. PMID- 26117603 TI - [Vitamin D deficit in hospitalized patients]. AB - We prospectively studied 60 consecutive patients in order to evaluate the prevalence of vitamin D deficiency. All of them were inpatients, and were evaluated from October 2013 through May 2014. Levels of 25 OH vitamin D were classified as sufficient (> 30 ng/ml), mild to moderate deficiency (15 to 30 ng/ml) and severe deficiency (< 15 ng/ml). The mean age was 72.1 +/- 19.5 years; 43 were females and 17 males. Five percent of the patients had normal values of vitamin D, 31.6% had mild to moderate deficit and 63.3% had severe deficit of the vitamin. Severe deficit was associated with hypoalbuminemia, compared with mild to moderate deficit and with sufficient values (2.98 g/dl vs. 3.52 g/dl and vs. 4.39 g/dl, respectively, p: 0.012) and low levels of serum calcium (8.35 mg/dl vs. 8.61 mg/dl and 9.8 mg/dl, respectively, p: 0.003). Although there was a trend of low vitamin D levels with increasing age, female sex, immobilization, higher levels of glucose and glycated haemoglobin, more duration of hospitalization, we didn't find any statistically significance difference between groups. Vitamin D deficiency is common in hospitalized patients. It correlates with low levels of serum albumin and calcium. Improving diagnosis and recognition of this condition may enable us to improve the management of this deficit. PMID- 26117604 TI - [Trends of tuberculosis in the Fifth Health Region, Buenos Aires Province, years 2000-2011]. AB - The aim of this study was to describe the trends in tuberculosis (TB) in the Fifth Health Region (RSV) in the Buenos Aires Province. A trend study allowed the evaluation of the average variation of change in the incidence rate (IR) using simple linear regression expressed as a mean annual variation (VAP). The number of reported TB cases and IR per 100 000 population of all TB cases, pulmonary TB (PTB) and bacteriologically confirmed PTB from January 1, 2000 to December 31, 2011, were analyzed by age groups: 0-14; 15-29 and over 64 years of age. The decline in IR was less than 5% for all forms of TB and lower for bacteriologically confirmed PTB cases. The highest rate of PTB and IR was concentrated in the age group of 15-29 years with stable or slightly increasing trend of IR in bacteriologically confirmed PTB. There were similar trends for bacteriologically confirmed PTB in children. The fastest decline in PTB IR occurred in 0-14 age group, while for cases over 64 years of age the decline was sustained over time. TB continues to be a health risk in RSV, with cases in younger age groups. Therefore, it remains necessary to strengthen TB control activities in this region. PMID- 26117605 TI - [Comparison of FRAX Score without bone mineral density determination and the criteria proposed by the Argentine Osteoporosis Society for the use of antiresorptive therapy in postmenopausal women]. AB - To identify patients at high risk of fracture using clinical risk factors could reduce health costs arising from the realization of a bone densitometry. The aim of this study was to compare the FRAX score without bone mineral density (BMD) with the criteria proposed by the Argentine Society of Osteoporosis (SAO) to consider starting antiresorptive treatment. We conducted an observational, cross sectional study where 330 postmenopausal women between 40 and 90 years of age were included. The number of treatments given if the FRAX tool without BMD had been followed was compared with the number of treatments indicated using the SAO criteria. Using the SAO criteria, 85 (25.8%) patients would initiate antiresorptive treatment compared with 15 (4.5%) using the FRAX without BMD (p = 0.0019). Among the 67 patients with a diagnosis of osteoporosis by BMD determination, all of them (100%) would have received treatment by using the SAO criteria compared with 10 (15%) using the FRAX score (p = 0.011). The use of FRAX without BMD significantly underestimates the number of patients who should receive antiresorptive treatment. In patients diagnosed with osteoporosis by BMD, the FRAX score underestimates the number of patients to be treated. PMID- 26117606 TI - [Current patterns of presentation of renal tumors]. AB - The aim of this paper is to describe the epidemiological characteristics, clinical management and pathologic patterns in a population with renal tumors in our institution. Prospective data collection was performed over a period of 4.5 years, from January 2010 to June 2014. A total of 819 cases (796 patients) were treated for renal mass during this period. The mean age was 60.7 years (SD 13.1). There were 553 (69.5%) males (male to female ratio: 2.2: 1). Twenty nine per cent (230 patients) were obese (BMI = 30). The diagnosis was incidental in 653 cases (79.7%), 48.8% presented one or more risk factors, being smoking the most frequent (34%). In 238 patients (29.9%) there was more than one comorbidity; 18% had preoperative creatinine = 1.3 mg/dl. Lesions were = 4 cm (cT1a) in 45% of the patients, and 10.8% (86) had metastases at diagnosis. The lesions were resected in 93.5% and actively monitored in 6.5% (not resected). In surgery treated patients, radical nephrectomy was performed in 51.5% of cases, and nephron sparing surgery in 48.5% of them. The laparoscopic approach was used in 56.2%. The pattern of presentation of renal masses is characterized by incidental diagnosis in early disease stages. Nephron sparing surgery is the first choice in nearly half of patients. Active surveillance has been used in a greater percentage than previously reported. PMID- 26117607 TI - [Primary HIV resistance in Buenos Aires metropolitan area]. AB - Surveillance of primary drug resistance is critical to optimize antiretroviral therapy (ART) for HIV. Mutations to be monitored are defined in a reference list of the World Health Organization (WHO), which does not include mutations for new drugs, such as rilpivirine. We undertook a retrospective analysis of medical records of ART naive patients treated at a specialized HIV/AIDS center, evaluating the prevalence of WHO mutations and mutations specific for rilpivirine. Ninety-one patients were included during 2011-2013, being male 71 (78.0%), and men who have sex with men 46 (50.5%). The median values for age, viral load, and CD4 counts were 33 years, 62 100 copies/mL, and 548 cells/MUl, retrospectively; 34 (37.3%) had early infection and 60 (65.9%) were asymptomatic. WHO mutations were found in 11 (12.1%) patients, two of whom presented multiple mutations. Seven mutations corresponded to non-nucleoside reverse transcriptase inhibitors, four to nucleoside analogues, and two to protease inhibitors. The most frequent mutations were K103N and M41L. No differences in mutation frequencies were found when compared by time post-infection, gender, sexual orientation, or CD4 count. Mutations conferring low-level resistance to rilpivirine were found in 3 (3.3%) patients; such mutations were E138A and E138G. The overall moderate primary resistance levels found in this study highlight the value of performing a resistance test before ART initiation in the served population. The observed prevalence of primary resistance to rilpivirine was low. PMID- 26117608 TI - [Celiac trunk compression syndrome by the median arcuate ligament. Laparoscopic approach]. AB - Median arcuate ligament syndrome (MALS), or celiac trunk compression syndrome, is caused by extrinsic compression of median arcuate ligament, prominent fibrous bands and periaortic nodal tissue. In many cases is asymptomatic, but it may manifests with symptoms such as postprandial abdominal pain or during exercise, nauseas, vomiting and weight loss. Trough less invasive diagnostic techniques, such as doppler ultrasound for screening and preoperative angiotomograhpy, it is possible to obtain good results, comparable to those with arteriography. Surgical treatment by laparoscopic approach is a safe and effective technique. A symptomatic case that required surgical treatment, a laparoscopic approach, with clinical and imaging improvement after the procedure, is presented. PMID- 26117609 TI - [Idiopathic and unilateral hypoglossal nerve palsy]. AB - The isolated unilateral palsy of the hypoglossal nerve is an unusual sign in daily medical practice. We present the case of a 74 year old man, without relevant medical history, who started with headache and difficulty to swallow. On the physical examination, he had isolated hypoglossal nerve palsy without evidence of tongue atrophy or fasciculation. The patient had a good spontaneous evolution. Idiopathic isolated hypoglossal nerve palsy requires an exhaustive evaluation with neuroimages and complementary exams. It usually presents partial or total spontaneous remission. PMID- 26117610 TI - [Hepatitis E virus-associated aplastic anemia. Report of a case]. AB - Hepatitis-associated aplastic anemia (HAAA) is a well-recognized clinical syndrome in which marrow failure follows the development of hepatitis; it can be observed in up to 5% in the aplastic anemia in West Europe and North American countries and 10% in the East Asia. Although hepatotropic and other viruses were suspected of causing HAAA, this hypothesis was rarely confirmed. Currently, the infection with hepatitis E virus represents the first cause of acute hepatitis in the world. Its genotype 3, the most frequent in Argentina and other Latin American countries, was associated with extrahepatic complications (renal, pancreatic, neurologic and hematologic). To our knowledge, only one case of hepatitis E virus-associated aplastic anemia has been previously reported, in Pakistan; the case presented here would be the first in Argentina. The patient was treated with thymoglobulin, cyclosporine, corticosteroids, filgastrim and transfusional support. She developed fungemia due to Candida tropicalis that remitted with equinocandins and therefore fever, pulmonary infiltrates and a solitary nodular cerebral image with serum galactomannan (DO index > 1.0 ng/ml) that resolved with voriconazol. She was discharged three months after her admission without transfusion requirements and normal hepatic values.With this in mind, it would be advisable to investigate hepatitis E (HEV) as a cause of HAAA in Argentina. PMID- 26117611 TI - [Facial diplegia with atypical paresthesia. A variant of Guillain-Barre syndrome]. AB - Guillain-Barre syndrome is an acute demyelinating disease which presents in a classic form with muscular weakness and the lack of reflexes. There are multiple variations and atypical forms of the disease, being facial diplegia with paresthesia one of them. Also, the absence of reflexes in this syndrome is typical but not constant, since 10% of patients present reflexes. We describe a case of atypical presentation with bilateral facial palsy, paresthesia, brisk reflexes and weakness in the lower limbs in a 33 year old woman. PMID- 26117612 TI - [Unilateral endobronchial valve in pulmonary emphysema]. PMID- 26117613 TI - [Posterior mitral leaflet cleft assessed by three-dimensional transthoracic echocardiography]. PMID- 26117614 TI - [On the prevalence of hypovitaminosis D in Argentina]. AB - Between 1987 and the date of the present issue, 10 reports have been published on the prevalence of the vitamin D deficit in Argentina. These studies were done investigating new born babies, children, adolescents, and healthy and institutionalized adults, living in southern, middle or northern cities of Argentina. The weighed prevalence of vitamin D deficit in those reports was 43.3% (436/1007). This figure may be lower than reality because it is not known whether the stratification (age and location of residence) of the sum of samples agree with that of the national population. Taking into account the obvious difficulties in carrying out such a research two areas for further research are suggested: a) an investigation on the solar exposure in summer needed to obviate (or not) the oral supplementation of vitamin D in winter, b) to determine the success of the schema of administration taking into account the current controversy between dose and optimum plasma levels of 25(HO)D3. In both instances, the end point should include some of the physiological functions alluded to in this editorial. PMID- 26117615 TI - [Liquid biopsy]. PMID- 26117616 TI - [Role of listening in teaching and medical practice]. PMID- 26117617 TI - [Better care for transplanted patients with kidney graft failure]. PMID- 26117618 TI - [About post-hospitalization cardiac mortality related to medical congresses]. PMID- 26117619 TI - Elbow hemiarthroplasty using a "triceps-on" approach for the management of acute distal humeral fractures. AB - BACKGROUND: Total elbow arthroplasty is an established option for the primary treatment of acute distal humeral fractures, but there are sparse data regarding elbow hemiarthroplasty (EHA) as an alternative. We present the outcome of EHA performed with a modular anatomic prosthesis and a "triceps-on" surgical technique. METHODS: Eighteen consecutive patients underwent EHA for an acute fracture. Two patients died, leaving a study group of 16 patients with minimum 2 year follow-up. Clinical evaluation included range of motion; Mayo Elbow Performance Score; Quick Disabilities of the Arm, Shoulder, and Hand score; and Oxford Elbow Score. Radiographic assessment looked at alignment, evidence of loosening, ulnar and radial head wear, heterotopic ossification, and whether healing of the condyles had occurred. RESULTS: Mean follow-up was 35 months (24 79 months). The mean scores were as follows: Mayo Elbow Performance Score, 89.6; shortened Disabilities of the Arm, Shoulder, and Hand score, 11.2; and Oxford Elbow Score, 43.7. The mean flexion and pronation-supination arcs were 116 degrees and 172 degrees respectively. Radial head wear was absent in 13 patients and mild in 3. Ulnar wear was absent in 6 patients, mild in 8, and moderate in 2. Wear was not associated with greater pain or inferior functional scores. There was no sign of aseptic loosening, and complete condylar bone union occurred in 15 elbows. There was 1 complication, a transient ulnar nerve neurapraxia that resolved without intervention. CONCLUSION: EHA with a modular anatomic implant using a triceps-on approach is a reliable technique for the management of acute unreconstructible distal humeral fractures in older patients. PMID- 26117620 TI - Are Statins out in the COLD? The STATCOPE Trial. AB - A cardiologist and respirologist examined the recent, neutral Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) for issues of relevance to cardiovascular risk reduction with statin medications. Although the potential benefit of the pleiotropic effects of statins on this inflammatory disease was not borne out, the effect over the longer term on total respiratory and cardiovascular morbidity and mortality remain unexplored. This study was unique as the only statin trial to date to use a national guideline (Adult Treatment Panel III) to exclude patients from the trial if at sufficient cardiovascular risk to warrant statin therapy. Furthermore, observed fatal and nonfatal cardiovascular events were shown to provide some evidence to suggest that statins might reduce cardiovascular events despite the low risk category and the relatively low levels of cholesterol. The magnitude of this beneficial trend paralleled the magnitude of lowering of low density lipoprotein cholesterol achieved in the active statin arm. Finally, the authors questioned whether the current standard of care adequately includes adherence to any national lipid guideline or adequate attention to the cardiovascular comorbidity of these patients. In conclusion, knowledge translation of the STATCOPE trial should at a minimum encourage assessment of cardiovascular risk in patients with chronic obstructive pulmonary disease, implementation of proven cardiovascular risk reduction therapies based on national guidelines, including statins, and plans to undertake a trial adequate in size and duration to address cardiovascular event reduction in patients not already eligible for evidence-based risk-reducing therapies. PMID- 26117621 TI - The Assessment of Atrial Electromechanical Delay in Patients With Acromegaly. AB - BACKGROUND: We aimed to evaluate whether atrial electromechanical delay (AEMD) measured by tissue Doppler imaging (TDI), which is an indicator for structural and electrical remodelling of the atria, is prolonged in patients with active or inactive acromegaly, or both, compared with a control group. METHODS: A total of 34 patients with acromegaly (18 active/16 inactive) and 35 patients as a control group were enrolled. Both intra- and inter-AEMD were calculated by TDI. The correlation between clinical variables and AEMD were analyzed. RESULTS: Both inter-AEMD and right and left intra-AEMD were prolonged in patients with acromegaly compared with the control group (P < 0.001, P < 0.001, and P = 0.004, respectively). Also, patients with active acromegaly showed higher inter-AEMD and right intra-AEMD compared with patients with inactive acromegaly (P < 0.05). There was no significant difference in left intra-AEMD between patients with active acromegaly and those with inactive acromegaly (P = 0.977). The growth hormone and insulin-like growth factor (IGF-1) levels positively correlated with inter-AEMD (r = 0.577; P < 0.001; r = 0.614; P < 0.001, respectively). Additionally, we found that inter-AEMD was significantly and positively correlated with relationship between maximal values of passive mitral inflow (E, PW-Doppler) and lateral early diastolic mitral annular velocities (e', TDI) (r = 0.316; P = 0.008). Only the serum IGF-1 level was independently associated with inter-AEMD in multivariate linear regression analysis (beta = 0.500; P = 0.011). CONCLUSIONS: Our study findings showed that both inter- and intra-AEMD are prolonged in patients with acromegaly. Also, AEMD was observed to be more prolonged in patients with active acromegaly than in those with inactive acromegaly. IGF-1 was an independent predictor of inter- AEMD in patients with acromegaly. Being a noninvasive, inexpensive, and simple technique, AEMD may be used as an indicator for atrial electrical and structural remodelling in patients with acromegaly. PMID- 26117622 TI - Percutaneous Coronary Interventions for Chronic Total Occlusions: More Benefit for the Patient or for the Interventionist's Ego? AB - Chronic total occlusions (CTOs) represent a common lesion subset observed in patients who undergo coronary angiography. During the past decade, the interest of the interventionist community in CTOs has exponentially grown with fast advancement in dedicated equipment and techniques, which has resulted in high rates of procedural success and low rates of complications. Although different observational studies have shown that CTO revascularization was associated with good clinical outcome, its real benefit for patients remains to be determined, particularly in the absence of randomized trials. In addition, compared with non CTO lesions, the American and European guidelines downgraded percutaneous coronary intervention in the setting of CTOs. In this viewpoint, we try to identify patients who would benefit from CTO recanalization, and discuss the issues that might improve the appropriateness of CTO percutaneous coronary intervention. PMID- 26117624 TI - Sequential inferior vena cava filter insertion and peripherally inserted central catheter placement through upper extremity veins. AB - PURPOSE: To report the sequential placement of inferior vena cava filter (IVCF) and peripherally inserted central catheter (PICC) using the same upper extremity venous access. MATERIAL AND METHODS: This is a retrospective study that reviewed the medical records of 379 consecutive patients who underwent IVCF insertion during a 39-month period at our center. Of these 379 patients, 28 patients had sequential insertion of an IVCF and a PICC through the same upper extremity venous access. The same vein entry site was used for placement of the IVCF followed by PICC insertion. Data collected included: indication and duration of IVCF and PICC placement, access site location, complications, and the type of IVCF. RESULTS: IVCFs were placed for prophylactic purposes in 15 patients (53.6%) and therapeutic purposes in 13 patients (46.4%). Right upper extremity veins were used for venous access in 27 patients (96.4%): brachial (n=16), basilic (n=9), and cephalic (n=2). The left basilic vein was used in one patient (3.6%). IVCFs were temporary in 20 patients (71.4%) and permanent in 8 patients (28.6%). There were no procedural complications. The OptEase filter was used in 23 patients (82.1%) and the TrapEase filter was used in 5 patients (17.9%). CONCLUSION: Simultaneous IVCF and PICC insertion using the same upper extremity venous access was feasible and safe in our series. This combined technique provides the patient with central venous access for repeated blood collections and intravenous therapy. PMID- 26117623 TI - Serial Optical Coherence Tomography Evaluation at 6, 12, and 24 Months After Biolimus A9-Eluting Biodegradable Polymer-Coated Stent Implantation. AB - BACKGROUND: The Nobori (Terumo Corporation, Tokyo, Japan) is a biolimus A9 eluting stent (BES) featured with a biodegradable polymer coated on the abluminal side only. We previously reported that favourable vessel healing was achieved at 6-12 months after BES implantation. However, detailed long-term vessel reaction after BES deployment is unclear. METHODS: Twenty-two BESs were serially evaluated using optical coherence tomography (OCT) at 6, 12, and 24 months after stenting. Average neointimal thickness, uncovered struts, and neointimal unevenness score (each cross-section as maximum neointimal thickness in 1 cross section divided by the average neointimal thickness of the same cross-section) were manually measured. In addition, we evaluated the percentage of struts with peri-strut low intensity area (a region around stent struts that homogenously showed less intensity than the surrounding tissue, which suggests fibrin deposition or impaired neointima maturation), thrombi, and atherogenic neointimas (neointimas containing a diffuse border and poor-signal region with invisible struts due to marked signal attenuation). RESULTS: Serial OCT observation revealed a small gradual increase in neointimal thickness from 6 to 24 months (73 +/- 24 MUm; 81 +/- 26 MUm; and 108 +/- 35 MUm, respectively, P = 0.001) with a nonsignificant decrease in the lumen area (6.36 +/- 1.98 mm(2); 6.18 +/- 2.04 mm(2); and 5.87 +/ 2.06 mm(2); P = 0.72). Frequency of uncovered struts (3.89 +/- 3.91%; 1.55 +/- 1.63%; and 0.23 +/- 0.67%; P = 0.001), neointimal unevenness score (1.95 +/- 0.18% to 1.86 +/- 0.19% to 1.78 +/- 0.17; P = 0.012), percentage of thrombi (5%, 0%, and 0%; P = 0.37) and peri-strut low-intensity area (6.8%, 5.1%, and 1.6%; P = 0.017) decreased from 6 to 12 and 24 months. Atherogenic neointima was not observed in the event-free OCT cohort. CONCLUSIONS: The Nobori stent achieved acceptable long-term vessel healing, mostly without adverse vessel reactions. PMID- 26117625 TI - STK4 (MST1) deficiency in two siblings with autoimmune cytopenias: A novel mutation. AB - Combined immunodeficiencies (CIDs) are heterogeneous group of disorders characterized by abrogated/impaired T cell development and/or functions that resulted from diverse genetic defects. In addition to the susceptibility to infections with various microorganisms, the patients may have lymphoproliferation, autoimmunity, inflammation, allergy and malignancy. Recently, three groups have independently reported patients having mutations in STK4 gene that cause a novel autosomal recessive (AR) CID. We describe here two siblings with a novel STK4 mutation identified during the evaluation of a group of patients with features highly overlapping with those of DOCK-8 deficiency, a form of AR hyperimmunoglobulin E syndrome. The patients' clinical features include autoimmune cytopenias, viral skin (molluscum contagiosum and perioral herpetic infection) and bacterial infections, mild onychomycosis, mild atopic and seborrheic dermatitis, lymphopenia (particularly CD4 lymphopenia), and intermittent mild neutropenia. Determination of the underlying defect and reporting the patients are required for the description of the phenotypic spectrum of each immunodeficiency. PMID- 26117634 TI - Graduate Medical Education Financing and Governance Reform: How Does the Institute of Medicine's Report Impact Pediatrics? PMID- 26117626 TI - Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura. AB - NF-kappaB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-kappaB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.916G>A (p.D306N), which affects our patient, his mother, and his sister. This mutation did not affect NEMO expression; however, an immunoprecipitation assay revealed reduced ubiquitylation upon CD40-stimulation in the patient's cells. Functional studies have demonstrated reduced phosphorylation and degradation of IkappaBalpha, affecting NF-kappaB recruitment into the nucleus. The patient presented with clinical features of ectodermal dysplasia, immunodeficiency, and immune thrombocytopenic purpura, the latter of which has not been previously reported in a patient with NEMO deficiency. His mother and sister displayed incontinentia pigmenti indicating that, in addition to amorphic mutations, hypomorphic mutations in NEMO can affect females. PMID- 26117635 TI - 50 Years Ago in The Journal of Pediatrics: Primary Liver Cell Carcinoma Associated with Biliary Cirrhosis Due to Congenital Bile Duct Atresia. PMID- 26117636 TI - 50 Years Ago in The Journal of Pediatrics: A Long-Term Study of Cerebrospinal Leukemia. PMID- 26117637 TI - 50 Years Ago in The Journal of Pediatrics: "Hand, Foot, and Mouth Disease" in Children: An Epidemic Associated with Coxsakie Virus A-16. PMID- 26117638 TI - 50 Years Ago in The Journal of Pediatrics: Fatal Infection in a Newborn Infant Due to Herpes Simplex Virus. PMID- 26117639 TI - 50 Years Ago in The Journal of Pediatrics: The Relationship between Obesity in Adolescence and Early Growth. PMID- 26117640 TI - Differentiated Thyroid Cancer in Children: Prevalence and Predictors in a Large Cohort with Thyroid Nodules Followed Prospectively. AB - We retrospectively analyzed the findings of a prospective cohort of 75 children referred for thyroid nodules between 2008 and 2013. Prevalence of papillary differentiated thyroid carcinoma was 18.7%. Thyrotropin >2.5 mIU/L, multinodular goiter, solid nodules, irregular margins, and pathologic lymphadenopathies were identified as independent predictors of malignancy. PMID- 26117641 TI - Obstructive sleep apnea syndrome is associated with delayed growth. PMID- 26117642 TI - Prolonged postconcussive rest is not superior to usual care. PMID- 26117643 TI - Propanolol effectively treats significant infantile hemangiomas. PMID- 26117644 TI - Association of Autism with Cancer. PMID- 26117645 TI - Early peanut consumption is protective against peanut allergy development. PMID- 26117646 TI - Approach to Child-Friendly Health Care--The Council of Europe. PMID- 26117648 TI - Crystal structures of the apo form and a complex of human LMW-PTP with a phosphonic acid provide new evidence of a secondary site potentially related to the anchorage of natural substrates. AB - Low molecular weight protein tyrosine phosphatases (LMW-PTP, EC 3.1.3.48) are a family of single-domain enzymes with molecular weight up to 18 kDa, expressed in different tissues and considered attractive pharmacological targets for cancer chemotherapy. Despite this, few LMW-PTP inhibitors have been described to date, and the structural information on LMW-PTP druggable binding sites is scarce. In this study, a small series of phosphonic acids were designed based on a new crystallographic structure of LMW-PTP complexed with benzylsulfonic acid, determined at 2.1A. In silico docking was used as a tool to interpret the structural and enzyme kinetics data, as well as to design new analogs. From the synthesized series, two compounds were found to act as competitive inhibitors, with inhibition constants of 0.124 and 0.047 mM. We also report the 2.4A structure of another complex in which LMW-PTP is bound to benzylphosphonic acid, and a structure of apo LMW-PTP determined at 2.3A resolution. Although no appreciable conformation changes were observed, in the latter structures, amino acid residues from an expression tag were found bound to a hydrophobic region at the protein surface. This regions is neighbored by positively charged residues, adjacent to the active site pocket, suggesting that this region might be not a mere artefact of crystal contacts but an indication of a possible anchoring region for the natural substrate-which is a phosphorylated protein. PMID- 26117647 TI - Pentamidine analogs as inhibitors of [(3)H]MK-801 and [(3)H]ifenprodil binding to rat brain NMDA receptors. AB - The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [(3)H]MK-801 and the [(3)H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target. PMID- 26117649 TI - Prediction of feature genes in trauma patients with the TNF rs1800629 A allele using support vector machine. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha variant is closely linked to sepsis syndrome and mortality after severe trauma. We aimed to identify feature genes associated with the TNF rs1800629 A allele in trauma patients and help to direct them toward alternative successful treatment. METHODS: In this study, we used 58 sets of gene expression data from Gene Expression Omnibus to predict the feature genes associated with the TNF rs1800629 A allele in trauma patients. We applied support vector machine (SVM) classifier model for classification prediction combining with leave-one-out cross validation method. Functional annotation of feature genes was carried out to study the biological function using database for annotation, visualization, and integrated discovery (DAVID). RESULTS: A total of 133 feature genes were screened out and was well differentiated in the training set (14 patients with variant, 15 with wild type). Moreover, SVM classifier peaked in predictive accuracy with 100% correct rate in training set and 86.2% in testing set. Interestingly, functional annotation showed that feature genes, such as HMOX1 (heme oxygenase (decycling) 1) and RPS7 (ribosomal protein S7) were mainly enriched in terms of cell proliferation and ribosome. CONCLUSION: HMOX1 and RPS7 may be key feature genes associated with the TNF rs1800629 A allele and may play a crucial role in the inflammatory response in trauma patients. Moreover, the cell proliferation and ribosome pathway may contribute to the progression of severe trauma. PMID- 26117650 TI - Hybrid facial image feature extraction and recognition for non-invasive chronic fatigue syndrome diagnosis. AB - Due to an absence of reliable biochemical markers, the diagnosis of chronic fatigue syndrome (CFS) mainly relies on the clinical symptoms, and the experience and skill of the doctors currently. To improve objectivity and reduce work intensity, a hybrid facial feature is proposed. First, several kinds of appearance features are identified in different facial regions according to clinical observations of traditional Chinese medicine experts, including vertical striped wrinkles on the forehead, puffiness of the lower eyelid, the skin colour of the cheeks, nose and lips, and the shape of the mouth corner. Afterwards, such features are extracted and systematically combined to form a hybrid feature. We divide the face into several regions based on twelve active appearance model (AAM) feature points, and ten straight lines across them. Then, Gabor wavelet filtering, CIELab color components, threshold-based segmentation and curve fitting are applied to extract features, and Gabor features are reduced by a manifold preserving projection method. Finally, an AdaBoost based score level fusion of multi-modal features is performed after classification of each feature. Despite that the subjects involved in this trial are exclusively Chinese, the method achieves an average accuracy of 89.04% on the training set and 88.32% on the testing set based on the K-fold cross-validation. In addition, the method also possesses desirable sensitivity and specificity on CFS prediction. PMID- 26117651 TI - The double burden of neoliberalism? Noncommunicable disease policies and the global political economy of risk. AB - The growing prevalence of NCDs in low- and middle-income countries (LMICs) is now recognized as one of the major global health policy issues of the early 21st century. Current official approaches reflect ambivalence about how health policy should approach the social determinants of health identified by the WHO Commission on the topic that released its report in 2008, and in particular the role of macro-scale economic and social processes. Authoritative framing of options for NCD prevention in advance of the September, 2011 UN high-level meeting on NCDs arguably relied on a selective reading of the scientific (including social scientific) evidence, and foregrounded a limited number of risk factors defined in terms of individual behavior: tobacco use, unhealthy diet, alcohol (ab)use and physical inactivity. The effect was to reproduce at a transnational level the individualization of responsibility for health that characterizes most health promotion initiatives in high-income countries, ignoring both the limited control that many people have over their exposure to these risk factors and the contribution of macro-scale processes like trade liberalization and the marketing activities of transnational corporations to the global burden of NCDs. An alternative perspective focuses on "the inequitable distribution of power, money, and resources" described by the WHO Commission, and the ways in which policies that address those inequities can avoid unintentional incorporation of neoliberal constructions of risk and responsibility. PMID- 26117652 TI - Tricuspid regurgitation predicts cardiorenal syndrome in patients with hypertrophic cardiomyopathy. PMID- 26117653 TI - Iatrogenic atrial septal defect (iASD) after MitraClip system delivery: The key role of PaO2/FiO2 ratio in guiding post-procedural iASD closure. PMID- 26117654 TI - Comparative meta-analysis of balloon-expandable and self-expandable valves for transcatheter aortic valve replacement. AB - BACKGROUND: Balloon-expandable valves (BEVs) and self-expandable valves (SEVs) are two major types of valves utilized for transcatheter aortic valve replacement (TAVR). We conducted a meta-analysis of available studies to compare the safety and efficacy of these two valve types. METHODS: Medline search was conducted using standard search terms to determine eligible studies. Primary outcomes of the meta-analysis included death and stroke at 30days and 1year. Pooled estimates of procedural outcomes were also compared between the valve types. Analysis was performed for entire cohort and separately for patients undergoing transfemoral TAVR (TF-TAVR). RESULTS: Analysis of entire cohort revealed similar 30-day mortality in the SEV and BEV cohorts. There was no significant difference in the incidence of stroke at 30days between the two study groups. Both pooled comparisons demonstrated a significant heterogeneity with I(2)>50%, necessitating the use of random effect modeling. We observed a significantly higher incidence of new pacemaker implantation, aortic regurgitation>=2+ at 30days, valve embolization, and need for >1 valve following SEV implantation compared with BEV implantation. Analysis of TF-TAVR cohort showed higher 30day [IRR (95% CI): 1.34 (1.19-1.52)] but a similar 1-year mortality [IRR (95% CI): 1.07 (0.96-1.19)] for SEV compared to BEV implantation. CONCLUSION: Compared to BEV implantation, SEV implantation was associated with a similar risk of mortality and stroke at 30-day and 1-year follow-up duration. Analysis of the TF-TAVR cohort revealed a significantly higher mortality at 30days among patients undergoing SEV implantation, compared with BEV implantation. In addition, there was a significantly higher incidence of other adverse events noted above, following SEV implantation, compared with BEV implantation. PMID- 26117655 TI - Dynamic UltraFast 2D EXchange SpectroscopY (UF-EXSY) of hyperpolarized substrates. AB - In this work, we present a new ultrafast method for acquiring dynamic 2D EXchange SpectroscopY (EXSY) within a single acquisition. This technique reconstructs two dimensional EXSY spectra from one-dimensional spectra based on the phase accrual during echo times. The Ultrafast-EXSY acquisition overcomes long acquisition times typically needed to acquire 2D NMR data by utilizing sparsity and phase dependence to dramatically undersample in the indirect time dimension. This allows for the acquisition of the 2D spectrum within a single shot. We have validated this method in simulations and hyperpolarized enzyme assay experiments separating the dehydration of pyruvate and lactate-to-pyruvate conversion. In a renal cell carcinoma cell (RCC) line, bidirectional exchange was observed. This new technique revealed decreased conversion of lactate-to-pyruvate with high expression of monocarboxylate transporter 4 (MCT4), known to correlate with aggressive cancer phenotypes. We also showed feasibility of this technique in vivo in a RCC model where bidirectional exchange was observed for pyruvate lactate, pyruvate-alanine, and pyruvate-hydrate and were resolved in time. Broadly, the technique is well suited to investigate the dynamics of multiple exchange pathways and applicable to hyperpolarized substrates where chemical exchange has shown great promise across a range of disciplines. PMID- 26117656 TI - Dental health and diet in early medieval Ireland. AB - OBJECTIVE: With the aim to get a better picture of dental health, diet and nutrition in early medieval Ireland a population-based study focusing on several attributes of oral health in adult individuals was conducted. The study focused on possible differences between sexes and age groups in terms of frequency and distribution of studied pathologies in order to determine whether these differences result from different diets, cultural practices or are age-related. DESIGN: Permanent dentitions belonging to adult individuals from five Irish early medieval sites were examined for the evidence of caries, ante-mortem tooth loss, abscesses, calculus, alveolar bone resorption and tooth wear. All pathologies were analysed and presented by teeth and alveoli. RESULTS: A total of 3233 teeth and 3649 alveoli belonging to 167 individuals (85 males and 82 females) were included into the analysis. Males exhibited significantly higher prevalence of abscesses, heavy wear and alveolar bone resorption, while females exhibited significantly higher prevalence of calculus. All studied dento-alveolar pathologies showed a strong correlation with advanced age, except calculus in females. Additionally, dental wear associated with habitual activities was observed in two females. CONCLUSION: The results of the present study confirm the data gained by written sources and stable isotopes analyses suggesting the diet of the early Irish was rich in carbohydrates with only occasional use of meat. Furthermore, significant differences between the sexes in terms of recorded pathologies strongly suggest different nutritional patterns with females consuming foods mostly based on carbohydrates in comparison to males. The observed sex-differences might also occur due to differences between male and female sex such as reproductive biology and pregnancy, a somewhat different age distributions, but also as a result of different cultural practices between the sexes. PMID- 26117657 TI - Native state dynamics affects the folding transition of porcine pancreatic phospholipase A2. AB - Porcine pancreatic phospholipase A2, a small and disulfide rich protein, is extremely resistant against chemically or thermally induced unfolding. Despite this marked resistance, the protein displays broad unfolding transitions resulting in comparatively low apparent thermodynamic stability. Broad unfolding transitions may result from undetected folding intermediates, residual structures in the unfolded state or an inhomogeneity of the native state. Using circular dichroism, fluorescence, and NMR spectroscopy, we ruled out the existence of stably populated folding intermediates, whereas UV absorbance measurements hinted at stable residual structures in the unfolded state. These residual structures proved, however, to have no impact on the folding parameters. Studies by limited proteolysis, CD, and NMR spectroscopy under non-denaturing conditions suggested pronounced dynamics of the protein in the native state, which as long as unrestrained by acidic pH or bound Ca(2+) ions exert considerable influence on the unfolding transition. PMID- 26117658 TI - In vitro and in vivo studies on the degradation of high-purity Mg (99.99wt.%) screw with femoral intracondylar fractured rabbit model. AB - High-purity magnesium (HP Mg) takes advantage in no alloying toxic elements and slower degradation rate in lack of second phases and micro-galvanic corrosion. In this study, as rolled HP Mg was fabricated into screws and went through in vitro immersion tests, cytotoxicity test and bioactive analysis. The HP Mg screws performed uniform corrosion behavior in vitro, and its extraction promoted cell viability, bone alkaline phosphatase (ALP) activity, and mRNA expression of osteogenic differentiation related gene, i.e. ALP, osteopontin (OPN) and RUNX2 of human bone marrow mesenchymal stem cells (hBMSCs). Then HP Mg screws were implanted in vivo as load-bearing implant to fix bone fracture and subsequently gross observation, range of motion (ROM), X-ray scanning, qualitative micro computed tomography (MUCT) analysis, histological analysis, bending-force test and SEM morphology of retrieved screws were performed respectively at 4, 8, 16 and 24 weeks. As a result, the retrieved HP Mg screws in fixation of rabbit femoral intracondylar fracture showed uniform degradation morphology and enough bending force. However, part of PLLA screws was broken in bolt, although its screw thread was still intact. Good osseointegration was revealed surrounding HP Mg screws and increased bone volume and bone mineral density were detected at fracture gap, indicating the rigid fixation and enhanced fracture healing process provided by HP Mg screws. Consequently, the HP Mg showed great potential as internal fixation devices in intra-articular fracture operation. PMID- 26117659 TI - Rapid implantation of dissolving microneedles on an electrospun pillar array. AB - Dissolving microneedles (DMNs), designed to release drugs and dissolve after skin insertion, have been spotlighted as a novel transdermal delivery system due to their advantages such as minimal pain and tissue damage, ability to self administer, and no associated hazardous residues. The drug delivery efficacy of DMNs, however, is limited by incomplete insertion and the extended period required for DMN dissolution. Here, we introduce a novel DMN delivery system, DMN on an electrospun pillar array (DEPA), which can rapidly implant DMNs into skin. DMNs were fabricated on a pillar array covered by a fibrous sheet produced by electrospinning PLGA solution (14%, w/v). DMNs were implanted into the skin by manual application (press and vibration for 10 s) by tearing of the fibers hung on the 300-MUm pillars. Separation of DMNs from the fibrous sheet was dependent on both pillar height and the properties of the fibrous sheet. After evaluation of the implantation and dissolution of DMNs with diffusion of red dye by taking cross-sectional images of porcine skin, the hypoglycemic effect of insulin loaded DEPA was examined using a healthy mouse model. This DMN array overcomes critical issues associated with the low penetration efficiency of flat patch-based DMNs, and will allow realization of patient convenience with the desired drug efficacy. PMID- 26117660 TI - In vivo study of immunogenicity and kinetic characteristics of a quantum dot labelled baculovirus. AB - Nanomaterials conjugated with biomacromolecules, including viruses, have great potential for in vivo applications. Therefore, it is important to evaluate the safety of nanoparticle-conjugated macromolecule biomaterials (Nano-mbio). Although a number of studies have assessed the risks of nanoparticles and macromolecule biomaterials in living bodies, only a few of them investigated Nano mbios. Here we evaluated the in vivo safety profile of a quantum dot-conjugated baculovirus (Bq), a promising new Nano-mbio, in mice. Each animal was injected twice intraperitoneally with 50 MUg virus protein labelled with around 3*10( 5)nmol conjugated qds. Control animals were injected with PBS, quantum dots, baculovirus, or a mixture of quantum dots and baculovirus. Blood, tissues and body weight were analysed at a series of time points following both the first and the second injections. It turned out that the appearance and behaviour of the mice injected with Bq were similar to those injected with baculovirus alone. However, combination of baculovirus and quantum dot (conjugated or simply mixed) significantly induced stronger adaptive immune responses, and lead to a faster accumulation and longer existence of Cd in the kidneys. Thus, despite the fact that both quantum dot and baculovirus have been claimed to be safe in vivo, applications of Bq in vivo should be cautious. To our knowledge, this is the first study examining the interaction between a nanoparticle-conjugated virus and a living body from a safety perspective, providing a basis for in vivo application of other Nano-mbios. PMID- 26117662 TI - [Fetal abdominal cysts at the first trimester scan]. AB - OBJECTIVES: Abdominal cysts are seldom detected at the first trimester scan. The aim of this study is to ascertain their outcome, which is currently not established. METHODS: The French College of Fetal Ultrasound conducted a prospective observational study of 24months, collecting all cases of abdominal cysts discovered during the first trimester ultrasound. Cases of megacystis were excluded from the study. Ultrasound images, prenatal diagnosis expert reports and pregnancy outcomes were collected by sonographers after patient consent. RESULTS: Ten cases of abdominal cysts were collected. The cysts had a mean diameter of 15mm. They were anechoic in 5 cases, hyperechoic in 2 cases and mixed in 3 cases. In 6 of 10 cases, complete resolution was observed at 18WG with a good post-natal outcome; the five cases with anechoic images were associated with normal pediatric examination at birth and in the case of the resolved hyperechoic image, an isolated imperforate anus was observed. In the four cases of hyperechoic or mixed images that had not resolved, the outcome was poor with four termination of pregnancies, including two cases of cloacal dysgenesis. CONCLUSIONS: Abdominal cysts are rare at the first trimester scan. They resolve in two thirds of cases and are then associated with good outcome. When they do not resolve or when they are not strictly anechoic, they require a referral ultrasound examination at 18 and 22WG. PMID- 26117661 TI - The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties. AB - The goal of this study was to understand how the reconstituted HDL (rHDL) phospholipid (PL) composition affects its cholesterol efflux and anti inflammatory properties. An ApoA-I mimetic peptide, 5A, was combined with either SM or POPC. Both lipid formulations exhibited similar in vitro cholesterol efflux by ABCA1, but 5A-SM exhibited higher ABCG1- and SR-BI-mediated efflux relative to 5A-POPC (P < 0.05). Injection of both rHDLs in rats resulted in mobilization of plasma cholesterol, although the relative potency was 3-fold higher for the same doses of 5A-SM than for 5A-POPC. Formation of prebeta HDL was observed following incubation of rHDLs with both human and rat plasma in vitro, with 5A-SM inducing a higher extent of prebeta formation relative to 5A-POPC. Both rHDLs exhibited anti-inflammatory properties, but 5A-SM showed higher inhibition of TNF-alpha, IL 6, and IL-1beta release than did 5A-POPC (P < 0.05). Both 5A-SM and 5A-POPC showed reduction in total plaque area in ApoE(-/-) mice, but only 5A-SM showed a statistically significant reduction over placebo control and baseline (P < 0.01). The type of PL used to reconstitute peptide has significant influence on rHDL's anti-inflammatory and anti-atherosclerosis properties. PMID- 26117663 TI - Lemierre's syndrome: An unusual presentation. PMID- 26117664 TI - How to avoid venous thromboembolism in women at increased risk--with special focus on low-risk periods. AB - Venous thromboembolism (VTE) is a major cause of mortality during Western women's fertile life. Although half of thromboembolic events occur during times of low risk situations, almost all our knowledge is focused on medical thromboprophylaxis during high-risk situations. Thus, since we only use medical thromboprophylaxis at high-risk periods, lifestyle advice could be an attractive complement both during high- and low-risk situations. The knowledge of how lifestyle factors affect VTE risk has grown in recent years, and women at high risk are often highly motivated to make changes in order to reduce their risk. This review is focused on modifiable risk factors for VTE and advice that may be given to women at increased risk of VTE. PMID- 26117665 TI - The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes. AB - INTRODUCTION: Recent advances in molecular genetics have increased the identification of genes and mutations responsible for inherited forms of hearing loss (HL), enabling early detection of these cases. Approximately, 60% of early onset HL cases are due to genetic causes, of which 70% are non-syndromic. Of these, 75-80% are inherited in an autosomal recessive pattern (DFNB). Mutations in GJB2 gene, coding for connexin 26 (Cx26), are the major cause of autosomal recessive hereditary HL, but some GJB2 mutations are yet of unclear or controversial significance. OBJECTIVES: The aim of the present study was to identify the etiology of hearing loss, and correlate genotype-phenotype, in two Portuguese siblings with profound and moderate non-syndromic sensorineural bilateral HL. MATERIAL AND METHODS: The affected subjects and their parents underwent audiological and genetic study. Molecular analysis of GJB2 gene was performed, searching for mutations in the coding region and receptor splicing site by automated sequencing. RESULTS: The onset and the degree of HL were different in the two affected subjects. However, the same GJB2 genotype [p.Met34Thr]+[p.Arg184Pro] was identified in both siblings. The c.551G>C (p.Arg184Pro) and c.101T>C (p.Met34Thr) missense variants were inherited from the father and mother, respectively, both heterozygous carriers of these variants. CONCLUSION: The clinical and genetic data here presented suggest that the non syndromic sensorineural HL of these two Portuguese siblings might be due to the presence of p.Met34Thr and p.Arg184Pro variants in compound heterozygosity. If so, p.Met34Thr variant could have function as a hypomorphic allele that may cause HL depending on the opposing GJB2 allele. The observed phenotypic variability may not, however, be solely explained by variable expression of this genotype. A putative modifier gene or mutations in another HL-associated gene could probably be contributing to the severe HL in one of the siblings. PMID- 26117666 TI - Clinical experience with video Head Impulse Test in children. AB - BACKGROUND: A standardized diagnostic protocol for children's vestibular assessment is still missing in daily clinical life. As rotatory chair testing and caloric test are usually not tolerated well by children, the aim of our study was not only to evaluate the importance and practicability of the video head impulse test performed in children with and without balance problems, but also to outline a diagnostic algorithm for children with balance problems. METHODS: Fifty-five children aged 3-16 years have been included in this prospective monocentric study. Balance was assessed using results from health screening examinations of the participants and results from a specific dizziness questionnaire for children. The children were then divided in two groups: group I without any sign of vestibular development disorder and group II with possible signs for a pathological equilibrium development. Horizontal vestibulo-ocular reflex (HVOR) was assessed using a video-oculography system device (EyeSeeCam((c))). Gain at 40, 60, and 80ms and gain variance has been measured. Furthermore, it was evaluated how calibration of the system was tolerated by the participants, how the test itself was accomplishable in children, and which difficulties arose during testing. RESULTS: Reproducible test results were accomplished in 42 children (75%). Children with no balance problems in history showed a median gain of 1.02 (+/-0.28). A significant gain reduction between 40 and 80ms was found (P<0.05). Catch-up saccades were found in none of the children. Children with balance problems had a significantly reduced gain. (0.47+/-0.3; P<0.05) In this group, catch-up saccades could be detected in 4 out of 6 patients. For both groups, performing the test approximately took 20min, which is significantly longer than in adults (P<0.05). Calibration of the system with laser dots was easily doable in children aged 6 and older, whereas children between 3 and 5 years had better calibration results using colorful little icons. CONCLUSIONS: Video head impulse test is a sensitive and efficient vestibular test in children, which is tolerated well by children aged 3-16 years. Therefore, video head impulse test can be easily used as a screening tool to detect vestibular dysfunction in the pediatric population. PMID- 26117667 TI - [Viper bite at the external genitalia in a child]. AB - We report on a case of severe envenomation due to viper bites at the external genitalia in an 8-year-old child. The grade III poisoning involved hemostatic disorders and severe swelling. The patient consulted in a timely manner and recovered rapidly after antivenom FAV Africa((r)) administration. PMID- 26117668 TI - Reviewing the safety of GH replacement therapy in adults. AB - CONTEXT: Systematic data on safety of growth hormone (GH) replacement therapy in adult GH deficiency is lacking. OBJECTIVE: To systematically describe safety of adult GH replacement therapy on glucose metabolism and long term safety. DESIGN: A systematic web-based search of PubMed was performed guided by the Standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). OUTCOME: Randomised controlled trials of >=3 months and open trials for >=12 months with more than 50 adult patients (50 patient years, prospective and retrospective) including adverse event reporting as well as articles on mortality primarily on adult onset patients, reporting mortality ratios on GH treated patients, were included for the review. RESULTS: Based on the defined selection criteria 94 studies were included. The short-term early placebo controlled trials did not demonstrate an increased frequency of diabetes mellitus (DM) and the long term open studies did not consistently show an increased incidence of DM during GH replacement. The concern that long-term GH replacement might increase the risk of primary cancer, secondary neoplasia after tumour treatment and recurrence of previous tumours was not evident in the study data. CONCLUSION: Based on available data, short- and long-term adult GH replacement in patients with severe GH deficiency and hypopituitarism is safe. However, the small number of subjects, limitation of long-term of GH treatment data and absence of an adequate control population is still a limitation for the interpretation of these data. PMID- 26117669 TI - Split table improves access for harvest of medial sural artery perforator flap. PMID- 26117670 TI - An important investment to control Acute Rheumatic Fever needs to run its course. PMID- 26117671 TI - Ethnic differences in acute hospitalisations for otitis media and elective hospitalisations for ventilation tubes in New Zealand children aged 0-14 years. AB - AIMS: This paper describes ethnic differences in acute hospitalisations for otitis media (OM) and elective hospitalisations for ventilation tube insertion in New Zealand children aged 0-14 years. Ethnic differences in first attendances at Ear Nose and Throat (ENT) outpatient clinics are also described. METHOD: The analysis included all hospital admissions of children aged 0-14 years during 2002 2008 which met the following criteria: Acute admissions with an ICD-10-AM primary diagnosis code of otitis media; and elective admissions with a primary procedure code of ventilation tube insertion. First attendances at ENT outpatient clinics during 2007-2008 were also reviewed. Explanatory variables included ethnicity, gender, age, and NZ Deprivation Index decile. RESULTS: Among 0-4 year olds, Maori and Pacific children were more likely to be admitted acutely for otitis media than European children. In contrast, both Maori and Pacific children had lower rates of elective admissions for ventilation tube insertion, with ethnic differences being most marked for children from the most deprived areas. Maori and Pacific children aged 5-14 years also had higher acute otitis media admission rates than European children. In contrast to their younger counterparts however, they also had higher rates of ventilation tube insertion. Exploration of ENT outpatient data for children 0-4 years revealed similar first appointment rates for European and Maori children, but lower rates for Pacific and Asian children. For the 5-14 age group, first appointment rates were higher for Maori and Pacific children than for European children. However, Maori and Pacific children in both age groups had higher rates of non-attendance at their first ENT appointments than European children. CONCLUSION: This study highlights ethnic differences in access to ventilation tubes amongst New Zealand's 0-4 year olds, with the greatest inequalities being seen for Maori, Pacific and Asian children living in the most deprived areas. For Maori and Pacific children, such differences cannot be attributed to lower rates of AOM or OME compared to European children. The fact that similar patterns are not seen for children aged 5-14 years potentially suggests that routine Well Child hearing screening may be playing a role in identifying unmet need in this older age group. Such disparities also suggest that factors over and above OM prevalence may be influencing access to ventilation tubes. Further research is required to determine why Maori and Pacific children (0-4 years) have similar/lower ENT appointment rates than European children, despite a higher burden of middle ear disease, as well as higher non-attendance rates at outpatient clinics. Given the importance of early detection and treatment of OM for children's ongoing well-being and education, a greater understanding of the reasons for these inequalities is urgently required. PMID- 26117672 TI - Whooping cough-where are we now? A review. AB - AIMS: This paper describes the recent trends of pertussis and vaccine uptake in New Zealand based on notifications and immunisation registration information since 2011. It highlights the current risk for the infant in the first months after birth and the crucial role a pertussis booster in pregnancy could play. It also aims to show that protection of infants by the acellular pertussis vaccine can be improved by timely immunisation even in a situation of improving overall uptake rates that are nearing the national target of 95%. METHODS: We analysed New Zealand notification data for pertussis, extracted from EpiSurv between August 2011 and December 2013, which included the period of the last epidemic. Pertussis immunisation coverage data were extracted from the National Immunisation Register (NIR). Population estimates were based on 2006 census data. Deprivation was analysed using the New Zealand Deprivation Index 2006. RESULTS: Despite immunisation coverage at 12 months having exceeded 90% New Zealand experienced a large epidemic from 2011 to 2014, with several hundred infant hospitalisations and three deaths. Notification data indicated an average annual rate of pertussis in the New Zealand population of 102 per 100,000 with the highest rates in the youngest age groups. While an overall increase in immunisation coverage in New Zealand was evident and the timeliness showed improvement across ethnic groups and deprivation deciles, there was a marked geographical variation within DHBs and between ethnic groups. CONCLUSIONS: Given the recent published evidence, pertussis vaccination should be offered to all mothers between weeks 28 and 38 of pregnancy. Further improvements are still possible in coverage at 6 months, particularly in Maori and but also in Pacific populations, as well as in more deprived populations. DHBs work towards achieving the 95% target can contribute to the improvement in the timeliness of immunisation. PMID- 26117673 TI - The role of echocardiography in Staphylococcus aureus bacteraemia at Auckland City Hospital. AB - AIMS: Current guidelines recommend echocardiography in all episodes of Staphylococcus aureus bacteraemia (SAB). This study aimed to determine whether a very low-risk group of patients with SAB could be found in whom echocardiography was of no incremental diagnostic value for the diagnosis of infective endocarditis. METHODS: Using the ANZCOSS dataset, we identified 574 eligible episodes of adult SAB at Auckland District Health Board (ADHB) between 2007 and 2012, and retrospectively obtained additional microbiological and clinical data. Prevalence of IE was determined using the modified Duke's criteria for diagnosis of IE. Multivariate logistic regression analysis was used to determine whether risk factors were independently associated with IE, and we also assessed their negative predictive value (NPV). RESULTS: Transthoracic and/or transoesophageal echocardiography was performed in 370 (65%) episodes of SAB. The prevalence of clinically definite and clinically possible IE was 5.6% and 8.5%, respectively. Thirty day all-cause mortality was 11.7%. The factors with the highest NPV when absent in hospital-acquired SAB were non central venous line-associated bacteraemia (100%), persistent bacteraemia (96%), and presence of a prosthetic valve or cardiac rhythm management (CRM) device (95%). When none of these three criteria were present the NPV was 100% (99-100%). CONCLUSIONS: A group of very low risk patients was found in our study: central line-associated SAB without prosthetic valves / CRM devices and without persistent bacteraemia. These patients had no episodes of IE and echocardiography is of no incremental diagnostic benefit. PMID- 26117674 TI - HIV-associated tuberculosis in Auckland. AB - AIM: New Zealand has low rates of disease caused by to Mycobacterium tuberculosis (TB) and Human Immunodeficiency Virus (HIV). This study is the first to describe a New Zealand cohort of patients with HIV-associated TB. METHOD: We retrospectively reviewed the clinical records, laboratory data and chest radiographs of all patients who were diagnosed with HIV-associated TB and who commenced treatment for TB disease at Auckland City Hospital between January 1997 and July 2009. RESULTS: During the 12-and-a-half year study period, 40 patients were diagnosed with HIV-associated TB. The median age was 37 years and the median CD4 count was 130 cells/mm3. Only 2 patients were New Zealand born. Twenty-four (60%) patients had known HIV infection prior to their diagnosis of TB disease. Two patients with known HIV infection and positive tuberculin skin tests had not received treatment for latent tuberculosis infection (LTBI). Twenty-three (58%) patients received antiretroviral treatment during their TB treatment. There were 21 episodes of treatment interruption or immune reconstitution inflammatory syndrome. Three (8%) patients died. CONCLUSIONS: New Zealand continues to have a low incidence of HIV-associated TB. Early HIV diagnosis with universal screening and the treatment of LTBI in persons living with HIV infection is key to minimising the disease burden. PMID- 26117675 TI - Efficacy of intralesional triamcinolone injections for benign refractory oesophageal strictures at Counties Manukau Health, New Zealand. AB - BACKGROUND AND AIMS: Refractory benign strictures of the oesophagus can present a significant clinical challenge and may require repeated attempts at dilatation. Intralesional triamcinolone injections have been used in a limited number of studies to aid in the dilatation of benign, refractory oesophageal strictures. It is hypothesised that intralesional steroid injection inhibits the scar formation, thereby reducing the need for dilatations. The purpose of this study was to assess if steroid injection reduces the need for serial endoscopic dilatations and aids in maintaining oesophageal patency. METHOD: We report a case series of 25 patients with refractory oesophageal strictures. The mean age was 75 years and range between 41-95 years. The etiology of strictures consisted of peptic (68%), anastomotic (4%), radiation induced (16%) and eosinophilic oesophagitis (12%). Majority (75%) were distal in location. Triamcinolone (40-80 mg) was injected via 25-gauge sclerotherapy catheter in a four quadrantic manner in aliquots of 0.5 ml each into the proximal end of the stricture and also into the stricture itself after dilatation. Dilatation was carried out with over the guidewire Savary Gilliard or through the scope (CRE) Balloon dilators depending upon the preference of the endoscopist. Dilatations were continued every 4-6 weeks until asymptomatic and/or endoscopic resolution of stricture. Periodic Dilatation Index (PDI) was calculated by the number of dilatations required over the duration of time in months. RESULTS: The number of dilatations reduced from mean of 3.12 to 1.41 in the peptic strictures but there was no decrease in the other groups. However, the triamcinolone injection resulted in reducing the periodic dilatation index in all groups except the eosinophilic oesophagitis. The rate ratio of PDI before and after intralesional triamcinolone injection use being 0.45 with 95% confidence interval [0.30 -0.68] (p=0.0005). Furthermore triamcinolone injections showed a trend to increase the maximal achieved diameter of the strictures. CONCLUSION: This study demonstrates the efficacy of triamcinolone intralesional steroids in reducing the requirement for repeated dilatations in refractory peptic strictures of oesophagus. Strictures related to eosinophilic oesophagitis failed to demonstrate similar efficacy. PMID- 26117676 TI - Barriers to successful cessation among young late-onset smokers. AB - AIMS: To understand the barriers to cessation among young late-onset smokers (young adults who started smoking daily after turning 18). Such information is crucial to the development of interventions aimed at reducing the high smoking prevalence among young adults. METHOD: The New Zealand Smoking Monitor is a fortnightly telephone survey of current smokers and recent quitters. This study focused on responses from a group of late-onset smokers aged 18 to 28 years (N = 111), who were temporarily (for 11 fortnights) added to the monitor. RESULTS: Most respondents had low nicotine dependence and were actively trying to quit (81% had made at least one attempt that lasted 24 hours or longer in the last year). One-half had high self-efficacy to quit and three-quarters did not intend to use cessation aids. Smoking was tightly linked to drinking alcohol and conferred social benefits (eg, 51% agreed "smoking helped me to socialise"). CONCLUSION: The tendency not to use cessation aids, strong links between smoking and drinking, and the social benefits of smoking may act as barriers to successful cessation among young late-onset smokers. Policies and interventions aimed at breaking associations between smoking, drinking and socialising (eg, smokefree bars) could be effective for this group. PMID- 26117677 TI - Karyotypes, confined blood chimerism, and confusion: a case of genetic sex mislabelling and its potential consequences. AB - Disorders of sex development (DSD) encompass a range of conditions, and the management of infants with DSD can be extremely complex. However, the misdiagnosis of a normal infant as a case of DSD may lead to unfortunate long term consequences for the individual and the family. We report a case of confined blood chimerism masking as 46 XY gonadal dysgenesis in a female from a twin pair with discordant genders, which led to incorrect sex determination at birth. The potentially serious consequences of a wrong DSD diagnosis are discussed, including the removal of normal ovaries. This case emphasises the importance of confirming a blood karyotype where there is discordance with the clinical phenotype and, where possible, identifying whether functional gonadal tissue is present. PMID- 26117678 TI - Domperidone safety: a mini-review of the science of QT prolongation and clinical implications of recent global regulatory recommendations. AB - AIMS: In New Zealand, domperidone is approved for gastrointestinal motility and nausea and vomiting. The European Medicines Agency (EMA) recently concluded that domperidone poses a significant risk of sudden cardiac death (SCD) and has restricted use in Europe. This paper reviews the risk of QT prolongation and cardiac adverse effects with domperidone and provide information to allow prescribers to make informed decisions on usage. METHODS: A search of two bibliographic databases, the European Medicines Agency (EMA) website, Micromedex, Lexicomp and reference texts was undertaken for domperidone related reports of QT prolongation, cardiac arrhythmias and/or SCD. The New Zealand Centre for Adverse Drugs Reaction Monitoring was also contacted for cardiac adverse event reports with domperidone. RESULTS: Over 30 published papers, EMA documents and other information sources were collated, including two studies that met thorough QT study (TQT) criteria (ICH-E14). The first TQT1 was negative while the second was marginally positive. Reports of QT prolongation, ventricular arrhythmias and SCD were located (predominantly high/very high-dose IV domperidone). With oral domperidone, a Dutch case-controlled study reported an adjusted odds ratio of SCD of 11.4 (95% CI 1.99-65.2), based on only three patients out of 1,366 cases of SCD. A second nested case-controlled study calculated an odds ratio of ventricular arrhythmia or SCD of 1.59 (1.28-1.98) vs. placebo. DISCUSSION: Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk. PMID- 26117679 TI - Not a simple back pain. PMID- 26117680 TI - Recalcitrant peripheral spondyloarthritis treated with radiotherapy. PMID- 26117681 TI - Direct access GP referral for ETT functions as a virtual clinic. PMID- 26117682 TI - Uptake of new medicines: the Pharmaceutical Management Agency of New Zealand (PHARMAC) in the international context. PMID- 26117683 TI - Improving our strategy to prevent and control measles outbreaks. PMID- 26117684 TI - Pregnancy complications in women with polycystic ovary syndrome. AB - BACKGROUND: The great majority of studies performed so far concerning women diagnosed with polycystic ovary syndrome (PCOS) have focused on diagnosis, menstrual cycle abnormalities, hirsutism and infertility. Although progress has been made in developing methods for achieving a pregnancy and reducing multiple gestations in women with PCOS, little attention has been paid to pregnancy complications and subsequent child outcomes. This review aims to summarize current knowledge regarding the clinical and pathophysiological features of pregnancy and children in women with PCOS. METHODS: A literature search up to April 2015 was performed in PubMed, Medline, the Cochrane Library and Web of Science without language restriction. All articles were initially screened for title and abstract and full texts of eligible articles were subsequently selected. Systematic reviews with meta-analysis were initially included for each specific subject. Recent randomised controlled trials (RCTs), which were not included in the systematic reviews, were also included. In addition to evidence from meta-analyses or RCTs, we used non-randomized prospective, uncontrolled prospective, retrospective and experimental studies. When specific data for patients with PCOS were lacking, results from general population studies were reported. RESULTS: Women with PCOS exhibit a clinically significant increased risk of pregnancy complications compared with controls. Data which were not adjusted for BMI or other confounders demonstrated in PCOS a 3-4-fold increased risk of pregnancy-induced hypertension and pre-eclampsia, a 3-fold increased risk of gestational diabetes and 2-fold higher chance for premature delivery. Features characteristic of PCOS, such as hyperandrogenism, obesity, insulin resistance and metabolic abnormalities, may contribute to the increased risk of obstetric and neonatal complications. Limited available data suggest that offspring of women with PCOS have an increased risk for future metabolic and reproductive dysfunction. Underlying pathophysiological mechanisms of pregnancy complications along with its association with health of offspring remain uncertain. To date, the strategies for prevention and management of pregnancy complications in women with PCOS, and whether long-term health of these women is influenced, and to what extent, by pregnancy and/or pregnancy complications, remain to be elucidated. CONCLUSIONS: Women with PCOS show an increased risk of pregnancy complications. Heterogeneous aetiological factors involved in PCOS and associated co-morbidities may all be involved in compromised pregnancy and child outcomes. In women with PCOS, a possible relationship with genetic, environmental, clinical and biochemical factors involved in this complex condition, as well as with pregnancy complications and long-term health for both mother and child, remains to be established. PMID- 26117685 TI - Proximal Row Carpectomy. AB - Proximal row carpectomy (PRC) has earned a respected place in the hand surgeon's armamentarium. Prerequisites for the standard PRC are good cartilage on the proximal pole of capitate and in the lunate fossa of radius. If there is cartilage damage on the proximal pole of capitate, the modification of Salomon and Eaton is a reasonable alternative to the standard PRC. The most important surgical step is preservation of the radioscaphocapitate ligament. Good long-term results can be achieved, and with careful patient selection the operation can be done successfully in people who use their hands for heavy work. PMID- 26117686 TI - Metformin for the treatment of gestational diabetes: An updated meta-analysis. AB - OBJECTIVE: To assess the efficacy of metformin and insulin in the treatment of pregnant women with gestational diabetes mellitus (GDM). METHODS: A meta-analysis was conducted by including randomized controlled trials comparing metformin and insulin in GDM. An electronic search was conducted to identify relevant studies. Data were synthesized by a random effects meta-analysis model. A Bayesian analysis was also performed to account for uncertainties in the treatment efficacy. RESULTS: Eight clinical trials involving 1712 individuals were included in the final analysis. The pooled estimates of metformin-insulin differences were very small and statistically non-significant in fasting plasma glucose, postprandial plasma glucose and HbA1c, measured at 36-37 weeks of gestation. Notably, 14-46% of those receiving metformin required additional insulin. Compared with the insulin group, metformin treatment was associated with a lower incidence of neonatal hypoglycemia (relative risk, RR 0.74; 95% CI 0.58-0.93; P=0.01) and of neonatal intensive care admission (RR 0.76; 95% CI 0.59-0.97; P=0.03). Bayesian analysis revealed that the efficacy of metformin was consistently higher than insulin with a probability of over 98% on these two neonatal complications. Other outcomes were not significantly different between the two treatment groups. CONCLUSION: In women with gestational diabetes, metformin use and insulin therapy have comparable glycemic control profile, but metformin use was associated with lower risk of neonatal hypoglycemia. PMID- 26117687 TI - Endocytosis of a maltose permease is induced when amylolytic enzyme production is repressed in Aspergillus oryzae. AB - In the filamentous fungus Aspergillus oryzae, amylolytic enzyme production is induced by the presence of maltose. Previously, we identified a putative maltose permease (MalP) gene in the maltose-utilizing cluster of A. oryzae. malP disruption causes a significant decrease in alpha-amylase activity and maltose consumption, indicating that MalP is a maltose transporter required for amylolytic enzyme production in A. oryzae. Although the expression of amylase genes and malP is repressed by the presence of glucose, the effect of glucose on the abundance of functional MalP is unknown. In this study, we examined the effect of glucose and other carbon sources on the subcellular localization of green fluorescence protein (GFP)-tagged MalP. After glucose addition, GFP-MalP at the plasma membrane was internalized and delivered to the vacuole. This glucose induced internalization of GFP-MalP was inhibited by treatment with latrunculin B, an inhibitor of actin polymerization. Furthermore, GFP-MalP internalization was inhibited by repressing the HECT ubiquitin ligase HulA (ortholog of yeast Rsp5). These results suggest that MalP is transported to the vacuole by endocytosis in the presence of glucose. Besides glucose, mannose and 2 deoxyglucose also induced the endocytosis of GFP-MalP and amylolytic enzyme production was inhibited by the addition of these sugars. However, neither the subcellular localization of GFP-MalP nor amylolytic enzyme production was influenced by the addition of xylose or 3-O-methylglucose. These results imply that MalP endocytosis is induced when amylolytic enzyme production is repressed. PMID- 26117688 TI - The Aspergillus nidulans bimC4 mutation provides an excellent tool for identification of kinesin-14 inhibitors. AB - Centrosome amplification is a hallmark of many types of cancer cells, and clustering of multiple centrosomes is critical for cancer cell survival and proliferation. Human kinesin-14 HSET/KFIC1 is essential for centrosome clustering, and its inhibition leads to the specific killing of cancer cells with extra centrosomes. Since kinesin-14 motor domains are conserved evolutionarily, we conceived a strategy of obtaining kinesin-14 inhibitors using Aspergillus nidulans, based on the previous result that loss of the kinesin-14 KlpA rescues the non-viability of the bimC4 kinesin-5 mutant at 42 degrees C. However, it was unclear whether alteration of BimC or any other non-KlpA protein would be a major factor reversing the lethality of the bimC4 mutant. Here we performed a genome wide screen for bimC4 suppressors and obtained fifteen suppressor strains. None of the suppressor mutations maps to bimC. The vast majority of them contain mutations in the klpA gene, most of which are missense mutations affecting the C terminal motor domain. Our study confirms that the bimC4 mutant is suitable for a cell-based screen for chemical inhibitors of kinesin-14. Since the selection is based on enhanced growth rather than diminished growth, cytotoxic compounds can be excluded. PMID- 26117689 TI - MRI and (1)H MRS findings of hepatobilary changes and cholangiocarcinoma development in hamsters infected with Opisthorchis viverrini and treated with N nitrosodimethylamine. AB - 3 T MRI and (1)H MRS were useful for quantitative investigation of the serial development of hepatobiliary changes in Opisthorchis viverrini infection in hamsters, and the differential diagnosis of cholangiocacinoma (CCA) development from bile duct changes and normal condition is unclear. In this study, we investigated the serial development of hepatobiliary changes and CCAgenesis in O. viverrini-infected and N-nitrosodimethylamine (NDMA) treated hamsters (ON group) using 3 T MRI and (1)H MRS and the results were compared with those either in the O. viverrini-infected group (OV group) and uninfected normal controls. In the ON group, CCAs were first found at 9 weeks post-infection, with sizes of ~2 mm. The typical MR signal characteristics of CCA were hypo- and occasionally isointensity signal on T1-weighted images, and mild-moderate to hyper-intensity signal on T2 weighted images compared to the liver parenchyma. T2-weighted images with fat suppression revealed dilatation of the intra- and extrahepatic bile ducts, and often defined the anatomical level of biliary obstruction, cystic lesions, liver abscesses, and CCA which was starting seen of these noticeable abnormalities at 5 weeks onwards. The results of fibrosis grading using MR images showed a positive correlation (r=0.90, P<0.038 by Spearman's rank correlation test) with those of the histopathological grading. In addition, 3.0 T (1)H MRS showed elevated choline and decreased lipids levels in the liver tissues of the ON group. In conclusion, MRI and (1)H MRS are useful for the quantitative investigation of the serial development of hepatobilary changes and CCA in hamsters, and are potentially useful as early diagnostic tools for CCA. PMID- 26117690 TI - Theoretical considerations in measurement of time discrepancies between input and myocardial time-signal intensity curves in estimates of regional myocardial perfusion with first-pass contrast-enhanced MRI. AB - The purpose of this study was to develop a method to determine time discrepancies between input and myocardial time-signal intensity (TSI) curves for accurate estimation of myocardial perfusion with first-pass contrast-enhanced MRI. Estimation of myocardial perfusion with contrast-enhanced MRI using kinetic models requires faithful recording of contrast content in the blood and myocardium. Typically, the arterial input function (AIF) is obtained by setting a region of interest in the left ventricular cavity. However, there is a small delay between the AIF and the myocardial curves, and such time discrepancies can lead to errors in flow estimation using Patlak plot analysis. In this study, the time discrepancies between the arterial TSI curve and the myocardial tissue TSI curve were estimated based on the compartment model. In the early phase after the arrival of the contrast agent in the myocardium, the relationship between rate constant K1 and the concentrations of Gd-DTPA contrast agent in the myocardium and arterial blood (LV blood) can be described by the equation K1={dCmyo(tpeak)/dt}/Ca(tpeak), where Cmyo(t) and Ca(t) are the relative concentrations of Gd-DTPA contrast agent in the myocardium and in the LV blood, respectively, and tpeak is the time corresponding to the peak of Ca(t). In the ideal case, the time corresponding to the maximum upslope of Cmyo(t), tmax, is equal to tpeak. In practice, however, there is a small difference in the arrival times of the contrast agent into the LV and into the myocardium. This difference was estimated to correspond to the difference between tpeak and tmax. The magnitudes of such time discrepancies and the effectiveness of the correction for these time discrepancies were measured in 18 subjects who underwent myocardial perfusion MRI under rest and stress conditions. The effects of the time discrepancies could be corrected effectively in the myocardial perfusion estimates. PMID- 26117691 TI - Unenhanced breast MRI (STIR, T2-weighted TSE, DWIBS): An accurate and alternative strategy for detecting and differentiating breast lesions. AB - PURPOSE: To assess the role of STIR, T2-weighted TSE and DWIBS sequences for detecting and characterizing breast lesions and to compare unenhanced (UE)-MRI results with contrast-enhanced (CE)-MRI and histological findings, having the latter as the reference standard. MATERIALS AND METHODS: Two hundred eighty consecutive patients (age range, 27-73 years; mean age+/-standard deviation (SD), 48.8+/-9.8years) underwent MR examination with a diagnostic protocol including STIR, T2-weighted TSE, THRIVE and DWIBS sequences. Two radiologists blinded to both dynamic sequences and histological findings evaluated in consensus STIR, T2 weighted TSE and DWIBS sequences and after two weeks CE-MRI images searching for breast lesions. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy for UE-MRI and CE-MRI were calculated. UE-MRI results were also compared with CE- MRI. RESULTS: UE-MRI sequences obtained sensitivity, specificity, diagnostic accuracy, PPV and NPV values of 94%, 79%, 86%, 79% and 94%, respectively. CE-MRI sequences obtained sensitivity, specificity, diagnostic accuracy, PPV and NPV values of 98%, 83%, 90%, 84% and 98%, respectively. No statistically significant difference between UE-MRI and CE-MRI was found. CONCLUSION: Breast UE-MRI could represent an accurate diagnostic tool and a valid alternative to CE-MRI for evaluating breast lesions. STIR and DWIBS sequences allow to detect breast lesions while T2 weighted TSE sequences and ADC values could be useful for lesion characterization. PMID- 26117692 TI - A higher dimensional homodyne filter for phase sensitive partial Fourier reconstruction of magnetic resonance imaging. AB - The aim of this paper is to introduce procedural steps for extension of the 1D homodyne phase correction for k-space truncation in all gradient encoding directions. Compared to the existing method applied to 2D partial k-space, signal losses introduced by the phase correction filter are observed to be minimal for the modified approach. In addition, the modified form of phase correction retains the inherent property of homodyne filtering for elimination of incidental phase artifacts due to truncation. In parallel imaging, this new form of homodyne filtering is shown to be effective for minimizing the signal losses, when each of the channel k-spaces is truncated along both phase and frequency-encode directions. This is illustrated with 2D partial k-space for flow compensated multichannel susceptibility weighted imaging. Extension of this method to 3D partial k-space shows improved reconstruction of flow information in phase contrast magnetic resonance angiography with reduced blur and enhanced background suppression. PMID- 26117693 TI - Comparison of single voxel brain MRS AT 3T and 7T using 32-channel head coils. AB - PURPOSE: The purpose of this study was to compare magnetic resonance spectroscopy (MRS) of three different regions of the human brain between 3 and 7 Tesla, using the same subjects and closely matched methodology at both field strengths. METHODS: A semi-LASER (sLASER) pulse sequence with TE 32ms was used to acquire metabolite spectrum along with the water reference at 3T and 7T using similar experimental parameters and hardware at both field strengths (n=4 per region and field). Spectra were analyzed in LCModel using a simulated basis set. RESULTS: Signal-to-noise ratio (SNR) at 7T was higher compared to 3T, and linewidths (in ppm) at both field strengths were comparable in ppm scale. Of the 13 metabolites reported in the paper, most metabolites were measured with higher precision at 7T in all three regions. CONCLUSION: The study confirms gains in SNR and measurement precision at 7T in all three representative brain regions using the sLASER pulse sequence coupled with a 32-channel phased-array head coil. PMID- 26117694 TI - Using 7.0T MRI T2 mapping to detect early changes of the cartilage matrix caused by immobilization in a rabbit model of immobilization-induced osteoarthritis. AB - OBJECTIVE: The goal of this study was to detect early changes in the cartilage matrix caused by immobilization in a rabbit model of immobilization-induced osteoarthritis (OA) by T2 mapping with 7.0T MRI. MATERIALS AND METHODS: Left knee joints of 28 mature rabbits were immobilized at 180 degrees of extension with orthopedic casting tape for 1, 2, or 3weeks (n=7 rabbits each). No immobilization was performed in the control group (n=7 rabbits). T2 mapping was performed after 1, 2, and 3weeks. Osteochondral specimens harvested from the trochlea groove (TG) and medial femoral condyle (MFC) were subjected to histologic, immunohistochemical, and microscopic evaluation, followed by biochemical assays for water, glycosaminoglycan (GAG), and collagen. The ability of T2 mapping to reveal changes in the cartilage matrix was further assessed. RESULTS: Rabbits demonstrated elevated T2 values (9.9% in TG, 10.6% in MFC), a dulled cartilage surface, reduced Safranin-O staining, and decreased GAG content (14.2% in TG and MFC) after 2weeks, with cartilage surface softening, irregularity, and markedly reduced GAG content by 3weeks. T2 values were correlated positively with water (r=0.836 in TG, r=0.821 in MFC) and negatively with GAG content (r=-0.945 in TG, r=-0.957 in MFC), but had no discernible relationship with collagen content (r= 0.196 in TG, r=-0.213 in MFC). CONCLUSIONS: 7.0T MRI T2 mapping can be used to detect early changes of the cartilage matrix caused by immobilization in an immobilization-induced OA model. PMID- 26117695 TI - Structural information revealed by the dispersion of ADC with frequency. AB - Diffusion MRI provides a non-invasive means to characterize tissue microstructure at varying length scales. Temporal diffusion spectra reveal how the apparent diffusion coefficient (ADC) varies with frequency. When measured using oscillating gradient spin echo sequences, the manner in which ADC disperses with gradient frequency (which is related to the reciprocal of diffusion time) provides information on the characteristic dimensions of restricting structures within the medium. For example, the dispersion of ADC with oscillating gradient frequency (DeltafADC) has been shown to correlate with axon sizes in white matter and provide novel tissue contrast in images of mouse hippocampus and cerebellum. However, despite increasing interest in applying frequency-dependent ADC to derive novel information on tissue, the interpretations of ADC spectra are not always clear. In this study, the relation between ADC spectra and restricting dimensions are further elucidated and used to derive novel image contrast related to the sizes of intrinsic microstructures. PMID- 26117696 TI - Intrahepatic portal vein blood volume estimated by non-contrast magnetic resonance imaging for the assessment of portal hypertension. AB - PURPOSE: To investigate the feasibility of estimating the portal vein blood volume that flows into the intrahepatic volume (IHPVBV) in each cardiac cycle using non-contrast MR venography technique as a surrogate marker of portal hypertension (PH). MATERIALS AND METHODS: Ten patients with chronic liver disease and clinical symptoms of PH (40% males, median age: 54.0, range: 44-73 years old) and ten healthy volunteers (80% males, median age: 54.0, range: 44-66 years old) were included in this study. A non-contrast Triple-Inversion-Recovery Arterial Spin-Labeling (TIR-ASL) technique was used to quantify the IHPVBV in one and two cardiac cycles. Liver (LV) and spleen volumes (SV) were measured by manual segmentation from anatomical MR images as morphological markers of PH. All images were acquired in a 1.5T Philips Achieva MR scanner. RESULTS: PH patients had larger SV (P=0.02) and lower liver-to-spleen ratio (P=0.02) compared with healthy volunteers. The median IHPVBV in healthy volunteers was 13.5cm(3) and 26.5cm(3) for one and two cardiac cycles respectively, whereas in PH patients a median volume of 3.1cm(3) and 9.0cm(3) was observed. When correcting by LV, the IHPVBV was significantly higher in healthy volunteers than PH patients for one and two cardiac cycles. The combination of morphological information (liver-to-spleen ratio) and functional information (IHPVBV/LV) can accurately identify the PH patients with a sensitivity of 90% and specificity of 100%. CONCLUSION: Results show that the portal vein blood volume that flows into the intrahepatic volume in one and two cardiac cycles is significantly lower in PH patients than in healthy volunteers and can be quantified with non-contrast MRI techniques. PMID- 26117697 TI - Motion detection improvement of a pencil-beam navigator echo using a gradient reversal technique. AB - PURPOSE: To develop and demonstrate the feasibility of a pencil-beam navigator using a gradient reversal technique for reducing signal contamination from undesired excitation for precise motion detection and correction. MATERIALS AND METHODS: The navigator echo was obtained using normal and reversed gradient waveforms sequentially in three-dimensional spoiled gradient-recalled echo imaging. These two signals were combined in the complex domain for generating the final navigator data, which were used for detecting the diaphragm motion to nullify the side lobe effects with the smallest radius from the beam center. The navigator signals were compared with and without the proposed technique in phantom and human scans. In addition, navigator-gated imaging was performed in the human scans. RESULTS: In a phantom experiment, the proposed technique diminished signals from a phantom placed outside the beam's area. In human scans, the proposed technique reduced undesired signals in the navigator data for all subjects. The resultant images had fewer motion-induced ghosts than the images from the conventional technique for 8 subjects out of 10. CONCLUSIONS: We have demonstrated that the gradient reversal technique reduced undesired signals in a pencil-beam navigator. This technique can be an alternative for free-breathing abdominal scan when the conventional navigator technique cannot detect the patient's respiratory motion precisely. PMID- 26117698 TI - Comparative quantification of dietary supplemented neural creatine concentrations with (1)H-MRS peak fitting and basis spectrum methods. AB - Magnetic resonance spectroscopy (MRS) is an analytical procedure that can be used to non-invasively measure the concentration of a range of neural metabolites. Creatine is an important neurometabolite with dietary supplementation offering therapeutic potential for neurological disorders with dysfunctional energetic processes. Neural creatine concentrations can be probed using proton MRS and quantified using a range of software packages based on different analytical methods. This experiment examines the differences in quantification performance of two commonly used analysis packages following a creatine supplementation strategy with potential therapeutic application. Human participants followed a seven day dietary supplementation regime in a placebo-controlled, cross-over design interspersed with a five week wash-out period. Spectroscopy data were acquired the day immediately following supplementation and analyzed with two commonly-used software packages which employ vastly different quantification methods. Results demonstrate that neural creatine concentration was augmented following creatine supplementation when analyzed using the peak fitting method of quantification (105.9%+/-10.1). In contrast, no change in neural creatine levels were detected with supplementation when analysis was conducted using the basis spectrum method of quantification (102.6%+/-8.6). Results suggest that software packages that employ the peak fitting procedure for spectral quantification are possibly more sensitive to subtle changes in neural creatine concentrations. The relative simplicity of the spectroscopy sequence and the data analysis procedure suggest that peak fitting procedures may be the most effective means of metabolite quantification when detection of subtle alterations in neural metabolites is necessary. The straightforward technique can be used on a clinical magnetic resonance imaging system. PMID- 26117699 TI - Retrospectively-gated CINE (23)Na imaging of the heart at 7.0 Tesla using density adapted 3D projection reconstruction. AB - PURPOSE: Implementation, evaluation and application of a pulse sequence for retrospectively-gated sodium magnetic resonance imaging of the human heart. METHODS: Measurements were conducted at a magnetic field strength of 7.0 Tesla. A 3D projection reconstruction technique using a standard (ST) and a golden angle (GA) acquisition scheme for short echo time (23)Na MR was applied. Data were acquired continuously without cardiac triggering using a free breathing regime. Arbitrary phases of the cardiac cycle were reconstructed using synchronization with a physiological trigger signal and different temporal resolutions. Phantom measurements and examinations of healthy subjects were performed to evaluate the performance of the ST and GA acquisition schemes. A signal-to-background ratio (SBR)--that compromises both the signal-to-noise ratio and artifacts--was calculated for benchmarking the GA and ST scheme. RESULTS: In phantom measurements, the measured SBR of the GA acquisition scheme was up to 88% higher versus ST. Undersampling artifacts were reduced in GA compared to the ST sampling scheme. Whole heart coverage sodium images could be reconstructed with a nominal spatial resolution of (6 mm)(3) and a temporal resolution of Deltat=0.1 s for covering the entire cardiac cycle. Changes in overall heart volume and myocardial wall thickness throughout the cardiac cycle were clearly visible in the reconstructed images. For the in vivo data and the imaging protocol used, GA provided a mean SBR of 38.0+/-5.5 while ST provided a mean SBR of 37.2+/-2.2. CONCLUSION: Retrospectively-gated CINE (23)Na imaging of the heart at 7.0 T using density-adapted 3D projection reconstruction is feasible. The GA acquisition scheme is superior to the ST acquisition. PMID- 26117700 TI - Evaluation of EPI distortion correction methods for quantitative MRI of the brain at high magnetic field. AB - High field MRI has been applied to high-resolution structural and functional imaging of the brain. Echo planar imaging (EPI) is an ultrafast acquisition technique widely used in diffusion imaging, functional MRI and perfusion imaging. However, it suffers from geometric and intensity distortions caused by static magnetic field inhomogeneity, which is worse at higher field strengths. Such susceptibility artifacts are particularly severe in relation to the small size of the mouse brain. In this study we compared different distortion correction methods, including nonlinear registration, field map-based, and reversed phase encoding-based approaches, on quantitative imaging of T1 and perfusion in the mouse brain acquired by spin-echo EPI with inversion recovery and pseudo continuous arterial spin labeling, respectively, at 7 T. Our results showed that the 3D reversed phase-encoding correction outperformed other methods in terms of geometric fidelity, and that conventional field map-based correction could be improved by combination with affine transformation to reduce the bias in the field map. Both methods improved quantification with smaller fitting error and regional variation. These approaches offer robust correction of EPI distortions at high field strengths and hence could lead to more accurate co-registration and quantification of imaging biomarkers in both clinical and preclinical applications. PMID- 26117701 TI - Collapsed fat navigators for brain 3D rigid body motion. AB - PURPOSE: To acquire high-resolution 3D multi-slab echo planar imaging data without motion artifacts, using collapsed fat navigators. METHODS: A fat navigator module (collapsed FatNav) was added to a diffusion-weighted 3D multi slab echo planar imaging (DW 3D-MS EPI) sequence, comprising three orthogonal echo planar imaging readouts to track rigid body head motion in the image domain and performing prospective motion correction. The stability, resolution and accuracy of the navigator were investigated on phantoms and healthy volunteers. RESULTS: The experiments on phantoms and volunteers show that the navigator, depicting projections of the subcutaneous fat in of the head, is capable of correcting for head motion with insignificant bias compared to motion estimates derived from the water-signaling DWI images. Despite that this projection technique implies a non-sparse image appearance, collapsed FatNav data could be highly accelerated with parallel imaging, allowing three orthogonal 2D EPI readouts in about 6ms. CONCLUSION: By utilizing signal from the leading fat saturation RF pulse of the diffusion sequence, only the readout portion of the navigator needs to be added, resulting in a scan time penalty of only about 5%. Motion can be detected and corrected for with a 5-10Hz update frequency when combined with a sequence like the DW 3D-MS EPI. PMID- 26117702 TI - Alteration of brain regional homogeneity of monkeys with spinal cord injury: A longitudinal resting-state functional magnetic resonance imaging study. AB - PURPOSE: To investigate the longitudinal brain regional homogeneity (ReHo) changes in nonhuman primate after spinal cord injury (SCI) by resting-state functional magnetic resonance imaging (fMRI). METHODS: Three adult female rhesus monkeys underwent unilateral thoracic cord injury. A resting-state fMRI examination was performed in the healthy stage and 4, 8, and 12 weeks after the injury. The ReHo value of each voxel in the monkey brain was calculated and compared between pre- and post-SCI monkeys with paired t test. The regions of interest (ROIs) in the significantly changed ReHo regions were set. The correlations between the ReHo change and the time after injury were also determined. RESULTS: Compared with those in healthy period, the ReHo values of the left premotor cortex and the anterior cingulate cortex (ACC) in post-SCI rhesus monkeys significantly increased in 4-week follow-up examinations. The ReHo values of posterior cingulate cortex, left precuneus, left temporal parietooccipital area, and bilateral superior parietal lobules decreased at 8 week follow-up examinations. In 12-week follow-up examinations, the ReHo values of the left postcentral gyrus, right caudate nucleus, and superior temporal gyrus increased. Correlation analysis showed positive correlations between left ACC and the postoperative time. CONCLUSION: SCI can change the regional synchronism of brain activity in sensorimotor system and the default mode network. These findings may help us to understand the potential pathophysiological changes in the central nervous system after SCI. PMID- 26117703 TI - Dynamic contrast-enhanced MRI and CT provide comparable measurement of blood brain barrier permeability in a rodent stroke model. AB - In the current management of acute ischemic stroke (AIS), clinical criteria are used to estimate the risk of hemorrhagic transformation (HT), which is a devastating early complication. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computed tomography (DCE-CT) may serve as physiologically based decision making tools to more reliably assess the risk of HT. Before these tools can be properly validated, the comparability of the blood-brain barrier (BBB) permeability measurements they generate should be assessed. Sixteen rats were subjected to a transient middle cerebral artery occlusion before successively undergoing DCE-CT and DCE-MRI at 24-hours. BBB permeability (K(trans)) values were generated from both modalities. A correlation of R=0.677 was found (p<0.01) and the resulting relationship was [DCE-CT=(0.610*DCE MRI)+4.140]. A variance components analysis found the intra-rat coefficient of variation to be 0.384 and 0.258 for K(trans) values from DCE-MRI and DCE-CT respectively. Permeability measures from DCE-CT were 22% higher than those from DCE-MRI. The results of this study demonstrate for the first time comparability between DCE-CT and DCE-MRI in the assessment of AIS. These results may provide a foundation for future clinical trials making combined use of these modalities. PMID- 26117704 TI - Grey matter volume differences associated with gender in children with attention deficit/hyperactivity disorder: A voxel-based morphometry study. AB - Female participants have been underrepresented in previous structural magnetic resonance imaging reports on attention-deficit/hyperactivity disorder (ADHD). In this study, we used optimized voxel-based morphometry to examine grey matter volumes in a sample of 33 never-medicated children with combined-type ADHD and 27 typically developing (TD) children. We found a gender-by-diagnosis interaction effect in the ventral anterior cingulate cortex (ACC), whereby boys with ADHD exhibited reduced volumes compared with TD boys, while girls with ADHD showed increased volumes when compared with TD girls. Considering the key role played by the ventral ACC in emotional regulation, we discuss the potential contribution of these alterations to gender-specific symptoms' profiles in ADHD. PMID- 26117705 TI - Exploring Tree-Like and Non-Tree-Like Patterns Using Genome Sequences: An Example Using the Inbreeding Plant Species Arabidopsis thaliana (L.) Heynh. AB - Genome sequence data contain abundant information about genealogical history, but methods for extracting and interpreting this information are not yet fully developed. We analyzed genome sequences for multiple accessions of the selfing plant, Arabidopsis thaliana, with the goal of better understanding its genealogical history. As expected from accessions of the same species, we found much discordance between nuclear gene trees. Nonetheless, we inferred the optimal population tree under the assumption that all discordance is due to incomplete lineage sorting. To cope with the size of the data (many genes and many taxa), our pipeline is based on parallel computing and divides the problem into four taxon trees. However, just because a population tree can be estimated does not mean that the assumptions of the multispecies coalescent model hold. Therefore, we implemented a new, nonparametric test to evaluate whether a population tree adequately explains the observed quartet frequencies (the frequencies of gene trees with each resolution of each four-taxon set). This test also considers other models: panmixia and a partially resolved population tree, that is, a tree in which some nodes are collapsed into local panmixia. We found that a partially resolved population tree provides the best fit to the data, providing evidence for tree-like structure within A. thaliana, qualitatively similar to what might be expected between different, closely related species. Further, we show that the pattern of deviation from expectations can be used to identify instances of introgression and detect one clear case of reticulation among ecotypes that have come into contact in the United Kingdom. Our study illustrates how we can use genome sequence data to evaluate whether phylogenetic relationships are strictly tree-like or reticulating. PMID- 26117706 TI - [Latissimus dorsi myocutaneous flap combined with implant in breast reconstruction: The technique of the dorsal bra]. AB - The latissimus dorsi myocutaneous flap combined with an implant is an effective breast reconstruction solution especially in irradiated patients. The authors describe the specific technical aspects that allow them to optimize the results of this intervention. In the back, the skin paddle is drawn in the shape of a horizontal spindle so as to conceal the residual scar under the bra. In breast area, a J-shaped contraincision barring the mastectomy scar ensures a harmonious positioning of the skin paddle to the inferolateral part of the breast. After a 180 degrees rotation, the latissimus dorsi muscle envelops the implant like a bra. Its upper edge is attached at the bottom to define the new submammary fold. Under the pectoralis major muscle, its distal end comes to fill the decollete above the implant. PMID- 26117707 TI - The role of the intensive care unit environment and health-care workers in the transmission of bacteria associated with hospital acquired infections. AB - The goal of this study was to attempt to determine the rate of contamination of health-care workers' (HCWs) hands and environmental surfaces in intensive care units (ICU) by the main bacteria associated with hospital acquired infections (HAIs) in Tehran, Iran. A total of 605 and 762 swab samples were obtained from six ICU environments and HCWs' hands. Identification of the bacterial isolates was performed according to standard biochemical methods, and their antimicrobial susceptibility was determined based on the guidelines recommended by clinical and laboratory standards institute (CLSI). The homology of the resistance patterns was assessed by the NTSYSsp software. The most frequent bacteria on the HCWs' hands and in the environmental samples were Acinetobacter baumannii (1.4% and 16.5%, respectively), Staphylococcus aureus (5.9% and 8.1%, respectively), S. epidermidis (20.9% and 18.7%, respectively), and Enterococcus spp. (1% and 1.3%, respectively). Patients' oxygen masks, ventilators, and bed linens were the most contaminated sites. Nurses' aides and housekeepers were the most contaminated staff. Imipenem resistant A. baumannii (94% and 54.5%), methicillin-resistant S. aureus (MRSAs, 59.6% and 67.3%), and vancomycin resistant Enterococci (VREs, 0% and 25%) were detected on the hands of ICU staff and the environmental samples, respectively. Different isolates of S. aureus and Enterococcus spp. showed significant homology in these samples. These results showed contamination of the ICU environments and HCWs with important bacterial pathogens that are the main risk factors for HAIs in the studied hospitals. PMID- 26117708 TI - Trends in the patterns of IgM and IgG antibodies in febrile persons with suspected dengue in Barbados, an English-speaking Caribbean country, 2006-2013. AB - Long-term seroprevalence studies of dengue have provided a measure of the degree of endemicity and future trends in disease prevalence and severity. In this study, we describe the seroprevalence of dengue antibodies in febrile persons with suspected acute dengue in Barbados. It is a retrospective population-based study of all febrile persons with suspected dengue from 2006 to 2013. All of the cases had IgM and IgG antibodies in the blood sample drawn between days 3 and 5 of their illness. Among the 8296 cases that were tested for IgM antibodies, 3037 (36.6%) had recent dengue infection. In the age groups <5 years, 5-20 years and >20 years, 23.3%, 39.6% and 35.5% had acute infection, respectively. Of the 7227 cases with documented IgG results, 5473 (75.7%) were positive and had a past infection. In the age groups <5 years, 5-20 years and >20 years, 31.2%, 65.2% and 86.6%, respectively, had a past infection (IgG positive). During the first 5 years of life, 10-20% of febrile persons investigated for dengue had a positive IgM and a negative IgG titer, between 5 and 10% had a positive IgM and IgG titer, 5% had a positive IgG and a negative IgM titer, and between 45% and 65% had a negative IgM and a negative IgG titer. Throughout the study period, between 12% and 20% of febrile persons failed to show any evidence of current or previous dengue. In the age groups <5 years, 5-20 years and >20 years, 45.0%, 18.8% and 7.2%, respectively, had no evidence of recent or past dengue (both IgM and IgG negative). Between 37% and 59% of the febrile persons had serological evidence of past dengue in the absence of any current dengue. In conclusion, the pattern of IgG antibodies in this study was comparable to those in countries known to be hyperendemic for dengue. The age of infection is likely to shift to younger adults and children who are more likely to have severe dengue in the future. PMID- 26117709 TI - Molecular analysis of rpoB gene mutations in rifampicin resistant Mycobacterium tuberculosis isolates by multiple allele specific polymerase chain reaction in Puducherry, South India. AB - BACKGROUND: rpoB gene mutations in Mycobacterium tuberculosis (MTB) make the bacteria resistant to rifampicin. Thus, these mutations are surrogate markers for multi-drug resistance (MDR). The objective of this study was to evaluate an allele-specific multiplex-polymerase chain reaction (MAS-PCR) assay to detect mutations at codons 516, 526 and 531 of the rpoB gene. METHODS: In total, 127 M. tuberculosis clinical isolates were subjected to standard drug susceptibility tests. A MAS-PCR assay was then performed to detect mutations in the rpoB gene. Three different allele-specific PCR assays were performed (single-step MAS-PCR) and the amplified products were sequenced. RESULTS: Of the 127 isolates, 69 (54.3%) were multidrug resistant M. tuberculosis (MDR-TB), 21 (16.5%) were rifampicin mono-resistant and 37 (29.1%) were drug susceptible. The frequency of mutations at codons 531, 526 and 516 was 54.4%, 18.9% and 5.6%, respectively. A triple mutation was found in 4 (4.4%) isolates. Mutations in regions other than the 81-bp region were observed at codons 413 (11.1%), 511 (12.2%) and 521 (15.6%) of the rpoB gene. CONCLUSIONS: The simplicity and specificity of the MAS-PCR assay allows for easy implementation in clinical laboratories to detect rifampicin drug resistance in MDR-TB strains. PMID- 26117710 TI - How registered nurses, licensed practical nurses and resident aides spend time in nursing homes: An observational study. AB - BACKGROUND: Calls for improved conditions in nursing homes have pointed to the importance of optimizing the levels and skills of care providers. Understanding the work of care providers will help to determine if staff are being used to their full potential and if opportunities exist for improved efficiencies. OBJECTIVES: To explore the activities of care providers in different nursing homes and to identify if variations exist within and across homes and shifts. METHODS: A multi-centre cross-sectional observational work flow study was conducted in seven different nursing homes sites in one Canadian province. Data were collected by a research assistant who conducted 368 h of observation. The research assistant collected data by following an identical route in each site and recording observations on staff activities. RESULTS: Findings indicate staff activities vary across roles, sites and shifts. Licensed practical nurses (nursing assistants) have the greatest variation in their role while registered nurses have the least amount of variability. In some sites both registered nurses and licensed practical nurses perform activities that may be safely delegated to others. Care providers spend as much as 53.7% of their time engaged in non-value added activities. CONCLUSIONS: There may be opportunities for registered nurses and licensed practical nurses to delegate some of their activities to non regulated workers. The time care providers spend in non-value activities suggest there may be opportunities to improve efficiencies within the nursing home setting. PMID- 26117711 TI - What do we know about rheumatoid arthritis patients' support needs for self management? A scoping review. AB - BACKGROUND: Self-management support is essential to perform self-management behavior. To provide this support in an effective way, insight in the needs for self-management support is necessary. OBJECTIVE: To give an overview of self management support needs from the perspective of rheumatoid arthritis patients to help nurses to improve self-management. DESIGN: We conducted a scoping review for the period of January 2002 to May 2013 using the following inclusion criteria: (1) studies on adult patients aged 18 years and older, (2) studies from the perspective of rheumatoid arthritis patients, (3) studies reporting results on support needs, and (4) empirical studies using any design. DATA SOURCES: We searched in PubMed, CINAHL, and PsycINFO. REVIEW METHODS: Following the steps of a scoping review, we (1) identified the research question, (2) identified relevant studies, (3) selected studies, (4) charted the data, and (5) collated, summarized, and reported results. We incorporated the optional sixth step of consultation of a multidisciplinary panel of professionals and patients to validate our findings. RESULTS: Seventeen articles were included. Our review shows that rheumatoid arthritis patients have informational, emotional, social and practical support needs. We found an information need for various topics, e.g. exercises and medication. Patients express a need for emotional support in daily life, given through other RA patients, colleagues and supervisors and nurses. For information needs, emotional and social support it is important that it is tailored to the individual needs of the patient. CONCLUSION: The most important support needs for self-management mentioned by rheumatoid arthritis patients are more informational, social and practical support and emotional support. Considering patients' perspective as a starting point for delivering support for self-management can lead to the development of nursing interventions tailored to the needs of rheumatoid arthritis patients. PMID- 26117712 TI - High-definition fiber tractography for the evaluation of perilesional white matter tracts in high-grade glioma surgery. AB - Conventional white matter (WM) imaging approaches, such as diffusion tensor imaging (DTI), have been used to preoperatively identify the location of affected WM tracts in patients with intracranial tumors in order to maximize the extent of resection and potentially reduce postoperative morbidity. DTI, however, has limitations that include its inability to resolve multiple crossing fibers and its susceptibility to partial volume effects. Therefore, recent focus has shifted to more advanced WM imaging techniques such as high-definition fiber tractography (HDFT). In this paper, we illustrate the application of HDFT, which in our preliminary experience has enabled accurate depiction of perilesional tracts in a 3-dimensional manner in multiple anatomical compartments including edematous zones around high-grade gliomas. This has facilitated accurate surgical planning. This is illustrated by using case examples of patients with glioblastoma multiforme. We also discuss future directions in the role of these techniques in surgery for gliomas. PMID- 26117713 TI - Brain acetylcholine and choline concentrations and dynamics in a murine model of the Fragile X syndrome: age, sex and region-specific changes. AB - Fragile X syndrome is a learning disability caused by excess of CGG repeats in the 5' untranslated region of the Fragile X gene (FMR1) silencing its transcription and translation. We used a murine model of this condition, Fmr1 knock-out mice (KO) to study acetylcholine (ACh) metabolism and compared it to that of wild-type control mice (WT). Brain endogenous ACh (D0ACh), free choline (D0Ch), their deuterated variants D4ACh and D4Ch and mole ratios (AChMR and ChMR) were measured by gas chromatography-mass spectrometry in the cerebral hemisphere, cerebral cortex, hippocampus and cerebellum, following D4Ch administration. Regression analysis indicated a significant decrease with age (negative slope) of D4ACh, AChMR, D4Ch and ChMR in WT mice. Age dependence was only present for D4ACh and AChMR in KO mice. Analysis of variance with age as covariate indicated a significant greater D4Ch in the cerebral cortex of KO females when compared to WT females. Contrasts between sexes within genotypes indicated lower D0Ch in cortex and cerebellum of female KO mice but not in WT and lower D4Ch in hippocampus of female KO and WT mice. In conclusion, after adjusting for age, D0ACh concentrations and synthesis from deuterium-labeled Ch were similar in KO and control WT mice in all brain regions. In contrast, significant changes in Ch dynamics were found in hippocampus and cerebral cortex of KO mice that might contribute to the pathogenesis of FXS. PMID- 26117714 TI - TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. AB - Tumor necrosis factor (TNF) is the prototypic pro-inflammatory cytokine. It is central to host defense and inflammatory responses but under certain circumstances also triggers cell death and tissue degeneration. Its pleiotropic effects often lead to opposing outcomes during the development of immune-mediated diseases, particularly those affecting the central nervous system (CNS). The reported contradictions may result from lack of precision in discussing TNF. TNF signaling comprises at minimum a two-ligand (soluble and transmembrane TNF) and two-receptor (TNFR1 and TNFR2) system, with ligands and receptors both differentially expressed and regulated on different cell types. The "functional multiplicity" this engenders is the focus of much research, but there is still no general consensus on functional outcomes of TNF signaling in general, let alone in the CNS. In this review, evidence showing the effects of TNF in the CNS under physiological and pathophysiological conditions is placed in the context of major advances in understanding of the cellular and molecular mechanisms that govern TNF function in general. Thus the roles of TNF signaling in the CNS shift from the conventional dichotomy of beneficial and deleterious, that mainly explain effects under pathological conditions, to incorporate a growing number of "essential" and "desirable" roles for TNF and its main cellular source in the CNS, microglia, under physiological conditions including regulation of neuronal activity and maintenance of myelin. An improved holistic view of TNF function in the CNS might better reconcile the expansive experimental data with stark clinical evidence that reduced functioning of TNF and its dominant pro inflammatory receptor, TNFR1, are risk factors for the development of multiple sclerosis. It will also facilitate the safe translation of basic research findings from animal models to humans and propel the development of more selective anti-TNF therapies aimed at selectively inhibiting deleterious effects of this cytokine while maintaining its essential and desirable ones, in the periphery and the CNS. PMID- 26117715 TI - Increased expression of the proton-sensing G protein-coupled receptor Gpr65 during retinal degeneration. AB - The retina is a metabolically highly active tissue that is sensitive to pH changes. Blinding diseases of the retina are often characterized by degeneration of photoreceptor cells altering the acid-base homeostasis of the tissue microenvironment and by an accompanying inflammatory response. GPR4, GPR65 and GPR68 are G protein-coupled receptors that aid cells to sense and survive conditions of acidic pH and inflammatory cells express Gpr65 enhancing their viability. Hence, we investigated expression and function of these proton-sensing GPRs in the normal and degenerating retina. We observed increased retinal expression of Gpr65, but not of Gpr4 and Gpr68, in mouse models of both inherited (rd10) and induced (light damage) retinal degeneration. Lack of GPR65 slightly accelerated photoreceptor degeneration in rd10 mice and resulted in a strong activation of microglia after light-injury. Since GPR65 was dispensable for normal retinal development, function and aging as evidenced by the evaluation of Gpr65(-/-) mice, our results indicate that the proton-sensing G protein-coupled receptor GPR65 may be involved in a mechanism that supports survival of photoreceptors in the degenerating retina. PMID- 26117716 TI - Age and sex differences in c-Fos expression and serum corticosterone concentration following LPS treatment. AB - Exposure to an immune challenge during peripuberty/adolescence, but not in adulthood, can cause enduring alterations in reproductive and non-reproductive behaviors. This suggests that the peripubertal/adolescent brain might respond differently to a stressor, like an immune challenge, than the adult brain. The goal of this study was to examine whether there are age and sex differences in the acute response to an immune challenge. To examine this research question, we investigated c-Fos expression in various brain regions. Corticosterone (CORT) concentration in the serum was quantified to examine hypothalamic-pituitary adrenal axis (HPA-axis) responsiveness. Results showed that lipopolysaccharide (LPS; a bacterial endotoxin) treatment, induced a significant increase in the number of c-Fos immunoreactive cells in adult male and female mice compared to their saline controls. However, in peripubertal/adolescent mice, LPS treatment failed to increase the number of c-Fos immunoreactive cells in both male and female mice compared to their saline controls. LPS treatment also significantly increased serum CORT concentration in all mice regardless of sex and age. However, adult female mice treated with LPS showed significantly greater serum CORT concentration compared to adult and peripubertal/adolescent males and peripubertal/adolescent females treated with LPS. These findings support our hypothesis and suggest that there are important age and sex differences in acute immune response, which may allude to mechanisms for the enduring behavioral alterations, observed previously in mice exposed to an immune challenge during puberty but not in adulthood. PMID- 26117717 TI - Developmental investigation of age at sexual debut and subsequent sexual risk behaviours: a study of high-risk young black males. AB - Background The purpose of this study was to identify unmediated associations of early sexual debut (ESD) on the current safer sex practices of young Black men (YBM). METHODS: A cross-sectional study of YBM (n=697) attending clinics treating sexually transmissible diseases (STIs) in three cities was conducted. ESD was dichotomised at the age of 13 years and under. A series of regression models were used to test the moderating effects of ESD and perceived parental monitoring (PPM). A regression model also tested the effect of years of sexual experience (YSE) on sexual risk behaviours, while controlling for ESD. RESULTS: Mean age of debut was 13.95 years. ESD results varied with significance for pregnancy (P<0.001), sexual partners (P<0.001), and ever having chlamydia (assessed by self report), but this final association was only found for older males (P=0.03). PPM held no moderating effect on any of the sexual risk outcomes. YSE was correlated with an increase in recent unprotected vaginal sex (AOR=1.19, 95%CI=1.10-1.27) and having a pregnant partner at the time of enrolment (AOR=1.30, 95%CI=1.17 1.43). CONCLUSIONS: The findings provide mixed evidence for unmediated associations of ESD among young Black males. The study strongly posits that ESD may actually be a mediating variable rather than a causal explanation for sexual risk. The findings also suggest that advancing YSE foster diminishing vigilance in safer sex practices. These outcomes should be utilised to inform intervention development. PMID- 26117718 TI - The sustainable development agenda and the end of AIDS. PMID- 26117720 TI - Michel Sidibe: working to end AIDS as a public health threat. PMID- 26117719 TI - Defeating AIDS--advancing global health. PMID- 26117721 TI - AIDS and global health: the path to sustainable development. PMID- 26117722 TI - Homogeneously modified immunoglobulin domains for therapeutic application. AB - The field of therapeutic antibodies has been revolutionized over the past decade, led by the development of novel antibody-modification technologies. Besides the huge success achieved by therapeutic monoclonal antibodies, a diversity of antibody derivatives have emerged with hope to outperform their parental antibodies. Here we review the recent development of methodologies to modify immunoglobulin domains and their therapeutic applications. The innovative genetic and chemical approaches enable novel and controllable modifications on immunoglobulin domains, producing homogeneous therapeutics with new functionalities or enhanced therapeutic profiles. Such therapeutics, including antibody-drug conjugates, bispecific antibodies, and antibody/Fc fusion proteins, have demonstrated great prospects in the treatment of cancer, auto-immune diseases, infectious diseases, and many other disorders. PMID- 26117723 TI - Arbitration of discrepant BI-RADS 0 recalls by a third reader at screening mammography lowers recall rate but not the cancer detection rate and sensitivity at blinded and non-blinded double reading. AB - PURPOSE: To evaluate the characteristics of low suspicion lesions (BI-RADS 0) at blinded and non-blinded double reading of screening mammograms and to determine the potential effect of arbitration of discrepant BI-RADS 0 recalls by a third reader on screening outcome. METHODS: We included a series of 84,927 consecutive digital screening mammograms, double read in a blinded (43,184 screens) or non blinded (41,743 screens) fashion, between July 2009 and July 2011. Discrepant readings were routinely recalled for further evaluation. During 2 years of follow up, radiology, surgical and pathology reports were collected of all recalled women. Arbitration of discrepant BI-RADS 0 recalls (only one radiologist assigning a BI-RADS 0 score) was retrospectively performed by a third screening radiologist. RESULTS: At blinded and non-blinded double reading, 32.0% and 32.5% of recalls were assigned BI-RADS 0 with a positive predictive value (PPV) of 7.2% and 6.8%, respectively. Compared to non-blinded double reading, BI-RADS 0 recalls at blinded double reading showed a higher discrepancy rate (9.0 versus 4.3 per 1000 screens, p < 0.001) and false positive recall rate (10.1 versus 8.4 per 1000 screens, p = 0.012). Arbitration of discrepant BI-RADS 0 recalls would have significantly lowered recall rate (from 3.4% to 2.8% at blinded double reading, p < 0.001, and from 2.8% to 2.5% at non-blinded double reading, p = 0.008), without a decrease in cancer detection rate (from 7.50/00 to 7.30/00, p = 0.751, and from 6.60/00 to 6.50/00, p = 0.832, respectively) and program sensitivity (from 83.2% to 81.2%, p = 0.453, and from 76.0% to 74.6%, p = 0.667, respectively). Arbitration would have significantly increased the PPV at blinded double reading (from 22.3% to 26.3%, p = 0.015). CONCLUSION: We advise arbitration of discrepant BI-RADS 0 recalls, at (non-)blinded double reading of screening mammograms, to reduce recall rates and improve the PPV of recall at blinded double reading. PMID- 26117724 TI - Closed reduction of displaced or dislocated mandibular condyle fractures in children using threaded Kirschner wire and external rubber traction. AB - Most surgeons agree that closed treatment provides the best results for condylar fractures in children. Nevertheless, treatment of the paediatric mandibular condyle fracture that is severely displaced or dislocated is controversial. The purpose of this study was to investigate the long-term clinical and radiological outcomes following the treatment of displaced or dislocated condylar fractures in children using threaded Kirschner wire and external rubber traction. This procedure can strengthen the advantage of closed reduction and make up for the shortcomings of open reduction. From March 1, 2005 to December 25, 2011, 11 children aged between 4 and 12 years with displaced or dislocated mandibular condyle fractures were treated using threaded Kirschner wire and external rubber traction under portable C-arm fluoroscopy. All patients had unilateral displaced or dislocated condylar fractures. The follow-up period ranged from 24 to 42 months (mean 29.3 months). Normal occlusion and pain-free function of the temporomandibular joint, without deviation or limitation of jaw opening, was achieved in all patients. This closed reduction technique in displaced or dislocated condylar fractures in children offers a reliable solution in preventing the unfavourable sequelae of closed treatment and the open technique, such as altered morphology, functional disturbances, and facial nerve damage. PMID- 26117725 TI - Confrontations with Difficult Patients: The Good, the Bad, and the Ugly. PMID- 26117726 TI - Cardiologist Point of View on the Exercise Echocardiography and Multidetector Computed Tomography for the Evaluation of Acute Chest Pain. PMID- 26117727 TI - Response to letter to the Editor regarding 'Classification algorithms for the identification of structural injury in TBI using brain electrical activity'. PMID- 26117728 TI - Trancriptomic profiling revealed the signatures of acute immune response in tilapia (Oreochromis niloticus) following Streptococcus iniae challenge. AB - Streptococcus iniae is the most significant bacterial disease of tilapia throughout the world, and commonly leads to tremendous economic losses. In contrast to other important fish species, our knowledge about the molecular mechanisms of tilapia in response to bacterial infection is still limited. Here, therefore, we utilized RNA-seq to first profiling of host responses in tilapia spleen following S. iniae infection at transcriptome level. A total of 223 million reads were obtained and assembled into 192,884 contigs with average length 844 bp. Gene expression analysis between control and infected samples at 5 h, 50 h, and 7 d revealed 1475 differentially expressed genes. In particular, the differentially expressed gene set was dramatically induced as early as 5 h, and rapidly declined to basal levels at 50 h. Enrichment and pathway analysis of the differentially expressed genes revealed the centrality of the pathogen attachment and recognition, cytoskeletal rearrangement and immune activation/inflammation in the pathogen entry and host inflammatory responses. Understanding of these responses can highlight mechanisms of tilapia host defense, and expand our knowledge of teleost immunology. Our findings will set a foundation of valuable biomarkers for future individual, strain, and family-level studies to evaluate immune effect of vaccine and individual response in host defense mechanisms to S. iniae infection, to select disease resistant families and strains. PMID- 26117729 TI - The immune response of cephalopods from head to foot. AB - Cephalopods are a diverse group of marine molluscs that have proven their worth in a vast array of ways, ranging from their importance within ecological settings and increasing commercial value, to their recent use as model organisms in biological research. However, despite their acknowledged importance, our understanding of basic cephalopod biology does not equate their ecological, societal, and scientific significance. Among these undeveloped research areas, cephalopod immunology stands out because it encompasses a wide variety of scientific fields including many within the biological and chemical sciences, and because of its potential biomedical and commercial relevance. This review aims to address the current knowledge on the topic of cephalopod immunity, focusing on components and functions already established as part of the animals' internal defense mechanisms, as well as identifying gaps that would benefit from future research. More specifically, the present review details both cellular and humoral defenses, and organizes them into sensor, signaling, and effector components. Molluscan, and particularly cephalopod immunology has lagged behind many other areas of study, but thanks to the efforts of many dedicated researchers and the assistance of modern technology, this gap is steadily decreasing. A better understanding of cephalopod immunity will have a positive impact on the health and survival of one of the most intriguing and unique animal groups on the planet, and will certainly influence many other areas of human interest such as ecology, evolution, physiology, symbiosis, and aquaculture. PMID- 26117730 TI - Effects of artificial infection of Litopenaeus vannamei by Micrococcus lysodeikticus and WSSV on the activity of immunity related enzymes. AB - In this study, the activities of 5 immunity related enzymes namely acid phosphatase (ACP), alkaline phosphatase (AKP), phenoloxidase (PO), peroxidase (POD) and lysozyme phosphatase (LZM)) of Litopenaeus vannamei after they have been injected with different concentrations of Micrococcus lysodeikticus and the white spot syndrome virus (WSSV) were examined. The cumulative mortality at 0, 24, 48, 72, 96 h was obtained. Copy numbers of WSSV in L. vannamei after a single infection, secondary infection and concurrent infection were measured. Hemolymph samples of M. lysodeikticus and WSSV injected shrimp were collected at 0, 6, 12 24, 48, 72, 78, 84, 96 and 120 h. The results were: (i) The cumulative mortality of L. vannamei increased as the shrimp were infected with higher concentration of the bacteria; (ii) The most sensitive changes of ACP, AKP and LZM were in the 6.2 * 10(5), 6.2 * 10(6), 6.2 * 10(7) cfu/mL M. lysodeikticus group; (iii) ACP but LZM were more sensitive to M. lysodeikticus than WSSV, and AKP, PO and POD is more sensitive to WSSV; (iv) The copies of WSSV in the co-injected group were higher than WSSV-single infection and WSSV-bacteria-secondary infection group at 48 h. The amount of WSSV in L. vannamei of concurrent infection and WSSV-bacteria secondary infection groups were higher than that of the WSSV-single infection group. PMID- 26117731 TI - Transcriptome profiling analysis of naked carp (Gymnocypris przewalskii) provides insights into the immune-related genes in highland fish. AB - The naked carp, Gymnocypris przewalskii, is one of the dominant aquaculture fish species in Qinghai Province, China. Its wild stocks have severely suffered from overfishing, and the farming species are vulnerable to various pathogens infections. Here we report the first immune-related tissues transcriptome of a wild naked carp using a deep sequencing approach. A total of 158,087 unigenes are generated, 2687 gill-specific gene and 3215 kidney-specific genes are identified, respectively. Gene ontology analysis shows that 51,671 unigenes are involved in three major functional categories: biological process, cellular component, and molecular function. Further analysis shows that numerous consensus sequences are homologous to known immune-related genes. Pathways mapping annotate 56,270 unigenes and identify a large number of immune-related pathways. In addition, we focus on the immune-related genes and gene family in Toll-like receptor signaling pathway involved in innate immunity, including toll-like receptors (TLRs), interferon regulatory factors (IRFs), interleukins (ILs) and tumor necrosis factors (TNFs). Eventually, we identify 5 TLRs, 4 IRFs, 3 ILs and 2 TNFs with a completed coding sequence though mining the transcriptome data. Phylogeny analysis shows these genes of naked carp are mostly close to zebrafish. Protein domain and selection pressure analyses together show that all these genes are highly conserved in gene sequence and protein domain structure with other species, and purifying selection underwent in these genes, implied functionally important features are conserved in the genes above. Intriguingly, we detect positive selection signals in naked carp TLR4, and significant divergence occurred among tested species TLR4, suggested that naked carp TLR4 function may be affected. Finally, we identify 23,867 simple sequence repeat (SSR) marks in this transcriptome. Taken together, this study not only contributes a large number of candidate genes in naked carp immunity, and also helps improve current understanding of immunogenetics basis and evolutionary history of immune related genes and gene family in highland fish species. PMID- 26117732 TI - Construction of extracellular microenvironment to improve surface endothelialization of NiTi alloy substrate. AB - To mimic extracellular microenvironment of endothelial cell, a bioactive multilayered structure of gelatin/chitosan pair, embedding with vascular endothelial growth factor (VEGF), was constructed onto NiTi alloy substrate surface via a layer-by-layer assembly technique. The successful fabrication of the multilayered structure was demonstrated by scanning electron microscopy, atomic force microscopy, contact angle measurement, attenuated total reflection fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy, respectively. The growth behaviors of endothelial cells on various NiTi alloy substrates were investigated in vitro. Cytoskeleton observation, MTT assay, and wound healing assay proved that the VEGF-embedded multilayer structure positively stimulated adhesion, proliferation and motogenic responses of endothelial cells. More importantly, the present system promoted the nitric oxide production of endothelial cells. The approach affords an alternative to construct extracellular microenvironment for improving surface endothelialization of a cardiovascular implant. PMID- 26117733 TI - Silk fibroin/sodium alginate composite nano-fibrous scaffold prepared through thermally induced phase-separation (TIPS) method for biomedical applications. AB - To mimic the natural fibrous structure of the tissue extracellular matrix, a nano fibrous silk fibroin (SF)/sodium alginate (SA) composite scaffold was fabricated by a thermally-induced phase-separation method. The effects of SF/SA ratio on the structure and the porosity of the composite scaffolds were examined. Scanning electron microscopy and porosity results showed that the 5SF/1SA and 3SF/1SA scaffolds possessed an excellent nano-fibrous structure and a porosity of more than 90%. Fourier transform infrared, X-ray diffraction, and differential scanning calorimetry results indicated the physical interaction between SF and SA molecules and their good compatibility in the 5SF/1SA and 3SF/1SA scaffolds, whereas they showed less compatibility in the 1SF/1SA scaffold. Cell culture results showed that MG-63 cells can attach and grow well on the surface of the SF/SA scaffolds. The nano-fibrous SF/SA scaffold can be potentially used in tissue engineering. PMID- 26117734 TI - Four-order stiffness variation of laser-fabricated photopolymer biodegradable scaffolds by laser parameter modulation. AB - The effects of various fabrication parameters of our Mask Projection Excimer Laser StereoLithography (MPExSL) system were investigated. We demonstrate that laser parameters directly change the physical properties (stiffness, thermal degradation, and height/thickness) of the poly(propylene fumarate) (PFF) scaffold structures. The tested parameters were the number of pulses, fluence per pulse and laser repetition rate. We present a four-order tuning capability of MPExSL fabricated structures' stiffness without altering the resin composition or using cumbersome post-treatment procedures. Thermogravimetric analysis and differential scanning calorimetry confirmed this tuning capability. Prototype-segmented scaffold designs are presented and analyzed to further expand the concept and exploit this in situ stiffness tuning capability of the scaffolds for tissue engineering and regenerative medicine applications. PMID- 26117735 TI - Study on torsional fretting wear behavior of a ball-on-socket contact configuration simulating an artificial cervical disk. AB - A ball-on-socket contact configuration was designed to simulate an artificial cervical disk in structure. UHMWPE (ultra high molecular weight polyethylene) hot pressed by powders and Ti6Al4V alloy were selected as the material combination of ball and socket. The socket surface was coated by a ~500 nm C-DLC (carbon ion implantation-diamond like carbon) mixed layer to improve its surface nano hardness and wear resistance. The torsional fretting wear behavior of the ball-on socket model was tested at different angular displacements under 25% bovine serum lubrication with an axial force of 100 N to obtain more realistic results with that in vivo. The fretting running regimes and wear damage characteristics as well as wear mechanisms for both ball and socket were studied based on 2D (two dimension) optical microscope, SEM (scanning electron microscope) and 3D (three dimension) profiles. With the increase of angular displacement amplitude from 1 degrees to 7 degrees , three types of T-theta (Torsional torque-angular displacement amplitude) curves (i.e., linear, elliptical and parallelogram loops) corresponding to running regimes of PSR (partial slip regime), MR (mixed regime) and SR (slip regime) were observed and analyzed. Both the central region and the edge zone of the ball and socket were damaged. The worn surfaces were characterized by wear scratches and wear debris. In addition, more severe wear damage and more wear debris appeared on the central region of the socket at higher angular displacement amplitude. The dominant damage mechanism was a mix of surface scratch, adhesive wear and abrasive wear for the UHMWPE ball while that for the coated socket was abrasive wear by PE particles and some polishing and rolling process on the raised overgrown DLC grains. The frictional kinetic behavior, wear type, damage region and damage mechanism for the ball-on-socket model revealed significant differences with those of a ball-on-flat contact while showing better consistency with that of in vitro cervical prosthesis simulations according to the literature. PMID- 26117736 TI - Synthesis of pH sensitive gold nanoparticles for potential application in radiosensitization. AB - Synthesis of gold nanoparticles (GNPs) for in-vivo applications involves reduction of chloroauric acid by a biologically important molecule which itself undergoes redox reaction during physiological processes in human body. But the GNPs often prepared by this method are not stable enough. In order to stabilize these particles, surfactants are used which may or may not be compatible for in vivo applications. Is there any other way to stabilize these particles in solution? In this work, the answer to this question is explored and a detailed study of the mechanism of the formation of GNPs is done to understand the basis of stabilization of nanoparticles without using a stabilizer. Chloroauric acid is reduced by L-tryptophan (Trp) in buffered medium and the formation mechanism is studied both visually and by UV-vis spectroscopy. The pH dependent structure of Trp was found to play an important role not only in the formation of stable GNPs but also in the stabilization of redispersed nanoparticles. pH sensitive property of the synthesized GNPs was utilized to make the GNPs accumulate at polar-non polar liquid-liquid interface similar to hypoxic tumor tissue environment. Mechanistic study of the formation of GNPs by gas chromatography throws light on intermediate decarboxylation process. On the other hand, fluorescence study gives information about the interaction of Trp with GNPs. PMID- 26117737 TI - In-situ photo-assisted deposition of silver particles on hydrogel fibers for antibacterial applications. AB - Silver nanoparticles (AgNPs) have attracted intensive research interest and have been recently incorporated in polymers, medical devices, hydrogels and burn dressings to control the proliferation of microorganisms. In this study a novel silver antibacterial coating was deposited for the first time on hydrogel fibers through an in-situ photo-chemical reaction. Hydrogel blends obtained by mixing different percentages of silver-treated and untreated fibers were characterized by thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT IR), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). Four different fluids, such as phosphate buffered saline (PBS), simulated body fluid (SBF), chemical simulated wound fluid (cSWF), and deionized water (DI water), were used for evaluating the swelling properties. The results obtained confirmed that the presence of silver did not affect the properties of the hydrogel. Moreover, the results obtained through inductively coupled plasma mass spectrometry (ICP-MS) demonstrated very low silver release values, thus indicating the perfect adhesion of the silver coating to the substrate. Good antibacterial capabilities were demonstrated by any hydrogel blend on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) through agar diffusion tests and optical density readings. PMID- 26117738 TI - Chitin dipentanoate as the new technologically usable biomaterial. AB - In this article, the synthesis of novel biopolymer, chitin dipentanoate (Di-O Valeryl Chitin, DVCH) has been described. DVCH is a chitin derivative esterified with two valeryl groups at positions 3 and 6 of the N-acetylglucosamine units and it is soluble in common organic solvents like ethanol, methanol, acetone, dichloromethane, 1,2-dichloroethane, N,N-dimethylmethanamide, N,N dimethylacetamide and ethyl acetate. Highly efficient synthesis (degree of esterification close to 2) of DVCH was achieved by employing a huge excess of valeric anhydride used as both the acylation agent and the reaction medium in the presence of perchloric acid as catalyst. Studies on the DVCH synthesis were aimed at finding optimal conditions (temperature, reaction time) to obtain DVCH with high reaction yield and desirable physicochemical properties. Biological data demonstrate that DVCH is non-cytotoxic in vitro and doesn't exert irritating or allergic effects to animal skin. Thanks to its filmogenic properties, it can be used to manufacture threads, foils, foams and non-woven materials. Moreover, DVCH can be easily processed by salt-leaching method to prepare highly porous structures exhibiting open-cell architecture, that can be further employed in wound dressing therapies and scaffolds for tissue engineering. PMID- 26117739 TI - Electrically stimulated osteogenesis on Ti-PPy/PLGA constructs prepared by laser assisted processes. AB - This work describes a versatile laser-based protocol for fabricating micro patterned, electrically conductive titanium-polypyrrole/poly(lactic-co glycolic)acid (Ti-PPy/PLGA) constructs for electrically stimulated (ES) osteogenesis. Ti supports were patterned using fs laser ablation in order to create high spatial resolution microstructures meant to provide mechanical resistance and physical cues for cell growth. Matrix Assisted Pulsed Laser Evaporation (MAPLE) was used to coat the patterned Ti supports with PPy/PLGA layers acting as biocompatible surfaces having chemical and electrical properties suitable for cell differentiation and mineralization. In vitro biological assays on osteoblast-like MG63 cells showed that the constructs maintained cell viability without cytotoxicity. At 24 h after cell seeding, electrical stimulation with currents of 200 MUA was applied for 4 h. This treatment was shown to promote earlier onset of osteogenesis. More specifically, the alkaline phosphatase activity of the stimulated cultures reached the maximum before that of the non-stimulated ones, i.e. controls, indicating faster cell differentiation. Moreover, mineralization was found to occur at an earlier stage in the stimulated cultures, as compared to the controls, starting with Day 6 of cell culture. At later stages, calcium levels in the stimulated cultures were higher than those in control samples by about 70%, with Ca/P ratios similar to those of natural bone. In all, the laser-based protocol emerges as an efficient alternative to existing fabrication technologies. PMID- 26117740 TI - Electrochemical detection of hydrogen peroxide on platinum-containing tetrahedral amorphous carbon sensors and evaluation of their biofouling properties. AB - Hydrogen peroxide is the product of various enzymatic reactions, and is thus typically utilized as the analyte in biosensors. However, its detection with conventional materials, such as noble metals or glassy carbon, is often hindered by slow kinetics and biofouling of the electrode. In this study electrochemical properties and suitability to peroxide detection as well as ability to resist biofouling of Pt-doped ta-C samples were evaluated. Pure ta-C and pure Pt were used as references. According to the results presented here it is proposed that combining ta-C with Pt results in good electrocatalytic activity towards H2O2 oxidation with better tolerance towards aqueous environment mimicking physiological conditions compared to pure Pt. In biofouling experiments, however, both the hybrid material and Pt were almost completely blocked after immersion in protein-containing solutions and did not produce any peaks for ferrocenemethanol oxidation or reduction. On the contrary, it was still possible to obtain clear peaks for H2O2 oxidation with them after similar treatment. Moreover, quartz crystal microbalance experiment showed less protein adsorption on the hybrid sample compared to Pt which is also supported by the electrochemical biofouling experiments for H2O2 detection. PMID- 26117741 TI - Alternative approach of cell encapsulation by Volvox spheres. AB - Volvox sphere is a bio-mimicking concept of a biomaterial structure design able to encapsulate chemicals, drugs and/or cells. The aim of this study was to prepare Volvox spheres encapsulating AML12 liver cells and mesenchymal stem cells (MSCs) via a high voltage electrostatic field system. The results demonstrated that AML12 liver cells and MSCs could be successfully encapsulated into the inner spheres and the outer sphere of the Volvox spheres. The improved cell viability of MSCs was achieved by the addition of collagen and polyethylene glycol into the preparation components of the Volvox spheres. Collagen material potentially provides extracellular matrix-like structure for cell adhesion while polyethylene glycol provides a void/loose space for permeability of metabolites. The encapsulated MSCs were able to differentiate into hepatocytes or hepatocyte-like cells and express liver cell markers including albumin, alpha feto-protein and cytokeratin 18. The encapsulated cells secreted albumin to about 140 ng on day 14. Based on these observations, we conclude that Volvox spheres can be used as an alternative approach to encapsulate multiple types of cells, here AML12 hepatocyte cell line and MSCs. Nevertheless, efforts are still needed to improve the viability of the encapsulated cells and increase the differentiation of MSCs into functional liver cells. PMID- 26117742 TI - Effect of discarded keratin-based biocomposite hydrogels on the wound healing process in vivo. AB - Biocompatible keratin-based hydrogels prepared by electron beam irradiation (EBI) were examined in wound healing. As the EBI dose increased to 60 kGy, the tensile strength of the hydrogels increased, while the percentage of elongation of the hydrogels decreased. After 7 days, the dehydrated wool-based hydrogels show the highest mechanical properties (the % elongation of 1341 and the tensile strength of 6030 g/cm(2) at an EBI dose of 30 kGy). Excision wound models were used to evaluate the effects of human hair-based hydrogels and wool-based hydrogels on various phases of healing. On post-wounding days 7 and 14, wounds treated with either human hair-based or wool-based hydrogels were greatly reduced in size compared to wounds that received other treatments, although the hydrocolloid wound dressing-treated wound also showed a pronounced reduction in size compared to an open wound as measured by a histological assay. On the 14th postoperative day, the cellular appearances were similar in the hydrocolloid wound dressing and wool-based hydrogel-treated wounds, and collagen fibers were substituted with fibroblasts and mixed with fibroblasts in the dermis. Furthermore, the wound treated with a human hair-based hydrogel showed almost complete epithelial regeneration, with the maturation of immature connective tissue and hair follicles and formation of a sebaceous gland. PMID- 26117743 TI - Interaction and effectiveness of antimicrobials along with healing-promoting agents in a novel biocellulose wound dressing. AB - An ideal wound dressing should keep the wound moist, allow oxygen permeation, adsorb wound exudate, accelerate re-epithelialization for wound closure, reduce pain and healing time, and prevent infection. Our novel biocellulose-based wound dressing was composed of three components: 1) biocellulose (BC), intended to create a moist and oxygen-permeated environment with exudate adsorption; 2) silk sericin (SS) known for its enhancement of collagen type I production, which is critical for re-epithelialization; and 3) the antiseptic polyhexamethylene biguanide (PHMB). To deliver an effective BC wound dressing, the interactions between the components (PHMB vs. SS) needed to be thoroughly analyzed. In this study, we investigated important parameters such as the loading sequence, loading concentration, and loading amount of the active compounds to ensure that the BC wound dressing could provide both antimicrobial activity and promote collagen production during healing. The loading sequence of SS and PHMB into BC was critical to maintain PHMB antimicrobial activity; silk sericin needed to be loaded before PHMB to avoid any negative impacts. The minimum PHMB concentration was 0.3% w/v for effective elimination of all tested bacteria (Bacillus subtilis, Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa). The amounts of SS and PHMB in BC were optimized to ensure that the dressings released the optimal amounts of both SS to enhance fibroblast collagen production and PHMB for effective antimicrobial activity. PMID- 26117744 TI - In vitro study of improved wound-healing effect of bioactive borate-based glass nano-/micro-fibers. AB - Because of the promising wound-healing capability, bioactive glasses have been considered as one of the next generation hard- and soft-tissue regeneration materials. The lack of understanding of the substantial mechanisms, however, indicates the need for further study on cell-glass interactions to better interpret the rehabilitation capability. In the present work, three bioactive glass nano-/micro-fibers, silicate-based 45S5, borate-based 13-93B3 and 1605 (additionally doped with copper oxide and zinc oxide), were firstly compared for their in vitro soaking/conversion rate. The results of elemental monitoring and electron microscopic characterization demonstrated that quicker ion releasing and glass conversion occurred in borate-based fibers than that of silicate-based one. This result was also reflected by the formation speed of hydroxyapatite (HA). This process was further correlated with original boron content and surrounding rheological condition. We showed that an optimal fiber pre-soaking time (or an ideal dynamic flow rate) should exist to stimulate the best cell proliferation and migration ability. Moreover, 13-93B3 and 1605 fibers showed different glass conversion and biocompatibility properties as well, indicating that trace amount variation in composition can also influence fiber's bioactivity. In sum, our in vitro rheological module closely simulated in vivo niche environment and proved a potentially improved wound-healing effect by borate-based glass fibers, and the results shall cast light on future improvement in bioactive glass fabrication. PMID- 26117745 TI - Silica-polyethylene glycol hybrids synthesized by sol-gel: Biocompatibility improvement of titanium implants by coating. AB - Although metallic implants are the most used in dental and orthopaedic fields, they can early fail due to low tissue tolerance or osseointegration ability. To overcome this drawback, functional coatings can be applied on the metallic surface to provide a firm fixation of the implants. The objective of the present study was twofold: to synthesize and to characterize silica/polyethylene glycol (PEG) hybrid materials using sol-gel technique and to investigate their capability to dip-coat titanium grade 4 (Ti-gr4) substrates to improve their biological properties. Various hybrid systems have been synthesized by changing the ratio between the organic and inorganic phases in order to study the influence of the polymer amount on the structure and, thus, on the properties of the coatings. Fourier transform infrared (FTIR) spectroscopy and solid state Nuclear Magnetic Resonance (NMR) allowed us to detect the formation of hydrogen bonds between the inorganic sol-gel matrix and the organic component. SEM analysis showed that high PEG content enables to obtain crack free-coating. Moreover, the effective improvement in biological properties of Ti-gr4 implants has been evaluated by performing in vitro tests. The bioactivity of the hybrid coatings has been showed by the hydroxyapatite formation on the surface of SiO2/PEG coated Ti-gr4 substrates after soaking in a simulated body fluid and the lack of cytotoxicity by the WST-8 Assay. The results showed that the coated substrates are more bioactive and biocompatible than the uncoated ones and that the bioactivity is not significantly affected by PEG amount whereas its addition makes the films more biocompatible. PMID- 26117746 TI - In situ hydroxyapatite nanofiber growth on calcium borate silicate ceramics in SBF and its structural characteristics. AB - A novel calcium silicate borate Ca11Si4B2O22 ceramic was firstly prepared by the conventional solid-state reaction. In vitro hydroxyapatite mineralization was investigated by soaking the ceramics in simulated body fluid (SBF) solutions at body temperature (37 degrees C) for various time periods. Scanning electron microscopy (SEM) and X-ray diffraction analysis (XRD) measurements were applied to investigate the samples before and after the immersion of ceramics in SBF solution. The elemental compositions of a hydroxyapatite layer on the ceramics during the mineralization were confirmed by X-ray energy-dispersive spectra (EDS). Meanwhile, the bending strength and elastic modulus of Ca11Si4B2O22 ceramics were also measured, which indicate that the biomaterials based on Ca11Si4B2O22 ceramics possess bioactivity and might be a potential candidate as biomaterials for hard tissue repair. The bioactive mineralization ability was evaluated on the base of its crystal structural characteristics, i.e., silanol (Si-OH) and B-OH groups can be easily induced on the surface of Ca11Si4B2O22 ceramics soaked in SBF solutions. PMID- 26117747 TI - Effect of silk protein surfactant on silk degumming and its properties. AB - The silk protein surfactant (SPS) first used as a silk degumming agent in this study is an amino acid-type anionic surfactant that was synthesized using silk fibroin amino acids and lauroyl chloride. We studied it systematically in comparison with the traditional degumming methods such as sodium carbonate (Na2CO3) and neutral soap (NS). The experimental results showed that the sericin can be completely removed from the silk fibroin fiber after boiling the fibers three times for 30 min and using a bath ratio of 1:80 (g/mL) and a concentration of 0.2% SPS in an aqueous solution. The results of the tensile properties, thermal analysis, and SEM all show that SPS is similar to the NS, far superior to Na2CO3. In short, SPS may be used as an environmentally friendly silk degumming/refining agent in the silk textile industry and in the manufacture of silk floss quilts. PMID- 26117748 TI - Electrophoretic deposition of ZnO/alginate and ZnO-bioactive glass/alginate composite coatings for antimicrobial applications. AB - Two organic/inorganic composite coatings based on alginate, as organic matrix, and zinc oxide nanoparticles (n-ZnO) with and without bioactive glass (BG), as inorganic components, intended for biomedical applications, were developed by electrophoretic deposition (EPD). Different n-ZnO (1-10 g/L) and BG (1-1.5 g/L) contents were studied for a fixed alginate concentration (2 g/L). The presence of n-ZnO was confirmed to impart antibacterial properties to the coatings against gram-negative bacteria Escherichia coli, while the BG induced the formation of hydroxyapatite on coating surfaces thereby imparting bioactivity, making the coating suitable for bone replacement applications. Coating composition was analyzed by thermogravimetric analysis (TG), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDS) analyses. Scanning electron microscopy (SEM) was employed to study both the surface and the cross section morphology of the coatings. Polarization curves of the coated substrates made in cell culture media at 37 degrees C confirmed the corrosion protection function of the novel organic/inorganic composite coatings. PMID- 26117749 TI - Effect of carbon on the microstructure, mechanical properties and metal ion release of Ni-free Co-Cr-Mo alloys containing nitrogen. AB - This paper investigated the effect of carbon addition on the microstructure and tensile properties of Ni-free biomedical Co-29Cr-6Mo (mass%) alloys containing 0.2 mass% nitrogen. The release of metal ions by the alloys was preliminarily evaluated in an aqueous solution of 0.6% sodium chloride (NaCl) and 1% lactic acid, after which samples with different carbon contents were subjected to hot rolling. All specimens were found to primarily consist of a gamma-phase matrix due to nitrogen doping, with only the volume fraction of M23C6 increasing with carbon concentration. Owing to the very fine size of these carbide particles (less than 1 MUm), which results from fragmentation during hot rolling, the increased formation of M23C6 increased the 0.2% proof stress, but reduced the elongation-to-failure. Carbon addition also increased the amount of Co and Cr released during static immersion; Co and Cr concentrations at the surfaces, which increased with increasing the bulk carbon concentrations, possibly enhanced the metal ion release. However, only a very small change in the Mo concentration was noticed in the solution. Therefore, it is not necessarily considered a suitable means of improving the strength of biomedical Co-Cr-Mo alloys, even though it has only to date been used in this alloy system. The results of this study revealed the limitations of the carbon strengthening and can aid in the design of biomedical Co-Cr-Mo-based alloys that exhibit the high durability needed for their practical application. PMID- 26117750 TI - Bioinspired synthesis of polydopamine/Ag nanocomposite particles with antibacterial activities. AB - Mussel-inspired chemistry (polydopamine) offers great opportunities to develop inexpensive and efficient process for many types of materials with complex shapes and functions in a mild and friendly environment. This paper describes a facile, yet green approach to synthesize polydopamine/silver (PDA/Ag) nanocomposite particles with a combination use of polydopamine chemistry and electroless metallization of Ag. In this approach, monodisperse spherical polydopamine particles are first synthesized by the oxidation and self-polymerization of dopamine (monomer) in an alkaline water-ethanol solution at room temperature, which are served as the active templates for secondary reactions due to the abundant catechol and amine groups on the surface. Subsequently, the silver precursor-[Ag(NH3)2](+) ions introduced are easily absorbed onto the surface of the PDA particles, and are immediately in situ reduced to metallic Ag nanoparticles with the help of these active catechol and amine groups. During the preparation, no additional reductants, toxic reagents and intricate instruments are needed. These as-synthesized PDA/Ag nanocomposite particles are ideal candidates for antibacterial application because they do not show significant cytotoxicity against HEK293T human embryonic kidney cells in the in vitro cytotoxicity assay, whereas demonstrate enhanced antibacterial abilities against Escherichia coli (Gram-negative bacteria) and Staphylococcus aureus (Gram positive bacteria) in the antibacterial assays. Owing to their excellent cytocompatibilities and antibacterial activities, these PDA/Ag nanocomposite particles can be considered as the promising antibacterial materials for future biomedical applications. PMID- 26117751 TI - Osteogenic differentiation of MC3T3-E1 cells on poly(L-lactide)/Fe3O4 nanofibers with static magnetic field exposure. AB - Proliferation and differentiation of bone-related cells are modulated by many factors such as scaffold design, growth factor, dynamic culture system, and physical simulation. Nanofibrous structure and moderate-intensity (1 mT-1 T) static magnetic field (SMF) have been identified as capable of stimulating proliferation and differentiation of osteoblasts. Herein, magnetic nanofibers were prepared by electrospinning mixture solutions of poly(L-lactide) (PLLA) and ferromagnetic Fe3O4 nanoparticles (NPs). The PLLA/Fe3O4 composite nanofibers demonstrated homogeneous dispersion of Fe3O4 NPs, and their magnetism depended on the contents of Fe3O4 NPs. SMF of 100 mT was applied in the culture of MC3T3-E1 osteoblasts on pure PLLA and PLLA/Fe3O4 composite nanofibers for the purpose of studying the effect of SMF on osteogenic differentiation of osteoblastic cells on magnetic nanofibrous scaffolds. On non-magnetic PLLA nanofibers, the application of external SMF could enhance the proliferation and osteogenic differentiation of MC3T3-E1 cells. In comparison with pure PLLA nanofibers, the incorporation of Fe3O4 NPs could also promote the proliferation and osteogenic differentiation of MC3T3-E1 cells in the absence or presence of external SMF. The marriage of magnetic nanofibers and external SMF was found most effective in accelerating every aspect of biological behaviors of MC3T3-E1 osteoblasts. The findings demonstrated that the magnetic feature of substrate and microenvironment were applicable ways in regulating osteogenesis in bone tissue engineering. PMID- 26117752 TI - Effect of molecular weight reduction by gamma irradiation on chitosan film properties. AB - The present work aimed the influence of molecular weight (MW) reduction by irradiation with (60)Co and polymer concentration on some physical properties of chitosan films. Irradiation of chitosan with a MW of 275.221 kDa and 74.74% of deacetylation degree was performed using a (60)Co source to provide doses of 5, 10, 20 and 50 kGy to obtain chitosans with molecular weights of 247.847, 221.563, 126.469 and 77.063 kDa, respectively. Films were prepared via the solution casting method. Film-forming solutions (FFS) of chitosan irradiated or not, were prepared at 1.5 and 2% (w/v) in a solution of lactic acid at 1% (v/v) and 0.1% (v/v) of Tween 80. The FFS were poured into glass plates of 400 cm(2) and dried at 60 degrees C during 10h without airflow. The decrease of MW and increase of chitosan concentration increased the tensil strength and water vapor permeability while decreased the elongation at break of the films. The chitosan MW did not significantly influence (p>0.05) the water solubility of films within a same polymer concentration. There was a decrease in the films' brightness with the increase of concentration and a decrease of the MW of irradiated chitosan, while the b* values of films increased and there was an increasing tendency of their apparent opacity. PMID- 26117753 TI - Photoelastic analysis of stresses transmitted by complete dentures lined with hard or soft liners. AB - Stresses transmitted on the alveolar bone ridge by lined conventional complete mandibular dentures can decrease the bone absorption level. The aim of this in vitro study was to evaluate the stresses induced on the alveolar bone ridge of lined conventional complete mandibular dentures by using photoelastic analysis. One maxillary and three mandibular conventional dentures were developed for the following treatments: 1 - Unlined denture (control), 2 - Denture lined with resin based material, and 3 - Denture lined with silicone-based material. The photoelastic analysis took place with the dentures in the position of maximum intercuspation, and the mandibular photoelastic models were axially loaded with 10 kgf (98 N). Unlined denture (control) presented stresses along the model, especially on the anterior and left lateral sides with less stresses on the right side. On the left lateral side, the denture base lined with resin-based material demonstrated similar stresses to that of the control; however, lower stresses occurred in the premolar and retromolar regions. Denture bases lined with silicone-based material showed decreased fringe orders and homogeneous distribution of induced stresses. Both lined dentures exhibited lower stresses when compared to unlined dentures. Silicone-based material provided a more homogeneous distribution of stresses. PMID- 26117754 TI - Analysis of the biomechanical behavior of short implants: The photo-elasticity method. AB - The aim of this study was to analyze the stress distribution of short implants supporting single unit or splinted crowns by the photo-elasticity method. Four photo-elastic models were produced: A (3.75*7 mm); B (3.75*7 mm, 3.75*7 mm and 3.75*7 mm); C (3.75*10 mm, 3.75*7 mm and 3.75*7 mm); D (3.75*13 mm, 3.75*7 mm and 3.75*7 mm). The prostheses were made with Ni-Cr alloy. A load of 100 N in the axial and oblique directions was applied, totaling 380 applications, individually capturing their images in each model. The data were randomized and analyzed qualitatively and quantitatively by 2 examiners. The oblique loading was significantly more damaging. The increase in length was favorable for stress distribution (p<0.05). The splinting was beneficial for the transmission of stresses mainly (p<0.05). The splinting of the crowns, as well as increasing the length of the first implant and axial loading was most beneficial in the stress distribution. Short splinted implants behaved better than single unit implants. Increasing of the length of the first implant significantly improved the stress distribution in all analyzed situations. PMID- 26117755 TI - One-pot synthesis of porphyrin functionalized gamma-Fe2O3 nanocomposites as peroxidase mimics for H2O2 and glucose detection. AB - Meso-tetrakis(4-carboxyphenyl)-porphyrin-functionalized gamma-Fe2O3 nanoparticles (H2TCPP-gamma-Fe2O3) were successfully prepared by one-pot method under hydrothermal conditions and were found to possess intrinsic peroxidase-like activity. The H2TCPP-gamma-Fe2O3 nanocomposites can catalytically oxidize peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2 to produce a blue color reaction, which can be easily observed by the naked eye. Furthermore, kinetic studies indicate that the H2TCPP-gamma-Fe2O3 nanocomposites have an even higher affinity to TMB than that of the natural enzyme, horseradish peroxidase (HRP). On the basis of the high activity, the reaction provides a simple, sensitive and selective method for colorimetric detection of H2O2 over a range of 10-100 MUM with a minimum detection limit of 1.73 MUM. Moreover, H2TCPP gamma-Fe2O3/glucose oxidase (GOx)/TMB system provides a novel colorimetric sensor for glucose and shows good response toward glucose detection over a range of 5-25 MUM with a minimum detection limit of 2.54 MUM. The results indicated that it is a simple, cheap, convenient, highly selective, sensitive and easy handling colorimetric assay. Results of a fluorescent probe suggest that the catalase mimic activity of the H2TCPP-gamma-Fe2O3 nanocomposites effectively catalyze the decomposition of H2O2 into H2O and O2. PMID- 26117756 TI - Collagen based film with well epithelial and stromal regeneration as corneal repair materials: Improving mechanical property by crosslinking with citric acid. AB - Corneal disease can lead to vision loss. It has become the second greatest cause of blindness in the world, and keratoplasty is considered as an effective treatment method. This paper presents the crosslinked collagen (Col)-citric acid (CA) films developed by making use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). The results showed that the Col-CA films had necessary optical performance, water content. The collagenase resistance of CA crosslinked films was superior to that of EDC crosslinked films. And CA5 film (Col:CA:EDC:NHS=60:3:10:10) had the best mechanical properties. Cell experiments showed that CA5 film was non-cytotoxic and human corneal epithelial cells could proliferate well on the films. Lamellar keratoplasty showed that the CA5 film could be sutured in the rabbit eyes and was epithelialized completely in about 10 days, and the transparency was restored quickly in 30+/-5 days. No inflammation and corneal neovascularization were observed at 6 months. Corneal stroma had been repaired; stromal cells and neo-stroma could be seen in the area of operation from the hematoxylin-eosin stained histologic sections and anterior segment optical coherence tomography images. These results indicated that Col-CA films were highly promising biomaterials that could be used in corneal tissue engineering and a variety of other tissue engineering applications. PMID- 26117757 TI - Fabrication of an electrochemical sensor based on computationally designed molecularly imprinted polymer for the determination of mesalamine in real samples. AB - A novel electrochemical sensor based on mesalamine molecularly imprinted polymer (MIP) film on a glassy carbon electrode was fabricated. Density functional theory (DFT) in gas and solution phases was developed to study the intermolecular interactions in the pre-polymerization mixture and to find the suitable functional monomers in MIP preparation. On the basis of computational results, o phenylenediamine (OP), gallic acid (GA) and p-aminobenzoic acid (ABA) were selected as functional monomers. The MIP film was cast on glassy carbon electrode by electropolymerization of solution containing ternary monomers and then followed by Ag dendrites (AgDs) with nanobranch deposition. The surface feature of the modified electrode (AgDs/MIP/GCE) was characterized by scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). Under the optimal experimental conditions, the peak current was proportional to the concentration of mesalamine ranging from 0.05 to 100 MUM, with the detection limit of 0.015 MUM. The proposed sensor was applied successfully for mesalamine determination in real samples. PMID- 26117758 TI - Coatings of nanostructured pristine graphene-IrOx hybrids for neural electrodes: Layered stacking and the role of non-oxygenated graphene. AB - The need to enhance charge capacity in neural stimulation-electrodes is promoting the formation of new materials and coatings. Among all the possible types of graphene, pristine graphene prepared by graphite electrochemical exfoliation, is used in this work to form a new nanostructured IrOx-graphene hybrid (IrOx-eG). Graphene is stabilized in suspension by IrOx nanoparticles without surfactants. Anodic electrodeposition results in coatings with much smaller roughness than IrOx-graphene oxide. Exfoliated pristine graphene (eG), does not electrodeposit in absence of iridium, but IrOx-nanoparticle adhesion on graphene flakes drives the process. IrOx-eG has a significantly different electronic state than graphene oxide, and different coordination for carbon. Electron diffraction shows the reflection features expected for graphene. IrOx 1-2 nm cluster/nanoparticles are oxohydroxo-species and adhere to 10nm graphene platelets. eG induces charge storage capacity values five times larger than in pure IrOx, and if calculated per carbon atom, this enhancement is one order magnitude larger than the induced by graphene oxide. IrOx-eG coatings show optimal in vitro neural cell viability and function as cell culture substrates. The fully straightforward electrochemical exfoliation and electrodeposition constitutes a step towards the application of graphene in biomedical systems, expanding the knowledge of pristine graphene vs. graphene oxide, in bioelectrodes. PMID- 26117759 TI - Bio-functional nano-coatings on metallic biomaterials. AB - Metals and their alloys have been widely used in all aspects of science, engineering and medicine. Metals in biomedical devices are used due to their inertness and structural functions. They are generally preferred over polymers or ceramics and are especially desirable in applications where the implants are subjected to static, dynamic or cyclic loads that require a combination of strength and ductility. In biomedicine, the choice of a specific biomaterial is governed by many factors that include biocompatibility, corrosion resistance, controlled degradability, modulus of elasticity, fatigue strength and many other application specific criterions. Nanotechnology is driving newer demands and requirements for better performance of existing materials and presents an opportunity for surface modification of metals in response to demands on the surface of metals for their biomedical applications. Self-assembled monolayers (SAMs) are nanosized coatings that present a flexible method of carrying out surface modification of biomaterials to tailor its surface properties for specific end applications. These nanocoatings can serve primary functions such as surface coverage, etch protection and anti-corrosion along with a host of other secondary chemical functions such as drug delivery and biocompatibility. We present a brief introduction to surface modification of biomaterials and their alloys followed by a detailed description of organic nanocoatings based on self assembled monolayers and their biomedical applications including patterning techniques and biological applications of patterned SAMs. PMID- 26117760 TI - Replication of microchannel structures in WC-Co feedstock using elastomeric replica moulds by hot embossing process. AB - Hot embossing is a net shaping process that is able to produce the micro components of polymers with intrinsic and complex shapes at lower cost compared with machining and injection moulding. However, the emboss of hard metals, such as WC-Co, is more challenging due to their high thermal conductivity and ease of agglomeration. Thus, a WC-Co alloy mixed with a wax-based binder feedstock was selected. The formed feedstock exhibited pseudo-plastic flow and was successfully embossed (green part). Here, we developed a novel process that is used to replicate polymer microfluidic chips while simultaneously reducing the channel surface roughness of the mould insert, yielding optical-grade (less than 100 nm surface roughness) channels and reservoirs. This paper concerns the replication of metallic microfluidic mould inserts in WC-Co and the parameters associated with feedstock formation via a hot embossing process. A suitable formulation for micro-powder hot embossing has been established and characterised by thermogravimetric analyses and measurements of mixing torques to verify and quantify the homogeneity of the proposed feedstocks. The relative density of the samples increased with processing temperature, and almost fully dense materials were obtained. In this work, the effects of the sintering temperature on the physical properties were systematically analysed. The evolution of the metal surface morphology during the hot embossing process was also investigated. The results indicate that the feedstock can be used to manufacture micro-fluidic die mould cavities with a low roughness, proper dimensions and good shape retention. The shrinkage of the sintered part was approximately 19-24% compared with that of the brown part. PMID- 26117761 TI - Susceptibility to corrosion of laser welding composite arch wire in artificial saliva of salivary amylase and pancreatic amylase. AB - In this study, laser-welded composite arch wire (CAW) with a copper interlayer was exposed to artificial saliva containing salivary amylase or pancreatic amylase, and the resultant corrosion behavior was studied. The purpose was to determine the mechanisms by which salivary amylase and pancreatic amylase contribute to corrosion. The effects of amylase on the electrochemical resistance of CAW were tested by potentiodynamic polarization measurements. The dissolved corrosion products were determined by ICP-OES, and the surfaces were analyzed by SEM, AFM and EDS. The results showed that both exposure to salivary amylase and pancreatic amylase significantly improved the corrosion resistance of CAW. Even isozyme could have different influences on the alloy surface. When performing in vitro research of materials to be used in oral cavity, the effect of alpha amylase should be taken into account since a simple saline solution does not entirely simulate the physiological situation. PMID- 26117762 TI - Calcium orthophosphate deposits: Preparation, properties and biomedical applications. AB - Since various interactions among cells, surrounding tissues and implanted biomaterials always occur at their interfaces, the surface properties of potential implants appear to be of paramount importance for the clinical success. In view of the fact that a limited amount of materials appear to be tolerated by living organisms, a special discipline called surface engineering was developed to initiate the desirable changes to the exterior properties of various materials but still maintaining their useful bulk performances. In 1975, this approach resulted in the introduction of a special class of artificial bone grafts, composed of various mechanically stable (consequently, suitable for load bearing applications) implantable biomaterials and/or bio-devices covered by calcium orthophosphates (CaPO4) to both improve biocompatibility and provide an adequate bonding to the adjacent bones. Over 5000 publications on this topic were published since then. Therefore, a thorough analysis of the available literature has been performed and about 50 (this number is doubled, if all possible modifications are counted) deposition techniques of CaPO4 have been revealed, systematized and described. These CaPO4 deposits (coatings, films and layers) used to improve the surface properties of various types of artificial implants are the topic of this review. PMID- 26117763 TI - Structural properties of pepsin-solubilized collagen acylated by lauroyl chloride along with succinic anhydride. AB - The structural properties of pepsin-solubilized calf skin collagen acylated by lauroyl chloride along with succinic anhydride were investigated in this paper. Compared with native collagen, acylated collagen retained the unique triple helix conformation, as determined by amino acid analysis, circular dichroism and X-ray diffraction. Meanwhile, the thermostability of acylated collagen using thermogravimetric measurements was enhanced as the residual weight increased by 5%. With the temperature increased from 25 to 115 degrees C, the secondary structure of native and acylated collagens using Fourier transform infrared spectroscopy measurements was destroyed since the intensity of the major amide bands decreased and the positions of the major amide bands shifted to lower wavenumber, respectively. Meanwhile, two-dimensional correlation spectroscopy revealed that the most sensitive bands for acylated and native collagens were amide I and II bands, respectively. Additionally, the corresponding order of the groups between native and acylated collagens was different and the correlation degree for acylated collagen was weaker than that of native collagen, suggesting that temperature played a small influence on the conformation of acylated collagen, which might be concluded that the hydrophobic interaction improved the thermostability of collagen. PMID- 26117764 TI - A modified emulsion gelation technique to improve buoyancy of hydrogel tablets for floating drug delivery systems. AB - The use of buoyant or floating hydrogel tablets is of particular interest in the sustained release of drugs to the stomach. They have an ability to slow the release rates of drugs by prolonging their absorption window in the upper part of the gastrointestinal (GI) tract. In this study we synthesized bioactive hydrogels that have sustainable release rates for drugs in the stomach based on a hydrogel preparation technique that employs emulsifying surfactants. The emulsion gelation technique, which encapsulates oil droplets within the hydrogels during crosslinking, was used to decrease their specific gravity in aqueous environments, resulting in floating drug release depots. Properties such as swelling, buoyancy, density and drug release were manipulated by changing the polymer concentrations, surfactant percentages and the oil:polymer ratios. The relationship between these properties and the hydrogel's floating lag time was documented. The potential for this material to be used as a floating drug delivery system was demonstrated. PMID- 26117765 TI - Synthesis and characterization of magnetite/silver/antibiotic nanocomposites for targeted antimicrobial therapy. AB - The article is devoted to preparation and characterization of magnetite/silver/antibiotic nanocomposites for targeted antimicrobial therapy. Magnetite nanopowder was produced by thermochemical technique; silver was deposited on the magnetite nanoparticles in the form of silver clusters. Magnetite/silver nanocomposite was investigated by XRD, SEM, TEM, AFM, XPS, EDX techniques. Adsorptivity of magnetite/silver nanocomposite towards seven antibiotics from five different groups was investigated. It was shown that rifampicin, doxycycline, ceftriaxone, cefotaxime and doxycycline may be attached by physical adsorption to magnetite/silver nanocomposite. Electrostatic surfaces of antibiotics were modeled and possible mechanism of antibiotic attachment is considered in this article. Raman spectra of magnetite, magnetite/silver and magnetite/silver/antibiotic were collected. It was found that it is difficult to detect the bands related to antibiotics in the magnetite/silver/antibiotic nanocomposite spectra due to their overlap by the broad carbon bands of magnetite nanopowder. Magnetic measurements revealed that magnetic saturation of the magnetite/silver/antibiotic nanocomposites decreased on 6-19 % in comparison with initial magnetite nanopowder. Pilot study of antimicrobial properties of the magnetite/silver/antibiotic nanocomposites were performed towards Bacillus pumilus. PMID- 26117766 TI - Silver nanoparticles with antimicrobial activities against Streptococcus mutans and their cytotoxic effect. AB - Microbial resistance represents a challenge for the scientific community to develop new bioactive compounds. The goal of this research was to evaluate the antimicrobial activity of silver nanoparticles (AgNPs) against a clinical isolate of Streptococcus mutans, antibiofilm activity against mature S. mutans biofilms and the compatibility with human fibroblasts. The antimicrobial activity of AgNPs against the planktonic clinical isolate was size and concentration dependent, with smaller AgNPs having a lower minimum inhibitory concentration. A reduction of 2.3 log in the number of colony-forming units of S. mutans was observed when biofilms grown in a CDC reactor were exposed to 100 ppm of AgNPs of 9.5+/-1.1 nm. However, AgNPs at high concentrations (>10 ppm) showed a cytotoxic effect upon human dermal fibroblasts. AgNPs effectively inhibited the growth of a planktonic S. mutans clinical isolate and killed established S. mutans biofilms, which suggests that AgNPs could be used for prevention and treatment of dental caries. Further research and development are necessary to translate this technology into therapeutic and preventive strategies. PMID- 26117767 TI - Biomimetic synthesized chiral mesoporous silica: Structures and controlled release functions as drug carrier. AB - This work initially illustrated the formation mechanism of chiral mesoporous silica (CMS) in a brand new insight named biomimetic synthesis. Three kinds of biomimetic synthesized CMS (B-CMS, including B-CMS1, B-CMS2 and B-CMS3) were prepared using different pH or stirring rate condition, and their characteristics were tested with transmission electron microscope and small angle X-ray diffraction. The model drug indomethacin was loaded into B-CMS and drug loading content was measured using ultraviolet spectroscopy. The result suggested that pH condition influenced energetics of self-assembly process, mainly packing energetics of the surfactant, while stirring rate was the more dominant factor to determine particle length. In application, indomethacin loading content was measured to be 35.3%, 34.8% and 35.1% for indomethacin loaded B-CMS1, indomethacin loaded B-CMS2 and indomethacin loaded B-CMS3. After loading indomethacin into B-CMS carriers, surface area, pore volume and pore diameter of B-CMS carriers were reduced. B-CMS converted crystalline state of indomethacin to amorphous state, leading to the improved indomethacin dissolution. B-CMS1 controlled drug release without burst-release, while B-CMS2 and B-CMS3 released indomethacin faster than B-CMS1, demonstrating that the particle length, the ordered lever of multiple helixes, the curvature degree of helical channels and pore diameter greatly contributed to the release behavior of indomethacin loaded B-CMS. PMID- 26117768 TI - A novel squid pen chitosan/hydroxyapatite/beta-tricalcium phosphate composite for bone tissue engineering. AB - Squid pen chitosan was used in the fabrication of biocomposite scaffolds for bone tissue engineering. Hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) obtained from waste mussel shells were used as the calcium phosphate source. The composite was prepared using 2.5% tripolyphosphate (TPP) and 1% glycerol as a cross-linker and plasticizer, respectively. The weight percent (wt.%) ratios of the ceramic components in the composite were 20/10/70, 30/20/50 and 40/30/30 (HA/beta-TCP/Chi). The biodegradation rate and structural properties of the scaffolds were investigated. Scanning electron microscopy (SEM) and microCT(MUCT) results indicated that the composites have a well defined lamellar structure with an average pore size of 200 MUm. The porosity of the composites decreased from 88 to 56% by increasing the ratio of HA/beta-TCP from 30 to 70%. After 28 days of incubation in a physiological solution, the scaffolds were degraded by approximately 30%. In vitro investigations showed that the composites were cytocompatible and supported the growth of L929 and Saos-2 cells. The obtained data suggests that the squid pen chitosan composites are potential candidates for bone regeneration. PMID- 26117769 TI - Three-dimensional dynamic fabrication of engineered cartilage based on chitosan/gelatin hybrid hydrogel scaffold in a spinner flask with a special designed steel frame. AB - Cartilage transplantation using in vitro tissue engineered cartilage is considered a promising treatment for articular cartilage defects. In this study, we assessed the advantages of adipose derived stem cells (ADSCs) combined with chitosan/gelatin hybrid hydrogel scaffolds, which acted as a cartilage biomimetic scaffold, to fabricate a tissue engineered cartilage dynamically in vitro and compared this with traditional static culture. Physical properties of the hydrogel scaffolds were evaluated and ADSCs were inoculated into the hydrogel at a density of 1*10(7) cells/mL and cultured in a spinner flask with a special designed steel framework and feed with chondrogenic inductive media for two weeks. The results showed that the average pore size, porosity, swelling rate and elasticity modulus of hybrid scaffolds with good biocompatibility were 118.25+/ 19.51 MUm, 82.60+/-2.34%, 361.28+/-0.47% and 61.2+/-0.16 kPa, respectively. ADSCs grew well in chitosan/gelatin hybrid scaffold and successfully differentiated into chondrocytes, showing that the scaffolds were suitable for tissue engineering applications in cartilage regeneration. Induced cells cultivated in a dynamic spinner flask with a special designed steel frame expressed more proteoglycans and the cell distribution was much more uniform with the scaffold being filled mostly with extracellular matrix produced by cells. A spinner flask with framework promoted proliferation and chondrogenic differentiation of ADSCs within chitosan/gelatin hybrid scaffolds and accelerated dynamic fabrication of cell-hydrogel constructs, which could be a selective and good method to construct tissue engineered cartilage in vitro. PMID- 26117770 TI - Novel artificial hip joint: A layer of alumina on Ti-6Al-4V alloy formed by micro arc oxidation. AB - In many hip replacement surgeries, monolithic alumina is used as a femoral head due to its high wear resistance. However, it is liable to fracture under load bearing operations in artificial joints. We propose a promising way to overcome this limitation by forming a dense alumina layer onto a relatively tough substrate such as Ti-6Al-4V alloy to obtain high wear resistance on a material that can sustain relatively high toughness. For this purpose, Al metal powders were deposited onto Ti-6Al-4V alloy by cold spraying in N2 atmosphere. Interfacial adhesion between Al and the Ti alloy was improved by the formation of a reaction layer of Al3Ti between them by heating at 640 degrees C for 1h in air. Subsequently, micro-arc oxidation treatment was performed to oxidize Al. The oxidized layer was composed of an outer porous layer of gamma-alumina and inner most dense layer of alpha-alumina. The alpha-alumina layer was almost fully densified and exhibited high Vickers hardness almost equal to that of alumina ceramics used as the femoral head. Thus, the newly developed dense alumina/Ti alloy can be potentially used to produce the reliable bearing surfaces of artificial hip joint. PMID- 26117771 TI - Bone tissue engineering using silica-based mesoporous nanobiomaterials:Recent progress. AB - Bone disorders are of significant concern due to increase in the median age of our population. It is in this context that tissue engineering has been emerging as a valid approach to the current therapies for bone regeneration/substitution. Tissue-engineered bone constructs have the potential to alleviate the demand arising from the shortage of suitable autograft and allograft materials for augmenting bone healing. Silica based mesostructured nanomaterials possessing pore sizes in the range 2-50 nm and surface reactive functionalities have elicited immense interest due to their exciting prospects in bone tissue engineering. In this review we describe application of silica-based mesoporous nanomaterials for bone tissue engineering. We summarize the preparation methods, the effect of mesopore templates and composition on the mesopore-structure characteristics, and different forms of these materials, including particles, fibers, spheres, scaffolds and composites. Also, the effect of structural and textural properties of mesoporous materials on development of new biomaterials for production of bone implants and bone cements was discussed. Also, application of different mesoporous materials on construction of manufacture 3-dimensional scaffolds for bone tissue engineering was discussed. It begins by giving the reader a brief background on tissue engineering, followed by a comprehensive description of all the relevant components of silica-based mesoporous biomaterials on bone tissue engineering, going from materials to scaffolds and from cells to tissue engineering strategies that will lead to "engineered" bone. PMID- 26117772 TI - Thermo-responsive poly(N-isopropylacrylamide)-grafted hollow fiber membranes for osteoblasts culture and non-invasive harvest. AB - Hollow fiber membrane (HFM) culture system is one of the most important bioreactors for the large-scale culture and expansion of therapeutic cells. However, enzymatic and mechanical treatments are traditionally applied to harvest the expanded cells from HFMs, which inevitably causes harm to the cells. In this study, thermo-responsive cellulose acetate HFMs for cell culture and non-invasive harvest were prepared for the first time via free radical polymerization in the presence of cerium (IV). ATR-FTIR and elemental analysis results indicated that the poly(N-isopropylacrylamide) (PNIPAAm) was covalently grafted on HFMs successfully. Dynamic contact angle measurements at different temperatures revealed that the magnitude of volume phase transition was decreased with increasing grafted amount of PNIPAAm. And the amount of serum protein adsorbed on HFMs surface also displayed the same pattern. Meanwhile osteoblasts adhered and spread well on the surface of PNIPAAm-grafted HFMs at 37 degrees C. And Calcein AM/PI staining, AB assay, ALP activity and OCN protein expression level all showed that PNIPAAm-grafted HFMs had good cell compatibility. After incubation at 20 degrees C for 120 min, the adhering cells on PNIPAAm-grafted HFMs turned to be round and detached after being gently pipetted. These results suggest that thermo-responsive HFMs are attractive cell culture substrates which enable cell culture, expansion and the recovery without proteolytic enzyme treatment for the application in tissue engineering and regenerative medicine. PMID- 26117773 TI - Improvement in glucose biosensing response of electrochemically grown polypyrrole nanotubes by incorporating crosslinked glucose oxidase. AB - In this paper a novel enzymatic glucose biosensor has been reported in which platinum coated alumina membranes (AnodiscTMs) have been employed as templates for the growth of polypyrrole (PPy) nanotube arrays using electrochemical polymerization. The PPy nanotube arrays were grown on AnodiscTMs of pore diameter 100 nm using potentiostatic electropolymerization. In order to optimize the polymerization time, immobilization of glucose oxidase (GOx) was first performed using physical adsorption followed by measuring its biosensing response which was examined amperometrically for increasing concentrations of glucose. In order to further improve the sensing performance of the biosensor fabricated for optimum polymerization duration, enzyme immobilization was carried out using cross linking with glutaraldehyde and bovine serum albumin (BSA). Approximately six fold enhancement in the sensitivity was observed in the fabricated electrodes. The biosensors also showed a wide range of linear operation (0.2-13 mM), limit of detection of 50 MUM glucose concentration, excellent selectivity for glucose, notable reliability for real sample detection and substantially improved shelf life. PMID- 26117774 TI - Study of the ion-channel behavior on glassy carbon electrode supported bilayer lipid membranes stimulated by perchlorate anion. AB - In this paper, a kind of didodecyldimethylammonium bromide (DDAB) layer membranes was supported on a glassy carbon electrode (GCE). We studied the ion channel behavior of the supported bilayer lipid membrane by scanning electrochemical microscopy (SCEM) in tris(2,2'-bipyridine) ruthenium(II) solution. Perchlorate anion was used as a presence of stimulus and ruthenium(II) complex cations as the probing ions for the measurement of SECM, the lipid membrane channel was opened and exhibited the behavior of distinct SECM positive feedback curve. The channel was in a closed state in the absence of perchlorate anions while reflected the behavior of SECM negative feedback curve. The rates of electron transfer reaction in the lipid membranes surface were detected and it was dependant on the potential of SECM. PMID- 26117775 TI - Bioactivity and cell proliferation in radiopaque gel-derived CaO-P2O5-SiO2-ZrO2 glass and glass-ceramic powders. AB - In this study, 10 mol% ZrO2 was added to a 27CaO-5P2O5-68SiO2 (mol%) base composition synthesized via a simple sol-gel method. This composition is similar to that of a frequently investigated bioactive gel-glass. The effects of ZrO2 on the in vitro bioactivity and MG-63 cell proliferation of the glass and its derivative polycrystalline (glass-ceramic) powder were investigated. The samples were characterized using thermo-gravimetric and differential thermal analysis (TG/DTA), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) coupled to energy dispersive X-ray spectroscopy (EDS). Release of Si, Ca, P and Zr into simulated body fluid (SBF) was determined by inductively coupled plasma (ICP). Upon heat treatment at 1000 degrees C, the glass powder crystallized into an apatite-wollastonite-zirconia glass-ceramic powder. Hydroxycarbonate apatite (HCA) formation on the surface of the glass and glass-ceramic particles containing ZrO2 was confirmed by FTIR and SEM. Addition of ZrO2 to the base glass composition decreased the rate of HCA formation in vitro from one day to three days, and hence, ZrO2 could be employed to control the rate of apatite formation. However, the rate of HCA formation on the glass-ceramic powder containing ZrO2 crystal was equal to that in the base glassy powder. Tests with a cultured human osteoblast-like MG-63 cells revealed that the glass and glass-ceramic materials stimulated cell proliferation, indicating that they are biocompatible and are not cytotoxic in vitro. Moreover, zirconia clearly increased osteoblast proliferation over that of the Zr-free samples. This increase is likely associated with the lower solubility of these samples and, consequently, a smaller variation in the media pH. Despite the low solubility of these materials, bioactivity was maintained, indicating that these glassy and polycrystalline powders are potential candidates for bone graft substitutes and bone cements with the special feature of radiopacity. PMID- 26117776 TI - Viscoplastic response of tooth enamel under cyclic microindentation. AB - Cyclic microindentations were performed on the occlusal surface and axial section of tooth enamel, using the Berkovich indenter. Under the action of a cyclic indentation load, the indenter continuously penetrated into the tooth enamel and reached a quasi-steady state at which the penetration depth per cycle was a constant. At the quasi-steady state, both the amplitude of the indentation depth and the penetration depth per cycle for the cyclic indentation of the axial section are larger than those for the indentation of the occlusal section under the same loading condition. The energy dissipation per cycle consists of two contributions; one is the plastic energy dissipated per cycle due to the propagation of the plastic zone underneath the indentation and the other is the energy dissipation due to the viscous flow during the cyclic indentation. Both the penetration depth and the plastic energy dissipated per cycle at the quasi steady state are independent of the maximum applied load and increase with increasing the amplitude of the cyclic indentation load. PMID- 26117777 TI - Molecularly imprinted electrochemical sensor for the highly selective and sensitive determination of melamine. AB - A selective and sensitive molecularly imprinted electrochemical sensor was developed for the determination of melamine. Carbon nanotube-ionic liquid composite was used as a carrier to enhance the number of imprinted cavities and then improve the selectivity and sensitivity of the sensor. The proposed sensor showed a linear relationship with the concentration of melamine in the range of 0.4 to 9.2 MUM, with a detection limit of 0.11 MUM. The sensor was successfully applied to the determination of melamine in milk products with good recovery. PMID- 26117778 TI - Antimicrobial activity, DNA cleavage, thermal analysis data and crystal structure of some new CdLX2 complexes: A supramolecular network. AB - Some new cadmium(II) Schiff base complexes CdLX2 (where X=Cl(-), Br(-), I(-), SCN(-) and N3(-) and L=N,N-bis((E)-3-(4-(dimethylamino)phenyl)allylidene)benzene 1,2-diamine) were synthesized and characterized by elemental analysis, FT-IR, UV visible, (1)HNMR spectra, and conductivity measurements. Moreover, the structure of the CdLI2 was determined by single crystal X-ray crystallography. CdLI2 crystallizes in a triclinic system with space group P 1. The molecular structure shows distorted tetrahedral coordination geometry. The CH....pi and pi-pi stacking interactions connect the molecules to a supramolecular network. The thermal properties of the compounds were investigated from the room temperature to 800 degrees C with a heating rate of 10 degrees C/min and decomposition activation parameters were evaluated from the TG/DTG plots. Antibacterial/antifungal activities of the compounds were screened by the disk diffusion method against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis and the fungi strain Aspergillus niger and Candida albicans. The antimicrobial activities were determined for all compounds and the complexation was found to enhance the inhibitory activity. Finally, the DNA cleavage potential of the compounds was investigated by agarose gel electrophoresis method. PMID- 26117779 TI - Synthesis and characterization of silane coated magnetic nanoparticles/glycidylmethacrylate-grafted-maleated cyclodextrin composite hydrogel as a drug carrier for the controlled delivery of 5-fluorouracil. AB - A novel drug delivery system (DDS), 3-methacryloxypropyl trimethoxy silane coated magnetic nanoparticles polymerized with glycidylmethacrylate-grafted-maleated cyclodextrin (MPTMS-MNP-poly-(GMA-g-MACD)) was prepared in the presence of ethyleneglycoldimethacrylate as cross-linker and a,a'-azobisisobutyronitrile as initiator and characterized by means of SEM, FT-IR, XRD, DLS, VSM and TEM. The encapsulation efficiency (EE) and drug loading efficiency (DLE) of the DDS were tested using various formulations of DDS. The DDS showed activity against gram positive and negative bacteria. The cytotoxicity studies were also performed using MCF-7 (human breast carcinoma) cells and found that the drug carrier is biocompatible and it shows sustained and controlled release of drug to the targeted site. The drug release mechanism was found to obey non-Fickian diffusion (n=0.709) method where polymer relaxation and drug diffusion played important roles in drug release. In this DDS, advantages of core magnetic nanoparticles and host-guest interactions of beta-CD were combined for the controlled delivery of 5 Fluorouracil (5-FU) to maintain the therapeutic index of the drug. PMID- 26117780 TI - Curcumin-reduced graphene oxide sheets and their effects on human breast cancer cells. AB - Curcumin (as a natural reductant material) was utilized for green reduction and functionalization of chemically exfoliated graphene oxide (GO) sheets. The pi-pi attachment of the curcumin molecules onto the curcumin-reduced graphene oxide (rGO) sheets was confirmed by Raman and Fourier transform infrared spectroscopies. Zeta potential of the GO sheets decreased from about -40 mV to 20 mV, after the green reduction and functionalization. The probable cytotoxicity of the curcumin-rGO sheets was studied through their interactions with two human breast cancer cell lines (MDA-MB-231 and SKBR3 cell lines) and a normal cell line (mouse fibroblast L929 cell line). The curcumin-rGO sheet with concentrations <70 MUg/mL in the cell culture medium, not only exhibited no significant toxicity and/or cell morphological changes, but also caused some cell growths (~25% after 48 h incubation time). Nevertheless, at 70 MUg/mL, initiation of some cell morphological changes was observed. At higher concentrations (e.g., 100 MUg/mL), some slight cytotoxic effects (resulting in ~15-25% cell destruction) were detected by MTT assay. In addition, the interaction of the rGO sheets and cells resulted in apoptosis as well as morphological transformation of the cells (from elongated to roundup morphology). These results indicated the concentration dependent toxicity of functionalized-rGO nanomaterials (here, curcumin-rGO) at the threshold concentration of ~100 MUg/mL. PMID- 26117781 TI - Insulin-like growth factor binding protein-3 affects osteogenic efficacy on dental implants in rat mandible. AB - Insulin like growth factor binding protein-3 (IGFBP-3) in bone cells and its utilization in dental implants have not been well studied. The aim of this study was to determine the osteogenic efficacy of chitosan gold nanoparticles (Ch-GNPs) conjugated with IGFBP-3 coated titanium (Ti) implants. Ch-GNPs were conjugated with IGFBP-3 plasmid DNA through a coacervation process. Conjugation was cast over Ti surfaces, and cells were seeded on coated surfaces. For in vitro analysis the expression of different proteins was analyzed by immunoblotting. For in vivo analysis, Ch-GNP/IGFBP-3 coated implants were installed in rat mandibles. Four weeks post-implantation, mandibles were examined by microcomputed tomography (MUCT), immunohistochemistry, hematoxylin & eosin and tartrate resistance acid phosphatase staining. In vitro overexpressed Ch-GNP/IGFBP-3 coated Ti surfaces was associated with activation of extracellular signal related kinase (ERK), inhibition of the stress activated protein c-Jun N-terminal kinase (JNK) and enhanced bone morphogenetic protein (BMP)-2 and 7 compared to control. Further, in vivo, Ch-GNP/IGFBP-3 coated implants were associated with inhibition of implant induced osteoclastogenesis molecules, receptor activator of nuclear factor kappa-B ligand (RANKL) and enhanced expression of osteogenic molecules including BMP2/7 and osteopontin (OPN). The MUCT analysis demonstrated that IGFBP 3 increased the volume of newly formed bone surrounding the implants compared to control (n=5; p<0.05). These results support the view that IGFBP-3 overexpression diminishes osteoclastogenesis and enhances osteogenesis of Ti implants, and can serve as a potent molecule for the development of good implantation. PMID- 26117782 TI - Ultra-trace silver-doped hydroxyapatite with non-cytotoxicity and effective antibacterial activity. AB - Hydroxyapatite (HAp) nanocrystals as the main inorganic component in hard tissue have been extensively studied for bone regeneration and dental implant treatment. However, failure of surgical reconstruction often occurs owing to the lack of effective antibacterial ability of HAp. It is still a challenge to develop artificial HAp with both efficient antibacterial ability and proper biological properties. Herein, a series of ultra-trace Ag-doped HAp nanocrystals have been elaborately prepared with the optimal doping concentration from 0.27 ppm to 2.2 ppm, which present non-cytotoxicity while possess effective bacteria reduction ability. Ultra-trace Ag-doped HAp nanocrystals possess higher protein adsorption than pure HAp nanocrystals due to the trace doping-induced less negative surface potential. The ultra-trace Ag-doped HAp nanocrystals showed effectively antibacterial ability, non-cytotoxicity and enhanced adsorbability that made them ideal materials for various biocompatible and antibacterial applications. PMID- 26117783 TI - Transformation of amorphous calcium carbonate to rod-like single crystal calcite via "copying" collagen template. AB - Collagen Langmuir films were prepared by spreading the solution of collagen over deionized water, CaCl2 solution and Ca(HCO3)2 solution. Resultant collagen Langmuir monolayers were then compressed to a lateral pressure of 10 mN/m and held there for different duration, allowing the crystallization of CaCO3. The effect of crystallization time on the phase composition and microstructure of CaCO3 was investigated. It was found that amorphous calcium carbonate (ACC) was obtained at a crystallization time of 6 h. The amorphous CaCO3 was transformed to rod-like single crystal calcite crystals at an extended crystallization time of 12 h and 24 h, via "copying" the symmetry and dimensionalities of collagen fibers. Resultant calcite crystallites were well oriented along the longitudinal axis of collagen fibers. The ordered surface structure of collagen fibers and electrostatic interactions played key roles in tuning the oriented nucleation and growth of the calcite crystallites. The mineralized collagen possessing both desired mechanical properties of collagen fiber and good biocompatibility of calcium carbonate may be assembled into an ideal biomaterial for bone implants. PMID- 26117784 TI - Bone-like apatite coating on functionalized poly(etheretherketone) surface via tailored silanization layers technique. AB - Poly(etheretherketone) (PEEK) is a rigid semi-crystalline polymer with outstanding mechanical properties, bone-like stiffness and suitable biocompatibility that has attracted much interest as a biomaterial for orthopedic and dental implants. However, the bio-inert surface of PEEK limits its biomedical applications when direct osteointegration between the implants and the host tissue is desired. In this work, -PO4H2, -COOH and -OH groups were introduced on the PEEK surface by further chemical treatments of the vinyl-terminated silanization layers formed on the hydroxylation-pretreated PEEK surface. Both the surface-functionalized and pristine specimens were characterized by X-ray photoelectron spectroscopy (XPS), attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and water contact angle measurements. When placed in 1.5 strength simulated body fluid (SBF) solution, apatite was observed to form uniformly on the functionalized PEEK surface and firmly attach to the substrate. The characterized results demonstrated that the coating was constituted by poorly crystallized bone-like apatite and the effect of surface functional groups on coating formation was also discussed in detail. In addition, in vitro biocompatibility of PEEK, in terms of pre-osteoblast cell (MC3T3-E1) attachment, spreading and proliferation, was remarkably enhanced by the bone-like apatite coating. Thus, this study provides a method to enhance the bioactivity of PEEK and expand its applications in orthopedic and dental implants. PMID- 26117785 TI - Optoelectronic studies on heterocyclic bases of deoxyribonucleic acid for DNA photonics. AB - The optoelectronics study of large molecules, particularly pi-stacking molecules, such as DNA is really an extremely difficult task. We perform first electronic structure calculations on the heterocyclic bases of 2'-deoxyribonucleic acid based on Lorentz-Fresnel dispersion theory. In the UV-VIS range of spectrum, many of the optoelectronic parameters for DNA four bases namely adenine, guanine, cytosine and thymine are calculated and discussed. The results demonstrate that adenine has the highest hyperpolarizability, whereas thymine has the lowest hyperpolarizability. Cytosine has the lower average oscillator energy and the higher lattice energy. Thymine infers the most stable nucleic base with the lower phonon energy. Thymine also has the highest average oscillator energy and the lower lattice energy. Moreover, the four nucleic acid bases have large band gap energies less than 5 eV with a semiconducting behavior. Guanine shows the smallest band gap and the highest Fermi level energy, whereas adenine elucidates the highest band gap energy. PMID- 26117786 TI - Thermal treatment of bentonite reduces aflatoxin b1 adsorption and affects stem cell death. AB - Bentonites are clays that highly adsorb aflatoxin B1 (AFB1) and, therefore, protect human and animal cells from damage. We have recently demonstrated that bentonite protects the neural crest (NC) stem cells from the toxicity of AFB1. Its protective effects are due to the physico-chemical properties and chemical composition altered by heat treatment. The aim of this study is to prepare and characterize the natural and thermal treatments (125 to 1000 degrees C) of bentonite from Criciuma, Santa Catarina, Brazil and to investigate their effects in the AFB1 adsorption and in NC cell viability after challenging with AFB1. The displacement of water and mineralogical phases transformations were observed after the thermal treatments. Kaolinite disappeared at 500 degrees C and muscovite and montmorillonite at 1000 degrees C. Slight changes in morphology, chemical composition, and density of bentonite were observed. The adsorptive capacity of the bentonite particles progressively reduced with the increase in temperature. The observed alterations in the structure of bentonite suggest that the heat treatments influence its interlayer distance and also its adsorptive capacity. Therefore, bentonite, even after the thermal treatment (125 to 1000 degrees C), is able to increase the viability of NC stem cells previously treated with AFB1. Our results demonstrate the effectiveness of bentonite in preventing the toxic effects of AFB1. PMID- 26117787 TI - Strontium substituted hydroxyapatites: Synthesis and determination of their structural properties, in vitro and in vivo performance. AB - The objective of this study is to present a detailed report related to the synthesis and characterization of strontium substituted hydroxyapatites. Based on this purpose, hydroxyapatite (HAp) bioceramics with different amounts of strontium (e.g., 0, 0.45, 0.90, 1.35, 1.80 and 2.25 at.%) were prepared using a sol-gel method. The effects of Sr substitution on the structural properties and biocompatibility of the samples were studied by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) techniques, in vitro and in vivo tests. All the samples composed of the nanoparticles ranging from 21 to 27 nm. The presence of Sr at low levels influenced the crystal size, crystallinity degree, lattice parameters and volume of the unit cell of the HAp. Both in vitro conditions and soaking period in simulated body fluid (SBF) significantly affected these properties. Especially, the (Ca+Sr)/P molar ratio gradually decreases with increasing soaking period in SBF. Animal experiments revealed the bone formation and osseointegration for all samples, and as compared with other groups, more reasonable, were observed for the sample with the lowest Sr content. PMID- 26117788 TI - Silver activation on thin films of Ag-ZrCN coatings for antimicrobial activity. AB - Nowadays, with the increase of elderly population and related health problems, knee and hip joint prosthesis are being widely used worldwide. However, failure of these invasive devices occurs in a high percentage thus demanding the revision of the chirurgical procedure. Within the reasons of failure, microbial infections, either hospital or subsequently-acquired, contribute in high number to the statistics. Staphylococcus epidermidis (S. epidermidis) has emerged as one of the major nosocomial pathogens associated with these infections. Silver has a historic performance in medicine due to its potent antimicrobial activity, with a broad-spectrum on the activity of different types of microorganisms. Consequently, the main goal of this work was to produce Ag-ZrCN coatings with antimicrobial activity, for the surface modification of hip prostheses. Thin films of ZrCN with several silver concentrations were deposited onto stainless steel 316 L, by DC reactive magnetron sputtering, using two targets, Zr and Zr with silver pellets (Zr+Ag target), in an atmosphere containing Ar, C2H2 and N2. The antimicrobial activity of the modified surfaces was tested against S. epidermidis and the influence of an activation step of silver was assessed by testing samples after immersion in a 5% (w/v) NaClO solution for 5 min. The activation procedure revealed to be essential for the antimicrobial activity, as observed by the presence of an inhibition halo on the surface with 11 at.% of Ag. The morphology analysis of the surface before and after the activation procedure revealed differences in silver distribution indicating segregation/diffusion of the metallic element to the film's surface. Thus, the results indicate that the silver activation step is responsible for an antimicrobial effect of the coatings, due to silver oxidation and silver ion release. PMID- 26117789 TI - Effects of gas produced by degradation of Mg-Zn-Zr Alloy on cancellous bone tissue. AB - Mg-Zn-Zr alloy cylinders were implanted into the femoral condyles of Japanese big ear white rabbits. X-ray showed that by 12 weeks following implantation the implant became obscure, around which the low-density area appeared and enlarged. By 24 weeks, the implant was more obscure and the density of the surrounding cancellous bone increased. Scanning electron microscopy examination showed bone tissue on the surface of the alloy attached by living fibers at 12 weeks. Micro CT confirmed that new bone tissue on the surface of the residual alloy implant increased from 12 weeks to 24 weeks. By 12 weeks, many cavities in the cancellous bone tissue around the implant were noted with a CT value, similar to gas value, and increasing by 24 weeks (P<0.01). Histological examination of hard tissue slices showed that bone tissue was visibly attached to the alloy in the femoral condyle at 12 weeks. The trabecular bone tissues became more intact and dense, and the cavities were filled with soft tissue at 24 weeks. In general, gas produced by the degradation of the Mg-Zn-Zr alloy can cause cavitation within cancellous bone, which does not affect osteogenesis of Mg alloy. PMID- 26117790 TI - 5-Fluorouracil intercalated iron oxide@layered double hydroxide core-shell nano composites with isotropic and anisotropic architectures for shape-selective drug delivery applications. AB - We report the synthesis, characterization and in vitro release behavior of anti cancer drug carrying iron oxide@layered double hydroxide core-shell nanocomposites with sizes ranging from 40 to 300 nm, good drug loading capacities and soft ferromagnetic properties. HRTEM analyses verified that nearly spherical isotropic carriers were obtained by coating spherical magnetite particles while anisotropic carriers were obtained by coating spindle-shaped hematite particles. They both displayed a fluctuating in vitro release profile with a higher release percentage for the anisotropic carrier. PMID- 26117791 TI - Fabrication of scalable and structured tissue engineering scaffolds using water dissolvable sacrificial 3D printed moulds. AB - One of the major challenges in producing large scale engineered tissue is the lack of ability to create large highly perfused scaffolds in which cells can grow at a high cell density and viability. Here, we explore 3D printed polyvinyl alcohol (PVA) as a sacrificial mould in a polymer casting process. The PVA mould network defines the channels and is dissolved after curing the polymer casted around it. The printing parameters determined the PVA filament density in the sacrificial structure and this density resulted in different stiffness of the corresponding elastomer replica. It was possible to achieve 80% porosity corresponding to about 150 cm(2)/cm(3) surface to volume ratio. The process is easily scalable as demonstrated by fabricating a 75 cm(3) scaffold with about 16,000 interconnected channels (about 1m(2) surface area) and with a channel to channel distance of only 78 MUm. To our knowledge this is the largest scaffold ever to be produced with such small feature sizes and with so many structured channels. The fabricated scaffolds were applied for in-vitro culturing of hepatocytes over a 12-day culture period. Smaller scaffolds (6*4 mm) were tested for cell culturing and could support homogeneous cell growth throughout the scaffold. Presumably, the diffusion of oxygen and nutrient throughout the channel network is rapid enough to support cell growth. In conclusion, the described process is scalable, compatible with cell culture, rapid, and inexpensive. PMID- 26117792 TI - Investigations on the performance of poly(o-anisidine)/graphene nanocomposites for the electrochemical detection of NADH. AB - The electrocatalytic oxidation of dihydronicotinamide adenine dinucleotide (NADH) based on poly(o-anisidine)/graphene (POA/GR) nanocomposites modified glassy carbon electrode (GCE) was explored for the first time. POA/GR nanocomposites were synthesized via chemical oxidative polymerization method. X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and UV-Vis spectroscopy results demonstrate that nanocomposites are successfully synthesized. An intriguing composite structure was observed using different ratios of o-anisidine monomer and graphene. The electrical properties and electrochemical properties of these nanocomposites are investigated by impedance spectroscopy technique and cyclic voltammetric (CV) method, respectively. The synthesized nanocomposites were used to modify glassy carbon electrode (GCE), and the modified electrodes were found to exhibit electrocatalytic activity for oxidation of NADH at low potential range of +0.045 V in a neutral environment. The fabricated sensor based on POA/GR31-modified GCE exhibited enhanced current response with very high sensitivity of 47.1 MUA MUM( 1) for the detection of NADH. The developed POA/GR-modified GCE exhibited excellent reproducibility, stability, and selectivity for the determination of NADH. The practical analytical utility of the proposed method was demonstrated by NADH spiked ascorbic acid (AA) and the results confirmed that the proposed method is suitable for the determination of NADH in the presence of AA. This can open up new opportunities for simple and selective detection of NADH and provide a promising platform for biosensor designs. PMID- 26117793 TI - Production and characterization of chitosan/gelatin/beta-TCP scaffolds for improved bone tissue regeneration. AB - Recently, bone tissue engineering emerged as a viable therapeutic alternative, comprising bone implants and new personalized scaffolds to be used in bone replacement and regeneration. In this study, biocompatible scaffolds were produced by freeze-drying, using different formulations (chitosan, chitosan/gelatin, chitosan/beta-TCP and chitosan/gelatin/beta-TCP) to be used as temporary templates during bone tissue regeneration. Sample characterization was performed through attenuated total reflectance-Fourier transform infrared spectroscopy, X-ray diffraction and energy dispersive spectroscopy analysis. Mechanical characterization and porosity analysis were performed through uniaxial compression test and liquid displacement method, respectively. In vitro studies were also done to evaluate the biomineralization activity and the cytotoxic profile of the scaffolds. Scanning electron and confocal microscopy analysis were used to study cell adhesion and proliferation at the scaffold surface and within their structure. Moreover, the antibacterial activity of the scaffolds was also evaluated through the agar diffusion method. Overall, the results obtained revealed that the produced scaffolds are bioactive and biocompatible, allow cell internalization and show antimicrobial activity against Staphylococcus aureus. Such, make these 3D structures as potential candidates for being used on the bone tissue regeneration, since they promote cell adhesion and proliferation and also prevent biofilm development at their surfaces, which is usually the main cause of implant failure. PMID- 26117794 TI - Review of beetle forewing structures and their biomimetic applications in China: (I) On the structural colors and the vertical and horizontal cross-sectional structures. AB - This paper discusses the progress made in China in terms of the structural colors, microstructure and mechanical properties of the beetle forewing. 1) The forewing microstructures can be classified into six phases, the first three of which are characterized by sandwich, multilayer and fiber layer structures, respectively. The fracture behaviors resulting from these three phases suggest that different scale microstructures or coupled adjacent scale microstructures can determine the macroscopic mechanical behavior of the forewing. 2) The forewing colors are derived from three features: regulation of the structural parameters of the internal optical structures, i.e., a sculpted multilayer composite two-dimensional nanopillar structure grating system; scattering on the three-dimensional surface of the bowl-shaped structure; and reversible color changes due to changes in the physical microstructure of fluffs. Their formation mechanisms were clarified, and fibers with ecological biomimetic structural colors have been developed. 3) Beetles exhibit a lightweight sectional frame structure with a trabecular core structure. Both of the joints on the left and right are concave-convex butt-joint structures with burrs, which provide an efficient docking mechanism with high intensity. The forewing of dichotoma exhibits a non-equiangular layered structure, which results in anisotropy in its tensile strength. Finally, the authors propose potential new research directions for the next 20 years. PMID- 26117795 TI - Review of beetle forewing structures and their biomimetic applications in China: (II) On the three-dimensional structure, modeling and imitation. AB - This paper reviews the research progress made in China regarding the microstructure of the forewing trabeculae, their anti-peeling and anti collisional mechanical properties, the three-dimensional (3D) microstructures of the forewings, their modeling, and their mechanical properties. We focus on 1) the distribution of the trabeculae in two types of beetles with a six-fold difference in density, the structure of the trabeculae and a proposed 3D model with an integrated trabeculae-honeycomb structure; 2) finite element analyses and experimental results showing that the average anti-peeling strength in the presence of trabeculae can be as much as approximately three-fold greater than that in the absence of trabeculae; 3) the strengthening mechanisms of these structures and describe an optimized double thin-walled biomimetic structure that possesses excellent absorption and buffering properties; 4) the development of technologies to produce fully integrated honeycomb plates with short fibers as a reinforced composite material and the verification that these plates are strong and lightweight and exhibit good integrity. Finally, we note the shortcomings in China in this field of research and propose possible future research directions in the field of biomimetic functional materials. PMID- 26117796 TI - Words or graphics to present a Discrete Choice Experiment: Does it matter? AB - OBJECTIVE: To test whether presenting attribute levels in words or graphics generates different results with respect to attribute level interpretation, relative importance and participation probabilities. METHODS: Parents of 959 newborns completed a DCE questionnaire that contained two versions of the same nine choice tasks in which the attribute levels were presented in words or graphics. Five attributes related to the decision of parents to vaccinate their newborn against rotavirus were included. Mixed-logit models were conducted to estimate the relative importance of the attribute levels. RESULTS: Respondents who started with the choice tasks in words produced the most consistent answer patterns. All respondents significantly preferred words to graphics. Part-worth utilities and the relative importance of the attribute levels differed based on the words and graphics data, resulting in different probabilities to participate in vaccination. CONCLUSIONS: Words were preferred over graphics, resulted in higher choice consistency, and showed more valid attribute level estimates. Graphics did not improve respondents' understanding of the attribute levels. PRACTICE IMPLICATIONS: Future research on the use of either words or graphics is recommended in order to establish guidelines on how to develop a valid presentation method for attribute levels in the choice tasks of a DCE. PMID- 26117797 TI - Visuospatial working memory is severely impaired in Balint syndrome patients. AB - Although it has been proposed that visuospatial working memory may be impaired in Balint syndrome patients, neither a systematic study concerning this proposal nor a comparison with patients having right-parietal damage has been made. Visuospatial working memory was assessed for six Balint syndrome patients and members of two control groups-one composed of individuals with right-parietal damage (n = 15) and a second of age- and gender-matched healthy individuals (n = 26). We placed special emphasis on patients with a mild form of Balint syndrome who can judge positional relationships between two objects. First, the participants were subjected to delayed visuospatial matching tasks. Next, their visuospatial-temporal integration abilities were assessed using a shape-from moving-dots task. Visuospatial working memory was impaired for Balint syndrome patients compared with controls according to the results of the tests. The differences between the Balint syndrome and control subjects remained when only data for patients with the mild form of Balint syndrome were included. We conclude that visuospatial working memory may be severely impaired in Balint syndrome patients and, therefore, might influence their inability to properly execute movements and behaviours associated with daily living. PMID- 26117798 TI - Lessons from reverse-genetic studies of lncRNAs. AB - The functions of long noncoding RNAs (lncRNAs) have mainly been studied using cultured cell lines, and this approach has revealed the involvement of lncRNAs in a variety of biological processes, including the epigenetic control of gene expression, post-transcriptional regulation of mRNA, and cellular proliferation and differentiation. Recently, increasing numbers of studies have investigated the functions of lncRNAs using gene-targeted model mice, largely confirming the physiological importance of lncRNA-mediated regulation in individual animals. In some cases, however, the results obtained by studies using knockout mice have been somewhat inconsistent with those of the preceding cell-based analyses. In this review, I will summarize the lessons that we are learning from the reverse genetic studies of lncRNAs, namely the importance of noncoding DNA elements, the weak correlation between expression level and phenotypic prominence, the existence of tissue- and condition-specific phenotypes and incomplete penetrance, and the function of lncRNAs as precursor molecules. This article is part of a Special Issue entitled: Clues to long noncoding RNA taxonomy1, edited by Dr. Tetsuro Hirose and Dr. Shinichi Nakagawa. PMID- 26117799 TI - Editorial overview: Environmental microbiology: Revisiting the physiology of microorganisms on the single cell scale. PMID- 26117800 TI - Abraham Guz memorial: Still unresolved hypotheses: Lung reflexes and perceptions of breathing. AB - This article constitutes a review of the studies performed by the group of the late A. Guz and other authors on the subjects of lung reflexes and perceptions of respiration. The experimental data suggest that the lung inflation and deflation reflexes are present in man, mediated by large myelinated afferent nerve fibres in the vagus nerves, but that the inflation reflex is weaker than in animals, possibly due to central neuronal inhibition. The authors of animal results on the deflation reflex differ as to the afferent fibres involved in the vagi, but it is argued, on the basis of the data, that the preferred hypothesis is that increased activity of the large myelinated mediates the inflation reflex, and decreased activity in these same fibres mediates the deflation reflex. Smaller myelinated fibres are thought to mediate cough and increased breathing in response to airway irritation, while small non-myelinated C fibres mediate hyperpnoea in response to parenchymal congestion and various disease states. The unpleasant sensation at the break point of breath-holding is not chemically mediated but may depend on a complex response involving vagal afferent, phrenic efferent and phrenic afferent pathways. Other experiments in humans on perception of various unpleasant respiratory sensations are discussed with unclear conclusions. PMID- 26117801 TI - Guidelines for incorporating scientific knowledge and practice on rare diseases into higher education: neuronal ceroid lipofuscinoses as a model disorder. AB - This article addresses the educational issues associated with rare diseases (RD) and in particular the Neuronal Ceroid Lipofuscinoses (NCLs, or CLN diseases) in the curricula of Health Sciences and Professional's Training Programs. Our aim is to develop guidelines for improving scientific knowledge and practice in higher education and continuous learning programs. Rare diseases (RD) are collectively common in the general population with 1 in 17 people affected by a RD in their lifetime. Inherited defects in genes involved in metabolism are the commonest group of RD with over 8000 known inborn errors of metabolism. The majority of these diseases are neurodegenerative including the NCLs. Any professional training program on NCL must take into account the medical, social and economic burdens related to RDs. To address these challenges and find solutions to them it is necessary that individuals in the government and administrative authorities, academia, teaching hospitals and medical schools, the pharmaceutical industry, investment community and patient advocacy groups all work together to achieve these goals. The logistical issues of including RD lectures in university curricula and in continuing medical education should reflect its complex nature. To evaluate the state of education in the RD field, a summary should be periodically up dated in order to assess the progress achieved in each country that signed up to the international conventions addressing RD issues in society. It is anticipated that auditing current practice will lead to higher standards and provide a framework for those educators involved in establishing RD teaching programs world-wide. PMID- 26117803 TI - Thermodynamic evaluation of vesicles shed by erythrocytes at elevated temperatures. AB - Erythrocytes undergo structural transformation and shed small vesicles at elevated temperatures. To characterize mechanisms of the phenomenon, the Arrhenius and Eyring equations were used for analysis of the literature, experimental data on vesiculation of human and rat erythrocytes after the temperature was elevated by physical exercise or by exposure to external heat. The thermodynamic analysis of the data showed that erythrocyte transformation, vesicle release, and other associated processes are driven by entropy with enthalpy-entropy compensation. It is suggested that the physical state of the hydrated cell membrane is responsible for the compensation. The increase of vesicle number related to elevated temperatures may be indicative of the heat stress level and serve as diagnostic of erythrocyte stability and human performance. PMID- 26117802 TI - Evaluating adverse rural crash outcomes using the NHTSA State Data System. AB - INTRODUCTION: The population-based rate of motor vehicle crash mortality is consistently higher in rural locations, but it is unclear how much of this disparity might be due to geographic barriers or deficiencies in emergency medical services (EMS). We sought to analyze separately factors associated with the occurrence of a severe injury and those associated with death after injury had occurred. METHODS: Data from all police-reported crashes in 11 states from 2005-2007 were obtained through the National Highway Traffic Safety Administration (NHTSA) State Data System (SDS). Logistic regression was used to estimate factors associated with (1) death; (2) severe (incapacitating or fatal) injury; and (3) death given severe injury. Models included covariates related to the person, vehicle, and event; county location was specified using Rural-Urban Continuum Codes (RUCC). RESULTS: Older age, not wearing a belt, ejection, alcohol involvement, high speed, and early morning times were associated with increased risk of both severe injury and death. Controlling for these factors, and restricting analysis to persons who had suffered a severe injury, the adjusted odds ratio (aOR) associated with death was higher for counties classified rural (RUCC 6-7, aOR 1.23, 95% CI 1.16-1.31) or very rural (RUCC 8-9, aOR 1.31, 95% CI 1.18-1.46). CONCLUSIONS: Persons severely injured in crashes are more likely to die if they are in rural locations, possibly due to EMS constraints. As NHTSA-SDS data become more available and more uniform, they may be useful to explore specific factors contributing to this increased risk. PMID- 26117804 TI - A non-foaming proteosurfactant engineered from Ranaspumin-2. AB - Advances in biological surfactant proteins have already yielded a diverse range of benefits from dramatically improved survival rates for premature births to artificial photosynthesis. Presented here is the design, development, and analysis of a novel biosurfactant protein we call Surfactant Resisting Foam formatioN (SRFN). Starting with the Tungara frog's foam forming protein Ranaspumin-2, we have engineered a new surfactant protein with a destabilized hinge region to alter the kinetics and equilibrium of the protein structural transition from aqueous globular form to an extended surfactant structure at the air/water interface. SRFN is capable of approximately the same total surface tension reduction, but with the unique property of forming quickly collapsible foams. The difference in foam formation is attributed to the destabilizing glycine substitutions engineered into the hinge region. Surfactants used specifically to increase wettability, such as those used in agricultural applications would benefit from this new proteosurfactant since foamed liquid has greater wind resistance and decreased dispersal. Indeed, given growing concern of organsilicone surfactant effects on declining bee populations, biological surfactant proteins have several unique advantages over more common amphiphiles in that they can be renewably sourced, are environmentally friendly, degrade readily into non-toxic byproducts, and reduce surface tension without deleterious effects on cell membranes. PMID- 26117805 TI - Targeting delivery of tocopherol and doxorubicin grafted-chitosan polymeric micelles for cancer therapy: In vitro and in vivo evaluation. AB - In this study, we report the development of a novel, redox-sensitive chitosan based targeted drug delivery system, containing two drugs. We determined whether the synthesized polymeric micelles (HPTOC-DOX) were suitable as a drug carrier. The formation of HPTOC-DOX micelles was confirmed by (1)H NMR. HPTOC-DOX formed micelles of approximately 151.9-311.2nm in size in aqueous solution. Analysis of the drug release profile of HPTOC-DOX in different pH conditions (pH 5.2, 6.2, and 7.4) indicated that DOX was released from HPTOC-DOX micelles at acidic pH (5.2 or 6.2), while almost no DOX was released at pH 7.4. In vitro cell cytotoxicity and hemolysis assays indicated that HPTOC-DOX micelles safely deliver anti-cancer drugs and decrease the cytotoxicity of DOX. In vitro anti cancer activity assays, confocal laser scanning microscopy analysis of SK-BR-3 cells, and in vivo anti-tumor activity in SK-BR-3-derived tumor-bearing mice were used to evaluate synergistic drug effects and the effect of the targeting peptide (anti-human epidermal growth factor receptor 2 [HER2] target peptide, epitope form; LTVSPWY) on receptor-mediated endocytosis. PMID- 26117806 TI - Multidisciplinary Support for Healthcare Transitioning Across an Urban Healthcare Network. AB - BACKGROUND: A successful transition from pediatric to adult oriented health care is a vital process in maintaining a patient-centered medical home for youth with special health care needs (YSHCNs). We assessed practices of pediatric providers who transition YSCHNs to adult-oriented medical care in a large urban academic healthcare network. METHODS: A cross-sectional Web-based survey was distributed to 376 generalist and subspecialist pediatric providers. Survey assessed provider reported utilization of 11 Essential Steps adapted from the 2002 Consensus Statement on Health Care Transitions for YSHCNs, and recent transitioning literature. Compliance score (CS11) was calculated as a sum of steps completed. Additional items assessed knowledge of transitioning literature and respondent demographics. RESULTS: Survey achieved a 28% response rate (n=105), of whom 84 reported assisting transitioning YSHCNs. Only 16.7% of these respondents were compliant with 7 or more of the 11 Essential Steps. Respondents who identified social work or nursing were more likely to have CS11 scores >=7 compared to those without and were more likely to be compliant with specific steps. CONCLUSION: We found limited and incomplete utilization of recommended transitioning steps for YSHCNs by pediatric providers within a large urban healthcare network. Access to support from social work and nursing was associated with greater utilization of specific recommended steps, and with more optimal compliance. Further research needs to assess the transitioning practices of all members of the multidisciplinary team and whether operationalizing healthcare transition for YSHCNs as a multidisciplinary activity impacts the transitioning process and patient outcomes. PMID- 26117807 TI - Congruence of Transition Perspectives Between Adolescents With Perinatally Acquired HIV and Their Guardians: An Exploratory Qualitative Study. AB - Youth with perinatally-acquired HIV infection (PHIV) routinely survive into adulthood requiring transition to adult care. Research underscores the importance of assessing transition perspective congruence between adolescents and guardians. Interviews focused on transition decisions were conducted with 18 adolescents with PHIV and their guardians recruited from a southeastern US pediatric infectious disease clinic. Transcribed responses were coded as congruent or divergent. Adolescents and guardians held congruent views that the transition process had not started. Fewer dyads agreed upon the level of adolescent and guardian involvement in transition decisions. Providers should assess congruence of adolescent and guardian perspectives regarding transition-related decisions. PMID- 26117808 TI - Fluorescence imaging using synthetic GFP chromophores. AB - Green fluorescent protein and related proteins carry chromophores formed within the protein from their own amino acids. Corresponding synthetic compounds are non fluorescent in solution due to photoinduced isomerization of the benzylideneimidiazolidinone core. Restriction of this internal rotation by binding to host molecules leads to pronounced, up to three orders of magnitude, increase of fluorescence intensity. This property allows using GFP chromophore analogs as fluorogenic dyes to detect metal ions, proteins, nucleic acids, and other hosts. For example, RNA aptamer named Spinach, which binds to and activates fluorescence of some GFP chromophores, was proved to be a unique label for live cell imaging of specific RNAs, endogenous metabolites and target proteins. Chemically locked GFP chromophores are brightly fluorescent and represent potentially useful dyes due to their small size and high water solubility. PMID- 26117809 TI - Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent. AB - Jalili syndrome (JS) (MIM#217080) is a rare genetic disorder characterized by the comorbid appearance of cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI). JS is an autosomal recessive inherited disorder caused by different mutations, all with a linkage at achromatopsia locus 2 q11 on the metal transporter gene CNNM4. The case report presented here describes JS with distinct phenotypic variations such as situs inversus totalis (SIT) along with additional ophthalmic findings such as keratoconus and ectopia lentis. It is the first case of JS reported from the Indian subcontinent, affecting a male patient of Muslim faith from an area having high fluoride levels in the ground water. A positive history of consanguineous marriage among his family members of past generations was also evident. PMID- 26117810 TI - Immunoprofile of c-MET/PI3K signaling in human salivary gland tumors. AB - OBJECTIVE: The aim of this study was to analyze the expression pattern of proteins in the HGF/c-MET/PI3K signaling pathway in salivary gland tumors (SGTs) and to correlate the findings with the proliferative index and clinical parameters. STUDY DESIGN: We assembled tissue microarrays (TMAs) of 108 cases of SGTs, including 69 cases of pleomorphic adenoma (PA), 24 cases of adenoid cystic carcinoma (AdCC), and 15 cases of mucoepidermoid carcinoma (MEC). An immunohistochemical analysis of hepatocyte growth factor (HGF), MET phosphorylation (p-MET), protein kinase B (AKT) phosphorylation (p-AKT), and Ki 67 proteins was performed. RESULTS: Benign and malignant SGTs presented similar scores of HGF-positive cells (P = .36), whereas, malignant SGTs exhibited higher levels of p-MET (P = .001) and p-AKT (P = .001) than benign SGTs. No correlation of HGF, p-MET, or p-AKT expression was observed with clinical parameters. PA had a lower proliferative index than either AdCC (P = .001) or MEC (P = .001). CONCLUSIONS: The salivary gland carcinomas exhibited increased activation of the HGF pathway, as evidenced by the phosphorylation of the MET receptor, and increased activation of the PI3K pathway, as indicated by p-AKT. These data suggest that the HGF/c-MET/PI3K signaling pathway is active in SGTs, especially in malignant neoplasms. PMID- 26117811 TI - Ultrasonographic renal volume in Chinese children: Results of 1683 cases. AB - BACKGROUND: At present, little information has been made available in the evaluation of renal volume in pediatric groups of different ages. PURPOSE: The purposes of the study are to evaluate the relationship between anthropometric measurements and renal volume measured with three-dimensional ultrasonography in Chinese children who have normal kidneys, and to attempt to develop reliable reference values of renal volume to estimate the renal sizes. METHODS: A total of 1572 Chinese Han children suffering from stomachache, cryptorchidism and neurogenic enuresis with no history of renal disease or pathological abnormalities that might affect measurements, aged 1month to 12years (mean, 5.64years) were examined bilateral kidneys by ultrasonography. The measurements of renal volume were determined using QLAB software in IU22 units (Philips Medical Systems, Holland). Anthropometric indices including sex, age, height and weight were collected for reviewed analysis. RESULTS: A total of 1683 children were included, and renal volume of 1572 cases (93.4%) was accepted. There was no significant difference between renal volumes of male and female separately in left and right kidneys (P=0.844 and P=0.621, respectively), whereas there was a significant difference between mean left and right renal volumes (P=0.000). Age, height and weight were all significant correlations with renal volume (R(2), 0.885 and 0.913 for the left and right kidneys, respectively, both P=0.000), and age was the strongest correlation with renal volume (r, 0.472 and 0.399 for the left and right kidneys, respectively) among the anthropometric indices. We drew regression equations to estimate renal volume as follows: left renal volume (cm(3))=0.441*age+0.156*height+0.398*weight+6.677 and right renal volume (cm(3))=0.256*age+0.195*height+0.632*weight+1.788, and developed reference values of renal volume separately for the left and right kidneys in different age groups. CONCLUSIONS: Regression equations have been developed, which define the renal volume from three-dimensional ultrasonography and may assist pediatricians in monitoring renal growth and detecting of unsuspected bilateral increases or decreases in renal size. PMID- 26117812 TI - Neurobiological Phenotypes of Familial Chronic Pain in Adolescence: A Pilot fMRI Study. AB - Parental history of chronic pain has been associated with self-reported pain in adolescent offspring. This suggests that there may be neurobiological mechanisms associated with pain heritability. Because emotional circuitry is an important component of pain processing and may also influence cognition, we used functional magnetic resonance imaging to examine affective processing and cognitive control using an Emotional Go/NoGo task in youth with (FH + Pain, n = 8) and without (FH Pain, n = 8) a parental history of chronic pain (mean age = 14.17 +/- .34 years). FH + Pain youth had widespread reductions in brain activity within limbic and visual processing regions during processing of positively valenced emotional stimuli, as well as reduced frontoparietal response while processing negatively valenced emotional stimuli compared with their peers. In addition, during inhibition within a positive emotional context, FH + Pain youth had reduced cognitive control and salience-related brain activity. On the other hand, default mode-related brain response was increased during inhibitory control within a negative emotional context in these adolescents compared with their peers (P/alpha < .05). The current findings indicate differences in both emotional processing and cognitive control brain response in FH + Pain compared with FH - Pain youth, suggesting that both affective and executive functioning pathways may be important markers related to the intergenerational transmission of pain. Perspective: This is the first study to examine neurobiological markers of pain risk in adolescents with a family history of chronic pain. These findings may aid in the identification of neural phenotypes related to vulnerability for the onset of pain in at-risk youth. PMID- 26117813 TI - Bidirectional Association Between Depression and Fibromyalgia Syndrome: A Nationwide Longitudinal Study. AB - Several cross-sectional studies have reported a common comorbidity between depression and fibromyalgia syndrome (FMS). However, a bidirectional temporal association between these 2 distinct diseases has rarely been investigated. Using the Taiwan National Health Insurance Research Database, 25,969 patients with FMS and without any psychiatric disorder and 17,142 patients with depression and without FMS between 2000 and 2008 were enrolled and separately compared with age- and sex-matched (1:4) control groups. Patients with FMS who developed a new-onset depression and those with depression who developed new-onset FMS were identified during follow-up (to the end of 2011). The conditional Cox regression analyses, after adjustment for demographic data and medical comorbidities, showed that the patients with FMS were associated with an increased risk (hazard ratio [HR] 7.46, 95% confidence interval [CI] 6.77-8.22) of subsequent depression and that those with depression were associated with an increased risk (HR 6.28, 95% CI 5.67 6.96) of subsequent FMS. Our results supported a bidirectional temporal association between depression and FMS. Each disease occurring first may increase the risk of the other subsequently. Further study may be necessary to determine the underlying mechanism between depression and FMS and to clarify whether a prompt intervention for depression or FMS may decrease the risk of the other later in life. Perspective: Our study supported a bidirectional temporal association between depression and FMS such that each disease occurring first may increase the risk of the other subsequently. This result may imply a shared pathophysiology between FMS and depression, but further investigation is needed. PMID- 26117814 TI - Polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) mitigation in the pyrolysis process of waste tires using CO2 as a reaction medium. AB - Our work reported the CO2-assisted mitigation of PAHs and VOCs in the thermo chemical process (i.e., pyrolysis). To investigate the pyrolysis of used tires to recover energy and chemical products, the experiments were conducted using a laboratory-scale batch-type reactor. In particular, to examine the influence of the CO2 in pyrolysis of a tire, the pyrolytic products including C1-5 hydrocarbons (HCs), volatile organic carbons (VOCs), and polycyclic aromatic hydrocarbons (PAHs) were evaluated qualitatively by gas chromatography (GC) with mass spectroscopy (MS) as well as with a thermal conductivity detector (TCD). The mass balance of the pyrolytic products under various pyrolytic conditions was established on the basis of their weight fractions of the pyrolytic products. Our experimental work experimentally validated that the amount of gaseous pyrolytic products increased when using CO2 as a pyrolysis medium, while substantially altering the production of pyrolytic oil in absolute content (7.3-17.2%) and in relative composition (including PAHs and VOCs). Thus, the co-feeding of CO2 in the pyrolysis process can be considered an environmentally benign and energy efficient process. PMID- 26117815 TI - Non-radiation risk factors for leukemia: A case-control study among chornobyl cleanup workers in Ukraine. AB - BACKGROUND: Occupational and environmental exposure to chemicals such as benzene has been linked to increased risk of leukemia. Cigarette smoking and alcohol consumption have also been found to affect leukemia risk. Previous analyses in a large cohort of Chornobyl clean-up workers in Ukraine found significant radiation related increased risk for all leukemia types. We investigated the potential for additional effects of occupational and lifestyle factors on leukemia risk in this radiation-exposed cohort. METHODS: In a case-control study of chronic lymphocytic and other leukemias among Chornobyl cleanup workers, we collected data on a range of non-radiation exposures. We evaluated these and other potential risk factors in analyses adjusting for estimated bone marrow radiation dose. We calculated Odds Ratios and 95% Confidence Intervals in relation to lifestyle factors and occupational hazards. RESULTS: After adjusting for radiation, we found no clear association of leukemia risk with smoking or alcohol but identified a two-fold elevated risk for non-CLL leukemia with occupational exposure to petroleum (OR=2.28; 95% Confidence Interval 1.13, 6.79). Risks were particularly high for myeloid leukemias. No associations with risk factors other than radiation were found for chronic lymphocytic leukemia. CONCLUSIONS: These data - the first from a working population in Ukraine - add to evidence from several previous reports of excess leukemia morbidity in groups exposed environmentally or occupationally to petroleum or its products. PMID- 26117816 TI - Tea consumption in pregnancy as a predictor of pesticide exposure and adverse birth outcomes: The MIREC Study. AB - INTRODUCTION: Pesticide residues in tea may contribute to exposure during pregnancy; however, the impact on maternal and infant health is not well understood. The aim of this study was to determine whether tea intake in the first trimester was associated with elevated concentrations of various pesticides in maternal blood or urine. Further, we examined the relationship between tea consumption and adverse birth outcomes. METHODS: Data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canada pregnancy cohort, were used. All singleton, live births (n=1898) with available biomarkers were included in the analyses. Descriptive statistics were used to characterize the population. The geometric means (GM) of organochlorine (OC) pesticide constituents or metabolites in maternal plasma (lipid adjusted) and organophosphate (OP) pesticide metabolites (adjusted for specific gravity) in maternal urine were calculated for participants who drank regular, green or herbal tea in the first trimester and for those who did not. Differences between groups were examined using chi-square or t-tests. Associations between frequency of drinking tea and adverse birth outcomes were examined using logistic regression (preterm birth and small-for-gestational-age) or generalized linear models (birthweight decile and head circumference). RESULTS: The GM of the OC pesticide constituent trans-nonachlor was 2.74 mg/g lipid, and for metabolites oxychlordane and p,p'-DDE this was 1.94 ng/g lipid and 55.8 ng/g lipid, respectively. OP pesticide metabolite concentrations adjusted for specific gravity, were dimethylphosphate (GM: 3.19 ug/L), dimethylthiophosphate (GM: 3.29 ug/L), dimethyldithiophosphate (GM: 0.48 ug/L), diethlphosphate (GM: 2.46), and diethylthiophosphate (GM: 0.67 ug/L). There was no significant difference in mean concentrations for these OC or OP pesticide constituents or metabolites between tea drinkers - of any type - and non-tea drinkers. Further, no association was found between tea intake and adverse birth outcomes. CONCLUSIONS: Pesticide concentrations did not differ by tea intake. Further, tea intake in the first trimester was not associated with adverse birth outcomes. In this study population, there was no evidence for concern about tea intake being a source of the OP or OC pesticide metabolites measured or adversely affecting birth outcomes; however, tea intake was lower than national Canadian data for women of reproductive age. PMID- 26117817 TI - The mussel caging approach in assessing biological effects of wastewater treatment plant discharges in the Gulf of Finland (Baltic Sea). AB - Biological effects of wastewater treatment plant (WWTP) effluents were investigated in Baltic mussels (Mytilus trossulus) caged for one month 800m and 1100m from the WWTP discharge site and at a reference site 4km away. Significant antioxidant, genotoxic and lysosomal responses were observed close to the point of the WWTP discharge. Passive samplers (POCIS) attached to the cages indicated markedly higher water concentrations of various pharmaceuticals at the two most impacted sites. Modeling the dispersal of a hypothetical passive tracer compound from the WWTP discharge site revealed differing frequencies and timing of the exposure periods at different caging sites. The study demonstrated for the first time the effectiveness of the mussel caging approach in combination with passive samplers and the application of passive tracer modeling to examine the true exposure patterns at point source sites such as WWTP pipe discharges in the Baltic Sea. PMID- 26117818 TI - Determination of mercury and vanadium concentration in Johnius belangerii (C) fish in Musa estuary in Persian Gulf. AB - The main aim of this study was to determine the concentrations of mercury and vanadium in Johnius belangerii (C) fish in the Musa estuary. A total of 67 fishes were caught from the Musa estuary during five intervals of 15days in the summer of 2013. After biometric measurements were conducted, the concentrations of mercury and vanadium were measured in the muscle tissue of fish using a direct method analyzer (DMA) and a graphite furnace atomic absorption spectrophotometer, respectively. The mean concentration of mercury and vanadium in the muscle tissue of fish was 3.154+/-1.981 and 2.921+/-0.873mg/kg w.w, respectively. The generalized linear model (GLM) analysis showed a significantly positive relationship among mercury concentration, length, and weight (P=0.000). In addition, there was a significantly negative relationship between vanadium concentration and fish length (P=0.000). A reverse association was found between concentrations of mercury and vanadium. Mercury concentration exceeded the allowable standards of the Environmental Protection Agency (EPA), the World Health Organization (WHO), and the Food and Drug Administration (FDA) in J. belangerii (C). PMID- 26117819 TI - Drugging PI3K in cancer: refining targets and therapeutic strategies. AB - The phosphatidylinositol-3 kinase (PI3K) pathway is one of the most frequently activated pathogenic signalling routes in human cancers, making it a rational and important target for innovative anticancer drug development and precision medicine. The three main classes of PI3K inhibitors currently in clinical testing comprise dual pan-Class I PI3K/mTOR inhibitors, pan-Class I PI3K inhibitors lacking significant mTOR activity and isoform-selective PI3K inhibitors. A major step forward in recent years is the progression of over 30 small molecule PI3K inhibitors into clinical trials and the first regulatory approval of the PI3Kdelta inhibitor idelalisib for multiple B-cell malignancies. This review article focuses on the progress made in the discovery and development of novel PI3K inhibitors, with an emphasis on antitumour activity and tolerability profiles for agents that have entered clinical trials. We also discuss the key issues of drug resistance, patient selection approaches and rational targeted combinations. Finally, we envision the future development and use of PI3K inhibitors for the treatment of patients with a range of malignancies. PMID- 26117820 TI - Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6 diphenyl-1,2,4-triazin-3(2H)-one derivatives bearing 5-substituted 1,3,4 oxadiazole as potential anti-inflammatory and analgesic agents. AB - A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 MUM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme. PMID- 26117822 TI - Predicting activity approach based on new atoms similarity kernel function. AB - Drug design is a high cost and long term process. To reduce time and costs for drugs discoveries, new techniques are needed. Chemoinformatics field implements the informational techniques and computer science like machine learning and graph theory to discover the chemical compounds properties, such as toxicity or biological activity. This is done through analyzing their molecular structure (molecular graph). To overcome this problem there is an increasing need for algorithms to analyze and classify graph data to predict the activity of molecules. Kernels methods provide a powerful framework which combines machine learning with graph theory techniques. These kernels methods have led to impressive performance results in many several chemoinformatics problems like biological activity prediction. This paper presents a new approach based on kernel functions to solve activity prediction problem for chemical compounds. First we encode all atoms depending on their neighbors then we use these codes to find a relationship between those atoms each other. Then we use relation between different atoms to find similarity between chemical compounds. The proposed approach was compared with many other classification methods and the results show competitive accuracy with these methods. PMID- 26117821 TI - Metronidazole-triazole conjugates: activity against Clostridium difficile and parasites. AB - Metronidazole has been used clinically for over 50 years as an antiparasitic and broad-spectrum antibacterial agent effective against anaerobic bacteria. However resistance to metronidazole in parasites and bacteria has been reported, and improved second-generation metronidazole analogues are needed. The copper catalysed Huigsen azide-alkyne 1,3-dipolar cycloaddition offers a way to efficiently assemble new libraries of metronidazole analogues. Several new metronidazole-triazole conjugates (Mtz-triazoles) have been identified with excellent broad spectrum antimicrobial and antiparasitic activity targeting Clostridium difficile, Entamoeba histolytica and Giardia lamblia. Cross resistance to metronidazole was observed against stable metronidazole resistant C. difficile and G. lamblia strains. However for the most potent Mtz-triazoles, the activity remained in a therapeutically relevant window. PMID- 26117823 TI - The study of dual COX-2/5-LOX inhibitors by using electronic-topological approach based on data on the ligand-receptor interactions. AB - Structural and electronic factors influencing selective inhibition of cyclooxygenase-2 and 5-lipoxygenase (COX-2/5-LOX) were studied by using Electronic-Topological Method combined with Neural Networks (ETM-NN), molecular docking, and Density Functional Theory (DFT) in a large set of molecules. The results of the ETM-NN calculations allowed for the selection of pharmacophoric molecular fragments, which could be taken as a basis for a system capable of predicting the COX-2/5-LOX inhibitory activity. For the more effective extraction of the pharmacophoric molecular fragments, docking of molecules into the active sites of the two enzymes was carried out to get data on the ligand-receptor interaction. To make an assessment of these interactions, stabilization energies were calculated by using Natural Bond Orbital (NBO) analysis. Docking and data on the electronic structures of active sites of enzymes helped to reveal effectively the peculiarities of the ligand-receptor binding. The system for the selective COX-2/5-LOX inhibitory activity prediction that has been developed as the result of the ETM-NN study recognized correctly 93% of compounds as highly active ones. Thus, this system can be successfully used for carrying out computer screening and synthesis of potent inhibitors of COX-2/5-LOX with diverse molecular skeletons. PMID- 26117824 TI - Triterpenoid saponins from the root bark of Schima superba and their cytotoxic activity on B16 melanoma cell line. AB - Eight new oleanane-type triterpenoid saponins, schisusaponins A-H, along with eight known triterpenoid saponins, were isolated from the root bark of Schima superb (Theaceae). Their structures were elucidated on the basis of extensive spectroscopic analyses and chemical methods. The cytotoxicity of the new compounds against B16 melanoma cells was assessed. Among the isolated new saponins, schisusaponins C and E showed more potent effects (with IC50 values of 10.08 and 10.89 MUM) than vinblastine (with an IC50 value of 19.48 MUM). PMID- 26117825 TI - Structure determination of the neutral exopolysaccharide produced by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1. AB - The neutral exopolysaccharide (NPS) of Lactobacillus delbrueckii subsp. bulgaricus strain OLL1073R-1 was purified and characterized. The molecular mass was 5.0*10(6) g/mol. Sugar and absolute configuration analyses gave the following composition: d-Glc, 1; d-Gal, 1.5. The NPS was also submitted to periodate oxidation followed by borohydride reduction and Smith degradation. Sugar and methylation analyses, (1)H and (13)C nuclear magnetic resonance, and mass spectrometry of the NPS or of its specifically modified products allowed determining the repeating unit sequence: {2)Glc(alpha1-3)Glc(beta1-3)[Gal(beta1 4)]Gal(beta1-4)Gal(alpha1-}n. The structure is compared to that of exopolysaccharides produced by other Lactobacillus bulgaricus strains. PMID- 26117826 TI - Paying less but harvesting more: the effect of unconscious acceptance in regulating frustrating emotion. AB - Previous studies indicate that emotion regulation may occur unconsciously, without the cost of cognitive effort, while conscious acceptance may enhance negative experiences despite having potential long-term health benefits. Thus, it is important to overcome this weakness to boost the efficacy of the acceptance strategy in negative emotion regulation. As unconscious regulation occurs with little cost of cognitive resources, the current study hypothesizes that unconscious acceptance regulates the emotional consequence of negative events more effectively than does conscious acceptance. Subjects were randomly assigned to conscious acceptance, unconscious acceptance and no-regulation conditions. A frustrating arithmetic task was used to induce negative emotion. Emotional experiences were assessed on the Positive Affect and Negative Affect Scale while emotion- related physiological activation was assessed by heart-rate reactivity. Results showed that conscious acceptance had a significant negative affective consequence, which was absent during unconscious acceptance. That is, unconscious acceptance was linked with little reduction of positive affect during the experience of frustration, while this reduction was prominent in the control and conscious acceptance groups. Instructed, conscious acceptance resulted in a greater reduction of positive affect than found for the control group. In addition, both conscious and unconscious acceptance strategies significantly decreased emotion-related heart-rate activity (to a similar extent) in comparison with the control condition. Moreover, heart-rate reactivity was positively correlated with negative affect and negatively correlated with positive affect during the frustration phase relative to the baseline phase, in both the control and unconscious acceptance groups. Thus, unconscious acceptance not only reduces emotion-related physiological activity but also better protects mood stability compared with conscious acceptance. This suggests that the clinical practice of acceptance therapy may need to consider using the unconscious priming of an accepting attitude, instead of intentionally instructing people to implement such a strategy, to boost the efficacy of acceptance in emotion regulation. PMID- 26117827 TI - High-throughput sequencing-based genome-wide identification of microRNAs expressed in developing cotton seeds. AB - MicroRNAs (miRNAs) have been shown to play critical regulatory roles in gene expression in cotton. Although a large number of miRNAs have been identified in cotton fibers, the functions of miRNAs in seed development remain unexplored. In this study, a small RNA library was constructed from cotton seeds sampled at 15 days post-anthesis (DPA) and was subjected to high-throughput sequencing. A total of 95 known miRNAs were detected to be expressed in cotton seeds. The expression pattern of these identified miRNAs was profiled and 48 known miRNAs were differentially expressed between cotton seeds and fibers at 15 DPA. In addition, 23 novel miRNA candidates were identified in 15-DPA seeds. Putative targets for 21 novel and 87 known miRNAs were successfully predicted and 900 expressed sequence tag (EST) sequences were proposed to be candidate target genes, which are involved in various metabolic and biological processes, suggesting a complex regulatory network in developing cotton seeds. Furthermore, miRNA-mediated cleavage of three important transcripts in vivo was validated by RLM-5' RACE. This study is the first to show the regulatory network of miRNAs that are involved in developing cotton seeds and provides a foundation for future studies on the specific functions of these miRNAs in seed development. PMID- 26117828 TI - Evolutionary annotation of conserved long non-coding RNAs in major mammalian species. AB - Mammalian genomes contain tens of thousands of long non-coding RNAs (lncRNAs) that have been implicated in diverse biological processes. However, the lncRNA transcriptomes of most mammalian species have not been established, limiting the evolutionary annotation of these novel transcripts. Based on RNA sequencing data from six tissues of nine species, we built comprehensive lncRNA catalogs (4,142 42,558 lncRNAs) covering the major mammalian species. Compared to protein- coding RNAs, expression of lncRNAs exhibits striking lineage specificity. Notably, although 30%-99% human lncRNAs are conserved across different species on DNA locus level, only 20%-27% of these conserved lncRNA loci are detected to transcription, which represents a stark contrast to the proportion of conserved protein-coding genes (48%-80%). This finding provides a valuable resource for experimental scientists to study the mechanisms of lncRNAs. Moreover, we constructed lncRNA expression phylogenetic trees across nine mammals and demonstrated that lncRNA expression profiles can reliably determine phylogenic placement in a manner similar to their coding counterparts. Our data also reveal that the evolutionary rate of lncRNA expression varies among tissues and is significantly higher than those for protein-coding genes. To streamline the processes of browsing lncRNAs and detecting their evolutionary statuses, we integrate all the data produced in this study into a database named PhyloNONCODE (http://www.bioinfo.org/phyloNoncode). Our work starts to place mammalian lncRNAs in an evolutionary context and represent a rich resource for comparative and functional analyses of this critical layer of genome. PMID- 26117829 TI - Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. AB - BACKGROUND: We previously showed that pretreatment detection of androgen receptor splice variant-7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer is associated with resistance to abiraterone and enzalutamide, but not to taxane chemotherapies. Here, we conducted serial measurements of AR-V7 and evaluated patterns of longitudinal AR-V7 dynamics over the course of multiple sequential therapies. PATIENTS AND METHODS: Metastatic prostate cancer patients treated at Johns Hopkins with AR-directed therapies or taxane chemotherapies underwent serial liquid biopsies for CTC-based AR-V7 analysis at baseline, during therapy, and at progression. We used a CTC enrichment platform followed by multiplexed reverse-transcription polymerase chain reaction analysis to detect full-length androgen receptor and AR-V7 transcripts. Patients selected for inclusion in this report were those who provided >=4 CTC samples, at least one of which was AR-V7 positive, over the course of >=2 consecutive therapies. RESULTS: We identified 14 patients who received a total of 37 therapies and contributed 70 CTC samples for AR-V7 analysis during a median follow-up period of 11 months. Three patients remained AR-V7 positive during the entire course of therapy. The remainder underwent transitions in AR-V7 status: there were eight instances of 'conversions' from AR V7-negative to -positive status (during treatment with first-line androgen deprivation therapy, abiraterone, enzalutamide, and docetaxel), and six instances of 'reversions' from AR-V7-positive to -negative status (during treatment with docetaxel and cabazitaxel). CONCLUSIONS: AR-V7 is a dynamic marker, and transitions in AR-V7 status may reflect selective pressures on the tumor exerted by therapeutic interventions. While 'conversions' to AR-V7-positive status were observed with both AR-directed therapies and taxane chemotherapies, 'reversions' to AR-V7-negative status only occurred during taxane therapies. Serial blood based AR-V7 testing is feasible in routine clinical practice, and may provide insights into temporal changes in tumor evolution. PMID- 26117830 TI - Phase I/II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma. AB - BACKGROUND: The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD. RESULTS: Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). CONCLUSION: Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy. PMID- 26117831 TI - The management of opiate use disorders in France: results of an observational survey of general practitioners. AB - BACKGROUND: When opioid-agonist treatments were approved in France in 1995, opiate use disorders began to be managed and treated by general practitioners (GPs), who have since then been encouraged to treat substance use disorders (SUDs) for heroin and other illegal substances. The objective of this study was to describe rates of: 1) SUDs in general practices in France; 2) characteristics of GPs treating SUDs; and 3) clinical practices surrounding SUDs. To place these data in the context of SUD treatment, we also gathered information from practicing SUD specialists. METHODS: Between December 2011 and January 2012, a nationally representative sample of GPs and SUD specialists were interviewed by phone, using a 12-item questionnaire that covered number of SUD patients, types of SUDs, and treatments. Data collected were confidential, and analysis was blinded with regard to physician identity. RESULTS: Forty-four percent of GPs and 68 % of specialists were included in the analysis. The mean number of patients estimated to have been seen at least once in the previous year was 3036 for GPs and 920 for specialists. Ninety-six percent of GPs reported having patients with SUDs. Tobacco, alcohol, and psychoactive drugs were the SUDs most frequently encountered by GPs, whereas tobacco, alcohol, heroin, and cannabis were most frequently encountered by specialists. Forty-three percent of GPs saw at least one patient with a heroin use disorder (HUD), and 82 % of GPs treating patients with HUDs had prescribed an opioid-agonist treatment during the previous 12 months. CONCLUSIONS: The results of this study suggest that a large number of GPs now treat patients with opiate use disorders and that doctors appear to be convinced of the benefits of opioid-agonist therapy and have overcome their initial concerns. This represents a significant change in practice patterns since the introduction of opioid-agonist treatments in France. PMID- 26117832 TI - Morphology Alters Fluid Transport and the Ability of Organisms to Mix Oceanic Waters. AB - Mixing in the ocean is opposed by the stratification of fluid, such that density of seawater increases with greater depth. The mechanisms by which mixing occurs have been attributed largely to physical processes that include atmospheric forcing, tides, and internal waves. Biogenic mixing, another potential source of mixing in the ocean, may generate significant transport of fluid during diel vertical migrations of organisms. Biogenic mixing is not limited to the near surface or to regions of rough bottom topography, as are other physical mixing processes, and may contribute significantly to the energy budget of mixing in mid ocean. "Fluid drift", a mechanism first described by Charles Galton Darwin, has been identified as a mechanism that allows for long-distance, vertical transport of fluid by the smallest of swimming organisms. However, little is known about how fluid drift varies with morphology and behavior of swimming organisms. We conducted numerical simulations of theoretical and experimentally measured flows of swimming medusae (Phyllorhiza sp.), and compared the volume of the drift induced by these flows. Our numerical simulations of fluid drift showed that morphology coupled with swimming behavior alters the transport of fluid both spatially and temporally. Given empirical velocity field data, the methods presented here allow us to systematically compare fluid transport across taxa, and enable us to deduce the potential of swimming organisms to influence fluid transport. PMID- 26117833 TI - Outrun or Outmaneuver: Predator-Prey Interactions as a Model System for Integrating Biomechanical Studies in a Broader Ecological and Evolutionary Context. AB - Behavioral studies performed in natural habitats provide a context for the development of hypotheses and the design of experiments relevant both to biomechanics and to evolution. In particular, predator-prey interactions are a model system for integrative study because success or failure of predation has a direct effect on fitness and drives the evolution of specialized performance in both predator and prey. Although all predators share the goal of capturing prey, and all prey share the goal of survival, the behavior of predators and prey are diverse in nature. This article presents studies of some predator-prey interactions sharing common predation strategies that reveal general principles governing the behaviors of predator and prey, even in distantly related taxa. Studies of predator-prey interactions also reveal that maximal performance observed in a laboratory setting is not necessarily the performance that determines fitness. Thus, considering locomotion in the context of predation ecology can aid in evolutionarily relevant experimental design. Classification by strategy reveals that displaying unpredictable trajectories is a relevant anti predator behavior in response to multiple predation strategies. A predator's perception and pursuit of prey can be affected indirectly by divergent locomotion of similar animals that share an ecosystem. Variation in speed and direction of locomotion that directly increases the unpredictability of a prey's trajectory can be increased through genetic mutation that affects locomotor patterns, musculoskeletal changes that affect maneuverability, and physical interactions between an animal and the environment. By considering the interconnectedness of ecology, physical constraints, and the evolutionary history of behavior, studies in biomechanics can be designed to inform each of these fields. PMID- 26117835 TI - Tobacco Dependence Treatment Training Programs: An International Survey. AB - INTRODUCTION: In line with Article 14 guidelines for the WHO Framework Convention on Tobacco Control, we aimed to assess the progress in training individuals to deliver tobacco cessation treatment. METHODS: Cross-sectional web-based survey in May-September 2013 among 122 experts in tobacco control and training from 84 countries (73% response rate among 115 countries surveyed). We measured training program prevalence, participants, and challenges faced. RESULTS: Overall, 21% (n = 18/84) of countries, mostly low and middle-income countries (LMICs; P = .002), reported no training program. Among 66 countries reporting at least one training program, most (84%) trained healthcare professionals but 54% also trained other individuals including community health workers, teachers, and religious leaders. Most programs (54%) cited funding challenges, although stability of funding varied by income level. Government funding was more commonly reported in higher income countries (high 56%, upper middle 50%, lower middle 27%, low 25%; P = .03) while programs in LMICs relied more on nongovernmental organizations (high 11%, upper middle 37%, lower middle 27%, low 38%; P = .02). CONCLUSIONS: One in five countries reported having no tobacco treatment training program representing little progress in terms of training individuals to deliver tobacco treatment in LMICs. Without more trained tobacco treatment providers, one of the tenets of Article 14 is not yet being met and health inequalities are likely to widen. More effort and resources are needed to ensure that healthcare worker educational programs include training to assess tobacco use and deliver brief advice and that training is available for individuals outside the healthcare system in areas with limited healthcare access. PMID- 26117836 TI - Smoking Patterns and Receipt of Cessation Services Among Pregnant Women in Argentina and Uruguay. AB - INTRODUCTION: The 5A's (Ask, Advise, Assess, Assist, and Arrange) strategy, a best-practice approach for cessation counseling, has been widely implemented in high-income countries for pregnant women; however, no studies have evaluated implementation in middle-income countries. The study objectives were to assess smoking patterns and receipt of 5A's among pregnant women in Buenos Aires, Argentina and Montevideo, Uruguay. METHODS: Data were collected through administered questionnaires to women at delivery hospitalizations during October 2011-May 2012. Eligible women attended one of 12 maternity hospitals or 21 associated prenatal care clinics. The questionnaire included demographic data, tobacco use/cessation behaviors, and receipt of the 5A's. Self-reported cessation was verified with saliva cotinine. RESULTS: Overall, of 3400 pregnant women, 32.8% smoked at the beginning of pregnancy; 11.9% quit upon learning they were pregnant or later during pregnancy, and 20.9% smoked throughout pregnancy. Smoking prevalence varied by country with 16.1% and 26.7% who smoked throughout pregnancy in Argentina and Uruguay, respectively. Among pregnant smokers in Argentina, 23.8% reported that a provider asked them about smoking at more than one prenatal care visit; 18.5% were advised to quit; 5.3% were assessed for readiness to quit, 4.7% were provided assistance, and 0.7% reported follow-up was arranged. In Uruguay, those percentages were 36.3%, 27.9%, 5.4%, 5.6%, and 0.2%, respectively. CONCLUSIONS: Approximately, one in six pregnant women smoked throughout pregnancy in Buenos Aires and one in four in Montevideo. However, a low percentage of smokers received any cessation assistance in both countries. Healthcare providers are not fully implementing the recommended 5A's intervention to help pregnant women quit smoking. PMID- 26117837 TI - Proarrhythmia Risk Assessment in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Using the Maestro MEA Platform. AB - Evaluation of stem cell-derived cardiomyocytes (SC-CM) using multi-electrode array (MEA) has attracted attention as a novel model to detect drug-induced arrhythmia. An experiment was conducted to determine if MEA recording from human induced pluripotent SC-CM (hiPSC-CM) could assess proarrhythmic risk. Ten hERG blockers, 4 Na(+) blockers, and 1 IKs blocker were evaluated blindly. Eight drugs are associated with Torsades de Pointes (TdP) and 4 are not. Multiple parameters, including field potential duration (FPD), Na(+) slope, Na(+) amplitude, beat rate (BR), and early after-depolarization (EAD) were recorded. Minimum effective concentrations (MEC) that elicited a significant change were calculated. Our results determined that FPD and EAD were unable to distinguish torsadogenic from benign compounds, Na(+) slope and amplitude could not differentiate Na(+) channel blockade from hERG blockade, BR had an inconsistent response to pharmacological treatment, and that hiPSC-CM were, in general, insensitive to IKs inhibition. A ratio was calculated that relates MEC for evoking FPD prolongation, or triggering EAD, to the human therapeutic unbound Cmax (MEC/Cmax). The key finding was that the ratio was sensitive, but specificity was low. Consistently, the ratio had high positive predictive value and low negative predictive value. In conclusion, MEA recordings of hiPSC-CM were sensitive for FPD and EAD detection, but unable to distinguish agents with low- and high-risk for TdPs. Although some published reports suggested great potential for MEA recordings in hSC-CM to assess preclinical cardiac toxicity, the current evaluation implies that this model would have a high false-positive rate in regard to proarrhythmic risk. PMID- 26117838 TI - Growth suppressor lingerer regulates bantam microRNA to restrict organ size. AB - The evolutionarily conserved Hippo signaling pathway plays an important role in organ size control by regulating cell proliferation and apoptosis. Here, we identify Lingerer (Lig) as a growth suppressor using RNAi modifying screen in Drosophila melanogaster. Loss of lig increases organ size and upregulates bantam (ban) and the expression of the Hippo pathway target genes, while overexpression of lig results in diminished ban expression and organ size reduction. We demonstrate that Lig C-terminal exhibits dominant-negative function on growth and ban expression, and thus plays an important role in organ size control and ban regulation. In addition, we provide evidence that both Yki and Mad are essential for Lig-induced ban expression. We also show that Lig regulates the expression of the Hippo pathway target genes partially via Yorkie. Moreover, we find that Lig physically interacts with and requires Salvador to restrict cell growth. Taken together, we demonstrate that Lig functions as a critical growth suppressor to control organ size via ban and Hippo signaling. PMID- 26117839 TI - PTPROt maintains T cell immunity in the microenvironment of hepatocellular carcinoma. AB - Intratumoral T cells play a central role in anti-tumor immunity, and the balance between T effector cells (Teff) and regulatory T cells (Treg) affects the prognosis of cancer patients. However, educated by tumor microenvironment, T cells frequently fail in their responsibility. In this study, we aimed to investigate the role of truncated isoform of protein tyrosine phosphatase receptor-type O (PTPROt) in T cell-mediated anti-tumor immunity. We recruited 70 hepatocellular carcinoma (HCC) patients and 30 healthy volunteers for clinical investigation, and analyzed cellular tumor immunity by using ptpro(-/-) C57BL/6 mice and NOD/SCID mice. PTPROt expression was significantly downregulated in human HCC-infiltrating T cells due to the hypoxia microenvironment; PTPROt expression highly correlated with the intratumoral Teff/Treg ratio and clinicopathologic characteristics. Moreover, PTPROt deficiency attenuated T cell mediated anti-tumor immunity and remarkably promoted mouse HCC growth. Mechanistically, deletion of PTPROt decreased Teff quantity and quality through phosphorylation of lymphocyte-specific tyrosine kinase, but increased Treg differentiation through phosphorylation of signal transducer and activator of transcription 5. In support of the Teff/Treg homeostasis, PTPROt serves as an important tumor suppressor in HCC microenvironment. PMID- 26117840 TI - E-selectin ligand complexes adopt an extended high-affinity conformation. AB - E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewis(x) (sLe(x)). Efficient leukocyte recruitment under vascular flow conditions depends on an increased lifetime of E-selectin/ligand complexes under tensile force in a so-called catch bond binding mode. Co-crystal structures of a representative fragment of the extracellular E-selectin region with sLe(x) and a glycomimetic antagonist thereof reveal an extended E-selectin conformation, which is identified as a high affinity binding state of E-selectin by molecular dynamics simulations. Small angle X-ray scattering experiments demonstrate a direct link between ligand binding and E-selectin conformational transition under static conditions in solution. This permits tracing a series of concerted structural changes connecting ligand binding to conformational stretching as the structural basis of E-selectin catch-bond-mediated leukocyte recruitment. The detailed molecular view of the binding site paves the way for the design of a new generation of selectin antagonists. This is of special interest, since their therapeutic potential was recently demonstrated with the pan-selectin antagonists GMI-1070 (Rivipansel). PMID- 26117841 TI - Nutrigenetics of cholesterol metabolism: observational and dietary intervention studies in the postgenomic era. AB - Cholesterol metabolism is a well-defined responder to dietary intakes and a classic biomarker of cardiovascular health. For this reason, circulating cholesterol levels have become key in shaping nutritional recommendations by health authorities worldwide for better management of cardiovascular disease, a leading cause of mortality and one of the most costly health problems globally. Data from observational and dietary intervention studies, however, highlight a marked between-individual variability in the response of cholesterol metabolism to similar dietary protocols, a phenomenon linked to genetic heterogeneity. This review summarizes the postgenomic evidence of polymorphisms within cholesterol associated genes relative to fasting circulating cholesterol levels under diverse nutritional conditions. A number of cholesterol-related gene-diet interactions are confirmed, which may have clinical importance, supporting a deeper look into the rapidly emerging field of nutrigenetics for meaningful conclusions that may eventually lead to genetically targeted dietary recommendations in the era of personalized nutrition. PMID- 26117842 TI - The EuroSCORE: a neglected measure of medium-term survival following cardiac surgery. AB - OBJECTIVES: EuroSCORE is used to predict operative mortality following cardiac surgery. There are limited data to assess the ability of EuroSCORE to predict medium- to long-term survival. We aimed to test the ability of EuroSCORE to predict mid-term survival following cardiac surgery. METHODS: We analysed prospectively collected data from all patients undergoing cardiac surgery in an urban tertiary cardiac centre over a 6-year period. All-cause mortality following cardiac surgery was determined via Office of National Statistics data. Patients were grouped into all comers, coronary artery bypass graft (CABG), isolated aortic valve replacement (AVR), isolated mitral valve repair and replacement (MVR) and combined AVR/MVR and CABG. Each group was separated into EuroSCORE quartiles. Kaplan-Meier curves were used to calculate 6-year actuarial survival. Log-rank test was used to calculate the P-value. C-statistic discriminated the ability of the EuroSCORE to predict medium-term survival. RESULTS: A total of 9022 consecutive patients were identified. The mean age was 66.86 years, 73.7% were male. The cases were grouped according to their additive EuroSCORE into 0-5 (n = 5369), 6-10 (n = 3059), 11-15 (n = 506) and >15 (n = 93). Median follow-up was 2.92 years. The 6-year survival was 88.5, 71.8, 52.5 and 39.5%, respectively. The P-value for all operative categories was significant. The C-statistic was 0.68 (all comers), 0.72 for isolated MVR, 0.65 (isolated CABG), 0.62 (isolated AVR) and 0.69 (combined AVR/MVR and CABG). CONCLUSIONS: Additive EuroSCORE may be used to predict medium-term survival in patients undergoing cardiac surgery; increasing additive EuroSCORE resulting in significant decreases in survival. It is a good predictive tool for patients undergoing isolated MVR and a fair tool for patients undergoing the remaining operative procedures studied. PMID- 26117843 TI - Robotic thoracic surgery versus video-assisted thoracic surgery for lung cancer: a meta-analysis. AB - OBJECTIVES: There are two different minimally invasive approaches, robotic thoracic surgery (RTS) and video-assisted thoracic surgery (VATS), which are performed for lung cancer resection. This meta-analysis aimed to compare the perioperative outcomes of RTS with those of VATS for patients with lung cancer. METHODS: We searched articles indexed in the PubMed and ScienceDirect databases that met our predefined criteria, published up to January 2015. A meta-analysis was performed by combining the results of reported incidences of perioperative morbidity and mortality. The relative risk (RR) was used as a summary statistic. RESULTS: Eight eligible articles with 3379 subjects were considered in the analysis (8 articles for morbidity, while 4 articles for mortality). Overall, pooled analysis indicated that perioperative morbidity and mortality were similar between RTS and VATS (morbidity: RR, 1.02; 95% CI, 0.94-1.10; P = 0.605; mortality: RR, 0.28; 95% CI, 0.06-1.25; P = 0.095). No evidence of publication bias was observed. CONCLUSIONS: This meta-analysis showed that RTS resulted in similar outcomes compared with VATS cases. RTS appears to be an appropriate alternative to VATS, which is associated with improved outcomes compared with open thoracotomy. RTS should be studied further in selected centres and compared with VATS in a randomized fashion to better define its potential advantages and disadvantages. PMID- 26117844 TI - Synchrotron Radiation Sheds Fresh Light on Plant Research: The Use of Powerful Techniques to Probe Structure and Composition of Plants. AB - While synchrotron radiation is a powerful tool in material and biomedical sciences, it is still underutilized in plant research. This mini review attempts to introduce the potential of synchrotron-based spectroscopic and imaging methods and their applications to plant sciences. Synchrotron-based Fourier transform infrared spectroscopy, X-ray absorption and fluorescence techniques, and two- and three-dimensional imaging techniques are examined. We also discuss the limitations of synchrotron-based research in plant sciences, specifically the types of plant samples that can be used. Despite limitations, the unique features of synchrotron radiation such as high brightness, polarization and pulse properties offer great advantages over conventional spectroscopic and imaging tools and enable the correlation of the structure and chemical composition of plants with biochemical function. Modern detector technologies and experimental methodologies are thus enabling plant scientists to investigate aspects of plant sciences such as ultrafast kinetics of biochemical reactions, mineral uptake, transport and accumulation, and dynamics of cell wall structure and composition during environmental stress in unprecedented ways using synchrotron beamlines. The potential for the automation of some of these synchrotron technologies and their application to plant phenotyping is also discussed. PMID- 26117845 TI - Treatment. Financial incentives failed to provide substantial motivation. PMID- 26117846 TI - SSI. ALJ failed to justify assessment in disability benefits case. PMID- 26117847 TI - A military court reverses decision against enlistee with HIV. PMID- 26117848 TI - Prisoner wrongly treated for HIV may proceed with charge. PMID- 26117849 TI - Criminal. Man who exposed partner to HIV not guilty of wanton cruelty. PMID- 26117850 TI - Cell counts in children rebound after treatment. PMID- 26117851 TI - CDC launches prevention efforts focused on PrEP, high-risk groups. PMID- 26117852 TI - Endiandric Acid Derivatives and Other Constituents of Plants from the Genera Beilschmiedia and Endiandra (Lauraceae). AB - Plants of the Lauraceae family are widely used in traditional medicine and are sources of various classes of secondary metabolites. Two genera of this family, Beilschmiedia and Endiandra, have been the subject of numerous investigations over the past decades because of their application in traditional medicine. They are the only source of bioactive endiandric acid derivatives. Noteworthy is that their biosynthesis contains two consecutive non-enzymatic electrocyclic reactions. Several interesting biological activities for this specific class of secondary metabolites and other constituents of the two genera have been reported, including antimicrobial, enzymes inhibitory and cytotoxic properties. This review compiles information on the structures of the compounds described between January 1960 and March 2015, their biological activities and information on endiandric acid biosynthesis, with 104 references being cited. PMID- 26117856 TI - GAO says data on unmet HIV housing needs insufficient. PMID- 26117854 TI - Introduction to Oxidative Stress in Biomedical and Biological Research. AB - Oxidative stress is now a well-researched area with thousands of new articles appearing every year. We want to give the reader here an overview of the topics in biomedical and basic oxidative stress research which are covered by the authors of this thematic issue. We also want to give the newcomer a short introduction into some of the basic concepts, definitions and analytical procedures used in this field. PMID- 26117857 TI - [Laser Tuning Performance Testing and Optimization in TDLAS Oxygen Measuring Systems]. AB - TDLAS (tunable diode laser absorption spectroscopy) technology, with its unmatched advantages such as high selectivity molecular spectra, fast response, high sensitivity, non-contact measuring, become the preferred scheme for combustion process diagnosis, and can be effectively used for oxygen measuring. DFB (distributed feedback) laser diode with its small size, low power consumption, long service life, narrow linewidth, tunable wavelength has become the main choice of the TDLAS system. Performance of laser tuning characteristics is a key factor restricting TDLAS's measuring performance. According to TDLAS oxygen measuring system's working requirements, a simple experimental method was used to test and analyze tuning characteristics such as wavelength current, power current and wavelength temperature of a 764 nm DFB laser diode in the system. Nonlinear distortion of tuning curves was obvious, which affects oxygen measuring accuracy. The laser spectra's characteristics such as narrow linewidth, high side mode suppression ratio and wide wavelength tuning range are obvious, while its wavelength-current tuning curve with a tuning rate of about 0.023 nm x mA(-1) is not strictly linear. The higher the temperature the greater the threshold current, the PI curve is not strictly linear either. Temperature tuning curve is of good linearity, temperature-wave-length tuning rate keeps constant of about 0.056 nm/DEG C. Temperature tuning nonlinearity can be improved by high temperature control accuracy, and current power nonlinearity can be improved by setting the reference light path. In order to solve the wavelength current tuning nonlinear problems, the method of DA controlling injection current was considered to compensate for non-linear wavelength current tuning according to DFB laser diode tuning mechanism and polynomial fitting of test results. In view of different type of lasers, this method needs only one polynomial fitting process before the system's initial work. The compensation scheme is reasonable and the realization is simple, what's more, it does not affect the measuring process. The experiments prove that XI curve's linear fit residuals are less than 1 MUm after compensation, far less than those of before compensation 22 pm, the compensation effect is obvious, which provided a basis for various oxygen parameters' TDLAS measuring and inversion. PMID- 26117853 TI - RNA-Mediated Regulation of HMGA1 Function. AB - The high mobility group protein A1 (HMGA1) is a master regulator of chromatin structure mediating its major gene regulatory activity by direct interactions with A/T-rich DNA sequences located in the promoter and enhancer regions of a large variety of genes. HMGA1 DNA-binding through three AT-hook motifs results in an open chromatin structure and subsequently leads to changes in gene expression. Apart from its significant expression during development, HMGA1 is over-expressed in virtually every cancer, where HMGA1 expression levels correlate with tumor malignancy. The exogenous overexpression of HMGA1 can lead to malignant cell transformation, assigning the protein a key role during cancerogenesis. Recent studies have unveiled highly specific competitive interactions of HMGA1 with cellular and viral RNAs also through an AT-hook domain of the protein, significantly impacting the HMGA1-dependent gene expression. In this review, we discuss the structure and function of HMGA1-RNA complexes during transcription and epigenomic regulation and their implications in HMGA1-related diseases. PMID- 26117858 TI - Study on the Low Temperature Photoluminescence Spectra of II-VI Group Telluride Bulk Crystals. AB - The dominant point defects in II-VI group telluride bulk crystals grown from melt usually varied due to different growth conditions and cooling history, in turn affect the electrical and optical behaviors of corresponding single crystals and devices. Low temperature photoluminescence (PL) spectra acts as a contact-less and non-destructive technique, can be used to evaluate the behaviors of point defects and impurities in the as-grown telluride bulk crystals. With the purpose of comparing the defect structures in un-doped ZnTe and CdTe crystals grown under Te-rich condition, 8. 6 K PL spectra were obtained. The conductivity type and resistivity were investigated by Hall-effect measurements at room temperature (RT). For p-type low resistivity ZnTe crystal, the intensity of. free electron to neutral acceptor (e, A(0)) transition is higher than the donor-acceptor pair (DAP) transition, which predominates in the PL spectra. However, in the contrary, DAP peak dominates the PL emissions for n-type high resistivity CdTe. This difference is mainly attributed to the distinct properties of the grown-in point defects due to different growth. velocities and cooling processes. In terms of the un-doped CdZnTe crystal grown under stoichiometry, neutral donor bound exciton (D(0), X) emission is predominated in the 9.2 K PL spectra, with the intensity of (e, A(0)) peak is higher than DAP peak, which then overlaps to each other when the temperature higher then 15 K. In the case of In-doped CdZnTe crystal grown by Te-rich situation, A-center emission is clearly observed, which introduces an energy level approximately of 0.15 eV, with the intensity proportional to the concentration of indium dopant. This defect is seemingly related to the complex of [In(Cd)+V(Cd)2-]- formed by a shallow donor In(Cd) and Cd vacancy. PMID- 26117859 TI - [A Algorithm of the Singular Value Decomposition for Three-Way Array]. AB - A algorithm of the singular value decomposition for three-way array is proposed in this paper. The algorithm is suitable to deal with the actual problems of pattern recognition and classification model with three-way array data. Similar to the algorithm of the singular value decomposition for matrix, the algorithm is obtained by saving the problem of extremum subject to constraint conditions. Comparing with the existent algorithms of trilinear decomposition the algorithm is simple and fast in calculation, suitable to deal with the actual bigger data problems. The algorithm is easy to expand into the situation for multi-way array spectral data. PMID- 26117860 TI - [Influence of Argon Content on Plasma Temperature of Single Filament in Dielectric Barrier Discharge]. AB - The single filament (also referred to as monofilament) which composed of two parts including the center spot and the outer halo is observed and researched for the first time in dielectric barrier discharge, which filled with gas-mixture of argon and air. The pictures taken from the experiment show that the diameter of the monofilament decreases with the increasing of the content of the argon in the argon-air mixture, and at the same time there is an obvious difference on brightness between the center spot and the outer halo. All of these phenomenons suggest that the center spot and the outer halo are probably in different plasma state. The micro character of the center spot and the outer halo is researched seriously in the experiment by the time-resolved measurement with optical method. Three plasma temperatures of the center spot and the outer halo in single filament in different argon content are studied in details by using optical emission spectra. The emission spectra of the N2 second positive band (C3 pi(u) - > B3 pig) are measured, from which the molecule vibrational temperature of the center spot and the outer halo are calculated. Based on the relative intensity of the N2 line at 391.4 nm and the N2 line at 394. 1 nm, the changing relationship of the average electron energy of the center spot and the outer halo with argon content is investigated. The spectral lines of Ar I 763.2 nm (2P6 --> 1S5) and 772.077 nm (2P2 --> 1S3) are chosen to estimate electron excitation temperature of the center spot and the outer halo by the relative intensity ratio method. The results show that the optical signal corresponding to the first lasge pulse is the center spot, whose signal intensity is a litter weaker; and the optical signal containing the whole pulse is the outer halo, whose signal intensity is stronger. The three plasma temperatures including the molecule vibrational temperature, average electron energy and electron excitation temperature of the outer halo are higher than those of the spot at the same argon content without exception. In addition, the molecule vibrational temperature of the center spot and the outer halo decrease with the argon content increases from 30% to 50%, while on the other hand, electron excitation temperature and average electron energy are decrease gradually. PMID- 26117861 TI - [Research on L-Ascorbic Acid and Thiamine Based on Wide-Band Terahertz Spectroscopy Technique]. AB - We employed terahertz time-domain spectra (THz-TDS) and Fourier transform infrared spectra (FTIR) to measure the terahertz spectroscopy of L-ascorbic acid and thiamine in the frequency region ranging from 0.10 to 3.50 THz. Molecular models of two vitamins have been shown, and based on above two spectroscopies, we compared the differences about the absorption spectra between the L-ascorbic acid and the thiamine. The measured results show that the absorption spectra obtained based on THz-TDS and FTIR are completely consistent in the frequency range of 0.70 to 3.00 THz. New fingerprint peaks obtained by the FTIR in the low frequency region from 0.30 to 0.50 THz in terms of high sensitive silicon bolometer detector, which are not found by the THz-TDS. Furthermore, several bands at 8.75, 8.85, 9.00, 9.30 and 10.30 THz, fingerprint peaks have been found in the frequency region from 8.00 to 12.00 THz for the thiamine sample obtained by the FTIR. Measurement results indicate the absorption spectra depend on the ratio of polyethylene powder mixed with the L-ascorbic acid. L-ascorbic acid has a lower absorption ability at THz band, so pure samples should be used for testing experiment. In addition, we calculated the refractive index for the two samples. This study has important implications for the discriminatory analysis of vitamins and the establishment of vitamin spectroscopy standard database. PMID- 26117862 TI - [Research on Application of Fourier Transform Infrared Spectrometry in the Diagnosis of Lymph Node Metastasis in Gastric Cancer]. AB - To explore the feasibility of quick intraoperative in situ and noninvasive diagnosis of lymph node metastasis in gastric cancer by Fourier transform infrared (FTIR) spectrometry. FTIR spectra of surgically removed fresh lymph nodes were measured by FTIR via probe of attenuated total reflection (ATR). For each spectrum, 13 bands were indentified and assigned between 3 000 and 1 000 cm( 1). Peaks in the spectra were measured and relative intensity ratios were calculated and compared between the spectra of Metastatic lymph nodes (MLN) and Non-metastatic lymph nodes (NMLN). Standard statistic analysis was performed. 720 lymph nodes were measured in 38 gastric cancer patients. Results show that there were significant differences between the FTIR of 540 MLN and 180 NMLN. (1) For the band related to nucleic acid: The ratios of I1240/I1460 (p = 0.015) and I1080/I1460 (p = 0.034) increased in MLN, which shows that the relative quantity of nucleic acid was more in MLN than that in NMLN. (2) For the bands related to protein: The ratios of I1640 /I1460 (p = 0.001) and I146/I1460 (p = 0.027) increased in MLN, which shows that the relative quantity of protein was more in MLN. (3) For the bands related to lipid: The ratio of I2855/I460 and I1740/I1460 decreased in MLN FTIR spectrum, indicating the lower relative quantity of lipid in MLN. (4) For the bands related to carbohydrate: The ratio of I1160/I1460 (p = 0.023) decreased in MLN FTIR spectrum, indicating the lower relative quantity of carbohydrate in MLN. The results demonstrate that the FTIR spectroscopy technique maybe develop into a promising method for in situ and quick intraoperative differential diagnosis of lymph node metastasis in gastric cancer. PMID- 26117863 TI - [Infrared Spectrum Studies of Hydrocarbon Generation and Structure Evolution of Peat Samples During Pyrolysis and Microbial Degradation]. AB - Hydrocarbon generation and structural evolution would be occurred in the process of from coal-forming material (i. e. peat sample) transforming to the coal. While Fourier Transform Infrared Spectroscopy (FTIR) have a special advantages in analyzing molecular structure of samples. For understanding the characteristics of hydrocarbon generation and structural evolution of coal-forming material during the process of pyrolysis and microbial degradation, based on the physical simulation experiments of closed pyrolysis and anaerobic microbial degradation, the generation potential of thermogenic gas and biogenic gas were studied in this paper, and characteristics of molecular structure evolution and its mechanism was analyzed by FTIR technology. Results show that cumulative gas yields of hydrocarbon gases (mainly for methane) increased with experiment temperature. The gas yield of non-hydrocarbon gas (mainly for CO2) exhibited two peaks at 250 and 375 degrees C. The degradation ability of anaerobe on coal samples weakened with the maturity increasing and there was no gas generation on the pyrolysis samples with maturity from 1.6% to 1.8%. After pyrolysis, the content of hydroxyl in peat sample decreased first and then increased with the pyrolysis temperature increasing. The content of aldehyde carbonyl, methylene and phosphate reduced. The content of aromatic esters decreased with nonlinear. The bone of S-O in stretching vibration appeared after 350 degrees C and its content increased with temperature. This shows that the sulfocompound restrains the activity of methanogenic bacteria. After degradation by anaerobe, the relative content of hydroxyl, aldehyde carbonyl, aromatic esters, methylene and phosphate in peat sample dropped significantly. It is shown that the intermolecular force between these groups weakened. PMID- 26117864 TI - [Establishment and Application of Model for Determining Oil Content of Cottonseed Using Near Infrared Spectroscopy]. AB - Cotton is one of the important oil crops, and it is great significance for screening and identification of breeding materials to establish a method of the rapid, nondestructive testing of cotton seed oil content. In this study, near infrared diffuse reflection spectroscopy of 118 high and low oil materials were adopted to establish models for fast nondestructive determining oil content of cottonseed using near infrared spectroscopy (NIR). One hundred and six cottonseed samples as calibration set that covered the range of seed oil content for upland cotton were used in this experiment. The spectral data of cottonseed were processed using the first derivative and multiplicative scatter correction (MSC). The correction NIR model of oil content was built based on partial least squares (PLS) method with the spectral regions 5 446-8 848 cm(-1) and main components (5). The determination coefficient (R2) of calibration model was 0.975, standard error of calibration (SEC) was 0.67. The authors test the model's actual ability to predict using external validation set. The correlation coefficient (r) of predicted values and the chemistry value was 0.978, the range of prediction error was 0.1% - 1.7%. The model established has good predictability. The oil content of 784 breeding stocks were predicted by NIR model, statistical analysis of predictable. results elucidated that the NIR model of oil content developed can be well applied to selective breeding and oil related study in cotton. PMID- 26117865 TI - [Study on Archaeological Lime Powders from Taosi and Yinxu Sites by FTIR]. AB - Archaeological lime powders samples from Taosi and Yinxu sites, natural limestone and experimentally prepared lime mortar were investigated by means of Fourier transform infrared spectrometry (FTIR) to identify the raw material of lime powders from Taosi and Yinxu sites. Results show that nu2/nu4 ratio of calcite resulted from carbonation reaction of man-made lime is around 6.31, which is higher than that of calcite in natural limestone and reflects the difference in the disorder of calcite crystal structure among the natural limestone and prepared lime mortar. With additional grinding, the values of v2 and nu4 in natural limestone and prepared lime mortar decrease. Meanwhile, the trend lines of nu2 versus nu4 for calcite in experimentally prepared lime mortar have a steeper slope when compared to calcite in natural limestone. These imply that nu2/nu4 ratio and the slope of the trend lines of nu2 versus nu4 can be used to determine the archaeological man-made lime. Based on the experiment results, it is possible that the archaeological lime powder from Taosi and Yinxu sites was prepared using man-made lime and the ancient Chinese have mastered the calcining technology of man-made lime in the late Neolithic period about 4 300 years ago. PMID- 26117867 TI - [Quality Analysis of Peanut Seed by Visible/Near-Infrared Spectra]. AB - In this paper, three representative varieties of peanut seeds were selected for the experiment based on visible/near-infrared reflectance spectroscopy living in the wavelength rang from 600 to 1 100 nm. Firstly, spectral datas ware collected by the near-infrared fiber optic spectrometer, and the spectral features of the original spectral dates were extracted by the wavelet analysis. Then the principal component analysis (PCA) was used for cluster analysis of spectral features. Finally, the four principal components were applied as the inputs, the varieties category as the output and the Mahalanobis distance as the discriminant function of the recognition model, so a linear discriminant analysis model was established. In the 50 samples of each varieties, 30 samples were randomly selected as the training set, and the remaining 20 samples as the predictor set. The recognition model for three peanut varieties have a recognition rate of 95% on average. As the experimental results show that this method is reliable and effectively, and a new method to distinguish and discriminate the quality of peanut seeds was put forword. PMID- 26117866 TI - [The Interaction of Oil Microcapsule Wall Materials between Whey Protein and Acacia]. AB - The interaction between whey protein and acacia which were used as wall material was studied on the formation of the oils microcapsules by the FTIR Spectroscopy and Computer Aided Analysis. The results indicated that whey protein changed obviously in amide A and amide I by high pressured homogenization and spray drying. The amide A moved from 3 406.5 cm(-1) to 3 425.4 cm(-1) which was possibly due to covalent cross-linking between whey protein and acacia. Furthermore the amide I moved from 1 648.6 cm(-1) to 1 654.7 cm(-1) for intramolecular hydrogen bonding of protein had been weaken. After Gaussian fitting on amide I , it was found that the content of secondary structure of alpha-helix content and beta-folding in whey protein reduced from 19.55% to 17.50% and from 30.59% to 25.63%, respectively. This suggests that protein intramolecular hydrogen bonding force was abated, resulting in abating the rigid structure of the protein molecules and enhancing of the toughness structure. The protein molecules showed some flexibility. The result of SDS-PAGE electrophoresis showed that whey protein--gum Arabic complexes produced covalent products in larger molecular weight. During the spray-drying process, covalent cross-linking produced between whey protein and gum Arabic which improved emulsifying activity of the complex whey protein and gum Arabic produced covalent cross-linking and improved the complex emulsifying activity. Observing the surface structure of the fish oil microcapsule by SEM, the compound of whey protein and acacia as wall material was proved better toughness, less micropore, and more compact structure. PMID- 26117868 TI - Determination of Carbon Dioxide in Refined Titanium Tetrachloride by Infrared Spectroscopy. AB - Refined TiCl4 is the key procedure in producing titanium sponge. Besides, the content of carbon and oxygen (C and O) impurities in titanium sponge and that of C and O impurities in refined TiCl4 presents the 4-times enrichment relationship. Therefore, the content control of the C and O impurities in refined TiCl4 becomes the key part for the quality control of titanium material. In order to control the oxygen and carbon, there is the need to analyze the source of C and O impurities so that strict control can be conducted over the impurities of refined TiCl4. Determination of CO2 in refined TiCl4 was significant for analysis of its impurities. CO2 could be determined by infrared spectroscopy due to its infrared characteristic spectrum line. However, normal infrared absorption cell was not fit for the sample analysis, because TiCl4 easily reacted with moisture in the air and immediately was hydrolyzed to form highly corrosive hydrochloric acid smoke. According to Lambert-Beer Law, which means the concentration (c(xi)) and absorbance(A) - length (L) curve's slope have direct ratio. The infrared absorption cell with the window film of ZnSe (phi10 mm x 1 mm, wavenumers: 7 800 440 cm(-1)) and the glass cell (optical path: 42, 22, 12, 7 and 4 mm) was assembled and utilized in determination of the CO2 in refined TiCl4 by standard addition method. The detection limit of CO2 was 0.92 mg x kg(-1), the regression equation was Y = 0.031 1X, R = 0.997 2; With standard addition method, the regression equation of CO2 was Y = 0.131 7X, R = 0.998 6, it's good in linearity relation, the CO2 content in refined TiCl4 is determined to be 1.53 mg x kg(-1) and SD up to 0.04 x mg x kg(-1). RSD of the method precision is between 0.53% 1.27%, while recovery rate is between 89.2%-96.8%. This infrared absorption device was safe, simple and convenient, easily removable and washable, and re useable. The method could conduct the quantitative analysis over the CO2 content in refined TiCl4 through adding standard sample for one time, it could meet the requirement of determination of CO2 in refined TiCl4. PMID- 26117869 TI - [Infrared Spectra Characteristics of the Silicate Nickel Ores: A Comparison Study on Different Ore Samples from Indonesia and China]. AB - The silicate nickel ores developed in the lateritic nickel deposit, from Kolonodale, Sulawesi Island, Indonesia, and Yuanjiang, Yunnan province, China, were selected for the present study. The X-ray diffraction and Fourier infrared spectra were used to analyze the mineralogical attribute of laterite nickel ores from two different places. The results show that these two different silicate nickel ores have unique infrared spectra characteristics individually, which contributes to the ore classification. The silicate nickel ores from Kolonodale deposit, Indonesia, can be classified as the serpentine type, the montmorillonite + serpentine type, and the garnierite type. While, the silicate nickel ores from Yuanjiang deposit, China, can be classified as the serpentine type and the talc + serpentine type. Moreover, the mineral crystallinity of Yuanjiang nickel ores is generally better than Kolonodale nickel ores. According to the advantage of infrared absorption spectra in distinguishing mineral polytypes, it can be determined that lizardite is the main mineral type in the silicate nickel ores of the two deposits, and there is no obvious evidence of chrysotile and antigorite's existence. The characteristic of infrared absorption spectra also shows that frequency change of OH libration indicates Ni (Fe) replacing Mg in the serpentine type nickel-bearing mineral, that is, OH libration of serpentine moves to higher frequency, with the proportion of Ni (Fe) replacing Mg increasing. PMID- 26117870 TI - [Effect on Fermi Resonance by Some External Fields: Investigation of Fermi Resonance According to Raman Spectra]. AB - Fermi resonance is a phenomenon of molecular vibrational coupling and energy transfer occurred between different groups of a single molecule or neighboring molecules. Many properties of Fermi resonance under different external fields, the investigation method of Raman spectroscopy as well as the application of Fermi resonance, etc need to be developed and extended further. In this article the research results and development about Fermi resonance obtained by Raman spectral technique were introduced systematically according to our work and the results by other researchers. Especially, the results of the behaviors of intramolecular and intermolecular Fermi resonance of some molecules under some external fields such as molecular field, pressure field and temperature field, etc were investigated and demonstrated in detail according to the Raman spectra obtained by high pressure DAC technique, temperature variation technique as well as the methods we planed originally in our group such as solution concentration variation method and LCOF resonance Raman spectroscopic technique, and some novel properties of Fermi resonance were found firstly. Concretely, (1) Under molecular field. a. The Raman spectra of C5H5 N in CH3 OH and H2O indicates that solvent effect can influence Fermi resonance distinctly; b. The phenomena of the asymmetric movement of the Fermi resonance doublets as well as the fundamental involved is tuned by the Fermi resonance which had not been found by other methods were found firstly by our variation solution concentration method; c. The Fermi resonance properties can be influenced distinctly by the molecular group reorganization induced by the hydrogen bond and anti-hydrogen bond in solution; d. Fermi resonance can occurred between C7 H8 and m-C8H10, and the Fermi resonance properties behave quite differently with the solution concentration; (2) Under pressure field. a. The spectral lines shift towards high wavenumber with increasing pressure, and frequency difference Delta varies with pressure, which induced the change of W; b. The W of nui + nu4 nu3 of CCl4 in C6H6 decreased more quickly in solution than in pure liquid with increasing pressure and the Fermi resonance disappeared ahead of that in pure liquid, which indicates that the phenomenon of Fermi resonance induced by pressure effect can reveal the mechanism of some solvent effects. (3) Under temperature field. a. The Fermi resonance properties of different molecules behave quite differently with temperature. For an instance, the one of CO2 can be influenced distinctly by temperature, while the one of CS2 behaves no change with temperature. This article offers systematic theoretical and experimental support to the investigation of identification and assignment of molecular spectral line, the confirmation of molecular conformation and conformers, the effect of hydrogen bond on molecular structure and properties, etc. PMID- 26117871 TI - [Raman Spectroscopy Measurement System of Dual Wavelength Laser Module]. AB - Fluorescence interference is one of common interference factors during detection of Raman spectroscopy, while shifted-excitation Raman difference spectroscopy (SERDS) is an effective detection means to reject it. SERDS excites the test substance by two laser with different wavelengths, then difference the obtained Raman spectroscopies. SERDS can eliminate the fluorescence interference effectively, because the fluorescence backgrounds of the two spectroscopies are the same while the Raman peaks are translated. The key factor of SERDS is the stability of the two excitation light wavelengths, the instability of wavelength difference would seriously affect the characteristics of the Raman peak reproduction. In this paper, the Raman spectroscopy measurement system is presented, where dual wavelength laser module can stably produce two bunch of excitation light (respectively 784.7 and 785.8 nm), which satisfies the requirements of SERDS detection. The major factors influencing wavelength of the laser are laser power and temperature. The system monitors them in real time to guarantee the stability of exciting light's wavelength. The hardware framework of this measurement system is mainly composed of ARM, dual wavelength laser module as well as its driving circuit, temperature control circuit, a digital optical switch, a spectrometer; the software of this system can achieve the Raman spectrogram automatically and then carry on the subsequent processing. The stability tests of this system for drive current and laser temperature are done. The experimental results demonstrate that the range of current proves to be less than 0.01 mA, the range of temperature less than 0.004 degrees C. The system can guarantee the stability of excitation wavelength effectively. Finally, perform the Raman spectroscopy detection to sesame oil of some brand and get good results. PMID- 26117872 TI - [Raman Signal Enhancement for Gas Detection Using a Near Concentric Cavity]. AB - The detection of dissolved gases in seawater plays an important role in ocean observation and exploration. Raman spectroscopy has a great advantage in simultaneous multiple species detection and is thus regarded as a favorable choice for ocean application. However, its sensitivity remains insufficient, and a demand in enhancements is called! for before putting Raman spectroscopy to actual use in marine studies In this work, we developed a near-concentric cavity, in which laser beam could be trapped and reflected back and forth, for the purpose of intensifying Raman signals. The factors that would influence Raman signals were taken into account. The result show that the smaller angle between collection direction and optical axis of reflection mirror, the stronger the signal and signal to noise ratio (SNR) is. With a collection angle of 30 degrees, our Near-concentric Cavity System managed to raise the SNR to a figure about 16 times larger than that of common methods applying 90 degrees. Moreover, the alignment pattern in our system made it possible to excel concentric cavity with a 3 times larger SNR. Compared with the single-pass Raman signal, the signal intensity of our near-concentric cavity was up to 70 times enhanced. According to the obtained results of CO2 measurement, it can be seen that the new system provides a limit of detection(LOD) for CO2 about 0.19 mg x L(-1) using 3-sigma criterion standard, and the LOD of 11.5 MUg x L(-1) for CH4 was evaluated with the theoretical cross section values of CO2 and CH4. PMID- 26117873 TI - Feasibility Study on Quantitative Analysis of Sulfide Concentration and pH of Marine Sediment Pore Water via Raman Spectroscopy. AB - Marine sediment pore water is one of the important objects in the study of global environmental change, marine geology and biogeochemistry. Anoxic pore water in highly reducing deep-sea sediments commonly contains a large amount of dissolved sulfide (H2S and HS-). The sulfide species within sediment pore water are significant not only because the importance of themselves, but also because they exist as a function of pH which is another key parameter in pore water study. As degassing and chemical equilibrium altering are both inevitable, concentrations of sulfide species and pH value of marine sediment pore water acquired with traditional non-in situ technologies are of great uncertainty, and cannot represent the real geochemistry information. However, the recent deployment of an in situ laser Raman pore water sampler allows us to observe spectral sulfide signals of marine sediments in situ and in real time, which provide us a new technique to solve this problem. Sulfide species in water have a relatively strong Raman signal, which often appears in the form of a characteristic overlapping peak between 2 550 - 2 620 cm(-1) and can be decomposed into HS- at 2 572 cm(-1) and H2S at 2 592 cm(-1). In the present paper, quantitative analysis of H2S and HS- with Raman spectroscopy is proved practicable and the accuracy is good. The pH of pore water is an important influencing factor of the diagenetic processes. As H2S and HS- are conjugate acid-base pairs, sulfide species within pore water exist as a function of pH and their concentration ratio depend on pH. This relationship is also shown in the Raman spectrum. To formulate the pore water pH calculation, sulfide solutions with pH range from 6.11 to 13.05 were prepared and their Raman spectra were observed. It is verified that the morphology of overlapping peaks change regularly with pH values. This phenomenon provides us the possibility of measuring the pH of pore water in situ via Raman spectroscopy. Based on peaks decomposition and correlativity analysis, we propose here a novel in situ pH measuring method for sediment pore water containing sulfide. This method can be used to measure the pH of pore water when the overlapping peak of sulfide is resolvable. The application scope of this pH measuring method in this study is 6.11 - 8.32, which covers almost all pH value of marine sediment pore water already known. The study provides additional technical reference for obtaining high-fidelity information of marine sediment pore water. PMID- 26117874 TI - [Studies on Effect of Alkali Pretreatment on Anaerobic Digestion of Rice Straw with Confocal Raman Microscopy]. AB - NaOH pretreatment is a convenient and effective method which is widely used in rice straw anaerobic digestion. But the mechanism of the alkaline (NaOH) hydrolysis of biopolymers compositions and polymeric cross-linked network structures of rice straw cell wall need further study. This paper firstly studied the effect and mechanism of alkali pretreatment on anaerobic digestion and biogas production of rice straw by using a combination of confocal Raman microscopy and transmission electron microscope. First, the original rice straw and the rice straw pretreated by NaOH were taken for mapping scanning by confocal Raman microscopy with micron-scale spatial resolution. Then principal component analysis was adopted to extract main information of Raman spectra, it could be found that the two types of samples were respectively presented with ray-like distribution in the first two principal component space, which were with cumulative contribution of 99%. And there was a clear boundary between the two types of samples without any overlapping, indicating that there was a significant difference of Raman spectral characteristic between original rice leaf and rice leaf pretreated by NaOH. Further analysis of the loading weights of the first two principal components showed that the Raman peaks at 1 739, 1 508 and 1 094 cm(-1) were the important bands, and these three Raman peaks were attributed to the scattering of hemicellulose, cellulose and lignin respectively. Following, chemical imaging analysis of hemicellulose, cellulose and lignin were achieved by combining these Raman peaks and microscopic image information. It could be found that the NaOH pretreatment resulted in a loss of dense spatial uniformity structure of tissue and great decreases of the contents of these three ingredients, particularly lignin. It can be concluded that it is feasible to non destructively measure hemicellulose, lignin and cellulose in rice straw tissue by confocal Raman microscopy, and to achieve chemical imaging analysis of the three ingredients in tissue, and this research will be much help for revealing the promotion mechanism of NaOH pretreatment for the rice straw fermentation and biogas production. PMID- 26117875 TI - [The Influence of Runoff Pollution to DOM Features in an Urban Wastewater Treatment Plant]. AB - Combined with wastewater treatment process, the sewage in sunny and rainy day was collected from a wastewater treatment plant in Chongqing. Three-dimensional fluorescence spectra was used to investigate the characteristic fluorescence of dissolved organic matter (DOM). DOM dissolved organic carbon (DOC), chemical oxygen demand (COD), fluorescence index (f450/500) and fluorescence intensity ratio gamma (A, C) of fulvic acid in ultraviolet and visible region were used to analyze the impact of rain runoff pollution on sewage DOM. According to the experimental data, the DOM fluorescence fingerprints of this wastewater treatment plant were quite different from typical municipal sewage, and the main component was tryptophan with low excitation wavelength (Peak S), then the tryptophan with long wavelength excitation (Peak T) followed. A2/O process had an approximative degradation of the protein-like both in sunny day and rainy day, but had a better degradation of fulvic-like, DOC and COD in rainy day than that in sunny day. Morever, the fluorescence peaks got red-shifted after the biological treatment. The differences of DOM fluorescence fingerprint between sunny and rainy day were significant, the fluorescence center of UV fulvic (Peak A) in rainy day getting blue-shifted obviously, shifting from 240 - 248/390 - 440 to 240 - 250/370 - 400 nm. Although the DOM types in sunny and rainy day were the same, the source of fulvic got more complex by runoff and the component ratio of DOM also changed. Compared with the sunny day, the proportion of Peak S in DOM dereased by 10%, and the proportion of Peak A increased by 7% in rainy day. PMID- 26117876 TI - [Secondary Alterations Influence on Fluorescence Color and Spectral Parameters of Crude Oil and Oil Inclusion]. AB - Based on oil samples and rock samples in several petroliferous basins, this paper studied that secondary alterations influence on fluorescence color and spectral parameters of crude oil and oil inclusions by using microscopic fluorescent spectral and geochemical parameters. The results demonstrated that secondary alterations influence on spectral parameters by changing the ratio of saturated hydrocarbon and aromatic hydrocarbon (saturation/aromatics). Biodegradation and water washing lead to redshift of fluorescence parameters while evaporative fractionation and oil cracking lead to blueshift. Beside, mixed oil lead to redshift and blueshift. The secondary alterations and main period of accumulation in research area were recognized by frequency histogram of crude oil and oil inclusion. The relationship between QF-535 and the parameters measuring the secondary alterations could the extent of secondary alterations from which crude oil suffered. In the microscopic fluorescence test, oil inclusions suffered from stretch or leakage, thermal cracking and photooxidation should be rejected. PMID- 26117877 TI - [Quantum Chemistry Calculation of Ponceau 4R Molecule Structure and Research on the Fluorescence Mechanism]. AB - The molecule structures of Ponceau 4R in ground state and the excited state were optimized by employing the Gaussian 09W program package. In addition, the electronic structure and frontier orbital of the ground state, the emission wavelength of the excited state was also investigated. And then, the Edinburgh FLS920P fluorescence spectrometer was applied to the measurement of the fluorescence spectra of cochineal solution, and the emission spectra was obtained. The calculated emission wavelength had a good coincidence with the experiment data, which indicates that the optimized structures mentioned above are reasonable. The structures comparison between the ground state and the excited state was also performed to analyze the mechanism of fluorescence spectrum. It can be concluded that the molecule structure of excited state is nearly planar, so Ponceau 4R is thought to have strong fluorescent characteristics, the emission fluorescence is the result of transition from orbit 139 to orbit 137. PMID- 26117878 TI - [Investigation on Inhibitory Capacities of Seventeen Herbal Extracts on Oxidative Stress using Ultraviolet and Fluorescence Spectroscopy]. AB - Diabetic patients usually suffer from complications and the long-term secondary complications are the main cause of morbidity and mortality. The hyperglycemia induced oxidative stress is one of the important pathogenesis of diabetic complications, while the oxidative stress is associated with the lipid peroxidation reaction and the formation of advanced glycation end products (AGEs). Our study was focus on the pathogenesis of diabetic complications and based on the oxidative stress reaction. In this research, the oxidative stress inhibiting effects of seventeen herbal extracts were studied based on spectroscopic methodology. The capacities of herbal extracts against the lipid peroxidation reaction of rat liver in vitro were investigated using spectrophotometric method. It showed that the inhibitory activity of Radix Scutellariae and Flos Sophorae Immaturus were better than other herbal extracts. Additionally, the herbal extracts rich in flavonoids, alkaloids and lignanoids showed good inhibitory activities on the lipid peroxidation reaction. On the contrary, the saponin-rich herbal extracts possessed weak inhibitory effects. We applied the BSA/glucose (fructose) system combined with fluorescent spectroscopy to determine the inhibitory activities of herbal extracts in glycation model reactions. The results showed that the AGEs formation inhibitory activity of Flos Sophorae Immaturus, Radix Scutellariae and Rhizoma Anemarrhenae were better than others in the BSA/glucose (fructose) system by fluorescene analysis. The results demonstrated that the herbal extracts rich in flavonoids were found to be more effective than that of those herbal extracts as alkaloids and terpenoids class in inhibiting oxidative stress, while the saponin-rich herbal extracts showed weak inhibitory activities against oxidative stress. The Flos Sophorae Immaturus and Radix Scutellariae extracts had better inhibitory activity to the oxidative stress, so their pharmacological activity could be explored in further investigations. These results demonstrated in this assay could provide a reference for the study of pharmacological activity, and thus lays the foundation for the further study of the application of natural products in the prevention and treatment of diabetic complications. PMID- 26117879 TI - [A Fluorescent Chemical Sensor Based on MgAl-8-HQ LDH Composite Particle for the Selective Detection of Fe3+]. AB - In order to achieve the highly selective and Simple detection for ferric ion, strong-fluorescent 8-hydroxyquinoline (8-HQ) Mg-Al layered double hydroxide(Mg(chi)Al-8-HQ LDH) was designed and prepared by 8-HQ's intercalation and ready coordination based on adjustment of Al3+ on Mg-Al layered double hydroxides (MgAl LDH) laminates. Meanwhile its structure and property were characterized by IR, XRD, UV-Vis and fluorescent spectrometer. IR analysis showed coordinate bonds of C-O-Al and C-N-Al between 8-HQ and Al3+ were generated. XRD revealed that 8-HQ had already inserted in MgAl LDH laminates, and it made (003) diffraction peaks move to low 2theta angle direction, and the diffraction peak intensity was enhanced with the molar ratio of Mg and Al increasing. Because the coordination reaction between 8-HQ and Al3+ in MgAl LDH laminates took place, it induced the absorption peak of 8-HQ at 314 nm disappeared, at the same time the transition absorption peak at 376 nm between metal ions and ligands appeared. As demonstrated by fluorescence spectroscopic analysis, fluorescence intensity of Mg(chi)Al-8-HQ LDH increased with the content of Al3+ reducing, when the molar ratio of Magnesium and Aluminium ion is 4 : 1, its fluorescence intensity enhanced more significantly than 8-hydroxyquinoline aluminum. Through the research on the influence of metal ions on the fluorescence spectra of Mg4 Al-8 HQ LDH particle, it was found that the particle to metal ions exhibited significant selection and difference, especially with high selectivity for Fe3+ ion. The effect of [Fe3+] on the color and fluorescence intensity of Mg4Al-8-HQ LDH particle solution was further studied, and the results showed that the solution varied from light yellow to dark green with the content of Fe3+ in 10( 6) to 10(-2) mol x L(-1) increasing, so it can implement colorimetric sensing for Fe3+ in the above range. And at the same time its fluorescence intensity significantly decreased, and its fluorescence could be completely quenched, when [Fe3+] was 10(-3) mol x L(-1). When -log[Fe3+] was in 3 to 6, negative correlation function appeared between -log[Fe3+] and its fluorescence intensity, so it could implement fluorescence sensing detection for Fe3+ with high selectivity and sensitivity. According to the above research results, a new method of fluorescent and colorimetric dual sensor detection of Fe3+ by Mg4Al-8 HQ LDH particle was successfully established. PMID- 26117880 TI - [Rapid Identification of Cistanche via Fluorescence Spectrum Imaging Technology Combined with Principal Components Analysis and Fisher Distinction]. AB - In order to explore rapid reliable Hebra cistanche detection methods, identification of 3 different sources of Hebra cistanche: cistanche deserticola, cistanche tubulosa, sand rossia is studied via fluorescent spectral imaging technology combined with pattern recognition. It is found in experiment that cistanche samples have obvious fluorescence properties. Forty fluorescence spectral images of 3 different sources of Hebra cistanche samples are collected through fluorescent spectral imaging system. After carrying on denoising and binarization processing to these images, the spectral curves of each sample was drawn according to the spectral cube. The obtained spectra data in the 450 - 680 nm wavelength range is regarded as the study object of discriminant analysis. Then, principal component analysis (PCA) is applied to reduce the dimension of spectroscopic data of the three kinds of cistanche and fisher distinction is used in combination to classify them; During the experiment were compared the effects of three methods of data preprocessing on the model: multiplicative scatter correction (MSC), standard normal variable correction (SNV) and first-order differential (FD) and then according to the cumulative contribution rate of the principal component and the effect of number of factors on the discriminant model to optimize the number of principal components factor. The results showed that. identification of the best after the first derivative pretreatment then the first four principal components is extracted to carry on fisher discriminant, discriminant model of 3 different sources of Hebra cistanche is set up through PCA combined with fisher discriminant the precision of original discrimination is 100%, recognition rate of the cross validation is 95%. It was thus shown that the fluorescent spectral imaging technology combined with principal components analysis and fisher distinction can be used for the identification study of 3 different sources of Hebra cistanche and has the advantages of easy operation, speediness, reliability. PMID- 26117881 TI - Contrastive Research of the Y3Al5O12: Ce3+ Yellow Phosphors Prepared by Different Methods. AB - Ce3+ doped Y3Al5O12 : Ce3+ yellow phosphors are prepared by the high-temperature solid-state method, sol-gel method and hydrothermal-pyrolysis methods. The influences of the preparation methods on the phase, morphology and photoluminescence properties of the YAG : Ce3+ yellow phosphors are investigated by XRD, FESEM and PL, respectively. The results indicate that the three methods all realize the substitution of Ce3+ ions for Y3+ ions, and that the cubic crystalline structure of the Ce(3+)-doped YAG phosphors is unchanged. The samples prepared by the high-temperature solid-state method present an irregular sphere like morphology, with a large sample size; the sol-gel method produces nanoparticles with a notable particle agglomeration; and the samples prepared by the hydrothermal-pyrolysis method present a well-distributed sphere-like structure with a diameter of 10 MUm. According to the fluorescence spectrum, the three samples are excited by blue light with a wavelength of 460 nm, and a big broadband emission at 550 nm is observed. However, due to the differences in the morphology and size, these samples present very different luminous intensities and quantum efficiencies. PMID- 26117882 TI - [The Effect of Observation Geometry on Polarized Skylight Spectrum]. AB - Study on polarized skylight spectral characters while observation geometry changing in different solar zenith angles (SZA), viewing zenith angles (VZA) or relative azimuth angles (RAA). Simulation calculation of cloudless daylight polarimetric spectrum is realized based on the solver, vector discrete ordinate method, of radiative transfer equation. In the Sun's principal and perpendicular plane, the spectral irradiance data, varying at wavelengths in the range between 0.4 and 3 MUm, are calculated to extend the atmospheric polarization spectral information under the conditions: the MODTRAN solar reference spectrur is the only illuminant source; the main influencing factors of polarized radiative transfer include underlying surface albedo, aerosol layers and components, and the absorption of trace gases. Simulation analysis results: (1) While the relative azimuth angle is zero, the magnitude of spectrum U/I is lower than 10( 7) and V/I is negligible, the degree of polarization and the spectrum Q/I are shaped like the letter V or mirror-writing U. (2) In twilight, when the Sun is not in FOV of the detector, the polarization of the daytime sky has two maximum near 0.51 and 2.75 MUm, and a minimum near 1.5 MUm. For arbitrary observation geometry, the spectral signal of V/I may be ignored. According to observation geometry, choosing different spectral bands or polarized signal will be propitious to targets detection. PMID- 26117883 TI - [Study on Chemical Kinetic Effect of Dielectric Barrier Discharge Plasma]. AB - To reveal the mechanism of plasma (assisted the ignition process of methane/air further, schematic of dielectric barrier discharge plasma system with atmospheric air was designed and set up, the emission spectrum of dielectric barrier discharge plasma with atmospheric air was measured, and the active particles produced by the interaction of dielectric barrier discharge plasma with atmospheric air were analyzed with the spectrum technology, the ignition model and calculation methods of sensitivity analysis and reaction path analysis were given, effects of NO and O3 on the ignition delay time were simulated, and the chemical kinetics mechanism of NO and O3 assisted ignition was revealed via sensitivity analysis and reaction path analysis. The results show that main excited particles of N2 and O3 are generated via effect of plasma on the atmospheric air, which are converted into active particles of NO(xi) and O3 in the end, the life of which are longer than any other active particles, effects of plasma on the ignition is simplified as effects of NO(xi) and O3 on the ignition; NO and O3 could reduce the ignition delay time significantly, but the amplitude decrease with increase of the initial temperature, this is because the rate of ignition is decided by the oxidation rate of CH3, the oxidized pathway of CH3 is R155 and R156 for auto-ignition and their rates are slower when temperature is low, so the ignition delay time of methane/air is longer; NO could reduce the ignition delay time significantly because of the oxidized pathway of CH3 is changed to R327 CH3O2 + NO = CH3O + NO2, R328 CH3 + NO2 = CH3O + NO for NO(xi) (assisted ignition process from R155 and R156 for auto-ignition; and the chemical kinetic effect is the dominating factor of O3 on the ignition and which change the reaction path. PMID- 26117884 TI - [Effect of Helium on Diamond Films Deposited Using Microwave PCVD]. AB - Optical emission spectroscopy (OES) was used to in situ diagnose the CH4-H2-He plasma in order to know the effect of helium on the diamond growth by microwave plasma chemical vapor deposition (MPCVD). The spatial distribution of radicals in the plasma as a function of helium addition was studied. The diamond films deposited in different helium volume fraction were investigated using scanning electron microscope (SEM) and Raman spectroscopy. The results show that the spectra intensity of radicals of H(alpha), H(beta), H(gamma), CH and C2 increases with the increasing of helium volume fraction, especially, that of radical H(alpha) has the most improvement. The spectrum space diagnosis results show that the uniformity of C2, CH radicals in the plasma tends to poor due to the helium addition and resulted in a different thickness along the radial direction The measurement of deposition rate shows that the addition of helium is useful for the improvement of the growth rate of diamond films, due to relative concentration of carbon radicals was increased. The deposition rate increases by 24% when the volume fraction of He was increased from 0 vol. % to 4.7 vol.%. The micrographs of SEM reveal that with the increasing of helium volume fraction, the diamond films' crystallite orientation changes from (111) to disorder and a twins growth becomes obvious. The secondary nucleation density during growth increases because the high relatively concentration of C2 radicals under higher helium volume fraction (4.7 vol. %). In addition, the substrate was etched and sputtered by the plasma, which introduced metallic atoms into the plasma during the deposition of diamond films. Eventually, the existing of secondary nucleation and impurity atoms lead to the appearance of twins and results in the compressive dress. PMID- 26117885 TI - [Estimation and Visualization of Nitrogen Content in Citrus Canopy Based on Two Band Vegetation Index (TBVI)]. AB - Nitrogen is a necessary and important element for the growth and development of fruit orchards. Timely, accurate and nondestructive monitoring of nitrogen status in fruit orchards would help maintain the fruit quality and efficient production of the orchard, and mitigate the pollution of water resources caused by excessive nitrogen fertilization. This study investigated the capability of hyperspectral imagery for estimating and visualizing the nitrogen content in citrus canopy. Hyperspectral images were obtained for leaf samples in laboratory as well as for the whole canopy in the field with ImSpector V10E (Spectral Imaging Ltd., Oulu, Finland). The spectral datas for each leaf sample were represented by the average spectral data extracted from the selected region of interest (ROI) in the hyperspectral images with the aid of ENVI software. The nitrogen content in each leaf sample was measured by the Dumas combustion method with the rapid N cube (Elementar Analytical, Germany). Simple correlation analysis and the two band vegetation index (TBVI) were then used to develop the spectra data-based nitrogen content prediction models. Results obtained through the formula calculation indicated that the model with the two band vegetation index (TBVI) based on the wavelengths 811 and 856 nm achieved the optimal estimation of nitrogen content in citrus leaves (R2 = 0.607 1). Furthermore, the canopy image for the identified TBVI was calculated, and the nitrogen content of the canopy was visualized by incorporating the model into the TBVI image. The tender leaves, middle-aged leaves and elder leaves showed distinct nitrogen status from highto low-levels in the canopy image. The results suggested the potential of hyperspectral imagery for the nondestructive detection and diagnosis of nitrogen status in citrus canopy in real time. Different from previous studies focused on nitrogen content prediction at leaf level, this study succeeded in predicting and visualizing the nutrient content of fruit trees at canopy level. This would provide valuable information for the implementation of individual tree-based fertilization schemes in precision orchard management practices. PMID- 26117886 TI - [Optical Constants Determination of Zinc Selenide by Inversing Transmittance Spectrogram Transmittance Spectra Measurement and Thermal Radiative Physical Parameters Inversion of Diesel Fuel]. AB - A novel inversion method of optical constants of diesel fuel that is one of semitransparent liquid was developed based on spectral transmittance radio inversion calculation of optical cell with glass-liquid fuel-glass configuration, which was validated by measured the optical constants of water. The measurements of transmittance spectrogram of optical cell filled with diesel fuel in the infrared wavelength 2 - 15 MUm at normal incidence were investigated by Bruke V70 FTIR spectrometer. The optical constants and thermal radiative physcial parameters of diesel fuel were achieved. The results show that, (1) The optical constants of water determined by the new method (IDTM) have good agreement with previously data sets. (2) The optical constants calculation precision of the IDTM is similar with MCDTM, which is higher than SODTM and SDTM. (3) The transmittance capability of diesel fuel in the infrared wavelength 2 - 15 MUm are weak, and there exist five absorption peaks, which are respectively 2.4, 3.4, 6.2, 7.3 and 13.8 MUm. (4) The spectral selectivity of optical constants and thermal radiative physcial parameters of diesel fuel are stronger, whose values are urgently varied with different wavelenths. PMID- 26117887 TI - [Monitoring of Crack Propagation in Repaired Structures Based on Characteristics of FBG Sensors Reflecting Spectra]. AB - In order to improve the security of aircraft repaired structures, a method of crack propagation monitoring in repaired structures is put forward basing on characteristics of Fiber Bragg Grating (FBG) reflecting spectra in this article. With the cyclic loading effecting on repaired structure, cracks propagate, while non-uniform strain field appears nearby the tip of crack which leads to the FBG sensors' reflecting spectra deformations. The crack propagating can be monitored by extracting the characteristics of FBG sensors' reflecting spectral deformations. A finite element model (FEM) of the specimen is established. Meanwhile, the distributions of strains which are under the action of cracks of different angles and lengths are obtained. The characteristics, such as main peak wavelength shift, area of reflecting spectra, second and third peak value and so on, are extracted from the FBGs' reflecting spectral which are calculated by transfer matrix algorithm. An artificial neural network is built to act as the model between the characteristics of the reflecting spectral and the propagation of crack. As a result, the crack propagation of repaired structures is monitored accurately and the error of crack length is less than 0.5 mm, the error of crack angle is less than 5 degree. The accurately monitoring problem of crack propagation of repaired structures is solved by taking use of this method. It has important significance in aircrafts safety improvement and maintenance cost reducing. PMID- 26117888 TI - [Synthesis and Characterization of PAM Derivative Weak Gel]. AB - Weak gel with PAM cross-linked radical reaction was prepared by being incorporated to side chain of PAM. The structure, gel for ming process and the influence of NaCl concentration to apparent viscosity of gel were studied. The results show that the crosslinking ratios influence to crosslinking time, gel breaking time and gel strength. The crosslinking time decreases and gel strength slightly increases with increase of crosslinking ratio. Apparent viscosity of Polyacrylamide derivative crosslinking system increases with increase of NaCl concentration. The weak gel has good salt tolerance ability. PMID- 26117889 TI - [Mixed-Spectral Spatial Information Decomposition Model of Water Hyperspectral Inversion]. AB - The effect of Mixed-hyperspectral in the water is difficult in quantitative remote sensing of water. Studies have shown that the only scalar spectrum information is difficult to solve the problem of complex mixed spectra of water. Besides the spectral information, spatial distribution of information is one of the obvious characteristics of the broad waters pollution, and can be used as a useful complement to the remote sensing information and facilitate water complex spectral unmixing. Taking Chaohu as an example, the paper applies the HJ-1A HSI hyperspectral data and the supplemental surface spectral measurement data to discuss the mixed spectra of lake water by spatial statistics and genetic algorithm theory. By using the spatial variogram of geostatistics to simulate the distribution difference of two adjacent pixels, the space-informational decomposition model of mixed spectral in lake water is established by co-kriging genetic algorithm, which is a improved algorithm applying the spatial variogram function of neighborhood pixel as the constraint of the objective function of the genetic algorithm. Finally, the model inversion results of suspended matter concentration are verified. Compared with the conventional spectral unmixing model, the results show the correlation coefficient of the predicted and measured value of suspended sediment concentration is 0.82, the root mean square error 9.25 mg x L(-1) by mixed spectral space information decomposition model, so the correlation coefficient is increased by 8.9%, the root mean square error reduced by 2.78 mg x L(-1), indicating that the model of suspended matter concentration has a strong predictive ability. Therefore, the effective combination of spatial and spectral information of water, can avoid inversion result distortion due to weak spectral signal of water color parameters, and large amount of calculation of information extraction because of the high spectral band numbers, and also provides an effective way to solve spectral mixture model of complex water and improve the accuracy of model inversion. PMID- 26117890 TI - [Estimating Biomass Burned Areas from Multispectral Dataset Detected by Multiple Satellite]. AB - Biomass burning makes up an important part of both trace gases and particulate matter emissions, which can efficiently degrade air quality and reduce visibility, destabilize the global climate system at regional to global scales. Burned area is one of the primary parameters necessary to estimate emissions, and considered to be the largest source of error in the emission inventory. Satellite based fire observations can offer a reliable source of fire occurrence data on regional and global scales, a variety of sensors have been used to detect and map fires in two general approaches: burn scar mapping and active fire detection. However, both of the two approaches have limitations. In this article, we explore the relationship between hotspot data and burned area for the Southeastern United States, where a significant amount of biomass burnings from both prescribed and wild fire took place. MODIS (Moderate resolution imaging spectrometer) data, which has high temporal-resolution, can be used to monitor ground biomass. burning in time and provided hot spot data in this study. However, pixel size of MODIS hot spot can't stand for the real ground burned area. Through analysis of the variation of vegetation band reflectance between pre- and post-burn, we extracted the burned area from Landsat-5 TM (Thematic Mapper) images by using the differential normalized burn ratio (dNBR) which is based on TM band4 (0.84 MUm) and TM band 7(2.22 MUm) data. We combined MODIS fire hot spot data and Landsat-5 TM burned scars data to build the burned area estimation model, results showed that the linear correlation coefficient is 0.63 and the relationships vary as a function of vegetation cover. Based on the National Land Cover Database (NLCD), we built burned area estimation model over different vegetation cover, and got effective burned area per fire pixel, values for forest, grassland, shrub, cropland and wetland are 0.69, 1.27, 0.86, 0.72 and 0.94 km2 respectively. We validated the burned area estimates by using the ground survey data from National interagency Fire Center (NIFC), our results are more close to the ground survey data than burned area from Global Fire Emissions Database (GFED) and MODIS burned area product (MCD45), which omitted many small prescribed fires. We concluded that our model can provide more accurate burned area parameters for developing fire emission inventory, and be better for estimating emissions from biomass burning. PMID- 26117891 TI - [Application of Hyperspectral Imaging for Visualization of Nitrogen Content in Pepper Leaf with Different Positions]. AB - In order to estimate pepper plant growth rapidly and accurately, hyperspectral imaging technology combined with chemometrics methods were employed to realize visualization of nitrogen content (NC) distribution. First, pepper leaves were picked up with the leaf number based on different leaf positions, and hyperspectral data of these leaves were acquired. Then, SPAD and NC value of leaves were measured, respectively. After acquirement of pepper leaves' spectral information, random-frog (RF) algorithm was chosen to extract characteristic wavelengths. Finally, five characteristic wavelengths were selected respectively, and then those characteristic wavelengths and full spectra were used to establish partial least squares regression (PLSR) models, respectively. As a result, SPAD predicted model had an excellent performance of R(C) = 0.970, R(CV) = 0.965, R(P) = 0.934, meanwhile evaluation parameters of NC predicted model were R(C) = 0.857, R(CV) = 0.806, R(P) = 0.839. Lastly, according to the optimal models, SPAD and NC of each pixel in hyperspectral images of pepper leaves were calculated and their distribution was mapped. In fact, SPAD in plant can reflect the NC. In this research, the change trend of both was similar, so the conclusions of this research were proved to be corrected. The results revealed that it was feasible to apply hyperspectral imaging technology for mapping SPAD and NC in pepper leaf, which provided a theoretical foundation for monitoring plant growth and distribution of nutrients. PMID- 26117892 TI - Review of Extraordinary Optical Transmission: Theory and Application in Biochemical Analysis. AB - Extraordinary optical transmission (EOT) has attracted increasing attention from researchers around the world since its discovery in 1998. In attempt to interpret this abnormal phenomenon caused by nano-hole array structures, the majority of academia take the theory of surface plasmon resonance as the main reason, though minors resort to other theories. Nevertheless, significant amount of research has revealed the factors that are associated with EOT spectra. In particular, the association of molecules with the surface of the nano-hole array can be linearly related to the red-shifted change of EOT spectrum, lending EOT based nano-hole array a unique capability of detecting biochemical events. Such biochemical analysis is label-free, real-time, highly sensitive, promising great potentials in miniaturization of EOT-based advanced instrument. By summarizing the research progress, achievements, and trends of EOT, including its theory and application in biochemical analysis, this paper aims to provide reasonably-deep insights into this exciting area. To this end, EOT is firstly briefly introduced, followed by its physical mechanism and effects. Then recent advances in EOT-based biochemical analysis is presented, with a focus on three representative research teams. Finally, an outlook on the EOT-based biochemical analysis is given. PMID- 26117893 TI - Determination of Silicon in Gasoline by Directly Measuring under Organic Phase Using Inductively Coupled Plasma Optical Emission Spectroscopy. AB - A simple and accurate method was developed for determining silicon in gasoline using inductively coupled plasma optical emission spectroscopy (ICP-OES). For sample inroduction a Burgener nubulizer and a Cyclonic spray chamber were used. A gasoline sample was diluted with isooctane and then introduced into the cooled spray chamber of the ICP-OES. Good linearity was achieved in the silicon concentration range 0.1 - 10.0 mg x kg(-1), and the correlation coefficient was 0.999 96. The detection limit for silicon was 0.012 mg x kg(-1) and the silicon recoveries from gasoline samples were 95.8% - 98.4%, with relative standard deviations of less than 3.0% The method was proved to be simple, reliable and highly sensitive, and suitable for determining silicon in samples of motor gasoline, ethanol-gasoline and methanol-gasoline fuel mixtures those containing not more than 15% (V/V) oxygenates. PMID- 26117894 TI - Experimental Study of Coaxial Cylinder Dielectric Barrier Discharge in Ar/NH3 Mixtures under the Atmosphere-Pressure. AB - An atmosphere-pressure Dielectric Barrier Discharge in Ar/NH3 mixtures between cylinder electrodes is studied by Optical Emission Spectroscopy and the main particles of atmosphere-pressure Ar/NH3 DBD plasma are NH, N, N+, N2, Ar, H(alpha) and OH. NH is decomposition products of NH3, and NH(c 1pi) and NH(A 3pi) are two kinds of excited-state neutral particles and produced by penning ionization of Ar* and NH3. The nitrogen active atom is detected at 674.5 nm which may provide the experimental foundation for the synthesis of epsilon-Fe3N ferroparticles by the atmosphere-pressure Ar/NH3 DBD plasma. The intensities of main particles are analyzed at different NH3 flow rate and applied voltage peak peak value. The results show that the spectral line intensities of various particles increase with the rise of the applied voltage peak-peak value at the same NH3 flow rate, and first increase and then decrease with the increase of the NH3 flow rate at the same applied voltage peak-peak value. The applied voltage peak-peak value being kept constant, the spectral line intensity of nitrogen active atom first increases and then decreases with the increase of the NH3 flow rate. When NH3 flow rate is 20 mL x min(-1), the spectral line intensity of nitrogen active atom reaches a maximum at the same applied voltage peak-peak value. The spectral line intensity of nitrogen active atom decreases gradually with increasing the applied voltage peak-peak value at the same NH3 flow rate and it is mainly because of the translation of discharge mode from multi-pulse APGD to filamentary discharge in the atmosphere-pressure Ar/NH3 DBD. The microdischarge channels overlap and the microdischarges affect each other in multi-pulse APGD; hence the increasing rate of the spectral line intensity is quicker in multi-pulse APGD than in filamentary discharge with increasing the applied voltage peak-peak value. When the applied voltage peak-peak value is up from 4 600 to 6 400 V, the single-pulse and two-pulse APGD mode which are two kinds of homogeneous DBD mode are found in the atmosphere-pressure Ar/NH3 DBD and the increasing rate of the spectral line intensity is quicker in multi-pulse APGD than in filamentary discharge which is beneficial to synthesize epsilon-Fe3N ferroparticles. PMID- 26117895 TI - [A Study on Quantitative Evaluation of Damage in Conservation of Ceramics from Huaguangjiao I Shipwreck with ICP-AES]. AB - ICP-AES was used to determine the elemental composition of solutions in different conservation steps for understanding the impact of cleaning agents on ceramics from Huaguangjiao I shipwreck. The results showed that high content in solution of Al, Fe, Mg ions, which can be indexes to reflect the damage in conservation of ceramics. According to these indexes, we discovered that agents of strong cleaning ability bring more damage to ceramic samples. Meanwhile, the state of preservation of the ceramics was closely related to the damage in conservation. Ceramics in an excellent state of preservation endure less damage than that in bad state. We also found that each cleaning agent cause certain degree of damage on porcelains, even neutral reagent, like deionized water. Moreover, moderate cleaning reagent, when using a long time, bring the same degree of damage as the strong acid. Therefore, in actual protection procedure, for conservation ceramics safe and effective, damage of each cleaning agents and cumulative damage should be considered. PMID- 26117896 TI - [Determination of Acid-Insoluble Aluminum Content in Steel by Laser-Induced Breakdown Spectroscopy]. AB - Laser-induced breakdown spectroscopy (LIBS) has become a very attractive and popular chemical analysis technique in material science for its advantage of rapid analysis, non-contact measurement, micro surface analysis and online analysis. In this paper, LIBS were used to determine insoluble aluminum content by analyzing the scanning data on massive steel samples. Abnormal data were discarded by Nalimov criterion, and the remaining data was used to calculate the average and the standard deviation. The threshold to distinguish acid-insoluble aluminum and soluble aluminum was identified as the average value plus triple standard deviation. Two different mathematical models were proposed to calculate insoluble aluminum content, respectively according to the ratio of the total acid insoluble aluminium signal strength to total aluminum signal strength and acid insoluble signal number to total aluminum signal number. The total aluminum content was determined by the calibration curve. Insoluble aluminum content of certified reference materials and plate blank samples obtained by mathematical model is coincident to chemical wet method results. The result according to total acid-insoluble aluminium signal strength is much better. LIBS can be used as a rapid analysis method to characterize insoluble aluminum content in steel samples. PMID- 26117897 TI - [Quantitative Analysis of Copper Impurity in Silver Jewellery by Laser-Ablation Laser-Induced Breakdown Spectroscopy]. AB - High spectral analysis sensitivity can be achieved with orthogonal dual wavelength dual-pulse laser-ablation laser-induced breakdown spectroscopy under minimal sample ablation. Therefore, the contradiction between spatial resolution and analytical sensitivity existed in single-pulse laser-induced breakdown spectroscopy can be resolved fundamentally in this technique. In order to eliminate the influence of different experimental parameters to the signal intensities and final results of quantitative analysis, the correlation between copper atomic emission and silver atomic emission was studied experimentally in this technique for silver jewellery samples. It was demonstrated that the intensity of atomic emission of copper at 324.75 nm and that of silver at 328.07 nm was linearly correlated with high correlation coefficient. Therefore, it was possible to eliminate the influence of different experimental parameters, such as geometrical arrangement and pulse energy of the ablation laser to the signal of copper atomic emission by selecting 328.07 nm line of silver as internal standard. A quantitative analysis of copper impurity in silver jewellery can be realized by using orthogonal dual-wavelength dual-pulse laser-ablation laser induced breakdown spectroscopy. A calibration curve of copper was successfully built based on internal standard method while selecting 328.07 nm line of silver as internal standard. The limit of detection of copper in silver matrix was determined to be 44 ppm in this technique when the crater's diameter was about 17 MUm under current experimental condition. PMID- 26117898 TI - [Experimental Conditions of Laser Induced Breakdown Spectroscopy of Metal Elements in Cement]. AB - Laser induced breakdown spectroscopy (LIBS) is a widely used material element detection technology. Because of its detection result is affected by many factors, and therefore, analysing and comparising the different experimental conditions have important significance for LIBS. Experimental sample produced by Beichuan County, Sichuan Province, China, which is ordinary Portland cement P. O42.5, using eight-channel fiber optic spectrometer AvaSpec-2048-USB2-RM, delay trigger DG645 for LIBS testing. Several metallic elements as Mg, Al, Na, K, which affect cement's technical indicators were analyzed. Mainly compares the effect of laser frequency, the same point measurement times on different metal element spectral signal intensity, the optimum experimental parameters under the condition of this experiment: 10 Hz was the best laser frequency. When laser frequency is 10 Hz, the spectrum intensity of elements Mg, Al, Na, K were increased by 67.66%, 47.88%, 84.59%, 43.36% than 8 Hz. Because the tablet samples in place, the surface will have a small amount of oxidation and deliquescence, in order to measure 10 times for an average income results were recorded under the condition, with third, four records of results for the best. PMID- 26117899 TI - [The Emission Spectroscopy of Nitrogen Discharge under Low Voltage at Room Temperature]. AB - A set of direct current (DC) discharge device of N2 plasma was developed, carbon nanotubes (CNT) modified ITO electrode was used as anode, aluminum plate as cathode, with -80 MUm separation between them. Nitrogen emission spectra was observed at room temperature and low DC voltage (less than 150 V), and the emission spectrometry was used to diagnose the active species of the process of nitrogen discharge. Under DC discharge, the strongest energy band N2 (C3pi(u)), the weak Gaydon's Green system N2 (H3 -Phi(u)-G3 Delta(g)) and the emission line of nitrogen atoms (4 p-4 p0) at 820 nm were observed. Found that metastable state of nitrogen molecules were the main factors leading to a series of excited state nitrogen atoms and nitrogen ionization. Compared the emission spectra under DC with that under alternating current (AC) (1.1 kV), and it can be seen that under DC the spectra band of nitrogen atoms can be obviously observed, and there was a molecular band in the range of 500 - 800 nm. The effect of oxygen and hydrogen on the emission spectra of nitrogen was investigated. The results showed that the oxygen inhibited the luminescence intensity of nitrogen, but the shape of spectra unchanged. All of the second positive system, Gaydon's Green system and atomic lines of nitrogen can be observed. The second positive system and Gaydon's Green system of nitrogen will be greatly affected when the volume ratio of nitrogen and hydrogen greatly affected is 1 : 1, which was due to the hydrogen. The hydrogen can depresse nitrogen plasma activation, and make the Gaydon's Green System disappeared. CNT modified ITO electrode can reduce the breakdown voltage, and the optical signal generated by the weakly ionized gas can be observed by the photo multiplier tube at low voltage of 10 V. PMID- 26117900 TI - [In Situ Analysis of Element Geochemistry in Submarine Basalt in Hydrothermal Areas from Ultraslow Spreading Southwest Indian Ridge]. AB - In this study, we analyze element geochemistry of submarine basalt in situ, which is sampled in hydrothermal areas from ultraslow spreading Southwest Indian Ridge, including the fresh basalt rocks (B19-9, B15-13) and altered basalt (B5-2). And we can confirm that altered mineral in B5-2 is celadonite by microscope and Raman Spectrum. Furthermore, amygdaloidal celadonites are analyzed by electron microprobe (EPMA) and EDS-line scanning. The results show that K-contents decrease and Na-contents increase from the core to the edge in these altered minerals, indicating the transition from celadonite to saponite. Celadonite is an altered minerals, forming in low temperature (< 50 degrees C) and oxidizing condition, while saponite form in low water/rock and more reducing condition. As a result, the transition from celadonite to saponite suggests environment change from oxidizing to reducing condition. Using the result of EPMA as internal standard, we can analyze rare earth elements (REE) in altered mineral in situ. Most of result show positive Eu anomaly (Delta(Eu)), indicating hydrothermal fluid transform from oxidizing to reducing, and reducing fluid rework on the early altered minerals. Comparison with REE in matrix feldspar both in altered and unaltered zoning, we find that reducing fluid can leach REE from the matrix feldspar, leading to lower total REE concentrations and positive Eu anomaly. So leaching process play an important role in hydrothermal system. PMID- 26117901 TI - [Mineral Spectrum Change Analysis under the Conditions of Different Particle Size]. AB - Mineral particle size is an important factor affecting mineral spectrum characteristics, so to explore the changes of the mineral spectrum curves under different particle sizes and the spectrum difference of different minerals under the same particle size are the keys of hyperspectral remote sensing information mineral identification and the theoretical basis of research on spectral differences of different particle -sizes. Six kinds of collected minerals were observed by spectrometer to get the reflectivity spectrum curve and first order differential spectral curve under different particle sizes, and the spectral characteristics of various kinds of minerals under different particle sizes were analyzed. At the same time, spectrum difference of different mineral under the same particle size was compared to explore possible wavelengths of hyperspectral remote sensing mineral identify. Results show that the spectrum curves of various minerals have a larger difference with the change of the particle size, but change law is not the same. The whole spectrum curve of hypersthene will be decreased with the increase of particle size, and the spectrum curve at a specific wavelength range of antigorite, hematite, kaolinite and chlorite will be decreased with the increase of particle size, and there is no direct correlation between the spectrum of olivine and the particle size. Under the same size, different mineral spectral reflectance change a lot in most band range and it provides the possibility for high precision identification of mineral. Antigorite, kaolinite and chlorite all have more absorption peaks of narrow width and smaller intensity than the other minerals. Spectrum curves of hematite, olivine and hypersthene are relatively smooth, and the number of the absorption and reflection peaks is relatively small. This study aims at providing basic data and theoretical support for mineral spectral library construction and mineral hyperspectral identification technology. PMID- 26117902 TI - Evaluation of Field Portable X-Ray Fluorescence Performance for the Analysis of Ni in Soil. AB - As a rapid, in-situ analysis method, Field portable X-ray fluorescence spectrometry (FP-XRF) can be widely applied in soil heavy metals analysis field. Whereas, some factors may affect FP-XRF performance and restrict the application. Studies have proved that FP-XRF has poorer performance when the concentration of target element is low, and soil moisture and particle size will affect FP-XRF performance. But few studies have been conducted in depth. This study took an example of Ni, demonstrated the relationship between Ni concentration and FP-XRF performance on accuracy and precision, and gave a critical value. Effects of soil moisture and particle size on accuracy and precision also had been compared. Results show that, FP-XRF performance is related to Ni concentration and the critical value is 400 mg x kg(-1). Relative standard deviation (RSD) and relative uncertainty decrease while the Ni concentration is below 400 mg x kg(-1), hence FP-XRF performance improves with increasing Ni concentration in this range; RSD and relative uncertainty change little while the Ni concentration is above 400 mg x kg(-1), hence FP-XRF performance does not have correlation with Ni concentration any more. For in-situ analysis, the relative uncertainty contributed by soil moisture is 3.77%, and the relative certainty contributed by particle size is 0.56%. Effect of soil moisture is evidently more serious than particle size both on accuracy and precision. PMID- 26117903 TI - [Comporison Sduty of Microstructure by Metallographicalk on the Polarized Light and Texture by XRD of CC 5083 and CC 5182 Aluminium Alloy after Cold Rolling and Recrystallization]. AB - At present the study of relation between microstructure, texture and performance of CC 5083 aluminium alloy after cold tolling and recrystallization processes is still finitude. So that the use of the CC 5083 aluminium alloy be influenced. Be cased into electrical furnace, hot up with unlimited speed followed the furnace hot up to different temperature and annealed 2h respectively, and be cased into salt-beth furnace, hot up quickly to different temperature and annealed 30 min respectively for CC 5083 and CC 5182 aluminum alloy after cold roling with 91.5% reduction. The microstructure be watched use metallographic microscope, the texture be inspected by XRD. The start temperature of recrystallization and grain grow up temperature within annealing in the electric furnace of CC 5083 aluminum alloy board is 343 degrees C, and the shap of grain after grow up with long strip (the innovation point ); The start temperature of recrystallization within annealling in the salt bath furnace of CC 5083 is 343 degrees C. The start temperature and end temperature of recrystallization within annealling of CC 5083 and CC 5182 aluminum alloy is 371 degrees C. The grain grow up outstanding of cold rooled CC 5152 aluminum alloy after annealed with 454 degrees C in the electric furnace and salt bath furnace. The start temperature of grain grow up of CC 5083 alluminurn alloy annealed in the electric furnace and salt bath furnace respectively is higher than the start temperature of grain grow up of CC 5182 alluminum alloy annealed in the electric furnace and salt bath furnace respectively. The strat temperature of recrystallization grain grow up is higher than which annealled with other three manner annealing process. The recrystallization temperature of CC 5182 annealed in the salt bath furnace is higher than which annealed in the electric furnace. The recrystallization temperature of the surface layer of CC 5083 and CC 5182 aluminum alloy is higher than the inner layer (the innovation point). There is a difference each other of the structure and the texture of the four manner annealing aluminum alloy (the innovation point). There is a little difference at the recrystallization processes course reflectived by the observe results of structure transform and by the examination results of texture transmission. PMID- 26117904 TI - [The Prediction Algorithm of the Optimal X-Ray Tube Voltage in Variable Energy Imaging]. AB - X-ray variable energy imaging can obtain the sectional information of complicated structural component successively, and get the whole information by multi spectrum fusion. Now the energy parameters of X ray imaging mainly depend on man made setting with the certain step voltage. However this modulation doesn't match to the attenuation thickness variation of the object. Therefore, this paper proposes an optimum tube voltage prediction algorithm based on variable energy imaging. It extracts the effective thickness (ET) and near the effective thickness (NET) in the image sequences which are acquired by pre-scanning the detected object. Then it establishes a physical model between image gray, tube voltage and X ray spectrum. And the model of voltage and gray difference between the ET (high quality area) and NET (prediction area) is also established. On the basis of these two models, the optimal imaging energy forecasting model of NET is modeled. Then, solve the model and get the optimal voltage for NET. At last, by the experiment of the steel blocks with different thickness, testify this prediction algorithm. The results compared with the actual values showed that the prediction algorithm can accurately predict 3 or 4 mm at low voltage and 7 or 10 mm at high voltage. Prediction accuracy is over 95%. PMID- 26117905 TI - [Object Separation from Medical X-Ray Images Based on ICA]. AB - X-ray medical image can examine diseased tissue of patients and has important reference value for medical diagnosis. With the problems that traditional X-ray images have noise, poor level sense and blocked aliasing organs, this paper proposes a method for the introduction of multi-spectrum X-ray imaging and independent component analysis (ICA) algorithm to separate the target object. Firstly image de-noising preprocessing ensures the accuracy of target extraction based on independent component analysis and sparse code shrinkage. Then according to the main proportion of organ in the images, aliasing thickness matrix of each pixel was isolated. Finally independent component analysis obtains convergence matrix to reconstruct the target object with blind separation theory. In the ICA algorithm, it found that when the number is more than 40, the target objects separate successfully with the aid of subjective evaluation standard. And when the amplitudes of the scale are in the [25, 45] interval, the target images have high contrast and less distortion. The three-dimensional figure of Peak signal to noise ratio (PSNR) shows that the different convergence times and amplitudes have a greater influence on image quality. The contrast and edge information of experimental images achieve better effects with the convergence times 85 and amplitudes 35 in the ICA algorithm. PMID- 26117906 TI - [Contrast of Z-Pinch X-Ray Yield Measure Technique]. AB - Resistive bolometer and scintillant detection system are two mainly Z-pinch X-ray yield measure techniques which are based on different diagnostic principles. Contrasting the results from two methods can help with increasing precision of X ray yield measurement. Experiments with different load material and shape were carried out on the "QiangGuang-I" facility. For Al wire arrays, X-ray yields measured by the two techniques were largely consistent. However, for insulating coating W wire arrays, X-ray yields taken from bolometer changed with load parameters while data from scintillant detection system hardly changed. Simulation and analysis draw conclusions as follows: (1) Scintillant detection system is much more sensitive to X-ray photons with low energy and its spectral response is wider than the resistive bolometer. Thus, results from the former method are always larger than the latter. (2) The responses of the two systems are both flat to Al plasma radiation. Thus, their results are consistent for Al wire array loads. (3) Radiation form planar W wire arrays is mainly composed of sub-keV soft X-ray. X-ray yields measured by the bolometer is supposed to be accurate because of the nickel foil can absorb almost all the soft X-ray. (4) By contrast, using planar W wire arrays, data from scintillant detection system hardly change with load parameters. A possible explanation is that while the distance between wires increases, plasma temperature at stagnation reduces and spectra moves toward the soft X-ray region. Scintillator is much more sensitive to the soft X-ray below 200 eV. Thus, although the total X-ray yield reduces with large diameter load, signal from the scintillant detection system is almost the same. (5) Both Techniques affected by electron beams produced by the loads. PMID- 26117907 TI - [Searching for Rare Celestial Objects Automatically from Stellar Spectra of the Sloan Digital Sky Survey Data Release Eight]. AB - There are many valuable rare and unusual objects in spectra dataset of Sloan Digital Sky Survey (SDSS) Data Release eight (DR8), such as special white dwarfs (DZ, DQ, DC), carbon stars, white dwarf main-sequence binaries (WDMS), cataclysmic variable (CV) stars and so on, so it is extremely significant to search for rare and unusual celestial objects from massive spectra dataset. A novel algorithm based on Kernel dense estimation and K-nearest neighborhoods (KNN) has been presented, and applied to search for rare and unusual celestial objects from 546 383 stellar spectra of SDSS DR8. Their densities are estimated using Gaussian kernel density estimation, the top 5 000 spectra in descend order by their densities are selected as rare objects, and the top 300 000 spectra in ascend order by their densities are selected as normal objects. Then, KNN were used to classify the rest objects, and simultaneously K nearest neighbors of the 5 000 rare spectra are also selected as rare objects. As a result, there are totally 21 193 spectra selected as initial rare spectra, which include error spectra caused by deletion, redden, bad calibration, spectra consisting of different physically irrelevant components, planetary nebulas, QSOs, special white dwarfs (DZ, DQ, DC), carbon stars, white dwarf main-sequence binaries (WDMS), cataclysmic variable (CV) stars and so on. By cross identification with SIMBAD, NED, ADS and major literature, it is found that three DZ white dwarfs, one WDMS, two CVs with company of G-type star, three CVs candidates, six DC white dwarfs, one DC white dwarf candidate and one BL Lacertae (BL lac) candidate are our new findings. We also have found one special DA white dwarf with emission lines of Ca II triple and Mg I, and one unknown object whose spectrum looks like a late M star with emission lines and its image looks like a galaxy or nebula. PMID- 26117908 TI - [Optical Design of Miniature Infrared Gratings Spectrometer Based on Planar Waveguide]. AB - In order to miniaturize an infrared spectrometer, we analyze the current optical design of miniature spectrometers and propose a method for designing a miniature infrared gratings spectrometer based on planar waveguide. Common miniature spectrometer uses miniature optical elements to reduce the size of system, which also shrinks the effective aperture. So the performance of spectrometer has dropped. Miniaturization principle of planar waveguide spectrometer is different from the principle of common miniature spectrometer. In planar waveguide spectrometer, the propagation of light is limited in a thin planar waveguide, which looks like the whole optical system is squashed flat. In the direction parallel to the planar waveguide, the light through the slit is collimated, dispersed and focused. And a spectral image is formed in the detector plane. This propagation of light is similar to the light in common miniature spectrometer. In the direction perpendicular to the planar waveguide, light is multiple reflected by the upper and lower surfaces of the planar waveguide and propagates in the waveguide. So the size of corresponding optical element could be very small in the vertical direction, which can reduce the size of the optical system. And the performance of the spectrometer is still good. The design method of the planar waveguide spectrometer can be separated into two parts, Czerny-Turner structure design and planar waveguide structure design. First, by using aberration theory an aberration-corrected (spherical aberration, coma, focal curve) Czerny-Turner structure is obtained. The operation wavelength range and spectral resolution are also fixed. Then, by using geometrical optics theory a planar waveguide structure is designed for reducing the system size and correcting the astigmatism. The planar waveguide structure includes a planar waveguide and two cylindrical lenses. Finally, they are modeled together in optical design software and are optimized as a whole. An infrared planar waveguide spectrometer is designed using this method. The operation wavelength range is 8 - 12 MUm, the numerical aperture is 0.22, and the linear array detector contains 64 elements. By using Zemax software, the design is optimized and analyzed. The results indicate that the size of the optical system is 130 mm x 125 mm x 20 mm and the spectral resolution of spectrometer is 80 nm, which satisfy the requirements of design index. Thus it is this method that can be used for designing a miniature spectrometer without movable parts and sizes in the range of several cubic centimeters. PMID- 26117909 TI - [Portable High-Precision System for CH4 Concentration Detection in Mines based on the Laser Mode-Hopping]. AB - In order to detect rapid, portable concentration of methane in the mine, meanwhile, the system included a high sensitivity and a long working period, designed differential optical absorption spectroscopy method based on mode hopping of semiconductor laser, and established wireless detection system for concentration of methane in the mine. Output wavelengths of the semiconductor laser occurred mode-hopping by modulation current of the system, so it obtained the two wavelengths close to the laser, and one is on the characteristic absorption peak of methane, while the other is not substantially absorbed. When the two beams of light were illuminated test chamber, methane concentration of the gas chamber was solved by Bill Lambert law with the difference of the light intensity between the two beams. Light source used DFB single mode semiconductor laser from Japan Anritsu company. Experimental results show that, when the modulation current increased from 20.0 to 60.0 mA, output wavelength occurred mode-hopping when the modulation current reached 48.3 mA, and output wavelength changed to 1 651.020 nm from 1 650.888 nm. By HITRAN spectrum database, it showed that the position of the wavelength 1 650.888 nm can be used for characteristic absorption peaks, while the wavelength 1 651.020 nm was suitable for reference wavelength. On this basis, the standard concentrations of methane gas was tested in the sealed container, test data of the system was compared to the H-BD5GD410 HC portable methane detector. Test results of the system and the H-BD5GD410-HC portable methane detector were similar, but with the constant concentration increased, the detection error of the system is relatively stable, slightly better than the portable methane detector. Detection error of system were less than 0.050%, under the conditions that there were without the use of expensive phase lock or inspection phase circuit, to achieve the accuracy of better than 0.10% concentration of methane detected in the mine. PMID- 26117910 TI - [An Effective Wavelength Detection Method Based on Echelle Spectra Reduction]. AB - Echelle spectrometer with high dispersion, high resolution, wide spectral coverage, full spectrum transient direct-reading and many other advantages, is one of the representative of the advanced spectrometer. In the commercialization trend of echelle spectrometer, the method of two-dimension spectra image processing is becoming more and more important. Currently, centroid extraction algorithm often be used first to detect the centroid position of effective facula and then combined with echelle spectrum reduction method to detect the effective wavelength, but this method is more difficult to achieve the desired requirements. To improve the speed, accuracy and the ability of imaging error correction during detecting the effective wavelength, an effective wavelength detection method based on spectra reduction is coming up. At the beginning, the two-dimension spectra will be converted to a one-dimension image using echelle spectra reduction method instead of finding centroid of effective facula. And then by setting appropriate threshold the one-dimension image is easy to be dealing with than the two-dimension spectra image and all of the pixel points stand for effective wavelength can be detected at one time. Based on this new idea, the speed and accuracy of image processing have been improved, at the same time a range of imaging errors can be compensated. Using the echelle spectrograph make a test applying this algorithm for data processing to check whether this method is fit for the spectra image processing or not. Choosing a standard mercury lamp as a light source during the test because the standard mercury lamp have a number of known characteristic lines which can be used to examine the accuracy of wavelength detection. According to experimental result, this method not only increase operation speed but improve accuracy of wavelength detection, also the imaging error lower than 0.05 mm (two pixel) can be corrected, and the wavelength accuracy would up to 0.02 nm which can satisfy the requirements of echelle spectrograph for image processing. PMID- 26117911 TI - [In-Flight Radiometric Calibration for ZY-3 Satellite Multispectral Sensor by Modified Reflectance-Based Method]. AB - Through integrating multi-spectral sensor characteristics of ZY-3 satellite, a modified reflectance-based method is proposed and used to achieve ZY-3 satellite multispectral sensor in-flight radiometric calibration. This method chooses level 1A image as data source and establishes geometric model to get an accurate observation geometric parameters at calibration site according to the information provided in image auxiliary documentation, which can reduce the influences on the calibration accuracy from image resampling and observation geometry errors. We use two-point and multi-points methods to calculate the absolute radiometric calibration coefficients of ZY-3 satellite multispectral sensor based on the large campaign at Dongying city, Shan Dong province. Compared with ZY-3 official calibration coefficients, multi-points method has higher accuracy than two-point method. Through analyzing the dispersion between each calibration point and the fitting line, we find that the residual error of water calibration site is larger than others, which of green band is approximately 67.39%. Treating water calibration site as an error, we filter it out using 95.4% confidence level as standard and recalculate the calibration coefficients with multi-points method. The final calibration coefficients show that the relative differences of the first three bands are less than 2% and the last band is less than 5%, which manifests that the proposed radiometric calibration method can obtain accurate and reliable calibration coefficients and is useful for other similar satellites in future. PMID- 26117912 TI - [PROINFLAMMATORY CYTOKINES IN COMBINATION OF CORONARY HEART DISEASE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE]. AB - Chronic obstructive pulmonary disease and coronary heart disease frequently occur in combination. Systemic inflammation concomitant with protracted COPD is the pathogenetic mechanism of CHD. High concentration of the markers of systemic inflammation is associated with deterioration of atherosclerosis, its complications, and CHD progression. PMID- 26117913 TI - [THE INFLUENCE OF CHRONIC HEPATITIS C ON ATHEROSCLEROSIS PROGRESSION]. AB - We analysed the data of domestic andforeign authors on the relationship between hepatitis C and atherosclerosis. The possible role of the former condition as a risk factor of atherosclerosis even in very young patients is due to the properties of hepatitis C virus, mediators of inflammation, and metabolic disorders. PMID- 26117914 TI - [THE FUNCTIONAL DIFFERENCE BETWEEN VISCERAL FATTY CELLS AND SUBCUTANEOUS ADIPOYTES]. AB - Visceral fatty cells evolved in the course of phylogenesis millions of years earlier than subcutaneous adipocytes. The pool of visceral fatty cells have realized biological functions of trophology and homeostasis since early phylogenesis whereas subcutaneous adipocytes have performed the phylogenetically younger locomotary function. The former cells, unlike the latter ones have no insulin receptors. Both realize biological reactions of exotrophy, storage, and endotrophy. The most usual cause of obesity is the compromised reaction of fatty acid (FA) deposition in the form of triglycerides (TG). It accounts for the disordered function of visceral fatty cells (metabolic syndrome) and insulin dependent adipocytes (obesity) frequently leading to metabolic "pandemics". Fatty cells absorb FA in the form of non-polar TG, store them in lipid "droplets" and release FA into the intercellular medium in the form of polar non-esterified FA. Visceral fatty cells have formed in paracrine enterocyte communities where the TG transporting microsomal protein gave rise to early chylomicrons. Visceral fatty cells and subcutaneous adipocytes are phylogenetically, functionally and pathogenetically different entities that should be regarded separately. Similar to all cells of the loose connective tissue, they secreted many humoral mediators of paracrine regulation when other means of regulation were inexistent. Leptin and adiponectin are specific mediators of visceral fatty cells and subcutaneous adipocytes respectively. PMID- 26117915 TI - [ANALYSIS OF F.M.DOSTOEVSKII'S HEALTH, PERSONALITY, AND WORKS FROM THE GENETIC STANDPOINT. PART 1]. AB - The data on Dostoevsky's epilepsy are ambiguous and often contradictory. It prompted consideration of certain genetic aspects of the writer's pedigree for the clarification of this issue. The phenomenon of Dostoevsky's genius was for the first time contemplated from the standpoint of the contribution of genetic factors to his creative work. It was shown that Dostoevsky's ancestry can not be a source of hereditary predisposition to epilepsy. The available data question the genuine nature of his disease. Characteristic of Dostoevsky's ancestry is the wide occurrence of "creativeness" genes. Their cumulation together with a number of other factors verified in the writer can account for the phenomenon of his genius. PMID- 26117916 TI - [GENDER-SPECIFIC DIFFERENCES OF ENDOTHELIAL NITRIC OXIDE SYNTHASE E298D POLYMORPHISM AND THE RISK OF STROKE]. AB - Genetic factors can account for the differences in the frequency of stroke between men and women. Despite the scarcity of special clinico-genetic studies of stroke frequency in the two genders, analysis of association between DNA polymorphism and risk of stroke may reveal the influence of genetic factors on the sex-related predisposition to cerebrovascular diseases. The present work was aimed to study the relationship between frequent polymorphisms -786T > C of endothelial nitric oxide synthase (NOS3) gene E298D and the risk of stroke in men and women. 904 DNA samples were obtained from unrelated Russian residents of Central Russia including 480 stroke patients and 424 healthy volunteers. Genotyping was performed by PCR in real time with allele discrimination using TaqMan probes. The homoygous genotype of NOS3 gene E298D was found to be associated with an increased risk of stroke in men (OR 2.60; 95% CI 1.28-5.29, p = 0.01). Neither men nor women showed association of polymorphism -786T > C with the predisposition to stroke. The E298D genotype in men was associated with the enhanced risk of both ischemic (OR 2.38; 95% CI 1.14-4.96, p = 0.02) and hemorrhagic (OR 5,58; 95% CI 1.95-16.05, p = 0.003) stroke. Thus, NOS3 gene E298D polymorphism is a reliable predictor of predisposition to various pathogenetic variants of stroke only in men. PMID- 26117917 TI - [CLINICAL AND PHARMACOLOGICAL FACTORS INFLUENCING RESISTANCE TO CLOPIDOGREL IN PATIENTS WITH CARDIOVASCULAR DISEASES]. AB - We analysed clinical and pharmacological factors influencing resistance to clopidogrel in 250 patients with cardiovascular diseases during 18 months. It was shown that the risk ofresistance depends on the form of coronary heart disease, carbohydrate metabolism, the AA genotype of CYP2C19*2 and TBS1 genes. The cardiovascular events significantly morefrequently occurred during 12 and 18 months in resistant diabetics and in the patients with an allele lacking the *2/*3 CYP2C9 gene function and AT/TT polymorphism of the thromboxane synthase gene TBS1. PMID- 26117918 TI - [BIOMARKER CONTENT AND ROLE IN HOSPITAL PERIOD OF ACUTE CORONARY SYNDROME]. AB - The study involved 172 patients with coronary heart diseases (CHD) of whom 146 presented with acute coronary syndrome (ACS) including 88 with myocardial infarction (MI), 58 with unstable angina (UA) and 26 with FC II-III stable angina (SA). Interleukin (IL-6, 10), natriuretic peptide (NT-proBNP) levels in blood and 6-hydroxymelatonin level in urine were determined on days 1-3 after hospitalization. These daytime values in ACS were higher than in SA whereas the melatonin level at night was higher in SA than in ACS. Patients with ACS in the absence of ST elevation had higher IL and melatonin (night) levels but lower NT proBNP and melatonin daytime levels than patients with ACS and elevated ST segment. IL-6 , 10 and melatonin (night and daytime) levels in MI were lower and NT-proBNP level higher than in UA. IL-6, 10 and melatonin daytime levels increased in uncomplicated ACS while melatonin (night) and NT-proBNP levels were higher in complicated ACS. PMID- 26117919 TI - [THE RISK OF ACUTE RENAL LESIONS AND ITS PROGNOSTIC SIGNIFICANCE IN PATIENTS WITH CHRONIC RENAL DISEASE UNDERGOING CARDIAC SURGICAL INTERVENTION]. AB - AIM: to determine the frequency and risk factors of acute renal lesions (ARL) and their prognostic significance in patients with chronic renal disease (CRD) undergoing surgical intervention. MATERIALS AND METHODS: The study included 1122 patients (586 men and 536 women) aged 32-68 (mean 62.3 +/- 5.2) years who underwent correction of valvular defects, aortocoronary bypass surgery or their combination). Initial glomerular filtration rate was higher than 90 ml/min/l.73 m2 in 656 patients (group 1) and 89-60 ml/min/l/73 m2 in 470 ones (group 2). ARL were diagnosed based on the serum creatinine level using RIFLE criteria. RESULTS: In the early postoperative period, ARL were diagnosed in 23.9% of the patients in group I and 38.7% of those in group 2 (p < 0.001). Intra-hospital lethality in group 1 was 4.9% (14.1% in patients with ARL) and 12.1% in group 2 (18.1% iin patients with ARL). In group 2, 47.9% of the patients with ARL experienced regress of renal dysfunction during 12 months compared with 56.9% ones without ARL. The progress of CRD was documented in 11% of group 2 patients with ARL and in (4.5% without AR (p = 0.013). 5.7% of the patients in group 1 developed CRD after ARL. 4.9% of the patients in group 2 needed programmed hemodialysis. CONCLUSION: The development of ARL in patients with CRD is associated with unfvouravle cardiovascular prognosis following cardiosurgery. PMID- 26117920 TI - [THE ROLE OF BIOLOGICAL MEMBRANES IN DIFFERENTIAL DIAGNOSTICS OF SALMONELLA AND ACUTE ALCOHOL GASTROENTERITIS]. AB - We evaluated the influence of Salmonella infection and alcohol on biological membranes from the content of serum phospholipid fraction known to be a component ofenterocyte membranes. Any change of membrane phospholipid content leads to a change of their blood level. The study included 50 patients with acute alcohol gastroenteritis, 50 ones with salmonella gastroenteritis, and 50 healthy subjects. Both salmonellosis and alcohol caused differently directed changes in biological membranes. The mechanism of diarrhea in patients with salmonella and acute alcohol gastroenteritis is different. Diarrhea associated with alcohol gastroenteritis is due to enhanced viscosity of biomembranes that decreases in salmonella gastroenteritis. It suggests different approaches to the treatment of these conditions. The membrane destruction coefficient below 2 is an additional proof of alcoholic etiology of gastroenteritis whereas its value above 3 confirms the involvement of salmonellosis in pathogenesis of gastroenteritis. PMID- 26117921 TI - [ACUTE PANCREATITIS OF PREGNANCY]. AB - The study included 78 pregnant women with acute pancreatiis. Group 1 contained 43 4-37 weeks pregnant women and group 2 35 non-pregnant women. Control group was comprised of 30 women with physiological pregnancy. Comparative analysis of peculiarities of the clinical course of acute pancreatitis showed its similar manifestations in all three groups. However pregnancy itself variability of pancreatitis symptoms and their similarity to those of other acute surgical and obstetric pathologies, high (25.6) percent ofpainlessforms, late detection and inadequate treatment pose difficultiesfor diagnostics and delay the onset of pathogenetic therapy. The study of endogenous intoxication markers (leukocytic index, medium molecular weight molecules, circulating immune complexes, total endotoxins) revealed endotoxicosis in the pregnant women with acute pancreatitis that has negative effect on the fetoplacental complex and the development of pregnancy; moreover pancreatitis increases the risk of premature delivery up to 79.21%. The results of the study dictate the necessity of the searchfor new safe treatment and rehabilitation modalities for ptregnant women with acute pancreatitis. PMID- 26117922 TI - [THE INFLUENCE OF CYTOFLAVIN AND CARDIOXIPIN ON THE PARAMETERS OF 24-HOUR ARTERIAL PRESSURE MONITORING IN PATIENTS WITH CHRONIC CEREBRAL CIRCULATION INSUFFICIENCY, ARTERIAL HYPERTENSION AND HYPERCHOLESTEROLEMIA]. AB - This comparative study of the influence of cytoflavin and cardioxipin on the parameters of 24-hour arterial pressure monitoring in 56 patients with chronic cerebral circulation insufficiency, arterial hypertension and hypercholesterolemia included 32 women and 24 men aged 42-72 years divided into 3 groups matchedfor the stage of diseases, age, sex, severity of AH, total cholesterol level, and antihypertensive therapy. Patients of group 1 were treated without cytoflavin and cardioxipin. Those in group 2 received daily i/v droplet infusion of 10 mg/kg cardioxipin (20-30 droplets/min). Patients of group 3 were given daily i/v droplet infusion of 10 ml cytoflavin in 200 ml 0.9% sodium chloride solution for 10 days. 24-hour arterial pressure monitoring was used to estimate the influence of the two drugs on systolic and diastolic pressure, its daily rhythm, AP variability and frequency of elevation. The study showed that both therapeutic modalities improved daily AP rhythm as manifested in a significant increase of the number of patients with the dipper rhythm and a decrease in the number of systolic/diastolic non-dipper patients. Moreover cytoflavin significantly decreased the number of systolic over-dippers compared with control group. PMID- 26117923 TI - [OPTIMIZATION OF SURGICAL STRATEGY FOR THE TREATMENT OF THYROID NODULES]. AB - This retrospective analysis of the results of surgical treatment involved 1006 patients with thyroid nodules operated at P V Mandryka Medical Educational and Scientific Centre in 1990-2007. Organ-preserving surgery was necessary to minimize the frequency ofpostoperative complications and maintain the hormone producing thyroid function. The results of analysis of morphological structure of both nodular and surrounding healthy tissues were used to plan optimal extirpation of the thyroid nodule from the surrounding tissue. Circulatory disturbances with the appearance of fibrotic changes occurred in 69.7% of the cases; thyroiditis developed in 38.8% of the patients. Analysis of repeated operations showed that the risk of relapse depends on etiology and morphological structure ofthe nodule rather than the extent of surgical intervention. Organ preserving surgery and consideration of endocrinologicalfactors ensured successful treatment of 89.3% of the patients. PMID- 26117924 TI - [THE USE OF THE METHOD FOR DETERMINING THE "ORTHOPEDIC INDEX" IN THE TREATMENT OF PATIENTS WITH FEMORAL NECK FRACTURE]. AB - The choice of surgical strategy for the treatment of femoral neck fracture is a serious challenge to modern traumatology and orthopedics. Group I of this study was comprised of patients in whom orthopedic age was determined by our original method including assessment of the quality of life based on the SF-36 questionnaire. The somatic state of the patients was evaluated from the Charlson index and bone quality in the surgical area by densitometry. Patients of the control group were treated by the standard methods adopted in this country and abroad. It was shown that the difference between orthopedic and calendar ages results in the increase of the frequency of complications. The clinical and statistical results of the study indicate that the new method permits to reduce the number of revision interventions, decrease postoperative lethality, and improve the patients' quality of life. PMID- 26117925 TI - [Peripheral ulcerative keratitis]. AB - Ulcerative keratitis is frequently associated with collagen vascular diseases and presents a predilection for peripheral corneal localization, due to the distinct morphologic and immunologic features of the limbal conjunctiva, which provides access for the circulating immune complexes to the peripheral cornea via the capillary network. Deposition of immune complexes in the terminal ends of limbal vessels initiates an immune-mediated vasculitis process, with inflammatory cells and mediators involvement by alteration of the vascular permeability. Peripheral ulcerative keratitis generally correlates with exacerbations of the background autoimmune systemic disease. Associated sceritis, specially the necrotizing form, is usually observed in severe cases, which may evolve in corneal perforation and loss of vision. Although the first-line of treatment in acute phases is represented by systemic administration of corticosteroids, immunosuppressive and cytotoxic agents are necessary for the treatment of peripheral ulcerative keratitis associated with systemic diseases. PMID- 26117926 TI - [Proliferative diabetic retinopathy -- therapeutic approach (clinical case)]. AB - We present the case of a 54 year old pacient diagnosed with neglected insulin dependent diabetes and proliferative diabetic retinopathy. Surgery was recommended and we practiced posterior vitrectomy, endolaser and heavy silicone oil endotamponade. Post-operative evolution was favorable. PMID- 26117927 TI - [Rhegmatogenous retinal detachment in a patient with previous penetrating keratoplasty (clinical case)]. AB - We present the case of a 54 year old patient diagnosed with rhegmatogenous retinal detachment and perforating keratoplasty. Surgery is recommended and we performed posterior vitrectomy, endolaser, and internal heavy oil tamponade. The post-operative course was favorable. PMID- 26117928 TI - [Ocular toxocariasis--case report]. AB - Ocular Toxocariasis is a parasitosis caused by Toxocara catis/canis larvae localized in the eye. The most frequent clinical manifestations are the central retinal granuloma, peripheral retinal granuloma and chronic endophthalmitis. Secondary complications due to the presence of parasite in the posterior segment of the eye may have significant consequences on visual function. We present the case of a 23 years old patient, admitted for progressive decrease of the right eye BCVA during the last 6 months. After performing clinical examination and serological tests we established the diagnosis of ocular Toxocariasis. The patient presented a particular form of the disease consisting in the presence of both a central retinal granuloma and a peripheral one. We performed 23G pars plana vitrectomy and membrane peeling. VA improved as soon as the first month after surgery. PMID- 26117929 TI - [Treatment for penetrating wound caused by metallic intraocular foreign body]. AB - INTRODUCTION: Penetrating wounds with intraocular foreign body are ophthalmologic emergencies due to their severity and complexity and may require multiple surgeries for final resolution. CASE REPORT: 30-years-old patient with penetrating wound and metallic intraocular foreign body in the posterior vitreous requires successive operations for IOFB extraction, lensectomy, posterior vitrectomy for rhegmatogenous retinal detachment and then silicone oil extraction with final visual acuity 0, 4 PH. PMID- 26117930 TI - [Changes in intraocular pressure depending on posture]. AB - Glaucoma is an important eye disease that, left untreated, causes irreversible blindness by affecting optic nerve threads. Decreasing intraocular pressure and maintaining it at a low level throughout the day is one of the objectives of antiglaucoma therapy. METHODS: This is a prospective study conducted on a sample of 80 patients who presented at "Emergency Eye Hospital" Bucharest between 1st of December 2013 30th of July 2014. Patients were divided into two groups: 40 patients with glaucoma and 40 patients without glaucoma (control group). THE OBJECTIVE OF THE STUDY: To determine changes in intraocular pressure that may occur depending on body posture and the correlations between changes in intraocular pressure and glaucoma, obesity, hypertension. These IOP changes may be important in the progression of glaucoma regarding that one third of our time is spent on supine position during night. RESULTS AND CONCLUZIONS: IOP varies from sitting down to supine position. IOP increases in supine in most patients (with or without glaucoma) with an average of 1.25 mmHg. The increase among patients with glaucoma is higher (1.67 mmHg) compared to those without glaucoma (0.82 mmHg). In patients with hypertension and glaucoma, IOP increased with 2.62 mmHg. In patients with hypertension and obesity IOP increased with 2.5 mmHg. PMID- 26117931 TI - MANAGEMENT OF DIABETIC RETINOPATHY, PREVALENCE AND CLINICAL CLASSIFICATION. AB - AIMS: To ascertain the prevalence of diabetic retinopathy--DR, based on the duration of the diabetes mellitus--DM and to compare it with data from relevant literature and other referent clinics. MATERIAL AND METHODS: In this study are included the patients with diabetes mellitus type 1 insulin-dependent--DMID and diabetes mellitus type 2 non-insulin-dependent--DMNID. The duration of diabetes in the examined patients varied from 5 till 30 years. We have applied examination by ophthalmoscope, slit lamp bio-microscopy with Volk and Goldman lens, optical coherence tomography--OCT as well as fluorescein angiography--FAG. Have been included the treated patients with DR, from September 2004-2014. RESULTS: In diabetic patients suffering for a period of 5 years, the prevalence of DR is 10%. In diabetic patients suffering over 30 years, the prevalence of DR is varied from 82% until 97%. CONCLUSION: Diabetic retinopathy, undertakes a multidisciplinary approach in all patients with diabetes to achieve optimal blood glucose control HbA1c levels 7.0% or lower and to adequately manage systolic blood pressure less than 140 mmHg and serum LDL cholesterol of less than 2.5 mmol/L and triglycerides of less than 2.0 mmol/L. Always should be assessed visual acuity at the time of DR examination. PMID- 26117932 TI - [Preliminary results of treatment with aflibercept]. AB - The paper presents the first results concerning the Aflibercept (Eylea) treatment, the last antiVEGF approved for treatment of the age related macular degeneration (AMD), neovascular form and for macular edema due to the central retinal vein occlusion. The treatment was applied to patients presenting AMD, ME and other diseases: myopic and idiopatic choroidal neovascularisation, central serous choroidopathy (CSC) or diabetic macular edema (DME). The results were good: improvement of the visual acuity, resolution of the intraretinal fluids and macular edema. Although we did not notice major side-effects, resistance or tachyphylaxis, we noticed some recurrences. PMID- 26117933 TI - [Communication between clinicians and laboratorians in semen analysis]. AB - By direct communication between clinicians and laboratorians, obstacles between clinical work and laboratory diagnosis were unequivocally found at an academic conference. Many clinical physicians feel disappointed and frustrated at the laboratory diagnosis by semen analysis and frankly express their expectations, as to recognize the role and significance of laboratory diagnosis, understand the value of routine semen analysis, work out the puzzles in the analysis of sperm morphology, fulfil the requirements for the identification of cells in semen, and obtain responses from and initiate discussions among laboratorians about the relevant questions. Both laboratorians and clinicians are appealing for strengthened management and earlier establishment of national standards and operating specifications for laboratory diagnosis by semen analysis. PMID- 26117934 TI - [Expression of a testis-specific gene 1700001022RIK in mice and its bioinformatic analysis]. AB - OBJECTIVE: To identify the expression characteristics of the 1700001022RIK (RIKEN cDNA 1700001022) gene in mice and explore its function by bioinformatic analysis. METHODS: Using the expression profile of gene microarray, we detected the expression of a new testis-specific gene, 1700001022RIK, in mice. We analyzed its expression characteristics in the testis tissue and their changes in different developmental stages of the testis by RT-PCR, real-time RT-PCR, Western blot, and immunohistochemistry. We performed bioinformatic analysis using a bioinformatic software. RESULTS: The 1700001022RIK gene was specifically expressed in the mouse testis in an age-dependent manner, most highly in the adult mice. The 1700001022RIK protein was mainly expressed in the spermatogonia, spermatocytes, and round spermatids of the adult mice. Bioinformatic analysis showed that the 1700001022RIK protein amino acid sequence had a high similarity in human and mice, which indicated that this gene was highly conserved in mammals. CONCLUSION: 1700001022RIK is a testis-specific gene mainly expressed in the spermatogonia, spermatocytes, and round spermatids of seminiferous tubules, which might be involved in the regulation of spermatogenesis. PMID- 26117935 TI - [Expressions of HO-2 and CO in the corpus cavernosum of castrated rats]. AB - OBJECTIVE: To explore the expressions of HO-2 and CO in the corpus cavernosum of castrated rats in order to further study the pathogenesis of erectile dysfunction (ED). METHODS: We randomly divided 72 male SD rats into four groups: normal control, sham operation, castration, and castration + ZnPP. We detected intracavernous pressure (ICP) and penile erection in the basic condition and after apomorphine (APO) induction, determined the expression of the HO-2 protein in the corpus cavernosum by laser scanning confocal microscopy, and measured the level of CO by spectrophotometry during different periods of penile erection. RESULTS: The ICP in the basic condition and that after APO induction and the rate of penile erection were decreased significantly in the castration group ([11.68 +/- 0.69] mmHg, [54.81 +/- 3.86] mmHg, and 33.3%) and the castration + ZnPP group ([11.20 +/- 0.71] mmHg, [41.17 +/- 5.41] mmHg, and 22.2%) as compared with the normal control ([22.83 +/- 2.66] mmHg, [66.92 +/- 7.77] mm-Hg, and 100%) and the sham operation group ([23.35 +/-2.22] mmHg, [70.43 ?7. 22] mmHg, and 100%) (all P <0. 01). After APO induction, ICP in the castration + ZnPP group was remarkably reduced in comparison with that in the castration group (P < 0.01), and so was the expression of the HO-2 protein before and during penile erection in the castration (445.4 +/- 23.7 and 847.4 +/- 35.0) and the castration + ZnPP group (390.1 +/- 29.7 and 526.0 +/- 52.5) compared with the normal control (512.7 +/ 57.4 and 1145.2 +/- 89.8) and the sham operation group (583.7 +/- 8.0 and 1016.3 +/- 79.8), the expression of the HO-2 protein significantly decreased in the castration group (445.4 +/- 23.7 and 847.4 +/- 35.0) (P < 0.05 or 0.01), markedly lower in the castration + ZnPP than in the castration group during penile erection (P < 0.01) but with no significant differences among the four groups after it. Before, during and after penile erection, the levels of CO were remarkably decreased in the castration ([20.59 +/- 1.01], [32.53 +/- 1.26], and [18.71 +/- 1.22] x 10(-7) nmol/L) and the castration +ZnPP group ([12.52 +/- 1.05], [21.90 +/- 1.02], and [16.56 +/- 0.55] x 10(-7) nmol/L) as compared with the normal control ([26.76 +/- 1.41], [48.25 +/- 1.01], and [27.10 +/- 1.58 ] x 10(-7) nmol/L) and the sham operation group ([25.41 +/- 2.09], [ 47.90 +/- 1.22], and [25.67 +/- 1.20] x 10(-7) nmol/L) (P < 0.05 or 0.01), significantly lower in the castration + ZnPP than in the castration group during penile erection (P < 0.01). CONCLUSION: Decreased expressions of HO-2 and CO may correlate with erectile dysfunction in castrated rats. PMID- 26117936 TI - [Endoplasmic reticulum stress promotes the apoptosis of testicular germ cells in hyperlipidemic rats]. AB - OBJECTIVE: To investigate the role of endoplasmic reticulum stress in the apoptosis of testicular germ cells in hyperlipidemic rats. METHODS: We randomly assigned 42 four-week-old male Wistar rats into a normal control group (n = 12) and a high-fat group (n = 30) to be fed on a normal diet and a high-fat diet, respectively, for 10 weeks. Then we measured the concentrations of triglyceride (TG) and total cholesterol (TC) in the serum using an automatic biochemistry analyzer, detected the apoptosis of testicular germ cells by TUNEL staining, and determined the protein and mRNA expressions of GRP78 and. caspase-12 in the testis tissue by immunohistochemistry and RT-PCR, respectively. RESULTS: The concentrations of TG and TC were significantly increased in the animals of the high-fat group ([3.00 +/- 0.92] and [3.04 +/- 0.39] mmol/L) as compared with the control rats ([1.43 +/- 0.41] and [1.55 +/- 0.23] mmol/L) (P < 0.01), and so was the apoptosis index of the testicular germ cells ([37.17 +/- 2.74]% vs [5.16 +/- 0.81]%, P < 0.01). The high-fat group, in comparison with the control, also showed remarkably upregulated protein and mRNA expressions of GRP78 (0.32 +/- 0.03 and 0.86 +/- 0.05 vs 0.19 +/- 0.01 and 0.37 +/- 0.03, P < 0.01) and caspase 12 (0.34 +/- 0.02 and 0.87 +/- 0.01 vs 0.12 +/- 0.01 and 0.34 +/- 0.03, P < 0.01) in the testis tissue. CONCLUSION: The apoptosis of testicular germ cells is increased in hyperlipidemic rats, which may be attributed to endoplasmic reticulum stress. PMID- 26117937 TI - [Ten significantly differentially expressed genes in prostate cancer: Screening and verification]. AB - OBJECTIVE: To screen and verify differentially expressed genes in prostate cancer. METHODS: Using DNA microarray, we screened differentially expressed genes in prostate cancer tissue and its adjacent tissue followed by verification by PCR. RESULTS: A total of 1 444 genes were found to be differentially expressed (differentiation >= 1.5-fold; P<= 0.05) in the prostate cancer tissue, of which 769 (53%) were up-regulated and 675 (47%) down-regulated. Fifty percent of the differentially expressed genes showed a 1.5- to 2-fold differentiation, including 396 up-regulated and 182 down-regulated ones. Additionally, 308 up-regulated and 334 down-regulated genes exhibited a >2- to 5-fold, 46 up-regulated and 78 down regulated genes a > 5- to 10-fold, and 19 up-regulated and 81 down-regulated genes a > 10-fold differentiation. Verification by subjecting 15 most significantly up-regulated and another 15 most markedly down-regulated genes to quantitative real-time PCR (qRT-PCR) showed that most of the genes had a transcriptional profile similar to that in the microarray data, with a Pearson correction coefficient of 0.83 between the microarray data and qRT-PCR results. Totally, 10 significantly differentially expressed genes were identified. CONCLUSION: DNA microarray analysis provides reliable information on differentially expressed genes in prostate cancer and benign tissues. The 10 significantly differentially expressed genes verified by qRT-PCR could possibly become new bio-markers and specific molecules for tumor identification. PMID- 26117938 TI - [Correlation of FOXA1 with the malignancy and progression of prostate cancer]. AB - OBJECTIVE: To study the relationship of the expression of FOXA1 in the prostate cancer (PCa) tissue with the Gleason score and clinical staging of PCa and with castration-resistant PCa (CRPC). METHODS: Using the immunohistochemical method, we detected the expressions of FOXA1 and Ki-67 in the pathological sections of 35 cases of PCa and 21 cases of benign prostatic hyperplasia (BPH). Then we analyzed their correlation with the Gleason score and TNM staging of PCa and that with CRPC. RESULTS: The positive expression of FOXA1 was significantly higher in the PCa than in the BPH tissue (P < 0.001) and was positively correlated with that of Ki-67 (P < 0.001) as well as with the Gleason score (P = 0.027) and clinical staging of PCa (P = 0.002), but showed no correlation with CRPC (P = 0.391). CONCLUSION: The positive expression of FOXA1 is increased in PCa, most significantly in the advanced stage of the tumor. PMID- 26117939 TI - [Changes of CD4 + CD25 + Foxp3 + regulatory T cells in the peripheral blood and their correlation with insulin resistance in different stages of prostate cancer]. AB - OBJECTIVE: To investigate the changes of CD4 + CD25 + Foxp3 + regulatory T cells in the peripheral blood mononuclear cells (PBMC) and their association with insulin resistance in different stages of prostate cancer (PCa). METHODS: Using flow cytometry, we counted the CD4+ CD25 + Foxp3 + regulatory T cells in the PBMCs of 62 PCa patients (5 cases of TNM stage I, 16 cases of stage II, 21 cases of stage III, and 20 cases of stage IV) and 42 normal healthy controls, and calculated their proportion in the CD4+ T-lymphocytes. We determined the levels of fast blood glucose (FBG) and fast insulin (FINS) for the insulin resistance index (HOMA-IR), obtained the serum IGF-1 level by ELISA, and analyzed the relationship of the count and proportion of CD4+ CD25+ Foxp3+ regulatory T cells with insulin resistance by comparison between the PCa patients and normal healthy controls. RESULTS: Compared with the control group, the PCa patients showed significantly increased HOMA-IR (3.68 +/- 1.42 vs 6.68 +/- 1.66), decreased level of serum IGF-1 ([164.56 +/- 30.58] vs [96.39 +/- 21.21] ng/ml), and elevated count ([1.99 +/- 0.78 ] x 10(7) vs [3.55 +/- 0.29] x 10(7)) and proportion ([5.33 +/- 0.65] vs [13.88 +/- 0.96]%) of CD4 + CD25 + Foxp3 regulatory T cells in the PBMCs. The TNM stage was correlated positively with the count and percentage of CD4 + CD25+ Foxp3 + regulatory T cells and HOMA-IR, but negatively with the level of serum IGF-1. Meanwhile, the count and percentage of CD4 + CD25 + Foxp3 + regulatory T cells were found to have a positive correlation with HOMA-IR (r = 0.722 and 0.689, P < 0.01) but a negative correlation with the level of serum IGF 1 (r = -0.747 and -0.896, P < 0.01). CONCLUSION: The count and proportion of CD4+ CD25 + Foxp3 + regulatory T cells in the peripheral blood and insulin resistance increase with the elevated stage of PCa. CD4 + CD25 + Foxp3 + regulatory T cells may be involved in the occurrence and progression of PCa by regulating insulin resistance. PMID- 26117940 TI - [Selection of the sites for microsurgical vasoepididymostomy: A report of 56 cases of epididymal obstructive azoospermia]. AB - OBJECTIVE: To explore the prediction of the site for microsurgical vasoepididymostomy (VE) in the treatment of epididymal obstructive azoospermia (OA). METHODS: This study involved 56 infertile men with confirmed OA whose obstruction was suspected to be in the epididymis. Based on their medical history and results of preoperative physical examination and ultrasonography, we predicted the sites for VE. We performed surgical scrotal exploration for the status of epididymal obstruction, conducted palpation and microscopic observation for the epididymal tubules to be anastomosed, and finally decided on the sites for VE by making sure of the presence of motile sperm in the epididymal fluid of the patients. After surgery, we followed up the patients for the rate of pregnancy. RESULTS: All the patients received bilateral scrotal ultrasonography and surgical scrotal exploration, totaling 112 procedures, including 98 VE procedures. The accuracy rate of the predicted sites for VE was 80.5% (153/190) by medical history and physical examination, 80.3% (90/112) based on the results of ultrasonography, and 87.4% (90/103) according to the first selected epididymal tubules. Of the 28 patients followed up for more than 12 months, motile sperm were found in 19 (67.9% ) at 2 to 12 months and spontaneous pregnancies were achieved in 10 (35.7%), all with the anastomotic sites in the corpus or cauda. CONCLUSION: Medical history and physical examination contribute to the selection of anastomotic sites and non-invasive scrotal ultrasonography is effective and practical for positioning epididymal obstruction. The epididymal tubules with motile sperm for anastomosis could be easily obtained from the most dilated ones in indurated epididymides. PMID- 26117941 TI - [Penile necrosis resulting from post-circumcision microwave diathermy: A report of 9 cases]. AB - OBJECTIVE: To investigate the pathogenesis and treatment of penile necrosis resulting from microwave diathermy following circumcision. METHODS: We retrospectively analyzed the clinical data about 9 cases of penile necrosis resulting from postoperative microwave diathermy following circumcision. The 9 males, aged 20 - 39 (mean 26) years, underwent traditional circumcision for redundant prepuce or phimosis in other hospitals, followed by microwave diathermy for 30 - 60 minutes daily, which resulted in penile necrosis. With no response to conservative therapy, the patients were referred to our hospital at 3 -30 days postoperatively. Of the 9 patients, 5 presented with dry gangrene and 4 with moist gangrene. Six of the patients underwent partial penectomy, including 1 that received penis lengthening.3 months later, while the other 3 underwent total penectomy for total penile necrosis followed by penile reconstruction 3 months later, with deep inferior epigastric perforator (DIEP) flaps and by implantation of the 12th costal cartilage in 2 cases and with epigastric groin island flaps and by urethroplasty in the other. RESULTS: The patients were followed up for 2 - 8 years, and all could urinate smoothly in the standing position. Of the 6 men treated by partial penectomy, 1 received penis lengthening and achieved a penile length of 7 cm and 5 had the remaining penile length of 3 -5 cm, 4 with erectile function and the other 2 capable of sexual intercourse. The 3 men treated by total penectomy achieved nearly normal external appearance of the penis, with a finalized length of (11.7 +/- 1.3) cm, a circumference of (11.4 +/- 2.1) cm, and a normal feel of the skin. Of the 3 cases of penile reconstruction, 2 achieved sufficient erectile hardness of the penis (grade 3) for sexual intercourse, while the other 1 remained impotent. CONCLUSION: Post-circumcision microwave diathermy may result in penile necrosis, for the management of which, early debridement is necessitated and penile lengthening or reconstruction can be performed according to the severity of the lesion and needs of the patient. PMID- 26117942 TI - [Relationship between anogenital distance and cryptorchidism in human newborns]. AB - OBJECTIVE: To explore the relation of the anogenital distance (AGD) with cryptorchidism in male newborns. METHODS: This study included 350 male infants delivered in two community hospitals between September 2013 and September 2014. Within 24 hours after birth, a pediatric surgeon measured the AGD of the neonates and determined whether they had cryptorchidism. According to the testicular position, we divided the undescended testes into three types: upper scrotal, inguinal, and non-palpable. RESULTS: Totally 39 cases of cryptorchidism were found in the 350 newborns. The AGD of the cryptorchidism infants was significantly shorter than that of the normal neonates ([2.01 +/- 0.22] vs [2.35 +/- 0.19] cm, P < 0.01), and statistically significant differences remained even when preterm and low birth-weight infants were excluded ([2.32 +/- 0.14] vs [2.06 +/- 0.19] cm; (2.37 +/- 0.17) cm vs (2.12 +/- 0.12) cm, all P < 0.01). The newborns with higher-position cryptorchidism had a shorter AGD, though with no significant difference (F = 0.434, P > 0.05). No significant differences were observed in the AGD between unilateral and bilateral cryptorchidism ([1.96 +/- 0.13] vs [2.02 +/- 0.17] cm, P > 0.05). CONCLUSION: Shorter AGD is associated with a higher incidence of cryptorchidism in male newborns. AGD could serve as a potential biomarker for disruption of androgen action during the male programming window period. PMID- 26117943 TI - [Morinda officinalis extract repairs cytoxan-impaired spermatogenesis of male rats]. AB - OBJECTIVE: To study the effect of Morinda officinalis (MO) extract on cytoxan (CTX) -impaired spermatogenesis of adult male SD rats. METHODS: We randomly divided 56 adult male SD rats into seven groups of equal number: blank control, CTX model, CTX + NS, CTX + 10 g/kg MO, CTX + 20 g/kg MO, CTX + 30 g/kg MO, and CTX + 40 g/kg MO. We made the models of impaired spermatogenesis in the SD rats by intraperitoneal injection of CTX and treated the animal models by intragastric administration of MO at the concentrations of 10, 20, 30, and 40 g per kg per d, respectively. After two weeks of medication, we observed the changes in the body weight, testicular and epididymal indexes, and microstructure of the testis tissue, measured the mean seminiferous tubule diameter (MSTD) , and obtained testicular biopsy scores (TBS) in different groups, followed by comparative analyses. RESULTS: After treatment, the CTX + NS group showed no remarkable differences in the body weight ([234.83 +/- 28.77] g) and epididymal index (2.71 +/- 0.34) from those of the four CTX + MO groups, but exhibited a significantly lower testicular index ([12.15 +/- 1.04] g) than those in the CTX + 20 g/kg MO ([13.71 +/- 0.97] g), CTX + 30 g/kg MO, ([13.30 +/- 0.29] g), and CTX + 40 g/kg MO group ([13.48 +/- 0.51] g) (P < 0.05). Light microscopy revealed obvious pathological changes of the testis tissue in the CTX + NS group and significantly ameliorated structures of the seminiferous tubules in the CTX + MO 10, 20, 30, and 40 g/kg groups, with the MSTD of (204.78 +/- 11.03), (216.55 +/- 10.93), (218.03 +/- 11.23), and (218.59 +/- 14.06) MUm, respectively, and the TBS of 9.03 +/- 0.39, 9.69 +/- 0.26, 9.83 +/- 0.18, and 9.89 +/- 0.11, respectively, all significantly higher than (189.74 +/- 8.55) MUm and 5.95 +/- 1.21 in the CTX + NS group (P < 0.05). The efficacy of MO extract was increased in a concentration dependent manner. CONCLUSION: Morinda officinalis extract can repair cytoxan induced damage to rat spermatogenesis, with may achieve the best effect at the concentrations of 30 and 40 g per kg per d. PMID- 26117944 TI - [Efficacy of Qilin Pills combined with sertraline in the treatment of secondary non-consolidated kidney qi premature ejaculation]. AB - OBJECTIVE: To observe the clinical effectiveness of Qilin Pills combined with sertraline in the treatment of secondary non-consolidated kidney qi premature ejaculation (PE). METHODS: A total of 120 patients with secondary non consolidated kidney qi PE were randomly assigned to groups A (aged [35.5 +/- 5.4] yr), B (aged [36.2 +/- 5.7] yr), and C (aged [35.2 +/- 5.3] yr) in the ratio of 1:1:1 to receive Qilin Pills (once 6 g, bid), sertraline (once 50 mg, qd), and Qilin Pills plus sertraline, respectively, all for 4 weeks. The intravaginal ejaculatory latency time (IELT) and PE diagnostic tool (PEDT) scores were obtained before and after medication and at 1 month after drug withdrawal, and comparative analyses were made among the three groups of patients. RESULTS: The IELT was dramatically prolonged in groups A, B, and C after treatment ([3.23 +/- 1.84], [3.87 +/- 2.43], and [5.92 +/- 3.11] min) and at 1 month after drug withdrawal ([1.85 +/- 1.27], [1.52 +/- 1.06], and [ 4.26 +/- 1.88 ] min) as compared with the baseline ([0.88 +/- 0.45], [0.84 +/- 0.47], and [0.85 +/- 0.50] min) (P < 0.01), even longer in group C than in A and B (P < 0.01). The PEDT scores of the three groups were 5.1 +/- 1.8, 4.9 +/- 1.7, and 3.8 +/- 1.2 after treatment and 8.2 +/- 2.4, 8.1 +/- 2.4, and 6.5 +/- 2.1 at 1 month after drug withdrawal, significantly improved in comparison with 13.2 +/- 3.2, 12.8 +/- 3.1, and 13.1 +/- 3.4 before treatment (P < 0.01), even more significantly in group C than in A and B (P < 0.01). CONCLUSION: Qilin Pills combined with sertraline has a definite efficacy in the treatment of secondary non-consolidated kidney qi PE and therefore deserves wide clinical application. PMID- 26117945 TI - [Efficacy and safety of phosphodiesterase inhibitors for erectile dysfunction in diabetic men: A meta analysis]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of phosphodiesterase 5 (PDE-5) inhibitors for erectile dysfunction (ED) in patients with diabetes mellitus and provide some evidence for the clinical treatment of the disease. METHODS: We searched MedMed, EMbase, Cochrane Library, CNKI, Wan Fang Data, VIP and ZADL for randomized controlled trials on PDE-5 inhibitors for ED in diabetic men and evaluated the methodology of the included trials with the Jadad scale. We used the erectile function domain in the IIEF (IIEF-EF), IIEF questions (IIEF-Q) 3 and 4, SEP-2 and -3, and Global Assessment Questions (GAQ) as the main evaluation indexes and employed the Review Manager 5. 1. 0 software for meta analysis. RESULTS: A total of 13 studies were included, which were all high quality trials with Jadad score > 3. The IIEF-EF scores in 10 of the included studies were subjected to meta analysis using the random-effect model (REM), with a weighted mean difference (WMD) of 5.64 (95% CI 4.41 - 6.83, P < 0.001). The fixed-effect model (FEM) analysis of the IIEF-Q scores in 6 of the studies showed the WMD to be 0.96 (95% CI 0.83 -1.08, P < 0.001) for IIEF-Q3 and 1.11 (95% CI 0.98 - 1.25, P < 0.001) for IIEF-Q4. FEM analysis of the SEP-2 scores showed WMD = 17.67 (95% CI 12. 38 - 22. 97, P < 0.001) in 2 of the studies, and that of the SEP-3 scores WMD = 23.64 (95% CI 17. 49 - 29.79, P < 0.001) in 5 of the studies. The GAQ scores in 11 of the studies were subjected to REM analysis, with OR = 6. 20 and 95% CI 3.65 - 10.52 (P < 0.001). REM analysis was performed on the adverse reactions in 11 of the studies, with OR = 7.43 and 95% CI 4.11 - 13.44 (P < 0.001). CONCLUSION: PDE-5 inhibitors can effectively and safely improve erectile function in patients with diabetes mellitus. PMID- 26117946 TI - [MicroRNAs and prostate cancer]. AB - Prostate cancer (PCa) is one of the most common malignancies in the urinary system of males. A growing number of studies have shown that microRNAs, as small ribonucleic acid molecules and a class of non-coding small RNAs, are closely related with PCa and a variety of microRNAs are abnormally expressed in it. This article focuses on the roles of microRNAs in the occurrence and progression of PCa, with a description of differentially expressed microRNAs in PCa and an analysis of their association with its prognosis as well as their correlation with chemotherapy, androgen receptors, and metastasis of PCa. PMID- 26117947 TI - [Penile rehabilitation after radical pelvic surgery]. AB - Prostate cancer, bladder cancer, and rectal cancer are common malignancies in the male pelvis. The incidence rate of erectile dysfunction (ED) following radical prostatectomy, cystectomy or rectal cancer surgery is about 25% - 100%. The main cause of post-surgery ED is mainly attributed to injury of neurovascular bundles, which may lead to reduced oxygenation in and fibrosis of the penile tissue. Early penile rehabilitation after surgery can improve or restore the erectile function of the patients. This article focuses on penile rehabilitation after radical pelvic surgery. PMID- 26117948 TI - [Fosfomycin for urogenital tract infections: Advances in studies]. AB - Fosfomycin (FOM) is an antibiotic with a small relative molecular weight (138.1) and a long half-life, and has a unique chemical structure and antibacterial mechanisms. It exerts a bactericidal activity by inhibiting the early synthesis of bacterial cell walls. It is also a broad-spectrum antibiotic with a good drug tolerance and compliance and a low pressure to bacterial resistance, but no cross resistance with other antibiotics. Recent studies show the effectiveness of FOM in the treatment of acute uncomplicated urinary tract infections and urogenital tract infections as well, such as prostatitis and epididymitis. This review focuses on the clinical application of FOM in the treatment of infectious diseases of the urogenital tract. PMID- 26117950 TI - [Plasma-Activated Solution: Mechanism of Action, Clinical Application, and Industrialization]. PMID- 26117949 TI - [Visionary Approach to Neurosurgery]. PMID- 26117951 TI - Gastric Hyperplastic Polyp with Xanthoma Observed by Magnification Narrow-Band Imaging Endoscopy and Endoscopic Ultrasonography : Report of a Case. AB - We experienced an extremely rare case of gastric hyperplastic polyp with xanthoma. A 73-year-old Japanese man was transferred to our hospital from a referral hospital for further evaluation of a pedunculated gastric polyp and early gastric cancer. Esophagogastroduodenoscopy (EGD) revealed a yellow-whitish pedunculated polyp arising from the anterior wall of the fornix. Magnification narrow-band imaging (NBI) endoscopy revealed extended and tortuous microcapillaries and a swollen interfoveolar pattern on the polyp's surface, but there was no sign of malignancy. Endoscopic ultrasonography (EUS) revealed an irregularity of the first layer and a thickened second layer. The third layer was intact. A hyperechoic area was seen in the thickened second layer. Endoscopic submucosal dissection (ESD) for early carcinoma of the antrum and endoscopic mucosal resection (EMR) for a polyp in the fornix were performed in one session. Histological examination of the specimen of the fornix polyp revealed lengthened, branched and dilatated gastric foveolae and a tight sheet of foamy histiocytes in the stroma. The background mucosa of the polyp was atrophic. The pathologic evidence was gastric hyperplastic polyp with proliferation of xanthoma. The early cancer of the antrum was intramucosal tubular adenocarcinoma and was resected curatively. PMID- 26117952 TI - [Preparation and characteristics of aerogel-based bioactive materials used in dentistry]. AB - A variety of bioactive materials have been investigated as substitute materials for diseased or damaged bone tissues in dentistry. The aim of this study was to prepare mesoporous silica containing biomaterials by sol-gel technology. These materials may be combinated with hydroxyapatite and beta-tricalcium phosphate, as bioactive agents. The synthesis and testing of important physical parameters were performed. Based on these measurements, the silica aerogel can be an applicable material in the dental field in the future. PMID- 26117953 TI - [Change in the incidence of diabetes mellitus in oral cancer patients based on a long-term comparative study]. AB - Our research is focused on the incidence of diabetes mellitus and glucose metabolic disorders among oral cancer patients and the frequency of different oral localizations of cancer. Diabetes mellitus affects 7% of the Hungarian population. This study uses data spanning 14 years, with 2 datasets of 1998-1999 and 2012-2013, collected first hand by the authors. These datasets have led us to examine the blood glucose level in 267 patients with histologically confirmed malignant tumours in the oral cavity. Diabetes mellitus was found in 59 of them (22.1%), The blood glucose was elevated in 32 cases (12%). The most frequent tumor locations among the diabetic patients: labial, lingual and gingival tumors gingivae. Comparative epidemiological study demonstrates that in 2012-2013 dataset there was an increased observed percentage of people with diabetes mellitus [17.6% to 22.1%]. The percentage of patients with IFG (impaired fasting glucose) also increased from 9.8% to 12%. Overall the number of patients with glucose metabolic disorders climbed from 27.4% to 34.1%, (p > 0.05). Our intention of this introductory analysis is to emphasize the close connection of these two very important disease groups, and the wider spread of diabetes mellitus. PMID- 26117954 TI - [Binding properties of components removable from dental base plate, analysed by Fourier-Transform Surface Plasmon Resonance (FT-SPR) method]. AB - In parallel with the emergence of new dental materials the number of allergic diseases is continuously increasing. Extremely small quantities of the allergens are capable to inducing an allergic reaction. Therefore it is particularly important to examine these materials as antigens and investigate their binding properties to proteins (e.g. formaldehyde, methacrylic acid, benzoyl peroxide...). The Fourier Transform Surface Plasmon Resonance Spectroscopy (FT SPR) is a suitable examination method for this type of procedure. FT-SPR measurement is performed at a fixed angel of incident light, and reflectivity is measured over a range of wavelength in the near infrared. The advantages of this method are the outstanding sensitivity, the label-free detection capability and the possibility of the real-time testing procedure. Formaldehyde and methacrylic acid are among the most common dental allergens. In our study we examined these molecules by FT-SPR spectroscopy. The aim of this work was to investigate the suitability of this method to the detection of these materials, with special focuses on the analysis and evaluation concentration-dependent measurements. Different concentrations (0.01 %-0.2%) of formaldehyde and methacrylic acid solutions were measured. The individual spectra were measured for all of the solutions, and calibration curves were calculated for the materials for the possibility of the determination of an unknown concentration. The results confirmed that the method is theoretically capable to detect hundred-thousandths scale concentration-changes in the solution flowing above the SPR-chip. The concentration-dependent studies had proved that the method capable to measure directly these materials and can provide appropriate calibration for quantitative determination. These experiments show the broad applicability of the FT-SPR method, which can greatly facilitate the mapping and understanding of biomolecular interactions in the future. PMID- 26117955 TI - [Changes of the innervation in the mucous membrane and glands of the tongue in early and late experimental diabetes mellitus]. AB - The number of the different neuropeptides-containing nerve fibres and immunocompetent cells was changed in diabetes mellitus (DM) in different organs. In this work we investigated the effect of DM on quantitation of the nerve fibres using immunhistochemistry. After two weeks of the DM the quantitiy of the different nerve fibres increased significantly both in the mucous membrane and glands of the tongue. The number of the immunocompetent cells (lymphocytes, plasma cells, mast cells) increased as well significantly. Some of these cells showed also immunoreactivity for substance P and neuropeptide Y. A few substance P cells were in very close relation to the SP immunoreactive nerve fibres. After four weeks of DM the number of the nerve fibres was decreased compared to the 2 weeks treatment, however, the number of them was higher compared to the control. The close correlation between the nerve fibres and immune cells might play a crucial role in maintaining the homeostasis in the mucous membrane and glands of the tongue as well as in the increasing inflammation and elimination of it. PMID- 26117956 TI - [Frequency of signs and symptoms of temporomandibular joint disorders, vertical orthodontic anomalies and their relationships based on screening of a large population]. AB - Altogether 4606 volunteers (2923 vomen, 1683 men) participated in the representative national epidemiological study to screen the alterations of temporomandibular joint (TMJ). The characteristic clinical signs and subjective complaints according to TMJ were evaluated by medical history taking and physical examination. Regarding the orthodontic anomalies, the vertical abnormalities (deep bite and open bite) were specifically noted. Clinical signs showing functional problems of TMJ were found in 45.19% of the screened population, mainly in the group of 35-44 year olds. The frequency of clicking and crepitation of TMJ was significantly higher in women compared to men (p < 0.05). The highest rate of clinical signs of TMJ disorders was found in the South-Transdanubian region, the lowest rate in the Middle-Transdanubian region, between these regions it was a significant difference regarding the frequency of deviation/deflexion (p < 0.05). Of the vertical abnormalities, deep bite occured most frequently in the 35-44 ys old age group. The prevalence of deep bite was higher among males than females in the whole screened population, but the difference was not statistically significant. Significant relationship was detected between deep bite and TMJ pain, deep bite and noises in the joint in the majority of the population. The most frequent anomaly in the South-Transdanubian region was deep bite, while the open bite occured most frequently in south middle part of Hungary. Conclusion: the Hungarian population needs well organized specific programs to improve the oral health including TMJ and orthodontic aspects. PMID- 26117958 TI - [Dr. Istvan Gera has received the Cross of the Hungarian Order of Merit]. PMID- 26117959 TI - California Blues Plan Insists It's Not-for-Profit. PMID- 26117960 TI - Spending on Compounded Drugs Goes Sky High. PMID- 26117961 TI - Medicaid expansion linked to diabetes diagnosis. PMID- 26117962 TI - Shopping for Health Care. PMID- 26117963 TI - A Conversation With Robert Wachter, MD. Reality Bytes: Medicine's Bumpy Ride Into the Digital Age. PMID- 26117964 TI - 3 New Biologics To Be Worth $14B in Sales by 2019. PMID- 26117965 TI - Operational Implications of Utilizing 2 Advanced Technologies for Rendering Short term Hemodynamic Support to Patients Presenting With Cardiogenic Shock: A View Through the Lens of Hospital Readmissions. AB - PURPOSE: Reducing hospital readmissions for critically ill patients is of concern to payers and providers alike. Patients in cardiogenic shock are often treated with devices to help support the functions of the heart while the patient undergoes treatment. This study compares the readmission experience of Medicare beneficiaries treated for cardiogenic shock (CS) using percutaneous ventricular assist devices (pVADs) vs. extracorporeal membrane oxygenation (ECMO), two types of advanced cardiac support devices. Hospital readmission is a surrogate for quality and cost. DESIGN AND METHODOLOGY: A retrospective comparison of readmission patterns of patients treated for CS using two advanced cardiac support devices during calendar years 2011 and 2012 was captured via the Medicare Inpatient Standard Analytic File (100% census file). A total of 649 eligible cases (pVAD, 517; ECMO, 132) with 90 days of follow-up documentation were included in this analysis. Baseline characteristics were compared, including demographics, admission type, and severity of illness, with the 2 groups generating clinically similar baseline profiles. Primary outcomes include 30- and 90-day readmissions, associated length of stay (LOS), and costs. RESULTS: At 90 days after initial hospitalization, the readmission rates in the pVAD and ECMO cohorts were 38.7% (200/517) and 53.0% (70/132), respectively. Overall, pVAD was associated with a 27.1% reduction in readmission (P = .004). With the use of pVAD, 90-day readmission costs were lower by $12,294 ($32,736 vs $20,442, a reduction of 37.6%, P=.02) and readmission LOS was shorter by approximately 8 days, (20.5 vs. 12.7 days, a 37.9% reduction, P = .002). Similar trends were observed at 30 days; however, only LOS was significantly reduced, by 7.0 days (P < .001). CONCLUSION: In clinically comparable cohorts, pVADs were associated with reduced risk of rehospitalization, lower cost, and shorter LOS, resulting in cost savings for payers and providers. Increased adoption of pVAD, as a technology to support patients in cardiogenic shock, may help hospitals deliver greater value to both government and commercial payers. PMID- 26117966 TI - New Eye Therapy Takes Aim At Limbal Stem Cell Deficiency. PMID- 26117967 TI - Increased colon cancer screening could save 200,000 lives by 2030. PMID- 26117968 TI - Combination of microbiological culture and multiplex PCR increases the range of vaginal microorganisms identified in cervical cancer patients at high risk for bacterial vaginosis and vaginitis. AB - BACKGROUND: Bacterial vaginosis (BV) and vaginitis in cervical cancer patients might becaused by mixed aerobic, anaerobic, and atypical bacteria. Since genital tract infections can be complicated, early and accurate identification of causal pathogens is vital. OBJECTIVES: The purpose of this study was i) to determinate if currently used aerobic culture methods are sufficiently sensitive to identify pathogens that can appear in the cervix of women after cancer treatment; ii) to investigate if molecular methods can improve the diagnostic process of BV and vaginitis, as well as broaden the range of detectable pathogens that would otherwise be difficult to cultivate. METHODS: A one-year hospital-based study was conducted in 2011/2012. Cervical swabs from 130 patients were examined by microbiological culture and multiplex PCR. RESULTS: Swab samples were positive for 107 and 93 women by microbiological culture and multiplex PCR, respectively The most common bacteria isolated from culture were: Escherichia coli, Enterococcus faecalis, Streptococcus agalactiae, and Staphylococcus aureus, and using the molecular technique were: Gardnerella vaginalis, Bacteroides fragilis, Ureoplasma ureoliticum/parvum, Mobiluncus curtisii and Atopobium vaginae. CONCLUSIONS: Multiplex PCR might contribute to the diagnosis of genital tract infections and it broadens the number of detectable microorganisms responsible for BV. Combination of these two methods may become the basis for standardized diagnosis of BV and vaginitis. PMID- 26117969 TI - Ovarian cancer and normal fallopian tube high WFDC2 expression does not correlate with HE4 serum level. AB - OBJECTIVES: Recent evidence suggests that epithelial ovarian cancer (EOC) does not derive from ovarian surface epithelium but from the tissues of Mullerian origin, particularly from the fallopian tube. HE4, a protein of Mullerian origin, seems to be promising marker for EOC detection and treatment monitoring. This study was designed to compare the expression of WFDC2 gene, encoding HE4 protein, in normal tissue of the ovary fallopian tube and EOC. The correlation between WFDC2 expression in cancer tissue and serum level of HE4 was additionally measured. MATERIAL AND METHODS: Tumor specimens were obtained from EOC patients during primary surgery before chemotherapy Samples of normal ovaries and fallopian tubes were collected from healthy patients operated for other reasons. Total RNA was isolated from the tissues and relative WFDC2 expression was evaluated by Real Time RT-qPCR. HE4 serum level in cancer patients was measured using COBAS System. RESULTS: EOC samples were distinguished by much higher WFDC2 expression in comparison to normal ovaries (p = 0.000016). Transcriptional activity of WFDC2 in EOC specimens and in normal fallopian tubes was comparable (p = 1.00). Additionally, lack of correlation between WFDC2 expression in cancer tissue and serum level of HE4 protein in ovarian cancer patients was observed (p = 0.3). CONCLUSIONS: High expression of WFDC2 was demonstrated for both, EOC and fallopian tube, as opposed to its low expression observed in normal ovaries suggesting that EOC is derived from fallopian tube rather than ovary Elevated HE4 serum concentration in EOC patients is not correlated with higher gene expression in cancer tissue. PMID- 26117970 TI - [Histological grading of endometrial carcinoma. Clinical and patomorphological analysis]. AB - OBJECTIVE: Retrospective clinical and pathomorphological analysis of patients undergoing surgery due to endometrial carcinoma; analysis of the correlation between histological grading of endometrial cancer and selected pathomorphological results. MATERIAL AND METHODS: Statistical analysis was based on the pathomorphological results in a group of 353 patients operated because of endometrial carcinoma at the Clinical Department of Gynecologic Oncology Medical University of Lodz, between 2003 and 2013. A possible correlation between histological grading, clinical staging, myometrial infiltration, parametrial invasion and nodal metastases to ilio-obturator lymph nodes was investigated. RESULTS: Among poorly differentiated carcinomas G3, myometrial infiltration above half of its thickness was observed in 67.44% of the cases, whereas in the G2 and G1 groups it was detected in 60.82% and 39.33% of the affected individuals, respectively. Parametrial invasion was found in 24.39% of G3 cases, i.e. 4.23 times more often than in G2 (5.76%) and 10.65 times more often than in G1 (2.29%). Nodal metastases to ilio-obturator lymph nodes were present in 27.50% of poorly 10.86% of moderately and 8.11% of well-differentiated carcinomas. Uterine appendages were infiltrated in 23.25% of G3 cases--3.45 times more than in G2 (6.73%) and 6.82 times more than in G1 (3.4 1%). CONCLUSIONS: Histologic grading for carcinoma at the time of diagnosis is significantly related to clinical staging. No correlation between patient age and carcinoma grading or its clinical staging was observed. Risk of lymph node invasion for well-differentiated carcinomas is similar to the risk for moderately differentiated carcinomas, and should also be an indication for lymphadenectomy in that group of patients. PMID- 26117971 TI - Evaluation of effectiveness of endovascular embolisation for the treatment of pelvic congestion syndrome--preliminary study. AB - OBJECTIVES: The Aim: The aim of the study was to evaluate the effectiveness, safety and clinical outcomes of endovascular embolisation of pelvic congestion syndrome (PCS). MATERIAL AND METHODS: This prospective, observational study carried out between January and May of 2014 encompassed 24 female patients aged 22-44 years (average - 31 years) diagnosed with PCS. Diagnosis of PCS was established by medical history physical examination, transvaginal Doppler ultrasound examination and confirmed by MRI. The patients were qualified for phlebography and ovarian vein embolization with 0.035" detachable coils and/or microcoils. Pelvic pain scores were assessed before and 3 months after the procedure with the visual analog scale (VAS; 0 - no pain, 10 - unbearable pain). RESULTS: Embolisation procedures were performed in 23 out of 24 patients. Nineteen patients underwent unilateral and 4 patients bilateral embolisation of the ovarian vein. In one case, safe and selective vessel catheterization was not possible due to the anatomical variant of venous flow. Nineteen patients underwent unilateral embolisation of the left ovarian vein. Four patients had the left and right ovarian veins embolized; in one of them, the internal iliac vein was additionally closed (the two-stage procedure). The technical success rate was 96%. Procedures lasted 23-78 minutes (32 minutes on average). An average of 40 ml of contrast was administered during the procedures. The total mean radiation dose at the reference point was 389 mGy (from 127 mGy to 1112 mGy). A decrease in pelvic pain intensity according to VAS was considered a clinical success. The median VAS pelvic pain score before the procedure was 8. Three months after the procedure median pelvic pain score decreased to 1 (p < 0.001). In two cases, the ovarian vein was injured and the contrast medium extravasated, which was clinically insignificant. In one case, a small injection site haematoma developed. CONCLUSION: Embolisation is a minimally invasive, effective and safe method of treatment for PCS. The cooperation between gynaecologists and interventional radiologists is essential for successful outcomes. PMID- 26117972 TI - Analysis of -11391G>A and +45>G polymorphisms of ADIPOQ gene in women with excessive weight gain during pregnancy. AB - OBJECTIVES: The aim of our study was to evaluate the frequency of genotypes and alleles of the -11391G>A and +45T>G polymorphisms of the ADIPOQ gene in Polish women with excessive weight gain during pregnancy. A possible correlation between these polymorphisms and selected clinical and anthropometric parameters has been analyzed. MATERIAL AND METHODS: A total of 153 pregnant Caucasian women of Polish origin with normal pre-pregnancy body mass were analyzed: 78 women with excessive weight gain (study group) and 75 women with normal weight gain during pregnancy (control group). The analysis of the polymorphisms was performed by PCR/RFLP. RESULTS: The influence of the -11391G>A polymorphism on body mass and BMI values at the end of pregnancy (p < 0.05) was observed. We also detected a correlation of the +45T>G polymorphism with body mass at the end of pregnancy and pre pregnancy WHR values (p < 0.05). CONCLUSIONS: The observed effect of the 11391G>A polymorphism on the parameters assessed at the end of pregnancy (BMI and body mass), suggests a protective role of the -11391A genetic variant in excessive weight gain. It is claimed that the mutated +45G allele of the +45T>G ADIPOQ polymorphism shows a possible connection with higher pre-pregnancy WHR values and body mass at the end of pregnancy Our findings suggest a possible contribution of the -11391G>A and +45T>G polymorphisms of the ADIPOQ gene to the pathomechanism of excessive weight gain in pregnant women from the Polish population. This observation should be confirmed in a larger sample size study PMID- 26117973 TI - [Chromosomal aberrations--the cause of spontaneous abortions]. AB - The genetic factor remains the most frequent cause of spontaneous abortions. Examination of the fetal tissue from spontaneous miscarriages shows that 75% of them were caused by abnormal karyotype. Other reasons, albeit rare, included submicroscopic genomic rearrangements, monogenic diseases, and polygenic inheritance disorders of the embryo. OBJECTIVE: The aim of the study was to analyze the incidence of chromosomal aberrations in material from the miscarriage. MATERIAL AND METHODS: The study included 47 samples of miscarriage material from 47 women. Fluorescent hybridization in-situ (FISH) was used for genetic examination. RESULTS: Chromosomal abnormalities were diagnosed in 72% of the samples, with trisomy 21 (25.5%), trisomy 16 (17%), and trisomy 18 (12.8%) as the most common. An abnormal number of copies of chromosome 18, 21, 22, indicating the coexistence of trisomy 18, 21, 22, was detected in 1 patient. It was another miscarriage in case of 14 subjects (29.8%). CONCLUSIONS: Chromosomal aberrations were diagnosed in the majority of fetal tissue samples from spontaneous miscarriages. More than one chromosomal aberration in a single embryo is an extremely rare occurrence. Miscarriage due to chromosomal aberrations occurred in the vast majority of women > 35 years of age. PMID- 26117974 TI - First trimester biochemical markers in twin pregnancies. AB - OBJECTIVE: Our aim was to investigate the first trimester serum markers and nuchal translucency (NT) measurements in twin pregnancies in our population. MATERIALS AND METHODS: We reviewed the results of all double tests that were performed in our hospital over a three-year period. Out of them, we selected all twins and compared them with a group of three times as many singleton controls. NT measurements and the first trimester serum markers from 49 twin pregnancies were compared to those of 147 pregnant women with normal singleton pregnancy RESULTS: There were no statistically significant differences in age, gestational age and maternal weight between the two groups (p > 0.05). We found similar NT measurements in the two groups. The median MoM of Pregnancy-Associated Plasma Protein A (PAPP-A) and fbeta-hCG levels in twins were statistically significantly higher than those in singleton pregnancies. Twelve percent of the twins (12.2%) were the result of assisted reproduction technologies. IVF versus naturally conceived pregnancies showed similar MoM of PAPP-A (2.2 vs. 1.2, respectively) and fbeta-hCG (Mann-Whitney U; p = 0.195 and p = 0.958). CONCLUSIONS: Our study revealed that median PAPP-A and fbeta-hCG levels for twins were less than twice those of singleton values. PMID- 26117975 TI - [Analysis of pregnancy, labor and neonatal course in babies with prenatally diagnosed complete atrioventricular heart block]. AB - INTRODUCTION: Complete heart block (third-degree atrioventricular block) is a defect of the conduction system of the heart, in which the impulse generated in the sinoatrial node does not propagate to the ventricles, and thus the latter contract independently of the atria. A third-degree atrioventricular block can be either congenital or acquired. In 60-70% of the cases, the congenital heart block results from destruction of the conduction system of the fetal heart by anti Ro/SSA and anti-La/SSB antibodies present in maternal serum. The antibodies are synthesized in the course of autoimmune maternal conditions, most often systemic lupus erythematosus or rarer rheumatoid arthritis, dermatomyositis or Sjogren's syndrome. The complete block can occur as an isolated defect or be associated with structural anomalies of the fetal heart. MATERIAL AND METHODS: A total of five patients whose fetuses were diagnosed with the third-degree atrioventricular block have been hospitalized at the Department of Obstetrics, Medical University of Gdansk between 2012 and 2014. RESULTS: We present the data of the five patients, hospitalized at the Department of Obstetrics, Medical University of Gdansk, whose fetuses were diagnosed prenatally with the complete heart block. The cases differ in terms of etiology clinical outcome, and postnatal treatment. All data are presented in Table I. CONCLUSIONS: We emphasize the role of appropriate pregnancy management and careful monitoring of the fetal condition. From obstetrical perspective, it is important to monitor the condition of fetuses with the third-degree atrioventricular block ultrasonographically and echocardiographically; in turn, cardiotocography is less useful in this setting. Therefore, a non-reactive cardiotocographic tracing should not constitute an indication for a preterm delivery. An affected fetus should be delivered in a tertiary center for perinatal care that cooperates with a pediatric cardiology center. An efficient program for cardologic prenatal care and close cooperation between obstetricians, neonatologists, pediatric cardiologists, and cardiac surgeons constitute the key to a successful outcome. PMID- 26117976 TI - Relation of platelet distribution width (PDW) and platelet crit (PCT) to preeclampsia. AB - OBJECTIVE: While the relationship between platelet crit (PCT), platelet distribution width (PDW) and hypertension has been well-documented, data on the association between PCT, PDW and preeclampsia are scant at best. In our study we aimed to investigate the possible correlation of PCT and PDW with preeclampsia and disease severity MATERIAL AND METHODS: A total of 110 preeclamptic and 100 healthy pregnant women were included in the study Baseline PCT and PDW were measured using an automatic blood counterin the entire study population. RESULTS: While there were no significant differences between the preeclampsia group and the control group in terms of hemoglobin and platelet counts, the PDW, mean platelet volume (MPV), systolic and diastolic blood pressure, proteinuria, WBC and Hs-CRP levels were significantly higher in the preeclampsia group. In addition, PCT level was significantly lower in the preeclampsia group as compared to controls. Moreover subgroup analysis revealed that PDW and MPV levels were significantly increased in severely preeclamptic patients when compared to mildly preeclamptic patients. CONCLUSIONS: Our study results revealed that PCT and PDW levels were associated with both, the presence and severity of preeclampsia. PMID- 26117977 TI - Perinatal outcome in women with inflammatory bowel disease. AB - INTRODUCTION: Inflammatory bowel disease (IBD) is a lifelong, chronic inflammatory condition of the gastrointestinal tract. IBD morbidity rate in Europe has been steadily growing for the last six decades. Women with IBD are often diagnosed during the childbearing years, which makes the influence of the disease on pregnancy and birth outcomes an important clinical issue. OBJECTIVES: The aim of the study was to estimate the influence of the IBD process among pregnant women on maternal, fetal and neonatal parameters. MATERIAL AND METHODS: A retrospective analysis of data on patients suffering from IBD, diagnosed before pregnancy who were admitted to the Department of Perinatology and Gynecology Polish Mother's Memorial Hospital Research Institute for delivery between 2009 2013, was conducted. IBD was diagnosed in 10 cases. The control group consisted of 10 healthy pregnant women near delivery RESULTS: IBD activity status at conception in women receiving continuous mesalazine treatment does not correlate with gestational age, birth weight, Apgar score or maternal platelet count at delivery in comparison to controls. IBD patients under mesalazine management had lower: i) maternal body mass index and platelet count, ii) neonatal birth weight and Apgar score as compared to controls. However, no impact of IBD on the frequency of congenital anomalies was noted. CONCLUSIONS: To the best of our knowledge, this has been the first study conducted among pregnant women with IBD in Poland. The analysis demonstrates that pharmacological treatment has a deteriorating influence on maternal weight gain in pregnancy as well as production and activity of platelets. Moreover, it diminishes fetal growth and worsens short-term neonatal condition. Further studies with larger sample size are necessary but the rarity of this complication limits the possibility of research therapeutic perspectives. PMID- 26117979 TI - Innovative therapy of ovarian cancer based on overexpression of CD44 receptor. AB - Ovarian carcinoma constitutes the main cause of cancer-related death among women. The curability rates remain low despite rapid advances in medicine. Thus, the search for new and improved methods continues, with CD44-targeting as one of them. CD44 is a cell-surface glycoprotein, which binds to its ligand--hyaluronic acid (HA)--and regulates crucial processes such as cell differentiation, proliferation and migration. Overexpression of CD44, observed in many ovarian cancer cells, is used in creating carriers for selective delivery of various drugs (paclitaxel, doxorubicin, camptothecin or cisplatin) to cancer cells. In this article, we summarized the current state of knowledge regarding CD44 targeting as a new and more efficient way of ovarian cancer treatment, with high potential and promising therapeutic perspectives. PMID- 26117978 TI - Assessment of patient acceptability of medical treatment in case of non-viable first trimester pregnancy. AB - OBJECTIVES: The aim of the present study was to assess patient acceptability and satisfaction with medical treatment (vaginal misoprostol) of non-viable first trimester pregnancy. MATERIAL AND METHODS: A total of 64 women, treated with vaginal misoprostol for non-viable first trimester pregnancy between October 2012 and December 2012 at the First Department of Obstetrics and Gynecology Medical University of Warsaw, were included in this questionnaire-based study. Questions pertaining to advantages and disadvantages of misoprostol treatment as compared to potential surgical intervention were used. The respondents also determined whether they would choose medical treatment if they were to decide again. The Visual Analogue Scale (VAS) was used to assess pain and bleeding intensity. RESULTS: Medical treatment was successful in 57 and surgical treatment was needed in 7 women. Average pain and bleeding intensity were 5.8 and 5.3, respectively. The most common side effects included diarrhea (27%), dizziness (22.2%), nausea (15.9%), and chills (15.6%). The most important advantages of misoprostol therapy were avoidance of the risk of uterine perforation (96.4%) and formation of intrauterine adhesions (74.6%), whereas the most significant disadvantages were prolonged bleeding (21.4%), pain (21.4%), and longer treatment duration (42.9%). Overall, 95.6% of the patients with successful treatment outcome declared they would choose this procedure if they were to decide again, as compared to 85.6% of women with treatment failure (p > 0.05). CONCLUSIONS: Medical treatment with vaginal misoprostol is acceptable and well-tolerated by the vast majority of women with non-viable first trimester pregnancy. Satisfaction is expressed by both, respondents with successful as well as unsuccessful treatment outcome. PMID- 26117980 TI - [Polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) risk]. AB - Gestational diabetes mellitus (GDM) is a common complication of pregnancy In the course of pregnancy elevated levels of hormones and other proteins having insulin antagonistic effects lead to higher insulin resistance in peripheral tissues, followed by hyperinsulinemia. Risk factors for the development of GDM have been well-established. However, the debate whether polycystic ovary syndrome (PCOS) may predispose to GDM continues. Patients with PCOS are often affected by obesity dyslipidemia, hyperinsulinemia, and tissue-specific insulin resistance. Obesity occurs in 50% of the cases, while tissue-specific insulin resistance is observed in 20-40% of the affected patients. This paper aims at systematizing risk factors that could contribute to the development of GDM, as well as reviewing literature reports and analyses on the occurrence of a potential correlation. PMID- 26117981 TI - Placenta accreta: review and 3 case reports. AB - Placenta accreta is characterized by excessive penetration of the villi into the myometrium, which obstructs its correct separation during stage III of labor. That in turn leads to a potentially life-threatening maternal hemorrhage. Until recently this pathology has been a rare occurrence but currently it is fifty times more prevalent. Placenta accreta is associated with high morbidity and the risk of maternal death, even despite advances in ultrasonographic diagnostics, well-established surgical treatment, and multi-disciplinary medical care. A dramatic rise in the rates of Cesarean section and intrauterine surgical procedure is considered to be the main factor responsible for the growing incidence of placenta accreta. It is especially frequent in women after a Cesarean section and with placenta previa covering the lower segment. A Cesarean section, combined with hysterectomy and application of various techniques to limit massive bleeding, is usually performed between 34-36 weeks of pregnancy before the onset of labor. Three cases of placenta accreta are presented. PMID- 26117982 TI - [Expression of melatonin receptors genes and genes associated with regulation of their activity in endometrial cancer]. AB - OBJECTIVES: The aim of the study was to evaluate transcription activity of melatonin receptors and genes associated with regulation of their activity in endometrial adenocarcinoma to identify probable diagnostic and prognostic molecular markers. MATERIAL AND METHODS: The material included endometrial adenocarcinoma tissue samples of histopathological grades G1, G2, G3, and normal endometrium. The molecular analysis was performed on 37 patient samples. Total RNA was extracted and used for the microarray HG-U133A analysis. Among 22 283 ID mRNA, only entities of genes associated with regulation of melatonin receptors activity were selected. qRT-PCR was employed for validation, what allowed to compare melatonin receptor genes activation in endometrial cancer tissues to the normal endometrium. RESULTS: The results of the microarray experiments showed that only 18 ID mRNA were differential in endometrial cancer samples as compared to the control at p-value<0.05 and FC(log2)>1.5. These genes were identified as differentially expressed in grade G2-ASMTL, GNA 11, PER2, PTGDS and in grade G3 GNA12, GNA 11. Silencing of RGS4 encoding RGP4, which regulates signal transmission by G protein, was observed in all cancer groups, independently of the histopathological grade. CONCLUSIONS: The profile expression of genes associated with regulation of melatonin receptors activity was different and dependent on the histopathological grade of endometrial cancer and can be an additional diagnostic and prognostic marker Statistically significant was the down-regulation of melatonin biosynthesis genes (ASMTL) and melatonin signal transmitters (GNA 11, GNA 12, RTGS). PMID- 26117983 TI - Diagnostic value of CA125, HE4, ROMA and logistic regression model in pelvic mass diagnostics - our experience. AB - OBJECTIVES: The aim of this study was to compare and evaluate the quality of CA 125, HE4, logistic regression model based on CA 125 and HE4, and ROMA algorithm in preoperational differential diagnostics of the ovarian tumors. MATERIAL AND METHODS: To the study 110 patients enrolled. Based on histopatological examination of removed tumors, they were divided into study group (56 cancer patients) and control one (nonmalignant 54 patients). Serum CA 125 and HE4 concentrations were measured following a standard procedure. RESULTS: A commonly accepted referential value for CA 125 is 35 IU/ml. In our study this cut-off value yielded very low sensitivity and specificity results (85.2% and 63.6%, respectively). When we adopted HE4 normal value to be 140 pM,the sensitivity and specificity obtained in the investigated population was 68.5% and 94.6%, respectively When the cut-off value for HE4 was adopted as 74 pM, the sensitivity improved considerably (88.9%), but specificity decreased to 85.7%. In case of CA 125 when we adopted Ca 125 normal value to be 77 IU/ml, the sensitivity and specificity obtained in the investigated population was 81.5% and 83.6%, respectively In analysis based on combination of biomarkers, the highest sensitivity was obtained for the logistic regression model based on CA 125 and HE4 (89.5%). A little bit lower sensitivity was achieved for HE4 used as a single diagnostic test (88.9%). The highest specificity was observed for ROMA algorithm (94.5%). This means that ROMA algorithm is the best diagnostic tool to differentiate between the malignant and non-malignant ovarian tumors. CONCLUSIONS: 1. ROMA algorithm yielded the highest specificity and slightly lower sensitivity in the case of differential diagnosis between malignant and non malignant ovarian tumors. Therefore, it should become a basic tool in the ovarian tumors diagnosis prior to a surgery 2. HE4 as a single diagnostic test (based on one marker) was found to be better suited to the ovarian tumor differential diagnosis than CA 125 test. 3. Combined test, based on double marker analysis, should be applied and then the risk of the ovarian cancer should be calculated. This approach is more effective than single marker analysis. PMID- 26117984 TI - [Micrometastases in sentinel lymph node in endometrial cancer patients]. AB - BACKGROUND: Detection of micrometastases in sentinel lymph nodes (SLN) extends our knowledge of lymphatic spread in endometrial cancer, although its clinical significance has not yet been confirmed. OBJECTIVES: The aim of study was to determine the incidence of SLN micrometastases and to analyze the association between micrometastases and disease relapse. MATERIAL AND METHODS: Fifty-four patients with endometrioid endometrial cancer underwent routine surgical therapy and sentinel lymph node biopsy (SLNB). SLNB was performed using two techniques: cervical injection of 99mTc-labelled albumin or blue dye and fundal injection of blue dye. SLNs were subjected to ultrastaging with immunohistochemistry (AE1/AE3, 150um). RESULTS: At least one SLN was detected in 51 patients (94.4%) and bilateral SLN detection was achieved in 80.4%. Nodal macrometastases were found in 3 patients (6.3%). SLNB enabled us to detect nodal macrometastases in 2 out of those 3 patients. In the third case, detection of SLN micrometastasis allowed to correctly determine the nodal status, thus avoiding the false negative result of SLNB. In 48 patients with detected 184 SLNs, there were 4 patients (8.3%) with micrometastases and 4 (8.3%) with ITC foci. No significant associations between the presence of risk factors (grade, myometrial invasion, cervical invasion, lymphovascular space invasion) and incidence of micrometastases and/or ITC foci in SLNs were found. CONCLUSIONS: Detection of micrometastases may result in lower false-negative rate, thus increasing SLNB safety. PMID- 26117985 TI - Comparison of tissue trauma after abdominal, vaginal and total laparoscopic hysterectomy. AB - OBJECTIVE: The aim of the study was to compare the extent of tissue trauma atter abdominal hysterectomy(AH), vaginal hysterectomy (VH), and total laparoscopic hysterectomy (TLH) using biochemical markers. MATERIAL AND METHODS: Seventy-one patients requiring hysterectomy for benign uterine diseases were enrolled in the study and divided into three treatment groups: AH (n=24), VH (n=23), and TLH (n=24). Blood samples for assay of interleukin-6 (IL-6) and creatine phosphokinase (CPK) were collected pre-, intra-operatively and 2, 6 and 24 h after surgery. RESULTS: Serum levels of IL-6, and CPK were significantly elevated over basal values after surgery in all groups. IL-6 and CPK levels were significantly higher after AH as compared to VH and TLH. IL-6 concentrations were significantly higher in the VH group than the TLH group (p=0.00 1). There were no significant differences in CPK levels between the VH and TLH groups (p=0.824). TLH group had the smallest decrease in blood hemoglobin concentration and the shortest hospital stay CONCLUSIONS: AH causes more tissue trauma as compared to VH and TLH. Owing to the fact that TLH is associated with less tissue trauma and offers significant clinical benefits, including less blood loss and shorter hospital stay it should be considered in women with benign gynecologic conditions, especially in experienced centers. PMID- 26117986 TI - The contribution of Hind III C>G PAI-1 gene polymorphism in etiology of recurrent miscarriages. AB - OBJECTIVES: The goal of the study was to assess the relationship of HindIII C>G PAI-1 gene polymorphism with increased risk of recurrent miscarriages. MATERIAL AND METHODS: A whole of 152 women with a history of at least two miscarriages were classified into analysis. The study group was divided twice (114 subjects with 2 miscarriages and 38 subjects with >3 miscarriages, 123 subjects with miscarriages at <13gw, and 29 subjects with miscarriages in <21 gw). The controls consisted of 180 women with a positive history of at least one pregnancy and birth of a healthy term newborn, and a negative history of miscarriage. The analysed polymorphisms were determined by PCR/RFLP methods. RESULTS: The occurrence of HindIII GG genotype in the whole study group was 25.7% and 20.0% in controls (OR= 1.38, p=0. 14). HindIII G allele was also observed more frequently in the whole study group (45.7% vs. 42.2% in controls, OR=1. 15, p=0.20). The occurrence of HindIII GG genotype was higher in the subgroup of women with >3 miscarriages (31.6% vs. 20.0% in controls, OR= 1.85, p=0.09). HindIII G allele was also noted more frequently in the subgroup of women with >3 miscarriages (50.0% vs. 42.2% in controls, OR=1.37, p=0. 13). A tendency of higher frequency of HindIII GG genotype and HindIII G allele was also noted in the subgroup of patients with miscarriages in the first and second trimester (HindIII GG: 31.0% vs. 20.0% in controls, OR= 1.80, p=O. 14, HindIII G: 51.7% vs. 42.2% in controls, OR=1.4 7, p=0.11). CONCLUSIONS: Mutated HindIII G allele and HindIII GG genotype of HindIII C>G polymorphism probably augment the risk of recurrent miscarriages. PMID- 26117987 TI - [Fetal cardiac interventions - are we ready for them?]. AB - OBJECTIVE: The aim of the study was to analyze types and methods of intrauterine fetal cardiac interventions performed between June 2011 and December 2013, and to assess the perinatal management of the neonates. METHODS: The program was developed after analysis of the available literature, practical individual training in Linz, Austria, and simulation of the procedure in a dissecting-room. The rules for anesthesia in pregnant women and their fetuses were developed. The interventions were performed in fetuses with critical cardiac defects, in the operating room, under ultrasonographic control. The protocol was approved by the Local Bioethics Committee at the Centre of Postgraduate Medical Education. MATERIAL: We included fetuses with critical aortic stenosis (n=29), critical pulmonary stenosis (n=2), and closed or extremely restricted foramen ovale (n=7). Between June 2011 and December 2013, the team comprised of JD, MD and AK conducted 42 interventions in 35 fetuses, including 32 balloon aortic valvuloplasties (in 29 fetuses), 2 pulmonary valvuloplasties, 4 balloon atrial septostomies and 4 atrial septal stent placement. Three fetuses required both, aortic valvuloplasty and fenestration of the atrial septum. RESULTS: Out of the 42 procedures, 41 (97%) were technically successful. We recorded 3 cases of fetal demise associated with the intervention. We modulated the protocol of anesthesia given to pregnant women, switching from general to local anesthesia with intravenous sedation. We always provided additional fetal anesthesia with fentanyl and atracurium via the umbilical vein. CONCLUSIONS: Based on our 2.5 year experience, it seems safe to conclude that all types of fetal cardiac interventions may be successfully conducted at Polish centers. The procedures are safe for the pregnant women and improve fetal status. Most of the neonates treated prenatally were referred in good general condition to a tertiary pediatric cardiology and cardiac surgery center PMID- 26117989 TI - Assessment of the diet components of pregnant women as predictors of risk of preterm birth and born baby with low birth weight. AB - OBJECTIVE: The diet of pregnant women is an important factor in the development of the fetus. In our study we wanted to determine the diet of women who gave birth to healthy children at term (AGA), preterm (PTB) and small for gestational age neonates (SGA). Based on the analysis of dietary components we wanted predict the likelihood of giving birth AGA, PTB and SGA. METHODS: The content of components in the women's diets were estimated based on the dietary questionnaire. The large number of variables analyzed in the diet was reduced using factor analysis. Next, the prediction of pre-maturity and SGA based on previously selected factors was analyzed. For this purpose, two independent methods were used: discriminant function analysis and ROC analysis. RESULTS: Factor analysis resulted in nine factors containing at least one variable of the factor load being greater than 0.7. Analysis of variance only showed differences between the AGA and preterm groups. The study of discriminant function showed that three factors significantly affect the discriminative power to classify cases into AGA and preterm groups. ROC analysis confirmed diagnostic usefulness factor 1 (fatty acids) in classifying cases into AGA and preterm groups. CONCLUSION: Based on the analysis of dietary components of women one can predict the likelihood of giving birth to a healthy child at term and prematurely For AGA the predicting factor is a higher content of short and medium chain fatty acids in a woman's diet. PMID- 26117988 TI - The evaluation of homocysteine level in patients with preeclampsia. AB - OBJECTIVES: The aim of the study was to evaluate the correlation between preeclampsia and blood plasma homocysteine levels. MATERIAL AND METHODS: The research was conducted in a group of 114 pregnant patients who were subdivided into three groups consisting of: 30 women with severe preeclampsia, 24 with mild preeclampsia, and 60 healthy pregnant controls. Patient data included age, parity body mass index (BMI), systolic and diastolic blood pressure, homocysteine, folic acid, vitamin B12, hematocrit, hemoglobin, blood urine nitrogen, uric acid and urine analysis. RESULTS: There were no differences in the demographic characteristics (age, gravidity and BMI) among the groups. Mean serum homocysteine level was significantly higher in the preeclamptic group as compared to controls (p<0.01). Mean homocysteine level in the control group was significantly lower than in the severe and mild preeclampsia groups, respectively (p<0.001 vs. p<0.05). There were no statistically significant differences in homocysteine levels between mild and severe preeclampsia groups (p>0.05). Although there were statistically significant differences among the three groups in terms of BUN, creatinine, AST ALT and LDH, no statistically significant differences in serum folic acid, vitamin B12 and hemoglobin levels were found. CONCLUSIONS: Plasma homocysteine levels are significantly elevated in patients with preeclampsia and are not correlated with disease severity PMID- 26117990 TI - The role of insulin and selected adipocytokines in patients with polycystic ovary syndrome (PCOS) - a literature review. AB - Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. It is manifested by hyperandrogenism, polycystic ovaries on ultrasound, oligomenorrhoea and anovulation. PCOS patients are more vulnerable to metabolic disorders: insulin resistance, obesity endothelium dysfunction, atherosclerosis, and activation of proinflammatory factors. This association shows that PCOS might be an ovarian manifestation of a metabolic syndrome. Insulin resistance is also strongly correlated with reproductive failure. Approximately 100 factors, secreted in adipose tissue, are responsible for its regulation. Adipocytokines have been found to play an important role in regulating insulin sensitivity Abnormal levels of adipokines are detected in patients with insulin resistance. Studies indicate that these factors, and their different activity in PCOS women, may affect changes observed in their metabolism and, especially may participate in the development of insulin resistance. There are several adipokines whose role has been thoroughly investigated and many that we still know very little about, for example apein and visfatin. Counseling PCOS patients about the possibility of developing metabolic syndrome, diabetes mellitus, and cardiovascular diseases should be a standard of care. PMID- 26117991 TI - [Levonorgestrel-releasing intrauterine system Mirena(r) (Bayer) for the prevention and treatment of endometrial adenocarcinoma and the incidence of other malignancies in women]. AB - The use of hormone-releasing intrauterine devices has been on the increase for the last three decades. To date, evidence of their long-term efficiency is available. The aim of the present paper was to briefly review beneficial prophylactic effects of the levonorgestrel-releasing intrauterine system on the incidence of a variety of malignancies in women. Such an influence is of a particular importance in the light of the currently observed increased prevalence of endometrial and cervical adenocarcinomas. Low-dose releasing intrauterine systems are also available, but the hard evidence-based medical data have been derived primarily for Mirena(r) (Bayer) device, which topically releases from 20 to 14 pg of levonorgestrel daily. Consequently the risk of developing endometrial carcinoma in Mirena(r) users is lowered by as much as 50% compared with the general population risk To a lesser extent, the intrauterine system decreases the risk for cervical adenocarcinoma and squamous cell carcinoma, as well as ovarian, pancreas, and lung carcinomas. In one population-based study Mirena(r) increased the risk for breast carcinoma by approximately 20%, whereas a number of other studies failed to demonstrate such a hazard. In the recent decades of the increased predominance of insulin resistance and obesity and an occurrence of hormone-dependent carcinomas at earlier age, a broad application of levonorgestrel-releasing intrauterine systems may become a particularly important component of primary prevention of malignancies in women. Both obese and overweight patients seem perfect candidates for such a hormonal intervention. PMID- 26117992 TI - [The role of Wnt/beta-catenin pathway and LRP5 protein in metabolism of bone tissue and osteoporosis etiology]. AB - Osteoporosis is a metabolic bone disease, manifested by decreased bone mineral density microarchitectural disturbances of bone tissue, and increased risk of bone fractures. Owing to large-scale morbidity particularly among postmenopausal women, nowadays osteoporosis constitutes a significant global health problem. In recent years, much attention has been paid to the role of signaling Wnt/beta catenin pathway and LRP protein in the pathomechanism of osteoporosis, indicating a possible contribution of polymorphic variants of the candidate LRP5 gene to disease development. The goal of our study is to present contemporary research on signaling Wnt/beta-catenin pathway and mechanism of LRP protein action in the process of bone tissue metabolism and etiology of osteoporosis. PMID- 26117993 TI - Toxic epidermal necrolysis complicating antibiotic treatment of puerperal endometritis: a case report. AB - The aim of the study is to describe a case report of Lyell syndrome (toxic epidermal necrolysis) involving 63% of body surface which has been associated with antibiotic therapy of mild peurperal endometritis in woman 3 weeks postpartum. Lyell syndrome is a severe life-threatening condition developing due to idiosyncrazy (alergic reaction type IV), most commonly after administration of drugs. Incidence quoted in literature is around 1:1-2000000. Illness severity can be assessed using a SCORTEN scoring system, which predicts patient mortality based on seven independent factors. Lyell syndrome is a very rare but potentially lethal complication of antibiotic treatment. PMID- 26117994 TI - [Recommendations of the Polish Gynecological Society regarding application of "Prevomit" in obstetrics]. PMID- 26117995 TI - [TAKING CARE OF THE PERSON WHO IS SUFFERING AND FACING DEATH]. PMID- 26117996 TI - [FACTORS THAT INTERFERE WITH PATIENT'S SLEEP IN THE HOSPITAL]. AB - The sleep disorders are quite common in hospitalized patients, but are also undervalued by health professionals. The identification of factors that interfere with sleep patients has been the subject of numerous studies. OBJECTIVE: To identify factors that interfere with the patient's sleep in the hospital. METHODOLOGY: We performed a research on EBSCO (CINAHL with Full Text; MEDLINE with Full Text; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; Database of Abstracts of Reviews of Effects; Medlatina), LILACS (full text available) andSCIELO (Brazil, Spain andPortugal), andsearch full-text articles, publishedfrom 1 January 2007 to 31 December2012. The PI[C]O method was used, and selected six articles from a total of thirty-six. RESULTS: We identify 20 factors that interfere with the patient's sleep in the hospital and describe particular aspects relevant to each of these factors. CONCLUSION: The factors that interfere with the patient's sleep in the hospital were grouped into External (Environmental and Associated to care) and Internal (Physiological and Psychological). The results allow us to realize that these factors are identified, but they still persist in services, interfering with the patient's sleep. Awareness of health professionals is the first step to adopt the measures suggested in this article, in order to reduce the impact of these factors on the patient's sleep in the hospital. PMID- 26117997 TI - [NURSING ETHICS ISSUES IN PALLIATIVE CARE]. AB - The aim of this paper is to describe the essential anthropological categories of terminal illness and the main attitudes of nurses for their care and the ethical criteria for indication and application of palliative therapies. We conclude that ethical attitudes of care in palliative care nursing are based in anthropological categories of dying process; the access granted to nurse by the patient and family within their privacy generates a relational context where communication can be made more effective and thus facilitate the coping existential, spiritual and psychosocial in illness and the process of diagnostic and prognostic information. The qualitative and quantitative clinical information provided by the nursing professional to multidisciplinary team on the evaluation of the effectiveness of care outcomes and therapies in the context of terminal illness assistance allows establishing a plan of treatment appropriate ethically. PMID- 26117998 TI - [NASO-OROGASTRIC TUBE IN PAEDIATRIC PATIENTS. REVIEW OF METHODS OF CONFIRMATION OF PLACEMENT]. AB - Nasogastric tube (NGT) placement is a frequent procedure in the paediatric population. Nasogastric and orogastric tubes are commonly used in hospitalized children, in the paediatric emergency departments and in critical care departments. They have diagnostic, therapeutic, descompression or evacuation of gastric aspirates objectives. Making a blind placement of nasogastric tubes, involve that nasogastric tube could be misplaced in 4.7 % to 69 % of cases. An accurate method for confirmation of nasogastric tube positioning is therefore needed. Chest X-ray remains the only hundred per cent reliable method (gold standard), but it only confirms tube positioning at the exact time of the X-ray. Non-radiologic verification methods provide an accurate alternative and contribute to decrease radiation exposure for pediatric patients. Non-radiologic methods to verify appropiate placement of tubes are many and are supported by different degrees of evidence in the literature: measurement of tube length from point of entry; auscultation; placing the tube in water to assess bubbling; aspiration of stomach or intestinal contents for visual inspection; pH testing; use of CO2 monitoring devices, or combinations of these methods. In this article we thoroughly review the reliability and safety of these non radiologic methods for the verification of nasogastric tube placement. PMID- 26117999 TI - [TREATMENT OF ATTENTION DEFICIT AND HYPERACTIVITY DISORDER (ADHD): NURSING IMPLICATIONS]. AB - OBJECTIVE: This review aims to know the role of the nurse in ADHD treatment, identifying the most appropriate therapeutic options between nursing interventions and pharmacological treatment. DEVELOPMENT: In ADHD, the role of the nurse is to respond family needs about the effectiveness of medication, behavior modification treatment and other alternatives. There are family interventions of psychoeducation that assist the child in the recovery process. Through the education for health, the nurse should promote the combination of behavioral therapy and pharmacological as the only one able to improve child's quality of life. CONCLUSIONS: Nurses have a privileged role due to its experience in education for health; this contributes to being a competent agent that provides families essential information about the disease treatment. Spanish schools are lacking a figure that represent health as a relevant subject in the vital process, hence the need of the school nurse. PMID- 26118000 TI - [INEFFECTIVE MANAGEMENT OF THERAPEUTIC REGIMEN AND NONCOMPLIANCE AND ITS RELATIONSHIP WITH EPISODES WONCA]. AB - At the present time, failure to follow prescribed treatments is a problem of deep draft of health systems. The problem is both clinical and economic. Nurses are main responsible, within the health system, to ensure the proper monitoring of therapeutic guidelines agreed with the patients, by themselves or by other health care professionals. The aim of this work is to determine the health problems (expressed through the ICPC-WONCA classification) in which occurs more often no tracking treatments, following a nurse methodology, specifically relating ICPC codes with patients diagnosed with <> or <> of NANDA-I classification. METHOD: It has been made a descriptive and retrospective study. The data used are drawn from the clinical history of OMI-AP (manager) of all patients of all health centers in the Madrid region, during 2006, 2007 and 2008. RESULTS: 36.1 % ofpatients who fail or do not properly handle the treatment were classified with ICPC code K86 uncomplicated hypertension; 33.2 % with non-insulin dependent diabetes T90; 8 % with A13 treatment fear; and 5.6% with Obesity T8. There are no differences between men and women regarding compliance and the age group over 50 years is having major problems in monitoring their treatment. PMID- 26118002 TI - [HEALTH EDUCATION: PHYSICAL EXERCISE IN THE ELDERLY]. PMID- 26118001 TI - [NON-ONCOLOGIC CHRONIC PAIN TREATMENT WITH OPIATES]. AB - Non-oncologic chronic pain is a very common symptom. It causes great impact on daily activities of people who suffer it. The incidence of this type of pain is rising due to the increase in life expectancy. The most affected population is geriatric population. Back pain, osteoarthritic pain and neuropathic pain are the most prevalent types of non-oncologic chronic pain. Opiates, among other analgesic drugs, are used to alleviate this type of pain. Opiates are divided into minor opiates (tramadol, codeine) and major opiates (morphine, fentanyl, oxycodone, methadone). Opiates are very effective to treat pain, but they also have important adverse effects that we must know and try to prevent. One of these adverse effects is the opiates ability to cause dependence, tolerance, addiction and other aberrant behaviors. Terminology of these concepts is sometimes confusing. It is necessary to be careful and control the patient periodically in order to avoid these aberrant behaviors. However, if health professionals take precautions to prevent these behaviors, the risk is considerably reduced. Controlling patients on opiate treatment is essential to achieve a correct use if these drugs. PMID- 26118003 TI - [NURSING MANAGEMENT: CREATION OF A HOSPITAL COMPLEX. AREA II OF THE MURCIA HEALTH CARE SERVICE (CARTAGENA)]. AB - INTRODUCTION: This paper analyzes, by a descriptive study, the closing of the Basic Hospital of the Defence the restructuration of the Santa Maria del Rosell University Hospital, and the moving of both to a new hospital: the Santa Lucia University Hospital. This process was carried out in coordination with a coincident objective: the creation of an only management staff for the area. The aim is the analysis of the opening of a hospital complex that coincided with the restructuration of the health area. METHODOLOGY: This paper analyzes the actions in relation to the scheduling, training and moving, that concerned above 600 hospital beds and 275.000 inhabitants. Analyzes the intervention in infrastructures, logistics and training. The whole process is seen from de nursery point of view, as a professional stratus that knows the roles of the hospital and personnel. The period of the study comprises since October2010, beginning of the activity in the new hospital, to November 2011, moment of the effective culmination of the move. RESULT: The result of the works carried out was the transfer of people and roles in a very short time (eleven months). All the patients were moved without any event. CONCLUSION: During the whole process healthcare continuity was obtained, whit the less economic impact, as in patients and professionals. From the point of view of future and practical implications, the basis for a modern and qualified provision of services have been established; and best results from means provided have been obtained in relation to health care quality. PMID- 26118007 TI - [Why health sciences?]. PMID- 26118008 TI - [SCIENTIFIC PRODUCTION ON THANATOLOGY IN NURSING JOURNALS: SYSTEMATIC REVIEW]. AB - OBJECTIVE: Analyze the scientific production on Thanatology published in nursing journals. METHODOLOGY: Systematic review, with quantitative approach, that aimed the characterization of the articles with regard to the year and journal of publication, and its Qualis CAPES, thematic approach, methodological focus, description of training area and qualification of authors. RESULTS: According to the selection criteria of the sample, 36 articles whose publication period was between the years 1986 and 2011 were extracted for analysis. It was noted the predominance of studies published in journals with high quality strata (A1 and A2), use of qualitative method and nurses educators as authors. The focus of the studies encompassed six central themes, and the prevailing ones were: "Thanatology in the academic training" and "The nurse in face of the dying process of patients and families under their cares". CONCLUSION: It is clear that the issue still presents itself in a timid manner, requiring an increased production on the subject. PMID- 26118009 TI - [OPINION OF HEALTH PROFESSIONALS ON ADHERENCE AND MANAGEMENT OF LONG-TERM TREATMENTS IN ADOLESCENTS]. AB - OBJECTIVE: To assess opinion of health professionals about adherence and management of long-term treatments in adolescents in a tertiary hospital. METHOD: A cross-sectional study was carried out in the Vall d'Hebron University Hospital in Barcelona, Spain. Participants were health professionals who care adolescents with solid organ transplant, hematologic disease, diabetes, cystic fibrosis or HIV+. Data collection was performed by self-administered questionnaire, developed specifically for this study. RESULTS: A total of 105 professionals (70%) participated in the study, 80% were nurses, 56% of them indicated that treatment compliance was good. 43% indicated that adherence was not addressed well and 79% of professionals did not have planned time to conduct health education related to treatment. 19.5% of nurses and 72.2% of physicians reported having adherence assessment tools. 39% of participants made suggestions for improvement. CONCLUSIONS: Almost half of the professional indicate that the adherence is not adequately addressed. It is important to evaluate adherence to treatment to identify causes of low compliance and establish and evaluate appropriate interventions. PMID- 26118010 TI - [AUTONOMY, INFORMATION AND NURSING CARE]. AB - This article discusses the need for nurses to actively participate in the process of information to patients/users, especially when the news are bad. It reviews the concept of autonomy and proposes the care as ethical model for information and communication to help the person to understand his situation and make decisions. This way, it focuses the nurse's responsibility in the information and creation of spaces and contexts that promote and respect the autonomy of people with a health problem. PMID- 26118011 TI - [RELEVANCE OF NURSES ON THE PREANALYTIC PHASE AND PATIENT SAFETY IMPLICATIONS]. AB - INTRODUCTION: Nowadays, the patient's safety is considered one of the pillars in a high quality clinical assistance. Inside three steps of laboratory process, it is in the first one, the preanalytical, where most mistakes are made. Nurses are very involved in the development of this period because it is where is included the sampling. METHODOLOGY: We reviewed the literature with the aim to identify the most frequent mistakes, the related factors, the measures taken for its detection and prevention. It emphasizes the importance of nurses in this area, as many of the errors are related to sampling. CONCLUSIONS: We conclude that it is very important to establish suitable andsafe clinical practice standards, identifying improvement areas and planning training programs which contributes to decrease the mistake risk and clinical variability, with special mention to the nurses at this stage. PMID- 26118012 TI - [AT ROOM NUMBER 324]. AB - Hello, my name is Rosa and I have breast cancer. My story begins at a general medical examination. I will remember for my whole life the exactly worlds that changed everything: "You have breast cancer". In relation to a case a description of the stages that patients who are suffering from a terminal illness use to go through. We try to go in depth into the feelings world, illness clinical details are leaving behind. PMID- 26118013 TI - [NEURALLY ADJUSTED VENTILATORY ASSIST (NAVA)]. AB - Neurally Adjusted Ventilatory Assist (NAVA) is a new mode of mechanic ventilation and it's based on the electrical signal of the dia- phragm activity (Edi) for the ventilation control. This signal directly represents the central ventilatory drive reflecting the duration, frequency and intensity that the patient wants to ventilate. To capture the diaphragmatic electrical impulse, is required some specific electrodes inserted in a probe nasogastric tube. For this mode, depending upon proper placement positioning and care (probe Edi), the nurse is essential for their proper functioning. PMID- 26118015 TI - [Invisibility of the nursing profession in literature]. PMID- 26118014 TI - [EVOLUTION OF THE ACCESSIBILITY OF HEALTH CENTERS IN SPAIN. MONITORING OF THE LAST SEVENTY YEARS]. AB - INTRODUCTION: The accessibility of the population to health centers in Spain has evolved to over the past decades, linked to the welfare state and changes in the health skills. The aim of this review is to describe the evolution of accessibility and its impact on the population. METHODOLOGY: We used bibliographic databases to search for articles related to the purpose of reviewing and between 1940 and 2013. We have selected those items with higher quality and that helped to build the review of the proposed topic. RESULTS: The accessibility to health centers in Spain is linked to the performance of public attention in the last seventy years. On the one hand, the appearance of Compulsory Health Insurance (SOE) and the creation of Social Security made almost all of the Spanish population had health coverage. On the other hand, the application of principles such as justice and equity brought to the surface many hospitals with the aim of bringing the most assistance to the population. In the early twenty-first century, with an enormous growth of hospitals and a global economic crisis, we see the need to locate health facilities under the principle of spatial economic efficiency or economic rationality. CONCLUSIONS: In a current environment of crisis, the consequences of hyperaccessibility are analyzed (unsustainable health system, population polypharmacy, etc. ) and a more efficient healthcare system is searched. It is also necessary to consider the relationship between the hyperaccessibility and the frequent attendance of population to the health services, and the relationship between hyperaccessibility and polypharmacy. PMID- 26118016 TI - [Midwives: the nurse facing the beginning of human life]. PMID- 26118017 TI - [Nursing care of the terminal patient]. PMID- 26118019 TI - [HEALTH-IMPROVING REMEDIES ON THE BASIS OF SMECTITE(r)]. AB - The review is devoted to the issues of using smectites in medicine. Modern information concerning smectite composition, structure, physico-chemical properties and reasonability of using them with health-improving purposes is presented. Special attention is given to smectite sorbtional and ionic properties and their unique mineral composition. Characterization is given to modern preparation based on smectites, including developed in Ukraine dietary additives of the series Smectovit(r). PMID- 26118021 TI - [LIFE QUALITY OF CHILDREN WITH SMALL ANOMALIES OF HEART DEVELOPMENT, BORN TO PARENTS IRRADIATED IN CHILDHOOD IN THE CHERNOBYL ACCIDENT]. AB - The study involved 162 children with small anomalies of heart development (SAHD) in core group (children born to parents evacuated from the 30-km zone in childhood) and 39 children in the control group. Quality of life of adolescents was assessed by questionnaire MOS-SF-36 in the Russified version (changed by International reseach centre of life quality, Russia, St. Petersburg, 1998). In children of main group with SAHD, was established systemic pathological process involving not only the cardiovascular system, but also an autonomic nervous systems, hemostasis, upper gastro-intestinal tract, hepatobiliary, urinary system, musculoskeletal system and others, which causes polymorphic clinical picture. Quality of life in children with SAHD, born from parents evacuated from the 30-km Chernobyl zone in childhood was reduced in comparison with practically healthy children. The quality life reduction relate, primarily, physical functioning. Clinical polymorphism and reduced quality of life require the development of approaches to improve diagnosis, treatment and rehabilitation of these patients. PMID- 26118020 TI - [THE DYNAMICS OF THE INCIDENCE OF OPPORTUNISTIC INFECTIONS AND SOMATIC DISEASES HIV-INFECTED PATIENTS WHO RECEIVED INPATIENT TREATMENT IN 2006-2011]. AB - To the article a brief historical review and modern data are driven about the state of HIV-infection in the Odessa area, morbidity of HIV is analysed--the infected patients, passing treatment in stationary section of the Odessa regional centre from a prophylaxis and fight against AIDS during the last six year, drawn conclusion about efficiency of introduction of potent antiretroviral therapy. PMID- 26118022 TI - [PECULIARITIES OF THE COURSE OF PREGNANCY, THE IMPLICATIONS OF DELIVERY IN WOMEN WITH PREECLAMPSIA IN THE CONDITIONS OF NATURAL IODINE DEFICIENCY]. AB - The level of preeclampsia in 2.2 times higher in mountain regions as compared with lowland. In the presence of concomitant pathology of the thyroid gland on a background of natural iodine deficiency in pregnancy complicated with recurrent pregnancy loss in 2.8 times more primary placental insufficiency in 3.6 times, oligohydramnios 1.5 times, premature rupture of the amniotic fluid in 1.9 times, anemia, preeclampsia develops at earlier periods of gestation and more difficult to correct medication, in most cases becomes more severe. PMID- 26118023 TI - [THE SYSTEMIC IMMUNITY CELLULAR LINK REACTION IN PATIENTS WITH TRAUMATIC ILLNESS]. AB - The effect of trauma on parameters of cellular immunity changes is studied. The study includes 52 patients with various forms of traumatic illness, aged 18-69 years (37.91-4.28). The control group consisted of 16 patients who underwent routine surgery not related to the pathology of musculoskeletal system. All patients of the main group were divided into 3 groups according to severity of the condition. Analysis of parameters of cellular link of immune system was performed by defining subpopulations of T-lymphocytes in indirect immunofluorescence method using a panel of monoclonal antibodies for CD3, CD4, CD8, CD22 lymphocytes' receptors and calculation of integrated indicators. The highest expression (immune disorders of II-III grades) of changes of cellular immunity observed in patients with severe traumatic: illness (expand clinical picture). Surgical intervention, even without traumatic injury significantly impact cellular immunity, but in patients with traumatic illness immunity violation were significantly higher than in comparison groups patients except immunoregulatory index. PMID- 26118024 TI - [GOUT AND HYPERTENSION]. AB - Gout is the most common rheumatic disease in the adult population. Hypertension is one of the most common comorbidities of gout. The combination of hypertension with metabolic abnormalities is the great importance. In patients with hypertension the high uric acid is an independent predictor of increased risk of cardiovascular events (including fatal cardiac events), and overall mortality. The review considers the pathogenic mechanisms by which uric acid participate in the development and progression of cardiovascular diseases, including hypertension, and the analysis of antihypertensive therapy in patients with gout. PMID- 26118025 TI - [DIAGNOSIS OF ISCHEMIC HEART DISEASE CAUSED BY TORTUOSITY OF CORONARY ARTERIES]. AB - This article is devoted to the problems of diagnostics of coronary artery tortuosity phenomenon. Given the lack of literature about the role of phenomenon tortuosity of coronary arteries in the genesis of ischemic myocardial damage, the purpose of study was to determine the clinical relevance as well as necessity for prevention and treatment of this vascular anomaly. Therefore were analyzed medical history, laboratory and clinical database as well as data functional studies of the heart and cardiovascular system in 1404 patients which were divided into four groups on the results of coronary angiography. The results of the study indicate tortuosity of coronary arteries may be independent and additional burdening factor in the development of ischemic heart disease. PMID- 26118026 TI - [BCL1 POLYMORPHISM OF GLUCOCORTICOID RECEPTOR GENE AND RESPIRATORY DISEASES]. AB - The article analyses the results of investigating the connection between BCL1 polymorphism of glucocorticoid receptor gene and respiratory diseases. Its role in increasing sensitivity to glucocorticoids is proved here. The authors investigated the association of Bcl1 polymorphism with predisposition to bronchial asthma, chronic obstructive pulmonary disease, with the nicotine addiction degree and with progressing disorders of pulmonary function in cystic fibrosis. PMID- 26118027 TI - [IMMUNOHISTOCHEMICAL EXPRESSION OF UBIQUITIN PROTEIN IN PERITUMORAL TISSUE OF PATIENTS WITH TESTICULAR GERM CELL TUMORS]. AB - For the purpose of definition of features immunohistochemical expression of protein Ubiquitin in peritumoral testicular tissue, which can be characterised as precancerous changes, the 40 patients with testicular germ cell tumors are investigated. In peritumoral testicular tissue in patients with disturbance of spermatogenesis. which make 95 %, it is taped: intensifying in seminiferous tubules of ubiquitination processes, testifying about intensive proteolysis of considerable quantity of the damaged intracellular proteins, occurrence of atypical germ cells (TIN), which differ from normal spermatogenesis cells authentically lower of nuclear and cytoplasmatic expression of protein Ubiquitin, and also disturbance of ubiquitination processes in Leydig cells in the form of intensifying of cytoplasmatic expression and total disappearance of nuclear expression of protein Ubiquitin. The received results testify to the important role of structural and functional disturbances of ubiquitin-proteolysis system components at the initial stages of testicular tissue carcinogenesis. PMID- 26118028 TI - [RETROSPECTIVE EVALUATION OF THE EPIDEMIC OF INFLUENZA A (H1N1) IN UKRAINE FROM THE POINT OF PATHOLOGY]. AB - Based on the analysis of clinical records and pathological studies on the 140 who died during the flu epidemic in Ukraine A/H1N1/California/04/09 using data from the Epidemiological Monitoring of the situation at that time identified the most significant components of this experience to optimize the health and social events in similar circumstances PMID- 26118029 TI - [THE INFLUENCE OF MODERN ORTHOPEDIC CONSTRUCTIONS ON THE CONDITION OF PERIODONTAL TISSUES OF PATIENTS WITH GENERALIZED PERIODONTITIS]. AB - Patients with generalized periodontitis studied the effect of the partial removable denture made from acrylic met and thermoplastic materials on the state of periodontal tissues. The results of clin- ical studies have shown a significant improvement in oral hygiene, positive change in activity indi- cators current generalized periodontitis: patients for whom orthopedic constructions are made of thermoplastic mass, reduce the depth of periodontl pockets, tooth mobility, bleeding and inflamma- tion of the interdental, papillae and the gingival margin. PMID- 26118030 TI - [DYNAMICS OF DENTAL CARIES' INDEXES IN CHILDREN WITH DENTOALVEOLAR ANOMALIES UNDER THE INFLUENCE OF PREVENTIVE MEASURES]. AB - Frequency dentition anomalies in children and adolescents according to different authors, ranging from rising 50.8 to 81%. Anomalies of dental systems lead to aesthetic and functional disturbances affecting the child's psyche, and often lead to the development of dental caries and periodontal diseases. So, the purpose of our study was to investigate the dynamics of dental caries' indexes in children with dentoalveolar anomalies under the influence of preventive measures. We observed 50 children aged 12, who were divided into four groups. The most effective prophylactic complex in terms of reduction of growth of caries (59.4%) was the one that involved the use of "Tooth Mousse" (applying to the surface of the teeth 5 minutes after eating one time a day, in the morning after brushing teeth), "Osteovit" (one tablet three times a day), "Pektodent--dentifrice? (dental cleaning powder twice a day--in the morning and evening). This complex creates conditions for increasing the resistance of hard dental tissues, resulting in low levels of intensity of caries in children. PMID- 26118031 TI - [EFFICIENCY OF COMBINATION OF ROFLUMILAST AND QUERCETIN FOR CORRECTION OXYGEN- INDEPENDENT MECHANISMS AND PHAGOCYTIC ACTIVITY OF MACROPHAGE CELLS OF PATIENTS WITH ACUTE EXACERBATION OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE WHEN COMBINED WITH CORONARY HEART DISEASE]. AB - Studied oxygen independent reaction and phagocytic activity of macrophage cells of patients with chronic obstructive pulmonary disease (COPD) II-III stage when combined with coronary heart disease (CHD). The increasing oxygen independent reactions monocytes and neutrophils and a decrease of the parameters that characterize the functional state of phagocytic cells, indicating a decrease in the functional capacity of macrophage phagocytic system (MPS) in patients with acute exacerbation of COPD, which runs as its own or in combination with stable coronary heart disease angina I-II. FC. Severity immunodeficiency state in terms of cellular component of nonspecific immunity in patients with acute exacerbation of COPD II-III stage in conjunction with the accompanying CHD increases with the progression of heart failure. Inclusion of basic therapy of COPD exacerbation and standard treatment of coronary artery disease and drug combinations Roflumilastand quercetin causes normalization of phagocytic indices MFS, indicating improved immune status and improves myocardial perfusion in terms of daily ECG monitoring. PMID- 26118032 TI - [PLEURECTOMY--AS THE LEADING METHOD OF FUNCTIONAL PATIENTS REHABILITATION WITH CHRONIC TUBERCULOUS PLEURISY]. AB - The authors are analyzing the epidemic situation in Ukraine and the epidemiology of chronic tuberculous pleuritis (CTP). They are suggesting 206 pleurectomy results of operated patiens. Restrictive type of venting disorders before surgery occurred are in 26.4% cases, 36.2% and 100%, respectively at 1; 2 and 3 stages of CTP. Reducing the number of patients with this type of violations occurred if 6.9 times, 11.7 times and 3.3 times respectively to operated in case of 1, 2 and 3 stages of CTP. Improvements and other positive functional parameters are submitted. The authors conclusion: pleurectomy is the method of functional rehabilitation at CTP cases. PMID- 26118033 TI - [DYNAMICS OF CYTOKINES IN INFANTS WITH ACUTE OBSTRUCTIVE BRONCHITIS AND THYMOMEGALIA]. AB - The article contains the information about pro- and anti-inflammatory cytokines in infants with acute obstructive bronchitis and thymus hypertrophy. The content of IL-6 and IL-10 has been de- termined in 101 children in acute period of disease and during early convalescence. It was found the increasing of production of proinflammatory IL-6 and a low level of anti-inflammatory IL-10 in the first days of illness in all children with thymomegalia. During convalescence in patients with acute obstructive bronchitis and thymomegalia IL-6 level was decreasing, and the level of IL-10 was in- creasing, but it did not amount to the level of healthy children. PMID- 26118034 TI - [DIFFERENTIAL DIAGNOSIS OF TUMOROID-LIKE ABSCESS AND LUNG CANCER]. AB - The purpose of work is development and clarification of roentgenology displays of tumoroidea variant of abscess of lungs for differential diagnostics him with the cancer of lungs. Practically in most cases abscess of lungs there is a necessity of leadthrough of differential diagnostics with in a number of nosology forms, including with the cavernous form of peripheral cancer of lungs. The features of flow of roentgenologic picture of tumoroidea variant are resulted, alike symptoms, differ ences and signs which allow to set a correct diagnosis, are resulted, the value of follow-up of roent genologic research and use of computed tomography is underlined. PMID- 26118035 TI - [HOW TO PERFORM THE CONVERSION DURING LAPAROSCOPIC CHOLECYSTECTOMY]. AB - The aim of the work was the rationale for the choice of access in the performance of conversion in laparoscopic cholecystectomy. In our study, conversion was performed in 34 (2.78%) cases of 1222 laparoscopic cholecystectomies: when the LCE for chronic cholecystitis--17 (1.6%) cases of 1065, for acute cholecystitis- 17 (10.8%) of 157. The most common access for conversion are oblique access Kocher and upper-middle access. Choice of approach for the implementation of the conversion depends on the cause of conversion. PMID- 26118036 TI - [THE STUDY OF RESPONSE TO TYROSINE KINASE INHIBITORS THERAPY IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA DEPENDING ON SOCAL SCORE]. AB - The study included 426 patients with CML in chronic phase treated with imatinib. The level of response to therapy was assessed according to the recommendations of the European Leukemia Net. Socal score determined at the beginning of the disease and was calculated by the appropriate formula. Low risk (n = 150) at 12 months TKI therapy the optimal response was achieved in (66.7 +/- 3.8) % of patients, suboptimal--in (20.0 +/- 3.3) %, treatment failure is indicated at (13.3 +/- 2.8) %. In the intermediate risk group patients (n = 160) at 12 months of treatment the optimal response was obtained in (22.5 +/- 3.3) % of patients, suboptimal--in (36.9 +/- 3.8) %, the ineffectiveness of treatment--in (40.6 +/- 3.9) %. In the high risk group at 12 months of therapy the optimal response achieved in (6.9 +/- 2.4) % of patients, suboptimal response--in (19.8 +/- 3.7) % and treatment failure in (73.3 +/- 4.1) %. A statistically significant difference between the level of response and Socal score are determined. These data suggest about a distinct role Socal score in formation of response to TKI therapy. PMID- 26118037 TI - [COMBINED HONDROPROTECTION IN REHABILITATION OF PATIENTS WITH DIABETES MELLITUS WITH DIABETIC ARTHROPATHY]. AB - The efficacy and tolerability of combined chondroprotectors Teraflex(r) in patients with diabetes mellitus type 1 and 2, complicated by arthropathy were investigated. It was established, that Tera- flex(r) therapy positively influences on the development of diabetic arthropathy (reducing intensity of pain, increasing the range of movements and reduced volume of the affected joints, increasing the functionality of the patient). In addition, an analysis of the impact of chondroprotectors on the level of sugar among patients.It was found, that it is necessary to control blood sugar while taking chondroprotectors and if needed, increasing the dose of hypoglycohaemic drugs during this period. PMID- 26118038 TI - [THE TOXIC EFFECTS OF CHEMOTHERAPY ON THE GASTROINTESTINAL TRACT]. AB - Chemotherapy in modern oncology is one of the main methods of treatment, along with surgery and radiotherapy techniques. More than 60% of patients receiving chemotherapy at different stages of treatment. Recently, modern chemotherapy has become more urgent personal approach to the choice of drugs and their doses, aimed at reducing the toxicity of chemotherapy. Complications of chemotherapy significantly degrade the effectiveness of the treatment of patients with malignant tumors, because they require lower doses of anticancer drug, or lengthening the intervals between cycles of chemotherapy, which affects treatment outcomes and quality of life. PMID- 26118039 TI - [OPTIMIZING PROPHYLAXIS OF BEHAVIORAL RISK FACTORS IN THE PRACTICE OF A HEALTH PRACTITIONER]. AB - A functionally organizational model of the work of a medical worker has been elaborated on the basis of the prophylaxis of diseases of the circulatory system whose basis is a correction of behavioral risk factors. PMID- 26118040 TI - [NEW INFORMATION FROM EXPERIENCE HYGIENIC EVALUATION OF HIGH TECHNOLOGY PREPARATION NANOMETALS AND POTENTIAL RISKS THEIR INFLUENCE ON THE WORKERS]. AB - Identify and prevent possible adverse effects of nanostructures under conditions of industrial production is the primary hygienic problem is not resolved at this time. In order to approach to solve a series of physiological, hygienic and toxicological studies. Study of harmful production factors in different technologies of metal nanoparticles, analyzed the health of workers employed in manufacturing them. Also established specific mechanisms of toxicity of nanosilver nanometals for example, the technique of hygienic control over the content in the air of the working area metal nanoparticles, the data on the existing approaches to the hygienic standardization of nanoscale objects in the breathing zone of workers. PMID- 26118041 TI - [PREVALENCE OF ATRIAL RHYTHM DISTURBANCES IN CARDIAC PATIENTS WITH COMORBIDITIES]. AB - Atrial arrhythmias are the most common among all cardiac arrhythmias. The prevalence of atrial arrhythmias is increasing worldwide and has an impact on health indicators such as the loss of ability to work and mortality and increases the overall cardiovascular risk and/or heart disease occurence. This study indicates a high prevalence of atrial arthythmias in patients with ischemic heart disease and requires more detailed study in order to develop methods of preventing the onset of cardiac rhythm disorders. PMID- 26118042 TI - [BIOCHEMICAL MARKERS OF MYOCARDIAL DAMAGE IN CHILDREN AFTER SURGICAL CORRECTION OF CONGENITAL HEART DISEASE]. AB - The results of observations of 184 children from the CHD after surgical correction on which explored the biochemical markers of myocardial injury in serum--myocardial fraction of creatine kinase and galectin-3. The relationship between increased serum concentrations of these markers, clinical and paraclinical characteristics of examined children. PMID- 26118043 TI - [THE CHARACTERISTICS OF CARDIOVASCULAR SYSTEM IN CHILDREN WITH INFLUENZA INFECTION]. AB - Clinical changes in the cardiovascular system observed in most patients. The extent and nature of these changes may depend on the characteristics of epidemic outbreaks, such as virus, immune responsiveness, age composition patients. Flu like lesions of the cardiovascular system in most cases occurring beneficial- quickly disappear change of heart, normal pulse and blood pressure. PMID- 26118044 TI - [MEDICAL AND SOCIAL INSPECTION AS A PART OF THE REHABILITATION OF CHILDREN WITH JUVENILE RHEUMATOID ARTHRITIS]. AB - Provided evaluation of the medical and social inspection of the dcotrors consultative commission of Vinnytsya regional childrens hospital in children with juvenile rheumatoid arthritis (JRA). Patients with JRA that got position of the child-invalid are given individual program of the rehabilitation that includes medical, professional, sport and physical, social adaptation that gives ability control recommendations for both--physicians and parents. PMID- 26118045 TI - [CLINICAL FEATURES AND OPTIMIZATION OF THE TREATMENT OF CHILDREN WITH COMBINATION GASTRODUODENAL PATHOLOGY AND PRIMARY HYPERTENSION]. AB - The paper present dynamic of clinical picture, daily blood pressure monitoring results and subjective assessment of functional status in children with combination of chronic gastroduodenal pathology and primary hypertension when L carnitine used with the standard treatment regimen. PMID- 26118046 TI - [POLYMORPHISM OF GLUTHATIONE-S-TRANSFERASE P1 IN CHILDREN WITH REFLUX ESOPHAGITIS]. AB - The distribution of allele and genotype frequencies of genes of xenobiotic detoxication (CYP2E1--PstI, RsaI, DraI; ADH, ALDH, NAT2, GSTP1, GSTM1, GSTT1) was examined in 147 patients with reflux-esophagitis (RE) and 50 conditionally healthy children 12-18 years. The frequency of AA genotype of GSTP1 gene and A allele was significantly higher in patients with RE as compared with healthy children (chi2 = 4.93; P = 0.03 and chi2 = 5.94; P = 0.01 respectively). PMID- 26118047 TI - [EVALUATION OF TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE IN CHILDREN BY MEANS OF RESEARCH QUALITY OF LIFE]. AB - By means of special enquire it is analyzed main indexes of life quality in children prior to treatment and after one-month course of gastroesophageal reflux disease therapy. During the leading analysis of questioning results with the help of Gastrointestinal Symptom Rating Scale it is established the decrease of indexes according to the next scale: reflux syndrome, abdominal pain, dyspeptic syndrome and summary according to all the scales. PMID- 26118048 TI - [ADVANTAGES OF CALIPEROMETRIC ASSESSMENT METHODS OF FAT DEPOSITION IN CHILDREN]. AB - The aim was to assess the nutritional status of children by skin fold measuring (caliperometric) method. In surveyed children were found changes characteristic of prolonged unhealthy diet at physiologically inadequate qualitative composition of the diet. It is noted that the benefits of caliperometric method is the ease of use and high sensitivity to changes in nutritional status. PMID- 26118049 TI - [EFFECT OF FEEDING METHOD ON THE DEVELOPMENT OF ATOPY IN NEWBORNS AT RISK]. AB - The analysis of risk factors for the realization of allergy was carried out; the effect of genetic factors on the atopy development at the ages of 6 and 12 months was analyzed; incidence (prevalence) structure at the ages of 6 and 12 months was analyzed; based on the studies of the effects of feeding, nature of the formulas, and the terms of formula administration the conclusions about the methods of optimization of feeding of newborns at risk were drawn. PMID- 26118050 TI - [THERAPY OF TRANSIENT LACTASE INSUFFICIENCY OF CHILDREN IN PECTORAL AGE]. AB - Thus, we have discovered that the children of the first half-year of life have different degrees of severity of transient lactase insufficiency basing on the results of hydrogen respiratory test. It was set that the starting dose of enzyme lactase must depend on the degree of severity of displays of transient lactase insufficiency, taking into account the indexes of hydrogen respiratory test. PMID- 26118051 TI - [TO THE ROLE OF NUTRITION IN THE HEALTHY LIFESTYLE OF YOUNG PEOPLS]. AB - We have studied 159 young peoples. The age of young peoples at the time of the survey was 15-18 years. It has been shown that the young peopls nutrition was not optimal. Most of them have asthenic and intoxication types of complaints and exhibit acute chronic diseases. Microelemental profiles of medical students reveal significant deficiency of essential elements and accumulation of toxic elements. PMID- 26118052 TI - [FEATURES OF TREATMENT OF EOSINOPHILIC ESOPHAGITIS IN SCHOOLCHILDREN]. AB - The inclusion of probiotic L. reuteri into the complex therapy of eosinophilic esophagitis significantly affect the outcomes of children--there was significant decrease in the number of eosinophils in the esophageal mucosa of children. PMID- 26118053 TI - [BREASTFEEDING AND FORMATION OF POSTNATAL ANXIETY]. AB - This article has been performed the investigation of psychological characteristics in mothers with the breastfeeding, the mixed feeding, the artificial feeding. There has been identified factors of the unfavourable prognosis for the postnatal anxiety. PMID- 26118054 TI - [THE EFFECTIVENESS OF A 10-DAY DRUG THERAPY IN CHILDREN WITH CHRONIC GASTRODUODENAL PATHOLOGY ASSOCIATED WITH CAGA-POSITIVE STRAINS OF HELICOBACTER PYLORI]. AB - The results of triple Helicobacter-therapy (omeprazole, amoxicillin, nifuratel) in the treatment of chronic gastroduodenal pathology in children depending on the duration of it's use. The effectiveness of drug therapy was evaluated in terms of eradication of Helicobacter pylori and dynamics of pain, dyspeptic syndrome and astenovegetative syndrome. PMID- 26118055 TI - [ROLE OF PSYCHOLOGICAL FACTORS IN THE ETIOLOGY OF ASTHMA IN CHILDREN]. AB - Influence of psychological factors was studied on appearance and motion of bronchial asthma for children. Straight proportional dependence is set between weight of flow of illness and united influence of psychological factors on a background biological propensity to the allergy for a patient. An additional stress factor--non-acceptance of display of emotions of child that complicates the flow of disease parents is educed. PMID- 26118056 TI - [THE VALUE OF RECURRENT BRONCHIAL OBSTRUCTION ASSOCIATED WITH RESPIRATORY INFECTIONS IN INFANTS]. AB - It is shown that recurrent bronchial obstruction with nonallergic genesis is a significant problem for young children. Further researches of this disease are needed in order to develop differentiated therapies. PMID- 26118057 TI - [HEMATOLOGICAL INDEXES IN DIAGNOSIS OF OBSTRUCTIVE BRONCHITIS IN CHILDREN]. AB - The main aim of the study was determination of leukocyte indexes and identify their possible use to diagnose obstructive bronchitis in children. PMID- 26118058 TI - [CHILDREN WITH COMMUNITY-ACQUIRED PNEUMONIA HAVE DEFICIENCY OF VITAMINS]. AB - In Ukraine about 90 thousand children and adolescents under the age of 17 years are sick with pneumonia every year. Community-acquired pneumonia continues to be a common and serious illness. In this open single center study involved 120 children of both sexes. We received deficient content of the serum trace elements. PMID- 26118059 TI - [CONGENITAL TUBERCULOSIS IN PRETERM NEWBORN]. AB - The paper presents a rare clinical case--congenital tuberculosis in a premature newborn. PMID- 26118060 TI - [A STUDY OF OCCURRENCE FREQUENCY OF C677T POLYMORPHISM OF THE GENE MTHFR AND PLASMA FOLATE LEVELS IN PATIENTS WITH UNIPOLAR DEPRESSION]. AB - This study focuses on the problem of finding an effective diagnostic algorithm to identify unipolar depression by examining the C677T MTHFR gene polymorphism and features of folate metabolism in patients with unipolar depression. The study proves that C677T MTHFR gene polymorphism is significantly associated with unipolar depression, which can be used to improve the quality of depression identification, as well as forming new ways of diagnosis. PMID- 26118061 TI - [COMORBIDITIES IN PATIENTS WITH ENDOMETRIAL HYPERPLASIA]. AB - The aim was to evaluate the prevalence of concomitant somatic pathology in patients with endometrial hyperplasia. It is shown that the incidence of endometrial hyperplastic processes of combination and somatic pathology is 50%. The main types of comorbid diseases are obesity, metabolic syndrome, gastrointestinal and cardiovascular disorders. PMID- 26118062 TI - [GENETIC ASPECTS OF CHRONIC GLOMERULONEPHRITIS]. AB - The aim of our work was to determine the the gene polymorphism of IL-1beta in children with chronic glomerulonephritis. there has been defined the frequency of combinations of allelic variants of cytokines genes of IL-1beta and IL-10 in chronic glomerulonephritis in children and found the connection of allelic polymorphism with the disease course, indices of hemopoiesis and IL-1beta in serum. The presence of C/T genotype is associated with increased production of interleukin-1beta in serum. Genetic polymorphism of genes of interleukin can be a new marker of progression of chronic kidney disease. PMID- 26118063 TI - [AUTONOMOUS AND VERTEBRAL DYSFUNCTION IN CHILDREN]. AB - An analysis has shown association between a vertebral dysfunction and dysfunction in the autonomic nervous system in children. Medical follow-up and electroencephalography, myographic and rheoencephalography findings has allowed concluding over clinical importance of the complaints on the back pain and changes in the cervical part of a backbone for diagnostics, prevention and treatment of autonomous dysfunction. PMID- 26118064 TI - [FEATURES OF CLINICAL COURSE OF INFECTIOUS MONONUCLEOSIS IN CHILDREN DEPENDENT ON ETIOLOGY]. AB - The article highlights the clinical features of infectious mononucleosis in children (based on the analysis of the data for children of different ages treated in Odessa clinical hospital of infectious diseases in connection with infectious mononucleosis) based on etiological factors. PMID- 26118065 TI - [BACTERIAL FACTORS AND INTRAUTERINE INFECTION OF THE NEWBORN]. AB - The role and value of the bacterial factor in development pre-natal infection of newborns is studied. It is considered microflora of patrimonial ways of pregnant women, as basic pathogenesis factor of an ascending way infection of newborns. On an example of the spent bacteriological researches correlation communication between microflora of patrimonial ways, placenta and an ascending way infection of newborns is shown. PMID- 26118066 TI - [FEATURES OF LIPID METABOLISM IN ANIMALS EXPOSED TO BACTERIAL LIPOPOLYSACCHARIDE]. AB - Endotoxinemia was caused in rats by the lipopolysaccharide (LPS) oral application at the doses 40 mkg/kg and 200 mkg/kg. The increase of the content of triglycerides in the blood serum and in the liver was established. Besides, the LPS oral application at the dose 200 MUKappaGamma/KappaGamma the increase of the content of cholesterol in the liver was established. PMID- 26118067 TI - [PANCREATIC EXOCRINE INSUFFICIENCY AND ITS CORRECTION IN CHILDREN WITH TYPE I DIABETES IN COMBINATION WITH CELIAC DISEASE]. AB - The results of the examination of patients with type I children,which was diagnosed with celiac disease and pancreatic exocrine insufficiency. To correct the PEN used pancreatin preparations and studied its effectiveness. PMID- 26118068 TI - [EFFECTIVE SCREENING METHODS FOR CARBOHYDRATE METABOLISM DISORDERS]. AB - There has been a significant increase in diabetes morbidity in the past years. Prolonged asymptomatic progression of disease presents a problem and leads to late diagnosis and development of complications. Present study shows efficiency of screening measures to determine actual spread of carbohydrate metabolism disorders among residents of Odessa, frequency of type 2 diabetes mellitus risk factors determination and prevention of complications. PMID- 26118069 TI - [THE CASE OF THE INCONTINENTIA PIGMENTI SYNDROME IN A NEWBORN]. AB - The paper describes the case of a rare hereditary disease--Incontinentia Pigmenti syndrome incontinence of pigment in newborn. PMID- 26118070 TI - [HEARING LOSS AMONG NEONATES, EARLY DIAGNOSTICS]. AB - Early determination of hear loss among neonates and its' rehabilitation is extremely important factor for verbal and psychoemotional development of a child, with further possibility of residue hear using for treatment which is more effective during the first year of life. PMID- 26118071 TI - [HEALTH STATUS AND DEVELOPMENT OF CHILDREN BORN USING IVF]. AB - In the work the analysis of incidence, the dynamics of physical development during the first year of life among 28 children born using IVF was conducted. It was found out that during the first year of life these children have certain patterns of growth and development, as well as a wide range of diagnosed pathology. Thereby observing children of this category should be optimized. PMID- 26118072 TI - [MODERN EDUCATIONAL TECHNOLOGY MASTERING PRACTICAL SKILLS OF GENERAL PRACTITIONERS]. AB - The article presents the experience of postgraduate training of general practitioners--family medicine. Identified current trends, forms and methods of pedagogical innovations that enhance the quality of learning and mastering the practical skills of primary professionals providing care. PMID- 26118073 TI - [THE IMPLEMENTATION OF THE RIGHTS OF CHILDREN-PATIENTS IN THE PROVISION OF MEDICAL CARE IN UKRAINE]. AB - The author found that legal regulation of medical care of children in Ukraine need to improve the effectiveness. The key of efficiency of this process is the establishing the principle of providing of the rights of children-patients in the provision of medical care in Ukraine with the special attention to the best interests of the child. PMID- 26118074 TI - [FREQUENCY OF IMMUNOGLOBULIN E DEFICIENCY AMONG PATIENTS WITH IMMUNODEPENDENT DISORDERS]. AB - Isolated IgE deficiency is one of the most common primary immunodeficiency, which is still underestimated cause of health disorders of modern man. Recent genetic studies report that the cause of the IgE deficiency is immune dysregulation caused by polymorphisms of the gene, which is responsible for the synthesis of activation-induced cytidinedeaminase (AICDA). The Institute of Immunology and Allergology at Bogomolets NMU during the years 2012-2014 were examined 5298 patients with a range of different diseases, which could be suspected violations of immunity. All patients were conducted comprehensive immunological study, and 4476 of them were examined for content of total serum IgE. The criterion for the selection of patients for follow-up began serum IgE < 10 kIU/l. Serum immunoglobulin E was determined by ELISA. Serum IgE < 10 IU/ml was detected in 342 patients (7%). Average reduction in the study group made up (5.30 +/- 1.31) IU/ml. Partial deficiency (5-10 kIU/l) was detected in 212 patients (4%), while the total--130 (3%). For follow-up, we are clinically selected group of patients with deficiency of IgE (n = 60) and control group (n = 30). All patients were distributed as per clinical syndromes, and the frequency of their manifestations: sinopulmonary syndrome (63%), gastrointestinal syndrome (13%), autoimmune manifestations (10%), allergic reactions (7%) and chronic fatigue syndrome (7%). The levels of serum IgG, IgA, IgM in the study group were within the age norm (IgG = 1160.00 mg/dl +/- 2.88 mg/dl, IgA = 138 g/l +/- 37 mg/dl, IgM = 114 mg/dl +/- 30 mg/dl). However, only a small proportion of patients was observed decrease in other classes of immunoglobulins in 8 patients with IgG < 700 mg/dL in 16 patients with IgA < 90 mg/dl and 6 patients with decreased serum IgM < 90 mg/dl. These patients were examined the levels of serum IgG subclasses and sIgA levels in saliva. Significant violations by cellular immunity in determining lymphocyte subpopulations by flow cytometry using monoclonal antibodies also were found. Phagocytic indices were also no significant abnormalities. An important aspect of clinical deficiency of immunoglobulin E is its association with diseases of bacterial origin (H. influenza, M. catarrhalis, Str. pneumoniae), indicating a protective role of these antibodies in the mucosa of the respiratory tract. Thus, isolated IgE deficiency is associated with sustained decrease in serum concentrations of immunoglobulin E (< 10 kIU/l) in patients with normal immune status of other indicators that require dispensary and treatment. The results of their study indicate a high incidence of the IgE-deficiency among the population and its high incidence among the humoral defects. PMID- 26118075 TI - [IMMUNE AND ATOPIC STATUS OF SCHOOL-AGE CHILDREN WITH ASTHMA, GIVEN THE ASTHMA PHENOTYPE]. AB - 25 students of the phenotypes of early-onset and late-onset asthma were investigated. In statistically significant majority of patients with early-onset asthma was detected skin hypersensitivity to household and epidermal allergens and clear trend to higher concentrations of IL-4 in the serum, which indirectly indicates on atopic reactivity. Almost every second child with late-onset asthma, had a high level of IL-8 (more than 7.62 pg/ml), while the odds ratio detection of increased serum concentrations of IL-8 was 3.1 (95% CI 1.6-6) that was assotiate with neutrophil-mediated immune response. There were defined clinical and epidemiological risk and diagnostic value of atopic reactivity indices for the verification study asthma phenotypes. PMID- 26118076 TI - [FEATURES IMMUNITY IN CHILDREN WITH BRONCHOPULMONARY DYSPLASIA]. AB - The study of the immune system in 131 children with bronchopulmonary dysplasia at the time of remission and exacerbation. Found that children with bronchopulmonary dysplasia inherent low absolute number of lymphocytes, accompanied by increased cytotoxic lymphocytes (CD8, CD 16), oxygendependence ability of granulocytes, and activation of the acute phase of immunoglobulin (IgM), in the absence of clinical signs of exacerbation. In acute respiratory disease, a somewhat paradoxical, cellular immune response with decreased lymphocyte activation against cytotoxic cells. While the dynamics of increase of cytotoxic markers in acute respiratory disease is unsatisfactory, indicating that the depletion of cellular reactivity circuit immunity. PMID- 26118077 TI - [IMMUNOLOGICAL REACTIVITY AND CORRECTION OF IMMUNOLOGICAL DISORDERS BY BIOLOGICAL MEDICINES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS]. AB - The results of systemic immunological reactivity research were presented in 97 patients with chronic obstructive pulmonary disease (COPD) exacerbations. The patients were randomized on two groups. 67 patients, which additionally to standard anti-inflammatory therapy were prescribed different combinations of homotoxicological medicines, entered in a clinical group. The homotoxicological medicines such as Lymphomyosot, Galium-Heel(r), Traumeel S, Echinacea compositum S, Bronchalis-Heel(r), Mucosa compositum were prescribed according to the value of immune-regulatory index and type of T-cells immune disorders. 30 patients, which got standard anti-inflammatory therapy, entered in the group. of comparison. For the patients of clinical group immunological values were improved after the conducted treatment, unlike the patients of group of comparison in which an immunodeficiency was deepened. PMID- 26118078 TI - [METHODS OF MATHEMATICAL MODELING IN MORPHOLOGICAL DIAGNOSTICS OF CHORNOBYL FACTOR INFLUENCE ON PROSTATE GLAND OF COAL MINERS-- THE CHERNOBYL DISASTER FIGHTERS]. AB - The morphometric estimation of parenchyma and stroma condition included the determination of 25 parameters in a prostate gland at 27 persons. The mathematical model of morphogenesis of prostate gland was created by Bayes' method. The method of differential diagnosis of a prostate gland tissues' changes conditioned by the influence of the Chernobyl factor and/or unfavorable terms of the work in underground coal mines have been worked out. Its practical use provides exactness and reliability of the diagnosis (not less than 95%), independence from the level of the qualification and personal experience of the doctor, allows us to unify, optimize and individualize the diagnostic algorithms, answer the requirements of evidential medicine. PMID- 26118079 TI - [LYMPHOCYTES MEMBRANES FATTY ACID SPECTRUM IN PATIENTS WITH CORONARY HEART DISEASE]. AB - Lymphocytes phospholipid membranes fatty acid spectrum was studied in patients with coronary heart disease. The study involved 77 patients aged 45 to 72 years. Significant decrease of the oleic fatty acid relative content was determined, which violates the lymphocytes membranes structure and possibly negatively affect their functioning. The relative content of arachidonic, palmitic and stearic saturated fatty acids composition of lymphocytes lipids increased. The result indicate that in patients with coronary heart disease increasing polyunsaturated fatty acids elongation in lymphocytes. These changes in the lipid blood, lymphocytes state can explain the observed increase in lymphocytes functional activity. PMID- 26118080 TI - [TREATMENT AND PREVENTION OF COMBINED CARDIO-RESPIRATORY PATHOLOGY IN EXACERBATION OF CHRONIC OBSTRUCTIVE-PULMONARY DISEASE (new approach)]. AB - The features of the course of exacerbations of chronic obstructive pulmonary disease (COPD) in combination with coronary heart disease in the form of stable angina, and with the threat of destabilizing its course. The changes of the cardiovascular system in patients with a background of clinical symptoms in patients with acute exacerbation of COPD II-III stages. A differentiated approaches to anti-inflammatory and cardio protective action of drug combinations Roflumilast and quercetin as components of adjuvant therapy in patients with combined cardiovascular disease. PMID- 26118081 TI - [ASSESSING THE IMPACT OF CARDIAC DYSSYNCHRONY ON QUALITY OF LIFE IN PATIENTS WITH CHRONIC HEART FAILURE IN COMBINATION WITH TYPE 2 DIABETES MELLITUS]. AB - In the article considers the influence of type 2 diabetes mellitus (T2DM) and cardiac dyssyn- chrony (DYS) on health-related quality of life (HRQoL) in patients with chronic heart failure (CHF) by means of Minnesota Living with Heart Failure Questionnaire (MLHFQ). It was found a negative impact of T2DM both on the overall assessment; and on the physical and emotional components of the HRQoL.in patients with CHE DYS also has a negative effect on HRQoL both in patients with isolated CHF and patients with CHF and concomitant T2DM, but its influence is mediated mainly by physical component. There were a number of factors that contribute to the DYS development in patients of studied groups identified, including the poor state of carbohydrate and lipid metabolism compensation, activation of systemic inflammation. It is expedient to study HRQoL to optimize therapeutic strategies in these patients. PMID- 26118082 TI - [CYTYOGENETIC MARKERS OF BRONCHIAL ASTHMA IN CHILDREN]. AB - The learning of cytyogenetic special of cariotip in children with the bronchial asthma maked by course of the investigation of prometahyases chromosomes of limphocytes of the periferic bloods. The quantity of association of acrocentric chromosome was analised. The 82 children in age 6-18 years old with the bronchial asthma and with the different control were learned by results of asthma--test control. In children with the noncontrol bronchial asthma the big frequency of of association of acrocentric chromosome 13-15 (D-D), 21-22 (G-G) n 13-15--21-22 (D G) were received. In patients with the bronchial asthma the lover mitotic activity by healthy were marked (P(N) < 0.05). With the degree of activity it was decreased. PMID- 26118083 TI - [THE CLINIC AND FUNCTIONAL PECULIARITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE'S COURSE, ACCOMPANIED WITH METABOLIC SYNDROME]. AB - The article contains the data's of clinical course peculiarities, heart geometry construction and the systemic inflammatory processes activity in patients with chronic obstructive pulmonary disease, accompanied with metabolic syndrome. It was determined, that there high level of inflammatory processes activity, the big disturbances in heart geometry construction and more year pointes were te characteristic features of combined pathology. PMID- 26118084 TI - [THE DIAGNOSTIC VALUE OF THE INDICES OF METABOLIC AND PHAGOCYTIC ACTIVITY OF SEGMENTED GRANULOCYTES OF BLOOD IN VERIFICATION ATOPIC PHENOTYPE ASTHMA IN CHILDREN]. AB - The purpose of research--the study of the diagnostic value of indicators of metabolic and phagocytic activity of effector cells (eosinophils, neutrophils) in atopic asthma (ABA) in children. To achieve this goal were formed two clinical groups. Group I included 25 children with ABA, in II clinical group consisted of 26 patients with a diagnosis of asthma without evidence of atopy. In group I there is a tendency to reduce the metabolic activity of blood eosinophil according to NBT-test, the intracellular content of cationic proteins, peroxidase, and their phagocytic activity. Stimulation level NBT test blood eosinophil less than 0,2 c. u. in conjunction with other tests can be used to verify the ABA, as declines in phagocytic activity (less than 60%) and phagocytic number (less than 2 c. u.) of eosinophilic granulocytes blood associated with a significantly higher risk of having atopic asthma. PMID- 26118085 TI - [ANALYSIS OF MUTATION IN CODON 531 rpoB GENE, ASSOCIATED WITH RIFAMPICIN RESISTANCE AMONG SAMPLES OF MYCOBACTERIUM TUBERCULOSIS THAT WAS ISOLATED FROM THE PATIENTS]. AB - In the conditions of high relative density of multidrug resistant tuberculosis in Ukraine, rapid diagnostics of M. tuberculosis susceptibility to antituberculous drugs is the important tool in treatment of patients with lung tuberculosis. 78 patients with lung TB that were treated in TB dispensary in Kharkiv during 2004 2005 years were analyzed. Mutations in 531 codon of rpoB gene of isolates M. tuberculosis were studied. Among 48 (61.5%) resistant isolates of M tuberculosis according to phenotypic method, mutations were found only at 29 (60.4%) isolates. Among 30 (38.5%) phenotypic sensitive M. tuberculosis isolates only 1 (3.3%) isolate had mutation in rpoB gene M. tuberculosis. PMID- 26118086 TI - [PARTICULARITIES OF CARBOHYDRATE METABOLISM IN PATIENTS WITH PULMONARY TUBERCULOSIS WITH PRECLINICAL DISORDERS GLICEMIA]. AB - Studied concentration of lactate and pyruvate in patiens with lung tuberculosis with disorders of tolerance to glucosis and glukemic disorders on an empty stomach and in patiens, wich had not such disorders. In patiens with preclinical disorders glicemia discovered increasing to concentrations of lactate and pyruvate in blood. This is indicative of more deep breaches of quality to oxidation the glucose in energetic aerobic reaction, in particular, in tricarboxylic acids cycle. Effect this is a deterioration energy status of the cells. Excess of the formation lactate and pyruvate on background of the effect anty-insulin hormone prevalence and relative insufficiency of the insulin realizes the independent contribution to development hyperglicemia disorders. PMID- 26118087 TI - [REPRODUCTIVE FUNCTION DISORDERS IN WOMEN WITH PULMONARY TUBERCULOSIS]. AB - The article presents analysis of ultrasound examination of 45 reproductive age women with pulmonary tuberculosis and diseases of genitalia, among them high portion of genital tuberculosis. It is shown high diagnostic value of sonography and dopplerometry in early determination of reproductive function disorders in women with tuberculosis. PMID- 26118088 TI - [SODIUM SUCCINATE AS METHOD OF INTENSIVE CARE OPTIMIZATION OF NEWBORNS' MULTIORGAN FAILURE SYNDROM]. AB - With the aim of ascertainment of pathogenesis of newborns' multiorgan failure syndrom it was made a research of lactat, pyruvate, urea containing and succinatedehydrogenase activity of newborns venous blood with sequences to perinatal infection and perinatal asphyxia. Was set the reliable increase of concentration of lactat, pyruvate and their ratio, that demonstrates the presence of cellular energy deficit. There was direct correlation communication between concentrations of pyruvate and urea. In the application of sodium succinate to reduce the content of lactic and pyruvic acids, their ratio, increase the activity of succinatedehydrogenase, which is evidence of improved mitochondrial energy production, as well as reduces the frequency of gastrointestinal insufficiency implementation. PMID- 26118089 TI - [ESTIMATION OF GAS EXCHANGE IN PATIENTS WITH COMMUNITY-ACQUIRED PNEUMONIA DURING NON-INVASIVE VENTILATION]. AB - The problem of respiratory support due to pneumonia, complicated by severe respiratory failure, both in Ukraine and worldwide is very complex and challenging. More than half of the critical ICU patients undergoing mechanical ventilation, develop nosocomial infection, which can be avoided by using non invasive ventilation (NIV). But its use in pneumonia is unclear. The aim of the study was to assess the parameters of gas exchange in patients with severe community-acquired pneumonia who were conducted non-invasive ventilation. NIV was performed in 18 patients with severe community-acquired pneumonia. At different stages of respiratory support blood gas analysis was perfodrmed. A statistically significant (P < 0.05) increase in the partial pressure of oxygen in arterial blood was observed during NIV compared to spontaneous breathing--(74.30 +/- 18.51) mm Hg vs (47.20 +/- 10.46) mm Hg. The mean value of hemoglobin oxygen saturation of arterial blood during spontaneous breathing was (80.4 +/- 9.9)%, in the same group with NIV support the value was (94.5 +/- 2.6)% (P < 0.05). NIV did not significantly affect the elimination of carbon dioxide and pH levels. NIV in patients with respiratory failure due to severe community-acquired pneumonia ensured adequate gas exchange parameters. PMID- 26118090 TI - [EXPERIENCE OF DIAGNOSTICS AND MEDICAL TREATMENT OF THE DIEULAFOYS DISEASE]. AB - The article is dedicated to the features of diagnostics and medical treatment of the Dieulafoys disease. Clinical description of six cases of foregoing pathology is resulted. The morphological features ulcers Dieulafoy are described. One fatal outcome of disease is analysed. PMID- 26118091 TI - [INFLUENCE OF HYPERICUM PERFORATUM L. HERB POLYPHENOLS PREPARATION WITH MINERALS ON THE STATE OF PERIODONTAL CONNECTIVE TISSUE MATRIX OF RATS IN CONDITION OF PERIODONTITIS MODELING]. AB - In experiments on 22 white 1.5-month-old rats-males there were studied influence of Hypericum perforatum L. and minerales from Dyovit(r) on periodont's tissues under periodontits modelling. Examined preparation normalizes level of glicosaminoglicanes in gum, but did not completely show protective effects relative to collagen's fraction. In periodont's bone preparation decreases resorbrtion; increases activity of AlP and in the same time normalizes activity of AcP. PMID- 26118092 TI - [INFLUENCE OF REAMBERIN(r) AND CYCLOFERON(r) ON CONCETRATION OF "AVERAGE MOLECULES" IN SERUM OF PATIENTS WITH RECCURENT DEPRESSIVE DISORDERS IN OUTPATIENT OBSERVATION]. AB - The influence Reamberin(r) and Cycloferon(r) concentration "average molecules" in the serum of patients with the recurrent depressive disorders (RDD) was investigated. It was set that the use of these drugs helps to normalize the concentration of "average molecules". which indicates that the elimination of the syndrome of "metabolic" intoxication. Based on the data, we can consider it appropriate inclusion Reamberin(r) and Cycloferon(r) in the therapeutic treatment of patients with RDR. PMID- 26118093 TI - [USAGE OF PRONORAN(r) FOR TREATMENT OF ELDERLY PATIENTS WITH MILD COGNITIVE IMPAIRMENT]. AB - Evaluated the effectiveness of Pronoran(r) for treatment of elderly patients with syndrome of mild cognitive impairment (MCI) with underlying dyscirculatory encephalopathy. The study involved 48 people: I (main) group--27 patients who in addition to basic therapy received Pronoran(r), II (control) group--21 patients, received only basic therapy. We found that exposure to a 3-month treatment course for patients of the I (main) group showed significant improvement in terms of indicators characterizing orientation in space, short-term memory, counting ability, concentration, psychomotor pace, ability to learn. In addition, the treatment course was accompanied by improved emotional state, positive changes in the coefficients of the spectral power qEEG for patients. At the same time, the patients in the II (control) group didn't show significant changes in the studied parameters. PMID- 26118094 TI - [SELENIUM EFFICIENCY IN PROPHYLAXIS AND COMPLEX TREATMENT OF DIFFUSE GOITER]. AB - Efficiency of the combined prophylaxis and treatment of a diffuse goiter by preparations of sele- nium and iodine at 54 patients--men at the age of 41-50 years with the diagnosis of a diffuse goiter of 1st and 2nd degree was investigated. The diagnosis of a diffuse goiter was based on palpatory and ultrasonic research of the thyroid gland, which volume was compared with a body surface area. All surveyed have been divided into three groups. Patients of the first group accepted preparations of selenium and the iodine throughout three months, the second group--iodine preparations, in control group only dynamic supervision was spent. Thyroid gland volume at men who constantly used iodated salt and had no palpatory signs of a goiter was also measured for control. In the group which members accepted selenium and iodine preparations, at 11,8 % of patients was noted reduction of thyroid volume to normal and was revealed more expressed reduction of thyroid volume (for 2.15 sm3/M2 +/- 0.07 sm3/M2), than at monotherapy by iodine preparations (for 0.92 sm3/M2 +/- 0.17 sm3/M2). The conclusion was made that it is possible to recommend selenium preparations in a dose of 100 mkg a day together with preparations of iodine for prophylaxis and treatment of a diffuse goiter in conditions of the combined insufficiency in consumption of selenium and light deficiency of iodine. PMID- 26118095 TI - [STATE OF DEVELOPMENT OF HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE EUROPE AND WORLD]. AB - In this review, we summarize information about the current trends in hematopoietic stem cells transplantation (HSCT) in Europe and world. HSCT has represented one of the most innovative and highly expensive method of treatment for a set of malignant and non-malignant disorders. Differences in the number of HSCT and transplant rates (number of HSCT per 10 million inhabitants), indications and types of transplantations between countries have been reported. They were attributed mainly to differences in the economic situation of the countries and differences in prevalence of certain types of diseases. The gross national income per capita, health care expenditures per capita, number of transplant teams per 1 million inhabitants and team experience are the main impact factors influencing on transplant activity. These data provide a basis for health care planning, preparation of normative acts and future research in Ukraine for rapid expansion HSCT PMID- 26118096 TI - [THE STATE OF HEALTH CARE FOR WORKING IN HAZARDOUS AND DANGEROUS CONDITIONS]. AB - This article raised questions of problematic health care of workers in hazardous conditions at the present stage. Shows the characteristics of the existing models of health care of working population in Ukraine. Attention is focused on the development of the most effective model of health care of workers for the prevention of occupational diseases. PMID- 26118097 TI - [EVALUATION OF THE EFFECTIVENESS OF ADDITIONAL PROFESSIONAL EDUCATION ON THE BASIS OF HEALTH CARE FACILITY]. AB - In this study we tested methods of facility learning of health care workers as part of a modern model of quality management of medical services. The statistical and qualitative analysis of the effectiveness of additional training in emergency medical care at the health facility using an adapted curriculum and special mannequins. Under the guidance of a certified instructor focus group of 53 doctors and junior medical specialists studied 22 hours. According to a survey of employees trained their level of selfassessment of knowledge and skills sigificantly increased. Also significantly increased the proportion of correct answers in a formalized testing both categories of workers. Using androgological learning model, mannequins simulators and training in small groups at work create the most favorable conditions for effective individual and group practical skills of emergency medicine. PMID- 26118098 TI - [THE SPECIFICITY OF THE PHYSIOLOGICAL REACTIONS IN ADJUSTMENT DISORDER OF INTERNATIONAL STUDENTS]. AB - In the article the adaptive capacity of the cardiovascular system and the level of physical condition of students. The evaluation of physical performance at a particular index in overall physical stamina. The study establishes certain changes between those that characterized the functional state and adaptive capacity of the cardiovascular system of the body of students. Comparative characteristics of the components of the process of adaptation of students. Identified the need to study the problems of adaptation and correction of maladjustment in the learning process. PMID- 26118099 TI - [ANALYSIS OF THE ORGANIZATION OF HEALTH SURVEILLANCE AT DIFFERENT HISTORICAL STAGES OF DEVELOPMENT OF UKRAINE]. AB - This article examines the emergency and evolution of health surveillance in Ukraine until the early twentieth century, the impact of administrative reforms of the XIX century on the formation and maintenance functions of sanitary inspection. PMID- 26118100 TI - [Prokopchuk Vyacheslav Savich (75th anniversary of birth)]. PMID- 26118101 TI - [Farnesoid X receptor regulates glucose and lipid metabolisms]. AB - As a member of nuclear receptor superfamily, farnesoid X receptor (FXR) has been shown to regulate numerous metabolic pathways, which include playing an important role in bile acid metabolism, maintaining lipid and glucose homeostasis when FXR is activated. With the prevalence of the glucose and lipids disorder, FXR attracts increasing attention. It may be a potential target for the treatment of type 2 diabetes mellitus and lipid disorders. PMID- 26118102 TI - ["PEG dilemma" for liposomes and its solving approaches]. AB - Polyethylene glycol (PEG) is extensively used to increasing the in vivo and in vitro stability of liposomes. However, PEGylated liposomes also produce some negative effects with further research, such as low cellular uptake, poor "endosomal escape" of pH sensitive liposome (PSL) and accelerated blood clearance (ABC) phenomenon, and this situation is referred as the "PEG dilemma". "PEG dilemma" posed severe challenges for the targeted delivery of PEGylated liposomes loaded anticancer drugs, effective intracellular release of PEGylated PSL encapsulated gene and protein drugs, and repeated administration of PEGylated liposomes. Therefore, it is urgent to solve the "PEG dilemma". This review focused on the definition, classification of "PEG dilemma", and discussed several possible approaches to overcome "PEG dilemma". PMID- 26118103 TI - [Research progress of p70 ribosomal protein S6 kinase inhibitors]. AB - p70 ribosomal protein S6 kinase (p70S6K), an important member of AGC family, is a kind of multifunctional Ser/Thr kinases, which plays an important role in mTOR signaling cascade. The p70 ribosomal protein S6 kinase is closely associated with diverse cellular processes such as protein synthesis, mRNA processing, glucose homeostasis, cell growth and apoptosis. Recent studies have highlighted the important role of S6K in cancer, which arose interests of scientific researchers for the design and discovery of anti-cancer agents. Herein, the mechanisms of S6K and available inhibitors are reviewed. PMID- 26118104 TI - [Biological ingredient analysis of traditional Chinese medicines utilizing metagenomic approach based on high-throughput-sequencing and big-data-mining]. AB - The quality of traditional Chinese medicines (TCMs) has been mainly evaluated based on chemical ingredients, yet recently more attentions have been paid on biological ingredients, especially for pill-based preparations. It is a key approach to establish a fast, accurate and systematic method of biological ingredient analysis for realization of modernization, industrialization and internationalization of TCMs. The biological ingredient analysis of TCM preparations could be abstracted as the identification of multiple species from a biological mixture. The metagenomic approach based on high-throughput-sequencing (HTS) and big-data-mining has been considered as one of the most effective methods for multiple species analysis of a biological mixture, which would also be helpful for the analysis of biological ingredients in TCMs. Simultaneous identification of diverse species, including the prescribed species, adulterants, toxic species, protected species and even the biological impurities introduced through production process, could be achieved by selecting appropriate DNA biomarkers, as well as applying large-scale sequence comparison and data mining. By this approach, it is prospective to offer an evaluation basis for the effectiveness, safety and legality of TCM preparations. PMID- 26118105 TI - [Pandanus tectorius derived caffeoylquinic acids inhibit lipid accumulation in HepG2 hepatoma cells through regulation of gene expression involved in lipid metabolism]. AB - The fruit of Pandanus tectorius (PTF) has a long history of use as a folk medicine to treat hyperlipidemia in Hainan province, South China. Our previous studies have shown that the n-butanol extract of PTF is rich in caffeoylquinic acids and has an adequate therapeutic effect on dyslipidemic animals induced by high-fat diet. In this work, seven caffeoylquinic acids isolated from PTF were screened for the lipid-lowering activity in HepG2 hepatoma cells. Oil-Red O staining, microscopy and intracellular triglyceride (TG) and total cholesterol (TC) quantification showed that 3-O-caffeoylquinic acid (3-CQA), 3, 5-di-O caffeoylquinic acid (3,5-CQA), and 3,4,5-tri-O-caffeoylquinic acid (3,4,5-CQA) significantly inhibited lipid accumulation induced by oleic acid and decreased intracellular levels of TC and TG in a dose-dependent manner. These three caffeoylquinic acids showed no significant cytotoxicity at concentrations of 1 50 MUmol x L(-1) as determined by MTT assay. Realtime quantitative PCR revealed that 3-CQA and 3, 5-CQA significantly increased the expression of lipid oxidation related genes PPARalpha, CPT-1 and ACOX1 while 3-CQA, 3, 5-CQA and 3,4,5-CQA decreased the expression of lipogenic genes SREBP-1c, SREBP-2, HMGR, ACC, FAS. Overall, 3-CQA, 3, 5-CQA and 3, 4, 5-CQA may be the principal hypolipidemic components in PTF which can decrease intracellular lipid accumulation through up regulating the expression of lipid oxidative genes and down-regulating the expression of lipogenic genes. PMID- 26118106 TI - [The mechanism of rosiglitazone compound based on network pharmacology]. AB - Applications of network pharmacology are increasingly widespread and methods abound in the field of drug development and pharmacological research. In this study, we choose rosiglitazone compound as the object to predict the targets and to discuss the mechanism based on three kinds of prediction methods of network pharmacology. Comparison of the prediction result has identified that the three kinds of prediction methods had their own characteristics: targets and pathways predicted were not in accordance with each other. However, the calcium signaling pathway could be predicted in the three kinds of methods, which associated with diabetes and cognitive impairment caused by diabetes by bioinformatics analysis. The above conclusion indicates that the calcium signaling pathway is important in signal pathway regulation of rosiglitazone compound, which provides a clue to further explain the mechanism of the compound and also provides a reference for the selection and application of methods of network pharmacology in the actual research. PMID- 26118107 TI - [A more accurate and efficient fluorescent probe of Caspase-8 activity based on flow cytometric fluorescence resonance energy transfer]. AB - As a classic fluorescent detect technique, fluorescence resonance energy transfer (FRET) has been widely used in biological researches. Researchers have developed a series of fluorescence detect probes which were based on FRET. Caspase family plays an important role in apoptosis pathway, especially Caspase-8 which located, at the initial of death receptor mediated apoptosis pathway, whose its activation can trigger subsequent precaspases' activation and lead to apoptosis. So it is of great significance to detect the activation of Caspase-8 in apoptosis assay. In this study, a fluorescent probe based on FRET has been designed which can detect the activity change of Caspase-8 in cells. To identify the effectiveness and specificity of the probe, we measure the Caspase-8 activity under the Caspase-8 specifically activated apoptosis inducer RGD-TRAIL with the flow cytometry FRET detection platform. The results show that the probe can respond to the activity change of Caspase-8 in apoptotic cells, and the change can be quantified rapidly by flow cytometry. The study provides a more efficient and convenient detection method of Caspase-8 activity in living cells. PMID- 26118108 TI - [The effect of Connexin43 downregulation on biological functions of HUVEC]. AB - Connexin43 has been shown to play a pivotal role in wound healing process. Wound repair is enhanced by acute downregulation of connexin43, by increasing proliferation and migration of keratinocyte and fibroblast. Angiogenesis is also a central feature of wound repair, but little is known about the effects of connexin43 modulation on functions of endothelial cells. We used connexin43 specific small interference RNA (siRNA) to reduce the expression of connexin43 in human umbilical vein endothelial cell (HUVEC), and investigated the effects of connexin43 downregulation on intercellular communication, viability, proliferation, migration and angiogenic activity of HUVEC. Treatment of siRNA markedly reduced the expression of connexin43 by -80% in HUVEC (P < 0.05), and decreased the intercellular communication by -65% (P < 0.05). The viability, proliferation, migration and angiogenic activity of HUVEC decreased significantly (P < 0.05), compared with that of the normal cells. The results suggest that temporally downregulation of connexin43 expression at early stage of wound to inhibit the abnormal angiogenesis characterized with leaky and inflamed blood vessels, maybe a prerequisite for coordinated normal healing process. PMID- 26118109 TI - [Transplacental transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia of MDCKII/MDCKII-BCRP cell line]. AB - To study the transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia, MDCKII-BCRP and MDCKII cell models was used. MDCKII-BCRP and MDCKII cell monolayer model was used to investigate the bi-direction transport of sotalol, propranolol, propafenone, procainamide and flecainide. Drug concentrations were measured by HPLC-UV or chemiluminescence. The apparent permeability coefficient (P(app)), efflux rate (R(E)) and net efflux rate (R(net)) were calculated. Drugs with R(net) greater than 1.5 were further investigated using cellular accumulation experiments with or without a BCRP inhibitor. The R(net) of sotalol, propranolol, propafenone and procainamide were less than 1.5, while R(net) of flecainide with concentrations of 20 and 5 MUmol x L(-1) were 1.6 and 1.9, respectively. The results showed that the transport of flecainide on MDCKII-BCRP cell monolayer could be mediated by BCRP; and the affinity increased when the concentration of flecainide decreased. Cellular accumulation experiments further suggested that accumulation of flecainide in MDCKII-BCRP cells was significantly lower than that in MDCKII cells in a concentration-dependent manner. BCRP inhibitor quercetin (50 MUmol x L(-1)) significantly increased the accumulation of flecainide in MDCKII-BCRP cells (P < 0.05). Our preliminary data showed that flecainide but not sotalol, propranolol, propafenone or procainamide can be a substrate of BCRP. Thus the effect of flecainide may be affected by the BCRP in the maternal placental trophoblast membrane layer when treating fetal tachyarrhythmia. PMID- 26118110 TI - [Metabolomic approach to evaluating the effect of the mixed decoction of kelp and licorice on system metabolism of SD rats]. AB - The aim of the study is to evaluate the effects of the single and mixed decoction of Thallus laminariae (kelp) and Glycyrrhiza glabra (licorice) on the metabolism and their difference. The mixed decoction of kelp and licorice and the single decoction were made and intragastrically administered to the SD rats. The effect on system metabolism, the toxicity of liver and kidney were assessed by GC-MS profiling of the endogenous molecules in serum, routine biochemical assays and histographic inspection of tissues from SD rats, separately. The mixed decoction of kelp and licorice induced more obvious pathological abnormalities in SD rats than a single decoction of kelp, while the extracts of licorice did not show any pathological change. Neither the mixed, nor the single decoction showed abnormal histopathology. After intragastric administration of extracts for 5 days, the mixed decoction induced a decrease of ALT (no significant change in the groups of single decoction) and an increase of BUN (so did the single decoction of kelp). Metabolomic profile of the molecules in serum revealed that the metabolic patterns were all obviously affected for the three groups, i.e., the mixed and single decoction of kelp and licorice. The rats given with the single decoction of kelp showed a similar pattern to that of the mixed decoction, indicating that the kelp primarily contributed the perturbation of metabolism for the mixed decoction. All three groups induced a decrease of branched chain amino acids, TCA cycle intermediates and glycolysis intermediates (e.g., pyruvic acid and lactic acid) and an increase of 3-hydroxybutyric acid. Kelp decoction showed stronger potential in reducing TCA cycle intermediates and glycolysis intermediates than the other two groups, while the levels of branched chain amino acids were the lowest after licorice extracts were given. These results suggested that the effect of the mixed decoction on metabolism was closely associated with both kelp and licorice. The continuous administration of single decoction of kelp and the mixed decoction of licorice and kelp resulted in pathological abnormalities in kidney of SD rats. The mixed decoction of kelp and licorice distinctly perturbed sera molecules and hence system metabolism, which showed associated with those of kelp and licorice. Although the metabolic effect was associated with both kelp and licorice, the results suggested kelp contributed to it primarily. PMID- 26118111 TI - [Study of change in activity of hepatic drug metabolism enzymes in rat model of chronic unpredictable mild stress]. AB - This study aimed to explore the impact of depression caused by chronic unpredictable mild stress (CUMS) on in vivo activity of six kinds of CYP450 isoforms in rats. According to 'Katz' method, the model of CUMS was established. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphan were chosen as probe substrates of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1 and CYP2D2 of rats. Plasma concentration of six kinds of CYP450 in control group and model group were determined by LC-MS/MS and computed pharmacokinetic parameters. Consequently, metabolism of theophylline and chlorzoxazone accelerated significantly (P < 0.01), but tolbutamide, dextromethorphan, omeprazole and midazolam had no significant difference. The present study proved that depression caused by CUMS had strong induction to CYP1A2 and medium induction to CYP2E1. PMID- 26118112 TI - [Design, synthesis and anti-platelet aggregation activities of ligustrazine tetrahydroisoquinoline derivatives]. AB - Abstract: Fifteen novel ligustrazine-tetrahydroisoquinoline derivatives were designed and synthesized according to the association principle of pharmaceutical chemistry. The structures were identified by IR, NMR and ESI-MS. The inhibitory activities of platelet aggregation induced by ADP and AA have been measured by Bron method. Preliminary pharmacological results showed that compounds 7g, 7h and 7n had potent inhibitory activity against platelet aggregation induced by AA, and the compound 7o showed significant inhibitory activity against platelet aggregation induced by ADP. PMID- 26118113 TI - [Design, synthesis, antibacterial and anti-cell proliferation activities of [1,2,4]triazino[3,4-h] [1,8]naphthyridine-8-one-7-carboxylic acid derivatives]. AB - To discover novel fluoroquinolone lead compounds as possible anti-infective or/and antitumor chemotherapies, combination principle of pharmacophore-based drug design, a series of novel tricyclic fluoroquinolone title compounds, [1,2,4]triazino[3,4-h][1,8]naphthyridine-8-one-7-carboxylic acid derivatives ( 5a 5p), were designed and synthesized with a fused [1,2,4]-triazine ring unit. Their structures were characterized by spectral data and elemental analysis and the in vitro antibacterial and anti-cell proliferation activities were also evaluated. The results showed that the titled compounds exhibited more significant inhibitory activities against drug-resistant bacteria (Methicillin-resistant Staphylococcus aureus and multi drug-resistant Escherichia coli strains) and three tested cancer cell lines (human hepatoma SMMC-7721, murine leukemia L1210 and human murine leukemia HL60 cells). Interestingly, SAR showed that compounds with electron-donating groups attached to benzene ring had stronger antibacterial activity than antitumor activity, but electron-withdrawing compounds displayed more potential antitumor activity than antibacterial activity, especially antitumor activity of nitro compounds was comparable to comparison doxorubicin. Thus, novel triazine-fused tricyclic fluoroquinolones as potent anti-infective or/and antitumor lead compounds are valuable to pay attention and for further development. PMID- 26118114 TI - A new aurone glycoside from Veratrum dahuricum (Turcz.) Loes. f. AB - To study the chemical constituents of Veratrum dahuricum (Turcz.) Loes. f., a new aurone glycoside named as (Z)-7, 4'-dimethoxy-6-hydroxyl-aurone-4-O-beta glucopyranoside was isolated from the 95% ethanol extracts of the rhizomes and roots of Veratrum dahuricum (Turcz.) Loes. f. by repeated column chromatography on silica gel and recrystallization. Its structure was established by extensive spectroscopic analyses, and its cytotoxicities against HepG-2, MCF7 and A549 cell lines were measured in vitro. PMID- 26118115 TI - [UPLC/Q-TOF MS and NMR plant metabolomics approach in studying the effect of growth year on the quality of Polygala tenuifolia]. AB - Growth year is one of the important factors for the quality of Polygala tenufolia. In this study, primary metabolites and secondary metabolites were compared in 1, 2 and 3 years old P. tenufolia cultivated in Shaanxi Heyang. The samples were subjected to ultra-high performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (Q-TOF MS) and nuclear magnetic resonance (NMR) analysis, and the obtained data were analyzed using principal component analysis (PCA) and other statistical analysis methods. In addition, content and correlation of different metabolites were also calculated. The results showed no significance between main component contents in 2 year-old and 3 year-old P. Tenufolia, but 1 year-old was statistically different. The contents of primary metabolites, such as fructose, sucrose, and choline increased as time goes on, while glycine and raffinose decreased. The contents of secondary metabolites, such as onjisaponin Fg, polygalasaponin XXVIII, polygalasaponin XXXII increased, while polygalaxanthone III and parts of oligosaccharide multi ester including tenuifoliose A, tenuifoliose C, tenuifoliose C2 and tenuifoliose H decreased with the extension of the growth years. Growth years has important impact on the quality of P. tenuifolia and the existing growing years of commodity P. tenuifolia have its scientific evidence. This study supplied a new method for the quality evaluation of Chinese medicinal materials. PMID- 26118116 TI - [Effects of stable isotope labeled internal standard on determination of ivabradine and N-demethylivabradine in human plasma]. AB - This study aims to develop a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of ivabradine and N demethylivabradine in human plasma, and investigate effects of stable isotope labeled (SIL) internal standard (IS) on ivabradine. The analytes and IS were extracted from plasma by protein precipitation with acetonitrile, and chromatographied on a Capcell PAK C18 (100 mm x 4.6 mm, 5 MUm) column using a mobile phase of methanol and 5 mmol x L(-1) ammonium acetate. Multiple reaction monitoring with electrospray ionization (ESI) was used in the positive mode for mass spectrometric detection. The effect of ivabradine isotope peak [M+H+3] + on IS and the effect of SIL IS purity on ivabradine were evaluated. An appropriate concentration of SIL IS was chosen to permit method selectivity and linearity of the assay over the required range. The standard curves were demonstrated to be linear in the range of 0.100 to 60.0 ng x mL(-1) for ivabradine, and 0.050 0 to 20.0 ng x mL(-1) for N-demethylivabradine. The intra and inter day precision and accuracy were within the acceptable limits for all concentrations. Besides, the interaction between IS and ivabradine did not impact the determination of analytes. This method was successfully applied to a pharmacokinetic study of hydrogen sulfate ivabradine sustained release tablets on Chinese healthy volunteers. PMID- 26118117 TI - [Quality by design based high shear wet granulation process development for the microcrystalline cellulose]. AB - The design space of the high shear wet granulation process was established and validated within the framework of quality by design (QbD). The system of microcrystalline cellulose-de-ioned water was used in this study. The median granule size and bulk density of granules were identified as critical quality attributes. Plackeet-Burmann experimental design was used to screen these factors as follows: dry mixing time, the impeller and chopper speed of dry mixing, water amount, water addition time, wet massing time, the impeller and chopper speed of wet massing and drying time. And the optimization was implemented with the central composite experimental design based on screened critical process parameters. The design space of the high shear wet granulation process was established based on the quadratic polynomial regression model. Since the P values of both models were less than 0.05 and values of lack of fit were more than 0.1, the relationship between critical quality attributes and critical process parameters could be well described by the two models. The reliability of design space, illustrated by overlay plot, was improved with the addition of 95% confidence interval. For those granules whose process parameters were in the design space, the granule size could be controlled within 250 to 355 MUm, and the bulk density could be controlled within a range of 0.4 to 0.6 g x cm(-3). The robustness and flexibility of the high shear wet granulation process have been enhanced via the establishment of the design space based on the QbD concept. PMID- 26118118 TI - [Construction of the first genetic linkage map of Salvia miltiorrhiza Bge. using SSR, SRAP and ISSR markers]. AB - The first genetic linkage map of Salvia miltiorrhiza was constructed in 94 F1 individuals from an intraspecific cross by using simple sequence repeat (SSR), sequence-related amplified polymorphism (SRAP) and inter-simple sequence repeat (ISSR) markers. A total of 93 marker loci in the linkage map, consisting of 53 SSR, 38 SRAP and 2 ISSR locus were made up of eight linkage groups, covered a total length of 400.1 cm with an average distance of 4.3 cm per marker. The length of linkage groups varied from 3.3 -132 cm and each of them included 2-23 markers, separately. The result will provide important basis for QTL mapping, map based cloning and association studies for commercially important traits in S. miltiorrhiza. PMID- 26118119 TI - [Bioinformatics analysis of DNA demethylase genes in Lonicera japonica Thunb]. AB - The DNA demethylase genes are widespread in plants. Four DNA demethylase genes (LJDME1, LJDME2, LJDME3 and LJDME4) were obtained from transcriptome dataset of Lonicera japonica Thunb by using bioinformatics methods and the proteins' physicochemical properties they encoded were predicted. The phylogenetic tree showed that the four DNA demethylase genes and Arabidopsis thaliana DME had a close relationship. The result of gene expression model showed that four DNA demethylase genes were different between species. The expression levels of LJDME1 and LJDME2 were even more higher in Lonicera japonica var. chinensis than those in L. japonica. LJDME] and LJDME2 maybe regulate the active compounds of L. japonica. This study aims to lay a foundation for further understanding of the function of DNA demethylase genes in L. japonica. PMID- 26118120 TI - Best Practices In The Emergency Department Management Of Children With Special Needs. AB - Children with special needs have a wide variety of physical and developmental challenges. These children often have medical devices, subtle presentations, and behavioral or psychiatric issues that demand consideration when delivering emergency care. Some of the more common issues include the evaluation and management of complications in devices such a gastrostomy/jejunostomy feeding tubes, cerebroventricular shunts, and tracheostomy tubes, as well as impediments to the performance of common emergency procedures (eg, laceration repair, sedation for imaging) on children with developmental or behavioral disorders. This review will examine each of these circumstances and provide guidance on the best approaches to managing these patients. PMID- 26118121 TI - WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty ninth report. AB - The Expert Committee on Specifications for Pharmaceutical Preparations works towards clear, independent and practical standards and guidelines for the quality assurance of medicines. Standards are developed by the Committee through worldwide consultation and an international consensus-building process. The following new guidelines were adopted and recommended for use. Revised procedure for the development of monographs and other texts for The International Pharmacopoeia; Revised updating mechanism for the section on radiopharmaceuticals in The International Pharmacopoeia; Revision of the supplementary guidelines on good manufacturing practices: validation, Appendix 7: non-sterile process validation; General guidance for inspectors on hold-time studies; 16 technical supplements to Model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products; Recommendations for quality requirements when plant-derived artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients; Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability: revision; Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products: revision; and Good review practices: guidelines for national and regional regulatory authorities. PMID- 26118123 TI - Microarray analysis of differentially expressed genes regulating lipid metabolism during melanoma progression. AB - A new hallmark of cancer involves acquisition of a lipogenic phenotype which promotes tumorigenesis. Little is known about lipid metabolism in melanomas. Therefore, we used BRB (Biometrics Research Branch) class comparison tool with multivariate analysis to identify differentially expressed genes in human cutaneous melanomas, compared with benign nevi and normal skin derived from the microarray dataset (GDS1375). The methods were validated by identifying known melanoma biomarkers (CITED1, FGFR2, PTPRF, LICAM, SPP1 and PHACTR1) in our results. Eighteen genes regulating metabolism of fatty acids, lipid second messengers and gangliosides were 2-9 fold upregulated in melanomas of GDS-1375. Out of the 18 genes, 13 were confirmed by KEGG pathway analysis and 10 were also significantly upregulated in human melanoma cell lines of NCI-60 Cell Miner database. Results showed that melanomas upregulated PPARGC1A transcription factor and its target genes regulating synthesis of fatty acids (SCD) and complex lipids (FABP3 and ACSL3). Melanoma also upregulated genes which prevented lipotoxicity (CPT2 and ACOT7) and regulated lipid second messengers, such as phosphatidic acid (AGPAT-4, PLD3) and inositol triphosphate (ITPKB, ITPR3). Genes for synthesis of pro-tumorigenic GM3 and GD3 gangliosides (UGCG, HEXA, ST3GAL5 and ST8SIA1) were also upregulated in melanoma. Overall, the microarray analysis of GDS-1375 dataset indicated that melanomas can become lipogenic by upregulating genes, leading to increase in fatty acid metabolism, metabolism of specific lipid second messengers, and ganglioside synthesis. PMID- 26118122 TI - Angiotensin II inhibits Na+/K+ATPase activity in pulmonary artery smooth muscle cells via glutathionylation and with the involvement of a 15.6 kDa inhibitor protein. AB - The role of angiotensin II in regulating Na+/K(+)-ATPase activity has been investigated in bovine pulmonary artery smooth muscle cells (BPASMCs). Our study reveals that angiotensin II inhibits the Na+/K+ATPase activity via glutathionylation of the pump with the involvement of an increase in NADPH oxidase-derived O2*-. Additionally, angiotensin II treatment to the cells increases the inhibitory potency of the 15.6 kDa inhibitor towards the Na+/K+ATPase activity. PMID- 26118124 TI - Up-regulation of NLRC5 and NF-kappaB signaling pathway in carrier chickens challenged with Salmonella enterica Serovar Pullorum at different persistence periods. AB - The immune performance, SNPs and expression levels of candidate genes (IL1-beta, Nramp1, TLR4, MyD88, NF-kappaB and NLRC5) were analyzed in carrier chickens of a Chinese indigenous breed infected with Salmonella enterica Serovar Pullorum at different persistence periods (12, 19 and 24 weeks of age). Carrier birds at 19 weeks of age presented significant difference in most immune parameters, as compared to carriers at 12 and 24 weeks of age, while no significant difference in most immune parameters was observed between carriers at 12 and 24 weeks of age. The genotype distributions of IL1-beta and TLR4 presented significant differences between carriers and healthy birds. The expression levels of most candidate genes in carriers at 19 weeks of age were significantly higher than that in carriers at 12, 24 weeks of age and healthy birds and reached 1% level of significance between carriers at 19 weeks of age and healthy birds. The expression patterns of all genes, but IL-1fl and NLRC5 between carriers at 12 and 24 weeks of age in all tissues were similar. Compared with carriers at 12 weeks of age, IL1-beta was significantly down-regulated, but NLRC5 was significantly up regulated in carriers at 24 weeks of age. Our study demonstrated that immune performance of carrier birds was severely impaired at age of sexual maturation and NLRC5 might play as a negative mediator of NF-kappaB pathway involved in immune response to asymptomatic infection by S. Pullorum. The TLR4/MyD88/NF kappaB pathway might be suitable for study on S. Pullorum infection in Chinese indigenous breeds. PMID- 26118125 TI - Umbilical cord mesenchymal stem cells in neurological disorders: A clinical study. AB - We investigated the intrathecally administrated unbilical cord mesenchymal stem cells (UC-MSCs) by lumbar puncture and assessed the technical difficulties and effects in various neurological conditions. One hundred patients underwent subarachnoid placement of UC-MSCs between December 2006 and May 2010 in the Affiliated Hospital of Medicine. Technical difficulties in patients in the form of localization of subarachnoid space, number of attempts, and post-procedural complications were evaluated. Functional evaluation was done using Hauser Ambulation Index (HAI) by the stem cell transplant team on a regular basis. All patients were followed-up for more than 1 yr after the treatment. Clinical symptoms, related biochemical index and photographic examinations were observed regularly. We encountered technical difficulties in 31 patients (31%) in the form of general anesthesia supplementation and difficulty localizing the lumbar space. Side effects (headache, low-grade fever, low back pain and lower limb pain) were observed in 22 (22%) patients, which were treated with symptomatic therapy within 48 h. One year after the treatment, functional indices improved in 47 patients (47%): 12 patients with spinal cord injury, 11 patients with cerebral palsy, 9 patients with post-traumatic brain syndrome, 9 patients with post-brain infarction syndrome, 3 patients with spinocerebellar ataxias, and 3 patients with motor neuron disease. In conclusion, intrathecal administration of UC-MSCs is a safe and effective way to treat neurological disorders. Our encouraging results of intrathecal administration of UC-MSCs indicate the potential of restoration of lost tissue and improvement of function in patients with profound neurological defects and inefficient conventional cure. These data support expanded double blind, placebo-controlled studies for this treatment modality. PMID- 26118126 TI - Protective effect of alcoholic extract of stem of Entada pursaetha in dextran sulphate sodium-induced colitis in mice. AB - Oxidative stress has been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). Entada pursaetha has been demonstrated to have antioxidant and anti-inflammatory effects. In this study, we investigated the effects of stem of alcoholic extract of E. pursaetha (PSE) in dextran sodium sulfate (DSS)-induced colitis in mice. The protective effect of PSE was determined at three different doses of 30, 100 and 300 mg/kg body weight by oral gavage for 7 days. Morphological (colon length and colon weight/length ratio), clinical (disease activity index) and macroscopic (damage score) features were determined using standard criteria. Lipid peroxides (determined as malonaldehyde; MDA), enzymatic (superoxide dismutase; SOD and catalase; CAT) and non- enzymatic antioxidants (reduced glutathione; GSH), nitrate and nitrite (NOx) levels and myeloperoxidase (PO) activity in colon tissues were determined. The DSS damaged the colonic tissue, increased MPO activity, lipid peroxidation and NOx levels, reduced the antioxidant enzymes and glutathione and lowered the body weight. PSE significantly reduced the inflammation of colon and reversed the increase in MPO activity induced by DSS. It also significantly increased the SOD and catalase activities and did not elicit any effect on depleted levels of GSH in the colonic tissue. In addition, PSE also significantly decreased colonic NOx and MDA levels compared to DSS-treated mice; reduced both infiltration of inflammatory cells and the mucosal damage in colon on histopathological examination. The results suggested the protective potential of PSE in DSS-induced colitis and this might be attributed to its anti-inflammatory and antioxidant activities. PMID- 26118127 TI - Physiological responses of Catla catla larvae fed with Achyranthes aspera seed enriched diet and exposed to UV-B radiation. AB - The antioxidant and growth stimulating properties of seeds of Achyranthes aspera were evaluated on UV-B irradiated Catla catla (catla) larvae. Catla larvae (initial weight: 1.2 +/- 0.01 mg) were fed with four different diets--D1, D2 and D3 containing 0.1, 0.25 and 0.5% seeds of A. aspera and D4, control diet for 35 days. The larvae were then exposed to UV-B radiation (80 MUW/cm2) on every alternate day for 20 days. Survival, growth, tissue glutamic oxaloacetic transminase (GOT), tissue glutamate pyruvate transminase (GPT), thiobarbituric acid reactive substances (TBARS) and nitric oxide synthase (NOS) were studied in larvae on day-21 of irradiation. Significantly (P < 0.05) higher survival and average weight were found in D3 diet fed fish compared to the other groups. Survival rate was 8-16% higher in seed enriched diet fed groups, compared to the control one. Higher levels of GOT and GPT found in control diet fed larvae showed the degree of tissue damage due to UV-B exposure. Significantly (P < 0.05) lower level of GPT in D3 indicated the UV-B protective effect of the seed of A. Aspera (earlier, the presence of ecdysterone, essential fatty acids and amino acids, polyphenolic compounds, steroids, etc. has been reported from seed). TBARS which indicated the level of tissue lipid peroxidation were significantly (P < 0.05) higher in control group, compared to the other feeding schemes. NOS level was significantly (P < 0.05) higher in D2 and D3, compared to the D1 and control groups. In conclusion, supplementation of A. aspera seed (0.5%) improved the physiological condition (in terms of reduce lipid oxidation and better immune system) and gave bioprotection to catla larvae challenged with UV-B stress. PMID- 26118128 TI - Comparison of activity of OsDmc1A recombinase of rice (Oryza sativa) in presence of Ca2+ and Mg2+ ions. AB - Recombinases are known to play an important role in the homology search and strand exchange during meiosis as well as homologous recombination (HR)-mediated DNA repair specifically require Mg2+ ion for their activity. The Ca2+ has been shown to stimulate the strand exchange activity of hDmc1 and ScDmc1 by forming the extended filaments on DNA. Oryza sativa disrupted meiotic cDNA1A (OsDmc1A), a homologue of yeast and human Dmc1 from rice shows the hallmark functions of recombinase. Here, we report the effects of Ca2+ and Mg2+ on OsDmc1A activity from rice (Oryza sativa). OsDmc1A showed a concentration-dependent binding with both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) substrates in presence of Mg2+ or Ca2+. The ssDNA and dsDNA binding activities, as well as renaturation activity of OsDmc1A were similar in the presence of Ca2+ or Mg2+. Increasing the Ca2+ or Mg2+ increased the DNA binding, renaturation and strand exchange of OsDmc1A. But, OsDmc1A showed only a slight stimulation of strand exchange activity in presence of Ca2+, when compared the activity in presence of Mg2+. Electron microscopy showed that OsDmc1A formed ring-like structures in presence of Mg2+ or Ca2+. However, OsDmc1A formed filament like structures with both ss and dsDNA in presence of Mg2+ or Ca2+. Taken together, Ca2+ did not affect OsDmc1A recombinase activity significantly. PMID- 26118129 TI - Structural and functional analysis of chitinase gene family in wheat (Triticum aestivum). AB - Chitinases are the hydrolytic enzymes which protect plants against pathogen attack. However, the precise role of chitinases in disease resistance has not been explored in wheat. In the present study, in silico approach, including secondary structure analysis, detailed signature pattern study, cis-acting regulatory elements survey, evolutionary trends and three-dimensional molecular modeling was used for different chitinase classes of wheat (Triticum aestivum). Homology modeling of class I, II, IV and 3 chitinase proteins was performed using the template crystal structure. The model structures were further refined by molecular mechanics methods using different tools, such as Procheck, ProSA and Verify3D. Secondary structure studies revealed greater percentage of residues forming a helix conformation with specific signature pattern, similar to casein kinase II phosphorylation site, amidation site, N-myristoylation (N-MYR) site and protein kinase C phoshorylation site. The expression profile suggested that wheat chitinase gene was highly expressed in cell culture and callus. We found that wheat chitinases showed more functional similarity with rice and barley. The results provide insight into the evolution of the chitinase family, constituting a diverse array of pathogenesis-related proteins. The study also provides insight into the possible binding sites of chitinase proteins and may further enhance our knowledge of fungal resistance mechanism in plants. PMID- 26118130 TI - Thermostable, alkaline and detergent-tolerant lipase from a newly isolated thermophilic Bacillus stearothermophilus. AB - Lipases are the enzymes of choice for laundry detergent industries, owing to their triglyceride removing ability from the soiled fabric, which eventually reduces the usage of phosphate-based chemical cleansers in the detergent formulation. In this study, a novel thermo-alkaline lipase-producing strain identified as Bacillus stearothermophilus was isolated from the soil samples of olive oil mill. Enhanced lipase production was observed at 55 degrees C, pH 11 and after 48 h of incubation. Among the substrates tested, xylose (a carbon source), peptone (a nitrogen source) and olive oil at a concentration of 1% were suitable substrates for enhancing lipase production. MgSO4 and Tween-80 were suitable substrates for maximizing lipase production. The enzyme was purified to homogeneity by a single CM-Sephadex column chromatography and revealed molecular mass of 67 kDa. The enzyme (BL1) was active over a wide range of pH from 9.0 to 13.0, with an optimum at pH 11.0, exhibited maximal activity at 55 degreesC and retained more than 70% of its activity after incubation at 70 degrees C or pH 13 for 0.5 h or 24 h, respectively. The enzyme hydrolyzed both short and long-chain triacylglycerols at comparable rates. BL1 was studied in a preliminary evaluation for use in detergent formulation solutions. This novel lipase showed extreme stability towards non-ionic and anionic surfactants after pre-incubation for 1 h at 40 degrees C, and good stability towards oxidizing agents. Additionally, the enzyme showed excellent stability and compatibility with various commercial detergents, suggesting its potential as an additive in detergent formulations. PMID- 26118131 TI - Effect of covalent attachment of neomycin on conformational and aggregation properties of catalase. AB - The carboxylic groups of glutamic acid and aspartic acid residues of catalase (CAT) were chemically modified using the treatment of the enzyme with 1-ethyl-3 (3'-dimethylamino) carbodiimide hydrochloride (EDC) and neomycin. The effect of covalent attachment of neomycin on the enzymatic activity, conformational and aggregation properties of CAT was investigated. The modification of CAT with different concentrations of neomycin showed two different types of behavior, depending up on the concentration range of neomycin. In the concentration range from 0.0 to 5.2 mM, neomycin-modified CAT, compared to the native enzyme exhibited higher a-helix content, reduced surface hydrophobicity, little enhancement in CAT activity and a better protection against thermal aggregation, whereas at concentrations greater than 5.2 mM, the modified enzyme exhibited a significant decrease in CAT activity and an increase in random coil content which may result in disorder in the protein structure and increase in thermal aggregation. This modification is a rapid and simple approach to investigate the role of aspartate and glutamate residues in the structure, function and folding of CAT. PMID- 26118132 TI - Estimation of the use of fibrin and collagen membranes as carriers for platelet derived growth factor-BB (PDGF-BB) in the presence of amoxicillin. AB - The effect of homogeneous fibrin (Fb), collagen (Coll) and composite fibrin heparin (Fb-Hp), fibrin-collagen (Fb-Coll) membranes on in vitro release of platelet-derived growth factor (PDGF-BB) was evaluated in the presence or absence of amoxicillin using of the ELISA immunoassay test. Amoxicillin concentration was determined spectrophotometrically at 272 nm. The process of the PDGF-BB growth factor and amoxicillin release from the studied membranes was of a two-phase nature in the majority of the systems analysed. The PDGF-BB was released in the highest amount from the Coll membrane (M7) without the presence of amoxicillin- 546.2 +/- 7.47 pg, t0.5 = 0.88 h and 202.5 +/- 6.83 pg, t0.5 = 26.65 h during the first phase and second phase, respectively. The lowest PDGF-BB release was observed from composite M4 (Fb-Hp) membrane--5.88 +/- 0.81 pg, t0.5 = 1.69 h; and 110.2 +/- 6.48 pg, t0.5 = 855.6 h during first and second phase respectively. An optimal release of amoxicillin was observed in the case of the composite M6 (Fb Coll) membrane--only in the second phase: 64.2 +/- 7.8 MUg, t0.5 = 83.5 h. The lowest and delayed amoxicillin release was achieved for M4 membrane (approx. 17.1 +/- 1.12 MUg, t0.5 = 46.5 h). The results of the PDGF-BB release and amoxicillin from membranes indicated a correlation between the level of release and composition of the film. Our results suggested that fibrin and collagen membranes may be beneficial to enhance periodontal bone regeneration. PMID- 26118133 TI - Bile salt incorporated polypyrrole thin film for ethanol sensing. AB - Polypyrrole (PPy)-bile salt composite was used for sensing ethanol vapor. PPy was synthesized by interface polymerization for subsequent fabrication of thin film of its composite with bile salt, by in-situ co-dispersion method and then exposed to ethanol vapour. Sensing was visualized through changes in morphological, structural and optical characterizations. The ethanol exposed film showed larger agglomeration as revealed in its surface morphology on scanning electron microscope (SEM) and greater crystallinity as seen through X-Ray diffraction (XRD). Fourier transform infra red (FTIR) and nuclear magnetic resonance spectroscopy (NMR) of the ethanol incorporated film also gave signature of the presence of bile salt and alcohol. Alcohol incorporation pattern resulted in increase in electrical conductance from 7.08539 x 10(-5) mA/V to 8.0356 x 10(-5) mA/V, as determined from current voltage characterizations. Average molecular weight (M(n)) obtained from gel permeation chromatography changed from 6160 to 10300 on ethanol intake. Photoluminescence (PL) intensity was quenched and the PL peak shifted from 430 to 409 on ethanol exposure. Changes in morphological, structural, optical and electrical properties of the composite on ethanol exposure showed its prospective application for sensing ethanol. PMID- 26118134 TI - Vascular endothelial growth factor insertion/deletion gene polymorphism in West Indian patients of type 2 diabetes and diabetic nephropathy. AB - Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes. Vascular endothelial growth factor (VEGF) is a potent multi-functional cytokine which plays a key role in the pathogenesis of DN. In this study, we evaluated the possible association of the VEGF gene (I/D) polymorphisms with DN in type 2 diabetes patients in West Indian population. Genotyping (I/D) of the VEGF gene polymorphism was done by the polymerase chain reaction. A total of 103 patients with type 2 diabetes, 102 patients with DN, 108 patients with non diabetic nephropathy and 143 healthy controls were genotyped. The frequency of VEGF genotype distribution and biochemical parameters like creatinine and HbA1c were compared in diabetic, diabetic nephropathy, non diabetic nephropathy and control groups. We found significant difference in creatinine level in DN and NDN groups on comparison with control group. Our study suggests that I/D polymorphism in the promoter region of the VEGF gene is not associated with DN in type 2 diabetes patients, but might have a role in development of non-diabetic nephropathy. PMID- 26118135 TI - Research Workshop on Diagnostics and Therapeutic Immunology: Report. PMID- 26118136 TI - The Combined Influence of Psychological Factors on Biomarkers of Renal Functioning in African Americans. AB - OBJECTIVE: African Americans are disproportionately affected by chronic kidney disease (CKD). Recent research has documented that psychological-factors have a significant influence on the progression and treatment of CKD. However, extant evidence exists that has examined the link between psychological factors and renal function in African Americans. The purpose of the study was to determine if psychological factors were associated with several biomarkers of renal functioning in this group. PARTICIPANTS: 129 African American participants, with a mean age of 44.4 years (SD = 12.25). DESIGN AND SETTING: Data were analyzed from a cross-sectional study entitled Stress and Psychoneuroimmunological Factors in Renal Health and Disease. MAIN PREDICTOR MEASURES: Participants completed the Beck Depression Inventory-II, Cook Medley Scale, and Perceived Stress Scale-10. MAIN OUTCOME MEASURES: Systolic blood pressure, as well as blood and urine samples, were collected and served as biomarkers of renal functioning. RESULTS: Our findings indicated that psychological factors were not associated with renal functioning. Age, sex, and systolic blood pressure emerged as significant predictors of renal functioning. CONCLUSIONS: Depressive symptomatology, perceived stress, and hostility did not influence renal functioning in this sample. This unexpected finding may be attributed to the fact that this sample population was not elevated on depressive symptoms, perceived stress, or hostility. Elevated levels of these psychological factors, as well as other psychological factors associated with the CKD, may be more influential on renal functioning in African Americans. PMID- 26118137 TI - Racial/Ethnic Disparities in Mental Health Service Utilization among Youth Participating in Negative Externalizing Behaviors. AB - PURPOSES: Racial/ethnic differences in mental health service utilization were examined among youth who reported participating in negative externalizing behaviors. METHODS: The study utilized merged data from the 2007-2010 National Survey on Drug Use and Health (NSDUH) to examine differences in utilization of inpatient or outpatient mental health services not related to substance or alcohol use by White, Black and Hispanic youth who reported engaging in negative externalizing behaviors ("acting out"). Differences in service utilization in these groups were assessed using logistic regression models. RESULTS: Race/ethnicity was a significant predictor of outpatient mental health service use. Black and Hispanic children were less likely to use outpatient services. Inpatient service use decreased with increasing income. Parental presence in the household increased the likelihood of outpatient service use for minorities. CONCLUSION: Racial/ethnic minority youth in the United States continue to use outpatient mental health services at lower rates. This may lead to high prevalence of untreated negative externalizing behaviors among minority adolescent groups and, in turn, lead to use of inpatient services from systems such as juvenile justice and foster care. Such severe treatment alternatives can be prevented if timely and culturally tailored outpatient intervention is provided. PMID- 26118138 TI - Discrimination and Depression among Urban Hispanics with Poorly Controlled Diabetes. AB - OBJECTIVES: We had three objectives for our study: 1) to describe the prevalence and burden of experiences of discrimination among Hispanics with poorly controlled diabetes; 2) to evaluate associations among discrimination experiences and their burden with comorbid depression among Hispanics with poorly controlled diabetes; and 3) to evaluate whether discrimination encountered in the health care context itself was associated with comorbid depression for Hispanic adults with diabetes. DESIGN: We conducted a cross-sectional analysis of baseline data of a randomized controlled trial (RCT). SETTING: We collected data in the context of an RCT in a clinical setting in New York City. PARTICIPANTS: Our sample comprised 221 urban-dwelling Hispanics, largely of Caribbean origin. MAIN OUTCOME MEASURES: The main outcome measure was major depression, measured by the Euro-D (score > 3). RESULTS: Of 221 participants, 58.8% reported at least one experience of everyday discrimination, and 42.5% reported at least one major experience of discrimination. Depression was associated significantly with counts of experiences of major discrimination (OR = 1.46, 95% CI = 1.09 - 1.94, P = .01), aggregate counts of everyday and major discrimination (OR = 1.13, 95% CI = 1.02 - 1.26, P = .02), and the experience of discrimination in getting care for physical health (OR = 6.30, 95% CI= 1.10-36.03). CONCLUSIONS: Discrimination may pose a barrier to getting health care and may be associated with depression among Hispanics with diabetes. Clinicians treating Caribbean-born Hispanics should be aware that disadvantage and discrimination likely complicate a presentation of diabetes. PMID- 26118139 TI - Racial and Ethnic Differences in Mental Distress among Stroke Survivors. AB - OBJECTIVE: African Americans, Hispanics and some Asian subgroups have a higher stroke incidence than non-Hispanic Whites (NHW). Additionally, African Americans and Hispanics have worse stroke outcomes than non-Hispanic Whites. Thus, we explored racial and ethnic differences in mental distress, a known risk factor for post-stroke disability. METHODS: National Health Interview Survey data from 2000-2010 were used to identify 8,324 community dwelling adults with self reported stroke. Serious mental distress was identified by the Kessler-6 scale. Logistic regression models assessed racial/ethnic associations with serious mental distress after adjusting for demographics, comorbidities, disability, health care utilization and socioeconomic factors. RESULTS: Serious mental distress was identified in 9% of stroke survivors. Hispanics (14%) were more likely to have serious mental distress than African Americans (9%), non-Hispanic Whites (9%) and Asians (8%, P = .02). After adjustment, Hispanics (OR = 1.06, 95% CI .76-1.48) and Asians (.84, 95% Cl .37-1.90) had a similar odds of serious mental distress while African Americans had a lower odds of serious mental distress (OR = .61, 95% CI .48-.78) compared with non-Hispanic Whites. Younger age, low levels of education and insurance were important predictors of serious mental distress among Hispanics. CONCLUSION: Serious mental distress is highly prevalent among US stroke survivors and is more common in Hispanics than NHWs, African Americans and Asians. Further study of the role of mental distress in ethnic differences in post-stroke disability is warranted. PMID- 26118141 TI - The Effect of Pulse Pressure on All-Cause and Cardiovascular-Specific Mortality Risks in US Adults. AB - OBJECTIVES: To examine the effect of pulse pressure on all-cause and cardiovascular-specific mortality risks and whether this effect varies with sex and race/ethnicity among adults who participated in the third National Health and Nutrition Examination Survey and were followed to December 31, 2006. DESIGN: Cohort/Longitudinal. SETTING: United States. MAIN OUTCOME MEASURE: All-cause and cardiovascular-specific mortality. METHODS: Hazard rates and 95% confidence intervals (CI) for all-cause and cardiovascular-specific mortality associated with the pulse pressure quartiles (Q) were estimated through Cox proportional regression before and after controlling for selected characteristics. RESULTS: Relative to adults with pulse pressure in the first quartile, death rate for all cause mortality was 29% (95% CL: 1.03, 1.62) and 54% (95% CI: 1.22, 1.95) higher in adults with pulse pressures in Q3 and Q4, respectively, after adjustment for all study covariates. These associations were further observed in Whites and Mexican Americans only. For cardiovascular-specific mortality, the adjusted death rates for Q3 and Q4 were 57% (95% CI: 1.00, 2.44) and 76% (95% Cl: 1.16, 2.67). CONCLUSIONS: Our findings suggest that pulse pressure could be associated with all-cause and CVD-specific mortality risk among US adults. PMID- 26118140 TI - Serious Psychological Distress and Diabetes Management among American Indians and Alaska Natives. AB - OBJECTIVE: Our study examined associations between serious psychological distress and blood glucose level (HbA1c) and body mass index (BMI) among American Indian and Alaska Native (AI/AN) participants in a cardiovascular disease prevention program. DESIGN: Using linear regression, we assessed the relationships between serious psychological distress and HbA1c and BMI at baseline and one year later. SETTING, PARTICIPANTS, AND INTERVENTION: AI/AN participants were aged 18 years, diagnosed with type 2 diabetes, and enrolled in the Special Diabetes Project for Indians Healthy Heart Project. MAIN OUTCOME MEASURES: Outcomes were percentage of HbA1c and BMI, measured at enrollment and first annual exam. Both outcomes were continuous measures in all analyses. RESULTS: Serious psychological distress was associated at baseline with increased HbA1c in the unadjusted and adjusted models (adjusted b = .17%, P < 0.01). Serious psychological distress also was associated at baseline with increased BMI (.635 kg/m2, P = .01) and at one year with increased BMI (0.174 kg/m2, P = .01) in the unadjusted model. After adjustment for demographic and health characteristics, these relationships were no longer significant. CONCLUSIONS: Cross-sectional baseline findings are consistent with existing literature. One-year findings suggest need for further inquiry into mediators of psychological distress and examination of additional diabetes specific health outcomes. Additional years of observation may be needed to disentangle relationships between serious psychological distress and BMI. PMID- 26118142 TI - Stroke Disparities: Disaggregating Native Hawaiians from other Pacific Islanders. AB - OBJECTIVES: To compare the clinical characteristics of Native Hawaiians (NH) and other Pacific Islanders (PI) who are hospitalized with ischemic stroke. DESIGN: Retrospective, cross-sectional analysis of medical records. SETTING: Tertiary, Primary Stroke Center in Honolulu, Hawaii. PATIENTS: Consecutive patients with race/ethnicity identified as NH or PI who were hospitalized for ischemic stroke between January 2006 and December 2012. OUTCOME MEASURES: Age, sex, cardiovascular risk factors, intravenous tissue plasminogen activator (IV-tPA) utilization rate and hospital length of stay. RESULTS: A total of 561 patients (57% NH and 43% PI) were studied. PI were younger (59 +/- 13 years vs 62 +/- 14 years, P = .002), had higher prevalence of diabetes mellitus (58% vs 41%, P < .0001) and prosthetic valve (6% vs 2%, P = .007), lower prevalence of smoking (14% vs 21%, P = .03), lower HDL cholesterol (38 +/- 11 mg/dL vs 41 +/- 13 mg/dL, P = .004), and higher discharge diastolic blood pressure (79 +/- 15 vs 76 mm Hg +/- 14 mm Hg, P = .04) compared to NH. No difference was seen in other cardiovascular risk factors. The IV-tPA utilization rate (5% vs 6%, P = .48) and the hospital length of stay (10 +/- 17 days vs 10 +/- 49 days, P = .86) were not different between the two groups. CONCLUSION: Native Hawaiians and other Pacific Islanders with ischemic stroke have modestly different age of stroke presentation and burden of risk factors compared to each other. Disaggregating these two racial groups may be important to unmask any potential clinical differences in future studies. PMID- 26118143 TI - A Pilot study Evaluating a Community-based Intervention Focused on the ISHIB IMPACT Cardiovascular Risk Reduction Toolkit in African American Patients with Uncontrolled Hypertension. AB - OBJECTIVE: To evaluate blood pressure (BP) control utilizing the International Society on Hypertension in Blacks (ISHIB) cardiovascular risk reduction toolkit in an African American community with uncontrolled hypertension. METHODS: This is a randomized controlled pilot study conducted in two Baltimore community-based physicians' offices assigned adults (18-64 years) with uncontrolled hypertension (systolic blood pressure [SBP] <= 169 mm Hg; diastolic blood pressure [DBP] <= 109 mm Hg). The study compares usual care to a community-based intervention. In the usual care group, the patients' BP was managed by the treating physician based on their normal office patient care protocol. In the intervention group, usual care was provided but, a community health worker also gave comprehensive education and assessment to the patients based on the ISHIB IMPACT cardiovascular toolkit during study initiation and follow-up visits. The main outcome of study was change in BP from baseline to six months. A secondary outcome was the proportion of patients achieving BP < 135/< 85 mm Hg at six months. RESULTS: Fifty-four African American patients were enrolled; 37 completed six months of follow-up (usual care, n = 25; intervention, n = 12). At six months the mean (95% CI) change from baseline in SBP was significantly greater in the intervention group vs the usual care group: -34.75 (-46.55 to -22.95) mm Hg vs -5.65 (-12.84 to 1.54) mm Hg (P < .001). Mean (95% CI) change in DBP from baseline to six months was significantly greater for the intervention group vs the usual care group: -16.19 (-24.00 to -8.39) mm Hg vs -4.36 (-8.26 to -0.46) mm Hg (P = .009). Median change in BP was significantly greater for SBP in the intervention group compared with the usual care group (P = .007), but not for DBP (P = .197). The proportion of patients achieving BP < 135/ <85 at six months was 83% (10/12) in the intervention group vs 60% (15/25) in the usual care group (P = .263). CONCLUSIONS: This pilot study on the ISHIB IMPACT toolkit in managing uncontrolled hypertension in the African American community suggests better control of systolic BP and a tendency to better hypertension control with the community-based intervention. The findings support further studies in clinical settings serving African American hypertensive patients to assess effectiveness of approaches for improving BP control and related outcomes. PMID- 26118145 TI - Fasting Serum Glucose and Cholesterol as Predictors of Cardiovascular Reactivity to Acute Stress in a Sample of African American College Students. AB - OBJECTIVE: African Americans are at a greater risk of cardiovascular hyperactivity to stress than Caucasians; however the risk factors for this activity are not clearly delineated for African Americans. The purpose of this study was to determine the ability of fasting serum cholesterol concentration and fasting serum glucose (FSG) to predict cardiovascular reactivity to stress in African Americans. DESIGN, SETTING, PARTICIPANTS: Serum cholesterol concentration and FSG levels were measured in 48 (40 women, 8 men) African American college students aged 18-30 years. Heart rate, cardiac output, stroke volume, mean arterial pressure and systolic and diastolic blood pressure were measured as the participants viewed a racially noxious scene on a digital video disc. Measurements were taken prior to the scene (pre stressor period), during the scene (stressor period), and while the participant recovered from the scene (recovery period). RESULTS: A multiple regression analysis revealed that total serum cholesterol and LDL significantly predicted diastolic blood pressure during the pre-stressor period. FSG significantly predicted mean arterial pressure during the recovery period, and predicted stroke volume during the pre-stressor period, stressor period, and the recovery period. CONCLUSIONS: FSG was a better predictor of cardiovascular reactivity to stress than serum cholesterol concentration, predicting mean arterial pressure and stroke volume. This finding may be due to the association of glucose with diabetes, which is more prevalent in African Americans. PMID- 26118144 TI - Implementation of an Adjunct Strategy to Reduce Blood Pressure in Blacks with Uncontrolled Hypertension: a Pilot Project. AB - A high prevalence of uncontrolled hypertension among Blacks is a major cause of racial health disparities in the United States. We established a community/academic partnership to improve hypertension control in Blacks receiving medical care at a federally qualified health center in Milwaukee. The defining components of our program included: six group sessions (one/month), based on the American Heart Association's Simple Seven curriculum and designed to motivate and empower patients to manage their blood pressure; active involvement of a community health worker; and ongoing participation of a community advisory board. The study design included a matched control group not exposed to the intervention. Patients in both groups received their usual medical care. Overall, compared to baseline, systolic blood pressure decreased at both 6 and 12 months (P < 0.004); however, the reduction of blood pressure in the intervention and control groups did not differ significantly (P = .62). Based on written responses to a questionnaire and structured focus group interviews after completing the six month program, participants reported that the intervention was effective. In retrospect, they suggested that more attention might have been given to spirituality and stress reduction. Larger and longer-term studies will be required to evaluate the added value of this type of intervention. PMID- 26118148 TI - Psychometric Properties of the Family Support Scale Adapted for African American Women with Type 2 Diabetes Mellitus. AB - OBJECTIVE: The purpose of our study was two-fold: 1) adapt and test a social support measure specific to the experiences of African American women with type 2 diabetes mellitus (T2DM); 2) examine its relationship to psychosocial measures. RESEARCH DESIGN AND METHODS: 200 rural African American women with uncontrolled T2DM participating in a randomized controlled trial completed surveys at baseline on their social support, empowerment, self-care, self-efficacy, depression and diabetes distress. Exploratory factor analysis and correlation analysis were conducted to test the psychometric properties of the Dunst Family Support Scale adapted for AA women with T2DM (FSS-AA T2DM) and its relationship with other psychosocial measures. RESULTS: The 16 items of the FSS-AA T2DM loaded onto three distinct factors: parent and spouse/partner support, community and medical support, and extended family and friends support. Reliability for the entire scale was good (Cronbach's alpha = .90) and was acceptable to high across these three factors (Cronbach's alpha of .86, .83, and .83 respectively). All three factors were significantly correlated with self-reported empowerment, self-care, self-efficacy, depression and diabetes distress, although the pattern was different for each factor. FSS-AA-T2DM showed good concurrent validity when compared with similar items on the Diabetes Distress Scale. CONCLUSION: The FSS AA T2DM, a 16-item scale measuring social support among rural African American women with T2DM, is internally consistent and reliable. Findings support the utility of this screening tool in this population, although additional testing is needed with other groups in additional settings. PMID- 26118146 TI - Rationale and Design of the Echocardiographic Study of Hispanics/Latinos (ECHO SOL). AB - BACKGROUND: Information regarding the prevalence and determinants of cardiac structure and function (systolic and diastolic) among the various Hispanic background groups in the United States is limited. METHODS AND RESULTS: The Echocardiographic Study of Latinos (ECHO-SOL) ancillary study recruited 1,824 participants through a stratified-sampling process representative of the population-based Hispanic Communities Health Study - Study of Latinos (HCHS-SOL) across four sites (Bronx, NY; Chicago, Ill; San Diego, Calif; Miami, Fla). The HCHS-SOL baseline cohort did not include an echo exam. ECHO-SOL added the echocardiographic assessment of cardiac structure and function to an array of existing HCHS-SOL baseline clinical, psychosocial, and socioeconomic data and provides sufficient statistical power for comparisons among the Hispanic subgroups. Standard two-dimensional (2D) echocardiography protocol, including M mode, spectral, color and tissue Doppler study was performed. The main objectives were to: 1) characterize cardiac structure and function and its determinants among Hispanics and Hispanic subgroups; and 2) determine the contributions of specific psychosocial factors (acculturation and familismo) to cardiac structure and function among Hispanics. CONCLUSION: We describe the design, methods and rationale of currently the largest and most comprehensive study of cardiac structure and function exclusively among US Hispanics. ECHO-SOL aims to enhance our understanding of Hispanic cardiovascular health as well as help untangle the relative importance of Hispanic subgroup heterogeneity and sociocultural factors on cardiac structure and function. PMID- 26118147 TI - Participant Retention in a Longitudinal National Telephone Survey of African American Men and Women. AB - OBJECTIVE: The purpose of this article is to describe participant demographic factors related to retention, and to report on retention strategies in a national study of African Americans re-contacted 2.5 years after an initial baseline telephone interview. DESIGN & SETTING: The Religion and Health in African Americans (RHIAA) study was originally developed as a cross-sectional telephone survey to examine relationships between religious involvement and health-related factors in a national sample of African Americans. The cohort was re-contacted on average of 2.5 years later for a follow-up interview. PARTICIPANTS: RHIAA participants were 2,803 African American men (1,202) and women (1,601). INTERVENTIONS: RHIAA used retention strategies consistent with recommendations from Hunt and White. Participants also received a lay summary of project findings. MAIN OUTCOME MEASURES: Retention at the follow-up interview. RESULTS: Retention rates ranged from 39%- 41%. Retained participants tended to be older and female. In age- and sex-adjusted analyses, retained participants were more educated, single, and in better health status than those not retained. There was no difference in religious involvement in adjusted analyses. CONCLUSIONS: Although overall retention rates are lower than comparable longitudinal studies, RHIAA was not originally designed as a longitudinal study and so lacked a number of structures associated with long-term studies. However, this project illustrates the feasibility of conducting lengthy cold call telephone interviews with an African American population and helps to identify some participant factors related to retention and study strategies that may aid in retention. PMID- 26118149 TI - Factors Associated with Underestimation of Weight Status among Caucasian, Latino, Filipino, and Korean Americans--DiLH Survey. AB - OBJECTIVE: To describe weight misperception and to examine the influence of sociodemographic factors on underestimation of weight status in Caucasian, Latino, Filipino, and Korean Americans. DESIGN: Data from 886 non-pregnant adults who participated in a cross-sectional survey administered in English, Spanish, and Korean were analyzed. The actual weight status derived from the participants' body mass index (BMI) categories and their perceived weight status were compared. A multiple logistic regression model was used to explore if underestimation of weight status was associated with ethnicity, sex, and education level. RESULTS: Caucasians, Latinos, Filipinos, and Koreans represented 19.4%, 26.8%, 27.4%, and 26.4%, respectively, of the total sample of 886. Overall, two in three participants correctly perceived their weight status, but 42% of Latinos underestimated their weight status and 22% of Koreans overestimated their weight status. Latino ethnicity, male, and low education (high school) were related to greater underestimation of weight status (P < .05). In contrast, Korean ethnicity was related to less underestimation of weight status (P < .05). CONCLUSIONS: Misperception of weight status should be counted in any efforts to develop a weight management intervention for Latino and Korean Americans. PMID- 26118150 TI - Obesity and Cardiovascular Diseases in a High-Risk Population: Evidence-Based Approach to CHD Risk Reduction. AB - BACKGROUND: Obesity is becoming a worldwide public health problem and it is expected to worsen as its prevalence is increasing in children and adolescents. This report examined the distribution of major cardiovascular disease (CVD) risk factors and the effect of life-style changes on coronary heart disease (CHD) risk prediction in a high risk obese African Americans. METHODS: We examined the baseline distribution of CVD risk factors in 515 obese African Americans, with mean BMI of 42.9 +/- 6.8 kg/m2, and prospectively the effect of a 6-month low salt, low-fat diet and aerobic-exercise intervention program on risk reduction. RESULTS: Prevalence of hypertension, dyslipidemia, and diabetes mellitus were 57%, 27% and 24% respectively. Metabolic syndrome was present in 36% and 39% met two features of the syndrome. The 10-year risk prediction for developing CHD ranged from 4% to 17% for women and 6% to 29% for men. After 6 months of life style changes, many of the risk factors improved, and the CHD risk scores decreased from 6% to 4% in the women and 16% to 13% in the men. CONCLUSION: The high prevalence and increasing incidence of obesity and associated cardiovascular risk emphasizes the need to focus on obesity reduction in this high risk population. PMID- 26118152 TI - Racial Disparities in Behavior Risk Factors and Diabetes Preventive Health Care among Asian/Pacific Islanders with Type 2 Diabetes. AB - OBJECTIVE: To estimate behavior risk factors and diabetes preventive health care among Asian/Pacific Islanders (API) diagnosed with type 2 diabetes. DESIGN: Population-based telephone survey. PARTICIPANTS: APIs and non-Hispanic Whites (NHW) surveyed in the 2009 Behavioral Risk Factor Surveillance System (BRFSS) data. MAIN OUTCOME MEASURES: Diabetes preventive health care (taking insulin, taking educational classes, receiving flu shot and pneumococcal vaccine, blood sugar check, cholesterol check, HbA1C check, and eye and foot examination), behavior risk factors (fruit and vegetable consumption, physical exercise, smoking and binge drinking). RESULTS: By constructing the logistic regression model, odds ratios (OR) were calculated to compare the risk factors and preventive care between NHW and API groups. Compared with NHW, the APIs were significantly less likely to check their blood sugar at least once a day (OR = .59, 95% CI = .393-.886), got flu shots (OR = .597, 95% CI = .394-.903) and have had pneumococcal vaccines (OR = .455, 95% CI = .296-.7). The results also showed that APIs eat more fruits, are more likely to be physically active, and are less likely to participate in binge drinking and smoking. There are no differences between these two groups for diabetes education, having seen professionals for diabetes within past year, having cholesterol or HbA1C checked in past year, and having an eye or foot exam in past year. CONCLUSIONS: Our results can inform the best intervention strategies to deliver diabetes preventive health care services for the APIs with type 2 diabetes and to help NHWs reduce risk factors for diabetes. PMID- 26118151 TI - Lean Mass and Fat Mass as Contributors to Physical Fitness in an Overweight and Obese African American Population. AB - OBJECTIVE: To determine the association of lean vs fat mass with fitness in healthy, overweight and obese African Americans from families with early-onset coronary disease. DESIGN: Cross-sectional study. SETTING: Baltimore, Maryland. PARTICIPANTS: 191 healthy, overweight, sedentary African Americans (69% women; aged 44.8 +/- 11 years; body mass index 34 +/- 5 kg/m2). MAIN OUTCOME MEASURES: Anthropometrics, smoking, blood pressure, lipids, c-reactive protein, and glucose were assessed with standard methods; body composition was determined by dual energy X-ray absorptiometry; cardiorespiratory fitness was expressed as VO(2peak) attained during a maximal treadmill test. RESULTS: In both men and women, greater lean mass was independently associated with higher VO(2peak) (P < .05) and explained > 21% of the variance in VO(2peak), adjusted for body mass index, fat mass, important covariables, and nonindependence of families. CONCLUSIONS: In this cross-sectional study, lean mass was the key determinant of cardiorespiratory fitness, independent of sex, age, and magnitude of obesity. These data provide a strong rationale for examining whether interventions that increase lean mass may also improve fitness, even among high-risk overweight and obese African Americans. PMID- 26118153 TI - Effect of Race on the Prevalence of Congenital Malformations among Newborns in the United States. AB - BACKGROUND: Racial variability in certain prenatal risk factors, such as prenatal vitamin supplementation and termination of pregnancy for fetal anomaly, has altered the racial prevalence of congenital malformation (CM). Analysis of a single large representative population is required to analyze current racial differences in prevalence of CM in the United States. METHOD: This is a population-based cross-sectional study to analyze racial differences in prevalence of CM diagnoses. We reviewed all live births in the 2008 Nationwide Inpatient Sample (NIS) database and determined birth prevalence of 55 selected CM diagnoses in Caucasians. We then calculated the relative risk of these CM diagnoses in African American, Hispanics and Asians relative to Caucasians. RESULT: Overall CM prevalence was 29.2 per 1,000 in a cohort of 1,048,252 live births of which 51% were Caucasians. Compared to Caucasian, risk of overall CM was lower in African Americans (RR = .9, CI .8-9) and Hispanics (RR = .9, CI .8 .9). Risk of overall CM was similar in Caucasians and Asians. Relative to the Caucasians, African Americans had lower risk of cardiac, genitourinary, and craniofacial malformations but higher risk of musculoskeletal malformations. Hispanics had lower risk of genitourinary and gastrointestinal malformation. Asians had higher risk of craniofacial and musculoskeletal malformation. CONCLUSIONS: This is a comprehensive description of racial difference in risk of CM in the United States. Observed racial differences in risk of CM may be related to genetic susceptibilities, to cultural or social differences that could modify exposures, or to the many potential combinations between susceptibilities and exposures. PMID- 26118154 TI - Clinical experience with BIAsp 30: Results from the Bangladesh cohort of the global A1chieve study. AB - The aim of A1chieve was to remedy the deficit of data on the efficacy and safety of insulin analogues in routine clinical care in less well-resourced developed countries. To present results from the Bangladesh cohort of the A1chieve study receiving BIAsp 30 +/- oral anti diabetic drugs. A1chieve was a 6-month, observational study of 66,726 people with type 2 diabetes, started on insulin detemir, insulin aspart or biphasic insulin aspart (BIAsp 30) in 28 countries across four continents. A total of 1,093 subjects were recruited from 49 sites in Bangladesh and 580 subjects initiated on BIAsp 30 were studied. In the entire cohort, treatment with BIAsp 30 for 24 weeks significantly reduced mean HbA(1c) (2.8%, p < 0.001), fasting plasma glucose (4.0 mmol/L, p < 0.001) and post prandial plasma glucose (6.6 mmol/L, p < 0.001) levels from baseline. The rate of overall hypoglycaemic events in the entire cohort also reduced significantly at 24 weeks (1.86 to 0.02 events/person year, p < 0.0001). BIAsp 30 can be considered as a safe and effective option for initiating as well as intensifying insulin therapy for type 2 diabetes. PMID- 26118155 TI - Percutaneous nephrolithotomy--a versatile technique for both simple and complex renal stone. AB - Percutaneous Nephrolithotomy is currently the preferred first line treatment for simple & complex renal calculi. The technique also being used increasingly for smaller stones that have failed ESWL. Aim of the study is to share our experience in PCNL in course of time. This study was conducted from January 2009 to December 2012, 131 patient's with 142 renal units of 5-75 yrs of age, PCNL were performed in NIKDU, BSMMU & JBFH. Stone were classified into simple (isolated renal pelvis or isolated calyceal stones) or complex (partial or complete staghorn stones, renal pelvic stone with accompanying calyceal stones). The stone size was 1.5-5cm approximately. We asses our initial puncture technique, need for multi-tract, supra 12th rib access, stone free rate, operative duration, postoperative complication, number of transfusion and hospital stay. Operative durations were 60 min -180 minutes. Puncture technique improved in course of time. 14 patients need multi-puncture and tract, all are supra 12th access. Out of 142 renal units 120 (83%) were stone free after first procedure, another 22 need and auxiliary procedure, (5 2nd look PCNL, 6 URS, 11 ESWL) to become stone free result in a 95% stone free rate. Complications occurred in 17 procedures which dealt accordingly. This study revealed PCNL is an effective, versatile safe and cosmetically acceptable procedure for all age groups in simple and complex renal stone. PMID- 26118156 TI - Comparison of transvaginal and transabdominal ultrasonography in the diagnosis of ectopic pregnancy. AB - This cross sectional study was carried out in the department of Radiology and Imaging, Dhaka Medical College Hospital from July 2008 to June 2010 to compare the accuracy of transvaginal ultrasonography and transabdominal ultrasonography in the diagnosis of clinically suspected cases of ectopic pregnancy. Initially 60 patients with clinical suspicion of ectopic pregnancy were included in this study after analyzing selection criteria 30 patients underwent both transvaginal and transabdominal ultrasonography. 'Histopathological diagnosis' was considered gold standard against which accuracies of two diagnostic modalities were compared. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of transabdominal ultrasonography as a diagnostic modality in evaluation of suspected ectopic pregnancy were 73.1%, 75%, 95%, 30% and 73.3% respectively where as transvaginal ultrasonography was found to have 92.3% sensitivity, 75% specificity, 96% positive predictive value, 60% negative predictive value and 90% accuracy. Transvaginal ultrasonography was superior to transabdominal ultrasonography in the evaluation of suspected ectopic pregnancies so, transvaginal ultrasonography is important for early and accurate diagnosis of ectopic pregnancy. PMID- 26118157 TI - An open randomized controlled trial to compare the efficacy of two fixed dose combinations of artemesinin based combinations for uncomplicated falciparum malaria in Bangladesh. AB - National Malaria Control Program (NMCP) of Bangladesh has introduced Artemisinin Based Combination (ACT), Coartem(R) (Artemether-Lumefantrine (AL), fixed dose combination, in the confirmed cases of uncomplicated P. falciparum malaria since 2004. Despite the reduction of mortality due to malaria, the development and spread of anti-malarial drug resistance wordwide posing a threat to the health services and will make it difficult to control malaria in Bangladesh in future. We need to have an alternative to Coartem which could be Artesunate-amodiaquine (AA) in a fixed dose combination (FDC), a cheaper altenative not yet evidenced to be effective and safe to our population. In this study we compared the efficacy and safety of Artemether + Lumefantrene (FDC, Coartem) with Artesunate +Amodiaquine tablets (100/270 mg FDC) for the treatment of uncomplicated P. falciparum malaria in three high risk multi-drug resistant malaria prevalent areas of Bangladesh. It was an open label randomized controlled trial conducted between December 2008 and November 2009 in 4 upazillas in patients over the age 12 to 60 years diagnosed as a case of uncomplicated P. falciparum malaria. The outcome of the cases were measured as clinical response, parasitological response, defervescence time and parasite clearance time. Drug safety was assessed by comparing the adverse events. A total of 252 cases were randomized to receive Artesunate + Amodiaquine (AA group, 147 cases) and Artemether + Lumefantrene (AL group, 106 cases), one lost to follow up at day 28 in AA group. The distribution of the cases was comparable by age, sex and study sites. Treatment success' response was observed 100% in the AL group and AA group had 99%, two failures with AA were late treatment failures and the difference was not statistically significant (p > .1). The parasitological sensitive (S) response was observed in 97% of cases in AL group and 95% in the AA group, and was not a statistically significant difference. There was no significant difference in deffervescence time and parasite clearance time between two groups of cases. No serious adverse events were observed. The frequencies of minor adverse events were insignificantly different between the two treatment groups. The two ACT regimen, AA and AL had no significant difference in efficacy and safety for treatment of Uncomplicated Malaria in Bangladesh. However, there were few more failures with AA regimen compared to AL regimen, which was not statistically significant. Both these regimens can be used alternatively by the NMCP of Bangladesh as first-line treatment option. PMID- 26118158 TI - Double balloon enteroscopy: Bangladesh experience. AB - Double balloon enteroscopy (DBE) is a newly developed endoscopic modality for diagnosis and treatment of small bowel disorders. The aim of this study was to evaluate the diagnostic and therapeutic impact of DBE in patient with suspected small bowel disease. This was a prospective study. Sixty one double balloon enteroscopy procedures (30 antegrade 31 retrograde) were done in thirty six patients (20M/16F, mean age 40 +/- 12.5 range 16-65 years ) at gastroenterology department, Sir Salimullah Medical College, Dhaka between October 2011 and September 2012. Indications for DBE included chronic abdominal pain 14 (38.9%), obscure GI bleeding 11 (30.56%), Small bowel obstruction 05 (13.89%), and chronic diarrhea 06 (16.67%). The morphologic findings were ulcerations 13 (36.11%), growth 03 (8.33%), vascular ectasia 03 (8.33%) and polyp 01 (2.78%). Therapeutic interventions were performed in one patient only. No serious complications were observed. Diagnostic yields in case of chronic abdominal pain, chronic diarrhea, obscure GI bleeding and small bowel obstruction were 50%, 66%, 63% and 40% respectively. The findings were adenocarcinoma 04 (11%), lymphoma 03 (8.4%), tuberculosis 03 (8.4%), non specific findings 05 (13.9%), IPSID 01(2.8%), Crohn's disease 01 (2.8%), vascular ectasia 03 (8.33%) and normal 16 (44.44%). DBE is well tolerated, feasible and useful technique for the diagnosis as well as treatment of small intestinal disorders. PMID- 26118159 TI - Comparison of modified Friedewald's formula with direct measurement of low density lipoprotein cholesterol in Bangladeshi population. AB - A modification of Friedewald's formula to estimate serum low-density lipoprotein cholesterol (LDLC) up to serum triglyceride (TG) level of 11.3 mmol/L in Bangladeshi population has recently been published. The aim of this study was to compare the modified formula with direct measurement of LDLC in Bangladeshi population in a different setting. One thousand and fifty two specimens from adult subjects were analyzed. Serum total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), LDLC and TG were measured by standard methods. The modified Friedewald's formula was applied to estimate LDL cholesterol concentration. Results were expressed as mean +/- SD and calculated LDLC was compared with measured LDLC by two-tailed paired t test, Bland-Altman plot for absolute bias, Pearson's correlation coefficients of calculated LDLC with measured LDLC and Passing & Bablok regression equation of calculated LDLC against measured LDLC. The mean +/- SD of measured LDLC was 2.98 +/- 0.82 mmol/L. LDLC calculated by modified Friedewald's formula was 2.77 +/- 0.86 mmol/L. The mean absolute bias was -0.20 +/- 0.32 mmol/L, Pearson's correlation coefficient (r) was 0.9293 (P < 0.0001) and Passing & Bablok regression equation was y = - 0.3856+1.0597x for modified formula up to serum TG <= 11.3 mmol/L. Compared to original Friedewald's formula, performance of the modified Friedewald's formula was better up to serum TG <= 4.52 mmol/L. The study reveals that the modified Friedewald's formula may be used to calculate LDLC approximately in Bangladeshi population. PMID- 26118160 TI - Microbial contamination in herbal medicines available in Bangladesh. AB - Plants have long been used as herbal medicines in many countries. However, microbial contamination of these medicines may affect human health. Present study was performed to assess the pathogenic proliferation in the locally available commercial herbal oral medicines. The pathogenic load was compared with the microbiological standard given by the British Pharmacopoeia. Out of 85 oral liquid samples, 2 were found to be highly contaminated with a total aerobic bacterial load of 1.24 x 10(5) cfu/ml, 10 samples were contaminated with fungi (1.2 x 10(4)-6.3 x 10(4) cfu/ml). Tests for specific pathogens were carried out. One sample showed contamination by coliforms but none of the samples were contaminated by Salmonella spp. and Shigella spp. Among 40 semisolid samples, one showed to be contaminated with bacteria (1.93 x 10(5) cfu/g) and 5 samples consisted of fungal load ranging between 1.5 x 10(4)-2.2 x 10(4) cfu/g. The presence of bacteria and fungi in these samples thus suggest the fact that aseptic handling is necessary during processing of oral herbal medicines. PMID- 26118161 TI - Ocular injury: Prevalence in different rural population of Bangladesh. AB - This population based cross-sectional study was conducted on 8283 persons of all ages in five districts, selected conveniently, to assess the magnitude of ocular injuries, their causes and consequences in rural Bangladesh. Six Upazilas from five districts and from each Upazila one Union was selected randomly. One village, the ultimate cluster, was then selected conveniently from each Union. All people (n = 8283) in the 8 villages were then surveyed. Out of 8283 population (ranging from 1-120 years) surveyed, 167(2%) had history and/or evidence of past ocular trauma with a yearly incidence of 6.2 per 1000 per year. Study demonstrated a female predominance with male to female ratio being roughly 4:5. Majority (82%) had at least one episode of trauma in their life-time with mean age at 1st trauma being 20 years. Nearly 40% of the traumas were caused by blunt objects followed by penetrating object (22.3%) and sharp instrument (18.1%) with home being the primary place of occurrence (55.1%). Evidence of ocular trauma was found on eye-lid (15%), conjunctiva (11.4%) and cornea (10.2%) as scars. The older participants (>= 30 years), females, illiterates, agriculture labors, housewives and household workers were more likely to receive trauma. Majority (86.8%) of the subjects received treatment following injury. The median time lapsed between injuries and receiving first treatment was 5 days and that between injury and visiting an eye-specialist was 18 days. Self-treatment and treatment from over-the-counter comprised 45% and 42.1% respectively followed by eye-specialists (25.5%), village quack (22.8%), graduate doctors (19.3%) and traditional healers (6.9%). About 87% received conservative management, with 12.4% needing hospitalization. Most of the injured (92.8%) and non-injured (95.2%) eyes had normal vision before trauma as informed by the respondents. Following trauma, 18% had impaired, 10.7% severely impaired vision and about 6% were blind. Job abstinence due to trauma was 53% with median wage loss being 10 days. The study concludes that point-prevalence of ocular trauma in rural area is around 2% with blunt objects commonly causing the trauma and one in every 16 trauma-hit case undergo blind. Addressing blindness from ocular trauma, should, therefore, be a priority for eye care programs in rural Bangladesh. PMID- 26118162 TI - Comparison of P2Y12 receptor inhibition by clopidogrel and prasugrel in patients undergoing percutaneous coronary intervention. AB - Dual antiplatelet treatment (DAPT) with aspirin and clopidogrel is vital after percutaneous coronary intervention (PCI). Clopidogrel and prasugrel act on P2Y12 platelet surface receptors. Both these P2Y12 inhibitors are pro-drugs and depend on cytochrome system of the liver for their conversion to active metabolite. There is growing concern regarding suboptimal response in platelet inhibition by clopidogrel. Verify Now system got approval by Federal Drug Administration, USA, for assessing platelet function as its result is almost comparable to gold standard Light Transmission Aggregometry (LTA). There are no data on the prevalence of clopidogrel resistance in Bangladeshi population. Prasugrel, as an antiplatelet drug, is a newer introduction in this country. This study will show light on the efficacy of these drugs on our population especially in patients who undergo PCI where DAPT is mandatory. A total 120 (60 diabetics) patients with Acute Coronary Syndrome (ACS), were alternatively given 600 mg clopidogrel loading dose (LD) followed by 75 mg maintenance dose (MD) daily or 60 mg LD of prasugrel followed by 10 mg MD daily. Five samples of blood were taken at different time intervals over a period of 2 weeks. Measurement of percent inhibition of P2Y12 was done by VerifyNow. Patients who showed less than 20% inhibition (clopidogrel resistant) at any stage were switched to prasugrel. The outcomes of clopidogrel, prasugrel and clopidogrel switched to prasugrel groups were then compared. Nearly half (46.7%) of the patients in the clopidogrel group was found resistant to the drug as opposed to none in the prasugrel group. No difference was found between diabetic and non-diabetic subjects with respect to drug resistance. Intracoronary blood samples showed high degree of platelet inhibition with prasugrel. There was a gradual decline of platelet inhibition over two weeks with prasugrel. Almost fifty percent of the population is clopidogrel resistant in our study. Prasugrel is a much more potent antiplatelet drug and should be preferred in patients undergoing PCI. Prasugrel may also show resistance over time. PMID- 26118163 TI - Auto-analyzer based screening of microcytic hypochromic ratio to differentiate thalassaemia and non thalassemic microcytosis. PMID- 26118164 TI - Newborn hearing screening: what are we missing? AB - The objectives of the study were to demonstrate hearing status in newborns at first screening by Transient Evoked Otoacoustic Emissions and to find out the relationship between abnormal hearing screening and known risk factors. This study was conducted in the department of neonatology of Bangabandhu Sheikh Mujib Medical University in collaboration with department of otolaryngology and department of obstetrics and gynaecology. This prospective observational study included a cohort of 168 neonates from Neonatal Intensive Care Unit and neonatal Nursery (Minimal care unit). All were screened for hearing impairment using Transient Evoked Otoacoustic Emissions in out-patient department of otolaryngology by a trained audiologist before discharge from hospital. Risk factors analysed were according to the criteria of American Academy of Pediatrics. Of the total neonates screened, Refer rate was 32.7% irrespective of presence or absence of risk factors. Small for gestational age, in-utero infections, ototoxic medications, birth weight < 1500, sepsis/meningitis, hyperbilirubinemia were found to be significant risk factors (p < 0.0001). It can be recommended that hearing screening should be universally done for all newborns. PMID- 26118165 TI - Antimicrobial resistance and in vitro biofilm-forming ability of Enterococci spp. isolated from urinary tract infection in a tertiary care hospital in Dhaka. AB - The biofilm mode of life conveys a survival advantage to the microorganism associated with it. Biofilm on an indwelling urinary catheter consists of adherent microorganisms, their extra cellular products, and host components deposited on the catheter and thus biofilm on urinary catheters results in persistent infections that are resistant to antimicrobial therapy. This study was done during the period of January 2010 to December 2010. Fifty nine enterococci isolated from 1203 urine samples were speciated by conventional microbiological methods and examined for their ability to form biofilm by microtitre plate assay and antimicrobial susceptibility testing by disc diffusion method for 10 clinically relevant antibiotics respectively. Biofilm producing Enterococci were more frequently found in catheterized than in non catheterized patient (p < 0.004). Enterococcus faecium showed increased resistantance to multiple antibiotic than Enterococcus faecalis. Significant relationship was found between biofilm production with antibiotic resistance to amoxicillin, co-trimoxazole, ciprofloxacin, gentamycin, cefotaxime, and cefuroxime. This study demonstrated a high propensity among the isolates of Enterococci to form biofilm and a significant association of biofilms with multiple drug resistance. PMID- 26118166 TI - Role of sonohysterography in evaluation of abnormally thickened endometrium causing abnormal uterine bleeding with histopathological correlation. AB - This prospective randomized study was carried out in the department of Radiology and Imaging in collaboration with the department of Obstetrics and Gynecology of Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag and Dhaka Medical College Hospital (DMCH) during the period of January 2003 to December 2004. The aim of this study was to establish sonohyterography as a sensitive tool and superior to Transvaginal Sonography (TVS) for detection of endometrial pathology in women with abnormal uterine bleeding (AUB) and its validity by determining sensitivity, specificity, accuracy, positive predictive value and negative predictive value. For this purpose, a total number of 40 patients who had thickened endometrium (cut off level < 15 mm for pre menopausal and < 5 mm for post menopausal patients) detected on transabdominal or transvaginal sonography were selected. TVS and TV-SH were done in all these patients and findings were then compared with the final histopathological diagnosis. In our study, we found TV-SH has sensitivity of 100%, specificity of 80% and accuracy of 97.5% compared to TVS (94%, 66.66% and 90% respectively) in detection of endometrial pathology in women with AUB. TV-SH can thus be regarded as one of the most sensitive, specific and accurate modality in detecting and excluding endoluminal masses as the cause of AUB. It can be considered as the initial examination in the evaluation of all women with AUB. PMID- 26118167 TI - Cadaver study of the volume of the ovary in Bangladeshi women. AB - Reproductive age, ovarian reserve and reproductive capability may be determined from the volume of the ovary. A cross-sectional, descriptive study was done in the Department of Anatomy, Dhaka Medical College, Dhaka, from January to December 2009, to see the variation in the volume of the ovary with age in Bangladeshi women. The study was performed on 140 post mortem human ovaries collected from 70 unclaimed female dead bodies which were in the morgue under examination in the Department of Forensic Medicine, Dhaka Medical College, Dhaka. The samples were divided into three age-groups including group A (10-13 years), group B (1445 years) & group C (46-52 years). Group A is pre-menarche group, group B represents reproductive age and group C is post menopausal group. The length, breadth and thickness of each ovary were measured by using a slide calipers. Then the volume of each ovary was determined by the product of its length, breadth and thickness multiplied by 0.524, according to the Prolate ellipsoid formula. The mean volume of the right ovary was found higher than that of the left one in all age groups (p < 0.001). The difference in mean volume of the ovary between group A & group B, group B & group C (p < 0.001) and group A & group C (p < 0.01) were also statistically significant. The volume of the ovary increases with age and then gradually starts to decrease from menopause. PMID- 26118168 TI - Physicians knowledge and attitude of opioid availability, accessibility and use in pain management in Bangladesh. AB - This survey was conducted on 1000 physicians with pain management responsibilities practicing in 47 districts in Bangladesh. The response rate was 58.3%. The physicians had a mean of 21 years in practice. It was notable that 66% of the physicians had seen cancer patients in the last 12 months and 63% had seen patients with advanced stage cancer where opioids are considered as the mainstay of treatment. It was discouraging that 85% of the physicians preferred to prescribe pethidine, when patients needed opioids for severe pain. 53% of the physicians were not aware of the 'Bangladesh Narcotics law, 1990'. 89% of the physicians would restrict opioid dosage in pain management to prevent drug tolerance or addiction. Oncology physicians displayed significantly higher knowledge scores. The results demonstrated physicians' poor knowledge, attitude and perceived barriers regarding opioids. Effective education strategies need to be addressed using the study result. PMID- 26118169 TI - Modulation of oxidative stress by enalapril and valsartan in adrenaline treated rats: a comparative study. AB - Angiotensin (Ang II) II is known to promote oxidative stress in acute myocardial infarction (AMI). Inhibition of renin angiotensin system (RAS) or blockade of Ang II receptors may therefore be effective in reducing oxidative stress during AMI. The study evaluates and compares the protective effect of Angiotensin Converting Enzyme (ACE) inhibitor and AT1 receptor blocker in adrenaline induced oxidative stress in rats. Rats were treated with two successive injections of adrenaline subcutaneously at a dose of 2 mg/kg administered 24 hours apart. In other two groups of rats enalapril (30 mg/kg) or valsartan (30 mg/kg) were given orally once daily through intragastric tube for 2 weeks and then two injections of adrenaline were administered 24 hours apart. Serum Aspertate Transaminase (AST), plasma Malonde Aldehyde (MDA), erythrocyte GSH and serum vitamin E levels were measured 24 hours after the 2nd injection of adrenaline in all the groups. Administration of adrenaline caused significant increase (p < 0.001) in serum AST and plasma MDA levels and decrease (p < 0.001) in erythrocyte GSH and serum vitamin E levels. Pre-treatment of enalapril or valsartan for 14 days reduced (p < 0.001) serum AST and plasma MDA levels and increased the concentration of erythrocyte GSH in enalapril pre-treated group (p < 0.01) and in valsartan pre treated group (p < 0.05). Pre-treatment of enalapril or valsartan also increased (p < 0.01) serum vitamin E levels in adrenaline treated rats. However, no significant difference was noted between the effect of enalapril and valsartan on serum AST, plasma MDA, erythrocyte GSH and serum vitamin E levels. It may be concluded that both enalapril and valsartan offered cardioprotection in adrenaline induced oxidative stress, but the protection afforded by valsartan was not superior to enalapril. PMID- 26118170 TI - Comparison of coronary CT angiography with conventional coronary angiography in the diagnosis of coronary artery disease. AB - Noninvasive CT coronary angiography is a promising coronary imaging technique. In spite of the unprecedented temporal and spatial resolution and the inability to perform therapeutic interventions in the same session multi-detector computed tomography (MDCT) has been considering a promising alternative, non invasive tool for coronary artery imaging due to its high sensitivity and specificity for the detection of significant coronary artery stenosis. To evaluate the diagnostic accuracy of 64-slice MDCT for assessing haemodynamically significant stenoses of the coronary arteries in comparison with the conventional standard cardiac angiography. Fifty patients scheduled for conventional coronary angiography at the department of Radiology and Imaging, United Hospital, Dhaka were enrolled between July 2007 and June 2008. All patients underwent both conventional and MDCT angiography within mean 10.70 days. Overall sensitivity of 64-slice MDCT for the detection of stenosis <= 50%, stenosis > 50%, and stenosis > 75% was 90.0%, 83.8%, and 80.7%, respectively, and specificity was 96.5%, 98.4%, and 98.3% respectively and accuracy was 96.0 %, 96.5%, and 96.6% respectively. Contrast enhanced 64-slice MDCT allows the identification of coronary stenosis with excellent accuracy. Measurements of stenosis derived by MDCT correlated well with conventional angiogram. A major limitation is the insufficient ability of CT to exactly quantify the degree of stenosis. PMID- 26118171 TI - Students' perceptions of the educational environment in an Iranian Medical School, as measured by The Dundee Ready Education Environment Measure. AB - Learning environment is found to be important in determining students' academic success and learning. The goal of this study was to investigate the viewpoints of medical students toward learning environment based on The Dundee Ready Education Environment Measure (DREEM) at Rafsanjan University of Medical Sciences (RUMS). This descriptive study was conducted using the Persian DREEM questionnaire. All medical students in basic and clinical courses except internship students (fifth and sixth year) were approached to participate during the study period, of which 223 provided consent and completed the survey. Data were analyzed by SPSS-17, t test and ANOVA statistical tests were used. The mean total score was 113.8 +/- 17.31 (out of a maximum of 200, 56.9%) indicating relative satisfaction with the perceived environment. There were no individual areas of excellence. Some items scored consistently badly indicating cause for concern. The highest score were related to Academic Self-Perception (64.11%) and learning (57.2%) domains. The lowest score were related to Teachers (55.9%), Social Self-Perceptions (56.6%) and atmosphere (55.8%) domains. Basic science students perceived the environment to be significantly more positive than preclinical students (p < 0.05). Native and married students perceived the environment to be significantly more positive (p < 0.05). Second and fourth year students were significantly higher than the others (P < 0.01). There was significant difference between mean scores of total mean DREEM and sub-domains by year of enrolment (p = 0.001). This tool identified areas of concern within RUMS medical school. Further use of the DREEM as a monitoring tool would be useful to re-evaluate the environment following appropriate intervention. To create an appropriate educational environment and reduce the deficits in order to provide a better learning environment with facilitate and supportive system for students. PMID- 26118172 TI - Gastrointestinal stromal tumor of the rectum: An analysis of six cases. PMID- 26118173 TI - Prevention of blindness due to agriculture related ocular trauma in Bangladesh: A nationwide campaign. PMID- 26118174 TI - Application of New Reference Procedure for ALP Measurement in the Clinical Laboratory. AB - BACKGROUND: Alkaline phosphatase (ALP) is routinely analyzed in clinical laboratories for the comprehensive assessment of hepatic and osteal diseases. The official reference measurement procedure (RMP) of ALP was released by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) in 2011. However, most of the commercial kits still trace back to the old version (1983). There was a difference between the trace measurement procedure and the RMP. Therefore, the discrepancy among clinical systems and application of the new RMP for ALP in clinical laboratories was studied. METHODS: According to the recommendation of the IFCC, the RMP for ALP (2011) was reproduced. The reference measurement system (RMS) for serum ALP and 19 clinical systems were included in the external quality assessment (EQA). The relative bias was calculated between the clinical systems' results and RMS, as well as each clinical system and the average value of all clinical systems. The qualified rates (passing score in percentage) for the 19 clinical systems were compared by using two different standards. In the comparison experiment, two clinical systems were evaluated before and after calibration by RMP. The clinical acceptability at the medical decision point was evaluated. RESULTS: The performance of the reproduced RMP for ALP was: total imprecision was 0.33% and 0.42% at 336.9 U/L and 138.74 U/L, respectively. The accuracy was in the acceptable range. Excellent linearity was obtained for linear regression (R = 0.9998). In the EQA experiment, the relative bias of clinical systems and RMP ranged from -26.36% to 19.49%, and the majority of them had a negative value. Relative bias of clinical systems and the average value of 19 clinical systems ranged from -24.28% to 33.48%. The qualified rate for clinical systems was 53% - 89% evaluated by Standard 1 and was 95% - 100% evaluated by Standard 2. In the comparison experiment, the relative bias for the two clinical systems decreased and both of the clinical systems showed less relative bias at the medical decision points after calibration by RMP. CONCLUSIONS: There was a much higher discrepancy among clinical systems for the testing of serum ALP. Traceability and standardization would likely be improved for clinical systems by the application of RMP for ALP (2011) in clinical laboratories. PMID- 26118175 TI - National Survey on Internal Quality Control for HbA(1c) Analytical Instruments in 331 Hospital Laboratories of China. AB - BACKGROUND: The narrow gap of HbA1 value of mass fraction between "normal" (< 6.0%) and "diabetes" (>= 6.5%) necessitates tight control of inter-assay standardization, assay precision, and trueness. This survey was initiated to obtain knowledge of the current situation of internal quality control (IQC) practice for HbA(1c) in China and find out the most appropriate quality specifications. METHODS: Data of IQC for HbA(1c) in 331 institutions participating in the national proficiency testing (PT) programs in China were evaluated using four levels of quality specifications, and the percentages of laboratories meeting the quality requirement were calculated to find out the most appropriate quality specifications for control materials of HbA(1c) in China. RESULTS: The IQC data varied vastly among 331 clinical laboratories in China. The measurement of control materials covered a wide range from 4.52% to 12.24% (inter quartile range) and there were significant differences among the CVs of different methods, including LPLC, CE-HPLC, AC-HPLC, immunoturbidimetry, and others. Among the four main methods, CE-HPLC and AC-HPLC achieved a better precision. CONCLUSIONS: As we can see, the performance of laboratories for HbA(1c) has yet to be improved. Clinical laboratories in China should improve their performance with a stricter imprecision criteria. PMID- 26118176 TI - The Application of Six Sigma Techniques in the Evaluation of Enzyme Measurement Procedures in China. AB - BACKGROUND: Recently, Six Sigma techniques have been adopted by clinical laboratories to evaluate laboratory performance. Measurement procedures in laboratories can be categorized as "excellent", "good", and "improvement needed" based on sigma (sigma) metrics of sigma >= 6, 3 <= sigma < 6, and sigma < 3, respectively. The quality goal index (QGI) was further investigated for measurement procedures with sigma <= 3. Improvements of the procedures were recommended based on QGI: QGI < 0.8 indicates that the precision of the procedure needs to be improved; QGI > 1.2 indicates that the trueness of the procedure needs to be improved; 0.8 <= QGI <= 1.2 indicates that both the precision and trueness of the procedure need to be improved. METHODS: Fresh frozen sera containing seven enzymes (ALT, ALP, AMY, AST, CK, GGT, and LDH) were sent to 78 clinical laboratories in China. The biases for measurement procedures in each laboratory (Bias) were calculated based on the target values assigned by 18 laboratories performing IFCC (International Federation of Clinical Chemistry and Laboratory medicine) recommended reference methods. The imprecision of each measurement procedure was represented by coefficient variations (CV) calculated based on internal quality control (IQC) data. The sigma and QGI values were calculated as follows: sigma = (TEa-Bias)/CV; QGI = Bias/(1.5 x CV). TEa is allowable total error for each enzyme derived from biological variation. RESULTS: Our study indicated that 7.9% (6/76, ALP) to 31.0% (18/58, AMY) of the participating laboratories were scored as "excellent" (sigma >= 6), 21.1% (16/76, ALP) to 41.3% (31/75, CK) of the laboratories were scored as "good" (3 <= sigma < 6), and 31.0% (18/58, AMY) to 71.1% (54/76, ALP) of the laboratories need to improve their enzyme measurement procedures (sigma < 3). For those with sigma < 3, QGIs were further calculated. Based on QGI values, 8.6% (5/58, AMY) to 35.9% (28/78, LDH) of the laboratories (QGI < 0.8) need to improve the precision of the procedures, 8.0% (6/75, CK) to 52.6% (40/76, ALP) of the laboratories (QGI <= 1.2) need to improve the trueness of the procedures; and 2.7% (2/75, AST) to 16.3% (8/49, GGT) of the laboratories (0.8 <= QGI <= 1.2) need to improve both the precision and trueness of the procedures. CONCLUSIONS: Even though rapid progress has been made to standardize serum enzyme measurements in China in recent years, our study using Six Sigma techniques still suggested that approximately 31.1% to 71.0% of the laboratories need to improve their enzyme measurement procedures, either in terms of precision, trueness, or both. PMID- 26118177 TI - Circulating microRNA Signatures Associated with Childhood Asthma. AB - BACKGROUND: MicroRNAs (miRNAs) exist stably and reproducibly in plasma and may be used as biomarkers for various diseases. Little is known about circulating miRNAs in the peripheral blood of juvenile patients with asthma. METHODS: In this study, we used hybridization arrays to compare the miRNA expression profiles among 6 juvenile patients with or without asthma. Using quantitative PCR (qPCR), we verified the expression levels of these miRNAs in plasma from patients with asthma (n = 40) and healthy subjects (n = 14). RESULTS: Our results showed that the levels of plasma miR-Let7C, miR-486, and miR-1260a in childhood asthma patients were significantly higher than in healthy controls (p < 0.01). Additionally, miR-1260a is correlated with the treatment schedule of these patients and patients with long treatment times had higher expression of miR 1260a than short treatment times; miR494 was significantly associated with challenge, and miR-3162-3p was significantly associated with MEF25 in asthma patients suggesting a potential correlation of miRNA levels with clinical disease parameters. Receiver operator characteristic analysis confirmed that the levels of miR-3162-3p could be used to discriminate childhood asthma patients from healthy subjects (area under the curve of 0.821), suggesting it may be a potential diagnostic biomarker. CONCLUSIONS: These results indicate that circulating miR-3162-3p and miR-1260a should be further evaluated as potential non-invasive biomarkers in diagnosis and treatment for childhood asthma. PMID- 26118178 TI - Expression Analysis of Aurora-C and Survivin, Two Testis-Specific Genes, in Patients with Colorectal Cancer. AB - BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer related death worldwide. The high frequency of positive families shows the importance of public awareness and screening strategies in those families. Cancer/testis (CT) antigens such as Aurora-C and Survivin are a group of antigens expressed in various tumor types of human cancers. Therefore, the aim of this study was to investigate the expression of Aurora-C and Survivin genes in malignant and normal tissues and their correlation to clinicopathological characteristics. METHODS: Tumor samples were obtained from 33 patients and adjacent non-tumorous tissues from 7 patients were also used as control. Patients were diagnosed with various stages of colorectal cancer. The level of Aurora-C and Survivin genes were evaluated by using real-time quantitative Polymerase Chain Reaction. RESULTS: The expression pattern of Survivin and Aurora-C revealed significant changes in tumor tissues when compared with normal tissues (p < 0.05). Also, these expressions were associated with the grade of disease and tumor size. There was no significant relationship between the expression of Survivin and Aurora-C genes (p > 0.05). CONCLUSIONS: In conclusion, the overexpression of Aurora-C and Survivin genes may play an important role in the development of colorectal cancer and may play a potential role in cancer therapy. PMID- 26118179 TI - The Role of Remote Ischemic Preconditioning in Ischemia-Reperfusion Injury in Rabbits with Transplanted Lung. AB - BACKGROUND: To observe the influence of remote ischemic preconditioning (R-IPC) and remote ischemic perconditioning (R-IPER) on the lower limbs of rabbits with lung allograft ischemia-reperfusion injury (IRI). METHODS: Sixty rabbits were randomly divided into one of four groups: control (C), classic ischemic preconditioning (C-IPC), R-IPC, and R-IPER. The allogeneic lung transplantation model was established in rabbits, and the protective effects of R-IPC and R-IPER on transplanted lungs were determined and compared to classic ischemic preconditioning (C-IPC) IRI. Changes in blood oxygen were measured in each group before and after transplantation. After transplantation, levels of serum malondialdehyde (MDA), superoxide dismutase (SOD), and tumor necrosis factor alpha (TNF-alpha), lung wet/dry weight ratio, as well as quantitative and organizational differences in the lungs were analyzed. RESULTS: After reperfusion, blood oxygen values in the R-IPC group and C-IPC groups were higher than in the C and R-IPER groups at 60 minutes and 120 minutes after transplantation (p < 0.05). Serum SOD content in the R-IPC and C-IPC groups was higher than in the C and R-IPER groups (p < 0.05) after reperfusion. Serum MDA, TNF-alpha level, and lung wet/dry weight ratio and quantitative measurements of histological damage were lower in the R-IPC and the C-IPC groups than those in the C and R-IPER groups (p < 0.05). No statistically significant differences were observed between the L-IP and the C-IP groups or between the R-IPER and the C groups. CONCLUSIONS: Classic preconditioning and remote preconditioning of rabbit lung allograft IRI had similar protective effects. The lower limb ischemia with the remote processing method used in this experiment did not produce a protective effect for lung allograft IRI. PMID- 26118180 TI - Clinical and Biochemical Profile of Tyrosinemia Type 1 in Tunisia. AB - BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by a defect of fumarylacetoacetate hydrolase. This study aimed to estimate the prevalence of HT1 in Tunisia and report its clinical, biochemical and genetic features. METHODS: During the last 25 years, 69 patients were diagnosed with HT1 based on clinical features and increased succinylacetone (SA) in blood and urine. SA was detected by GC-MS after oximation and quantified by a spectrophotometric method. Nine prenatal diagnoses for HT1 have been done and nine unrelated patients were screened for the hotspot IVS6-1(G-T) mutation using PCR. RESULTS: Using the Hardy-Weinberg formula, the incidence of HT1 was estimated at 1/14804 births in Tunisia. According to clinical form, 21 patients (30%) had the acute form and 48 patients (70%) had the chronic form. Mean plasma and urine SA were higher in the acute form (24 and 193 MUmol/L vs. 9 and 90 MUmol/L, respectively). Diagnosis of HT1 was done for 4 fetuses. The hotspot IVS6-1(G-T) mutation was found in six of nine explored patients. CONCLUSIONS: The incidence of HT1 is relatively high in Tunisia with a predominance of the chronic form. It is important to diagnose the disease as early as possible to prevent unfavorable issues. Prenatal diagnosis should be recommended to minimize the recurrence of the disease. PMID- 26118181 TI - The Platelet Parameters as Inflammatory Markers in Preschool Children with Atopic Eczema. AB - BACKGROUND: Mean platelet volume has been frequently used as an inflammatory marker in various diseases associated with inflammation. In this study, we compared platelet parameter levels between preschool children with and without atopic eczema (AE). METHODS: Preschool children with AE and age-matched healthy children were included in the study. Complete blood count was assessed in children with AE while platelet parameters were compared between children with and without AE. RESULTS: One hundred twenty eight pediatric patients (78 boys, mean age: 14 months) diagnosed with AE and 128 healthy patients (71 boys, mean age: 12 months ) were included in the study. There were no statistically significant differences between the genders (p = 0.375) and ages (p = 0.273) of both groups. WBC (p = 0.952), Hb (p = 0.370), MCV (p = 0.314) and RDW values (p = 0.124), and platelet counts (p = 0.198) of both groups were similar. In the AE group, while the MPV value was found to be higher (p = 0.003), mean PDW value (p = 0.025) and PLT/MPV ratio were found to be lower (p = 0.021). In addition, there was no correlation between the severity of AE and MPV (rho; 0.1, p = 0.257), PDW (rho; -0.1, p = 0.269) and PLT/MPV (rho; 0.07, p = 0.432) ratio. CONCLUSIONS: In patients with AE, as a sign of inflammation, PDW value and PLT/MPV ratio decrease while MPV value increases. This study has also shown that there is no association between the severity of AE and platelet parameters. PMID- 26118182 TI - Reduction of Serum Cytokeratin-3A9 is Associated with Chemotherapeutic Response in Patients with Non-Small Cell Lung Cancer. AB - BACKGROUND: Many tumor markers have been analyzed for applications in diagnosis, prognosis, and monitoring of cancer. Currently chemotherapy is routinely performed for patients with non-small cell lung cancer (NSCLC). The purpose of this study was to examine the serum tumor biomarker of cytokeratin (CK)-3A9 level in patients with NSCLC and its potential correlation with chemotherapeutic response. METHODS: The serum samples of 196 NSCLC patients, 84 healthy controls, and 87 benign lung disease patients were provided for measurement of CK-3A9 and carcinoembryonic antigen (CEA). Serum CK-3A9 concentration was examined using a chemoluminescent method. The potential correlation between serum CK18-3A9 concentration and chemotherapeutic response was analyzed in 124 patients with advanced NSCLC (stages III and IV). RESULTS: The serum CK-3A9 levels in NSCLC patients pre-chemotherapy were significantly higher than those of healthy controls and benign lung disease patients (p < 0.01). CK-3A9 was related to Union for International Cancer Control (UICC) stages (p < 0.01) and histological classification (p < 0.05), but not related to age, gender, smoking status, and chemotherapy regimen (all p > 0.05). The testing results of serum CK-3A9 levels showed a higher sensitivity than that for CEA (48.2% and 39.5%, respectively). The chemotherapeutic response in the 124 patients with advanced NSCLC included 0 complete response (CR), 50 partial response (PR), 65 no change (NC), and 9 progression disease (PD). Post-chemotherapy CK-3A9 levels were significantly decreased compared to pre-chemotherapy (p < 0.05). The serum CK-3A9 levels in patients who achieved PR declined significantly compared to those who did not respond (SD + PD) after 2 cycles chemotherapy (p < 0.05). CONCLUSIONS: CK-3A9 appeared to be a new biomarker for reliable, cost-effective prediction of the efficacy of chemotherapy in patients with advanced NSCLC, although the results should be confirmed in larger studies. PMID- 26118183 TI - Correlations Among Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Titers and Viral Load in Chinese Patients with Chronic Hepatitis B. AB - BACKGROUND: This study aimed to provide a detailed and comprehensive analysis of serum hepatitis B surface antigen (HBsAg), HBeAg, and serum hepatitis B virus (HBV) DNA in Chinese patients with chronic hepatitis B (CHB), predominantly genotypes B and C. METHODS: HBV serological markers, HBsAg titer, HBeAg titer, and HBV DNA were detected and genotyped in 129 Chinese patients with CHB. RESULTS: HBeAg-positive CHB patients were younger, had higher serum alanine aminotransferase, aspartate transaminase, and HBV DNA levels and were more likely to be infected with HBV genotype C. The median HBsAg titer was significantly higher in HBeAg-positive compared with HBeAg-negative CHB patients (3.73 versus 2.93; p < 0.01), and the median HBsAg titer was significantly higher in patients with genotype C. The correlation between HBsAg titer and HBV DNA was stronger in HBeAg-positive CHB patients (r = 0.56; p < 0.01). HBeAg titer was positively correlated with serum HBsAg titer (r = 0.77; p < 0.01) and serum HBV DNA (r = 0.72; p < 0.01). CONCLUSIONS: This study detected key differences in HBsAg expression between HBeAg-positive and HBeAg-negative CHB patients, which may have practical implications for the use of quantitative serological clinical biomarkers. PMID- 26118184 TI - Ischemia-Modified Albumin is not Elevated in Deep Venous Thrombosis. AB - BACKGROUND: In this article, we aimed to determine the diagnostic role of ischemia-modified albumin (IMA) in the evaluation of patients with deep venous thrombosis (DVT). METHODS: Fifty-five patients with a diagnosis of DVT and 47 healthy subjects as the control group were included in the study. Blood samples of the patients were obtained within the first 24 hours after DVT diagnosis for IMA analysis. Patient and control groups were compared with respect to IMA levels. RESULTS: We found that HDL and albumin levels were significantly higher in the control group. However, we could not determine a significant increase in IMA levels in patients with DVT when compared to the control group. CONCLUSIONS: Our study revealed that IMA is not a useful marker in the diagnosis of DVT. PMID- 26118185 TI - Prognostic Value of Plasma Visfatin Level for Chinese Patients with Severe Carbon Monoxide Poisoning. AB - BACKGROUND: This prospective observatory study was designed to investigate whether plasma visfatin might serve as a marker of prognosis in patients with severe carbon monoxide (CO) poisoning. METHODS: A total of 52 consecutive patients with severe CO poisoning and 52 gender- and age- matched healthy subjects were enrolled in the study, and their plasma visfatin levels were determined using an enzyme-linked immunosorbent assay. The clinical outcomes, including in-hospital mortality, 6-month mortality, and poor outcome (Glasgow Outcome Scale score of 1 - 3), were recorded. RESULTS: Plasma visfatin levels were statistically significantly higher in patients than in healthy controls (97.4 +/- 28.0 ng/mL vs. 12.1 +/- 3.7 ng/mL; p < 0.001). Multivariate logistic regression analysis showed that plasma visfatin level was an independent prognostic predictor of in-hospital mortality [odds ratio (OR), 1.214; 95% confidence interval (CI), 1.103 - 1.425; p < 0.001], 6-month mortality (OR, 1.269; 95% CI, 1.085 - 1.534; p < 0.001), and 6-month poor outcome (OR, 1.302; 95% CI, 1.023 - 1.520; p < 0.001). Moreover, receiver operating characteristic curves showed that plasma visfatin level had high predictive value for in hospital mortality [area under curve (AUC), 0.931; 95% CI, 0.832 - 1.000], 6 month mortality (AUC, 0.894; 95% CI, 0.801 - 0.987), and 6-month poor outcome (AUC, 0.886; 95% CI, 0.796 - 0.977). CONCLUSIONS: Plasma visfatin levels are significantly higher in patients with severe CO poisoning and could be a useful biomarker to predict short- and long-term clinical outcome after severe CO poisoning. PMID- 26118186 TI - Diagnostic Accuracies of the TUNEL, SCD, and Comet Based Sperm DNA Fragmentation Assays for Male Infertility: a Meta-analysis Study. AB - BACKGROUND: Recent studies have provided new insights into the diagnostic value of sperm DNA fragmentation (SDF) for male factor sterility. This study aimed to systematically evaluate the diagnostic accuracy of the SDF test for male infertility. METHODS: Eligible studies were retrieved by searching electronic databases. The quality of the studies was assessed on the basis of quality assessment for studies of diagnostic accuracy (QUADAS) criteria tool. The bivariate metaanalysis model was employed to summarize the diagnostic indices and plot the summary receiver operator characteristic (SROC) curve by using Meta-disc 1.4 software. Influence analysis, meta-regression, and publication bias assay were all conducted through Stata 12.0 software. RESULTS: Our bivariate random effect meta-analysis yielded an AUC (area under curve) value of 0.9211 with a sensitivity (95% confidence interval) of 0.80 (0.78 - 0.82) and specificity of 0.83 (0.80 - 0.86) for the use of the SDF test in differentiating infertile males from normal fertile controls. Moreover, our subgroup analysis suggested that SDF analysis with a single TUNEL test resulted in an AUC value of 0.9506, with a pooled sensitivity of 0.77 (0.74 - 0.80) and specificity of 0.91 (0.87 - 0.94), while SCD and Comet assays displayed a combined sensitivity of 0.77 (0.67 - 0.81) or 0.91 (0.88 - 0.94), and specificity of 0.84 (0.75 - 0.91) or 0.63 (0.54 - 0.70), accompanied by an AUC value of 0.8408 or 0.9473. CONCLUSIONS: The SDF assay confers a relatively high diagnostic accuracy for infertility detection, among which the TUNEL based methodology seems to achieve higher accuracy than the SCD and Comet assays. PMID- 26118187 TI - Wnt5a Promotes Cytokines Production and Cell Proliferation in Human Hepatic Stellate Cells Independent of Canonical Wnt Pathway. AB - BACKGROUND: Wnt5a is involved in the activation of human hepatic stellate cells (HSC) and related with the occurrence of liver fibrosis. As the function and mechanism that Wnt5a mediates HSC activation remains unclear, we sought to investigate them. METHODS: Wnt5a levels were determined in the HSC cell line LX-2 after lipopolysaccharide (LPS) and TNF-alpha stimulation. HSC cells showing stable and efficient overexpression or featuring knockdown of Wnt5a were constructed by a lentivirus system. Regulation of cytokine and collagen expressions were confirmed by quantitative PCR or ELISA in stable LX-2 cell lines showing Wnt5a overexpression or knockdown. Proliferation was determined by 5 ethynyl-2'-deoxyuridine labeling. Relevant signaling pathways were identified using specific protein antibodies. RESULTS: LPS and TNF-alpha induced Wnt5a expression in LX-2 cells. Compared with control cells, an increase in IL-10, IL 6, COL1, and COL3 secretion in a stable LX-2 cell line showing Wnt5a overexpression was observed. Knockdown of Wnt5a obviously reduced the production of IL-1beta, IL-6, COL1, and COL3. Wnt5a overexpression promoted LX-2 proliferation, while Wnt5a knockdown dramatically inhibited cell proliferation. Compared with the effects of Wnt5a knockdown cells, Wnt5a-overexpressing cells triggered the phosphorylation of c-Jun N-terminal kinase (JNK) and beta-catenin, which leads to beta-catenin degradation and inactivates the canonical Wnt/beta catenin pathway. CONCLUSIONS: Wnt5a regulates inflammatory cytokine and collagen production and cell proliferation, which is independent of the canonical Wnt signaling pathway. The results reveal a new signaling mechanism in HSC activation and could provide a new strategy for hepatic fibrosis treatment. PMID- 26118188 TI - Expression Analysis of p16, c-Myc, and mSin3A in Non-small Cell Lung Cancer by Computer Aided Scoring and Analysis (CASA). AB - BACKGROUND: Immunohistochemical analysis (IHC) of tissue microarray (TMA) slides enables large sets of tissue samples to be analyzed simultaneously on a single slide. However, manual evaluation of small cores on a TMA slide is time consuming and error prone. METHODS: We describe a computer aided scoring and analysis (CASA) method to allow facile and reliable scoring of IHC staining using TMA containing 300 non-small cell lung cancer (NSCLC) cases. In the two previous published papers utilizing our TMA slides of lung cancer we examined 18 proteins involved in the chromatin machinery. We developed our study using more proteins of the chromatin complex and several transcription factors that facilitate the chromatin machinery. Then, a total of 78 antibodies were evaluated by CASA to derive a normalized intensity value that correlated with the overall staining status of the targeting protein. The intensity values for TMA cores were then examined for association to clinical variables and predictive significance individually and with other factors. RESULTs: Using our TMA, the intensity of several protein pairs were significantly correlated with an increased risk of death in NSCLC. These included c-Myc with p16, mSin3A with p16 and c-Myc with mSinA. Predictive values of these pairs remained significant when evaluated based on standard IHC scores. CONCLUSIONS: Our results demonstrate the usefulness of CASA as a valuable tool for systematic assessment of TMA slides to identify potential predictive biomarkers using a large set of primary human tissues. PMID- 26118189 TI - Assessment of a One-Step Intracellular Staining in Th1, Th2 and Th17 Cells of Clinical Samples. AB - BACKGROUND: Flow cytometry is a potent tool to dissect the phenotypes and functions of cell subsets by measuring multiple parameters on a single-cell basis. However, intracellular staining may be time consuming and more steps, particularly in cytokines, could be problematic for its use in daily routine or in large cohort testing. Lately, a novel reagent has been developed to perform intracellular staining in one step. The objective of our study was thus to assess this new method in comparison with the reference technique by focusing on CD4+ T cell subsets such as Th1, Th2, and Th17 cells in clinical samples. METHODS: Peripheral blood was collected from 10 children with aplastic anemia and 10 healthy volunteers and stained using the reference and one-step methods. Different subsets of CD4+ T-cells, which are defined as Th1, Th2 and Th17 cells, were investigated by flow cytometry. The repetitive experiment was designed to study intraassay precision. Correlations were studied using Pearson's correlation coefficient test. RESULTS: When comparing results obtained with the two techniques, no statistical differences between the percentages of Th1, Th2, and Th17 cells were observed. Besides, a nice correlation between percentages of Th1 cells obtained with the two different methods was identified in the global population (r: 0.777, p < 0.01). Likewise, percentages of Th2 cells (r: 0.875, p < 0.01), and Th17 cells (r: 0.886, p < 0.01) were strongly correlated between reference and one-step procedures. Importantly, flow cytometry staining obtained with the one-step method was very robust with a nice intra-assay precision and a better discriminative power and repeatability. CONCLUSIONS: With better staining quality and a shorter realization time, one-step intracellular staining may provide an efficient way for daily routine testing of Th1, Th2 and Th17 cells, as well as for further research. PMID- 26118190 TI - Validity of Tissue Microarray by Immunohistochemistry. AB - BACKGROUND: Tissue microarrays (TMAs) extract designated areas of tissue paraffin blocks in several units that are millimeters in diameter in a cylindrical fashion, array dozens of these tissue specimens, and then re-embed them. Here, a TMA was utilized to analyze renal cell carcinoma (RCC) specimens with anti-FABP7 and anti-Brn2 antibodies. METHODS: Paraffin-embedded specimens from 114 RCC patients were immunostained with anti-FABP7 and anti-Brn2 antibodies to examine the rate of agreement between the staining of TMA grafts compared to conventional tissue slice grafts. The staining area of the tumor was also examined. RESULTS: The positive ratio of anti-FABP7 was 74% and of anti-Brn2 was 57%. The rate of agreement of each antibody was 100% regardless of tumor size before extraction. CONCLUSIONS: Immunostaining of TMA slices might be effective for the analysis of RCC specimens. PMID- 26118191 TI - A Rapid, Accurate and Simple Screening Method for Spinal Muscular Atrophy: High Resolution Melting Analysis Using Dried Blood Spots on Filter Paper. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutation of the survival of the motor neuron 1 (SMN1) gene. More than 95% of SMA patients carry a homozygous deletion of SMN1. SMA can be screened for by polymerase chain reaction and high-resolution melting analysis (PCR-HRMA) using DNA extracted from dried blood spots (DBSs) stored on filter paper. However, there are two major problems with this approach. One is the frequent poor quality/quantity of DNA extracted from DBSs on filter paper, and the other is the difficulty in designing primer sets or probes to separate allele-specific melting curves. In this study, we addressed these problems and established a rapid, accurate and simple screening system for SMA with PCR-HRMA using DNA extracted from DBSs on filter paper. METHODS: Seventy individuals were assayed in this study, 42 SMA patients and 28 controls, all of whom had been previously been screened for SMA by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) using DNA extracted from freshly collected blood. In this study, the DNA of each individual was extracted from dried blood that had been spotted onto cards and stored at room temperature (20 - 25 degrees C) for between 1 and 8 years. PCR amplification of 30 or 45 cycles was performed using 50 ng of DNA and was immediately followed by HRMA. SMN1 and SMN2 products were co-amplified using a previously designed primer set (R111 and 541C770) containing two single nucleotide differences. RESULTS: The absorbance ratio at 260/280 of DNA extracted from DBSs ranged from 1.49 to 2.1 (mean +/- SD; 1.66 +/- 0.12), suggesting high-purity DNA. Thirty cycles of PCR amplification were insufficient to amplify the target alleles; PCR with 45 cycles was, however, successful in 69 out of 70 samples. PCR-HRMA using the R111/541C770 primer set enabled separation of the normalized melting curves of the samples with no SMN1 from those with SMN1 and SMN2. CONCLUSIONS: DBSs on filter paper can be a good source of DNA for the diagnosis of diseases and PCR-HRMA using DNA extracted from DBSs is an alternative method to detect the SMN1 deletion. These findings suggest that the SMA screening system using PCR-HRMA with DBSs on filter paper is practicable in a large population study over a long time period. PMID- 26118192 TI - Confirmed False Positive Proteinuria in Patients with Systemic Lupus Erythematosus Taking Hydroxychloroquine: a Spot Sample Measurement. AB - BACKGROUND: A false-positive screening result is associated with harmful treatment or follow-up costs. This study aimed to estimate the rate of false positive proteinuria with the dipstick in patients with systemic lupus erythematosus (SLE) taking hydroxychloroquine. METHODS: A total of 334 patients with a positive dipstick and confirmed by total urine protein with quantification assay were enrolled. The experimental group included those with SLE taking hydroxychloroquine, and the rest was the control group. The difference of the rate of false positive in the dipstick was analyzed using the chi-square test and odds ratio (OR) between groups. Qualitative tracking of potential interference in the dipstick was performed. RESULTS: The results revealed that the rate of false positive with a dipstick for the experimental and control groups were 29.5% and 5.0% (p = 0.000), respectively. The OR with 95% confidence interval (CI) of the rate of false positive for the experimental group with respect to the control group was 5.95 (95% CI: 2.80 - 12.65). Qualitative tracking showed that the dipstick was influenced to become false-positive when hydroxychloroquine concentration was >= 30 mg/dL. CONCLUSIONS: Hydroxychloroquines like plaquenil or geniquin may lead to a high rate of false positive with the dipstick method. A quantification assay is recommended for proteinuria measurement in patients with SLE taking hydroxychloroquines. PMID- 26118193 TI - Application of Hyperbaric Oxygen Reduce Oxidative Damage of Plasmatic Carbonyl Proteins and 8-OHdG by Activating Glutathion Peroxidase. AB - BACKGROUND: It is postulated that application of hyperbaric oxygenation may induce the production of radicals after HBO. Higher oxygenation and transport of oxygen increase the mitochondrial energy turnover, whereas inner mitochondrial radical formation decreases. METHODS: Several markers of oxidative stress in healthy volunteers (n = 21), including plasma carbonyl proteins (CP), malondialdehyde (MDA), oxidized LDL (oxLDL), 8-hydroxy-deoxyguanosine (8-OHdG), and erythrocyte glutathione peroxidase (GPx) activity are measured before, during, and after HBO. RESULTS: Median plasma concentrations of CP decreased significantly during HBO compared to CP levels before HBO (from 77.1 to 61.7 pmol/mg; p < 0.001) and increased again after HBO (to 78.1 pmol/mg; p = 0.035). 8 OHdG decreased significantly during HBO (8.1 ng/mL; p < 0.001) and remained constant after HBO (8.1 ng/mL) compared to "before HBO" (9.4 ng/mL). MDA increased significantly from 0.92 MUM (before HBO) to 1.26 MUM (during HBO, p < 0.01) and decreased again to 1.00 MUM (after HBO, p = 0.023). Erythrocyte GPx activity also increased significantly during HBO (26.5 +/- 14.7; p = 0.005), but not after HBO (25.6 +/- 17.2 IU/mg). A negative correlation was observed between GPx and MDA only during HBO (r = -0.518; p = 0.016). CONCLUSIONS: We assume that higher oxygen consumption decreases, on the one hand, the inner mitochondrial generation of free radicals and, on the other, RONS by activation of detoxifying enzymes like GPx. PMID- 26118194 TI - Relationship Between an Osteoprotegerin Gene Polymorphism and Diabetic Vascular Complications. AB - BACKGROUND: Osteoprotegerin (OPG), which was recently identified as a vascular marker, is increased in patients with diabetes mellitus (DM). This study evaluated the frequency of the OPG gene single nucleotide A163G polymorphism and its association with diabetic microvascular and macrovascular complications. METHODS: The A163G polymorphism of the OPG gene was assessed in the peripheral blood of 116 patients with type 2 DM and 107 healthy subjects by polymerase chain reaction and restriction fragment length polymorphism. Microvascular and macrovascular complications were evaluated in diabetic patients. RESULTS: Statistical analysis showed no significant difference in distribution of the OPG A163G polymorphism in the diabetic and control groups. Similarly, this polymorphism was not associated with microvascular or macrovascular complications. CONCLUSIONS: This OPG polymorphism does not play a role in the development of microvascular and macrovascular complications in patients with DM. PMID- 26118195 TI - Sensitivity and Specificity of a Loop-Mediated Isothermal Amplification Assay for the Detection of Mycoplasma Pneumonia from Nasopharyngeal Swab Samples Compared with those of Real-time PCR. AB - BACKGROUND: The aim of this study was to determine the sensitivity and specificity of a loop-mediated isothermal amplification (LAMP) assay kit for the detection of Mycoplasma pneumonia (Eiken Chemical Co., Ltd, Tokyo, Japan) from nasopharyngeal swab samples compared with those of real-time PCR. METHODS: Nasopharyngeal swab samples taken from 223 patients aged 3 - 18 years who were suspected of having respiratory tract infections associated with Mycoplasma pneumonia were used in this study. The samples were tested both by the LAMP assay and by real-time PCR for detection of Mycoplasma pneumonia. RESULTS: The sensitivity and specificity of the LAMP assay for the detection of Mycoplasma pneumonia were 99.1% (105/106) and 100.0% (117/117), respectively. CONCLUSIONS: The LAMP assay for the detection of Mycoplasma pneumonia is an accurate and fast assay that is suitable as a diagnostic tool in the acute phase of Mycoplasma pneumonia infection. PMID- 26118196 TI - Relationship between Serum Sialic Acid and Hemostatic Markers in Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: Serum sialic acid (SA) is an acute phase response marker. Additionally, it is an independent risk factor for atherosclerotic disease and is higher in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to determine the association of SA with blood coagulation and fibrinolysis in T2DM patients. METHODS: The levels of serum SA and blood coagulation and fibrinolysis markers were measured in patients with T2DM. The associations of SA with hemostatic markers and other variables were assessed. RESULTS: There were significant correlations between SA and fibrinogen, D-dimer, factor (F) IX, and platelet (PLT) that were independent of smoking, body mass index (BMI), waist-to-hip ratio, hemoglobin A(1c) (HbA1c), fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (TC) to high-density lipoprotein cholesterol (HDL-C) ratio, and antithrombotic therapy history. Based on logistic regression analyses, the highest tertile groups of fibrinogen, D-dimer, F VIII, F IX, and PLT showed a significantly increased risk of high SA compared with the lowest tertiles after adjusting for age, gender, and antithrombotic therapy history. SA also significantly correlated with duration of diabetes, BMI, FPG, TG, low-density lipoprotein cholesterol (LDL-c), TC-to-HDL-C ratio, and albumin to-creatinine ratio (ACR). CONCLUSIONS: Elevated serum SA levels are associated with increased coagulability and higher risk of thrombus formation in T2DM patients. PMID- 26118197 TI - Zinc Finger Protein 259 (ZNF259) Polymorphisms are Associated with the Risk of Metabolic Syndrome in a Han Chinese Population. AB - BACKGROUND: Zinc finger protein 259 (ZNF259) binds to the cytoplasmic domain of epidermal growth factor receptor (EGFR) in quiescent cells and contributes tolipid metabolism. This case and control study investigated the association between ZNF259 single nucleotide polymorphisms (SNPs) and metabolic syndrome (MetS). METHODS: This study included 1,812 MetS patients and 2,036 controls from the Jilin province of Northeastern China. MetS was diagnosed using the International Diabetes Federation (IDF) criteria. Three ZNF259 SNPs (rs964184, rs2075290 and rs2075294) were genotyped using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). RESULTS: There were significant differences between metabolic syndrome and healthy control subjects for the ZNF259 rs964184 and rs2075290 genotypes. The minor alleles of both SNPs were associated with an increased risk of MetS and associated conditions (elevated triglycerides, elevated blood pressure, increased abdominal obesity, fasting hyperglycemia, and low HDL-C; p < 0.05). The distribution of haplotype G G-G (rs964184, rs2075290 and rs2075294) was significantly different between MetS patients and controls (OR = 1.39; 95% CI, 1.24 - 1.56; p < 0.01). CONCLUSIONS: This study demonstrated that ZNF259 variants were associated with elevated MetS risk in a Han Chinese population from the Jilin province of Northeastern China. PMID- 26118198 TI - Mitochondrial DNA 4401A>G and 4435A>G Mutations Associated with Essential Hypertension Testing Method. AB - BACKGROUND: Establish a method to identify simultaneously mitochondrial DNA 4401A>G and 4435A>G mutations associated with essential hypertension. METHODS: The whole genomic DNA of samples carrying mitochondrial DNA 4401A>G and 4435A>G mutations, double mutation (mtDNA 4401A>G and 4435A>G) as well as wild type were used as templates. Specifically amplified mtDNA 234 bp fragments between 4344 - 4577 using nested PCR and digested the PCR purified products simultaneously with two restriction enzymes BfaI and NlaIII. The products were identified by polyacrylamide gel electrophoresis. RESULTS: Electrophoresis results showed that electrophoresis bands were specific among different samples. CONCLUSIONS: This study established a convenient, accurate, and suitable for clinical determination of mtDNA 4401 A>G and 4435A>G mutations associated with essential hypertension testing using the new method. PMID- 26118199 TI - Interaction of Hb Grey Lynn (Vientiane) [alpha91(FG3)Leu>Phe (alpha1)] with Hb E [beta26(B8) Glu>Lys] and alpha(+)-thalassemia: Molecular and Hematological Analysis. AB - BACKGROUND: Hemoglobin (Hb) Grey Lynn is a Hb variant caused by a mutation at codon 91 of alpha1-globin gene whereas Hb E is a common beta-globin chain variant among Southeast Asian population. We report two hitherto undescribed conditions of Hb Grey Lynn found in Thai individuals. METHODS: The study was done on two unrelated Thai subjects. Hematological parameters were recorded and Hb analysis was carried out using automated Hb analyzers. Mutations were identified by DNA analysis. Hematological features of the patients were compared with those of various forms of Hb Grey Lynn documented previously. RESULTS: Hb and DNA analyses identified a heterozygous Hb Grey Lynn in one patient and a double heterozygous Hb Grey Lynn and Hb E with alpha(+)-thalassemia in another. Interaction of alpha(Grey Lynn) with beta(E) chains leads to the formation of a new Hb variant, namely the Hb Grey Lynn E (alpha(GL)2beta(E)2), detectable by liquid chromatography (10.3%) but masked by Hb E on capillary electrophoresis. CONCLUSIONS: Interaction of these multiple globin gene defects could lead to complex hemoglobinopathies requiring combined analysis with multiple Hb analyzers followed by DNA testing to provide accurate diagnosis of the cases. PMID- 26118200 TI - Improved Target Cell Selection and Counting Method for UroVysion Fluorescence in Situ Hybridization. AB - BACKGROUND: The UroVysion Bladder Cancer Kit requires morphological analysis of 4', 6-diamino-2-phenylindole (DAPI)-stained nuclei to identify target cells for fluorescence in situ hybridization (FISH) signals. Reproducibility and efficiency of target cell selection and counting was evaluated by combining immunofluorescence staining of cytokeratin 7 (CK7) and proliferating cell nuclear antigen (PCNA) with DAPI staining. METHODS: The reactivities to CK7, PCNA, and DAPI were compared between those for different ratios of T24 human bladder carcinoma cells and of cells from the urine of five healthy subjects. Two technicians independently performed five replicate cell counts of urine samples from four bladder cancer patients and one healthy subject. RESULTS: The positive staining rates for CK7 and PCNA were similar to DAPI, but our method showed enhanced inter-observer repeatability and reduced operating time for signal counting. CONCLUSIONS: Our proposed method showed better reproducibility and lesser operational time for signal counting than the DAPI method alone. PMID- 26118201 TI - UriSed as an Alternative to Phase-Contrast Microscopy in the Differentiation between Glomerular and Non-Glomerular Hematuria. AB - BACKGROUND: Differentiation between glomerular and non-glomerular hematuria by observation of the erythrocyte morphology using phase-contrast is a time consuming and labor-intensive procedure that requires skilled personnel. This paper has the purpose to evaluate the performance of UriSed (also called sediMAX in some countries) as an alternative to the phase-contrast microscopic analysis of erythrocyte morphology. METHODS: 312 urine samples with hematuria were analyzed by UriSed and by phase-contrast microscopy. Based on the presence of codocytes and/or acanthocytes, samples were classified as non-glomerular and glomerular. Kappa correlation was used to assess the agreement between both methods. RESULTS: Our data showed excellent agreement between erythrocyte morphology analyzed by both methods (r = 0.974, kappa = 0.9484, p < 0.001) with only 8 samples presenting discordant results. CONCLUSIONS: UriSed proved to be a precise and accurate alternative to the gold standard phase-contrast microscopy. PMID- 26118202 TI - Preanalysis in Serum Hepcidin Measurement. AB - BACKGROUND: Hepcidin is a 25-amino peptide hormone that regulates iron homeostasis. Its serum quantification helps to provide the right therapeutic choice in iron-deficiency anemia and anemia in chronic diseases. Diurnal levels of serum iron might affect hepcidin secretion during the day. Blood collection time is an important part of the preanalytical phase of its quantification. METHODS: During the period 2013 - 2014, we collected blood samples for serum hepcidin quantification in 100 healthy controls. The samples were collected in vacuettes with serum separator gel at three different times during the day: 07:30 - 08:30, 12:00 - 13:00, and 16:00 - 17:00 hours. Hepcidin levels were measured with an ELISA method. RESULTS: We found a significant difference in serum hepcidin levels during the chosen three blood taking times. The normal range for Bulgarian population is 3.05 MUg/L - 37.75 MUg/L. The measured levels were: at 07:30 - 08:30 hours 12.2 MUg/L (5.5 MUg/L - 23.6 MUg/L), 12:00 - 13:00 hours 14.1 MUg/L (7.1 MUg/L - 27.2 MUg/L), and 16:00 - 17:00 hours 16.5 MUtg/L (9.9 MUg/L - 29.6 MUpg/L) 10.7 < r < 1.0; p < 0.5 between 07:30 - 08:30 and 12:00 - 13:00 hours and p < 0.05 between 07:30 - 08:30 hours and 16:00 - 17:00 hours and 12:00 13:00 hours and 16:00 - 17:00 hours]. No significant differences were found for transferrin saturation between measured groups [0.1 < r < 0.3; p > 0.5]. CONCLUSIONS: In order to obtain the most correct results for serum hepcidin quantification (especially in border to referent range levels) in the preanalytical phase, it is important to consider the time of blood sampling. PMID- 26118203 TI - [Transborder assistance. New health rights for European citizens]. PMID- 26118204 TI - [THERAPEUTIC GUIDE IN VENOUS ULCERS]. AB - The treatment of venous ulcers and wounds in general, is a complex and important public health problem, with personal effects, family and health, without addressing the economic impact includes assistance, care of patients with ulcerative lesions. The increase in life expectancy, driven by improved socio sanitary conditions that this aging population, facilitates the emergence of chronic diseases may be complicated by the presence of skin ulcers. There is no doubt that the best way to treat a skin ulcer is avoiding to occur, hence the importance of early diagnosis and risk factors act alone them. In relation to venous ulcers is crucial, provide local treatment, act on the cause, because if not, relapse is the norm in this type of injury. Currently, the moist wound healing, is an important step in solving earlier of these chronic wounds. This has meant that the pharmaceutical industry has been involved in researching and creating different types of dressings, having specific activity at different stages of venous ulcer healing, ie inflammatory phase, proliferative and remodeling. The proliferation of these products has been increasing over the years, not surprisingly, are described therapeutic 12 families that are applied in the management, care of these injuries. The fact of existing therapeutic options highlights the ineffectiveness of these products individually. Therefore, the nurse will not forget that the optimal treatment of venous ulcers, necessarily involves choosing the right product for every type and stage of the lesion. In this decision process, strongly influenced by the specific characteristics of each patient and injury, the nurse will take into account a lot of factors when choosing the product, not forgetting that an ulcer is not cured with a single therapeutic element, several products being used throughout the process to evolutionary venous ulcer until complete resolution. PMID- 26118205 TI - [GUIDE DEVELOPMENT OF A PROCESS MODEL OF NURSE APPLYING VIRGINIA HENDERSON AND TAXONOMY NANDA]. AB - This study aims to develop a practical guide to applying the nur- sing model recognized Virginia Henderson NANDA taxonomy and nursing process. PMID- 26118206 TI - [NURSING ACTION BEFORE THE TERMINAL PATIENT PHYSICAL CARE]. AB - Palliative care is a group of actions performed by nurses in order to increase the comfort and well-being of patients with terminal illnesses. The World Health Organization (WHO) defines this term as: An approach that improves the quality of life of patients and their families facing the problem associated with life threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual [1]. Cicely Mary Strode Saunders is considered as the precursor of the palliative care, who explained the need to change the Palliative Care Units in order to improve the quality of life of patients with terminal illnesses. Palliative care is necessary for patients with a terminal illness. In such cases, the life expectancy is less than six months. Human being is considered a biopsychosocial model. For this reason, the nurse must take into account all the requirements arising from these three dimensions of the human being. In this essay, we deal with palliative care in patients with terminal illnesses, considering the role of the nurse as an important reference when teaching palliative care to the main carer. PMID- 26118207 TI - [INTERFACE SELECTION IN NON-INVASIVE MECHANICAL VENTILATION IN CRITICALLY ILL PATIENT]. AB - BACKGROUND: Non-invasive ventilation is used with a mechanical ventilator and an interface that is interposed between the patient and the ventilator without invading the airway. It is an alternative to the artificial airway in situations of acute respiratory insufficiency. OBJECTIVE: Determine if the selection of an appropriate interface to the contour of the patient's face and the pathology involves the triumph or failure of the procedure, deeming it is a dependent variable in the success of the NIV. METHOD: Research bibliographic in PubMed, with secondary search in the Cochrane Library and CUIDEN. Includes the articles published since 2000 in adults. No limitations have been imposed on study design, type of intervention or results of the publications. The articles are reviewed to determine their relevance and draw conclusions. The heterogeneity of designs prevents statistical combination of results and a review was conducted descriptive. RESULTS: There were 67 publications of which 28 were rejected by may not be related to the reason for this study, 12 to be made in pediatric population, 8 per language, 2 to be carried out on animals and 1 to be duplicated. The 16 included studies attest to the effectiveness of the NIV with studies not comparable between different interfaces. CONCLUSIONS: The consulted evidence suggests the benefits of NIV it insisting on the great importance of the interface to tolerance and successful of the technique. The studies are heterogeneous in its design but the authors suggest continue developing better interfaces, with greater tolerance and fewer complications. PMID- 26118208 TI - [SYSTEMATIC REVIEW OF NURSING PROFESSIONAL ROLE IN SOCIAL HEALTH INEQUALITIES IN THE IMMIGRANT POPULATION]. AB - The current situation in Spain has led to increase social inequalities in health in the population. Immigrants without economic resources are the most vulnerable group with high rates of morbidity and mortality. For this reason, the Commission on Social Determinants of Health (CSDH) was created by developing a conceptual framework to classify the inequality factors, and thus, politically designing actions in order to reduce this problem. The nursing professional collaboration in developing effective policies to reduce health inequalities would be a new framework, because this profession possesses unique knowledge of people who are cared with social problem. One of the main problems identified by nurses in the immigrant population is social isolation, being developed in this text one of the nursing diagnoses included in a immigrant person care plan with social inequality in health. PMID- 26118209 TI - [MENTORING IN NURSING, A PHENOMENOLOGICAL APPROACH]. AB - The essay explains that mentoring, originally established to improve student trajectories, reflects a deeper improvement of the people involved in the process. The method used is the analysis of the mentoring experience from participant observation and phenomenology of lived processes. The results reveal that the early analysis of risk factors present in academics--socio psychological, family and institutional matters, that may affect the student experience in its passage through the academic unit--, requires the intervention of a preventive nature and monitoring operating variables. In addition, tutoring is a teaching experience which is consolidated with the daily life from the human relationship established between the mentor and the mentee, from the position of the older adult and experience is a state meet demand related care. However, in the tutorial process face to face, usually with academic aspects, therefore, the teaching function is fulfilled but operated in particular. By helping to find meaning to knowledge not understood, this function is still performed if tutors pairs learn to know each other that occasionally is the mirror which reflects the own story. While they are recognizing the problems of the mentee, the mentor will exorcise his ghosts. Therefore, we argue that, although originally born tutoring to abate dropout rates, failure and increase retention and degree, over time, has become a process of improving people. PMID- 26118210 TI - [INDUCED HYPOTHERMIA AFTER CARDIAC ARREST]. AB - INTRODUCTION: Sudden cardiac death in adults remains a challenge in cardiovascular medicine. Cardiac arrest often drives neurological damage resulting from cerebral hypoxia, causing a series of cellulose tissue alterations that lead to brain injury. Therapeutic hypothermia decreases oxygen demand acting as protection to the brain. OBJECTIVES: To describe the casuistry of hypothermia after retourn of spontaneous circulation (ROSC) at Bellvitge University Hospital (BUH) from 2009 to 2012. Develop a tracking sheet of the induced hypothermia process. Reflect professional experience of induced hypothermia after cardiac arrest through a case. METHODOLOGY: Retrospective descriptive study of the 54 cases, 45 men and 9 women, aged between ages 57 (15 to 80) years old treated with hypothermia after ROSC at BUH. Analysis of sociodemographic variables, specific variables and description of the inclusion criteria for hypothermia. Design of nursing record to express standardized care to undertake during the HI and its pilot trial. Monitoring a 60 years old patient who suffers cardiopulmonary arrest and is subjected to hypothermia. RESULTS: Leading cause of cardiopulmonary arrest is acute coronary syndrome (ACS) (63%). Most representative initial rhythm is pulseless ventricular tachycardia/ventricular fibrillation (PVT/VF) (68.5%). There is longer survival in patients whose CPR is less than 30 minutes. The.target temperature of the patients was 33 degrees C for 24 hours, except for 5 patients who were stopped because of hemodynamic instability. At discharge, 54% were exitus, 4% had severe encephalopathy, 11% mild encephalopathy and 31% without neurological sequel. The applicability of the nursing record that was created for the HI process was checked, which allowed a fast overview of the procedure. It describes the clinical status of the case on admission, during the HI, at 48 hours, at discharge from the coronary care unit (CCU) and at discharge. DISCUSSION: The data collected between 2009 and 2012 of patients with cardiopulmonary arrest candidates to hypothermia showed a favorable neurological recovery within the surviving patients. Additionally, patients with cardiopulmonary arrest not prolonged have a better prognosis agreeing with ROSC previous studies. CONCLUSIONS: Hypothermia is a viable therapy for patients who have undergone cardiopulmonary arrest. It is important to make a specific assessment of each case as well as agree the track record of care applied to these patients to subsequently allow their assessment. PMID- 26118213 TI - Health Literacy: A Rx for Patient Success. PMID- 26118211 TI - [Mouth and dental health education for the elderly]. PMID- 26118214 TI - Pigmented Epithelioid Angiomyolipoma of the Kidney. AB - Extensive melanin pigment in an epithelioid angiomyolipoma, a potentially malignant and locally aggressive renal tumor, has been rarely reported. A 53-year old, asymptomatic man with no significant past medical history underwent partial nephrectomy for a right kidney mass discovered on CT scan. Grossly, the mass was 4 cm, well-circumscribed, dark, brown-black. Microscopically, nests of large, clear-to-eosinophilic cells with mildly atypical, vesicular nuclei and prominent nucleoli were separated by striking vascular network. Abundant, brown-black, coarsely granular pigment was noted. The tumor stained with HMB-45 and MART-1 and was negative for broad spectrum cytokeratin, CK-7, CD-10, RCC antigen, EMA, vimentin, SMA, desmin, synaptophysin, chromogranin, and S 100. Fontana-Masson stain confirmed presence of melanin. Thick-walled vessels, spindle cells, and fat were absent. The patient had no family history of tuberous sclerosis. Close follow-up was recommended. It is important to differentiate this entity from melanoma, pigmented renal cell carcinoma, and pigmented paraganglioma. PMID- 26118215 TI - Top 10 FACTS YOU FACTS YOU SHOULD KNOW About Spirometry. PMID- 26118216 TI - Clinical Problem-Solving Case: All's Well That Ends Swell. PMID- 26118217 TI - Public Health in Mississippi: Advances in the Last Two Decades. PMID- 26118219 TI - Just Doing Some Reframing. PMID- 26118218 TI - There is "Power in Numbers". PMID- 26118220 TI - Evaluation of certain food additives. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, including flavouring agents, and to prepare specifications for identity and purity. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of and assessment of dietary exposure to food additives, including flavouring agents. A summary follows of the Committee's evaluations of technical, toxicological and dietary exposure data for eight food additives (Benzoe tonkinensis; carrageenan; citric and fatty acid esters of glycerol; gardenia yellow; lutein esters from Tagetes erecta; octenyl succinic acid modified gum arabic; octenyl succinic acid-modified starch; paprika extract; and pectin) and eight groups of flavouring agents (aliphatic and alicyclic hydrocarbons; aliphatic and aromatic ethers; ionones and structurally related substances; miscellaneous nitrogen-containing substances; monocyclic and bicyclic secondary alcohols, ketones and related esters; phenol and phenol derivatives; phenyl-substituted aliphatic alcohols and related aldehydes and esters; and sulfur-containing heterocyclic compounds). Specifications for the following food additives were revised: citric acid; gellan gum; polyoxyethylene (20) sorbitan monostearate; potassium aluminium silicate; and Quillaia extract (Type 2). Annexed to the report are tables summarizing the Committee's recommendations for dietary exposures to and toxicological evaluations of all of the food additives and flavouring agents considered at this meeting. PMID- 26118221 TI - Measurement of Change in the Knowledge and Attitude about Leprosy in Physiotherapy Students Undergoing Intensive One Week Training in Leprosy. AB - Leprosy is a disease that causes not only physical problems, but also mental and social problems. In the post integration era, every health care professional needs to understand about leprosy, to be able to diagnose and treat them. Physiotherapy students, in their usual syllabus, have minimal exposure to leprosy, in spite of the fact that they have a major role in preventing impairments and disabilities caused by leprosy, as well as treating such impairments. In order to educate physiotherapy students on leprosy, a one-week intensive training course was organised. This study was done to assess if the intensive training to physiotherapy students resulted in increase in their knowledge on leprosy and change their attitude positively. A batch consisting of 42 physiotherapy students went through the one-week training programme. The improvement in knowledge and attitude were assessed through a pre-test and a post test design. Results showed that there was significant improvement in knowledge (53.05%) and brought positive change in attitude (75.0%). Such training programmes are recommended for all physiotherapy students. PMID- 26118222 TI - Determinants of rural women's participation in India's National Leprosy Eradication Programme. AB - A multistage representative random sample of women and men from each of the 3 states of Bihar, Uttar Pradesh and West Bengal, from the rural blocks where the Leprosy Mission Hospitals were located were selected during 2010 to identify relevant factors that are preventing active participation of women and suggest corrective steps. Adult men and women were interviewed in depth, using a detailed checklist by the first author. A total of 1239 respondents 634 women and 605 men, were interviewed, only 44 women (7%) claimed that they had earlier participated in leprosy work, about 92% of the women felt that they had the potential to take part in leprosy work, and 70% showed willingness to participate. Factors that would encourage and facilitate more women to participate in leprosy work, included financial support (32.8%), convincing the family to grant permission (88%), and delegating them to work in proximity to their residences (15%). Some women respondents (11.0%) felt that they would provide their services voluntarily for social good. Women suggested that work should be delegated as per their capabilities and skills, and they should be given proper orientation, training and guidance. Hardly 5% of ASHA's in the clusters examined participated in leprosy related work, which needs stringent steps to re-orient and encourage them to undertake leprosy related work. It is concluded that rural Indian women are keen to play an important role in the national leprosy eradication program, with minimal support from the government and nongovernmental agencies in a truly community-based approach. This will benefit vast numbers of leprosy affected women as well as others. PMID- 26118223 TI - Treatment Behaviour of Leprosy Patients on Time Scale. AB - Leprosy is not a disease of modern civilization and industrialization, but its origin is as old as 4600 BC. Although the cure of leprosy is possible by MDT, there are certain misbelieves in the mind of leprosy patients leads to delay in disease reporting. Wandering of the patient from one healer to another healer also one of the cause that delays the start of MDT. It is known fact that the delayed response in getting medical treatment for leprosy causes permanent physical deformities in the patient. This study is aimed to identify the treatment behavior of leprosy patients on time scale. A total of 251 study subjects were selected randomly attending the Skin & VD OPD of S S Hospital of IMS, BHU, Varanasi. Questions related to treatment behavior on time scale were administered to leprosy patients aged 15 years or above by the interviewer himself. Time gap to start the initial treatment was significantly less in MB cases (5.3 months) as compared to PB cases (7.2 months). MB cases wasted significantly more time with allopathic treatment other than MDT. Urban patients (1.3 months) wasted more time with homeopathy than the rural patients (0.9 months). More than half the cases (51.4%) went for the treatment within three months of noticing symptoms of leprosy. There is a considerable delay in starting the MDT after noticing the first symptom of leprosy. As early as possible, measures to start the proper treatment i.e. MDT should be taken to avoid permanent disability due to leprosy. PMID- 26118224 TI - HIV, HCV & Leprosy co-infection. AB - In the era where Hansen's disease has achieved elimination status in India, co infection with HIV can possibly cause a resurgence of this disease. A young intravenous drug abuser was found to have triple affliction, where HIV and HCV infection were discovered on testing after the patient was clinically diagnosed to have Hansen's disease. To our knowledge, there has been no case reported where leprosy was seen with HIV and HCV infection. We are reporting a patient with lepromatous Hansen's disease in type 2 reaction in whom HIV and HCV was incidentally diagnosed. PMID- 26118225 TI - Disabilities in leprosy--The new concepts. AB - The concept of disabilities has undergone changes in recent years and disability is no longer a mere physical dysfunction. It includes activity limitations, stigma, discrimination, and social participation restrictions. In addition to the presence of an illness or impairment, the understanding of disability now explores the relationship between disease/illness/impairment, the persons functioning within daily activities/social roles, and the social, cultural, and physical environments that enable or limit an individual's ability to participate fully in his or her community and daily lives. International Classification of Functioning Disability and Health (ICF) has recognized several dimensions of disability viz., body structure and function (and impairment thereof), activity (and activity restrictions) and participation (and participation restrictions). It also recognizes the role of physical and social environmental factors in affecting disability outcomes and has shifted the focus from the cause of disability to its effect, thereby emphasizing the role of the environment (physical, cultural, social, political) rather than focusing on disability as a 'medical' or 'biological' dysfunction. There is not much information available about these relationships in leprosy related disabilities. Studies are required in different patient groups having different socio-cultural background to develop a better understanding of these issues. Accordingly the need for services can be worked out for rehabilitation of the patients released from the treatment and "Cure". PMID- 26118226 TI - [The cyber-family practitioner and his cyber-patient]. PMID- 26118227 TI - [Computers in the consultation: can we stay patient-centered?]. AB - Eletronic health records (EHR) are now part of most medical practices in many countries including Switzerland. Their use facilitates access and exchange of information among health professionals, improves the quality of medical care and decreases the number of medical errors. Even patients express their satisfaction with the use of EHR. However, it has been observed that use of EHR can modify patient-physician communication. The present article describes the different elements linked to EHR which can enhance or inhibit patient-physician communication. It also suggests strategies for improving it. PMID- 26118228 TI - [The use of internet in medicine is no longer an option]. AB - Internet is currently the most efficient source of information for doctors in their daily practice. Even though some training is necessary, it is easy to use the internet in medicine. Schematic though it may be, we can say only two websites are necessary: a research engine and a medical website. Progressively, each doctor then discovers websites that meet his/her needs. PMID- 26118229 TI - [Patients, doctors and the internet]. AB - The majority of the Swiss population uses the internet to seek information about health. The objective is to be better informed, before or after the consultation. Doctors can advise their information-seeking patients about high quality websites, be it medical portals or websites dedicated to a specific pathology. Doctors should not see the internet as a threat but rather as an opportunity to strengthen the doctor-patient relationship. PMID- 26118230 TI - ["MonDossierMedical.ch": an efficient tool for sharing medical data between patients and doctors]. AB - "MonDossierMedical.ch" is a project led by the canton of Geneva, making it possible for every patient to access his own electronic health record (EHR) and to share the medical files with his doctors. It was introduced across the canton in mid-2013, and provided to all patients free of charge. it is based on the first Swiss-wide e-health-compliant pilot project "e-toile". The canton of Geneva developed "e-toile" as a public-private partnership together with Swiss Post and it was launched in 2009 in some of the canton's municipalities. Back then, Geneva's EHR represented the first Swiss attempt to link all healthcare professionals in the treatment chain. Today, it serves more than 4,600 patients and 380 physicians. This number is growing regularly, as well as the health care institutions (physicians, private hospitals, labs) joining the community. Added value tools, such as a shared care plan and a shared medication list will make the platform even more attractive. PMID- 26118231 TI - [The informatics: a remarkable tool for teaching general internal medicine]. AB - INTERMED training implies a three week course, integrated in the "primary care module" for medical students in the first master year at the school of medicine in Lausanne. INTERMED uses an innovative teaching method based on repetitive sequences of e-learning-based individual learning followed by collaborative learning activities in teams, named Team-based learning (TBL). The e-learning takes place in a web-based virtual learning environment using a series of interactive multimedia virtual patients. By using INTERMED students go through a complete medical encounter applying clinical reasoning and choosing the diagnostic and therapeutic approach. INTERMED offers an authentic experience in an engaging and safe environment where errors are allowed and without consequences. PMID- 26118232 TI - [Doctors and the benefits and dangers of social networks]. AB - Social networks have many different uses. Most young people use them for experimentation and innovation. Social networks help young people get familiar with the digital world, and develop themselves in interrelation with their peers. But social networks can also be used to avoid relationships in the real world, or to practice different forms of harassment. A specific danger lies in forgetting that a great number of people can have access to personal information posted online. Doctors should be particularly aware of this issue. PMID- 26118233 TI - [Jaddo-- the general practitioner blogger]. PMID- 26118234 TI - [Misophonia and contemporary psychiatry]. PMID- 26118235 TI - [German Measles has been eradicated in Americas thanks to vaccination]. PMID- 26118236 TI - [A glass of Champagne!]. PMID- 26118237 TI - [A german view of digestive physiology and intestines in humans]. PMID- 26118238 TI - [Allergies: should we introduce peanuts early ?]. PMID- 26118239 TI - [Alcohol: good or not?]. PMID- 26118240 TI - [23andMed: Geneticist Jean-Louis Mandel's personal experience]. PMID- 26118241 TI - [Creation of a cardiology and pediatric cardiac surgery university hospital in Roman Switzerland]. PMID- 26118242 TI - [Neuchatel's hospital: an evaluation study of three scenarios]. PMID- 26118243 TI - [ New law on assisted reproduction: a necessary tinkering]. PMID- 26118244 TI - THE RELEVANCE OF HANS SELYE'S WORK IN THE FIELD OF OTORHINOLARYNGOLOGY. PMID- 26118245 TI - PERSONAL RECOLLECTIONS OF DR. HANS SELYE AND OF HIS INSTITUT DE MeDECINE ET DE CHIRURGIE EXPeRIMENTALES (IMCE). AB - This article is a short personal recollection of Dr. Hans Selye (HS) and of his institute in order to show, first, why and how he influenced us; second, who he was as a person, human being, physician, scientist, professor, mentor; third, what was the structure and functioning of the Institut de Medecine et Chirurgie Experimentales (IMCE) and fourth, what HS' contributions and accomplishments were. PMID- 26118246 TI - SELYE'S CONCEPT OF PLURICAUSAL DISEASES AND ITS IMPACT ON REGULATORY SCIENCE. AB - Science assumed in recent decades an increasingly important role in the regulatory field. Regulatory science is now regarded as established specific brunch of science. A disturbing anomaly, the emergence of fraudulent data is of major concern both in the field of research and in the regulation. Hans Selye's work on stress, on several forms of pluricausal diseases and on other experimental models came into the focus of interest on the occasion of the Selye Symposium - 2013 held in May 2013 at the Hungarian Academy of Sciences in Budapest. PMID- 26118247 TI - HANS SELYE 70 YEARS LATER: STEROIDS, STRESS ULCERS & H. PYLORI. AB - Although Hans Selye is mostly known for his discovery & development of the stress concept, he also introduced the first physiologically sound, structure-activity classification of steroids that was also based on the chemical structure of steroids in 1943. He not only introduced the names of glucocorticoids & mineralocorticoids but discovered the anti- & pro-inflammatory properties, respectively, of these steroids in animal models. Furthermore, he not only described the first stress-induced gastric ulcers in rats (1936) & characterized the first human 'stress ulcers' during the air-raids in London during World War 11 (1943). Thus, Selye was a much more productive & creative scientist than it is generally considered. PMID- 26118248 TI - HANS SELYE AND THE STRESS RESPONSE: FROM "THE FIRST MEDIATOR" TO THE IDENTIFICATION OF THE HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR. AB - Selye pioneered the stress concept that is ingrained in the vocabulary of daily life. This was originally build on experimental observations that divers noxious agents can trigger a similar triad of endocrine (adrenal enlargement), immune (involution of thymus) and gut (gastric erosion formation) responses as reported in a letter to Nature in 1936. Subsequently, he articulated the underlying mechanisms and hypothesized the existence of a "first mediator" in the hypothalamus able to orchestrate this bodily changes. However he took two generations to identify this mediator. The Nobel Laureate, Roger Guillemin, a former Selye's PhD student, demonstrated in 1955 the existence of a hypothalamic factor that elicited adrenocorticotropic hormone release from the rat pituitary and named it corticotropin releasing factor (CRF). In 1981, Wylie Vale, a former Guillemin's Ph Student, characterized CRF as 41 amino acid and cloned the CRF1 and CRF2 receptors. This paves the way to experimental studies establishing that the activation of the CRF signaling pathways in the brain plays a key role in mediating the stress-related endocrine, behavioral, autonomic and visceral responses. The unraveling of the biochemical coding of stress is rooted in Selye legacy continues to have increasing impact on the scientific community. PMID- 26118249 TI - EVEN VISITING SCIENTISTS COULD MAKE DISCOVERIES IN MONTREAL. AB - This publication summarizes the scientific adventure with Professor Selye, and focuses on the specific effect of rare metal salts on reticuloendothelial functions. Rare earth metal ions markedly affect the functions of cells involved in inflammatory and immunological phenomena. The Kupffer cell blockade induced by GdCl3 is a generally accepted method for investigation of the physiological and pathophysiological roles of Kupffer cells. Potential beneficial effects of macrophage blockade have been demonstrated in different shock states, liver injury and obstructive jaundice. PMID- 26118250 TI - CENTRAL NEUROENDOCRINE MECHANISMS OF GASTROPROTECTION. AB - Selye recognized the importance of activation of hypothalamic-pituitary-adrenal axis during stress and the connection between central nervous system and neuroendocrine regulation. This concept basically contributed to initiation of the studies, which revealed the importance of brain gut axis in regulation of gastric mucosal integrity. Several neuropeptides, such as thyreotrop releasing hormones, adrenomedullin, peptide YY, amylin, opioid peptides, nociceptin, nocisatin, substance P, ghrelin, leptin, orexin-A, angiotensin II were shown to induce gastroprotective effect injected centrally. Though the involvement of dorsal vagal complex and vagal nerves in conveying the central action to the periphery has been well documented, additional mechanisms have also been raised. The interaction between neuropeptides further component that may modify the gastric mucosal resistance to noxious stimulus. PMID- 26118251 TI - OLD AND NEW NEUROENDOCRINE MOLECULES: SOMATOSTATIN, CYSTEAMINE, PANTETHINE AND KYNURENINE. AB - The aim of this review is to commemorate Hans Selye, endocrinologist, the most famous researchers of stress and to briefly summarize the major features of somatostatin (SST), cysteamine (CysA) and patethine (PAN) in neuroendocrinological aspect, which are closely related to his scientific work. In addition, some metabolites of kynurenine pathway (KP) were also mentioned in this paper, as new, possible target molecules in neuroendocrinology. R. Guillemin and A. V. Schally were the main pioneers of the discovery of SST in the 1970's. SST primarily is known as an inhibitor of growth hormone secretion and additionally reduces the gastric acid and pepsin release and also the gastroduodenal mucosal blood flow. These effects are very important in the pathophysiology of peptic ulcer bleeding, which is related to the CysA-evoked perforating duodenal ulcer experimental stress model in rats developed by Selye and Szabo. CysA is a naturally occurring duodenal ulcerogen, which depletes SST in the gastric mucosa and certain brain regions. Furthermore, in addition to depleting SST, CysA also causes adrenocortical necrosis, suggesting an interaction between the central/peripheral nervous system and the neuroendocrine system. The antioxidant PAN, formulated besides the CysA, has similar effects: it attenuates the levels of SST and prolactin in the cerebral cortex and hypothalamus through the accumulation of CysA within cells throughout the body. As new perspectives the KP may be involved in the modulation of neuroendrocrine processes: different agonists and antagonists of glutamate receptors regulate the hypothalamic-pituitary-adrenal axis and kynurenic acid augments the anxiolytic stress responses in neonatal chicks. The pro-inflammatory cytokine-induced and the toxic heavy oil contaminations-evoked alterations in the KP indirectly contribute to the development of neuroendocrine disorders. In summary, there have been highly important developments in neuroendocrinology since the early findings of Selye. Although there are as yet relatively few data about the potential role of kynurenines in neuroendocrinology, the results already achieved are extremely noteworthy and immensely promising. PMID- 26118252 TI - A PSYCHIATRIST'S PERSPECTIVES ON STRESS, STEROIDS AND MENTAL ILLNESS. AB - The relationship between stress and mental illness has been extensively studied and there is a growing consensus that the occurrence of mental illness rather depends on a combination of factors than is caused by stressful external events. Significant hypothalamus pituitary adrenal axis abnormalities were observed among others in major depressive disorder and bipolar disorder. In both disorders, the extent of change in cortisol level was related to the severity of illness and to cognitive changes. Exogenous use of synthetic steroids also frequently resulted in severe psychiatric symptoms. In conclusion changes in the level of steroid hormones may cause impairments in the brain. PMID- 26118253 TI - Catecholamines and stress. AB - A brief survey is offering of debates on two long-standing questions in stress studies and theories: 1) question of stress nonspecificity (i.e. homo- or heterogeneity in stress responses), and 2) what is the functional role of central catecholamines in stress mechanisms, especially in stress signal-transduction and in the realization of stress responses. PMID- 26118254 TI - THE SURPRISING DUAL ACTION OF GLUCOCORTICOIDS. AB - Glucocorticoid hormones may have dual action on the stomach: physiological gastroprotective and pathological proulcerogenic one. In physiological conditions, even in acute stress situations, glucocorticoids have an adaptive effect on the stomach and, therefore, are gastroprotective. The findings that we review in this article suggest that glucocorticoids released during acute stress are naturally occurring protective factors that play an important role in maintenance of the gastric mucosal integrity. PMID- 26118255 TI - HANS SELYE: AN INSPIRING TEACHER. AB - The present writing is a recollection of Hans Selye, as an educator of graduate and post-graduate students. His main aim in teaching his students was to encourage originality and significance of all scientific research. PMID- 26118256 TI - STRESS IN THE CLASSIFICATION OF PITUITARY TUMORS. FOCUS ON AGGRESSIVE PITUITARY ADENOMAS. AB - After a brief summary of the stress concept and the contribution of Dr. Hans Selye, this publication focuses on the classification of pituitary neoplasms and the difficulties to provide conclusive information on the prognosis of various pituitary tumor types. The term "aggressive pituitary tumors" was introduced. These tumors have a rapid cell proliferation rate. At present, the assessment of Ki-67 nuclear labeling index appears to be the simplest and most reliable method to evaluate tumor cell multiplication. Further studies on pituitary tumor biomarkers are needed. PMID- 26118257 TI - [VALIDATION OF THE HUNGARIAN MDS-UPDRS: WHY DO WE NEED A NEW PARKINSON SCALE?]. AB - BACKGROUND: The Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has been published in 2008 as the successor of the original UPDRS. The MDS-UPDRS organizing team developed guidelines for the development of official non-English translations consisting of four steps: translation/back-translation, cognitive pretesting, large field testing, and clinimetric analysis. The aim of this paper was to introduce the new MDS-UPDRS and its validation process into Hungarian. METHODS: Two independent groups of neurologists translated the text of the MDS-UPDRS into Hungarian and subsequently back-translated into English. After the review of the back translated English version by the MDS-UPDRS translation administration team, cognitive pretesting was conducted with ten patients. Based on the results of the initial cognitive pretesting, another round was conducted. For the large field testing phase, the Hungarian official working draft version of MDS-UPDRS was tested with 357 patients with Parkinson's disease (PD). Confirmatory factor analyses (CFA) determined whether the factor structure for the English-language MDS-UPDRS could be confirmed in data collected using the Hungarian Official Draft Version. To become an official translation, the Comparative Fit Index (CFI) had to be >= 0.90 compared to the English-language version. RESULTS: For all four parts of the Hungarian MDS-UPDRS, the CFI was >= 0.94. CONCLUSION: The overall factor structure of the Hungarian version was consistent with that of the English version based on the high CFIs for all the four parts of the MDS-UPDRS in the CFA; therefore, this version was designated as the "OFFICIAL GUNGARIAN VERSION OF THE MDS-UPDRS'. PMID- 26118259 TI - [Dilemma of further therapeutic step in remitting-relapsing multiple sclerosis in case of ineffectiveness of first-line treatment: fingolimod or natalizumab?]. PMID- 26118258 TI - ASSOCIATION OF TEMPORAL LOBE INFLAMMATORY LEUKOENCEPHALOPATHY WITH TWO B CELL MALIGNANCIES. AB - Identification of etiological connections among virtually distinct diseases in a patient may be sometimes challenging. We report a unique case with two B cell malignancies and an inflammatory leukoencephalopathy. Three days prior to admission, the elderly male patient developed fatigue, headaches, recurrent vomiting, memory disturbances, depression and somnolence. Clinical, laboratory and imaging evaluations as well as post mortem histological studies were performed. Simultaneous presence of primary central nervous system B cell lymphoma, temporal lobe inflammatory leukoencephalopathy and multiple (smoldering) myeloma, was revealed by the detailed work up in the treatment-naive patient. Based on recent data from genomic studies, we propose that a sequential evolution of molecular pathology lead to the co-occurrence of multiple myeloma and primary central nervous system B cell lymphoma in this patient, and interpret the development of the temporal lobe leukoencephalopathy as a likely paraneoplastic complication of smoldering myeloma. PMID- 26118261 TI - Evidence of the Construct Validity of the Scale of Economic Abuse. AB - This study investigated the construct validity of the Scale of Economic Abuse (SEA). Evidence of construct validity was assessed by examining the relationship between the SEA and an economic outcome, financial resources, as perceived by participants. A sample of 93 women with abusive partners were recruited from a domestic violence organization and interviewed 3 times over a period of 4 months. Hierarchical linear modeling was used to examine the relationship between economic abuse and financial resources over time, controlling for the effects of physical and psychological abuse. The findings indicate that baseline economic abuse was significantly related to baseline financial resources, and within-woman change in economic abuse was significantly predicted change in financial resources over time. The findings suggest that the SEA measures what it is intended to measure: an economic dimension of intimate partner abuse that has damaging economic consequences. PMID- 26118262 TI - Gender and the Acceptance of Retaliatory Violence Among Acquaintance, Dating, and Marital Relationships. AB - Those who contemplate retaliatory violence against female intimate partners face two conflicting social norms: chivalry norms that discourage violence against women and social norms that may excuse or even support hitting back when one is victimized. Using a sample of 400 undergraduates, this study examines the degree to which norms discouraging violence against women extend to retaliatory acts of violence and whether normative protection of women varies across type of relationship. Findings indicate that relationship status affects men's approval of retaliation by women but not their approval of retaliation by men. In contrast, relationship status affects women's approval of retaliation by men but not their approval of retaliation by women. These findings are consistent with the idea that both men and women subscribe to chivalry norms that inhibit male aggression toward women. Norms that discourage retaliation against women are not limited to wives. Both men and women are more supportive of women's retaliation against men than men's retaliation against women. Men are particularly likely to endorse retaliation by wives against their husbands. PMID- 26118263 TI - What Happens After I Hit? A Qualitative Analysis of the Consequences of Dating Violence for Female Perpetrators. AB - OBJECTIVES: The primary goal of this study is to qualitatively examine reinforcing and punishing consequences following the perpetration of physical aggression by women in dating relationships because recent theoretical conceptualizations of intimate partner violence have emphasized an examination of such consequences. METHOD: Participants were 25 undergraduate women in current dating relationships who reported previous perpetration of physical dating violence and completed a qualitative, theoretically based interview on the consequences of their aggression perpetration. RESULTS: Findings demonstrated that violent episodes resulted in both reinforcing and punishing consequences, with 100% of instances resulting in reinforcing consequences for the perpetrator and 76% classified as punishing, which were divided into 15 different classes of outcomes. CONCLUSIONS: These findings suggest that dating violence prevention programming could focus their efforts on increasing use of nonaggressive behaviors leading to reinforcing outcomes among dating couples during conflict resolution. This also has important implications for theoretical models of intimate partner violence. PMID- 26118264 TI - An Examination of Emotion Regulation and Alcohol Use as Risk Factors for Female Perpetrated Dating Violence. AB - Dating violence is a serious problem among college students. Research indicates that females perpetrate as much, if not more, psychological and physical aggression against their dating partners relative to their male counterparts. Unfortunately, there is considerably less research on risk factors for female perpetrated dating violence, hindering efforts aimed at preventing violence in their relationships. This study examined 2 risk factors for female-perpetrated dating violence, namely alcohol use and emotion regulation, within a sample of undergraduate female college students (N = 379). Using structural equation modeling, results demonstrated that emotion regulation was associated with psychological aggression perpetration, and this was partially mediated by alcohol use. Moreover, a 2-chain mediation was present, such that emotion regulation deficits predicted alcohol use, which in turn predicted psychological aggression, which finally predicted physical aggression. These findings are consistent with theoretical models of dating violence and indicate that intervention programs should focus their efforts on increasing adaptive emotion regulation, decreasing alcohol use, and reducing psychological aggression. PMID- 26118265 TI - The Relation of Severity and Type of Community Violence Exposure to Emotional Distress and Problem Behaviors Among Urban African American Adolescents. AB - Severity level and type of exposure to community violence were examined to determine their effect on emotional distress and problem behaviors among 234 low income urban African American early adolescents. There were 4 violence exposure scales developed from a principal component analysis of the Richters and Martinez (1993) exposure to violence scale: moderate and severe witnessing and moderate and severe victimization. Regression analyses indicated that moderate victimization was the most consistent predictor of emotional distress and behavioral problems, whereas moderate witnessing did not relate to any of the dependent variables. Severe victimization predicted depression and delinquency, whereas severe witnessing predicted posttraumatic stress disorder symptoms and delinquency. Witnessing and victimization scales based on severity of exposure better represented the experience than combining all data into a single exposure or simply witnessing and victimization scales. PMID- 26118266 TI - Reducing the Harm of Criminal Victimization: The Role of Restitution. AB - Restitution is a court-ordered payment by offenders to their victims to cover the victims' economic losses resulting from the crime. These losses can be substantial and can harm victims and victims' families both directly and indirectly. But most victims do not receive reparation for their injuries, both because judges do not always impose restitution and because of problems with collecting restitution payments, even if there is a court order to do so. In this article, we review the literature on restitution and suggest that this compensatory mechanism is necessary to restore victims to where they were before the crime occurred. But monetary restitution alone is not sufficient. Making victims whole requires not only financial compensation from the offender but also procedural, informational, and interpersonal justice from the criminal justice system. PMID- 26118267 TI - Understanding Ecological Factors Associated With Bullying Across the Elementary to Middle School Transition in the United States. AB - This study examines sociodemographic characteristics and social-environmental factors associated with bullying during the elementary to middle school transition from a sample of 5th-grade students (n = 300) in 3 elementary schools at Time 1. Of these, 237 participated at Time 2 as 6th-grade students. Using cluster analyses, we found groups of students who reported no increase in bullying, some decrease in bullying, and some increase in bullying. Students who reported increases in bullying also reported decreases in school belongingness and teacher affiliation and increases in teacher dissatisfaction. Students who reported decreases in bullying also reported decreases in victimization. These findings suggest that changes across the transition in students' relations to school and their teachers are predictive of changes in bullying. PMID- 26118268 TI - Risk Factors in Arrest of Rural and Urban Female Victims of Intimate Partner Violence. AB - This study used a sample of women who obtained protective orders (N = 709) from urban and rural communities and identified risk factors in arrest for victims of intimate partner violence 12 months after the protective order was obtained. Lower social support, higher loneliness, living in a rural community, substance abuse/dependency, a history of prior arrest, engaging in illegal behavior, and younger age were all identified as significant predictors of arrest at follow-up. The findings highlight the need for support and resources in vulnerable populations to reduce the risk of offending and recidivism. Implications for reentry programs and services for victimized women at risk are discussed. PMID- 26118269 TI - Cumulative Effects of Multiple Forms of Violence and Abuse on Women. AB - Little is known about how patterns of workplace bullying contribute to the negative effects of lifetime violence. Analysis of longitudinal data from a study of women's health after separating from an abusive partner revealed that 76% of 229 women had experienced workplace bullying. Workplace bullying was associated with child sexual abuse, adult sexual assault, and ongoing partner abuse. Timing was critical, with those experiencing past workplace bullying having poorer health and fewer personal and social resources than those experiencing none, ongoing, or past and ongoing bullying. Lifetime sexual harassment (54%) was associated with higher posttraumatic stress disorder symptomology and greater likelihood of leaving workplaces and physical bullying (16%) with poorer health and personal, social, and economic resources. These findings highlight the importance of including bullying in studying lifetime violence. PMID- 26118270 TI - Improving Systematic Response in the Face of Homicide: Family and Friends of Homicide Victims Service Needs. AB - Homicide is a pressing issue in America. This study used qualitative data obtained from focus groups of family and friends of homicide victims (FFHV) to assess and better meet the needs of victims post homicide. The study results posit myriad changes to the systematic response to homicide. The article concludes with recommendations for training and resources, with specific attention to legal, law enforcement, medical, and behavioral health providers. PMID- 26118271 TI - Keeping Victims Informed: Service Providers' and Victims' Experiences Using Automated Notification Systems. AB - Automated victim notification is often touted as an effective and efficient means for providing victims timely and accurate information of their offenders' court events and status changes at reduced burden to the criminal justice system. Today, 47 states, the District of Columbia, and Puerto Rico have some form of automated notification system. Researchers surveyed 1,246 service providers and 723 victims to examine their awareness and use of, satisfaction with, and experiences using automated notification systems. Findings indicate that service providers are aware of and use automated notification; however, less than one quarter of victim respondents were registered for automated notification services. Service providers and victims who use automated notification services report high overall satisfaction; however, they also report challenges in using these systems. Service providers offer several recommendations for improving automated notification systems. PMID- 26118272 TI - My Air Force Story. PMID- 26118273 TI - Meaningful Recognition: Recognizing the "soft skills" of Nursing. PMID- 26118274 TI - Primary Care Nurse Practitioner: Not Just Colds & Coughs. PMID- 26118275 TI - A Student's Perspective on Nurse Advocacy. PMID- 26118276 TI - What should you do if you received a 4-5-320(c) notification letter from the Tennessee Department of Health? PMID- 26118277 TI - Bottom-Up Change. PMID- 26118278 TI - Finding Refuge in Nursing: The Role of Ethics. PMID- 26118279 TI - Bullying: One Nurses' Story. PMID- 26118280 TI - The Disturbing Increase in Sexual Misconduct and Sexual Boundary Issues. PMID- 26118281 TI - It's a job. PMID- 26118282 TI - Cautiously optimistic. PMID- 26118283 TI - Quarter of four-year-olds failing to flourish. PMID- 26118284 TI - Childhood obesity the result of two different 'epidemics'. PMID- 26118285 TI - Charity warns of carbon monoxide poisoning dangers. PMID- 26118286 TI - Breast milk 'protects against severe intestinal disease'. PMID- 26118287 TI - Eczema on trial. PMID- 26118288 TI - 'Midwives should not act as gatekeepers to the maternity services'. PMID- 26118289 TI - An update on vitamin D deficiency and at risk groups. AB - Vitamin D is required for healthy bones. We need sunlight and good renal and liver function for the synthesis of vitamin D, although it can also be taken in diet. Severe deficiency causes the bone diseases rickets and osteomalacia. Supplementation with vitamin D can help prevent low birth weight and non vertebral fractures. Roles for vitamin D in other aspects of health are controversial. PMID- 26118290 TI - Demonstrating effective support to parents with learning disabilities. Part 1. PMID- 26118291 TI - At a glance: common (abdominal) surgical conditions in children. AB - In children, surgical conditions of the abdomen can present with rather non specific symptoms akin to other common, self-limiting pathologies. These factors can impede diagnosis and the rapid specialist management that is often required. Community practitioners are often the first health professional to see the sick child and advise their caregivers. Therefore it is of upmost importance that they are equipped and confident in their knowledge of the potential surgical conditions that they may encounter in their clinical practice. Suspicion of a serious surgical disorder or a deteriorating child warrants prompt referral to a medical professional. This article aims to provide an overview of the most common abdominal surgical conditions in children and to provide information and suggestions to the community practitioner in order to broadly enhance their outcomes. PMID- 26118292 TI - The day England's Chief Nurse shadowed me. PMID- 26118293 TI - Will the FDAC effectively safeguard children? PMID- 26118294 TI - 'Don't let process stop progress'. PMID- 26118295 TI - Female genital mutilation: everyone's business. PMID- 26118296 TI - Lead from the front. PMID- 26118297 TI - Enuresis: ensuring school readiness. PMID- 26118298 TI - [Present condition and new vista of the future in robotic-assisted laparoscopic surgeries]. AB - The introduction of robotic surgical system is one of the most exciting topic in the field of the surgery. In this symposium, we presented and explained the present condition of robotic-assisted laparoscopic surgeries performed in the department of Urology, Gastroenterology and Gynecology of the Hokkaido University Hospital. By using this surgical system, laparoscopic surgery, which is generally considered to be difficult, can be safely performed by surgeons. Especially in radical prostatectomy against localized prostate cancer, this surgical approach brought the decrease in peri- and postoperative problems including blood loss and postoperative urinary incontinence in comparison with open or laparoscopic radical prostatectomy. We wish that this symposium would help the audience to understand the present condition and new vista of the future in robotic-assisted laparoscopic surgeries. PMID- 26118299 TI - Pigment epithelium-derived factor inhibits the growth of human esophageal squamous cell carcinoma by suppressing neovascularization. AB - INTRODUCTION: Neovascularization consists of angiogenesis and vasculogenesis during which bone marrow-derived endothelial progenitor cells (EPCs) are mobilized for blood vessel formation. Pigment epithelium-derived factor (PEDF) is known to be a potent inhibitor of angiogenesis in some solid carcinomas. However, the effects of PEDF on human esophageal squamous cell carcinoma (ESCC) and vasculogenesis are still unknown. The purpose of this research was to investigate the effect of PEDF on angiogenesis, tumor growth, and vasculogenesis in ESCC. MATERIALS AND METHODS: The PEDF gene was transduced to the TE8 ESCC cell line not secreting endogenous PEDF and the HEC 46 cell line originally secreting endogenous PEDF by lentivirus-based vectors expressing PEDF. In vitro endothelial cell proliferation and migration assays were performed using the supernatant derived from PEDF-overexpressing cells. In in vivo experiments, the effects of PEDF on chronological tumor growth, intratumoral microvessel density (MVD), tumor cell apoptosis, and the frequency of EPCs in peripheral blood and tumor tissues were examined in murine subcutaneous tumor models. RESULTS: PEDF inhibited endothelial cell proliferation and migration in vitro and showed potent in vivo antitumor properties by inhibiting MVD in the human ESCC cell line that did not secrete endogenous PEDF. However, in the cell line secreting endogenous PEDF, additional PEDF gene transfer showed no inhibition of angiogenesis and no subsequent antitumor properties. With respect to vasculogenesis, PEDF was found to have potential to suppress vasculogenesis; the frequency of EPCs both in peripheral blood and tumor tissue was decreased in mice implanted with PEDF overexpressing TE8 and HEC46 cells. CONCLUSION: PEDF may have potent antiangiogenic and antitumor effects in ESCC cells naturally not secreting endogenous PEDF and can be expected to be applied as gene therapy in the future. PMID- 26118300 TI - Evaluation of a new system for chest tomosynthesis: aspects of image quality of different protocols determined using an anthropomorphic phantom. AB - OBJECTIVE: To compare the image quality obtained with the different protocols in a new chest digital tomosynthesis (DTS) system. METHODS: A chest phantom was imaged with chest X-ray equipment with DTS. 10 protocols were used, and for each protocol, nine acquisitions were performed. Four observers visually rated the quality of the reconstructed section images according to pre-defined quality criteria in four different classes. The data were analysed with visual grading characteristics (VGC) analysis, using the vendor-recommended protocol [12-s acquisition time, source-to-image distance (SID) 180 cm] as reference, and the area under the VGC curve (AUCVGC) was determined for each protocol and class of criteria. RESULTS: Protocols with a smaller swing angle resulted in a lower image quality for the classes of criteria "disturbance" and "homogeneity in nodule" but a higher image quality for the class "structure". The class "demarcation" showed little dependency on the swing angle. All protocols but one (6.3 s, SID 130 cm) obtained an AUCVGC significantly <0.5 (indicating lower quality than reference) for at least one class of criteria. CONCLUSION: The study indicates that the DTS protocol with 6.3 s yields image quality similar to that obtained with the vendor recommended protocol (12 s) but with the clinically important advantage for patients with respiratory impairment of a shorter acquisition time. ADVANCES IN KNOWLEDGE: The study demonstrates that the image quality may be strongly affected by the choice of protocol and that the vendor-recommended protocol may not be optimal. PMID- 26118302 TI - An online open-source tool for automated quantification of liver and myocardial iron concentrations by T2* magnetic resonance imaging. AB - OBJECTIVE: To assess whether an online open-source tool would provide accurate calculations of T2(*) values for iron concentrations in the liver and heart compared with a standard reference software. METHODS: An online open-source tool, written in pure HTML5/Javascript, was tested in 50 patients (age 26.0 +/- 18.9 years, 46% males) who underwent T2(*) MRI of the liver and heart for iron overload assessment as part of their routine workup. Automated truncation correction was the default with optional manual adjustment provided if needed. The results were compared against a standard reference measurement using commercial software with manual truncation (CVI(42)((r)) v. 5.1; Circle Cardiovascular Imaging; Calgary, AB). RESULTS: The mean liver T2(*) values calculated with the automated tool was 4.3 ms [95% confidence interval (CI) 3.1 to 5.5 ms] vs 4.26 ms using the reference software (95% CI 3.1 to 5.4 ms) without any significant differences (p = 0.71). In the liver, the mean difference was 0.036 ms (95% CI -0.1609 to 0.2329 ms) with a regression correlation coefficient of 0.97. For the heart, the automated T2(*) value was 26.0 ms (95% CI 22.9 to 29.0 ms) vs 25.3 ms (95% CI 22.3 to 28.3 ms), p = 0.28. The mean difference was 0.72 ms (95% CI 0.08191 to 1.3621 ms) with a correlation coefficient of 0.96. CONCLUSION: The automated online tool provides similar T2(*) values for the liver and myocardial iron concentrations as compared with a standard reference software. ADVANCES IN KNOWLEDGE: The online program provides an open-source tool for the calculation of T2(*) values, incorporating an automated correction algorithm in a simple and easy-to-use interface. PMID- 26118301 TI - Imaging intracellular and systemic in vivo gold nanoparticles to enhance radiotherapy. AB - Nanoparticles offer alternative options in cancer therapy both as drug delivery carriers and as direct therapeutic agents for cancer cell inactivation. More recently, gold nanoparticles (AuNPs) have emerged as promising radiosensitizers achieving significantly elevated radiation dose enhancement factors when irradiated with both kilo-electron-volt and mega-electron-volt X-rays. Use of AuNPs in radiobiology is now being intensely driven by the desire to achieve precise energy deposition in tumours. As a consequence, there is a growing demand for efficient and simple techniques for detection, imaging and characterization of AuNPs in both biological and tumour samples. Spatially accurate imaging on the nanoscale poses a serious challenge requiring high- or super-resolution imaging techniques. In this mini review, we discuss the challenges in using AuNPs as radiosensitizers as well as various current and novel imaging techniques designed to validate the uptake, distribution and localization in mammalian cells. In our own work, we have used multiphoton excited plasmon resonance imaging to map the AuNP intracellular distribution. The benefits and limitations of this approach will also be discussed in some detail. In some cases, the same "excitation" mechanism as is used in an imaging modality can be harnessed to make it also a part of therapy modality (e.g. phototherapy)-such examples are discussed in passing as extensions to the imaging modality concerned. PMID- 26118303 TI - Antimicrobial peptides: has their time arrived? PMID- 26118304 TI - Evaluation of organic matter removal and electricity generation by using integrated microbial fuel cells for wastewater treatment. AB - A floating all-in-one type of microbial fuel cell (Fa-MFC) that allows simple operation and installation in existing wastewater reservoirs for decomposition of organic matter was designed. A prototype cell was constructed by fixing a tubular floater to an assembly composed of a proton-exchange membrane and an air-cathode. To compare anode materials, carbon-cloth anodes or carbon-brush anodes were included in the assembly. The fabricated assemblies were floated in 1-L beakers filled with acetate medium. Both reactors removed acetate at a rate of 133-181 mg/L/d. The Fa-MFC quipped with brush anodes generated a 1.7-fold higher maximum power density (197 mW/m(2)-cathode area) than did that with cloth anodes (119 mW/m(2)-cathode area). To evaluate the performance of the Fa-MFCs on more realistic substrates, artificial wastewater, containing peptone and meat extract, was placed in a 2-L beaker, and the Fa-MFC with brush anodes was floated in the beaker. The Fa-MFC removed the chemical oxygen demand of the wastewater at a rate of 465-1029 mg/L/d, and generated a maximum power density of 152 mW/m(2)-cathode area. When the Fa-MFC was fed with actual livestock wastewater, the biological oxygen demand of the wastewater was removed at a rate of 45-119 mg/L/d, with electricity generation of 95 mW/m(2)-cathode area. Bacteria related to Geobacter sulfurreducens were predominantly detected in the anode biofilm, as deduced from the analysis of the 16S rRNA gene sequence. PMID- 26118305 TI - Clinical significance of serum apolipoproteins as a predictor of coronary heart disease risk in Korean men. AB - OBJECTIVE: Although serum apolipoprotein measurement is known to be associated with coronary heart disease (CHD) risk, there is only limited information about the clinical significance of lipid profiles such as ApoA, ApoB and A/B ratio in predicting CHD risk in Asians. Therefore, this cohort study was conducted to evaluate the longitudinal effects of baseline serum apolipoprotein measurements on CHD risk in Korean men. DESIGN: Initially, an intermediate and high Framingham risk score (FRS)-free cohort of 23 918 healthy Korean men was followed until 2010. FRS was calculated for each man and divided into three levels of risk <10% (low), 10-19% (intermediate) and >=20% (high). More-than-a-moderate CHD risk group (participants with FRS >= 10%) and high CHD risk group (participants with FRS >= 20%) were defined as our two dependent variables. Cox proportional hazards models were performed. RESULTS: In the more-than-a-moderate CHD risk group, the total and average follow-up periods were 83340.2 and 3.48 person-years, respectively, and 3763 (15.7%) incident cases developed between 2006 and 2010. In the high CHD risk group, the total and average follow-up periods were 87868.8 and 3.67 person-years, respectively, and 344 (1.4%) incident cases developed between 2006 and 2010. Multivariate-adjusted analyses showed a strong statistically significant relationship between the quintile groups of apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA-1) and apolipoprotein B/apolipoprotein A-1 (ApoB/A-1) ratio and both the more-than-a-moderate CHD risk and high CHD risk. CONCLUSIONS: Serum ApoB, ApoA-1 and ApoB/A-1 ratio levels are independently associated with CHD risk in Korean men. PMID- 26118306 TI - Introduction to the special issue on Cognitive bias modification: Taking a step back to move forward? AB - Cognitive bias modification (CBM) research holds important theoretical and clinical potential. CBM represents one of the most exciting translational developments in experimental psychopathology research in recent years. Despite theoretical and methodological advances in the past 15 years, the clinical efficacy of CBM, to-date, has been disappointing. However, it is important to remember that the CBM therapeutics literature is only in its early stages of scientific development. We argue that the potential for novel approaches to CBM to contribute to disseminable psychological interventions is strong and has yet to be realized. Accordingly, we propose 5 inter-related steps that may help advance the basic and clinical science of CBM: (1) Innovation and refinement of the methodology to modify information-processing bias; (2) Advancing understanding of the nature of processing biases in order to guide their modification; (3) Conceptualizing and studying the moderating and mediating mechanisms underlying the modification of information-processing bias and their effects on maladaptation; (4) Focus on augmenting existing validated treatments, by targeting psychobehavioral processes proximally linked to information processing biases; (5) Encouraging publication of methodologically strong, mixed and unexpected findings. Finally, we introduce papers in the special issue with respect to each of these future directions. These papers provide important new conceptual and methodological perspectives to advance CBM research. PMID- 26118307 TI - Predicting clinical severity based on substitutions near epitope A of influenza A/H3N2. AB - Epitopes are the main targets for specific antibodies in the host defense systems. Recent studies have shown that amino acid (aa) substitutions located within the influenza A/H3N2 hemagglutinin 1 (HA1) epitopes A-E, particularly in A and B, result in antigenic drift. Viruses with such drift mutations may have resulted in more severe influenza-related illness during influenza epidemics between late 2012 and early 2015. We sought to quantify vaccine mismatches in epitopes A-E of the HA1 protein, and correlate these with the severity of the patient's illness. The influenza A/H3N2 clinical samples were collected between April 2009 and November 2013 (n=206). Patients were clinically stratified into groups with mild, moderate, and severe influenza-like illness (ILI). The impact of the number of aa mismatches in each of epitopes A-E, gender, age groups (?18, 19-64, ?65 years), and comorbidities on the likelihood that patients would suffer moderate and/or severe ILI due to influenza A/H3N2 infection were assessed. A higher number of aa mismatches in epitope A between the vaccine and locally circulating viruses correlated with more severe influenza infection, although this correlation was most significant with pre-existing comorbidities. A practical application of this finding would be to monitor patients (especially those in high-risk groups) infected with such viruses more closely, as they are at increased risk of developing more serious disease. Epidemiologically, it was of interest to note that viruses from subclade 3A of Victoria/208 strain were not detected in Singapore between 2009 and 2012. By contrast, these viruses were detected at a prevalence of up to 40% in the 2011-2012 influenza seasons in other regions of the Northern and Southern hemispheres. Such findings support the rationale for more regionally customized seasonal influenza vaccine compositions to optimize the protection of the population against locally circulating virus strains. PMID- 26118308 TI - "Atypical touch perception in MTS may derive from an abnormally plastic self representation". AB - Mirror Touch Synesthetes (MTSs) feel touch while they observe others being touched. According to the authors, two complementary theoretical frameworks, the Threshold Theory and the Self-Other Theory, explain Mirror Touch Synesthesia (MTS). Based on the behavioral evidence that in MTSs the mere observation of touch is sufficient to elicit self-other merging (i.e., self-representation changes), a condition that in non-MTSs just elicits self-other sharing (i.e., mirroring activity without self-other blurring), and on the rTPJ anatomical alterations in MTS, we argue that MTS may derive from an abnormally plastic self representation and atypical multisensory integrative mechanisms. PMID- 26118309 TI - Effect of Mucosal Cytokine Administration on Selective Expansion of Vaginal Dendritic Cells to Support Nanoparticle Transport. AB - PROBLEM: The capacity of antigen-carrying vaccine nanoparticles (NPs) administered vaginally to stimulate local immune responses may be limited by the relatively low numbers of antigen-presenting cells (APCs) in the genital mucosa. Because inflammation is associated with increased susceptibility to sexually transmitted infections, we sought to increase APC numbers without causing inflammation. METHOD OF STUDY: In this study, we evaluated intravaginal delivery of chemokines, growth factors, or synthetic adjuvants to expand APCs in reproductive tissues. RESULTS: We found that granulocyte-macrophage colony stimulating factor (GM-CSF) stimulated expansion of CD11b+ dendritic cells (DCs) within 24 hr of intravaginal administration, with no effect on Langerhans cells or macrophages. Expansion of the CD11b+ DC population was not associated with increased inflammatory cytokine production, and these cells retained phagocytic function. CONCLUSION: Our data suggest that non-inflammatory expansion of mucosal APCs by intravaginal GM-CSF could be used as an adjuvanting strategy to potentiate the genital immune response to nanoparticulate mucosal vaccines. PMID- 26118310 TI - Rapid-sequence intubation using a videolaryngoscope and tube-balloon esophageal blocker in a seated position. PMID- 26118311 TI - Assessing analgesic efficiency of single-injection thoracic paravertebral block after mastectomy. PMID- 26118312 TI - Thoracic epidural analgesia in a child with multiple traumatic rib fractures. AB - The morbidity and mortality associated with blunt thoracic trauma are significant and can be multisystem in nature. Of these, pulmonary complications, including ventilatory impairment secondary to pain, have been recognized to be the most consequential. Although several analgesic strategies have emerged, thoracic epidural analgesia (TEA) has arguably demonstrated superior efficacy and is used frequently in adults. Unfortunately, TEA is rarely used in children after blunt thoracic trauma, but may be of considerable benefit. This low rate of use likely reflects one or more of several factors potentially encountered when considering the use of TEA in pediatric chest wall trauma. Among them are (1) uncertainty regarding safety and efficacy; (2) the technical challenges of pediatric thoracic epidural placement, including technique and equipment concerns; and (3) drug selection, dosing, and toxicity. The following case review describes the successful application of TEA in a 4-year-old boy after multiple traumatic rib fractures and associated pneumothorax and pulmonary contusion. PMID- 26118313 TI - Seizure characteristics of epilepsy in childhood after acute encephalopathy with biphasic seizures and late reduced diffusion. AB - OBJECTIVE: The aim of this study was to clarify characteristics of post encephalopathic epilepsy (PEE) in children after acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), paying particular attention to precise diagnosis of seizure types. METHODS: Among 262 children with acute encephalopathy/encephalitis registered in a database of the Tokai Pediatric Neurology Society between 2005 and 2012, 44 were diagnosed with AESD according to the clinical course and magnetic resonance imaging (MRI) findings and were included in this study. Medical records were reviewed to investigate clinical data, MRI findings, neurologic outcomes, and presence or absence of PEE. Seizure types of PEE were determined by both clinical observation by pediatric neurologists and ictal video-electroencephalography (EEG) recordings. RESULTS: Of the 44 patients after AESD, 10 (23%) had PEE. The period between the onset of encephalopathy and PEE ranged from 2 to 39 months (median 8.5 months). Cognitive impairment was more severe in patients with PEE than in those without. Biphasic seizures and status epilepticus during the acute phase of encephalopathy did not influence the risk of PEE. The most common seizure type of PEE on clinical observation was focal seizures (n = 5), followed by epileptic spasms (n = 4), myoclonic seizures (n = 3), and tonic seizures (n = 2). In six patients with PEE, seizures were induced by sudden unexpected sounds. Seizure types confirmed by ictal video-EEG recordings were epileptic spasms and focal seizures with frontal onset, and all focal seizures were startle seizures induced by sudden acoustic stimulation. Intractable daily seizures remain in six patients with PEE. SIGNIFICANCE: We demonstrate seizure characteristics of PEE in children after AESD. Epileptic spasms and startle focal seizures are common seizure types. The specific seizure types may be determined by the pattern of diffuse subcortical white matter injury in AESD and age-dependent reorganization of the brain network. PMID- 26118314 TI - The neutral metallopeptidase NMP1 of Trichoderma guizhouense is required for mycotrophy and self-defence. AB - Trichoderma guizhouense NJAU 4742 (Harzianum clade) can suppress the causative agent of banana wild disease Fusarium oxysporum f. sp. cubense 4 (Foc4). To identify genes involved in this trait, we used T-DNA insertional mutagenesis and isolated one mutant that was unable to overgrow Foc4 and had reduced antifungal ability. Using the high-efficiency thermal asymmetric interlaced-PCR, the T-DNA was located in the terminator of a neutral metalloprotease gene (encoding a MEROPS family M35 protease), which was named nmp1. The antifungal activity of the mutant was recovered by retransformation with wild-type nmp1 gene. The purified NMP1 (overexpressed in Pichia pastoris) did not inhibit the growth and germination of other fungi in vitro. Its addition, however, partly recovered the antifungal activity of the mutant strain against some fungi. The expression of nmp1 is induced by the presence of fungi and by dead fungal biomass, but the time course of transcript accumulation following the physical contact depends on mode of interaction: it increases in cases of long-lasting parasitism and decreases if the prey fungus is dead shortly after or even before the contact (predation). We thus conclude that NMP1 protein of T. guizhouense has major importance for mycotrophic interactions and defence against other fungi. PMID- 26118315 TI - BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. AB - BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247. PMID- 26118316 TI - Distinct molecular abnormalities underlie unique clinical features of essential thrombocythemia in children. PMID- 26118317 TI - Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: Modern surgical resection as a feasible alternative to transarterial chemoemolization. AB - OBJECTIVE: To analyse the impact of liver resection (LR) in patients with Hepatocellular Carcinoma (HCC) within the Barcelona-Clinic-Liver-Cancer (BCLC)-B stage. METHODS: Analysis of patients with BCLC-B HCC treated with LR or transarterial chemoembolization (TACE) between 2007 and 2012 in our hospital. Survival/recurrence analyses were performed by log-rank tests and Cox multivariate models. Further analyses were specifically obtained for the HCC subclassification (B1-2-3-4) proposed recently. RESULTS: Eighty patients were treated (44-TACE/36-LR). Number of nodules was [1.8(1.1)], being multinodular in 50% of cases. Although resected patients had a higher hospital stay than those who underwent TACE (14 +/- 13 vs 7 +/- 6; P = 0.004), the rate and severity of complications was lower measured by Dindo-Clavien scale (P < 0.05). Overall survival was 40% with a median follow-up of 29.5 months (0.07-96.9). Five-years survival rates were 62.9%, 28.1% and 15.4%, respectively (P = 0.004) for B1, B2 and B3-4 stages. Cox model showed that only total bilirubin [OR = 2.055(1.23 3.44)] and BCLC subclassification B3-4 [OR = 2.439(1.04-5.7)] and B2 [OR = 2.79(1.35-5.77)] vs B1 were independent predictors of 5-years-survival. In B1 patients, surgical approach led a significant decrease in 5-years recurrence-rate (25% vs 60%; P = 0.018). In the surgical subgroup analysis, better results were observed if well/moderate differentiation combined with no microvascular-invasion (VI) in 5-years-survival (84.6%; P = 0.001) and -recurrence (23.1%; P = 0.041), respectively. These survival and recurrence trends were remarkable in B1 stages. CONCLUSIONS: Management of Intermediate BCLC-B HCC stage should be more complex and include updated criteria regarding B-stage subclassifications, VI and tumour differentiation. Modern surgical resection would offer improved survival benefit with acceptable safety in selected BCLC-B stage patients. PMID- 26118318 TI - Efficacy and acceptability of antidepressants on the continuum of depressive experiences in patients with cancer: Systematic review and meta-analysis. AB - BACKGROUND: Patients with cancer are particularly vulnerable to depressive experiences, ranging from severe emotional reactions to proper depressive syndromes, including major depression. These experiences may deeply affect the course and outcome of the disease. The aim of this study was to assess the efficacy acceptability of antidepressants on the continuum of depressive experiences in patients suffering from cancer. METHODS: MEDLINE, EMBASE, PsycINFO, CENTRAL, as well as websites of regulatory agencies, clinical trial repositories and pharmaceutical companies, were systematically searched for published and unpublished randomised trials assessing the efficacy of antidepressants versus placebo in patients with cancer. Efficacy of antidepressants at the end of the study was the primary outcome. The review protocol was registered with PROSPERO (CRD42014013440). RESULTS: A total of 19 studies contributed to the analysis. Antidepressants (particularly the selective serotonin-reuptake inhibitors and mianserin) were more effective than placebo in relieving depressive experiences in both patients with major depression or depressive symptoms (standardised mean difference -0.596, 95% confidence interval -1.041 to -0.150), as well as in patients with other cancer-related distressing symptoms (standardised mean difference -0.229, 95% confidence interval -0.419 to 0.039). We found evidence that efficacy was positively associated with length of treatment. No differences between antidepressants and placebo were found in terms of overall acceptability. CONCLUSIONS: Antidepressants should be considered as one treatment option for relieving the burden of depressive experiences in patients with cancer. PMID- 26118319 TI - Structural and Mechanistic Insights into Fast Lithium-Ion Conduction in Li4SiO4 Li3PO4 Solid Electrolytes. AB - Solid electrolytes that are chemically stable and have a high ionic conductivity would dramatically enhance the safety and operating lifespan of rechargeable lithium batteries. Here, we apply a multi-technique approach to the Li-ion conducting system (1-z)Li4SiO4-(z)Li3PO4 with the aim of developing a solid electrolyte with enhanced ionic conductivity. Previously unidentified superstructure and immiscibility features in high-purity samples are characterized by X-ray and neutron diffraction across a range of compositions (z = 0.0-1.0). Ionic conductivities from AC impedance measurements and large-scale molecular dynamics (MD) simulations are in good agreement, showing very low values in the parent phases (Li4SiO4 and Li3PO4) but orders of magnitude higher conductivities (10(-3) S/cm at 573 K) in the mixed compositions. The MD simulations reveal new mechanistic insights into the mixed Si/P compositions in which Li-ion conduction occurs through 3D pathways and a cooperative interstitial mechanism; such correlated motion is a key factor in promoting high ionic conductivity. Solid-state (6)Li, (7)Li, and (31)P NMR experiments reveal enhanced local Li-ion dynamics and atomic disorder in the solid solutions, which are correlated to the ionic diffusivity. These unique insights will be valuable in developing strategies to optimize the ionic conductivity in this system and to identify next-generation solid electrolytes. PMID- 26118320 TI - Tuning the morphology of g-C3N4 for improvement of Z-scheme photocatalytic water oxidation. AB - Solar-driven water oxidation is the key step for overall water splitting that efficiently harvests and converts solar energy into fuels; the development of a highly efficient photocatalyst that can mediate water oxidation has become an appealing challenge. Herein, we report a facile two-step process to decorate silver phosphate (Ag3PO4) particles on different types of graphitic carbon nitrides (g-C3N4) as composite photocatalysts for water oxidation. For all the Ag3PO4/g-C3N4 materials, an in situ Z-scheme is created by the generation of Ag nanoparticles which act as a cross-linking bridge between Ag3PO4 and g-C3N4 in the composite, resulting in better charge separation and higher catalytic performance. A detailed analysis emphasizes the importance of the g-C3N4 on the chemical, photophysical, and catalytic properties of the composite materials. Our results show that the alteration of the morphology dominates the performance of the composite materials. PMID- 26118321 TI - Constitutive presence of antibiotic resistance genes within the bacterial community of a large subalpine lake. AB - The fate of antibiotic resistance genes (ARGs) in environmental microbial communities is of primary concern as prodromal of a potential transfer to pathogenic bacteria. Although of diverse origin, the persistence of ARGs in aquatic environments is highly influenced by anthropic activities, allowing potential control actions in well-studied environments. However, knowledge of abundance and space-time distribution of ARGs in ecosystems is still scarce. Using quantitative real-time PCR, we investigated the presence and the abundance of twelve ARGs (against tetracyclines, beta-lactams, aminoglycosides, quinolones and sulphonamides) at different sampling sites, depths and seasons, in Lake Maggiore, a large subalpine lake, and in the area of its watershed. We then evaluated the correlation between each ARG and a number of ecological parameters in the water column in the deepest part of the lake. Our results suggest the constitutive presence of at least four ARGs within the bacterial community with a high proportion of bacteria potentially resistant to tetracyclines and sulphonamides. The presence of these ARGs was independent of the total bacterial density and temperature. The dynamics of tet(A) and sulII genes were, however, positively correlated with dissolved oxygen and negatively to chlorophyll a, suggesting that the resistant microbes inhabit specific niches. These observations indicate that the lake is a reservoir of antibiotic resistances, highlighting the need of a deeper understanding of the sources of ARGs and the factors allowing their persistence in waters. PMID- 26118322 TI - The IFCC-Siemens Specialized Conference: Biomarkers in neuropsychiatric disorders. PMID- 26118323 TI - Obituary. PMID- 26118324 TI - Effect on patient anxiety of lidocaine infiltration into nasal packing after septoplasty: prospective, controlled study. AB - OBJECTIVE: This prospective, controlled study investigated the effect on patient anxiety of lidocaine infiltration into nasal packing following septoplasty. METHODS: The study included 50 patients who underwent septoplasty operation. Patient anxiety levels were measured 24 hours pre-operatively; 48 hours post operatively, before saline or lidocaine infiltration; and 15 minutes after lidocaine or saline infiltration into the packing. The patients were asked to mark their level of pain during pack removal on a visual analogue scale. RESULTS: Hamilton Anxiety Scale scores for lidocaine infiltration patients were: 15.1 +/- 7.4 pre-operatively; 16 +/-7.6 post-operatively, before infiltration; and 13.7 +/ 6.6 at 15 minutes after infiltration. The scores for saline infiltration patients were: 16.3 +/- 6.8 pre-operatively, 16.4 +/- 5.5 before infiltration and 16.1 +/- 6.1 after infiltration. The visual analogue scale pain score was 5.3 +/- 2.0 in the lidocaine study group and 7.5 +/- 1.8 in the control saline group. CONCLUSION: Infiltration of lidocaine into nasal packing significantly reduced patient pain. Patients developed mild to moderate anxiety before nasal packing removal. Use of techniques without nasal packing can be recommended after septoplasty to ease patient post-operative discomfort. PMID- 26118325 TI - Sepsis as a risk factor for neonatal morbidity in extremely preterm infants. AB - AIM: This study evaluated sepsis as a risk factor for neonatal morbidities and investigated the association between specific pathogens and neonatal morbidities. METHODS: This was a nationwide Swedish prospective cohort study, consisting of the 497 extremely premature children, who were born before 27 weeks of gestation between 2004 and 2007 and survived their first year of life. Neonatal sepsis was evaluated as a risk factor for neonatal morbidity using multiple logistic linear regression analyses. RESULTS: We found that 326 (66%) of the infants had at least one sepsis episode and coagulase-negative staphylococci was the most common pathogen. Definite sepsis, with an odds ratio (OR) of 1.6, was associated with severe bronchopulmonary dysplasia, but not clinical sepsis (OR 1.1). Definite sepsis was also associated with a prolonged hospital stay (OR 1.6). Sepsis was not significantly associated with a higher risk of retinopathy of prematurity or intraventricular haemorrhage. CONCLUSION: Extremely preterm infants face a great risk of acquiring neonatal sepsis, with coagulase-negative staphylococci being the most common pathogen in this population. Definite sepsis seemed to be a risk factor for severe bronchopulmonary dysplasia and prolonged hospital stay, but the associations were weaker than in previous studies. PMID- 26118326 TI - Structural determinants of dual contraceptive use among female sex workers in Gulu, northern Uganda. AB - OBJECTIVE: To describe the characteristics of female sex workers (FSWs) who do and do not use dual contraceptives (i.e. male condoms plus a non-barrier method) in Gulu, northern Uganda. METHODS: The present analysis was based on data gathered as part of a questionnaire-based, cross-sectional study conducted between May 2011 and January 2012. FSWs aged 14 years or older were recruited through peer-led or sex worker-led outreach and community-based services. Logistic regression was used to identify correlates of dual contraceptive use. RESULTS: Among the 400 FSWs who participated, 180 (45.0%) had ever used dual contraceptives. In the multivariate model, dual contraceptive use was positively associated with older age (adjusted odds ratio [AOR] 1.09, 95% confidence interval [CI] 1.04-1.15; P=0.001), prior unintended pregnancy (AOR 1.53, 95% CI 1.01-2.34; P=0.046), and HIV testing (AOR 5.22, 95% CI 1.75-15.57; P=0.003). Having to rush sexual negotiations owing to police presence was negatively associated with dual contraceptive use (AOR 0.65, 95% CI 0.42-1.00; P=0.050). CONCLUSION: Although a history of unintended pregnancy and accessing HIV testing might promote contraceptive use, criminalized work environments continue to pose barriers to uptake of sexual and reproductive health services among FSWs in post conflict northern Uganda. Integrated links between HIV and sexual health programs could support contraceptive uptake among FSWs. PMID- 26118327 TI - Retroperitoneal hemorrhage presenting as a vaginal hematoma after a spontaneous vaginal delivery. PMID- 26118328 TI - Misoprostol versus prostaglandin E2 gel for labor induction in premature rupture of membranes after 34 weeks of pregnancy. AB - BACKGROUND: Both misoprostol and prostaglandin E2 (PGE2) gel are used for labor induction in women with premature rupture of membranes (PROM). OBJECTIVES: To evaluate studies comparing the effects of misoprostol and PGE2 gel in labor induction. SEARCH STRATEGY: Databases including Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant papers. SELECTION CRITERIA: Randomized controlled trials comparing the use of misoprostol and PGE2 gel for labor induction in women with PROM were included. DATA COLLECTION AND ANALYSIS: For meta-analyses, the Mantel-Haenszel method was used for dichotomous data, and the inverse variance method was used for continuous data. MAIN RESULTS: Four randomized controlled studies (n=615) were included. There were no significant differences between the two groups in the induction-to delivery interval (mean difference -4.44 hours; 95% confidence interval [CI] 9.35 to 0.48), rate of cesarean delivery (odds ratio [OR] 0.90; 95% CI 0.44 1.85), and rate of neonatal intensive care unit admission (OR 0.89; 95% CI 0.57 1.38). Women receiving misoprostol had a significantly higher rate of tachysystole than did those receiving PGE2 gel (OR 4.84; 95% CI 2.46-9.54). CONCLUSIONS: Misoprostol is as efficacious and safe as PGE2 gel for labor induction in women with PROM. PMID- 26118329 TI - A systematic review of doctors' experiences and needs to support the care of women with female genital mutilation. AB - BACKGROUND: Female genital mutilation (FGM) involves partial or complete removal of the external female genitalia or other injury for non-therapeutic reasons. Little is known about the knowledge and skills of doctors who care for affected women and their practice in relation to FGM. OBJECTIVES: To examine the FGM experiences and educational needs of doctors. SEARCH STRATEGY: A structured search of five bibliographic databases was undertaken to identify peer-reviewed research literature published in English between 2004 and 2014 using the keywords "female genital mutilation," "medical," "doctors," "education," and "training." SELECTION CRITERIA: Observational, quasi-experimental, and non-experimental descriptive studies were suitable for inclusion. DATA COLLECTION AND ANALYSIS: A narrative synthesis of the study findings was undertaken and themes were identified. MAIN RESULTS: Ten papers were included in the review, three of which were from low-income countries. The analysis identified three themes: knowledge and attitudes, FGM-related medical practices, and education and training. CONCLUSIONS: There is a need for improved education and training to build knowledge and skills, and to change attitudes concerning the medicalization of FGM and reinfibulation. PMID- 26118330 TI - Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review. AB - Studies of the effects on pregnancy outcomes of in utero exposure to phthalates, contaminants that are widely present in the environment, have yielded conflicting results. In addition, the mode of assessment of exposure varies between studies. The aim of this review was therefore to establish a current state of knowledge of the phthalates and metabolites involved in unfavorable pregnancy outcomes. Extant data were analyzed to determine which biomarker is the best suited to assess the relation between in utero exposure to phthalates and pregnancy outcomes. This review of the literature was conducted using the database of PubMed. A search was made of studies investigating exposure to phthalates and the following birth outcomes: preterm birth (gestational age <37 weeks), change in gestational age, change in body size at birth (birth weight, length, head circumference), anti androgenic function, decreased anogenital distance, cryptorchidism, hypospadias and congenital malformation. The methodological approach adopted in each study was examined, in particular the methods used for exposure assessment (biomarkers and/or questionnaire). Thirty-five studies were included. Premature birth and decreased anogenital distance were the most commonly reported outcomes resulting from a moderate level of exposure to phthalates. The principal metabolites detected and involved were primary metabolites of di-2(ethylhexyl)-phthalate (DEHP) and di-n-butyl-phthalate (DnBP). No clear conclusion could be drawn with regard to gestational age at birth, body size at birth and congenital malformations. In epidemiological studies, maternal urine is the most suitable matrix to assess the association between in utero exposure to phthalates and pregnancy outcomes: in contrast to other matrices (cord blood, amniotic fluid, meconium and milk), sampling is easy, non-invasive and, can be repeated to assess exposure throughout pregnancy. Oxidative metabolites are the most relevant biomarkers since they are not prone to external contamination. Further epidemiological studies are required during pregnancy to i) determine the role of phthalates other than DEHP [currently replaced by various substitution products, in particular diisononyl-phthalate (DiNP)]; ii) establish the effect of phthalates on other outcomes (body size adjusted for gestational age, and congenital malformations); iii) determine the pathophysiological pathways; and iv) identify the most suitable time for biomarker determination of in utero exposure to phthalates. PMID- 26118331 TI - Oncological control associated with surgical resection of isolated retroperitoneal lymph node recurrence of renal cell carcinoma. AB - OBJECTIVE: To evaluate the outcome of patients after surgical resection of isolated retroperitoneal lymph node (RPLN) recurrence of renal cell carcinoma (RCC) using a multicentre international cohort. PATIENTS AND METHODS: In all, 50 patients were identified who underwent resection of isolated RPLN recurrence of RCC at four institutions after nephrectomy for pTany Nany M0 disease. Progression free (PFS) and cancer-specific survival (CSS) were estimated using the Kaplan Meier method. Cox proportional hazards regression models were used to assess the association of clinicopathological characteristics with disease progression. RESULTS: The median (interquartile range, IQR) age at resection was 57.0 (50.0 62.5) years. The median (IQR) time to RPLN recurrence after nephrectomy was 12.6 (6.9-39.5) months, with no significant difference in median time to RPLN recurrence between patients with N+ disease at nephrectomy (10.7 [6.5-24.6] months) and those with Nx/pN0 disease at nephrectomy (13.7 [8.7-44.2] months) (P = 0.66). The median (IQR) size of the RPLN recurrence before resection was 2.6 (1.9-5) cm. The most common site for RPLN recurrence was within the interaortocaval region (34%). The median (IQR) follow-up after RPLN resection for patients alive at last follow-up was 28.0 (13.7-51.2) months. During follow-up, 26 patients developed RCC recurrence, at a median (IQR) of 9.9 (4.0-18.5) months after RPLN resection. Of those who developed a secondary recurrence, disease was again isolated to the retroperitoneum in seven patients. In all, 11 patients subsequently died, including 10 who died from disease. The median PFS after RPLN resection was 19.5 months, with a 3- and 5-year PFS of 40.5% and 35.4%, respectively. We also found that RPLN recurrence at <=12 months after nephrectomy was associated with a significantly inferior median PFS (12.3 months) compared with RPLN recurrence at >12 months after nephrectomy (47.6 months; P = 0.003). Moreover, on multivariate analysis, a shorter time to recurrence remained associated with a significantly increased risk for subsequent disease progression (hazard ratio 3.51; P = 0.005). CONCLUSION: Surgical resection of isolated RPLN recurrence from RCC may result in durable cancer control in appropriately selected patients. Recurrence at <=12 months after nephrectomy was associated with a significantly increased risk of progression after resection, underscoring the importance of this variable for risk stratification. Thus, we recommend that, in the setting of isolated RPLN recurrence of RCC (in patients without precluding comorbidities), careful consideration with the patients and medical oncology colleagues be undertaken about the relative and individualised benefits of surgical resection, systemic therapy, and surveillance. PMID- 26118332 TI - The stigma of mental illness in Arab families: a concept analysis. AB - ACCESSIBLE SUMMARY: The stigma of mental illness varies significantly from culture to culture and from person to person. To date, little is known about how mental illness stigma manifests within the Arab community. This study aimed at bringing clarity to the concept of 'mental illness stigma' as it applies to Arab families. Nursing's holistic and patient-centered approach is integral to helping Arab patients and their families appropriately incorporate individual values, beliefs, and cultural perspectives into treatment plans. This study establishes a scientific alert for professionals at all levels to avoid making false generalizations about a specific culture that are not based on specific research findings from that culture. ABSTRACT: Accessing mental health services is a critical step towards reducing the burden of mental illness. The stigma of mental illness is one of the most common reasons for not seeking mental health care leading to negative health consequences and undue suffering for many individuals and their families. Stigma is embedded in its social context. What may be considered acceptable in one society may be considered unacceptable and open to stigmatization in other societies. Arabs have a shared set of values, beliefs, and traditions that are substantially different from those of Westerners. Further, in most Arab countries, formal mental health resources are scarce and people with mental illness experience the compounded disadvantages of poverty and illness stigma. To date, little is known about how mental illness stigma manifests within the Arab community making it difficult to design and test interventions that support Arab individuals with mental illness and their families in treatment seeking and adherence. Using Rodger's concept analysis method, we examined how 'mental illness stigma' operates within an Arab context as a first step towards elucidating culturally competent approaches to treatment. This analysis provides a foundation for future work in the areas of mental illness diagnosis, education, and treatment that reflect the unique characteristics of Arab culture. PMID- 26118333 TI - Exploring the safety of chemotherapy for treating breast cancer during pregnancy. AB - INTRODUCTION: The diagnosis of breast cancer during pregnancy (BCP) represents a unique challenge to the patient, her family and the treating physician. The proper management of this critical clinical situation is crucial, and requires a multidisciplinary approach. A proper understanding of the safety of chemotherapy during pregnancy is a vital step to avoid detrimental consequences on the mother and the fetus. AREAS COVERED: The aim of this article is to review the available evidence on the safety of chemotherapy administration in managing BCP. EXPERT OPINION: The rule of thumb of chemotherapy - avoiding first trimester exposure and starting therapy in the second trimester - can be considered applicable for classic agents that are used in managing pregnant breast cancer patients. Anthracycline-based regimens are considered the standard of care in managing BCP. Recently, a growing amount of data suggests the safety of taxanes during pregnancy. Pregnancy in cancer patients should be considered as "high risk": once the systemic treatment is initiated, regular fetal monitoring is highly recommended. Emerging data are available on the relative long-term safety secondary to anthracycline exposure during pregnancy. A continued monitoring of the health of individuals with prenatal exposure to chemotherapy into adulthood is recommended for the possible occurrence of long-term side effects. PMID- 26118334 TI - Actin stabilization induces apoptosis in cultured porcine epithelial cell rests of Malassez. AB - AIM: To test whether actin stabilization by jasplakinolide induces inhibition of cell viability and apoptosis in epithelial cell rests of Malassez (ERM). METHODOLOGY: ERM derived from porcine were spread in a 96-well dish (5 * 10(4) /well) using Dulbecco's modified Eagle's medium. The actin-specific stabilization reagent, jasplakinolide, was incorporated into the culture medium and incubated for 24 h. To evaluate cell viability, the WST-1 assay was carried out and absorption (450 nm) was measured. To detect apoptotic cells, monoclonal antibody to single-strand DNA (ssDNA) was used and absorption (405 nm) was measured. Actin stabilization and apoptosis induced by jasplakinolide were morphologically investigated by staining with Alexa Fluor 568 phalloidin and observed under a fluorescent microscope. As a negative control, DMSO was used instead of jasplakinolide. Differences between the jasplakinolide-treated group and the control group were analysed statistically using the Student's t-test. RESULTS: Cell viability decreased in a concentration-dependent manner, and cell viability in the jasplakinolide-treated ERM was lower than that in nontreated ERM (n = 16, P < 0.01). Apoptotic cells in the jasplakinolide-treated ERM were more frequently detected compared to that in nontreated ERM (n = 16, P < 0.01). Morphologically, shrinkage, irregular forms and fragmentation of nuclei suggesting apoptotic bodies were observed in jasplakinolide-treated ERM, whilst actin filaments were extended in non-treated ERM. CONCLUSION: Actin stabilization by jasplakinolide inhibited cell viability and induced apoptosis in epithelial cell rests of Malassez. PMID- 26118335 TI - Burden of disease of reoperations in instrumental spinal surgeries in Germany. AB - PURPOSE: To estimate the incidence of instrumental spinal surgeries (ISS) and consecutive reoperations and to calculate the related resource utilization and costs. METHODS: ISS and subsequent reoperations were identified retrospectively using surgery codes in claims data. The study period included January 01, 2009 to December 31, 2011. The reoperation rate was calculated for 1 year after the primary ISS. Resource utilization and costs were analyzed by group comparison. RESULTS: A total of 3316 incident ISS patients were identified in 2010 with an annual reoperation rate of 9.98% (95% CI 8.98-11.02%). Mean costs per patient were ?11,331 per ISS and ?11,370 per reoperation, with ?8432 directly attributed to the reoperation and ?2938 to additional resources. CONCLUSIONS: Costs of ISS and subsequent reoperations have a significant impact on health insurances budgets. The annual cost of reoperations exceeds the direct cost of the primary surgery driven by the need for further inpatient and outpatient care. PMID- 26118336 TI - Vertebral coplanar alignment technique: a surgical option for correction of adult thoracic idiopathic scoliosis. AB - PURPOSE: Previous studies have demonstrated vertebral coplanar alignment (VCA) as an effective surgical option for adolescent idiopathic scoliosis (AIS). The purpose of this study is to analyze the outcome of VCA for the surgical correction of adult idiopathic scoliosis (AdIS). METHODS: 35 AdIS patients (mean age: 24.2 years) undergoing VCA-instrumentation were reviewed. The main thoracic curve and thoracic kyphosis (TK, T5-T12) were evaluated preoperatively, immediate postoperatively, and at the final follow-up (>1 year). All patients were stratified by the TK modifier before surgery: "+" (TK, >40 degrees ), "-" (TK, <10 degrees ), and "N" (TK, 10 degrees -40 degrees ) for normal. The apical vertebral body-to-rib ratio (AVB-R), rib hump (RH), and rotational angle to sacrum (RAsac) were measured to assess the correction of rotational deformity. Quality of life was evaluated with SRS-20 questionnaires. RESULTS: The main thoracic curve (59.1 degrees vs. 19.3 degrees , P < 0.001) and rotational deformity (AVB-R: 2.4 vs. 1.7 %, P < 0.001, RH: 34.9 vs. 19.1 mm, P < 0.001, RAsac: 19.6 degrees vs. 11.9 degrees , P < 0.001) were significantly reduced with surgery. Sagittal deformity improved significantly in group "+" (51.4 degrees vs. 31.6 degrees , P < 0.001) and group "-" (6.2 degrees vs. 20.1 degrees , P < 0.001), while no significant postoperative change in TK was observed in group "N" (23.5 degrees vs. 26.3 degrees , P = 0.270). Patients were followed for an average of 18.7 months with no significant loss of correction. SRS scores improved greatly from 57.7 preoperatively to 71.6 at the final follow up. CONCLUSIONS: VCA can be effectively used for the correction of the coronal and rotational deformity, with better sagittal profile restoration in adult thoracic idiopathic scoliosis with sagittal malalignment. PMID- 26118338 TI - Synthesis of C-5, C-2' and C-4'-neomycin-conjugated triplex forming oligonucleotides and their affinity to DNA-duplexes. AB - Neomycin-conjugated homopyrimidine oligo 2'-deoxyribonucleotides have been synthesized on a solid phase and their potential as triplex forming oligonucleotides (TFOs) with DNA-duplexes has been studied. For the synthesis of the conjugates, C-5, C-2' and C-4'-tethered alkyne-modified nucleoside derivatives were used as an integral part of the standard automated oligonucleotide chain elongation. An azide-derived neomycin was then conjugated to the incorporated terminal alkynes by Cu(I)-catalyzed 1,3-dipolar cycloaddition (the click chemistry). Concentrated ammonia released the desired conjugates in acceptable purity and yields. The site of conjugation was expectedly important for the Hoogsteen-face recognition: C-5-conjugation showed a notable positive effect, whereas the influence of the C-2' and C-4'-modification remained marginal. In addition to conventional characterization methods (UV- and CD spectroscopy), (19)F NMR spectroscopy was applied for the monitoring of triplex/duplex/single strand-conversions. PMID- 26118337 TI - How to find the optimal partner--studies of snurportin 1 interactions with U snRNA 5' TMG-cap analogues containing modified 2-amino group of 7 methylguanosine. AB - Snurportin 1 is an adaptor protein that mediates the active nuclear import of uridine-rich small nuclear RNAs (U snRNA) by the importin-beta receptor pathway. Its cellular activity influences the overall transport yield of small ribonucleoprotein complexes containing N(2),N(2),7-trimethylguanosine (TMG) capped U snRNA. So far little is still known about structural requirements related to molecular recognition of the trimethylguanosine moiety by snurportin in solution. Since these interactions are of a great biomedical importance, we synthesized a series of new 7-methylguanosine cap analogues with extended substituents at the exocyclic 2-amino group to gain a deeper insight into how the TMG-cap is adapted into the snurportin cap-binding pocket. Prepared chemical tools were applied in binding assays using emission spectroscopy. Surprisingly, our results revealed strict selectivity of snurportin towards the TMG-cap structure that relied mainly on its structural stiffness and compactness. PMID- 26118339 TI - Synthesis and anti-Trypanosoma cruzi activity of new 3-phenylthio-nor-beta lapachone derivatives. AB - We report herein a straightforward and efficient one-step reaction to prepare new nor-beta-lapachone derivatives tethered with phenylthio groups at position 3 of the furan ring. We have screened the compounds on bloodstream trypomastigotes of Trypanosoma cruzi, the causative agent of Chagas disease, aimed at finding a new prototype with high trypanocidal activity. The new compounds possess a broad range of activity (IC50/24h from 9.2 to 182.7 MUM), higher than the original quinone (391.5 MUM) and four of them higher than standard drug benznidazole (103.6 MUM). The most active was compound 13b (9.2 MUM), being 11 times active than benznidazole and the less toxic derivative to heart muscle cells. PMID- 26118340 TI - Determinants of Obesity in the Hispanic Preschool Population: An Integrative Review. AB - OBJECTIVE(S): The purpose of this integrative review was to identify factors associated with obesity in Hispanic preschool children. DESIGN AND SAMPLE: Integrative research review based on strategies described by Whittemore and Knafl. Thirty-five research reports using qualitative and/or quantitative methods and including a majority of participants (parents or preschool-aged children) of Hispanic ethnicity. MEASURES: Data were analyzed using the Matrix Method. RESULTS: Decreased physical activity of the child and increased maternal body mass index were found as contributors to obesity in the preschool, Hispanic population. The relationship between maternal feeding practices and beliefs, food choices and childhood obesity are widely studied with little consistency in findings across studies. CONCLUSIONS: Public health nurses can work with communities to promote physical activity and safe outdoor places for exercise. In addition, they can advocate for the availability of healthy food choices in neighborhood schools. Maternal feeding practices, acculturation, and the child's environment require further research. PMID- 26118341 TI - Small extracellular vesicles as tumor biomarkers for glioblastoma. AB - Small extracellular organelles such as exosomes and microvesicles are currently being studied as a novel way to track tumor progression, pseudoprogression, and treatment monitoring. Their role in intercellular communication shows potential in the treatment of even the most formidable cancers. Glioblastoma (GBM) is the most common malignancy of the brain and has no known cure. A large emphasis has been placed on trying to improve the prognosis of this aggressive primary brain tumor. It has recently been discovered that small extracellular vesicles, mainly exosomes and microvesicles, play a role in the cell signaling process that leads to uncontrollable cell growth indicative of a tumor state. Here we describe the role of exosomes and microvesicles as a tumor biomarker for tracking the progression of different types of cancer, with an emphasis on GBM. PMID- 26118342 TI - Editorial overview: Physiology and metabolism: Plant metabolism: globules to global, modules to models. PMID- 26118343 TI - Advantage of Pulsatility in Left Ventricular Reverse Remodeling and Aortic Insufficiency Prevention During Left Ventricular Assist Device Treatment. AB - BACKGROUND: A continuous flow (CF) left ventricular assist device (LVAD) has various advantages over a pulsatile flow (PF) LVAD, but the extent of preventing aortic insufficiency (AI) by each type of LVAD remains controversial. METHODS AND RESULTS: Of 86 patients with non-ischemic cardiomyopathy who underwent LVAD implantation between 2006 and 2015, 20 propensity score-matched patients with PF LVADs and 20 with CF LVADs were enrolled in this study. There were no significant differences in the baseline variables of both groups. During the 6-month LVAD treatment, the LV ejection fraction of the PF group was significantly higher than that of the CF group; the PF group also had a wider pulse pressure and less enlargement of the aortic root (P<0.05 for all). Patients in the PF group experienced more frequent opening of the native aortic valve and less AI than those in the CF group (P<0.05 for both). The PF LVAD was explanted in 5 patients (25%), and a CF LVAD was explanted in 1 patient (5%). CONCLUSIONS: Compared with CF LVADs, PF LVADs seem to have an advantage in improving LV reverse remodeling and preventing AI. It may be best to incorporate pulsatility into current CF LVADs while retaining their existing benefits. PMID- 26118344 TI - Clinical Characteristics of Patients With Acute Myocardial Infarction Who Did Not Undergo Primary Percutaneous Coronary Intervention- Report From the MIYAGI-AMI Registry Study. AB - BACKGROUND: In the current era of primary percutaneous coronary intervention (PCI), some patients with acute myocardial infarction (AMI) still do not undergo primary PCI. METHODS AND RESULTS: To examine the clinical characteristics of AMI patients who did not undergo primary PCI, we analyzed patients enrolled between 2002 and 2010 in the MIYAGI-AMI Registry Study, in which all AMI patients in the Miyagi prefecture have been prospectively registered. Among a total of 8,640 patients, 1,879 (21.7%) did not undergo primary PCI and their in-hospital mortality was significantly worse compared with those who did (21.4% vs. 6.4%, P<0.01). Multivariate analysis demonstrated that female sex was significantly associated with non-performance of primary PCI [odds ratio (95% confidence interval): 1.40 (1.22-1.61), P<0.001], along with age [1.01 (1.01-1.02), P<0.001] and heart failure on admission [2.69 (2.29-3.16), P<0.001]. When dividing by age, the non-performance rate of primary PCI in females showed a U-shaped prevalence, whereas it simply increased with aging in males. Importantly, female patients aged <80 years had a significantly higher non-performance rate of primary PCI compared with male patients, regardless of the severity of AMI. CONCLUSIONS: These results indicate that in the current PCI era, various factors, including aging, heart failure on admission and sex differences, are associated with non performance of primary PCI, which remain to be resolved in order to further improve critical care of AMI. PMID- 26118345 TI - The emerging role of adiponectin in cerebrovascular and neurodegenerative diseases. AB - Adiponectin is an anti-atherogenic protein secreted by adipose cells that improves insulin sensitivity. Notably, adiponectin receptors are expressed in the brain, suggesting that adiponectin signaling disruption may impact neurologic function. Recently, studies have demonstrated the association of adiponectin levels with cerebrovascular disorders and neurodegenerative diseases (NDDs), and these results have drawn significant attention. In this review, we discuss the association between the adiponectin levels and the incidence, progression, and prognosis of cerebrovascular disorders and NDDs. We describe the controversial issues surrounding current studies and present our hypothesis concerning the possible mechanism underlying adiponectin function in neurological disorders. Finally, we explicate obstacles preventing clinical adiponectin administration, including available routes of drug delivery and the central nervous system regulation of adiponectin. Collectively, the data assembled herein serve as a comprehensive reference regarding the role of adiponectin in neurological disorders to support the future clinical potential of adiponectin as a therapeutic agent. PMID- 26118346 TI - Analysis of the Papal Benediction Sign: The ulnar neuropathy of St. Peter. AB - The origin of the Papal Benediction Sign has been a source of controversy for many generations of medical students. The question has been whether the Papal Benediction Sign posture is the result of an injury to the median nerve or to the ulnar nerve. The increasingly popular use of online "chat rooms" and the vast quantities of information available on the internet has led to an increasing level of confusion. Looking in major anatomy texts, anatomy and board review books as well as numerous internet sites the answer remains unresolved. Through the analysis of functional anatomy of the hand, cultural and religious practices of the early centuries of the Common Era and church art a clear answer emerges. It will become apparent that this hand posture results from an ulnar neuropathy. PMID- 26118347 TI - The Proliferation of Dosage Thresholds in Opioid Prescribing Policies and Their Potential to Increase Pain and Opioid-Related Mortality. PMID- 26118348 TI - Modification of a PAMPA model to predict passive gastrointestinal absorption and plasma protein binding. AB - The Parallel Artificial Membrane Permeability Assay (PAMPA) is a well-known high throughput screening (HTS) technique for predicting in vivo passive absorption. In this technique, two compartments are separated by an artificial membrane that mimics passive permeability through biological membranes such as the dermal layer, the gastrointestinal tract (GIT), and the blood brain barrier (BBB). In the present study, a hexadecane artificial membrane (HDM)-PAMPA was used to predict the binding of compounds towards the human plasma using a mixture of human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP). The ratio of HSA and AGP was equivalent to that found in the human plasma for both proteins (~20:1). A pH gradient (5.0-7.4) was performed to increase the screening capacity and overcome the issue of passive permeability for acidic and amphoteric compounds. With this assay, the prediction of passive GIT absorption was maintained and the compounds were discriminated according to their permeability (on a no-to-high scale). The plasma protein binding (PPB) was estimated via the correlation of the differences between the amount of compound crossing the artificial membrane in assays conducted with and without protein using only a two end-point measurement. The use of a mixture of HSA and AGP to modulate drug permeation was compared to the use of the same concentrations of HSA and AGP used separately. The addition of HSA alone in the acceptor compartment was sufficient for estimating PPB, while it was demonstrated that AGP alone could enable the estimation of AGP binding. PMID- 26118349 TI - A case study exploring employment factors affecting general practice nurse role development. AB - AIM: The aim of this study was to explore the factors affecting role development in practice nursing in the United Kingdom. BACKGROUND: General practice is currently central to National Health Service reform, producing favourable conditions for the practice nurse role to be further strengthened and developed. However, the literature has continued to describe evidence that practice nurses are a disempowered, isolated group with many constraints reducing their ability to respond to opportunities to develop their role. The rationale for conducting the study was therefore to provide a greater understanding about the constraining factors and their influence on practice nurses wishing to develop their role. METHOD: The method used to conduct the research followed a case approach, as the subject being investigated was complex with multiple inter-related factors and the approach was exploratory. The cases comprised six UK general practices and the participants within each case were a practice nurse, a GP and a practice manager. FINDINGS: A combination of factors was found to contribute to the way the practice nurse role evolves. These are education, practice culture, practice nurse personal characteristics and empowerment. Empowerment holds the key to maximising the conditions favourable to practice nurse role evolution. This is not, however, a 'single' factor; it represents the combined synergistic effects of practice culture and practice nurse personal characteristics on creating an empowering environment. The inter-relationship between these was captured in a framework and given the title 'empowering employment principles'. CONCLUSION: The 'empowering employment principles' illustrate the features most conducive to role evolution, thus providing a tool for practice nurses and their employers to enhance opportunities for nurses to develop their role. PMID- 26118350 TI - Quality of life in old age - a concept analysis. AB - AIM: To identify existing definitions of quality of life in old age and to determine the most suitable for evaluating outcomes of nursing care for older adults. BACKGROUND: Promoting quality of life is a central concern of nursing care for older persons. There is, however, a lack of clarity about the meaning of this concept. Attributes of quality of life are often confused with those factors influencing them. DESIGN: Concept analysis according to Walker and Avant. METHOD: A search was carried out in the databases MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO((r)) and Gerolit for the years 1992-2013. Excerpts dealing with definitions, antecedents, consequences and empirical referents of the concept were compiled. RESULTS: Three basic concepts for quality of life were identified: satisfying life conditions, subjective general well being and subjective fulfilment of dimensions of human life. DISCUSSION: Satisfying life conditions are antecedent to the other concepts. It is not suitable to view such conditions as an outcome of nursing care for older adults because an outcome has to be a consequence. General well-being is likely to remain stable over time and changing conditions due to adaptation taking place. Fulfilment of dimensions of human life as a multidimensional inner state may be more sensitive to changing conditions. CONCLUSION: Fulfilment of dimensions of human life is the most suitable definition of quality of life in old age as an outcome of nursing care. Studies are needed to decide whether it is responsive to changing circumstances. IMPLICATIONS FOR PRACTICE: Fulfilment of dimensions of human life should be assessed to provide care that meets the needs of clients. PMID- 26118351 TI - Poor utility of the atopy patch test in infants with fresh rectal bleeding. PMID- 26118352 TI - Patients perception of self-administrated medication in the treatment of hereditary angioedema. AB - BACKGROUND: Early therapy of hereditary angioedema (HAE) decreases morbidity, improves outcomes, decreases absenteeism, and possibly decreases mortality. This can be accomplished best with self-therapy. Previously, the authors examined barriers to self-therapy from the perspective of the nurse and the physician, but data are lacking on what patients perceive as major barriers to self-administered therapy for HAE. OBJECTIVE: To identify those barriers in a prospective fashion by patient interview. METHODS: After approval from the institutional review board, a telephone survey was performed of patients with HAE from a database of patients who were recently seen in the clinic. The survey focused on anxiety, depression, stress, concerns regarding method of administration, the ability to inject themselves, and what they perceived as barriers to providing self-care. RESULTS: Ninety-two patients were contacted and 59 agreed to participate. With 69% of those patients currently undergoing self-administered treatment, the results showed minimal depression and anxiety, a high satisfaction with treatment, and significant compliance with treatment. Most of those not yet on self-administered therapy wanted to start despite being satisfied with the care received in the emergency department. They also believed care at home would be optimal. The main concern of the 2 groups was not being able to treat themselves in the event of an HAE attack. CONCLUSION: From these data, it is obvious that most patients are willing to self-treat. This suggests that physicians should encourage self-treatment of HAE to improve outcomes and quality of life of patients with HAE. PMID- 26118353 TI - Incidence of childhood abuse among women with psychiatric disorders compared with healthy women: Data from a tertiary care centre in India. AB - Childhood abuse has been recognized as a precursor and a maintaining factor for adult psychopathology. There are very few studies that have investigated the incidence of childhood abuse in adult women with psychiatric disorders. Hence, this current investigation is an attempt to study and compare the incidence of childhood abuse (physical, emotional and sexual) among women seeking treatment for psychiatric disorders to healthy women. Using consecutive sampling, women seeking treatment for psychiatric disorders (N=609) and a group of age-education matched healthy women (N=100) were recruited for the study from a tertiary mental health-care hospital in India. The participants were screened for childhood abuse using the ISPCAN Child Abuse Screening Tool - Retrospective (ICAST)-R (I-CAST R, International Society for the Prevention of Child Abuse and Neglect (ISPCAN) and The United Nations Children's Fund (UNICEF), 2009). Emotional abuse was significantly more common among women with psychiatric disorders compared with healthy women (p<0.05). On overall abuse, there was a trend to significance in women with psychiatric disorders compared with healthy women (p=0.07). There was no statistically significant difference between the two groups on physical and sexual abuse (all p>0.13). There was no statistically significant difference in all three types of abuse across disorder categories, though the report was more among women with severe mental disorders. Women with psychiatric disorders reported more emotional and overall abuse compared with healthy women. Sexual and physical abuse was similar in both groups. It is likely that more emotional abuse predisposes these women to psychiatric disorders. PMID- 26118354 TI - Perfusion SPECT, SISCOM and PET (18)F-FDG in the assessment of drug- refractory epilepsy patients candidates for epilepsy surgery. AB - AIMS: Brain perfusion SPECT (ictal-interictal), SPECT images and subtraction ictal SPECT coregistered to MRI (SISCOM) and (18)F-FDG-PET (interictal), play an important role in the pre-surgical diagnosis of patients with medically refractory epilepsy. This study aimed to establish: the reproducibility of visual ictal-interictal SPECT and SISCOM analysis altogether with the capacity of SPECT, SISCOM and PET to determine the epileptogenic zone. MATERIAL AND METHODS: (99m)Tc HMPAO SPECT ictal-interictal and SISCOM (Analyze 7.0) were performed on 47 refractory epilepsy patients (24 F, 19-60 yrs). In 13 patients, SISCOM was also performed using a new program (Focus DET). Ictal-interictal SPECT and SISCOM images were analysed independently by two nuclear medicine physicians (observer 1 and 2). Kappa concordance coefficient was used to evaluate the reproducibility. In sixteen patients, SPECT, SISCOM and PET findings were compared with the resected area during the surgery, and surgical outcome using Engel scale or with the stereo EEG-(SEEG). RESULTS: The ictal-interictal SPECT interobserver agreement was 91%, Kappa index 0.86, SISCOM (Analyze 7.0) interobserver agreement percentage was 82%, Kappa index 0.80, Analyze 7.0 showed a higher inconclusive results than visual SPECT analysis. SISCOM FocusDET interobserver agreement was 92%, Kappa index 0.87, with lower inconclusive results than Analyze 7.0. SPECT, SISCOM and PET combined findings identified 87% seizure onset zone: 79% temporal, 26% parieto-temporal and 7% frontal. CONCLUSIONS: Ictal-interictal SPECT and SISCOM showed a high reproducibility in this sample of patients with drug refractory epilepsy. SPECT,SISCOM and PET combined findings improved detection of epileptogenic zone in comparison with the individual assessment. PMID- 26118355 TI - Controlled Anisotropic Growth of Co-Fe-P from Co-Fe-O Nanoparticles. AB - A facile approach to bimetallic phosphides, Co-Fe-P, by a high-temperature (300 degrees C) reaction between Co-Fe-O nanoparticles and trioctylphosphine is presented. The growth of Co-Fe-P from the Co-Fe-O is anisotropic. As a result, Co Fe-P nanorods (from the polyhedral Co-Fe-O nanoparticles) and sea-urchin-like Co Fe-P (from the cubic Co-Fe-O nanoparticles) are synthesized with both the nanorod and the sea-urchin-arm dimensions controlled by Co/Fe ratios. The Co-Fe-P structure, especially the sea-urchin-like (Co(0.54)Fe(0.46))2P, shows enhanced catalysis for the oxygen evolution reaction in KOH with its catalytic efficiency surpassing the commercial Ir catalyst. Our synthesis is simple and may be readily extended to the preparation of other multimetallic phosphides for important catalysis and energy storage applications. PMID- 26118356 TI - The Spanish Validation of the Accommodation and Enabling Scale for Eating Disorders Among Carers: A Pilot Study. AB - Literature suggests that families may accommodate patients' symptoms in attempts to alleviate family conflict and stress. These accommodating and enabling behaviours may have a negative impact on carers and those they care for. There are no self-report questionnaires validated in Spanish to measure accommodation among relatives of patients with an eating disorder. The aim of this study was to examine the psychometric properties of the Spanish version of the Accommodation and Enabling Scale for Eating Disorders (AESED-S) among relatives of eating disorder patients. A cross-sectional study of 90 relatives was carried out to explore the factor structure, reliability and validity of the AESED-S. The internal consistency of the Spanish version of the AESED subscales was good, ranging from .89 to .81. The correlation of the five subscales with conceptually related measures (negative caregiving experience and distress) supports the convergent validity of this instrument in this sample. Results indicated that the Spanish version of the AESED provides a reliable and valid tool for assessing family accommodation in the context of having a relative with an eating disorder. PMID- 26118357 TI - Facial angiofibromas of tuberous sclerosis treated with topical sirolimus in an Indian patient (commentary on article by Resham J. Vasani). PMID- 26118358 TI - Efficient coupling of acoustic modes in microfluidic channel devices. AB - This work introduces a new numerical simulation approach to acoustic microfluidic chip design based on coupled-resonator theory. A simplified acoustofluidic device operating in the transverse elastic mode is investigated and optimized for maximal pressure standing wave amplitude. This design approach provides insights into the symmetry and frequency characteristics of acoustic chip resonances that cannot be obtained from analysis based on wave propagation arguments. The new approach reveals that optimal performance requires spatial symmetry-matching and frequency-matching of the full device's elastic resonance to the channel's acoustic resonance. Symmetry selection is demonstrated for a three terminal piezoelectric transducer actuation scheme showing suppression of opposite symmetry and enhancement of same-symmetry acoustic modes. Excitation of ultrasonic waves exhibits the anti-crossing behaviour predicted by coupled mode theory with the acoustic mode splitting into two distinct branches. Increased efficiency of energy transfer from the transducer into the fluid, with its corresponding increase in pressure amplitude, suggests a potential path toward significant increases in acoustic separator performance. PMID- 26118359 TI - Context influences the interplay of endocrine axes across the day. AB - The current investigation examined stressors upon the coupling of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. Emphasis is placed on the moderating role of context and time. One hundred and eighteen adolescent males and females provided up to 32 diurnal saliva samples across a visit to a research lab. This visit constituted a day-long stress through which the impact on HPA-HPG axis coupling could be assessed. We tested four models of HPA-HPG axis coupling across the lab day. Sex and stress hormones operated synchronously (beta = .404, p < .001), and the coupling of sex and stress hormones was moderated by the stress of the lab day (beta = .010, p = .05). This pattern of co-elevation did not appear to be moderated by the distal experience of early life adversity. Findings suggest that the notion of "stress" must disentangle proximal and distal challenges, each of which appears to impact neurobiological processes. PMID- 26118360 TI - Examining the relation between respiratory sinus arrhythmia and depressive symptoms in emerging adults: A longitudinal study. AB - Major depressive disorder (MDD) is a debilitating and prevalent disorder associated with lower quality of life and substantial economic burden. Recently, there has been strong interest in respiratory sinus arrhythmia (RSA) as a biological predictor of later depression. Theoretical work suggests that higher resting RSA indexes physiological flexibility and better emotion regulation whereas lower RSA may mark vulnerability for psychopathology. However, empirical findings have varied. This study examined whether lower resting RSA predicted later depressive symptoms in a sample of healthy young adults across one year (n=185). Results indicate that year one (Y1) resting RSA predicted Y2 depressive symptoms. This finding remained significant when accounting for the stability of RSA and depressive symptoms across both time points and when including trait anxiety, body mass index, and medication use in statistical models. Findings provide further support for RSA as a promising biological marker for understanding and predicting depressive symptoms. PMID- 26118361 TI - Mild and Robust Redox-Neutral Pd/C-Catalyzed Lignol beta-O-4' Bond Cleavage Through a Low-Energy-Barrier Pathway. AB - Invited for this month's cover is the group of Joseph Samec at Uppsala University. The image shows that native lignin beta-O-4' bond model compounds react at very mild and accurately tuned redox-neutral conditions while other models have higher hydrogen and temperature demands. The Communication itself is available at 10.1002/cssc.201500117. PMID- 26118362 TI - Metal-Mediated Production of Isocyanates, R3 EN=C=O from Dinitrogen, Carbon Dioxide, and R3 ECl. AB - A highly efficient and versatile chemical cycle has been developed for the production of isocyanates through the molecular fixation of N2 , CO2 and R3 ECl (E=C, Si, and Ge). Key steps include a 'one-pot' photolytic N-N bond cleavage of a Group 6 dinuclear dinitrogen complex with in situ trapping by R3 ECl to provide a metal terminal imido complex that can engage in simultaneous nitrene-group transfer and oxygen-atom transfer to generate an intermediate metal terminal oxo complex with release of the isocyanate product. Reaction of the oxo complex with additional equivalents of R3 ECl regenerates a metal dichloride that is the precursor for dinuclear dinitrogen starting material. PMID- 26118363 TI - Influence of the molecular-oriented structure of ionic liquids on the crystallinity of aluminum hydroxide prepared by a sol-gel process in ionic liquids. AB - The influence of the structure of ionic liquids on the crystallinity of aluminum hydroxide (Al(OH)3) prepared by a sol-gel process with aluminum isopropoxide (Al(OPr(i))3) in imidazolium-based ionic liquids was investigated. When Al(OH)3 was prepared in ionic liquids having long alkyl chains, such as 1-butyl-3 methylimidazolium salts and 1-methyl-3-octylimidazolium salts, highly crystalline products were obtained. In contrast, Al(OH)3 obtained using the 1-ethyl-3 methylimidazolium salt was an amorphous material, indicating that hydrophobic interaction of the alkyl tail of the imidazolium cation of the ionic liquid strongly affects the crystallinity of sol-gel products and the local structure of the ionic liquid. Moreover, the crystallinity of Al(OH)3 prepared in ionic liquids increased relative to the amount of additional water (ionic liquid/water = 1.28/2.0-3.5/0.2, w/w). In the case of addition of a small amount of water (ionic liquid/water = 3.5/0.2, w/w), the product was amorphous. These results implied that the presence of an ionic liquid and a sufficient amount of water was crucial for the successful synthesis of sol-gel products with high crystallinity. (1)H NMR analyses revealed a shift of the peak associated with the imidazolium cation upon addition of water, which suggested that the molecular orientation of the ionic liquid was similar to that of a micelle. PMID- 26118364 TI - Mechanistic Insights into the Post-Cyclization Isomerization in Gold-Catalyzed 7 exo-dig-Hydroarylations. AB - The subsequent double-bond isomerization in the synthesis of dibenzocycloheptenes and their heteroaromatic analogues was investigated. In the case of biphenyls, a basic additive completely prevented an isomerization to the thermodynamic product. With electron-rich intramolecular heteroaromatic nucleophiles, the isomerization was still observed, but the kinetic product can be obtained by careful control of the reaction times in most cases. Mechanistic studies demonstrated that a slow isomerization is also possible with the gold catalyst at elevated temperatures, but much faster isomerization rates were observed with acidic additives. An observed initiation period for the gold-catalyzed isomerization indicates that not the homogenous catalyst, but a decomposition product of it may be the catalytically active species. PMID- 26118365 TI - Heat-set gels formed from easily accessible gelators of a succinamic acid derivative (SAD) and a primary alkyl amine (R-NH2). AB - Currently, the design and construction of an intelligent stimuli-responsive gel system is still a significant challenge. We present here a new gel system from which the formation of heat-set gels, conventional gels and irreversible heat-set gels can be achieved in aromatic solvents. This gel system is based on two component gelators containing a succinamic acid derivative (SAD) and a primary alkyl amine (R-NH2). With the increase of temperature to 85 degrees C, a rarely reported reversible heat-set gel (gel formation with the increase of temperature) is afforded. Upon addition of fatty acids into two-component gelators, a conventional gel (gel formation with the decrease of temperature) is formed. When the fatty acid is replaced with dicarboxylic acid, a new heat-set gel is generated, which is irreversible and thermally super-stable. X-ray diffraction analysis reveals that the formation of a reversible heat-set gel relies on electrostatic interactions, hydrogen bonds, and hydrophobic interactions. These two-component gelators show a perfect gel system for the formation of diverse gels including heat-set gels, conventional gels and irreversible heat-set gels. The tunable strategy demonstrated in this letter may provide a new way for creation of more functional gels in gel science. PMID- 26118366 TI - Responsive etalon based on PNIPAM@SiO2 composite spacer with rapid response rate and excellent repeatability for sensing application. AB - In this paper, we demonstrate a responsive etalon fabricated through combining colloidal lithography and surface-initiated atom-transfer radical polymerization (SI-ATRP). The responsive etalon is simply constructed with one responsive spacer sandwiched by two reflective layers, and the middle responsive spacer is constructed by grafting thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) brushes on a SiO2 nanosphere array. The etalon possesses one single interference peak in the visible region, and the interference peak changes sensitively against the concentration of the external stimulant (water vapor) or the temperature of the system, owing to the responsiveness of the PNIPAM brush. Importantly, the as prepared etalon shows a rapid response rate and excellent stability, and it is also handy to realize the miniaturization and integration of the responsive etalon based on a conventional micro-fabrication method. These features all make the as-prepared responsive etalon an attractive candidate for future sensing applications. We believe such responsive etalons are promising for the fabrication of smart photonic materials and optical sensors that may be useful in tissue engineering, medical diagnosis, public security, and biochip areas. PMID- 26118367 TI - Elastic properties of van der Waals epitaxy grown bismuth telluride 2D nanosheets. AB - Bismuth telluride (Bi2Te3) two-dimensional (2D) nanosheets prepared by van der Waals epitaxy were successfully detached, transferred, and suspended for nano indentation measurements to be performed on freestanding circular nanosheets. The Young's modulus acquired by fitting linear elastic behaviors of 26 samples (thickness: 5-14 nm) is only 11.7-25.7 GPa, significantly smaller than the bulk in-plane Young's modulus (50-55 GPa). Compliant and robust Bi2Te3 2D nanosheets suggest the feasibility of the elastic strain engineering of topological surface states. PMID- 26118368 TI - Synthesis of Fluorophores that Target Small Molecules to the Endoplasmic Reticulum of Living Mammalian Cells. AB - The endoplasmic reticulum (ER) plays critical roles in the processing of secreted and transmembrane proteins. To deliver small molecules to this organelle, we synthesized fluorinated hydrophobic analogues of the fluorophore rhodol. These cell-permeable fluorophores are exceptionally bright, with quantum yields of around 0.8, and they were found to specifically accumulate in the ER of living HeLa cells, as imaged by confocal laser scanning microscopy. To target a biological pathway controlled by the ER, we linked a fluorinated hydrophobic rhodol to 5-nitrofuran-2-acrylaldehyde. In contrast to an untargeted nitrofuran warhead, delivery of this electrophilic nitrofuran to the ER by the rhodol resulted in cytotoxicity comparable to the ER-targeted cytotoxin eeyarestatin I, and specifically inhibited protein processing by the ubiquitin-proteasome system. Fluorinated hydrophobic rhodols are outstanding fluorophores that enable the delivery of small molecules for targeting ER-associated proteins and pathways. PMID- 26118369 TI - Two Cases of Pathological Complete Response to Neoadjuvant Chemoradiation Therapy in Pancreatic Cancer. AB - Neoadjuvant chemoradiation therapy (NACRT) is increasingly used in patients with a potentially or borderline resectable pancreatic ductal adenocarcinoma (PDA) and it has been shown to improve survival and reduce locoregional metastatic disease. It is rare for patients with PDA to have a pathological complete response (pCR) to NACRT, but such patients reportedly have a good prognosis. We report the clinicopathological findings of two cases of pCR to NACRT in PDA. Both patients underwent pancreatectomy after NACRT (5-fluorouracil, mitomycin C, cisplatin, and radiation). Neither had residual invasive carcinoma and both showed extensive fibrotic regions with several ducts regarded as having pancreatic intraepithelial neoplasia 3/carcinoma in situ in their post-therapy specimens. It is noteworthy that both patients had a history of a second primary cancer. They both had comparatively good outcomes: one lived for 9 years after the initial pancreatectomy and the other is still alive without recurrence after 2 years. PMID- 26118371 TI - Transformation of photophysical properties from solution to solid state in alkoxy cyano-diphenylacetylene molecules. AB - Detailed photophysical properties of cyano and mono (MA)/bis alkoxy (DA) substituted diphenylacetylene moieties with different alkyl chain lengths (methyl (1), octyl (8) and dodecyl (12)) were investigated in solution and the solid state in an effort to determine the effect of self-aggregation on these properties. The solvated molecules showed a minimal bathochromic shift with an increase of solvent polarity in their absorption spectra, whereas a significant shift was observed in the emission spectra. This could be attributed to the relatively low change in dipole moment between ground and Franck-Condon excited states and luminescence arising from the intramolecular charge transfer state with a dipole moment significantly higher than that of the ground state. In solid state the emission quantum yields of these materials were significantly higher than in solution. For DA1, polymorphic materials with distinct photophysical properties were obtained. The DA1 materials obtained by fast precipitation (DA1) showed broad fluorescence with peaks at 398, 467 and 535 nm upon excitation at different wavelengths. Detailed analysis of absorption, emission and excitation spectra and lifetime experiments indicated that these peaks could be attributed to the monomer, J- and H-type aggregates respectively. Whereas the crystals obtained by slow crystallization (DA1C) showed only one emission peak at around 396 nm attributed to the monomer. This is supported by the single crystal X-ray structure which consists of a monomer molecule having minimal interaction with nearest neighbour molecules. PMID- 26118373 TI - Tenax extraction as a simple approach to improve environmental risk assessments. AB - It is well documented that using exhaustive chemical extractions is not an effective means of assessing exposure of hydrophobic organic compounds in sediments and that bioavailability-based techniques are an improvement over traditional methods. One technique that has shown special promise as a method for assessing the bioavailability of hydrophobic organic compounds in sediment is the use of Tenax-extractable concentrations. A 6-h or 24-h single-point Tenax extractable concentration correlates to both bioaccumulation and toxicity. This method has demonstrated effectiveness for several hydrophobic organic compounds in various organisms under both field and laboratory conditions. In addition, a Tenax bioaccumulation model was developed for multiple compounds relating 24-h Tenax-extractable concentrations to oligochaete tissue concentrations exposed in both the laboratory and field. This model has demonstrated predictive capacity for additional compounds and species. Use of Tenax-extractable concentrations to estimate exposure is rapid, simple, straightforward, and relatively inexpensive, as well as accurate. Therefore, this method would be an invaluable tool if implemented in risk assessments. PMID- 26118374 TI - In response: Current evidence and implications--An academic perspective. PMID- 26118375 TI - The challenge: Pollinator risk assessment--Past, present, and future. PMID- 26118376 TI - In response: The challenge of implementing a sustainable and highly sophisticated risk-assessment scheme, able to address the realistic potential hazards as well as the needs of our pollinators--An industry view on the key challenges and guidance. PMID- 26118377 TI - In response: Challenges for future risk assessments--A governmental perspective. PMID- 26118378 TI - Letter to the Editor. PMID- 26118380 TI - Corrigendum. PMID- 26118379 TI - Letter to the Editor. PMID- 26118382 TI - The assessment of coronary heart disease risk factors correlated with demographic and social data in post-coronary intervention patients in Polish population. AB - BACKGROUND: Cardiovascular diseases are the main cause of death in Europe, accounting for over 4 million deaths each year. Smoking cigarettes, an unhealthy diet and no physical activity constitute important risk factors. Educational program was conducted among patients after coronary angioplasty. Data on patients' knowledge of risk factors of coronary heart disease, recommended behavior, secondary prevention methods, and side effects were collected and analyzed in conjunction with demographic and social factors. One questionnaire included details about 20 patients. The questionnaire included demographic data (gender, education, place of residence), epidemiological (height, weight, waist size), interview on coronary heart disease risk factors, medications and side effects. METHODS: The educational program involved 19,316 patients above 18 years old after percutaneous coronary intervention (PCI). The basic tool was a standardized questionnaire consisting of visit forms. RESULTS: Despite PCI, 20.5% of patients smoke cigarettes, more often men, younger, less educated. 35.7% of patients believe that limiting physical activity after successful coronary intervention is beneficial--more often older, lower educated, with higher body mass index, from smaller towns. 85% of patients (mainly women, younger, higher educated, coming from bigger cities) claim to be aware which products are beneficial for the cardiovascular system and which have a negative influence. 8% of patients after PCI do not control their blood pressure at all--more often men, younger people with lower level of education and coming from smaller towns. 44% of patients happened to forget to take or ran out of some medications--more often those with lower level of education. CONCLUSIONS: It is essential to implement to clinical practice educational programs for post-coronary intervention patients. These patients are at highest risk of having cardiovascular events. Educational programs should be addressed to all post-coronary intervention patients, especially to those coming from small towns. A limitation of the survey was that patients were not divided into acute coronary syndrome patients and stable coronary heart disease ones. It was not specified what time after the coronary intervention the patients were included into the research. PMID- 26118383 TI - Dimensional crossover in the quantum transport behaviour of the natural topological insulator Aleksite. AB - Three-dimensional topological insulators comprise topologically protected surface states displaying massless, Dirac-like linear dispersion with spin-momentum locking. Electrical conduction through such surface states has been documented to manifest itself in a two-dimensional character of the angle-dependent magnetotransport behavior. Here, we explore the size-dependent electronic properties of nanostructures made of the lead-containing mineral Aleksite, a naturally occurring topological insulator. Compared to its sister compound Kawazulite, a member of the well-studied Tetradymite crystal class, the crystal structure of Aleksite is distinguished by its lack of any counterpart within the group of synthetic topological insulators. Low temperature Hall measurements on thin Aleksite nanosheets reveal a significant carrier mobility on the order of 1000 cm(2)/(Vs), and a high carrier density of n = 3.9 * 10(25) m(-3). Importantly, for Aleksite nanoribbons with a width below 150 nm, a 1D weak antilocalization effect along with 1D universal conductance fluctuations emerges, which transforms into 2D behavior for larger ribbon widths. PMID- 26118384 TI - Religious Involvement and Perceptions of Control: Evidence from the Miami-Dade Health Survey. AB - This study uses data collected through the 2011 Miami-Dade Health Survey (n = 444) to test whether religious involvement is associated with three distinct control beliefs. Regression results suggest that people who exhibit high levels of religious involvement tend to report higher levels of the sense of control, self-control, and the health locus of control than respondents who exhibit low levels of religious involvement. Although this study suggests that religious involvement can promote perceptions of control over one's own life, this pattern is apparently concentrated at the high end of the distribution for religious involvement, indicating a threshold effect. PMID- 26118386 TI - Policy of high-dose tranexamic acid for treating postpartum hemorrhage after vaginal delivery. AB - OBJECTIVE: To assess whether a policy of routine administration of high-dose tranexamic acid (TA) at the diagnosis of postpartum hemorrhage (PPH) reduces blood loss after vaginal birth. METHODS: This controlled single-center before-and after study of all women with PPH >= 500 ml after vaginal birth took place from January 2011 through March 2012; the control group included those seen from January 2011 through August 2011, and the case patients those from September 2011 through March 2012. Our protocol for the management of PPH was modified effective September 2011 to include administration of high-dose TA (4 g of TA intravenously then 1 g/h for 6 h) once blood loss reached 800 ml. Our primary objective was to assess the efficacy of this policy in reducing blood loss in PPH. RESULTS: Maternal characteristics did not differ between the two groups. Mean estimated blood loss was not significantly lower in the TA group (n = 138) than in the control group (n = 151) (respectively, 915.7 +/- 321 ml versus 944.8 +/- 313.8 ml; p = 0.47). The difference between pre- and post-delivery hemoglobin levels were lower in the TA group (-2.6 g/dl +/- 1.2 versus -2.9 g/dl +/- 1.3; p = 0.09), but it was not significant. Postpartum iron sucrose injections were significantly less frequent in the TA than the control group (2.2% versus 9.9%; p < 0.05). CONCLUSIONS: A policy of high-dose TA in PPH after vaginal deliveries was not associated with a significant reduction of blood loss. PMID- 26118385 TI - Cortical actin networks induce spatio-temporal confinement of phospholipids in the plasma membrane--a minimally invasive investigation by STED-FCS. AB - Important discoveries in the last decades have changed our view of the plasma membrane organisation. Specifically, the cortical cytoskeleton has emerged as a key modulator of the lateral diffusion of membrane proteins. Cytoskeleton dependent compartmentalised lipid diffusion has been proposed, but this concept remains controversial because this phenomenon has thus far only been observed with artefact-prone probes in combination with a single technique: single particle tracking. In this paper, we report the first direct observation of compartmentalised phospholipid diffusion in the plasma membrane of living cells using a minimally invasive, fluorescent dye labelled lipid analogue. These observations were made using optical STED nanoscopy in combination with fluorescence correlation spectroscopy (STED-FCS), a technique which allows the study of membrane dynamics on a sub-millisecond time-scale and with a spatial resolution of down to 40 nm. Specifically, we find that compartmentalised phospholipid diffusion depends on the cortical actin cytoskeleton, and that this constrained diffusion is directly dependent on the F-actin branching nucleator Arp2/3. These findings provide solid evidence that the Arp2/3-dependent cortical actin cytoskeleton plays a pivotal role in the dynamic organisation of the plasma membrane, potentially regulating fundamental cellular processes. PMID- 26118387 TI - Homocysteine elicits an M1 phenotype in murine macrophages through an EMMPRIN mediated pathway. AB - INTRODUCTION: Hyperhomocysteinemia (HHcy) is associated with inflammatory diseases and is known to increase the production of reactive oxygen species (ROS), matrix metalloproteinase (MMP)-9, and inducible nitric oxide synthase, and to decrease endothelial nitric oxide production. However, the impact of HHcy on macrophage phenotype differentiation is not well-established. It has been documented that macrophages have 2 distinct phenotypes: the "classically activated/destructive" (M1), and the "alternatively activated/constructive" (M2) subtypes. We hypothesize that HHcy increases M1 macrophage differentiation through extracellular matrix metalloproteinase inducer (EMMPRIN), a known inducer of matrix metalloproteinases. METHODS: murine J774A.1 and Raw 264.7 macrophages were treated with 100 and 500 MUmol/L Hcy, respectively, for 24 h. Samples were analyzed using Western blotting and immunocytochemistry. RESULTS: Homocysteine treatment increased cluster of differentiation 40 (CD40; M1 marker) in J774A.1 and Raw 264.7 macrophages. MMP-9 was induced in both cell lines. EMMPRIN protein expression was also increased in both cell lines. Blocking EMMPRIN function by pre-treating cells with anti-EMMPRIN antibody, with or without Hcy, resulted in significantly lower expression of CD40 in both cell lines by comparison with the controls. A DCFDA assay demonstrated increased ROS production in both cell lines with Hcy treatment when compared with the controls. CONCLUSION: Our results suggest that HHcy results in an increase of the M1 macrophage phenotype. This effect seems to be at least partially mediated by EMMPRIN induction. PMID- 26118388 TI - How mirror-touch informs theories of synesthesia. AB - Ward and Banissy provide an excellent overview of the state of mirror-touch research in order to advance this field. They present a comparison of two prominent theoretical approaches for understanding mirror-touch phenomena. According to the threshold theory, the phenomena arise as a result of a hyperactive mirror neuron system. According to the Self-Other Theory, they are due to disturbances in the ability to distinguish the self from others. Here, we explore how these two theories can inform theories of synesthesia more generally. We conclude that both theories are not suited as general models of synesthesia. PMID- 26118389 TI - Reduction of phosphorus, nitrogen and microorganisms in pilot scale sand filter beds containing biotite, treating primary wastewater. AB - In sparsely populated areas, sand filter beds play an important role in wastewater treatment. As the need to improve the removal of nutrients increases, reactive filter materials represent one potential way to improve the reliability of current systems. We tested a pilot-scale multi-layer biotite filter for its ability to remove phosphorus, nitrogen, organic matter and enteric microorganisms with the importance of each layer in a multi-layer biotite filter being examined. In the experimental setup, the filters were fed with a raw wastewater influent mimicking the usual daily rhythm of water consumption and the reduction effects of the variable loads were examined during the experiment time of 54 weeks. It was observed that the reduction efficiency of the phosphorus was good (87%) during normal and under loading sequences but the reduction achieved for nitrogen was poor (27%). During and after overloading sequences, the phosphorus reduction was poor (46.5%) whereas the nitrogen reduction improved (to 66.7%). The reduction of organic matter was good during all sequences. The reductions of enteric microorganisms were at a level of 2-3 log10 units already after a single sand layer. For Escherichia coli, reductions of more than 5 log10 units were found after the wastewater had passed through a multilayer biotite filter during all sequences. It is concluded that the inclusion of a biotite layer improves the reliability of the filter bed. However, the proper scaling of the unit is essential in order to guarantee that the filter remains in aerobic conditions. PMID- 26118390 TI - Enterococcal endocarditis revisited. AB - The Enterococcus species is the third main cause of infective endocarditis (IE) worldwide, and it is gaining relevance, especially among healthcare-associated cases. Patients with enterococcal IE are older and have more comorbidities than other types of IE. Classical treatment options are limited due to the emergence of high-level aminoglycosides resistance (HLAR), vancomycin resistance and multidrug resistance in some cases. Besides, few new antimicrobial alternatives have shown real efficacy, despite some of them being recommended by major guidelines (including linezolid and daptomycin). Ampicillin plus ceftriaxone 2 g iv./12 h is a good option for Enterococcus faecalis IE caused by HLAR strains, but randomized clinical trials are essential to demonstrate its efficacy for non HLAR EFIE and to compare it with ampicillin plus short-course gentamicin. The main mechanisms of resistance and treatment options are also reviewed for other enterococcal species. PMID- 26118391 TI - Prehospital Transfer Pathway and Mortality in Patients Undergoing Primary Percutaneous Coronary Intervention. AB - BACKGROUND: It is recommended that not only door-to-balloon time but also prehospital delay for primary percutaneous coronary intervention (PCI) should be improved. We investigated the effect of prehospital transfer pathway on onset-to balloon time and prognosis in patients with ST-segment elevation myocardial infarction (STEMI) in Japan. METHODS AND RESULTS: We analyzed data from 540 consecutive patients with primary PCI for STEMI. Patient clinical data and mortality were compared between patients who visited the family physician or non PCI-capable hospitals and were then transferred to PCI-capable centers (indirect transfer patients), and those who directly visited PCI-capable centers (direct transfer patients). Onset-to-balloon time was longer in indirect transfer patients than in direct transfer patients (mean, 270 min; range, 180-480 min vs. 180 min, 120-240 min; P<0.001). In addition, patient prognosis was evaluated on Cox proportional regression analysis. Cardiac death and all-cause death were significantly higher in indirect transfer patients (odds ratios [OR], 2.17; 95% confidence intervals [95% CI]: 1.17-4.01, P=0.01; OR, 1.71; 95% CI: 1.09-2.68, P=0.02). These results were confirmed using propensity score matching for adjusted analyses. CONCLUSIONS: Patients with indirect transfer to regional emergency departments of PCI centers had longer onset-to-balloon time and worse prognosis than those with direct transfer. PMID- 26118392 TI - Treatment of severe non-infectious uveitis in high-risk conditions (Part 2): systemic infections; management and safety issues. AB - INTRODUCTION: Management of patients with severe immune-mediated uveitis requires the use of immunosuppressive (IS) drugs in selected cases. This may be particularly challenging in certain patients with associated conditions, which may increase the risk of side effects or modify guidelines for the use of such drugs. Chronic viral and mycobacterial infections in the setting of non infectious uveitis create a number of diagnostic but also therapeutic dilemmas to clinicians because they can be exacerbated by IS therapies with detrimental effects. AREAS COVERED: In this review, we will focus on very specific chronic infections that can be affected by IS therapies: human immunodeficiency virus infection, chronic hepatitis virus infection and tuberculosis. The main aim of this review is to provide an updated and comprehensive practical guide for practitioners regarding the therapeutic decision-making and management of patients with non-infectious uveitis affected by the aforementioned infectious conditions. EXPERT OPINION: Clinicians should be aware of the risk of viral and mycobacterial reactivation of an underlying infection during IS therapy. However, most of these conditions do not represent an absolute contraindication if one were able to apply an appropriate prior screening and close monitoring of such therapy. PMID- 26118393 TI - Wound dehiscence in a sample of 1 776 cystectomies: identification of predictors and implications for outcomes. AB - OBJECTIVE: To investigate the incidence and predictors of wound dehiscence in patients undergoing radical cystectomy (RC). PATIENTS AND METHODS: In all, 1 776 patient records with Current Procedural Terminology (CPT) codes for radical cystectomy (RC) were extracted from the American College of Surgeons National Quality Improvement Program (ACS-NSQIP) between 2005 and 2012. Stratification was made based on the occurrence of postoperative wound dehiscence, defined as loss of integrity of fascial closure. Descriptive and logistic regression models were used to identify predictors of postoperative wound dehiscence. The implications of wound dehiscence on peri- and postoperative outcomes such as complications, mortality, prolonged length of stay (>11 days), and prolonged operative time (>411 min), were assessed. RESULTS: Of 1 776 patients analysed, 57 (3.2%) had a documented wound dehiscence. In multivariable analyses, chronic obstructive pulmonary disease (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.0-4.0; P = 0.03) and high body mass index (OR 2.3, 95% CI 1.3-4.4; P = 0.008) were significant predictors of wound dehiscence. While female gender had significantly lower proportions of wound dehiscence, multivariable analyses did not confirm this (OR 0.4, 95% CI 0.4-1.4; P = 0.75). CONCLUSIONS: Our study is the first to identify predictors of wound dehiscence after RC in a large, contemporary multi institutional cohort. Identifying patients at risk of postoperative wound complications may guide the use of preventative measures at the time of surgery. PMID- 26118394 TI - Differential expression of immunohistochemical markers in primary lung and breast cancers enriched for triple-negative tumours. AB - AIMS: In breast cancer patients presenting with a lung lesion, the distinction between lung and breast origin is clinically important. Lung and breast cancers are both CK7(+) /CK20(-) , so additional immunohistochemical markers are needed. METHODS AND RESULTS: We examined the expression of oestrogen receptor (ER), progesterone receptor (PR), thyroid transcription factor-1 (TTF-1), gross cystic disease fluid protein-15 (GCDFP-15), p63 and Wilms' tumour 1 (WT1) in a series of tissue microarrays comprising 266 non-small-cell lung cancers and 837 primary breast cancers enriched for triple-negative tumours (TNBC). Staining for ER, PR, TTF-1 and GCDFP-15 was present in 63%, 49%, 0% and 25% of breast and 6%, 9%, 59% and 1% of lung cancers, respectively. Strong staining for p63 was present in 63 (97%) lung squamous cell carcinomas and only eight (9%) TNBC. WT1 nuclear staining was rare; however, cytoplasmic staining was identified in 49 (40%) TNBC and 10 (5%) lung cancers. Cluster analysis segregated TNBC from lung cancers with TTF-1 and/or p63 staining favouring lung origin, and GCDFP-15 or WT1 staining favouring breast origin. Cancers negative for all four markers (17%) were 60% breast and 40% lung origin. CONCLUSION: An immunohistochemical panel incorporating ER, TTF-1, GCDFP-15, p63 and WT1 can help to distinguish lung cancer from metastatic breast cancer, including TNBC. PMID- 26118395 TI - The impact of assertive outreach teams on hospital admissions for psychosis: a time series analysis. AB - Although the assertive outreach model was developed in the United States and imported to the United Kingdom to date, there is only limited evidence to support its wide-scale implementation within the United Kingdom. This is the first study to have combined a large dataset with this type of research method to explore the impact of assertive outreach teams on hospital admissions. The introduction and expansion of assertive outreach teams was associated with reducing hospital admissions for people with psychosis. This study found a consistent summer peak in hospital admissions which community and in-patient mental health nurses should take account of and plan for. Ever since the Mental Health Policy Implementation Policy Guide paved the way for the introduction of the Assertive Outreach Treatment (AOT) model in England, the impact of this approach has been the subject of considerable debate but limited evaluation. To date, most of the evidence supporting this model has originated from outside the United Kingdom. A central aim of the AOT was to reduce the need for in-patient treatment. We aimed to assess the impact of the AOT model on hospital admissions for people with psychosis in England. Interrupted time series analysis was used in this study to evaluate the impact of the policy change. Following the introduction of the AOT model, a statistically significant reduction in hospital admissions for psychosis was found. In addition, we observed a repeated, annual summer peak in admissions. This study adds to the international evidence which supports the effectiveness of the AOT model in reducing hospital admissions for people with severe mental health problems. We offer five suggested implications for mental health nurses and clients based on our findings. PMID- 26118396 TI - Transcriptome sequencing reveals both neutral and adaptive genome dynamics in a marine invader. AB - Species invasions cause significant ecological and economic damage, and genetic information is important to understanding and managing invasive species. In the ocean, many invasive species have high dispersal and gene flow, lowering the discriminatory power of traditional genetic approaches. High-throughput sequencing holds tremendous promise for increasing resolution and illuminating the relative contributions of selection and drift in marine invasion, but has not yet been used to compare the diversity and dynamics of a high-dispersal invader in its native and invaded ranges. We test a transcriptome-based approach in the European green crab (Carcinus maenas), a widespread invasive species with high gene flow and a well-known invasion history, in two native and five invasive populations. A panel of 10 809 transcriptome-derived nuclear SNPs identified significant population structure among highly bottlenecked invasive populations that were previously undifferentiated with traditional markers. Comparing the full data set and a subset of 9246 putatively neutral SNPs strongly suggested that non-neutral processes are the primary driver of population structure within the species' native range, while neutral processes appear to dominate in the invaded range. Non-neutral native range structure coincides with significant differences in intraspecific thermal tolerance, suggesting temperature as a potential selective agent. These results underline the importance of adaptation in shaping intraspecific differences even in high geneflow marine invasive species. They also demonstrate that high-throughput approaches have broad utility in determining neutral structure in recent invasions of such species. Together, neutral and non-neutral data derived from high-throughput approaches may increase the understanding of invasion dynamics in high-dispersal species. PMID- 26118397 TI - Differential effects of low birthweight and intrauterine growth restriction on umbilical cord blood insulin-like growth factor concentrations. AB - OBJECTIVE: Alterations in the growth hormone-insulin-like growth factor (IGF) axis have been considered as a causal factor for intrauterine growth restriction (IUGR) and for the increased risk of metabolic disease in later life. We compared members of the IGF axis in umbilical cord blood between IUGR neonates, small for gestational age without foetal restriction (SGA) and appropriate for gestational age (AGA) neonates. DESIGN: Prospective controlled multicenter study. PATIENTS: Sixteen ultrasound-proven IUGR, 8 SGA and 40 AGA neonates. MEASUREMENTS: Concentrations of total IGF-I and total IGF-II by immunoassays, bioactive IGF by cell-based bioassay and IGFBP-I in mixed venous and arterial umbilical cord blood samples at birth. Auxological parameters at birth. RESULTS: IGF-I concentrations in IUGR [17.7 MUg/l (CI 13.8;21.6)] were clearly below those in AGA [48.3 MUg/l (CI 43.7;52.9)] and SGA neonates [36.0 MUg/l (CI 26.6;45.4)]. IGF-II levels were significantly reduced in IUGR [201.4 MUg/l (CI 190.2;212.6)] compared to AGA neonates [231.2 MUg/l (CI 220.6;241.9)]. A trend for lower IGF-II concentrations was observed in IUGR when compared to SGA neonates [232.0 MUg/l (CI 207.2;256.8)]. These differences could not be explained by confounding. For IGFBP 1, a trend towards higher values in IUGR was observed. CONCLUSIONS: Low IGF-I cord blood concentrations in hypotrophic neonates after IUGR might not only result from low birthweight per se, but also reflect prenatal placental environment. Alterations of the IGF axis could be in the causal pathway of IUGR and thus constitute a potential surrogate marker for IUGR in the assessment of foetal programming. PMID- 26118398 TI - Uncovering the abilities of Agaricus bisporus to degrade plant biomass throughout its life cycle. AB - The economically important edible basidiomycete mushroom Agaricus bisporus thrives on decaying plant material in forests and grasslands of North America and Europe. It degrades forest litter and contributes to global carbon recycling, depolymerizing (hemi-)cellulose and lignin in plant biomass. Relatively little is known about how A. bisporus grows in the controlled environment in commercial production facilities and utilizes its substrate. Using transcriptomics and proteomics, we showed that changes in plant biomass degradation by A. bisporus occur throughout its life cycle. Ligninolytic genes were only highly expressed during the spawning stage day 16. In contrast, (hemi-)cellulolytic genes were highly expressed at the first flush, whereas low expression was observed at the second flush. The essential role for many highly expressed plant biomass degrading genes was supported by exo-proteome analysis. Our data also support a model of sequential lignocellulose degradation by wood-decaying fungi proposed in previous studies, concluding that lignin is degraded at the initial stage of growth in compost and is not modified after the spawning stage. The observed differences in gene expression involved in (hemi-)cellulose degradation between the first and second flushes could partially explain the reduction in the number of mushrooms during the second flush. PMID- 26118399 TI - A service evaluation of HDU-related adenotonsillectomy cancellations in one hundred and sixty-nine children at a University Teaching Hospital. PMID- 26118400 TI - Physicians' Practice, Attitudes Toward, and Knowledge of Cancer Pain Management in China. AB - SUBJECT: To evaluate physicians' current practice, attitudes toward, and knowledge of cancer pain management in China. METHODS: We conducted a face-to face survey of physicians (oncologists, internists, hematologists) who are responsible for the care of cancer patient of 11 general hospitals in Sichuan, China between December 2011 and December 2013. Statistical analyses were performed using SPSS (SPSS, Chicago, IL) software. SETTING AND DESIGN: A 23-item questionnaire was designed and distributed to 550 physicians in 11 medical facilities in China. RESULTS: Five hundred (90.90%) physicians responded. About one-third (32.6%) of physicians assessed patients' pain rarely, and 85.5% never or occasionally treated patients' cancer pain together with psychologists. More than half of physicians indicated that opioid dose titration in patients with poor pain control and assessment of the cause and severity of pain were urgently needed knowledge for cancer pain management. Inadequate assessment of pain and pain management (63.0%), patients' reluctance to take opioids (62.2%), and inadequate staff knowledge of pain management (61.4%) were the three most frequently cited barriers to physicians' pain management. CONCLUSIONS: Physicians' positive attitudes toward cancer pain management need to be encouraged, and active professional analgesic education programs are needed to improve pain management in China. PMID- 26118401 TI - Regulatory T-cell Subpopulations in Severe or Early-onset Preeclampsia. AB - PROBLEM: A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. OBJECTIVE: Utilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. METHOD OF STUDY: Six color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (one early-onset, one severe and 16 both), 20 women with normal pregnancy, and 20 non pregnant controls. RESULTS: No differences were found in major Treg populations including CD127(low) CD25(+) /CD127(ow) FOXP3(+) , resting (FOXP3(dim) CD45RA(+) ), and activated (FOXP3(bright) CD45RA(-) ) Treg cells, whereas preeclamptic women showed increased CTLA-4(+) and CCR4(+) proportions within resting/activated Treg populations. Corticosteroid treatment prior to blood sampling (n = 10) affected the distribution of Treg populations. CONCLUSIONS: Although we found no major alterations in circulating Treg frequencies, differences in CTLA-4(+) and CCR4(+) frequencies suggest a migratory defect of Treg cells in preeclampsia. Corticosteroid treatment should be taken into account when evaluating Treg cells. PMID- 26118402 TI - Generational reproductive outcomes in Wistar rats maternally exposed to Ricinus communis oil at different stages of gestation. AB - Fetal programming hypothesis presupposes that stimulus or insult acting during critical periods of uterine growth and development may permanently alter tissue structure and function. Ricinus communis oil (RCO) has been reported to possess/used as laxative, labor-inducing and estrogenic properties. Generational reproductive effects of maternal exposure to RCO was investigated in rats. A total of 25 pregnant rats randomly assigned to five equal groups were treated with distilled water (control, group 1), RCO (950 mg/kg p.o.) during gestation days (GD) 1-7, 7-14, 14-21 and 1-21, respectively. Birth weight, morphometric data, anogenital distance (AGD), pubertal age, sperm parameters, hormonal profile, organ weight and histopathology were determined in the first (F1) and second (F2) filial generations. Results showed a significant decrease (P<0.05) in birth weight/morphometric data in male pups from the GD 1-7 and 7-14 groups. AGD decreased significantly in RCO-treated F1 males. Pubertal age of F1 females decreased significantly (P<0.05) compared with controls. At postnatal day 90, F1 males from the RCO-treated group showed significant decrease in testis weight, body weight, sperm count, motility and normal morphology. Testosterone levels were significantly decreased in RCO-treated F1 males, which also showed testicular interstitial edema and epididymal hypospermia. Only pubertal indexes were altered in F2 rats. Maternal exposure to RCO at early gestation periods impaired androgen-mediated reproductive end points in the first generation of rats. RCO exhibits endocrine disrupting capabilities. PMID- 26118403 TI - Presenting parasitological data: the good, the bad and the error bar. AB - Visual displays of data in the parasitology literature are often presented in a way which is not very informative regarding the distribution of the data. An example being simple barcharts with half an error bar on top to display the distribution of parasitaemia and biomarkers of host immunity. Such displays obfuscate the shape of the data distribution through displaying too few statistical measures to explain the spread of all the data and selecting statistical measures which are influenced by skewness and outliers. We describe more informative, yet simple, visual representations of the data distribution commonly used in statistics and provide guidance with regards to the display of estimates of population parameters (e.g. population mean) and measures of precision (e.g. 95% confidence interval) for statistical inference. In this article we focus on visual displays for numerical data and demonstrate such displays using an example dataset consisting of total IgG titres in response to three Plasmodium blood antigens measured in pregnant women and parasitaemia measurements from the same study. This tutorial aims to highlight the importance of displaying the data distribution appropriately and the role such displays have in selecting statistics to summarize its distribution and perform statistical inference. PMID- 26118404 TI - A Family of Potent Ru(II) Photosensitizers with Enhanced DNA Intercalation: Bimodal Photokillers. AB - A new family of Ru(II)-based photosensitizers was synthesized and systematically characterized. The ligands employed to coordinate the ruthenium metal center were the commercially available 2,2'-bipyridine and a pyridine-quinoline hybrid bearing an anthracene moiety. The complexes obtained carry either PF6- or Cl(-) counterions. These counterions determine the complexes' hydrophobic or hydrophilic character, respectively, therefore dictating their solubility in biologically related media. All photosensitizers exhibit characteristic, relatively strong and wide UV-Vis absorption spectral profiles. Their high efficiency in generating cytotoxic singlet oxygen was established (up to PhiDelta ~0.8). Moreover, the interaction of these photosensitizers with double-stranded DNA was studied fluoro- and photospectroscopically and their binding affinities were found to be of the order of 3 * 10(7) M(-1) . All complexes are photocytotoxic to DU145 human prostate cancer cells. The highest light-induced toxicity was conferred by the photosensitizers bearing Cl(-) counterions, probably due to the looser ionic "chaperoning" of Cl(-) , in comparison to PF6-, leading to higher cell internalization. PMID- 26118405 TI - Developing integrated clinical reasoning competencies in dental students using scaffolded case-based learning - empirical evidence. AB - INTRODUCTION: This study provides empirical evidence of the development of integrated clinical reasoning in the discipline-based School of Dentistry, University of Pretoria, South Africa. Students were exposed to case-based learning in comprehensive patient care (CPC) in the preclinical year of study, scaffolded by means of the four-component instructional design model for complex learning. METHODS: Progress test scores of third- to fifth-year dental students, who received case-based teaching and learning in the third year (2009-2011), were compared to the scores of preceding fourth- and fifth-year cohorts. These fourth- and fifth-year cohorts received content-based teaching concurrently with their clinical training in CPC. The progress test consisted of a complex case study and 32 MCQs on tracer conditions. Students had to gather the necessary information and had to make diagnostic and treatment-planning decisions. RESULTS: Preclinical students who participated in the case-based teaching and learning achieved similar scores compared to final-year students who received lecture-based teaching and learning. Final-year students who participated in the case-based learning made three more correct clinical decisions per student, compared to those who received content-based teaching. Students struggled more with treatment planning than with diagnostic decisions. CONCLUSION: The scaffolded case-based learning appears to contribute to accurate clinical decisions when compared to lecture-based teaching. It is suggested that the development of integrated reasoning competencies starts as early as possible in a dental curriculum, perhaps even in the preclinical year of study. Treatment-planning should receive particular attention. PMID- 26118406 TI - Catalytic Properties of Intramembrane Aspartyl Protease Substrate Hydrolysis Evaluated Using a FRET Peptide Cleavage Assay. AB - Chemical details of intramembrane proteolysis remain elusive despite its prevalence throughout biology. We developed a FRET peptide assay for the intramembrane aspartyl protease (IAP) from Methanoculleus marisnigri JR1 in combination with quantitative mass spectrometry cleavage site analysis. IAP can hydrolyze the angiotensinogen sequence, a substrate for the soluble aspartyl protease renin, at a predominant cut site, His-Thr. Turnover is slow (min(-1) * 10(-3)), affinity and Michaelis constant (Km) values are in the low micromolar range, and both catalytic rates and cleavage sites are the same in detergent as reconstituted into bicelles. Three well-established, IAP-directed inhibitors were directly confirmed as competitive, albeit with modest inhibitor constant (Ki) values. Partial deletion of the first transmembrane helix results in a biophysically similar but less active enzyme than full-length IAP, indicating a catalytic role. Our study demonstrates previously unappreciated similarities with soluble aspartyl proteases, provides new biochemical features of IAP and inhibitors, and offers tools to study other intramembrane protease family members in molecular detail. PMID- 26118407 TI - Synthesis of Tricyclo[4,3,1,0(1,5)]decane Core of Plumisclerin A Using Pauson Khand Annulation and SmI2-Mediated Radical Cyclization. AB - An efficient synthesis of the tricyclo[4,3,1,0(1, 5)]decane core (B/C/D rings) of plumisclerin A, a unique cytotoxic marine diterpenoid, is described. A Pauson Khand reaction and a SmI2-mediated radical 1,4-conjugate addition successfully served as key reactions for construction of the fully functionalized 5,6-fused rings and the highly strained cyclobutanol moiety with correct relative stereochemistries, respectively. PMID- 26118408 TI - Atomic species identification at the (101) anatase surface by simultaneous scanning tunnelling and atomic force microscopy. AB - Anatase is a pivotal material in devices for energy-harvesting applications and catalysis. Methods for the accurate characterization of this reducible oxide at the atomic scale are critical in the exploration of outstanding properties for technological developments. Here we combine atomic force microscopy (AFM) and scanning tunnelling microscopy (STM), supported by first-principles calculations, for the simultaneous imaging and unambiguous identification of atomic species at the (101) anatase surface. We demonstrate that dynamic AFM-STM operation allows atomic resolution imaging within the material's band gap. Based on key distinguishing features extracted from calculations and experiments, we identify candidates for the most common surface defects. Our results pave the way for the understanding of surface processes, like adsorption of metal dopants and photoactive molecules, that are fundamental for the catalytic and photovoltaic applications of anatase, and demonstrate the potential of dynamic AFM-STM for the characterization of wide band gap materials. PMID- 26118409 TI - Stable ferrofluids of magnetite nanoparticles in hydrophobic ionic liquids. AB - Ferrofluids (FFs) of metal oxide nanoparticles in ionic liquids (ILs) are a potentially useful class of magnetic materials for many applications because of their properties related to temperature/pressure stability, hydrophobicity, viscosity and recyclability. In this work, the screening of several designer surfactants for their stabilizing capabilities has resulted in the synthesis of stable FFs of superparamagnetic 7 +/- 2 nm magnetite (Fe3O4) nanoparticles in the hydrophobic IL 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C(R)MIM][NTf2]). The designed and synthesized 1-butyl-3-(10-carboxydecyl)-1H imidazol-3-ium bromide (ILC10-COOH) surfactant that combines the same imidazole moiety as the IL with a long alkyl chain ensured compatibility with the IL and increased the steric repulsion between the magnetite nanoparticles sufficiently such that stable dispersions of up to 50 wt% magnetite were obtained according to stability tests in the presence of a magnetic field (0.5-1 Tesla). Cryo transmission electron microscopy (cryo-TEM) of the IL-based FFs allowed direct visualization of the surfactant-stabilized nanoparticles in the ILs and the native, hardly aggregated state of their dispersion. PMID- 26118410 TI - Characterization of triple-phase computed tomography in dogs with pancreatic insulinoma. AB - Little information is available regarding triple-phase computed tomography (CT) of canine pancreatic insulinoma. A few case reports with small numbers of cases have indicated that hyper-attenuation in the arterial phase was a common finding on multi-phasic CT in dogs with insulinoma. Our purpose was to clarify the characteristic findings of dogs with insulinoma on triple-phase CT. Nine dogs with insulinoma that underwent triple-phase CT were included in the present study. Attenuation patterns in the arterial phase indicated hypo-attenuation in 4 cases and hyper-attenuation in 2 cases. In the remaining 3 cases, 1 case showed hypo-attenuation and 1 case showed hyper-attenuation in the pancreatic phase, and 1 case presented hyper-attenuation in the later phase. Altogether, 5 cases showed hypo and 4 cases showed hyper-attenuation in at least one phase. The enhancement pattern was homogenous in 7 cases and heterogeneous in 2 cases. Tumor margins were well-defined in 5 cases and ill-defined in 4 cases. Capsule formation was present in 5 cases and absent in 4 cases. In conclusion, it is important to note that hypo-attenuation was as common as hyper-attenuation in dogs with insulinoma in triple-phase CT in at least one phase. Additionally, mass lesions were most conspicuous not only in the arterial phase but in the pancreatic and later phases in some cases. Therefore, it is important to perform triple-phase CT and notice about variable findings for the detection of canine pancreatic insulinoma. PMID- 26118411 TI - Relationship between blood calcium level and ST peak interval of electrocardiographic variables in peripartum Holstein cows. AB - The association between blood calcium levels and electrocardiographic variables was compared in 137 normal parturient and 36 peripartum recumbent Holstein cows to determine whether hypocalcemia in peripartum dairy cows can be rapidly diagnosed using electrocardiograph. Inverse of STc (ST peak interval/SS interval(0.5)) and blood ionized calcium or serum calcium concentrations were strongly correlated, and both correlation coefficients were 0.81 (P<0.001). The 95% prediction interval indicated that cows with STc >0.385 +/- 0.001 sec are very likely to be hypocalcemic (blood ionized or serum calcium concentrations of <0.9 mmol/l or <7.5 mg/dl, respectively). These findings indicate that hypocalcemia in parturient cows can be non-invasively estimated using the STc. PMID- 26118412 TI - Binding Behaviors for Different Types of DNA G-Quadruplexes: Enantiomers of [Ru(bpy)2(L)](2+) (L=dppz, dppz-idzo). AB - Polymorphic DNA G-quadruplex recognition has attracted great interest in recent years. The strong binding affinity and potential enantioselectivity of chiral [Ru(bpy)2 (L)](2+) (L=dipyrido[3,2-a:2',3'-c]phenazine, dppz-10,11-imidazolone; bpy=2,2'-bipyridine) prompted this investigation as to whether the two enantiomers, Delta and Lambda, can show different effects on diverse structures with a range of parallel, antiparallel and mixed parallel/antiparallel G quadruplexes. These studies provide a striking example of chiral-selective recognition of DNA G-quadruplexes. As for antiparallel (tel-Na(+)) basket G quadruplex, the Lambda enantiomers bind stronger than the Delta enantiomers. Moreover, the behavior reported here for both enantiomers stands in sharp contrast to B-DNA binding. The chiral selectivity toward mixed parallel/antiparallel (tel-K(+)) G-quadruplex of both compounds is weak. Different loop arrangements can change chiral complex selectivity for both antiparallel and mixed parallel/antiparallel G-quadruplex. Whereas both Delta and Lambda isomers bind to parallel G-quadruplexes with comparable affinity, no appreciable stereoselective G-quadruplex binding of the isomers was observed. In addition, different binding stoichiometries and binding modes for Delta and Lambda enantiomers were confirmed. The results presented here indicate that chiral selective G-quadruplex binding is not only related to G-quadruplex topology, but also to the sequence and the loop constitution. PMID- 26118413 TI - Cytokines as biomarkers of Crimean-Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is a potentially severe disease caused by CCHF virus. As in other viral hemorrhagic fevers, it is considered that the course and outcome of the disease depend on the viral load and the balance among the immune response mediators, and that a fatal outcome is the result of a "cytokine storm." The level of 27 cytokines was measured in serum samples taken from 29 patients during the acute phase of the disease. Two cases were fatal. Among survivors, significant differences between severe and non-severe cases were observed in the levels of IP-10, and MCP-1, while the levels of IL-1b, IL-5, IL 6, IL-8, IL-9, IL-10, IL-15, IP-10, MCP-1, TNF-alpha, and RANTES differed significantly between fatal and non-fatal cases (P < 0.05). RANTES was negatively correlated with the outcome of the disease. A striking similarity with the cytokine patterns seen in Ebola virus disease was observed. A weak Th1 immune response was seen. The viral load was positively correlated with IL-10, IP-10, and MCP-1 levels, and negatively correlated with the ratio IL-12/IL-10. Especially IP-10 and MCP-1 were significantly associated with the viral load, the severity and outcome of the disease, and they could act as biomarkers and, probably, as potential targets for treatment strategies design. PMID- 26118414 TI - Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-beta cascade. AB - Macrophages have important functions in tissue homeostasis, but the exact mechanisms regarding wide spectrum of macrophage phenotype remain unresolved. In this study, we report that mouse bone marrow derived naive macrophages produce prostaglandin E2 (PGE2 ) endogenously, resulting in anti-inflammatory gene expression upon differentiation induced by macrophage colony stimulating factor (M-CSF). Cyclooxygenase (COX) inhibition by indomethacin reduced endogenous PGE2 production of macrophages and subsequently reduced arg1, IL10 and Mrc1, YmI and FizzI gene expressions. Of note, PGE2 phosphorylates CREB via EP2 and EP4 receptor ligation, thereby transcriptionally increasing C/EBP-beta expression in BALB/c bone marrow derived macrophages. Activated CREB directly binds to the CREB responsive element of the C/EBP-beta promoter, such that PGE2 ultimately reinforces arg1, IL10 and Mrc1 gene expression. Cyclic AMP activator forskolin also phosphorylated CREB and induced the C/EBP-beta cascade, but this was completely blocked by the PKA inhibitor, H89. Consequently, M-CSF grown macrophages inhibited T-cell proliferation but the inhibition ability was reduced when the COX is inhibited by indomethacin or macrophage C/EBP-beta expression was decreased by siRNA transduction. Our results collectively describe the molecular basis for homeostatic macrophage differentiation by endogenous PGE2 . PMID- 26118417 TI - A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization. AB - In this paper, we reviewed the purification and characterization methods of the alpha-carbonic anhydrase (CA, EC 4.2.1.1) class. Six genetic families (alpha-, beta-, gamma-, delta-, zeta- and eta-CAs) all know to date, all encoding such enzymes in organisms widely distributed over the phylogenetic tree. Starting from the manuscripts published in the 1930s on the isolation and purification of alpha CAs from blood and other tissues, and ending with the recent discovery of the last genetic family in protozoa, the eta-CAs, considered for long time an alpha CA, we present historically the numerous and different procedures which were employed for obtaining these catalysts in pure form. alpha-CAs possess important application in medicine (as many human alpha-CA isoforms are drug targets) as well as biotechnological processes, in which the enzymes are ultimately used for CO2 capture in order to mitigate the global warming effects due to greenhouse gases. Recently, it was discovered an involvement of CAs in cancerogenesis as well as infection caused by pathogenic agents such as bacteria, fungi and protozoa. Inhibition studies of CAs identified in the genome of the aforementioned organisms might lead to the discovery of innovative drugs with a novel mechanism of action. PMID- 26118416 TI - A simple, xeno-free method for oligodendrocyte generation from human neural stem cells derived from umbilical cord: engagement of gelatinases in cell commitment and differentiation. AB - Oligodendrocyte progenitors (OPCs) are ranked among the most likely candidates for cell-based strategies aimed at treating neurodegenerative diseases accompanied by dys/demyelination of the central nervous system (CNS). In this regard, different sources of stem cells are being tested to elaborate xeno-free protocols for efficient generation of OPCs for clinical applications. In the present study, neural stem cells of human umbilical cord blood (HUCB-NSCs) have been used to derive OPCs and subsequently to differentiate them into mature, GalC expressing oligodendrocytes. Applied components of the extracellular matrix (ECM) and the analogues of physiological substances known to increase glial commitment of neural stem cells have been shown to significantly increase the yield of the resulting OPC fraction. The efficiency of ECM components in promoting oligodendrocyte commitment and differentiation prompted us to investigate the potential role of gelatinases in those processes. Subsequently, endogenous and ECM metalloproteinases (MMPs) activity has been compared with that detected in primary cultures of rat oligodendrocytes in vitro, as well as in rat brains in vivo. The data indicate that gelatinases are engaged in gliogenesis both in vitro and in vivo, although differently, which presumably results from distinct extracellular conditions. In conclusion, the study presents an efficient xeno free method of deriving oligodendrocyte from HUCB-NSCs and analyses the engagement of MMP-2/MMP-9 in the processes of cell commitment and maturation. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118415 TI - Granulocyte transfusions for preventing infections in people with neutropenia or neutrophil dysfunction. AB - BACKGROUND: Despite modern antimicrobials and supportive therapy, bacterial and fungal infections are still major complications in people with prolonged disease related or therapy-related neutropenia. Since the late 1990s there has been increasing demand for donated granulocyte transfusions to treat or prevent severe infections in people who lack their own functional granulocytes. This is an update of a Cochrane review first published in 2009. OBJECTIVES: To determine the effectiveness and safety of prophylactic granulocyte transfusions compared with a control population not receiving this intervention for preventing all-cause mortality, mortality due to infection, and evidence of infection due to infection or due to any other cause in people with neutropenia or disorders of neutrophil function. SEARCH METHODS: We searched for randomised controlled trials (RCTs) and quasi-RCTs in the Cochrane Central Register of Controlled Trials (Cochrane Library 2015, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), CINAHL (from 1937), theTransfusion Evidence Library (from 1980) and ongoing trial databases to April 20 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi RCTs comparing people receiving granulocyte transfusions to prevent the development of infection with a control group receiving no granulocyte transfusions. Neonates are the subject of another Cochrane review and were excluded from this review. There was no restriction by outcomes examined, but this review focuses on mortality, mortality due to infection and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Twelve trials met the inclusion criteria. One trial is still ongoing, leaving a total of 11 trials eligible involving 653 participants. These trials were conducted between 1978 and 2006 and enrolled participants from fairly comparable patient populations. None of the studies included people with neutrophil dysfunction. Ten studies included only adults, and two studies included children and adults. Ten of these studies contained separate data for each arm and were able to be critically appraised. One study re-randomised people and therefore quantitative analysis was unable to be performed.Overall, the quality of the evidence was very low to low across different outcomes according to GRADE methodology. This was due to many of the studies being at high risk of bias, and many of the outcome estimates being imprecise.All-cause mortality was reported for nine studies (609 participants). There was no difference in all-cause mortality over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (seven studies; 437 participants; RR 0.92, 95% CI 0.63 to 1.36, very low-quality evidence).Mortality due to infection was reported for seven studies (398 participants). There was no difference in mortality due to infection over 30 days between people receiving prophylactic granulocyte transfusions and those that did not (six studies; 286 participants; RR 0.69, 95% CI 0.33 to 1.44, very low quality evidence).The number of people with localised or systemic bacterial or fungal infections was reported for nine studies (609 participants). There were differences between the granulocyte dose subgroups (test for subgroup differences P = 0.01). There was no difference in the number of people with infections over 30 days between people receiving prophylactic granulocyte transfusions and those that did not in the low-dose granulocyte group (< 1.0 x 10(10) granulocytes per day) (four studies, 204 participants; RR 0.84, 95% CI 0.58 to 1.20; very low quality evidence). There was a decreased number of people with infections over 30 days in the people receiving prophylactic granulocyte transfusions in the intermediate-dose granulocyte group (1.0 x 10(10) to 4.0 x 10(10) granulocytes per day) (4 studies; 293 participants; RR 0.40, 95% CI 0.26 to 0.63, low-quality evidence).There was a decreased number of participants with bacteraemia and fungaemia in the participants receiving prophylactic granulocyte transfusions (nine studies; 609 participants; RR 0.45, 95% CI 0.30 to 0.65, low-quality evidence).There was no difference in the number of participants with localised bacterial or fungal infection in the participants receiving prophylactic granulocyte transfusions (six studies; 296 participants; RR 0.75, 95% CI 0.50 to 1.14; very low-quality evidence).Serious adverse events were only reported for participants receiving granulocyte transfusions and donors of granulocyte transfusions. AUTHORS' CONCLUSIONS: In people who are neutropenic due to myelosuppressive chemotherapy or a haematopoietic stem cell transplant, there is low-grade evidence that prophylactic granulocyte transfusions decrease the risk of bacteraemia or fungaemia. There is low-grade evidence that the effect of prophylactic granulocyte transfusions may be dose-dependent, a dose of at least 10 x 10(10) per day being more effective at decreasing the risk of infection. There is insufficient evidence to determine any difference in mortality rates due to infection, all-cause mortality, or serious adverse events. PMID- 26118418 TI - Protein tyrosine phosphatase 1B inhibitors isolated from Artemisia roxburghiana. AB - Artemisia roxburghiana is used in traditional medicine for treating various diseases including diabetes. The present study was designed to evaluate the antidiabetic potential of active constituents by using protein tyrosine phosphatase 1B (PTP1B) as a validated target for management of diabetes. Various compounds were isolated as active principles from the crude methanolic extract of aerial parts of A. roxburghiana. All compounds were screened for PTP1B inhibitory activity. Molecular docking simulations were performed to investigate the mechanism behind PTP1B inhibition of the isolated compound and positive control, ursolic acid. Betulinic acid, betulin and taraxeryl acetate were the active PTP1B principles with IC50 values 3.49 +/- 0.02, 4.17 +/- 0.03 and 87.52 +/- 0.03 uM, respectively. Molecular docking studies showed significant molecular interactions of the triterpene inhibitors with Gly220, Cys215, Gly218 and Asp48 inside the active site of PTP1B. The antidiabetic activity of A. roxburghiana could be attributed due to PTP1B inhibition by its triterpene constituents, betulin, betulinic acid and taraxeryl acetate. Computational insights of this study revealed that the C-3 and C-17 positions of the compounds needs extensive optimization for the development of new lead compounds. PMID- 26118419 TI - Interaction exists between matriptase inhibitors and intestinal epithelial cells. AB - The type II trypsin-like transmembrane serine protease matriptase, is mainly expressed in epithelial cells and one of the key regulators in the formation and maintenance of epithelial barrier integrity. Therefore, we have studied the inhibition of matriptase in a non-transformed porcine intestinal IPEC-J2 cell monolayer cultured on polyester membrane inserts by the non-selective 4-(2 aminoethyl)-benzosulphonylfluoride (AEBSF) and four more selective 3 amidinophenylalanine-derived matriptase inhibitors. It was found that suppression of matriptase activity by MI-432 and MI-460 led to decreased transepithelial electrical resistance (TER) of the cell monolayer and to an enhanced transport of fluorescently labelled dextran, a marker for paracellular transport between apical and basolateral compartments. To this date this is the first report in which the inhibition of matriptase activity by synthetic inhibitors has been correlated to a reduced barrier integrity of a non-cancerous IPEC-J2 epithelial cell monolayer in order to describe interaction between matriptase activity and intestinal epithelium in vitro. PMID- 26118421 TI - Reversible Switching of Redox-Active Molecular Orbitals and Electron Transfer Pathways in Cu(A) Sites of Cytochrome c Oxidase. AB - The Cu(A) site of cytochrome c oxidase is a redox hub that participates in rapid electron transfer at low driving forces with two redox cofactors in nearly perpendicular orientations. Spectroscopic and electrochemical characterizations performed on first and second-sphere mutants have allowed us to experimentally detect the reversible switching between two alternative electronic states that confer different directionalities to the redox reaction. Specifically, the M160H variant of a native Cu(A) shows a reversible pH transition that allows to functionally probe both states in the same protein species. Alternation between states exerts a dramatic impact on the kinetic redox parameters, thereby suggesting this effect as the mechanism underlying the efficiency and directionality of Cu(A) electron transfer in vivo. These findings may also prove useful for the development of molecular electronics. PMID- 26118420 TI - Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents. AB - Resveratrol is a natural polyphenol with plethora of biological activities. Resveratrol has previously shown to decrease DNA-methyltransferase (DNMT) enzymes expression and to reactivate silenced tumor suppressor genes. Currently, it seems that no resveratrol analogs have been developed as DNMT inhibitors. Recently, we reported the synthesis of resveratrol-salicylate derivatives and by examining the chemical structure of these analogs, we proposed that these compounds could exhibit DNMT inhibition especially that they resembled NSC 14778, a compound we previously identified as a DNMT inhibitor by virtual screening. Indeed, using in vitro DNMT inhibition assay, some of the resveratrol-salicylate analogs we screened in this work that showed selective inhibition against DNMT3 enzymes which were greater than resveratrol. A molecular docking study revealed key binding interactions with DNMT3A and DNMT3B enzymes. In addition, the most active analog, 10 showed considerable cytotoxicity against three human cancer cells; HT 29, HepG2 and SK-BR-3, which was greater than resveratrol. Further studies are needed to understand the anticancer mechanisms of these derivatives. PMID- 26118422 TI - No associations between objectively measured physical activity and spinal pain in 11-15-year-old Danes. AB - BACKGROUND: Physical activity is thought to play a role in spinal pain (neck pain, mid back pain, low back pain) in children and adolescents, either as a risk or protective factor, but current evidence is conflicting. The overall aim of this study was to determine the cross-sectional and longitudinal associations between different levels of objectively measured physical activity, i.e. sedentary; moderate and vigorous; vigorous physical activity, and spinal pain in 11-15-year-old Danes. METHODS: Data were collected at baseline (2010) (n = 906) and at follow-up 2 years later (n = 625) in a school-based prospective cohort study. Physical activity was measured using the Actigraph GT3X Triaxial Activity Monitor, which measures the intensity of physical activity over time. This was worn for 1 week and spinal pain was assessed via e-survey that participants completed during school time. Potential confounders included in the multivariable analyses were sex, anthropometry, physical fitness, social status and psychosocial factors. In the longitudinal study, analyses stratified by baseline pain status were performed. RESULTS: There were neither cross-sectional nor longitudinal associations between different levels of objectively measured physical activity and spinal pain over the 2-year period. CONCLUSION: Objectively measured physical activity was not associated with spinal pain. However, it remains to be seen whether there is an association over a longer follow-up period. Future research should focus on the more qualitative aspects of physical activity, such as different sports activities. PMID- 26118424 TI - Human preservation techniques in anatomy: A 21st century medical education perspective. AB - Anatomy is the cornerstone of education for healthcare professionals with the use of human material providing an excellent teaching tool in the modern curricula. The ability and quality of preservation of human remains has enabled such use. The introduction of formaldehyde as a preservative in 1893 was an important step in the history of preservation. With the European Union directive on the use of formaldehyde and its expected banning, anatomists are trying to find a more convenient and safe substitute. In this review, we compare the different techniques used based on the need for embalming, fixative used, period of preservation and the features of the embalmed specimen. The fact that embalming is used in different disciplines, multiple purposes and described in different languages has led to the development of ambiguous interchangeable terminology. Overall, there is a lack of information specifically classifying, listing and comparing different embalming techniques, and this may be due to the fact that no internationally recognized experimental standards are adhered to in this field. Anatomists strive to find an embalming technique that allows the preserved specimen to accurately resemble the living tissue, preserve the body for a long period of time and reduces health risk concerns related to working with cadavers. There is a need for embalming to shift to an independent modern day science with well-founded research at the heart of it. While this may take time and agreement across nations, we feel that this review adds to the literature to provide a variety of different methods that can be employed for human tissue preservation depending on the desired outcome. PMID- 26118423 TI - Fast, multi-frequency, and quantitative nanomechanical mapping of live cells using the atomic force microscope. AB - A longstanding goal in cellular mechanobiology has been to link dynamic biomolecular processes underpinning disease or morphogenesis to spatio-temporal changes in nanoscale mechanical properties such as viscoelasticity, surface tension, and adhesion. This requires the development of quantitative mechanical microscopy methods with high spatio-temporal resolution within a single cell. The Atomic Force Microscope (AFM) can map the heterogeneous mechanical properties of cells with high spatial resolution, however, the image acquisition time is 1-2 orders of magnitude longer than that required to study dynamic cellular processes. We present a technique that allows commercial AFM systems to map quantitatively the dynamically changing viscoelastic properties of live eukaryotic cells at widely separated frequencies over large areas (several 10's of microns) with spatial resolution equal to amplitude-modulation (AM-AFM) and with image acquisition times (tens of seconds) approaching those of speckle fluorescence methods. This represents a ~20 fold improvement in nanomechanical imaging throughput compared to AM-AFM and is fully compatible with emerging high speed AFM systems. This method is used to study the spatio-temporal mechanical response of MDA-MB-231 breast carcinoma cells to the inhibition of Syk protein tyrosine kinase giving insight into the signaling pathways by which Syk negatively regulates motility of highly invasive cancer cells. PMID- 26118425 TI - Recent Patents, Formulation and Characterization of Nanoliposomes. AB - Nanoliposome has been introduced for nanoscale bilayer lipid vesicles. These are the nano version of liposomes, having cell-specific targeting, required to achieve a desired drug concentration at the target site for optimum therapeutic efficacy, possibly by minimizing the adverse effects on healthy cells and tissues. Nanoliposomes possess impending applications in the fields of nanotechnology, e.g. cancer therapy, cosmetics, diagnosis, gene delivery, agriculture and food technology. Nano liposomes can be formulated by Sonication technique, Extrusion method, Emulsification evaporation method and Lipid layer hydration method. Authors have performed detailed patent and literature survey on PubMed, PubMed Central, Spingerlink and Elsevier based reviews and research articles on nanoliposomes. An attempt has been made to highlight the various formulation methods including the patented technologies, applications and characterization of nanoliposomes. PMID- 26118426 TI - Highly Efficient C-SeCF3 Coupling of Aryl Iodides Enabled by an Air-Stable Dinuclear Pd(I) Catalyst. AB - Building on our recent disclosure of catalysis at dinuclear Pd(I) sites, we herein report the application of this concept to the realization of the first catalytic method to convert aryl iodides into the corresponding ArSeCF3 compounds. Highly efficient C-SeCF3 coupling of a range of aryl iodides was achieved, enabled by an air-, moisture-, and thermally stable dinuclear Pd(I) catalyst. The novel SeCF3 -bridged dinuclear Pd(I) complex 3 was isolated, studied for its catalytic competence and shown to be recoverable. Experimental and computational data are presented in support of dinuclear Pd(I) catalysis. PMID- 26118427 TI - Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection. AB - Alisporivir is a cyclophilin inhibitor with pan-genotypic anti-hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL-1 study assessed alisporivir as interferon (IFN)-free therapy in treatment-naive patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once-daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg-IFN); or arm 5, Peg-IFN and RBV. Patients receiving IFN-free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg-IFN from weeks 6 to 24. Overall, 300 patients received ALV based regimens. In arm 1 to arm 4, the intent-to-treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg-IFN/RBV. Per-protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN-free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg-IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN-free regimens were numerically higher in genotype 3- than in genotype 2-infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN-free ALV treatment showed markedly better safety/tolerability than IFN-containing regimens. CONCLUSIONS: ALV plus RBV represents an effective IFN-free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN-free combination regimens with direct-acting antiviral drugs deserve exploration in future trials. PMID- 26118428 TI - Survival of patients with multiple brain metastases treated with whole-brain radiotherapy. AB - AIM: To report the survival outcomes of patients with multiple brain metastases treated with whole-brain radiotherapy. PATIENTS & METHODS: From 2004 to 2012, patients with brain metastases treated with whole-brain radiotherapy were included. Overall survival (OS) was calculated from the start of radiation treatment. Univariate and multivariate proportional hazard model of OS was conducted. Generalized R(2) statistic (ranged from 0 to 1) was calculated to determine the association with the outcome. RESULTS: Nine-hundred-ninety-one patients were included. The actuarial median OS time was 2.7 months (95% CI: 2.5 2.9). Patients of older age (>65 years), lower Karnofsky performance status, not postoperative and patients with gastrointestinal, genitourinary or lung as opposed to breast cancer were more likely to have a shorter survival. CONCLUSION: Short median survival of 2.7 months may reflect poorer prognosis of patients referred due to large amount of referrals for radiosurgery. Prognostic factors for survival should be considered at consultation. PMID- 26118429 TI - Aortic dimensions in Turner syndrome. AB - In Turner syndrome, linear growth is less than the general population. Consequently, to assess stature in Turner syndrome, condition-specific comparators have been employed. Similar reference curves for cardiac structures in Turner syndrome are currently unavailable. Accurate assessment of the aorta is particularly critical in Turner syndrome because aortic dissection and rupture occur more frequently than in the general population. Furthermore, comparisons to references calculated from the taller general population with the shorter Turner syndrome population can lead to over-estimation of aortic size causing stigmatization, medicalization, and potentially over-treatment. We used echocardiography to measure aortic diameters at eight levels of the thoracic aorta in 481 healthy girls and women with Turner syndrome who ranged in age from two to seventy years. Univariate and multivariate linear regression analyses were performed to assess the influence of karyotype, age, body mass index, bicuspid aortic valve, blood pressure, history of renal disease, thyroid disease, or growth hormone therapy. Because only bicuspid aortic valve was found to independently affect aortic size, subjects with bicuspid aortic valve were excluded from the analysis. Regression equations for aortic diameters were calculated and Z-scores corresponding to 1, 2, and 3 standard deviations from the mean were plotted against body surface area. The information presented here will allow clinicians and other caregivers to calculate aortic Z-scores using a Turner based reference population. (c) 2015 Wiley Periodicals, Inc. PMID- 26118430 TI - Endocrine-disrupting effect of the ultraviolet filter benzophenone-3 in zebrafish, Danio rerio. AB - The chemical ultraviolet (UV) filter benzophenone-3 (BP-3) is suspected to be an endocrine disruptor based on results from in vitro and in vivo testing. However, studies including endpoints of endocrine adversity are lacking. The present study investigated the potential endocrine-disrupting effects of BP-3 in zebrafish (Danio rerio) in the Fish Sexual Development Test (Organisation for Economic Co operation and Development TG 234) and a 12-d adult male zebrafish study. In TG 234, exposure from 0 d to 60 d posthatch caused a monotone dose-dependent skewing of the phenotypic sex ratio toward fewer males and more female zebrafish (no observed effect concentration [NOEC]: 191 MUg/L, lowest observed effect concentration [LOEC]: 388 MUg/L). Besides, gonad maturation was affected in both female fish (NOEC 191 MUg/L, LOEC 388 MUg/L) and male fish (NOEC 388 MUg/L, LOEC 470 MUg/L). Exposure to BP-3 did not affect the vitellogenin concentration in TG 234. After 12 d exposure of adult male zebrafish, a slight yet significant increase in the vitellogenin concentration was observed at 268 MUg/L but not at 63 MUg/L and 437 MUg/L BP-3. Skewing of the sex ratio is a marker of an endocrine mediated mechanism as well as a marker of adversity, and therefore the conclusion of the present study is that BP-3 is an endocrine-disrupting chemical in accordance with the World Health Organization's definition. PMID- 26118432 TI - NASN 2015 Endowment Fundraising Events. PMID- 26118431 TI - Use of nicorandil is Associated with Increased Risk for Gastrointestinal Ulceration and Perforation- A Nationally Representative Population-based study. AB - Nicorandil is a vasodilatory drug used to relieve angina symptoms. Several healthcare products regulatory agencies have issued a warning associating the use of nicorandil and gastrointestinal (GI) ulceration. We aimed to evaluate the association between use of nicorandil and GI ulceration/perforation. A population based cohort study involving 1 million randomly sampled participants in Taiwan's National Health Insurance Research Database was carried out. We estimated the association between use of nicorandil and GI ulceration/perforation by a Cox proportional hazards regression model. A nicorandil-specific propensity score (PS) was also created for adjustment of 75 covariates and matching. 25.8% (183/710) of nicorandil-treated patients developed new GI ulcer events and 1.6% (20/1254) developed new GI perforation events in the three-year follow-up period, as compared to 9.3% (61,281/659,081) and 0.3% (2,488/770,537) in the general population comparator cohort. Patients treated with nicorandil were at significantly increased risk of GI ulcer (PS adjusted hazard ratio 1.43, 95% CI, 1.23 to 1.65, 6848 excess cases per 100,000 person years) or GI perforation (aHR 1.60, 95% CI 1.02-2.51, 315 excess cases per 100,000 person years) compared with the nicorandil unexposed population. Our finding may warn the clinicians to weigh the overall risk-benefit balance of nicorandil treatment in patients. PMID- 26118433 TI - NASN Legislative Priorities for 2015. PMID- 26118434 TI - Performance-Enhancing Drugs and the High School Athlete. AB - A performance-enhancing drug (PED) is any substance that is used to increase muscle mass, dull pain, reduce weight, or ease stress. The use of PEDs is a growing concern among adolescents, due in part to the pressures to perform, the influence of professional role models, and a general lack of education about the dangers of these substances. Use of performance enhancers has been identified in middle school as well as high school age students. This article details the school nurse's role in identifying youth who are using a PED, providing education for students and families, and referring for treatment if needed. Although PED use is not as prevalent as use of other illicit drugs, PEDs still pose a threat to adolescent physical and mental health. Discussion about PED use can open the door to discussion about use of other substances. PMID- 26118435 TI - Framework for 21st Century School Nursing Practice: An Overview. PMID- 26118436 TI - Two-Dimensional Layered Heterostructures Synthesized from Core-Shell Nanowires. AB - Controlled stacking of different two-dimensional (2D) atomic layers will greatly expand the family of 2D materials and broaden their applications. A novel approach for synthesizing MoS2 /WS2 heterostructures by chemical vapor deposition has been developed. The successful synthesis of pristine MoS2 /WS2 heterostructures is attributed to using core-shell WO3-x /MoO3-x nanowires as a precursor, which naturally ensures the sequential growth of MoS2 and WS2 . The obtained heterostructures exhibited high crystallinity, strong interlayer interaction, and high mobility, suggesting their promising applications in nanoelectronics. The stacking orientations of the two layers were also explored from both experimental and theoretical aspects. It is elucidated that the rational design of precursors can accurately control the growth of high-quality 2D heterostructures. Moreover, this simple approach opens up a new way for creating various novel 2D heterostructures by using a large variety of heteronanomaterials as precursors. PMID- 26118437 TI - Multimodality therapy approaches, local and systemic treatment, compared with chemotherapy alone in recurrent glioblastoma. AB - BACKGROUND: Long-term local control in Glioblastoma is rarely achieved and nearly all patients relapse. In this study we evaluated the clinical effect of different treatment approaches in recurrent patients. METHODS: Forty-three patients, with median age of 51 years were evaluated for salvage treatment: re-resection and/or re-irradiation plus chemotherapy or chemotherapy alone. Response was recorded using the Response Assessment in Neuro-Oncology criteria. Hematologic and non hematologic toxicities were graded according to Common Terminology Criteria for Adverse Events 4.0. Twenty-one patients underwent chemotherapy combined with local treatment, surgery and/or radiation therapy, and 22 underwent chemotherapy only. RESULTS: The median follow up was 7 months (range 3-28 months). The 1 and 2 years Progression Free Survival was 65 and 10 % for combined treatment and 22 and 0 % for chemotherapy alone (p < 0.01). The 1 and 2-years overall survival was 69 and 29 % for combined and 26 and 0 % for chemotherapy alone (p < 0.01). No toxicity greater than grade 2 was recorded. CONCLUSION: These data showed that in glioblastoma recurrence the combination of several approaches in a limited group of patients is more effective than a single treatment alone. This stress the importance of multimodality treatment whenever clinically feasible. PMID- 26118438 TI - Association between number of prostate biopsies and patient-reported functional outcomes after radical prostatectomy: implications for active surveillance protocols. AB - OBJECTIVES: To evaluate whether the number of preoperative prostate biopsies affects functional outcomes after radical prostatectomy (RP). METHODS: We identified patients treated with RP at our institution between 2008 and 2011. At 6 and 12 months postoperatively, the patients completed questionnaires assessing erectile and urinary function. Patients with preoperative incontinence or erectile dysfunction or who did not complete the questionnaire were excluded. Primary outcomes were urinary and erectile function at 12 months postoperatively. We used logistic regression to estimate the impact of number of prostate biopsies on functional outcomes after adjusting for demographic and clinical factors. RESULTS: We identified 2 712 patients treated with RP between 2008 and 2011. Most of the patients (80%) had one preoperative prostate biopsy, 16% had two, and 4% had at least three. On adjusted analysis, erectile function at 12 months was not significantly different for patients with two (odds ratio [OR] 1.25; 95% confidence interval [CI] 0.90, 1.75) or three or more (OR 1.52; 95% CI 0.84, 2.78) biopsies, compared with those with one biopsy. Similarly, urinary function at 12 months was not significantly different for patients with two (0.84, 95% CI 0.64, 1.10) or three or more (0.99, 95% CI 0.60, 1.61) biopsies compared with those with one. CONCLUSIONS: We did not find evidence that a greater number of preoperative prostate biopsies adversely affected erectile or urinary function at 12 months after RP. PMID- 26118439 TI - A Simple Technique for Closing Multiple Muscular and Apical Ventricular Septal Defects. AB - BACKGROUND: Multiple ventricular septal defects (VSDs) are difficult to close. In this report, we describe a simple and safe technique of closing multiple muscular and apical VSDs. METHODS: Between January 2010 and December 2013, 52 patients with a muscular VSD either in isolation or in association with other congenital heart disease underwent surgery using this technique in which a black silk thread was passed through the suspected VSD opening into the left ventricle and brought out through the mitral valve and the interatrial septum. Sutures were placed around the silk thread to close the VSD. RESULTS: Out of 52 patients, 34 were male; age ranged from 45 days to 5.5 years. In addition to the large subaortic/lage muscular VSD, three additional VSDs were present in 34 patients, two additional VSDs were present in 13 patients, and five patients had "Swiss Cheese septum." The VSDs were mid-muscular in 35 patients and were apical in 17 patients. Eleven patients had associated complex lesions. Intraoperative transesophageal echocardiograms did not reveal any significant residual shunt in any of these patients. There was no step-up on oximetry. There was one hospital death due to sepsis. Follow-up was available in 48 patients; three patients were lost to follow-up. At follow-up, no patient had a residual VSD. CONCLUSION: The biventricular approach through trans-right atrial, trans-interatrial septum using a thread through the hole method for closing multiple muscular VSD is effective with no persistent residual defects. PMID- 26118440 TI - Psychosocial interventions for people with diabetes and co-morbid depression. A systematic review. AB - AIMS AND OBJECTIVES: To examine the effectiveness of psychosocial interventions on depressive symptoms and glycaemic control of adults with Type 1 or 2 diabetes and co-morbid depression. BACKGROUND: Diabetes is a chronic disease that affects as many as 382 million people in the world. Diabetes management is a challenging daily task which can be overwhelming and lead to depression. Both diabetes and co morbid depression have a negative bidirectional influence on each other, which is detrimental for the individual's quality of life. This co-morbidity places a huge burden on the individual, family, health care system, and the economy, with an associated 50-75% increase in health care costs. DESIGN: A systematic review. METHODS: Four electronic databases were searched including Cochrane Library, CINAHL, MEDLINE, and PsycINFO for articles written in English from the year 1998 to 2013. Data extraction of vital information from included studies was conducted and the effect sizes were calculated for the outcomes. RESULTS: Ten interventional primary studies were retrieved from the search; six were randomised studies. Nine out of ten studies reported that psychosocial interventions were effective for depression with effect sizes ranging from small (-0.24) to large (-1.74). No effect was found for the glycaemic control outcome. The interventions came in a myriad of intervention type, delivery method, duration, and intensity, therefore a meta-analysis was not conducted. The review found that nurses were competent in delivering psychosocial interventions for this population. Methodological quality was below average amongst the study with various biases present. CONCLUSIONS: The results and effect sizes were promising but due to the high number of bias risks, it cannot be determined if psychosocial interventions were found to be effective in people with diabetes and co-morbid depression. RELEVANCE TO CLINICAL PRACTICE: Psychosocial interventions have the potential to make improvements in depression, alleviating the global burden on people with diabetes, keeping in mind the best intervention modality tailoring to the client's needs and preferences. Nurses and other health professionals involved in caring for this group are in a good stead to carry out these interventions. PMID- 26118441 TI - Mitigating procedural pain during venipuncture in a pediatric population: A randomized factorial study. AB - BACKGROUND: Evidence suggests that a significant number of children receive less than optimal management of procedure-related pain. OBJECTIVES: To determine if there was a difference in the perceived pain associated with a venipuncture procedure in a group of pediatric patients based on the preparatory intervention used during the procedure and, to determine if age, sex, or ethnic group were associated with the effectiveness of the preparatory interventions used. DESIGN: A quasi-experimental, 3*4 factorial design was used. SETTING: Participants were recruited from a non-profit, regional hospital in the southeast United States. PARTICIPANTS: Participants were recruited from children between the ages of 18 months and 17 years who were admitted to the facility. Criteria for inclusion was the first needle stick during admission with a parent or guardian present, English as the primary language. Potential participants were excluded if they had previous experience with any of the preparatory interventions, were sedated, unconscious, hemodynamically unstable, developmentally delayed for their age, or had a known chronic condition. Of the 285 participants consented to participate, 173 children completed the process including 35 (20.2%) toddlers, 34(19.7%) preschool and 65 (37.6%) school age children, and 39 (22.5%) adolescents. There were 77 (44.5%) females and 96 (55.5%) males; and 101 (58.4%) non-Hispanic white children and 72 (41.6%) minority children. METHODS: Children were randomized to one of three treatment interventions. There was a purposeful effort to include representative numbers of each age group, ethnic group, and sex and in each treatment group. Measures of pain before and after the procedure included an observational measure completed by the parent/guardian and a self-report measure completed by the two older age groups. FINDINGS: There were no statistically significant differences among treatment groups based on the observational measures of pain or the self-report measures of pain. There was a statistically significant interaction between ethnic group and treatment group (p=0.006) based on the observational measure of pain which was also found between ethnic group and treatment group (p=.04) based on self-report scores in school age children and adolescents. CONCLUSION: Findings support the use of both mechanical vibration and topical anesthetic as effective in children regardless of age group or sex. Further, the interaction between ethnic group and treatment contributes to a growing body of knowledge that suggests ethnic group is an important factor in the pain response and requires further study in an effort to better customize approaches to pain management in children. PMID- 26118442 TI - Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain. AB - Blood-brain barrier inhibits most of drugs and genetic materials from reaching the brain. So, developing high efficiency carriers for gene and drug delivery to the brain, is the challenging area in pharmaceutical sciences. This investigation aimed to target DNA to brain using Serine-Arginine-Leucine (SRL) functionalized PAMAM dendrimers as a novel gene delivery system. The SRL peptide was linked on G4 PAMAM dendrimers using bifunctional PEG. DNA was then loaded in these functionalized nanoparticles and their physicochemical properties and cellular uptake/distribution evaluated by AFM, NMR, FTIR and fluorescence and confocal microscopy. Also, biodistribution and brain localization of nanoparticles were studied after IV injection of nanoparticles into rat tail. Unmodified nanoparticles were used as control in all evaluations. In vitro studies showed that SRL-modified nanoparticles have good transfection efficacy and low toxicity. Results also showed that SRL is a LRP ligand and SRL-modified nanoparticles internalized by clathrin/caveolin energy-dependent endocytosis to brain capillary endothelial cells. After intravenous administration, the SRL-modified nanoparticles were able to cross the blood-brain barrier and enter the brain parenchyma. Our result showed that, SRL-modified nanoparticles provide a safe and effective nanocarrier for brain gene delivery. PMID- 26118443 TI - Concentrations of dimethylaniline and other metabolites in milk and tissues of dairy cows treated with lidocaine. AB - Lidocaine is a topical anaesthetic drug used in dairy cows for laparotomy (caesarean section, abomasal displacement). Because there are no registered drugs for this indication, it can be applied under the so-called Cascade rules (off label use), with the restriction that the off-label withdrawal periods of 7 days for milk and 28 days for meat are taken into account. In animals, lidocaine is rapidly metabolised into various metabolites, one being 2,6-dimethylaniline (DMA) which is reported to possess carcinogenic and mutagenic properties and detected also in milk. To investigate whether the off-label withdrawal periods are long enough to exclude the presence of lidocaine and DMA, and potential other metabolites, in edible products, a study was performed with eight dairy cows treated with lidocaine by injection in the abdominal muscles. At various time points blood samples, milk and urine were collected. Four animals were slaughtered 3.5 h after treatment, the other four after 48.5 h. The injection site, meat, liver and kidney were analysed for levels of lidocaine, DMA, monoethylglycinexylidide (MEGX) and 3-OH-lidocaine. It was shown that DMA is an important metabolite in dairy cows and can be detected in both meat and milk. In addition, also MEGX, 3-OH-lidocaine and three other metabolites were identified and to some extent quantified. These metabolites were 4-OH-lidocaine, lidocaine-N oxide and 4-hydroxy-DMA. The latter compound was the most important metabolite in urine. However, levels in milk and meat decreased rapidly after the application. Overall, it can be concluded that the off-label withdrawal times of 7 and 28 days for milk and meat, respectively, guarantee the absence of detectable levels of lidocaine and metabolites. PMID- 26118444 TI - Fetal programming of overweight through the microbiome: boys are disproportionately affected. AB - Maternal and childhood obesity in pregnancy are worrisome public health issues facing our world today. New gene sequencing methods have advanced our knowledge of the disruptive effect of birth interventions and postnatal exposures on the maturation of gut microbiota and immunity during infancy. Yet, little is known about the impact of maternal pregnancy overweight on gut microbes and related processes, and how this may affect overweight risk in offspring. To address this gap in knowledge, we surveyed human studies for evidence in children, infants and pregnant women to piece together the limited literature and generate hypotheses for future investigation. From this literature, we learned that higher Lactobacillus yet lower Bacteroides spp. colonization of gut microbiota within 3 months of birth predicted risk for infant and child overweight. The abundance of bifidobacteria and staphylococci also appeared to play a role in the association with overweight, as did infant fecal immunoglobulin A levels, glycoproteins of the gut immune system that are acquired from breast milk and produced by the infant. We proposed that pregnancy overweight influences the compositional structure of gut microbiota in infants through vertical transfer of microbiota and/or their metabolites during pregnancy, delivery and breastfeeding. Finally, we brought forward emerging evidence on sex dimorphism, as well as ethnic and geographic variation, in reported associations between maternal overweight induced gut microbiota dysbiosis and overweight risk. PMID- 26118445 TI - Right Aortic Arch Detected Prenatally: A Rare Case With Bilateral Arterial Duct and Nonconfluent Pulmonary Arteries. AB - We describe a rare case of right aortic arch (RAA) and nonconfluent pulmonary arteries. RAA and a right-sided arterial duct (AD) were identified on the prenatal scan, but a second left-sided AD and disconnection of the left pulmonary artery were missed. The missed diagnosis in fetal life adversely affected postnatal management. We suggest that fetuses with a prenatal diagnosis of RAA and right-sided AD be delivered in tertiary care centres to rule out an association with bilateral AD and nonconfluent pulmonary arteries after birth. Prompt postnatal diagnosis will enable preservation of flow in the disconnected pulmonary artery through prostaglandin E1 infusion until surgical reconstruction. PMID- 26118446 TI - Right Bundle Branch Block-Like Pattern During Ventricular Pacing: A Surface Electrocardiographic Mapping Technique to Locate the Ventricular Lead. AB - BACKGROUND: In patients with paced rhythm, a right bundle branch block (RBBB) like pattern may suggest inadvertent left ventricular (LV) lead placement. However, in most cases, the lead is indeed in the right ventricle as intended. METHODS: We performed a retrospective analysis of postimplantation electrocardiograms (ECGs) for the period 2000-2013 to determine the prevalence of a RBBB-like pattern. A 12-lead ECG was recorded in the standard position and with displacement of leads V1-V2 to the fifth and sixth intercostal spaces (ICSs), assessing the ability of this manoeuvre to unmask a concealed LBBB-like pattern. Patients with true LV pacing, both endocardial and epicardial, were used as controls (n = 10). RESULTS: A total of 943 patients were analyzed. The prevalence of RBBB-like pattern was 8.1% (n = 77), and 26 patients were included in the study. Displacement of leads V1-V2 to the fifth ICS resulted in transition to a LBBB-like pattern with a QS wave in V1 in 14 of 26 patients (sensitivity, 53%; specificity, 100%), whereas displacement to the sixth ICS resulted in a QS pattern in all patients (sensitivity and specificity, 100%). In all patients in the control group, the ECG depicted a RBBB configuration with leads V1-V2 in the standard position, as well as at the fifth and sixth ICSs. CONCLUSIONS: In patients with paced rhythm and a RBBB-like pattern on the 12-lead ECG, displacement of leads V1-V2 to the sixth ICS accurately identifies the presence of true right ventricular pacing. PMID- 26118447 TI - suPAR: A New Biomarker for Cardiovascular Disease? AB - The fundamental role of inflammation in cardiovascular disease (CVD) has prompted interest in numerous biomarkers that detect subclinical levels of inflammation. Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker that correlates significantly with cardiovascular events and outperforms traditional markers of inflammation such as C-reactive protein (CRP) in prognosticating a range of CVDs. Furthermore, of particular interest is the suggestion that suPAR reflects a pathophysiological pathway more closely linked with subclinical organ damage than CRP. We provide the first comprehensive review of suPAR in CVD and explore its function and usefulness in predicting cardiovascular events. PMID- 26118448 TI - Statin Use and Incident Diabetes Explained by Bias Rather Than Biology. AB - The evidence supporting a link between statin use and incident diabetes is seemingly robust; it has been observed in multiple prospective randomized trials and confirmed by meta-analyses. However, differences in survival among statin vs placebo-treated patients in randomized trials might have caused bias with respect to diabetes surveillance. Bias might have been further exaggerated from the strong association between diabetes and cardiovascular events, which were the primary end points in major statin trials. Meta-analyses of randomized trials have demonstrated a 9% increase in the odds of incident diabetes among patients who receive statins compared with placebo (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.17) and a 12% increase of high-dose statin therapy vs low doses (OR, 1.12; 95% CI, 1.04-1.22). To simulate the possible effect of bias in these meta-analyses, each pooled trial was modified by assuming that 10% of the patients who experienced primary end points subsequently developed diabetes undetected. Meta-analyses of these simulated trials attenuated the association to a nonsignificant level among placebo-controlled trials (simulated OR, 1.04; 95% CI, 0.98-1.10), and high- vs low-dose trials (simulated OR, 1.07; 95% CI, 1.00 1.15). Our results demonstrate how a small influence of bias in each randomized trial could have contributed substantially to the observed association between statin use and diabetes. PMID- 26118449 TI - One-Year Coverage by Optical Coherence Tomography of a Bioresorbable Scaffold Neocarina: Is It Safe to Discontinue Dual-Antiplatelet Therapy? PMID- 26118450 TI - Brain Natriuretic Peptide Levels and the Occurrence of Subclinical Pulmonary Edema in Healthy Lowlanders at High Altitude. AB - BACKGROUND: High altitude (HA) pulmonary edema (PE) results from complex and misunderstood interactions between adaptation mechanisms. We assessed the occurrence of subclinical PE and brain natriuretic peptide (BNP) levels among nonacclimatized individuals during an expedition on Mount Elbrus (5642 m). METHODS: Seven subjects underwent assessment of vital signs, Lake Louise Score, ultrasound lung comets using handheld echography and circulating BNP using capillary testing at different stages of ascension, in addition to baseline echocardiography. Friedman tests were used to compare serial measurements. RESULTS: Heart rate, Lake Louise Score (P < 0.0001) and blood pressure (P = 0.037) increased during ascension; oxygen saturation decreased (P < 0.0001). BNP increased (40.7 +/- 16.8 vs 19.7 +/- 3.04 pg/mL; P < 0.01) after the summit, as did ultrasound lung comet count throughout ascension (P < 0.0001), but both parameters were not correlated (r = 0.36; P = 0.42). Post-summit peak BNP correlated with baseline left ventricular mass index (r = -0.79; P = 0.033). CONCLUSION: This study confirms the high incidence of subclinical PE during subacute exposure to hypobaric hypoxia and enhancement of this phenomenon after exertion. Although not correlated with the degree of PE, BNP levels increased after sustained effort at HA, but not at rest. Further investigation is needed to determine the mechanisms underlying the BNP response at HA and its usefulness as a monitoring tool during expeditions. PMID- 26118451 TI - The Ethics of Denying Prehospital STEMI Bypass to Patients With Do Not Resuscitate Orders. PMID- 26118452 TI - Multiple Coronary Arteries to Left Atrial Fistulae: An Uncommon Complication of Radiofrequency Ablation for Atrial Fibrillation. AB - A 64-year-old man had undergone catheter radiofrequency ablation (RFA) 3 times in the previous 3 years because of recurrent symptomatic atrial fibrillation. Five months after the third RFA procedure, unusually colored Doppler flows that drained into the left atrium (LA) were newly identified. Coronary computed tomographic angiography indicated the presence of multiple small fistulae reaching from the right and left circumflex coronary arteries to the LA, and this was confirmed using coronary angiography. This case shows that the multiple RFA procedures induced coronary neovascularization and fistulae formation after ischemic injuries to the LA. PMID- 26118453 TI - Hyponatremia in hospitalised patients with heart failure in internal medicine: Analysis of the Spanish national minimum basic data set (MBDS) (2005-2011). AB - OBJECTIVE: Hyponatremia is the most common electrolyte disorder seen in clinical practice. Numerous studies have reported increased inhospital mortality associated to this condition, which is also an independent predictor of comorbidity in patients admitted with heart failure (HF). The objective of this study is to assess the incidence, average length of stay, associated comorbidities, readmissions and mortality caused by hyponatremia in admissions for acute heart failure from the Spanish national minimum basic data set (MBDS). MATERIALS AND METHODS: Data from the Spanish national minimum basic data set (MBDS) of discharged patients who were initially diagnosed with heart failure (HF) from all internal medicine (IM) departments of Spanish National Health System (SNS) hospitals between 2005 and 2011 were analysed (ICD-9: 428; DRGs 127 and 544). A descriptive data analysis was conducted comparing the diagnosis codes and administrative variables of heart failure patients with and without hyponatremia. The chi-square test was used for qualitative variables and the Student's t test for quantitative variables. A bivariate analysis was used to detect statistical differences in the mortality of both groups, as well as mean age, Charlson index, average length of stay and readmissions. A multivariate logistic regression analysis was performed, taking intrahospital mortality and hospital readmissions as dependent variables, and age, gender, comorbidity according to the Charlson index and hyponatremia as independent variables. RESULTS: A total of 504,860 patients with acute heart failure were identified, of whom 11,095 (2.2%) presented with HNa. A gradual year-on-year increase of hyponatremia codification (both primary and secondary diagnosis) was observed at discharge throughout the study period (from 1.6% in 2005 to 2.8% in 2011; p<0.0001). Overall mortality due to any cause in patients with hyponatremia was 17% (1937 patients) versus 11% in non-hyponatremic patients (53,820 patients). The probability of readmission for patients with hyponatremia was 22% versus 17% in the non-hyponatremic group. Hyponatremia was associated to a higher rate of mortality during hospitalisation for acute heart failure with an odds ratio (OR) of 1.58, 95% CI, 1.50-1.66 (p<0.05). Hyponatremia maintained statistical significance in the regression model after adjusting for gender, OR 0.919 (95% CI 0.902-0.936); age, OR 1.061 (95% CI 1.060-1.062); and Charlson index, OR 1.388 (95% CI 1.361-1.461). CONCLUSIONS: Hyponatremia is associated to an increased rate of mortality and readmission in patients admitted for acute heart failure in SNS hospitals. Our study identified a statistically significant association between hyponatremia and increased intrahospital mortality independent of age, gender and the Charlson comorbidity index. During the defined follow-up period the discharge reports showed an increased codification of hyponatremia. PMID- 26118454 TI - Comparison of differentiated thyroid cancer in children and adolescents (<=20 years) with young adults. AB - CONTEXT: Age is a major prognostic factor in differentiated thyroid cancer (DTC). It is not clear if paediatric DTC has a different histopathological profile and outcome than DTC in adult patients <45 years of age. OBJECTIVE: To assess whether DTC in children and adolescents differs from young age group by comparing paediatric DTC (age <= 20) with DTC in patients >20 to <45 years of age. PATIENTS AND METHODS: We studied all cases of paediatric DTC seen during the period 1998 2011. We compared this group with a large sample of 213 consecutive adult patients in the age group >20 to <45 years seen during the period 1998-1999 in terms of their pathological features, extent of the disease and long-term outcome. Both groups were managed by the same team at a single institution. RESULTS: A total of 310 DTC were studied including 97 paediatric patients [median age 17 years (range, 8-20)] and 213 young adult patients [median age 33 years (range, 20.5-44.9)]. There was no difference in gender distribution, tumour subtypes, size and tumour multifocality, but there was a significantly higher rate of extrathyroidal extension [40/75 (53.3%) vs 81/213 (38.0%), P = 0.03], lymph node [57/73 (78%) vs 102/183 (55.7%), P < 0.0001] and distant metastases [16/97 (16.5%) vs 8/213 (3.8%), P < 0.0001] in the paediatric than the adult groups. Kaplan-Meier analysis showed a higher risk of persistent/recurrent disease in the paediatric group than adults (log-rank test 0.03). However, there was no mortality secondary to DTC in both groups. CONCLUSION: Paediatric DTC is distinct from DTC in the young adults (age >20 to <45 years). It is characterized by a higher rate of extrathyroidal extension, lymph node and distant metastases and a higher risk of persistent/recurrent DTC. PMID- 26118455 TI - Crystal-storing histiocytosis: a clinicopathological study of 13 cases. AB - AIMS: Crystal-storing histiocytosis (CSH) is a rare lesion composed of histiocytes with abnormal intralysosomal accumulation of immunoglobulin (Ig) as crystals, reported in patients with plasmacytic/lymphoplasmacytic neoplasms. The aims of this study were to report the clinicopathological features of 13 patients with CSH, and to describe the proteomic composition of the crystals in three cases analysed by mass spectrometry (MS). METHODS AND RESULTS: There were seven men and six women, with a median age of 60 years (range, 33-79 years). CSH was generalized in one patient (8%) and localized in 12 (92%) patients, involving various sites. CSH was associated with a low-grade B-cell lymphoma with plasmacytoid differentiation or a plasma cell neoplasm in all cases. In 10 (77%) cases, CSH represented >50% of the neoplastic infiltrate. According to immunohistochemical studies, histiocytes were positive for monotypic kappa in 5 (50%) cases, and for monotypic lambda in 4 (40%) cases; in 1 (10%) case, the results were equivocal. MS analysis of the histiocyte contents in all three tested cases showed a predominance of variable-region fragments of Ig light and/or heavy chains. CONCLUSIONS: CSH is frequently associated with an underlying lymphoplasmacytic neoplasm. MS findings suggest that Ig alterations and/or possibly defects in the ability of histiocytes to process Ig play a role in pathogenesis. PMID- 26118456 TI - Bisphosphonates in patients with renal cell carcinoma and bone metastases: a sunitinib global expanded-access trial subanalysis. AB - AIM: To investigate retrospectively the effects of bone metastases and bisphosphonates in sunitinib-treated metastatic renal cell carcinoma patients. PATIENTS & METHODS: Patients in Groups (Gp) 1 and 2, but not Gp3, had bone metastases. Gp2 received bisphosphonates following standard practice. RESULTS: Gp2 had less favorable prognosis than Gp1. Gp3 had fewer metastases and the best prognosis. More serious adverse events occurred in Gp2 versus Gp1. The difference in overall survival between Gp1 and Gp2 was not significant after adjusting for covariates. Significantly shorter overall survival in Gp1 versus Gp3 persisted after adjusting for covariates. CONCLUSION: Bone metastases may have a negative prognostic impact in metastatic renal cell carcinoma. Bisphosphonates may have delayed early disease progression for prognostically worse sunitinib/bisphosphonate-treated patients. PMID- 26118457 TI - Effectiveness of anatomic criteria for predicting parotid tumour location. AB - OBJECTIVE: We evaluated the accuracy, positive predictive value (PPV), negative predictive value (NPV), specificity and sensitivity of eight anatomic landmarks to differentiate parotid deep lobe tumours from superficial lobe tumours: the lateral margin of the retromandibular vein (RMV), a straight line from the facial nerve trunk (FN trunk) to the mandibular ramus (FN line), a straight line from the FN trunk to the RMV (tRMV), a straight line from the FN trunk to the lateral margin of the masseter (tMasseter), a straight line from the ipsilateral vertebral posterior end to the RMV (U-line), an arc with a radius of 8.5 mm centred on the mandibular ramus (Conn's arc), a straight line from the lateral surface of the masseter muscle to the lateral margin of the RMV (rMasseter) and an angle from the FN line, tumour and the lateral margin of the masseter muscle (FTM angle). METHODS: A total of 181 patients with a parotid gland tumour who underwent parotidectomy at a tertiary hospital were identified retrospectively from May 2005 to May 2013. Pre-operative computed tomography and intraoperative findings were compared to evaluate each landmark. RESULTS: rMasseter (accuracy: 85.5%, PPV: 90.0%, NPV: 85.12%, specificity: 98.1%, sensitivity: 22.2%) and tMasseter (accuracy: 86.3%, PPV: 80.0%, NPV: 87.1%, specificity: 97.1%, sensitivity: 44.4%) showed superior results as diagnostic criteria. CONCLUSION: rMasseter and tMasseter were useful as anatomic landmarks to differentiate a parotid deep lobe tumour from a superficial lobe tumour. PMID- 26118458 TI - Hypoxic and hypercapnic ventilatory responses in rats with polycystic ovaries. AB - In female rats, a single injection of estradiol valerate (EV) results in effects that are similar to those observed in women with polycystic ovary syndrome (PCOS). We hypothesized that EV-induced PCOS affects breathing control based on evidence showing an influence of sex hormones on ventilation. To test this hypothesis, we studied the effects of EV treatment on the ventilation of female rats in air, in 7% CO2 and in 7% O2, at 30, 45 and 60 days after EV injection. The group examined 30 days after EV treatment showed a 61% reduction in the hypercapnic ventilatory response compared to the control group. Basal ventilation, hypoxic ventilatory response, and body temperature were not affected. These results, suggest that the hormonal changes observed in PCOS may result in a temporary inhibition of the central chemoreflex but do not influence basal ventilation or the hypoxic peripheral chemoreflex. PMID- 26118459 TI - Expression of SANT/HTH Myb mRNA, a plant morphogenesis-regulating transcription factor, changes due to viroid infection. AB - Potato spindle tuber viroid (PSTVd) belongs to plant-pathogenic, circular, non coding RNAs. Its propagation is accompanied by (mis)regulation of host genes and induction of pathogenesis symptoms including changes of leaf morphogenesis depending on the strength of viroid variant. We found strong genotype-dependent suppression of tomato morphogenesis-regulating transcription factor SANT/HTH-Myb (SlMyb) due to viroid pathogenesis. Its relative mRNA level was found to be significantly decreased in PSTVd-sensitive tomato (cvs Rutgers and Heinz 1706) due to degradation processes, but increased in PSTVd-tolerant (cv. Harzfeuer). In heterologous system of Nicotiana benthamiana, we observed a SlMyb-associated necrotic effect in agroinfiltrated leaf sectors during ectopic overexpression. Leaf sector necroses were accompanied by activation of nucleolytic enzymes but were suppressed by a strongly pathogenic PSTVd variant. Contrary to that, PSTVd's effect was inhibited by the silencing suppressor p19. It was found that in both, Solanum lycopersicum leaves and N. benthamiana leaf sectors, SlMyb mRNA degradation was significantly stronger in viroid-infected tissues. Necroses induction as well as gene silencing experiments using the SANT/HTH-Myb homologues revealed involvement of this Myb in physiological changes like distortions in flower morphogenesis and growth suppression. PMID- 26118460 TI - A Common Mutation of Long QT Syndrome Type 1 in Japan. AB - BACKGROUND: Previous studies of long QT syndrome (LQTS) have revealed the presence of country-specific hot spots in KCNQ1 mutations, and the purpose of this study was to evaluate the influence of a common mutation on clinical phenotypes in Japanese LQT1 patients. METHODS AND RESULTS: We retrospectively studied the frequency of each mutation in 190 LQT1 Japanese probands and evaluated the clinical severity of LQT1 among carriers with a common mutation. We also compared it with that of carriers with other mutations. In the Japanese cohort, the most common mutation was p. A344spl (c.1032 G>A), comprising a substitution of a guanine for an adenine at the last base of exon 7, and it was found in 17 probands (8.9%). Regarding the clinical characteristics of A344spl carriers, the mean age-of-onset was 10+/-4 years, >40% were symptomatic, and the mean corrected QT interval was 461+/-30 ms. The prognosis for carriers of the A344spl mutation (n=31) was intermediate between that for the A341V mutation reported to be associated with severe phenotypes (n=24) and other mutations (n=290). CONCLUSIONS: The A344spl mutation was a frequent LQTS genotype in Japan, which indicates that the influence of country-specific hot spots should be considered when studying LQT1 clinical phenotypes. PMID- 26118461 TI - Impact of Ross Operation on Outcome in Young Female Adult Patients Wanting to Have Children. AB - BACKGROUND: The most appropriate valve substitute at aortic valve replacement (AVR) for young female adult patients wanting to have children is unclear. METHODS AND RESULTS: Between 1992 and 2013, 12 consecutive female patients aged >18 (median, 22.5 years; range, 18-34 years) underwent Ross operation (Ross group). Between 1984 and 2013, 9 consecutive female patients aged >18 (median, 30 years; range, 22-39 years) underwent AVR with bioprosthesis (bioprosthesis group). There was 1 late mortality in the bioprosthesis group, due to prosthetic valve endocarditis (PVE). Freedom from reoperation for aortic valve at 15 years was 90.0% in the Ross group, and 57.1% in the bioprosthesis group (log-rank, P=0.098). One in the Ross group underwent reoperation for aortic regurgitation (AR), whereas 4 in the bioprosthesis group did so for aortic stenosis (AS) in 2, combined AS and AR in 1, and PVE in 1. Five patients in the Ross group and 3 in the bioprosthesis group had 7 and 4 uneventful pregnancies, respectively. AR progressed during the perinatal period in a total of 7 of 11 pregnancies. No AS was seen at discharge, after 5 years, or during pregnancy in the Ross group. CONCLUSIONS: The long-term outcome of Ross operation for female patients wanting to have children is excellent. Although subclinical pulmonary autograft valve regurgitation during pregnancy was often observed, pulmonary autograft stenosis did not occur, therefore it would be an ideal option for patients wanting to have children. PMID- 26118463 TI - Induction chemotherapy with cetuximab, vinorelbine-cisplatin followed by thoracic radiotherapy and concurrent cetuximab, vinorelbine-cisplatin in patients with unresectable stage III non-small cell lung cancer. AB - OBJECTIVES: The modest benefits from concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC) warrant a more effective treatment regimen. We herein report mature data of a phase I/II study testing the addition of cetuximab to induction vinorelbine/cisplatin (NP) followed by concurrent cetuximab NP and thoracic radiation in patients with unresectable stage III NSCLC. MATERIALS AND METHODS: Eligible patients were treated with weekly cetuximab (initial dose 400 mg/m2, day 1, week 1; maintenance dose 250 mg/m2 from week 2 to the end of CCRT) and induction vinorelbine (25 mg/m2, days 1 and 8) and cisplatin (75 mg/m2, day 1) every 3 weeks for 2 cycles from week 2. Concomitant thoracic radiation (60-66 Gy/2 Gy) and two cycles of NP (vinorelbine 12.5 mg/m2, days 1 and 8; cisplatin 25mg/m2, days 1 to 3, every 3 weeks) were started from week 7. The primary endpoints were toxicities; the secondary endpoints encompassed response rate and survival. RESULTS: In total, 27 patients were enrolled, and 24 completed the full regimen. No treatment-related death occurred. Severe (CTCAE Grade 3 or high) adverse events were experienced by 81% patients (22/27), mostly haematologic. Severe non-haematologic toxicities including nausea/vomiting, intestinal obstruction, pulmonary infection and esophagitis, each of which was detected in <7% of patients. With a median follow up of 26.7 months, the median survival was 26.7 months, with 1- and 2-year survival rates of 88.9% and 51.9%, respectively. Six patients remained progression-free to date, and the median progression-free survival was 13.5 months. The overall response rate was 63% and 77.8% after the induction and CCRT phases, respectively. CONCLUSION: Weekly cetuximab with induction vinorelbine/cisplatin followed by concurrent cetuximab vinorelbine/cisplatin thoracic radiation is feasible with a manageable toxicity profile and clinically active. PMID- 26118464 TI - Risk of congenital disease in 46 infected fetuses according to gestational age of primary human cytomegalovirus infection in the mother. AB - Given the difficulty in establishing the exact time of HCMV transmission from mother to fetus, HCMV intrauterine infection was investigated in 46 infected fetuses/newborns by correlating maternal and fetal parameters with clinical outcome according to the time interval between the onset of maternal infection and prenatal diagnosis. In detail, 17/28 (60.7%) asymptomatic and 18/18 (100%) symptomatic fetuses/newborns were infected as a consequence of a primary maternal HCMV infection acquired <=8 weeks of gestational age, while 11/28 (39.3%) asymptomatic and 0/18 (0%) symptomatic fetuses/newborns were congenitally infected when maternal infection was acquired >8 weeks' gestation. Symptomatic fetal infections appeared to be associated with a maternal primary infection occurring at <= 8 weeks' gestation. Cordocentesis performed at 20 weeks' gestation should be restricted to high risk infected fetuses. PMID- 26118462 TI - Reduced insulin-receptor mediated modulation of striatal dopamine release by basal insulin as a possible contributing factor to hyperdopaminergia in schizophrenia. AB - Schizophrenia is a severe and chronic neuropsychiatric disorder which affects 1% of the world population. Using the brain imaging technique positron emission tomography (PET) it has been demonstrated that persons with schizophrenia have greater dopamine transmission in the striatum compared to healthy controls. However, little progress has been made as to elucidating other biological mechanisms which may account for this hyperdopaminergic state in this disease. Studies in animals have demonstrated that insulin receptors are expressed on midbrain dopamine neurons, and that insulin from the periphery acts on these receptors to modify dopamine transmission in the striatum. This is pertinent given that several lines of evidence suggest that insulin receptor functioning may be abnormal in the brains of persons with schizophrenia. Post-mortem studies have shown that persons with schizophrenia have less than half the number of cortical insulin receptors compared to healthy persons. Moreover, these post mortem findings are unlikely due to the effects of antipsychotic treatment; studies in cell lines and animals suggest antipsychotics enhance insulin receptor functioning. Further, hyperinsulinemia - even prior to antipsychotic use - seems to be related to less psychotic symptoms in patients with schizophrenia. Collectively, these data suggest that midbrain insulin receptor functioning may be abnormal in persons with schizophrenia, resulting in reduced insulin-mediated regulation of dopamine transmission in the striatum. Such a deficit may account for the hyperdopaminergic state observed in these patients and would help guide the development of novel treatment strategies. We hypothesize that, (i) insulin receptor expression and/or function is reduced in midbrain dopamine neurons in persons with schizophrenia, (ii) basal insulin should reduce dopaminergic transmission in the striatum via these receptors, and (iii) this modulation of dopaminergic transmission by basal insulin is reduced in the brains of persons with schizophrenia. PMID- 26118465 TI - Ultrastructure of the three anterior cruciate ligament bundles. AB - The anterior cruciate ligament (ACL) can be morphologically separated into not only two, but three bundles: the anteromedial-medial bundle (AM-MB), the anteromedial-lateral bundle (AM-LB), and the posterolateral bundle (PLB). Our hypothesis was that the three bundles differ in their microstructures. The purpose of this study was to clarify the microstructural differences among the three bundles. The normal ACLs of six fresh frozen cadavers were harvested. After the AM-MB, AM-LB, and PLB were identified, their fibril structures were analyzed using a transmission electron microscope. The fibril orientation, distribution pattern, and the mass average diameter of the fibrils (MAD) were compared among the AM-MBs, AM-LBs, and PLBs. The AM-MB and AM-LB fibrils were arranged mostly in the longitudinal direction, while the PLB fibrils were not aligned in a uniform direction. The fibril diameter distribution pattern of AM-MBs showed a bi-modal pattern due to the existence of small-diameter (30-40 nm) and large-diameter fibrils (70-80 nm), while that of the AM-LBs and PLBs had a unimodal pattern with one prominent high peak at a diameter of 50-60 nm. The mean MAD of the AM-MBs (83.2 - 11.2 nm) was significantly larger than that of the PLBs (66.8 - 7.7 nm), while it showed no significant difference compared to that of the AM-LBs (77.6 - 12.3 nm). The three ACL bundles have different ultrastructures. The AM-MB predominantly includes thick, uni-directionally oriented fibrils like tendons, while the PLB consists of thinner, multi-directionally oriented fibrils. The AM LB shows an intermediate structure between the AM-MB and the PLB. PMID- 26118466 TI - The Pattern of Opioid Management by Australian General Practice Trainees. AB - OBJECTIVE: With escalating opioid prescribing come individual and public health harms. To inform quality improvement measures, understanding of opioid prescribing is essential. We aimed to establish consultation-level prevalence and associations of opioid prescribing. DESIGN: A cross-sectional secondary analysis from a longitudinal multisite cohort study of general practitioner (GP) vocational trainees: "Registrar Clinical Encounters in Training." SETTING: Four of Australia's seventeen GP Regional Training Providers, during 2010-13. SUBJECTS: GP trainees. METHODS: Practice and trainee demographic data were collected as well as patient, clinical and educational data of 60 consecutive consultations of each trainee, each training term. Outcome factors were any opioid analgesic prescription and initial opioid analgesic prescription for a specific problem for the first time. RESULTS: Overall, 645 trainees participated. Opioids comprised 4.3% prescriptions provided for 3.8% of patients. Most frequently prescribed were codeine (39.9%) and oxycodone (33.4%). Prescribing was for acute pain (29.3%), palliative care (2.6%) or other indications (68.1%). Most prescribing involved repeat prescriptions for pre-existing problems (62.7% of total). Other associations included older patients; prescriber and patient male gender; Aboriginal/Torres Strait Islander status; rural and disadvantaged locations; longer consultations; and generation of referrals, follow-up, and imaging requests. Opioid initiation was more likely for new patients with new problems, but otherwise associations were similar. Trainees rarely reported addiction risk-mitigation strategies. CONCLUSIONS: Most opioids were prescribed as maintenance therapy for non-cancer pain. Demographic associations with opioid analgesic prescribing resemble those presenting for opioid dependency treatment. Our findings should inform measures by regulators and medical educators supporting multimodal pain management. PMID- 26118467 TI - Self-Powered Human-Interactive Transparent Nanopaper Systems. AB - Self-powered human-interactive but invisible electronics have many applications in anti-theft and anti-fake systems for human society. In this work, for the first time, we demonstrate a transparent paper-based, self-powered, and human interactive flexible system. The system is based on an electrostatic induction mechanism with no extra power system appended. The self-powered, transparent paper device can be used for a transparent paper-based art anti-theft system in museums or for a smart mapping anti-fake system in precious packaging and documents, by virtue of the advantages of adding/removing freely, having no impairment on the appearance of the protected objects, and being easily mass manufactured. This initial study bridges the transparent nanopaper with a self powered and human-interactive electronic system, paving the way for the development of smart transparent paper electronics. PMID- 26118468 TI - Among-lake reciprocal transplants induce convergent expression of immune genes in threespine stickleback. AB - Geographic variation in parasite communities can drive evolutionary divergence in host immune genes. However, biotic and abiotic environmental variation can also induce plastic differences in immune function among populations. At present, there is little information concerning the relative magnitudes of heritable vs. induced immune divergence in natural populations. We examined immune gene expression profiles of threespine stickleback (Gasterosteus aculeatus) from six lakes on Vancouver Island, British Columbia. Parasite community composition differs between lake types (large or small, containing limnetic- or benthic-like stickleback) and between watersheds. We observed corresponding differences in immune gene expression profiles among wild-caught stickleback, using a set of seven immune genes representing distinct branches of the immune system. To evaluate the role of environmental effects on this differentiation, we experimentally transplanted wild-caught fish into cages in their native lake, or into a nearby foreign lake. Transplanted individuals' immune gene expression converged on patterns typical of their destination lake, deviating from their native expression profile. Transplant individuals' source population had a much smaller effect, suggesting relatively weak genetic underpinning of population differences in immunity, as viewed through gene expression. This strong environmental regulation of immune gene expression provides a counterpoint to the large emerging literature documenting microevolution and genetic diversification of immune function. Our findings illustrate the value of studying immunity in natural environmental settings where the immune system has evolved and actively functions. PMID- 26118469 TI - A local application of mesenchymal stem cells and cyclosporine A attenuates immune response by a switch in macrophage phenotype. AB - The immunosuppressive effects of systemically administered mesenchymal stem cells (MSCs) and immunosuppressive drugs have been well documented. We analysed the mechanisms underlying the therapeutic effect of MSCs applied locally in combination with non-specific immunosuppression in a mouse model of allogeneic skin transplantation. The MSC-seeded and cyclosporine A (CsA)-loaded nanofibre scaffolds were applied topically to skin allografts in a mouse model and the local immune response was assessed and characterized. MSCs migrated from the scaffold into the side of injury and were detected in the graft region and draining lymph nodes (DLNs). The numbers of graft-infiltrating macrophages and the production of nitric oxide (NO) were significantly decreased in recipients treated with MSCs and CsA, and this reduction correlated with impaired production of IFNgamma in the graft and DLNs. In contrast, the proportion of alternatively activated macrophages (F4/80+ CD206+ cells) and the production of IL-10 by intragraft macrophages were significantly upregulated. The ability of MSCs to alter the phenotype of macrophages from the M1 type into an M2 population was confirmed in a co-culture system in vitro. We suggest that the topical application of MSCs in combination with CsA induces a switch in macrophages to a population with an alternatively activated 'healing' phenotype and producing elevated levels of IL-10. These alterations in macrophage phenotype and function could represent one of the mechanisms of immunosuppressive action of MSCs applied in combination with CsA. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118471 TI - Abstracts of the 1st Congress of the European Academy of Neurology, Berlin, Germany, June 2015. PMID- 26118470 TI - Corrigendum: reduced IFNlambda4 activity is associated with improved HCV clearance and reduced expression of interferon-stimulated genes. PMID- 26118472 TI - Incidence and care-related costs of severe hypoglycaemia requiring emergency treatment in Andalusia (Spain): the PAUEPAD project. AB - AIMS: Hypoglycaemia is a serious medical emergency. The need for emergency medical service care and the costs of hypoglycaemic emergencies are not completely known. METHODS: This was a retrospective observational study using Public Company for Health Emergencies (EPES) data for hypoglycaemia in 2012. The EPES provides emergency medical services to the entire population of Andalusia, Spain (8.5 million people). Data on event type, onsite treatments, emergency room visits or hospitalization were collected. Medical costs were estimated using the public rates for healthcare services. RESULTS: From a total of 1 137 738 emergency calls that requested medical assistance, 8683 had a primary diagnosis of hypoglycaemia (10.34 per 10 000 person-years). The incidence of severe hypoglycaemic episodes requiring emergency treatment in the estimated population with diabetes was 80 episodes per 10 000 person-years. A total of 7479 episodes (86%) required an emergency team to visit the patient's residence. The majority of cases (64%) were addressed in the residence, although 1784 (21%) cases were transferred to hospital. A total of 5564 events (65%) involved patients aged > 65 years. Overall mortality was 0.32% (28 cases). The total annual cost of attending a hypoglycaemic episode was ?6 093 507, leading to an estimated mean direct cost per episode of ?702 +/- 565. Episodes that required hospital treatment accounted for 49% of the total costs. CONCLUSIONS: Hypoglycaemia is a common medical emergency that is associated with high emergency medical service utilization, resulting in a significant economic impact on the health system. PMID- 26118473 TI - Swallowable smart pills for local drug delivery: present status and future perspectives. AB - Smart pills were originally developed for diagnosis; however, they are increasingly being applied to therapy - more specifically drug delivery. In addition to smart drug delivery systems, current research is also looking into localization systems for reaching the target areas, novel locomotion mechanisms and positioning systems. Focusing on the major application fields of such devices, this article reviews smart pills developed for local drug delivery. The review begins with the analysis of the medical needs and socio-economic benefits associated with the use of such devices and moves onto the discussion of the main implemented technological solutions with special attention given to locomotion systems, drug delivery systems and power supply. Finally, desired technical features of a fully autonomous robotic capsule for local drug delivery are defined and future research trends are highlighted. PMID- 26118475 TI - Detection of alloantibody-mediated complement activation: A diagnostic advance in monitoring kidney transplant rejection? AB - OBJECTIVE: Antibody-mediated rejection (ABMR) is an important cause of kidney allograft injury. In the last two decades, detection of complement split product C4d along transplant capillaries, a footprint of antibody-mediated classical complement activation, has evolved as a useful diagnostic marker of ABMR. While it was recognized that ABMR may occur also in the absence of C4d, numerous studies have shown that C4d deposition may indicate a more severe rejection phenotype associated with poor graft survival. Such studies suggest a possible diagnostic benefit of ex vivo monitoring the complement-activating capability of circulating alloantibodies. DESIGN AND METHODS: We reviewed the literature between 1993 and 2015, focusing on in vivo (biopsy work-up) and in vitro detection (modified bead array technology) of HLA antibody-triggered classical complement activation in kidney transplantation. RESULTS: Precise HLA antibody detection methods, in particular Luminex-based single antigen bead (SAB) assays, have provided a valuable basis for the design of techniques for in vitro detection of HLA antibody-triggered complement activation reflected by C1q, C4 or C3 split product deposition to the bead surface. Establishing such assays it was recognized that deposition of complement products to SAB, which critically depends on antibody binding strength, may be a cardinal trigger of the prozone effect, a troublesome in vitro artifact caused by a steric interference with IgG detection reagents. False-low IgG results, especially on SAB with extensive antibody binding, have to be considered when interpreting studies analyzing the diagnostic value of complement in relation to standard IgG detection. Levels of complement-fixing donor-specific antibodies (DSA) were shown to correlate with the results of standard crossmatch tests, suggesting potential application for crossmatch prediction. Moreover, while the utility of pre-transplant complement detection, at least in crossmatch-negative transplant recipients, is controversially discussed, a series of studies have shown that the appearance of post-transplant complement-fixing DSA may be associated with C4d deposition in transplant capillaries and a particular risk of graft failure. CONCLUSIONS: The independent value of modified single antigen bead assays, as compared to a careful analysis of standard IgG detection, which may be affected considerably by complement dependent artifacts, needs to be clarified. Whether they have the potential to improve the predictive accuracy of our current diagnostic repertoire warrants further study. PMID- 26118474 TI - The development of a high-performance liquid chromatography-tandem mass spectrometric method for simultaneous quantification of morphine, morphine-3-beta glucuronide, morphine-6-beta-glucuronide, hydromorphone, and normorphine in serum. AB - OBJECTIVES: Development and validation of a selective, robust high-performance liquid chromatography-tandem mass spectrometric (HPLC/MS-MS) method for the quantification of morphine, morphine-3-beta-glucuronide, morphine-6-beta glucuronide, hydromorphone, and normorphine in human serum. DESIGN AND METHODS: Drug-free human serum samples spiked with morphine, morphine-3-beta-glucuronide, morphine-6-beta-glucuronide, hydromorphone, and normorphine were prepared by protein precipitation using methanol containing the internal standards. Samples were injected onto a Thermo Scientific AccuCore PFP column for chromatographic separation. Detection was achieved using a Thermo Scientific TSQ Vantage mass spectrometer. Assay validation followed the new Clinical and Laboratory Standards Institute (CLSI) C62-A guidelines. RESULTS: The analytical measuring range for all analytes was determined to be 5 to 1000 ng/mL. Intra- and inter-assay precision for three quality control levels were <= 7.0% and <= 13.5%, respectively. Carryover, stability, linearity, matrix effects, extraction and processing efficiency and method comparison characteristics were acceptable relative to the CLSI C62 guidelines. CONCLUSION: The validation of this HPLC MS/MS method demonstrated a robust and rapid assay for the quantification of morphine, morphine-3-beta-glucuronide, morphine-6-beta-glucuronide, hydromorphone, and normorphine. PMID- 26118477 TI - Local divergence of thermal reaction norms among amphibian populations is affected by pond temperature variation. AB - Although temperature variation is known to cause large-scale adaptive divergence, its potential role as a selective factor over microgeographic scales is less well understood. Here, we investigated how variation in breeding pond temperature affects divergence in multiple physiological (thermal performance curve and critical thermal maximum [CTmax]) and life-history (thermal developmental reaction norms) traits in a network of Rana arvalis populations. The results supported adaptive responses to face two main constraints limiting the evolution of thermal adaptation. First, we found support for the faster-slower model, indicating an adaptive response to compensate for the thermodynamic constraint of low temperatures in colder environments. Second, we found evidence for the generalist-specialist trade-off with populations from colder and less thermally variable environments exhibiting a specialist phenotype performing at higher rates but over a narrower range of temperatures. By contrast, the local optimal temperature for locomotor performance and CTmax did not match either mean or maximum pond temperatures. These results highlight the complexity of the adaptive multiple-trait thermal responses in natural populations, and the role of local thermal variation as a selective force driving diversity in life-history and physiological traits in the presence of gene flow. PMID- 26118478 TI - Systematic review of ground reaction force measurements in cats. AB - Although orthopaedic abnormalities in cats are frequently observed radiographically, they remain clinically underdiagnosed, and kinetic motion analysis, a fundamental aspect of orthopaedic research in dogs and horses, is not commonly performed. More information obtained with non-invasive measurement techniques to assess normal and abnormal gait in cats would provide a greater insight into their locomotion and biomechanics and improve the objective measurement of disease alterations and treatment modalities. In this systematic review, 12 previously performed studies that investigated ground reaction force measurements in cats during locomotion were evaluated. The aims of these studies, the measurement methods and equipment used, and the outcomes of parameters used to assess both sound and diseased cats are summarised and discussed. All reviewed studies used pressure sensitive walkways to gain data and all provided an acclimatisation period as a prerequisite for measurements. In sound cats during walking, the forelimb peak vertical force was greater than in the hindlimb and the peak vertical force in the hindlimb was greater in cats than in dogs. This review confirms that ground reaction forces can be used to evaluate lameness and treatment effects in the cat. PMID- 26118476 TI - Soluble Immune Mediators and Vaginal Bacteria Impact Innate Genital Mucosal Antimicrobial Activity in Young Women. AB - INTRODUCTION: Innate activity against Escherichia coli in female genital secretions may represent contributions from vaginal bacteria and host soluble immune mediators. We analyzed the relationship between E. coli inhibitory activity, soluble immune mediators, and vaginal bacteria in participants in MTN 004, a placebo-controlled trial of VivaGel((r)) , a candidate product for topical HIV pre-exposure prophylaxis. METHODS: Escherichia coli inhibitory activity was quantified by colony reduction assay. Endocervical concentrations of interleukin (IL)-1beta, IL-6, IL-12p40, macrophage inflammatory protein (MIP)-1alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), lactoferrin, and secretory leukocyte protease inhibitor (SLPI) were quantified to generate a cumulative mediator score. Vaginal bacteria were characterized by quantitative cultures. RESULTS: In the two placebo arms, higher soluble immune mediator score was associated with greater E. coli inhibitory activity (beta = 17.49, 95% CI [12.77, 22.21] and beta = 13.28, 95% CI [4.76, 21.80]). However, in the VivaGel arm, higher concentrations of E. coli (beta = -3.80, 95% CI [-6.36, -1.25]) and group B Streptococcus (beta = -3.91, 95% CI [-6.21, -1.60]) were associated with reduced E. coli inhibitory activity. CONCLUSIONS: Both host mediators and vaginal bacteria impact E. coli inhibition in genital secretions. The relative contributions of host mediators and bacteria varied between women who used VivaGel vs placebos. PMID- 26118479 TI - Detection of indoxyl sulfate levels in dogs and cats suffering from naturally occurring kidney diseases. AB - Indoxyl sulfate (IS), a protein-bound uraemic toxin, has been found to accumulate in the serum of people with renal diseases and is associated with free radical induction, nephrotoxicity cardiovascular toxicity, and osteoblast cytotoxicity. Although IS has been studied in humans and in experimental models, the role of IS in dogs and cats with kidney disease has not been investigated. A high performance liquid chromatography system was applied to detect plasma IS concentrations in non-azotaemic animals (63 dogs, 16 cats) and in animals with renal azotaemia (66 dogs, 69 cats). The IS levels of azotaemic animals were significantly higher (P <0.01) than those of non-azotaemic animals (median [IQR] 20.4 (9.5) mg/L vs. 7.2 (8.8) mg/L for dogs; median [IQR] 21 (18.9) mg/L vs. 14.8 (12.3) mg/L for cats). The IS level was significantly correlated with blood urea nitrogen, serum creatinine and phosphate concentrations. Dogs with acute kidney injury had significantly higher IS levels (P <0.01) than those with chronic kidney diseases (CKD) (median [IQR] 57.7 (40.8) mg/L vs. 17.7 (25.1) mg/L). When CKD was graded using the International Renal Interest Society (IRIS) staging system, IS levels were correlated with CKD severity in both dogs and cats. The IS concentration is directly related to loss of renal function. Further studies are necessary to determine whether measurement of IS provides any additional diagnostic or prognostic information in dogs and cats with kidney disease. PMID- 26118480 TI - A simple procedure to improve the surface passivation for single molecule fluorescence studies. AB - The single-molecule fluorescence technique is becoming a general and mature tool to probe interactions and dynamics of biomolecules with ultra high precision and accuracy. However, nonspecific adsorption of biomolecules to the flow cells remains a major experimental riddle for the study of many complex biological systems, especially those exhibiting low binding affinity and presenting with weakly populated intermediates. Many novel surface passivation methods have been introduced to reduce nonspecific interactions. Here, we present an effective and inexpensive method to significantly reduce nonspecific binding of biomolecules in conventional poly (ethylene glycol) (PEG)-based surface passivation protocols, without additional exogenous effects. In particular, we propose a simple 10 min Tween-20 treatment for the PEG passivated surface, which could further increase the hydrophilicity of the surface and thus promote passivation efficacy by about 5 to 10 times. We anticipate that this new procedure will find broad practical applications and extend the current reaches of single-molecule fluorescence studies. PMID- 26118481 TI - How far can a single hydrogen bond tune the spectral properties of the GFP chromophore? AB - Photoabsorption of the hydrogen-bonded complex of a neutral and an anionic Green Fluorescent Protein chromophore has been studied using a new dual-detection approach to action-absorption spectroscopy. Following absorption of one photon, dissociation through a single channel ensures that the full absorption spectrum is measured. Our theoretical account of the spectral shape reveals that the anionic 0-0 transition (464 nm) is blue-shifted compared to that of the wild-type protein (478 nm) due to the stronger H-bond in the dimer, and represents an upper bound for that of the isolated anion. At the same time, the apparent effect of the H-bond for the neutral chromophore is as large as 0.5 eV, red-shifting the absorption maximum of the isolated neutral (340 nm) to that measured in the dimer (393 nm) and various proteins (~395 nm). This shift results from changes in the topography of potential-energy surfaces in the Franck-Condon region of the H bonded systems. PMID- 26118482 TI - Effect of 808 nm Diode Laser on Swimming Behavior, Food Vacuole Formation and Endogenous ATP Production of Paramecium primaurelia (Protozoa). AB - Photobiomodulation (PBM) has been used in clinical practice for more than 40 years. To clarify the mechanisms of action of PBM at cellular and organism levels, we investigated its effect on Paramecium primaurelia (Protozoa) irradiated by an 808 nm infrared diode laser with a flat-top handpiece (1 W in CW). Our results led to the conclusion that: (1) the 808 nm laser stimulates the P. primaurelia without a thermal effect, (2) the laser effect is demonstrated by an increase in swimming speed and in food vacuole formation, (3) the laser treatment affects endogenous adenosine triphosphate (ATP) production in a positive way, (4) the effects of irradiation dose suggest an optimum exposure time of 50 s (64 J cm(-2) of fluence) to stimulate the Paramecium cells; irradiation of 25 s shows no effect or only mild effects and irradiation up to 100 s does not increase the effect observed with 50 s of treatment, (5) the increment of endogenous ATP concentration highlights the positive photobiomodulating effect of the 808 nm laser and the optimal irradiation conditions by the flat-top handpiece. PMID- 26118483 TI - Discovery a novel organic solvent tolerant esterase from Salinispora arenicola CNP193 through genome mining. AB - An esterase gene, encoding a 325-amino-acid protein (SAestA), was mined form obligate marine actinomycete strain Salinispora arenicola CNP193 genome sequence. Phylogenetic analysis of the deduced amino acid sequence showed that the enzyme belonged to the family IV of lipolytic enzymes. The gene was cloned, expressed in Escherichia coli as a His-tagged protein, purified and characterized. The molecular weight of His-tagged SAestA is ~38 kDa. SAestA-His6 was active in a temperature (5-40 degrees C) and pH range (7.0-11.0), and maximal activity was determined at pH 9.0 and 30 degrees C. The activity was severely inhibited by Hg(2+), Cu(2+), and Zn(2+). In particular, this enzyme showed remarkable stability in presence of organic solvents (25%, v/v) with log P>2.0 even after incubation for 7 days. All these characteristics suggested that SAestA may be a potential candidate for application in industrial processes in aqueous/organic media. PMID- 26118484 TI - Injectable biopolymer based hydrogels for drug delivery applications. AB - Biopolymer based pH-sensitive hydrogels were prepared using chitosan (CS) with polyethylene glycol (PEG) of different molecular weights in the presence of silane crosslinker. The incorporated components remain undissolved in different swelling media as they are connected by siloxane linkage which was confirmed by Fourier transform infrared spectroscopy. The swelling in water was enhanced by the addition of higher molecular weight PEG. The swelling behaviour of the hydrogels against pH showed high swelling in acidic and basic pH, whereas, low swelling was examined at pH 6 and 7. This characteristic pH responsive behaviour at neutral pH made them suitable for injectable controlled drug delivery. The controlled release analysis of Cefixime (CFX) (model drug) loaded CS/PEG hydrogel exhibited that the entire drug was released in 30 min in simulated gastric fluid (SGF) while in simulated intestinal fluid (SIF), 85% of drug was released in controlled manner within 80 min. This inferred that the developed hydrogels can be an attractive biomaterial for injectable drug delivery with physiological pH and other biomedical applications. PMID- 26118485 TI - Effects of Bush Sophora Root polysaccharide and its sulfate on immuno-enhancing of the therapeutic DVH. AB - Bush Sophora Root polysaccharide (BSRPS) and its sulfate, sulfated Bush Sophora Root polysaccharide (sBSRPS), possess the antiviral activities against duck hepatitis A virus. However their antiviral mechanisms are still not clear. This paper reported their immuno-enhancing roles in the therapeutic effects for duck virus hepatitis (DVH). The effects of BSRPS and sBSRPS on stimulating lymphocyte proliferation were investigated by MTT methods. After that, ducklings were challenged with DHAV and treated with BSRPS and sBSRPS. Meanwhile, the total antibody (Ab), cytokines including interferon gamma (IFN-gamma), hepatocyte growth factor (HGF), interleukin (IL)-2, IL-6 and IL-8 were determined by enzyme linked immuno sorbent assay methods. The results showed that BSRPS owned a fine hepatoprotective effect with stable HGF producing ability. Sulfated modification was able to increase the proliferation rates of B and T lymphocytes and the secretions of total Ab, IFN-gamma and IL-2, as comparison with those of BSRPS group. In summary, both of them exhibited immuno-enhancing effects on the therapeutic effects for DVH, and the capacity of sBSRPS was stronger than that of BSRPS. PMID- 26118486 TI - Characterization and in vitro antioxidant activity of Albizia stipulata Boiv. gum exudates. AB - The objective of the present study is to characterize the physicochemical properties and to determine the in vitro antioxidant activity of Albizia stipulata Boiv. gum exudates collected from Northeast India. The total carbohydrate, uronic acid and protein contents, monosaccharide composition and the molecular weight distribution of the purified gum was determined. The powder flow property and preliminary compressibility test were performed on the dried gum exudates. Fourier transform infrared spectroscopy (FTIR) study was performed to analyze the functional groups present in the structure. Differential scanning calorimetry (DSC) and thermogravimetry (TGA/DTA) analyses were performed to study the thermal stability of the gum. The antioxidant properties of the gum were evaluated by determining 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl scavenging activities and reducing power. The total carbohydrate and protein contents of the gum were found to be 75.17+/-3.21% and 2.60+/-1.05% respectively. The viscosity of 2% aqueous solution of the gum exhibited non-Newtonian type of flow showing pH dependent swelling. Arabinose and galactose were found to be the main monosaccharides present in the gum exudates and the molecular weight distribution of the gum was also found to be polydispersed. Results from DPPH, hydroxyl scavenging and reducing power studies showed the gum possesses antioxidant properties. PMID- 26118487 TI - Effect of cyclic freeze-thawing process on the structure and properties of collagen. AB - The influence of freeze-thawing cycles (named 'N') on the rheological and thermal properties of bovine skin collagen solution was investigated using a rheometer and differential scanning calorimetry (DSC). The results of dynamic frequency sweep tests showed that the elasticity of collagen increased as N increased to 3, 5 and 7. Especially, after the freeze-thawing cycles of N=7, the recovery capacity of collagen remarkably increased (from 17.76% to 74.98%) and the hysteresis loop areas of collagen also became larger (from 95.53 to 218.24 Pa/s). Moreover, DSC and non-isothermal kinetic analysis revealed that although the freeze-thawing process had little impact on the thermal denaturation temperature, the endothermic enthalpy was increased by 73% when N=7, as estimated from the area under the endothermic peak and from the Friedman isoconversional method. In addition, as observed by atomic force microscopy (AFM), the fibers of collagen became thicker after the process of freeze-thawing cycles, indicating that the aggregation of collagen molecules was enhanced in the process of freeze-thawing. Meanwhile, the morphology of freeze-thawed collagen sponge examined by scanning electron microscopy (SEM) exhibited a porous network structure, and the pores became more regular with increasing N. PMID- 26118488 TI - Entropic Uncertainty Relation and Information Exclusion Relation for multiple measurements in the presence of quantum memory. AB - The Heisenberg uncertainty principle shows that no one can specify the values of the non-commuting canonically conjugated variables simultaneously. However, the uncertainty relation is usually applied to two incompatible measurements. We present tighter bounds on both entropic uncertainty relation and information exclusion relation for multiple measurements in the presence of quantum memory. As applications, three incompatible measurements on Werner state and Horodecki's bound entangled state are investigated in details. PMID- 26118490 TI - The EEG in genetic generalized epilepsies. PMID- 26118489 TI - Nitrous oxide-induced slow and delta oscillations. AB - OBJECTIVES: Switching from maintenance of general anesthesia with an ether anesthetic to maintenance with high-dose (concentration >50% and total gas flow rate >4 liters per minute) nitrous oxide is a common practice used to facilitate emergence from general anesthesia. The transition from the ether anesthetic to nitrous oxide is associated with a switch in the putative mechanisms and sites of anesthetic action. We investigated whether there is an electroencephalogram (EEG) marker of this transition. METHODS: We retrospectively studied the ether anesthetic to nitrous oxide transition in 19 patients with EEG monitoring receiving general anesthesia using the ether anesthetic sevoflurane combined with oxygen and air. RESULTS: Following the transition to nitrous oxide, the alpha (8 12 Hz) oscillations associated with sevoflurane dissipated within 3-12 min (median 6 min) and were replaced by highly coherent large-amplitude slow-delta (0.1-4 Hz) oscillations that persisted for 2-12 min (median 3 min). CONCLUSIONS: Administration of high-dose nitrous oxide is associated with transient, large amplitude slow-delta oscillations. SIGNIFICANCE: We postulate that these slow delta oscillations may result from nitrous oxide-induced blockade of major excitatory inputs (NMDA glutamate projections) from the brainstem (parabrachial nucleus and medial pontine reticular formation) to the thalamus and cortex. This EEG signature of high-dose nitrous oxide may offer new insights into brain states during general anesthesia. PMID- 26118491 TI - EEG after sleep deprivation is a sensitive tool in the first diagnosis of idiopathic generalized but not focal epilepsy. AB - OBJECTIVES: Electroencephalography (EEG) is an essential tool in the diagnosis of epilepsy. EEG after sleep deprivation might increase the likelihood of finding specific epileptiform abnormalities. However conflicting data exist concerning the sensitivity and specificity of this method. We aimed to evaluate the role of EEG after sleep deprivation in the first diagnosis of epilepsy. METHODS: We analyzed retrospectively the medical histories of patients who underwent at least one unspecific standard EEG and a subsequent EEG after sleep deprivation during the time period from 2001 to 2014 at the University Hospital Zurich because of suspected epilepsy. RESULTS: Out of 237 patients who fulfilled all inclusion criteria, 69 were finally diagnosed with epilepsy. Seventeen of them showed interictal epileptiform patterns in EEGs after sleep deprivation, giving this method an overall sensitivity of 25%. Sensitivity of EEG after sleep deprivation was superior in patients with primary generalized epilepsies compared to patients with focal epilepsies (64% vs. 17%, p=0.0011). Overall EEG after sleep deprivation was not more sensitive than a subsequent repeated standard EEG in a subgroup of 55 patients (22% vs. 9%; p=0.065). CONCLUSION: After an unspecific standard EEG, EEG after sleep deprivation is a useful tool to increase diagnostic sensitivity in patients with idiopathic generalized epilepsy but not in those with focal epilepsy. SIGNIFICANCE: This study provides further evidence about the usefulness of EEG after sleep deprivation as an additional diagnostic tool in epilepsy. PMID- 26118492 TI - Extraction of an incisor embedded within the nasal cavity in two guinea pigs. AB - Oral examination of two guinea pigs revealed that the unilateral incisor was absent. On radiographic examination, the incisor was identified within the nasal cavity in both patients. Under anesthesia in both patients, the skin was incised from the nostril to 1.5 cm proximal, and the premaxilla and part of the maxilla were exposed. The bone was removed using a surgical drill, and the incisor was exposed in the nasal cavity. The root was grasped with forceps and carefully extracted as it was degraded and very fragile. Diagnosis was easy using oral and radiographic examination. In guinea pig patients where an incisor is absent on oral examination, this condition should be considered. PMID- 26118493 TI - Epidemiology of Cranial Cruciate Ligament Disease Diagnosis in Dogs Attending Primary-Care Veterinary Practices in England. AB - OBJECTIVE: To estimate the prevalence and risk factors for a diagnosis of cranial cruciate ligament (CCL) disease in dogs and to describe the management of such cases attending primary-care veterinary practices. STUDY DESIGN: Historical cohort with a nested case-control study. SAMPLE POPULATION: Nine hundred and fifty-three dogs diagnosed with CCL disease from 171,522 dogs attending 97 primary-care practices in England. METHODS: Medical records of dogs attending practices participating in the VetCompass project that met selection criteria were assessed. Univariate and multivariate logistic regression methods were used to evaluate association of possible risk factors with diagnosis of CCL disease. RESULTS: The prevalence of CCL disease diagnosis was estimated at 0.56% (95% confidence interval 0.52-0.59). Compared with crossbred dogs, Rottweilers, West Highland White Terriers, Golden Retrievers, Yorkshire Terriers, and Staffordshire Bull Terriers showed increased odds of CCL disease diagnosis while Cocker Spaniels showed reduced odds. Increasing bodyweight within breeds was associated with increased odds of diagnosis. Dogs aged over 3 years had increased odds of diagnosis compared with dogs aged less than 3 years. Neutered females had 2.1 times the odds of diagnosis compared with entire females. Insured dogs had 4 times the odds of diagnosis compared with uninsured dogs. Two-thirds of cases were managed surgically, with insured and heavier dogs more frequently undergoing surgery. Overall, 21% of cases were referred, with referral more frequent in heavier and insured dogs. Referred dogs more frequently had surgery and an osteotomy procedure. CONCLUSION: Breed predispositions and demographic factors associated with diagnosis and case management of CCL disease in dogs identified in this study can be used to help direct future research and management strategies. PMID- 26118494 TI - Tea Catechins Protect Goat Skeletal Muscle against H2O2-Induced Oxidative Stress by Modulating Expression of Phase 2 Antioxidant Enzymes. AB - To study the mechanisms of tea catechins (TCs) in goat muscles against oxidative stress, skeletal muscle cells (SMCs) induced by H2O2 or not were incubated with TCs or 3H-1,2-dithiole-3-thione (D3T) and were defined as H2O2, H2O2D3T, H2O2TC, D3T, and TC treatments, respectively. Results showed that, similar to effects of D3T, TCs regulated mRNA and protein expression of antioxidant enzymes by suppressing Keap1 protein expression in SMCs from 1.58 +/- 0.12 to 0.71 +/- 0.21 and 1.03 +/- 0.11 in H2O2TC and TC groups, respectively; however, effects differed in oxidative condition of cells and among enzymes. In stressed cells, TCs increased catalase and glutathione S-transferases (GST) activities (P < 0.001), whereas both enzymes' activities decreased (P < 0.001) to 2.97 +/- 0.37 U/mg protein or 42.1 +/- 1.85 mU/mg protein, respectively, in unstressed SMCs. Subsequently, an in vivo experiment in goats fed grain supplemented with TCs or D3T following infusion with H2O2 was conducted to further verify mechanisms of TC action. As seen in vitro, TCs reduced Keap1 protein expression (P < 0.001) from 2.11 +/- 0.37 to 1.34 +/- 0.13 and 1.43 +/- 0.23 in H2O2TC and TC groups, respectively, in muscle. However, dietary TCs increased plasma CuZn superoxide dismutase and GST activities (P < 0.001) regardless of oxidative stress. Moreover, feeding TCs to goats under both conditions increased meat color and tenderness (P <= 0.001). In conclusion, TCs protected goat muscles against oxidative stress and subsequently improved meat quality by modulating phase 2 antioxidant enzymes and Keap1 expression. PMID- 26118495 TI - Influence of acoustic anisotropy in paratellurite on quasicollinear acousto-optic interaction. AB - The influence of paratellurite acoustic anisotropy on the quasicollinear acousto optic diffraction characteristics was examined. In the presented case the quasicollinear geometry of acousto-optic diffraction is realized with the use of acoustic beam reflection from one of the crystal surfaces. The simulations were based on the solution of acoustic beams propagation problem for anisotropic media previously presented in Balakshy and Mantsevich (2012). It is shown that media inhomogeneity affects the distribution of the acoustic energy in the ultrasound beam and the shape of wave fronts. The acoustic beam structure influences the characteristics of quasicollinear acousto-optic diffraction causing transformation of acousto-optic device transmission function shape and reducing the diffraction efficiency. PMID- 26118497 TI - A practical and highly sensitive C3N4-TYR fluorescent probe for convenient detection of dopamine. AB - The C3N4-tyrosinase (TYR) hybrid is a highly accurate, sensitive and simple fluorescent probe for the detection of dopamine (DOPA). Under optimized conditions, the relative fluorescence intensity of C3N4-TYR is proportional to the DOPA concentration in the range from 1 * 10(-3) to 3 * 10(-8) mol L(-1) with a correlation coefficient of 0.995. In the present system, the detection limit achieved is as low as 3 * 10(-8) mol L(-1). Notably, these quantitative detection results for clinical samples are comparable to those of high performance liquid chromatography. Moreover, the enzyme-encapsulated C3N4 sensing arrays on both glass slide and test paper were evaluated, which revealed sensitive detection and excellent stability. The results reported here provide a new approach for the design of a multifunctional nanosensor for the detection of bio-molecules. PMID- 26118496 TI - Gender differences in the structure of risk for alcohol use disorder in adolescence and young adulthood. AB - BACKGROUND: Gender differences in the prevalence of alcohol use disorder (AUD) have motivated the separate study of its risk factors and consequences in men and women. However, leveraging gender as a third variable to help account for the association between risk factors and consequences for AUD could elucidate etiological mechanisms and clinical outcomes. METHOD: Using data from a large, community sample followed longitudinally from 17 to 29 years of age, we tested for gender differences in psychosocial risk factors and consequences in adolescence and adulthood after controlling for gender differences in the base rates of AUD and psychosocial factors. Psychosocial factors included alcohol use, other drug use, externalizing and internalizing symptoms, deviant peer affiliation, family adversity, academic problems, attitudes and use of substances by a romantic partner, and adult socio-economic status. RESULTS: At both ages of 17 and 29 years, mean levels of psychosocial risks and consequences were higher in men and those with AUD. However, the amount of risk exposure in adolescence was more predictive of AUD in women than men. By adulthood, AUD consequences were larger in women than men and internalizing risk had a stronger relationship with AUD in women at both ages. CONCLUSIONS: Despite higher mean levels of risk exposure in men overall, AUD appears to be a more severe disorder in women characterized by higher levels of adolescent risk factors and a greater magnitude of the AUD consequences among women than men. Furthermore, internalizing symptoms appear to be a gender-specific risk factor for AUD in women. PMID- 26118498 TI - Reductive Insertion of Elemental Chalcogens into Boron-Boron Multiple Bonds. AB - The syntheses of sulfur- and selenium-bridged cyclic compounds containing boron stabilized by N-heterocyclic carbenes (NHCs) have been achieved by the reductive insertion of elemental chalcogens into boron-boron multiple bonds. The three pairs of bonding electrons between the boron atoms in the triply bonded diboryne enabled six-electron reduction reactions, resulting in the formation of [2.2.1] bicyclic systems wherein bridgehead boron atoms are spanned by three chalcogen bridges. A similar reaction using a diborene (boron-boron double bond) resulted in the reductive transfer of both pairs of bonding electrons to three sulfur atoms, yielding a NHC-stabilized trisulfidodiborolane. The demonstration of these six- and four-electron reductions lends support to the presence of three and two pairs of bonding electrons between the boron atoms of the diboryne and diborene, respectively, a fact that may be useful in future discussions on bond order. PMID- 26118500 TI - Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis. AB - As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role. PMID- 26118501 TI - The downregulation of BAP1 expression by BCR-ABL reduces the stability of BRCA1 in chronic myeloid leukemia. AB - BCR-ABL induces an intrinsic genetic instability in chronic myeloid leukemia (CML). The protein breast cancer 1, early onset (BRCA1)-associated protein 1 (BAP1) is a deubiquitinase interacting with the DNA repair regulator BRCA1 and is frequently inactivated in many cancers. Here, we report that BAP1 mRNA and protein levels are downregulated in a BCR-ABL1-expressing hematopoietic cell line (UT-7/11). A decrease of BAP1 transcripts is also observed in newly diagnosed CML patients. Moreover, BAP1 protein levels are low or undetectable in CD34(+) cells from CML patients at diagnosis as compared with CD34(+) cells from normal donors. In addition, BRCA1 protein level is reduced in BCR-ABL1-expressing UT-7/11 cells. Finally, the enforced expression of BAP1 is associated with BRCA1 protein deubiquitination and restoration. These results demonstrate BAP1 as a major link with the BCR-ABL-induced downregulation of BRCA1 in CML. PMID- 26118499 TI - Novel therapeutic strategies for multiple myeloma. AB - Multiple myeloma (MM) is a plasma-cell malignancy which remains incurable despite the recent emergence of multiple novel agents. Importantly, recent genetic and molecular analyses have revealed the complexity and heterogeneity of this disease, highlighting the need for therapeutic strategies to eliminate all clones. Moreover, the bone marrow microenvironment, including stromal cells and immune cells, plays a central role in MM pathogenesis, promoting tumor cell growth, survival, and drug resistance. New classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy; however, novel therapeutic approaches are still urgently needed to further improve patient outcomes. In this review, we discuss the recent advances and future strategies to ultimately develop MM therapies with curative potential. PMID- 26118502 TI - Inactivation of Eed impedes MLL-AF9-mediated leukemogenesis through Cdkn2a dependent and Cdkn2a-independent mechanisms in a murine model. AB - Polycomb repressive complex 2 (PRC2) is a chromatin regulator with central roles in development and cancer. The canonical function of PRC2 is the trimethylation of histone 3 on lysine residue 27. This epigenetic modification is associated with gene silencing. Both tumor suppressor and oncogenic functions have been reported for PRC2, depending on cellular context. In leukemia mediated by the leukemogenic fusion MLL-AF9, complete ablation of canonical PRC2 function by genetic inactivation of the core component embryonic ectoderm development (Eed) or by combined pharmacologic inhibition of the PRC2 methyltransferases EZH2 and EZH1 has a strong anti-leukemic effect, and this effect has been linked to de repression of the PRC2 target locus Cdkn2a. We asked whether inactivation of Cdkn2a is sufficient to restore leukemic activity of Eed-inactivated MLL-AF9 leukemia cells, using combined genetic inactivation of Cdkn2a and Eed. We found that Cdkn2a inactivation partially rescues in vitro and in vivo growth of Eed inactivated MLL-AF9 cells. However, the growth of Eed-null Cdkn2a-null MLL-AF9 cells in the absence of Cdkn2a remained severely compromised in vitro and in vivo, compared with that of their Eed-floxed Cdkn2a-null counterparts. RNA sequencing analysis revealed that several genes previously implicated in inefficient growth of MLL-AF9-transformed cells, including Gata2, Egr1, and Cdkn2b were de-repressed as a consequence of Eed inactivation. Furthermore, we found that direct binding targets of MLL fusion proteins are negatively enriched in Eed-inactivated Cdkn2a-null MLL-AF9-transformed cells. Our data indicate that interference with PRC2 function affects MLL-AF9-mediated leukemogenesis by both Cdkn2a-dependent and Cdkn2a-independent mechanisms. PMID- 26118504 TI - Manual therapies and hypoalgesia: What are the mechanisms? PMID- 26118505 TI - Re: Transmission of muscle force to fascia during exercise [Thomas Findley, M.D, Ph.D, Hans Chaudhry, Ph.D, Sunil Dhar, Ph.D. Journal of Bodywork & Movement Therapies (2015) 19, 119-123]. PMID- 26118506 TI - Findley & Chaudhry's response to Sharkey. PMID- 26118503 TI - Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond. AB - Leukemias harboring mixed-lineage leukemia gene (MLL1) abnormalities are associated with poor clinical outcomes, and new therapeutic approaches are desperately needed. Rearrangement of the MLL1 gene generates chimeric proteins that fuse the NH3 terminus of MLL1 to the COOH terminus of its translocation partners. These MLL1 fusion oncoproteins drive the expression of homeobox genes such as HOXA cluster genes and myeloid ecotropic viral integration site 1 homolog (MEIS1), which are known to induce leukemic transformation of hematopoietic progenitors. Genomewide histone methylation studies have revealed that the abnormal expression of MLL1 fusion target genes is associated with high levels of H3K79 methylation at these gene loci. The only known enzyme that catalyzes methylation of H3K79 is disruptor of telomeric-silencing 1-like (DOT1L). Loss-of function mouse models, as well as small molecular inhibitors of DOT1L, illustrate that leukemias driven by MLL1 translocations are dependent on DOT1L enzymatic activity for proliferation and for the maintenance of HOXA gene expression. Furthermore, DOT1L also appears to be important for HOXA gene expression in other settings including leukemias with select genetic abnormalities. These discoveries have established a foundation for disease-specific therapies that target chromatin modifications in highly malignant leukemias harboring specific genetic abnormalities. This review focuses on the molecular mechanisms underlying MLL1 translocation-driven leukemogenesis and the latest progress on DOT1L-targeted epigenetic therapies for MLL1-rearranged and other leukemias. PMID- 26118507 TI - Response to Dommerholt and Gerwin: Did we miss the point? PMID- 26118508 TI - Reliability of ultrasound thickness measurement of the abdominal muscles during clinical isometric endurance tests. AB - The study was designed to evaluate the intra-examiner reliability of ultrasound (US) thickness measurement of abdominal muscles activity when supine lying and during two isometric endurance tests in subjects with and without Low back pain (LBP). A total of 19 women (9 with LBP, 10 without LBP) participated in the study. Within-day reliability of the US thickness measurements at supine lying and the two isometric endurance tests were assessed in all subjects. The intra class correlation coefficient (ICC) was used to assess the relative reliability of thickness measurement. The standard error of measurement (SEM), minimal detectable change (MDC) and the coefficient of variation (CV) were used to evaluate the absolute reliability. Results indicated high ICC scores (0.73-0.99) and also small SEM and MDC scores for within-day reliability assessment. The Bland-Altman plots of agreement in US measurement of the abdominal muscles during the two isometric endurance tests demonstrated that 95% of the observations fall between the limits of agreement for test and retest measurements. Together the results indicate high intra-tester reliability for the US measurement of the thickness of abdominal muscles in all the positions tested. According to the study's findings, US imaging can be used as a reliable method for assessment of abdominal muscles activity in supine lying and the two isometric endurance tests employed, in participants with and without LBP. PMID- 26118509 TI - Accuracy of the Fonseca anamnestic index in the identification of myogenous temporomandibular disorder in female community cases. AB - The aim of the present study was to evaluate the accuracy of the Fonseca anamnestic index (FAI) in the identification of myogenous temporomandibular disorder (TMD). Two hundred and three female volunteers participated in this study, 117 with myogenous TMD and 86 without TMD. The Research Diagnostic Criteria for Temporomandibular Disorders were first applied as the gold standard for the diagnosis. The volunteers then answered the 10 items on the FAI, which furnished a score ranging from 0 to 100 points. The receiver operating characteristic (ROC) was used to determine the accuracy of the diagnosis (area under the curve) and the best cutoff point of the tool. Thus, FAI demonstrated a high degree of accuracy for the diagnosis of myogenous TMD (area under the ROC curve of 0.940). The best cutoff point was a score of 47.50. Thus, a score ranging from 0 to 45 points corresponds to the absence of myogenous TMD and scores ranging from 50 to 100 points identifies individuals with the disorder. In conclusion, the high degree of diagnostic accuracy demonstrates that the FAI can be employed for the identification of myogenous TMD in female community cases. PMID- 26118510 TI - The effect of chronic shoulder pain on maximal force of shoulder abduction. AB - The aim of this study was to determine if chronic shoulder pain had an effect on arm abduction strength and recruitment strategies of the serratus anterior, middle deltoid, and upper trapezius. METHOD: The maximal isometric force at 30 degrees arm abduction and the electromyographic activity of the serratus anterior, middle deltoid, and upper trapezius were recorded for 14 subjects with unilateral chronic shoulder pain and 11 healthy subjects. RESULTS: Relative to the group without pain, the group with chronic shoulder pain showed no significant difference in maximal force production during isometric arm abduction. The Mann-Whitney tests showed no differences in the activation of the serratus anterior, middle deltoid, and upper trapezius between the two groups. DISCUSSION AND CONCLUSION: Subjects with chronic shoulder pain of mild to moderate intensity showed no difference from healthy subjects in arm abduction maximal strength, and recruitment patterns of serratus anterior, middle deltoid, and upper trapezius. PMID- 26118511 TI - Ultrasound imaging of the diagonal dimension of the deep cervical flexor muscles: A reliability study on healthy subjects. AB - The purpose of this study is to assess the reliability of a new ultrasound imaging (USI) parameter and procedure for the evaluation of the size of the deep cervical flexor (DCF) muscles. Thirty-one healthy male subjects (21.6 +/- 2.5 years old) participated in this study. Two images of the diagonal dimension (DD) of the DCF of the subjects, at 1.5 fingerbreadths below the laryngeal prominence of the thyroid cartilage in a relaxed state, were taken on separate days with a 1 week interval. The intraclass correlation coefficient between the days was 0.82 (95% confidence interval, 0.65-0.91). The standard error of measurement and minimal detectable change were 0.8 mm and 2.1 mm, respectively. The results indicated that the DD may be used as a reliable USI parameter to measure the DCF thickness in healthy subjects. PMID- 26118512 TI - Assessment of postural stability in patients with cerebellar disease using gyroscope data. AB - This study examines a relatively new method of studying and quantifying human postural stability in patients with degenerative cerebellar disease. Trunk sway and feet sway were measured during quiet stance. To test the method, ten patients and eleven healthy subjects performed two different stance tasks: standing with eyes open on a firm surface and standing with eyes closed on a foam support surface. Data were recorded using three body-worn gyroscopes (Xsens Technologies B.V.) to measure roll and pitch angular movements of the lower trunk, and left and right foot. The pitch versus roll plots of the trunk and feet were created, and the areas of the convex hull shapes were calculated. It was found that the area of the convex hull of the pitch versus roll plots is suitable for the identification of postural instability disorders caused by degenerative cerebellar disease. PMID- 26118513 TI - Clinical analysis and baropodometric evaluation in diagnosis of abnormal foot posture: A clinical trial. AB - Foot posture involves the integration of sensory information from the periphery of the body. This information generates precise changes through fine adjustments that compensate for the continuous, spontaneous sway of the body in the standing position. Orthopedic insoles are one of the therapeutic resources indicated for assisting in this process. Evaluation of these podal influences, by clinical examination and/or the assistance of baropodometry becomes crucial. Thus, the aim of the present study was determine the combination of the components of orthopedic insoles using two different evaluation methods. Forty healthy female volunteers between 18 and 30 years participated in the study. The volunteers were submitted to two different evaluations: clinical analysis and baropodometry. During the exams, different insole components were tested. The statistical analysis of the two evaluations revealed differences regarding the normalization of posture following the application of the insole components and in the determination of the combination of these components. The findings suggest that the clinical analysis is a fast and accurate method for determining the immediate benefits of the postural insole components and is therefore the more indicated method for the evaluation of foot posture, but does not present a concrete foundation to differentiate it with respect to baropodometric evaluation in the assessment and diagnosis of foot posture, however, a greater difficulty was encountered in achieving posture normalization when using information obtained through baropodometry. PMID- 26118514 TI - Sirsasana (headstand) technique alters head/neck loading: Considerations for safety. AB - BACKGROUND: This study examined the weight-bearing responsibility of the head and neck at moments of peak force during three headstand techniques. METHODS: Three matched groups of 15 each (18-60 years old) were formed based upon lower limb entry/exit technique: symmetrical extended, symmetrical flexed, and asymmetrical flexed. All 45 practitioners performed 3 headstands. Kinematics and kinetics were analyzed to locate peak forces acting on the head, loading rate, center of pressure (COP) and cervical alignment. FINDINGS: During entry, symmetrical extended leg position trended towards the lowest loads as compared to asymmetrical or symmetrical flexed legs (Cohen's d = 0.53 and 0.39 respectively). Also, symmetrical extended condition produced slower loading rates and more neutral cervical conditions during loading. INTERPRETATION: Subjects loaded the head with maximums of 40-48% of total body weight. The data support the conclusion that entering the posture with straight legs together may reduce the load and the rate of change of that load. PMID- 26118515 TI - Effect of remote after-effects of resistive static contraction of the pelvic depressors on improvement of restricted wrist flexion range of motion in patients with restricted wrist flexion range of motion. AB - The objective of the study was to compare the effects of remote after-effects of resistive static contraction of the pelvic depressors (RSCPD) with after-effects of static contraction of upper extremity muscles (SCUE) on improvement of the maximal active range of motion (MAROM) for patients with restricted wrist flexion range of motion (ROM) due to upper limb pain and dysfunction. The participants were 10 outpatients with restricted wrist joints. The mean (SD) age was 53.7 (4.4) years (range, 34-81). The subjects performed two exercise protocols (SCUE and RSCPD) in random order. One-way repeated measures ANOVA showed significant main effects in evaluation of the change in MAROM and IEMG activities for different conditions (after rest, after SCUE, and after RSCPD). The remote after effects of RSCPD, but not those of SCUE, caused significant improvement in MAROM for restricted wrist flexion ROM. PMID- 26118516 TI - Massage treatment and medial tibial stress syndrome; A commentary to provoke thought about the way massage therapy is used in the treatment of MTSS. AB - As students and practitioners we are taught about the treatment and causative factors of medial shin pain, in particular' shin splints' or the more recent term; medial tibial stress syndrome (MTSS). During the years there have been many theories, conjecture and misunderstandings about the mechanisms of 'shin splints/medial tibial stress syndrome' however the ramifications of these mechanisms on how massage treatment is delivered have not being discussed. The evidence for the treatment of MTSS is largely clinical with little evidence of any treatment being proven to be effective in treating MTSS. The aim of this article is to present a summary of the mechanisms of MTSS and a commentary to provoke thought about the way massage therapy is used in the treatment of MTSS based on these mechanisms. PMID- 26118517 TI - Long-term benefits of somatosensory training to improve balance of elderly with diabetes mellitus. AB - We evaluate the effects of somatosensory training on the mean amplitude of the center of pressure (COP) in the upright position and the sustained benefits after 6-month. Twelve elderly patients with type II diabetes (T2DM) participated in the study. Patients with T2DM were allocated to the somatosensory protocol, which consisted of a circuit composed of 13 stations with different textures. The rehabilitation protocol was applied twice a week during the period of 12 weeks. Upright balance, in 2 situations (fixed platform with eyes open and closed) to evaluate the mean amplitude of COP oscillation in the anterior-posterior and medial-lateral directions and the total area of COP oscillation. Outcomes were assessed at baseline, post-exercise and 6-month follow-up. The somatosensory training protocol was beneficial to reduce the AP oscillation of the COP, remaining after 6 months of the end of intervention in elderly with T2DM. PMID- 26118518 TI - Effect of massage on DOMS in ultramarathon runners: A pilot study. AB - In recent years, the popularity of ultramarathons has increased. During these competitions, musculoskeletal problems are very common. Among the more frequent of those problems is the onset of muscle pain, which is defined in the literature as delayed-onset muscle soreness (DOMS). The present study aimed to collect epidemiological data regarding the onset of musculoskeletal problems during the Tor des Geants (International ultramarathon race of 330 km in length and 24,000 m in elevation difference) and to describe the effects of massage on reducing pain and overall perceived improvement in a sample of 25 athletes who complained of DOMS. Two hundred and twenty-one treatments were performed on 220 ultramarathon runners, of which 207 were males and 34 were females; the age group most represented ranged from 40 to 50 years. The most common symptom was pain, which occurred in more than 95% of cases, and the most affected area was the lower extremities (90% of subjects). In the analysed subjects, treatment with massage generated a significant (p < 0.0001) improvement. The numeric pain rating scale (NPRS) value was 3.6 points on average (SD 2.1) after massage, and there were no cases of worsening DOMS after massage as determined using the patient global impression of change (PGIC). The values of minimal clinically important difference (MCID) in DOMS management were calculated on the basis of the ROC curves and two other anchor-based methods in the PGIC and were 2.8-3.9 points on the NPRS. In the context analysed, massage was an effective treatment to reduce DOMS during the onset of symptoms. PMID- 26118519 TI - Neuroscience education in addition to trigger point dry needling for the management of patients with mechanical chronic low back pain: A preliminary clinical trial. AB - The objective of the current study was to determine the short-term effects of trigger point dry needling (TrP-DN) alone or combined with neuroscience education on pain, disability, kinesiophobia and widespread pressure sensitivity in patients with mechanical low back pain (LBP). Twelve patients with LBP were randomly assigned to receive either TrP-DN (TrP-DN) or TrP-DN plus neuroscience education (TrP-DN + EDU). Pain intensity (Numerical Pain Rating Scale, 0-10), disability (Roland-Morris Disability Questionnaire-RMQ-, Oswestry Low Back Pain Disability Index-ODI), kinesiophobia (Tampa Scale of Kinesiophobia-TSK), and pressure pain thresholds (PPT) over the C5-C6 zygapophyseal joint, transverse process of L3 vertebra, second metacarpal, and tibialis anterior muscle were collected at baseline and 1-week after the intervention. Patients treated with TrP-DN + EDU experienced a significantly greater reduction of kinesiophobia (P = 0.008) and greater increases in PPT over the transverse process of L3 (P = 0.049) than those patients treated only with TrP-DN. Both groups experienced similar decreases in pain, ODI and RMQ, and similar increases in PPT over the C5/C6 joint, second metacarpal, and tibialis anterior after the intervention (all, P > 0.05). The results suggest that TrP-DN was effective for improving pain, disability, kinesiophobia and widespread pressure sensitivity in patients with mechanical LBP at short-term. The inclusion of a neuroscience educational program resulted in a greater improvement in kinesiophobia. PMID- 26118520 TI - Effects of Alexander Technique training experience on gait behavior in older adults. AB - Heightened fall risk, potentially caused by aging-related changes in gait, is a serious health issue faced by older adults. The Alexander Technique is thought to improve balance and motor function; however, the technique's effect on gait has not been studied. The purpose of this study was to examine the effect of Alexander Technique training in older adults on the temporospatial characteristics of gait and medio-lateral center of mass displacement during fast and comfortably paced over-ground walking. Six licensed Alexander Technique teachers and seven controls between the ages of 60 and 75 years of age participated in the study. Alexander Technique teachers exhibited a reduction in medio-lateral center of mass displacement during fast paced walking compared to comfortably paced walking that was not present in controls. Due to this difference Alexander Technique teachers displayed a smaller medio-lateral Center of Mass displacement compared to controls during fast paced walking. Alexander Technique teachers also demonstrated significantly smaller stride width and lower gait timing variability compared to controls. These findings, which suggest superior control of dynamic stability during gait and potentially reduced fall risk in Alexander Technique teachers, warrant further study. PMID- 26118521 TI - A critical overview of the current myofascial pain literature - July 2015. AB - The current overview includes thirty articles published in the recent past about myofascial pain, trigger points (TrPs) and related topics. In the Basic Research section, several interesting new studies are reviewed addressing the presence of TrPs in patients with low back pain, episodic migraine, or following a meniscectomy. An animal study of the impact of laser fluency opens the door to future studies regarding optimal dosage of low-level laser therapy in the treatment of individuals with TrPs. Six papers focus on TrP dry needling (DN), two on manual therapies, and two on injection therapy. On of the injection papers discusses the occurrence of a cardiac tamponade, which is a very rare potential complication of invasive needling therapies that can easily be avoided with proper needling techniques. Several review studies and other clinical studies conclude this overview. PMID- 26118522 TI - Physical activity, fear avoidance, and chronic non-specific pain: A narrative review. AB - BACKGROUND: Chronic non-specific pain (CNSP) and physical inactivity have become increasingly prevalent in the United States; however, the associations between the two remain unclear. The lack of clarity may be due to the presence of a third variable, the individual's pain coping strategy. OBJECTIVES: We had three specific aims. 1) To review the associations between fear-avoidance beliefs and behaviors, and levels of physical activity and disability. 2) To review the theoretical mechanisms behind chronic non-specific pain and the potential mediating role of physical activity. 3) Finally, to report the most commonly recommended interventions for fear-avoidant individuals suffering with chronic pain. CONCLUSIONS: Further investigation is needed to fully understand the associations between physical activity, chronic non-specific pain, and fear avoidant beliefs and behaviors. Precise relationships notwithstanding, there is strong evidence to suggest that physical activity is an integral piece to the chronic non-specific pain puzzle. For this reason, it is incumbent upon clinicians to strongly recommend participation in regular, yet properly progressed, physical activity to chronic non-specific pain sufferers. PMID- 26118523 TI - Effects of Pilates method in elderly people: Systematic review of randomized controlled trials. AB - The Pilates method has been widely used in physical training and rehabilitation. Evidence regarding the effectiveness of this method in elderly people is limited. Six randomized controlled trials studies involving the use of the Pilates method for elderly people, published prior to December 2013, were selected from the databases PubMed, MEDLINE, Embase, Cochrane, Scielo and PEDro. Three articles suggested that Pilates produced improvements in balance. Two studies evaluated the adherence to Pilates programs. One study assessed Pilates' influence on cardio-metabolic parameters and another study evaluated changes in body composition. Strong evidence was found regarding beneficial effects of Pilates over static and dynamic balance in women. Nevertheless, evidence of balance improvement in both genders, changes in body composition in woman and adherence to Pilates programs were limited. Effects on cardio-metabolic parameters due to Pilates training presented inconclusive results. Pilates may be a useful tool in rehabilitation and prevention programs but more high quality studies are necessary to establish all the effects on elderly populations. PMID- 26118524 TI - Cognitive function and exercise training for chronic renal disease patients: A literature review. AB - OBJECTIVE: Cognitive impairment is very often noted in patients with Chronic Kidney Disease (CKD). Even though, exercise is considered to be a quantifiable activity that improves cognition in animals and humans, it seems that few studies have examined the relationship between cognitive function and CKD from the perspective of physical activity and cognitive performance. Thus, this evidence based review summarizes the present level of knowledge regarding the effects of exercise training on cognitive function in CKD patients. DATA SOURCES: A comprehensive literature search was conducted in PubMed and Scopus from May 2014 through June 2014, by using the Cochrane and PRISMA guidelines. REVIEW METHODS: Eligibility of the studies based on titles, abstracts and full-text articles was determined by two reviewers. Studies were selected using inclusion and exclusion criteria. We included only those studies that: assessed cognitive function in humans and animals using validated neuropsychological methods in chronic renal diseases patients; used exercise training protocols; addressed randomized control trials or controlled trials or clinical trials designed to evaluate cognitive impairment; and articles that were written in English. Studies were excluded when they concerned behavioral approaches and underpowered studies. RESULTS: According to the current review only a few studies have examined the issue of cognitive function in CKD patients. These studies indicate that these patients often exhibit cognitive impairment, which is highly associated with poor outcomes. It has been supported that exercise training can induce positive changes in brain metabolism favoring better scores in cognitive function in Chronic Kidney Disease patients although the physiological mechanisms, which explain the influence of physical activity on cognition, have focused on changes in neurotransmitters, neurotrophins and vasculature. CONCLUSION: Systematic exercise training seems to improve cognitive function in Chronic Kidney Disease patients but further research is warranted to further clarify the mechanisms involved. PMID- 26118525 TI - Fascial eponyms may help elucidate terminological and nomenclatural development. AB - It has been reported that at least 700 anatomical eponyms were in existence at the end of the 19th century, yet the number of eponyms expressly relating to fasciae is unknown, and these anatomical expressions have yet to be described as a group. This study accordingly aimed to assemble a comprehensive-as-possible list of these terms, to investigate their customary usage, and to consider whether their existence might usefully shed light on contemporary fascia-relating terminological development. A search for fascia-relating eponyms incorporated within a range of English language anatomical and medical publications during the past 400 years resulted in the discovery of 44 eponyms that explicitly refer to aspects of fascia. This article outlines and discusses the origin, meaning, and use of these terms, and concludes that an understanding of the history of fascial eponyms may be of value when addressing contemporary concerns with the language used to describe fascia. PMID- 26118526 TI - A unifying neuro-fasciagenic model of somatic dysfunction - Underlying mechanisms and treatment - Part II. AB - This paper offers an extensive review of the main fascia-mediated mechanisms underlying various therapeutic processes of clinical relevance for manual therapy. The concept of somatic dysfunction is revisited in light of the several fascial influences that may come into play during and after manual treatment. A change in perspective is thus proposed: from a nociceptive model that for decades has viewed somatic dysfunction as a neurologically-mediated phenomenon, to a unifying neuro-fascial model that integrates neural influences into a multifactorial and multidimensional interpretation of manual therapeutic effects as being partially, if not entirely, mediated by the fascia. By taking into consideration a wide spectrum of fascia-related factors - from cell-based mechanisms to cognitive and behavioural influences - a model emerges suggesting, amongst other results, a multidisciplinary-approach to the intervention of somatic dysfunction. Finally, it is proposed that a sixth osteopathic 'meta model' - the connective tissue-fascial model - be added to the existing five models in osteopathic philosophy as the main interface between all body systems, thus providing a structural and functional framework for the body's homoeostatic potential and its inherent abilities to heal. PMID- 26118527 TI - The immediate effect of bilateral self myofascial release on the plantar surface of the feet on hamstring and lumbar spine flexibility: A pilot randomised controlled trial. AB - BACKGROUND: Self myofascial release (SMR) via a tennis ball to the plantar aspect of the foot is widely used and advocated to increase flexibility and range of movement further along the posterior muscles of a proposed "anatomy train". To date there is no evidence to support the effect of bilateral SMR on the plantar aspect of the feet to increase hamstring and lumbar spine flexibility. AIM: The primary aim was to investigate the immediate effect of a single application of SMR on the plantar aspect of the foot, on hamstring and lumbar spine flexibility. The secondary aim was to evaluate the method and propose improvements in future research. DESIGN: A pilot single blind randomised control trial. PARTICIPANTS: Twenty four healthy volunteers (8 men, 16 women; mean age 28 years +/- 11.13). METHOD: Participants underwent screening to exclude hypermobility and were randomly allocated to an intervention (SMR) or control group (no therapy). Baseline and post intervention flexibility was assessed by a sit-and-reach test (SRT). A one way between groups analysis of covariance (ANCOVA) was conducted to compare between group outcome SRT measurements. Baseline pre-intervention and control SRT measurements were used as the covariate in the analysis. RESULTS: There was a significant increase (p = 0.03) in the intervention SRT outcome measurements compared to the control group, with a large effect size. CONCLUSION: An immediate clinical benefit of SMR on the flexibility of the hamstrings and lumbar spine was indicated and suggestions for methodological improvements may inform future research. PMID- 26118528 TI - About eccentric exercise. PMID- 26118529 TI - Does anterior knee pain severity and function relate to the frontal plane projection angle and trunk and hip strength in women with patellofemoral pain? AB - The aim of the present study was to determine the relationship between knee pain severity and function with the frontal plane projection angle (FPPA) and trunk and hip peak torque (PT) in women with patellofemoral pain (PFPS). Twenty-two women with PFPS were assessed. Knee pain severity (KPS) was assessed with an 11 point visual analog scale and function with an Anterior Knee Pain Scale. The FPPA was recorded with a digital camera. PT of extensors, abductors, and the lateral rotators of hip and lateral core stability were measured with a handheld dynamometer. FPPA was the only predictor for the KPS. Regarding predictors of function, PT of lateral core stability and the extensor and abductor of the hip explained 41.4% of the function. Increase in FPPA was associated with greater KPS, and the lowest PT of lateral core stability, hip abductors, and extensors was associated with lower function in women with PFPS. PMID- 26118530 TI - Common postural defects among music students. AB - Postural quality during musical performance affects both musculoskeletal health and the quality of the performance. In this study we examined the posture of 100 students at a Higher Conservatory of Music in Spain. By analysing video tapes and photographs of the students while performing, a panel of experts extracted values of 11 variables reflecting aspects of overall postural quality or the postural quality of various parts of the body. The most common postural defects were identified, together with the situations in which they occur. It is concluded that most students incur in unphysiological postures during performance. It is hoped that use of the results of this study will help correct these errors. PMID- 26118531 TI - Sparing your spine. PMID- 26118532 TI - Membrane Protein Properties Revealed through Data-Rich Electrostatics Calculations. AB - The electrostatic properties of membrane proteins often reveal many of their key biophysical characteristics, such as ion channel selectivity and the stability of charged membrane-spanning segments. The Poisson-Boltzmann (PB) equation is the gold standard for calculating protein electrostatics, and the software APBSmem enables the solution of the PB equation in the presence of a membrane. Here, we describe significant advances to APBSmem, including full automation of system setup, per-residue energy decomposition, incorporation of PDB2PQR, calculation of membrane-induced pKa shifts, calculation of non-polar energies, and command-line scripting for large-scale calculations. We highlight these new features with calculations carried out on a number of membrane proteins, including the recently solved structure of the ion channel TRPV1 and a large survey of 1,614 membrane proteins of known structure. This survey provides a comprehensive list of residues with large electrostatic penalties for being embedded in the membrane, potentially revealing interesting functional information. PMID- 26118533 TI - Atomic Modeling of an Immature Retroviral Lattice Using Molecular Dynamics and Mutagenesis. AB - Defining the molecular interaction between Gag proteins in an assembled hexagonal lattice of immature retrovirus particles is crucial for elucidating the mechanisms of virus assembly and maturation. Recent advances in cryo-electron microscopy have yielded subnanometer structural information on the morphology of immature Gag lattices, making computational modeling and simulations feasible for investigating the Gag-Gag interactions at the atomic level. We have examined the structure of Rous sarcoma virus (RSV) using all-atom molecular dynamics simulations and in vitro assembly, to create the first all-atom model of an immature retroviral lattice. Microseconds-long replica exchange molecular dynamics simulation of the spacer peptide (SP)-nucleocapsid (NC) subdomains results in a six-helix bundle with amphipathic properties. The resulting model of the RSV Gag lattice shows features and dynamics of the capsid protein with implications for the maturation process, and confirms the stabilizing role of the upstream and downstream regions of Gag, namely p10 and SP-NC. PMID- 26118534 TI - Global RNA Fold and Molecular Recognition for a pfl Riboswitch Bound to ZMP, a Master Regulator of One-Carbon Metabolism. AB - ZTP, the pyrophosphorylated analog of ZMP (5-amino-4-imidazole carboxamide ribose 5'-monophosphate), was identified as an alarmone that senses 10-formyl tetrahydroflate deficiency in bacteria. Recently, a pfl riboswitch was identified that selectively binds ZMP and regulates genes associated with purine biosynthesis and one-carbon metabolism. We report on the structure of the ZMP bound Thermosinus carboxydivorans pfl riboswitch sensing domain, thereby defining the pseudoknot-based tertiary RNA fold, the binding-pocket architecture, and principles underlying ligand recognition specificity. Molecular recognition involves shape complementarity, with the ZMP 5-amino and carboxamide groups paired with the Watson-Crick edge of an invariant uracil, and the imidazole ring sandwiched between guanines, while the sugar hydroxyls form intermolecular hydrogen bond contacts. The burial of the ZMP base and ribose moieties, together with unanticipated coordination of the carboxamide by Mg(2+), contrasts with exposure of the 5'-phosphate to solvent. Our studies highlight the principles underlying RNA-based recognition of ZMP, a master regulator of one-carbon metabolism. PMID- 26118536 TI - Risk of endocrine disruption to fish in the Yellow River catchment in China assessed using a spatially explicit model. AB - The global water availability assessment (GWAVA) model, incorporating regional water abstractions and reservoir information, was used to model the human-sourced steroid estrogens estrone (E1) and estradiol (E2) in the Yellow River catchment (China). The river flows in the main stem were calibrated using gauged flows. Following a review of Chinese data on estrogen discharge from a range of sewage treatment plants, low, median, and high discharge rates were identified and used as best, expected, and worst-case scenarios, respectively. For any given location, the temporal variation of modeled estrogen levels was summarized using the mean and upper 90th percentile, which is where the model predicts 90% of values would be below this concentration. The predicted means and 90th percentiles for E1 were comparable to previous E1 measurements reported in the river. For the whole catchment, only 19% (mean value) of the river system by length was predicted to exceed 1 ng/L E2 equivalents (EEQs) using expected estrogen sewage discharge. Only 3% of the network by length was predicted to exceed the dangerously high 10 ng/L EEQ when considering 90th percentile concentrations. The highest exposures were in the Fen and Wei tributaries. Endocrine disruption risk from estrogens was predicted to be minimal in the main stem. Only in the worst-case discharge scenario and 90th percentile predicted concentrations were the most downstream river reaches of the main stem predicted to be at risk. Reservoirs appeared to be helpful in reducing estrogen concentrations thanks to longer water residence facilitating biodegradation. PMID- 26118537 TI - Nitrosative Stress in the Nervous System: Guidelines for Designing Experimental Strategies to Study Protein S-Nitrosylation. AB - Reactive nitrogen species, such as nitric oxide (NO), exert their biological activity in large part through post-translational modification of cysteine residues, forming S-nitrosothiols. This chemical reaction proceeds via a process that we and our colleagues have termed protein S-nitrosylation. Under conditions of normal NO production, S-nitrosylation regulates the activity of many normal proteins. However, in degenerative conditions characterized by nitrosative stress, increased levels of NO lead to aberrant S-nitrosylation that contributes to the pathology of the disease. Thus, S-nitrosylation has been implicated in a wide range of cellular mechanisms, including mitochondrial function, proteostasis, transcriptional regulation, synaptic activity, and cell survival. In recent years, the research area of protein S-nitrosylation has become prominent due to improvements in the detection systems as well as the demonstration that protein S-nitrosylation plays a critical role in the pathogenesis of neurodegenerative and other neurological disorders. To further promote our understanding of how protein S-nitrosylation affects cellular systems, guidelines for the design and conduct of research on S-nitrosylated (or SNO-)proteins would be highly desirable, especially for those newly entering the field. In this review article, we provide a strategic overview of designing experimental approaches to study protein S-nitrosylation. We specifically focus on methods that can provide critical data to demonstrate that an S-nitrosylated protein plays a (patho-)physiologically-relevant role in a biological process. Hence, the implementation of the approaches described herein will contribute to further advancement of the study of S-nitrosylated proteins, not only in neuroscience but also in other research fields. PMID- 26118535 TI - Structure of a Bud6/Actin Complex Reveals a Novel WH2-like Actin Monomer Recruitment Motif. AB - In budding yeast, the actin-binding protein Bud6 cooperates with formins Bni1 and Bnr1 to catalyze the assembly of actin filaments. The nucleation-enhancing activity of Bud6 requires both a "core" domain that binds to the formin and a "flank" domain that binds monomeric actin. Here, we describe the structure of the Bud6 flank domain in complex with actin. Two helices in Bud6(flank) interact with actin; one binds in a groove at the barbed end of the actin monomer in a manner closely resembling the helix of WH2 domains, a motif found in many actin nucleation factors. The second helix rises along the face of actin. Mutational analysis verifies the importance of these Bud6-actin contacts for nucleation enhancing activity. The Bud6 binding site on actin overlaps with that of the formin FH2 domain and is also incompatible with inter-subunit contacts in F actin, suggesting that Bud6 interacts only transiently with actin monomers during filament nucleation. PMID- 26118538 TI - To what extent will 5-aminolevulinic acid change the face of malignant glioma surgery? AB - Glioma surgery is an essential part of glioma management; however, fully achieving the goal of surgery has been uncommon. The goal of surgery is 'maximal safe resection' with the accepted target for maximal being complete resection of the contrast-enhancing tumor. This ideal result was obtained in less than 30% of cases in centers of excellence until a few years ago. The development of fluorescence-guided surgery using 5-aminolevulinic acid has initiated a radical change. Over the past 5 years, various groups have published rates of complete resection of the enhancing tumor that exceed 80%. In the coming years, as the use of the technology expands, complete resection should become a common, predictable result at many centers. Consequently, adjuvant therapies that benefit from resection could play a bigger role, resection could be incorporated as a variable in randomized trials and distant recurrence might become a more common problem. PMID- 26118539 TI - Intracellular Self-Assembly of Taxol Nanoparticles for Overcoming Multidrug Resistance. AB - Multidrug resistance (MDR) remains the biggest challenge in treating cancers. Herein we propose the intracellular self-assembly of nanodrugs as a new strategy for overcoming MDR. By employing a biocompatible condensation reaction, we rationally designed a taxol derivative Ac-Arg-Val-Arg-Arg-Cys(StBu)-Lys(taxol)-2 cyanobenzothiazole (CBT-Taxol) which could be subjected to furin-controlled condensation and self-assembly of taxol nanoparticles (Taxol-NPs). In vitro and in vivo studies indicated that, compared with taxol, CBT-Taxol showed a 4.5-fold or 1.5-fold increase in anti-MDR effects, respectively, on taxol-resistant HCT 116 cancer cells or tumors without being toxic to the cells or the mice. Our results demonstrate that structuring protease-susceptible agents and assembling them intracellularly into nanodrugs could be a new optimal strategy for overcoming MDR. PMID- 26118540 TI - Chandipura virus perturbs cholesterol homeostasis leading to neuronal apoptosis. AB - Chandipura virus (CHPV; genus Vesiculovirus, family Rhabdoviridae) induces neuronal death through the Fas-mediated extrinsic apoptosis pathway. What propels this apoptosis remains unclear, although oxysterols have been reported to be key players in neurodegeneration. In our study of CHPV-infected brain samples, we observed over-expression of genes such as apolipoprotein E, Cyp46a1, Srebf-1 and Nsdhl. This backs up the hypothesis that CHPV replication demands cholesterol that is supplied by apolipoprotein E through low density lipid receptors, lipid metabolism being pivotal for viral replication. We were able to illustrate this with over-expression of low density lipid receptors in CHPV-infected neurons. An upsurge of cholesterol concentration has been observed in neurons, triggering the expression of Cyp46a1 enzyme and culminating into the conversion of cholesterol to 24(S)-hydroxycholesterol. Increased 24(S)-hydroxycholesterol concentration is toxic to neurons, propelling neuronal apoptosis through the Fas-mediated extrinsic apoptosis pathway. For the first time, perturbation of cholesterol homeostasis in brain is shown to be utilized by the viruses for both maturation and the release of its matured virions outside the cells for continuous neuropathogenesis. PMID- 26118541 TI - Bioactive Proteins and Peptides from Soybeans. AB - Dietary proteins from soybeans have been shown to offer health benefits in vivo and/or in vitro either as intact proteins or in partially digested forms also called bioactive peptides. Upon oral administration and absorption, soy-derived bioactive peptides may induce several physiological responses such as antioxidative, antimicrobial, antihypertensive, anticancer and immunomodulatory effects. There has therefore been a mounting research interest in the therapeutic potential of soy protein hydrolysates and their subsequent incorporation in functional foods and 'Food for Specified Health Uses' (FOSHU) related products where their biological activities may assist in the promotion of good health or in the control and prevention of diseases. This mini review discusses relevant patents and gives an overview on bioactive proteins and peptides obtainable from soybeans. Processes for the production and formulation of these peptides are given, together with specific examples of their therapeutic potential and possible areas of application. PMID- 26118542 TI - Symptom clusters in patients presenting to the emergency department with possible acute coronary syndrome differ by sex, age, and discharge diagnosis. AB - OBJECTIVES: To identify classes of individuals presenting to the ED for suspected ACS who shared similar symptoms and clinical characteristics. BACKGROUND: Describing symptom clusters in undiagnosed patients with suspected ACS is a novel and clinically relevant approach, reflecting real-world emergency department evaluation procedures. METHODS: Symptoms were measured using a validated 13-item symptom checklist. Latent class analysis was used to describe symptom clusters. RESULTS: The sample of 874 was 37% female with a mean age of 59.9 years. Four symptom classes were identified: Heavy Symptom Burden (Class 1), Chest Symptoms and Shortness of Breath (Class 2), Chest Symptoms Only (Class 3), and Weary (Class 4). Patients with ACS were more likely to cluster in Classes 2 and 3. Women and younger patients were more likely to group in Class 1. CONCLUSIONS: Further research is needed to determine the value of symptom clusters in the ED triage and management of suspected ACS. PMID- 26118543 TI - Cross-resistance and baseline susceptibility of Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) to cyantraniliprole in the south of China. AB - BACKGROUND: The oriental leafworm moth, Spodoptera litura Fab. (Lepidoptera: Noctuidae), is a widely distributed polyphagous insect pest in Asia that has been shown to be resistant to various types of insecticide. The newly registered anthranilic diamide cyantraniliprole provided novel insight and great opportunities to control S. litura. RESULTS: In this study, the susceptibilities of S. litura collected from South China to cyantraniliprole were measured by standard leaf-disc bioassay, and obvious variation in susceptibility was observed among the 17 field populations, with LC50 values varying from 0.206 to 1.336 mg AI L(-1). Significant correlations were detected between the LC50 values of cyantraniliprole and chlorantraniliprole (P < 0.05). However, no significant correlation (P > 0.05) was observed between the two anthranilic diamides and other insecticides with different action mechanisms (delcamethrin, chlorpyrifos, indoxacarb and emamectin benzoate). Piperonyl butoxide showed obvious synergism in Lab-Sus, ZC14 and cyantraniliprole-resistant strains, while diethyl maleate and S,S,S-tributylphorotrithioate had no obvious synergistic effects in any of the strains tested. CONCLUSION: These results revealed obvious regional variation in cyantraniliprole susceptibilities among populations of S. litura from different areas, and potential cross-resistance to chlorantraniliprole, which suggested that S. litura could develop resistance to cyantraniliprole. Detoxification enzymes might not be involved in the observed tolerance in field collected populations and the cyantraniliprole-resistant strain. PMID- 26118544 TI - Early versus delayed postoperative radiotherapy for treatment of low-grade gliomas. AB - BACKGROUND: In most people with low-grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. OBJECTIVES: To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low-grade intracranial gliomas in people who had initial biopsy or surgical resection. SEARCH METHODS: We searched up to September 2014 the following electronic databases: the Cochrane Register of Controlled Trials (CENTRAL, Issue 8, 2014), MEDLINE (1948 to Aug week 3, 2014), and EMBASE (1980 to Aug week 3, 2014) to identify trials for inclusion in this Cochrane review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt-60 sources, intensity modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta-analyses using a random effects model with inverse variance weighting. MAIN RESULTS: We included one large, multi-institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy is associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but does not significantly improve overall survival (OS). The median progression-free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P value < 0.0001; 311 participants; 1 trail; low quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P value = 0.872; 311 participants; 1 trail; low quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P value = 0.0329, respectively). AUTHORS' CONCLUSIONS: Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who undergo early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation-induced malignant transformation of LGG. However, it remains unclear whether there are differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated. PMID- 26118545 TI - Free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta): III. Dental eruption patterns and dental pathology. AB - This article describes the dental eruption patterns, dentition, and dental wear, including tooth loss and breakage, of the free-ranging population of rhesus monkeys (Macaca mulatta) on Cayo Santiago (CS), Puerto Rico, ranging from 24 hr to 25 years old. Of the 694 monkeys on the island in the year 1985, 688 (99.1%; 366 males, 322 females) were captured and the dentition of 685 subjects (98.7% of the total population; 366 males, 319 females) was examined. Animals ranged in age from less than 24 hr to 331 months (27.58 years), encompassing the entire life span of the CS macaques. Results demonstrated that the first deciduous teeth appeared as early as the third day of life and that the sequence of dental eruption was comparable to the pattern observed in laboratory rhesus. However, there were slight differences in the age of eruption of individual teeth. For example, the canines and third molars erupted about a year later in the CS macaques compared to some laboratory rhesus. Overall, CS rhesus had good oral health and dental condition although tooth wear, loss, and breakage were common in aged animals, especially in males. This report, combined with earlier studies on morphological characteristics and skeletal remains of the CS macaques, provides the basis for further studies on the biology, genetics, life history, and effects of the environment on rhesus monkeys. PMID- 26118546 TI - Abstracts of the Annual Meeting of the Hungarian Society for Microbiology and EU FP-7 PROMISE Regional Meeting, October 15-17, 2014, Keszthely, Hungary. PMID- 26118547 TI - Abstracts of the 17(th) International Congress of the Hungarian Society for Microbiology, July 8-10, 2015, Budapest, Hungary. PMID- 26118548 TI - Distribution and phylogenetic analysis of Culex flavivirus in mosquitoes in China. AB - Culex flavivirus (CxFV) is an insect-specific virus of the genus Flavivirus. CxFV strains have been isolated from Cx. pipiens, Cx. quinquefasciatus, and other Cx. species in Asia, Africa, North America, Central America and South America. CxFV was isolated for the first time in China in 2006. As this is a novel flavivirus, we explored the distribution and genetic characteristics of Culex flavivirus in China. A total of 46,649 mosquitoes were collected in seven provinces between 2004 and 2012 and were analysed in 871 pools. 29 CxFV RNAs from Cx. pipiens, Cx. tritaeniorhynchus, Anopheles Sinensis, and Culex spp. tested positive for CxFV in real-time RT-PCR. 6 CxFV strains were isolated from Cx. species collected in Shandong, Henan, and Shaanxi provinces, while no virus or viral RNA was detected in samples from Sichuan, Chongqing, Hubei, and Fujian. Phylogenetic analysis of the envelope gene indicated that Chinese strains formed a robust subgroup of genotype 1, together with viruses from the United States and Japan. This study demonstrates that the geographic distribution of CxFV in China is widespread, but geographical boundaries to spread are apparent. Our findings suggest that CxFV can infect various mosquito species in nature. PMID- 26118549 TI - Hydroboration of Alkynes with Zwitterionic Ruthenium-Borate Complexes: Novel Vinylborane Complexes. AB - Building upon previous studies on the synthesis of bis(sigma)borate and agostic complexes of ruthenium, the chemistry of nido-[(Cp*Ru)2 B3 H9] (1) with other ligand systems was explored. In this regard, mild thermolysis of nido-1 with 2 mercaptobenzothiazole (2-mbzt), 2-mercaptobenzoxazole (2-mbzo) and 2 mercaptobenzimidazole (2-mbzi) ligands were performed which led to the isolation of bis(sigma)borate complexes [Cp*RuBH3 L] (2 a-c) and beta-agostic complexes [Cp*RuBH2 L2] (3 a-c; 2 a, 3 a: L=C7 H4 NS2 ; 2 b, 3 b: L=C7 H4 NSO; 2 c, 3 c: L=C7 H5 N2 S). Further, the chemistry of these novel complexes towards various diphosphine ligands was investigated. Room temperature treatment of 3 a with [PPh2 (CH2 )n PPh2 ] (n=1-3) yielded [Cp*Ru(PPh2 (CH2 )n PPh2 )-BH2 (L2)] (4 a-c; 4 a: n=1; 4 b: n=2; 4 c: n=3; L=C7 H4 NS2). Mild thermolysis of 2 a with [PPh2 (CH2)n PPh2 ] (n=1-3) led to the isolation of [Cp*Ru(PPh2 (CH2)n PPh2 )(L)] (L=C7 H4 NS2 5 a-c; 5 a: n=1; 5 b: n=2; 5 c: n=3). Treatment of 4 a with terminal alkynes causes a hydroboration reaction to generate vinylborane complexes [Cp*Ru(R-C=CH2 )BH(L2)] (6 and 7; 6: R=Ph; 7: R=COOCH3; L=C7 H4 NS2). Complexes 6 and 7 can also be viewed as eta-alkene complexes of ruthenium that feature a dative bond to the ruthenium centre from the vinylinic double bond. In addition, DFT computations were performed to shed light on the bonding and electronic structures of the new compounds. PMID- 26118550 TI - Influence of the metal work function on the photocatalytic properties of TiO2 layers on metals. AB - The photocatalytic properties of titanium dioxide (TiO2 ) layers on different metal plates are investigated. The metal-semiconductor interface can be described as a Schottky contact, and is part of a depletion layer for the majority carriers in the semiconductor. Many researchers have demonstrated an increase in the photocatalytic activity, due to the formation of a metal-semiconductor contact that are obtained by deposition of small metal islands on the semiconductor. Nevertheless, the influence of a Schottky contact remains uncertain, sparking much interest in this field. The immobilization of nanoparticulate TiO2 layers by dip-coating on different metal substrates results in the formation of a Schottky contact. The recombination rate of photoinduced electron-hole pairs decreases at this interface provided that the thickness of the thin TiO2 layer has a similar magnitude to the depletion layer. The degradation of dichloroacetic acid in aqueous solution and of acetaldehyde in a gas mixture is investigated to obtain information concerning the influence of the metal work function of the back contact on the efficiency of the photocatalytic process. PMID- 26118552 TI - S100A4 and its role in metastasis - computational integration of data on biological networks. AB - Characterising signal transduction networks is fundamental to our understanding of biology. However, redundancy and different types of feedback mechanisms make it difficult to understand how variations of the network components contribute to a biological process. In silico modelling of signalling interactions therefore becomes increasingly useful for the development of successful therapeutic approaches. Unfortunately, quantitative information cannot be obtained for all of the proteins or complexes that comprise the network, which limits the usability of computational models. We developed a flexible computational framework for the analysis of biological signalling networks. We demonstrate our approach by studying the mechanism of metastasis promotion by the S100A4 protein, and suggest therapeutic strategies. The advantage of the proposed method is that only limited information (interaction type between species) is required to set up a steady state network model. This permits a straightforward integration of experimental information where the lack of details are compensated by efficient sampling of the parameter space. We investigated regulatory properties of the S100A4 network and the role of different key components. The results show that S100A4 enhances the activity of matrix metalloproteinases (MMPs), causing higher cell dissociation. Moreover, it leads to an increased stability of the pathological state. Thus, avoiding metastasis in S100A4-expressing tumours requires multiple target inhibition. Moreover, the analysis could explain the previous failure of MMP inhibitors in clinical trials. Finally, our method is applicable to a wide range of biological questions that can be represented as directional networks. PMID- 26118551 TI - Metabolome progression during early gut microbial colonization of gnotobiotic mice. AB - The microbiome has been implicated directly in host health, especially host metabolic processes and development of immune responses. These are particularly important in infants where the gut first begins being colonized, and such processes may be modeled in mice. In this investigation we follow longitudinally the urine metabolome of ex-germ-free mice, which are colonized with two bacterial species, Bacteroides thetaiotaomicron and Bifidobacterium longum. High-throughput mass spectrometry profiling of urine samples revealed dynamic changes in the metabolome makeup, associated with the gut bacterial colonization, enabled by our adaptation of non-linear time-series analysis to urine metabolomics data. Results demonstrate both gradual and punctuated changes in metabolite production and that early colonization events profoundly impact the nature of small molecules circulating in the host. The identified small molecules are implicated in amino acid and carbohydrate metabolic processes, and offer insights into the dynamic changes occurring during the colonization process, using high-throughput longitudinal methodology. PMID- 26118553 TI - The effect of electron correlation on the adsorption of hydrogen fluoride and water on magnesium fluoride surfaces. AB - We have performed periodic density functional and periodic local MP2 calculations for the adsorption of hydrogen fluoride and water on the four low index surfaces (001), (100), (101) and (110) of magnesium fluoride. While the adsorption of HF is described well using B3LYP, MP2 is required for a good description of the adsorption of H2O. Post-optimization dispersion corrections of B3LYP are found to consistently overestimate the adsorption energy. The coordination of surface cations, the presence of hydroxyls on the surface, as well as the coverage appear to play an equally important role in the adsorption. PMID- 26118554 TI - Isoprenoid Biosynthesis in Pathogenic Bacteria: Nuclear Resonance Vibrational Spectroscopy Provides Insight into the Unusual [4Fe-4S] Cluster of the E. coli LytB/IspH Protein. AB - The LytB/IspH protein catalyzes the last step of the methylerythritol phosphate (MEP) pathway which is used for the biosynthesis of essential terpenoids in most pathogenic bacteria. Therefore, the MEP pathway is a target for the development of new antimicrobial agents as it is essential for microorganisms, yet absent in humans. Substrate-free LytB has a special [4Fe-4S](2+) cluster with a yet unsolved structure. This motivated us to use synchrotron-based nuclear resonance vibrational spectroscopy (NRVS) in combination with quantum chemical-molecular mechanical (QM/MM) calculations to gain more insight into the structure of substrate-free LytB. The apical iron atom of the [4Fe-4S](2+) is clearly linked to three water molecules. We additionally present NRVS data of LytB bound to its natural substrate, (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) and to the inhibitors (E)-4-amino-3-methylbut-2-en-1-yl diphosphate and (E)-4-mercapto-3 methylbut-2-en-1-yl diphosphate. PMID- 26118555 TI - Comparison of a Commercial Accelerometer with Polysomnography and Actigraphy in Children and Adolescents. AB - STUDY OBJECTIVES: To evaluate the reliability and validity of the commercially available Fitbit Ultra (2012) accelerometer compared to polysomnography (PSG) and two different actigraphs in a pediatric sample. DESIGN AND SETTING: All subjects wore the Fitbit Ultra while undergoing overnight clinical polysomnography in a sleep laboratory; a randomly selected subset of participants also wore either the Ambulatory Monitoring Inc. Motionlogger Sleep Watch (AMI) or Phillips-Respironics Mini-Mitter Spectrum (PRMM). PARTICIPANTS: 63 youth (32 females, 31 males), ages 3-17 years (mean 9.7 years, SD 4.6 years). MEASUREMENTS: Both "Normal" and "Sensitive" sleep-recording Fitbit Ultra modes were examined. Outcome variables included total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE). Primary analyses examined the differences between Fitbit Ultra and PSG using repeated-measures ANCOVA, with epoch-by-epoch comparisons between Fitbit Ultra and PSG used to determine sensitivity, specificity, and accuracy. Intra-device reliability, differences between Fitbit Ultra and actigraphy, and differences by both developmental age group and sleep disordered breathing (SDB) status were also examined. RESULTS: Compared to PSG, the Normal Fitbit Ultra mode demonstrated good sensitivity (0.86) and accuracy (0.84), but poor specificity (0.52); conversely, the Sensitive Fitbit Ultra mode demonstrated adequate specificity (0.79), but inadequate sensitivity (0.70) and accuracy (0.71). Compared to PSG, the Fitbit Ultra significantly overestimated TST (41 min) and SE (8%) in Normal mode, and underestimated TST (105 min) and SE (21%) in Sensitive mode. Similar differences were found between Fitbit Ultra (both modes) and both brands of actigraphs. CONCLUSIONS: Despite its low cost and ease of use for consumers, neither sleep-recording mode of the Fitbit Ultra accelerometer provided clinically comparable results to PSG. Further, pediatric sleep researchers and clinicians should be cautious about substituting these devices for validated actigraphs, with a significant risk of either overestimating or underestimating outcome data including total sleep time and sleep efficiency. PMID- 26118556 TI - Psychological Effect of an Analogue Traumatic Event Reduced by Sleep Deprivation. AB - STUDY OBJECTIVE: To examine the effect of sleep deprivation compared to sleep, immediately after experimental trauma stimuli on the development of intrusive memories to that trauma stimuli. DESIGN: Participants were exposed to a film with traumatic content (trauma film). The immediate response to the trauma film was assessed, followed by either total sleep deprivation (sleep deprived group, N = 20) or sleep as usual (sleep group, N = 22). Twelve hours after the film viewing the initial psychological effect of the trauma film was measured and for the subsequent 6 days intrusive emotional memories related to the trauma film were recorded in daily life. SETTING: Academic sleep laboratory and participants' home environment. PARTICIPANTS: Healthy paid volunteers. MEASUREMENTS AND RESULTS: On the first day after the trauma film, the psychological effect as assessed by the Impact of Event Scale - Revised was lower in the sleep deprived group compared to the sleep group. In addition, the sleep deprived group reported fewer intrusive emotional memories (mean 2.28, standard deviation [SD] 2.91) compared to the sleep group (mean 3.76, SD 3.35). Because habitual sleep/circadian patterns, psychological health, and immediate effect of the trauma film were similar at baseline for participants of both groups, the results cannot be accounted for by pre-existing inequalities between groups. CONCLUSIONS: Our findings suggest that sleep deprivation on one night, rather than sleeping, reduces emotional effect and intrusive memories following exposure to experimental trauma. PMID- 26118557 TI - Obstructive Sleep Apnea in Patients with Congenital Long QT Syndrome: Implications for Increased Risk of Sudden Cardiac Death. AB - BACKGROUND: Congenital long QT syndrome (LQTS) is a familial arrhythmogenic cardiac channelopathy characterized by prolonged ventricular repolarization and increased risk of torsades de pointes-mediated syncope, seizures, and sudden cardiac death (SCD). QT prolongation corrected for heart rate (QTc) is an important diagnostic and prognostic feature in LQTS. Obstructive sleep apnea (OSA) has been increasingly implicated in the pathogenesis of cardiovascular disease, including arrhythmias and SCD. We tested the hypothesis that the presence of concomitant OSA in patients with LQTS is associated with increased QT intervals, both during sleep and while awake. METHODS AND RESULTS: Polysomnography with simultaneous overnight 12-lead electrocardiography (ECG) was recorded in 54 patients with congenital LQTS and 67 control subjects. OSA was diagnosed as apnea-hypopnea index (AHI) >= 5 events/h for adults and AHI > 1 event/h for children. RR and QT intervals were measured from the 12-lead surface ECG. QTc was determined by the Bazett formula. Respiratory disturbance index, AHI, and arousal index were significantly increased in patients with LQTS and with OSA compared to those without OSA and control subjects. QTc during different sleep stages and while awake was also significantly increased in patients with LQTS and OSA compared to those without OSA. Severity of OSA in patients with LQTS was directly associated with the degree of QTc. CONCLUSIONS: The presence and severity of obstructive sleep apnea (OSA) in patients with congenital long QT syndrome (LQTS) is associated with increased QT prolongation corrected for heart rate, which is an important biomarker of sudden cardiac death (SCD). Treatment of OSA in LQTS patients may reduce QT prolongation, thus reducing the risk of LQT triggered SCD. PMID- 26118558 TI - An Economic Evaluation of Home Versus Laboratory-Based Diagnosis of Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: We conducted an economic analysis of the HomePAP study, a multicenter randomized clinical trial that compared home-based versus laboratory based testing for the diagnosis and management of obstructive sleep apnea (OSA). DESIGN: A cost-minimization analysis from the payer and provider perspectives was performed, given that 3-mo clinical outcomes were equivalent. SETTING: Seven academic sleep centers. PARTICIPANTS: There were 373 subjects at high risk for moderate to severe OSA. INTERVENTIONS: Subjects were randomized to either home based limited channel portable monitoring followed by unattended autotitration with continuous positive airway pressure (CPAP), versus a traditional pathway of in-laboratory sleep study and CPAP titration. MEASUREMENTS AND RESULTS: From the payer perspective, per subject costs for the laboratory-based pathway were $1,840 (95% confidence interval [CI] $1,660, $2,015) compared to $1,575 (95% CI $1,439, $1,716) for the home-based pathway under the base case. Costs were $264 (95% CI $39, $496, P = 0.02) in favor of the home arm. From the provider perspective, per subject costs for the laboratory arm were $1,697 (95% CI $1,566, $1,826) compared to $1,736 (95% CI $1,621, $1,857) in the home arm, for a difference of $40 (95% CI -$213, $142, P = 0.66) in favor of the laboratory arm under the base case. The provider operating margin was $142 (95% CI $85, $202,P < 0.01) in the laboratory arm, compared to a loss of -$161 (95% CI -$202, -$120, P < 0.01) in the home arm. CONCLUSIONS: For payers, a home-based diagnostic pathway for obstructive sleep apnea with robust patient support incurs fewer costs than a laboratory-based pathway. For providers, costs are comparable if not higher, resulting in a negative operating margin. CLINICALTRIALSGOV IDENTIFIER: NCT00642486. PMID- 26118559 TI - Work and Sleep--A Prospective Study of Psychosocial Work Factors, Physical Work Factors, and Work Scheduling. AB - STUDY OBJECTIVES: There is limited knowledge about the prospective relationship between major work characteristics (psychosocial, physical, scheduling) and disturbed sleep. The current study sought to provide such knowledge. DESIGN: Prospective cohort, with measurements on two occasions (T1 and T2) separated by two years. SETTING: Naturalistic study, Sweden. PARTICIPANTS: There were 4,827 participants forming a representative sample of the working population. MEASUREMENTS AND RESULTS: Questionnaire data on work factors obtained on two occasions were analyzed with structural equation modeling. Competing models were compared in order to investigate temporal relationships. A reciprocal model was found to fit the data best. Sleep disturbances at T2 were predicted by higher work demands at T1 and by lower perceived stress at T1. In addition, sleep disturbances at T1 predicted subsequent higher perception of stress, higher work demands, lower degree of control, and less social support at work at T2. A cross sectional mediation analysis showed that (higher) perceived stress mediated the relationship between (higher) work demands and sleep disturbances; however, no such association was found longitudinally. CONCLUSIONS: Higher work demands predicted disturbed sleep, whereas physical work characteristics, shift work, and overtime did not. In addition, disturbed sleep predicted subsequent higher work demands, perceived stress, less social support, and lower degree of control. The results suggest that remedial interventions against sleep disturbances should focus on psychosocial factors, and that such remedial interventions may improve the psychosocial work situation in the long run. PMID- 26118560 TI - Attention-Deficit/Hyperactivity Disorder (ADHD) Symptoms in Pediatric Narcolepsy: A Cross-Sectional Study. AB - STUDY OBJECTIVES: To evaluate the frequency, severity, and associations of symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with narcolepsy with and without cataplexy. DESIGN: Cross-sectional survey. SETTINGS: Four French national reference centers for narcolepsy. PATIENTS: One hundred eight consecutively referred children aged younger than 18 y with narcolepsy, with (NwC, n = 86) or without cataplexy (NwoC, n = 22), and 67 healthy controls. INTERVENTIONS: The participants, their families, and sleep specialists completed a structured interview and questionnaires about sleep, daytime sleepiness, fatigue, and ADHD symptoms (ADHD-rating scale based upon Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR] symptoms), and use of psychostimulants for the treatment of narcolepsy (administered in 68.2%). Polysomnographic measures were collected. MEASUREMENTS AND RESULTS: Clinically significant levels of ADHD symptoms were found in 4.8% of controls compared with 35.3% in patients with NwoC (P < 0.001) and 19.7% in patients with NwC (P < 0.01). Total ADHD scores were 6.4 (95% confidence interval [CI]: 4.5, 9.0) in controls compared with 14.2 (95% CI: 10.6, 18.9; P < 0.001), in patients with NwoC and 12.2 (95% CI: 9.8, 15.3; P < 0.01) in patients with NwC; subscores of inattention and hyperactivity/impulsivity were also significantly higher in both narcolepsy groups compared with controls. No difference was found between the NwC and NwoC groups for any ADHD measure. ADHD symptom severity was associated with increased levels of sleepiness, fatigue, and insomnia. Compared with the 34 untreated patients, the 73 patients treated with psychostimulants (modafinil in 91%) showed a trend toward lower narcolepsy symptoms but not lower ADHD symptoms. CONCLUSIONS: Pediatric patients with narcolepsy have high levels of treatment-resistant attention deficit/hyperactivity disorder (ADHD) symptoms. The optimal treatment for ADHD symptoms in these patients warrants further evaluation in longitudinal intervention studies. PMID- 26118561 TI - Behaviorally Assessed Sleep and Susceptibility to the Common Cold. AB - STUDY OBJECTIVES: Short sleep duration and poor sleep continuity have been implicated in the susceptibility to infectious illness. However, prior research has relied on subjective measures of sleep, which are subject to recall bias. The aim of this study was to determine whether sleep, measured behaviorally using wrist actigraphy, predicted cold incidence following experimental viral exposure. DESIGN, MEASUREMENTS, AND RESULTS: A total of 164 healthy men and women (age range, 18 to 55 y) volunteered for this study. Wrist actigraphy and sleep diaries assessed sleep duration and sleep continuity over 7 consecutive days. Participants were then quarantined and administered nasal drops containing the rhinovirus, and monitored over 5 days for the development of a clinical cold (defined by infection in the presence of objective signs of illness). Logistic regression analysis revealed that actigraphy- assessed shorter sleep duration was associated with an increased likelihood of development of a clinical cold. Specifically, those sleeping < 5 h (odds ratio [OR] = 4.50, 95% confidence interval [CI], 1.08-18.69) or sleeping between 5 to 6 h (OR = 4.24, 95% CI, 1.08 16.71) were at greater risk of developing the cold compared to those sleeping > 7 h per night; those sleeping 6.01 to 7 h were at no greater risk (OR = 1.66; 95% CI 0.40-6.95). This association was independent of prechallenge antibody levels, demographics, season of the year, body mass index, psychological variables, and health practices. Sleep fragmentation was unrelated to cold susceptibility. Other sleep variables obtained using diary and actigraphy were not strong predictors of cold susceptibility. CONCLUSIONS: Shorter sleep duration, measured behaviorally using actigraphy prior to viral exposure, was associated with increased susceptibility to the common cold. PMID- 26118562 TI - Insufficient Sleep and Risk of Prostate Cancer in a Large Swedish Cohort. AB - STUDY OBJECTIVE: There are some data to suggest that insufficient sleep, including short sleep duration and sleep disruption, may be associated with an increased risk of cancer. We investigated the association between sleep duration and sleep disruption and risk of prostate cancer. DESIGN: Prospective cohort study. SETTING: Sweden. PARTICIPANTS: A total of 14,041 men in the Swedish National March Cohort. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Habitual sleep duration and sleep disruption were self-reported in 1997. Prostate cancer diagnoses, including lethal (metastases at diagnosis or death from prostate cancer) and advanced (stage T4, N1, or M1 at diagnosis or death from prostate cancer), were determined from linkage to nationwide cancer registries through 2010. We conducted Cox proportional hazards regression adjusted for potential confounding variables. During 13 years of follow-up, we identified 785 cases of incident prostate cancer, including 118 lethal and 127 advanced cases. Four percent of men reported sleeping 5 h or less a night, and 2% reported sleeping 9 h or more per night. We found no association between sleep duration and risk of prostate cancer overall or for advanced/lethal disease. We also did not find an association between prostate cancer and sleep disruption, as defined by difficulty falling asleep, difficulty maintaining sleep, sleep quality, and restorative power of sleep. CONCLUSIONS: In this large prospective study from Sweden, we found no association between habitual sleep duration or sleep disruption and risk of prostate cancer. PMID- 26118563 TI - Influence of particle size, an elongated particle geometry, and adjuvants on dendritic cell activation. AB - Modern subunit vaccines have many benefits compared to live vaccines such as convenient and competitive large scale production, better reproducibility and safety. However, the poor immunogenicity of subunit vaccines usually requires the addition of potent adjuvants or drug delivery vehicles. Accordingly, researchers are investigating different adjuvants and particulate vaccine delivery vehicles to boost the immunogenicity of subunit vaccines. Despite the rapidly growing knowledge in this field, a comparison of different adjuvants is sparsely found. Until today, little is known about efficient combinations of the different adjuvants and particulate vaccine delivery vehicles. In this study we compared three adjuvants with respect to their immune stimulatory potential and combined them with different particulate vaccine delivery vehicles. For this reason, we investigated two types of polyI:C and a CL264 base analogue and combined these adjuvants with differently sized and shaped particulate vaccine delivery vehicles. A high molecular weight polyI:C combined with a spherical nano-sized particulate vaccine delivery vehicle promoted the strongest dendritic cells activation. PMID- 26118564 TI - When is dispersal for dispersal? Unifying marine and terrestrial perspectives. AB - Recent syntheses on the evolutionary causes of dispersal have focused on dispersal as a direct adaptation, but many traits that influence dispersal have other functions, raising the question: when is dispersal 'for' dispersal? We review and critically evaluate the ecological causes of selection on traits that give rise to dispersal in marine and terrestrial organisms. In the sea, passive dispersal is relatively easy and specific morphological, behavioural, and physiological adaptations for dispersal are rare. Instead, there may often be selection to limit dispersal. On land, dispersal is relatively difficult without specific adaptations, which are relatively common. Although selection for dispersal is expected in both systems and traits leading to dispersal are often linked to fitness, systems may differ in the extent to which dispersal in nature arises from direct selection for dispersal or as a by-product of selection on traits with other functions. Our analysis highlights incompleteness of theories that assume a simple and direct relationship between dispersal and fitness, not just insofar as they ignore a vast array of taxa in the marine realm, but also because they may be missing critically important effects of traits influencing dispersal in all realms. PMID- 26118565 TI - Methodology of patient care for elevated PSA after prostate cancer treatment: A primary care perspective. AB - Prostate cancer (PCa) remains one of the most common cancers in men. Each year there are 230,000 new cases and it causes nearly 30,000 deaths. Elevations in prostate-specific antigen (PSA) after treatment with radiation or surgery can indicate the presence of PCa recurrence. About 15-18% of men treated for PCa will have an elevation of their PSA, which is a source of great concern and will lead to a management discussion with the patient. Approximately 25-33% of men with PCa will experience a recurrence of their cancer after surgery or radiation. This article will discuss the different options for men with a rising PSA after definitive therapy or an attempt at curative treatment for PCa. The purpose of this article is to help the primary care doctor, internist and geriatrician to become knowledgeable about the treatment options of recurrent PCa so that they can participate in the discussion with the patient and help the patient reach a decision regarding treatment and management of the elevated PSA levels, which signal recurrent disease. PMID- 26118566 TI - Tibial Stems in Revision Total Knee Arthroplasty: Is There an Anatomic Conflict? AB - Tibial stems are frequently used in revision total knee arthroplasty (TKA). We investigated the effect of tibial stems on final component alignment and tray position. Thirty 3D reconstructed cadaveric tibial models were classified according to canal bow angle. After virtual implantation of 120 mm and 200 mm stemmed tibial components, deviation from native mechanical axis was measured. Tibial alignment valgus malposition of up to three degrees occurred and most pronounced with 120 mm stems. Canal alignment using 200 mm stems deviated tray position medially and posteriorly. Mild to moderate valgus bowing of the tibial canal is not uncommon (57% in our series) possibly leading to valgus malalignment. Anatomic conflict between the tibial mechanical axis and intramedullary canal can exist, with alignment and tray placement implications. PMID- 26118567 TI - To Cement or Not? Two-Year Results of a Prospective, Randomized Study Comparing Cemented Vs. Cementless Total Knee Arthroplasty (TKA). AB - The optimal mode of fixation in total knee arthroplasty (TKA) is a subject of debate. We enrolled 100 TKA patients randomized to cemented or cementless fixation. Knee Society Scores (KSS), Oxford scores and pain visual analog scales (VAS) were collected pre-operatively and post-operatively. Two-year follow-up was obtained for 93 patients. The mean VAS trended higher for the cementless group at 4 months (P=0.06). At 2 years, the KSS functional scores, Oxford scores, and self reported questions for satisfaction, less pain and better function were similar but the cemented group had higher KSS clinical scores (96.4 vs. 92.3, P=0.03). More radiolucencies were seen in cementless knees (P<0.001). The cementless group had one revision for instability and one cemented knee was revised for infection. Cementless TKA showed equivalent survivorship (revision for any reason as the endpoint) compared to cemented TKA at this early follow-up. Close monitoring of radiolucencies is important with continued follow-up. PMID- 26118568 TI - Complications Following Direct Anterior Hip Procedures: Costs to Both Patients and Surgeons. AB - A systematic review of the literature on clinical outcomes following direct anterior approach (DAA) hip arthroplasty was performed. An aggregated 11,810 hip procedures were analyzed for intraoperative and early postoperative complications. The most common complication following DAA hip arthroplasty was nerve dysfunction (2.8%) followed by intraoperative fractures (2.3%). Postoperative dislocation, wound complications, and revision THA within the first 12 months were reported in 1.2% of cases. Thus, while DAA hip arthroplasty can be successfully performed, it is not without complications. Without definitive evidence of clinical superiority, surgeons considering switching to DAA should benchmark their personal complication rates against published reports. PMID- 26118569 TI - Sex difference in the association between obesity and asthma in U.S. adults: Findings from a national study. AB - BACKGROUND: Obesity and asthma are both prevalent in the U.S. The a few studies that have examined the differences in association between obesity and asthma by sex provided mixed results. Reason for the sex differences is not well understood. OBJECTIVE: Using U.S. nationally representative data we aimed to examine the association between obesity and asthma and potential sex differences. METHODS: Data were obtained from the 2012 National Health Interview Survey (n = 33,153 adults, 4197 had asthma). Asthma was determined by a positive response to the question "Has a doctor or health care professional ever told you had asthma?" Obesity was determined as a Body Mass Index (BMI)>=30. Obese status was categorized as BMI = 30-34.9 (Class I obesity), BMI = 35-39.9 (Class II obesity), and BMI>=40 (Class III obesity). RESULTS: The prevalence of asthma was 12.6% (11.0% in men, 14.2% in women), and was higher in the obese than non-obese individuals (16.6% vs. 11.1%, p < 0.0001). After controlling for potential confounders, Class I obesity (OR = 1.27, 95% CI = 1.11-1.44), Class II obesity (OR = 1.55, 95% CI = 1.31-1.84), Class III obesity (OR = 1.85, 95% CI = 1.54 2.21) were positively associated with asthma. The association between Class III obesity and asthma was stronger in women than men (2.11 (1.70-2.63) vs. 1.40 (1.01-1.96), p < 0.05), although the sex difference in the association between BMI and asthma was not significant. Positive associations between class II and class III obesity and asthma were observed among young and middle-aged women compared to young and middle-aged men. Stratified by allergic status, obesity remained being positively associated with asthma. CONCLUSION: The prevalence of asthma was higher in women than men. Obesity (and BMI) was positively associated with asthma, overall or stratified by allergic status. The association between Class III obesity and asthma was stronger in women. Obesity and sex may be taken into consideration for the management of asthmatic patients. PMID- 26118570 TI - Abdominal Ultrasound Examination Findings in 534 Hyperthyroid Cats Referred for Radioiodine Treatment Between 2007-2010. AB - BACKGROUND: The prevalence of concurrent disease in hyperthyroid cats is unknown. OBJECTIVES: To identify the prevalence of concurrent intra-abdominal disease using abdominal ultrasound examination (AUS) in hyperthyroid cats referred for radioactive iodine treatment (RIT) and to determine whether the requirement for pretreatment AUS is justified. ANIMALS: Five hundred and thirty-four client-owned cats diagnosed with hyperthyroidism and referred for RIT. METHODS: Retrospective study. Age, breed, sex, body weight, clinical signs, total serum T4 concentration, blood urea nitrogen (BUN) concentration, serum creatinine concentration, urine specific gravity (USG), AUS results, and biopsy or cytology results, or both (if obtained) were collected from the medical records. RESULTS: The prevalence of concurrent disease identified using AUS in hyperthyroid cats referred for RIT was 36.1%; 22.8% of the cats in the study had renal disease and 2.4% had confirmed neoplasia. Significant differences in median USG (P value 0.032) and median BUN (P value 0.028) were found between cats that had abnormal kidneys on AUS compared to those with normal-appearing kidneys. Only 2.2% of the cats were not treated with RIT as a result of changes identified on AUS and subsequently obtained cytology or biopsy results. CONCLUSIONS AND CLINICAL IMPORTANCE: The results indicate that pretreatment AUS in hyperthyroid cats referred for RIT is unnecessary in most patients. PMID- 26118571 TI - Effects of rapamycin treatment on pancreatic fibrosis, cellular apoptosis and oxidative stress in experimental chronic pancreatitis model. AB - PURPOSE: Rapamycin reduces hepatic fibrosis by inhibiting hepatic stellate cell activation. The present study investigated whether rapamycin treatment could modify the degree of fibrosis, cellular apoptosis and oxidative stress (OS) in an experimental model of CP. METHODS: Fifty-five male, Sprague-Dawley rats weighing 200-400g were randomized into four groups. CP was induced by intraductal trinitrobenzene sulfonic acid (TNBS) infusion in group A (n = 15) and group B (n = 15). Group C (n = 15) received intraductal TNBS and was killed for histologic confirmation at four weeks. Group D (n = 10) received intraductal saline instead of TNBS. Group A and group D received oral rapamycin (2 mg/kg/d) for two weeks after CP was induced while group B received oral tap water instead of rapamycin. Blood and pancreatic tissue specimens were collected and oxidative stress parameters, fibrosis and cellular apoptosis were determined. RESULTS: Tissue and blood malondialdehyde (MDA) levels were significantly lower in rapamycin treated group compared to controls (p < 0.001). Superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) activities were also significantly higher in the active treatment group (p < 0.001 for both). Tissue and blood MDA, SOD, GSH-Px measurements was similar in rapamycin group and pancreatic cannulation group (p > 0.05). Histopathologic fibrosis scores were similar in rapamycin and control groups. Apoptotic cell counts tended to be lower in rapamycin treated animals. CONCLUSIONS: Administration of rapamycin alleviated OS and, in part, prevented apoptotic cell death in experimental CP, but did not reduce fibrosis. PMID- 26118572 TI - Treatment of chronic hepatitis C in children with pegylated interferon and ribavirin: the impact of dose. AB - INTRODUCTION: In the last years children with chronic hepatitis C (CHC) have been treated with Pegylated Interferon alpha (PEG-IFNalpha) and ribavirin (RBV). Treatment can cause several side effects that require reduction or interruption of therapy. The relationship between dose of PEG-IFNalpha and response to therapy has not been clearly evaluated. Aim of this study was to evaluate the impact of the dose of PEG-IFNalpha2b and RBV on the efficacy of therapy. PATIENTS AND METHODS: All children with CHC treated with PEG-IFNalpha2b and RBV, observed at the Paediatric Liver Unit of University Federico II of Naples from 1996 to 2006 were evaluated. RESULTS: Sixteen children with CHC treated with combined therapy were enrolled. Seven out of 16 patients (43.7%) achieved rapid virological response; 13/16 patients (81.2%) achieved early virological response; 5/16 patients (31.25%) relapsed; 1 patient resulted non responder. According to percentage of expected dose, our patients were divided into two groups: the first group included 7 patients that performed an overall dosage of PEG-IFNalpha2b >= 75% of the scheduled full dose; the second group included 9 patients that performedm PEG-IFNalpha2b dose < 75% of scheduled full dose. No difference was noted in terms of sustained virological response. CONCLUSIONS: Modifications of therapy due to PEG-IFNalpha-related adverse events are frequent in children with CHC, but dose adjustments do not seem to impair efficacy of therapy. PMID- 26118573 TI - Survival in patients with hypoechoic muscularis propria lesions suggestive of gastrointestinal stromal tumors in gastric wall. AB - BACKGROUND: Subepithelial lesions (SEL) on upper gastrointestinal endoscopy are frequently encountered and referred to endoscopic ultrasound (EUS). Management of small gastric hypoechoic SELs of muscularis propria (MP) is controversial since EUS-assisted fine needle aspiration may be inconclusive, and surgical excision may be too invasive. We aimed to analyze our gastric MP-SELs in terms of survival and confounding factors. METHODS: Data from gastric hypoechoic MP-SELs suggestive of gastrointestinal stromal tumor (GIST) by EUS were retrospectively reviewed. Surgically resected GISTs were stratified according to the current pathological risk criteria. RESULTS: Sixty-one patients were identified. The mean age was 55.5 +/- 13.2 years and 45.6% were male. Mean follow-up duration was 53.4 +/- 26.7 (12 110) months. Twenty-eight (45.9%) patients were managed conservatively (diameter 15.3 +/- 10.1 mm). There were no metastasis- or tumor-related deaths and no significant size changes (>= 5 mm) in this group during follow-up. Thirty-three (54.1%) patients underwent complete resection (diameter 34.2 +/- 14.1 mm) among which 25 (75.8%) had the final diagnosis of GIST; 2 (8.0%), 14 (56%) and 6 (24%) patients were classified in no-risk, very-low-risk, low-risk categories respectively, while 2 (8.0%) were in moderate-risk and only 1 (4.0%) was in high risk category. CONCLUSIONS: The excellent survival of patients with small hypoechoic gastric MP-SELs with conservative management represents indolent course of those lesions. We suggest re- consideration of the recommendations in the current guidelines towards extending the follow-up intervals for small MP SELs. PMID- 26118574 TI - Quality assessment of colonoscopy in Flanders: a voluntary survey among Flemish gastroenterologist. AB - Colonoscopy is an important endoscopic examination for the diagnosis and treatment of pathological conditions of the colon, like polyps and colorectal cancer. However, several factors determine the quality of colonoscopy and thus the quality of polyp and colorectal cancer detection. The Flemish Society of Gastroenterology (VVGE) performed a voluntary on-line registry among its members to identify quality of colonoscopy in Flanders, Belgium. 64 gastroenterologists voluntarily registered 4276 consecutive colonoscopies performed during a 3 month study period. Colonoscopy quality indicators were prospectively collected and analysed. Results showed a low voluntary participation rate (17%), acceptable overall adenoma detection rate of 20,5% and colorectal cancer interval rate of 5,4%. Complications were low (perforation 0,1% and major bleeding 1,5%). The current study showed that in Flanders, Belgium on-line registration of colonoscopy quality indicators is feasible and that quality of colonoscopy in daily practice meets the expectations of (inter)national guidelines. However, further improvement of the registry and an open debate on the quality control of colonoscopy in Flanders is warranted (Belgian Registry B30020096548). PMID- 26118575 TI - Clinical and scientific aspects related to biosimilars in inflammatory bowel diseases (IBD): position document of the Belgian IBD Research & Development Group (BIRD). PMID- 26118576 TI - Diverticulitis: new insights on the traditional point of view. AB - Diverticulosis of the colon is a common disease with an increasing incidence in Western countries. Recent literature has shown some changes in the traditional approach of this disease. The theory that diverticulosis is caused by a reduced intake of dietary fibre, is doubtful. There might be some chemical and histological overlap between diverticulitis, inflammatory bowel disease and irritable bowel disease. High quality clinical study found no effect for antibiotics in acute, uncomplicated diverticulitis. Cyclic administration of mesalazine and rifaximin result in reduced symptoms of diverticular disease. For the treatment of diverticular abscesses, percutaneous drainage shows promising results. Recurrence of acute diverticulitis is rare and most serious complications are linked to the first episode. Recent evidence does not support the traditional recommendation for elective surgery after two episodes of acute diverticulitis any more. This review summarizes the last evidence in diverticular disease and diverticulitis. PMID- 26118577 TI - Distal intestinal obstruction in CF patients. AB - Distal intestinal obstruction syndrome (DIOS) - the incomplete of complete intestinal obstruction by intestinal contents in the terminal ileum and proximal colon- is frequently seen in cystic fibrosis (CF) patients. Diagnosis is based on suggestive symptoms of abdominal pain in the right lower quadrant, a palpable mass on examination and signs of obstruction on plain radiography. Treatment consists of intensive laxative treatment with oral laxatives and enemas. Surgery only serves as the last resort for patients not responding to medical therapy, because of the well-known high rate of peri- and postoperative morbidity of surgery in CF patients. In this article we present 3 cases of DIOS, followed by a review of the relevant literature. PMID- 26118578 TI - Ecstasy induced acute hepatic failure. Case reports. AB - 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine derivative known as ecstasy, has stimulating and hallucinogenic properties. It has become a substance that is widely used especially by young people. Hepatotoxicity is one of the rare side effects of this substance and can be fatal. Ecstasy-induced fulminant hepatitis has been reported in case reports. The clinical course and the prognosis of the cases may differ. In this article, two cases in whom ecstasy induced fulminant hepatic failure had developed and who were treated with liver transplantation, and one case which recovered with treatment, have been presented. PMID- 26118579 TI - A meaningless finding for gastroenterologist : Ano-rectal malformation in adult. PMID- 26118580 TI - Wernicke encephalopathy in a patient with severe acute pancreatitis. PMID- 26118581 TI - Solitary cavernous lymphangioma of the duodenum: a case report. AB - Duodenal lymphangioma is an extremely rare benign tumor of the gastrointestinal tract. In this case report, we describe the case of a 39-year-old Lebanese female with cystic lymphangioma of the duodenum diagnosed by exploratory laparotomy and immunohistochemical analysis. Herein our findings are described. PMID- 26118582 TI - IgG4-related cholangitis: Case report and literature review. AB - CASE PRESENTATION: We describe a case of a patient who presents with jaundice, elevated cholestatic liver enzymes, an extreme weight loss and a midcholedochal stricture very suspect for a cholangiocarcinoma. In the conviction of malignancy, although the absence of anatomopathological prove, the patient underwent a choledochal resection. The anatomopathological specimen revealed no malignancy. In the year following resection, the patient keeps presenting with bile duct strictures and further weight loss. Ultimately the diagnosis of Ig G4-related cholangitis is withheld. Therapy with corticosteroids is initiated with a spectacular clinical, biochemical and radiographical result. DISCUSSION: IgG4 related cholangitis is the biliary presentation of IgG4-related disease, a recently discovered entity of fibroinflammatory masses which can affect virtually every organ in the body. It is characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis and a presence of > 30 IgG4-positive plasma cells per high power field. Main differential diagnosis contains cholangiocarcinoma and primary sclerosing cholangitis. Corticoids are cornerstone of therapy, with azathioprine frequently used as a maintenance in case of relapse. CONCLUSIONS: With this case we want to draw the attention to a rather uncommon cause of biliary obstruction, easily mistaken for a cholangiocarcinoma. PMID- 26118583 TI - Idiopathic acute eosinophilic hepatitis: does it exists? AB - Until now, "eosinophilic hepatitis" has not been recognized as a separate disease entity. We report a case of a middle-aged women with an acute febrile, severe cholestatic hepatitis accompanied with rash and quincke oedema, and an elevated serum IgE level. Liver biopsy showed lymphocytic inflammation with a remarkably high number of eosinophils. She responded rapidly to methylprednisolone treatment, which could be quickly tapered off and stopped without relapse. The term 'idiopathic acute eosinophilic hepatitis' seems to be the best fitting diagnostic term. PMID- 26118584 TI - Deadly Air. PMID- 26118585 TI - How to handle esophageal metaplasia in 2014: a practical guide. AB - Metaplasia of the esophagus is a precursor of esophageal adenocarcinoma, a cancer with a poor prognosis and an increasing incidence. Guidelines for surveillance are proposed by all professional societies with small differences in timing. However, there is still no consensus on the definition of Barrett's esopaghus (only intestinal metaplasia or all subtypes). The goal of surveillance of esophageal metaplasia has evolved from early detection of cancer to early detection of pre-cancerous metaplasia to allow endoscopic therapy. The endoscopic therapy has the intention to stage, to cure, to prevent progression and to prevent metachronous lesions to develop. Firm indications for endoscopic therapy are high rade dysplasia and mEAC. The actual treatment is EMR/ESD for all visual abnormalities and areas of cancer on biopsies, followed by RFA for the remaining metaplasia. For low grade dysplasia (LGD), surveillance versus RFA is still under discussion. The main reason for this is the wide interobserver variability with large differences in evolution between confirmed and unconfirmed LGD. The endoscopic treatment allows complete remission of dysplasia in most cases and of metaplasia in the majority of cases, with low complication rates and acceptable morbidity (treatable stenosis). However, a median of 3 treatments is usually required to achieve remission, and recurrence is as high as 15% in the following 5 years. Strategies to reduce recurrence like chemotherapy or anti-reflux surgery need to be explored better and can actually not decrease or replace surveillance. PMID- 26118586 TI - Spreading patterns, prognostic factors and treatment outcomes of nasopharyngeal papillary adenocarcinoma and salivary gland-type carcinomas. AB - OBJECTIVES: In this study, we aim to analyse the different spreading patterns, prognostic factors and treatment outcomes of nasopharyngeal papillary adenocarcinoma (NPAC) and salivary gland-type carcinomas (NPCs). DESIGN, SETTING AND PARTICIPANT: The current study report on a retrospective analysis of oncologic outcome of 76 pathologically confirmed consecutive cases of nasopharyngeal adenocarcinomas (NAC), including 31 NPAC, 33 adenoid cystic carcinomas (ACC) and 12 mucoepidermoid carcinomas (MEC). MAIN OUTCOME MEASURE: Overall survival rates (OS) and disease-free survival rates (DFS). RESULTS: In 12 patients with cranial nerve (CN) palsy, there were ACC (n = 9), NPAC (n = 2) and MEC (n = 1) (P = 0.016). CT-/MRI-detected CN involvements were found in 22 patients. Lymph node metastasis was observed in 25.8% of NPAC (n = 8), 12.1% of ACC (n = 4) and 8.3% of MEC (n = 1). Significant differences were observed in 5 year overall survival (OS) and disease-free survival (DFS) rates between patients with and without CT-/MRI-detected CN involvement (P = 0.002 and P = 0.002, respectively), and similar results were found between patients with and without lymph node metastasis (P = 0.002 and P = 0.018, respectively). In 37 patients with early-stage disease (stages I-II), significant differences were observed in 5-year OS and DFS rates between the surgical and non-surgical treated groups (P = 0.031 and P = 0.012, respectively). In 39 patients with advanced-stage disease (stages III-IV), significant or marginally differences were observed in DFS and OS between the chemoradiotherapy and non-chemoradiotherapy groups (P = 0.007 and P = 0.062, respectively). CONCLUSIONS: ACC has a higher CN invasion than NPAC and MEC, and NPAC has the highest rate of lymphatic metastases. CT-/MRI-detected CN involvements and lymph node metastasis indicate a negative impact on the prognosis. The outcome of surgical patients in our series is encouraging in early stage NPAC and NPCs, and chemoradiotherapy may be the optimal treatment for the advanced-stage patients. PMID- 26118587 TI - Self-management support for chronic pain in primary care: a cross-sectional study of patient experiences and nursing roles. AB - AIMS: The aim of this study was to describe chronic pain self-management from the perspective of individuals living with chronic pain in the context of primary care nursing. BACKGROUND: Self-management is a key chronic pain treatment modality and support for self-managing chronic pain is mainly provided in the context of primary care. Although nurses are optimally suited to facilitate self management in primary care, there is a need to explore opportunities for optimizing their roles. DESIGN: Two cross-sectional studies. METHODS: The Chronic Pain Self-Management Survey was conducted in 2011-2012 to explore the epidemiology and self-management of chronic pain in Canadian adults. The questionnaire was distributed to 1504 individuals in Ontario. In 2011, the Primary Care Nursing Roles Survey was distributed to 1911 primary care nurses in Ontario to explore their roles and to determine the extent to which chronic disease management strategies, including support for self-management, were implemented in primary care. RESULTS: Few respondents to the pain survey identified nurses as being the 'most helpful' facilitator of self-management while physicians were most commonly cited. Seventy-six per cent of respondents used medication to manage their chronic pain. Few respondents to the nursing survey worked in practices with specific programmes for individuals with chronic pain. Individuals with chronic pain identified barriers and facilitators to self managing their pain and nurses identified barriers and facilitators to optimizing their role in primary care. CONCLUSION: There are several opportunities for primary care practices to facilitate self-management of chronic pain, including the optimization of the primary care nursing role. PMID- 26118588 TI - Clinical evaluation of dengue RNA, NS1, and IgM for diagnosis of dengue in Southern China. AB - In 2014, a large outbreak of dengue occurred in Guangzhou, China. This outbreak prompted us to evaluate NS1 and RNA for the early diagnosis of acute dengue infection, in addition to the combination with IgM antibody. We aimed to find the differences of three assays about dengue diagnosis. This study was an evaluation of diagnosis test. Based on WHO criteria 2009, dengue RNA, NS1, and IgM/IgG were detected from 294 patients (180 dengue patients, 114 non-dengue patients) by three diagnostic kits made in China. The chi(2) test, sensitivity, and specificity were used in statistical analysis. The ratios of dengue patients with low platelet counts (<100 * 10(9) /L 32.2%) or white blood cell counts (<4.0 * 10(9) /L 58.9%) were significantly higher compared to non-dengue patients (P < 0.05). Dengue NS1 was shown sensitive (93.9%) for diagnostic use. RNA had a better performance with 98.1% of sensitivity from day 1 to day 4 after illness onset. IgM performed better at day 5 or more with 74.0% of sensitivity. The diagnostic rate using a combination of RNA and IgM was 97.8% and 96.7% using NS1 and IgM. A patient with low platelet and white blood cell counts needs additional tests for dengue during an epidemic. RNA and NS1 were most valuable for early diagnosis of dengue, whereas IgM was best suited as a supplementary method for patients at day 5 or more after illness onset. PMID- 26118589 TI - Chronic Pain, Comorbid Medical Conditions, and Associated Risk Factors in Kuwait: Gender and Nationality Differences. AB - OBJECTIVE: Chronic pain is an international health problem that imposes enormous costs on societies around the world. There is good reason to suspect that chronic pain is a serious health issue in Kuwait and is associated with comorbid medical conditions like diabetes. The aim of this study is to examine the report of pain and incidence of medical comorbidities among a large convenience sample of patients treated at a private rehabilitation center in Kuwait and to examine differences in patient groups based on age, gender, and Kuwaiti nationality. METHODS: This study examined intake data from 2,103 patients treated at a rehabilitation center in Kuwait. Most of the subjects were female (55.4%) and averaged 43.3 years of age (+/-14.5, range 18-88). Sixty nine percent were Kuwaiti citizens and 57.9% were employed. RESULTS: Marked differences in pain and health-related conditions were found between Kuwaiti nationals and non-Kuwaitis, with significantly increased incidences of hypertension, osteoarthritis, diabetes, asthma, osteoporosis, and cardiac and respiratory problems among the Kuwaitis (P < 0.001). Notable gender differences were also identified with women reporting more intense, widespread pain, and reporting more comorbid medical problems compared with men (P < 0.001). CONCLUSIONS: This extensive survey study that found female Kuwaitis to have a higher incidence of pain and medical comorbidities than males and non-Kuwaitis highlights the role of cultural factors in contributing to pain and comorbid medical conditions. This information is critical in organizing resources to implement adequate healthcare services and behavioral interventions in Kuwait and other Arab countries to improve pain and health-related conditions. PMID- 26118590 TI - High Sensitive CRP Level Is Associated With Intermediate and High Syntax Score in Patients With Acute Coronary Syndrome. AB - High sensitive C-reactive protein (hs-CRP) levels are associated with short- and long-term mortality in patients with acute coronary syndrome (ACS). We investigated whether baseline hs-CRP levels are associated with burden of coronary atherosclerosis assessed by SYNTAX score (SXScore).We enrolled 321 patients with ACS who underwent coronary angiography. The patients were divided into tertiles according to the SXScore: low SXScore (<= 22), and intermediate high SXScore (>= 23).Subjects in the intermediate-high SXScore tertile had higher serum hs-CRP levels compare to low SXScore tertile patients (7.7 +/- 3.4 mg/L versus 4.9 +/- 2.5 mg/L, P < 0.001). The mean age of patients and prevalance of diabetes in the intermediate-high SXScore tertile were significantly higher than in the low SXScore tertile (63 +/- 13 versus 58 +/- 12 years P = 0.001 for age, P = 0.007 for diabetes). Multivariate logistic regression analysis showed that the strongest predictors of high SXScore were increased serum hs-CRP levels (OR: 1.14) together with multivessel disease (OR: 0.23), left ventricular ejection fraction (LVEF) (OR: 0.90), and troponin levels (OR: 1.12).Serum hs-CRP levels on admission in patients with ACS could predict the severity and complexity of coronary atherosclerosis together with multivessel disease, LVEF, and troponin levels. Thus, increased serum levels of hs-CRP were one of the strong predictors of high SXScore in ACS patients. PMID- 26118591 TI - Beating Heart Versus Arrested Heart Isolated Tricuspid Valve Surgery. AB - We analyzed the long-term results of two surgical techniques (beating versus non beating) for isolated tricuspid valve (TV) surgery.The long-term results of 92 consecutive patients who underwent isolated TV surgery were analyzed. We compared patients with beating heart (BH) surgery (n = 48) with patients undergoing arrested heart (AH) surgery (n = 44).BH surgery was more frequently chosen in urgent/emergent operations (P = 0.029) and in redo-operations (P < 0.001). Preoperatively, the rates of renal insufficiency (P = 0.002) and EuroSCORE (P = 0.019) were higher in the BH group than in the AH group. There were no differences in perioperative outcomes and 30-day mortality between the groups. However, freedom from reoperation was significantly lower in the BH group compared to the AH group (P = 0.039). We observed a trend towards lower survival rates at 1, 5, and 10 years in the BH group (77%, 54%, and 41%) compared to those of the AH group (86%, 75%, and 72%, P = 0.062). Multivariate Cox hazard model analysis revealed preoperative heart rhythm (P = 0.014, odds ratio [OR] = 2.296) and EuroSCORE (P = 0.022, OR = 1.049) as independent risk factors for mortality after isolated TV surgery.The superiority of BH surgery over AG surgery was not proven. Surgical intervention should be considered early, since patients with elevated EuroSCORES and arrhythmia have significantly higher mortality rates. PMID- 26118592 TI - Sodium Hydroxide Pinpoint Pressing Permeation Method for the Animal Modeling of Sick Sinus Syndrome. AB - Sodium hydroxide pinpoint pressing permeation (SHPPP) was investigated in order to build a rat model of sick sinus syndrome (SSS), which is easy to operate and control the degree of damage, with fewer complications and applicable for large and small animals.Thirty healthy Wistar rats (15 males and 15 females, weighing 250-350 g) were randomly divided into 3 groups, namely a formaldehyde thoracotomy wet compressing group (FTWC), formaldehyde pinpoint pressing permeation group (FPPP) group, and SHPPP group. The number of surviving rats, heart rate (HR), sinoatrial node recovery time (SNRT), corrected SNRT (CSNRT), and sinoatrial conduction time (SACT) were recorded 3 days, one week, and two weeks after modeling.The achievement ratio of modeling was 10% in the FTWC group, 40% in the FPPP group, and 70% in the SHPPP group, and the differences were statistically significant (chi(2) = 7.250, P = 0.007). Meanwhile, the HR was reduced by about 37% in these 3 groups 3 days after modeling, while the reduction was maintained only in SHPPP (P > 0.05) and the HR was re-elevated in the FTWC and FPPP groups 2 weeks after modeling (P < 0.05). Additionally, the SNRT, cS-NRT, and SACT were significantly prolonged compared with pre-modeling in all 3 groups (P < 0.01).SHPPP was the best method with which to build an SSS model with stable and lasting low HR and high success rate of modeling, which might be helpful for further studies on the SSS mechanisms and drugs. PMID- 26118593 TI - Mutation Analysis of KCNQ1, KCNH2 and SCN5A Genes in Taiwanese Long QT Syndrome Patients. AB - Long QT syndrome (LQTS) is a genetic cardiac disease. Gene mutation affects the structure or function of ion channels that are associated with a high risk of sudden death. The goal of this study was to determine the frequency of KCNQ1, KCNH2, and SCN5A mutations in LQTS in a Taiwanese population. Genomic DNA was extracted from peripheral blood samples obtained from 5 patients with LQTS and the family members of 3 LQTS patients. High resolution melting (HRM) analysis and direct DNA sequencing were used to characterize the KCNQ1, KCNH2, and SCN5A genetic variations. HRM analysis was successfully optimized for 14 of the 16 exons of the KCNQ1, 5 of the 15 exons of the KCNH2, and 23 of the 27 exons of the SCN5A. HRM and direct DNA sequencing was applied to the cohort of 5 cases and some of their family. The genetic testing revealed two pathogenic mutations (p.T309I in KCNQ1 and p.R744fs in KCNH2) and all of the mutational frequencies in KCNQ1 and KCNH2 were 20%. In the two patients who carry the pathogenic mutation presenting with recurrent syncope due to ventricular fibrillation, an implantable cardioverter defibrillator was implanted. We also discovered 11 polymorphisms in KCNQ1, 3 in KCNH2, and 5 in SCN5A. Two-fifths of cases (40%) presented with one of the three major LQTS-causing gene mutations. PMID- 26118594 TI - Early Phase Arterial Reaction Following Drug-Eluting and Bare-Metal Stent Implantation in Patients With ST-Segment Elevation Myocardial Infarction. AB - The early phase arterial reaction after implantation of second-generation drug eluting stents (2nd DES) and baremetal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear.The MECHANISM pilot study is a multi-center prospective registry that enrolled 24 STEMI patients (from 11 centers) who had undergone implantation of everolimus-eluting (n = 6), biolimus A9-eluting (n = 6) or zotarolimus-eluting stents (n = 6), or BMS (n = 6). Scheduled optical coherence tomography (OCT) was performed 2 weeks after implantation, and images were independently analyzed at a core laboratory in a blinded fashion. Intra-stent thrombus was quantitatively analyzed in terms of the maximal area and the percentage of cross-sections with thrombus (the numbers of cross-section with thrombus * 100 divided by total number of cross-sections within the stented segment). More than 90% of struts were already covered 2 weeks after the index procedure, regardless of the stent type. There were no differences in stent diameter, minimal lumen diameter, minimal lumen area, neointimal thickness, or the frequencies of malapposed and uncovered struts among the 4 groups. The quantity of intra-stent thrombus also did not differ among the 4 groups.The results of this pilot study suggest that the 2-week vascular responses seem to be similar among 2nd DES and BMS in STEMI patients. Considering the possible advantage of 2nd DES in the prevention of restenosis, 2nd DES are a feasible option for the treatment of patients with STEMI. PMID- 26118595 TI - Predictors of Atrial Septal Defect Occluder Dislodgement. AB - The aim of this study was to identify the factors that influence atrial septal occluder dislodgement in adults and children.From June 2003 to June 2013, a total of 213 patients (115 adults and 98 children) diagnosed with secundum atrial septal defects (ASD) underwent transcatheter closure of their defects with an atrial septal occluder (ASO) in our hospital. The ASO was implanted under transesophageal echocardiography (TEE) guidance. Ten patients suffered from ASO dislodgement, and the other 203 patients comprised the successful group. We compared the preprocedural data related to general demographics, defects, margins, and minor post-implantation complications between the two groups with the goal of identifying the factors that affected ASO dislodgement.Univariate logistic regression analyses identified a high Qp/Qs value, the Qp/Qs ratio > 3.13, ASO size, ASO size greater than 32 mm, ASO size/BSA ratio > 15.13 and IAS erosion, floppiness or aneurysm formation as factors with significant predictive value. Multivariate analysis revealed that a Qp/Qs ratio > 3.13, and interatrial septum (IAS) erosion, floppiness and aneurysm formation post-implantation were independent predictors of ASO dislodgement (P = 0.001 and P = 0.006, respectively) in both adults and children.Percutaneous device closure of ASDs is safe and effective in the current era. The Qp/Qs ratio > 3.13 and IAS erosion, floppiness or aneurysm formation post-implantation might be predictors of ASO dislodgement in adults and children. PMID- 26118596 TI - Erratum: Pathological Role of Adipose Tissue Dysfunction in Cardio-Metabolic Disorders. PMID- 26118597 TI - Effects of different exercise durations on Keap1-Nrf2-ARE pathway activation in mouse skeletal muscle. AB - The purpose of this study was to investigate the effects of acute exercise stress on the nuclear factor-erythroid2 p45-related factor 2 (Nrf2)/antioxidant response element (ARE) transactivation, Kelch-like ECH-associated protein 1 (Keap1) cytosolic protein and Nrf2 nucleoprotein expressions, Nrf2 target genes mRNA expressions, and glutathione redox (GSH/GSSG) ratio level; with a particular focus on the changes in Keap1-Nrf2-ARE pathway activation following different durations of exercise. Wild-type mice (C57BL/6J, two months old) were separated into one-hour and six-hour treadmill running groups, as well as a non-exercise control group (n = 10 in each group). Measurements of Nrf2/ARE transactivation, Nrf2 nucleoprotein expressions, Keap1 cytosolic protein expression, Nrf2 target genes' mRNA expressions (superoxide dismutase-1 [SOD1], superoxide dismutase-2 [SOD2], gamma-glutamyl cysteine ligase-modulatory [GCLm], gamma-glutamyl cysteine ligase-catalytic [GCLc], glutathione reductase [GR], glutathione peroxidase-1 [Gpx1], catalase [CAT], and hemoxygenase-1 [Ho-1]), and GSH/GSSG ratio were carried out immediately after exercise. The results showed significant increases in Keap1-Nrf2-ARE pathway activation and the mRNA expressions of six measured enzymes in skeletal muscle after six hours of exercise; while in the one-hour exercise group, there was no change in Keap1-Nrf2-ARE pathway activation and only two enzymes' mRNA expressions were increased. It is suggested that the changes in Keap1-Nrf2-ARE pathway activation and its target genes' mRNA expressions were dependent on the exercise duration, with longer duration associated with higher responses. PMID- 26118598 TI - Routine versus selective contrast imaging to identify the need for early re intervention following laparoscopic fundoplication: A retrospective cohort study. AB - BACKGROUND: The prompt recognition of complications is essential in reducing morbidity following anti-reflux surgery. Consequently, many centres employ a policy of routine post-operative contrast studies. The study aimed to examine whether routine contrast studies more effectively recognised early post-operative complications following anti-reflux surgery compared with selective use. METHODS: This was a retrospective analysis of 240 adults who had undergone primary anti reflux surgery. Selective use of water-soluble contrast swallows was employed for 115 patients (Group 1) while 125 patients (Group 2) had routine studies. RESULTS: 10 (0.9%) patients from Group 1 underwent contrast studies, four (40%) of which were abnormal. Routine studies in Group 2 identified thirty-two abnormalities (27%) however the inter-group difference was not significant (p = 0.32). Only one case from group 2 required immediate re-intervention. This was not statistically significant (p = 0.78). Multivariate analysis found no significant association between selective or routine imaging and re-intervention rates. One patient from group 2 presented three days following discharge with wrap migration requiring reoperation despite a normal post-operative study. CONCLUSION: Routine use of contrast imaging following anti-reflux and hiatus hernia surgery is not necessary. It does not identify a significantly greater number of post-operative complications in comparison to selective use. Additionally, routine use of contrast studies does not ensure the diagnosis of all complications in the post operative period. PMID- 26118599 TI - Retrospective analysis of short term outcomes after spleen-preserving distal pancreatectomy for sodid pseudopapillary tumours. AB - Solid pseudopapillary pancreatic tumour (SPN) is a rare pancreatic tumour representing 0.1%-3% of all exocrine pancreatic tumours. Most SPN show benign and low-grade malignant behaviour; malignant degeneration is observed in 10-15% of the patients. More than 40% of SPN involve the tail of the pancreas leading to a minimal invasive distal pancreatectomy approach. In this report we present the case of a young 22 Caucasian woman suffering from SPN who successfully underwent laparoscopic spleen-preserving distal pancreatectomy. Postoperative course was uneventful. A CT scan control at six months was negative for recurrences. We have also made an analysis of all the laparoscopic treatment of SPN reported in English literature. PMID- 26118600 TI - Percutaneous CT-guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in locally advanced pancreatic cancer: Our preliminary experience. AB - INTRODUCTION: Irreversible electroporation (IRE) is a non-thermal ablation technique recently used in pancreatic cancer. In our prospective study we evaluated safety, feasibility and efficacy of a neoadjuvant protocol based on CT guided percutaneous IRE followed by chemotherapy in patients with locally advanced pancreatic cancer (LAPC). METHODS: We performed CT-guided percutaneous IRE in 20 patients with LAPC, followed by a combination of gemcitabine (1000 mg/mq) and oxaliplatin (100 mg/mq) biweekly. Imaging follow-up was performed by a contrast enhanced CT scan at 1, 3, 6 months and then every 3 months. RESULTS: No major complications occurred. Two patients died 3 and 4 months after IRE because of rapidly progressive disease. In the remaining 18 patients 6-month imaging follow-up showed a mean lesions volumetric decrease percentage of 42.89% (95% Confidence Interval: 34.90-54.88%). Thanks to lesions downstaging, three patients underwent R0 resection. At last available follow-up (mean follow-up 91 months; range 6-14), imaging showed no disease progression or post-surgical relapse in all 18 cases. The mean estimated survival was 12,950 months (95% CI: 11,570 14,332). CONCLUSIONS: Our preliminary study suggests that IRE followed by chemotherapy is safe, feasible and effective in producing local control of LAPC, with a possible downstaging effect to resectable lesions. PMID- 26118601 TI - Usefulness of intraoperative ultrasonography in liver resections due to colon cancer metastasis. AB - INTRODUCTION: Intraoperative ultrasonography (IOUS) of the liver has been used both as an aid for intraoperative anatomical definition and for the detection of new lesions. The present study aimed to evaluate the impact of IOUS and to identify factors that can predict the detection of new lesions intraoperatively. METHODS: In this observational and prospective study, with a cross-sectional design, patients with colorectal cancer metastases who underwent hepatectomy were selected. Abdominal computed tomography, magnetic resonance imaging, and positron emission tomography were the preoperative evaluation tests. All patients underwent IOUS performed by the same surgeon. The intraoperative findings were compared with the preoperative tests results. RESULTS: In total, 56 hepatectomies were evaluated. Half of the patients were men, with a mean age of 57 (30-85) years. New lesions were found intraoperatively in 12 patients (21.4% of cases) and were detected on both palpation and ultrasonography in 11 of these patients. Ultrasonography helped to revise the surgical plans by providing additional information in 35.7% of cases. On multivariate analysis, the presence of more than 4 preoperative nodules was predictive of the intraoperative occurrence of new lesions. CONCLUSIONS: IOUS remains the only way to evaluate the relationships between tumors, liver vascular structures, and bile ducts intraoperatively. Alone, IOUS was not useful for identifying new lesions intraoperatively, as all new lesions were also detected on palpation. The number of lesions diagnosed on preoperative tests influenced the probability of identifying new lesions intraoperatively. There may be additional influential factors. PMID- 26118602 TI - Pancreatic fistula following pancreatoduodenectomy. Evaluation of different surgical approaches in the management of pancreatic stump. Literature review. AB - Pancreatoduodenectomy is the gold standard operation for malignant and benign diseases of the pancreas and periampullary region. Even if improvements in intensive care management and surgical technique have dramatically reduced postoperative mortality after pancreatic surgery, morbidity remains high (30 50%), also in specialized pancreatic units. In order to reduce postoperative complications, particularly pancreatic fistula, different surgical techniques and their modifications have been proposed. In order to determine the better management of the pancreatic stump after pancreatoduodenectomy, the Authors analysed and compared derivative - pancreaticojejunal, pancreaticogastrostomy - vs no-derivative technique - pancreatic stump closure (duct ligation or mechanical suture, duct occlusion by fibrin glue or cyanoacrylate). A systematic research of the English literature, including major meta-analysis articles, clinical randomized trials, retrospective studies and systematic reviews was performed, analysing the risk factors and the incidence of short-medium term postoperative complications. Up to now, even if derivative procedures are preferred as gold standard the best method to deal a pancreatic stump is still controversial and remains matter of research. Pancreatic surgeons must have more than one technique for managing the pancreatic remnant. PMID- 26118603 TI - Distal pancreatectomy with splenic preservation: A short-term outcome analysis of the Warshaw technique. AB - INTRODUCTION: Spleen-preserving left pancreatectomy (SPDP) with splenic vessels preservation (SVP) or without (Warshaw technique, WT) has been described with robotic, laparoscopy and open surgery. Nevertheless, significant data on medium- and long-term follow-up are still not available, since data in literature are scarce and the level of evidence is low. METHODS: In this retrospective study, we describe and compare short and medium term results of spleen-preserving distal pancreatectomy in eight patients. RESULTS: In WT group the duration and the intraoperative bleeding was superior than SVP group. The incidence of perigastric collateral vessels and presence of submucosal varices evidenced at CT scan was 66% in WT group, while only one case occurred in SVP group. DISCUSSION: The limit of laparoscopic approach is the fact that it needs advanced laparoscopic skills, which might result in intraoperative bleeding and splenectomy. The most of literature considered salvage WT intraoperatively performed in case of classical SVP and not only elective WT. The consequence is that there is no difference in immediate postoperative results (operative time, intraoperative bleeding, hospital stay) that are in favour of SVP because WT is performed only in case of failure in preserving the splenic vessels. In fact when this intervention is performed electively, the procedure time is reduced as well as the intraoperative bleeding. CONCLUSIONS: WT is safe and feasible, even if there are not definitive evidences that demonstrate it is superior to classic SVP. RCTs are needed to determine advantages and disadvantages of WT compared to the classic SVP. PMID- 26118604 TI - A novel approach to prevent post-operative ileus after continuous-flow left ventricular assist device implantation: A retrospective cohort study. AB - INTRODUCTION: Patients with postoperative ileus (POI), a common post-surgical event, experience intense discomfort. Various treatments targeting prevention of POI have shown to have an unpredictable effect. We introduced a novel postoperative bowel management protocol in patients implanted with a continuous flow left ventricular assist device (CF-LVAD). The effect of this protocol on POI was evaluated. METHODS: Patients receiving an old bowel management protocol (OBMP; 01/2007-03/2009) were compared with those receiving a new bowel management protocol (NBMP; 04/2009-12/2013). The OBMP consisted of advancing the diet as tolerated, bisacodyl suppositories and enemas with the goal of a bowel movement (BM) every 3 days. The NBMP consisted of clear liquids until first BM is achieved, then full liquids until the second BM, then advancing to goal diet. Docusate is given on postoperative day (POD) 1 and bisacodyl PR on POD2 with enemas if ileus develops. Enemas are added POD3 if no BM has occurred. Polyethylene glycol is considered daily for patients prone to constipation. The goal is a BM every 2 days. Patients were made nil per os (NPO) with any signs of ileus. RESULTS: One hundred eighteen patients were implanted with CF-LVADs during the study period. The incidence of ileus significantly decreased from 19% in the OBMP group to 4% percent in the NBMP group (p < 0.05). In-hospital mortality was not different between the two groups (6% vs. 2% p = 0.35). CONCLUSIONS: A novel postoperative bowel management protocol successfully decreased the incidence of POI following CF-LVAD implant surgery at our institution. PMID- 26118605 TI - Conservative management and parenchyma-sparing resections of pancreatic neuroendocrine tumors: Literature review. AB - BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are uncommon entities. pNETs are often small, slow growing, clinically silent neoplasms. However, they have an almost unpredictable biological behaviour with a not negligible malignant potential. Surgery still represents the treatment of choice, but the high morbidity associated to the enucleation or the formal pancreatectomy should be considered in the decision of the proper treatment. Management of these neoplasms is still debated, and indications for a conservative observational approach and for parenchyma sparing resections are not yet standardized. METHOD: We review the state of art on the indications for the conservative management of pNETs. Searches on MEDLINE database were performed to identify articles reporting prognostic systems, biochemical screening, observational management, medical treatment and surgical strategies for pNETs. DISCUSSION: Currently, an accurate 'wait-and-see' policy is recommended by the European Neuroendocrine Tumor Society (ENETS) only for non-functioning pNETs (NF-pNETs) <2 cm. A biochemical screening, based on sampling of serum levels of pancreatic polypeptide (PP) and chromogranin A, can address to early conservative surgery for MEN-1 associated NF-pNETs <2 cm to prevent their malignant transformation. The subtotal (80%) distal pancreatectomy first proposed by Thompson, often with the enucleation of possible pancreatic head tumors, still represents a good compromise between oncological radicality and prevention of pancreatic endocrine/exocrine insufficiency caused by standard radical resections for the treatment of inherited syndromes associated with NF-pNETs >2 cm and symptomatic F-pNETs of any size. CONCLUSION: More studies are needed to further clarify and predict the biologic behaviour of pNETs and increase the indications for conservative observational management and parenchyma sparing pancreas resections. PMID- 26118606 TI - Macrocystic serous cystadenoma of the pancreas: Report of 4 cases. AB - BACKGROUND: Macrocystic serous cystadenomas (MaSCA) are rare benign tumor of the pancreas which represent an atypical macroscopic morphologic variant of serous cystadenomas (SCA). They are characterized by a limited number of cysts with a diameter of >2 cm and share imaging features overlapping those of mucinous cystic neoplasm (MCN) and branch-duct intraductal papillary mucinous neoplasm (BD-IPMN), thus frequently making the pre-operative radiologic diagnosis difficult. MATERIALS AND METHODS: Four cases of MaSCA, which were surgically treated in our structure, are reported. RESULTS: Two women (62 and 39 year-old) presented with upper abdominal pain and palpable mass underwent CT with evidence of a lobulated cystic neoformation (98 * 70 and 94 * 75 mm respectively) originating from the body and the tail of the pancreas respectively. They underwent distal pancreatectomy for suspected MCN. A 38 year-old woman underwent laparoscopic distal pancreatectomy because of the incidental finding of an unilocular cystic lesion in the pancreatic tail (23 mm) of indeterminate origin (MCN, SCA or metastasis). In a 40 year-old woman, admitted for acalculous acute pancreatitis, an unilocular cystic lesion in the body of the pancreas (62 mm) was detected and confirmed after 2 months at CT, therefore she underwent distal pancreatectomy for suspected pseudocyst or SCA. In all of the 4 patients the histological examination of the specimens revealed a MaSCA. CONCLUSION: Imaging techniques have a low diagnostic power in terms of differentiation of MaSCA from malignant lesions (as MCNs and BD-IPMN). In the clinical practise of MaSCA, surgery appears to gain indications that are wider than those correlated to the pathologic outcome, because of the necessity of a correct differential diagnosis from potentially malignant cystic tumors and the frequent symptoms requiring treatment. PMID- 26118607 TI - "Ductal adenocarcinoma in anular pancreas". AB - INTRODUCTION: The annular pancreas is a congenital anomaly in which pancreatic tissue partially or completely surrounds the second portion of the duodenum. Its often located above of papilla of Vater (85%), rarely below (15%). This pancreatic tissue is often easily dissociable to the duodenum but there is same cases where it the tissue is into the muscolaris wall of the duodenum. MATERIAL AND METHODS: We describe three case of annular pancreas hospitalized in our facility between January 2004 and January 2009. There were 2 male 65 and 69 years old respectively and 1 female of 60 years old, presented complaining of repeated episodes of mild epigastric pain. Laboratory tests (including tumor markers), a direct abdomen X-ray with enema, EGDS and total body CT scan were performed to study to better define the diagnosis. EUS showed the presence of tissue infiltrating the muscle layer all around the first part of duodenum. Biopsies performed found the presence of pancreatic tissue with focal areas of adenocarcinoma. Subtotal gastrectomy with Roux was performed. The histological examinations shows an annular pancreas of D1 with multiple focal area of adenocarcinoma. (T1aN0M0). RESULTS: We performed a follow up at 5 years. One patients died after 36 months for cardiovascular hit. Two patients, one male and one female, was 5-years disease-free. DISCUSSION: Annular pancreas is an uncommon congenital anomaly which usually presents itself in infants and newborn. Rarely it can present in late adult life with wide range of clinical severities thereby making its diagnosis difficult. Pre-operative diagnosis is often difficult. CT scan can illustrate the pancreatic tissue encircling the duodenum. ERCP and MRCP are useful in outlining the annular pancreatic duct. Surgery still remains necessary to confirm diagnosis and bypassing the obstructed segment. PMID- 26118608 TI - Surgical management of hydatid liver disease. AB - BACKGROUND: large retrospective clinical study describing the long-term experience of a single center in the surgical management of liver echinococcosis in an endemic area. METHODS: 232 patients were operated for liver hydatid disease between 1978 and 2012. Seventy-three patients (Group A) underwent a radical procedure (total pericystectomy or hepatectomy), while 145 (Group B) were treated with a more conservative method (partial cystectomy, with external drainage, omentoplasty or capitonnage) and 14 (Group C) received a combination of total and partial cystectomies. Morbidity, mortality, post-operative complications and recurrence rates in the long-term setting were retrospectively evaluated. RESULTS: Group A patients were treated with zero mortality and a morbidity rate of 10.95%. No recurrence was documented. In Group B, mortality reached 2.76%, (p = 0.153 compared to Group A) morbidity 24.13% (p = 0.021) and there were 10 cases of relapse (6.9%) at three-year complete follow-up (p = 0.989). Extrahepatic sites of disease were not uncommon. DISCUSSION: radical surgical procedures were better tolerated by patients and yielded better results in terms of recurrence rates. PMID- 26118609 TI - The use of intraoperative ultrasound for diagnosis and stadiation in pancreatic head neoformations. AB - The intraoperative staging of the pancreatic cancer is important to make a proper treatment. For this reason the intraoperative echography is playing an important role in the right treatment choice. The intraoperative echography, that can be performed with an open or laparoscopic probe, is used to confirm the preoperative diagnosis and assess the pancreatic cancer resecability. The intraoperative echography (IOUS) or laparoscopic intraoperative echography (LIOUS) are useful to identify the patients with a non resecable cancer and perform a faster neoadjuvant treatment. The LIOUS can also avoid an useless laparotomy. The aim of this study is to assess, both in our experience and in the cited literature, the concordance rate between the pancreatic cancer preoperative staging, performed with TC and MRI (when it is available), and intraoperative staging, performed with intraoperative laparotomic or laparoscopic echography. MATERIAL AND METHODS: We have analyzed the treatment management of 34 patients, who were candidate to major surgery for suspected pancreatic head cancer and who underwent to intraoperative LIOUS or IOUS staging from 2001 to 2012. RESULTS: LIOUS and IOUS have allowed to detect cases in which preoperative diagnosis, proved by CT and MRI, was not agreeing with intraoperative diagnosis (22 patients on 34, 64% discordance rate), avoiding the execution of a demolitive and uneseful surgery in order to guarantee the surveillance and life's quality of patients. CONCLUSION: We suggest to perform in every patients undergone to pancreatic surgery an intraoperative ultrasound exam, to detect unresecable and unpredicted lesions. PMID- 26118610 TI - Intrarectal migration of mesh following Rectopexy: Case series and review of literature. AB - INTRODUCTION: Mesh rectopexy for complete rectal prolapse is associated with complications such as fecal impaction, constipation and rarely recurrence. Mesh erosion following rectopexy is rare. We report three such cases managed successfully in our unit. PRESENTATION OF CASES: All three patients presented with constipation. In addition, one patient had sense of incomplete evacuation and another had protrusion of mesh through anal canal with recurrence of rectal prolapse. There was a delayed presentation in one patient at 15 years after initial surgery, while other two presented at 2 years and 5 years following rectopexy. Diagnosis was made by either per rectal examination or sigmoidoscopy. Two patients underwent trans abdominal removal of mesh along with anterior resection of rectum. In one patient, mesh was removed by transanal approach and sutured rectopexy was added to tackle the recurrent prolapse. All patients are symptom free on follow up with no recurrence of prolapse. DISCUSSION: Mesh erosion following rectopexy has multifactorial aetiology with diverse presentation. It is important to recognise this significantly morbid complication as it amenable to surgical correction. Management depends up on the location of erosion, the severity of mesh protrusion into rectal lumen and the degree of fibrosis around the area of mesh. CONCLUSION: The management of mesh erosion following rectopexy should be individualized. Although it is complex, acceptable functional outcome and quality of life can be achieved with proper treatment. PMID- 26118611 TI - Cystic pancreatic neuroendocrine tumors: To date a diagnostic challenge. AB - OBJECTIVE: Cystic PNETs are an uncommon neoplasms increasingly detected in current clinical practice which often present a diagnostic challenges to both the experienced radiologist and pathologist. The aim of this study was to review the available literature to summarize current data that compare and evaluate both the clinical and pathologic features of cystic pancreatic neuroendocrine tumors. MATERIALS AND METHODS: A systematic review of the current literature was performed using the search engines EMBASE and PubMed to identify all studies reporting on cystic pancreatic neuroendocrine tumors. The MeSH search terms used were "cystic pancreatic neuroendocrine tumors", "endocrine neoplasms", and "pancreatic cysts". Multiple combinations of the keywords and MeSH terms were used. RESULTS: The clinical evaluation of cystic pancreatic lesions appears to suffer from same limitations despite the improvement in the diagnostic tools. Subsequently, we highlight diagnostic pitfalls and differential diagnosis of these cystic tumors. In this review we discuss current advances in the application of the imaging modalities and characteristics features with special emphasize on endoscopic ultrasound (EUS), and EUS guide fine needle aspiration (EUS-FNA). CONCLUSIONS: Cystic neuroendocrine tumor in the pancreas underlines the clinical impact of endoscopic ultrasound in the work-up of patients with unclear lesions in the pancreas. EUS-FNA cytology and cyst fluid analysis is a useful adjunct to abdominal imaging for the diagnosis of pancreatic cystic lesions. Due to the evident diagnostic difficulties, we hypothesize that cyst fluid characteristics, including cytomorphological features, is the most accurate test to achieve a preoperative diagnosis and to provide a basis for prognostic prediction. PMID- 26118612 TI - FDG-PET nodal staging does not correlate with histopathological nodal stage for oesophageal cancers. AB - OBJECTIVE: To investigate whether pre-operative N-stage (nodal stage) based on FDG-PET for oesophageal cancers, correlates with final histopathology. Additionally, we assessed if N-stage differs for squamous cell cancers compared with adenocarcinomas and if neoadjuvant therapy alters these results. BACKGROUND: Our current understanding of oesophageal cancer biology means that personalisation of multimodality therapy is based on accurate clinical staging, allied with patient co morbidities and patient preference. METHODS: We conducted a retrospective review of consecutive oesophagectomy cases performed over a ten year period (between 2002 and 2013) from a single tertiary centre. A total of 161 patients were identified in the study period. RESULTS: Overall, 103 specimens with 1402 lymph nodes were included. For both Adenocarcinomas (AC) and Squamous Cell Carcinomas (SCC), there was no significant difference between the N-stage determined by CT vs. FDG-PET (p > 0.05). For AC, there was statistically significant under-reporting of the N-stage by PET compared with the final histopathology (p < 0.01). Subgroup analysis showed that neoadjuvant therapy vs. adjuvant therapy alone did not alter the bias for under-reporting of the N-stage for adenocarcinoma by PET-CT (Bland-Altman bias 0.76 vs. bias 0.75). CONCLUSION: There is little doubt that PET-CT provides useful information in determining metastatic disease however its use in evaluating nodal burden is limited. Theoretically, this should not preclude patients from receiving definitive surgical management but the decision regarding neoadjuvant treatment based on locoregional disease may be affected. PMID- 26118613 TI - Biological mechanism of shockwave in bone. AB - Shockwave is a rapid, short duration acoustic wave that carries energy and can propagate through tissue medium. This kind of physical force can be a mechanical stimulus that induces biological effects in living tissue. Extracorporeal shockwave therapy (ESWT) acts as a mechanical stimulus which promotes biological healing processes through a mechanotransduction. The biological effects of ESWT are reported such as tissue regeneration, wound healing, angiogenesis, bone remodeling, and anti-inflammation. Until now, however, little is known about the basic mechanism of action of this type of therapy. This article describes the molecular mechanism on the current status of ESWT with pre-clinical and clinical applications for treating disorders in bone. PMID- 26118614 TI - Laparoscopic perspectives for distal biliary obstruction. AB - BACKGROUND: In patients affected by distal biliary obstruction deemed unsuitable for pancreatoduodenectomy, biliary diversion is the only proposable option. Defined goals of this treatment are: relief from jaundice preventing its related complications, reduction of in-hospital stay and adequate control of pain. Palliation can be obtained either by surgical or conservative procedures (endoscopic stenting or percutaneous treatment). Considering early complications' incidence, surgical approach has always been reserved for low surgical risk patients with longer survival perspectives, while recently developed long-lasting patency stents enlarged mini-invasive application resort. Comparative studies on these therapeutic options favour the conservative one in respect of conventional open surgery, but data on minimally invasive surgery to pursue palliative aims are lacking. We present our six-years casuistic and results referring to laparoscopic biliary diversions. METHODS: We analyzed results obtained in distal biliary neoplastic obstruction management between December 2008 and November 2014. During this period, selected patients considered unsuitable for pancreatoduodenectomy were scheduled to receive a laparoscopic biliary decompression. Perioperative variables and 30-days postoperative outcomes have been prospectively collected. RESULTS: In the six-years period, 12 patients affected by distal biliary neoplastic obstruction were submitted to laparoscopic palliative bypass. Four procedures were proposed for distal biliary cancer, one for advanced periampullary cancer and seven for pancreatic head cancer. Ten hepatico-jejunal bypasses and two choledochoduodenostomies have been performed. No conversions to open surgery were encountered in this series. Main operative time was 85 min, main blood loss was 75 ml and main hospitalization was 4.5 days. According to Clavien Dindo Classification one class II and one class IIIb complications occurred. CONCLUSIONS: Although the restricted number of patients, our results suggest that laparoscopic biliary bypass could be a valid option in managing distal biliary obstructions, resulting in low perioperative morbidity, effective long term palliation of symptoms and improved quality of life. PMID- 26118615 TI - Robotic pylorus-preserving pancreaticoduodenectomy: Technical considerations. AB - Laparoscopy has revolutionized the way of thinking abdominal surgery, however, to date there are still limitations making it difficult to apply this technique to some types of surgical procedures considered technically demanding even when performed by open surgery, such as the pancreaticoduodenectomy. This technical note provides a complete description of the surgical procedure performed for the execution of a robotic pancreaticoduodenectomy through the use of the "Da Vinci Si" robotic system. Robotic systems represent a real evolution in minimally invasive surgery. We wish to emphasize this concept, highlighting the application of this technology to complex procedures in digestive surgery. PMID- 26118616 TI - Can early serum lipase measurement be routinely implemented to rule out clinically significant pancreatic fistula after pancreaticoduodenectomy? AB - INTRODUCTION: Postoperative pancreatic fistula (POPF) is the most significant cause of morbidity and mortality after pancreaticoduodenectomy (PD). We evaluated the role of postoperative serum lipase concentration in ruling out POPF in the immediate post-operative period. MATERIALS AND METHODS: We retrospectively analysed 98 consecutive PD performed between January 2009 and December 2014, investigating the correlation between postoperative day 1 (POD1) serum lipase concentration and POPF development. RESULTS: 29 patients (29.5%) developed POPF [grade A, 17 (17.3%); grade B, 8 (8.1%); grade C, 4 (4%)]. A receiver operating characteristic (ROC) analysis was conducted to determine the threshold value of POD1 serum lipase associated with clinically significant POPF (AUC = 0.76, 95% CI 0.64-0.86, P = 0.01). Such threshold was <= 44.5 U/L and its sensitivity and specificity were 92% and 66%, respectively. The positive and negative predictive values (PPV, NPV) were 31% and 98%, respectively. CONCLUSION: Early routinely measurement of serum lipase proved to be helpful in ruling out clinically relevant POPF (CR-POPF). In our cohort, a POD1 cut-off of <= 44.5 U/L allowed early and accurate identification of patients with low probability to develop clinically significant POPF, who can eventually be selected for enhanced post operative recovery with significant clinical and economic benefits. PMID- 26118617 TI - A brief history of clinical xenotransplantation. AB - Between the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century, with grafts from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff advocated the transplantation of slices of chimpanzee testis into elderly men, believing that the hormones produced by the testis would rejuvenate his patients. In 1963-4, when human organs were not available and dialysis was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost 9 months before suddenly dying from what was believed to be an electrolyte disturbance. The first heart transplant in a human ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient died within 2 h. Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992 he obtained patient survival for 70 days following a baboon liver transplant. The first clinical pig islet transplant was carried out by Groth in 1993. Today, genetically-modified pigs offer hope of a limitless supply of organs and cells for those in need of a transplant. PMID- 26118618 TI - Long-term survival after curative resection for pancreatic ductal adenocarcinoma- Surgical treatment. AB - INTRODUCTION: Recent reports have demonstrated improvement in the 5-years serviva with resecate ductal adenocarcinoma. The aim of study is to determinate the factor influencing long-term survival after DCP. MATERIALS AND METHODS: We have critically reviewed a group of 85 patients how were admitted to our department with diagnosis of ductal adenocarcinoma of the head of pancreas between January 1974 and January 1998. RESULTS: Patients were stratified according to stage using TNM classification; in stage I 31 patients with 5 T1aN0M0 disease, 11 patients with T1bN0M0 and 15 patients T2N0M0 disease. By contrast, in stage III 54 patients with 48 patients T2N1M0 and 6 patients with T3N1M0. Tumour size was recorded for 72 patients with a median of 3.8 cm. The R1 dissection was performed in 67 patients. The R2 resection was performed in 18 patients. In our series we verified and analysed the histopathologic features of 5 patients with 15-years survival (5.8%). The features regard age, male or female, tumours size, stage and positive lymph node resection. DISCUSSION: We found a specifically subset of patients where the combination of prognostic factors, in particular, negative surgical margins R0, tumour size <= 30 mm and the absence of lymph node metastasis independently reduced the mortality indicating that earlier tumour detection and histologically curative resection are important factors contributing to long term survival and healing of ductal adenocarcinoma of the head of the pancreas. PMID- 26118619 TI - Multimodality Imaging of the Reconstructed Breast. AB - The purpose of this article is to illustrate the imaging characteristics and pathologic findings associated with various types of breast reconstruction in women who have undergone mastectomy to treat breast cancer. As the use of breast reconstruction becomes more prevalent, it is imperative that radiologists interpreting imaging studies identify normal and abnormal imaging findings associated with differing breast reconstruction techniques, recognize imaging manifestation of expected complications, and reliably distinguish these from malignancy. PMID- 26118620 TI - Determination of the active transport of fucoidan derived from Okinawa Mozuku across the human intestinal Caco-2 cells as assessed by size-exclusion chromatography. AB - INTRODUCTION: In order to clarify the mechanism of fucoidan transport, we developed the chromatographic determination method. METHOD: A size-exclusion chromatography (SEC) method for the determination of Okinawa-fucoidan using Develosil 300 Diol-5 (60*8.0mm I.D., 30nm pore-diameter) with the eluent containing 1% non-ionic detergent is developed. Determination range (UV at 210nm) is from 0 to 100ng of fucoidan with the linear calibration line inserting to zero. RESULTS: A transport activity of fucoidan is demonstrated by using Caco-2 cells (model of gut transport system); i.e., the initial transport velocity 12nmol/h/mg of protein (25-fold slower rate as compared to a bacterial l-alanine active-transport activity 300nmol/h/mg of protein) is found to occur. Since this fucoidan transport is inhibited by 10mM sodium azide (respiration inhibitor) and 0.05mM FCCP (uncoupler), this transport by Caco-2 cells is found to be an active one requiring energy-source. On the other hand, colchicine (inhibitor of phagocytosis/pinocytosis) and mannitol (putative competitive-inhibitor of tight junction transport) cannot inhibit the fucoidan transport at all. CONCLUSION: We firstly report that the active transport occurs for such a high molecular-weight sulphated-polyfucose of fucoidan in vitro using Caco-2 cells. PMID- 26118621 TI - A UPLC-MS/MS method for simultaneous determination of danshensu, protocatechuic aldehyde, rosmarinic acid, and ligustrazine in rat plasma, and its application to pharmacokinetic studies of Shenxiong glucose injection in rats. AB - A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of the four major active ingredients, danshensu, protocatechuic aldehyde, rosmarinic acid, and ligustrazine, in the traditional Chinese medicine Shenxiong glucose injection in rat plasma. Acidified and alkalized plasma samples were extracted using ethyl acetate, and separated on a Waters C18 column (2.1mm*50mm, 1.7MUm) by using a gradient mobile phase system of acetonitrile-water containing 0.1% formic acid and luteoloside as an internal standard. Electrospray ionization in the positive-ion mode and multiple reaction monitoring were used to identify and quantitate the active components. All calibration curves showed good linearity (r>0.994) over the concentration range, with a lower limit of quantification (LLOQ) between 0.02 and 0.21MUg/mL. The precision of the in vivo study was evaluated by intra- and inter-day assays, and the percentage of relative standard deviation was within 15%. Moreover, satisfactory extraction efficiency was obtained (between 83.94 and 117.81%) by liquid-liquid extraction. The validated method was successfully applied in a pharmacokinetic study in rats after intravenous administration of Shenxiong glucose injection. The results showed that the four bioactive ingredients in Shenxiong glucose injection have linear pharmacokinetic properties in rats after intravenous injection within the administered dose range and partially different ones compared to single ingredient. PMID- 26118622 TI - Generation of induced pluripotent stem cells from domestic goats. AB - The creation of genetically modified goats provides a powerful approach for improving animal health, enhancing production traits, animal pharming, and for ensuring food safety all of which are high-priority goals for animal agriculture. The availability of goat embryonic stem cells (ESCs) that are characteristically immortal in culture would be of enormous benefit for developing genetically modified animals. As an alternative to long-sought goat ESCs, we generated induced pluripotent stem cells (iPSC) by forced expression of bovine POU5F1, SOX2, MYC, KLF4, LIN-28, and NANOG reprogramming factors in combination with a MIR302/367 cluster, delivered by lentiviral vectors. In order to minimize integrations, the reprogramming factor coding sequences were assembled with porcine teschovirus-1 2A (P2A) self-cleaving peptides that allowed for tri cistronic expression from each vector. The lentiviral-transduced cells were cultured on irradiated mouse feeder cells in a semi-defined, serum-free medium containing fibroblast growth factor (FGF) and/or leukemia inhibitory factor (LIF). The resulting goat iPSC exhibit cell and colony morphology typical of human and mouse ESCs-that is, well-defined borders, a high nuclear-to-cytoplasmic ratio, a short cell-cycle interval, alkaline phosphatase expression, and the ability to generate teratomas in vivo. Additionally, these goat iPSC demonstrated the ability to differentiate into directed lineages in vitro. These results constitute the first steps in establishing integration and footprint-free iPSC from ruminants. Mol. Reprod. Dev. 82: 709-721, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26118623 TI - Sperm storage across multiple scales--a reply to Marques, Garcia, and Ames. PMID- 26118624 TI - Gold Nanorods Indirectly Promote Migration of Metastatic Human Breast Cancer Cells in Three-Dimensional Cultures. AB - Gold nanomaterials are intensively studied for applications in disease detection, diagnosis and therapeutics, and this has motivated considerable research to determine their interaction with biomolecules, cells and cell behaviors. However, few studies look at how nanomaterials alter the extracellular matrix (ECM) and cell-ECM interactions. Nanomaterials in the body would interact with the entire cellular environment, and it is imperative to account for this when studying the impact of nanomaterials on living systems. Furthermore, recent evidence finds that migration rates of cells in 2D can be affected by nanomaterials, and uptake of the nanomaterials is not necessary to exert an effect. In this study, three dimensional nested type I collagen matrices were utilized as a model ECM to study how gold nanorods affect the migration of MDA-MB-231 human breast cancer cells. Spontaneous cell migration through collagen containing gold nanorods was found to increase with increasing concentrations of gold nanorods, independent of intracellular uptake of the nanorods. Gold nanorods in the collagen matrix were found to alter collagen mechanical properties and structure, molecular diffusion, cellular adhesion, cell morphology, mode of migration and protease expression. Correlation between decreased cellular adhesion and rounded cell morphology and locomotion in nanorod-containing collagen suggests the induction of an amoeboid like migratory phenotype. PMID- 26118625 TI - High resolution MRI evaluation of meniscal volume and anthropometric correlations. AB - The purpose of this study was to digitally determine meniscal volumes, and compare them with linear and surface area anthropometric measurements to evaluate these measurements for meniscal allograft sizing. Eighteen subjects (10 male and 8 female; mean age 37.5 years) underwent 3.0 T knee magnetic resonance imaging (MRI) of the dominant leg. The following morphometric measurements were evaluated: medial meniscal volume (MMV), lateral meniscal volume (LMV), tibial plateau width (TPW), width of the femoral condyles (WFC), and tibial plateau surface area (TPSA). MMV and LMV were compared to TPW, WFC, and TPSA. Meniscal volume and TPW were correlated to height and body-mass index (BMI) and stratified by gender. Statistical analysis included coefficient of determination (r(2)) between MRI-based MMV, LMV, TPW, TPSA, WFC, height, BMI, and gender. Significance was set at the P = 0.05 level. The mean MMV was 2275 mm(3) and the mean LMV was 2102 mm(3). TPW correlated well with meniscal volumes (r(2) > 0.62). WFC and TPSA correlated with meniscal volumes in the range of 0.40 < r(2) < 0.61. Height, BMI, and gender correlated poorly with total meniscal volume and TPW with values of r(2) < 0.44. Medial and lateral menisci have statistically similar volumes. TPW had the greatest utility for volumetric meniscal sizing. MRI-based TPW can be considered as a statistically accurate measurement for determining meniscal volumes and meniscal size. PMID- 26118626 TI - Basal sympathetic predominance in periodic limb movements in sleep with obstructive sleep apnea. AB - Because the impact of periodic limb movements in sleep (PLMS) is controversial, no consensus has been reached on the therapeutic strategy for PLMS in obstructive sleep apnea (OSA). To verify the hypothesis that PLMS is related to a negative impact on the cardiovascular system in OSA patients, this study investigated the basal autonomic regulation by heart rate variability (HRV) analysis. Sixty patients with mild-to-moderate OSA who underwent polysomnography (PSG) and completed sleep questionnaires were analysed retrospectively and divided into the PLMS group (n = 30) and the non-PLMS group (n = 30). Epochs without any sleep events or continuous effects were evaluated using HRV analysis. No significant difference was observed in the demographic data, PSG parameters or sleep questionnaires between the PLMS and non-PLMS groups, except for age. Patients in the PLMS group had significantly lower normalized high frequency (n-HF), high frequency (HF), square root of the mean of the sum of the squares of difference between adjacent NN intervals (RMSSD) and standard deviation of all normal to normal intervals index (SDNN-I), but had a higher normalized low frequency (n-LF) and LF/HF ratio. There was no significant difference in the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Short-Form 36 and the Hospital Anxiety and Depression Scale between the two groups. After adjustment for confounding variables, PLMS remained an independent predictor of n-LF (beta = 0.0901, P = 0.0081), LF/HF ratio (beta = 0.5351, P = 0.0361), RMSSD (beta = 20.1620, P = 0.0455) and n-HF (beta = -0.0886, P = 0.0134). In conclusion, PLMS is related independently to basal sympathetic predominance and has a potentially negative impact on the cardiovascular system of OSA patients. PMID- 26118627 TI - Wnt1a maintains characteristics of dermal papilla cells that induce mouse hair regeneration in a 3D preculture system. AB - Hair follicle morphogenesis and regeneration depend on intensive but well orchestrated interactions between epithelial and mesenchymal components. Therefore, an alternative strategy to reproduce the process of epithelial mesenchymal interaction in vitro could use a 3D system containing appropriate cell populations. The 3D air-liquid culture system for reproducibly generating hair follicles from dissociated epithelial and dermal papilla (DP) cells combined with a collagen-chitosan scaffold is described in this study. Wnt-CM was prepared from the supernatant of Wnt1a-expressing bone marrow mesenchymal stem cells (BM MSCs) that maintain the hair-inducing gene expression of DP cells. The collagen chitosan scaffold cells (CCS cells) were constructed using a two-step method by inoculating the Wnt-CM-treated DP cells and epidermal (EP) cells into the CCS. The cells in the air-liquid culture formed dermal condensates and a proliferative cell layer in vitro. The CCS cells were able to induce hair regeneration in nude mice. The results demonstrate that Wnt-CM can maintain the hair induction ability of DP cells in expansion cultures, and this approach can be used for large-scale preparation of CCS cells in vitro to treat hair loss. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118628 TI - Low iodine diet in differentiated thyroid cancer: a review. AB - Radioactive iodine (RAI) ablation is a beneficial, adjuvant therapy for the management of differentiated thyroid cancer (DTC) after thyroidectomy. The goal of RAI is to destroy remnant thyroid and microscopic cancerous tissue. Radioactive iodine uptake is enhanced by elevating TSH levels and initiating a low iodine diet (LID) prior to ablation. An ideal LID should preferably not exceed 50 mcg/day of dietary iodine for 1-2 weeks, although the duration may be shortened to a week with a structured patient education programme. A pre-ablation spot urinary iodine concentration (UIC) of <100 mcg/l and/or a urinary iodine to creatinine ratio (UICR) of <100 mcg/gCr would support an adequate LID preparation. Hyponatraemia, most likely due to iatrogenic hypothyroidism, is a potential side effect associated with LID and occurs during and a few days after the LID. Although the overall incidence of hyponatraemia is low, patients at high risk (older age, female sex, use of thiazide diuretics) may benefit from serum sodium monitoring. The existing evidence on the impact of LID on RAI ablation has been largely inconsistent due to retrospective study designs and the lack of an objective measurement of urinary iodine levels. Future large prospective randomized control trials are needed to elucidate and confirm the crucial role of LID in achieving successful RAI ablation and greater disease-free survival in DTC. PMID- 26118629 TI - Cidea improves the metabolic profile through expansion of adipose tissue. AB - In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative. PMID- 26118630 TI - Gypsophila elegans isoorientin attenuates CCl4-induced hepatic fibrosis in rats via modulation of NF-kappaB and TGF-beta1/Smad signaling pathways. AB - The hepatoprotective effect of Gypsophila elegans isoorientin (GEI) was evaluated using a hepatic fibrosis model induced by CCl4 in rats. The results revealed that GEI significantly prevented CCl4-induced liver injury and fibrosis, as evidenced by the attenuation of histopathological changes, the decrease in serum aminotransferase, and the inhibition of collagen accumulation. GEI strongly inhibited lipid peroxidation and recruited anti-oxidative defense system. Moreover, GEI alleviated pro-inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6 via inhibiting nuclear factor-kappaB (NF-kappaB) activation. In addition, GEI down-regulated the phosphorylation of Smad2/3 and up-regulated the level of hepatic Smad7, thereby inhibiting TGFbeta1/Smad signaling pathway. In conclusion, our findings indicate that GEI can inhibit CCl4-induced hepatic fibrosis, which may be ascribed to its radical scavenging action, antioxidant activity, and modulation of NF-kappaB and TGF-beta1/Smad signaling pathways. PMID- 26118632 TI - Efficacy of HBV-pulsed DCs in combination with entecavir in patients with chronic hepatitis B infection. AB - Dendritic cells (DCs) are multifunctional cells that initiate adaptive immune responses. Patients with chronic hepatitis B virus (HBV) infection have reduced numbers of DCs which may be functionally impaired, a defect that may contribute to viral persistence. Autologous DC-based immunotherapy is considered to be a treatment option for chronic HBV infection (CHB). We evaluated the therapeutic efficacy of HBV-pulsed DCs in combination with the antiviral drug entecavir in patients with CHB. Eighty patients were divided into four groups: HBV-pulsed DCs only, HBV-pulsed DCs plus entecavir, entecavir only, and an untreated control group. Patients on combination therapy exhibited greater antiviral responses than patients on either monotherapy. The combination of HBV-pulsed DCs and entecavir resulted in the largest reduction in serum viral DNA levels and the highest percentage of virologic response. In addition, combination therapy resulted in viral e antigen (HBeAg) loss and seroconversion. These results suggest that the combination of HBV-pulsed autologous DCs and entecavir could be therapeutically advantageous for patients with CHB. PMID- 26118631 TI - Resolvin D1 protects against hepatic ischemia/reperfusion injury in rats. AB - OBJECTIVE: Inflammatory responses play an important role in the tissue damage during hepatic ischemia/reperfusion (I/R). Some resolvins have been shown to have protective properties in reducing I/R injury in the heart and kidney. The aim of the study was to investigate the effects of resolvin D1 (RvD1) on hepatic I/R. METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6h of reperfusion. Rats received either RvD1 (5 MUg/kg) or vehicle by intravenous injection prior to ischemia. On the basis of treatment with RvD1, some rats further received the PI3K inhibitor LY294002. Blood and tissue samples from the groups were collected after 6-h reperfusion. RESULTS: Our results indicate that the RvD1 receptor ALX/FPR2 is present in liver, and that pretreatment with RvD1 prior to I/R insult significantly blunted I/R-induced elevations of alanine aminotransferase (AST) and aspartate aminotransferase (ALT), and significantly improved the histological status of the liver. Moreover, RvD1 significantly inhibited inflammatory cascades, as demonstrated by attenuations of IL-6, TNF-alpha and myeloperoxidase levels. Reduced apoptosis, and increased phosphorylation of Akt, were observed in the RvD1 group compared with the control I/R group. These effects of RvD1 on hepatic I/R injury were diminished by the PI3K inhibitor. CONCLUSIONS: Administration of RvD1 prior to hepatic I/R attenuates hepatic injury, at least in part through inhibition of inflammatory response and enhancement of phosphorylation of Akt. PMID- 26118633 TI - Saikosaponin-D reduces cisplatin-induced nephrotoxicity by repressing ROS mediated activation of MAPK and NF-kappaB signalling pathways. AB - The nephrotoxicity induced by cisplatin (DDP) severely limits the clinical efficacy of this widely used anticancer agent. The observed nephrotoxicity may be the result of DDP-induced inflammation and apoptosis. Saikosaponin-D (SSD), a triterpenoid saponin, has numerous pharmacological properties. The goal of the present study was to investigate whether and how SSD protected against DDP induced nephrotoxicity. Non-cytotoxic levels of SSD significantly increased the viability rate, improved the nuclear morphology, and attenuated the caspase-3 activation and programmed apoptosis of DDP-treated HK-2 cells. In addition, SSD treatment markedly inhibited the release of tumour necrosis factor (TNF)-alpha, interleukin-1beta (IL-1beta), and interleukin-6 (IL-6), as well as the production of nitric oxide and the expression of inducible nitric oxide synthase (iNOS) by these cells. More importantly, SSD effectively blocked the DDP-induced activation of NF-kappaB, P38, JNK, and MAPKs. Furthermore, we found that U0126 (a specific inhibitor of MAPKs) strongly inhibited the IKK/IkappaB/NF-kappaB-dependent release of pro-inflammatory cytokines and iNOS gene expression. Finally, we demonstrated that SSD decreased the level of reactive oxygen species (ROS) accumulation and that the specific ROS scavenger N-acetylcysteine (NAC) markedly inhibited the DDP-induced activation of MAPK and phosphorylation of the downstream signal NF-kappaB, which in turn reduced the levels of pro-inflammatory cytokine release and iNOS gene expression. Our results suggest that the SSD mediated alleviation of DDP-induced nephrotoxicity was due to uncoupling of the ROS, P38, and JNK/NF-kappaB signalling pathways. PMID- 26118635 TI - Fractional anisotropy in the substantia nigra in Parkinson's disease: a complex picture. AB - BACKGROUND AND PURPOSE: This study employs magnetic resonance imaging (MRI) diffusion tensor imaging to compare diffusion measures in the brains of patients with Parkinson's disease (PD) with healthy controls using longitudinal data. METHODS: One-hundred and twenty-two patients and 34 controls were included at baseline. The MRI investigations were repeated after 1, 3 and 5 years. The diffusion measures were quantified using fractional anisotropy and mean, radial and axial diffusion (FA, MD, RD, AD). Regions of interest included the anterior, middle and posterior substantia nigra (SN), but also other areas. Linear models were used to test for the effect of disease and hemispheric lateralization. The P value was set at 0.05 (Bonferroni corrected). RESULTS: Fractional anisotropy and AD were increased in the three nigral subareas in PD (P < 0.01), but MD and RD were unaltered. The right SN had higher FA than the left in all subareas (P < 0.01). MD and AD were increased in the right anterior part (P < 0.04), whereas MD and RD were decreased in the right middle and posterior parts (P < 0.001). The left middle cerebellar peduncle had increased FA and AD (P < 0.001) and decreased MD and RD (P < 0.01) compared to the right. Diffusion measures did not progress over time and side differences were not related to disease or lateralization of symptoms. CONCLUSIONS: Increased FA in the SN in PD indicates gliosis and inflammation in the nuclei, but possibly also intrusion of surrounding fibres into the shrinking structure. The hemispheric side differences of diffusion might reflect natural lateralization of connectivity, but their relation to PD must be studied further. PMID- 26118634 TI - Chronic alcohol consumption inhibits melanoma growth but decreases the survival of mice immunized with tumor cell lysate and boosted with alpha galactosylceramide. AB - Alcohol consumption increases the incidence of multiple types of cancer. However, how chronic alcohol consumption affects tumor progression and host survival remains largely unexplored. Using a mouse B16BL6 melanoma model, we studied the effects of chronic alcohol consumption on s.c. tumor growth, iNKT cell antitumor immune response, and host survival. The results indicate that although chronic alcohol consumption inhibits melanoma growth, this does not translate into increased host survival. Immunizing mice with a melanoma cell lysate does not significantly increase the median survival of water-drinking, melanoma-bearing mice, but significantly increases the median survival of alcohol-consuming, melanoma-bearing mice. Even though survival is extended in the alcohol-consuming mice after immunization, the median survival is not different from the immunized mice in the water-drinking group. Immunization with tumor cell lysate combined with alpha-galatosylceramide activation of iNKT cells significantly increases host survival of both groups of melanoma-bearing mice compared to their respective non-immunized counterparts; however, the median survival of the alcohol-consuming group is significantly lower than that of the water-drinking group. Alcohol consumption increases NKT cells in the thymus and blood and skews NKT cell cytokine profile from Th1 dominant to Th2 dominant in the tumor-bearing mice. In summary, these results indicate that chronic alcohol consumption activates the immune system, which leads to the inhibition of s.c. melanoma growth and enhances the immune response to immunization with melanoma lysate. With tumor progression, alcohol consumption accelerates iNKT cell dysfunction and compromises antitumor immunity, which leads to decreased survival of melanoma bearing mice. PMID- 26118636 TI - International central adjudication committee in the PLATO trial: independent body of experts or friendly family picnic? AB - The International Central Adjudication Committee (ICAC) is responsible for blinded independent assessment of complex clinical events in randomized trials. In this study, we analyze the constituence and impact of the ICAC in the PLATO trial. The PLATO ICAC was entirely governed by two academic institutions, Duke Clinical Research Institute (DCRI) and Uppsala Clinical Research Center (UCRC). Both co-chairman, all coordinators and half of the adjudicators in the PLATO ICAC belonged to either DCRI or UCRC. Among the other adjudicators representing USA, Canada and Australia, majority had DCRI ties, including at least five former Duke cardiology fellows. Furthermore, both co-chairmen are listed as adjudicators, representing obvious conflict. In the PLATO trial, the sponsor representatives were involved in selecting the ICAC members. Finally, 21 out of the 50 adjudicators represented Sweden, the homeland of the PLATO sponsor and primary investigator. Heavy selection bias in the ICAC constituence, lack of independence and potential control of the ICAC by the study sponsor may influence PLATO outcomes, and should be avoided in the future. PMID- 26118638 TI - Outpatient medical abortion is safe and effective through 70 days gestation. AB - Data show that an outpatient regimen of 200-mg mifepristone followed by a single dose of misoprostol is safe and effective for medical abortion for up to 70 days from last menstrual period (LMP). Yet, many clinics only provide services up to 63 days LMP, and some practice guidelines do not recommend the higher gestational age limit. We review the studies published to date that include women 64 to 70 days LMP and conclude that outpatient medical abortion is safe and effective in this interval and that there are no clinically meaningful differences between outcomes at 57 to 63 days LMP and 64 to 70 days LMP. Updating clinical protocols and revising the Food and Drug administration label for Mifeprex(r) to change the indication for termination of pregnancies through 70 days LMP will give women more choices and expand access to safe abortion services. PMID- 26118637 TI - Whole Brain Volume Measured from 1.5T versus 3T MRI in Healthy Subjects and Patients with Multiple Sclerosis. AB - BACKGROUND: Whole brain atrophy is a putative outcome measure in monitoring relapsing-remitting multiple sclerosis (RRMS). With the ongoing MRI transformation from 1.5T to 3T, there is an unmet need to calibrate this change. We evaluated brain parenchymal volumes (BPVs) from 1.5T versus 3T in MS and normal controls (NC). METHODS: We studied MS [n = 26, age (mean, range) 43 (21 55), 22 (85%) RRMS, Expanded Disability Status Scale (EDSS) 1.98 (0-6.5), timed 25 foot walk (T25FW) 5.95 (3.2-33.0 seconds)] and NC [n = 9, age 45 (31-53)]. Subjects underwent 1.5T (Phillips) and 3T (GE) 3-dimensional T1-weighted scans to derive normalized BPV from an automated SIENAX pipeline. Neuropsychological testing was according to consensus panel recommendations. RESULTS: BPV-1.5T was higher than BPV-3T [mean (95% CI) + 45.7 mL (+35.3, +56.1), P < .00001], most likely due to improved tissue-CSF contrast at 3T. BPV-3T showed a larger volume decrease and larger effect size in detecting brain atrophy in MS versus NC [-74.5 mL (-126.5, -22.5), P = .006, d = .92] when compared to BPV-1.5T [-51.3.1 mL ( 99.8, -2.8), P = .04, d = .67]. Correlations between BPV-1.5T and EDSS (r = -.43, P = .027) and BPV-3T and EDSS (r = -.49, P = .011) and between BPV-1.5T and T25FW (r = -.46, P = .018) and BPV-3T and T25FW (r = -.56, P = .003) slightly favored 3T. BPV-cognition correlations were significant (P < .05) for 6 of 11 subscales to a similar degree at 1.5T (r range = .44-.58) and 3T (r range = .43-.53). CONCLUSIONS: Field strength may impact whole brain volume measurements in patients with MS though the differences are not too divergent between 1.5T and 3T. PMID- 26118639 TI - Negligible nuclear introgression despite complete mitochondrial capture between two species of chipmunks. AB - The idea that species boundaries can be semipermeable to gene flow is now widely accepted but the evolutionary importance of introgressive hybridization remains unclear. Here we examine the genomic contribution of gene flow between two hybridizing chipmunk species, Tamias ruficaudus and T. amoenus. Previous studies have shown that ancient hybridization has resulted in complete fixation of introgressed T. ruficaudus mitochondrial DNA (mtDNA) in some populations of T. amoenus, but the extent of nuclear introgression is not known. We used targeted capture to sequence over 10,500 gene regions from multiple individuals of both species. We found that most of the nuclear genome is sorted between these species and that overall genealogical patterns do not show evidence for introgression. Our analysis rules out all but very minor levels of interspecific gene flow, indicating that introgressive hybridization has had little impact on the overall genetic composition of these species outside of the mitochondrial genome. Given that much of the evidence for introgression in animals has come from mtDNA, our results underscore that unraveling the importance introgressive hybridization during animal speciation will require a genome-wide perspective that is still absent for many species. PMID- 26118640 TI - Mouse pups lacking collapsin response mediator protein 4 manifest impaired olfactory function and hyperactivity in the olfactory bulb. AB - Members of the collapsin response mediator protein (CRMP) family are reported to be involved in the pathogenesis of various neuronal disorders, including schizophrenia and autism. One of them, CRMP4, is reported to participate in aspects of neuronal development, such as axonal guidance and dendritic development. However, no physiological or behavioral phenotypes in Crmp4 knockout (Crmp4-KO) mice have been identified, making it difficult to elucidate the in vivo roles of CRMP4. Focusing on the olfaction process because of the previous study showing strong expression of Crmp4 mRNA in the olfactory bulb (OB) during the early postnatal period, it was aimed to test the hypothesis that Crmp4-KO pups would exhibit abnormal olfaction. Based on measurements of their ultrasonic vocalizations, impaired olfactory ability in Crmp4-KO pups was found. In addition, c-Fos expression, a marker of neuron activity, revealed hyperactivity in the OB of Crmp4-KO pups compared with wild-types following exposure to an odorant. Moreover, the mRNA and protein expression levels of glutamate receptor 1 (GluR1) and 2 (GluR2) were exaggerated in Crmp4-KO pups relative to other excitatory and inhibitory receptors and transporters, raising the possibility that enhanced expression of these excitatory receptors contributes to the hyperactivity phenotype and impairs olfactory ability. This study provides evidence for an animal model for elucidating the roles of CRMP4 in the development of higher brain functions as well as for elucidating the developmental regulatory mechanisms controlling the activity of the neural circuitry. PMID- 26118641 TI - Total mineralization of sulfamethoxazole and aromatic pollutants through Fe2+ montmorillonite catalyzed ozonation. AB - The catalytic activity and selectivity of montmorillonite exchanged with Na(+), Fe(2+), Co(2+), Ni(2+) and Cu(2+) cations were comparatively investigated in the ozonation of sulfamethoxazole (SMX). Chlorobenzene, benzoic acid, 4-nitrobenzoic acid, 3-hydroxybenzaldehyde, 4-nitrophenol and phenol were used as probe molecules having structural similarity with SMX oxidation intermediates. UV-vis spectrophometry and chemical oxygen demand (COD) measurements showed that Fe(II) Mt and, to a lesser extent, Co(II)-Mt produce total mineralization of all organic substrates in less than 40 min. Combined HPLC-mass spectrometry revealed a reverse proportionality between the degradation time and molecular size of the organic substrates. Oxalic acid was recognized as a common bottleneck in the ozonation of any organic substrates. Ozonation initially obeyed a first order kinetics, but adsorption took place after 3-5 min, inducing changes in the mechanisms pathways. These findings may be useful for tailoring optimum oxidative treatment of waters without accumulation of hazardous derivatives. PMID- 26118642 TI - Lysosomal mTORC2/PHLPP1/Akt Regulate Chaperone-Mediated Autophagy. AB - Chaperone-mediated autophagy (CMA), a selective form of degradation of cytosolic proteins in lysosomes, contributes to maintenance of proteostasis and to the cellular adaptation to stress. CMA substrates are delivered by a cytosolic chaperone to the lysosomal surface, where, upon unfolding, they are internalized through a membrane translocation complex. The molecular components that participate in CMA substrate targeting and translocation are well characterized, but those involved in CMA regulation remain mostly unknown. In this study, we have identified that CMA is under the positive control of the phosphatase PHLPP1 that associates with the lysosomal membrane and counteracts the inhibitory effect of mTORC2 on CMA. Lysosomal Akt, a target of the mTORC2/PHLPP1 kinase-phosphatase pair, modulates CMA activity by controlling the dynamics of assembly and disassembly of the CMA translocation complex at the lysosomal membrane. The lysosomal mTORC2/PHLPP1/Akt axis could become a target to restore CMA dysfunction in aging and disease. PMID- 26118644 TI - Recruitment of endocytosis in sonopermeabilization-mediated drug delivery: a real time study. AB - Microbubbles (MBs) in combination with ultrasound (US) can enhance cell membrane permeability, and have the potential to facilitate the cellular uptake of hydrophilic molecules. However, the exact mechanism behind US- and MB-mediated intracellular delivery still remains to be fully understood. Among the proposed mechanisms are formation of transient pores and endocytosis stimulation. In our study, we investigated whether endocytosis is involved in US- and MB-mediated delivery of small molecules. Dynamic fluorescence microscopy was used to investigate the effects of endocytosis inhibitors on the pharmacokinetic parameters of US- and MB-mediated uptake of SYTOX Green, a 600 Da hydrophilic model drug. C6 rat glioma cells, together with SonoVue((r)) MBs, were exposed to 1.4 MHz US waves at 0.2 MPa peak-negative pressure. Collection of the signal intensity in each individual nucleus was monitored during and after US exposure by a fibered confocal fluorescence microscope designed for real-time imaging. Exposed to US waves, C6 cells pretreated with chlorpromazine, an inhibitor of clathrin-mediated endocytosis, showed up to a 2.5-fold significant increase of the uptake time constant, and a 1.1-fold increase with genistein, an inhibitor of caveolae-mediated endocytosis. Both inhibitors slowed down the US-mediated uptake of SYTOX Green. With C6 cells and our experimental settings, these quantitative data indicate that endocytosis plays a role in sonopermeabilization-mediated delivery of small molecules with a more predominant contribution of clathrin mediated endocytosis. PMID- 26118645 TI - Morphological and charge transport properties of amorphous and crystalline P3HT and PBTTT: insights from theory. AB - We explore the relation between the morphological and the charge transport properties of poly(3-hexylthiophene) (P3HT) and poly(2,5-bis(3-alkylthiophen-2 yl)thieno[3,2-b]thiophene) (PBTTT) semiconductor polymers in both amorphous and crystalline phases. Using molecular dynamics to simulate bulk supercells and the Marcus theory to analyze the transport properties we found that amorphous systems display a reduced hole mobility due to the loss of nematic order and pi-pi stacking leading to a reduction in the electronic coupling between two chains. In the crystal phase, PBTTT displays a larger charge mobility than P3HT due to the interdigitation of the side chains enhancing the stability of the conjugated rings on the backbones. This more stable pi-pi stacking reduces the energetic disorder with respect to P3HT and increases the electronic coupling. In contrast, in the amorphous phase, PBTTT displays a reduced charge mobility with respect to P3HT due to the absence of side chains attached to the thienothiophenes, which increases their fluctuations and the energetic disorder. In addition, we show that it is possible to calculate the reorganization energy neglecting the side chains of the polymers and thus saving computational time. Within this approximation, we obtained mobility values matching the experimental measurements, thus confirming that the side chains are crucial to shape the morphology of the polymeric systems but are not involved in the charge transport process. PMID- 26118643 TI - Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. AB - Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered 15 phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic. PMID- 26118646 TI - The exception proves the rule. PMID- 26118647 TI - New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration. AB - Neuronal circuits in the adult brain have long been viewed as static and stable. However, research in the past 20 years has shown that specialized regions of the adult brain, which harbor adult neural stem cells, continue to produce new neurons in a wide range of species. Brain plasticity is also observed after injury. Depending on the extent and permissive environment of neurogenic regions, different organisms show great variability in their capacity to replace lost neurons by endogenous neurogenesis. In Zebrafish and Drosophila, the formation of new neurons from progenitor cells in the adult brain was only discovered recently. Here, we compare properties of adult neural stem cells, their niches and regenerative responses from mammals to flies. Current models of brain injury have revealed that specific injury-induced genetic programs and comparison of neuronal fitness are implicated in brain repair. We highlight the potential of these recently implemented models of brain regeneration to identify novel regulators of stem cell activation and regenerative neurogenesis. PMID- 26118648 TI - Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification. AB - The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701, and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition, and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 MUM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future. PMID- 26118649 TI - Signal intensity of the pancreas on magnetic resonance imaging: Prediction of postoperative pancreatic fistula after a distal pancreatectomy using a triple-row stapler. AB - BACKGROUND/OBJECTIVES: The aim of this study was to evaluate the impact of the pancreatic signal intensity (SI) on magnetic resonance imaging (MRI) findings for predicting the development of pancreatic fistula (PF) after a distal pancreatectomy (DP) involving a triple-row stapler closure. METHODS: A multivariate logistic regression analysis was used to identify risk factors for clinical PF, as defined by the International Study Group on Pancreatic Fistula grade B or C. The pancreas-to-muscle SI ratio was evaluated using fat-suppressed T1-weighted MRI. RESULTS: Of the 41 enrolled patients, 8 (19.5%) developed clinical PF. The pancreatic thickness (>=15 mm) and SI ratio (>=1.3) were identified as independent predictors of clinical PF in a multivariate analysis. Clinical PF was observed in one patient with a thick pancreas and a low SI ratio (14.3%), whereas it was observed in 60% of the patients with a thick pancreas and a high SI ratio. The area under the receiver operating characteristic curve for a predictive model consisting of the two factors was 0.87 (95% confidence interval, 0.75 to 0.99), the level of which tended to be greater than that for pancreatic thickness alone (0.81, p = 0.09). CONCLUSIONS: The SI ratio as evaluated using MRI might be useful for predicting clinical PF in patients with the pancreatic thickness >=15 mm after DP involving a stapler closure. PMID- 26118650 TI - Stratification of pancreatic tissue samples for molecular studies: RNA-based cellular annotation procedure. AB - BACKGROUND/OBJECTIVES: Meaningful profiling of pancreatic cancer samples is particularly challenging due to their complex cellular composition. Beyond tumor cells, surgical biopsies contain desmoplastic stroma with infiltrating inflammatory cells, adjacent normal parenchyma, and "non-pancreatic tissues". The risk of misinterpretation rises when the heterogeneous cancer tissues are sub divided into smaller fragments for multiple analytic procedures. Pre-analytic histological evaluation is the best option to characterize pancreatic tissue samples. Our aim was to develop a complement or alternative procedure to determine the cellular composition of pancreatic cancerous biopsies, basing on intra-analytic molecular annotation. A standard process for sample stratification at a molecular level does not yet exist. Particularly in the case of retrospective or data depository-based studies, when hematoxylin-eosin stained sections are not available, it supports the correct interpretation of expression profiles. METHODS: A five-gene transcriptional signature (RNACellStrat) was defined that allows cell type-specific stratification of pancreatic tissues. Testing biopsy material from biobanks with this procedure demonstrated high correspondence of molecular (qRT-PCR and microarray) and histologic (hematoxylin eosin stain) evaluations. RESULTS: Notably, about a quarter of randomly selected samples (tissue fragments) were exposed as inappropriate for subsequent clinico pathological interpretation. CONCLUSIONS: Via immediate intra-analytical procedure, our RNA-based stratification RNACellStrat increases the accuracy and reliability of the conclusions drawn from diagnostic and prognostic molecular information. PMID- 26118651 TI - Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases. AB - Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy. PMID- 26118652 TI - Ex-Vivo Evaluation of a Modified Teno Fix((r)) Device Repair Pattern Versus a 3 Loop Pulley for Repair of Equine Flexor Tendons. AB - OBJECTIVE: To compare the load to ultimate failure, load to a 2 mm gap, mode of failure, and gap at failure (mm) of the Teno Fix((r)) (TF) to the 3-loop pulley (3LP) for repair of equine tendon lacerations. The use of 4TF devices versus 5TF devices on load to ultimate failure and load to a 2 mm gap was also compared. STUDY DESIGN: Ex vivo biomechanical study; unbalanced incomplete block (horse) design. SAMPLES: Cadaveric equine forelimb superficial digital flexor tendon (n = 20 paired tendons). METHODS: Ten tendon pairs were selected randomly and repaired with a 3LP and 4TF pattern, and 10 tendon pairs repaired with a 3LP and 5TF pattern. Load to ultimate failure, load to a 2 mm gap, mode of failure, and gap at failure were obtained using materials testing. RESULTS: The 3LP had a significantly greater ultimate load to failure (P < .001, respectively) and a significantly higher load to a 2 mm gap than both TF repairs (P < .001, respectively). The most frequent mode of failure was suture pull-out for the 3LP and anchor pull-out for the TF. Gap at failure was significantly larger in the 3LP than both TF repairs (P < .001). The ultimate load to failure was significantly higher for the 5TF than the 4TF (P = .004) but there was no significant difference in load to a 2 mm gap, or gap at failure between both TF repairs (P = .11, P = .15, respectively). CONCLUSIONS: Neither TF repair was stronger than the 3LP in load to ultimate failure and load to a 2 mm gap. Addition of a fifth TF device significantly increased the load to ultimate failure but did effect the load to a 2 mm gap over the 4TF. PMID- 26118653 TI - Truly Absorbed Microbial Protein Synthesis, Rumen Bypass Protein, Endogenous Protein, and Total Metabolizable Protein from Starchy and Protein-Rich Raw Materials: Model Comparison and Predictions. AB - This study was carried out to measure truly absorbed microbial protein synthesis, rumen bypass protein, and endogenous protein loss, as well as total metabolizable protein, from starchy and protein-rich raw feed materials with model comparisons. Predictions by the DVE2010 system as a more mechanistic model were compared with those of two other models, DVE1994 and NRC-2001, that are frequently used in common international feeding practice. DVE1994 predictions for intestinally digestible rumen undegradable protein (ARUP) for starchy concentrates were higher (27 vs 18 g/kg DM, p < 0.05, SEM = 1.2) than predictions by the NRC-2001, whereas there was no difference in predictions for ARUP from protein concentrates among the three models. DVE2010 and NRC-2001 had highest estimations of intestinally digestible microbial protein for starchy (92 g/kg DM in DVE2010 vs 46 g/kg DM in NRC-2001 and 67 g/kg DM in DVE1994, p < 0.05 SEM = 4) and protein concentrates (69 g/kg DM in NRC-2001 vs 31 g/kg DM in DVE1994 and 49 g/kg DM in DVE2010, p < 0.05 SEM = 4), respectively. Potential protein supplies predicted by tested models from starchy and protein concentrates are widely different, and comparable direct measurements are needed to evaluate the actual ability of different models to predict the potential protein supply to dairy cows from different feedstuffs. PMID- 26118654 TI - The interpretation of logical connectives in Turkish. AB - This study investigated how Turkish-speaking children and adults interpret negative sentences with disjunction (English or) and ones with conjunction (English and). The goal was to see whether Turkish-speaking children and adults assigned the same interpretation to both kinds of sentences and, if not, to determine the source of the differences. Turkish-speaking children and adults were found to assign different interpretations to negative sentences with disjunction just in case the nouns in the disjunction phrase were marked with accusative case. For children, negation took scope over disjunction regardless of case marking, whereas, for adults, disjunction took scope over negation if the disjunctive phrases were case marked. Both groups assigned the same interpretation to negative sentences with conjunction; both case-marked and non case-marked conjunction phrases took scope over negation. The findings are taken as evidence for a 'subset' principle of language learnability that dictates children's initial scope assignments. PMID- 26118655 TI - Galantamine-loaded PLGA nanoparticles, from nano-emulsion templating, as novel advanced drug delivery systems to treat neurodegenerative diseases. AB - Polymeric nanoparticles could be promising drug delivery systems to treat neurodegenerative diseases. Among the various methods of nanoparticle preparation, nano-emulsion templating was used in the present study to prepare galantamine-loaded nano-emulsions by a low-energy emulsification method followed by solvent evaporation to obtain galantamine-loaded polymeric nanoparticles. This approach was found to be suitable because biocompatible, biodegradable and safe nanoparticles with appropriate features (hydrodynamic radii around 20 nm, negative surface charge and stability higher than 3 months) for their intravenous administration were obtained. Encapsulation efficiencies higher than 90 wt% were obtained with a sustained drug release profile as compared to that from aqueous and micellar solutions. The enzymatic activity of the drug was maintained at 80% after its encapsulation into nanoparticles that were non-cytotoxic at the required therapeutic concentration. Therefore, novel galantamine-loaded polymeric nanoparticles have been designed for the first time using the nano-emulsification approach and showed the appropriate features to become advanced drug delivery systems to treat neurodegenerative diseases. PMID- 26118656 TI - Toward Naphthocyclinones: Doubly Connected Octaketide Dimers with a Bicyclo[3.2.1]octadienone Core by Thiolate-Mediated Cyclization. AB - A viable method is reported for the synthesis of the bicyclo[3.2.1]octadienone scaffold in naturally occurring octaketide dimers. The procedure employs a reductive cyclization reaction mediated by an unusual ethanedithiol monosodium salt. PMID- 26118657 TI - Involvement of epidermal growth factor receptors and mitogen-activated protein kinase in progestin-induction of sperm hypermotility in Atlantic croaker through membrane progestin receptor-alpha. AB - The intracellular pathways mediating rapid, nongenomic progestin stimulation of sperm motility remain unclear. The role of epidermal growth factor receptors (Egfr and ErbB2) and mitogen-activated protein kinase (Mapk) in membrane progestin receptor-alpha (mPRalpha)-mediated progestin stimulation of sperm hypermotility was examined in a teleost, Atlantic croaker. Inhibition of upstream regulators of Egfr, intracellular tyrosine kinase (Src) with PP2, and matrix metalloproteinase (MMP) with Ilomastat, abolished progestin-initiated sperm hypermotility by 17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S; 20 nM) and a specific mPRalpha agonist, Org OD 02-0 (20 nM). Pretreatment of croaker sperm with EGFR inhibitors, AG1478 (5 MUM) and RG13022 (50 MUM), the ErbB2 inhibitor, AG879 (5 nM), or the MEK1/2 inhibitor, U0126 (500 nM) blocked progestin stimulation of sperm motility. Levels of phosphorylated extracellular-related kinase 1 and 2 (P-Erk1/2) were increased after 20beta-S treatment. These results demonstrate that progestin-mediated hypermotility via mPRalpha in croaker sperm involves activation of the Egfr, ErbB2 and Mapk pathways. PMID- 26118658 TI - Butyltins, polyaromatic hydrocarbons, organochlorine pesticides, and polychlorinated biphenyls in sediments and bivalve mollusks in a mid-latitude environment from the Patagonian coastal zone. AB - Butyltins (BTs), polyaromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs), and polychlorinated biphenyls (PCBs) were assessed in a mid-latitude environment of the Patagonian coast, distant from significant pollutant sources. Bioaccumulation processes through bottom sediment resuspension were suggested by BTs level (expressed as ng of tin [Sn] g(-1) dry wt) found in surface sediment (G and c.1424C>T) in exon 9, altering 2 adjacent codons (p.Ser475Ala and p.Arg476Trp). These amino acid changes are in a highly conserved domain of the GUSB protein and nontolerable to maintain function. Moreover, the p.Arg476Trp mutation previously has been identified in human patients. None of the other clinically healthy cats had these mutations. CONCLUSIONS AND CLINIC IMPORTANCE: The diagnostic approach to MPS disorders is delineated. This is only the second mutation known to cause MPS VII in cats. Similarly, 2 different mutations have been described in MPS VII dogs, thereby showing the molecular heterogeneity of MPS VII in companion animals. PMID- 26118696 TI - Differences in the purification and solution properties of PurC gene products from Streptococcus pneumoniae and Bacillus anthracis. AB - 4-(N-succino)-5-aminoimidazole-4-carboxamide ribonucleotide synthetase (PurC) is a key enzyme in the de novo purine biosynthetic pathway of bacteria and an ideal target pathway for the discovery of antimicrobials. Bacillus anthracis (Ba) and Streptococcus pneumoniae (Sp) are two of the bacteria shown to be severe detriments to public health. To be able to carry out the experimentation that leads to drug discovery, high yields of pure soluble recombinant protein must first be obtained. We studied two recombinant PurC proteins from B. anthracis and S. pneumoniae, using Escherichia coli as the host cells. These two proteins, with very similar amino acid sequences, exhibit very different solution properties, leading to a large difference in yields during protein purification under the same conditions. The yield for SpPurC (>50mG per gram of cells) is ten times greater than that for BaPurC (<5mG per gram of cells). The BaPurC samples in solution consisted of oligomers and dimers, with dimers as its functional form. Comparing the yields of dimers, SpPurC is 25 times greater than that for BaPurC (~2mG per gram of cell). Our studies suggest that the difference in exposed hydrophobic surface area is responsible for the difference in yields under the same conditions. PMID- 26118697 TI - The effect of rare codons following the ATG start codon on expression of human granulocyte-colony stimulating factor in Escherichia coli. AB - Presence of the rare codons resulted from the difference in codon usages among organisms is considered as an obstacle to heterologous gene expression. This is especially important for the expression of the genes with eukaryotic origin in Escherichia coli. The N-terminus of human granulocyte colony stimulating factor (hG-CSF) contains amino acids whose coding sequences belong to the rare codons in E. coli. In this study, the effect of rare codons on hG-CSF expression level was evaluated through introducing silent mutations in the 5'-end of the coding sequence. E. coli BL21 (DE3) was used as an expression host. The constructs with the rare codons at the positions following the ATG initiation site of hG-CSF elevated the expression level up to 53-56% of the total cell proteins. This effect may be explained either by the rare codons effects on the early elongation region to reduce ribosome traffic jams in the rest of transcript or by their impacts on reduction of GC content at the beginning region. Mfold RNA server and prediction of the 5' mRNA secondary structure showed the less stable mRNA secondary structure is, the more hG-CSF expression level would be. However, the minimum free energy of the secondary structure individually, could not indicate this correlation between all constructs. This finding seems empirically important in designing the synthetic genes for production of the recombinant protein in E. coli. PMID- 26118698 TI - Expression, purification and crystallization of the (3R)-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis. AB - The (3R)-hydroxyacyl-ACP dehydratase HadAB, involved in the biosynthetic pathway for mycolic acid (MA) of Mycobacterium tuberculosis, catalyzes the third step in the fatty acid (FA) elongation cycle, which is an ideal and actual target for anti-tubercular agent. Though HadAB is predicted to be a member of the hotdog superfamily, it shares no sequence identity with typical hotdog fold isoenzyme FabZ. To characterize the significance of HadAB from the perspective of structural biology, large amount of pure HadAB complex is required for biochemical characterization and crystallization. Here, we used a unique expression and purification method. HadA and HadB were cloned separately and co expressed in Escherichia coli. After GST affinity chromatography, two steps of anion exchange chromatography and gel filtration, the purity of the protein as estimated by SDS-PAGE was >95%. Using hanging-drop vapor-diffusion method, crystals were obtained and diffracted X-rays to 1.75A resolution. The crystal belongs to space group P41212, with unit-cell parameters a=b=82.0A, c=139.8A, alpha=beta=gamma=90.0 degrees . PMID- 26118699 TI - An improved expression system for the VC1 ligand binding domain of the receptor for advanced glycation end products in Pichia pastoris. AB - The receptor for the advanced glycation end products (RAGE) is a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily and binds a variety of unrelated ligands sharing a negative charge. Most ligands bind to the extracellular V or VC1 domains of the receptor. In this work, V and VC1 of human RAGE were produced in the methylotrophic yeast Pichia pastoris and directed to the secretory pathway. Fusions to a removable C-terminal His-tag evidenced proteolytic processing of the tag by extracellular proteases and also intracellular degradation of the N-terminal portion of V-His. Expression of untagged forms was attempted. While the V domain was retained intracellularly, VC1 was secreted into the medium and was functionally active in binding AGEs. The glycosylation state of VC1 was analyzed by mass spectrometry and peptide-N glycosidase F digestion. Like RAGE isolated from mammalian sources, the degree of occupancy of the N-glycosylation sites was full at Asn25 and partial at Asn81 which was also subjected to non-enzymatic deamidation. A simple procedure for the purification to homogeneity of VC1 from the medium was developed. The folded state of the purified protein was assessed by thermal shift assays. Recombinant VC1 from P. pastoris showed a remarkably high thermal stability as compared to the protein expressed in bacteria. Our in vivo approach indicates that the V and C1 domains constitute a single folding unit. The stability and solubility of the yeast-secreted VC1 may be beneficial for future in vitro studies aimed to identify new ligands or inhibitors of RAGE. PMID- 26118701 TI - Automated detection and classification of teardrop cells by a novel RBC module using digital imaging/microscopy. PMID- 26118700 TI - An improved method for high-level soluble expression and purification of recombinant amyloid-beta peptide for in vitro studies. AB - Amyloid-beta (Abeta) peptide mediates several neurodegenerative diseases. The 42 amino acid (Abeta1-42) is the predominant form of peptide found in the neuritic plaques and has been demonstrated to be neurotoxic in vivo and in vitro. The availability of large quantities of Abeta peptide will help in several biochemical and biophysical studies that may help in exploring the aggregation mechanism and toxicity of Abeta peptide. We report a convenient and economical method to obtain such a peptide biologically. Synthetic oligonucleotides encoding Abeta1-42 were constructed and amplified through the polymerase cycling assembly (also known as assembly PCR), followed by the amplification PCR. Abeta1-42 gene was cloned into pET41a(+) vector for expression. Interestingly, the addition of 3% (v/v) ethanol to the culture medium resulted in the production of large amounts of soluble Abeta fusion protein. The Abeta fusion protein was subjected to a Ni-NTA affinity chromatography followed by enterokinase digestion, and the Abeta peptide was purified using glutathione Sepharose affinity chromatography. The peptide yield was ~15mg/L culture, indicating the utility of this method for high-yield production of soluble Abeta peptide. Sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis and immunoblotting with anti-His antibody confirmed the identity of purified Abeta fusion protein and Abeta peptide. In addition, this method provides an advantage over the chemical synthesis and other conventional methods used for large-scale production of recombinant Abeta peptide. PMID- 26118702 TI - Basal cell carcinoma arising within port-wine stains with no preceding radiotherapy. PMID- 26118703 TI - Reliability of the INSTI(r) rapid test for the diagnosis of HIV-1 non-B subtypes and recombinant variants. AB - Data regarding the efficacy of Rapid HIV tests (RHTs) in detecting non-B subtype HIV-1 are limited. We evaluated the sensitivity of the INSTI(r) test for the detection of HIV-1 antibodies for the diagnosis of HIV-1 non-B subtypes and recombinant variants. We identified adults with HIV-1 infection due to non-B subtypes and recombinant variants. The participants were re-tested with INSTI(r) test. We included 258 patients. Overall, the INSTI(r) test sensitivity was 98.4% (95%CI: 96.9-99.9%). For the major CRF_02AG subtype, the sensitivity was 99.0% (95%CI: 97.1-100%). The HIV INSTI(r) test is reliable for the detection of various non-B HIV-1 antibodies. PMID- 26118704 TI - Suboptimal Treatment of Diabetic Peripheral Neuropathic Pain in the United States. AB - OBJECTIVE: Approximately one third of patients with diabetic peripheral neuropathy (DPN) also experience neuropathic pain, resulting in a significant health care burden, and reduced quality of life. Pregabalin, duloxetine, and tapentadol extended-release are approved for treating diabetic peripheral neuropathic pain (DPNP), but many other medications are commonly used "off-label" with various degrees of success. We examined US health insurance claims to determine the current DPNP treatment patterns. METHODS: This retrospective analysis used the MarketScan claims database to identify adults with continuous health plan enrollment for 12 months pre- and postindex who were initially diagnosed with DPN between 2006 and 2011 and were provided a prescription for a medication reported to be beneficial for treating DPNP (anticonvulsants, antidepressants, opioids, or topical agents). We evaluated the frequency and types of medication dispensed within 1 year after first diagnosis, treatment adherence, and patterns of treatment alteration. RESULTS: Overall, 12,074 patients met inclusion criteria, with 66.6% initiating an anticonvulsant (gabapentin 45.0%; pregabalin 21.6%), and 5.2% initiating duloxetine. Patients commonly received less than the recommended dose of prescribed medication, and adherence was suboptimal for all treatments. It is estimated that up to 50% of patients discontinued their initial treatment within 3 months of initiation. CONCLUSIONS: Newly diagnosed patients with DPNP are most commonly prescribed anticonvulsants. Many patients receive lower than recommended dosages, potentially resulting in poor outcomes. Initial treatments are frequently discontinued, indicating low levels of satisfaction and/or poor tolerability. New therapies with improved efficacy and better tolerability are urgently needed for DPNP. PMID- 26118705 TI - [Effects of prenatal yoga: a systematic review of randomized controlled trials]. AB - OBJECTIVES: While several studies on the preventive and therapeutic effects of prenatal yoga (maternity yoga) have been reported in recent years, there has been no systematic review on the effects of prenatal yoga based on randomized controlled trials (RCT). The purpose of this study, therefore, was to systematically review the literature to clarify the effects of prenatal yoga in RCT focusing on the contents of the intervention, the intervention means, and the frequency of practice. METHODS: The literature search was performed using the electronic database, PubMed. The inclusion criteria were RCT, pregnant women, and yoga intervention. RESULTS: In total, 54 citations were found; of these, eight studies (10 reports) were included in the final analysis. In four studies on healthy pregnant women, significant improvement in pain and pleasure at delivery, duration of delivery, perceived stress levels during pregnancy, anxiety levels, depression, pregnancy-related experiences, quality of life, and interpersonal relationships were compared to those in the control group. In two studies on depressed pregnant women, one reported that depression, anxiety levels, anger levels, leg pain, and back pain significantly improved with yoga, while the other found no differences from the control group. In one study of high-risk pregnant women with morbidity factors such as obesity or advanced age, yoga resulted in significantly fewer cases of pregnancy-induced hypertension, gestational diabetes, and intrauterine growth restriction, as well as a decrease in perceived stress levels. In one study on pregnant women with pelvic pain, the median pain score was lower in the yoga group. Regarding the contents of the intervention, while the two studies for depressed pregnant women only included physical postures, the remaining six studies also included breathing technique and meditation. Interventions were performed using lectures by instructors alone or together with self-teaching. The frequency of the intervention varied within each study. CONCLUSION: The findings suggest that prenatal yoga may help reduce pelvic pain. It may also improve mental condition (stress, depression, anxiety, etc.), physical condition (pain and pleasure at the delivery, etc.), and perinatal outcomes (obstetrical complications, delivery time, etc.). However, further studies are needed. The contents of the intervention, the intervention means, and the frequency varied with each study. Thus, it is necessary to further examine the content of effective interventions, intervention means, and frequency that suit participant's characteristics and each outcome. Further research in this field, particularly randomized controlled trials, is merited. PMID- 26118706 TI - [Nationally representative score of the Japanese language version of the 13-item 7-point sense of coherence scale]. AB - OBJECTIVES: The amount of research relating to evaluation of intervention programs with regard to sense of coherence, a concept of salutogenic stressor coping capacity, is increasing in Japan. However, a nationally representative score of the Japanese version of the sense of coherence scale has not yet been reported. The aim of this study was to describe the 13-item, 7-point Japanese sense of coherence scale (SOC-13), with scoring by sex and age group, and to examine the relationships between the score and locality and city size. METHODS: Four thousand Japanese men and women were selected by stratified random sampling, and a cross-sectional, self-administered questionnaire survey was conducted using the placement method. Responses were obtained from 2,067 individuals (response rate: 51.7%). This study analyzed 956 men and 1,107 women (mean age [standard deviation]: 50.0 [14.3]). RESULTS: The mean score on the SOC-13 was 59.0 (12.2) in all participants, 59.1 (11.8) in men, and 58.9 (12.5) in women. No significant difference was found between men and women (P=0.784). ANOVA and multiple comparison for age difference showed a clear relationship (P<0.05) between higher age and a higher SOC-13 score. Moreover, the results of main and interaction effects in ANCOVA, with independent variables for locality (11 segments) and city size (four segments), were not significant when controlled for age. CONCLUSION: A nationally representative score for the Japanese SOC-13 was acquired. In future research, application of the SOC-13 in Japan for clinical studies is anticipated based on the nationally representative score. PMID- 26118707 TI - [An autochthonous outbreak of dengue type 1 in Tokyo, Japan 2014]. AB - OBJECTIVES: An outbreak of autochthonous dengue fever was reported in August 2014, with cases suspected mainly from Yoyogi Park in Tokyo. This is the first epidemic of dengue fever in Japan since 1945. METHODS: From August to October 2014, the following measures were taken to control the outbreak: 1) risk communication and information sharing; 2) active case finding; 3) vector surveillance in affected sites; and 4) laboratory testing. We also reviewed the surveillance data as reported to the National Epidemiological Surveillance of Infectious Diseases during the 44 epidemiological weeks. results: An official dengue fever call center was set up temporarily for the general public and 3,005 calls were received. The Tokyo Metropolitan Government issued 39 press releases regarding patients and nine related to dengue virus (DENV) detection and vector control activities for the media. Confirmed autochthonous dengue fever cases were reported between the 35th and 44th epidemiological weeks. Out of 160 cases of outbreak, 108 (67.5%) confirmed cases were reported in Tokyo. The estimated illness onset dates were between August 9 and October 7, and estimated dates of infections were between August 3 and October 3, 2014. The data suggest that the infective mosquitoes had already been present in Yoyogi Park at the end of July 2014. During the weekly vector surveillance at Yoyogi Park, a total of 1,152 adult mosquitoes, of which 856 (73.3%) were Aedes mosquitoes, were collected over 11 weeks by a light trap with dry ice. DENV was detected from adult Aedes mosquito samples collected on the 2nd, 9th, and 16th of September, 2014. Serum samples from 240 suspected cases were examined at the Tokyo Metropolitan Institute of Public Health, and 78 were positive for the DENV NS1 antigen, DENV specific IgM antibody, or DENV nucleic acid with reverse transcriptase polymerase chain reaction (RT-PCR) (NS1: 66 cases; IgM: 50 cases; PCR: 57 cases). Genetic analysis of DENV-positive serum and mosquito samples found all to be categorized as DENV-serotype 1 (gene type I). Phylogenetic analysis of the envelope protein genome sequence from patients and mosquitoes in Tokyo revealed more than 99% similarity with each other and with the strain from the first outbreak-associated patient in Saitama. CONCLUSION: Measures important for control of infectious disease epidemic were learned during this recent indigenous dengue outbreak in Tokyo. It also highlighted the importance of preparedness for epidemics of indigenous or imported infectious diseases, especially in light of the fact that Tokyo is in preparation for the Olympic and Paralympic Games in 2020. PMID- 26118708 TI - [Incidence of bicycle-related accidents and subsequent injury in community dwelling older adults: understanding potential accidents]. AB - OBJECTIVES: This study investigated 1) the incidence of bicycle-related accidents and subsequent injuries and 2) the number of injuries (accidents) reported to the police (i.e., examining the number of potential accidents) among community dwelling Japanese older adults, after examining the percentage of those who were regular cyclists. METHODS: Based on local resident registration, we mailed questionnaires to 7083 community-dwelling older adults. The questionnaire included questions about the incidence of bicycle-related accidents and subsequent injury within a year, the degree of injury and presence or absence of reporting that injury (bicycle-related accident) to the police. For the bicycle related accident, we asked regarding both riding and pedestrian accidents (i.e., accidents caused by a bicycle when walking). RESULTS: Excluding the blank responses (n=3539, 50.0%), the targets for analysis were 3098 older adults in riding accidents and 2861 older adults in pedestrian accidents. The results showed that 63.0% of older adults (n=1953) routinely rode a bicycle. Among them, 9.4% (n=184) experienced riding accidents, and 3.4% (n=98) experienced pedestrian accidents caused by a bicycle. For the riding accidents, 76.1% (n=140) had some injuries, and for the pedestrian accidents, 55.1% (n=54) had some injuries. Furthermore, in 70.2% (n=59) and 76.9% (n=20) of riding and pedestrian accidents, respectively, those who went to the hospital for treatment of their injury (i.e., injury requiring treatment) did not report the accident to the police. CONCLUSION: The present study revealed that there are many potential bicycle related accidents in older adults. This suggests that there may be a large gap in the national survey data between reported bicycle-related accidents and the actual number of incidents in older adults. PMID- 26118709 TI - Intracellular ROS Generation Mediates Maleimide-induced Cytotoxicity in Leukemia Cells. AB - Maleimides consist of an important class of compounds easily synthesized with multiple functional group modification that provides expressive pharmacological properties including, antitumoral activity, mediated mainly by oxidative stress. For this reason, the present study was designed to evaluate the cytotoxicity and the role of reactive oxygen species (ROS) in maleimide-induced cell death. Cell viability assays were performed to determine the cell death type in leukemia cell line induced by the compounds. The oxidative stress in maleimidetreated cells was characterized by antioxidant enzymes activities, intracellular ROS generation, and lipid peroxidation. In addition, we evaluated mitochondrial membrane potential and ATP level. Maleimide derivatives exhibited cytotoxic effects in leukemia cells with significantly increased ROS generation. However, cell viability was partly restored by catalase-treated cells. Caspases activities and caspase-independent key genes related to apoptosis were not altered by maleimides, suggesting necrosis as the main cell death process. Maleimide-induced necrosis was associated with oxidative stress, as an imbalance between ROS levels and glutathione reductase (GR) activity. This damage was also demonstrated by loss of mitochondrial membrane potential (MMP) and ATP depletion in cells treated with maleimide derivatives. These findings strongly confirmed that maleimide derivatives promoted cell death in leukemia cells triggered by oxidative stress, indicating that these compounds might be promising antitumor agents or lead molecules. PMID- 26118710 TI - Acetogenins as Potential Anticancer Agents. AB - Acetogenins (ACG) are naturally occurring compounds that are chemically one of the least investigated families. In the review, we have provided a comprehensive listing of 133 of these compounds for which anti-tumor activity has been documented within the literature. We have compiled and studied their chemical structure, in-vitro as well as in-vivo anticancer biological activity. We observed that the relative potency of acetogenins can be categorized as adjacent bis-THF ACGs > nonadjacent bis-THF ACGs > mono-THF ACGs > linear-THF ACGs. Among adjacent bis-THF ACGs, asiminocin (A100), asiminecin (A101), asiminacin (A102) and asimin (A103) are the most active compounds with in-vitro activity (ED50) in the range of 10(-9) to 10(-12) MUg/mL. For the nonadjacent bis-THF ACGs, gigantecin (A53) exhibited better cytotoxicity as compared to others in the series with an ED50 in the range of 10(-6) to 10(-8) MUg/mL. Similarly, muricatetrocin-C (A36), a mono-THF and coriadienin (A116) a linear ACG has been reported to show promising cytotoxicity with an ED50 of 10(-5) MUg/mL. Moreover, in-vivo studies indicate that compounds like bullatacin (A83), desacetyluvaricin (A76), bullatalicin (A58) and annonacin (A8) have demonstrated significant activity in mouse models and thereby exhibiting potential for lead development as a potential anticancer agent/drug. Also, globally oncologists are looking towards compounds from natural origin that inhibits the growth of resistant tumor cells. We find that several acetogenins like bullatacin (A83), motrilin (A95), asimicin (A77), trilobacin (A96), annonacin (A8), gigantetronenin (A108) and squamocin (A73) are efficacious in suppressing the proliferation of the MDR MCF-7/Adr cells. The present analysis suggests that acetogenins can act as yet another important source for obtaining promising lead compounds in order to contribute to cancer prevention, however, in future extensive in-vivo studies in animal models will be needed to provide insight for lead development. PMID- 26118711 TI - Screening Novel SAHA Derivatives as Anti-lung Carcinoma Agents: Synthesis, Biological Evaluation, Docking Studies and Further Mechanism Research between Apoptosis and Autophagy. AB - Four suberoylanilide hydroxamic acid (SAHA) derivatives (N34, N4I, N4B, N24) were designed and synthesized on the basis of our previous studies on N25. Assays for anti-proliferative activity and histone deacetylase (HDAC) activity were performed against human lung cancer (SPC-A-1, LTEP-a-2, NCI-H1650) and normal lung cells (MRC-5), which were compared with those of SAHA. Molecular docking was used to theoretically confirm the receptor-binding ability of N34. Ultimately, N34 was validated as the best HDAC inhibitor candidate. Furthermore, the effects of N34 on the levels of apoptosis- and autophagy-associated proteins caspase-3, caspase-9, Bcl-2 and Beclin-1 in SPC-A-1 cells were evaluated. N34 exerted more evident effects on human lung cancer than the other three SAHA derivatives did. PMID- 26118712 TI - Arsenic trioxide Alters the MicroRNA Expression Profile of U87 glioblastoma. AB - MicroRNAs (miRNAs) have a major role in cancer pathogenesis, cells growth and apoptosis. We studied the dysregulation of miRNAs after the induction of apoptosis by 4 MUM dose of ATO in glioblastoma cell line, U87. The anticancer effect of ATO was verified using MTT, BrdU cell proliferation assay and flow cytometric analysis. Differential expressions of 88 cancer-related miRNAs were analyzed by real-time reverse transcription PCR using miRNA PCR cancer-array system. The fold changes of miRNAs were calculated by comparing the results of treated to untreated control. Among the 88 cancer-related miRNAs, 2-fold upregulation was detected in 26 miRNAs and downregulation in 10 miRNAs compared to the control. The role of some of the miRNAs with significant changes was investigated by searching the literature and studying their roles in apoptosis, cell cycle and in various cellular signalling pathways. Our results showed that ATO modified the expression of a significant number of cancer-related miRNAs in glioblastoma cell line; most of these especially the upregulated miRNAs, were known as tumor suppressors with extensive roles in cancer associated processes and pathways. This study supports the mediatory role of miRNAs in anticancer effect of ATO. PMID- 26118713 TI - Mitogen-activated Protein Kinase Kinase 6-fusion Protein (MAP2K6-FP) Potentiates the Anti-tumor effects of Paclitaxel in Ovarian Cancer. AB - OBJECTIVE: To investigate the antitumor effects of a mitogen-activated protein kinase (MAPK) kinase fusion protein, TAT-OSBP-MKK6E (MAP2K6-FP), and paclitaxel as single agents and in combination against HO8910 human ovarian cancer cells. METHODS: We previously synthesized a MAPK kinase-recombinant fusion protein, MAP2K6-FP, that contains three domains: a protein transduction domain TAT, a human ovarian cancer HO8910 cell-specific binding peptide (OSBP), and a potential anti-tumor effector domain MKK6 (E). The HO8910 cells were exposed to MAP2K6-FP, paclitaxel, or both for 24 h. The antiproliferative effects were determined using the Cell Counting Kit-8 assay. Antitumor synergy was determined by computing the combination index. The in vivo antitumor effects of both drugs as single agents and in combination were tested using HO8910 cells implanted subcutaneously in female BALBC/c nude mice. TUNEL assay, immunohistochemical evaluation, and western blotting were performed to investigate the mechanism of action. RESULTS: A synergistic anti-proliferative effect was observed between MAP2K6-FP and paclitaxel at multiple drug concentrations, resulting in combination indices ranging from 0.3-0.85. In vivo testing against HO8910 cells in a xenograft tumor model indicated that both drugs were effective as single agents and that MAP2K6 FP and paclitaxel in combination had a synergistic antitumor effect. The combination treatment resulted in significantly altered caspase-3, vascular endothelial growth factor (VEGF), and proliferating cell nuclear antigen expression compared to treatment with the single agents (P<0.05). CONCLUSION: Both MAP2K6-FP and paclitaxel can inhibit cell proliferation and induce apoptosis in ovarian cancer HO8910 cells. Interestingly, the combination of MAP2K6-FP and paclitaxel had a synergistic antitumor effect on HO8910 cells, which induced apoptosis by increasing caspase-3 expression and decreasing VEGF expression. PMID- 26118714 TI - The novel NADPH oxidase 4 inhibitor GLX351322 counteracts glucose intolerance in high-fat diet-treated C57BL/6 mice. AB - In type 2 diabetes, it has been proposed that pancreatic beta-cell dysfunction is promoted by oxidative stress caused by NADPH oxidase (NOX) overactivity. Five different NOX enzymes (NOX1-5) have been characterized, among which NOX1 and NOX2 have been proposed to negatively affect beta-cells, but the putative role of NOX4 in type 2 diabetes-associated beta-cell dysfunction and glucose intolerance is largely unknown. Therefore, we presently investigated the importance of NOX4 for high-fat diet or HFD-induced glucose intolerance using male C57BL/6 mice using the new NOX4 inhibitor GLX351322, which has relative NOX4 selectivity over NOX2. In HFD-treated male C57BL/6 mice a two-week treatment with GLX351322 counteracted non-fasting hyperglycemia and impaired glucose tolerance. This effect occurred without any change in peripheral insulin sensitivity. To ascertain that NOX4 also plays a role for the function of human beta-cells, we observed that glucose- and sodium palmitate-induced insulin release from human islets in vitro was increased in response to NOX4 inhibitors. In long-term experiments (1-3 days), high-glucose induced human islet cell reactive oxygen species (ROS) production and death were prevented by GLX351322. We propose that while short-term NOX4-generated ROS production is a physiological requirement for beta-cell function, persistent NOX4 activity, for example, during conditions of high-fat feeding, promotes ROS mediated beta-cell dysfunction. Thus, selective NOX inhibition may be a therapeutic strategy in type 2 diabetes. PMID- 26118715 TI - Depletion of mitoferrins leads to mitochondrial dysfunction and impairment of adipogenic differentiation in 3T3-L1 preadipocytes. AB - Dysregulation of iron homeostasis is a potential risk factor for type 2 diabetes mellitus (T2DM) and insulin resistance. Iron transported into mitochondria by mitoferrins is mainly utilized for the biosynthesis of iron-sulfur clusters, heme, and other cofactors. Recent studies revealed that mitochondrial dysfunction leads to impaired adipogenesis and insulin insensitivity in adipocytes. However, it is unknown whether mitochondrial iron import and iron status affect the biogenesis and function of mitochondria during adipogenic differentiation. In this study, we used double knockdown of mitoferrin 1 and mitoferrin 2 (Mfrn1/2) to investigate the role of mitochondrial iron homeostasis in mitochondrial bioenergetic function and adipogenic differentiation. The results showed that depletion of Mfrn1/2 in 3T3-L1 preadipocytes impaired the biosynthesis of iron sulfur proteins in mitochondria due to a decrease in mitochondrial iron content. This was associated with a decrease in mitochondrial oxygen consumption rate and intracellular ATP level in adipocytes with Mfrn1/2 knockdown. Remarkably, Mfrn1/2 deficiency reduced the expression of adipogenic genes and lipid production during adipogenic differentiation. Moreover, insulin-induced glucose uptake and Akt phosphorylation at the Ser473 residue were decreased concurrently in adipocytes differentiated from 3T3-L1 preadipocytes after knockdown of Mfrn1/2. These findings suggest that dysregulation of mitochondrial iron metabolism elicited by knockdown of Mfrn1/2 results in mitochondrial dysfunction, which culminates in the compromise of differentiation and insulin insensitivity of adipocytes. This scenario may explain the recent findings that iron deficiency or alterations in iron metabolism are associated with the pathogenesis of T2DM. PMID- 26118716 TI - Melatonin protects hepatocytes against bile acid-induced mitochondrial oxidative stress via the AMPK-SIRT3-SOD2 pathway. AB - Mitochondrial oxidative damage is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Melatonin, an indolamine synthesized in the pineal gland, shows a wide range of physiological functions, and is under clinical investigation for expanded applications. Melatonin has demonstrated efficient protective effects against various types of oxidative damage in the liver system. This study investigates the protective effects of melatonin pretreatment on glycochenodeoxycholic acid (GCDCA)-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. Melatonin markedly decreased mitochondrial ROS (mROS) production in L02 cells treated with 100 MUM GCDCA, and inhibited GCDCA-stimulated cytotoxicity. Notably, melatonin exerted its hepatoprotective effects by upregulating sirtuin 3 (SIRT3) activity and its expression level, thus regulating superoxide dismutase 2 (SOD2) acetylation and inhibiting the production of mROS induced by GCDCA. Moreover, siRNA targeting SIRT3 blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT3/SOD2 signaling. Importantly, melatonin-activated SIRT3 activity was completely abolished by AMP-activated, alpha 1 catalytic subunit (AMPK) siRNA transfection. Similar results were obtained in rat with bile duct ligation or BDL. In summary, our findings indicate that melatonin is a novel hepatoprotective small molecule that functions by elevating SIRT3, stimulating SOD2 activity, and suppressing mitochondrial oxidative stress at least through AMPK, and that SIRT3 may be of therapeutic value in liver cell protection for GCDCA-induced hepatotoxicity. PMID- 26118717 TI - Nrf2-ARE signals mediated the anti-oxidative action of electroacupuncture in an MPTP mouse model of Parkinson's disease. AB - Oxidative stress and neuroinflammation are early events associated with dopaminergic neuronal degeneration in Parkinson's disease (PD). Previous studies indicated that electroacupuncture (EA) stimulation is effective in protecting dopaminergic neurons from degeneration in a 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) mouse model of PD. In this study, we further characterized the effect of EA on MPTP-induced oxidative responses in the mouse dopamine system. We found that subacute administration of MPTP enhanced lipid and protein oxidation and reduced expression of endogenous antioxidant enzymes (such as superoxide dismutase and catalase) in the striatum. MPTP also reduced expression of an antioxidant transcription factor, nuclear factor-E2-related factor-2 (Nrf2), and Nrf2-regulated antioxidant enzymes (nicotinamide adenine dinucleotide phosphate quinone oxidoreductase-1 and heme oxygenase-1) in the striatum and/or midbrain. Using human placental alkaline phosphatase (hPAP) as a reporter of Nrf2-regulated gene expression in hPAP transgenic mice, we found that MPTP suppressed hPAP expression in the striatum and midbrain. Application of EA at an effective frequency (100 Hz) was sufficient to reverse these changes induced by MPTP. In addition, EA reduced microglia activation and astrogliosis in the striatum and midbrain, increased tyrosine hydroxylase levels in the striatum, and improved vertical movement in MPTP mice. These results provide further evidence supporting that EA produces a series of anti-oxidative effects that effectively counteract with the oxidative stress in the nigrostriatal dopamine system induced by MPTP in a mouse model of PD. PMID- 26118718 TI - Rechargeable Battery: The Essential Tool for the New Era of Neuromodulation. PMID- 26118719 TI - Improving Vascular Neurosurgical Skills in an Era of Diminished Microsurgical Exposure. PMID- 26118720 TI - Julius Caesar's Epilepsy: Was It Caused by A Brain Arteriovenous Malformation? AB - Julius Caesar (100-44 BC) was one of the most charismatic political figures in history. Best remembered for his military achievements, he was also a writer, historian, and statesman. Through his constitutional reforms, he played an important role in the events that led to the end of the Roman Republic and the birth of the Roman Empire. Historical sources reveal that Julius Caesar suffered from headaches, seizures, and personality changes. In this essay, we highlight the life of Julius Caesar, with emphasis on the potential origin of his sickness. Although a definitive diagnosis obviously cannot be made, as new published studies showed a possible cerebrovascular etiology, a new hypothetical diagnosis is presented. PMID- 26118721 TI - Delay in Arrival to Care in Perpetrator-Identified Nonaccidental Head Trauma: Observations and Outcomes. AB - BACKGROUND: Children who sustained nonaccidental head trauma (NAHT) are at severe risk for mortality within the first 24 hours after presentation. OBJECTIVE: Extent of delay in seeking medical attention may be related to patient outcome. METHODS: A 10-year, single-institution, retrospective review of 48 cases treated at a large tertiary Children's Hospital reported to the New York State Central Registrar by the child protection team was conducted. The perpetrator was identified in 28 cases on the basis of confession or conviction. The medical and legal records allowed for identification of time of injury and the interval between injury and arrival to the hospital; this information was categorized as follows: <6 hours (without delay); 6-12 hours (moderate delay); and >12 hours (severe delay). The King's Outcome Scale for Childhood Head Injury (KOSCHI) score was recorded for each case. RESULTS: All children were 3 years of age or younger (2.1-34 months) and predominantly male (68%; 19/28). On arrival, 61% of patients (17/28) presented with moderate or severe delay. A low arrival Glasgow Coma Scale (GCS) score (P < 0.0001) and extracranial injuries (P < 0.0061) correlated with worse clinical patient outcomes. Patients with an arrival GCS score <7 predominantly arrived without delay or with moderate delay. Patients presenting without delay or with severe delay were more likely to have a higher KOSCHI outcome score on discharge (P < 0.0426). Four of the 6 patients who died presented after moderate delay. CONCLUSION: Patients presenting to medical care 6 12 hours after NAHT (moderate delay) appeared to have worse outcomes than those presenting earlier or later. PMID- 26118722 TI - Onyx Embolization of a Ruptured Rotundum Foreman Artery Aneurysm in a Patient with Moyamoya Disease: A Case Report. AB - BACKGROUND: Hemorrhage caused by the rupture of a rotundum foreman artery pseudoaneurysm in Moyamoya disease (MMD) is rarely reported. CASE DESCRIPTION: We report a case of 46-year-old man with MMD presenting with left temporal lobe hemorrhage. Cerebral angiogram showed a pseudoaneurysm located on the rotundum branch of the left internal maxillary artery, which anastomosed with a pial vessel. Using onyx 18, we successfully embolized the pseudoaneurysm. The patient was discharged neurologically intact. CONCLUSION: Given the difficulties and risks of surgery, onyx embolization of rotundum foreman artery aneurysm accompanied with MMD is feasible and effective. PMID- 26118723 TI - Long-Term Outcome of Arthroscopic Resection Arthroplasty With or Without Interposition for Thumb Basal Joint Arthritis. AB - PURPOSE: To report results on 144 cases following arthroscopic resection arthroplasty (ARA) with or without interposition for basal joint arthritis. METHODS: Cases undergoing ARA for thumb carpometacarpal osteoarthritis between 2004 and 2011 were prospectively enrolled (n = 178). Data were collected before surgery and after surgery at 1, 3, 6, and 12 months and annually thereafter. Patients were excluded for less than 1-year follow-up or concomitant procedures that interfered with evaluation of the variable of interest (interposition). Human acellular dermal matrix (GRAFTJACKET) was the most commonly used interposition. Outcomes on 19 cases of interposition using collagen bioimplant (OrthADAPT) and porous polyurethaneurea (Artelon) scaffolds were also reported. Comparative analyses were performed on 52 patients with GRAFTJACKET interposition and on 73 without. Mean follow-up was 7.4 and 5.6 years with and without interposition, respectively. Descriptive statistics were evaluated on all baseline variables. Raw change scores of grip, pinch, and pain outcomes were evaluated. Confounding variables at a significance level of P less than .05 were adjusted for in linear mixed models, and an analysis of covariance was employed through an unstructured type of variance-covariance matrix. RESULTS: Change scores from baseline to 1 year for the interposition group for pain (numerical rating scale, 0-10), pinch, and grip was -5.8, 3.3, and 7, respectively, and 5.1, 2.1, and 9 for the noninterposition group. Postoperative mean satisfaction was 4.7 and 4.4 for the with- and without-interposition groups, respectively. There were 4 failures with and 2 without interposition. Artelon and OrthADAPT did poorly with unacceptably high failure rates. CONCLUSIONS: This study suggested that interposition is not necessary following ARA for thumb basal joint arthritis. Because arthroscopic interposition of material contributes to health care costs in terms of patient and facility costs without clear benefit to the patient, routine use of expensive interposition products should be abandoned or carefully evaluated with a prospective randomized controlled trial. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26118724 TI - Experimental approaches to investigate effector translocation into host cells in the Ustilago maydis/maize pathosystem. AB - The fungus Ustilago maydis is a pathogen that establishes a biotrophic interaction with Zea mays. The interaction with the plant host is largely governed by more than 300 novel, secreted protein effectors, of which only four have been functionally characterized. Prerequisite to examine effector function is to know where effectors reside after secretion. Effectors can remain in the extracellular space, i.e. the plant apoplast (apoplastic effectors), or can cross the plant plasma membrane and exert their function inside the host cell (cytoplasmic effectors). The U. maydis effectors lack conserved motifs in their primary sequences that could allow a classification of the effectome into apoplastic/cytoplasmic effectors. This represents a significant obstacle in functional effector characterization. Here we describe our attempts to establish a system for effector classification into apoplastic and cytoplasmic members, using U. maydis for effector delivery. PMID- 26118725 TI - Fiber-Optic-Based Micro-Probe Using Hexagonal 1-in-6 Fiber Configuration for Intracellular Single-Cell pH Measurement. AB - Single-cell research is essential for understanding cell heterogeneity, cell differentiation, and carcinogenesis, among other important cellular processes. New techniques for intracellular pH monitoring are urgently needed to gain new insights into single-cell responses to external stimuli. In this study, fiber optic reflection-based pH micro (MU)-probes (tip diameter: 500-3000 nm) were designed and fabricated using a novel hexagonal 1-in-6 fiber configuration. An organic-modified silicate (OrMoSils) sol-gel doped with a pH-sensitive dye, 2',7' bis(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF), were coated onto the probe sensing tip for pH detection. These probes enabled neutral pH monitoring and quasi-real-time data acquisition (response time: 20 +/- 5 s). The fluorescence signals of the newly developed probes were found to correlate linearly with pH (R(2) = 0.9869 when coupling laser power was at 8.2 mW) within a biologically relevant pH range (6.18-7.80). The pH resolution was 0.038 pH unit. The miniaturized probes were validated in single human lung cancer A549 cells to demonstrate applicability in single-cell experiments. In summary, novel pH MU probes with excellent resolution and response times within a biologically relevant pH range were developed, and they can be used for measuring pH changes in single cells. PMID- 26118726 TI - Physiological time structure of the tibialis anterior motor activity during sleep in mice, rats and humans. AB - The validation of rodent models for restless legs syndrome (Willis-Ekbom disease) and periodic limb movements during sleep requires knowledge of physiological limb motor activity during sleep in rodents. This study aimed to determine the physiological time structure of tibialis anterior activity during sleep in mice and rats, and compare it with that of healthy humans. Wild-type mice (n = 9) and rats (n = 8) were instrumented with electrodes for recording the electroencephalogram and electromyogram of neck muscles and both tibialis anterior muscles. Healthy human subjects (31 +/- 1 years, n = 21) underwent overnight polysomnography. An algorithm for automatic scoring of tibialis anterior electromyogram events of mice and rats during non-rapid eye movement sleep was developed and validated. Visual scoring assisted by this algorithm had inter-rater sensitivity of 92-95% and false-positive rates of 13-19% in mice and rats. The distribution of the time intervals between consecutive tibialis anterior electromyogram events during non-rapid eye movement sleep had a single peak extending up to 10 s in mice, rats and human subjects. The tibialis anterior electromyogram events separated by intervals <10 s mainly occurred in series of two-three events, their occurrence rate in humans being lower than in mice and similar to that in rats. In conclusion, this study proposes reliable rules for scoring tibialis anterior electromyogram events during non-rapid eye movement sleep in mice and rats, demonstrating that their physiological time structure is similar to that of healthy young human subjects. These results strengthen the basis for translational rodent models of periodic limb movements during sleep and restless legs syndrome/Willis-Ekbom disease. PMID- 26118731 TI - Regenerative therapy for hippocampal degenerative diseases: lessons from preclinical studies. AB - Increase in life expectancy has put neurodegenerative diseases on the rise. Amongst these, degenerative diseases involving hippocampus like Alzheimer's disease (AD) and temporal lobe epilepsy (TLE) are ranked higher as it is vulnerable to excitotoxicity induced neuronal dysfunction and death resulting in cognitive impairment. Modern medicines have not succeeded in halting the progression of these diseases rendering them incurable and often fatal. Under such scenario, regenerative studies employing stem cells or their by-products in animal models of AD and TLE have yielded encourageing results. This review focuses on the distinct cell types, such as hippocampal cell lines, neural precursor cells, embryonic stem cells derived neural precursor cells, induced pluripotent stem cells, induced neurons and mesenchymal stem cells, which can be employed to rescue hippocampal functions in neurodegenerative diseases like AD and TLE. Besides, the divergent mechanisms through which cell based therapy confer neuroprotection, current impediments and possible improvements in stem cell transplantation strategies are discussed. Authors are aware of the voluminous literature available on this issue and have made a sincere attempt to put forth the current status of research in the field of cell based therapy concurrently discussing the promise it holds for combating neurodegenerative diseases like AD and TLE in the near future. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118732 TI - The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link? AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antinuclear antibodies (ANAs) in association with systemic inflammation and organ damage. In addition to genetic factors, a contribution of infection to disease induction has been proposed. In the pathogenesis of lupus, immune complexes of ANAs with nuclear antigens can form and both deposit in the tissue and stimulate cytokine production to intensify inflammation. As such, the extracellular release of nuclear antigens to form pathogenic immune complexes is an important step in the pathway to disease. This release has been considered the consequence of cell death, with apoptotic cells the relevant source of nuclear material. While apoptosis could serve this role, other death forms may act similarly. Among these death forms, pyroptosis, which can be induced by inflammasome activation during infection, has features suggesting involvement in lupus. Thus, unlike apoptosis, pyroptosis is a pro inflammatory process. Furthermore, pyroptosis leads to the release of intracellular contents including HMGB1 and ATP, both of which can act as DAMPs (death associated molecular patterns) to stimulate further inflammation. Importantly, pyroptosis can lead to the release of intact nuclei, suggesting a relationship to events in the formation of LE cells. While the role of pyroptosis in SLE is hypothetical at this time, further analysis of this death form should provide new insights into lupus pathogenesis and provide the missing link between infection and the initiation of lupus by products of dead and dying cells. PMID- 26118733 TI - Decarbonylative organoboron cross-coupling of esters by nickel catalysis. AB - The Suzuki-Miyaura cross-coupling is a metal-catalysed reaction in which boron based nucleophiles and halide-based electrophiles are reacted to form a single molecule. This is one of the most reliable tools in synthetic chemistry, and is extensively used in the synthesis of pharmaceuticals, agrochemicals and organic materials. Herein, we report a significant advance in the choice of electrophilic coupling partner in this reaction. With a user-friendly and inexpensive nickel catalyst, a range of phenyl esters of aromatic, heteroaromatic and aliphatic carboxylic acids react with boronic acids in a decarbonylative manner. Overall, phenyl ester moieties function as leaving groups. Theoretical calculations uncovered key mechanistic features of this unusual decarbonylative coupling. Since extraordinary numbers of ester-containing molecules are available both commercially and synthetically, this new 'ester' cross-coupling should find significant use in synthetic chemistry as an alternative to the standard halide based Suzuki-Miyaura coupling. PMID- 26118734 TI - 'It makes a difference, coming here': A qualitative exploration of clinic attendance among young adults with type 1 diabetes. AB - OBJECTIVE: Young adulthood is a time of significant challenges and risks for people with type 1 diabetes. Poor outpatient clinic attendance is common among young adults with type 1 diabetes. The aim of this qualitative study was to develop a theory explaining attendance at a hospital-based diabetes clinic. DESIGN: Using a grounded theory methodology, data were collected through semi structured qualitative interviews. METHOD: Twenty-nine people (21 young adults with type 1 diabetes and eight service providers) from one hospital-based diabetes clinic were interviewed. Interviews were audio-recorded, transcribed, and analysed according to grounded theory methodology. RESULTS: Relationships between young adults and service providers is the core category of this theory. Collaborative relationships between young adults and service providers increased the perceived value of attendance and reduced the vulnerability of young adults to the barriers within the existing service, such as meeting unfamiliar service providers. Relationships between young adults and service providers were developed following opportunities for contact (e.g., structured education programme or crisis of diabetes), and facilitated engagement with the service and further attendance. Barriers to clinic attendance included young adults' negative perceptions of their diabetes self-management and a lack of value associated with attending. CONCLUSION: The diabetes clinic was described as an important and valued resource by young adults and service providers. Collaborative relationships between young adults and service providers enhanced service provision in this study. According to the results of this study, clinic attendance may be improved by increasing opportunities for relationship development between service providers and young adults. Statement of contribution What is already known on this subject? Attendance by young adults at hospital based diabetes clinics is important to support self-management. Young adults with type 1 diabetes are at risk of clinic non-attendance. What does this study add? This study presents an explanatory theory of clinic attendance among young adults with type 1 diabetes. According to this theory: Barriers within existing models of service delivery prevent collaboration and may contribute to non-attendance. Relationships between service users and providers can establish or maintain regular clinic attendance by fostering the engagement of young adults with diabetes clinics. PMID- 26118735 TI - Recent advances in targeted therapy for glioblastoma. AB - Glioblastomas are the most common form of brain tumor with a very dismal prognosis. While a standard treatment regimen of surgery followed by chemo/radiotherapy is currently used, this has only marginally improved the survival time of patients with little benefit on tumor recurrence. Although many molecular targets have already been identified and tested in clinical trials, very few are approved for use in clinics. Efforts are ongoing to target newer molecules that could be used for drug development. This review provides up-to date information on the drugs and their molecular targets, which are currently in different stages of clinical trials. Since multiple signaling pathways are deregulated, it appears that the use of combination drugs along with personalized targeting approach would provide better therapy in the future. PMID- 26118736 TI - Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions? AB - Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid((r)) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid((r)) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid((r)) quickly improved haemodynamics. However, beneficial effects of Intralipid((r)) were less clear after myocardial ischemia. PMID- 26118738 TI - Evaluating methods for estimating local effective population size with and without migration. AB - Effective population size is a fundamental parameter in population genetics, evolutionary biology, and conservation biology, yet its estimation can be fraught with difficulties. Several methods to estimate Ne from genetic data have been developed that take advantage of various approaches for inferring Ne . The ability of these methods to accurately estimate Ne , however, has not been comprehensively examined. In this study, we employ seven of the most cited methods for estimating Ne from genetic data (Colony2, CoNe, Estim, MLNe, ONeSAMP, TMVP, and NeEstimator including LDNe) across simulated datasets with populations experiencing migration or no migration. The simulated population demographies are an isolated population with no immigration, an island model metapopulation with a sink population receiving immigrants, and an isolation by distance stepping stone model of populations. We find considerable variance in performance of these methods, both within and across demographic scenarios, with some methods performing very poorly. The most accurate estimates of Ne can be obtained by using LDNe, MLNe, or TMVP; however each of these approaches is outperformed by another in a differing demographic scenario. Knowledge of the approximate demography of population as well as the availability of temporal data largely improves Ne estimates. PMID- 26118737 TI - INTER- AND INTRAFRACTION MOTION FOR STEREOTACTIC RADIOSURGERY IN DOGS AND CATS USING A MODIFIED BRAINLAB FRAMELESS STEREOTACTIC MASK SYSTEM. AB - Precise and accurate patient positioning is necessary when doing stereotactic radiosurgery (SRS) to ensure adequate dosing to the tumor and sparing of normal tissues. This prospective cross-sectional study aimed to assess feasibility of a commercially available modified frameless SRS positioning system for use in veterinary radiotherapy patients with brain tumors. Fifty-one dogs and 12 cats were enrolled. Baseline and verification CT images were acquired. The verification CT images from 32 dogs and five cats had sufficient images for fusion to baseline CT images. A rigid box-based fusion was performed to determine interfraction motion. Forty-eight dogs and 11 cats were assessed for intrafraction motion by cine CT. Seventy percent of dogs and 60% of cats had interfraction 3D vector translational shifts >1 mm, with mean values of 1.9 mm in dogs, and 1.8 mm in cats. In dogs muscle wasting was weakly correlated with translational shifts. The maximum angular interfraction motion observed was 6.3 degrees (roll), 3.5 degrees (pitch), and 3.3 degrees (yaw). There was no correlation between angular interfraction motion and weight, brachycephaly, or muscle wasting. Fifty-seven percent of dogs and 50% of cats had respiration related intrafraction motion. Of these, 4.5% of dogs and 10% of cats had intrafraction motion >1 mm. This study demonstrates the modified Brainlab system is feasible for SRS in dogs and cats. The smaller cranial size and difference in anatomy increases setup uncertainty in some animals beyond limits usually accepted in SRS. Image-guided positioning is recommended to achieve clinically acceptable setup accuracy (<1 mm) for SRS. PMID- 26118739 TI - Anesthetic effects of isoflurane on the tonotopic map and neuronal population activity in the rat auditory cortex. AB - Since its discovery nearly four decades ago, sequential microelectrode mapping using hundreds of recording sites has been able to reveal a precise tonotopic organization of the auditory cortex. Despite concerns regarding the effects that anesthesia might have on neuronal responses to tones, anesthesia was essential for these experiments because such dense mapping was elaborate and time consuming. Here, taking an 'all-at-once' approach, we investigated how isoflurane modifies spatiotemporal activities by using a dense microelectrode array. The array covered the entire auditory cortex in rats, including the core and belt cortices. By comparing neuronal activity in the awake state with activity under isoflurane anesthesia, we made four observations. First, isoflurane anesthesia did not modify the tonotopic topography within the auditory cortex. Second, in terms of general response properties, isoflurane anesthesia decreased the number of active single units and increased their response onset latency. Third, in terms of tuning properties, isoflurane anesthesia shifted the response threshold without changing the shape of the frequency response area and decreased the response quality. Fourth, in terms of population activities, isoflurane anesthesia increased the noise correlations in discharges and phase synchrony in local field potential (LFP) oscillations, suggesting that the anesthesia made neuronal activities redundant at both single-unit and LFP levels. Thus, while isoflurane anesthesia had little effect on the tonotopic topography, its profound effects on neuronal activities decreased the encoding capacity of the auditory cortex. PMID- 26118740 TI - Investigation of practical approaches to evaluating cumulative dose for cone beam computed tomography (CBCT) from standard CT dosimetry measurements: a Monte Carlo study. AB - A function called Gx(L) was introduced by the International Commission on Radiation Units and Measurements (ICRU) Report-87 to facilitate measurement of cumulative dose for CT scans within long phantoms as recommended by the American Association of Physicists in Medicine (AAPM) TG-111. The Gx(L) function is equal to the ratio of the cumulative dose at the middle of a CT scan to the volume weighted CTDI (CTDIvol), and was investigated for conventional multi-slice CT scanners operating with a moving table. As the stationary table mode, which is the basis for cone beam CT (CBCT) scans, differs from that used for conventional CT scans, the aim of this study was to investigate the extension of the Gx(L) function to CBCT scans. An On-Board Imager (OBI) system integrated with a TrueBeam linac was simulated with Monte Carlo EGSnrc/BEAMnrc, and the absorbed dose was calculated within PMMA, polyethylene (PE), and water head and body phantoms using EGSnrc/DOSXYZnrc, where the body PE body phantom emulated the ICRU/AAPM phantom. Beams of width 40-500 mm and beam qualities at tube potentials of 80-140 kV were studied. Application of a modified function of beam width (W) termed Gx(W), for which the cumulative dose for CBCT scans f (0) is normalized to the weighted CTDI (CTDIw) for a reference beam of width 40 mm, was investigated as a possible option. However, differences were found in Gx(W) with tube potential, especially for body phantoms, and these were considered to be due to differences in geometry between wide beams used for CBCT scans and those for conventional CT. Therefore, a modified function Gx(W)100 has been proposed, taking the form of values of f (0) at each position in a long phantom, normalized with respect to dose indices f 100(150)x measured with a 100 mm pencil ionization chamber within standard 150 mm PMMA phantoms, using the same scanning parameters, beam widths and positions within the phantom. f 100(150)x averages the dose resulting from a CBCT scan over the 100 mm length. Like the Gx(L) function, the Gx(W)100 function showed only a weak dependency on tube potential at most positions for the phantoms studied. The results were fitted to polynomial equations from which f (0) within the longer PMMA, PE, or water phantoms can be evaluated from measurements of f 100(150)x. Comparisons with other studies, suggest that these functions may be suitable for application to any CT or CBCT scan acquired with stationary table mode. PMID- 26118741 TI - [Continuity of care from the acute care hospital: Results]. AB - OBJECTIVE: To describe the profile of patients treated by a Continuity of Care Manager in an acute-care center during the first six months of its activity, as well as the profile of patients treated and the resource allocation. METHOD: A prospective cross-sectional study was conducted on patients with complex care needs requiring continuity of care liaison, and who were attended by the Continuity of Care Nurse during the period from October 2013 to March 2014. Patient characteristics, their social environment and healthcare resource allocation were registered and analyzed. RESULTS: A total of 1,034 cases of demand that corresponded to 907 patients (women 55.0%; age 80.57+/-10.1; chronic 47.8%) were analyzed, of whom 12.2% were readmitted. In the multivariate model, it was observed that the variables associated with readmission were polypharmacy (OR: 1.86; CI: 1.2-2.9) and fall history prior to admission (OR: 0.586; CI: 0.36 2-88). CONCLUSIONS: Patients treated by a Continuity of Care Nurse are over 80 years, with comorbidities, geriatric syndromes, complex care, and of life needs, to whom an alternative solution to hospitalization is provided, thus preventing readmissions. PMID- 26118742 TI - Single layer of MX3 (M = Ti, Zr; X = S, Se, Te): a new platform for nano electronics and optics. AB - A serial of two-dimensional titanium and zirconium trichalcogenides nanosheets MX3 (M = Ti, Zr; X = S, Se, Te) were investigated based on first-principles calculations. The evaluated low cleavage energy indicates that stable two dimensional monolayers can be exfoliated from their bulk crystals in the experiment. Electronic studies reveal the very rich electronic properties in these monolayers, including metallic TiTe3 and ZrTe3, direct band gap semiconductor, TiS3, and indirect band gap semiconductors, TiSe3, ZrS3 and ZrSe3. The band gaps of all the semiconductors are between 0.57 and 1.90 eV, which implies their potential applications in nano-electronics. In addition, the calculated effective masses demonstrate the highly anisotropic conduction properties for all the semiconductors. Optically, TiS3 and TiSe3 monolayers exhibit good light absorption in the visible and near-infrared region, respectively, indicating their potential applications in optical devices. In particular, the highly anisotropic optical absorption of the TiS3 monolayer suggests it could be used in designing nano-optical waveguide polarizers. PMID- 26118743 TI - Psychosocial Correlates of Patients Being Physically Restrained within the First 7 Days in an Acute Psychiatric Admission Ward: Retrospective Case Record Review. AB - OBJECTIVE: Clinically, patients' characteristics may predict the use of physical restraint in a psychiatric ward. This study aimed to explore significant psychosocial variables in predicting the risk for application of physical restraint with intention of identifying patients at high risk for physical restraint at the time of admission to an acute psychiatric setting. METHODS: The case records of 335 adult patients aged > 18 years, who were treated in 4 acute psychiatric admission wards of a public hospital in Hong Kong from 1 November 2013 to 28 February 2014, were retrospectively reviewed. RESULTS: Results of statistical analysis indicated involuntary admission, current use of psychiatric medications, no history of violent behaviour, age, and depression as significant predictors of use of physical restraint. The model accounted for 28.5% to 38.5% of the variance in the use of physical restraint. Overall, this model had a success rate of 77.6%. CONCLUSION: It was concluded that 39.7% of inpatients admitted to the acute psychiatric admission ward had been restrained at least once in the first 7 days. Significant predictors of restraint included involuntary admission, current use of psychiatric medications, no history of violent behaviour, age, and depression; all of which could be regarded as risk factors for restraint. PMID- 26118744 TI - Co-morbidity of Obsessive-compulsive Disorder and Other Anxiety Disorders with Child and Adolescent Mood Disorders. AB - OBJECTIVE: To assess the co-morbidity of obsessive-compulsive disorder (OCD) and other anxiety disorders in child and adolescent mood disorders. METHODS: A total of 100 patients aged < 18 years with mood disorders according to the DSM-IV-TR were screened for OCD and other anxiety disorders using Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version. RESULTS: The prevalence of co-morbid anxiety disorders was 22%; OCD was present in 4%, and subthreshold obsessive-compulsive symptoms were present in 2%. Among others, 8% had panic disorder, 7% had generalised anxiety disorder, 3% had separation anxiety disorder, and 1% had social phobia; multiple anxiety disorders were present in 3% of patients. CONCLUSION: Co-morbid anxiety disorder was found in one-fifth of children and adolescents with mood disorder. PMID- 26118745 TI - Comparative Study of Neurological Soft Signs in Patients with Schizophrenia or Obsessive-compulsive Disorder, and Healthy Controls. AB - OBJECTIVE: The primary objective of this study was to examine neurological soft signs in patients with obsessive-compulsive disorder compared with patients with schizophrenia and a control group in the Indian setting. The secondary objective was to find any correlation between age at onset and neurological soft signs scores, as well as that between severity of obsessive-compulsive disorder symptoms (total Yale-Brown Obsessive Compulsive Scale score) and neurological soft signs scores. METHODS: This was a cross-sectional hospital-based study of 135 individuals (45 patients with schizophrenia, 45 patients with obsessive compulsive disorder who were attending the psychiatric outpatient department of Sawai Man Singh Medical College, Jaipur, India, and 45 matched healthy controls) from 20 June 2013 to 22 December 2014. After applying strict inclusion and exclusion criteria, the participants completed the study instruments (Cambridge Neurological Inventory [Part 2] and Yale-Brown Obsessive Compulsive Scale). Their socio-demographic data were also recorded. RESULTS: The neurological soft signs total score and domain scores (motor coordination, sensory integration, and disinhibition) were significantly higher in patients with schizophrenia (p < 0.05) than in the obsessive-compulsive disorder group or the control group. The obsessive-compulsive disorder group did not significantly differ from the control group in terms of neurological soft signs scores. No correlation was found between neurological soft signs scores and age at onset as well as that between neurological soft signs scores and total Yale-Brown Obsessive Compulsive Scale score. CONCLUSION: Neurological soft signs assessed by the Cambridge Neurological Inventory and Yale-Brown Obsessive Compulsive Scale, which discriminate patients with schizophrenia from controls, appear to be relatively specific to schizophrenia. Further studies are required to explore neurological soft signs in patients with obsessive-compulsive disorder. PMID- 26118746 TI - Association of Clozapine with Seizures: A Brief Report Involving 222 Patients Prescribed Clozapine. AB - OBJECTIVE: To study the prevalence and incidence of seizures in patients prescribed clozapine. METHODS: The treatment records of 222 patients commenced on clozapine were retrospectively reviewed during the period of January 2007 to June 2014 to evaluate the prevalence of seizures before and after starting clozapine. RESULTS: The majority of patients commenced on clozapine were male (65%), single (65%), and unemployed (57%). The mean (+/- standard deviation) dose of clozapine was 277.9 +/- 102.5 mg/day. A history of seizure was present in 6 patients who were also prescribed antiepileptic medication; of these 6 patients, only 1 case had recurrence of seizure while taking clozapine due to poor compliance with ongoing antiepileptic medication. The incidence rate of new-onset seizure with clozapine was 6% (12/216). Most patients who developed seizures were male, aged between 24 and 41 years, and had a long duration of illness (>= 10 years). The risk of seizure was associated with the dose of clozapine used: 3% (5/159) with dose up to 300 mg/day, 8% (4/49) with 325 to 500 mg/day, and 38% (3/8) in those receiving > 500 mg/day. More than half of the patients (7/12) who developed seizures while prescribed clozapine were managed with reduction in the dose of clozapine. In one-third of cases (4/12) an antiepileptic medication was added and in 1 case, clozapine was stopped. All patients who continued on clozapine remained seizure-free at follow-up that ranged from 6 months to 4 years. CONCLUSION: The incidence of seizures with clozapine was 6% and the risk of seizures increased with higher doses. PMID- 26118747 TI - Maternal Filicide among Women Admitted to Forensic Psychiatric Institutions in Malaysia: Case Series. AB - OBJECTIVES: To examine the characteristics of maternal filicide and describe the adverse life events experienced by women who have committed filicide and been hospitalised in forensic psychiatric institutions in Malaysia. METHODS: Registration records from 2000 through 2012 of female patients from 2 main forensic psychiatric institutions in Malaysia were reviewed. The medical records of patients who had committed maternal filicide were selected and descriptively evaluated. RESULTS: A total of 18 cases of maternal filicide were identified. Family dysfunction that presented with marital discord, domestic violence, or husband with substance abuse was the main stress experienced by the women. Three social circumstances, including an adolescent who became a victim of date rape; immigrants who experienced sexual abuse; and filicide-suicide precipitated by financial difficulties were highlighted. CONCLUSION: Women who committed filicide had experienced various difficulties in their life. The presence of such life events might alert mental health professionals to investigate the possibility of filicide among their patients. PMID- 26118748 TI - Interpersonal Psychotherapy for Postnatal Anxiety Disorder. AB - Interpersonal psychotherapy is one of two evidence-based formal psychotherapies for perinatal mood disorders. It is a time-limited, non-transference / cognitive based therapy that focuses on communication and social support and can be easily conducted in a perinatal clinic setting. There is limited patient access to interpersonal psychotherapy in Hong Kong because the therapy is not widely disseminated. This case report aimed to illustrate the principles and techniques of interpersonal psychotherapy in perinatal psychiatry, and to raise interest among mental health professionals in Hong Kong in this evidence-based treatment. PMID- 26118750 TI - Chronic low level arsenic exposure evokes inflammatory responses and DNA damage. AB - The cross-sectional study investigated the impact of chronic low level arsenic (As) exposure (11-50MUg/L) on CD14 expression and other inflammatory responses in rural women of West Bengal enrolled from control (As level <10MUg/L; N, 131) and exposed area (As level 11-50MUg/L, N, 142). Atomic absorption spectroscopy revealed that As level in groundwater was higher in endemic areas (22.93+/-10. 1 vs. 1.61+/-0.15, P<0.0001) and showed a positive correlation [Pearsons r, 0.9281; 95% confidence interval, 0.8192-0.9724] with As content in nails of the exposed women. Flow cytometric analysis showed that CD 14 expression on monocytes was significantly higher (P<0.001) in exposed women and positively correlated with groundwater As [Pearsons r, 0.9191; 95% confidence interval, 0.7584-0.9745]. Leucocytes and airway cells of As exposed women exhibited up regulation of an inflammatory mediator, tumor necrosis factor-alpha (TNF-alpha) and transcription factor, nuclear factor-kappaB (NF-kappaB) (P<0.0001). Plasma pro inflammatory cytokines like - TNF-alpha, interleukins (ILs) - IL-6, IL-8, IL-12 were elevated whereas anti-inflammatory cytokine IL-10 was depleted in the exposed women. Sputa of the exposed women had elevated activity of inflammatory markers - MMP-2 and MMP-9 whereas sera were observed with only increased activity of MMP-9. Airway cells of the exposed women had exacerbated DNA damage than control. Level of oxidative DNA adducts like 8-hydroxy-2'-deoxyguanosine (8OHdG) were also enhanced in plasma of exposed women. Therefore it might be indicated that low level As exposure elicited a pro-inflammatory profile which might have been contributed in part by CD14 expressing monocytes and prolong persistence of pulmonary and systemic inflammation might have promoted oxidative DNA damage in the rural women. PMID- 26118749 TI - Monocyte and macrophage plasticity in tissue repair and regeneration. AB - Heterogeneity and high versatility are the characteristic features of the cells of monocyte-macrophage lineage. The mononuclear phagocyte system, derived from the bone marrow progenitor cells, is primarily composed of monocytes, macrophages, and dendritic cells. In regenerative tissues, a central role of monocyte-derived macrophages and paracrine factors secreted by these cells is indisputable. Macrophages are highly plastic cells. On the basis of environmental cues and molecular mediators, these cells differentiate to proinflammatory type I macrophage (M1) or anti-inflammatory or proreparative type II macrophage (M2) phenotypes and transdifferentiate into other cell types. Given a central role in tissue repair and regeneration, the review focuses on the heterogeneity of monocytes and macrophages with current known mechanisms of differentiation and plasticity, including microenvironmental cues and molecular mediators, such as noncoding RNAs. PMID- 26118751 TI - Serum levels of nerve growth factor (NGF) in patients with major depression disorder and suicide risk. AB - Nerve growth factor (NGF) is an important member of the neurotrophins group and their involvement in the pathophysiology of major depression disorder (MDD) and suicide risk (SR) has been recently suggested. The aim of this study is to evaluate the changes in NGF serum levels in individuals with MDD and with or without risk of suicide, in subjects from a young population-based sample. This is a paired cross-sectional study nested in a population-based study. Individuals were rated for MDD and SR by a diagnostic interview--Mini International Neuropsychiatric Interview (M.I.N.I). The total population of the sample was comprised of 141 subjects distributed in three groups: 47 healthy controls, 47 subjects with current depressive episode without SR (MDD) and 47 subjects with current depressive episode and with SR (MDD + SR). NGF serum levels were significantly reduced in the MDD and MDD + SR groups when compared with controls (p <= 0.001). However, there were no differences in NGF levels between the MDD and MDD + SR groups (p = 1.000). These results suggest that reduced NGF serum levels can be a possible biomarker of MDD. PMID- 26118752 TI - Childhood abuse, family history and stressors in older patients with bipolar disorder in relation to age at onset. AB - OBJECTIVES: The aim of this study is to explore the family history of psychiatric disorders, childhood abuse, and stressors in older patients with Bipolar Disorder (BD) and the association of these variables with the age at onset of BD. METHODS: The Questionnaire for Bipolar Disorder (QBP) and the Mini International Neuropsychiatric Interview (MINI-Plus) were obtained from 78 patients aged 60 and over to determine diagnosis, age at onset of the first affective episode, childhood abuse, family history of psychiatric disorders and past and recent stressful life events. RESULTS: Increased family history of psychiatric disorders was the only factor associated with an earlier age at onset of BD. Less family history of psychiatric disorders and more negative stressors were significantly associated with a later age at onset of the first (hypo)manic episode. LIMITATIONS: Age at onset, history of childhood abuse, and past stressful life events were assessed retrospectively. Family members of BD patients were not interviewed. CONCLUSIONS: Our findings suggest that age at onset can define distinct BD phenotypes. More specifically there was a stronger heredity of BD and other psychiatric disorders in patients with an early age of onset of BD. Negative stressors may play a specific role in patients with a late age at onset of a first (hypo)manic episode. PMID- 26118753 TI - Validity of Beck Depression Inventory for the assessment of depressive mood in chronic heart failure patients. AB - Prevalence of depression is high in patients with chronic heart failure (CHF), and depressive mood is considered as a risk factor for major cardiovascular events and mortality in CHF patients. The validity of self-administered 21-item Beck Depression Inventory (BDI) in CHF patients might be questioned. CHF actually shares overlapping symptoms with depression and such an overlap may overestimate the impact of depression on cardiac outcomes. We tested the convergent validity of the French version of BDI by reference to the interview-based Montgomery Asberg Depression Rating Scale (MADRS) in a population of 73 patients participating in the multicenter French PANIC Cohort of 321 CHF patients. Both depression scores were associated with NYHA functional class and the number of previous hospitalizations related to CHF, but not with the other indexes of cardiac severity (left ventricular ejection fraction and 6-min-walk test). MADRS scores were also associated with gender and history of depression. A strong correlation was found between BDI and MADRS scores (rho = 0.72; p < 0.001). This correlation persisted after adjustment for gender, NYHA functional class, number of previous hospitalizations and history of depression (rho = 0.68; p < 0.001). Moreover, the z score difference between standardized BDI and standardized MADRS scores was associated with none of the sociodemographic or clinical characteristics of our population, except for the depression severity at MADRS. In particular, no overestimation or underestimation of self-assessed depression was found in case of more severe CHF. These findings suggest that the BDI is a reliable instrument to assess depression in CHF patients. PMID- 26118754 TI - The relationship between depression and generalized anxiety during intensive psychological and pharmacological treatment. AB - BACKGROUND: In the present study we examined the relationship between depressive symptoms and generalized anxiety symptoms during intensive cognitive-behavioral and pharmacological treatment. METHOD: Individuals (n = 157) with major depressive disorder (MDD; n = 83), generalized anxiety disorder (GAD; n = 29) and their combination (n = 45) who attended an intensive partial hospital treatment program, completed daily self-report measures of depression and generalized anxiety. Treatment included empirically-based cognitive-behavioral interventions in both individual and group format, as well as pharmacotherapy. RESULTS: Multilevel linear modeling indicated that for all diagnostic groups, changes in depressive symptoms led to changes in generalized anxiety symptoms to a greater extent than vice versa during treatment. Moreover, changes in depressive symptoms fully mediated changes in generalized anxiety symptoms, whereas changes in generalized anxiety symptoms only partially mediated the changes in depressive symptoms. LIMITATIONS: Partial hospital setting. CONCLUSIONS: Our results suggest that depressive symptoms may play a prominent role in the process of change in both MDD and GAD. This has implications for the classification of GAD as well as for choosing early treatment targets for individuals with comorbid MDD and GAD. PMID- 26118755 TI - Effectiveness of a stepped care intervention for anxiety and depression in people with diabetes, asthma or COPD in primary care: A randomized controlled trial. AB - BACKGROUND: Depression and anxiety are common in people with a chronic somatic disease. Although guidelines recommend stepped care, the effectiveness of this approach has not been evaluated in people with diabetes, asthma, or COPD in primary care. METHODS: 3559 People were sent screening questionnaires (41% response). Of 286 persons with anxiety and/or depression (Generalized Anxiety Disorder questionnaire, GAD-7, cut-off >= 8 and/or Patient Health Questionnaire, PHQ-9, cut-off >= 7), 46 were randomized into the intervention (stepped care and monitoring of symptoms; n = 23) or control (usual care) group (n = 23). Main outcomes were symptoms of anxiety and depression after the 12-months intervention and six months post intervention. Analysis of covariance was first adjusted for condition and baseline GAD-7/PHQ-9 scores and additionally for age, sex and education. RESULTS: The intervention group had a significantly lower level of anxiety symptoms at the end of the program (GAD-7 6 +/- 6 vs. 9 +/- 6; Cohen's d = 0.61). This effect was still present six months post intervention. The effect on depression was statistically significant in the first model (PHQ-9 6 +/- 4 vs. 9 +/- 6; p = 0.035), but not in the fully adjusted model (p = 0.099), despite a large effect size (d = 0.63). At six months post intervention there was no statistically significant difference in symptoms of depression between the two groups although the difference in symptoms was still clinically significant (Cohen's d = 0.61). LIMITATIONS: Many people were screened, but relatively few participated in the randomized controlled trial. CONCLUSIONS: Stepped care with monitoring resulted in a lower level of symptoms of anxiety and depression in people with a chronic condition. PMID- 26118756 TI - A two-layer structured PbI2 thin film for efficient planar perovskite solar cells. AB - In this paper, a two-layer structured PbI2 thin film was constructed by the spin coating procedure using a 0.80 M PbI2 solution in DMF and subsequent close-spaced vacuum thermal evaporation using PbI2 powder as a source. The bottom PbI2 thin film was compact with a sheet-like appearance, parallel to the FTO substrate, and can be easily converted to a compact perovskite thin film to suppress the charge recombination of the electrons of the TiO2 conduction band and the holes of the spiro-OMeTAD valence band. The top PbI2 thin film was porous with nano-sheet arrays, perpendicular to the FTO substrate, and can be easily converted to a porous perovskite thin film to improve the hole migration from the perovskite to spiro-OMeTAD and the charge separation at the perovskite/spiro-OMeTAD interface. The planar perovskite solar cells based on the two-layer structured PbI2 thin film exhibited a photoelectric conversion efficiency of 11.64%, along with an open-circuit voltage of 0.90 V, a short-circuit photocurrent density of 19.29 mA cm(-2) and a fill factor of 0.67. PMID- 26118757 TI - Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus. AB - The pathological hallmarks of Alzheimer's disease (AD) include amyloid beta (Abeta) accumulation, neurofibrillary tangle formation, synaptic dysfunction and neuronal loss. In this study, we investigated the neuroprotection of novel osmotin, a plant protein extracted from Nicotiana tabacum that has been considered to be a homolog of mammalian adiponectin. Here, we observed that treatment with osmotin (15 MUg/g, intraperitoneally, 4 hr) at 3 and 40 days post intracerebroventricular injection of Abeta1-42 significantly ameliorated Abeta1 42-induced memory impairment in mice. These results revealed that osmotin reverses Abeta1-42 injection-induced synaptic deficits, Abeta accumulation and BACE-1 expression. Treatment with osmotin also alleviated the Abeta1-42-induced hyperphosphorylation of the tau protein at serine 413 through the regulation of the aberrant phosphorylation of p-PI3K, p-Akt (serine 473) and p-GSK3beta (serine 9). Moreover, our western blots and immunohistochemical results indicated that osmotin prevented Abeta1-42-induced apoptosis and neurodegeneration in the Abeta1 42-treated mice. Furthermore, osmotin attenuated Abeta1-42-induced neurotoxicity in vitro.To our knowledge, this study is the first to investigate the neuroprotective effect of a novel osmotin against Abeta1-42-induced neurotoxicity. Our results demonstrated that this ubiquitous plant protein could potentially serve as a novel, promising, and accessible neuroprotective agent against progressive neurodegenerative diseases such as AD. PMID- 26118758 TI - Medulloepithelioma with peculiar clinical presentation, stem cell phenotype and aberrant DNA-methylation profile. AB - We present a 21-year-old male with a neck mass diagnosed as medulloepithelioma. Despite aggressive chemo- and radio-therapy, the tumor metastasized and proved fatal after seventeen months. The tumor demonstrated robust immunohistochemical expression of multiple markers of embryonic/neural stem cells and embryogenesis from the paraffin embedded tissue. The tumor, expressing LIN28A but negative for the 19q13.42 amplicon, also lacked the characteristic methylation profile for medulloepithelioma and other tumors with similar morphology. The expression of embryonic markers may explain its unresponsiveness to therapy and poor prognosis. Therapies targeted at embryonic cell phenotypes may hold the key for successfully treating cancers with embryonal phenotypes or tumors harboring cells with embryonal phenotypes. PMID- 26118759 TI - Tongue Protrusion Strength in Arousal State Is Predictive of the Airway Patency in Obstructive Sleep Apnea. AB - Contraction of the genioglossus affects either tongue protrusion strength or dilating forces of the upper airway. The upper airway in patients with obstructive sleep apnea (OSA) is thought to collapse during sleep, at least in part because of a sleep related reduction in genioglossus muscle activity. Thus, although tongue protrusion strength by genioglossus activity during sleep contributes to the maintenance of airway patency in patients with OSA, the relationship between tongue protrusion strength in the arousal state and obstructive sleep apnea has not been fully elucidated. Conventional method of tongue protrusion strength cannot be used to evaluate in edentulous subjects and/or subjects with the decreased biting force. In this study, employing a novel measurement method that does not require biting a transducer, we investigated relationships between the tongue protrusion strength and polysomnographic findings. We enrolled twenty normal subjects and 26 subjects with OSA. All subjects completed the measurement of tongue protrusion strength. Each subject with OSA was evaluated by full polysomnography. The degree of tongue protrusion strength was assessed by maximum voluntary contraction against the tongue depressor connected with a strain gauge dynamometer. The tongue protrusion strength was negatively correlated with obstructive apnea time, apnea index (AI) and the percent of sleep stage 2 (r = -0.61, p < 0.0001, r = -0.41 p = 0.03 and r = -0.39 p = 0.04, respectively). Tongue protrusion strength measured in the arousal state is predictive of the airway patency during sleep in OSA. PMID- 26118760 TI - Cinnamaldehyde in a Novel Intravenous Submicrometer Emulsion: Pharmacokinetics, Tissue Distribution, Antitumor Efficacy, and Toxicity. AB - The purpose of our research is to find a new lipid emulsion to deliver a low water-soluble compound, cinnamaldehyde (CA). Its characteristics, pharmacokinetics, antitumor efficacy, and toxicity were evaluated. The mean particle size, zeta potential, and encapsulation efficiency of the submicromemter emulsion of CA (SME-CA) were 130 +/- 5.92 nm, -25.7 +/- 6.00 mV, and 99.5 +/- 0.25%, respectively. The area under the curve from 0 h to termination time (AUC(0 t)) of SME-CA showed a significantly higher value than that of CA (589 +/- 59.2 vs 375 +/- 83.5 ng h/L, P < 0.01). Tissue distribution study showed various changes; among them, a 27% higher concentration was found in brain tissue when using SME-CA at 15 min after administration. For the efficacy evaluation, SME-CA exhibited 8- and 11-fold antitumor activity in the depression of HeLa and A549 cell lines with the IC50 decreasing to 0.003 and 0.001 mmol/L, respectively. The LD50 values of CA and SME-CA in mice were 74.8 and 125 mg/kg, suggesting increased safety from the new formulation. The new formulation exhibited lower toxicity, higher antitumor activity, and a more satisfactory pharmacokinetic property, which displayed great potential for future pharmacological application. PMID- 26118761 TI - Four- and Sixfold Tandem-Domino Reactions Leading to Dimeric Tetrasubstituted Alkenes Suitable as Molecular Switches. AB - A highly efficient palladium-catalyzed fourfold tandem-domino reaction consisting of two carbopalladation and two C-H-activation steps was developed for the synthesis of two types of tetrasubstituted alkenes 3 and 6 with intrinsic helical chirality starting from substrates 1 and 4, respectively. A sixfold tandem-domino reaction was also developed by including a Sonogashira reaction. 20 compounds with different substitution patterns were prepared with yields of up to 97 %. Structure elucidation by X-ray crystallography confirmed helical chirality of the two alkene moieties. Photophysical investigations of some of the compounds showed pronounced switching properties through light-controlled changes of their stereochemical configuration. PMID- 26118762 TI - Extranodal hematopoietic neoplasms and mimics in the head and neck: an update. AB - The head and neck region is a common site for extranodal lymphomas, second only to the gastrointestinal tract; and 12% to 15% of all head and neck tumors are lymphomas. Non-Hodgkin lymphomas are most common, and Hodgkin lymphoma occurs rarely at extranodal sites in the head and neck. Most non-Hodgkin lymphomas of the head and neck region are of B-cell lineage, and the Waldeyer ring is the most common site. Head and neck lymphomas have distinctive epidemiological and clinicopathologic features, including an association with immunosuppression, infectious organisms, or autoimmune disorders; site-specific differences (eg, thyroid gland versus ocular adnexa) for common lymphomas, such as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; and genetic differences that provide insights into etiology. Furthermore, the diagnosis of non-Hodgkin lymphomas at extranodal sites implies differences in prognosis and therapeutic implications with lymphomas at nodal sites. In this review, we discuss various types of non-Hodgkin lymphomas and Hodgkin lymphoma, focusing on unique aspects related to the head and neck region. We also discuss a number of newer entities that are clinically indolent as well as mimics of lymphoma that can occur in the head and neck region, including infectious mononucleosis, Kikuchi-Fujimoto disease, Kimura disease, Castleman disease, and immunoglobulin G4-related disease. PMID- 26118763 TI - Manganese toxicity to tropical freshwater species in low hardness water. AB - Elevated manganese (Mn) is a common contaminant issue for mine water discharges, and previous studies have reported that its toxicity is ameliorated by H(+), Ca(2+), and Mg(2+) ions. In the present study, the toxicity of Mn was assessed in a high risk scenario, that is, the slightly acidic, soft waters of Magela Creek, Kakadu National Park, Northern Territory, Australia. Toxicity estimates were derived for 6 tropical freshwater species (Chlorella sp., Lemna aequinoctialis, Amerianna cumingi, Moinodaphnia macleayi, Hydra viridissima, and Mogurnda mogurnda). Low effect chronic inhibition concentration (IC10) and acute lethal concentration (LC05) values ranged between 140 MUg L(-1) and 80,000 MUg L(-1), with 3 of the species tested (M. macleayi, A. cumingi, and H. viridissima) being more sensitive to Mn than all but 1 species in the international literature (Hyalella azteca). A loss of Mn was observed on the final day for 2 of the H. viridissima toxicity tests, which may be a result of the complex speciation of Mn and biological oxidation. International data from toxicity tests conducted in natural water with a similar physicochemistry to Magela Creek water were combined with the present study's data to increase the sample size to produce a more reliable species sensitivity distribution. A 99% protection guideline value of 73 MUg L(-1) (33-466 MUg L(-1)) was derived; the low value of this guideline value reflects the higher toxicity of Mn in slightly acidic soft waters. PMID- 26118767 TI - A case-control study of risk factors for death from 2009 pandemic influenza A(H1N1): is American Indian racial status an independent risk factor? AB - Historically, American Indian/Alaska Native (AI/AN) populations have suffered excess morbidity and mortality from influenza. We investigated the risk factors for death from 2009 pandemic influenza A(H1N1) in persons residing in five states with substantial AI/AN populations. We conducted a case-control investigation using pandemic influenza fatalities from 2009 in Alaska, Arizona, New Mexico, Oklahoma and Wyoming. Controls were outpatients with influenza. We reviewed medical records and interviewed case proxies and controls. We used multiple imputation to predict missing data and multivariable conditional logistic regression to determine risk factors. We included 145 fatal cases and 236 controls; 22% of cases were AI/AN. Risk factors (P 45 years vs. <18 years], pre existing medical conditions (mOR 7.1), smoking (mOR 3.0), delayed receipt of antivirals (mOR 6.5), and barriers to healthcare access (mOR 5.3). AI/AN race was not significantly associated with death. The increased influenza mortality in AI/AN individuals was due to factors other than racial status. Prevention of influenza deaths should focus on modifiable factors (smoking, early antiviral use, access to care) and identifying high-risk persons for immunization and prompt medical attention. PMID- 26118769 TI - Immunomodulatory Effects of Soybeans and Processed Soy Food Compounds. AB - Inflammation is an immune response against both internal and external antigens in organisms, particularly in mammals, and includes both uncontrolled chronic and low-grade inflammations. Uncontrolled chronic inflammation often leads to severe diseases such as vascular disease, arthritis, cancer, diabete, allergy, and autoimmunity. On the other hand, low-grade inflammation is recognized as a relationship between obesity and risk of metabolic syndrome. Elevated production of pro-inflammatory cytokines and mediators is commonly observed in patients with uncontrolled or low-grade inflammation-associated diseases. Plants have been generated phytochemicals to overcome inflammations and infections through evolution. Phytochemicals belong to alkaloids, polyphenols, flavonoids, coumarins, and terpenoids. The consumption of soybeans plays a role in immune modulation through their components such as isoflavones, saponins, and anthocyanins. Recently, it was reported that the application of phytochemicals into patients with inflammatory diseases improves their symptoms. Therefore, it is important to identify novel phytochemicals with immunomodulatory activities. This review introduces and discusses recent advances and patents regarding soybean or processed soy food compounds which exhibit immunomodulatory activity in immune diseases, particularly allergy, by mediating the suppression of inflammatory pathways. PMID- 26118768 TI - Estimating minimally important difference (MID) in PROMIS pediatric measures using the scale-judgment method. AB - OBJECTIVE: To assess minimally important differences (MIDs) for several pediatric self-report item banks from the National Institutes of Health Patient-Reported Outcomes Measurement Information System((r)) (PROMIS((r))). METHODS: We presented vignettes comprising sets of two completed PROMIS questionnaires and asked judges to declare whether the individual completing those questionnaires had an important change or not. We enrolled judges (including adolescents, parents, and clinicians) who responded to 24 vignettes (six for each domain of depression, pain interference, fatigue, and mobility). We used item response theory to model responses to the vignettes across different judges and estimated MID as the point at which 50 % of the judges would declare an important change. RESULTS: We enrolled 246 judges (78 adolescents, 85 parents, and 83 clinicians). The MID estimated with clinician data was about 2 points on the PROMIS T-score scale, and the MID estimated with adolescent and parent data was about 3 points on that same scale. CONCLUSIONS: The MIDs enhance the value of PROMIS pediatric measures in clinical research studies to identify meaningful changes in health status over time. PMID- 26118770 TI - Soybean and Processed Soy Foods Ingredients, and Their Role in Cardiometabolic Risk Prevention. AB - Soybeans contain various components with potential health benefits effects, but the impact of soy foods and processed soy foods on human health has gone progressively characterized. Soy foods are the traditional Asian diets; however because of their intended health benefits they have gone popular in Westerners, especially postmenopausal women. There are lots of biologically active soybean constituents that might lead to the possible health benefits of soy, and almost consideration has concentrated on the isoflavones, which have both hormonal and nonhormonal activities. The various other constituents of soybeans (saponins, soy protein or peptides, lecithin, and flavonoids) have differing biological activities. These include hormonal, immunological, bacteriological and digestive effects. This review is the broad assessment of the literature comprehensive the health effects of soy constituents that are of superlative interest. The health benefits of soy foods on four diseases-cardiovascular disease (CVD), non alcoholic fatty liver disease (NAFLD), obesity and diabetes-are the focus of the review. PMID- 26118771 TI - Heterogeneity of Notch signaling in astrocytes and the effects of GFAP and vimentin deficiency. AB - Astrocytes have multiple roles in the CNS including control of adult neurogenesis. We recently showed that astrocyte inhibition of neurogenesis through Notch signaling depends on the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Here, we used real-time quantitative PCR to analyze gene expression in individual mouse astrocytes in primary cultures and in GFAP(POS) or Aldh1L1(POS) astrocytes freshly isolated from uninjured, contralesional and lesioned hippocampus 4 days after entorhinal cortex lesion. To determine the Notch signaling competence of individual astrocytes, we measured the mRNA levels of Notch ligands and Notch1 receptor. We found that whereas most cultured and freshly isolated astrocytes were competent to receive Notch signals, only a minority of astrocytes were competent to send Notch signals. Injury increased the fraction of astrocyte subpopulation unable to send and receive Notch signals, thus resembling primary astrocytes in vitro. Astrocytes deficient of GFAP and vimentin showed decreased Notch signal sending competence and altered expression of Notch signaling pathway-related genes Dlk2, Notch1, and Sox2. Furthermore, we identified astrocyte subpopulations based on their mRNA and protein expression of nestin and HB-EGF. This study improves our understanding of astrocyte heterogeneity, and points to astrocyte cytoplasmic intermediate filaments as targets for neural cell replacement strategies. PMID- 26118772 TI - The Mo-Mo Quintuple Bond as a Ligand to Stabilize Transition-Metal Complexes. AB - Herein, we report the employment of the Mo-Mo quintuple bonded amidinate complex to stabilize Group 10 metal fragments {(Et3P)2M} (M=Pd, Pt) and give rise to the isolation of the unprecedented delta complexes. X-ray analysis unambiguously revealed short contacts between Pd or Pt and two Mo atoms and a slight elongation of the Mo-Mo quintuple bond in these two compounds. Computational studies show donation of the Mo-Mo quintuple-bond delta electrons to an empty sigma orbital on Pd or Pt, and back-donation from a filled Pd or Pt dpi orbital into the Mo-Mo delta* level (LUMO), consistent with the Dewar-Chatt-Duncanson model. PMID- 26118773 TI - Cell-permeable mitochondrial ubiquinol-cytochrome c reductase binding protein induces angiogenesis in vitro and in vivo. AB - Ubiquinol-cytochrome c reductase binding protein (UQCRB), a component of the mitochondrial complex III, has been recently implicated in angiogenesis. Targeting mitochondria to balance vascular homeostasis has been widely recognized. However, the effect of UQCRB replenishment by direct delivery remains unknown. To explore the biological function of UQCRB in angiogenesis, a novel protein transduction domain (PTD)-conjugated UQCRB fusion protein was generated. PTD-UQCRB localized to mitochondria as does endogenous UQCRB. Treatment with PTD UQCRB generated mitochondrial reactive oxygen species (mROS) without cytotoxicity, following hypoxia inducible factor-1alpha (HIF-1alpha) stabilization and downstream vascular endothelial growth factor (VEGF) expression. Accordingly, PTD-UQCRB induced angiogenesis in vitro and PTD-UQCRB pro-angiogenic activity was further validated in matrigel plug assay and in cutaneous wound-healing mouse models in vivo. Together, these results demonstrate that UQCRB plays a role in angiogenesis and the developed cell-permeable PTD UQCRB can be utilized as a pro-angiogenic agent. PMID- 26118774 TI - Survivin in survival of hepatocellular carcinoma. AB - Survivin is an anti-apoptotic protein belonging to the inhibitor of apoptosis protein (IAP) family. It is involved in the regulation of important physiological and pathological processes in cells and functions to inhibit cell apoptosis and promote cell proliferation. Normally and terminally differentiated tissues are nearly negative for survivin. In contrast, survivin is highly expressed in most human tumor tissues, including hepatocellular carcinoma (HCC). The abnormal overexpression of survivin is closely related to the malignant biological behaviors of tumors. During the development and progression of HCC, the high level of survivin expression promotes cancer cell proliferation, inhibits cancer cell apoptosis, induces tumor stromal angiogenesis, reduces the sensitivity of cancer cells to radiotherapy and chemotherapy, and ultimately affects the prognosis of patients with HCC. Survivin expression is regulated by a large number of factors. The latest discovery indicated that the transcription factor octamer-binding transcription factor 4 (OCT4) enhances the expression of survivin though cyclin D1 (CCND1), which, in part, accounts for tumor cell proliferation, recurrence and metastasis. Survivin plays key roles in HCC, which renders it an ideal target for the treatment of HCC. The present article reviews the research progress on the relationship between survivin and HCC and on the HCC treatment strategies targeting survivin. PMID- 26118776 TI - Icariside II-induced mitochondrion and lysosome mediated apoptosis is counterbalanced by an autophagic salvage response in hepatoblastoma. AB - In this study, the anti-cancer effect of Icariside II (IS), a natural plant flavonoid, against hepatoblastoma cells and the underlying mechanisms were investigated. The in vitro and in vivo studies show that IS decreased the viability of human hepatoblastoma HepG2 cells in a concentration- and time dependent manner and inhibited tumor growth in mice transplanted with H22 liver carcinomas. IS impaired mitochondria and lysosomes as evidenced by signs of induced mitochondrial and lysosomal membrane permeabilization, resulting in caspase activation and apoptosis. SQSTM1 up-regulation and autophagic flux measurements demonstrated that IS exposure also impaired autophagosome degradation which resulted in autophagosome accumulation, which plays a pro survival role as the genetic knockdown of LC3B further sensitized the IS-treated cells. Electron microscopy images showed that autophagosome engulfs IS-impaired mitochondria and lysosomes, thus blocking cytotoxicity induced by further leakage of the hydrolases from lysosomes and pro-apoptosis members from mitochondria. In conclusion, these data suggest that IS plays multiple roles as a promising chemotherapeutic agent that induces cell apoptosis involving both mitochondrial and lysosomal damage. PMID- 26118775 TI - AML sensitivity to YM155 is modulated through AKT and Mcl-1. AB - HL60 and U937 (acute myeloid leukemia (AML) cell lines) were assessed for sensitivity to YM155, and found to have distinct sensitive and resistant phenotypes, respectively. In HL60 cells, YM155 inhibition of growth proliferation was due to apoptosis which was measured by annexin V/PI staining. YM155 induced apoptosis through activation of intrinsic and extrinsic pathways that also culminated in caspase-3 activity and PARP cleavage. YM155 sensitivity was partially associated with this compound's ability to down-regulate survivin transcription since this was more pronounced in the HL60 cell line. However, marked differences were also observed in XIAP, Bcl-2, and Mcl-1L, and Mcl-1s. Furthermore, YM155 treatment completely inhibited production of total Akt protein in HL60, but not U937 cells. Importantly, Akt activity (pAkt-Ser473) levels were maintained in YM155 treated U937 cells which may help stabilize other anti apoptotic proteins. Combination treatments with an Akt inhibitor, MK-2206, reduced levels of pAkt-Ser473 in U937 cells and synergistically sensitized them to YM155 cytotoxicity. Collectively our results indicate that Akt signaling may be an important factor mediating YM155 response in AML, and combinatorial therapies with Akt inhibitors could improve treatment efficacy in YM155-resistant cells. PMID- 26118777 TI - Promyelocytic leukemia protein induces arsenic trioxide resistance through regulation of aldehyde dehydrogenase 3 family member A1 in hepatocellular carcinoma. AB - Clinical response of hepatocellular carcinoma (HCC) to arsenic trioxide (ATO) has been poor. Promyelocytic leukemia protein (PML) is central to ATO treatment efficacy of acute promyelocytic leukemia. We examine impacts of PML expression on the effectiveness of ATO treatment in HCC. We show that increased PML expression predicts longer survival and lower cancer recurrence rates after HCC resection. However, high PML expression dampens the anti-tumor effects of ATO in HCC cells. Gene microarray analysis shows that reduced PML expression significantly down regulates expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1). ALDH3A1 depression facilitates accumulation of ATO-induced reactive oxygen species. Chromatin immunoprecipitation analysis and promoter activity assays confirm that PML regulates ALDH3A1 expression through binding to the promoter region of ALDH3A1. Clinically, ATO treatment decreases the disease progression rate in advanced HCC patients with negative PML expression. In conclusion, PML confers a favorable prognosis in HCC patients, but it induces ATO resistance through ALDH3A1 up-regulation in HCC cells. ATO is effective for HCC patients with negative PML expression. Combined with an ALDH3A1 inhibitor, ATO may be efficacious in patients with positive PML expression. PMID- 26118778 TI - The last fossil primate in North America, new material of the enigmatic Ekgmowechashala from the Arikareean of Oregon. AB - OBJECTIVE: Primates were common in North America through most of the Eocene, but vanished in the Chadronian, about 35 million years ago. In the Arikareean, about 6 million years later, the enigmatic primate Ekgmowechashala appeared in the Great Plains and Oregon. This taxon shows little resemblance to other North American primates and its phylogenetic position has long been debated. New material of this taxon allows a revised assessment of its age and how it is related to other primates. METHODS: Recently collected Ekgmowechashala specimens from the Turtle Cove Member of the John Day Formation in Oregon are described. These specimens are compared to previously collected material from South Dakota and Nebraska, as well as other fossil primates from North America and Asia. RESULTS: Study of the John Day material allows diagnosis of a new, distinct species. Comparison of Ekgmowechashala to a pair of recently described Asian primates, Muangthanhinius and Bugtilemur, suggests that it is a strepsirrhine adapiform, rather than an omomyid. The well-defined stratigraphy and dated marker beds of the Turtle Cove Member provide a refined age for Ekgmowechashala occurrences in Oregon, during the Oligocene (early Arikareean). CONCLUSIONS: The age and morphology of these ekgmowechashaline taxa suggest that the group originated in Asia and dispersed to North America in the Oligocene, after the extinction of other primates in North America. Contemporaneous occurrences of Ekgmowechashala in Oregon and the Great Plains indicate the last non-human primates vanished in North America about 26 million years ago. PMID- 26118779 TI - [Drainage of amoebic liver abscess by single incision laparoscopic surgery. Report of a case]. AB - BACKGROUND: Single incision laparoscopic surgery has increased recently due to successful results, achieved in several procedures. The aim of the present work is to present the first case in which single incision laparoscopy is used for the drainage of an amoebic liver abscess. CLINICAL CASE: A 44-year-old man presented with intense right upper quadrant pain, generalised jaundice, tachycardia, fever, hepatomegaly and a positive Murphy's sign. Laboratory results revealed an increased plasma bilirubin, elevated alkaline phosphatase and transaminases, leucocytosis, negative viral panel for hepatitis, and positive antibodies against Entamoeba histolytica. On an abdominal computed tomography a 15 * 12.1 cm hypodense lesion was observed in the patient's liver, identified as an amoebic liver abscess. Analgesics and antibiotics were started and subsequently the patient was submitted to laparoscopic drainage of the abscess using a single port approach. Drainage and irrigation of the abscess was performed. Four days later the patient was discharged without complications. CONCLUSION: Management of amoebic liver abscess is focused on the elimination of the infectious agent and obliteration of the abscess cavity in order to prevent its complications, especially rupture. Laparoscopic surgery has proved to be a safe and effective way to manage this entity. PMID- 26118780 TI - [Bilateral brachial plexus block. Case report and systematic review]. AB - BACKGROUND: The bilateral brachial plexus block is considered a contraindication, due to the possible development of complications, such as: toxicity from local anaesthetics or bilateral diaphragmatic paralysis. However, with the real time visualisation provided by the ultrasound scan, these complications have decreased and it is a safer procedure. CLINICAL CASES: Four cases are presented where the bilateral block was performed using guided ultrasound, as the patients were unable to receive general anaesthesia due to a history of adverse effects or the use of opioids in the post-operative or by the prediction of a difficult airway associated with obesity. A systematic review of the literature from January 1993 to June 2013, was also performed by using a search in the MEDLINE, EMBASE, ARTEMISA, LILACS, Google data bases, in Spanish and English language with the following words: bilateral brachial plexus block, bilateral interscalene block, bilateral infraclavicular block, bilateral supraclavicular block, bilateral lateral supraclavicular block, bilateral axillary block, ultrasound-guided bilateral brachial plexus block. CONCLUSION: Based on the evidence found, ultrasound-guided bilateral brachial plexus block in selected patients and expert hands, is no longer a contraindication. PMID- 26118781 TI - [Nesidioblastosis in the adult: a case report]. AB - BACKGROUND: Nesidioblastosis is a rare cause of endocrine disease which represents between 0.5% - 5% of cases. This has been associated with other conditions, such as in patients previously treated with insulin or sulfonylurea, in anti-tumour activity in pancreatic tissue of patients with insulinoma, and in patients with other tumours of the Langerhans islet cells. In adults it is presented as a diffuse dysfunction of beta cells of unknown cause. CLINICAL CASE: The case concerns 46 year-old female, with a history of Sheehan syndrome of fifteen years of onset, and with repeated events characterized with hypoglycaemia in the last three years. Body scan was performed with octreotide, revealing an insulinoma in the pancreatic region. A distal pancreatectomy was performed on the patient. The study reported a pancreatic fragment 8.5 * 3 * 1.5 cm with abnormal proliferation of pancreatic islets in groups of varying size, some of them in relation to the ductal epithelium. Histopathology study was showed positive for chromogranin, confirmed by positive synaptophysin, insulin and glucagon, revealing islet hyperplasia with diffuse nesidioblastosis with negative malignancy. The patient is currently under metabolic control and with no remission of hypoglycaemic events. CONCLUSIONS: Nesidioblastosis is a disease of difficult diagnosis should be considered in all cases of failure to locate an insulinoma, as this may be presented in up to 4% of persistent hyperinsulinaemic hypoglycaemia. PMID- 26118782 TI - [Intraoral paratrichosis after autograft]. AB - BACKGROUND: Radial graft is one of the optimal treatments for reconstruction after tongue cancer, but it is not free of side effects. Hypertrichosis over the graft, causing an intraoral paratrichosis, might downgrade the quality of life and even require further interventions. CLINICAL CASE: The case is presented of a 58 year-old man, who developed hypertrichosis after surgery for tongue carcinoma. DISCUSSION: The therapeutic options, from choosing a graft from less hairy areas to laser depilation or de-epithelisation of the graft are discussed. CONCLUSIONS: Intraoral paratrichosis is a serious complication that can produce dysphagia, nauseas, and vomiting, and can evolve into mal nutrition and produce an important decrease in life quality of our patients. PMID- 26118783 TI - [Rib cage ostheosynthesis. Literature review and case reports]. AB - BACKGROUND: Fractures of the chest wall include sternum and rib fractures. Traditionally they are managed conservatively due to the anatomy of the rib cage that allows most of them to remain stable and to form a callus that unites the fractured segments. In spite of this management, some patients present with chronic pain or instability of the wall which makes them require some type of fixation. The present article performs a literature review based on 4 cases. CLINICAL CASES: The first case was a 61 year-old man with blunt chest trauma, with a great deformity of the chest wall associated with subcutaneous emphysema, and pneumothorax. The second case was a 51 year-old man with blunt chest trauma, initially managed at another institution, who despite treatment, had persistent pain and dyspnoea. The third case was a 30 year-old man that suffered a motor vehicle accident, with resulting pain and crepitation of the rib cage and with diagnostic images showing multiple rib fractures. The last case is a 62 year-old man that fell down the stairs, with blunt chest trauma with high intensity pain, dyspnoea and basal ipsilateral hypoventilation. CONCLUSION: Rib fracture fixation offers a good alternative in selected patients to decrease associated morbidity, leading to a patient's fast return to his or her working life. PMID- 26118784 TI - Flavobacterium maris sp. nov. isolated from shallow sediments of the Sea of Japan. AB - An aerobic, gram-negative, yellow-pigmented, and non-motile bacterium designated KMM 9535(T) was isolated from a marine sediment sample obtained from the Sea of Japan seashore and subjected to a phylogenetic and phenotypic study. On the basis of 16S rRNA gene sequence analysis, strain KMM 9535(T) was placed to the genus Flavobacterium sharing the highest sequence similarities to Flavobacterium ahnfeltiae KCTC 32467(T) (99.3%), Flavobacterium jumunjinense KCTC 23618(T) (96.5%), Flavobacterium ponti KCTC 22802(T) (96.3%), Flavobacterium urocaniciphilum JCM 19142(T) (96.1%), and Flavobacterium gelidilacus LMG 21477(T) (95.8%). The DNA-DNA hybridization value between strain KMM 9535(T) and the closest related F. ahnfeltiae KCTC 32467(T) was 33%. Strain KMM 9535(T) grew at 5 36 degrees C and in the presence of 0-3% (w/v) NaCl. It contained MK-6 as the predominant menaquinone, and the major fatty acids were iso-C15:0, iso-C17:1, iso C15:1, and iso-C17:0 3-OH. The DNA G+C content was 28.8 mol%. On the basis of the results obtained, it is proposed strain KMM 9535(T) to be classified as a novel species of the genus Flavobacterium, Flavobacterium maris sp. nov., with the type strain of the species KMM 9535(T) (=NRIC 0920(T) = KCTC 42093(T)). PMID- 26118785 TI - Consumption of polyunsaturated fat improves the saturated fatty acid-mediated impairment of HDL antioxidant potential. AB - SCOPE: The present study aimed to compare the effects of diets containing high fat, high-cholesterol and saturated fatty acids (HFHC-SFA) and HFHC polyunsaturated fatty acids-containing (HFHC-PUFA) diets on two major antiatherogenic functions of HDL, the HDL antioxidant function and the macrophage to-feces reverse cholesterol transport. METHODS AND RESULTS: Experiments were carried out in mice fed a low-fat, low-cholesterol (LFLC) diet, an HFHC-SFA diet or an HFHC-PUFA diet in which SFAs were partly replaced with an alternative high linoleic and alpha-linolenic fat source. The HFHC-SFA caused a significant increase in serum HDL cholesterol and phospholipids as well as elevated levels of oxidized HDL and oxidized LDL. Replacing SFA with PUFA significantly reduced the levels of these oxidized lipoproteins and enhanced the ability of HDL to protect LDL from oxidation. The SFA-mediated impairment of HDL antioxidant potential was not associated with the cholesterol content of the diet, obesity or insulin resistance. In contrast, the effect of the HFHC diets on fecal macrophage-derived cholesterol excretion was independent of the fatty acid source. CONCLUSION: SFA intake impairs the antioxidant potential of HDL and increases serum levels of oxidized lipoprotein species whereas the antioxidant potential of HDL is enhanced after PUFA consumption. PMID- 26118786 TI - Grading Osteoarthritic Changes of the Zygapophyseal Joints from Radiographs: A Reliability Study. AB - OBJECTIVE: This study tested the reliability of a 5-point ordinal scale used to grade the severity of degenerative changes of zygapophyseal (Z) joints on standard radiographs. METHODS: Modifications were made to a Kellgren grading system to improve agreement for grading the severity of osteoarthritic changes in lumbar Z joints. These included adding 1 grade of no degeneration, multiple radiographic views, and structured examiner training. Thirty packets of radiographic files were obtained, which included representation of all 5 grades including no degeneration (0) and Kellgren's 4-point (1-4) joint degeneration classification criteria. Radiographs were digitized to create a radiographic atlas that was given to examiners for individual study and blinded evaluation sessions. Intrarater and interrater agreement was determined by weighted kappa (kappaw) from the examination of 79 Z joints (25 packets). RESULTS: Using the modified scale and after training, examiners demonstrated a moderate-to substantial level of interrater agreement (kappaw = 0.57, 0.60, and 0.68). Intrarater agreement was moderate (kappaw = 0.42 and 0.54). CONCLUSIONS: The modified Kellgren 5-point grading system provides acceptable intrarater and interrater reliability when examiners are adequately trained. This grading system may be a useful method for future investigations assessing radiographic osteoarthritis of the Z joints. PMID- 26118787 TI - Direct Evidence for a [4+2] Cycloaddition Mechanism of Alkynes to Tantallacyclopentadiene on Dinuclear Tantalum Complexes as a Model of Alkyne Cyclotrimerization. AB - A dinuclear tantalum complex, [Ta2 Cl6 (MU-C4 Et4)] (2), bearing a tantallacyclopentadiene moiety, was synthesized by treating [(eta(2) EtC=CEt)TaCl3 (DME)] (1) with AlCl3 . Complex 2 and its Lewis base adducts, [Ta2 Cl6 (MU-C4 Et4 )L] (L=THF (3 a), pyridine (3 b), THT (3 c)), served as more active catalysts for cyclotrimerization of internal alkynes than 1. During the reaction of 3 a with 3-hexyne, we isolated [Ta2 Cl4 (MU-eta(4):eta(4)-C6 Et6)(MU eta(2):eta(2)-EtC=CEt)] (4), sandwiched by a two-electron reduced MU eta(4):eta(4) -hexaethylbenzene and a MU-eta(2):eta(2)-3-hexyne ligand, as a product of an intermolecular cyclization between the metallacyclopentadiene moiety and 3-hexyne. The formation of arene complexes [Ta2 Cl4 (MU-eta(4):eta(4) C6 Et4 Me2)(MU-eta(2):eta(2)-Me3 SiC=CSiMe3)] (7 b) and [Ta2 Cl4 (MU eta(4):eta(4)-C6 Et4 RH)(MU-eta(2):eta(2)-Me3 SiC=CSiMe3)] (R=nBu (8 a), p-tolyl (8 b)) by treating [Ta2 Cl4 (MU-C4 Et4)(MU-eta(2):eta(2) -Me3 SiC=CSiMe3)] (6) with 2-butyne, 1-hexyne, and p-tolylacetylene without any isomers, at room temperature or low temperature were key for clarifying the [4+2] cycloaddition mechanism because of the restricted rotation behavior of the two-electron reduced arene ligands without dissociation from the dinuclear tantalum center. PMID- 26118788 TI - Botulinum toxin type A for Holmes tremor secondary to thalamic hemorrhage. PMID- 26118789 TI - Oxygen reduction reaction activity and structural stability of Pt-Au nanoparticles prepared by arc-plasma deposition. AB - The oxygen reduction reaction (ORR) activity and durability of various Au(x)/Pt100 nanoparticles (where x is the atomic ratio of Au against Pt) are evaluated herein. The samples were fabricated on a highly-oriented pyrolytic graphite substrate at 773 K through sequential arc-plasma depositions of Pt and Au. The electrochemical hydrogen adsorption charges (electrochemical surface area), particularly the characteristic currents caused by the corner and edge sites of the Pt nanoparticles, decrease with increasing Au atomic ratio (x). In contrast, the specific ORR activities of the Au(x)/Pt100 samples were dependent on the atomic ratios of Pt and Au: the Au28/Pt100 sample showed the highest specific activity among all the investigated samples (x = 0-42). As for ORR durability evaluated by applying potential cycles between 0.6 and 1.0 V in oxygen saturated 0.1 M HClO4, Au28/Pt100 was the most durable sample against the electrochemical potential cycles. The results clearly showed that the Au atoms located at coordinatively-unsaturated sites, e.g. at the corners or edges of the Pt nanoparticles, can improve the ORR durability by suppressing unsaturated-site induced degradation of the Pt nanoparticles. PMID- 26118790 TI - Structure Elucidation and Activity of Kolossin A, the D-/L-Pentadecapeptide Product of a Giant Nonribosomal Peptide Synthetase. AB - The largest continuous bacterial nonribosomal peptide synthetase discovered so far is described. It consists of 15 consecutive modules arising from an uninterrupted, fully functional gene in the entomopathogenic bacterium Photorhabdus luminescens. The identification of its cryptic biosynthesis product was achieved by using a combination of genome analysis, promoter exchange, isotopic labeling experiments, and total synthesis of a focused collection of peptide candidates. Although it belongs to the growing class of D-/ L-peptide natural products, the encoded metabolite kolossin A was found to be largely devoid of antibiotic activity and is likely involved in interspecies communication. A stereoisomer of this peculiar natural product displayed high activity against Trypanosoma brucei rhodesiense, a recalcitrant parasite that causes the deadly disease African sleeping sickness. PMID- 26118791 TI - The influence of male takeovers on female dispersal in Colobus vellerosus. AB - Male takeovers affect male tenure, female mate choice and ultimately, individual reproductive success in group-living primates. In social systems with female philopatry and high male reproductive skew, male takeovers largely determine female mate choice, whereas in species with female dispersal, females have the option of deserting a new male. We focused on a species with facultative female dispersal to investigate which factors promote female desertion of males after takeover, using 15 cases (12 for which we have complete data on the takeover process and the female dispersal outcome). These cases took place in nine groups of Colobus vellerosus between 2001 and 2013 at the Boabeng-Fiema Monkey Sanctuary, Ghana. Quick takeovers were usually achieved by single adult males and were never followed by female dispersal. Slow takeovers involved several males, and these takeovers were regularly accompanied by female emigration. Infant attacks and infanticide by males occurred during both kinds of takeovers, but females with dependent offspring never dispersed, regardless of whether their infant was attacked or killed by the new male(s). Subadult females, who were not constrained by the presence of infants, dispersed more often after slow takeovers than after quick takeovers. Whether female dispersal post-takeover is an expression of female mate choice, or occurs to avoid the social upheaval surrounding slow takeovers, remains to be investigated. Am. J. Primatol. 79:e22436, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26118792 TI - Microbial population dynamics in response to Pectobacterium atrosepticum infection in potato tubers. AB - Endophytes are microbes and fungi that live inside plant tissues without damaging the host. Herein we examine the dynamic changes in the endophytic bacterial community in potato (Solanum tuberosum) tuber in response to pathogenic infection by Pectobacterium atrosepticum, which causes soft rot in numerous economically important crops. We quantified community changes using both cultivation and next generation sequencing of the 16S rRNA gene and found that, despite observing significant variability in both the mass of macerated tissue and structure of the endophytic community between individual potato tubers, P. atrosepticum is always taken over by the endophytes during maceration. 16S rDNA sequencing revealed bacteria from the phyla Proteobacteria, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, Verrucomicrobia, Acidobacteria, TM7, and Deinococcus Thermus. Prior to infection, Propionibacterium acnes is frequently among the dominant taxa, yet is out competed by relatively few dominant taxa as the infection proceeds. Two days post-infection, the most abundant sequences in macerated potato tissue are Gammaproteobacteria. The most dominant genera are Enterobacter and Pseudomonas. Eight days post-infection, the number of anaerobic pectolytic Clostridia increases, probably due to oxygen depletion. These results demonstrate that the pathogenesis is strictly initiated by the pathogen (sensu stricto) and proceeds with a major contribution from the endophytic community. PMID- 26118794 TI - Global policy and access to new hepatitis C therapies for people who inject drugs. AB - People who inject drugs (PWID) are disproportionately affected by hepatitis C virus (HCV). This review outlines policy recommendations made in the 2014 World Health Organisation (WHO) Guidelines on Screening, Care and Treatment of HCV and their relevance to PWID. It also canvasses issues that will affect translation of these global guidelines into practice. The first global HCV guidelines released by WHO have recently advocated targeted HCV testing for PWID, assessment of liver disease and support for alcohol reduction during care. They also strongly advocate treatment using currently licensed direct-acting antiviral agents for all individuals, in particular PWID as a key affected population. New HCV treatment regimens have the potential to cure more than 90% of treated individuals. Scaling-up treatment among PWID has the potential to improve individual and population health by reducing HCV transmission, improving quality of life and supporting behaviour modifications that lead to less risk-taking over time. PWID face several barriers to accessing HCV care and treatment that need to be overcome. Testing services need re-orientation toward PWID, individuals need to be informed of their results and provided with direct linkage to ongoing care. Health services need to provide care in the community using simpler, cheaper and more accessible modes of delivery. Healthcare costs and pharmaceutical costs need to be minimised so PWID, who are highly marginalised, can access HCV treatment. Sustained scale-up of treatment for PWID could simultaneously improve individual health and achieve the goal of eliminating HCV transmission among this high-risk and vulnerable group. PMID- 26118793 TI - Association of Sphingosine-1-phosphate (S1P)/S1P Receptor-1 Pathway with Cell Proliferation and Survival in Canine Hemangiosarcoma. AB - BACKGROUND: Sphingosine-1-phosphate (S1P) is a key biolipid signaling molecule that regulates cell growth and survival, but it has not been studied in tumors from dogs. HYPOTHESIS/OBJECTIVES: S1P/S1P1 signaling will contribute to the progression of hemangiosarcoma (HSA). ANIMALS: Thirteen spontaneous HSA tissues, 9 HSA cell lines, 8 nonmalignant tissues, including 6 splenic hematomas and 2 livers with vacuolar degeneration, and 1 endothelial cell line derived from a dog with splenic hematoma were used. METHODS: This was a retrospective case series and in vitro study. Samples were obtained as part of medically necessary diagnostic procedures. Microarray, qRT-PCR, immunohistochemistry, and immunoblotting were performed to examine S1P1 expression. S1P concentrations were measured by high-performance liquid chromatography/mass spectrometry. S1P signaling was evaluated by intracellular Ca(2+) mobilization; proliferation and survival were evaluated using the MTS assay and Annexin V staining. RESULTS: Canine HSA cells expressed higher levels of S1P1 mRNA than nonmalignant endothelial cells. S1P1 protein was present in HSA tissues and cell lines. HSA cells appeared to produce low levels of S1P, but they selectively consumed S1P from the culture media. Exogenous S1P induced an increase in intracellular calcium as well as increased proliferation and viability of HSA cells. Prolonged treatment with FTY720, an inhibitor of S1P1 , decreased S1P1 protein expression and induced apoptosis of HSA cells. CONCLUSIONS AND CLINICAL IMPORTANCE: S1P/S1P1 signaling pathway functions to maintain HSA cell viability and proliferation. The data suggest that S1P1 or the S1P pathway in general could be targets for therapeutic intervention for dogs with HSA. PMID- 26118795 TI - Impact of tobacco prices and smoke-free policy on smoking cessation, by gender and educational group: Spain, 1993-2012. AB - BACKGROUND: To evaluate the effect of tobacco prices and the implementation of smoke-free legislation on smoking cessation in Spain, by educational level, across the period 1993-2012. METHODS: National Health Surveys data for the above two decades were used to calculate smoking cessation in people aged 25-64 years. The relationship between tobacco prices and smoking quit-ratio was estimated using multiple linear regression adjusted for time and the presence of smoke-free legislation. The immediate as well as the longer-term impact of the 2006 smoke free law on quit-ratio was estimated using segmented linear regression analysis. The analyses were performed separately in men and women with high and low education, respectively. RESULTS: No relationship was observed between tobacco prices and smoking quit-ratio, except in women having a low educational level, among whom a rise in price was associated with a decrease in quit-ratio. The smoke-free law altered the smoking quit-ratio in the short term and altered also pre-existing trends. Smoking quit-ratio increased immediately after the ban - though this increase was significant only among women with a low educational level - and then decreased in subsequent years except among men with a high educational level. CONCLUSION: A clear relationship between tobacco prices and smoking quit-ratio was not observed in a recent period. After the implementation of smoke-free legislation the trend in the quit ratio in most of the socio economic groups was different from the trend observed before implementation, so existing inequalities in smoking quit-ratio were not widened or narrowed. PMID- 26118796 TI - Laws prohibiting peer distribution of injecting equipment in Australia: A critical analysis of their effects. AB - The law is a key site for the production of meanings around the 'problem' of drugs in public discourse. In this article, we critically consider the material discursive 'effects' of laws prohibiting peer distribution of needles and syringes in Australia. Taking the laws and regulations governing possession and distribution of injecting equipment in one jurisdiction (New South Wales, Australia) as a case study, we use Carol Bacchi's poststructuralist approach to policy analysis to critically consider the assumptions and presuppositions underpinning this legislative and regulatory framework, with a particular focus on examining the discursive, subjectification and lived effects of these laws. We argue that legislative prohibitions on the distribution of injecting equipment except by 'authorised persons' within 'approved programs' constitute people who inject drugs as irresponsible, irrational, and untrustworthy and re-inscribe a familiar stereotype of the drug 'addict'. These constructions of people who inject drugs fundamentally constrain how the provision of injecting equipment may be thought about in policy and practice. We suggest that prohibitions on the distribution of injecting equipment among peers may also have other, material, effects and may be counterproductive to various public health aims and objectives. However, the actions undertaken by some people who inject drugs to distribute equipment to their peers may disrupt and challenge these constructions, through a counter-discourse in which people who inject drugs are constituted as active agents with a vital role to play in blood-borne virus prevention in the community. Such activity continues to bring with it the risk of criminal prosecution, and so it remains a vexed issue. These insights have implications of relevance beyond Australia, particularly for other countries around the world that prohibit peer distribution, but also for other legislative practices with material-discursive effects in association with injecting drug use. PMID- 26118797 TI - Performance and image enhancing drug injectors' access to needle syringe programs: Responding to a public policy dilemma. AB - BACKGROUND: The number of people who inject performance and image enhancing drugs (PIEDs) attending Australian needle syringe programs (NSPs) has increased recently with cost and capacity implications for this already stretched public health program. The need to prioritise populations' NSP access poses dilemmas for a program that has always sought to minimise entry barriers. METHODS: To assess their injecting-related risk of HIV and HCV, the Kirketon Road Centre (KRC) surveyed PIEDs injectors attending its two NSPs in inner Sydney in late 2013. Demographic, injecting risk, HIV and HCV testing, and NSP access data were analysed and then compared with similar data collected in the Australian Needle Syringe Program Survey (ANSPS) and the NSW NSP Enhanced Data Collection (NNEDC) survey conducted in the state of NSW in the same time period. RESULTS: PIEDs injectors surveyed (n=103) were predominantly male (99%) and only one reported ever receptive needle syringe sharing any injecting equipment. KRC participants were similar to the other survey populations in having rarely ever injected intravenously (6%); being tested for HIV and HCV in the last year (44% and 32% respectively), and reporting low rates of HCV (0%). But they were much more likely to be gay or bisexual (42% vs 2% and 4% in the NSW surveys, p<0.001). Compared to their heterosexual counterparts at KRC, this subgroup was older (35 vs 31 years, p=0.011), and more likely to: have been injecting for <3 years (70% vs 44%, p=0.025); to have ever been tested for HIV (88% vs 46%, p<0.001); to have been tested for HIV and HCV in the last year (72% vs 24%, p<0.001 and 51% vs 19%, p=0.001 respectively); and to report being HIV positive (9% vs 0%, p<0.001). CONCLUSIONS: PIEDs injectors with no other risk factors were at low risk of HIV and HCV, informing KRC's more targeted approach to their health needs. This included providing PIEDs-focused health information and promoting more frequent BBI testing, while encouraging injecting equipment access through other legal sources. This is a case study of how evidence can help resolve public policy dilemmas at the local level, thereby ensuring that scarce public health resources continue to be directed towards those people who inject drugs most at risk of BBIs. PMID- 26118798 TI - Community attitudes towards harm reduction services and a newly established needle and syringe automatic dispensing machine in an inner-city area of Sydney, Australia. AB - BACKGROUND: Automatic dispensing machines (ADMs) are an inexpensive method of increasing needle and syringe distribution to people who inject drugs but widespread implementation has been limited. The operation of ADMs in Australia has been met with apparent community opposition despite national data indicating support for harm reduction. Key community concerns include perceived increases in crime and drug use. This study aimed to examine community-level support for a newly implemented ADM in an inner-city Sydney area known for high levels of drug use. METHODS: Attitudes to harm reduction and ADMs were assessed via a brief face to-face survey of local residents (n=118) and businesses (n=35) located within the vicinity of needle and syringe program (NSP) services including the ADM. Participation was voluntary and no reimbursement was provided. Univariate analysis assessed statistically significant differences between residents' and businesses' knowledge of, and support for, a range of harm reduction initiatives, both generally and in the local area. Univariate logistic regression models were used to determine factors associated with indicating support for an ADM locally. RESULTS: The response rate was higher among businesses (60%) compared to residents living in street-accessible dwellings (42%). Participants indicated support for fixed-site NSPs in general (83%) and locally (77%). Support for ADMs was slightly lower - 67% indicated support for ADMs generally and 60% locally. Negative opinions regarding ADMs (believing that they encourage drug use, attract drug users to the area and increase drug-related crime) were found to be significantly associated with a lower likelihood of indicating support for ADMs locally. CONCLUSION: Despite media reports suggesting widespread community concern, there was general community support for harm reduction, including ADMs. While it is important that harm reduction services are aware of community concerns and respond appropriately, such responses should be considered and interpreted against a broader backdrop of support. PMID- 26118799 TI - The effect of introducing point-of-care or dried blood spot analysis on the uptake of hepatitis C virus testing in high-risk populations: A systematic review of the literature. AB - BACKGROUND: Testing for hepatitis C virus (HCV) infection typically relies upon blood samples taken by traditional phlebotomy for laboratory processing. Novel testing methods, including using dried blood spots (DBS) and point-of-care (PoC) testing enable easier access to high risk populations who have less frequent contact with healthcare professionals. Many of these individuals have been exposed to HCV but have not previously been tested. We aimed to establish whether the availability of these novel testing methods increased either uptake of testing or the number of new diagnoses of HCV. METHODS: The PubMed, Cochrane and SCOPUS databases were searched for terms relating to the study. References and associated bibliographies were also examined for further relevant articles. Studies were included if they contained quantitative data on frequency of testing and/or new diagnoses following the introduction of PoC and/or DBS testing of high risk populations. Studies were then examined for findings and limitations and graded upon the quality of evidence provided. RESULTS: No studies were found which introduced PoC testing and determined its effect on frequency of testing or new diagnoses. Six studies were identified in which DBS testing was introduced and its effect evaluated. Two of the studies were randomised controlled trials, two were prospective cohort studies, one was an ecological study and one was a clinical audit. Populations studied included those attending substance misuse clinics, prisons and needle exchanges. Injection drug use was the commonest risk factor for HCV. Five of the six studies provided evidence that the introduction of DBS testing increased the number of tests, new diagnoses or both. CONCLUSION: Current evidence indicates that DBS testing availability may increase the uptake of testing for HCV in high-risk populations. There is currently no evidence regarding the efficacy of PoC testing in these populations. PMID- 26118800 TI - Comparative study of halogen- and hydrogen-bond interactions between benzene derivatives and dimethyl sulfoxide. AB - The halogen bond, similar to the hydrogen bond, is an important noncovalent interaction and plays important roles in diverse chemistry-related fields. Herein, bromine- and iodine-based halogen-bonding interactions between two benzene derivatives (C6 F5 Br and C6 F5 I) and dimethyl sulfoxide (DMSO) are investigated by using IR and NMR spectroscopy and ab initio calculations. The results are compared with those of interactions between C6 F5 Cl/C6 F5 H and DMSO. First, the interaction energy of the hydrogen bond is stronger than those of bromine- and chlorine-based halogen bonds, but weaker than iodine-based halogen bond. Second, attractive energies depend on 1/r(n) , in which n is between three and four for both hydrogen and halogen bonds, whereas all repulsive energies are found to depend on 1/r(8.5) . Third, the directionality of halogen bonds is greater than that of the hydrogen bond. The bromine- and iodine-based halogen bonds are strict in this regard and the chlorine-based halogen bond only slightly deviates from 180 degrees . The directional order is iodine-based halogen bond>bromine-based halogen bond>chlorine-based halogen bond>hydrogen bond. Fourth, upon the formation of hydrogen and halogen bonds, charge transfers from DMSO to the hydrogen- and halogen-bond donors. The CH3 group contributes positively to stabilization of the complexes. PMID- 26118801 TI - High-sensitivity troponin assays for the early rule-out or diagnosis of acute myocardial infarction in people with acute chest pain: a systematic review and cost-effectiveness analysis. AB - BACKGROUND: Early diagnosis of acute myocardial infarction (AMI) can ensure quick and effective treatment but only 20% of adults with emergency admissions for chest pain have an AMI. High-sensitivity cardiac troponin (hs-cTn) assays may allow rapid rule-out of AMI and avoidance of unnecessary hospital admissions and anxiety. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of hs-cTn assays for the early (within 4 hours of presentation) rule-out of AMI in adults with acute chest pain. METHODS: Sixteen databases, including MEDLINE and EMBASE, research registers and conference proceedings, were searched to October 2013. Study quality was assessed using QUADAS-2. The bivariate model was used to estimate summary sensitivity and specificity for meta-analyses involving four or more studies, otherwise random-effects logistic regression was used. The health-economic analysis considered the long-term costs and quality-adjusted life years (QALYs) associated with different troponin (Tn) testing methods. The de novo model consisted of a decision tree and Markov model. A lifetime time horizon (60 years) was used. RESULTS: Eighteen studies were included in the clinical effectiveness review. The optimum strategy, based on the Roche assay, used a limit of blank (LoB) threshold in a presentation sample to rule out AMI [negative likelihood ratio (LR-) 0.10, 95% confidence interval (CI) 0.05 to 0.18]. Patients testing positive could then have a further test at 2 hours; a result above the 99th centile on either sample and a delta (Delta) of >= 20% has some potential for ruling in an AMI [positive likelihood ratio (LR+) 8.42, 95% CI 6.11 to 11.60], whereas a result below the 99th centile on both samples and a Delta of < 20% can be used to rule out an AMI (LR- 0.04, 95% CI 0.02 to 0.10). The optimum strategy, based on the Abbott assay, used a limit of detection (LoD) threshold in a presentation sample to rule out AMI (LR- 0.01, 95% CI 0.00 to 0.08). Patients testing positive could then have a further test at 3 hours; a result above the 99th centile on this sample has some potential for ruling in an AMI (LR+ 10.16, 95% CI 8.38 to 12.31), whereas a result below the 99th centile can be used to rule out an AMI (LR- 0.02, 95% CI 0.01 to 0.05). In the base-case analysis, standard Tn testing was both most effective and most costly. Strategies considered cost-effective depending upon incremental cost-effectiveness ratio thresholds were Abbott 99th centile (thresholds of < L6597), Beckman 99th centile (thresholds between L6597 and L30,042), Abbott optimal strategy (LoD threshold at presentation, followed by 99th centile threshold at 3 hours) (thresholds between L30,042 and L103,194) and the standard Tn test (thresholds over L103,194). The Roche 99th centile and the Roche optimal strategy [LoB threshold at presentation followed by 99th centile threshold and/or Delta20% (compared with presentation test) at 1-3 hours] were extendedly dominated in this analysis. CONCLUSIONS: There is some evidence to suggest that hs-CTn testing may provide an effective and cost-effective approach to early rule-out of AMI. Further research is needed to clarify optimal diagnostic thresholds and testing strategies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005939. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26118802 TI - Improvement of a headspace solid phase microextraction-gas chromatography/mass spectrometry method for the analysis of wheat bread volatile compounds. AB - An improved method based on headspace solid phase microextraction combined with gas chromatography-mass spectrometry (HS-SPME/GC-MS) was proposed for the semi quantitative determination of wheat bread volatile compounds isolated from both whole slice and crust samples. A DVB/CAR/PDMS fibre was used to extract volatiles from the headspace of a bread powdered sample dispersed in a sodium chloride (20%) aqueous solution and kept for 60min at 50 degrees C under controlled stirring. Thirty-nine out of all the extracted volatiles were fully identified, whereas for 95 other volatiles a tentative identification was proposed, to give a complete as possible profile of wheat bread volatile compounds. The use of an array of ten structurally and physicochemically similar internal standards allowed to markedly improve method precision with respect to previous HS-SPME/GC MS methods for bread volatiles. Good linearity of the method was verified for a selection of volatiles from several chemical groups by calibration with matrix matched extraction solutions. This simple, rapid, precise and sensitive method could represent a valuable tool to obtain semi-quantitative information when investigating the influence of technological factors on volatiles formation in wheat bread and other bakery products. PMID- 26118803 TI - Identification of chemical warfare agents from vapor samples using a field portable capillary gas chromatography/membrane-interfaced electron ionization quadrupole mass spectrometry instrument with Tri-Bed concentrator. AB - A field-portable gas chromatograph-mass spectrometer (Hapsite ER system) was evaluated for the detection of chemical warfare agents (CWAs) in the vapor phase. The system consisted of Tri-Bed concentrator gas sampler (trapping time: 3s( 1)min), a nonpolar low thermal-mass capillary gas chromatography column capable of raising temperatures up to 200 degrees C, a hydrophobic membrane-interfaced electron ionization quadrupole mass spectrometer evacuated by a non-evaporative getter pump for data acquisition, and a personal computer for data analysis. Sample vapors containing as little as 22MUg sarin (GB), 100MUg soman (GD), 210MUg tabun (GA), 55MUg cyclohexylsarin (GF), 4.8MUg sulfur mustard, 390MUg nitrogen mustard 1, 140MUg of nitrogen mustard 2, 130MUg nitrogen mustard 3, 120MUg of 2 chloroacetophenone and 990MUg of chloropicrin per cubic meter could be confirmed after Tri-Bed micro-concentration (for 1min) and automated AMDIS search within 12min. Using manual deconvolution by background subtraction of neighboring regions on the extracted ion chromatograms, the above-mentioned CWAs could be confirmed at lower concentration levels. The memory effects were also examined and we found that blister agents showed significantly more carry-over than nerve agents. Gasoline vapor was found to interfere with the detection of GB and GD, raising the concentration limits for confirmation in the presence of gasoline by both AMDIS search and manual deconvolution; however, GA and GF were not subject to interference by gasoline. Lewisite 1, and o-chlorobenzylidene malononitrile could also be confirmed by gas chromatography, but it was hard to quantify them. Vapors of phosgene, chlorine, and cyanogen chloride could be confirmed by direct mass spectrometric detection at concentration levels higher than 2, 140, and 10mg/m(3) respectively, by bypassing the micro-concentration trap and gas chromatographic separation. PMID- 26118804 TI - Development of a full automation solid phase microextraction method for investigating the partition coefficient of organic pollutant in complex sample. AB - A fully automated solid phase microextraction (SPME) depletion method was developed to study the partition coefficient of organic compound between complex matrix and water sample. The SPME depletion process was conducted by pre-loading the fiber with a specific amount of organic compounds from a proposed standard gas generation vial, and then desorbing the fiber into the targeted samples. Based on the proposed method, the partition coefficients (Kmatrix) of 4 polyaromatic hydrocarbons (PAHs) between humic acid (HA)/hydroxypropyl-beta cyclodextrin (beta-HPCD) and aqueous sample were determined. The results showed that the logKmatrix of 4 PAHs with HA and beta-HPCD ranged from 3.19 to 4.08, and 2.45 to 3.15, respectively. In addition, the logKmatrix values decreased about 0.12-0.27 log units for different PAHs for every 10 degrees C increase in temperature. The effect of temperature on the partition coefficient followed van't Hoff plot, and the partition coefficient at any temperature can be predicted based on the plot. Furthermore, the proposed method was applied for the real biological fluid analysis. The partition coefficients of 6 PAHs between the complex matrices in the fetal bovine serum and water were determined, and compared to ones obtained from SPME extraction method. The result demonstrated that the proposed method can be applied to determine the sorption coefficients of hydrophobic compounds between complex matrix and water in a variety of samples. PMID- 26118805 TI - Pressurized liquid extraction for the determination of cannabinoids and metabolites in hair: Detection of cut-off values by high performance liquid chromatography-high resolution tandem mass spectrometry. AB - Hair analysis has become a routine procedure in most forensic laboratories since this alternative matrix presents clear advantages over classical matrices; particularly wider time window, non-invasive sampling and good stability of the analytes over time. There are, however, some major challenges for the analysis of cannabinoids in hair, mainly related to the low concentrations of 11-nor-9 carboxy-Delta(9)-tetrahydrocannabinol (THC-COOH), that is the major metabolite. In this study a fast, accurate and sensitive method for the determination of cannabinol, cannabidiol, THC and THC-COOH in hair has been developed. The extraction of analytes from hair (50mg) is based on an automated pressurized liquid extraction (PLE) using water modified with the surfactant sodium dodecyl sulphate as eluent phase. PLE extract is then cleaned up by SPE using polymeric reversed phase cartridges Strata XL before the injection in the HPLC-HRMS/MS system. Chromatographic conditions obtained with a fused-core column allowed a good separation of the analytes in less than 4min. The whole procedure has been validated according to SWGTOX guidelines. The LLOQs obtained for THC-COOH and the other analytes were respectively 0.1 and 2pg/mg. To the best of our knowledge, this is the first LC-MS/MS based method that allows the detection of THC-COOH in hair at values lower than the cut-off. PMID- 26118806 TI - Exogenous factors contributing to column bed heterogeneity: Part 1: Consequences of 'air' injections in liquid chromatography. AB - It has been shown that not only the packing homogeneity, but also factors external to the column bed, such as, frits and distributors can have important effects on the column performance. This current communication is the first in a series focusing on the impact of exogenous factors on the column bed heterogeneity. This study is based on several observations by us and others that chromatographic runs often, for technical reasons, include more or less portions of air in the injections. It is therefore extremely important to find out the impact of air on the column performance, the reliability of the results derived from analyses where air was injected, and the effect on the column homogeneity. We used a photographic approach for visualising the air transport phenomena, and found that the air transport through the column is comprised of many different types of transport phenomena, such as laminal flow, viscous fingering like flows, channels and bulbs, and pulsations. More particularly, the air clouds within the column definitely interact in the adsorption, i.e. mobile phase adsorbed to the column surface is displaced. In addition, irrespective of the type of air transport phenomena, the air does not penetrate the column homogeneously. This process is strongly flow dependent. In this work we study air transport both in an analytical scale and a semi-prep column. PMID- 26118807 TI - Rapid analysis of charge variants of monoclonal antibodies using non-linear salt gradient in cation-exchange high performance liquid chromatography. AB - A method is proposed for rapid development of a short, analytical cation exchange high performance liquid chromatography method for analysis of charge heterogeneity in monoclonal antibody products. The parameters investigated and optimized include pH, shape of elution gradient and length of the column. It is found that the most important parameter for development of a shorter method is the choice of the shape of elution gradient. In this paper, we propose a step by step approach to develop a non-linear sigmoidal shape gradient for analysis of charge heterogeneity for two different monoclonal antibody products. The use of this gradient not only decreases the run time of the method to 4min against the conventional method that takes more than 40min but also the resolution is retained. Superiority of the phosphate gradient over sodium chloride gradient for elution of mAbs is also observed. The method has been successfully evaluated for specificity, sensitivity, linearity, limit of detection, and limit of quantification. Application of this method as a potential at-line process analytical technology tool has been suggested. PMID- 26118808 TI - Comparison of the single molecule activity distributions of recombinant and non recombinant bovine intestinal alkaline phosphatase. AB - Single molecule assays were performed on bovine intestinal alkaline phosphatase and the recombinant enzyme expressed in Pichia pastoris using a capillary electrophoresis-based method. The catalytic rates for the bovine and recombinant enzymes were found to be 11,000+/-7000min(-1) (N=161) and 12,000+/-7000min(-1) (N=173), respectively. Mean catalytic rates and variances did not differ significantly between the enzyme from both sources. Furthermore, the distribution of catalytic rates were indistinguishable. PMID- 26118809 TI - Expression, activation and characterization of porcine trypsin in Pichia pastoris GS115. AB - Trypsin is a typical member of serine protease families, specifically cleaving the carboxyl group of peptides at the basic amino acids arginine and lysine. The gene fragment of porcine trypsin with its propeptide coding sequence was optimized and synthesized according to the codon usage bias of Pichia pastoris. The optimized sequence was integrated into the genome of P. pastoris GS115 using the vector pHBM905A. The yield of the recombinant protein was 0.48mg/ml with a maximum activity of 19.2U/ml after 96-h induction in a 5-l fermenter. An optimum activity for the recombinant trypsin was observed at 35 degrees C and pH 8.5. This is the first time to express the porcine trypsinogen with P. pastoris expression system. This report also found that the propeptide was cleaved from the recombinant protein and the enzymogen was transferred into trypsin at the later phase of the fed-batch cultivation. In particular, the activation process can be initiated by changing pH. PMID- 26118810 TI - ["All inclusive"? Opportunities and risks of school inclusion from the perspective of child and adolescent psychiatry]. PMID- 26118811 TI - [Inclusion - pediatric and adolescent psychiatry aspects]. AB - The Convention on the Rights of Persons with Disabilities became legally binding in Germany in March 2009. "Inclusion" is the major concept-all people with any kind of handicap must have the same rights to full and effective participation and inclusion in society. Preceding inclusion come adjustments in society with regard to ethical, legislative, administrative, conceptual, structural, economical, and thus also to healthcare-political frameworks, in order to make disabilities are as far as possible no longer a handicap in an individual's everyday life. This review first outlines the present social status influencing the development of children, a child's welfare, and especially the healthcare of children and adolescents with psychiatric disorders and conditions indicating barriers to inclusion. It focuses on those articles of the UN convention which are relevant with regard to ethical attitude, epidemiology, healthcare framework, diagnostics, therapy, teaching, and research with respect to child and adolescent psychiatry. The analysis points to a significant backlog demand in child psychiatric healthcare, teaching, and research. PMID- 26118812 TI - [International aspects of inclusion in schools]. AB - The term inclusion (=admittance, involvement) is used almost synonymously for the concept of the joint schooling of children with and without intellectual disabilities, language disabilities, physical handicaps, or mental disorders. This article addresses the current state of inclusion in Germany as well as the international situation, such as the Salamanca Declaration of the UNESCO, the "Individuals with Disabilities Act" (IDEA) in the United States as well as European developments, particularly in Great Britain, Austria, and Russia. Even though, from a political perspective, the decision in favor of inclusion seems irreversible, there appears to be a lack an agreement on the modality and timeframe. Thus, the average percentage of students with special education needs in Germany amounts to only 28.2%. The reasons behind this situation are presently being analyzed and discussed. A question of key importance concerns the benefit for the persons concerned, since that should be the measure of the success of inclusion. This question will most likely be validly answered only for individual subgroups of disabilities. This field still requires extensive research. PMID- 26118813 TI - [An inclusive misunderstanding--why noncategorization in special education for people with emotional and social behavior disorders complicates the cooperation with child and adolescent psychiatry]. AB - The welcomed coeducation of children and adolescents with and without disabilities is going into dangerous territory since it has become burdened with a number of illusionary expectations. The constraints applied by real-life and meaningful circumstances should be taken into account, especially for children with emotional and social behavior disorders. Practicable prevention and intervention measurements cannot be generated without profound knowledge about disorders among this heterogeneous group of people. Abandoning all previously relevant terminology ("noncategorization"), demanded by some radical inclusion advocates, leads to a situation that is helplessly confronted with its duties but lacks the basic skills and the necessary support stemming from an interdisciplinary dialogue. The contact with child and adolescent psychiatry is threatened to the disadvantage of the profession. PMID- 26118814 TI - [School well-being of students with and without special educational needs--a comparison of students in inclusive and regular classes]. AB - OBJECTIVE: The present study examines the academic well-being of students with and without special educational needs (SEN) in inclusive classes compared to students from regular classes in which no child with SEN is taught. In addition, the relationships between the school well-being and emotional problems, conduct problems, hyperactivity/inattention, peer relationship problems and prosocial behavior are analyzed. METHOD: A total of 1115 students from the 4th and 7th grade (37 % 4th graders, 63 % 7th graders) participated in the survey, 126 of whom had been diagnosed as having SEN. The subscale Well-Being at School taken from the FEESS 3-4 (Rauer & Schuck, 2004) and the SDQ (Goodman, 1997) were used for measurement. RESULTS: Results indicate high reliabilities for the subscale Well-Being in School for students both with and without SEN for both grades 4 and 7. Furthermore, it could be shown that the variance explained for school well being can be connected to elements on the students' individual level as well as on the class-specific level. Significant predictors of school well-being were sex, behavioral difficulties and strengths as well as the school grade. The SEN status (no SEN vs. SEN) and the class setting (regular vs. inclusive class) did not influence the school well-being significantly. PMID- 26118815 TI - [Guided self-help interventions for parents of children with ADHD--concept, referral and effectiveness in a nationwide trial. An observational study]. AB - OBJECTIVES: The effects of guided self-help interventions for parents of children with ADHD have already been proven in randomized controlled trials. The objective of this study was to assess the effectiveness of this novel form of intervention under routine care conditions in a nationwide trial. METHOD: Registered pediatricians as well as child and youth psychiatrists enrolled 274 children between 6 and 12 years old (83.6% male) diagnosed with ADHD to a self-help program for parents of children with ADHD. The program lasted for 1 year and consisted of eight booklets with advice for parenting children with ADHD as well as complementary telephone consultations (14 calls, up to 20 minutes each). The course of the ADHD symptoms and the comorbid symptoms as well as the development of the child's individual problems were assessed in a pre-post design. RESULTS: 63% of the enrolled parents adhered to the program until the end. The families who cancelled the program did not differ concerning the severity of ADHD symptoms, but they did more often show an impaired familial and social background, and their children received pharmacological treatment more often. Three-fourths of the children who completed the program had received pharmacological treatment at the beginning of the program. The children had more severe ADHD symptoms than a clinical control group. During the intervention, ADHD symptoms as well as psychosocial functioning improved with large effect sizes of d>0.9. Additionally, comorbid oppositional and emotional symptoms decreased. CONCLUSIONS: These results indicate that guided self-help programs for families with children with ADHD are effective, also as an addition to pharmacological treatment. PMID- 26118819 TI - In silico study of VP35 inhibitors: from computational alanine scanning to essential dynamics. AB - In recent years the Ebola virus has spread through several countries in Africa, highlighting the need to develop new treatments for this disease and boosting a new research effort on this subject. The Ebola virus Viral Protein 35 (VP35) carries out multiple functions necessary for virus replication and infection, in particular interfering with (IFN)-alpha/beta signaling. Recently, VP35 has been crystallized in complex with small organic molecules able to inhibit its interaction with viral nucleoproteins, thus reducing Ebola infections of cultured cells. In this work, starting from these structures, we carry out a computational study aimed at investigating the energetic and dynamical aspects of the interaction between VP35 and its ligands at the atomic level. Molecular dynamics simulations, computational alanine scanning, root mean square fluctuations bootstrap analysis and essential dynamics analysis were performed. Our results expand the experimental ones obtained in previous works, adding information about the interactions landscape with the identification of a set of new hot-spots residues exerting a critical function in the protein-ligand interaction. Moreover we characterized the dynamics of the complexes, showing that the presence of ligands modifies the overall protein dynamics as well as the behavior of particular protein segments. PMID- 26118820 TI - The evolutionary ecology of deception. AB - Through dishonest signals or actions, individuals often misinform others to their own benefit. We review recent literature to explore the evolutionary and ecological conditions for deception to be more likely to evolve and be maintained. We identify four conditions: (1) high misinformation potential through perceptual constraints of perceiver; (2) costs and benefits of responding to deception; (3) asymmetric power relationships between individuals and (4) exploitation of common goods. We discuss behavioural and physiological mechanisms that form a deception continuum from secrecy to overt signals. Deceptive tactics usually succeed by being rare and are often evolving under co-evolutionary arms races, sometimes leading to the evolution of polymorphism. The degree of deception can also vary depending on the environmental conditions. Finally, we suggest a conceptual framework for studying deception and highlight important questions for future studies. PMID- 26118822 TI - Eveningness relates to burnout and seasonal sleep and mood problems among young adults. AB - AIMS: Diurnal preference towards eveningness among adults has been associated with unhealthy habits and a range of health hazards, such as sleeping problems and higher odds for depression. We wanted to analyse whether diurnal preference towards eveningness is associated with more severe symptoms regarding sleep problems and mental disorders among young adults. METHODS: Our sample consists of 469 young adults, aged 18-29 years, from the Mental Health in Early Adulthood Study in Finland (MEAF) conducted in 2003-2005. Chronotype was based on the assessment of one question that was asked first in 2000-2001 and the second time in 2003-2005. Those 73 participants who changed their chronotype were excluded from the main analysis, but separate analyses were performed with this group. RESULTS: Concerning sleep, E-types reported higher dependency on alarm clocks (p < 0.001), and E-types and I-types had more problems in feeling refreshed after waking up (p < 0.0001 and p < 0.05 respectively) than M-types. Regarding mental health, E-types and I-types had lower odds for any lifetime DSM-IV Axis I disorder (p < 0.05 and p < 0.01 respectively) than M-types. CONCLUSIONS: Our results are in line with previous findings that those with the diurnal preference towards eveningness have more frequently three or more lifetime mental disorders, more sleeping problems, more seasonal variation in mood and behaviour, and more burnout compared with those with the diurnal preference towards morningness. PMID- 26118823 TI - Development of a cost-efficient novel method for rapid, concurrent genotyping of five common single nucleotide polymorphisms of the brain derived neurotrophic factor (BDNF) gene by tetra-primer amplification refractory mutation system. AB - Brain derived neurotrophic factor (BDNF) is a molecular trophic factor that plays a key role in neuronal survival and plasticity. Single nucleotide polymorphisms (SNPs) of the BDNF gene have been associated with specific phenotypic traits in a large number of neuropsychiatric disorders and the response to psychotherapeutic medications in patient populations. Nevertheless, due to study differences and occasionally contrasting findings, substantial further research is required to understand in better detail the association between specific BDNF SNPs and these psychiatric disorders. While considerable progress has been made recently in developing advanced genotyping platforms of SNPs, many high-throughput probe- or array-based detection methods currently available are limited by high costs, slow processing times or access to advanced instrumentation. The polymerase chain reaction (PCR)-based, tetra-primer amplification refractory mutation system (T ARMS) method is a potential alternative technique for detecting SNP genotypes efficiently, quickly, easily, and cheaply. As a tool in psychopathology research, T-ARMS was shown to be capable of detecting five common SNPs in the BDNF gene (rs6265, rs988748, rs11030104, 11757G/C and rs7103411), which are all SNPs with previously demonstrated clinical relevance to schizophrenia and depression. The present technique therefore represents a suitable protocol for many research laboratories to study the genetic correlates of BDNF in psychiatric disorders. Copyright Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118824 TI - Job characteristics and burnout: The moderating roles of emotional intelligence, motivation and pay among bank employees. AB - This study investigated the prediction of burnout from job characteristics, emotional intelligence, motivation and pay among bank employees. It also examined the interactions of emotional intelligence, motivation, pay and job characteristics in the prediction of burnout. Data obtained from 230 (Males = 127, Females = 103) bank employees were analysed using Pearson's Product Moment Correlation and multiple regression analysis. Results showed that theses variables jointly and separately negatively predicted burnout components. The results further indicated that emotional intelligence, motivation and pay separately interacted with some job characteristic components to negatively predict some burnout components. The findings imply that emotional intelligence, motivation and pay could be considered by counsellors when designing interventions to reduce burnout among bank employees. PMID- 26118825 TI - Adalimumab treatment optimization for psoriasis: Results of a long-term phase 2/3 Japanese study. AB - The tumor necrosis factor-alpha inhibitor, adalimumab, is approved to treat moderate-to-severe plaque psoriasis (40 mg every-other-week or 80 mg every-other week following inadequate response at 40 mg in Japan). This open-label extension (OLE) trial evaluated the optimal adalimumab dose for long-term efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis following a prior 24-week, phase 2/3, randomized, double-blind study. Of the 169 patients from the phase 2/3 trial, 147 entered the OLE on 40 mg (n = 89) or 80 mg (n = 58) adalimumab every-other-week. Patients on 40 mg with Psoriasis Area and Severity Index (PASI) of less than 50 could escalate to 80 mg. At week 52 (28 of OLE), patients entering the OLE on 80 mg were reduced to 40 mg, with the option to re escalate. For patients entering the OLE on 40 mg, final PASI 50/75/90 response rates were 85.1%/73.3%/60.4%, respectively, including effects of dose escalation. Among patients whose dose was escalated, final PASI 50/75/90 response rates were 70.0%/53.3%/36.7%, respectively. For patients entering the OLE on 80 mg, final PASI 50/75/90 response rates were 92.5%/84.9%/73.6%, respectively, including effects of dose re-escalation. Overall incidence rates of adverse events (AE) and injection-site reaction AE declined over time; rates for serious AE and infections were generally stable. Clinically meaningful efficacy of adalimumab was sustained to 4 years. Dose escalation to 80 mg every-other-week for patients with suboptimal response to 40 mg every-other-week, and dose reduction to 40 mg every-other-week for patients satisfactorily controlled on 80 mg every-other week, are viable strategies for adalimumab optimization. PMID- 26118826 TI - High-yield lithiation of azobenzenes by tin-lithium exchange. AB - The lithiation of halogenated azobenzenes by halogen-lithium exchange commonly leads to substantial degradation of the azo group to give hydrazine derivatives besides the desired aryl lithium species. Yields of quenching reactions with electrophiles are therefore low. This work shows that a transmetalation reaction of easily accessible stannylated azobenzenes with methyllithium leads to a near quantitative lithiation of azobenzenes in para, meta, and ortho positions. To investigate the scope of the reaction, various lithiated azobenzenes were quenched with a variety of electrophiles. Furthermore, mechanistic (119) Sn NMR spectroscopic studies on the formation of lithiated azobenzenes are presented. A tin ate complex of the azobenzene was detected and characterized at low temperature. PMID- 26118828 TI - Hydrogenated TiO2 nanobelts as highly efficient photocatalytic organic dye degradation and hydrogen evolution photocatalyst. AB - TiO2 nanobelts have gained increasing interest because of its outstanding properties and promising applications in a wide range of fields. Here we report the facile synthesis of hydrogenated TiO2 (H-TiO2) nanobelts, which exhibit excellent UV and visible photocatalytic decomposing of methyl orange (MO) and water splitting for hydrogen production. The improved photocatalytic property can be attributed to the Ti(3+) ions and oxygen vacancies in TiO2 nanobelts created by hydrogenation. Ti(3+) ions and oxygen vacancies can enhance visible light absorption, promote charge carrier trapping, and hinder the photogenerated electron-hole recombination. This work offers a simple strategy for the fabrication of a wide solar spectrum of active photocatalysts, which possesses significant potential for more efficient photodegradation, photocatalytic water splitting, and enhanced solar cells using sunlight as light source. PMID- 26118827 TI - Acceleration of skin regeneration in full-thickness burns by incorporation of bFGF-loaded alginate microspheres into a CMCS-PVA hydrogel. AB - Two important issues in skin tissue engineering are the vascularization and regeneration of the dermis. Basic fibroblast growth factor (bFGF) is known to promote angiogenesis and accelerate wound healing. Direct delivery of bFGF to the wound area, however, would lead to a loss of bioactivity. To this end, bFGF loaded alginate microspheres (Ms) were fabricated and incorporated into carboxymethyl chitosan (CMCS)-poly(vinyl alcohol) (PVA) to form a composite hydrogel. Scanning electron microscopy (SEM) results indicated that the incorporation of Ms does not significantly affect the inner structure of CMCS PVA. In an in vitro study, the release of bFGF from Ms-CMCS-PVA in a sustained manner retained higher bioactivity over a 2-week period. Full-thickness burn wounds were created in the dorsal area of rats for in vivo evaluation of skin regeneration treated with CMCS-PVA hydrogel, with and without bFGF. Compared with the control, CMCS-PVA and bFGF-CMCS-PVA groups, the bFGF/Ms-CMCS-PVA group revealed significantly faster wound recovery rates, with re-epithelialization and regeneration of the dermis. Moreover, the bFGF/Ms-CMCS-PVA group had the highest density of newly formed and mature blood vessels during the 2 mweek treatment period. The ability of the bFGF/Ms-CMCS-PVA hydrogel to accelerate wound healing in a full-thickness burn model suggests its potential for use in dermal tissue regeneration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118829 TI - Nicotine and metabolites determination in human plasma by ultra performance liquid chromatography-tandem mass spectrometry: a simple approach for solving contamination problem and clinical application. AB - A quantitative method using ultra performance liquid chromatography-tandem mass spectrometry is described for simultaneous determination of nicotine and its metabolites (cotinine and trans-3'- hydroxycotinine) in human plasma. Aliquots of 0.25 mL of plasma specimens were used for analysis, and 3 analytes were extracted by liquid-liquid extraction. The main problem was blank plasma contamination with environmental nicotine. Activated charcoal was used to avoid this analytical interference. For optimized chromatographic performance, a basic mobile phase consisting of 0.2% ammonia in water (mobile phase A, pH10.6) and acetonitrile (mobile phase B) was selected. The analytes were separated on a 50 mm * 2.1 mm BEH C18 column, 1.7 MUm particle size, and quantified by MS/MS using multiple reaction monitoring (MRM) in positive mode. The chromatographic separation was achieved in 3 min followed by 1.2 min of column equilibration. The calibration curves were linear in the concentration range of 10-1000 ng/mL with correlation coefficients exceeding 0.99. Within-day precisions and between-day precisions (CV, %) were <15 %. The accuracy expressed as bias was within +/-15% for all analytes. The recovery values ranged from 50% to 97%. The ions used for quantification of nicotine, cotinine and 3-OH-cotinine were 166.9 > 129.7; 176.9 > 79.7; 192.9 > 79.7 m/z, respectively. The original blank sample preparation solved the problem of contamination in a cost-effective and efficient way. The validated method has been routinely used for analysis of nicotine and metabolites and determination of hydroxycotinine/cotinine metabolic ratio. This biomarker seems to be interesting at predicting response of nicotine patch replacement therapies. PMID- 26118830 TI - A new likelihood ratio metric for the psychomotor vigilance test and its sensitivity to sleep loss. AB - The Psychomotor Vigilance Test (PVT) is a widely used assay of behavioural alertness sensitive to the effects of sleep loss and circadian misalignment. However, there is currently no accepted PVT composite outcome metric that captures response slowing, attentional lapses and compensatory premature reactions observed typically in sleep-deprived subjects. We developed a novel likelihood ratio metric (LRM) based on relative frequency distributions in 50 categories of reaction times (RT) and false starts in alert and sleep-deprived subjects (acute total sleep deprivation: n = 31 subjects). The LRM had the largest effect size both in a 33-h total sleep deprivation protocol [1.96; 95% confidence interval (CI): 1.61-2.44; followed by response speed 1/RT, effect size 1.93, 95% CI: 1.55-2.65] and in a chronic partial sleep restriction protocol (1.22; 95% CI: 0.96-1.59; followed by response speed 1/RT, effect size 1.21, 95% CI: 0.94-1.59; 5 nights at 4 h sleep per night; n = 43 subjects). LRM scores correlated highly with response speed (R(2 ) = 0.986), and less well with five other common PVT outcome metrics (R(2 ) = 0.111-0.886). In conclusion, the new LRM is a sensitive PVT outcome metric with high statistical power that takes subtle sleep loss-related changes in the distribution of reaction times (including false starts) into account, is not prone to outliers, does not require baseline data and can be calculated and interpreted easily. Congruence between LRM and PVT response speed and their similar effect size rankings support the use of response speed as the primary, most sensitive and most parsimonious standard PVT outcome metric for determining neurobehavioural deficits from sleep loss. PMID- 26118831 TI - Pharmacy-randomized intervention delivering HIV prevention services during the syringe sale to people who inject drugs in New York City. AB - BACKGROUND: Pharmacy syringe access may be an opportunity to provide HIV prevention resources to persons who inject drugs (PWID). We examined the impact of a pharmacy-randomized intervention to reduce injection risk among PWID in New York City. METHODS: Pharmacies (n=88) were randomized into intervention, primary control, and secondary control arms. Intervention pharmacies received in-depth harm reduction training, recruited syringe customers who inject drugs into the study, and provided additional services (i.e., HIV prevention/medical/social service referrals, syringe disposal containers, and harm reduction print materials). Primary control pharmacies recruited syringe customers who inject drugs and did not offer additional services, and secondary control pharmacies did not recruit syringe customers (and are not included in this analysis) but participated in a pharmacy staff survey to evaluate intervention impact on pharmacy staff. Recruited syringe customers underwent a baseline and 3-month follow-up ACASI. The intervention effect on injection risk/protective behavior of PWID was examined. RESULTS: A total of 482 PWID completed baseline and follow-up surveys. PWID were mostly Hispanic/Latino, male, and mean age of 43.6 years. After adjustment, PWID in the intervention arm were more likely to report always using a sterile syringe vs. not (PR=1.24; 95% CI: 1.04-1.48) at 3-month follow up. CONCLUSIONS: These findings present evidence that expanded pharmacy services for PWID can encourage sterile syringe use which may decrease injection risk in high HIV burdened Black and Latino communities. PMID- 26118832 TI - Associations between deployment, military rank, and binge drinking in active duty and Reserve/National Guard US servicewomen. AB - BACKGROUND: Prior studies of mostly male U.S. service members suggest service characteristics such as deployment with combat exposure and lower rank may be a risk factor for alcohol misuse. However, these relationships have not been examined among servicewomen who may be at high risk for experiencing deployment related stressors and associated health consequences. This cross-sectional report of US servicewomen in the Reserve or National Guard (RNG) and active component (AC) sought to examine these associations. METHODS: A Midwestern community sample of currently serving and veteran servicewomen (N=1339) completed structured telephone interviews. The Generalized Linear Model was used to examine associations between service characteristics, any binge drinking, and frequency of recent binge drinking after adjusting for demographics. RESULTS: After adjusting for demographics, deployment to Iraq or Afghanistan was associated with greater odds of reporting a binge drinking episode, compared to no deployment, among servicewomen in the AC but not RNG. Deployment to Iraq or Afghanistan was also associated with more days binge drinking in both groups compared to servicewomen not deployed. Lower ranking servicewomen also reported higher odds of a binge drinking episode and higher frequency of binge drinking in both the RNG and AC. CONCLUSIONS: Service characteristics including deployment to Iraq or Afghanistan (vs. those not deployed) and lower rank (vs. officers) may be a risk factor for recent binge drinking and higher frequency of binge drinking among servicewomen, after adjusting for demographic covariates. Public health and clinical implications are discussed. PMID- 26118834 TI - The Association Between Medicolegal and Professional Concerns and Chest Pain Admission Rates. AB - OBJECTIVES: For patients in whom acute coronary syndrome (ACS) is a concern, disposition decisions are complex and multifactorial and have traditionally been a source of considerable variation. An important factor in disposition decisions for these patients may be physician-perceived medicolegal risk and related professional concerns. The study aim was to determine, at the point of care, how much less frequently physicians report that they would admit possible ACS patients if there was either zero or a defined medicolegal risk. METHODS: This was a point-of-care emergency physician survey. Research assistants approached physicians at or immediately following the moment of disposition decisions for patients who were being admitted for ACS. The primary outcome measures were the proportion of physicians reporting that patients would not have been admitted if medicolegal issues were of no concern and the proportion of physicians reporting that patients would not have been admitted if there was an "acceptable miss rate" of 1% to 2% for ACS patients. RESULTS: During the 3-month study period, 576 patients were admitted to an inpatient unit or to the ED observation protocol. Physicians were approached in 271 cases, and 259 surveys were completed. When presented with hypothetical zero medicolegal risk, physicians answered that they would not have admitted the patients in 30% of cases. With a hypothetical 1% to 2% acceptable miss rate, physicians indicated that they would not have admitted the patients in 29% of the cases. CONCLUSIONS: ED medicolegal and professional concerns may substantially increase admissions for possible ACS. An acceptable miss rate or a zero medicolegal risk environment could potentially lead to a major reduction in admissions that physicians feel to be clinically unnecessary. PMID- 26118833 TI - Effects of active anti-methamphetamine vaccination on intravenous self administration in rats. AB - BACKGROUND: d-Methamphetamine (METH) addiction is a serious public health concern for which successful treatment remains elusive. Immunopharmacotherapy has been shown to attenuate locomotor and thermoregulatory effects of METH. The current study investigated whether active vaccination against METH could alter intravenous METH self-administration in rats. METHODS: Male Sprague-Dawley rats (Experiment 1: N=24; Experiment 2: N=18) were vaccinated with either a control keyhole-limpet hemocyanin conjugate vaccine (KLH) or a candidate anti-METH vaccine (MH6-KLH) or. Effects of vaccination on the acquisition of METH self administration under two dose conditions (0.05, 0.1mg/kg/inf) and post acquisition dose-substitution (0, 0.01, 0.05, 0.20mg/kg/inf, Experiment 1; 0.01, 0.05, 0.10, 0.15mg/kg/inf, Experiment 2) during steady-state responding were investigated. Plasma METH concentrations were determined 30min after an acute challenge dose of 3.2mg/kg METH. RESULTS: Active vaccination inhibited the acquisition of METH self-administration under the 0.1mg/kg/inf dose condition, with 66% of the MH6-KLH-vaccinated rats compared to 100% of the controls reaching criteria, and produced transient and dose-dependent effects on self administration during the maintenance phase. Under the 0.05mg/kg/inf dose condition, MH6-KLH-vaccinated rats initially self-administered more METH than controls, but then self-administration decreased across the acquisition phase relative to controls; a subsequent dose-response assessment confirmed that MH6 KLH-vaccinated rats failed to acquire METH self-administration. Finally, plasma METH concentrations were higher in MH6-KLH-vaccinated rats compared to controls after an acute METH challenge, and these were positively correlated with antibody titers. CONCLUSIONS: These data demonstrate that active immunopharmacotherapy for METH attenuates the acquisition of METH self-administration. PMID- 26118835 TI - Etiology of aseptic meningitis and clinical characteristics in immune-competent adults. AB - Viral meningitis is the most common cause of aseptic meningitis. Use of the polymerase chain reaction (PCR) has increased the ability to determine the etiology of viral meningitis. This study used PCR analysis to evaluate the etiology of aseptic meningitis in 177 previously healthy adults over a 5-year period, as well as analyzing the clinical characteristics, cerebrospinal fluid (CSF) findings, and prognosis according to each etiology. The most frequent cause of aseptic meningitis was enterovirus (EV), followed by varicella zoster virus (VZV). Patients with EV meningitis were significantly younger than those with VZV meningitis. The percentage of lymphocytes in white blood cell counts and protein concentrations in the CSF differed significantly among patients with EV, VZV and meningitis of undetermined etiology. Younger age and lower percentage of lymphocyte and protein level in CSF analysis may be suggestive of EV meningitis. Further prospective studies are warranted to identify the correlations between the clinical characteristics and the etiologies of meningitis. PMID- 26118836 TI - N-Nicotinoyl tyramine, a novel niacinamide derivative, inhibits melanogenesis by suppressing MITF gene expression. AB - We synthesized and investigated the inhibitory effects of a novel niacinamide derivative, N-nicotinoyltyramine (NNT) on melanogenesis. NNT inhibited melanin production in B16F10 murine melanoma cells stimulated with alpha-melanocyte stimulating hormone (alpha-MSH), in human melanocyte and in three-dimensional cultured human skin model. NNT did not affect the catalytic activity of tyrosinase, but acted as an inhibitor of microphthalmia-associated transcription factor (MITF) and tyrosinase expressions in B16F10 cells. These findings suggest that the hypopigmentary effect of NNT results from the down-regulation of MITF and subsequently of tyrosinase, although NNT did not directly inhibit tyrosinase activity. In addition, safety of NNT was verified through performing neural stem cell morphology assay and Human repeated insult patch test as whitening agent. Our findings indicate that NNT may be a potential and non-skin irritant whitening agent for use in cosmetics and in the medical treatment of pigmentary disorders. PMID- 26118837 TI - Insights into possible cell-death markers in the diatom Skeletonema marinoi in response to senescence and silica starvation. AB - Diatoms are a hugely diverse microalgal class, which possesses unique biological features and complex metabolic pathways and may activate sophisticated mechanisms to respond to environmental changes. Abiotic stress factors may limit growth rate of diatoms, but may also trigger intracellular signaling pathways that cause cells to undergo programmed cell death (PCD). Here we investigate the gene expression of different target genes related to cell death, namely programmed cell death 4 (PDCD4), tumor susceptibility gene 101 (TSG101), developmental and cell death (DCD) domain, death specific protein (DSP) and metacaspase (MC), using RT-qPCR in the cosmopolitan coastal centric diatom species Skeletonema marinoi, which contributes significantly to phytoplankton blooms in temperate waters. To this end, we undertook a detailed study of the best reference genes to analyze gene expression in S. marinoi under different experimental conditions (i.e. in different growth phases or under silica starvation). Results showed that DSP gene expression had a clear and constant increase along the S. marinoi growth curve reaching its maximum during the senescent phase. On the contrary, PDCD4, DCD, TSG101 and MC did not show any significant variation. These findings indicate that the DSP gene is a possible PCD marker induced by aging in this diatom species. In contrast, levels of DSP transcripts induced by silica starvation were relatively low compared to those induced by cell aging suggesting differential activation and/or regulation of the PCD machinery in response to different stressful conditions. Our study also expands the list of reference genes available for the diatom S. marinoi for normalization of RT-qPCR data of cells cultivated under different growth phases or under silica starvation. PMID- 26118838 TI - A Plasmodium alpha/beta-hydrolase modulates the development of invasive stages. AB - The bud emergence (BEM)46 proteins are evolutionarily conserved members of the alpha/beta-hydrolase superfamily, which includes enzymes with diverse functions and a wide range of substrates. Here, we identified a Plasmodium BEM46-like protein (PBLP) and characterized it throughout the life cycle of the rodent malaria parasite Plasmodium yoelii. The Plasmodium BEM46-like protein is shown to be closely associated with the parasite plasma membrane of asexual erythrocytic stage schizonts and exo-erythrocytic schizonts; however, PBLP localizes to unique intracellular structures in sporozoites. Generation and analysis of P. yoelii knockout (Deltapblp) parasite lines showed that PBLP has an important role in erythrocytic stage merozoite development with Deltapblp parasites forming fewer merozoites during schizogony, which results in decreased parasitemia when compared with wild-type (WT) parasites. Deltapblp parasites showed no defects in gametogenesis or transmission to mosquitoes; however, because they formed fewer oocysts there was a reduction in the number of developed sporozoites in infected mosquitoes when compared with WT. Although Deltapblp sporozoites showed no apparent defect in mosquito salivary gland infection, they showed decreased infectivity in hepatocytes in vitro. Similarly, mice infected with Deltapblp sporozoites exhibited a delay in the onset of blood-stage patency, which is likely caused by reduced sporozoite infectivity and a discernible delay in exo erythrocytic merozoite formation. These data are consistent with the model that PBLP has an important role in parasite invasive-stage morphogenesis throughout the parasite life cycle. PMID- 26118839 TI - Analysis of Nickel Defect in Diamond with Photoluminescence upon Excitation near 200 nm. AB - Photoluminescent (PL) spectra of synthetic diamond powders at temperatures between 10 and 300 K were excited with synchrotron radiation in the wavelength range 125-375 nm. Prominent spectral PL features were detected at 484.6 and 489.0 nm (2.559 and 2.535 eV), associated with nickel defect. During our measurement of PL excitation (PLE) spectra of Ni defect in diamond, we observed a distinct PLE line at 215 nm for the first time. We thereby suggest the use of UV-PL spectra excited in the region 200-220 nm to analyze and to identify nickel defect in diamonds. PMID- 26118840 TI - Regulation of B Cell to Plasma Cell Transition within the Follicular B Cell Response. AB - Persistent humoral immunity depends on the follicular B cell response and on the generation of somatically mutated high-affinity plasma cells and memory B cells. Upon activation by an antigen, cognately activated follicular B cells and follicular T helper (TFH ) cells initiate germinal centre (GC) reaction during which high-affinity effector cells are generated. The differentiation of activated follicular B cells into plasma cells and memory B cells is guided by complex selection events, both at the cellular and molecular level. The transition of B cell into a plasma cell during the GC response involves alterations in the microenvironment and developmental state of the cell, which are guided by cell-extrinsic signals. The developmental cell fate decisions in response to these signals are coordinated by cell-intrinsic gene regulatory network functioning at epigenetic, transcriptional and post-transcriptional levels. PMID- 26118841 TI - Forebrain NR2B overexpression enhancing fear acquisition and long-term potentiation in the lateral amygdala. AB - N-methyl-d-aspartic acid (NMDA) receptor-dependent long-term potentiation (LTP) at the thalamus-lateral amygdala (T-LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T-LA synapses remains speculative. In the present study, using transgenic mice with forebrain-specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long-term depression (LTD) at the T-LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T-LA synapses in these transgenic mice, AMPA and NMDA receptor-mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor-mediated currents in these transgenic mice. Consistent with enhanced LTP at T-LA synapses, NR2B-transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild-type littermates. Our results demonstrate that up-regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T-LA synapses. PMID- 26118842 TI - The Art of Reflection: Turning the Strange into the Familiar. AB - There are a great many useful articles on the dynamics and pragmatics of reflecting teams but few articles address what constitutes a good or inept reflection and why. I provide a conceptual model for thinking about what a good reflection does, distinguishing it from a nice reflection. With some further refinements in place, I then illustrate how reflections can be part of any relationship, not just clinical ones. We have opportunities to make them and to recognize when others make them to us. By using examples from my personal life-as a grandmother, daughter, radio listener, cancer survivor, and client-I attempt to ease the personal/professional binary, a project of mine for the last 35 years. In the second part of the article, I address how writing can serve reflection. Although best offered at the moment one is called for, it is never too late for a reflection. Writing allows people to offer reflections after the fact to those who have shared their stories. Sometimes, it is to ourselves we offer those reflections, when the reflector has long since dropped the thread of obligation or interest. I provide an example of working with iconic imagery to unpack meaning so that reflection can eventually take place, allowing integration to proceed, facilitating the strange becoming the familiar. PMID- 26118843 TI - [What factors help to explain satisfaction with Primary Health care in Spain?]. AB - OBJECTIVES: To find out the factors that determine satisfaction with public primary health care in Spain. The work has considered a wide group of potential determining factors of that satisfaction, which are organised into 3 blocks of variables: Those related to the perceived quality in the care received, socioeconomic, and those relative to the state of health. MATERIAL AND METHODS: The micro data of the Barometro Sanitario (BS) of 2013, which are representative at a national level, were employed. After a prior first descriptive analysis, 2 multivariate models were estimated: One in which satisfaction is considered as being of a cardinal nature (regression model), and another in which it is contemplated as being of an ordinal nature (ordered probit model). RESULTS: There were practically no differences between the results obtained with one or other of the multivariate models. Not all the variables considered were statistically significant. Of the 3 blocks of variables studied, the one related to the perceived quality in the care received in the health centre exerts the greatest relevance in the explanation of satisfaction. CONCLUSIONS: The results obtained show that, by means of the management of the variables related to the perception of quality of care in health centres, public administrators and health professionals may have a highly favourable influence on the levels of satisfaction of primary health care patients. PMID- 26118844 TI - Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy. AB - A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable. PMID- 26118845 TI - Direct 17O NMR experimental evidence for Al-NBO bonds in Si-rich and highly polymerized aluminosilicate glasses. AB - By using solid-state (17)O NMR spectroscopy, we provide the first direct experimental evidence for bonds between Al and non-bridging oxygen (NBO) ions in aluminosilicate glasses based on rare-earth (RE) elements, where RE = {Lu, Sc, Y}. The presence of ~10% Al-NBO moieties out of all NBO species holds regardless of the precise glass composition, at odds with the conventional structural view that Al-NBO bonds are absent in highly polymerized and Si-rich aluminosilicate glass networks. PMID- 26118846 TI - ICREA Workshop: from model systems to crops - challenges for a new era in plant biology. PMID- 26118847 TI - Blood flow restricted exercise for athletes: A review of available evidence. AB - OBJECTIVES: This study aimed to collate current evidence regarding the efficacy of various blood flow restriction (BFR) strategies for well-trained athletes, and to provide insight regarding how such strategies can be used by these populations. DESIGN: Review article. METHODS: Studies that had investigated the acute or adaptive responses to BFR interventions in athletic participants were identified from searches in MEDLINE (PubMed), SPORTDiscus (EBSCO) and Google Scholar databases up to April 2015. The reference lists of identified papers were also examined for relevant studies. RESULTS: Twelve papers were identified from 11 separate investigations that had assessed acute and adaptive responses to BFR in athletic cohorts. Of these, 7 papers observed enhanced hypertrophic and/or strength responses and 2 reported alterations in the acute responses to low-load resistance exercise when combined with BFR. One paper had examined the adaptive responses to moderate-load resistance training with BFR, 1 noted improved training responses to low-work rate BFR cardiovascular exercise, and 1 reported on a case of injury following BFR exercise in an athlete. CONCLUSIONS: Current evidence suggests that low-load resistance training with BFR can enhance muscle hypertrophy and strength in well-trained athletes, who would not normally benefit from using light loads. For healthy athletes, low-load BFR resistance training performed in conjunction with normal high-load training may provide an additional stimulus for muscular development. As low-load BFR resistance exercise does not appear to cause measureable muscle damage, supplementing normal high-load training using this novel strategy may elicit beneficial muscular responses in healthy athletes. PMID- 26118848 TI - Variability of physical performance and player match loads in professional rugby union. AB - OBJECTIVES: To examine the within- and between-player variability of physical performance and player match loads in professional rugby union. DESIGN: A single cohort, observational study. METHODS: Physical match performance data were collected from 28 male, professional, English Championship players over 15 competitive matches. Using microsensors, the variables selected for analysis were total distance, low-speed running distance, high-speed running distance, very high-speed running distance, total impacts, repeated high-intensity efforts, body load (PlayerLoadTM), and low velocity (<7.2kmh(-1)) body load. Ratings of perceived exertion represented match internal loads. Variability was quantified using the coefficient of variation, with the meaningful interpretation of change in physical performance and match loads calculated using magnitude-based inferences. RESULTS: We found large between-match (within-player) variation for high-speed running distance (27.6%; +/-90% confidence limits 6.9% [forwards], 20.1%; +/-4.1% [backs]), very high-speed running distance (68%; +/-19%, 34.1%; +/ 7.5%), total impacts (24.0%; +/-5.9%, 36.4%; +/-7.9%) and repeated high-intensity efforts (18.7%; +/-4.4%, 39.5%; +/-8.8%), with moderate variability for match ratings of perceived exertion (8.2%; +/-1.8%, 10.8%; +/-2.1%), body load (7.3%; +/-1.7%, 10.0%; +/-2.0%) and low velocity body load (8.9%; +/-2.0%, 10.7%; +/ 2.1%). Threshold values for likely substantial between-match changes in high intensity physical performance measures ranged from 21% to 76%, and were ~10% for match ratings of perceived exertion, body load and low velocity body load. CONCLUSIONS: Within- and between-player variability of high-intensity activity in professional rugby union is large, yet ratings of perceived exertion, body load and low velocity body load appear more stable by comparison and may be interpreted with greater accuracy. PMID- 26118849 TI - Interventions preventing ankle sprains; previous injury and high-risk sport participation as predictors of compliance. AB - OBJECTIVES: To describe the association between participants' person-related potential predictor variables and cumulative compliance with interventions for preventing ankle sprains: neuromuscular training, wearing an ankle brace, and a combined training and bracing. DESIGN: Secondary analysis of compliance data from a randomized controlled trial (RCT) comparing measures preventing ankle ligament injuries. METHODS: Ordinal regression with a backward selection method was used to obtain a descriptive statistical model linking participants' person-related potential predictor variables with the monthly cumulative compliance measurements for three interventions preventing ankle ligament injuries. RESULTS: Having had a previous ankle injury was significantly associated with a higher compliance with all of the preventive measures trialed. Overall compliance with bracing and the combined intervention was significantly lower than the compliance with NM training. Per group analysis found that participating in a high-risk sport, like soccer, basketball, and volleyball, was significantly associated with a higher compliance with bracing, or a combined bracing and NM training. In contrast, participating in a high-risk sport was significantly associated with a lower per group compliance with NM training. CONCLUSIONS: Future studies should include at least registration of previous ankle sprains, sport participation (high- or low risk), experience in NM training, and hours of sport exposure as possible predictors of compliance with interventions preventing ankle sprains. Practitioners should take into account these variables when prescribing preventive neuromuscular training or bracing. PMID- 26118850 TI - Decarboxylative functionalization of cinnamic acids. AB - Decarboxylative functionalization of alpha,beta-unsaturated carboxylic acids is an emerging area that has been developed significantly in recent years. This critical review focuses on the different decarboxylative functionalization reactions of cinnamic acids leading to the formation of various C-C and C heteroatom bonds. Apart from metal carboxylates, decarboxylation in cinnamic acids has been achieved efficiently under metal-free conditions, particularly via the use of hypervalent iodine reagents. We believe this review will encourage organic chemists to develop vinylic decarboxylation in a more appealing way with an understanding of new mechanistic insight. PMID- 26118851 TI - Understanding the local actions of lipids in bone physiology. AB - The adult skeleton is a metabolically active organ system that undergoes continuous remodeling to remove old and/or stressed bone (resorption) and replace it with new bone (formation) in order to maintain a constant bone mass and preserve bone strength from micro-damage accumulation. In that remodeling process, cellular balances--adipocytogenesis/osteoblastogenesis and osteoblastogenesis/osteoclastogenesis--are critical and tightly controlled by many factors, including lipids as discussed in the present review. Interest in the bone lipid area has increased as a result of in vivo evidences indicating a reciprocal relationship between bone mass and marrow adiposity. Lipids in bones are usually assumed to be present only in the bone marrow. However, the mineralized bone tissue itself also contains small amounts of lipids which might play an important role in bone physiology. Fatty acids, cholesterol, phospholipids and several endogenous metabolites (i.e., prostaglandins, oxysterols) have been purported to act on bone cell survival and functions, the bone mineralization process, and critical signaling pathways. Thus, they can be regarded as regulatory molecules important in bone health. Recently, several specific lipids derived from membrane phospholipids (i.e., sphingosine-1 phosphate, lysophosphatidic acid and different fatty acid amides) have emerged as important mediators in bone physiology and the number of such molecules will probably increase in the near future. The present paper reviews the current knowledge about: (1 degrees ) bone lipid composition in both bone marrow and mineralized tissue compartments, and (2 degrees ) local actions of lipids on bone physiology in relation to their metabolism. Understanding the roles of lipids in bone is essential to knowing how an imbalance in their signaling pathways might contribute to bone pathologies, such as osteoporosis. PMID- 26118852 TI - Gene expression profiles of Vibrio parahaemolyticus in the early stationary phase. AB - Vibrio (V.) parahaemolyticus is an aquatic bacterium capable of causing foodborne gastroenteritis. In the environment or the food chain, V. parahaemolyticus cells are usually forced into the stationary phase, the common phase for bacterial survival in the environment. So far, little is known about whole genomic expression of V. parahaemolyticus in the early stationary phase compared with the exponential growth phase. We performed whole transcriptomic profiling of V. parahaemolyticus cells in both phases (exponential and early stationary phase). Our data showed in total that 172 genes were induced in early stationary phase, while 61 genes were repressed in early stationary phase compared with the exponential phase. Three functional categories showed stable gene expression in the early stationary phase. Eleven functional categories showed that up regulation of genes was dominant over down-regulation in the early stationary phase. Although genes related to endogenous metabolism were repressed in the early stationary phase, massive regulation of gene expression occurred in the early stationary phase, indicating the expressed gene set of V. parahaemolyticus in the early stationary phase impacts environmental survival. SIGNIFICANCE AND IMPACT OF THE STUDY: Vibrio (V.) parahaemolyticus is one of the main bacterial causes of foodborne intestinal infections. This bacterium usually is forced into stationary phase in the environment, which includes, e.g. seafood. When bacteria are in stationary phase, physiological changes can lead to a resistance to many stresses, including physical and chemical challenges during food processing. To the best of our knowledge, highlighting the whole genome expression changes in the early stationary phase compared with exponential phase, as well as the investigation of physiological changes of V. parahaemolyticus such as the survival mechanism in the stationary phase has been the very first study in this field. PMID- 26118854 TI - Global harmonization of safety regulations for the use of industrial robots permission of collaborative operation and a related study by JNIOSH. AB - In December 2013, the Japanese Ministry of Health, Labour and Welfare (MHLW) partially amended the safety regulations for use of industrial robots so that "collaborative operation" could be performed at Japanese worksites as allowed in the ISO standard for industrial robots. In order to show global harmonization of Japanese legislation on machinery safety and problems with applying ISO safety standards to Japanese worksites, this paper reports the progress of a research study which have been conducted in National Institute of Occupational Safety and Health, Japan from 2011 to the present at the request of MHLW to examine the necessity and effect of the amendment. In the first phase of this study, a questionnaire survey was conducted among domestic robot manufacturers and users. The obtained results revealed their potential demand for the collaborative operation and problems concerning their risk assessment and rule-based risk reduction. To solve the problems, we propose a method based on an investigation result of the regulatory framework for safety of machinery in the European Union. Furthermore, a model of robot system capable of demonstrating the collaborative operation and risk reduction measures which is being developed to support appropriate implementation of the amendment is also described. PMID- 26118853 TI - Detection and mapping of illicit drugs and their metabolites in fingermarks by MALDI MS and compatibility with forensic techniques. AB - Despite the proven capabilities of Matrix Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS) in laboratory settings, research is still needed to integrate this technique into current forensic fingerprinting practice. Optimised protocols enabling the compatible application of MALDI to developed fingermarks will allow additional intelligence to be gathered around a suspect's lifestyle and activities prior to the deposition of their fingermarks while committing a crime. The detection and mapping of illicit drugs and metabolites in latent fingermarks would provide intelligence that is beneficial for both police investigations and court cases. This study investigated MALDI MS detection and mapping capabilities for a large range of drugs of abuse and their metabolites in fingermarks; the detection and mapping of a mixture of these drugs in marks, with and without prior development with cyanoacrylate fuming or Vacuum Metal Deposition, was also examined. Our findings indicate the versatility of MALDI technology and its ability to retrieve chemical intelligence either by detecting the compounds investigated or by using their ion signals to reconstruct 2D maps of fingermark ridge details. PMID- 26118855 TI - Analysis of thermal characteristics of electrical wiring for load groups in cattle barns. AB - The purpose of the current study is to analyze the thermal characteristics of electrical wirings depending on the number of operating load by connecting four types of electrical wirings that are selected by surveying the conditions for the electric fans, automatic waterers and halogen warm lamps that were installed in cattle barns in different years. The conditions of 64 cattle barns were surveyed and an experimental test was conducted at a cattle barn. The condition-survey covered inappropriate design, construction and misuse of electrical facility, including electrical wiring mostly used, and the mode of load current was evaluated. The survey showed that the mode of load current increased as the installation year of the fans, waterers and halogen lamps became older. Accordingly, the cattle barn manager needed to increase the capacity of the circuit breaker, which promoted the degradation of insulation of the electrical wires' sheath and increased possibility for electrical fires in the long-run. The test showed that the saturation temperature of the wire insulated sheath increased depending on the installation year of the load groups, in case of VCTFK and VFF electric wires, therefore, requiring their careful usage in the cattle barns. PMID- 26118856 TI - Isomer pattern and elimination of dioxins in workers exposed at a municipal waste incineration plant. AB - The aim of this study was to clarify patterns of serum concentrations of dioxins in the employees of a waste incineration plant and to estimate elimination rates and half-lives of serum dioxin isomers, and the maximum serum concentrations of dioxin isomers at the time of plant shutdown. Sixteen subjects participating 3 times or more in annual health examinations during an 8-yr period from 2000 to 2007 were recruited for this study. Serum concentrations of dioxins expressed as TEQ/g lipid decreased gradually after plant shutdown with the highest decrease observed in polychlorinated dibenzofurans (PCDFs) followed by polychlorinated deibenzo-p-dioxins (PCDDs) and then coplanar PCBs. The serum toxic equivalency (TEQ) concentrations of PCDF and PCDD congeners in the employees were higher than those in the general population survey by the Ministry of the Environment, Japan, whereas the serum concentrations of coplanar PCBs were similar to those in the general population. The estimated half-lives and elimination rates of PCDDs and PCDFs in the highly exposed workers increased compared with the moderately exposed workers. The estimated geometric mean serum concentrations of PCDDs, PCDFs and total dioxins at the time of plant shutdown were 35, 53 and 107 pg TEQ/g lipid, respectively. PMID- 26118857 TI - Surgery in neuro-oncolgy with a focus on stereotactic radiosurgery. AB - Veronica Chiang is jointly appointed as Associate Professor in Neurosurgery and Therapeutic Radiology at the Yale School of Medicine. Dr Chiang became the Medical Director of the Yale New Haven Hospital Gamma Knife Center in 2006 where currently over 300 patients are treated each year. She is predominantly interested in the management of brain metastases and now works closely with Medical Oncologists, Radiation Oncologists, Pathologists and Radiologists in the development of new treatment paradigms for patients with brain metastases as well as understanding the effects of these treatments on the normal brain. PMID- 26118858 TI - Reversible alpha-Hydrogen and alpha-Alkyl Elimination in PC(sp(3))P Pincer Complexes of Iridium. AB - Despite significant progress in recent years, the cleavage of unstrained C(sp(3)) C(sp(3)) bonds remains challenging. A C-C coupling and cleavage reaction in a PC(sp(3))P iridium pincer complex is mechanistically studied; the reaction proceeds via the formation of a carbene intermediate and can be described as a competition between alpha-hydrogen and alpha-alkyl elimination; the latter process was observed experimentally and is an unusual way of C(sp(3))-C(sp(3)) bond scission, which has previously not been studied in detail. Mechanistic details that are based upon kinetic studies, activation parameters, and DFT calculations are also discussed. A full characterization of a C-C agostic intermediate is presented. PMID- 26118859 TI - Gold-Catalyzed Proto- and Deuterodeboronation. AB - A mild gold-catalyzed protodeboronation reaction, which does not require acid or base additives and can be carried out in "green" solvents, is described. As a result, the reaction is very functional-group-tolerant, even to acid- and base sensitive functional groups, and should allow for the boronic acid group to be used as an effective traceless directing or blocking group. The reaction has also been extended to deuterodeboronations for regiospecific ipso-deuterations of aryls and heteroaryls from the corresponding organoboronic acid. Based on density functional theory calculations, a mechanism is proposed that involves nucleophilic attack of water at boron followed by rate-limiting B-C bond cleavage and facile protonolysis of a Au-sigma-phenyl intermediate. PMID- 26118860 TI - Spatio-temporal patterns of pesticide residues in the Turia and Jucar Rivers (Spain). AB - A study was conducted on the occurrence of 50 pesticides in water and sediments of Turia and Jucar Rivers (Valencian Community, Eastern Spain) for a period of two consecutive years each, 2010/2011 and 2012/2013, respectively to assess the contribution of agriculture and urban activities on pesticide pollution. The results showed that mean concentrations of pesticides ranged from =360 degrees (Group B). A lesion corresponding to an enlarged fallopian tube and mesovarium containing dilated veins between the uterus and twisted ovary is referred to as a "mass-like swelling". RESULTS: A mass-like swelling occurred more often in Group B (p < 0.05) and had the highest correlation with torsion angles >=360 degrees . A mass-like swelling lacking enhancement or a high-density area was significantly different between the groups (p < 0.05) and was also indicative of torsion angles >=360 degrees . CONCLUSION: A mass-like swelling alone or with a high-density area or lack of enhancement suggests an ovarian torsion angle >=360 degrees . The presence of these findings predict ovarian necrosis and may allow ovary-sparing treatment. PMID- 26118890 TI - Humanized mouse models of human cytomegalovirus infection. AB - The generation of humanized mouse models in which immune deficient mice are engrafted with human tissues allows for the direct in vivo investigation of human restricted viruses. These humanized mouse models have been developed and improved over the past 30 years. It is now possible to achieve high levels of human cell engraftment producing human myeloid and lymphoid lineage cells. Humanized mouse models have been increasingly utilized in the study of human cytomegalovirus (HCMV), a human-specific beta-herpesvirus that infects myeloprogenitor cells and establishes a life-long latency in the infected host. This review focuses on the strengths and limitations of the current humanized mouse models used to study HCMV replication, pathogenesis and treatment. PMID- 26118891 TI - Analysis of volatile components from Melipona beecheii geopropolis from Southeast Mexico by headspace solid-phase microextraction. AB - A head space solid-phase microextraction method combined with gas chromatography mass spectrometry was developed and optimised to extract and analyse volatile compounds of Melipona beecheii geopropolis. Seventy-three constituents were identified using this technique in the sample of geopropolis collected. The main compounds detected include beta-fenchene (14.53-15.45%), styrene (8.72-9.98%), benzaldehyde (7.44-7.82%) and the most relevant volatile components presents at high level in the geopropolis were terpenoids (58.17%). PMID- 26118892 TI - Early-onset childhood vitiligo is associated with a more extensive and progressive course. AB - OBJECTIVES: Vitiligo commonly presents in children, with half of all cases developing before 20 years of age. Although studies have characterized differences between pediatric and adult vitiligo, little is known about vitiligo presenting in early childhood. The purpose of this study was to compare clinical features of early-onset (<3 years old) and later-onset (3-18 years old) childhood vitiligo. METHODS: This retrospective case series examined patients given a diagnosis of vitiligo in a pediatric dermatology practice at an academic medical center from 1990 to 2014. Characteristics of the early- and later-onset groups were compared by chi(2) and t test for categorical and continuous variables, respectively. RESULTS: Of the 208 children in the study, 31 had early-onset and 177 had later-onset disease. Early-onset vitiligo was associated with higher percentages of body surface area involvement and increased rates of disease progression during an average 1.9 years of follow-up. There were no significant differences between the 2 groups in repigmentation, vitiligo type, halo nevi, gender ratio, or personal and family history of autoimmune diseases. LIMITATIONS: This was a retrospective, single-institution study. CONCLUSION: Patients given a diagnosis of vitiligo at younger ages tend to have more extensive and progressive disease. PMID- 26118893 TI - Sprite streamer initiation from natural mesospheric structures. AB - Sprites are large, luminous electrical discharges in the upper atmosphere caused by intense cloud-to-ground lightning flashes, manifesting an impulsive coupling mechanism between lower and upper atmospheric regions. Their dynamics are governed by filamentary streamer discharges whose propagation properties have been well studied by past work. However, how they are initiated is still under active debate. It has recently been concluded that ionospheric/mesospheric inhomogeneities are required for their initiation, but it is an open question as to what the sources of those inhomogeneities are. Here we present numerical simulation results to demonstrate that naturally-existing, small-scale mesospheric structures such as those created by gravity waves via instability and breaking are viable sources. The proposed theory is supported by a recent, unique high-speed observation from aircraft flying at 14-km altitude. The theory naturally explains many aspects of observed sprite streamer initiation and has important implications for future observational work. PMID- 26118894 TI - Ring Expansion to 1-Bromo-1-alumacyclonona-2,4,6,8-tetraene by Insertion of Two Alkyne Molecules into the Al-C Bonds. AB - Treatment of 1-bromo-2,3,4,5-tetraethylalumole (1) with 3-hexyne afforded the corresponding product 1-bromo-1-alumacyclonona-2,4,6,8-tetraene (2), accompanied by the formation of hexaethylbenzene. In the crystalline state, 2 forms a Br bridged dimer with a pseudo C2-symmetric and twisted AlC8 nine-membered ring. Deuterium-labeling experiments and DFT calculations on the reaction of 1 with 3 hexyne suggested that 1-bromo-1-alumacyclohepta-2,4,6-triene, which is formed by the insertion of one molecule of 1-hexyne into the Al-C bond of alumole 1, is the key intermediate for the generation of 2 as well as hexaethylbenzene. PMID- 26118895 TI - Molecular profiling of gliomas: potential therapeutic implications. AB - Gliomas are the most common primary malignant brain tumor. Over the last decade, significant advances have been made in the molecular characterization of this tumor group, identifying predictive biomarkers or molecular actionable targets, and paving the way to molecular-based targeted therapies. This personalized therapeutic approach is effective and illustrated in the present review. Among many molecular abnormalities, BRAF mutation and mTOR activation in pilocytic astrocytomas and subependymal giant cell astrocytomas are actionable targets sensitive to vemurafenib and everolimus, respectively. Chromosome arms 1p/19q co deletion and IDH mutational status are pivotal in driving delivery of early procarbazine, lomustine and vincristine chemotherapy in anaplastic oligodendroglial tumors. Although consensus to assess MGMT promoter methylation is not reached yet, it may be useful in predicting resistance to temozolomide in elderly patients. PMID- 26118896 TI - Chemogenetic ablation of dopaminergic neurons leads to transient locomotor impairments in zebrafish larvae. AB - To determine the impact of a controlled loss of dopaminergic neurons on locomotor function, we generated transgenic zebrafish, Tg(dat:CFP-NTR), expressing a cyan fluorescent protein-nitroreductase fusion protein (CFP-NTR) under the control of dopamine transporter (dat) cis-regulatory elements. Embryonic and larval zebrafish express the transgene in several groups of dopaminergic neurons, notably in the olfactory bulb, telencephalon, diencephalon and caudal hypothalamus. Administration of the pro-drug metronidazole (Mtz) resulted in activation of caspase 3 in CFP-positive neurons and in a reduction in dat positive cells by 5 days post-fertilization (dpf). Loss of neurons coincided with impairments in global locomotor parameters such as swimming distance, percentage of time spent moving, as well as changes in tail bend parameters such as time to maximal bend and angular velocity. Dopamine levels were transiently decreased following Mtz administration. Recovery of some of the locomotor parameters was observed by 7 dpf. However, the total numbers of dat-expressing neurons were still decreased at 7, 12, or 14 dpf, even though there was evidence for production of new dat-expressing cells. Tg(dat:CFP-NTR) zebrafish provide a model to correlate altered dopaminergic neuron numbers with locomotor function and to investigate factors influencing regeneration of dopaminergic neurons. PMID- 26118897 TI - Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat. AB - Marijuana use by adolescents has been on the rise since the early 1990s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Delta-9 tetrahydrocannabinol (THC) exposure, we used [(3)H] CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24h post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents. PMID- 26118898 TI - The use of non-adult vertebral dimensions as indicators of growth disruption and non-specific health stress in skeletal populations. AB - OBJECTIVE: Traditional methods of detecting growth disruption have focused on deficiencies in the diaphyseal length of the long bones. This study proposes the implementation of vertebral measurements (body height and transverse diameter of the neural canal) from non-adults (0-17 years) as a new methodology for the identification of growth disruption. METHODS: Measurements of vertebral body height and transverse diameter were taken from 96 non-adult skeletons and 40 adult skeletons from two post-medieval sites in England (Bow Baptist, London and Coronation Street, South Shields). Non-adult measurements were plotted against dental age to construct vertebral growth profiles through which inter-population comparisons could be made. RESULTS: Results demonstrated that both sites experienced some growth retardation in infancy, evident as deficiencies in transverse diameter. However, analysis of vertebral body height revealed different chronologies of growth disruption between the sites, with a later age of attainment of skeletal maturity recorded in the Bow Baptist sample. DISCUSSION: These vertebral dimensions undergo cessation of growth at different ages, with transverse diameter being "locked-in" by ~1-2 years of age, while vertebral body height may continue to grow into early adulthood. These measurements can therefore provide complementary information regarding the timing of growth disruption within archaeological populations. Non-adult vertebral measurements can increase our osteobiographical understanding of the timings of episodes of health stress, and allow for the analysis of growth when other skeletal elements are fragmentary. PMID- 26118899 TI - Current practices in percutaneous nephrolithotomy in Mexico: results of a nation wide electronic survey. AB - Practice patterns and choice of technological instruments in PCNL are not always standardized. There are no previous reports on the PCNL practice tendencies and patterns in Latin America. The aim of the study is to describe the current practice patterns of PCNL among the members of the Mexican Society of Urology ("Sociedad Mexicana de Urologia"). Observational and descriptive study. A 9-item closed questionnaire on PCNL practice patterns was answered by members of the Mexican Society of Urology in a secure website hosted survey after e-mail invitation. A descriptive numerical and graphical analysis was performed. A total of 90 contestants were registered out of 492 potential participants. PCNL is performed by 80% of the participants, with an average of 16 procedures per year. Percutaneous tracts are commonly obtained by urologists on the same day of the procedure. Sequential and telescopic dilators are equally preferred over balloons. The pneumatic litotriptor is the most common choice and CT scan and X ray are equally used as follow-up. The practice patterns of PCNL from Mexican urologists are different from other international reports. Influence of socio economic circumstances is inferred. PMID- 26118900 TI - Duration of Dual Antiplatelet Therapy After Drug-eluting Stents Implantation: The Jury Is Still Out. PMID- 26118901 TI - Preparation and characterization of erythromycin molecularly imprinted polymers based on distillation-precipitation polymerization. AB - Erythromycin-imprinted polymers with excellent recognition properties were prepared by an innovative strategy called distillation-precipitation polymerization. The interaction between erythromycin and methacrylic acid was studied by ultraviolet absorption spectroscopy, and the as-prepared materials were characterized by Fourier-transform infrared spectroscopy and scanning electron microscopy. Moreover, their binding performances were evaluated in detail by static, kinetic and selective sorption tests. It was found that the molecularly imprinted polymers afforded good morphology, monodispersity, and high adsorption capacity when the fraction of the monomers was 7 vol% in the whole reaction system, and the adsorption data for imprinted polymers correlated well with the Langmuir model. The maximum capacity of the imprinted and the non imprinted polymers for adsorbing erythromycin is 44.03 and 19.95 mg/g, respectively. The kinetic studies revealed that the adsorption process fitted a pseudo-second-order kinetic model. Furthermore, the imprinted polymers display higher affinity toward erythromycin, compared with its analogue roxithromycin. PMID- 26118902 TI - Mechanistic insights on the iodine(III)-mediated alpha-oxidation of ketones. AB - The synthesis of alpha-substituted carbonyl compounds is of great importance due to their ubiquity in both natural and man-made biologically active compounds. The field of hypervalent iodine chemistry has been a great contributor to access these molecules. For example, the alpha-oxidation of carbonyl compounds has been one of the most investigated iodine(III)-mediated stereoselective transformations. Yet, it is also the transformation that has met the most challenge in terms of achieving high stereoselectivities. The different mechanistic pathways of the iodine(III)-mediated alpha-tosyloxylation of ketones have been investigated. The calculations suggest an unprecedented iodine(III) promoted enolization process. Indications that iodonium intermediates could serve as proficient Lewis acids are reported. This concept could have broad impact and foster new developments in the field of hypervalent iodine chemistry. PMID- 26118903 TI - Quantifying epitope presentation using mass spectrometry. AB - Understanding the absolute quantities of MHC-bound epitopes (pMHC) presented on the surface of cells has long been a critical missing element in our knowledge of antigen presentation to T cells. Until recently, attaining such information has been restricted to the use of pMHC complex-specific monoclonal antibodies or T cell assays probing fractionated peptides eluted from cells. Although successful in a variety of cases, such approaches are limited in their scope and feasibility due to the nature of the reagents they are reliant upon. Here we report on the advancement of targeted mass spectrometry techniques to provide simultaneous and direct measurements of the relative and absolute levels of pMHC molecules and its potential for impact upon the field of antigen processing and presentation. PMID- 26118905 TI - Diastereodivergent Asymmetric 1,4-Addition of Oxindoles to Nitroolefins by Using Polyfunctional Nickel-Hydrogen-Bond-Azolium Catalysts. AB - Diastereodivergency is a challenge for catalytic asymmetric synthesis. For many reaction types, the generation of one diastereomer is inherently preferred, while the other diastereomers are not directly accessible with high efficiency and require circuitous synthetic approaches. Overwriting the inherent preference by means of a catalyst requires control over the spatial positions of both reaction partners. We report a novel polyfunctional catalyst type in which a Ni(II) bis(phenoxyimine) unit, free hydroxy groups, and an axially chiral bisimidazolium entity participate in the stereocontrol of the direct 1,4-addition of oxindoles to nitroolefins. Both epimers of the 1,4-adduct are accessible in excess on demand by changes to the ligand constitution and configuration. As the products have been reported to be valuable precursors to indole alkaloids, this method should allow access to their epimeric derivatives. PMID- 26118904 TI - Trends in gastric cancer incidence: a period and birth cohort analysis in a well defined French population. AB - BACKGROUND: The incidence of gastric cancer has declined over the past decades. Little is known about trends by site and histological subtype. The aim of this study was to analyze changes in gastric cancer incidence patterns in a French well-defined population. METHODS: Data on patients with an epithelial gastric cancer diagnosed between 1982 and 2011 were collected by the population-based digestive cancer registry of Burgundy (n = 4694). Time trends in gastric cancer incidence by period of diagnosis and birth cohort were analyzed by sex, subsite, and histological type. RESULTS: There was a decrease in incidence rates for antral carcinomas (-2.6 % per year in males, -2.5 % per year in females; p < 0.001) and corpus carcinomas (-3.3 % and -3.2 %, respectively; p < 0.001). Annual percentage changes were not significant for fundus carcinomas in both sexes and cardia carcinoma in females, although they increased in males (+1.0 % per year; p < 0.02).When comparing the 1900 cohort and the 1950 cohort, there was a five- to sevenfold decrease in the cumulative risk at 0-79 years for corpus and antral carcinomas in both sexes and a threefold decrease for fundus carcinomas. There were minor variations for cardia carcinomas. There was a decrease of incidence both by period of diagnosis and by birth cohort for adenocarcinoma and colloid carcinoma. It was more marked for undifferentiated carcinoma. The variation for signet-ring carcinoma was minor. CONCLUSION: Temporal variations in incidence rates of gastric cancer differed according to subsite and histology, suggesting different etiological factors. Available analytical studies provide an explanation for the reported trends by subsite. PMID- 26118906 TI - The Anthelmintic Drug Niclosamide Inhibits the Proliferative Activity of Human Osteosarcoma Cells by Targeting Multiple Signal Pathways. AB - Osteosarcoma (OS) is the most common primary malignant tumor of bone with a high propensity for lung metastasis. Despite significant advances in surgical techniques and chemotherapeutic regimens over the past few decades, there has been minimal improvement in OS patient survival. There is an urgent need to identify novel antitumor agents to treat human OS. Repurposing the clinically used drugs represents a rapid and effective approach to the development of new anticancer agents. The anthelmintic drug niclosamide has recently been identified as a potential anticancer agent in human cancers. Here, we investigate if niclosamide can be developed as an anti-OS drug. We find that niclosamide can effectively inhibit OS cell proliferation and survival at low micromolar concentrations. Cell migration and wounding closure are significantly inhibited by niclosamide. Niclosamide induces cell apoptosis and inhibits cell cycle progression in OS cells. Analysis of niclosamide's effect on 11 cancer-related signal pathway reporters reveals that three of them, the E2F1, AP1, and c-Myc responsive reporters, are significantly inhibited. To a lesser extent, the HIF1alpha, TCF/LEF, CREB, NFkappaB, Smad/TGFbeta, and Rbpj/Notch pathway reporters are also inhibited, while the NFAT and Wnt/beta-catenin reporters are not significantly affected by niclosamide treatment. We demonstrate that the expression of c-Fos, c-Jun. E2F1, and c-Myc in OS cells is effectively inhibited by niclosamide. Furthermore, niclosamide is shown to effectively inhibit tumor growth in a mouse xenograft tumor model of human osteosarcoma cells. Taken together, these results strongly suggest that niclosamide may exert its anticancer activity in OS cells by targeting multiple signaling pathways. Future investigations should be directed to exploring the antitumor activity in clinically relevant OS models and ultimately in clinical trials. PMID- 26118907 TI - An Innovative Fluorescent Semi-quantitative Methylation-specific PCR Method for the Determination of MGMT Promoter Methylation is Reflecting Intra-tumor Heterogeneity. AB - High grade gliomas (HGG) are usually associated with a very dismal prognosis, which was moderately improving in the last decade with the introduction of the alkylating agent temozolomide in their treatment. The methylation status of MGMT (O6 methylguanine DNA-methyltransferase) promoter is one of the strongest predictive and prognostic factors for the patient chemoresponse. For instance, the molecular method of assessment for MGMT promoter status is not standardized. In this background, we developed a fluorescent capillary gel electrophoresis based methylation specific-PCR. This technique allowed a semi-quantitative estimate of the relative ratio between methylated and unmethylated alleles. The efficacy and accuracy of the technique was assessed in a retrospective cohort of 178 newly diagnosed adult HGGs, who were homogeneously treated. First, we analyzed the impact on survival of different cut-off points in the MGMT promoter methylation and, to go further, we correlated these different rates to other well known prognostic molecular factors involved in adult HGGs. This strategy allowed to validate our technique as a very sensitive technique (detection of a low methylation percentage, < 5%), which was feasible in fresh-frozen as well as in FFPE samples and had the propensity to detect intra-tumor heterogeneity. This technique identified a new sub-group of anaplastic oligodendrogliomas or oligoastrocytomas defined by a minor methylation and a worse outcome and, therefore, will help to substratify accurately into more homogeneous subgroups of methylated tumors. PMID- 26118908 TI - Advanced lipid systems containing beta-carotene: stability under UV-vis radiation and application on porcine skin in vitro. AB - Phospholipid-based nanostructures, bicelles and bicosomes, are proposed as carriers of the antioxidant beta-carotene. The stability of these nanostructures and their carotenoid cargo was evaluated in an oxidation environment induced by ultraviolet A, visible and infrared A radiation (UVA-VIS-IRA). Additionally, the effect of these nanoaggregates on non-irradiated and irradiated skin microstructure was studied. The characterization of the lipid systems was performed using dynamic light scattering (DLS) and cryo-transmission electron microscopy (Cryo-TEM) and lipid peroxidation of the systems was determined by thiobarbituric acid (TBARS) assay. Moreover, the stability of beta-carotene in these lipid systems under this radiation was investigated using Raman spectroscopy. The results showed that the particle size of the bicelles did not change due to radiation. However, the size of the bicosomes increased slightly after irradiation. The TBARS assay showed the absence of peroxides in the bicelles and bicosomes, indicating the preservation of the lipid molecules under the radiation used. Raman experiments showed that bicosomes protected beta carotene from degradation induced by radiation better than liposomes or dissolution in chloroform. With respect to the skin microstructure, no changes after irradiation were observed via freeze substitution transmission electron microscopy (FSTEM). This technique also showed the presence of vesicular structures in the stratum corneum (SC) after treatment with bicosomes. PMID- 26118909 TI - Characteristics of alpha males in Nepal gray langurs. AB - In species with strong male-male competition, access to females in multimale multifemale groups is usually regulated via a dominance hierarchy. The highest ranking (alpha) male often has priority of access and sires most offspring. The alpha male can change in three basic ways: (i) a recent immigrant or a resident challenges and becomes the new alpha; (ii) formation of a new group; (iii) succession-becoming alpha after higher ranking males have left. When, in a given primate population, the alpha male changes in different ways, two questions arise: (a) which is the most successful tactic and (b) do male attributes, such as age, aggressiveness or propensity to commit infanticide, affect the outcome? We examined these questions in the seasonally breeding Nepal gray langurs (Semnopithecus schistaceus) at Ramnagar, where new alpha males were either recent immigrants or residents. Success was measured as alpha tenure, residency duration, and the number of offspring sired (paternity exclusion based on DNA analysis, 28 infants). We documented 12 alpha-male tenures across two multimale multifemale groups between 1991 and 1997. The predominant mode of change was the immigrant tactic. Age had no effect perhaps because alpha males were among the youngest adult males in their group. As expected, infanticidal males performed similarly to non-infanticidal ones. Alpha tenure was highly variable and longer for immigrant alphas and hyper-aggressive ones. However, none of the tactics or attributes examined resulted in significantly longer residencies or more offspring, likely because of the timing of immigrations and stochastic effects (i.e., the number of conceptions occurring per alpha tenure). The influence of female mate choice on male reproductive success requires further investigation. Furthermore, it remains to be examined why resident alpha males-with their presumed better knowledge of their opponents -performed so poorly. Am. J. Primatol. 79:e22437, 2017. (c) 2015 Wiley Periodicals, Inc. PMID- 26118910 TI - Sleep neurobiology and critical care illness. AB - The intensive care unit (ICU) environment is not propitious for restoring sleep and many studies have reported that critically ill patients have severe sleep disruptions. However, sleep alterations in critically ill patients are specific and differ significantly from those in ambulatory patients. Polysomnographic patterns of normal sleep are frequently lacking in critically ill patients and the neurobiology of sleep is important to consider regarding alternative methods to quantify sleep in the ICU. This article discusses elements of sleep neurobiology affecting the specificity of sleep patterns and sleep alterations in patients admitted to the ICU. PMID- 26118911 TI - Circadian dysrhythmias in the intensive care unit. AB - Circadian rhythms underlie nearly all physiologic functions and organ systems. Circadian abnormalities have attendant implications for critical illness survival. The intensive care unit (ICU) environment, with its lack of diurnal variation in sound, light, and social cues, may precipitate circadian dysrhythmias. Additional features of critical care, including mechanical ventilation and sedation, likely perpetuate circadian misalignment. Critical illness itself, from sepsis to severe brain injury, can compromise circadian health. Use of daylight, time-restricted feedings, and administration of melatonin can possibly restore circadian rhythm. However, further study is necessary to assess the effectiveness of these interventions and their impact on ICU outcomes. PMID- 26118912 TI - Sleep and the endocrine system. AB - In this article, the effect of sleep and sleep disorders on endocrine function and the influence of endocrine abnormalities on sleep are discussed. Sleep disruption and its associated endocrine consequences in the critically ill patient are also reviewed. PMID- 26118913 TI - Obesity hypoventilation syndrome in the critically ill. AB - This article summarizes available data on the obesity hypoventilation syndrome and its pertinence to intensivists, outlines clinical and pathophysiologic aspects of the disease, discusses multidisciplinary treatments, and reviews the available literature on outcomes specific to the critically ill patient. PMID- 26118914 TI - Noninvasive ventilation in critically ill patients. AB - Since its first application in the late 1980s, noninvasive ventilation (NIV) has been the first-line intervention for certain forms of acute respiratory failure. NIV may be delivered through the patient's mouth, nose, or both using noninvasive intermittent positive pressure ventilation or continuous positive airway pressure. When applied appropriately, NIV may reduce morbidity and mortality and may avert iatrogenic complications and infections associated with invasive mechanical ventilation. This article provides physicians and respiratory therapists with a comprehensive, practical guideline for using NIV in critical care. PMID- 26118915 TI - Restless legs syndrome. AB - Restless legs syndrome is a common sensorimotor disorder characterized by an urge to move, and associated with uncomfortable sensations in the legs (limbs). Restless legs syndrome can lead to sleep-onset or sleep-maintenance insomnia, and occasionally excessive daytime sleepiness, all leading to significant morbidity. Brain iron deficiency and dopaminergic neurotransmission abnormalities play a central role in the pathogenesis of this disorder, along with other nondopaminergic systems, although the exact mechanisms are still. Intensive care unit patients are especially vulnerable to have unmasking or exacerbation of restless legs syndrome because of sleep deprivation, circadian rhythm disturbance, immobilization, iron deficiency, and use of multiple medications that can antagonize dopamine. PMID- 26118917 TI - Perioperative issues and sleep-disordered breathing. AB - Sleep-disordered breathing in the perioperative setting poses an increase in both perceived and demonstrated challenges for health care providers. Some of these challenges relate to identifying patients at high risk for obstructive sleep apnea prior to surgery. Other management challenges include identifying the proper monitoring techniques, using the correct mix of pharmacologic and nonpharmacologic strategies to manage these patients, and identifying the proper and safe disposition strategy after surgery. Additional populations, such as pediatrics and the morbidly obese, are also highlighted, which may help address questions in populations that are frequently managed in the critical care setting postoperatively. PMID- 26118916 TI - Congestive heart failure and central sleep apnea. AB - Congestive heart failure (CHF) is among the most common causes of admission to hospitals in the United States, especially in those over age 65. Few data exist regarding the prevalence CHF of Cheyne-Stokes respiration (CSR) owing to congestive heart failure in the intensive care unit (ICU). Nevertheless, CSR is expected to be highly prevalent among those with CHF. Treatment should focus on the underlying mechanisms by which CHF increases loop gain and promotes unstable breathing. Few data are available to determine prevalence of CSR in the ICU, or how CSR might affect clinical management and weaning from mechanical ventilation. PMID- 26118918 TI - Seizures in sleep: clinical spectrum, diagnostic features, and management. AB - Sleep is disrupted in most patients hospitalized in the intensive care unit and the disturbances are even more profound in patients impacted by epilepsy. Nocturnal seizures must be differentiated from other common nocturnal events, such as delirium, parasomnias, and sedation. Many antiepileptic drugs produce undesirable side effects on sleep architecture that may further predispose patients to insomnia during the night and excessive sedation and hypersomnolence during the day. Failure to recognize, correctly diagnose, and adequately manage these disturbances may lead to more prolonged hospitalization, increased risk for nosocomial infections, poorer health-related qualify of life, and greater health care financial burden. PMID- 26118920 TI - Sleep in traumatic brain injury. AB - More than one-half million patients are hospitalized annually for traumatic brain injury (TBI). One-quarter demonstrate sleep-disordered breathing, up to 50% experience insomnia, and half have hypersomnia. Sleep disturbances after TBI may result from injury to sleep-regulating brain tissue, nonspecific neurohormonal responses to systemic injury, ICU environmental interference, and medication side effects. A diagnosis of sleep disturbances requires a high index of suspicion and appropriate testing. Treatment starts with a focus on making the ICU environment conducive to normal sleep. Treating sleep-disordered breathing likely has outcome benefits in TBI. The use of sleep promoting sedative-hypnotics and anxiolytics should be judicious. PMID- 26118919 TI - Neuromuscular disorders and sleep in critically ill patients. AB - Sleep-disordered breathing (SDB) is a frequent presenting manifestation of neuromuscular disorders and can lead to significant morbidity and mortality. If not recognized and addressed early in the clinical course, SDB can lead to clinical deterioration with respiratory failure. The pathophysiologic basis of SDB in neuromuscular disorders, clinical features encountered in specific neuromuscular diseases, and diagnostic and management strategies for SDB in neuromuscular patients in the critical care setting are reviewed. Noninvasive positive pressure ventilation has been a crucial advance in critical care management, improving sleep quality and often preventing or delaying mechanical ventilation and improving survival in neuromuscular patients. PMID- 26118921 TI - Sedation in critically ill patients. AB - Sedation in the intensive care unit (ICU) is a topic that has been frequently researched, and debate still exists as to what are the best sedative agents for critically ill patients. There is increasing interest in sleep and circadian rhythm disturbances in the ICU and how they may impact on outcomes. In addition to patient-related and ICU environmental factors that likely impact sleep and circadian rhythm in the ICU, sedative and analgesic medications may also play a role. PMID- 26118922 TI - Delirium in critically ill patients. AB - Delirium in the intensive care unit (ICU) is a common diagnosis, with an incidence ranging between 45% and 87%. Delirium represents a significant burden both to the patient and to the health care system, with a 3.2-fold increase in 6 month mortality and annual US health care costs up to $16 billion. In this review, the diagnosis, epidemiology, and risk factors for delirium in the ICU are discussed. The pathophysiology of delirium and evolving prevention and treatment modalities are outlined. PMID- 26118923 TI - Sleep and circadian rhythms in the intensive care unit. PMID- 26118924 TI - Chemical and Metabolic Profiling of Si-Ni Decoction Analogous Formulae by High performance Liquid Chromatography-Mass Spectrometry. AB - Along with an indispensable role in healthcare system of China for centuries, Traditional Chinese Medicine (TCM) shows increasing usages as complementary therapy in western countries. To improve our understanding on their therapeutic effects, it's critical to unveil chemical compositions of TCM formula, the predominant form of therapy in TCM. However, intrinsic chemical complexity makes it a challenging task to perform analysis on each individual TCM formula even with most current state-of-art analytic techniques available. In this work we approached this question by focusing on analogous formulae, a unique category of TCM formulae grouped together based on shared herbs and/or similar TCM syndromes. Systematic chemical profiling on five Si-Ni decoctions (SNs) for cardiovascular diseases was performed by multistage MS and high-resolution MS (HR-MS) experiments. A total of 83 compounds, including alkaloids, flavonoids, ginsenosides, bile acids and triterpenoids, were described. Analysis on SNs treated rats detected 55 prototype compounds and 39 metabolites in the systemic circulation in vivo, which may contribute directly to their observed clinical efficacies. This approach offers great advantage to speed up identification of chemical compositions of formula and reveal the difference among these analogous formulae that may be related to diverse clinical effects. PMID- 26118925 TI - Endoscopic Balloon Dilation of Esophageal Strictures in 9 Horses. AB - BACKGROUND: Medical treatment of esophageal strictures in horses is limited and the use of balloon dilatation is described in few cases. Long-term follow up after balloon dilatation and the use of intralesional corticosteroids has not been evaluated. OBJECTIVES: To describe the use of endoscopic guided, esophageal balloon dilatation in horses for cervical and thoracic esophageal strictures and administration of intralesional corticosteroids at the time of dilatation. ANIMALS: Nine horses from the hospital population with benign esophageal strictures. METHODS: Retrospective study: Medical records were reviewed from horses presented to the William R. Pritchard, Veterinary Medical Teaching Hospital at UC Davis from 2002 to 2013. Records were searched using the key words: equine, horse, balloon dilatation, bougienage, and esophageal stricture. RESULTS: Nine horses with esophageal strictures were treated with esophageal balloon dilatation. Five horses survived (survival at writing ranged from 2 to 11 years after discharge) and all nonsurvivors were <1 year of age and presented with concurrent problems or developed complications including megaesophagus, unresolved esophageal obstruction requiring esophagostomy, or severe aspiration pneumonia. Four horses were treated with intralesional corticosteroids with no adverse effects noted in the survivors (n = 3). Four horses available for long term follow up were alive at 2, 5, 6, and 11 years after presentation and 3 of these horses were being fed a hay-based diet. CONCLUSIONS: Resolution of esophageal strictures in the horse can be performed successfully, safely, and under standing sedation using balloon dilatation. Intralesional corticosteroids might reduce the incidence of recurrent strictures. PMID- 26118926 TI - Anesthesia for liver transplantation. AB - Patients with end stage liver disease (ESLD) have complex problems such as cirrhotic cardiomyopathy, coronary artery disease, hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), hepatic encephalopathy, intracranial hypertension, (ICP), left ventricular outflow tract obstruction (LVOTO), high Model of end liver disease (MELD) scores, hyponatremia, and coagulopathies. The anesthesia management for liver transplantation can be very complex, dynamic and challenging. Anesthesia agents affect hepatic blood flow and anesthetic drug distribution, metabolism and elimination maybe altered in end stage liver disease. Other non-anesthetic agents such as nitric oxide, epoprosterenol, THAM, hypertonic saline, fibrinogen concentrates, fresh frozen plasma, platelets, packed red blood cells, recombinant plasminogen activator, calcium chloride, epinephrine etc. may play a vital role in the perioperative management of these patients. Intraoperative hemostasis and coagulation management can be very arduous as these patients may bleed or be at risk for thrombosis. Monitoring modalities such as Thromboelastography (TEG), Transcranial Doppler (TCD), Transesophageal Echocardiography (TEE), Bispectral Index (BIS) and Optic Nerve Sheath Diameter (ONSD) ultrasound play a significant role in various circumstances. Surgical techniques include complete or partial occlusion of the inferior vena cava (IVC) with or without use of venovenous bypass (VVBP) or portocaval shunts. Post reperfusion syndrome (PRS) is a crucial event in this procedure, where patients may experience arrhythmia and/or cardiac arrest. Anesthetic handling of this phase has been recapitulated in detail. Provision of anesthesia services to the living liver transplant donor and pain management has been outlined. PMID- 26118929 TI - Antagonistic functionalized nucleation and oxidative degradation in combustive formation of pyrene-based clusters mediated by triplet O and O2 : theoretical study. AB - Polycyclic aromatic hydrocarbons (PAHs) and carbonaceous nanoparticles can be oxidized right from their inception and all through their growth. Oxidation can also promote their degradation. This modelistic density functional theory (DFT) study explores, in a descriptive manner, if oxidation can mediate the earliest stages of nucleation ("functionalized nucleation"), though contrasted by mass declension triggered by oxidation itself. Initial O ((3) P) attack onto pyrene, chosen as a representative of a generic small PAH or nascent soot lamella, forms an oxyl diradical intermediate that can evolve into an open-shell epoxide, phenol, or ketone species or, alternatively, undergo mass depletion from the beginning (without impeding further additions). Open-shell intermediates can add O or O2 ((3) Sigmag (-) ) and ethyne, in any order, and open the way, through formation of carbon and oxygen bridges, to the addition of a second molecule of pyrene, whereas formation of direct carbon-carbon links between the two PAH-like parts might also occur. PMID- 26118928 TI - HMG-CoA Reductase Inhibitors Bind to PPARalpha to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. AB - Neurotrophins are important for neuronal health and function. Here, statins, inhibitors of HMG-CoA reductase and cholesterol lowering drugs, were found to stimulate expression of neurotrophins in brain cells independent of the mevalonate pathway. Time-resolved fluorescence resonance energy transfer (FRET) analyses, computer-derived simulation, site-directed mutagenesis, thermal shift assay, and de novo binding followed by electrospray ionization tandem mass spectrometry (ESI-MS) demonstrates that statins serve as ligands of PPARalpha and that Leu331 and Tyr 334 residues of PPARalpha are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARalpha-mediated transcriptional activation of cAMP-response element binding protein (CREB). Accordingly, simvastatin increases CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of Ppara null mice receiving full-length lentiviral PPARalpha, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARalpha. This study identifies statins as ligands of PPARalpha, describes neurotrophic function of statins via the PPARalpha-CREB pathway, and analyzes the importance of PPARalpha in the therapeutic success of simvastatin in an animal model of Alzheimer's disease. PMID- 26118930 TI - Morphometric analysis and developmental comparison of embryos from carriers with balanced chromosomal rearrangements in preimplantation genetic diagnosis cycles. AB - The morphological parameters of embryos from 22 carriers with balanced chromosomal rearrangements (CRs) were quantified and evaluated to determine their possible link to chromosomal composition. The morphometric characteristics of 168 embryos diagnosed by fluorescence in situ hybridisation were measured using an imaging tool and then analysed retrospectively. The mean zygotic diameter of normal-balanced embryos was significantly smaller compared with that of abnormal embryos (P=0.015). In addition, the reduction in total cytoplasmic volume for Day 3 embryos was significantly lower in normal or balanced embryos than in abnormal embryos (P=0.027). Moreover, the pronuclear volumes of embryos that failed to reach the blastocyst stage were significantly smaller compared with those of blastocysts (P=0.016). These findings indicate that morphometric characteristics are correlated with developmental outcomes as well as with chromosomal composition in embryos from balanced CR carriers. However, an effective indicator of developmental outcomes may not accurately reflect chromosomal composition. Combining morphometric and traditional qualitative assessment may increase the precision and standardisation of embryo evaluation as well as contributing to improved efficiency of preimplantation genetic diagnosis by selecting embryos with high developmental potential and preferentially testing embryos predicted to have a low risk of chromosomal imbalance. PMID- 26118931 TI - The BIG Score and Prediction of Mortality in Pediatric Blunt Trauma. AB - OBJECTIVES: To examine the association between in-hospital mortality and the BIG (composed of the base deficit [B], International normalized ratio [I], Glasgow Coma Scale [G]) score measured on arrival to the emergency department in pediatric blunt trauma patients, adjusted for pre-hospital intubation, volume administration, and presence of hypotension and head injury. We also examined the association between the BIG score and mortality in patients requiring admission to the intensive care unit (ICU). STUDY DESIGN: A retrospective 2001-2012 trauma database review of patients with blunt trauma <= 17 years old with an Injury Severity score >= 12. Charts were reviewed for in-hospital mortality, components of the BIG score upon arrival to the emergency department, prehospital intubation, crystalloids >= 20 mL/kg, presence of hypotension, head injury, and disposition. RESULTS: 50/621 (8%) of the study patients died. Independent mortality predictors were the BIG score (OR 11, 95% CI 6-25), prior fluid bolus (OR 3, 95% CI 1.3-9), and prior intubation (OR 8, 95% CI 2-40). The area under the receiver operating characteristic curve was 0.95 (CI 0.93-0.98), with the optimal BIG cutoff of 16. With BIG <16, death rate was 3/496 (0.006, 95% CI 0.001 0.007) vs 47/125 (0.38, 95% CI 0.15-0.7) with BIG >= 16, (P < .0001). In patients requiring admission to the ICU, the BIG score remained predictive of mortality (OR 14.3, 95% CI 7.3-32, P < .0001). CONCLUSIONS: The BIG score accurately predicts mortality in a population of North American pediatric patients with blunt trauma independent of pre-hospital interventions, presence of head injury, and hypotension, and identifies children with a high probability of survival (BIG <16). The BIG score is also associated with mortality in pediatric patients with trauma requiring admission to the ICU. PMID- 26118932 TI - An Update on Pediatric Atopic Dermatitis and Food Allergies. PMID- 26118927 TI - NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. AB - NAD(+) has emerged as a vital cofactor that can rewire metabolism, activate sirtuins, and maintain mitochondrial fitness through mechanisms such as the mitochondrial unfolded protein response. This improved understanding of NAD(+) metabolism revived interest in NAD(+)-boosting strategies to manage a wide spectrum of diseases, ranging from diabetes to cancer. In this review, we summarize how NAD(+) metabolism links energy status with adaptive cellular and organismal responses and how this knowledge can be therapeutically exploited. PMID- 26118933 TI - Immunization of sea bream (Sparus aurata) juveniles against Photobacterium damselae subsp. piscicida by short bath: Effect on some pro-inflammatory molecules and the Mx gene expression. AB - Cytokines are a family of proteins derived from macrophages, lymphocytes, granulocytes, mast cells and epithelial cells and can be divided into interferons (IFNs), Interleukins (ILs) and Tumor Necrosis factors (TNFs) among others. The presence of cytokines in a wide number of fish species has been proved and several molecules types have been already cloned and sequenced. In this work some proinflamatory molecules and Mx gene were detected in the liver of vaccinated sea bream juveniles with an average body weight of 5 g. The method of immunization was by short bath and three different bacterins against the marine pathogen Photobacterium damselae subsp. piscicida were designed and used to immunize fish. Five genes encoding for five different molecules were analyzed by real time PCR: IL-1beta, IL Ir-2, Cox-2, Mx and TNFalpha. Gene expression was quantified along four days after fish immunization and results were compared among groups. Results show that the heat-inactivated vaccine stimulates the up-regulation of IL-1beta, IL Ir-2, Cox-2 and TNFalpha genes whereas the UV-light inactivated vaccine was the unique vaccine which stimulates the expression of Mx gene. The present is a novel study that shows by the first time the effect of the inactivation process of vaccines on the expression levels of genes involved in the defense against Photobacterium damselae subsp piscicida. PMID- 26118934 TI - The effect of banana (Musa acuminata) peels hot-water extract on the immunity and resistance of giant freshwater prawn, Macrobrachium rosenbergii via dietary administration for a long term: Activity and gene transcription. AB - The non-specific immune parameters, disease resistance and immune genes expressions in Macrobrachium rosenbergii were evaluated at 120 days of post feeding the diets containing the extracts of banana, Musa acuminate, fruit's peel (banana peels extract, BPE) at 0, 1.0, 3.0 and 6.0 g kg(-1). Results showed that prawns fed with a diet containing BPE at the level of 1.0, 3.0 and 6.0 g kg(-1) for 120 days had a significantly higher survival rate (30.0%, 40.0% and 56.7%, respectively) than those fed with the control diet after challenge with Lactococcus garvieae for 144 h, and the respective relative survival percentages were 22.2%, 33.3%, and 51.9%, respectively. Dietary BPE supplementation at 3.0 and/or 6.0 g kg(-1) for 120 days showed a significant increase total haemocyte count (THC), granular cell (GC), superoxide dismutase (SOD) activity, phenoloxidase (PO) activity, transglutaminase (TG) activity, and phagocytic activity and clearance efficiency to L. garvieae infection, and meanwhile, the significant decrease in haemolymph clotting times and respiratory bursts (RBs) per haemocyte of prawns were revealed. Furthermore, the mRNA expressions of prophenoloxidase (proPO), lipopolysaccharide and beta-1,3-glucan binding protein (LGBP), peroxinectin (PE), transglutaminase (TG), and crustin (CT) were significantly increased. We therefore recommend that BPE can be used as an immunomodulator for prawns through dietary administration at 6.0 g kg(-1) for a long term (over 120 days) to modify immune responses and genes expression following the enhanced resistance against pathogens. PMID- 26118935 TI - The efficacy and safety of rabbit anti-thymocyte globulin vs rabbit anti-T lymphocyte globulin in peripheral blood stem cell transplantation from unrelated donors. AB - The comparative efficacy and safety of antithymocyte globulin (ATG) at fixed doses in patients undergoing allogeneic peripheral blood stem cell transplantation from unrelated donors (UR-PBSCT) has not been evaluated. In this study, the records of 56 patients and 54 patients who received pre-transplant ATG Thymoglobulin (ATG-T) at a total dose of 10 mg/kg and ATG- Fresenius (ATG-F) at a total dose of 20 mg/kg, respectively, were retrospectively analyzed. ATG-F patients had a significantly lower probability of developing chronic graft-vs host disease (cGVHD) than those treated with ATG-T (p = 0.04). ATG-F was associated with a non-significant trend towards lower relapse rates and higher survival at 3- and 5-years of follow-up compared with ATG-T. A significantly greater proportion of ATG-T patients experienced chills and high fever than ATG-F patients (p < 0.01). The current findings suggest that ATG-F may more effectively and safely prevent cGVHD without increasing relapse rates in patients undergoing UR-PBSCT. PMID- 26118936 TI - The Reliability of the Reflux Finding Score Among General Otolaryngologists. AB - BACKGROUND: The reflux finding score (RFS) is a validated clinical severity scale for findings of laryngopharyngeal reflux (LPR) on fiberoptic laryngoscopy. To our knowledge, there have been no studies to determine whether severity of patient symptoms influence the RFS; in addition, the reliability of the RFS has not been tested for general otolaryngologists. OBJECTIVES: The objectives of this study were (1) to determine whether the RFS for LPR is influenced by symptoms of reflux and (2) to determine the inter-rater reliability for general otolaryngologists in diagnosing LPR using the RFS. METHODS: Ten general otolaryngologists were selected to participate. Participants were asked to complete an Internet survey consisting of flexible endoscopic videos of larynges with varying physical findings of reflux and grade the severity of reflux using the RFS. The videos were randomly shown with and without accompanying patient symptoms. RESULTS: Our data suggest that patient symptoms influence the RFS. Inter-rater reliability for general otolaryngologists using the RFS is fair. CONCLUSIONS: Among general otolaryngologists in our study, the reliability and objectivity of the RFS in diagnosing reflux cannot be demonstrated. PMID- 26118937 TI - Maternal cardiac and obstetric performance in consecutive pregnancies in women with heart disease. AB - OBJECTIVE: Second pregnancies are usually less complicated than first pregnancies, and have a better outcome in terms of fetal growth. We studied a group of women with heart disease to assess whether their second pregnancy was less complicated and resulted in a larger baby. DESIGN: Retrospective case control study. SETTING: Tertiary referral academic obstetric unit. POPULATION: First and second pregnancies in 77 women with congenital and acquired heart disease and in 154 control women were identified. METHODS: Data were collected from medical and obstetric records. MAIN OUTCOME MEASURES: Cardiac complications, obstetric complications, intra-partum events, birthweight and perinatal complications. RESULTS: The rate of obstetric complication was greater in first pregnancies in both the heart disease and the control groups (38% versus 26%, cf. 20% versus 17%). In the heart disease group, the rate of cardiac complications was similar in first and second pregnancies (9% versus 6%). Overall, significantly more perinatal complications were seen in the heart disease group, with no significant difference between first and second pregnancies (36% versus 27%, cf. 14% versus 12%). Median birthweight was significantly higher in second pregnancies in the control group (3308 versus 3519 g P < 0.001), but not significantly different between pregnancies in the heart disease group (3014 versus 3133 g, P = 0.19). CONCLUSIONS: This case control study demonstrates that women with mild to moderate heart disease have similar pregnancy outcomes in consecutive pregnancies. However, while the median birthweight was higher in the control second pregnancies, it was not increased in the women with heart disease. TWEETABLE ABSTRACT: A study of women with heart disease to assess whether their second pregnancy was less complicated. PMID- 26118938 TI - Preparation of biodegradable PEGylated pH/reduction dual-stimuli responsive nanohydrogels for controlled release of an anti-cancer drug. AB - A facile and efficient method was developed to prepare the monodisperse biodegradable PEGylated pH and reduction dual-stimuli sensitive poly[methacrylic acid-co-poly(ethylene glycol) methyl ether methacrylate-co-N,N bis(acryloyl)cystamine] (PMPB) nanohydrogels with dried particle size below 200 nm via one-step distillation precipitation polymerization as a drug delivery system (DDS) for the controlled release of a wide-spectrum anti-cancer drug, doxorubicin hydrochloride (DOX). Under normal physiological media, the nanohydrogels possessed high drug encapsulation efficiency (more than 96%) within 48 h and exhibited good stability with a trifle premature drug release. However, rapid DOX release was achieved at lower pH or in the presence of reductive reagent glutathione (GSH) with a cumulative release of more than 85% within 30 h. Furthermore, the nanohydrogels manifested nontoxicity on HepG2 cells at a concentration of 10 MUg mL(-1) or lower. Based on the excellent characteristics of the nanohydrogels, such as low toxicity, impressive biodegradability, sharp dual responsiveness, adequate drug loading capacity and a high drug encapsulation efficiency, they were supposed to have potential application in the area of cancer therapy. PMID- 26118940 TI - Reduction of aggression evoked by sounds using noncontingent reinforcement and time-out. AB - Some individuals with developmental disabilities engage in problem behavior to escape or avoid auditory stimuli. In this study, a 6-year-old boy with autism engaged in severe aggression in the presence of specific sounds. Following an assessment based on the procedures described by McCord, Iwata, Galensky, Ellingson, and Thomson (2001), we treated negatively reinforced behavior using noncontingent reinforcement and time-out from positive reinforcement in the absence of extinction. Treatment was effective in reducing aggression across multiple sounds. PMID- 26118939 TI - Position Statement on the management of continuous subcutaneous insulin infusion (CSII): The Italian Lazio experience. AB - This document has been developed by a group of Italian diabetologists with extensive experience in continuous subcutaneous insulin infusion (CSII) therapy to provide indications for the clinical management of CSII in diabetic patients (both type 1 and type 2) based on delivery mode operating in Italy. Although the potential benefits of pump therapy in achieving glycemic goals is now accepted, such results cannot be obtained without specific knowledge and skills being conveyed to patients during ad hoc educational training. To ensure that these new technologies reach their full effectiveness, as demonstrated theoretically and clinically, a careful assessment of the overall therapeutic and educational process is required, in both qualitative and quantitative terms. Therefore, to ensure the cost-effectiveness of insulin pump therapy and to justify reimbursement of therapy costs by the National Health System in Italy, in this article we present a model for diabetes and healthcare centers to follow that provides for different levels of expertise in the field of CSII therapy. This model will guarantee the provision of excellent care during insulin pump therapies, thus representing the basis for a successful outcome and expansion of this form of insulin treatment in patients with diabetes while also keeping costs under control. PMID- 26118941 TI - Return to competition, re-injury, and impact on performance of preseason shoulder injuries in Major League Baseball pitchers. AB - OBJECTIVE: Major league baseball (MLB) pitchers are vulnerable to overuse injury of the upper extremity, especially in the shoulder. Injuries sustained in the preseason may have negative impact on performance following return. The goal of this study was to document the frequency of preseason shoulder injury in these athletes, as well as risk for re-injury and impact on performance following return from injury. METHODS: A comprehensive search of MLB injury information from 2001 to 2010 of public databases yielded a cohort of MLB pitchers who sustained preseason shoulder injuries. These databases were utilized to obtain information regarding return to MLB competition, re-injury, and performance following return from injury. All performance metrics were compared to those of an age-matched control cohort. RESULTS: A total of 74 pitchers were identified who sustained a preseason shoulder injury. Only 39 (53%) returned that same season to pitch in the MLB competition. Of those that returned, nearly 50% of players were re-designated on the Disabled List during the return season. There was a decline in performance in earned run average and batting average against in the year of return. Compared to age-matched control pitchers, those with preseason shoulder injury had lower performance metrics across a number of outcomes. CONCLUSION: Preseason shoulder injury in MLB pitchers has the potential to result in high re-injury rates and decreased subsequent performance. PMID- 26118942 TI - Clinical and histological aspect of erythema dyschromicum perstans in Korea: A review of 68 cases. AB - Erythema dyschromicum perstans (EDP) is a hypermelanotic disorder of the idiopathic variety characterized by blue-gray macules in healthy individuals. It has been described mainly in patients from tropical areas of Central and South America. Our aim was to evaluate EDP in Korea through the analysis of retrospective case series with EDP and to describe the clinical and histopathological features. It was a retrospective study (2002-2012) of EDP confirmed by review of clinical photographs and biopsy specimens. The files of 68 patients with EDP from six tertiary medical centers in Korea were included in this study. Of the 68 patients, 29 were male and 39 female. The age of patients ranged 3-76 years (mean, 33.9). Clinically, the majority of patients had lesions on the trunk (n = 47, 69.1%); the neck was affected in 27 cases, the upper extremities in 26, the face in 22 and the lower extremities in 16. Peripheral erythematous borders were observed in 12 patients (17.6%) and 11 patients had itching sensation at the lesion. Histopathologically, dermal melanophages and pigment incontinence were the most common findings. A follow up of more than 1 year was obtained in 51 patients. Of these, only one patient experienced complete clearance without recurrence. Our study illustrates the clinical and histopathological findings of EDP in Koreans. Our multicenter data may contribute to the understanding of EDP. PMID- 26118943 TI - Utilization and likelihood of radiologic diagnostic imaging in patients with implantable cardiac defibrillators. AB - PURPOSE: To examine imaging utilization in a matched cohort of patients with and without implantable cardioverter defibrillators (ICD) and to project magnetic resonance imaging (MRI) utilization over a 10-year period. MATERIALS AND METHODS: The Truven Health MarketScan Commercial claims and Medicare Supplemental health insurance claims data were used to identify patients with continuous health plan enrollment in 2009-2012. Patients with ICDs were identified using ICD-9 and CPT codes, and matched to patients with the same demographic and comorbidity profile, but no record of device implantation. Diagnostic imaging utilization was compared across the matched cohorts, in total, by imaging categories, and in subpopulations of stroke, back pain, and joint pain. MRI use in the nonimplant group over the 4-year period was extrapolated out to 10 years for ICD-indicated patients. RESULTS: A cohort of 18,770 matched patients were identified; average age 65.5 +/- 13.38 and 21.9% female. ICD patients had significantly less MRI imaging (0.23 0.70 SD vs. 0.00 0.08 SD, P < 0.0001) than nonimplant patients. Among patients with records of stroke/transient ischemic attack (TIA) (ICD 5%, nonimplant 4%) and accompanying diagnostic imaging, 44% of nonimplant patients underwent MRI vs. 1% of ICD patients (P < 0.0001). Forecast models estimated that 53% to 64% of ICD-eligible patients may require an MRI within 10 years. CONCLUSION: MRI utilization is lower in ICD patients compared to nonimplant patients, yet the burden of incident stroke/TIA, back, and joint pain suggests an unmet need for MR-conditional devices. PMID- 26118945 TI - Targeted neural differentiation of murine mesenchymal stem cells by a protocol simulating the inflammatory site of neural injury. AB - Damaged neural tissue is regenerated by neural stem cells (NSCs), which represent a rare and difficult-to-culture cell population. Therefore, alternative sources of stem cells are being tested to replace a shortage of NSCs. Here we show that mouse adipose tissue-derived mesenchymal stem cells (MSCs) can be effectively differentiated into cells expressing neuronal cell markers. The differentiation protocol, simulating the inflammatory site of neural injury, involved brain tissue extract, fibroblast growth factor, epidermal growth factor, supernatant from activated splenocytes and electrical stimulation under physiological conditions. MSCs differentiated using this protocol displayed neuronal cell morphology and expressed genes for neuronal cell markers, such as neurofilament light (Nf-L), medium (Nf-M) and heavy (Nf-H) polypeptides, synaptophysin (SYP), neural cell adhesion molecule (NCAM), glutamic acid decarboxylase (GAD), neuron specific nuclear protein (NeuN), betaIII-tubulin (Tubb3) and microtubule associated protein 2 (Mtap2), which are absent (Nf-L, Nf-H, SYP, GAD, NeuN and Mtap2) or only slightly expressed (NCAM, Tubb3 and Nf-M) in undifferentiated cells. The differentiation was further enhanced when the cells were cultured on nanofibre scaffolds. The neural differentiation of MSCs, which was detected at the level of gene expression, was confirmed by positive immunostaining for Nf-L protein. The results thus show that the simulation of conditions in an injured neural tissue and inflammatory environment, supplemented with electrical stimulation under physiological conditions and cultivation of cells on a three dimensional (3D) nanofibre scaffold, form an effective protocol for the differentiation of MSCs into cells with neuronal markers. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26118944 TI - Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings. AB - BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT. PMID- 26118946 TI - Macrocyclic Gd(3+) complexes with pendant crown ethers designed for binding zwitterionic neurotransmitters. AB - A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1) s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (~80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved. PMID- 26118947 TI - Are overdoses treated by ambulance services an opportunity for additional interventions? A prospective cohort study. AB - AIMS: To assess whether people who inject drugs (PWID) and who are treated for overdose by ambulance services have a greater mortality risk compared with other PWID, and to compare mortality risk within potentially critical time-periods (1 week, 1 month, 3 months, 6 months, 1 year, 5 years) after an overdose attendance with the mortality risk within potentially non-critical time-periods (time before and/or after critical periods). DESIGN: A prospective cohort study. SETTING: Oslo, Norway. PARTICIPANTS: A total of 172 PWID street-recruited in 1997 and followed-up until the end of 2004. MEASUREMENTS: Interview data linked to data from ambulance records, Norwegian Correctional Services, Opioid Substitution Treatment records and National Cause of Death Registry. Separate Cox regression models (one for each critical time-period) were estimated. FINDINGS: Ambulance services treated 54% of the participants for an overdose during follow-up. The mortality rate was 2.8 per 100 person-years for those with an overdose and 3.3 for those without; the adjusted hazard ratio (HR) was 1.3 (95% CI = 0.6, 2.6, P = 0.482). Mortality risk was greater in all but the shortest critical time-period following ambulance attendance than in the non-critical periods. The mortality risk remained significantly elevated during critical periods, even when adjusted for total time spent in prison and substitution treatment. The HR ranged from 9.4 (95% CI = 3.5, 25.4) in the month after an overdose to 13.9 (95% CI = 6.4, 30.2) in the 5-year period. CONCLUSIONS: Mortality risk among people who inject drugs is significantly greater in time-periods after an overdose attendance than outside these time-periods. PMID- 26118948 TI - Radiation Testing of the GERD Stimulation Therapy System Using a Particle Accelerator. AB - OBJECTIVE: This testing was conducted to determine if exposure from a particle accelerator used to treat cancer patients would alter the performance of the EndoStim(r) neurostimulator when programmed either passively or actively and while being irradiated. METHODS: A total of 12 EndoStim Lower Esophageal Sphincter (LES) Stimulation System implantable neurostimulators were investigated in this research. Included were six each of the EndoStim I and EndoStim II. Half were used for passive testing, with the remaining half for active testing. Bremsstrahlung x-rays were delivered having a nominal energy of 18 MV at a rate of 6 Gy/min. A total dose of 80 Gy was achieved in testing minimally. RESULTS: Monitoring of stimulation frequency, amplitude, pulse width, stimulation time, and voltage was conducted using software developed by EndoStim along with an oscilloscope. No observed changes to the intended stimulation were noted and all scheduled parameter magnitudes were achieved with device operation. All functional parameter changes were within +/-10% from baseline. CONCLUSIONS: EndoStim I and EndoStim II implant pulse generators appear to be immune to x-ray radiation from the particle accelerator at energies up to 18 MV, at dose rates of up to 6 Gy/min, and up to cumulative doses of minimally 80 Gy. As there were no observable effects on neurostimulation requirements, the EndoStim LES Stimulation System implantable neurostimulators are capable of withstanding direct radiation. The recommendations of the manufacturer should be followed further regarding the labeling requirements for insured safety to patients. PMID- 26118949 TI - EXAMINING LONG-TERM EFFECTS OF AN INFANT MENTAL HEALTH HOME-BASED EARLY HEAD START PROGRAM ON FAMILY STRENGTHS AND RESILIENCE. AB - Infant Mental Health based interventions aim to promote the healthy development of infants and toddlers through promoting healthy family functioning to foster supportive relationships between the young child and his or her important caregivers. This study examined impacts of an Infant Mental Health home-based Early Head Start (IMH-HB EHS) program on family functioning. The sample includes 152 low-income families in the Midwestern United States, expectant or parenting a child younger than 1 year of age, who were randomly assigned to receive IMH-HB EHS services (n = 75) or to a comparison condition (n = 77). Mothers who received IMH-HB EHS services reported healthier psychological and family functioning, outcomes that are consistent with the IMH focus, when their children were between the ages of 3 and 7 years of age. Specifically, mothers in the IMH-HB EHS group reported healthier family functioning and relationships, better coping skills needed to advocate for their families, and less stress in the parenting role versus those in the comparison condition. The study also examined support seeking coping, some of which changed differently over time based on program group assignment. Overall, findings suggest that the gains families achieve from participating in IMH-HB EHS services are maintained after services cease. PMID- 26118950 TI - Docosahexaenoic acid inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by decreasing the excitability of DRG neurons. AB - Diabetes mellitus is a common metabolic disease in human beings with characteristic symptoms of hyperglycemia, chronic inflammation and insulin resistance. One of the most common complications of early-onset diabetes mellitus is peripheral diabetic neuropathy, which is manifested either by loss of nociception or by allodynia and hyperalgesia. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown the potential of anti-inflammation and modulating neuron excitability. The present study investigated the effects of docosahexaenoic acid (DHA) on the excitability of dorsal root ganglion (DRG) neurons in streptozotocin (STZ)-induced diabetes rats. The effects of DHA on the allodynia and hyperalgesia of diabetic rats were also evaluated. Dietary DHA supplementation effectively attenuated both allodynia and hyperalgesia induced by STZ injection. DHA supplementation decreased the excitability of DRG neurons by decreasing the sodium currents and increasing potassium currents, which may contribute to the effect of alleviating allodynia and hyperalgesia in diabetic rats. The results suggested that DHA might be useful as an adjuvant therapy for the prevention and treatment of painful diabetic neuropathy. PMID- 26118951 TI - Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma. AB - Ipilimumab, an antibody that blocks cytotoxic T lymphocyte-associated antigen 4 (CTLA-4; CD152), was approved by the Food and Drug Administration in 2011 for the treatment of unresectable stage III or IV malignant melanoma. Although the addition of this particular immunotherapy has broadened treatment options, immune related adverse events (irAEs) are associated with ipilimumab therapy, including dermatologic effects, colitis and diarrhea, endocrine effects, hepatotoxicity, ocular effects, renal effects, neurologic effects, and others. In this article, a critical evaluation of the underlying mechanisms of irAEs associated with anti CTLA-4 therapy is presented. Additionally, potentially beneficial effects of combinational therapies to alleviate ipilimumab-induced irAEs in malignant melanoma are discussed. Future research is warranted to elucidate the efficacy of such combination therapies and specific biomarkers that would help to predict a clinical response to ipilimumab in patients with malignant melanoma. PMID- 26118953 TI - Peroxisome proliferator-activated receptor gamma coactivator 1 alpha protects cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 signaling pathway. AB - Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) is a crucial coregulator interacting with multiple transcriptional factors in the regulation of cardiac hypertrophy. The present study revealed that PGC-1alpha protected cardiomyocytes from hypertrophy by suppressing calcineurin-nuclear factor of activated T cells c4 (NFATc4) signaling pathway. Overexpression of PGC 1alpha by adenovirus infection prevented the increased protein and messenger RNA expression of NFATc4 in phenylephrine (PE)-treated hypertrophic cardiomyocytes, whereas knockdown of PGC-1alpha by RNA silencing augmented the expression of NFATc4. An interaction between PGC-1alpha and NFATc4 was observed in both the cytoplasm and nucleus of neonatal rat cardiomyocytes. Adenovirus PGC-1alpha prevented the nuclear import of NFATc4 and increased its phosphorylation level of NFATc4, probably through repressing the expression and activity of calcineurin and interfering with the interaction between calcineurin and NFATc4. On the contrary, PGC-1alpha silencing aggravated PE-induced calcineurin activation, NFATc4 dephosphorylation, and nuclear translocation. Moreover, the binding activity and transcription activity of NFATc4 to DNA promoter of brain natriuretic peptide were abrogated by PGC-1alpha overexpression but were enhanced by PGC-1alpha knockdown. The effect of PGC-1alpha on suppressing the calcinuerin NFATc4 signaling pathway might at least partially contribute to the protective effect of PGC-1alpha on cardiomyocyte hypertrophy. These findings provide novel insights into the role of PGC-1alpha in regulation of cardiac hypertrophy. PMID- 26118954 TI - Frequency Shifts of a Quartz Crystal Microbalance Calculated with the Frequency Domain Lattice-Boltzmann Method: Application to Coupled Liquid Mass. AB - In recent years the quartz crystal microbalance (QCM) has seen an impressive evolution from a film-thickness monitor to a surface-analytical instrument with capabilities much beyond gravimetry. In particular, the instrument has often been applied to adsorbates from a liquid phase and, also, to samples with structure in the surface plane. In order to quantitatively predict frequency shifts induced by such samples from a model, one needs to compute the in-phase component of the area-averaged periodic tangential stress at the resonator surface. A method is described which performs this task, making use of a variant of the Lattice Boltzmann (LB) method. The algorithm differs from the conventional LB method in that it deals with oscillatory flows and only covers linear hydrodynamics. The adsorption of small particles (mimicking proteins) was chosen as an example to test the performance. These samples are acoustically thin, which simplifies the calculations. Also, the material's finite compliance can be neglected in this limit. The simulations predict the amount of solvent trapped between neighboring particles, which contributes to the adsorbate's apparent mass. The unknown amount of hydrodynamically coupled liquid is a serious problem in the interpretation of QCM experiments. On an experimental level, the amount of trapped solvent can be estimated from the comparison of the optical layer thickness (determined with ellipsometry) and the acoustic layer thickness (determined with a QCM). Since the amount of trapped liquid decreases when neighboring particles aggregate into clusters, this analysis can lead to a statement on the degree of clustering. The LB-based simulations show, though, that the relation between the cluster geometry and the amount of trapped solvent is highly nontrivial. The details of the geometry do matter. The LB-based algorithm can calculate the amount of trapped solvent for user-specified particle shapes, orientations, interparticle distances, and also distributions thereof. It is an essential step in the quantitative interpretation of QCM results obtained on thin samples with in-plane structure. PMID- 26118952 TI - Targeting the inflammasome in rheumatic diseases. AB - Activation of the inflammasome, a protein complex responsible for many cellular functions, including the activation of the proinflammatory cytokines interleukin (IL)-1beta and IL-18, has been identified as a key participant in many rheumatic diseases including autoimmune, inflammatory, and autoinflammatory syndromes. This review will discuss the recent advances in understanding the role of this complex in various rheumatic diseases. Furthermore, it will focus on available therapies, which directly and indirectly target the inflammasome and its downstream cytokines to quiet inflammation and possibly dampen autoimmune processes. PMID- 26118956 TI - A simple analytical method for heterogeneity corrections in low dose rate prostate brachytherapy. AB - In low energy brachytherapy, the presence of tissue heterogeneities contributes significantly to the discrepancies observed between treatment plan and delivered dose. In this work, we present a simplified analytical dose calculation algorithm for heterogeneous tissue. We compare it with Monte Carlo computations and assess its suitability for integration in clinical treatment planning systems. The algorithm, named as RayStretch, is based on the classic equivalent path length method and TG-43 reference data. Analytical and Monte Carlo dose calculations using Penelope2008 are compared for a benchmark case: a prostate patient with calcifications. The results show a remarkable agreement between simulation and algorithm, the latter having, in addition, a high calculation speed. The proposed analytical model is compatible with clinical real-time treatment planning systems based on TG-43 consensus datasets for improving dose calculation and treatment quality in heterogeneous tissue. Moreover, the algorithm is applicable for any type of heterogeneities. PMID- 26118955 TI - Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor. AB - Cytoadhesion of Plasmodium falciparum-infected erythrocytes to endothelial protein C receptor (EPCR) is associated with severe malaria. It has been postulated that parasite binding could exacerbate microvascular coagulation and endothelial dysfunction in cerebral malaria by impairing the protein C-EPCR interaction, but the extent of binding inhibition has not been fully determined. Here we expressed the cysteine-rich interdomain region (CIDRalpha1) domain from a variety of domain cassette (DC) 8 and DC13 P. falciparum erythrocyte membrane protein 1 proteins and show they interact in a distinct manner with EPCR resulting in weak, moderate and strong inhibition of the activated protein C (APC)-EPCR interaction. Overall, there was a positive correlation between CIDRalpha1-EPCR binding activity and APC blockade activity. In addition, our analysis from a combination of mutagenesis and blocking antibodies finds that an Arg81 (R81) in EPCR plays a pivotal role in CIDRalpha1 binding, but domains with weak and strong APC blockade activity were distinguished by their sensitivity to inhibition by anti-EPCR mAb 1535, implying subtle differences in their binding footprints. These data reveal a previously unknown functional heterogeneity in the interaction between P. falciparum and EPCR and have major implications for understanding the distinct clinical pathologies of cerebral malaria and developing new treatment strategies. PMID- 26118957 TI - Lysosome-Related Effector Vesicles in T Lymphocytes and NK Cells. AB - Lysosome-related secretory organelles combine metabolic functions of conventional lysosomes with an inducible secretory potential. Specialized variants of such bi functional organelles are present in several haematopoietic cell types that store, mobilize and/or secrete effector proteins, for example in mast cells, macrophages or cytotoxic effector cells. In the case of T lymphocytes and NK cells, it was believed that secretory lysosomes serve as a common storage and transport compartment for the most relevant cytotoxic effector proteins including FasL, perforin, granzymes and granulysin. However, recent observations suggest that cytotoxic effector cells might be able to mobilize two distinct lysosomal entities in order to react to differential stimulation with either FasL surface appearance or degranulation-associated release of perforin and granzymes. This assumption is supported by the proteomic characterization of enriched organelles from T and NK cells. FasL-associated light lysosomes biochemically segregate from morphologically distinct heavy lysosomes that preferentially contain granzymes, perforin and mature granulysin. Here, we briefly summarize the current knowledge about cargo proteins that are stored and transported in secretory vesicles and how these vesicles might be generated and mobilized. In addition, we describe common features and major differences of the two distinct effector organelles and discuss how these observations might expand existing models of cytotoxic effector function. PMID- 26118958 TI - Molecular-based allergy diagnosis of allergic bronchopulmonary aspergillosis in Aspergillus fumigatus-sensitized Japanese patients. AB - BACKGROUND: Distinguishing between patients with allergic bronchopulmonary aspergillosis (ABPA) and Aspergillus fumigatus (Af)-sensitized asthmatic patients without ABPA is sometimes difficult owing to the IgE-cross-reactivity between Af and other fungal allergens. OBJECTIVE: To establish the usefulness of molecular based allergy diagnostics using allergen components from Af in distinguishing ABPA from Af-sensitized asthma without ABPA. METHODS: Sera from Japanese patients with ABPA (n = 53) and Af-sensitized asthma without ABPA (n = 253) were studied. The levels of IgE and IgG antibodies to allergen components from Af and IgE antibodies to different fugal allergen extracts were measured by ImmunoCAP. Comorbid atopic dermatitis (AD) was taken into consideration in the sensitization profile analysis. RESULTS: Patients with ABPA possessed significantly higher levels of IgE antibodies to Asp f 1, and Asp f 2 than asthmatic patients without ABPA. The areas under the receiver operating characteristic curves for the levels of IgE to Asp f 1 and Asp f 2 as diagnostic markers of ABPA were 0.75 and 0.78, respectively. The presence of IgE positivity to Asp f 1 and/or Asp f 2 resulted in increased sensitivity while losing little specificity. Comorbid AD was associated with higher levels of IgE to Asp f 6 (manganese superoxide dismutase from Af, a ubiquitous pan-allergen in fungi) and low but positive levels of IgE to other Af-components, which hampered the serological discrimination of ABPA. CONCLUSIONS AND CLINICAL RELEVANCE: The levels of IgE to Asp f 1 and/or Asp f 2 can effectively differentiate ABPA from Af-sensitized asthma, suggesting that the amounts of IgE specific for these molecules are markers for genuine Af sensitization in ABPA. However, comorbid AD must be taken into consideration in the interpretation of high IgE to Asp f 6. Establishing of IgE-sensitization profiles using panel of Af-allergen components provides valuable information for distinguishing genuine vs. cross-reactive sensitization in Af-sensitized patients. PMID- 26118959 TI - The Association between High-Deductible Health Plan Transition and Contraception and Birth Rates. AB - OBJECTIVE: To evaluate the association between employer-mandated enrollment into high-deductible health plans (HDHPs) and contraception and birth rates among reproductive-age women. DATA SOURCES/STUDY SETTING: Using data from 2002 to 2008, we examined 1,559 women continuously enrolled in a Massachusetts health plan for 1 year before and after an employer-mandated switch from an HMO to a HDHP, compared with 2,793 matched women contemporaneously enrolled in an HMO. STUDY DESIGN: We used an individual-level interrupted time series with comparison series design to examine level and trend changes in clinician-provided contraceptives and a differences-in-differences design to assess annual birth rates. DATA COLLECTION/EXTRACTION METHODS: Employer, plan, and member characteristics were obtained from enrollment files. Contraception and childbirth information were extracted from pharmacy and medical claims. PRINCIPAL FINDINGS: Monthly contraception rates were 19.0-24.0 percent at baseline. Level and trend changes did not differ between groups (p = .92 and p = .36, respectively). Annual birth rates declined from 57.1/1,000 to 32.7/1,000 among HDHP members and from 61.9/1,000 to 56.2/1,000 among HMO controls, a 40 percent relative reduction in odds of childbirth (odds ratio = 0.60; p = .02). CONCLUSIONS: Women who switched to HDHPs experienced a lower birth rate, which might reflect strategies to avoid childbirth-related out-of-pocket costs under HDHPs. PMID- 26118960 TI - Small conjugate-based theranostic agents: an encouraging approach for cancer therapy. AB - The advances in genomics, proteomics, and bioinformatics have directed the development of new anticancer agents to reduce drug abuse and increase safe and specific drug treatment. Theranostics, combining therapy and diagnosis, is an appealing approach for chemotherapy in medicine which exhibits improved biodistribution, selective cancer targeting ability, reduced toxicity, masked drug efficacy, and minimum side effects. The role of diagnosis tools in theranostics is to collect the information of the diseased state before and after specific treatment. Magnetic particle-, mesoporous silica-, various carbon allotrope-, and polymer nanoparticle-based theranostic systems are well accepted and clinically significant. Currently, small conjugate-based systems have received much attention for cancer treatment and diagnosis. The structural architecture of these systems is relatively simple, compact, biocompatible, and unidirectional. In this tutorial review, we summarize the latest developments on small conjugate based theranostic agents for tumor treatment and diagnosis using fluorescence and magnetic resonance imaging (MRI). PMID- 26118961 TI - TBX20 loss-of-function mutation associated with familial dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of congestive heart failure, sudden cardiac death and cardiac transplantation. Aggregating evidence highlights the genetic origin of DCM. However, DCM is a genetically heterogeneous disorder, and the genetic components underlying DCM in most cases remain unknown. METHODS: The coding regions and splicing junction sites of the TBX20 gene were sequenced in 120 unrelated patients with idiopathic DCM. The available close relatives of the index patient carrying an identified mutation and 300 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX20. The functional characteristics of the mutant TBX20 were assayed in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous TBX20 mutation, p.F256I, was identified in a family with DCM transmitted in an autosomal dominant fashion, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 600 control chromosomes and the altered amino acid was completely conserved evolutionarily among various species. Functional assays revealed that the mutant TBX20 had significantly diminished transcriptional activity. Furthermore, the mutation markedly reduced the synergistic activation of TBX20 with NKX2-5 or GATA4. CONCLUSIONS: This study links TBX20 loss-of-function mutation to idiopathic DCM in humans for the first time, providing novel insight into the molecular mechanism underpinning DCM. PMID- 26118962 TI - Uncovering category specificity of genital sexual arousal in women: The critical role of analytic technique. AB - Based on analytic techniques that collapse data into a single average value, it has been reported that women lack category specificity and show genital sexual arousal to a large range of sexual stimuli including those that both match and do not match their self-reported sexual interests. These findings may be a methodological artifact of the way in which data are analyzed. This study examined whether using an analytic technique that models data over time would yield different results. Across two studies, heterosexual (N = 19) and lesbian (N = 14) women viewed erotic films featuring heterosexual, lesbian, and gay male couples, respectively, as their physiological sexual arousal was assessed with vaginal photoplethysmography. Data analysis with traditional methods comparing average genital arousal between films failed to detect specificity of genital arousal for either group. When data were analyzed with smoothing regression splines and a within-subjects approach, both heterosexual and lesbian women demonstrated different patterns of genital sexual arousal to the different types of erotic films, suggesting that sophisticated statistical techniques may be necessary to more fully understand women's genital sexual arousal response. Heterosexual women showed category-specific genital sexual arousal. Lesbian women showed higher arousal to the heterosexual film than the other films. However, within subjects, lesbian women showed significantly different arousal responses suggesting that lesbian women's genital arousal discriminates between different categories of stimuli at the individual level. Implications for the future use of vaginal photoplethysmography as a diagnostic tool of sexual preferences in clinical and forensic settings are discussed. PMID- 26118963 TI - The perceptions of a surgical cure. PMID- 26118964 TI - Tubal ligation could reduce mortality in endometrial cancer. PMID- 26118965 TI - Routine screening with CT not justified for occult cancer. PMID- 26118966 TI - Epidemiological features of viral encephalitis in Cangzhou of China with use of multiplex RT-PCR for five RNA viruses. AB - OBJECTIVE: With use of multiplex RT-PCR testing the five RNA viruses associated with viral encephalitis, the aim of research is to find out the epidemiological features of viral encephalitis in Cangzhou of China. METHODS: Patients hospitalized in Cangzhou central hospital with the diagnosis of viral encephalitis from January 2010 to December 2012 were retrospectively analyzed. The sensitivity and specificity of multiplex RT-PCR was compared with ELISA through testing CSF samples of enterovirus (EVs), Japanese encephalitis virus (JEV), mumps virus (MUV), measles virus (MV) and rubella virus (RV). RESULTS: Disease incidence of viral encephalitis in Cangzhou of China was 18.6 per 100 thousand, and the main pathogen focused on EVs, MUV, JEV, MV and RV, which positive rate were 27.8%, 14.4%, 12.2%, 6.7% and 3.3% respectively. The sensitivity and specificity were all higher than ELISA. CONCLUSION: The most common pathogens responsible for viral encephalitis in Cangzhou, Hebei province, China, were EVs, and the multiplex RT-PCR was a rapid, sensitive, accurate method of testing the viruses responsible for causing these illnesses. PMID- 26118967 TI - 1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity. AB - Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the NaphthaladynTM series, with compounds 23 and 29 being the most active (IC50 of 19.1 +/- 0.3 and 18.5 +/- 1.7 MUM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 MUM). The results introduce 29 as an optimised GTP competitive lead NaphthaladynTM compound for the further development of naphthalimide-based dynI GTPase inhibitors. PMID- 26118968 TI - Diluted bitumen causes deformities and molecular responses indicative of oxidative stress in Japanese medaka embryos. AB - This study characterized the toxicity and physiological effects of unweathered diluted bitumen (Access Western Blend dilbit; AWB) to fish. Embryos of Japanese medaka (Oryzias latipes) were exposed for 17 days to dilutions of physically dispersed (water accommodated fraction; WAF) and chemically-dispersed (chemically enhanced WAF; CEWAF) dilbit. AWB dilbit exposure was not lethal to medaka, but resulted in a high prevalence of blue sac disease (BSD), impaired development, and abnormal or un-inflated swim bladders at hatch. Physiological effects were indicated by the relative mRNA levels of key genes associated with, among others, cell cycling and the response to mutations (p53), xenobiotic metabolism (ahr, arnt2), phase I (cyp1a) and II processes associated with oxidative stress (cat, g6pdh, hsp70, gst, gpx, gsr, nfe2, and sod). AWB dilbit treatment increased p53 and cyp1a transcript levels (1.5-fold and >15-fold, respectively), with significant, but less pronounced changes in indicators of oxidative stress and metabolism. The exposure-related changes in embryotoxicity and mRNA synthesis were consistent with metabolism of polycyclic aromatic hydrocarbons (PAHs) to reactive and toxic metabolites. Medaka embryos responded similarly to WAF and CEWAF treatments, but CEWAF was about 100 times more efficient in delivering toxic concentrations of PAHs. The toxicity of chemically-dispersed nujol, a non toxic mineral oil used as an experimental control, suggested that a portion of the observed effects of AWB could be attributed to excess dispersant in solution. This first study of the physiological effects of dilbit toxicity to fish embryos provides a baseline to compare toxicity between dilbit and conventional crude oils, and the groundwork for the development of molecular biomarkers of the sensitivity and level of risk of native Canadian fish species to dilbit exposure. PMID- 26118969 TI - Simple fluorescence-based high throughput cell viability assay for filamentous fungi. AB - Filamentous fungi are important model organisms to understand the eukaryotic process and have been frequently exploited in research and industry. These fungi are also causative agents of serious diseases in plants and humans. Disease management strategies include in vitro susceptibility testing of the fungal pathogens to environmental conditions and antifungal agents. Conventional methods used for antifungal susceptibilities are cumbersome, time-consuming and are not suitable for a large-scale analysis. Here, we report a rapid, high throughput microplate-based fluorescence method for investigating the toxicity of antifungal and stress (osmotic, salt and oxidative) agents on Magnaporthe oryzae and compared it with agar dilution method. This bioassay is optimized for the resazurin reduction to fluorescent resorufin by the fungal hyphae. Resazurin bioassay showed inhibitory rates and IC50 values comparable to the agar dilution method and to previously reported IC50 or MICs for M. oryzae and other fungi. The present method can screen range of test agents from different chemical classes with different modes of action for antifungal activities in a simple, sensitive, time and cost effective manner. SIGNIFICANCE AND IMPACT OF THE STUDY: A simple fluorescence-based high throughput method is developed to test the effects of stress and antifungal agents on viability of filamentous fungus Magnaporthe oryzae. This resazurin fluorescence assay can detect inhibitory effects comparable to those obtained using the growth inhibition assay with added advantages of simplicity, time and cost effectiveness. This high throughput viability assay has a great potential in large-scale screening of the chemical libraries of antifungal agents, for evaluating the effects of environmental conditions and hyphal kinetic studies in mutant and natural populations of filamentous fungi. PMID- 26118970 TI - A new glaucoma hypothesis: a role of glymphatic system dysfunction. AB - In a recent review article titled "A new look at cerebrospinal fluid circulation", Brinker et al. comprehensively described novel insights from molecular and cellular biology as well as neuroimaging research, which indicate that cerebrospinal fluid (CSF) physiology is much more complex than previously believed. The glymphatic system is a recently defined brain-wide paravascular pathway for CSF and interstitial fluid exchange that facilitates efficient clearance of interstitial solutes, including amyloid-beta, from the brain. Although further studies are needed to substantiate the functional significance of the glymphatic concept, one implication is that glymphatic pathway dysfunction may contribute to the deficient amyloid-beta clearance in Alzheimer's disease. In this paper, we review several lines of evidence suggesting that the glymphatic system may also have potential clinical relevance for the understanding of glaucoma. As a clinically acceptable MRI-based approach to evaluate glymphatic pathway function in humans has recently been developed, a unique opportunity now exists to investigate whether suppression of the glymphatic system contributes to the development of glaucoma. The observation of a dysfunctional glymphatic system in patients with glaucoma would provide support for the hypothesis recently proposed by our group that CSF circulatory dysfunction may play a contributory role in the pathogenesis of glaucomatous damage. This would suggest a new hypothesis for glaucoma, which, just like Alzheimer's disease, might be considered then as an imbalance between production and clearance of neurotoxins, including amyloid-beta. PMID- 26118971 TI - Comorbidity and survival among women with ovarian cancer: evidence from prospective studies. AB - The relationship between comorbidity and ovarian cancer survival has been controversial so far. Therefore, we conducted a meta-analysis to summarize the existing evidence from prospective studies on this issue. Relevant studies were identified by searching the PubMed, EMBASE, and ISI Web of Science databases through the end of January 2015. Two authors independently performed the eligibility evaluation and data abstraction. Random-effects models were used to estimate summary hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival. Eight prospective studies involving 12,681 ovarian cancer cases were included in the present study. The summarized HR for presence versus absence of comorbidity was 1.20 (95% CI = 1.11-1.30, n = 8), with moderate heterogeneity (I(2) = 31.2%, P = 0.179). In addition, the summarized HR for the highest compared with the lowest category of the Charlson's comorbidity index was 1.68 (95% CI = 1.50-1.87, n = 2), without heterogeneity (I(2) = 0%, P = 0.476). Notably, a significant negative impact of comorbidity on ovarian cancer survival was observed in most subgroup analyses stratified by the study characteristics and whether there was adjustment for potential confounders. In conclusion, the findings of this meta-analysis suggest that underlying comorbidity is consistently associated with decreased survival in patients with ovarian cancer. Comorbidity should be taken into account when managing these patients. PMID- 26118972 TI - Impact of Antimicrobial Lipopeptides from Bacillus sp. on Suppression of Fusarium Yellows of Tatsoi. AB - Iturin A and surfactin are antimicrobial lipopeptides produced by antagonistic Bacillus spp. We herein demonstrated that both lipopeptides amended the soil mediated suppression of the soil-borne disease, Fusarium yellows of tatsoi (Brassica rapa var. rosularis). Significant disease suppression was conferred by the amendments of purified iturin A or surfactin to soil. However, an excess amount of iturin A or surfactin to soil resulted in the loss of disease suppression activity. PMID- 26118973 TI - Integrating NiCo Alloys with Their Oxides as Efficient Bifunctional Cathode Catalysts for Rechargeable Zinc-Air Batteries. AB - The lack of high-efficient, low-cost, and durable bifunctional electrocatalysts that act simultaneously for the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) is currently one of the major obstacles to commercializing the electrical rechargeability of zinc-air batteries. A nanocomposite CoO-NiO-NiCo bifunctional electrocatalyst supported by nitrogen doped multiwall carbon nanotubes (NCNT/CoO-NiO-NiCo) exhibits excellent activity and stability for the ORR/OER in alkaline media. More importantly, real air cathodes made from the bifunctional NCNT/CoO-NiO-NiCo catalysts further demonstrated superior performance to state-of-the-art Pt/C or Pt/C+IrO2 catalysts in primary and rechargeable zinc-air batteries. PMID- 26118975 TI - Access to 3-O-Functionalized N-Acetylneuraminic Acid Scaffolds. AB - Direct access to 3-O-functionalized 2-alpha-N-acetylneuraminides and their corresponding 2,3-dehydro-2-deoxy-N-acetylneuraminic acid derivatives is described. Initially, a stereoselective ring-opening of the key intermediate N acetylneuraminic acid (Neu5Ac) 2,3-beta-epoxide with an alcohol provided the 3 hydroxy alpha-glycoside. O-Alkylation of the C3 hydroxyl group generated novel 3 O-functionalized Neu5Ac derivatives that provided the corresponding unsaturated derivatives upon elimination. PMID- 26118974 TI - Managing teenage/young adult (TYA) brain tumors: a UK perspective. AB - Tumors of the CNS are among the commonest malignancies occurring in teenage/young adult patients (i.e., those aged between 15 and 24 years). The treatment of this patient population is challenging. Adolescence and young adulthood are a turbulent period of life, with physical, emotional, social and cognitive changes. Best practice advocates their treatment in dedicated teenage/young adult units, with multidisciplinary team input and access to clinical trials. Treatment of CNS malignancies is dependent upon histological subtype and staging, with varying combinations of surgery, radiotherapy and chemotherapy used. Clinical trials directly targeted at this patient population are rare; treatments are based on pediatric protocols as studies have demonstrated improved outcomes in patients (with other malignancies) treated as such. Scope for improvement lies in minimizing patient risk of recurrence and long-term sequelae of treatment. Molecular characterization of tumors may provide further information. PMID- 26118976 TI - Lack of TAFI increases brain damage and microparticle generation after thrombolytic therapy in ischemic stroke. AB - BACKGROUND: Thrombin-activatable fibrinolysis inhibitor (TAFI) plays an important role in coagulation and fibrinolysis. Whereas TAFI deficiency may lead to a haemorrhagic tendency, data from TAFI knockout mice (TAFI-/-) are controversial and no differences have been reported in these animals after ischemic stroke. There are also no data regarding the role of circulating microparticles (MPs) in TAFI-/-. OBJECTIVES: to examine the effect of tPA on the rate of intracranial haemorrhage (ICH) and on MPs generated in a model of ischemic stroke in TAFI-/- mice. METHODS: Thrombin was injected into the middle cerebral artery (MCA) to analyse the effect of tPA (10mg/Kg) on the infarct size and haemorrhage in the absence of TAFI. Immunofluorescence for Fluoro-Jade C was performed on frozen brain slides to analyse neuronal degeneration after ischemia. MPs were isolated from mouse blood and their concentrations calculated by flow cytometry. RESULTS: Compared with saline, tPA significantly increased the infarct size in TAFI-/- mice (p<0.05). Although plasma fibrinolytic activity (fibrin plate assay) was higher in these animals, no macroscopic or microscopic ICH was detected. A positive signal for apoptosis and degenerating neurons was observed in the infarct area, being significantly higher in tPA treated TAFI-/- mice (p<0.05). Interestingly, higher numbers of MPs were found in TAFI-/- plasma as compared to wild type, after stroke (p<0.05). CONCLUSIONS: TAFI deficiency results in increased brain damage in a model of thrombolysis after ischemic stroke, which was not associated with bleeding but with neuronal degeneration and MP production. PMID- 26118978 TI - Long-term functional outcomes after total tongue reconstruction: Consideration of flap types, volume, and functional results. AB - OBJECTIVE: The purpose of this study is to evaluate the long-term results of flap volume change, swallowing capacity, speech intelligibility, and differences between vertical rectus musculocutaneous (VRAM) and anterolateral musculocutaneous (ALT) free flaps in total tongue reconstruction. PATIENTS AND METHODS: We retrospectively analyzed the medical records of 31 patients who underwent total tongue reconstruction with VRAM (24 cases) and ALT flap (7 cases). The mean age of patients was 52.09 +/- 2.25 years. The tumor types were as follows: squamous cell carcinoma (28 cases), adenoid cystic carcinoma (2 cases), and metastatic cancer (1 case). The flap volume was determined based on clinical and imaging examinations. Swallowing and speech function were analyzed using seven-point rating scales. RESULTS: All flaps survived eventually after surgery; however, 1 patient underwent VRAM flap experienced partial flap necrosis, wound dehiscence in 4 patients underwent VRAM flap, and infection in 3 patients (VRAM; 2 patients, ALT; 1 patient). The mean follow-up period was 3.97 +/- 0.54 years. The volume of the flaps remained relatively constant over time. The swallowing capacity positively correlated with the flap volume (P < 0.0001); however, the speech intelligibility did not correlate with the flap volume in analysis of total cohort. There were no statistical differences in functional outcomes between the two types of reconstructed flaps (P > 0.05). CONCLUSION: The preservation of flap volume was important to achieve superior swallowing capacity; however, it was insufficient to promote the speech outcome. The functional outcomes did not differ depending on the type of flap. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:190-196, 2017. PMID- 26118977 TI - EFTUD2 deficiency in vertebrates: Identification of a novel human mutation and generation of a zebrafish model. AB - BACKGROUND: Congenital microphthalmia and coloboma are severe developmental defects that are frequently associated with additional systemic anomalies and display a high level of genetic heterogeneity. METHODS: To identify the pathogenic variant in a patient with microphthalmia, coloboma, retinal dystrophy, microcephaly, and other features, whole exome sequencing analysis of the patient and parental samples was undertaken. To further explore the identified variant/gene, expression and functional studies in zebrafish were performed. RESULTS: Whole exome sequencing revealed a de novo variant, c.473_474delGA, p.(Arg158Lysfs*4), in EFTUD2 which encodes a component of the spliceosome complex. Dominant mutations in EFTUD2 cause Mandibulofacial Dysostosis, Guion Almeida type, which does not involve microphthalmia, coloboma, or retinal dystrophy; analysis of genes known to cause these ocular phenotypes identified several variants of unknown significance but no causal alleles in the affected patient. Zebrafish eftud2 demonstrated high sequence conservation with the human gene and broad embryonic expression. TALEN-mediated disruption was employed to generate a c.378_385 del, p.(Ser127Aspfs*23) truncation mutation in eftud2. Homozygous mutants displayed a reduced head size, small eye, curved body, and early embryonic lethality. Apoptosis assays demonstrated a striking increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells in the developing brain, eye, spinal cord, and other tissues starting at 30 hours postfertilization. CONCLUSION: This study reports a novel mutation in EFTUD2 in a Mandibulofacial Dysostosis, Guion-Almeida type patient with unusual ocular features and the generation of a first animal model of eftud2 deficiency. The severe embryonic phenotype observed in eftud2 mutants indicates an important conserved role during development of diverse tissues in vertebrates. PMID- 26118980 TI - Correlation of High Mobility Group Box-1 Protein (HMGB1) with Clinicopathological Parameters in Primary Retinoblastoma. AB - HMGB1 is considered to be DNA chaperone as it binds without any specificity. It is the structural protein which alters nuclear homeostasis and genomic stability of chromatin. Its role in retinoblastoma (Rb) remains unclear. The aim of the present study was to evaluate the expression of HMGB1 protein in primary enucleated retinoblastomas. Expression of HMGB1 in 69 prospective cases of primary retinoblastoma were assessed by immunohistochemistry and reverse transcriptase PCR (RT-PCR) technique and correlated with clinicopathological parameters. Immunohistochemical staining revealed expression of HMGB1 in 55.07 % (38/69) cases. Semi-quantitative RT-PCR was performed on 31 fresh tumor tissues. mRNA expression was observed in 77.41 % (24/31) cases. Expression of HMGB1 was statistically significant with poor tumor differentiation (p = 0.0440) & optic nerve invasion (p = 0.0128). HMGB1 expression was frequently seen in poorly differentiated tumors and those with histopathological high risk factors. Therefore, HMGB1 may contribute to tumor invasiveness and could serve as a poor prognostic marker in Rb. PMID- 26118981 TI - Phylogenetic analysis of Bunyamwera and Ngari viruses (family Bunyaviridae, genus Orthobunyavirus) isolated in Kenya. AB - Orthobunyaviruses, tri-segmented, negative-sense RNA viruses, have long been associated with mild to severe human disease in Africa, but not haemorrhagic fever. However, during a Rift Valley fever outbreak in East Africa in 1997-1998, Ngari virus was isolated from two patients and antibody detected in several others with haemorrhagic fever. The isolates were used to identify Ngari virus as a natural Orthobunyavirus reassortant. Despite their potential to reassort and cause severe human disease, characterization of orthobunyaviruses is hampered by paucity of genetic sequences. Our objective was to obtain complete gene sequences of two Bunyamwera virus and three Ngari virus isolates from recent surveys in Kenya and to determine their phylogenetic positioning within the Bunyamwera serogroup. Newly sequenced Kenyan Bunyamwera virus isolates clustered closest to a Bunyamwera virus isolate from the same locality and a Central African Republic isolate indicating that similar strains may be circulating regionally. Recent Kenyan Ngari isolates were closest to the Ngari isolates associated with the 1997 1998 haemorrhagic fever outbreak. We observed a temporal/geographical relationship among Ngari isolates in all three gene segments suggesting a geographical/temporal association with genetic diversity. These sequences in addition to earlier sequences can be used for future analyses of this neglected but potentially deadly group of viruses. PMID- 26118982 TI - Significance of EGFR signaling pathway genetic alterations in radically resected non-small cell lung cancers from a Polish cohort. One institutional study. AB - PURPOSE: We evaluated the distribution and clinical impact of EGFR, KRAS and HER2 copy number gains and EGFR, KRAS and BRAF activating mutations in resected non small cell lung cancers (NSCLCs) from 151 Polish patients. MATERIALS AND METHODS: Quantitative PCR and DNA sequencing were used for copy number evaluation and mutational analysis, respectively. RESULTS: An increased EGFR CN was found in 21.2% of the tumors, more commonly of the non-squamous histology (P=0.029), larger in size (P=0.004) and those obtained from women (P=0.040). HER2 copy gain was observed in 21.8% of the patients, more frequently with lymph node metastases (P=0.048) and stage IIIA disease (P=0.061). KRAS gain was found in 29.3% of the tumors, and was not associated with patients' clinicopathological features. No BRAF mutations were found. EGFR and KRAS mutation frequency and associations with clinicopathological characteristics did not differ significantly from those previously described for the NSCLC patients of Caucasian ethnicity. Strong associations existed between most of the analyzed alterations. In the multivariate model, EGFR mutations constituted an independent prognostic factor of the disease recurrence in adenocarcinoma patients (HR 7.20; 95%CI 1.31-39.48; P=0.023), while an increased EGFR copy number tended to indicate a shorter overall survival (HR 4.85; 95%CI 0.92-25.58; P=0.062). CONCLUSIONS: EGFR pathway genes alterations are frequent in NSCLCs from Polish patients and have a prognostic potential for patients' clinical outcome after a curative tumor resection. Gene CN evaluation by quantitative PCR provides comparable results and enables assay standardization, yet the optimal scoring system needs to be developed. PMID- 26118983 TI - Role of the flavonoid-rich fraction in the antioxidant and cytotoxic activities of Bauhinia forficata Link. (Fabaceae) leaves extract. AB - Bauhinia forficata Link. is utilised as an antidiabetic in Brazilian folk medicine; furthermore, its antioxidant properties suggest a potential usefulness in the prevention of diabetes complications associated with oxidative stress. The contribution of a flavonoid-rich fraction (FRF), HPLC-PDA-ESI-MS characterised, to the antioxidant and cytotoxic properties of B. forficata hydro-alcoholic leaves extract was evaluated for the first time. Both extract and FRF showed radical-scavenging activity and reducing power with a strong relationship with the flavonoid content found; hence, flavonoids are mainly responsible for the primary antioxidant activity of B. forficata extract. The extract significantly decreased FO-1 cell viability at the higher concentrations. FRF did not exert any effect; thus, flavonoids do not appear to be responsible for the cytotoxicity of the extract. The extract resulted virtually non-toxic against both Artemia salina and normal human lymphocytes, demonstrating potential selectivity in inhibiting cancer cell growth. Finally, no antimicrobial activity was observed against the bacteria and yeasts tested. PMID- 26118984 TI - Peri-Surgical Nutrition: Perspectives and Perceptions. AB - Peri-surgical nutrition of veterinary patients is in its infancy, with considerable research to be performed to help improve quality of life in our small animal patients. Clues from human immunonutrition may be starting places for investigation. Considerations for future investigations should include essential nutrients, the underlying disease process, therapeutic goals, and species (dog or cat). There are guidelines for caloric requirements. Planning for nutritional support before surgery takes place is likely to be beneficial to patient outcomes. Taking into account case history, method of feeding, metabolic abnormalities, and possible immunonutrition should be part of a complete surgical nutritional plan. PMID- 26118985 TI - Experimental evidence of new tetragonal polymorphs of silicon formed through ultrafast laser-induced confined microexplosion. AB - Ordinary materials can transform into novel phases at extraordinary high pressure and temperature. The recently developed method of ultrashort laser-induced confined microexplosions initiates a non-equilibrium disordered plasma state. Ultra-high quenching rates overcome kinetic barriers to the formation of new metastable phases, which are preserved in the surrounding pristine crystal for subsequent exploitation. Here we demonstrate that confined microexplosions in silicon produce several metastable end phases. Comparison with an ab initio random structure search reveals six energetically competitive potential phases, four tetragonal and two monoclinic structures. We show the presence of bt8 and st12, which have been predicted theoretically previously, but have not been observed in nature or in laboratory experiments. In addition, the presence of the as yet unidentified silicon phase, Si-VIII and two of our other predicted tetragonal phases are highly likely within laser-affected zones. These findings may pave the way for new materials with novel and exotic properties. PMID- 26118986 TI - A Phosphine-Coordinated Boron-Centered Gomberg-Type Radical. AB - The P-coordinated boryl radical [Ph2P(naphthyl)BMes] (Mes=mesityl) was prepared by (electro)chemical reduction of the corresponding borenium salt or bromoborane. Electron paramagnetic resonance (EPR) analysis in solution and DFT calculations indicate large spin density on boron (60-70%) and strong P-B interactions (P->B sigma donation and B->P negative hyperconjugation). The radical is persistent in solution and participates in a Gomberg-type dimerization process. The associated quinoid-type dimer has been characterized by single-crystal X-ray diffraction. PMID- 26118987 TI - Glucose is a positive modulator for the activation of human recombinant glycine receptors. AB - The inhibitory glycine receptor (GlyR), a cys-loop ion channel receptor, mediates rapid synaptic inhibition in spinal cord, brainstem and higher centres of the mammalian central nervous system. Here, modulation of GlyR function by glucose and fructose was examined in recombinant alpha1 and alpha1/beta GlyRs using patch clamp methods. Glucose was a positive modulator of the receptor, reducing the average EC50 for glycine up to 4.5-fold. Glucose reduced cell-to-cell variability of glycine-mediated currents by stabilizing receptors with low EC50. Pre incubation with sugars for several hours also produced augmentation of current responses that persisted after sugar removal. Potentiation by sugars was most significant in the range between 5 and 20 mM, with EC50 values ~ 10 mM, i.e. at physiological levels. Addition of glucose had no significant influence on responses mediated by the other GlyR agonists like taurine, beta-alanine or ivermectin, indicating that glucose specifically augmented glycine receptor mediated responses, and did not act through indirect metabolic effects. Receptor modulation by glucose may account for differences in constants reported in the literature and may be clinically relevant for disorders with elevated blood glucose levels. Glucose and related sugars are essential metabolites. We identified glucose and fructose as positive modulators of the human inhibitory glycine receptor, a neuronal ligand-gated ion channel. Receptor-mediated currents were enhanced at physiological concentrations (~ 10 mM of sugar). Direct modulation of a synaptic receptor by glucose is relevant in clinical cases of elevated blood glucose, and may be considered in experimental protocols. PMID- 26118988 TI - Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010 - 2014). AB - INTRODUCTION: The proteolytic activity of neutrophil elastase (NE) not only destroys pathogens but also degrades host matrix tissues by generating a localized protease-antiprotease imbalance. In humans, NE is well known to be involved in various acute and chronic inflammatory diseases, such as chronic obstructive pulmonary disease, emphysema, asthma, acute lung injury, acute respiratory distress syndrome and cystic fibrosis. The regulation of NE activity is thought to represent a promising therapeutic approach, and NE is considered as an important target for the development of novel selective inhibitors to treat these diseases. AREAS COVERED: This article summarizes and analyzes patents on NE inhibitors and their therapeutic potential based on a review of patent applications disclosed between 2010 and 2014. EXPERT OPINION: According to this review of recent NE inhibitor patents, all of the disclosed inhibitors can be classified into peptide- and non-peptide-based groups. The non-peptide NE inhibitors include heterocyclics, uracil derivatives and deuterium oxide. Among the heterocyclic analogs, derivatives of pyrimidinones, tetrahydropyrrolopyrimidinediones, pyrazinones, benzoxazinones and hypersulfated disaccharides were introduced. The literature has increasingly implicated NE in the pathogenesis of various diseases, of which inflammatory destructive lung diseases remain a major concern. However, only a few agents have been validated for therapeutic use in clinical settings to date. PMID- 26118989 TI - Using isotopic evidence to assess the impact of migration and the two-layer hypothesis in prehistoric Northeast Thailand. AB - OBJECTIVES: The nature of the agricultural transition in Southeast Asia has been a topic of some debate for archaeologists over the past decades. A prominent model, known as the two-layer hypothesis, states that indigenous hunter-gatherers were subsumed by the expansion of exotic Neolithic farmers into the area around 2000 BC. These farmers had ultimate origins in East Asia and brought rice and millet agriculture. Ban Non Wat is one of the few archaeological sites in Southeast Asia where this model can potentially be tested. The site is located in the Mun River valley of Northeast Thailand, and divided into 12 phases that span over 2,000 years, from about 1750 BC to the end of the Iron Age (ca. 500 AD). These phases exhibit successive cultural changes, and current interpretation of the site is of an early hunter-gatherer population, with agriculturalists immigrating into the later phases. METHODS: We analyzed strontium, oxygen, and carbon isotopes in tooth enamel from over 150 individuals, dating from the Neolithic to Iron Age, to assess extrinsic origins and differences in diet between early and later phases. RESULTS: We find evidence of dietary and cultural differences between groups at Ban Non Wat during its early occupation, but little evidence for immigration from distinct environments beyond the Khorat Plateau of Northeast Thailand. CONCLUSIONS: The lack of consistent isotopic differences between early and later Neolithic occupants at Ban Non Wat means that the site does not conclusively support the two-layer hypothesis. PMID- 26118990 TI - Statistical models suggest presence of two distinct subpopulations of miniature EPSCs in fast-spiking interneurons of rat prefrontal cortex. AB - Properties of excitatory synaptic responses in fast-spiking interneurons (FSIs) and pyramidal neurons (PNs) are different; however, the mechanisms and determinants of this diversity have not been fully investigated. In the present study, voltage-clamp recording of miniature excitatory post-synaptic currents (mEPSCs) was performed of layer 2-3 FSIs and PNs in the medial prefrontal cortex of rats aged 19-22days. The average mEPSCs in the FSIs exhibited amplitudes that were two times larger than those of the PNs and with much faster rise and decay. The mEPSC amplitude distributions in both cell types were asymmetric and in FSIs, the distributions were more skewed and had two-times larger coefficients of variation than in the PNs. In PNs but not in FSIs, the amplitude distributions were fitted well by different skewed unimodal functions that have been used previously for this purpose. In the FSIs, the distributions were well approximated only by a sum of two such functions, suggesting the presence of at least two subpopulations of events with different modal amplitudes. According to our estimates, two-thirds of the mEPSCs in FSIs belong to the high-amplitude subpopulation, and the modal amplitude in this subpopulation is approximately two times larger than that in the low-amplitude subpopulation. Using different statistical models, varying binning size, and data subsets, we confirmed the robustness and consistency of these findings. PMID- 26118991 TI - Acute Toxic Effects of the Herbicide Formulation Focus((r)) Ultra on Embryos and Larvae of the Moroccan Painted Frog, Discoglossus scovazzi. AB - For regulatory and scientific purposes, there is a need to understand the sensitivity of a wider variety of wild species of amphibians and the sensitivities within their life stages to chemicals of widespread use such as herbicides. We investigated the acute toxic effects of the herbicide formulation Focus Ultra [with the active ingredient (a.i.) cycloxydim plus solvent naphtha and sodium dioctylsulphosuccinate as added substances] on embryos and early stage larvae of the Moroccan painted frog (Discoglossus scovazzi). Different clinical signs (twitching, convulsion, and narcosis) occurred at 40 and 80 mg/L in embryos (4 and 8 mg a.i./L) and narcotic effects (total immobilization or irregular escape responses) at 10, 15, and 20 mg/L in larvae (1, 1.5, and 2 mg a.i./L). Growth inhibition (total length), starting at 20 mg/L in embryos and 2.5 mg/L in larvae (2 and 0.25 mg a.i./L, respectively) was understood as sign of toxicity (retardation) and not as sign of teratogenicity. However, the connection to teratogenesis remained unclear though total length reduction occurred at concentrations <20 % of the 96-h LC50 value and at a minimum concentration that inhibits growth of only 17 % of the 96-h LC50 value. Starting at 20 mg/L, mortality in embryos significantly increased and at 15 mg/L in early larvae (2 and 1.5 mg a.i./L, respectively). Mortality of larvae was enhanced during the first 24 h of exposure to 15 and 20 mg/L (1.5 and 2 mg a.i./L). Morphology of the embryos remained unobtrusive. In contrary, axial malformations significantly increased in the early larvae starting at 10 mg/L (1 mg a.i./L), a concentration free of lethal effects. In all considered end points, larvae were significantly more sensitive than embryos, probably because of developmental and physiological properties or different exposure and bioavailability of the compound. Focus Ultra induced comparable lethal and immobilization effects in D. scovazzi as it does to standard test organisms in pesticide approval. However, to validate the apparent safety in the field, which is based on calculated surface water concentrations of the a.i., more data on real contamination levels is necessary (e.g., peak concentrations, concentrations of added substances). Furthermore, sufficient buffer strips between the farmland and amphibian ponds must be considered, and the effects of the substance on terrestrial life stages have not been assessed yet. PMID- 26118992 TI - The Effects of the LandguardTM A900 Enzyme on the Macroinvertebrate Community in the Salinas River, California, United States of America. AB - Agricultural use of organophosphate pesticides are responsible for surface water toxicity in California and has led to a number of impaired water body listings under section 303(d) of the Clean Water Act. Integrated passive-treatment systems can reduce pesticide loading in row crop runoff, but they are only partially effective for the more soluble organophosphates. The LandguardTM enzyme has been effectively proven as an on-farm management practice for the removal of chlorpyrifos and diazinon in furrow runoff, but it has not been used in larger scale treatment because of concerns regarding the potential impact on in-stream macroinvertebrates after chronic use. A first-order agricultural creek was treated with the Landguard enzyme for 30 days approximately 450 m upstream of its intersection with the Salinas River. Toxicity and pesticide chemistry were measured in the creek during treatment as well as in the river both upstream and downstream of the creek input before and after treatment. Benthic macroinvertebrates were also surveyed in the river before and after enzyme treatment. Low concentrations of organophosphate pesticides were detected in the creek, but Landguard removed detected concentrations of chlorpyrifos. Toxicity detected in the creek was likely caused by pyrethroid pesticides, and no toxicity was detected in river samples. There were no differences in habitat or macroinvertebrate assemblages between upstream and downstream samples or between pre- and post-treatment samples. These results indicate that chronic treatment of the creek with Landguard enzyme had no impact on macroinvertebrate community structure in the river. PMID- 26118993 TI - Plant diversity drives soil microbial biomass carbon in grasslands irrespective of global environmental change factors. AB - Soil microbial biomass is a key determinant of carbon dynamics in the soil. Several studies have shown that soil microbial biomass significantly increases with plant species diversity, but it remains unclear whether plant species diversity can also stabilize soil microbial biomass in a changing environment. This question is particularly relevant as many global environmental change (GEC) factors, such as drought and nutrient enrichment, have been shown to reduce soil microbial biomass. Experiments with orthogonal manipulations of plant diversity and GEC factors can provide insights whether plant diversity can attenuate such detrimental effects on soil microbial biomass. Here, we present the analysis of 12 different studies with 14 unique orthogonal plant diversity * GEC manipulations in grasslands, where plant diversity and at least one GEC factor (elevated CO2 , nutrient enrichment, drought, earthworm presence, or warming) were manipulated. Our results show that higher plant diversity significantly enhances soil microbial biomass with the strongest effects in long-term field experiments. In contrast, GEC factors had inconsistent effects with only drought having a significant negative effect. Importantly, we report consistent non significant effects for all 14 interactions between plant diversity and GEC factors, which indicates a limited potential of plant diversity to attenuate the effects of GEC factors on soil microbial biomass. We highlight that plant diversity is a major determinant of soil microbial biomass in experimental grasslands that can influence soil carbon dynamics irrespective of GEC. PMID- 26118994 TI - Conditional Degradation of Plasmodium Calcineurin Reveals Functions in Parasite Colonization of both Host and Vector. AB - Functional analysis of essential genes in the malarial parasite, Plasmodium, is hindered by lack of efficient strategies for conditional protein regulation. We report the development of a rapid, specific, and inducible chemical-genetic tool in the rodent malaria parasite, P. berghei, in which endogenous proteins engineered to contain the auxin-inducible degron (AID) are selectively degraded upon adding auxin. Application of AID to the calcium-regulated protein phosphatase, calcineurin, revealed functions in host and vector stages of parasite development. Whereas depletion of calcineurin in late-stage schizonts demonstrated its critical role in erythrocyte attachment and invasion in vivo, stage-specific depletion uncovered roles in gamete development, fertilization, and ookinete-to-oocyst and sporozoite-to-liver stage transitions. Furthermore, AID technology facilitated concurrent generation and phenotyping of transgenic lines, allowing multiple lines to be assessed simultaneously with significant reductions in animal use. This study highlights the broad applicability of AID for functional analysis of proteins across the Plasmodium life cycle. PMID- 26118997 TI - Comparison of biological fitness in crosses between subspecies of Meccus phyllosomus (Hemiptera: Reduviidae: Triatominae) in southern Mexico. AB - Understanding the biological parameters of some triatomine subspecies of Meccus phyllosomus (Burmeister) is a crucial first step in estimating the epidemiologic importance of this group. Biological parameters related to hatching, lifetime, number of blood meals to molt, percentage of females at the end of the cycle, number of laid eggs, and mortality for each instar of 3 M. phyllosomus subspecies [M. p. mazzottii (Usinger), M. p. pallidipennis (Stal), and M. p. phyllosomus] and their laboratory hybrids were evaluated and compared. No significant differences (P > 0.05) were found among the experimental hybrids (MaPa, MaPhy, PaPhy) and reciprocal cohorts. In 5 (hatching, number of blood meals to molt, accumulative mortality, percentage of females, and mean number of laid eggs) of the 6 studied parameters (with the exception of development time), the hybrid cohorts had better fitness results than the parental cohorts involved in each set of crosses. The increase in hybrid fitness found in our study could lead to an increase in the epidemiologic risks caused by transmission of Trypanosoma cruzi to humans. PMID- 26118998 TI - Indachlorins: nonplanar indanone-annulated chlorin analogues with panchromatic absorption spectra between 300 and 900 nm. AB - Indaphyrins, pyrrole-modified porphyrins containing a cleaved pyrrole beta,beta' bond and two annulated indanone moieties, possess unusually broadened and redshifted UV/Vis spectra because of their pi-expanded chromophores. The parent free base indaphyrin has been crystallographically characterized, highlighting its strongly ruffled conformation incorporating a helimeric twist. It was shown to be susceptible to regiospecific derivatizations at the opposite side of the ring-cleaved pyrrole (dihydroxylation, followed by functional group transformations of the resulting diol functionality), generating indaphyrin-based chlorin analogues, indachlorins, that incorporate a dihydroxypyrroline, pyrrolindione, oxazolone, or a morpholine moiety. Structural modifications resulted in further broadening and hyper- and bathochromic shifts of the optical spectra, some of which possess a nearly panchromatic absorption between 300 to well above 900 nm. The extents to which these modifications affect their solid state conformations were analyzed. PMID- 26118995 TI - Global Mapping of the Inc-Human Interactome Reveals that Retromer Restricts Chlamydia Infection. AB - Chlamydia trachomatis is a leading cause of genital and ocular infections for which no vaccine exists. Upon entry into host cells, C. trachomatis resides within a membrane-bound compartment-the inclusion-and secretes inclusion membrane proteins (Incs) that are thought to modulate the host-bacterium interface. To expand our understanding of Inc function(s), we subjected putative C. trachomatis Incs to affinity purification-mass spectroscopy (AP-MS). We identified Inc-human interactions for 38/58 Incs with enrichment in host processes consistent with Chlamydia's intracellular life cycle. There is significant overlap between Inc targets and viral proteins, suggesting common pathogenic mechanisms among obligate intracellular microbes. IncE binds to sorting nexins (SNXs) 5/6, components of the retromer, which relocalizes SNX5/6 to the inclusion membrane and augments inclusion membrane tubulation. Depletion of retromer components enhances progeny production, revealing that retromer restricts Chlamydia infection. This study demonstrates the value of proteomics in unveiling host pathogen interactions in genetically challenging microbes. PMID- 26118996 TI - Parasite Calcineurin Regulates Host Cell Recognition and Attachment by Apicomplexans. AB - Apicomplexans invade a variety of metazoan host cells through mechanisms involving host cell receptor engagement and secretion of parasite factors to facilitate cellular attachment. We find that the parasite homolog of calcineurin, a calcium-regulated phosphatase complex central to signal transduction in eukaryotes, also contributes to host cell invasion by the malaria parasite Plasmodium falciparum and related Toxoplasma gondii. Using reverse-genetic and chemical-genetic approaches, we determine that calcineurin critically regulates and stabilizes attachment of extracellular P. falciparum to host erythrocytes before intracellular entry and has similar functions in host cell engagement by T. gondii. Calcineurin-mediated Plasmodium invasion is strongly associated with host receptors required for host cell recognition, and calcineurin function distinguishes this form of receptor-mediated attachment from a second mode of host-parasite adhesion independent of host receptors. This specific role of calcineurin in coordinating physical interactions with host cells highlights an ancestral mechanism for parasitism used by apicomplexans. PMID- 26119000 TI - Fundus Tessellation: Prevalence and Associated Factors: The Beijing Eye Study 2011. AB - PURPOSE: To examine the prevalence of fundus tessellation and its associated factors. DESIGN: Population-based study. PARTICIPANTS: The Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6+/-9.8 years (range, 50-93 years). METHODS: Participants underwent a comprehensive ophthalmic examination. By using 45 degrees color fundus photographs of the macula and optic disc, fundus tessellation, defined as variation in the visibility of the large choroidal vessels, was differentiated into 3 grades. MAIN OUTCOME MEASURES: Fundus tessellation. RESULTS: Assessment of fundus tessellation was available for 3442 individuals (99.6%) or 6789 eyes (98.6%). In multivariate analysis, a higher degree of fundus tessellation (mean, 0.84+/-0.79) was associated with older age (P < 0.001; standardized correlation coefficient beta, 0.14), male sex (P < 0.001; beta, -0.08), lower body mass index (P = 0.04; beta, 0.03), worse best corrected visual acuity (P < 0.001; beta, 0.05), thinner subfoveal choroidal thickness (P < 0.001; beta, -0.51), longer axial length (P < 0.001; beta, 0.11), larger parapapillary beta zone (P < 0.001; beta, 0.08), lower prevalence of intermediate age-related macular degeneration (AMD) (P = 0.02; beta, -0.04), and lower prevalence of late AMD (P = 0.007; beta, -0.04). If parapapillary beta zone was dropped, higher glaucoma prevalence (P = 0.003) was associated with a higher degree of fundus tessellation. Prevalence of diabetes mellitus and retinal vein occlusions, mean blood pressure, and intraocular pressure were not (P > 0.10) associated with fundus tessellation. In a reverse manner, thinner subfoveal choroidal thickness was associated with a higher degree of fundus tessellation (P < 0.001; beta, -0.49) in the multivariate analysis. Subfoveal choroidal thickness decreased from 322+/-90 MUm (95% confidence interval [CI], 317-327) in eyes without fundus tessellation to 229+/-80 MUm in eyes with grade 1, to 122+/-52 MUm in eyes with grade 2, and to 81+/-37 MUm in eyes with grade 3 of fundus tessellation. CONCLUSIONS: Fundus tessellation is a surrogate for choroidal thinness and may be a clinical sign for a leptochoroid. After adjusting for ocular and systemic parameters, fundus tessellation also is associated with a larger parapapillary beta zone and higher glaucoma prevalence, and a lower prevalence of intermediate and late AMD. Its association with lower visual acuity warrants further investigation. PMID- 26118999 TI - Paraproteinemic Keratopathy: The Expanding Diversity of Clinical and Pathologic Manifestations. AB - PURPOSE: To describe 7 patients with paraproteinemic keratopathy and to highlight the clinical and pathologic diversity of this rare entity and the importance of timely, systemic evaluation. DESIGN: Retrospective, multicenter collaborative case series. PARTICIPANTS: Seven patients with paraproteinemic keratopathy. METHODS: Clinical and pathologic records were reviewed to identify patients with well-documented corneal immunoglobulin deposits. Detailed ophthalmologic and medical histories were assembled. In 6 patients, corneal tissue was evaluated histochemically and immunohistochemically; in selected cases, corneal tissue was evaluated by in situ hybridization and ultrastructurally. MAIN OUTCOME MEASURES: Visual acuity and anterior segment examination at presentation and follow-up; local therapy; systemic diagnosis and management; and histopathologic, immunohistochemical, in situ hybridization, and ultrastructural findings. RESULTS: Seven patients were identified with corneal immunoglobulin deposition. In addition to previously reported crystalline, nummular, patch-like, and lattice like corneal opacities, prominent corneal vascularization was present in 2 patients mimicking interstitial keratitis and limbal stem cell deficiency. All patients had evidence of paraproteinemia in a setting of monoclonal gammopathy of undetermined significance, smoldering plasma cell myeloma, or Waldenstrom macroglobulinemia. Corneal findings were the first manifestation of systemic disease in 4 patients, and the diagnosis was not suspected in 3 of these patients. Pathologic evaluation of biopsied corneal and conjunctival tissues demonstrated immunoglobulin deposits. Previously unreported ultrastructural patterns in the cornea were noted: large scroll-like immunotactoid deposits, immune complex-like deposits, and randomly arranged fibrils morphologically intermediate between amyloid and immunotactoid deposits. Surgical intervention to improve vision was performed in 4 patients, with recurrence of deposits in 3 patients. Three patients underwent systemic therapy with diminution of the deposits and improvement in vision in 1 patient. CONCLUSIONS: The clinical and pathologic expressions of corneal immunoglobulin deposits are protean and present a diagnostic challenge. Early recognition of this rare entity is important to address the potentially serious associated systemic disease. PMID- 26119001 TI - Frizzled-4 Variations Associated with Retinopathy and Intrauterine Growth Retardation: A Potential Marker for Prematurity and Retinopathy. AB - PURPOSE: To present the association between mutations affecting the Wnt-signaling receptor protein (FZD4), inherited vitreoretinopathies, and retinopathy of prematurity (ROP). DESIGN: Retrospective analysis of prospective samples at a tertiary referral center. PARTICIPANTS: Patients referred to our practice for management of a variety of pediatric vitreoretinopathies were offered participation in an ophthalmic biobank (421 participants with vitreoretinopathies were included in this study). Full-term healthy infants (n = 98) were recruited to the study as controls. METHODS: Patients with various vitreoretinopathies were prospectively enrolled in an ophthalmic biobank, approved by the Human Investigation Committee at William Beaumont Hospital. Retrospective genetic analysis of the FZD4 gene was performed (Sanger sequencing). Participants with a diagnosis of familial exudative vitreoretinopathy (FEVR), Norrie disease, Coats' disease, bilateral persistent fetal vasculature, and ROP were reviewed for the presence of a FZD4 variant. Data retrieval included status of retinopathy (including staging when possible), gestational age (GA), birth weight (BW) (when available), and family and birth histories. MAIN OUTCOME MEASURES: The association of FZD4 variants with the presence of vitreoretinopathy. RESULTS: The sequence variation p.[P33S(;)P168S] is the most prevalent FZD4 variant and is statistically significant for ROP and FEVR (P = 4.6E-04 and P = 2.4E-03, respectively) compared with full-term newborns (P = 1.7E-01). In addition, infants expressing the sequence variation tended to have significantly lower BWs for respective GA (P = 0.04). This suggests that the FZD4 p.[P33S(;)P168S] variant may be a risk factor for retinopathy and restricted intrauterine growth. CONCLUSIONS: Testing for FZD4 gene mutations is useful in patients with suspected FEVR and ROP. The relatively high prevalence of the p.[P33S(;)P168S] variant in ROP and intrauterine growth restriction suggests that it also may be a marker for increased risk of developing ROP and preterm birth. PMID- 26119002 TI - Post-embryonic development in the mite suborder Opilioacarida, with notes on segmental homology in Parasitiformes (Arachnida). AB - In order to study homology among the major lineages of the mite (super)order Parasitiformes, developmental patterns in Opilioacarida are documented, emphasizing morphology of the earliest, post-embryonic instars. Developmental patterns are summarized for all external body structures, based on examination of material in four different genera. Development includes an egg, a 6-legged prelarva and larva, three 8-legged nymphal instars, and the adults, for the most complete ontogenetic sequence in Parasitiformes. The prelarva and larva appear to be non-feeding. Examination of cuticular structures over ontogeny allows development of an updated model for body segmentation and sensillar distribution patterns in Opilioacarida. This model includes a body made up of a well-developed ocular segment plus at most 17 additional segments. In the larvae and protonymphs each segment may carry up to six pairs of sensilla (setae or lyrifissures) arranged is distinct series (J, Z, S, Sv, Zv, Jv). The post-protonymphal instars add two more series (R and Rv) but no extra segments. This basic model is compatible with sensillar patterns in other Parasitiformes, leading to the hypothesis that all taxa in that (super)order may have the same segmental ground plan. The substantial segmental distortion implied in the model can be explained using a single process involving differential growth in the coxal regions of all appendage-bearing segments. PMID- 26119003 TI - Seasonal analysis of Rickettsia species in ticks in an agricultural site of Slovakia. AB - Many rickettsiae of the spotted fever group are emerging pathogens causing serious diseases associated with vertebrate hosts. Ixodidae ticks are known as their vectors. Investigation of the relative abundance of questing Ixodes ricinus and their infection with Rickettsia spp. in an agricultural site comprising a game reserve in Slovakia was the aim of this study. In total, 2198 I. ricinus (492 larvae, 1503 nymphs and 203 adults) were collected by flagging the vegetation along 100 m(2) transects in Rozhanovce (eastern Slovakia): 334, 595 and 1269 in 2011, 2012 and 2013, respectively. Considering questing nymphs and adults, the highest relative density of 81 individuals/100 m(2) was observed in May 2013, the lowest of 0.3 individuals/100 m(2) in March 2012. A total of 1056 ticks (853 nymphs, 100 females and 103 males; 2011: n = 329, 2012: n = 509 and 2013: n = 218) were individually screened by PCR-based methods for the presence of Rickettsia spp. The overall prevalences were 7.3% for nymphs, 15% for females, 7.8% for males; 7.0% in 2011, 8.4% in 2012, and 8.7% in 2013. The maximum prevalences were observed in July in nymphs and in May in adults. Sequencing showed infection with R. helvetica in 73 ticks (72.6% nymphs, 16.4% females, 11% males) and with R. monacensis in 11 ticks (8 nymphs, 3 females). The results showed the circulation of pathogenic Rickettsia species in the agricultural site and a potential risk for humans to encounter infected ticks. PMID- 26119004 TI - Three-Component Azidation of Styrene-Type Double Bonds: Light-Switchable Behavior of a Copper Photoredox Catalyst. AB - [Cu(dap)2]Cl effectively catalyzes azide addition from the Zhdankin reagent to styrene-type double bonds, and subsequent addition of a third component to the benzylic position. In the presence of light, a photoredox cycle is implicated with polar components such as methanol or bromide adding to a benzylic cation. In the absence of light, by contrast, double azidation takes place to give diazides. Therefore, regioselective double functionalization can be achieved in good to excellent yields, with a switch between light and dark controlling the degree of azidation. PMID- 26119005 TI - Anharmonic simulations of the vibrational spectrum of sulfated compounds: application to the glycosaminoglycan fragment glucosamine 6-sulfate. AB - Mid-infrared spectroscopy coupled with mass spectrometry is an appealing tool for the sequencing and structural elucidation of functional modifications in biopolymers, as it offers direct spectroscopic identification of the functionality where the traditional mass spectrometric approach is insufficient. Whereas the gas phase vibrational spectroscopy of peptides (and to a lesser extent saccharides) has been widely investigated, sulfation has attracted much less attention, despite its prevalence in natural polymers. The simulation of the vibrational spectra of such functionalized compounds is however notoriously challenging, which impairs the interpretation of spectroscopic data in terms of structure. Driven by a striking case of such a failure for a sulfated glycosaminoglycan fragment, we elaborate on an original hybrid GVPT2 anharmonic approach. This strategy offers a significantly improved accuracy in the description of the sulfate modes, without the recourse to empirical scaling factors, and with a greatly reduced computational cost which is otherwise prohibitive for molecules of this size. Alternatively, we propose a selection of reasonably accurate harmonic methods with adequate scaling factors optimized on a set of benchmark compounds. PMID- 26119006 TI - Population status of chimpanzees in the Masito-Ugalla Ecosystem, Tanzania. AB - More than 75 percent of Tanzania's chimpanzees live at low densities on land outside national parks. Chimpanzees are one of the key conservation targets in the region and long-term monitoring of these populations is essential for assessing the overall status of ecosystem health and the success of implemented conservation strategies. We aimed to assess change in chimpanzee density within the Masito-Ugalla Ecosystem (MUE) by comparing results of re-walking the same line transects in 2007 and 2014. We further used published remote sensing data derived from Landsat satellites to assess forest cover change within a 5 km buffer of these transects over that same period. We detected no statistically significant decline in chimpanzee density across the surveyed areas of MUE between 2007 and 2014, although the overall mean density of chimpanzees declined from 0.09 individuals/km(2) in 2007 to 0.05 individuals/km(2) in 2014. Whether this change is biologically meaningful cannot be determined due to small sample sizes and large, entirely overlapping error margins. It is therefore possible that the MUE chimpanzee population has been stable over this period and indeed in some areas (Issa Valley, Mkanga, Kamkulu) even showed an increase in chimpanzee density. Variation in chimpanzee habitat preference for ranging or nesting could explain variation in density at some of the survey sites between 2007 and 2014. We also found a relationship between increasing habitat loss and lower mean chimpanzee density. Future surveys will need to ensure a larger sample size, broader geographic effort, and random survey design, to more precisely determine trends in MUE chimpanzee density and population size over time. PMID- 26119007 TI - Graphene-coated materials using silica particles as a framework for highly efficient removal of aromatic pollutants in water. AB - The substantial aggregation of pristine graphene nanosheets decreases its powerful adsorption capacity and diminishes its practical applications. To overcome this shortcoming, graphene-coated materials (GCMs) were prepared by loading graphene onto silica nanoparticles (SiO2). With the support of SiO2, the stacked interlamination of graphene was held open to expose the powerful adsorption sites in the interlayers. The adsorption of phenanthrene, a model aromatic pollutant, onto the loaded graphene nanosheets increased up to 100 fold compared with pristine graphene at the same level. The adsorption of GCMs increased with the loading amount of the graphene nanosheets and dramatically decreased with the introduction of oxygen-containing groups in the graphene nanosheets. The highly hydrophobic effect and the strong pi-pi stacking interactions of the exposed graphene nanosheets contributed to their superior adsorption of GCMs. An unusual GCM peak adsorption coefficient (Kd) was observed with the increase in sorbate concentration. The sorbate concentration at peak Kd shifted to lower values for the reduced graphene oxide and graphene relative to the graphene oxide. Therefore, the replacement of water nanodroplets attached to the graphene nanosheets through weak non-hydrogen bonding with phenanthrene molecules via strong pi-pi stacking interactions is hypothesized to be an additional adsorption mechanism for GCMs. PMID- 26119009 TI - Life cycle assessment of three different management options for spent alkaline batteries. AB - The potential environmental impact of Landfilling, Incineration and Recycling of spent household alkaline batteries collected in continental Portugal was compared using LCA methodology and the Recipe Impact Assessment method. Major contributors and improvement opportunities for each system were identified and scenarios for 2012 and 2016 legislation targets were evaluated. For 13 out of the 18 impact categories, the Recycling system is the worst alternative, Incineration is the worst option for 4 and Landfill is the worst option only for one impact category. However if additionally in each system the recovery of materials and energy is taken into account there is a noticeable advantage of the Recycling system for all the impact categories. The environmental profiles for 2012 and 2016 scenarios (25% and 45% recycling rates, respectively) show the dominance of the Recycling system for most of the impact categories. Based on the results of this study, it is questioned whether there are environmental benefits of recycling abroad the household alkaline batteries collected in continental Portugal and, since the low environmental performance of the Recycling system is particularly due to the international transport of the batteries to the recycling plant, is foreseen that a recycling facility located in Portugal, could bring a positive contribution to the environmental impact of the legislation compliance. PMID- 26119010 TI - Recycling of a fine, heavy fluff automobile shredder residue by density and differential fragmentation. AB - A compilation of the physical properties of materials which might typically occur in automobile shredder residue and an analysis of their suitability for the separation of materials in fine (<15mm) heavy fluff ASR (fhf-ASR) is presented. Differences in density and resistance to crushing of fhf-ASR materials were identified as potentially the most suitable low cost, technologically simple means for the separating this waste into its three principal components - metals, minerals (glass/stones) and organics (plastics). Results presented of laboratory scale tests demonstrate that fhf-ASR can in large part be separated into three principal components. Tests were conducted with 0.63-2.0mm and 2-10mm fractions. Recovery of plastics by density separations were conducted with water only jigs for the 2-10mm fraction and shaker tables for the 0.63-2mm fraction. Comparisons are presented of the separations of glass and stones from metals obtained by linear screening and vibratory screening of roller mill and impact mill crushing products of the high density 2-10mm fraction. Equipment used for these tests are of a laboratory or demonstrative scale. It is reasonable to anticipate that industrial scale processing would produce significantly better results. The 2 15mm fraction was found to constitute 91.6% of the fhf-ASR sampled. The metals content of the 2-10mm portion of this fraction was upgraded from 2.5% to 31% and 76.9% with recoveries varying inversely with grade from 91.9% to 40.1%. From 63.6% to 17.1% with a recovery of 93.5% of the organic materials. A residual product of fine sand of crushed glass/stones of 99.4% purity recovered 71.3% of these. PMID- 26119008 TI - Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs. AB - BACKGROUND: Nonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy. HYPOTHESIS/OBJECTIVES: The primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine. ANIMALS: Forty-seven client owned dogs with measurable MCT. METHODS: Toceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone. RESULTS: The MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy. CONCLUSIONS AND CLINICAL IMPORTANCE: Combined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT. PMID- 26119011 TI - Degradation of municipal solid waste in simulated landfill bioreactors under aerobic conditions. AB - In this study the municipal solid waste degradation processes in simulated landfill bioreactors under aerobic and anaerobic conditions is investigated. The effect of waste aeration on the dynamics of the aerobic degradation processes in lysimeters as well as during anaerobic processes after completion of aeration is presented. The results are compared with the anaerobic degradation process to determine the stabilization stage of waste in both experimental modes. The experiments in aerobic lysimeters were carried out at small aeration rate (4.41?10(-3)lmin(-1)kg(-1)) and for two recirculation rates (24.9 and 1.58lm( 3)d(-1)). The change of leachate and formed gases composition showed that the application of even a small aeration rate favored the degradation of organic matter. The amount of CO2 and CH4 released from anaerobic lysimeter was about 5 times lower than that from the aerobic lysimeters. Better stabilization of the waste was obtained in the aerobic lysimeter with small recirculation, from which the amount of CO2 produced was larger by about 19% in comparison with that from the aerobic lysimeter with large leachate recirculation. PMID- 26119012 TI - Environmental and economic performance of plasma gasification in Enhanced Landfill Mining. AB - This paper describes an environmental and economic assessment of plasma gasification, one of the viable candidates for the valorisation of refuse derived fuel from Enhanced Landfill Mining. The study is based on life cycle assessment and life cycle costing. Plasma gasification is benchmarked against conventional incineration, and the study indicates that the process could have significant impact on climate change, human toxicity, particulate matter formation, metal depletion and fossil depletion. Flue gas emission, oxygen usage and disposal of residues (plasmastone) are the major environmental burdens, while electricity production and metal recovery represent the major benefits. Reductions in burdens and improvements in benefits are found when the plasmastone is valorised in building materials instead of landfilling. The study indicates that the overall environmental performance of plasma gasification is better than incineration. The study confirms a trade-off between the environmental and economic performance of the discussed scenarios. Net electrical efficiency and investment cost of the plasma gasification process and the selling price of the products are the major economic drivers. PMID- 26119014 TI - Bone Metastasis-Related MicroRNAs: New Targets for Treatment? AB - MicroRNAs (miRNAs) are a new class of small noncoding RNAs of 19-25 nucleotides that function as negative posttranscriptional gene regulators. MiRNAs hybridize to the 3' untranslated region (UTR) of target mRNAs and repress translation or mediate mRNA cleavage. MiRNAs critically regulate tumorigenesis and progression by targeting oncogenes, tumor suppressor genes, or genes related to proliferation, angiogenesis, and apoptosis. Different tumor types and tumors at different stages exhibit unique miRNA profiles. MiRNAs show promise as potential biomarkers for cancer diagnostics, progression, and response to treatment. The role of miRNAs in promoting bone metastases is under investigated. We summarize recent findings on the mechanisms by which miRNAs may regulate bone metastatic spread of breast cancer, prostate cancer, lung cancer and multiple myeloma. We review similarities and differences in miRNA profiles that may explain the variety of molecular pathways underling metastatic spread to the skeleton in different cancers. Finally, we discuss the exciting potential of using miRNAs as diagnostics and therapeutic targets to reduce the risk of bone metastases in cancer, from the perspective of data provided by recent pre-clinical and clinical studies. PMID- 26119013 TI - Does rumination mediate the relationship between mindfulness and depressive relapse? AB - OBJECTIVES: Major depressive disorder is a significant mental illness that is highly likely to recur, particularly after three or more previous episodes. Increased mindfulness and decreased rumination have both been associated with decreased depressive relapse. The aim of this study was to investigate whether rumination mediates the relationship between mindfulness and depressive relapse. DESIGN: This prospective design involved a secondary data analysis for identifying causal mechanisms using mediation analysis. METHODS: This study was embedded in a pragmatic randomized controlled trial of mindfulness-based cognitive therapy (MBCT) in which 203 participants (165 females, 38 males; mean age: 48 years), with a history of at least three previous episodes of depression, completed measures of mindfulness, rumination, and depressive relapse over a 2 year follow-up period. Specific components of mindfulness and rumination, being nonjudging and brooding, respectively, were also explored. RESULTS: While higher mindfulness scores predicted reductions in rumination and depressive relapse, the relationship between mindfulness and relapse was not found to be mediated by rumination, although there appeared to be a trend. CONCLUSIONS: Our results strengthen the argument that mindfulness may be important in preventing relapse but that rumination is not a significant mediator of its effects. The study was adequately powered to detect medium mediation effects, but it is possible that smaller effects were present but not detected. PRACTITIONER POINTS: Mindfulness may be one of several components of MBCT contributing to prevention of depressive relapse. Although the original rationale for MBCT rested largely on a model of relapse causally linked to rumination, our findings suggest that the mechanism by which mindfulness impacts relapse is more complex than a simple effect on rumination. PMID- 26119015 TI - Reliability of the anterior functional device in recording the centric relations of patients with posterior tooth loss. AB - STATEMENT OF THE PROBLEM: The recording of centric relations (CRs) in patients with posterior tooth loss is a process that is subject to inaccuracy. A number of techniques and devices, including the anterior functional device (AFD), have been developed in the pursuit of better results. PURPOSE: The purpose of this in vivo study was to evaluate the reliability of the AFD for the recording of the CR in participants with different types of posterior tooth loss. MATERIAL AND METHODS: Two CR records were obtained (CR1, CR2), and 2 maximal intercuspal position records were obtained (MIP1, MIP2) by a single operator at intervals of 5 minutes. This study included 45 participants of both sexes aged between 18 and 65 years who were divided into 3 groups. The first group had intercalated tooth loss (n=19), the second group had distal extensions (n=11), and the third group had no tooth loss (n=15). The distance between the CR and MIP was termed the condylar displacement and was measured in millimeters in the vertical, horizontal, and transversal planes with a condylar position indicator (CPI). The condylar displacements between the CR and MIP in both stages of the study (D1 and D2) were compared with the CPI after mounting the casts on a semiadjustable articulator. Repeated-measures analyses of variance with one factor were used to compare the records for each group in each of the planes: right vertical (RV), left vertical (LV), horizontal right (HR), horizontal left (HL), and transverse (T) (alpha=.05). No significant differences between the records in any of the planes (RV, LV, HR, HL, or T) were observed; thus, the means of the records of each plane were used to compare the groups (the intercalated tooth loss, distal extension, and no tooth loss groups). The means of the records of the HR and HL planes were compared by ANOVA because the data were normally distributed. The means of the records of the RV, LV, and T planes were compared by using nonparametric Kruskal-Wallis tests because the data were non-normally distributed. RESULTS: No statistically significant difference (P >.05) was found between the condylar displacements for any of the studied variables in the 3 considered groups: RV (.512), LV (.690), HR (.179), HL (.494), and T (.644). CONCLUSIONS: Repeatability of the condylar displacement was observed between the CR and MIP (D1, D2), which indicates the reliability of the AFD method for recording the CR in participants with posterior tooth loss. The AFD was demonstrated to be a user-friendly tool and permitted the recording and evaluation of excursive movements with tracings. PMID- 26119016 TI - Accuracy of mechanical torque-limiting devices for dental implants. AB - STATEMENT OF PROBLEM: A common complication in implant dentistry is unintentional implant screw loosening. The critical factor in the prevention of screw loosening is the delivery of the appropriate target torque value. Mechanical torque limiting devices (MTLDs) are the most frequently recommended devices by the implant manufacturers to deliver the target torque value to the screw. Two types of MTLDs are available: friction-style and spring-style. Limited information is available regarding the influence of device type on the accuracy of MTLDs. PURPOSE: The purpose of this study was to determine and compare the accuracy of spring-style and friction-style MTLDs. MATERIAL AND METHODS: Five MTLDs from 6 different dental implant manufacturers (Astra Tech/Dentsply, Zimmer Dental, Biohorizons, Biomet 3i, Straumann [ITI], and Nobel Biocare) (n=5 per manufacturer) were selected to determine their accuracy in delivering target torque values preset by their manufacturers. All torque-limiting devices were new and there were 3 manufacturers for the friction-style and 3 manufacturers for the spring-style. The procedure of target torque measurement was performed 10 times for each device and a digital torque gauge (Chatillon Model DFS2-R-ND; Ametek) was used to record the measurements. Statistical analysis used nonparametric tests to determine the accuracy of the MTLDs in delivering target torque values and Bonferroni post hoc tests were used to assess pairwise comparisons. RESULTS: Median absolute difference between delivered torque values and target torque values of friction-style and spring-style MTLDs were not significantly different (P>.05). Accuracy of Astra Tech and Zimmer Dental friction-style torque-limiting devices were significantly different than Biohorizons torque-limiting devices (P<.05). CONCLUSIONS: There is no difference between the accuracy of new friction style MTLDs and new spring-style MTLDs. All MTLDs fell within +/-10% of the target torque value. Astra Tech and Zimmer Dental friction-style torque-limiting devices were significantly more accurate than Biohorizons (C) torque-limiting devices (P<.05); however, all the torque-limiting devices fell within +/-10% of the target torque value preset by the manufacturers. PMID- 26119017 TI - Fatigue resistance of ultrathin CAD/CAM complete crowns with a simplified cementation process. AB - STATEMENT OF PROBLEM: Traditional tooth preparation for complete crowns requires a substantial amount of hard tissue reduction. This is in contrast with the principles of minimally invasive dentistry. An ultrathin complete crown preparation is proposed instead. PURPOSE: The purpose of this in vitro study was to assess the fatigue resistance and failure mode of computer-aided design and computer-aided manufacturing (CAD/CAM) ultrathin complete molar crowns placed with self-adhesive cement. Different restorative materials (resin nanoceramic [RNC], feldspathic ceramic [FEL], and lithium disilicate [LD]) were compared. MATERIAL AND METHODS: Forty-five extracted molars with a standardized crown preparation were restored with the Cerec 3 CAD/CAM system using FEL, LD, or RNC (n=15). FEL and LD restorations were etched with hydrofluoric acid and silanated. RNC restorations and all preparations were treated with airborne-particle abrasion. All restorations (thickness=0.7 mm) were cemented with RelyX Unicem II Automix cement and submitted to cyclic isometric loading, beginning with a load of 200 N (5000 cycles) and followed by stages of 400, 600, 800, 1000, 1200, and 1400 N at a maximum of 30 000 cycles each. The specimens were loaded until failure or for a maximum of 185 000 cycles. The failure mode was categorized as "catastrophic," "possibly reparable," or "reparable." The groups were compared using life table survival analysis (log rank test at alpha=.05). Previously published data from the same authors about traditional complete crowns (thickness 1.5 mm) using the same experimental design were included for comparison. RESULTS: All specimens survived the fatigue test until the 600 N step. RNC, LD, and FEL failed at an average load of 1014 N (1 survival), 1123 N (2 survivals), and 987 N (no survivals), and no difference in survival rate was found. No catastrophic failures were reported after the fatigue test. Comparison with previously published data showed that 1.5-mm thick complete crowns demonstrated higher survival rates than the ultrathin restorations, independent of the material. CONCLUSIONS: The fatigue resistance of ultrathin complete molar crowns (placed with a simplified cementation process) made of RNC, LD, and FEL was not significantly different. All materials survived the normal range of masticatory forces. All failures were re-restorable. Regular crowns of 1.5 to 2.0 mm thickness may present higher survival rates than ultrathin ones. PMID- 26119018 TI - Cemented implant restoration: A technique for minimizing adverse biologic consequences. AB - The purpose of this technique was to eliminate excess cement from the implant restoration by using a 2-step cementation process. A custom acrylic resin abutment, a duplicate of the titanium abutment, is fabricated before the restoration is cemented. At cementation, cement is placed inside the restoration, which is placed onto the acrylic resin abutment outside the mouth. The majority of the excess cement from inside the restoration is expressed onto the acrylic resin abutment. The restoration is then placed on the titanium abutment inside the mouth. The result is a minimum amount of excess cement expressed intraorally. This technique minimizes the adverse biological consequences of leaving excess cement beneath implant-supported restorations. PMID- 26119019 TI - Accuracy of computer-guided surgery: A comparison of operator experience. AB - STATEMENT OF PROBLEM: Even though high-precision technologies have been used in computer-guided implant surgery, studies have shown that linear and angular deviations between the planned and placed implants can be expected. PURPOSE: The purpose of this study was to evaluate the effect of operator experience on the accuracy of implant placement with a computer-guided surgery protocol. MATERIAL AND METHODS: Ten surgically experienced and 10 surgically inexperienced operators participated in this study. Each operator placed 1 dental implant (Replace Select) on the partially edentulous mandibular model that had been planned with software by following a computer-guided surgery (NobelGuide) protocol. Three dimensional information of the planned and placed implants were then superimposed. The horizontal and vertical linear deviations at both the apex and platform levels and the angular deviation were measured and compared between the experienced and inexperienced groups with the independent t test with Bonferroni adjustment (alpha=.01). The magnitude and direction of the horizontal deviations were also measured and recorded. RESULTS: No significant differences were found in the angular and linear deviations between the 2 groups (P>.01). Although not statistically significant (P>.01), the amount of vertical deviation in the coronal direction of the implants placed by the inexperienced operators was about twice that placed by the experienced operators. Overall, buccal apical deviations were most frequent and of the highest magnitude. CONCLUSIONS: When a computer guided protocol was used, the accuracy of the vertical dimension (depth of implant placement) was most influenced by the operator's level of experience. PMID- 26119020 TI - Interdisciplinary treatment of an adult with bilateral cleft lip and palate with missing premaxilla: The prosthodontic perspective. AB - Conventional orthognathic surgery and orthodontic techniques occasionally fail to completely correct the occlusal relationship and esthetic deficits of patients with cleft lip and palate and severe midface deficiency. Prosthodontic rehabilitation is often required to establish adequate occlusion and provide a more proportional facial appearance. This clinical report describes the interdisciplinary management of an adult with complete bilateral cleft lip and palate who was treated with distraction osteogenesis using a rigid external distraction device for maxillary advancement and his prosthodontic rehabilitation with a dual path removable partial overdenture to develop definitive facial and dental esthetic form. PMID- 26119021 TI - Lateralized modulation of posterior alpha oscillations in children. AB - The evidence for a functionally inhibitory role of alpha oscillations is growing stronger, mostly derived from studies in healthy adults investigating spatial attention. It remains unexplored if the modulation of alpha band oscillations plays a similar functional role in typically developing children. The aim of this study was to characterize alpha modulations in children in relation to attentional performance. To this end, the posterior alpha activity (8-12Hz) in children between 7 and 10years old was measured using EEG while they performed a visuospatial covert attention task. We found that the alpha activity decreased in the hemisphere contralateral to the attended hemifield, whereas it relatively increased in the other hemisphere. In addition, we found that the degree of lateralized alpha modulation predicted performance on the attention task by negatively predicting the response time on invalid trials. Of note, children who were behaviorally less influenced by spatial cueing also were children with a clear lateralized alpha modulation pattern, with a significantly stronger alpha lateralization in the left hemisphere than children who were influenced more by spatial cueing. In addition, a bias to the right visual field such as that commonly observed in children, was significantly smaller or absent in the children influenced least by spatial cueing. Among all children, the magnitude of this visual field bias was positively related to the ability to modulate alpha activity. In conclusion, we have shown that the pattern of alpha oscillations modulated by attention is already present in 7-10year old typically developing children. Although a similar pattern is observed in adults, the consequences for behavior are different. The fact that alpha modulation is already present at this age opens up the possibility of using hemispheric alpha lateralization as a tool to study the physiological basis of attention deficits in clinical disorders such as ADHD. PMID- 26119022 TI - Top-down attention regulates the neural expression of audiovisual integration. AB - The interplay between attention and multisensory integration has proven to be a difficult question to tackle. There are almost as many studies showing that multisensory integration occurs independently from the focus of attention as studies implying that attention has a profound effect on integration. Addressing the neural expression of multisensory integration for attended vs. unattended stimuli can help disentangle this apparent contradiction. In the present study, we examine if selective attention to sound pitch influences the expression of audiovisual integration in both behavior and neural activity. Participants were asked to attend to one of two auditory speech streams while watching a pair of talking lips that could be congruent or incongruent with the attended speech stream. We measured behavioral and neural responses (fMRI) to multisensory stimuli under attended and unattended conditions while physical stimulation was kept constant. Our results indicate that participants recognized words more accurately from an auditory stream that was both attended and audiovisually (AV) congruent, thus reflecting a benefit due to AV integration. On the other hand, no enhancement was found for AV congruency when it was unattended. Furthermore, the fMRI results indicated that activity in the superior temporal sulcus (an area known to be related to multisensory integration) was contingent on attention as well as on audiovisual congruency. This attentional modulation extended beyond heteromodal areas to affect processing in areas classically recognized as unisensory, such as the superior temporal gyrus or the extrastriate cortex, and to non-sensory areas such as the motor cortex. Interestingly, attention to audiovisual incongruence triggered responses in brain areas related to conflict processing (i.e., the anterior cingulate cortex and the anterior insula). Based on these results, we hypothesize that AV speech integration can take place automatically only when both modalities are sufficiently processed, and that if a mismatch is detected between the AV modalities, feedback from conflict areas minimizes the influence of this mismatch by reducing the processing of the least informative modality. PMID- 26119023 TI - Inferior-frontal cortex phase synchronizes with the temporal-parietal junction prior to successful change detection. AB - The inferior frontal gyrus (IFG) and the temporo-parietal junction (TPJ) are believed to be core structures of human brain networks that activate when sensory top-down expectancies guide goal directed behavior and attentive perception. But it is unclear how activity in IFG and TPJ coordinates during attention demanding tasks and whether functional interactions between both structures are related to successful attentional performance. Here, we tested these questions in electrocorticographic (ECoG) recordings in human subjects using a visual detection task that required sustained attentional expectancy in order to detect non-salient, near-threshold visual events. We found that during sustained attention the successful visual detection was predicted by increased phase synchronization of band-limited 15-30 Hz beta band activity that was absent prior to misses. Increased beta-band phase alignment during attentional engagement early during the task was restricted to inferior and lateral prefrontal cortex, but with sustained attention it extended to long-range IFG-TPJ phase synchronization and included superior prefrontal areas. In addition to beta, a widely distributed network of brain areas comprising the occipital cortex showed enhanced and reduced alpha band phase synchronization before correct detections. These findings identify long-range phase synchrony in the 15-30 Hz beta band as the mesoscale brain signal that predicts the successful deployment of attentional expectancy of sensory events. We speculate that localized beta coherent states in prefrontal cortex index 'top-down' sensory expectancy whose coupling with TPJ subregions facilitates the gating of relevant visual information. PMID- 26119024 TI - The number of objects determines visual working memory capacity allocation for complex items. AB - The goal of the present study was to examine whether visual working memory (WM) capacity allocation is determined solely by complexity, with the number of objects being redundant, as suggested by flexible resource models. Participants performed the change detection task with random polygons as stimuli, while we monitored the contralateral delay activity (CDA), an electrophysiological marker whose amplitude rises as WM load increases. In Experiment 1, we compared the WM maintenance of one whole polygon to a single half of the polygon, equating the number of items but varying the complexity level. Additionally, we compared the whole polygon to two halves of a polygon, thus roughly equating perceptual complexity but manipulating the number of items. The results suggested that only the number of objects determined WM capacity allocation: the CDA was identical when comparing one whole polygon to one polygon half, even though these conditions differed in complexity. Furthermore, the CDA amplitude was lower in the whole polygon condition relative to the two halves condition, even though both contained roughly the same amount of information. Experiment 2 extended these results by showing that two polygon halves that moved separately but then met and moved together were gradually integrated to consume similar WM capacity as one polygon half. Additionally, in both experiments we found an object benefit in accuracy, corroborating the important role of objects in WM. Our results demonstrate that WM capacity allocation cannot be explained by complexity alone. Instead, it is highly sensitive to objecthood, as suggested by discrete slot models. PMID- 26119025 TI - New insights on the viral and host factors contributing to the airway pathogenesis caused by the respiratory syncytial virus. AB - The respiratory syncytial virus (RSV) is the most prevalent etiological agent of lower respiratory tract infections and the first cause of hospitalization in infants due to respiratory disease worldwide. However, efforts to develop safe and effective vaccines and antivirals have been challenged by an incomplete understanding of the RSV pathogenesis and the host immune response to RSV infection in the airways. Here, we discuss recent advances in understanding the interaction between RSV and the epithelium to induce pathogenesis in the airways, such as the role of the RSV NS2 protein in the airway epithelium, as well as the events involved in the RSV entry process. In addition, we summarize the cellular factors produced by airway epithelial cells (AECs) in response to RSV infection that lead to the activation of innate and adaptive immune responses, inducing lung inflammation and disease. Further, we discuss the possible contribution of a recently identified cytokine, thymic stromal lymphopoitein (TSLP), in the lung immunopathology caused by RSV. PMID- 26119026 TI - Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation. AB - Lung nociceptors initiate cough and bronchoconstriction. To elucidate if these fibers also contribute to allergic airway inflammation, we stimulated lung nociceptors with capsaicin and observed increased neuropeptide release and immune cell infiltration. In contrast, ablating Nav1.8(+) sensory neurons or silencing them with QX-314, a charged sodium channel inhibitor that enters via large-pore ion channels to specifically block nociceptors, substantially reduced ovalbumin- or house-dust-mite-induced airway inflammation and bronchial hyperresponsiveness. We also discovered that IL-5, a cytokine produced by activated immune cells, acts directly on nociceptors to induce the release of vasoactive intestinal peptide (VIP). VIP then stimulates CD4(+) and resident innate lymphoid type 2 cells, creating an inflammatory signaling loop that promotes allergic inflammation. Our results indicate that nociceptors amplify pathological adaptive immune responses and that silencing these neurons with QX-314 interrupts this neuro-immune interplay, revealing a potential new therapeutic strategy for asthma. PMID- 26119028 TI - Prosthetic heart valves in pregnancy, outcomes for women and their babies: a systematic review and meta-analysis. AB - BACKGROUND: Historically, pregnancies among women with prosthetic heart valves have been associated with an increased incidence of adverse outcomes. OBJECTIVES: Systematic review to assess risk of adverse pregnancy outcomes among women with a prosthetic heart valve(s) over the last 20 years. SEARCH STRATEGY: Electronic literature search of Medline, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature and Embase to find recent studies. SELECTION CRITERIA: Studies of pregnant women with heart valve prostheses including trials, cohort studies and unselected case series. DATA COLLECTION AND ANALYSIS: Primary analysis calculated absolute risks and 95% confidence intervals (CI) for pregnancy outcomes using a random effects model. The Freeman-Tukey transformation was utilised in secondary analysis due to the large number of individual study outcomes with zero events. MAIN RESULTS: Eleven studies capturing 499 pregnancies among women with heart valve prostheses, including 256 mechanical and 59 bioprosthetic, were eligible for inclusion. Pooled estimate of maternal mortality was 1.2/100 pregnancies (95% CI 0.5-2.2), for mechanical valves subgroup 1.8/100 (95% CI 0.5-3.7) and bioprosthetic subgroup 0.7/100 (95% CI 0.1-4.5), overall pregnancy loss 20.8/100 pregnancies (95% CI 9.5-35.1), perinatal mortality 5.0/100 births (95%CI 1.8-9.8) and thromboembolism 9.3/100 pregnancies (95% CI 4.0-16.5). CONCLUSIONS: Women with heart valve prostheses experienced higher rates of adverse outcomes than expected in a general obstetric population; however, lower than previously reported. Women with bioprostheses had significantly fewer thromboembolic events compared to women with mechanical valves. Women should be counselled pre-pregnancy about risk of maternal death and pregnancy loss. Vigilant surveillance by a multidisciplinary team throughout the perinatal period remains warranted for these women and their infants. TWEETABLE ABSTRACT: Metaanalysis suggests improvement in #pregnancy outcomes among women with #heartvalveprostheses. PMID- 26119027 TI - Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes. AB - The precise regulation of cerebral blood flow is critical for normal brain function, and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). Using optical imaging we investigated blood flow regulation at various sites on the vascular tree in living mice. Optogenetic, whisker stimulation, or cortical spreading depolarization caused microvascular diameter or flow changes in SMC but not pericyte-covered microvessels. During early stages of brain ischemia, transient SMC but not pericyte constrictions were a major cause of hypoperfusion leading to thrombosis and distal microvascular occlusions. Thus, capillary pericytes are not contractile, and regulation of cerebral blood flow in physiological and pathological conditions is mediated by arteriolar SMCs. PMID- 26119029 TI - Combined effects of sex hormone-binding globulin and sex hormones on risk of incident type 2 diabetes. AB - BACKGROUND: The aim of the present study was to investigate the combined effects of sex hormone-binding globulin (SHBG) and sex hormones on the risk of type 2 diabetes (T2D). METHODS: A nested case-control study of Chinese participants in the Environment, Inflammation and Metabolic Diseases Study (2008-13) was performed. Of the 3510 subjects free of diabetes, 145 men and 87 women developed diabetes over the 5-year follow-up. One age- and sex-matched control subject was selected for each case. Baseline concentrations of SHBG, estradiol, testosterone, and dehydroepiandrosterone sulfate (DHEA-S) were divided into tertiles and subjects were classified as having low, intermediate and high levels accordingly. RESULTS: After multivariate adjustment, men with low SHBG levels had a fourfold greater risk of T2D than men with high SHBG levels. Conversely, men with high estradiol levels had a fourfold greater risk of T2D than men with low estradiol levels. Men with low SHBG + high estradiol had a 20-fold greater risk of T2D than men with high SHBG + low estradiol (odds ratio [OR] 20.23; 95% confidence interval [CI] 4.62-51.33). These risk associations in men were not observed for testosterone or DHEA-S, alone or in combination with SHBG. Compared with low SHBG, the risk of T2D decreased with increasing SHBG tertile (OR 0.92 [95% CI 0.21-4.53], 0.14 [95% CI 0.10-0.74]; Ptrend = 0.043) after multivariate adjustment in women. Estradiol, testosterone, and DHEA-S levels showed no association with T2D in women. CONCLUSION: Low SHBG in conjunction with high estradiol has an additive detrimental effect on the risk of T2D in men. PMID- 26119030 TI - Behavioral treatment of rumination: Research and clinical applications. AB - This brief review describes research on rumination treatment that emphasizes functional analysis, recent intervention methods (supplemental feeding, fixed time stimulus presentation, continuous access to preferred stimulation), clinical implications, and procedural recommendations. PMID- 26119031 TI - A holistic measurement model of movement competency in children. AB - Different countries have different methods for assessing movement competence in children; however, it is unclear whether the test batteries that are used measure the same aspects of movement competence. The aim of this paper was to (1) investigate whether the Test of Gross Motor Development (TGMD-2) and Korperkoordinations Test fur Kinder (KTK) measure the same aspects of children's movement competence and (2) examine the factorial structure of the TGMD-2 and KTK in a sample of Australian children. A total of 158 children participated (M age = 9.5; SD = 2.2). First, confirmatory factor analysis examined the independent factorial structure of the KTK and TGMD-2. Second, it was investigated whether locomotor, object control and body coordination loaded on the latent variable Movement Competency. Confirmatory factor analysis indicated an adequate fit for both the KTK and TGMD-2. An adequate fit was also achieved for the final model. In this model, locomotor (r = .86), object control (r = .71) and body coordination (r = .52) loaded on movement competence. Findings support our hypothesis that the TGMD-2 and KTK measure discrete aspects of movement competence. Future researchers and practitioners should consider using a wider range of test batteries to assess movement competence. PMID- 26119032 TI - Nodular cystic fat necrosis related to chronic minor local ischemia. PMID- 26119033 TI - Triexponential function analysis of diffusion-weighted MRI for diagnosing prostate cancer. AB - BACKGROUND: To evaluate more detailed information noninvasively through on diffusion and perfusion in prostate cancer (PCa) using triexponential analysis of diffusion-weighted imaging (DWI). METHODS: Sixty-three prostate cancer patients underwent preoperative 3.0 Tesla MRI including eight b-values DWI. Triexponential analysis was performed to obtain three diffusion coefficients (Dp , Df , Ds ), as well as fractions (Fp , Ff , Fs ). Each diffusion parameter for cancerous lesions and normal tissues was compared and the relationship between diffusion parameters and Gleason score (GS) was assessed. K(trans) , Ve , and the ratios of intracellular components measured in histopathological specimens were compared with diffusion parameters. RESULTS: Dp was significantly greater for cancerous lesions than normal peripheral zone (PZ) (P < 0.001), whereas Dp in transition zone (TZ) showed no significant difference (P = 0.74, 95% confidence interval (CI) = -4.69-6.48). Ds was significantly smaller for each cancerous lesions in PZ and TZ (P < 0.001, respectively). There was no significant difference in Df between cancerous lesions and normal tissues in PZ and TZ (P = 0.07, 95% CI = 0.29-0.12 and P = 0.53, 95% CI = -3.51-2.29, respectively). D obtained with biexponential analysis were significantly smaller in cancerous lesions than in normal tissue in PZ and TZ (P < 0.001 for both), while D* in PZ and TZ showed no significant difference (P = 0.14, 95% CI = -1.60-0.24 and P = 0.31, 95% CI = 3.43-1.16, respectively). Dp in PZ and TZ showed significant correlation with K(trans) (R = 0.85, P < 0.001; R = 0.81, P < 0.001, respectively), while D(*) in PZ obtained with biexponential analysis showed no such correlation (P = 0.08, 95% CI = -0.14-0.30). Fs was significantly correlated with intracellular space fraction evaluated in histopathological specimens in PZ and TZ cancer (R = 0.41, P < 0.05; R = 0.59, P < 0.001, respectively). Ff and Fs correlated significantly with GS in PZ and TZ cancer (PZ: R = -0.44, P < 0.05; R = 0.37, P < 0.05, TZ: R = -0.59, P < 0.05; R = 0.57, P < 0.05, respectively). CONCLUSION: Triexponential analysis is a noninvasive approach that can provide more detailed information regarding diffusion and perfusion of PCa than biexponential analysis. PMID- 26119035 TI - The efficacy of a novel collagen-gelatin scaffold with basic fibroblast growth factor for the treatment of vocal fold scar. AB - Vocal fold scar remains a therapeutic challenge. Basic fibroblast growth factor (bFGF) was reported to have regenerative effects for vocal fold scar, although it has the disadvantage of rapid absorption in vivo. A collagen-gelatin sponge (CGS) can compensate for the disadvantage by providing a sustained release system. The current study evaluated the efficacy of CGS combined with bFGF on vocal fold scar, using rat fibroblasts for an in vitro model and a canine in vivo model. We prepared fibroblasts from scarred vocal folds (sVFs) in rats and showed that bFGF accelerated cell proliferation and suppressed expression levels of cleaved caspase 3 and alpha-smooth muscle actin. Has 1, Has 3, Fgf2, Hgf and Vegfa mRNA levels were significantly upregulated, while Col1a1 and Col3a1 were dose dependently downregulated, with a maximum effect at 100 ng/ml bFGF. In an in vivo assay, 6 weeks after lamina propria stripping, beagles were divided into three groups: CGS alone (CGS group); CGS with bFGF (7 ug/cm2 ; CGS + bFGF group); or a sham-treated group. Vibratory examination revealed that the glottal gap was significantly reduced in the bFGF group and the two implanted groups, whereas the CGS + bFGF group showed higher mucosal wave amplitude. Histological examination revealed significantly restored hyaluronic acid and elastin redistribution in the CGS + bFGF group and reductions in dense collagen deposition. These results provide evidence that CGS and bFGF combination therapy may have therapeutic potential and could be a promising tool for treating vocal fold scar. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26119034 TI - Astaxanthin prevents pulmonary fibrosis by promoting myofibroblast apoptosis dependent on Drp1-mediated mitochondrial fission. AB - Promotion of myofibroblast apoptosis is a potential therapeutic strategy for pulmonary fibrosis. This study investigated the antifibrotic effect of astaxanthin on the promotion of myofibroblast apoptosis based on dynamin-related protein-1 (Drp1)-mediated mitochondrial fission in vivo and in vitro. Results showed that astaxanthin can inhibit lung parenchymal distortion and collagen deposition, as well as promote myofibroblast apoptosis. Astaxanthin demonstrated pro-apoptotic function in myofibroblasts by contributing to mitochondrial fission, thereby leading to apoptosis by increasing the Drp1 expression and enhancing Drp1 translocation into the mitochondria. Two specific siRNAs were used to demonstrate that Drp1 is necessary to promote astaxanthin-induced mitochondrial fission and apoptosis in myofibroblasts. Drp1-associated genes, such as Bcl-2-associated X protein, cytochrome c, tumour suppressor gene p53 and p53-up-regulated modulator of apoptosis, were highly up-regulated in the astaxanthin group compared with those in the sham group. This study revealed that astaxanthin can prevent pulmonary fibrosis by promoting myofibroblast apoptosis through a Drp1-dependent molecular pathway. Furthermore, astaxanthin provides a potential therapeutic value in pulmonary fibrosis treatment. PMID- 26119036 TI - How to Make Weak Noncovalent Interactions Stronger. AB - By employing noncovalent interactions, chemists have constructed a variety of molecular aggregates with well-defined structures and fascinating properties. In fabricating stable and large molecular assemblies, noncovalent interactions with high binding strength are needed. This Concept summarizes some strategies to modify and optimize the structures of building blocks for making weak noncovalent interactions stronger. The strategies include: 1) Preorganization of binding sites; 2) spatial confinement effects; 3) multivalent enhancement; 4) synergistic binding with multiple forces. Examples of the fabrication of supramolecular architectures by utilizing these strategies are presented and discussed. Guidance is offered in the construction and fabrication of stable molecular assemblies and supramolecular materials. PMID- 26119038 TI - Naloxone--does over-antagonism matter? Evidence of iatrogenic harm after emergency treatment of heroin/opioid overdose. AB - AIM: To analyse drug users' views and experiences of naloxone during emergency resuscitation after illicit opiate overdose to identify (i) any evidence of harm caused by excessive naloxone dosing ('over-antagonism'); and (ii) implications for the medical administration of naloxone within contemporary emergency settings. DESIGN: Re-analysis of a large qualitative data set comprising 70 face to-face interviews conducted within a few hours of heroin/opioid overdose occurring, observations from hospital settings and a further 130 interviews with illicit opiate users. Data were generated between 1997 and 1999. SETTING: Emergency departments, drug services and pharmacies in two Scottish cities. PARTICIPANTS: Two hundred illicit opiate users: 131 males and 69 females. FINDINGS: Participants had limited knowledge of naloxone and its pharmacology, yet described it routinely in negative terms and were critical of its medical administration. In particular, they complained that naloxone induced acute withdrawal symptoms, causing patients to refuse treatment, become aggressive, discharge themselves from hospital and take additional street drugs to counter the naloxone effects. Participants believed that hospital staff should administer naloxone selectively and cautiously, and prescribe counter-naloxone medication if dosing precipitated withdrawals. In contrast, observational data indicated that participants did not always know that they had received naloxone and hospital doctors did not necessarily administer it incautiously. CONCLUSIONS: Opiate users in urban Scotland repeatedly report harm caused by naloxone over-antagonism, although this is not evident in observational data. The concept of contemporary legend (a form of folklore that can be based on fact and provides a means of communicating and negotiating anxiety) helps to explain why naloxone has such a feared reputation among opiate users. PMID- 26119037 TI - Placental development during early pregnancy in sheep: estrogen and progesterone receptor messenger RNA expression in pregnancies derived from in vivo-produced and in vitro-produced embryos. AB - Sex steroids are important regulators of angiogenesis and growth in reproductive tissues, including the placenta. In experiment (exp.) 1, to examine the expression of a suite of sex steroid receptors throughout early pregnancy, maternal (caruncular [CAR]) and fetal (fetal membranes [FM]) placental tissues were collected on days 14 to 30 after mating and on day 10 after estrus (nonpregnant controls). In exp. 2, to examine the hypothesis that assisted reproductive technology would affect the expression of the same suite of sex steroid receptors, pregnancies were achieved through natural mating (NAT) or transfer of embryos from natural mating (NAT-ET), in vitro fertilization (IVF), or in vitro activation (IVA), and CAR and FM were collected on day 22. In exp. 1, for CAR messenger RNA (mRNA) expression of estrogen receptors (ESR) 1 and 2, nuclear (n) progesterone receptors (PGR) and membrane (m) PGRalpha, beta, and gamma were affected (P < 0.02) by pregnancy stage, as were ESR1, nPGR, and mPGRalpha, beta, and gamma for FM (P < 0.03). In exp. 2, for CAR, mRNA expression of ESR1 and nPGR was decreased (P < 0.001) in NAT-ET, IVF, and IVA groups compared with NAT. For FM, mRNA expression of ESR1 tended to be greater (P = 0.10) in the IVA group compared with NAT and NAT-ET, and GPER1 was greater (P < 0.05) in NAT-ET and IVF compared with NAT. These data establish the normal pattern of sex steroid receptor mRNA expression in maternal and fetal placenta during early pregnancy in sheep, and in addition, suggest that altered expression of placental sex steroid receptors may be an early event leading to poor placental vascularization and growth after assisted reproductive technology. PMID- 26119039 TI - PCR-based retrospective evaluation of diagnostic samples for emergence of porcine deltacoronavirus in US swine. AB - Porcine deltacoronavirus (PDCoV) was first identified in Hong Kong in a regional surveillance study for Coronaviruses in 2012 and was detected for the first time in United States (US) swine in February 2014. However, it remains unknown if PDCoV had been introduced into the US prior to that time period. In the present study, 1734 clinical samples (903 cases) submitted to the Iowa State University Veterinary Diagnostic Laboratory (ISU VDL) for enteric disease diagnosis between October 2012 and December 2013 were tested retrospectively for PDCoV using a virus-specific real-time reverse transcription (RT) PCR targeting conserved region of the membrane gene. PDCoV genome was first detected in a fecal sample collected on August 19th 2013 from Minnesota. Subsequently, PDCoV was observed in samples collected on August 20th and August 27th from Iowa and on August 29th from Illinois. Therefore, with available samples submitted to the ISU VDL, it can be inferred that PDCoV has been present in US swine at least since August 2013. PMID- 26119040 TI - Predictors of Spinal Cord Stimulation Success. AB - INTRODUCTION: As many as 30% of spinal cord stimulation (SCS) patients fail to obtain long-term pain coverage, even with the strictest parameters of a successful trial, unremarkable psychological assessment, and ideal placement of the permanent device. Why these patients either never receive adequate benefit or lose benefit remains elusive. METHODS: We perform a retrospective review of our prospective database of SCS patients undergoing surgery for routine indications. Six-month postoperative follow-up data were available for 57 patients. Two providers who routinely saw the patients were asked to independently grade the patient's outcome in a blinded fashion on a Global Outcome Ratings scale of 1 to 10, with 5 being 50% improvement at 6 months postoperation. A score of less than 5 was deemed a failure. The impact of body mass index (BMI), random drug screen results, workers' compensation status, depression, and smoking were assessed. RESULTS: We report a phi correlation of 0.350 between smoking and failure (p = 0.017). Smoking status is correlated with both lead migration revisions (phi = 0.269) (p = 0.044) and with revision due to new pain symptoms (phi = 0.241) (p = 0.072). Further, there is a trend of correlation (phi = 0.289) between drug use and patients (N = 3) who underwent device removal (p = 0.045). In this cohort, worker's compensation status, BMI, and depression did not impact outcome. CONCLUSIONS: Tobacco use correlates with less success with SCS at 6-month follow up. Whether that is because of issues with healing and our transmission of signals to the periphery warrants further exploration. These data provide further evidence that tobacco cessation is important to surgical results. PMID- 26119041 TI - Faithful expression of imprinted genes in donor cells of SCNT cloned pigs. AB - To understand if the genomic imprinting status of the donor cells is altered during the process of SCNT (somatic cell nuclear transfer), cloned pigs were produced by SCNT using PEF (porcine embryonic fibroblast) and P-PEF (parthenogenetic-PEF) cells as donors. Then, the gene expression and methylation patterns of H19, IGF2, NNAT and MEST were compared between PEF vs. C-PEF (cloned PEF), P-PEF vs. CP-PEF (cloned-P-PEF), respectively. Taken together, the results revealed that there was no significant difference in the expression of imprinted genes and conserved genomic imprints between the donor and cloned cells. PMID- 26119042 TI - Formulation of attractive toxic sugar bait (ATSB) with safe EPA-exempt substance significantly diminishes the Anopheles sergentii population in a desert oasis. AB - Attractive toxic sugar bait (ATSB) is a highly effective method which targets mosquitoes based on their sugar foraging behavior, by presenting baits of attractive compounds in combination with sugar and oral toxin to local mosquito populations. Environmental concerns and insecticide selection-pressure have prompted investigations of novel, ecologically-harmless substances which can be used as insecticides. This study examined the efficacy of microencapsulated garlic-oil as the oral toxin component of ATSB for controlling Anopheles sergentii populations inhabiting desert-surrounded wetlands in Israel. ATSB solution containing 0.4% encapsulated garlic oil was applied to local vegetation around a streamlet located in the lower Jordan Valley. To determine the propensity of bait ingestion, and assess the potential ecological impact of the method, mosquito and non-target specimens were collected and tested for the presence of natural plant- or attractive sugar bait (ASB)-derived sugars. Over the experimental period, biting-pressure values in the ATSB treatment site decreased by 97.5%, while at the control site, treated with non-toxic ASB, no significant changes were observed. Approximately 70% of the mosquitoes collected before both treatments, as well as those captured following the application of ASB at the control site, were found to have ingested sugar prior to capture. Non target insects were minimally affected by the treatment when ATSB was applied to foliage of non-flowering plants. Of the non-Diptera species, only 0.7% of the sampled non-target insects were found to have ingested ASB-solution which was applied to green vegetation, compared with 8.5% which have foraged on ASB-derived sugars applied to flowering plants. Conversely, a high proportion of the non target species belonging to the order Diptera, especially non-biting midges, were found to have ingested foliage-applied ASB, with more than 36% of the specimens collected determined to have foraged on bait-derived sugars. These results prove that food-grade, EPA-exempt microencapsulated garlic oil is a highly effective insecticide which can be utilized for mosquito population control. The relatively short half-life of this active ingredient makes it a suitable for use in areas where repeated application is possible, limiting the accumulation of deleterious compounds and ensuring minimal environmental impact when applied in accordance with label recommendations. PMID- 26119043 TI - Leptin augments protective immune responses in murine macrophages and enhances potential of miltefosine against experimental visceral leishmaniasis. AB - Adverse side effects and drug resistance issues are the two most important drawbacks which influence the widespread use of existing antileishmanial drugs. Use of immune stimulating agent with standard antileishmanial might be helpful to minimize the toxic effect of drug, shorten the dose regimen and delay the emergence of resistance. In the present study, we explored the in vitro immunomodulatory potential of an immunomodulator, leptin with lower concentration of standard drug, miltefosine. The level of Th1/Th2 cytokines, production of nitric oxide and reactive oxygen species and phagocytic activity was assessed by ELISA, Griess reaction and flow cytometric analysis, respectively. Leptin at a concentration of 15MUg/mL showed heightened level of Th1 cytokines and nitric oxide generation from murine macrophages (J-774A.1 cells). Leptin (15MUg/mL) also reduces the effective concentration of miltefosine by 2-folds from 7.5MUM to 3.7MUM. When given in conjunction with lower concentration of miltefosine (4MUM), leptin (15MUg/mL) significantly (***p<0.001) elevated the level of IL-12 (7.7 fold), TNF-alpha (8.1 fold) and nitric oxide (6.6 fold) along with markedly (***p<0.001) suppressed level of IL-10 and TGF-beta when compared with untreated infected macrophages. Leptin plus miltefosine also induces the phagocytic ability (**p<0.01) of macrophages in comparison to leptin alone and miltefosine alone treated groups. These finding illustrate that leptin activates host macrophages to generate protective immune response for the successful elimination of Leishmania parasite at lower concentration of miltefosine and has potential for further exploration in experimental animal model of visceral leishmaniasis (VL). PMID- 26119045 TI - A radiomics model from joint FDG-PET and MRI texture features for the prediction of lung metastases in soft-tissue sarcomas of the extremities. AB - This study aims at developing a joint FDG-PET and MRI texture-based model for the early evaluation of lung metastasis risk in soft-tissue sarcomas (STSs). We investigate if the creation of new composite textures from the combination of FDG PET and MR imaging information could better identify aggressive tumours. Towards this goal, a cohort of 51 patients with histologically proven STSs of the extremities was retrospectively evaluated. All patients had pre-treatment FDG-PET and MRI scans comprised of T1-weighted and T2-weighted fat-suppression sequences (T2FS). Nine non-texture features (SUV metrics and shape features) and forty-one texture features were extracted from the tumour region of separate (FDG-PET, T1 and T2FS) and fused (FDG-PET/T1 and FDG-PET/T2FS) scans. Volume fusion of the FDG PET and MRI scans was implemented using the wavelet transform. The influence of six different extraction parameters on the predictive value of textures was investigated. The incorporation of features into multivariable models was performed using logistic regression. The multivariable modeling strategy involved imbalance-adjusted bootstrap resampling in the following four steps leading to final prediction model construction: (1) feature set reduction; (2) feature selection; (3) prediction performance estimation; and (4) computation of model coefficients. Univariate analysis showed that the isotropic voxel size at which texture features were extracted had the most impact on predictive value. In multivariable analysis, texture features extracted from fused scans significantly outperformed those from separate scans in terms of lung metastases prediction estimates. The best performance was obtained using a combination of four texture features extracted from FDG-PET/T1 and FDG-PET/T2FS scans. This model reached an area under the receiver-operating characteristic curve of 0.984 +/- 0.002, a sensitivity of 0.955 +/- 0.006, and a specificity of 0.926 +/- 0.004 in bootstrapping evaluations. Ultimately, lung metastasis risk assessment at diagnosis of STSs could improve patient outcomes by allowing better treatment adaptation. PMID- 26119044 TI - Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis. AB - Plasmodium falciparum-infected erythrocytes (IRBC) expressing the domain cassettes (DC) 8 and 13 of the cytoadherent ligand P. falciparum erythrocyte membrane protein 1 adhere to the endothelial protein C receptor (EPCR). By interfering with EPCR anti-coagulant and pro-endothelial barrier functions, IRBC adhesion could promote coagulation and vascular permeability that contribute to the pathogenesis of cerebral malaria. In this study, we examined the adhesion of DC8- and DC13-expressing parasite lines to endothelial cells from different microvasculature, and the consequences of EPCR engagement on endothelial cell function. We found that IRBC from IT4var19 (DC8) and IT4var07 (DC13) parasite lines adhered to human brain, lung and dermal endothelial cells under shear stress. However, the relative contribution of EPCR to parasite cytoadherence on different types of endothelial cell varied. We also observed divergent functional outcomes for DC8 cysteine-rich interdomain region (CIDR)alpha1.1 and DC13 CIDRalpha1.4 domains. IT4var07 CIDRalpha1.4 inhibited generation of activated protein C (APC) on lung and dermal endothelial cells and blocked the APC-EPCR binding interaction on brain endothelial cells. IT4var19 CIDRalpha1.1 inhibited thrombin-induced endothelial barrier dysfunction in lung endothelial cells, whereas IT4var07 CIDRalpha1.4 inhibited the protective effect of APC on thrombin induced permeability. Overall, these findings reveal a much greater complexity of how CIDRalpha1-expressing parasites may modulate malaria pathogenesis through EPCR adhesion. PMID- 26119046 TI - New Insights and Biomarkers for Type 1 Diabetes: Review for Scandinavian Journal of Immunology. AB - The increasing incidence of type 1 diabetes observed in the past 60 years has spawned massive efforts in multiple research fields to elucidate the aetiology of this disease. While GWAS studies provide a good genetic basis for the current knowledge, it is clear that environmental triggers and their influence in disease prevalence and origin are highly important. The realization of disease heterogeneity has created a requirement for better biomarkers to complement the known autoantibody markers and to more successfully predict the severity and onset time of the disease. Such biomarkers would be needed both for prevention as well as for monitoring disease activity and response to preventive and therapeutic measures. Systematic holistic approaches concentrating on the triggering molecular mechanisms, pancreatic beta cells, immune response, as well as the influence of diet and environment, are necessary to understand the disease pathogenesis and find a cure. The current genomic knowledge is being broadened with accompanying studies in epigenetics and transcriptomic regulation, metabolomics, proteomics and lipidomics, covering the whole system from beta cells, the profile and cellular balance of the infiltrating lymphocytes, to gut microbiota and viral infections. Here we highlight interesting recent findings in type 1 diabetes research. PMID- 26119047 TI - Nitrogen-containing bisphosphonate therapy: assessment of the alveolar bone structure in rats - a blind randomized controlled trial. AB - This study aimed to assess the effect of zoledronic acid exposure on structures of the alveolar bone of rats. The sample was composed of 42 male Wistar rats. Animals in the T1 and T2 groups received weekly doses of 0.2 mg/kg intraperitoneal zoledronic acid for 3 weeks, while animals in the T3 group received the same treatment for 8 weeks. The control groups C1, C2 and C3 received equivalent doses of saline. The first upper molars of Wistar rats in the C2, T2, C3 and T3 groups were extracted. Cone-beam computerized tomography scans were performed, and the image density was analysed by grey levels. The presence and type of inflammatory infiltrate, vascularization and bone necrosis were assigned by histological qualitative scores. Histomorphometric analysis of bone density was performed in the groups without extraction. No significant differences were found in the bone grey density estimated by grey-level value and histomorphometric analysis between the C1 and T1 groups (P > 0.05). The grey levels in the T3 group were lower (P < 0.05) than in the C3 group, corresponding to the bone defect. Histological assessments showed the presence of bone necrosis in the T3 group and lower levels of bone remodelling in the test groups (T2 and T3) compared to the control groups (C2 and C3). The results of qualitative analyses did not differ significantly between the groups (P > 0.05). Zoledronic acid-exposed animals showed maxillary changes including reduced grey levels, the presence of bone necrosis and a higher prevalence of inflammatory signs. PMID- 26119048 TI - Barriers and Facilitators for Sustainability of Tele-Homecare Programs: A Systematic Review. AB - OBJECTIVE: To identify the barriers and facilitators for sustainability of tele homecare programs implemented by home health nursing agencies for chronic disease management. DATA SOURCES: English-language articles on home telehealth in the CINAHL, PubMed/MEDLINE, PsychInfo, Web of Science, and Cochrane Reviews databases published from January 1996 to December 2013. STUDY DESIGN: We performed a systematic literature review. Data extraction using PRISMA guidelines and quality appraisal using the Mixed Methods Appraisal Tool (MMAT) were conducted on relevant empirical studies. Thematic analysis across the studies and narrative summaries were used to synthesize the findings from the included studies. PRINCIPAL FINDINGS: Of the initial 3,920 citations, we identified 16 articles of moderate quality meeting our inclusion criteria. Perceptions on effectiveness of tele-homecare programs for achieving intended outcomes; tailoring of tele homecare programs to patient characteristics and needs; relationship and communication between patient, nurse, and other health care professional users of tele-homecare; home health organizational process and culture; and technology quality, capability, and usability impacted the sustainability of tele-homecare programs. CONCLUSIONS: The findings of this systematic review provide implications for sustained usage of tele-homecare programs by home health nursing agencies and can help such programs realize their potential for chronic disease management. PMID- 26119049 TI - [Global risk management]. AB - Risk management is a fundamental component of any successful company, whether it is in economic, societal or environmental aspect. Risk management is an especially important activity for companies that optimal security challenge of products and services is great. This is the case especially for the health sector institutions. Risk management is therefore a decision support tool and a means to ensure the sustainability of an organization. In this context, what methods and approaches implemented to manage the risks? Through this state of the art, we are interested in the concept of risk and risk management processes. Then we focus on the different methods of risk management and the criteria for choosing among these methods. Finally we highlight the need to supplement these methods by a systemic and global approach including through risk assessment by the audits. PMID- 26119050 TI - High-alkali low-temperature polysulfide pulping (HALT) of Scots pine. AB - High-alkali low-temperature polysulfide pulping (HALT) was effectively utilised to prevent major polysaccharide losses while maintaining the delignification rate. A yield increase of 6.7 wt% on wood was observed for a HALT pulp compared to a conventionally produced kappa number 60 pulp with comparable viscosity. Approximately 70% of the yield increase was attributed to improved galactoglucomannan preservation and 30% to cellulose. A two-stage oxygen delignification sequence with inter-stage peroxymonosulphuric acid treatment was used to ensure delignification to a bleachable grade. In a comparison to conventional pulp, HALT pulp effectively maintained its yield advantage. Diafiltration trials indicate that purified black liquor can be directly recycled, as large lignin fractions and basically all dissolved polysaccharides were separated from the alkali-rich BL. PMID- 26119051 TI - Bioethanol production from sodium hydroxide/hydrogen peroxide-pretreated water hyacinth via simultaneous saccharification and fermentation with a newly isolated thermotolerant Kluyveromyces marxianu strain. AB - In this study, bioethanol production from NaOH/H2O2-pretreated water hyacinth was investigated. Pretreatment of water hyacinth with 1.5% (v/v) H2O2 and 3% (w/v) NaOH at 25 degrees C increased the production of reducing sugars (223.53 mg/g dry) and decreased the cellulose crystallinity (12.18%), compared with 48.67 mg/g dry and 22.80% in the untreated sample, respectively. The newly isolated Kluyveromyces marxianu K213 showed greater ethanol production from glucose (0.43 g/g glucose) at 45 degrees C than did the control Saccharomyces cerevisiae angel yeast. The maximum ethanol concentration (7.34 g/L) achieved with K. marxianu K213 by simultaneous saccharification and fermentation (SSF) from pretreated water hyacinth at 42 degrees C was 1.78-fold greater than that produced by angel yeast S. cerevisiae at 30 degrees C. The present work demonstrates that bioethanol production achieved via SSF of NaOH/H2O2-pretreated water hyacinth with K. marxianu K213 is a promising strategy to utilize water hyacinth biomass. PMID- 26119052 TI - Evaluation of functional microbial community's difference in full-scale and lab scale anaerobic digesters feeding with different organic solid waste: Effects of substrate and operation factors. AB - Samples taken from the full-scale and lab-scale anaerobic digesters feeding with different organic solid waste were investigated with assessment of the substrate effects. To understand the substrate effects on the microbial community diversity, heterogeneity, and functional structure, twelve samples were analyzed by constructing 16S rRNA gene clone libraries and statistical analysis. Microbial diversity varied according to substrate types and operating parameters. With acetoclastic methanogen of genus Methanosaeta predominated in full scale and Methanosarcina predominated in the lab-scale digesters, a significant difference archaeal communities were found. Principal component analysis clearly indicates that both bacterial and archaeal communities create independent clusters according to substrate types. However, the relationship between acetogenic bacteria and the acetoclastic methanogens had a similar variation tends in most of full-scale and lab-scale reactors. Canonical correlation analysis and variance partitioning analysis implied that bacterial and archaeal community variations were significantly affected by substrate and the operation conditions. PMID- 26119053 TI - Hydrothermal microwave valorization of eucalyptus using acidic ionic liquid as catalyst toward a green biorefinery scenario. AB - The application of the acidic ionic liquid (IL), 1-butyl-3-methylimidazolium hydrogensulfate ([bmim]HSO4), as a catalyst in the hydrothermal microwave treatment (HMT) and green upgradation of eucalyptus biomass has been investigated. The process was carried out in a microwave reactor system at different temperatures (140-200 degrees C) and evaluated for severities. The xylooligosaccharides (XOS, refers to a DP of 2-6) yield up to 5.04% (w/w) of the initial biomass and 26.72% (w/w) of xylan were achieved. Higher temperature resulted in lower molecular weight product, and enhanced the concentration of monosaccharides and byproducts. The morphology and structure of the solid residues were performed using an array of techniques, such as SEM, XRD, FTIR, BET surface area, and CP/MAS (13)C NMR, by which the increase of crystallinity, the destruction of surface structure, and the changes in functional groups and compositions were studied after the pretreatment, thus significantly enhancing the enzymatic hydrolysis. PMID- 26119054 TI - The first known case of alanine aminotransferase deficiency diagnosed during pregnancy. PMID- 26119055 TI - A concise guide to sustainable PEMFCs: recent advances in improving both oxygen reduction catalysts and proton exchange membranes. AB - The rising interest in fuel cell vehicle technology (FCV) has engendered a growing need and realization to develop rational chemical strategies to create highly efficient, durable, and cost-effective fuel cells. Specifically, technical limitations associated with the major constituent components of the basic proton exchange membrane fuel cell (PEMFC), namely the cathode catalyst and the proton exchange membrane (PEM), have proven to be particularly demanding to overcome. Therefore, research trends within the community in recent years have focused on (i) accelerating the sluggish kinetics of the catalyst at the cathode and (ii) minimizing overall Pt content, while simultaneously (a) maximizing activity and durability as well as (b) increasing membrane proton conductivity without causing any concomitant loss in either stability or as a result of damage due to flooding. In this light, as an example, high temperature PEMFCs offer a promising avenue to improve the overall efficiency and marketability of fuel cell technology. In this Critical Review, recent advances in optimizing both cathode materials and PEMs as well as the future and peculiar challenges associated with each of these systems will be discussed. PMID- 26119056 TI - Diagnostic use of recombinant Tha p 2 in the allergy to Thaumetopoea pityocampa. AB - Thaumetopoea pityocampa causes allergies and skin and ocular lesions. No commercial tools are currently available for the clinical diagnosis of this allergy. We aimed to develop an in vitro method for the diagnosis of this allergy to avoid patients undergoing in vivo tests with insect extracts. Recombinant Tha p 2 was produced and used in an ELISA validated with 15 allergic patients. Subsequently, 42 subjects recruited from a random sampling cross-sectional study were analysed. The ELISA sensitivity and specificity were 93.3% and 100%, respectively, for the allergic patients and 71.4% and 95.3%, respectively, for the epidemiological study. The positive ELISA results correlated with the skin prick test areas with the whole body and the setae extracts. Professional exposure and short latency of symptoms onset were risk factors for a positive result in the ELISA. In conclusion, our ELISA is very useful for T. pityocampa allergy diagnosis and for epidemiologic testing. PMID- 26119057 TI - To Twitter to Woo: Harnessing the power of social media (SoMe) in nurse education to enhance the student's experience. AB - This paper explores some of the difficulties, challenges and rewards for student nurses and nurse academics when harnessing social media (SoMe) as part of the overall learning experience. The paper draws upon data in the form of student voices, captured through an online planned Twitter chat. This data analysis provides the basis of a case study on the student experience in practice placements. A planned 1 h Twitter chat took place in June 2013, specifically aimed at student nurses. What transpired was an illuminating debate, eliciting responses from around the globe about learning in practice, mentors, and student support that lasted over 3 h. More importantly, the Twitter chat also included qualified nurses and mentors, listening and responding in real time, offering thoughts and solutions to how support and mentoring could be improved. This was in contrast to how students, locally, currently use a paper based questionnaire to give feedback in isolation. The authenticity of this feedback is often compromised by university link lecturers' who often provide a more sanitised version of this feedback to clinical placement. This paper explores whether it is possible to facilitate a realignment and capture the zeitgeist in order to provide the opportunity for enhancing learning in practice. PMID- 26119058 TI - Towards antivirals against chikungunya virus. AB - Chikungunya virus (CHIKV) has re-emerged in recent decades, causing major outbreaks of chikungunya fever in many parts of Africa and Asia, and since the end of 2013 also in Central and South America. Infections are usually associated with a low mortality rate, but can proceed into a painful chronic stage, during which patients may suffer from polyarthralgia and joint stiffness for weeks and even several years. There are no vaccines or antiviral drugs available for the prevention or treatment of CHIKV infections. Current therapy therefore consists solely of the administration of analgesics, antipyretics and anti-inflammatory agents to relieve symptoms. We here review molecules that have been reported to inhibit CHIKV replication, either as direct-acting antivirals, host-targeting drugs or those that act via a yet unknown mechanism. This article forms part of a symposium in Antiviral Research on "Chikungunya discovers the New World." PMID- 26119059 TI - Effects of sub-acute methanol extract treatment of Calliandra portoricensis root bark on antioxidant defence capacity in an experimental rat model. AB - BACKGROUND: The attendant side effects associated with some synthetic drugs used in the management of diseases have led to the search for safer alternative therapies that are relatively cheaper with minimal side effects. METHODS: The methanol extract of Calliandra portoricensis root bark (CPRB) was orally administered at the doses of 5, 10, 20, and 25 mg/kg body weight for 14 consecutive days of 5 rats in each group. The control rats were given distilled water. RESULTS: The 95% methanol extract of CPRB significantly (p<0.05) scavenged NO* and OH* radicals compared to vitamin C. The level of lipid peroxidative products (malondialdehyde, MDA) was significantly (p<0.05) attenuated in a dose dependent manner. Antioxidant enzymes including superoxide dismutase and catalase were significantly (p<0.05) exercabated in both liver and kidney in a dose dependent manner. Furthermore, serum AST, alanine aminotransaminase and gamma glutamyltransferase (GGT) activity depicted non-significant (p>0.05) increase in the treated animals. The histological examination showed mild vacuolar, portal congestion and cell infiltration by mononuclear of the hepatic tissues. CONCLUSIONS: The study then concluded that a therapeutic dose of the methanol extract of CPRB triggered the antioxidant defence systems in male rats. It is, therefore, recommended that the doses should be carefully and clinically chosen because higher doses may cause some health risks. PMID- 26119061 TI - Probing heterobivalent binding to the endocytic AP-2 adaptor complex by DNA-based spatial screening. AB - The double helical DNA scaffold offers a unique set of properties, which are particularly useful for studies of multivalency in biomolecular interactions: (i) multivalent ligand displays can be formed upon nucleic acid hybridization in a self-assembly process, which facilitates spatial screening (ii) valency and spatial arrangement of the ligand display can be precisely controlled and (iii) the flexibility of the ligand display can be adjusted by integrating nick sites and unpaired template regions. Herein we describe the use of DNA-based spatial screening for the characterization of the adaptor complex 2 (AP-2), a central interaction hub within the endocytic protein network in clathrin-mediated endocytosis. AP-2 is comprised of a core domain and two, so-called appendage domains, the alpha- and the beta2-ear, which associate with cytoplasmatic proteins required for the formation or maturation of clathrin/AP-2 coated pits. Each appendage domain has two binding grooves which recognize distinct peptide motives with micromolar affinity. This provides opportunities for enhanced interactions with protein molecules that contain two (or more) different peptide motives. To determine whether a particular, spatial arrangement of binding motifs is required for high affinity binding we probed the distance-affinity relationships by means of DNA-programmed spatial screening with self-assembled peptide-DNA complexes. By using trimolecular and tetramolecular assemblies two different peptides were positioned in 2-22 nucleotide distance. The binding data obtained with both recombinant protein in well-defined buffer systems and native AP-2 in brain extract suggests that the two binding sites of the AP-2 alpha appendage can cooperate to provide up to 40-fold enhancement of affinity compared to the monovalent interaction. The distance between the two recognized peptide motives was less important provided that the DNA duplex segments were connected by flexible, single strand segments. By contrast, the experiments with a more rigid, duplex-spaced assembly revealed marked distance dependencies. Consequences for the function of adaptor proteins are discussed. PMID- 26119060 TI - Formation of chloroform and tetrachloroethene by Sinorhizobium meliloti strain 1021. AB - The mechanisms and organisms involved in the natural formation of volatile organohalogen compounds (VOX) are largely unknown. We provide evidence that the common and widespread soil bacterium Sinorhizobium meliloti strain 1021 is capable of producing up to 3338.6 +/- 327.8 ng l(-1) headspace volume of chloroform (CHCl3 ) and 807.8 +/- 13.5 ng l(-1) headspace volume of tetrachloroethene (C2 Cl4 ) within 1 h when grown in soil extract medium. Biotic VOX formation has been suggested to be linked to the activity of halogenating enzymes such as haloperoxidases. We tested if the observed VOX formation by S. meliloti can be attributed to one of its chloroperoxidases (Smc01944) that is highly expressed in the presence of H2 O2. However, addition of 10 mmol l(-1) H2 O2 to the S. meliloti cultures decreased VOX formation by 52% for chloroform and 25% for tetrachloroethene, while viable cell numbers decreased by 23%. Interestingly, smc01944 gene expression increased 450-fold. The quantification of extracellular chlorination activity in cell suspension experiments did not provide evidence for a role of S. meliloti chloroperoxidases in the observed VOX formation. This suggests that a momentarily unknown mechanism which requires no H2 O2 might be responsible for the VOX formation by S. meliloti. Regardless of the underlying mechanism our results suggest that the soil bacterium S. meliloti might be an important source of VOX in soils. SIGNIFICANCE AND IMPACT OF THE STUDY: Volatile organohalogen compounds (VOX) strongly influence atmospheric chemistry and Earth's climate. Besides anthropogenic emissions they are naturally produced by either abiotic or biotic pathways in various environments. Particularly in soils, microbial processes drive the natural halogen cycle but the direct link to microbial VOX formation has not been studied in detail yet. In this study we provide evidence that the common and widespread soil bacterium Sinorhizobium meliloti strain 1021 forms chloroform and tetrachloroethene. The potential contribution of S. meliloti to soil VOX release could significantly influence soil and atmospheric chemistry. PMID- 26119062 TI - Process of formulating USDA's Expanded Flavonoid Database for the Assessment of Dietary intakes: a new tool for epidemiological research. AB - The scientific community continues to be interested in potential links between flavonoid intakes and beneficial health effects associated with certain chronic diseases such as CVD, some cancers and type 2 diabetes. Three separate flavonoid databases (Flavonoids, Isoflavones and Proanthocyanidins) developed by the USDA Agricultural Research Service since 1999 with frequent updates have been used to estimate dietary flavonoid intakes, and investigate their health effects. However, each of these databases contains only a limited number of foods. The USDA has constructed a new Expanded Flavonoids Database for approximately 2900 commonly consumed foods, using analytical values from their existing flavonoid databases (Flavonoid Release 3.1 and Isoflavone Release 2.0) as the foundation to calculate values for all the twenty-nine flavonoid compounds included in these two databases. Thus, the new database provides full flavonoid profiles for twenty nine predominant dietary flavonoid compounds for every food in the database. Original analytical values in Flavonoid Release 3.1 and Isoflavone Release 2.0 for corresponding foods were retained in the newly constructed database. Proanthocyanidins are not included in the expanded database. The process of formulating the new database includes various calculation techniques. This article describes the process of populating values for the twenty-nine flavonoid compounds for every food in the dataset, along with challenges encountered and resolutions suggested. The new expanded flavonoid database released on the Nutrient Data Laboratory's website would provide uniformity in estimations of flavonoid content in foods and will be a valuable tool for epidemiological studies to assess dietary intakes. PMID- 26119063 TI - A model of caregiver paediatric HIV disclosure decision-making. AB - Many of the over 3 million HIV-positive children will only be told of their status as adolescents. Knowing one's status may increase treatment adherence, reduce onward HIV transmission, increase trust in caregivers and maximise available support. Yet deciding whether, what, how and when to tell HIV-positive children about their condition is challenging for caregivers. We systematically review HIV disclosure theories before presenting a process model of caregiver paediatric HIV disclosure decision-making. The model, consisting of both a pre intention and a post-intention stage, integrates individual and contextual determinants. It aims to be situationally specific, broadly applicable and consistent with the empirical literature. Research and practice implications are discussed. PMID- 26119064 TI - Prediction of development and maintenance of high albuminuria during chronic renin-angiotensin suppression by plasma proteomics. AB - BACKGROUND: High albuminuria is a strong predictor of development of cardiovascular events in hypertensive patients. The search for predictors identifying patients at risk of developing high albuminuria or presenting a more rapid progression in this parameter may represent an effective strategy for adequate intervention and better outcome. METHODS AND RESULTS: Initially we investigated 24 patients presenting with normoalbuminuria, de novo albuminuria and sustained albuminuria. Plasma proteomics disclosed an upregulation of ceruloplasmin (CP), haptoglobin (HP) and alpha 1-acid glycoprotein (ORM1) that in a second step were selected for validation using turbidimetry assay in a cohort of 105 subjects. The validation showed that HP and ORM1 proteins were increased in patients presenting with very high albuminuria and potential irreversible kidney damage. CP and HP correlated positively with albuminuria values in normoalbuminuric patients. Finally, the levels of ORM1 and CP were increased in patients who progressed in their levels of albuminuria. CONCLUSIONS: Our findings show that these proteins may potentially be useful for predicting the development of high albuminuria and to monitor renal damage. PMID- 26119065 TI - Evolutionary rescue can be impeded by temporary environmental amelioration. AB - Rapid evolutionary adaptation has the potential to rescue from extinction populations experiencing environmental changes. Little is known, however, about the impact of short-term environmental fluctuations during long-term environmental deterioration, an intrinsic property of realistic environmental changes. Temporary environmental amelioration arising from such fluctuations could either facilitate evolutionary rescue by allowing population recovery (a positive demographic effect) or impede it by relaxing selection for beneficial mutations required for future survival (a negative population genetic effect). We address this uncertainty in an experiment with populations of a bacteriophage virus that evolved under deteriorating conditions (gradually increasing temperature). Periodic environmental amelioration (short periods of reduced temperature) caused demographic recovery during the early phase of the experiment, but ultimately reduced the frequency of evolutionary rescue. These experimental results suggest that environmental fluctuations could reduce the potential of evolutionary rescue. PMID- 26119066 TI - Catalytic Stereoinversion of L-Alanine to Deuterated D-Alanine. AB - A combination of an achiral pyridoxal analogue and a chiral base has been developed for catalytic deuteration of L-alanine with inversion of stereochemistry to give deuterated D-alanine under mild conditions (neutral pD and 25 degrees C) without the use of any protecting groups. This system can also be used for catalytic deuteration of D-alanine with retention of stereochemistry to give deuterated D-alanine. Thus a racemic mixture of alanine can be catalytically deuterated to give an enantiomeric excess of deuterated D-alanine. While catalytic deracemization of alanine is forbidden by the second law of thermodynamics, this system can be used for catalytic deracemization of alanine with deuteration. Such green and biomimetic approach to catalytic stereocontrol provides insights into efficient amino acid transformations. PMID- 26119068 TI - Potential Paths for the Hydrogen-Bond Relaxing With (H2O)N Cluster Size. AB - Relaxation of the inter- and intra-molecular interactions for the hydrogen bond (O:H-O) between undercoordinated molecules determines the unusual behavior of water nanodroplets and nanobubbles. However, probing such potentials remains unreality. Here we show that the Lagrangian solution [Huang et al., J. Phys. Chem. B, 2013. 117: 13639] transforms the observed H-O bond (x = H) and O:H nonbond (x = L) lengths and phonon frequencies (dx, ?x) [Sun et al., J. Phys. Chem. Lett., 2013. 4: 2565] into the respective force constants and bond energies (kx, Ex) and hence enables the mapping of the potential paths for the O:H-O bond relaxing with water cluster size. Results show that molecular undercoordination not only reduces the molecular size (dH) with enhanced H-O energy from the bulk value of 3.97 to 5.10 eV for a H2O monomer, but also enlarges the molecular separation (dL) with reduced O:H energy from 95 to 35 meV for a dimer. The H-O energy gain raises the melting point from bulk value 273 to 310 K for the skin and the O:H energy loss lowers the freezing temperature from bulk value 258 to 202 K for 1.4 nm sized droplet, by dispersing the quasisolid phase boundaries. PMID- 26119067 TI - Singapore's regional health systems-a data-driven perspective on frequent admitters and cross utilization of healthcare services in three systems. AB - INTRODUCTION: With population health management being a priority in the Singapore, this paper aims to provide a data-driven perspective of the population health management initiatives to aid program planning and serves as a baseline for evaluation of future implemented programs. METHODS: A database with information on patient demographics, health services utilization, cost, diagnoses and chronic disease information from 2008 to 2013 for three regional health systems in Singapore was used for analysis. Patients with three or more inpatient admissions were considered as "Frequent Admitters." Health service utilization was quantified, and cross utilization of services was studied. One-year readmission rate for inpatients was studied, and a predictive model for readmission or death was developed. RESULTS: There were a total of 2.8 M patients in the database. Frequent admitters accounted for 0.9% of all patients with an average cost per patient of S$29 547. Of these, 89% had chronic diseases. Cross utilization of health services showed that 8.2% of the patients utilized services from more than one hospital with 19.6% utilizing hospital and polyclinic services in 2013. The highest risk of readmission or death was for those patients who had five or more inpatient episodes in each of the preceding 2 years. CONCLUSION: By understanding the profile of the patients and their utilization patterns in the three regional health systems, our study will help clinicians and decision makers design appropriate integrated care programs for patients with the aim of covering the healthcare needs for the enitre population across the healthcare spectrum in Singapore. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26119069 TI - Tea consumption is not associated with reduced plasma folate concentration among Chinese pregnant women. AB - BACKGROUND: The aim of this study was to evaluate the relationship between tea consumption and plasma folate concentration in populations with high and low prevalence of neural tube defects (NTDs) in China. METHODS: Cross-sectional survey was conducted in three cities/counties in China, in which 1724 pregnant women during early second trimester were recruited and interviewed about tea consumption and folic acid use in 2011 to 2012. A total of 5-ml nonfasting blood sample was collected and plasma folate concentration was determined by microbiological assay. RESULTS: Approximately 16.2% of the women reported that they had ever drank tea during and before the current pregnancy, women with higher educational level, and those who resided in urban were more likely to drink tea. Most of them prefer green tea (55.2%); 13.6% of women drank tea ">6 times/week," and 29.0% of them drank "less than once a week." The median of plasma folate concentration was 48.7 nmol/L in women who drank tea while it is 45.2 nmol/L in women who did not drink tea, with no statistical difference. The results showed there was no association between tea drinking and plasma folate concentration in Chinese pregnant women stratified by folic acid supplementation and other selected characteristics. CONCLUSION: Low level of tea drinking is not associated with decreased plasma folate concentration in the Chinese populations with high and low prevalence of NTDs. PMID- 26119071 TI - Mineral Composition of Phosphate-Induced Calcification in a Rat Aortic Tissue Culture Model. AB - AIM: High phosphorus conditions promote vascular calcification (VC) in both chronic kidney disease (CKD) patients and experimental models. However, the composition of medial calcification has not been accurately determined, so the objective of this study was to evaluate the mineral composition of calcification in a tissue culture model, not a cell culture system. METHODS: Aortic rings obtained from male Sprague-Dawley rats were incubated in serum-supplemented medium for 10 days. The inorganic phosphate (Pi) concentration of the medium was increased to induce VC, which was assessed by histology, imaging, and spectroscopy. The mineral composition of the calcification was analyzed using Fourier transform infrared (FTIR) spectroscopic imaging, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX) mapping. RESULTS: The calcium content significantly increased only in aortic rings cultured for 10 days in the high-Pi medium (HiP: 3.8 mmol/L). The concentration of the phosphate transporter Pit-1 in the aortic tissue exposed to HiP was higher than that in the control incubated sections. The FTIR images and spectra indicated that PO4(3-) was mostly distributed as hydroxyapatite in the medial calcification of aortic rings cultured in HiP. A small quantity of carbonate was identified. The SEM-EDX overlay map demonstrated that phosphorus and calcium simultaneously accumulated and localized in the area of medial calcification induced by exposure to HiP. CONCLUSION: This is the first report of accurate determination of the chemical composition of aortic medial calcification. Exposure to high Pi concentration augments aortic calcification via an increase in Pit-1, which mainly contains calcium phosphate. PMID- 26119070 TI - Identification of BST-2/tetherin-induced hepatitis B virus restriction and hepatocyte-specific BST-2 inactivation. AB - BST-2/tetherin is an interferon-inducible antiviral protein that blocks the release of various enveloped viruses, including HIV-1. Hepatitis B virus (HBV), a major cause of liver disease, belongs to the Hepadnaviridae family of enveloped DNA viruses. Whether BST-2 regulates HBV production is largely unknown. In this report, we have demonstrated that HBV particle release is modulated by BST-2 in a cell type-dependent fashion. In HEK293T cells, ectopically expressed or interferon-induced BST-2 strongly inhibited HBV release. BST-2 co-localized with HBV surface protein at multivesicular bodies (MVBs) and physically interacted with HBV particles. However, exogenous BST-2-induced HBV restriction was weak in Huh-7 hepatoma cells, and the interferon-induced anti-HBV effect was independent of BST-2 induction in hepatic L02 cells. Notably, HBV could promote HIV-1 DeltaVpu virus release from BST-2-positive HepG2 hepatoma cells but not HeLa cells, whereas Vpu failed to efficiently inhibit BST-2-induced HBV restriction. HBx exhibited an enhanced interaction and co-localization with BST-2 in hepatocytes. These observations indicate that BST-2 restricts HBV production at intracellular MVBs but is inactivated by HBV through a novel mechanism requiring hepatocyte-specific cellular co-factors or a hepatocyte-specific environment. Further understanding of BST-2-induced HBV restriction may provide new therapeutic targets for future HBV treatments. PMID- 26119072 TI - Teen Pregnancy Prevention: Sexuality the Magic Bullets. PMID- 26119073 TI - Indoor Tanning, Skin Cancer and the Young Female Patient: A Review of the Literature. AB - Young, non-Hispanic white females represent the population most likely to use indoor tanning facilities. This population may be at increased risk of skin cancer as recent meta-analyses support a strong association between cutaneous malignancy and indoor tanning. Public perception of the purported health benefits of indoor tanning may be partially to blame for the popularity of tanning salons as a desire to prepare skin prior to sun exposure is among the most commonly cited motivations for indoor tanning. Improving education and counseling to address misconceptions regarding tanning safety will require the participation of healthcare providers for both physical and psychological screenings as well as for information dissemination. This review presents the association between tanning bed use and skin cancer, biological effects of UV radiation exposure, UV burden associated with tanning devices, public perception of tanning, demographic and psychological profile of indoor tanners, and current legislation regulating tanning bed use. PMID- 26119074 TI - The Interpretation of Repeat Positive Results for Gonorrhea and Chlamydia in Children. AB - BACKGROUND: The diagnosis of gonorrhea and/or chlamydia in a prepubertal child beyond the neonatal period is confirmatory of mucosal contact with infective bodily secretions and therefore highly concerning for sexual abuse. When such a diagnosis is made, a report to protective authorities is warranted so that safety and potential criminal activity may be evaluated concurrent with the medical management. Occasionally, despite perceived adequate medical management and protective safety plans, a child may present with a repeat positive result for sexually transmitted infections. In this scenario, it is important for medical providers to carefully consider and be aware of the possible reasons for the repeat positive result: (1) treatment failure, (2) a new infection from repeated abuse, or (3) a false-positive result due to the limitations of nonculture testing. CASE: Prepubertal sisters were diagnosed with gonorrhea and Chlamydia and treated with antibiotics, and the individual identified as having sexually abused them was removed from the home. SUMMARY AND CONCLUSION: Over a 4-month period, both children continued to have positive testing for chlamydia via the nucleic acid amplification test and/or culture. Concurrent with using alternate antibiotic treatment options, protective authorities were alerted to the fact that this was likely a reinfection. The investigative team later determined that a second adult, who tested positive for gonorrhea and chlamydia, was also sexually abusing both girls. Disclosures of abuse regarding both adult individuals were deemed credible by authorities and supported with collateral information. PMID- 26119076 TI - Anti-adipogenic effect of epiberberine is mediated by regulation of the Raf/MEK1/2/ERK1/2 and AMPKalpha/Akt pathways. AB - It has been reported that alkaloids derived from Coptis chinensis exert anti adipogenic activity on 3T3-L1 adipocytes by downregulating peroxisome proliferation-activity receptor-gamma (PPAR-gamma) and CCAAT/enhancer binding protein-alpha (C/EBP-alpha). However, the signaling-based mechanism of the inhibitory role of epiberberine in the early stages of 3T3-L1 adipocyte differentiation is uncharacterized. Here, we show that epiberberine had inhibitory effects on adipocyte differentiation and significantly decreased lipid accumulation by downregulating an adipocyte-specific transcription factor, sterol regulatory element-binding protein-1 (SREBP-1). Furthermore, we observed that epiberberine markedly suppressed the differentiation-mediated phosphorylation of components of both the Raf/mitogen-activated protein kinase 1 (MEK1)/extracellular signal-regulated protein kinase 1/2 (ERK1/2) and AMP activated protein kinase-alpha1 (AMPKalpha)/Akt pathways. In addition, gene expression of fatty acid synthase (FAS) was significantly inhibited by treatment with epiberberine during adipogenesis. These results indicate that the anti adipogenic mechanism of epiberberine is associated with inhibition of phosphorylation of Raf/MEK1/ERK1/2 and AMPKalpha/Akt, followed by downregulation of the major transcription factors of adipogenesis, such as PPAR-gamma, C/EBP alpha, and SREBP-1, and FAS. Taken together, this study suggests that the anti adipogenic effect of epiberberine is mediated by downregulation of the Raf/MEK1/ERK1/2 and AMPKalpha/Akt pathways during 3T3-L1 adipocyte differentiation. Moreover, the anti-adipogenic effects of epiberberine were not accompanied by modulation of beta-catenin. PMID- 26119077 TI - Salmonella Typhimurium outbreak associated with a contaminated food container in a school in Sichuan Province, China. AB - On 13 June 2013, a fever and diarrhoea outbreak occurred in a boarding school in Sichuan Province. We conducted a field investigation and compared food exposure of 81 case students and 104 control students (years 7 and 8) in order to identify the source of infection. There were 401 cases identified (399 students and two cooks). The attack rates were 23-46% in nursery, primary, and secondary schools, but 0% in the high school. Eighty-five percent of case students, consumed cowpea salad compared to 60% of control students at lunch on 12 June (odds ratio 3.1, 95% confidence interval 1.3-7.8). The cowpeas were stored at room temperature for 3 h in a bucket previously used to store raw ingredients. The bucket was cleaned using water without a disinfectant. There were two buckets of cowpea, one for the high-school students and another for the other students. This Salmonella outbreak was likely caused by the cowpea salad due to cross-contamination via a storage bucket. PMID- 26119078 TI - Targeting microRNAs in heart failure. AB - MicroRNAs play pivotal roles in cardiac disease, and their therapeutic modulation raises exciting and unique opportunities, as well as challenges in the path toward clinical development and implementation. In this review, we provide a detailed overview of recent studies highlighting the important role of microRNAs in heart failure (HF) and the potential use of microRNA-based technology for diagnosis, prevention, and treatment of HF. We will focus on the strategies presently used for microRNA-based therapy by discussing their use and drawbacks, as well as the challenges and future directions for their development in the context of human HF. PMID- 26119079 TI - Phytochemical constituents and chemosystematic significance of Chrozophora tinctoria (L.) Raf. AB - Twelve compounds were isolated from Chrozophora tinctoria (L.) Raf. They were identified as kaempferol, kaempferol 3-O-beta-glucopyranoside, kaempferol 3-O-(6" alpha-rhamnopyranosyl)-beta-glucopyranoside, quercetin, quercetin 3-O-beta glucopyranoside, quercetin 3-O-(6"-alpha-rhamnopyranosyl)-beta-glucopyranoside, apigenin, apigenin 7-O-beta-glucopyranoside, acacetin, gallic acid, methyl gallate and beta-sitosterol-3-O-beta-glucopyranoside. Their structures were elucidated by chemical and spectral methods. Furthermore, chemosystematics of the isolated compounds is briefly discussed. It was indicated that C. tinctoria is the only species of Chrozophora that has the capability to synthesis kaempferol aglycone and their glycosides, and the finding is supported by its distinct morphological and anatomical aspects. PMID- 26119080 TI - Ipsilateral single stage conversion from BAHA to cochlear implant. AB - Profound unilateral sensorineural hearing loss is an indication for the placement of a bone anchored hearing aid. In a few unfortunate patients who later develop contralateral hearing loss, a cochlear implant becomes a good option. We present our experience in these cases and discuss our technique for single stage conversion from a bone anchored hearing aid to a cochlear implant. PMID- 26119081 TI - Endoscopic surgical management of inspiratory stridor in newborns and infants. AB - OBJECTIVE: Compare the incidence of endoscopic surgical treatment of patients with laryngomalacia to other aerodigestive pathology who may present with similar symptoms. METHODS: Consecutive case series with chart review of endoscopic surgical intervention in infants, aged 12 months or less, presenting with inspiratory stridor, in the absence of syndromic condition or prior history of intubation. RESULTS: A total of 30 patients were identified. The average age at the time of surgical intervention was 2.7 months. Endoscopic surgical management was directed at laryngomalacia (70%), vallecular cysts (23.3%), and anterior glottic webs (6.7%). All patients had nearly immediate resolution of the stridor and feeding difficulties. None required revision surgery, modified diets, or alternative means of enteric nutrition. CONCLUSIONS: Laryngomalacia was the most commonly encountered surgical indication for stridulous newborns and infants with severe symptoms. Like most previous descriptions, patients responded well to supraglottoplasty. Vallecular cysts accounted for about one-quarter of the infants treated. Clinicians should carefully consider the presence of other airway pathology, which may mimic laryngomalacia, in non-syndromic infants without a previous history of intubation. Endoscopic surgical management may be safe and effective. PMID- 26119082 TI - Lost cold Antarctic deserts inferred from unusual sulfate formation and isotope signatures. AB - The Antarctic ice cap significantly affects global ocean circulation and climate. Continental glaciogenic sedimentary deposits provide direct physical evidence of the glacial history of the Antarctic interior, but these data are sparse. Here we investigate a new indicator of ice sheet evolution: sulfates within the glaciogenic deposits from the Lewis Cliff Ice Tongue of the central Transantarctic Mountains. The sulfates exhibit unique isotope signatures, including delta(34)S up to +500/00 for mirabilite evaporites, Delta(17)O up to +2.30/00 for dissolved sulfate within contemporary melt-water ponds, and extremely negative delta(18)O as low as -22.20/00. The isotopic data imply that the sulfates formed under environmental conditions similar to today's McMurdo Dry Valleys, suggesting that ice-free cold deserts may have existed between the South Pole and the Transantarctic Mountains since the Miocene during periods when the ice sheet size was smaller than today, but with an overall similar to modern global hydrological cycle. PMID- 26119083 TI - Towards a feasible and scalable production of bio-xerogels. AB - HYPOTHESIS: The synthesis process of carbon xerogels is limited, mainly due to two drawbacks that prevent their introduction onto the market: (i) the long time required for producing the material and (ii) the reagents used for the synthesis, which are costly and harmful to the environment. Microwave radiation is expected to produce a reduction in time of more than 90%, while the use of tannin instead of resorcinol will probably result in a cost-effective carbonaceous material. EXPERIMENTS: Resorcinol-tannin-formaldehyde xerogels containing different amounts of tannin, either with or without a surfactant (sodium dodecyl sulphate), were synthesized by means of two different heating methods: conventional and microwave heating. The effects of the surfactant, the heating method and the addition of tannin upon the porous structure and the chemical composition of the final materials were evaluated. FINDINGS: It was found that the addition of surfactant is essential for obtaining highly porous xerogels when using tannins. The heating method also plays an important role, as conventionally synthesized samples display a greater volume of large pores. However, tannins are less sensitive to microwave radiation and their use results in tannin-formaldehyde xerogels that have a porous structure and chemical composition similar to those of resorcinol formaldehyde xerogels. PMID- 26119084 TI - Synthesis of 1D Fe3O4/P(MBAAm-co-MAA) nanochains as stabilizers for Ag nanoparticles and templates for hollow mesoporous structure, and their applications in catalytic reaction and drug delivery. AB - One-dimensional (1D) magnetic Fe3O4/P(MBAAm-co-MAA) nanochains were prepared by distillation-precipitation polymerization of MBAAm and MAA in the presence of Fe3O4 nanoparticles as building blocks under a magnetic heating stirrer, which played two critical roles: serving as magnetic field to induce the self-assembly of Fe3O4 nanoparticles into 1D nanochains and providing thermal energy to induce the polymerization of MAA and MBAAm on the surface of the Fe3O4 nanoparticles. The thickness of the P(MBAAm-co-MAA) layer can be easily tuned by adjusting the successive polymerization steps. The polymer layer that contained carboxyl groups was used as stabilizers for loading Ag nanoparticles and the reaction locus for deposition of outer silica layer via a sol-gel method in presence of C18TMS as the pore directing agent for tri-layer nanochains. The corresponding hollow mesoporous silica nanochains with movable maghemite cores (gamma-Fe2O3@mSiO2) were produced after removal of the polymer mid-layer and the alkyl groups of the pore directing agent via calcination of the tri-layer nanochains at high temperature. The Fe3O4/P(MBAAm-co-MAA)/Ag nanochains exhibited a highly catalytic efficiency and well reusable property toward the reduction of nitrophenol. Furthermore, the gamma-Fe2O3@mSiO2 nanochains possessed hollow mesoporous structure and high specific surface area (197.2 m(2) g(-1)) were used as a drug carrier, which displayed a controlled release property. PMID- 26119085 TI - Metal-Free Radical [2+2+1] Carbocyclization of Benzene-Linked 1,n-Enynes: Dual C(sp(3))-H Functionalization Adjacent to a Heteroatom. AB - A new metal-free oxidative radical [2+2+1] carbocyclization of benzene-linked 1,n enynes with two C(sp(3))-H bonds adjacent to the same heteroatom is described. This method achieves two C(sp(3))-H oxidative functionalizations and an annulation, thus providing efficient and general access to a variety of fused five-membered carbocyclic hydrocarbons. PMID- 26119086 TI - Mycobacterium tuberculosis virulence: insights and impact on vaccine development. AB - The existing TB vaccine, the attenuated Mycobacterium bovis strain BCG, is effective in protecting infants from severe forms of the disease, while its efficacy in protecting adults from pulmonary TB is poor. In the last two decades, a renewed interest in TB resulted in the development of several candidate vaccines that are now entering clinical trials. However, most of these vaccines are based on a common rationale and aim to induce a strong T-cell response against Mycobacterium tuberculosis. Recent advancements in the understanding of M. tuberculosis virulence determinants and associated pathogenic strategies are opening a new and broader view of the complex interaction between this remarkable pathogen and the human host, providing insights at molecular level that could lead to a new rationale for the design of novel antitubercular vaccines. A vaccination strategy that simultaneously targets different steps in TB pathogenesis may result in improved protection and reduced TB transmission. PMID- 26119087 TI - Dickkopf-related protein 3 is a potential Abeta-associated protein in Alzheimer's Disease. AB - Amyloid-beta (Abeta) is the most prominent protein in Alzheimer's disease (AD) senile plaques. In addition, Abeta interacts with a variety of Abeta-associated proteins (AAPs), some of which can form complexes with Abeta and influence its clearance, aggregation or toxicity. Identification of novel AAPs may shed new light on the pathophysiology of AD and the metabolic fate of Abeta. In this study, we aimed to identify new AAPs by searching for proteins that may form soluble complexes with Abeta in CSF, using a proteomics approach. We identified the secreted Wnt pathway protein Dickkopf-related protein 3 (Dkk-3) as a potential Abeta-associated protein. Using immunohistochemistry on human AD brain tissue, we observed that (i) Dkk-3 co-localizes with Abeta in the brain, both in diffuse and classic plaques. (ii) Dkk-3 is expressed in neurons and in blood vessel walls in the brain and (iii) is secreted by leptomeningeal smooth muscle cells in vitro. Finally, measurements using ELISA revealed that (iv) Dkk-3 protein is abundantly present in both cerebrospinal fluid and serum, but its levels are similar in non-demented controls and patients with AD, Lewy body dementia, and frontotemporal dementia. Our study demonstrates that Dkk-3 is a hitherto unidentified Abeta-associated protein which, given its relatively high cerebral concentrations and co-localization with Abeta, is potentially involved in AD pathology. In this study, we propose that Dickkopf-related protein-3 (Dkk 3) might be a novel Amyloid-beta (Abeta) associated protein. We demonstrate that Dkk-3 is expressed in the brain, especially in vessel walls, and co-localizes with Abeta in senile plaques. Furthermore, Dkk-3 levels in cerebrospinal fluid strongly correlate with Abeta40 levels, but were not suitable to discriminate non demented controls and patients with dementia. PMID- 26119088 TI - Deep soil carbon dynamics are driven more by soil type than by climate: a worldwide meta-analysis of radiocarbon profiles. AB - The response of soil carbon dynamics to climate and land-use change will affect both the future climate and the quality of ecosystems. Deep soil carbon (>20 cm) is the primary component of the soil carbon pool, but the dynamics of deep soil carbon remain poorly understood. Therefore, radiocarbon activity (Delta14C), which is a function of the age of carbon, may help to understand the rates of soil carbon biodegradation and stabilization. We analyzed the published 14C contents in 122 profiles of mineral soil that were well distributed in most of the large world biomes, except for the boreal zone. With a multivariate extension of a linear mixed-effects model whose inference was based on the parallel combination of two algorithms, the expectation-maximization (EM) and the Metropolis-Hasting algorithms, we expressed soil Delta14C profiles as a four parameter function of depth. The four-parameter model produced insightful predictions of soil Delta14C as dependent on depth, soil type, climate, vegetation, land-use and date of sampling (R2=0.68). Further analysis with the model showed that the age of topsoil carbon was primarily affected by climate and cultivation. By contrast, the age of deep soil carbon was affected more by soil taxa than by climate and thus illustrated the strong dependence of soil carbon dynamics on other pedologic traits such as clay content and mineralogy. PMID- 26119089 TI - Echinococcosis: A 15-year epidemiological, clinical and outcome overview. AB - OBJECTIVE: To analyze the epidemiological and clinical characteristics and mortality of patients with cystic echinococcosis (CE) in northern Spain. PATIENTS AND METHODS: A retrospective study of the medical records of patients diagnosed with CE and hospitalized from 1997 to 2011 in a University Hospital. RESULTS: A total of 76 patients (44 men) were diagnosed with CE. The mean age was 57.8 years (SD: 19.1 years; range: 14.9-92.7). The yearly average incidence was 1.08 cases/100,000 inhabitants. The highest incidence was registered in patients aged 70-79 years (22.7% of all cases). Liver was the main organ involved (92.1%), followed by lung (6.6%) and peritoneum (1.3%). Fifty-five patients (72%) received treatment: 2 (3.6%) medical treatment with albendazole, 27 (49%) surgical treatment, 3 (5.4%) medical treatment combined with cyst drainage, and 23 (42%) combined medical and surgical treatment. Eight patients had a recurrence. Twenty four (31.2%) patients died. No patient's death was attributed directly to hydatidosis, though mortality was significantly higher in the untreated vs. the treated patient group (57% vs. 22%, p=0.003). CONCLUSIONS: Hydatidosis treatment and diagnostic approaches remain heterogeneous. The liver continues being the main organ affected. Mortality was higher in patients who did not receive treatment. However, this result might have been influenced by other factors, mainly age. PMID- 26119090 TI - Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. AB - Mammalian exchange protein directly activated by cAMP isoform 1 (EPAC1), encoded by the RAPGEF3 gene, is one of the two-membered family of cAMP sensors that mediate the intracellular functions of cAMP by acting as guanine nucleotide exchange factors for the Ras-like Rap small GTPases. Extensive studies have revealed that EPAC1-mediated cAMP signaling is highly coordinated spatiotemporally through the formation of dynamic signalosomes by interacting with a diverse array of cellular partners. Recent functional analyses of genetically engineered mouse models further suggest that EPAC1 functions as an important stress response switch and is involved in pathophysiological conditions of cardiac stresses, chronic pain, cancer and infectious diseases. These findings, coupled with the development of EPAC specific small molecule modulators, validate EPAC1 as a promising target for therapeutic interventions. PMID- 26119092 TI - The largest relative testis size among primates and aseasonal reproduction in a nocturnal lemur, Mirza zaza. AB - OBJECTIVES: Testis size is an indirect indicator of a species' mating system, along with sexual size and canine dimorphism, existence and usage of mating and advertisement calls as well as the spatial distribution of males and females ready to mate in solitary species. Upon its recent discovery, the northern giant mouse lemur Mirza zaza was suggested to have a polygynandrous mating system and to exhibit seasonal breeding. We tested these predictions in a field study in Sahamalaza National Park, NW Madagascar. MATERIALS AND METHODS: We caught 12 M. zaza, before and during the suggested mating period and obtained standard field morphometric measurements, including testes size. RESULTS: We show that M. zaza has the highest relative testis volume among primates, indicating strong sperm competition and polygynandrous mating. In addition, based on inferred age of captured animals, observed mating behavior, a female caught in met-estrus and data from captivity, we suggest M. zaza to be one of the few lemurs that breed aseasonally. DISCUSSION: Future field work on this endangered species is required to illuminate the causes and consequences of intense promiscuity and aseasonal breeding despite strong habitat seasonality, which distinguish M. zaza from most other nocturnal lemurs. PMID- 26119091 TI - Embryonal Fyn-associated substrate (EFS) and CASS4: The lesser-known CAS protein family members. AB - The CAS (Crk-associated substrate) adaptor protein family consists of four members: CASS1/BCAR1/p130Cas, CASS2/NEDD9/HEF1/Cas-L, CASS3/EFS/Sin and CASS4/HEPL. While CAS proteins lack enzymatic activity, they contain specific recognition and binding sites for assembly of larger signaling complexes that are essential for cell proliferation, survival, migration, and other processes. All family members are intermediates in integrin-dependent signaling pathways mediated at focal adhesions, and associate with FAK and SRC family kinases to activate downstream effectors regulating the actin cytoskeleton. Most studies of CAS proteins to date have been focused on the first two members, BCAR1 and NEDD9, with altered expression of these proteins now appreciated as influencing disease development and prognosis for cancer and other serious pathological conditions. For these family members, additional mechanisms of action have been defined in receptor tyrosine kinase (RTK) signaling, estrogen receptor signaling or cell cycle progression, involving discrete partner proteins such as SHC, NSP proteins, or AURKA. By contrast, EFS and CASS4 have been less studied, although structure function analyses indicate they conserve many elements with the better-known family members. Intriguingly, a number of recent studies have implicated these proteins in immune system function, and the pathogenesis of developmental disorders, autoimmune disorders including Crohn's disease, Alzheimer's disease, cancer and other diseases. In this review, we summarize the current understanding of EFS and CASS4 protein function in the context of the larger CAS family group. PMID- 26119093 TI - Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer. AB - OBJECTIVES: Combining histone deacetylase inhibitors and chemotherapy is synergistic. This phase I study combined escalating vorinostat doses with constant doses of carboplatin and gemcitabine for the treatment of recurrent platinum-sensitive ovarian cancer. The objectives of this study were to determine the maximally tolerated dose of this combination; secondary objectives included preliminary response rate of this regimen and toxicity profile. METHODS: Fifteen patients with relapsed ovarian cancer were enrolled into this phase I study. Doses of carboplatin and gemcitabine were AUC 4 on day 1 and 1000 mg/m(2) on days 1 and 8, respectively; cycles were administered every 21 days. Vorinostat was tested using four different schedules. The first dose level (DL A) tested vorinostat as daily oral dosing from days 1 to 14. DL B tested twice daily (BID) vorinostat dosing on days 1-3 and 8-10. DL C tested BID vorinostat dosing on days 1, 2, 8, and 9, starting vorinostat 1 day prior to initiation of carboplatin and gemcitabine, and DL D tested vorinostat on days 1 and 2 with chemotherapy starting on day 2. RESULTS: All four DLs tested resulted in dose-limiting toxicities, and no MTD was determined. Toxicities were mostly hematologic. Seven patients were evaluable for RECIST assessment, and six of them had partial responses (PR) via RECIST. CONCLUSIONS: Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early. PMID- 26119094 TI - Residents' Experience in Breast Cancer Care. AB - OBJECTIVE: General surgeons commonly treat breast cancer (BC), hence necessitating adequate training during residency. We examined surgery residents' exposure to these conditions across postgraduate years (PGYs) to assess the proximity of involvement to commencement. STUDY DESIGN: We examined the BC operative profile by PGY using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File (ACS NSQIP PUF, 2008-2011). Operations were classified using the Surgical Council on Resident Education curriculum complexity categories. Univariate analysis was performed using chi square, Fisher exact, analysis of variance, and Kruskal-Wallis tests, as appropriate. RESULTS: Of 58,413 BC operations, 23,996 involved PGY1 to PGY5 residents. A Surgical Council on Resident Education complexity was assigned to 97.7% of operations studied (n = 23,432). PGY was inversely proportional to the number of operations performed. PGY1 to PGY3 residents covered most essential common operations (PGY1-3, 72% vs PGY4-5, 28%; p < 0.001). PGY1 and PGY2 residents covered more than half of the complex operations (PGY1-2, 55% [n = 359] vs PGY3-5, 45% [n = 288]; p = 0.033). CONCLUSIONS: Although junior residents perform most of the BC cases in surgical residency, residents do participate in operations for BC across the continuum of the training years. Program directors should consider trainees' career aspirations to ensure adequate exposure to the operative and nonoperative management of this common disease before the transition to independent practice. PMID- 26119095 TI - Understanding Quality Issues in Your Surgical Department: Comparing the ACS NSQIP With Traditional Morbidity and Mortality Conferences in a Canadian Academic Hospital. AB - INTRODUCTION: Review of surgical complications in traditional morbidity and mortality (M&M) rounds remains an important mechanism to identify and discuss quality-of-care issues. This process relies on case selection by providers; therefore, complications identified for review may differ from those captured in comprehensive quality programs such as the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). Additionally, although the ACS NSQIP captures robust data on complications in surgical wards, without strategies to disseminate this information to staff and improve practice, minimal change may result. The objective of this study was to compare complications identified by the ACS NSQIP with those captured in M&M conferences at a large Canadian academic hospital. METHODS: Retrospective medical record reviews of all patients admitted to the general surgery unit from March 2012 to March 2013 were reviewed. Number and types of complications were recorded for cases that were both submitted and reviewed in M&M rounds and those cases that were submitted but not reviewed. These complications were compared with those extracted from our local ACS NSQIP database. RESULTS: A total of 1348 general surgical procedures were performed. The ACS NSQIP captured complications in 143 patients compared with 58 patients identified for review in M&M rounds. Both the methods identified similar proportions of major and minor complications (ACS NSQIP 52% major, 48% minor; M&M 58% major, 42% minor). More postoperative deaths were entered into the ACS NSQIP (12) than in M&M conferences (8 reviewed and 2 submitted). The ACS NSQIP identified higher proportions of surgical site infections and readmissions. However, M&M conferences captured additional complications in patients who did not undergo surgery and identified potential quality issues in patients who did not ultimately experience an adverse outcome. CONCLUSIONS: M&M rounds and the ACS NSQIP provide important and potentially complementary data on surgical quality. Incorporating the ACS NSQIP outcomes data into traditional M&M conferences may help to optimize quality improvement efforts. PMID- 26119096 TI - Preferences and Outcomes for Chemotherapy Teaching in a Postgraduate Obstetrics and Gynecology Training Program. AB - PURPOSE: To determine whether chemotherapy teaching is a desired component of postgraduate training programs in obstetrics and gynecology and assess its effect on practicing clinicians. METHOD: After obtaining institutional review board approval, 99 individuals who completed postgraduate training at a single academic medical center between 2005 and 2013 were invited to complete an online survey. Descriptive statistics were used to summarize responses. RESULTS: Of the 99 individuals, 68 (68%) completed the survey. Respondents included physicians currently practicing in both academic medicine (n = 36, 52.9%) and private practice (n = 24, 35.2%). Most respondents (n = 60, 88.2%) indicated that chemotherapy teaching was a desired feature of their training and expressed a preference for both formal didactics and direct clinical involvement (n = 55, 80.2%). Benefits identified by respondents included improved insight into the management of symptoms commonly associated with chemotherapy (n = 55, 82.1%) and an enhanced ability to counsel patients referred for oncology care (n = 48, 70.5%). All respondents who pursued training in gynecologic oncology following residency (n = 6) indicated that chemotherapy teaching favorably affected their fellowship experience. Of the 6 gynecologic oncologists, 3 (50%) who responded also indicated that chemotherapy teaching during residency improved their performance in fellowship interviews. CONCLUSION: Chemotherapy teaching was a desired feature of postgraduate training in general obstetrics and gynecology at the institution studied. Consideration should be given to creating curricula that incorporate the principles and practice of chemotherapy and address the needs of obstetrics and gynecology trainees who intend to pursue both general and subspecialty practice. PMID- 26119097 TI - Comprehensive Middle-Fidelity Simulator for Training in Aortic Root Surgery. AB - OBJECTIVES: The current training in aortic root surgery is affected by several factors: complexity of surgical procedures and the complex 3-dimensional anatomy of the aortic root. The aortic root simulator proposed in this study is an additional low-cost, reusable, and portable tool to improve surgical skills in a middle-fidelity model. METHODS: The aortic root surgery simulator is a self-made portable box that can be used for an unrestricted number of procedures. It is supplied with a self-made aortic root substitute, which was tested to simulate the flexible property of the aortic root components. The building process is detailed in this study. Aortic root procedures were performed by use of this simulator, in which surgical handling was tested. The total cost was calculated in euros. RESULTS: Building the aortic root simulator resulted in the development of a new training tool for aortic root surgery. The use of silicone led to the construction of the aortic root components with similar diameters and properties as those of a real aortic root, which permitted performing the surgical procedures in unrestricted numbers. This involved the aortic valve including all types of aortic valve replacements such as interrupted and semicontinuous, and all types of aortic root procedures like enlargement, remodeling, reimplantation, and replacement. Moreover, the silicone allowed modeling of various pathological replicas of the aortic valve, which resulted in facilitating the practice of aortic valve repair techniques according to El Khoury's classification. The cost was approximately ?1. CONCLUSION: Surgical skills in aortic root surgery could be improved by using a middle-fidelity simulator. The high cost of the training for residents and junior surgeons could be reduced effectively through the use of this low-cost, portable, reusable simulator and its accessories (aorta and valves). Familiarity with performing the surgical procedures could reduce the time consumed in the operation room. PMID- 26119098 TI - Early Results from the Flexibility in Surgical Training Research Consortium: Resident and Program Director Attitudes Toward Flexible Rotations in Senior Residency. AB - OBJECTIVE: To assess the attitudes of residents and program directors (PDs) involved in flexible training to gauge satisfaction with this training paradigm and elicit limitations. DESIGN: Anonymous surveys were sent to residents and PDs in participant programs. Respondents were asked to rate responses on a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree). SETTING: A total of 9 residency programs that are collaborating to prospectively study the effect of flexible tracks on resident performance and outcome. PARTICIPANTS: A total of 138 residents who were in clinical years 4 and 5 and 10 PDs. RESULTS: Of the 138 possible residents, 100 responded to the resident survey (72.5% response rate). Among resident respondents, 33% were participating in a flexible track option. The most frequently listed specialties of focus were cardiothoracic surgery (19%), vascular surgery (13%), acute care surgery (11%), colorectal surgery (8%), surgical oncology (7%), and pediatric surgery (7%). Participants in flexible tracks tended to strongly agree that their career would be enhanced by flexible rotations; interestingly, of those not in flexible tracks, most tended to also agree that flexible rotations would enhance their future careers. Flexible track participants report receiving greater autonomy on flexible rotations and believe they would be better prepared for fellowship and career. They express overall very high satisfaction with the flexible experience. Limitations expressed by residents (in flexible tracks or not) include uncertainty for how this paradigm serves those interested in comprehensive general surgery, concern about scheduling difficulties, and some displeasure in missing high-volume general surgery rotations in lieu of specialty-focused rotations. The PD survey was completed by 8 of 9 PDs for a response rate of 89%. All the respondents agreed or strongly agreed that careers of residents are enhanced by flexible rotations and that important operative and clinical experiences are gained. Overall, 87.5% of PD respondents agreed or strongly agreed that those in flexible tracks have greater opportunities for mentorship in their chosen field. PDs also expressed high levels of satisfaction with flexible rotations. Limitations include concerns that the flexibility option presents scheduling difficulties and does not go far enough in reforming postgraduate education. CONCLUSIONS: This survey of 9 residency programs participating in flexible tracks indicates satisfaction with this training option. The role of comprehensive general surgery as a training end point and scheduling difficulties remain as major challenges. Outcomes of graduates in these tracks and control peers are being prospectively evaluated. PMID- 26119099 TI - Copper(II) complexation of tacrine hybrids with potential anti-neurodegenerative roles. AB - The complexity and multifactorial nature of neurodegenerative diseases turn quite difficult the development of adequate drugs for their treatment. Multi-target analogues, in conjugation with natural moieties, have been developed in order to combine acetylcholinesterase (AChE) inhibition with antioxidant properties, metal binding capacity and inhibition of amyloid-beta (Abeta) aggregation. Due to the recent interest on natural-based drugs and also the importance of studying the role of transition metal ions in the disease process, we herein evaluate the copper chelating capacity and inhibitory ability for self- and Cu-induced Abeta1 42 aggregation of two nature-base hybrid model compounds obtained from conjugation of a tacrine moiety with a S-allylcystein (1) or S-propargylcystein (2) moiety. Both compounds show a moderate chelating power towards Cu(II) (pCu 7.13-7.51, CL/CCu=10, CCu=10(-6)M, pH7.4), with predominant formation of 1:1 complex species (CuL, CuH-1L) for which the coordination sphere involves the N amide and the NH2 amine of the cysteine derivative as well as the NH of tacrine. The compounds are able to improve the inhibition of Abeta aggregation in the presence of Cu(II) and this is slightly more relevant for the allyl derivative (1), a stronger copper chelator, than for the propargyl (2). Moreover, the presence of a chloro atom in the tacrine moiety and the size of the chain length between the two NH groups appeared also to improve the inhibition capacity for Abeta aggregation. PMID- 26119100 TI - Synthesis of Polysubstituted gamma-Butenolides via a Radical Pathway: Cyclization of alpha-Bromo Aluminium Acetals and Comparison with the Cyclization of alpha Bromoesters at High Temperature. AB - Polysubstituted butenolides were obtained in good to high yields from alpha bromoesters derived from propargyl alcohols by a one-pot reaction involving the radical cyclization of alpha-bromo aluminium acetals, followed by the oxidation of the resulting cyclic aluminium acetals in an Oppenauer-type process and migration of the exocyclic C=C bond into the alpha,beta-position. Comparison with the direct cyclization of alpha-bromoesters at high temperature and under high dilution conditions is described. Deuterium-labelling experiments allowed us to uncover "invisible" 1,5-hydrogen atom transfers (1,5-HATs) that occur during these cyclization processes, together with the consequences of the latter in the epimerization of stereogenic centres. Compared to the classical approach, the cyclization of aluminium acetals proved to be highly chemoselective and its efficiency was illustrated by the short total syntheses of optically enriched gamma-butenolides isolated from Plagiomnium undulatum and from Kyrtuhrix maculans. PMID- 26119101 TI - New insights into pri-miRNA processing and accumulation in plants. AB - MicroRNAs (miRNAs) regulate many biological processes such as development, metabolism, and others. They are processed from their primary transcripts called primary miRNA transcripts (pri-miRNAs) by the processor complex containing the RNAse III enzyme, DICER-LIKE1 (DCL1), in plants. Consequently, miRNA biogenesis is controlled through altering pri-miRNA accumulation and processing, which is crucial for plant development and adaptation to environmental changes. Plant pri miRNAs are transcribed by DNA-dependent RNA polymerase II (Pol II) and their levels are determined through transcription and degradation, whereas pri-miRNA processing is affected by its structure, splicing, alternative splicing, loading to the processor and the processor activity, which involve in many accessory proteins. Here, we summarize recent progresses related to pri-miRNA transcription, stability, and processing in plants. PMID- 26119103 TI - Contact between the beta1 and beta2 Segments of alpha-Synuclein that Inhibits Amyloid Formation. AB - Conversion of the intrinsically disordered protein alpha-synuclein (alpha-syn) into amyloid aggregates is a key process in Parkinson's disease. The sequence region 35-59 contains beta-strand segments beta1 and beta2 of alpha-syn amyloid fibril models and most disease-related mutations. beta1 and beta2 frequently engage in transient interactions in monomeric alpha-syn. The consequences of beta1-beta2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double-cysteine mutant alpha-synCC, with a disulfide linking beta1 and beta2, is aggregation-incompetent and inhibits aggregation and toxicity of wild-type alpha-syn. We show that alpha-syn delays the aggregation of amyloid-beta peptide and islet amyloid polypeptide involved in Alzheimer's disease and type 2 diabetes, an effect enhanced in the alpha-synCC mutant. Tertiary interactions in the beta1-beta2 region of alpha-syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach. PMID- 26119102 TI - A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone. AB - Validated biomarkers are needed to improve risk assessment and treatment decision making for women with ductal carcinoma in situ (DCIS) of the breast. The Oncotype DX DCIS Score (DS) was shown to predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 Cp units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone. PMID- 26119104 TI - Water as a morphological probe to study polymer-filler interfaces: an original application of thermoporosimetry. AB - This paper is devoted to the characterization of polymer-filler interfaces by thermoporosimetry using water as a probe. Composites of EVA filled with aluminium hydroxide with high filler content for the required fire retardant properties have been studied. After water sorption at 90 degrees C, the composites have been analyzed by thermoporosimetry using water as a morphological probe. This technique first allowed studying the influence of the filler content and the specific surface area on the water uptake. The study with drying steps and two molecular probes (water and cyclohexane) has highlighted that water is confined at the interface and thus thermoporosimetry is a powerful tool to characterize interfaces in EVA-ATH composites. PMID- 26119105 TI - Need for speed: Sexual maturation precedes social maturation in gray mouse lemurs. AB - The life history of mammals underlies a fast-slow continuum, ranging from "slow" species with large body size, delayed sexual maturation, low fertility, and long lifespan, to "fast" species showing the opposite traits. Primates fall into the "slow" category, considering their relatively low offspring numbers and delayed juvenile development. However, social and sexual maturation processes do not necessarily have to be completed simultaneously. The comparison of the timeframes for sexual and social maturation is largely lacking for primates, with the prominent exception of humans. Here, we compare both maturation processes in a basal primate, the gray mouse lemur, which ranges in many aspects at the fast end of the slow-fast life history continuum among primates. We compared the patterns and frequencies of various social and solitary behaviors in young adults (YA, 12 13 months old) and older individuals (A, >=2 years) of both sexes outside estrus. Observations were conducted during mix-sexed dyadic encounter experiments under controlled captive conditions (eight dyads per age class). Results indicate that although all young adults were sexually mature, social maturation was not yet completed in all behavioral domains: Age-dependent differences were found in the number of playing dyads, female marking behavior, female aggression, and social tolerance. Thus, this study provides a first indication that social maturation lags behind sexual maturation in an ancestral nocturnal primate model, indicating that these two developmental schemes may have been decoupled early and throughout the primate lineage. PMID- 26119106 TI - Thickness of a metallic film, in addition to its roughness, plays a significant role in SERS activity. AB - In this paper we evaluate the effect of roughness and thickness of silver film substrates, fabricated on glass and polydimethylsiloxane (PDMS) templates, on surface-enhanced Raman Spectroscopy (SERS) activity. While the silver substrates obtained on glass templates exhibit nm-scale roughness, the silver substrates on PDMS templates show larger roughness, on the order of 10 s of nm. These roughness values do not change significantly with the thickness of the silver film. The SERS intensities of 4-aminothiophenol (ATP) deposited on these substrates strongly depend on both roughness and thickness, with more significant contribution from the roughness on thinner films. FEM simulations of the electric field intensities on surfaces of different thicknesses for rough and flat surfaces suggest higher localized plamons on thinner, rough surfaces. This study indicates that, besides roughness, the thickness of the metallic layer plays a significant role in the SERS activity. PMID- 26119107 TI - Unaffected features of BSA stabilized Ag nanoparticles after storage and reconstitution in biological relevant media. AB - Silver-coated orthopedic implants and silver composite materials have been proposed to produce local biocidal activity at low dose to reduce post-surgery infection that remains one of the major contributions to the patient morbidity. This work presents the synthesis combined with the characterization, colloidal stability in biological relevant media, antimicrobial activity and handling properties of silver nanoparticles (Ag-NP) before and after freeze dry and storage. The nanomaterial was synthesized in aqueous solution with simple, reproducible and low-cost strategies using bovine serum albumin (BSA) as the stabilizing agent. Ag-NP were characterized by means of the size distribution and morphology (UV-vis spectra, dynamic light scattering measurements and TEM images), charge as a function of the pH (zeta potential measurements) and colloidal stability in biological relevant media (UV-vis spectra and dynamic light scattering measurements). Further, the interactions between the protein and Ag-NP were evaluated by surface enhanced Raman spectroscopy (SERS) and the antimicrobial activity was tested with two bacteria strains (namely Staphylococcus aureus and Staphylococcus epidermidis) mainly present in the infections caused by implants and prosthesis in orthopedic surgery. Finally, the Ag-NP dispersed in aqueous solution were dried and stored as long-lasting powders that were easily reconstituted without losing their stability and antimicrobial properties. The proposed methods to stabilize Ag-NP not only produce stable dispersions in media of biological relevance but also long-lasting powders with optimal antimicrobial activity in the nanomolar range. This level is much lower than the cytotoxicity determined in vitro on osteoblasts, osteoclasts and osteoarthritic chondrocytes. The synthesized Ag-NP can be incorporated as additive of biomaterials or pharmaceutical products to confer antimicrobial activity in a powdered form in different formulations, dispersed in aqueous and non-aqueous solutions or coated on the surface of different materials. PMID- 26119108 TI - Dosimetric evaluation of whole-breast radiation therapy: clinical experience. AB - Radiation therapy of the intact breast is the standard therapy for preventing local recurrence of early-stage breast cancer following breast conservation surgery. To improve patient standard of care, there is a need to define a consistent and transparent treatment path for all patients that reduces significance variations in the acceptability of treatment plans. There is lack of consistency among institutions or individuals about what is considered an acceptable treatment plan: target coverage vis-a-vis dose to organs at risk (OAR). Clinical trials usually resolve these issues, as the criteria for an acceptable plan within the trial (target coverage and doses to OAR) are well defined. We developed an institutional criterion for accepting breast treatment plans in 2006 after analyzing treatment data of approximately 200 patients. The purpose of this article is to report on the dosimetric review of 623 patients treated in the last 18 months to evaluate the effectiveness of the previously developed plan acceptability criteria and any possible changes necessary to further improve patient care. The mean patient age is 61.6 years (range: 25.2 to 93.0 years). The mean breast separation for all the patients is 21.0cm (range: 12.4 to 34.9cm), and the mean planning target volume (PTV_eval) (breast volume for evaluation) is 884.0cm(3) (range: 73.6 to 3684.6cm(3)). Overall, 314 (50.4%) patients had the disease in the left breast and 309 (49.6%) had it in the right breast. A total of 147 (23.6%) patients were treated using the deep inspiration breath-hold (DIBH) technique. The mean normalized PTV_eval receiving at least 92% (V92% PD) and 95% (V95% PD) of the prescribed dose (PD) are more than 99% and 97%, respectively, for all patients. The mean normalized PTV_eval receiving at least 105% (V105% PD) of the PD is less than 1% for all groups. The mean homogeneity index (HI), uniformity index (UI), and conformity index (CI) for the PTV_eval are 0.09 (range: 0.05 to 0.15), 1.07 (range: 0.46 to 1.11), and 0.98 (range: 0.92 to 1.0), respectively. Our data confirm the significant advantage of using DIBH to reduce heart dose when compared with the free-breathing technique. The p values analyses of the results for the V5Gy, V10Gy, V15Gy, V20Gy, and V30Gy for the heart comparing DIBH and free-breathing techniques are well less than 0.05 (i.e., p < 0.05). However, similar analyses for the lung give values greater than 0.05 (i.e., p > 0.05), indicating that there is no significant difference in lung dose comparing the 2 treatment techniques. PMID- 26119109 TI - Validation of the "Metroticket" model in a cohort of patients transplanted for hepatocellular carcinoma in southern Brazil. AB - This retrospective study evaluated the ability of the Metroticket model to predict five-yr post-transplant survival in patients with hepatocellular carcinoma (HCC) based only on explant data. Five-yr survival after transplant was estimated using the Metroticket Calculator, and observed survival was calculated using the Kaplan-Meier method. Metroticket-predicted survival was compared between deceased and surviving patients using the Mann-Whitney test. The accuracy of Metroticket estimates in discriminating between these two patient groups was assessed using the c-statistic. Median patient age (n = 109) was 55.7 yr, and 72.5% of the sample were men. Metroticket-predicted and observed post-transplant survival at five yr was 71.1% and 58.7%, respectively. Predictions were calculated using the explant data of the 64 survivors and 45 deceased patients. Median five-yr survival was 72.9% in the former and 69.7% in the latter. The c statistic of the Metroticket model for distinguishing surviving from deceased patients was 0.55. In this cohort, the Metroticket model was unable to accurately predict five-yr post-transplant survival based only on explant data. PMID- 26119110 TI - Quantifying workspace and forces of surgical dissection during robot-assisted neurosurgery. AB - BACKGROUND: A prerequisite for successful robot-assisted neurosurgery is to use a hand-controller matched with characteristics of real robotic microsurgery. This study reports quantified data pertaining to the required workspace and exerted forces of surgical tools during robot-assisted microsurgery. METHODS: A surgeon conducted four operations in which the neuroArm surgical system, an image-guided computer-assisted manipulator specifically designed to perform robot-assisted neurosurgery, was employed to surgically remove brain tumors. The position, orientation, and exerted force of surgical tools were measured during operations. RESULTS: Workspace of the neuroArm manipulators, for the cases studied, was 60*60*60 mm(3) while it offered orientation ranges of 103 degrees , 62 degrees and 112 degrees . The surgical tools exerted a maximum force of 1.86 N with frequency band of less than 20 Hz. CONCLUSIONS: This data provides important information specific to neurosurgery that can be used to select among commercially available, or further design a customized, haptic hand-controller for robot-assisted neurosurgical systems. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26119111 TI - Confronting inequities: A scoping review of the literature on pharmacist practice and health-related disparities. AB - BACKGROUND: An expanding body of literature is exploring the presence and impact of health and health care disparities among marginalized populations. This research challenges policy makers, health professionals, and scholars to examine how unjust and avoidable inequities are created at the societal, institutional, and individual level, and explore strategies for mitigating challenges. OBJECTIVES: Recognizing the significance of this broader conversation, this scoping review provides an overview of pharmacy-specific research attentive to health-related disparities. METHODS: Following Arksey and O'Malley's framework, a rigorous screening process yielded 93 peer-reviewed and 23 grey literature articles, each analyzed for core themes. RESULTS: Lending critical insight to how pharmacy practice researchers are conceptualizing and measuring health inequities, this review highlights three paths of inquiry evident across this literature, including research focused on what pharmacists know about marginalized groups, how pharmacists perceive these groups, and how they provide services. Striving to drive research and practice forward, this review details research gaps and opportunities, including a need to expand the scope of research and integrate knowledge. CONCLUSIONS: As pharmacists endeavor to provide equitable and impactful patient care, it is essential to understand challenges, and build strong evidence for meaningful action. PMID- 26119112 TI - Synthesis and Biological Evaluation of Hexahydropyrrolo[2,3-b]Indole Derivatives as Fungicides against Phytopathogenic Fungi. AB - Eighteen hexahydropyrrolo[2,3-b]indole derivatives were synthesized and evaluated their in vitro antifungal activities against five phytopathogenic fungal strains through the mycelium growth rate method. Analysis of the structure-activity relationship on these synthesized compounds revealed that the introduction of benzyl or substituted benzyl group at the C-3a or N-8 position of the pyrroloindoline scaffold conferred higher antifungal activity against all tested phytopathogenic fungi than compound 4a (both C-3a and N-8 positions are prenyl groups). Especially, compound 4r, among all the tested compounds, showed the most effective antifungal activity against Fusarium coeruleum, and Fusarium graminearum with IC50 values of 4.61 and 5.02 MUg/mL, respectively. Moreover, all synthesized compounds 4a-4r displayed higher activities against Curvularia lunata than the positive control thiabendazole, a commercial agricultural fungicide. PMID- 26119113 TI - A molecular approach towards the taxonomy of fresh water prawns Macrobrachium striatum and M. equidens (Decapoda, Palaemonidae) using mitochondrial markers. AB - Genus Macrobrachium includes freshwater prawns which inhabit most diverse habitats ranging from low saline areas to inland hill streams and impounded water bodies. Being morphologically conserved, this genus has been exposed to severe disputes related to their taxonomy, systematics and phylogeny. Macrobrachium striatum and M. equidens represent two morphologically related congeneric species within this genus. Earlier, M. striatum was considered as a striped form of M. equidens. Though these species are now well-described morphologically and differentiated into two species, no molecular level investigation has been carried out in support of their speciation. We report a study on M. striatum and M. equidens with emphasis to their molecular data through mitochondrial markers (16S ribosomal RNA and cytochrome oxidase subunit I). Results obtained from developed molecular markers of the two species revealed considerable genetic differentiation between them. Phylogram generated using Minimum evolution and Neighbour joining analyses differentiated M. striatum and M. equidens as two independent species. Genetic distance data showed high interspecific divergence (ranging from 3.9% to 17.0% for 16S rRNA sequences and 13.8% to 21.0% for COI sequences) between M. striatum and M. equidens confirming the findings of phylogram. Hence, it could be delineated that M. striatum and M. equidens represent two distinct species within genus Macrobrachium with emphasis to their morphology and genetics. PMID- 26119114 TI - Complete mitochondrial genome of a hydrocarbon-producing green alga Botryococcus braunii strain Showa. AB - Complete mitochondrial genome of Botryococcus braunii strain Showa was assembled and annotated. It contains 31 protein-coding genes, 23 tRNA genes and 3 rRNA (23S, 16S, 5S rRNA) genes. The 31 protein-coding genes include 5 atp genes, 3 cox genes, 9 nad genes, 12 ribosomal protein genes, cob and tatC genes. The presence of extra non-coding regions makes it currently the largest mitochondrial genome in Trebouxiophyceae. Phylogenetic analysis showed Botryococcus braunii strain Showa clustered into Trebouxiophyceae clade and had close genetic relationship with algae Coccomyxa sp. C-169. PMID- 26119115 TI - The complete mitochondrial genome of the killifish Orestias sp. (Cyprinodontiformes, Cyprinodontidae) from the high Andean range. AB - The killifish genus Orestias is endemic to freshwater ecosystems in the High Andes of Peru, Bolivia and Chile. Phylogenetic and phylogeographic studies with partial mitochondrial genes have failed to resolve relationship among species, needing more comprehensive approaches. In this study, we described the complete mitochondrial genome of Orestias sp. from Lirima, northern Chile, with the aim to provide useful data for phylogenetic purposes and species delimitation. The mitochondrial genome was assembled with 2.6 million of reads obtained through an Ion Torrent (chip 318) sequencer. The circular sequence of 16,617 bp showed the following nucleotide composition: A, 26.7%, C, 27.1%, G, 17.0%, and T, 29.2%. Gene composition and structure were similar to other fish sequences available, and comprised 13 protein-coding genes, 12S and 16S rRNA, 22 tRNA genes, and a control region. PMID- 26119116 TI - The complete chloroplast genome sequence of the mulberry Morus notabilis (Moreae). AB - The complete chloroplast genome of the mulberry Morus notabilis (Moreae) has been reconstructed from the whole-genome Illumina sequencing data. The circular genome is 158,680 bp in size, and comprises a pair of inverted repeat (IR) regions of 25,717 bp each, a large single-copy (LSC) region of 87,470 bp and a small single copy (SSC) region of 19,776 bp. The total A+T content is 63.6%, while the corresponding values of the LSC, SSC and IR region are 65.9%, 70.7% and 57.1%, respectively. The chloroplast genome contains 129 genes, including 84 protein coding genes (PCGs), eight ribosomal RNA (rRNA) genes and 37 transfer RNA (tRNA) genes. The maximum likelihood (ML) phylogenetic analysis revealed that M. notabilis was more related to its congeners than to the others. PMID- 26119117 TI - Complete plastid genome of Astragalus mongholicus var. nakaianus (Fabaceae). AB - The first complete plastid genome (plastome) of the largest angiosperm genus, Astragalus, was sequenced for the Korean endangered endemic species A. mongholicus var. nakaianus. Its genome is relatively short (123,633 bp) because it lacks an Inverted Repeat (IR) region. It comprises 110 genes, including four unique rRNAs, 30 tRNAs, and 76 protein-coding genes. Similar to other closely related plastomes, rpl22 and rps16 are absent. The putative pseudogene with abnormal stop codons is atpE. This plastome has no additional inversions when compared with highly variable plastomes from IRLC tribes Fabeae and Trifolieae. Our phylogenetic analysis confirms the non-monophyly of Galegeae. PMID- 26119118 TI - Complete mitogenomes of King angelfish (Holacanthus passer) and Queen angelfish (Holacanthus ciliaris) (Teleostei: Pomacanthidae). AB - In this study, we used the next-generation sequencing method to deduce two complete mitogenomes of King angelfish (Holacanthus passer) and Queen angelfish (Holacanthus ciliaris) for the first time. The assembled mitogenome consists of 16,620 bp in H. passer and 16,606 bp in H. ciliaris, showing 95% identities each other. Both mitogenomes follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes, and a non-coding control region of D-loop. D-loop contains 903 bp in H. passer and 888 bp in H. ciliaris and locates between tRNA-Pro and tRNA-Phe. The overall GC content is 45.8% for H. passer and 46.2% for H. ciliaris. Complete mitogenomes of King angelfish and Queen angelfish deduced in this study provide essential and important DNA molecular data for further phylogenetic and evolutionary analysis for marine angelfish. PMID- 26119119 TI - Mitochondrial DNA control region of three mackerels, genus Rastrelliger: structure, molecular diversity and phylogenetic relationship. AB - The complete mitochondrial control regions (CR) of three mackerels (Rastrelliger spp.) were examined and analyzed. The CR contained three domains, in which three termination-associated sequences (TAS-I, TAS-II and TAS-III), two central conserved sequence blocks (CSB-E, CSB-D), three conserved sequence blocks (CSB-I, CSB-II, and CSB-III) and a putative promoter were detected. Molecular indices analyses of the aligned complete CR sequences showed high level of haplotype diversities and genetic divergences among the three species. The intraspecific divergence among species of this genus ranked from 0.25% to 1.62% and interspecific divergence from 1.90% to 4.30%. The phylogenetic tree shows monophyly with R. brachysoma as a basal species of Rastrelliger. Applying the average divergence rate for fish control regions, the results suggest that the time of separation among Rastrelligers could have occurred in the middle Pleistocene era. PMID- 26119120 TI - The complete mitogenome of Ginkgo-toothed beaked whale (Mesoplodon ginkgodens) (Chordata: Ziphiidae). AB - In this study, we used the next-generation sequencing method to deduce the complete mitogenome of Ginkgo-toothed beaked whale (Mesoplodon ginkgodens) for the first time. The nucleotide composition was asymmetric (33.3% A, 25.3% C, 12.6% G, and 28.7% T) with an overall GC content of 37.9%. The length of the assembled mitogenome was 16,339 bp and follows the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes, and a non-coding control region of D-loop. The D-loop contains 870 bp and is located between tRNA-Pro and tRNA-Phe. The complete mitogenome of Ginkgo toothed beaked whale deduced in this study provides essential and important DNA molecular data for further phylogenetic and evolutionary analysis for cetaceans. PMID- 26119121 TI - The complete mitochondrial genome of the polychaete, Goniada japonica (Phyllodocida, Goniadidae). AB - The study determined the complete mitochondrial genome (mitogenome) of the polychaete, Goniada japonica, which was first reported in the family of Goniadidae. A total of 7162 reads were generated by Illumina HiSeq2500 platform (Illumina Inc., San Diego, CA) with an average depth of 58.41*. The mitogenome of G. japonica was 15,327 bp in size and consists of 37 typical genes (13 protein coding genes, 2 rRNA genes and 22 tRNA genes) and a putative control region. All the 37 genes were encoded on the heavy strand whose nucleotide compositions were 35.08% of A, 33.69% of T, 11.66% of G, and 19.57% of C, showing a lower content of G + C (31.23%). The gene order of 15 major coding genes was identical to that of the Nereididae species. Phylogenetic analysis showed that G. japonica has a closer relationship with Tylorrhynchus heterochaetus of Nereididae. PMID- 26119122 TI - The complete chloroplast genome sequence of Amentotaxus argotaenia (Taxaceae). AB - The complete chloroplast genome sequence of Amentotaxus argotaenia was determined in this study. The genome is 136 657 bp in length and lacks one inverted repeat region. The overall GC content of the genome is 35.85% (protein-coding genes, 36.90%; tRNA genes, 53.31%; rRNA genes, 52.99%; introns, 36.10%; intergenic spacers, 31.03%). The A. argotaenia chloroplast genome contains 118 unique genes, including 83 protein-coding genes, 31 tRNA genes, and four rRNA genes. Ten protein-coding genes and six tRNA genes have one intron, while ycf3 contains two. The coding regions occupy 60.27% of the genome length and the gene density is estimated to be 0.88 genes/kb. A maximum likelihood phylogenetic analysis suggested that Amentotaxus is sister to Taxus within the Taxaceae family. PMID- 26119123 TI - The complete mitochondrial genomes of two orb-weaving spider Cyrtarachne nagasakiensis (Strand, 1918) and Hypsosinga pygmaea (Sundevall, 1831) (Araneae: Araneidae). AB - The complete mitogenomes of Cyrtarachne nagasakiensis and Hypsosinga pygmaea are determined to be 14,402 and 14,193 bp in length, with the A + T content of 75.7% and 76.1%, respectively. All protein-coding genes in both spiders start with the initiation codons (ATT, ATA, TTA or TTG) that are usually used in Araneae mitogenomes, and terminate with canonical stop codon TAA or TAG except for ND5 in both spiders and ND4L in H. pygmaea, which end with the incomplete codon TA or T instead. Most of the tRNAs lack the potential to form the typically cloverleaf shaped secondary structures and none of tandem repeats are present in the control regions of both spider mitogenomes. The phylogenetic analysis based on the Bayesian inference dataset shows a good resolution of relationship of C. nagasakiensis and H. pygmaea in Araneidae. PMID- 26119124 TI - Complete mitogenomes of Barred angelfish (Paracentropyge multifasciata) and Purplemask angelfish (Paracentropyge venusta) (Teleostei: Pomacanthidae). AB - In this study, we used the next-generation sequencing method to deduce two complete mitogenomes of Barred angelfish (Paracentropyge multifasciata) and Purplemask angelfish (Paracentropyge venusta) for the first time. The assembled mitogenome, consisting of 16 502 bp and 16 641 bp, showing 88.6% identity each other. Both mitogenome follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, 2 ribosomal RNAs genes and a non-coding control region of D-loop. D-loop contains 787 bp in P. multifasciata and 923 bp in P. venusta and locates between tRNA-Pro and tRNA-Phe. The overall GC content is 46.5% for P. multifasciata and 46.2% for P. venusta. Complete mitogenomes of P. multifasciata and P. venusta provide essential and important DNA molecular data for phylogenetic and evolutionary analysis for marine angelfish. PMID- 26119125 TI - Complete chloroplast genome sequence of Adenophora remotiflora (Campanulaceae). AB - The complete chloroplast genome of Adenophora remotiflora was determined in this study. The total genome size was 171 724 bp in length, containing a pair of inverted repeats of 27 437 bp, which were separated by large single copy and small single copy of 105 555 bp and 11 295 bp, respectively. The overall GC contents of the plastid genome were 38.8%. One hundred and twelve unique genes were annotated, including 78 protein coding genes, 30 tRNA genes and 4 rRNA genes. In these genes, 15 genes contained one intron and 2 genes had two introns. A phylogenetic tree showed that Adenophora remotiflora was closely related to Hanabusaya asiatica. PMID- 26119126 TI - Description of the mitochondrial genome of the tree coral Dendrophyllia arbuscula (Anthozoa, Scleractinia). AB - Dendrophylliidae is one of the few monophyletic families within the Scleractinia that embraces zooxanthellate and azooxanthellate species represented by both solitary and colonial forms. Among the exclusively azooxanthellate genera, Dendrophyllia is reported worldwide from 1 to 1200 m deep. To date, although three complete mitochondrial (mt) genomes from representatives of the family are available, only that from Turbinaria peltata has been formally published. Here we describe the complete nucleotide sequence of the mt genome from Dendrophyllia arbuscula that is 19 069 bp in length and comprises two rDNAs, two tRNAs, and 13 protein-coding genes arranged in the canonical scleractinian mt gene order. No genes overlap, resulting in the presence of 18 intergenic spacers and one of the longest scleractinian mt genome sequenced to date. PMID- 26119127 TI - The complete chloroplast genome sequence of Fagopyrum cymosum. AB - Fagopyrum cymosum is a traditional medicinal plant. In this study, the complete chloroplast genome of Fagopyrum cymosum is presented. The total genome size is 160,546 bp in length, containing a pair of inverted repeats (IRs) of 32,598 bp, separated by large single copy (LSC) and small single copy (SSC) of 84,237 bp and 11,014 bp, respectively. Overall GC contents of the genome were 36.9%. The chloroplast genome harbors 126 annotated genes, including 91 protein coding genes, 29 tRNA genes, and six rRNA genes. Eighteen genes contain one or two introns. Phylogenetic analyses indicated a clear evolutionary relationship among species of Caryophyllales. PMID- 26119128 TI - Complete mitogenomes of Whitetail angelfish (Centropyge flavicauda) and Orangeback angelfish (Centropyge acanthops) (Teleostei: Pomacanthidae). AB - Whitetail Angelfish (Centropyge flavicauda) and Orangeback Angelfish (Centropyge acanthops) are known as pygmy angelfish due to their small body size (usually less than two inches). In this study, we used the next-generation sequencing method to deduce two complete mitogenomes of C. flavicauda and C. acanthops for the first time. The assembled mitogenome, consisting of 16 747 bp and 16 748 bp, was showing 99.2% identity each other. Both mitogenome follow the typical vertebrate arrangement, including 13 protein coding genes, 22 transfer RNAs, two ribosomal RNAs genes and a non-coding control region of D-loop. D-loop contains 895 bp in C. flavicauda and 896 bp in C. acanthops and locates between tRNA-Pro and tRNA-Phe. The overall GC content is 46.4% for C. flavicauda and C. acanthops. Complete mitogenomes of C. flavicauda and C. acanthops provide essential and important DNA molecular data for phylogenetic and evolutionary analysis for marine angelfish. PMID- 26119130 TI - Concordant species delimitation from multiple independent evidence: A case study with the Pachytriton brevipes complex (Caudata: Salamandridae). AB - Mitochondrial DNA (mtDNA) sequence data are widely used to delimit species. However, owing to its strict maternal inheritance in most species, mtDNA tracks female dispersion and dispersal only. The accuracy of mtDNA-derived species delimitation is often not explicitly tested using other independent evidence, such as nuclear DNA (nDNA) data, morphological data, or ecological data. Because species are independent evolutionary lineages that can form testable hypotheses, we present a multi-evidence case study on species delimitation that combines statistical approaches with spatially explicit ecological analysis. Montane salamanders of the Pachytriton brevipes complex (Salamandridae) from southeastern China exhibit conservative morphology and variable color patterning that impede species diagnosis. Recent studies proposed splitting P. brevipes into four species based on deep mtDNA divergence but also found discordance between mtDNA and nDNA trees. In this study, we test evolutionary independence of these hypothesized species lineages using two coalescent-based Bayesian methods (Bayes factor and BP&P). Despite significant conflict between mtDNA gene tree and the species phylogeny, the results reinforce the inference of at least four species in the complex as opposed to the one species recognized for over 130 years. Correlative ecological niche modeling and statistical analysis of environmental data indicate that suitable habitats for each species are isolated by incompatible intervening lowland regions, so the likelihood of gene flow among species is very low, which means species lineages should maintain their evolutionary independence. We demonstrate that concordance among independent evidence confirms species status, which forms the basis for accurate assessment of regional biodiversity. PMID- 26119129 TI - Improving thermal dose accuracy in magnetic resonance-guided focused ultrasound surgery: Long-term thermometry using a prior baseline as a reference. AB - PURPOSE: To investigate thermal dose volume (TDV) and non-perfused volume (NPV) of magnetic resonance-guided focused ultrasound (MRgFUS) treatments in patients with soft tissue tumors, and describe a method for MR thermal dosimetry using a baseline reference. MATERIALS AND METHODS: Agreement between TDV and immediate post treatment NPV was evaluated from MRgFUS treatments of five patients with biopsy-proven desmoid tumors. Thermometry data (gradient echo, 3T) were analyzed over the entire course of the treatments to discern temperature errors in the standard approach. The technique searches previously acquired baseline images for a match using 2D normalized cross-correlation and a weighted mean of phase difference images. Thermal dose maps and TDVs were recalculated using the matched baseline and compared to NPV. RESULTS: TDV and NPV showed between 47%-91% disagreement, using the standard immediate baseline method for calculating TDV. Long-term thermometry showed a nonlinear local temperature accrual, where peak additional temperature varied between 4-13 degrees C (mean = 7.8 degrees C) across patients. The prior baseline method could be implemented by finding a previously acquired matching baseline 61% +/- 8% (mean +/- SD) of the time. We found 7%-42% of the disagreement between TDV and NPV was due to errors in thermometry caused by heat accrual. For all patients, the prior baseline method increased the estimated treatment volume and reduced the discrepancies between TDV and NPV (P = 0.023). CONCLUSION: This study presents a mismatch between in treatment and post treatment efficacy measures. The prior baseline approach accounts for local heating and improves the accuracy of thermal dose-predicted volume. PMID- 26119131 TI - Pirfenidone-induced photoleukomelanoderma in a patient with idiopathic pulmonary fibrosis. AB - This is believed to be the first report of pirfenidone-induced photoleukomelanoderma. We discuss the male predominance of photosensitivity induced by pirfenidone. Both ultraviolet (UV)-A and UV-B seemed to be included within the action spectrum of this disorder. Although pirfenidone is a key drug for the treatment of idiopathic pulmonary fibrosis, clinicians should be aware of the high prevalence of photosensitivity and perform sufficient patient education for comprehensive photoprotection before prescription. PMID- 26119133 TI - Cardiac disease in pregnancy - some good news. PMID- 26119134 TI - Changes in the rate of nicotine metabolism across pregnancy: a longitudinal study. AB - AIMS: Increased nicotine metabolism during pregnancy could explain why nicotine replacement therapy (NRT) appears to be less effective on smoking cessation in pregnancy than in non-pregnant smokers, but little is known about nicotine metabolism across pregnancy. This study was conducted to determine when changes in nicotine metabolism occur during pregnancy and to describe the magnitude of these changes. DESIGN: Longitudinal cohort study of pregnant smokers' nicotine metabolite ratio (NMR). SETTING AND PARTICIPANTS: 101 pregnant smokers recruited from hospital antenatal clinics in Nottingham, UK were asked to provide saliva samples at 8-14 weeks (n = 98), 18-22 weeks (n = 65), 32-36 weeks gestation (n = 47), 4 weeks postpartum (n = 44) and 12 weeks postpartum (n = 47). MEASUREMENTS: Nicotine metabolite ratio (NMR) was measured using the ratio of cotinine to its primary metabolite trans-3'-hydroxycotinine. Multi-level modelling was used to detect any overall difference in NMR between time points. The 12 week postpartum NMR was compared with the NMRs collected antenatally and 4 weeks postpartum. FINDINGS: NMR changed over time (p = 0.0006). Compared with NMR at 12 weeks postpartum, NMR was significantly higher at 18-22 weeks (26% higher, 95% CI 12% to 38%) and 32-36 weeks (23% higher, 95% CI 9% to 35%). There was no significant difference between the 8-14 weeks gestation or 4 weeks postpartum NMR and 12 weeks postpartum. CONCLUSIONS: Nicotine metabolism appears to be faster during pregnancy; this faster metabolism is apparent from 18 to 22 weeks of pregnancy and appears to fall by 4 weeks after childbirth. PMID- 26119132 TI - The circulating transcriptome as a source of non-invasive cancer biomarkers: concepts and controversies of non-coding and coding RNA in body fluids. AB - The gold standard for cancer diagnosis remains the histological examination of affected tissue, obtained either by surgical excision, or radiologically guided biopsy. Such procedures however are expensive, not without risk to the patient, and require consistent evaluation by expert pathologists. Consequently, the search for non-invasive tools for the diagnosis and management of cancer has led to great interest in the field of circulating nucleic acids in plasma and serum. An additional benefit of blood-based testing is the ability to carry out screening and repeat sampling on patients undergoing therapy, or monitoring disease progression allowing for the development of a personalized approach to cancer patient management. Despite having been discovered over 60 years ago, the clear clinical potential of circulating nucleic acids, with the notable exception of prenatal diagnostic testing, has yet to translate into the clinic. The recent discovery of non-coding (nc) RNA (in particular micro(mi)RNAs) in the blood has provided fresh impetuous for the field. In this review, we discuss the potential of the circulating transcriptome (coding and ncRNA), as novel cancer biomarkers, the controversy surrounding their origin and biology, and most importantly the hurdles that remain to be overcome if they are really to become part of future clinical practice. PMID- 26119136 TI - Increasing physical activity of children during school recess. AB - Physical activity is crucial for children's health. Fitbit accelerometers were used to measure steps of 6 elementary students during recess. The intervention included reinforcement, self-monitoring, goal setting, and feedback. Steps taken during the intervention phase (M = 1,956 steps) were 47% higher than in baseline (M = 1,326 steps), and the percentage of recess spent in moderate-to-vigorous physical activity was higher during intervention (M = 25%) than in baseline (M = 4%). These methods successfully increased steps during recess and could be used to increase steps in other settings. PMID- 26119137 TI - WNT/beta-catenin signaling affects cell lineage and pluripotency-specific gene expression in bovine blastocysts: prospects for bovine embryonic stem cell derivation. AB - Despite many attempts, true bovine embryonic stem cells (bESC) still remain elusive. The WNT pathway has been associated with stem cell control in vertebrates and its role in pluripotency maintenance has been proven for several mammalian species, including rodents and primates. Thus, we have aimed to investigate the effect of WNT activation on pluripotency marker gene expression in the inner cell mass (ICM) and the trophectoderm (TE) and to study the derivation potential of primary bESC lines from blastocysts obtained in the presence of the glycogen synthase kinase 3 inhibitor (GSK3i). WNT activity clearly exerted a positive effect on pluripotency gene expression in developing bovine embryos, manifested by upregulation of OCT4, NANOG, REX1, SOX2, c-MYC, and KLF4 in the ICM and downregulation of CDX2 in the TE. However, the prolonged exposition of preimplantation embryos to the GSK3i resulted in reduced potential to form primary ESC-like colonies. The results of bESC derivation experiments allowed us to speculate that the derived cell lines may share features of both naive and primed ESCs. Similar to mouse epiblast stem cells and human ESCs, the derived lines grew as flat monolayer colonies intolerant to passaging as single cells. JAK/STAT signaling was indispensable for proper colony formation and proliferation, yet LIF alone was inefficient to support self-renewal. Concomitant with the naive state of mouse ESCs, WNT activity supported by LIF had beneficial effects on cell culture propagation, survival after passage, morphology, and pluripotency-related marker gene expression. Moreover, colonies derived in the presence of LIF and GSK3i maintained KLF4 transcription over several passages, whereas EpiSCs virtually do not express KLF4. PMID- 26119135 TI - Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency. AB - OBJECTIVE: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease. METHODS: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published. RESULTS: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages. CONCLUSION: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach. PMID- 26119138 TI - Surfactant-free Gd(3+)-ion-containing carbon nanotube MRI contrast agents for stem cell labeling. AB - There is an ever increasing interest in developing new stem cell therapies. However, imaging and tracking stem cells in vivo after transplantation remains a serious challenge. In this work, we report new, functionalized and high performance Gd(3+)-ion-containing ultra-short carbon nanotube (US-tube) MRI contrast agent (CA) materials which are highly-water-dispersible (ca. 35 mg ml( 1)) without the need of a surfactant. The new materials have extremely high T1 weighted relaxivities of 90 (mM s)(-1) per Gd(3+) ion at 1.5 T at room temperature and have been used to safely label porcine bone-marrow-derived mesenchymal stem cells for MR imaging. The labeled cells display excellent image contrast in phantom imaging experiments, and TEM images of the labeled cells, in general, reveal small clusters of the CA material located within the cytoplasm with 10(9) Gd(3+) ions per cell. PMID- 26119139 TI - Classification models for subthreshold generalized anxiety disorder in a college population: Implications for prevention. AB - Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders on college campuses and often goes unidentified and untreated. We propose a combined prevention and treatment model composed of evidence-based self help (SH) and guided self-help (GSH) interventions to address this issue. To inform the development of this stepped-care model of intervention delivery, we evaluated results from a population-based anxiety screening of college students. A primary model was developed to illustrate how increasing levels of symptomatology could be linked to prevention/treatment interventions. We used screening data to propose four models of classification for populations at risk for GAD. We then explored the cost considerations of implementing this prevention/treatment stepped-care model. Among 2489 college students (mean age 19.1 years; 67% female), 8.0% (198/2489) met DSM-5 clinical criteria for GAD, in line with expected clinical rates for this population. At-risk Model 1 (subthreshold, but considerable symptoms of anxiety) identified 13.7% of students as potentially at risk for developing GAD. Model 2 (subthreshold, but high GAD symptom severity) identified 13.7%. Model 3 (subthreshold, but symptoms were distressing) identified 12.3%. Model 4 (subthreshold, but considerable worry) identified 17.4%. There was little overlap among these models, with a combined at risk population of 39.4%. The efficiency of these models in identifying those truly at risk and the cost and efficacy of preventive interventions will determine if prevention is viable. Using Model 1 data and conservative cost estimates, we found that a preventive intervention effect size of even 0.2 could make a prevention/treatment model more cost-effective than existing models of "wait-and-treat." PMID- 26119140 TI - Predicting short-term positive affect in individuals with social anxiety disorder: The role of selected personality traits and emotion regulation strategies. AB - Recently, research has provided support for a moderate, inverse relationship between social anxiety and dispositional positive affect. However, the dynamics of this relationship remain poorly understood. The present study evaluates whether certain personality traits and emotion regulation variables predict short term positive affect for individuals with social anxiety disorder and healthy controls. Positive affect as measured by two self-report instruments was assessed before and after two tasks in which the participant conversed with either a friend or a romantic partner. Tests of models examining the hypothesized prospective predictors revealed that the paths did not differ significantly across diagnostic group and both groups showed the hypothesized patterns of endorsement for the emotion regulation variables. Further, a variable reflecting difficulty redirecting oneself when distressed prospectively predicted one measure of positive affect. Additional research is needed to explore further the role of emotion regulation strategies on positive emotions for individuals higher in social anxiety. PMID- 26119141 TI - BDNF Val66Met, stress, and positive mothering: Differential susceptibility model of adolescent trait anxiety. AB - Etiological research has indicated the gene-environment interaction (G * E) on adolescent anxiety. This study aimed to examine how the BDNF Val66Met polymorphism interacted with stressful life events and positive mothering to influence youth trait anxiety. The study sample included 780 community adolescents of Chinese Han ethnicity (M = 13.6, 51.3% females). Participants' trait anxiety, exposure to stressful life events, and mother's warmth-reasoning were assessed by self-reported questionnaires. We found that BDNF Val66Met polymorphism significantly moderated the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. The influences were significantly greater in adolescents carrying one or two Val allele than those with Met/Met genotype. Moreover, the G * E interactions were more consistent with the differential susceptibility than the diathesis-stress model. Adolescents carrying Val allele who were more susceptible to adversity were also more likely to benefit from supportive experiences. These findings provide novel evidence for the role of BDNF Val66Met as a genetic susceptibility modulating the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. We speculate that BDNF Val66Met may moderate anxious youths' responses to mindfulness-based stress reduction program and family-based treatment targeting the enhancement of positive parenting. PMID- 26119142 TI - Effects of pre-incubation of eggs in fresh water and varying sperm concentration on fertilization rate in sterlet sturgeon, Acipenser ruthenus. AB - Standardization of fertilization protocols for sterlet Acipenser ruthenus is crucial for improving reproductive techniques and for conservation purposes. Our objectives were to determine the number of sperm (tested 430,000:1, 43,000:1, 4300:1, 430:1 sperm to egg) required to fertilize eggs and explore how pre incubation of eggs in freshwater for 0min, 0.5min, 1min, and 10min interacts with different sperm ratios. Fertilization success ranged from 29.7% at 430:1 to 84.2% at 430,000:1. Pre-incubation time had no effect on fertilization success at 430,000:1 and 43,000:1 sperm to egg ratios, while it was significant at the 4300:1 and 430:1 ratios. The use of adequate experimental suboptimal sperm to egg ratio revealed a positive effect of pre-incubation time, such that at the 430:1 ratio, 0.5min pre-incubation increased the fertilization rate than 10min. At 0min pre-incubation the proportion of fertilized eggs increased at the 430,000:1 ratio, while at 1min fertilization increased at the 4300:1 ratio. At the 10min pre-incubation time, fertilization increased at the 43,000:1 ratio. Moreover, at the 0.5min pre-incubation time, the 43,000:1 ratio increased the fertilization rate than the 430:1 ratio. Generally, for 430:1 ratio, the fertilization rate is lower than in control. Transmission electron microscopy showed that pre incubation of eggs in water for <10min does not trigger a cortical reaction or the formation of a perivitelline space. Results suggest that with a low sperm to egg ratio 0.5 to 1min pre-incubation of eggs in freshwater prior to fertilization can enhance fertilization rate of sterlet. PMID- 26119144 TI - A new isoflavanone from the trunk of Horsfieldia pandurifolia. AB - A new isoflavanone, 2,2'-epoxy-4'-methoxy-3,7-dihydroxyisoflavanone (1), and a new natural coumaranone, 2-hyroxy-2-(4'-methoxybenzyl)-6-methoxy-3-coumaranone (2), along with 26 known compounds, were first isolated from the trunk of Horsfieldia pandurifolia. Their structures were elucidated by the means of spectroscopic analysis. Compound 1 was assessed for its cytotoxicity against five human tumour lines (HL-60, SMMC-7721, A-549, MCF-7 and SW-480), and the result showed that it has no activity. PMID- 26119145 TI - Glycogen-rich clear cell carcinoma of the breast showing carcinomatous lymphangiosis and extremely aggressive clinical behavior. PMID- 26119146 TI - Reproductive aging and MCM8/9. PMID- 26119147 TI - The higher-order molecular organization of p62/SQSTM1. PMID- 26119148 TI - The 'inflammatory' control of hematopoietic stem cells. PMID- 26119149 TI - Repair of chromosomal breaks by NHEJ. PMID- 26119150 TI - Healed by our inner fish? PMID- 26119151 TI - SUMO in the DNA damage response. PMID- 26119152 TI - GWAS reveal novel IgA nephropathy risk loci. PMID- 26119153 TI - Bidirectional talk between AhR and Oct4. PMID- 26119154 TI - Ubiquitin signals the demise of AMPA receptors. PMID- 26119155 TI - Mitochondriolus: assembling mitoribosomes. PMID- 26119156 TI - Treg: tolerance vs immunity. PMID- 26119157 TI - Vimentin gets a new glow from zinc. PMID- 26119158 TI - CX3CR1 in multiple sclerosis. PMID- 26119160 TI - Development of decellularized scaffolds for stem cell-driven tissue engineering. AB - Organ transplantation is an effective treatment for chronic organ dysfunctioning conditions. However, a dearth of available donor organs for transplantation leads to the death of numerous patients waiting for a suitable organ donor. The potential of decellularized scaffolds, derived from native tissues or organs in the form of scaffolds has been evolved as a promising approach in tissue regenerative medicine for translating functional organ replacements. In recent years, donor organs, such as heart, liver, lung and kidneys, have been reported to provide acellular extracellular matrix (ECM)-based scaffolds through the process called 'decellularization' and proved to show the potential of recellularization with selected cell populations, particularly with stem cells. In fact, decellularized stem cell matrix (DSCM) has also emerged as a potent biological scaffold for controlling stem cell fate and function during tissue organization. Despite the proven potential of decellularized scaffolds in tissue engineering, the molecular mechanism responsible for stem cell interactions with decellularized scaffolds is still unclear. Stem cells interact with, and respond to, various signals/cues emanating from their ECM. The ability to harness the regenerative potential of stem cells via decellularized ECM-based scaffolds has promising implications for tissue-regenerative medicine. Keeping these points in view, this article reviews the current status of decellularized scaffolds for stem cells, with particular focus on: (a) concept and various methods of decellularization; (b) interaction of stem cells with decellularized scaffolds; (c) current recellularization strategies, with associated challenges; and (iv) applications of the decellularized scaffolds in stem cell-driven tissue engineering and regenerative medicine. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26119161 TI - Genetic markers of type 2 diabetes: Progress in genome-wide association studies and clinical application for risk prediction. AB - Type 2 diabetes (T2D) has become a leading public health challenge worldwide. To date, a total of 83 susceptibility loci for T2D have been identified by genome wide association studies (GWAS). Application of meta-analysis and modern genotype imputation approaches to GWAS data from diverse ethnic populations has been key in the effort to discover T2D loci. Genetic information is expected to play a vital role in the prediction of T2D, and many efforts have been made to develop T2D risk models that include both conventional and genetic risk factors. Yet, because most T2D genetic variants identified have small effect size individually (10%-20% increased risk of T2D per risk allele), their clinical utility remains unclear. Most studies report that a genetic risk score combining multiple T2D genetic variants does not substantially improve T2D risk prediction beyond conventional risk factors. In this article, we summarize the recent progress of T2D GWAS and further review the incremental predictive performance of genetic markers for T2D. PMID- 26119162 TI - Effect of serum-derived albumin scaffold and canine adipose tissue-derived mesenchymal stem cells on osteogenesis in canine segmental bone defect model. AB - Composite biological and synthetic grafts with progenitor cells offer an alternative approach to auto- or allografts for fracture repair. This study was conducted to evaluate osteogenesis of autologous serum-derived albumin (ASA) scaffolds seeded with canine adipose tissue-derived mesenchymal stem cells (Ad MSCs) in a canine segmental bone defect model. ASA scaffold was prepared with canine serum using cross-linking and freeze-drying procedures. Beta-tricalcium phosphate (beta-TCP) was mixed at the cross-linking stage. Ad-MSCs were seeded into the scaffold and incubated for one day before implantation. After 16 weeks, the grafts were harvested for histological analysis. The dogs were divided into five groups: control, ASA scaffolds with and without Ad-MSCs, and ASA scaffolds including beta-TCP with and without Ad-MSCs. ASA scaffolds with Ad-MSCs had a significantly larger area of increased opacity at the proximal and distal host cortex-implant interfaces in radiographs 16 weeks after implantation compared to the groups with beta-TCP (p < 0.05). Histomorphometric analysis showed that ASA scaffolds with Ad-MSCs had significantly greater new bone formation than other groups (p < 0.05). These results suggest that Ad-MSCs seeded into ASA scaffolds enhanced osteogenesis in the bone defect model, but that beta-TCP in the ASA scaffold might prevent penetration of the cells required for bone healing. PMID- 26119163 TI - Isolation and immunomodulatory activity of bursal peptide, a novel bursal peptide from the chicken bursa of Fabricius. AB - The bursa of Fabricius (BF), which is unique to birds, serves as the central humoral immune organ and plays a significant role in B lymphocyte differentiation. In this study, a new bursal peptide (BP-IV) was isolated from BF, which promoted colony-forming unit pre-B formation and regulated B cell differentiation. BP-IV also exerted immunomodulatory effects on antigen-specific immune responses via both humoral and cellular immunity in chicken and mice that had been immunized with inactivated avian influenza virus (AIV; H9N2 subtype), including enhancing AIV-specific antibody and cytokine production. The results of this study provided novel insights into the use of a potential candidate reagent for B cell development and future immuno-pharmacological use. PMID- 26119164 TI - Laparoscopic ovariectomy in dogs: comparison between laparoendoscopic single-site and three-portal access. AB - This study was conducted to evaluate the feasibility and therapeutic safety of laparoendoscopic single-site ovariectomy (LESS-OVE) and 3-portal laparoscopic ovariectomy (Lap-OVE) in dogs. Ten female mixed breed dogs were included in the study. Dogs were divided into group 1 (LESS-OVE; n = 5) and group 2 (Lap-OVE; n = 5). All procedures were performed by laparoscopic-skilled surgeons, and the anesthetic protocol was the same for all patients. In both groups, the ovarian vascular pedicle and ligaments were transected using a bipolar vessel sealer/divider device. The mean total surgical time was slightly longer in LESS OVE (36.6 +/- 3.5 min) than Lap-OVE (32.0 +/- 3.0 min); however, the differences were not significant. Perioperative complications were not reported in any group. Both laparoscopic techniques were shown to be equally feasible and safe for patients. However, surgeons found LESS-OVE to require more skill than Lap-OVE. Therefore, additional studies should be conducted to evaluate this novel approach in clinical veterinary practice, and a proper laparoscopic training program for veterinary surgeons should be developed. PMID- 26119165 TI - Chitosan hemostatic dressing for control of hemorrhage from femoral arterial puncture site in dogs. AB - Removal of an introducer-sheath from a femoral artery after completing transarterial embolization of a patent ductus arteriosus can cause life threatening hemorrhage in dogs. In the present study, the effectiveness of chitosan acetate dressing in 10 experimental dogs was tested. Under general anesthesia, an introducer-sheath was placed into the femoral artery with percutaneous puncture using Seldinger's technique. The outer diameter of the introducer-sheaths varied from 3.0 to 4.0 mm with an introducer/artery ratio of 80 to 123%. The artery's diameter was measured using ultrasonography. Following removal of the introducer-sheath, a chitosan acetate dressing was applied to the wound and held in place with manual compression for 10 min. Successful hemostasis was reached on 12 arteries. However, on two arteries, hemorrhage was uncontrollable and led to a hypovolemic shock during 10 min of manual compression. Possible causes of the negative outcome in two dogs were their old age and an introducer-sheath with a too large diameter. The chitosan acetate dressing was easy to use and the artery remained patent. Dogs could walk directly after recovery from anesthesia and their femoral arteries were saved. In conclusion, the outer diameter of the introducer-sheath should not exceed 3 mm or the inner diameter of the artery. PMID- 26119166 TI - Cloned foal derived from in vivo matured horse oocytes aspirated by the short disposable needle system. AB - Transvaginal ultrasound-guided follicle aspiration is one method of obtaining recipient oocytes for equine somatic cell nuclear transfer (SCNT). This study was conducted: (1) to evaluate the possibility of oocyte aspiration from pre ovulatory follicles using a short disposable needle system (14-G) by comparing the oocyte recovery rate with that of a long double lumen needle (12-G); (2) to investigate the developmental competence of recovered oocytes after SCNT and embryo transfer. The recovery rates with the short disposable needle vs. the long needle were not significantly different (47.5% and 35.0%, respectively). Twenty six SCNT embryos were transferred to 13 mares, and one mare delivered a live offspring at Day 342. There was a perfect identity match between the cloned foal and the cell donor after analysis of microsatellite DNA, and the mitochondrial DNA of the cloned foal was identical with that of the oocyte donor. These results demonstrated that the short disposable needle system can be used to recover oocytes to use as cytoplasts for SCNT, in the production of cloned foals and for other applications in equine embryology. PMID- 26119168 TI - Elevated level of renal xanthine oxidase mRNA transcription after nephropathogenic infectious bronchitis virus infection in growing layers. AB - To assess relationships between xanthine oxidase (XOD) and nephropathogenic infectious bronchitis virus (NIBV) infection, 240 growing layers (35 days old) were randomly divided into two groups (infected and control) of 120 chickens each. Each chicken in the control and infected group was intranasally inoculated with 0.2 mL sterile physiological saline and virus, respectively, after which serum antioxidant parameters and renal XOD mRNA expression in growing layers were evaluated at 8, 15 and 22 days post-inoculation (dpi). The results showed that serum glutathione peroxidase and superoxide dismutase activities in the infected group were significantly lower than in the control group at 8 and 15 dpi (p < 0.01), while serum malondialdehyde concentrations were significantly higher (p < 0.01). The serum uric acid was significantly higher than that of the control group at 15 dpi (p < 0.01). In addition, the kidney mRNA transcript level and serum activity of XOD in the infected group was significantly higher than that of the control group at 8, 15 and 22 dpi (p < 0.05). The results indicated that NIBV infection could cause the increases of renal XOD gene transcription and serum XOD activity, leading to hyperuricemia and reduction of antioxidants in the body. PMID- 26119170 TI - Genetic characterization of bovine viral diarrhea virus strains in Beijing, China and innate immune responses of peripheral blood mononuclear cells in persistently infected dairy cattle. AB - To acquire epidemiological data on the bovine viral diarrhea virus (BVDV) and identify cattle persistently infected (PI) with this virus, 4,327 samples from Holstein dairy cows were screened over a four-year period in Beijing, China. Eighteen BVD viruses were isolated, 12 from PI cattle. Based on genetic analysis of their 5'-untranslated region (5'-UTR), the 18 isolates were assigned to subgenotype BVDV-1m, 1a, 1d, 1q, and 1b. To investigate the innate immune responses in the peripheral-blood mononuclear cells of PI cattle, the expression of Toll-like receptors (TLRs), RIG-I-like receptors, interferon-alpha (IFN alpha), IFN-beta, myxovirus (influenza virus) resistance 1 (MX1), and interferon stimulatory gene 15 (ISG15) was assessed by qPCR. When compared with healthy cattle, the expression of TLR-7, IFN-alpha, and IFN-beta mRNA was downregulated, but the expression of MX1 and ISG-15 mRNA was upregulated in PI cattle. Immunoblotting analysis revealed that the expression of interferon regulatory factor 3 (IRF-3) and IRF-7 was lower in PI cattle than in healthy cattle. Thus, BVDV-1m and 1a are the predominant subgenotypes in the Beijing region, and the strains are highly divergent. Our findings also suggest that the TLR-7/IRF-7 signaling pathway plays a role in evasion of host restriction by BVDV. PMID- 26119172 TI - Profiling of antimicrobial resistance and plasmid replicon types in beta lactamase producing Escherichia coli isolated from Korean beef cattle. AB - In this study, 78 isolates of Escherichia coli isolated from Korean beef cattle farms were investigated for the production of extended-spectrum beta-lactamase (ESBL) and/or AmpC beta-lactamase. In the disc diffusion test with ampicillin, amoxicillin, cephalothin, ceftiofur, cefotaxime, ceftazidime, and cefoxitin, 38.5% of the isolates showed resistance to all of ampicillin, amoxicillin, and cephalothin. The double disc synergy method revealed that none of the isolates produced ESBL or AmpC beta-lactamases. DNA sequencing showed that all isolates encoded genes for TEM-1-type beta-lactamase. Moreover, 78.2% of the isolates transferred the TEM-1-type beta-lactamase gene via conjugation. In plasmid replicon typing of all donors, IncFIB and IncFIA were identified in 71.4% and 41.0% of plasmids, respectively. In transconjugants, IncFIB and IncFIA were the most frequent types detected (61.5% and 41.0%, respectively). Overall, the present study indicates that selection pressures of antimicrobials on beta lactamases in beef cattle may be low relative to other livestock animals in Korea. Moreover, to reduce selection pressure and dissemination of beta lactamase, the long-term surveillance of antimicrobial use in domestic beef cattle should be established. PMID- 26119173 TI - Success, failure and ambiguity of the dilution effect among competitors. AB - It remains challenging to predict variation in the magnitude of disease outbreaks. The dilution effect seeks to explain this variation by linking multiple host species to disease transmission. It predicts that disease risk increases for a focal host when host species diversity declines. However, when an increase in species diversity does not reduce disease, we are often unable to diagnose why. Here, we increase mechanistic and predictive clarity of the dilution effect with a general trait-based model of disease transmission in multi host communities. Then, we parameterise and empirically test our model with a multi-generational case study of planktonic disease. The model-experiment combination shows that hosts that vary in competitive ability (R*) and potential to spread disease (R0 ) can produce three qualitatively disparate outcomes of dilution on disease: the dilution effect can succeed, fail, or be ambiguous/irrelevant. PMID- 26119174 TI - Analytical and clinical performance of Abbott RealTime MTB, an assay for detection of Mycobacterium tuberculosis in pulmonary specimens. AB - Nucleic acid amplification test (NAAT)-based assays provide fast and sensitive results compared to conventional TB tests. The performance of the new Abbott Molecular MTB assay for the qualitative detection of MTB complex using the automated m2000TM system or manual sample preparation is summarized in this paper. The assay detects eight MTB complex subspecies. The observed limit of detection (LOD) when used to test an MTB H37Rv panel was 2.45 colony forming units (cfu)/mL, while the claimed assay LOD with this MTB strain is 17 cfu/mL. No cross reactivity, or carryover were observed in the study. The clinical sensitivity of the assay was 93% overall; 99% in smear positive, culture positive specimens, and 81% in smear negative, culture positive samples. The clinical specificity was 97%. The inhibition rate in the study was 0.34%. The data suggest that Abbott RealTime MTB is a reliable, robust and sensitive assay for the molecular detection of MTB. PMID- 26119176 TI - The Role of Patient Factors, Cancer Characteristics, and Treatment Patterns in the Cost of Care for Medicare Beneficiaries with Breast Cancer. AB - OBJECTIVE: To characterize Medicare expenditures on initial breast cancer care and examine variation in expenditures across hospital referral regions (HRRs). DATA SOURCE: We identified 29,110 women with localized breast cancer diagnosed in 2005-2008 and matched controls from the Surveillance, Epidemiology, and End Results-Medicare linked database. STUDY DESIGN: Using hierarchical generalized linear models, we estimated per patient Medicare expenditure on initial breast cancer care across HRRs and assessed the contribution of patient, cancer, and treatment factors to regional variation via incremental models. PRINCIPAL FINDINGS: Mean Medicare expenditure for initial breast cancer care was $19,255 per patient. The average expenditures varied from $15,053 in the lowest-spending HRR quintile to $23,480 in the highest-spending HRR quintile. Patient sociodemographic, comorbidity, and tumor characteristics explained only 1.8 percent of the difference in expenditures between the lowest- and highest spending quintiles, while use of specific treatment modalities explained 14.5 percent of the difference. Medicare spending on radiation therapy differed the most across the quintiles, with the use of intensity modulated radiation therapy increasing from 1.7 percent in the lowest-spending quintile to 11.6 percent in the highest-spending quintile. CONCLUSIONS: Medicare expenditures on initial breast cancer care vary substantially across regions. Treatment factors are major contributors to the variation. PMID- 26119175 TI - Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy. AB - Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel-Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch through Notch1/Jagged1 signaling, Wnt by Wnt/beta- catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2- dependent and TGF-beta-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy. PMID- 26119178 TI - Putative role of border cells in generating spontaneous morphological activity within Kolliker's organ. AB - Kolliker's organ is a transient epithelial structure, comprising a major part of the organ of Corti during pre-hearing stages of development. The auditory system is spontaneously active during development, which serves to retain and refine neural connections. Kolliker's organ is considered a key candidate for generating such spontaneous activity, most likely through purinergic (P2 receptor) signalling and inner hair cell (IHC) activation. Associated with the spontaneous neural activity, ATP released locally by epithelial cells induces rhythmic morphological changes within Kolliker's organ, the purpose of which is not understood. These changes are accompanied by a shift in cellular refractive index, allowing optical detection of this activity in real-time. Using this principle, we investigated the origin of spontaneous morphological activity within Kolliker's organ. Apical turns of Wistar rat cochleae (P9-11) were dissected, and the purinergic involvement was studied following acute tissue exposure to a P2 receptor agonist (ATPgammaS) and antagonist (suramin). ATPgammaS induced a sustained darkening throughout Kolliker's organ, reversed by suramin. This effect was most pronounced in the region closest to the inner hair cells, which also displayed the highest frequency of intrinsic morphological events. Additionally, suramin alone induced swelling of this region, suggesting a tight regulation of cell volume by ATP-mediated mechanisms. Histological analysis of cochlear tissues demonstrates the most profound volume changes in the border cell region immediately adjacent to the IHCs. Together, these results underline the role of purinergic signalling in initiating morphological events within Kolliker's organ, and suggest a key involvement of border cells surrounding IHCs in regulating this spontaneous activity. PMID- 26119179 TI - Synaptic encoding and processing of auditory information in physiology and disease. PMID- 26119177 TI - Decreased temporal precision of neuronal signaling as a candidate mechanism of auditory processing disorder. AB - The sense of hearing is the fastest of our senses and provides the first all-or none action potential in the auditory nerve in less than four milliseconds. Short stimulus evoked latencies and their minimal variability are hallmarks of auditory processing from spiral ganglia to cortex. Here, we review how even small changes in first spike latencies (FSL) and their variability (jitter) impact auditory temporal processing. We discuss a number of mouse models with degraded FSL/jitter whose mutations occur exclusively in the central auditory system and therefore might serve as candidates to investigate the cellular mechanisms underlying auditory processing disorders (APD). PMID- 26119180 TI - Influence of Guest Exchange on the Magnetization Dynamics of Dilanthanide Single Molecule-Magnet Nodes within a Metal-Organic Framework. AB - Multitopic organic linkers can provide a means to organize metal cluster nodes in a regular three-dimensional array. Herein, we show that isonicotinic acid N-oxide (HINO) serves as the linker in the formation of a metal-organic framework featuring Dy2 single-molecule magnets as nodes. Importantly, guest solvent exchange induces a reversible single-crystal to single-crystal transformation between the phases Dy2(INO)4(NO3)2?2 solvent (solvent=DMF (Dy2-DMF), CH3CN (Dy2 CH3CN)), thereby switching the effective magnetic relaxation barrier (determined by ac magnetic susceptibility measurements) between a negligible value for Dy2 DMF and 76 cm(-1) for Dy2-CH3CN. Ab initio calculations indicate that this difference arises not from a significant change in the intrinsic relaxation barrier of the Dy2 nodes, but rather from a slowing of the relaxation rate of incoherent quantum tunneling of the magnetization by two orders of magnitude. PMID- 26119181 TI - Integrated care in action: opening the "black box" of implementation. AB - The aim of this contribution is to explain how healthcare professionals implement policies for integrated care. More specifically, we aim to understand how these policies are received, interpreted and executed by primary care professionals. By opening the "black box" of policy implementation, we also explain how and why the process of implementation of the same policy diverges in practice. The research is framed according to both the neo-institutional and the change management perspectives. The empirical investigation is conducted through a documental analysis and a multiple-embedded case study. The results show that three forces affect and explain differences in the implementation processes: the unstable level of internal communication among the professionals involved, the limited use of power to resist to change and the poor learning process on the part of both the professionals and policy makers. The pressure of external institutions does not play a role in shaping the process. Through our study, we further knowledge about how healthcare professionals implement policies for integrated care, and we believe this is interesting, according to emerging evidence that variations in the effectiveness of policy outcomes may be explained by choices and potential distortions made during the initial stages of the policy implementation process. Copyright (c) 2015 John Wiley & Sons, Ltd. StartCopTextCopyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26119182 TI - CD21 -/low B cells: A Snapshot of a Unique B Cell Subset in Health and Disease. AB - B cells represent one of the cellular components of the immune system that protects the individual from invading pathogens. In response to the invader, these cells differentiate into plasma cells and produce large amounts of antibodies that bind to and eliminate the pathogen. A hallmark of autoimmune diseases is the production of autoantibodies i.e. antibodies that recognize self. Those that are considered pathogenic can damage tissues and organs, either by direct binding or when deposited as immune complexes. For decades, B cells have been considered to play a major role in autoimmune diseases by antibody production. However, as pathogenic autoantibodies appear to derive mainly from T cell dependent responses, T cells have been the focus for many years. The successful treatment of patients with autoimmune diseases with either B cell depletion therapy (rituximab) or inhibition of B cell survival (belimumab), suggested that not only the autoantibodies but also other B cell features are important. This has caused a surge of interest in B cells and their biology resulting in the identification of various subsets e.g. regulatory B cells, several memory B cell subsets etc. Also, in other conditions such as chronic viral infections and primary immunodeficiency, several B cell subsets with unique characteristics have been identified. In this review, we will discuss one of these subsets, a subset that is expanded in conditions characterized by chronic immune stimulation. This B cell subset lacks, or expresses low, surface levels of the complement receptor 2 (CD21) and has therefore been termed CD21(-/low) B cells. PMID- 26119184 TI - Regulation and mechanism of leptin on lipid metabolism in ovarian follicle cells from yellow catfish Pelteobagrus fulvidraco. AB - The present study was conducted to determine the effect of leptin on lipid metabolism in ovarian follicle cells of yellow catfish Pelteobagrus fulvidraco. For that purpose, primary ovarian follicle cells were isolated from yellow catfish, cultured and subjected to different treatments (control, 0.1% DMSO, 500ng/ml leptin, 500ng/ml leptin plus 100MUM wortmannin, 500ng/ml leptin plus 50nM AG490, respectively) for 48h. Intracellular triglyceride (TG) content, the activities (CPT I, FAS, G6PD, and 6PGD) and/or expression level of several enzymes (CPT I, FAS, G6PD, 6PGD, ACCa and ACCb), as well as the mRNA expression of transcription factors (PPARalpha, PPARgamma and SREBP-1) involved in lipid metabolism were determined. Recombinant human leptin (rt-hLEP) incubation significantly reduced intracellular TG content, activities and mRNA levels of FAS, G6PD and 6PGD, SREBP-1 and PPARgamma, but enhanced activity and mRNA level of CPT I, PPARalpha and ACCa. Specific inhibitors AG490 and wortmannin of JAK STAT and IRS-PI3K signaling pathways prevented leptin-induced changes, indicating that JAK-STAT and IRS-PI3K signaling pathways were involved in the process of leptin-induced changes of lipid metabolism. Based on these observations above, for the first time, our study indicated that leptin reduced lipid deposition by activating lipolysis and suppressing lipogenesis in ovarian follicles of yellow catfish, and both JAK-STAT and IRS-PI3K signaling pathways were involved in the changes of leptin-induced lipid metabolism. PMID- 26119183 TI - Bacterial population and biodegradation potential in chronically crude oil contaminated marine sediments are strongly linked to temperature. AB - Two of the largest crude oil-polluted areas in the world are the semi-enclosed Mediterranean and Red Seas, but the effect of chronic pollution remains incompletely understood on a large scale. We compared the influence of environmental and geographical constraints and anthropogenic forces (hydrocarbon input) on bacterial communities in eight geographically separated oil-polluted sites along the coastlines of the Mediterranean and Red Seas. The differences in community compositions and their biodegradation potential were primarily associated (P < 0.05) with both temperature and chemical diversity. Furthermore, we observed a link between temperature and chemical and biological diversity that was stronger in chronically polluted sites than in pristine ones where accidental oil spills occurred. We propose that low temperature increases bacterial richness while decreasing catabolic diversity and that chronic pollution promotes catabolic diversification. Our results further suggest that the bacterial populations in chronically polluted sites may respond more promptly in degrading petroleum after accidental oil spills. PMID- 26119185 TI - Effects of age and reproductive experience on the distribution of prolactin and growth hormone secreting cells in the anterior pituitary of a passerine. AB - Plasma prolactin (PRL) is released from lactotrophs in the anterior pituitary. As plasma PRL levels rise during incubation in domestic fowl, the number of lactotrophs (PRL-immunoreactive, PRL-IR cells) increases while the number of growth hormone secreting cells, somatotrophs (GH-IR cells), declines. We measured plasma PRL levels using radioimmunoassay (RIA) and examined the distribution of lactotrophs and somatotrophs in the anterior pituitary of breeding and nonbreeding zebra finches of known ages with and without prior breeding experience using fluorescent immunohistochemistry (IHC). Plasma PRL levels were higher in breeding than in nonbreeding birds, regardless of age, sex, or previous breeding history. PRL-IR cells were localized primarily, but not exclusively, to the cephalic aspect of the anterior pituitary (AP) and along the ventral margin. Birds with prior reproductive experience had more PRL-IR cells than birds with no prior reproductive experience and breeders had slightly higher PRL-IR cell counts than did nonbreeders, but there was no correlation between the number of PRL-IR cells and plasma PRL levels. GH-IR cells were concentrated in the caudal aspect of the AP with some cells in the cephalic lobe, but numbers did not differ between any of the groups studied. An increase in PRL-IR cells corresponded with an increase in GH-IR cells. An increase in lactotroph number with reproductive experience in zebra finches may facilitate future reproductive events by allowing for more robust PRL secretion and increased reproductive success. PMID- 26119186 TI - Long-term follow-up of essential thrombocythemia patients treated with anagrelide: subgroup analysis according to JAK2/CALR/MPL mutational status. AB - BACKGROUND: Anagrelide represents a treatment option for essential thrombocythemia, although its place in therapy remains controversial. AIM: To assess the impact of mutational status in response rates and development of adverse events during long-term use of anagrelide. METHODS: We retrospectively evaluated 67 patients with essential thrombocythemia treated with anagrelide during 68 (4-176) months. RESULTS: Mutational frequencies were 46.3%, 28.3%, and 1.5% for JAK2V617F, CALR and MPL mutations. Anagrelide yielded a high rate of hematologic responses, which were complete in 49.25% and partial in 46.25%, without differences among molecular subsets. The rate of thrombosis during treatment was one per 100 patient-years, without excess bleeding. Anemia was the major adverse event, 30.3% at 5-yr follow-up, being more frequent in CALR(+) (P < 0.05). Myelofibrotic transformation developed in 14.9% (12.9%, 21%, and 12.5% in JAK2V617F(+), CALR(+), and triple-negative patients, respectively, P = NS) and those treated >60 months were at higher risk, OR (95% CI) 9.32 (1.1-78.5), P < 0.01, indicating the need for bone marrow monitoring during prolonged treatment. CONCLUSION: Although CALR(+) patients were at higher risk of developing anemia, anagrelide proved effective among all molecular subsets, indicating that mutational status does not seem to represent a major determinant of choice of cytoreductive treatment among essential thrombocythemia therapies. PMID- 26119187 TI - Microbiological diversity associated with the spontaneous wet method of coffee fermentation. AB - The evaluation of the microbiota present during coffee wet fermentation was done in two distinct regions of Minas Gerais, Brazil: one farm in the South of Minas Gerais (Lavras=L) and another farm in the savannah region (Monte Carmelo=MC). The yeast population ranged from 2.48 to 4.92 log CFU/g and from 2 to 4.81 log CFU/g, the mesophilic bacteria population ranged from 3.83 to 8.47 log CFU/g and from 5.37 to 7.36 log CFU/g, and the LAB population ranged from 2.57 to 5.66 log CFU/g and from 3.40 to 4.49 log CFU/g in the L and MC farms, respectively. Meyerozyma caribbica and Hanseniaspora uvarum were the dominant yeasts in coffee wet fermentation at L farm, and Torulaspora delbrueckii was the dominant yeast at MC farm. The species Staphylococcus warneri and Erwinia persicina were the predominant bacteria at L farm, and Enterobacter asburiae and Leuconostoc mesenteroides were the dominant species at MC farm. Lactic acid was the principal acid detected, reaching 2.33 g/kg at L farm and 1.40 g/kg at MC farm by the end of the process. The volatiles composition was similar for roasted coffee from the two different regions and furans, acids, and alcohol were the main groups detected. Temporal Dominance Sensation (TDS) analyses showed that the coffee beverage from L farm was dominated by citrus and herbaceous sensory characteristics, while the coffee from MC farm was dominated by citrus, herbaceous, and nuts sensory characteristics. Evaluating the microbiota in these two regions was important in improving the knowledge of the microbial species present during coffee wet fermentation in Brazil. PMID- 26119188 TI - Potential spoilage yeasts in winery environments: Characterization and proteomic analysis of Trigonopsis cantarellii. AB - Wine microbiota is complex and includes a wide diversity of yeast species. Few of them are able to survive under the restrictive conditions of dry red wines. In our study we detected and identified seven yeast species of the order Saccharomycetales that can be considered potential spoilers of wines due to physiological traits such as acidogenic metabolism and off-odor generation: Arthroascus schoenii, Candida ishiwadae, Meyerozyma guilliermondii, Pichia holstii, Pichia manshurica, Trigonopsis cantarellii, and Trigonopsis variabilis. Based on the prevalence of T. cantarellii isolates in the wine samples of our study, we further characterized this species, determined molecular and phenotypic features, and performed a proteomic analysis to identify differentially expressed proteins at mid-exponential growth phase in the presence of ethanol in the culture broth. This yeast species is shown to be able to grow in the presence of ethanol by expressing heat shock proteins (Hsp70, Hsp71) and a DNA damage-related protein (Rad24), and to be able to confer spoilage characteristics on wine. PMID- 26119189 TI - Prediction of spoilage of tropical shrimp (Penaeus notialis) under dynamic temperature regimes. AB - The spoilage activity of Pseudomonas psychrophila and Carnobacterium maltaromaticum, two tropical shrimp (Penaeus notialis) spoilage organisms, was assessed in cooked shrimps stored at 0 to 28 degrees C. Microbiological, chemical and sensory analyses were performed during storage. P. psychrophila had a higher growth rate and showed a higher spoilage activity at temperatures from 0 to 15 degrees C, while at 28 degrees C, C. maltaromaticum had a higher growth rate. The spoilage activity of P. psychrophila was found to be higher in cooked shrimp than in fresh shrimp. Observed shelf-life data of shrimps stored at constant temperatures were used to validate a previously developed model that predicts tropical shrimp shelf-life at constant storage temperatures. Models predicting the growth of the spoilage organisms as a function of temperature were constructed. The validation of these models under dynamic storage temperatures simulating temperature fluctuation in the shrimp supply chain showed that they can be used to predict the shelf-life of cooked and fresh tropical shrimps. PMID- 26119190 TI - Restoring the selectivity of modified charcoal cefoperazone deoxycholate agar for the isolation of Campylobacter species using tazobactam, a beta-lactamase inhibitor. AB - Extended spectrum beta-lactamase (ESBL) producing Escherichia coli have emerged as a contaminant on modified charcoal cefoperazone deoxycholate agar (mCCDA) when attempting to selectively isolate Campylobacter spp. from poultry. E. coli are particularly problematic given their ability to grow under microaerophilic conditions and have been shown to outcompete Campylobacter species making Campylobacter detection or enumeration difficult. This paper recommends a novel method for restoring the selectivity of mCCDA using tazobactam, a beta-lactamase inhibitor. The method significantly inhibited ESBL E. coli growth in spiked or naturally contaminated broiler caecal samples (p<=0.01) when compared to conventional mCCDA. This effect was seen at concentrations as low as 1mg/L tazobactam. TmCCDA(1) was found to inhibit up to 8 log10 CFU/mL of ESBL E. coli in mixed pure cultures and 7.5 log10 CFU/mL in caecal samples. Furthermore TmCCDA concentrations up to 10 mg/L had no statistically significant inhibitory effect (p>=0.05) on the recovery of a panel of 27 Campylobacter jejuni and 5 Campylobacter coli isolates when compared to conventional mCCDA. From this study it is suggested that tazobactam, which is more chemically stable than clavulanic acid or sulbactam, is more suitable for restoring the selectivity of mCCDA for the detection or isolation of campylobacters. PMID- 26119191 TI - Influence of 1 Alpha, 25-Dihydroxyvitamin D3 on T Helper 17 Cells and Related Cytokines in Systemic Lupus Erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Emerging data suggests that T helper 17 (Th17) cells play a pathogenic role in SLE and the increased number of these cells correlates with disease activity. In recent years, 1alpha, 25-dihydroxyvitamin D3 (1,25VitD3) has been considered as an immunomodulatory factor. OBJECTIVE: To investigate the effect of 1,25VitD3 on Th17 cells and on the expression of related cytokines in SLE patients. METHOD: Thirty SLE patients (newly diagnosed or in remission) were sampled for 10 ml whole blood to isolate peripheral blood mononuclear cells (PBMCs) using Ficoll-Hypaque density gradient centrifugation. Isolated cells were cultured in the presence and absence of 50 nM 1,25VitD3. After incubation, cells were harvested and stimulated for 4-5 hours with phorbol myristate acetate (PMA) and ionomycin in the presence of brefeldin A. IL-17 secreting cells were analyzed by flowcytometry. RNA was extracted from cultured cells, cDNA was synthesized, and the expression levels of IL-6, IL-17, IL-23 and TGF-beta genes were assessed by real-time PCR. RESULTS: The percentage of Th17 cells (CD3+CD8- IL-17+ T cells) decreased significantly in 1,25VitD3-treated cells (3.67 +/- 2.43%) compared to untreated cells (4.65 +/- 2.75%)( p=0.003). The expression of TGF-beta up regulated (1.38-fold) and the expression of IL-6 (50%), IL-17 (27%) and IL-23 (64%) down regulated after 1,25VitD3 treatment. CONCLUSION: This study showed that 1,25VitD3 modulates Th17 related pathways in SLE patients and revealed the immunomodulatory effect of 1,25VitD3 on the Th17 mediated autoimmunity. PMID- 26119192 TI - Effect of Neutrophils on Nitric Oxide Production from Stimulated Macrophages. AB - BACKGROUND: During the initial phase of an infection, there is an upregulation of inducible nitric oxide synthase in the macrophages for the production of nitric oxide. This is followed by the recruitment of polymorphonuclear leukocytes (neutrophils) which release arginase. Arginase competes with inducible nitric oxide synthase for a common substrate L-arginine. OBJECTIVE: To investigate whether the entry of neutrophils and release of arginase can interfere with nitric oxide production from stimulated mouse macrophages. METHODS: Neutrophils were isolated from human blood and stimulated with cytodex-3 beads. Cultured macrophages were stimulated with lipopolysaccharide and interferon gamma with or without N (G)-nitro-L-arginine methyl ester or N (omega)-hydroxy-nor-L-arginine. Measurement of NO2-/NO3- and urea were done using the spectrophotometer. RESULTS: A significantly higher level of nitric oxide production from stimulated macrophages was observed compared to control. There was a decrease in nitric oxide production when stimulated macrophages were treated with the supernatant from activated neutrophils (p<0.05). CONCLUSION: Arginase from neutrophils can modulate nitric oxide production from activated macrophages which may affect the course of infection by intracellular bacteria. PMID- 26119193 TI - Lipopolysaccharide Induced Activation of Toll Like Receptor 4 in Isolated Rat Heart Suggests a Local Immune Response in Myocardium. AB - BACKGROUND: Myocardial dysfunction is one of the major complications in patients with sepsis where there is a relationship between the blood level of cytokines and the onset of myocardial depression. In many cases of sepsis, the presence of Lipopolysaccharide (LPS) has been established. LPS Binding Protein (LBP) bound endotoxin is recognized by CD14/toll-like receptor-4 (TLR4) complexes in innate immune cells which stimulates TNF-alpha release. OBJECTIVES: To investigate whether isolated rat heart is capable of producing TNF-alpha locally through TLR4 activation by LPS. METHODS: Using langendorff method, LPS in 120 mL of the modified Krebs-Henseleit buffer solution (KHBS) at final concentration of 1 ug/mL was perfused at recycling mode. The effect of LPS on cardiac function was evaluated. To assess the TLR4 activity and TNF-alpha release, western blotting, real time-PCR, and ELISA were used. RESULTS: Compared with control, coronary perfusion pressure (CPP) as well as left ventricular developed pressure (LVDP), maximum and minimum rates of the left ventricular developed pressure (dP/dtmax; dP/dtmin; p<0.001) were depressed to a maximum level after 180 minutes recycling with LPS. This myocardial depression was associated with a significant increase in TLR4 expression (p<0.01), MyD88 activity (p<0.01) and TNF-alpha (p<0.05) concentration in the heart tissue. CONCLUSION: The results of this study show that heart is capable of producing TNF-alpha through TLR4 and MyD88 activation independent of classic immune system and suggest a local immune response. PMID- 26119194 TI - Investigating the Association of IL-17A and IL-17F with Susceptibility to Pre eclampsia in Iranian Women. AB - BACKGROUND: Pre-eclampsia (PE) is one of the most important and life-threatening pregnancy disorders that affect at least 3-5% of all pregnancies. Imbalance in helper T cell functions may play a role in predisposing to PE or severity of the disease. Elevated frequencies of Th17 cells in the peripheral blood of PE patients have been reported. Several single nucleotide polymorphisms (SNP) within IL-17 gene have been identified that may affect the IL-17 production. OBJECTIVES: To investigate the association between IL-17A (-197A/G) and IL-17F (+7488T/C) gene polymorphisms and susceptibility to PE in a group of Iranian women. Moreover, to study any correlation of the polymorphisms data with the level of IL 17, at mRNA level in the paternal and maternal parts of the placentas and also at protein level in the peripheral and placental blood samples. METHODS: A group of 261 PE patients and 278 age-matched healthy women with at least two previous normal pregnancies formed the cases and controls of this study. IL-17A (-197A/G) and IL-17F (+7488T/C) polymorphisms were genotyped using PCR-RFLP method. The protein level of IL-17A was assessed in the sera of 40 PE and 40 healthy women using ELISA method and mRNA expression was also measured in placental samples of 19 PE and 19 control women using Q-PCR technique. RESULTS: Statistical analysis indicated that there were no differences in genotype, allele or haplotype frequencies regarding the studied SNPs between cases and controls. The level of IL-17A was elevated in the placental blood and the fetal tissue at protein and mRNA levels (p< 0.009 and p<0.000, respectively) in PE as compared with the healthy women. CONCLUSIONS: The effect of IL-17 cytokine in pre-eclampsia is not due to the studied cytokine polymorphisms but local production of IL-17 might have an effect on the predisposition to the disease. PMID- 26119195 TI - Increased Expression of Two Alternative Spliced Variants of CD1d Molecule in Human Gastric Cancer. AB - BACKGROUND: CD1d presents glycolipid antigens to invariant natural killer T (iNKT) cells. The role of CD1d in the development of peptic ulcer and gastric cancer has not been revealed, yet. OBJECTIVE: To clarify the expression of alternatively spliced variants of CD1d in peptic ulcer and gastric cancer. METHODS: Patients with dyspepsia were selected and divided into three groups of non-ulcer dyspepsia (NUD), peptic ulcer disease (PUD), and gastric cancer (GC), according to their endoscopic and histopathological examinations. H. pylori infection was diagnosed by rapid urease test and histopathology. The expression levels of V2, V4, and V5 spliced variants of CD1d molecule were determined by quantitative Reverse Transcriptase PCR. RESULTS: Relative gene expression levels of V4 were higher in GC patients (n=37) than those in NUD (n=49) and PUD (n=51) groups (p<0.05 and p<0.01, respectively). Moreover, GC patients showed higher expression levels of V5 compared to NUD and PUD groups (p<0.001 and p<0.001, respectively). Positive correlation coefficients were attained between V4 and V5 expression in patients with PUD (r=0.734, p<0.0001) and GC (r=0.423, p<0.01), but not in patients with NUD. Among NUD patients, the expression levels of V4, but not V5, were higher in H. pylori-positive patients than in H. pylori-negative ones (p<0.01). CONCLUSION: Collectively, both membrane-bound (V4) and soluble (V5) isoforms of CD1d were over-expressed in gastric tumor tissues, suggesting that they are involved in anti-tumor immune responses. PMID- 26119196 TI - Childhood Autoimmune Hepatitis in Bahrain: a Tertiary Center Experience. AB - BACKGROUND: Autoimmune hepatitis (AIH) in childhood has variable modes of presentation, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. In AIH, the liver biopsy histopathology shows inflammation in addition to presence of serum autoimmune antibodies and increased levels of immunoglobulin G (IgG). OBJECTIVES: To investigate the situation of childhood autoimmune hepatitis in Bahrain and to compare it with other studies worldwide. METHODS: A retrospective study describing the AIH pediatric cases diagnosed during the period of Jan 2005 to Dec 2009. We report the clinical, biochemical, histopathological, and immunological findings, mainly autoimmune profile, in addition to response to treatment, of Bahraini children with autoimmune hepatitis. RESULTS: Five Bahraini children, three females and two males were diagnosed as autoimmune hepatitis during the study period. Their ages at presentation ranged from 9 to 15 (median 10.6) years. One of our patients had a fulminating type. Two had other autoimmune related conditions, namely autoimmune sclerosing cholangitis and ulcerative colitis. All were AIH type 1. Variable response to conventional immunosuppressive therapy was found, from an excellent response with good prognosis, to cirrhosis, hepatic failure and liver transplantation. CONCLUSION: Childhood AIH is a rare medical problem in Bahrain, with both sexes affected and a variable response to immunosuppressive therapy. PMID- 26119197 TI - The Effect of HLA-DRB1 on Cholecystitis. AB - BACKGROUND: Cholecystitis is one of the major digestive diseases. Its prevalence is particularly high in some populations. Significant risk factors associated with cholecystitis include age, sex, obesity, diet, parity and type 2 diabetes. OBJECTIVE: To determine the association between HLA-DRB1 and cholecystitis. METHODS: This case-control study included forty Iraqi Arab patients who had cholecystitis with multiple calculi treated by cholecystectomy admitted in the surgical ward at Al-Kindy Teaching Hospital Baghdad between September -2013 to June -2014. The control group consisted of forty healthy volunteers among the staff of Al-Kindy College of Medicine. Control and cholecystitis patients groups were typed for identifying the DRB1* alleles using DNA-based methodology (PCR SSOP). RESULTS: There was an increased frequency of HLA-DRB1*0301 in patients with cholecystitis compared with healthy controls (p=0.0442, odd ratio=4.1111, 95% CI: 1.0372-16.2949). CONCLUSION: HLA-DRB1*0301, as a genetic factor, seems to have an association with cholecystitis. PMID- 26119198 TI - Q2DSTD NMR deciphers epitope-mapping variability for peptide recognition of integrin alphavbeta6. AB - Integrin alphavbeta6 is a cell surface arginine-glycine-aspartic acid (RGD) specific heterodimeric glycoprotein that is only expressed on epithelia during processes of tissue remodelling, including cancer. The specificity and molecular nature of interactions toward this integrin are poorly understood and new insights into such processes are important to cell biologists and pharmaceutical drug discovery. This study demonstrates the application of quantitative two dimensional saturation transfer (Q2DSTD) NMR to obtain precise details of peptide interactions with integrin alphavbeta6 and their correlation to specificity for the integrin. This approach highlights subtle but significant differences in ligand contact by three related 21-mer peptides: FMDV2, an alphavbeta6 specific peptide and DBD1 and LAP2T1 peptides that bind many alphav integrins in addition to alphavbeta6. FMDV2 and DBD1 differ only by the cyclisation of DBD1; a process that removes alphavbeta6 specificity. Q2DSTD NMR demonstrates these peptides experience significantly different interactions with the integrin; FMDV contacts primarily through four residues: 6Leu, 10Leu, 12Val and 13Leu, whereas DBD1 and LAP2T1 have more widespread contacts across their sequences. Q2DSTD NMR combined two-dimensional STD with quantitation by considering the relaxation of the ligand (CRL) to provide precise ligand contact information. This study also examines the role of CRL in the Q2DSTD process and how quantitation modifies STD data and unravels epitope-mapping variability to provide precise results that differentiate interactions at the atomic level for each peptide. PMID- 26119199 TI - Clinical and microbiological features of infective endocarditis caused by aerococci. AB - PURPOSE: To define the clinical presentation of aerococcal infective endocarditis (IE) and the prevalence of synergy between penicillin and gentamicin on aerococcal isolates. METHODS: Cases of aerococcal IE between 2002 and 2014 were identified in the Swedish Registry of Infective Endocarditis (SRIE). MALDI-TOF MS was used to confirm species determination. The medical records were analysed and compared to cases reported to the SRIE caused by other pathogens. RESULTS: Sixteen cases of aerococcal IE, fourteen with Aerococcus urinae and two with Aerococcus sanguinicola, were confirmed. Etest-based methods and time-kill experiments suggested synergy between penicillin and gentamicin towards seven of fifteen isolates. The patients with aerococcal IE were significantly older than those with streptococci or Staphylococcus aureus IE. Most of the patients had underlying urinary tract diseases or symptoms suggesting a urinary tract focus of the infection. Seven patients with aerococcal IE presented with severe sepsis but ICU treatment was needed only in one patient and there was no fatality. Valve exchange surgery was needed in four patients and embolization was seen in three patients. CONCLUSIONS: This report is the largest on aerococcal IE and suggests that the prognosis is relatively favourable despite the fact that the patients are old and have significant comorbidities. PMID- 26119202 TI - Combined Cisplatin-Based Chemoembolization and Radiation Therapy for Hepatocellular Carcinoma Invading the Main Portal Vein. AB - PURPOSE: To evaluate the safety and survival outcome of chemoembolization plus radiation therapy (RT) in patients with hepatocellular carcinoma (HCC) with main portal vein (PV) tumor thrombosis. MATERIALS AND METHODS: This retrospective study evaluated 151 patients with HCC and main PV involvement (101 with Child Pugh class A liver function and 50 with Child-Pugh class B liver function) treated with combined cisplatin-based chemoembolization and RT. Medical records, imaging, and laboratory studies were reviewed, and complications, survival, and mortality rates were determined. RESULTS: After chemoembolization, major complications occurred in 19.9% of patients, with the rate of major complications significantly higher in Child-Pugh class B cases than in Child-Pugh class A cases (32% vs 13.9%; P = .016). The 30-day mortality rate was 0.7%. One hundred forty seven patients received adjuvant RT an average of 17.4 days after chemoembolization for main PV tumor thrombosis. Adjuvant RT could not be performed in four patients because of intolerance of the initial chemoembolization. There were no major complications after RT. The objective tumor response at 6 months was 25.2%, with a median survival of 12 months (14 mo in Child-Pugh class A cases and 8 mo in Child-Pugh class B cases). Patients with Child-Pugh class B liver function with extrahepatic metastases, no tumor response, and absence of second-line sorafenib treatment had poor survival. CONCLUSIONS: Chemoembolization combined with RT improves survival, with a median survival of 12 months in patients with HCC with main PV involvement. PMID- 26119203 TI - Midterm Clinical and Radiologic Outcomes after Percutaneous Interspinous Spacer Treatment for Neurogenic Intermittent Claudication. AB - PURPOSE: To evaluate the midterm clinical and radiologic outcome of percutaneous interspinous process spacer (IPS) treatment for neurogenic intermittent claudication (NIC) in patients who fail conservative treatment. METHODS: Consecutive patients with NIC, lumbar spinal stenosis confirmed on magnetic resonance imaging, failure of conservative management for at least 6 months, and treatment with percutaneous IPS were included. Visual analog scale (VAS) and Oswestry Disability Index (ODI) scores were recorded at baseline, 1 month, 1 year and 3 years after treatment. Spinal canal and foraminal cross-sectional areas were calculated from multidetector computed tomography at baseline and 1 year. RESULTS: There were 80 patients treated with 94 IPS devices; 83% of patients received a single IPS; 78% of IPS devices were placed at L4-L5. An IPS dislocation was the single periprocedural major complication. VAS score of 8.1 +/ 2 before treatment was reduced to 4.4 +/- 2 at 1 month after treatment (P = .0001); ODI score of 23.3 +/- 10 before treatment was reduced to 11.7 +/- 8.5 at 1 month after treatment (P = .0001). These significant reductions were durable at 1-year and 3-year follow-up evaluations (P < .01). Spinal canal and foraminal cross-sectional area increased by 15% at 1 year (P = .0001). CONCLUSIONS: Patients with NIC who failed conservative treatment and were treated with percutaneous IPS achieved significant gains in pain relief and reduced disability that remained durable at 3-year clinical follow-up evaluation. This outcome was accompanied by significant increases in spinal canal and foraminal cross sectional areas at the treated level. PMID- 26119204 TI - Irreversible Electroporation Can Effectively Ablate Hepatocellular Carcinoma to Complete Pathologic Necrosis. AB - PURPOSE: To describe full explant pathology and radiographic correlation in patients with hepatocellular carcinoma (HCC) treated with irreversible electroporation (IRE) who subsequently underwent liver transplant. MATERIALS AND METHODS: In a retrospective study, 6 patients who had undergone IRE for HCC and subsequent orthotopic liver transplant during the period 2011-2013 were evaluated. Of the 6 patients, 4 had Child-Pugh class A cirrhosis, and 2 had class B cirrhosis. Irreversible electroporation was performed for a single focal HCC with median tumor diameter of 22 mm (range, 6-26 mm). After IRE, follow-up multiphasic cross-sectional imaging was performed at 1 month and every 3 months thereafter until liver transplant. Mean time between IRE and transplant was 10 months (range, 3-17 mo). Assessment of imaging response was based on modified Response Evaluation Criteria In Solid Tumors. Liver explants were evaluated for necrosis and viable carcinoma in IRE-treated tumors. RESULTS: After IRE, all tumors showed a complete response on follow-up imaging. Five tumors showed complete pathologic necrosis without any viable carcinoma, sharply demarcated from the surrounding hepatic parenchyma. Bile ducts within the treatment area were preserved. A single tumor treated with a bipolar IRE probe had < 5% viable carcinoma cells at the periphery. CONCLUSIONS: This study demonstrates the efficacy of IRE for HCC based on pathologic evaluation and correlation to radiologic findings. PMID- 26119205 TI - A Neapolitan miracle. AB - The Italian scientific renaissance, that started when the Second World War was drawing to a close and reached its apex early in the Sixties--is widely discussed in literature. But there is also a second, maybe less visible but not less important renaissance in the Italian scientific world of the Fifties and Sixties: the Neapolitan renaissance, in which biophysics plays an important role. PMID- 26119206 TI - Are gluten-free foods healthier than non-gluten-free foods? An evaluation of supermarket products in Australia. AB - Despite tremendous growth in the consumption of gluten-free (GF) foods, there is a lack of evaluation of their nutritional profile and how they compare with non GF foods. The present study evaluated the nutritional quality of GF and non-GF foods in core food groups, and a wide range of discretionary products in Australian supermarkets. Nutritional information on the Nutrition Information Panel was systematically obtained from all packaged foods at four large supermarkets in Sydney, Australia in 2013. Food products were classified as GF if a GF declaration appeared anywhere on the product packaging, or non-GF if they contained gluten, wheat, rye, triticale, barley, oats or spelt. The primary outcome was the 'Health Star Rating' (HSR: lowest score 0.5; optimal score 5), a nutrient profiling scheme endorsed by the Australian Government. Differences in the content of individual nutrients were explored in secondary analyses. A total of 3213 food products across ten food categories were included. On average, GF plain dry pasta scored nearly 0.5 stars less (P< 0.001) compared with non-GF products; however, there were no significant differences in the mean HSR for breads or ready-to-eat breakfast cereals (P>= 0.42 for both). Relative to non-GF foods, GF products had consistently lower average protein content across all the three core food groups, in particular for pasta and breads (52 and 32% less, P< 0.001 for both). A substantial proportion of foods in discretionary categories carried GF labels (e.g., 87% of processed meats), and the average HSR of GF discretionary foods were not systematically superior to those of non-GF products. The consumption of GF products is unlikely to confer health benefits, unless there is clear evidence of gluten intolerance. PMID- 26119207 TI - Is high job control a risk factor for poor quality of life in workers with high autism spectrum tendencies? A cross-sectional survey at a factory in Japan. AB - OBJECTIVES: To examine the effect of autism spectrum (AS) tendencies and psychosocial job characteristics on health-related quality of life (HRQOL) among factory workers. METHODS: A questionnaire survey was administered to 376 Japanese factory employees from the same company (response rate: 83.6%) in 2010. Psychosocial job characteristics, including job demand, job control, and social support, were evaluated using the Job Content Questionnaire (JCQ). AS tendencies was assessed using the Autism-Spectrum Quotient (AQ), and HRQOL was assessed using the Medical Outcomes Study Short-Form General Health Survey (SF-8). Associations were investigated using multiple logistic regression analysis adjusted for confounders. RESULTS: In the multivariate analysis, AQ was positively (odds ratio [OR]: 3.94; 95% confidence interval [CI]: 1.70-9.73) and social support in the workplace was inversely (OR: 0.25; 95% CI: 0.10-0.57) associated with poor mental HRQOL. No significant interaction was observed between AQ and JCQ subitems. Only social support was inversely associated with poor physical HRQOL (OR and 95% CI for medium social support: 0.45 and 0.21 0.94), and a significant interaction between AQ and job control was observed (p=0.02), suggesting that high job control was associated with poor physical HRQOL among workers with high AQ, whereas low job control tended to be associated with poor physical HRQOL among others. CONCLUSIONS: Our results suggest that AS tendencies have a negative effect on workers' HRQOL and social support is a primary factor in maintaining HRQOL. Moreover, a structured work environment can maintain physical HRQOL in workers with high AS tendencies since higher job control will be stressful. PMID- 26119208 TI - Gender and educational level modify the relationship between workplace mistreatment and health problems: a comparison between South Korea and EU countries. AB - OBJECTIVES: This study investigated effects of workers' cultural and personal characteristics on the relationship between workplace mistreatment and health problems in both South Korea and EU Countries. METHODS: Data were obtained from nationally representative interview surveys: the third Korean Working Conditions Survey (KWCS) in 2011 (50,032 participants) and fifth European Working Conditions Survey (EWCS) in 2010 (41,302 participants). The Pressure-State-Response model was adapted to explore differences in the relationship between mistreatment and health problems according to country, and logistic regression analysis was used after stratification of moderating factors. Workplace mistreatment, such as discrimination, violence, harassment, and self-reported health problems, were assessed by gender and educational level. RESULTS: Among KWCS participants, there were 4,321 victims (14.70%) of workplace mistreatment; among EWCS participants, there were 5,927 victims (17.89%). There was a significant positive association between workplace mistreatment and self-reported health problems. A stronger association was found among workers with higher educational levels in Korea (2- to 4-fold higher odds for mental and physical health problems), but there was no significant difference by education level in workers of EU Countries. Female Koreans who worked alone had a higher risk of health problems related to workplace mistreatment than other gender compositions in the workplace (the OR for psychological symptoms reached 6.631). In contrast, the gender composition of the work place did not significantly affect EU workers. CONCLUSIONS: Workplace mistreatment is significantly associated with physical and mental health problems, especially among workers with higher educational levels and females who work alone in Korea. PMID- 26119209 TI - No stress after 24-hour on-call shifts? AB - OBJECTIVES: Irregular sleep patterns can adversely affect physiological functions and have been associated with increased physiological and psychological stress. Nocturnal work of physicians during 24-hour on-call shifts (OCS) disrupts the sleep/wake cycle. Chronic exposure to distress has been shown to affect cardiovascular homeostasis and to impair performance in neurocognitive and simulated clinical tasks. METHODS: In a prospective cohort study, biochemical and physiological stress parameters were assessed in 11 female and 9 male physicians (median age: 32 years, range 26-42 years) before a normal working day and after a 24-hour OCS in internal medicine. In addition, various tests of attentional performance (TAP) were conducted. RESULTS: The levels of thyroid stimulating hormone (TSH) were significantly higher after a 24- hour OCS, while there were no significant changes in cortisol, epinephrine, and norepinephrine levels. Heart rate variability and skin resistance increased following an OCS, although the differences were not statistically significant. Intrinsic alertness was comparable, while phasic alertness was significantly improved following a 24-hour OCS. Focused attention tended to be better following a night shift. There was no correlation with age or medical working experience; however, men experienced more stress than women. CONCLUSIONS: Following a 24-hour OCS, (i) TSH may be an early and sensitive biochemical predictor of stress; (ii) other classical biochemical stress parameters do not depict the psychological stress perceived by physicians; (iii) there may be a mismatch between experienced and objective stress levels; (iv) neurocognitive functions are not impaired, while performance may even be improved; and (v) men might be more sensitive to distress. PMID- 26119210 TI - Antibodies as a source of anti-infective peptides: an update. AB - This review focuses on antibodies (Abs) and their function in immune protection, with particular emphasis on microbicidal Abs. Some aspects of Abs and Ab-drug conjugates as targeting therapeutic agents are also discussed. The main aim, however, is devoted to Ab-derived peptides modulating functions of the immune system and to the latest experimental evidence of Abs as a source of anti infective and antitumor peptides derived from their complementarity determining regions and constant regions. PMID- 26119211 TI - Canopy warming caused photosynthetic acclimation and reduced seed yield in maize grown at ambient and elevated [CO2 ]. AB - Rising atmospheric CO2 concentration ([CO2 ]) and attendant increases in growing season temperature are expected to be the most important global change factors impacting production agriculture. Although maize is the most highly produced crop worldwide, few studies have evaluated the interactive effects of elevated [CO2 ] and temperature on its photosynthetic physiology, agronomic traits or biomass, and seed yield under open field conditions. This study investigates the effects of rising [CO2 ] and warmer temperature, independently and in combination, on maize grown in the field throughout a full growing season. Free-air CO2 enrichment (FACE) technology was used to target atmospheric [CO2 ] to 200 MUmol mol(-1) above ambient [CO2 ] and infrared heaters to target a plant canopy increase of 3.5 degrees C, with actual season mean heating of ~2.7 degrees C, mimicking conditions predicted by the second half of this century. Photosynthetic gas-exchange parameters, leaf nitrogen and carbon content, leaf water potential components, and developmental measurements were collected throughout the season, and biomass and yield were measured at the end of the growing season. As predicted for a C4 plant, elevated [CO2 ] did not stimulate photosynthesis, biomass, or yield. Canopy warming caused a large shift in aboveground allocation by stimulating season-long vegetative biomass and decreasing reproductive biomass accumulation at both CO2 concentrations, resulting in decreased harvest index. Warming caused a reduction in photosynthesis due to down-regulation of photosynthetic biochemical parameters and the decrease in the electron transport rate. The reduction in seed yield with warming was driven by reduced photosynthetic capacity and by a shift in aboveground carbon allocation away from reproduction. This field study portends that future warming will reduce yield in maize, and this will not be mitigated by higher atmospheric [CO2 ] unless appropriate adaptation traits can be introduced into future cultivars. PMID- 26119212 TI - Licit and illicit substance use among people who inject drugs and the association with subsequent suicidal attempt. AB - AIM: To estimate associations between recent licit and illicit substance use and subsequent suicide attempt among people who inject drugs (PWID). DESIGN: Secondary analysis of longitudinal data from a prospective cohort study of PWID followed bi-annually between 2004 and 2011. SETTING: Montreal, Canada. PARTICIPANTS: Seven hundred and ninety-seven PWID who reported injection drug use in the previous 6 months, contributing to a total of 4460 study visits. The median number of visits per participant was five (interquartile range: 3-8). MEASUREMENTS: An interviewer-administered questionnaire eliciting information on socio-demographic factors, detailed information on substance use patterns and related behaviours, mental health markers and suicide attempt. The primary exposure variables examined were past-month use of alcohol [heavy (>= 60 drinks); moderate (one to 59 drinks); none], sedative-hypnotics, cannabis, cocaine, amphetamine and opioids [regular (>= 4 days); occasional (1-3 days); none]. The outcome was a binary measure of suicide attempt assessed in reference to the previous 6 months. FINDINGS: In multivariate analyses, a positive association was found among licit substances between heavy alcohol consumption [adjusted odds ratio (AOR) = 2.05; 95% confidence interval (CI) = 1.12-3.75], regular use of sedative-hypnotics (AOR = 1.89; 95% CI = 1.21-2.95) and subsequent attempted suicide. Among illicit substances, occasional use of cannabis (AOR = 1.84; 95% CI = 1.09-3.13) had a positive association with subsequent suicide attempt. No statistically significant association was found for the remaining substances. CONCLUSION: Among people who inject drugs, use of alcohol, sedative-hypnotics and cannabis, but not cocaine, amphetamine or opioids, appears to be associated with an increased likelihood of later attempted suicide. PMID- 26119213 TI - Automatic fusion of lateral cephalograms and digital volume tomography data perspective for combining two modalities in the future. AB - OBJECTIVES: This article investigates the combination of three-dimensional (3D) digital volume tomography data with two-dimensional (2D) cephalograms in dentomaxillofacial imaging. METHODS: An automatic hierarchical method to adjust the geometrical relations of these two modalities is presented. The approach is tested on phantom and patient case data, where the feasibility, usability and potential possibilities of the presented innovative method are highlighted. Digitally reconstructed radiographs are computed by casting rays through the 3D volume to get a 2D projection of the volume to produce realistic simulated cephalograms. Different similarity measures are considered based on variations of statistical and deterministic optimization procedures. Stability, precision and accuracy of the method are investigated. RESULTS: The presented algorithm demonstrates a reasonable solution of the corresponding 2D/3D registration problem. Exemplary results from phantom and patient case data are presented. Tooth movement could be determined, in contrast to the 2D lateral cephalogram, separated for each side in all three spatial directions. CONCLUSIONS: Achieved results are highlighted from a clinical point of view and demonstrate the clinical benefit in daily praxis. PMID- 26119214 TI - Reducing an already low dental diagnostic X-ray dose: does it make sense? Comparison of three cost-utility analysis methods used to assess two dental dose reduction measures. AB - OBJECTIVES: To find a method that is suitable for providing an objective assessment of the cost effectiveness of a dose-reducing measure used for diagnostic dental X-ray exposures. METHODS: Three cost-utility analysis (CUA) methods were evaluated by comparing their assessments of two dose-reduction measures, a rectangular collimator and the combination of two devices that reduce the radiation dose received during orthodontic lateral cephalography. The following CUA methods were used: (1) the alpha value (AV), a monetary valuation of dose reduction used in the nuclear industry; (2) the value of a statistical life for valuation of the reduction in stochastic adverse effects; and (3) the time-for-time method, based on the postulate that risk reduction is effective when the number of years of life gained is more than the years that an average worker must work to earn the costs of the risk-reducing measure. The CUA methods were used to determine the minimum number of uses that was required for the dose reducing device to be cost effective. The methods were assessed for coherence (are comparable results achieved for comparable countries?) and adaptability (can the method be adjusted for age and gender of specific patient groups?). RESULTS: The performance of the time-for-time method was superior to the other methods. Both types of dose-reduction devices tested were assessed as cost effective after a realistic number of uses with all three methods except low AVs. CONCLUSIONS: CUA for the methods of X-ray dose reduction can be performed to determine if investment in low dose reduction is cost effective. The time-for-time method proved to be a coherent and versatile method for performing CUA. PMID- 26119215 TI - Risks, Outcomes, and Evidence-Based Interventions for Girls in the US Juvenile Justice System. AB - The proportion of the juvenile justice population that comprises females is increasing, yet few evidence-based models have been evaluated and implemented with girls in the juvenile justice system. Although much is known about the risk and protective factors for girls who participate in serious delinquency, significant gaps in the research base hamper the development and implementation of theoretically based intervention approaches. In this review, we first summarize the extant empirical work about the predictors and sequelae of juvenile justice involvement for girls. Identified risk and protective factors that correspond to girls' involvement in the juvenile justice system have been shown to largely parallel those of boys, although exposure rates and magnitudes of association sometimes differ by sex. Second, we summarize findings from empirically validated, evidence-based interventions for juvenile justice-involved youths that have been tested with girls. The interventions include Functional Family Therapy, Multisystemic Therapy, Multidimensional Family Therapy, and Treatment Foster Care Oregon (formerly known as Multidimensional Treatment Foster Care). We conclude that existing evidence-based practices appear to be effective for girls. However, few studies have been sufficiently designed to permit conclusions about whether sex-specific interventions would yield any better outcomes for girls than would interventions that already exist for both sexes and that have a strong base of evidence to support them. Third, we propose recommendations for feasible, cost-efficient next steps to advance the research and intervention agendas for this under-researched and underserved population of highly vulnerable youths. PMID- 26119216 TI - Unique characteristics in Japanese dermatitis herpetiformis. PMID- 26119217 TI - New polyurethane/docosane microcapsules as phase-change materials for thermal energy storage. AB - Polyurethane microcapsules were prepared by mini-emulsion interfacial polymerization for encapsulation of phase-change material (n-docosane) for energy storage. Three steps were followed with the aim to optimize synthesis conditions of the microcapsules. First, polyurethane microcapsules based on silicone oil core as an inert template with different silicone oil/poly(ethylene glycol)/4,4' diphenylmethane diisocyanate wt % ratio were synthesized. The surface morphology of the capsules was analyzed by scanning electronic microscopy (SEM) and the chemical nature of the shell was monitored by Fourier transform infrared spectroscopy (FT-IR). Capsules with the silicone oil/poly(ethylene glycol)/4,4' diphenylmethane diisocyanate 10/20/20 wt % ratio showed the best morphological features and shell stability with average particle size about 4 MUm, and were selected for the microencapsulation of the n-docosane. In the second stage, half of the composition of silicone oil was replaced with n-docosane and, finally, the whole silicone oil content was replaced with docosane following the same synthetic procedure used for silicone oil containing capsules. Thermal and cycling stability of the capsules were investigated by thermal gravimetric analysis (TGA) and the phase-change behavior was evaluated by differential scanning calorimetry (DSC). PMID- 26119218 TI - Carbon Nanotube Driver Circuit for 6 * 6 Organic Light Emitting Diode Display. AB - Single-walled carbon nanotube (SWNT) is expected to be a very promising material for flexible and transparent driver circuits for active matrix organic light emitting diode (AM OLED) displays due to its high field-effect mobility, excellent current carrying capacity, optical transparency and mechanical flexibility. Although there have been several publications about SWNT driver circuits, none of them have shown static and dynamic images with the AM OLED displays. Here we report on the first successful chemical vapor deposition (CVD) grown SWNT network thin film transistor (TFT) driver circuits for static and dynamic AM OLED displays with 6 * 6 pixels. The high device mobility of ~45 cm(2)V(-1)s(-1) and the high channel current on/off ratio of ~10(5) of the SWNT TFTs fully guarantee the control capability to the OLED pixels. Our results suggest that SWNT-TFTs are promising backplane building blocks for future OLED displays. PMID- 26119219 TI - [Radioresistance parameters in head and neck cancers and methods to radiosensitize]. AB - Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact. PMID- 26119220 TI - Angioedema induced by cardiovascular drugs: new players join old friends. AB - During the last years, two new cardiovascular drug classes, namely inhibitors of DPP IV or neprilysin, have been developed. In both cases, there is clinical evidence for their potential to induce angioedema as known already from blockers of the renin-angiotensin-aldosterone system (RAAS). The majority of angioedema induced by DPP IV inhibitors occurs during concomitant treatment with ACEi and is therefore likely mediated by overactivation of bradykinin type 2 receptors (B2). In striking contrast, the molecular pathways causing angioedema induced by neprilysin inhibitors, that is, sacubitril, are unclear, although a contribution of bradykinin appears likely. Nevertheless, there is no clinical evidence suggesting that inhibition of B2 might relieve the symptoms and/or prevent invasive treatment including coniotomy or tracheotomy in angioedema caused by these drugs. Therefore, the risk of angioedema should always be considered, especially in ambulatory care situations where patients have no rapid access to intensive care. PMID- 26119221 TI - Return to work after total hip and knee arthroplasty: results from a clinical study. AB - The aim of this study was to measure return to work and duration until return to work in patients undergoing total hip or knee arthroplasty (THA or TKA). This prospective study included patients under 65 years of age, undergoing THA or TKA, who provided information on their work status preoperatively (paid work yes/no and working hours) and 1 year thereafter (paid work yes/no, working hours and time until return to work). Seventy-one THA and 64 TKA patients had a paid job preoperatively. The employment rates 1 year postoperatively were 64/71 (90 %) after THA and 53/64 (83 %) after TKA. Of those who returned to work, 9/64 (14 %) of THA patients and 10/53 (19 %) of TKA patients worked less hours than preoperatively [mean decrease of 16 (SD 11.5) and 14 (SD 13.0) hours, respectively]. The mean time to return to work was 12.5 (SD 7.6) and 12.9 (SD 8.0) weeks in THA and TKA, respectively. The majority of working patients who underwent THA or TKA returned to work, after approximately 12 weeks. A considerable proportion of the patients returning to work worked less hours than preoperatively. More research into patients who do not return or decrease their working hours is needed. PMID- 26119223 TI - Effects of memantine on hippocampal long-term potentiation, gamma activity, and sensorimotor gating in freely moving rats. AB - Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, is used for treatment of patients with Alzheimer's disease. The mechanisms of memantine in relieving cognitive and behavioral symptoms are unclear, and this study attempts to elucidate its action on network and synaptic functions of the hippocampus. The effects of memantine on electrographic activity and hippocampal long-term potentiation (LTP) were investigated in freely moving rats. Basal dendritic excitation on hippocampal CA1 pyramidal cells showed a robust LTP after theta frequency primed bursts, and the LTP was higher after 5-10 mg/kg intraperitoneal (ip) memantine pretreatment, as compared with saline pretreatment. Injection of scopolamine (5 mg/kg ip) before memantine failed to block the LTP-enhancing effect of memantine. Memantine as compared with saline pretreatment did not affect the LTP after an afterdischarge induced by high-frequency (200-Hz) train stimulation. Memantine (5 or 10 mg/kg ip) significantly enhanced gamma oscillations in the hippocampal local field potentials of 40-100 Hz during walking and awake immobility. Memantine at 10 mg/kg ip, but not at 5 mg/kg ip, increased prepulse inhibition of the acoustic startle response, while both 5 and 10 mg/kg ip memantine enhanced the acoustic startle response as compared with saline-injected rats. These electrophysiological and behavioral effects of memantine are unique among N-methyl-D-aspartate receptor antagonists but are consistent with memantine's effects in improving cognitive and sensorimotor functions of Alzheimer's patients. PMID- 26119224 TI - Stroke risk interacts with Alzheimer's disease biomarkers on brain aging outcomes. AB - Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways. PMID- 26119225 TI - NLRP3 inflammasome activation by mitochondrial reactive oxygen species plays a key role in long-term cognitive impairment induced by paraquat exposure. AB - Exposure to environmental toxins such as pesticides is implicated in increasing Alzheimer's disease risk. In this study, we investigated the long-term effects of paraquat exposure on cognition of Alzheimer's disease animal model APP/PS1 mice and wild-type (WT) mice. Our results showed that APP/PS1 mice had exacerbated cognition impairment and elevated Abeta levels at 5 months after paraquat exposure, and that WT mice had cognition impairment at 5 and 16 months after paraquat exposure. In addition, increased mitochondrial oxidative stress and augmented brain inflammation were observed in both paraquat-exposed APP/PS1 mice and WT mice. Interestingly, activation of NLRP3 inflammasome, which triggers inflammation in response to mitochondrial stress, was enhanced in paraquat exposed mice. Moreover, transgenic mice overexpressing Prdx3, a key enzyme in detoxifying mitochondrial H2O2, had suppressed NLRP3 inflammasome activation, reduced brain inflammation, and attenuated cognition impairment after paraquat exposure. Together, our results indicate that NLRP3 inflammasome activation induced by mitochondrial reactive oxygen species plays a key role in mediating paraquat-induced long-term cognition decline by elevating brain inflammation. PMID- 26119227 TI - Oral nifedipine or intravenous labetalol for severe hypertension? PMID- 26119226 TI - Randomised clinical trial: a placebo-controlled study of intravenous golimumab induction therapy for ulcerative colitis. AB - BACKGROUND: Tumour necrosis factor alpha (TNFalpha)-antagonism effectively treats ulcerative colitis (UC). The golimumab clinical programme evaluated subcutaneous (SC) and intravenous (IV) induction, and SC maintenance regimens, in TNFalpha antagonist-naive patients with moderate-to-severe active UC despite conventional treatment. AIM: To evaluate dose-response relationship, select IV golimumab induction doses for continued development, and evaluate the safety and efficacy of selected doses. METHODS: Adults with Mayo scores of 6-12 and endoscopic subscores >=2 were enrolled into this multicentre, randomised, double-blind, placebo-controlled, integrated Phase 2/3 dose-finding/dose-confirming study. In Phase 2, 176 patients were randomised (1:1:1:1) to a single IV infusion of placebo, 1-, 2- or 4-mg/kg golimumab. While Phase 2 data were analysed to select doses for continued development, 71 additional patients were randomised. Phase 3 enrolment stopped after 44 additional patients were randomised (1:1:1) to placebo, 2- or 4-mg/kg golimumab. Due to insufficient power for the Phase 3 primary endpoint analysis (clinical response at week 6), efficacy analyses are considered exploratory and include all randomised patients. RESULTS: No dose response was observed in Phase 2; however, higher serum golimumab exposure was associated with greater proportions of patients achieving more favourable clinical outcomes, clinical response and greater improvement in Mayo scores compared with placebo-treated patients and those with lower serum concentrations. Among all randomised patients, numerically greater proportions were in clinical response at week 6 in the 2- and 4-mg/kg golimumab groups compared with placebo [44.0% (33/75) and 41.6% (32/77) vs. 30.1% (22/73)]. CONCLUSIONS: Efficacy with single-dose golimumab IV induction was lower than expected and less than observed in the SC induction study. No new safety findings were observed. ClinicalTrials.gov Number, NCT00488774. PMID- 26119228 TI - Complete reversion of anti-infliximab immunization by methotrexate combination in a patient with psoriasis. PMID- 26119229 TI - Association Between Older Age and Increasing Gleason Score. AB - INTRODUCTION: In order to help inform the discussion about the risks versus benefits of prostate cancer screening among older men, we determined whether advanced age is associated with a higher probability of harboring high-grade or high-risk disease. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 383,039 men diagnosed with prostate cancer in 2004-2011. The percentage of patients diagnosed with low-, intermediate , or high-risk disease or a Gleason score of 6, 7, or 8 to 10 was calculated by age range. As a secondary analysis, we examined whether this relationship was different in 2010-2011 versus 2007-2008 (before and after the 2009 publication of screening trials). RESULTS: The probability of Gleason score 8 to 10 or high-risk disease increased significantly with increasing age. The percentage of Gleason score 8 to 10 disease among men ages 50 to 54, 70 to 74, and 80 to 84 years was 8.9%, 16.2%, and 28.5%, respectively, and the percentage of high-risk disease was 14.3%, 22.4%, and 38.7% (P < .001). There were similar relationships among men with stage T1c disease. In addition, older men experienced a significant increase in the relative probability of high-risk or high-grade disease from 2007-2008 to 2010-2011. CONCLUSION: In this large US-based cohort, older men had a much higher probability of high-grade or high-risk prostate cancer. Physicians and patients should take into account the higher risk of more aggressive or advanced disease in older men when discussing the risks and benefits of prostate-specific antigen screening with healthy older men with a substantial life expectancy. PMID- 26119230 TI - Treatment Sequencing in Metastatic Castration-Resistant Prostate Cancer: A Clinical Commentary. PMID- 26119231 TI - Fragment-based similarity searching with infinite color space. AB - Fragment-based searching and abstract representation of molecular features through reduced graphs have separately been used for virtual screening. Here, we combine these two approaches and apply the algorithm RedFrag to virtual screens retrospectively and prospectively. It uses a new type of reduced graph that does not suffer from information loss during its construction and bypasses the necessity of feature definitions. Built upon chemical epitopes resulting from molecule fragmentation, the reduced graph embodies physico-chemical and 2D structural properties of a molecule. Reduced graphs are compared with a continuous-similarity-distance-driven maximal common subgraph algorithm, which calculates similarity at the fragmental and topological levels. The performance of the algorithm is evaluated by retrieval experiments utilizing precompiled validation sets. By predicting and experimentally testing ligands for endothiapepsin, a challenging model protease, the method is assessed in a prospective setting. Here, we identified five novel ligands with affinities as low as 2.08 MUM. PMID- 26119232 TI - The combined and second exposure effect of copper (II) and chlortetracycline on fresh water algae, Chlorella pyrenoidosa and Microcystis aeruginosa. AB - In the experiment, Chlorella pyrenoidosa and Microcystis aeruginosa were chosen to test the individual, combined and second exposure effect of Cu(2+) and chlortetracycline (CTC). The 96 h EC50s of each test were calculated, with the ranges of 0.972-15.6 MUmol/L (Cu(2+)), 29.5-102.5 MUmol/L (CTC), 14.4-78.9 MUmol/L (mixture). The combined toxicities were evaluated with toxicity units (TU) method. The toxicity of complex of Cu(2+) and chlortetracycline was analyzed using concentration addition (CA) model. In the initial test, the combined effect of the two substances was partly additive to C. pyrenoidosa and antagonistic to M. aeruginosa, while in the second exposure test, the combined effect was synergistic to both algae. The biochemical indicators measured in the experiment included chlorophyll fluorescence (Fv/Fm), MDA content, SOD activity and content of soluble proteins. When under combined stress, the biochemical features of both algae were significantly different between the initial test and the second exposure test. PMID- 26119233 TI - Increase in intracellular Ca(2+) level by phenylsulfamide fungicides, tolylfluanid and dichlofluanid, in rat thymic lymphocytes. AB - Tolylfluanid, a phenylsulfamide fungicide, is one of the many pesticides that are frequently detected in crops. Therefore, its health risk is a concern. Micromolar concentrations of tolylfluanid induce chromosomal aberrations and micronuclei in mammalian lymphocytes. The findings prompted us to study the cellular actions of tolylfluanid and another frequently detected pesticide, dichlofluanid, at submicromolar and micromolar concentrations. Of the cellular actions of chemicals, the action on cellular Ca(2+) homeostasis is important since Ca(2+) is involved in cell signaling and death. Consequently, in this study, the effects of phenylsulfamide fungicides were examined on rat thymocytes by using fluorescent probes in order to further characterize the cellular actions of phenylsulfamide fungicides. Both phenylsulfamide fungicides exhibited biphasic, early and late, increase in intracellular Ca(2+) levels. The early phase was dependent on intracellular Ca(2+) release and increased membrane Ca(2+) permeability. The late phase was owing to Ca(2+) influx via activation of store-operated Ca(2+) channels and the further increase of membrane ionic permeability. Voltage-dependent Ca(2+) channels were not involved. The increases in intracellular Ca(2+) levels by phenylsulfamide fungicides were observed at drug concentrations of 0.1 MUM or more (up to 10 MUM). Thus, it is plausible that micromolar concentrations of phenylsulfamide fungicides deregulate intracellular Ca(2+) homeostasis in rat thymocytes. Both phenylsulfamide fungicides at 10 MUM promoted the transition from intact living cells to living cells with phosphatidylserine-exposed membranes. This was not the case for phenylsulfamide fungicides at 3 MUM. The potency of tolylfluanid was similar to that of dichlofluanid. Although the information on residual concentrations of tolylfluanid and dichlofluanid is very limited, their residual concentrations do not reach micromolar levels. It is unlikely that humans will develop adverse effects on exposure to phenylsulfamide fungicides under present environmental conditions. PMID- 26119234 TI - Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation. AB - Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady-state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53 dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53 dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53 null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T cell leukemia and lymphoma. Together, these data highlight coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation. PMID- 26119235 TI - Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes. AB - Direct lineage reprogramming induces dramatic shifts in cellular identity, employing poorly understood mechanisms. Recently, we demonstrated that expression of Neurog2 or Ascl1 in postnatal mouse astrocytes generates glutamatergic or GABAergic neurons. Here, we take advantage of this model to study dynamics of neuronal cell fate acquisition at the transcriptional level. We found that Neurog2 and Ascl1 rapidly elicited distinct neurogenic programs with only a small subset of shared target genes. Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co expression with Insm1 was required for glutamatergic maturation. Cultured astrocytes gradually became refractory to reprogramming, in part by the repressor REST preventing Neurog2 from binding to the NeuroD4 promoter. Notably, in astrocytes refractory to Neurog2 activation, the underlying neurogenic program remained amenable to reprogramming by exogenous NeuroD4. Our findings support a model of temporal hierarchy for cell fate change during neuronal reprogramming. PMID- 26119237 TI - Chronic social isolation affects thigmotaxis and whole-brain serotonin levels in adult zebrafish. AB - The popularity of the zebrafish has been growing in behavioral brain research. Previously utilized mainly in developmental biology and genetics, the zebrafish has turned out to possess a complex behavioral repertoire. For example, it is a highly social species, and individuals form tight groups, a behavior called shoaling. Social isolation induced changes in brain function and behavior have been demonstrated in a variety of laboratory organisms. However, despite its highly social nature, the zebrafish has rarely been utilized in this research area. Here, we investigate the effects of chronic social isolation (lasting 90 days) on locomotor activity and anxiety-related behaviors in an open tank. We also examine the effect of chronic social isolation on levels of whole-brain serotonin and dopamine and their metabolites. We found that long-term social deprivation surprisingly decreased anxiety-related behavious during open-tank testing but had no effect on locomotor activity. We also found that serotonin levels, decreased significantly in socially isolated fish, but levels of dopamine and metabolites of these neurotransmitters 5HIAA and DOPAC, respectively, remained unchanged. Our results imply that the standard high density housing employed in most zebrafish laboratories may not be the optimal way to keep these fish, and open a new avenue towards the analysis of the biological mechanisms of social behavior and of social deprivation induced changes in brain function using this simple vertebrate model organism. PMID- 26119236 TI - Generation of Cynomolgus Monkey Chimeric Fetuses using Embryonic Stem Cells. AB - Because of their similarity to humans, non-human primates are important models for studying human disease and developing therapeutic strategies. Establishment of chimeric animals using embryonic stem cells (ESCs) could help with these investigations, but has not so far been achieved. Here, we show that cynomolgus monkey ESCs (cESCs) grown in adjusted culture conditions are able to incorporate into host embryos and develop into chimeras with contribution in all three germ layers and in germ cell progenitors. Under the optimized culture conditions, which are based on an approach developed previously for naive human ESCs, the cESCs displayed altered growth properties, gene expression profiles, and self renewal signaling pathways, suggestive of an altered naive-like cell state. Thus our findings show that it is feasible to generate chimeric monkeys using ESCs and open up new avenues for the use of non-human primate models to study both pluripotency and human disease. PMID- 26119238 TI - Effect of selective and non-selective serotonin receptor activation on L-DOPA induced therapeutic efficacy and dyskinesia in parkinsonian rats. AB - Selective activation of 5-HT1 receptors has been shown to produce near to full suppression of L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease; however, a reduction of the therapeutic effect of L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the serotonin precursor 5 hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting L-DOPA efficacy. To directly compare the effects of selective versus non-selective serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist eltoprazine and 5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in L-DOPA-primed dyskinetic rats. About 50% reduction of LID was observed with 0.1 mg/kg and 24 mg/kg of eltoprazine and 5-HTP, respectively; we then compared the effect of the two drugs, individually and in combination, on L DOPA-induced stepping test in L-DOPA-naive parkinsonian animals and LID over three weeks of L-DOPA treatment. Results showed that eltoprazine induced significant worsening of L-DOPA-mediated performance in the stepping test, while 5-HTP did not. Interestingly, combination of 5-HTP with eltoprazine prevented the reduction in the forelimb use induced by eltoprazine. Moreover, 5-HTP and eltoprazine given individually showed similar efficacy also upon chronic treatment, and had additive effect in dampening the appearance of LID when given in combination. Finally, chronic administration of eltoprazine and/or 5-HTP did not affect striatal serotonin innervation, compared to l-DOPA alone, as measured by serotonin transporter expression. PMID- 26119239 TI - Potentiation of the expression of cocaine-induced sensitization by a conditioned stressor. AB - Repeated exposures to physical stressors cross-sensitize to the locomotor activating effects of psychostimulants in rodents. In the present study, we examined the effect of a conditioned stressor on expression of cocaine-induced sensitization in rats. We determined whether a mint odor cue previously paired with footshock stress (FS) would elicit a sensitized locomotor response in cocaine pre-exposed rats. Rats were given once daily injections of cocaine (30 mg/kg, i.p.) or saline for 6 days in activity monitoring chambers. Subsequently, and in a different and distinct context, equal numbers of rats in each drug condition were exposed to 10 min of brief, intermittent FS or no FS, either in the presence or absence of the mint odor cue. Upon re-exposure to the activity chambers (in which cocaine exposures had been given), all rats previously exposed to cocaine showed robust conditioned locomotion. In response to a cocaine challenge (10 mg/kg, i.p.), cocaine relative to saline pre-exposed rats showed a sensitized locomotor response. Finally, in those cocaine pre-exposed rats that had been given prior odor-FS pairings, concurrent delivery of the cocaine challenge and presentation of the odor cue markedly potentiated the expression of sensitization. To our knowledge, this is the first report of a facilitation of cocaine-induced locomotor sensitization by a conditioned stressor. PMID- 26119240 TI - Behavioral effects of deep brain stimulation of different areas of the Papez circuit on memory- and anxiety-related functions. AB - Deep brain stimulation (DBS) has gained interest as a potential therapy for advanced treatment-resistant dementia. However, possible targets for DBS and the optimal stimulation parameters are not yet clear. Here, we compared the effects of DBS of the CA1 sub-region of the hippocampus, mammillothalamic tract, anterior thalamic nucleus, and entorhinal cortex in an experimental rat model of dementia. Rats with scopolamine-induced amnesia were assessed in the object location task with different DBS parameters. Moreover, anxiety-related side effects were evaluated in the elevated zero maze and open field. After sacrifice, we applied c Fos immunohistochemistry to assess which memory-related regions were affected by DBS. When comparing all structures, DBS of the entorhinal cortex and CA1 sub region was able to restore memory loss when a specific set of stimulation parameters was used. No anxiety-related side effects were found following DBS. The beneficial behavioral performance of CA1 DBS rats was accompanied with an activation of cells in the anterior cingulate gyrus. Therefore, we conclude that acute CA1 DBS restores memory loss possibly through improved attentional and cognitive processes in the limbic cortex. PMID- 26119241 TI - Tunable Molecular Logic Gates Designed for Imaging Released Neurotransmitters. AB - Tunable dual-analyte fluorescent molecular logic gates (ExoSensors) were designed for the purpose of imaging select vesicular primary-amine neurotransmitters that are released from secretory vesicles upon exocytosis. ExoSensors are based on the coumarin-3-aldehyde scaffold and rely on both neurotransmitter binding and the change in environmental pH associated with exocytosis to afford a unique turn-on fluorescence output. A pH-functionality was directly integrated into the fluorophore pi-system of the scaffold, thereby allowing for an enhanced fluorescence output upon the release of labeled neurotransmitters. By altering the pH-sensitive unit with various electron-donating and -withdrawing sulfonamide substituents, we identified a correlation between the pKa of the pH-sensitive group and the fluorescence output from the activated fluorophore. In doing so, we achieved a twelvefold fluorescence enhancement upon evaluating the ExoSensors under conditions that mimic exocytosis. ExoSensors are aptly suited to serve as molecular imaging tools that allow for the direct visualization of only the neurotransmitters that are released from secretory vesicles upon exocytosis. PMID- 26119242 TI - Nanostructured conductive polymers for advanced energy storage. AB - Conductive polymers combine the attractive properties associated with conventional polymers and unique electronic properties of metals or semiconductors. Recently, nanostructured conductive polymers have aroused considerable research interest owing to their unique properties over their bulk counterparts, such as large surface areas and shortened pathways for charge/mass transport, which make them promising candidates for broad applications in energy conversion and storage, sensors, actuators, and biomedical devices. Numerous synthetic strategies have been developed to obtain various conductive polymer nanostructures, and high-performance devices based on these nanostructured conductive polymers have been realized. This Tutorial review describes the synthesis and characteristics of different conductive polymer nanostructures; presents the representative applications of nanostructured conductive polymers as active electrode materials for electrochemical capacitors and lithium-ion batteries and new perspectives of functional materials for next-generation high energy batteries, meanwhile discusses the general design rules, advantages, and limitations of nanostructured conductive polymers in the energy storage field; and provides new insights into future directions. PMID- 26119243 TI - Rapid differentiation of mycobacteria by simplex real-time PCR with melting temperature calling analysis. AB - AIMS: This study aimed to develop a rapid, simple and cost-effective method for the differentiation of Mycobacterium species. METHODS AND RESULTS: A total of 80 clinical mycobacterial isolates belonging to 12 different species and 16 reference strains of 16 different species were differentiated by the simplex real time PCR coupled with melting temperature calling analysis. By comparing their melting profiles with those of the reference strains, all clinical mycobacterial isolates were differentiated as Mycobacterium tuberculosis complex or nontuberculous mycobacteria, and the latter were further divided into five groups. In comparison with 16S-23S internal transcribed spacer sequencing method as the gold standard method, both sensitivity and specificity of the assay were 100% when it was used for the differentiation between Myco. tuberculosis complex and nontuberculous mycobacteria. CONCLUSIONS: The simplex real-time PCR coupled with melting temperature calling analysis could be an alternative method for the differentiation between Myco. tuberculosis complex and nontuberculous mycobacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Rapid differentiation of mycobacteria could shorten the diagnostic time of mycobacterial diseases. It is also helpful for achieving optimal therapy and appropriate patient management. PMID- 26119244 TI - Peripheral arterial disease decreases muscle torque and functional walking capacity in elderly. AB - OBJECTIVES: The aim of this study is to compare values of force-velocity and functional walking capacity in elderly patients with intermittent claudication with respect to the control group. MATERIALS AND METHODS: The study involved 135 individuals: 85-peripheral arterial disease (PAD) group diagnosed with stage II chronic lower limb ischemia, according to Fontaine's classification, and 50 control group. The studies included an assessment of walking capacity using a six minute walk test (6MWT) and measurement of force-velocity parameters (peak torque PTQ, total work-TW, average power-AVGP) of the lower limbs obtained by means of a functional dynamometry under isokinetic conditions. RESULTS: The peripheral arterial disease group is characterized by significantly lower values of force velocity parameters compared to the control group (p<0.005). Walking capacity in this group is significantly reduced due to significant differences in the distance covered (p<0.0001), walking speed (p<0.01), and its intensity (p<0.01). Further, a positive correlation was found between the maximum distance specified in the six-minute walk test and lower limb muscle strength in the isokinetic test. CONCLUSIONS: Mean values of all force-velocity parameters and walk distance were significantly higher in the control group than in the peripheral arterial disease group. In the PAD group, in both men and women, the value of the agonist/antagonist ratio of both lower limbs are lower in men and women comparing to the control group. A rehabilitation program for patients with intermittent claudication must consider exercises improving strength, exercise capacity, and endurance in patients with PAD. PMID- 26119245 TI - The pathogenic role of the inflammasome in neurodegenerative diseases. AB - The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogen-derived or damage-derived molecular patterns, pro-caspase-1, and an adaptor called ASC (apoptotic speck containing protein with a CARD), which results in caspase-1 maturation. Caspase-1 then mediates the release of pro-inflammatory cytokines such as IL-1beta and IL-18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis. We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro caspase-1 to the mature form of caspase-1 which cleaves pro-IL-1beta and pro-IL 18 into their mature forms of IL-1beta and IL-18. PMID- 26119246 TI - Complex structural dynamics of nanocatalysts revealed in Operando conditions by correlated imaging and spectroscopy probes. AB - Understanding how heterogeneous catalysts change size, shape and structure during chemical reactions is limited by the paucity of methods for studying catalytic ensembles in working state, that is, in operando conditions. Here by a correlated use of synchrotron X-ray absorption spectroscopy and scanning transmission electron microscopy in operando conditions, we quantitatively describe the complex structural dynamics of supported Pt catalysts exhibited during an exemplary catalytic reaction-ethylene hydrogenation. This work exploits a microfabricated catalytic reactor compatible with both probes. The results demonstrate dynamic transformations of the ensemble of Pt clusters that spans a broad size range throughout changing reaction conditions. This method is generalizable to quantitative operando studies of complex systems using a wide variety of X-ray and electron-based experimental probes. PMID- 26119247 TI - Stacked and H-Bonded Cytosine Dimers. Analysis of the Intermolecular Interaction Energies by Parallel Quantum Chemistry and Polarizable Molecular Mechanics. AB - Until now, atomistic simulations of DNA and RNA and their complexes have been executed using well calibrated but conceptually simple pair-additive empirical potentials (force fields). Although such simulations provided many valuable results, it is well established that simple force fields also introduce errors into the description, underlying the need for development of alternative anisotropic, polarizable molecular mechanics (APMM) potentials. One of the most abundant forces in all kinds of nucleic acids topologies is base stacking. Intra- and interstrand stacking is assumed to be the most essential factor affecting local conformational variations of B-DNA. However, stacking also contributes to formation of all kinds of noncanonical nucleic acids structures, such as quadruplexes or folded RNAs. The present study focuses on 14 stacked cytosine (Cyt) dimers and the doubly H-bonded dimer. We evaluate the extent to which an APMM procedure, SIBFA, could account quantitatively for the results of high-level quantum chemistry (QC) on the total interaction energies, and the individual energy contributions and their nonisotropic behaviors. Good agreements are found at both uncorrelated HF and correlated DFT and CCSD(T) levels. Resorting in SIBFA to distributed QC multipoles and to an explicit representation of the lone pairs is essential to respectively account for the anisotropies of the Coulomb and of the exchange-repulsion QC contributions. PMID- 26119249 TI - Using 'appreciative inquiry' in India to improve infection control practices in maternity care: a qualitative study. AB - BACKGROUND: Infections acquired during childbirth are a common cause of maternal and perinatal mortality and morbidity. Changing provider behaviour and organisational settings within the health system is key to reducing the spread of infection. OBJECTIVE: To explore the opinions of health personnel on health system factors related to infection control and their perceptions of change in a sample of hospital maternity units. DESIGN: An organisational change process called 'appreciative inquiry' (AI) was introduced in three maternity units of hospitals in Gujarat, India. AI is a change process that builds on recognition of positive actions, behaviours, and attitudes. In-depth interviews were conducted with health personnel to elicit information on the environment within which they work, including physical and organisational factors, motivation, awareness, practices, perceptions of their role, and other health system factors related to infection control activities. Data were obtained from three hospitals which implemented AI and another three not involved in the intervention. RESULTS: Challenges which emerged included management processes (e.g. decision-making and problem-solving modalities), human resource shortages, and physical infrastructure (e.g. space, water, and electricity supplies). AI was perceived as having a positive influence on infection control practices. Respondents also said that management processes improved although some hospitals had already undergone an accreditation process which could have influenced the changes described. Participants reported that team relationships had been strengthened due to AI. CONCLUSION: Technical knowledge is often emphasised in health care settings and less attention is paid to factors such as team relationships, leadership, and problem solving. AI can contribute to improving infection control by catalysing and creating forums for team building, shared decision making and problem solving in an enabling environment. PMID- 26119250 TI - Are human hands and feet affected by climate? A test of Allen's rule. AB - OBJECTIVES: In recent years, several studies have shown that populations from cold, high-latitude regions tend to have relatively shorter limbs than populations from tropical regions, with most of the difference due to the relative length of the zeugopods (i.e., radius, ulna, tibia, fibula). This pattern has been explained either as the consequence of long-term climatic selection or of phenotypic plasticity, with temperature having a direct effect on bone growth during development. The aims of this study were to test whether this pattern of intra-limb proportions extended to the bones of the hands and feet, and to determine whether the pattern remained significant after taking into account the effects of neutral evolutionary processes related to population history. MATERIALS AND METHODS: Measurements of the limb bones, including the first metatarsal and metacarpal, were collected for 393 individuals from 10 globally distributed human populations. The relationship between intra-limb indices and minimum temperature was tested using generalized least squares regression, correcting for spatial autocorrelation. RESULTS: The results confirmed previous observations of a temperature-related gradient in intra-limb proportions, even accounting for population history. This pattern extends to the hands, with populations from cold regions displaying a relatively shorter and stockier first metacarpal; however, the first metatarsal appears to be wider but not shorter in cold-adapted populations. DISCUSSION: The results suggest that climatic adaptation played a role in shaping variation in limb proportions between human populations. The different patterns shown by the hands and feet might be due to the presence of evolutionary constraints on the foot to maintain efficient bipedal locomotion. PMID- 26119251 TI - Single layers of WS2 nanoplates embedded in nitrogen-doped carbon nanofibers as anode materials for lithium-ion batteries. AB - Single layers of WS2 nanoplates are uniformly embedded in nitrogen-doped carbon nanofibers (WS2@NCNFs) via a facile electrospinning method. Crystallization of the single-layered WS2 nanoplates and in situ nitrogen doping into the carbon nanofibers were simultaneously accomplished during a two-step heat treatment. The distinctive structure of the WS2@NCNFs enables outstanding electrochemical performances. PMID- 26119253 TI - Spatial analysis of exposure to traffic-related air pollution at birth and childhood atopic asthma in Toronto, Ontario. AB - Findings from the Toronto Child Health Evaluation Questionnaire (TCHEQ) study indicate that early childhood exposure to traffic-related air pollution (TRAP) is related to the onset of atopic childhood asthma. To test this hypothesis further, we investigated whether spatial patterns in the birth neighbourhood of TCHEQ subjects with atopic asthma (136 of 909 schoolchildren in grades 1-2) could be explained by TRAP and other risk factors. If a causal relationship exists between early childhood residential exposure to TRAP and the development of atopic asthma, we hypothesise that (1) clusters of current asthma should exist around the place of residence at birth, and (2) accounting for residential concentrations of TRAP at birth should explain some of the autocorrelation. Several high asthma clusters were observed. Adjusting for TRAP completely explained one cluster; elsewhere, clusters were only partially explained by TRAP. Findings suggest that exposure during early childhood to TRAP in Toronto is an important contributor to the development of the atopic asthma phenotype and reveal the likely importance of other risk factors not measured in the fixed effects of the model. PMID- 26119252 TI - Let there be bioluminescence: development of a biophotonic imaging platform for in situ analyses of oral biofilms in animal models. AB - In the current study, we describe a novel biophotonic imaging-based reporter system that is particularly useful for the study of virulence in polymicrobial infections and interspecies interactions within animal models. A suite of luciferase enzymes was compared using three early colonizing species of the human oral flora (Streptococcus mutans, Streptococcus gordonii and Streptococcus sanguinis) to determine the utility of the different reporters for multiplexed imaging studies in vivo. Using the multiplex approach, we were able to track individual species within a dual-species oral infection model in mice with both temporal and spatial resolution. We also demonstrate how biophotonic imaging of multiplexed luciferase reporters could be adapted for real-time quantification of bacterial gene expression in situ. By creating an inducible dual-luciferase expressing reporter strain of S. mutans, we were able to exogenously control and measure expression of nlmAB (encoding the bacteriocin mutacin IV) within mice to assess its importance for the persistence ability of S. mutans in the oral cavity. The imaging system described in the current study circumvents many of the inherent limitations of current animal model systems, which should now make it feasible to test hypotheses that were previously impractical to model. PMID- 26119254 TI - Anticipation of electric shocks modulates low beta power and event-related fields during memory encoding. AB - In humans, the temporal and oscillatory dynamics of pain anticipation and its effects on long-term memory are largely unknown. Here, we investigated this open question by using a previously established behavioral paradigm in combination with magnetoencephalography (MEG). Healthy human subjects encoded a series of scene images, which was combined with cues predicting an aversive electric shock with different probabilities (0.2, 0.5 or 0.8). After encoding, memory for the studied images was tested using a remember/know recognition task. Behaviorally, pain anticipation did not modulate recollection-based recognition memory per se, but interacted with the perceived unpleasantness of the electric shock [visual analogue scale rating from 1 (not unpleasant) to 10 (highly unpleasant)]. More precisely, the relationship between pain anticipation and recollection followed an inverted u-shaped function the more unpleasant the shocks were rated by a subject. At the physiological level, this quadratic effect was mimicked in the event-related magnetic fields associated with successful memory formation ('DM effect') ~450ms after image onset at left frontal sensors. Importantly, across all subjects, shock anticipation modulated oscillatory power in the low beta frequency range (13-20Hz) in a linear fashion at left temporal sensors. Taken together, our findings indicate that beta oscillations provide a generic mechanism underlying pain anticipation; the effect on subsequent long-term memory, on the other hand, is much more variable and depends on the level of individual pain perception. As such, our findings give new and important insights into how aversive motivational states can drive memory formation. PMID- 26119255 TI - Readout-segmented echo-planar imaging in diffusion-weighted MR imaging of acute infarction of the brainstem and posterior fossa: comparison of single-shot echo planar diffusion-weighted sequences. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical usefulness of readout-segmented echo-planar imaging (rs-EPI) in the diagnosis of acute infarction of the brainstem and posterior fossa, by comparing its results with those of single-shot echo-planar imaging (ss-EPI) at 3-T magnetic resonance imaging. MATERIALS AND METHODS: Twenty-nine patients with acute infarctions of the brainstem and posterior fossa underwent both ss-EPI and rs-EPI. Two readers independently assessed two sets of diffusion-weighted (DW) images for the qualitative comparison of image quality. Signal-to-noise ratio (SNR), lesion contrast, and contrast-to-noise ratio (CNR) were calculated for the assessment of image parameters. RESULTS: There were no significant differences in the conspicuity of acute infarction upon qualitative comparison; however, distinctions of anatomical structures, susceptibility artifact, the presence of uncertain high signal intensity in the brain parenchyma, and overall image quality were significantly better in rs-EPI DW images. There were no significant differences in SNR, lesion contrast, CNR, and apparent diffusion coefficient values of acute infarction and normal thalamus between rs-EPI and ss-EPI. CONCLUSION: rs-EPI DWI is a clinically useful technique for evaluating lesions in the brainstem and posterior fossa by producing high-resolution DW images with reduced susceptibility artifact. However, there are no significant differences in the conspicuity of acute infarctions in the brainstem and posterior fossa between rs-EPI and ss-EPI. PMID- 26119256 TI - Ilioinguinal-iliohypogastric block used to rescue ineffective transversus abdominis plane block after cesarean delivery. PMID- 26119257 TI - Scleroderma and pulmonary hypertension complicating two pregnancies: use of neuraxial anesthesia, general anesthesia, epoprostenol and a multidisciplinary approach for cesarean delivery. AB - Literature regarding the anesthetic care of patients with scleroderma during labor and delivery is limited to remote case reports. No recent publications provide information on the anesthetic management of patients with coexisting pulmonary hypertension. This report describes the anesthetic and multidisciplinary management of two pregnant patients with concomitant scleroderma and pulmonary hypertension undergoing cesarean delivery; one with neuraxial anesthesia and one with general anesthesia. Considerations for neuraxial and general anesthesia in patients with concurrent scleroderma and pulmonary hypertension are discussed. PMID- 26119258 TI - A systematic review of the effects of adding neostigmine to local anesthetics for neuraxial administration in obstetric anesthesia and analgesia. AB - BACKGROUND: Drugs used in obstetric patients must accomplish two goals: efficacy and safety for both mother and fetus. Neostigmine has been co-administered epidurally and intrathecally with local anesthetics and other adjuncts in the obstetric setting. The aim of this meta-analysis was to assess the efficacy and incidence of adverse events related to the use of neostigmine in obstetric anesthesia. METHODS: A meta-analysis of randomized-controlled human trials was conducted using the data sources Google Scholar and PubMed (updated 1 November 2014). Inclusion criteria were: random allocation to treatment; comparison of neostigmine or neostigmine with local anesthetics and/or other adjuvants versus placebo or placebo with local anesthetics and/or other adjuvants; and approval by an ethics committee. RESULTS: The use of neostigmine as an adjuvant in neuraxial anesthesia is associated with a reduction in the dose of local anesthetic during labor analgesia and postoperative analgesia following cesarean section: mean reduction of local anesthetic (ropivacaine or bupivacaine) vs. control -4.08 (95% CI -6.7 to -1.5) mg/h (P=0.002). The risk of nausea was increased vs. control with intrathecal neostigmine (OR 8.99 [95% CI 4.74 to 17.05], P <0.001) but not with epidural neostigmine (OR 0.97 [95% CI 0.46 to 2.05], P=0.94). Use of neuraxial neostigmine was associated with a decrease in the risk of pruritus but there was no increase in the incidence of hypotension, dizziness or sedation and no effect on the incidence of abnormal fetal heart rate patterns or Apgar scores. CONCLUSIONS: Neuraxial administration of neostigmine significantly reduces local anesthetic consumption without serious adverse side effects to the mother or fetus. However, neostigmine is only recommended for epidural administration as intrathecal use significantly increases the incidence of maternal nausea and vomiting. PMID- 26119259 TI - Chronic adhesive arachnoiditis after repeat epidural blood patch. AB - Epidural blood patching is an effective treatment for postdural puncture headache but has potential risks. Arachnoiditis is a very rare disabling condition and few cases have been described following an epidural blood patch. We present a case of chronic adhesive arachnoiditis in a parturient treated with a repeat epidural blood patch. A healthy 29-year-old woman had an accidental dural puncture following epidural insertion during labour. Initial treatment of postdural puncture headache with an epidural blood patch was ineffective and was therefore repeated. She gradually developed severe neurological symptoms consistent with arachnoiditis confirmed with magnetic resonance imaging. Despite intensive multimodal treatment with analgesics and physiotherapy, her neurological condition remains unresolved two years later. This serious but rare complication should encourage caution when treating parturients with postdural puncture headache with a repeat epidural blood patch. PMID- 26119260 TI - The impact of poor psychosocial work environment on non-work-related sickness absence. AB - PURPOSE: We aimed to analyse the impact of psychosocial work environment on non work-related sickness absence (NWRSA) among a prospective cohort study, stratified using a random sampling technique. METHODS: Psychosocial variables were assessed among 15,643 healthy workers using a brief version of the Spanish adaptation of Copenhagen Psychosocial Questionnaire. A one year follow-up assessed the total count of NWRSA days. Zero-inflated negative binomial regression was used for multivariate analyses. RESULTS: After adjusting for covariates, low levels of job control and possibilities for development (Odds Ratio [OR]: 1.17; 95% CI: 1.01-1.36 [men]; OR: 1.39 95% CI: 1.09-1.77 [women]), poor social support and quality of leadership (OR: 1.29; 95% CI: 1.11-1.50 [men]; OR: 1.28; 95% CI: 1.01-1.63 [women]), and poor rewards (OR: 1.34; 95% CI: 1.14 1.57 [men]; OR: 1.30; 95% CI: 1.01-1.66 [women]) predicted a total count of sickness absence greater than zero, in both men and women. Double presence was also significantly associated with NWRSA different than 0, but only among women (OR: 1.40; 95% CI: 1.08-1.81). Analyses found no association between psychosocial risk factors at work and the total count (i.e., number of days) of sickness absences. CONCLUSIONS: The results suggest that work-related psychosocial factors may increase the likelihood of initiating an NWRSA episode, but were not associated with the length of the sickness absence episode. Among our large cohort we observed that some associations were gender-dependent, suggesting that future research should consider gender when designing psychosocial interventions aimed at decreasing sickness absences. PMID- 26119261 TI - Parasitic helminths and their beneficial impact on type 1 and type 2 diabetes. AB - It is estimated that by the year 2035 almost 600 million people will suffer from diabetes. In the case of type 2 diabetes, the strongest increase of diabetes incidence occurs in developing and newly industrialized countries. This increase correlates not only with a progressing sedentary lifestyle and nutritional changes, but also environmental changes. Similarly, the increase of type 1 diabetes incidence in industrialized countries over the past decades cannot be explained by genetic factors alone, suggesting that environmental changes are also involved. One such environmental change is a reduced exposure to pathogens because of improved hygiene. Parasitic helminths modulate the immune system of their hosts and induce type 2 as well as regulatory immune responses. As pro inflammatory immune responses are crucial for the onset of both type 1 and type 2 diabetes, helminth-induced immunomodulation may prevent diabetes onset and ameliorate insulin sensitivity. Several epidemiological studies in human and experimental animal models support such a protective effect of helminths for autoimmune diabetes. Recent studies further suggest that helminths may also provide such a beneficial effect for type 2 diabetes. In this review we summarize studies that investigated parasitic helminths and helminth-derived products and their impact on both type 1 and type 2 diabetes highlighting potential protective mechanisms. PMID- 26119263 TI - Trait rumination moderates the effect of mentation type on heart rate responses to stressor recall. AB - Ruminative thought about stressors has been linked to extended post-stressor cardiovascular activation, which in turn predicts negative long-term health outcomes. Past work indicates that the nature of thought (mental imagery or verbal thought) may shape cardiovascular responses. Some evidence suggests that individuals with rumination tendencies may be especially vulnerable to stress related cardiovascular activation, although it is unclear to what extent type of thought (imagery or verbal thought) influences this relationship. This study included a laboratory stressor followed by a stressor recall task in which mentation type was manipulated. Healthy undergraduate students (N = 138; 47% female) underwent a speech stressor and then were randomly assigned to complete a stressor recall task using either mental imagery or verbal-linguistic mentation. Heart rate (HR) and blood pressure (BP) were measured throughout. Self-report trait rumination was measured at baseline. Results indicated that trait rumination and mentation type interacted to predict HR. Individuals with high trait rumination scores had significantly greater increases in HR during the verbal-linguistic conditions compared to the mental imagery conditions. There were no mentation type differences in the low trait ruminators, no differences in BP and no main effects of trait rumination. Results suggest that mentation type may be a key in understanding the relationship between rumination and cardiovascular activation, especially for trait ruminators. PMID- 26119262 TI - A Cell-Permeable ATP Analogue for Kinase-Catalyzed Biotinylation. AB - ATP analogues have been powerful compounds for the study of kinase-catalyzed phosphorylation. However, the cell impermeability of ATP analogues has largely limited their use to in vitro lysate-based experiments. Herein, we report the first cell-permeable ATP analogue, ATP-polyamine-biotin (APB). APB is shown to promote biotin labeling of kinase substrates in live cells and has future applications in phosphoprotein purification and analysis. More generally, these studies provide a foundation for the development of additional cell-permeable ATP analogues for cell-signaling research. PMID- 26119264 TI - Paleo-soraphens: chemical total syntheses and biological studies. AB - The soraphens are natural products that exhibit a molecular structure different from what would have been expected by following its polyketidal assembly line. The most significant differences are the presence of a hemiketal instead of a trisubstituted double bond and a double bond at C9 and C10 where a saturated carbon chain was expected. We were interested in the biological activity of the soraphens with architectures as described by the polyketide synthase since we hypothesized that these modifications reflect the evolutionary optimization of the soraphens. Herein we describe four additional derivatives of the so-called paleo-soraphens and their biological profiling to provide a picture of the hypothetical evolutionary optimization of this family of natural products. The syntheses required a unified and convergent strategy and their biological profiling was performed with the aid of impedance measurements. The results of these biological experiments are consistent with the proposed evolutionary optimization of the soraphens. PMID- 26119265 TI - Monitoring a CuO gas sensor at work: an advanced in situ X-ray absorption spectroscopy study. AB - X-ray absorption near edge structure (XANES) and electrical measurements were used to elucidate the local structure and electronic changes of copper(II) oxide (CuO) nanostructures under working conditions. For this purpose, a sample holder layout was developed enabling the simultaneous analysis of the spectroscopic and electrical properties of the sensor material under identical operating conditions. The influence of different carrier gases (e.g., air and N2) on the CuO nanostructures behavior under reducing conditions (H2 gas) was studied to analyze how a particular gas atmosphere can modify the oxidation state of the sensor material in real time. PMID- 26119266 TI - Screening wild and semi-free ranging great apes for putative sexually transmitted diseases: Evidence of Trichomonadidae infections. AB - Sexually transmitted diseases (STDs) can persist endemically, are known to cause sterility and infant mortality in humans, and could have similar impacts in wildlife populations. African apes (i.e., chimpanzees, bonobos, and to a lesser extent gorillas) show multi-male mating behavior that could offer opportunities for STD transmission, yet little is known about the prevalence and impact of STDs in this endangered primate group. We used serology and PCR-based detection methods to screen biological samples from wild and orphaned eastern chimpanzees and gorillas (N = 172 individuals, including adults, and juveniles) for four classes of pathogens that either commonly cause human STDs or were previously detected in captive apes: trichomonads, Chlamydia spp., Treponema pallidum (syphilis and yaws), and papillomaviruses. Based on results from prior modeling and comparative research, we expected STD prevalence to be highest in females versus males and in sexually mature versus immature individuals. All samples were negative for Chlamydia, Treponema pallidum, and papillomaviruses; however, a high percentage of wild chimpanzee urine and fecal samples showed evidence of trichomonads (protozoa). Analysis revealed that females were more likely than males to have positive urine-but not fecal-samples; however, there was no evidence of age (sexual maturity) differences in infection status. Sequence analysis of chimpanzee trichomonad samples revealed a close relationship to previously described trichomonads within the genus Tetratrichomonas. Phylogenetic comparisons to archived sequences from multiple vertebrate hosts suggests that many of the chimpanzee parasites from our study are likely transmitted via fecal oral contact, but the transmission of some Tetratrichomonas sequence-types remains unknown and could include sexual contact. Our work emphasizes that only a fraction of infectious agents affecting wild apes are presently known to science, and that further work on great ape STDs could offer insights for the management of endangered great apes and for understanding human STD origins. PMID- 26119267 TI - Body diffusion kurtosis imaging: Basic principles, applications, and considerations for clinical practice. AB - Technologic advances enable performance of diffusion-weighted imaging (DWI) at ultrahigh b-values, where standard monoexponential model analysis may not apply. Rather, non-Gaussian water diffusion properties emerge, which in cellular tissues are, in part, influenced by the intracellular environment that is not well evaluated by conventional DWI. The novel technique, diffusion kurtosis imaging (DKI), enables characterization of non-Gaussian water diffusion behavior. More advanced mathematical curve fitting of the signal intensity decay curve using the DKI model provides an additional parameter Kapp that presumably reflects heterogeneity and irregularity of cellular microstructure, as well as the amount of interfaces within cellular tissues. Although largely applied for neural applications over the past decade, a small number of studies have recently explored DKI outside the brain. The most investigated organ is the prostate, with preliminary studies suggesting improved tumor detection and grading using DKI. Although still largely in the research phase, DKI is being explored in wider clinical settings. When assessing extracranial applications of DKI, careful attention to details with which body radiologists may currently be unfamiliar is important to ensure reliable results. Accordingly, a robust understanding of DKI is necessary for radiologists to better understand the meaning of DKI-derived metrics in the context of different tumors and how these metrics vary between tumor types and in response to treatment. In this review, we outline DKI principles, propose biostructural basis for observations, provide a comparison with standard monoexponential fitting and the apparent diffusion coefficient, report on extracranial clinical investigations to date, and recommend technical considerations for implementation in body imaging. PMID- 26119268 TI - A case of intraductal tubulopapillary neoplasm of pancreas with severe calcification, a potential pitfall in diagnostic imaging. AB - We experienced a case of intraductal tubulopapillary neoplasms (ITPN) of the pancreas with severe calcification, which complicated image diagnosis. A pancreas head tumor was detected in a Japanese female in her 50s. Early enhancement by contrast-enhanced CT and coarse calcification suggested a neuroendocrine tumor, although the obstruction and dilation of the main pancreatic duct appeared to be an intraductal tumor. An endoscopic ultrasound-guided fine needle aspiration biopsy specimen revealed adenocarcinoma tissue. Pancreaticoduodenectomy was performed, and the patient has been well without evidence of recurrence for over 10 months. Pathological examination on the resected specimen revealed that the tumor showed papillary and tubulo-cribriform growth patterns. Together with typical immunohistochemical results, the final diagnosis of ITPN was made. Characteristically, this case showed extensive calcification of both psammoma body-type and non psammoma body-type with foamy macrophage aggregation. This is the first report of ITPN with two types of calcification and macrophage. Since calcification might be one of the characteristic histological findings in ITPN as shown in our case, the possibility of ITPN should be also considered when calcification is detected in pancreatic lesions by various imaging modalities. PMID- 26119270 TI - Spleen function after preservation in a physiological solution. AB - BACKGROUND: The purpose of this study was to evaluate the morphology and function of implanted autogenous spleen tissue after 24 h of preservation in a physiological solution. MATERIAL AND METHODS: Thirty-five male rats were divided into seven groups (n = 5): group 1, without surgical procedure; group 2, total splenectomy; group 3, total splenectomy and immediate implant of autogenous spleen tissue; group 4, total splenectomy and preservation of the entire spleen in lactated Ringer solution at room temperature for 24 h, followed by spleen sectioning and implantation; group 5, total splenectomy, followed by spleen sectioning and preservation in lactated Ringer solution at room temperature for 24 h and subsequent implantation of the slices; group 6, total splenectomy and preservation of the entire spleen in lactated Ringer solution at 4 degrees C for 24 h, followed by spleen sectioning and implantation; and group 7, total splenectomy, the spleen was sliced and preserved in lactate Ringer solution at 4 degrees C for 24 h, followed by implantation of the slices. After 90 d, scintigraphic studies using sulfur colloid labeled with 99mTc of the liver, lungs, spleen, implants, and a blood clot were performed. Hematological (erythrogram, leukogram, and platelets) and histologic studies were carried out. RESULTS: The autogenous splenic implants regenerated in all animals that received those implants preserved at 4 degrees C and immediately after excision. The scintigraphic study showed a better phagocytic function in groups 1, 3, 6, and 7. No difference was observed in the hematological study. CONCLUSIONS: Spleen tissue preserved in lactated Ringer solution at 4 degrees C for 24 h maintains its vitality and capacity to recover hematological and phagocytic functions. PMID- 26119269 TI - Adverse Outcome Pathways and Drug-Induced Liver Injury Testing. AB - Drug-induced liver injury is a prominent reason for premarketing and postmarketing drug withdrawal and can be manifested in a number of ways, such as cholestasis, steatosis, and fibrosis. The mechanisms driving these toxicological processes have been well characterized and have been emdedded in adverse outcome pathway frameworks in recent years. This review evaluates these constructs and simultaneously illustrates their use in the preclinical testing of drug-induced liver injury. PMID- 26119271 TI - Warming barium sulfate improves esophageal leak detection in pig model. AB - BACKGROUND: Barium esophagograms have poor sensitivity in detecting leaks. We hypothesized that heating barium would decrease viscosity, facilitate extravasation, and enhance its sensitivity in detecting esophageal leaks. METHODS: We characterized the viscosity of barium at increasing temperatures. We measured the radiopacity of barium at 25 degrees C and 50 degrees C. We determined the smallest diameter defect in esophagus that barium can detect by perforating a porcine esophageal segment with angiocatheters of various diameters, injecting barium at 25 degrees C, and observing extravasation of contrast. We repeated this with barium heated to 30 degrees C, 40 degrees C, 50 degrees C, and 70 degrees C. To determine the ability of barium to detect a staple line leak, we perforated a stapled esophageal segment by air insufflation, injected barium at different temperatures, and monitored extravasation. We used Visipaque, a water-soluble contrast agent, for comparison in all experiments. RESULTS: The viscosity of barium decreased with increasing temperature. The radiopacity of barium did not change with increasing temperature and was higher than that of Visipaque (P < 0.001). The size of the smallest detectable leak decreased from 2.1 mm with barium at 25 degrees C to 1.3 mm at 40 degrees C and 1.1 mm with Visipaque (P < 0.0001). The sensitivity of staple line leak detection increased from 0% for barium at 25 degrees C to 80% (P = 0.02) with barium at 40 degrees C. There was no significant difference in sensitivity between barium at 40 degrees C and Visipaque. CONCLUSIONS: Barium warmed to 40 degrees C offers the best sensitivity of esophageal leak detection without compromising radiopacity. Barium at 40 degrees C may be the optimum choice for swallow study to detect esophageal leaks. PMID- 26119272 TI - Circulating CD133(+)/ESA(+) cells in colorectal cancer patients. AB - BACKGROUND: Tumor initiating cells are a small subset of cancer cells responsible for tumor growth and recurrence. The status of tumor initiating cells was measured using the surface markers CD133 (prominin-1) and ESA (epithelial specific antigen). The aims of this study were to investigate the significance of CD133(+)/ESA(+) cells in mesenteric venous blood (MVB) and tumor mass (TM) for overall survival (OS) and disease-free survival (DFS) in colorectal cancer (CRC) patients undergoing curative resection. MATERIALS AND METHODS: A total of 229 CRC patients undergoing curative resection were prospectively enrolled in the study. Using CD133 and ESA as surface markers, CD133(+)/ESA(+) cells were enumerated from MVB and TM using flow cytometry. RESULTS: We analyzed the presence of CD133(+)/ESA(+) cells in TM from 158 patients and found no correlation to patient DFS, OS, or clinical stage. In 135 patients, an analysis of CD133(+)/ESA(+) cells in MVB showed an inverse correlation with both DFS and OS (P = 0.014 and P = 0.008, respectively). It exhibited an increase-then-decrease pattern with the peak in stage II patients. A multivariate Cox analysis demonstrated that the status of CD133(+)/ESA(+) cells in MVB, but not the TM, was a significant prognostic factor for DFS and OS (P = 0.003 and P = 0.011, respectively). CONCLUSIONS: The status of CD133(+)/ESA(+) cells in MVB, but not in TM, could be a useful indicator for predicting tumor recurrence and a prognostic marker for CRC patients. PMID- 26119273 TI - Quality and outcomes reporting in trauma using International Statistical Classification for Diseases, Ninth Revision codes. AB - BACKGROUND: Use of the trauma and injury severity score (TRISS) for quality and outcomes assessment is challenged by the need for laborious collection of demographic and physiological data. We hypothesize that a novel stratification approach based on International Statistical Classification for Diseases, Ninth Revision (ICD-9) data that are readily available for trauma patients provides a more accurate and more easily obtainable alternative to TRISS with the potential for widespread use. METHODS: Data from the ACS National Trauma Data Bank were used to train and evaluate a regularized logistic regression model for mortality and linear regression models for hospital length of stay (HLOS) and intensive care unit length of stay (ILOS) using ICD-9 diagnostic and procedural codes. Model training was performed on data from 2008 (n = 124,625) and evaluation on data from 2009 (n = 120,079). The discrimination and calibration of each model based on ICD-9 codes were compared with those of TRISS. RESULTS: The mortality model using ICD-9 codes was comparable with that of TRISS in terms of the area under the receiver operating characteristic curve (0.922 versus 0.921, P = not significant.) and achieved better results in terms of both integrated discrimination improvement (0.106, P < 0.001) and Hosmer-Lemeshow chi-squared value (294.15 versus 2043.20). The HLOS and ILOS models using ICD-9 codes also demonstrated improvements in both R(2) (0.64 versus 0.30 for HLOS, 0.68 versus 0.34 for ILOS) and root mean-squared error (7.06 versus 8.62 for HLOS, 4.15 versus 9.54 for ILOS). CONCLUSIONS: Use of ICD-9 codes for stratification provides a more accurate and more broadly applicable approach to quality and outcomes assessment in trauma patients than the labor-intensive gold standard of TRISS. PMID- 26119274 TI - Ultrasound microbubbles enhance human beta-defensin 3 against biofilms. AB - BACKGROUND: The infection of orthopedic implantation devices with Staphylococcus has been a serious concern within the biomaterial community. Treatments are not always successful because of antibiotic-resistant bacteria biofilm infection. Recent studies have shown that combination of antibiotics with low-frequency ultrasound (US) can enhance the bactericidal activity effectively against the formation of biofilms in vitro pilot study. Meanwhile, microbubbles evolved as targeted drug-delivery agents can provide nuclei for inertial cavitation and lower the threshold for US-induced cavitation. Human beta-defensin 3 (HBD-3) is a cationic antimicrobial peptide considered particularly promising for future bactericidal employment and has effect on antibiotic-resistant Staphylococcus biofilms. But the effect has not been reported when combined with US-targeted microbubble destruction (UTMD) in vivo. METHODS: In this study, we evaluated the effect of HBD-3 combined with UTMD on two tested Staphylococcus by the spread plate method, crystal violet staining, confocal laser scanning microscopy, scanning electron microscopy, and real-time polymerase chain reaction. RESULTS: In the study, we found that the biofilm densities, the percentage of live cells, and the viable counts of two tested Staphylococcus that recovered from the biofilm on the titanium surface in mice were significantly decreased in the group of the HBD-3 combined with UTMD, compared with those of other groups. Furthermore, in the experiment, we found out that UTMD could enhance HBD-3 activity, which inhibits the biofilm-associated genes expression of icaAD and the methicillin-resistance genes expression of MecA by promoting the icaR expression simultaneously. CONCLUSIONS: The combination of HBD-3 with UTMD can play a significant role on the elimination of the antibiotic-resistant Staphylococcus biofilms in vivo. PMID- 26119275 TI - Protective effect of crocetin against burn-induced intestinal injury. AB - BACKGROUND: Oxidative stress and inflammation exert central roles in burn-induced intestinal injury. Crocetin, a natural carotenoid compound from gardenia fruits and saffron, has been shown to inhibit oxidative stress and inflammatory response. However, the possibility of crocetin to be used in the treatment of intestinal injury after burn injury has not been investigated. The purpose of the present study was to investigate the effects and potential mechanisms of crocetin in burn-induced intestinal injury. MATERIALS AND METHODS: Several free radical generating and lipid peroxidation models were used to systematically assess the antioxidant activities of crocetin in vitro. A common burn model was used to induce the intestinal injury in rats. Changes in the levels of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, tumor necrosis factor alpha, interleukin 6, polymorphonuclear neutrophil accumulation, intestinal permeability, and intestinal histology were examined. RESULTS: In several models of antioxidant activity, crocetin exhibited marked inhibitory action against free radicals and lipid peroxidation. Crocetin increased levels of antioxidant enzymes and reduced intestinal oxidative injury in burn models. In addition, crocetin inhibited polymorphonuclear neutrophil accumulation, ameliorated tumor necrosis factor alpha and interleukin 6 levels, intestinal permeability, and histological changes. CONCLUSIONS: Crocetin treatment may protect against burn-induced small intestinal injury, possibly by inhibiting burn-induced oxidative stress and inflammatory response. PMID- 26119276 TI - Diabetic foot infection caused by community-associated methicillin-resistant Staphylococcus aureus (USA300). PMID- 26119277 TI - Nanosilver pathophysiology in earthworms: Transcriptional profiling of secretory proteins and the implication for the protein corona. AB - Previously we have identified lysenin as a key protein constituent of the secretome from Eisenia fetida coelomocytes and revealed its critical importance in priming interactions between the cells and the protein corona around nanosilver. As alterations of the protein environment can directly affect the corona composition, the extent to which nanoparticles influence the cells' protein secretion profile is of remarkable interest that has rarely acquired attention. Here, we have probed transcriptional responses of E. fetida coelomocytes to the representative nanosilver NM-300K (15 nm) in a time-dependent manner (2, 4, 8 and 24 h at a low-cytotoxic concentration), and examined the implication of the temporal changes in transcriptional profiles of secretory proteins with a particular reference to that of lysenin. NM-300K was accumulated in/at the cells and lysenin was, after transient induction, gradually suppressed over time indicating a negative feedback cycle. This may limit further enrichment of lysenin in the corona and thereby decrease the lysenin-assisted uptake of the nanoparticles. Other differentially expressed genes were those involved in metal stress (likewise in AgNO3-stressed cells) and in Toll-like receptor (TLR) signaling. This offers an intriguing perspective of the nanosilver pathophysiology in earthworms, in which the conserved pattern recognition receptor TLRs may play an effector role. PMID- 26119278 TI - Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors. AB - Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S is the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low-molecular-weight inhibitors for cathepsin F have not yet been developed. An active site mapping with 52 dipeptide nitriles, reacting as covalent-reversible inhibitors, was performed to draw structure-activity relationships for the non-primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N-(4-phenylbenzoyl) leucylglycine nitrile) and 12 (N-(4-phenylbenzoyl)leucylmethionine nitrile) were found to be potent inhibitors of human cathepsin F, with Ki values <10 nM. With all dipeptide nitriles from our study, a 3D activity landscape was generated to visualize structure-activity relationships for this series of cathepsin F inhibitors. PMID- 26119279 TI - Delayed Trigeminal Motor Denervation after Pontine Hemorrhage. AB - Pontine hemorrhage is a life-threatening emergency which may result in high mortality and devastating disability. Trigeminal denervation is usually caused by neoplasms and trauma but rarely occurs after pontine hemorrhage. Herein, we present a patient with delayed trigeminal motor denervation who presents with progressive atrophy of the right temporalis and masseter muscles 1 year after pontine hemorrhage. Details of the pathogenesis and correlation between clinical, electrophysiological, and radiological findings are addressed. PMID- 26119281 TI - Axo-glial communication through neurexin-neuroligin signaling regulates myelination and oligodendrocyte differentiation. AB - Axonal transsynaptic signaling between presynaptic neurexin (NX) and postsynaptic neuroligin (NL) is essential for many properties of synaptic connectivity. Here, we demonstrate the existence of a parallel axo-glial signaling pathway between axonal NX and oligodendritic (OL) NL3. We show that this pathway contributes to the regulation of myelinogenesis, the maintenance of established myelination, and the differentiation state of the OL using in vitro models. We first confirm that NL3 mRNA and protein are expressed in OLs and in OL precursors. We then show that OLs in culture form contacts with non-neuronal cells exogenously expressing NL3's binding partners NX1alpha or NX1beta. Conversely, blocking axo-glial NX-NL3 signaling by saturating NX with exogenous soluble NL protein (NL-ECD) disrupts interactions between OLs and axons in both in vitro and ex vivo assays. Myelination by OLs is tied to their differentiation state, and we find that blocking NX-NL signaling with soluble NL protein also caused OL differentiation to stall at an immature stage. Moreover, in vitro knockdown of NL3 in OLs with siRNAs stalls their development and reduces branching complexity. Interestingly, inclusion of an autism related mutation in the NL blocking protein attenuates these effects; OLs differentiate and the dynamics of OL-axon signaling occur normally as this peptide does not disrupt NX-NL3 axo-glial interactions. Our findings provide evidence not only for a new pathway in axo-glial communication, they also potentially explain the correlation between altered white matter and autism. GLIA 2015;63:2023-2039. PMID- 26119280 TI - Shp-2 contributes to anti-RSV activity in human pulmonary alveolar epithelial cells by interfering with the IFN-alpha-induced Jak/Stat1 pathway. AB - Src homology phosphotyrosyl phosphatase 2 (Shp-2) is a ubiquitously expressed protein that is involved in a variety of cellular processes, including antiviral interferon signalling pathways. In this study, we investigated the role of Shp-2 in the host cell interactions of human respiratory syncytial virus (RSV). We report significant changes in the expression of Shp-2 in human pulmonary alveolar epithelial cells (A549) upon RSV infection. We also report that blocking Shp-2 does not affect viral replication or virus-induced interferon-alpha (IFN-alpha) production. Interestingly, whereas A549 cells were activated by IFN-alpha, the blocking of Shp-2 resulted in increased viral replication that was associated with the reduced expression of the IFN-stimulated genes of 2',5'-oligoadenylate synthetases and Mx1, and the concomitant inhibition of Stat1 tyrosine phosphorylation. Our findings suggest that Shp-2 contributes to the control of RSV replication and progeny production in pulmonary alveolar epithelial cells by interfering with IFN-alpha-induced Jak/Stat1 pathway activation rather than by affecting the production of IFN-alpha itself. PMID- 26119283 TI - The role of leptin in psoriasis comprises a proinflammatory response by the dermal fibroblast. PMID- 26119284 TI - Anti-osmotic and antioxidant activities of gigantol from Dendrobium aurantiacum var. denneanum against cataractogenesis in galactosemic rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium aurantiacum var. denneanumis widespread in southern China, locally known as "Shihu", "Huangcao" or "Fengdou", has long been used in traditional Chinese medicine for antipyretic, immunomodulatory, anti-aging effects and eye benefiting. AIM OF THIS STUDY: To investigate the effects of gigantol extracted from the stem of D. aurantiacum var. denneanum on the formation of galactose-induced cataractogenesis and the potential mechanisms underlying these effects. MATERIALS AND METHODS: Cataract lens models were induced by d-galactose both in vitro and in vivo. The transparency of the rat lenses in vitro and in vivo was observed with an anatomical microscope and a slit lamp microscope. The differential protein and action targets of gigantol were determined and compared among the control group, model group, and gigantol group using two-dimensional electrophoresis and mass spectrometry (MS). Enzyme kinetics was used to show the ability of gigantol to respress aldose reductase (AR) and inducible nitric oxide synthase (iNOS). Quantitative real-time PCR (RT-qPCR). was used to detect repression of the expression of AR and iNOS genes. Molecular docking and dynamic simulation were used to predict the interaction points and combination patterns between gigantol, AR, and iNOS. RESULTS: Gigantol was found to prevent galactose-induced damage to the rat lenses both in vitro and in vivo, to delay lens turbidity, and to keep the lenses transparent. Differential proteomes, MS, and RT-qPCR showed AR and iNOS to be the target proteins of gigantol. Gigantol reduced the galactose induced AR and iNOS mRNA expression by 51.2% and 60.9%, respectively. The IC50 of gigantol for inhibition of AR and iNOS activities were 65.67 MUg/mL and 8.768 MUg/mL, respectively. Gigantol-AR binding sites were Trp111, His110, Tyr48, and Trp20, and gigantol-iNOS binding sites were Ile195 and Gln257. The main forms of interaction were hydrophobic forces, hydrogen bonds, and van der Waals forces. CONCLUSION: Gigantol extracted from D. aurantiacum var. denneanum was found to inhibit galactose-induced formation of cataracts through repression of the gene expression and activity of AR and iNOS. PMID- 26119285 TI - A double-blind, placebo-controlled randomized trial of Serratulae quinquefoliae folium, a new source of beta-arbutin, in selected skin hyperpigmentations. AB - BACKGROUND: Arbutin is one of the most effective lightening substances. Serratula quinquefolia is a new source of its beta-anomer. The HPLC method showed that the solid content of this compound in the dried plant raw material accounts for 6.86%. The leaves of Serratula quinquefolia do not contain hydroquinone. AIMS: To assess the efficacy of the aqueous extract from' leaf of five-leaf serratula as a skin-lightening agent. PATIENTS/METHODS: We did a randomized, placebo-controlled, double-blind trial. The study involved 102 women aged 26-55, with two kinds of hyperpigmentary diseases: melasma and lentigo solaris. Patients were randomly assigned to one of the treatment groups: a study group (N = 54) or a control group (N = 48). The study group applied the cream with the aqueous extract from leaf of five-leaf serratula containing 2.51% of arbutin. The cream was applied twice a day on the discolored side for 8 weeks. RESULTS: The experimental data showed that the cream with the extract causes decreased level of melanin in the skin pigmentation spot. Clinical effect in the form of lightening and evening skin tone on the discolored side was observed in 75.86% of the female patients with melasma and 56.00 % of the female patients with lentigo solaris. CONCLUSIONS: The cream with the aqueous extract from leaf of five-leaf serratula proved to be an effective and safe preparation for lightening skin discolorations (66.67 % of the female patients in the study group). PMID- 26119286 TI - Statistical analysis of electronic excitation processes: Spatial location, compactness, charge transfer, and electron-hole correlation. AB - We report the development of a set of excited-state analysis tools that are based on the construction of an effective exciton wavefunction and its statistical analysis in terms of spatial multipole moments. This construction does not only enable the quantification of the spatial location and compactness of the individual hole and electron densities but also correlation phenomena can be analyzed, which makes this procedure particularly useful when excitonic or charge resonance effects are of interest. The methods are first applied to bianthryl with a focus on elucidating charge-resonance interactions. It is shown how these derive from anticorrelations between the electron and hole quasiparticles, and it is discussed how the resulting variations in state characters affect the excited state absorption spectrum. As a second example, cytosine is chosen. It is illustrated how the various descriptors vary for valence, Rydberg, and core excited states, and the possibility of using this information for an automatic characterization of state characters is discussed. PMID- 26119287 TI - An evaluation of resistance to change with unconditioned and conditioned reinforcers. AB - Several reinforcer-related variables influence a response's resistance to change (Nevin, 1974). Reinforcer type (i.e., conditioned or unconditioned) is a reinforcer-related variable that has not been studied with humans but may have clinical implications. In Experiment 1, we identified unconditioned and conditioned reinforcers of equal preference. In Experiments 2, 3, and 4, we reinforced participants' behavior during a baseline phase using a multiple variable-interval (VI) 30-s VI 30-s schedule with either conditioned (i.e., token) or unconditioned (i.e., food; one type of reinforcement in each component) reinforcement. After equal reinforcement rates across components, we introduced a disruptor. Results of Experiments 2 and 3 showed that behaviors were more resistant to extinction and distraction, respectively, with conditioned than with unconditioned reinforcers. Results of Experiment 4, however, showed that when prefeeding disrupted responding, behaviors were more resistant to change with unconditioned reinforcers than with conditioned reinforcers. PMID- 26119282 TI - The role of the intensive care unit in real-time surveillance of emerging pandemics: the Italian GiViTI experience. AB - The prompt availability of reliable epidemiological information on emerging pandemics is crucial for public health policy-makers. Early in 2013, a possible new H1N1 epidemic notified by an intensive care unit (ICU) to GiViTI, the Italian ICU network, prompted the re-activation of the real-time monitoring system developed during the 2009-2010 pandemic. Based on data from 216 ICUs, we were able to detect and monitor an outbreak of severe H1N1 infection, and to compare the situation with previous years. The timely and correct assessment of the severity of an epidemic can be obtained by investigating ICU admissions, especially when historical comparisons can be made. PMID- 26119288 TI - Gestational Weight Gain and Overweight in Children Aged 3-6 Years. AB - OBJECTIVE: To determine whether gestational weight gain (GWG) was associated with increased odds of childhood overweight after accounting for pre-pregnancy BMI. METHODS: In a prospective cohort study based on a premarital and perinatal health care system in China, data of 100 612 mother-child pairs were obtained. The main exposure was GWG as both a continuous and categorical variable. The outcome measure was overweight, defined by age- and sex-specific cutoff values for body mass index (BMI) in children aged 3-6 years. RESULTS: A 1-kg increase in maternal GWG was associated with an increase of 0.009 (95% confidence interval [CI]: 0.007 0.010, P < 0.001) in children's mean BMI; in the subgroup of pre-pregnancy overweight/obese mothers, the increase in children's BMI was 0.028 (95% CI, 0.017 0.039, P < 0.001). Excessive GWG played an important role in childhood overweight when adequate GWG was used as the reference, with an odds ratio (OR) of 1.21 (95% CI, 1.12-1.29). The risk was highest (OR 2.22; 95% CI, 1.79-2.76) in the children of mothers who were overweight/obese before pregnancy and gained excessive weight during pregnancy. CONCLUSIONS: Greater maternal GWG was associated with greater offspring BMI, and the risk of overweight was doubled in children whose mothers were overweight/obese before pregnancy and gained excessive weight during pregnancy. As a result, maintenance of appropriate weight gain during pregnancy and prophylaxis of maternal overweight/obesity before pregnancy should be a strategy for preventing childhood overweight/obesity. PMID- 26119289 TI - The Risk of Opioid Intoxications or Related Events and the Effect of Alcohol Related Disorders: A Retrospective Cohort Study in German Patients Treated with High-Potency Opioid Analgesics. AB - INTRODUCTION: Intoxications involving prescription opioids are a major public health problem in many countries. When taken with opioids, alcohol can enhance the effects of opioids, particularly in the central nervous system. However, data quantifying the impact of alcohol involvement in opioid-related intoxications are limited. METHODS: Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), we conducted a retrospective cohort study based on users of high-potency opioid (HPO) analgesics during the years 2005-2009. HPO use was classified as extended-release, immediate-release or both. We calculated incidence rates (IRs) for opioid intoxications or related events as well as adjusted IR ratios (aIRR) comparing HPO-treated patients with alcohol-related disorders (ARDs) to those without ARDs overall and within each HPO category. RESULTS: During the study period, 308,268 HPO users were identified with an overall IR of 340.4 per 100,000 person-years [95 % confidence interval (CI) 325.5 355.7]. The risk was highest when patients received concomitant treatment with extended- and immediate-release HPOs (IR 1093.8; 95 % CI 904.6-1310.9). ARDs increased the risk during HPO use by a factor of 1.7 and the highest aIRR was seen when comparing patients simultaneously exposed to extended- and immediate release HPOs with ARDs to those without ARD also after excluding patients with potential improper/non-medical HPO use. CONCLUSIONS: Physicians should be aware of these elevated risks in HPO patients with ARDs. Active patient education by healthcare providers regarding the risk of opioid intoxications or related events due to alcohol in conjunction with HPOs is warranted. PMID- 26119290 TI - Detection and characterisation of Complement protein activity in bovine milk by bactericidal sequestration assay. AB - While the Complement protein system in human milk is well characterised, there is little information on its presence and activity in bovine milk. Complement forms part of the innate immune system, hence the importance of its contribution during milk ingestion to the overall defences of the neonate. A bactericidal sequestration assay, featuring a Complement sensitive strain, Escherichia coli 0111, originally used to characterise Complement activity in human milk was successfully applied to freshly drawn bovine milk samples, thus, providing an opportunity to compare Complement activities in both human and bovine milks. Although not identical in response, the levels of Complement activity in bovine milk were found to be closely comparable with that of human milk. Differential counts of Esch. coli 0111 after 2 h incubation were 6.20 and 6.06 log CFU/ml, for raw bovine and human milks, respectively - the lower value representing a stronger Complement response. Exposing bovine milk to a range of thermal treatments e.g. 42, 45, 65, 72, 85 or 95 degrees C for 10 min, progressively inhibited Complement activity by increasing temperature, thus confirming the heat labile nature of this immune protein system. Low level Complement activity was found, however, in 65 and 72 degrees C heat treated samples and in retailed pasteurised milk which highlights the outer limit to which high temperature, short time (HTST) industrial thermal processes should be applied if retention of activity is a priority. Concentration of Complement in the fat phase was evident following cream separation, and this was also reflected in the further loss of activity recorded in low fat variants of retailed pasteurised milk. Laboratory based churning of the cream during simulated buttermaking generated an aqueous (buttermilk) phase with higher levels of Complement activity than the fat phase, thus pointing to a likely association with the milk fat globule membrane (MFGM) layer. PMID- 26119291 TI - Primary cutaneous rhabdomyosarcoma: Case report and review of published work. PMID- 26119292 TI - The Blood-Brain Barrier as a Focus of Drug Metabolism and Pharmacokinetics Research. PMID- 26119293 TI - The Graphene Flagship-A Giant European Research Project. PMID- 26119294 TI - Using the Neptune project to benefit Australian aquatic animal health research. AB - Diseases of aquatic animals have had, and continue to have, a significant impact on aquatic animal health. In Australia, where fisheries and aquaculture are important industries, aquatic species have been subject to serious disease outbreaks, including pilchard herpesvirus, the cause of one of the largest wild fish kills ever recorded. At the same time, there is a consensus that Australia's parasite fauna are largely unknown, and that aquatic animal health information is difficult to access. Managing aquatic animal diseases is challenging because they may be entirely new, their hosts may be new to aquaculture, and specialist expertise and basic diagnostic tools may be lacking or absent. The Neptune project was created in response to these challenges, and it aims to increase awareness of aquatic animal diseases, improve disease management, and promote communication between aquatic animal health professionals in Australia. The project consists of an online database, a digital microscopy platform containing a whole-slide image library, a community space, and online communications technology. The database contains aquatic animal health information from published papers, government reports, and other sources, while the library contains slides of key diseases both endemic and exotic to Australia. These assets make Neptune a powerful resource for researchers, students, and biosecurity officials. PMID- 26119295 TI - Anisakidae in beluga whales Delphinapterus leucas from Hudson Bay and Hudson Strait. AB - A total of 190 nematodes was isolated from the stomachs of 13 beluga whales Delphinapterus leucas from the Arctic part of Hudson Bay and Hudson Strait. Infection intensity ranged from 1 to 57 specimens and prevalence was 84.62%. Morphological examination of the nematodes revealed the presence of 3 species: Pseudoterranova decipiens sensu lato, Contracaecum osculatum s.l., and Anisakis simplex s.l. Molecular analysis by PCR-based restriction fragment length polymorphism (PCR-RFLP) resulted in the identification of 4 species: Pseudoterranova bulbosa, Contracaecum osculatum A and C, and Anisakis simplex sensu stricto. The nematodes were present in 3 developmental stages: L3 (159 specimens), L4 (16 larvae), and adults (15 worms: 11 males and 4 females). PMID- 26119296 TI - Modulation of Hsp60 in response to coral brown band disease. AB - Brown band disease (BrB), a virulent coral disease characterized by a dense concentration of ciliates ingesting coral tissue, is responsible for ongoing coral losses on Indo-Pacific reefs. Although several efforts have been made to identify the microbial communities associated with BrB and study the disease ecology, less attention has been given to the effect of ciliate presence on coral physiology. Levels of the mitochondrial heat shock protein 60-kDa (Hsp60, a biomarker indicative of cellular stress) were analyzed in apparently healthy coral polyps located at different distances along the advancing front of infection in Acropora muricata colonies affected by BrB in a Maldivian reef. Different Hsp60 levels were found in different parts of the same colony. Starting from a basal protein level in the healthy control colonies, a down-regulation of Hsp60 expression was detected near the ciliate band, indicating that the Hsp60 defense activity was probably already compromised due to the rapid progression rate of the BrB ciliate on the diseased branches and/or to the etiology of the disease. Moving away from the band, the Hsp60 levels gradually returned to a state comparable to that found in the control, showing that cellular damage was confined to areas near the infection. In conclusion, we propose the analysis of Hsp60 modulation as a useful tool for examining physiological variations that are not detected at the morphological level in corals subjected to epizootic diseases, while providing new insights into the immune response of corals. PMID- 26119297 TI - Goldfish Carassius auratus susceptibility to viral hemorrhagic septicemia virus genotype IVb depends on exposure route. AB - We assessed the susceptibility of goldfish Carassius auratus to infection by genotype IVb of the viral hemorrhagic septicemia virus. Goldfish were infected by intraperitoneal injections of 106 plaque-forming units (pfu) fish-1, single bath exposure of 105 pfu ml-1 for 24 h, or consumption of 0.4 g of commercial fish feed soaked in 107 pfu per 8 fish. The mortality rate of intraperitoneal-infected goldfish was 10 to 32%, although the virus was detected by quantitative RT-PCR in 77% (65/84) of the survivors at the end of the 42 d trial, suggesting a carrier state. Severe gross lesions were observed in many of the moribund and dead goldfish such as hemorrhaging in the skin, fin, liver, kidney, brain, intestine, and eye as well as abdominal distension, bilateral exophthalmia, and splenomegaly. There was minimal morbidity or mortality in the immersion, feeding, or control groups. PMID- 26119298 TI - Morphological and molecular characterization of Thelohanellus hoffmanni sp. nov. (Myxozoa) infecting goldfish Carassius auratus auratus. AB - A new species of the genus Thelohanellus Kudo, 1933 (Myxosporea, Bivalvulida) was isolated from the fins of goldfish Carassius auratus auratus (Linnaeus 1758). The fish had been imported from China by an Austrian retailer. Nodules from the margins of the fins contained pyriform myxospores with a singular polar capsule. In valvular view, the spores measured 12.2 um in length and 6.4 um in width. In sutural view, the thickness was 2.9 um. The polar capsule measured 4.2 * 3.1 um and contained a polar filament with 8 to 9 coils. Histological sections showed plasmodia of 0.2 to 4.0 mm diameter with the earlier developmental stages of the parasite in the periphery and the mature spores closer to the center. In the transmission electron microscope examination, the different developmental stages could be observed. Morphological data, host specificity, tissue tropism, and molecular analysis of the small subunit rDNA identify this parasite as a new species of Thelohanellus, which we have named Thelohanellus hoffmanni sp. nov. PMID- 26119299 TI - Induction of mild enterocolitis in zebrafish Danio rerio via ingestion of Vibrio anguillarum serovar O1. AB - Vibrio anguillarum is the etiological agent of a fatal hemorrhagic disease known as vibriosis that affects a wide range of fish species, causing severe economic losses. Several investigations have been carried out to elucidate the virulence mechanisms of this pathogen and to develop rapid detection techniques and effective disease-prevention strategies. The aim of our study was to evaluate the most effective way to induce mild enteritis in a fish model, in order to allow further applications. The experiments were carried out using 2 methods of administration of V. anguillarum serotype O1 to adult zebrafish Danio rerio: via intraperitoneal injection and via ingestion of infected Artemia nauplii. The results showed that the intraperitoneal administration often caused massive fish death due to severe systemic involvement. In our experiments, the effect of intraperitoneal infection was evident 48 h post infection, with cumulative mortality within 7 d post infection with severe histopathological changes in kidney hematopoietic tissue and in the intestine. In contrast, oral infection via Artemia did not show systemic involvement and only a moderate degree of inflammatory influx of the mucosa, a partial recovery at 12 d post infection, and no mortality. For these reasons, oral infection with live food appears to be the most effective method to induce mild enteritis with a local inflammatory response. PMID- 26119300 TI - Effect of a phytogenic feed additive on the susceptibility of Onchorhynchus mykiss to Aeromonas salmonicida. AB - In recent years, feed additives have increasingly been adopted by the aquaculture industry. These supplements not only offer an alternative to antibiotics but have also been linked to enhanced growth performance. However, the literature is still limited and provides contradictory information on their effectiveness. This is mainly due to the wide variety of available products and their complex mechanisms of action. Phytogenic feed additives have been shown to have antimicrobial effects and can improve growth performance. In the present study, we investigated the susceptibility of several fish pathogenic bacteria to a phytogenic essential oil product in vitro. In addition, we determined the protective effect of a commercial phytogenic feed additive containing oregano, anis and citrus oils on the resistance of rainbow trout Oncorhynchus mykiss to infection by Aeromonas salmonicida. The bacterium was administered through 3 different routes: intra peritoneal injection, immersion in a bacterial solution and cohabitation with infected fish. Mortality rates were significantly lower in infected rainbow trout that had received the feed additive: the overall mortality rate across all routes of infection was 18% in fish fed a diet containing the additive compared to 37% in fish that received unsupplemented feed. The route of infection also significantly impacted mortality, with average mortality rates of 60, 17.5 and 5% for intra-peritoneal injection, immersion and cohabitation, respectively. In general, fish were better protected against infection by immersion than infection by injection. PMID- 26119301 TI - Pseudomonas fluorescens: identification of Fur-regulated proteins and evaluation of their contribution to pathogenesis. AB - Pseudomonas fluorescens is a Gram-negative bacterium and a common pathogen to a wide range of farmed fish. In a previous study, we found that the ferric uptake regulator gene (fur) is essential to the infectivity of a pathogenic fish isolate of P. fluorescens (wild-type strain TSS). In the present work, we conducted comparative proteomic analysis to examine the global protein profiles of TSS and the P. fluorescens fur knockout mutant TFM. Twenty-eight differentially produced proteins were identified, which belong to different functional categories. Four of these proteins, viz. TssP (a type VI secretion protein), PspA (a serine protease), OprF (an outer membrane porin), and ClpP (the proteolytic subunit of an ATP-dependent Clp protease), were assessed for virulence participation in a model of turbot Scophthalmus maximus. The results showed that the oprF and clpP knockouts exhibited significantly reduced capacities in (1) resistance against the bactericidal effect of host serum, (2) dissemination into and colonization of host tissues, and (3) inducing host mortality. In contrast, mutation of tssP and pspA had no apparent effect on the pathogenicity of TSS. Purified recombinant OprF, when used as a subunit vaccine, induced production of specific serum antibodies in immunized fish and elicited significant protection against lethal TSS challenge. Antibody blocking of the OprF in TSS significantly impaired the ability of the bacteria to invade host tissues. Taken together, these results indicate for the first time that in pathogenic P. fluorescens, Fur regulates the expression of diverse proteins, some of which are required for optimal infection. PMID- 26119302 TI - Vibrio tapetis isolated from vesicular skin lesions in Dover sole Solea solea. AB - Vibrio tapetis is primarily known as the causative agent for brown ring disease in bivalves, although it has been isolated from cultivated fish during mortalities on farms. Here we describe the first isolation of V. tapetis from wild-caught and subsequently captive-held Dover sole Solea solea. Pathological features consisted of multifocal circular greyish-white skin discolourations evolving into vesicular lesions and subsequent ulcerations on the pigmented side. On the non-pigmented side, multiple circular lesions-white at the center and red at the edges-were evident. Histological examination of the vesicular lesions revealed dermal fluid-filled spaces, collagen tissue necrosis and a mixed inflammatory infiltrate, with large numbers of small rod-shaped bacteria. In the deep skin lesions, loss of scales and dermal connective tissue, with degeneration and fragmentation of the myofibres bordering the ulceration, were noted. Serotyping, DNA-DNA hybridization and REP- and ERIC-PCR techniques showed that the retrieved isolates displayed a profile similar to the representative strain of genotype/serotype O2 which originally was isolated from carpet-shell clam Venerupis decussata and to which isolates obtained from wedge sole Dicologoglossa cuneata were also closely related. PMID- 26119303 TI - Specific PCR for Myxobolus arcticus SSU rDNA in juvenile sockeye salmon Oncorhynchus nerka from British Columbia, Canada. AB - A PCR for the specific detection of the salmon brain parasite Myxobolus arcticus (Pugachev and Khokhlov, 1979) was developed using primers designed to amplify a 1363 base pair fragment of the small subunit rDNA. The assay did not amplify DNA from 5 other Myxobolus species or from 7 other myxozoan species belonging to 5 other genera. For juvenile sockeye salmon Oncorhynchus nerka (Walbaum) collected from Chilko Lake, British Columbia (BC), Canada, in 2011, the prevalence by PCR was 96%, in contrast to 71% by histological examination of brain tissue. In 2010, the histological prevalence was 52.5%. Sequence identity between M. arcticus from Chilko Lake and other sites in BC ranged from 99.7 to 99.8% and was 99.6% for a Japanese sequence. In contrast, an M. arcticus sequence from Norway shared 95.3% identity with the Chilko Lake sequence, suggesting misidentification of the parasite. Chilko Lake sockeye salmon were previously reported free of infection with M. arcticus, and more research is required to understand the processes involved in the local and global dispersion of this parasite. PMID- 26119304 TI - Hypericum Perforatum Hydroalcoholic Extract Mitigates Motor Dysfunction and is Neuroprotective in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease. AB - Parkinson's disease is the second most common neurodegenerative disorder with selective and progressive decline of nigral dopaminergic neurons. Hypericum perforatum L. (H. perforatum, St. John's wort) has been traditionally used for management of different disorders, especially mild-to-moderate depression. This study was conducted to evaluate the effect of H. perforatum extract against unilateral striatal 6-hydroxydopamine (6-OHDA) toxicity and to unmask some involved mechanisms. Intrastriatal 6-OHDA-lesioned rats were treated with H. perforatum hydroalcoholic extract at a dose of 200 mg/kg/day started 1 week pre surgery for 1 week post-surgery. The extract attenuated apomorphine-induced rotational behavior, decreased the latency to initiate and the total time on the narrow beam task, lowered striatal level of malondialdehyde and enhanced striatal catalase activity and reduced glutathione content, normalized striatal expression of glial fibrillary acidic protein, tumor necrosis factor alpha with no significant effect on mitogen-activated protein kinase, lowered nigral DNA fragmentation, and prevented damage of nigral dopaminergic neurons with a higher striatal tyrosine hydroxylase immunoreactivity. These findings reveal the beneficial effect of H. perforatum via attenuation of DNA fragmentation, astrogliosis, inflammation, and oxidative stress. PMID- 26119305 TI - Neuroprotective Effect of Lutein on NMDA-Induced Retinal Ganglion Cell Injury in Rat Retina. AB - Lutein injection is a possible therapeutic approach for retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate its protective effects in retinal ganglion cells (RGCs) against N-methyl-D-aspartate (NMDA)-induced retinal damage in vivo. Retinal damage was induced by intravitreal NMDA injection in rats. Each animal was given five daily intraperitoneal injections of Lutein or vehicle along with intravitreal NMDA injections. Electroretinograms were recorded. The number of viable RGCs was quantified using the retinal whole-mount method by immunofluorescence. Proteins were measured by Western blot assays. Lutein reduced the retinal damage and improved the response to light, as shown by an animal behavior assay (the black-and-white box method) in rats. Furthermore, Lutein treatment prevented the NMDA-induced reduction in phNR wave amplitude. Lutein increased RGC number after NMDA-induced retina damage. Most importantly, Bax, cytochrome c, p-p38 MAPK, and p-c-Jun were all upregulated in rats injected with NMDA, but these expression patterns were reversed by continuous Lutein uptake. Bcl-2, p-GSK-3beta, and p-Akt in the Lutein-treated eyes were increased compared with the NMDA group. Lutein has neuroprotective effects against retinal damage, its protective effects may be partly mediated by its anti-excitability neurotoxicity, through MAPKs and PI3K/Akt signaling, suggesting a potential approach for suppressing retinal neural damage. PMID- 26119307 TI - [Bone and Nutrition. Calcium intake and bone health]. AB - Calcium is undoubtedly an essential nutrient. Many studies have confirmed a significant relationship between the intake of calcium, and bone quantity and density. With regard to Japanese dietary reference intake values, the reference calcium intake values have been determined while considering bone quantity. However, a correlation between calcium intake and bone fractures has not been established. In osteoporosis treatment and prevention guidelines, the recommended calcium preparation grade for osteoporosis treatment has been set at a low level. However, to ensure appropriate effectiveness of osteoporosis treatment, it is necessary to take an appropriate amount of calcium. In recent years, the calcium intake level for Japanese people has tended to decline, which emphasizes the need for taking an appropriate amount of calcium in the diet. PMID- 26119308 TI - [Bone and Nutrition. Bone and phosphorus intake]. AB - Phosphorus is necessary for bone mineralization. Although adequate phosphorus intake is essential for skeletal mineralization, it is reported that excessive phosphorus intake can induce deleterious effect on bone. Recently, since the Japanese diet has been westernized, phosphorus intake by the meat and dairy products has increased. Furthermore, along with the development of processed foods, excessive intake of inorganic phosphorus from food additives has become a problem. An adverse effect on parathyroid hormone (PTH) secretion from high phosphorus intake was seen only when calcium intake was inadequate. Dietary calcium to phosphorus ratio can be considered as one of the indicators that can predict the health of the bone. PMID- 26119306 TI - The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease with the symptom of cognitive impairment. The deposition of amyloid beta (Abeta) peptide is believed to be the primary cause to neuronal dystrophy and eventually dementia. Abeta is the proteolytic product from its precursor amyloid precursor protein (APP) by beta- and gamma- secretase. An optional cleavage by alpha secretase happens inside the Abeta domain. ADAM17 is supposed to be the regulated alpha-secretase of APP. Enhanced activity of ADAM17 leads to the increasing secretion of neuroprotective soluble APP alpha fragment and reduction of Abeta generation, which may be benefit to the disease. ADAM17 is then considered the potential therapeutic target for AD. Microglia activation and neuroinflammation is another important event in AD pathogenesis. Interestingly, ADAM17 also participates in the cleavage of many other membrane-bound proteins, especially some inflammatory factors related to microglia activation. The facilitating role of ADAM17 in inflammation and further neuronal damage has also been illustrated. In results, the activation of ADAM17 as the solution to AD may be a tricky task. The comprehensive consideration and evaluation has to be carried out carefully before the final treatment. In the present review, the distinct role of ADAM17 in AD-related APP shedding and neuroinflammatory microglial activation will be carefully discussed. PMID- 26119309 TI - [Bone and Nutrition. Vitamin D intake and bone]. AB - Vitamin D insufficiency is one of the risk factors of osteoporosis. To know the vitamin D intake for the prevention of bone loss and fracture, it is necessary to evaluate the appropriate serum 25-hydroxyvitamin D (25-D) concentration for bone health, and the vitamin D intake to maintain its concentration. Although vitamin D intake 15 and 20 MUg/d have been set as RDA (Recommended Dietary Allowance) in USA/Canada DRIs (Dietary reference intakes), 5.5 MUg/d has been set as AI (adequate intake) in Japanese DRIs (2015). While reference values in Japan and USA/Canada were quite different, both DRIs are common in that it aim to maintain the serum 25-D concentration to more than 50 nmol/L. In the present review, vitamin D intakes and bone health, vitamin D status in Japanese people, DRIs for vitamin D and improvement of vitamin D insufficiency are reviewed. PMID- 26119310 TI - [Bone and Nutrition. The association of vitamin K intake and bone health]. AB - The association of vitamin K with bone mineral density has been reported in some previous cohort studies and intervention studies. In cohort studies, higher vitamin K1 intake was associated with lower fracture incidence. Some intervention studies have described that vitamin K1 and vitamin K2 (menaquinone-4 : MK-4) supplementation were modestly efficacious in preventing fracture, but not in preserving bone mass. Although dietary reference intake (adequate intake : AI) for vitamin K was increased from previous value, current AI was determined as the dose sufficient to maintain normal blood coagulation with little mentioning to bone. Vitamin K intake greater than the current AI would be required for the bone health. PMID- 26119311 TI - [Bone and Nutrition. The vitamin D functions in osteoblasts and osteocytes]. AB - The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1alpha,25 (OH) (2)D(3)), plays a key role in mineral and bone homeostasis. 1alpha,25 (OH) (2)D(3), through binding to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily, regulates the expression of many genes in osteoblasts and osteocytes. The VDR functions in a largely 1alpha,25 (OH) (2)D(3)-controlled manner by interacting directly with vitamin D response elements located within regulatory regions that are linked to cell-specific target genes. However, the mechanism of VDR action on these bone cell types remains largely unknown. While the direct actions of 1alpha,25 (OH) (2)D(3) on bone cells are complex and include both cell autonomous and paracrine mechanisms. In this review, we discuss how the VDR affects the transcriptional response of these cells and contribute to bone homeostasis. PMID- 26119312 TI - [Bone and Nutrition. Effect of isoflavones on bone health]. AB - Effects of isoflavones on bone health in postmenopausal women are expected, since it shows weak estrogenic activity. In the observational study in Asia, association between intake of soy foods or isoflavone and bone mineral density and fracture prevention has been observed. In the meta-analysis of intervention trials of isoflavone in 60 years or less of postmenopausal women, 75 mg by day about 6 months to 1 year intervention of isoflavones induced suppression of significant decline of bone resorption markers in the urine was observed. On the other hand, intended for Westerners women in the study intervened isoflavones with calcium and vitamin D simultaneously, it is not observed effectiveness of isoflavones on the bone. Such a difference might be due to diversity in the individual metabolic capacity for isoflavones as well as the effects of presence or absence of other co-interventions nutrients. PMID- 26119313 TI - [Bone and Nutrition. Functional foods for bone and cartilage tissues : Evidence for the action of collagen peptides]. AB - Collagen peptides, including glucosamine, are well-known functional food materials that act on bone and cartilage tissues. Collagen peptides are used at a volume of about 6,000 tons per year as a raw material in Japan. Evidence for the action of collagen peptides for both bone and cartilage tissues has accumulated both at basic research level (in vivo and in vitro ) and clinically. To confirm the clinical effect of these peptides and clearly identify their mechanism of action at the molecular level, further clinical studies comprising disease-free subjects, alongside basic research studies, are required. PMID- 26119314 TI - [Bone and Nutrition. A novel function of phosphorus]. AB - Phosphorus is an essential nutrient for bone formation by forming hydroxyapatite with calcium. Simultaneously, phosphorus is also a component of high energy bond of ATP, nucleic acids, and phospholipids. Recent studies have demonstrated that excess or lack of dietary phosphorus intake may cause vascular dysfunction, cardiac hypertrophy, and impaired glucose tolerance. Here, we introduce recent findings about the effects of high or low dietary phosphorus intake on several organs except for bone. PMID- 26119315 TI - [Bone and Nutrition. Vitamin D independent calcium absorption]. AB - Vitamin D endocrine system is required for normal calcium and bone homeostasis. Trans-epithelial calcium absorption is initiated with calcium entry into the intestinal epithelial cells from luminal fluid through calcium permeable channels, and those expressions are strongly supported by vitamin D action. On the other hands, dietary treatment, mineral supplementation or restriction, successfully improves intestinal calcium absorption in global vitamin D receptor knock-out (VDR KO) mice, though vitamin D dependent active transport pathway is lacking. Dietary rescue of intestinal calcium absorption provided a positive calcium balance in this mouse model, and suggested that the major role of vitamin D function on calcium homeostasis was considered to be intestinal active absorption. To elucidate the entire process of intestinal calcium absorption, vitamin D independent calcium transport system was characterized into either trans-cellular or para-cellular process. PMID- 26119316 TI - [Bone and Nutrition. A prospect of calcium sensing receptor]. AB - Following the discovery of the calcium-sensing receptor (CaSR) in 1993, its pivotal role in disorders of calcium homeostasis was demonstrated. Compelling evidence suggests that the CaSR plays multiple roles extending well beyond not only regulating the level of extracellular Ca(2+), but also controlling diverse and crucial roles in human physiology and pathophysiology. This review covers current knowledge of the role of the CaSR in disorders of calcium homeostasis (familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, autosomal dominant hypocalcemia, primary and secondary hyperparathyroidism, hypercalcemia of malignancy) as well as unrelated diseases such as breast and colorectal cancer, Alzheimer's disease and pancreatitis. In addition, it examines the use or potential use of CaSR agonists or antagonists in the management of disorders as diverse as hyperparathyroidism and Alzheimer's disease. PMID- 26119317 TI - [Bone and Nutrition. The relationship between iron and phosphate metabolism]. AB - Fibroblast growth factor 23 (FGF23) is an essential hormone for phosphate metabolism. It has been shown that intravenous administration of some iron formulations including saccharated ferric oxide induces hypophosphatemic osteomalacia with high FGF23 levels. On the other hand, iron deficiency promotes FGF23 and induces hypophosphatemia in patients with autosomal dominant hypophosphatemic rickets (ADHR). While iron and phosphate metabolism is connected, the detailed mechanism of this connection remains to be clarified. PMID- 26119318 TI - [Bone and Nutrition. Sclerostin and bone metabolism]. AB - Osteocytes orchestrate bone resorption and bone formation by controlling osteoclast and osteoblast activity. On the other hand, osteocytes secret FGF23 (fibroblast growth factor 23), FGF23 acts on the kidney to control phosphate homeostasis. Sclerostin is also released from osteocytes and it regulated osteoblast activity through Wnt/beta-catenin pathway. Therefore, an antibody that targets sclerostin is currently in phase- III clinical trials for the treatment of osteoporosis and it is expected as new therapeutics. PMID- 26119319 TI - [Bone and Nutrition. Nutritional management of osteoporosis]. AB - Calcium intake was negatively associated with bone resorption marker such as DPD, NTX, and P1NP in Japanese postmenopausal osteoporotic patients. Not only to suppress bone resorption but also to keep higher hip bone mineral density were observed in the patients with higher intake of calcium than 800mg/day and higher vitamin D condition (more than 50nmol/L of serum 25 (OH) D). Higher calcium intake than 800mg/day from dairy and Tofu products, higher intake of vitamin D than 10MUg/day from fish, and higher intake of vitamin K from vegetables should be recommended in Japanese postmenopausal osteoporotic patients. We should also pay attention to their losing weight and excess intake of these nutrients from supplements. PMID- 26119320 TI - [Bone and Nutrition. Nutrition care of renal osteodystrophy]. AB - Renal osteodystrophy is the damage of bone morphology by CKD and treatment and occurred abnormal bone metabolism through renal dysfunction. It demonstrated that the control of P and Ca improves to normalization of mineral metabolism. Protein energy wasting and malnutrition are common in patients with CKD stage 5 and has been associated with life prognosis. In CKD patients, nutritional management is a critical role of treatment. Also it may be important of nutritional management that control P and Ca and improve nutritional status in renal osteodystrophy patients. PMID- 26119321 TI - Highly Robust Palladium(II) alpha-Diimine Catalysts for Slow-Chain-Walking Polymerization of Ethylene and Copolymerization with Methyl Acrylate. AB - A series of sterically demanding alpha-diimine ligands bearing electron-donating and electron-withdrawing substituents were synthesized by an improved synthetic procedure in high yield. Subsequently, the corresponding Pd complexes were prepared and isolated by column chromatography. These Pd complexes demonstrated unique properties in ethylene polymerization, including high thermal stability and high activity, thus generating polyethylene with a high molecular weight and very low branching density. Similar properties were observed for ethylene/methyl acrylate copolymerization. Because of the high molecular weight and low branching density, the generated polyethylene and ethylene/methyl acrylate copolymer were semicrystalline solids. The (co)polymers had unique microstructures originating from the unique slow-chain-walking activity of these Pd complexes. PMID- 26119322 TI - Coral population dynamics across consecutive mass mortality events. AB - Annual coral mortality events due to increased atmospheric heat may occur regularly from the middle of the century and are considered apocalyptic for coral reefs. In the Arabian/Persian Gulf, this situation has already occurred and population dynamics of four widespread corals (Acropora downingi, Porites harrisoni, Dipsastrea pallida, Cyphastrea micropthalma) were examined across the first-ever occurrence of four back-to-back mass mortality events (2009-2012). Mortality was driven by diseases in 2009, bleaching and subsequent diseases in 2010/2011/2012. 2009 reduced P. harrisoni cover and size, the other events increasingly reduced overall cover (2009: -10%; 2010: -20%; 2011: -20%; 2012: 15%) and affected all examined species. Regeneration was only observed after the first disturbance. P. harrisoni and A. downingi severely declined from 2010 due to bleaching and subsequent white syndromes, while D. pallida and P. daedalea declined from 2011 due to bleaching and black-band disease. C. microphthalma cover was not affected. In all species, most large corals were lost while fission due to partial tissue mortality bolstered small size classes. This general shrinkage led to a decrease of coral cover and a dramatic reduction of fecundity. Transition matrices for disturbed and undisturbed conditions were evaluated as Life Table Response Experiment and showed that C. microphthalma changed the least in size-class dynamics and fecundity, suggesting they were 'winners'. In an ordered 'degradation cascade', impacts decreased from the most common to the least common species, leading to step-wise removal of previously dominant species. A potentially permanent shift from high- to low-coral cover with different coral community and size structure can be expected due to the demographic dynamics resultant from the disturbances. Similarities to degradation of other Caribbean and Pacific reefs are discussed. As comparable environmental conditions and mortality patterns must be expected worldwide, demographic collapse of many other coral populations may soon be widespread. PMID- 26119323 TI - Endovascular stent thrombectomy: the new standard of care for large vessel ischaemic stroke. AB - BACKGROUND: Results of initial randomised trials of endovascular treatment for ischaemic stroke, published in 2013, were neutral but limited by the selection criteria used, early-generation devices with modest efficacy, non-consecutive enrollment, and treatment delays. RECENT DEVELOPMENTS: In the past year, six positive trials of endovascular thrombectomy for ischaemic stroke have provided level 1 evidence for improved patient outcome compared with standard care. In most patients, thrombectomy was performed in addition to thrombolysis with intravenous alteplase, but benefits were also reported in patients ineligible for alteplase treatment. Despite differences in the details of eligibility requirements, all these trials required proof of major vessel occlusion on non invasive imaging and most used some imaging technique to exclude patients with a large area of irreversibly injured brain tissue. The results indicate that modern thrombectomy devices achieve faster and more complete reperfusion than do older devices, leading to improved clinical outcomes compared with intravenous alteplase alone. The number needed to treat to achieve one additional patient with independent functional outcome was in the range of 3.2-7.1 and, in most patients, was in addition to the substantial efficacy of intravenous alteplase. No major safety concerns were noted, with low rates of procedural complications and no increase in symptomatic intracerebral haemorrhage. WHERE NEXT?: Thrombectomy benefits patients across a range of ages and levels of clinical severity. A planned meta-analysis of individual patient data might clarify effects in under-represented subgroups, such as those with mild initial stroke severity or elderly patients. Imaging-based selection, used in some of the recent trials to exclude patients with large areas of irreversible brain injury, probably contributed to the proportion of patients with favourable outcomes. The challenge is how best to implement imaging in clinical practice to maximise benefit for the entire population and to avoid exclusion of patients with smaller yet clinically important potential to benefit. Although favourable imaging identifies patients who might benefit despite long delays from symptom onset to treatment, the proportion of patients with favourable imaging decreases with time. Health systems therefore need to be reorganised to deliver treatment as quickly as possible to maximise benefits. On the basis of available trial data, intravenous alteplase remains the initial treatment for all eligible patients within 4.5 h of stroke symptom onset. Those patients with major vessel occlusion should, in parallel, proceed to endovascular thrombectomy immediately rather than waiting for an assessment of response to alteplase, because minimising time to reperfusion is the ultimate aim of treatment. PMID- 26119324 TI - Regulation of oogenesis in honey bee workers via programed cell death. AB - Reproductive division of labour characterises eusociality. Currently little is known about the mechanisms that underlie the 'sterility' of the worker caste, but queen pheromone plays a major role in regulating the reproductive state. Here we investigate oogenesis in the young adult honey bee worker ovary in the presence of queen pheromone and in its absence. When queen pheromone is absent, workers can activate their ovaries and have well-developed follicles. When queen pheromone is present, even though workers have non-activated ovaries, they continually produce oocytes which are aborted at an early stage. Therefore, irrespective of the presence of the queen, the young adult worker ovary contains oocytes. By this means young workers retain reproductive plasticity. The degeneration of the germ cells in the ovarioles of workers in the presence of queen pheromone has the morphological hallmarks of programmed cell death. Therefore the mechanistic basis of 'worker sterility' relies in part on the regulation of oogenesis via programmed cell death. Our results suggest that honey bees have co-opted a highly conserved checkpoint at mid-oogenesis to regulate the fertility of the worker caste. PMID- 26119325 TI - Dispersive growth and laser-induced rippling of large-area singlelayer MoS2 nanosheets by CVD on c-plane sapphire substrate. AB - Vapor-phase growth of large-area two-dimensional (2D) MoS2 nanosheets via reactions of sulfur with MoO3 precursors vaporized and transferred from powder sources onto a target substrate has been rapidly progressing. Recent studies revealed that the growth yield of high quality singlelayer (SL) MoS2 is essentially controlled by quite a few parameters including the temperature, the pressure, the amount/weight of loaded source precursors, and the cleanup of old precursors. Here, we report a dispersive growth method where a shadow mask is encapsulated on the substrate to 'indirectly' supply the source precursors onto the laterally advancing growth front at elevated temperatures. With this method, we have grown large-area (up to millimeters) SL-MoS2 nanosheets with a collective in-plane orientation on c-plane sapphire substrates. Regular ripples (~1 nm in height and ~50 nm in period) have been induced by laser scanning into the SL-MoS2 nanosheets. The MoS2 ripples easily initiate at the grain boundaries and extend along the atomic steps of the substrate. Such laser-induced ripple structures can be fundamental materials for studying their effects, which have been predicted to be significant but hitherto not evidenced, on the electronic, mechanical, and transport properties of SL-MoS2. PMID- 26119326 TI - How actin/myosin crosstalks guide the adhesion, locomotion and polarization of cells. AB - Cell-tissue-tissue interaction is determined by specific short range forces between cell adhesion molecules (CAMs) and ligands of the tissue, long range repulsion forces mediated by cell surface grafted macromolecules and adhesion induced elastic stresses in the cell envelope. This interplay of forces triggers the rapid random clustering of tightly coupled linkers. By coupling of actin gel patches to the intracellular domains of the CAMs, these clusters can grow in a secondary process resulting in the formation of functional adhesion microdomains (ADs). The ADs can act as biochemical steering centers by recruiting and activating functional proteins, such as GTPases and associated regulating proteins, through electrostatic-hydrophobic forces with cationic lipid domains that act as attractive centers. First, I summarize physical concepts of cell adhesion revealed by studies of biomimetic systems. Then I describe the role of the adhesion domains as biochemical signaling platforms and force transmission centers promoting cellular protrusions, in terms of a shell string model of cells. Protrusion forces are generated by actin gelation triggered by molecular machines (focal adhesion kinase (FAK), Src-kinases and associated adaptors) which assemble around newly formed integrin clusters. They recruit and activate the GTPases Rac-1 and actin gelation promoters to charged membrane domains via electrostatic-hydrophobic forces. The cell front is pushed forward in a cyclic and stepwise manner and the step-width is determined by the dynamics antagonistic interplay between Rac-1 and RhoA. The global cell polarization in the direction of motion is mediated by the actin-microtubule (MT) crosstalk at adhesion domains. Supramolecular actin-MT assemblies at the front help to promote actin polymerization. At the rear they regulate the dismantling of the ADs through the Ca(++)-mediated activation of the protease calpain and trigger their disruption by RhoA mediated contraction via stress fibers. This article is part of a Special Issue entitled: Mechanobiology. PMID- 26119327 TI - Neuronal and metastatic cancer cells: Unlike brothers. AB - During development neuronal cells traverse substantial distances across the developing tissue. In the mature organism, however, they are bound to the confines of the nervous system. Likewise metastatic cancer cells have the potential to establish auxiliary tumor sites in remote tissues or entirely different organs. The epithelial-mesenchymal transition is the transformation of proliferative cancer cells into a highly invasive state, which facilitates the crossing of tissue boundaries and migration across various environments. This review contributes a first look into the parallels and contrasts between physical aspects of neuronal and metastatic cancer cells. PMID- 26119328 TI - Electrochemical properties of fiber-in-tube- and filled-structured TiO2 nanofiber anode materials for lithium-ion batteries. AB - Phase-pure anatase TiO2 nanofibers with a fiber-in-tube structure were prepared by the electrospinning process. The burning of titanium-oxide-carbon composite nanofibers with a filled structure formed as an intermediate product under an oxygen atmosphere produced carbon-free TiO2 nanofibers with a fiber-in-tube structure. The sizes of the nanofiber core and hollow nanotube were 140 and 500 nm, respectively. The heat treatment of the electrospun nanofibers at 450 and 500 degrees C under an air atmosphere produced grey and white filled-structured TiO2 nanofibers, respectively. The initial discharge capacities of the TiO2 nanofibers with the fiber-in-tube and filled structures and the commercial TiO2 nanopowders were 231, 134, and 223 mA h g(-1) , respectively, and their corresponding charge capacities were 170, 100, and 169 mA h g(-1) , respectively. The 1000th discharge capacities of the TiO2 nanofibers with the fiber-in-tube and filled structures and the commercial TiO2 nanopowders were 177, 64, and 101 mA h g(-1) , respectively, and their capacity retentions measured from the second cycle were 89, 82, and 52 %, respectively. The TiO2 nanofibers with the fiber-in-tube structure exhibited low charge transfer resistance and structural stability during cycling and better cycling and rate performances than the TiO2 nanofibers with filled structures and the commercial TiO2 nanopowders. PMID- 26119329 TI - A water resources simulation gaming model for the Invitational Drought Tournament. AB - A system dynamics-based simulation gaming model, developed as a component of Agriculture and Agri-Food Canada's Invitational Drought Tournament (IDT; Hill et al., 2014), is introduced in this paper as a decision support tool for drought management at the river-basin scale. This IDT Model provides a comprehensive and integrated overview of drought conditions, and illustrates the broad effects of socio-economic drought and mitigation strategies. It is intended to provide a safe, user-friendly experimental environment with fast run-times for testing management options, and to promote collaborative decision-making and consensus building. Examples of model results from several recent IDT events demonstrate potential effects of drought and the short-to longer-term effectiveness of policies selected by IDT teams; such results have also improved teams' understanding of the complexity of water resources systems and their management trade-offs. The IDT Model structure and framework can also be reconfigured quickly for application to different river basins. PMID- 26119330 TI - Handling preference heterogeneity for river services' adaptation to climate change. AB - Climate projection models for the Southern Mediterranean basin indicate a strong drought trend. This pattern is anticipated to affect a range of services derived from river ecosystems and consecutively deteriorate the sectoral outputs and household welfare. This paper aims to evaluate local residents' adaptation preferences for the Piave River basin in Italy. A Discrete Choice Experiment accounting for adaptation scenarios of the Piave River services was conducted and the collected data were econometrically analyzed using Random Parameters Logit, Latent Class and Covariance Heterogeneity models. In terms of policy-relevant outcomes, the analysis indicates that respondents are willing to pay for adaptation plans. This attitude is reflected on the compensating surplus to sustain the current state of the Piave, which corresponds to a monthly contribution of 80? per household. From an econometric point of view, the results show that it is not sufficient to take solely into account general heterogeneity, provided that distinct treatment of the heterogeneity produces rather different welfare estimates. This implies that analysts should examine a set of criteria when deciding on how to better approach heterogeneity for each empirical data set. Overall, non-market values of environmental services should be considered when formulating cost-effective adaptation measures for river systems undergoing climate change effects and appropriate heterogeneity approximation could render these values unbiased and accurate. PMID- 26119331 TI - Assessing the quality of the ecological component of English Environmental Statements. AB - Environmental Impact Assessment (EIA) is a key tool to help ensure sustainable built development in more than 200 countries worldwide. Ecology is frequently a component of EIA and early reviews of Ecological Impact Assessment (EcIA) chapters identified scope for improvement at almost every stage of the EcIA process, regardless of country. However, there have been no reviews of UK EcIA chapters since 2000, despite important changes in biodiversity and planning legislation, policy and guidance. In addition, no UK EcIA chapter reviews have attempted to assign a grade or score to EcIA chapters (as has been done for reviews of US, Finnish and Indian EcIA chapters). Furthermore, no EcIA chapter reviews have attempted to use a scoring system to identify which variables determine EcIA chapter information content, beyond straightforward comparisons of EcIA chapters before and after the introduction of guidelines. A variant of the Biodiversity Assessment Index (BAI) was used to assign scores between zero and one to EcIA chapters based on a series of 47 questions drawn from EU legislation and professional guidance. 112 EcIA chapters for proposed developments that were subsequently granted planning permission in England were assessed. The mean BAI score was less than 0.5, indicating the presence of considerable information gaps in the majority of EcIA chapters. Of 13 predictor variables identified as having the potential to affect EcIA chapter quality, 10 were identified as significantly related to the BAI scores. A backward stepwise Generalized Linear Model identified the use of professional guidance, the ecological consultancy type and the length of the EcIA chapter as having the greatest combined explanatory power. As a result, several recommendations are made to help improve future EcIA chapter content, including formal EcIA chapter review, publicising the professional guidance to consultants, the provision of training and the introduction of an accreditation scheme for consultants involved in EcIA This approach could be replicated in other countries that conduct EIA. Context-dependent EcIA chapter review criteria (as in this paper) would help to identify targeted recommendations for improvement. Alternatively, a global set of review criteria could highlight areas of best practice that could then be exported to other countries. PMID- 26119332 TI - Coagulation/flocculation process with polyaluminum chloride for the remediation of oil sands process-affected water: Performance and mechanism study. AB - This study investigated the application of polyaluminum chloride (PACl) for the treatment of the oil sands process-affected water (OSPW). These coagulants are commonly used in water treatment with the most effective species reported to be Al13. PACl with 83.6% Al13 was synthesized using the slow base titration method and compared with a commercially available PACl in terms of aluminum species distribution, coagulation/flocculation (CF) performance, floc morphology, and contaminant removal. Both coagulants were effective in removing suspended solids, achieving over 96% turbidity removal at all applied coagulant doses (0.5-3.0 mM Al). The removal efficiencies of metals varied among different metals depending on their pKa values with metal cations having pKa values (Fe, Al, Ga, and Ti) below OSPW pH of 6.9-8.1 (dose dependent) being removed by more than 90%, while cations with higher pKa values (K, Na, Ca, Mg and Ni) had removals of less than 40%. Naphthenic acids were not removed due to their low molecular weights, negative charges, and hydrophilic characteristics at the OSPW pH. At the highest applied coagulant dose of 3.0 mM Al, the synthetic PACl reduced Vibrio fischeri inhibition effect to 43.3 +/- 3.0% from 49.5 +/- 0.4% in raw OSPW. In contrast, no reduction of toxicity was found for OSPW treated with the commercial PACl. Based on water quality and floc analyses, the dominant CF mechanism for particle removal during OSPW treatment was considered to be enmeshment in the precipitates (i.e., sweep flocculation). Overall, the CF using synthesized PACl can be a valuable pretreatment process for OSPW to create wastewater that is more easily treated by downstream processes. PMID- 26119333 TI - Kinetics of trypsin-catalyzed hydrolysis determined by isothermal titration calorimetry. AB - Isothermal titration calorimetry (ITC) was applied to determine enzymatic activity and inhibition. We measured the Michaelis-Menten kinetics for trypsin catalyzed hydrolysis of two substrates, casein (an insoluble macromolecule substrate) and Nalpha-benzoyl-dl-arginine beta-naphthylamide (a small substrate), and estimated the thermodynamic parameters in the temperature range from 20 to 37 degrees C. The inhibitory activities of reversible (small molecule benzamidine) and irreversible (small molecule phenylmethanesulfonyl fluoride and macromolecule alpha1-antitrypsin) inhibitors of trypsin were also determined. We showed the usefulness of ITC for fast and direct measurement of inhibition constants and half-maximal inhibitory concentrations and for predictions of the mechanism of inhibition. ITC kinetic assays could be an easy and straightforward way to estimate Michaelis-Menten constants and the effectiveness of inhibitors as well as to predict the inhibition mechanism. ITC efficiency was found to be similar to that of classical spectrophotometric enzymatic assays. PMID- 26119334 TI - Sensitive voltammetric determination of thymol in essential oil of Carum copticum seeds using boron-doped diamond electrode. AB - Essential oil of Carum copticum seeds, obtained from a local shop, was extracted and content of thymol was analyzed using square-wave voltammetry at boron-doped diamond electrode. The effect of various parameters, such as pH of supporting electrolyte and square-wave voltammetric parameters (modulation amplitude and frequency), was examined. In Britton-Robinson buffer solution (pH 4), thymol provided a single and oval-shaped irreversible oxidation peak at +1.13 V versus silver/silver chloride potassium electrode (3M). Under optimal experimental conditions, a plot of peak height against concentration of thymol was found to be linear over the range of 4 to 100MUM consisting of two linear ranges: from 4 to 20MUM (R(2)=0.9964) and from 20 to 100MUM (R(2)=0.9993). The effect of potential interferences such as p-cymene and gamma-terpinene (major components in essential oil of C. copticum seeds) was evaluated. Thus, the proposed method displays a sufficient selectivity toward thymol with a detection limit of 3.9MUM, and it was successfully applied for the determination of thymol in essential oil of C. copticum seeds. The Prussian blue method was used for validation of the proposed electroanalytical method. PMID- 26119335 TI - Accuracy of Self-Reported Health Care Use in a Population-Based Sample of Homeless Adults. AB - OBJECTIVE: To assess the accuracy of self-reported ambulatory care visits, emergency department (ED) encounters, and overnight hospitalizations in a population-based sample of homeless adults. DATA SOURCE: Self-report survey data and administrative health care utilization databases. STUDY DESIGN: Self-reported health care use in the past 12 months was compared to administrative encounter records among 1,163 homeless adults recruited in 2004-2005 from shelters and meal programs in Toronto, Ontario. DATA EXTRACTION METHODS: Self-reported health care use was assessed using a structured face-to-face survey. Each participant was linked to administrative databases using a unique personal health number or their first name, last name, sex, and date of birth. PRINCIPAL FINDINGS: The sensitivity of self-report for ambulatory care visits, ED encounters, and overnight hospitalizations was 89, 80, and 73 percent, respectively; specificity was 37, 83, and 91 percent. The mean difference between self-reported and documented number of encounters in the past 12 months was +1.6 for ambulatory care visits (95 percent CI = 0.4, 2.8), -0.6 for ED encounters (95 percent CI = 0.8, -0.4), and 0.0 for hospitalizations (95 percent CI = 0.0, 0.1). CONCLUSIONS: Adults experiencing homelessness are quite accurate reporters of their use of health care, especially for ED encounters and hospitalizations. PMID- 26119336 TI - Farm exposures are associated with lower percentage of circulating myeloid dendritic cell subtype 2 at age 6. AB - BACKGROUND: Early life farm exposures have been shown to decrease the risk of allergic diseases. Dendritic cells (DCs) may mediate asthma-protective effect of farm exposures as they play an important role in the development of immunity and tolerance. Our aim was to investigate whether the numbers and phenotypes of circulating DCs at age 6 are associated with farming, asthma, and atopy in a selected sample of French and Finnish children from the PASTURE study. METHODS: We studied 82 farm and 86 nonfarm children with and without asthma. Using flow cytometry, BDCA1+ CD11c+ myeloid DC1s (mDC1), BDCA3+(high) mDC2s and BDCA2+ plasmacytoid DCs (pDCs) were identified and expressions of CD86, immunoglobulin like transcript 3 (ILT3) and ILT4 were analyzed. Questionnaires were used to assess prenatal and lifetime patterns of farm exposures and to define asthma. Atopic sensitization was defined by specific IgE measurements. RESULTS: The percentage of mDC2 cells was lower in farm children (0.033 +/- 0.001) than in nonfarm children (0.042 +/- 0.001; P = 0.008). Similar associations were found between mDC2 percentage and prenatal (P = 0.02) and lifetime exposure to farm milk (P = 0.03) and stables (P = 0.003), but these associations were not independent from farming. Asthma was positively associated with ILT4 + mDCs (P = 0.04) and negatively with CD86 + pDCs (P = 0.048) but only in nonfarm children. CONCLUSIONS: Inverse association between farm exposure and mDC2 percentage suggest that this DC subset may play a role in farm-related immunoregulation. PMID- 26119337 TI - A new curvularin glycoside and its cytotoxic and antibacterial analogues from marine actinomycete Pseudonocardia sp. HS7. AB - Five curvularin macrolides (1-5) were isolated from the cultured broth of marine actinomycete Pseudonocardia sp. HS7 that was obtained from the cloacal aperture of sea cucumber Holothuria moebii. The structures of these isolates were characterized as (11S,15R)-11-hydroxycurvularin (1), (11R,15R)-11 hydroxycurvularin (2), curvularin-7-O-alpha-D-glucopyranoside (3), trans dehydrocurvularin (4) and curvularin (5) based on their NMR and HRESIMS data as well as chemical degradation. Compound 3 is a new macrolide with a rare alpha-D glucopyranose substituent. Compounds 1-4, 5a and 5c (the acyl products of 5), suppressed the proliferation of all six tested cancer cell lines and 4 is the most active compound with IC50 values ranging from 0.59 to 3.39 MUM. The 11 hydroxycurvularins 1 and 2 also showed antibacterial activity inhibiting the growth of Escherichia coli. PMID- 26119338 TI - Pliocene cooling enhanced by flow of low-salinity Bering Sea water to the Arctic Ocean. AB - Warming of high northern latitudes in the Pliocene (5.33-2.58 Myr ago) has been linked to the closure of the Central American Seaway and intensification of North Atlantic Deep Water. Subsequent cooling in the late Pliocene may be related to the effects of freshwater input from the Arctic Ocean via the Bering Strait, disrupting North Atlantic Deep Water formation and enhancing sea ice formation. However, the timing of Arctic freshening has not been defined. Here we present neodymium and lead isotope records of detrital sediment from the Bering Sea for the past 4.3 million years. Isotopic data suggest the presence of Alaskan glaciers as far back as 4.2 Myr ago, while diatom and C37:4 alkenone records show a long-term trend towards colder and fresher water in the Bering Sea beginning with the M2 glaciation (3.3 Myr ago). We argue that the introduction of low salinity Bering Sea water to the Arctic Ocean by 3.3 Myr ago preconditioned the climate system for global cooling. PMID- 26119339 TI - Investigation of multipotent postnatal stem cells from human maxillary sinus membrane. AB - Maxillary sinus membrane (MSM) elevation is a common surgical technique for increasing bone height in the posterior maxilla prior to dental implant placement. However, the biological nature of bone regeneration in MSM remains largely unidentified. In this study, MSM tissue was obtained from 16 individuals during orthognathic surgery and used to isolate MSM stem cells (MSMSCs) by single colony selection and STRO-1 cell sorting. The cell characteristics in terms of colony-forming ability, cell surface antigens, multi-differentiation potential and in vivo implantation were all evaluated. It was found that MSMSCs were of mesenchymal origin and positive for mesenchymal stem cell (MSC) markers such as STRO-1, CD146, CD29 and CD44; furthermore, under defined culture conditions, MSMSCs were able to form mineral deposits and differentiate into adipocytes and chondrocytes. When transplanted into immunocompromised rodents, MSMSCs showed the capacity to generate bone-like tissue and, importantly, maintain their MSC characteristics after in vivo implantation. These findings provide cellular and molecular evidence that MSM contains stem cells that show functional potential in bone regeneration for dental implant. PMID- 26119340 TI - The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity. AB - Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti aging interventions in mammals. PMID- 26119341 TI - The Developmental Rules of Neural Superposition in Drosophila. AB - Complicated neuronal circuits can be genetically encoded, but the underlying developmental algorithms remain largely unknown. Here, we describe a developmental algorithm for the specification of synaptic partner cells through axonal sorting in the Drosophila visual map. Our approach combines intravital imaging of growth cone dynamics in developing brains of intact pupae and data driven computational modeling. These analyses suggest that three simple rules are sufficient to generate the seemingly complex neural superposition wiring of the fly visual map without an elaborate molecular matchmaking code. Our computational model explains robust and precise wiring in a crowded brain region despite extensive growth cone overlaps and provides a framework for matching molecular mechanisms with the rules they execute. Finally, ordered geometric axon terminal arrangements that are not required for neural superposition are a side product of the developmental algorithm, thus elucidating neural circuit connectivity that remained unexplained based on adult structure and function alone. PMID- 26119342 TI - Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C. AB - We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, "gene looping" factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction. PMID- 26119343 TI - Influence of CBCT parameters on the output of an automatic edge-detection-based endodontic segmentation. AB - OBJECTIVES: To determine the optimal CBCT settings for an automatic edge detection-based endodontic segmentation procedure by assessing the accuracy of the root canal measurements. METHODS: 12 intact teeth with closed apexes were cut perpendicular to the root axis, at pre-determined levels to the reference plane (the first section made before acquisition). Acquisitions of each specimen were performed with Kodak 9000((r)) 3D (76 um, 14 bits; Kodak Carestream Health, Trophy, France) by using different combinations of milliamperes and kilovolts. Three-dimensional images were displayed and root canals were segmented with the MeVisLab software (edge-detection-based method; MeVis Research, Bremen, Germany). Histological root canal sections were then digitized with a 0.5- to 1.0-um resolution and compared with equivalent two-dimensional cone-beam reconstructions for each pair of settings using the Pearson correlation coefficient, regression analysis and Bland-Altman method for the canal area and Feret's diameter. After a ranking process, a Wilcoxon paired test was carried out to compare the pair of settings. RESULTS: The best pair of acquisition settings was 3.2 mA/60 kV. Significant differences were found between 3.2 mA/60 kV and other settings (p < 0.05) for the root canal area and for Feret's diameter. CONCLUSIONS: The quantitative analyses of the root canal system with the edge-detection-based method could depend on acquisition parameters. Improvements in segmentation still need to be carried out to ensure the quality of the reconstructions when we have to deal with closer outlines and because of the low spatial resolution. PMID- 26119344 TI - Evaluation of the effective dose of cone beam CT and multislice CT for temporomandibular joint examinations at optimized exposure levels. AB - OBJECTIVES: To compare the effective dose to patients from temporomandibular joint examinations using a dental CBCT device and a multislice CT (MSCT) device, both before and after dose optimization. METHODS: A Promax((r)) 3D (Planmeca, Helsinki, Finland) dental CBCT and a LightSpeed VCT((r)) (GE Healthcare, Little Chalfont, UK) multislice CT were used. Organ doses and effective doses were estimated from thermoluminescent dosemeters at 61 positions inside an anthropomorphic phantom at the exposure settings in clinical use. Optimized exposure protocols were obtained through an optimization study using a dry skull phantom, where four observers rated image quality taken at different exposure levels. The optimal exposure level was obtained when all included criteria were rated as acceptable or better by all observers. RESULTS: The effective dose from a bilateral examination was 184 uSv for Promax 3D and 113 uSv for LightSpeed VCT before optimization. Post optimization, the bilateral effective dose was 92 uSv for Promax 3D and 124 uSv for LightSpeed VCT. CONCLUSIONS: At optimized exposure levels, the effective dose from CBCT was comparable to MSCT. PMID- 26119345 TI - [Hyper-reactive malarial splenomegaly]. AB - Hyper-reactive malarial splenomegaly is a rare and severe form of chronic malaria. This condition is a common cause of splenomegaly in endemic areas. The pathophysiology of hyper-reactive malarial splenomegaly involves an intense immune reaction (predominantly B cell-driven) to repeated/chronic infections with Plasmodium sp. The diagnosis may be difficult, due to a poorly specific clinical presentation (splenomegaly, fatigue, cytopenias), a long delay between residence in a malaria-endemic area and onset of symptoms, and a frequent absence of parasites on conventional thin and thick blood smears. A strongly contributive laboratory parameter is the presence of high levels of total immunoglobulin M. When the diagnostic of hyper-reactive malarial splenomegaly is considered, search for anti-Plasmodium antibodies and Plasmodium nucleic acids (genus and species) by PCR is useful. Diagnosis of hyper-reactive malarial splenomegaly relies on the simultaneous presence of epidemiological, clinical, biological and follow-up findings. Regression of both splenomegaly and hypersplenism following antimalarial therapy allows the differential diagnosis with splenic lymphoma, a common complication of hyper-reactive malarial splenomegaly. Although rare in Western countries, hyper-reactive malarial splenomegaly deserves increased medical awareness to reduce the incidence of incorrect diagnosis, to prevent progression to splenic lymphoma and to avoid splenectomy. PMID- 26119346 TI - Feasibility of immediate placement of single-tooth implants in the aesthetic zone: a 1-year randomized controlled trial. AB - AIM: To assess whether outcome of immediate implant placement and immediate provisionalization after 1 year was non-inferior to immediate implant placement and delayed provisionalization regarding Marginal Bone Level (MBL). MATERIALS AND METHODS: Forty patients with a failing tooth in the aesthetic zone were randomly assigned for immediate implant placement with immediate (n = 20) or delayed (n = 20) provisionalization. Follow-up was at 1 month and after 1 year. The study was powered to detect a difference in MBL of <0.9 mm. Apart from MBL, soft tissue peri-implant parameters, aesthetic indexes and patient satisfaction were assessed. RESULTS: After 1 year, MBL changes were -0.75 +/- 0.69 mesially and 0.68 +/- 0.65 distally mm for the immediate group and -0.70 +/- 0.64 and -0.68 +/ 0.64 mm for the delayed group respectively (NS). Regarding differences in means, non-inferiority was observed after 1 year (mesially: Group A versus B: difference in mean 0.08 mm (95% CI -0.38 to 0.53, p = 0.71 distally: Group A versus B: difference in mean 0.09 mm (95% CI -0.37 to 0.56 mm, p = 0.66).No significant differences in the other outcome variables were observed. CONCLUSIONS: This study showed that immediate placement and immediate provisionalization was non-inferior to immediate placement with delayed provisionalization. In addition, although not powered for these outcome variables, no clinically relevant differences in other outcomes were observed (www.isrtcn.com: ISRCTN57251089). PMID- 26119347 TI - Supramolecularly Regulated Ligands for Asymmetric Hydroformylations and Hydrogenations. AB - Herein we report the use of polyether binders as regulation agents (RAs) to enhance the enantioselectivity of rhodium-catalyzed transformations. For reactions of diverse substrates mediated by rhodium complexes of the alpha,omega bisphosphite-polyether ligands 1-5,a-d, the enantiomeric excess (ee) of hydroformylations was increased by up to 82 % (substrate: vinyl benzoate, 96 % ee), and the ee value of hydrogenations was increased by up to 5 % (substrate: N (1-(naphthalene-1-yl)vinyl)acetamide, 78 % ee). The ligand design enabled the regulation of enantioselectivity by generation of an array of catalysts that simultaneously preserve the advantages of a privileged structure in asymmetric catalysis and offer geometrically close catalytic sites. The highest enantioselectivities in the hydroformylation of vinyl acetate with ligand 4 b were achieved by using the Rb[B(3,5-(CF3)2 C6 H3)4] (RbBArF) as the RA. The enantioselective hydrogenation of the substrates 10 required the rhodium catalysts derived from bisphosphites 3 a or 4 a, either alone or in combination with different RAs (sodium, cesium, or (R,R)-bis(1-phenylethyl)ammonium salts). This design approach was supported by results from computational studies. PMID- 26119348 TI - Increase of widespread A, B1 and D Escherichia coli clones producing a high diversity of CTX-M-types in a Portuguese hospital. AB - AIM: To characterize temporal shifts in extended-spectrum beta-lactamases (ESBLs) and clones of clinical Escherichia coli isolates. MATERIALS & METHODS: All ESBL producing E. coli isolates from a Portuguese hospital (n = 112; June 2006-June 2007 and January-December 2010) were characterized by identification of phylogenetic groups, ESBL-types and virulence genes, XbaI-PFGE and MLST. RESULTS: We observed a substantial increase in widespread E. coli clones from phylogroups A, B1 and D (e.g., ST10, ST23, ST117, ST155, ST648) producing mainly CTX-M-1, 14, -32 or SHV-12, along with a decrease in the proportion of the predominant CTX M-15-producing B2-ST131 clone. CONCLUSION: The amplification of diverse CTX-M producing A, B1 and D clonal complexes, which have been long identified in Portuguese nonclinical settings, unveils a role for these reservoirs in the landscape of ESBL-producing E. coli in the clinical setting. PMID- 26119351 TI - Synthesis and characterization of novel niccolites [(CH3)2NH2][Fe(III)M(II)(HCOO)6] (M(II) = Zn, Ni, Cu). AB - We report the synthesis, X-ray diffraction, thermal, magnetic, Raman and IR studies of three heterometallic MOFs, [(CH3)2NH2][Fe(III)M(II)(HCOO)6] with M = Zn (DMFeZn), Ni (DMFeNi) and Cu (DMFeCu), crystallizing in the niccolite type structure. DMFeZn and DMFeNi crystallize in the trigonal structure (space group P3[combining macron]1c) while DMFeCu crystallizes in the monoclinic structure (space group C2/c). Magnetic investigation shows that DMFeZn remains paramagnetic down to the lowest temperature obtained in our experiment while DMFeNi and DMFeCu exhibit ferromagnetic order below 42 and 28.5 K, respectively. IR and Raman data confirm the structural model of the monoclinic DMFeCu and show evidence for stronger hydrogen bonds when compared to trigonal DMFeZn and DMFeNi. A different hydrogen bond network in the monoclinic DMFeCu when compared to trigonal DMFeZn and DMFeNi is responsible for the different behavior of these compounds upon cooling, that is, DMFeCu exhibits a sign of short range ordering of dimethylammonium cations at low temperatures while the trigonal analogues show evolution of dynamic disorder into static disorder. PMID- 26119350 TI - Alcohol Attributable Fraction for Injury Morbidity from the Dose-Response Relationship of Acute Alcohol Consumption: Emergency Department Data from 18 Countries. AB - AIMS: To calculate the alcohol-attributable fraction (AAF) of injury morbidity by volume of consumption prior to injury based on newly reported relative risk (RR) estimates. DESIGN: AAF estimates based on the dose-response RR estimates obtained from previous pair-matched case-crossover fractional polynomial analysis of mean volume in volume categories were calculated from the prevalence of drinking prior to injury in each volume category. SETTING: Thirty-seven emergency departments (EDs) across 18 countries. PARTICIPANTS: Probability samples of patients, with equal representation of each shift for each day of the week, totaling 14,026 who arrived at the ED within six hours of injury from ED studies conducted between 2001 and 2011. MEASUREMENTS: AAF was analyzed by gender, age (18-30; >30), cause of injury (traffic, assault, fall, other), and country detrimental drinking pattern (DDP). FINDINGS: For the EDs analyzed, 16.4% of all injuries were estimated to be attributable to alcohol, and the AAF did not vary by age but was over twice as large for males (20.6%; 19.3-21.8) than for females (8.6%; 7.5 9.7%). While females were at greater risk of injury than males at higher volume levels, lower prevalence of women drinking at higher levels contributed to overall lower AAF for women. Assault-related injuries showed the largest AAF (44.1%; 37.6-42.6). AAF was slightly higher for injuries from falls (14.3%; 12.9 15.7) than motor vehicle crashes (11.1%; 9.3-12.9). AAF was higher in those countries with a DDP of 3 (18.6; 17.5-19.7) and 4 (19.4%; 17.3-21.6) than those with a DDP of 2 (12.0%; 10.5-13.5). CONCLUSIONS: Alcohol-attributable injuries presenting in emergency departments are higher for males than females, for violence-related injuries compared with other types of injury, and for countries with more detrimental drinking patterns compared with those with less detrimental patterns. PMID- 26119349 TI - Meta-analysis of metabolic syndrome and benign prostatic hyperplasia in Chinese patients. AB - PURPOSE: To investigate the impact of metabolic syndrome (MetS) on benign prostatic hyperplasia (BPH), focusing on MetS and its relationship with prostate volume and prostate-specific antigen (PSA) in Chinese patients by performing a meta-analysis. METHODS: We systematically searched the PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and VIP databases from inception to November 2014. All studies investigating the impact of MetS on prostate volume and PSA among BPH patients were included. Pooled mean difference (WMD) and 95% confidence interval (CI) were used to analyze the difference between patients with MetS and those without MetS. RESULTS: Sixteen studies enrolled 1895 BPH patients, of whom 2224 had MetS. Compared with those without MetS, BHP patients with MetS had significantly higher total prostate volume (WMD 10.15 ml; 95% CI 7.37-12.93) and serum PSA level (WMD 0.53 ng/ml; 95% CI 0.17-0.88), respectively. In addition, annual prostate growth rate in patients with MetS was higher (WMD 0.49 ml/year; 95% CI 0.24-0.73) than in those without MetS. CONCLUSIONS: This meta-analysis supports that the presence of MetS increases total prostate volume and annual prostate growth rate in Chinese BPH patients. Future studies are needed to explain the detailed underlying mechanisms. PMID- 26119352 TI - Nicotine administration in the wake-promoting basal forebrain attenuates sleep promoting effects of alcohol. AB - Nicotine and alcohol co-abuse is highly prevalent, although the underlying causes are unclear. It has been suggested that nicotine enhances pleasurable effects of alcohol while reducing aversive effects. Recently, we reported that nicotine acts via the basal forebrain (BF) to activate nucleus accumbens and increase alcohol consumption. Does nicotine suppress alcohol-induced aversive effects via the BF? We hypothesized that nicotine may act via the BF to suppress sleep-promoting effects of alcohol. To test this hypothesis, adult male Sprague-Dawley rats were implanted with sleep-recording electrodes and bilateral guides targeted toward the BF. Nicotine (75 pmol/500 nL/side) or artificial cerebrospinal fluid (ACSF; 500 nL/side) was microinjected into the BF followed by intragastric alcohol (ACSF + EtOH and NiC + EtOH groups; 3 g/kg) or water (NiC + W and ACSF + W groups; 10 mL/kg) administration. On completion, rats were killed and processed to localize injection sites in the BF. The statistical analysis revealed a significant effect of treatment on sleep-wakefulness. While rats exposed to alcohol (ACSF + EtOH) displayed strong sleep promotion, nicotine pre-treatment in the BF (NiC + EtOH) attenuated alcohol-induced sleep and normalized sleep-wakefulness. These results suggest that nicotine acts via the BF to suppress the aversive, sleep-promoting effects of alcohol, further supporting the role of BF in alcohol-nicotine co-use. PMID- 26119353 TI - Novel association between serum pentraxin-2 levels and advanced fibrosis in well characterised patients with non-alcoholic fatty liver disease. AB - BACKGROUND: Pentraxin-2 (PTX-2), a serum protein, inhibits inflammation and fibrosis, and recombinant PTX-2 is being tested as an anti-fibrotic agent. AIM: To evaluate the association between serum PTX-2 levels and fibrosis stage in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Serum pentraxin 2 levels were compared between four groups of well-characterised patients including NAFLD with no fibrosis, NAFLD with mild-moderate fibrosis (stage 1-2), NAFLD with advanced fibrosis (stage 3-4), and age-sex matched non-NAFLD controls. RESULTS: Sixty subjects were included in the study. The mean age was 58.9 years, 68% were male and 58% were Caucasian. In univariate analysis, serum PTX-2 levels significantly decreased from non-NAFLD controls to mild NAFLD with no fibrosis, to NAFLD with mild-moderate fibrosis and were lowest in patients with NAFLD and advanced fibrosis, in a dose-dependent manner (P < 0.0001). In multivariable adjusted analyses controlling for age, sex, albumin, and CRP, the results remained consistent and statistically significant. Serum PTX-2 level had an AUROC of 0.84 (95% CI: 0.71-0.97) for the diagnosis of NAFLD, and an AUROC of 0.77 (95% CI: 0.65-0.90) for the diagnosis of advanced fibrosis in NAFLD. Serum PTX-2 levels also decreased with increasing liver stiffness as estimated by magnetic resonance elastography (r = -0.31, P = 0.02). CONCLUSIONS: PTX-2 levels are significantly lower in patients with NAFLD compared to non-NAFLD controls, and decline further in patients with advanced fibrosis. PTX-2 may therefore be both a biomarker of disease and a potential target for anti-fibrotic therapy with the recombinant pentraxin-2. PMID- 26119354 TI - Synthesis, crystal structures, and two-photon absorption of a series of cyanoacetic acid triphenylamine derivatives. AB - A specific series of chromophores (CN1, CN2, CN3, and CN4) have been synthesized, in which contained a triphenylamine moiety as the electron donor (D), a cyanoacetic acid moiety as the electron acceptor (A), vinylene or phenylethyne as the pi-bridge, and ethyoxyl groups as auxiliary electron donor (D') to construct the D-pi-A or D'-D-pi-A molecular configuration. Photophysical properties of them were systematically investigated. These results show that the chromophores display a solvatochromism (blue shift) and large Stokes shifts for their absorption bands with increasing polarity of the solvent. Furthermore, the chromophore CN4 shows the strongest intensity of two-photon excited fluorescence and largest two-photon absorption cross section (2783 GM) in the near infrared region. Finally, the connections between the structures and properties are systematically investigated relying on the information from linear and nonlinear optical properties, crytsal structures and quantum chemical calculation. PMID- 26119355 TI - Scheduling the blended solution as industrial CO2 absorber in separation process by back-propagation artificial neural networks. AB - It is believe that 80% industrial of carbon dioxide can be controlled by separation and storage technologies which use the blended ionic liquids absorber. Among the blended absorbers, the mixture of water, N-methyldiethanolamine (MDEA) and guanidinium trifluoromethane sulfonate (gua) has presented the superior stripping qualities. However, the blended solution has illustrated high viscosity that affects the cost of separation process. In this work, the blended fabrication was scheduled with is the process arranging, controlling and optimizing. Therefore, the blend's components and operating temperature were modeled and optimized as input effective variables to minimize its viscosity as the final output by using back-propagation artificial neural network (ANN). The modeling was carried out by four mathematical algorithms with individual experimental design to obtain the optimum topology using root mean squared error (RMSE), R-squared (R(2)) and absolute average deviation (AAD). As a result, the final model (QP-4-8-1) with minimum RMSE and AAD as well as the highest R(2) was selected to navigate the fabrication of the blended solution. Therefore, the model was applied to obtain the optimum initial level of the input variables which were included temperature 303-323 K, x[gua], 0-0.033, x[MDAE], 0.3-0.4, and x[H2O], 0.7-1.0. Moreover, the model has obtained the relative importance ordered of the variables which included x[gua]>temperature>x[MDEA]>x[H2O]. Therefore, none of the variables was negligible in the fabrication. Furthermore, the model predicted the optimum points of the variables to minimize the viscosity which was validated by further experiments. The validated results confirmed the model schedulability. Accordingly, ANN succeeds to model the initial components of the blended solutions as absorber of CO2 capture in separation technologies that is able to industries scale up. PMID- 26119356 TI - Molecular structure, IR spectra, and chemical reactivity of cisplatin and transplatin: DFT studies, basis set effect and solvent effect. AB - Three different density functional theory (DFT) methods were employed to study the molecular structures of cis-diamminedichloroplatinum(II) (CDDP) and trans diamminedichloroplatinum(II) (TDDP). The basis set effect on the structure was also investigated. By comparing the optimized structures with the experimental data, a relatively more accurate method was chosen for further study of the IR spectra and other properties as well as the solvent effect. Nineteen characteristic vibrational bands of the title compounds were assigned and compared with available experimental data. The number of characteristic peaks for the asymmetric stretching and deformation vibrations of N-H can serve as a judgment for the isomer between CDDP and TDDP. Significant solvent effect was observed on the molecular structures and IR spectra. The reduced density gradient analysis was performed to study the intramolecular interactions of CDDP and TDDP, and the nature of changes in the structures caused by the solvent was illustrated. Several descriptors determined from the energies of frontier molecular orbitals (HOMO and LUMO) were applied to describe the chemical reactivity of the title compounds. The molecular electrostatic potential (MESP) surfaces showed that the amino groups were the most favorable sites that nucleophilic reagents tend to attack, and CDDP was easier to be attacked by nucleophilic reagents than TDDP. PMID- 26119357 TI - Exploring protein solution structure: Second moments of fluorescent spectra report heterogeneity of tryptophan rotamers. AB - Trp fluorescent spectra appear as a log-normal function but are usually analyzed with lambdamax, full width at half maximum, and the first moment of incomplete spectra. Log-normal analyses have successfully separated fluorescence contributions from some multi-Trp proteins but deviations were observed in single Trp proteins. The possibility that disparate rotamer environments might account for these deviations was explored by moment spectral analysis of single Trp mutants spanning the sequence of tear lipocalin as a model. The analysis required full width Trp spectra. Composite spectra were constructed using log-normal analysis to derive the inaccessible blue edge, and the experimentally obtained spectra for the remainder. First moments of the composite spectra reflected the site-resolved secondary structure. Second moments were most sensitive for spectral deviations. A novel parameter, derived from the difference of the second moments of composite and simulated log-normal spectra correlated with known multiple heterogeneous rotamer conformations. Buried and restricted side chains showed the most heterogeneity. Analyses applied to other proteins further validated the method. The rotamer heterogeneity values could be rationalized by known conformational properties of Trp residues and the distribution of nearby charged groups according to the internal Stark effect. Spectral heterogeneity fits the rotamer model but does not preclude other contributing factors. Spectral moment analysis of full width Trp emission spectra is accessible to most laboratories. The calculations are informative of protein structure and can be adapted to study dynamic processes. PMID- 26119358 TI - Sensory and circuit mechanisms mediating lower urinary tract reflexes. AB - Neural control of continence and micturition is distributed over a network of interconnected reflexes. These reflexes integrate sensory information from the bladder and urethra and are modulated by descending influences to produce different physiological outcomes based on the information arriving from peripheral afferents. Therefore, the mode of activation of primary afferents is essential in understanding the action of spinal reflex pathways in the lower urinary tract. We present an overview of sensory mechanisms in the bladder and urethra focusing on their spinal integration, identify the cardinal spinal reflexes responsible for continence and micturition, and describe how their functional role is controlled via peripheral afferent activity. PMID- 26119359 TI - Oral application of lactic acid bacteria following treatment with antibiotics inhibits allergic airway inflammation. AB - AIMS: To investigate whether lactic acid bacteria (LAB) can exhibit anti-allergy properties in antibiotics-treated mice model. METHODS AND RESULTS: Antibiotic treatment affected the composition of the intestinal microbiota and its metabolites, and thus has a mild effect on Th1/Th2 balance. Oral administration of Streptococcus thermophilus CCFM218 (ST218) could not fully repair antibiotic induced damage to the intestinal microbiota and its metabolites, and restore them to their original condition. But ST218 treatment revealed a strong suppressive effect on airway inflammation characterized by reduced inflammatory cell infiltration and levels of Th2 cytokines in lung tissues, which was associated with an enhanced mucosal tolerance. CONCLUSIONS: These results showed that ST218 could alleviate allergic responses in mice treated with antibiotics, primarily through the modulation of mucosal and systemic responses rather than the restoration of the intestinal microbiota. SIGNIFICANCE AND IMPACT OF THE STUDY: The rise in incidence in allergies may correlate with the widespread and liberal use of antibiotics. This study affirmed that one species of LAB ST218 significantly reduces allergic airway inflammation in antibiotic-treated mice model. PMID- 26119360 TI - Preparation and use of varied natural tools for extractive foraging by bonobos (Pan Paniscus). AB - OBJECTIVES: The tool-assisted extractive foraging capabilities of captive (zoo) and semi-captive (sanctuary) bonobo (Pan paniscus) groups were compared to each other and to those known in wild chimpanzee (Pan troglodytes) cultures. MATERIALS AND METHODS: The bonobos were provided with natural raw materials and challenged with tasks not previously encountered, in experimental settings simulating natural contexts where resources requiring special retrieval efforts were hidden. They were shown that food was buried underground or inserted into long bone cavities, and left to tackle the tasks without further intervention. RESULTS: The bonobos used modified branches and unmodified antlers or stones to dig under rocks and in the ground or to break bones to retrieve the food. Antlers, short sticks, long sticks, and rocks were effectively used as mattocks, daggers, levers, and shovels, respectively. One bonobo successively struck a long bone with an angular hammer stone, completely bisecting it longitudinally. Another bonobo modified long branches into spears and used them as attack weapons and barriers. Bonobos in the sanctuary, unlike those in the zoo, used tool sets to perform sequential actions. DISCUSSION: The competent and diverse tool-assisted extractive foraging by the bonobos corroborates and complements the extensive information on similar tool use by chimpanzees, suggesting that such competence is a shared trait. Better performance by the sanctuary bonobos than the zoo group was probably due to differences in their cultural exposure and housing conditions. The bonobos' foraging techniques resembled some of those attributed to Oldowan hominins, implying that they can serve as referential models. PMID- 26119362 TI - CaCO3 and SrCO3 bioprecipitation by fungi isolated from calcareous soil. AB - The urease-positive fungi Pestalotiopsis sp. and Myrothecium gramineum, isolated from calcareous soil, were examined for their properties of CaCO3 and SrCO3 biomineralization. After incubation in media amended with urea and CaCl2 and/or SrCl2 , calcite (CaCO3 ), strontianite (SrCO3 ), vaterite in different forms [CaCO3 , (Cax Sr1-x )CO3 ] and olekminskite [Sr(Sr,Ca)(CO3 )2 ] were precipitated, and fungal 'footprints' were observed on mineral surfaces. The amorphous precipitate mediated by Pestalotiopsis sp. grown with urea and equivalent concentrations of CaCl2 and SrCl2 was identified as hydrated Ca and Sr carbonates by Fourier transform infrared spectroscopy. Liquid media experiments showed M. gramineum possessed the highest Sr(2+) removal ability, and ~ 49% of supplied Sr(2+) was removed from solution when grown in media amended with urea and 50 mM SrCl2 . Furthermore, this organism could also precipitate 56% of the available Ca(2+) and 28% of the Sr(2+) in the form of CaCO3 , SrCO3 and (Cax Sr1 x )CO3 when incubated in urea-amended media and equivalent CaCl2 and SrCl2 concentrations. This is the first report of biomineralization of olekminskite and coprecipitation of Sr into vaterite mediated by fungi. These findings suggest that urease-positive fungi could play an important role in the environmental fate, bioremediation or biorecovery of Sr or other metals and radionuclides that form insoluble carbonates. PMID- 26119364 TI - Micro-nano structured Ni-MOFs as high-performance cathode catalyst for rechargeable Li-O2 batteries. AB - Rechargeable Li-O2 batteries with high theoretical energy density urgently require efficient cathode catalysts to improve their electrochemical performance. Here we first demonstrated the application of Ni-based organic frameworks of Ni(4,4'-bipy)(H3BTC) (4,4'-bipy = 4,4'-bipyridine; H3BTC = 1,3,5 benzenetricarboxylic acid) (Ni-MOFs) as high-performance cathode catalysts for rechargeable Li-O2 batteries. It is found that Ni-MOFs with a three-dimensional (3D) micro-nano structure, open catalytic sites and large specific surface area can guarantee the free transfer of O2 and effective contact between the electrolyte and the catalytic sites. Preliminary testing of Ni-MOFs showed that they possess an extremely high capacity of 9000 mA h g(-1), a high round-trip efficiency of 80%, and a respectable cycling of 170 cycles without obvious voltage drop. Furthermore, plastic rechargeable Li-O2 batteries with Ni-MOFs as the cathode catalyst have been assembled, displaying an energy density of 478 Wh kg(-1). This study leads to both fundamental and technological advances of Ni MOFs as the cathode for rechargeable Li-O2 batteries. PMID- 26119363 TI - Ascending and descending thoracic aorta calcification in type 2 diabetes mellitus. AB - BACKGROUND: Calcification of the thoracic aorta is a risk factor for cardiovascular disease and peripheral arterial disease but has not been well studied in diabetics. In addition, many studies consider aortic calcium as a single anatomic entity, whereas calcification of the ascending and descending portions of the thoracic aorta may represent separate phenotypes. We sought to characterize the prevalence of ascending and descending aortic calcium among diabetics and to assess their associations with cardiovascular risk factors, coronary artery calcium, and peripheral arterial disease. METHODS: Within the Penn Diabetes Heart Study, a cross-sectional study of subjects with type 2 diabetes mellitus but without coronary or renal disease, we quantified Agatston scores of the ascending and descending thoracic aorta in 1739 subjects (63% male, 61% Caucasian). Multivariate logistic and Tobit regressions were used to assess associations with cardiovascular risk factors, coronary calcium, and peripheral arterial disease. RESULTS: Of all subjects, 54% had thoracic aortic calcium; of these, 37% had calcium solely in the ascending thoracic aorta and 20% solely in the descending thoracic aorta. In multivariate regression, age, Caucasian race, systolic blood pressure, low-density lipoprotein cholesterol, smoking, and diabetes duration were independently associated with calcium of both the ascending and descending thoracic aorta (P < .001 for all). Ascending and descending aortic calcium were each independently associated with coronary calcium in multivariate regression, but only calcification of the descending thoracic aortic was associated with low ankle-brachial index. CONCLUSION: Ascending and descending thoracic aortic calcium have similar associations with traditional cardiovascular risk factors in diabetics and are independently associated with coronary artery calcium. Only calcium in the descending aorta is associated with peripheral arterial disease. Delineation of both phenotypes may provide information about the individualized vascular disease and risk profile of patients with type 2 diabetes mellitus. PMID- 26119365 TI - Parametric Investigation of Batch Adsorption of Proteins onto Polymeric Particles. AB - BACKGROUND: Effective bimolecular adsorption of proteins onto solid matrices is characterized by in-depth understanding of the biophysical features essential to optimize the adsorption performance. RESULTS: The adsorption of bovine serum albumin (BSA) onto anion-exchange Q-sepharose solid particulate support was investigated in batch adsorption experiments. Adsorption kinetics and isotherms were developed as a function of key industrially relevant parameters such as polymer loading, stirring speed, buffer pH, protein concentration and the state of protein dispersion (solid/aqueous) in order to optimize binding performance and adsorption capacity. Experimental results showed that the first order rate constant is higher at higher stirring speed, higher polymer loading, and under alkaline conditions, with a corresponding increase in equilibrium adsorption capacity. Increasing the stirring speed and using aqueous dispersion protein system increased the adsorption rate, but the maximum protein adsorption was unaffected. Regardless of the stirring speed, the adsorption capacity of the polymer was 2.8 mg/ml. However, doubling the polymer loading increased the adsorption capacity to 9.4 mg/ml. CONCLUSIONS: The result demonstrates that there exists a minimum amount of polymer loading required to achieve maximum protein adsorption capacity under specific process conditions. PMID- 26119366 TI - Efficacy of topical antibiotic administration on the inhibition of perioperative oral bacterial growth in oral cancer patients: a preliminary study. AB - Parenteral antibiotic prophylaxis is the current standard of therapy in clean contaminated oral cancer surgery. Nevertheless, the incidence of surgical site infection (SSI) in oral oncological surgery is relatively high, especially in major surgery with reconstruction and tracheotomy. The aims of this study were to investigate the perioperative condition related to microorganisms in the oral cavity and to examine the efficacy of the topical administration of tetracycline in reducing the number of bacteria in the oropharyngeal fluid during intubation. The number of oral bacteria was measured during intubation in patients undergoing major oral cancer surgery. The efficacy of the topical administration of tetracycline or povidone iodine gel in reducing the bacteria was then investigated. Bacteria in the oropharyngeal fluid grew from 10(6)CFU/ml to 10(8)CFU/ml during the 3h after intubation (CFU, colony-forming units). When tetracycline was applied to the dorsum of the tongue, oral bacteria decreased immediately to 10(5)CFU/ml, and the number of bacteria in the oropharyngeal fluid was maintained below 10(7)CFU/ml for 7h. The concentration of tetracycline in the oropharyngeal fluid was extremely high for several hours after topical administration. The topical administration of tetracycline could reduce oral bacteria in patients undergoing clean-contaminated oral cancer surgery. This method is expected to be effective in the prevention of SSI. PMID- 26119367 TI - Sufficient Immunosuppression with Thymoglobulin Is Essential for a Successful Haplo-Myeloid Bridge in Haploidentical-Cord Blood Transplantation. AB - In haploidentical (haplo)-cord blood (CB) transplantations, early haplo donor engraftment serves as a myeloid bridge to sustainable CB engraftment and is associated with early neutrophil recovery. The conditioning regimens as published for haplo-cord protocols usually contain serotherapy, such as rabbit antithymocyte globulin (ATG) (Thymoglobulin, Genzyme, Cambridge, MA). However, reducing or omitting serotherapy is an important strategy to improve early immune reconstitution after transplantation. The need for serotherapy in successful haplo-cord transplantation, defined as having a haplo-derived myeloid bridge to CB engraftment, has not been investigated before. Two consecutive cohorts of patients underwent transplantation with haplo-CB. The first group underwent transplantation with haplo-CB for active infection and/or an underlying condition with expected difficult engraftment without a conventional donor available. They received a single unit (s) CB and haplo donor cells (CD34(+) selected, 5 * 10(6) CD34(+)/kg). The second cohort included patients with poor-risk malignancies, not eligible for other treatment protocols. They received a sCB and haplo donor cells (CD19/alphabetaTCR-depleted; 5 * 10(6) CD34(+)/kg). Retrospectively in both cohorts, active ATG (Thymoglobulin) levels were measured and post-hematopoietic cell transplantation area under the curve (AUC) was calculated. The influence of ATG exposure for having a successful haplo-myeloid bridge (early haplo donor engraftment before CB engraftment and no secondary neutropenia) and transplantation-related mortality (TRM) were analyzed as primary endpoints. Twenty patients were included (16 in the first cohort and 4 in the second cohort). In 58% of evaluable patients, there was no successful haplo-derived myeloid bridge to CB engraftment, for which a low post-transplantation ATG exposure appeared to be a predictor (P <.001). TRM in the unsuccessful haplo bridge group was 70% +/- 16% versus 12% +/- 12% in the successful haplo-bridge group (P = .012). In conclusion, sufficient in vivo T depletion with ATG is required for a successful haplo-myeloid bridge to CB engraftment. PMID- 26119369 TI - Metallocorroles as photocatalysts for driving endergonic reactions, exemplified by bromide to bromine conversion. AB - Photochemical oxidation of halide anions by visible light has been suggested for solar energy conversion processes. Post-transition metallocorroles are now disclosed as very efficient catalysts for the photoinduced transformation of bromide to bromine. The advantages of these catalysts are that they are very stable under the reaction conditions and that the energy levels of the oxidizing HOMO and the reducing LUMO are easily tuned. Insights into the mechanism of action obtained in this work is predicted to be very useful for the design of other systems that rely on photocatalysis for driving endergonic reactions. PMID- 26119368 TI - Being stuck in a vice: The process of coping with severe depression in late life. AB - Articles describing older persons' experiences of coping with severe depression are, to our knowledge, lacking. This article is methodologically grounded in phenomenological hermeneutics, inspired by Paul Ricoeur, and applies a descriptive design with in-depth interviews for producing the data. We included 18 older persons, 13 women and 5 men, with a mean age of 77.9 years, depressed to a severe or moderate degree, 1-2 weeks after admission to a hospital for treatment of depression. We found the metaphor "being in a vice" to capture the essence of meaning from the participants' stories, and can be understood as being stuck in an immensely painful existence entirely dominated by depression in late life. This is the first article where coping in older men and women experiencing the most severe phase of depression is explored. PMID- 26119370 TI - Intracellular delivery cellulose-based bionanogels with dual temperature/pH response for cancer therapy. AB - Polysaccharide-based crosslinked nanogles (bionanogels) exhibiting multiple stimuli-responsive release of encapsulated therapeutics hold a great potential as tumor-targeting intracelluar durg delivery nanocarriers. Herein, we report the synthesis of monodisperse dual temperature/acidic pH-responsive bionanogels (DuR BNGs) by aqueous crosslinking polymerization through temperature-induced self association method. The DuR-BNGs have prolonged colloidal stability and negligible non-specific interactions with proteins. In response to acidic pH at higher temperature (above lower critical solution temperature), they exhibit synergistic release of anticancer drugs as a consequence of both acidic pH sensitivity of carboxymethyl cellulose and temperature-induced volume change of grafted thermoresponsive copolymers. In vitro cell culture results suggest that new colloidally-stable DuR-BNG is a promising candidate promoting dual stimuli responsive drug release for cancer therapy. PMID- 26119371 TI - Fluorescence behavior of globular proteins from their bulk and thin film conformations in presence of mono-, di- and tri-valent ions. AB - Photoluminescence behavior of globular proteins, lysozyme and bovine serum albumin (BSA), from their bulk and thin film conformations have been studied in presence of mono-, di- and tri-valent ions by using fluorescence and UV-Vis spectroscopy at two different temperatures and the morphology of the protein thin films have been studied by using atomic force microscopy. Protein- and ion dependent dynamic and static quenching behaviors have been identified. While dynamic quenching is observed for lysozyme for all the three different valent ions, BSA shows no quenching for mono-valent (Na(+)) ions, dynamic quenching for di-valent (Ni(2+)) ions and static quenching for tri-valent (Fe(3+)) ions at pH~5.5. After heat treatment, as the conformation of the protein molecules changes, the quenching efficiency for lysozyme in presence of ions decreases but shows enhancement for BSA. In thin film geometry, the molecular conformation of both lysozyme and BSA modifies on the solid surfaces and hence quenching efficiency also modifies in comparison with that of bulk and as a result the quenching efficiency for lysozyme increases but decreases for the BSA film. PMID- 26119372 TI - Blood coagulation and platelet adhesion on polyaniline films. AB - Polyaniline is a promising conducting polymer with still increasing application potential in biomedicine. Its surface modification can be an efficient way how to introduce desired functional groups and to control its properties while keeping the bulk characteristics of the material unchanged. The purpose of the study was to synthetize thin films of pristine conducting polyaniline hydrochloride, non conducting polyaniline base and polyaniline modified with poly(2-acrylamido-2 methyl-1-propanesulfonic acid) (PAMPSA) and investigate chosen parameters of their hemocompatibility. The modification was performed either by introduction of PAMPSA during the synthesis or by reprotonation of polyaniline base. The polyaniline hydrochloride and polyaniline base had no impact on blood coagulation and platelet adhesion. By contrast, the polyaniline reprotonated with PAMPSA completely hindered coagulation thanks to its interaction with coagulation factors Xa, Va and IIa. The significantly lower platelets adhesion was also found on this surface. Moreover, this film maintains its conductivity at pH of 6, which is an improvement in comparison with standard polyaniline hydrochloride losing most of its conductivity at pH of 4. Polyaniline film with PAMPSA introduced during synthesis had an impact on platelet adhesion but not on coagulation. The combined conductivity, anticoagulation activity, low platelet adhesion and improved conductivity at pH closer to physiological, open up new possibilities for application of polyaniline reprotonated by PAMPSA in blood-contacting devices, such as catheters or blood vessel grafts. PMID- 26119373 TI - A nano-micro alternating multilayer scaffold loading with rBMSCs and BMP-2 for bone tissue engineering. AB - In this study, we develop a nano-micro alternating multilayer scaffold for bone tissue engineering by incorporation of monodispersed calcium alginate microbeads into electrospun polymer nanofibers. Both rat bone marrow mesenchymal stem cells (rBMSCs) and bone morphogenetic protein-2 (BMP-2) are simultaneously loaded into the microbeads, which are generated from a microfluidic device. The layer number of the scaffold can be readily controlled by alternately repeating the electrospinning and the microfluidic processes. Alkaline phosphatase (ALP) activity and Alizarin Red S staining results demonstrate that this rBMSCs and BMP 2 loaded nano-micro alternating multilayer scaffold presents an outstanding osteogenic effect in vitro. Histological and immunohistochemical assessments further reveal that this multilayer scaffold has a significant capability of ectopic bone formation in vivo, enabling this newly developed scaffold to be suitable for wide applications in tissue engineering. PMID- 26119374 TI - Stick-slip water penetration into capillaries coated with swelling hydrogel. AB - We have observed intriguing stick-slip behavior during capillary pressure driven filling of borosilicate microtubes coated with hydrogel on their inner wall. Swelling of hydrogel upon exposure to a translating waterfront is accompanied by "stick-and-slip" motion. This results in the macroscopic filling velocity for water penetration into glass capillaries coated with poly(N-isopropylacrylamide) (PNIPAM) being constant throughout the filling process, and reduced by three orders of magnitude when compared to filling of uncoated capillaries. A simple scaling analysis is used to introduce a possible explanation by considering the mechanisms responsible for pinning and unpinning of the contact line. The explanation assumes that the time scale for water diffusion into a hydrogel film and the resulting swelling/change of the local meniscus contact angle define the duration of each "stick" event. The "slip" length scale is in turn established by the elastocapillary deformation of dry hydrogel at the pinning point of the contact line. The sequential dynamics of these processes then determine the rate of water filling into a swelling capillary. Collectively, these experimental and theoretical results provide a new conceptual framework for liquid motion confined by soft, dynamically evolving polymer interfaces, in which the system creates an energy barrier to further motion through elasto-capillary deformation, and then lowers the barrier through diffusive softening. This insight has implications for optimal design of microfluidic and lab-on-a-chip devices based on stimuli responsive smart polymers. PMID- 26119375 TI - Differences in cancer drug assessment between Spain and the United Kingdom. AB - OBJECTIVES: There is no Spanish Government agency resembling the National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK) that carries out a centralised evaluation and makes decisions about funding. Therefore, we aim to assess the differences between NICE and the Spanish bodies in terms of their respective processes. We compare the decisions concerning cancer drugs in the assessments made by NICE/Single Technology Appraisal with assessments made by MADRE methodology. METHODS: We included all cancer drugs assessed by NICE and all MADRE reports made using a shared reports process (GENESIS) and reports from Catalonia (CAMDHA) and Andalucia (GFTHA). We compared the number of drugs assessed, the decisions taken by NICE and Spanish organizations and timelines. RESULTS: Between January 2011 and December 2013 NICE appraised 24 cancer drugs. In Spain, 44 reports were produced using MADRE methodology. For the 14 drugs assessed by both NICE and Spanish bodies, NICE rejected a high proportion of the drugs (50% versus 26%). GENESIS, with a median of 8 months, made decisions more quickly than NICE (13.5 months) and GFTHA (17 months). The slowest organisation was CAMDHA (24.5 months). CONCLUSIONS: More drugs are assessed in Spain than by NICE because there are more organisations in Spain doing this work and their processes are simpler. NICE rejects more drugs as it uses cost-effectiveness thresholds that lead to a 'not-recommended' decision, and Spanish bodies recommend cancer drugs for subgroups of patients where better results can be obtained. Timelines are better for Spanish Committees, probably because of the greater number of steps in the appraisal process by NICE. PMID- 26119376 TI - Bioturbation/bioirrigation effect on thallium released from reservoir sediment by different organism types. AB - Bioturbation can remobilize heavy metal in the sediments and may pose a risk for aquatic biota. The effects of bioturbation/bioirrigation by three different riverine organism types (Tubificid, Chironomid larvae, and Loach) on thallium release from contaminated sediment (10.0 +/- 1.1 mg Tl/kg sediment, dry wt.) were evaluated in this study. The bioturbation by the epibenthos clearly caused an increased turbidity in the overlying water, and the effect was in the order of Loach > Chironomid larvae > Tubificid. A significant release of Tl into the water column via the resuspended sediment particles was observed, especially for Loach. During the first few days, the leaching of dissolved Tl from sediment into water was fast, and the dissolved Tl under bioturbation/bioirrigation was much higher than the control group. However, after 14 days, the bioturbation/bioirrigation process seemed to suppress the release of Tl from the sediment particles to water, especially for sediment with Loach. This may partly be due to the sorption or coprecipitation of Tl simultaneous with the formation of iron and manganese hydrous oxides with increased pH values as a consequence of phytoplankton growth. Linear regression analysis confirmed that both the total and particulate Tl concentrations had good correlations with particulate Fe and Mn concentrations as well as turbidity in the overlying water. Additionally, planktonic bacteria may oxidize the Tl(I) to Tl(III), resulting in a reduced solubility of Tl by which Tl(OH)3 becomes the predominant form of Tl. PMID- 26119377 TI - A comparison of methods used to calculate normal background concentrations of potentially toxic elements for urban soil. AB - To meet the requirements of regulation and to provide realistic remedial targets there is a need for the background concentration of potentially toxic elements (PTEs) in soils to be considered when assessing contaminated land. In England, normal background concentrations (NBCs) have been published for several priority contaminants for a number of spatial domains however updated regulatory guidance places the responsibility on Local Authorities to set NBCs for their jurisdiction. Due to the unique geochemical nature of urban areas, Local Authorities need to define NBC values specific to their area, which the national data is unable to provide. This study aims to calculate NBC levels for Gateshead, an urban Metropolitan Borough in the North East of England, using freely available data. The 'median + 2MAD', boxplot upper whisker and English NBC (according to the method adopted by the British Geological Survey) methods were compared for test PTEs lead, arsenic and cadmium. Due to the lack of systematically collected data for Gateshead in the national soil chemistry database, the use of site investigation (SI) data collected during the planning process was investigated. 12,087 SI soil chemistry data points were incorporated into a database and 27 comparison samples were taken from undisturbed locations across Gateshead. The SI data gave high resolution coverage of the area and Mann Whitney tests confirmed statistical similarity for the undisturbed comparison samples and the SI data. SI data was successfully used to calculate NBCs for Gateshead and the median+2MAD method was selected as most appropriate by the Local Authority according to the precautionary principle as it consistently provided the most conservative NBC values. The use of this data set provides a freely available, high resolution source of data that can be used for a range of environmental applications. PMID- 26119378 TI - Long-term combined chemical and manure fertilizations increase soil organic carbon and total nitrogen in aggregate fractions at three typical cropland soils in China. AB - Soil organic carbon (SOC), total nitrogen (TN), microbial biomass carbon (MBC) and nitrogen (MBN) are important factors of soil fertility. However, effects of the combined chemical fertilizer and organic manure or straw on these factors and their relationships are less addressed under long-term fertilizations. This study addressed changes in SOC, TN, MBC and MBN at 0-20 cm soil depth under three 17 years (September 1990-September 2007) long-term fertilization croplands along a heat and water gradient in China. Four soil physical fractions (coarse free and fine free particulate organic C, cfPOC and ffPOC; intra-microaggregate POC, iPOC; and mineral associated organic C, MOC) were examined under five fertilizations: unfertilized control, chemical nitrogen (N), phosphorus (P) and potassium (K) (NPK), NPK plus straw (NPKS, hereafter straw return), and NPK plus manure (NPKM and 1.5NPKM, hereafter manure). Compared with Control, manure significantly increased all tested parameters. SOC and TN in fractions distributed as MOC > iPOC > cfPOC > ffPOC with the highest increase in cfPOC (329.3%) and cfPTN (431.1%), and the lowest in MOC (40.8%) and MTN (45.4%) under manure. SOC significantly positively correlated with MBC, cfPOC, ffPOC, iPOC and MOC (R(2) = 0.51-0.84, P < 0.01), while TN with cfPTN, ffPTN, iPTN and MTN (R(2) = 0.45-0.79, P < 0.01), but not with MBN, respectively. Principal component analyses explained 86.9-91.2% variance of SOC, TN, MBC, MBN, SOC and TN in each fraction. Our results demonstrated that cfPOC was a sensitive SOC indicator and manure addition was the best fertilization for improving soil fertility while straw return should take into account climate factors in Chinese croplands. PMID- 26119379 TI - Historical levels of heavy metals reconstructed from sedimentary record in the Hejiang River, located in a typical mining region of Southern China. AB - Historical levels of Pb, Zn, Cd, Cr, Cu, Ni, As, Fe, Al and Mn were found in C1 and C2 sediment cores from the Hejiang River, which is located in a typical mining region of Southern China, the levels date back approximately 57 and 83 years. Temporal variations in the core C1 around the mining peaked in the 1960s, after which they exhibited a decreasing trend, which reflects successful government management. Historical events such as the Pacific War and China's first 5-year economic plan were recorded in core C2, which was collected from the downstream portion of the Hejiang River. Enrichment factors (EF), geo accumulation (Igeo), and excess flux indicate that severe contamination occurred during the period between 1956 and 1985 due to the release of high amounts of mining waste from human activities around the core C1 region. The highest EF value was displayed by As (67); this was followed by Pb (64), Cd (39), and Zn (35). In contrast, the core C2 sediments exhibited minor pollution because of dilution from tributaries (the Fu River and the Daning River) that do not flow through the mined area and because C2 was farther from the source of the metals. The results of the risk assessment codes (RAC) for both cores indicate that Cd posed a high risk to the local environment. Principal component analysis (PCA) and correlation analysis (CA) revealed that accumulation of heavy metals was mainly due to mining pollution. PMID- 26119380 TI - Evaluation of the environmental performance of alternatives for polystyrene production in Brazil. AB - The global demand for polystyrene is supposed to reach an overall baseline of 23.5 million tons by 2020. The market has experienced the effects of such growth, especially regarding the environmental performance of the production processes. In Brazil, renewable assets have been used to overcome the adverse consequences of this expansion. This study evaluates this issue for the production of Brazilian polystyrene resins, general-purpose polystyrene (GPPS) and high-impact polystyrene (HIPS). The effects of replacing fossil ethylene with a biobased alternative are also investigated. Life Cycle Assessment is applied for ten scenarios, with different technological approaches for renewable ethylene production and an alternative for obtaining bioethanol, which considers the export of electricity. The fossil GPPS and HIPS show a better performance than the partially renewable sources in terms of Climate Change (CC), Terrestrial Acidification (TA), Photochemical Oxidant Formation (POF), and Water Depletion (WD). The exception is Fossil Depletion (FD), a somewhat predictable result. The main environmental loads associated with the renewable options are related to the sugarcane production. Polybutadiene fails to provide greater additional impact to HIPS when compared to GPPS. With regard to obtaining ethylene from ethanol, Adiabatic Dehydration (AD) technology consumes less sugarcane than Adiabatic Dehydration at High Pressure (ADHP), which leads to gains in TA and POF. In contrast, ADHP was more eco-friendly for WD because of its lower water losses and in terms of CC because of the advantageous balance of fossil CO2(eq) at the agricultural stage and the lower consumption of natural gas in ethylene production. The electricity export is an auspicious environmental opportunity because it can counterbalance some of the negative impacts associated with the renewable route. According to a "cradle-to-grave" perspective, the partially renewable resins show a more favorable balance of carbon. This difference increases when sequestration and biogenic carbon emissions are considered. PMID- 26119381 TI - Toxicity of chlortetracycline and its metal complexes to model microorganisms in wastewater sludge. AB - Complexation of antibiotics with metals is a well-known phenomenon. Wastewater treatment plants contain metals and antibiotics, thus it is essential to know the effect of these complexes on toxicity towards microorganisms, typically present in secondary treatment processes. In this study, stability constants and toxicity of chlortetracycline (CTC) and metal (Ca, Mg, Cu and Cr) complexes were investigated. The calculated stability constants of CTC-metal complexes followed the order: Mg-CTC>Ca-CTC>Cu-CTC>Cr-CTC. Gram positive Bacillus thuringiensis (Bt) and Gram negative Enterobacter aerogenes (Ea) bacteria were used as model microorganisms to evaluate the toxicity of CTC and its metal complexes. CTC-metal complexes were more toxic than the CTC itself for Bt whereas for Ea, CTC and its metal complexes showed similar toxicity. In contrast, CTC spiked wastewater sludge (WWS) did not show any toxic effect compared to synthetic sewage. This study provides evidence that CTC and its metal complexes are toxic to bacteria when they are biologically available. As for WWS, CTC was adsorbed to solid part and was not biologically available to show measurable toxic effects. PMID- 26119382 TI - Assessment of wastewater treatment alternatives for small communities: An analytic network process approach. AB - The selection of the most appropriate wastewater treatment (WWT) technology is a complex problem since many alternatives are available and many criteria are involved in the decision-making process. To deal with this challenge, the analytic network process (ANP) is applied for the first time to rank a set of seven WWT technology set-ups for secondary treatment in small communities. A major advantage of ANP is that it incorporates interdependent relationships between elements. Results illustrated that extensive technologies, constructed wetlands and pond systems are the most preferred alternatives by WWT experts. The sensitivity analysis performed verified that the ranking of WWT alternatives is very stable since constructed wetlands are almost always placed in the first position. This paper showed that ANP analysis is suitable to deal with complex decision-making problems, such as the selection of the most appropriate WWT system contributing to better understand the multiple interdependences among elements involved in the assessment. PMID- 26119383 TI - Application of factor analysis and electrical resistivity to understand groundwater contributions to coastal embayments in semi-arid and hypersaline coastal settings. AB - Groundwater contributions and sources of salinity to Oso Bay in south Texas were investigated using multivariate statistical analysis of geochemical data and multitemporal electrical resistivity tomography surveys. Both analysis of geochemical data and subsurface imaging techniques identified two commonalities for the investigated system: 1) hypersaline water occurs near the groundwater/surface water interface during wet conditions creating reverse hydraulic gradients due to density effects. The development and downward movement of these fluids as continuous plumes deflect fresher groundwater discharge downward and laterally away from the surface; and 2) more pronounced upwelling of fresher groundwater occurs during drought periods when density inversions are more defined and are expected to overcome dispersion and diffusion processes and create sufficiently large-enough unstable gradients that induce density difference convection. Salinity mass-balance models derived from time-difference resistivity tomograph and in-situ salinity data reaffirm these findings indicating that groundwater upwelling is more prominent during dry to wet conditions in 2013 (~545.5m(3)/d) and is less pronounced during wet to dry conditions in 2012 (~262.7 m(3)/d) for the 224 m(2) area surveyed. Findings show that the highly saline nature of water in this area and changes in salinity regimes can be attributed to a combination of factors, namely: surface outflows, evapoconcentration, recirculation of hypersaline groundwaters, and potential trapped oil field brines. Increased drought conditions will likely exacerbate the rate at which salinity levels are increasing in bays and estuaries in semi-arid regions where both hypersaline groundwater discharge and high evaporation rates occur simultaneously. PMID- 26119384 TI - Nitrous oxide production and consumption by denitrification in a grassland: Effects of grazing and hydrology. AB - Denitrification is generally recognized as a major mechanism contributing to nitrous oxide (N2O) production, and is the only known biological process for N2O consumption. Understanding factors controlling N2O production and consumption during denitrification will provide insights into N2O emission variability, and potentially predict capacity of soils to serve as sinks or sources of N2O. This study investigated the effects of hydrology and grazing on N2O production and consumption in a grassland based agricultural watershed. A batch incubation study was conducted on soils (0-10 cm) collected along a hydrological gradient representing isolated wetland (Center), transient zone (Edge) and pasture upland (Upland), from both grazed and ungrazed areas. Production and consumption potentials of N2O were quantified on soils under four treatments, including (i) ambient condition, and amended with (ii) NO3(-), (iii) glucose-C, and (iv) NO3(-) +glucose-C. The impacts of grazing on N2O production and consumption were not observed. Soils in hydrologically distinct zones responded differently to N2O production and consumption. Under ambient conditions, both production and consumption rates of Edge soils were higher than those observed for Center and Upland soils. Results of amended incubations suggested NO3(-) was a key factor limiting N2O production and consumption rates in all hydrological zones. Over 5-d incubation with NO3(-) amendment, cumulative production and consumption of N2O for Center soils were 1.6 and 3.3 times higher than Edge soils, and 3.6 and 7.6 times higher than Upland soils, respectively. However, cumulative N2O net production for Edge soils was the highest, with 2 to 3 times higher than Upland and Center soils. Our results suggest that the transient areas between wetland and upland are likely to be "hot spots" of N2O emissions in this ecosystem. Wetlands within agricultural landscapes can potentially function to reduce both NO3(-) leaching and N2O emissions. PMID- 26119385 TI - High fluvial export of dissolved organic nitrogen from a peatland catchment with elevated inorganic nitrogen deposition. AB - This study investigates seasonal concentrations and fluxes of nitrogen (N) species under stormflow and baseflow conditions in the peat dominated Kinder River catchment, south Pennines, UK. This upland region has experienced decades of high atmospheric inorganic N deposition. Water samples were collected fortnightly over one year, in combination with high resolution stormflow sampling and discharge monitoring. The results reveal that dissolved organic nitrogen (DON) constitutes ~54% of the estimated annual total dissolved nitrogen (TDN) flux (14.3 kg N ha(-1) yr(-1)). DON cycling in the catchment is influenced by hydrological and biological controls, with greater concentrations under summer stormflow conditions. Dissolved organic carbon (DOC) and DON are closely coupled, with positive correlations observed during spring, summer and autumn stormflow conditions. A low annual mean DOC:DON ratio (<25) and elevated dissolved inorganic N concentrations (up to 63MUmoll(-1) in summer) suggest that the Kinder catchment is at an advanced stage of N saturation. This study reveals that DON is a significant component of TDN in peatland fluvial systems that receive high atmospheric inputs of inorganic N. PMID- 26119386 TI - The build-up dynamic and chemical fractionation of Cu, Zn and Cd in road deposited sediment. AB - This study investigates the build-up dynamics of heavy metals on impervious urban surfaces with different antecedent dry-weather periods (ADPs) and land-use types. Solid-phase concentration (mg/kg), surface load (mg/m(2)), and chemical fractionation of Zn, Cu and Cd in bulk- and size-fractionated road-deposited sediment were determined. The inherent correlations among particle size distribution, ADP, land use, and chemical fractionation were analysed by hierarchical cluster analysis. Results show a clear build-up phenomenon of Cu and Zn at a city commercial centre and a highway area. Cd had complex build-up patterns. With regard to chemical fractionation, Zn and Cd could pose higher risks than Cu to aquatic biota after a longer ADP. Special attention should be paid to the significant risk in a rural area because of the high proportion of exchangeable chemical fractionation in terms of the unstable Cd component. Hierarchical cluster analysis indicates that ADP had a strong influence on build up processes of sediments and associated metals. The metal contents were very dependent on the particle size distribution. However, the chemical fractionation of metals was dependent to a lesser extent on the land-use type. PMID- 26119387 TI - Physico-chemical characteristics affect the spatial distribution of pesticide and transformation product loss to an agricultural brook. AB - Diffuse entry of pesticide residues from agriculture into rivers is spatially unevenly distributed. Therefore, the identification of critical source areas (CSAs) may support water quality management in agricultural catchments. In contrast to former studies, we followed the hypothesis that not only hydrological and topographical characteristics but also physico-chemical properties of pesticide residues have a major influence on their loss to rivers and on corresponding formation of CSAs. We designed a virtual experiment, i.e. a numerical experiment as close as possible to environmental conditions, in a headwater catchment where pronounced spatial differences in hydrological transport processes were identified in the past. 144 scenarios with different combinations of adsorption coefficients (KOC = 10-1000 ml/g) and transformation half-lives (DT50 = 3-60 days) for pesticide parent compounds (PCs) and their transformation products (TPs) were simulated using the catchment-scale spatially distributed reactive transport model ZIN-AgriTra. Export fractions of substances in the virtual experiment ranged from 0.001-15% for pesticides and 0.001-1.8% for TPs. The results of the scenario investigations suggest that more of the calculated export mass variability could be attributed to KOC than to DT50 for both PCs and TPs. CSAs for TPs were spatially more equally distributed in the catchment than for PC export which was likely an effect of changing physico chemical properties during transformation. The ranking of highest export fields was different between PCs and TPs for most of the investigated scenarios but six fields appeared among the top ten export fields in 95% of the scenarios, which shows the influence of site characteristics such as tile drains or soil properties in the catchment. Thus, the highest export fields were determined by a combination of site characteristics and substance characteristics. Therefore, despite the challenge of widely differing physico-chemical characteristics of pesticides on the market, these characteristics are an important consideration when delineating pesticide residue CSAs. PMID- 26119388 TI - The utility of ground-penetrating radar and its time-dependence in the discovery of clandestine burials. AB - In the field of forensic investigation burial is a relatively common method of hiding a corpse. The location of clandestine graves is, however, a particularly difficult task in which multiple forensic disciplines such as anthropology, botany or archaeology can provide valuable assistance. The use of GPR (ground penetrating radar) has recently been introduced as a method in the detection of these graves, but what is the true potential of this tool in an operative search scenario? In this study a total of 11 pig carcasses were buried in two wooded areas, each presenting a similar soil composition. The animals were subsequently exhumed at regular intervals, ranging from 2 to 111 weeks, using systematic GPR analysis of the burial sites and archaeological recovery of the subjects that were then autopsied. GPR proved to be useful in recognizing anomalies at the chosen depths of burial and appeared to be dependent on the state of decay of the samples, producing only slight anomalous readings in the presence of skeletal remains: at 92 weeks from burial the difference in signal was weak and at 111 weeks GPR survey offered no helpful information as to burial location. The experiment, in this particular context, determined the technique as being successful in the presence of recent burials, highlighting the need for a multidisciplinary approach in the operative search for buried human remains. PMID- 26119390 TI - Theoretical study of the dark photochemistry of 1,3-butadiene via the chemiexcitation of Dewar dioxetane. AB - Excited-state chemistry is usually ascribed to photo-induced processes, such as fluorescence, phosphorescence, and photochemistry, or to bio- and chemiluminescence, in which light emission originates from a chemical reaction. A third class of excited-state chemistry is, however, possible. It corresponds to the photochemical phenomena produced by chemienergizing certain chemical groups without light - chemiexcitation. By studying Dewar dioxetane, which can be viewed as the combination of 1,2-dioxetane and 1,3-butadiene, we show here how the photo isomerization channel of 1,3-butadiene can be reached at a later stage after the thermal decomposition of the dioxetane moiety. Multi-reference multiconfigurational quantum chemistry methods and accurate reaction-path computational strategies were used to determine the reaction coordinate of three successive processes: decomposition of the dioxetane moiety, non-adiabatic energy transfer from the ground to the excited state, and finally non-radiative decay of the 1,3-butadiene group. With the present study, we open a new area of research within computational photochemistry to study chemically-induced excited-state chemistry that is difficult to tackle experimentally due to the short-lived character of the species involved in the process. The findings shall be of relevance to unveil "dark" photochemistry mechanisms, which might operate in biological systems under conditions of lack of light. These mechanisms might allow reactions that are typical of photo-induced phenomena. PMID- 26119389 TI - Transcriptome-wide measurement of plant RNA secondary structure. AB - RNAs fold into intricate and precise secondary structures. These structural patterns regulate multiple steps of the RNA lifecycle, while also conferring catalytic and scaffolding functions to certain transcripts. Therefore, a full understanding of RNA posttranscriptional regulation requires a comprehensive picture of secondary structure. Here, we review several high throughput sequencing-based methods to globally survey plant RNA secondary structure. These methods are more accurate than computational prediction, and more scalable than physical techniques such as crystallography. We note hurdles to reliably measuring secondary structure, including RNA-binding proteins, RNA base modifications, and intramolecular duplexes. Finally, we survey the functional knowledge that has been gleaned from each of these methods, and identify some unanswered questions that remain. PMID- 26119391 TI - EBV-positive diffuse large B-cell lymphoma of the elderly involving Warthin tumor. PMID- 26119392 TI - Juvenile social relationships reflect adult patterns of behavior in wild geladas. AB - Unlike many mammals, primates spend much of their lives as reproductively immature juveniles. During the juvenile period, they develop social relationships and physical skills that both facilitate survival to adulthood and impact adult fitness. In this study, we use 2 years of observational data to examine the development of these skills across the juvenile period in a wild cercopithecine primate, the gelada (Theropithecus gelada). As adults, male and female geladas require different skills to be successful; we therefore expected sex differences in social behavior and partner choice during the juvenile period to already reflect these sex-specific trajectories. For example, males, who disperse at puberty and ultimately must challenge other adult males for access to mates, should invest in high-energy play-fighting with other males to develop fighting and rival assessment skills. In contrast, philopatric females, who remain with their close kin throughout their lives, should invest more in forming less physical and more-social bonds with other females within their group. As predicted, sex differences that foreshadowed sex-specific adult roles were apparent in play rates, the average number of play partners per individual, grooming partner types and social partner preferences. Males played more and had more play partners than same-age females. Males also groomed more often with individuals from outside their natal group than females, although no sex difference was observed in either grooming rates or number of grooming partners per individual. Females stopped playing earlier than males, and instead invested in grooming relationships with close relatives. Additionally, we found that individual play and grooming rates were temporally consistent for both males and females (i.e., from one year to the next year), suggesting that individuals exhibit stable behavioral phenotypes. We conclude by discussing how early life in geladas may shape adult behavior and reproductive strategies. PMID- 26119393 TI - Classifying CT/MR findings in patients with suspicion of hepatocellular carcinoma: Comparison of liver imaging reporting and data system and criteria free Likert scale reporting models. AB - PURPOSE: To compare the Liver Imaging Reporting and Data System (LI-RADS) and a criteria-free Likert scale (LS) reporting models for classifying computed tomography/magnetic resonance imaging (CT/MR) findings of suspicious hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Imaging data of 281 hepatic nodules in 203 patients were retrospectively included. Imaging characteristics including diameter, arterial hyperenhancement, washout, and capsule were reviewed independently by two groups of readers using LI-RADS and LS (range, score 1-5). LS is primarily based on the overall impression of image findings without using fixed criteria. Interreader agreement (IRA), intraclass agreement (ICA), and diagnostic performance were determined by Fleiss, Cohen's kappa (kappa), and logistic regression, respectively. RESULTS: There were 167 contrast-enhanced CT (CECT) versus 114 MR data. Overall, IRA was moderate (kappa = 0.47, 0.52); IRA was moderate-to-good for arterial hyperenhancement, washout, and capsule (kappa = 0.56-0.69); excellent for diameter and tumor embolus (kappa = 0.99). Overall, ICA between LI-RADS and LS was moderate (kappa = 0.44-0.50); ICA was good for scores 1-2 (kappa = 0.71-0.90), moderate for scores 3 and 5 (kappa = 0.41-0.52), but very poor for score 4 (kappa = 0.11-0.19). LI-RADS produced significantly lower accuracy (78.6% vs. 87.2%) and sensitivity (72.1% vs. 92.8%), higher specificity (97.3% vs. 71.2%) and positive likelihood ratio (+LR: 26.32 vs. 3.23) in diagnosis of HCC. CECT produced relatively low IRA, ICA, and diagnostic ability against MR. CONCLUSION: There were substantial variations in liver observations between LI-RADS and LS. Further study is needed to investigate ICA between CECT and MR. PMID- 26119395 TI - Parent, Alkylated, and Sulfur/Oxygen-Containing Polycyclic Aromatic Hydrocarbons in Mainstream Smoke from 13 Brands of Chinese Cigarettes. AB - China has the world's largest population of smokers with serious health consequences, yet we know a very limited spectrum of hazardous chemicals in cigarette smoke even for carcinogenic polycyclic aromatic hydrocarbons (PAHs). Here, we chose 13 popular cigarette brands sold in China markets, collected particulate matters in mainstream smoke using filter pads and an automatic smoking machine, and analyzed 56 PAHs, including 31 parent, 18 alkylated, and 7 sulfur/oxygen-containing PAHs (S/O PAHs). The 56 PAHs in mainstream smoke totaled from 244.2 +/- 28.5 to 10254.8 +/- 481.5 ng cig(-1); parent, alkylated, and S/O PAHs shared 16-23%, 64-74%, and 6-18%, respectively. Benzo[a]pyrene (BaP) ranged 1.1-41.6 ng cig(-1), while BaP equivalent concentrations (BaPeq) ranged 3.6-120.2 ng cig(-1), but contributions to BaPeq by individual carcinogenic PAH species varied with cigarette brands. When these cigarette smoke source profiles were pooled together with those of other combustion ones available in the literature, we found that widely used diagnostic ratios of parent PAHs failed to distinguish cigarette smoke from other combustion sources, except that the ratio indeno[1,2,3 cd]pyrene/(indeno[1,2,3-cd]pyrene + benzo[g,h,i]perylene) can largely separate cigarette smoke from vehicular emissions and that the ratio of Retene/(Retene + chrysene) can further discriminate cigarette smoke from coal combustion when alkylated PAHs are involved. PMID- 26119394 TI - Impact of exogenous stress on TGF-beta inducible early gene 1 in human skin cells. PMID- 26119396 TI - Single nucleotide polymorphisms of TNF-Alpha gene in febrile seizures. AB - Febrile seizures (FS) is the most common seizure disorder during childhood. This study was performed in 78 patients with FS and 137 control subjects to assess polymorphisms of the TNF-alpha gene at positions -308 and -238, using the polymerase chain reaction and the sequence specific primers method. The highest positive allelic association that made the patients susceptible to FS was seen for TNF-alpha -238/G (p<0.0001). The GG genotype at TNF-alpha -238 was significantly higher in the patients with FS, compared to the controls (p=0.0001). Also, GA genotype at the same position was significantly lower in patients than in controls (P=0.0001). The GG haplotype had a significant positive association at TNF-alpha (308, 238) while GA haplotype showed a negative association (P<0.001). Our data support the idea that TNF-alpha single-nucleotide polymorphisms play a role in the pathogenesis of FS. PMID- 26119398 TI - A novel missense mutation of RYR1 in familial idiopathic hyper CK-emia. AB - Persistent elevation of serum creatine kinase (CK) without any symptoms has been called idiopathic hyper CK-emia (IHCK). We examined a four-generation Japanese pedigree of familial IHCK. The multipoint linkage analysis of the pedigree showed seven clear peaks of logarithm of odds (LOD) scores (>1.4). By the exome sequencing followed by multiple filtering processes, we identified one novel heterozygous nonsynonymous single nucleotide variant (SNV), c.7034G>C, p.S2345T in the ryanodine receptor 1 gene, RYR1 cosegregated with IHCK in the pedigree. Mutation Taster predicted this substitution as "disease causing" (p=0.999). The PolyPhen-2 and PANTHER subPSEC scores for the substitution are 0.911 (possibly damaging) and -3.56 (probably damaging), respectively. We confirmed the absence of the SNV in 511 healthy Japanese individuals excluding the possibility of a normal variant with a very low frequency. Immunohistochemistry and Western blotting of biopsy samples consistently showed the expression level of RYR1 reduced in the patient. In real-time RT-PCR, the mRNA expression level of RYR1 was also significantly reduced in the patient (p=0.009). These results suggest that the novel nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect. We conclude that the SNV in the RYR1 gene is one of the responsible genes of IHCK. PMID- 26119399 TI - Resequencing of early growth response 2 (EGR2) gene revealed a recurrent patient specific mutation in schizophrenia. AB - Abnormal myelination is considered as part of the pathophysiology of schizophrenia. We resequenced the genomic DNA of the EGR2, which has a specific function in the myelination of peripheral nervous system, in 543 schizophrenic patients and 554 non-psychotic controls. We identified six known SNPs, which were not associated with schizophrenia. Nevertheless, we discovered 24 rare mutations, some of them were patient-specific, including a recurrent mutation (p.P173_Y174insP), which might be associated with the pathogenesis of schizophrenia. PMID- 26119397 TI - Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice. AB - The dysferlin-deficient A/J mouse strain represents a homologous model for limb girdle muscular dystrophy 2B. We evaluated the disease phenotype in 10 month old A/J mice compared to two dysferlin-sufficient, C57BL/6 and A/JOlaHsd, mouse lines to determine which functional end-points are sufficiently sensitive to define the disease phenotype for use in preclinical studies in the A/J strain. A/J mice had significantly lower open field behavioral activity (horizontal activity, total distance, movement time and vertical activity) when compared to C57BL/6 and A/JoIaHsd mice. Both A/J and A/JOIaHsd mice showed decreases in latency to fall with rotarod compared to C57BL/6. No changes were detected in grip strength, force measurements or motor coordination between these three groups. Furthermore, we have found that A/J muscle shows significantly increased levels of the pro inflammatory cytokine TNF-alpha when compared to C57BL/6 mice, indicating an activation of NF-kappaB signaling as part of the inflammatory response in dysferlin-deficient muscle. Therefore, we assessed the effect of celastrol (a potent NF-kappaB inhibitor) on the disease phenotype in female A/J mice. Celastrol treatment for four months significantly reduced the inflammation in A/J muscle; however, it had no beneficial effect in improving muscle function, as assessed by grip strength, open field activity, and in vitro force contraction. In fact, celastrol treated mice showed a decrease in body mass, hindlimb grip strength and maximal EDL force. These findings suggest that inhibition of inflammation alone may not be sufficient to improve the muscle disease phenotype in dysferlin-deficient mice and may require combination therapies that target membrane stability to achieve a functional improvement in skeletal muscle. PMID- 26119400 TI - Endocrine-disrupting chemicals, risk of type 2 diabetes, and diabetes-related metabolic traits: A systematic review and meta-analysis. AB - BACKGROUND: Elevated blood or urinary concentrations of endocrine-disrupting chemicals (EDCs) may be related to increased risk of type 2 diabetes (T2D). The aim of the present study was to assess the role of EDCs in affecting risk of T2D and related metabolic traits. METHODS: MEDLINE was searched for cross-sectional and prospective studies published before 8 March 2014 into the association between EDCs (dioxin, polychlorinated biphenyl [PCB], chlorinated pesticide, bisphenol A [BPA], phthalate) and T2D and related metabolic traits. Three investigators independently extracted information on study design, participant characteristics, EDC types and concentrations, and association measures. RESULTS: Forty-one cross-sectional and eight prospective studies from ethnically diverse populations were included in the analysis. Serum concentrations of dioxins, PCBs, and chlorinated pesticides were significantly associated with T2D risk; comparing the highest to lowest concentration category, the pooled relative risks (RR) were 1.91 (95% confidence interval [CI] 1.44-2.54) for dioxins, 2.39 (95% CI 1.86 3.08) for total PCBs, and 2.30 (95% CI 1.81-2.93) for chlorinated pesticides. Urinary concentrations of BPA and phthalates were also associated with T2D risk; comparing the highest to lowest concentration categories, the pooled RR were 1.45 (95% CI 1.13-1.87) for BPA and 1.48 (95% CI 0.98-2.25) for phthalates. Further, EDC concentrations were associated with indicators of impaired fasting glucose and insulin resistance. CONCLUSIONS: Persistent and non-persistent EDCs may affect the risk of T2D. There is an urgent need for further investigation of EDCs, especially non-persistent ones, and T2D risk in large prospective studies. PMID- 26119401 TI - AMPK-mediated regulation of neuronal metabolism and function in brain diseases. AB - The AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a key energy sensor in a wide variety of tissues. This kinase has been a major drug target for metabolic diseases (e.g., type 2 diabetes) and cancers. For example, metformin (an activator of AMPK) is a first-line diabetes drug that protects against cancers. Abnormal regulation of AMPK has been implicated in several brain diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Given the emerging importance of neurodegenerative diseases in our aging societies, this review features the recent studies that have delineated the functions of AMPK in brain diseases and discusses their potential clinical implications or roles as drug targets in brain diseases. PMID- 26119402 TI - Complement C4a inhibits the secretion of hepatitis B virus screened by surface enhanced laser desorption ionization time-flight mass spectrometry-based ProteinChip analysis. AB - PURPOSE: Chronic hepatitis B (CHB) is a kind of chronic liver disease caused by persistent hepatitis B virus (HBV) infection. The study aims to seek the factors of host resistance to HBV and investigate their roles. EXPERIMENTAL DESIGN: Protein profiles of 58 healthy controls and 121 CHB patients were obtained by SELDI-TOF/MS. Predicted protein was validated by ELISA. Protein expression was evaluated by Western blot in the persistently HBV expressing cell line HepG2.2.15 and non-HBV expressing cell line HepG2. The level of HBV DNA was subsequently detected by quantitative real-time PCR in HepG2.2.15 cells with complement C4a treatment. RESULTS: Significantly altered protein peaks were found through statistical analysis, and m/z 4300 was predicted by databases and successfully matched with the fragment of complement C4a. According to ELISA, serum complement C4a was found to be significantly lower in CHB patients compared with healthy controls (p < 0.001) and the area under receiver operating characteristics curve is 0.78. Furthermore, complement C4a showed lower expression in HepG2.2.5 cells and the secretion of HBV DNA was inhibited by complement C4a. CONCLUSIONS AND CLINICAL RELEVANCE: The present study implied the important role of complement C4a in inhibiting the HBV DNA secretion in CHB. PMID- 26119403 TI - A Single-Center Randomized Trial of Intraoperative Zero-Balanced Ultrafiltration During Cardiopulmonary Bypass for Patients With Impaired Kidney Function Undergoing Cardiac Surgery. AB - OBJECTIVES: The authors investigated whether zero-balance ultrafiltration (Z-BUF) during bypass significantly improves clinical and cost outcomes or biomarkers of kidney injury for patients with preoperative kidney impairment (estimated glomerular filtration rate [eGFR]<60 mL/minute) undergoing cardiac surgery. DESIGN: A single-center randomized controlled trial recruited, patients between 2010 and 2013, with a 12-months follow-up. SETTING: Hospital. PARTICIPANTS: One hundred ninety-nine patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Patients were assigned randomly to receive zero balance ultrafiltration (Z-BUF) or not, with stratification for degree of kidney dysfunction and diabetes. MEASUREMENTS AND MAIN RESULTS: The authors assessed clinical efficacy and kidney function biomarkers. Cumulative probability of discharge from the intensive care unit (ICU) was assessed by Kaplan-Meier plots and was found not to be significantly different between the two trial arms (p = 0.61). After adjusting for EuroSCORE, diabetes, eGFR, cardioplegia types and type of surgery in a Cox proportional hazard model, hazard ratios (HR) for ICU length of stay between the Z-BUF and no-Z-BUF groups was not significantly different: HR (95% CI): 0.89 (0.66, 1.20; p = 0.44). In contrast, significant reductions in postoperative chest infections and the composite of clinical endpoints (death, strokes, and myocardial infarctions) in the Z-BUF group were observed. In addition, Z-BUF significantly abrogated the rise in the kidney damage markers urinary NGAL/creatinine ratio, urea, creatinine and eGFR during CPB and adverse events risks. CONCLUSIONS: Z-BUF during bypass surgery is associated with significant reductions in morbidity and biomarkers of CPB-induced acute kidney injury soon after CPB, which are indicative of clearance of inflammatory/immune mediators from the circulation. PMID- 26119405 TI - Chest Ultrasound: A New, Easy, and Radiation-Free Tool to Detect Retrosternal Clot After Pediatric Cardiac Surgery. PMID- 26119404 TI - Narrow, Highly Mobile Structure in the Right Atrium: Large Eustachian Valve, Prominent Chiari Network, Thrombus, Vegetation, or Flail Tricuspid Chordae Tendineae? PMID- 26119406 TI - Preoperative Echocardiography First Diagnosed and Intraoperative Echocardiography Altered the Surgical Plan in Intravenous Leiomyomatosis. PMID- 26119407 TI - An Unusual Case of Hypoxemia Improving Overnight in Idiopathic Pulmonary Fibrosis. PMID- 26119408 TI - Association of Robotic Totally Endoscopic Coronary Artery Bypass Graft Surgery Associated With a Preliminary Cardiac Enhanced Recovery After Surgery Program: A Retrospective Analysis. AB - OBJECTIVES: The robotic totally endoscopic coronary artery bypass graft (TECAB) surgery reduces patients' recovery time. The present trial investigated the feasibility and safety of an initial enhanced recovery after surgery (ERAS) path for patients undergoing robotic beating-heart TECAB and compared it with both conventional surgery and traditional perioperative care. It was hypothesized that the preliminary ERAS pathway associated with a beating-heart TECAB procedure could have a synergistic effect on postoperative patient care. DESIGN: Observational retrospective study. SETTING: University hospital. PARTICIPANTS: Patients scheduled for coronary artery bypass graft and undergoing robotic beating-heart TECAB (n = 38) were compared with those undergoing standard surgery and perioperative care (n = 33). The outcomes were the possibility of tracheal extubation at the end of the surgery and the incidence of postoperative complications. MEASUREMENTS AND MAIN RESULTS: The main comorbidities were similar between the 2 groups. Extubation on the operating table in the TECAB group was possible in all cases without requiring prompt endotracheal tube reinsertion. The proportion of patients transfused was significantly lower in the TECAB group (p = 0.009). In addition, the duration of intensive care unit and hospital stay were reduced significantly by 24 hours and by 4 days, respectively, in the TECAB group compared with the standard group (p< 0.05). CONCLUSIONS: The present results suggested that a program coupling a beating-heart TECAB with a preliminary ERAS path for patients requiring a single coronary revascularization is feasible and safe. This approach could reduce postoperative mechanical ventilation time, transfusion rate, and both intensive care unit and hospital stay. PMID- 26119409 TI - CASE 1-2016 Problem-Solving in Transcatheter Aortic Valve Replacement: Cardiovascular Collapse, Myocardial Stunning, and Mitral Regurgitation. PMID- 26119410 TI - Meta-Analysis of Sodium Bicarbonate Therapy for Prevention of Cardiac Surgery Associated Acute Kidney Injury. AB - OBJECTIVE: The aim of this study was to determine whether or not perioperative administration of sodium bicarbonate had a preventive effect on cardiac surgery associated acute kidney injury (CSA-AKI) as shown in randomized controlled trials. DESIGN: The authors conducted a systematic review and meta-analysis using MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and KoreaMed. SETTING: The authors searched MEDLINE, EMBASE, CENTRAL, and KoreaMed without language and date restrictions. They used both MeSH and free text terms to identify relevant studies. Electronic searches were undertaken on July 31, 2014. PARTICIPANTS: Five randomized controlled studies included in this review. MEASUREMENTS AND MAIN RESULTS: There were no differences in the development of CSA-AKI among patients in the sodium bicarbonate group compared with those in the control group (5 trials, 1,092 patients; n = 233 of 547 in sodium bicarbonate (SB) group versus 225 of 545 in control group (SC); risk ratio (RR), 0.95; 95% confidence interval (CI), 0.74-1.22. Also, there were no statistical differences in in-hospital mortality (3 trials, 573 patients; n = 21 of 288 in SB versus 14 of 285 in SC; RR, 1.44; 95% CI, 0.76-2.72), need for renal replacement therapy (4 trials, 1,000 patients; n = 21 of 503 in SB versus 23 of 497 in SC; RR, 0.90; 95% CI, 0.50-1.60), length of stay in the intensive care unit (ICU) (hours) (4 trials, n = 969 patients, weighted men difference (WMD), 2.17; 95% CI, -1.15-5.49), and length of ventilation (hours) (4 trials, 969 patients; WMD, 0.34; 95% CI,-0.80-1.48). CONCLUSIONS: Perioperative administration of sodium bicarbonate did not reduce the rate of CSA-AKI in randomized controlled trials. Therefore, use of perioperative administration of sodium bicarbonate for the prevention of CSA-AKI is questionable. PMID- 26119411 TI - Recurrent Seizures Following Cardiac Surgery: Risk Factors and Outcomes in a Historical Cohort Study. AB - OBJECTIVES: To determine the risk factors for and outcomes after recurrent seizures (RS) in patients following cardiac surgery. DESIGN: A historical cohort study. SETTING: A single-center university teaching hospital. PARTICIPANTS: Cardiac surgery patients from April 2003 to September 2010 experiencing postoperative seizures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into an isolated seizure group and an RS group. Risk factors for RS were determined using logistic regression. Intermediate-term follow-up was conducted by phone. Of 7,280 consecutive patients undergoing cardiac surgery, 61 (0.8%) experienced postoperative seizure and 36 (59%) of those experienced at least 1 recurrence. Of these, 32 (89%) experienced RS within 24 hours of the first seizure, and 29 (81%) had grand mal seizures. Preoperative creatinine >=120 MUmol/L (p = 0.02), time until first seizure occurred (<=4 hours; p = 0.01), and procedures involving the thoracic aorta were associated with RS (R(2) = 0.53, p<0.05). Patients with RS had longer intensive care unit stays (5.3 v 2.9 days, p = 0.03) and longer mechanical ventilation duration (53.3 v 15.0 hours, p = 0.01). At a median follow-up of 21 months for the RS group and 16 months for the isolated seizure group, restrictions, anticonvulsant use, morbidity, and mortality were similar between patients with isolated versus recurrent seizures. CONCLUSIONS: Higher preoperative creatinine, thoracic aortic surgery, and early seizure onset were associated with RS after cardiac surgery. When compared to isolated seizures, recurrence per se was not associated with significantly increased long-term morbidity or mortality. PMID- 26119412 TI - Rautenberg Factor: Transfusion Constraints During Cardiac Surgery. PMID- 26119414 TI - Enteric glia express proteolipid protein 1 and are a transcriptionally unique population of glia in the mammalian nervous system. AB - In the enteric nervous system (ENS), glia outnumber neurons by 4-fold and form an extensive network throughout the gastrointestinal tract. Growing evidence for the essential role of enteric glia in bowel function makes it imperative to understand better their molecular marker expression and how they relate to glia in the rest of the nervous system. We analyzed expression of markers of astrocytes and oligodendrocytes in the ENS and found, unexpectedly, that proteolipid protein 1 (PLP1) is specifically expressed by glia in adult mouse intestine. PLP1 and S100beta are the markers most widely expressed by enteric glia, while glial fibrillary acidic protein expression is more restricted. Marker expression in addition to cellular location and morphology distinguishes a specific subpopulation of intramuscular enteric glia, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes. To assess the similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine and compared their gene expression pattern to that of other types of glia. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oligodendrocytes, although there is no evidence of myelination in the murine ENS. GLIA 2015;63:2040 2057. PMID- 26119415 TI - Seroincidence of non-typhoid Salmonella infections: convenience vs. random community-based sampling. AB - The incidence of reported infections of non-typhoid Salmonella is affected by biases inherent to passive laboratory surveillance, whereas analysis of blood sera may provide a less biased alternative to estimate the force of Salmonella transmission in humans. We developed a mathematical model that enabled a back calculation of the annual seroincidence of Salmonella based on measurements of specific antibodies. The aim of the present study was to determine the seroincidence in two convenience samples from 2012 (Danish blood donors, n = 500, and pregnant women, n = 637) and a community-based sample of healthy individuals from 2006 to 2007 (n = 1780). The lowest antibody levels were measured in the samples from the community cohort and the highest in pregnant women. The annual Salmonella seroincidences were 319 infections/1000 pregnant women [90% credibility interval (CrI) 210-441], 182/1000 in blood donors (90% CrI 85-298) and 77/1000 in the community cohort (90% CrI 45-114). Although the differences between study populations decreased when accounting for different age distributions the estimates depend on the study population. It is important to be aware of this issue and define a certain population under surveillance in order to obtain consistent results in an application of serological measures for public health purposes. PMID- 26119416 TI - Golden retriever cystic uveal disease: a longitudinal study of iridociliary cysts, pigmentary uveitis, and pigmentary/cystic glaucoma over a decade in western Canada. AB - OBJECTIVES: To determine the incidence of iridociliary cysts, pigmentary uveitis (PU)/pigmentary cystic glaucoma (PCG) in golden retriever dogs in western Canada, the progression of iridociliary cysts to PU/PCG, and a mode of inheritance for this disorder. ANIMAL STUDIED: A total of 830 golden retriever dogs from Alberta, Saskatchewan, and Manitoba from 2004 to 2014 were studied. PROCEDURE: Data were compiled from Canine Eye Registry Foundation (CERF) or Orthopedic Foundation for Animals (OFA) records (n = 630) and clinical consultations (n = 200) for a retrospective assessment of iridociliary cysts, PU, and PCG. RESULTS: Total incidence of iridociliary cysts and PU from CERF/OFA data were 4.8% (n = 30/630) and 5.9% (n = 37/630), respectively. Incidence of PU increased with ages >4 years (12.7%, n = 32/251). Dogs diagnosed with thin-walled, attached iridociliary cysts had a high risk of being diagnosed with PU or PCG upon re-examination (56.5%, n = 13/23). No dogs diagnosed with thick-walled, anterior chamber cysts (n = 7) developed PU or PCG within the time frame of the study. Data from clinical consultations confirmed that PU carried a poor prognosis for the affected eyes as 44.9% (n = 22/49) of dogs progressed to PCG. PU- and PCG-affected dogs followed a familial pattern and there was an association with thin-walled iridociliary cysts. Pedigree analysis suggested an autosomal dominant mode of inheritance with partial penetrance. CONCLUSIONS: Thin-walled iridociliary cysts are associated with PU and PCG. All breeding golden retriever dogs should be examined annually by an ophthalmologist. The incidence of this disorder is higher in western Canada than previous reports in North America. PMID- 26119413 TI - Translational aspects of cardiac cell therapy. AB - Cell therapy has been intensely studied for over a decade as a potential treatment for ischaemic heart disease. While initial trials using skeletal myoblasts, bone marrow cells and peripheral blood stem cells showed promise in improving cardiac function, benefits were found to be short-lived likely related to limited survival and engraftment of the delivered cells. The discovery of putative cardiac 'progenitor' cells as well as the creation of induced pluripotent stem cells has led to the delivery of cells potentially capable of electromechanical integration into existing tissue. An alternative strategy involving either direct reprogramming of endogenous cardiac fibroblasts or stimulation of resident cardiomyocytes to regenerate new myocytes can potentially overcome the limitations of exogenous cell delivery. Complimentary approaches utilizing combination cell therapy and bioengineering techniques may be necessary to provide the proper milieu for clinically significant regeneration. Clinical trials employing bone marrow cells, mesenchymal stem cells and cardiac progenitor cells have demonstrated safety of catheter based cell delivery, with suggestion of limited improvement in ventricular function and reduction in infarct size. Ongoing trials are investigating potential benefits to outcome such as morbidity and mortality. These and future trials will clarify the optimal cell types and delivery conditions for therapeutic effect. PMID- 26119417 TI - Resolution of Roth spots in chronic myeloid leukaemia after treatment with imatinib. PMID- 26119418 TI - Image reconstruction from phased-array data based on multichannel blind deconvolution. AB - In this paper we consider image reconstruction from fully sampled multichannel phased array MRI data without knowledge of the coil sensitivities. To overcome the non-uniformity of the conventional sum-of-square reconstruction, a new framework based on multichannel blind deconvolution (MBD) is developed for joint estimation of the image function and the sensitivity functions in image domain. The proposed approach addresses the non-uniqueness of the MBD problem by exploiting the smoothness of both functions in the image domain through regularization. Results using simulation, phantom and in vivo experiments demonstrate that the reconstructions by the proposed algorithm are more uniform than those by the existing methods. PMID- 26119419 TI - Towards the identification of multi-parametric quantitative MRI biomarkers in lupus nephritis. AB - PURPOSE: To identify potential biomarkers of the renal impairment in lupus nephritis using a multi-parametric renal quantitative MRI (qMRI) protocol including diffusion weighted imaging (DWI), blood oxygen level dependent (BOLD), arterial spin labeling (ASL) and T1rho MRI between a cohort of healthy volunteers and lupus nephritis (LN) patients. MATERIALS AND METHODS: The renal qMRI protocol was performed twice with repositioning in between on 10 LN patients and 10 matched controls at 1.5 T. Navigator-gated and breath-hold acquisitions followed by non-rigid image registration were used to control respiratory motion. The repeatability of the 4 MRI modalities was evaluated with the intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Unpaired t-test and stepwise logistic regression were carried out to evaluate qMRI parameters between the LN and control groups. RESULTS: The reproducibility of the 4 qMRI modalities ranged from moderate to good (ICC=0.4-0.91, wsCV<=12%) with a few exceptions. T1rho MRI and ASL renal blood flow (RBF) demonstrated significant differences between the LN and control groups. Stepwise logistic regression yielded only one significant parameter (medullar T1rho) in differentiating LN from control groups with 95% accuracy. CONCLUSION: A reasonable degree of test-retest repeatability and accuracy of a multi-parametric renal qMRI protocol has been demonstrated in healthy volunteers and LN subjects. T1rho and ASL RBF are promising imaging biomarkers of LN. PMID- 26119420 TI - Determination of blood circulation times of superparamagnetic iron oxide nanoparticles by T2* relaxometry using ultrashort echo time (UTE) MRI. AB - Blood circulation is an important determinant of the biodistribution of superparamagnetic iron oxide nanoparticles. Here we present a magnetic resonance imaging (MRI) technique based on the use of ultrafast echo times (UTE) for the noninvasive determination of blood half-lives at high particle concentrations, when conventional pulse sequences fail to produce a useful MR signal. Four differently coated iron oxide nanoparticles were administered intravenously at a dose of 500 MUmol Fe/kg bodyweight and UTE images of C57BL/6 mice were acquired on a 1-T ICON scanner (Bruker). T2* relaxometry was done by acquiring UTE images with echo times of 0.1, 0.8 and 1.6 ms. Blood circulation time was then determined by fitting an exponential curve to the time course of the measured relaxation rates. Circulation time was shortest for particles coated with malic acid (t1/2=23 min) and longest for particles coated with tartaric acid (t1/2=63 min). UTE-based T2* relaxometry allows noninvasive determination of blood circulation time and is especially useful when high particle concentrations are present. PMID- 26119421 TI - Spatial variations in magnetic resonance-based diffusion of articular cartilage in knee osteoarthritis. AB - PURPOSE: To evaluate a pulse sequence combining stimulated echo diffusion preparation with a 3D segmented spoiled gradient echo (SPGR) acquisition for diffusion tensor imaging (DTI) of knee cartilage in healthy and osteoarthritis (OA) populations for early diagnosis and characterization of OA. METHODS: Diffusion-weighted images of 40 subjects (20 healthy, 20 OA) at baseline and 20 subjects (10 healthy, 10 OA) at one year were obtained. The subjects were classified according to Kellgren Lawrence (KL) and whole organ magnetic resonance imaging scoring (WORMS) method acquired at 3 T. Cartilage full thickness and laminar mean diffusivity (MD) and fractional anisotropy (FA) values were quantified. The reproducibility of MD and FA values was assessed in five healthy human subjects based on test-retest scans. RESULTS: In general, the full thickness MD values were higher in subjects with knee OA compared to healthy controls in both the baseline and follow up cohort. Laminar analysis MD and FA results were significantly different (p<0.05) between the bone-articular and articular layer with the articular layer having higher MD and lower FA value compared to the bone layer. The global reproducibility error was 6.5% for MD and 11.6% for FA. CONCLUSION: The diffusion-weighted stimulated echo-based sequence may be used as a valuable tool for early diagnosis and characterization of knee OA at 3 T in the future. PMID- 26119422 TI - 3D T1 relaxometry pre and post gadoxetic acid injection for the assessment of liver cirrhosis and liver function. AB - PURPOSE: To assess the diagnostic value of a 3D dual-flip-angle (DFA) T1 mapping technique with whole liver coverage before and after gadoxetic acid injection for assessment of cirrhosis and liver function, compared to blood tests (APRI: aspartate aminotransferase-to-platelet ratio index). MATERIALS AND METHODS: A total of 133 patients who underwent gadoxetic acid-enhanced liver MRI including a 3D FLASH DFA-T1 mapping sequence before and 20min post-contrast (hepatobiliary phase, HBP) were included in this retrospective IRB approved study. T1 values (msec) were measured on pre-contrast and during HBP in liver parenchyma, DeltaT1 (%) was calculated as [(T1 pre-T1 post)/T1 pre]*100. T1 and DeltaT1 values were compared between cirrhotic and non-cirrhotic patients and between patients stratified using Child-Pugh and Model for End-Stage Liver Disease (MELD) scores using Mann-Whitney U test. Diagnostic performance of T1 mapping parameters vs. APRI for diagnosing cirrhosis and for assessing degree of liver dysfunction was evaluated using ROC analysis. RESULTS: Fifty non-cirrhotic and 83 cirrhotic patients [Child-Pugh A (n=41), B (n=31) and C (n=11)] were included. There was no significant difference in pre-contrast T1 values between cirrhotic and non cirrhotic patients. T1-HBP and DeltaT1 values were significantly different in patients with cirrhosis (p<0.0001) and higher MELD scores (>17) (p=0.003). DeltaT1 showed significant strong correlations with Child-Pugh and MELD scores (r=-0.7, p<0.0001; r=-0.56, p<0.001 respectively). Similar AUCs (p=0.9) for detection of liver cirrhosis were observed for T1 HBP (0.83), DeltaT1 (0.86) and APRI (0.85); however APRI showed limited sensitivity (<=55%) in comparison with DeltaT1 (74.7%) and T1 HBP (80.7%). CONCLUSION: 3D DFA-T1 mapping sequence used before and after gadoxetic acid injection is useful for the diagnosis of cirrhosis and for the assessment of liver function. PMID- 26119423 TI - Comparative exploration of hydrogen sulfide and water transmembrane free energy surfaces via orthogonal space tempering free energy sampling. AB - Hydrogen sulfide (H2 S), a commonly known toxic gas compound, possesses unique chemical features that allow this small solute molecule to quickly diffuse through cell membranes. Taking advantage of the recent orthogonal space tempering (OST) method, we comparatively mapped the transmembrane free energy landscapes of H2 S and its structural analogue, water (H2 O), seeking to decipher the molecular determinants that govern their drastically different permeabilities. As revealed by our OST sampling results, in contrast to the highly polar water solute, hydrogen sulfide is evidently amphipathic, and thus inside membrane is favorably localized at the interfacial region, that is, the interface between the polar head-group and nonpolar acyl chain regions. Because the membrane binding affinity of H2 S is mainly governed by its small hydrophobic moiety and the barrier height inbetween the interfacial region and the membrane center is largely determined by its moderate polarity, the transmembrane free energy barriers to encounter by this toxic molecule are very small. Moreover when H2 S diffuses from the bulk solution to the membrane center, the above two effects nearly cancel each other, so as to lead to a negligible free energy difference. This study not only explains why H2 S can quickly pass through cell membranes but also provides a practical illustration on how to use the OST free energy sampling method to conveniently analyze complex molecular processes. (c) 2015 Wiley Periodicals, Inc. PMID- 26119424 TI - Osteology and Cartilaginous Elements of Trilepida salgueiroi (Amaral, 1954) (Scolecophidia: Leptotyphlopidae). AB - Morphological and anatomical studies on the Leptotyphlopidae have increased in the past 10 years, providing important data on the systematics of this group, mainly focused on the skull and lower jaw morphology. However, most studies are based on a single specimen, rarely combining more than one single method of assessing morphological information. Therefore, several data on postcranial morphology, sexual dimorphism, and ontogenetic and intraspecific variation of leptotyphlopids remain poorly understood. Herein, we provide a detailed description of the cranial and postcranial skeleton of Trilepida salgueiroi based on more than 20 specimens (including males, females and juveniles), as well as a description of osteology and cartilaginous elements through the use of combined methodologies such as X-ray scanning, high resolution CT-scanning, and clearing and staining of articulated and disarticulated specimens. We also provide data on the presence/absence of dimorphic and intraspecific variation of the observed characters. The presence of a statolithic mass in the cavum vestibuli differs from the pattern found in other scolecophidians. A correlation of dorsal vertebrae with ventral and subcaudal scales was found (1:1), as well as total number of vertebrae with middorsal scales (1:1), thoracolumbar vertebrae and ventral scales (1:1), and a higher number of caudal vertebra with subcaudal scales (1.23:1). Intraspecific variation was found in several elements of the skull, lower jaw, pelvic girdle and vertebral number, but no evidence of sexual dimorphism was found in any of the species characters analysed. The homologies of several elements are discussed, although still remaining poorly understood and unknown. PMID- 26119425 TI - Use of Flow Cytometry for Quantitative Analysis of Metabolism of Viable but Non culturable (VBNC) Salmonella. AB - A simple and rapid assay method for analysis of the metabolic activity of viable but non-culturable (VBNC) Salmonella was established. An environmental isolate of Salmonella Enteritidis (SE), grown to the logarithmic phase, rapidly lost its culturability during incubation with 1-10 mM H2O2 in Luria-Bertani (LB) medium. To assess the viability of the bacteria, we measured 3 different metabolic activities: Respiratory activity by 5-cyano-2,3-ditolyl-tetrazolium chloride (CTC) reduction, glucose uptake assessed with 2-[N-(7-nitrobenz-2-oxa-1,3-diazol 4-yl)amino]-2-deoxyglucose (2-NBDG), and DNA synthesis activity evaluated by 5 ethynyl-2'-deoxyuridine (EdU) incorporation. These activities were analyzed by both confocal laser-scanning microscopy and flow cytometry, together with colony formation assays on LB-agar plates. The results showed that some of the H2O2 treated SE cells were in the VBNC state and that the extent of H2O2-induced decrease in each metabolic activity varied according to the activity. That is, glucose-uptake activity was not markedly changed, being kept at the highest level; whereas the respiratory activity was less than that of the glucose-uptake, and DNA synthesis activity was the lowest among them. These results suggest that the VBNC state might be characterized by different metabolic activities that vary and correspond to the kind and strength of the stress, threatening bacterial survival in an adverse environment. PMID- 26119426 TI - Many private mutations originate from the first few divisions of a human colorectal adenoma. AB - Intratumoural mutational heterogeneity (ITH) or the presence of different private mutations in different parts of the same tumour is commonly observed in human tumours. The mechanisms generating such ITH are uncertain. Here we find that ITH can be remarkably well structured by measuring point mutations, chromosome copy numbers, and DNA passenger methylation from opposite sides and individual glands of a 6 cm human colorectal adenoma. ITH was present between tumour sides and individual glands, but the private mutations were side-specific and subdivided the adenoma into two major subclones. Furthermore, ITH disappeared within individual glands because the glands were clonal populations composed of cells with identical mutant genotypes. Despite mutation clonality, the glands were relatively old, diverse populations when their individual cells were compared for passenger methylation and by FISH. These observations can be organized into an expanding star-like ancestral tree with co-clonal expansion, where many private mutations and multiple related clones arise during the first few divisions. As a consequence, most detectable mutational ITH in the final tumour originates from the first few divisions. Much of the early history of a tumour, especially the first few divisions, may be embedded within the detectable ITH of tumour genomes. PMID- 26119428 TI - Frequency of metabolic syndrome in patients with knuckle pads. AB - Knuckle pads are hyperkeratotic, benign skin lesions that we commonly observe in obese patients. There is no study that investigates the association between metabolic syndrome (MetS) and knuckle pads. We aimed to investigate the frequency of MetS in patients with knuckle pads. Forty-seven patients with knuckle pads and 46 age- and sex-matched controls were enrolled. The presence of MetS was evaluated according to National Cholesterol Education Program-Adult Treatment Panel III criteria. In the patient group, waist circumference (P < 0.01), body mass index (BMI; P < 0.01), and systolic (P < 0.01) and diastolic blood pressure (P < 0.01) were higher than controls, and most of the patients had a history of hypertension (P < 0.01). The presence of MetS was found in 66% of the patients with knuckle pads and in 52.2% of the controls (P = 0.25). In the patient group, compared with controls, more patients had blood pressure above reference values or were on antihypertensive therapy (70.2% and 43.5%, P = 0.017, respectively), and had greater waist circumference value (93.6% and 76.1%, P = 0.038, respectively). The presence of the other three criteria were similar in both groups. Although we found similar MetS frequency in both groups, patients with knuckle pads should be examined for the presence of MetS components, especially abdominal obesity and hypertension. PMID- 26119429 TI - The influence of salt concentration on the chemical, ripening and sensory characteristics of Iranian white cheese manufactured by UF-Treated milk. AB - Iranian White cheese was manufactured from ultrafiltered cows' milk using different concentrations of salt consisting of 1, 2.5, 4% and salt free. Chemical composition, proteolysis, counts for lactic acid bacteria and sensory evaluation were examined during 90 d of ripening. It was found that the use of different salt concentrations significantly influenced all chemical composition, proteolysis, total number of lactic acid bacteria and sensory characteristics of the cheeses. Increasing the salt concentrations caused a proportional decrease in proteolysis determined by both urea-PAGE of caseins and RP-HPLC of peptides. With increased salt concentration, total number of lactic acid bacteria decreased. Cheeses with 1 and 2.5% salt were suitable and acceptable in odour and flavour that may be due to the proportional level of proteolysis products. In conclusion, reducing salt concentration from 4 to 2.5 and 1% had no ineligible effect on the quality and acceptability of the cheese. PMID- 26119427 TI - Radical Oxygen Species, Exercise and Aging: An Update. AB - It is now well established that reactive oxygen species (ROS) play a dual role as both deleterious and beneficial species. In fact, ROS act as secondary messengers in intracellular signalling cascades; however, they can also induce cellular senescence and apoptosis. Aging is an intricate phenomenon characterized by a progressive decline in physiological functions and an increase in mortality, which is often accompanied by many pathological diseases. ROS are involved in age associated damage to macromolecules, and this may cause derangement in ROS mediated cell signalling, resulting in stress and diseases. Moreover, the role of oxidative stress in age-related sarcopenia provides strong evidence for the important contribution of physical activity to limit this process. Regular physical activity is considered a preventive measure against oxidative stress related diseases. The aim of this review is to summarize the currently available studies investigating the effects of chronic and/or acute physical exercise on the oxidative stress process in healthy elderly subjects. Although studies on oxidative stress and physical activity are limited, the available information shows that acute exercise increases ROS production and oxidative stress damage in older adults, whereas chronic exercise could protect elderly subjects from oxidative stress damage and reinforce their antioxidant defences. The available studies reveal that to promote beneficial effects of physical activity on oxidative stress, elderly subjects require moderate-intensity training rather than high-intensity exercise. PMID- 26119431 TI - A Mousetrap for Carbenium Ions: NMR Detectives at Work. PMID- 26119430 TI - Assessment of methylation status of locoregional lymph nodes in lung cancer using EBUS-NA. AB - Hypermethylation of the promoter region of tumor suppressor genes is associated with carcinogenesis in lung cancer (LC). Endobronchial ultrasound with needle aspiration (EBUS-NA) is a semi-invasive method for obtaining cell blocks from lymph nodes, which can be used for epigenetic analyses. To establish the relationship between methylation status of p16, DAPK, RASSF1a, APC and CDH13 genes in lymph nodes sampled by EBUS-NA, tumor staging and prognosis. Methylation status of DAPK, p16, RASSF1a, APC and CDH13 genes was assessed in EBUS-NA cell blocks from LC patients and related to stage and survival. Eighty-five consecutive patients [mean age 67 (SD 8)] were included. Methylation of >=1 gene was found in 43 malignant nodes (67 %). A higher prevalence of RASSF1a methylation was observed in small cell lung cancer patients [9/10 (90 %) vs. 15/53 (28 %); p < 0.001 chi(2) test]. Methylation of APC and/or p16 was related to advanced staging in non-small cell lung cancer (NSCLC) [15/29 (52 %) vs. 6/24 (25 %), p = 0.048, chi(2) test]. Patients with NSCLC showing methylation of APC and/or p16 had also lower 6-month survival (p = 0.019, log rank test), which persisted after adjustment for age and subtyping (HR = 6, 95 % CI [1.8-19.5], p = 0.003, Cox regression). Epigenetic analyses are feasible in EBUS-NA cell blocks and may identify methylation patterns associated with worse prognosis. Methylation of p16 and APC genes in NSCLC patients was associated with advanced staging and lower 6-month survival. PMID- 26119432 TI - Screening for gestational diabetes in India: Where do we stand? PMID- 26119433 TI - Evaluation of the prevalence of gestational diabetes mellitus in North Indians using the International Association of Diabetes and Pregnancy Study groups (IADPSG) criteria. AB - OBJECTIVE: Currently, there is controversy regarding the diagnosis of gestational diabetes mellitus (GDM) as per the newer International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. We studied the prevalence and associations of GDM in North Indians, diagnosed by the IADPSG criteria. PATIENTS AND METHODS: We conducted a cross-sectional study on 332 pregnant women, predominantly belonging to lower and middle socioeconomic strata. The women were screened for GDM between 24 weeks and 28 weeks of gestation by 75g oral glucose tolerance test (OGTT) and GDM diagnosed by the IADPSG criteria. RESULTS: The prevalence of GDM was 41.9% [95% Confidence interval (CI) 36.6-47.2%]. Amongst the women diagnosed to have GDM, 91.4% had abnormal fasting plasma glucose (FPG), while 1-h and 2-h post-glucose (PG) levels were abnormal in 18.7% and 17.3% of women, respectively. No maternal factors were significantly associated with GDM. Birth weight of the neonates was similar in women with GDM as compared to those with normal glucose tolerance. In the entire group, fasting glucose levels were associated with the weight of the patient while 1-h PG levels were associated with weight, height, socioeconomic score, and parity. CONCLUSIONS: There is a very high prevalence rate of GDM using the IADPSG criteria in North Indian women of low and middle socioeconomic strata. Further studies are needed to assess the utility of applying these criteria in settings with limited resources. PMID- 26119434 TI - Toxicoepidemiology of acute poisoning cases in a secondary care hospital in rural South India: A five-year analysis. AB - OBJECTIVE: To ascertain the trend of poisoning cases admitted to the Government District Headquarters Hospital, a secondary care center in Udhagamandalam, Nilgiris District, Tamil Nadu, India, over a five-year period. MATERIALS AND METHODS: The number of cases that presented to the hospital annually (incidence, mortality, and case fatality rates), socio-demographic pattern, and the nature of the poison were noted. RESULTS: A total of 1860 poisoning cases (80 deaths) were reported during the period from October 2008 to September 2013. The incidence of poisoning was found to increase every year. The average incidence was 1.60 per 1000 population, while the average case fatality rate and mortality rates were 40.51 and 0.07, respectively. A total of 1148 (62%) were males. The majority of cases were seen in the 21-30 age group (41.24%). The poisonings were largely deliberate self-harm (n = 1,755; 94.35%), followed by accidental (n = 85; 4.57%). Agrochemicals were the main choice of poisoning agents and among these, organophosphates were the major cause. CONCLUSION: The data generated can help policy makers take decisions on the sale and availability of pesticides in this region. PMID- 26119435 TI - Short-term outcomes of a program developed to inculcate research essentials in undergraduate medical students. AB - BACKGROUND: Participation in research during undergraduate studies may increase students' interest in research and inculcate research essentials in them. AIMS: The purpose of this study was to evaluate the effectiveness of the mentored student project (MSP) program. SETTINGS AND DESIGN: In the MSP program, students in groups (n = 3 to 5) undertook a research project, wrote a scholarly report, and presented the work as a poster presentation with the help of a faculty mentor. To begin with, the logic model of the program was developed to identify short-term outcomes of the program on students, mentors, and the institution. A quasi-experimental design was used to measure the outcomes. MATERIALS AND METHODS: A mixed method evaluation was done using a newly-developed questionnaire to assess the impact of the MSP on students' attitude, a multiple-choice question (MCQs) test to find out the impact on students' knowledge and grading of students' project reports and posters along with a survey to check the impact on skills. Students' satisfaction regarding the program and mentors' perceptions were collected using questionnaires. Evidence for validity was collected for all the instruments used for the evaluation. STATISTICAL ANALYSIS: Non-parametric tests were used to analyze data. Based on the scores, project reports and posters were graded into A (>70% marks), B (60-69% marks), and C (<59% marks) categories. The number of MSPs that resulted in publications, conference presentation and departmental collaborations were taken as impact on the institution. RESULTS: Students' response rate was 91.5%. The students' attitudes regarding research changed positively (P = 0.036) and score in the MCQ test improved (P < 0.001) after undertaking MSP. Majority of project reports and posters were of grade A category. The majority of the items related to skills gained and satisfaction had a median score of 4. The MSPs resulted in inter-departmental and inter institutional collaborations, 14 publications and 15 conference presentations. An area for improvement noted was to have the MSP implemented in the curriculum without increasing students' overall workload and stress. CONCLUSION: The study identified strengths and weaknesses of the MSP program. Our model of undergraduate research project may be incorporated in undergraduate medical programs to foster positive attitude and knowledge base about scientific research and to instil research skills among students. PMID- 26119436 TI - Allergic Rhinitis: A neglected disease - A community based assessment among adults in Delhi. AB - BACKGROUND AND OBJECTIVES: Allergic Rhinitis is rather erroneously viewed as a trivial disease. It is important in that it can significantly affect quality of life. There is paucity of community based prevalence studies on the disease in India. This study was planned to assess the prevalence of allergic rhinitis in adults, the proportion of asthmatics among them, risk factors associated and treatment seeking behaviour among the patients. MATERIALS AND METHODS: A community based cross sectional study was conducted in Mehrauli, South Delhi among 1200 adults, aged 30 years and over selected by systematic random sampling from two randomly selected wards. A pre-tested questionnaire was used to collect information regarding symptoms, risk factors and treatment seeking behaviour. Allergic Rhinitis was diagnosed as per ARIA guidelines. Spirometry was done to diagnose asthma among them. Multivariate logistic regression analysis was done to find the association of risk factors with disease. RESULTS: The prevalence of Allergic Rhinitis was found to be 11% (132 subjects) and 33.3% (44 patients) among them also had asthma. Overcrowding (aOR = 6.4), absence of cross ventilation (aOR = 2.5), occupational exposure to dust/ smoke (aOR = 2.1), tobacco smoking (aOR = 2.1), family history of allergic diseases (aOR = 2.7) and clinical allergy (aOR = 10.2) were found to be independent risk factors associated with Rhinitis. More patients of Rhinitis with asthma (75%) took treatment, relative to those without asthma (40%) who, mostly relied on home remedies (42%) or, did not seek any treatment (18%) (P = 0.031). Interpretations and Conclusion: The burden of Allergic Rhinitis is high with a considerable overlap with asthma. These allergic diseases and emphasize the importance of early and regular treatment. PMID- 26119437 TI - Postoperative coagulopathy after live related donor hepatectomy: Incidence, predictors and implications for safety of thoracic epidural catheter. AB - BACKGROUND: Coagulopathy after living donor hepatectomy (LDH) may endanger donor safety during removal of thoracic epidural catheter (TEC). The present study was conducted to evaluate the extent and duration of immediate postoperative coagulopathy after LDH. MATERIALS AND METHODS: A retrospective analysis of perioperative record of LDH over three years was conducted after IRB approval. Variables such as age, gender, BMI, ASA classification, liver volume on CT scan, preoperative and postoperative INR, platelet count (PC) and ALT of each donor for five days was noted. In addition, duration of surgery, remnant as percentage total liver volume (Remnant%), blood loss, day of peak in PC and INR were also noted. Coagulopathy was defined as being present if INR exceeded 1.5 or platelet count fell below 1 * 10 5 /mm 3 on any day. Data was analyzed using SPSS 20 for Windows. Between group comparison was made using the Student 't' test for continuous variables and chi square test for categorical variables. Univariate analysis was done. Multiple logistic regression analysis was used to find independent factor associated with coagulopathy. RESULTS: Eighty four (84) donors had coagulopathy on second day (mean INR 1.9 +/- 0.42). Low BMI, % of remnant liver and duration of surgery were independent predictors of coagulopathy. Right lobe hepatectomy had more coagulopathy than left lobe and low BMI was the only independent predictor. There was no correlation of coagulopathy with age, gender, blood loss, presence of epidural catheter, postoperative ALT or duration of hospital stay. High INR was the main contributor for coagulopathy. CONCLUSIONS: Coagulopathy is seen after donor hepatectomy. We recommend removal of the epidural catheter after the fifth postoperative day when INR falls below 1.5. PMID- 26119439 TI - Pulmonary choriostoma in a case of tuberous sclerosis complex. AB - A 52 years old lady was diagnosed to have Tuberous Sclerosis Complex (TSC) on the basis of 2 major and one minor criterion. She had family history of similar complaints in her sister and two sons. There was involvement of kidney in the form of angiomyolipoma, skin in the form of facial angiofibroma and teeth with a dental pit. She had an unusual lung involvement in the form of multiple small choristomas. Choristoma was diagnosed on transbronchial lung biopsy and was present in the form of disorganised striated muscles. The reported pulmonary manifestations of TCS i.e. lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) are types of hamartomas. Hamartomas and choristomas are both types of disorganized tissue. 'Choristoma'of lung in TSC however is not reported. Clinopathological correlation of pulmonary hamartoma and choristoma, and treatment in TSC has been discussed. PMID- 26119438 TI - Sildenafil in pediatric pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease of varied etiologies. Although PAH has no curative treatment, a greater understanding of pathophysiology, technological advances resulting in early diagnosis, and the availability of several newer drugs have improved the outlook for patients with PAH. Sildenafil is one of the therapeutic agents used extensively in the treatment of PAH in children, as an off-label drug. In 2012, the United States Food and Drug Administration (USFDA) issued a warning regarding the of use high dose sildenafil in children with PAH. This has led to a peculiar situation where there is a paucity of approved therapies for the management of PAH in children and the use of the most extensively used drug being discouraged by the regulator. This article provides a review of the use of sildenafil in the treatment of PAH in children. PMID- 26119440 TI - A case of paraneoplastic bullous pemphigoid in association with squamous cell carcinoma of lung. AB - Bullous pemphigoid is a chronic, autoimmune, acquired subepidermal blistering disorder. It is idiopathic in origin, and mainly seen in elderly individuals. Association between bullous pemphigoid and internal malignancies is reported in the literature, but the exact causal relation is not established. Paraneoplastic bullous pemphigoid is rarely reported in lung cancers, especially in squamous cell variety. So their presence should raise the suspicion of various internal malignancies including lung cancer. It is presented mainly with tense, large blisters over the erythematous base or over normal skin. Subepidermal blisters with tissue eosinophilia are characteristic histopathological features of bullous pemphigoid. Direct immunofluorescence shows linear deposits of IgG - complement complex along the dermoepidermal junction. Conventional treatment of bullous pemphigoid along with treatment of lung cancer (surgery, chemotherapy, radiotherapy) may result in successful resolution of skin lesions. Here, we report a rare association of paraneoplastic bullous phemphigoid and squamous cell carcinoma of lung in a 76-year-old male to increase the awareness among the clinicians regarding this variety of cutaneous paraneoplastic manifestation of lung cancer. PMID- 26119441 TI - A typical case of myoclonic epilepsy with ragged red fibers (MERRF) and the lessons learned. AB - Mitochondrial diseases have a special predilection to involve the brain in view of its high metabolic demand and the tendency for the formation of excitatory neurotransmitters when there is deficiency of intracellular ATP. These diseases have a great phenotypic variation and need a high degree of suspicion. However, some specific syndromes are well defined, both genotypically and phenotypically. Some of the drugs are potentially fatal mitochondrial poisons and an insight into that may be lifesaving as well as prevent serious morbidities.We report a typical case of myoclonic epilepsy with ragged red fibers (MERRF) with classical phenotype and genotype. There was rapid multiaxial deterioration with the introduction of sodium valproate which partly reversed on introducing mitochondrial cocktail and withdrawal of the offending drug.Sodium valproate, phenobarbitone, chloramphenicol and many anti-viral agents are mitochondrial poisons that increase the morbidity and mortality in patients with mitochondrial disease. More harm to the patient can be avoided with insight into this information. PMID- 26119442 TI - A successful twin pregnancy in a patient with HbE-beta-thalassemia in western India. AB - Improvements in medical facilities have helped a large number of clinically severe hemoglobin E (HbE)-beta-thalassemia patients reach adulthood. Consequently, there is a new challenge, that of managing women with HbE-beta thalassemia during pregnancy. In particular, they have a high risk of abortion, preterm delivery, intrauterine growth restriction, and thromboembolism. A 27-year old HbE-beta-thalassemia patient on regular transfusion, who was splenectomized and heptatitis C (HCV)-positive, conceived for the first time without any infertility treatment. However, there was incomplete abortion with heavy bleeding at 3 months of gestation, which required bilateral uterine artery angiography. The angiogram showed the left uterine artery to be moderately hypertrophied. This was embolized with 300-500 micron polyvinyl alcohol (PVA) to stop the bleeding. Soon after, she conceived again with a twin pregnancy, and at 33.3 weeks of gestation, there was a normal delivery of twin girls without any postpartum hemorrhage or perineal tear. Both babies were given prematurity care. The mother and children were both normal up till the last follow-up 18 months after delivery, and both the girls are HbE heterozygous. Thorough monitoring of endocrine functions along with proper management of transfusions and iron overload can help in reducing the complications related to pregnancy in these patients. PMID- 26119443 TI - Symptoms of degeneration of the pyramidal tracts in conventional magnetic resonance imaging and diffusion tensor imaging in a young woman with primary lateral sclerosis. AB - Primary lateral sclerosis (PLS) is one of the forms of motor neuron disease (MND), affecting only upper motor neurons. The diagnosis of PLS should be made on different diagnostic criteria, for example, Pringle or Gordon, but it is usually a diagnosis of exclusion. There are no characteristic findings in standard laboratory and electrophysiological assessment. We present details of a 31-year old woman who had suffered from progressive paraparesis with right-side predominance. Conventional MRI of brain and spinal cord and diffusion tensor imaging (DTI) studies showed Hyperintense lesions in the upper part of the cervical spinal cord at the level C1 in lateral funicules, in the medulla oblongata at the pyramidal decussation and in the midbrain. Brain DTI revealed changes along the corticospinal tracts on fractional anisotropy (FA) maps. MRI of the thoracic spinal cord showed in T2-weighted images hyperintensive regions in the course of the lateral corticospinal tracts. This aided in PLS recognition. PMID- 26119444 TI - Congenital bronchial atresia misdiagnosed as pulmonary tuberculosis. PMID- 26119445 TI - Challenges in the diagnosis of breast cancer in the elderly. PMID- 26119446 TI - Echinacea-associated acute cholestatic hepatitis. PMID- 26119447 TI - Operation theatre utilization and efficiency. PMID- 26119448 TI - Performing audit in histopathology. PMID- 26119449 TI - Surgical safety checklist: Productive, nondisruptive, and the "right thing to do". PMID- 26119450 TI - Controlling legs for locomotion-insights from robotics and neurobiology. AB - Walking is the most common terrestrial form of locomotion in animals. Its great versatility and flexibility has led to many attempts at building walking machines with similar capabilities. The control of walking is an active research area both in neurobiology and robotics, with a large and growing body of work. This paper gives an overview of the current knowledge on the control of legged locomotion in animals and machines and attempts to give walking control researchers from biology and robotics an overview of the current knowledge in both fields. We try to summarize the knowledge on the neurobiological basis of walking control in animals, emphasizing common principles seen in different species. In a section on walking robots, we review common approaches to walking controller design with a slight emphasis on biped walking control. We show where parallels between robotic and neurobiological walking controllers exist and how robotics and biology may benefit from each other. Finally, we discuss where research in the two fields diverges and suggest ways to bridge these gaps. PMID- 26119451 TI - National multi-institutional cooperative on urolithiasis in children: Age is a significant predictor of urine abnormalities. AB - INTRODUCTION: Pediatric nephrolithiasis is a growing problem and prior studies have shown the greatest increase in nephrolithiasis in the adolescent population. Metabolic abnormalities have historically been cited as the primary cause of pediatric nephrolithiasis; however, dietary and other factors such as obesity have also been studied with mixed results. OBJECTIVE: We reviewed the charts of pediatric patients with a history of nephrolithiasis to determine the number and types of metabolic abnormalities present on 24-h urine analysis. STUDY DESIGN: We retrospectively reviewed the charts of all pediatric patients with a history of nephrolithiasis from 1999-2013 across four different institutions. The subjects were excluded if they had a history of spina bifida, neurogenic bladder, cerebral palsy, isolated bladder stones, or if they were on medical therapy for nephrolithiasis before the first 24-h urine collection. RESULTS: There were 206 subjects included in the analysis with an average age of 13 (+/-3.9) years. The patients were stratified into two age groups based on an apparent bimodal distribution of metabolic abnormalities, <=10 years and >10 years of age. Metabolic abnormalities were present in 130 children (63.1%) and there was a difference between the groups, with children <=10 years more likely to have a metabolic abnormality compared with those >10 years of age (75% vs. 60.6%, p = 0.0443) on univariate analysis. In children <=10 years hypercalciuria was the most common disorder present (48.4%), and in children >10 years hypocitraturia was the most common disorder present (26.1%). Children <=10 years of age were more likely to have normal volume (p = 0.006), elevated urinary oxalate (p = 0.0351), elevated urinary calcium (p < 0.001), elevated supersaturation of calcium phosphate (p < 0.001), and elevated supersaturation of calcium oxalate (p = 0.002). On multivariate analysis, children <=10 years of age were more likely to have normal volume, hyperoxaluria, elevated supersaturation of calcium phosphate and a trend towards hypercalciuria (Table). DISCUSSION: Our study reveals that younger children are more likely to have a metabolic abnormality present on 24-h urine analysis. This has important implications when deciding on treatment options, with younger children potentially requiring more aggressive management with medical therapy. Older children were more likely to have low urinary volume and their most common metabolic abnormality was hypocitraturia. Although dietary factors have not been established as the definitive reason behind the rising incidence of nephrolithiasis in the adolescent population, older children may benefit more from diet modification with a strong focus on increasing volume intake. CONCLUSION: We found differences in younger compared with older age groups in terms of the number and types of metabolic disorders present. Children <=10 years of age were more likely to have a metabolic disorder including elevations in calcium, oxalate and supersaturation of calcium phosphate, while children >10 years of age were more likely to have low urinary volume. These differences have important implications for future investigative studies on the rising incidence as well as the best course of treatment for children with nephrolithiasis. PMID- 26119452 TI - Is combined inner preputial inlay graft with tubularized incised plate in hypospadias repair worth doing? AB - BACKGROUND: It has been noted that after tubularized incised plate urethroplasty (TIP) repair, the final meatal position is glanular but not at the optimum position. Inner preputial inlay graft combined with tubularized incised plate (G TIP) has been proposed for redo urethroplasty. We extended this indication to be the standard technique for primary hypospadias repair. We conduct this prospective study to obtain a wide, slit-like appearance neomeatus at the optimum position in the glans proper and to judge if hypospadias repair complications differ from TIP repair in the published data in the literature. PATIENTS AND METHODS: This prospective study included 230 consecutive patients who underwent this technique. The study was conducted from November 2011 to August 2014 for all hypospadias cases to be repaired in a single stage regardless of the width and depth of urethral plate or the glans size and shape. Localization of the meatus was glanular in 13 patients, coronal in 75, distal penile in 112, mid penile in 25 and proximal in five. The urethral plate was incised deeply and extended distally beyond the end of the plate by 3 mm in glans proper. The mucosal graft was harvested from the inner prepuce, inlayed and quilted in the incised urethral plate. The neourethra was created over a urethral catheter in two layers. The vascular dartos flap was mobilized dorsally and moved ventrally to cover the neourethral suture line as a barrier. RESULTS: The follow-up period ranged from 5 to 36 months. Excellent cosmetic and functional results were achieved in 221 of 230 patients (96.09%). Neither meatal stenosis nor urethral diverticulum were encountered. An excellent glanular position of a wide slit-like neomeatus was achieved using this technique. Nine patients (3.91%) developed urethrocutaneous fistula. Excellent urinary stream was reported by parents. CONCLUSIONS: Combined inner preputial graft with TIP urethroplasty secures the optimal glanular position of a wide slit-like neomeatus because of extension of the incision beyond the end of the plate, thus optimizing functional and cosmetic outcome with no meatal stenosis. PMID- 26119453 TI - Hydrophobic Cysteine Poly(disulfide)-based Redox-Hypersensitive Nanoparticle Platform for Cancer Theranostics. AB - Selective tumor targeting and drug delivery are critical for cancer treatment. Stimulus-sensitive nanoparticle (NP) systems have been designed to specifically respond to significant abnormalities in the tumor microenvironment, which could dramatically improve therapeutic performance in terms of enhanced efficiency, targetability, and reduced side-effects. We report the development of a novel L cysteine-based poly (disulfide amide) (Cys-PDSA) family for fabricating redox triggered NPs, with high hydrophobic drug loading capacity (up to 25 wt% docetaxel) and tunable properties. The polymers are synthesized through one-step rapid polycondensation of two nontoxic building blocks: L-cystine ester and versatile fatty diacids, which make the polymer redox responsive and give it a tunable polymer structure, respectively. Alterations to the diacid structure could rationally tune the physicochemical properties of the polymers and the corresponding NPs, leading to the control of NP size, hydrophobicity, degradation rate, redox response, and secondary self-assembly after NP reductive dissociation. In vitro and in vivo results demonstrate these NPs' excellent biocompatibility, high selectivity of redox-triggered drug release, and significant anticancer performance. This system provides a promising strategy for advanced anticancer theranostic applications. PMID- 26119454 TI - Paid Support Workers for Adults with Intellectual Disabilities; Their Current Knowledge of Hearing Loss and Future Training Needs. AB - BACKGROUND: People with intellectual disabilities are more likely to have hearing loss than the general population. For those unable to self-advocate, the responsibility of detection and management falls to their caregivers. METHODS: This is the first cycle of a project using action research methodology to improve services. Twenty care workers were interviewed to understand their knowledge of hearing loss and hearing aids. Themes were generated using thematic analysis. FINDINGS: This group was better qualified than their peers but received minimal training in hearing loss. They were unable to accurately estimate expected prevalence and had a negative perception of hearing aids. Only 7% of service users were known to have hearing loss. CONCLUSIONS: Current training is not sufficient to provide the skills for detection and management of hearing problems. This group had clear ideas on methods of learning. Working in collaboration is necessary to achieve long-term change to practice. PMID- 26119455 TI - Signaling Control of Differentiation of Embryonic Stem Cells toward Mesendoderm. AB - Mesendoderm (ME) refers to the primitive streak in mammalian embryos, which has the ability to further differentiate into mesoderm and endoderm. A better understanding on the regulatory networks of ME differentiation of embryonic stem (ES) cells would provide important insights on early embryo patterning and a possible guidance for ES applications in regenerative medicine. Studies on developmental biology and embryology have offered a great deal of knowledge about key signaling pathways involved in primitive streak formation. Recently, various chemically defined recipes have been formulated to induce differentiation of ES cells toward ME in vitro, which greatly facilitate the elucidation of the regulatory mechanisms of different signals involved in ME specification. Among the extrinsic signals, transforming growth factor-beta/Activin signaling and Wnt signaling have been shown to be the most critical ones. On another side, intrinsic epigenetic regulation has been indicated to be important in ME determination. In this review, we summarize the current understanding on the extrinsic and intrinsic regulations of ES cells-to-ME differentiation and the crosstalk among them, aiming to get a general overview on ME specification and primitive streak formation. PMID- 26119456 TI - A case of sudden cardiac death following Domperidone self-medication. AB - The phenomenon of sudden cardiac death is usually related to the worsening of existing heart conditions leading to ventricular arrhythmia (VA). One of the well known triggers of SCD is drug-induced prolongation of the QT interval, such as that caused by Domperidone (D). Despite its risk to prolong the QT interval and associated narrow therapeutic index, D is available as an over-the-counter (OTC) drug in many countries such as Italy, Ireland, Netherlands, China, South Africa, Mexico, New Zealand and Chile to treat gastroesophageal reflux and functional dyspepsia. The present paper reports a case of SCD that occurred some hours after D self-administration in a 47-year-old female subject with mitral valve prolapse, thus, predisposed to both VA and SCD. Despite the risks related to D administration, to the best of our knowledge, this particular issue has not been discussed in the medico-legal literature. For this reason, the forensic implications of D administration are discussed focusing on issues related to the self-administration as an OTC drug (as seen in this case), administration to incapacitated subjects, prescription to patients with contraindications and the off-label drug use of D at high and hazardous concentrations to stimulate lactation. PMID- 26119457 TI - Diarylethene Self-Assembled Monolayers: Cocrystallization and Mixing-Induced Cooperativity Highlighted by Scanning Tunneling Microscopy at the Liquid/Solid Interface. AB - Stimulus control over 2D multicomponent molecular ordering on surfaces is a key technique for realizing advanced materials with stimuli-responsive surface properties. The formation of 2D molecular ordering along with photoisomerization was monitored by scanning tunneling microscopy at the octanoic acid/highly oriented pyrolytic graphite interface for a synthesized amide-containing diarylethene, which underwent photoisomerization between the open- and closed ring isomers and also a side-reaction to give the annulated isomer. The nucleation (Kn) and elongation (Ke) equilibrium constants were determined by analysis of the concentration dependence of the surface coverage by using a cooperative model at the liquid/solid interface. It was found that the annulated isomer has a very large equilibrium constant, which explains the predominantly observed ordering of the annulated isomer. It was also found that the presence of the closed-ring isomer induces cooperativity into the formation of molecular ordering composed of the open-ring isomer. A quantitative analysis of the formation of ordering by using the cooperative model has provided a new view of the formation of 2D multicomponent molecular ordering. PMID- 26119458 TI - Acoustic Radiation Force Impulse Elastography in the Diagnosis of Thyroid Nodules: Useful or Not Useful? AB - The goal of this study is to evaluate the diagnostic performance of acoustic radiation force impulse (ARFI) elastography for differentiating benign from malignant thyroid nodules. One hundred and seventy-four pathologically proven thyroid nodules (139 benign, 35 malignant) in 154 patients (mean age: 49.2 +/- 12.1 y; range: 16-72 y) were included in this study. Conventional ultrasound (US) and ARFI elastography using virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ) were performed to examine the thyroid nodules. Two blinded readers with different amounts of experience independently scored the likelihood of malignancy on the basis of a five-point scale in three different image-reading sets. The diagnostic performances among different image-reading sets and between the two readers were compared. The diagnostic specificity of both readers improved significantly after reading the VTI images or both VTI and VTQ images (all p < 0.05). After review of the results of both VTI and VTQ, the numbers of correctly diagnosed nodules increased in nodules <1.0 cm for both readers and in both nodular goiter and papillary thyroid carcinoma for the junior reader (p < 0.05). The nodules with definite diagnoses (i.e., confidence levels including definite benign and definite malignant cases) increased after review of VTI and VTQ images versus conventional US for the senior reader (p < 0.05). In conclusion, adding ARFI elastography improves the specificity in diagnosing malignant thyroid nodules compared with conventional US on its own. ARFI elastography particularly facilitates the specific diagnosis for thyroid nodules smaller than 1.0 cm. ARFI elastography is also able to increase the diagnostic confidence of the readers. PMID- 26119459 TI - Experimental application of ultrafast imaging to spectral tissue characterization. AB - Ultrasound ultrafast imaging (UI) allows acquisition of thousands of frames per second with a sustained image quality at any depth in the field of view. Therefore, it would be ideally suited to obtain good statistical sampling of fast moving tissues using spectral-based techniques to derive the backscatter coefficient (BSC) and associated quantitative parameters. In UI, an image is formed by insonifying the medium with plane waves steered at different angles, beamforming them and compounding the resulting radiofrequency images. We aimed at validating, experimentally, the effect of these beamforming protocols on the BSC, under both isotropic and anisotropic conditions. Using UI techniques with a linear array transducer (5-14 MHz), we estimated the BSCs of tissue-mimicking phantoms and flowing porcine blood at depths up to 35 mm with a frame rate reaching 514 Hz. UI-based data were compared with those obtained using single element transducers and conventional focusing imaging. Results revealed that UI compounded images can produce valid estimates of BSCs and effective scatterer size (errors less than 2.2 +/- 0.8 and 0.26 +/- 0.2 dB for blood and phantom experiments, respectively). This work also describes the use of pre-compounded UI images (i.e., steered images) to assess the angular dependency of circulating red blood cells. We have concluded that UI data sets can be used for BSC spectral tissue analysis and anisotropy characterization. PMID- 26119460 TI - Lumbar Ultrasound Image Feature Extraction and Classification with Support Vector Machine. AB - Needle entry site localization remains a challenge for procedures that involve lumbar puncture, for example, epidural anesthesia. To solve the problem, we have developed an image classification algorithm that can automatically identify the bone/interspinous region for ultrasound images obtained from lumbar spine of pregnant patients in the transverse plane. The proposed algorithm consists of feature extraction, feature selection and machine learning procedures. A set of features, including matching values, positions and the appearance of black pixels within pre-defined windows along the midline, were extracted from the ultrasound images using template matching and midline detection methods. A support vector machine was then used to classify the bone images and interspinous images. The support vector machine model was trained with 1,040 images from 26 pregnant subjects and tested on 800 images from a separate set of 20 pregnant patients. A success rate of 95.0% on training set and 93.2% on test set was achieved with the proposed method. The trained support vector machine model was further tested on 46 off-line collected videos, and successfully identified the proper needle insertion site (interspinous region) in 45 of the cases. Therefore, the proposed method is able to process the ultrasound images of lumbar spine in an automatic manner, so as to facilitate the anesthetists' work of identifying the needle entry site. PMID- 26119461 TI - Use of Endoscopic Ultrasound to Evaluate Large Gastric Folds: Features Predictive of Malignancy. AB - The aim of this study was to investigate with endoscopic ultrasound (EUS) the features of the gastric wall that can be used to predict malignant disease in patients with large gastric folds. We retrospectively reviewed the EUS findings of 65 patients (26 with benign and 39 with malignant disease) with large gastric folds on endoscopy and EUS and analyzed the predictors of malignant disease (e.g., gastric wall thickness, preservation of five-layered structure, thickened layers). Gastric wall thickness (>=9.8 mm), thickened deep layer, thickened muscularis propria and non-preserved wall layer structures were significantly more prevalent in patients with malignant disease on EUS. Among them, gastric wall thickness (>=9.8 mm) (odds ratio = 6.72, 95% confidence interval = 1.23 36.73, p = 0.028) and thickened muscularis propria (odds ratio = 37.14, 95% confidence interval = 7.02-196.49, p < 0.001) were significantly associated with malignant disease. Our data indicate that EUS is a useful tool for assessing large gastric folds and that gastric wall thickness (>=9.8 mm) and thickened muscularis propria are significant features predictive of malignant disease on EUS. PMID- 26119462 TI - Quantifying the Antiviral Effect of IFN on HIV-1 Replication in Cell Culture. AB - Type-I interferons (IFNs) induce the expression of hundreds of cellular genes, some of which have direct antiviral activities. Although IFNs restrict different steps of HIV replication cycle, their dominant antiviral effect remains unclear. We first quantified the inhibition of HIV replication by IFN in tissue culture, using viruses with different tropism and growth kinetics. By combining experimental and mathematical analyses, we determined quantitative estimates for key parameters of HIV replication and inhibition, and demonstrate that IFN mainly inhibits de novo infection (33% and 47% for a X4- and a R5-strain, respectively), rather than virus production (15% and 6% for the X4 and R5 strains, respectively). This finding is in agreement with patient-derived data analyses. PMID- 26119463 TI - Electron microscopic morphometry of isolated rat brain porosome complex. AB - Porosomes are the universal secretory portals at the cell plasma membrane where secretory vesicles dock and transiently fuse via the kiss-and-run mechanism of cellular secretion, to release intravesicular cargo to the outside of the cell. During last two decades discovery of porosome and a great volume of work from different laboratories provide molecular insights on the structure, function, and composition of the porosome complex, especially the neuronal porosome. In rat neurons 12-17 nm cup-shaped lipoprotein porosomes present at presynaptic membrane. They possess a central plug and sometimes are with docked synaptic vesicles. Although earlier studies have greatly progressed our understanding of the morphology and the proteome and limited lipidome of the neuronal porosome complex, the current study was carried out to determine the morphology of the bare protein backbone of the neuronal porosome complex. Results from our study demonstrate that although the eight-fold symmetry of the immunoisolated porosome is maintained, and the central plug is preserved in the isolated structures, there is a loss in the average size of the porosome complex, possibly due to a loss of lipids from the complex. PMID- 26119465 TI - Optimal Normalization Tests for Muscle Activation of the Levator Scapulae, Pectoralis Minor, and Rhomboid Major: An Electromyography Study Using Maximum Voluntary Isometric Contractions. AB - OBJECTIVE: To identify maximum voluntary isometric contraction (MVIC) test positions for the deeper-lying scapulothoracic muscles (ie, levator scapulae, pectoralis minor, rhomboid major), and to provide a standard set of a limited number of test positions that generate an MVIC in all scapulothoracic muscles. DESIGN: Cross-sectional study. SETTING: Physical and rehabilitation medicine department. PARTICIPANTS: Healthy subjects (N=21). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mean peak electromyographic activity from levator scapulae, pectoralis minor, and rhomboid major (investigated with fine-wire electromyography) and from upper trapezius, middle trapezius, lower trapezius, and serratus anterior (investigated with surface electromyography) during the performance of 12 different MVICs. RESULTS: The results indicated that various test positions generated similar high mean electromyographic activity and that no single test generated maximum activity for a specific muscle in all subjects. The results of this study support using a series of test positions for normalization procedures rather than a single exercise to increase the likelihood of recruiting the highest activity in the scapulothoracic muscles. CONCLUSIONS: A standard set of 5 test positions was identified as being sufficient for generating an MVIC of all scapulothoracic muscles: seated T, seated U 135 degrees , prone T-thumbs up, prone V-thumbs up, and supine V-thumbs up. A standard set of test positions for normalization of scapulothoracic electromyographic data that also incorporates the levator scapulae, pectoralis minor, and rhomboid major muscles is 1 step toward a more comprehensive understanding of normal and abnormal muscle function of these muscles and will help to standardize the presentation of scapulothoracic electromyographic muscle activity. PMID- 26119464 TI - Patient Satisfaction and Perceived Quality of Care Among Older Adults According to Activity Limitation Stages. AB - OBJECTIVE: To examine whether patient satisfaction and perceived quality of medical care are related to stages of activity limitations among older adults. DESIGN: Cross-sectional study. SETTING: Medicare Current Beneficiary Survey (MCBS) for calendar years 2001 to 2011. PARTICIPANTS: A population-based sample (N=42,584) of persons aged >=65 years living in the community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: MCBS questions were categorized under 5 patient satisfaction and perceived quality dimensions: care coordination and quality, access barriers, technical skills of primary care physicians, interpersonal skills of primary care physicians, and quality of information provided by primary care physicians. Persons were classified into a stage of activity limitation (0-IV) derived from self-reported difficulty levels performing activities of daily living (ADL) and instrumental ADL. RESULTS: Compared with older beneficiaries with no limitations at ADL stage 0, the adjusted odds ratios (ORs) for stage I (mild) to stage III (severe) for satisfaction with care coordination and quality ranged from .85 (95% confidence interval [CI], .80-.92) to .79 (95% CI, .70-.89). Compared with ADL stage 0, satisfaction with access barriers ranged from OR=.81 (95% CI, .76-.87) at stage I to a minimum of OR=.67 (95% CI, .59-.76) at stage III. Similarly, compared with older beneficiaries at ADL stage 0, perceived quality of the technical skills of their primary care physician ranged from OR=.87 (95% CI, .82-.94) at stage I to a minimum of OR=.81 (95% CI, .72-.91) at stage III. CONCLUSIONS: Medicare beneficiaries at higher stages of activity limitation, although not necessarily the highest stage of activity limitation, reported less satisfaction with medical care. PMID- 26119466 TI - Gait Deviation Index Correlates With Daily Step Activity in Children With Cerebral Palsy. AB - OBJECTIVES: To examine the association between the Gait Deviation Index (GDI), a multivariate measure of overall gait impairment, and measures of both community walking performance and walking capacity within the clinic setting in ambulatory children with cerebral palsy. DESIGN: Cross-sectional study. SETTING: Gait analysis, 6-minute walk test (6MWT), and self-selected walking speed (WS) were conducted in laboratory and clinic settings. Activity monitoring was done in participants' community environment. PARTICIPANTS: Children with cerebral palsy (N=55; age range, 6-18y) with Gross Motor Function Classification System levels I to III. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The GDI was derived from gait analysis data as a measure of overall gait impairment; an activity monitor was used to capture community walking performance, and the 6MWT and WS were the clinic-based measures of walking capacity. RESULTS: Fifty-five children had a median GDI of 78.86 (range, 53.07-105.34). A moderate association was found between the GDI and daily step count (Spearman rho=.58; 95% confidence interval [CI], .37-.74; P<.0001). Weaker associations were found between the GDI and 6MWT (Spearman rho=.4718; 95% CI, .2283-.6597; P<.0003) and between the GDI and WS (Spearman rho=.3949; 95% CI, .1368-.6028; P<.0028). CONCLUSIONS: The GDI has a moderate association with daily step count, which suggests that interventions that positively change gait kinematics may also affect community walking performance. Although the GDI's deviation from the normal value provides valuable information, other measures are required to provide a complete picture of a child's walking capacity and performance. PMID- 26119467 TI - eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS identified asthma genes. AB - BACKGROUND: Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. METHODS: Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94). RESULTS: For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 * 10(-11) and 5.4 * 10(-4) , respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 * 10(-4) and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 * 10(-6) ) but not in BAL. CONCLUSIONS: Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted. PMID- 26119468 TI - A new iridoid diglucoside from Harpagophytum procumbens. AB - A new iridoid diglucoside has been isolated from an aqueous extract of Harpagophytum procumbens secondary roots, together with six known compounds. Its structure has been assigned as 6'-O-glucopyranosyl-8-O-trans-coumaroylharpagide by spectroscopic means. PMID- 26119469 TI - The deubiquitinating enzyme AMSH1 is required for rhizobial infection and nodule organogenesis in Lotus japonicus. AB - Legume-rhizobium symbiosis contributes large quantities of fixed nitrogen to both agricultural and natural ecosystems. This global impact and the selective interaction between rhizobia and legumes culminating in development of functional root nodules have prompted detailed studies of the underlying mechanisms. We performed a screen for aberrant nodulation phenotypes using the Lotus japonicus LORE1 insertion mutant collection. Here, we describe the identification of amsh1 mutants that only develop small nodule primordia and display stunted shoot growth, and show that the aberrant nodulation phenotype caused by LORE1 insertions in the Amsh1 gene may be separated from the shoot phenotype. In amsh1 mutants, rhizobia initially became entrapped in infection threads with thickened cells walls. Some rhizobia were released into plant cells much later than observed for the wild-type; however, no typical symbiosome structures were formed. Furthermore, cytokinin treatment only very weakly induced nodule organogenesis in amsh1 mutants, suggesting that AMSH1 function is required downstream of cytokinin signaling. Biochemical analysis showed that AMSH1 is an active deubiquitinating enzyme, and that AMSH1 specifically cleaves K63-linked ubiquitin chains. Post-translational ubiquitination and deubiquitination processes involving the AMSH1 deubiquitinating enzyme are thus involved in both infection and organogenesis in Lotus japonicus. PMID- 26119470 TI - Enhancing Clinical Content and Race/Ethnicity Data in Statewide Hospital Administrative Databases: Obstacles Encountered, Strategies Adopted, and Lessons Learned. AB - OBJECTIVES: Eight grant teams used Agency for Healthcare Research and Quality infrastructure development research grants to enhance the clinical content of and improve race/ethnicity identifiers in statewide all-payer hospital administrative databases. PRINCIPAL FINDINGS: Grantees faced common challenges, including recruiting data partners and ensuring their continued effective participation, acquiring and validating the accuracy and utility of new data elements, and linking data from multiple sources to create internally consistent enhanced administrative databases. Successful strategies to overcome these challenges included aggressively engaging with providers of critical sources of data, emphasizing potential benefits to participants, revising requirements to lessen burdens associated with participation, maintaining continuous communication with participants, being flexible when responding to participants' difficulties in meeting program requirements, and paying scrupulous attention to preparing data specifications and creating and implementing protocols for data auditing, validation, cleaning, editing, and linking. In addition to common challenges, grantees also had to contend with unique challenges from local environmental factors that shaped the strategies they adopted. CONCLUSIONS: The creation of enhanced administrative databases to support comparative effectiveness research is difficult, particularly in the face of numerous challenges with recruiting data partners such as competing demands on information technology resources. Excellent communication, flexibility, and attention to detail are essential ingredients in accomplishing this task. Additional research is needed to develop strategies for maintaining these databases when initial funding is exhausted. PMID- 26119471 TI - Functional Genetic Variation in Dopamine Signaling Moderates Prefrontal Cortical Activity During Risky Decision Making. AB - Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task (BART). The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the BART during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1, and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7777 allelic combinations) was tested on brain function in an independently defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that the combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting the cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function, and decision making vary as a function of dopamine signaling capacity. PMID- 26119472 TI - Brain Activity During Cocaine Craving and Gambling Urges: An fMRI Study. AB - Although craving states are important to both cocaine dependence (CD) and pathological gambling (PG), few studies have directly investigated neurobiological similarities and differences in craving between these disorders. We used functional magnetic resonance imaging (fMRI) to assess brain activity in 103 participants (30 CD, 28 PG, and 45 controls) while they watched videos depicting cocaine, gambling, and sad scenarios to investigate the neural correlates of craving. We observed a three-way urge type * video type * diagnostic group interaction in self-reported craving, with CD participants reporting strong cocaine cravings to cocaine videos, and PG participants reporting strong gambling urges to gambling videos. Neuroimaging data revealed a diagnostic group * video interaction in anterior cingulate cortex/ventromedial prefrontal cortex (mPFC), activating predominantly to cocaine videos in CD participants, and a more dorsal mPFC region that was most strongly activated for cocaine videos in CD participants, gambling videos in PG participants, and sad videos in control participants. Gender * diagnosis * video interactions identified dorsal mPFC and a region in posterior insula/caudate in which female but not male PG participants showed increased responses to gambling videos. Findings illustrate both similarities and differences in the neural correlates of drug cravings and gambling urges in CD and PG. Future studies should investigate diagnostic- and gender-specific therapies targeting the neural systems implicated in craving/urge states in addictions. PMID- 26119474 TI - Primary osteosarcoma of the ovary. PMID- 26119475 TI - Elevated non-esterified fatty acid concentrations hamper bovine oviductal epithelial cell physiology in three different in vitro culture systems. AB - Elevated non-esterified fatty acids (NEFAs) have been recognized as an important link between lipolytic metabolic conditions and impaired fertility in high yielding dairy cows. However, NEFA effects on the oviductal micro-environment currently remain unknown. We hypothesize that elevated NEFAs may contribute to the complex pathology of subfertility by exerting a negative effect on bovine oviductal epithelial cell (BOEC) physiology. Therefore, the objectives of this study were to elucidate direct NEFA effects on BOEC physiology in three different in vitro cell culture systems. Bovine oviductal epithelial cells (four replicates) were mechanically isolated, pooled, and cultured as conventional monolayers, as explants, and in a polarized cell culture system with Dulbecco's modified Eagle's medium/F12-based culture medium. Bovine oviductal epithelial cells were exposed to an NEFA mixture of oleic, stearic, and palmitic acids for 24 hours at both physiological and pathologic concentrations. A control (0 MUM NEFA) and a solvent control (0 MUM NEFA + 0.45% ethanol) group were implemented. Bovine oviductal epithelial cells physiology was assessed by means of cell number and viability, a sperm binding assay, transepithelial electric resistance (TER), and a wound-healing assay. Bovine oviductal epithelial cell morphology was assessed by scanning electron microscopy on cell polarity, presence of microvilli and cilia, and monolayer integrity. Bovine oviductal epithelial cell number was negatively affected by increasing NEFAs, however, cell viability was not. Sperm binding affinity significantly decreased with increasing NEFAs and tended (P = 0.051) to be more affected by the direction of NEFA exposure in the polarized cell culture system. The absolute TER increase after NEFA exposure in the control (110 +/- 11 Omega.cm(2)) was significantly higher than that in all the other treatments and was also different depending on the exposure side. Bidirectional exposed monolayers were even associated with a significant TER reduction (-15 +/- 10 Omega.cm(2); P < 0.05). Cell proliferation capacity showed a decreased cell migration with increasing NEFA concentrations but was irrespective of the exposure side. Bovine oviductal epithelial cell morphology was not affected. In conclusion, in an in vitro setting, NEFAs exert a negative effect on BOEC physiology but not morphology. Ultimately, these physiological alterations in its microenvironment may result in suboptimal development of the pre-implantation embryo and a reduced reproductive outcome in dairy cattle. PMID- 26119473 TI - Prognostic role of copeptin after stroke: A systematic review and meta-analysis of observational studies. AB - Copeptin, the C-terminal part of provasopressin, has emerged as a novel prognostic marker after hemorrhagic or ischemic stroke. The aim of this study was to quantitatively assess the prognostic significance of plasma copeptin level on functional outcome and mortality in patients with acute stroke using a meta analysis of the available evidence. Thirteen relevant studies from 2,746 patients were finally included in our study. An elevated plasma copeptin level was associated with an increased risk of unfavorable outcome and mortality after stroke (OR 1.77; 95% CI, 1.44-2.19 and OR 3.90; 95% CI 3.07-4.95, respectively). The result of the pooled measure on standardized mean difference (SMD) was that plasma copeptin levels were found to be significantly higher in patients who died compared to survivors (SMD 1.70; 95% CI, 1.36-2.03). A stratified analysis by study region showed significant differences in SMD of copeptin, and the heterogeneity among studies was significantly decreased. However, the positive association of copeptin with poor prognosis after stroke was consistent in each stratified analysis. The present meta-analysis suggests that early measurement of plasma copeptin could provide better prognostic information about functional outcome and mortality in patients with acute stroke. PMID- 26119477 TI - A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism. AB - Isothiocyanates are small molecules characterized by high chemical reactivity that allows them to interact readily with cellular constituents eliciting a plethora of biological activities. They are present exclusively in cruciferous vegetables, as glucosinolates, the intake of which has been associated with cancer chemoprevention. When the physical structure of these vegetables is disturbed, e.g. during mastication, the enzyme myrosinase is released and converts the glucosinolates to isothiocyanates (R-N=C=S), where R can be aliphatic or aromatic. Although sulforaphane, an aliphatic isothiocyanate, has received most attention worldwide, the most extensively studied aromatic isothiocyanate is phenethyl isothiocyanate (PEITC), and there are substantial differences in biological activity between the two sub-classes. In animal cancer models, PEITC effectively antagonized the carcinogenicity of chemicals, especially nitrosocompounds. A principal mechanism of their action is to protect the integrity of DNA by decreasing the levels of the genotoxic metabolites of chemical carcinogens. Extensive studies established that PEITC modulates the metabolism of the tobacco-specific carcinogenic nitrosamine 4-(methylnitrosamino) 1-(3-pyridyl)-1-butanone (NNK) by inhibiting its cytochrome P450-mediated bioactivation. Moreover, PEITC is a potent inducer of detoxification enzymes such as quinone reductase, glutathione S-transferase and glucuronosyl transferase. PEITC is rapidly absorbed and is characterized by a large bioavailability; Cmax concentrations achieved in plasma after dietary intake are sufficient to modulate carcinogen metabolism. PEITC is primarily metabolized by glutathione conjugation and is excreted in the urine and bile as the mercapturate. The ability of PEITC to perturb carcinogen metabolism through modulation of cytochrome P450 and phase II detoxification enzymes is comprehensively and critically reviewed. PMID- 26119476 TI - Two-dimensional polyacrylamide gel electrophoresis of Bali bull (Bos javanicus) seminal plasma proteins and their relationship with semen quality. AB - The present study evaluated the relationship between Bali bull (Bos javanicus) seminal plasma proteins and different semen quality parameters. Semen samples from 10 mature Bali bulls were evaluated for conventional semen parameters (general motility, viability, and normal morphology), sperm functionality (acrosome reaction, sperm penetration rate, sperm penetration index), sperm kinetics (computer-assisted semen analysis parameters such as sperm velocity), and sperm morphology (acrosome and membrane integrity). Frozen-thawed semen with higher sperm motility, viability, acrosome integrity, and membrane integrity (P < 0.05) are consistently higher in acrosome reaction and sperm penetration assay. Three bulls showed the highest, four bulls displayed the medium, and the remaining three bulls showed the lowest for all sperm parameters and SPA. The proteome maps of seminal plasma from high-quality and low-quality Bali bulls were also established. Seminal plasma of both high-quality and low-quality Bali bulls was subjected to two-dimensional SDS-PAGE with isoelectric point ranged from 3 to 10 and molecular weight from 10 to 250 kDa. Approximately 116 spots were detected with Blue Silver stain, and of these spots, 29 were selected and identified by MALDI-TOF/TOF-MS/MS. A majority of the proteins visualized in the seminal plasma two-dimensional maps was successfully identified. An essential group of the identified spots represented binder of sperm 1 (BSP1), clusterin, spermadhesin, tissue inhibitor of metalloproteinases 2 (TIMP-2), and phospholipase A2 (PLA2). Other proteins found in high abundance included seminal ribonuclease, serum albumin, cationic trypsin, and peptide similar to beta2 microglobulin. Thus, a reference map of Bali bull seminal plasma proteins has been generated for the very first time and can be used to relate protein pattern changes to physiopathologic events that may influence Bali bull reproductive performance. PMID- 26119478 TI - Crystal engineering of energetic materials: co-crystals of Ethylenedinitramine (EDNA) with modified performance and improved chemical stability. AB - In the area of energetic materials, co-crystallization is emerging as a new technology for modifying or enhancing the properties of existing energetic substances. Ethylenedinitramine (EDNA) is a known energetic material which requires attention partly due to its chemical instability originating with its two highly acidic protons. In order to stabilize EDNA, a co-crystallization approach targeting the acidic protons using a series of co-crystallizing agents with suitable hydrogen-bond acceptors was employed. Fifteen attempted co crystallizations resulted in eight successful outcomes and six of these were crystallographically characterized and all showed evidence of hydrogen bonds to the intended protons. Calculated detonation properties and experimental thermal and impact data for the co-crystals were obtained and compared with those of pure EDNA. The co-crystal of EDNA and 1,2-bis(4-pyridyl)ethylene was recognized as a more thermally stable alternative to EDNA while the co-crystal of EDNA and pyrazine N,N'-dioxide showed comparable detonation strengths (and much improved chemical stability) compared with that of EDNA. The co-crystals EDNA:4,4' bipyridine and EDNA:pyrazine N,N'-dioxide were found to be about 50 % less impact sensitive than EDNA, all of which illustrate how co-crystallizations can be utilized for successfully modifying specific aspects of energetic materials. PMID- 26119479 TI - Delafloxacin, a non-zwitterionic fluoroquinolone in Phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics and clinical efficacy. AB - Delafloxacin is a fluoroquinolone lacking a basic substituent in position 7. It shows MICs remarkably low against Gram-positive organisms and anaerobes and similar to those of ciprofloxacin against Gram-negative bacteria. It remains active against most fluoroquinolone-resistant strains, except enterococci. Its potency is further increased in acidic environments (found in many infection sites). Delafloxacin is active on staphylococci growing intracellularly or in biofilms. It is currently evaluated as an intravenous and intravenous/oral stepdown therapy in Phase III trials for the treatment of complicated skin/skin structure infections. It was also granted as Qualified Infectious Disease Product for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, due to its high activity on pneumococci and atypical pathogens. PMID- 26119480 TI - The views of parents who experience intergenerational poverty on parenting and play: a qualitative analysis. AB - BACKGROUND: There is minimal literature on how parents experiencing intergenerational poverty view their role as parents and the value they place on children's play. The objective of this study was to examine how these parents view their parenting role and their beliefs about children's play. METHODS: Thirteen mothers of preschool-aged children who experienced intergenerational poverty were recruited to the study. Semi-structured interviews were conducted and were analysed using interpretive phenomenological analysis. RESULTS: Parents described their role as guiding their children to become 'good' people, to teach them skills and provide a routine within the home. There were two disconnections in the data including the view that whilst parenting was hard and lonely, it was also a private matter and participants preferred not to seek support. A second disconnection was in terms of their beliefs about play. Parents believed that whilst play was valuable to their child's development, it was not their role to play with children. However, if parents did play with their child, they noticed positive changes in their child's behaviour. CONCLUSION: The views of parents who experienced intergenerational poverty were similar to other reported findings in parenting studies. However, the current sample differed on not seeking help for support as well as not seeing their role as playing with their children, even though occasions of joining their child in play were associated with a positive change in their relationship with their child. This has implications for communicating about parenting issues with parents who have experienced intergenerational poverty. PMID- 26119481 TI - Functional differences between the arteries perfusing gas exchange and nutritional membranes in the late chicken embryo. AB - The chicken extraembryonic arterial system comprises the allantoic arteries, which irrigate the gas exchange organ (the chorioallantoic membrane, CAM) and the yolk sac (YS) artery, which irrigates the nutritional organ (the YS membrane). We compared, using wire myography, the reactivity of allantoic and YS arteries from 19-day chicken embryos (total incubation 21 days). The contractions induced by KCl, the adrenergic agonists norepinephrine (NE, nonselective), phenylephrine (alpha1), and oxymetazoline (alpha2), electric field stimulation (EFS), serotonin, U46619 (TP receptor agonist), and endothelin (ET)-1 and the relaxations induced by acetylcholine (ACh), sodium nitroprusside (SNP, NO donor), forskolin (adenylate cyclase activator), and isoproterenol (beta-adrenergic agonist) were investigated. Extraembryonic allantoic arteries did not show alpha adrenergic-mediated contraction (either elicited by exogenous agonists or EFS) or ACh-induced (endothelium-dependent) relaxation, whereas these responses were present in YS arteries. Interestingly, the intraembryonic segment of the allantoic artery showed EFS- and alpha-adrenergic-induced contraction and ACh mediated relaxation. Moreover, glyoxylic acid staining showed the presence of catecholamine-containing nerves in the YS and the intraembryonic allantoic artery, but not in the extraembryonic allantoic artery. Isoproterenol- and forskolin-induced relaxation and ET-1-induced contraction were higher in YS than in allantoic arteries, whereas serotonin- and U46619-induced contraction and SNP induced relaxation did not significantly differ between the two arteries. In conclusion, our study demonstrates a different pattern of reactivity in the arteries perfusing the gas exchange and the nutritional membranes of the chicken embryo. PMID- 26119482 TI - Early second-hand smoke exposure and child and adolescent mental health: evidence from Hong Kong's 'Children of 1997' birth cohort. AB - BACKGROUND AND AIMS: Second-hand smoke (SHS) exposure is associated negatively with childhood behavioural problems in western settings. In a developed non western setting, we estimated the associations of early SHS exposure during the prenatal and postnatal periods with several aspects of adolescent mental health. DESIGN: Multivariable linear regression was used to estimate the adjusted associations of pre- and postnatal SHS exposure with adolescent mental health. SETTING: Hong Kong. PARTICIPANTS: Population-representative "Children of 1997" birth cohort. Behavioural problems at ~11 years were available for 5598, self esteem at ~11 years for 6937 and depressive symptoms at ~13 years for 5797. MEASUREMENTS: SHS was categorized as no SHS exposure, occasional prenatal SHS exposure from non-parental sources, daily prenatal SHS exposure from non-parental sources, postnatal SHS exposure from non-parental sources, prenatal and postnatal SHS exposure from non-parental sources, occasional paternal smoking, daily paternal smoking and any maternal smoking. Behavioural problems were assessed from parent-reported Rutter score, self-esteem from self-reported Culture-Free Self-Esteem Inventory score and depressive symptoms from self-reported Patient Health Questionnaire-9 score. FINDINGS: Prenatal SHS exposure from non-parental sources was associated with behavioural problems at ~11 years (1.24, 95% confidence interval 0.20-2.28) adjusted for sex, age of assessment, survey mode (for depressive symptoms only), socio-economic position (SEP), mother's birthplace, gestational age and parity; paternal smoking and maternal smoking were associated with more mental health problems but also with lower SEP. CONCLUSIONS: In Hong Kong, prenatal second-hand tobacco smoke exposure appears to be a risk factor for behavioural problems at age 11 years independent of socio economic position. PMID- 26119483 TI - AEE-active cyclic tetraphenylsilole derivatives with ~100% solid-state fluorescence quantum efficiency. AB - Two new strongly AEE active (I/I0 ~ 94) tetraphenylsilole-containing cyclosiloxanes with cyan emissions (lambdaem = 500 nm) and ~100% solid state fluorescence quantum yields are reported. The intra- and intermolecular C-Hpi interactions in the crystal play a major role in the observed high solid state fluorescence quantum yields. PMID- 26119484 TI - Novel peroxisome proliferator-activated receptor gamma mutation in a family with familial partial lipodystrophy type 3. AB - OBJECTIVE: Familial partial lipodystrophy type 3 (FPLD3) is an autosomal dominant disorder with loss of subcutaneous adipose tissue at the extremities and metabolic complications such as insulin resistance, hypertriglyceridaemia and hypertension. The aim of this study was to characterize the molecular basis of a family of 5 affected members with FPLD3. METHODS: A 61-year-old female index patient and her relatives were assessed by detailed clinical and biochemical examinations. Sequence analysis of the LMNA and PPARG gene was performed. Structure analysis of the identified mutation was carried out using published X ray crystal structures. RESULTS: A novel heterozygous PPARG mutation c.1040A>C was identified in all 5 patients of the family but not in unaffected controls. The resulting amino acid substitution p.Lys347Thr is located at the ligand binding domain (LBD) of the protein and is predicted to disrupt critical molecular interactions to the helix 12 of the LBD. CONCLUSIONS: A novel PPARG mutation leading to FPLD3 is described. The results emphasize the importance of the clinical diagnosis and of further molecular genetic analyses in patients with clinical signs of FPLD but unremarkable LMNA findings. PMID- 26119485 TI - Mutual induction of transcription factor PPARgamma and microRNAs miR-145 and miR 329. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are known to control mRNA translation. Most miRNAs are transcribed from specific genes with well-defined promoters located throughout the genome. The mechanisms that control miRNA expression under normal and pathological conditions are not yet understood clearly. Peroxisome proliferator-activated receptor (PPAR) gamma is a ligand activated transcription factor that is extensively distributed in the CNS. PPARgamma activation induces neuroprotection by modulating genes that contain peroxisome proliferator response elements (PPREs) in their promoters. We presently evaluated if PPARgamma modulates miRNA expression. When adult rats were treated with PPARgamma agonist rosiglitazone, expression of 28 miRNAs altered significantly (12 up- and 16 down-regulated; 3-119 fold) in the cerebral cortex compared to vehicle-treated controls. In silico analysis showed 1-5 PPREs in the putative promoter regions (within 1 Kb upstream of the transcription start site) of these miRNA genes. Cotransfection with a PPARgamma constitutively expressing vector significantly induced the miR-145 and miR-329 promoter vectors (each have four PPREs), which was curtailed by point mutations of PPREs in their promoters. Interestingly, the PPARgamma promoter has binding sites for both these miRNAs and transfection with miR-329 mimic and miR-145 mimic induced the PPARgamma expression. Thus, these studies show a cyclical induction of miRNAs and PPARgamma, indicating that the pleiotropic beneficial effects of PPARgamma agonists might be modulated in part by miRNAs and their down-stream mRNAs. We proposed that promoters of many microRNAs contain the binding sites for the transcription factor PPARgamma. Activation of PPARgamma modulates the expression of these microRNAs. Two such PPARgamma-responsive microRNAs (miR-145 and miR-329) bind to PPARgamma promoter to induce its expression. This indicates the presence of a feedback loop by which transcription factors and microRNAs can modulate each other. PMID- 26119486 TI - Augmented renal clearance in critically ill patients: etiology, definition and implications for beta-lactam dose optimization. AB - The renal clearance of antibiotics may be elevated in some critically ill patients. This paper reviews this recently described phenomenon, referred to as augmented renal clearance (ARC). ARC is considered to be driven by pathophysiological elevation of glomerular filtration, and is defined as a creatinine clearance >130mL/min/173m(2). This in turn promotes very low antibiotic concentrations. This effect may lead to adverse clinical outcomes, particularly with beta-lactam antibiotics, as they require prolonged exposure for optimal antibacterial activity. The use of extended or continuous infusions is an effective strategy to improve exposure. However, because the effect of ARC is potentially quite variable, regular therapeutic drug monitoring (TDM) may be necessary to ensure all patients achieve effective concentrations. PMID- 26119487 TI - The global challenge of new classes of antibacterial agents: an industry perspective. AB - With rising antibiotic resistance and the fear of returning to the pre-penicillin era, incentives are being provided for developing novel antibiotics. The hurdles faced by antibiotic developers include the difficulty in discovering novel chemicals that have selectivity and the increased regulatory scrutiny for safety and efficacy. Furthermore, the demonstration of superiority is essential in order to rationalize pricing and to assure a return on investment. Suggestions are provided to overcome each of these hurdles in order to prevent the antibiotic pipeline from running dry. PMID- 26119488 TI - Treatment of bacterial infections in obese adult patients: how to appropriately manage antimicrobial dosage. AB - Obese patients may require bigger initial antimicrobial doses but the optimal approach to maintenance dose selection is limited. Key pharmacokinetic system parameters are higher in obese patients but often not proportional to total body weight (TBW). Fixed-dose selection risks under exposure while TBW-based dosing risks over exposure in obese patients. Alternate body size descriptors limit overdosing in obesity that is vital for antimicrobials with a narrow therapeutic index. Maintenance dose calculation of antimicrobials in obese patients is challenging in the absence of therapeutic drug monitoring. Approaches to antimicrobial dose selection in obesity based on estimated kidney function serves as a lesser but clinically applicable alternative. PMID- 26119489 TI - The use of probiotics in aquaculture. AB - This study aims to present comprehensive notes for the use of probiotics in aquaculture. Probiotics have been proven to be positive promoters of aquatic animal growth, survival and health. In aquaculture, intestines, gills, the skin mucus of aquatic animals, and habitats or even culture collections and commercial products, can be sources for acquiring appropriate probiotics, which have been identified as bacteria (Gram-positive and Gram-negative) and nonbacteria (bacteriophages, microalgae and yeasts). While a bacterium is a pathogen to one aquatic animal, it can bring benefits to another fish species; a screening process plays a significant role in making a probiotic species specific. The administration of probiotics varies from oral/water routine to feed additives, of which the latter is commonly used in aquaculture. Probiotic applications can be either mono or multiple strains, or even in combination with prebiotic, immunostimulants such as synbiotics and synbiotism, and in live or dead forms. Encapsulating probiotics with live feed is a suitable approach to convey probiotics to aquatic animals. Dosage and duration of time are significant factors in providing desired results. Several modes of actions of probiotics are presented, while some others are not fully understood. Suggestions for further studies on the effects of probiotics in aquaculture are proposed. PMID- 26119490 TI - Maximum ingested food size in captive anthropoids. AB - OBJECTIVES: Maximum ingested food size (Vb ) is an empirically tested performance variable that can shed light on feeding energetics and adaptation in the masticatory system. Until now, this variable had been tested in strepsirrhines alone among primates. Here, we present the first data on Vb in a broad sample of anthropoid primates and describe scaling patterns. MATERIALS AND METHODS: Vb data on anthropoids were collected under captive conditions at the Philadelphia Zoo and compared with published data on strepsirrhines. Data on Vb were scaled against individual body mass and were compared with experimentally determined toughness and stiffness values for the test foods. RESULTS: Unlike in strepsirrhines, where essentially Vb scales isometrically with body mass, Vb in anthropoids scales with negative allometry. There is a significant effect of food material properties on Vb , although bite size in anthropoids varies less based on food properties than in strepsirrhines. Large folivorous strepsirrhines follow the anthropoid trend in bite size scaling, but large frugivorous ones take especially large bites. DISCUSSION: Negative scaling of bite size in the anthropoids sampled could be due to reduced adaptation for gape. Some early anthropoids likely evolved adaptations for maximizing mechanical advantage and fatigue resistance in the chewing muscles, resulting in reduced gape. This might have channeled them toward smaller bites of more-resistant foods and away from taking large bites. This might also be the case for some folivorous strepsirrhines. PMID- 26119491 TI - Hydrophobically Modified Halloysite Nanotubes as Reverse Micelles for Water-in Oil Emulsion. AB - An easy strategy to obtain inorganic reverse micelles based on halloysite nanotubes (HNTs) and alkyltrimethylammonium bromides has been developed. The selective modification of the HNTs external surface with cationic surfactants endows to generate tubular nanostructures with a hydrophobic shell and a hydrophilic cavity. The influence of the surfactants alkyl chain on the HNTs functionalization degree has been investigated. The dynamic behavior of the surfactant/HNT hybrids in solvents with variable polarity has been correlated to their affinity toward hydrophobic media explored through partition experiments. The water-in-oil emulsion is able to solubilize copper sulfate, proving the incorporation and the loading of hydrophilic compounds into the HNTs lumen. Here we have fabricated ecocompatible reverse micelles with tunable hydrophobic/hydrophilic interface that might be suitable for industrial and biological applications as well as for selective organic synthesis. PMID- 26119492 TI - A novel cholinergic epithelial cell with chemosensory traits in the murine conjunctiva. AB - We recently identified a specialized cholinergic cell type in tracheal and urethral epithelium that utilizes molecules of the canonical taste transduction signaling cascade to sense potentially harmful substances in the luminal content. Upon stimulation, this cell initiates protective reflexes. Assuming a sentinel role of such cells at mucosal surfaces exposed to bacteria, we hypothesized their occurrence also in ocular mucosal surfaces. Utilizing a mouse strain expressing eGFP under the promoter of the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT-eGFP), we observed a cholinergic cell in the murine conjunctiva. Singular cholinergic cells reaching the epithelial surface with slender processes were detected in fornical, but neither in bulbar nor palpebral epithelia. These cells were found neither in the lacrimal canaliculi, nor in the lacrimal sac and the nasolacrimal duct. Cholinergic conjunctival epithelial cells were immunoreactive for components of the canonical taste transduction signaling cascade, i.e. alpha-gustducin, phospholipase Cbeta2 and the monovalent cation channel TRPM5. Calcitonin gene-related peptide- and substance P-immunoreactive sensory nerve fibers were observed extending into the conjunctival epithelium approaching slender ChAT-eGFP-positive cells. In addition, we noted both ChAT eGFP expression and alpha-gustducin-immunoreactivity, albeit in different cell populations, in occasionally occurring lymphoid follicles of the nictitating membrane. The data show a previously unidentified cholinergic cell in murine conjunctiva with chemosensory traits that presumably utilizes acetylcholine for signaling. In analogy to similar cells described in the respiratory and urethral epithelium, it might serve to detect bacterial products and to initiate protective reflexes. PMID- 26119494 TI - Marine protist diversity in European coastal waters and sediments as revealed by high-throughput sequencing. AB - Although protists are critical components of marine ecosystems, they are still poorly characterized. Here we analysed the taxonomic diversity of planktonic and benthic protist communities collected in six distant European coastal sites. Environmental deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) from three size fractions (pico-, nano- and micro/mesoplankton), as well as from dissolved DNA and surface sediments were used as templates for tag pyrosequencing of the V4 region of the 18S ribosomal DNA. Beta-diversity analyses split the protist community structure into three main clusters: picoplankton-nanoplankton-dissolved DNA, micro/mesoplankton and sediments. Within each cluster, protist communities from the same site and time clustered together, while communities from the same site but different seasons were unrelated. Both DNA and RNA-based surveys provided similar relative abundances for most class-level taxonomic groups. Yet, particular groups were overrepresented in one of the two templates, such as marine alveolates (MALV)-I and MALV-II that were much more abundant in DNA surveys. Overall, the groups displaying the highest relative contribution were Dinophyceae, Diatomea, Ciliophora and Acantharia. Also, well represented were Mamiellophyceae, Cryptomonadales, marine alveolates and marine stramenopiles in the picoplankton, and Monadofilosa and basal Fungi in sediments. Our extensive and systematic sequencing of geographically separated sites provides the most comprehensive molecular description of coastal marine protist diversity to date. PMID- 26119495 TI - Serum Free Light Chain Assessment Early After Stem Cell Transplantation as a Prognostic Factor in Multiple Myeloma. AB - BACKGROUND: Multiple myeloma is an incurable cancer commonly treated with stem cell transplantation (SCT). Response is traditionally evaluated 100 days after SCT, both to allow for hematopoietic reconstitution and due to immunoglobulins' long half-lives. Free light chains (FLC) have significantly shorter half-lives and may provide evidence of response or treatment failure earlier after SCT. PATIENTS AND METHODS: We retrospectively studied 83 consecutive patients with multiple myeloma who underwent SCT and found 69 who had FLC measured 30 or 60 days after SCT. Using conventional FLC response criteria, we considered a patient to be at high risk for early relapse if he or she failed to experience a partial response by day 30 or 60. RESULTS: After a median overall follow-up of only 335 days, these high-risk patients had significantly shorter progression-free survival (median, 98 vs. 335 days, P = .001) and overall survival (366 days vs. median not reached, P = .016). CONCLUSION: Early FLC assessment either 1 or 2 months after SCT using standard FLC response criteria was able to identify a subset of patients at high risk of early relapse, and these patients may benefit from earlier interventions. PMID- 26119496 TI - Probing the nature and resistance of the molecule-electrode contact in SAM-based junctions. AB - It is challenging to quantify the contact resistance and to determine the nature of the molecule-electrode contacts in molecular two-terminal junctions. Here we show that potentiodynamic and temperature dependent impedance measurements give insights into the nature of the SAM-electrode interface and other bottlenecks of charge transport (the capacitance of the SAM (C(SAM)) and the resistance of the SAM (R(SAM))), unlike DC methods, independently of each other. We found that the resistance of the top-electrode-SAM contact for junctions with the form of Ag(TS) SC(n)//GaO(x)/EGaIn with n = 10, 12, 14, 16 or 18 is bias and temperature independent and hence Ohmic (non-rectifying) in nature, and is orders of magnitude smaller than R(SAM). The C(SAM) and R(SAM) are independent of the temperature, indicating that the mechanism of charge transport in these SAM-based junctions is coherent tunneling and the charge carrier trapping at the interfaces is negligible. PMID- 26119497 TI - Biliary amphotericin B pharmacokinetics and pharmacodynamics in critically ill liver transplant recipients receiving treatment with amphotericin B lipid formulations. AB - Fungal cholangitis is a potentially life-threatening condition. As amphotericin B (AmB) has a broad antimycotic spectrum, in this study its biliary penetration and activity was determined in two patients treated with liposomal AmB (L-AmB) and in one patient receiving AmB colloidal dispersion (ABCD). Biliary and plasma AmB levels were quantified by high-performance liquid chromatography after purification by solid-phase extraction. For assessment of biliary AmB activity, isolates of Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei were incubated in porcine bile at AmB concentrations of 0.025-5.00 mg/L. In addition, patient bile samples retrieved for AmB quantification were inoculated with the same Candida strains. Biliary AmB concentrations were lower and displayed a slower rise and decline than plasma levels. The highest penetration ratio, as expressed by the ratio between the area under the AmB concentration-time curve in bile and plasma (liberated AmB) over the sampling period (AUC0-n bile/AUC0-n LI plasma), was 0.28. Proliferation of C. albicans and C. tropicalis in bile was similar to that in culture medium, whereas growth of C. glabrata was diminished and proliferation of C. krusei was absent in bile. In comparison with culture medium, AmB activity decreased in spiked porcine bile. In all but one patient bile sample, fungal growth was delayed or lacking even when AmB was not detectable. However, no fungicidal effect was observed in patient bile at AmB concentrations up to 1.28 mg/L. Thus, a reliable response of fungal cholangitis to treatment with L-AmB or ABCD cannot be anticipated. PMID- 26119499 TI - Energy Storage Materials from Nature through Nanotechnology: A Sustainable Route from Reed Plants to a Silicon Anode for Lithium-Ion Batteries. AB - Silicon is an attractive anode material in energy storage devices, as it has a ten times higher theoretical capacity than its state-of-art carbonaceous counterpart. However, the common process to synthesize silicon nanostructured electrodes is complex, costly, and energy-intensive. Three-dimensional (3D) porous silicon-based anode materials have been fabricated from natural reed leaves by calcination and magnesiothermic reduction. This sustainable and highly abundant silica source allows for facile production of 3D porous silicon with very good electrochemical performance. The obtained silicon anode retains the 3D hierarchical architecture of the reed leaf. Impurity leaching and gas release during the fabrication process leads to an interconnected porosity and the reductive treatment to an inside carbon coating. Such anodes show a remarkable Li ion storage performance: even after 4000 cycles and at a rate of 10 C, a specific capacity of 420 mA h g(-1) is achieved. PMID- 26119498 TI - A second component of the SltA-dependent cation tolerance pathway in Aspergillus nidulans. AB - The transcriptional response to alkali metal cation stress is mediated by the zinc finger transcription factor SltA in Aspergillus nidulans and probably in other fungi of the pezizomycotina subphylum. A second component of this pathway has been identified and characterized. SltB is a 1272 amino acid protein with at least two putative functional domains, a pseudo-kinase and a serine-endoprotease, involved in signaling to the transcription factor SltA. Absence of SltB activity results in nearly identical phenotypes to those observed for a null sltA mutant. Hypersensitivity to a variety of monovalent and divalent cations, and to medium alkalinization are among the phenotypes exhibited by a null sltB mutant. Calcium homeostasis is an exception and this cation improves growth of sltDelta mutants. Moreover, loss of kinase HalA in conjunction with loss-of-function sltA or sltB mutations leads to pronounced calcium auxotrophy. sltA sltB double null mutants display a cation stress sensitive phenotype indistinguishable from that of single slt mutants showing the close functional relationship between these two proteins. This functional relationship is reinforced by the fact that numerous mutations in both slt loci can be isolated as suppressors of poor colonial growth resulting from certain null vps (vacuolar protein sorting) mutations. In addition to allowing identification of sltB, our sltB missense mutations enabled prediction of functional regions in the SltB protein. Although the relationship between the Slt and Vps pathways remains enigmatic, absence of SltB, like that of SltA, leads to vacuolar hypertrophy. Importantly, the phenotypes of selected sltA and sltB mutations demonstrate that suppression of null vps mutations is not dependent on the inability to tolerate cation stress. Thus a specific role for both SltA and SltB in the VPS pathway seems likely. Finally, it is noteworthy that SltA and SltB have a similar, limited phylogenetic distribution, being restricted to the pezizomycotina subphylum. The relevance of the Slt regulatory pathway to cell structure, intracellular trafficking and cation homeostasis and its restricted phylogenetic distribution makes this pathway of general interest for future investigation and as a source of targets for antifungal drugs. PMID- 26119500 TI - Discovery of a 6-(pyridin-3-yl)benzo[d]thiazole template for optimization of hedgehog and PI3K/AKT/mTOR dual inhibitors. AB - Vismodegib is the first FDA approved cancer therapy based on inhibition of aberrant hedgehog signaling. Like most cancer therapies, vismodegib suffered from resistance, even during clinical development. Numerous reports demonstrated that simultaneous blockage of hedgehog and PI3K/AKT/mTOR pathways resulted in significantly superior outcomes compared with single agent alone in a number of animal disease models. The dual hedgehog and PI3K/AKT/mTOR inhibition represented a promising approach not only to overcoming the resistance but also to delaying its onset. Here we report a series of compounds based on a 6-(pyridin-3 yl)benzo[d]thiazole template which have demonstrated significant inhibition of both hedgehog and PI3K/AKT/mTOR signaling pathways. This new scaffold can serve as a lead for further optimization. PMID- 26119501 TI - Structure-activity relationships of furazano[3,4-b]pyrazines as mitochondrial uncouplers. AB - Chemical mitochondrial uncouplers are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. These uncouplers have potential for the treatment of diseases such as obesity, Parkinson's disease, and aging. We have previously identified a novel mitochondrial protonophore, named BAM15, which stimulates mitochondrial respiration across a broad dosing range compared to carbonyl cyanide p trifluoromethoxyphenylhydrazone (FCCP). Herein, we report our investigations on the structure-activity relationship profile of BAM15. Our studies demonstrate the importance of the furazan, pyrazine, and aniline rings as well as pKa in maintaining its effective protonophore activity. PMID- 26119502 TI - Salting-out and salting-in: competitive effects of salt on the aggregation behavior of soy protein particles and their emulsifying properties. AB - Emulsions stabilized by protein particles have gained increasing research attention due to their combined advantages of biocompatibility and superior stability. In this study, colloidal particles consisting of soy protein isolates (SPIs) prepared through a heat-treatment procedure are used to make oil-in-water emulsions at a protein concentration of 10 g L(-1) and a pH of 5.91. We investigate parallelly the effects of NaCl on the stability and rheological properties of the particle suspensions and their stabilized emulsions at salt concentrations of 0, 100 and 400 mM. The aggregation behavior of the particles is strongly dependent on the NaCl concentration, showing signs of sedimentation at low NaCl concentration (100 mM) but redispersion again at high NaCl concentration (400 mM). The extensive particle aggregation is beneficial to the formation of a continuous interfacial film for the emulsions, and hence results in a remarkable increase of creaming stability and interfacial viscoelastic moduli. The results can be explained in terms of two competitive effects of NaCl: salting-out and salting-in, which are attributed to complex electrostatic interactions between the particles as a function of NaCl concentration. The delicate balance between salting-out and salting-in provides an interesting insight into the nature of underlying protein particle interactions in aqueous suspensions and a possible mechanism for tailoring their emulsifying properties via salt effects. PMID- 26119503 TI - Brief report: Moving prevention into schools: The impact of a trauma-informed school-based intervention. AB - Adolescents in disadvantaged communities have high rates of exposure to stress and trauma, which can negatively impact emotion regulation and executive functioning, increasing likelihood of school problems. This pilot study evaluated RAP Club, a 12-session school-based trauma-informed group intervention co facilitated by a mental health counselor and young adult community member that utilizes evidence-based cognitive-behavioral and mindfulness strategies. Seventh and eighth graders at two urban public schools serving low-income communities were assigned to receive RAP Club (n = 29) or regular school programming (n = 20). RAP Club improved teacher-rated emotion regulation, social and academic competence, classroom behavior, and discipline. Higher program dose predicted improvements in several teacher-rated outcomes. Student self-report outcomes, however, did not vary by study group or dose. Even students with low baseline depression showed improvement in teacher-rated outcomes following program participation, supporting a model of universal program delivery to all students. Findings suggest RAP Club merits further study. PMID- 26119504 TI - Development and validation of an UPLC-MS/MS method for the quantification of tamoxifen and its main metabolites in human scalp hair. AB - The aim of this study was to validate an earlier developed high-performance highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method for quantification of tamoxifen and its three main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl tamoxifen) in scalp hair. This non-invasive method might, by segmental analysis of hair, be useful in the determination of the concentration of drugs and its metabolites over time, which can be used to study a wide variety of clinical relevant questions. Hair samples (150-300 hair strands, cut as close to the scalp as possible from the posterior vertex region of the head) were collected from female patients taking tamoxifen 20mg daily (n=19). The analytes were extracted using a liquid-liquid extraction procedure with carbonate buffer at pH 8.8 and a mixture of n-hexane/isopropranol method, followed by UPLC-MS/MS chromatography, based on an earlier validated method. The calibration curves were linear in the range of 1.00-200 pmol for tamoxifen and N-desmethyl-tamoxifen, with lower limit of quantitation of 1.00 pmol and 0.100-20.0 pmol with lower limit of quantitation of 0.100 pmol for endoxifen and 4-hydroxy-tamoxifen. Assay performance was fair with a within-run and between-run variability less than 9.24 at the three quality control samples and less than 15.7 for the lower limit of quantitation. Importantly, a steep linear decline was observed from distal to proximal hair segments. Probably, this is due to UV exposure as we showed degradation of tamoxifen and its metabolites after exposure to UV-light. Furthermore, higher concentrations of tamoxifen were found in black hair samples compared to blond and brown hair samples. We conclude that measurement of the concentration of tamoxifen and its main metabolites in hair is possible, with the selective, sensitive, accurate and precise UPLC-MS/MS method. However, for tamoxifen, it seems not possible to determine exposure over time with segmental analysis of hair, probably largely due to the effect of UV irradiation. Further research should therefore focus on quantification of other anticancer drugs, in segmented scalp hair, that are less sensitive to UV irradiation. PMID- 26119505 TI - Simultaneous determination of leucine, isoleucine and valine in Beagle dog plasma by HPLC-MS/MS and its application to a pharmacokinetic study. AB - Leucine (Leu), isoleucine (Ile) and valine (Val) are three branched-chain amino acids (BCAAs), which have been widely used as dietary supplements for professional athletes and patients with liver failure or catabolic diseases. To date, no pharmacokinetic studies of BCAAs in vivo useful for the assessment of clinical effect following daily intake has been reported. Thus in this study, an HPLC-MS/MS method for simultaneous determination of Leu, Ile and Val in Beagle dog plasma using homoarginine as the internal standard was developed and validated in terms of specificity, linearity, precision, accuracy, and stability. This assay method was then applied to a pharmacokinetic study of BCAAs in dogs following oral administration of 0.25 g/kg and 0.50 g/kg BCAAs. The HPLC-MS/MS method was found to be sensitive and reproducible for quantification of BCAAs in dog plasma and successfully applied to the pharmacokinetic study. All these BCAAs were well absorbed with a substantial increase in the plasma concentration after a baseline modification. No statistical significance was identified in different gender group and no drug accumulation was observed following multiple doses. PMID- 26119507 TI - Improving photocatalytic performance of ZnO via synergistic effects of Ag nanoparticles and graphene quantum dots. AB - Herein, we reported a simple and "green" method for preparing the ternary photocatalyst Ag-graphene quantum dots (GQDs)-ZnO. In this method, an aqueous solution of GQDs not only acted as a substituent for the organic solvent for preparing the ZnO precursor but was also used as a reducing agent for the in situ synthesis of Ag nanoparticles (NPs). X-ray diffraction analysis and scanning electron microscopy were employed to confirm the effects of the GQD solution as a solvent on the ZnO structure. Transmission electron microscopy confirmed the synthesis of Ag NPs in the GQD solution as well as the formation of close interconnections between them. Furthermore, photocatalytic tests involving the degradation of Rhodamine B showed that the synthesized ternary photocatalyst displayed excellent visible-light photocatalytic activity, which was much higher than that of pure ZnO and binary photocatalysts such as Ag-ZnO and GQDs-ZnO. We believe that this method will lead to the "green" synthesis of hybrid metal/carbon/semiconductor photocatalysts with higher photocatalytic activities. PMID- 26119506 TI - Pivotal Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in Inflammatory Pulmonary Diseases. AB - Mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2) is exclusively regulated by p38 MAPK in vivo. Upon activation of p38 MAPK, MK2 binds with p38 MAPK, leading to phosphorylation of TTP, Hsp27, Akt, and Cdc25 that are involved in regulation of various essential cellular functions. In this review, we discuss current knowledge about molecular mechanisms of MK2 in regulation of TNF-alpha production, NADPH oxidase activation, neutrophil migration, and DNA damage-induced cell cycle arrest which are involved in the molecular pathogenesis of acute lung injury, pulmonary fibrosis, and non-small-cell lung cancer. Collectively current and emerging new information indicate that developing MK2 inhibitors and blocking MK2-mediated signal pathways are potential therapeutic strategies for treatment of inflammatory and fibrotic lung diseases and lung cancer. PMID- 26119509 TI - Contrasting responses to novelty by wild and captive orangutans. AB - Several studies have suggested that wild primates tend to behave with caution toward novelty, whereas captive primates are thought to be less neophobic, more exploratory, and more innovative. However, few studies have systematically compared captive and wild individuals of the same species to document this "captivity effect" in greater detail. Here we report the responses of both wild and captive orangutans to the same novel items. Novel objects were presented to wild orangutans on multiple platforms placed in the canopy and equipped with motion-triggered video cameras. The same and different novel objects were also presented to orangutans in two different zoos. The results demonstrate extreme conservatism in both Bornean and Sumatran wild orangutans, who gradually approached the novel objects more closely as they became familiar, but avoided contact with them over many encounters spanning several months. Their zoo-living conspecifics, in contrast, showed an immediate neophilic response. Our results thus confirm the "captivity effect." To the various ecological explanations proposed before (reduced risk and increased time and energy balance for captive individuals relative to wild ones), we add the social information hypothesis, which claims that individuals confronted with novel items preferentially rely on social cues whenever possible. This caution toward novelty disappears when human caretakers become additional role models and can also be eroded when all experience with novelty is positive. PMID- 26119511 TI - Three-dimensional imaging of vitiligo. PMID- 26119512 TI - An Ultrahigh Precision, High-Frequency Dissolved Inorganic Carbon Analyzer Based on Dual Isotope Dilution and Cavity Ring-Down Spectroscopy. AB - We present a novel method for continuous and automated shipboard measurements of dissolved inorganic carbon concentration ([DIC]) in surface water. The method is based on dual isotope dilution and cavity ring-down spectroscopy (DID-CRDS). In this method, seawater is continuously sampled and mixed with a flow of NaH(13)CO3 solution that is also enriched in deuterated water (the spike). The isotopic composition of CO2 (delta(13)C(spiked_sample)) derived from the DIC in the mixture, and the D/H ratio of the mixed water (deltaD(spiked_sample)), are measured by CRDS analyzers. The D/H of the water in the mixture allows accurate estimates of the mixing ratio of the sample and the spike. [DIC] of the sample is then calculated from the mixing ratio, [DI(13)C] of the spike, and delta(13)C(spiked_sample). In the laboratory, the precision of the method is <0.02% (+/-0.4 MUmol kg(-1) when [DIC] = 2000 MUmol kg(-1)). A shipboard test was conducted in the Delaware Bay and Estuary. For 2 min average [DIC], a precision of <0.03% was achieved. Measurements from the DID-CRDS showed good agreement with independent measurements of discrete samples using the well-established coulometric method (mean difference = -1.14 +/- 1.68 MUmol kg(-1)), and the nondispersive infrared(NDIR)-based methods (mean difference = -0.9 +/- 4.73 MUmol kg(-1)). PMID- 26119510 TI - Biomechanical Screening of Cell Therapies for Vocal Fold Scar. AB - Candidate cell sources for vocal fold scar treatment include mesenchymal stromal cells from bone marrow (BM-MSC) and adipose tissue (AT-MSC). Mechanosensitivity of MSC can alter highly relevant aspects of their behavior, yet virtually nothing is known about how MSC might respond to the dynamic mechanical environment of the larynx. Our objective was to evaluate MSC as a potential cell source for vocal fold tissue engineering in a mechanically relevant context. A vibratory strain bioreactor and cDNA microarray were used to evaluate the similarity of AT-MSC and BM-MSC to the native cell source, vocal fold fibroblasts (VFF). Posterior probabilities for each of the microarray transcripts fitting into specific expression patterns were calculated, and the data were analyzed for Gene Ontology (GO) enrichment. Significant wound healing and cell differentiation GO terms are reported. In addition, proliferation and apoptosis were evaluated with immunohistochemistry. Results revealed that VFF shared more GO terms related to epithelial development, extracellular matrix (ECM) remodeling, growth factor activity, and immune response with BM-MSC than with AT-MSC. Similarity in glycosaminoglycan and proteoglycan activity dominated the ECM analysis. Analysis of GO terms relating to MSC differentiation toward osteogenic, adipogenic, and chondrogenic lineages revealed that BM-MSC expressed fewer osteogenesis GO terms in the vibrated and scaffold-only conditions compared to polystyrene. We did not evaluate if vibrated BM-MSC recover osteogenic expression markers when returned to polystyrene culture. Immunostaining for Ki67 and cleaved caspase 3 did not vary with cell type or mechanical condition. We conclude that VFF may have a more similar wound healing capacity to BM-MSC than to AT-MSC in response to short-term vibratory strain. Furthermore, BM-MSC appear to lose osteogenic potential in the vibrated and scaffold-only conditions compared to polystyrene, potentially attenuating the risk of osteogenesis for in vivo applications. PMID- 26119513 TI - Double transcatheter valve-in-valve therapy: A viable alternative for high-risk patients. PMID- 26119514 TI - Pig model gets to the dogma. PMID- 26119515 TI - Number of pigs born alive in parity 1 sows associated with lifetime performance and removal hazard in high- or low-performing herds in Japan. AB - Reproductive performance, lifetime performance and removal hazard were studied in commercial herds in order to detect prolific sows at an early-stage. Reproductive performance measurements that we assessed were number of pigs born alive (PBA) per litter, weaning-to-first-mating interval and farrowing rate (FR). Lifetime performance measurements included lifetime average PBA and lifetime average nonproductive days. In total, 213,514 parity records and 47,024 lifetime records of 96 herds were included. Sows were categorized into three groups based on the lower and upper 25th percentiles of PBA in parity 1:8 pigs or fewer, 9-12 pigs and 13 pigs or more. The herds were classified into high- and low-performing herds on the basis of the 50th percentile of pigs weaned per mated female per year. To compare the measurements between the sow groups taking account for the herd productivity groups, multivariate and single response models were applied to reproductive performance from first-farrowing and lifetime performance, respectively. A hazard model was fitted to survival data. Sows having 13 or more PBA in parity 1 had 1.0-1.4 more PBA per litter in all subsequent parities (P<0.05), 1.2-1.5% higher FR in parities 2-4 (P<0.05) and 3.4-3.7 higher lifetime average PBA than sows having 8 or lower PBA (P<0.01). However, there were no differences between the sow groups for weaning-to-first-mating interval in any parity (P>0.05). There were two-way interactions between the sow and herd groups for FR in parity 2 (P=0.01) and lifetime average nonproductive days (P=0.046). In low-performing herds, sows having 13 or more PBA in parity 1 had 3.9% higher FR at their next farrowings than sows having 8 or fewer PBA (P<0.05), although no such difference was found for high-performing herds (P>0.05). Sows in the low performing herds with 13 or more PBA in parity 1 also had 2.3 fewer lifetime average nonproductive days than sows having 8 or fewer PBA (P=0.01), although again no similar difference was found for high-performing herds (P=0.96). The removal hazards for sows having 13 or more PBA in parity 1 were lower than those for sows having 8 or fewer PBA (P<0.01), with no difference in hazards between the herd groups (P=0.62). In conclusion, PBA in parity 1 may help predict a prolific sow or low PBA sow. PMID- 26119516 TI - Primary angle-closure glaucoma: an update. AB - Primary angle-closure glaucoma is potentially a devastating disease, responsible for half of glaucoma-related blindness worldwide. Angle closure is characterized by appositional approximation or contact between the iris and trabecular meshwork. It tends to develop in eyes with shallow anterior chambers, anteriorly positioned or pushed lenses, and angle crowding. Risk of primary angle-closure glaucoma is high among women, the elderly and the hyperopic, and it is most prevalent in Asia. Investigation into genetic mechanisms of glaucoma inheritance is underway. Diagnosis relies on gonioscopy and may be aided by anterior segment optical coherence tomography and ultrasound biomicroscopy. Treatment is designed to control intraocular pressure while monitoring changes to the angle and optic nerve head. Treatment typically begins with medical management through pressure reducing topical medications. Peripheral iridotomy is often performed to alleviate pupillary block, while laser iridoplasty has been found effective for mechanisms of closure other than pupillary block, such as plateau iris syndrome. Phacoemulsification, with or without goniosynechialysis, both in eyes with existing cataracts and in those with clear lenses, is thus far a viable treatment alternative. Long-term research currently underway will examine its efficacy in cases of angle closure in early stages of the disease. Endoscopic cyclophotocoagulation is another treatment option, which can be combined with cataract surgery. Trabeculectomy remains effective therapy for more advanced cases. PMID- 26119517 TI - Inhibition of neuronal nitric oxide synthase improves microregional O2 balance in cerebral ischemia-reperfusion. AB - Objectives Return of regional cerebral blood flow (rCBF) in focal cerebral ischaemia may not ensure proper distribution of blood flow to meet metabolic demand. This study was performed to determine how inhibition of neuronal nitric oxide synthase (NOS) during ischaemia-reperfusion would affect microregional O2 supply/consumption balances and their variation. Methods Twenty minutes before middle cerebral artery (MCA) occlusion, a NOS inhibitor 7-nitroindazole (7-NI) 50 mg/kg ip (7-NI group) or vehicle (control group) was administered. At 1 hour of ischaemia and 2 hours of reperfusion, rCBF, the size of cortical infarct and arteriolar and venular O2 saturations (20-60 MUm in diameter) using cryomicrospectrophotometry were determined. Results Ischaemia-reperfusion decreased the average venular O2 saturation and the ratio of O2 supply/consumption. But, 7-NI treatment improved the average O2 supply/consumption ratio and venular O2 saturation (57.6 +/- 1.3 vs 52.0 +/- 3.8%) in ischaemia-reperfusion. The heterogeneity of venular O2 saturations reported as coefficient of variation (CV = 100 * SD/mean) was much smaller in the 7-NI than the control group (8.8 vs 15.5). The number of veins with low O2 saturation ( < 50%) was also smaller with the 7-NI (4/70) than the control group (18/70). The size of cortical infarct was smaller with 7-NI treatment. Discussion Our data suggest that inhibition of neuronal NOS by 7-NI improved microregional O2 balance in the ischaemic-reperfused cortex (IR-C). The improvement in microregional O2 balance could be one of the contributing factors to the reduced size of cortical infarct. PMID- 26119518 TI - Early Medical Treatment of Children and Adolescents With Gender Dysphoria: An Empirical Ethical Study. AB - PURPOSE: The Endocrine Society and the World Professional Association for Transgender Health published guidelines for the treatment of adolescents with gender dysphoria (GD). The guidelines recommend the use of gonadotropin-releasing hormone agonists in adolescence to suppress puberty. However, in actual practice, no consensus exists whether to use these early medical interventions. The aim of this study was to explicate the considerations of proponents and opponents of puberty suppression in GD to move forward the ethical debate. METHODS: Qualitative study (semi-structured interviews and open-ended questionnaires) to identify considerations of proponents and opponents of early treatment (pediatric endocrinologists, psychologists, psychiatrists, ethicists) of 17 treatment teams worldwide. RESULTS: Seven themes give rise to different, and even opposing, views on treatment: (1) the (non-)availability of an explanatory model for GD; (2) the nature of GD (normal variation, social construct or [mental] illness); (3) the role of physiological puberty in developing gender identity; (4) the role of comorbidity; (5) possible physical or psychological effects of (refraining from) early medical interventions; (6) child competence and decision making authority; and (7) the role of social context how GD is perceived. Strikingly, the guidelines are debated both for being too liberal and for being too limiting. Nevertheless, many treatment teams using the guidelines are exploring the possibility of lowering the current age limits. CONCLUSIONS: As long as debate remains on these seven themes and only limited long-term data are available, there will be no consensus on treatment. Therefore, more systematic interdisciplinary and (worldwide) multicenter research is required. PMID- 26119519 TI - Nanocomposite semi-solid redox ionic liquid electrolytes with enhanced charge transport capabilities for dye-sensitized solar cells. AB - The ability of Pt nanostructures to induce the splitting of the I?I bond in iodine (triiodide) molecules is explored here to enhance electron transfer in the iodine/iodide redox couple. Following the dispersal of Pt nanoparticles at 2 % (weight) level, charge transport was accelerated in triiodide/iodide-containing 1,3-dialkylimidazolium room-temperature ionic liquid. If both Pt nanoparticles and multi-walled carbon nanotubes were introduced into the ionic-liquid-based system, a solid-type (nonfluid) electrolyte was obtained. By using solid-state voltammetric (both sandwich-type and microelectrode-based) methodology, the apparent diffusion coefficients for charge transport increased to approximately 1*10(-6) cm(2) s(-1) upon the incorporation of the carbon-nanotube-supported iodine-modified Pt nanostructures. A dye-sensitized solar cell comprising TiO2 covered with a heteroleptic Ru(II) -type sensitizer (dye) and the semisolid triiodide/iodide ionic liquid electrolyte admixed with carbon-nanotube-supported Pt nanostructures yielded somewhat higher power conversion efficiencies (up to 7.9 % under standard reporting conditions) than those of the analogous Pt-free system. PMID- 26119520 TI - Anticholinergic Accumulation: A Slumbering Interaction between Drugs and Food Supplements. AB - Many compounds display anticholinergic effects which might give rise to cognitive impairment and even delirium. These side effects are caused by their ability to bind to muscarinic receptors in our brain. Especially with combination of compounds, these serious effects are seen. This phenomenon, known as anticholinergic accumulation, is especially seen in the elderly. A classification of drugs for anticholinergic side effects has been made based on clinical observations, the ACB score. Here, we aimed to substantiate this classification by comparing the affinity of numerous drugs for the muscarinic receptors to the ACB score. Additionally, a number of supplements were screened. The affinity of the compounds was determined by their ability to displace the radioligand [(3)H]pirenzepine of the muscarinic receptor induced by these compounds. Our results show that the affinity of a compound for the muscarinic receptors correlated with its ACB score. Also food supplements appeared to bind to these muscarinic receptors. Moreover, several drug-drug, supplement-supplement and supplement-drug combinations had an affinity that is higher than the affinity of single compounds. This explains the phenomenon of anticholinergic accumulation. In conclusion, care should be taken to drug-drug and supplement-drug combinations with respect to anticholinergic accumulation. PMID- 26119521 TI - Mechanisms underlying AQP4 accumulation in astrocyte endfeet. AB - The brain-blood interface holds the key to our understanding of how cerebral blood flow is regulated and how water and solutes are exchanged between blood and brain. The highly specialized astrocytic membranes that enwrap brain microvessels are salient constituents of the brain-blood interface. These endfoot membranes contain a distinct set of molecules that is anchored to the subendothelial basal lamina forming an endfoot-basal lamina junctional complex. Here we explore the mechanisms underpinning the formation of this complex. By use of a tailor made model system we show that endothelial cells promote AQP4 accumulation by exerting an inductive effect through extracellular matrix components such as agrin, as well as through a direct mechanical interaction with the endfoot processes. Through the compounds they secrete, the endothelial cells also increase AQP4 expression. The present data suggest that the highly specialized gliovascular interface is established through inductive processes that include both chemical and mechanical factors. GLIA 2015;63:2073-2091. PMID- 26119522 TI - RAD51 G135C genetic polymorphism and their potential role in gastric cancer induced by Helicobacter pylori infection in Bhutan. AB - In order to evaluate the role of the RAD51 G135C genetic polymorphism on the risk of gastric cancer induced by Helicobacter pylori infection, we determined allele frequency and genotype distribution of this polymorphism in Bhutan--a population documented with high prevalence of gastric cancer and extremely high prevalence of H. pylori infection. The status of RAD51 G135C was examined by restriction fragment length polymorphism analysis of PCR amplified fragments and sequencing. Histological scores were evaluated according to the updated Sydney system. G135C carriers showed significantly higher scores for intestinal metaplasia in the antrum than G135G carriers [mean (median) 0.33 (0) vs. 0.08 (0), P = 0.008]. Higher scores for intestinal metaplasia of G135C carriers compared to those of G135G carriers were also observed in H. pylori-positive patients [0.3 (0) vs. 0.1 (0), P = 0.002] and H. pylori-positive patients with gastritis [0.4 (0) vs. 0.1 (0), P = 0.002] but were not found in H. pylori-negative patients. Our findings revealed that a combination of H. pylori infection and RAD51 G135C genotype of the host showed an increasing score for intestinal metaplasia. Therefore, RAD51 G135C might be the important predictor for gastric cancer of H. pylori-infected patients. PMID- 26119523 TI - Evaluation of systemic absorption and renal effects of topical ophthalmic flurbiprofen and diclofenac in healthy cats. AB - OBJECTIVE: To investigate systemic absorption and renal effects of topically applied ophthalmic flurbiprofen and diclofenac in healthy cats. ANIMALS STUDIED: Twelve domestic shorthair cats. PROCEDURES: Cats were randomly assigned to two treatment groups (n = 6) and administered one drop (approximately 40 MUL) of either flurbiprofen 0.03% or diclofenac 0.1% in both eyes four times daily (6 am, 12 pm, 6 pm, and 12 am) for 14 days. Blood samples were collected on days 0, 4, 8, 14, 16, and 17 and analyzed by liquid chromatography and mass spectrometry for flurbiprofen and diclofenac plasma concentrations. A complete blood count (CBC), serum chemistry, and urinalysis were analyzed at the beginning of the study (Day 0) and at the end of topical drug administration (Day 15). RESULTS: Both drugs demonstrated systemic absorption. Flurbiprofen was detected (mean +/- SD) at day 4 (237 +/- 65 ng/mL), day 8 (396 +/- 91 ng/mL), day 14 (423 +/- 56 ng/mL), day 16 (350 +/- 66 ng/mL), and day 17 (270 +/- 62 ng/mL), and diclofenac was detected (mean +/- SD) at day 4 (130 +/- 44 ng/mL), day 8 (131 +/- 25 ng/mL), day 14 (150 +/- 36 ng/mL), and sporadically on day 16 [corrected]. Flurbiprofen plasma concentration decreased slowly over 48 h after the last dose. No clinically significant abnormalities were noted in the serum blood urea nitrogen, creatinine, or urine specific gravity at the end of topical drug administration compared to the beginning of the study. CONCLUSIONS: Flurbiprofen and diclofenac were systemically absorbed after topical administration four times daily to both eyes of healthy cats. Flurbiprofen reached higher plasma concentrations compared to diclofenac. PMID- 26119524 TI - Autologous stem cell transplantation outcomes in elderly patients with B cell Non Hodgkin Lymphoma. AB - The precise role of autologous haematopoietic stem cell transplantation (ASCT) remains unclear in patients over 60 years of age. There is potential for increased procedural morbidity and mortality, and differences in disease biology that could impact outcomes. We performed a retrospective single-centre review of 81 elderly B-cell Non-Hodgkin Lymphoma patients undergoing ASCT. Five-year overall survival (OS) and progression-free survival (PFS) was 54.7% and 49.1% respectively. Non-relapse mortality (NRM) at 100 days and 1 year was 1.3% and 2.5%, suggesting no major excess compared to younger cohorts. OS and PFS were significantly worse in those over 65 years compared to those aged 60-64 (47.6% vs. 57.7%, P = 0.0437, and 27.6% vs. 57.7%, P = 0.0052 at 5 years). This resulted largely from an increased relapse risk (RR) (53.8% vs. 30.1%, P = 0.0511) rather than excess NRM, and age remained independently significant for PFS on multivariate analyses [Hazard ratio 2.56 (1.35-4.84, P = 0.0052) for PFS and 1.89 (0.99-3.61, P = 0.054) for OS]. Our data adds to the growing body of evidence demonstrating that ASCT can be an effective treatment strategy with an acceptable safety profile in selected elderly patients. Further evaluation of its overall benefit is warranted, however, in those over 65 years of age, as RR appears to be considerably higher. PMID- 26119525 TI - Fluoride as a factor initiating and potentiating inflammation in THP1 differentiated monocytes/macrophages. AB - It is well known that exposure to fluorides lead to an increased ROS production and enhances the inflammatory reactions. Therefore we decided to examine whether cyclooxygenases (particular COX-2) activity and expression may be changed by fluoride in THP1 macrophages and in this way may change the prostanoids biosynthesis. In the present work we demonstrate that fluoride increased concentration of PGE2 and TXA2 in THP1 macrophages. Following exposure to 1-10 MUM NaF, COX-2 protein and COX-2 transcript increased markedly. COX-2 protein up regulation probably is mediated by ROS, produced during fluoride-induced inflammatory reactions. Additional fluoride activates the transcription factor, nuclear factor (NF)-kappaB, which is involved in the up-regulation of COX-2 gene expression. This study indicated that even in small concentrations fluoride changes the amounts and activity of COX-1 and COX-2 enzymes taking part in the initiating and development of inflammatory process. PMID- 26119526 TI - Associations of Angiotensin-Converting Enzyme Insertion/Deletion, Angiotensin II Receptor A1166C, and Endothelial Nitric Oxide Synthase 4b/a Gene Polymorphisms With Pregnancy Hypertensive Disorders: A Meta-Analysis. AB - There have been numerous studies concerning the associations of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D), angiotensin II receptor 1 (AT1R) gene A1166C, and endothelial nitric oxide synthase (eNOS) gene 4b/a polymorphisms with risk of pregnancy hypertensive disorders (PHDs). However, the results are inconsistent. A total of 83 eligible studies (10,354/18,446 cases/controls) were included in this meta-analysis. Pooled odds ratios with corresponding 95% confidence intervals were used to calculate these associations. The effects of ethnicity and types of PHDs were also considered. Results showed significant associations between the ACE gene polymorphism and PHDs in all of the populations except that in Africa. The associations also existed in AT1R, eNOS gene polymorphism and PHDs in part of the gene models in the overall population. These results indicated the ACE gene polymorphism was associated with an increased risk of PHDs, whereas the eNOS and AT1R gene polymorphism only have increased susceptibility to PHDs in part of the gene models. PMID- 26119527 TI - Is molecular alignment an indispensable requirement in the MIA-QSAR method? AB - For a decade, the multivariate image analysis applied to quantitative structure activity relationship (MIA-QSAR) approach has been successfully used in the modeling of several chemical and biological properties of chemical compounds. However, the key pitfall of this method has been its exclusive applicability to congeneric datasets due to the prerequisite of aligning the chemical images with respect to the basic molecular scaffold. The present report aims to explore the use of the 2D-discrete Fourier transform (2D-DFT) as a means of opening way to the modeling, for the first time, of structurally diverse noncongruent chemical images. The usability of the 2D-DFT in QSAR modeling of noncongruent chemical compounds is assessed using a structurally diverse dataset of 100 compounds, with reported inhibitory activity against MCF-7 human breast cancer cell line. An analysis of the statistical parameters of the built regression models validates their robustness and high predictive power. Additionally, a comparison of the results obtained with the 2D-DFT MIA-QSAR approach with those of the DRAGON molecular descriptors is performed, revealing superior performance for the former. This result represents a milestone in the MIA-QSAR context, as it opens way for the possibility of screening for new molecular entities with the desired chemical or therapeutic utility. PMID- 26119528 TI - Vagal Fibers Form Associations With Interstitial Cells of Cajal During Fetal Development. AB - Vagal intramuscular arrays (IMAs) have been shown to form complexes with intramuscular interstitial cells of Cajal (ICC). We tested the hypothesis that associations between vagal nerve endings and ICC arise in fetal development. Intraganglionic laminar endings (IGLEs) and IMAs were identified by applying 1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanineperchlorate (DiI) to vagal nerve trunks and myenteric plexus (MP) and intramuscular (IM) ICC were immunolabeled with antibodies to c-Kit in fetal and early postnatal mice (E16-P7). At E16, c Kit immunoreactive cells were abundant in the primordial smooth muscle, with early ICC networks discernable by E18 and ongoing organization at P1 and P7. The distribution of vagal endings was found to change during the course of development, with significantly more putative IGLEs in the prenatal compared to the postnatal period and less IMAs in the prenatal compared to postnatal period. Associations of ICC with both IGLEs and IMAs were detected as early as E16 and were maintained into postnatal life. These findings suggest that vagal fibers begin to associate with ICC during prenatal development. Future studies will be needed to determine the mechanisms through which vagal endings and ICC interact. PMID- 26119529 TI - Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters. AB - Protein phosphorylation plays a key role in regulating nearly all intracellular biological events. However, poorly developed phospho-specific antibodies and low phosphoprotein abundance make it difficult to study phosphoproteins. Cellular protein phosphorylation data have been obtained using phosphoproteomic approaches, but the detection of low-abundance or fast-cycling phosphorylation sites remains a challenge. Enrichment of phosphoproteins together with phosphopeptides may greatly enhance the spectrum of low-abundance but biologically important phosphoproteins. Previously, we used 14-3-3zeta to selectively enrich for HeLa cell lysate phosphoproteins. However, because 14-3-3 does not isolate phosphoproteins lacking the 14-3-3-binding motif, we looked for other domains that could complementarily enrich for phosphoproteins. We here assessed and characterized the phosphoprotein binding domains Pin1-WW, CHEK2-FHA, and DLG1-GK. Using a strategy based on affinity chromatography, phosphoproteins were collected from the lysates of HeLa cells treated with phosphatase inhibitor or cAMP activator. We identified different subsets of phosphoproteins associated with WW or FHA after calyculin A, okadaic acid, or forskolin treatment. Our Kinase-Oriented Substrate Screening (KiOSS) method, which used phosphoprotein binding domains, showed that WW and FHA are applicable and useful for the identification of novel phospho-substrates for kinases and can therefore be used as biological filters for comprehensive phosphoproteome analysis. PMID- 26119531 TI - My Daughter's Hair Won't Grow. PMID- 26119530 TI - Short-term monocular deprivation alters early components of visual evoked potentials. AB - KEY POINTS: Short-term monocular deprivation in adult humans produces a perceptual boost of the deprived eye reflecting homeostatic plasticity. Visual evoked potentials (VEPs) to transient stimuli change after 150 min of monocular deprivation in adult humans. The amplitude of the C1 component of the VEP at a latency of about 100 ms increases for the deprived eye and decreases for the non deprived eye after deprivation, the two effects being highly negatively correlated. Similarly, the evoked alpha rhythm increases after deprivation for the deprived eye and decreases for the non-deprived eye. The data demonstrate that primary visual cortex excitability is altered by a short period of monocular deprivation, reflecting homeostatic plasticity. ABSTRACT: Very little is known about plasticity in the adult visual cortex. In recent years psychophysical studies have shown that short-term monocular deprivation alters visual perception in adult humans. Specifically, after 150 min of monocular deprivation the deprived eye strongly dominates the dynamics of binocular rivalry, reflecting homeostatic plasticity. Here we investigate the neural mechanisms underlying this form of short-term visual cortical plasticity by measuring visual evoked potentials (VEPs) on the scalp of adult humans during monocular stimulation before and after 150 min of monocular deprivation. We found that monocular deprivation had opposite effects on the amplitude of the earliest component of the VEP (C1) for the deprived and non-deprived eye stimulation. C1 amplitude increased (+66%) for the deprived eye, while it decreased (-29%) for the non deprived eye. Source localization analysis confirmed that the C1 originates in the primary visual cortex. We further report that following monocular deprivation, the amplitude of the peak of the evoked alpha spectrum increased on average by 23% for the deprived eye and decreased on average by 10% for the non deprived eye, indicating a change in cortical excitability. These results indicate that a brief period of monocular deprivation alters interocular balance in the primary visual cortex of adult humans by both boosting the activity of the deprived eye and reducing the activity of the non-deprived eye. This indicates a high level of residual homeostatic plasticity in the adult human primary visual cortex, probably mediated by a change in cortical excitability. PMID- 26119532 TI - Case of generalized eruptive keratoacanthoma with probable Sjogren's syndrome. PMID- 26119533 TI - Association of a genetic marker at the bovine Janus kinase 2 locus (JAK2/RsaI) with milk production traits of four cattle breeds. AB - In addition to the main components of the somatotrophic axis (GH/GHR/IGF-I/IGF IR), great importance in the control of growth and development is also attached to the Janus kinase 2 (JAK2) pathway. Induced by the GH/GHR complex, JAK2 activates signal transducer and activator of transcription 5 (STAT5), and in consequence, may be involved in the regulation of expression of insulin-like growth factor I (IGF-I) in the mammary gland. Silent mutation (rs110298451) has been identified within exon 20 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A total of 904 individuals of four dairy or dual-purpose breeds (Polish Holstein-Friesian, Montbeliarde, Simmental and Jersey) were genotyped. A genotypic imbalance in the populations was observed. In the case of dual-purpose breeds (Montbeliarde and Simmental), the frequencies of both alleles were almost equal. In contrary, the JAK2G allele was predominant in the Polish Holstein-Friesian breed while JAK2A allele in Jersey. A pronounced relationship between JAK2/RsaI polymorphism and milk production traits was found where, irrespective of breed and lactation order, the GG genotype was significantly associated with higher milk, protein and fat yields, as compared to the AA genotype. Heterozygous individuals were generally characterised by intermediate values of the analysed milk traits. It can be argued that the JAK2 gene polymorphism is a potential marker for milk production traits. However, due to the fact that rs110298451 SNP does not directly affect amino acid sequence, other association studies involving missense mutation should also be performed. PMID- 26119535 TI - Cobalt Boryl Complexes: Enabling and Exploiting Migratory Insertion in Base-Metal Mediated Borylation. AB - Cobalt boryl complexes, which have only been sporadically reported, can be accessed systematically with remarkable (but controllable) variation in the nature of the M-B bond. Complexes incorporating a very strong trans sigma-donor display unparalleled inertness, reflected in retention of the M-B bond even in the presence of extremely strong acid. By contrast, the use of the strong pi acceptor CO in the trans position, results in significant Co-B elongation and to labilization of the boryl ligand via unprecedented CO migratory insertion. Such chemistry provides a pathway for the generation of coordinative unsaturation, thereby enabling ligand substitution and/or substrate assimilation. Alkene functionalization by boryl transfer, a well-known reaction for noble metals such as Rh or Pt, can thus be effected by an 18-electron base-metal complex. PMID- 26119534 TI - Delivering CBT to Rural Latino Children with Anxiety Disorders: A Qualitative Study. AB - Qualitative methods were used to understand community perspectives about ways to deliver cognitive behavior therapy (CBT) to rural Latino youth with anxiety. First, four focus groups were conducted with 28 bilingual Latino mental health providers to examine perceptions of CBT using telephone based, therapist supported bibliotherapy, and bibliotherapy without therapist support. Second, qualitative interviews were conducted with 15 Latino parents from a rural community to better understand attitudes toward CBT, and modes of service delivery. Qualitative findings revealed that parents were mostly positive about psychotherapy, and the core elements of CBT for anxiety. However, both parents and providers emphasized the need for adaptations to address practical and perceived barriers to treatment, such as time, convenience, homework, and literacy. Many parents spoke favorably of a telephone-based approach that could address many of their perceived barriers, while providers were expressed more negative views. Such findings are important for data-driven treatment development efforts. PMID- 26119536 TI - Chondrocyte differentiation for auricular cartilage reconstruction using a chitosan based hydrogel. AB - Tissue engineering with the use of biodegradable and biocompatible scaffolds is an interesting option for ear repair. Chitosan-Polyvinyl alcohol-Epichlorohydrine hydrogel (CS-PVA-ECH) is biocompatible and displays appropriate mechanical properties to be used as a scaffold. The present work, studies the potential of CS-PVA-ECH scaffolds seeded with chondrocytes to develop elastic cartilage engineered-neotissues. Chondrocytes isolated from rabbit and swine elastic cartilage were independently cultured onto CS-PVA-ECH scaffolds for 20 days to form the appropriate constructs. Then, in vitro cell viability and morphology were evaluated by calcein AM and EthD-1 assays and Scanning Electron Microscopy (SEM) respectively, and the constructs were implanted in nu/nu mice for four months, in order to evaluate the neotissue formation. Histological analysis of the formed neotissues was performed by Safranin O, Toluidine blue (GAG's), Verhoeff-Van Gieson (elastic fibers), Masson's trichrome (collagen) and Von Kossa (Calcium salts) stains and SEM. Results indicate appropriate cell viability, seeded with rabbit or swine chondrocyte constructs; nevertheless, upon implantation the constructs developed neotissues with different characteristics depending on the animal species from which the seeded chondrocytes came from. Neotissues developed from swine chondrocytes were similar to auricular cartilage, while neotissues from rabbit chondrocytes were similar to hyaline cartilage and eventually they differentiate to bone. This result suggests that neotissue characteristics may be influenced by the animal species source of the chondrocytes isolated. PMID- 26119537 TI - Tuneable bioinspired lens. AB - Bioinspired lenses that rely on changes of curvature to achieve focus are interesting candidates for miniaturized tuneable lenses as they require fewer mechanical moving parts compared to their conventional counter-parts. The lens described in this manuscript closely mimics the design and actuation principle of the vertebrate lens. It consists of a liquid lens encapsulated in a transparent polymer membrane. Application of a radial strain changes the curvature of the lens thereby changing its focal length. The unstrained lens has a focal length of 50 mm, which rises to a value of 100 mm at a maximum radial strain of 0.67%. This range compares favourably to both biological lenses and other published examples of biomimetic lenses. Finally we point out a few routes to improve the quality of the lens and expand its focal length range. PMID- 26119538 TI - A Near-Infrared-Emissive Alkynyl-Protected Au24 Nanocluster. AB - An alkynyl-protected gold nanocluster [Au24(C=CPh)14(PPh3)4](SbF6)2 has been prepared by a direct reduction method. Single-crystal X-ray diffraction reveals that the molecular structure contains a Au22 core that is made of two Au13 centered cuboctahedra that share a square face. Two staple-like PhC=C-Au-C=CPh motifs are located around the center of the rod-like Au22 core. This Au24 nanocluster is highly emissive in the near-infrared region with lambda(max)=925 nm and the nature of the HOMO-LUMO transition is investigated by time-dependent DFT calculations. PMID- 26119539 TI - Eye disorders reported with the use of mefloquine (Lariam((r))) chemoprophylaxis- A drug safety database analysis. AB - BACKGROUND: Between 80 and 90 million travellers visit malaria endemic areas annually and many require malaria chemoprophylaxis. The characterization of the risk and nature of eye disorders occurring during the use of malaria chemoprophylaxis is relevant for travel medicine advisors. METHODS: We did a database analysis on eye disorder adverse events reported for mefloquine (as Lariam(r)) using the F. Hoffmann-La Roche global drug safety database for the time frame February 1984 to January 18th, 2011. These adverse event reports were reviewed by a trained ophthalmologist. The analysis focused on 3 categories of eye disorders--Category 1: visual acuity; Category 2: anatomical parts of the eye and Category 3: neuro-ophthalmic events. To put our analysis in context, an extensive literature search on "mefloquine" and "eye disorders" was conducted. RESULTS: A total of 591 cases with 695 events assigned to the "Eye disorder" SOC in individuals exposed to mefloquine chemoprophylaxis were reported. The highest proportion of events (n = 493, 70.9%) was in Category 1: visual acuity (mainly visual impairment and blurred vision), followed by Category 3: neuro-ophthalmic events (n = 124, 17.8%). The majority of visual adverse events were non-serious but 37.7% (n = 223) of cases were classified as serious. Nine events of maculopathy were reported and 48 cases with 53 events described symptoms of optic neuropathy. CONCLUSIONS: Mefloquine, like other anti-malarials, may be associated with eye disorders. Prescribers of anti-malarials should inform travellers regarding the risk of potential ocular side effects. Users of chemoprophylaxis who experience visual disorders should be referred to an ophthalmologist. PMID- 26119541 TI - Epidemiology of elephantiasis with special emphasis on podoconiosis in Ethiopia: A literature review. AB - Elephantiasis is a symptom of a variety of diseases that is characterized by the thickening of the skin and underlying tissues, especially in the legs, male genitals and female breasts. Some conditions having this symptom include: Elephantiasis nostras, due to longstanding chronic lymphangitis; Elephantiasis tropica or lymphatic filariasis, caused by a number of parasitic worms, particularly Wuchereria bancrofti; non-filarial elephantiasis or podoconiosis, an immune disease caused by heavy metals affecting the lymph vessels; proteus syndrome, the genetic disorder of the so-called Elephant Man, etc. Podoconiosis is a type of lower limb tropical elephantiasis distinct from lymphatic filariasis. Lymphatic filariasis affects all population at risk, whereas podoconiosis predominantly affects barefoot subsistence farmers in areas with red volcanic soil. Ethiopia is one of the countries with the highest number of podoconiosis patients since many people are at risk to red-clay soil exposure in many parts of the country. The aim of this review was to know the current status and impact of podoconiosis and its relevance to elephantiasis in Ethiopia. To know the epidemiology and disease burden, the literatures published by different scholars were systematically reviewed. The distribution of the disease and knowledge about filarial elephantiasis and podoconiosis are not well known in Ethiopia. It is relatively well studied in southern Ethiopia but data from other parts of the country are limited. Moreover, programmes that focus on diagnosis, treatment, prevention and control of filarial elephantiasis and podoconiosis are also non-existent even in endemic areas. Furthermore, the disease mapping has not been carried out country-wide. Therefore, in order to address these gaps, Ethiopian Ministry of Health needs to take initiative for undertaking concrete research and mapping of the disease in collaboration with stakeholders. PMID- 26119540 TI - Immigration, helminths and eosinophilia: A complex triad. PMID- 26119542 TI - Molecular determination of antifolate resistance associated point mutations in Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes among the field samples in Arunachal Pradesh. AB - BACKGROUND & OBJECTIVES: Antimalarial resistance in P. falciparum malaria parasite creates a serious obstacle in malaria control programme. Keeping this in mind, in the present study antifolate resistance associated point mutations in P. falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthetase (Pfdhps) genes among the field samples in Arunachal Pradesh were determined. METHODS: Blood samples were collected from 145 suspected malaria patients/healthy control subjects in malarious areas of Lohit and Changlang districts of Arunachal Pradesh, India during January 2012 to December 2013. RESULTS: In microscopic slide examination, 51.03% (74/145) were found malaria positive. Plasmodium falciparum mono-infection was observed in 62.16% (46/74) of total malaria positive cases. Polymerase chain reaction (PCR) was employed in all the P. falciparum positive samples for detection of 648 bp of Pfdhfr and 710 bp of Pfdhps genes. All the amplified products were analysed for detection of single nucleotide polymorphisms in dhfr and dhps genes. A total of four different genotypes of Pfdhfr gene were observed, of which double mutant allele ANRNI was mostly prevalent and it was found in 65.22% (30/46) cases. Likewise, four different haplotypes of Pfdhps gene were detected, of which triple mutant allele AGEAA shares 69.57% (32/46) followed by other haplotypes. In Pfdhfr-Pfdhps two locus mutations analysis, two isolates in Changlang district had shown quintuple mutant haplotype AIRNL-AGEAA, likely to be associated with treatment failure. The P. falciparum two locus dhfr-dhps haplotype (ANRNI-AGEAA) was observed in 56.52% (26/46) cases. INTERPRETATION & CONCLUSION: Overall, high grade of sulphadoxine pyrimethamine resistance associated genetic polymorphisms were observed among the P. falciparum parasite population in Arunachal Pradesh during the study period. PMID- 26119543 TI - Landmark-based geometric morphometric analysis of wing shape among certain species of Aedes mosquitoes in District Dehradun (Uttarakhand), India. AB - BACKGROUND & OBJECTIVES: Insect wing morphology has been used in many studies to describe variations among species and populations using traditional morphometrics, and more recently geometric morphometrics. A landmark-based geometric morphometric analysis of the wings of three species of Aedes (Diptera: Culicidae), viz. Ae. aegypti, Ae. albopictus and Ae. pseudotaeniatus, at District Dehradun was conducted belling on the fact that it can provide insight into the population structure, ecology and taxonomic identification. METHODS: Adult Aedes mosquito specimens were randomly collected using aerial nets and morphologically examined and identified. The landmarks were identified on the basis of landmark based geometric morphometric analysis thin-plate spline (mainly the software tps Util 1.28; tps-Dig 1.40; tps-Relw 1.53; and tps-Spline 1.20) and integrated morphometrics programme (mainly twogroup win8 and PCA win8) were utilized. RESULTS: In relative warp (RW) analysis, the first two RW of Ae. aegypti accounted for the highest value (95.82%), followed by Ae. pseudotaeniatus (90.89%), while the lowest (90.12%) being recorded for Ae. albopictus. The bending energies of Ae. aegypti and Ae. pseudotaeniatus were quite identical being 0.1882 and 0.1858 respectively, while Ae. albopictus recorded the highest value of 0.9774. The mean difference values of the distances among Aedes species performing Hotelling's T 2 test were significantly high, predicting major differences among the taxa. In PCA analysis, the horizontal and vertical axis summarized 52.41 and 23.30% of variances respectively. The centroid size exhibited significant differences among populations (non-parametric Kruskal Wallis test, H = 10.56, p < 0.01). INTERPRETATION & CONCLUSION: It has been marked out that the geometric morphometrics utilizes powerful and comprehensive statistical procedures to analyze the shape differences of a morphological feature, assuming that the studied mosquitoes may represent different genotypes and probably come from one diverse gene pool. PMID- 26119544 TI - Detection of dengue virus in individual Aedes aegypti mosquitoes in Delhi, India. AB - BACKGROUND & OBJECTIVES: Delhi, the capital city of India, has so far witnessed several outbreaks of dengue fever since 1967 (last one reported in 2013). Improved virological and entomological surveillance are the only tools that can help in prevention of dengue as well as in the development of dengue control programmes. The aim of the study was to conduct a prospective field study to detect dengue virus in adult Aedes aegypti mosquitoes collected from various localities represented by different socioeconomic groups in Delhi. METHODS: The study areas were selected and categorized into high, medium and low income groups on the basis of socioeconomical characteristics of the resident population, where dengue cases were reported during the past three years by MCD. Dengue viral infection was detected in the head squash of each adult mosquito by immunofluorescent assay (IFA) employing monoclonal antibodies against dengue virus (DENV). A total of 2408 females and 1206 males of Ae. aegypti were collected and tested by IFA. RESULTS: Out of 2408 Ae. aegypti females, 14 were found positive, with minimum infection rate (MIR) of 5.8 per 1000 mosquitoes. Among the 18 study areas, 11 localities were found positive for dengue virus infection. Low income group (LIG) areas showed highest mosquito infectivity (9.8), followed by medium income group (MIG), i.e. 6.2; while least was observed in high income group (HIG), i.e. 1.3. No vertical transmission of dengue virus could be detected in 1206 Ae. aegypti males collected. INTERPRETATION & CONCLUSION: The study concludes that there was high MIR in the identified localities of low and medium income groups. Estimation of MIR in a female Aedes mosquito in the existing arsenals for dengue surveillance would be an added advantage for early warning of dengue outbreak. The presence of infected mosquitoes in identified localities of Delhi was alarming and require rigorous vector surveillance so that the severe outbreaks can be prevented. PMID- 26119545 TI - Comparison of E and NS1 antigens capture ELISA to detect dengue viral antigens from mosquitoes. AB - BACKGROUND & OBJECTIVES: In the absence of an effective vaccine or specific antiviral therapy against dengue infection, the only available control measure remains focusing on the incrimination and reduction of vector (mosquito) populations to suppress virus transmission. Diagnosis of dengue in laboratory can be carried out using several approaches, however, their sensitivity and specificity vary from test-to-test. This study was conducted to evaluate the sensitivity and stability of viral envelope (E) and NS1 antigens detected by ELISA in dengue virus infected mosquitoes. METHODS: An in-house developed E-ELISA to detect dengue E antigens was first characterized by using cross-reactive monoclonal antibody (mAb) 42-3 and rabbit polyclonal antibodies as the capture and detector antibodies, respectively. The sensitivity of E-ELISA was compared with the Platelia Dengue NS1 Ag kit using experimentally infected or field-caught mosquitoes. RESULTS: Our results demonstrated that the E-ELISA was capable of detecting viral antigens with the sensitivity of 69.57, 100, 52.38 and 66.67% for DENV-1 to DENV-4 infected mosquito pools, respectively. This was comparable to the Platelia Dengue NS1 Ag kit, detecting 100% of DENV-1 infected mosquito pools. Among 124 field-collected mosquito pools collected in the vicinity of localized outbreak areas; both E-ELISA and NS1 Ag kit confirmed nine RT-PCR positive samples with sensitivity and concordance rate up to 100%. INTERPRETATION & CONCLUSION: With the future potential of antigen capture ELISA to be used in the resource deprived regions, the study showed that E-ELISA has similar sensitivity and antigen stability as NS1 Ag kit to complement the current established virological surveillance in human. The improvement of the sensitivity in detecting DENV-3/4 will be needed to incorporate this method into routine mosquito surveillance system. PMID- 26119546 TI - Effectiveness and feasibility of methanol extracted latex of Calotropis procera as larvicide against dengue vectors of western Rajasthan, India. AB - BACKGROUND & OBJECTIVES: Identification of novel effective larvicide from natural resources is essential to combat developing resistances, environmental concerns, residue problems and high cost of synthetic insecticides. Results of earlier laboratory findings have shown that Calotropis procera extracts showed larvicidal, ovicidal and refractory properties towards ovipositioning of dengue vectors; further, latex extracted with methanol was found to be more effective compared to crude latex. For testing efficacy and feasibility of extracted latex in field, the present study was undertaken in different settings of Jodhpur City, India against dengue vectors. METHODS: Study areas were selected based on surveillance design for the control of dengue vectors. During the study period domestic and peri-domestic breeding containers were treated with methanol extracted latex and mortality was observed after 24 h as per WHO guidelines. Latex was manually collected from internodes of Calotropis procera and extracted using methanol (AR) grade. RESULTS: Methanol extracted latex of C. procera was found effective and feasible larvicide against dengue vectors in the field conditions. Cement tanks, clay pots and coolers (breeding sites) were observed as key containers for the control of dengue transmission. INTERPRETATION & CONCLUSION: Today environmental safety is considered to be very important. Herbal composition prepared by the extraction of latex of C. procera can be used as an alternative approach for the control of dengue vectors. This will reduce the dependence on expensive products and stimulate local efforts to enhance the public involvement. PMID- 26119547 TI - Boric acid ovicidal trap for the management of Aedes species. AB - BACKGROUND & OBJECTIVES: The use of low concentrations of boric acid as a potential and effective control agent for the eggs and immature stages of Aedes aegypti L. and Aedes albopictus Skuse (Diptera: Culicidae) is found to be safe and effective as compared to synthetic chemical insecticides. The study aims to determine the ovicidal concentration of boric acid, its effective concentration for oviposition attraction and the larval mortality concentration for Ae. aegypti and Ae. albopictus. METHODS: The ovicidal concentration of boric acid was determined by incubating the eggs in different concentrations of boric acid (0.1, 0.25, 0.5, 0.75 and 1%). Different dilutions of boric acid were taken in the oviposition cup and the ovicidal concentration, effective concentration for oviposition attraction and the mean survival/mortality rate of III and IV instar Ae. aegypti and Ae. albopictus larvae were determined. RESULTS: The ovicidal concentration of boric acid for 100% mortality in Aedes sp eggs is 1%. Effective concentration for the oviposition attraction is 0.5%. At 1% concentration, larvae of both the species died within 24 h. INTERPRETATION & CONCLUSION: Boric acid is less toxic compared to different pesticides, and in low concentrations, it attracts the ovipositing female Aedes sp as well as fertile males. Dilute boric acid solution is an effective ovitrap since the eggs laid by mosquitoes either die or the larvae that hatch out from them do not survive in boric acid. Boric acid kills the males that come in contact with the solution, which are attracted to the trap by the females hovering around. PMID- 26119548 TI - Vectorial capacity of Culex gelidus (Theobald) mosquitoes to certain viruses of public health importance in India. AB - BACKGROUND & OBJECTIVES: Culex gelidus, a widely prevalent mosquito in India and Southeast Asia region, is an important vector of Japanese encephalitis virus (JEV). Experimental studies have shown its potential to transmit West Nile, Kunjin, Murray Valley encephalitis and Ross River viruses. An attempt was therefore made to study its susceptibility and vector competence to some of the arboviruses of public health importance in India. METHODS: Mosquitoes were infected with six viruses, viz. JEV, chikungunya (CHIKV), Chandipura (CHPV), Chittoor (CHITV), Ingwavuma (INGV) and Umbre (UMBV) by intra thoracic inoculation to determine virus susceptibility and vector competence. Growth kinetics of the viruses were studied by determining the titres of inoculated mosquitoes on different days post-infection by titration in Vero E6 cells. Vector competence was studied by detecting the presence of the viruses in saliva of infected mosquitoes. RESULTS: All the six viruses were replicated in Cx. gelidus. JEV, CHPV, CHIKV and CHITV yielded > 5 log10TCID50/ml virus while UMBV and INGV yielded approx 4log10TCID50/ml virus. JEV, CHIKV and CHITV could be detected in the saliva of the infected mosquitoes, while CHPV, INGV and UMBV could not be detected in the saliva of the infected mosquitoes. INTERPRETATION & CONCLUSION: Replication potential and vector competence of Cx. gelidus to some of the viruses of public health importance in India, viz. JEV, CHIKV, CHITV etc, pose a serious threat to general population, especially in the wake of spurt in its population in certain parts of India. PMID- 26119549 TI - Susceptibility status of Aedes aegypti (L.) (Diptera: Culicidae) to temephos from three districts of Tamil Nadu, India. AB - BACKGROUND & OBJECTIVES: Dengue is the most rapidly expanding arboviral disease in India. Aedes aegypti is the primary vector of dengue fever. Chemical insecticides have long been used in the vector control programmes along with other control measures. However, continuous use of insecticides targeting Ae. aegypti may lead to development of insecticide resistance. Though resistance in Ae. aegypti has been reported, the mutation in ace-1 gene associated with temephos resistance is not reported in natural populations. The present study aims to evaluate the susceptibility/resistance status of Ae. aegypti to temephos from three districts of Tamil Nadu. METHODS: Ae. aegypti larvae were sampled from different locations in three districts, viz., Dharmapuri, Salem and Namakkal. The standard WHO larval bioassay, biochemical assays and spotting of specific mutation (G119S) in the acetylcholinesterase gene, which is associated with organophosphate resistance, were carried out by PCR and sequencing. RESULTS: The results showed that larvae from Namakkal (NKL) population had an alteration in their susceptibility status (RR = 6.9 fold), while the other populations were moderately susceptible to insecticides. Biochemical assay showed increased activity for alpha- and beta-esterase in NKL, as well as evidence of acetylcholinesterase insensitivity. G119S mutation was detected in this population with high frequency of 0.24. INTERPRETATION & CONCLUSION: The high activity of esterase, mixed-function oxidase (MFO) and ace-1 mutation frequency were closely associated with temephos resistance. Early detection of resistance alleles in natural vector population could be useful for the successful implementation of insecticide resistance management strategies. The results of this study provide baseline data on temephos resistance in Ae. aegypti populations. PMID- 26119550 TI - Evaluation of knowledge of the healthcare personnel working in Giresun province regarding Crimean-Congo hemorrhagic fever before and after educational training. AB - BACKGROUNDS & OBJECTIVES: Crimean-Congo hemorrhagic fever (CCHF) is a highly fatal and contagious tick-borne viral disease. Healthcare workers (HCWs) should know how and with which symptoms can CCHF patients attend to hospitals, and be aware of nosocomial transmission capability. The aim of this study was to investigate the knowledge of HCWs working in Giresun province regarding CCHF. METHODS: This research was carried out during an educational programme arranged for healthcare personnel working in district state hospitals in June 2012. In total, 428 workers completed a self-administered questionnaire including personal demographic characteristics, general knowledge of CCHF disease, knowledge of nosocomial transmission and infection control during hospitalization. RESULTS: Almost all participants (95.3%) knew that the workers in livestock and agriculture were at risk. About 93.5% of participants knew that tick bite is the cause of CCHF transmission. In contrast to this high ratio, only 73 and 77% workers knew that CCHF can be transmitted by direct contact with animal's or patient's blood and body fluids, but after imparting relevant information in the form of one hour lecture given by a doctor expertised in infectious diseases, 92% gave correct answers. Nearly, all healthcare workers were aware that ticks should be removed by using fine-tipped tweezers without crushing (90.7%). Doctors were the most and the laboratory personnel the least well-informed groups. The knowledge degree significantly increased from 67.48 +/- 13.89 to 80.92 +/- 10.80 points after providing the CCHF related information (p<0.05). INTERPRETATION & CONCLUSION: It was observed that the healthcare personnel working in district state hospitals of the province were moderately aware of CCHF disease. There is possibility of achieving improvement in their knowledge by educating them regarding CCHF and such educational programmes should be conducted from time-to time. PMID- 26119551 TI - Molecular detection of scrub typhus in Tirupati, Andhra Pradesh, India. PMID- 26119552 TI - First observations of homodynamic populations of Aedes albopictus (Skuse) in Southwest Europe. PMID- 26119553 TI - Declining trend of malaria in Car Nicobar Island, inhabited by the Nicobarese tribe: Plausible factors. PMID- 26119554 TI - Residual microfilaraemia in rural pockets of South India after five rounds of DEC plus albendazole administration as part of the LF elimination campaign. PMID- 26119555 TI - Four Decades of the Chemistry of Planar Hypercoordinate Compounds. AB - The idea of planar tetracoordinate carbon (ptC) was considered implausible for a hundred years after 1874. Examples of ptC were then predicted computationally and realized experimentally. Both electronic and mechanical (e.g., small rings and cages) effects stabilize these unusual bonding arrangements. Concepts based on the bonding motifs of planar methane and the planar methane dication can be extended to give planar hypercoordinate structures of other chemical elements. Numerous planar configurations of various central atoms (main-group and transition-metal elements) with coordination numbers up to ten are discussed herein. The evolution of such planar configurations from small molecules to clusters, to nanospecies and to bulk solids is delineated. Some experimentally fabricated planar materials have been shown to possess unusual electrical and magnetic properties. A fundamental understanding of planar hypercoordinate chemistry and its potential will help guide its future development. PMID- 26119556 TI - Mathematical modelling of spatial sorting and evolution in a host-parasite system. AB - There have been numerous empirical and agent-based modelling studies on the spatial self-structuring of traits, particularly in regard to dispersal ability (termed spatial sorting) of cane toads in northern Australia, but few mathematical modelling studies. In this study, we formulate a reaction-diffusion based partial-integro-differential equation model based on an earlier model by Bouin et al. (2012) to examine this spatial self-structuring of traits in both a cane toad population and lungworm parasite population, which evolves with the cane toad population. In particular, the traits we focus on are dispersal ability for the cane toad population and both prepatent period and larval size for the lungworm parasite population. Apart from the spatial self-structuring of these traits, our results confirm a number of observations made in empirical and agent based studies; particularly, that there is a noticeable lag between the host and parasite population which is critically dependent on the parasite functional response to host densities, that older populations regress back to lower dispersal speeds and that spatial sorting can still occur with a disadvantage in reproductivity and/or survival in more motile individuals. Moreover, we find that such a disadvantage in reproductivity and/or survival is unlikely to be large if spatial sorting is to have a noticeable effect on the rate of range expansion, as it has been observed to have over the last 60 years in northern Australia. PMID- 26119557 TI - [Completeness assessment of the Breton registry of congenital abnormalities: A checking tool based on hospital discharge data]. AB - BACKGROUND: Exhaustiveness is required for registries. In the Breton registry of congenital abnormalities, cases are recorded at the source. We use hospital discharge data in order to verify the completeness of the registry. In this paper, we present a computerized tool for completeness assessment applied to the Breton registry. METHODS: All the medical information departments were solicited once a year, asking for infant medical stays for newborns alive at one year old and for mother's stays if not. Files were transmitted by secure messaging and data were processed on a secure server. An identity-matching algorithm was applied and a similarity score calculated. When the record was not linked automatically or manually, the medical record had to be consulted. The exhaustiveness rate was assessed using the capture recapture method and the proportion of cases matched manually was used to assess the identity matching algorithm. RESULTS: The computerized tool bas been used in common practice since June 2012 by the registry investigators. The results presented concerned the years 2011 and 2012. There were 470 potential cases identified from the hospital discharge data in 2011 and 538 in 2012, 35 new cases were detected in 2011 (32 children born alive and 3 stillborn), and 33 in 2012 (children born alive). There were respectively 85 and 137 false-positive cases. The theorical exhaustiveness rate reached 91% for both years. The rate of exact matching amounted to 68%; 6% of the potential cases were linked manually. CONCLUSION: Hospital discharge databases contribute to the quality of the registry even though reports are made at the source. The implemented tool facilitates the investigator's work. In the future, use of the national identifying number, when allowed, should facilitate linkage between registry data and hospital discharge data. PMID- 26119558 TI - Palladium-catalyzed mono-alpha-arylation of acetone at room temperature. AB - The first examples of acetone mono-alpha-arylation at room temperature are described, enabled by use of a [Pd(cinnamyl)Cl]2 /JosiPhos catalyst system. (Hetero)aryl chloride, bromide, and iodide electrophiles featuring or lacking ortho-substitution, and comprising a range of functionalities (e.g., alkoxy, cyano, fluoro, trifluoromethyl, or alkenyl) and heteroaryl motifs (e.g., pyrrole, pyridine, isoquinoline, quinoline, quinaldine, (benzo)thiophene, benzothiazole, or benzodioxole) were successfully accommodated. Proof-of-principle experiments confirm that other (hetero)aryl methyl ketones can also be employed in such room temperature mono-alpha-arylations. The established substrate scope is the most extensive reported to date for acetone mono-alpha-arylation under any conditions, and more generally represents the first room temperature ketone mono-alpha arylations employing a structurally diverse set of (hetero)aryl chlorides. PMID- 26119559 TI - Long-term cancer control outcomes in patients with clinically high-risk prostate cancer treated with robot-assisted radical prostatectomy: results from a multi institutional study of 1100 patients. AB - BACKGROUND: Long-term cancer control outcomes in clinically high-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP) remain unknown. OBJECTIVE: To report on long-term biochemical recurrence (BCR) free survival, clinical recurrence (CR)-free survival, and salvage therapy rates in these patients. Given the heterogeneity of high-risk patients, a second objective was to stratify them according to their BCR risk (using preoperative parameters), in an effort to counsel them better preoperatively regarding their cancer control outcomes. DESIGN, SETTING, AND PARTICIPANTS: We evaluated 1100 D'Amico high-risk PCa patients who underwent RARP between 2002 and 2013 at three tertiary care centers. OUTCOME MEASURES AND STATISTICAL ANALYSES: Outcomes consisted of BCR-free survival, CR-free survival, and salvage therapy rates. Regression tree analysis stratified patients into novel risk groups based on preoperative characteristics and corresponding BCR risk. Kaplan-Meier curves estimated BCR-free survival, CR-free survival, and salvage therapy rates in the entire cohort and after stratification according to the novel risk groups (RGs). RESULTS AND LIMITATIONS: Median age and prostate-specific antigen (PSA) were 63 yr and 6.5 ng/ml, respectively. Biopsy Gleason score (GS) was >=8 in 57.7%. Mean follow-up was 53 mo (median: 49 mo). At 10 yr, BCR-free survival, CR-free survival, and salvage therapy rates were 50%, 87%, and 37%, respectively. Regression tree analysis stratified patients into five novel RGs): RG1, very low risk (GS <=6); RG2, low risk (PSA <=10 ng/ml; GS: 7); RG3, intermediate risk (PSA <=10 ng/ml; GS >=8); RG4, high risk (PSA >10 ng/ml; GS: 7); RG5, very high risk (PSA >10 ng/ml; GS >=8). In these RGs, the 10-yr BCR-free survival rates were 86%, 70%, 36%, 31%, and 26% (p<0.001), respectively; the 10-yr CR-free survival rates were 99%, 96%, 85%, 67%, and 55% (p<0.001), respectively; and the 10-yr salvage therapy rates were 9.8%, 16%, 42%, 47%, and 64% (p<0.001), respectively. CONCLUSIONS: Most patients with clinically high-risk PCa treated with RARP alone remain CR free at long term. Nonetheless, almost 37% of the patients at 10 yr require salvage therapy. Our novel tool allows accurate stratification of these heterogeneous patients according to their BCR, CR, and salvage therapy risks. This may help inform patients preoperatively about their cancer control outcomes postoperatively. PATIENT SUMMARY: Robot-assisted radical prostatectomy confers lasting long-term oncologic control in most high-risk prostate cancer patients. Our novel risk grouping might serve as a useful tool for setting expectations and counseling patients regarding their cancer control outcomes. PMID- 26119560 TI - Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guerin. AB - The response of non-muscle-invasive bladder cancer (NMIBC) to intravesical immunotherapy with bacillus Calmette-Guerin (BCG) depends on adequate stimulation of an immune response. Although BCG has been used for decades, we lack tools to accurately predict response in individual patients. To address this deficiency, we initiated a clinical trial in patients with intermediate- and high-risk NMIBC. BCG was administered according to the Southwest Oncology Group protocol. Urine samples were collected for cytokine assay at baseline, immediately before and after BCG instillation at 6 wk, and immediately before and after the third BCG instillation of the first maintenance course. Levels of 12 cytokines were measured, and changes from baseline were calculated after treatment. A total of 130 patients were enrolled. Increases in single cytokines correlated with recurrence, but the best predictor of recurrence was changes in a combination of cytokines. A nomogram (CyPRIT) constructed using urinary levels of nine inducible cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ra, TRAIL, IFN-gamma, IL-12[p70], and TNF alpha) predicted the likelihood of recurrence with 85.5% accuracy (95% confidence interval 77.9-93.1%)." This cytokine panel and nomogram have potential for identifying patients at risk of tumor recurrence during BCG treatment to guide modification of the dose and duration of BCG immunotherapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT01007058. PMID- 26119561 TI - Does Stepwise Voltage Ramping Protect the Kidney from Injury During Extracorporeal Shockwave Lithotripsy? Results of a Prospective Randomized Trial. AB - BACKGROUND: Renal damage is more frequent with new-generation lithotripters. However, animal studies suggest that voltage ramping minimizes the risk of complications following extracorporeal shock wave lithotripsy (SWL). In the clinical setting, the optimal voltage strategy remains unclear. OBJECTIVE: To evaluate whether stepwise voltage ramping can protect the kidney from damage during SWL. DESIGN, SETTING, AND PARTICIPANTS: A total of 418 patients with solitary or multiple unilateral kidney stones were randomized to receive SWL using a Modulith SLX-F2 lithotripter with either stepwise voltage ramping (n=213) or a fixed maximal voltage (n=205). INTERVENTION: SWL. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was sonographic evidence of renal hematomas. Secondary outcomes included levels of urinary markers of renal damage, stone disintegration, stone-free rate, and rates of secondary interventions within 3 mo of SWL. Descriptive statistics were used to compare clinical outcomes between the two groups. A logistic regression model was generated to assess predictors of hematomas. RESULTS AND LIMITATIONS: Significantly fewer hematomas occurred in the ramping group(12/213, 5.6%) than in the fixed group (27/205, 13%; p=0.008). There was some evidence that the fixed group had higher urinary beta2 microglobulin levels after SWL compared to the ramping group (p=0.06). Urinary microalbumin levels, stone disintegration, stone-free rate, and rates of secondary interventions did not significantly differ between the groups. The logistic regression model showed a significantly higher risk of renal hematomas in older patients (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.05; p=0.04). Stepwise voltage ramping was associated with a lower risk of hematomas (OR 0.39, 95% CI 0.19-0.80; p=0.01). The study was limited by the use of ultrasound to detect hematomas. CONCLUSIONS: In this prospective randomized study, stepwise voltage ramping during SWL was associated with a lower risk of renal damage compared to a fixed maximal voltage without compromising treatment effectiveness. PATIENT SUMMARY: Lithotripsy is a noninvasive technique for urinary stone disintegration using ultrasonic energy. In this study, two voltage strategies are compared. The results show that a progressive increase in voltage during lithotripsy decreases the risk of renal hematomas while maintaining excellent outcomes. TRIAL REGISTRATION: ISRCTN95762080. PMID- 26119562 TI - Re: Marlon Perera, Matthew J. Roberts, Suhail A.R. Doi, Damien Bolton. Prostatic urethral lift improves urinary symptoms and flow while preserving sexual function for men with benign prostatic hyperplasia: a systematic review and meta-analysis. Eur Urol 2015;67:704-13. PMID- 26119564 TI - Conversion of cheese whey into a fucose- and glucuronic acid-rich extracellular polysaccharide by Enterobacter A47. AB - Cheese whey was used as the sole substrate for the production of extracellular polysaccharides (EPS) by Enterobacter A47. An EPS concentration of 6.40 g L(-1) was reached within 3.2 days of cultivation, corresponding to a volumetric productivity of 2.00 g L(-1) d(-1). The produced EPS was mainly composed of glucuronic acid (29 mol%) and fucose (29 mol%), with lower contents of glucose and galactose (21 mol% each) and a total acyl groups content of 32 wt.%. The polymer had an average molecular weight of 1.8*10(6) Da, with a polydispersity index of 1.2, and an intrinsic viscosity of 8.0 dL g(-1). EPS aqueous solutions (1.0 wt.% in 0.01 M NaCl, at pH 8.0) presented a shear thinning behavior with a viscosity of the first Newtonian plateau approaching 0.1 Pas. This novel glucuronic acid-rich polymer possesses interesting rheological properties, which, together with its high content of glucuronic acid and fucose, two bioactive sugar monomers, confers it a great potential for use in high-value applications, such as cosmetics and pharmaceuticals. PMID- 26119563 TI - Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3beta. AB - Abnormal tau hyperphosphorylation is an early pathological marker of Alzheimer's disease (AD), however, the upstream factors that regulate tau phosphorylation are not illustrated and there is no efficient strategy to arrest tau hyperphosphorylation. Here, we find that activation of endogenous EphB2 receptor by ligand stimulation (ephrinB1/Fc) or by ectopic expression of EphB2 plus the ligand stimulation induces a remarkable tau dephosphorylation at multiple AD associated sites in SK-N-SH cells and human embryonic kidney cells that stably express human tau (HEK293-tau). In cultured hippocampal neurons and the hippocampus of human tau transgenic mice, dephosphorylation of tau proteins was also detected by stimulation of EphB2 receptor. EphB2 activation inhibits glycogen synthase kinase-3beta (GSK-3beta), a crucial tau kinase, and activates phosphatidylinositol-3-kinase (PI3K)/Akt both in vitro and in vivo, whereas simultaneous inhibition of PI3K or upregulation of GSK-3beta abolishes the EphB2 stimulation-induced tau dephosphorylation. Finally, we confirm that ephrinB1/Fc treatment induces tyrosine phosphorylation (activation) of EphB2, while deletion of the tyrosine kinase domain (VM) of EphB2 eliminates the receptor stimulation induced GSK-3beta inhibition and tau dephosphorylation. We conclude that activation of EphB2 receptor kinase arrests tau hyperphosphorylation through PI3K /Akt-mediated GSK-3beta inhibition. Our data provide a novel membranous target to antagonize AD-like tau pathology. PMID- 26119565 TI - alpha-Synuclein interactions with phospholipid model membranes: Key roles for electrostatic interactions and lipid-bilayer structure. AB - alpha-Synuclein is a small presynaptic protein that is critically implicated in the onset of Parkinson's disease and other neurodegenerative disorders. It has been assumed that the pathogenesis of alpha-synuclein is associated with its aggregation, while for its physiological function, binding of alpha-synuclein to the synaptic vesicle membrane appears to be most important. The present study investigated the mechanism of alpha-synuclein binding to the lipid membrane. Upon binding to negatively charged small unilamellar vesicles consisting of 1,2 dipalmitoyl-sn-glycero-3-phosphoglycerol or 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoglycerol in the liquid-crystalline state, alpha-synuclein undergoes conformational transition from its native unfolded form to an alpha-helical structure. The positively charged N-terminal part of alpha-synuclein is likely to be involved in interactions with the negatively charged lipid surface. alpha Synuclein did not associate with vesicles consisting of the zwitterionic (neutral) lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine or 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine. The data obtained by circular dichroism spectroscopy, fluorescence anisotropy measurements, differential scanning calorimetry, and calcein efflux assays indicate that in addition to electrostatic interactions, hydrophobic interactions are important in the association of alpha synuclein with membranes. The mechanism of alpha-synuclein binding to lipid membranes is primarily dependent on the surface charge density of the lipid bilayer and the phase state of the lipids. We propose that alpha-synuclein has a lipid ordering effect and thermally stabilises vesicles. PMID- 26119566 TI - Interfacial stabilization of the antitumoral drug Paclitaxel in monolayers of GM1 and GD1a gangliosides. AB - Molecular interactions between the anti-cancer agent Paclitaxel (Ptx), and two gangliosides with different sialic acid content, GM1 and GD1a, were investigated using the Langmuir film balance technique. Ptx showed interfacial activity reducing the air/water surface tension by 18 mN.m(-1). However, the drug was able to insert into preformed ganglioside monolayers at much higher surface pressures, indicating a preferential interaction of Ptx with GM1 and GD1a. Compression isotherms of binary mixtures of Ptx and GM1 or GD1a also indicated non-ideal mixed monolayers in which the drug became stabilized at the interface in the presence of gangliosides. Ptx reached much higher surface pressure values in the mixed monolayers than those sustained in pure Ptx, although partial desorption of the drug from the interface into the subphase was also observed at high Ptx contents. The mean molecular area of the mixtures showed condensation, mainly in the case of GD1a, whereas Ptx induced a decrease in the compressibility of monolayers when mixed with either GM1 or GD1a. Additionally, Brewster angle microscopy analysis indicated that higher amounts of Ptx are present at the mixed ganglioside/Ptx interface when compared to pure drug monolayers. Finally, GD1a micelles increased in size in the presence of Ptx, whereas GM1 micelles kept their diameter, according to dynamic light scattering measurements, which could be explained by the different properties of ganglioside monolayers. The results obtained on ganglioside-Ptx interactions allowed interpreting the different Ptx loading capacity of GM1 and GD1a, enabling them to act as potential drug carriers. PMID- 26119567 TI - A new phenolic compound with antioxidant activity from the branches and leaves of Pyrus pashia. AB - The branches and leaves of Pyrus pashia are used to cure abdominal pain and diarrhoea in Chinese folk medicine. A new phenilic compound, 4-O-beta-d glucopyranosylbenzyl-benzoate ester (1), along with 21 known ones (2-22) were isolated from the branches and leaves of this plant. Compounds 2 and 3 displayed remarkable antioxidant activities against 1,1-diphenyl-2-picrylhydrazyl radical (IC50 = 13.26 +/- 0.04 MUM, 13.28 +/- 0.11 MUM, respectively), which were at the same grade as positive control rutin. The caffeoyl group in compounds 2 and 3 was supposed to play an important role in the antioxidant activities. PMID- 26119568 TI - A conserved role for CUP-SHAPED COTYLEDON genes during ovule development. AB - The evolution of plant reproductive strategies has led to a remarkable diversity of structures, especially within the flower, a structure characteristic of the angiosperms. In flowering plants, sexual reproduction depends notably on the development of the gynoecium that produces and protects the ovules. In Arabidopsis thaliana, ovule initiation is promoted by the concerted action of auxin with CUC1 (CUP-SHAPED COTYLEDON1) and CUC2, two genes that encode transcription factors of the NAC family (NAM/ATAF1,2/CUC). Here we highlight an additional role for CUC2 and CUC3 in Arabidopsis thaliana ovule separation. While CUC1 and CUC2 are broadly expressed in the medial tissue of the gynoecium, CUC2 and CUC3 are expressed in the placental tissue between developing ovules. Consistent with the partial overlap between CUC1, CUC2 and CUC3 expression patterns, we show that CUC proteins can physically interact, both in yeast cells and in planta. We found that the cuc2;cuc3 double mutant specifically harbours defects in ovule separation, producing fused seeds that share the seed coat, and suggesting that CUC2 and CUC3 promote ovule separation in a partially redundant manner. Functional analyses show that CUC transcription factors are also involved in ovule development in Cardamine hirsuta. Additionally we show a conserved expression pattern of CUC orthologues between ovule primordia in other phylogenetically distant species with different gynoecium architectures. Taken together these results suggest an ancient role for CUC transcription factors in ovule separation, and shed light on the conservation of mechanisms involved in the development of innovative structures. PMID- 26119569 TI - Cost-Effectiveness Analysis of a Capitated Patient Navigation Program for Medicare Beneficiaries with Lung Cancer. AB - OBJECTIVE: To assess the cost-effectiveness of implementing a patient navigation (PN) program with capitated payment for Medicare beneficiaries diagnosed with lung cancer. DATA SOURCES/STUDY SETTING: Cost-effectiveness analysis. STUDY DESIGN: A Markov model to capture the disease progression of lung cancer and characterize clinical benefits of PN services as timeliness of treatment and care coordination. Taking a payer's perspective, we estimated the lifetime costs, life years (LYs), and quality-adjusted life years (QALYs) and addressed uncertainties in one-way and probabilistic sensitivity analyses. DATA COLLECTION/EXTRACTION METHODS: Model inputs were extracted from the literature, supplemented with data from a Centers for Medicare and Medicaid Services demonstration project. PRINCIPAL FINDINGS: Compared to usual care, PN services incurred higher costs but also yielded better outcomes. The incremental cost and effectiveness was $9,145 and 0.47 QALYs, respectively, resulting in an incremental cost-effectiveness ratio of $19,312/QALY. One-way sensitivity analysis indicated that findings were most sensitive to a parameter capturing PN survival benefit for local-stage patients. CE-acceptability curve showed the probability that the PN program was cost-effective was 0.80 and 0.91 at a societal willingness-to-pay of $50,000 and $100,000/QALY, respectively. CONCLUSION: Instituting a capitated PN program is cost-effective for lung cancer patients in Medicare. Future research should evaluate whether the same conclusion holds in other cancers. PMID- 26119572 TI - Bacterial physiology: Obg controls bacterial persistence. PMID- 26119570 TI - Discovery of microbial natural products by activation of silent biosynthetic gene clusters. AB - Microorganisms produce a wealth of structurally diverse specialized metabolites with a remarkable range of biological activities and a wide variety of applications in medicine and agriculture, such as the treatment of infectious diseases and cancer, and the prevention of crop damage. Genomics has revealed that many microorganisms have far greater potential to produce specialized metabolites than was thought from classic bioactivity screens; however, realizing this potential has been hampered by the fact that many specialized metabolite biosynthetic gene clusters (BGCs) are not expressed in laboratory cultures. In this Review, we discuss the strategies that have been developed in bacteria and fungi to identify and induce the expression of such silent BGCs, and we briefly summarize methods for the isolation and structural characterization of their metabolic products. PMID- 26119571 TI - HIV-1 assembly, release and maturation. AB - Major advances have occurred in recent years in our understanding of HIV-1 assembly, release and maturation, as work in this field has been propelled forwards by developments in imaging technology, structural biology, and cell and molecular biology. This increase in basic knowledge is being applied to the development of novel inhibitors designed to target various aspects of virus assembly and maturation. This Review highlights recent progress in elucidating the late stages of the HIV-1 replication cycle and the related interplay between virology, cell and molecular biology, and drug discovery. PMID- 26119573 TI - Permethyl Cobaltocenium (Cp*2Co+) as an Ultra-Stable Cation for Polymer Hydroxide Exchange Membranes. AB - Hydroxide (OH(-))-exchange membranes (HEMs) are important polymer electrolytes enabling the use of affordable and earth-abundant electrocatalysts for electrochemical energy-conversion devices such as HEM fuel cells, HEM electrolyzers, and HEM solar hydrogen generators. Many HEM cations exist, featuring desirable properties, but new cations are still needed to increase chemical stability at elevated temperatures. Here we introduce the permethyl cobaltocenium [(C5Me5)2Co(III)(+) or Cp(*)2Co(+)] as an ultra-stable organic cation for polymer HEMs. Compared with the parent cobaltocenium [(C5H5)2Co(III)(+) or Cp2Co(+)], Cp(*)2Co(+) has substantially higher stability and basicity. With polysulfone as an example, we demonstrated the feasibility of covalently linking Cp(*)2Co(+) cation to polymer backbone and prepared Cp(*)2Co(+)-functionalized membranes as well. The new cation may be useful in designing more durable HEM electrochemical devices. PMID- 26119574 TI - Detection of bacterioplankton using PCR probes as a diagnostic indicator for drowning; the Leicester experience. AB - Bodies found immersed in water can pose difficulties to the investigating authorities. Pathologists may be assisted with the diagnosis by the use of tests such as the analysis for diatoms or the levels of strontium in the blood, although there is a recognised level of uncertainty associated with these tests. Recent work from Japan has shown that using molecular approaches, most recently real-time polymerase chain reaction (PCR) assays with TaqMan probes for bacterioplankton, it is possible to undertake rapid, less laborious, high throughput tests to differentiate freshwater from marine bacterioplankton and in doing so provide a molecular diagnostic test to assist in the diagnosis of drowning. We report the experiences of a United Kingdom forensic pathology unit in the use of this PCR based system for the diagnosis of drowning. We applied this technique to 20 adult and child cadavers from 4 bath, 12 freshwater, 2 brackish and 2 salt water scenes both from within the United Kingdom and abroad. Drowning was concluded to be the cause of death in 16 of these 20 cases and the PCR method supported this conclusion in 12 of these 16 cases. The PCR did not provide evidence of drowning in the four cases where death was from other causes. We illustrate that this PCR method provides a rapid diagnostic supportive test for the diagnosis of drowning that can be applied to United Kingdom autopsy practice. PMID- 26119575 TI - The lived experience of parents enabling participation of their child with a physical disability at home, at school and in the community. AB - PURPOSE: The aim of this study was to provide an in-depth exploration and understanding of parents' thoughts, feelings and concerns they experience while reflecting on their actions, challenges and needs in enabling their child's participation at home, at school and in the community. METHOD: A naturalistic inquiry with thirteen Dutch parents using interpretative phenomenological analysis. RESULTS: Analysis revealed three super-ordinate themes: "Parents' experiences and concerns about systems, laws and regulations", "Parents' experiences and thoughts about physical and/or social environment" and "Parents' experiences and feelings of finding and/or enabling an activity". Parents' often expressed feelings of disappointment derived from being misunderstood, from dealing with the complexity of systems, from hindrance of participation of their children by the social and the physical environment, and from the lack of leisure activities for their child. It is primarily restrictions in the physical and social environments that urge them to take actions, to experience challenges and think of needs. CONCLUSIONS: In-depth exploration and understanding of parents' articulated matters must be shared and taken seriously by policymakers and service providers. Parents' knowledge and experiences should be of major relevance to improve paediatric rehabilitation and other services for children with a physical disability. Implications for Rehabilitation To achieve tailored pediatric rehabilitation, involvement and needs of parents in enhancing their child's participation ought to be acknowledged. Active use of parents' experiences and knowledge regarding the participation of their child on different levels of decision making may improve daily services in pediatric rehabilitation. Aiming for optimal participation of a child with a physical disability at home, at school and in the community, the focus of pediatric rehabilitation needs to shift towards enabling, social and physical, environments. PMID- 26119576 TI - Quality of life of Finnish children with cerebral palsy. AB - PURPOSE: The aim of this study was to examine the quality of life (QOL) of Finnish children with cerebral palsy (CP) in different parts of Finland from the children's and caregivers' perspectives. The acceptability of the Finnish version of the CP QOL-Child questionnaire for clinical use is also evaluated. METHOD: This study was conducted in 2010-2013 as a part of the national CP-project. It is based on validated CP QOL-Child questionnaires. Children between 9 and 12 years were asked to fill in the child-self-report version. Caregivers who had a 4- to 12-year-old child with CP filled in parent-proxy reports. RESULTS: Responses were obtained from 63 children and 161 caregivers. The response rates were 63 and 60%, respectively. Overall QOL was reported to be fairly good with no significant regional differences within Finland. Children reported significantly higher QOL in all QOL-domains except "social wellbeing and acceptance" than their caregivers did. The results showed acceptable levels of internal consistency of the Finnish version of the CP QOL-Child. CONCLUSIONS: QOL of children with CP is quite good in Finland. However, barriers to participation and the impact of disability and pain impair QOL. The Finnish version of the CP QOL-Child questionnaire is an appropriate clinical tool to assess QOL. IMPLICATIONS FOR REHABILITATION: The used questionnaire provides an effective tool to identify areas for targeting support actions and to set goals for rehabilitation plans. The study brings forward the voices of children. It was found that pain has a great role in QOL, which should be taken into account when making rehabilitation plans. The participation of children with CP should be strengthened in every possible ways. PMID- 26119577 TI - Cultural influences on exercise participation and fall prevention: a systematic review and narrative synthesis. AB - PURPOSE: We aim to provide a systematic review of qualitative research evidence relevant to the experiences and perceptions of program providers and participants from culturally and linguistically diverse (CALD) backgrounds regarding (i) exercise and (ii) fall prevention programs for older people. METHOD: Using a narrative synthesis approach, we reviewed published journal articles reporting qualitative data. Electronic and manual literature searches were conducted to identify 19 publications that met the inclusion criteria. Of these, 16 discussed exercise and three focused on broader fall prevention programs. However, no studies were identified that explored the perspective of the program providers. RESULTS: An overarching theme emerged identifying the influence of cultural values and perceptions on program participation. Also, identified were motivational, social and environmental influences. CONCLUSION: Exercise and fall prevention interventions need to be culturally appropriate and utilise the positive influences of social support, especially from physicians and family. While these findings can be used to inform the delivery of programs to these population groups, future studies should focus specifically on experiences and perceptions of older CALD people of fall prevention programs as well as the perspectives of program providers. Implications for Rehabilitation Program participation is influenced by cultural values and motivational, social and environmental factors. The meaning and importance of exercise can vary between and within cultures. Exercise and fall prevention interventions need to be culturally appropriate and utilise the positive influences of social support, especially from physicians and family. Providing information that falls can be prevented and the reasons why behaviours need to change will be more likely to encourage older people from CALD backgrounds to contemplate participation. PMID- 26119578 TI - Screening and facilitating further assessment for cognitive impairment after stroke: application of a shortened Montreal Cognitive Assessment (miniMoCA). AB - PURPOSE: The purpose of this study is to examine the performance of a shortened version of the MoCA (miniMoCA), as a clinical cognitive impairment screening tool in stroke rehabilitation patients. METHODS: Cognitive status was assessed using the MoCA and Cognistat in 72 patients. Agreement between the tests was assessed using the Kappa statistic. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of a miniMoCA to a MoCA score <26 was also examined. RESULTS: A significant level of agreement was found between the MoCA and miniMoCA to the Cognistat in classifying patients by level of cognitive function. The miniMoCA showed a sensitivity of 93% and specificity of 92% (PPV 98%, NPV 75%) to abnormal MoCA scores (<26). CONCLUSIONS: This study extends the utility of the miniMoCA as an optimal brief screening tool for cognitive impairment in stroke patients. Further research is needed to determine the validity of the miniMoCA against a neuropsychological test. IMPLICATIONS FOR REHABILITATION: Although the Montreal Cognitive Assessment (MoCA) is a recommended tool to screen for cognitive impairment in stroke patients, its lengthy administration can lead to inconsistent screening of patients for post stroke cognitive function. In the current work, a shortened version of the MoCA (miniMoCA) was administered in a sample of stoke inpatients, utilizing only five of the eight original subtests. The proposed miniMoCA was found to streamline the administration of this screen test, while maintaining a heightened level of sensitivity for accurately identifying which patients do not require a more in depth cognitive assessment. PMID- 26119579 TI - European roe deer antlers as an environmental archive for fallout (236)U and (239)Pu. AB - Anthropogenic (236)U and (239)Pu were measured in European roe deer antlers hunted between 1955 and 1977 which covers and extends beyond the period of intensive nuclear weapons testing (1954-1962). The antlers were hunting trophies, and hence the hunting area, the year of shooting and the approximate age of each animal is given. Uranium and plutonium are known to deposit in skeletal tissue. Since antler histology is similar to bone, both elements were expected in antlers. Furthermore, roe deer shed their antlers annually, and hence antlers may provide a time-resolved environmental archive for fallout radionuclides. The radiochemical procedure is based on a Pu separation step by anion exchange (Dowex 1 * 8) and a subsequent U purification by extraction chromatography using UTEVA((r)). The samples were measured by Accelerator Mass Spectrometry at the VERA facility (University of Vienna). In addition to the (236)U and (239)Pu concentrations, the (240)Pu/(239)Pu isotopic ratios were determined with a mean value of 0.172 +/- 0.023 which is in agreement with the ratio of global fallout (~0.18). Rather high (236)U/(238)U ratios of the order of 10(-6) were observed. These measured ratios, where the (236)U arises only from global fallout, have implications for the use of the (236)U/(238)U ratio as a fingerprint for nuclear accidents or releases from nuclear facilities. Our investigations have shown the potential to use antlers as a temporally resolved archive for the uptake of actinides from the environment. PMID- 26119580 TI - Impact of fluoroquinolones on human microbiota. Focus on the emergence of antibiotic resistance. AB - The aggregate of microorganisms residing on the surface of the skin, in the oropharynx and in the GI tract, known as the human microbiota, play a major role as natural reservoirs for bacterial resistance to antibiotics. Fluoroquinolones (FQ) are among the most prescribed antibiotics and a major increase in FQ resistance is occurring worldwide. High concentrations of FQ are found in microbial ecosystems explaining their profound effect on the clinically relevant bacteria that compose them. Yet, because of different local pharmacokinetics, distinct selective pressures occur in the different microbiota. Here we review the qualitative and quantitative impact of FQ on the three main human microbiota and their consequences, particularly in terms of emergence of antibiotic resistance. Finally, we review potential actions that could decrease the impact of FQs on microbiota. PMID- 26119581 TI - Duplex-selective ruthenium-based DNA intercalators. AB - We report the design and synthesis of small molecules that exhibit enhanced luminescence in the presence of duplex rather than single-stranded DNA. The local environment presented by a well-known [Ru(dipyrido[3,2-a:2',3'-c]phenazine)L2 ](2+) -based DNA intercalator was modified by functionalizing the bipyridine ligands with esters and carboxylic acids. By systematically varying the number and charge of the pendant groups, it was determined that decreasing the electrostatic interaction between the intercalator and the anionic DNA backbone reduced single-strand interactions and translated to better duplex specificity. In studying this class of complexes, a single Ru(II) complex emerged that selectively luminesces in the presence of duplex DNA with little to no background from interacting with single-stranded DNA. This complex shows promise as a new dye capable of selectively staining double- versus single-stranded DNA in gel electrophoresis, which cannot be done with conventional SYBR dyes. PMID- 26119582 TI - The furoxan nitric oxide donor, PRG150, evokes dose-dependent analgesia in a rat model of painful diabetic neuropathy. AB - Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is often intractable. Elevated nitric oxide (NO) from neuronal and non-neuronal sources in the somatosensory system is implicated in the pathobiology of peripheral neuropathic pain. However, in diabetes, nitrergic nerve degeneration to deplete NO bioactivity appears causal in the pathogenesis of irreversible autonomic neuropathy, another long term complication of diabetes. Hence, this study hypothesized that progressive NO depletion may underpin the pathobiology of PDN and that NO donors may alleviate PDN. Diabetes was induced in rats with intravenous streptozotocin (STZ) at 70 mg/kg and confirmed if blood glucose levels (BGLs) on day 10 post-STZ were >=15 mmol/L. Analgesic efficacy of subcutaneous (s.c.) bolus doses of the furoxan NO donor, PRG150 was assessed in the STZ-diabetic rat model of PDN at 10-, 14- and 24-weeks post-STZ relative to the sydnominine NO donor, SIN-1 and its prodrug, molsidomine. PRG150 produced dose-dependent analgesia in STZ-diabetic rats whereas SIN-1 and molsidomine evoked neuro-excitatory side-effects, but not analgesia. The 1000-fold larger doses of PRG150 needed to produce analgesia at 14- and 24-weeks (800 pmol/kg) c.f. 10-weeks (8 fmol/kg) post-STZ in rats, suggest that progressive NO depletion is also causal in PDN. Importantly, doses of PRG150 up to 10 000 fold higher than the analgesic dose did not produce hypotension in rats. The 50-fold greater release of NO by SIN-1 c.f. PRG150 in vitro, may underpin the neuro-excitatory rather than analgesic effects of SIN-1/molsidomine. PRG150 is worthy of further investigation as a potential novel analgesic for PDN. PMID- 26119583 TI - Relationship of three different types of low-carbohydrate diet to cardiometabolic risk factors in a Japanese population: the INTERMAP/INTERLIPID Study. AB - PURPOSE: Low-carbohydrate diets (LCD) are a popular dietary strategy for weight reduction. The effects of LCD on long-term outcome vary depending on type of LCD, possibly due to the fact that effects on cardiometabolic risk factors may vary with different types of LCD. Accordingly, we studied these relations. METHODS: We assessed serum concentrations of high-density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), high-sensitivity C-reactive protein (CRP), total cholesterol, glycated hemoglobin, and uric acid, and nutrient intakes by standardized methods in men and women ages 40-59 years from four population samples of Japanese in Japan (553 men and 544 women, combined). For people consuming usual, animal-based, and plant-based LCDs, we calculated LCD scores, based on relative level of fat, protein, and carbohydrate, by modifying the methods of Halton et al. Instead of calculating scores based on animal or vegetable fat, we used saturated fatty acids (SFA) or monounsaturated fatty acids (MUFA) + polyunsaturated fatty acids (PUFA). RESULTS: In multivariate regression analyses with adjustment for site, age, sex, BMI, smoking, alcohol intake, physical activity, and years of education, all three LCD scores were significantly positively related to HDLc (all P < 0.001), but not to LDLc. The plant-based LCD score was significantly inversely related to log CRP (coefficient = -0.010, P = 0.018). CONCLUSIONS: All three LCD scores were significantly positively related to HDLc. The plant-based LCD score was significantly inversely related to CRP. Carbohydrate intake below 50 % of total energy with higher intakes of vegetable protein and MUFA + PUFA, and lower intakes of SFA may be favorable for reducing cardiometabolic risk factors. PMID- 26119584 TI - Impacts of New Zealand's lowered minimum purchase age on context-specific drinking and related risks. AB - AIMS: The minimum purchase age (MPA) for alcohol in New Zealand (NZ) was reduced from 20 to 18 years in 1999. We assessed the degree to which this change was associated with alterations in uses of drinking contexts, drinking and related problems. METHODS: NZ National Alcohol Surveys among people 14+ years of age provided demographics, frequencies and amounts consumed in drinking places, and problem measures for 1995, 2000 and 2004. Censored regression estimates of parameters of a context-specific dose-response model identified MPA-associated changes in drinking and problems. RESULTS: The lowered MPA was associated with more frequent drinking at pubs/nightclubs among the newly of-age 18-19-year-olds (b = 15.26, P = 0.009), moderated drinking quantities at these places (b = -0.94, P = 0.034) and greater quantities consumed at home (b = 1.01, P = 0.010) and others' homes (b = 0.87; P = 0.029). Drinking frequency and quantity in the 16-17 year age group increased at home (b = 22.11, P = 0.040 and b = 1.22, P = 0.002) and others' homes (b = 11.65, P = 0.002 and b = 0.91, P = 0.021). Problems associated with drinking contexts changed post-MPA (G(2) >= 27.45, P <= 0.002), specifically increased association with drinking in pubs/nightclubs (b = 0.09, P < 0.001) across both age groups. CONCLUSIONS: The 1999 change in New Zealand's minimum purchase age for alcohol from 20 to 18 years appears to have been associated with substantive changes in uses of drinking contexts, drinking and associated drinking problems among 16-19-year-olds. PMID- 26119585 TI - The CDKAL1 gene is associated with impaired insulin secretion and glucose-related traits: the Cardiometabolic Risk in Chinese (CRC) study. AB - OBJECTIVE: Insulin secretion and insulin resistance, which affect metabolic homoeostasis, each have a significant genetic component. Cyclin- dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1 (CDKAL1) rs10946398, a novel body mass index (BMI)-associated locus specifically in the Asian population, may impair insulin secretion and may be associated with insulin resistance and type 2 diabetes. Our objective was to investigate the impact of the rs10946398 polymorphism of CDKAL1 on insulin secretion, insulin resistance and glucose-related traits in the Chinese population. SUBJECTS AND METHODS: The study samples were based on a community-based health examination survey conducted in central China. Indices of insulin resistance and insulin secretion were derived from fasting glucose measurements and oral glucose tolerance tests (OGTTs). Using multivariate linear regression models, the relationships between the rs10946398 polymorphism of CDKAL1 and insulin secretion, insulin resistance and quantitative glucose-related traits were investigated in 2313 participants. RESULTS: The CDKAL1 rs10946398 C allele showed a significant association with decreased insulin secretion (beta = -0.05, P < 0.0005), but not with insulin resistance (beta = 0.02, P = 0.08). We also found that the CDKAL1 rs10946398 C allele was significantly associated with glucose-related traits (fasting glucose, fasting insulin, 2-h glucose and HbA1c). There was no significant relationship between rs10946398 and other metabolic traits. CONCLUSIONS: rs10946398 of CDKAL1 was associated with markers of impaired insulin secretion. It is reasonable to infer that the relationship between CDKAL1 and metabolic diseases is mediated by its effect on glucose-related traits. PMID- 26119586 TI - SorCS1 variants and amyloid precursor protein (APP) are co-transported in neurons but only SorCS1c modulates anterograde APP transport. AB - Processing of amyloid precursor protein (APP) into amyloid-beta peptide (Abeta) is crucial for the development of Alzheimer's disease (AD). Because this processing is highly dependent on its intracellular itinerary, altered subcellular targeting of APP is thought to directly affect the degree to which Abeta is generated. The sorting receptor SorCS1 has been genetically linked to AD, but the underlying molecular mechanisms are poorly understood. We analyze two SorCS1 variants; one, SorCS1c, conveys internalization of surface-bound ligands whereas the other, SorCS1b, does not. In agreement with previous studies, we demonstrate co-immunoprecipitation and co-localization of both SorCS1 variants with APP. Our results suggest that SorCS1c and APP are internalized independently, although they mostly share a common post-endocytic pathway. We introduce functional Venus-tagged constructs to study SorCS1b and SorCS1c in living cells. Both variants are transported by fast anterograde axonal transport machinery and about 30% of anterograde APP-positive transport vesicles contain SorCS1. Co-expression of SorCS1b caused no change of APP transport kinetics, but SorCS1c reduced the anterograde transport rate of APP and increased the number of APP-positive stationary vesicles. These data suggest that SorCS1 and APP share trafficking pathways and that SorCS1c can retain APP from insertion into anterograde transport vesicles. Altered APP trafficking is thought to modulate its processing. SorCS1 has been suggested to function in APP trafficking. We analyzed if the two SorCS1 variants, SorCS1b and SorCS1c, tie APP to the cell surface or modify its internalization and intracellular targeting. We observed co localization and vesicular co-transport of APP and SorCS1, but independent internalization and sorting through a common post-endocytic pathway. Co expression of one variant, SorCS1c, reduced anterograde APP transport. These data demonstrate that SorCS1 and APP share trafficking pathways and that SorCS1c can retain APP from insertion into anterograde transport vesicles. PMID- 26119587 TI - Systematic investigation of phthalocyanines, naphthalocyanines, and their aza analogues. Effect of the isosteric aza-replacement in the core. AB - A series of zinc complexes of phthalocyanine, naphthalocyanine and their aza analogues with alkylsulfanyl substituents was synthesized and characterized by UV vis and MCD spectroscopy, and their redox properties were investigated using CV, DPV, and SWV approaches as well as spectroelectrochemical methods. Aggregation, photostability, singlet oxygen production, and fluorescence quantum yields of the target complexes were studied as a function of the stepwise substitution of the aromatic C-H fragments by nitrogen atoms. The electronic structure and vertical excitation energies of the target compounds were probed by DFT-PCM and TDDFT-PCM approaches. Introduction of additional nitrogens into the structure leads to a hypsochromic shift of the Q-band and makes the macrocycle strongly electron deficient and more photostable. The impact on the photophysics is limited. The relationships between the type of macrocycle and the studied properties were defined. PMID- 26119588 TI - Quantification of viable but nonculturable Salmonella spp. and Shigella spp. during sludge anaerobic digestion and their reactivation during cake storage. AB - AIMS: The presence of viable but nonculturable (VBNC) bacterial pathogens which often fail to be detected by cultivation and can regain the cultivability if the living conditions improve were reported. The objective of this study was to determine the occurrence of VBNC Salmonella spp. and Shigella spp. in the biosolids during anaerobic digestion and its reactivation during the cake storage. METHODS AND RESULTS: The occurrence of VBNC Salmonella spp. and Shigella spp. during mesophilic, temperature-phased, thermophilic anaerobic digestion of sewage sludge and the subsequent storage were studied by RT-qPCR and most probable number (MPN) method. The VBNC incidence of Salmonella spp. and Shigella spp. during thermophilic digestion was four orders of magnitude higher than those of mesophilic digestion. Accordingly, higher resuscitation ratio of VBNC pathogens was also achieved in thermophilic digested sludge. As a result, the culturable Salmonella typhimurium contents in thermophilic digested sludge after cake storage were two orders of magnitude higher than mesophilic digestion. Both quantitative PCR and reverse transcription quantitative PCR assay results showed the two bacterial counting numbers remained stable throughout the cake storage. CONCLUSIONS: The results indicate that the increase in the culturable Salmonella spp. and Shigella spp. after centrifugal dewatering was attributed to the resuscitation from the VBNC state to the culturable state. SIGNIFICANCE AND IMPACT OF THE STUDY: Thermophilic anaerobic digestion mainly induced Salmonella spp. and Shigella spp. into VBNC state rather than killed them, suggesting that the biological safety of sewage sludge by temperature-phased anaerobic digestion should be carefully assessed. PMID- 26119589 TI - Biomechanical and biophysical environment of bone from the macroscopic to the pericellular and molecular level. AB - Bones with complicated hierarchical configuration and microstructures constitute the load-bearing system. Mechanical loading plays an essential role in maintaining bone health and regulating bone mechanical adaptation (modeling and remodeling). The whole-bone or sub-region (macroscopic) mechanical signals, including locomotion-induced loading and external actuator-generated vibration, ultrasound, oscillatory skeletal muscle stimulation, etc., give rise to sophisticated and distinct biomechanical and biophysical environments at the pericellular (microscopic) and collagen/mineral molecular (nanoscopic) levels, which are the direct stimulations that positively influence bone adaptation. While under microgravity, the stimulations decrease or even disappear, which exerts a negative influence on bone adaptation. A full understanding of the biomechanical and biophysical environment at different levels is necessary for exploring bone biomechanical properties and mechanical adaptation. In this review, the mechanical transferring theories from the macroscopic to the microscopic and nanoscopic levels are elucidated. First, detailed information of the hierarchical structures and biochemical composition of bone, which are the foundations for mechanical signal propagation, are presented. Second, the deformation feature of load-bearing bone during locomotion is clarified as a combination of bending and torsion rather than simplex bending. The bone matrix strains at microscopic and nanoscopic levels directly induced by bone deformation are critically discussed, and the strain concentration mechanism due to the complicated microstructures is highlighted. Third, the biomechanical and biophysical environments at microscopic and nanoscopic levels positively generated during bone matrix deformation or by dynamic mechanical loadings induced by external actuators, as well as those negatively affected under microgravity, are systematically discussed, including the interstitial fluid flow (IFF) within the lacunar-canalicular system and at the endosteum, the piezoelectricity at the deformed bone surface, and the streaming potential accompanying the IFF. Their generation mechanisms and the regulation effect on bone adaptation are presented. The IFF-induced chemotransport effect, shear stress, and fluid drag on the pericellular matrix are meaningful and noteworthy. Furthermore, we firmly believe that bone adaptation is regulated by the combination of bone biomechanical and biophysical environment, not only the commonly considered matrix strain, fluid shear stress, and hydrostatic pressure, but also the piezoelectricity and streaming potential. Especially, it is necessary to incorporate bone matrix piezoelectricity and streaming potential to explain how osteoblasts (bone formation cells) and osteoclasts (bone resorption cells) can differentiate among different types of loads. Specifically, the regulation effects and the related mechanisms of the biomechanical and biophysical environments on bone need further exploration, and the incorporation of experimental research with theoretical simulations is essential. PMID- 26119590 TI - Formation of Highly Ordered Spherical Aggregates from Drying Microdroplets of Colloidal Suspension. AB - The formation of highly ordered spherical aggregates of silica nanoparticles by the evaporation of single droplets of an aqueous colloidal suspension levitated (confined) in the electrodynamic quadrupole trap is reported. The transient and final structures formed during droplet evaporation have been deposited on a silicon substrate and then studied with SEM. Various successive stages of the evaporation-driven aggregation of nanoparticles have been identified: formation of the surface layer of nanoparticles, formation of the highly ordered spherical structure, collapse of the spherical surface layer leading to the formation of densely packed spherical aggregates, and rearrangement of the aggregate into the final structure of a stable 3D quasi-crystal. The evaporation-driven aggregation of submicrometer particles in spherical symmetry leads to sizes and morphologies of the transient and final structures significantly different than in the case of aggregation on a substrate. The numerical model presented in the article allows us to predict and visualize the observed aggregation stages and their dynamics and the final aggregates observed with SEM. PMID- 26119591 TI - Phylogenetic relationships within the Cercocebus-Mandrillus clade as indicated by craniodental morphology: Implications for evolutionary biogeography. AB - OBJECTIVE: The African papionin primates commonly known as mangabeys form a diphyletic group with white-eyelid mangabeys (Cercocebus) being most closely related to drills and mandrills (Mandrillus). However, the phylogenetic relationships among members of the Cercocebus-Mandrillus clade have not been investigated in detail, particularly from a morphological perspective. Early studies of white-eyelid mangabeys considered C. agilis to best represent the ancestral lineage and C. torquatus as the most derived species, the result of multiple biogeographic dispersal events. More recently, a sister-clade relationship between Mandrillus and either C. chrysogaster or C. torquatus has been proposed. MATERIALS AND METHODS: Here we present the results of phylogenetic analyses based on 206 craniodental characters (103 representing males and females separately) of four species of Cercocebus and both species of Mandrillus. RESULTS: When all species of the Cercocebus-Mandrillus clade are analyzed without molecular constraints, results suggest that C. torquatus may indeed be more closely related to mandrills and drills than to other Cercocebus taxa. However, this topology lacks strong statistical support and may be attributable to incomplete lineage sorting and/or reticulation. When we employ a molecular backbone to constrain Cercocebus and Mandrillus monophyly, C. torquatus appears most basal, while C. agilis and C. chrysogaster form a derived clade. DISCUSSION: The molecular backbone view is also congruent with recent genetic analyses and assessments based on the fossil record, but awaits confirmation with additional data. This phylogeny suggests that Cercocebus and Cercocebus + Mandrillus arose in western equatorial Africa with subsequent dispersals westward, eastward, and possibly southward over the last > 3 million years. Am J Phys Anthropol 158:227 241, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26119592 TI - The impact of Cystic Fibrosis Transmembrane Regulator Disruption on cardiac function and stress response. AB - BACKGROUND: Altered cardiac function has been observed in cystic fibrosis transmembrane regulator (CFTR) knockout mice. However, whether this alteration is a direct effect of CFTR disruption in the heart, or is secondary due to systemic loss of CFTR, remains to be elucidated. METHODS: Cardiac function of mice with muscle-specific or global knockout of CFTR was evaluated at baseline and under beta-stimulation by MRI in vivo. Myocyte contractility and Ca2+ transients were measured in vitro. RESULTS: Both CFTR knockout models showed increased twist and torsion at baseline. Response to beta-stimulation was unaltered in muscle specific CFTR knockout mice and was slightly decreased in global CFTR knockout mice. Aortic diameter was also decreased in both mouse models. No difference was observed in myocyte contractility and Ca2+ transients. CONCLUSIONS: CFTR disruption leads to increased myocardial contractility at baseline, which may trigger untoward myocardial remodeling in CF patients that is independent of lung diseases. PMID- 26119594 TI - Unconventional membrane lipid biosynthesis in Xanthomonas campestris. AB - All bacteria are surrounded by at least one bilayer membrane mainly composed of phospholipids (PLs). Biosynthesis of the most abundant PLs phosphatidylethanolamine (PE), phosphatidylglycerol (PG) and cardiolipin (CL) is well understood in model bacteria such as Escherichia coli. It recently emerged, however, that the diversity of bacterial membrane lipids is huge and that not yet explored biosynthesis pathways exist, even for the common PLs. A good example is the plant pathogen Xanthomonas campestris pv. campestris. It contains PE, PG and CL as major lipids and small amounts of the N-methylated PE derivatives monomethyl PE and phosphatidylcholine (PC = trimethylated PE). Xanthomonas campestris uses a repertoire of canonical and non-canonical enzymes for the synthesis of its membrane lipids. In this minireview, we briefly recapitulate standard pathways and integrate three recently discovered pathways into the overall picture of bacterial membrane biosynthesis. PMID- 26119595 TI - 2D ultrathin core-shell Pd@Pt(monolayer) nanosheets: defect-mediated thin film growth and enhanced oxygen reduction performance. AB - An operational strategy for the synthesis of atomically smooth Pt skin by a defect-mediated thin film growth method is reported. Extended ultrathin core shell structured d@Pt(monolayer) nanosheets (thickness below 5 nm) exhibit nearly seven-fold enhancement in mass-activity and surprisingly good durability toward oxygen reduction reaction as compared with the commercial Pt/C catalyst. PMID- 26119596 TI - Identification of the transcriptional regulators by expression profiling infected with hepatitis B virus. AB - BACKGROUND: The molecular pathogenesis of infection by hepatitis B virus with human is extremely complex and heterogeneous. To date the molecular information is not clearly defined despite intensive research efforts. Thus, studies aimed at transcription and regulation during virus infection or combined researches of those already known to be beneficial are needed. AIMS: With the purpose of identifying the transcriptional regulators related to infection of hepatitis B virus in gene level, the gene expression profiles from some normal individuals and hepatitis B patients were analyzed in our study. METHODS: In this work, the differential expressed genes were selected primarily. The several genes among those were validated in an independent set by qRT-PCR. Then the differentially co expression analysis was conducted to identify differentially co-expressed links and differential co-expressed genes. Next, the analysis of the regulatory impact factors was performed through mapping the links and regulatory data. In order to give a further insight to these regulators, the co-expression gene modules were identified using a threshold-based hierarchical clustering method. Incidentally, the construction of the regulatory network was generated using the computer software. RESULTS: A total of 137,284 differentially co-expressed links and 780 differential co-expressed genes were identified. These co-expressed genes were significantly enriched inflammatory response. The results of regulatory impact factors revealed several crucial regulators related to hepatocellular carcinoma and other high-rank regulators. Meanwhile, more than one hundred co-expression gene modules were identified using clustering method. CONCLUSIONS: In our study, some important transcriptional regulators were identified using a computational method, which may enhance the understanding of disease mechanisms and lead to an improved treatment of hepatitis B. However, further experimental studies are required to confirm these findings. PMID- 26119597 TI - Regional variation in energy storage strategies in American glass eels from Eastern Canada. AB - Energy status was analyzed in glass eels captured during two early waves of arrival at the mouths of the Mersey River, Nova Scotia, Canada (MR), and Grande Riviere-Blanche, Quebec, Canada (GRB), and according to their salinity preference (freshwater, brackish, or saltwater). Glass eels captured in the GRB estuary were larger, more pigmented, and exhibited higher whole-body glycogen, phospholipid, and sterol and wax ester contents. Those from MR had a higher condition index and a higher whole-body triacylglycerol content, suggesting different patterns of storage and/or use of energy reserves. Within a river, a delay of two weeks in estuarine arrival was characterized by significantly lower energy reserves. No differences in energy storage were observed according to salinity preference. Thus, the results revealed the occurrence of different energy storage strategies according to glass eel migration distance and duration, but not according to salinity preference. PMID- 26119598 TI - Is gill cortisol concentration a good acute stress indicator in fish? A study in rainbow trout and zebrafish. AB - Cortisol is the main biomarker of physiological stress in fish. It is usually measured in plasma, which requires blood collection. Though cortisol is produced in the anterior kidney, it can diffuse easily through cell membranes due to its lipophilic nature. Taking advantage of that, some non-invasive techniques have been developed to measure cortisol directly in the water from fish-holding tanks, in skin mucus or in scales. In this study, we explored the possibility to analyze fish cortisol from gill filaments as a reliable acute stress marker. Our results show that gill cortisol levels correlate well with plasma cortisol levels in both rainbow trout and zebrafish exposed or not to an acute stress protocol. Measuring cortisol in gill filaments increases the available possibilities for stress assessment in fish. Although this approach should yet be tested for its use with other stressors, it has several advantages: In relatively large fish (i.e. above 30 g) gill cortisol levels could be measured in vivo. Sampling of gill biopsies is very fast and easy, and the procedure does not induce stress if properly performed, making it an ideal option for in vivo stress assessment. In small fish, the use of gill tissue to measure cortisol has important technical advantages with respect to the current methods using whole-body homogenates. Gill homogenates could be used directly for ELISA cortisol analysis, avoiding the need of tedious and expensive cortisol extraction protocols, and, since no organic solvent is required, contributing for a more environmentally friendly analysis. PMID- 26119599 TI - Hatching behavior of eastern long-necked turtles (Chelodina longicollis): The influence of asynchronous environments on embryonic heart rate and phenotype. AB - Variable temperatures within a nest cause asynchronous development within clutches of freshwater turtle embryos, yet synchronous hatching occurs and is thought to be an important survival strategy for hatchlings. Metabolic compensation and circadian rhythms in heart rates of embryonic turtles indicate the potential of communication between embryos in a nest. Heart rates were used to identify metabolic circadian rhythms in clutches of an Australian freshwater turtle (Chelodina longicollis) and determine whether embryos metabolically compensate and hatch synchronously when incubated in asynchronous environments. The effects of a group environment during incubation on egg development and incubation period were also investigated during the final 3 weeks of development. Chelodina longicollis hatch synchronously and metabolically compensate so that less advanced embryos catch up to more advanced clutch-mates. Heart rates of embryos remained stable from week 4-7 in asynchronous (M=89 bpm) and synchronous (M=92 bpm) groups and declined in the final 2 weeks of incubation (M=72 and 77 bpm). Circadian rhythms were present throughout development and diel heart rates of embryos in asynchronous groups showed less deviation from the mean (M=-0.5 bpm) than synchronous groups (M=-4 bpm). Eggs incubated in groups had a significantly shorter incubation period than eggs incubated individually. Phenotypic traits including size, performance, and growth of all hatchlings were not affected. Egg position within a turtle nest is important for coordinating development throughout incubation and facilitating synchronous hatching. PMID- 26119600 TI - Biosensing by Tandem Reactions of Structure Switching, Nucleolytic Digestion, and DNA Amplification of a DNA Assembly. AB - phi29 DNA polymerase (phi29DP) is able to carry out repetitive rounds of DNA synthesis using a circular DNA template by rolling circle amplification (RCA). It also has the ability to execute 3'-5' digestion of single-stranded but not double stranded DNA. A biosensor engineering strategy is presented that takes advantage of these two properties of phi29DP coupled with structure-switching DNA aptamers. The design employs a DNA assembly made of a circular DNA template, a DNA aptamer, and a pre-primer. The DNA assembly is unable to undergo RCA in the absence of cognate target owing to the formation of duplex structures. The presence of the target, however, triggers a structure-switching event that causes nucleolytic conversion of the pre-primer by phi29DP into a mature primer to facilitate RCA. This method relays target detection by the aptamer to the production of massive DNA amplicons, giving rise to dramatically enhanced detection sensitivity. PMID- 26119602 TI - Thriving in the Midst of Distractions. PMID- 26119601 TI - Poor mobility predicts adverse outcome better than other frailty indices in patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Surgical risk scoring systems are poor at predicting outcome in patients undergoing transcatheter aortic valve implantation (TAVI). Frailty indices might more accurately predict outcome. AIMS: To examine multiple frailty indices as markers of performance to see whether they predict outcomes both in the shorter (30 days) and longer terms (5 years) in patients who have undergone TAVI. METHODS: Frailty indices (Mobility; Brighton Mobility Index, New York Heart Association (NYHA), Karnofsky Performance Index, Canadian Study Health Association (CSHA) clinical frailty scale, and Katz Index of Dependence) were assessed in 312 consecutive TAVI patients. Mortality tracking was obtained from the Office of National Statistics as of May 2014. RESULTS: Mean age was 81.2 +/- 7.0 years; 53.2% were male. Mean Logistic EuroSCORE and STS were 17.4 +/- 9.4 and 4.6 +/- 2.8, respectively. Mean peak aortic valve gradient and aortic valve area were 79.1 +/- 28.0 mm Hg and 0.72 +/- 0.25 cm(2) , respectively. 30-day mortality was 4.8%; long-term mortality (maximum 5.8 years, mean 2.2 +/- 1.5 years) was 25.3%. Both univariate and multivariate analyses confirmed poor mobility (defined as severe impairment of mobility secondary to musculoskeletal or neurological dysfunction (Euroscore II risk)), as the best predictor of adverse outcome over both the short-term (OR 4.03, 95% CI (1.36-11.96), P = 0.012 (30 days)) and longer term (OR 2.15, 95% CI (1.33-3.48), P = 0.002, (2.2 +/- 1.5 years.)). CONCLUSION: Poor mobility predicts worse survival among patients undergoing TAVI, both in the shorter and longer terms. Our data suggest that mobility impairment, of either neurological or musculoskeletal etiology, is an appropriate screening measure when considering patients for TAVI. PMID- 26119604 TI - A Few Minutes With Brigid Gillespie. PMID- 26119605 TI - Can Efficient Smoke Evacuation Limit Aerosolization of Bacteria? AB - Preventing surgical site infections requires knowledge of the sources of wound contamination. One possible source of wound contamination is bacteria aerosolized in diathermy plume (ie, surgical smoke). This study used an experimental model of porcine tissue embedded with Serratia marcescens to determine the extent of viable bacteria present in surgical plume. The results showed that only blended current electrosurgery, not laser plume or coagulation electrosurgery, contains viable bacteria. Further, the study revealed that placing a suction device near the electrosurgical site reduced the number of aerosolized viable bacteria. Therefore, evacuating the electrosurgical plume may help reduce contamination of the surgical wound. Nurses may wish to advocate for the use of air suction devices as one way to protect patients from surgical site infections. PMID- 26119606 TI - Postoperative Care of Patients Undergoing Same-Day Laparoscopic Cholecystectomy. AB - Elective laparoscopic cholecystectomies are common outpatient surgical procedures. After briefly discussing cholecystectomy and its indications, best practices in phase I, phase II, and phase III recovery are discussed. Typical pharmaceutical regimens for controlling pain and postoperative nausea and vomiting are summarized. By implementing best practices, nurses can prevent and recognize complications. The criteria for discharge, extended recovery, and inpatient admission are discussed, along with the required patient discharge teaching using the teach-back technique, as well as patient and family teaching needs in the immediate postoperative period. Nurses can optimize the patient's surgical experience and promote safety by implementing best practices in all phases of recovery from laparoscopic cholecystectomy. PMID- 26119607 TI - Back to Basics: Patient and Family Engagement. AB - Patient and family engagement is an active involvement in health care between patients, families, and their caregivers. Perioperative nurses should be active proponents of implementing patient engagement activities in the perioperative setting. This article introduces basic patient engagement concepts and how they can be implemented in the perioperative setting. PMID- 26119608 TI - Robotic-Assisted Thoracic Surgery for Early-Stage Lung Cancer: A Review. AB - This review evaluates the benefits and disadvantages associated with the use of robotic-assisted technology in performing lobectomies in patients with early stage lung cancer. The author conducted a literature search of Ovid(r), MEDLINE(r), PubMed(r), and CINAHL(r) for articles published from 2005 to 2013. Search criteria included key terms such as robot, robotic, robotic-assisted lobectomy, and lung cancer. Of 922 articles, the author included a total of 12 research-based published studies in the analysis and incorporated the findings into an evidence table. Results showed that robotic-assisted lobectomies are feasible safe procedures for patients with stage 1A or 1B lung cancer; however, there is a steep learning curve and long-term randomized studies evaluating robotic-assisted lobectomy and conventional posterolateral thoracotomy or video assisted thoracic lobectomy are needed. For patient safety, perioperative nurses should be aware of the length of time and experience required to perform these procedures, the costs, techniques, benefits, and disadvantages. PMID- 26119609 TI - Perioperative Nursing Leaders Implement Clinical Practice Guidelines Using the Iowa Model of Evidence-Based Practice. AB - Many health care organizations, nursing leaders, and individual clinicians are not providing care consistently based on evidence and many are not aware of the evidence that is available. Preventable complications have an adverse effect on hospital reimbursement and the burden is placed on hospital personnel and nursing leaders to use current evidence to improve care and prevent complications, such as surgical site infections. Using AORN resources, leadership involvement and ownership, and implementing a theoretical model will contribute to implementing daily evidence-based practice and help to decrease the chasm between research and practice. PMID- 26119610 TI - Crisis Management of Hypotension in the OR. AB - Perioperative nurses play a pivotal role in coordinating care during crises, employing their nursing skills to foster a positive outcome and collaborating with their colleagues and peers to achieve the desired resolution. Whether caring for a patient during a liver transplantation or one undergoing removal of a cyst, perioperative nurses know that a drop in the blood pressure may signal a momentary phenomenon or a critical event that can become a crisis. It is important for nurses to understand how the color of the patient's tissue, the strength of a pulse, or the downward trending of blood pressure readings can affect how well blood is distributed throughout the body and eventually adversely affect cellular viability with prolonged hypotension. Integrating the patient's objective data (ie, blood pressure readings, pulse oximetry) and subjective cues (ie, skin color) are important perioperative nursing skills that demonstrate clinical patient advocacy and judgment and are crucial for the successful treatment of hypotension. PMID- 26119611 TI - Using Personality Indicators to Enhance Nurse Leader Communication. PMID- 26119612 TI - Auditing Clinical Practice: Ensuring High Reliability at an Australian Hospital. PMID- 26119613 TI - Speaking Up to Reduce Noise in the OR. PMID- 26119615 TI - Clostridium difficile Relapse Secondary to Medication Access Issue. PMID- 26119616 TI - Computer Simulation Shows the Effect of Communication on Day of Surgery Patient Flow. AB - To improve patient flow in a surgical environment, practitioners and academicians often use process mapping and simulation as tools to evaluate and recommend changes. We used simulations to help staff visualize the effect of communication and coordination delays that occur on the day of surgery. Perioperative services staff participated in tabletop exercises in which they chose the delays that were most important to eliminate. Using a day-of-surgery computer simulation model, the elimination of delays was tested and the results were shared with the group. This exercise, repeated for multiple groups of staff, provided an understanding of not only the dynamic events taking place, but also how small communication delays can contribute to a significant loss in efficiency and the ability to provide timely care. Survey results confirmed these understandings. PMID- 26119617 TI - Pressure Mapping Comparison of Four OR Surfaces. AB - Mortality and health care costs associated with hospital-acquired pressure ulcers (HAPUs) increase yearly. After four hours of surgery, the risk of developing a pressure ulcer increases by 33% for every 30 minutes of surgery. Prolonged immobility, lower blood pressures, and increased surface interface pressure may hinder the blood supply delivered to the skin, eventually leading to pressure ulcers. We measured and compared four different OR surfaces to identify the most effective pressure redistribution surface for prolonged OR procedures. The best surface attributes that provide efficient pressure redistribution should have the following properties: the lowest average interface pressure, the lowest peak interface pressure, and the highest skin contact area. Although all surfaces had similar average interface pressures, the air-inflated static seat cushion had the best pressure redistribution properties in the sacral region compared with the other surfaces tested. PMID- 26119618 TI - 3-D Storybook: Effects on Surgical Knowledge and Anxiety Among Four- to Six-Year Old Surgical Patients. AB - Inadequate surgical knowledge potentiates anxiety; however, no methodology simultaneously addresses anxiety and surgical knowledge. Our quasi-experimental study determined the effectiveness of a three-dimensional (3-D) storybook in increasing surgical knowledge and decreasing anxiety among young children scheduled for planned or required major surgeries. We studied 20 randomly assigned participants who received either the 3-D storybook or traditional health teaching. A presurgical knowledge questionnaire and modified Yale Preoperative Anxiety Scale assessed surgical knowledge and anxiety. Data were analyzed with one-way and repeated-measures multivariate analysis of variance. Results showed that both groups had higher knowledge scores (F = 8.94; P = .008) and lower anxiety scores (F = 5.13; P = .036) after the intervention. The children who received information from the 3-D storybook exhibited a significantly higher posttest knowledge score (F = 11.71; P = .003) and lower anxiety score (F = 10.05; P = .005) than the traditionally educated group of children. The 3-D storybook effectively increased surgical knowledge and decreased anxiety and could be used as an alternative method to prepare pediatric surgical patients. PMID- 26119619 TI - Intra-operative digital specimen radiology reduces re-operation rates in therapeutic mammaplasty for breast cancer. AB - BACKGROUND: The aim of this study was to evaluate our experience with intra operative imaging of therapeutic mammaplasty specimens at Edinburgh Breast Unit. METHODS: A retrospective review was performed of patients who underwent therapeutic mammaplasty in Edinburgh Breast Unit between 2007 and 2013 who had intraoperative specimen radiography. RESULTS: 98 (100%) patients who underwent therapeutic mammaplasty for breast cancer had intra-operative imaging using the faxitron((r)) system. 3 out of those 97 (3%) patients had a re-operation because of positive margins confirmed pathologically on cavity excision specimens, but only 1 out of 3 (1%) patients had residual breast cancer present within the re excision specimen. None required mastectomy. Median age was 58 (range 34-81). Median follow up was 3.1 years (range 6 months - 5.5 years). There was no local recurrence or conversion to mastectomy in this group. CONCLUSION: Complete excision rate in patients who had intra-operative imaging during therapeutic mammaplsty procedure was 97% in our group. Faxitron((r)) system is a useful adjunct in helping to achieve low incomplete excision rates. PMID- 26119620 TI - Ion specificity of macromolecules in crowded environments. AB - Macromolecular crowding plays a significant role in the solubility and stability of biomacromolecules. In this work, the thermo-sensitive poly(N isopropylacrylamide) (PNIPAM) has been employed as a model system to study the specific ion effects on the solubility of macromolecules in crowded environments of dextran and polyethylene glycol (PEG). Our study demonstrates that crowding agents can interact with either anions or PNIPAM chains. The chaotropic anion SCN(-) interacts with dextran but does not interact with PEG. Both Cl(-) and CH3COO(-) do not interact with dextran and PEG. On the other hand, dextran can interact with PNIPAM as a hydrogen-bond donor, whereas PEG interacts with PNIPAM as a hydrogen-bond acceptor. The salting-in effect exerted by SCN(-) on PNIPAM is weakened in the crowded environment of dextran but is strengthened in the crowded environment of PEG due to the distinct anion-crowder interactions. In parallel, the salting-out effect generated by Cl(-) and CH3COO(-) on PNIPAM is weakened by the crowding of dextran but is strengthened by the crowding of PEG because of the different macromolecule-crowder interactions. Our study reveals that the ion specificity of macromolecules is altered significantly changing from dilute solutions to crowded environments. PMID- 26119621 TI - Electronic medical record analysis of emergency room visits and hospitalizations in individuals with epilepsy and mental illness comorbidity. AB - OBJECTIVE: Epilepsy is a chronic neurological condition that significantly increases risk of injury and premature death. Rates of mental illness are also disproportionately high in those with epilepsy, which can be attributed in part to the stress and stigma associated with epilepsy. Psychiatric conditions generally complicate the management of epilepsy, and understanding how psychiatric comorbidity affects use of crisis-based health resources could inform care approaches that help improve epilepsy care. To better understand effects of psychiatric comorbidity on epilepsy burden, we conducted a 5-year retrospective analysis of data from a large safety-net healthcare network and compared the occurrence of negative health events (NHEs), defined as emergency department (ED) visits and hospitalizations, among individuals with epilepsy and mental illness (E-MI) vs. those with epilepsy alone (E). METHODS: Electronic health record (EHR) data from a large Midwestern U.S. safety-net healthcare system were queried to identify a study population of adults >=18years with a diagnosis of epilepsy, with or without mental illness. We assessed demographic and clinical characteristics for each of the 5years and compared NHEs between subgroups with E MI vs. E. An additional analysis focused on those individuals who remained in the healthcare system over the entire 5-year study time frame (January, 2010 to December, 2014). Annual and cumulative NHE counts and hospital length of stay for individuals with E-MI and E were assessed, as were hospital discharge diagnoses. RESULTS: The number (approximately 2000) and demographic characteristics of individuals with epilepsy who received care each year of the study period was relatively consistent. In 2014, mean age of individuals with epilepsy was 48 (range: 18-95), 48.2% were women, 51.5% were White, 37.9% were African-American, and 8.6% were Hispanic. In 2014, there were 1616 (78.6%) individuals in the subgroup with E and 439 (21.4%) in the subgroup with E-MI. Most clinical and demographic variables between the subgroups with E-MI and E were similar, except that individuals with E-MI were less likely to be employed or commercially insured. Overall, NHEs were common, with over 1/4 (27.5%) of all individuals with epilepsy having an ED visit during the year, 13.7% having hospitalization, and 34.2% having either an ED visit or hospitalization. Individuals with E-MI had significantly more NHEs compared to individuals with epilepsy only, as evidenced by higher rates of any NHE (p<.001), ED visits (p<.001), and hospitalizations (p<.001). The cumulative differential in ED and hospital use between subgroups with E-MI and E was substantial over a 5-year time period. While most NHEs were directly related to seizures for the overall group, substance-use complications appeared as a top reason for hospitalization only in the group with E-MI. CONCLUSIONS: Individuals with E-MI made up just over 20% of all people with epilepsy in a safety-net system and had higher rates of NHEs than those without mental illness. Better and earlier identification of individuals with E-MI, assistance with self-management including helping individuals to optimize ambulatory care settings as opposed to the ED, and treatment for substance use disorders could eventually reduce NHEs in this vulnerable subgroup of individuals with epilepsy. PMID- 26119622 TI - Validation of diagnostic tests for depressive disorder in drug-resistant mesial temporal lobe epilepsy. AB - PURPOSE: This study aimed to evaluate the diagnostic accuracy of the Hamilton Rating Scale for Depression (HRSD), the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), and the Hospital Anxiety and Depression Scale-Depression subscale (HADS-D) as diagnostic tests for depressive disorder in drug-resistant mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). METHODS: One hundred three patients with drug-resistant MTLE HS were enrolled. All patients underwent a neurological examination, interictal and ictal video-electroencephalogram (V-EEG) analyses, and magnetic resonance imaging (MRI). Psychiatric interviews were based on DSM-IV-TR criteria and ILAE Commission of Psychobiology classification as a gold standard; HRSD, BDI, HADS, and HADS-D were used as psychometric diagnostic tests, and receiver operating characteristic (ROC) curves were used to determine the optimal threshold scores. RESULTS: For all the scales, the areas under the curve (AUCs) were approximately 0.8, and they were able to identify depression in this sample. A threshold of >=9 on the HRSD and a threshold of >=8 on the HADS-D showed a sensitivity of 70% and specificity of 80%. A threshold of >=19 on the BDI and HADS-D total showed a sensitivity of 55% and a specificity of approximately 90%. The instruments showed a negative predictive value of approximately 87% and a positive predictive value of approximately 65% for the BDI and HADS total and approximately 60% for the HRSD and HADS-D. CONCLUSIONS: HRSD>=9 and HADS-D>=8 had the best balance between sensitivity (approximately 70%) and specificity (approximately 80%). However, with these thresholds, these diagnostic tests do not appear useful in identifying depressive disorder in this population with epilepsy, and their specificity (approximately 80%) and PPV (approximately 55%) were lower than those of the other scales. We believe that the BDI and HADS total are valid diagnostic tests for depressive disorder in patients with MTLE-HS, as both scales showed acceptable (though not high) specificity and PPV for this type of study. PMID- 26119623 TI - Factors influencing the photocatalytic activity of rutile TiO2 nanorods with different aspect ratios for dye degradation and Cr(VI) photoreduction. AB - Shape-controlled rutile TiO2 nanorods (NRs) with large {110} and small {111} exposed facets were prepared by hydrothermal treatment of a peroxo titanic acid (PTA) solution. The aspect ratio of the NRs was controlled by the pH of the PTA solution and the addition of polyvinyl alcohol (PVA) or polyvinyl pyrrolidone (PVP). The spatial separation of reduction and oxidation sites, where {110} facets act as reduction sites and {111} facets as oxidation ones, was revealed by tracking the distribution of Pt and PbO2 deposited on the NR surfaces. The MB degradation activity depended on the aspect ratio of the rutile NRs because of the different separation efficiencies of photo-generated carriers on different facets. Meanwhile, the Cr(VI) reduction activity was governed by the slight shift of the conduction-band potential of the rutile NRs estimated from Mott-Schottky plots, which may be caused by the variation of the content of {110} facets in the rutile NRs. Among the prepared rutile NRs, the sample prepared using a PTA solution at pH 4 containing 10 mg of PVA showed higher activity for photocatalytic Cr(VI) reduction than Degussa P25. These results provide a feasible method to design efficient TiO2 photocatalysts with tunable photoreactivity for environmental applications. PMID- 26119624 TI - Tests for detecting overdispersion in models with measurement error in covariates. AB - Measurement error in covariates can affect the accuracy in count data modeling and analysis. In overdispersion identification, the true mean-variance relationship can be obscured under the influence of measurement error in covariates. In this paper, we propose three tests for detecting overdispersion when covariates are measured with error: a modified score test and two score tests based on the proposed approximate likelihood and quasi-likelihood, respectively. The proposed approximate likelihood is derived under the classical measurement error model, and the resulting approximate maximum likelihood estimator is shown to have superior efficiency. Simulation results also show that the score test based on approximate likelihood outperforms the test based on quasi-likelihood and other alternatives in terms of empirical power. By analyzing a real dataset containing the health-related quality-of-life measurements of a particular group of patients, we demonstrate the importance of the proposed methods by showing that the analyses with and without measurement error correction yield significantly different results. PMID- 26119625 TI - The bacteriology of hidradenitis suppurativa: a systematic review. AB - Hidradenitis suppurativa (HS) is a chronic inflammatory disabling skin disease consisting of recurrent nodules, sinuses, fistulas and scarring involving the intertriginous regions. HS is often a therapeutic challenge and most treatments are off-label. A better understanding of aetiology and pathogenesis of HS may facilitate the development of effective treatment. Although the clinical presentation is strongly reminiscent of bacterial infection, the role of bacteria remains controversial. Studies have isolated an array of different bacteria specimens. Consistent findings of Gram-positive cocci and Gram-positive rods including Staphylococus aureus, coagulase-negative staphylococci (CoNS) and Corynebacterium species in deep tissue samples have been demonstrated in HS and may constitute a central target for the immune system. Efficacy of antibiotics, that is rifampicin, clindamycin or tetracycline, supports a microbial role in disease pathogenesis. However, these antibiotics also work as immunomodulators of especially T cells, and the underlying mechanisms may therefore be more complex. We performed a systematic review of previous studies investigating the bacterial flora in hidradenitis suppurativa. We searched PubMed, EMBASE, Royal Danish Library and Cochrane library (search date 11 December 2014). A total of 66 papers were identified and nine papers published between 1988 and 2014 matched our inclusion criteria, yielding bacteriological data of a total of 324 patients with HS (mean age 36.8 years and female/male ratio 215/109). This overview of the bacteriology may aid researchers and physicians exploring the potential role of bacteria in HS. Furthermore, to stimulate a broader debate, we also present different viewpoints on the possible role of bacteria in HS. PMID- 26119626 TI - Mercury concentrations in Atlantic bottlenose dolphins (Tursiops truncatus) inhabiting the Indian River Lagoon, Florida: Patterns of spatial and temporal distribution. AB - Bottlenose dolphins (Tursiops truncatus) inhabiting the Indian River Lagoon, FL (IRL) have tissue mercury concentrations among the highest reported worldwide. Analysis of total mercury (THg) concentrations in blood collected between 2003 and 2012 showed a significant linear decrease over time (p=0.04). Significant differences in the spatial distribution of THg in resident IRL dolphins were also observed with a general gradient in concentration from north to south. Evaluation of local biogeochemistry and accumulation of mercury in prey species is needed to better understand factors influencing the distribution of Hg in the apex predator. Analyses of temporal and spatial patterns of exposure to THg in this sentinel species may have implications for both ecosystem and public health in the region. PMID- 26119627 TI - Short-term impact of deep sand extraction and ecosystem-based landscaping on macrozoobenthos and sediment characteristics. AB - We studied short-term changes in macrozoobenthos in a 20m deep borrow pit. A boxcorer was used to sample macrobenthic infauna and a bottom sledge was used to sample macrobenthic epifauna. Sediment characteristics were determined from the boxcore samples, bed shear stress and near-bed salinity were estimated with a hydrodynamic model. Two years after the cessation of sand extraction, macrozoobenthic biomass increased fivefold in the deepest areas. Species composition changed significantly and white furrow shell (Abra alba) became abundant. Several sediment characteristics also changed significantly in the deepest parts. Macrozoobenthic species composition and biomass significantly correlated with time after cessation of sand extraction, sediment and hydrographical characteristics. Ecosystem-based landscaped sand bars were found to be effective in influencing sediment characteristics and macrozoobenthic assemblage. Significant changes in epifauna occurred in deepest parts in 2012 which coincided with the highest sedimentation rate. We recommend continuing monitoring to investigate medium and long-term impacts. PMID- 26119628 TI - Pollutant tracking for 3 Western North Atlantic sea grasses by remote sensing: Preliminary diminishing white light responses of Thalassia testudinum, Halodule wrightii, and Zostera marina. AB - Sea grasses are foundation species for estuarine ecosystems. The available light for sea grasses diminishes rapidly during pollutant spills, effluent releases, disturbances such as intense riverine input, and tidal changes. We studied how sea grasses' remote-sensing signatures and light-capturing ability respond to short term light alterations. In vivo responses were measured over the entire visible-light spectra to diminishing white-light on whole-living-plants' spectral reflectance, including 6h of full oceanic-light fluences from 10% to 100%. We analyzed differences by various reflectance indices. We compared the sea grasses species responses of tropical vs. temperate and intertidals (Halodule wrightii, and Zostera marina) vs. subtidal (Thalassia testudinum). Reflectance diminished with decreasing light intensity that coincided with greater accessory pigment stimulation (anthocyanin, carotenoids, xanthins). Chlorophyll a and Chlorophyll b differed significantly among species (Thalassia vs. Halodule). Photosynthetic efficiency diminished at high light intensities. The NDVI index was inadequate to perceive these differences. Our results demonstrate the leaf-level utility of data to remote sensing for mapping sea grass and sea grass stress. PMID- 26119629 TI - THE IMPACT OF SOCIOECONOMIC FACTORS ON QUALITY OF LIFE OF PATIENTS WITH CHRONIC KIDNEY DISEASE IN GREECE. AB - BACKGROUND: Quality of Life (QoL) is often poor in people undergoing dialysis and this sometimes contributes to the high rate of morbidity and mortality. The aim of our study is to assess the QoL of patients on haemodialysis in Greece and discuss the socio-demographic factors that affect QoL in this period of financial crisis. DESIGN/PATIENTS: Patients with CKD not on dialysis, plus those undergoing Haemodialysis (HD) and Peritoneal Dialysis (PD) were invited to complete the SF 36 questionnaire electronically, supervised by a trained nurse. Patients were asked about their marital status, education level and monthly household income. Additionally, patients were requested to comment on their subjective financial difficulties. RESULTS: A total of 172 patients were enrolled in the study, 39 of them were undergoing PD, 90 on HD and 43 had CKD. Among those with CKD, on HD and PD, 9.3%, 17.8% and 23.1%, respectively, had 'some/a lot' difficulties in copying with financial problems. The physical component summary score was significant lower in HD, while the summary score of the mental component showed no differences between the groups. In multiple linear regression analysis, age and dialysis had significantly negative correlations with physical functioning scores. Those who were divorced or widowed tended to perform worse in physical scores compared with those who were married. Mental scores were affected only by coping with financial difficulties. CONCLUSIONS: In general terms, people with CKD patients present with a poor QoL. Apart from the burden of the renal disease per se, social and economic factors (divorce, financial difficulties) seem to aggravate their status, especially in this period of financial crisis. PMID- 26119630 TI - Calcium phosphate nanocoatings and nanocomposites, part I: recent developments and advancements in tissue engineering and bioimaging. AB - A number of materials have been applied as implant coatings and as tissue regeneration materials. Calcium phosphate holds a special consideration, due to its chemical similarity to human bone and, most importantly, its dissolution characteristics, which allow for bone growth and regeneration. The applications of molecular and nanoscale-based biological materials have been and will continue to play an ever increasing role in enhancing and improving the osseointegration of dental and orthopedic implants. More recently, extensive research efforts have been focused on the development and applications of fluorescent nanoparticles and nanocoatings for in vivo imaging and diagnostics as well as devising methods of adding luminescent or fluorescent capabilities to enhance the in vivo functionality of calcium phosphate-based biomedical materials. PMID- 26119631 TI - Which shoulder motions cause subacromial impingement? Evaluating the vertical displacement and peak strain of the coracoacromial ligament by ultrasound speckle tracking imaging. AB - BACKGROUND: Subacromial impingement is a common cause of shoulder pain and one cause of rotator cuff disease. We aimed to identify which shoulder motions cause subacromial impingement by measuring the vertical displacement and peak strain of the coracoacromial ligament using ultrasound speckle tracking imaging. METHODS: Sixteen shoulders without shoulder disability were enrolled. All subjects were men, and the average age was 28.6 years. The vertical displacement and peak strain of the coracoacromial ligament were analyzed by the motion tracing program during the following active assisted motions (active motion controlled by the examiner): (1) forward flexion in the scapular plane, (2) horizontal abduction in the axial plane, (3) external rotation with the arm at 0 degrees abduction (ER0), (4) internal rotation with the arm at 0 degrees abduction (IR0), (5) internal rotation with the arm at 90 degrees abduction (IR90), and (6) internal rotation at the back (IRB). RESULTS: The mean vertical displacement of the coracoacromial ligament during forward flexion (2.2 mm), horizontal abduction (2.2 mm), and IR90 (2.4 mm) was significantly greater than that during the other motions (ER0, -0.7 mm; IR0, 0.5 mm; IRB, 1.0 mm; P < .003). The mean peak strain was significantly higher in forward flexion (6.88%), horizontal abduction (6.58%), and IR90 (4.88%) than with the other motions (ER0, 1.42%; IR0, 1.78%; IRB, 2.61%; P < .003). CONCLUSIONS: Forward flexion, horizontal abduction, and IR90 showed higher vertical displacement and peak strain of the coracoacromial ligament, causing subacromial impingement. It is recommended that patients with impingement syndrome or a repaired rotator cuff avoid these shoulder motions. PMID- 26119632 TI - Assessment of the optimal shoulder outcome score for reverse shoulder arthroplasty. AB - BACKGROUND: With growing attention being paid to quality and cost-effectiveness in health care, outcome evaluations are becoming increasingly important. This determination can be especially difficult in reverse shoulder arthroplasty (RSA) given the complex pathology and extensive disabilities in this patient population. This study evaluated the use of 3 validated questionnaires used to assess outcomes for RSA. METHODS: Using a database of patients treated with RSA, we assessed preoperative and postoperative Constant-Murley Scores, American Shoulder and Elbow Surgeons Scores, and Subjective Shoulder Values in 148 shoulders. The outcomes at each scoring period were described, and the scores were compared with one another as well as with active range of motion. RESULTS: There were no significant differences in the mean improvement of any of the scores. Improvements in all of the outcome scales were correlated with each other and with improvement in forward elevation but not with external rotation. Multivariate regression analysis the 3 outcome measures was able to predict 38.9% of the variation in improvement in functional outcomes (forward elevation). This was only slightly greater than that provided by improvements in the outcome variable Constant-Murley score alone (36.7%). CONCLUSIONS: The 3 shoulder outcome scores evaluated, regardless of whether they were patient reported or physician based, appear to appropriately reflect improvements after RSA with equal validity. The objective physician-assessed Constant-Murley score had the strongest correlation with function of the arm, and use of a combination of all 3 outcome scores did not increase the ability to predict range of motion compared with using the Constant-Murley score alone. PMID- 26119633 TI - The management of recurrent shoulder instability in patients with epilepsy: a 15 year experience. AB - BACKGROUND: The purpose of this study was to review our experience with recurrent shoulder instability in epileptic patients and to discuss factors influencing its management. METHODS: A retrospective review was conducted at a single facility. All patients with epilepsy and recurrent shoulder instability were included for study. RESULTS: A consecutive series of 33 patients with 49 unstable shoulders presented during a 15-year period. Mean age at the time of the index dislocation was 20 years (range, 9-31). There were 24 patients with 36 anteriorly unstable shoulders, 6 patients with 8 posteriorly unstable shoulders, and 3 patients with 5 multidirectionally unstable shoulders. A large Hill-Sachs lesion was present in 21 shoulders. Glenoid bone loss was seen in 11 cases and involved >25% of the anterior-inferior margin in 6 cases and >50% in 2 cases. Thirty-six shoulders in 31 patients underwent surgery. Ongoing postoperative instability was found in 61% (22 of 36 shoulders) of the anterior group, 38% (3 of 8 shoulders) of the posterior group, and 40% (2 of 5 shoulders) of the multidirectional group. Skeletal reconstruction was found to be associated with a significantly lower rate of recurrence compared with an isolated soft tissue repair (P = .004). Glenohumeral arthrosis was found in 17 patients (22 shoulders) a mean of 12 years (range, 5-20) after the index dislocation. CONCLUSION: The presence of bone loss and degenerative changes are the principal factors affecting the specific surgical strategy employed to treat shoulder instability in patients with epilepsy. PMID- 26119635 TI - Anatomical study of the infraorbital foramen: A basis for successful infraorbital nerve block. AB - Detailed knowledge of variations of the infraorbital foramen (IOF) and the establishment of a constant reference point for needle insertion are important for safe and successful regional block and for avoiding iatrogenic injury to the nerve during surgery in the midfacial region. Infraorbital foramina from 133 sides of 67 dry intact adult skulls of undetermined gender were examined for variations in shape, number, location in relation to bony landmarks, and relationship to the maxillary teeth. The angles of needle insertion in the sagittal and Frankfurt planes were determined. The infraorbital foramina were located at an average distance of 6.33 +/- 1.39 mm below the infraorbital margin, 25.69 +/- 2.37 mm from the median plane, 15.19 +/- 1.70 mm from the lateral margin of the piriform aperture, and 28.41 +/- 2.82 mm above the maxillary alveolar border. The average angles of needle insertion through the IOF with the sagittal and Frankfurt planes were 21.14 degrees +/- 10.10 degrees and 31.79 degrees +/- 7.68 degrees , respectively. Multiple foramina were found in 21% of the hemi-skulls. The foramen was less than 2 mm in size in 23.31% of the hemi skulls. The position of the IOF with respect to the maxillary teeth varied from the interval between the canine and first premolar to the first molar, but in half of the specimens it lay in line with the second maxillary premolar tooth. The observations made in this study should be useful for planning infraorbital nerve block or surgery around the IOF. PMID- 26119634 TI - 3D scapular orientation on healthy and pathologic subjects using stereoradiographs during arm elevation. AB - BACKGROUND: Alterations of the scapular kinematics in different pathologic conditions have been widely studied. However, results have shown considerable discrepancies concerning the direction and the amplitude of scapular movement. The lack of consistency in the literature probably has several explanations. The purpose of this study was to analyze scapular orientation with the arm at rest and with 90 degrees lateral elevation in healthy and pathologic subjects by use of stereoradiographs. MATERIALS AND METHODS: All participants (n = 65) underwent a clinical examination and magnetic resonance imaging of the shoulder to assess rotator cuff status. Participants were separated into 3 groups: healthy, rotator cuff tear (RCT), and RCT and subacromial impingement syndrome (RCT+ SIS). A 3 dimensional model of the scapula was fitted to each low-dose stereoradiograph acquired with the arm at rest and 90 degrees arm elevation. RESULTS: Orientation of the scapula with the arm at rest was not significantly different between groups. During lateral elevation, scapular orientation was not significantly different between the healthy group and the RCT group. However, upward rotation was significantly reduced in the RCT + SIS group. CONCLUSION: Alterations of scapular kinematics in symptomatic subjects are multifactorial. We observed a link between clinically assessed subacromial impingement and scapular orientation during lateral elevation of the arm. PMID- 26119636 TI - Calling all Campy--how routine investigation and molecular characterization impacts the understanding of campylobacteriosis epidemiology--Alaska, United States, 2004-2013. AB - Unlike most jurisdictions in the United States, Alaska performs pulsed-field gel electrophoresis (PFGE) characterization of all Campylobacter sp. isolates at the state public health laboratory--a practice that started in 2002. Moreover, in order to ensure early detection and response to campylobacteriosis outbreaks, the Alaska Section of Epidemiology has investigated all incident Campylobacter sp. case reports since 2004. This report summarizes the public health impact of routine incident case investigations and molecular characterization of all Campylobacter sp. isolates. In sum, we found that these efforts have contributed to better characterization of the epidemiology of campylobacteriosis in Alaska, and facilitated more rapid outbreak detection, more public health investigations, and earlier public health interventions. PMID- 26119637 TI - Exploring the potential of sequential simulation. AB - CONTEXT: Several recent papers have highlighted the need for better integrated care to improve health care for children and families. Our team spent a year exploring the potential of 'Sequential Simulation' (SqS) as a teaching tool to address this need with young people and multidisciplinary teams. SqS allows the simulation of a series of key events or 'crunch points' that come together to represent the patient journey, and highlights the impact of individuals on this journey. The pilot SqS was based on an adolescent with asthma - a common condition that requires excellent multidisciplinary care with the patient at the centre. INNOVATION: The SqS was designed using transportable sets and audio visual equipment to create realism. Actors were employed to play the roles of the young person and mother and health professionals played themselves. The SqS was run at different events with varied audiences, including young people, health professionals and teachers. It was used to explore the difficulties that can arise during a patient journey, the importance of communication throughout, and to highlight the significance of each individual in the patient experience. RESULTS: The SqS was met with enthusiasm and felt to be an innovative and effective way of promoting better teamwork and communication. It was well received at a school asthma education event for pupils and community teams, demonstrating its varied potential. The year was the first step in the introduction of this exciting new concept that has the potential to help promote better integrated care for paediatric patients and their families. Our team spent a year exploring the potential of 'Sequential Simulation' as a teaching tool [to provide better integrated care]. PMID- 26119638 TI - Highly stable Na2/3 (Mn0.54 Ni0.13 Co0.13 )O2 cathode modified by atomic layer deposition for sodium-ion batteries. AB - For the first time, atomic layer deposition (ALD) of Al2 O3 was adopted to enhance the cyclic stability of layered P2-type Na2/3 (Mn0.54 Ni0.13 Co0.13 )O2 (MNC) cathodes for use in sodium-ion batteries (SIBs). Discharge capacities of approximately 120, 123, 113, and 105 mA h g(-1) were obtained for the pristine electrode and electrodes coated with 2, 5, and 10 ALD cycles, respectively. All electrodes were cycled at the 1C discharge current rate for voltages between 2 and 4.5 V in 1 M NaClO4 electrolyte. Among the electrodes tested, the Al2 O3 coating from 2 ALD cycles (MNC-2) exhibited the best electrochemical stability and rate capability, whereas the electrode coated by 10 ALD cycles (MNC-10) displayed the highest columbic efficiency (CE), which exceeded 97 % after 100 cycles. The enhanced electrochemical stability observed for ALD-coated electrodes could be a result of the protection effects and high band-gap energy (Eg =9.00 eV) of the Al2 O3 coating layer. Additionally, the metal-oxide coating provides structural stability against mechanical stresses occurring during the cycling process. The capacity, cyclic stability, and rate performance achieved for the MNC electrode coated with 2 ALD cycles of Al2 O3 reveal the best results for SIBs. This study provides a promising route toward increasing the stability and CE of electrode materials for SIB application. PMID- 26119639 TI - Carotid Subclavian Bypass and Stent Grafting for Mycotic Pseudoaneurysm of Right Subclavian Artery. AB - BACKGROUND: The occurrence of mycotic pseudoaneurysms of the subclavian artery (SA) is rare. Only 3 cases of a combined open and endovascular treatment of true SA aneurysms have been reported. Conventional treatment for SA pseudoaneurysms is invasive thoracic surgery. Ours is a novel approach for mycotic pseudoaneurysm. METHODS: A 72 year-old man with gastric cancer developed vocal cord paralysis because of a mycotic pseudoaneurysm of the right SA, after Hickman line insertion. Because of the close proximity between the pseudoaneurysm at the origin of the SA and the innominate and common carotid arteries, a combined endovascular and open carotid SA bypass was performed. RESULTS: At 1-year follow up, he recovered well, remained cancer-free, with resolution of the pseudoaneurysm. Both the anastomoses and stents remained widely patent. CONCLUSIONS: This case represents the first reported successful treatment of a mycotic SA pseudoaneurysm through a combined open bypass and covered stenting, with encouraging outcomes at 1-year follow-up. PMID- 26119640 TI - Ruptured Mycotic Aortic Aneurysm after Bacille Calmette-Guerin Therapy. AB - To report a case of a ruptured mycotic abdominal aortic aneurysm (MAA) after intravesical Bacille Calmette-Guerin (BCG) therapy because of bladder carcinoma. A 57-year-old male patient was admitted to our hospital for follow-up computed tomography 14 months after transurethral resection of a papillary carcinoma of the bladder and intravesical BCG therapy. The CT scan revealed a ruptured MAA aneurysm and the patient underwent an endovascular repair with an aorto-bi-iliac stent graft. A ruptured MAA is a rare but lethal complication after BCG instillation therapy. The standard therapy is the open reconstruction but according to the literature an endovascular therapy in combination with long-term antibiotics should be considered as a bridging or a definite solution. PMID- 26119641 TI - Review of pharmacotherapy options for the management of obesity. AB - PURPOSE: To highlight the prevalence and impact of obesity in the United States and provide nurse practitioners (NPs) with an overview of pharmacotherapy options for treatment of overweight and obese individuals. DATA SOURCE: A comprehensive review of the literature was conducted using multiple databases, including PubMed, MEDLINE, and Ovid. Keywords used to obtain relevant articles included obesity and drug, or orlistat, topiramate/phentermine, lorcaserin, bupropion/naltrexone, and liraglutide. CONCLUSIONS: Obesity is a prevalent disease with more than two thirds of Americans being considered overweight and one third being obese. Obesity places patients at an increased risk for many comorbidities that impact patient health as well as public health. There are currently five approved medications for the chronic management of obesity, two of which were approved in 2014. These pharmacological therapies are options to aid weight loss in patients that are obese or those who are overweight with additional risk factors. IMPLICATIONS FOR PRACTICE: NPs can assist patients struggling with their weight. With new pharmacotherapy options, there is an opportunity to add to diet and exercise in order to achieve increased weight loss. A decrease in obesity would potentially alleviate the burden on the healthcare system, both socially and economically, and improve patient quality of life. PMID- 26119643 TI - Erratum. PMID- 26119642 TI - Chronic Pain in HIV-Infected Patients: Relationship to Depression, Substance Use, and Mental Health and Pain Treatment. AB - OBJECTIVE: As the advent of highly active antiretroviral therapy, HIV has become a chronic disease for most individuals in developed countries. Chronic pain is a common occurrence for HIV-infected patients and has an impact on quality of life and antiretroviral adherence. The objective of this study was to examine relationships between chronic pain and depression, substance use, mental health treatment, and pain treatment in HIV-infected patients. DESIGN: Cross-sectional study. SETTING: Three primary care sites where HIV+ patients receive treatment. SUBJECTS: Two hundred and thirty eight HIV-infected primary care patients. METHODS: We collected self-report and chart-review information on demographics, HIV clinical status, chronic pain, depression, substance use, mental health treatment, and pain treatment. We collected data between October 2012 and November 2013. RESULTS: Of the patients enrolled in this study, 107 reported no chronic pain, 24 reported mild chronic pain, and 107 reported moderate-severe chronic pain. Participants in the moderate-severe pain group were more likely to have high levels of depressive symptoms than those in the no chronic pain group. Similarly, there was a significant relationship between chronic pain status and interference with life activities due to pain. Participants with moderate-severe chronic pain were more likely to be taking an antidepressant medication than those with mild chronic pain, and more likely to be taking a prescription opioid than the other two groups. We did not find a significant relationship between problematic substance use and chronic pain status. CONCLUSIONS: Despite pharmacologic treatment, moderate-severe chronic pain and elevated depression symptoms are common among HIV-infected patients and frequently co-occur. PMID- 26119645 TI - Erratum. PMID- 26119644 TI - Introduction: Role of mental health professionals in the care of infertile patients. AB - The authors of this Views and Reviews describe the evolution of the role of mental health counseling in infertility care. As the use of assisted reproductive technologies and third-party reproduction has grown, so too has the interest and demand for mental health services. A historical perspective is presented that sets the stage for subsequent discussions of key areas where mental health practitioners are able to contribute to the utility and outcomes of infertile patients as well as those involved in their care. This series of articles stresses the value of more comprehensive integration of mental health support into infertility practice and highlights practical opportunities to do so. PMID- 26119646 TI - Endoscopic extraction of Fasciolopsis buski presenting as acute upper GI bleeding in a child. PMID- 26119647 TI - Novel technique for the management of staple line leaks after sleeve gastrectomy. PMID- 26119648 TI - Novel endoscopic approach for a large intraluminal duodenal ("windsock") diverticulum. PMID- 26119649 TI - Endoscopic management of stomal stenosis after Roux-en-Y gastric bypass. PMID- 26119650 TI - Double peroral endoscopic myotomy for achalasia. PMID- 26119651 TI - Role of Narrowband Ultraviolet B Phototherapy in the Treatment of Childhood Psoriasis in Asian Children. AB - Narrowband ultraviolet B (NBUVB) phototherapy is a well-established treatment modality for psoriasis. We performed a retrospective analysis of children of East Asian descent with psoriasis treated with NBUVB phototherapy at the National Skin Centre, Singapore, over a 5-year period between 2004 and 2008 and found that NBUVB phototherapy is safe and effective for the treatment of psoriasis in children of East Asian descent. PMID- 26119652 TI - Robotic liver resection for malignancy: Current status, oncologic outcomes, comparison to laparoscopy, and future applications. AB - Utilization of robotic techniques for resection of the liver is slowly gaining acceptance in specific situations and is now being applied to more challenging endeavors, such as major hepatectomy for cancer. This review provides a summary of robotic applications in liver surgery, with specific attention perioperative outcomes, oncologic outcomes, cost, and comparison to conventional laparoscopic techniques of liver resection. We also discuss future applications of robotic assisted liver surgery. PMID- 26119653 TI - Predictors and Outcomes of Routine Versus Optimal Medical Therapy in Stable Coronary Heart Disease. AB - Although randomized studies have shown optimal medical therapy (OMT) to be as efficacious as revascularization in stable coronary heart disease (CHD), the application of OMT in routine practice is suboptimal. We sought to understand the predictors of receiving OMT in stable CHD and its impact on clinical outcomes. All patients with stable CHD based on coronary angiography from October 2008 to September 2011 were identified in Ontario, Canada. OMT was defined as concurrent use of beta blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and statin. Aspirin use was not part of the OMT definition because of database limitations. Multivariable hierarchical logistic models identified predictors of OMT in the 12 months after angiography. Cox proportional hazard models with time-varying covariates for OMT and revascularization status examined differences in death and nonfatal myocardial infarction (MI). In these models, patients transitioned among 4 mutually exclusive treatment groups: no OMT and no revascularization, no OMT and revascularization, OMT and no revascularization, OMT and revascularization. Our cohort had 20,663 patients. Over a mean period of 2.5 years, 8.7% had died. Only 61% received OMT within 12 months. The strongest predictor of receiving OMT at 12 months was OMT before the angiogram (odds ratio 14.40, 95% confidence interval [CI] 13.17 to 15.75, p <0.001). Relative to no OMT and nonrevascularized patients, patients on OMT and revascularized had the greatest reduction in mortality (hazard ratio 0.52, 95% CI 0.45 to 0.60, p <0.001) and nonfatal MI (hazard ratio 0.74, 95% CI 0.64 to 0.84, p <0.001). In conclusion, our study highlights the low rate of OMT in stable CHD. Patients who received both OMT and revascularization achieved the greatest reduction in mortality and nonfatal MI. PMID- 26119654 TI - On-Statin Resistin, Leptin, and Risk of Recurrent Coronary Events After Hospitalization for an Acute Coronary Syndrome (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Study). AB - Resistin is an adipokine secreted by macrophages and inflammatory cells linked to insulin resistance and inflammation. Leptin is an adipokine regulator of appetite and obesity. Although circulating levels of both have been associated with atherosclerosis, few data have reported their relation to coronary events in the context of statin therapy. This study measured on-statin levels of both resistin and leptin through enzyme-linked immunosorbent assay in a nested case-control cohort (n = 176 cases with coronary death, myocardial infarction, or unstable angina pectoris observed in follow-up matched 1:1 to 176 controls) derived from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 study, a randomized controlled trial of atorvastatin 80 mg/day versus pravastatin 40 mg/day in patients with a recent acute coronary syndrome. Resistin demonstrated a moderate association with high-sensitivity C reactive protein (hsCRP; Spearman rho = 0.25, p <0.0001). On-statin resistin levels were linked to recurrent coronary events in conditional logistic regression analysis adjusted for additional risk factors including hsCRP and history of diabetes (tertile 3 vs 1 adjusted odds ratio 2.08; 95% confidence interval [CI] 1.04 to 4.19). An additive risk was noted when patients were stratified by resistin and glycated hemoglobin levels. In contrast, leptin levels were associated with obesity, diabetes, triglycerides, and hsCRP (p <0.001 for each) but demonstrated no association with recurrent coronary events (tertile 3 vs 1 adjusted odds ratio 0.72; 95% CI 0.28 to 1.83). In conclusion, on-statin resistin, but not leptin, is an independent marker of residual risk for recurrent coronary events in patients after hospitalization for an acute coronary syndrome. PMID- 26119655 TI - Meta-Analysis of Comparison of the Newer Oral P2Y12 Inhibitors (Prasugrel or Ticagrelor) to Clopidogrel in Patients With Non-ST-Elevation Acute Coronary Syndrome. AB - Newer oral P2Y12 inhibitors are more potent and have faster onset of action than clopidogrel. However, the efficacy and safety in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) are not well studied. A systemic search of MEDLINE and EMBASE databases was performed to identify randomized clinical trials comparing newer oral P2Y12 inhibitors (prasugrel or ticagrelor) to clopidogrel in patients with NSTE-ACS. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and stroke (major cardiovascular events [MACE]). Secondary outcomes were individual components of the primary outcome, all-cause mortality, and Thrombolysis In Myocardial Infarction (TIMI) major and minor bleeding. A total of 31,470 patients with NSTE-ACS from 4 randomized clinical trials were included (newer oral P2Y12 inhibitors: 15,951; clopidogrel: 15,519). Newer oral P2Y12 inhibitors significantly decreased MACE (relative risk [RR] 0.87, 95% confidence interval [CI] 0.80 to 0.95) and MI (RR 0.85, 95% CI 0.75 to 0.96) and showed a trend toward reduction of cardiovascular death (RR 0.89, 95% CI 0.71 to 1.01). There was a significant increase in TIMI major bleeding (RR 1.27, 95% CI 1.07 to 1.50) and TIMI major or minor bleeding (RR 1.20, 95% CI 1.02 to 1.42). Results were largely similar when stratified by ticagrelor versus prasugrel (pinteraction >0.05) except for increased TIMI major/minor bleeding with prasugrel than ticagrelor (pinteraction = 0.01). In conclusion, in patients with NSTE-ACS, newer oral P2Y12 inhibitors decrease MACE and MI at the expense of a significant increase in the risk of bleeding. Treatment of 1,000 patients with newer oral P2Y12 inhibitors will prevent 16 MACE and 13 MIs at the expense of increase in 6 major bleeding events. PMID- 26119656 TI - The neutrophil function and lymphocyte profile of milk from bovine mammary glands infected with Streptococcus dysgalactiae. AB - Streptococcus dysgalactiae is a bacterium that accounts for a notable proportion of both clinical and subclinical intramammary infections (IMIs). Thus, the present study explores the function of milk neutrophils and the lymphocyte profile in mammary glands naturally infected with Streptococcus dysgalactiae. Here, we used 32 culture-negative control quarters from eight clinically healthy dairy cows with low somatic cell counts and 13 S. dysgalactiae-infected quarters from six dairy cows. Using flow cytometry, we evaluated the percentage of milk monocytes/macrophages and neutrophils, expression of CD62L, CD11b and CD44 by milk neutrophils, the levels of intracellular reactive oxygen species (ROS) production and phagocytosis of Staphylococcus aureus by milk neutrophils, and neutrophil viability. Furthermore, the percentages of B cell (CD21(+)) and T lymphocyte subsets (CD3(+)/CD4(+)/CD8(-); CD3(+)/CD8(+)/CD4(-); and CD3(+)/CD8( )/CD4(-)), and the expression of CD25 by T milk lymphocytes (CD3(+)) and T CD4(+) milk cells were also assessed by flow cytometry using monoclonal antibodies. The present study showed a higher SCC and percentage of milk neutrophils, and a decrease in the percentage of milk monocytes/macrophages from S. dysgalactiae infected quarters when compared to uninfected ones. We also observed a higher expression of CD11b by milk neutrophils and a tendency toward a decrease in neutrophil apoptosis rate in S. dysgalactiae-infected quarters. In addition, the S. dysgalactiae-infected quarters had higher percentages of milk T cells (CD3(+)) and their subset CD3(+)CD8(+)CD4(-) cells. Overall, the present study provided new insights into S. dysgalactiae IMIs, including distinct lymphocyte profiles, and a tendency toward an inhibition of apoptosis in milk neutrophils. PMID- 26119657 TI - Flexible flapping wings with self-organized microwrinkles. AB - Bio-inspired flapping wings with a wrinkled wing membrane were designed and fabricated. The wings consist of carbon fibre-reinforced plastic frames and a polymer film with microscale wrinkles inspired by bird feathers and the corrugations of insect wings. The flexural and tensile stiffness of the wrinkled film can be controlled by modifying the orientations and waveforms of the wrinkles, thereby expanding the design space of flexible wings for micro flapping wing aerial robots. A self-organization phenomenon was exploited in the fabrication of the microwrinkles such that microscale wrinkles spanning a broad wing area were spontaneously created. The wavy shape of these self-organized wrinkles was used as a mould, and a Parylene film was deposited onto the mould to form a wrinkled wing film. The effect of the waveforms of the wrinkles on the film stiffness was investigated theoretically, computationally and experimentally. Compared with a flat film, the flexural stiffness was increased by two orders of magnitude, and the tensile stiffness was reduced by two orders of magnitude. To demonstrate the effect of the wrinkles on the actual deformation of the flapping wings and the resulting aerodynamic forces, the fabricated wrinkled wings were tested using a tethered electric flapping mechanism. Chordwise unidirectional wrinkles were found to prevent fluttering near the trailing edge and to produce a greater aerodynamic lift compared with a flat wing or a wing with spanwise wrinkles. Our results suggest that the fine stiffness control of the wing film that can be achieved by tuning the microwrinkles can improve the aerodynamic performance of future flapping-wing aerial robots. PMID- 26119658 TI - Scientific Fireworks to Celebrate the 50th Anniversary of the Burgenstock Conference. PMID- 26119659 TI - Biomass Oxidation: Formyl C-H Bond Activation by the Surface Lattice Oxygen of Regenerative CuO Nanoleaves. AB - An integrated experimental and computational investigation reveals that surface lattice oxygen of copper oxide (CuO) nanoleaves activates the formyl C-H bond in glucose and incorporates itself into the glucose molecule to oxidize it to gluconic acid. The reduced CuO catalyst regains its structure, morphology, and activity upon reoxidation. The activity of lattice oxygen is shown to be superior to that of the chemisorbed oxygen on the metal surface and the hydrogen abstraction ability of the catalyst is correlated with the adsorption energy. Based on the present investigation, it is suggested that surface lattice oxygen is critical for the oxidation of glucose to gluconic acid, without further breaking down the glucose molecule into smaller fragments, because of C-C cleavage. Using CuO nanoleaves as catalyst, an excellent yield of gluconic acid is also obtained for the direct oxidation of cellobiose and polymeric cellulose, as biomass substrates. PMID- 26119661 TI - Inhibition of abscission layer formation by an interaction of two seed-shattering loci, sh4 and qSH3, in rice. AB - Loss of seed shattering was one of the key phenotypic changes selected for in the domestication of many crop species. Asian cultivated rice, Oryza sativa L., was domesticated from its wild ancestor, O. rufipogon, and three seed-shattering loci, qSH1, sh4 and qSH3, have been reported to be involved in the loss of seed shattering in cultivated rice. Here, we analysed the seed-shattering behaviour of wild rice using introgression lines carrying the cultivated alleles from O. sativa Nipponbare in the genetic background of wild rice, O. rufipogon W630. We first carried out fine mapping of the qSH3 region and found that the qSH3 locus is localized in an 850-kb region on chromosome 3. We then analysed the effects of the Nipponbare alleles at sh4 and qSH3 on seed-shattering behaviour in wild rice, as a mutation at qSH1 was not commonly found in rice cultivars. Seed-shattering behaviour did not change in the two types of introgression line independently carrying the Nipponbare-homozygous alleles at sh4 or qSH3 in the genetic background of wild rice. However, the introgression lines having the Nipponbare homozygous alleles at both sh4 and qSH3 showed a reduction in the degree of seed shattering. Histological and scanning electron microscopy analyses revealed that abscission layer formation was inhibited around the vascular bundles in these lines. Since the qSH3 region, as well as sh4, has been shown to be under artificial selection, the interaction of mutations at these two loci may have played a role in the initial loss of seed shattering during rice domestication. PMID- 26119660 TI - Effects of intra- and interspecific competition on the sensitivity of Daphnia magna populations to the fungicide carbendazim. AB - The ecological risk assessment of pesticides is generally based on toxicity data obtained from single-species laboratory experiments and does not take into account ecological interactions such as competition or predation. Intraspecific and interspecific competition are expected to result in additional stress and might increase the sensitivity of aquatic populations to pesticide contamination. To test this hypothesis, the effects of the fungicide carbendazim were assessed on the population dynamics of the micro-crustacean Daphnia magna under different levels of intraspecific and interspecific competition for an algal food resource, using the rotifer Brachionus calyciflorus as competing species. The experiments were performed in glass jars with three different carbendazim concentrations (i.e., 50, 100 and 150 ug/L), and had a duration of 25 days, with a 4-day pre treatment period in which competition was allowed to take place and a 21-day exposure period. The endpoints evaluated were D. magna total population abundance and population structure. Results of these experiments show that competition stress on its own had a significant influence on shaping D. magna population's structure, however, a different response was observed in the intraspecific and interspecific competition experiments. The use of a 4-day pre-treatment period in the intraspecific experiment already led to an absence of interactive effects due to the quick abundance confluence between the different intraspecific treatments, thus not allowing the observation of interactive effects between competition and carbendazim stress. Results of the interspecific competition experiment showed that rotifers were quickly outcompeted by D. magna and that D. magna even profited from the rotifer presence through exploitative competition, which alleviated the original stress caused by the algal resource limitation. These experiments suggest that competition interactions play an important role in defining population-level effects of pesticides in a more complex way than was hypothesized ("increasing competition leading to a sensitivity increase"), as the interspecific experiment showed. Therefore, these should be taken into account in the extrapolation of single-species toxicity data to protect higher levels of biological organization. PMID- 26119662 TI - Drosophila Ogg1 is required to suppress 8-oxo-guanine accumulation following oxidative stress. AB - Reactive oxygen species (ROS) generated during energy production processes are a major cause of oxidative DNA damage. A DNA glycosylase encoded by the Ogg1 gene removes oxidized guanine bases and is widely conserved. However, the biological role of the gene in individual organisms has not yet been characterized in Drosophila, which is a suitable model to study the influence of oxidative damage on senescence. Here, we performed a genetic analysis to confirm that Ogg1 plays an essential role in the removal of 8-oxo-guanines from nuclei. We first confirmed by quantitative real-time PCR that Ogg1 mRNA expression was reduced by 30-55% in Ogg1 mutants and in flies expressing inducible Ogg1 dsRNA compared to control flies. We then showed that additional accumulation of 8-oxo-guanines occurred in the nuclei of epithelial midgut cells after paraquat feeding in flies with downregulated Ogg1 expression. We confirmed that a transposon possessing the UAS sequence was integrated in the 5'-UTR of the Ogg1 alleles and that it is oriented in the same transcriptional direction as the gene. Using the Gal4/UAS system, which enables us to induce ectopic expression in Drosophila, we induced overexpression of Ogg1 by 40-fold. We observed a lower amount of 8-oxo-guanine in the midgut epithelial cells of adults overexpressing Ogg1. These genetic data strongly suggest that the Drosophila Ogg1 ortholog CG1795 plays an essential role in the suppression of 8-oxo-guanines, consistent with its role in other organisms. Although adult flies with reduced Ogg1 expression failed to show elevated sensitivity to paraquat, those with Ogg1 overexpression showed resistance to oxidative stress by paraquat feeding and had a significantly longer lifespan in normal feeding conditions. These observations are consistent with the hypothesis that oxidative DNA damage by ROS accumulation is a major contributor to senescence. PMID- 26119663 TI - Molecular phylogenetic characterization of common murine rodents from Manipur, Northeast India. AB - The Indian subcontinent and Southeast Asia are hotspots of murine biodiversity, but no species from the Arakan Mountain system that demarcates the border between the two areas has been subjected to molecular phylogenetic analyses. We examined the mitochondrial cytochrome b gene sequences in six murine species (the Rattus rattus species complex, R. norvegicus, R. nitidus, Berylmys manipulus, Niviventer sp. and Mus musculus) from Manipur, which is located at the western foot of the mountain range. The sequences of B. manipulus and Niviventer sp. examined here were distinct from available congeneric sequences in the databases, with sequence divergences of 10-15%. Substantial degrees of intrapopulation divergence were detected in R. nitidus and the R. rattus species complex from Manipur, implying ancient habitation of the species in this region, while the recent introduction by modern and prehistoric human activities was suggested for R. norvegicus and M. musculus, respectively. In the nuclear gene Mc1r, also analyzed here, the R. rattus species complex from Manipur was shown to possess allelic sequences related to those from the Indian subcontinent in addition to those from East Asia. These results not only fill gaps in the phylogenetic knowledge of each taxon examined but also provide valuable insight to better understand the biogeographic importance of the Arakan Mountain system in generating the species and genetic diversity of murine rodents. PMID- 26119664 TI - Genetic diversity and population structure of the long-tailed goral, Naemorhedus caudatus, in South Korea. AB - The long-tailed goral, Naemorhedus caudatus, is an internationally endangered species. This species is distributed throughout Northeastern Asia including Northeastern China, the Russian Far East and the Korean peninsula. The population size of long-tailed gorals is currently decreasing in South Korea, and thus effective conservation of the animal is urgently needed. Although the evolution and phylogeny of this animal have been studied, population genetic studies are needed to design effective conservation and management strategies. To evaluate the present status of genetic diversity and genetic structure of long-tailed gorals in South Korea, we investigated genetic variability among 68 goral individuals from different regions, including 11 captive zoo animals, at 12 microsatellite loci. The level of genetic diversity was moderate in wild goral populations, but lower in the captive group. The goral population from the lower northeast region of South Korea was distinct from the upper northeast population, probably due to the natural climatic and geographic conditions. The genetic characteristics of the captive group were more similar to those of the upper northeast population than the lower northeast, confirming that the zoo animals originated in the Seorak Mountain range. Direct translocations between the upper and lower northeast populations are not currently recommended considering the natural population structure and the moderate levels of genetic diversity in the two populations. This study highlights the importance of genetic information in designing effective conservation strategies and translocations of endangered animals, including the Korean goral. PMID- 26119665 TI - CG-containing oligonucleotides and transcription factor-binding motifs are enriched in human pericentric regions. AB - Unsupervised data mining capable of extracting a wide range of information from big sequence data without prior knowledge or particular models is highly desirable in an era of big data accumulation for research on genes, genomes and genetic systems. By handling oligonucleotide compositions in genomic sequences as high-dimensional data, we have previously modified the conventional SOM (self organizing map) for genome informatics and established BLSOM for oligonucleotide composition, which can analyze more than ten million sequences simultaneously and is thus suitable for big data analyses. Oligonucleotides often represent motif sequences responsible for sequence-specific binding of proteins such as transcription factors. The distribution of such functionally important oligonucleotides is probably biased in genomic sequences, and may differ among genomic regions. When constructing BLSOMs to analyze pentanucleotide composition in 50-kb sequences derived from the human genome in this study, we found that BLSOMs did not classify human sequences according to chromosome but revealed several specific zones, which are enriched for a class of CG-containing pentanucleotides; these zones are composed primarily of sequences derived from pericentric regions. The biological significance of enrichment of these pentanucleotides in pericentric regions is discussed in connection with cell type and stage-dependent formation of the condensed heterochromatin in the chromocenter, which is formed through association of pericentric regions of multiple chromosomes. PMID- 26119666 TI - beta-Globin gene cluster haplotypes of Hb D-Los Angeles in Mazandaran Province, Iran. AB - Several types of hemoglobin D (Hb D) are distinguishable by DNA analysis, and the aim of this study was to identify the types of Hb D variant and beta-globin gene haplotypes linked to Hb D in Mazandaran Province, northern Iran. Fifty five individuals were identified as Hb D carriers, and PCR-RFLP analysis revealed that all 55 had the Hb D-Los Angeles type. To identify haplotypes associated with the beta(D) allele, family linkage analysis, using the PCR-RFLP method for seven polymorphisms in the beta-globin gene cluster, was carried out on families of 23 of these 55 individuals. We observed three different haplotypes in association with Hb D-Los Angeles. In most cases (91.4%) beta(D) alleles were linked to haplotype I [+ - - - - + +]. Haplotype II [- + + - + + +] and an atypical haplotype [- + + - - + -] were each in association with the beta(D) allele in only one case (4.3%). This is the first report worldwide of the [- + + - - + -] haplotype in association with Hb D-Los Angeles. We conclude that more than 90% of the evaluated Hb D-Los Angeles alleles in Mazandaran have the same origin, and the two rare haplotypes may represent different genetic origins and/or other molecular events, such as gene conversion or recombination, in the region. PMID- 26119667 TI - Corrigendum: Mitochondrial genetic diversity, phylogeny and population structure of Hydropotes inermis in South Korea. PMID- 26119669 TI - Prolapse Recurrence after Transvaginal Mesh Removal. AB - PURPOSE: We determined the rate of pelvic organ prolapse recurrence after transvaginal mesh removal. MATERIALS AND METHODS: Following institutional review board approval a longitudinally collected database of women undergoing transvaginal mesh removal for complications after transvaginal mesh placement with at least 1 year minimum followup was queried for pelvic organ prolapse recurrence. Recurrent prolapse was defined as greater than stage 1 on examination or the need for reoperation at the site of transvaginal mesh removal. Outcome measures were based on POP-Q (Pelvic Organ Prolapse Quantification System) at the last visit. Patients were grouped into 3 groups, including group 1--recurrent prolapse in the same compartment as transvaginal mesh removal, 2--persistent prolapse and 3--prolapse in a compartment different than transvaginal mesh removal. RESULTS: Of 73 women 52 met study inclusion criteria from 2007 to 2013, including 73% who presented with multiple indications for transvaginal mesh removal. The mean interval between insertion and removal was 45 months (range 10 to 165). Overall mean followup after transvaginal mesh removal was 30 months (range 12 to 84). In group 1 (recurrent prolapse) the rate was 15% (6 of 40 patients). Four women underwent surgery for recurrent prolapse at a mean 7 of months (range 5 to 10). Two patients elected observation. The rate of persistent prolapse (group 2) was 23% (12 of 52 patients). Three women underwent prolapse reoperation at a mean of 10 months (range 8 to 12). In group 3 (de novo/different compartment prolapse) the rate was 6% (3 of 52 patients). One woman underwent surgical repair at 52 months. CONCLUSIONS: At a mean 2.5-year followup 62% of patients (32 of 52) did not have recurrent or persistent prolapse after transvaginal mesh removal and 85% (44 of 52) did not undergo any further procedure for prolapse. Specifically for pelvic organ prolapse in the same compartment as transvaginal mesh removal 12% of patients had recurrence, of whom 8% underwent prolapse repair. PMID- 26119668 TI - Evaluation and Management of the Adolescent Varicocele. AB - PURPOSE: Varicocele is one of the most common genital conditions referred to pediatric urologists. Most adolescents with varicocele are asymptomatic and their fertility future (and surgery benefit) is largely unknown. This review assesses varicocele evaluation, management and indications for repair, as well as types and success of varicocelectomy. MATERIALS AND METHODS: A systematic literature review was performed on EmbaseTM, PubMed(r) and Google ScholarTM for adolescent varicocele. Original research articles and relevant reviews were examined, and a synopsis of these data was generated for a comprehensive review of clinical adolescent varicocele management. RESULTS: The prevalence of adolescent varicocele is similar to the adult population. While ultrasound is the most sensitive method for determining testicular volumes, orchidometer measurement may be adequate to gauge significant discordance. Significant hypotrophy of the affected testis with poor total testicular volume may indicate a testis at risk and warrant surgical repair. Similar findings have been noted with an associated high peak retrograde venous flow. Testicular hypotrophy often resolves following surgery but may also improve spontaneously if followed through adolescence. Continued scrotal pain despite adequate support or serial abnormal semen analysis in Tanner stage V boys is an indication for varicocelectomy. Artery and lymphatic sparing techniques (microscopic subinguinal or laparoscopic) are associated with the lowest risk of recurrence and complications. CONCLUSIONS: Overtreatment and under treatment are medically and financially costly. Abnormal serial semen analysis with or without testicular hypotrophy is an indication for varicocele repair. If observation remains the treatment, followup with an adult urologist should be encouraged until paternity is achieved. PMID- 26119670 TI - PnPP-19, a Synthetic and Nontoxic Peptide Designed from a Phoneutria nigriventer Toxin, Potentiates Erectile Function via NO/cGMP. AB - PURPOSE: We designed a peptide, PnPP-19, comprising the potential active core of the Phoneutria nigriventer native toxin PnTx2-6. We investigated its role on erectile function, and its toxicity and immunogenicity. MATERIALS AND METHODS: Erectile function was evaluated by the intracavernous pressure-to-mean arterial pressure ratio during electrical field stimulation on rat pelvic ganglia. Cavernous strips were contracted with phenylephrine and relaxation was induced by electrical field stimulation with or without PnPP-19 (10(-8) M). Activity on sodium channels was evaluated by electrophysiological screening of transfected channels on Xenopus oocytes and dorsal root ganglion cells. Antibodies were detected by indirect enzyme-linked immunosorbent assay in mice previously treated with the peptide. Histopathological studies were performed with mouse organs treated with different doses of PnPP-19. RESULTS: PnPP-19 was able to potentiate erection at 4 and 8 Hz in vivo and ex vivo. It showed no toxicity and low immunogenicity in mice, and did not affect sodium channels or rat hearts. PnPP-19 increased cyclic guanosine monophosphate levels at 8 Hz. This effect was inhibited by L-NAME (10(-4) M). Erectile function was partially inhibited by 7 nitroindazole (10(-5) M), a selective inhibitor of neuronal nitric oxide synthase. CONCLUSIONS: PnPP-19 potentiates erection in vivo and ex vivo via the nitric oxide/cyclic guanosine monophosphate pathway. It does not affect sodium channels or rat hearts and shows no toxicity and low immunogenicity. These findings make it a promising candidate as a novel drug in the therapy of erectile dysfunction. PMID- 26119671 TI - Age is Associated with Upgrading at Confirmatory Biopsy among Men with Prostate Cancer Treated with Active Surveillance. AB - PURPOSE: Active surveillance is increasingly recommended for older men with low risk prostate cancer. Although older men have higher all cause mortality, they also have higher prostate cancer specific mortality. We hypothesized that older age is associated with an increased risk of Gleason score upgrading at confirmatory biopsy when controlling for prostate volume. MATERIALS AND METHODS: We retrospectively reviewed data on 1,130 patients with prostate cancer who were treated with active surveillance from 1991 through 2011. We included 646 patients with clinical Gleason 6 or less, stage T2a or less prostate cancer, a confirmatory biopsy within 2 years of diagnostic biopsy and prostate magnetic resonance imaging before confirmatory biopsy. The primary outcome was Gleason score upgrading to 7 or greater on confirmatory biopsy. We used logistic regression to estimate the effect of age on upgrading, adjusting for magnetic resonance imaging prostate volume and other potential confounders. RESULTS: Median age was 66 years (IQR 61-72) and median magnetic resonance imaging prostate volume was 41 ml (IQR 29-55). At confirmatory biopsy disease was upgraded in 55 of 646 patients (9%) and unchanged in 290 (45%) and biopsy was negative in 297 (46%). Older age was associated with higher odds of upgrading (adjusted OR 1.05, 95% CI 1.01-1.09, p=0.009). Larger prostate volume was associated with lower odds of upgrading (adjusted OR 0.80/10 ml increase, 95% CI 0.7-0.9, p=0.012). CONCLUSIONS: Our findings suggest that older age is associated with an increased risk of misclassification on diagnostic biopsy. Older men who are interested in active surveillance should be counseled about the risks and benefits of confirmatory biopsy. PMID- 26119672 TI - Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study. AB - PURPOSE: Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response. MATERIALS AND METHODS: Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry. RESULTS: Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p<0.001). The values for cancer specific survival were 76% and 56%, respectively (p<0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p=0.23) or cancer specific survival (55% vs 51%, p=0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5 9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials. CONCLUSIONS: Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression. PMID- 26119673 TI - Risk factors for merchant seafarer repatriation due to injury or illness at sea. AB - BACKGROUND: Repatriation represents a serious outcome of illness or injury among seafarers at sea. The aim of this study was to describe repatriation patterns due to injury and illness in a seafarer cohort, and determine risk factors for repatriation. MATERIALS AND METHODS: The study analysed a telemedicine database of 3,921 seafarer injury and illness cases over a 4 year period using descriptive statistics and logistic regression. RESULTS: There were 61 repatriations over the study period (1.6% of cases). Most repatriations were due to illness (38; 62.3%) as opposed to injury (23; 37.7%). Back injuries and gastrointestinal illness were the most frequent causes of repatriations. Using logistic regression, nationality was identified as a significant risk factor for repatriation. CONCLUSIONS: This study emphasizes illness as a major cause of seafarer repatriation, and suggests opportunities for future studies to identify potentially modifiable risk factors. PMID- 26119674 TI - Referring cruise ship patients to specialists in Norway--a welfare state with a national health care system. AB - Northern Europe is a popular cruise destination, but many non-Scandinavian cruise ship's doctors who are used to enthusiastic service from specialists ashore, get frustrated when referring passengers or crew to out-patient medical evaluation. Norway's national health care system is described and used as an example of medical conditions in a welfare state with a relatively well-functioning national health care system: Emergency cases are usually promptly admitted. Out-patient specialist consultations are available in public polyclinics, but waiting time can be considerable, also for patients from ships. Private specialists are fully booked weeks in advance and do not work from Friday to Monday and during holidays. Public and private medical service capacity is significantly reduced during the summer months. Hence, most specialists ashore are not eager to see demanding ship patients. Ship's doctors should limit referral to conditions that require specific procedures that are not available on the vessel but are necessary for the patient to be able to continue cruising or working aboard. Crewmembers who are unfit for work aboard, should instead be signed off and repatriated for diagnostic work-up and follow-up at home. In cases of hospitalisation or necessary referral ashore, the ship's doctor should always confer in advance with the company's ship's port agents and make necessary shore side arrangements through them. PMID- 26119675 TI - Different serotypes of dengue virus (DENV) imported by Polish travellers from dengue endemic areas to Poland. AB - BACKGROUND: Dengue viruses are the most widespread arboviruses (transmitted mainly by Aedes aegypti and Ae. albopictus mosquitoes), which have shown an unexpected geographic expansion. There are four dengue virus serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. Subsequent infections increase the risk of developing severe dengue fever. MATERIALS AND METHODS: Samples from travellers returning from the endemic area of dengue fever were examined with the reverse transcription-polymerase chain reaction method. Primers amplified 743 bp fragment of the NS5 and 3'UTR genomic region of mosquito-borne flaviviruses of JEV group were used. RESULTS: The sequences from the 10 examined patients were compared to available DENV sequences in GenBank database and the basic local alignment search tool (BLAST) results confirmed that the infective virus was DENV-1 (6 patients), DENV-2 (2 patients) and DENV-3 (2 patients). CONCLUSIONS: For the first time in Poland, dengue virus serotypes were determined in travellers returning from dengue-endemic areas. PMID- 26119676 TI - Fever of unknown origin in returning travellers. AB - The aim of the article is to discuss issues associated with the occurrence of febrile illnesses in leisure and business travellers, with a particular emphasis on fevers of unknown origin (FUO). FUO, apart from diarrhoeas, respiratory tract infections and skin lesions, are one of the most common health problems in travellers to tropical and subtropical countries. FUO are manifestations of various diseases, typically of infectious or invasive aetiology. In one out of 3 cases, the cause of a fever in travellers returning from the hot climate zone is malaria, and therefore diagnostic tests should first aim at ruling out this specific disease entity. Other illnesses with persistent fever include dengue, enteric fever, viral hepatitis A, bacterial diarrhoeas and rickettsioses. Fever may also occur in travellers suffering from diseases of non-tropical origin, e.g. cosmopolitan respiratory tract or urinary tract infections, also, fever may coexist with other illnesses or injuries (skin rashes, bites, burns). PMID- 26119677 TI - A case of severe stinging caused by venomous marine animal, "Portuguese man of war" (Physalia species) in all probability. AB - There are about 150 million jellyfish stings every year. "Portuguese man of war" is responsible for substantial proportion of stings worldwide. The biggest risk from a jellyfish stings may come from incorrect management. A 42-year-old woman was severely stung by venomous marine animal while bathing in waters of the Thai Gulf. It was most likely "Portuguese man of war". The patient didn't remember while being rescued. Looking at damages it seems that first aid was incorrect. Inappropriate and delayed management caused disfiguring scars. On the ground of this case, first aid for "Portuguese man of war" stings is reminded. PMID- 26119678 TI - Predicted nine-year risk of diabetes among professional divers: a prospective study. AB - BACKGROUND: The purpose of this study was to assess diabetes predictive score for professional divers followed-up in one medical centre in France. MATERIALS AND METHODS: This prospective study, performed during 2013, included professional divers who were followed in a French maritime medicine centre. Data about their professional history of diving and dive profiles were collected. The clinical and biological data collected included: age, waist circumference, biometrics, body mass index, smoking status, blood pressure, practicing sports, glycaemia, triglyceridaemia, total cholesterolaemia, HDL and LDL cholesterolaemia. The predicted 9-year risk of diabetes was calculated according to the DESIRE score. Data were analysed using Epidata(r) software, by Pearson c2 test or by Fisher's exact test, by analysis of variance or Kruskal-Wallis test, and by Spearman correlation coefficient. RESULTS: Out of the 64 deep-sea divers taking part in the study, diabetes risk was estimated for 60 divers. The predictive 9-year risk of diabetes was higher than 10% for 31.7% of the divers and higher than 30% for 6.7% of the divers. CONCLUSIONS: In France, people with diabetes have been declared definitely medically unfit to dive. The interest to assess the prevalence of risk factors and the predictive risk of diabetes arises from the need for prevention. PMID- 26119679 TI - Mortality among retired offshore divers in Norway. AB - BACKGROUND: Health effects of diving have been observed in divers who have not experienced any diving related accidents. The aim of the study was to study total, and cause specific mortality, in Norwegian retired professional offshore divers. MATERIALS AND METHODS: We carried out a mortality follow-up from 1997 to 2013 in a group of men, born 1930-1973. The diving cohort consisted of 386 male professional divers diving in the North Sea in the pioneer period from 1965 to 1990, of which 25 were dead. 1,467,769 Norwegian males were used as referents. This population was linked to the Norwegian Cause of Death Registry. RESULTS: Twenty five (6.5%) professional offshore divers had died. No differences were observed between divers and referents for overall mortality or for non-violent deaths, adjusted for year of birth. CONCLUSIONS: In this cohort of retired North Sea divers, the mortality pattern did not differ from that of the expected mortality. PMID- 26119680 TI - Descriptive study of job satisfaction and job dissatisfaction in a sample of Croatian seafarers. AB - BACKGROUND: Given the general lack of studies on well-being in Croatian seafarers, the aim of this study was to determine the level and sources of their job satisfaction and job dissatisfaction. MATERIALS AND METHODS: This descriptive study was conducted on a sample of Croatian seafarers (n = 530), employed in various functions on cargo ships. Using an online survey, we examined overall job satisfaction, and satisfaction with some specific aspects of work. Participants additionally responded to two open questions relating to the sources of their job satisfaction and job dissatisfaction, and these data were analysed using a qualitative approach. RESULTS AND CONCLUSIONS: The results showed a moderate level of overall job satisfaction, while analysis of the 10 specific facets indicated that the participants are, on average, most satisfied with payment, and least satisfied with the achieved benefits and work organisation on board. The results of the qualitative analysis showed that among the main sources of job satisfaction are: financial stability and security, the ratio of work days to days off, and the quality of days off, and the nature and dynamics of the work. On the other hand, sources of dissatisfaction relate primarily to: separation from home and family, the status of Croatian seafarers in the Republic of Croatia, and working and living conditions on board. PMID- 26119681 TI - Seafarer fatigue: a review of risk factors, consequences for seafarers' health and safety and options for mitigation. AB - BACKGROUND: The consequences of fatigue for the health and safety of seafarers has caused concern in the industry and among academics, and indicates the importance of further research into risk factors and preventive interventions at sea. This review gives an overview of the key issues relating to seafarer fatigue. MATERIALS AND METHODS: A literature study was conducted aiming to collect publications that address risk factors for fatigue, short-term and long term consequences for health and safety, and options for fatigue mitigation at sea. Due to the limited number of publications that deals with seafarers, experiences from other populations sharing the same exposures (e.g. shift work) were also included when appropriate. RESULTS: Work at sea involves multiple risk factors for fatigue, which in addition to acute effects (e.g., impaired cognition, accidents) contributes through autonomic, immunologic and metabolic pathways to the development of chronic diseases that are particularly prevalent in seafarers. CONCLUSIONS: Taking into account the frequency of seafarer fatigue and the severity of its consequences, one should look into the efficacy of the current legislative framework and the industry's compliance, the manning of the international merchant fleet, and optimised working, living and sleeping conditions at sea. Considering circumstances at sea, e.g. working in shifts and crossing time zones, that cannot be altered, further assessment of the potentials of preventive interventions including fatigue prediction tools and individual fatigue mitigation management systems is recommended. PMID- 26119682 TI - Ship doctor's qualification--the fast track? PMID- 26119683 TI - The Chemistry of Redox-Flow Batteries. AB - The development of various redox-flow batteries for the storage of fluctuating renewable energy has intensified in recent years because of their peculiar ability to be scaled separately in terms of energy and power, and therefore potentially to reduce the costs of energy storage. This has resulted in a considerable increase in the number of publications on redox-flow batteries. This was a motivation to present a comprehensive and critical overview of the features of this type of batteries, focusing mainly on the chemistry of electrolytes and introducing a thorough systematic classification to reveal their potential for future development. PMID- 26119685 TI - Moving toward Ylide-Stabilized Carbenes. AB - The effect of ylide substitution at the alpha position to the carbene carbon (Cc ) atom on the stability and sigma-donating ability of a number of cyclic carbenes has been studied theoretically. The stabilities of all of the carbenes were investigated from an evaluation of their singlet-triplet energy gaps and stabilization energies. All carbenes were found to have a stable singlet state. The energy of the sigma-symmetric lone-pair orbital at the Cc atom increases as a result of the introduction of ylide centers near to the Cc atom. This indicates an enhanced sigma-donating ability of the ylide-containing carbenes. The calculated carbonyl-stretching frequencies of the corresponding rhodium complexes, proton affinities, and nucleophilicity index values correlate well with the sigma basicity of the carbenes. PMID- 26119684 TI - French guidelines for the management of chikungunya (acute and persistent presentations). November 2014. PMID- 26119686 TI - Dietary protein and lifespan across the metamorphic boundary: protein-restricted larvae develop into short-lived adults. AB - Restriction of nutrients in the adult diet extends lifespan across a diverse range of species, but less is known about the long-term effects of developmental dietary restriction. In particular, it is not known whether adult lifespan is influenced by developmental caloric restriction or macronutrient balance. We used the nutritional geometry approach to independently manipulate protein and carbohydrate contents of the larval diet in the neriid fly, Telostylinus angusticollis, and measured adult lifespan. We found that adult male and female lifespan was shortest when larvae were fed a protein restricted diet. Thus, protein restriction in the larval diet has the opposite effect of protein restriction in the adult diet (which prolongs life in this species and across a wide range of taxa). Adult lifespan was unaffected by larval dietary carbohydrate. These patterns persisted after controlling for larval diet effects on adult body size. We propose that larval and adult protein sources are used for distinct metabolic tasks: during development, dietary protein is used to build a durable soma that enhances adult lifespan, although excessive protein consumption partially reverses this effect. PMID- 26119687 TI - Hepatocellular nodules expressing markers of hepatocellular adenomas in Budd Chiari syndrome and other rare hepatic vascular disorders. AB - BACKGROUND & AIMS: A broad range of hepatocellular nodules has been reported in hepatic vascular disorders. It is not clear whether hepatocellular adenoma (HCA) in this context share the same characteristics as conventional HCA. The aim of this study was to carry out a retrospective multicenter survey of hepatocellular nodules associated with hepatic vascular disorders. METHODS: Forty-five cases were reviewed, including 32 Budd-Chiari syndrome (BCS). Benign nodules were subtyped using the HCA immunohistochemical panel. RESULTS: Nodules with a HCA morphology were observed in 11 cases. Six originated in BCS: two were liver fatty acid binding protein (LFABP) negative (one with malignant transformation); two expressed glutamine synthetase (GS) and nuclear b-catenin, two expressed C reactive protein (CRP). Among three cases with portal vein agenesis, one nodule was LFABP negative, two expressed GS and nuclear b-catenin, both with malignant transformation. In a Fallot tetralogy case, there were multiple LFABP negative nodules with borderline features and in a hepatoportal sclerosis case, the nodule looked like an inflammatory HCA. Two additional cases had nodules expressing CRP, without typical characteristics of inflammatory HCA. CONCLUSION: HCA of different immunohistochemical phenotype can develop in hepatic vascular disorders; they may have a different behavior compared to conventional HCA and be more at risk of malignant transformation. PMID- 26119688 TI - Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterised by fibro stenosing strictures involving extrahepatic and/or large intrahepatic bile ducts. Mechanisms leading to bile duct injury are poorly understood. We aimed to study the biliary tree stem cell compartment located in peribiliary glands of extrahepatic and large intrahepatic bile ducts and its role in the pathogenesis of biliary fibrosis in PSC. METHODS: Specimens containing extrahepatic or large intrahepatic bile ducts were obtained from normal liver (n=6), liver explants from patients with PSC (n=11), and primary biliary cirrhosis (n=6). Specimens were processed for histology, immunohistochemistry and immunofluorescence. RESULTS: In PSC samples, progressive hyperplasia and mucinous metaplasia of peribiliary glands were observed in large ducts with fibrosis, but not in inflamed ducts without fibrosis. Peribiliary gland hyperplasia was associated with progressive biliary fibrosis and the occurrence of dysplastic lesions. Hyperplasia of peribiliary glands was determined by the expansion of biliary tree stem cells, which sprouted towards the surface epithelium. In PSC, peribiliary glands and myofibroblasts displayed enhanced expression of Hedgehog pathway components. Peribiliary glands in ducts with onion skin-like fibrosis expressed epithelial-to-mesenchymal transition traits associated with components of Hedgehog pathway, markers of senescence and autophagy. CONCLUSIONS: The biliary tree stem cell compartment is activated in PSC, its activation contributes to biliary fibrosis, and is sustained by the Hedgehog pathway. Our findings suggest a key role for peribiliary glands in the progression of bile duct lesions in PSC and could explain the associated high risk of cholangiocarcinoma. PMID- 26119689 TI - Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages. AB - Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease. PMID- 26119690 TI - Intravenous immunoglobulin enhances the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria. AB - Intravenous immunoglobulin (IVIG) is periodically administered to immunocompromised patients together with antimicrobial agents. The evidence that supports the effectiveness of IVIG is mostly based on data from randomized clinical trials; the underlying mechanisms are poorly understood. A recent study revealed that killing of multidrug-resistant bacteria and drug-sensitive strains by neutrophils isolated from healthy donors is enhanced by an IVIG preparation. However, the effectiveness of IVIG in immunocompromised patients remains unclear. The present study found that IVIG increased both killing activity and O2(-) release by neutrophils isolated from six patients receiving immune-suppressive drugs after hematopoietic stem cell transplantation (HSCT); these neutrophils killed both multidrug-resistant extended-spectrum beta-lactamase-producing Escherichia coli (E. coli) and multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa). Moreover, IVIG increased the autophagy of the neutrophils, which is known to play an important role in innate immunity. These results suggest that IVIG promotes both the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria. PMID- 26119691 TI - Lateral diffusion contributes to FRET from lanthanide-tagged membrane proteins. AB - Diffusion can enhance Forster resonance energy transfer (FRET) when donors or acceptors diffuse distances that are similar to the distances separating them during the donor's excited state lifetime. Lanthanide donors remain in the excited state for milliseconds, which makes them useful for time-resolved FRET applications but also allows time for diffusion to enhance energy transfer. Here we show that diffusion dramatically enhances FRET between membrane proteins labeled with lanthanide donors. This phenomenon complicates interpretation of experiments that use long-lived donors to infer association or proximity of mobile membrane proteins, but also offers a method of monitoring diffusion in membrane domains in real time in living cells. PMID- 26119692 TI - Establishment and characterization of a reconstructed Chinese human epidermis model. AB - OBJECTIVES: In vitro reconstructed human epidermis is a powerful tool for both basic research and industrial applications in dermatology, pharmacology and the cosmetic field. METHODS: By growing keratinocytes of Chinese origin on a collagen matrix after a submerged culture followed by an air-liquid interface culture, an in vitro reconstructed Chinese human epidermis model was obtained. This Chinese epidermis model was further characterized. RESULTS: The reconstructed human epidermis model (China EpiSkin model) exhibits morphological features similar to native skin and shows similar expression profile of proliferation (Ki67) and differentiation (K14 and K10 cytokeratins, filaggrin) markers. Corneodesmosomes, lamellar lipids, desmosomes, keratohyalin granules, keratin filaments and membrane-coating granules are also observed at the ultrastructure level. Moreover, China EpiSkin model contains most of the major lipid classes normally found in the native skin and potentially could present the properties of skin barrier. More importantly, the model production achieves high reproducibility and low intra- and inter-batch variations. CONCLUSION: This is the first reconstructed Chinese human epidermis model reported to meet the high quality standard with industrialized production criteria. This China EpiSkin model can be used for both skin research and safety assessment in vitro. PMID- 26119693 TI - Thermal properties of tannin extracted from Anacardium occidentale L. using TGA and FT-IR spectroscopy. AB - The chemical nature of the polyphenols of cashew kernel testa has been determined. Testa contains tannins, which present large molecular complexity and has an ancient use as tanning agents. The use of tannins extracted from cashew testa, considered in many places as a waste, grants an extra value to the cashew. In this work we have analysed through high performance liquid chromatography, infrared spectroscopy (FT-IR) and thermo gravimetric analysis the average molecular weight, main functional groups and thermal properties of tannins extracted from Anacardium occidentale L. The results of these analyses are compared with the commercial grade tannic acid. The FT-IR spectra showed bands characteristic of C = C, C-C and OH bonds. This important bioactive compound present in the cashew nut kernel testa was suggested as an interesting economical source of antioxidants for use in the food and nutraceutical industry. PMID- 26119694 TI - JMJ24 binds to RDR2 and is required for the basal level transcription of silenced loci in Arabidopsis. AB - Transposable elements (TEs) and repetitive sequences are ubiquitously present in eukaryotic genomes which are in general epigenetically silenced by DNA methylation and/or histone 3 lysine 9 methylation (H3K9me). RNA-directed DNA methylation (RdDM) is the major pathway that initiates de novo DNA methylation in Arabidopsis and sets up a self-reinforcing silencing loop between DNA methylation and H3K9me. However, a key issue is the requirement of a basal level transcript from the target loci to initiate the RNA-based silencing. How the heterochromatic silenced loci are transcribed remains largely unknown. Here, we show that JMJ24, a JmjC domain-containing protein counteracts H3K9me to promote basal level transcription of endogenous silenced loci in Arabidopsis. JMJ24 functionally resembles the fission yeast JmjC protein Epe1. The transcript promoted by JMJ24 is, at least in part, processed to small RNA to initiate the RdDM. Genome-wide transcriptome profiling indicates that transcript levels of TEs are more likely regulated by JMJ24, compared with protein-coding genes. Our data suggest that JMJ24 plays a conserved role in promoting basal level transcription of endogenous silenced loci to reinforce the silencing. We also provide evidence of a physical association between JMJ24 and RNA-dependent RNA polymerase 2 (RDR2), which represents an evolved property of the RNA silencing pathway. PMID- 26119697 TI - How controlled release technology can aid gene delivery. AB - INTRODUCTION: Many types of gene delivery systems have been developed to enhance the level of gene expression. Controlled release technology is a feasible gene delivery system which enables genes to extend the expression duration by maintaining and releasing them at the injection site in a controlled manner. This technology can reduce the adverse effects by the bolus dose administration and avoid the repeated administration. Biodegradable biomaterials are useful as materials for the controlled release-based gene delivery technology and various biodegradable biomaterials have been developed. AREAS COVERED: Controlled release based gene delivery plays a critical role in a conventional gene therapy and genetic engineering. In the gene therapy, the therapeutic gene is released from biodegradable biomaterial matrices around the tissue to be treated. On the other hand, the intracellular controlled release of gene from the sub-micro-sized matrices is required for genetic engineering. Genetic engineering is feasible for cell transplantation as well as research of stem cells biology and medicine. EXPERT OPINION: DNA hydrogel containing a sequence of therapeutic gene and the exosome including the individual specific nucleic acids may become candidates for controlled release carriers. Technologies to deliver genes to cell aggregates will play an important role in the promotion of regenerative research and therapy. PMID- 26119695 TI - Availability of New Medicaid Patient Appointments and the Role of Rural Health Clinics. AB - OBJECTIVE: To examine the willingness to accept new Medicaid patients among certified rural health clinics (RHCs) and other nonsafety net rural providers. DATA SOURCES: Experimental (audit) data from a 10-state study of primary care practices, county-level information from the Area Health Resource File, and RHC information from the Center for Medicare and Medicaid Services. STUDY DESIGN: We generate appointment rates for rural and nonrural areas by patient-payer type (private, Medicaid, self-pay) to then motivate our focus on within-rural variation by clinic type (RHC vs. non-RHC). Multivariate linear models test for statistical differences and assess the estimates' sensitivity to the inclusion of control variables. DATA COLLECTION: The primary data are from a large field study. PRINCIPAL FINDINGS: Approximately 80 percent of Medicaid callers receive an appointment in rural areas-a rate more than 20 percentage points greater than nonrural areas. Importantly, within rural areas, RHCs offer appointments to prospective Medicaid patients nearly 95 percent of the time, while the rural (nonsafety net) non-RHC Medicaid rate is less than 75 percent. Measured differences are robust to covariate adjustment. CONCLUSIONS: Our study suggests that RHC status, with its alternative payment model, is strongly associated with new Medicaid patient acceptance. Altering RHC financial incentives may have consequences for rural Medicaid enrollees. PMID- 26119696 TI - Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates. AB - How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, beta-endorphin (10-100 nmol) and GRP (1-10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike beta-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100-1000 nmol) and nociceptin-orphanin FQ (3-30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1-17) (10-100 nmol) dose-dependently attenuates both beta-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch eliciting effects by beta-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans. PMID- 26119698 TI - Polyarteritis nodosa associated with necrosis of the tongue: a rare presentation in an adult patient. AB - Polyarteritis nodosa is a rare form of vasculitis of the medium-sized vessels, which leads to the formation of microaneurysms, thrombosis, organ ischaemia, and necrosis. Involvement of the oral cavity is rare. To our knowledge, this is the first case of localised polyarteritis nodosa in an adult with ulceration of the tongue and necrosis at the onset of the disease. The patient made a full recovery after the use of strong immunosuppressants. PMID- 26119699 TI - Effect of maxillary advancement on the change in the soft tissues after treatment of patients with class III malocclusion. AB - The aesthetic outcome of treatment has become increasingly important to patients having orthognathic surgery. The aim of this observational cohort study based on clinical records was to evaluate the effect of maxillary advancement on changes to the soft tissues. We studied 53 patients with class III malocclusion (29 women and 24 men, mean (SD) age 28 (11) years). We identified all patients treated between 1 January 2002 and 30 December 2013 who could be monitored postoperatively for 6 months. To study the effect of maxillary advancement on changes to the soft tissue we distinguished between patients who had had less than 6mm, and those with 6mm advancement or more. In those who had had less than 6mm, we found no significant changes in the soft tissue in the region of the nasolabial angle. However, the lip-chin- throat angle (p=0.016), cervical length (p=0.002), lower lip (p=0.007) and upper lip distance (p=0.0001) from the aesthetic line changed significantly. On the other hand, the changes to the soft tissue in the submental and nasolabial regions were significant in patients with 6mm advancement or more, and indicated a clear improvement in the aesthetic outcome of this region. This aesthetic change for the good in the submental and nasolabial regions after maxillary advancement of 6mm or more should be considered when planning treatment, and reduction in the mandibular setback will reduce the risk of development of a double chin. PMID- 26119700 TI - Chin wing osteotomy for the correction of hyper-divergent skeletal class III deformity: technical modification. PMID- 26119701 TI - Evaporation of low-volatility components in polymeric dental resins. AB - OBJECTIVES: This study provides measurement of the volatility of selected photoinitiators and monomers used in dental adhesive resins. A detailed determination of the spatial and temporal character of camphorquinone (CQ) volatilization with respect to air flow conditions as well as media viscosity is assessed to gauge the effect of evaporative loss on the photopolymerization process and the photopolymers formed. METHODS: Vapor pressures of materials are measured by thermogravimetric analysis. A quantitative model assuming one dimensional Fickian diffusion with surface evaporation is presented and compared with measured photoinitiator volatilization from viscous and non-viscous resin samples, obtained by spectrophotometry and confocal microscopy. Model resins are prepared and subject to airthinning followed by photocuring, monitored in real time by Fourier transform infrared spectrometry. RESULTS: Vapor pressure measurements of the individual components of the adhesive resin span nearly four orders of magnitude, with the photoinitiator CQ near the middle (0.6Pa) and the monomer HEMA at the upper end (10Pa). We see depth-averaged CQ loss from non viscous open films, while depthresolved measurements of viscous droplets show strong surface-localized CQ depletion. Good agreement is observed between measurements and the model. Finally, air-thinning of samples prepared with more volatile photoinitiator and monomer is shown to cause longer induction times, slower early-stage polymerization rates and lower late-stage degree of conversion. SIGNIFICANCE: Widely used compounds with vapor pressures as low as 0.6Pa (0.001Torr) undergo significant volatilization from samples ventilated under conditions generally representative to clinically used air-thinning procedures, with the potential to adversely affect the photopolymerization of both viscous and non-viscous resins. The inverse relationship between air thinning and adhesive bond strength, observed elsewhere, may be partially caused by this same effect. PMID- 26119702 TI - Hexaarylbiimidazoles as visible light thiol-ene photoinitiators. AB - OBJECTIVES: The aim of this study is to determine if hexaarylbiimidazoles (HABIs) are efficient, visible light-active photoinitiators for thiol-ene systems. We hypothesize that, owing to the reactivity of lophyl radicals with thiols and the necessarily high concentration of thiol in thiol-ene formulations, HABIs will effectively initiate thiol-ene polymerization upon visible light irradiation. METHODS: UV-vis absorption spectra of photoinitiator solutions were obtained using UV-vis spectroscopy, while EPR spectroscopy was used to confirm radical species generation upon HABI photolysis. Functional group conversions during photopolymerization were monitored using FTIR spectroscopy, and thermomechanical properties were determined using dynamic mechanical analysis. RESULTS: The HABI derivatives investigated exhibit less absorptivity than camphorquinone at 469nm; however, they afford increased sensitivity at this wavelength when compared with bis(2,4,6-trimethylbenzoyl)-phenylphosphineoxide. Photolysis of the investigated HABIs affords lophyl radicals. Affixing hydroxyhexyl functional groups to the HABI core significantly improved solubility. Thiol-ene resins formulated with HABI photoinitiators polymerized rapidly upon irradiation with 469nm. The glass transition temperatures of the thiol-ene resin formulated with a bis(hydroxyhexyl)-functionalized HABI and photopolymerized at room and body temperature were 49.5+/-0.5 degrees C and 52.2+/-0.1 degrees C, respectively. SIGNIFICANCE: Although thiol-enes show promise as continuous phases for composite dental restorative materials, they show poor reactivity with the conventional camphorquinone/tertiary amine photoinitiation system. Conversely, despite their relatively low visible light absorptivity, HABI photoinitiators afford rapid thiol-ene photopolymerization rates. Moreover, minor structural modifications suggest pathways for improved HABI solubility and visible light absorption. PMID- 26119704 TI - Clinical experience with the use of daptomycin in a tertiary care teaching hospital in Barcelona, Spain. AB - AIM: We reviewed the clinical use of daptomycin in daily practice. MATERIALS & METHODS: Efficacy and safety were assessed in 175 consecutive patients given daptomycin for at least 72 h. RESULTS: Daptomycin was given as rescue treatment in 50.9% of cases. Bloodstream infection (34.8%) and skin/soft-tissue infection (19.4%) were the most frequent. In 62.3% of patients, the dose of <= 6 mg/kg/day was administered. Staphylococcus spp. were isolated in 52.6% of cases (MRSA in 9.5%, CoNS in 34.3%) and Enterococcus spp. in 8.7%. Clinical success was 75% and microbiological eradication 48.6%. Two patients discontinued daptomycin due to hemolytic anemia of unlikely and possible relationship with daptomycin, respectively. CONCLUSION: Daptomycin was effective and well tolerated in patients with severe Gram-positive infections. PMID- 26119705 TI - Mu opioid receptor activation enhances regulator of G protein signaling 4 association with the mu opioid receptor/G protein complex in a GTP-dependent manner. AB - The interaction of Regulator of G protein Signaling 4 (RGS4) with the rat mu opioid receptor (MOR)/G protein complex was investigated. Solubilized MOR from rat brain membranes was immunoprecipitated in the presence of RGS4 with antibodies against the N-terminus of MOR (anti-MOR10-70 ). Activation of MOR with [D-Ala(2) , N-Me-Phe(4) , Gly(5) -ol] enkephalin (DAMGO) during immunoprecipitation caused a 150% increase in Goalpha and a 50% increase in RGS4 in the pellet. When 10 MUM GTP was included with DAMGO, there was an additional 72% increase in RGS4 co-immunoprecipitating with MOR (p = 0.003). Guanosine 5'-O (3-thiotriphosphate) (GTPgammaS) increased the amount of co-precipitating RGS4 by 93% (compared to DAMGO alone, p = 0.008), and the inclusion of GTPgammaS caused the ratio of MOR to RGS4 to be 1 : 1 (31 fmoles : 28 fmoles, respectively). GTPgammaS also increased the association of endogenous RGS4 with MOR. In His6 RGS4/Ni(2+) -NTA agarose pull down experiments, 0.3 MUM GTPgammaS tripled the binding of Goalpha to His6 RGS4, whereas the addition of 100 MUM GDP blocked this effect. Importantly, activation of solubilized MOR with DAMGO in the presence of 100 MUM GDP and 0.3 MUM GTPgammaS increased Goalpha binding to His6 RGS4/Ni(2+) NTA agarose (p = 0.001). Regulators of G protein Signaling (RGS) shorten the time that G proteins are active. Activation of the mu opioid receptor (MOR) causes GTP to bind to and to activate Go (alphaobetagamma). RGS4 then binds to the activated alphao-GTP/MOR complex and accelerates the intrinsic GTPase of alphao. After alphao dissociates from MOR, RGS4 remains bound to the C-terminal region of MOR. PMID- 26119706 TI - Indication bias or protopathic bias? PMID- 26119707 TI - Isocentric C-arm three-dimensional navigation versus conventional C-arm assisted C1-C2 transarticular screw fixation for atlantoaxial instability. AB - OBJECTIVE: The Isocentric C-arm 3D navigation has been widely used in superior cervical surgeries in recent years. Several clinical researches reported that navigation system was an effective support device for treatment of atlantoaxial instability. But there were few studies about the advantages of navigation system compared to conventional C-arm fluoroscopy in C1-C2 transarticular screw fixation for atlantoaxial instability. The aim of the study was to evaluate the precision of computer-assisted C1-C2 transarticular screw fixation (Magerl's technique) for atlantoaxial instability and compare the clinical results with conventional C-arm fluoroscopy. METHODS: Forty-two patients diagnosed as atlantoaxial instability who underwent C1-C2 transarticular screw fixation under two different fluoroscopy methods were studied. The Iso-C 3D navigation group included 18 patients and the other 24 patients were in the conventional C-arm group. The clinical and radiographic results were recorded and compared between the two groups. Patients were followed up with clinical examination and radiographs at a mean of 18.4 months. RESULTS: There were no significant differences between two groups in the mean age, gender, and causes of atlantoaxial instability. The mean blood loss in the navigation group was 236.1 +/- 28.5 mL versus 308.3 +/- 21.2 mL in the conventional C-arm group. The radiation time was significantly reduced using 3D navigation (48.8 +/- 1.05 s versus 60.3 +/- 2.23 s). Overall, 97.2 % (35/36) of 3D navigated screws and 91.7 % (44/48) of fluoroscopy screws were placed into the C1-C2 transarticular passages. Thirty-nine of forty patients showed evidence of solid fusion after 12 months on cervical plain radiographies or CT scans. CONCLUSIONS: On comparing the two imaging techniques, it was found that using Iso C 3D navigation can improve accuracy of the C1-C2 transarticular screws, decrease intra-operative fluoroscopic time and blood loss, and not prolong the operative time. This study demonstrates that Iso-C 3D navigation is a safe and effective means of guiding C1-C2 transarticular screw fixation for atlantoaxial instability. PMID- 26119708 TI - The efficacy of pedicle screw instrument in treatment of irreducible atlantoaxial dislocation. AB - OBJECTIVE: To explore the effect of pedicle screw instrument in treatment of irreducible atlantoaxial dislocation. PATIENTS AND METHOD: From June 2003 to February 2009, 14 cases of atlas dislocation with upper cervical cord compression were enrolled and anterior transoral soft tissue release combined with posterior reduction and pedicle screw fixation were performed. CT, MRI and radiograph were used preoperatively, and screw placement and bone graft were administered in all cases intraoperatively. Cervical collars were used for 3 months. RESULTS: Screws were successfully placed in atlas in all cases. The average follow-up period was 18 months. Bone fusion was observed in all cases without the following complications: neurologic symptoms, internal fixation failure and redislocation. Neurological recovery was observed in all 14 cases. CONCLUSIONS: Pedicle screw instrument has the following advantages in atlas and axis injury treatment: direct screw placement, short-segment fusion, intraoperative reduction and high fusion rate, which should be a better surgical method for the treatment of atlantoaxial dislocation. PMID- 26119709 TI - Thermal necrosis induced by electrocauterization as a local adjuvant therapy in local aggressive bone tumors, what is the safe limit for surgical margins? An experimental study. AB - OBJECTIVE: In the current study, it was aimed to investigate the temperature change in the cavity wall and pathologic necrosis occurred during cauterization, which was applied at different voltages and time intervals. MATERIALS AND METHODS: The right tibias of 32 male rabbits were used. Three 2-mm-diameter holes were created on the cortical surface of the tibia using a hand-held drill. Using an electrocautery device, 55 mV was applied for 3 and 5 s and 65 mV was applied for 3 and 5 s. Maximum temperatures at 3 and 6 mm distance from the application site were measured. Biopsy specimens obtained at 3 and 6 mm distance from the application site were evaluated microscopically for bone cell viability and periosteal necrosis. RESULTS: Thirty-two rabbits were divided into four groups. In all groups, periosteal bone cells located at the region, extending from the application site to 3 mm distance, died. In this region, application of 55 mV for 3 s caused peripheral necrosis. There were significant differences between the four groups in terms of maximum temperatures measured at 3 mm distance from the application site (p = 0.027). On the other hand, no significant differences were noted between the four groups in terms of maximum temperatures measured at 6 mm distance from the application site (p > 0.05). CONCLUSIONS: Cauterization of the cavity wall in the spray mode at 55 mV for 3 s after tumor resection caused necrosis in the cavity wall, extending from the application site to 3 mm distance. LEVEL OF EVIDENCE: Experimental animal study, Level II. PMID- 26119710 TI - Comparison of pain relief between patient-controlled epidural analgesia and patient-controlled intravenous analgesia for patients undergoing spinal fusion surgeries. AB - INTRODUCTION: This meta-analysis aimed to compare the postoperative analgesic effects of patient-controlled epidural analgesia (PCEA) and patient-controlled intravenous analgesia (PCIA) for patients undergoing spinal fusion surgeries. METHOD: Relevant articles were identified using computerized and manual search strategies. Statistical analyses were undertaken by the CMA 2.0 statistical software. RESULTS: Nine cohort studies with a total of 436 patients undergoing spinal fusion surgeries were incorporated in the present meta-analysis. There were significant differences between the PCEA and PCIA groups in the visual analogue scale score of patients undergoing spinal fusion [standardized mean difference = 0.27, 95 % confidence interval (95 % CI) = 0.070-0.470, P = 0.008]. However, no obvious difference was observed in the rate of side effects between the PCIA and PCEA groups (side effects: odds ratio = 0.957, 95 % CI = 0.536 1.708, P = 0.882). CONCLUSION: Our findings suggested that PCEA may be more effective in relieving pain than PCIA for patients undergoing spinal fusion surgeries. PMID- 26119711 TI - Nurses aged over 50 and their perceptions of flexible working. AB - AIM: To explore the experiences and needs of older nurses in relation to flexible working and the barriers and facilitators to implementation within workplaces. BACKGROUND: An ageing nursing workforce and anticipated nursing workforce shortages require effective approaches to workforce retention. METHOD: A mixed method approach (focus group and individual interviews) with nurses aged over 50 (n = 46) combined with analysis of district health board (DHB) flexible working policies. RESULTS: Participants had a good understanding of flexible working and recognised the importance of balancing their own needs with those of their organisation. Participants had legitimate reasons for making requests and became frustrated when turned down. They recommended job sharing, shorter shifts, no night shift and greater recognition of their work to improve retention. There was discrepancy between organisational policy (where this existed) and implementation. CONCLUSION: Organisations should review flexible working policies, ensuring these are understood and implemented at the unit level. Training of nurse managers is recommended. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers must recognise the individual needs of nurses, be cognisant of workplace policies regarding flexible working, ensure these are implemented consistently and make the effort to recognise the work of older nurses. PMID- 26119712 TI - Characteristics and outcomes of Italian patients from the observational, multicentre, hypopituitary control and complications study (HypoCCS) according to tertiles of growth hormone peak concentration following stimulation testing at study entry. AB - OBJECTIVE: To determine whether characteristics and outcomes of Italian patients in the observational global Hypopituitary Control and Complication Study (HypoCCS) differed according to the degree of GH deficiency (GHD). DESIGN: Patients were grouped by tertiles of stimulated GH peak concentration at baseline (Group A lowest tertile, n = 342; Group B middle tertile, n = 345; Group C highest tertile, n = 338). RESULTS: Baseline demographics, lipid levels, body mass index categories and mean Framingham cardiovascular risk indexes were similar in the three groups and remained substantially unchanged over time, with no subsequent significant between-group differences (except mean levels of triglycerides increased in the highest tertile group). GHD was adult-onset for >75% of patients in all groups. The percentage of patients with multiple pituitary deficiencies was higher in Group A than in the other groups; isolated GHD was reported with highest frequency in Group C. Patients in Group A received the lowest mean starting dose of GH. Hyperlipidaemia at baseline was reported in 35.1%, 31.1% and 24.7% of patients in groups A, B and C, respectively (P = 0.029). Mean duration of GH treatment was 7.21, 5.45 and 4.96 years, respectively. The proportion of patients with adverse events did not differ significantly between groups, with a low prevalence over time of diabetes and cancer. CONCLUSIONS: In Italian patients from HypoCCS, the level of GH deficit did not influence changes over time in metabolic parameters or adverse event profile, despite differences in GHD severity at baseline and in the starting GH dose. PMID- 26119713 TI - Antioxidant and antiproliferative activities of polysaccharide fractions from litchi pulp. AB - Three litchi polysaccharide fractions (LPFs), LP-4, LP-6 and LP-8, were obtained by fractional precipitation using 40%, 60% and 80% ethanol, respectively. The physicochemical properties, chemical antioxidant, and cellular antioxidant and antiproliferative activities of the three polysaccharide fractions were compared. LP-6 contained the highest contents of uronic acid and binding protein among the three fractions, whereas LP-8 contained the least. Amino acid composition analysis of the binding protein revealed that LP-6 contained the most acidic and aromatic amino acids. However, LP-8 contained more galactose and mannose than LP 4 and LP-6. LP-6 exhibited the highest chemical antioxidant activities, with an oxygen radical absorbance capacity of 28.14 MUmol TE per g DW. LP-8 exhibited higher cellular antioxidant activity and a greater inhibitory effect on the proliferation of A549, HepG2 and MGC-803 cells at a concentration of 100-800 MUg mL(-1) than LP-4 and LP-6. In summary, the different LPFs exhibited different antioxidant and antiproliferative activities with differential physicochemical properties. PMID- 26119714 TI - A review of melanized (black) fungal contamination in pharmaceutical products- incidence, drug recall and control measures. AB - The aim of this study was to describe the incidence of contamination of pharmaceutical products by melanized fungi and to consider control measures in relation to bioburden and cleanrooms. This study reviews and analyses pharmaceutical product recalls and offers incidence rates of fungal detection from a typical cleanrooms. The recalls include some serious cases which resulted in the loss of life. Of different types of fungal contamination incidences some of the most damaging have been due to melanized fungi ('black mould'), such as Exserohilum rostratum. The focus of the article is with melanized fungi. The study concludes that, from the review of recent pharmaceutical product recalls, fungal contamination is either increasingly common within cleanroom environments or the accuracy of sampling and the level of reporting has risen. The prevalence of melanized fungi in pharmaceutical facilities rests on specific virulence factors particular to these types of fungi, which are outlined. The article identifies a gap in the way that such fungi are screened for using available cultural methods. The article provides some control strategies, including assessing the suitability of disinfectants and biocides, for reducing the risk of melanized fungal incidences within the pharmaceutical facility. Understanding the fungal risk to pharmaceutical products remains a poorly understood and often overlooked aspect of pharmaceutical microbiology. This article helps to identify this risk and offer some guidance to those involved with pharmaceutical products manufacture in relation to bio-contamination control strategies. PMID- 26119715 TI - Body mass as a confounding variable when predicting group size from orbit diameter and neocortex ratio. PMID- 26119718 TI - Percutaneous management of patients with acute coronary syndromes from unprotected left main disease: A comprehensive review and presentation of a treatment algorithm. AB - The patient with acute coronary syndrome, particularly with myocardial infarction, from an unprotected left main coronary stenosis represents one of the highest risk subgroups with mortality exceeding 25-50%. Once a patient develops cardiogenic shock, the risk of death during index hospitalization is exceedingly high. Percutaneous coronary intervention may improve short- and long-term outcome, particularly if performed prior to shock development. Should the patient survive index hospitalization, survival tends to be rather good. This review summarizes current knowledge and proposes a clinical algorithm for evaluation and treatment. (c) 2015 Wiley Periodicals, Inc. PMID- 26119717 TI - Inhibition of ligand-independent constitutive activation of the Met oncogenic receptor by the engineered chemically-modified antibody DN30. AB - An awesome number of experimental and clinical evidences indicate that constitutive activation of the Met oncogenic receptor plays a critical role in the progression of cancer toward metastasis and/or resistance to targeted therapies. While mutations are rare, the common mechanism of Met activation is overexpression, either by gene amplification ('addiction') or transcriptional activation ('expedience'). In the first instance ligand-independent kinase activation plays a major role in sustaining the transformed phenotype. Anti-Met antibodies directed against the receptor binding site behave essentially as ligand (Hepatocyte Growth Factor, HGF) antagonists and are ineffective to counteract ligand-independent activation. The monovalent chimeric MvDN30 antibody fragment, PEGylated to extend its half-life, binds the fourth IPT domain and induces 'shedding' of the Met extracellular domain, dramatically reducing both the number of receptors on the surface and their phosphorylation. Downstream signaling is thus inhibited, both in the absence or in the presence of the ligand. In vitro, MvDN30 is a strong inhibitor not only of ligand-dependent invasive growth, sustained by both paracrine and autocrine HGF, but notably, also of ligand-independent growth of 'Met-addicted' cells. In immunocompromised mice, lacking expression of Hepatocyte Growth Factor cross-reacting with the human receptor - thus providing, by definition, a model of 'ligand-independent' Met activation - PEGylated MvDN30 impairs growth of Met 'addicted' human gastric carcinoma cells. In a Met-amplified patient-derived colo-rectal tumor (xenopatient) MvDN30-PEG overcomes the resistance to EGFR targeted therapy (Cetuximab). The PEGylated MvDN30 is thus a strong candidate for targeting tumors sustained by ligand-independent Met oncogenic activation. PMID- 26119719 TI - The ignored pandemic of typhoid. PMID- 26119720 TI - Which tissues are best for microbiological diagnosis in patients with pyogenic vertebral osteomyelitis undergoing needle biopsy? AB - Identification of the causative microorganism is important in the management of pyogenic vertebral osteomyelitis (PVO). The aim of this study was to investigate whether culture positive rates differ between needle biopsy sites in patients with PVO, and which tissues are best for microbiological diagnosis. Between January 2005 and December 2013, we conducted a retrospective cohort study of PVO patients who had soft-tissue abscesses (paraspinal or psoas abscesses) and who received needle biopsy for microbiological diagnosis. Needle biopsy sites were classified into two anatomical categories: vertebral bodies, or soft tissues (intervertebral discs, paraspinal abscesses, or psoas abscesses). A generalized estimating equation model was developed to identify factors associated with tissue-culture positivity. During the study period a total of 136 tissues were obtained by needle biopsy from 128 PVO patients with soft-tissue abscesses. The culture positive rates of vertebral bodies and soft tissues were 39.7% (29/73), and 63.5% (40/63), respectively (p < 0.05). In a multivariate analysis, male gender (adjusted odds ratio (aOR) 2.24, 95% CI 1.00-5.02), higher C-reactive protein (aOR 1.07, 95% CI 1.01-1.15), positive blood culture (aOR 2.57, 95% CI 1.01-6.59), and soft tissues as biopsy site compared with vertebral bodies (aOR 2.28, 95% CI 1.08-4.78) were independent factors associated with tissue culture positivity. Soft tissues were the best sites for microbiological diagnosis in PVO patients undergoing needle biopsy. PMID- 26119721 TI - Revival of old antibiotics: structuring the re-development process to optimize usage. PMID- 26119722 TI - Fever in melanoma: new drugs or bugs? PMID- 26119723 TI - Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France. AB - We studied a cohort of 110 823 patients treated with oral hypoglycaemic agents for type 2 diabetes in southeastern France from 1 January 2008 to 31 December 2011, to identify influenza vaccination coverage trends and the patient and physician correlates of influenza vaccine (IFV) uptake. We used French national health insurance fund (NHIF) databases to identify these patients and collect data on their IFV reimbursement claims (IFVC) and patient and physician characteristics. We used multilevel multivariate polytomous logistic regressions to test the correlates of IFVC. Between 2008 and 2011 the annual IFVC rate varied from 33.7% to 32.3% in the 18-64 age group and from 69.5% to 61.1% in the 65 + age group, among whom we saw a clear trend towards reduced vaccination after 2008. In the younger group, the probability of regular vaccination each year from 2008 to 2011 increased with diabetes severity and duration, comorbidities, and the number of general practitioner and nurse visits; it was higher among patients seeing endocrinologists and lower among low-income patients than in other patients. In the older group, there was no association with either diabetes severity or physician specialty. These results suggest different patterns of correlates of influenza vaccination according to age. Endocrinologists might help to improve IFV uptake in the younger group of patients with type 2 diabetes. Communication strategies regarding influenza vaccination should be adapted to age, and collaboration between healthcare professionals should be reinforced to achieve vaccination objectives for these patients. PMID- 26119724 TI - Acclimation of Emiliania huxleyi (1516) to nutrient limitation involves precise modification of the proteome to scavenge alternative sources of N and P. AB - Limitation of marine primary production by the availability of nitrogen or phosphorus is common. Emiliania huxleyi, a ubiquitous phytoplankter that plays key roles in primary production, calcium carbonate precipitation and production of dimethyl sulfide, often blooms in mid-latitude at the beginning of summer when inorganic nutrient concentrations are low. To understand physiological mechanisms that allow such blooms, we examined how the proteome of E. huxleyi (strain 1516) responds to N and P limitation. We observed modest changes in much of the proteome despite large physiological changes (e.g. cellular biomass, C, N and P) associated with nutrient limitation of growth rate. Acclimation to nutrient limitation did however involve significant increases in the abundance of transporters for ammonium and nitrate under N limitation and for phosphate under P limitation. More notable were large increases in proteins involved in the acquisition of organic forms of N and P, including urea and amino acid/polyamine transporters and numerous C-N hydrolases under N limitation and a large upregulation of alkaline phosphatase under P limitation. This highly targeted reorganization of the proteome towards scavenging organic forms of macronutrients gives unique insight into the molecular mechanisms that underpin how E. huxleyi has found its niche to bloom in surface waters depleted of inorganic nutrients. PMID- 26119725 TI - Asymmetric Synthesis of Axially Chiral Isoquinolones: Nickel-Catalyzed Denitrogenative Transannulation. AB - The first Ni(0)/bis(oxazoline)-catalyzed asymmetric denitrogenative transannulation of 1,2,3-benzotriazin-4(3H)-ones with bulky internal alkynes to form novel axially chiral isoquinolones in an atroposelective manner has been developed. This method provides direct asymmetric access to axially chiral isoquinolones with excellent functional-group tolerance in excellent yields and stereoselectivities from readily available starting materials under mild reaction conditions. These axially chiral isoquinolones exhibit high cytotoxicity against a number of human cancer cell lines. DFT calculations reveal the nature of the transition state in the key annulation step. PMID- 26119726 TI - Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy. AB - Radiotherapy is an essential component of treatment for more than half of newly diagnosed cancer patients. The response to radiotherapy varies widely between individuals and although advances in technology have allowed the adaptation of radiotherapy fields to tumour anatomy, it is still not possible to tailor radiotherapy based on tumour biology. A biomarker of intrinsic radiosensitivity would be extremely valuable for individual dosing, aiding decision making between radical treatment options and avoiding toxicity of neoadjuvant or adjuvant radiotherapy in those unlikely to benefit. This systematic review summarises the current evidence for biomarkers under investigation as predictors of radiotherapy benefit. Only 10 biomarkers were identified as having been evaluated for their radiotherapy-specific predictive value in over 100 patients in a clinical setting, highlighting that despite a rich literature there were few high-quality studies for inclusion. The most extensively studied radiotherapy predictive biomarkers were the radiosensitivity index and MRE11; however, neither has been evaluated in a randomised controlled trial. Although these biomarkers show promise, there is not enough evidence to justify their use in routine practice. Further validation is needed before biomarkers can fulfil their potential and predict treatment outcomes for large numbers of patients. PMID- 26119727 TI - Neurocognitive Effects Following Cranial Irradiation for Brain Metastases. AB - About 90% of patients with brain metastases have impaired neurocognitive function at diagnosis and up to two-thirds will show further declines within 2-6 months of whole brain radiotherapy. Distinguishing treatment effects from progressive disease can be challenging because the prognosis remains poor in many patients. Omitting whole brain radiotherapy after local therapy in good prognosis patients improves verbal memory at 4 months, but the effect of higher intracranial recurrence and salvage therapy rates on neurocognitive function beyond this time point is unknown. Hippocampal-sparing whole brain radiotherapy and postoperative stereotactic radiosurgery are investigational techniques intended to reduce toxicity. Here we describe the changes that can occur and review technological, pharmacological and practical approaches used to mitigate their effect in clinical practice. PMID- 26119728 TI - Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium. AB - Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate. We confirmed the molecular and functional differences within the basal population by using single-cell qRT-PCR and further lineage labeling. Additionally, we show that self-renewal of short-lived secretory cells is a feature of homeostasis. We have thus revealed early luminal commitment of cells that are morphologically indistinguishable from stem cells. PMID- 26119729 TI - The Nuclear PolyA-Binding Protein Nab2p Is Essential for mRNA Production. AB - Polyadenylation of mRNA is a key step in eukaryotic gene expression. However, despite the major impact of poly(A) tails on mRNA metabolism, the precise roles of poly(A)-binding proteins (PABPs) in nuclear mRNA biogenesis remain elusive. Here, we demonstrate that rapid nuclear depletion of the S. cerevisiae PABP Nab2p leads to a global loss of cellular mRNA, but not of RNA lacking poly(A) tails. Disappearance of mRNA is a nuclear event, but not due to decreased transcription. Instead, the absence of Nab2p results in robust nuclear mRNA decay by the ribonucleolytic RNA exosome in a polyadenylation-dependent process. We conclude that Nab2p is required to protect early mRNA and therefore constitutes a crucial nuclear mRNA biogenesis factor. PMID- 26119730 TI - Suppression of PGC-1alpha Is Critical for Reprogramming Oxidative Metabolism in Renal Cell Carcinoma. AB - Long believed to be a byproduct of malignant transformation, reprogramming of cellular metabolism is now recognized as a driving force in tumorigenesis. In clear cell renal cell carcinoma (ccRCC), frequent activation of HIF signaling induces a metabolic switch that promotes tumorigenesis. Here, we demonstrate that PGC-1alpha, a central regulator of energy metabolism, is suppressed in VHL deficient ccRCC by a HIF/Dec1-dependent mechanism. In VHL wild-type cells, PGC 1alpha suppression leads to decreased expression of the mitochondrial transcription factor Tfam and impaired mitochondrial respiration. Conversely, PGC 1alpha expression in VHL-deficient cells restores mitochondrial function and induces oxidative stress. ccRCC cells expressing PGC-1alpha exhibit impaired tumor growth and enhanced sensitivity to cytotoxic therapies. In patients, low levels of PGC-1alpha expression are associated with poor outcome. These studies demonstrate that suppression of PGC-1alpha recapitulates key metabolic phenotypes of ccRCC and highlight the potential of targeting PGC-1alpha expression as a therapeutic modality for the treatment of ccRCC. PMID- 26119731 TI - The Mitochondrial Calcium Uniporter Matches Energetic Supply with Cardiac Workload during Stress and Modulates Permeability Transition. AB - Cardiac contractility is mediated by a variable flux in intracellular calcium (Ca(2+)), thought to be integrated into mitochondria via the mitochondrial calcium uniporter (MCU) channel to match energetic demand. Here, we examine a conditional, cardiomyocyte-specific, mutant mouse lacking Mcu, the pore-forming subunit of the MCU channel, in adulthood. Mcu(-/-) mice display no overt baseline phenotype and are protected against mCa(2+) overload in an in vivo myocardial ischemia-reperfusion injury model by preventing the activation of the mitochondrial permeability transition pore, decreasing infarct size, and preserving cardiac function. In addition, we find that Mcu(-/-) mice lack contractile responsiveness to acute beta-adrenergic receptor stimulation and in parallel are unable to activate mitochondrial dehydrogenases and display reduced bioenergetic reserve capacity. These results support the hypothesis that MCU may be dispensable for homeostatic cardiac function but required to modulate Ca(2+) dependent metabolism during acute stress. PMID- 26119732 TI - Assembly of the Ebola Virus Nucleoprotein from a Chaperoned VP35 Complex. AB - Ebolavirus NP oligomerizes into helical filaments found at the core of the virion, encapsidates the viral RNA genome, and serves as a scaffold for additional viral proteins within the viral nucleocapsid. We identified a portion of the phosphoprotein homolog VP35 that binds with high affinity to nascent NP and regulates NP assembly and viral genome binding. Removal of the VP35 peptide leads to NP self-assembly via its N-terminal oligomerization arm. NP oligomerization likely causes a conformational change between the NP N- and C terminal domains, facilitating RNA binding. These functional data are complemented by crystal structures of the NP degrees -VP35 complex at 2.4 A resolution. The interactions between NP and VP35 illuminated by these structures are conserved among filoviruses and provide key targets for therapeutic intervention. PMID- 26119733 TI - Maternal dazap2 Regulates Germ Granules by Counteracting Dynein in Zebrafish Primordial Germ Cells. AB - Primordial germ cells (PGCs) are the stem cells of the germline. Generally, germline induction occurs via zygotic factors or the inheritance of maternal determinants called germ plasm (GP). GP is packaged into ribonucleoprotein complexes within oocytes and later promotes the germline fate in embryos. Once PGCs are specified by either mechanism, GP components localize to perinuclear granular-like structures. Although components of zebrafish PGC germ granules have been studied, the maternal factors regulating their assembly and contribution to germ cell development are unknown. Here, we show that the scaffold protein Dazap2 binds to Bucky ball, an essential regulator of oocyte polarity and GP assembly, and colocalizes with the GP in oocytes and in PGCs. Mutational analysis revealed a requirement for maternal Dazap2 (MDazap2) in germ-granule maintenance. Through molecular epistasis analyses, we show that MDazap2 is epistatic to Tdrd7 and maintains germ granules in the embryonic germline by counteracting Dynein activity. PMID- 26119734 TI - Plk1 and Mps1 Cooperatively Regulate the Spindle Assembly Checkpoint in Human Cells. AB - Equal mitotic chromosome segregation is critical for genome integrity and is monitored by the spindle assembly checkpoint (SAC). We have previously shown that the consensus phosphorylation motif of the essential SAC kinase Monopolar spindle 1 (Mps1) is very similar to that of Polo-like kinase 1 (Plk1). This prompted us to ask whether human Plk1 cooperates with Mps1 in SAC signaling. Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. We conclude that Plk1 strengthens the robustness of SAC establishment at the onset of mitosis and supports SAC maintenance during prolonged mitotic arrest. PMID- 26119735 TI - mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation. AB - The mammalian target of rapamycin complex 1 (mTORC1) regulates activation of immune cells and cellular energy metabolism. Although glycolysis has been linked to immune functions, the mechanisms by which glycolysis regulates NLRP3 inflammasome activation remain unclear. Here, we demonstrate that mTORC1-induced glycolysis provides an essential mechanism for NLRP3 inflammasome activation. Moreover, we demonstrate that hexokinase 1 (HK1)-dependent glycolysis, under the regulation of mTORC1, represents a critical metabolic pathway for NLRP3 inflammasome activation. Downregulation of glycolysis by inhibition of Raptor/mTORC1 or HK1 suppressed both pro-IL-1beta maturation and caspase-1 activation in macrophages in response to LPS and ATP. These results suggest that upregulation of HK1-dependent glycolysis by mTORC1 regulates NLRP3 inflammasome activation. PMID- 26119736 TI - Identification of Hemagglutinin Residues Responsible for H3N2 Antigenic Drift during the 2014-2015 Influenza Season. AB - Influenza vaccines must be updated regularly because influenza viruses continuously acquire mutations in antibody binding sites of hemagglutinin (HA). The majority of H3N2 strains circulating in the Northern Hemisphere during the 2014-2015 season are antigenically mismatched to the A/Texas/50/2012 H3N2 vaccine strain. Recent H3N2 strains possess several new HA mutations, and it is unknown which of these mutations contribute to the 2014-2015 vaccine mismatch. Here, we use reverse genetics to demonstrate that mutations in HA antigenic site B are primarily responsible for the current mismatch. Sera isolated from vaccinated humans and infected ferrets and sheep had reduced hemagglutination inhibition and in vitro neutralization titers against reverse-genetics-derived viruses possessing mutations in the HA antigenic site B. These data provide an antigenic explanation for the low influenza vaccine efficacy observed during the 2014-2015 influenza season. Furthermore, our data support the World Health Organization's decision to update the H3N2 component of future vaccine formulations. PMID- 26119737 TI - Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia. AB - Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. PMID- 26119738 TI - Natural Loss of Mps1 Kinase in Nematodes Uncovers a Role for Polo-like Kinase 1 in Spindle Checkpoint Initiation. AB - The spindle checkpoint safeguards against chromosome loss during cell division by preventing anaphase onset until all chromosomes are attached to spindle microtubules. Checkpoint signal is generated at kinetochores, the primary attachment site on chromosomes for spindle microtubules. Mps1 kinase initiates checkpoint signaling by phosphorylating the kinetochore-localized scaffold protein Knl1 to create phospho-docking sites for Bub1/Bub3. Mps1 is widely conserved but is surprisingly absent in many nematode species. Here, we show that PLK-1, which targets a substrate motif similar to that of Mps1, functionally substitutes for Mps1 in C. elegans by phosphorylating KNL-1 to direct BUB-1/BUB-3 kinetochore recruitment. This finding led us to re-examine checkpoint initiation in human cells, where we found that Plk1 co-inhibition significantly reduced Knl1 phosphorylation and Bub1 kinetochore recruitment relative to Mps1 inhibition alone. Thus, the finding that PLK-1 functionally substitutes for Mps1 in checkpoint initiation in C. elegans uncovered a role for Plk1 in species that have Mps1. PMID- 26119739 TI - Microtubule-Associated Protein EB3 Regulates IP3 Receptor Clustering and Ca(2+) Signaling in Endothelial Cells. AB - The mechanisms by which the microtubule cytoskeleton regulates the permeability of endothelial barrier are not well understood. Here, we demonstrate that microtubule-associated end-binding protein 3 (EB3), a core component of the microtubule plus-end protein complex, binds to inositol 1,4,5-trisphosphate receptors (IP3Rs) through an S/TxIP EB-binding motif. In endothelial cells, alpha thrombin, a pro-inflammatory mediator that stimulates phospholipase Cbeta, increases the cytosolic Ca(2+) concentration and elicits clustering of IP3R3s. These responses, and the resulting Ca(2+)-dependent phosphorylation of myosin light chain, are prevented by depletion of either EB3 or mutation of the TxIP motif of IP3R3 responsible for mediating its binding to EB3. We also show that selective EB3 gene deletion in endothelial cells of mice abrogates alpha-thrombin induced increase in endothelial permeability. We conclude that the EB3-mediated interaction of IP3Rs with microtubules controls the assembly of IP3Rs into effective Ca(2+) signaling clusters, which thereby regulate microtubule-dependent endothelial permeability. PMID- 26119740 TI - Piwi Is a Key Regulator of Both Somatic and Germline Stem Cells in the Drosophila Testis. AB - The Piwi-piRNA pathway is well known for its germline function, yet its somatic role remains elusive. We show here that Piwi is required autonomously not only for germline stem cell (GSC) but also for somatic cyst stem cell (CySC) maintenance in the Drosophila testis. Reducing Piwi activity in the testis caused defects in CySC differentiation. Accompanying this, GSC daughters expanded beyond the vicinity of the hub but failed to differentiate further. Moreover, Piwi deficient in nuclear localization caused similar defects in somatic and germ cell differentiation, which was rescued by somatic Piwi expression. To explore the underlying molecular mechanism, we identified Piwi-bound piRNAs that uniquely map to a gene key for gonadal development, Fasciclin 3, and demonstrate that Piwi regulates its expression in somatic cyst cells. Our work reveals the cell autonomous function of Piwi in both somatic and germline stem cell types, with somatic function possibly via its epigenetic mechanism. PMID- 26119741 TI - Reciprocal Regulation between Enterovirus 71 and the NLRP3 Inflammasome. AB - Enterovirus 71 (EV71) is the major etiological agent of hand, foot, and mouth disease (HFMD). Early studies showed that EV71-infected patients with severe complications exhibited elevated plasma levels of IL-1beta, indicating that EV71 may activate inflammasomes. Our current study demonstrates that the NLRP3 inflammasome plays a protective role against EV71 infection of mice in vivo. EV71 replication in myeloid cells results in the activation of the NLRP3 inflammasome and secretion of IL-1beta. Conversely, EV71 counteracts inflammasome activation through cleavage of NLRP3 by viral proteases 2A and 3C, which cleave NLRP3 protein at the G493-L494 or Q225-G226 junction, respectively. Moreover, EV71 3C interacts with NLRP3 and inhibits IL-1beta secretion when expressed in mammalian cells. These results thus reveal a set of reciprocal regulations between enterovirus 71 and the NLRP3 inflammasome. PMID- 26119742 TI - The Mitochondrial Calcium Uniporter Selectively Matches Metabolic Output to Acute Contractile Stress in the Heart. AB - In the heart, augmented Ca(2+) fluxing drives contractility and ATP generation through mitochondrial Ca(2+) loading. Pathologic mitochondrial Ca(2+) overload with ischemic injury triggers mitochondrial permeability transition pore (MPTP) opening and cardiomyocyte death. Mitochondrial Ca(2+) uptake is primarily mediated by the mitochondrial Ca(2+) uniporter (MCU). Here, we generated mice with adult and cardiomyocyte-specific deletion of Mcu, which produced mitochondria refractory to acute Ca(2+) uptake, with impaired ATP production, and inhibited MPTP opening upon acute Ca(2+) challenge. Mice lacking Mcu in the adult heart were also protected from acute ischemia-reperfusion injury. However, resting/basal mitochondrial Ca(2+) levels were normal in hearts of Mcu-deleted mice, and mitochondria lacking MCU eventually loaded with Ca(2+) after stress stimulation. Indeed, Mcu-deleted mice were unable to immediately sprint on a treadmill unless warmed up for 30 min. Hence, MCU is a dedicated regulator of short-term mitochondrial Ca(2+) loading underlying a "fight-or-flight" response that acutely matches cardiac workload with ATP production. PMID- 26119744 TI - Nucleation and propagation of voltage-driven wrinkles in an inflated dielectric elastomer balloon. AB - Dielectric elastomer (DE) transducers frequently undergo voltage-induced large deformation, which may lead to mechanical instabilities. Here, we investigate wrinkle formation and propagation on the surface of a DE membrane mounted on an air chamber and subjected to a step voltage. Our experiments show that the geometric characteristics of the wrinkle morphology and the nucleation sites depend on the inflation pressure and the applied voltage. As the inflation pressure increases, the critical voltage used to nucleate the wrinkle decreases, while the location where the wrinkle nucleates shifts from the center to the boundary of the membrane. Moreover, by increasing the amplitude of the applied voltage, wrinkle morphology changes from stripe-like wrinkles to labyrinth-like wrinkles. Furthermore, we develop an analytical model to validate the experimental observations and map out the various wrinkle morphologies as a function of the applied pressure and voltage. A three dimensional phase diagram is constructed to help design new soft actuators. PMID- 26119743 TI - Lam6 Regulates the Extent of Contacts between Organelles. AB - Communication between organelles is crucial for eukaryotic cells to function as one coherent unit. An important means of communication is through membrane contact sites, where two organelles come into close proximity allowing the transport of lipids and small solutes between them. Contact sites are dynamic in size and can change in response to environmental or cellular stimuli; however, how this is regulated has been unclear. Here, we show that Saccharomyces cerevisiae Lam6 resides in several central contact sites: ERMES (ER/mitochondria encounter structure), vCLAMP (vacuole and mitochondria patch), and NVJ (nuclear vacuolar junction). We show that Lam6 is sufficient for expansion of contact sites under physiological conditions and necessary for coordination of contact site size. Given that Lam6 is part of a large protein family and is conserved in vertebrates, our work opens avenues for investigating the underlying principles of organelle communication. PMID- 26119745 TI - Selection on a genetic polymorphism counteracts ecological speciation in a stick insect. AB - The interplay between selection and aspects of the genetic architecture of traits (such as linkage, dominance, and epistasis) can either drive or constrain speciation [1-3]. Despite accumulating evidence that speciation can progress to "intermediate" stages-with populations evolving only partial reproductive isolation-studies describing selective mechanisms that impose constraints on speciation are more rare than those describing drivers. The stick insect Timema cristinae provides an example of a system in which partial reproductive isolation has evolved between populations adapted to different host plant environments, in part due to divergent selection acting on a pattern polymorphism [4, 5]. Here, we demonstrate how selection on a green/melanistic color polymorphism counteracts speciation in this system. Specifically, divergent selection between hosts does not occur on color phenotypes because melanistic T. cristinae are cryptic on the stems of both host species, are resistant to a fungal pathogen, and have a mating advantage. Using genetic crosses and genome-wide association mapping, we quantify the genetic architecture of both the pattern and color polymorphism, illustrating their simple genetic control. We use these empirical results to develop an individual-based model that shows how the melanistic phenotype acts as a "genetic bridge" that increases gene flow between populations living on different hosts. Our results demonstrate how variation in the nature of selection acting on traits, and aspects of trait genetic architecture, can impose constraints on both local adaptation and speciation. PMID- 26119746 TI - A Visual Pathway for Looming-Evoked Escape in Larval Zebrafish. AB - Avoiding the strike of an approaching predator requires rapid visual detection of a looming object, followed by a directed escape maneuver. While looming-sensitive neurons have been discovered in various animal species, the relative importance of stimulus features that are extracted by the visual system is still unclear. Furthermore, the neural mechanisms that compute object approach are largely unknown. We found that a virtual looming stimulus, i.e., a dark expanding disk on a bright background, reliably evoked rapid escape movements. Related stimuli, such as dimming, receding, or bright looming objects, were substantially less effective, and angular size was a critical determinant of escape initiation. Two photon calcium imaging in retinal ganglion cell (RGC) axons revealed three retinorecipient areas that responded robustly to looming stimuli. One of these areas, the optic tectum, is innervated by a subset of RGC axons that respond selectively to looming stimuli. Laser-induced lesions of the tectal neuropil impaired the behavior. Our findings demonstrate a visually mediated escape behavior in zebrafish larvae exposed to objects approaching on a collision course. This response is sensitive to spatiotemporal parameters of the looming stimulus. Our data indicate that a subset of RGC axons within the tectum responds selectively to features of looming stimuli and that this input is necessary for visually evoked escape. PMID- 26119747 TI - A Recently Evolved Alternative Splice Site in the BRANCHED1a Gene Controls Potato Plant Architecture. AB - Amplification and diversification of transcriptional regulators that control development is a driving force of morphological evolution. A major source of protein diversity is alternative splicing, which leads to the generation of different isoforms from a single gene. The mechanisms and timing of intron evolution nonetheless remain unclear, and the functions of alternative splicing generated protein isoforms are rarely studied. In Solanum tuberosum, the BRANCHED1a (BRC1a) gene encodes a TCP transcription factor that controls lateral shoot outgrowth. Here, we report the recent evolution in Solanum of an alternative splice site in BRC1a that leads to the generation of two BRC1a protein isoforms with distinct C-terminal regions, BRC1a(Long) and BRC1a(Short), encoded by unspliced and spliced mRNA, respectively. The BRC1a(Long) C-terminal region has a strong activation domain, whereas that of BRC1a(S) lacks an activation domain and is predicted to form an amphipathic helix, the H domain, which prevents protein nuclear targeting. BRC1a(Short) is thus mainly cytoplasmic, while BRC1a(Long) is mainly nuclear. BRC1a(Long) functions as a transcriptional activator, whereas BRC1a(Short) appears to have no transcriptional activity. Moreover, BRC1a(Short) can heterodimerize with BRC1a(Long) and act as a dominant-negative factor; it increases BRC1a(Long) concentration in cytoplasm and reduces its transcriptional activity. This alternative splicing mechanism is regulated by hormones and external stimuli that control branching. The evolution of a new alternative splicing site and a novel protein domain in Solanum BRC1a led to a multi-level mechanism of post transcriptional and post-translational BRC1a regulation that effectively modulates its branch suppressing activity in response to environmental and endogenous cues. PMID- 26119748 TI - Pattern-Induced Covert Category Learning in Songbirds. AB - Language is uniquely human, but its acquisition may involve cognitive capacities shared with other species. During development, language experience alters speech sound (phoneme) categorization. Newborn infants distinguish the phonemes in all languages but by 10 months show adult-like greater sensitivity to native language phonemic contrasts than non-native contrasts. Distributional theories account for phonetic learning by positing that infants infer category boundaries from modal distributions of speech sounds along acoustic continua. For example, tokens of the sounds /b/ and /p/ cluster around different mean voice onset times. To disambiguate overlapping distributions, contextual theories propose that phonetic category learning is informed by higher-level patterns (e.g., words) in which phonemes normally occur. For example, the vowel sounds /Iota/ and /e/ can occupy similar perceptual spaces but can be distinguished in the context of "with" and "well." Both distributional and contextual cues appear to function in speech acquisition. Non-human species also benefit from distributional cues for category learning, but whether category learning benefits from contextual information in non-human animals is unknown. The use of higher-level patterns to guide lower level category learning may reflect uniquely human capacities tied to language acquisition or more general learning abilities reflecting shared neurobiological mechanisms. Using songbirds, European starlings, we show that higher-level pattern learning covertly enhances categorization of the natural communication sounds. This observation mirrors the support for contextual theories of phonemic category learning in humans and demonstrates a general form of learning not unique to humans or language. PMID- 26119749 TI - Locomotion and Task Demands Differentially Modulate Thalamic Audiovisual Processing during Active Search. AB - Active search is a ubiquitous goal-driven behavior wherein organisms purposefully investigate the sensory environment to locate a target object. During active search, brain circuits analyze a stream of sensory information from the external environment, adjusting for internal signals related to self-generated movement or "top-down" weighting of anticipated target and distractor properties. Sensory responses in the cortex can be modulated by internal state, though the extent and form of modulation arising in the cortex de novo versus an inheritance from subcortical stations is not clear. We addressed this question by simultaneously recording from auditory and visual regions of the thalamus (MG and LG, respectively) while mice used dynamic auditory or visual feedback to search for a hidden target within an annular track. Locomotion was associated with strongly suppressed responses and reduced decoding accuracy in MG but a subtle increase in LG spiking. Because stimuli in one modality provided critical information about target location while the other served as a distractor, we could also estimate the importance of task relevance in both thalamic subdivisions. In contrast to the effects of locomotion, we found that LG responses were reduced overall yet decoded stimuli more accurately when vision was behaviorally relevant, whereas task relevance had little effect on MG responses. This double dissociation between the influences of task relevance and movement in MG and LG highlights a role for extrasensory modulation in the thalamus but also suggests key differences in the organization of modulatory circuitry between the auditory and visual pathways. PMID- 26119750 TI - SPD-2/CEP192 and CDK Are Limiting for Microtubule-Organizing Center Function at the Centrosome. AB - The centrosome acts as the microtubule-organizing center (MTOC) during mitosis in animal cells. Microtubules are nucleated and anchored by gamma-tubulin ring complexes (gamma-TuRCs) embedded within the centrosome's pericentriolar material (PCM). The PCM is required for the localization of gamma-TuRCs, and both are steadily recruited to the centrosome, culminating in a peak in MTOC function in metaphase. In differentiated cells, the centrosome is often attenuated as an MTOC and MTOC function is reassigned to non-centrosomal sites such as the apical membrane in epithelial cells, the nuclear envelope in skeletal muscle, and down the lengths of axons and dendrites in neurons. Hyperactive MTOC function at the centrosome is associated with epithelial cancers and with invasive behavior in tumor cells. Little is known about the mechanisms that limit MTOC activation at the centrosome. Here, we find that MTOC function at the centrosome is completely inactivated during cell differentiation in C. elegans embryonic intestinal cells and MTOC function is reassigned to the apical membrane. In cells that divide after differentiation, the cellular MTOC state switches between the membrane and the centrosome. Using cell fusion experiments in live embryos, we find that the centrosome MTOC state is dominant and that the inactive MTOC state of the centrosome is malleable; fusion of a mitotic cell to a differentiated or interphase cell results in rapid reactivation of the centrosome MTOC. We show that conversion of MTOC state involves the conserved centrosome protein SPD 2/CEP192 and CDK activity from the mitotic cell. PMID- 26119751 TI - A Secreted MIF Cytokine Enables Aphid Feeding and Represses Plant Immune Responses. AB - Aphids attack virtually all plant species and cause serious crop damages in agriculture. Despite their dramatic impact on food production, little is known about the molecular processes that allow aphids to exploit their host plants. To date, few aphid salivary proteins have been identified that are essential for aphid feeding, and their nature and function remain largely unknown. Here, we show that a macrophage migration inhibitory factor (MIF) is secreted in aphid saliva. In vertebrates, MIFs are important pro-inflammatory cytokines regulating immune responses. MIF proteins are also secreted by parasites of vertebrates, including nematodes, ticks, and protozoa, and participate in the modulation of host immune responses. The finding that a plant parasite secretes a MIF protein prompted us to question the role of the cytokine in the plant-aphid interaction. We show here that expression of MIF genes is crucial for aphid survival, fecundity, and feeding on a host plant. The ectopic expression of aphid MIFs in leaf tissues inhibits major plant immune responses, such as the expression of defense-related genes, callose deposition, and hypersensitive cell death. Functional complementation analyses in vivo allowed demonstrating that MIF1 is the member of the MIF protein family that allows aphids to exploit their host plants. To our knowledge, this is the first report of a cytokine that is secreted by a parasite to modulate plant immune responses. Our findings suggest a so-far unsuspected conservation of infection strategies among parasites of animal and plant species. PMID- 26119753 TI - Upconversion luminescence behavior of single nanoparticles. AB - Upconversion nanoparticles (UCNPs) have made a significant and valuable contribution to materials science, photophysics, and biomedicine due to their specific spectroscopic characteristics. However, the ensemble spectroscopy of UCNPs is limited because of the electronic behavior in average effect, which ignores the fact that these nanoparticles are heterogeneous. With regards to the research focus on heterogeneous intrinsic structures, unique photophysical phenomena, and advanced applications, the optical characterization of single UCNPs have been promoted to the frontier development of the UCNPs community. In this review, we give an overview of the importance of single UCNPs characterization, typical principles of UC, and single particle detection methods. Considerable emphasis is placed on the specific spectroscopic study of single UCNPs, which shows fantastic photophysical phenomena beyond ensemble measurement. Parallel efforts are devoted to the current applications of single UCNPs. PMID- 26119752 TI - Genomic Evidence that Sexual Selection Impedes Adaptation to a Novel Environment. AB - Sexual selection is widely appreciated for generating remarkable phenotypic diversity, but its contribution to adaptation and the purging of deleterious mutations is unresolved. To provide insight into the impact of sexual selection on naturally segregating polymorphisms across the genome, we previously evolved 12 populations of Drosophila serrata in a novel environment employing a factorial manipulation of the opportunities for natural and sexual selection. Here, we genotype more than 1,400 SNPs in the evolved populations and reveal that sexual selection affected many of the same genomic regions as natural selection, aligning with it as often as opposing it. Intriguingly, more than half of the 80 SNPs showing treatment effects revealed an interaction between natural and sexual selection. For these SNPs, while sexual selection alone often caused a change in allele frequency in the same direction as natural selection alone, when natural and sexual selection occurred together, changes in allele frequency were greatly reduced or even reversed. This suggests an antagonism between natural and sexual selection arising from male-induced harm to females. Behavioral experiments showed that males preferentially courted and mated with high-fitness females, and that the harm associated with this increased male attention eliminated the female fitness advantage. During our experiment, females carrying otherwise adaptive alleles may therefore have disproportionally suffered male-induced harm due to their increased sexual attractiveness. These results suggest that a class of otherwise adaptive mutations may not contribute to adaptation when mating systems involve sexual conflict and male mate preferences. PMID- 26119754 TI - A precise automatic system for the hair assessment in hair-care diagnosis applications. AB - BACKGROUND/PURPOSE: One emerging subject in medical image processing is to quantitatively assess the health and the properties of cranial hairs, including density, diameter, length, level of oiliness, and others. This information helps hair specialists with making a more accurate diagnosis and the therapy required. We develop a practical hair counting algorithm. This analytic system calculates the number of hairs on a scalp using a digital microscope camera, providing accurate information for both the hair specialist and the patient. Our proposed hair counting algorithm is substantially more accurate than the Hough-based one, and is robust to curls, oily scalp, noise-corruption, and overlapping hairs, under various levels of illumination. Rather than manually counting the hairs on a person's scalp, the proposed system determines the density, diameter, length, and level of oiliness of the hairs. METHODS: We propose an automated system for counting the amount of hairs in the microscopy images. To reduce the effect of bright spots, we develop a robust morphological algorithm for color to smooth out the color and preserve the fidelity of the hair. Then, we utilize a modified Hough transform algorithm to detect the different hair lengths and to reduce any false detection due to noise. Our proposed system enables us to look at curved hairs as multiple pieces of straight lines. To avoid missing hairs when the thinning process is applied, we use edge information to discover any hidden or overlapping hairs. Finally, we employ a mutually associative regression method to label a group of line segments into a meaningful 'hair'. RESULTS: We demonstrated a novel approach for accurately computing the number of hairs, and successfully solved the three main obstacles in automated hair counting, including (i) oily and moist hairs, (ii) wavy and curly hairs, and (iii) under-estimation of the number of hairs occurs when hairs cross and occlude each other. The framework of this paper can be seen as the first step toward intelligent computer-aided medical image processing for cosmetic treatment applications. CONCLUSIONS: The goal of this study was to develop an automated hair counting system for clinical application using the microscope image from the hairs. The proposed method reduces the frequent errors and variances encountered when hairs are manually counted by human assessors. This clinical intelligent system can diagnose the health condition of a person's hair and can be applied in therapy recommendations by doctors for their patients. PMID- 26119755 TI - Crystallization of zirconia based thin films. AB - The crystallization kinetics of amorphous 3 and 8 mol% yttria stabilized zirconia (3YSZ and 8YSZ) thin films grown by pulsed laser deposition (PLD), spray pyrolysis and dc-magnetron sputtering are explored. The deposited films were heat treated up to 1000 degrees C ex situ and in situ in an X-ray diffractometer. A minimum temperature of 275 degrees C was determined at which as-deposited amorphous PLD grown 3YSZ films fully crystallize within five hours. Above 325 degrees C these films transform nearly instantaneously with a high degree of micro-strain when crystallized below 500 degrees C. In these films the t'' phase crystallizes which transforms at T > 600 degrees C to the t' phase upon relaxation of the micro-strain. Furthermore, the crystallization of 8YSZ thin films grown by PLD, spray pyrolysis and dc-sputtering are characterized by in situ XRD measurements. At a constant heating rate of 2.4 K min(-1) crystallization is accomplished after reaching 800 degrees C, while PLD grown thin films were completely crystallized already at ca. 300 degrees C. PMID- 26119756 TI - MiRNA-Mediated Regulation of the SWI/SNF Chromatin Remodeling Complex Controls Pluripotency and Endodermal Differentiation in Human ESCs. AB - MicroRNAs and chromatin remodeling complexes represent powerful epigenetic mechanisms that regulate the pluripotent state. miR-302 is a strong inducer of pluripotency, which is characterized by a distinct chromatin architecture. This suggests that miR-302 regulates global chromatin structure; however, a direct relationship between miR-302 and chromatin remodelers has not been established. Here, we provide data to show that miR-302 regulates Brg1 chromatin remodeling complex composition in human embryonic stem cells (hESCs) through direct repression of the BAF53a and BAF170 subunits. With the subsequent overexpression of BAF170 in hESCs, we show that miR-302's inhibition of BAF170 protein levels can affect the expression of genes involved in cell proliferation. Furthermore, miR-302-mediated repression of BAF170 regulates pluripotency by positively influencing mesendodermal differentiation. Overexpression of BAF170 in hESCs led to biased differentiation toward the ectoderm lineage during EB formation and severely hindered directed definitive endoderm differentiation. Taken together, these data uncover a direct regulatory relationship between miR-302 and the Brg1 chromatin remodeling complex that controls gene expression and cell fate decisions in hESCs and suggests that similar mechanisms are at play during early human development. PMID- 26119757 TI - Wind tunnel study of ammonia transfer from a manure pit fitted with a dairy cattle slatted floor. AB - In dairy cattle systems, most of the feces and urine go to the pit. At the manure pit level, mass transfer of NH3 ([Formula: see text]) has many factors, but practical difficulties hamper a controlled field evaluation. In this study, we propose a methodology for the determination of an alternative, more practical, pit transfer coefficient of NH3 (PTC), and compare it with [Formula: see text] determined from other scientific studies. The aims of this research study were: (1) to develop a wind tunnel set-up which mimics air flow patterns between the slats and above a clean section of a slatted floor section, featuring an aqueous NH3-emitting solution; and (2) to assess how air velocity, turbulence intensity, NH3 concentration ([NH3]) and PTC are influenced by inlet airflow ventilation rate (VR) forced deflection of the air above the slats into the manure pit through varying the deflection angle (DA) of a deflection panel and varying pit headspace height (HH). Main conclusions were: (1) the calculated PTC values presented a good fit to the power function of the air speed near the slats (u) (p < .001) while the average PTC (0.0039 m s(-1)) was comparable to [Formula: see text] values obtained from other studies, by remaining within the range of average values of 0.0015-0.0043 m s(-1); (2) VR and DA significantly impacted [NH3] profiles and PTC (p < .001) and (3) changing slurry pit from 0.10 to 0.90 m HH did not significantly impact [NH3] or PTC (p = .756 and p = .854, respectively). PMID- 26119758 TI - A visible light induced photoelectrochemical aptsensor constructed by aligned ZnO@CdTe core shell nanocable arrays/carboxylated g-C3N4 for the detection of Proprotein convertase subtilisin/kexin type 6 gene. AB - It was reported that Proprotein convertase subtilisin/kexin type 6 (PCSK6) can promote the progression of rheumatoid arthritis to a higher aggressive status. In this work, a novel visible light induced photoelectrochemical (PEC) platform was designed to detect PCSK6 gene. ZnO@CdTe nanocable arrays/carboxylated g-C3N4 used as the PEC signal generator. Hexagonal ZnO nanorods grew on ITO electrode firstly. CdTe were then electrodeposited on the ZnO nanorods surface to enhance the photogenerated h(+)/e(-) separation efficiency. Carboxylated g-C3N4 was utilized to improve h(+)/e(-) separation efficiency and anchor the capture probes of PCSK6 gene by the covalent bonding effect. The 5' and 3' primers captured PCSK6 ssDNA by the specific recognition. The linear range was 10 pg/mL to 20.0 ng/mL with a detection limit of 2 pg/mL. PMID- 26119759 TI - Optimal treatment allocation for placebo-treatment comparisons in trials with discrete-time survival endpoints. AB - In many randomized controlled trials, treatment groups are of equal size, but this is not necessarily the best choice. This paper provides a methodology to calculate optimal treatment allocations for longitudinal trials when we wish to compare multiple treatment groups with a placebo group, and the comparisons may have unequal importance. The focus is on trials with a survival endpoint measured in discrete time. We assume the underlying survival process is Weibull and show that values for the parameters in the Weibull distribution have an impact on the optimal treatment allocation scheme in an interesting way. Additionally, we incorporate different cost considerations at the subject and measurement levels and determine the optimal number of time periods. We also show that when many events occur at the beginning of the trial, fewer time periods are more efficient. As an application, we revisit a risperidone maintenance treatment trial in schizophrenia and use our proposed methodology to redesign it and compare merits of our optimal design. PMID- 26119760 TI - Medicolegal Issues in Endoscopic Sinus Surgery and Complications. AB - Complications occur during and after endoscopic sinus surgery. Complications leading to temporary or most commonly permanent injury often are involved in litigation for malpractice. This article concentrates on areas of importance that are considered during medicolegal deliberations. PMID- 26119761 TI - Does Image-Guided Surgery Reduce Complications? AB - Image-guided surgery (IGS) is progressively used in endoscopic sinus surgery (ESS), and surgeon comfort with the technology has increased. It remains a challenge to determine if the use of IGS in ESS leads to a reduction in surgical complications and improved outcomes. Current literature does not show a clear reduction in surgical complications. The routine use of IGS in ESS as a deterrent to medicolegal liability is not substantiated by recent reported data. There are particular situations in which IGS may be helpful, but its use is likely not required for routine ESS and seems best left to surgeon discretion. PMID- 26119762 TI - Get on the ecosystem services bandwagon. PMID- 26119764 TI - Life cycle assessment in market, research, and policy: Harmonization beyond standardization. AB - This article introduces the special series "LCA in Market Research and Policy: Harmonization beyond standardization," which was generated from the 19th SETAC Life Cycle Assessment (LCA) Case Study Symposium held November 2013, in Rome, Italy. This collection of invited articles reflects the purpose of symposium and focuses on how LCA can support the decision-making process at all levels (i.e., in industry and policy contexts) and how LCA results can be efficiently communicated and used to support market strategies. PMID- 26119766 TI - Uncertainty in health Canada's drinking water aesthetic classifications. PMID- 26119767 TI - Monte Carlo-based distance analysis using unit mass resolution ICP-MS data for shellfish site of origin verification. PMID- 26119768 TI - Internet-based platforms for science communication. PMID- 26119769 TI - Pharmaceutical residues in the water cycle--Communicating precautionary measures. PMID- 26119771 TI - Plasma miR-15b-5p, miR-338-5p, and miR-764 as Biomarkers for Hepatocellular Carcinoma. AB - BACKGROUND: Recently, increasing research evidence indicates that miRNA plays important roles in oncogenesis of hepatocellular carcinoma (HCC). The objective of this study was to investigate the potential of plasma miRNAs as biomarkers for HCC determination. MATERIAL AND METHODS: This trial included 4 phases: (i) miRNAs in tumor tissues were screened with a miRNA array for determining candidate miRNAs. (ii) Candidate miRNAs were measured by RT-qPCR in plasma of 10 HCC patients before and after surgery (7-10 days) for target miRNAs that displayed a pattern of postoperative decrease. (iii) Plasma levels of target miRNAs in 37 HCC patients, 29 cirrhosis patients, and 31 healthy controls were measured by RT-qPCR for determining potential biomarkers. (iv) The powers of biomarkers for differentiating HCC were validated and the correlations with clinicopathological variables of HCC patients were analyzed. RESULTS: miRNA array demonstrated an abnormal expression of 92 miRNAs in tumor tissues compared to adjacent non-tumor tissues. Of those molecules with an over-expressed level in tumor tissues and preoperative plasmas, a decrease in postoperative plasma was observed in miR-15b 5p, miR-338-5p, and miR-764. Plasma levels of these miRNAs in HCC patients were higher than in the other 2 groups (P<0.05). Receiver-operator characteristic (ROC) curve analyses suggested these plasma miRNAs could be useful biomarkers for determining HCC. miR-338-5p yielded an area under the ROC curve (AUC) of 0.799 (74.5% sensitivity and 82.8% specificity) and 0.909 (72.3% sensitivity and 99.68% specificity) to discriminate HCC patients from cirrhosis patients and healthy controls, respectively. The expression level of miR-338-5p was negatively correlated with the level of AFP (r=-0.306, P=0.036), and the expression level of miR-764 was positively correlated with the tumor size (r=0.371, P=0.01). CONCLUSIONS: Circulating miR-15b-5p, miR-338-5p, and miR-764 may be biomarkers for diagnosis of HCC. PMID- 26119772 TI - THE IMPACT OF CONTROLLED FLUID AND SALT INTAKE TRAINING IN PATIENTS UNDERGOING HAEMODIALYSIS. AB - BACKGROUND: Serious complications can occur when patients have difficulty in adhering to fluid and salt recommendations. OBJECTIVES AND DESIGN: This study was designed as an experimental study with the aims of evaluating the effects of controlled fluid and salt intake training on the intra-dialytic process and on the level of patients' knowledge. The factors that had an impact on the training process were also evaluated. The effectiveness of the planned training was evaluated at 0, 1, 3 and 6 months. RESULTS: There were no significant differences in salt intake exceeding 3 g per day (p > 0.05) between the preliminary and final test, although a statistically significant change was observed at months 1 and 3. The effectiveness of the training decreased by the end of the 3rd month. A statistically significant change was obtained prior to and after the training at months 0, 1, 3 and 6 with respect to the rates of daily fluid intake exceeding 1,500 ml, hypovolaemia, hypervolaemia, awareness of salt-rich food and correct calculation of daily fluid intake by the patients. Also a significant reduction was observed in the volume of oedema after the training. The patients' age, gender, marital status and educational background did not have a significant effect on daily salt intake of more than 3 g, daily fluid intake of more than 1,500 ml, and level of knowledge regarding fluid and salt control. CONCLUSIONS: The training was effective at some time points in decreasing salt and fluid intake. This training should be repeated at certain intervals for the behavioural changes to become permanent. PMID- 26119773 TI - Update of mortality attributable to diabetes for the IDF Diabetes Atlas: Estimates for the year 2013. AB - BACKGROUND: Mortality is an important measure of population health and is often used to assign priorities in health interventions. Estimating mortality due to diabetes has been challenging because more than a third of countries of the world have no reliable data available on mortality. Moreover estimating mortality attributable to Diabetes is especially challenging since most people die of a related vascular complication such as cardiovascular disease or renal failure. AIMS: The aim of the study was to provide estimate of the number of deaths attributable to diabetes for the year 2013. METHODS: A computerized disease model was used to obtain the estimates. Using WHO life tables for 2010 and IDF diabetes prevalence estimates for 2013, age and sex-specific relative risks of death for persons with diabetes were calculated, in order to estimate the number of deaths attributable to diabetes in people 20-79 years of age. RESULTS: This model estimated that globally, 8.4% of all-cause deaths were attributable to diabetes in adults aged 20-79 years, almost 5.1 million deaths. A sensitivity analysis adjusting relative risks by 20% found that the estimate of diabetes-attributable mortality to lie between 5.1% of total mortality (3.3 million deaths) and 10.1% of total mortality (6.6 million deaths). The highest rates of diabetes attributable mortality were found to be 25.7% in South-East Asian women aged between 50 and 59 years old. The highest number of deaths attributable to diabetes was found in countries with large populations: 1271,000 in China, 1065,000 deaths in India, 386,400 in Indonesia, 197,300 in the Russian Federation and 192,700 in the United States of America. CONCLUSIONS: Overall, 1 in 12 of global all-cause deaths were estimated to be attributable to diabetes in adults. In general, the number and proportion of deaths was slightly higher in women than in men. PMID- 26119774 TI - Work-related accidents among the Iranian population: a time series analysis, 2000 2011. AB - BACKGROUND: Work-related accidents result in human suffering and economic losses and are considered as a major health problem worldwide, especially in the economically developing world. OBJECTIVES: To introduce seasonal autoregressive moving average (ARIMA) models for time series analysis of work-related accident data for workers insured by the Iranian Social Security Organization (ISSO) between 2000 and 2011. METHODS: In this retrospective study, all insured people experiencing at least one work-related accident during a 10-year period were included in the analyses. We used Box-Jenkins modeling to develop a time series model of the total number of accidents. RESULTS: There was an average of 1476 accidents per month (1476.05+/-458.77, mean+/-SD). The final ARIMA (p,d,q) (P,D,Q)s model for fitting to data was: ARIMA(1,1,1)*(0,1,1)12 consisting of the first ordering of the autoregressive, moving average and seasonal moving average parameters with 20.942 mean absolute percentage error (MAPE). CONCLUSIONS: The final model showed that time series analysis of ARIMA models was useful for forecasting the number of work-related accidents in Iran. In addition, the forecasted number of work-related accidents for 2011 explained the stability of occurrence of these accidents in recent years, indicating a need for preventive occupational health and safety policies such as safety inspection. PMID- 26119775 TI - Role of binary toxin in the outcome of Clostridium difficile infection in a non 027 ribotype setting. AB - Binary toxin (BT) has been associated with strains causing more severe Clostridium difficile infection (CDI), such as ribotype 027. Data on the outcome of patients having BT present in ribotypes other than 027 are scarce. Our objective was to investigate the association between BT isolates and outcome of CDI in a non-027 ribotype setting. We prospectively included CDI episodes (January-June 2013 and March-June 2014) from symptomatic patients aged >2 years. Epidemiological and clinical data were recorded. BT genes were detected using multiplex PCR. During the study period, we identified 326 episodes of CDI, of which 319 were available for molecular analysis. Of these, 54 (16.9%) were caused by C. difficile strains with BT. Most (90.7%) isolates with BT were ribotype 078/126. CDI patients with BT-positive strains did not differ from those with BT negative strains in terms of recurrence (13.0% vs. 15.5%, P = 0.835), treatment failure (0.0% vs. 2.3%, P = 0.594), overall mortality (11.1% vs. 9.1%, P = 0.612), or CDI-related mortality (0.0% vs. 1.9%, P = 0.612). Multivariate regression revealed no association between BT and poor outcome. In conclusion, in a non-027 setting, we found that most BT isolates were 078/126 and were not associated with poor outcome. PMID- 26119776 TI - Synthesis of cyclic carbonates from epoxides and carbon dioxide by using organocatalysts. AB - The synthesis of cyclic carbonates through coupling of carbon dioxide with epoxides is 100 % atom economical and is already performed on an industrial scale. Its impact regarding the use of carbon dioxide as a renewable carbon source is expected to grow significantly in the near future, so that the development of efficient catalysts is of high interest in academia and industry. To improve the carbon footprint and sustainability of the cycloaddition reaction, the use of organocatalytic methods is a promising approach. Herein, available metal-free catalysts for the preparation of cyclic carbonates are described and elaborated concerning the overall sustainability of the process. Therefore, the required reaction conditions, as well as the activity of the catalysts and their reusability, are compared and evaluated. In addition to ammonium-, phosphonium-, or imidazolium-based single-component catalysts and their supported analogues, the growing field of research concerning dual catalysts are also discussed in detail. PMID- 26119777 TI - Practical guidance on the recognition of uncontrolled asthma and its management. AB - PURPOSE: To highlight the significance of asthma in primary care and offer a practitioner-friendly interpretation of the asthma guidelines for the busy provider, while introducing new treatment options currently in clinical trials, such as the once-daily long-acting anticholinergic bronchodilator tiotropium Respimat. DATA SOURCES: Articles with relevant adult data published between 2004 and 2015 were identified via PubMed. Additional references were obtained by reviewing bibliographies from selected articles. CONCLUSIONS: In the United States, uncontrolled or symptomatic asthma is common, with rates of 46%-78% in primary care. Uncontrolled asthma has a substantial impact on patients' quality of life and represents a significant healthcare burden. Nurse practitioners can improve patients' asthma control through education, monitoring, assessment, and treatment. Although asthma management guidelines are readily available, the authors recognize that nurse practitioners see patients with multiple comorbidities, all of which have treatment guidelines of their own. IMPLICATIONS FOR PRACTICE: Nurse practitioners have a compelling opportunity as frontline caregivers and patient educators to recognize and assess uncontrolled asthma, along with determining the steps necessary to help patients gain and maintain symptom control. PMID- 26119778 TI - Role modelling in medical education: the importance of teaching skills. AB - OBJECTIVES: By observation of role models, and participation in activities, students develop their attitudes, values and professional competencies. Literature suggests that clinical skills and knowledge, personality, and teaching skills are three main areas that students consider central to the identification of positive role models. The aim of this study was to explore junior medical students' opinions of the ideal attributes of a good role model in clinical tutors. METHODS: The study was conducted with one cohort (n = 301) of students who had completed year 1 of the medical programme in 2013. All students were asked to complete a questionnaire regarding the ideal attributes of a good role model in a clinical tutor. The questionnaire consisted of seven closed items and one open-ended question. RESULTS: The response rate to the questionnaire was 265/301 (88%). Although students found all three key areas important in a good role model, students emphasised the importance of excellence in teaching skills. Specifically, students see good role models as being able to provide a constructive learning environment, a good understanding of the curriculum and an ability to cater to the learning needs of all students. Students see good role models as being able to provide a constructive learning environment CONCLUSION: While acknowledging the importance of a patient-centred approach, as well as clinical knowledge and skills, our findings reinforce the importance of the actual teaching abilities of role models within medical education. PMID- 26119779 TI - Oxidation pathways underlying the pro-oxidant effects of apigenin. AB - Apigenin, a natural flavone, is emerging as a promising compound for the treatment of several diseases. One of the hallmarks of apigenin is the generation of intracellular reactive oxygen species (ROS), as judged by the oxidation of reduced dichlorofluorescein derivatives seen in many cell types. This study aimed to reveal some mechanisms by which apigenin can be oxidized and how apigenin derived radicals affect the oxidation of 5-(and-6)-chloromethyl-2',7' dichlorodihydrofluorescein (H(2)DCF), a probe usually employed to detect intracellular ROS. Apigenin induced a rapid oxidation of H(2)DCF in two different immortalized cell lines derived from rat and human hepatic stellate cells. However, apigenin did not generate ROS in these cells, as judged by dihydroethidium oxidation and extracellular hydrogen peroxide production. In cell free experiments we found that oxidation of apigenin leads to the generation of a phenoxyl radical, which directly oxidizes H(2)DCF with catalytic amounts of hydrogen peroxide. The net balance of the reaction was the oxidation of the probe by molecular oxygen due to redox cycling of apigenin. This flavonoid was also able to deplete NADH and glutathione by a similar mechanism. Interestingly, H(2)DCF oxidation was significantly accelerated by apigenin in the presence of horseradish peroxidase and xanthine oxidase, but not with other enzymes showing peroxidase-like activity, such as cytochrome c or catalase. We conclude that in cells treated with apigenin oxidation of reduced dichlorofluorescein derivatives does not measure intracellular ROS and that pro- and antioxidant effects of flavonoids deduced from these experiments are inconclusive and must be confirmed by other techniques. PMID- 26119780 TI - MKK3 deletion improves mitochondrial quality. AB - Sepsis, a severe response to infection, leads to excessive inflammation and is the major cause of mortality in intensive care units. Mitochondria have been shown to influence the outcome of septic injury. We have previously shown that MAP kinase kinase 3 (MKK3)(-/-) mice are resistant to septic injury and MKK3(-/-) macrophages have improved mitochondrial function. In this study we examined processes that lead to improved mitochondrial quality in MKK3(-/-) mouse embryonic fibroblasts (MEFs) and specifically the role of mitophagy in mitochondrial health. MKK3(-/-) MEFs had lower inflammatory cytokine release and oxidant production after lipopolysaccharide (LPS) stimulation, confirming our earlier observations. MKK3(-/-) MEFs had better mitochondrial function as measured by mitochondrial membrane potential (MMP) and ATP, even after LPS treatment. We observed higher mitophagy in MKK3(-/-) MEFs compared to wild type (WT). Transmission electron microscopy studies showed longer and larger mitochondria in MKK3(-/-) MEFs, indicative of healthier mitochondria. We performed a SILAC (stable isotope labeling by/with amino acids in cell culture) study to assess differences in mitochondrial proteome between WT and MKK3(-/-) MEFs and observed increased expression of tricarboxylic acid (TCA) cycle enzymes and respiratory complex subunits. Further, inhibition of mitophagy by Mdivi1 led to loss in MMP and increased cytokine secretion after LPS treatment in MKK3(-/-) MEFs. In conclusion, this study demonstrates that MKK3 influences mitochondrial quality by affecting the expression of mitochondrial proteins, including TCA cycle enzymes, and mitophagy, which consequently regulates the inflammatory response. Based on our results, MKK3 could be a potential therapeutic target for inflammatory diseases like sepsis. PMID- 26119781 TI - Thioredoxin-dependent regulation of AIF-mediated DNA damage. AB - The thioredoxin (Trx) system is one major redox system in mammalian cells. One of its component, Trx, is involved in redox homeostasis and many cellular biological processes through participating in disulfide reduction, S-nitrosylation/S denitrosylation reactions and protein-protein interactions. In this study, we report the identification of a novel interaction between cytosolic/nuclear Trx1 and apoptosis inducing factor (AIF), and the redox sensitivity and biological significance of the Trx-AIF interaction was characterized. Cytosolic Trx1 but not mitochondrial Trx2 was observed to interact with AIF under physiological conditions and Trx1's active site cysteines were crucial for the interaction. Under oxidative stress conditions, Trx-AIF interaction was disrupted. When the treated cells were allowed to recover from oxidative stress by means of removal of the oxidants, interaction between Trx1 and AIF was re-established time dependently, which underpins the biological relevance of a Trx-dependent redox regulation of AIF-mediated cell death. Indeed, in times of oxidative stress, nuclear translocation of AIF was found to occur concurrently with perturbations to the Trx-AIF interaction. Once localized in the nucleus, reduced Trx1 hindered the interaction between AIF and DNA, thereby bringing about an attenuation of AIF mediated DNA damage. In conclusion, characterization of the Trx-AIF interaction has led to an understanding of the effect of reduced Trx1 on possibly regulating AIF-dependent cell death through impeding AIF-mediated DNA damage. Importantly, identification of the novel interaction between Trx1 and AIF has provided opportunities to design and develop therapeutically relevant strategies that either promote or prevent this protein-protein interaction for the treatment of different disease states. PMID- 26119782 TI - ENOS deficiency causes podocyte injury with mitochondrial abnormality. AB - The contribution of endothelial nitric oxide synthase (eNOS) to podocyte integrity remains unclear. This study therefore examined podocytes and mitochondrial abnormalities in eNOS deficient mice. Absence of eNOS caused glomerular hypertrophy, along with occasional glomerular sclerosis and mesangiolysis. While many glomeruli did not have such advanced lesions, ultrastructural analysis showed cellular hypertrophy, vacuolization, lysosomal enlargement, and microvillus formation in podocytes of eNOS knockout (KO) mice. Increased oxidative stress was associated with mitochondrial abnormalities, including an increase in number, coupled with a reduction in size, of mitochondria in podocytes of eNOS-KO mice. While the levels of expression of several mitochondrial proteins were not altered, the d-17 mutation in mitochondrial DNA was significantly associated with the eNOS deficiency. Renal ATP level in the renal cortex and mitochondrial respiration in the primary podocytes were significantly lower in eNOS-KO mice, suggesting that renal mitochondria may be functionally impaired. Podocytes cultured with endothelial conditioned medium lacking NO consistently showed a greater degree of mitochondrial fragmentation and an increase in mitochondrial oxidative stress, with these mitochondrial alterations rescued by an NO donor. In conclusion, eNOS may be necessary to maintain podocyte integrity, especially mitochondrial function. PMID- 26119783 TI - Roles of Nrf2 in cell proliferation and differentiation. AB - The Keap1-Nrf2 system plays pivotal roles in defense mechanisms by regulating cellular redox homeostasis. Nrf2 is an inducible transcription factor that activates a battery of genes encoding antioxidant proteins and phase II enzymes in response to oxidative stress and electrophilic xenobiotics. The activity of Nrf2 is regulated by Keap1, which promotes the ubiquitination and subsequent degradation of Nrf2 under normal conditions and releases the inhibited Nrf2 activity upon exposure to the stresses. Though an impressive contribution of the Keap1-Nrf2 system to the protection from exogenous and endogenous electrophilic insults has been well established, a line of evidence has suggested that the Keap1-Nrf2 system has various novel functions, particularly in cell proliferation and differentiation. Because the proliferation and differentiation of diverse cell types are often influenced and modulated by the cellular redox balance, Nrf2 has been considered to control these cellular processes by regulating the cellular levels of reactive oxygen species (ROS). In addition, analyses of the genome-wide distribution of Nrf2 have identified new sets of Nrf2 target genes whose products are involved in cell proliferation and differentiation but not necessarily in the regulation of oxidative stress. Considering the most characteristic features of Nrf2 as an inducible transcription factor, a newly emerged concept proposes that the Keap1-Nrf2 system translates environmental stresses into regulatory network signals in cell fate determination. In this review, we introduce the contribution of Nrf2 to lineage-specific differentiation, maintenance and differentiation of stem cells, and proliferation of normal and cancer cells, and we discuss how the response to fluctuating environments modulates cell behavior through the Keap1-Nrf2 system. PMID- 26119784 TI - Cyclic nitroxide radicals attenuate inflammation and Hyper-responsiveness in a mouse model of allergic asthma. AB - The effects of stable cyclic nitroxide radicals have been extensively investigated both in vivo and in vitro demonstrating anti-inflammatory, radioprotective, anti-mutagenic, age-retardant, hypotensive, anti-cancer and anti teratogenic activities. Yet, these stable radicals have not been evaluated in asthma and other airway inflammatory disorders. The present study investigated the effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (TPL) and 3 carbamoyl-proxyl (3-CP) in a mouse model of ovalbumin (OVA)-induced allergic asthma. Both 3-CP and TPL were non-toxic when administered either orally (1% w/w nitroxide-containing chow) or via intraperitoneal (IP) injection (~300 mg/kg). Feeding the mice orally demonstrated that 3-CP was more effective than TPL in reducing inflammatory cell recruitment into the airway and in suppressing airway hyper-responsiveness (AHR) in OVA-challenged mice. To characterize the optimal time-window of intervention and mode of drug administration, 3-CP was given orally during allergen sensitization, during allergen challenge or during both sensitization and challenge stages, and via IP injection or intranasal instillation for 3 days during the challenge period. 3-CP given via all modes of delivery markedly inhibited OVA-induced airway inflammation, expression of cytokines, AHR and protein nitration of the lung tissue. Oral administration during the entire experiment was the most efficient delivery of 3-CP and was more effective than dexamethasone a potent corticosteroid used for asthma treatment. Under a similar administration regimen (IP injection before the OVA challenge), the effect of 3-CP was similar to that of dexamethasone and even greater on AHR and protein nitration. The protective effect of the nitroxides, which preferentially react with free radicals, in suppressing the increase of main asthmatic inflammatory markers substantiate the key role played by reactive oxygen and nitrogen species in the molecular mechanism of asthma. The present results demonstrate the therapeutic potential of nitroxides for the treatment of asthma. PMID- 26119785 TI - Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model. AB - Because 5-year survival rates for patients with metastatic melanoma remain below 25%, there is continued need for new therapeutic approaches. For some tumors, pharmacologic ascorbate treatment may have a beneficial antitumor effect and may work synergistically with standard chemotherapeutics. To investigate this possibility in melanoma, we examined the effect of pharmacologic ascorbate on B16 F10 cells. Murine models were employed to compare tumor size following treatment with ascorbate, and the chemotherapeutic agents dacarbazine or valproic acid, alone or in combination with ascorbate. Results indicated that nearly all melanoma cell lines were susceptible to ascorbate-mediated cytotoxicity. Compared to saline controls, pharmacologic ascorbate decreased tumor size in both C57BL/6 (P < 0.0001) and NOD-scid tumor bearing mice (P < 0.0001). Pharmacologic ascorbate was superior or equivalent to dacarbazine as an antitumor agent. Synergy was not apparent when ascorbate was combined with either dacarbazine or valproic acid; the latter combination may have additional toxicities. Pharmacologic ascorbate induced DNA damage in melanoma cells, as evidenced by increased phosphorylation of the histone variant, H2A.X. Differences were not evident in tumor samples from C57BL/6 mice treated with pharmacologic ascorbate compared to tumors from saline-treated controls. Together, these results suggest that pharmacologic ascorbate has a cytotoxic effect against melanoma that is largely independent of lymphocytic immune functions and that continued investigation of pharmacologic ascorbate in cancer treatment is warranted. PMID- 26119786 TI - OKN-007 decreases free radical levels in a preclinical F98 rat glioma model. AB - Free radicals are associated with glioma tumors. Here, we report on the ability of an anticancer nitrone compound, OKN-007 [Oklahoma Nitrone 007; a disulfonyl derivative of alpha-phenyl-tert-butyl nitrone (PBN)] to decrease free radical levels in F98 rat gliomas using combined molecular magnetic resonance imaging (mMRI) and immunospin-trapping (IST) methodologies. Free radicals are trapped with the spin-trapping agent, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), to form DMPO macromolecule radical adducts, and then further tagged by immunospin trapping by an antibody against DMPO adducts. In this study, we combined mMRI with a biotin-Gd-DTPA-albumin-based contrast agent for signal detection with the specificity of an antibody for DMPO nitrone adducts (anti-DMPO probe), to detect in vivo free radicals in OKN-007-treated rat F98 gliomas. OKN-007 was found to significantly decrease (P < 0.05) free radical levels detected with an anti-DMPO probe in treated animals compared to untreated rats. Immunoelectron microscopy was used with gold-labeled antibiotin to detect the anti-DMPO probe within the plasma membrane of F98 tumor cells from rats administered anti-DMPO in vivo. OKN 007 was also found to decrease nuclear factor erythroid 2-related factor 2, inducible nitric oxide synthase, 3-nitrotyrosine, and malondialdehyde in ex vivo F98 glioma tissues via immunohistochemistry, as well as decrease 3-nitrotyrosine and malondialdehyde adducts in vitro in F98 cells via ELISA. The results indicate that OKN-007 effectively decreases free radicals associated with glioma tumor growth. Furthermore, this method can potentially be applied toward other types of cancers for the in vivo detection of macromolecular free radicals and the assessment of antioxidants. PMID- 26119787 TI - Nitric oxide diffusion to red blood cells limits extracellular, but not intraphagosomal, peroxynitrite formation by macrophages. AB - Macrophage-derived nitric oxide ((*)NO) participates in cytotoxic mechanisms against diverse microorganisms and tumor cells. These effects can be mediated by (*)NO itself or (*)NO-derived species such as peroxynitrite formed by its diffusion-controlled reaction with NADPH oxidase-derived superoxide radical anion (O(2)(*-)). In vivo, the facile extracellular diffusion of (*)NO as well as different competing consumption routes limit its bioavailability for the reaction with O(2)(*-) and, hence, peroxynitrite formation. In this work, we evaluated the extent by which (*)NO diffusion to red blood cells (RBC) can compete with activated macrophages-derived O(2)(*-) and affect peroxynitrite formation yields. Macrophage-dependent peroxynitrite production was determined by boron-based probes that react directly with peroxynitrite, namely, coumarin-7-boronic acid (CBA) and fluorescein-boronate (Fl-B). The influence of (*)NO diffusion to RBC on peroxynitrite formation was experimentally analyzed in co-incubations of (*)NO and O(2)(*-)-forming macrophages with erythrocytes. Additionally, we evaluated the permeation of (*)NO to RBC by measuring the intracellular oxidation of oxyhemoglobin to methemoglobin. Our results indicate that diluted RBC suspensions dose-dependently inhibit peroxynitrite formation, outcompeting the O(2)(*-) reaction. Computer-assisted kinetic studies evaluating peroxynitrite formation by its precursor radicals in the presence of RBC are in accordance with experimental results. Moreover, the presence of erythrocytes in the proximity of (*)NO and O(2)(*-)-forming macrophages prevented intracellular Fl-B oxidation pre-loaded in L1210 cells co-cultured with activated macrophages. On the other hand, Fl-B coated latex beads incorporated in the macrophage phagocytic vacuole indicated that intraphagosomal probe oxidation by peroxynitrite was not affected by nearby RBC. Our data support that in the proximity of a blood vessel, (*)NO consumption by RBC will limit the extracellular formation (and subsequent cytotoxic effects) of peroxynitrite by activated macrophages, while the intraphagosomal yield of peroxynitrite will remain unaffected. PMID- 26119788 TI - beta-Arrestin-1 protects against endoplasmic reticulum stress/p53-upregulated modulator of apoptosis-mediated apoptosis via repressing p-p65/inducible nitric oxide synthase in portal hypertensive gastropathy. AB - Portal hypertensive gastropathy (PHG) is a serious cause of bleeding in patients, and is associated with portal hypertension. beta-Arrestins (beta-arrestin-1 and beta-arrestin-2) are well-established mediators of endocytosis of G-protein coupled receptors (GPCRs), ubiquitination, and G-protein-independent signaling. The role of beta-arrestin-1 (beta-arr1) in mucosal apoptosis in PHG remains unclear. The aim of this study was to investigate the involvement of beta-arr1 in PHG via its regulation of endoplasmic reticulum (ER) stress/p53-upregulated modulator of apoptosis (PUMA) apoptotic signaling. Gastric mucosal injury and apoptosis were studied in PHG patients and in PHG mouse models. The induction of beta-arr1 and the ER stress/PUMA signaling pathway were investigated, and the mechanisms of beta-arr1-regulated gastric mucosal apoptosis were analyzed in vivo and in vitro experiments. beta-arr1 and ER stress/PUMA signaling elements were markedly induced in the gastric mucosa of PHG patients and mouse models. Blockage of ER stress demonstrably attenuated the mucosal apoptosis of PHG, while targeted deletion of beta-arr1 significantly aggravated the injury and ER stress/PUMA mediated apoptosis. beta-arr1 limited the activation of p65 to repress TNF-alpha induced inducible nitric oxide synthase (iNOS) expression and NO release, which could regulate ER stress/PUMA-mediated mucosal apoptosis in PHG. In vivo and in vitro experiments further demonstrated that beta-arr1 protected against mucosal apoptosis by repressing TNF-alpha-induced iNOS expression via inhibiting the activation of p65. These results indicated that beta-arr1 regulated ER stress/PUMA-induced mucosal epithelial apoptosis through suppression of the TNF alpha/p65/iNOS signaling pathway activation and that beta-arr1 is a potential therapeutic target for PHG. PMID- 26119789 TI - Reviving out-of-copyright medical illustrations for use in medical curricula. PMID- 26119790 TI - Accumulation of gamma-aminobutyric acid in soybean by hypoxia germination and freeze-thawing incubation. AB - BACKGROUND: gamma-Aminobutyric acid (GABA) can be synthesised by the GABA shunt and polyamine degradation pathway in plants under hypoxia stress and lower temperature. The hypoxia germination freeze-thawing incubation was used as a new technique for accumulating more GABA in soybean. RESULTS: Results showed that glutamate decarboxylase (GAD) and diamine oxidase (DAO) activity as well as GABA content increased during germination within 24 h under hypoxia. However, the contents of dry matters and protein decreased. When the hypoxia-treated sprouts were frozen at -18 degrees C for 12 h and thawed at 25 degrees C for 6 h, GABA content increased drastically to 7.21-fold of the non-frozen sprouts. Subsequently, the freeze-thawing sprouts were ground into homogenates and incubated. GABA content was 14.20-fold of the only-soaked seeds when homogenates was incubated at 45 degrees C for 80 min within 400 umol L(-1) pyridoxine (VB6) (pH 6.5). CONCLUSION: The hypoxia germination freeze-thawing incubation was an effective method for accumulating GABA in soybean. During incubation, DAO was more important for GABA formation in homogenate of germinated soybean compared with GAD. PMID- 26119791 TI - Expression and intracellular localization of TBC1D9, a Rab GTPase-accelerating protein, in mouse testes. AB - Membrane trafficking in male germ cells contributes to their development via cell morphological changes and acrosome formation. TBC family proteins work as Rab GTPase accelerating proteins (GAPs), which negatively regulate Rab proteins, to mediate membrane trafficking. In this study, we analyzed the expression of a Rab GAP, TBC1D9, in mouse organs and the intracellular localization of the gene products. Tbc1d9 showed abundant expression in adult mice testis. We found that the Tbc1d9 mRNA was expressed in primary and secondary spermatocytes, and that the TBC1D9 protein was expressed in spermatocytes and round spermatids. In 293T cells, TBC1D9-GFP proteins were localized in the endosome and Golgi apparatus. Compartments that were positive for the constitutive active mutants of Rab7 and Rab9 were also positive for TBC1D9 isoform 1. In addition, TBC1D9 proteins were associated with Rab7 and Rab9, respectively. These results indicate that TBC1D9 is expressed mainly in spermatocytes, and suggest that TBC1D9 regulates membrane trafficking pathways related to Rab9- or Rab7-positive vesicles. PMID- 26119792 TI - Maternal-infant separation impedes changes in feeding behavior during estrous cycle of rats. AB - Traumatic and stressful events during childhood are associated with the development of eating disorders. We conducted an animal study to test if association stress in childhood affects ingestive behavior later in life by using female rats that have an adjusted estrous cycle. First, electrical impedance of the vagina was conducted to test estrous cycle adjustment. Second, the effects of 6 h per day maternal separation from birth to weaning, which models a psychologically stressful experience in childhood, was used to test feeding behavior during an ovarian cycle in female adult rats with matched estrous cycles. Food and water intake in maternal separated and non-separated rats was measured in each estrous phase. Non-separated rats showed periodical changes, but maternal separated rats showed no significant changes in food and water intake during an estrous cycle. An opposing tendency for food and water intake was seen between maternal separated and non-separated rats. These observations suggest that electrical impedance of the vagina showed the highest value in the estrous phase of rats housed in a reversed light-dark cycle, and maternal separation was found to disturb changes in feeding behavior during the estrous cycle. PMID- 26119793 TI - Clinical Implications of Tapering Chronic Opioids in a Veteran Population. AB - OBJECTIVE: To determine if patients receiving chronic opioid therapy can be tapered to lower opioid doses without a subsequent increase in pain. DESIGN: Retrospective and prospective chart review at a VA Medical Center. METHODS: Patients were included in the review if they were prescribed opioids chronically for at least 90 consecutive days and if a plan to taper opioid doses was agreed upon. Patients 89 years of age and older, patients with cancer, and patients exhibiting aberrant behavior were excluded. The primary endpoint was to determine the percent reduction of morphine equivalents (ME) over a 12-month period. Secondary endpoints included percent reduction of ME at 3 and 6 months, change in pain perception at 3, 6, and 12 months, and change in the number of adjuvant medications prescribed at 3, 6, and 12 months. Data were analyzed utilizing descriptive statistics. RESULTS: A total of 50 patient charts were included in the study. The average percent reduction of opioid doses was 46% over a 12-month period. Seventy percent of patients either experienced no change in pain or had less pain when comparing baseline to 12 months. An equal percentage of patients either had no change in the number of adjuvant medications prescribed or had more adjuvant medications prescribed when comparing baseline to 12 months. CONCLUSIONS: Patients in the population studied can be successfully tapered to lower opioid doses and may not necessarily experience more pain. PMID- 26119794 TI - Gerhard Quinkert (1927-2015). PMID- 26119795 TI - An Intriguing Case of Bright Red Blood per Rectum. Pneumatosis Cystoids Intestinalis. PMID- 26119796 TI - A Spiraling Case of Persistent Dysphagia. Diffuse Esophageal Spasm. PMID- 26119797 TI - Pancreatic Duct Dilatation in Elderly Patient With Abdominal Pain. Partial Supradiaphragmatic Herniation of the Pancreas. PMID- 26119798 TI - An Unusual Case of Abdominal Pain and Diarrhea. Tension-free Vaginal Tape Eroding Into the Ascending Colon. PMID- 26119799 TI - A Rare Gastric Tumor in a Young Woman. Gastric Plexiform Angiomyxoid Myofibroblastic Tumor. PMID- 26119800 TI - Infantile Bullous Pemphigoid Treated Using Intravenous Immunoglobulin: Case Report and Review of the Literature. AB - We report a 5-month-old girl diagnosed with bullous pemphigoid who initially did not respond to systemic corticosteroids and dapsone but rapidly improved after the addition of intravenous immunoglobulin (IVIG) infusions. A literature search revealed anecdotal cases of infantile bullous pemphigoid treated with IVIG, although variable treatment regimens were used, and some resistant cases required additional medications such as rituximab for clinical remission. PMID- 26119801 TI - The trefoil with single fruit sign in muscle magnetic resonance imaging is highly specific for dystrophinopathies. AB - BACKGROUND: The purpose of this study was to evaluate the diagnostic value of the trefoil (three leaflets formed by relative sparing of the sartorius, gracilis, and adductor longus) with single fruit sign (relative sparing of the semitendinosus) in the evaluation of thigh muscle magnetic resonance imaging (MRI) for dystrophinopathies. METHODS: Five examiners blinded to any clinical data analyzed muscle MRI scans from 166 patients with dystrophinopathies (124 cases confirmed genetically and 42 cases confirmed by immunohistochemistry) and from 244 control patients, all treated in our hospital from 2011 to 2014. The controls were patients with other neuromuscular disorders and with dystrophinopathies excluded by genetic testing and/or muscle biopsy. Examiners assessed the presence or absence of the trefoil with single fruit sign approximately at the middle thigh cross-section. Results were analyzed for diagnostic accuracy and inter-examiner agreement. RESULTS: Sensitivity of the trefoil with single fruit sign for all patients with dystrophinopathies was 41.6% (95% confidence interval (CI) of 34.0-49.5). However, specificity was 99.2% (95% CI 97.1-99.9). The positive predictive value (PPV) was 97.2% and negative predictive value (NPV) was 71.4%. Inter-examiner agreement was substantial (Kappa=0.66). The 69 dystrophinopathy patients whose MRIs exhibited the sign were significantly older than the 97 dystrophinopathy patients whose MRIs did not (Z= 3.970, P<0.001). CONCLUSIONS: The trefoil with single fruit sign is a potential imaging marker for diagnosis of dystrophinopathies. PMID- 26119802 TI - Focal liver lesions detection: Comparison of respiratory-triggering, triggering and tracking navigator and tracking-only navigator in diffusion-weighted imaging. AB - PURPOSE: To compare low b value (10s/mm(2)) spin-echo echo-planar (SE-EP) diffusion-weighted imaging (DWI) acquired with respiratory-triggering (RT), triggering and tracking navigator (TT), tracking only navigator (TRON) techniques for image quality and focal liver lesions (FLL) detection in non-cirrhotic patients. MATERIAL AND METHODS: This bi-centric study was approved by the institutional review boards; informed consent was obtained. Eighty-three patients were prospectively included and SE-EP-DWI with RT, TT and TRON techniques were performed. DWI sequences were randomized and independently analyzed by two readers. The qualitative evaluation was based on a 3-point score for axial artifacts (motion, ghost, susceptibility artifacts and distortion) and stair-step artifacts. Sensitivity of FLL detection was calculated for all lesions together and after lesion size stratification (<= 10 mm, >10-20mm and >20mm). The standard of reference consisted of a retrospective reading of the conventional MRI, the three DWI sequences and by follow-up (12 months): a total of 409 FLL were detected. Data between sequences was compared with non-parametric tests. Cohen's kappa coefficient was used for inter-observer agreement. RESULTS: Image quality was comparable for RT and TT. TRON showed statistically significantly more axial artifacts for the two readers (p<0.05). Stair-step artifacts were not statistically significantly different between DWI sequences. Overall sensitivities for RT, TT, TRON were 85%, 86%, 82% and 86%, 89% 83%, respectively, for readers 1 and 2. The inter-observer agreement was very good. CONCLUSION: Image quality was better for RT and TT compared to TRON. Overall sensitivities for FLL detection were comparable between techniques and readers. PMID- 26119803 TI - Symptomatic intracranial vertebral artery atherosclerotic stenosis (>=70%) with concurrent contralateral vertebral atherosclerotic diseases in 88 patients treated with the intracranial stenting. AB - PURPOSE: To investigate the safety, effect and instent restenosis rate of Wingspan stenting in treating patients with intracranial vertebral artery atherosclerotic stenosis (70-99%) concurrent with contralateral vertebral artery atherosclerotic diseases. MATERIALS AND METHODS: Eighty-eight patients with severe symptomatic intracranial vertebral artery atherosclerotic stenosis (>=70%) combined with contralateral vertebral artery atherosclerotic diseases were treated with the Wingpsan stent. All the baseline, cerebral angiography, success rate, perioperative complications, clinical and imaging follow-up data were prospectively analyzed. RESULTS: The success rate of stenting was 100%, and the mean stenotic rate was reduced from prestenting (84.9+/-6.8)% to poststenting (17.2+/-5.9)%. The perioperative stroke rate was 1.1%. Among eighty patients (90.9%) with clinical follow-up 8-62 months (mean 29.3+/-17.2) poststenting, five (6.3%) had posterior circulation TIA only, three (3.8%) had mild stroke in the posterior circulation but recovered completely, and another five patients greater than 70 years old died of non-ischemic stroke. Imaging follow-up in 46 patients (52.3%) 5-54 months (mean 9.9+/-9.9) following stenting revealed instent restenosis in 12 patients (26.1%) including 7 (58.3%) symptomatic restenosis. Age and residual stenosis were the two factors to significantly (P<0.05) affect instent restenosis. CONCLUSION: Wingspan stenting in the intracranial vertebral artery atherosclerotic stenosis combined with contralateral vertebral artery atherosclerotic diseases has a low perioperative stroke rate and a good preventive effect on long-term ischemic stroke, but the instent restenosis rate is a little high. PMID- 26119804 TI - Protonation-Dependent Base Flipping at Neutral pH in the Catalytic Triad of a Self-Splicing Bacterial Group II Intron. AB - NMR spectroscopy has revealed pH-dependent structural changes in the highly conserved catalytic domain 5 of a bacterial group II intron. Two adenines with pK(a) values close to neutral pH were identified in the catalytic triad and the bulge. Protonation of the adenine opposite to the catalytic triad is stabilized within a G(syn)-AH(+) (anti) base pair. The pH-dependent anti-to-syn flipping of this G in the catalytic triad modulates the known interaction with the linker region between domains 2 and 3 (J23) and simultaneously the binding of the catalytic Mg(2+) ion to its backbone. Hence, this here identified shifted pK(a) value controls the conformational change between the two steps of splicing. PMID- 26119805 TI - Commercial sheep flocks--fatty acid and fat-soluble antioxidant composition of milk and cheese related to changes in feeding management throughout lactation. AB - Fatty acids (FAs), tocopherols and retinoids were analysed in raw milk and cheese from six commercial sheep flocks monitored from early lactation in winter to late lactation in summer. In winter, animals received concentrate and forage indoors; in early spring, animals grazed part-time on cultivated or natural valley grasslands; and from mid spring on, animals were kept outdoors constantly on mountain natural pastures. Mountain grazing in late lactation significantly increased the amount of healthy desirable unsaturated FAs such as C18:1t11 (VA), C18:2c9t11 (RA), C18:2t11c13, C18:3c9c12c15 (ALA) and C20:5c5c8c11c14c17 (EPA), and those of alpha-tocopherol and alpha-tocotrienol of milk and cheese. Stepwise discriminant analysis was applied to classify cheese samples according to seasonal feeding management. The multivariate approach was able to discriminate beyond doubt mountain cheeses from those of indoor feeding and part-time valley grazing. PMID- 26119806 TI - Evaluation of microelement contents in Clethra barbinervis as food for human and animals in contrasting geological areas. AB - The young leaves of Clethra barbinervis Sieb. et Zucc, which is a deciduous tree species found in secondary forests widely in Japan, are used in spring as a local traditional food by local populations, and the bark of this plant is also preferred by sika deer, Cervus nippon. However, C. barbinervis has been known to accumulate heavy metals in its leaves. Then, we aimed to clarify the characteristics of microelement contents in C. barbinervis and to discuss the value of this species as food for humans and animals through the analysis of seasonal changes and distribution in various organs of C. barbinervis growing under two different geological conditions. We found that C. barbinervis is an accumulating and tolerant plant for Ni, Co and Mn. It accumulates Ni from serpentine soil containing Ni at high concentration, and Co and Mn from acidic soils based on crystalline schist. The seasonal variation in element concentrations in leaves indicates that the young leaves contain Cu at high concentration and that eating them in spring season may be advantageous to humans, due to the associated increase in Cu intake. The high concentrations of Cu and Zn in the bark of C. barbinervis might explain why deer prefer to eat the bark of this species. PMID- 26119807 TI - Impact of olfactory and auditory priming on the attraction to foods with high energy density. AB - ?]?Recent research suggests that non-attentively perceived stimuli may significantly influence consumers' food choices. The main objective of the present study was to determine whether an olfactory prime (a sweet-fatty odour) and a semantic auditory prime (a nutritional prevention message), both presented incidentally, either alone or in combination can influence subsequent food choices. The experiment included 147 participants who were assigned to four different conditions: a control condition, a scented condition, an auditory condition or an auditory-scented condition. All participants remained in the waiting room during15 min while they performed a 'lure' task. For the scented condition, the participants were unobtrusively exposed to a 'pain au chocolat' odour. Those in the auditory condition were exposed to an audiotape including radio podcasts and a nutritional message. A third group of participants was exposed to both olfactory and auditory stimuli simultaneously. In the control condition, no stimulation was given. Following this waiting period, all participants moved into a non-odorised test room where they were asked to choose, from dishes served buffet-style, the starter, main course and dessert that they would actually eat for lunch. The results showed that the participants primed with the odour of 'pain au chocolat' tended to choose more desserts with high energy density (i.e., a waffle) than the participants in the control condition (p = 0.06). Unexpectedly, the participants primed with the nutritional auditory message chose to consume more desserts with high energy density than the participants in the control condition (p = 0.03). In the last condition (odour and nutritional message), they chose to consume more desserts with high energy density than the participants in the control condition (p = 0.01), and the data reveal an additive effect of the two primes. PMID- 26119808 TI - Consumers' view on determinants to food satisfaction. A qualitative approach. AB - The objective of this study was to gain a better understanding of the multiple determinants to food satisfaction from a consumer perspective. The study includes two focus groups with a total of 20 consumers varying in gender, age, employment and food interest. The results were divided into sections based on the main themes that arose from analysing the focus groups; i) sensory properties, ii) physical wellbeing, iii) expectations and desires, iv) the food context and v) comparison of the importance of the various determinants to satisfaction. Factors important for food satisfaction appear before as well as during and after intake. Before intake, the important factors are; expectations and desires based on memories about previous food experiences and the context in which the food is perceived. Physical wellbeing was mentioned important for the feeling of satisfaction, included in physical wellbeing is the experience of an appropriate energy level after intake. In general the sensory experience seems to be the primary determinant to satisfaction. The hedonic experience of eating could be enhanced by the social company and knowledge about the food inclusive health value and origin. Findings from the study will prospectively be used to develop a questionnaire. The questionnaire will be applied in case studies to measure factors influential in food satisfaction. PMID- 26119809 TI - Special issue of Appetite: The proceedings of the American University Symposium on Childhood Obesity and Cognition. PMID- 26119810 TI - "It's like giving him a piece of me.": Exploring UK and Israeli women's accounts of motherhood and feeding. AB - OBJECTIVE: The present study explored how Israeli and UK mothers integrate feeding into their conceptualisations of mothering 2-6 months post-partum. BACKGROUND: The nature and importance of motherhood is subject to differential contextual, cultural, political and historical influences. We set out to compare experiences of motherhood and feeding between these two countries using a qualitative approach. METHODS: Forty one women (mean age 36.4 +/- 2.7 years) from Israel and the UK, mostly married or in a committed relationship were interviewed about their experience of pregnancy, motherhood and feeding. Data were analysed thematically. RESULTS: The experience of motherhood in the early postnatal period was dominated, for all mothers, by the experience of breastfeeding and clustered around three representations of mothering, namely; 1) a devoted mother who ignores her own needs; 2) a mother who is available for her infant but acknowledges her needs as well; and 3) a struggling mother for whom motherhood is a burden. Such representations existed within both cultural groups and sometimes coexisted within the same mothers. UK women described more struggles within motherhood whereas a tendency towards idealising motherhood was observed for Israeli women. CONCLUSION: There are similarities in the ways that UK and Israeli women experienced motherhood and feeding. Where family life is strongly emphasized, mothers reported extremes of idealism and burden and associated an "ideal" mother with a breastfeeding mother. Where motherhood is represented as just one of many roles women take up, they are more likely to represent a "good enough" approach to mothering. Understanding the experience of motherhood and feeding in different cultural settings is important to provide the context for postnatal care specifically where mothers are reluctant to share problems or difficulties encountered. PMID- 26119811 TI - Response of appetite and potential appetite regulators following intake of high energy nutritional supplements. AB - BACKGROUND: The net clinical benefit of high-energy nutritional supplements (HENSDs) consumption is lower than expected. OBJECTIVES: To investigate the extent to which consumption of oral HENSD in the fasted state reduces energy intake in slim females during consecutive breakfast and lunch, and whether this relates to changes in appetite and metabolic appetite regulators. DESIGN: Twenty three females of 24.4 +/- 2.8 years with BMI of 18.2 +/- 0.8 kg/m(2) consumed HENSD (2.5 MJ) or PLACEBO (0.4 MJ) in fasted state in a single blind randomized cross-over study. Appetite and metabolic rate measurements and blood collection were conducted prior to and during 240 min after the intake of the supplements. Energy intake was recorded during ad libitum buffet breakfast and lunch served 60 min and 240 min post supplementation respectively. RESULTS: Energy intake during breakfast was significantly (P < 0.01) lower in the HENSD trial but the net cumulative effect on energy intake was 1.07 +/- 0.34 MJ higher in the HENSD compared to PLACEBO. Plasma concentration of CCK and PYY and insulin and were significantly (P < 0.05) higher in the HENSD trial while appetite measures were not significantly different between HENSD and PLACEBO trials. Correlations for the within participant relations between the responses of plasma hormones and appetite scores were significant (P < 0.05) for PYY and insulin but not CCK. The energy expended above resting metabolic rate was significantly (P < 0.05) higher in the HENDS trial but relative increase in energy expenditure was not significantly different between the two trials. CONCLUSION: Oral high-energy nutritional supplements have a partial and relatively short lived suppressive action on energy intake and can be expected to increase net energy intake by approximately half the energy value of the supplement consumed. PMID- 26119812 TI - Individual differences in the interoceptive states of hunger, fullness and thirst. AB - Interoception is the ability to perceive internal bodily states. This involves the detection and awareness of static and changing afferent signals from the viscera, motivational states, affective reactions, and associated cognitions. We examined whether there are individual differences in any or all of these aspects of ingestion-related interoception and their possible causes. Individual variation in almost all aspects of interoception was documented for hunger, fullness and thirst - including how participants use, prioritise and integrate visceral, motivational, affective and cognitive information. Individual differences may arise from multiple causes, including genetic influences, developmental changes hypothesised to result from child feeding practices, and from conditions such as depression, anxiety, eating disorders and certain subtypes of obesity. A nutritionally poor diet, and dietary restraint, may also affect ingestion-related interoception. Finally, certain forms of brain injury, notably to the medial temporal lobes are associated with impaired ingestion related interoception. We conclude by examining the practical and theoretical consequences of these individual differences. PMID- 26119813 TI - The prognostic value of white blood cell count-to-mean platelet volume ratio in patients with acute coronary syndrome. PMID- 26119814 TI - Pyridyl-functionalised 3H-1,2,3,4-triazaphospholes: synthesis, coordination chemistry and photophysical properties of low-coordinate phosphorus compounds. AB - Novel conjugated, pyridyl-functionalised triazaphospholes with either tBu or SiMe3 substituents at the 5-position of the N3 PC heterocycle have been prepared by a [3+2] cycloaddition reaction and compared with structurally related, triazole-based systems. Photoexcitation of the 2-pyridyl-substituted triazaphosphole gives rise to a significant fluorescence emission with a quantum yield of up to 12 %. In contrast, the all-nitrogen triazole analogue shows no emission at all. DFT calculations indicate that the 2-pyridyl substituted systems have a more rigid and planar structure than their 3- and 4-pyridyl isomers. Time dependent (TD) DFT calculations show that only the 2-pyridyl-substituted triazaphosphole exhibits similar planar geometry, with matching conformational arrangements in the lowest energy excited state and the ground state; this helps to explain the enhanced emission intensity. The chelating P,N-hybrid ligand forms a Re(I) complex of the type [(N^N)Re(CO)3 Br] through the coordination of nitrogen atom N(2) to the metal centre rather than through the phosphorus donor. Both structural and spectroscopic data indicate substantial pi-accepting character of the triazaphosphole, which is again in contrast to that of the all nitrogen-containing triazoles. The synthesis and photophysical properties of a new class of phosphorus-containing extended pi systems are described. PMID- 26119815 TI - Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations. AB - We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ~ 350,000) and height (n ~ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction. PMID- 26119816 TI - The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease. AB - The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. PMID- 26119817 TI - A Powerful Pathway-Based Adaptive Test for Genetic Association with Common or Rare Variants. AB - In spite of the success of genome-wide association studies (GWASs), only a small proportion of heritability for each complex trait has been explained by identified genetic variants, mainly SNPs. Likely reasons include genetic heterogeneity (i.e., multiple causal genetic variants) and small effect sizes of causal variants, for which pathway analysis has been proposed as a promising alternative to the standard single-SNP-based analysis. A pathway contains a set of functionally related genes, each of which includes multiple SNPs. Here we propose a pathway-based test that is adaptive at both the gene and SNP levels, thus maintaining high power across a wide range of situations with varying numbers of the genes and SNPs associated with a trait. The proposed method is applicable to both common variants and rare variants and can incorporate biological knowledge on SNPs and genes to boost statistical power. We use extensively simulated data and a WTCCC GWAS dataset to compare our proposal with several existing pathway-based and SNP-set-based tests, demonstrating its promising performance and its potential use in practice. PMID- 26119819 TI - Serine 350 of human pregnane X receptor is crucial for its heterodimerization with retinoid X receptor alpha and transactivation of target genes in vitro and in vivo. AB - The human pregnane X receptor (hPXR), a member of the nuclear receptor superfamily, senses xenobiotics and controls the transcription of genes encoding drug-metabolizing enzymes and transporters. The regulation of hPXR's transcriptional activation of its target genes is important for xenobiotic detoxification and endobiotic metabolism, and hPXR dysregulation can cause various adverse drug effects. Studies have implicated the putative phosphorylation site serine 350 (Ser(350)) in regulating hPXR transcriptional activity, but the mechanism of regulation remains elusive. Here we investigated the transactivation of hPXR target genes in vitro and in vivo by hPXR with a phosphomimetic mutation at Ser(350) (hPXR(S350D)). The S350D phosphomimetic mutation reduced the endogenous expression of cytochrome P450 3A4 (an hPXR target gene) in HepG2 and LS180 cells. Biochemical assays and structural modeling revealed that Ser(350) of hPXR is crucial for formation of the hPXR-retinoid X receptor alpha (RXRalpha) heterodimer. The S350D mutation abrogated heterodimerization in a ligand-independent manner, impairing hPXR-mediated transactivation. Further, in a novel humanized transgenic mouse model expressing the hPXR(S350D) transgene, we demonstrated that the S350D mutation alone is sufficient to impair hPXR transcriptional activity in mouse liver. This transgenic mouse model provides a unique tool to investigate the regulation and function of hPXR, including its non-genomic function, in vivo. Our finding that phosphorylation regulates hPXR activity has implications for development of novel hPXR antagonists and for safety evaluation during drug development. PMID- 26119820 TI - Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen. AB - The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging. PMID- 26119821 TI - Collaborating with Alexander Scriabine and the Miles Institute for Preclinical Pharmacology. AB - This article represents a timely opportunity to express my affection, admiration and gratitude to Professor David Triggle. David was my Ph.D. advisor as well as a key consultant in the 1980s and early 1990s for research programs at Miles Institute for Preclinical Pharmacology in West Haven, CT, the U.S. research operation of Bayer AG, in the areas of Ca(2+) and K(+) channel ligands. The binding methodology developed in his laboratory was used to search for an endogenous ligand for L-type Ca(2+) channels. We did not find the substance that we were searching for, a genetically-determined, competitive inhibitor for the 1,4-dihydropyridine binding site, but instead isolated the endogenous ligand for the brain's own marijuana, anandamide. Devane, Mechoulam and coworkers first discovered that this compound was the endogenous ligand for delta-9 tetrahydrocannabinol, the active substance in cannabis. The endogenous endocannabinoid system is now the target of many exciting new approaches to drug discovery. PMID- 26119822 TI - From B.Sc. to Ph.D., my shuffle off to Buffalo. AB - From the fall of 1978 until the summer of 1982, I was a graduate student in the Laboratory of Dr. David Triggle in the Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo. This contribution permits me the opportunity to take you back in time into David's laboratory and tell you the story of how my early research career was borne and to provide a glimpse into some of the accomplishments that David, I and my fellow graduates students made. The central theme of my research was to bring together the many events that controlled the contraction of guinea-pig ileal longitudinal muscle, from the binding of muscarinic agonists, the movement of mono- and divalent cations that control depolarization to contraction itself and the differences between muscarinic and non-muscarinic mediated contraction and tachyphylaxis. From these studies, we were able to provide concrete data supporting a fluid muscarinic receptor-effector coupling model that challenged the concept of spare receptors. We also were able to develop methods to quantitate the binding sites for dihydropyrine calcium channel antagonists thereby opening the door to a flood of studies that furthered our understanding of these clinically employed drugs, providing a new target to elucidate the mechanism(s) of action of drugs that act outside of and within the central nervous system. PMID- 26119818 TI - Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes. AB - Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding. PMID- 26119823 TI - Duration of opioid receptor blockade determines biotherapeutic response. AB - Historically, studies on endogenous and exogenous opioids and their receptors focused on the mediation of pain, with excess opiate consumption leading to addiction. Opioid antagonists such as naloxone and naltrexone blocked these interactions, and still are widely used to reverse drug and alcohol overdose. Although specific opioid antagonists have been designed for mu, delta, and kappa opioid receptors, the general antagonists remain the most effective. With the discovery of the opioid growth factor (OGF)-OGF receptor (OGFr) axis as a novel biological pathway involved in homeostasis of replicating cells and tissues, the role of opioid receptor antagonists was expanded. An intermittent OGFr blockade by low dosages of naltrexone resulted in depressed cell replication, whereas high (or sustained) dosages of naltrexone that conferred a continuous OGFr blockade resulted in enhanced growth. More than 3 decades of research have confirmed that the duration of opioid receptor blockade, not specifically the dosage, by general opioid antagonists determines the biotherapeutic outcome. Dysregulation of the OGF-OGFr pathway is apparent in a number of human disorders including diabetes, multiple sclerosis, and cancer, and thus opioid antagonist disruption of interaction prevails as a therapeutic intervention. We review evidence that the duration of opioid receptor blockade is correlated with the magnitude and direction of response, and discuss the potential therapeutic effectiveness of continuous receptor blockade for treatment of diabetic complications such as corneal defects and skin wounds, and of intermittent receptor blockade by low dosages of naltrexone for treatment of autoimmune diseases and cancer. PMID- 26119825 TI - Acetyl aspartic acid, a novel active ingredient, demonstrates potential to improve signs of skin ageing: from consumer need to clinical proof. AB - BACKGROUND: The megatrend of population ageing is leading to a growing demand for "anti-ageing" treatments, especially to prevent or treat skin ageing. Facing an increasing offer, consumers are choosing more and more skin care products supported by a scientific rationale, active ingredients and clinical proof of efficacy. OBJECTIVE: Considering consumer expectations, this research led to the discovery of acetyl aspartic acid (A-A-A), a novel active ingredient to improve sagging skin and loss of skin firmness. RESULTS: This supplement is featuring seven manuscripts aiming at presenting the research and investigations from consumer insights, discovery of A-A-A, its in vitro activity confirmation, safety assessment, formulation and its dermal absorption to the clinical proof of efficacy, investigated through two pilots' double bind randomized and placebo controlled studies on photo-aged skin. CONCLUSION: This extensive research enabled us to discover A-A-A, as an active ingredient with potential to repair sign of skin ageing and supported by clinical proof of efficacy. This active ingredient will be soon launched in a commercial innovative skin care range, delivering desirable anti-wrinkle and skin lifting benefits. PMID- 26119824 TI - Influence of human behavior on cholera dynamics. AB - This paper is devoted to studying the impact of human behavior on cholera infection. We start with a cholera ordinary differential equation (ODE) model that incorporates human behavior via modeling disease prevalence dependent contact rates for direct and indirect transmissions and infectious host shedding. Local and global dynamics of the model are analyzed with respect to the basic reproduction number. We then extend the ODE model to a reaction-convection diffusion partial differential equation (PDE) model that accounts for the movement of both human hosts and bacteria. Particularly, we investigate the cholera spreading speed by analyzing the traveling wave solutions of the PDE model, and disease threshold dynamics by numerically evaluating the basic reproduction number of the PDE model. Our results show that human behavior can reduce (a) the endemic and epidemic levels, (b) cholera spreading speeds and (c) the risk of infection (characterized by the basic reproduction number). PMID- 26119826 TI - Exploring diterpene metabolism in non-model species: transcriptome-enabled discovery and functional characterization of labda-7,13E-dienyl diphosphate synthase from Grindelia robusta. AB - Grindelia robusta or gumweed, is a medicinal herb of the sunflower family that forms a diverse suite of diterpenoid natural products. Its major constituents, grindelic acid and related grindelane diterpenoids accumulate in a resinous exudate covering the plants' surfaces, most prominently the unopened composite flower. Recent studies demonstrated potential pharmaceutical applications for grindelic acid and its synthetic derivatives. Mining of the previously published transcriptome of G. robusta flower tissue identified two additional diterpene synthases (diTPSs). We report the in vitro and in vivo functional characterization of an ent-kaurene synthase of general metabolism (GrTPS4) and a class II diTPS (GrTPS2) of specialized metabolism that converts geranylgeranyl diphosphate (GGPP) into labda-7,13E-dienyl diphosphate as verified by nuclear magnetic resonance (NMR) analysis. Tissue-specific transcript abundance of GrTPS2 in leaves and flowers accompanied by the presence of an endocyclic 7,13 double bond in labda-7,13E-dienyl diphosphate suggest that GrTPS2 catalyzes the first committed reaction in the biosynthesis of grindelic acid and related grindelane metabolites. With the formation of labda-7,13E-dienyl diphosphate, GrTPS2 adds an additional function to the portfolio of monofunctional class II diTPSs, which catalytically most closely resembles the bifunctional labda-7,13E-dien-15-ol synthase of the lycopod Selaginella moellendorffii. Together with a recently identified functional diTPS pair of G. robusta producing manoyl oxide, GrTPS2 lays the biosynthetic foundation of the diverse array of labdane-related diterpenoids in the genus Grindelia. Knowledge of these natural diterpenoid metabolic pathways paves the way for developing biotechnology approaches toward producing grindelic acid and related bioproducts. PMID- 26119827 TI - The Problem of Origins and Origins of the Problem: Influence of Language on Studies Concerning the Anomeric Effect. AB - Cause and effect: In science, language is often subordinated to empirical data, but words can influence our ability to understand and communicate science. This Essay argues that imprecise language has confounded studies that probe the interactions underlying the anomeric effect and related phenomena. PMID- 26119828 TI - A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine. AB - INTRODUCTION: AVP-825, formerly 'OptiNose Sumatriptan,' is an investigational Breath-Powered(TM) Bi-Directional(TM) intranasal delivery system containing low dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology. AREAS COVERED: This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies. EXPERT OPINION: AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP 825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability. PMID- 26119829 TI - Morphological study of boar sperm during their passage through the female genital tract. AB - Once deposited in the female tract, sperm face a series of challenges that must be overcome to ensure the presence of an adequate normal sperm population close to the site of fertilization. Our aim was to evaluate the influence of the uterine milieu on boar sperm morphology. In experiment 1, sperm morphology was evaluated in the backflow (60 min after insemination) and within the uterotubal junction (UTJ) (collected ~24 h after insemination) following intrauterine sperm deposition (n = 6) and compared with the morphology of the sperm in the insemination dose. In experiment 2, the influence of the uterine fluid (UF) on sperm morphological modifications was evaluated. For this purpose, ejaculated (n = 4) and epididymal (n = 4) sperm were in vitro incubated with or without UF for 2 and 24 h. In both experiments, sperm were classified as normal, having a cytoplasmic droplet (proximal or distal) or having tail defects. The results of experiment 1 pointed to an increase in morphologically abnormal sperm collected in the backflow (27.70%) and a reduction of the same in the UTJ (2.12%) compared with the insemination dose (17.75%) (P < 0.05). In experiment 2, incubation of ejaculated sperm with UF did not provoke any morphological modifications; however, when epididymal sperm were incubated with UF, a pronounced increase in the percentage of normal sperm was evident after 24 h compared with the initial dose (from 25.77% to 53.58%, P < 0.05), mainly due to distal cytoplasmatic droplet shedding (53.22 vs. 20.20%). In conclusion, almost all the sperm that colonize the UTJ had a normal morphology, with part of the abnormal sperm having been discarded in the backflow and part selected/modified on their way to the oviduct. UF seems to influence cytoplasmic distal droplet removal, as demonstrated previously in seminal plasma. PMID- 26119830 TI - Targeting bone metastases in prostate cancer: improving clinical outcome. AB - Bone metastases develop in most patients with metastatic castration-resistant prostate cancer (mCRPC). They affect the structural integrity of bone, manifesting as pain and skeletal-related events (SREs), and are the primary cause of patient disability, reduced quality of life (QOL) and death. Understanding the pathophysiology of bone metastases resulted in the development of agents that improve clinical outcome, suggesting that managing both the systemic disease and associated bone events is important. Historically, the treatment of CRPC bone metastases with early radiopharmaceuticals and external beam radiation therapy was largely supportive; however, now, zoledronic acid and denosumab are integral to the therapeutic strategy for mCRPC. These agents substantially reduce skeletal morbidity and improve patient QOL. Radium-223 dichloride is the first bone targeting agent to show improved survival and reduced pain and symptomatic skeletal events in patients with mCRPC without visceral disease. Five other systemic agents are currently approved for use in mCRPC based on their ability to improve survival. These include the cytotoxic drugs docetaxel and cabazitaxel, the hormone-based therapies, abiraterone and enzalutamide, and the immunotherapeutic vaccine sipuleucel-T. Abiraterone and enzalutamide are able to reduce SREs and improve survival in this setting. Novel agents targeting tumour and bone cells are under clinical development. PMID- 26119831 TI - Toxicity of aged gasoline exhaust particles to normal and diseased airway epithelia. AB - Particulate matter (PM) pollution is a leading cause of premature death, particularly in those with pre-existing lung disease. A causative link between particle properties and adverse health effects remains unestablished mainly due to complex and variable physico-chemical PM parameters. Controlled laboratory experiments are required. Generating atmospherically realistic aerosols and performing cell-exposure studies at relevant particle-doses are challenging. Here we examine gasoline-exhaust particle toxicity from a Euro-5 passenger car in a uniquely realistic exposure scenario, combining a smog chamber simulating atmospheric ageing, an aerosol enrichment system varying particle number concentration independent of particle chemistry, and an aerosol deposition chamber physiologically delivering particles on air-liquid interface (ALI) cultures reproducing normal and susceptible health status. Gasoline-exhaust is an important PM source with largely unknown health effects. We investigated acute responses of fully-differentiated normal, distressed (antibiotics-treated) normal, and cystic fibrosis human bronchial epithelia (HBE), and a proliferating, single-cell type bronchial epithelial cell-line (BEAS-2B). We show that a single, short-term exposure to realistic doses of atmospherically-aged gasoline-exhaust particles impairs epithelial key-defence mechanisms, rendering it more vulnerable to subsequent hazards. We establish dose-response curves at realistic particle concentration levels. Significant differences between cell models suggest the use of fully-differentiated HBE is most appropriate in future toxicity studies. PMID- 26119832 TI - Provision and effect of quit-smoking counselling by primary care midwives. AB - OBJECTIVE: we aimed to evaluate the provision of quit-smoking counselling by midwives in the Netherlands and its effect on smoking behaviour and birth weight. DESIGN: quasi-experimental study in which we collected information from pregnant women who smoke throughout their pregnancy by extracting data from electronic patient files. SETTING: primary care midwifery practices. PARTICIPANTS: 851 pregnant women who smoke, treated between 2011 and 2014. INTERVENTION: quit smoking counselling. MEASUREMENTS AND FINDINGS: the midwives decided to provide quit-smoking counselling to the participant or not. Non-counselled women were used as the control group. The primary outcome parameter was quit smoking, defined as 'quit smoking by end of pregnancy'. At intake, 67% of the women smoked 1-9 cigarettes a day, 23% smoked 10-20 cigarettes a day and 4% more than 20 cigarettes a day. The midwives began counselling with 42% of the participants, but seldom completed all the counselling steps. The average quit rate was 10% and average birth weight of the babies was 3200g. We found no difference in quit rate or birth weight between counselled women and those who were not. However, the data suggested that counselling is more effective when more steps of counselling are completed. KEY CONCLUSIONS: no effect was found of quit-smoking counselling on quit-smoking rate or birth weight. Possibly, counselling is effective when provided extensively throughout pregnancy. IMPLICATIONS FOR PRACTICE: our study shows that provision of counselling can be improved. PMID- 26119833 TI - Widespread tsunami-like waves of 23-27 June in the Mediterranean and Black Seas generated by high-altitude atmospheric forcing. AB - A series of tsunami-like waves of non-seismic origin struck several southern European countries during the period of 23 to 27 June 2014. The event caused considerable damage from Spain to Ukraine. Here, we show that these waves were long-period ocean oscillations known as meteorological tsunamis which are generated by intense small-scale air pressure disturbances. An unique atmospheric synoptic pattern was tracked propagating eastward over the Mediterranean and the Black seas in synchrony with onset times of observed tsunami waves. This pattern favoured generation and propagation of atmospheric gravity waves that induced pronounced tsunami-like waves through the Proudman resonance mechanism. This is the first documented case of a chain of destructive meteorological tsunamis occurring over a distance of thousands of kilometres. Our findings further demonstrate that these events represent potentially dangerous regional phenomena and should be included in tsunami warning systems. PMID- 26119835 TI - Characterization of hepatic fatty acids in mice with reduced liver fat by ultra short echo time (1)H-MRS at 14.1 T in vivo. AB - Alterations in the hepatic lipid content (HLC) and fatty acid composition are associated with disruptions in whole body metabolism, both in humans and in rodent models, and can be non-invasively assessed by (1)H-MRS in vivo. We used (1)H-MRS to characterize the hepatic fatty-acyl chains of healthy mice and to follow changes caused by streptozotocin (STZ) injection. Using STEAM at 14.1 T with an ultra-short TE of 2.8 ms, confounding effects from T2 relaxation and J coupling were avoided, allowing for accurate estimations of the contribution of unsaturated (UFA), saturated (SFA), mono-unsaturated (MUFA) and poly-unsaturated (PUFA) fatty-acyl chains, number of double bonds, PU bonds and mean chain length. Compared with in vivo (1) H-MRS, high resolution NMR performed in vitro in hepatic lipid extracts reported longer fatty-acyl chains (18 versus 15 carbons) with a lower contribution from UFA (61 +/- 1% versus 80 +/- 5%) but a higher number of PU bonds per UFA (1.39 +/- 0.03 versus 0.58 +/- 0.08), driven by the presence of membrane species in the extracts. STZ injection caused a decrease of HLC (from 1.7 +/- 0.3% to 0.7 +/- 0.1%), an increase in the contribution of SFA (from 21 +/- 2% to 45 +/- 6%) and a reduction of the mean length (from 15 to 13 carbons) of cytosolic fatty-acyl chains. In addition, SFAs were also likely to have increased in membrane lipids of STZ-induced diabetic mice, along with a decrease of the mean chain length. These studies show the applicability of (1)H MRS in vivo to monitor changes in the composition of the hepatic fatty-acyl chains in mice even when they exhibit reduced HLC, pointing to the value of this methodology to evaluate lipid-lowering interventions in the scope of metabolic disorders. PMID- 26119836 TI - Bacterial meningitis: insights into pathogenesis and evaluation of new treatment options: a perspective from experimental studies. AB - Bacterial meningitis is associated with high mortality and morbidity rates. Bacterial components induce an overshooting inflammatory reaction, eventually leading to brain damage. Pathological correlates of neurofunctional deficits include cortical necrosis, damage of the inner ear and hippocampal apoptosis. The hippocampal dentate gyrus is important for memory acquisition and harbors a neuronal stem cell niche, thus being potentially well equipped for regeneration. Adjuvant therapies aimed at decreasing the inflammatory reaction, for example, dexamethasone, and those protecting the brain from injury have been evaluated in animal models of the disease. They include nonbacteriolytic antibiotics (e.g., daptomycin), metalloproteinase inhibitors and modulators of the immunological response, for example, granulocyte colony-stimulating factor. Increasing research interest has recently been focused on interventions aimed at supporting regenerative processes. PMID- 26119834 TI - Dynamic aberrant NF-kappaB spurs tumorigenesis: a new model encompassing the microenvironment. AB - Recently it was discovered that a transient activation of transcription factor NF kappaB can give cells properties essential for invasiveness and cancer initiating potential. In contrast, most oncogenes to date were characterized on the basis of mutations or by their constitutive overexpression. Study of NF-kappaB actually leads to a far more dynamic perspective on cancer: tumors caused by diverse oncogenes apparently evolve into cancer after loss of feedback regulation for NF kappaB. This event alters the cellular phenotype and the expression of hormonal mediators, modifying signals between diverse cell types in a tissue. The result is a disruption of stem cell hierarchy in the tissue, and pervasive changes in the microenvironment and immune response to the malignant cells. PMID- 26119837 TI - The law of mass action and the pharmacological concentration-effect curve: resolving the paradox of apparently non-dose-related adverse drug reactions. AB - BACKGROUND: Adverse drug reactions are sometimes described as being 'non-dose related' because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non-dose-related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox. METHODS: We searched for published adverse drug reactions that have been described as non-dose-related and analysed them. RESULTS: We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect. CONCLUSIONS AND IMPLICATIONS: If an adverse drug reaction appears to be non-dose-related, the reasons should be sought, having these mechanisms in mind. PMID- 26119839 TI - Rapid diagnostics for Ebola in emergency settings. PMID- 26119838 TI - ReEBOV Antigen Rapid Test kit for point-of-care and laboratory-based testing for Ebola virus disease: a field validation study. AB - BACKGROUND: At present, diagnosis of Ebola virus disease requires transport of venepuncture blood to field biocontainment laboratories for testing by real-time RT-PCR, resulting in delays that complicate patient care and infection control efforts. Therefore, an urgent need exists for a point-of-care rapid diagnostic test for this disease. In this Article, we report the results of a field validation of the Corgenix ReEBOV Antigen Rapid Test kit. METHODS: We performed the rapid diagnostic test on fingerstick blood samples from 106 individuals with suspected Ebola virus disease presenting at two clinical centres in Sierra Leone. Adults and children who were able to provide verbal consent or assent were included; we excluded patients with haemodynamic instability and those who were unable to cooperate with fingerstick or venous blood draw. Two independent readers scored each rapid diagnostic test, with any disagreements resolved by a third. We compared point-of-care rapid diagnostic test results with clinical real time RT-PCR results (RealStar Filovirus Screen RT-PCR kit 1.0; altona Diagnostics GmbH, Hamburg, Germany) for venepuncture plasma samples tested in a Public Health England field reference laboratory (Port Loko, Sierra Leone). Separately, we performed the rapid diagnostic test (on whole blood) and real-time RT-PCR (on plasma) on 284 specimens in the reference laboratory, which were submitted to the laboratory for testing from many clinical sites in Sierra Leone, including our two clinical centres. FINDINGS: In point-of-care testing, all 28 patients who tested positive for Ebola virus disease by RT-PCR were also positive by fingerstick rapid diagnostic test (sensitivity 100% [95% CI 87.7-100]), and 71 of 77 patients who tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92.2% [95% CI 83.8-97.1]). In laboratory testing, all 45 specimens that tested positive by RT-PCR were also positive by the rapid diagnostic test (sensitivity 100% [95% CI 92.1-100]), and 214 of 232 specimens that tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92.2% [88.0-95.3]). The two independent readers agreed about 95.2% of point-of-care and 98.6% of reference laboratory rapid diagnostic test results. Cycle threshold values ranged from 15.9 to 26.3 (mean 22.6 [SD 2.6]) for the PCR positive point-of-care cohort and from 17.5 to 26.3 (mean 21.5 [2.7]) for the reference laboratory cohort. Six of 16 banked plasma samples from rapid diagnostic test-positive and altona-negative patients were positive by an alternative real-time RT-PCR assay (the Trombley assay); three (17%) of 18 samples from individuals who were negative by both the rapid diagnostic test and altona test were also positive by Trombley. INTERPRETATION: The ReEBOV rapid diagnostic test had 100% sensitivity and 92% specificity in both point-of-care and reference laboratory testing in this population (maximum cycle threshold 26.3). With two independent readers, the test detected all patients who were positive for Ebola virus by altona real-time RT-PCR; however, this benchmark itself had imperfect sensitivity. FUNDING: Abundance Foundation. PMID- 26119840 TI - Cerebral fat embolism after bone fractures. PMID- 26119841 TI - How mechanisms of habitat preference evolve and promote divergence with gene flow. AB - Habitat preference may promote adaptive divergence and speciation, yet the conditions under which this is likely are insufficiently explored. We use individual-based simulations to study the evolution and consequence of habitat preference during divergence with gene flow, considering four different underlying genetically based behavioural mechanisms: natal habitat imprinting, phenotype-dependent, competition-dependent and direct genetic habitat preference. We find that the evolution of habitat preference generally requires initially high dispersal, is facilitated by asymmetry in population sizes between habitats, and is hindered by an increasing number of underlying genetic loci. Moreover, the probability of habitat preference to emerge and promote divergence differs greatly among the underlying mechanisms. Natal habitat imprinting evolves most easily and can allow full divergence in parameter ranges where no divergence is possible in the absence of habitat preference. The reason is that imprinting represents a one-allele mechanism of assortative mating linking dispersal behaviour very effectively to local selection. At the other extreme, direct genetic habitat preference, a two-allele mechanism, evolves under restricted conditions only, and even then facilitates divergence weakly. Overall, our results indicate that habitat preference can be a strong reproductive barrier promoting divergence with gene flow, but that this is highly contingent on the underlying preference mechanism. PMID- 26119842 TI - GJB2 and mitochondrial 12S rRNA susceptibility mutations in sudden deafness. AB - Genetic susceptibility may play an important role in the pathogenesis of sudden deafness. However, the specific genes involved are largely unknown. We sought to explore the frequency of GJB2 and mitochondrial 12S rRNA susceptibility mutations in patients with sudden deafness. Between September 2011 and May 2012, 62 consecutive patients with sudden deafness were seen. In 50 of these, no etiological factors for sudden deafness were found. We detected GJB2 and mitochondrial 12S rRNA variants by direct sequencing in these 50 patients and in 53-aged matched controls with normal hearing. In addition, we undertook functional analyses of the mitochondrial mutations which we detected, applying structural and phylogenetic analysis. GJB2 sequencing identified six mutations, including three pathogenic mutations (c.235delC, c.299-300delAT, c.109G>A) and three polymorphisms, in the study participants, giving an allele frequency of 15.0 %. A homozygous c.109G>A mutation was detected in two participants. A total of 16 variants in mitochondrial 12S rRNA gene were identified in the participants. No significant differences were found in GJB2 heterozygosity or in mitochondrial 12S rRNA variants between patients with sudden deafness and in controls. Our results suggest that the homozygous GJB2 c.109G>A mutation may be a cause of sudden deafness involving both ears. This finding should increase awareness of the likely role of genetic factors in the etiology of sudden deafness in general. PMID- 26119843 TI - Prognostic impact of second primary tumors in head and neck cancer. AB - The incidence of Second Primary Tumors in the upper aerodigestive tract varies from 5 to 30 %. Most of them are located either in the same anatomical region or in the lungs, and are related to a poor overall survival. Our objective is to assess the incidence of Second Primary Tumors, factors related to its outcome, frequent associations, and impact on overall survival. 27 patients with Second Primary Tumors were reviewed out of 307 with head and neck cancer, between 2002 and 2011. Patients had a minimum follow-up period of 3 years, or until their death after the last treatment. Sex: 85.2 % were male; male:female ratio of 23:4. The mean age of appearance for the primary tumor was 66.8 years. Only 1 patient had a synchronous Second Primary Tumor, while 26 had metachronous Second Primary Tumors. Second neoplasms were grouped into synchronous and metachronous for statistical analysis. The following parameters were considered: age at diagnosis of the first tumor, gender, smoking and persistence of the habit, primary tumor's location in the larynx, association between two squamous cell carcinomas (index and second primary tumor), and radiotherapy for the primary tumor. The incidence of Second Primary Tumors was 8.79 %. Overall survival of metachronous tumors was 95 months (7.9 years). The primary tumor's location that prevailed when developing a Second Primary Tumor was the larynx. Regarding the histology, the most common association was head and neck squamous cell carcinoma with head and neck squamous cell carcinoma (9 patients). The Second Primary Tumor was the cause of death in 51.9 % of the patients and its most frequent location was the lungs. 19 patients underwent radiotherapy. Second Primary Tumors are common in the head and neck. The authors would like to enforce the importance of an extended follow up, since second neoplasms worsen considerably the patient's prognosis. Patients who keep on smoking after treatment decrease even more their overall survival. PMID- 26119844 TI - Calcium plus vitamin D supplementation influences biomarkers of inflammation and oxidative stress in overweight and vitamin D-deficient women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. AB - OBJECTIVE: This study was conducted to determine the effects of calcium plus vitamin D supplementation on inflammatory factors and biomarkers of oxidative stress among overweight vitamin D-deficient women with polycystic ovary syndrome (PCOS). DESIGN, PATIENTS AND MEASUREMENTS: This randomized double-blind placebo controlled clinical trial was performed among 104 overweight vitamin D-deficient women diagnosed with PCOS aged 18-40 years. Participants were randomly divided into four groups. Group A received 1000 mg calcium daily and vitamin D placebo weekly (N = 26), group B 50000 IU vitamin D weekly and calcium placebo daily (N = 26), group C 1000 mg calcium daily plus 50000 IU vitamin D weekly (N = 26) and group D calcium placebo daily plus vitamin D placebo weekly (N = 26) for 8 weeks. Fasting blood samples were taken at baseline and 8 weeks after intervention to measure inflammatory factors and biomarkers of oxidative stress. RESULTS: After 8 weeks, individuals taking calcium plus vitamin D supplements had greater decreases in homoeostatic model assessment beta-cell function (HOMA-B) score ( 11.1 vs -8.6, -3.4 and 13.7, respectively, P = 0.03), serum high-sensitivity C reactive protein (hs-CRP) (-948.3 vs 802.3, -383.8 and 618.2 ng/ml, respectively, P = 0.04) and plasma malondialdehyde (MDA) concentrations (-0.6 vs -0.5, -0.1 and 0.6 MUmol/l, respectively, P = 0.009), and significant increases in plasma total antioxidant capacity (TAC) (35.2 vs 21.1, 22.5 and -153.8 mmol/l, respectively, P = 0.006) and glutathione (GSH) levels (216.0 vs 3.9, -47.5 and -160.8 MUmol/l, respectively, P = 0.001) compared with calcium alone, vitamin D alone and placebo groups. Calcium plus vitamin D cosupplementation did not influence plasma NO and catalase levels. CONCLUSIONS: We found that calcium plus vitamin D cosupplementation for 8 weeks among overweight and vitamin D-deficient women with PCOS had beneficial effects on inflammatory factor and biomarkers of oxidative stress. PMID- 26119845 TI - Liraglutide subcutaneous injection for weight loss: where does it fit? PMID- 26119846 TI - Effects of thonningianin A in natural foods on apoptosis and cell cycle arrest of HepG-2 human hepatocellular carcinoma cells. AB - The anti-cancer activities of Thonningianin A on the HepG-2 human hepatocellular carcinoma cell line were evaluated by MTT assay, flow cytometry, quantitative real-time PCR and western blotting. Results showed that Thonningianin A effectively inhibited the proliferation of HepG-2 cells by inducing apoptosis, as evidenced by increase in the sub-G1 cell population, DNA fragmentation, and increase in the content of reactive oxygen species. Activation of caspase-9 and the subsequent activation of caspase-3 indicated that Thonningianin A-induced apoptosis is caspase-dependent. Thonningianin A also disrupted the mitochondrial membrane potential (Deltapsim) and down-regulated the Bcl-xL mRNA expression in HepG-2 cells. Thonningianin A induced cell cycle arrest by changing the cyclin D1 and CDK4 mRNA expression levels. Moreover, western blotting showed that Thonningianin A significantly down-regulated the NF-kappa-B cell survival pathway, along with up-regulation of the expression level of phosphorylated P38 and down-regulation of the expression level of phosphorylated ERK. The anti cancer activity of Thonningianin A was confirmed by the characteristic patterns of DNA fragmentation and cell cycle arrest, suggesting that Th A is an effective antitumor ingredient in natural plant foods, and is worthy of further study. PMID- 26119847 TI - Population-specific stature estimation from long bones in the early medieval Pohansko (Czech Republic). AB - OBJECTIVES: We tested the effect of population-specific linear body proportions on stature estimation. MATERIALS AND METHODS: We used a skeletal sample of 31 males and 20 females from the Early Medieval site at Pohansko (Breclav, Central Europe) and a comparative Central European Early Medieval sample of 45 males and 28 females. We developed new population-specific equations for the Pohansko sample using anatomical reconstructions of stature, then compared percentage prediction errors (%PEs) of anatomical stature from limb bone lengths using the derived Pohansko equations with those previously derived from more general European and other Early Medieval samples. RESULTS: Among general European equations, the lowest %PEs for the Pohansko sample were obtained using the equations of Formicola and Franceschi: Am J Phys Anthropol 100 (1996) 83-88 and Ruff et al.: Am J Phys Anthropol 148 (2012) 601-617. However, unexpectedly, the choice between tibial latitudinal variants proposed by Ruff et al.: Am J Phys Anthropol 148 (2012) 601-617 appeared to be sex-specific, with northern and southern variants producing lower %PEs for males and females, respectively. Equations from Breitinger: Anthropol Anz 14 (1937) 249-274, Bach: Anthropol Anz 29 (1965) 12-21, and Sjovold: Hum Evol 5 (1990) 431-447 provided poor agreement with anatomical stature. When applied to the comparative Central European Early Medieval sample, our new formulae have generally lower %PE than previously derived formulae based on other European Early Medieval samples (Maijanen and Niskanen: Int J Osteoarchaeol 20 (2010) 472-480; Vercellotti et al.: Am J Phys Anthropol 140 (2009) 135-142. CONCLUSIONS: The best agreement with anatomical stature among our newly developed equations was obtained using femoral+tibial length, followed by femoral length. Upper limb bone lengths resulted in higher %PEs. Variation in the tibia is likely to contribute most to potential bias in stature estimation. Am J Phys Anthropol 158:312-324, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26119848 TI - Consistent antioxidant and antihypertensive effects of oral sodium nitrite in DOCA-salt hypertension. AB - Hypertension is a common disease that includes oxidative stress as a major feature, and oxidative stress impairs physiological nitric oxide (NO) activity promoting cardiovascular pathophysiological mechanisms. While inorganic nitrite and nitrate are now recognized as relevant sources of NO after their bioactivation by enzymatic and non-enzymatic pathways, thus lowering blood pressure, mounting evidence suggests that sodium nitrite also exerts antioxidant effects. Here we show for the first time that sodium nitrite exerts consistent systemic and vascular antioxidant and antihypertensive effects in the deoxycorticosterone-salt (DOCA-salt) hypertension model. This is particularly important because increased oxidative stress plays a major role in the DOCA-salt hypertension model, which is less dependent on activation of the renin angiotensin system than other hypertension models. Indeed, antihypertensive effects of oral nitrite were associated with increased plasma nitrite and nitrate concentrations, and completely blunted hypertension-induced increases in plasma 8 isoprostane and lipid peroxide levels, in vascular reactive oxygen species, in vascular NADPH oxidase activity, and in vascular xanthine oxidoreductase activity. Together, these findings provide evidence that the oral administration of sodium nitrite consistently decreases the blood pressure in association with major antioxidant effects in experimental hypertension. PMID- 26119849 TI - Histoplasmosis diagnosed after arthroscopy of the knee: case report. AB - Fungal arthritis is a rare complication of arthroscopic surgeries, but its possibility should always be considered due its deleterious effects on any joint. Infection caused by the fungus Histoplasma capsulatum is the most common cause of respiratory tract infections by fungi, meanwhile histoplasmosis arthritis is more rare than all other fungal infections. However, their atypical forms of arthritis and the importance of early diagnosis and treatment cannot be over-emphasized. Herein we report a case of knee monoarthritis in an immunocompetent patient with histoplasmosis arthritis following an arthroscopic meniscetomy, diagnosed by synovial biopsy and culture performed during a second arthroscopic procedure. The joint was debrided in this second intervention and the patient received itraconazole initially and fluconazole latter on. The arthritis subsided after 10 months of treatment. PMID- 26119850 TI - Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species. AB - The antifungal activity of some statins against different fungal species has been reported. Thus, at the first moment, the in vitro antifungal activity of simvastatin, atorvastatin and pravastatin was tested against Candida spp. and Cryptococcus spp. Then, in a second approach, considering that the best results were obtained for simvastatin, this drug was evaluated in combination with antifungal drugs against planktonic growth and tested against biofilms of Candida spp. and Cryptococcus spp. Drug susceptibility testing was performed using the microdilution broth method, as described by the Clinical and Laboratory Standards Institute. The interaction between simvastatin and antifungals against planktonic cells was analyzed by calculating the fractional inhibitory concentration index. Regarding biofilm susceptibility, simvastatin was tested against growing biofilm and mature biofilm of one strain of each tested yeast species. Simvastatin showed inhibitory effect against Candida spp. and Cryptococcus spp. with minimum inhibitory concentration values ranging from 15.6 to 1000 mg L(-1) and from 62.5 to 1000 mg L(-1), respectively. The combination of simvastatin with itraconazole and fluconazole showed synergism against Candida spp. and Cryptococcus spp., while the combination of simvastatin with amphotericin B was synergistic only against Cryptococcus spp. Concerning the biofilm assays, simvastatin was able to inhibit both growing biofilm and mature biofilm of Candida spp. and Cryptococcus spp. The present study showed that simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species. PMID- 26119851 TI - Urine alpha1-microglobulin is a better marker for early tubular dysfunction than beta2-microglobulin among tenofovir-exposed human immunodeficiency virus-infected men who have sex with men. AB - OBJECTIVES: Men who have sex with men are at risk of tenofovir nephrotoxicity due to its wide use in both treatment and prophylaxis for human immunodeficiency virus infection, but little is known about the urinary biomarkers of early renal dysfunction in this population. This study aims to identify useful biomarkers of early renal dysfunction among human immunodeficiency virus-infected men who have sex with men exposed to tenofovir. METHODS: In a cross-sectional study urinary alpha1-microglobulin, beta2-microglobulin, N-acetyl-beta-d-glucosaminidase and albumin were measured and expressed as the ratio-to-creatinine in 239 human immunodeficiency virus-infected men who have sex with men who were treatment naive or receiving antiretroviral therapy with tenofovir-containing or non tenofovir-containing regimens. Additionally, 56 patients in the non antiretroviral therapy group started a tenofovir-containing regimen and were assessed after 3 and 6 months on antiretroviral therapy. RESULTS: Both the frequency of alpha1-microglobulin proteinuria (alpha1-microglobulin-creatinine ratio >25.8mg/g) and the median urinary alpha1-microglobulin-creatinine ratio were higher in the tenofovir disoproxil fumarate group than the other two groups (all p<0.05). A higher frequency of beta2-microglobulin proteinuria (beta2 microglobulin-creatinine ratio >0.68mg/g) was also observed in the tenofovir group (28.9%) compared to the non-tenofovir group (13.6%, p=0.024). There were no significant differences between groups for N-acetyl-beta-d-glucosaminidase and albumin. In the longitudinal study, the median urinary alpha1-microglobulin creatinine ratio after 3 and 6 months on tenofovir-containing therapy (16.8 and 17.3mg/g) was higher than baseline (12.3mg/g, p=0.023 and 0.011, respectively), while no statistically important changes were observed in urinary beta2 microglobulin-creatinine ratio or in the other biomarkers after 3 and 6 months on antiretroviral therapy (all p>0.05). CONCLUSION: Urinary alpha1-microglobulin seems to be a more sensitive and stable indicator of tubular dysfunction than urinary beta2-microglobulin for assessing tenofovir-related nephrotoxicity and can be significantly altered after tenofovir exposure. PMID- 26119852 TI - Natural killer cells in hepatitis B virus infection. AB - Natural killer cells are a unique type of lymphocytes with cytotoxic capacity, and play important roles against tumors and infections. Recently, natural killer cells have been increasingly valued in their effects in hepatitis B virus infection. Since hepatitis B virus is not cytopathic, the subsequent antiviral immune responses of the host are responsible for sustaining the liver injury, which may result in cirrhosis and even hepatocellular carcinoma. Many studies have confirmed that natural killer cells participate in anti-hepatitis B virus responses both in the early phase after infection and in the chronic phase via cytolysis, degranulation, and cytokine secretion. However, natural killer cells play dichotomic roles: they exert antiviral and immunoregulatory functions whilst contribute to the pathogenesis of liver injury. Here, we review the roles of natural killer cells in hepatitis B virus infection, introducing novel therapeutic strategies for controlling hepatitis B virus infection via the modulation of natural killer cells. PMID- 26119853 TI - MRSA from Santa Catarina State, Southern Brazil: intriguing epidemiological differences compared to other Brazilian regions. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most frequently isolated agents in both nosocomial and community settings. It is a constant challenge for antibacterial therapy. Therefore, it becomes essential to understand the epidemiology of MRSA isolates in the institution and/or region to guide empirical therapy. The objective of this study was to evaluate the epidemiological characteristics of MRSA isolates in the state of Santa Catarina, Brazil, and determine if there is a clonal spread. We evaluated 124 clinical isolates of MRSA obtained from various anatomical sites from patients in the state of Santa Catarina in Southern Brazil. The antimicrobial susceptibility profile was evaluated by disk diffusion and minimum inhibitory concentration (MIC) was determined by Etest and broth macrodilution. SCCmec types were determined by multiplex PCR and the clonal relationship among isolates was assessed by pulsed field gel electrophoresis. Antimicrobials that have demonstrated lower rates of resistance were tetracycline (20.2%), sulfamethoxazole-trimethoprim (20.2%) and chloramphenicol (12.9%). We did not detect any resistance to glycopeptides, daptomycin, linezolid, and tigecycline. SCCmec type III was predominant (54%), followed by type II (21.8%), consistent with other Brazilian studies. Twenty-six clones were observed grouping 72 (58%) isolates and no clonal relationship was observed between our isolates and the major epidemic clones circulating in Brazil. An intriguing distinct MRSA epidemiology was observed in Santa Catarina, compared to other Brazilian regions. PMID- 26119854 TI - Protocatechuic Acid from Alpinia oxyphylla Induces Schwann Cell Migration via ERK1/2, JNK and p38 Activation. AB - Alpinia oxyphylla MIQ (Alpinate Oxyphyllae Fructus, AOF) is an important traditional Chinese medicinal herb whose fruits is widely used to prepare tonics and is used as an aphrodisiac, anti salivary, anti diuretic and nerve-protective agent. Protocatechuic acid (PCA), a simple phenolic compound was isolated from the kernels of AOF. This study investigated the role of PCA in promoting neural regeneration and the underlying molecular mechanisms. Nerve regeneration is a complex physiological response that takes place after injury. Schwann cells play a crucial role in the endogenous repair of peripheral nerves due to their ability to proliferate and migrate. The role of PCA in Schwann cell migration was determined by assessing the induced migration potential of RSC96 Schwann cells. PCA induced changes in the expression of proteins of three MAPK pathways, as determined using Western blot analysis. In order to determine the roles of MAPK (ERK1/2, JNK, and p38) pathways in PCA-induced matrix-degrading proteolytic enzyme (PAs and MMP2/9) production, the expression of several MAPK-associated proteins was analyzed after siRNA-mediated inhibition assays. Treatment with PCA induced ERK1/2, JNK, and p38 phosphorylation that activated the downstream expression of PAs and MMPs. PCA-stimulated ERK1/2, JNK and p38 phosphorylation was attenuated by individual pretreatment with siRNAs or MAPK inhibitors (U0126, SP600125, and SB203580), resulting in the inhibition of migration and the uPA related signal pathway. Taken together, our data suggest that PCA extract regulate the MAPK (ERK1/2, JNK, and p38)/PA (uPA, tPA)/MMP (MMP2, MMP9) mediated regeneration and migration signaling pathways in Schwann cells. Therefore, PCA plays a major role in Schwann cell migration and the regeneration of damaged peripheral nerve. PMID- 26119855 TI - Creation of a transcatheter fenestration in children with failure of Fontan circulation: Focus on extracardiac conduit connection. AB - OBJECTIVES: We report our experience with a transcatheter technique to bypass the lung and to thus improve single-ventricle preload and reduce venous congestion in Fontan patients. BACKGROUND: In the absence of a dedicated power source to serve the pulmonary circulation and a significantly elevated transpulmonary pressure gradient, fenestration of the Fontan circulation is an option to improve hemodynamics in patients by relieving excessive systemic venous pressure. METHODS AND RESULTS: From 2005 to 2011, 22 transcatheter fenestrations were performed without any major complications in 19 patients (median age 3.2 years, interquartile range (IQR) 2.7-3.7 years)) with failing Fontan circulation and exceeding systemic venous pressure. In 16 patients, the procedure was performed for acute postoperative failure 1-24 days after surgery. After perforation of the conduit and atrial wall by a Brockenbrough needle and gradual balloon dilation, premounted stents were expanded to create a diabolo configuration with flaring stent edges, leaving a slight but definitive central waist. The procedure resulted in regression of pleural effusions and a significant decrease in systemic venous pressure. Clinical improvement was observed in 16 of the 19 treated patients. Follow-up demonstrated sustained fenestration in 85% of treated patients for at least 24 months. CONCLUSION: Transcatheter creation of a Fontan fenestration is a safe approach despite the anatomic gap between the extracardiac conduit cavity and the atrial wall. Stent implantation allows defining the diameter of the fenestration, reduces spontaneous occlusion, and ensures sustained clinical improvement. PMID- 26119856 TI - Marked elevation of procalcitonin level can lead to a misdiagnosis of anaphylactic shock as septic shock. AB - The case of a 74-year-old woman who presented with hyperthermia and hypotension is reported. Laboratory test results revealed marked elevation of C-reactive protein (CRP) and procalcitonin (PCT) levels. The clinical presentation and laboratory test results were suggestive of septic shock. No infectious focus was identified. The shock recurred after what was subsequently understood to be an unintended re-challenge with risedronate sodium. Drug-induced anaphylactic shock was finally diagnosed. Anaphylactic shock may be misdiagnosed as septic shock in patients who present with markedly elevated PCT levels. PMID- 26119857 TI - Multidrug-resistant and heteroresistant Mycobacterium tuberculosis and associated gene mutations in Ethiopia. AB - BACKGROUND: The prevalence of multidrug-resistant tuberculosis (TB) among new and retreatment cases in 2011 in Ethiopia was 2.7% and 17.9%, respectively. However, data on heteroresistance and gene mutation profiles of Mycobacterium tuberculosis were not documented. METHODS: A cross-sectional study was conducted on 413 TB positive clinical specimens submitted between 2012 and 2014 to Bahir Dar Regional Laboratory Center for confirmation of multidrug resistance. Resistance determining genes were analyzed using a line probe assay. RESULTS: Of 413M. tuberculosis isolates, 150 (36.3%) were multidrug-resistant, 19 (4.6%) were resistant only to rifampicin, and 26 (6.3%) were resistant to isoniazid. Of 169 rifampicin-resistant and 176 isoniazid-resistant isolates, only eight (4.7%) showed rifampicin heteroresistance and only two (1.13%) showed isoniazid heteroresistance. Failing of the rpoB WT8 gene with corresponding hybridization of rpoB MUT3 (S531L substitution) accounted for 85 (50.3%) rifampicin-resistant mutations. Among 176 isoniazid-resistant isolates, 155 (88.1%) strains had the Ser315Thr1 substitution. CONCLUSIONS: The prevalence of multidrug-resistant M. tuberculosis was high in the study area. Ser531Leu and Ser315Thr1 substitutions were the highest gene mutations for rifampicin and isoniazid, respectively. PMID- 26119859 TI - Specific global responses to N and Fe nutrition in toxic and non-toxic Microcystis aeruginosa. AB - The bloom-forming cyanobacteria species Microcystis aeruginosa includes toxic and non-toxic (microcystin-producing) strains. Certain stress conditions stimulate synthesis of microcystin (MCYST) and enhance the binding of the MCYST molecule to proteins. In this quantitative proteomic study, we compared the response of a wild-type toxic strain PCC 7806, an mcyH(-) knockout non-toxic strain, and a naturally occurring non-toxic strain, PCC 7005, after 8 days in low iron (Fe) and nitrogen (N) starvation in order to assess the benefit of MCYST synthesis in non optimal conditions. Fe limitation increased MCYST synthesis and caused an accumulation of phycobilisome proteins and the ferric iron transporter FutA only in the toxic PCC 7806 but not the non-toxic strains. In N starvation, photosynthetic, C and N metabolism proteins were more abundant in the non-toxic strains, as were chaperones and proteases. Significant interaction between nutrient availability and toxicity existed for thioredoxin peroxidase and several thioredoxin-regulated proteins. We propose a competition of MCYST for binding sites in thioredoxin-regulated proteins during oxidative stress (low Fe) but not in growth-limiting conditions (low N). This then leads to differences in the regulation of C:N metabolism in toxic and non-toxic M. aeruginosa in nutrient replete and nutrient-limited conditions. PMID- 26119860 TI - Versatile Design Principles for Facile Access to Unstrained Conjugated Organoborane Macrocycles. AB - A facile and versatile approach was developed to access ambipolar boron containing macrocycles. Two examples of new conjugated cyclic motifs are presented with carbazole moieties as donors and borane moieties as acceptors embedded into the ring system. They were first predicted using computational methods. Possible targets with appropriately shaped pi-conjugated bridges that minimize the overall ring strain were identified and their geometry was optimized by DFT methods. The synthetic demonstration was then accomplished using organometallic condensation reactions under high dilution conditions. The resulting monodisperse macrocycles provide important insights into the design principles necessary for the preparation of new unstrained macrocycles with interesting optical and electronic characteristics. The current research also offers a more general approach to conjugated ambipolar B/N macrocycles as a promising new family of (opto)electronic materials. PMID- 26119861 TI - Design and evaluation of a Monte Carlo based model of an orthovoltage treatment system. AB - The aim of this study was to develop a flexible framework of an orthovoltage treatment system capable of calculating and visualizing dose distributions in different phantoms and CT datasets. The framework provides a complete set of various filters, applicators and x-ray energies and therefore can be adapted to varying studies or be used for educational purposes. A dedicated user friendly graphical interface was developed allowing for easy setup of the simulation parameters and visualization of the results. For the Monte Carlo simulations the EGSnrc Monte Carlo code package was used. Building the geometry was accomplished with the help of the EGSnrc C++ class library. The deposited dose was calculated according to the KERMA approximation using the track-length estimator. The validation against measurements showed a good agreement within 4-5% deviation, down to depths of 20% of the depth dose maximum. Furthermore, to show its capabilities, the validated model was used to calculate the dose distribution on two CT datasets. Typical Monte Carlo calculation time for these simulations was about 10 minutes achieving an average statistical uncertainty of 2% on a standard PC. However, this calculation time depends strongly on the used CT dataset, tube potential, filter material/thickness and applicator size. PMID- 26119862 TI - Fast isotropic banding-free bSSFP imaging using 3D dynamically phase-cycled radial bSSFP (3D DYPR-SSFP). AB - AIMS: Dynamically phase-cycled radial balanced steady-state free precession (DYPR SSFP) is a method for efficient banding artifact removal in bSSFP imaging. Based on a varying radiofrequency (RF) phase-increment in combination with a radial trajectory, DYPR-SSFP allows obtaining a banding-free image out of a single acquired k-space. The purpose of this work is to present an extension of this technique, enabling fast three-dimensional isotropic banding-free bSSFP imaging. METHODS: While banding artifact removal with DYPR-SSFP relies on the applied dynamic phase-cycle, this aspect can lead to artifacts, at least when the number of acquired projections lies below a certain limit. However, by using a 3D radial trajectory with quasi-random view ordering for image acquisition, this problem is intrinsically solved, enabling 3D DYPR-SSFP imaging at or even below the Nyquist criterion. The approach is validated for brain and knee imaging at 3 Tesla. RESULTS: Volumetric, banding-free images were obtained in clinically acceptable scan times with an isotropic resolution up to 0.56mm. CONCLUSION: The combination of DYPR-SSFP with a 3D radial trajectory allows banding-free isotropic volumetric bSSFP imaging with no expense of scan time. Therefore, this is a promising candidate for clinical applications such as imaging of cranial nerves or articular cartilage. PMID- 26119863 TI - Complications and follow up of subarachnoid hemorrhages. AB - Complications of subarachnoid hemorrhage are the major life threatening and functional components of the follow up of a ruptured aneurysm. Knowing how to identify these is a key challenge. They vary in type throughout the postoperative follow up period. The aim of this article is firstly to list the main complications of the acute phase (rebleeding, acute hydrocephalus, acute ischemic injury and non-neurological complications), the subacute phase (vasospasm) and the chronic phase of subarachnoid hemorrhages: (chronic hydrocephalus and cognitive disorders) and to describe their major clinical and radiological features. Secondly, we describe the long-term follow up strategy for patients who have suffered a subarachnoid hemorrhage and have been treated endovascularly or by surgery. This follow up involves a combination of clinical consultations, cerebral MRI and at least one review angiogram. PMID- 26119864 TI - Ultrasound shear wave velocity in skeletal muscle: A reproducibility study. AB - PURPOSE: The purpose of the study was threefold: to assess the reliability of shear wave velocities (SWV) measurements in normal skeletal muscles; to evaluate intra- and inter-operator reproducibility of measurements for a specific site of the muscle and for the mean value in the whole muscle. MATERIALS AND METHODS: Two sets of measurements were performed at three weeks intervals of each other on 16 volunteers by two radiologists on medial gastrocnemius and tibialis anterior muscles. Each muscle was evaluated in 5 different sites, with three measurements for each site in the transverse and longitudinal planes. Reliability of SWV measurements was assessed by means of intraclass correlation coefficient (ICC). RESULTS: Reliability of the three independent SWV measurements was excellent, slightly better in the longitudinal plane. Inter/intra-operator reproducibility per site was fair to good in the longitudinal plane and poor to fair in the transverse plane. For global values of the whole muscle, ICC showed good agreement in the longitudinal plane and fair agreement in the transverse plane. CONCLUSION: Quantitative SWV measurements are reliable when performed in rigorous conditions. In conditions that mirror clinical practice, inter/intra-operator reproducibility is moderate, better for longitudinal compared to transverse plane. PMID- 26119865 TI - Primary angiosarcoma of the breast: Diagnosis with computer-assisted MRI-guided radio-guided occult lesion localization (ROLL) technique. AB - Primary angiosarcoma of the breast is a rare type of breast cancer that represents approximately 0.04% of all primary breast tumors. We report herein a case of primary breast angiosarcoma that was only visible on magnetic resonance imaging (MRI) examination. The patient presented with a palpable right breast lump that was not visible either on ultrasonography and mammography. MRI showed a lesion of the right breast that presented washout kinetics. MRI-guided biopsy allowed histopathological examination of the tumor that was further confirmed as primary angiosarcoma. Subsequently, MRI guided ROLL (radio-guided occult lesion localization) technique was used for localizing the lesion prior to surgery. PMID- 26119866 TI - Damage control interventional radiology (DCIR) in prompt and rapid endovascular strategies in trauma occasions (PRESTO): A new paradigm. AB - This article proposes an innovative concept of interventional radiology for hemodynamically unstable trauma patients. Damage control interventional radiology (DCIR) is an aggressive and time-conscious algorithm that prioritizes saving life of the hemorrhaging patient in extremis which conventional emergency interventional radiology (CEIR) cannot efficiently do. Briefly, DCIR aims to save life while CEIR aims to control bleeding with a constant concern to time awareness. This article also presents the concept of "Prompt and Rapid Endovascular Strategies in Traumatic Occasions" (PRESTO) that entirely oversees and manages trauma patients from arrival to the trauma bay until initial completion of hemostasis with endovascular techniques. PRESTO's "Start soon and finish sooner" relies on the earlier activation of interventional radiology team but also emphasizes on a rapid completion of hemostasis in which DCIR has been specifically tailored. Both DCIR and PRESTO expand the role of IR and represent a paradigm shift in the realm of trauma care. PMID- 26119867 TI - MR imaging in the management of trachelectomy. PMID- 26119868 TI - Structure investigation of nanohybrid PDMA/silica hydrogels at rest and under uniaxial deformation. AB - Nano-hybrid hydrogels were prepared by cross-linking polymerization of N,N dimethylacrylamide (DMA) within a dispersion of silica nano-particles. Working at constant polymer/water ratio, the mechanical properties of hydrogels can be finely tuned by changing either the level of covalent cross-linker and/or the amount of particles that act as physical cross-linkers through specific adsorption of PDMA chains. Whatever is the cross-linking ratio (from 0 to 1 mol%), the introduction of silica nano-particles dramatically improves the mechanical behavior of hydrogels with a concomitant increase of stiffness and nominal strain at failure. The physical interactions being reversible in nature, the dynamics of the adsorption/desorption process of PDMA chains directly controls the time-dependence of the mechanical properties. Small angle neutron scattering experiments, performed in contrast matching conditions, show that silica particles, which repel themselves at short range, remain randomly dispersed during the formation of the PDMA network. Although PDMA chains readily interact with silica particles, no significant variation of the polymer concentration was observed in the vicinity of silica surfaces. Together with the time dependence of physical interactions pointed out by mechanical analyses, this result is attributed to the moderate adsorption energy of PDMA chains with silica surfaces at pH 9. From 2D SANS experiments, it was shown that strain rapidly gives rise to a non affine deformation of the hybrid network with shearing due to the transverse compression of the particles. After loading at intermediate deformation, the particles recover their initial distribution due to the covalent network that is not damaged in these conditions. That is no longer true at high deformation where residual anisotropy is observed. PMID- 26119869 TI - Combination of carbon dot and polymer dot phosphors for white light-emitting diodes. AB - We realized white light-emitting diodes with high color rendering index (85-96) and widely variable color temperatures (2805-7786 K) by combining three phosphors based on carbon dots and polymer dots, whose solid-state photoluminescence self quenching was efficiently suppressed within a polyvinyl pyrrolidone matrix. All three phosphors exhibited dominant absorption in the UV spectral region, which ensured the weak reabsorption and no energy transfer crosstalk. The WLEDs showed excellent color stability against the increasing current because of the similar response of the tricolor phosphors to the UV light variation. PMID- 26119870 TI - Transumbilical laparoendoscopic single-site surgery versus conventional laparoscopy for the resection of retroperitoneal paragangliomas. AB - OBJECTIVES: To compare transumbilical laparoendoscopic single-site surgery with conventional laparoscopy for the resection of retroperitoneal paragangliomas. METHODS: In the present case-control study, we compared 11 transumbilical laparoendoscopic single-site surgery procedures with 22 conventional laparoscopy procedures carried out to treat retroperitoneal paragangliomas between June 2004 and October 2013 at Peking Union Medical Hospital, Beijing, China. Operative time, estimated intraoperative blood loss, blood transfusions, intraoperative hypertension, intraoperative hypotension, highest intraoperative systolic blood pressure, lowest intraoperative systolic blood pressure, postoperative fatigue time, postoperative systematic inflammation reaction syndrome, 24-h postoperative visual analog scale scores, postoperative hospital stay duration, and postoperative complications were recorded and analyzed. RESULTS: There were no significant differences in patient characteristics. All surgical procedures were successfully completed in both groups. Minor complications occurred in one case in the laparoendoscopic single-site surgery group and in two cases in the conventional laparoscopy group. In the laparoendoscopic single-site surgery group, the operative time was longer than that in the conventional laparoscopy group (P = 0.001). There were no significant differences in terms of intraoperative hypertension, intraoperative hypotension, highest intraoperative systolic blood pressure, lowest intraoperative systolic blood pressure, estimated blood loss, postoperative fatigue time, postoperative hospital stay or systematic inflammation reaction syndrome between the two groups. The 24-h postoperative visual analog scale score was lower in the laparoendoscopic single-site surgery group (P = 0.002). No recurrence or metastases were observed over the duration of the postoperative follow up. CONCLUSIONS: In properly selected patients, transumbilical laparoendoscopic single-site surgery is a feasible, safe and effective procedure for the surgical treatment of retroperitoneal paragangliomas. PMID- 26119871 TI - Hessian facilitated analysis of optimally controlled quantum dynamics of systems with coupled primary and secondary states. AB - The efficacy of optimal control of quantum dynamics depends on the topology and associated local structure of the underlying control landscape defined as the objective as a function of the control field. A commonly studied control objective involves maximization of the transition probability for steering the quantum system from one state to another state. This paper invokes landscape Hessian analysis performed at an optimal solution to gain insight into the controlled dynamics, where the Hessian is the second-order functional derivative of the control objective with respect to the control field. Specifically, we consider a quantum system composed of coupled primary and secondary subspaces of energy levels with the initial and target states lying in the primary subspace. The primary and secondary subspaces may arise in various scenarios, for example, respectively, as sub-manifolds of ground and excited electronic states of a poly atomic molecule, with each possessing a set of rotational-vibrational levels. The control field may engage the system through electric dipole transitions that occur either (I) only in the primary subspace, (II) between the two subspaces, or (III) only in the secondary subspace. Important insights about the resultant dynamics in each case are revealed in the structural patterns of the corresponding Hessian. The Fourier spectrum of the Hessian is shown to often be complementary to mechanistic insights provided by the optimal control field and population dynamics. PMID- 26119872 TI - Near-anode focusing phenomenon caused by the coupling effect of early precipitation and backward electromigration in electrokinetic remediation of MSWI fly ashes. AB - As electrokinetic remediation (EKR) is used to remediate contaminated soil, the focusing phenomenon is always the inevitable problems needing to be solved during the process. In this paper, EKR was chosen to extract the heavy metals in the municipal solid waste incineration fly ashes (FAs). The focusing phenomenon of FA in the sample region of the rectangular electrolyser was comprehensively studied. The formation of the focusing band was monitored and the redistribution of concentration for Zn, Pb, Cu, and Cd were displayed. The major and minor phases of FA particles have greatly changed before and after the experiment. A variety of carbonate hydroxides and phosphate were found at the end of the test. There are two focusing bands at S2 and S5, separately for all the four elements and the focusing bands in the S2 zone forming at the early stage existed nearly throughout the entire process. The pH gradient between S1 and S2 was detected at the onset of the experiment, and until the 12 day, the gradient barrier was obviously dropped down. The coupling effect of precipitation hindering and backward electromigration of anions is considered as the dominant force for the formation of the focusing band, which is different from the pure ion-induced potential gradient well trapping effect near the anode. The FA matrix enhancing and nitric acid enhancing can alleviate the focusing phenomenon and increase the concentration ratios to some extent. PMID- 26119873 TI - The Current State of Naive Human Pluripotency. AB - Naive or ground state pluripotency is a cellular state in vitro which resembles cells of the preimplantation epiblast in vivo. This state was first observed in mouse embryonic stem cells and is characterized by high rates of proliferation, the ability to differentiate widely, and global hypomethylation. Human pluripotent stem cells (hPSCs) correspond to a later or "primed" stage of embryonic development. The conversion of hPSCs to a naive state is desirable as their features should facilitate techniques such as gene editing and more efficient differentiation. Here we review protocols which now allow derivation of naive human pluripotent stem cells by transgene expression or the use of media formulations containing inhibitors and growth factors and correlate this with pathways involved. Maintenance of these ground state cells is possible using a combination of basic fibroblast growth factor and human leukemia inhibitory factor together with dual inhibition of glycogen synthase kinase 3 beta, and mitogen-activated protein kinase kinase (MEK). Close similarity between the ground state hPSC and the in vivo preimplantation epiblast have been shown both by demonstrating similar upregulation of endogenous retroviruses and correlation of global RNA-seq data. This suggests that the human naive state is not an in vitro artifact. PMID- 26119874 TI - Low CD23 expression correlates with high CD38 expression and the presence of trisomy 12 in CLL. AB - Chronic lymphocytic leukemia (CLL) is characterized by a neoplastic B-cell population coexpressing CD5 and CD23; however, the expression of CD23 is variable. In human, two isotypes of CD23 have been identified and related to different functions. The aim of our study was to investigate the relative expression of the two CD23 isotypes in CLL and find possible correlation with other prognostic factors. The expression of CD23 isotypes was analyzed in 54 cases of CLL by polymerase chain reaction (PCR) and quantitative real-time PCR. The immunophenotype of CLL cells was characterized by flow cytometry. We demonstrated a higher CD23a than CD23b expression of CLL cells. Our results also revealed two subsets of CLL cases with a distinct CD23 isotype expression pattern. Thirty-two percent of the cases (group CLL1) showed both low mRNA level of CD23 isotypes and high protein levels of CD20 and CD38 in contrast to group CLL2 with high CD23 mRNA levels. By correlating these results to the presence of prognostic factors determined by fluorescence in situ hybridization, we found that the majority of the cases of group CLL1 (14/17) carried trisomy 12. In summary, our results confirm a high CD23a/CD23b ratio of the CLL cells and demonstrate that in a subset of CLL cases, low CD23 expression together with high CD20 and CD38 expressions may serve as a surrogate for trisomy 12. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26119875 TI - Different DNA methylation pattern of HPV16, HPV18 and HPV51 genomes in asymptomatic HPV infection as compared to cervical neoplasia. AB - Epigenetic alterations of human papillomavirus (HPV) genome play an important role in virus life cycle and carcinogenic progression. The aim of the current study was to investigate the correlation between the grade of cervical pathology and DNA methylation status within the L1 gene and the long control region (LCR) of HPV16, HPV18 and HPV51. HPV genomes were analyzed using bisulfite DNA modification procedure with the subsequent amplification of target DNA regions and sequencing. A collection of 202 cervical specimens was analyzed: 157 HPV16 positive specimens, 21 HPV18-positive specimens and 24 HPV51-positive specimens. This study revealed that methylation of CpG was significantly more prevalent in L1 gene as compared to LCR region of all three studied HPV types and the degree of DNA methylation level correlated with the severity of cervical neoplasia. An increased DNA methylation level of HPV16 promoter region in case of cervical cancer was determined. PMID- 26119876 TI - Hepatitis B "e" antigen-mediated inhibition of HBV replication fitness and transcription efficiency in vitro. AB - A mutation at nucleotide 1896 (G1896A) is the most common cause for the loss of HBeAg. In contrast to clinical data, cell culture studies report a high replicating phenotype for the G1896A mutant. Differences between the wild-type and the G1896A mutant in early steps of HBV replication including the synthesis of pre-genomic RNA and transcripts have not been investigated. The G1896A mutant is associated with higher replication fitness, transcription efficiency and higher levels of secreted HBsAg than the wild-type. Interestingly, trans complementation of the G1896A mutant with HBeAg lowers the replication fitness and transcriptionefficiency to levels comparable to that of the wild-type. Our results highlight the role of HBeAg in modulating the early steps in HBV replication. In sum, our findings highlight the role of HBeAg in regulating hepatitis B virus replication fitness and transcription efficiency and new insights on the early steps of replication in the G1896A mutant. PMID- 26119877 TI - Decreased health-related physical fitness in adults with ankylosing spondylitis: a cross-sectional controlled study. AB - OBJECTIVES: (1) Assess the health-related physical fitness of adults with ankylosing spondylitis (AS) and compare these to the general population, and (2) examine the relationships between physical fitness and condition-specific outcomes. DESIGN: Cross-sectional, controlled study. SETTING: Exercise research laboratory. PARTICIPANTS: Thirty-nine adults with AS (32 men, 7 women) and 39 age and gender-matched controls. INTERVENTION: Comprehensive physical fitness assessment, and completion of questionnaires assessing disease activity, physical function and quality-of-life. MAIN OUTCOME MEASURES: Body composition was assessed by bio-impedance analysis. Flexibility was measured with the Bath AS Metrology Index (BASMI). Cardiorespiratory fitness was assessed by submaximal treadmill test with breath-by-breath gas analysis and heart rate monitoring. Muscular strength and endurance were measured by isokinetic dynamometry of concentric knee flexion/extension. RESULTS: The AS group demonstrated significantly lower cardiorespiratory fitness [mean difference -1.3mLmin(-1)kg( 1) (95% CI -1.1 to -1.4)], flexibility [0.4 BASMI units (0.2 to 0.7)], muscular strength [-31.6 peak torque per body weight dominant knee extension (-56.1 to 7.1)], and increased body fat [0.4% (0.0 to 1.2)] compared to population controls (p<.05). There were significant associations between each fitness component and physical function (p<.05). Higher aerobic capacity was significantly associated with improved quality-of-life. Fitness was not significantly associated with disease activity. CONCLUSION: Adults with AS have significantly reduced health related physical fitness compared to population controls. Decreased body fat, and higher aerobic capacity, muscular fitness and flexibility are significantly associated with improved function. These findings have implications for clinicians assessing adults with AS, and for targeted-exercise prescription in this cohort. PMID- 26119878 TI - Stabilization of Silicon-Carbon Mixed Oxides. AB - The first carbene-stabilized silicon-carbon mixed oxide, (SiO2)2CO2 (4), was synthesized by CO2 oxidation of either carbene-stabilized disilicon, L:Si?Si:L (L: = :C{N(2,6-Pr(i)2C6H3)CH}2) (1), or carbene-stabilized Si2O3 (2) (which can be obtained via N2O oxidation of 1). The structure and bonding of 4 was probed by both experimental and computational methods. PMID- 26119881 TI - Paediatricians require more information before they routinely co-administer the meningococcal B vaccine with routine infant vaccines. AB - AIM: The four-component meningococcal serogroup B (4CMenB) vaccine was licensed by the European Medicines Agency in 2013. We evaluated current practice regarding multiple vaccines and the attitudes of paediatricians towards the 4CMenB before it became available in Austria in 2014. METHODS: We sent 1624 Austrian paediatricians an email invitation to participate in our nationwide web-based survey and 231 responded. RESULTS: Most participants regarded the 4CMenB vaccine as a long-needed and necessary tool against meningococcal B disease. However, most participants would not co-administer this vaccine with other routine infant vaccines. The survey showed that 58.9% of paediatricians already co-administered the hexavalent vaccine with the pneumococcal conjugate vaccine, but most of them would not add a third vaccine at the same visit. This was mainly due to lack of experience with the vaccine and also because they assumed that parents would not consent. Importantly, paediatricians said they wanted an explicit recommendation in the Austrian Immunisation Plan on the timing of the 4CMenB vaccine before they would confidently and routinely use it for infants. CONCLUSION: Paediatricians required more information for themselves and for parents before routinely co administering the 4CMenB vaccine. They also requested a national recommendation on its timing. PMID- 26119880 TI - Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression. AB - AIM: Aquaporins (AQPs) are the water-channels that play important roles in brain water homeostasis and in cerebral edema induced by brain injury. In this study we investigated the relationship between AQPs and a neuroprotective agent curcumin that was effective in the treatment of brain edema in mice with intracerebral hemorrhage (ICH). METHODS: ICH was induced in mice by autologous blood infusion. The mice immediately received curcumin (75, 150, 300 mg/kg, ip). The Rotarod test scores, brain water content and brain expression of AQPs were measured post ICH. Cultured primary mouse astrocytes were used for in vitro experiments. The expression of AQP1, AQP4 and AQP9 and NF-kappaB p65 were detected using Western blotting or immunochemistry staining. RESULTS: Curcumin administration dose dependently reduced the cerebral edema at d 3 post ICH, and significantly attenuated the neurological deficits at d 5 post ICH. Furthermore, curcumin dose dependently decreased the gene and protein expression of AQP4 and AQP9, but not AQP1 post ICH. Treatment of the cultured astrocytes with Fe(2+) (10-100 MUmol/L) dose-dependently increased the expression and nuclear translocation of NF-kappaB p65 and the expression of AQP4 and AQP9, which were partly blocked by co treatment with curcumin (20 MUmol/L) or the NF-kappaB inhibitor PDTC (10 MUmol/L). CONCLUSION: Curcumin effectively attenuates brain edema in mice with ICH through inhibition of the NF-kappaB pathway and subsequently the expression of AQP4 and AQP9. Curcumin may serve as a potential therapeutic agent for ICH. PMID- 26119882 TI - Peripheral arterial disease in patients with systemic lupus erythematosus: a prospective controlled study. AB - AIM: The aim of our study was to: (i) map out the presence of peripheral vascular disease in a sample of systemic lupus erythematosus (SLE) patients; and (ii) correlate our findings with disease characteristics, activity indices, traditional risk factors of atherosclerosis and thrombotic variables. METHODS: The study population comprised 120 SLE patients and 100 controls. Clinical data were collected for patients and controls with stress on clinical issues of SLE patients, including British Isles Lupus Assessment Group index score, anti-double stranded DNA titer C3 and C4 levels, and treatment taken, mainly steroids. Measurements of thrombotic variables were performed. Non-invasive arterial assessment was performed, including carotid duplex scanning and measurement of carotid artery intima-media thickness (IMT) and peripheral arterial assessment and measurement of ankle-brachial pressure index (ABPI). RESULTS: The mean age of SLE patients was 32 years and mean disease duration was 8 years. There were no statistically significant differences in the traditional vascular risk factors measured between SLE patients and controls. There were significantly higher plasma levels of thrombotic variables in SLE patients. The average IMT was statistically significantly greater in SLE patients compared to controls. Thirty SLE patients (25%) had an ABPI < 1.0 compared with six controls (6%), which was statistically significant. CONCLUSION: This study showed an increased prevalence of peripheral arterial disease in SLE patients as shown by the higher carotid artery IMT and lower ABPI in such patients compared with controls. Multiple risk factors are likely to be involved in such findings. PMID- 26119883 TI - Oxygen requirement as a screening tool for the detection of late pulmonary hypertension in extremely low birth weight infants. AB - BACKGROUND: Many extremely low birth weight infants develop pulmonary hypertension late in their clinical course, and over 60% go undetected by early screening echocardiography. At present, no standardised screening protocol exists for detecting late pulmonary hypertension in extremely low birth weight infants. We assessed the utility of oxygen supplementation as a predictor of late pulmonary hypertension. METHODS: A retrospective single-centre review of extremely low birth weight infants with no evidence of CHD and those surviving for >30 days was performed. The association between oxygen ?30% at day of life 30 and diagnosis of late pulmonary hypertension was estimated with an odds ratio and 95% confidence interval using logistic regression. Doppler echocardiography was used to diagnose pulmonary hypertension in the infants. RESULTS: A total of 230 infants met the study criteria. The incidence of late pulmonary hypertension was 8.3% (19/230). Infants with late pulmonary hypertension were more likely to have a lower mean birth weight (667.1+/-144 versus 799.3+/-140 g, p=0.001) and more likely to be small for gestational age (47.4 versus 14.2%, p=0.004). Oxygen requirement ?30% at day of life 30 was associated with increased risk of late pulmonary hypertension (odds ratio=3.77, 95% confidence interval=1.42-10.00, p=0.008) in univariate analysis and after adjusting for birth weight (odds ratio=2.47, 95% confidence interval=0.89-6.84, p=0.08). CONCLUSIONS: The need of oxygen supplementation ?30% at day of life 30 may be a good screening tool for detecting late pulmonary hypertension in extremely low birth weight infants. PMID- 26119884 TI - Lower prosthesis-specific 10-year revision rate with crosslinked than with non crosslinked polyethylene in primary total knee arthroplasty. AB - BACKGROUND AND PURPOSE: While highly crosslinked polyethylene has shown reduced in vivo wear and lower rates of revision for total hip arthroplasty, there have been few long-term studies on its use in total knee arthroplasty (TKA). We compared the rate of revision of non-crosslinked polyethylene to that of crosslinked polyethylene in patients who underwent TKA for osteoarthritis. PATIENTS AND METHODS: We examined data from the Australian Orthopaedic Association National Joint Replacement Registry on 302,214 primary TKA procedures with non-crosslinked polyethylene and 83,890 procedures with crosslinked polyethylene, all of which were performed for osteoarthritis. The survivorship of the different polyethylenes was estimated using the Kaplan-Meier method and was compared using proportional hazard models. RESULTS: The 10-year cumulative revision rate for non-crosslinked polyethylene was 5.8% (95% CI: 5.7-6.0) and for crosslinked polyethylene it was 3.5% (95% CI: 3.2-3.8) (> 6.5-year HR = 2.2 (1.5 3.1); p < 0.001). There was no effect of surgical volume or method of prosthesis fixation on outcome. There were 4 different TKA designs that had a minimum of 2,500 procedures in at least 1 of the polyethylene groups and a follow-up of >= 5 years. 2 of these, the NexGen and the Natural Knee II, had a lower rate of revision for crosslinked polyethylene. The Scorpio NRG/Series 7000 and the Triathlon Knee did not show a lower rate of revision for crosslinked polyethylene. INTERPRETATION: There is a lower rate of revision for crosslinked polyethylene in TKA, and this appears to be prosthesis-specific and when it occurs is most evident in patients < 65 years of age. The difference in revision rates was mainly due to revisions because of lysis and loosening. PMID- 26119885 TI - Diagnostic value and accuracy of imprint cytology evaluation during image-guided core needle biopsies: Review of our experience at a large academic center. AB - BACKGROUND: Several studies have emphasized the value of on-site evaluation of imprint cytology (IC) performed on core needle biopsies (CNB) of breast, prostate, and lung, in terms of adequacy. The aim of this study was to investigate the diagnostic value and accuracy of rapid on-site IC of CNB specimens performed for liver, lung, lymph node, bone, and soft tissue masses to evaluate whether on-site preliminary diagnosis is sufficiently accurate to allow earlier, more efficient planning of ancillary studies with decreased turnaround time. METHODS: This morphology-based, retrospective study was approved by our Institutional Review Board. A total of 252 consecutive CNBs with on-site IC on masses of liver, lung, lymph node, bone, and soft tissue were included in this study. IC was reviewed by two cytopathology fellows and two board-certified cytopathologists who gave a categorical diagnosis (malignant/benign/atypical) and exact diagnosis when possible. Preliminary diagnoses were compared with corresponding histological CNB diagnoses. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. RESULTS: Of the 252 cases reviewed, 30 cases were classified as atypical by IC and evaluated separately. Of the remaining 222 cases, IC classified an average of 154 (70%) as malignant, 54 (24%) as benign, and 14 (6%) as nondiagnostic. The corresponding distribution of histological diagnoses was 151 (68%) malignant and 71 (32%) benign. Overall correlation of correct IC diagnoses was 80%, with a correlation of 91% in malignant cases and 59% in benign cases. Sensitivity, specificity, PPV, and NPV were 96, 74, 92, and 87%, respectively. Diagnostic accuracy was 91%. There was no statistically significant difference in the accuracy of categorical diagnoses between IC and final histologic diagnosis. Atypical cases by IC were more likely to be malignant in lung and liver lesions (71% and 58%, respectively), than in lymph node, bone, or soft tissue lesions (17%, 0%, 0%, respectively). An exact diagnosis on IC was rendered in 113 (51%) cases, with an accuracy of 73%. Sensitivity, specificity, PPV, and NPV were 94, 41, 70, and 83%, respectively. CONCLUSION: Rapid on-site IC is a useful and valuable tool for evaluating adequacy of CNB as well as providing accurate information on a categorical basis (malignant versus benign), with greater diagnostic accuracy in cases of malignancy than for benign lesions. IC provides high sensitivity with high PPV in lung, liver, lymph node, bone, and soft tissue lesions. Exact preliminary diagnoses have good diagnostic accuracy. Considering the fundamentally different diagnostic and therapeutic approach based on histologic tumor type (e.g., in lung malignancies), on-site preliminary diagnosis may allow appropriate triaging of tissue for early planning of ancillary studies with decreased turnaround times. In addition, early diagnosis may reduce anxiety in patients and expedite treatment planning. PMID- 26119886 TI - Molecular engineering of organic dyes with a hole-extending donor tail for efficient all-solid-state dye-sensitized solar cells. AB - We report a new concept for the design of metal-free organic dyes (OD5-OD9) with an extended donor-pi-acceptor (D-pi-A) molecular framework, in which the donor terminal unit is attached by a hole-extending side chain to retard back electron transfer and charge recombination; the pi-bridge component contains varied thiophene-based substituents to enhance the light-harvesting ability of the device. The best dye (OD9) has a D-A-pi-A configuration with the hexyloxyphenylthiophene (HPT) side chain as a hole-extension component and a benzothiadiazole (BTD) internal acceptor as a pi-extension component. The co sensitization of OD9 with the new porphyrin dye LW24 enhanced the light harvesting ability to 800 nm; thus, a power conversion efficiency 5.5 % was achieved. Photoinduced absorption (PIA) and transient absorption spectral (TAS) techniques were applied to account for the observed trend of the open-circuit voltage (VOC ) of the devices. This work provides insights into the molecular design, photovoltaic performance, and kinetics of charge recombination. PMID- 26119887 TI - Rapid brief feedback intracerebral stimulation based on real-time desynchronization detection preceding seizures stops the generation of convulsive paroxysms. AB - OBJECTIVE: To investigate the abortion of seizure generation using "minimal" intervention in hippocampi using two rat models of human temporal lobe epilepsy. METHODS: The recording or stimulation electrodes were implanted into both hippocampi (CA1 area). Using the kainic acid (chronic: experiment duration 24 days) and the 4-aminopyridine (acute: experiment duration 2 h) models of paroxysms in rats, a real-time feedback stimulation paradigm was implemented, which triggered a short periodic electrical stimulus (5 Hz for 5 s) upon detecting a seizure precursor. Our seizure precursor detection algorithm relied on the monitoring of the real-time phase synchronization analysis, and detected/anticipated electrographic seizures as early as a few seconds to a few minutes before the behavioral and electrographic seizure onset, with a very low false-positive rate of the detection. RESULTS: The baseline mean seizure frequencies were 5.39 seizures per day (chronic) and 13.2 seizures per hour (acute). The phase synchrony analysis detected 88% (434 of 494) of seizures with a mean false alarm of 0.67 per day (chronic) and 83% (86 of 104) of seizures with a mean false alarm of 0.47 per hour (acute). The feedback stimulation reduced the seizure frequencies to 0.41 seizures per day (chronic) and 2.4 seizures per hour (acute). Overall, the feedback stimulation paradigm reduced seizure frequency by a minimum of 80% to a maximum of 100% in 10 rats, with 83% of the animals rendered seizure-free. SIGNIFICANCE: This approach represents a simple and efficient manner for stopping seizure development. Because of the short on-demand stimuli, few or no associated side effects are expected in clinical application in patients with epilepsy. Abnormal synchrony patterns are common features in epilepsy and other neurologic and psychiatric syndromes; therefore, this type of feedback stimulation paradigm could be a novel therapeutic modality for use in various neurologic and psychiatric disorders. PMID- 26119889 TI - Prediction impact curve is a new measure integrating intervention effects in the evaluation of risk models. AB - OBJECTIVE: We propose a new measure of assessing the performance of risk models, the area under the prediction impact curve (auPIC), which quantifies the performance of risk models in terms of their average health impact in the population. STUDY DESIGN AND SETTING: Using simulated data, we explain how the prediction impact curve (PIC) estimates the percentage of events prevented when a risk model is used to assign high-risk individuals to an intervention. We apply the PIC to the Atherosclerosis Risk in Communities (ARIC) Study to illustrate its application toward prevention of coronary heart disease. RESULTS: We estimated that if the ARIC cohort received statins at baseline, 5% of events would be prevented when the risk model was evaluated at a cutoff threshold of 20% predicted risk compared to 1% when individuals were assigned to the intervention without the use of a model. By calculating the auPIC, we estimated that an average of 15% of events would be prevented when considering performance across the entire interval. CONCLUSION: We conclude that the PIC is a clinically meaningful measure for quantifying the expected health impact of risk models that supplements existing measures of model performance. PMID- 26119888 TI - Towards allele-level human leucocyte antigens genotyping - assessing two next generation sequencing platforms: Ion Torrent Personal Genome Machine and Illumina MiSeq. AB - Human leucocyte antigens (HLA) typing has been a challenge due to extreme polymorphism of the HLA genes and limitations of the current technologies and protocols used for their characterization. Recently, next-generation sequencing techniques have been shown to be a well-suited technology for the complete characterization of the HLA genes. However, a comprehensive assessment of the different platforms for HLA typing, describing the limitations and advantages of each of them, has not been presented. We have compared the Ion Torrent Personal Genome Machine (PGM) and Illumina MiSeq, currently the two most frequently used platforms for diagnostic applications, for a number of metrics including total output, quality score per position across the reads and error rates after alignment which can all affect the accuracy of HLA genotyping. For this purpose, we have used one homozygous and three heterozygous well-characterized samples, at HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1. The total output of bases produced by the MiSeq was higher, and they have higher quality scores and a lower overall error rate than the PGM. The MiSeq also has a higher fidelity when sequencing through homopolymer regions up to 9 bp in length. The need to set phase between distant polymorphic sites was more readily achieved with MiSeq using paired-end sequencing of fragments that are longer than those obtained with PGM. Additionally, we have assessed the workflows of the different platforms for complexity of sample preparation, sequencer operation and turnaround time. The effects of data quality and quantity can impact the genotyping results; having an adequate amount of good quality data to analyse will be imperative for confident HLA genotyping. The overall turnaround time can be very comparable between the two platforms; however, the complexity of sample preparation is higher with PGM, while the actual sequencing time is longer with MiSeq. PMID- 26119890 TI - A core syllabus for the teaching of neuroanatomy to medical students. AB - There is increasingly a call for clinical relevance in the teaching of biomedical sciences within all health care courses. However, this presupposes that there is a clear understanding of what can be considered core material within the curricula. To date, the anatomical sciences have been relatively poorly served by the development of core syllabuses, particularly for specialized core syllabuses such as neuroanatomy. One of the aims of the International Federation of Associations of Anatomists (IFAA) and of the European Federation for Experimental Morphology (EFEM) is to formulate, on an international scale, core syllabuses for all branches of the anatomical sciences using Delphi Panels consisting of anatomists, scientists, and clinicians to initially evaluate syllabus content. In this article, the findings of a Delphi Panel for neuroanatomy are provided. These findings will subsequently be published on the IFAA website to enable anatomical (and other cognate learned) societies and individual anatomists, clinicians, and students to freely comment upon, and elaborate and amend, the syllabuses. The aim is to set internationally recognized standards and thus to provide guidelines concerning neuroanatomical knowledge when engaged in course development. PMID- 26119891 TI - Comparative analysis of the antioxidant and anticancer activities of chestnut inner shell extracts prepared with various solvents. AB - BACKGROUND: The chestnut inner shell (CIS) has long been used as a medicinal herb for strengthening the antioxidant in the cosmetic industry. However, little is known about the antioxidant and anticancer effects of the CIS. RESULTS: The antioxidant and anticancer effects of CIS extracts (CISEs) were investigated by the use of various methods and cancer cell lines, respectively. The total polyphenol content of CISEs using ethanol, methanol, butanol, ethyl acetate and water were 53.30, 43.98, 32.16, 26.79 and 11.53 mg gallic acid equivalents g(-1), respectively. The CISEs using ethanol and methanol exhibited high antioxidant activities in the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity, beta carotene bleaching and ferric reducing ability of plasma assays; the effects were equivalent to those of butylated hydroxytoluene. All CISEs at 2.5 mg mL(-1) were shown to have a cytotoxic effect over 50%, and the CISE using ethyl acetate at 0.6 mg mL(-1) was proved to have 90% cytotoxic effect against the tested cancer cells. CONCLUSION: The ethanol and methanol CISEs had potent antioxidant effects, and the ethyl acetate CISE had the highest cytotoxicity. These results suggest that CISEs could be used as functional ingredients for antioxidant and anticancer effects in foods as extraction solvents. PMID- 26119892 TI - Bilateral Decompression via Microscopic TubularCrossing Laminotomy (MTCL) for Lumbar Spinal Stenosis: Technique and Early Surgical Result. AB - The purpose of this study was to determine the feasibility and efficacy of bilateral decompression procedure via microscopic tubular crossing laminotomy (MTCL) for treating lumbar spinal stenosis (LSS). Seventeen patients with LSS underwent bilateral decompression via an MTCL procedure in which tubular retractor was placed. The mean age was 72 (range 59-84) years and there were 10 men and 7 women. All patients underwent pre- and postoperative dynamic lumbar x ray, magnetic resonance (MR) image, and computed tomography. To verify the efficacy of this technique, pre- and postoperative cross-sectional area (CSA) of thecal sac, facet resection, and fatty infiltration (FI) of multifidus were measured. Clinical results were evaluated using Oswestry Disability Index (ODI), back and leg visual analog scale (VAS). The mean follow-up period was 17.5 months (range 12.1-21.2). 70.5% of MTCL was performed at the level of L4-5 and one case of dural violation (5.8%) was noted at the level of L5-S1. The mean preoperative CSA was 70.5 mm(2) (range 25.1-87.6) and it increased to 198.8 mm(2) (range 177.3 219.2) postoperatively (p = 0.00). The mean facet resection rate was 18.4% (range 9.9-26.9) and no radiological instability was noted postoperatively. MR image showed no increase in FI of the multifidus after 12 months of follow-up (p = 0.53). Preoperative clinical symptoms improved significantly at postoperative 6 months and 12 months of follow-up. These results indicate that an MTCL with use of tubular retractor system can be an effective procedure to achieve neural decompression for the treatment of LSS and it may be beneficial in preserving both facet joint and multifidus muscle. PMID- 26119893 TI - Single-stage Anterior and Posterior Fusion Surgery for Correction of Cervical Kyphotic Deformity Using Intervertebral Cages and Cervical Lateral Mass Screws: Postoperative Changes in Total Spine Sagittal Alignment in Three Cases with a Minimum Follow-up of Five Years. AB - The surgical treatment of cervical kyphotic deformity remains challenging. As a surgical method that is safer and avoids major complications, the authors present a procedure of single-stage anterior and posterior fusion to correct cervical kyphosis using anterior interbody fusion cages without plating, as illustrated by three consecutive cases. Case 1 was a 78-year-old woman who presented with a dropped head caused by degeneration of her cervical spine. Case 2 was a 54-year old woman with athetoid cerebral palsy. She presented with cervical myelopathy and cervical kyphosis. Case 3 was a 71-year-old woman with cervical kyphotic deformity following a laminectomy. All three patients underwent anterior release and interbody fusion with cages and posterior fusion with cervical lateral mass screw (LMS) fixation. Postoperative radiographs showed that correction of kyphosis was 39 degrees in case 1, 43 degrees in case 2, and 39 degrees in case 3. In all three cases, improvement of symptoms was established without major perioperative complications, solid fusion was achieved, and no loss of correction was observed at a minimum follow-up of 61 months. We also report that preoperative total spine sagittal malalignment was improved after corrective surgery for cervical kyphosis and was maintained at the latest follow-up in all three cases. The combination of anterior fusion cages and LMS is considered a safe and effective procedure in cases of severe cervical kyphotic deformity. Preoperative total spine sagittal malalignment improved, accompanied by correction of cervical kyphosis, and was maintained at last follow-up in all three cases. PMID- 26119894 TI - Rate of Hanger Reflex Occurrence: Unexpected Head Rotation on Fronto-temporal Head Compression. AB - When the head is encircled with a wire clothes hanger and the unilateral fronto temporal region is compressed, the head rotates unexpectedly. As the mechanism is unclear, however, we have temporarily named this phenomenon as the "hanger reflex." We previously reported a case wherein this phenomenon was applied to treat cervical dystonia. Because little is known about this phenomenon, we determined how often this phenomenon is observed in healthy subjects. Study participants were 120 healthy Japanese adults (60 men and 60 women) aged 19-65 years. A wire clothes hanger was applied to each subject's head. The longer side of the hanger was attached over the volunteer's fronto-temporal regions on both sides of the head in succession (i.e., two applications per volunteer). We evaluated whether the subjects felt the sensation of head rotation by using a questionnaire. The sensation of head rotation was observed in 95.8% of subjects. There were five non-responders (4.2%). In 85.4% of the trials, head rotation was observed in the direction that coincided with the side compressed by the hanger. There were no differences in responses between genders. The incident rate of the hanger reflex was remarkably high and most likely represents a prevalent phenomenon in humans. The mechanism underlying the reflex remains unknown. Further research should be performed to elucidate the underlying causes of the hanger reflex, which represents a potential treatment for cervical dystonia. PMID- 26119895 TI - Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Disorders: Mini open TLIF and Corrective TLIF. AB - Minimally invasive transforaminal lumbar interbody fusion (TLIF) as a short fusion is widely accepted among the spine surgeons. However in the long fusion for degenerative kyphoscoliosis, corrective spinal fixation by an open method is thought to be frequently selected. Our objective is to study whether the mini open TLIF and corrective TLIF contribute to the improvement of the spinal segmental and global alignment. We divided the patients who performed lumbar fixation surgery into three groups. Group 1 (G1) consisted of mini-open TLIF procedures without complication. Group 2 (G2) consisted of corrective TLIF without complication. Group 3 (G3) consisted of corrective TLIF with instrumentation-related complication postoperatively. In all groups, the lumbar lordosis (LL) highly correlated with developing surgical complications. LL significantly changed postoperatively in all groups, but was not corrected in the normal range in G3. There were statistically significant differences in preoperative and postoperative LL and mean difference between the pelvic incidence (PI) and LL between G3 and other groups. The most important thing not to cause the instrumentation-related failure is proper correction of the sagittal balance. In the cases with minimal sagittal imbalance with or without coronal imbalance, short fusion by mini-open TLIF or long fusion by corrective TLIF contributes to good clinical results if the lesion is short or easily correctable. However, if the patients have apparent sagittal imbalance with or without coronal imbalance, we should perform proper correction of the sagittal spinal alignment introducing various technologies. PMID- 26119896 TI - Anatomical Reproducibility of a Head Model Molded by a Three-dimensional Printer. AB - We prepared rapid prototyping models of heads with unruptured cerebral aneurysm based on image data of computed tomography angiography (CTA) using a three dimensional (3D) printer. The objective of this study was to evaluate the anatomical reproducibility and accuracy of these models by comparison with the CTA images on a monitor. The subjects were 22 patients with unruptured cerebral aneurysm who underwent preoperative CTA. Reproducibility of the microsurgical anatomy of skull bone and arteries, the length and thickness of the main arteries, and the size of cerebral aneurysm were compared between the CTA image and rapid prototyping model. The microsurgical anatomy and arteries were favorably reproduced, apart from a few minute regions, in the rapid prototyping models. No significant difference was noted in the measured lengths of the main arteries between the CTA image and rapid prototyping model, but errors were noted in their thickness (p < 0.001). A significant difference was also noted in the longitudinal diameter of the cerebral aneurysm (p < 0.01). Regarding the CTA image as the gold standard, reproducibility of the microsurgical anatomy of skull bone and main arteries was favorable in the rapid prototyping models prepared using a 3D printer. It was concluded that these models are useful tools for neurosurgical simulation. The thickness of the main arteries and size of cerebral aneurysm should be comprehensively judged including other neuroimaging in consideration of errors. PMID- 26119897 TI - Inflammation Level after Decompression Surgery for a Rat Model of Chronic Severe Spinal Cord Compression and Effects on Ischemia-Reperfusion Injury. AB - Delayed neurological deterioration in the absence of direct spinal cord insult following surgical decompression is a severe postoperative complication in patients with chronic severe spinal cord compression (SCC). The spinal cord ischemia-reperfusion injury (IRI) has been verified as a potential etiology of the complication. However, the exact pathophysiologic mechanisms of the decompression-related IRI remain to be defined. In this study, we developed a practical rat model of chronic severe SCC. To explore the underlying role of inflammation in decompression-related IRI, immunoreactivity of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) before and after decompression were measured. In addition, expression level of TNF-alpha and IL-1beta was examined with Western blot. Immunohistochemical staining showed negative result in gray matters in the sham group and sham-decompression group. In the severe compression group, strong positive staining of TNF-alpha and IL-1beta were found, suggesting a dramatic infiltration of inflammatory cells in gray matters. Furthermore, the severe compression group showed a significant increase in expression level of TNF-alpha and IL-1beta as compared with the sham group (p < 0.05). In the severe compression-decompression group, both immunostaining and Western blot showed significant increase of TNF-alpha and IL-1beta levels in the spinal cord compared with the severe compression group (p < 0.05). The results demonstrated that surgical decompression plays a stimulative role in inflammation through increasing the expression of inflammatory cytokines in the rat model of chronic severe SCC injury. Inflammation may be one of the important pathological mechanisms of decompression-related IRI of chronic ischemia. PMID- 26119898 TI - Cervical Laminoplasty: The History and the Future. AB - Cervical laminoplasty was developed as an alternative to cervical laminectomy for treatment of cervical myelopathy, in which hinges are created to lift the lamina. Various techniques of laminoplasty have since been developed after two prototype techniques: Hirabayashi's open-door laminoplasty and Kurokawa's spinous process splitting (double-door) laminoplasty. Several in vitro studies report superior biomechanical stability of the cervical spine after laminoplasty compared with laminectomy. In clinical situation, randomized control studies are scarce and superiority of one procedure over another is not uniformly shown. Lack of hard evidence supporting the purported advantages of laminoplasty over laminectomy, that is, reduced rate of postoperative instability and kyphosis development, while preserving range of motion (ROM), has been a weak selling point. Currently, laminoplasty is performed by majority of spine surgeons in Japan, but is rarely performed in the United States and Europe. Recent development in laminoplasty is preservation of muscle attachment, which enabled dynamic stabilization of the cervical spine by neck extensor muscles. After treatment with new laminoplasty techniques with active postoperative neck ROM exercises, postoperative instability, kyphosis, axial neck pain, and loss of ROM seems minimal. Well designed clinical trials to show the effectiveness and long-term outcome of this surgical procedure are warranted. PMID- 26119899 TI - Anterior Cervical Spine Surgery for Degenerative Disease: A Review. AB - Anterior cervical spine surgery is an established surgical intervention for cervical degenerative disease and high success rate with excellent long-term outcomes have been reported. However, indications of surgical procedures for certain conditions are still controversial and severe complications to cause neurological dysfunction or deaths may occur. This review is focused mainly on five widely performed procedures by anterior approach for cervical degenerative disease; anterior cervical discectomy, anterior cervical discectomy and fusion, anterior cervical corpectomy and fusion, anterior cervical foraminotomy, and arthroplasty. Indications, procedures, outcomes, and complications of these surgeries are discussed. PMID- 26119900 TI - Surgical Strategies for Cervical Spinal Neurinomas. AB - Cervical spinal neurinomas are benign tumors that arise from nerve roots. Based on their location, these tumors can also take the form of a dumbbell-shaped mass. Treatment strategies for these tumors have raised several controversial issues such as appropriate surgical indications and selection of surgical approaches for cervical dumbbell-shaped spinal neurinomas. In this report, we review previous literature and retrospectively analyze cervical spinal neurinoma cases that have been treated at our hospital. Surgical indications and approaches based on tumor location and severity are discussed in detail. Thus, with advances in neuroimaging and neurophysiological monitoring, we conclude that appropriate surgical approaches and intraoperative surgical manipulations should be chosen on a case-by-case basis. PMID- 26119901 TI - Snapping Hip due to Gluteus Medius Tendinopathy: Ultrasound Imaging in the Diagnosis and Guidance for Prolotherapy. PMID- 26119903 TI - Community Factors in Differential Responses of Child Protective Services. AB - OBJECTIVE: In response to criticisms of the traditional investigative model of child protective services (CPS) as adversarial, a Differential Response Model has emerged, with investigative and noninvestigative alternative response (AR) paths. The purpose of this study was to identify relationships of county-level community variables to response paths. DESIGN AND SAMPLE: Secondary analysis used data from the National Child Abuse and Neglect Data System linked to county-level variables from the American Community Survey. The final dataset included 62,499 cases and 98 counties from five states. MEASURES: Multilevel modeling was used to analyze the binary outcome variable of CPS response path (AR, non-AR). Predictor variables included indicators at child, county, and state levels. RESULTS: County level variables (housing vacancy, child poverty, unemployment, and households with public assistance) were significant predictors (p < .05) of CPS response path and accounted for 12.30% of variability in the final three-level model. Individual variables (report source, maltreatment type, child age, race, and number of children in the report) were also significant predictors. CONCLUSION: County-level community variables have significant relationships with CPS response paths and impact how CPS units respond to new referrals. Research is needed to apply advanced multilevel analytic procedures to more accurately model nested relationships. PMID- 26119904 TI - Hazards with ordering troponin in patients with low pretest probability of acute coronary syndrome. AB - BACKGROUND: In clinical practice, we progressively rely on biomarkers, without estimating the pretest probability. There is not enough support for the use of cardiac troponin (cTn) I in the management of noncardiac patients. We studied the rate at which this test was ordered, the prevalence of detection of a positive result in noncardiac patients, and the impact of this incidental finding on clinical management. METHODOLOGY: Patients admitted from December 2011 to 2013 to our community hospital with diagnosis of noncardiac disease who had positive cTn were included. Data collected included final diagnosis, patient disposition, cardiac monitoring, cardiology consult, and cardiac biomarker testing. RESULTS: Cardiac troponin I was ordered for 1700 patients in our emergency department. Seven hundred fifty patients had a positive cTn. Of the 750 patients, 412 had a positive cTn without any clinical suspicion of an acute coronary syndrome. An incidental finding of a positive cTn leads to ordering of cTn on average 4 times during admission, cardiac monitoring of 379 (91.99%) patients for at least 1 day, and a cardiac consultation for 268 (63.65%) of these patients. None of these patients was candidates for an invasive cardiac intervention. Seventy-eight (19.17%) patients were admitted to the cardiac care unit and subsequently transferred to the medical intensive care unit. CONCLUSIONS: A positive cTn in patients diagnosed with a nonacute coronary syndrome was associated with increased cardiac biomarker testing, telemetry monitoring, and cardiology consults. This study supports adherence to national guidelines for the use of cTn, to reduce hospital cost and resource utilization. PMID- 26119905 TI - Overtreatment of gonorrhea and chlamydial infections in 2 inner-city emergency departments. AB - BACKGROUND: Infections with Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) are the most commonly reported sexually transmitted diseases in the United States. OBJECTIVES: The primary objective of this study was to estimate the incidence of overtreatment of GC and CT infections in the emergency department (ED). The secondary objective was to determine if there are clinical variables that predict infection with GC and CT. METHODS: A retrospective medical record review was performed at 2 inner-city hospitals. Records were obtained from the evaluation of female patients who presented to the ED between January 1, 2012, and December 31, 2012, who were tested for GC and CT infection. A standardized form was used to extract specific information from each medical record. RESULTS: Data were extracted from 538 medical records. Of the 522 ED visits, 32 (6%) yielded test results positive for either GC or CT, including 3 that were positive for both. Treatment was administered to 101 patients (19%) and declined by an additional 9 (2%). Of those receiving antibiotics, 87 of 101 (0.86; 95% confidence interval, 0.77-0.92) had negative test results. Of those not offered antibiotics, 17 of 412 (0.04; 95% confidence interval, 0.02-0.07) had positive test results. The overtreatment proportion was similar at hospitals (55/66 [0.83] and 32/35 [0.91], respectively). Of clinical variables that were considered, only age less than 19 years was statistically associated with a positive test result for GC and CT. CONCLUSION: The rate of overtreatment for GC and CT was 86%. The practice of empirical treatment should be reconsidered. PMID- 26119906 TI - Multidimensional Design of Anticancer Peptides. AB - The computer-assisted design and optimization of peptides with selective cancer cell killing activity was achieved through merging the features of anticancer peptides, cell-penetrating peptides, and tumor-homing peptides. Machine-learning classifiers identified candidate peptides that possess the predicted properties. Starting from a template amino acid sequence, peptide cytotoxicity against a range of cancer cell lines was systematically optimized while minimizing the effects on primary human endothelial cells. The computer-generated sequences featured improved cancer-cell penetration, induced cancer-cell apoptosis, and were enabled a decrease in the cytotoxic concentration of co-administered chemotherapeutic agents in vitro. This study demonstrates the potential of multidimensional machine-learning methods for rapidly obtaining peptides with the desired cellular activities. PMID- 26119908 TI - Minimally invasive transnasal approach to infratemporal fossa abscess. AB - BACKGROUND: Infratemporal fossa abscess following odontogenic infection is not rare, and usually occurs as a sequela of dental disease. Infratemporal fossa abscess was previously treated with the combination of buccal incision and temporal incision, or via a transoral approach. METHOD: This paper reports a case of infratemporal fossa abscess in a 51-year-old female. RESULTS: The abscess was drained transnasally via an endoscopic modified medial maxillectomy approach, preserving the inferior turbinate and nasolacrimal duct. The pain remitted the next day and trismus had diminished in one week. CONCLUSION: The transnasal approach with endoscopic modified medial maxillectomy is a direct, minimally invasive method that provides a direct field of view for drainage of infratemporal fossa abscess. This approach is recommended for infratemporal fossa abscess. PMID- 26119907 TI - Molecular characterization of heat-shock protein 90 gene and its expression in Gobiocypris rarus juveniles exposed to pentachlorophenol. AB - Heat-shock protein 90 (HSP90) is an abundant and highly conserved molecular chaperone, and it fulfills a housekeeping function in contributing to the folding, maintenance of structural integrity, and proper regulation of a subset of cytosolic proteins. In this study, the full-length 2693-bp cDNA of HSP90 was cloned by rapid amplification of cDNA ends (RACE) technique from the liver of rare minnow (Gobiocypris rarus) for the first time, designated as GrHSP90. The complete coding sequence of GrHSP90 is 2181 bp in length, which encodes a polypeptide of 726 amino acids with a predicted molecular mass of 83.4 kDa and a theoretical isoelectric point of 4.90. Phylogenetic tree analysis indicated that deduced protein GrHSP90 had extensive sequence similarities to other fish HSP90s. Tissue distribution showed that GrHSP90 was constitutively expressed in a wide range of tissues including gill, blood, brain, fin, gonad, heart, intestine, kidney, liver, muscle, spleen, skin, and swim bladder. The highest expression was found in the gonad. Furthermore, significant increase in GrHSP90 mRNA in the liver was observed after exposure to pentachlorophenol >=8 ug/L (p < 0.05). Our results suggest that GrHSP90 is indeed an ortholog of the HSP90 family and may be act as a biomarker to assess the effect of environmental contaminant. PMID- 26119909 TI - Glucagon and GLP-1 exhibit no synergistic enhancement of glucose-stimulated insulin secretion in mice. AB - The combination of glucagon and glucagon-like peptide-1 (GLP-1) has been suggested as an approach to target obesity, since the two hormones have complementary action on body weight. We examined whether complementary action of the two hormones also exist on insulin secretion. Female C57BL/6 mice were injected intravenously with glucose with or without GLP-1, glucagon or the combination of GLP-1 and glucagon at three different dose levels. Furthermore, freshly isolated mouse islets were incubated for 30min in the presence of 2.8, 11.1 or 16.7mmol/l glucose or with 11.1mmol/l glucose in the presence of 100nmol/l glucagon and/or GLP-1. It was found that at 1min after glucose injection alone, insulin rose to a peak level and this peak, as well as the 50min area under the insulin curve (AUC insulin) were dose-dependently augmented by GLP 1 and glucagon. However, peak insulin with the two hormones together (with glucose) was not higher than after either single administration at any of the tested doses, i.e., no additive of synergistic action was observed by the combination on glucose-stimulated insulin secretion. Similar results were observed when calculating insulin for the whole test period. Also in vitro, both glucagon and GLP-1 augmented insulin secretion; however, there was no difference between the combined stimulation of insulin secretion by GLP-1 and glucagon together compared with either hormone alone. Insulin sensitivity did not exhibit significant changes from the glucose only condition. We conclude that the acute combined administration of the strongly insulinotropic GLP-1 and glucagon, both in vivo and in vitro, did not induce any additive or synergistic action on glucose-stimulated insulin secretion. This shows that the risk of a marked insulinotropic action when the two compounds are given together most likely does not result in increased risk of hypoglycemia. PMID- 26119910 TI - Anion-, Solvent-, Temperature-, and Mechano-Responsive Photoluminescence in Gold(I) Diphosphine-Based Dimers. AB - A series of [Au2 (nixantphos)2](X)2 (nixantphos=4,6-bis(diphenylphosphino) phenoxazine; X=NO3, 1; CF3 COO, 2; CF3 SO3, 3; [Au(CN)2], 4; and BF4, 5) complexes that exhibit intriguing anion-switchable and stimuli-responsive luminescent photophysical properties have been synthesized and characterized. Depending on their anions, these complexes display yellow (3), orange (4 and 5), and red (1 and 2) emission colors. They exhibit reversible thermo-, mechano-, and vapochromic luminescence changes readily perceivable by the naked eye. Single crystal X-ray studies show that the [Au2 (nixantphos)2](2+) cations with short intramolecular Au???Au interactions are involved as donors in an infinite N-H???X (X=O and N) hydrogen-bonded chain formation with CF3 COO(-) (2 C) and aurophilically linked [Au(CN)2](-) counterions (4 C). Both crystals show thermochromic luminescence; their room temperature red (2 C) and orange (4 C) emission turns into yellow upon cooling to 77 K. They also exhibit reversible mechanochromic luminescence by changing their emission color from red to dark (2 C), and orange to red (4 C). Compounds 1-5 also display reversible mechanochromic luminescence, altering their emission colors between orange (1) or red (2) to dark, as well as between yellow (3) or orange (4 and 5) to red. Detailed photophysical investigations and correlation with solid-state structural data established the significant role of N?H???X interactions in the stimuli responsive luminescent behavior. PMID- 26119911 TI - Silver nanoparticles embedded mesoporous SiO2 nanosphere: an effective anticandidal agent against Candida albicans 077. AB - Candida albicans is a diploid fungus that causes common infections such as denture stomatitis, thrush, urinary tract infections, etc. Immunocompromised patients can become severely infected by this fungus. Development of an effective anticandidal agent against this pathogenic fungus, therefore, will be very useful for practical application. In this work, Ag-embedded mesoporous silica nanoparticles (mSiO2@AgNPs) have successfully been synthesized and their anticandidal activities against C. albicans have been studied. The mSiO2@AgNPs nanoparticles (d ~ 400 nm) were designed using pre-synthesized Ag nanoparticles and tetraethyl orthosilicate (TEOS) as a precursor for SiO2 in the presence of cetyltrimethyl ammonium bromide (CTAB) as an easily removable soft template. A simple, cost-effective, and environmentally friendly approach has been adopted to synthesize silver (Ag) nanoparticles using silver nitrate and leaf extract of Azadirachta indica. The mesopores, with size-equivalent diameter of the micelles (d = 4-6 nm), were generated on the SiO2 surface by calcination after removal of the CTAB template. The morphology and surface structure of mSiO2@AgNPs were characterized through x-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), particle size analysis (PSA), atomic force microscopy (AFM), field emission scanning electron microscopy (FESEM), Brunauer-Emmett-Teller (BET) and high-resolution transmission electron microscopy (HRTEM). The HRTEM micrograph reveals the well-ordered mesoporous structure of the SiO2 sphere. The antifungal activities of mSiO2@AgNPs on the C. albicans cell have been studied through microscopy and are seen to increase with increasing dose of mSiO2@AgNPs, suggesting mSiO2@AgNPs to be a potential antifungal agent for C. albicans 077. PMID- 26119912 TI - Examining the cognitive costs of counterfactual language comprehension: Evidence from ERPs. AB - Recent empirical research suggests that understanding a counterfactual event (e.g. 'If Josie had revised, she would have passed her exams') activates mental representations of both the factual and counterfactual versions of events. However, it remains unclear when readers switch between these models during comprehension, and whether representing multiple 'worlds' is cognitively effortful. This paper reports two ERP studies where participants read contexts that set up a factual or counterfactual scenario, followed by a second sentence describing a consequence of this event. Critically, this sentence included a noun that was either consistent or inconsistent with the preceding context, and either included a modal verb to indicate reference to the counterfactual-world or not (thus referring to the factual-world). Experiment 2 used adapted versions of the materials used in Experiment 1 to examine the degree to which representing multiple versions of a counterfactual situation makes heavy demands on cognitive resources by measuring individuals' working memory capacity. Results showed that when reference to the counterfactual-world was maintained by the ongoing discourse, readers correctly interpreted events according to the counterfactual world (i.e. showed larger N400 for inconsistent than consistent words). In contrast, when cues referred back to the factual-world, readers showed no difference between consistent and inconsistent critical words, suggesting that they simultaneously compared information against both possible worlds. These results support previous dual-representation accounts for counterfactuals, and provide new evidence that linguistic cues can guide the reader in selecting which world model to evaluate incoming information against. Crucially, we reveal evidence that maintaining and updating a hypothetical model over time relies upon the availability of cognitive resources. PMID- 26119913 TI - The significance of caudate volume for age-related associative memory decline. AB - Aging comes along with reduced gray matter (GM) volume in several cerebral areas and with cognitive performance decline in different cognitive domains. Moreover, regional GM volume is linked to specific cognitive sub processes in older adults. However, it remains unclear which regional changes in older individuals are directly associated with decreased cognitive performance. Moreover, most of the studies on this topic focused on hippocampal and prefrontal brain regions and their relation to memory and executive functioning. Interestingly, there are only a few studies that reported an association between striatal brain volume and cognitive performance. This is insofar surprising that striatal structures are (1) highly affected by age and (2) involved in different neural circuits that serve intact cognition. To address these issues, voxel-based morphometry (VBM) was used to analyze GM volume in 18 younger and 18 older adults. Moreover, several neuropsychological tests from different neuropsychological test batteries were applied to assess a broad range of cognitive domains. Older adults showed less GM volume than younger adults within frontal, striatal, and cerebellar brain regions. In the group of older adults, significant correlations were found between striatal GM volume and memory performance and between prefrontal/temporal GM volume and executive functioning. The only direct overlap between brain regions associated with regional atrophy and cognitive performance in older adults was found for the right caudate: older adults showed reduced caudate volume relative to younger adults. Moreover, caudate volume was positively correlated with associative memory accuracy in older adults and older adults showed poorer performances than younger adults in the respective associative memory task. Taken together, the current findings indicate the relevance of the caudate for associative memory decline in the aging brain. PMID- 26119914 TI - Effect of maternal exercise on biochemical parameters in rats submitted to neonatal hypoxia-ischemia. AB - Pregnancy is a critical period for brain metabolic programming, being affected by individual environment, such as nutrition, stress, and physical exercise. In this context, we previously reported a cerebral antioxidant upregulation and mitochondrial biogenesis in the offspring delivered from exercised mothers, which could provide neuroprotection against neonatal insults. Hypoxia-ischemia (HI) encephalopathy is one of the most studied models of neonatal brain injury; disrupting motor, cognitive, and learning abilities. Physiopathology includes oxidative stress, allied to mitochondria energy production failure, glutamatergic excitotoxicity, and cell death. In this study we evaluated the effect of maternal swimming during pregnancy on offspring's brain oxidative status evaluated fourteen days after HI stablishment. Swimming exercise was performed by female adult rats one week before and during pregnancy, in controlled environment. Their offspring was submitted to HI on postnatal day 7, and the brain samples for biochemical assays were obtained in the weaning. Contrary to our expectations, maternal exercise did not prevent the oxidative alterations observed in brain from HI-rats. In a general way, we found a positive modulation in the activities of antioxidant enzymes, measured two weeks after HI, in hippocampus, striatum, and cerebellum of pups delivered from exercised mothers. Reactive species levels were modulated differently in each structure evaluated. Considering the scenery presented, we concluded that HI elicited a neurometabolic adaptation in both brain hemispheres, particularly in hippocampus, parietal cortex, and cerebellum; while striatum appears to be most damaged. The protocol of aerobic maternal exercise was not enough to fully prevent HI-induced brain damages. PMID- 26119915 TI - Dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation. AB - Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. Oral DHEA administration elicits neuroprotection and cognitive improvement, but mechanisms underlying these functions in cerebral ischemia have remained unclear. Since DHEA is the endogenous ligand for the sigma-1 receptor (sigma1R), we determined whether oral DHEA administration prevents neuronal cell death and improves cognition via sigma1R stimulation in brain ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. Twenty-four hours after BCCAO ischemia, mice were administered DHEA (15 or 30mg/kg p.o.) daily for 11 consecutive days. Memory deficits following brain ischemia were improved by DHEA administration dose-dependently. Accordingly, DHEA administration significantly prevented neuronal cell death in the hippocampal CA1 region in BCCAO mice. Interestingly, DHEA administration rescued decreases in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) in the CA1 region. Moreover, DHEA administration significantly ameliorated decreases in adenosine 5' triphosphate (ATP) levels and decreased sigma1R expression levels in CA1 following BCCAO ischemia. Finally, co-treatment of mice with the sigma1R antagonist NE-100 (1mg/kg, p.o.) blocked DHEA effects on memory improvement and neuroprotection in ischemic mice. Taken together, DHEA prevents neuronal cell death and activates CaMKII via sigma1R stimulation, thereby improving cognitive deficits following brain ischemia. PMID- 26119917 TI - Adaptation of the cortical somatosensory evoked potential following pulsed pneumatic stimulation of the lower face in adults. AB - Cortical adaptation to sustained sensory input is a pervasive form of short-term plasticity in neurological systems. Its role in sensory perception in health and disease, or predicting long-term plastic changes resulting from sensory training offers insight into the mechanisms of somatosensory and sensorimotor processing. A 4-channel electroencephalography (EEG) recording montage was placed bilaterally (C3-P3, C4-P4, F7-P3, F8-P4) to characterize the short-term effects of pulsed pneumatic orofacial stimulation on the cortical somatosensory evoked potential (cSEP) in twenty neurotypical adults (mean age=21+/-2.88 years). A servo controlled pneumatic amplifier was used to deliver a repetitive series of pneumatic pulse trains (six 50-ms pulses, 5-second intertrain interval) through a linked pair of custom acetal homopolymer probes (aka TAC-Cells) adhered to the nonglabrous skin of the lower face proximal to the right oral angle to synchronously activate mechanoreceptive afferents in the trigeminal nerve. Blocks of pulse trains were counterbalanced among participants and delivered at two rates, 2 and 4Hz. TAC-Cell stimulation of the lower face consistently evoked a series of cSEPs at P7, N20, P28, N38, P75, N85, and P115. The spatial organization and adaptation of the evoked cSEP was dependent on stimulus pulse index (1-6 within the pulse train, p=.012), frequency of stimulus presentation (2 vs 4Hz, p<.001), component (P7-P115, p<.001), and recording montage (channels 1 4, p<.001). Early component latencies (P7-N20) were highly stable in polarity (sign) and latency, and consistent with putative far-field generators (e.g., trigeminal brainstem, ventroposteromedial thalamus). PMID- 26119916 TI - The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs) via calpain-1 inhibition in a mouse model: Relevance for Parkinson's disease therapy. AB - Lithium has recently been suggested to have neuroprotective effects in several models of neurodegenerative disease including Parkinson's disease (PD). Levodopa (l-Dopa) replacement therapy remains the most common and effective treatment for PD, although it induces the complication of l-Dopa induced dyskinesia after years of use. Here we examined the potential use of lithium in combination with l Dopa/Carbidopa for both reducing MPTP-induced abnormal involuntary movements (AIMs) as well as protecting against cell death in MPTP-lesioned mice. Chronic lithium administration (0.127% LiCl in the feed) in the presence of daily l Dopa/Carbidopa injection for a period of 2 months was sufficient to effectively reduce MPTP-induced AIMs in mice. Mechanistically, lithium was found to suppress MPTP-induced calpain activities in vivo coinciding with down-regulation of calpain-1 but not calpain-2 expression in both the striatum (ST) and the brain stem (BS). Calpain inhibition has previously been associated with increased levels of the rate-limiting enzyme in dopamine synthesis, tyrosine hydroxylase (TH), which is probably mediated by the up-regulation of the transcription factors MEF-2A and 2D. Lithium was found to induce up-regulation of TH expression in the ST and the BS, as well as in N27 rat dopaminergic cells. Further, histone acetyltransferase (HAT) expression was substantially up-regulated by lithium treatment in vitro. These results suggest the potential use of lithium in combination with l-Dopa/Carbidopa not only as a neuroprotectant, but also for reducing AIMs and possibly alleviating potential side-effects associated with the current treatment for PD. PMID- 26119918 TI - Neural measures of a Japanese consonant length discrimination by Japanese and American English listeners: Effects of attention. AB - This study examined automaticity of discrimination of a Japanese length contrast for consonants (mi?i vs. mi??i) in native (Japanese) and non-native (American English) listeners using behavioral measures and the event-related potential (ERP) mismatch negativity (MMN). Attention to the auditory input was manipulated either away from the auditory input via a visual oddball task (Visual Attend), or to the input by asking the listeners to count auditory deviants (Auditory Attend). Results showed a larger MMN when attention was focused on the consonant contrast than away from it for both groups. The MMN was larger for consonant duration increments than decrements. No difference in MMN between the language groups was observed, but the Japanese listeners did show better behavioral discrimination than the American English listeners. In addition, behavioral responses showed a weak, but significant correlation with MMN amplitude. These findings suggest that both acoustic-phonetic properties and phonological experience affects automaticity of speech processing. This article is part of a Special Issue entitled SI: Prediction and Attention. PMID- 26119919 TI - In vitro and in vivo dermal absorption assessment of acetyl aspartic acid: a compartmental study. AB - OBJECTIVE: The purpose of this study was to evaluate the dermal absorption of acetyl aspartic acid (A-A-A) through an in vitro and in vivo evaluation with human skin after 6 and 24 h of topical application of a cosmetic formulation containing A-A-A at 1%. METHODS: The in vitro experiment was carried out using the Franz diffusion cells system with ex vivo human skin samples. The profile of diffusion of A-A-A was evaluated after 6 and 24 h. The in vivo experiment was performed on human volunteers following a tape-stripping protocol after 6 h of topical application. A-A-A was quantified in the main skin compartments, that is the skin surface, the stratum corneum, the skin and the receptor fluid using LC MS analysis. RESULTS: The 24-h in vitro experiment confirmed the great penetration potential of A-A-A in all skin compartments. After 6 h of topical application, the removed tape strips from both in vitro and in vivo experiments were analysed and the profile of diffusion of A-A-A was determined, allowing also an in vitro/in vivo comparison. The diffusion profile observed on the in vitro skin penetration test is highly representative of the in vivo situation evaluated on volunteers. CONCLUSION: The combination of in vitro with in vivo data confirmed that A-A-A has the capacity to diffuse through the skin after topical application and reach the dermis as the targeted skin layer for potential anti ageing benefits. PMID- 26119920 TI - Nanocarrier-based antioxidant therapy: promise or delusion? AB - INTRODUCTION: Oxidative stress has generally been recognized as an important factor in the pathogenesis of human diseases, making antioxidant therapy a plausible strategy to either prevent or treat human disorders. Yet so far, numerous antioxidant-based clinical trials aimed at developing clinically approved protocols have been disappointing and many reasons for their failure are being discussed, including the limited bioavailability of most antioxidants. To overcome the hurdles associated with the direct administration of antioxidant molecules, a variety of nanotechnology-based drug delivery systems are being developed. All the strategies currently being explored, however, appear in our opinion to underappreciate the crucial role reactive oxygen and nitrogen species (RO/NS) play in the regulation of the metabolome, as revealed by recent progress made in redox biology. AREAS COVERED: We briefly review antioxidant-based clinical trials and discuss the functions of RO/NS as crucial intracellular messengers. We emphasize the probable existence of three distinct concentration levels of RO/NS: a physiological level reflecting their functions as messenger molecules, an elevated level crucial for activation of protective pathways and a toxic level causing oxidative damage to cellular components. EXPERT OPINION: Site specific, multifunctional nanodrug delivery systems able to sense the actual intracellular concentrations of RO/NS and release antioxidants accordingly in order to only neutralize the pathologic excess of RO/NS need to be developed. PMID- 26119922 TI - How information structure influences the processing of rhythmic irregularities: ERP evidence from German phrases. AB - This study explores the influence of focus and givenness on the cognitive processing of rhythmic irregularities occurring in natural speech. Previous ERP studies showed that even subtle rhythmic deviations are detected by the brain if attention is directed towards the rhythmic structure. By using question-answer pairs, it was investigated whether subtle rhythmic irregularities in form of stress clashes (two adjacent stressed syllables) and stress lapses (two adjacent unstressed syllables) are still perceived when presented in post-focus position in an answer sentence and attention is directed away from them, towards the meaning of the element in narrow focus position by the preceding wh-question. Moreover, by visually presenting the lexical-semantic input of the deviating structure in the question, the influence of rhythmical and lexical properties in these two forms of rhythmic deviations are disentangled. While words in the present stress clash condition do not deviate from lexical stress, stress lapses contain deviations from metrical and lexical stress. The data reveal an early negativity effect for stress clashes but not for stress lapses, supporting the assumption that they are processed differently. The absence of a negative component for stress lapses indicates that the metrical deviation alone is not salient enough to be registered in non-focus position. Moreover, the lack of a late positive component suggests that subtle rhythmic deviations are less perceivable and hence more acceptable when presented in non-focus position. Thus, these results show that attentional shift induced by information structure influences the degree of the processing of rhythm. PMID- 26119921 TI - The anatomical and functional specialization of the fusiform gyrus. AB - The fusiform gyrus (FG) is commonly included in anatomical atlases and is considered a key structure for functionally-specialized computations of high level vision such as face perception, object recognition, and reading. However, it is not widely known that the FG has a contentious history. In this review, we first provide a historical analysis of the discovery of the FG and why certain features, such as the mid-fusiform sulcus, were discovered and then forgotten. We then discuss how observer-independent methods for identifying cytoarchitectonical boundaries of the cortex revolutionized our understanding of cytoarchitecture and the correspondence between those boundaries and cortical folding patterns of the FG. We further explain that the co-occurrence between cortical folding patterns and cytoarchitectonical boundaries are more common than classically thought and also, are functionally meaningful especially on the FG and probably in high-level visual cortex more generally. We conclude by proposing a series of alternatives for how the anatomical organization of the FG can accommodate seemingly different theoretical aspects of functional processing, such as domain specificity and perceptual expertise. PMID- 26119923 TI - Risks of Venous Thromboembolism, Stroke, Heart Disease, and Myelodysplastic Syndrome Associated With Hematopoietic Growth Factors in a Large Population-Based Cohort of Patients With Colorectal Cancer. AB - PURPOSE: To determine the relationship between the receipt of colony-stimulating factors (CSFs) with erythropoiesis-stimulating agents (ESAs) and the risk of developing venous thromboembolism (VTE), stroke, heart disease, and myelodysplastic syndrome (MDS) in patients with colorectal cancer. METHODS: We studied 80,925 patients diagnosed with colorectal cancer at age >= 65 years in 1992-2009 from the nationwide 16 areas of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data. Cumulative incidence and the time to events Cox hazard regressions were used to explore the risks of outcomes in association with the receipt of CSFs and ESAs. RESULTS: Patients who received chemotherapy (CT) with both CSF and ESA were 58% more likely to develop VTE than those who received CT without CSF and ESA (hazard ratio, 1.58; 95% confidence interval, 1.43-1.76). The risk of stroke appeared to be not associated with the use of CSF and ESA, whereas the risk of heart disease was only significantly elevated in those patients who did not receive CT but received ESA. The risk of acute myeloid leukemia or MDS was significantly increased 4- to 9-fold in patients who received ESA, regardless of receipt of CT or CSF. CONCLUSION: The use of ESAs was significantly associated with a substantially increased risk of MDS in patients with colorectal cancer. The use of CSFs and ESAs was also significantly associated with a moderately increased risk of VTE and a slightly elevated risk of heart disease. PMID- 26119924 TI - Increased regulatory T cells in acute lymphoblastic leukemia patients. AB - INTRODUCTION: Regulation in adaptive immune response balances a fine line that prevents instigation of self-damage or fall into unresponsiveness permitting abnormal cell growth. Mechanisms that keep this balance in check include regulatory T cells (Tregs). Tregs consist of a small but heterogeneous population which may be identified by the phenotype, CD3+CD4+CD25+CD127-. Role of Tregs in pathogenesis of cancers is thus far supported by evidence of increased Tregs in various cancers and may contribute to poorer prognosis. Tregs may also be important in acute leukemias. OBJECTIVE: A review of the literature on Tregs in acute leukemias was conducted and Tregs were determined in B-cell acute lymphoblastic leukemias (ALLs). RESULTS: Studies on Tregs in B-cell ALL are few and controversial. We observed a significantly increased percentage of Tregs (mean +/- SD, 9.72 +/- 3.79% vs. 7.05 +/- 1.74%; P = 0.047) in the bone marrow/peripheral blood of ALL (n = 17) compared to peripheral blood of normal controls (n = 35). A positive trend between Tregs and age (R = 0.474, P = 0.055, n = 17) implicates this factor of poor prognosis in B-cell ALL. DISCUSSION: Tregs in cancer are particularly significant in immunotherapy. The manipulation of the immune system to treat cancer has for a long time ignored regulatory mechanisms inducible or in place. In lymphoma studies tumor-specific mechanisms that are unlike conventional methods in the induction of Tregs have been hypothesized. In addition, tumor-infiltrating Tregs may present different profiles from peripheral blood pictures. Tregs will continue to be dissected to reveal their mysteries and their impact on clinical significance. PMID- 26119926 TI - Methodology exploration of specimen preparation for atom probe tomography from nanowires. AB - Semiconductor nanowires have been intensively explored for applications in electronics, photonics, energy conversion and storage. A fundamental and quantitative understanding of growth-structure-property relationships is central to applications where nanowires exhibit clear advantages. Atom Probe Tomography (APT) is able to provide 3 dimensional quantitative elemental distributions at atomic-resolution and is therefore unique in understanding the growth-structure property relationships. However, the specimen preparation with nanowires is extremely challenging. In this paper, two ion beam free specimen preparation methods for APT are presented which are efficient for various nanowires. PMID- 26119927 TI - The evolving field of prognostication and risk stratification in MDS: Recent developments and future directions. AB - The clinical course of patients with myelodysplastic syndromes (MDS) is characterized by wide variability reflecting the underlying genetic and biological heterogeneity of the disease. Accurate prediction of outcomes for individual patients is an integral part of the evidence-based risk/benefit calculations that are necessary for tailoring the aggressiveness of therapeutic interventions. While several prognostication tools have been developed and validated for risk stratification, each of these systems has limitations. The recent progress in genomic sequencing techniques has led to discoveries of recurrent molecular mutations in MDS patients with independent impact on relevant clinical outcomes. Reliable assays of these mutations have already entered the clinic and efforts are currently ongoing to formally incorporate mutational analysis into the existing clinicopathologic risk stratification tools. Additionally, mutational analysis holds promise for going beyond prognostication to therapeutic selection and individualized treatment-specific prediction of outcomes; abilities that would revolutionize MDS patient care. Despite these exciting developments, the best way of incorporating molecular testing for use in prognostication and prediction of outcomes in clinical practice remains undefined and further research is warranted. PMID- 26119928 TI - Lack of genetic diversity across diverse immune genes in an endangered mammal, the Tasmanian devil (Sarcophilus harrisii). AB - The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction due to the spread of devil facial tumour disease. Polymorphisms in immune genes can provide adaptive potential to resist diseases. Previous studies in diversity at immune loci in wild species have almost exclusively focused on genes of the major histocompatibility complex (MHC); however, these genes only account for a fraction of immune gene diversity. Devils lack diversity at functionally important immunity loci, including MHC and Toll-like receptor genes. Whether there are polymorphisms at devil immune genes outside these two families is unknown. Here, we identify polymorphisms in a wide range of key immune genes, and develop assays to type single nucleotide polymorphisms (SNPs) within a subset of these genes. A total of 167 immune genes were examined, including cytokines, chemokines and natural killer cell receptors. Using genome-level data from ten devils, SNPs within coding regions, introns and 10 kb flanking genes of interest were identified. We found low polymorphism across 167 immune genes examined bioinformatically using whole-genome data. From this data, we developed long amplicon assays to target nine genes. These amplicons were sequenced in 29-220 devils and found to contain 78 SNPs, including eight SNPS within exons. Despite the extreme paucity of genetic diversity within these genes, signatures of balancing selection were exhibited by one chemokine gene, suggesting that remaining diversity may hold adaptive potential. The low functional diversity may leave devils highly vulnerable to infectious disease, and therefore, monitoring and preserving remaining diversity will be critical for the long-term management of this species. Examining genetic variation in diverse immune genes should be a priority for threatened wildlife species. This study can act as a model for broad scale immunogenetic diversity analysis in threatened species. PMID- 26119929 TI - Comparison of Cryotop and micro volume air cooling methods for cryopreservation of bovine matured oocytes and blastocysts. AB - This study was designed to compare the efficiency of the Cryotop method and that of two methods that employ a micro volume air cooling (MVAC) device by analyzing the survival and development of bovine oocytes and blastocysts vitrified using each method. In experiment I, in vitro-matured (IVM) oocytes were vitrified using an MVAC device without direct contact with liquid nitrogen (LN2; MVAC group) or directly plunged into LN2 (MVAC in LN2 group). A third group of IVM oocytes was vitrified using a Cryotop device (Cryotop group). After warming, vitrified oocytes were fertilized in vitro. There were no significant differences in cleavage and blastocyst formation rates among the three vitrified groups, with the rates ranging from 53.1% to 56.6% and 20.0% to 25.5%, respectively; however, the rates were significantly lower (P < 0.05) than those of the fresh control group (89.3% and 43.3%, respectively) and the solution control group (87.3% and 42.0%, respectively). In experiment II, in vitro-produced (IVP) expanded blastocysts were vitrified using the MVAC, MVAC in LN2 and Cryotop methods, warmed and cultured for survival analysis and then compared with the solution control group. The rate of development of vitrified-warmed expanded blastocysts to the hatched blastocyst stage after 24 h of culture was lower in the MVAC in LN2 group than in the solution control group; however, after 48-72 h of culture, the rates did not significantly differ between the groups. These results indicate that the MVAC method without direct LN2 contact is as effective as the standard Cryotop method for vitrification of bovine IVM oocytes and IVP expanded blastocysts. PMID- 26119925 TI - Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes. AB - Protein-protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A-D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, beta-sheets, and helices. PMID- 26119930 TI - Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. AB - Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after minimal exposure. Using a BAP1(+/-) mouse model, we found that, compared with their wild-type littermates, BAP1(+/-) mice exposed to low-dose asbestos fibers showed significant alterations of the peritoneal inflammatory response, including significantly higher levels of pro-tumorigenic alternatively polarized M2 macrophages, and lower levels of several chemokines and cytokines. Consistent with these data, BAP1(+/-) mice had a significantly higher incidence of mesothelioma after exposure to very low doses of asbestos, doses that rarely induced mesothelioma in wild-type mice. Our findings suggest that minimal exposure to carcinogenic fibers may significantly increase the risk of malignant mesothelioma in genetically predisposed individuals carrying germline BAP1 mutations, possibly via alterations of the inflammatory response. PMID- 26119931 TI - Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis. AB - CD44E is a frequently overexpressed variant of CD44 in gastric cancer. Mechanisms that regulate CD44 splicing and expression in gastric cancer remain unknown. Herein, we investigated the role of DARPP-32 (dopamine and cyclic adenosine monophosphate-regulated phosphoprotein, Mr 32000) in promoting tumor growth through regulation of CD44 splicing. Using western blot and quantitative real time PCR analysis, our results indicated that knockdown of endogenous DARPP-32 markedly reduces the expression of CD44 V8-V10 (CD44E). Using a quantitative splicing luciferase reporter system, we detected a significant increase in the reporter activity following DARPP-32 overexpression (P<0.001). Conversely, knocking down endogenous DARPP-32 significantly attenuated the splicing activity (P<0.001). Further experiments showed that DARPP-32 regulates the expression of SRp20 splicing factor and co-exists with it in the same protein complex. Inhibition of alternative splicing with digitoxin followed by immunoprecipitation and immunoblotting indicated that DARPP-32 has an important role in regulating SRp20 protein stability. The knockdown of endogenous DARPP-32 confirmed that DARPP-32 regulates the SRp20-dependent CD44E splicing. Using tumor xenograft mouse model, knocking down endogenous DARPP-32 markedly reduced SRp20 and CD44E protein levels with a decreased tumor growth. The reconstitution of SRp20 expression in these cells rescued tumor growth. In addition, we also demonstrated frequent co-overexpression and positive correlation of DARPP-32, SRp20 and CD44E expression levels in human gastric primary tumors. Our novel findings establish for the first time the role of DARPP-32 in regulating splicing factors in gastric cancer cells. The DARPP-32-SRp20 axis has a key role in regulating the CD44E splice variant that promotes gastric tumorigenesis. PMID- 26119932 TI - Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling. AB - It is well known that specific signal transduction inhibitors rarely suffice as anti-cancer agents. In most cases, tumors possess primary drug resistance due to their inherent heterogeneity, or acquire drug resistance due to genomic instability and acquisition of mutations. Here we expand our previous study of the novel compound, NT157, and show that it acts as a dual-targeting agent that invokes the blockage of two signal transduction pathways that are central to the development and maintenance of multiple human cancers. We show that NT157 targets not only IGF1R-IRS1/2, as previously reported, but also the Stat3 signaling pathway and demonstrates remarkable anti-cancer characteristics in A375 human melanoma cells and in a metastatic melanoma model in mice. PMID- 26119934 TI - Focal adhesion kinase-promoted tumor glucose metabolism is associated with a shift of mitochondrial respiration to glycolysis. AB - Cancer cells often gains a growth advantage by taking up glucose at a high rate and undergoing aerobic glycolysis through intrinsic cellular factors that reprogram glucose metabolism. Focal adhesion kinase (FAK), a key transmitter of growth factor and anchorage stimulation, is aberrantly overexpressed or activated in most solid tumors, including pancreatic ductal adenocarcinomas (PDACs). We determined whether FAK can act as an intrinsic driver to promote aerobic glycolysis and tumorigenesis. FAK inhibition decreases and overexpression increases intracellular glucose levels during unfavorable conditions, including growth factor deficiency and cell detachment. Amplex glucose assay, fluorescence and carbon-13 tracing studies demonstrate that FAK promotes glucose consumption and glucose-to-lactate conversion. Extracellular flux analysis indicates that FAK enhances glycolysis and decreases mitochondrial respiration. FAK increases key glycolytic proteins, including enolase, pyruvate kinase M2 (PKM2), lactate dehydrogenase and monocarboxylate transporter. Furthermore, active/tyrosine phosphorylated FAK directly binds to PKM2 and promotes PKM2-mediated glycolysis. On the other hand, FAK-decreased levels of mitochondrial complex I can result in reduced oxidative phosphorylation (OXPHOS). Attenuation of FAK-enhanced glycolysis re-sensitizes cancer cells to growth factor withdrawal, decreases cell viability and reduces growth of tumor xenografts. These observations, for the first time, establish a vital role of FAK in cancer glucose metabolism through alterations in the OXPHOS-to-glycolysis balance. Broadly targeting the common phenotype of aerobic glycolysis and more specifically FAK-reprogrammed glucose metabolism will disrupt the bioenergetic and biosynthetic supply for uncontrolled growth of tumors, particularly glycolytic PDAC. PMID- 26119933 TI - Glioma invasion mediated by the p75 neurotrophin receptor (p75(NTR)/CD271) requires regulated interaction with PDLIM1. AB - The invasive nature of glioblastoma renders them incurable by current therapeutic interventions. Using a novel invasive human glioma model, we previously identified the neurotrophin receptor p75(NTR) (aka CD271) as a mediator of glioma invasion. Herein, we provide evidence that preventing phosphorylation of p75(NTR) on S303 by pharmacological inhibition of PKA, or by a mutational strategy (S303G), cripples p75(NTR)-mediated glioma invasion resulting in serine phosphorylation within the C-terminal PDZ-binding motif (SPV) of p75(NTR). Consistent with this, deletion (DeltaSPV) or mutation (SPM) of the PDZ motif results in abrogation of p75(NTR)-mediated invasion. Using a peptide-based strategy, we identified PDLIM1 as a novel signaling adaptor for p75(NTR) and provide the first evidence for a regulated interaction via S425 phosphorylation. Importantly, PDLIM1 was shown to interact with p75(NTR) in highly invasive patient-derived glioma stem cells/tumor-initiating cells and shRNA knockdown of PDLIM1 in vitro and in vivo results in complete ablation of p75(NTR)-mediated invasion. Collectively, these data demonstrate a requirement for a regulated interaction of p75(NTR) with PDLIM1 and suggest that targeting either the PDZ domain interactions and/or the phosphorylation of p75(NTR) by PKA could provide therapeutic strategies for patients with glioblastoma. PMID- 26119935 TI - YAP activation protects urothelial cell carcinoma from treatment-induced DNA damage. AB - Current standard of care for muscle-invasive urothelial cell carcinoma (UCC) is surgery along with perioperative platinum-based chemotherapy. UCC is sensitive to cisplatin-based regimens, but acquired resistance eventually occurs, and a subset of tumors is intrinsically resistant. Thus, there is an unmet need for new therapeutic approaches to target chemotherapy-resistant UCC. Yes-associated protein (YAP) is a transcriptional co-activator that has been associated with bladder cancer progression and cisplatin resistance in ovarian cancer. In contrast, YAP has been shown to induce DNA damage associated apoptosis in non small cell lung carcinoma. However, no data have been reported on the YAP role in UCC chemo-resistance. Thus, we have investigated the potential dichotomous role of YAP in UCC response to chemotherapy utilizing two patient-derived xenograft models recently established. Constitutive expression and activation of YAP inversely correlated with in vitro and in vivo cisplatin sensitivity. YAP overexpression protected while YAP knockdown sensitized UCC cells to chemotherapy and radiation effects via increased accumulation of DNA damage and apoptosis. Furthermore, pharmacological YAP inhibition with verteporfin inhibited tumor cell proliferation and restored sensitivity to cisplatin. In addition, nuclear YAP expression was associated with poor outcome in UCC patients who received perioperative chemotherapy. In conclusion, these results suggest that YAP activation exerts a protective role and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of UCC. PMID- 26119936 TI - LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells. AB - The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20 30% of patients with non-small-cell lung cancer (NSCLC). Loss of LKB1-adenosine monophosphate-activated protein kinase (AMPK) signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations in energy metabolism and mitochondrial dysfunction. Loss of LKB1 expression altered the cellular response to erlotinib treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Furthermore, erlotinib selectively blocked mammalian target of rapamycin signaling, inhibited cell growth and activated apoptosis in LKB1-deficient cells. Erlotinib treatment also induced AMPK activation despite loss of LKB1 expression, which was partially reduced by the application of a calcium/calmodulin-dependent protein kinase kinase 2 inhibitor (STO-609) or calcium chelator (BAPTA-AM). These findings may have significant implications for the design of novel NSCLC treatments that target dysregulated metabolic and signaling pathways in LKB1-deficient tumors. PMID- 26119937 TI - MYC in pancreatic cancer: novel mechanistic insights and their translation into therapeutic strategies. AB - Owing to its aggressiveness, late detection and marginal therapeutic accessibility, pancreatic ductal adenocarcinoma (PDAC) remains a most challenging malignant disease. Despite scientific progress in the understanding of the mechanisms that underly PDAC initiation and progression, the successful translation of experimental findings into effective new therapeutic strategies remains a largely unmet need. The oncogene MYC is activated in many PDAC cases and is a master regulator of vital cellular processes. Excellent recent studies have shed new light on the tremendous functions of MYC in cancer and identified inhibition of MYC as a likewise beneficial and demanding effort. This review will focus on mechanisms that contribute to deregulation of MYC expression in pancreatic carcinogenesis and progression and will summarize novel biological findings from recent in vivo models. Finally, we provide a perspective, how regulation of MYC in PDAC may contribute to the development of new therapeutic approaches. PMID- 26119938 TI - Deacetylation of HSPA5 by HDAC6 leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses metastasis of breast cancer. AB - Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78 mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer. PMID- 26119939 TI - Immunomodulatory drugs target IKZF1-IRF4-MYC axis in primary effusion lymphoma in a cereblon-dependent manner and display synergistic cytotoxicity with BRD4 inhibitors. AB - Primary effusion lymphoma (PEL) is an aggressive type of non-Hodgkin lymphoma localized predominantly in body cavities. Kaposi's sarcoma-associated herpes virus (KSHV) is the causative agent of PEL. PEL is an incurable malignancy and has extremely poor prognosis when treated with conventional chemotherapy. Immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are Food and Drug Administration-approved drugs for the treatment of various ailments. IMiDs display pronounced antiproliferative effect against majority of PEL cell lines within their clinically achievable concentrations, by arresting cells at G0/G1 phase of cell cycle and without any induction of KSHV lytic cycle reactivation. Although microarray examination of PEL cells treated with lenalidomide revealed activation of interferon (IFN) signaling, blocking the IFN pathway did not block the anti-PEL activity of IMiDs. The anti-PEL effects of IMiDs involved cereblon dependent suppression of IRF4 and rapid degradation of IKZF1, but not IKZF3. Small hairpin RNA-mediated knockdown of MYC enhanced the cytotoxicity of IMiDs. Bromodomain (BRD) and extra-terminal domain (BET) proteins are epigenetic readers, which perform a vital role in chromatin remodeling and transcriptional regulation. BRD4, a widely expressed transcriptional coactivator, belongs to the BET family of proteins, which has been shown to co-occupy the super enhancers associated with MYC. Specific BRD4 inhibitors were developed, which suppress MYC transcriptionally. Lenalidomide displayed synergistic cytotoxicity with several structurally distinct BRD4 inhibitors (JQ-1, IBET151 and PFI-1). Furthermore, combined administration of lenalidomide and BRD4 inhibitor JQ-1 significantly increased the survival of PEL bearing NOD-SCID mice in an orthotopic xenograft model as compared with either agent alone. These results provide compelling evidence for clinical testing of IMiDs alone and in combination with BRD4 inhibitors for PEL. PMID- 26119940 TI - Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression. AB - Sex-determining region Y box 6 (SOX6) has been described as a tumor-suppressor gene in several cancers. Our previous work has suggested that SOX6 upregulated p21(Waf1/Cip1)(p21) expression in a p53-dependent manner; however, the underlying mechanism has remained elusive. In this study, we confirmed that SOX6 can suppress cell proliferation in vitro and in vivo by stabilizing p53 protein and subsequently upregulating p21. Co-immunoprecipitation and immunocytofluorescence assays demonstrated that SOX6 can promote formation of the p14ARF-HDM2-p53 ternary complex by promoting translocation of p14ARF (p14 alternate reading frame tumor suppressor) to the nucleoplasm, thereby inhibiting HDM2-mediated p53 nuclear export and degradation. Chromatin immunoprecipitation combined with PCR assay proved that SOX6 can bind to a potential binding site in the regulatory region of the c-Myc gene. Furthermore, we confirmed that SOX6 can downregulate the expression of c-Myc, as well as its direct target gene nucleophosmin 1 (NPM1), and that the SOX6-induced downregulation of NPM1 is linked to translocation of p14ARF to the nucleoplasm. Finally, we showed that the highly conserved high-mobility group (HMG) domain of SOX6 is required for SOX6-mediated p53 stabilization and tumor inhibitory activity. Collectively, these results reveal a new mechanism of SOX6-mediated tumor suppression involving p21 upregulation via the p14ARF-HDM2-p53 axis in an HMG domain-dependent manner. PMID- 26119941 TI - Evaluation of targeted therapies in advanced breast cancer: the need for large scale molecular screening and transformative clinical trial designs. AB - Breast cancer (BC) has been classified into four intrinsic subtypes through seminal studies employing gene expression profiling analysis of primary tumours, namely the luminal A and B subtypes, the human epidermal growth factor receptor 2 like subtype and the basal-like subtype. More recently, the emergence of high throughput genomic sequencing techniques, such as next-generation or massive parallel sequencing has expanded our understanding of the complex genomic landscapes of BC, with marked intertumour heterogeneity seen among different patients. In addition, increasing evidence indicates intratumour heterogeneity, with molecular differences observed within one patient, both spatially and longitudinally. These phenomena have an impact on the clinical development of molecularly targeted agents, with the classical paradigm of population-based clinical trials being no longer efficient. In the era of genomically driven oncology, three complementary tools can accelerate the clinical development of targeted agents for advanced BC as follows: (i) the implementation of molecular profiling of metastatic tumour lesions, as exemplified by the AURORA (Aiming to Understand the Molecular Aberrations in Metastatic Breast Cancer) programme; (ii) serial assessments of circulating tumour DNA, allowing a more thorough molecular interrogation of metastatic tumour burden; and (iii) new innovative clinical trial designs able to address the challenges of the increasing molecular fragmentation of BC. PMID- 26119942 TI - p63 controls cell migration and invasion by transcriptional regulation of MTSS1. AB - Metastasis is a multistep cell-biological process, which is orchestrated by many factors, including metastasis activators and suppressors. Metastasis Suppressor 1 (MTSS1) was originally identified as a metastasis suppressor protein whose expression is lost in metastatic bladder and prostate carcinomas. However, recent findings indicate that MTSS1 acts as oncogene and pro-migratory factor in melanoma tumors. Here, we identify and characterized a molecular mechanism controlling MTSS1 expression, which impinges on a pro-tumorigenic role of MTSS1 in breast tumors. We found that in normal and in cancer cell lines DeltaNp63 is able to drive the expression of MTSS1 by binding to a p63-binding responsive element localized in the MTSS1 locus. We reported that DeltaNp63 is able to drive the migration of breast tumor cells by inducing the expression of MTSS1. Notably, in three human breast tumors data sets the MTSS1/p63 co-expression is a negative prognostic factor on patient survival, suggesting that the MTSS1/p63 axis might be functionally important to regulate breast tumor progression. PMID- 26119943 TI - PML is required for telomere stability in non-neoplastic human cells. AB - Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARalpha in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis. PMID- 26119944 TI - Heat-shock factor 2 is a suppressor of prostate cancer invasion. AB - Heat-shock factors (HSFs) are key transcriptional regulators in cell survival. Although HSF1 has been identified as a driver of carcinogenesis, HSF2 has not been explored in malignancies. Here, we report that HSF2 suppresses tumor invasion of prostate cancer (PrCa). In three-dimensional organotypic cultures and the in vivo xenograft chorioallantoic membrane model HSF2 knockdown perturbs organoid differentiation and promotes invasiveness. Gene expression profiling together with functional studies demonstrated that the molecular mechanism underlying the effect on tumor progression originates from HSF2 steering the switch between acinar morphogenesis and invasion. This is achieved by the regulation of genes connected to, for example, GTPase activity, cell adhesion, extracellular matrix and actin cytoskeleton dynamics. Importantly, low HSF2 expression correlates with high Gleason score, metastasis and poor survival of PrCa patients, highlighting the clinical relevance of our findings. Finally, the study was expanded beyond PrCa, revealing that the expression of HSF2 is decreased in a wide range of cancer types. This study provides the first evidence for HSF2 acting as a suppressor of invasion in human malignancies. PMID- 26119945 TI - Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors. AB - Intratumoral heterogeneous MYCN amplification (hetMNA) is an unusual event in neuroblastoma with unascertained biological and clinical implications. Diagnosis is based on the detection of MYCN amplification surrounded by non-amplified tumor cells by fluorescence in situ hybridization (FISH). To better define the genetic features of hetMNA tumors, we studied the Spanish cohort of neuroblastic tumors by FISH and single nucleotide polymorphism arrays. We compared hetMNA tumors with homogeneous MNA (homMNA) and nonMNA tumors with 11q deletion (nonMNA w11q-). Of 1091 primary tumors, 28 were hetMNA by FISH. Intratumoral heterogeneity of 1p, 2p, 11q and 17q was closely associated with hetMNA tumors when analyzing different pieces for each case. For chromosome 2, 16 cases showed 2p intact, 4 focal gain at 2p24.3 and 8 MNA. The lengths of the smallest regions of overlap (SROs) for 2p gains and 1p deletions were between the SRO lengths observed in homMNA and nonMNA w11q- tumors. Co-occurrence of 11q- and +17q was frequently found with the largest SROs for both aberrations. The evidence for and frequency of different genetic subpopulations representing a hallmark of the hetMNA subgroup of NB indicates, on one hand, the presence of a considerable genetic instability with different SRO of either gains and losses compared with those of the other NB groups and highlights and, on the other hand, the need for multiple sampling from distant and macroscopically and microscopically distinct tumor areas. Narrowing down the different SRO for both deletions and gains in NB groups would be crucial to pinpointing the candidate gene(s) and the critical gene dosage with prognostic and therapeutic significance. This complexity of segmental chromosomal aberration patterns reinforces the necessity for a larger cohort study using FISH and pangenomic techniques to develop a suitable therapeutic strategy for these patients. PMID- 26119947 TI - Ultrasound diagnostics of the abdominal aorta: English version. AB - BACKGROUND AND OBJECTIVES: The ideal method for screening investigations is one which is as free as possible from side effects, is easily learnt, and can therefore be broadly used to detect abdominal aortic aneurysms (AAA) with a high degree of certainty. Although ultrasonography fulfils these criteria, the measurement method is not standardized. Different measurement methods are used in ultrasonography as well as in computed tomography (CT) studies and the measurement method is actually described sufficiently in only 57 % of cases. METHODS: This article provides a critical review of the current literature on measurement methods and the validity of ultrasonography for the determination of aortic diameter, particularly in AAA, and presents the measurement principles for making measurements as precisely as possible. RESULTS AND CONCLUSION: The most precise determination of aortic diameter is carried out by electrocardiogram (ECG) gating according to the leading-edge method with orthogonal slicing. Within the framework of screening investigations, sufficient measurement precision can be achieved by adherence to orthogonal slicing. Using these standardized measurement methods, ultrasonography shows valid and reproducible results even compared with CT and is the method of choice in screening investigations for AAA. PMID- 26119946 TI - Endothelial CXCR7 regulates breast cancer metastasis. AB - Atypical chemokine receptor CXCR7 (ACKR3) functions as a scavenger receptor for chemokine CXCL12, a molecule that promotes multiple steps in tumor growth and metastasis in breast cancer and multiple other malignancies. Although normal vascular endothelium expresses low levels of CXCR7, marked upregulation of CXCR7 occurs in tumor vasculature in breast cancer and other tumors. To investigate effects of endothelial CXCR7 in breast cancer, we conditionally deleted this receptor from vascular endothelium of adult mice, generating CXCR7(DeltaEND/DeltaEND) animals. CXCR7(DeltaEND/DeltaEND) mice appeared phenotypically normal, although these animals exhibited a modest 35+/-3% increase in plasma CXCL12 as compared with control. Using two different syngeneic, orthotopic tumor implant models of breast cancer, we discovered that CXCR7(DeltaEND/DeltaEND) mice had significantly greater local recurrence of cancer following resection, elevated numbers of circulating tumor cells and more spontaneous metastases. CXCR7(DeltaEND/DeltaEND) mice also showed greater experimental metastases following intracardiac injection of cancer cells. These results establish that endothelial CXCR7 limits breast cancer metastasis at multiple steps in the metastatic cascade, advancing understanding of CXCL12 pathways in tumor environments and informing ongoing drug development targeting CXCR7 in cancer. PMID- 26119948 TI - In the end it's a replication problem: What measuring telomere length can tell us about idiopathic pulmonary fibrosis. PMID- 26119949 TI - Wohlfahrtiimonas chitiniclastica-associated osteomyelitis: a rare case report. AB - Wohlfahrtiimonas chitiniclastica is a rare pathogen that was first isolated from a parasitic fly, Wohlfahrtia magnifica. It is a very rare but an emerging human pathogen reported only in Europe and South America. Recently, it is reported to be an egressing zoonotic pathogen from different geographical locations. The present case represents the first report of this pathogen from a patient suffering from osteomyelitis from India and so far no reports are available regarding the W. chitiniclastica associated infections in Asian countries. Clinical awareness of such emerging human pathogens is crucial for the infectious disease containment. PMID- 26119950 TI - Robust hyperpolarized (13)C metabolic imaging with selective non-excitation of pyruvate (SNEP). AB - In vivo metabolic imaging using hyperpolarized [1-(13)C]pyruvate provides localized biochemical information and is particularly useful in detecting early disease changes, as well as monitoring disease progression and treatment response. However, a major limitation of hyperpolarized magnetization is its unrecoverable decay, due not only to T1 relaxation but also to radio-frequency (RF) excitation. RF excitation schemes used in metabolic imaging must therefore be able to utilize available hyperpolarized magnetization efficiently and robustly for the optimal detection of substrate and metabolite activities. In this work, a novel RF excitation scheme called selective non-excitation of pyruvate (SNEP) is presented. This excitation scheme involves the use of a spectral selective RF pulse to specifically exclude the excitation of [1 (13)C]pyruvate, while uniformly exciting the key metabolites of interest (namely [1-(13)C]lactate and [1-(13)C]alanine) and [1-(13)C]pyruvate-hydrate. By eliminating the loss of hyperpolarized [1-(13)C]pyruvate magnetization due to RF excitation, the signal from downstream metabolite pools is increased together with enhanced dynamic range. Simulation results, together with phantom measurements and in vivo experiments, demonstrated the improvement in signal-to noise ratio (SNR) and the extension of the lifetime of the [1-(13)C]lactate and [1-(13)C]alanine pools when compared with conventional non-spectral selective (NS) excitation. SNEP has also been shown to perform comparably well with multi band (MB) excitation, yet SNEP possesses distinct advantages, including ease of implementation, less stringent demands on gradient performance, increased robustness to frequency drifts and B0 inhomogeneity as well as easier quantification involving the use of [1-(13)C]pyruvate-hydrate as a proxy for the actual [1-(13)C] pyruvate signal. SNEP is therefore a promising alternative for robust hyperpolarized [1-(13)C]pyruvate metabolic imaging with high fidelity. PMID- 26119951 TI - Beneficial Effects of Polygonum multiflorum on Hippocampal Neuronal Cells and Mouse Focal Cerebral Ischemia. AB - Beneficial effects of the water extract of Polygonum multiflorum (WEPM) and their mechanisms were investigated in HT22 hippocampal cells and hippocampus of middle cerebral artery occlusion (MCAO) mice. In HT22 cells against glutamate-induced oxidative stress, pretreatment with WEPM resulted in significantly reduced apoptotic neuronal death. Pretreatment with WEPM resulted in the suppression of ROS accumulation in connection with cellular Ca (2+) level after exposure to glutamate. Treatment with glutamate alone led to suppressed protein level of mature brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (CREB); however, pretreatment with either WEPM or anti oxidant N-acetyl-L-cysteine (NAC) resulted in the significant enhancement of levels of these proteins. In addition, levels of mature BDNF expression and CREB phosphorylation were increased by combined treatment with WEPM, NAC, and intracellular Ca (2+) inhibitor BAPTA compared to other treatment groups. In MCAO mice, we confirmed the critical role of mature BDNF expression and CREB phosphorylation by WEPM in the neurons of the hippocampus. Our results suggest that WEPM mainly exerted beneficial effects on hippocampal neurons through the suppression of ROS accumulation and up-regulation of mature BDNF expression and CREB phosphorylation. PMID- 26119952 TI - Butein Shows Cytotoxic Effects and Induces Apoptosis in Human Ovarian Cancer Cells. AB - Butein is a polyphenol, one of the compounds of chalcones, which are flavonoids that are widely biosynthesized in plants, and exhibits different pharmacological activities. Plants containing butein have been used in Chinese traditional medicine. Recently, it has been reported that butein suppresses proliferation and triggers apoptosis in various human cancer cells in vitro and in vivo. The aim of this study was to investigate its pro-apoptotic effect and mechanisms in two cultured human ovarian cancer cells (ES-2 and TOV-21G). The effects of butein on cell viability were assessed by a MTT assay at 3, 10, 30, and 100 MU/M. The apoptotic pathway related factors, including the mitochondrial transmembrane potential (MTP), cytochrome c, caspase cascade, and Bcl-2 family proteins, were examined. MTT assay revealed that butein was cytotoxic to both ovarian cancer cells in a dose- and time-dependent manner. JC-1 flow cytometry, cytochrome c, and caspase activity assays revealed that butein damaged the MTP, increased the level of cytosol cytochrome c and the activities of caspase-3, -8, and -9 in the two ovarian cancer cells. Western blot analysis revealed that butein down regulated the anti-apoptotic proteins Bcl-2 and Bcl-xL and increased the pro apoptotic proteins Bax and Bad. These findings suggest that butein-induced apoptosis in ovarian cancer cells via the activation of both extrinsic and intrinsic pathways. In addition, butein also down-regulated the expressions of the inhibitor of apoptosis (IAP) proteins, XIAP, survivin, CIAP-1, and CIAP-2. This indicates that the inhibition of IAP proteins was also involved in butein induced apoptosis. The results of our study suggest that butein may be a promising anticancer agent in treating ovarian cancer. PMID- 26119953 TI - Artemisia capillaris Thunberg Produces Sedative-Hypnotic Effects in Mice, Which are Probably Mediated Through Potentiation of the GABAA Receptor. AB - The Artemisia group of plants has long been used as a traditional remedy for various conditions. The present study assessed the sleep-promoting (sedative hypnotic) effects of Artemisia capillaris Thunberg (A. capillaris), and elucidated a possible mechanism behind its effect. ICR mice were given A. capillaris extract (oral) at different dosages (50, 100, 200, 300, or 400 mg/kg), distilled water (oral; control), or diazepam (intraperitoneal; reference drug). One hour after administration, locomotion (open-field test) and motor coordination (rota-rod test) were assessed. The extract's effect on pentobarbital induced sleep was also evaluated. Additionally, electroencephalographic (EEG) recordings were measured in rats. To evaluate a possible mechanism behind its effects, changes in chloride ( Cl (-)) ion influx were measured in human neuroblastoma cells. As compared to the control group, mice treated with A. capillaris demonstrated significantly decreased locomotor activity and impaired motor balance and coordination. The extract also shortened the onset and lengthened the duration of sleep induced by pentobarbital sodium. These effects were comparable to that induced by diazepam. Furthermore, A. capillaris-treated rats showed increased delta and decreased alpha EEG waves; an electroencephalographic pattern indicative of relaxation or sedation. In neuroblastoma cells, the extract dose-dependently increased Cl (-) ion influx, which was blocked by co-administration of bicuculline, a GABAA receptor competitive antagonist, suggesting that its effects are mediated through the GABAA receptor- Cl (-) ion channel complex. Altogether, the results of the present study demonstrate that A. capillaris possesses potent sedative-hypnotic effects, which are probably mediated through potentiation of the GABAA receptor- Cl (-) ion channel complex. PMID- 26119954 TI - Cinnamon and its Components Suppress Vascular Smooth Muscle Cell Proliferation by Up-Regulating Cyclin-Dependent Kinase Inhibitors. AB - Cinnamomum cassia bark has been used in traditional herbal medicine to treat a variety of cardiovascular diseases. However, the antiproliferative effect of cinnamon extract on vascular smooth muscle cells (VSMCs) and the corresponding restenosis has not been explored. Hence, after examining the effect of cinnamon extract on VSMC proliferation, we investigated the possible involvement of signal transduction pathways associated with early signal and cell cycle analysis, including regulatory proteins. Besides, to identify the active components, we investigated the components of cinnamon extract on VSMC proliferation. Cinnamon extract inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation and suppressed the PDGF-stimulated early signal transduction. In addition, cinnamon extract arrested the cell cycle and inhibited positive regulatory proteins. Correspondingly, the protein levels of p21 and p27 not only were increased in the presence of cinnamon extract, also the expression of proliferating cell nuclear antigen (PCNA) was inhibited by cinnamon extract. Besides, among the components of cinnamon extract, cinnamic acid (CA), eugenol (EG) and cinnamyl alcohol significantly inhibited the VSMC proliferation. Overall, the present study demonstrates that cinnamon extract inhibited the PDGF BB-induced proliferation of VSMCs through a G0/G1 arrest, which down-regulated the expression of cell cycle positive regulatory proteins by up-regulating p21 and p27 expression. PMID- 26119955 TI - The Inhibitory Effect of Angelica tenuissima Water Extract on Receptor Activator of Nuclear Factor-Kappa-B Ligand-Induced Osteoclast Differentiation and Bone Resorbing Activity of Mature Osteoclasts. AB - Angelica tenuissima has been traditionally used in oriental medicine for its therapeutic effects in headache, toothache, and flu symptoms. It also exerts anti inflammatory activity via the inhibition of the expression of cyclooxygenase-2 (COX-2). However, the effect of Angelica tenuissima on osteoclast differentiation has not been identified until recently. In this study, we first confirmed that Angelica tenuissima water extract (ATWE) significantly interrupted the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) in a dose-dependent manner without any cytotoxicity. Next, we clarified the underlying mechanisms linking the suppression effects of ATWE on the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastogenesis. At the molecular level, ATWE induced the dephosphorylation of c-Jun N-terminal kinase (JNK) and Akt and decreased the degradation of IkappaB in RANKL-dependent early signaling pathways. Subsequently, ATWE caused impaired activation of the protein and mRNA levels of c-Fos and nuclear factor of activated T cell c1 (NFATc1). Moreover, the disassembly of filamentous actin (F-actin) ring and anti resorptive activity of mature osteoclasts were triggered by ATWE treatment. Although ATWE did not enhance osteogenesis in primary osteoblasts, our results showed that ATWE is a potential candidate for anti-resorptive agent in osteoporosis, a common metabolic bone disorder. PMID- 26119956 TI - Traditional Chinese Herbal Medicine Penthorum chinense Pursh: A Phytochemical and Pharmacological Review. AB - Penthorum chinense Pursh (ganhuangcao), a traditional Chinese medicine, is used for the prevention and treatment of liver diseases, including hepatitis B, hepatitis C, and alcoholic liver damage. A wide range of investigations have been carried out on this herbal medicine from pharmacognosy to pharmaceuticals, as well as pharmacology. The extract of P. chinense was reported to have significant liver protective effects through anti-oxidation, reduction of key enzyme levels, inhibition of hepatitis B virus DNA replication, and promotion of bile secretion. Based on the current knowledge, flavonoids and phenols are considered to be responsible for P. chinense's bioactivities. The main purpose of this review is to provide comprehensive and up-to-date knowledge of the phytochemical and pharmacological studies performed on P. chinense during the past few decades. Moreover, it intends to provide new insights into the research and development of this herbal medicine. PMID- 26119957 TI - Alpha-Pinene Exhibits Anti-Inflammatory Activity Through the Suppression of MAPKs and the NF-kappaB Pathway in Mouse Peritoneal Macrophages. AB - In this study, we found that alpha-pinene (alpha-pinene) exhibits anti inflammatory activity through the suppression of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappa B (NF-kappaB) pathway in mouse peritoneal macrophages. alpha-Pinene is found in the oils of many coniferous trees and rosemary. We investigated the inhibitory effects of alpha-Pinene on inflammatory responses induced by lipopolysaccharide (LPS) using mouse peritoneal macrophages. alpha-Pinene significantly decreased the LPS-induced production of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO). alpha-Pinene also inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in LPS-stimulated macrophages. Additionally, the activations of MAPKs and NF-kappaB were attenuated by means of alpha-pinene treatment. These results indicate that alpha-pinene has an anti-inflammatory effect and that it is a potential candidate as a new drug to treat various inflammatory diseases. PMID- 26119958 TI - Anti-Colon Cancer Effects of 6-Shogaol Through G2/M Cell Cycle Arrest by p53/p21 cdc2/cdc25A Crosstalk. AB - Chemopreventive agents can be identified from botanicals. Recently, there has been strong support for the potential of 6-shogaol, a natural compound from dietary ginger (Zingiber officinale), in cancer chemoprevention. However, whether 6-shogaol inhibits the growth of colorectal tumors in vivo remains unknown, and the underlying anticancer mechanisms have not been well characterized. In this work, we observed that 6-shogaol (15 mg/kg) significantly inhibited colorectal tumor growth in a xenograft mouse model. We show that 6-shogaol inhibited HCT-116 and SW-480 cell proliferation with IC50 of 7.5 and 10 MUM, respectively. Growth of HCT-116 cells was arrested at the G2/M phase of the cell cycle, primarily mediated by the up-regulation of p53, the CDK inhibitor p21(waf1/cip1) and GADD45alpha, and by the down-regulation of cdc2 and cdc25A. Using p53(-/-) and p53(+/+) HCT-116 cells, we confirmed that p53/p21 was the main pathway that contributed to the G2/M cell cycle arrest by 6-shogaol. 6-Shogaol induced apoptosis, mainly through the mitochondrial pathway, and the bcl-2 family might act as a key regulator. Our results demonstrated that 6-shogaol induces cancer cell death by inducing G2/M cell cycle arrest and apoptosis. 6-Shogaol could be an active natural product in colon cancer chemoprevention. PMID- 26119959 TI - Antiproliferative and Pro-Apoptotic Activity of Diarylheptanoids Isolated from the Bark of Alnus japonica in Human Leukemia Cell Lines. AB - Alnus japonica Steud is a tree that grows in damp areas of mountain valleys and has been used as a traditional medicine in Asia. We investigated the antiproliferative activity of hirsutanone (Hir) and oregonin (Ore) in human cancer cell lines and elucidated their mechanisms of action. A cytotoxicity study using a panel of 12 human cancer and 4 normal cell lines indicated that Hir exhibited potent antiproliferative activity against 4 leukemia (Jurkat, U937, THP 1, and HL-60) and 2 colon cancer cell lines (HCT-15 and Colo205). Although Ore suppressed the cell growth of Jurkat and THP-1, its inhibitory potency was weaker than that of Hir. The IC50 values of Hir and Ore in Jurkat were 11.37 MUM and 22.16 MUM, respectively. Further analysis on Jurkat cells demonstrated that Hir caused a sequence of events involved in apoptosis, including nuclear morphological changes and accumulation of cells with sub-G1 DNA content. Hir led to the cleavage of poly(ADP-ribose) polymerase (PARP) and activation of caspase 3, -8, and -9. In addition, Hir-induced PARP cleavage was completely abolished by specific inhibitors to these caspases. Our data suggested that Hir is a potent antiproliferative compound against the 4 leukemia cell lines and the 2 colon cancer cell lines tested. Furthermore, Hir exerts antiproliferative actions via caspase-dependent apoptotic cell death. PMID- 26119960 TI - Maintenance Therapy Improves Survival Outcomes in Patients with Advanced Non small Cell Lung Cancer: A Meta-analysis of 14 Studies. AB - PURPOSE: The aim was to investigate whether maintenance therapy (MT) is sufficient or not to improve overall survival (OS) and progress-free survival (PFS) of advanced non-small cell lung cancer (NSCLC) patients. METHODS: Randomized controlled trials (RCTs) published between 1990 and 2013 were retrieved from PubMed, EMBASE, ISTP, clinicaltrials.org, and ASCO conference proceeding. Patients' characteristics, OS, progress-free survival, and hazard ratios were extracted. Data were analyzed using RevMan 5.2. Fourteen RCTs involving 6198 individuals were included. RESULTS: Compared with placebo, observation or best supportive care (BSC), patients receiving single agent (SA) MT had an improved OS (hazard ratio, HR 0.85, 95% CI 0.79-0.91; p < 0.05) and PFS (HR 0.65, 95% CI 0.57-0.73; p < 0.05). In a sub-group analysis of SA MT versus placebo, observation or BSC, we found that switch MT using SA provided an improved OS (HR 0.85, 95% CI 0.79-0.91; p < 0.05). For multiple agent (MA) versus SA MT, a prolonged PFS (HR 0.68, 95% CI 0.52-0.88; p < 0.05) but not OS (HR 0.96, 95% CI 0.86-1.07; p > 0.05) was observed for MA. A significant prolonged PFS was observed in MA switch MT (HR 0.71, 95% CI 0.58-0.86; p < 0.05) versus SA MT. However, no significant improvement in OS was observed for MA versus SA MT, indicating that switch MT (HR 0.90, 95% CI 0.73-1.12; p > 0.05) and continuous MT (HR 0.98, 95% CI 0.86-1.11; p > 0.05) showed similar effect on OS. CONCLUSION: SA switch MT is associated with improved OS and PFS in patients with advanced NSCLC. MA switch MT is sufficient to improve PFS, but not OS. PMID- 26119961 TI - 4beta-hydroxycholesterol as an endogenous CYP3A marker in cancer patients treated with taxanes. AB - AIM: Taxanes are anti-cancer agents used to treat several types of solid tumours. They are metabolized by cytochrome P450 (CYP) 3A, displaying a large pharmacokinetic (PK) variability. In this study, we evaluated the endogenous CYP3A4 marker 4beta-hydroxycholesterol (4beta-OHC) as a potential individual taxane PK predictor. METHODS: Serum 4beta-OHC and cholesterol concentrations were determined in 291 paclitaxel and 151 docetaxel-treated patients, and were subsequently correlated with taxane clearance. RESULTS: In the patients treated with paclitaxel, no clinically relevant correlations between the 4beta-OHC or 4beta-OHC : cholesterol ratio and paclitaxel clearance were found. In the patients treated with docetaxel, 4beta-OHC concentration was weakly correlated with docetaxel clearance in males (r = 0.35 P = 0.01, 95% CI 0.08, 0.58). Of the 10% patients with taxane outlier clearance values, 4beta-OHC did correlate with docetaxel clearance in males (r = 0.76, P = 0.03, 95% CI 0.12, 0.95). CONCLUSION: There was no clinical correlation between paclitaxel clearance and the CYP3A4 activity markers 4beta-OHC or the 4beta-OHC : cholesterol ratio. A weak correlation was observed between 4beta-OHC and docetaxel clearance, but only in males. This endogenous CYP3A4 marker has limited predictive value for taxane clearance in patients. PMID- 26119963 TI - Modelling wound closure in an epithelial cell sheet using the cellular Potts model. AB - We use a two-dimensional cellular Potts model to represent the behavior of an epithelial cell layer and describe its dynamics in response to a microscopic wound. Using an energy function to describe properties of the cells, we found that the interaction between contractile tension along cell-cell junctions and cell-cell adhesion plays an important role not only in determining the dynamics and morphology of cells in the monolayer, but also in influencing whether or not a wound in the monolayer will close. Our results suggest that, depending on the balance between cell-cell adhesion and junctional tension, mechanics of the monolayer can either correspond to a hard or a soft regime that determines cell morphology and polygonal organization in the monolayer. Moreover, the presence of a wound in a hard regime, where junctional tension is significant, can lead to two results: (1) wound closure or (2) an initial increase and expansion of the wound area towards an equilibrium value. Theoretical approximations and simulations allowed us to determine the thresholds in the values of cell-cell adhesion and initial wound size that allow the system to lead to wound closure. Overall, our results suggest that around the site of injury, changes in the balance between contraction and adhesion determine whether or not non-monotonous wound closure occurs. PMID- 26119962 TI - The antimicrobial propeptide hCAP-18 plasma levels in neutropenia of various aetiologies: a prospective study. AB - The underlying cause of neutropenia may be difficult to determine due to similar clinical presentation in many neutropenic conditions. The neutrophil protein hCAP 18 (pro-LL-37) is a major component of neutrophil secondary granules and in this prospective study we assessed the use of hCAP-18 levels in blood plasma for differential diagnosis of neutropenic patients (n = 133) of various aetiologies. Plasma levels of hCAP-18 were determined using immunoblot and ELISA. Patients with severe congenital neutropenia (n = 23) presented with the lowest levels of plasma hCAP-18 and differential diagnostic accuracy revealed high sensitivity (100%) and specificity (98.8%) for hCAP-18 ELISA. The correlation coefficient of the hCAP-18 ELISA versus immunoblotting was (R = 0.831) and that of the peptide LL-37 ELISA versus immunoblotting was (R = 0.405) (P < 0.001). Plasma hCAP-18 levels thus displayed high diagnostic value in differential diagnosis of chronic neutropenia. Neutropenic patients with Shwachman-Diamond syndrome, Barth syndrome, Cohen syndrome, acute myeloid leukaemia and specific granule deficiency presented with reduced plasma hCAP-18 levels as well. The blood plasma level of hCAP-18 was thus low in conditions in which the neutrophil antibacterial propeptide hCAP-18 is deficient, i.e. severe congenital neutropenia and neutrophil-specific granule deficiency, and in conditions in which bone marrow myelopoiesis is negatively affected. PMID- 26119964 TI - Positive effect of growth hormone treatment in maternal uniparental disomy chromosome 14. AB - OBJECTIVE: Maternal uniparental disomy of chromosome 14 (matUPD(14)) resembles Prader-Willi syndrome (PWS). As positive effects of growth hormone (GH) are observed in individuals with PWS, treatment with GH may be useful in individuals with matUPD(14) as well. The aim of this study was to investigate the effect of GH treatment on growth and body composition in children with matUPD(14). DESIGN: This is a prospective observational study of GH treatment in two girls with matUPD(14) during 2 years, and spontaneous growth in another matUPD(14) girl of similar age. PATIENTS: Three girls (patient A, B and C, aged 8.9, 11.4 and 12.7 years, respectively) with matUPD(14) were included in this study. MEASUREMENTS: Patients A and B were treated with GH during 2 years. Patient C was not treated with GH, as she was diagnosed at an age at which she attained near-final height. Main outcome measures included height, weight, body proportions, IGF-1, bone age, and DXA scan for body composition. RESULTS: In both treated girls, a considerable increase in height (from -2.3SD and -1.2SD to -1.2SD and -0.6SD, respectively) and IGF-1 levels (from +0.1SD and -1.4SD to +1.3SD and +0.9SD, respectively) and, in patient A, a decrease in weight (+1.2 SD to -0.7SD), and improved body composition (fat percentage from 51.5% to 45.4%) were found. Both experienced improved muscle strength. CONCLUSIONS: GH treatment in matUPD(14) cases can show beneficial effects on growth and body composition if started in time. Larger, international studies to determine detailed effectivity and side effects are suggested. PMID- 26119965 TI - Gaining a 'proper sense' of what happens out there: An 'Academic Bush Camp' to promote rural placements for students. AB - Undergraduates who undertake rural placements often choose a rural career. Reluctance from universities to send students to rural settings limits placement numbers. The Western Australian Centre for Rural Health (WACRH) invited allied health and nursing academics and clinical placement coordinators from Western Australian (WA) universities to an Academic Bush Camp. Based on situated learning theory, this camp modelled student programs through experiential learning and structured workshops. It aimed to build relationships and showcase innovative rural learning opportunities. OBJECTIVE: To build relationships and showcase innovative rural learning opportunities. DESIGN: An evaluation of a residential camp based on situated learning theory. SETTING: The camp stated and finished in Geraldton, WA and was centered in Mt Magnet, WA a remote town 600 kilometres northeast of Perth. PARTICIPANTS: WACRH invited allied health and nursing academics and clinical placement coordinators from Western Australian (WA) universities. INTERVENTION: This camp modelled student programs through experiential learning and structured workshops. Online pre- and post-camp questionnaires included open-ended questions and questions on a 5-point Likert scale. Responses were analysed in SPSS 22 using descriptive statistics and Wilcoxon signed-rank test. Follow-up phone interviews six months later assessed longer-term reflections and changes in student placement practice. MAIN OUTCOME MEASURES: The main outcome measure was whether the camp met participants' expectations, and their knowledge about and interest in WACRH's programs. RESULTS: Twelve academics from five WA universities and seven health disciplines attended. Nine had previously lived or worked rurally. The camp met participants' expectations and all would recommend the opportunity to a colleague. Many valued the interaction with community and clinical placement partners and would have preferred more of this. The camp increased awareness of WACRH's programs and benefits of longer rural placements and a service-learning environment. Six months later, participants' familiarity with WACRH's placement model, supports and staff had led to an enhanced willingness to place students. CONCLUSION: Rural academics can influence rural placement intentions by demonstrating the infrastructure, learning and academic support available. A camp experience increases metropolitan academics' awareness of rural placement programs and willingness to encourage student participation. Participants with rural backgrounds appeared more receptive to rural learning possibilities. PMID- 26119967 TI - Breast augmentation in transgender women and the lack of adherence amongst plastic surgeons to professional standards of care. PMID- 26119966 TI - Mathematical model reveals how regulating the three phases of T-cell response could counteract immune evasion. AB - T cells are key players in immune action against the invasion of target cells expressing non-self antigens. During an immune response, antigen-specific T cells dynamically sculpt the antigenic distribution of target cells, and target cells concurrently shape the host's repertoire of antigen-specific T cells. The succession of these reciprocal selective sweeps can result in 'chase-and-escape' dynamics and lead to immune evasion. It has been proposed that immune evasion can be countered by immunotherapy strategies aimed at regulating the three phases of the immune response orchestrated by antigen-specific T cells: expansion, contraction and memory. Here, we test this hypothesis with a mathematical model that considers the immune response as a selection contest between T cells and target cells. The outcomes of our model suggest that shortening the duration of the contraction phase and stabilizing as many T cells as possible inside the long lived memory reservoir, using dual immunotherapies based on the cytokines interleukin-7 and/or interleukin-15 in combination with molecular factors that can keep the immunomodulatory action of these interleukins under control, should be an important focus of future immunotherapy research. PMID- 26119968 TI - An investigation and comparison of the effectiveness of different exercise programmes in improving glucose metabolism and pancreatic beta cell function of type 2 diabetes patients. AB - BACKGROUND: Moderately intensive aerobic exercise can improve glucose metabolism and pancreatic beta cell function in diabetic patients. To date, there is no evidence to support the long-term effectiveness of home-based exercise interventions on these outcomes. OBJECTIVE: This study investigated the effectiveness of two moderately intense exercise programmes on glucose metabolism and pancreatic beta cell function in type 2 diabetes mellitus (T2DM) patients. METHODS: A randomised controlled trial of 120 T2DM patients (with a mean age of 55.54 +/- 9.09 years) was conducted. Patients were assigned by block randomisation to either an aerobic exercise group (AEG), an accumulated million steps group (AMSG), or a control group (CG); each consisting of 40 patients. Glucose metabolism and pancreatic beta cell function of patients were measured at three time intervals for 1 year. RESULTS: There was no difference in baseline scores, and respective compliance rates for the AEG and AMSG were 94.4% and 99.2%. After generalised estimating equation analysis, the AMSG results for glycated haemoglobin (HbA1c) were significantly lower than those of the CG. The insulinogenic index-acute insulin response (BIGTT-AIR ) of both exercise groups was significantly higher than that of the CG. The AMSG group improved their overall HbA1c and BIGTT-AIR results compared with the AEG group after 3 months exercise programme (T1 ) and 12 months of implementation (T2 ). CONCLUSION: This study demonstrates that regardless of the type of exercise intervention, it is potentially beneficially effective for glucose metabolism and pancreatic beta cell function in T2DM patients. The AMSG had better glucose metabolism and pancreatic beta cell function compared with those in the AEG. Nurses can easily integrate exercise interventions into T2DM patient care plans. PMID- 26119969 TI - Placental and fetal cysteine dioxygenase gene expression in mouse gestation. AB - Nutrient sulfate is important for fetal development. The fetus has a limited capacity to generate sulfate and relies on maternal sulfate supplied via the placenta. The gestational age when fetal sulfate generation begins is unknown but would require cysteine dioxygenase (CDO1) which mediates a major step of sulfate production from cysteine. We investigated the ontogeny of Cdo1 mRNA expression in mouse fetal and placental tissues, which showed increasing levels from embryonic day 10.5 and was localised to the decidua and several fetal tissues including nasal cavities and brain. These findings suggest a role for Cdo1 in sulfate generation from mid-gestation. PMID- 26119971 TI - Primary percutaneous coronary intervention by drug-eluting balloon angioplasty: the nonrandomized fourth arm of the DEB-AMI (drug-eluting balloon in ST-segment elevation myocardial infarction) trial. AB - OBJECTIVE: To evaluate a paclitaxel drug-eluting balloon (DEB) only strategy in primary percutaneous coronary intervention (PPCI), aiming at a comparison with bare metal stent (BMS) alone, DEB followed by BMS, and paclitaxel eluting stent (PES), as assessed in the randomized Drug Eluting Balloon in Acute ST-Segment Elevation Myocardial Infarction (DEB-AMI) trial. BACKGROUND: DEB-only seems an attractive strategy in PPCI, as it obviates the risk of stent thrombosis. METHODS: This study is a prospective registry with the same inclusion/exclusion criteria used in the DEB-AMI trial, as it constitutes the fourth, nonrandomized, treatment arm of this trial. Patients presenting with ST-elevation myocardial infarction were allocated to DEB-only (DIOR II, Eurocor GmbH, Bonn, Germany) after successful thrombus aspiration and predilatation. Primary endpoint was 6 month angiographic in-balloon/stent late-luminal loss (LLL). Secondary endpoints were in-balloon/stent binary restenosis and major adverse cardiac events (MACE: death, myocardial infarction, target-vessel revascularization). RESULTS: Forty patients underwent PPCI by DEB-only. Procedural success was achieved in 97.5% with bail-out stenting required in 10.0% of procedures. In DEB-only, LLL was 0.51 +/- 0.59 mm as compared to 0.74 +/- 0.57 mm in BMS (P = 0.44), 0.64 +/- 0.56 mm in DEB+BMS (P = 0.88) and 0.21 +/- 0.32 mm in PES (P < 0.01); in-balloon/stent binary restenosis rates were 22.2%, 23.8% (P = 0.67), 28.6% (P = 0.97), and 4.5% (P = 0.07), respectively; and MACE rates were 17.5%, 23.5% (P = 0.20), 20.0% (P = 0.26), and 4.1% (P = 0.90), respectively. No acute or late thrombotic events occurred in the DEB-only group. CONCLUSIONS: PPCI by DEB-only in selected patients yielded an angiographic outcome comparable to BMS alone and DEB followed by BMS. PES proved angiographic superiority to DEB-only. DEB-only is therefore a potential treatment alternative during PPCI in patients with contra-indications to drug-eluting stents. PMID- 26119970 TI - Effects of prenatal factors and temperament on infant cortisol regulation in low income Mexican American families. AB - Prenatal psychosocial exposures can significantly affect infant health and development. Infants with higher temperamental negativity are theorized to be more susceptible to environmental exposures. We evaluated the interaction of prenatal maternal exposures and infant temperamental negativity to predict infant cortisol response to mildly challenging mother-infant interaction tasks. Participants included 322 Mexican American mother-infant dyads (mother age 18-42; 82% Spanish-speaking; modal family income $10,000-$15,000). Mothers reported depressive symptoms and social support prenatally and infant temperamental negativity at 6 weeks postpartum. Salivary cortisol was collected from infants before and after mother-infant interaction tasks at 12 weeks. Higher prenatal maternal depressive symptoms and lower social support predicted higher cortisol among infants with higher temperamental negativity. Higher infant temperamental negativity predicted an increase in maternal distress and a decrease in social support from prenatal to 12 weeks postpartum. Interactive influences of maternal social-contextual factors and infant temperament may influence the development of infant neurobiological regulation and promote or strain maternal and infant adaptation over time. PMID- 26119972 TI - A case of XLF deficiency presented with diffuse large B cell lymphoma in the brain. PMID- 26119973 TI - Pyridylidene-Mediated Dihydrogen Activation Coupled with Catalytic Imine Reduction. AB - In recent years, dihydrogen activation at non-metallic centers has received increasing attention. A system in which dihydrogen is trapped by a pyridylidene intermediate that is generated from a pyridinium salt and a base is now reported. The dihydropyridine formed in this process can act as reducing agent towards organic electrophiles. By coupling the hydrogen-activation step with subsequent hydride transfer from the dihydropyridine to an imine, a catalytic process was established. Treatment of the N-phenylimine of phenyl trifluoromethyl ketone with 5-20 mol% of N-mesityl-3,5-bis(2,6-dimethylphenyl)pyridinium triflate and 0.3-1.0 equivalents of LiN(SiMe3)2 under 50 bar of hydrogen gas resulted in high conversion into the corresponding amine. PMID- 26119974 TI - Endomicrobium proavitum, the first isolate of Endomicrobia class. nov. (phylum Elusimicrobia)--an ultramicrobacterium with an unusual cell cycle that fixes nitrogen with a Group IV nitrogenase. AB - The bacterial tree contains many deep-rooting clades without any cultured representatives. One such clade is 'Endomicrobia', a class-level lineage in the phylum Elusimicrobia represented so far only by intracellular symbionts of termite gut flagellates. Here, we report the isolation and characterization of the first free-living member of this clade from sterile-filtered gut homogenate of defaunated (starch-fed) Reticulitermes santonensis. Strain Rsa215 is a strictly anaerobic ultramicrobacterium that grows exclusively on glucose, which is fermented to lactate, acetate, hydrogen and CO2. Ultrastructural analysis revealed a Gram-negative cell envelope and a peculiar cell cycle. The genome contains a single set of nif genes that encode homologues of Group IV nitrogenases, which were so far considered to have functions other than nitrogen fixation. We documented nitrogenase activity and diazotrophic growth by measuring acetylene reduction activity and (15)N2 incorporation into cell mass, and demonstrated that transcription of nifH and nitrogenase activity occur only in the absence of ammonium. Based on the ancestral relationship to 'Candidatus Endomicrobium trichonymphae' and other obligate endosymbionts, we propose the name 'Endomicrobium proavitum' gen. nov., sp. nov. for the first isolate of this lineage and the name 'Endomicrobia' class. nov. for the entire clade. PMID- 26119975 TI - Southern California tightens rules on air pollution. PMID- 26119976 TI - Dynamic photoinduced realignment processes in photoresponsive block copolymer films: effects of the chain length and block copolymer architecture. AB - A series of block copolymers composed of an amorphous poly(butyl methacrylate) (PBMA) block connected with an azobenzene (Az)-containing liquid crystalline (PAz) block were synthesized by changing the chain length and polymer architecture. With these block copolymer films, the dynamic realignment process of microphase separated (MPS) cylinder arrays of PBMA in the PAz matrix induced by irradiation with linearly polarized light was studied by UV-visible absorption spectroscopy, and time-resolved grazing incidence small angle X-ray scattering (GI-SAXS) measurements using a synchrotron beam. Unexpectedly, the change in the chain length hardly affected the realignment rate. In contrast, the architecture of the AB-type diblock or the ABA-type triblock essentially altered the realignment feature. The strongly cooperative motion with an induction period before realignment was characteristic only for the diblock copolymer series, and the LPL-induced alignment change immediately started for triblock copolymers and the PAz homopolymer. Additionally, a marked acceleration in the photoinduced dynamic motions was unveiled in comparison with a thermal randomization process. PMID- 26119977 TI - Emerging enantiomeric resolution materials with homochiral nano-fabrications. AB - The major scientific challenge of enantiomeric separation is to develop simple, rapid, and sensitive routine analytical methods. Generally, enantio-resolution is still based on "three-point interaction" theory, which indicates that homochiral sites are needed for enantio-selective interaction. However, in recent years, advanced materials with precise homochiral fabrication at the nanoscale have been synthesized, and have shown great potential in development of high-throughput enantio-resolution methods. This tutorial review summarizes fabrication and applications of homochiral materials for enantio-selective recognition and separation. These materials, which include intrinsic and restructured chiral metal surfaces, plasmonic nanostructures, coordination polymers, organic polymer sensors, and molecularly imprinted polymers, have been applied as sensors or chiral stationary phases (CSPs) for efficient enantio-resolution. PMID- 26119978 TI - Epidural spinal involvement of Erdheim-Chester disease causing myelopathy. AB - We present a 25-year-old woman with Erdheim-Chester disease (ECD) presenting with progressive myelopathy from multiple compressive spinal epidural lesions who required cervicothoracic decompression and fusion, and summarize the literature on epidural spinal involvement of ECD. ECD is a rare non-Langerhans histiocytosis affecting multiple organ systems through infiltration and characteristically causing multifocal osteosclerosis. Central nervous system involvement, particularly of the spine, is rare. PMID- 26119979 TI - Primary angiitis of the central nervous system presenting as a mass lesion. AB - We report a 51-year-old Asian man with primary angiitis of the central nervous system (PACNS) with atypical presentation as a mass lesion. PACNS is an uncommon condition causing inflammation and destruction of the blood vessels of the central nervous system. The aetiology is unclear and multiple mechanisms have been proposed. Its incidence is estimated at 2.4 per million per year, affecting patients of all ages (median 50 years) and more commonly Caucasian men. In Australia, 12 patients fulfilled the diagnostic criteria for PACNS between 1998 and 2009 at The Royal Melbourne Hospital, a university-affiliated tertiary referral centre. The accurate and timely diagnosis of PACNS is very challenging due to disease mimicry and the absence of specific serological tests. This patient illustrates additional diagnostic difficulty with his atypical PACNS presentation as a mass lesion. PMID- 26119980 TI - Hydrothermal synthesis, evolution, and electrochemical performance of LiMn0.5Fe0.5PO4 nanostructures. AB - LiMn0.5Fe0.5PO4 (LMFP) materials are synthesized by the hydrothermal approach in an organic-free and surfactant-free aqueous solution. The phase and morphological evolution of the material intermediates at different reaction temperatures and times are characterized by XRD, SEM and TEM, respectively. The results show that during temperature increase, the solubility product (Ksp) of the precursors (Li3PO4, Fe3(PO4)2 and (Mn,Fe)3(PO4)2) is the decisive parameter for the precipitation processes. Once the temperature locates at the range of 100-110 degrees C, the unstable precursors dissolve quickly and then LMFP nuclei are formed, followed by a dissolution-reprecipitation process. As the reaction progresses, the primary particles self-aggregate to form rod or plate particles to reduce the overall surface energy through oriented attachment (OA) and the Ostwald ripening (OR) mechanism. Moreover, the resultant concentration of the precursor significantly affects the crystal size of LMFP by altering the supersaturation degree of solution at the nucleation stage. The carbon coated LMFP nanostructure synthesized at 0.6 mol L(-1) (resultant concentration of PO4(3 )) delivers discharge capacities of 155, 100 and 81 mA h g(-1) at 0.1, 5 and 20 C rate, respectively. The understanding of nanostructural evolution and its influence on the electrochemical performance will pave a way for a high performance LMFP cathode. PMID- 26119981 TI - Decreasing effect and mechanism of moisture content of sludge biomass by granulation process. AB - Disposal of a high volume of sludge significantly raises water treatment costs. A method for cultivating aerobic granules in a sequencing batch airlift bioreactor to significantly produce lower moisture content is described. Results indicate that optimization of settling time and control of the shear stresses acted on the granules. The diameter of the granule was within the range of 1.0-4.0 mm, and its sludge volume index was stabilized at 40-50 mL g(-1). Its specific gravity was increased by a factor of 0.0392, and specific oxygen uptake rate reached 60.126 mg h(-1) g(-1). Moreover, the percentage of its moisture content in the reactor ranged from 96.73% to 97.67%, and sludge volume was reduced to approximately 60%, greatly due to the presence of extracellular polymeric substances in the granules, as well as changes in their hydrophobic protein content. The removal rate of chemical oxygen demand and [Formula: see text] reaches up to 92.6% and 98%, respectively. The removal rates of total phosphorus is over 85%. Therefore, aerobic granular sludge process illustrates a good biological activity. PMID- 26119982 TI - The Corepressor Rcor1 Is Essential for Normal Myeloerythroid Lineage Differentiation. AB - Based on its physical interactions with histone-modifying enzymes, the transcriptional corepressor Rcor1 has been implicated in the epigenetic regulation blood cell development. Previously, we have demonstrated that Rcor1 is essential for the maturation of definitive erythroid cells and fetal survival. To determine the functional role of Rcor1 in steady-state hematopoiesis in the adult, we used a conditional knockout approach. Here, we show that the loss of Rcor1 expression results in the rapid onset of severe anemia due to a complete, cell autonomous block in the maturation of committed erythroid progenitors. By contrast, both the frequency of megakaryocyte progenitors and their capacity to produce platelets were normal. Although the frequency of common lymphoid progenitors and T cells was not altered, B cells were significantly reduced and showed increased apoptosis. However, Rcor1-deficient bone marrow sustained normal levels of B-cells following transplantation, indicating a non-cell autonomous requirement for Rcor1 in B-cell survival. Evaluation of the myelomonocytic lineage revealed an absence of mature neutrophils and a significant increase in the absolute number of monocytic cells. Rcor1-deficient monocytes were less apoptotic and showed ~100-fold more colony-forming activity than their normal counterparts, but did not give rise to leukemia. Moreover, Rcor1(-/-) monocytes exhibited extensive, cytokine-dependent self-renewal and overexpressed genes associated with hematopoietic stem/progenitor cell expansion including Gata2, Meis1, and Hoxa9. Taken together, these data demonstrate that Rcor1 is essential for the normal differentiation of myeloerythroid progenitors and for appropriately regulating self-renewal activity in the monocyte lineage. PMID- 26119983 TI - Molecular descriptors calculation as a tool in the analysis of the antileishmanial activity achieved by two series of diselenide derivatives. An insight into its potential action mechanism. AB - A molecular modeling study has been carried out on two previously reported series of symmetric diselenide derivatives that show remarkable antileishmanial in vitro activity against Leishmania infantum intracellular amastigotes and in infected macrophages (THP-1 cells), in addition to showing favorable selectivity indices. Series 1 consists of compounds that can be considered as central scaffold constructed with a diaryl/dialkylaryl diselenide central nucleus, decorated with different substituents located on the aryl rings. Series 2 consists of compounds constructed over a diaryl diselenide central nucleus, decorated in 4 and 4' positions with an aryl or heteroaryl sulfonamide fragment, thus forming the diselenosulfonamide derivatives. With regard to the diselenosulfonamide derivatives (2 series), the activity can be related, as a first approximation, with (a) the ability to release bis(4-aminophenyl) diselenide, the common fragment which can be ultimately responsible for the activity of the compounds. (b) the anti-parasitic activity achieved by the sulfonamide pharmacophore present in the analyzed derivatives. The data that support this connection include the topography of the molecules, the conformational behavior of the compounds, which influences the bond order, as well as the accessibility of the hydrolysis point, and possibly the hydrophobicity and polarizability of the compounds. PMID- 26119984 TI - Designing of potential inhibitors against Staphylococcus aureus sortase A: Combined analogue and structure based approach with in vitro validation. AB - Staphylococcus aureus sortase A is an attractive target of Gram-positive bacteria that plays a crucial role in anchoring of surface proteins to peptidoglycan present in bacterial cell wall. Inhibiting sortase A is an elementary and essential effort in preventing the pathogenesis. In this context, in silico virtual screening of in-house database was performed using ligand based pharmacophore model as a filter. The developed pharmacophore model AAHR 11 consists of two acceptors, one hydrophobic and one ring aromatic feature. Top ranked molecule KKR1 was docked into the active site of the target. After profound analysis, it was analyzed and optimized based on the observations from its binding pose orientation. Upgraded version of KKR1 was KKR2 and has improved docking score, binding interactions and best fit in the binding pocket. KKR1 along with KKR2 were further validated using 100 ns molecular dynamic studies. Both KKR1 and KKR2 contain Indole-thiazolidine moiety and were synthesized. The disk diffusion assay has good initial results (ZI of KKR1, KKR2 were 24, 38 mm at 10 MUg/mL and ZI of Ampicillin was 22 at 10 MUg/mL) and calculated MICs of the molecules (KKR1 5.56+/-0.28 MUg/mL, KKR2 1.32+/-0.12 MUg/mL, Ampicillin 8+/-1.1 MUg/mL) were in good agreement with standard drug Ampicillin. KKR1 has shown IC50 of 1.23+/-0.14 MUM whereas the optimized lead molecule KKR2 show IC50 of 0.008+/ 0.07 MUM. Results from in silico were validated by in vitro studies and proved that indole-thiazolidine molecules would be useful for future development as lead molecules against S. aureus sortase A. PMID- 26119985 TI - Introducing biological features at diagnosis improves the relapse risk stratification in patients with acute promyelocytic leukemia treated with ATRA and chemotherapy. PMID- 26119986 TI - bioCSL Limited's 2009 clinical trial to assess the immunogenicity and safety of trivalent influenza vaccine in US children raises concern. PMID- 26119987 TI - Improving eye care follow-up adherence in diabetic patients with ocular abnormalities: the effectiveness of patient contracts in a free, pharmacy-based eye screening. AB - OBJECTIVES: Patient contracts are increasingly utilized in medical practice and have the potential to improve health outcomes in high-risk populations. However, as a relatively new tool, there has been limited research regarding the efficacy of patient contracts. Diabetic retinopathy (DR) is one of the leading causes of vision impairment in adults in the US and only 50-60% of adults with diabetes adhere to annual dilated fundus exam recommendations. This study aimed to evaluate the impact of patient contracts on follow-up adherence in diabetic patients with ocular abnormalities after a free, pharmacy-based eye screening. STUDY DESIGN: This prospective study implemented a non-invasive, non-mydriatic fundus camera in an urban, community-based pharmacy setting to screen for ocular diseases in patients with diabetes. Patients were assigned to the contract or non contract group. Patients who signed a contract agreed to: 1) review their results with their primary care doctor, 2) follow-up with an ophthalmologist if their results were abnormal, and 3) inform research staff if/when they completed an eye care appointment. All study participants and their primary care doctors were notified of their results via mail. Follow-up questionnaires were administered to all patients by telephone three months after the screening results. RESULTS: 500 patients were screened and 113 (22.6%) had abnormal results. Of the patients who had abnormal results, 83 (74.3%) were able to be contacted. Of the 83 patients who were able to be contacted, the majority of patients were African American (73.5%) and female (56.6%). The mean age was 54.7 years. Of those, 34 (41.0%) adhered to follow-up recommendations. There was no significant difference in follow-up adherence between the contract (38.1%) and non-contract group (43.9%) (P = 0.59). In addition, 70.4% of patients did not comply with at least one measure of the contract agreement. CONCLUSION: Contracts did not increase follow up adherence to eye appointments in diabetic patients with ocular abnormalities. The majority of patients did not comply with their contract and follow-up adherence was low in both groups. Most research has yielded mixed results regarding the efficacy of contracts in improving health outcomes. Therefore, different types of contracts or other patient-centered tools should be evaluated in order to increase follow-up adherence in patients at high risk for DR. PMID- 26119988 TI - Knowledge, attitudes and behaviours on doping and supplements in young football players in Italy. PMID- 26119989 TI - Population-level effects and recovery of aquatic invertebrates after multiple applications of an insecticide. AB - Standard risk assessment of plant protection products (PPP) combines "worst-case" exposure scenarios with effect thresholds using assessment (safety) factors to account for uncertainties. If needed, risks can be addressed applying more realistic conditions at higher tiers, which refine exposure and/or effect assessments using additional data. However, it is not possible to investigate the wide range of potential scenarios experimentally. In contrast, ecotoxicological mechanistic effect models do allow for addressing a multitude of scenarios. Furthermore, they may aid the interpretation of experiments such as mesocosm studies, allowing extrapolation to conditions not covered in experiments. Here, we explore how to use mechanistic effect models in the aquatic risk assessment of a model insecticide (Modelmethrin), applied several times per season but rapidly dissipating between applications. The case study focuses on potential effects on aquatic arthropods, the most sensitive group for this substance. The models provide information on the impact of a number of short exposure pulses on sensitive and/or vulnerable populations and, when impacted, assess recovery. The species to model were selected based on their sensitivity in laboratory and field (mesocosm) studies. The general unified threshold model for survival (GUTS) model, which describes the toxicokinetics and toxicodynamics of chemicals in individuals, was linked to 3 individual-based models (IBM), translating individual survival of sensitive organisms into population-level effects. The impact of pulsed insecticide exposures on populations were modeled using the spatially explicit IBM metapopulation model for assessing spatial and temporal effects of pesticides (MASTEP) for Gammarus pulex, the Chaoborus IBM for populations of Chaoborus crystallinus, and the "IdamP" model for populations of Daphnia magna. The different models were able to predict the potential effects of Modelmethrin applications to key arthropod species inhabiting different aquatic ecosystems; the most sensitive species were significantly impacted unless respective mitigation measures were implemented (buffer zones resulting in reduced exposure). As expected the impact was stronger in shallow ditches as compared to deeper pond scenarios. Furthermore, as expected, recovery depended on factors such as temperature (affecting population growth rate and number of generations) and the occurence of nonimpacted aquatic ecosystems (their frequency and connectivity). These model predictions were largely in line with field observations and/or the results of a mesocosm study, providing additional evidence on the suitability and reliability of the models for risk assessment purposes. Because of their flexibility, models may predict the likelihood of unacceptable effects-based on previously defined protection goals-for a range of insecticide exposure scenarios and freshwater habitats. PMID- 26119990 TI - Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors. AB - Urease is an important enzyme which breaks urea into ammonia and carbon dioxide during metabolic processes. However, an elevated activity of urease causes various complications of clinical importance. The inhibition of urease activity with small molecules as inhibitors is an effective strategy for therapeutic intervention. Herein, we have synthesized a series of 19 benzofurane linked N phenyl semithiocarbazones (3a-3s). All the compounds were screened for enzyme inhibitor activity against Jack bean urease. The synthesized N-phenyl thiosemicarbazones had varying activity levels with IC50 values between 0.077 +/- 0.001 and 24.04 +/- 0.14 MUM compared to standard inhibitor, thiourea (IC50 = 21 +/- 0.11 MUM). The activities of these compounds may be due to their close resemblance of thiourea. A docking study with Jack bean urease (PDB ID: 4H9M) revealed possible binding modes of N-phenyl thiosemicarbazones. PMID- 26119991 TI - Design, synthesis, and biological evaluation of new N(4)-Substituted 2'-deoxy-2' fluoro-4'-azido cytidine derivatives as potent anti-HBV agents. AB - A series of new 2'-deoxy-2'-beta-fluoro-4'-azido-beta-d-arabinofuranosyl cytidine derivatives bearing heteroatom-containing N(4)-substituents were designed and synthesized. Antiviral screening in HepG2.2.15 cells identified three analogs (1a, 1d &1g) with good anti-HBV activity and low cytotoxicty. Of them, compound 1g exhibited significant inhibitory activity on both HBV antigens secretion (EC50, HBsAg = 9 nM, EC50, HBeAg = 0.25 MUM) and viral DNA replication (intracellular, EC50 = 0.099 MUM; extracellular, EC50 < 0.01 MUM). PMID- 26119992 TI - Synthesis, cytotoxicity and antimicrobial activity of thiourea derivatives incorporating 3-(trifluoromethyl)phenyl moiety. AB - A total of 31 of thiourea derivatives was prepared reacting 3 (trifluoromethyl)aniline and commercial aliphatic and aromatic isothiocyanates. The yields varied from 35% to 82%. All compounds were evaluated in vitro for antimicrobial activity. Derivatives 3, 5, 6, 9, 15, 24 and 27 showed the highest inhibition against Gram-positive cocci (standard and hospital strains). The observed MIC values were in the range of 0.25-16 MUg/ml. Inhibitory activity of thioureas 5 and 15 against topoisomerase IV isolated from Staphylococcus aureus was studied. Products 5 and 15 effectively inhibited the formation of biofilms of methicillin-resistant and standard strains of Staphylococcus epidermidis. Moreover, all obtained thioureas were evaluated for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses. Compounds 5, 6, 8-12, 15 resulted cytotoxic against MT-4 cells (CC50 <= 10 MUM). PMID- 26119993 TI - Palladium-Catalyzed Intramolecular Insertion of Alkenes into the Carbon-Nitrogen Bond of beta-Lactams. AB - The carbon-nitrogen bond of beta-lactams is cleaved by palladium(0), and an alkene is intramolecularly inserted therein. The following reductive elimination produces nitrogen-containing benzo-fused tricycles in good to high yields. PMID- 26119995 TI - Leptin-induced mitochondrial fusion mediates hepatic lipid accumulation. AB - BACKGROUND: Leptin alleviates metabolic conditions such as insulin resistance and obesity, although the precise mechanism of action is unclear. Mitochondrial fusion/fission states affect energy balance, but the association between mitochondrial fusion and lipid metabolism is also unknown. The aim of this study was to determine whether mitochondrial fusion/fission state regulates lipid accumulation and to understand the role of leptin in mitochondrial function and its mechanism of action in metabolic regulation. METHODS: Primary mouse hepatocytes were isolated from C57BL/6J mice and treated with leptin (25 ng ml( 1)) for 3 days before determinations of mitochondrial morphology and fatty acid accumulation. Hyperglycemia in C57BL/6J mice was induced by providing a 30% fructose-rich diet (FRD) for 6 months, followed by intraperitoneal injections of leptin (1 mg kg(-1) per body weight) for 6 weeks (twice per week). RESULTS: Leptin triggered mitochondrial fusion and alleviated high glucose-induced fatty acid accumulation in primary hepatocytes by promoting mitochondrial fusion associated transcription factor peroxisome proliferative-activated receptor-alpha and co-activator peroxisome proliferative-activated receptor-gamma co-activator (PGC)-1alpha. In turn, these activate the fusion protein mitofusin 1 (Mfn-1). RNA silencing of Mfn-1 or PGC-1 blocked the inhibitory effect of leptin. Leptin treatment also elevated liver Mfn-1 and PGC-1alpha and improved lipid profiles in FRD mice. CONCLUSIONS: Mitochondrial fusion has a critical role in alleviating hepatic fatty acid accumulation. Leptin switches mitochondrial morphology via a PGC-1alpha-dependent pathway to improve hyperlipidemia. PMID- 26119996 TI - Parents have different perceptions of bed-wetting than children from six to 15 years of age. AB - AIM: Enuresis is a common childhood disorder that negatively affects children's social and psychological well-being. This study investigated the psychological and emotional problems of children in Taiwan who wet the bed between the ages of six and 15 by comparing feedback from the children, their parents and a control group. METHODS: This case study featured 93 children with primary nocturnal enuresis from enuresis clinics, and their parents, and 98 nonenuretic controls and parents from the local community. All the parents completed the Behavioural and Emotional Rating Scale (BERS) and all the children completed the Teenage Self Concept Scale (TSCS). T-scores were used for statistical comparisons and high scores related to higher self-concept. RESULTS: The parents and their children displayed different perceptions of enuresis, with more behavioural and emotional problems in enuretic children. Older children and children with more severe enuresis reported more difficulties, and low maternal education was also a risk factor. CONCLUSION: Parental attitudes and perceptions towards bed-wetting were different from their children's. The children's age, enuresis severity and their mothers' educational level were potential risk factors that affected well-being. Health practitioners need to facilitate communication between enuretic children and their parents in addition to monitoring their psychological well-being. PMID- 26119994 TI - Mesoderm-specific transcript (MEST) is a negative regulator of human adipocyte differentiation. AB - BACKGROUND: A growing body of evidence suggests that many downstream pathologies of obesity are amplified or even initiated by molecular changes within the white adipose tissue (WAT). Such changes are the result of an excessive expansion of individual white adipocytes and could potentially be ameliorated via an increase in de novo adipocyte recruitment (adipogenesis). Mesoderm-specific transcript (MEST) is a protein with a putative yet unidentified enzymatic function and has previously been shown to correlate with adiposity and adipocyte size in mouse. OBJECTIVES: This study analysed WAT samples and employed a cell model of adipogenesis to characterise MEST expression and function in human. METHODS AND RESULTS: MEST mRNA and protein levels increased during adipocyte differentiation of human multipotent adipose-derived stem cells. Further, obese individuals displayed significantly higher MEST levels in WAT compared with normal-weight subjects, and MEST was significantly correlated with adipocyte volume. In striking contrast to previous mouse studies, knockdown of MEST enhanced human adipocyte differentiation, most likely via a significant promotion of peroxisome proliferator-activated receptor signalling, glycolysis and fatty acid biosynthesis pathways at early stages. Correspondingly, overexpression of MEST impaired adipogenesis. We further found that silencing of MEST fully substitutes for the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) as an inducer of adipogenesis. Accordingly, phosphorylation of the pro-adipogenic transcription factors cyclic AMP responsive element binding protein (CREB) and activating transcription factor 1 (ATF1) were highly increased on MEST knockdown. CONCLUSIONS: Although we found a similar association between MEST and adiposity as previously described for mouse, our functional analyses suggest that MEST acts as an inhibitor of human adipogenesis, contrary to previous murine studies. We have further established a novel link between MEST and CREB/ATF1 that could be of general relevance in regulation of metabolism, in particular obesity-associated diseases. PMID- 26119997 TI - Effects of pharmaceutical cost containment policies on doctors' prescribing behavior: Focus on antibiotics. AB - OBJECTIVES: We analyzed the effect of the outpatient prescription incentive program and price cuts of listed medicines in South Korea on prescription drug expenditures and prescription behaviors, focusing on antibiotics for the most common infectious diseases. METHODS: We used the National Health Insurance claims data from January 1, 2009 through December 31, 2012. For 1625 primary clinics randomly sampled, we included all claims with principal diagnoses of acute upper respiratory tract infections (URTIs, J00-J06), acute lower respiratory tract infections (LRTIs, J20-J22), or otitis media (H65, H66). An interrupted time series analysis was conducted. RESULTS: Pharmaceutical spending per claim dropped immediately after the outpatient prescription incentive program only for otitis media (adults), but the secular trend shifted downward after the incentive program for all target diseases. The incentive program lowered the trend of antibiotic prescribing rate in otitis media (adults). The program was associated with an increase of the number of antibiotics prescribed in URTI (adults) and LRTI (children) and decrease in otitis media (adults). The broad markdown of drug prices reduced pharmaceutical expenditures immediately for all diseases, but without lasting effect. CONCLUSION: The direct financial incentives to physicians to reduce in prescription spending had the intended effect over time and can be an important tool to improve pharmaceutical spending management. PMID- 26119998 TI - Nuclear Localization and Gene Expression Modulation by a Fluorescent Sequence Selective p-Anisyl-benzimidazolecarboxamido Imidazole-Pyrrole Polyamide. AB - Synthetic pyrrole (P)-imidazole (I) containing polyamides can target predetermined DNA sequences and modulate gene expression by interfering with transcription factor binding. We have previously shown that rationally designed polyamides targeting the inverted CCAAT box 2 (ICB2) of the topoisomerase IIalpha (topo IIalpha) promoter can inhibit binding of transcription factor NF-Y, re inducing expression of the enzyme in confluent cells. Here, the A/T recognizing fluorophore, p-anisylbenzimidazolecarboxamido (Hx) was incorporated into the hybrid polyamide HxIP, which fluoresces upon binding to DNA, providing an intrinsic probe to monitor cellular uptake. HxIP targets the 5'-TACGAT-3' sequence of the 5' flank of ICB2 with high affinity and sequence specificity, eliciting an ICB2-selective inhibition/displacement of NF-Y. HxIP is readily taken up by NIH3T3 and A549 cells, and detected in the nucleus within minutes. Exposure to the polyamide at confluence resulted in a dose-dependent upregulation of topo IIalpha expression and enhanced formation of etoposide-induced DNA strand breaks. PMID- 26119999 TI - Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX. AB - Regulatory mechanisms underlying gammaH2AX induction and the associated cell fate decision during DNA damage response (DDR) remain obscure. Here, we discover a bromodomain (BRD)-like module in DNA-PKcs (DNA-PKcs-BRD) that specifically recognizes H2AX acetyl-lysine 5 (K5ac) for sequential induction of gammaH2AX and concurrent cell fate decision(s). First, top-down mass spectrometry of radiation phenotypic, full-length H2AX revealed a radiation-inducible, K5ac-dependent induction of gammaH2AX. Combined approaches of sequence-structure modeling/docking, site-directed mutagenesis, and biochemical experiments illustrated that through docking on H2AX K5ac, this non-canonical BRD determines not only the H2AX-targeting activity of DNA-PKcs but also the over-activation of DNA-PKcs in radioresistant tumor cells, whereas a Kac antagonist, JQ1, was able to bind to DNA-PKcs-BRD, leading to re-sensitization of tumor cells to radiation. This study elucidates the mechanism underlying the H2AX-dependent regulation of DNA-PKcs in ionizing radiation-induced, differential DDR, and derives an unconventional, non-catalytic domain target in DNA-PKs for overcoming resistance during cancer radiotherapy. PMID- 26120000 TI - Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases. AB - Serine hydrolase inhibitors, which facilitate enzyme function assignment and are used to treat a range of human disorders, often act by an irreversible mechanism that involves covalent modification of the serine hydrolase catalytic nucleophile. The portion of mammalian serine hydrolases for which selective inhibitors have been developed, however, remains small. Here, we show that N hydroxyhydantoin (NHH) carbamates are a versatile class of irreversible serine hydrolase inhibitors that can be modified on both the staying (carbamylating) and leaving (NHH) groups to optimize potency and selectivity. Synthesis of a small library of NHH carbamates and screening by competitive activity-based protein profiling furnished selective, in vivo-active inhibitors and tailored activity based probes for multiple mammalian serine hydrolases, including palmitoyl protein thioesterase 1, mutations of which cause the human disease infantile neuronal ceroid lipofuscinosis. PMID- 26120001 TI - Structural Basis for beta-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB. AB - The beta-carboline (betaC) alkaloids occur throughout nature and exhibit diverse biological activities. In contrast to betaC alkaloid synthesis in plants, the biosynthesis in microorganisms remains poorly understood. The recently reported McbB from Marinactinospora thermotolerans is a novel enzyme proposed to catalyze the Pictet-Spengler (PS) reaction of L-tryptophan and oxaloacetaldehyde to produce the betaC scaffold of marinacarbolines. In this study, we solved the crystal structure of McbB complexed with L-tryptophan at 2.48 A resolution, which revealed the novel protein folding of McbB and the totally different structure from those of other PS condensation catalyzing enzymes, such as strictosidine synthase and norcoclaurine synthase from plants. Structural analysis and site directed mutagenesis confirmed that the previously proposed catalytic Glu97 at the active-site center functions as an acid and base catalyst. Remarkably, the structure-based mutants R72A and H87A, with expanded active-site cavities, newly accepted bulky phenylglyoxal as the aldehyde substrate, to produce 1-benzoyl-3 carboxy-beta-carboline. PMID- 26120002 TI - DNA Electrochemistry Shows DNMT1 Methyltransferase Hyperactivity in Colorectal Tumors. AB - DNMT1, the most abundant human methyltransferase, is responsible for translating the correct methylation pattern during DNA replication, and aberrant methylation by DNMT1 has been linked to tumorigenesis. We have developed a sensitive signal on electrochemical assay for the measurement of DNMT1 activity in crude tissue lysates. We have further analyzed ten tumor sets and have found a direct correlation between DNMT1 hyperactivity and tumorous tissue. In the majority of samples analyzed, the tumorous tissue has significantly higher DNMT1 activity than the healthy adjacent tissue. No such correlation is observed in measurements of DNMT1 expression by qPCR, DNMT1 protein abundance by western blotting, or DNMT1 activity using a radiometric DNA labeling assay. DNMT1 hyperactivity can result from both protein overexpression and enzyme hyperactivity. DNMT1 activity measured electrochemically provides a direct measure of activity in cell lysates and, as a result, provides a sensitive and early indication of cancerous transformation. PMID- 26120003 TI - Quantitative Evaluation for Uncertainty of Information About Patients' Injury Severity in a Hospital Disaster: A Simulation Study Using Shannon's Information Theory. AB - INTRODUCTION: Reducing uncertainty about information on injury severity or number of patients is an important concern in managing equipment and rescue personnel in a disaster setting. A simplified disaster model was designed using Shannon's Information Theory to study the uncertainty of information in a triage scenario. Hypothesis A disaster triage scene with a specific number of injured patients represents a source of information regarding the extent of patients' disability. It is possible to quantify uncertainty of information regarding patients' incapacity as entropy if the information source and information arising from the source in Information Theory can be adapted to the disaster situation and the information on patients' incapacity that arises. METHODS: Five different scenarios of a fire disaster in a hospital were modeled. Information on patients' extent of impairment was converted to numerical values in relation to available equipment and the number of rescue personnel. Victims were 10 hospitalized patients with conditions of unknown severity. Triage criteria were created arbitrarily and consisted of four categories from Level 1 (able to walk) to Level 4 (cardiac arrest). The five situations were as follows: (1) Case 1: no triage officer; (2) Case 2: one triage officer; (3) Case 3: one triage officer and a message that six patients could walk; (4) Case 4: one triage officer and a message that all patients could obey commands; and (5) Case 5: one triage officer and a message that all patients could walk. Entropy in all cases and the amount of information newly given in Cases 2 through 5 were calculated. RESULTS: Entropies in Cases 1 through 5 were 5.49, 2.00, 1.60, 1.00, and 0.00 bits/symbol, respectively. These values depict the uncertainty of probability of the triage categories arising in each situation. The amount of information for the triage was calculated as 3.49 bits (ie, 5.49 minus 2.00). In the same manner, the amount of information for the messages in Cases 3 through 5 was calculated as 0.4, 1.0, and 2.0 bits, respectively. These amounts of information indicate a reduction in uncertainty regarding the probability of the triage levels arising. CONCLUSION: It was possible to quantify uncertainty of information about the extent of disability in patients at a triage location and to evaluate reduction of the uncertainty by using entropy based on Shannon's Information Theory. PMID- 26120004 TI - Vitamin D deficiency in critically ill children with sepsis. AB - BACKGROUND: Data on the prevalence of vitamin D deficiency (VDD) in critically ill children with sepsis and its association with illness severity and outcome are limited. AIM: To investigate the prevalence of VDD in critically ill children with sepsis. METHODS: One hundred and twenty-four critically ill children with sepsis aged 1-12 years were prospectively enrolled in a paediatric intensive care unit (PICU) in North India over a 1-year period. Demographic data, clinical signs and risk factors for VDD, Paediatric Index of Mortality III (PRISM III) score, and sequential organ failure assessment (SOFA) score were recorded. Plasma 25 hydroxy vitamin D [25(OH)D] levels were measured by ELISA within 24 hours of admission. The occurrence of septic shock, multiple organ dysfunction syndrome (MODS) and healthcare-associated infection (HCAI), need for mechanical ventilation and catecholamines, length of PICU stay and mortality were also recorded. Cases were compared with 338 apparently healthy children for baseline variables and vitamin D status. RESULTS: Prevalence of VDD [25(OH)D level < 50 nmol/L] was higher among critically ill children with sepsis compared to healthy controls (50.8% vs 40.2%, P = 0.04). VDD was not associated with any significant difference in baseline demographic variables or risk factors for VDD. Although there was a trend toward increased PRISM III score, septic shock, MODS, HCAI, need for mechanical ventilation and catecholamines, length of PICU stay, and mortality, the difference was not statistically significant. CONCLUSION: A high prevalence of VDD in critically ill children with sepsis was found but it was not associated with greater severity of illness or other clinical outcomes. PMID- 26120005 TI - Pulmonary sarcoidosis in a preschool patient. AB - Sarcoidosis is a rare disease, especially in the preschool age group where it usually presents with eye, joint, and skin involvement sparing the lungs. Multiple treatment regimes have been described with oral prednisolone being the usual first line treatment. We describe a case of a 4-year-old boy presenting with pulmonary sarcoidosis with no other organ involvement. The child was successfully managed with pulse intravenous methylprednisolone followed by oral prednisolone and has had a good outcome. This case reports a rare presentation of preschool sarcoidosis as well as the novel and successful use of pulse methylprednisolone in paediatric pulmonary sarcoidosis. PMID- 26120006 TI - Thiazolylidene-catalyzed cleavage of methyl oleate-derived alpha-hydroxy ketone to the corresponding free aldehydes. AB - The thiazolylidene-catalyzed cleavage of the alpha-hydroxy ketone derived from methyl oleate gave the corresponding aldehydes under nonoxidative conditions through a retro-benzoin process. The aldehydes produced are in equilibrium with their corresponding acyloins. To illustrate the synthetic utility of this protocol, the aldehydes were recovered by distillation. PMID- 26120007 TI - Sudden unexplained death in childhood: A comparison of cases with and without a febrile seizure history. AB - OBJECTIVE: We considered whether a subset of children with sudden unexplained death in childhood (SUDC) and a history of febrile seizures (FS) may parallel those in sudden unexpected death in epilepsy (SUDEP). The prevalence of a history of FS was examined, and factors that may distinguish SUDC cases with and without FS were described. METHODS: Characteristics were assessed in 123 consecutive children with SUDC reported to the SUDC program (4/1/11-3/31/14) by their parents. Parental interview covered the decedent's medical history, circumstances of death, environmental factors, cause of death, and family medical history. Features of SUDC cases were compared by FS history. RESULTS: Overall, 31.7% of SUDC cases had a history of FS, among which 74.4% had simple FS. Compared to those without a history of FS, a history of FS was associated with a greater median age at death (p = 0.03) and death during the weekdays (p = 0.02). Terminal fever was similar in those with and without FS. The median time from FS to death was 6.0 months (interquartile range [IQR] 3.0-10.0). In all SUDC cases, prone position at death, death during sleep, and unwitnessed deaths predominated. SIGNIFICANCE: There are parallels among SUDC, sudden infant deaths, and sudden unexpected death in epilepsy (SUDEP) with regard to prone position, unwitnessed deaths mostly during sleep, and male predominance. In children with SUDC and a history of FS, terminal fever may increase the risk for an unwitnessed terminal seizure. The greater than expected prevalence of a FS history and the proportion with terminal fever or illness in this cohort suggests that some SUDC deaths may be seizure related and therefore have potential commonalities with SUDEP. PMID- 26120008 TI - Ion pair liquid chromatography method for the determination of thiamine (vitamin B1) homeostasis. AB - A new method for reversed phase HPLC determination of thiamine and its major in vivo phosphorylation products, thiamine monophosphate (TMP) and thiamine pyrophosphate (TPP), was developed using tetrabutylammonium hydroxide as the ion pairing agent. The separation was performed on a Phenomenex Kinetex EVO C18 column with a gradient of a phosphate-buffered aqueous solution of the ion-pair reagent and methanol. The duty cycle for the assay was 13 min and pyrithiamine was successfully used as the internal standard for the first time in a thiamine HPLC measurement protocol. Detection of the fluorescence derivatives of the analytes as well as the IS allowed for lower detection limits in order to support biological applications in cell culture models. The linearity, sensitivity, specificity, accuracy and precision of the method were evaluated and met the requirements specified by the US Food and Drug Administration. The calibration curves proved to be linear and the method was validated over the range from 1.0 4000 nM for both cells and the media where complete recovery of the analytes was also achieved. PMID- 26120011 TI - A proposed new function of the cerebrospinal fluid. PMID- 26120010 TI - Evaluation of the effects of the weak CYP3A inhibitors atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects. AB - Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3 fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor. PMID- 26120009 TI - Epigenetic signaling in schizophrenia. AB - Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Psychiatric disorders such as schizophrenia and depression are complex and heterogeneous diseases with multiple and independent factors that may contribute to their pathophysiology, making challenging to find a link between specific elements and the underlying mechanisms responsible for the disorder and its treatment. Growing evidences suggest that epigenetic modifications in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychiatric conditions throughout life. This review focuses on recent advances that directly implicate epigenetic modifications in schizophrenia and antipsychotic drug action. PMID- 26120012 TI - Comparison of biochemical and immunological profile of pediatric patients with acute myeloid leukemia in relation to healthy individuals. AB - OBJECTIVE: To compare the biochemical and immunological profiles of pediatric patients with acute myeloid leukemia (AML) with healthy children and adolescents. METHODS: This was a cross-sectional study in which 21 therapy-naive patients with AML were compared with a group of 24 healthy individuals. The following data were analyzed: serum proteins, leucocytes and subgroups, erythrocytes, hematocrit, hemoglobin, platelets, cytokines in peripheral blood mononuclear cells cultures under spontaneous and BCG- or PHA-stimulated conditions, immunoglobulin A, and erythrocytic glutathione. Statistical analysis was performed using SPSS software, considering as significant p-values<0.05. RESULTS: Serum albumin levels were higher (p<0.0001) in the control group, as well as all the parameters related to red blood cells (p<0.0001). For leucocytes and subgroups, no statistical difference was found between the AML and the control groups. For cytokines, the concentrations were significantly higher under spontaneous and BCG-stimulated conditions for TNF-alpha, IL-6, IL-10, and IFN-gamma in the control group. Under PHA-stimulated conditions, the concentration was higher (p=0.002) only for IL-6. No difference was found between the two groups for the other cytokines and for IgA in the saliva. Erythrocytic glutathione was higher (p<0.0001) in AML patients. CONCLUSIONS: It was possible to characterize the biochemical and immunological profile of pediatric patients with AML, as well as highlight some significant differences in these parameters when comparing with healthy children and adolescents. PMID- 26120013 TI - CORRIGENDUM: Clinical Presentation, Management and Outcome of Japanese Patients With Acute Myocardial Infarction in the Troponin Era--Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET). AB - The authors apologize for the incorrect statement in the Methods section. The correct statement is shown below. Page 1256, right column, lines 10-12: Incorrect: Consecutive patients hospitalized within 48 h of onset of AMI at 28 Japanese medical institutions were enrolled between July 2013 and May 2014. Correct: Consecutive patients hospitalized within 48 h of onset of AMI at 28 Japanese medical institutions were enrolled between July 2012 and March 2014. PMID- 26120016 TI - Evaluation of one-year mortality after geriatric ankle fractures in patients admitted to nursing homes. AB - INTRODUCTION: The incidence of geriatric ankle fractures will undoubtedly increase as the population continues to grow. Many geriatric patients struggle to function independently after such injury and often require placement into nursing homes. The morbidity and mortality associated with nursing homes is well documented within the field of orthopaedic surgery. However, there is currently no study examining the mortality associated with nursing home placement following hospitalization for an ankle fracture. Therefore, the purpose of this study was to determine if geriatric patients admitted to nursing homes following an ankle fracture experience elevated mortality rates. METHODS: Patients were identified using diagnosis codes for ankle fractures from all 2008 part A Medicare claims, and those admitted to nursing homes were identified using a Minimum Data Set (MDS). The Medicare database was also analyzed for specific variables including over-all one year mortality, length of stay, age distribution, certain demographical characteristics, incidence of medical and surgical complications within 90 days, and the presence of comorbidities. Multivariate logistic regression analysis was used to determine if patients admitted to nursing homes had elevated mortality rates. RESULTS: 19,648 patients with ankle fractures were identified, and 11,625 (59.0%) of these patients went to a nursing home after hospitalization. Patients who went to a nursing home had higher Elixhauser and Deyo-Charlson comorbidity scores (p<0.0001). Nursing home patients also had significantly increased rates of postoperative medical and surgical complications. One year mortality was 6.9% for patients who did not go to a nursing home and 15.4% for patients who were admitted to a nursing home (p<0.0001). However, multivariate logistic regression analysis demonstrated no significant difference in one year mortality between patients admitted to nursing homes and those who were not (OR=1.1; 95% CI 0.99-1.24, p>0.05). DISCUSSION: Although admission to nursing home was significantly associated with increased mortality in a bivariate statistical model, this significance was lost during multivariate analysis. This suggests that other patient characteristics may play a more prominent role in determining one year mortality following geriatric ankle fractures. PMID- 26120017 TI - Femoral vein injury from a trochanteric hip fracture. PMID- 26120018 TI - Displaced proximal humeral fractures: when is surgery necessary? AB - BACKGROUND: Several therapeutic methods have been traditionally used in the treatment of displaced proximal humeral fractures; however, the indication of these treatments is still controversial. The purpose of this study was to compare the medium-term functional results of four methods commonly used in the treatment of proximal humeral fractures [conservative treatment, proximal humeral nails (PHN), percutaneous K-wiring (PKW), and locking-plates (LP)] taking into consideration the type of fracture and the age of the patients. METHODS: We conducted a retrospective cohort study on patients with proximal humeral fractures treated with one of the following methods: conservative treatment, PHN, PKW, or LP. Functional results were assessed using the absolute Constant score and the disabilities of the arm shoulder and hand score (DASH). The functional outcome was analysed according to age (>=65 years and <65 years) and fracture type (displaced 2-fragment and 3-4-fragment fractures). RESULTS: A total of 113 patients were included in the study, with a mean age of 65.3 SD 15.2 years and average follow-up time of 26.2 SD 12.6 months. Patients under 65 years had higher Constant scores when treated with PHN and PKW than those treated conservatively (77.2 vs. 54.7, p=0.01 and 74.0 vs. 54.7, p=0.03, respectively). Patients above 65 years had higher Constant scores when treated with PKW compared to PHN and conservative treatment (68.7 vs. 51.9, p=0.02 and 68.7 vs. 55.9, p=0.029, respectively). In 2-fragment fractures, PKW resulted in higher Constant scores than conservative treatment (70.4 vs. 53.9, p=0.048). No differences were found in the final outcome between patients treated with LP and those treated conservatively regardless of age, and fracture type. There were also no differences between any of the evaluated methods in the treatment of 3-4-fragment fractures. CONCLUSION: The use of PKW was associated with better functional results than conservative treatment in individuals of all ages, especially in patients with 2-fragment fractures; PKW also achieved better functional results than PHN in elderly patients. PHN was superior to conservative treatment in young individuals. No significant differences were found between LP and conservative treatment in any of the analysed categories. PMID- 26120019 TI - Pantaloon femoral vein graft as "neoaorta" in infected aortic disease. AB - Infected abdominal aortic disease and graft infections pose a significant challenge for the vascular surgeon. Thorough radical debridement, either preceded by extra-anatomic bypass or followed by in situ aortic replacement, is the mainstay of treatment. The role of endovascular repair by stent grafts is being increasingly described but is limited to relatively less virulent mycotic aneurysms or as a "bridging" option in sick patients with florid sepsis that necessitates eventual delayed definitive surgical management. Autologous femoral vein has been an excellent conduit for aortic bifurcation reconstruction in this setting. Although various configurations of femoral vein conduit have been described for aortobi-iliac reconstruction, an in-depth knowledge of the venous anatomy, physiology, mechanisms of "profundization," and techniques of harvest and graft preparation is essential for efficient conduct of the operation and its optimal outcomes. We review in detail these aspects of "pantaloon" femoral vein graft creation as a "neoaorta". PMID- 26120020 TI - The comparison of the technical parameters in endotracheal intubation devices: the Cmac, the Vividtrac, the McGrath Mac and the Kingvision. AB - Currently, there are plenty of videolaryngoscopes that appear on the market. They have different specifications. Some of these features favor the fact that they are more suited for educational purposes of future operators and others can be characterized with an excellent clinical use. In this study we compared four types of videolaryngoscopes. The aim of the study was to compare the technical specifications of the above-mentioned devices for usefulness in clinical practice and correlate these parameters with the subjective evaluation of these videolaryngoscopes usage performed in practice by an experienced medical staff. All devices considered in this study participated in another multicenter clinical study on the basis of which we completed the subjective evaluation of the operators. In order to examine the technical parameters of the equipment we established the cooperation with the Department of Microelectronics at Technical University of Lodz. Mechanical and optical parameters and the endoscopic tube current were taken into consideration. The C-MAC has a camera with the widest viewing angle (the OX axis-63.1, the axis OY-47.8), which in combination with the largest diagonal size of the display enables the operator to see the details relevant to clinical practice. It has also the strongest lamp intensity of the devices mentioned in this comparison (7800 Lx). In comparison of the clinical use in almost all compared parameters the Cmac D-blade is a winner, although for clinical education purpose we consider the Vividtrac a better device. PMID- 26120021 TI - Plasmonic Colloidosomes as Three-Dimensional SERS Platforms with Enhanced Surface Area for Multiphase Sub-Microliter Toxin Sensing. AB - Colloidosomes are robust microcapsules attractive for molecular sensing because of their characteristic micron size, large specific surface area, and dual-phase stability. However, current colloidosome sensors are limited to qualitative fluorogenic receptor-based detection, which restrict their applicability to a narrow range of molecules. Here, we introduce plasmonic colloidosome constructed from Ag nanocubes as an emulsion-based 3D SERS platform. The colloidosomes exhibit excellent mechanical robustness, flexible size tunability, versatility to merge, and ultrasensitivity in SERS quantitation of food/industrial toxins down to sub-femtomole levels. Using just 0.5 MUL of sample volumes, our plasmonic colloidosomes exhibit >3000-fold higher SERS sensitivity over conventional suspension platform. Notably, we demonstrate the first high-throughput multiplex molecular sensing across multiple liquid phases. PMID- 26120022 TI - Oxymatrine attenuated hypoxic-ischemic brain damage in neonatal rats via improving antioxidant enzyme activities and inhibiting cell death. AB - Oxymatrine (OMT), an active constituent of Chinese herb Sophora flavescens Ait, has been proved to possess anti-tumor, anti-oxidant, anti-inflammatory, and anti apoptotic activities. Previous study has demonstrated that OMT had protective roles on multiple in vitro and in vivo brain injury models including regulation of apoptosis-related proteins caspase-3, Bax and Bcl-2. In this study, we investigated whether this protective effect could apply to neonatal hypoxic ischemic brain damage. Seven-day-old Sprague-Dawley rats were treated with the left carotid artery ligation followed by exposure to 8% oxygen (balanced with nitrogen) for 2.5 h at 37 degrees C. In sham group rats, neither ligation nor hypoxia was performed. After two successive days intraperitoneal injection with OMT (30, 60 and 120 mg/kg), Nimodipine (1 mg/kg), and saline, brain infarct volume was estimated, histomorphology changes were performed by hematoxylin-eosin (HE) staining as well as electron microscopy. In addition, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC), as well as production of malondialdehyde (MDA) were assayed in ipsilateral hemisphere homogenates to evaluate the redox status after hypoxic-ischemic. Expression of apoptosis-related proteins Caspase 3, Bax and Bcl-2 in brain were analyzed by western-blot analysis and immunofluorescence. Administration of OMT significantly decreased brain infarct volume and the percentage of injured cells, and ameliorated histopathology and morphological injury as well. Furthermore, OMT obviously increased the activities of SOD, GSH-Px, CAT and T-AOC, and decreased MDA content. Western-blot analysis showed a marked decrease in Caspase-3 expression and increase in the ratio of Bcl 2/Bax after OMT (120 mg/kg) post-treatment as compared with hypoxic-ischemic group. These results suggest that OMT exerts a neuroprotective effect against hypoxic-ischemic brain damage in neonatal rats, which is likely to be mediated through increasing anti-oxidant enzyme activities and inhibiting cell death. PMID- 26120023 TI - Biofilms in chronic rhinosinusitis: what is new and where next? AB - BACKGROUND: Chronic rhinosinusitis is a common, heterogeneous condition. An effective means of mitigating disease in chronic rhinosinusitis patients remains elusive. A variety of causes have been implicated, with the biofilm theory gaining increasing prominence. OBJECTIVE: This article reviews the literature on the role of biofilms in chronic rhinosinusitis, in terms of pathophysiology and with regard to avenues for future treatment. METHODS: A systematic review of case series was performed using databases with independently developed search strategies, including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane library, and Zetoc, in addition to conference proceedings and a manual search of literature, with the last search conducted on 18 January 2014. The search terms included the following, used in various combinations to maximise the yield of articles identified: 'biofilms', 'chronic rhinosinusitis', 'DNase', 'extracellular DNA' and 'biofilm dispersal'. RESULTS: The existing evidence lends further support for the role of biofilms (particularly the Staphylococcus aureus phenotype) in more severe, recalcitrant disease and poorer surgical outcomes. CONCLUSION: Multimodality treatment, with a shift in paradigm to incorporate anti-biofilm strategies, is likely to form the mainstay of future recalcitrant chronic rhinosinusitis management. PMID- 26120024 TI - Calcium Hydride Catalyzed Highly 1,2-Selective Pyridine Hydrosilylation. AB - Reaction of the calcium hydride complex (DIPPnacnac-CaH?THF)2 with pyridine is much faster and selective than that of the corresponding magnesium hydride complex (DIPPnacnac = [(2,6-iPr2 C6 H3 )NC(Me)]2 CH). With a range of pyridine, picoline and quinoline substrates, exclusive transfer of the hydride ligand to the 2-position is observed and also at higher temperatures no 1,2->1,4 isomerization is found. The heteroleptic product DIPPnacnac-Ca(1,2 dihydropyridide)?(pyridine) shows fast ligand exchange into homoleptic calcium complexes and therefore could not be isolated. Calcium hydride reduction of isoquinoline gave well-defined homoleptic products which could be characterized by X-ray diffraction: Ca(1,2-dihydroisoquinolide)2 ?(isoquinoline)4 and Ca3 (1,2 dihydroisoquinolide)6 ?(isoquinoline)6 . The striking selectivity difference in the dearomatization of pyridines by Mg or Ca complexes could be explained by DFT theory and was utilized in catalysis. Whereas hydroboration of pyridine with pinacol borane with a calcium hydride catalyst gave only minor conversion, the hydrosilylation of pyridine and quinolines with PhSiH3 yields exclusively 1,2 dihydropyridine and 1,2-dihydroquinoline silanes with 80-90 % conversion. Similar results can be achieved with the catalyst Ca[N(SiMe3 )2 ]2 ?(THF)2 . These calcium complexes represent the first catalysts for the 1,2-selective hydrosilylation of pyridines. PMID- 26120025 TI - Molecular-scale quantitative charge density measurement of biological molecule by frequency modulation atomic force microscopy in aqueous solutions. AB - Surface charge distributions on biological molecules in aqueous solutions are essential for the interactions between biomolecules, such as DNA condensation, antibody-antigen interactions, and enzyme reactions. There has been a significant demand for a molecular-scale charge density measurement technique for better understanding such interactions. In this paper, we present the local electric double layer (EDL) force measurements on DNA molecules in aqueous solutions using frequency modulation atomic force microscopy (FM-AFM) with a three-dimensional force mapping technique. The EDL forces measured in a 100 mM KCl solution well agreed with the theoretical EDL forces calculated using reasonable parameters, suggesting that FM-AFM can be used for molecular-scale quantitative charge density measurements on biological molecules especially in a highly concentrated electrolyte. PMID- 26120026 TI - Predictive factors associated with adverse events in patients with toxic colitis: an analysis of the National Surgical Quality Improvement Project. AB - BACKGROUND: Toxic colitis (TC) is a potentially lethal complication of inflammatory bowel disease and infectious colitis. METHODS: The National Surgical Quality Improvement Project dataset was queried to identify emergent colectomy for a primary diagnosis of TC using International Classification of Diseases, Ninth Revision codes. The study endpoints were 30-day mortality and 30-day morbidity. We performed multivariate logistic regression analyses to study factors associated with 30-day mortality. RESULTS: Of the 189 TC patients, mortality for colectomy was 26.5%, 42.3% experienced pulmonary complications, 20.6% experienced sepsis complications, 17.5% experienced cardiovascular complications, 12.7% experienced renal complications, and 14.8% experienced wound complications. On multivariate analysis, independent factors associated with mortality were age 70 to 80 years (odds ratio [OR] 3.5), age greater than 80 (OR 22.2), female sex (OR 4.1), uremia blood urea nitrogen greater than 40 (OR 4.1), coagulopathy international normalized ratio greater than 2 (OR 7.7), preoperative respiratory failure (OR 2.73), and preoperative steroid use (OR 3.9). CONCLUSIONS: Patients with TC are very ill. Poor outcome is associated with older age, female sex, preoperative azotemia, preoperative respiratory failure, and chronic steroid use. These factors will help acute care surgeons in preoperative risk assessment and could be an important addition to decision-making strategies. PMID- 26120027 TI - Protective role of naringin against cisplatin induced oxidative stress, inflammatory response and apoptosis in rat striatum via suppressing ROS-mediated NF-kappaB and P53 signaling pathways. AB - Cisplatin (Cis) is an effective chemotherapeutic agent successfully used in the treatment of a wide range of malignancies while its usage is limited due to its dose-dependent toxicity. The present study was conducted to investigate the efficacy of naringin, an ubiquitous flavonoid, against Cis-induced striatum injury in Wistar aged rats. Briefly, the experimental procedures were divided in two sets of experiments. In the first, the animals were divided into 4 groups: control, Nar 25mg/kg, Nar 50mg/kg and Nar 100mg/kg. In the second, the animals were divided into 4 groups: Cis (5mg/kg/week for 5 consecutive weeks), Cis+Nar (25mg/kg), Cis+Nar (50mg/kg) and Cis+Nar (100mg/kg). The administration of Cis (5mg/kg/week for 5 consecutive weeks) resulted in a decline in the concentrations of reduced glutathione and ascorbic acid. The activity of membrane bound ATPases and glutathione peroxidase (GPx) were decreased while the activity of catalase (CAT) and superoxide dismutase (SOD) were increased. Further, in striatum tissue, Cis significantly enhance the mRNA gene expression of P53, nuclear factor kappaB pathway (NFkappaB) and tumor necrosis factor (TNF-alpha). Oxidative/nitrosative stress was evident in Cis group by increased malondialdehyde (MDA), protein carbonyls (PCO), reactive oxygen species (ROS) and nitrite concentration (NO). Naringin (25, 50 and 100mg/kg) administration was able to protect against deterioration in striatum tissue, abrogate the change in antioxidant enzyme activities and suppressed the increase in MDA, PCO, NO and TNF-alpha concentrations. Moreover, Nar inhibited P53, NFkB and TNF-alpha pathways mediated inflammation and apoptosis, and improved the histological changes induced by Cis. Thus, these findings demonstrated the neuroprotective nature of Nar by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in striatum tissue. These results imply that Nar has perfect effect against Cis-induced striatum injury in aged rats, which should be developed as an effective food and healthcare product for the treatment of brain injury in the future. PMID- 26120028 TI - Pre-clinical formulation screening, development and stability of acetyl aspartic acid for cosmetic application. AB - BACKGROUND: Acetyl aspartic acid (A-A-A) was discovered through gene array analysis with corresponding connectivity mapping (Cmap). Using an in silico and in vitro approach, A-A-A was found increased keratinocyte regeneration, inhibited dermal expression of MMP making this compound a potential active ingredient for cosmetic application. OBJECTIVES: To determine the conditions to successfully formulate A-A-A for skin delivery investigation and in vivo clinical assessment by the systematic approach of pre-formulation testing of the active, screening of formulation type on active delivery and stability evaluations. METHODS: Analytical evaluation of A-A-A was undertaken using LC-MS ESI method. Formulation stability was evaluated using Brookfield viscometer, pH analysis, optical microscopy and organoleptic evaluations. RESULTS: Analytical evaluation of A-A-A shows that pH significantly impacts chemical stability of the molecule. A-A-A containing formulae show minimal differences to vehicle product throughout the testing. CONCLUSION: A-A-A is an active that can be successfully formulated in a cosmetic o/w emulsion within defined pH considerations. PMID- 26120030 TI - Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier. AB - Pericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2(-/-) embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2(-/-) brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfrbeta. Tgfbeta-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgfbeta pathway components, including Tgfbeta2, Tgfbetar2, Alk5, and integrins alphaVbeta8, were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans. PMID- 26120029 TI - Thirst and sodium appetite in rats with experimental nephrotic syndrome. AB - Nephrotic syndrome is a renal disease accompanied by abnormal body fluid balance. The present experiments investigated the role of behavioral mechanisms in contributing to disordered fluid homeostasis in rats with experimentally-induced nephrotic syndrome. The studies examined water and sodium ingestion under ad libitum conditions and in response to dehydration-related challenges in rats made nephrotic by treatment with the antibiotic, adriamycin. Rats with nephrotic syndrome had greater ad libitum water intakes beginning 3 weeks after treatment, but daily sodium (0.3M NaCl) intakes were not affected. Nephrotic rats showed attenuated water and sodium intakes after combined treatment with furosemide (10mg/kg) and captopril (2mg/kg), reduced water intakes after 20h of water deprivation, and diminished water intakes, plasma renin activity and aldosterone secretion after subcutaneous isoproterenol (30 MUg/kg). However, the adriamycin treated animals had normal water intakes in response to subcutaneous hypertonic saline (4% at 0.75 ml/100g) and central injections of angiotensin II (10, 20, and 50 ng). The results suggest that water and sodium ingestion in response to hypovolemic/hypotensive stimuli are disturbed in nephrotic rats, and provide evidence that the disordered behaviors reflect disturbances of the peripheral renin-angiotensin-aldosterone system. PMID- 26120031 TI - Chloroplast Stromules Function during Innate Immunity. AB - Inter-organellar communication is vital for successful innate immune responses that confer defense against pathogens. However, little is known about how chloroplasts, which are a major production site of pro-defense molecules, communicate and coordinate with other organelles during defense. Here we show that chloroplasts send out dynamic tubular extensions called stromules during innate immunity or exogenous application of the pro-defense signals, hydrogen peroxide (H2O2) and salicylic acid. Interestingly, numerous stromules surround nuclei during defense response, and these connections correlate with an accumulation of chloroplast-localized NRIP1 defense protein and H2O2 in the nucleus. Furthermore, silencing and knockout of chloroplast unusual positioning 1 (CHUP1) that encodes a chloroplast outer envelope protein constitutively induces stromules in the absence of pathogen infection and enhances programmed cell death. These results support a model in which stromules aid in the amplification and/or transport of pro-defense signals into the nucleus and other subcellular compartments during immunity. PMID- 26120033 TI - RNA Binding Protein Nanos2 Organizes Post-transcriptional Buffering System to Retain Primitive State of Mouse Spermatogonial Stem Cells. AB - In many adult tissues, homeostasis relies on self-renewing stem cells that are primed for differentiation. The reconciliation mechanisms of these characteristics remain a fundamental question in stem cell biology. We propose that regulation at the post-transcriptional level is essential for homeostasis in murine spermatogonial stem cells (SSCs). Here, we show that Nanos2, an evolutionarily conserved RNA-binding protein, works with other cellular messenger ribonucleoprotein (mRNP) components to ensure the primitive status of SSCs through a dual mechanism that involves (1) direct recruitment and translational repression of genes that promote spermatogonial differentiation and (2) repression of the target of rapamycin complex 1 (mTORC1), a well-known negative pathway for SSC self-renewal, by sequestration of the core factor mTOR in mRNPs. This mechanism links mRNA turnover to mTORC1 signaling through Nanos2-containing mRNPs and establishes a post-transcriptional buffering system to facilitate SSC homeostasis in the fluctuating environment within the seminiferous tubule. PMID- 26120034 TI - The Prevalence of Hemoglobinopathies in Young Adolescents in the Province of Mugla in Turkey: Results of a Screening Program. AB - Thalassemia is an autosomal recessive inherited blood disorder. It is prevalent in Mediterranean countries such as Sardinia, Greece, Cyprus, Turkey, Lebanon and also Southeast Asia. Our aim was to investigate the carrier prevalence of thalassemia and other hemoglobinopathies in adolescents who live in Mugla Province, Turkey. We analyzed retrospectively the surveys conducted at primary schools between 1997 and 2013. Complete blood count (CBC) and high performance liquid chromatography (HPLC) were used to screen for thalassemia and hemoglobinopathies. Patients were diagnosed as having thalassemia trait if the mean corpuscular volume (MCV) was <= 80.0 fL, mean corpuscular hemoglobin (Hb) was <= 27.0 pg and Hb A2 levels were >= 3.5%. A total of 164,814 students were analyzed. The median age of the students was 13.5 years (minimum 13.0, maximum 14.0). The total number of students with abnormal HPLC results was 5861 (3.8%). There was a significant decrease in the newborn of new thalassemia patients found with screening programs for hemoglobinopathies in Mugla Province from 1997 to 2013. The number of students with abnormal HPLC results for thalassemia, sickle cell disease and other Hb traits were 3.2, 0.15 and 0.4%, respectively. It is important to recognize that including Hb, MCV, red blood cell (RBC) count and HPLC tests for carrier screening are necessary to find hemoglobinopathies. Our study supported that the number of new patients significantly decreased using these screening programs from 1997 to 2013. PMID- 26120032 TI - Deubiquitination of Ci/Gli by Usp7/HAUSP Regulates Hedgehog Signaling. AB - Hedgehog (Hh) signaling plays essential roles in animal development and tissue homeostasis, and its misregulation causes congenital diseases and cancers. Regulation of the ubiquitin/proteasome-mediated proteolysis of Ci/Gli transcription factors is central to Hh signaling, but whether deubiquitinase is involved in this process remains unknown. Here, we show that Hh stimulates the binding of a ubiquitin-specific protease Usp7 to Ci, which positively regulates Hh signaling activity through inhibiting Ci ubiquitination and degradation mediated by both Slimb-Cul1 and Hib-Cul3 E3 ligases. Furthermore, we find that Usp7 forms a complex with GMP-synthetase (GMPS) to promote Hh pathway activity. Finally, we show that the mammalian counterpart of Usp7, HAUSP, positively regulates Hh signaling by modulating Gli ubiquitination and stability. Our findings reveal a conserved mechanism by which Ci/Gli is stabilized by a deubiquitination enzyme and identify Usp7/HUASP as a critical regulator of Hh signaling and potential therapeutic target for Hh-related cancers. PMID- 26120035 TI - Direct Synthesis of Chiral Allenoates from the Asymmetric C-H Insertion of alpha Diazoesters into Terminal Alkynes. AB - The asymmetric C-H insertion of alpha-diazoesters into 1-alkynes was achieved using chiral cationic guanidinium salts and copper(I) complexes. Optically active 2,4-disubstituted allenoates were generated under mild reaction conditions from various alpha-diazoesters and 1-alkynes in high yield (up to 99%) and enantioselectivity (up to 97:3 e.r.). Control experiments excluded the possibility of an asymmetric isomerization of alkynoates. PMID- 26120036 TI - Shooting through time: new insights from transcriptomic data. AB - Plant evo-devo research aims to identify the nature of genetic change underpinning the evolution of diverse plant forms. A transcriptomic study comparing gene expression profiles in the meristematic shoot tips of three distantly related vascular plants suggests that different genes were recruited to regulate similar meristematic processes during evolution. PMID- 26120037 TI - Development of the larval migration inhibition test for comparative analysis of ivermectin sensitivity in cyathostomin populations. AB - Cyathostomins are the most prevalent parasitic pathogens of equids worldwide. These nematodes have been controlled using broad-spectrum anthelmintics; however, cyathostomin resistance to each anthelmintic class has been reported and populations insensitive to more than one class are relatively commonplace. The faecal egg count reduction test (FECRT) is considered the most suitable method for screening anthelmintic sensitivity in horses, but is subject to variation and is relatively time-consuming to perform. Here, we describe a larval migration inhibition test (LMIT) to assess ivermectin (IVM) sensitivity in cyathostomin populations. This test measures the paralysing effect of IVM on the ability of third stage larvae (L3) to migrate through a pore mesh. When L3 from a single faecal sample were examined on multiple occasions, variation in migration was observed: this was associated with the length of time that the L3 had been stored before testing but the association was not significant. Half maximal effective concentration (EC50) values were then obtained for cyathostomin L3 from six populations of horses or donkeys that showed varying sensitivity to IVM in previous FECRTs. Larvae from populations indicated as IVM resistant by FECRT displayed significantly higher EC50 values in the LMIT than L3 from populations classified as IVM sensitive or L3 from populations that had not been previously exposed to IVM or had limited prior exposure. The analysis also showed that EC50 values obtained using L3 from animals in which IVM faecal egg count reduction (FECR) levels had been recorded as <95% were significantly higher than EC50 values obtained using L3 from animals for which FECR was measured as >95%. For one of the populations, time that had elapsed since IVM administration had an effect on the EC50 value obtained, with a longer time since treatment associated with lower EC50 values. These results indicate that the LMIT has value in discriminating IVM sensitivity amongst cyathostomin populations, but several factors were identified that need to be taken into account when executing the test and interpreting the derived data. PMID- 26120039 TI - Early Dialysis and Adverse Outcomes After Hurricane Sandy. AB - BACKGROUND: Hemodialysis patients have historically experienced diminished access to care and increased adverse outcomes after natural disasters. Although "early dialysis" in advance of a storm is promoted as a best practice, evidence for its effectiveness as a protective measure is lacking. Building on prior work, we examined the relationship between the receipt of dialysis ahead of schedule before the storm (also known as early dialysis) and adverse outcomes of patients with end-stage renal disease in the areas most affected by Hurricane Sandy. STUDY DESIGN: Retrospective cohort analysis, using claims data from the Centers for Medicare & Medicaid Services Datalink Project. SETTING & PARTICIPANTS: Patients receiving long-term hemodialysis in New York City and the state of New Jersey, the areas most affected by Hurricane Sandy. FACTOR: Receipt of early dialysis compared to their usual treatment pattern in the week prior to the storm. OUTCOMES: Emergency department (ED) visits, hospitalizations, and 30-day mortality following the storm. RESULTS: Of 13,836 study patients, 8,256 (60%) received early dialysis. In unadjusted logistic regression models, patients who received early dialysis were found to have lower odds of ED visits (OR, 0.75; 95% CI, 0.63-0.89; P=0.001) and hospitalizations (OR, 0.77; 95% CI, 0.65-0.92; P=0.004) in the week of the storm and similar odds of 30-day mortality (OR, 0.80; 95% CI, 0.58-1.09; P=0.2). In adjusted multivariable logistic regression models, receipt of early dialysis was associated with lower odds of ED visits (OR, 0.80; 95% CI, 0.67-0.96; P=0.01) and hospitalizations (OR, 0.79; 95% CI, 0.66-0.94; P=0.01) in the week of the storm and 30-day mortality (OR, 0.72; 95% CI, 0.52 0.997; P=0.048). LIMITATIONS: Inability to determine which patients were offered early dialysis and declined and whether important unmeasured patient characteristics are associated with receipt of early dialysis. CONCLUSIONS: Patients who received early dialysis had significantly lower odds of having an ED visit and hospitalization in the week of the storm and of dying within 30 days. PMID- 26120040 TI - Immunogenetic heterogeneity in a widespread ungulate: the European roe deer (Capreolus capreolus). AB - Understanding how immune genetic variation is shaped by selective and neutral processes in wild populations is of prime importance in both evolutionary biology and epidemiology. The European roe deer (Capreolus capreolus) has considerably expanded its distribution range these last decades, notably by colonizing agricultural landscapes. This range shift is likely to have led to bottlenecks and increased roe deer exposure to a new range of pathogens that until recently predominantly infected humans and domestic fauna. We therefore investigated the historical and contemporary forces that have shaped variability in a panel of genes involved in innate and acquired immunity in roe deer, including Mhc-Drb and genes encoding cytokines or toll-like receptors (TLRs). Together, our results suggest that genetic drift is the main contemporary evolutionary force shaping immunogenetic variation within populations. However, in contrast to the classical view, we found that some innate immune genes involved in micropathogen recognition (e.g. Tlrs) continue to evolve dynamically in roe deer in response to pathogen-mediated positive selection. Most studied Tlrs (Tlr2, Tlr4 and Tlr5) had similarly high levels of amino acid diversity in the three studied populations including one recently established in southwestern France that showed a clear signature of genetic bottleneck. Tlr2 implicated in the recognition of Gram positive bacteria in domestic ungulates, showed strong evidence of balancing selection. The high immunogenetic variation revealed here implies that roe deer are able to cope with a wide spectrum of pathogens and to respond rapidly to emerging infectious diseases. PMID- 26120041 TI - Impact of heat stress on germinal vesicle breakdown and lipolytic changes during in vitro maturation of bovine oocytes. AB - Two studies were conducted with the overarching goal of determining the extent to which lipolytic changes relate to germinal vesicle breakdown (GVBD) in bovine oocytes matured under thermoneutral or hyperthermic conditions. To this end, cumulus-oocyte complexes underwent in vitro maturation for 0, 2, 4, 6 or 24 h at 38.5 (first study) or 38.5 and 41.0 C (second study; heat stress applied up through first 12 h only, then shifted to 38.5 C). Independent of maturation temperature, triglyceride and phospholipid content decreased markedly by 2 h of in vitro maturation (hIVM; P < 0.0005). Content was lowest at 24 hIVM with no detectable impact of heat stress when exposure occurred during first 12 hIVM. Germinal vesicle breakdown occurred earlier in oocytes experiencing heat stress with effects observed as soon as 4 hIVM (P < 0.0001). Germinal vesicle breakdown was associated with lipolytic changes (R(2) = 0.2123 and P = 0.0030 for triglyceride content; R(2) = 0.2243 and P = 0.0026 for phospholipid content). ATP content at 24 hIVM was higher in oocytes experiencing heat stress (P = 0.0082). In summary, GVBD occurs sooner in heat-stressed oocytes. Although marked decreases in triglyceride and phospholipid content were noted as early as 2 hIVM and preceded GVBD, lipolytic changes such as these are not likely serving as an initial driver of GVBD in heat-stressed oocytes because changes occurred similarly in oocytes matured at thermoneutral conditions. PMID- 26120043 TI - How short should short-term risk assessment be? Determining the optimum interval for START reassessment in a secure mental health service. AB - ACCESSIBLE SUMMARY: The Short-Term Assessment of Risk and Treatability (START) is a tool used in some mental health services to assess patients to see if they are at risk of violence, self-harm, self-neglect or victimization. The recommended time between assessments is 3 months but there is currently no evidence to show that this is best practice. We have investigated whether assessing at 1- or 2 month intervals would be more accurate and therefore facilitate more individualized risk management interventions. We found that many patients who were rated as low risk had been involved in risk behaviours before 3 months had passed; some patients who were rated at increased risk did not get involved in risk behaviours at all. Results are mixed for different outcomes but on balance, we think that the recommendation to conduct START assessment every 3 months is supported by the evidence. However, reassessment should be considered if risk behaviours are not prevented and teams should always consider whether risk management practices are too restrictive. ABSTRACT: The Short-Term Assessment of Risk and Treatability (START) guides assessment of potential adverse outcomes. Assessment is recommended every 3 months but there is no evidence for this interval. We aimed to inform whether earlier reassessment was warranted. We collated START assessments for N = 217 adults in a secure mental health hospital, and subsequent aggressive, self-harm, self-neglect and victimization incidents. We used receiver operating characteristic analysis to assess predictive validity; survival function analysis to examine differences between low-, medium-, and high risk groups; and hazard function analysis to determine the optimum interval for reassessment. The START predicted aggression and self-harm at 1, 2 and 3 months. At-risk individuals engaged in adverse outcomes earlier than low-risk patients. About half warranted reassessment before 3 months due to engagement in risk behaviour before that point despite a low-risk rating, or because of non engagement by that point despite an elevated risk rating. Risk assessment should occur at appropriate intervals so that management strategies can be individually tailored. Assessment at 3-month intervals is supported by the evidence. START assessments should be revisited earlier if risk behaviours are not prevented; teams should constantly re-evaluate the need for restrictive practices. PMID- 26120042 TI - In Vivo Fluorescence Immunohistochemistry: Localization of Fluorescently Labeled Cetuximab in Squamous Cell Carcinomas. AB - Anti-EGFR (epidermal growth factor receptor) antibody based treatment strategies have been successfully implemented in head and neck squamous cell carcinoma (HNSCC). Unfortunately, predicting an accurate and reliable therapeutic response remains a challenge on a per-patient basis. Although significant efforts have been invested in understanding EGFR-mediated changes in cell signaling related to treatment efficacy, the delivery and histological localization in (peri-)tumoral compartments of antibody-based therapeutics in human tumors is poorly understood nor ever made visible. In this first in-human study of a systemically administered near-infrared (NIR) fluorescently labeled therapeutic antibody, cetuximab-IRDye800CW (2.5 mg/m(2), 25 mg/m(2), and 62.5 mg/m(2)), we show that by optical molecular imaging (i.e. denominated as In vivo Fluorescence Immunohistochemistry) we were able to evaluate localization of fluorescently labeled cetuximab. Clearly, optical molecular imaging with fluorescently labeled antibodies correlating morphological (peri-)tumoral characteristics to levels of antibody delivery, may improve treatment paradigms based on understanding true tumoral antibody delivery. PMID- 26120038 TI - Dental Health and Mortality in People With End-Stage Kidney Disease Treated With Hemodialysis: A Multinational Cohort Study. AB - BACKGROUND: Dental disease is more extensive in adults with chronic kidney disease, but whether dental health and behaviors are associated with survival in the setting of hemodialysis is unknown. STUDY DESIGN: Prospective multinational cohort. SETTING & PARTICIPANTS: 4,205 adults treated with long-term hemodialysis, 2010 to 2012 (Oral Diseases in Hemodialysis [ORAL-D] Study). PREDICTORS: Dental health as assessed by a standardized dental examination using World Health Organization guidelines and personal oral care, including edentulousness; decayed, missing, and filled teeth index; teeth brushing and flossing; and dental health consultation. OUTCOMES: All-cause and cardiovascular mortality at 12 months after dental assessment. MEASUREMENTS: Multivariable-adjusted Cox proportional hazards regression models fitted with shared frailty to account for clustering of mortality risk within countries. RESULTS: During a mean follow-up of 22.1 months, 942 deaths occurred, including 477 cardiovascular deaths. Edentulousness (adjusted HR, 1.29; 95% CI, 1.10-1.51) and decayed, missing, or filled teeth score >= 14 (adjusted HR, 1.70; 95% CI, 1.33-2.17) were associated with early all-cause mortality, while dental flossing, using mouthwash, brushing teeth daily, spending at least 2 minutes on oral hygiene daily, changing a toothbrush at least every 3 months, and visiting a dentist within the past 6 months (adjusted HRs of 0.52 [95% CI, 0.32-0.85], 0.79 [95% CI, 0.64-0.97], 0.76 [95% CI, 0.58-0.99], 0.84 [95% CI, 0.71-0.99], 0.79 [95% CI, 0.65-0.95], and 0.79 [95% CI, 0.65-0.96], respectively) were associated with better survival. Results for cardiovascular mortality were similar. LIMITATIONS: Convenience sample of clinics. CONCLUSIONS: In adults treated with hemodialysis, poorer dental health was associated with early death, whereas preventive dental health practices were associated with longer survival. PMID- 26120044 TI - Black tea extract improves anti-oxidant profile in experimental diabetic rats. AB - OBJECTIVE: The purpose of this study was to investigate the in vivo anti-oxidant effect of black tea extract (BTE) supplemented to normal and alloxan-induced diabetic rats. METHODS: Black tea extract (BTE) was fed to control and experimental diabetic rats by gavage technique at a dose of 1 ml/100 g body weight/day. Markers of oxidative stress in blood were determined. RESULT: Results show a significant (P < 0.01) decrease (73%) in plasma anti-oxidant potential, increase in activity of plasma membrane redox system (122%), protein oxidation and lipid peroxidation in diabetic rats, BTE supplemented diabetic rats had improved anti-oxidant profile and lower protein and lipid peroxidation levels. Diabetic rats displayed lower intracellular glutathione (GSH), BTE supplementation improved GSH levels. CONCLUSION: Results of this study suggest that the 2.5% aqueous extract of black tea is effective to ameliorate diabetes associated oxidative stress parameters in experimental model of diabetes. PMID- 26120045 TI - Changes in the anti-oxidant system in adult epilepsy patients receiving anti epileptic drugs. AB - Anti-epileptic drugs (AEDs) have been widely used in patients with epilepsy. This study evaluated the adverse effects of two commonly prescribed AED monotherapies, carbamazepine (CBZ) and valproic acid (VPA). The aim of this study was to evaluate the influence of these anti-epileptic drugs on paraoxonase-1 (PON-1), glutathione S-transferase (GST) and acetyl cholinesterase (AChE) activities in the serum of adult patients with epilepsy. Of the 56 epileptic adults, 28 were given valproate, and the remaining 28 were given carbamazepine. Glutathione (GSH) levels in epilepsy patients receiving anti-epileptic drug treatment were insignificantly higher compared with controls. GST activity in epilepsy patients receiving anti-epileptic drug treatment was insignificantly lower compared with controls. PON1 and AChE activity in epilepsy patients receiving anti-epileptic drug treatment was significantly lower compared with controls. PON1 and AChE activities in the serum of patients treated with carbamazepine monotherapy were lower than in patients treated with valproic acid monotherapy. PMID- 26120047 TI - Reply to 'Indication bias or protopathic bias?'. PMID- 26120046 TI - Reading during the composition of multi-sentence texts: an eye-movement study. AB - Writers composing multi-sentence texts have immediate access to a visual representation of what they have written. Little is known about the detail of writers' eye movements within this text during production. We describe two experiments in which competent adult writers' eye movements were tracked while performing short expository writing tasks. These are contrasted with conditions in which participants read and evaluated researcher-provided texts. Writers spent a mean of around 13 % of their time looking back into their text. Initiation of these look-back sequences was strongly predicted by linguistically important boundaries in their ongoing production (e.g., writers were much more likely to look back immediately prior to starting a new sentence). 36 % of look-back sequences were associated with sustained reading and the remainder with less patterned forward and backward saccades between words ("hopping"). Fixation and gaze durations and the presence of word-length effects suggested lexical processing of fixated words in both reading and hopping sequences. Word frequency effects were not present when writers read their own text. Findings demonstrate the technical possibility and potential value of examining writers' fixations within their just-written text. We suggest that these fixations do not serve solely, or even primarily, in monitoring for error, but play an important role in planning ongoing production. PMID- 26120049 TI - A cross-sectional study of the clinical characteristics of cancer patients presenting to one tertiary referral emergency department. AB - INTRODUCTION: There is increasing evidence of cancer patients presenting to emergency departments (ED). The study aim was to analyse the characteristics of adult cancer patients presenting to one ED. Understanding cancer patient presentations could assist in the development of new models of care. METHODS: A 12 month retrospective audit was conducted of a random sample of cancer patients. Demographics and characteristic variables were analysed using descriptive, comparative and correlational statistics. RESULTS: The presentation rate for adult cancer patients was 1110 (2.4%) with 290 sampled. The common symptoms were fever (n = 54: 18.6%), abdominal pain (n = 34: 11.7%), and shortness of breath (n = 32: 11%). The majority of patients were allocated a Triage Category 2 (n = 94: 32.4%) or Triage Category 3 (n = 131: 45.2%). The majority of patients presented between 2 and 15 times. For patients administered antibiotics the average time was 119.8 minutes (SD +/- 85.5). The average ED length of stay was mean 8.08 hours with 271 patients (93.4%) admitted to the hospital. Of the 290 patients, 105 (36.2%) had died within 12 months of ED presentation. CONCLUSION: The study has shown that while cancer patients are only a small percentage of ED presentations the vast majority are allocated high triage codes, have high admission rates and high mortality rates. PMID- 26120048 TI - Functional conservation of an ancestral Pellino protein in helminth species. AB - The immune system of H. sapiens has innate signaling pathways that arose in ancestral species. This is exemplified by the discovery of the Toll-like receptor (TLR) pathway using free-living model organisms such as Drosophila melanogaster. The TLR pathway is ubiquitous and controls sensitivity to pathogen-associated molecular patterns (PAMPs) in eukaryotes. There is, however, a marked absence of this pathway from the plathyhelminthes, with the exception of the Pellino protein family, which is present in a number of species from this phylum. Helminth Pellino proteins are conserved having high similarity, both at the sequence and predicted structural protein level, with that of human Pellino proteins. Pellino from a model helminth, Schistosoma mansoni Pellino (SmPellino), was shown to bind and poly-ubiquitinate human IRAK-1, displaying E3 ligase activity consistent with its human counterparts. When transfected into human cells SmPellino is functional, interacting with signaling proteins and modulating mammalian signaling pathways. Strict conservation of a protein family in species lacking its niche signalling pathway is rare and provides a platform to examine the ancestral functions of Pellino proteins that may translate into novel mechanisms of immune regulation in humans. PMID- 26120050 TI - The Measurement of Stable Carbon Isotope Ratios of Eight Methamidophos Samples. AB - Between December 2007 and January 2008, people suffered from food poisoning in the Japanese prefectures of Chiba and Hyogo after eating frozen dumplings (gyoza) produced in China, which had very high concentrations (1490-19,290 ppm) of methamidophos (O,S-dimethyl phosphoramidothioate). Thus, we measured the stable carbon isotope ratio of methamidophos using GC/C/IRMS to identify the source. We analyzed seven methamidophos reagents and one Chinese agricultural methamidophos chemical (MTD600) that contained many impurities. The delta13C values of the seven methamidophos reagents and MTD600 ranged from -49.230/00 to -31.900/00, with an average SD of 0.200/00, very high precision. This difference (17.330/00) was very large compared with that in previous reports and may be attributable to the material itself and the chemical processing of methamidophos. Criminals can easily obtain pesticides such as methamidophos; therefore, it is very important to identify the pesticide source and distribution route using stable isotopic science in the future. PMID- 26120051 TI - Phytochemicals potently inhibit migration of metastatic breast cancer cells. AB - Cell migration is a major process that drives metastatic progression of cancers, the major cause of cancer death. Existing chemotherapeutic drugs have limited efficacy to prevent and/or treat metastasis, emphasizing the need for new treatments. We focus on triple negative breast cancer (TNBC), the subtype of breast cancer with worst prognosis and no standard chemotherapy protocols. Here we demonstrate that a group of natural compounds, known as phytochemicals, effectively block migration of metastatic TNBC cells. Using a novel cell micropatterning technology, we generate consistent migration niches in standard 96-well plates where each well contains a cell-excluded gap within a uniform monolayer of cells. Over time, cells migrate into and occupy the gap. Treating TNBC cells with non-toxic concentrations of phytochemicals significantly blocks motility of cells. Using a molecular analysis approach, we show that anti migratory property of phytochemicals is partly due to their inhibitory effects on phosphorylation of ERK1/2. This study provides a framework for future studies to understand molecular targets of phytochemicals and evaluate their effectiveness in inhibiting metastasis in animal models of cancer. PMID- 26120052 TI - Effect of testosterone treatment on cardiac biomarkers in a randomized controlled trial of men with type 2 diabetes. AB - OBJECTIVE: To assess the effect of testosterone treatment on cardiac biomarkers in men with type 2 diabetes (T2D). DESIGN: Randomized double-blind, parallel, placebo-controlled trial. PATIENTS: Men aged 35-70 years with T2D and a total testosterone level <=12.0 nmol/l (346 ng/dl) at high risk of cardiovascular events, median 10-year United Kingdom Prospective Diabetes Study (UKPDS) coronary heart disease (CHD) risk 21% (IQR 16%, 27%). Eighty-eight participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). MAIN OUTCOME MEASURES: N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs cTnT). RESULT: Testosterone treatment reduced NT-proBNP (mean adjusted difference (MAD) in change over 40 weeks across the testosterone and placebo groups, -17.9 ng/l [95% CI -32.4, -3.5], P = 0.047), but did not change hs-cTnT (MAD, 0.41 ng/l (95% CI -0.56, 1.39), P = 0.62). Six men, three in each group experienced an adverse cardiac event, displaying already higher baseline NT-proBNP (P < 0.01) and hs-cTnT levels (P = 0.01). At baseline, 10-year UKPDS CHD risk was associated positively with NT-proBNP (tau = 0.21, P = 0.004) and hs-cTnT (tau = 0.23, P = 0.003) and inversely with testosterone (total testosterone tau = -0.18, P = 0.02, calculated free testosterone tau = -0.19, P = 0.01), but there was no significant association between testosterone and cardiac biomarkers (P > 0.05). CONCLUSIONS: In this trial of men with T2D and high cardiovascular risk, testosterone treatment reduced NT-proBNP and did not change hs-cTnT. Further studies should determine whether men with increased cardiac biomarkers prior to testosterone therapy are at higher risk of testosterone treatment-associated adverse cardiac events. PMID- 26120053 TI - Time-course of vascular dysfunction of brachial artery after transradial access for coronary angiography. AB - BACKGROUND: Prior studies have demonstrated endothelial and smooth muscle brachial artery dysfunction after transradial cardiac catheterization for diagnostic coronary angiography. The duration of this vascular dysfunction is unknown. OBJECTIVE: To determine the time-course of endothelial and smooth muscle cell dysfunction in the upstream brachial artery after transradial cardiac catheterization. METHODS: We studied 22 consecutive patients with suspected coronary artery disease (age 64.4 +/- 7.7 years) undergoing diagnostic transradial cardiac catheterization. Using high-resolution vascular ultrasound, we measured ipsilateral brachial artery diameter changes during reactive hyperemia (endothelium-dependent dilatation) and administration of sublingual nitroglycerin (endothelium-independent dilatation). The measurements were taken at baseline (before cardiac catheterization), 6 h, 24 h, 1 week, and 1 month postprocedure. The contralateral brachial artery served as a control. RESULTS: Ipsilateral brachial artery diameter during endothelium-dependent dilatation decreased significantly compared with the contralateral diameters at 6 h and 24 h after transradial cardiac catheterization (3.22 vs. 4.11 and 3.29 vs. 4.11, respectively, P < 0.001). The administration of nitroglycerin did not affect this difference. At 1 week and 1 month postprocedure there was no significant difference in diameter of the ipsilateral versus the contralateral brachial artery. As expected the contralateral brachial artery showed no significant changes in diameter. CONCLUSION: Our results showed that transradial cardiac catheterization causes transient vascular endothelial and smooth muscle dysfunction of the ipsilateral brachial artery, which resolves within 1 week postprocedure. These findings strongly suggest the absence of systemic vascular dysfunction after transradial catheterization both immediately postprocedure as well as 1 week postprocedure. (c) 2015 Wiley Periodicals, Inc. PMID- 26120054 TI - Teens that fear screams: A comparison of fear conditioning, extinction, and reinstatement in adolescents and adults. AB - This study investigated differences between adolescents and adults on fear conditioning, extinction, and reinstatement (i.e., the recovery of conditioned fear following re-exposure to the unconditioned stimulus [US] post-extinction). Participants underwent differential conditioning (i.e., the Screaming Lady) where one neutral face (CS+) was followed by the same face expressing fear and a loud scream (US) while another neutral face (CS-) remained neutral. Extinction involved non-reinforced presentations of both CSs, after which participants were reinstated (2xUSs) or not. On two self-report measures, both ages showed conditioning, good extinction learning and retention, and reinstatement-induced relapse. However, only adolescents showed conditioning, extinction, and reinstatement on the eye tracking measure; relapse on this measure could not be assessed in adults given they did not show initial conditioning. Lastly, higher levels of depression predicted stronger conditioning and weaker extinction in adolescents only. These findings are discussed in terms of their implications for adolescent anxiety disorders. PMID- 26120055 TI - The effect of 2,5-di-(tert-butyl)-1,4-benzohydroquinone (TBQ) on intracellular Ca2+ handling in rat ventricular myocytes. AB - 2,5-Di-(tert-butyl)-1,4-benzohydroquinone (TBQ) is a reversible inhibitor of SERCA, potentially making it a useful tool to study the effects of SERCA inhibition in cardiac cells. However, it is unknown if TBQ also has effects on other components of ventricular Ca handling. The aim of these experiments was to characterise the effects of TBQ on Ca handling in rat ventricular myocytes and assess its suitability as a specific inhibitor of SERCA. This was achieved by voltage clamp via perforated patch and [Ca(2+)]i measurement using Fluo-3 AM. TBQ produced a fully reversible, concentration dependent decrease in the rate of systolic Ca decay. 10MUM TBQ decreased the amplitude of the systolic Ca transient by 48+/-5% and the rate of decay by 54+/-6%. SR Ca content was also reduced by 62+/-4%. However, 10MUM TBQ also decreased the peak L-type Ca current by 23+/-7%. At higher concentrations (100MUM), TBQ also activated an outward current with a current-voltage relationship consistent with a potassium current. This outward current was abolished by Glibenclamide (100MUM). These data show that TBQ can be used to reversibly inhibit SERCA. However, at concentrations that decrease SERCA activity, TBQ also decreases the L-type Ca current and (at higher concentrations) activates an outward current which appears to be an ATP dependent potassium current. We conclude that TBQ cannot be used as a specific inhibitor of SERCA in rat ventricular myocytes. PMID- 26120056 TI - Long-Term Effects of Neonatal Morphine Infusion on Pain Sensitivity: Follow-Up of a Randomized Controlled Trial. AB - Short-term and long-term effects of neonatal pain and its analgesic treatment have been topics of translational research over the years. This study aimed to identify the long-term effects of continuous morphine infusion in the neonatal period on thermal pain sensitivity, the incidence of chronic pain, and neurological functioning. Eighty-nine of the 150 participants of a neonatal randomized controlled trial on continuous morphine infusion versus placebo during mechanical ventilation underwent quantitative sensory testing and neurological examination at the age of 8 or 9 years. Forty-three children from the morphine group and 46 children from the placebo group participated in this follow-up study. Thermal detection and pain thresholds were compared with data from 28 healthy controls. Multivariate analyses revealed no statistically significant differences in thermal detection thresholds and pain thresholds between the morphine and placebo groups. The incidence of chronic pain was comparable between both groups. The neurological examination was normal in 29 (76%) of the children in the morphine group and 25 (61%) of the children in the control group (P = .14). We found that neonatal continuous morphine infusion (10 MUg/kg/h) has no adverse effects on thermal detection and pain thresholds, the incidence of chronic pain, or overall neurological functioning 8 to 9 years later. Perspective: This unique long-term follow-up study shows that neonatal continuous morphine infusion (10 MUg/kg/h) has no long-term adverse effects on thermal detection and pain thresholds or overall neurological functioning. These findings will help clinicians to find the most adequate and safe analgesic dosing regimens for neonates and infants. PMID- 26120057 TI - A Long-Lived Luminal Subpopulation Enriched with Alveolar Progenitors Serves as Cellular Origin of Heterogeneous Mammary Tumors. AB - It has been shown that the mammary luminal lineage could be maintained by luminal stem cells or long-lived progenitors, but their identity and role in breast cancer remain largely elusive. By lineage analysis using Wap-Cre mice, we found that, in nulliparous females, mammary epithelial cells (MECs) genetically marked by Wap-Cre represented a subpopulation of CD61+ luminal progenitors independent of ovarian hormones for their maintenance. Using a pulse-chase lineage-tracing approach based on Wap-Cre adenovirus (Ad-Wap-Cre), we found that Ad-Wap-Cre marked nulliparous MECs were enriched with CD61+ alveolar progenitors (APs) that gave rise to CD61- alveolar luminal cells during pregnancy/lactation and could maintain themselves long term. When transformed by different oncogenes, they could serve as cells of origin of heterogeneous mammary tumors. Thus, our study revealed a type of long-lived AP within the luminal lineage that may serve as the cellular origin of multiple breast cancer subtypes. PMID- 26120058 TI - Automated Identification and Localization of Hematopoietic Stem Cells in 3D Intravital Microscopy Data. AB - Measuring three-dimensional (3D) localization of hematopoietic stem cells (HSCs) within the bone marrow microenvironment using intravital microscopy is a rapidly expanding research theme. This approach holds the key to understanding the detail of HSC-niche interactions, which are critical for appropriate stem cell function. Due to the complex tissue architecture of the bone marrow and to the progressive introduction of scattering and signal loss at increasing imaging depths, there is no ready-made software to handle efficient segmentation and unbiased analysis of the data. To address this, we developed an automated image analysis tool that simplifies and standardizes the biological interpretation of 3D HSC microenvironment images. The algorithm identifies HSCs and measures their localization relative to surrounding osteoblast cells and bone collagen. We demonstrate here the effectiveness, consistency, and accuracy of the proposed approach compared to current manual analysis and its wider applicability to analyze other 3D bone marrow components. PMID- 26120060 TI - Precipitating Sodium Dodecyl Sulfate to Create Ultrastable and Stimulable Foams. AB - Ultrastable foams are made very simply by adding salt (NaCl or KCl) to sodium dodecyl sulfate. The addition of high concentrations of salt leads to the precipitation of the surfactant on the bubble surfaces and as crystals in the interstices between the bubbles. As a consequence, the ageing of the foams is stopped to make them stable indefinitely, or until they are heated above the melting temperature of the crystals. The use of KCl is shown to be much more effective than that of NaCl because potassium dodecyl sulfate has a higher melting temperature and faster rates of crystallization. The crystalline structures have been investigated inside the foam using small angle neutron scattering. The larger lattice spacing of the crystals formed with NaCl in comparison with KCl has been evidenced. These simple temperature stimulable foams could have many potential applications. PMID- 26120059 TI - Histone Demethylases KDM4A and KDM4C Regulate Differentiation of Embryonic Stem Cells to Endothelial Cells. AB - Understanding epigenetic mechanisms regulating embryonic stem cell (ESC) differentiation to endothelial cells may lead to increased efficiency of generation of vessel wall endothelial cells needed for vascular engineering. Here we demonstrated that the histone demethylases KDM4A and KDM4C played an indispensable but independent role in mediating the expression of fetal liver kinase (Flk)1 and VE-cadherin, respectively, and thereby the transition of mouse ESCs (mESCs) to endothelial cells. KDM4A was shown to bind to histones associated with the Flk1 promoter and KDM4C to bind to histones associated with the VE cadherin promoter. KDM4A and KDM4C were also both required for capillary tube formation and vasculogenesis in mice. We observed in zebrafish that KDM4A depletion induced more severe vasculogenesis defects than KDM4C depletion, reflecting the early involvement of KDM4A in specifying endothelial cell fate. These findings together demonstrate the essential role of KDM4A and KDM4C in orchestrating mESC differentiation to endothelial cells through the activation of Flk1 and VE-cadherin promoters, respectively. PMID- 26120061 TI - Distribution of omega-6 and omega-3 polyunsaturated fatty acids in the whole rat body and 25 compartments. AB - The steady state compositions of omega-6 and omega-3 polyunsaturated fatty acids (PUFA) throughout the various viscera and tissues within the whole body of rats have not previously been described in a comprehensive manner. Dams consumed diets containing 10wt% fat (15% linoleate and 3% alpha-linolenate). Male offspring (n=9) at 7-week of age were euthanized and dissected into 25 compartments. Total lipid fatty acids for each compartment were quantified by GC/FID and summed for the rat whole body; total n-6 PUFA was 12wt% and total n-3 PUFA was 2.1% of total fatty acids. 18:2n-6 accounted for 84% of the total n-6 PUFA, 20:4n-6 was 12%, 18:3n-3 was 59% of the total n-3 PUFA, 20:5n-3 was 2.1%, and 22:6n-3 was 32%. The white adipose tissue contained the greatest amounts of 18:2n-6 (1.5g) and 18:3n-3 (0.2g). 20:4n-6 was highest in muscle (60mg) and liver (57mg), while 22:6n-3 was greatest in muscle (46mg), followed by liver (27mg) and carcass (20mg). In terms of fatty acid composition expressed as a percentage, 18:2n-6 was the highest in the heart (13wt%), while 18:3n-3 was about 1.3wt% for skin, white adipose tissue and fur. 20:4n-6 was highest (21-25wt%) in the circulation, kidney, and spleen, while 22:6n-3 was highest in the brain (12wt%), followed by the heart (7.9wt%), liver (5.9wt%), and spinal cord (5.1wt%). Selectivity was greatest when comparing 22:6n-3 in brain (12%) to white adipose (0.08%) (68-fold) and 22:5n-6 in testes (15.6%) compared to white adipose (0.02%), 780-fold. PMID- 26120062 TI - Capillary droplet propulsion on a fibre. AB - A viscous liquid film coating a fibre becomes unstable and decays into droplets due to the Rayleigh-Plateau instability (RPI). Here, we report on the generation of uniform droplets on a hydrophobized fibre by taking advantage of this effect. In the late stages of liquid column breakup, a three-phase contact line can be formed at one side of the droplet by spontaneous rupture of the thinning film. The resulting capillary imbalance leads to droplet propulsion along the fibre. We study the dynamics and the dewetting speed of the droplet as a function of molecular weight as well as temperature and compare to a force balance model based on purely viscous dissipation. PMID- 26120063 TI - Preparation of a porous Sn@C nanocomposite as a high-performance anode material for lithium-ion batteries. AB - A porous Sn@C nanocomposite was prepared via a facile hydrothermal method combined with a simple post-calcination process, using stannous octoate as the Sn source and glucose as the C source. The as-prepared Sn@C nanocomposite exhibited excellent electrochemical behavior with a high reversible capacity, long cycle life and good rate capability when used as an anode material for lithium ion batteries. PMID- 26120064 TI - Total knee arthroplasty using patient-specific guides: Is there a learning curve? AB - BACKGROUND: Patient specific guides (PSG) have been reported to improve overall component alignment in total knee arthroplasty (TKA). With more surgeons likely to consider this method of TKA in the future, this study was performed to establish whether there is a learning curve with use of PSG in TKA. METHODS: Eighty-six consecutive PSG TKAs performed by one surgeon were retrospectively analyzed in two groups. The first 30 patients were compared to the second 56 patients with regards to their operative times and post-operative multi-planar alignments on computed tomography (CT) scan. RESULTS: Mean operative time was higher in the initial 30 cases compared to the second 56 cases (85 min vs. 78 min; p=0.001). No statistically significant differences were found in post operative TKA alignment between the two groups. CONCLUSIONS: This study suggests that there is a minimal learning curve with operative time associated with use of PSG in TKA. This study was unable to detect a significant learning curve with regards to restoration of mechanical knee alignment with the use of PSG in TKA. PMID- 26120065 TI - Metal containing cryptands as hosts for anions: evaluation of Cu(I)...X and pi...X interactions in halide-tricopper(I) complexes through relativistic DFT calculations. AB - More selective than crown ethers, cryptands arise as suitable hosts for several ions, with the size of the cavity and the behavior of the atoms belonging to the structure being the main factors governing their selectivity. Similar to metallacrowns, inorganic counterparts of crown ethers, the presence of metal centers in cryptands can offer significant advantages in terms of ion recognition as they provide positively charged sites, which allow them to encapsulate anions. Here, through density functional methodologies, we evaluate the preference of a tricopper(I) cryptand host toward a series of halide ions ranging from the hard fluoride to the soft iodide, where the more intense interactions are established with the hardest one, and the electrostatic term is the more relevant contributor to total interaction energy. Upon exploration of this electrostatic contribution in more detail, it is observed that as the guest becomes softer, the increase of higher order Coulombic terms, such as dipole-dipole, dipole-quadrupole, and quadrupole-quadrupole, acquires more relevance on going from 9.22% to 41.25%, denoting the key role and variation of such forces in inclusion systems with metal-containing hosts. PMID- 26120066 TI - Is Canine Eruption Velocity Affected by the Presence of Allograft Within a Repaired Alveolar Cleft? AB - PURPOSE: To assess the rate of canine eruption in alveolar clefts repaired with cancellous autograft versus cancellous autograft mixed with allograft. MATERIALS AND METHODS: This was a retrospective cohort study of patients in mixed dentition who underwent primary repair of uni- or bilateral alveolar cleft defects. Patients were divided into 2 groups based on the method of bony reconstruction (group 1, iliac crest autograft; group 2, iliac crest autograft harvested through a minimal access approach and mixed 1:2 with demineralized bone allograft). Secondary predictor variables were demographic and anatomic factors potentially related to canine eruption. The outcome variable was the velocity of canine eruption, measured as the change in vertical distance from the incisal edge to the maxillary occlusal plane (millimeters per month). Descriptive, bivariate, and linear regression statistics were computed. RESULTS: The study sample included 57 alveolar cleft defects; 19 were repaired with autograft alone and 38 were repaired with autograft plus allograft. The sample's mean age was 9.9 +/- 2.3 years at the time of repair. Thirty-one clefts (54.4%) were part of a bilateral deformity. Canine root formation was 50% complete at the time of surgery in most patients (59.6%). Mean duration of follow-up was 23.7 +/- 13.2 months. Mean canine eruption velocity was 0.20 +/- 0.18 mm per month and was not associated with the method of bony repair (P = .58). CONCLUSION: The use of allograft bone to augment bone graft volume results in similar rates of canine eruption compared with autograft bone alone. PMID- 26120067 TI - Cutaneous rash and dapsone-induced hypersensitivity syndrome a common manifestation in adult immune thrombocytopenia. Presentation and outcome in 16 cases. PMID- 26120068 TI - Postoperative adjuvant chemotherapy with S-1 alters recurrence patterns and prognostic factors among patients with stage II/III gastric cancer: A propensity score matching analysis. AB - BACKGROUND: A phase 3 evidence indicates that S-1 adjuvant is beneficial among East Asian patients with stage II/III gastric cancer (GC). However, little is known about the changes in prognostic factors and recurrence patterns after it has become widespread as a standard of care. The present study compared prognostic factors of patients with stage II/III GC treated with or without S-1 adjuvant with formulate appropriate risk stratification strategies. METHODS: We enrolled 171 patients with stage II/III GC, 92 patients who underwent gastrectomy alone, and 79 patients treated with S-1 adjuvant. To balance more strictly the essential variables including stage of progression, we conducted propensity score analysis and 70 pairs of patients were generated from each group. Prognostic factors were compared between the groups and initial recurrence patterns were investigated to explore reasons for the change. RESULTS: In concordance with the previous phase 3 trial, overall and recurrence-free survival were better for the S-1 adjuvant group. In the surgery alone group, carcinoembryonic antigen >= 5 ng/mL, total gastrectomy, vessel invasion, pT4, and stage 3 were identified as significant prognostic factors. In striking contrast, macroscopic tumor size >= 50 mm was the only significant prognostic factor for the S-1 adjuvant group. The lower overall recurrence rate of the S-1 adjuvant group was attributable mainly to a significant decrease of peritoneal recurrence. CONCLUSION: Prognostic factors changed substantially after implementation of S-1 adjuvant treatment. Macroscopic tumor size should be considered for patient stratification and selection of treatment options for patients with stage II/III GC. PMID- 26120069 TI - Role of BRAF V600E mutation as an indicator of the extent of thyroidectomy and lymph node dissection in conventional papillary thyroid carcinoma. AB - BACKGROUND: The extent of surgery for papillary thyroid carcinoma (PTC) is associated strongly with disease persistence, recurrence, and mortality. It is difficult, however, to determine the optimal extent for surgery. The BRAF mutation is well known for its diagnostic and prognostic value in PTC. Among the variants of PTC, the clinical importance of the BRAF mutation has been associated particularly with conventional PTC. The goal of this study was to clarify the role of the BRAF mutation as a determinant for the operative extent in conventional PTC. METHODS: Histopathology and BRAF mutation status of 3,019 patients with conventional PTC were analyzed. With regard to the extent of surgery in PTC, focus was given to the factors of tumor bilaterality, central lymph node metastasis (CLNM), and lateral lymph node metastasis. In addition, the prognostic impact of BRAF mutation on loco-regional recurrence was investigated. RESULTS: The BRAF mutation was found to be an independent indicator of tumor bilaterality (odds ratio [OR] 1.484, P = .010); however, it was not an independent indicator of CLNM (OR 1.167, P = .254) or lateral lymph node metastasis (OR 0.647, P = .384). Moreover, it was not an independent indicator of CLNM in either the therapeutic or prophylactic central neck dissection. Finally, BRAF mutation positivity did not increase the risk of loco-regional recurrence (adjusted hazard ratio = 0.829, P = .523). CONCLUSION: The BRAF mutation is a possible indicator for determining the extent of thyroidectomy required but not for the extent of lymph node dissection and prognosis in patients with conventional PTC. PMID- 26120070 TI - Clinical comparison of laparoscopic and open liver resection after propensity matching selection. AB - BACKGROUND: This study aimed to compare the radicality for and clinical advantages of laparoscopic liver resection, which is increasingly used, and the corresponding open procedure by propensity score matching analysis. METHODS: We analyzed 260 hepatocellular carcinoma patients who underwent initial liver resection at our department between January 2003 and June 2011, including 60 laparoscopic (the Lap group) and 200 open cases (the Open group). Propensity scores were calculated for each patient via the use of various clinicopathologic features as covariates, and patients' survival was compared. RESULTS: The Lap group had more women and patients of advanced age (n = 60) than the Open group (n = 200). Tumor size (2.3 cm vs 3.5 cm median), multiple tumors (18.3% vs 41.0%), vascular invasion (15.0% vs 36.5%), poor differentiation status (11.2% vs 24.5%), intraoperative bleeding (110 mL vs 420 mL; median), and operative time (277 minutes vs 312 minutes; median) were significantly more favorable in the Lap group than in the Open group because of a selection bias of the patients (Lap vs Open). The postoperative recurrence-free and overall survival rates were greater in the Lap group than in the Open group; however, when 35 patients from each group were analyzed after propensity score matching of clinicopathologic characteristics of the patients, intraoperative bleeding was lesser in the Lap group. The recurrence-free survival rates at 1, 3, and 5 years were 75.0%, 43.8%, and 43.8%, respectively, in the Lap group and 73.6%, 49.3%, and 37.2%, respectively, in the Open group, which indicated no significant differences (P = .954). Similarly, the overall survival rates at 1, 3, and 5 years were 93.9%, 82.1%, and 82.1%, respectively, in the Lap group and 94.3%, 85.2%, and 61.8%, respectively, in the Open group, indicating no significant differences between the 2 groups (P = .672). CONCLUSION: Our results indicate that laparoscopic liver resection is comparable with the corresponding open procedure in clinical safety and prognostic efficacy. PMID- 26120071 TI - Re: 'Preferred Strategy for Hemodialysis Access Creation in Elderly Patients'. PMID- 26120072 TI - Dealing with inter-expert variability in retinopathy of prematurity: A machine learning approach. AB - BACKGROUND AND OBJECTIVE: Understanding the causes of disagreement among experts in clinical decision making has been a challenge for decades. In particular, a high amount of variability exists in diagnosis of retinopathy of prematurity (ROP), which is a disease affecting low birth weight infants and a major cause of childhood blindness. A possible cause of variability, that has been mostly neglected in the literature, is related to discrepancies in the sets of important features considered by different experts. In this paper we propose a methodology which makes use of machine learning techniques to understand the underlying causes of inter-expert variability. METHODS: The experiments are carried out on a dataset consisting of 34 retinal images, each with diagnoses provided by 22 independent experts. Feature selection techniques are applied to discover the most important features considered by a given expert. Those features selected by each expert are then compared to the features selected by other experts by applying similarity measures. Finally, an automated diagnosis system is built in order to check if this approach can be helpful in solving the problem of understanding high inter-rater variability. RESULTS: The experimental results reveal that some features are mostly selected by the feature selection methods regardless the considered expert. Moreover, for pairs of experts with high percentage agreement among them, the feature selection algorithms also select similar features. By using the relevant selected features, the classification performance of the automatic system was improved or maintained. CONCLUSIONS: The proposed methodology provides a handy framework to identify important features for experts and check whether the selected features reflect the pairwise agreements/disagreements. These findings may lead to improved diagnostic accuracy and standardization among clinicians, and pave the way for the application of this methodology to other problems which present inter-expert variability. PMID- 26120073 TI - JTSA: an open source framework for time series abstractions. AB - BACKGROUND AND OBJECTIVE: The evaluation of the clinical status of a patient is frequently based on the temporal evolution of some parameters, making the detection of temporal patterns a priority in data analysis. Temporal abstraction (TA) is a methodology widely used in medical reasoning for summarizing and abstracting longitudinal data. METHODS: This paper describes JTSA (Java Time Series Abstractor), a framework including a library of algorithms for time series preprocessing and abstraction and an engine to execute a workflow for temporal data processing. The JTSA framework is grounded on a comprehensive ontology that models temporal data processing both from the data storage and the abstraction computation perspective. The JTSA framework is designed to allow users to build their own analysis workflows by combining different algorithms. Thanks to the modular structure of a workflow, simple to highly complex patterns can be detected. The JTSA framework has been developed in Java 1.7 and is distributed under GPL as a jar file. RESULTS: JTSA provides: a collection of algorithms to perform temporal abstraction and preprocessing of time series, a framework for defining and executing data analysis workflows based on these algorithms, and a GUI for workflow prototyping and testing. The whole JTSA project relies on a formal model of the data types and of the algorithms included in the library. This model is the basis for the design and implementation of the software application. Taking into account this formalized structure, the user can easily extend the JTSA framework by adding new algorithms. Results are shown in the context of the EU project MOSAIC to extract relevant patterns from data coming related to the long term monitoring of diabetic patients. CONCLUSIONS: The proof that JTSA is a versatile tool to be adapted to different needs is given by its possible uses, both as a standalone tool for data summarization and as a module to be embedded into other architectures to select specific phenotypes based on TAs in a large dataset. PMID- 26120074 TI - Error-processing abnormalities in pediatric anxiety and obsessive compulsive disorders. AB - Anxiety and obsessive compulsive disorders are among the earliest occurring psychopathology and may derive from atypical maturation of neural networks for error processing. Psychological models have alternately suggested that over detection of errors, excessive caring about errors, or failure of errors to elicit regulatory control could associate with the expression of anxiety. In this review article, the potential relevance of error processing for anxiety and obsessive compulsive disorders is described in the context of neurophysiological and functional magnetic resonance imaging (fMRI) research demonstrating altered brain response to errors in pediatric and adult patients. Finally, hypotheses about developmentally sensitive mechanisms of anxiety and obsessive compulsive disorders are drawn from the extant literature, and avenues for clinical translation are discussed. PMID- 26120075 TI - Pharmacodynamics and tolerability of repository corticotropin injection in healthy human subjects: A comparison with intravenous methylprednisolone. AB - Repository corticotropin injection (porcine adrenocorticotropic hormone [ACTH] analog) and intravenous methylprednisolone (IVMP) are used to treat inflammatory conditions such as multiple sclerosis (MS) exacerbations and rheumatoid arthritis. This multiple-dose, randomized, crossover, open-label study evaluated and compared pharmacodynamic outcomes in subjects who received ACTH analog (80 U subcutaneously) or IVMP (1 g) daily for 5 days. Specific outcome measures included IVMP and cortisol concentrations, total cortisol-equivalent exposure, immune cell population changes, and tolerability. IVMP and ACTH analog increased granulocyte numbers and decreased lymphocyte counts; effects on both were significantly less pronounced with ACTH analog. Based on total cortisol equivalent exposure (assuming linearity), administration of 80 U of ACTH analog equates to 30 mg IVMP. Because IVMP doses significantly higher than 30 mg are usually required to treat MS exacerbations, the lower cortisol-equivalent exposure of 80 U ACTH analog supports the hypothesis that efficacy of ACTH analog results from both steroid-dependent and -independent properties. Adverse events were mild in severity; subject incidence for adverse-event reporting was similar following both regimens. The clinical relevance of these findings in autoimmune disease populations is unknown and requires further evaluation. PMID- 26120076 TI - Fatty acids in bacterium Dietzia sp. grown on simple and complex hydrocarbons determined as FAME by GC-MS. AB - The influence of growth substrates on the fatty acids produced by Dietzia sp. A14101 has been studied to investigate how qualitative and semi-quantitative information on fatty acids correlates with the ability of this strain to access and utilize a wide range of water-immiscible HC-substrates by modifying the FA content and thus also the properties of the cellular membrane. After incubation on different substrates and media, the profiles of fatty acids (FA) were analyzed by gas chromatography and mass spectrometry (GC-MS). The equivalent chain length (ECL) index calibration system was employed to identify FA. The effect of each substrate on the cell surface charge and on the hydrophobicity of the cellular membrane was also investigated. The results indicate that the variation of the content of saturated fatty acids (SAT-FA) versus mono-unsaturated fatty acids (MUFA) was found to be the most pronounced while branched FA exhibited much less variation in spite of different substrate regimes. The regulation of the ratio of SAT-FA and MUFA seems to be coupled with the regulation of the charge and hydrophobicity of the outer cellular surface. The exposure to a water immiscible substrate led to the development of the negative cellular surface charge, production of carotenoid-type pigments and increased hydrophobicity of the cellular surface. The specific aspects of the adaptation mechanism could have implications for bioremediation and/or (M)EOR applications. PMID- 26120077 TI - Nanoscale reduction of graphene oxide thin films and its characterization. AB - In this paper, we report on a method to reduce thin films of graphene oxide (GO) to a spatial resolution better than 100 nm over several tens of micrometers by means of an electrochemical scanning probe based lithography. In situ tip-current measurements show that an edged drop in electrical resistance characterizes the reduced areas, and that the reduction process is, to a good approximation, proportional to the applied bias between the onset voltage and the saturation thresholds. An atomic force microscope (AFM) quantifies the drop of the surface height for the reduced profile due to the loss of oxygen. Complementarily, lateral force microscopy reveals a homogeneous friction coefficient of the reduced regions that is remarkably lower than that of native graphene oxide, confirming a chemical change in the patterned region. Micro Raman spectroscopy, which provides access to insights into the chemical process, allows one to quantify the restoration and de-oxidation of the graphitic network driven by the electrochemical reduction and to determine characteristic length scales. It also confirms the homogeneity of the process over wide areas. The results shown were obtained from accurate analysis of the shift, intensity and width of Raman peaks for the main vibrational bands of GO and reduced graphene oxide (rGO) mapped over large areas. Concerning multilayered GO thin films obtained by drop-casting we have demonstrated an unprecedented lateral resolution in ambient conditions as well as an improved control, characterization and understanding of the reduction process occurring in GO randomly folded multilayers, useful for large-scale processing of graphene-based material. PMID- 26120078 TI - Knowledge and Usage of Emergency Contraceptives Among University Students in Ghana. AB - Contraceptive use is an important strategy for the prevention of unwanted pregnancy and avoidance of induced abortion. Of all the contraception methods, emergency contraceptive (EC) offers the last chance to achieve this. However, few studies have documented the use of EC among young people in Ghana. This study explored knowledge and usage of EC as well as the factors associated with it among University of Cape Coast students. Data were obtained on the knowledge and usage of ECs among University of Cape Coast students in 2013. Logistic regression analysis was used to investigate the association between students' socio demographic characteristics and EC knowledge and use. More male students (72%) than females (59%) were sexually active. Fifty-seven percent of the respondents had ever heard of EC and 36% had ever used EC. Although males were more likely to be sexually active, females were more likely to have knowledge of EC use compared to males. The study underscores the need to increase awareness regarding EC among University students in order to offer them the opportunity that EC provides if other forms of contraceptives are missed. PMID- 26120079 TI - Peptide Fragments of Odin-Sam1: Conformational Analysis and Interaction Studies with EphA2-Sam. AB - Odin is a protein belonging to the ANKS family, and has two tandem Sam domains. The first, Odin-Sam1, binds to the Sam domain of the EphA2 receptor (EphA2-Sam); this interaction could be crucial for the regulation of receptor endocytosis and might have an impact on cancer. Odin-Sam1 associates with EphA2-Sam by adopting a "mid-loop/end-helix" model. In this study three peptide sequences, encompassing the mid-loop interacting portion of Odin-Sam1 and its C-terminal alpha5 helix, were designed. Their conformational properties were analyzed by CD and NMR. In addition, their abilities to interact with EphA2-Sam were investigated by SPR studies. The peptides adopt a predominantly disordered state in aqueous buffer, but a higher helical content is evident in the presence of the cosolvent trifluoroethanol. Dissociation constants towards EphA2-Sam were in the high micromolar range. The structural findings suggest further routes for the design of potential anti-cancer therapeutics as inhibitors of EphA2-Sam heterotypic interactions. PMID- 26120080 TI - Response to the Letter to the Editor: "The prognostic value of white blood cell count-to-mean platelet volume ratio in patients with acute coronary syndrome". PMID- 26120081 TI - Mitochondrial DNA copy number is reduced in male combat veterans with PTSD. AB - INTRODUCTION: Mitochondrial abnormalities may be involved in PTSD, although few studies have examined this. Mitochondrial DNA copy number (mtDNAcn) in blood cells is an emerging systemic index of mitochondrial biogenesis and function. The present study assessed mtDNAcn in male combat-exposed veterans with PTSD compared to those without PTSD as well as its correlation with clinical scales. METHODS: mtDNAcn was assessed with a TaqMan multiplex assay in granulocytes of 43 male combat veterans with (n=43) or without (n=44) PTSD. Twenty of the PTSD subjects had co-morbid major depressive disorder (MDD). The Clinician Administered PTSD Scale (CAPS), the Positive and Negative Affect Schedule (PANAS), the Early Trauma Inventory (ETI) and the Beck Depression Inventory II (BDI-II) were used for the clinical assessments. All analyses were corrected for age and BMI. RESULTS: mtDNAcn was significantly lower in subjects with PTSD (p<0.05). Within the PTSD group, those with moderate PTSD symptom severity had relatively higher mtDNAcn than those with mild or severe symptoms (p<0.01). Within the PTSD group, mtDNAcn was positively correlated with PANAS positive subscale ratings (p<0.01) but was not significantly correlated with PANAS negative subscale, ETI or BDI-II ratings. DISCUSSION: This study provides the first evidence of: (i) a significant decrease of mtDNAcn in combat PTSD, (ii) a possible "inverted-U" shaped relationship between PTSD symptom severity and mtDNAcn within PTSD subjects, and (iii) a direct correlation of mtDNAcn with positive affectivity within PTSD subjects. Altered mtDNAcn in PTSD may reflect impaired energy metabolism, which might represent a novel aspect of its pathophysiology. PMID- 26120083 TI - Demographic inference using genetic data from a single individual: Separating population size variation from population structure. AB - The rapid development of sequencing technologies represents new opportunities for population genetics research. It is expected that genomic data will increase our ability to reconstruct the history of populations. While this increase in genetic information will likely help biologists and anthropologists to reconstruct the demographic history of populations, it also represents new challenges. Recent work has shown that structured populations generate signals of population size change. As a consequence it is often difficult to determine whether demographic events such as expansions or contractions (bottlenecks) inferred from genetic data are real or due to the fact that populations are structured in nature. Given that few inferential methods allow us to account for that structure, and that genomic data will necessarily increase the precision of parameter estimates, it is important to develop new approaches. In the present study we analyze two demographic models. The first is a model of instantaneous population size change whereas the second is the classical symmetric island model. We (i) re-derive the distribution of coalescence times under the two models for a sample of size two, (ii) use a maximum likelihood approach to estimate the parameters of these models (iii) validate this estimation procedure under a wide array of parameter combinations, (iv) implement and validate a model rejection procedure by using a Kolmogorov-Smirnov test, and a model choice procedure based on the AIC, and (v) derive the explicit distribution for the number of differences between two non recombining sequences. Altogether we show that it is possible to estimate parameters under several models and perform efficient model choice using genetic data from a single diploid individual. PMID- 26120082 TI - Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis. AB - Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach. PMID- 26120084 TI - Response to Letter to the Editor: 'Human skin allografts: Storage medium at 4 degrees C and viability'. PMID- 26120085 TI - Facial burns from exploding microwaved foods: Case series and review. AB - INTRODUCTION: Microwave ovens allow for quick and simple cooking. However, the importance of adequate food preparation, prior to microwave cooking, and the consequences of inadequate preparation are not well-known. METHOD: The authors conducted a retrospective outcome analysis of all patients who sustained facial burns from microwaved foods and were treated at a UK regional burns unit over a six-year period. Patients were identified from clinical records. RESULTS: Eight patients presented following inadequate preparation of either tinned potatoes (n=4) or eggs (n=4). All patients sustained <2% total body surface area facial burns. Mean age was 41 years (range 21-68 years). Six cases (75%) had associated ocular injury. One received amniotic membrane grafts; this individual's vision remains poor twelve months after injury. DISCUSSION: Rapid dielectric heating of water within foods may produce high steam and vapour pressure gradients and cause explosive decompression [1,5,11]. Consumers may fail to recognise differential heating and simply cook foods for longer if they remain cool on the outer surface. Education on safe use and risks of microwave-cooked foods may help prevent these potentially serious injuries. CONCLUSION: Microwave ovens have become ubiquitous. The authors recognise the need for improved public awareness of safe microwave cooking. Burns resulting from microwave-cooked foods may have life-changing consequences. PMID- 26120086 TI - Perineal burn care: French working group recommendations. Burns 2014;40:655-663. PMID- 26120087 TI - The late clinical and forensic symptoms and signs of sulfur mustard. PMID- 26120088 TI - Validation of the prognostic burn index: a nationwide retrospective study. AB - BACKGROUND: The burn index (BI=full thickness total burn surface area [TBSA]+1/2 partial thickness TBSA) and prognostic burn index (PBI=BI+age) are clinically used particularly in Japan. However, few studies evaluated the validation of PBI with large sample size. We retrospectively investigated the relationships between PBI and mortality among burn patients using data from a nationwide database. METHODS: Data of all burn patients with burn index >=1 were extracted from the Japanese Diagnosis Procedure Combination (DPC) inpatient database from 1 July 2010 to 31 March 2013 (17,185 patients in 1044 hospitals). The primary endpoint was all-cause in-hospital mortality. RESULTS: Overall in-hospital mortality was 5.9% (1011/17,185). Mortality increased significantly as the PBI increased (Mantel-Haenszel trend test, P<0.001). The area under the receiver operating characteristic curve for PBI was 0.90 (95%CI, 0.90-0.91), and a PBI above a threshold of 85 showed the highest association with in-hospital mortality. Logistic regression analysis showed that PBI>=85 (odds ratio (OR), 14.6; 95%CI, 12.1-17.6), inhalation injury with mechanical ventilation (OR, 13.0; 95%CI, 10.8 15.7), Charlson Comorbidity Index>=2 (OR, 1.8; 95%CI, 1.5-2.3), and male gender (OR, 1.5; 95%CI, 1.3-1.8) were significant independent risk factors for death. CONCLUSIONS: Our study suggested that a PBI above a threshold of 85 was significantly associated with mortality. The PBI and mechanical ventilation were the most significant factors predicting in-hospital mortality, after adjustment for inhalation injury, comorbidity, and gender. PMID- 26120089 TI - Orofacial contracture management outcomes following partial thickness facial burns. AB - PURPOSE: To examine clinical outcomes following non-surgical exercise for contracture management post partial thickness orofacial burn. METHODS: A cohort of 229 patients with partial thickness orofacial burn was recruited over 3 years. Orofacial contracture management combining exercise and stretching was initiated within 48h of admission and continued until functional goals were consistently achieved. A second cohort of 120 healthy controls was recruited for normative comparison. Vertical and horizontal mouth opening measures were recorded at the start and completion of orofacial intervention for patients and once only for controls. RESULTS: At commencement of intervention, participants with orofacial burns had significantly (p<0.001) reduced vertical and horizontal mouth opening. Treatment duration averaged 30.7 days (SD=52.3). Post treatment significant (p<0.001) improvements in vertical and horizontal opening were noted. At treatment conclusion, a significant (p<0.01) difference remained between the burns cohort and control group for vertical mouth opening, though horizontal mouth opening was now statistically comparable to the controls. CONCLUSION: This study supports positive outcomes following orofacial contracture management for patients with partial thickness orofacial burn. Despite this, some functional loss remained with patients demonstrating persistent reduced vertical mouth opening at conclusion of treatment compared to their healthy counterparts. PMID- 26120090 TI - A novel approach to graft loss in burn using the CelluTomeTM epidermal harvesting system for spot grafting: a case report. PMID- 26120091 TI - Closing the health and nutrition gap in Odisha, India: A case study of how transforming the health system is achieving greater equity. AB - Health equity is high on the international agenda. This study provides evidence of how health systems can be strengthened to improve health equity in a low income state. The paper presents a case study of how the Government of Odisha in eastern India is transforming the health system for more equitable health and nutrition outcomes. Odisha has a population of over 42 million, high levels of poverty, and poor maternal and child health concentrated in its Southern districts and among Scheduled Tribe and Scheduled Caste communities. Conducted between 2008 and 2012 with the Departments of Health and Family Welfare, and Women and Child Development, the study reviewed a wide range of literature including policy and programme documents, evaluations and studies, published and grey material, and undertook secondary analysis of state level household surveys. It identifies innovative and expanded provision of health services, reforms to the management and development of human resources for health, and the introduction of a number of cash transfer and entitlement schemes as contributing to closing the gap between maternal and child health and nutrition outcomes of Scheduled Tribes, and the Southern districts, compared to the state average. The institutional delivery rate for Scheduled Tribes has risen from 11.7% in 2005-06 to 67.3% in 2011, and from 35.6% to 79.8% for all women. The social gradient has also closed for antenatal and postnatal care and immunisation. Nutrition indicators though improving are proving slower to budge. The paper identifies how political will, committed policy makers and fiscal space energised the health system to promote equity. Sustained political commitment will be required to continue to address the more challenging human resource, health financing and gender issues. PMID- 26120092 TI - Response to: "No evidence for improved TORS post-treatment feeding tube dependency rate relative to standard therapy in early stage oropharyngeal cancer". PMID- 26120093 TI - Socioeconomic characteristics of patients with oropharyngeal carcinoma according to tumor HPV status, patient smoking status, and sexual behavior. AB - OBJECTIVES: Patients with oropharyngeal cancer (OPC) have distinct risk factor profiles reflected in the human papillomavirus (HPV) status of their tumor, and these profiles may also be influenced by factors related to socioeconomic status (SES). The goal of this study was to describe the socioeconomic characteristics of a large cohort of patients with OPC according to HPV status, smoking status, and sexual behavior. MATERIALS AND METHODS: Patients with OPC prospectively provided information about their smoking and alcohol use, socioeconomic characteristics, and sexual behaviors. HPV status was determined by a composite of immunohistochemistry for p16 expression, HPV in situ hybridization, and PCR assay in 356 patients. Standard descriptive statistics and logistic regression were used to compare socioeconomic characteristics between patient subgroups. RESULTS: Patients with HPV-positive OPC had higher levels of education, income, and overall SES. Among patients with HPV-positive OPC, never/light smokers had more than 5 times the odds of having at least a bachelor's degree and being in the highest level of SES compared with smokers. Patients with HPV-positive OPC and those with higher levels of education and SES had higher numbers of lifetime any and oral sex partners, although not all of these differences were significant. CONCLUSION: Socioeconomic differences among subgroups of OPC patients have implications for OPC prevention efforts, including tobacco cessation, behavior modification, and vaccination programs. PMID- 26120094 TI - Human papillomavirus DNA and p16(INK4a) expression in hypopharyngeal cancer and in relation to clinical outcome, in Stockholm, Sweden. AB - OBJECTIVES: Hypopharyngeal cancer is a subset of head neck squamous cell carcinoma (HNSCC) with particularly poor prognosis. Human papillomavirus (HPV) is a risk factor for some HNSCC, and its presence is of prognostic value for certain subsites. However, its influence on survival in hypopharyngeal cancer has not been thoroughly investigated. Here we examine HPV DNA and p16(INK4a) (p16) overexpression in relation to clinical outcome. MATERIALS AND METHODS: Hypopharyngeal tumour biopsies from 82 patients diagnosed 2008-2013 were examined for presence of HPV DNA by a bead-based multiplex assay and for p16 expression by immunohistochemistry, and the obtained data compared to that acquired previously from 109 patients diagnosed 2000-2007 at the same clinic. A survival analysis was then performed on 142 patients (from both studies) treated with curative intent and a 3-year follow-up time. RESULTS: Of the tumour biopsies 3/82 (3.7%) were HPV16 DNA and p16 positive, while 12/82 (14.6%) were p16 positive, equivalent to that in the previous study. Overall 3-year survival was significantly more favourable for patients with HPV16 DNA and p16 positive tumours as compared to survival of the other patients (86% vs. 31%, p=0.0185). A similar but not statistically significant trend was found for disease specific survival. CONCLUSION: HPV DNA and p16 positive hypopharyngeal cancer was rare and had not increased, but had a better clinical outcome as compared to other HPV-unrelated hypopharyngeal cancer. In addition, p16 overexpression was not a suitable surrogate marker for presence of HPV or for prediction of survival in this type of cancer. PMID- 26120095 TI - Host selection by an insect herbivore with spatially variable density dependence. AB - Many species of phytophagous insects do not oviposit preferentially on plants that yield high offspring performance. One proposed explanation is that negatively density-dependent offspring performance would select for females that disperse eggs among plants to minimize competition. Recent work showing larval density dependence often varies substantially among plants suggests that ovipositing females should not only respond to the density of competitors but also to traits predictive of the strength of density dependence mediated by plants. In this study, we used field and greenhouse experiments to examine oviposition behavior in an insect herbivore that experiences density-dependent larval performance and variability in the strength of that density dependence among host-plant individuals. We found females moved readily among plants in the field and had strong preferences for plants that mediate weak offspring density dependence. Females, however, did not avoid plants with high densities of competitors, despite the fact that offspring performance declines steeply with density on most plants in natural populations. This means females minimize the effects of density dependence on their offspring by choosing plants that mediate only weak larval density dependence, not by choosing plants with low densities of competitors. Our results suggest that explaining the lack of positive preference performance correlations in many systems may not be as simple as invoking density dependence. Resource selection behavior may depend not just on the presence or absence of density-dependent offspring performance but also on variation in the strength of offspring density dependence among sites within populations. PMID- 26120096 TI - Guidelines in otorhinolaryngology: a critical view. PMID- 26120097 TI - High levels of sound pressure: acoustic reflex thresholds and auditory complaints of workers with noise exposure. AB - INTRODUCTION: The clinical evaluation of subjects with occupational noise exposure has been difficult due to the discrepancy between auditory complaints and auditory test results. This study aimed to evaluate the contralateral acoustic reflex thresholds of workers exposed to high levels of noise, and to compare these results to the subjects' auditory complaints. METHODS: This clinical retrospective study evaluated 364 workers between 1998 and 2005; their contralateral acoustic reflexes were compared to auditory complaints, age, and noise exposure time by chi-squared, Fisher's, and Spearman's tests. RESULTS: The workers' age ranged from 18 to 50 years (mean=39.6), and noise exposure time from one to 38 years (mean=17.3). We found that 15.1% (55) of the workers had bilateral hearing loss, 38.5% (140) had bilateral tinnitus, 52.8% (192) had abnormal sensitivity to loud sounds, and 47.2% (172) had speech recognition impairment. The variables hearing loss, speech recognition impairment, tinnitus, age group, and noise exposure time did not show relationship with acoustic reflex thresholds; however, all complaints demonstrated a statistically significant relationship with Metz recruitment at 3000 and 4000Hz bilaterally. CONCLUSION: There was no significance relationship between auditory complaints and acoustic reflexes. PMID- 26120099 TI - Resonant dielectrophoresis and electrohydrodynamics for high-sensitivity impedance detection of whole-cell bacteria. AB - We present the co-integration of CMOS-compatible Al/Al2O3 interdigitated microelectrodes (IDEs) with an electrokinetic-driven macroelectrode for sensitive detection of whole-cell bacteria in a microfluidic channel. Two frequency ranges applied to the macroelectrode were identified to notably increase the bacterial coverage of the impedimetric sensor per unit time. Around 10 kHz, the bacterial cells were directed towards the IDE center thanks to AC electroosmosis (AC-EO) and the sensor capacitance linearly increased, achieving a limit of detection (LoD) of 3.5 * 10(5) CFU mL(-1) after an incubation time of 20 min with Staphylococcus epidermidis. At 63 MHz precisely, a resonance effect due to the device was found to dramatically increase the trapping of S. epidermidis on the sensor periphery, due to the combined actions of short-range contactless dielectrophoresis (cDEP) and long-range Joule heating electrothermal (J-ET) flow. Thanks to a flow-based method, the bacterial cells were redirected towards the sensor center and an LoD of 10(5) CFU mL(-1) was achieved within 20 min of incubation, which is almost two orders of magnitude better than the impedimetric sensor alone. Analytical models and 2D simulations using the Maxwell stress tensor (MST) provide a comprehensive analysis of the experimental results, especially about the spectral balance between cDEP, AC-EO and J-ET accounting for the 33-nm thick insulating layer atop the electrodes. Electrode CMOS compatibility confers portability, miniaturization and affordability capabilities for building point-of-care (PoC) diagnostic tests in a lab-on-a-chip (LoC). PMID- 26120098 TI - Review of survival rates 20-years after conservative surgery for papillary thyroid carcinoma. AB - INTRODUCTION: A less extensive thyroidectomy could be used for patients in the low risk group. OBJECTIVE: To perform a critical follow-up after lobectomy with isthmusectomy for the treatment of papillary thyroid carcinoma in patients with a single nodule limited to the periphery of the lobe. METHODS: Thirty-one patients with thyroid papillary carcinoma operated on till 1993 were selected. They had undergone lobectomy with isthmusectomy. This is a retrospective cohort study in which the oncological outcome (contralateral and regional recurrence) and the reoperation complications (recurrent nerve paralysis/paresis and hypoparathyroidism) were evaluated. Descriptive analysis was employed. RESULTS: In the last decade (2003-2013), 6 (20%) contralateral recurrences were observed in the remaining lobe and in 1 of these cases (3%), contralateral lymph node metastases were noted. A completion thyroidectomy plus lymphadenectomy was performed, without modification of global survival. CONCLUSION: Because of the rate of 20% of contralateral recurrence after a 20-year follow-up, we suggest modification of the surgical paradigm for total thyroidectomy as an initial therapy. PMID- 26120101 TI - Prevention of sulfur diffusion using MoS2-intercalated 3D-nanostructured graphite for high-performance lithium-ion batteries. AB - We report new three-dimensional (3D)-nanostructured MoS2-carbonaceous materials in which MoS2 sheets are intercalated between the graphite layers that possess a multiply repeated graphite/MoS2/graphite structure which prevents the aggregation of MoS2 and diffusion of sulfur from carbonaceous materials, enhancing the cycling stability of Li-ion batteries. We developed an efficient and scalable process applicable to mass production for synthesizing non-aggregated MoS2 intercalated 3D hybrid-nanostructured graphite based on stress induced and microwave irradiation. X-ray diffraction, X-ray photospectroscopy, Raman spectroscopy, field emission scanning electron microscopy, and high-resolution transmission electron microscopy analyses demonstrated that the as-synthesized materials consisted of MoS2-intercalated 3D hybrid-nanostructured graphite platelets that had a multiply repeated graphite/MoS2/graphite structure. The obtained MoS2-graphite powder surpasses MoS2 as an anode material in terms of specific capacity, cyclic stability, and rate performances at high current densities for Li-ion batteries. The electrochemical impedance spectroscopy demonstrated that the graphite sheets not only reduced the contact resistance in the electrode but also facilitated electron transfer in the lithiation/delithiation processes. The superior electrochemical performances especially for the cycling stability of the Li-ion battery originate from prevention of the sulfur diffusion of the MoS2-intercalated 3D-nanostructured graphite. PMID- 26120100 TI - Accuracy of physician assessment of treatment preferences and health status in elderly patients with higher-risk myelodysplastic syndromes. AB - Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians' perception of patients' health status and the patients' preferences for involvement in treatment decisions. We examined 280 newly diagnosed higher-risk elderly MDS patients paired with their physicians. Survey tools included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) and the Control Preference Scale. Overall concordance was 49% for physician perception of patient preferences for involvement in treatment decisions. In 36.4% of comparisons there were minor differences and in 14.6% there were major differences. In 44.7% of the patients preferring a passive role, physicians perceived them as preferring an active or collaborative role. Absence of the patient's request for prognostic information (P=0.001) and judging the patient as having a poor health status (P=0.036) were factors independently associated with the physicians' attitude toward a lower degree of patient involvement in clinical decisions. Agreement on health status was found in 27.5% of cases. Physicians most frequently tended to overestimate health status of patients who reported low level health status. The value of decision aid-tools in the challenging setting of higher-risk MDS should be investigated to further promote patient-centered care. PMID- 26120102 TI - An investigation of a novel MnO2 network-Ni/PVDF double shell/core membrane as an anode for lithium ion batteries. AB - A novel MnO2 network-Ni/PVDF double shell/core fiber membrane is synthesized for the first time as an anode material for lithium ion batteries. The freestanding MnO2 nanosheet network is grown directly onto a conductive network-Ni/PVDF shell/core fiber membrane 3D current collector, avoiding the application of binders and conductive additives and simplifying the fabrication processing. The MnO2 nanosheet network can be tightly anchored to the Ni/PVDF fiber 3D current collector, and some small pores between the fibers and between the MnO2 nanosheets lead to fast charge transfer and ion transport. The unique MnO2 network-Ni/PVDF double shell/core fiber membrane exhibits a high charge/discharge capacity, long-term cycling stability and good rate capability. PMID- 26120103 TI - Dye-sensitized InGaN nanowire arrays for efficient hydrogen production under visible light irradiation. AB - Solar water splitting is a key sustainable energy technology for clean, storable and renewable source of energy in the future. Here we report that Merocyanine-540 dye-sensitized and Rh nanoparticle-decorated molecular beam epitaxially grown In0.25Ga0.75N nanowire arrays have produced hydrogen from ethylenediaminetetraacetic acid (EDTA) and acetonitrile mixture solution under green, yellow and orange solar spectra (up to 610 nm) for the first time. An apparent quantum efficiency of 0.3% is demonstrated for wavelengths 525-600 nm, providing a viable approach to harness deep-visible and near-infrared solar energy for efficient and stable water splitting. PMID- 26120104 TI - Fighting Stroke. PMID- 26120105 TI - Stroke detection and prevention in atrial fibrillation. PMID- 26120106 TI - In pursuit of normoglycaemia: the overtreatment of type 2 diabetes in general practice. PMID- 26120107 TI - The National Diabetes Prevention Programme: a pathway for prevention and wellbeing. PMID- 26120108 TI - Fit for work? How GPs' decisions about fitness to work can improve health. PMID- 26120110 TI - Continuity of care is very important. PMID- 26120111 TI - The inevitable demise of the independent contractor status. PMID- 26120112 TI - Patient co-payments for general practice. PMID- 26120113 TI - Tools of the Trade. PMID- 26120115 TI - Misshapen training. PMID- 26120116 TI - The teacher. PMID- 26120117 TI - A Digital Ache. PMID- 26120118 TI - RATs: Quality not Quantity. PMID- 26120119 TI - The Technophobe's Guide to the Digital Age. PMID- 26120120 TI - Prostate biopsy, childhood vaccination, oral health, and medical tourism. PMID- 26120121 TI - The NHS simply has to wake up to mobile. PMID- 26120122 TI - Law note: what treatment risks do I have to discuss with my patients? PMID- 26120123 TI - Unhistoric acts. PMID- 26120124 TI - Hope for US health care despite strong headwinds. PMID- 26120129 TI - Test in peace. PMID- 26120130 TI - Going beyond blame: reporting NHS medication errors in nursing home residents with diabetes. PMID- 26120131 TI - How can GPs and community health services work more effectively together? PMID- 26120132 TI - Street-level bureaucracy: an underused theoretical model for general practice? PMID- 26120133 TI - Cardiovascular risk assessment and lipid modification: NICE guideline. PMID- 26120134 TI - Receptionist rECognition and rEferral of Patients with Stroke (RECEPTS): unannounced simulated patient telephone call study in primary care. AB - BACKGROUND: Stroke is a leading cause of morbidity and mortality. Timely recognition and referral are essential for treatment. AIM: To examine the ability of receptionists in general practices to recognise symptoms of stroke and direct patients to emergency care. DESIGN AND SETTING: Unannounced simulated patient telephone calls and prospective cross-sectional survey study in general practices in the Birmingham and Solihull area. METHOD: A total of 52 general practices participated in a total of 520 simulated telephone calls, with 183 receptionists completing questionnaires. Logistic regression analyses were used to examine likelihood of referral for immediate care by ease of vignette recognition and number of common stroke symptoms present. RESULTS: General practice receptionists correctly referred 69% of simulated calls for immediate care. Calls classed as 'difficult' to recognise were less likely to be immediately referred. Compared with 'easy' calls: 'difficult' calls odds ratio (OR) 0.15, 95% confidence interval (CI) = 0.08 to 0.26; 'moderate' calls OR 0.55, 95% CI = 0.32 to 0.92. Similarly, calls including one or two 'FAST' symptoms were less likely to be referred immediately (compared with three FAST symptoms: one symptom OR 0.30, 95% CI = 0.13 to 0.72; two symptoms OR 0.35, 95% CI = 0.15 to 0.83). CONCLUSION: General practice receptionists refer patients with stroke for immediate care when they present with several symptoms; however, they are less likely to refer patients presenting with only one symptom or less common symptoms of stroke. Optimum management of acute stroke in primary care requires interventions that improve receptionists' knowledge of lesser-known stroke symptoms. PMID- 26120135 TI - Diagnostic inertia in obesity and the impact on cardiovascular risk in primary care: a cross-sectional study. AB - BACKGROUND: Prevalence of diagnostic inertia (DI), defined as a failure to diagnose disease, has not been analysed in patients with obesity. AIM: To quantify DI for cardiovascular risk factors (CVRF) in patients with obesity, and determine its association with the cardiovascular risk score. DESIGN AND SETTING: Cross-sectional study of people >=40 years attending a preventive programme in primary healthcare centres in Spain in 2003-2004. METHOD: All patients with obesity attending during the first 6 months of the preventive programme were analysed. Participants had to be free of CVD (myocardial ischaemia or stroke) and aged 40-65 years; the criteria used to measure SCORE (Systematic COronary Risk Evaluation). Three subgroups of patients with obesity with no personal history of CVRF but with poor control of risk factors were established. Outcome variable was DI, defined as poor control of risk factors and no action taken by the physician. Secondary variables were diabetes, fasting blood glucose (FBG), body mass index (BMI), and SCORE. Adjusted odds ratios (OR) was determined using multivariate logistic regression models. RESULTS: Of 8687 patients with obesity in the programme, 6230 fulfilled SCORE criteria. Prevalence of DI in the three subgroups was: hypertension, 1275/1816 (70.2%) patients affected (95% CI = 68.1 to 72.3%); diabetes, 335/359 (93.3%) patients affected (95% CI = 90.7 to 95.9%); dyslipidaemia subgroup, 1796/3341 (53.8%) patients affected (95% CI = 52.1 to 55.4%. Factors associated with DI for each subgroup were: for hypertension, absence of diabetes, higher BMI, and greater cardiovascular risk; for dyslipidaemia, diabetes, higher BMI, and greater cardiovascular risk (SCORE); and for diabetes, lower FBG levels, lower BMI, and greater cardiovascular risk. CONCLUSION: This study quantified DI in patients with obesity and determined that it was associated with a greater cardiovascular risk. PMID- 26120136 TI - Primary care organisational interventions for secondary prevention of ischaemic heart disease: a systematic review and meta-analysis. AB - BACKGROUND: Ischaemic heart disease (IHD) is the most common cause of death worldwide. AIM: To determine the long-term impact of organisational interventions for secondary prevention of IHD. DESIGN AND SETTING: Systematic review and meta analysis of studies from CENTRAL, MEDLINE((r)), Embase, and CINAHL published January 2007 to January 2013. METHOD: Searches were conducted for randomised controlled trials of patients with established IHD, with long-term follow-up, of cardiac secondary prevention programmes targeting organisational change in primary care or community settings. A random-effects model was used and risk ratios were calculated. RESULTS: Five studies were included with 4005 participants. Meta-analysis of four studies with mortality data at 4.7-6 years showed that organisational interventions were associated with approximately 20% reduced mortality, with a risk ratio (RR) for all-cause mortality of 0.79 (95% confidence interval [CI] = 0.66 to 0.93), and a RR for cardiac-related mortality of 0.74 (95% CI = 0.58 to 0.94). Two studies reported mortality data at 10 years. Analysis of these data showed no significant differences between groups. There were insufficient data to conduct a meta-analysis on the effect of interventions on hospital admissions. Additional analyses showed no significant association between organisational interventions and risk factor management or appropriate prescribing at 4.7-6 years. CONCLUSION: Cardiac secondary prevention programmes targeting organisational change are associated with a reduced risk of death for at least 4-6 years. There is insufficient evidence to conclude whether this beneficial effect is maintained indefinitely. PMID- 26120137 TI - GPs' views on managing advanced chronic kidney disease in primary care: a qualitative study. AB - BACKGROUND: Chronic kidney disease (CKD) has become a significant part of the GP's workload since the introduction of the National Institute for Health and Care Excellence guidelines in 2008. Patients with advanced CKD (stages G4 and G5) often have comorbidities, varied disease progression, and are likely to be older. GPs may experience difficulties with management decisions for patients with advanced CKD, including when to refer to nephrology. AIM: To explore GPs' views of managing patients with advanced CKD and referral to secondary care. DESIGN AND SETTING: Qualitative study with GPs in four areas of England: London, Bristol, Birmingham, and Stevenage. METHOD: Semi-structured interviews with 19 GPs. Transcribed interviews were thematically analysed. RESULTS: GPs had little experience of managing patients with advanced CKD, including those on dialysis or having conservative care (treatment without dialysis or a transplant), and welcomed guidance. Some GPs referred patients based on renal function alone and some used wider criteria including age and multimorbidity. GPs reported a tension between national guidance and local advice, and some had learnt from experience that patients were discharged back to primary care. GPs with more experience of managing CKD referred patients later, or sometimes not at all, if there were no additional problems and if dialysis was seen as not in the patient's interests. CONCLUSION: GPs want guidance on managing older patients with advanced CKD and comorbidities, which better incorporates agreement between local and national recommendations to clarify referral criteria. GPs are not generally aware of conservative care programmes provided by renal units, however, they appear happy to contribute to such care or alternatively, lead conservative management with input from renal teams. PMID- 26120138 TI - CrisprGE: a central hub of CRISPR/Cas-based genome editing. AB - CRISPR system is a powerful defense mechanism in bacteria and archaea to provide immunity against viruses. Recently, this process found a new application in intended targeting of the genomes. CRISPR-mediated genome editing is performed by two main components namely single guide RNA and Cas9 protein. Despite the enormous data generated in this area, there is a dearth of high throughput resource. Therefore, we have developed CrisprGE, a central hub of CRISPR/Cas based genome editing. Presently, this database holds a total of 4680 entries of 223 unique genes from 32 model and other organisms. It encompasses information about the organism, gene, target gene sequences, genetic modification, modifications length, genome editing efficiency, cell line, assay, etc. This depository is developed using the open source LAMP (Linux Apache MYSQL PHP) server. User-friendly browsing, searching facility is integrated for easy data retrieval. It also includes useful tools like BLAST CrisprGE, BLAST NTdb and CRISPR Mapper. Considering potential utilities of CRISPR in the vast area of biology and therapeutics, we foresee this platform as an assistance to accelerate research in the burgeoning field of genome engineering. PMID- 26120139 TI - MiDAS: the field guide to the microbes of activated sludge. AB - The Microbial Database for Activated Sludge (MiDAS) field guide is a freely available online resource linking the identity of abundant and process critical microorganisms in activated sludge wastewater treatment systems to available data related to their functional importance. Phenotypic properties of some of these genera are described, but most are known only from sequence data. The MiDAS taxonomy is a manual curation of the SILVA taxonomy that proposes a name for all genus-level taxa observed to be abundant by large-scale 16 S rRNA gene amplicon sequencing of full-scale activated sludge communities. The taxonomy can be used to classify unknown sequences, and the online MiDAS field guide links the identity to the available information about their morphology, diversity, physiology and distribution. The use of a common taxonomy across the field will provide a solid foundation for the study of microbial ecology of the activated sludge process and related treatment processes. The online MiDAS field guide is a collaborative workspace intended to facilitate a better understanding of the ecology of activated sludge and related treatment processes--knowledge that will be an invaluable resource for the optimal design and operation of these systems. PMID- 26120141 TI - From GED to College: Age Trajectories of Nontraditional Educational Paths. AB - Age patterns of secondary certification and college entry differ in complex and surprising ways for traditional graduates and GED recipients. Although GED recipients are less likely to enter college in their late teens, they catch up to traditional graduates in their 20s. Results show that adjusting for differences in the age trajectories of school continuation accounts for a substantial portion of the differences observed between the two groups. Important differences remain, however, in the type of college attended and the likelihood of college entry before age 21. Nonetheless, more GED recipients enroll in college than previous studies have suggested, and this interest in college identifies a useful place for policy to intervene to encourage school continuation for this group. PMID- 26120140 TI - BEAN 2.0: an integrated web resource for the identification and functional analysis of type III secreted effectors. AB - Gram-negative pathogenic bacteria inject type III secreted effectors (T3SEs) into host cells to sabotage their immune signaling networks. Because T3SEs constitute a meeting-point of pathogen virulence and host defense, they are of keen interest to host-pathogen interaction research community. To accelerate the identification and functional understanding of T3SEs, we present BEAN 2.0 as an integrated web resource to predict, analyse and store T3SEs. BEAN 2.0 includes three major components. First, it provides an accurate T3SE predictor based on a hybrid approach. Using independent testing data, we show that BEAN 2.0 achieves a sensitivity of 86.05% and a specificity of 100%. Second, it integrates a set of online sequence analysis tools. Users can further perform functional analysis of putative T3SEs in a seamless way, such as subcellular location prediction, functional domain scan and disorder region annotation. Third, it compiles a database covering 1215 experimentally verified T3SEs and constructs two T3SE related networks that can be used to explore the relationships among T3SEs. Taken together, by presenting a one-stop T3SE bioinformatics resource, we hope BEAN 2.0 can promote comprehensive understanding of the function and evolution of T3SEs. PMID- 26120142 TI - Neighborhood Foreclosures, Racial/Ethnic Transitions, and Residential Segregation. AB - In this article, we use data on virtually all foreclosure events between 2005 and 2009 to calculate neighborhood foreclosure rates for nearly all block groups in the United States to assess the impact of housing foreclosures on neighborhood racial/ethnic change and on broader patterns of racial residential segregation. We find that the foreclosure crisis was patterned strongly along racial lines: black, Latino, and racially integrated neighborhoods had exceptionally high foreclosure rates. Multilevel models of racial/ethnic change reveal that foreclosure concentrations were linked to declining shares of whites and expanding shares of black and Latino residents. Results further suggest that these compositional shifts were driven by both white population loss and minority growth, especially from racially mixed settings with high foreclosure rates. To explore the impact of these racially selective migration streams on patterns of residential segregation, we simulate racial segregation assuming that foreclosure rates remained at their 2005 levels throughout the crisis period. Our simulations suggest that the foreclosure crisis increased racial segregation between blacks and whites by 1.1 dissimilarity points, and between Latinos and whites by 2.2 dissimilarity points. PMID- 26120144 TI - Enhanced Wireless Power Transmission Using Strong Paramagnetic Response. AB - A method of quasi-static magnetic resonant coupling has been presented for improving the power transmission efficiency (PTE) in near-field wireless power transmission, which improves upon the state of the art. The traditional source resonator on the transmitter side is equipped with an additional resonator with a resonance frequency that is tuned substantially higher than the magnetic field excitation frequency. This additional resonator enhances the magnetic dipole moment and the effective permeability of the power transmitter, owing to a phenomenon known as the strong paramagnetic response. Both theoretical calculations and experimental results show increased PTE due to amplification of the effective permeability. In measurements, the PTE was improved from 57.8% to 64.2% at the nominal distance of 15 cm when the effective permeability was 2.6. The power delivered to load was also improved significantly, with the same 10 V excitation voltage, from 0.38 to 5.26 W. PMID- 26120143 TI - Reduction of hexavalent chromium by the thermophilic methanogen Methanothermobacter thermautotrophicus. AB - Despite the significant progress on iron reduction by thermophilic microorganisms, studies on their ability to reduce toxic metals are still limited, despite their common co-existence in high temperature environments (up to 70 degrees C). In this study, Methanothermobacter thermautotrophicus, an obligate thermophilic methanogen, was used to reduce hexavalent chromium. Experiments were conducted in a growth medium with H2/CO2 as substrate with various Cr6+ concentrations (0.2, 0.4, 1, 3, and 5 mM) in the form of potassium dichromate (K2Cr2O7). Time-course measurements of aqueous Cr6+ concentrations with the 1, 5-diphenylcarbazide colorimetric method showed complete reduction of the 0.2 and 0.4 mM Cr6+ solutions by this methanogen. However, much lower reduction extents of 43.6%, 13.0%, and 3.7% were observed at higher Cr6+ concentrations of 1, 3 and 5 mM, respectively. These lower extents of bioreduction suggest a toxic effect of aqueous Cr6+ to cells at this concentration range. At these higher Cr6+ concentrations, methanogenesis was inhibited and cell growth was impaired as evidenced by decreased total cellular protein production and live/dead cell ratio. Likewise, Cr6+ bioreduction rates decreased with increased initial concentrations of Cr6+ from 13.3 to1.9 uM h-1. X ray absorption near-edge structure (XANES) spectroscopy revealed a progressive reduction of soluble Cr6+ to insoluble Cr3+ precipitates, which was confirmed as amorphous chromium hydroxide by X-ray diffraction and selected area electron diffraction pattern. However, a small fraction of reduced Cr occurred as aqueous Cr3+. Scanning and transmission electron microscope observations of M. thermautotrophicus cells after Cr6+ exposure suggest both extra- and intracellular chromium reduction mechanisms. Results of this study demonstrate the ability of M. thermautotrophicus cells to reduce toxic Cr6+ to less toxic Cr3+ and its potential application in metal bioremediation, especially at high temperature subsurface radioactive waste disposal sites, where the temperature may reach ~70 degrees C. PMID- 26120145 TI - Chronicles of Gerhard-Henrik Armauer Hansen's Life and Work. AB - Gerhard-Henrik Armauer Hansen, a Norwegian scientist, discovered Mycobacterium leprae as the causative organism for leprosy, defying the hereditary affliction theory of the disease. He was born in Bergen, Norway in 1841 in a Danish family. After acquiring his medical degree in 1866 from the University of Oslo, he joined as an assistant physician in a leprosy hospital in Bergen. In 1873, he published his report claiming leprosy to be an infectious disease with a description of the infectious material in leprous tissue. His conviction of belief and an unstinted devotion to a lifetime of scientific research changed the way leprosy was approached as a disease. It was the fruit of his untiring work that the amended act of 1885 was passed, which resulted in steady decline in leprosy burden in Norway. In February 1912 he breathed his last, leaving behind an inspirational story of a brave heart scientist who fought all odds to unveil the truth for the benefit of mankind. PMID- 26120146 TI - Oral Lichen Planus: An Update on Etiology, Pathogenesis, Clinical Presentation, Diagnosis and Management. AB - The mouth is a mirror of health or disease, a sentinel or early warning system. The oral cavity might well be thought as a window to the body because oral manifestations accompany many systemic diseases. In many instances, oral involvement precedes the appearance of other symptoms or lesions at other locations. Oral lichen planus (OLP) is a chronic mucocutaneous disorder of stratified squamous epithelium of uncertain etiology that affects oral and genital mucous membranes, skin, nails, and scalp. LP is estimated to affect 0.5% to 2.0% of the general population. This disease has most often been reported in middle-aged patients with 30-60 years of age and is more common in females than in males. The disease seems to be mediated by an antigen-specific mechanism, activating cytotoxic T cells, and non-specific mechanisms like mast cell degranulation and matrix metalloproteinase activation. A proper understanding of the pathogenesis, clinical presentation, diagnosis of the disease becomes important for providing the right treatment. This article discusses the prevalence, etiology, clinical features, oral manifestations, diagnosis, complications and treatment of oral LP. PMID- 26120147 TI - Treatment of Refractory Chronic Urticaria. AB - Chronic spontaneous urticaria is a distressing disease encountered frequently in clinical practice. The current mainstay of therapy is the use of second generation, non-sedating antihistamines. However, in patients who do not respond satisfactorily to these agents, a variety of other drugs are used. This article examines the available literature for frequently used agents including systemic corticosteroids, leukotriene receptor antagonists, dapsone, sulfasalazine, hydroxychloroquine, H2 antagonists, methotrexate, cyclosporine A, omalizumab, autologous serum therapy, and mycophenolate mofetil, with an additional focus on publications in Indian literature. PMID- 26120149 TI - Shampoo and Conditioners: What a Dermatologist Should Know? AB - Dermatologists many a times encounter questions from patients and even colleagues asking about how to keep their hair looking clean, healthy and beautiful. Therefore, familiarity and a basic knowledge of the available hair care products will help them to guide their patients properly. A shampoo not only provides the cleaning of the scalp skin and hair as its primary function, but in addition also serves to condition and beautify hair and acts as an adjunct in the management of various scalp disorders. To achieve this, various ingredients in the correct proportion are mixed to provide a shampoo which is suitable for individuals having different hair types and hair need. Among the ingredients that go into the making of a shampoo are detergents, conditioners, thickeners, sequestering agents, pH adjusters, preservatives and specialty additives. Hair conditioners are designed to improve hair manageability, decrease hair static electricity and add luster. They are used in several ways depending upon the state of hair and requirement of the individual. This article attempts to put forward the basic and practical aspects regarding use of these products. PMID- 26120148 TI - Treatment of Pediculosis Capitis. AB - An endeavour to delineate the salient details of the treatment of head lice infestation has been made in the present article. Treatment modalities including over the counter permethrin and pyrethrin, and prescription medicines, including malathion, lindane, benzyl alcohol, spinosad are discussed. Salient features of alternative medicine and physical treatment modalities are outlined. The problem of resistance to treatment has also been taken cognizance of. PMID- 26120150 TI - Cowden Syndrome: Case Report, Update and Proposed Diagnostic and Surveillance Routines. AB - Cowden syndrome (CS) is an infrequent autosomal dominant multisystem genodermatosis, generally involving the skin, oral mucosa, thyroid, breast and gastrointestinal tract. It is characterized by a late onset in the 2(nd) or 3(rd) decade of life, an extraordinary potential for malignant transformation, especially of breast and thyroid, and an identifiable germline mutation. In 80% cases, the human tumor suppressor gene, phosphatase and tensin homolog (PTEN) is mutated; mutations involving KILLIN, SDH B/D, PIK3CA and AKT1 genes account for the rest of the cases. Its clinical signs are not only the "essential pearls" for early and accurate diagnosis of CS but also help timely detection of neoplasia as they precede development of cancer by several years. We describe the first Indian and the third world report of polydactyly with CS, review this entity highlighting on recent clinical developments and emphasize on regular and thorough screening for prompt identification and management of the potentially malignant growths. We have also designed a baseline workup routine as well as a detailed screening program for these patients. PMID- 26120151 TI - Response to Microneedling Treatment in Men with Androgenetic Alopecia Who Failed to Respond to Conventional Therapy. AB - INTRODUCTION: The efficacy of conventional therapy viz. finasteride and minoxidil in androgenetic alopecia (AGA) that is based on both preventing hair loss and promoting new hair growth, varies between 30% and 60%. This has led to a large number of patients unsatisfied who demand for a better cosmetic coverage over the scalp. Microneedling has recently been reported to be promising, effective and a safe treatment modality in the treatment of AGA. This augments the response of conventional therapy. MATERIALS AND METHODS: Four men with AGA were on finasteride and 5% minoxidil solution since 2 to 5 years. Though there was no worsening in their respective AGA stages with the therapy, they showed no new hair growth. They were subjected to microneedling procedure over a period of 6 months along with their ongoing therapy. Patients were assessed with the use of the standardized 7-point evaluation scale and patients' subjective hair growth assessment scale. The patients were followed up for 18 months post microneedling procedure to assess the sustainability of the response. RESULTS: All patients showed a response of + 2 to + 3 on standardized 7-point evaluation scale. The response in the form of new hair growth started after 8-10 sessions. The patients' satisfaction was more than 75% in three patients and more 50% in one patient, on patients' subjective hair growth assessment scale. The obtained results were sustained post procedure during 18 months follow-up period. CONCLUSION: Treatment with microneedling showed an accelerated response with addition of microneedling procedure leading to significant scalp density. This is the first case series to report the boosting effect of microneedling with respect to new hair follicle stimulation in patients with androgenetic alopecia who were poor responders to conventional therapy. PMID- 26120152 TI - Elephantine Psoriasis with Papillomatosis and Alternating Hypogranulosis and Hypergranulosis. AB - Psoriasis is a disease of considerable clinical and histopathological diversity. We report a rare case of elephantine psoriasis responding very well to methotrexate. Histopathology revealed abnormal papillomatosis with finger-like projections in addition to alternating orthokeratosis with overlying hypergranulosis and parakeratosis with overlying hypogranulosis. We believe that this finding may represent an odd histopathologic type in elephantine psoriasis. PMID- 26120153 TI - Spontaneous Acroangiodermatitis. AB - Acroangiodermatitis is a rare self-limited angioproliferative lesion which can be associated with congenital vascular malformations or acquired venous insufficiency. Despite of its benign character, differential diagnosis of this lesion is very important because it closely resembles Kaposi sarcoma. Here we present a 26-year-old male patient with unilateral, purplish-red colored papules on his right ankle which diagnosed as acroangiodermatitis and discuss histopathological features, differential diagnosis and treatment of this unusual condition. PMID- 26120154 TI - Dermoscopy to Detect Signs of Subclinical Nail Involvement in Chronic Plaque Psoriasis: A Study of 68 Patients. AB - BACKGROUND: Onychopathies constitute one of the major challenges faced by a dermatologist in terms of its early detection and diagnosis. Utility of dermoscope as a tool for detection is increasing by the day and its use in onychopathies needs to be explored. AIMS: To study the dermoscopic features of nails in patients of chronic plaque psoriasis. MATERIALS AND METHODS: In a cross sectional study, a total of 68 patients with chronic plaque psoriasis were recruited. Dermoscopy of nail plate was conducted and were compared with equal number of age and sex matched healthy volunteers. RESULTS: Forty-six patients showed dermoscopic findings. Twenty-two patients did not show any dermoscopic findings. Coarse pits (18/46, P < 0.0001), onycholysis (10/46, P < 0.001), oil drop sign (2/46, P = 0.12) and splinter hemorrhages (5/46, P = 0.05) were seen. In addition certain findings of interest were stout, globose, dilated, pink- to red-colored nail bed vessels arranged longitudinally at the onychodermal band surrounded by a prominent halo (9/46, P = 0.01). In contrast, splinter hemorrhages appeared as streaks and were purple in color. CONCLUSION: In a psoriasis patient, dermoscope can be a useful tool to detect early nail involvement in psoriasis and aid in differentiating it from other disorders of nails. PMID- 26120155 TI - Vaccines in Dermatology. AB - A vaccine is a biological preparation that improves immunity to a specific disease. More than two centuries have passed since the first successful vaccine for smallpox was developed. We've come a long way since. Today's vaccines are among the 21(st) century's most successful and cost-effective public health tools for preventing diseases. PMID- 26120156 TI - Multiple Familial Trichoepithelioma with an Adjacent Basal Cell Carcinoma, Transformation or Collision - A Case Report and Review of Literature. AB - Trichoepithelioma is a benign tumor of follicular origin that presents as small, skin-colored papules predominantly on the face. When more than one family member is affected, the disease is known as multiple familial trichoepithelioma (MFT). It is a rare autosomal dominant skin disease. Malignant transformation is very rare. We describe here a case that developed malignant neoplasm in a setting of multiple trichoepithelioma. PMID- 26120157 TI - Punctate Porokeratosis Palmaris et Plantaris. AB - Porokeratosis, a keratinization disorder, is probably a group of unrelated conditions with same distinctive histological appearance, featuring cornoid lamellae. A case of punctate porkeratosis in a 24 year old male patient is reported for its rarity. PMID- 26120158 TI - Unmasking Diogenes Syndrome. AB - Diogenes syndrome is characterized by extreme self-neglect, social withdrawal, and poor personal and domestic hygiene. We report a case of Diogenes syndrome presenting with dermatitis passivata. An unusual "mask" of dirt resembling a carapace, onset of neglect after awareness of a breast lump and resumption of personal grooming and social activities after removal of the lump and counseling were seen. PMID- 26120159 TI - Self-Mutilation in Neurodegeneration with Brain Iron Accumulation. AB - Neurodegeneration with brain iron accumulation (NBIA) is the term applied to a heterogeneous group of disorders resulting in iron deposition in the basal ganglia. Well-known phenotypic features are progressive regression with extra pyramidal involvement and a variable course. A 10-year-old child born to consanguineous parents presented with progressive generalized opisthotonic dystonia, retrocollis, oromandibular dyskinesias, apraxia for swallowing, optic atrophy and severe self-mutilation of lips. MR imaging showed brain iron accumulation. Other causes of self-mutilation were excluded. Early infantile onset, ophisthotonic dystonia with oromandibular dyskinesias and characteristic MR images are suggestive of NBIA. There is only one case reported in the literature of self-mutilation in this condition. PMID- 26120160 TI - Bilateral Multisegmental Zosteriform Leiomyoma Cutis: A Rare Entity. AB - Cutaneous leiomyomas are benign tumors derived from the smooth muscles of the skin. They are firm, skin-colored to brownish, frequently painful papules and nodules presenting either as a solitary tumor or multiple clustered lesions. Uncommon patterns of multiple leiomyoma cutis include linear, zosteriform, or dermatomal-like arrangement of lesions. We saw a 32-year-old man who presented with clusters of skin colored to reddish brown, occasionally painful papules and nodules distributed segmentally over C6 to T8 dermatomes on left side and T11 to L1 dermatomes on right side. Histopathology confirmed the diagnosis of cutaneous leiomyoma. The case is reported here for the occurrence of this benign cutaneous neoplasm in an extremely rare bilateral multisegmental distribution. PMID- 26120161 TI - Huge Nevus Lipomatosus Cutaneous Superficialis on Back: An Unusual Presentation. AB - Nevus lipomatosus cutaneous superficialis (NLCS) is a benign dermatosis, histologically characterized by the presence of mature ectopic adipocytes in the dermis. We hereby report a case of a 10-year-old boy who presented with multiple huge swellings on the scapular regions and lower back. The lesions were surmounted by small papules, along with peau-d orange appearance at places. Histology showed features consistent with NLCS. The case is being reported for the unusual clinical presentation. PMID- 26120162 TI - Lesch-Nyhan Syndrome in an Indian Child. AB - Hypoxanthine guanine phosphoribosyl transferase-1 (HGPRT-1) leading to Lesch Nyhan syndrome (LNS) is one of the important causes of self-mutilation. Hereby, we report a case of LNS in a three and half-year-old male child, who presented with characteristic self-mutilating behavior. He had history of developmental delay, difficulty in social interaction, attention deficit and features of autism. His serum blood biochemistry was normal except for low hemoglobin levels and raised serum uric acid levels. With a diagnosis of LNS, the child was treated with allopurinol. With various modalities of physical restraint, his self mutilating behavior came under control and currently the patient is being followed up. PMID- 26120163 TI - Uncommon Presentation of a Common Histiocytic Tumor: A Rare Entity. AB - Juvenile xanthogranuloma (JXG) is the most common form of non-Langerhans cell histiocytic lesion, characterized by benign, usually asymptomatic, self-healing yellowish brown papulonodular lesions of skin and other organs in the absence of metabolic disorder. The cells of origin of JXG are dermal dendrocytic cells. Histopathologically there is dermal infiltration of foamy or non-foamy histiocytes with or without giant cell. Immunohistochemistry shows CD68 positivity with CD1a and S-100 negativity of lesional cells although S-100 positive JXG have been reported. JXG may be associated with neurofibromatosis type one (NF 1) with increased risk of juvenile chronic myelogenous leukemia and other hematological malignancies. Our case was S-100 immunoreactive multiple, cutaneous JXGs with NF 1 without any visceral involvement or malignant complication. We are presenting this case due to its rarity. PMID- 26120164 TI - A Cross-Sectional Study of Anti-Hepatitis B Antibody Status in STD Patients: Need for Improved Immunization. PMID- 26120165 TI - Amifostine Before Radiotherapy: A Rare Cause of SJS-TEN Overlap. PMID- 26120166 TI - Isolated Palmar Lichen Nitidus-A Diagnostic Challenge: First Case from Eastern India. PMID- 26120167 TI - The Curious Case of Prolactin Hormone. PMID- 26120168 TI - Unilateral Exanthem. PMID- 26120169 TI - Intractable Pruritus Caused by Pigeon Mites. PMID- 26120170 TI - Idiopathic Thrombocytopenic Purpura Masquerading Paediatric SLE. PMID- 26120171 TI - Genital Porokeratosis: A Distinct Clinical Variant? PMID- 26120172 TI - Annular Erythematous Plaques on the Face, Trunk and Extremities of an Infant. PMID- 26120173 TI - Erratum: Effectiveness of a Multidisciplinary Itch Clinic in the Management of Chronic Pruritus: Erratum. PMID- 26120174 TI - Association of cytokine gene polymorphisms with psoriasis in cases from the Nile Delta of Egypt: Retraction. AB - [This retracts the article on p. 272 in vol. 56, PMID: 21772586.]. PMID- 26120175 TI - Evaluation of Organelle Changes in Promastigotes of Unresponsive Leishmania Tropica to Meglumine Antimoniate in Comparison with Sensitive and Standard Isolates by Electron Microscopy. AB - BACKGROUND: The control of leishmaniasis faces serious challenges because of resistance to the first-line antimonial drugs. We aimed to evaluate the differences in organelle changes of cultivated promastigotes obtained from skin lesions of sensitive and unresponsive isolates to meglumine antimoniate (Glucantime) by electron microscopy. MATERIAL AND METHODS: This study was done in Bam city, southeastern Iran, in which the incidence of disease has sharply increased since the earthquake in 2003. The samples were taken from 66 patients who were referred to the cutaneous leishmaniasis (CL) treatment center in Bam. A questionnaire was completed for each individual, recording their demographic characteristics and CL status. The scraping smears provided from the edge of active lesions with sterile blades were fixed with methanol, stained by Giemsa, and examined under a compound light microscope for amastigote form simultaneously. To prepare the specimens for transmission electron imaging, promastigotes were centrifuged and resuspened. RESULTS: Transmission electron microscopic study of the cultivated promastigotes revealed that there were alterations in the organelles and structures of sensitive isolates compared with unresponsive and standard ones. Organelles and structures such as mitochondria, kinetoplast, microtubules, cytoplasmic vacuoles, plasma membrane and vesicles were studied. The alterations such as disintegration of kinetoplast into thin filaments and condensation of kinetoplast DNA core, changes in size, number and location of vesicles and microtubules were observed. We noted intense cytoplasmic vacuolization, and considerable swelling of mitochondria. CONCLUSION: The significance and relevance of these changes might help understand drug resistance patterns and help localize the best target site for inactivating the organism. PMID- 26120176 TI - Evaluation of the Association Between Epstein-Barr Virus and Mycosis Fungoides. AB - INTRODUCTION: Mycosis fungoides (MF) is the most common cutaneous T-cell lymphomas. Despite extensive studies, etiopathogenesis of MF is unknown. Environmental, infectious and genetic factors have been proposed as potential risk factors of MF. Herpes virus family members, especially Epstein-Barr virus (EBV), have been among the viral factors of interest in recent years. The aim of this study was to investigate the possible association of EBV infection with MF. MATERIALS AND METHODS: This case-control study was performed on skin biopsy samples of 57 MF patients referred to Pathology Department of Mashhad Emam Reza Hospital from 2000 to 2011 and also on 57 melanocytic nevus samples matched with patients for age and sex. The presence of EBV in samples was evaluated by polymerase chain reaction. Statistical analysis of the data was conducted with the Statistical Package for the Social Sciences version 11.5 (SPSS Inc., Chicago, IL, USA). RESULTS: In this study, out of 57 MF samples, there were 34 male and 23 female patients, with male:female ratio of 1.04. Mean patient age was 51.4 years. There were 22 and 4 positive cases of EBV in the case and control groups, respectively. Chi-square statistical test showed that EBV was significantly higher in case group than control (P = 0.000). There was no correlation between the presence of EBV in samples with lesion type, age and gender of the patients. CONCLUSION: According to our study results, EBV is a likely etiologic agent or potential promoter in the pathogenesis of MF. PMID- 26120177 TI - Study of Oxidative Stress in Different Forms of Leprosy. AB - BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. India records the highest number of new leprosy cases in the world. Oxidative stress may play a significant role in leprosy. AIM: The aim of the study was to evaluate oxidative stress in various forms of leprosy and compared to healthy controls. MATERIALS AND METHODS: Seventy newly diagnosed, untreated leprosy patients were selected as cases and sixty healthy controls. Oxidative stress was evaluated by measuring serum malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. Student's unpaired t-test and Anova (Analysis of Variance) test were used for analysis of data. P < 0.05 was considered as significant. RESULTS: There was a statistically significant increase in the mean values of serum MDA level, MDA/SOD and a decrease in serum SOD activity in cases when compared to controls and the values were significantly associated with increased duration, bacterial load and multibacillary type in leprosy. CONCLUSION: Our study suggests that there was oxidative stress in leprosy. This warrants antioxidant supplementation to prevent tissue injury. PMID- 26120178 TI - Study of the Distribution of Malassezia Species in Patients with Pityriasis Versicolor in Kolar Region, Karnataka. AB - CONTEXT: Pityriasis versicolor is a superficial, chronically recurring fungal infection caused by Malassezia species. Recently it has been revised taxanomically into 14 species, in that only 7 species have been well studied in relation to pityriasis versicolor. AIMS: To identify Malassezia species isolated from patients with pityriasis versicolor and to find out any correlation between the species with clinical presentation of lesions. SETTINGS AND DESIGN: Prospective study comprising of 100 clinically diagnosed cases of pityriasis versicolor attending Dermatology Outpatient Department over a period of 1 year. MATERIALS AND METHODS: The clinical specimens were collected under aseptic precautions and subjected to culture on Sabouraud's Dextrose Agar overlaid with olive oil and modified Dixon agar. The isolates were identified by biochemical tests. STATISTICAL ANALYSIS USED: Statistical analysis was done using proportion, mean and chi-square test. RESULTS: Of the 100 cases, 73% were males, 26% were females and predominant age group was 21-30 years. Out of 100 samples, 70 yielded growth. The most common isolate was M. sympodialis (50%), followed by M. furfur (32.86%), M. globosa (14.28%) and M. slooffiae (2.86%). Among 100 cases, 74% had hypopigmented and 26% had hyperpigmented lesions. M. sympodialis and M. furur were predominantly isolated from hypopigmented lesions and M. globosa and M. slooffiae were found to be more common in hyperpigmented lesions. CONCLUSIONS: M. sympodialis was the most common isolate, followed by M. furfur, M. globosa and M. slooffiae. There was no significant difference in distribution of different species in patients with hypo or hyper pigmented lesions. PMID- 26120179 TI - Effectiveness of the Pulse Dye Laser Treatment in a Caucasian Women With Dermatosis Papulosa Nigra. AB - Dermatosis papulosa nigra (DPN) is a group of superficial, benign papules commonly in African-American and Asian persons. DPN is considered to be a form of seborrheic keratosis with a specific localization and it is less frequently described in the white population. Treatment modalities include cryosurgery, curettage, electrosurgery, shave removal, and different laser treatment. Pulsed dye laser (PDL) has traditionally been used to treat vascular lesions, but it has been shown to be effective in treatment of lentigines, ephelides, seborrheic keratosis, and rarely DPN. A 43-year-old white female presents with a 5 year-old history of hyperpigmented papules on malar region, neck and upper trunk. The patient is diagnosed with DPN based on her clinical and histopathological findings. The PDL treatment was used successfully. In our opinion PDL is an effective alternative cure option for DPN. PMID- 26120180 TI - Buschke-Fischer-Brauer Keratoderma: Linear Variety Associated with Hodgkin's Lymphoma. AB - Palmo-plantar keratodermas (PPKD) are a diverse group of acquired and hereditary disorders, characterized by excessive thickening of the skin of palms and soles. Here, we report a case of Type I or Buschke-Fischer-Brauer variant of punctate palmo-plantar keratoderma, in a 66-year-old gentleman. The association of our case with Hodgkin's lymphoma along with linear configuration of lesions on the palms evoked the current report. PMID- 26120181 TI - Granular Cell Tumor: An Uncommon Benign Neoplasm. AB - Granular cell tumor is a distinctly rare neoplasm of neural sheath origin. It mainly presents as a solitary asymptomatic swelling in the oral cavity, skin, and rarely internal organs in the middle age. Histopathology is characteristic, showing polyhedral cells containing numerous fine eosinophilic granules with indistinct cell margins. We present a case of granular cell tumor on the back of a 48-year-old woman which was painful, mimicking an adnexal tumor. PMID- 26120182 TI - Extranodal NK/T-cell Lymphoma Mimicking Erythema Multiforme. AB - Extranodal natural killer/T-cell lymphoma (ENKTL) is an extremely rare and an aggressive lymphoma. We report an interesting case of extranodal natural killer/T cell lymphoma in a middle-aged woman which mimicked erythema multiforme. The skin lesions of this case looked like erythema multiforme due to the tagetoid lesions and mucosal erosions. The two biopsies from her chest and scalp lesions were different. One exhibited the characteristics of CD4+ CD56+ CD8-mycosis fungoides whereas the other biopsy from her scalp showed classical ENKTL histopathological manifestation with positive CD56, cytotoxic proteins and Epstein-Barr virus encoded RNA (EBER). PMID- 26120183 TI - Erythema Multiforme-like Secondary to Paraphenylenediamine Due to Henna Tattoo Plus Residual Hypopigmentation. AB - Temporary henna tattoos or pseudotattoos have become increasingly widespread among children and adolescent. A generalized skin reaction, type erythema multiforme-like reaction is unusual, and rarely reported. We describe the case of a 7-year-old boy who reported erythematous papular bull's-eye shaped lesions and consolidated edema primarily in the upper and lower extremities. These lesions were compatibles with erythema multiforme-like reaction. He also showed an erythematous-eczematous lesion on his leg, shaped like a dolphin. In this area, a temporary henna tattoo was painted 1-month earlier. Patch test was positive for paraphenylenediamine (PPD). Skin reactions due to henna are rare. Most of the reactions are due to additives, especially PPD, an aniline derivative, which is added to speed up the process of skin dyeing and to give a darker brown to black color ("black" henna). As henna tattoos are becoming increasingly popular, prevention requires the annual provision of information to consumers, especially young people and their parents. PMID- 26120184 TI - Scleromyxedema: An Atypical Case. AB - Scleromyxedema is a rare, chronic and persistent idiopathic disorder characterized by a generalized papular eruption due to dermal mucin deposition with an increase in dermal collagen. Patients usually have associated paraproteinemia. We describe the case of a 59-year-old gentleman with features of scleromyxedema, who had severe pruritus, scalp involvement, unrestricted mobility and associated peripheral eosinophilia, but no monoclonal gammopathy. PMID- 26120185 TI - Co-Existence of Multicentric Castleman's Disease and Kaposi's Sarcoma. AB - Castleman's disease (CD) or giant lymph node hyperplasia is a rare disorder that can be unicentric or multicentric. Multicentric Castleman's disease (MCD) is manifested by generalized lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia, hematological abnormality, and constitutional symptoms. Human herpesvirus 8 (HHV-8) infection is present in nearly 100% MCD associated with HIV-1 infection, but in about 50% of cases of HIV negative. Herein, we report a 77-year-old man with systemic involvement and skin lesions on the anterior aspect of both legs in the previous site of saphenous vein angioplasty. Co-existence of MCD with Kaposi's sarcoma (KS) led us to present this rare case. PMID- 26120186 TI - Features of Antihistamine-Resistant Chronic Urticaria and Chronic Urticaria During Exacerbation. PMID- 26120187 TI - Severe Granulomatous Rosacea in a Boy Successfully Treated with Topical Azelaic Acid. PMID- 26120188 TI - A Case of Inflammatory Linear Verrucous Epidermal Nevus on the Upper Eyelid. PMID- 26120189 TI - Delayed Burn Blister. PMID- 26120190 TI - An Interesting Case Report of Azathioprine-Induced Anagen Effluvium. PMID- 26120191 TI - A Case of Gloves and Socks Syndrome and Related Eruptions Caused by Coxsackievirus A4 Infection Mimicking Adult-onset Still's Disease. PMID- 26120192 TI - Nipple Hyperkeratosis Due to Malassezia Furfur Showing Excellent Response to Itraconazole. PMID- 26120193 TI - Transfusion Associated Graft Versus Host Disease. PMID- 26120194 TI - Pseudoporphyria: A Case Report. PMID- 26120195 TI - A Case of Hyper Immunoglobulin-E Syndrome Associated with Scrotal Tongue and Intraoral Hyperpigmentation. PMID- 26120196 TI - Linear and Whorled Nevoid Hypermelanosis With Tetralogy of Fallot. PMID- 26120197 TI - Rapid Onset of Bullous Erythema Ab Igne: A Case Report of Atypical Presentation. PMID- 26120198 TI - Recurrent and Diffuse Eczema with Severe Itch and Peripheral Eosinophilia in Healthy Middle Aged Woman. PMID- 26120199 TI - Multiple Shiny Papules on the Shaft of the Penis. PMID- 26120200 TI - Foul Smelling Discharging Tumor-like Lesions in an Immune-compromised Adult Female. PMID- 26120201 TI - Multiple Hypopigmented Truncal Papules. PMID- 26120202 TI - Long-term disturbance dynamics and resilience of tropical peat swamp forests. AB - 1. The coastal peat swamp forests of Sarawak, Malaysian Borneo, are undergoing rapid conversion, predominantly into oil palm plantations. This wetland ecosystem is assumed to have experienced insignificant disturbance in the past, persisting under a single ecologically-stable regime. However, there is limited knowledge of the past disturbance regime, long-term functioning and fundamentally the resilience of this ecosystem to changing natural and anthropogenic perturbations through time. 2. In this study, long-term ecological data sets from three degraded peatlands in Sarawak were collected to shed light on peat swamp forest dynamics. Fossil pollen and charcoal were counted in each sedimentary sequence to reconstruct vegetation and investigate responses to past environmental disturbance, both natural and anthropogenic. 3. Results demonstrate that peat swamp forest taxa have dominated these vegetation profiles throughout the last c. 2000-year period despite the presence of various drivers of disturbance. Evidence for episodes of climatic variability, predominantly linked to ENSO events, and wildfires is present throughout. However, in the last c. 500 years, burning and indicators of human disturbance have elevated beyond past levels at these sites, concurrent with a reduction in peat swamp forest pollen. 4. Two key insights have been gained through this palaeoecological analysis: (i) peat swamp forest vegetation has demonstrated resilience to disturbance caused by burning and climatic variability in Sarawak in the late Holocene, however (ii) coincident with increased fire combined with human impact c. 500 years ago, these communities started to decline. 5.Synthesis. Sarawak's coastal peat swamps have demonstrated resilience to past natural disturbances, with forest vegetation persisting through episodes of fire and climatic variability. However, palaeoecological data presented here suggest that recent, anthropogenic disturbances are of a greater magnitude, causing the observed decline in the peat swamp forest communities in the last c. 500 years and challenging the ecosystem's persistence. This study greatly extends our knowledge of the ecological functioning of these understudied ecosystems, providing baseline information on the past vegetation and its response to disturbance. This understanding is central to developing management strategies that foster resilience in the remaining peat swamp forests and ensure continued provision of services, namely carbon storage, from this globally important ecosystem. PMID- 26120203 TI - AN EVALUATION OF PRIMARY DATA-COLLECTION MODES IN AN ADDRESS-BASED SAMPLING DESIGN. AB - As address-based sampling becomes increasingly popular for multimode surveys, researchers continue to refine data-collection best practices. While much work has been conducted to improve efficiency within a given mode, additional research is needed on how multimode designs can be optimized across modes. Previous research has not evaluated the consequences of mode sequencing on multimode mail and phone surveys, nor has significant research been conducted to evaluate mode sequencing on a variety of indicators beyond response rates. We conducted an experiment within the Racial and Ethnic Approaches to Community Health across the U.S. Risk Factor Survey (REACH U.S.) to evaluate two multimode case-flow designs: (1) phone followed by mail (phone-first) and (2) mail followed by phone (mail first). We compared response rates, cost, timeliness, and data quality to identify differences across case-flow design. Because surveys often differ on the rarity of the target population, we also examined whether changes in the eligibility rate altered the choice of optimal case flow. Our results suggested that, on most metrics, the mail-first design was superior to the phone-first design. Compared with phone-first, mail-first achieved a higher yield rate at a lower cost with equivalent data quality. While the phone-first design initially achieved more interviews compared to the mail-first design, over time the mail first design surpassed it and obtained the greatest number of interviews. PMID- 26120205 TI - The Minimum Legal Drinking Age and Crime. AB - We use variation from the minimum legal drinking age to estimate the causal effect of access to alcohol on crime. Using a census of arrests in California and a regression discontinuity design, we find that individuals just over age 21 are 5.9% more likely to be arrested than individuals just under 21. This increase is mostly due to assaults, alcohol-related offenses, and nuisance crimes. These results suggest that policies that restrict access to alcohol have the potential to substantially reduce crime. PMID- 26120206 TI - Update of the Photometric Calibration of the LASCO-C2 Coronagraph Using Stars. AB - We present an update to the photometric calibration of the LASCO-C2 coronagraph onboard the SOHO spacecraft. We obtained the new calibration using data from the beginning of the mission in 1996 until 2013. We re-examined the LASCO-C2 photometric calibration by comparing the past three calibrations and the present calibration with the goal of validating an in-flight calibration. We find a photometric calibration factor (PCF) that is very similar to the factor recently published in Gardes, Lamy, and Llebaria (Solar Phys.283, 667, 2013), which calculated a calibration between 1996 and 2009. The average of our PCF between 1999 and 2009 is the same, within our margin of error, as the average given by Gardes, Lamy, and Llebaria (Solar Phys.283, 667, 2013) during the same time period. However, we find a different evolution of the calibration over the lifetime of the LASCO-C2 instrument compared with past results. We find that the sensitivity of the instrument is decreasing by a constant 0.20 [+/-0.03] % per year. We also find no significant difference in the signal degradation before and after the SOHO interruption. We discuss the effects of this new PCF on the calibrated data set and the potential impact on scientific results derived from the previous calibration. PMID- 26120207 TI - Highly functionalized donor-acceptor cyclopropanes applied toward the synthesis of the Melodinus alkaloids. AB - A series of highly substituted vinylcyclopropanes were prepared and examined as reaction partners in a palladium-catalyzed (3 + 2) cycloaddition with nitrostyrenes. Described herein are our efforts to synthesize an elusive 1,1 divinylcyclopropane by several distinct approaches, and to apply surrogates of this fragment toward the synthesis of the Melodinus alkaloids. PMID- 26120208 TI - Total Synthesis of Nominal Cyclocinamide B and Investigation into the Identity of the Cyclocinamides. AB - The total synthesis of nominal cyclocinamide B, a cyclic peptide marine natural product, is reported together with an isomer of nominal cyclocinamide A. Initial attempts at the synthesis of the title compounds by inclusion of a turn inducer failed. However, direct synthesis succeeded in formation of the 14-membered cyclic peptide structure. Comparison of the data from all synthetic cyclocinamide A and B compounds with those of the natural products leads to the conclusion that the two natural products possess the same relative stereochemistry and that the true structures have not been defined. PMID- 26120209 TI - Electrophilic Carbonyl Activation: Competing Condensative Cyclizations of Tryptamine Derivatives. AB - A series of tryptamine derived bisindole substrates were subject to electrophilic activation of the functional grouping at their alpha-nitrogen in the form of iminium ions to enable cyclization onto the sterically hindered indole substructure. Our observations regarding divergent cyclization outcomes using electronically distinct bisindole substrates are described. Surprising preference for Friedel-Crafts alkylation reaction and evidence for an intriguing reversible spirocyclization are discussed. PMID- 26120210 TI - Oxazoles for click chemistry II: synthesis of extended heterocyclic scaffolds. AB - New routes to 2, 4, 5-trisubstituted oxazoles were established whereby the substitution pattern was established by the structure of the starting nonsymmetrical acyloins. 2-Chloromethyl-4, 5-disubstituted oxazoles were prepared by refinements of an earlier described process whereby chloroacetyl esters of symmetrical and non-symmetrical acyloins were cyclized using an ammonium acetate/acetic acid protocol. After substitution is effected, the azide moiety is then installed by substitution under mild conditions. While dibrominated and iodinated phenyloxazoles are required for further synthetic elaboration, the cyclization reaction was found to be very sensitive to the relative positions of the halogens in the starting materials. PMID- 26120211 TI - Synthesis and bioactivity of MSH4 oligomers prepared by an A2 + B2 strategy. AB - Oligomers incorporating the tetrapeptide MSH4, the minimum active sequence of melanocyte stimulating hormone, were synthesized by an A2 + B2 strategy involving microwave-assisted copper-catalyzed azide-alkyne cycloaddition. A2 contained an MSH4 core while B2 contained a (Pro-Gly)3 spacer. Soluble mixtures containing compounds with up to eight MSH4 units were obtained from oligomerizations at high monomer concentrations. The avidities of several oligomeric mixtures were evaluated by means of a competitive binding assay using HEK293 cells engineered to overexpress the melanocortin 4 receptor. When based on total MSH4 concentrations, avidities were only minimally enhanced compared with a monovalent control. The lack of variation in the effect of ligands on probe binding is consistent with high off rates for MSH4 in both monovalent and oligomeric constructs relative to that of the competing probe. PMID- 26120212 TI - Metalated nitriles: SNi' cyclizations with a propargylic electrophile. AB - A rare 5-exo-dig SNi' cyclization with magnesiated and lithiated nitriles affords a cis-fused hydrindane bearing an exocyclic allene. The cyclization of the dilithiated nitrile pits a stereoelectronic preference for a trans-hydrindane against a cyclization through a less strained transition structure to the corresponding cis-hydrindane. Computational modeling suggests that the dilithiated nitrile cyclizes to a cis-hydrindane because the preferred transition structure positions the lithium cation in a cone of electron density that bridges the nitrile-bearing carbon, an alkoxide, and an electron-rich alkyne functionality. PMID- 26120204 TI - Diffuse Optics for Tissue Monitoring and Tomography. AB - This review describes the diffusion model for light transport in tissues and the medical applications of diffuse light. Diffuse optics is particularly useful for measurement of tissue hemodynamics, wherein quantitative assessment of oxy- and deoxy-hemoglobin concentrations and blood flow are desired. The theoretical basis for near-infrared or diffuse optical spectroscopy (NIRS or DOS, respectively) is developed, and the basic elements of diffuse optical tomography (DOT) are outlined. We also discuss diffuse correlation spectroscopy (DCS), a technique whereby temporal correlation functions of diffusing light are transported through tissue and are used to measure blood flow. Essential instrumentation is described, and representative brain and breast functional imaging and monitoring results illustrate the workings of these new tissue diagnostics. PMID- 26120213 TI - Enantioselective synthesis of metacycloprodigiosin via the "Wasserman pyrrole". AB - A concise, nine-step enantioselective total synthesis of metacycloprodigiosin is reported. The synthesis provides increased step-efficiency over the previous racemic and enantioselective syntheses of this compound. Key features of the work include investigations into a convergent oxidative coupling reaction and subsequent ring-closing metathesis to deliver an advanced pyrrole intermediate we name the "Wasserman pyrrole" that can be converted to metacycloprodigiosin in one step. PMID- 26120214 TI - Surprisingly Facile C-H Activation in the Course of Oxime-Directed Catalytic Asymmetric Hydroboration. AB - Deuterium-labeling studies carried out in conjunction with investigations into the directed catalytic asymmetric hydroboration of unsaturated oxime ethers reveal a surprisingly facile ortho-metallation or sigma-bond metathesis pathway that that diverts the expected course of CAHB to a tandem C-H activation/hydroboration reaction pathway. PMID- 26120215 TI - Design and Synthesis of (2-(5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7 yl)cyclopropyl)methanamine as a Selective Serotonin 2C Agonist. AB - A conformationally restricted analog of a selective cyclopropane-bearing serotonin 2C agonist was designed and synthesized. A 2,2-dimethyl-2,3 dihydrobenzofuran scaffold was investigated as a constrained variant of a biologically active isopropyl phenyl ether. Construction of the required dimethyl 2,3-dihydrobenzofuran intermediate began using a procedure that relied on a microwave-assisted alkylation reaction. The synthesis of the designed compound as its HCl salt is reported in a total of 12 steps and 17% overall yield. Biological evaluation revealed the constrained analog to be a selective serotonin 2C agonist with modest potency. PMID- 26120216 TI - An expedient synthesis of maraviroc (UK-427,857) via C-H functionalization. AB - A new, concise synthesis of the CCR-5 receptor antagonist maraviroc (UK-427,857) from 3-phenyl-1-propanol has been completed in four steps featuring a site selective C-H functionalization. PMID- 26120217 TI - Integrating The Stereotype Content Model (Warmth And Competence) And The Osgood Semantic Differential (Evaluation, Potency, And Activity). AB - We integrate two prominent models of social perception dimensionality. In three studies, we demonstrate how the well-established semantic differential dimensions of evaluation and potency relate to the stereotype content model dimensions of warmth and competence. Specifially, using a correlational design (Study 1) and experimental designs (Studies 2 and 3), we found that semantic differential dimensions run diagonally across stereotype content model quadrants. Implications of integrating classic and modern approaches of social perception are discussed. PMID- 26120218 TI - LOGISTIC NETWORK REGRESSION FOR SCALABLE ANALYSIS OF NETWORKS WITH JOINT EDGE/VERTEX DYNAMICS. AB - Change in group size and composition has long been an important area of research in the social sciences. Similarly, interest in interaction dynamics has a long history in sociology and social psychology. However, the effects of endogenous group change on interaction dynamics are a surprisingly understudied area. One way to explore these relationships is through social network models. Network dynamics may be viewed as a process of change in the edge structure of a network, in the vertex set on which edges are defined, or in both simultaneously. Although early studies of such processes were primarily descriptive, recent work on this topic has increasingly turned to formal statistical models. Although showing great promise, many of these modern dynamic models are computationally intensive and scale very poorly in the size of the network under study and/or the number of time points considered. Likewise, currently used models focus on edge dynamics, with little support for endogenously changing vertex sets. Here, the authors show how an existing approach based on logistic network regression can be extended to serve as a highly scalable framework for modeling large networks with dynamic vertex sets. The authors place this approach within a general dynamic exponential family (exponential-family random graph modeling) context, clarifying the assumptions underlying the framework (and providing a clear path for extensions), and they show how model assessment methods for cross-sectional networks can be extended to the dynamic case. Finally, the authors illustrate this approach on a classic data set involving interactions among windsurfers on a California beach. PMID- 26120219 TI - Algebra for All: California's Eighth-Grade Algebra Initiative as Constrained Curricula. AB - BACKGROUND/CONTEXT: Across the United States, secondary school curricula are intensifying as a growing proportion of students enroll in high-level academic math courses. In many districts, this intensification process occurs as early as eighth grade, where schools are effectively constraining their mathematics curricula by restricting course offerings and placing more students into Algebra I. This paper provides a quantitative single-case research study of policy-driven curricular intensification in one California school district. RESEARCH QUESTIONS: (1a) What effect did 8th eighth grade curricular intensification have on mathematics course enrollment patterns in Towering Pines Unified schools? (2b) How did the distribution of prior achievement in Towering Pines math classrooms change as the district constrained the curriculum by universalizing 8th eighth grade Algebra? (3c) Did 8th eighth grade curricular intensification improve students' mathematics achievement? SETTING: Towering Pines is an immigrant enclave in the inner-ring suburbs of a major metropolitan area. The district's 10 middle schools together enroll approximately 4,000 eighth graders each year. The districts' students are ethnically diverse and largely economically disadvantaged. The study draws upon administrative data describing 8th eighth graders in the district in the 2004-20-05 through 2007-20-08 school years. INTERVENTION/PROGRAM/PRACTICE: During the study period, Towering Pines dramatically intensified middle school students' math curricula: In the 2004-20 05 school year 32% of the district's 8th eighth graders enrolled in Algebra or a higher- level mathematics course; by the 2007-20-08 school year that proportion had increased to 84%. RESEARCH DESIGN: We use an interrupted time-series design, comparing students' 8th eighth grade math course enrollments, 10th grade math course enrollments, and 10th grade math test scores across the four cohorts, controlling for demographics and prior achievement. FINDINGS/RESULTS: We find that students' odds of taking higher level mathematics courses increased as this district implemented the state's Algebra mandate. However, even as the district implemented a constrained curriculum strategy, mathematics achievement growth between 6th sixth and 10th grade slowed and the achievement advantages associated with 8th eighth grade Algebra declined. CONCLUSIONS/RECOMMENDATIONS: Our analyses suggest that curricular intensification increased the inclusiveness and decreased the selectivity of the mathematics tracking regime in Towering Pines middle schools. However, the findings suggest that this constrained curriculum strategy may have may have unintended negative consequences for student achievement. PMID- 26120220 TI - A Unified Family of Covariate-Adjusted Response-Adaptive Designs Based on Efficiency and Ethics. AB - Response-adaptive designs have recently attracted more and more attention in the literature because of its advantages in efficiency and medical ethics. To develop personalized medicine, covariate information plays an important role in both design and analysis of clinical trials. A challenge is how to incorporate covariate information in response-adaptive designs while considering issues of both efficiency and medical ethics. To address this problem, we propose a new and unified family of covariate-adjusted response-adaptive (CARA) designs based on two general measurements of efficiency and ethics. Important properties (including asymptotic properties) of the proposed procedures are studied under categorical covariates. This new family of designs not only introduces new desirable CARA designs, but also unifies several important designs in the literature. We demonstrate the proposed procedures through examples, simulations, and a discussion of related earlier work. PMID- 26120221 TI - Evaluation of geostatistical estimators and their applicability to characterise the spatial patterns of recreational fishing catch rates. AB - Western Australians are heavily engaged in recreational fishing activities with a participation rate of approximately 30%. An accurate estimation of the spatial distribution of recreational catch per unit effort (catch rates) is an integral component for monitoring fish population changes and to develop strategies for ecosystem-based marine management. Geostatistical techniques such as kriging can provide useful tools for characterising the spatial distributions of recreational catch rates. However, most recreational fishery data are highly skewed, zero inflated and when expressed as ratios are impacted by the small number problem which can influence the estimates obtained from the traditional kriging. The applicability of ordinary, indicator and Poisson kriging to recreational catch rate data was evaluated for three aquatic species with different behaviours and distribution patterns. The prediction performance of each estimator was assessed based on cross-validation. For all three species, the accuracy plot of the indicator kriging (IK) showed a better agreement between expected and empirical proportions of catch rate data falling within probability intervals of increasing size, as measured by the goodness statistic. Also, indicator kriging was found to be better in predicting the latent catch rate for the three species compared to ordinary and Poisson kriging. For each species, the spatial maps from the three estimators displayed similar patterns but Poisson kriging produced smoother spatial distributions. We show that the IK estimator may be preferable for the spatial modelling of catch rate data exhibiting these characteristics, and has the best prediction performance regardless of the life history and distribution patterns of those three species. PMID- 26120222 TI - Inter-rater reliability of cyclic and non-cyclic task assessment using the hand activity level in appliance manufacturing. AB - : This study evaluated the inter-rater reliability of the American Conference of Governmental Industrial Hygienists (ACGIH(r)) hand activity level (HAL), an observational ergonomic assessment method used to estimate physical exposure to repetitive exertions during task performance. Video recordings of 858 cyclic and non-cyclic appliance manufacturing tasks were assessed by sixteen pairs of raters using the HAL visual-analog scale. A weighted Pearson Product Moment-Correlation Coefficient was used to evaluate the agreement between the HAL scores recorded by each rater pair, and the mean weighted correlation coefficients for cyclic and non-cyclic tasks were calculated. Results indicated that the HAL is a reliable exposure assessment method for cyclic (r-bar w = 0.69) and non-cyclic work tasks (r-bar w = 0.68). When the two reliability scores were compared using a two sample Student's t-test, no significant difference in reliability (p = 0.63) between these work task categories was found. This study demonstrated that the HAL may be a useful measure of exposure to repetitive exertions during cyclic and non-cyclic tasks. RELEVANCE TO INDUSTRY: Exposure to hazardous levels of repetitive action during non-cyclic task completion has traditionally been difficult to assess using simple observational techniques. The present study suggests that ergonomists could use the HAL to reliably and easily evaluate exposures associated with some non-cyclic work tasks. PMID- 26120223 TI - Synthesis and Binding Affinity of Homologated Adenosine Analogues as A3 Adenosine Receptor Ligands. AB - Homologated analogues 3a and 3b of potent and selective A3 adenosine receptor ligands, IB-MECA and dimethyl-IB-MECA were synthesized from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose (4) via Co2(CO)8 catalyzed siloxymethylation as a key step. Unfortunately, homologated analogues 3a and 3b did not show significant binding affinities at three subtypes of adenosine receptors, indicating that free rotation, resulting from homologation, induced unfavorable interactions in the binding site of the receptor maybe due to the presence of many conformations. PMID- 26120224 TI - The integration quagmire: Why we need to watch our steps. PMID- 26120225 TI - Nephroprotective activity of Bilvadi agada in gentamicin induced nephrotoxicity in male Wistar rats. AB - BACKGROUND: Gentamicin (GM) nephrotoxicity accounts for 10-30% of the acute renal failure (ARF) among drug-induced ARF. In Ayurveda such side effects are considered as the poisonous effects of low potent poisons called gara visa. Bilvadi agada (BA), a classical formulation is indicated in gara visa and most of its ingredients have proven for their nephroprotective activity. AIM: The aim was to evaluate the effect of BA in GM-induced nephrotoxicity in male Wistar rats. MATERIALS AND METHODS: BA, GM, normal saline were procured from standard companies. SETTINGS AND DESIGNS: Eighteen male Wistar rats were randomly divided into three groups, viz. Control group which received normal saline intraperitoneal (i.p.) daily for 8 days; toxic group received GM 80 mg/kg/day i.p. for 8 days, and trial group received both GM 80 mg/kg/day i.p. and BA 216 mg/each rat weighing ~200 g orally 1 h after administration of GM. STATISTICS: All the values were expressed as mean +/- standard error and data were analyzed by applying one-way analysis of variance followed by Dunnett's test for multiple comparison. RESULTS: BA treated group showed a significant change (P < 0.05) in levels of serum creatinine, urine creatinine, and urine potassium. There was no significant change (P > 0.05) seen in serum potassium, sodium, chloride, calcium and phosphorus and urine sodium, chloride in all three groups. Glomerular congestion, interstitial edema, tubular necrosis, interstitial hemorrhage was reduced in BA treated group. The results of this study indicate that BA reduces GM-induced nephrotoxicity and it may be due to anti-inflammatory, immunomodulatory, diuretic and anti-oxidant properties of drugs. Further studies are necessary to explore the exact mechanism of BA in nephroprotection. PMID- 26120226 TI - Effect of Jyotismati seed oil on spatial and fear memory using scopolamine induced amnesia in mice. AB - BACKGROUND: Treatment of memory impairment associated with dementia such as Alzheimer's disease is still inadequate and requires development of new drugs. OBJECTIVE: The objective was to evaluate the memory enhancing effect of Celastrus paniculatus seed oil. MATERIALS AND METHODS: C. paniculatus seed oil was mixed with equal amount of pure ghee and administered orally to mice in the dose of 200 mg/kg/day. Piracetam was used as a standard nootropic. Elevated plus maze and passive avoidance tests were used as a models to test spatial and fear memory respectively. Scopolamine (3 mg/kg, i.p.), was used as an amnestic agent. RESULTS: Mice receiving C. paniculatus showed significant memory enhancement as compared to scopolamine group. The effect of C. paniculatus and combination of C. paniculatus with piracetam was comparable to that with piracetam alone. CONCLUSION: The present study demonstrates that C. paniculatus seed oil has memory enhancing effect and hence can be developed as a potential drug in the treatment of dementia. PMID- 26120228 TI - Antimalarial evaluation of the leaf latex of Aloe citrina and its major constituent. AB - BACKGROUND: Malaria is one of the major obstacles to the socioeconomic development of several developing countries. Adequate treatment of the disease is becoming increasingly difficult due to the worsening problems of drug resistance in many parts of the world. Therefore, increased efforts in antimalarial drug discovery are urgently needed. OBJECTIVES: This study was designed to evaluate the antimalarial activity of the leaf latex of Aloe citrina Carter and Brandham and its major constituent. MATERIALS AND METHODS: The leaf latex of A. citrina was dissolved in methanol and subjected to preparative thin layer chromatography. Structure of the isolated compound was determined on the basis of its electrospray-ionization tandem mass spectrometry, (1)H, (13)C NMR and DEPT spectral data. The latex and its isolated compound were tested for their in vivo antimalarial activity using a 4-day suppressive test against chloroquine sensitive ANKA strain of Plasmodium berghei in mice. RESULTS: Homonataloin A/B was isolated as a major component of the latex. Both the latex and isolated compound exhibited significant (P < 0.001) antimalarial activity at a dose of 400 mg/kg with parasite suppression of 60.59% and 67.52%, respectively. No significant adverse signs of toxicity were observed in mice treated with the leaf latex up to the highest dose (5000 mg/kg). CONCLUSION: The results of this study indicate that the antimalarial activity of the plant is attributed in part or in full to the presence of homonataloin A/B in the latex. It also validates the traditional use of the plant as an antimalarial agent. PMID- 26120227 TI - Evaluation of effects of Mandurabhasma on structural and functional integrity of small intestine in comparison with ferrous sulfate using an experimental model of iron deficiency anemia. AB - BACKGROUND: The present study was planned to assess effects of Mandurabhasma (MB) on structural and functional integrity of small intestine using an animal model of iron deficiency anemia (IDA) in rat. METHODS: IDA was induced by giving iron deficient diet and retro-orbital bloodletting for 21 days in Wistar female rats. Rats (n = 72) were divided into six groups: (i) Control group, (ii) IDA rats, (iii) IDA rats receiving vehicle, (iv) rats receiving ferrous sulfate (40 mg/kg), (vi) rats receiving a low dose (22.5 mg/kg) of MB, (vi) rats receiving a high dose (45 mg/kg) of MB. Treatment was conducted for a period of 21 days followed by an assessment of change in hemoglobin (Hb) levels, lactase levels, lipid peroxidation activity by measuring malondialdehyde (MDA) levels and jejunal morphometry. RESULTS: In the present study, the lactase activity was markedly reduced in iron-deficient rats. Our study has demonstrated that intestinal morphology and MDA levels were not altered in the animals with IDA as compared to normal animals. In phase II, improvement in Hb response to ferrous sulfate was accompanied by an improvement in lactase activity. However, it significantly increased MDA levels with derangement of the normal villous structure. Rats receiving a low dose of MB did not have increased MDA levels. It did not alter the jejunal villous structure and improved lactase activity, but hematinic activity was found to be less than that of ferrous sulfate. Rats receiving a high dose of MB showed significantly improved Hb as well as lactase levels. They exhibited damage to the villous structure and increased MDA levels, but the effects were significantly less as compared to ferrous sulfate group. CONCLUSION: Rats receiving a high dose of MB have shown improvement in hematinic and lactase levels comparable to those receiving ferrous sulfate. However, it causes lesser oxidative damage as compared to ferrous sulfate. This is an encouraging finding because it indicates the potential of MB to cause lesser gastrointestinal side effects compared to ferrous sulfate. PMID- 26120229 TI - Pharmacognostic study and development of quality control parameters for fruit, bark and leaf of Zanthoxylum armatum (Rutaceae). AB - CONTEXT: Zanthoxylum armatum (Rutaceae) fruit, bark and leaves are used for various conditions of ailments in traditional systems of medicine since ancient times. AIMS: This study is designed to lay down the various pharmacognostic and phytochemical standards which will be helpful to ensure the purity, safety, and efficacy of this medicinal plant. MATERIALS AND METHODS: Various methods including macroscopic, microscopic, physicochemical, and phytochemical methods were applied to determine the diagnostic features for the identification and standardization of intact and powdered drug of Z. armatum leaf, fruit, and bark. RESULTS: The shape, size, color, odor, surface characteristics were determined for the intact drug and powdered materials of leaf, bark and fruit of Z. armatum. Light and electron microscope images of cross-section of leaf and powdered microscopy revealed useful diagnostic features. Histochemical, phytochemical, physicochemical including fluorescence analysis of powdered drug proved useful to differentiate the powdered drug material. High performance liquid chromatography analysis showed the presence of important phytoconstituents such as gallic acid and rutin. CONCLUSION: The data generated from this study would be of help in the authentication of various parts of Z. armatum, an important constituent of various herbal drug formulations. The qualitative and quantitative microscopic features would prove useful for laying down pharmacopoeial standards. Morphology as well as various pharmacognostic aspects of different parts of the plant were studied and have been described here along with phytochemical, physicochemical studies, which will help in authentication and quality control. PMID- 26120230 TI - Effect of Calendula officinalis hydroalcoholic extract on passive avoidance learning and memory in streptozotocin-induced diabetic rats. AB - BACKGROUND: Medicinal plants, owing to their different mechanisms such as antioxidants effects, may improve learning and memory impairments in diabetic rats. Calendula officinalis (CO), has a significant antioxidant activity. AIMS: To examine the effect of hydroalcoholic extract of CO on passive avoidance learning (PAL) and memory in streptozotocin (STZ)-induced diabetic male rats. SETTINGS AND DESIGN: A total of 32 adult male Wistar rats were randomly allocated to four groups: Control, diabetic, control + extract of CO and diabetic control + extract of CO groups with free access to regular rat diet. SUBJECTS AND METHODS: Diabetes in diabetic rats was induced by single intraperitoneal injection of 60 mg/kg STZ. After confirmation of diabetes, oral administration of 300 mg/kg CO extract to extract-treated groups have been done. PAL was tested 8 weeks after onset of treatment, and blood glucose and body weight were measured in all groups at the beginning and end of the experiment. STATISTICAL ANALYSIS USED: The statistical analysis of data was performed by ANOVA followed by least significant difference post-hoc analysis. RESULTS: Diabetes decreased learning and memory. Effect of CO extract in retention test (after 24 and 48 h) has been shown a significant decrease in step-through latency and increase in time spent in the dark compartment part. Also the extract partially improved hyperglycemia and reduced body weight. CONCLUSION: Taken together, CO extract can improve PAL and memory impairments in STZ-diabetic rats. This improvement may be due to its antioxidant, anticholinergic activities or its power to reduce hyperglycemia. PMID- 26120231 TI - Innovative approach in the management of horse-shoe fistula-in-ano with Ksarasutra. AB - Fistula-in-ano is a common surgical problem. Horse-shoe fistulas usually have an internal opening in the posterior midline and extend anteriorly and laterally to one or both ischiorectal spaces by way of the deep potential space. The "Sambukavarta Bhagandara" described by Susruta can be correlated with the horse shoe type of fistula. In this condition, neither fistulotomy nor "Ksarasutra" treatment alone, are useful hence there is a need for newer innovative surgical techniques to tackle this challenging disease. An integral approach of incision and drainage of both the abscess on the arms of the horse-shoe fistula with Ksarasutra ligation at 6 o' clock position proves to be successful. We have tried the same technique with good results. No recurrence was found in the patients during the follow-up period of 6 months. A 45-year-old female with a known case of diabetes mellitus and hypertension approached with both right and left ischiorectal fossa inflammatory swelling. An innovative approach was used to manage horse-shoe fistula by making an additional opening below the anus at 6 o'clock position. Apamarga Ksarasutra (medicated thread made using apamarga) was ligated through the additional opening to the internal opening at 6 o'clock position for draining through both the cavities. Ksarasutra was changed weekly and the fistula healed completely by 3 months. PMID- 26120232 TI - A case study on the Ayurvedic management of cerebral palsy. AB - Cerebral palsy (CP) is the leading cause of childhood disability affecting function and development. CP is defined as a nonprogressive neuromotor disorder of cerebral origin. It cannot be correlated with any single disease or condition in Ayurveda, as it is a multi-factorial disease with clinical features of a wide variation. According to Vagbhata, it is classified in the disease categories of sahaja (hereditary) and garbhaja (congenital) and jataja (psychosomatic) type of diseases. Of the many types and subtypes of CP, none has any known "cure." Here, an effort was made to treat a 3-year-old male child with spastic type of CP using multiple Ayurveda treatment modalities. At the end of 94 days of treatment, Pancakarma procedures along with internal medication resulted in 10-15% improvement in the overall effect of therapy. PMID- 26120233 TI - Wound healing effect of Vimlapanakarma with Jatyadi tailam in diabetic foot. AB - INTRODUCTION: Diabetic Foot ulcer is the commonest burning problem in the society. Many histopathological studies show prolonged inflammatory phase in diabetic wounds. In Sushruta Samhita, Vimlapanakarma (gentle massage) quoted, as first line of treatment for Vranashotha (inflammation). CASE REPORT: A 70 yrs old male patient, presented with complaints of ulcer associated with severe pain and reddish skin discoloration over ventral aspect of 3(rd) toe of right foot since 2 months. Vimlapanakarma performed with Jatyadi taila around the wound for about 15 20 minutes daily for 10 days and follow-up done for period of 45 days. DISCUSSION: By Vimlapanakarma with Jatyadi taila there will be raised local temperature, due to which vasoconstriction is relieved and necessary nutrients, oxygen, insulin etc. are carried to the wound site, thereby improving the anoxic condition of wound. CONCLUSION: Vimlapanakarma showed significant role in wound healing of Diabetic Foot ulcer, in a short period of time 10 days with no recurrence seen till 45 days follow-up. PMID- 26120234 TI - Determination of in vitro free radical scavenging and antiproliferative effect of Pennisetum alopecuroides on cultured A549 human lung cancer cells. AB - CONTEXT: Pennisetum alopecuroides (Poaceae) is a grass predominantly distributed in tropics and sub tropics. It is used as a cattle feed in many regions. AIM: The objective of the present study was to investigate the in vitro free radical scavenging and antiproliferative activity of ethanol extract of P. alopecuroides (EEPA) on cultured A549 human lung cancer cell lines. SETTINGS AND DESIGN: The anti-oxidant activity of ethanol extract was evaluated at dose level 12.5, 25, 50, 100, and 200 MUg/ml. The in vitro antiproliferative activity was measured at doses of 10, 50, and 100 MUg/ml. MATERIALS AND METHODS: The free radical scavenging activity of the EEPA was determined by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) method and in vitro antiproliferative activity on A549 human lung cancer cells was conducted by using MTT assay method. RESULTS: The phytochemical screening revealed that the P. alopecuroides contained alkaloids, tannins, saponins, and flavonoids as the major secondary metabolites. The IC50 value of DPPH scavenging activity was found to be 44.41 MUg/ml and 31.02 MUg/ml for a mixture of EEPA and standard ascorbic acid, respectively. In vitro MTT assay showed that EEPA had anti-proliferation effects on A549 cells in a dose dependent manner. CONCLUSIONS: This is the 1(st) time a pharmacological exploration of P. alopecuroides grasses has been conducted. We have shown that P. alopecuroides exhibits good free radical scavenging and strong in vitro cytotoxic activities against human lung cancer cell lines. PMID- 26120235 TI - Bacterial contamination in Thai Ayurveda products. PMID- 26120236 TI - Element- and charge-state-resolved ion energies in the cathodic arc plasma from composite AlCr cathodes in argon, nitrogen and oxygen atmospheres. AB - The energy distribution functions of ions in the cathodic arc plasma using composite AlCr cathodes were measured as a function of the background gas pressure in the range 0.5 to 3.5 Pa for different cathode compositions and gas atmospheres. The most abundant aluminium ions were Al+ regardless of the background gas species, whereas Cr2+ ions were dominating in Ar and N2 and Cr+ in O2 atmospheres. The energy distributions of the aluminium and chromium ions typically consisted of a high-energy fraction due to acceleration in the expanding plasma plume from the cathode spot and thermalised ions that were subjected to collisions in the plasma cloud. The fraction of the latter increased with increasing background gas pressure. Atomic nitrogen and oxygen ions showed similar energy distributions as the aluminium and chromium ions, whereas the argon and molecular nitrogen and oxygen ions were formed at greater distance from the cathode spot and thus less subject to accelerating gradients. In addition to the positively charged metal and gas ions, negatively charged oxygen and oxygen containing ions were observed in O2 atmosphere. The obtained results are intended to provide a comprehensive overview of the ion energies and charge states in the arc plasma of AlCr composite cathodes in different gas atmospheres as such plasmas are frequently used to deposit thin films and coatings. PMID- 26120237 TI - Inclusive Discourse? Local Media Coverage of the Terri Schiavo Case. AB - This article contributes to a more systematic understanding of the role of mainstream media in deliberative processes by analyzing how inclusive local newspapers are of diverse perspectives on the Terri Schiavo case. Using both Pearson's chi-square test and multinomial logistic regression, we assess how ownership, state political ideology, geographic location, and news format affect what ideas are included in the debate over whether Terri Schiavo's hydration and nutrition tubes should be removed as well as the tone with which these ideas are discussed. We find that mainstream newspapers are relatively inclusive of diverse ideas and perspectives-regardless of whether the newspaper is independently or corporately owned, the political leanings of the target audience, and the geographic location of the outlet. However, we also find that local newspapers do significantly differ from one another in terms of the frequency and tone with which they include diverse viewpoints. Our research suggests that local outlets downplay ideas that are likely to be regarded as controversial by their target audiences. We conclude with a discussion of the implications of this research for understanding the role of media in deliberative democratic processes in the United States. PMID- 26120238 TI - NIR to NIR upconversion in KYb2F7: RE3+ (RE = Tm, Er) nanoparticles for biological imaging. AB - Until recently, many contrast agents widely used in biological imaging have absorbed and emitted in the visible region, limiting their usefulness for deeper tissue imaging. In order to push the boundaries of deep tissue imaging with non ionizing radiation, contrast agents in the near infrared (NIR) regime, which is not strongly absorbed or scattered by most tissues, are being sought after. Upconverting nanoparticles (UCNPs) are attractive candidates since their upconversion emission is tunable with a very narrow bandwidth and they do not photobleach or blink. The upconversion produced by the nanoparticles can be tailored for NIR to NIR by carefully choosing the lanthanide dopants and dopant ratios such as KYb2F7: RE3+ (RE = Tm, Er). Spectroscopic characterization was done by analyzing absorption, fluorescence, and quantum yield data. In order to study the toxicity of the nanoparticles Monkey Retinal Endothelial Cells (MREC) were cultivated in 24 well plates and then treated with nanoparticles at different concentrations in triplicate to obtain the optimal concentration for in vivo experiments. It will be shown that these UCNPs do not elicit a strong toxic response such as quantum dots and some noble metal nanoparticles. 3-D optical slices of nanoparticle treated fibroblast cells were imaged using a confocal microscope where the nucleus and cytoplasm were stained with DAPI and Alexa Fluor respectively. These results presented support the initial assumption, which suggests that KYb2F7: RE3+ would be excellent candidates for NIR contrast agents. PMID- 26120239 TI - Participation and Well-Being Among Older Adults Living with Chronic Conditions. AB - This study explored the unique contribution of participation (daily activities and social roles) in explaining well-being of older adults living with chronic conditions and examined which aspect of participation (accomplishment of participation or satisfaction with participation) was more important in describing their well-being. Two hundred older adults with chronic conditions completed the following assessments: Satisfaction with Life Scale to measure well being; Assessment of Life Habits to evaluate two aspects of participation: (a) accomplishment of daily activities and social roles and (b) level of satisfaction with participation; Interpersonal Support Evaluation List to assess level of social support and Affect Balance scale to measure level of balance confidence. In addition, participants' level of mobility was assessed using the Timed Up and Go test. Regression analysis was performed. Results indicated that number of chronic conditions, social support and satisfaction with participation had a significant contribution to well-being and altogether explained 31% of its variance whereas accomplishment of participation did not play as significant role in the model. In conclusion, participation has a unique contribution to older adults' well-being where satisfaction with participation rather than the accomplishment of activities is of importance. Additional aspects of participation and level of disability are key factors identified for further inquiry. PMID- 26120240 TI - QUANTIFYING THE MOTION OF MAGNETIC PARTICLES IN EXCISED TISSUE: EFFECT OF PARTICLE PROPERTIES AND APPLIED MAGNETIC FIELD. AB - This article presents a method to investigate how magnetic particle characteristics affect their motion inside tissues under the influence of an applied magnetic field. Particles are placed on top of freshly excised tissue samples, a calibrated magnetic field is applied by a magnet underneath each tissue sample, and we image and quantify particle penetration depth by quantitative metrics to assess how particle sizes, their surface coatings, and tissue resistance affect particle motion. Using this method, we tested available fluorescent particles from Chemicell of four sizes (100 nm, 300 nm, 500 nm, and 1 um diameter) with four different coatings (starch, chitosan, lipid, PEG/P) and quantified their motion through freshly excised rat liver, kidney, and brain tissues. In broad terms, we found that the applied magnetic field moved chitosan particles most effectively through all three tissue types (as compared to starch, lipid, and PEG/P coated particles). However, the relationship between particle properties and their resulting motion was found to be complex. Hence, it will likely require substantial further study to elucidate the nuances of transport mechanisms and to select and engineer optimal particle properties to enable the most effective transport through various tissue types under applied magnetic fields. PMID- 26120241 TI - Negative economic shocks and child schooling: Evidence from Rural Malawi. AB - This study investigates the impacts of negative economic shocks on child schooling in households of rural Malawi, one of the poorest countries in Sub Saharan Africa (SSA). Both individually-reported and community-level shocks are investigated. There is evidence that community level shocks negatively impact the school enrolment of children. The point estimates suggest that this effect is larger when shocks and school enrollment are reported by men as compared to women. But we cannot conclude with statistical confidence that the impact of idiosyncratic shocks is larger when reported by males than when reported by females. Similarly, although the point estimates suggest that the impact of community level shocks on the school enrolment of children is larger than that of idiosyncratic shocks, we cannot conclude with statistical significance that the impacts of community-level and idiosyncratic shocks are different. PMID- 26120242 TI - A Dual-Stream Neuroanatomy of Singing. AB - Singing requires effortless and efficient use of auditory and motor systems that center around the perception and production of the human voice. Although perception and production are usually tightly coupled functions, occasional mismatches between the two systems inform us of dissociable pathways in the brain systems that enable singing. Here I review the literature on perception and production in the auditory modality, and propose a dual-stream neuroanatomical model that subserves singing. I will discuss studies surrounding the neural functions of feedforward, feedback, and efference systems that control vocal monitoring, as well as the white matter pathways that connect frontal and temporal regions that are involved in perception and production. I will also consider disruptions of the perception-production network that are evident in tone-deaf individuals and poor pitch singers. Finally, by comparing expert singers against other musicians and nonmusicians, I will evaluate the possibility that singing training might offer rehabilitation from these disruptions through neuroplasticity of the perception-production network. Taken together, the best available evidence supports a model of dorsal and ventral pathways in auditory motor integration that enables singing and is shared with language, music, speech, and human interactions in the auditory environment. PMID- 26120243 TI - Can Social Ties be Harmful? Examining the Spread of Suicide in Early Adulthood. AB - Durkheim posited that social relationships protect individuals against suicide; however, substantial research demonstrates that suicide can spread through the very ties Durkheim theorized as protective. With this study, we use Waves I, III, and IV of the National Longitudinal Study of Adolescent Health, to investigate whether young adults' suicide attempts and thoughts are in part products of exposure to suicidal behaviors via their social relationships. We find that young adults who have had family members or friends attempt suicide are more likely to report suicide ideation or even suicide attempts, over both the short and long run. This finding is robust to many important controls for risk and protective factors for suicide. Our findings have implications for the sociology of suicide, not the least of which, is that social ties have the power to harm in addition to the power to protect. PMID- 26120245 TI - Anxiety, depression and smoking status among adults of Mexican heritage on the Texas-Mexico Border. AB - The goal of the current analysis is to examine relationships between smoking status and anxiety and depression among adults of Mexican heritage to inform the development of culturally relevant smoking cessations efforts. Mexican heritage residents (N=1,791) of the city of Brownsville, TX, aged 18 years or older, enrolled in the Cameron County Hispanic Cohort, were selected through two stage cluster sampling of randomly selected census tracts from the first and third quartile of SES using Census 2000. Among current smokers, anxiety and depression scores were highest among women who had not completed high school (p<0.05). Former smoking women, but not men, with at least a high school education and former smoking women born in the United States reported higher levels of anxiety and depression than never smoking women. Negative affective states may represent a greater barrier to smoking cessation among women than men. PMID- 26120244 TI - The Immigrant and Hispanic Paradoxes: A Systematic Review of Their Predictions and Effects. AB - A survey of the literature indicates that reported advantages of the Immigrant and Hispanic Paradox are inconsistent and equivocal. The healthy migrant hypothesis also suggests that current research approaches consider only "healthy" groups. Other methodological concerns include the simple underreporting of deaths, and that commonly used databases may not include all significant attributes and characteristics. We conducted a systematic review, synthesizing and identifying themes not explicitly found in the current literature. We also employ a simple quantitative index to assess the scholarly strength of references. Paradox protection appears uneven and is not generalizable across races, ethnicities, age groups and genders. In addition, acculturation, health behaviors and diet, ethnicity, acculturative stress, adolescence, undocumented and uninsured status, age of arrival in the United States and length of exposure, gender and age appear to be significant in predicting any beneficial effects. PMID- 26120246 TI - Hydra, a powerful model for aging studies. AB - Cnidarian Hydra polyps escape senescence, most likely due to the robust activity of their three stem cell populations. These stem cells continuously self-renew in the body column and differentiate at the extremities following a tightly coordinated spatial pattern. Paul Brien showed in 1953 that in one particular species, Hydra oligactis, cold-dependent sexual differentiation leads to rapid aging and death. Here, we review the features of this inducible aging phenotype. These cellular alterations, detected several weeks after aging was induced, are characterized by a decreasing density of somatic interstitial cell derivatives, a disorganization of the apical nervous system, and a disorganization of myofibers of the epithelial cells. Consequently, tissue replacement required to maintain homeostasis, feeding behavior, and contractility of the animal are dramatically affected. Interestingly, this aging phenotype is not observed in all H. oligactis strains, thus providing a powerful experimental model for investigations of the genetic control of aging. Given the presence in the cnidarian genome of a large number of human orthologs that have been lost in ecdysozoans, such approaches might help uncover novel regulators of aging in vertebrates. PMID- 26120247 TI - Compensation and Community Corrosion: Perceived Inequalities, Social Comparisons, and Competition Following the Deepwater Horizon Oil Spill. AB - : After disasters, victim compensation programs are typically associated with individual healing and community rebuilding. But post-disaster compensation systems also have the potential to introduce confusion and competition, further fraying the social fabric of communities affected by trauma. To assess the perceived effects of disaster compensation processes on community social relations, as well as the mechanisms that underlie such effects, we turn to the case of the Deepwater Horizon oil spill, after which BP implemented one of the largest compensation systems in U.S. HISTORY: Using data from interviews of residents of four Gulf Coast communities, we examine the extent to which this claims process hindered efforts to recover from this disaster. Our data suggest that while BP money helped some residents in the Gulf during a difficult economic time, many interviewees perceived uncertainty, randomness, and unevenness in the compensation process, which led to negative social comparisons and competition among community members. Because of this animosity, we argue that BP's compensation system was a disruptive mechanism that contributed to community corrosion and introduced another source of psychological stress into already traumatized areas. PMID- 26120248 TI - Maternal Factors as Moderators or Mediators of PTSD Symptoms in Very Young Children: A Two-Year Prospective Study. AB - Research has suggested that parenting behaviors and other parental factors impact the long-term outcome of children's posttraumatic stress disorder (PTSD) symptoms. In a sample of 62 children between the ages of one and six who experienced life-threatening traumas, PTSD was measured prospectively two years apart. Seven maternal factors were measured in a multi-method, multi-informant design. Both moderation and mediation models, with different theoretical and mechanism implications, were tested. Moderation models were not significant. Mediation models were significant when the mediator variable was maternal symptoms of PTSD or depression (measured at Time 1), self-report of maternal escape/avoidance coping (measured at Time 2), or self-report emotional sensitivity (measured at Time 2). Greater maternal emotional sensitivity was associated with greater Time 2 PTSD symptoms among children. Observational measures of emotional sensitivity as the mediator were not supported. Correlation of parents' and children's symptoms is a robust finding, however caution is warranted in attributing children's PTSD symptoms to insensitive parenting. PMID- 26120249 TI - Cubic Silica-Coated and Amine-Functionalized FeCo Nanoparticles with High Saturation Magnetization. AB - By systematically varying the reaction parameters in a liquid-phase reduction reaction, large FeCo nanocubes with tunable body diagonal lengths of 175, 350, and 450 nm were synthesized. The nanocubes were initially stabilized with poly(vinyl pyrrolidone) (PVP) and then coated with a relatively thin layer of silica (~55 nm thick), which allowed them to retain their cubic shape. The magnetization curves showed that the PVP-stabilized nanocubes exhibited a high saturation magnetization of 167 +/- 4 emu/g. The saturation magnetization, however, decreased upon coating with silica to 146 +/- 13 emu/g for the particles with 350 and 450 nm FeCo cores and 48 +/- 1 emu/g for the particles with 175 nm FeCo cores. The silica-coated FeCo nanocubes were then functionalized with 3 (aminopropyl)-trimethoxysilane (APTMS), and a layer of surface-bound nanoparticle was generated by exposing the resultant amine-functionalized nanocubes to self assembled monolayers (SAMs) on gold terminated with carboxylic-acid groups. PMID- 26120250 TI - Ecosystem service provision in a changing Europe: adapting to the impacts of combined climate and socio-economic change. AB - CONTEXT: Future patterns of European ecosystem services provision are likely to vary significantly as a result of climatic and socio-economic change and the implementation of adaptation strategies. However, there is little research in mapping future ecosystem services and no integrated assessment approach to map the combined impacts of these drivers. OBJECTIVE: Map changing patterns in ecosystem services for different European futures and (a) identify the role of driving forces; (b) explore the potential influence of different adaptation options. METHODS: The CLIMSAVE integrated assessment platform is used to map spatial patterns in services (food, water and timber provision, atmospheric regulation, biodiversity existence/bequest, landscape experience and land use diversity) for a number of combined climatic and socio-economic scenarios. Eight adaptation strategies are explored within each scenario. RESULTS: Future service provision (particularly water provision) will be significantly impacted by climate change. Socio-economic changes shift patterns of service provision: more dystopian societies focus on food provision at the expense of other services. Adaptation options offer significant opportunities, but may necessitate trade offs between services, particularly between agriculture- and forestry-related services. Unavoidable trade-offs between regions (particularly South-North) are also identified in some scenarios. CONCLUSIONS: Coordinating adaptation across regions and sectors will be essential to ensure that all needs are met: a factor that will become increasingly pressing under dystopian futures where inter regional cooperation breaks down. Integrated assessment enables exploration of interactions and trade-offs between ecosystem services, highlighting the importance of taking account of complex cross-sectoral interactions under different future scenarios of planning adaptation responses. PMID- 26120251 TI - More green infrastructure is required to maintain ecosystem services under current trends in land-use change in Europe. AB - Green infrastructure (GI), a network of nature, semi-natural areas and green space, delivers essential ecosystem services which underpin human well-being and quality of life. Maintaining ecosystem services through the development of GI is therefore increasingly recognized by policies as a strategy to cope with potentially changing conditions in the future. This paper assessed how current trends of land-use change have an impact on the aggregated provision of eight ecosystem services at the regional scale of the European Union, measured by the Total Ecosystem Services Index (TESI8). Moreover, the paper reports how further implementation of GI across Europe can help maintain ecosystem services at baseline levels. Current demographic, economic and agricultural trends, which affect land use, were derived from the so called Reference Scenario. This scenario is established by the European Commission to assess the impact of energy and climate policy up to 2050. Under the Reference Scenario, economic growth, coupled with the total population, stimulates increasing urban and industrial expansion. TESI8 is expected to decrease across Europe between 0 and 5 % by 2020 and between 10 and 15 % by 2050 relative to the base year 2010. Based on regression analysis, we estimated that every additional percent increase of the proportion of artificial land needs to be compensated with an increase of 2.2 % of land that qualifies as green infrastructure in order to maintain ecosystem services at 2010 levels. PMID- 26120252 TI - Hybrid monopole/loop coil array for human head MR imaging at 7T. AB - The monopole coil and loop coil have orthogonal radiofrequency (RF) fields and thus are intrinsically decoupled electromagnetically if they are laid out appropriately. In this study, we proposed a hybrid monopole/loop technique which could combine the advantages of both loop arrays and monopole arrays. To investigate this technique, a hybrid RF coil array containing 4 monopole channels and 4 loop channels was developed for human head MR imaging at 7T. In vivo MR imaging and g-factor results using monopole-only channels, loop-only channels and all channels of the hybrid array were acquired and evaluated. Compared with the monopole-only and loop-only channels, the proposed hybrid array has higher SNR and better parallel imaging performance. Sufficient electromagnetic decoupling and diverse RF magnetic field (B1) distributions of monopole channels and loop channels may contribute to this performance improvement. From experimental results, the hybrid monopole/loop array has low g-factor and excellent SNR at both periphery and center of the brain, which is valuable for human head imaging at ultrahigh fields. PMID- 26120253 TI - Abdominal aortic aneurysm screening program in Poland. AB - BACKGROUND: Screening for abdominal aortic aneurysms (AAA) is currently recommended by several vascular societies. In countries where it has been introduced the prevalence of AAAs differed greatly and was mainly related to cigarette smoking. The screening program also had an enormous impact on the decrease of AAA ruptures and reduced mortality rate. These facts have led to the introduction of the first screening program for AAAs in Poland. OBJECTIVE: The aim of the study was to determine the prevalence of AAAs among men aged 60 years and older undergoing ultrasound examination of the abdominal aorta. MATERIAL AND METHODS: A single ultrasonography of the abdomen was performed to assess the aorta from the renal arteries to the bifurcation and the diameter of the aorta was measured at its widest point. The cut-off value for determining an aortic aneurysm was set at a diameter of >= 30 mm. All ultrasonography measurements were performed by physicians in outpatient departments throughout the Kuyavian Pomeranian Province. Additionally, each subject had to fill out a questionnaire with demographic data, smoking habits, existing comorbidities and familial occurrence of AAAs. The study was conducted from October 2009 to November 2011. RESULTS: The abdominal aorta ultrasound examinations were carried out in 1556 men aged 60 years and older. The prevalence of AAA in the study population was 6.0 % (94 out of 1556). The average age of the men was 69 years (SD 6 years, range 60 92 years). In the study population 55 % of the men smoked or had smoked and 3 % were aware of the presence of AAAs in family members. There were three risk factors significantly associated with the presence of AAAs: age (p < 0.05), smoking (72.3 % vs 53.9 %, p = 0.004) and family history of AAAs (9.6 % vs 2.7 %, p = 0.017). CONCLUSION: The prevalence of AAAs among men in Poland is higher than in other European countries and the USA. The screening program for AAAs is an easy and reliable method for detecting early stages of the disease and risk factors which are the driving forces for the development of AAAs. PMID- 26120254 TI - Global Burden of Neural Tube Defects, Risk Factors, and Prevention. AB - Neural tube defects (NTDs), serious birth defects of the brain and spine usually resulting in death or paralysis, affect an estimated 300,000 births each year worldwide. Although the majority of NTDs are preventable with adequate folic acid consumption during the preconception period and throughout the first few weeks of gestation, many populations, in particular those in low and middle resource settings, do not have access to fortified foods or vitamin supplements containing folic acid. Further, accurate birth defects surveillance data, which could help inform mandatory fortification and other NTD prevention initiatives, are lacking in many of these settings. The burden of birth defects in South East Asia is among the highest in the world. Expanding global neural tube defects prevention initiatives can support the achievement of the United Nations Millennium Development Goal 4 to reduce child mortality, a goal which many countries in South East Asia are currently not poised to reach, and the 63rd World Health Assembly Resolution on birth defects. More work is needed to develop and implement mandatory folic acid fortification policies, as well as supplementation programs in countries where the reach of fortification is limited. PMID- 26120256 TI - The transdiagnostic dimension of psychosis: implications for psychiatric nosology and research. AB - If psychosis is a transdiagnostic dimension, the expression of which is governed by a dynamic set of contextual and emotional factors that are amenable to treatment, current approaches in psychiatric nosology and therapeutic research may need to be revised. The dominant approach to date is to clinically and conceptually situate psychotic symptoms in the construct of schizophrenia. However, schizophrenia, which has a lifetime prevalence of 1%, only represents the poor outcome fraction of a much broader spectrum of psychotic disorders which have a lifetime prevalence of 3.5%. Therefore, research findings in schizophrenia may reflect mechanisms of prognosis rather than fundamental associations with psychosis and other symptom domains per se. Similarly, the discovery that up to 30% of individuals with non-psychotic common mental disorders have subthreshold psychotic symptoms that situate them on the transdiagnostic dimension of psychosis - and which impact clinical severity and treatment response - indicates that the rigid separation between 'psychotic' and 'non-psychotic' hampers both clinical practice and research. Diagnostic manuals in psychiatry would benefit from a system of transdiagnostic dimensions, including a transdiagnostic dimension of psychosis. Introduction of transdiagnostic dimensions allows for a system combining a nomothetic (i.e., group-specific) categorical diagnosis with an idiographic (i.e., person-specific) combination of dimensional scores. The advantage of such a system is that it encourages consideration of how symptoms dynamically interact with each other in a network of psychopathology, and of how this network is impacted by the social world. PMID- 26120257 TI - Finding a solution to psychosis: the emergence of a new path. AB - The transition from a dichotomous diagnostic classification system to the more holistic approach to understanding mental disorders engendered by the so-called biopsychosocial model has definite advantages, but it runs the risk of sacrificing methodological rigor to achieve all-inclusiveness. The Special Article by Bebbington on understanding psychosis in this issue attempts to show that high-quality psychosocial epidemiological research on the development of psychosis can, at least partially, overcome these limitations. Bebbington's emphasis on the importance of non-psychotic symptoms such as disturbance in sleep and mood in the development of psychosis provides a new perspective on the conceptualization of psychosis, but I remain unconvinced about the usefulness of such symptoms in the differentiation of valid sub-categories of schizophrenia or other psychoses. PMID- 26120258 TI - Errata. AB - [This corrects the article DOI: 10.11919/j.issn.1002-0829.215010.][This corrects the article DOI: 10.11919/j.issn.1002-0829.215014.]. PMID- 26120255 TI - Unravelling psychosis: psychosocial epidemiology, mechanism, and meaning. AB - This paper reviews a revolution in our understanding of psychosis over the last 20 years. To a major extent, this has resulted from a process of cross fertilization between psychosocial epidemiology and cognitive behavior therapy for psychosis (CBT-p). This encouraged complementary strategies for the acquisition and analysis of data. These include the use of a range of dependent variables related to psychosis, and the exploitation of data from cross-sectional and longitudinal epidemiological surveys, virtual reality experiments, experience sampling methodology, and treatment trials. The key element is to investigate social and psychological measures in relation to each other. This research has confirmed the role of the external social world in the development and persistence of psychotic disorder. In addition, several psychological drivers of psychotic experiences have been identified. There is now persuasive evidence that the influence of social factors in psychosis is significantly mediated by non psychotic symptoms, particularly mood symptoms and other attributes of affect such as insomnia. Psychotic symptoms are also driven by reasoning biases such as jumping to conclusions and belief inflexibility, though little is known about social influences on such biases. It is now clear that there are many routes to psychosis and that it takes many forms. Treatment of all kinds should take account of this: the dependence of CBT-p on a detailed initial formulation in terms of psychological processes and social influences is an example of the required flexibility. Individual mediators are now being targeted in specific forms of CBT-p, with good effect. This in turn corroborates the hypothesized role of non-psychotic symptoms in mediation, and attests to the power of the approaches described. PMID- 26120259 TI - Prenatal choline and the development of schizophrenia. AB - BACKGROUND: The primary prevention of illness at the population level, the ultimate aim of medicine, seems out of reach for schizophrenia. Schizophrenia has a strong genetic component, and its pathogenesis begins long before the emergence of psychosis, as early as fetal brain development. Cholinergic neurotransmission at nicotinic receptors is a pathophysiological mechanism related to one aspect of this genetic risk. Choline activates these nicotinic receptors during fetal brain development. Dietary supplementation of maternal choline thus emerges as a possible intervention in pregnancy to alter the earliest developmental course of the illness. AIM: Review available literature on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development. METHODS: A Medline search was used to identify studies assessing effects of choline in human fetal development. Studies of other prenatal risk factors for schizophrenia and the role of cholinergic neurotransmission in its pathophysiology were also identified. RESULTS: Dietary requirements for choline are high during pregnancy because of its several uses, including membrane biosynthesis, one-carbon metabolism, and cholinergic neurotransmission. Its ability to act directly at high concentrations as a nicotinic agonist is critical for normal brain circuit development. Dietary supplementation in the second and third trimesters with phosphatidyl-choline supports these functions and is associated generally with better fetal outcome. Improvement in inhibitory neuronal functions whose deficit is associated with schizophrenia and attention deficit disorder has been observed. CONCLUSION: Prenatal dietary supplementation with phosphatidyl-choline and promotion of diets rich in choline-containing foods (meats, soybeans, and eggs) are possible interventions to promote fetal brain development and thereby decrease the risk of subsequent mental illnesses. The low risk and short (sixmonth) duration of the intervention makes it especially conducive to population-wide adoption. Similar findings with folate for the prevention of cleft palate led to recommendations for prenatal pharmacological supplementation and dietary improvement. However, definitive proof of the efficacy of prenatal choline supplementation will not be available for decades (because of the 20-year lag until the onset of schizophrenia), so public health officials need to decide whether or not promoting choline supplementation is justified based on the limited information available. PMID- 26120260 TI - Efficacy and safety of the Chinese herbal medicine shuganjieyu with and without adjunctive repetitive transcranial magnetic stimulation (rTMS) for geriatric depression: a randomized controlled trial. AB - BACKGROUND: Pharmacological treatment of geriatric depression is often ineffective because patients cannot tolerate adequate doses of antidepressant medications. AIM: Examine the efficacy and safety of shuganjieyu - the first Chinese herbal medicine approved for the treatment of depression by China's drug regulatory agency -- with and without adjunctive treatment with repetitive transcranial magnetic stimulation (rTMS) in the treatment of geriatric depression. METHODS: Sixty-five inpatients 60 or older who met ICD-10 criteria for depression were randomly assigned to an experimental group (shuganjieyu + rTMS) (n=36) or a control group (shuganjieyu + sham rTMS)(n=29). All participants received 4 capsules of shuganjieyu daily for 6 weeks. rTMS (or sham rTMS) was administered 20 minutes daily, five days a week for 4 weeks. Blinded raters used the Hamilton Rating Scale for Depression (HAMD-17) and the Treatment Emergent Symptom Scale to assess clinical efficacy and safety at baseline and 1, 2, 4, and 6 weeks after starting treatment. Over the six-week trial, there was only one dropout from the experimental group and two dropouts from the control group. RESULTS: None of the patients had serious side effects, but 40% in the experimental group and 50% in the control group experienced minor side effects that all resolved spontaneously. Both groups showed substantial stepwise improvement in depressive symptoms over the 6 weeks. Repeated measures ANOVA found no differences between the two groups. After 6 weeks, 97% of the experimental group had experienced a 25% or greater drop in the level of depression, but only 20% had experience a 50% or greater drop in the level of depression; the corresponding values in the control group were 96% and 19%. There were some minor, non-significant differences in the onset of the treatment effect between the different types of depressive symptoms, but by the second week of treatment all five HAMD-17 subscale scores had improved significantly in both groups. CONCLUSION: The Chinese herbal medicine shuganjieyu is effective and safe in the treatment of geriatric depression, but only a minority of patients have greater than 50% improvement in their depressive symptoms after 6 weeks of treatment. Adjunctive use of rTMS with shuganjieyu does not improve the overall outcome and does not significantly speed up the onset of action of shuganjieyu. PMID- 26120261 TI - Gene-based and pathway-based genome-wide association study of alcohol dependence. AB - BACKGROUND: The organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. AIM: Identify risk genes and risk gene pathways for alcohol dependence. METHODS: We conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample. RESULTS: We identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the 'cellextracellular matrix interactions' pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015<=p<=0.035) and AAs (0.025<=p<=0.050): the 'Na+/Cl- dependent neurotransmitter transporters' pathway and the 'other glycan degradation' pathway. CONCLUSION: These findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence. PMID- 26120262 TI - Are the revised diagnostic criteria for Alzheimer's disease useful in low- and middle-income countries? AB - Alzheimer's Disease (AD) is a leading cause of disease burden among elderly individuals that is increasingly important in middle-income countries like China where improvements in overall health (which increase longevity) and other factors are leading to a rapidly aging population. The diagnostic criteria for AD have recently been revised to reflect advances in the understanding of the condition over the past three decades. Different international organizations have proposed algorithms for diagnosing AD that subdivide the AD spectrum into overlapping stages and, in some cases, require the concurrent presence of memory impairment and specific biomarkers. There are, however, several substantial limitations to these revised criteria: highly trained clinicians are needed to make the fine discriminations between the stages; the role of the proposed biomarkers in the onset and course of AD remain uncertain; and assessment of these biomarkers requires the use of expensive, high-tech equipment by well-trained technicians. These problems limit the clinical utility of these diagnostic criteria, particularly in low-resource settings where the clinicians responsible for identifying and treating individuals with AD have limited training and where the equipment needed to identify the biomarkers are either non-existent or in short supply. PMID- 26120263 TI - Clinical and research value of the new diagnostic criteria for Alzheimer's disease. AB - The use of biomarkers in the diagnosis of Alzheimer's disease (AD) has been increasingly emphasized, but the feasibility and value of using biomarkers in clinical practice remain limited. However, the use of biomarkers in clinical and pharmaceutical research about AD may prove quite useful in clarifying the pathology underlying AD and, thus, help in the early identification of effective preventive and therapeutic interventions. Moreover, wide adoption of the new diagnostic criteria will improve comparability of research results across studies, and, thus, allow for the combination and comparison of study results using meta-analytic techniques - the types of analyses needed to definitively answer fundamental questions about the etiology, course, prevention, and treatment of AD. PMID- 26120264 TI - Case report of visual hallucinations in anxiety. AB - Hallucinations rarely occur in individuals with anxiety disorders. This case report describes a 36-year-old male with Social Phobia and Agoraphobia with Panic Attacks who had prominent visual hallucinations that were both distressing and incapacitating. Treatment with sertraline 200 mg/d, clonazepam 1 mg/d, and propranolol 20 mg/day for one month completely resolved both his anxiety and the hallucinations, after which he was able to return to his social and occupational life. The report underscores the fact that visual hallucinations are not always indicators of a psychotic disorder, they may be present across a spectrum of mental disorders. In cases where hallucinations occur in nonpsychotic disorders, treatment of the underlying condition usually simultaneously resolves the associated hallucinations without the need to resort to the use of antipsychotic medication. Detailed analyses of such unusual cases can help improve our understanding of the pathogenesis of psychotic-like symptoms. PMID- 26120266 TI - Improving Simulation-Based Algorithms for Fitting ERGMs. AB - Markov chain Monte Carlo methods can be used to approximate the intractable normalizing constants that arise in likelihood calculations for many exponential family random graph models for networks. However, in practice, the resulting approximations degrade as parameter values move away from the value used to define the Markov chain, even in cases where the chain produces perfectly efficient samples. We introduce a new approximation method along with a novel method of moving toward a maximum likelihood estimator (MLE) from an arbitrary starting parameter value in a series of steps based on alternating between the canonical exponential family parameterization and the mean-value parameterization. This technique enables us to find an approximate MLE in many cases where this was previously not possible. We illustrate these methods on a model for a transcriptional regulation network for E. coli, an example where previous attempts to approximate an MLE had failed, and a model for a well-known social network dataset involving friendships among workers in a tailor shop. These methods are implemented in the publicly available ergm package for R, and computer code to duplicate the results of this paper is included in the Supplemental Materials. PMID- 26120265 TI - Decision tree methods: applications for classification and prediction. AB - Decision tree methodology is a commonly used data mining method for establishing classification systems based on multiple covariates or for developing prediction algorithms for a target variable. This method classifies a population into branch like segments that construct an inverted tree with a root node, internal nodes, and leaf nodes. The algorithm is non-parametric and can efficiently deal with large, complicated datasets without imposing a complicated parametric structure. When the sample size is large enough, study data can be divided into training and validation datasets. Using the training dataset to build a decision tree model and a validation dataset to decide on the appropriate tree size needed to achieve the optimal final model. This paper introduces frequently used algorithms used to develop decision trees (including CART, C4.5, CHAID, and QUEST) and describes the SPSS and SAS programs that can be used to visualize tree structure. PMID- 26120267 TI - Graphical Models for Ordinal Data. AB - A graphical model for ordinal variables is considered, where it is assumed that the data are generated by discretizing the marginal distributions of a latent multivariate Gaussian distribution. The relationships between these ordinal variables are then described by the underlying Gaussian graphical model and can be inferred by estimating the corresponding concentration matrix. Direct estimation of the model is computationally expensive, but an approximate EM-like algorithm is developed to provide an accurate estimate of the parameters at a fraction of the computational cost. Numerical evidence based on simulation studies shows the strong performance of the algorithm, which is also illustrated on data sets on movie ratings and an educational survey. PMID- 26120268 TI - Rationale and Considerations for the Internet-Based Delivery of Parent-Child Interaction Therapy. AB - Given the enormous individual, familial, and societal costs associated with early disruptive behavior disorders, transformative efforts are needed to develop innovative options for overcoming traditional barriers to effective care and for broadening the availability of supported interventions. This paper presents the rationale and key considerations for a promising innovation in the treatment of early-onset disruptive behavior disorders-that is, the development of an Internet based format for the delivery of Parent-Child Interaction Therapy (PCIT) directly to families in their own homes. Specifically, we consider traditional barriers to effective care, and discuss how technological innovations can overcome problems of treatment availability, accessibility, and acceptability. We then detail our current Internet-delivered PCIT treatment program (I-PCIT), which is currently being evaluated across multiple randomized clinical trials relative to waitlist comparison, and to traditional in-office PCIT. Embedded video clips of children treated with I-PCIT are used to illustrate novel aspects of the treatment. PMID- 26120269 TI - A Web-Based Self-Management Program for Recent Combat Veterans With PTSD and Substance Misuse: Program Development and Veteran Feedback. AB - Combat veterans from the wars in Iraq and Afghanistan commonly experience posttraumatic stress disorder (PTSD) and substance use problems. In addition, these veterans often report significant barriers to receiving evidence-based mental health and substance use care, such as individual beliefs that treatment will be unhelpful, inconvenient, or that they should be able to handle their problems on their own. To increase access to treatment for this underserved population, a Web-based patient self-management program that teaches cognitive behavioral therapy (CBT) skills to manage PTSD symptoms and substance misuse was developed. This paper describes and provides results from an iterative, multistage process for developing the Web-based program and seeks to inform clinicians in the field about the preferences of veterans for using a Web-based CBT program. Systematic feedback was gathered from (a) three expert clinicians in the field, (b) focus groups of combat veterans (n = 18), and (c) individual feedback sessions with combat veterans (n = 34). Clinician feedback led to the incorporation of motivational strategies to increase participant engagement and an optional module that guides written trauma exposure work. Focus group feedback guided the research team to frame the program in a strength-based approach and allows for maximum flexibility, adaptability, interactivity, and privacy for veterans. In individual feedback sessions, veterans generally found the program likable, easy to use, and relevant to their experiences; critiques of the program led to revised content meant to increase clarity and participant interest. Our findings provide specific guidance for clinicians who are interested in developing or providing technology-based treatment, including the need to gather feedback from an intervention's target audience when adapting a psychotherapeutic intervention and that the treatment must be highly interactive and private to engage clients. PMID- 26120270 TI - Levels of selected oxidative stress markers in the vitreous and serum of diabetic retinopathy patients. AB - PURPOSE: In diabetes, an impaired antioxidant defense system contributes to the development of diabetic retinopathy. The main objective of this paper was to find correlations of oxidative stress parameters within and between the vitreous and serum in patients with type 2 diabetes who had developed proliferative diabetic retinopathy. METHODS: The study included and compared two groups of patients who underwent vitrectomy: 37 patients with type 2 diabetes and proliferative retinopathy (PDR), and 50 patients with non-diabetic eye disorders (NDED). Vascular endothelial growth factor (VEGF), advanced oxidized protein product (AOPP), and oxidative stress markers (direct lipid hydroperoxidation (LPO), malondialdehyde (MDA), total superoxide dismutase (SOD), and glutathione (GSH)) were measured in the vitreous and serum of both groups and correlated with one another, between humoral compartments and with gender, age, and serum glucose levels. RESULTS: In the vitreous of PDR patients, VEGF, LPO, and MDA (p<0.05) were increased and SOD values were slightly lowered (p<0.05) than in NDED patients. Vitreous AOPP and GSH showed no differences between the groups. In the serum, AOPP, MDA, and SOD were increased (p<0.05) and VEGF was slightly increased (p<0.05) in the PDR group compared to NDED. With regard to gender, similar changes were recorded for both groups, except for the lower serum MDA in males than females in the NDED group. Advanced age showed no significant effect on changes of measured parameters in the vitreous. In the serum, VEGF was positively correlated (p<0.05) and MDA and SOD negatively correlated (p<0.05) with increasing age. Among measured parameters within and between the vitreous and serum, several correlative links occurred in the PDR group that were not present in the NDED group. The most prominent correlation changes were between serum LPO and vitreal LPO, serum SOD and vitreal LPO, serum LPO and serum SOD, and vitreal VEGF and serum SOD. CONCLUSIONS: Among the selected oxidative stress markers, SOD and LPO were highly correlative in both the vitreous and serum in PDR compared to patients without metabolic disorders. Their correlations suggested that monitoring their mutual alterations might be informative during PDR development and should be considered in further research. PMID- 26120271 TI - Elevated LRP6 levels correlate with vascular endothelial growth factor in the vitreous of proliferative diabetic retinopathy. AB - PURPOSE: To measure intravitreal low-density lipoprotein receptor-related protein 6 (LRP6) and vascular endothelial growth factor (VEGF) levels in the eyes of patients with proliferative diabetic retinopathy (PDR) and to observe their correlation with PDR activity. METHODS: Fifty-five eyes of 55 patients were enrolled consecutively. Vitreous samples from 30 eyes with PDR and 25 eyes with nondiabetic macular disease were collected. Active PDR was present in 16 patients and quiescent PDR in 14 patients according to retinal neovascularization. LRP6 and VEGF concentrations in samples were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: ELISA revealed significant increases in the vitreous levels of VEGF in eyes affected with PDR compared to the controls (p<0.001). The mean concentrations of LRP6 were also higher in the vitreous samples from patients with PDR compared to the nondiabetic controls: 39.85 ng/ml and 15.48 ng/ml, respectively (p=0.002). In addition, the vitreous levels of LRP6 and VEGF were significantly higher in active PDR than in quiescent PDR (p=0.022 and p=0.015, respectively). Furthermore, a significant positive correlation was found between intravitreal levels of LRP6 and VEGF in patients with PDR (r=0.567, p=0.001). However, comparison of patients with PDR with controls revealed that the plasma levels of LRP6 were not significantly different between the two groups (p=0.636). CONCLUSIONS: LRP6 and VEGF levels in the vitreous body from patients with PDR were increased and correlated mutually. LRP6 may be a good diagnostic biomarker and a new therapeutic target for PDR. PMID- 26120272 TI - Characterization of cells from patient-derived fibrovascular membranes in proliferative diabetic retinopathy. AB - PURPOSE: Epiretinal fibrovascular membranes (FVMs) are a hallmark of proliferative diabetic retinopathy (PDR). Surgical removal of FVMs is often indicated to treat tractional retinal detachment. This potentially informative pathological tissue is usually disposed of after surgery without further examination. We developed a method for isolating and characterizing cells derived from FVMs and correlated their expression of specific markers in culture with that in tissue. METHODS: FVMs were obtained from 11 patients with PDR during diabetic vitrectomy surgery and were analyzed with electron microscopy (EM), comparative genomic hybridization (CGH), immunohistochemistry, and/or digested with collagenase II for cell isolation and culture. Antibody arrays and enzyme linked immunosorbent assay (ELISA) were used to profile secreted angiogenesis related proteins in cell culture supernatants. RESULTS: EM analysis of the FVMs showed abnormal vessels composed of endothelial cells with large nuclei and plasma membrane infoldings, loosely attached perivascular cells, and stromal cells. The cellular constituents of the FVMs lacked major chromosomal aberrations as shown with CGH. Cells derived from FVMs (C-FVMs) could be isolated and maintained in culture. The C-FVMs retained the expression of markers of cell identity in primary culture, which define specific cell populations including CD31-positive, alpha-smooth muscle actin-positive (SMA), and glial fibrillary acidic protein-positive (GFAP) cells. In primary culture, secretion of angiopoietin-1 and thrombospondin-1 was significantly decreased in culture conditions that resemble a diabetic environment in SMA-positive C-FVMs compared to human retinal pericytes derived from a non-diabetic donor. CONCLUSIONS: C-FVMs obtained from individuals with PDR can be isolated, cultured, and profiled in vitro and may constitute a unique resource for the discovery of cell signaling mechanisms underlying PDR that extends beyond current animal and cell culture models. PMID- 26120273 TI - Fasudil hydrochloride, a potent ROCK inhibitor, inhibits corneal neovascularization after alkali burns in mice. AB - PURPOSE: To investigate the effects and mechanisms of fasudil hydrochloride (fasudil) on and in alkali burn-induced corneal neovascularization (CNV) in mice. METHODS: To observe the effect of fasudil, mice with alkali-burned corneas were treated with either fasudil eye drops or phosphate-buffered saline (PBS) four times per day for 14 consecutive days. After injury, CNV and corneal epithelial defects were measured. The production of reactive oxygen species (ROS) and heme oxygenase-1(HO-1) was measured. The infiltration of polymorphonuclear neutrophils (PMNs) and the mRNA expressions of CNV-related genes were analyzed on day 14. RESULTS: The incidence of CNV was significantly lower after treatment with 100 MUM and 300 MUM fasudil than with PBS, especially with 100 MUM fasudil. Meanwhile, the incidences of corneal epithelial defects was lower (n=15, all p<0.01). After treatment with 100 MUM fasudil, the intensity of DHE fluorescence was reduced in the corneal epithelium and stroma than with PBS treatment (n=5, all p<0.01), and the number of filtrated PMNs decreased. There were significant differences between the expressions of VEGF, TNF-a, MMP-8, and MMP-9 in the 100 MUM fasudil group and the PBS group (n=8, all p<0.05). The production of HO-1 protein in the 100 MUM fasudil group was 1.52+/-0.34 times more than in the PBS group (n=5 sample, p<0.05). CONCLUSIONS: 100 MUM fasudil eye drops administered four times daily can significantly inhibit alkali burn-induced CNV and promote the healing of corneal epithelial defects in mice. These effects are attributed to a decrease in inflammatory cell infiltration, reduction of ROS, and upregulation of HO-1 protein after fasudil treatment. PMID- 26120274 TI - Vasodilatory mechanisms of unoprostone isopropyl in isolated porcine retinal arterioles. AB - PURPOSE: To clarify the vasodilatory mechanism of unoprostone isopropyl (UI), we examined its effects on the retinal microvascular diameter to determine the dependence on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. METHODS: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded the diametric responses to UI. RESULTS: The retinal arterioles dilated in response to UI in a dose-dependent (100 pM-10 uM) manner. The nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited UI-induced vasodilation. The large-conductance Ca2+-activated K channel (BKCa channel) blocker iberiotoxin also inhibited UI-induced vasodilation. The residual vasodilation after L-NAME was eliminated with co administration of iberiotoxin. CONCLUSIONS: UI elicits dilation of the retinal arterioles mediated by NO release and BKCa channel activation. PMID- 26120275 TI - Expression of WW domain-containing oxidoreductase WWOX in pterygium. AB - PURPOSE: Pterygium was traditionally regarded as a degenerative disease, but certain characteristics suggest that pterygium is probably premalignant tissue. The human WWOX gene, encoding the WW domain containing oxidoreductase (WWOX, FOR, or WOX1), is a candidate tumor suppressor gene. In this study, we investigated the WWOX gene and protein expression in pterygium. METHODS: Pterygium tissues were obtained from patients (n=16, primary=8, recurrent=8) who received surgical excisions. Each tissue sample was further divided into head and body regions. The WWOX gene and protein expression were examined with immunohistochemistry, western blot, and quantitative PCR. For comparison, normal superior temporal bulbar conjunctivas were used as controls. RESULTS: Compared to the controls, upregulation of WWOX and its Tyr33 phosphorylation was observed in the head region of all pterygium specimens. In the head and body of the pterygium specimens, WWOX expression was significantly higher than in the controls. In addition, WWOX expression was stronger in recurrent pterygia than in primary pterygia. CONCLUSIONS: Increased WWOX expression, especially in the head region, is probably due to the invasiveness of the pterygium. Our results indicate that WWOX may play a role in pterygium progression and recurrence. PMID- 26120277 TI - A Method to Represent Heterogeneous Materials for Rapid Prototyping: The Matryoshka Approach. AB - PURPOSE: The purpose of this paper is to present a new method for representing heterogeneous materials using nested STL shells, based, in particular, on the density distributions of human bones. DESIGN/METHODOLOGY/APPROACH: Nested STL shells, called Matryoshka models, are described, based on their namesake Russian nesting dolls. In this approach, polygonal models, such as STL shells, are "stacked" inside one another to represent different material regions. The Matryoshka model addresses the challenge of representing different densities and different types of bone when reverse engineering from medical images. The Matryoshka model is generated via an iterative process of thresholding the Hounsfield Unit (HU) data using computed tomography (CT), thereby delineating regions of progressively increasing bone density. These nested shells can represent regions starting with the medullary (bone marrow) canal, up through and including the outer surface of the bone. FINDINGS: The Matryoshka approach introduced can be used to generate accurate models of heterogeneous materials in an automated fashion, avoiding the challenge of hand-creating an assembly model for input to multi-material additive or subtractive manufacturing. ORIGINALITY/VALUE: This paper presents a new method for describing heterogeneous materials: in this case, the density distribution in a human bone. The authors show how the Matryoshka model can be used to plan harvesting locations for creating custom rapid allograft bone implants from donor bone. An implementation of a proposed harvesting method is demonstrated, followed by a case study using subtractive rapid prototyping to harvest a bone implant from a human tibia surrogate. PMID- 26120276 TI - Inherited retinal diseases in dogs: advances in gene/mutation discovery. AB - 1. Inherited retinal diseases (RDs) are vision-threatening conditions affecting humans as well as many domestic animals. Through many years of clinical studies of the domestic dog population, a wide array of RDs has been phenotypically characterized. Extensive effort to map the causative gene and to identify the underlying mutation followed. Through candidate gene, linkage analysis, genome wide association studies, and more recently, by means of next-generation sequencing, as many as 31 mutations in 24 genes have been identified as the underlying cause for canine RDs. Most of these genes have been associated with human RDs providing opportunities to study their roles in the disease pathogenesis and in normal visual function. The canine model has also contributed in developing new treatments such as gene therapy which has been clinically applied to human patients. Meanwhile, with increasing knowledge of the molecular architecture of RDs in different subpopulations of dogs, the conventional understanding of RDs as a simple monogenic disease is beginning to change. Emerging evidence of modifiers that alters the disease outcome is complicating the interpretation of DNA tests. In this review, advances in the gene/mutation discovery approaches and the emerging genetic complexity of canine RDs are discussed. PMID- 26120278 TI - Parton distributions in the LHC era: MMHT 2014 PDFs. AB - We present LO, NLO and NNLO sets of parton distribution functions (PDFs) of the proton determined from global analyses of the available hard scattering data. These MMHT2014 PDFs supersede the 'MSTW2008' parton sets, but they are obtained within the same basic framework. We include a variety of new data sets, from the LHC, updated Tevatron data and the HERA combined H1 and ZEUS data on the total and charm structure functions. We also improve the theoretical framework of the previous analysis. These new PDFs are compared to the 'MSTW2008' parton sets. In most cases the PDFs, and the predictions, are within one standard deviation of those of MSTW2008. The major changes are the [Formula: see text] valence quark difference at small [Formula: see text] due to an improved parameterisation and, to a lesser extent, the strange quark PDF due to the effect of certain LHC data and a better treatment of the [Formula: see text] branching ratio. We compare our MMHT PDF sets with those of other collaborations; in particular with the NNPDF3.0 sets, which are contemporary with the present analysis. PMID- 26120279 TI - Higgs production in association with a single top quark at the LHC. AB - We present a detailed study of Higgs boson production in association with a single top quark at the LHC, at next-to-leading order accuracy in QCD. We consider total and differential cross sections, at the parton level as well as by matching short distance events to parton showers, for both t-channel and s channel production. We provide predictions relevant for the LHC at 13 TeV together with a thorough evaluation of the residual uncertainties coming from scale variation, parton distributions, strong coupling constant and heavy quark masses. In addition, for t-channel production, we compare results as obtained in the 4-flavour and 5-flavour schemes, pinning down the most relevant differences between them. Finally, we study the sensitivity to a non-standard-model relative phase between the Higgs couplings to the top quark and to the weak bosons. PMID- 26120281 TI - On static black holes solutions in Einstein and Einstein-Gauss-Bonnet gravity with topology [Formula: see text]. AB - We study static black hole solutions in Einstein and Einstein-Gauss-Bonnet gravity with the topology of the product of two spheres, [Formula: see text], in higher dimensions. There is an unusual new feature of the Gauss-Bonnet black hole: the avoidance of a non-central naked singularity prescribes a mass range for the black hole in terms of [Formula: see text]. For an Einstein-Gauss-Bonnet black hole a limited window of negative values for [Formula: see text] is also permitted. This topology encompasses black strings, branes, and generalized Nariai metrics. We also give new solutions with the product of two spheres of constant curvature. PMID- 26120282 TI - Minimally Invasive Resection of Benign Esophageal Lesions. AB - Benign esophageal lesions include a wide variety of rare neoplasms, polyps, and cysts. In general, these lesions are asymptomatic and have little clinical importance. However, on occasion these lesions become symptomatic due to esophageal obstruction, airway obstruction, or compression of mediastinal structures. In these cases, as well as cases when it is unclear if the lesion is malignant or benign, surgical resection is recommended. Resection is most often performed by extramucosal enucleation, a procedure that is oftentimes well-suited for a minimally invasive approach. Here we discuss the general approach and operative techniques used for minimally invasive resection of benign esophageal lesions. PMID- 26120283 TI - Experimentally-induced Increases in Early Gesture Lead to Increases in Spoken Vocabulary. AB - Differences in vocabulary that children bring with them to school can be traced back to the gestures they produce at 1;2, which, in turn, can be traced back to the gestures their parents produce at the same age (Rowe & Goldin-Meadow, 2009b). We ask here whether child gesture can be experimentally increased and, if so, whether the increases lead to increases in spoken vocabulary. Fifteen children aged 1;5 participated in an 8-week at-home intervention study (6 weekly training sessions plus follow-up 2 weeks later) in which all were exposed to object words, but only some were told to point at the named objects. Before each training session and at follow-up, children interacted naturally with caregivers to establish a baseline against which changes in communication were measured. Children who were told to gesture increased the number of gesture meanings they conveyed, not only during training but also during interactions with caregivers. These experimentally-induced increases in gesture led to larger spoken repertoires at follow-up. PMID- 26120284 TI - Predicting Fault Prone Modules by the Dempster-Shafer Belief Networks. AB - This paper describes a novel methodology for predicting fault prone modules. The methodology is based on Dempster-Shafer (D-S) belief networks. Our approach consists of three steps: First, building the Dempster-Shafer network by the induction algorithm; Second, selecting the predictors (attributes) by the logistic procedure; Third, feeding the predictors describing the modules of the current project into the inducted Dempster-Shafer network and identifying fault prone modules. We applied this methodology to a NASA dataset. The prediction accuracy of our methodology is higher than that achieved by logistic regression or discriminant analysis on the same dataset. PMID- 26120285 TI - Ethnic Differences in Profiles of Mother-Child Interactions and Relations to Emerging School Readiness in African American and Latin American Children. AB - OBJECTIVE: This article examines ethnic similarities and differences in profiles of mother-child interaction qualities for low-income African American and Latin American mothers and associations with preschoolers' emerging school readiness. DESIGN: Videotaped mother-child interactions were collected at age 2.5 years from a sample of African American (n = 192) and Latin American (n = 210) families. Profiles of maternal behavior were identified in person-centered within-group analyses of five ratings of maternal behavior from the videotaped interactions. Mothering profile groups were examined for relations to child receptive language, behavior problems, and pre-academic school readiness measured at age 3.5 years. RESULTS: Latent class analyses yielded three similar profiles in the two ethnicities identified as Child-Oriented, Directive, and Harsh-Intrusive mothering, and a fourth profile of Withdrawn mothering only among the African American mothers. For African American children, Child-Oriented and Directive mothering were each associated with higher pre-academic school readiness and language scores than Harsh-Intrusive or Withdrawn mothering. For Latin American children, Child-Oriented mothering was associated with fewer child behavior problems than Harsh-Intrusive mothering, and higher school readiness scores than Directive mothering. CONCLUSIONS: Both similarities and differences were found between African American and Latin American families in observation- based mothering profiles and their linkages with preschoolers' school readiness. PMID- 26120286 TI - The Application of Electroencephalography to Investigate the Neural Bases of Parenting: A Review. PMID- 26120287 TI - Sexual Risk Behavior and STI Contraction Among Young Women With Prior Juvenile Justice Involvement. AB - Girls in the juvenile justice system are at increased risk for contracting HIV/AIDS. Sexual risk behavior was examined in 166 females with juvenile justice involvement who were followed from adolescence to young adulthood. Results indicated that childhood sexual abuse increased the incidence of unsafe sex during young adulthood, which was subsequently associated with contraction of a sexually transmitted infection (STI). Further, girls' comfort in talking with their partners about safer sex practices during adolescence moderated the association between childhood sexual abuse and unsafe sex, such that girls who had been sexually abused and were uncomfortable talking to their partners about safer sex during adolescence had an 8.5-fold increase in unsafe sex in young adulthood. The identification of behaviors amenable to intervention in the prevention of HIV/AIDS risk in this high-risk population is discussed. PMID- 26120288 TI - AM1/d-CB1: A Semiempirical Model for QM/MM Simulations of Chemical Glycobiology Systems. AB - A semiempirical method based on the AM1/d Hamiltonian is introduced to model chemical glycobiological systems. We included in the parameter training set glycans and the chemical environment often found about them in glycoenzymes. Starting with RM1 and AM1/d-PhoT models we optimized H, C, N, O, and P atomic parameters targeting the best performing molecular properties that contribute to enzyme catalyzed glycan reaction mechanisms. The training set comprising glycans, amino acids, phosphates and small organic model systems was used to derive parameters that reproduce experimental data or high-level density functional results for carbohydrate, phosphate and amino acid heats of formation, amino acid proton affinities, amino acid and monosaccharide dipole moments, amino acid ionization potentials, water-phosphate interaction energies, and carbohydrate ring pucker relaxation times. The result is the AM1/d-Chemical Biology 1 or AM1/d CB1 model that is considerably more accurate than existing NDDO methods modeling carbohydrates and the amino acids often present in the catalytic domains of glycoenzymes as well as the binding sites of lectins. Moreover, AM1/d-CB1 computed proton affinities, dipole moments, ionization potentials and heats of formation for transition state puckered carbohydrate ring conformations, observed along glycoenzyme catalyzed reaction paths, are close to values computed using DFT M06-2X. AM1/d-CB1 provides a platform from which to accurately model reactions important in chemical glycobiology. PMID- 26120289 TI - Synthesis of bis(indolyl)methanes Catalyzed by Triethylborane. AB - Triethylborane (TEB) was found to be a mild, efficient, and acid catalyst in electrophilic substitution reaction of indoles with aldehydes compounds to afford the corresponding bis(indolyl)methanes. Vibrindole A (5) and bis(indolyl)methanes derivatives 16 and 18 were synthesized using this methodology. Compound 16 is an intermediary in the synthesis of the natural bisindoles arsindoline B (2) and streptindole (6). The structure of vibrindole A (5) was unequivocally confirmed by a single crystal X-ray diffraction analysis. PMID- 26120290 TI - Domain adaptation of statistical machine translation with domain-focused web crawling. AB - In this paper, we tackle the problem of domain adaptation of statistical machine translation (SMT) by exploiting domain-specific data acquired by domain-focused crawling of text from the World Wide Web. We design and empirically evaluate a procedure for automatic acquisition of monolingual and parallel text and their exploitation for system training, tuning, and testing in a phrase-based SMT framework. We present a strategy for using such resources depending on their availability and quantity supported by results of a large-scale evaluation carried out for the domains of environment and labour legislation, two language pairs (English-French and English-Greek) and in both directions: into and from English. In general, machine translation systems trained and tuned on a general domain perform poorly on specific domains and we show that such systems can be adapted successfully by retuning model parameters using small amounts of parallel in-domain data, and may be further improved by using additional monolingual and parallel training data for adaptation of language and translation models. The average observed improvement in BLEU achieved is substantial at 15.30 points absolute. PMID- 26120291 TI - PERSONALITY DISORDERS AND THE PREDICTION OF ALCOHOL USE OUTCOMES FOR WOMEN: DIMENSIONAL VERSUS CATEGORICAL CLASSIFICATION. AB - The impending shift in DSM-5 from categorical to a hybrid categorical-dimensional diagnosis scheme has generated considerable interest in the relative merits of these respective approaches. This is particularly true for the diagnostically complex category of personality disorders (PDs). The present study assessed whether categorical or dimensional measures better predicted alcohol consumption in a sample of 102 women enrolled in a clinical trial comparing individual Cognitive Behavioral Therapy (CBT) to conjoint CBT for alcohol use disorders (AUD). Linear regression was used to evaluate whether each PD diagnosis (categorical), or the number of PD symptoms endorsed per PD (dimensional) better predicted percent days drinking over the course of six months of treatment. PD criteria (dimensional) better predicted drinking for Paranoid, Borderline, and Obsessive-Compulsive PDs, while diagnosis (categorical) was a better predictor only for Passive-Aggressive PD. Both schemes predicted drinking outcomes for Avoidant, Dependent, and Depressive PDs, and neither was predictive for Narcissistic PD. These findings suggest that the addition of a dimensional approach for PDs potentially enhances the prediction of alcohol use outcomes. PMID- 26120292 TI - Intermolecular [3+2] Annulation of Cyclopropylanilines with Alkynes, Enynes, and Diynes via Visible Light Photocatalysis. AB - One-step synthesis of carbocycles substituted with amines from simple starting materials remains rare. We recently developed intermolecular [3+2] annulation of cyclopropylanilines with alkenes and alkynes that enable this one-step synthesis. Herein, we report our findings for a fullscale study of the annulation. Significant expansion of the substrate scope for both cyclopropylanilines and alkynes is achieved. A range of structurally diverse carbocycles substituted with amines is prepared. PMID- 26120293 TI - Digital Plasmonic Patterning for Localized Tuning of Hydrogel Stiffness. AB - The mechanical properties of the extracellular matrix (ECM) can dictate cell fate in biological systems. In tissue engineering, varying the stiffness of hydrogels water-swollen polymeric networks that act as ECM substrates-has previously been demonstrated to control cell migration, proliferation, and differentiation. Here, "digital plasmonic patterning" (DPP) is developed to mechanically alter a hydrogel encapsulated with gold nanorods using a near-infrared laser, according to a digital (computer-generated) pattern. DPP can provide orders of magnitude changes in stiffness, and can be tuned by laser intensity and speed of writing. In vitro cellular experiments using A7R5 smooth muscle cells confirm cell migration and alignment according to these patterns, making DPP a useful technique for mechanically patterning hydrogels for various biomedical applications. PMID- 26120295 TI - Temperature-Induced Switchable Adhesion using Nickel-Titanium Polydimethylsiloxane Hybrid Surfaces. AB - A switchable dry adhesive based on a nickel-titanium (NiTi) shape-memory alloy with an adhesive silicone rubber surface has been developed. Although several studies investigate micropatterned, bioinspired adhesive surfaces, very few focus on reversible adhesion. The system here is based on the indentation-induced two way shape-memory effect in NiTi alloys. NiTi is trained by mechanical deformation through indentation and grinding to elicit a temperature-induced switchable topography with protrusions at high temperature and a flat surface at low temperature. The trained surfaces are coated with either a smooth or a patterned adhesive polydimethylsiloxane (PDMS) layer, resulting in a temperature-induced switchable surface, used for dry adhesion. Adhesion tests show that the temperature-induced topographical change of the NiTi influences the adhesive performance of the hybrid system. For samples with a smooth PDMS layer the transition from flat to structured state reduces adhesion by 56%, and for samples with a micropatterned PDMS layer adhesion is switchable by nearly 100%. Both hybrid systems reveal strong reversibility related to the NiTi martensitic phase transformation, allowing repeated switching between an adhesive and a nonadhesive state. These effects have been discussed in terms of reversible changes in contact area and varying tilt angles of the pillars with respect to the substrate surface. PMID- 26120294 TI - Regulation of the Stem Cell-Host Immune System Interplay Using Hydrogel Coencapsulation System with an Anti-Inflammatory Drug. AB - The host immune system is known to influence mesenchymal stem cell (MSC)-mediated bone tissue regeneration. However, the therapeutic capacity of hydrogel biomaterial to modulate the interplay between MSCs and T-lymphocytes is unknown. Here it is shown that encapsulating hydrogel affects this interplay when used to encapsulate MSCs for implantation by hindering the penetration of pro inflammatory cells and/or cytokines, leading to improved viability of the encapsulated MSCs. This combats the effects of the host pro-inflammatory T lymphocyte-induced nuclear factor kappaB pathway, which can reduce MSC viability through the CASPASE-3 and CAS-PASE-8 associated proapoptotic cascade, resulting in the apoptosis of MSCs. To corroborate rescue of engrafted MSCs from the insult of the host immune system, the incorporation of the anti-inflammatory drug indomethacin into the encapsulating alginate hydrogel further regulates the local microenvironment and prevents pro-inflammatory cytokine-induced apoptosis. These findings suggest that the encapsulating hydrogel can regulate the MSC-host immune cell interplay and direct the fate of the implanted MSCs, leading to enhanced tissue regeneration. PMID- 26120296 TI - Potential harmful health effects of inhaling nicotine-free shisha-pen vapor: a chemical risk assessment of the main components propylene glycol and glycerol. AB - BACKGROUND: A shisha-pen is an electronic cigarette variant that is advertised to mimic the taste of a water pipe, or shisha. The aim of this study was to assess the potential harmful health effects caused by inhaling the vapor of a nicotine free shisha-pen. METHODS: Gas chromatography analysis was performed to determine the major components in shisha-pen vapor. Risk assessment was performed using puff volumes of e-cigarettes and "normal" cigarettes and a 1-puff scenario (one time exposure). The concentrations that reached the airways and lungs after using a shisha-pen were calculated and compared to data from published toxicity studies. RESULTS: The main components in shisha-pen vapor are propylene glycol and glycerol (54%/46%). One puff (50 to 70 mL) results in exposure of propylene glycol and glycerol of 430 to 603 mg/m(3) and 348 to 495 mg/m(3), respectively. These exposure concentrations were higher than the points of departure for airway irritation based on a human study (propylene glycol, mean concentration of 309 mg/m(3)) and a rat study (glycerol, no-observed adverse effect level of 165 mg/m(3)). CONCLUSIONS: Already after one puff of the shisha-pen, the concentrations of propylene glycol and glycerol are sufficiently high to potentially cause irritation of the airways. New products such as the shisha-pen should be detected and risks should be assessed to inform regulatory actions aimed at limiting potential harm that may be caused to consumers and protecting young people to take up smoking. PMID- 26120280 TI - Search for patterns by combining cosmic-ray energy and arrival directions at the Pierre Auger Observatory. AB - Energy-dependent patterns in the arrival directions of cosmic rays are searched for using data of the Pierre Auger Observatory. We investigate local regions around the highest-energy cosmic rays with [Formula: see text] eV by analyzing cosmic rays with energies above [Formula: see text] eV arriving within an angular separation of approximately 15[Formula: see text]. We characterize the energy distributions inside these regions by two independent methods, one searching for angular dependence of energy-energy correlations and one searching for collimation of energy along the local system of principal axes of the energy distribution. No significant patterns are found with this analysis. The comparison of these measurements with astrophysical scenarios can therefore be used to obtain constraints on related model parameters such as strength of cosmic ray deflection and density of point sources. PMID- 26120297 TI - Prone Position Is Useful in Thoracoscopic Enucleation of Esophageal Leiomyoma. AB - A 36-year-old man was admitted to our institute due to the diagnosis of esophageal submucosal tumor detected by a periodical upper gastrointestinal endoscopic examination without any complaint. Thoracoscopic enucleation of the lesion with the preoperative clinical diagnosis of esophageal leiomyoma was performed under general anesthesia in the prone position. After immunohistochemical examination, the pathological diagnosis was leiomyoma. There was no remarkable event during the postoperative hospital stay, and the patient was discharged on the 12th day after surgery. This case report suggests that the prone position might be superior to the left lateral decubitus position in thoracoscopic enucleation of esophageal leiomyoma. PMID- 26120298 TI - Iatrogenic Colonic Perforation due to Computed Tomographic Colonography. AB - Although the complications of computed tomographic colonography (CTC) are very rare, CTC is associated with potential risk of colonic perforation. In the present report we describe two cases of colonic perforation secondary to CTC. In the first case with ascending colonic carcinoma, insertion of a rigid double balloon catheter caused direct rectal wall perforation. In the second case with obstructive colonic carcinoma, pneumoperitoneum developed due to automated carbon dioxide insufflation. Both patients were asymptomatic after examination and recovered without any complications. Based on the findings of the current cases, we recommend that a soft-tip catheter be used for CTC, and suggest that colonic perforation can occur even with automatic insufflation, depending on patient characteristics. PMID- 26120299 TI - Helicobacter suis-Infected Nodular Gastritis and a Review of Diagnostic Sensitivity for Helicobacter heilmannii-Like Organisms. AB - Helicobacter heilmannii-like organisms (HHLOs) are associated with mucosa associated lymphoid tissue lymphoma and peptic ulcer. However, the sensitivity of diagnostic tests for HHLOs, such as rapid urease test (RUT), urea breath test (UBT) and blood antibody, is not high. Tightly coiled spiral microorganisms were found in the gastric mucosal biopsy specimen of a 48-year-old asymptomatic woman. Her findings were positive for RUT and UBT, but negative for blood antibody and stool antigen against H. pylori. A 7-day course of esomeprazole, amoxicillin and clarithromycin was administered, resulting in the successful eradication of the HHLOs. Analysis of the 16S rRNA and urease genes suggested a diagnosis of the HHLO H. suis. The sensitivity results of RUT, UBT, culture, blood antibody, immunohistochemistry and stool antigen were 40.0, 14.8, 0, 23.1, 40.0 and 0%, respectively. We report asymptomatic nodular gastritis due to an HHLO. Histological techniques, most likely with smears, are expected to be the most effective method for diagnosing infections by HHLOs, and genetic diagnosis by polymerase chain reaction can be very useful to identify the species of HHLOs. PMID- 26120300 TI - A Case of Intestinal Mastocytosis Misdiagnosed as Crohn's Disease. AB - Systemic mastocytosis (SM) is a rare, heterogeneous and progressive disease, characterized by the accumulation of atypical mast cells in various organs, including the gastrointestinal tract. Gastrointestinal symptoms are present in up to 80% of patients with SM, the most common being abdominal pain, diarrhea, nausea and vomiting. Up to 50% of patients with SM do not have classical skin lesions at presentation, and in these patients the diagnosis of SM can be difficult for years. Here we report a case of SM that initially mimicked inflammatory bowel disease, although the patient showed poor response to steroid therapy. The right diagnosis was made only on the surgical specimen obtained after emergency surgery for intestinal obstruction. SM should therefore be considered in the diagnostic approach in patients with gastrointestinal symptoms not attributable to other pathologies and in cases of suspected inflammatory bowel disease with unusual course. PMID- 26120301 TI - Wilkie's Syndrome or Superior Mesenteric Artery Syndrome: Fact or Fantasy? AB - Superior mesenteric artery (SMA) syndrome (known as Wilkie's syndrome) is a rare cause of upper gastrointestinal obstruction. It is an acquired disorder in which acute angulation of the SMA causes compression of the third part of the duodenum between the SMA and the aorta. This is commonly due to loss of fatty tissue as a result of a variety of debilitating conditions. We report a 17-year-old female who presented with intermittent abdominal pain and intractable vomiting following significant weight loss after hospitalization for pneumonia. Symptoms persisted for 2 years and the patient underwent extensive invasive and non-invasive tests, but to no avail. Thereafter she developed acute high intestinal obstruction, which unraveled her diagnosis. This case emphasizes the challenges in the diagnosis of SMA syndrome and the need for increased awareness of this entity. This will improve early recognition in order to reduce irrelevant tests and unnecessary treatments. PMID- 26120302 TI - Rare Neurological Manifestation of Celiac Disease. AB - Celiac disease (CD) is an immune-mediated disease characterized by permanent gastrointestinal tract sensitivity to gluten in genetically predisposed individuals. It has varied clinical manifestations, ranging from gastrointestinal to extraintestinal, including neurological, skin, reproductive and psychiatric symptoms, which makes its diagnosis difficult and challenging. Known neurological manifestations of CD include epilepsy with or without occipital calcification, attention deficit hyperactivity disorder and ataxia, headache, neuropathies and behavior disorders. We present the case of a 14-year-old female with headaches and blurred vision for 1 year; she was noted to have papilledema on ophthalmic examination with increased cerebrospinal fluid opening pressure on lumber puncture and was diagnosed as a case of pseudotumor cerebri (PTC). Meanwhile her workup for chronic constipation revealed elevated tissue transglutaminase IgA and antiendomysial IgA antibodies. Upper gastrointestinal endoscopy with duodenal biopsy confirmed the diagnosis of CD. The patient was started on a gluten-free diet, leading to resolution of not only gastrointestinal symptoms but also to almost complete resolution of symptoms of PTC. This report describes the correlation of CD and PTC as its neurological manifestation. PMID- 26120303 TI - Impact of Endoscopic Ultrasound Procedures in Various Pancreatobiliary Disorders in Indonesia Based on a Case Series in a Private Hospital. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a common technique for assessing the pancreas and the biliary system; however, the potential complications have raised concern among endoscopists and patients. Recently, the need of endoscopic ultrasound (EUS) as an additional tool of assessment before the ERCP procedure has been increasing. The need of EUS in developing countries is still a matter of debate regarding the cost, investment, and training. Here, we report the significant impact of EUS on several unselected interesting cases of pancreatobiliary disorders. METHOD: We selected several interesting cases from the patients who underwent EUS at our private hospital in Jakarta, Indonesia. The EUS procedures were performed by one experienced endosonographer and one EUS trainee who are very experienced with transabdominal ultrasound. The equipment was an Olympus JF UCT 180 EUS scope which was connected to an Aloka IPF-1701C ultrasound machine (Tokyo, Japan). RESULTS: Five interesting cases were included from patients who underwent EUS due to pancreatobiliary disorders. The cases included recurrent pancreatitis due to pancreatic stone at the small branch that obstructed the main pancreatic duct, common bile duct (CBD) stone with insignificant duct dilatation, pancreatic head cancer with total obstruction at the distal CBD and portal vein infiltration, pancreas divisum in a young girl, and distal CBD mass that caused obstructive jaundice. CONCLUSIONS: The EUS procedure has shown a significant impact in managing patients with pancreatobiliary diseases. In most developing countries, EUS needs to be evaluated further regarding the cost, investment, and training. PMID- 26120304 TI - Diffuse Dermal Angiomatosis: A Clue to the Diagnosis of Atherosclerotic Vascular Disease. AB - Diffuse dermal angiomatosis (DDA) is a benign, acquired, reactive vascular proliferation. DDA is clinically characterized by painful purpuric plaque with central ulceration. The histopathologic hallmark is diffuse proliferation of endothelial cells that are arranged interstitially between collagen bundles of the reticular dermis. DDA has been reported in association with peripheral atherosclerotic disease, arteriovenous fistula and heavy smoking. We report the case of a 49-year-old Asian male with DDA who presented with a painful stellate shaped purpuric patch on the right thigh. Histopathologic examination showed proliferation of CD34-positive spindle cells in the dermis. Our patient underwent vascular bypass surgery along with tight control of cardiovascular risk factors, which yielded successful results. PMID- 26120305 TI - Blastomycosis and Pregnancy: An Unusual Postpartum Disease Course. AB - Blastomyces dermatitidis is responsible for systemic mycoses. It is predominantly caused by inhalation of spores and often manifests as pneumonia, which can potentially disseminate; however, direct cutaneous inoculation may also occur. Blastomycosis in the perigravid period is exceedingly rare. The partial immunosuppressive state induced by pregnancy can engender more severe infections and is associated with a risk of vertical transmission. Published cases describe postpartum symptomatic improvement accompanying immune reconstitution, even in the absence of treatment. We present a 31-year-old gravid female with multifocal cutaneous blastomycosis. After delivering a healthy full-term infant with no evidence of congenital infection, the patient's cutaneous lesions continued to worsen. At 6 weeks postpartum she was treated with oral itraconazole and demonstrated clinical improvement after 5 months of therapy. This case highlights the importance of prompt disease recognition, understanding of risk factors and initiation of appropriate antifungal therapy of blastomycotic infection occurring in the unique setting of pregnancy. PMID- 26120306 TI - Angiolymphoid Hyperplasia with Eosinophilia: A Case Report. AB - Angiolymphoid hyperplasia with eosinophilia is a rare disease considered as being a vascular malformation resulting from a subjacent arteriovenous shunt. It affects mostly the head of women between 20 and 40 years old and may present spontaneous involution. PMID- 26120307 TI - Wells' Syndrome Mimicking Facial Cellulitis: A Report of Two Cases. AB - Wells' syndrome (WS), or eosinophilic cellulitis, is an uncommon inflammatory dermatosis of unknown etiology that typically presents with pruritic cellulitis like plaques on the extremities. Therefore, WS is often misdiagnosed as bacterial cellulitis due to its similarity in presentation. Here, we report two cases of WS that masqueraded as bacterial facial cellulitis. Under treatment with oral prednisone and/or a combination therapy with levocetirizine and hydroxyzine, both patients showed a dramatic improvement of the skin lesions. These cases highlight the need for clinicians to consider WS in the differential diagnosis when evaluating a patient with facial cellulitis that does not respond to an initial antimicrobial regimen. In addition, our cases suggest that combination therapy with levocetirizine and hydroxyzine may be successfully used as corticosteroid sparing treatment or to prevent relapse after the discontinuation of corticosteroid treatment. PMID- 26120308 TI - Fatal Diaphragmatic Hernia following Radiofrequency Ablation for Hepatocellular Carcinoma: A Case Report and Literature Review. AB - An 81-year-old man was admitted to our hospital because of right quadrant abdominal pain. On admission, his liver function was Child-Pugh grade C (10 points). Computed tomography (CT) revealed a diaphragmatic herniation of bowel loops into the right thoracic cavity, accompanied by pleural effusion. Although diaphragmatic hernia was successfully repaired by emergency surgery, he died of liver failure 23 days after the surgery. A retrospective reading of CT images revealed the presence of diaphragmatic injury after radiofrequency ablation (RFA) which had been conducted 33 months before the development of diaphragmatic hernia. Of importance, the lesion of the diaphragmatic injury was located on the estimated needle track of RFA for hepatocellular carcinomas in segment 5 and segment 5/8, but not adjacent to their ablation areas. Subsequently, diaphragmatic perforation had been observed 24 months before admission. This suggests that diaphragmatic hernia caused by RFA is not necessarily due to thermal damage of ablation and is possibly life-threatening, at least in some patients with an impaired liver function. PMID- 26120309 TI - Primary Peritoneal Carcinoma Initially Presenting as Atypical Cervical Lymphadenopathy. AB - Primary peritoneal carcinoma (PPC) is a rare cancer arising from the extraovarian peritoneum and is of mullerian origin. PPC and epithelial ovarian carcinoma share similar clinical, histopathological, and immunohistochemical features. Clinical symptoms and findings include abdominal distension and ascites. We experienced 2 cases of PPC which initially presented with cervical lymphadenopathy. Here, we report the 2 cases and review the literature. PMID- 26120310 TI - Primary Adenoid Cystic Carcinoma of the Skin with Multiple Local Recurrences. AB - Primary adenoid cystic carcinoma (PACC) of the skin is a rare tumor with fewer than 70 cases studied in detail in the English literature. This type of tumor shows a prolonged course and a growth pattern usually manifested by multiple local recurrences and has a low potential for distant metastases. The most important modality for primary treatment is surgical resection followed by radiotherapy. We report a woman aged 43 years at the time of diagnosis, who presented with a slow-growing nodule in the right axilla without lymph node enlargement. A wide local excision was performed, and the histology revealed an adenoid cystic carcinoma. During the next 24 years, another four local recurrences were excised (the last one in 2015) and confirmed histologically to be adenoid cystic carcinoma. The patient was given 44 Gy of radiotherapy after the second surgery in 1996. PACC of the skin is a rare tumor with insufficient data concerning the efficacy of the surgical technique and chemotherapy and radiotherapy treatment, even more so in the case of multiple recurrences. After the last recurrence, the patient was offered an active follow-up based on the long tumor-free intervals in the past and because the site of the primary tumor allowed further surgical excisions in future recurrences. PMID- 26120311 TI - Metastatic Breast Cancer with Extensive Osseous Metastasis Presenting with Symptomatic Immune Thrombocytopenic Purpura and Anemia: A Case Report and Review of the Literature. AB - BACKGROUND: Immune thrombocytopenic purpura (ITP) is a rare acquired bleeding disorder with an estimated incidence of 1 in 10,000 people in the general population. The association of ITP with breast cancer is an even rarer entity with very limited reports in the English literature. CASE PRESENTATION: We report a case of a 51-year-old female with no significant past medical history who presented with sudden onset of malaise, syncope, gingival bleed and epistaxis. She was found to have severe thrombocytopenia (platelet count 6,000/MUl) and anemia (hemoglobin 7.2 g/dl). Her workup led to the diagnosis of metastatic ductal breast cancer with extensive bone metastasis. Bone marrow biopsy demonstrated myelophthisis which was initially thought to be consistent with her presentation of thrombocytopenia and anemia. Therefore, the patient was started on hormonal therapy for the treatment of her metastatic breast cancer. After 3 months of therapy, she did not improve and developed severe mucosal bleeding. Her clinical presentation was suspicious for ITP and immune-mediated anemia, and hence she was started on steroids and intravenous immunoglobulin. The patient had a dramatic response to therapy with normalization of her platelet count and hemoglobin within 2 weeks. CONCLUSION: To our knowledge, this is the first reported case of metastatic breast cancer presenting with symptomatic ITP and anemia, and both symptoms are postulated to be immune-mediated. PMID- 26120312 TI - Septic Cerebral Embolisation in Fulminant Mitral Valve Infective Endocarditis. AB - A 37-year-old male with known intravenous drug use was admitted with an acute onset of worsening confusion and speech impairment. His vitals and biochemical profile demonstrated severe sepsis, with a brain CT showing several lesions suspicious for cerebral emboli. He then went on to have a bedside transthoracic echocardiogram that was positive for vegetation on the mitral valve, with associated severe mitral regurgitation. Unfortunately, before he was stable enough to be transferred for valve surgery, he suffered an episode of acute pulmonary oedema requiring intubation and ventilation on intensive care unit. PMID- 26120313 TI - Case of Small Vessel Disease Associated with COL4A1 Mutations following Trauma. AB - With this case report, we would like to heighten the awareness of clinicians about COL4A1 as a single-gene disorder causing cerebral small vessel disease and describe a previously unreported pathogenic missense substitution in COL4A1 (p.Gly990Val) and a new clinical presentation. We identified a heterozygous putatively pathogenic mutation of COL4A1 in a 50-year-old female with a history of congenital cataracts and glaucoma who presented with multiple diffusion positive infarcts and areas of contrast enhancement following mild head trauma. We believe that this presentation of multiple areas of acute brain and vascular injury in the setting of mild head trauma is a new manifestation of this genetic disorder. Imaging findings of multiple acute infarcts and regions of contrast enhancement with associated asymptomatic old deep microhemorrhages and leukomalacia in adults after head trauma should raise a high suspicion for a COL4A1 genetic disorder. Radiographic patterns of significant leukoaraiosis and deep microhemorrhages can also be seen in patients with long-standing vasculopathy associated with hypertension, which our patient lacked. Our findings demonstrate the utility of genetic screening for COL4A1 mutations in young patients who have small vessel vasculopathy on brain imaging but who do not have significant cardiovascular risk factors. PMID- 26120314 TI - Anterior Chamber Iris Claw Lens for the Treatment of Aphakia in a Patient with Megalocornea. AB - Megalocornea in isolation is a rare congenital enlargement of the cornea greater than 13 mm in diameter. Patients with megalocornea are prone to cataract formation, crystalline lens subluxation, zonular deficiencies and dislocation of the posterior chamber intraocular lens (PCIOL) within the capsular bag. A 55-year old male with megalocornea in isolation developed subluxation of the capsular bag and PCIOL. The PCIOL and capsular bag were explanted, and the patient was subsequently implanted with an anterior chamber iris claw lens. An anterior chamber iris claw lens is an effective option for the correction of aphakia in patients with megalocornea. PMID- 26120315 TI - Foveal Exudative Macroaneurysm Treated with Intravitreal Ranibizumab. AB - PURPOSE: We report a case of a foveal macroaneurysm with long-standing macular edema in a rare location, successfully treated with intravitreal ranibizumab. METHODS: We report the case of a 52-year-old man with left eye long-term visual loss due to macular edema caused by a retinal macroaneurysm, localized about 400 MUm from the center of the fovea, and its response to 6 monthly ranibizumab intravitreal injections. His best-corrected visual acuity and morphological data evaluated by optical coherence tomography and fluorescein angiography are presented. RESULTS: His best-corrected visual acuity improved from 1/10 to 3/10 after the 3rd injection, and from 1/10 to 4/10 after the 6th one. The central retinal thickness was evaluated by optical coherence tomography and improved from 310 to 233 MUm, with the resolution of both the associated serous detachments and the cystoid macular edema; an almost complete reabsorption of the hard exudates at the end of the treatment was also observed. The macroaneurysm lumen almost obliterated after the 3rd injection and completely collapsed at the end of treatment. CONCLUSIONS: Intravitreal ranibizumab may be effective in the treatment of long-standing macular edema associated with foveal macroaneurysms. To the best of our knowledge, this is the first report of a retinal macroaneurysm located so close to the foveal avascular zone. PMID- 26120316 TI - Free-Floating Iris Cyst in a Patient with Recurrent Iritis. AB - PURPOSE: We describe an unusual clinical finding of a free-floating iris cyst in a patient with recurrent iritis. METHOD: The clinical finding of a free-floating iris cyst was recorded using slit-lamp photography. RESULTS: A 39-year-old male with a 5-year history of recurrent right iritis was found to have a small mobile iris cyst within his right anterior chamber, first identified 3 years ago. The patient did not experience any discomfort or visual symptoms resulting from the cyst. CONCLUSION: Surgical removal is not indicated for asymptomatic non progressive free-floating iris cysts. The significance of a free-floating iris cyst in the setting of recurrent iritis remains unknown. PMID- 26120317 TI - Sarcomatous Carcinoma of the Orbit: A Case Report and Review of the Literature. AB - Sarcomatous carcinomas (SCs) are rare tumours that contain malignant cells with epithelial and mesenchymal characteristics. SC rarely presents in the head and neck, and occurs even less often in the orbit. Only 8 cases of SCs located in the orbit or affecting the globe function have been described in the English literature. Here, we report a case of SC affecting the right orbit. SC is associated with a poor prognosis and advanced disease at presentation. Diagnosis is difficult, as histology often fails to definitively identify SC, necessitating a wide panel of molecular/immunological markers. Treatment options are generally aggressive but risky, and frequently yield poor results. Due to the rarity of SC, there has been little focus on the development of improved treatment options. PMID- 26120318 TI - Unusual Fundus Autofluorescence Appearance in a Patient with Hydroxychloroquine Retinal Toxicity. AB - PURPOSE: To report an unusual fundus autofluorescence aspect in a patient with suspected hydroxychloroquine retinal toxicity. METHOD: Case report of an unusual presentation of a patient treated for 9 consecutive years with a therapeutically recommended dose of hydroxychloroquine. RESULT: We report the case of a 53-year old Caucasian female treated with 400 mg hydroxychloroquine for rheumatoid arthritis over 9 years, currently on methotrexate and folinic acid, who stopped treatment 3 years ago. The cumulative dose is estimated at 1.314 kg. She recently noticed a reduction of vision in both eyes to 0.34 logMAR, with colour vision problems and major distortion in central vision. Fundus autofluorescence revealed minimal foveal pigmentary changes and more pronounced changes in the retina elsewhere. Foveal changes were confirmed by optical coherence tomography in both eyes. The patient did not report any colour perception difficulties or night vision problems and has no family history of any eye condition. Her visual field tested by an optician was full, with some central changes. CONCLUSION: Retinal toxicity from hydroxychloroquine can present in a different aspect than the commonly known retinal toxicity, and it happens even after years of cessation of the drug. The role of cumulative dose in toxicity is supported in this paper. PMID- 26120319 TI - Cerebral Microbleeds and White Matter Hyperintensities in Cognitively Healthy Elderly: A Cross-Sectional Cohort Study Evaluating the Effect of Arterial Stiffness. AB - BACKGROUND: Arterial stiffness reflects the ageing processes in the vascular system, and studies have shown an association between reduced cognitive function and cerebral small vessel disease. Small vessel disease can be visualized as white matter hyperintensities (WMH) and lacunar infarcts but also as cerebral microbleeds on brain magnetic resonance imaging (MRI). We aimed to investigate if arterial stiffness influences the presence of microbleeds, WMH and cognitive function in a population of cognitively healthy elderly. METHODS: The study population is part of the Swedish BioFinder study and consisted of 208 individuals without any symptoms of cognitive impairment, who scored >27 points on the Mini-Mental State Examination. The participants (mean age, 72 years; 59% women) underwent MRI of the brain with visual rating of microbleeds and WMH. Arterial stiffness was measured with carotid-femoral pulse wave velocity (cfPWV). Eight cognitive tests covering different cognitive domains were performed. RESULTS: Microbleeds were detected in 12% and WMH in 31% of the participants. Mean (+/-standard deviation, SD) cfPWV was 10.0 (+/-2.0) m/s. There was no association between the presence of microbleeds and arterial stiffness. There was a positive association between arterial stiffness and WMH independent of age or sex (odds ratio, 1.58; 95% confidence interval, 1.04-2.40, p < 0.05), but the effect was attenuated when further adjustments for several cardiovascular risk factors were performed (p > 0.05). Cognitive performance was not associated with microbleeds, but individuals with WMH performed slightly worse than those without WMH on the Symbol Digit Modalities Test (mean +/- SD, 35 +/- 7.8 vs. 39 +/- 8.1, p < 0.05). Linear regression revealed no direct associations between arterial stiffness and the results of the cognitive tests. CONCLUSIONS: Arterial stiffness was not associated with the presence of cerebral microbleeds or cognitive function in cognitively healthy elderly. However, arterial stiffness was related to the presence of WMH, but the association was attenuated when multiple adjustments were made. There was a weak negative association between WMH and performance in one specific test of attention. Longitudinal follow-up studies are needed to further assess the associations. PMID- 26120320 TI - Another Rare Unstable Hemoglobinopathy: Hemoglobin Casper/Southampton Associated with Moyamoya Disease. PMID- 26120321 TI - Accidental Thrombolysis in a Stroke Patient Receiving Apixaban. PMID- 26120322 TI - Plasma Catecholamine Profile of Subarachnoid Hemorrhage Patients with Neurogenic Cardiomyopathy. AB - PURPOSE: To investigate the connection between sympathetic function and neurogenic cardiomyopathy (NC), and to determine whether NC is mediated primarily by circulating adrenal epinephrine (EPI) or neuronally transmitted norepinephrine (NE), following subarachnoid hemorrhage (SAH). METHODS: This is a prospective observational investigation of consecutive severe-grade SAH patients. All participants had transthoracic echocardiography and serological assays for catecholamine levels - dopamine (DA), NE and EPI - within 48 h of hemorrhage onset. Clinical and serological independent predictors of NC were determined using multivariate logistic regression analyses, and the accuracy of predictors was assessed by receiver operating characteristic (ROC) curves. Multivariate linear regression analyses were used to evaluate correlations among the catecholamines. RESULTS: The investigation included a total of 94 subjects: the mean age was 55 years, 81% were female and 57% were Caucasian. NC was identified in approximately 10% (9/94) of cases. Univariate analyses revealed associations between NC and worse clinical severity (p = 0.019), plasma DA (p = 0.018) and NE levels (p = 0.024). Plasma NE correlated with DA levels (rho = 0.206, p = 0.046) and EPI levels (rho = 0.392, p < 0.001), but was predicted only by plasma EPI in bivariate [parameter estimate (PE) = 1.95, p < 0.001] and multivariate (PE = 1.89, p < 0.001) linear regression models. Multivariate logistic regression analyses consistently demonstrated the predictive value of clinical grade for NC (p < 0.05 for all analyses) except in models incorporating plasma NE, where NC was independently predicted by NE level (OR 1.25, 95% CI 1.01-1.55) over clinical grade (OR 4.19, 95% CI 0.874-20.1). ROC curves similarly revealed the greater accuracy of plasma NE [area under the curve (AUC) 0.727, 95% CI 0.56-0.90, p = 0.02] over clinical grade (AUC 0.704, 95% CI 0.55-0.86, p = 0.05) for identifying the presence or absence of NC. CONCLUSIONS: Following SAH, the development of NC is primarily related to elevated plasma NE levels. Findings implicate a predominantly neurogenic process mediated by neuronal NE (and not adrenal EPI), but cannot exclude synergy between the catecholamines. PMID- 26120324 TI - Measurement of Soluble and Total Hexavalent Chromium in the Ambient Airborne Particles in New Jersey. AB - Hexavalent chromium (Cr(VI)) in ambient airborne particulate matter (PM) is a known pulmonary carcinogen and may have both soluble and insoluble forms. The sum of the two forms is defined as total Cr(VI). Currently, there were no methods suitable for large-scale monitoring of total Cr(VI) in ambient PM. This study developed a method to measure total Cr(VI) in ambient PM. This method includes PM collection using a Teflon filter, microwave extraction with 3% Na2CO3-2% NaOH at 95 degrees C for 60 minutes, and Cr(VI) analysis by 1,5-diphenylcarbazide colorimetry at 540 nm. The recoveries of total Cr(VI) were 119.5 +/- 10.4% and 106.3 +/- 16.7% for the Cr(VI)-certified reference materials, SQC 012 and SRM 2700, respectively. Total Cr(VI) in the reference urban PM (NIST 1648a) was 26.0 +/- 3.1 mg/kg (%CV = 11.9%) determined by this method. The method detection limit was 0.33 ng/m3. This method and the one previously developed to measure ambient Cr(VI), which is soluble in pH ~9.0 aqueous solution, were applied to measure Cr(VI) in ambient PM10 collected from three urban areas and one suburban area in New Jersey. The total Cr(VI) concentrations were 1.05-1.41 ng/m3 in the winter and 0.99-1.56 ng/m3 in the summer. The soluble Cr(VI) concentrations were 0.03 0.19 ng/m3 in the winter and 0.12-0.37 ng/m3 in the summer. The summer mean ratios of soluble to total Cr(VI) were 14.3-43.7%, significantly higher than 4.2 14.4% in the winter. The winter concentrations of soluble and total Cr(VI) in the suburban area were significantly lower than in the three urban areas. The results suggested that formation of Cr(VI) via atmospheric chemistry may contribute to the higher soluble Cr(VI) concentrations in the summer. PMID- 26120323 TI - Endothelial Repair in Childhood Arterial Ischaemic Stroke with Cerebral Arteriopathy. AB - BACKGROUND: We have previously shown that recurrent arterial ischaemic stroke (AIS) in children with cerebral arteriopathy is associated with increased circulating endothelial cells and endothelial microparticles, consistent with ongoing endothelial injury. To date, however, little is known about endothelial repair responses in childhood AIS. We examined the relationship between the number and function of circulating endothelial progenitor cells (EPC), the levels of brain-derived neurotrophic factor (BDNF) and AIS recurrence. METHODS: Flow cytometry was used to identify peripheral blood mononuclear cells positive for CD34/kinase insert domain-containing receptor (KDR). In a subgroup of patients (5 in each group selected at random), monocytic EPC function was assessed by colony forming unit (EPC-CFU) capacity and incorporation into endothelial cell networks in Matrigel. BDNF was measured using ELISA. RESULTS: Thirty-five children, aged 12 years (range: 5-16.5; 9 males), with AIS and cerebral arteriopathy were studied; 10 had recurrent AIS. CD34+/KDR+ cells were significantly higher in recurrent AIS compared to non-recurrent AIS patients (p = 0.005) and controls (p = 0.0002). EPC-CFU and EPC incorporation into endothelial cell networks were significantly reduced in recurrent compared to non-recurrent AIS patients (p = 0.04 and p = 0.01, respectively). Levels of BDNF were significantly higher in recurrent compared to non-recurrent AIS patients (p = 0.0008) and controls (p = 0.0002). CONCLUSIONS: Children with recurrent AIS and cerebral arteriopathy had increased circulating CD34+/KDR+ cells and BDNF consistent with an endothelial repair response. However, EPC function was impaired. Future studies are needed to examine whether suboptimal endothelial repair contributes to childhood AIS recurrence. PMID- 26120325 TI - Two Oral Midazolam Preparations in Pediatric Dental Patients: A Prospective Randomised Clinical Trial. AB - Pharmacological sedation is an alternative behavior management strategy in pediatric dentistry. The aim of this study was to compare the behavioral and physiologic effects of "commercially midazolam syrup" versus "orally administered IV midazolam dosage form (extemporaneous midazolam (EF))" in uncooperative pediatric dental patients. Eighty-eight children between 4 to 7 years of age received 0.2-0.5 mg/kg midazolam in this parallel trial. Physiologic parameters were recorded at baseline and every 15 minutes. Behavior assessment was conducted objectively by Houpt scale throughout the sedation and North Carolina at baseline and during injection and cavity preparation. No significant difference in behavior was noted by Houpt or North Carolina scale. Acceptable behavior (excellent, very good, and good) was observed in 90.9% of syrup and 79.5% of EF subjects, respectively. Physiological parameters remained in normal range without significant difference between groups and no adverse effect was observed. It is concluded that EF midazolam preparation can be used as an acceptable alternative to midazolam syrup. PMID- 26120326 TI - Understanding the Link between Social Organization and Crime in Rural Communities. AB - Rural communities make up much of America's heartland, yet we know little about their social organization, and how elements of their social organization relate to crime rates. The current study sought to remedy this gap by examining the associations between two measures of social organization - collective efficacy and social trust - with a number of structural community characteristics, local crime rates, and perceptions of safety in a sample of 27 rural and small town communities in two states. Measures of collective efficacy, social trust, and perceived safety, were gathered from key community members in 2006; other measures were drawn from the 2000 Census and FBI Uniform Crime Reporting system. A series of competing hypotheses were tested to examine the relative importance of social trust and collective efficacy in predicting local crime rates. Results do not support the full generalization of the social disorganization model. Correlational analyses showed that neither collective efficacy nor social trust had a direct association with community crime, nor did they mediate the associations between community structural characteristics and crime. However, perceived safety mediated the association between community crime and both measures of social organization. Analyses suggest that social trust may be more important than collective efficacy when understanding the effect of crime on a community's culture in rural areas. Understanding these associations in rural settings can aid decision makers in shaping policies to reduce crime and juvenile delinquency. PMID- 26120327 TI - An overview of systematic reviews of normal labor and delivery management. AB - BACKGROUND: Despite the scientific and medical advances for management of complicated health issues, the current maternity care setting has increased risks for healthy women and their babies. The aim of this study was to conduct an overview of published systematic reviews on the interventions used most commonly for management of normal labor and delivery in the first stage of labor. MATERIALS AND METHODS: The online databases through March 2013, limited to systematic reviews of clinical trials were searched. An updated search was performed in April 2014. Two reviewers independently assessed data inclusion, extraction, and quality of methodology. RESULTS: Twenty-three reviews (16 Cochrane, 7 non-Cochrane), relating to the most common care practices for management of normal labor and delivery in the first stage of labor, were included. Evidence does not support routine enemas, routine perineal shaving, continuous electronic fetal heart rate monitoring, routine early amniotomy, and restriction of fluids and food during labor. Evidence supports continuity of midwifery care and support, encouragement to non-supine position, and freedom in movement throughout labor. There is insufficient evidence to support routine administration of intravenous fluids and antispasmodics during labor. More evidence is needed regarding delayed admission until active labor and use of partograph. CONCLUSIONS: Evidence-based maternity care emphasizes on the practices that increase safety for mother and baby. If policymakers and healthcare providers wish to promote obstetric care quality successfully, it is important that they implement evidence-based clinical practices in routine midwifery care. PMID- 26120328 TI - Impacts of insulin infusion protocol on blood glucose level and outcomes in acute coronary syndrome patients with diabetes mellitus. AB - BACKGROUND: Acute coronary syndrome is the most common disease in the world. Several studies suggest that hyperglycemia is associated with poor clinical outcomes in patients with coronary artery disease. The aim of this study was to investigate the impact of insulin infusion protocol and conventional therapy on the blood glucose level and outcomes in acute coronary syndrome patients with diabetes mellitus. MATERIALS AND METHODS: We studied 64 patients (32 in each group) with acute coronary syndrome and acute myocardial infarction, who were admitted to the coronary care unit in a hospital in Isfahan, Iran in 2012. Inclusion criterion was blood sugar (BS) of more than 180 mg/dl on admission. Patients in the intervention group received insulin with East Jefferson insulin infusion protocol for at least 4 h, and in the control group, the subjects received subcutaneous insulin (conventional therapy) for at least for 48 h. Independent t-test, Student's t-test, and Chi-square test were used to analyze the data. RESULTS: Groups were matched for baseline characteristics. Blood glucose was significantly reduced in the two groups (P < 0.001), and the mean blood glucose level in the interaction group was significantly less than in the control group (P = 0.0002). Hypoglycemia was 31.2% and 25% in the intervention and control groups, respectively. The frequency of hypoglycemia did not differ significantly between the two groups (P = 0.75). Time to reach target insulin level differed between the two groups (4.75 h in the intervention group and 36.93 h in the control group; P < 0.001). CONCLUSIONS: Our research showed that use of insulin infusion protocol is better in maintaining glycemia control compared to subcutaneous sliding scale method. The protocol allows nurses to commence and maintain the infusion more effectively and safely compared to the traditional method. PMID- 26120329 TI - Compilation of the neonatal palliative care clinical guideline in neonatal intensive care unit. AB - BACKGROUND: Clinical guidelines are important instruments for increasing the quality of clinical practice in the treatment team. Compilation of clinical guidelines is important due to special condition of the neonates and the nurses facing critical conditions in the neonatal intensive care unit (NICU). With 98% of neonatal deaths occurring in NICUs in the hospitals, it is important to pay attention to this issue. This study aimed at compilation of the neonatal palliative care clinical guidelines in NICU. MATERIALS AND METHODS: This study was conducted with multistage comparative strategies with localization in Isfahan in 2013. In the first step, the components of the neonatal palliative care clinical guidelines were determined by searching in different databases. In the second stage, the level of expert group's consensus with each component of neonatal palliative care in the nominal group and focus group was investigated, and the clinical guideline was written based on that. In the third stage, the quality and applicability were determined with the positive viewpoints of medical experts, nurses, and members of the science board of five cities in Iran. Data were analyzed by descriptive statistics through SPSS. RESULTS: In the first stage, the draft of neonatal palliative care was designed based on neonates', their parents', and the related staff's requirements. In the second stage, its rank and applicability were determined and after analyzing the responses, with agreement of the focus group, the clinical guideline was written. In the third stage, the means of indication scores obtained were 75%, 69%, 72%, 72%, and 68% by Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. CONCLUSIONS: The compilation of the guideline can play an effective role in provision of neonatal care in nursing. PMID- 26120330 TI - Investigation of the causes of maternal mortality using root cause analysis in Isfahan, Iran in 2013-2014. AB - BACKGROUND: Many maternal deaths caused are due to preventable causes during pregnancy and childbirth. Therefore, the detailed analysis of the root causes provides developing a plan and appropriate interventions to prevent these deaths occurring in the health system. This study aims to determine the causes of maternal mortality using root cause analysis (RCA) method. MATERIALS AND METHODS: This research is a descriptive explorative study. The data were collected from the files in the maternal health center and the interviews conducted with relevant personnel. The causes of maternal mortality and related reasons were determined by experts' team opinions and through a standard checklist of RCA. Causes consisted of the factors related to health services (human factors and structural factors), maternal family and social status, and maternal disease status. For each of these factors, analysis was performed to determine the root. In the end, interventional suggestions were developed to prevent the recurrence of similar deaths. RESULTS: Causes were classified into human factors, and structural factors in the area of planning and management and social status of mothers. The results showed that human factors were composed of lack of knowledge and skills in the medical team, unfamiliarity with their duties, lack of health care-based on protocols, etc. Structural factors included lack of follow-up after discharge and inadequate supervision of inspectors on academic qualified doctors. Maternal social and family status factor included lack of referral the mothers' to the health care center. CONCLUSIONS: Based on the RCA process, the most fundamental factor in creating these deaths was management errors at the level of universities and the Ministry of Health. These errors included inadequate supervision of medical education, failure to identify and introduce the instructions and guidelines related to the care of pregnant mothers by the health workers and experts, and lack of collective strategies to inform the public about the type and model of self-care in health centers. Based on the obtained results, the solutions proposed for elimination of root causes of maternal death are organizing sequential training courses tailored for the staff taking care of pregnant women, sending guidelines related to maternal health care to all private and public institutions, and informing the community to receive health care services by health centers and mass media. PMID- 26120331 TI - Effect of two polyethylene covers in prevention of hypothermia among premature neonates. AB - BACKGROUND: After the umbilical cord is cut, premature neonates face numerous problems including hypothermia. With regard to serious complications of hypothermia and incapability of conventional methods in preservation of neonates' temperature after admission, the researcher decided to conduct a study on the effects of two polyethylene covers in prevention of hypothermia among premature neonates. MATERIALS AND METHODS: This clinical trial was conducted on 96 neonates aged 28-32 weeks that randomly allocated, by drawing of lots, to three 32-subject groups as follows: Intervention group 1 (a plastic bag cover and a cotton hat), intervention group 2 (a plastic bag cover and a plastic hat), and a control group receiving routine care. Data were analyzed by descriptive and inferential statistics through SPSS V.14. RESULTS: Mean axillary temperatures in intervention groups 1 and 2 were different after admission and 1 and 2 h later, but this difference was not significant and the mean axillary temperature increased with time. Mean axillary temperature in the control group showed no significant difference at these time points and it did not increase with time. The mean temperatures in preterm infants were significantly higher in the intervention groups after admission and 1 and 2 h after birth, compared to the control group. Mean axillary temperature in intervention group 2 was significantly higher than in intervention group 1. CONCLUSIONS: Usage of a plastic bag cover and a plastic hat (with no risk of hyperthermia) is more effective in preventing hypothermia among neonates aged 28-32 weeks, compared to usage of a plastic bag cover and a cotton hat. PMID- 26120332 TI - Investigation of eating disorders in cancer patients and its relevance with body image. AB - BACKGROUND: Eating disorder is one of the most common health problems with clinical and psychological consequences, which can affect body image in cancer patients. Similar studies in this area for checking the status of this disorder and its relevance with body image in patients with cancer are limited. Therefore, this study was designed with the aim of determination of eating disorders in patients with cancer and their relevance with body image. MATERIALS AND METHODS: The research was a cross-correlation study. It was carried out in Sayed-Al Shohada Hospital affiliated to the Isfahan University of Medical Sciences in 2013. Two hundred and ten patients with cancer were selected and were asked tocomplete the demographic and disease characteristics questionnaire, the Multidimensional Body-Self Relations Questionnaire (MBSRQ), and eating disorders questionnaire. SPSS statistical software, version 14 was used for statistical analysis'-Test, analysis of variance (ANOVA), and Pearson correlation coefficient were used for analyzing the obtained data. RESULTS: The mean values of age, body mass index (BMI), and duration of illness were 48.2 +/- 13.20 years, 24.6 +/- 4.6kg/m(2), and 25.64 +/- 21.24months, respectively. Most patients were married (87%), without university education (96%), unemployed (67%), and with incomes below their requirement (52%). Most patients were diagnosed with breast cancer (36.5%). They received chemotherapy as the main treatment (56.2%). In addition, mean +/- SD of eating disorders and body image were 12.84 +/- 4.7 and184.40 +/- 43.68, respectively. Also, 49.7% of patients with cancer had an eating disorder. Among these, 29% had experiences of anorexia and 20.7% had bulimia. There was a significant negative correlation between the score of body image and eating disorders (r = -0.47, P = 0.01). CONCLUSIONS: Findings of this study showed that most patients with cancer had experienced symptoms of eating disorders. This may lead to a negative impact on the body image in these patients and may be the cause of further psychological and physical changes in these patients. The findings of this study can assist the healthcare team to pay more attention to eating disorders and body image in patients with cancer and also in considering the relationship of these issues in their evaluations. PMID- 26120333 TI - The relationship between different fatty acids intake and frequency of migraine attacks. AB - BACKGROUND: Migraine is a primary headache disorder that affects the neurovascular system. Recent studies have shown that consumption of some fatty acids such as omega-3 fatty acids improves migraine symptoms. The aim of the present study is to assess the association between usual intake of fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and saturated fatty acids (SFA) with the frequency of migraine attacks. MATERIALS AND METHODS: 105 migraine patients with age ranging from 15 to 50 years participated in this cross-sectional study. Usual dietary consumption was assessed by using a semi quantitative food frequency questionnaire (FFQ). Moreover, frequency of migraine attacks during 1 month period was determined in all participants. Data had been analyzed using independent sample t-test and linear regression test with adjustment of confounding variables. RESULTS: In this study, we found that lower intake of EPA (beta = -335.07, P = 0.006) and DHA (beta = -142.51, P = 0.001) was associated with higher frequency of migraine attacks. In addition, we observed similar relationship either in men or women. No significant association was found between dietary intake of SFA and the frequency of migraine attacks (beta = 0.032, P = 0.85). CONCLUSIONS: Frequency of migraine attacks was negatively associated with dietary intake of omega-3 polyunsaturated fatty acids. No significant relationship was found between SFA intake and migraine frequency. Further studies are required to shed light on our findings. PMID- 26120334 TI - Focusing on psychiatric patients' strengths: A new vision on mental health care in Iran. AB - BACKGROUND: Identifying and using the strengths of patients, in practice, is a new territory. Today, the need to educate nurses and psychiatric patients about positive psychology in practice and the importance of understanding and focusing on strengths is clear. However, little is known about the strengths the psychiatric patients use and experience. Thus, this study has been designed and conducted in order to understand how people with psychiatric disorders demonstrate their strengths. MATERIALS AND METHODS: In the present study, 13 semi structured, qualitative interviews with patients and 2 focus groups with nurses were carried out. In addition, a qualitative content analysis was used to identify significant strengths. RESULTS: Based on the results, the four main strengths consisted of: Finding a meaning in daily living, work as enduring strength, entertaining activities, and positive relationship. Patients also reported that health care providers rarely focused on patients' strengths, and experts confirmed these findings. Our findings indicate that patients' own strengths are a pivotal factor in getting through their illness from their perspective. CONCLUSIONS: Despite the enduring legacy of pessimism regarding psychiatric patients, these people have a repertoire of strengths. Nurses should, therefore, have a greater focus on eliciting and nourishing psychiatric patients' strengths in their care. It is suggested that the theoretical and practical aspects of patients' strengths be incorporated in nursing school curricula. PMID- 26120335 TI - The effect of pelvic floor muscle exercises program on sexual self-efficacy in primiparous women after delivery. AB - BACKGROUND: Selection and acceptance of appropriate sexual behavior and sexual function are made difficult by low sexual self-efficacy in the postpartum period. The general purpose of this research is to define the effects of an 8-week pelvic floor muscle exercise program on sexual self-efficacy in primiparous women after childbirth. MATERIALS AND METHODS: This clinical trial was performed on 79 primiparous women who referred to health care centers, Mashhad, Iran in 2013, 8 weeks after delivery, to receive health care services. They were selected by easy sampling. The samples were randomly assigned to either intervention or control group. The intervention group was trained in Kegel exercises for 8 weeks. Both groups were evaluated at 4 and 8 weeks. Data collection tools included: Demographic information, sexual self-efficacy, and Brink scale. Data were analyzed using repeated measures, Friedman test, t-test, and Mann-Whitney test. RESULTS: The results showed significant increase in pelvic floor muscle strength in the intervention group at 4 and 8 weeks after exercises (P < 0.0001), but no significant difference was observed in the control group (P = 0.368). There was a significant increase in sexual self-efficacy in the intervention (P < 0.0001) and control groups (P = 0.001) at 4 and 8 weeks after the start of the study. Comparison of the two groups showed a significant difference in sexual self efficacy after they performed these exercises (P = 0.001). CONCLUSIONS: The findings showed that 8-week pelvic muscle exercises increase the sexual self efficacy in women after delivery. PMID- 26120336 TI - The effect of an upper respiratory care program on incidence of ventilator associated pneumonia in mechanically ventilated patients hospitalized in intensive care units. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common side effect in patients with an endotracheal tube. This study aimed to evaluate the effect of an upper respiratory care program on the incidence of VAP in mechanically ventilated patients. MATERIALS AND METHODS: In this clinical trial, 62 patients with endotracheal tube were selected and randomly allocated to intervention or control group. In the intervention group, an upper respiratory care program was performed and in the control group, routine care was done. Modified Clinical Pulmonary Infection Questionnaire was completed before, and on the third, fourth, and fifth day after intervention. Data were analyzed by repeated measure analysis of variance (ANOVA), chi-square, and independent t-test through SPSS 13. RESULTS: The results of this study showed that until the fourth day, the incidence of VAP was similar in both intervention and control groups (P > 0.05), but on the fifth day, the incidence of VAP in the intervention group was significantly lower than in the control group (P < 0.05). CONCLUSIONS: The results of this study showed that in patients with an endotracheal tube, an upper respiratory care program may reduce the incidence of VAP. Therefore, in order to prevent VAP, nurses are recommended to perform this upper respiratory care program. PMID- 26120337 TI - Effect of stress inoculation training on the levels of stress, anxiety, and depression in cancer patients. AB - BACKGROUND: Cancer is a broad group (over 270 types) of diseases. This disease, like other chronic diseases, occurs in all ages and ethnic groups, and is considered as a major health problem. Stress is one of the most important psychological factors influencing the occurrence of physical diseases, and can lead to severe anxiety, depression, and negative effects on health. It can also make individuals vulnerable to physical diseases, and in the long term, leads to death. This study was conducted to determine the effect of inoculation training on stress, anxiety, and depression in cancer patients. MATERIALS AND METHODS: This study was conducted in 2013 as a clinical trial with convenient random sampling of patients from the chemotherapy clinic of Seyed Al-Shohada hospital of Isfahan. Forty patients with cancer who were eligible for the study were randomly assigned to either case or control group. The case and control groups had the same treatment plans, and the only difference was stress inoculation training administered in the case group, which was composed of eight 90-min sessions over 8 weeks. Data were collected using Depression, Anxiety, Stress Scales 42 (DASS 42) questionnaire and demographic questionnaire, and analyzed by analysis of covariance (ANCOVA) and t-test in SPSS. RESULTS: The results showed that there was a significant difference between case and control groups in terms of stress, anxiety, and depression (P < 0.001). Stress inoculation training reduced stress, anxiety, and depression in cancer patients. CONCLUSIONS: Stress inoculation training significantly reduced stress, anxiety, and depression. Therefore, teaching this skill and the strategies of coping with stress is recommended for these patients, in addition to medicational treatment. PMID- 26120338 TI - The effects of sesame oil on the prevention of amiodarone-induced phlebitis. AB - BACKGROUND: Phlebitis is the most common complication associated with peripheral intravenous infusion of amiodarone. The purpose of this study is to determine the effects of sesame oil on the prevention of amiodarone-induced phlebitis. MATERIALS AND METHODS: This is a double-blind randomized controlled trial. Thirty six patients hospitalized in a coronary care unit were randomly allocated into two groups using a convenience sampling method. Following peripheral intravenous cannulation, five drops of pure sesame oil were applied to the skin within a 10 cm radius of the infusion site prior to the administration of amiodarone in the intervention group. Sesame oil was rubbed on the skin at the infusion site every 6 h in the 24-h period of amiodarone infusion. In the control group, liquid paraffin, used as a placebo, was rubbed on the skin at the infusion site of amiodarone. Both groups were monitored for the development of phlebitis and its degree within the 24-h period of amiodarone infusion as well as 6 h after its administration. The incidence of phlebitis was confirmed and recorded by an assessor who was blind to the two groups. Data were analyzed using Statistical Package for Social Science (SPSS) version 18, and descriptive and inferential statistics such as Chi-square test, Kaplan-Meier, Hazard ratio, independent t test, and Fisher's exact test. RESULTS: There was a statistically significant difference between the two groups in their catheter survival after 30 h and 10 min (P < 0.001). Over 60% of the patients (61.1%) in the intervention group did not show any sign of phlebitis, while 16.7% and 22.2% of the patients manifested signs of grade 2 and 3 phlebitis, respectively. In the control group, 22.2% of the patients showed no signs of phlebitis, while 5.6%, 27.8%, and 44.4% of the patients exhibited signs of grade 2, 3, and 4 phlebitis, respectively. The statistical analysis showed significant differences in the degree of phlebitis (P = 0.006) and the onset of phlebitis development (P < 0.001) between the two groups. CONCLUSIONS: It is recommended to apply sesame oil topically to the infusion site of amiodarone so as to reduce the rate of the development of amiodarone-related phlebitis. PMID- 26120339 TI - The relationship between family functioning and self-esteem in female high school students of Isfahan, Iran, in 2013-2014. AB - BACKGROUND: One of the most critical periods of the life of a person is adolescence. During this period, individuals face many problems such as low self esteem. Self-esteem can be influenced by many factors such as school, friends, and inner personality, but it seems that the family has a crucial role in shaping self-esteem. Therefore, the present study aimed to determine the relationship between family functioning and self-esteem in female high school students in Isfahan, Iran. MATERIALS AND METHODS: This descriptive correlational study was performed with multi-stage random sampling method on 237 female high school students who met the inclusion criteria of the study. The data collection tools included Bloom's Family Functioning Scale and Pop's self-esteem questionnaire. The data obtained from the questionnaires were analyzed through SPSS software. RESULTS: The results showed that the majority of the samples examined had moderate level self-esteem (48.5%) and family function (56.5%). There was a significant correlation between the dimensions of family functioning and areas of self-esteem (except for lack of independence, and public, academic, and physical self-esteem). In addition, the correlation between family aspirations and self esteem (r = 0.636, P < 0.01) was higher than other variables. Moreover, across the dimensions of family functioning, a significant negative correlation was found between the lack of independence and the family self-esteem subscale. CONCLUSIONS: The results of the study showed that adolescents' self-esteem is highly correlated with their family's performance. Therefore, to enhance the self esteem of adolescents, family-centered empowerment programs should be planned and implemented by health service providers, especially nurses, in order to improve and enhance family functioning. PMID- 26120340 TI - Challenges in nursing continuing education: A qualitative study. AB - BACKGROUND: Nursing continuing education with development of knowledge, skill, and attitude results in improvement of nursing activity, and thus improves the health care in the society. If the education is not planned and implement properly, it affects the patient care. This study was designed to explore the challenges of nursing continuing education in Isfahan University of Medical Sciences hospitals. MATERIALS AND METHODS: The research was conducted from April 2012 to February 2013 in Isfahan, Iran. The sampling was begun with purposeful method and continued with snowball method. Thirty-nine participants were selected among the nurses of Alzahra, Kashani, and Noor hospitals, nursing and midwifery faculty, continuing education center, and the vice-chancellery for treatment. The participants were both learners and planners of continuing education program. In this descriptive explorative qualitative research, we interviewed 39 participants in five focus group and five individual interviews, until data saturation was achieved. We used semi-structured interviews and field notes for data gathering, and members checking, triangulation (data and method), peer debriefing, and peer review to increase the strength of data. Data were analyzed with thematic analysis method that was proposed by Broun and Clarke in 2006. RESULTS: Data analysis produced 175 initial codes, 8 subthemes, and 5 main themes. The main themes included: Learners related factors, teachers related factors, educational process related factors, inadequate facilities, and defective evaluation. CONCLUSIONS: According to the results, we need to revise the educational process in nursing continuing education. To achieve this goal, we need a team for needs assessment, planning, and evaluation. In addition, we must pay attention to educators' and learners' issues. PMID- 26120341 TI - Nurse-led action research project for expanding nurses' role in patient education in Iran: Process, structure, and outcomes. AB - BACKGROUND: Patient education is among the lowest met need of patients in Iran; therefore, expansion of that role can result in greater professional accountability. This study aimed to explain the practical science of the process, structure, and outcomes of a nurse-led action research project to expand the nurses' role in patient education in Iran. MATERIALS AND METHODS: This study was part of a participatory action research. Daily communications and monthly joint meetings were held from January 2012 to February 2014 for planning and management. These were based on the research protocol, and the conceptual framework included the Mobilizing for Action through Planning and Partnerships process by means of Leadership for Change skills. Data were produced and gathered through participant observations. Administrative data included project records, official documents, artifacts, news, and reports, which were analyzed through qualitative content analysis. RESULTS: A participatory project was established with three groups of participants organized from both academic and clinical fields. These consisted of a "core research support team," "two steering committees," and community representatives of clients and professionals as "feedback groups." A seven-stage process, named the "Nurse Educators: Al-Zahra Role Expansion Action Research" (NEAREAR) process, resulted from the project, in which strategic issues were gradually developed and implemented through 32 action plans and quality improvement cycles of action research. Audits and supervision evaluations showed meaningful changes in capacity building components. CONCLUSIONS: A nurse-led ad hoc structure with academic-clinical partnerships and strategic management process was suggested as a possible practical model for expanding nurses' educational role in similar contexts. Implications and practical science introduced in this action research could also be applicable for top managers and health system policy makers in a wider range of practice. PMID- 26120342 TI - Client satisfaction of maternity care in Lorestan province Iran. AB - BACKGROUND: Client satisfaction is an important indicator for assessment of the quality of care provided. Detecting patients dissatisfaction and trying to find the most effective and costly services is the basic way for improvement of service quality. The purpose of this study was to determine the satisfaction level of women in the maternity care centers (hospitals) of Lorestan University of Medical Sciences, Iran. MATERIALS AND METHODS: In this descriptive cross sectional study, the satisfaction level of 200 patients who received care during childbirth in province hospitals was assessed using a researcher-made questionnaire. Women in maternity care units completed the questionnaires. RESULTS: The mean maternity care satisfaction score was 66.6 +/- 3.5. The lowest satisfaction level was related to getting to know the delivery room (64%) and vaginal examination (66%). The highest satisfaction score was related to confidentiality of the information (86%) and trusting the midwife (84%). Regarding the environmental factors, the lowest satisfaction was related to respecting silence in the pain room (69.5%) and the highest was related to cleanliness and hygiene of the delivery room (84%). CONCLUSIONS: Our results suggest the relative satisfaction of women receiving care in the health centers of Lorestan province; but this level of satisfaction does not mean that the delivery of care in this province is perfect. By reviewing the policies and the existing care programs regarding promoting the quality of services, managers can increase clients' satisfaction. PMID- 26120343 TI - The effect of melody on the physiological responses of heel sticks pain in neonates. AB - BACKGROUND: During health care in the neonatal intensive care unit (NICU), infants undergo extremely painful procedures, which may cause problems, if not controlled, such as changes in the pattern of respiratory rate, heart rate, and blood oxygen saturation. The present study aimed to find the effect of melody on the physiological responses of neonates' heel stick pain. MATERIALS AND METHODS: This quasi-experimental study was conducted in Alzahra Hospital (Isfahan, Iran) for 5 months. Fifty infants were selected through convenient sampling method and were randomly assigned in equal numbers to two groups (n = 25). In the melody group (intervention), a selected melody was played for the infants at a distance of 1 m from them, with a sound intensity of 65 dB, from 3 minutes before, during, and after the heel stick procedure, respectively, and their physiological responses were observed with a monitoring system and recorded at the afore mentioned time periods. Physiological responses were also recorded in the control group (no intervention) 3 min before, during, and after the heel stick procedure, respectively. RESULTS: Means of respiratory and pulse rates in the melody and control groups showed a significant difference at different time points. But the mean blood oxygen saturation in the melody group showed no significant difference at different time points, although the difference was significant in the control group. CONCLUSIONS: The results showed that melody could maintain more balance in some physiological responses of infants, such as the respiratory rate and pulse rate during the Guthrie test. Therefore, melody is recommended to be used to prevent the destructive effects of pain in infants during painful procedures. PMID- 26120344 TI - Nurses' experience and role in infants with natal teeth. PMID- 26120345 TI - Personalized Medicine Across Disciplines and without Borders. Vural Ozdemir speaks to Hannah Wilson, Commissioning Editor. AB - Vural Ozdemir began his career as a medical doctor in Turkey in 1990, as a scientist at the Faculty of Medicine, University of Toronto (ON, Canada), where he obtained his MSc and PhD in clinical pharmacology (1998), and subsequently completed a 4-year postdoctoral fellowship in personalized medicine with the late Werner Kalow, a founding pioneer in the field of pharmacogenetics. Ozdemir contributed to the conception and development of the repeated drug administration (RDA) method as a novel way of measuring pharmacological heritability, pharmacogenetics of psychiatric drugs and studying the clinical role of CYP2D6 genetic variations for endogenous neurotransmitter metabolism in the human brain. Recognizing that scientific knowledge is a product of both technology and social systems that often remain unaccounted for (e.g., human values, distribution of power and human agency, immigration, racial disparities, socioeconomic class and equity), Ozdemir discovered the literature in the field of science and technology studies, a rich scholarly enquiry that asks fundamental questions and challenges assumptions regarding the backstage of technoscience, situates technology within its political context and makes hitherto unseen connections that frame science in ways that enable robust, responsible and sustainable innovation. From 2008 to 2012, Ozdemir was awarded a mid-career "science and society" fellowship in order to retool as independent faculty and senior scientist in science and technology studies (STS), conducting research on research and examining his own trade - pharmacogenetics science - as an insider on the outside. Recently, Ozdemir was awarded senior career support from the Scientific and Tehnological Research Council of Turkey, is an Associate Professor of both Communications and Human Genetics at the Faculty of Communications and serves as an advisor to the Rector for International Technology and Innovation Policy, Gaziantep University in Turkey. He is also a Visiting Professor (Global Health & Technology Foresight) at Amrita University in Kerala, India, and cofounder of the Data-Enabled Life Sciences Alliance (DELSA Global), an open innovation and knowledge translation platform in Seattle (WA, USA). Ozdemir was named as coinventor of 12 World Intellectual Property Organization (WIPO) indexed patents in personalized medicine and has authored more than 130 peer reviewed articles and chapters on the translation of omics technologies into public health action, global technology governance, diagnostics innovation strategy, history of bioethics and the ethics-of-bioethics. 'Science Peace Corps' and 'Microgrants for Big Data' are two new knowledge translation and science communication concepts developed by Ozdemir for the global governance of biotechnology. He is Editor-in-Chief of OMICS: A Journal of Integrative Biology, published by Mary Ann Liebert, Inc. (NY, USA). PMID- 26120346 TI - Effects of GUASHA on Heart Rate Variability in Healthy Male Volunteers under Normal Condition and Weightlifters after Weightlifting Training Sessions. AB - Objectives. This paper aims at exploring the effects of GUASHA on heart rate variability between healthy volunteers under normal condition and weightlifters after training sessions. Methods. Ten healthy male volunteers under normal condition and 15 male weightlifters after weightlifting training sessions were recruited into two groups. Electrocardiography was recorded before and immediately after 20-minute GUASHA. HRV was calculated in both the time domain and the frequency domain. Results. Stress index was reduced, while standard deviation of N-N intervals (SDNN), proportion derived by dividing the number of interval differences of successive N-N intervals greater than 50 ms, and root mean square of successive differences (RMSSD) were enhanced after GUASHA therapy in the two groups. The changes in SDNN and RMSSD were higher in the healthy men group than in the weightlifters group. In addition, low frequency was decreased whereas high frequency was significantly increased in healthy men after the GUASHA session. Conclusions. GUASHA therapy facilitates the parasympathetic nervous activity and modulates the balance between parasympathetic and sympathetic activities in both healthy men under normal condition and weightlifters after training sessions as indicated. Although the changes of the HRV parameters were similar in both groups, the responsiveness was more pronounced in healthy men than in male weightlifters. PMID- 26120347 TI - Endangered Uyghur Medicinal Plant Ferula Identification through the Second Internal Transcribed Spacer. AB - The medicinal plant Ferula has been widely used in Asian medicine, especially in Uyghur medicine in Xinjiang, China. Given that various substitutes and closely related species have similar morphological characteristics, Ferula is difficult to distinguish based on morphology alone, thereby causing confusion and threatening the safe use of Ferula. In this study, internal transcribed spacer 2 (ITS2) sequences were analyzed and assessed for the accurate identification of two salable Ferula species (Ferula sinkiangensis and Ferula fukangensis) and eight substitutes or closely related species. Results showed that the sequence length of ITS2 ranged from 451 bp to 45 bp, whereas guanine and cytosine contents (GC) were from 53.6% to 56.2%. A total of 77 variation sites were detected, including 63 base mutations and 14 insertion/deletion mutations. The ITS2 sequence correctly identified 100% of the samples at the species level using the basic local alignment search tool 1 and nearest-distance method. Furthermore, neighbor-joining tree successfully identified the genuine plants F. sinkiangensis and F. fukangensis from their succedaneum and closely related species. These results indicated that ITS2 sequence could be used as a valuable barcode to distinguish Uyghur medicine Ferula from counterfeits and closely related species. This study may broaden DNA barcoding application in the Uyghur medicinal plant field. PMID- 26120348 TI - Population-based human immunodeficiency virus 1 drug resistance profiles among individuals who experienced virological failure to first-line antiretroviral therapy in Henan, China during 2010-2011. AB - BACKGROUND: In Henan, China, first-line antiretroviral treatment (ART) was implemented early in a large number of treatment-experienced patients who were more likely to have a drug resistance. Therefore, we investigated the human immunodeficiency virus (HIV)-1 drug resistance profiles among patients in Henan who experienced virological failure to ART. METHOD: A cross-sectional survey was administered in 10 major epidemic cities from May 2010 to October 2011. Adult patients who experienced virological failure (virus load >=1,000 copies/mL) with >1 year of first-line antiretroviral treatment consented to provide blood for genotype resistance testing. The clinical and demographic data were obtained from the patients' medical records. Logistic regression analysis was performed to determine the factors associated with >=1 significant drug resistance mutation. RESULTS: We included 3,235 patients with integral information and valid genotypic resistance data. The city, age, CD4 counts, virus load, treatment duration, and World Health Organization stage were associated with drug resistance, and 64.76% of patients acquired drug resistance. The nucleoside reverse transcriptase inhibitor (NRTI), non-(N)NRTI, and protease inhibitor resistance mutations were found in 50.26, 63.12, and 1.30% of subjects, respectively. Thymidine analogue mutations, NNRTI and even multidrug resistance complex were quite common in this patient cohort. CONCLUSION: Multiple and complex patterns of HIV-1 drug resistance mutations were identified among individuals who experienced virological failure to first-line ART in Henan, China during 2010-2011. Therefore, timely virological monitoring, therapy adjustments, and more varieties of drugs and individualized treatment should be immediately considered in this patient population. PMID- 26120349 TI - Landmark precision and reliability and accuracy of linear distances estimated by using 3D computed micro-tomography and the open-source TINA Manual Landmarking Tool software. AB - INTRODUCTION: The wider availability of non-destructive and high-resolution methods, such as micro-computed tomography (micro-CT), has prompted its use in anatomical and morphometric studies. Yet, because of the actual scanning procedure and the processing of CT data by software that renders 3D surfaces or volumes, systematic errors might be introduced in placing landmarks as well as in estimating linear distances. Here we assess landmark precision and measurement reliability and accuracy of using micro-CT images of toad skulls and the TINA Manual Landmarking Tool software to place 20 landmarks and extract 24 linear distances. Landmark precision and linear distances calculated from 3D images were compared to the same landmarks and distances obtained with a 3D digitizer in the same skulls. We also compared landmarks and linear distances in 3D images of the same individuals scanned with distinct filters, since we detected variation in bone thickness or density among the individuals used. RESULTS: We show that landmark precision is higher for micro-CT than for the 3D digitizer. Distance reliability was very high within-methods, but decreased in 20 % when 3D digitizer and micro-CT data were joined together. Still, we did not find any systematic bias in estimating linear distances with the micro-CT data and the between methods errors were similar for all distances (around 0.25 mm). Absolute errors correspond to about 6.5 % of the distance's means for micro-CT resolutions and 3D digitizer comparisons, and to 3 % for the filter type analysis. CONCLUSIONS: We conclude that using micro-CT data for morphometric analysis results in acceptable landmark precision and similar estimates of most linear distances compared to 3D digitizer, although some distances are more prone to discrepancies between methods. Yet, caution in relation to the scale of the measurements needs to be taken, since the proportional between-method error is higher for smaller distances. Scanning with distinct filters does not introduce a high level of error and is recommended when individuals differ in bone density. PMID- 26120350 TI - Growth of curved and helical bacterial cells. AB - A combination of cell wall growth and cytoskeletal protein action gives rise to the observed bacterial cell shape. Aside from the common rod-like and spherical shapes, bacterial cells can also adopt curved or helical geometries. To understand how curvature in bacteria is developed or maintained, we examine how Caulobacter crescentus obtains its crescent-like shape. Caulobacter cells with or without the cytoskeletal bundle crescentin, an intermediate filament-like protein, exhibit two distinct growth modes, curvature maintenance that preserves the radius of curvature and curvature relaxation that straightens the cell (Fig. 1). Using a proposed mechanochemical model, we show that bending and twisting of the crescentin bundle can influence the stress distribution in the cell wall, and lead to the growth of curved cells. In contrast, after crescentin bundle is disrupted, originally curved cells will slowly relax towards a straight rod over time. The model is able to quantitatively capture experimentally observed curvature dynamics. Furthermore, we show that the shape anisotropy of the cross section of a curved cell is never greater than 4%, even in the presence of crescentin. PMID- 26120351 TI - The multifunctional Ebola virus VP40 matrix protein is a promising therapeutic target. AB - The highly virulent nature of Ebola virus, evident from the 2014 West African pandemic, highlights the need to develop vaccines or therapeutic agents that limit the pathogenesis and spread of this virus. While vaccines represent an obvious approach, targeting virus interactions with host proteins that critically regulate the virus lifecycle also represent important therapeutic strategies. Among Ebola virus proteins at this critical interface is its matrix protein, VP40, which is abundantly expressed during infection and plays a number of critical roles in the viral lifecycle. In addition to regulating viral transcription, VP40 coordinates virion assembly and budding from infected cells. Details of the molecular mechanisms underpinning these essential functions are currently being elucidated, with a particular emphasis on its interactions with host proteins that control virion assembly and egress. This review focuses on the strategies geared toward developing novel therapeutic agents that target VP40 specific control of host functions critical to virion transcription, assembly and egress. PMID- 26120352 TI - MU-Calpain as a Novel Target for Impairment of Nitric Oxide-Mediated Vascular Relaxation in Diabetes: A Mini Review. AB - Diabetes is one of the most prevalent metabolic disorders. In diabetes, incidence of coronary artery diseases and peripheral vascular diseases is increased 2- to 4 fold and 10-fold, respectively, compared to healthy individuals. In spite of extensive studies, the underlying mechanisms of endothelial dysfunction (ED), an early event in the development of vascular diseases, remain incompletely understood in diabetes. This mini-review discusses the role and signaling pathways of calpains - a family of Ca2+-sensitive intracellular proteases in nitric oxide (NO)-mediated ED in diabetes. We conclude that activation of calpains, especially MU-calpain, plays an important role in the pathogenesis of NO-mediated ED and inflammatory responses in diabetes which is mainly via endothelial Nitric Oxide Synthase (eNOS) inactivation/degradation in macro- and micro-vasculature. We review existing literature demonstrating that hyperhomocysteinemia, elevated plasma homocysteine level, potentiates hyperglycemia-induced ED via MU-calpain/PKCbeta2 activation-induced eNOS pThr497/495 and eNOS inactivation. MU-calpain may be a critical therapeutic target for NO-mediated ED in diabetes. PMID- 26120353 TI - An SEIV Epidemic Model for Childhood Diseases with Partial Permanent Immunity. AB - An SEIV epidemic model for childhood disease with partial permanent immunity is studied. The basic reproduction number R 0 has been worked out. The local and global asymptotical stability analysis of the equilibria are performed, respectively. Furthermore, if we take the treated rate tau as the bifurcation parameter, periodic orbits will bifurcate from endemic equilibrium when tau passes through a critical value. Finally, some numerical simulations are given to support our analytic results. PMID- 26120354 TI - Developing a New Computer-Aided Clinical Decision Support System for Prediction of Successful Postcardioversion Patients with Persistent Atrial Fibrillation. AB - We propose a new algorithm to predict the outcome of direct-current electric (DCE) cardioversion for atrial fibrillation (AF) patients. AF is the most common cardiac arrhythmia and DCE cardioversion is a noninvasive treatment to end AF and return the patient to sinus rhythm (SR). Unfortunately, there is a high risk of AF recurrence in persistent AF patients; hence clinically it is important to predict the DCE outcome in order to avoid the procedure's side effects. This study develops a feature extraction and classification framework to predict AF recurrence patients from the underlying structure of atrial activity (AA). A multiresolution signal decomposition technique, based on matching pursuit (MP), was used to project the AA over a dictionary of wavelets. Seven novel features were derived from the decompositions and were employed in a quadratic discrimination analysis classification to predict the success of post-DCE cardioversion in 40 patients with persistent AF. The proposed algorithm achieved 100% sensitivity and 95% specificity, indicating that the proposed computational approach captures detailed structural information about the underlying AA and could provide reliable information for effective management of AF. PMID- 26120355 TI - NUFFT-Based Iterative Image Reconstruction via Alternating Direction Total Variation Minimization for Sparse-View CT. AB - Sparse-view imaging is a promising scanning method which can reduce the radiation dose in X-ray computed tomography (CT). Reconstruction algorithm for sparse-view imaging system is of significant importance. The adoption of the spatial iterative algorithm for CT image reconstruction has a low operation efficiency and high computation requirement. A novel Fourier-based iterative reconstruction technique that utilizes nonuniform fast Fourier transform is presented in this study along with the advanced total variation (TV) regularization for sparse-view CT. Combined with the alternating direction method, the proposed approach shows excellent efficiency and rapid convergence property. Numerical simulations and real data experiments are performed on a parallel beam CT. Experimental results validate that the proposed method has higher computational efficiency and better reconstruction quality than the conventional algorithms, such as simultaneous algebraic reconstruction technique using TV method and the alternating direction total variation minimization approach, with the same time duration. The proposed method appears to have extensive applications in X-ray CT imaging. PMID- 26120356 TI - Deep Adaptive Log-Demons: Diffeomorphic Image Registration with Very Large Deformations. AB - This paper proposes a new framework for capturing large and complex deformation in image registration. Traditionally, this challenging problem relies firstly on a preregistration, usually an affine matrix containing rotation, scale, and translation and afterwards on a nonrigid transformation. According to preregistration, the directly calculated affine matrix, which is obtained by limited pixel information, may misregistrate when large biases exist, thus misleading following registration subversively. To address this problem, for two dimensional (2D) images, the two-layer deep adaptive registration framework proposed in this paper firstly accurately classifies the rotation parameter through multilayer convolutional neural networks (CNNs) and then identifies scale and translation parameters separately. For three-dimensional (3D) images, affine matrix is located through feature correspondences by a triplanar 2D CNNs. Then deformation removal is done iteratively through preregistration and demons registration. By comparison with the state-of-the-art registration framework, our method gains more accurate registration results on both synthetic and real datasets. Besides, principal component analysis (PCA) is combined with correlation like Pearson and Spearman to form new similarity standards in 2D and 3D registration. Experiment results also show faster convergence speed. PMID- 26120357 TI - Finger Vein Segmentation from Infrared Images Based on a Modified Separable Mumford Shah Model and Local Entropy Thresholding. AB - A novel method for finger vein pattern extraction from infrared images is presented. This method involves four steps: preprocessing which performs local normalization of the image intensity, image enhancement, image segmentation, and finally postprocessing for image cleaning. In the image enhancement step, an image which will be both smooth and similar to the original is sought. The enhanced image is obtained by minimizing the objective function of a modified separable Mumford Shah Model. Since, this minimization procedure is computationally intensive for large images, a local application of the Mumford Shah Model in small window neighborhoods is proposed. The finger veins are located in concave nonsmooth regions and, so, in order to distinct them from the other tissue parts, all the differences between the smooth neighborhoods, obtained by the local application of the model, and the corresponding windows of the original image are added. After that, veins in the enhanced image have been sufficiently emphasized. Thus, after image enhancement, an accurate segmentation can be obtained readily by a local entropy thresholding method. Finally, the resulted binary image may suffer from some misclassifications and, so, a postprocessing step is performed in order to extract a robust finger vein pattern. PMID- 26120359 TI - A polynomial delay algorithm for the enumeration of bubbles with length constraints in directed graphs. AB - BACKGROUND: The problem of enumerating bubbles with length constraints in directed graphs arises in transcriptomics where the question is to identify all alternative splicing events present in a sample of mRNAs sequenced by RNA-seq. RESULTS: We present a new algorithm for enumerating bubbles with length constraints in weighted directed graphs. This is the first polynomial delay algorithm for this problem and we show that in practice, it is faster than previous approaches. CONCLUSION: This settles one of the main open questions from Sacomoto et al. (BMC Bioinform 13:5, 2012). Moreover, the new algorithm allows us to deal with larger instances and possibly detect longer alternative splicing events. PMID- 26120358 TI - A Novel Application of Multiscale Entropy in Electroencephalography to Predict the Efficacy of Acetylcholinesterase Inhibitor in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of dementia. According to one hypothesis, AD is caused by the reduced synthesis of the neurotransmitter acetylcholine. Therefore, acetylcholinesterase (AChE) inhibitors are considered to be an effective therapy. For clinicians, however, AChE inhibitors are not a predictable treatment for individual patients. We aimed to disclose the difference by biosignal processing. In this study, we used multiscale entropy (MSE) analysis, which can disclose the embedded information in different time scales, in electroencephalography (EEG), in an attempt to predict the efficacy of AChE inhibitors. Seventeen newly diagnosed AD patients were enrolled, with an initial minimental state examination (MMSE) score of 18.8 +/- 4.5. After 12 months of AChE inhibitor therapy, 7 patients were responsive and 10 patients were nonresponsive. The major difference between these two groups is Slope 2 (MSE6 to 20). The area below the receiver operating characteristic (ROC) curve of Slope 2 is 0.871 (95% CI = 0.69-1). The sensitivity is 85.7% and the specificity is 60%, whereas the cut-off value of Slope 2 is -0.024. Therefore, MSE analysis of EEG signals, especially Slope 2, provides a potential tool for predicting the efficacy of AChE inhibitors prior to therapy. PMID- 26120360 TI - The use of routine outcome monitoring in child semi-residential psychiatry: predicting parents' completion rates. AB - BACKGROUND: Parents' perspectives on their children's treatment process and outcomes are valuable to treatment development and improvement. Participants' engagement in Routine Outcome Monitoring (ROM) has, however, been difficult and may particularly be so in specialized settings, such as semi-residential psychiatry. In this paper, the use of a web-based ROM system implemented in a child semi-residential psychiatric setting is described and predictors associated with low completion rates of questionnaires by parents are identified. METHODS: Parents and the multidisciplinary team of 46 children admitted to semi residential psychiatric treatment participated in this study and completed a battery of questionnaires in three month intervals. RESULTS: The overall completion rate of both parents during ROM assessment was 77 % compared to 83 % of all clinicians involved. Completion of questionnaires by parents was higher around first assessments and declined after a year treatment. For eight clients at least one of the parents stopped filling out questionnaires during ROM measuring. Logistic multilevel analyses revealed initial treatment factors associated with a low completion of questionnaires by parents during ROM: high comorbidity of the child on DSM Axis I, single parenthood, a higher parental educational level and having a weaker therapeutic alliance regarding goal setting. CONCLUSIONS: The findings in this paper demonstrate relatively high completion of questionnaires by clinicians and parents when using ROM in child semi-residential psychiatry. Strong administrative and electronic support undoubtedly contributed to this result. Clinicians are encouraged to motivate parents to mutually invest in ROM, and to take into account factors indicating a possible lower completion of questionnaires by parents. PMID- 26120361 TI - The effectiveness of psychosocial interventions for anxiety in children and adolescents with autism spectrum disorder: a systematic review and meta-analysis. AB - Anxiety is a common problem in children and adolescents with autism spectrum disorder (ASD). This meta-analysis aimed to systematically evaluate the evidence for the use of psychosocial interventions to manage anxiety in this population. Cognitive behavioural therapy (CBT) was the primary intervention modality studied. A comprehensive systematic search and study selection process was conducted. Separate statistical analyses were carried out for clinician-, parent , and self-reported outcome measures. Sensitivity analyses were conducted by removing any outlying studies and any studies that did not use a CBT intervention. A subgroup analysis was performed to compare individual and group delivery of treatment. Ten randomised control trials involving a total of 470 participants were included. The overall SMD was d = 1.05 (95 % CI 0.45, 1.65; z = 3.45, p = 0.0006) for clinician- reported outcome measures; d = 1.00 (95%CI 0.21, 1.80; z = 2.47, p = 0.01) for parent-reported outcome measures; and d = 0.65 (95%CI -0.10, 1.07; z = 1.63, p = 0.10) for self-reported outcome measures. Clinician- and parent-reported outcome measures showed that psychosocial interventions were superior to waitlist and treatment-as-usual control conditions at post-treatment. However, the results of self-reported outcome measures failed to reach significance. The sensitivity analyses did not significantly change these results and the subgroup analysis indicated that individual treatment was more effective than group treatment. The main limitations of this review were the small number of included studies as well as the clinical and methodological variability between studies. PMID- 26120362 TI - Metabolic engineering of microbes for branched-chain biodiesel production with low-temperature property. AB - BACKGROUND: The steadily increasing demand for diesel fuels calls for renewable energy sources. This has attracted a growing amount of research to develop advanced, alternative biodiesel worldwide. Several major disadvantages of current biodiesels are the undesirable physical properties such as high viscosity and poor low-temperature operability. Therefore, there is an urgent need to develop novel and advanced biodiesels. RESULTS: Inspired by the proven capability of wax ester synthase/acyl-coenzyme A, diacylglycerol acyltransferase (WS/DGAT) to generate fatty acid esters, de novo biosynthesis of fatty acid branched-chain esters (FABCEs) and branched fatty acid branched-chain esters (BFABCEs) was performed in engineered Escherichia coli through combination of the (branched) fatty acid biosynthetic pathway and the branched-chain amino acid biosynthetic pathway. Furthermore, by modifying the fatty acid pathway, we improved FABCE production to 273 mg/L and achieved a high proportion of FABCEs at 99.3 % of total fatty acid esters. In order to investigate the universality of this strategy, Pichia pastoris yeast was engineered and produced desirable levels of FABCEs for the first time with a good starting point of 169 mg/L. CONCLUSIONS: We propose new pathways of fatty acid ester biosynthesis and establish proof of concept through metabolic engineering of E. coli and P. pastoris yeast. We were able to produce advanced biodiesels with high proportions FABCEs and BFABCEs. Furthermore, this new strategy promises to achieve advanced biodiesels with beneficial low-temperature properties. PMID- 26120363 TI - Cytogenomic delineation and clinical follow-up of 10 Brazilian patients with Pallister-Killian syndrome. AB - BACKGROUND: Pallister-Killian syndrome (PKS) is a sporadic genetic disorder caused by the presence of a tissue-specific mosaicism for isochromosome 12p - i(12) (p10) and is characterized by facial dysmorphism including coarse facies, upslanting palpebral fissures, bitemporal alopecia, pigmentary skin anomalies, developmental delay, hypotonia and seizures. Although typical clinical features of PKS commonly exist, clinicians often do not raise the possibility of this diagnosis. RESULTS: We reviewed the medical records of 10 patients with confirmed PKS followed in our service (since 1990 to 2015). Age at diagnosis varied from prenatal to 3 years and clinical features were consistent with those described in the literature. In all patients, peripheral blood karyotypes were normal and cytogenomic study was performed in order to confirm the diagnosis. Three of these patients had PKS diagnosis confirmed by buccal smear MLPA. CONCLUSION: An early conclusion from our results demonstrated that MLPA on buccal smears is a good and non-invasive method to detect extra copies of 12p and should be considered as the first exam, before a skin biopsy for a fibroblast karyotype is performed. PMID- 26120364 TI - Birth of a child with trisomy 9 mosaicism syndrome associated with paternal isodisomy 9: case of a positive noninvasive prenatal test result unconfirmed by invasive prenatal diagnosis. AB - BACKGROUND: Non-invasive prenatal testing (NIPT) is currently used as a frontline screening test to identify fetuses with common aneuploidies. Occasionally, incidental NIPT results are conveyed to the clinician suggestive of fetuses with rare chromosome disease syndromes. We describe a child with trisomy 9 (T9) mosaicism where the prenatal history reported a positive NIPT result for T9 that was unconfirmed by conventional prenatal diagnosis. METHODS: NIPT was performed by low coverage whole genome plasma DNA sequencing. Karyotyping and fluorescent in situ hybridization (FISH) analysis with chromosome 9p-ter and 9q-ter probes was used to determine the somatic cell level of T9 mosaicism in the fetus and child. Quantitative fluorescent PCR (Q-PCR) of highly polymorphic short tandem repeat (STR) chromosome 9 markers was also performed to investigate the nature of the T9 mosaicism and the parental origin. RESULTS: A 22 month old girl presented with severe developmental delay, congenital cerebral dysplasia and congenital heart disease consistent with phenotypes associated with T9 mosaicism syndrome. Review of the prenatal testing history revealed a positive NIPT result for chromosome T9. However, follow up confirmatory karyotyping and FISH analysis of fetal cells returned a normal karyotype. Post-natal studies of somatic cell T9 mosaicism by FISH detected levels of approximately 20 % in blood and buccal cells. Q-PCR STR analysis of family DNA samples suggested that the T9 mosaicism originated by post-zygotic trisomic rescue of a paternal meiotic II chromosome 9 non-disjunction error resulting in the formation of two distinct somatic cell lines in the proband, one with paternal isodisomy 9 and one with T9. CONCLUSION: This study shows that NIPT may also be a useful screening technology to increase prenatal detection rates of rare fetal chromosome disease syndromes. PMID- 26120365 TI - Factors Associated With American Indian and White Adolescent Drug Selling in Rural Communities. AB - Relatively few studies have examined the correlates of adolescent drug selling in America, with most of these studies focusing on urban settings. The present study examines the risk and protective factors associated with drug selling among American Indian and white adolescents residing in a rural Northwestern state in the United States. Using survey data collected in 2010-2012, we conduct logistic regression analyses exploring the correlates of drug selling (n=568). Generally, we found support for prior explanations of drug selling, but identified some important race-specific differences. Specifically, we found that stress exposure was a risk factor for American Indians, but not whites. Conversely, academic achievement served as a protective factor for white adolescents but not American Indians. Our findings suggest that the race gap in rural drug selling can be explained by considering differences in social bonds, stress exposure, and exposure to substance using family and friends. PMID- 26120366 TI - Functional fingerprinting of human mesenchymal stem cells using high-throughput RNAi screening. AB - Mesenchymal stem cells (MSCs) are promising candidates for cellular therapies ranging from tissue repair in regenerative medicine to immunomodulation in graft versus host disease after allogeneic transplantation or in autoimmune diseases. Nonetheless, progress has been hampered by their enormous phenotypic as well as functional heterogeneity and the lack of uniform standards and guidelines for quality control. In this study, we describe a method to perform cellular phenotyping by high-throughput RNA interference in primary human bone marrow MSCs. We have shown that despite heterogeneity of MSC populations, robust functional assays can be established that are suitable for high-throughput and high-content screening. We profiled primary human MSCs against human fibroblasts. Network analysis showed a kinome fingerprint that differs from human primary fibroblasts as well as fibroblast cell lines. In conclusion, this study shows that high-throughput screening in primary human MSCs can be reliably used for kinome fingerprinting. PMID- 26120367 TI - First description of plasmid-mediated quinolone resistance determinants and beta lactamase encoding genes in non-typhoidal Salmonella isolated from humans, one companion animal and food in Romania. AB - BACKGROUND: Gastroenteritis attributable to Salmonella enterica and the continuous increase in antimicrobial resistance of this gut pathogen, which compromises the use of previously effective treatments, is of great concern for public health. This study was conducted in order to investigate the presence of plasmid-mediated quinolone resistance (PMQR) determinants and beta-lactamase encoding genes, in S. enterica, isolated from humans, one companion animal and food. Moreover, the study aimed to identify potential vehicles of transmission of resistant strains to humans, with focus on food products (meat). METHODS: A total of 20 S. enterica isolates recovered from food (chicken and pork meat), one companion animal and humans (stool samples), were examined for their serotype, antimicrobial susceptibility and the presence of PMQR and beta-lactamase-encoding genes. Moreover, the genetic relatedness of nine Salmonella Infantis and ten Salmonella Enteritidis isolates was analyzed by pulsed-field gel electrophoresis (PFGE). RESULTS: Among all isolates, 15 (75%) were multidrug-resistant (MDR) and the majority of them proved to be resistant to nalidixic acid and fluoroquinolones (FQs) (ciprofloxacin and levofloxacin). Twelve isolates (60%) harboured at least one PMQR gene [qnrA, qnrB, qnrS, aac (6')-Ib-cr or qepA] while seven isolates (35%) carried at least one beta-lactamase-encoding gene (bla TEM, bla PSE-1, bla SHV or bla CTX-M). Moreover, two or more PMQR or beta-lactamase encoding genes co-existed in a single S. enterica isolate. A number of nine Salmonella Infantis, as well as the majority of Salmonella Enteritidis isolates analyzed by PFGE proved to be closely related. CONCLUSIONS: The study demonstrated the co-existence of PMQR and beta-lactamase-encoding genes among the Salmonella isolates recovered and confirmed that multiple mechanisms might be involved in the acquisition and spread of resistance determinants. The close genetic relatedness between the clinical and foodborne S. enterica isolates, suggested that chicken meat might be a possible cause of human salmonellosis in our country, during the study period. Results of this study might improve understanding of the antimicrobial resistance mechanisms and transmission dynamics of Salmonella spp. Here, we report for the first time the presence of PMQR and beta-lactamase-encoding genes in S. enterica isolates, recovered from humans, one companion animal and food, in Romania. PMID- 26120368 TI - Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer's disease clinical trials. AB - INTRODUCTION: Most Alzheimer's disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region. METHODS: We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan. RESULTS: North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E epsilon4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan. CONCLUSIONS: These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials. PMID- 26120369 TI - Alzheimer's disease progression by geographical region in a clinical trial setting. AB - INTRODUCTION: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer's disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. METHODS: Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged >=55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). RESULTS: Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. CONCLUSIONS: These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00594568 - IDENTITY. Registered 11 January 2008. ClinicalTrials.gov NCT00762411 - IDENTITY2. Registered 26 September 2008 ClinicalTrials.gov NCT00905372 - EXPEDITION. Registered 18 May 2009 ClinicalTrials.gov NCT00904683 - EXPEDITION2. Registered 18 May 2009. PMID- 26120370 TI - The diversification of PHIS transposon superfamily in eukaryotes. AB - BACKGROUND: PHIS transposon superfamily belongs to DNA transposons and includes PIF/Harbinger, ISL2EU, and Spy transposon groups. These three groups have similar DDE domain-containing transposases; however, their coding capacity, species distribution, and target site duplications (TSDs) are significantly different. RESULTS: In this study, we systematically identified and analyzed PHIS transposons in 836 sequenced eukaryotic genomes using transposase homology search and structure approach. In total, 380 PHIS families were identified in 112 genomes and 168 of 380 families were firstly reported in this study. Besides previous identified PIF/Harbinger, ISL2EU, and Spy groups, three new types (called Pangu, NuwaI, and NuwaII) of PHIS superfamily were identified; each has its own distinctive characteristics, especially in TSDs. Pangu and NuwaII transposons are characterized by 5'-ANT-3' and 5'-C|TNA|G-3' TSDs, respectively. Both transposons are widely distributed in plants, fungi, and animals; the NuwaI transposons are characterized by 5'-CWG-3' TSDs and mainly distributed in animals. CONCLUSIONS: Here, in total, 380 PHIS families were identified in eukaryotes. Among these 380 families, 168 were firstly reported in this study. Furthermore, three new types of PHIS superfamily were identified. Our results not only enrich the transposon diversity but also have extensive significance for improving genome sequence assembly and annotation of higher organisms. PMID- 26120371 TI - Fundus autofluorescence in the diagnosis and monitoring of acute retinal necrosis. AB - BACKGROUND: Acute retinal necrosis (ARN), a vision threatening viral retinitis, is often diagnosed and treated based on clinical findings. These clinical features have been well characterized by various imaging modalities, but not using fundus autofluorescence (FAF), a noninvasive method of evaluating the neurosensory retina and retinal pigment epithelium (RPE) based on the detection of endogenous fluorophores. FINDINGS: A patient diagnosed with ARN was followed over a 10-month period to identify and document the fundus findings using FAF imaging. Pathological changes present at the level of the neurosensory retina and RPE in ARN can be detected and characterized using fundus autofluorescence imaging. CONCLUSIONS: The borders of disease activity in ARN correlate with high contrast changes in autofluorescence patterns to facilitate monitoring of disease progression. PMID- 26120372 TI - Health and Work at Older Ages: Using Mortality to Assess the Capacity to Work across Countries. PMID- 26120373 TI - Risks deter but pleasures allure: Is pleasure more important? AB - The pursuit of unhealthy behaviors, such as smoking or binge drinking, not only carries various downside risks, but also provides pleasure. A parsimonious model, used in the literature to explain the decision to pursue an unhealthy activity, represents that decision as a tradeoff between risks and benefits. We build on this literature by surveying a rural population in South Africa to elicit the perceived riskiness and the perceived pleasure for various risky activities and to examine how these perceptions relate to the pursuit of four specific unhealthy behaviors: frequent smoking, problem drinking, seatbelt nonuse, and risky sex. We show that perceived pleasure is a significant predictor for three of the behaviors and that perceived riskiness is a significant predictor for two of them. We also show that the correlation between the riskiness rating and behavior is significantly different from the correlation between the pleasure rating and behavior for three of the four behaviors. Finally, we show that the effect of pleasure is significantly greater than the effect of riskiness in determining drinking and risky sex, while the effects of pleasure and riskiness are not different from each other in determining smoking and seatbelt nonuse. We discuss how our findings can be used to inform the design of health promotion strategies. PMID- 26120374 TI - Two Aromatic Rings Coupled a Sulfur-Containing Group to Favor Protein Electron Transfer by Instantaneous Formations of pi?S:pi<->pi:S?pi or pi?pi:S<->pi:pi?S Five-Electron Bindings. AB - The cooperative interactions among two aromatic rings with a S-containing group are described, which may participate in electron hole transport in proteins. Ab initio calculations reveal the possibility for the formations of the pi?S:pi< >pi:S?pi and pi?pi:S<->pi:pi?S five-electron bindings in the corresponding microsurrounding structures in proteins, both facilitating electron hole transport as efficient relay stations. The relay functionality of these two special structures comes from their low local ionization energies and proper binding energies, which varies with the different aromatic amino acids, S containing residues, and the arrangements of the same aromatic rings according to the local microsurroundings in proteins. PMID- 26120375 TI - A Structural Model for a Self-Assembled Nanotube Provides Insight into Its Exciton Dynamics. AB - The design and synthesis of functional self-assembled nanostructures is frequently an empirical process fraught with critical knowledge gaps about atomic level structure in these noncovalent systems. Here, we report a structural model for a semiconductor nanotube formed via the self-assembly of naphthalenediimide lysine (NDI-Lys) building blocks determined using experimental 13C-13C and 13C 15N distance restraints from solid-state nuclear magnetic resonance supplemented by electron microscopy and X-ray powder diffraction data. The structural model reveals a two-dimensional-crystal-like architecture of stacked monolayer rings each containing ~50 NDI-Lys molecules, with significant pi-stacking interactions occurring both within the confines of the ring and along the long axis of the tube. Excited-state delocalization and energy transfer are simulated for the nanotube based on time-dependent density functional theory and an incoherent hopping model. Remarkably, these calculations reveal efficient energy migration from the excitonic bright state, which is in agreement with the rapid energy transfer within NDI-Lys nanotubes observed previously using fluorescence spectroscopy. PMID- 26120377 TI - IMAGE REGISTRATION ERROR ANALYSIS WITH APPLICATIONS IN SINGLE MOLECULE MICROSCOPY. AB - This paper is concerned with assessing localization errors emanating from the image registration of two monochromatic fluorescence microscopy images. Assuming an affine transform exists between images, registration in this setting typically involves using control points to solve a multivariate linear regression problem; however with measurement errors existing in both sets of variables the use of linear least squares is inappropriate. It is shown that image registration is an errors-in-variable problem and as such the correct method is to use generalized least squares. Traditionally this requires the measurement errors to be independent and identically distributed (iid); an assumption that is rarely satisfied in practical situations. An extension of the multivariate generalized least squares estimator that allows non-iid noise is applied. The distributional properties of the estimators are used to derive localization errors emanating from the image registration process in terms of photon counts and experimental parameters. PMID- 26120376 TI - Magnetic resonance guided high-intensity focused ultrasound ablation of musculoskeletal tumors. AB - This article reviews the fundamental principles and clinical experimental uses of magnetic resonance guided high-intensity focused ultrasound (MRgHIFU) ablation of musculoskeletal tumors. MRgHIFU is a noninvasive treatment modality that takes advantage of the ability of magnetic resonance to measure tissue temperature and uses this technology to guide high-intensity focused ultrasound waves to a specific focus within the human body that results in heat generation and complete thermal necrosis of the targeted tissue. Adjacent normal tissues are spared because of the accurate delivery of thermal energy, as well as, local blood perfusion that provides a cooling effect. MRgHIFU is approved by the Food and Drug Administration for the treatment of uterine fibroids and is used on an experimental basis to treat breast, prostate, liver, bone, and brain tumors. PMID- 26120378 TI - Tuning the Attempt Frequency of Protein Folding Dynamics via Transition-State Rigidification: Application to Trp-Cage. AB - The attempt frequency or prefactor (k0) of the transition-state rate equation of protein folding kinetics has been estimated to be on the order of 10(6) s(-1), which is many orders of magnitude smaller than that of chemical reactions. Herein we use the mini-protein Trp-cage to show that it is possible to significantly increase the value of k0 for a protein folding reaction by rigidifying the transition state. This is achieved by reducing the conformational flexibility of a key structural element (i.e., an alpha-helix) formed in the transition state via photoisomerization of an azobenzene cross-linker. We find that this strategy not only decreases the folding time of the Trp-cage peptide by more than an order of magnitude (to ~100 ns at 25 degrees C) but also exposes parallel folding pathways, allowing us to provide, to the best of our knowledge, the first quantitative assessment of the curvature of the transition-state free-energy surface of a protein. PMID- 26120379 TI - A Review of Programs, Components and Outcomes in Biomedical Research Faculty Development. AB - BACKGROUND/OBJECTIVE: To review, compare and synthesize current faculty development programs and components. Findings are expected to facilitate research that will increase the competency and competitiveness of less-established biomedical research faculty. METHODS: We reviewed the current literature on research faculty development programs, and report on their type, components, outcomes and limitations. RESULTS: Nineteen articles met inclusion criteria. There were no prospective studies; most were observational and all lacked a control group. Mentoring was the most successful program type, and guided and participatory learning the most successful enabling mechanism, in achieving stated program goals. CONCLUSIONS: Our findings are limited by the small number of current studies, wide variation in implementation, study design, and populations, and the lack of uniform metrics. However, results suggest that future prospective, randomized studies should employ quantitative criteria, and examine individual, human factors that predict "success." PMID- 26120381 TI - Use of dentomaxillofacial cone beam computed tomography in dentistry. AB - Cone-beam computed tomography (CBCT) was developed and introduced specifically for dento-maxillofacial imaging. CBCT possesses a number of advantages over medical CT in clinical practice, such as lower effective radiation doses, lower costs, fewer space requirements, easier image acquisition, and interactive display modes such as mutiplanar reconstruction that are applicable to maxillofacial imaging. However, the disadvantages of CBCT include higher doses than two-dimensional imaging; the inability to accurately represent the internal structure of soft tissues and soft-tissue lesions; a limited correlation with Hounsfield Units for standardized quantification of bone density; and the presence of various types of image artifacts, mainly those produced by metal restorations. CBCT is now commonly used for a variety of purposes in oral implantology, dento-maxillofacial surgery, image-guided surgical procedures, endodontics, periodontics and orthodontics. CBCT applications provide obvious benefits in the assessment of dentomaxillofacial region, however; it should be used only in correct indications considering the necessity and the potential hazards of the examination. PMID- 26120380 TI - Advances of multidetector computed tomography in the characterization and staging of renal cell carcinoma. AB - Renal cell carcinoma (RCC) accounts for approximately 90%-95% of kidney tumors. With the widespread use of cross-sectional imaging modalities, more than half of RCCs are detected incidentally, often diagnosed at an early stage. This may allow the planning of more conservative treatment strategies. Computed tomography (CT) is considered the examination of choice for the detection and staging of RCC. Multidetector CT (MDCT) with the improvement of spatial resolution and the ability to obtain multiphase imaging, multiplanar and three-dimensional reconstructions in any desired plane brought about further improvement in the evaluation of RCC. Differentiation of RCC from benign renal tumors based on MDCT features is improved. Tumor enhancement characteristics on MDCT have been found closely to correlate with the histologic subtype of RCC, the nuclear grade and the cytogenetic characteristics of clear cell RCC. Important information, including tumor size, localization, and organ involvement, presence and extent of venous thrombus, possible invasion of adjacent organs or lymph nodes, and presence of distant metastases are provided by MDCT examination. The preoperative evaluation of patients with RCC was improved by depicting the presence or absence of renal pseudocapsule and by assessing the possible neoplastic infiltration of the perirenal fat tissue and/or renal sinus fat compartment. PMID- 26120382 TI - Contrast-enhanced ultrasound imaging of the vasa vasorum of carotid artery plaque. AB - The vasa vasorum of carotid artery plaque is a novel marker of accurately evaluating the vulnerability of carotid artery plaque, which was associated with symptomatic cerebrovascular and cardiovascular disease. The presence of ultrasound contrast agents in carotid artery plaque represents the presence of the vasa vasorum in carotid artery plaque because the ultrasound contrast agents are strict intravascular tracers. Therefore, contrast-enhanced ultrasound (CEUS) is a novel and safe imaging modality for evaluating the vasa vasorum in carotid artery plaque. However, there are some issues that needs to be assessed to embody fully the clinical utility of the vasa vasorum in carotid artery plaque with CEUS. PMID- 26120383 TI - Risk management in radiology departments. AB - Medical imaging and interventional radiology sustained prompt changes in the last few years, mainly as a result of technology breakthroughs, rise in workload, deficit in workforce and globalization. Risk is considered to be the chance or possibility of incurring loss or of a negative event happening that may cause injury to patients or medical practitioners. There are various causes of risks leading to harm and injury in radiology departments, and it is one of the objectives of this paper to scrutinize some of the causes. This will drive to consideration of some of the approaches that are used in managing risks in radiology. This paper aims at investigating risk management in radiology, and this will be achieved through a thorough assessment of the risk control measures that are used in the radiology department. It has been observed that the major focus of risk management in such medical setting is to reduce and eliminate harm and injury to patients through integration of various medical precautions. The field of Radiology is rapidly evolving due to technology advances and the globalization of healthcare. This ongoing development will have a great impact on the level of quality of care and service delivery. Thus, risk management in radiology is essential in protecting the patients, radiologists, and the medical organization in terms of capital and widening of the reputation of the medical organization with the patients. PMID- 26120384 TI - Endovascular retrieval of a prematurely deployed covered stent. AB - Several techniques have been reported to address different endovascular device failures. We report the case of a premature deployment of a covered balloon mounted stent during endovascular repair of a post-traumatic carotid-cavernous fistula (CCF). A 50-year-old male suffered a fall resulting in loss of consciousness and multiple facial fractures. Five weeks later, he developed decreased left visual acuity, proptosis, chemosis, limited eye movements and cranial/orbit bruit. Cerebral angiography demonstrated a direct left CCF and endovascular repair with a 5.0 mm * 19 mm covered stent was planned. Once in the lacerum segment, increased resistance was encountered and the stent was withdrawn resulting in premature deployment. A 3 mm * 9 mm balloon was advanced over an exchange length microwire and through the stent lumen. Once distal to the stent, the balloon was inflated and slowly pulled back in contact with the stent. All devices were successfully withdrawn as a unit. The use of a balloon to retrieve a prematurely deployed balloon mounted stent is a potential rescue option if leaving the stent in situ carries risks. PMID- 26120385 TI - Viability of Escherichia coli ATCC 8739 in Nutrient Broth, Luria-Bertani Broth and Brain Heart Infusion over 11 Weeks. AB - BACKGROUND: Escherichia coli is a widely studied prokaryotic system. A recent study had demonstrated that reduced growth of E. coli after extended culture in Luria-Bertani broth is a result of depletion of fermentable sugars but able to sustain extended cell culture due to the presence of amino acids, which can be utilized as a carbon source. However, this had not been demonstrated in other media. The study aimed to determine the growth and viability of E. coli ATCC 8739 in 3 different media, Nutrient Broth (NB), Brain Heart Infusion (BHI) and Luria Bertani Broth (LB) over 11 weeks. METHODS: Growth of E. coli ATCC 8739 was determined by optical density. Viability was determined by serial dilution/spread plate enumeration. After 11 weeks, the media were exhausted by repeated culture. Glucose was added to the exhausted media to determine whether glucose is the growth-limiting factor. RESULTS: Our results showed that cell density in all 3 media increased to about 1 * 10(9) cells/ml by the end of week 1, from the inoculation density of 2.67 * 10(5) cells/ml, peaked at about 1 * 10(13) cells/ml at week 4, before declining to about 5 * 10(7) cells/ml at week 7. Cell density is highly correlated to genomic DNA content (r(2) = 0.93) but poorly correlated to optical density (r(2)< 0.2). Our results also showed that the spent media were able to support further growth after glucose-supplementation. CONCLUSION: NB, LB and BHI are able to support extended periods of culture and glucose depletion is the likely reason for declining cell growth. PMID- 26120386 TI - Purslane Effect on GLP-1 and GLP-1 receptor in type 2 diabetes. AB - BACKGROUND: The aim of this study was to examine the effect of purslane seeds in glucagon-like peptide-1 concentration and glucagon-like peptide-1 receptor in women with diabetes. METHODS: This was a quasi-experimental study. The population was consisted of the city of Sari where diabetic women with diabetes II who had no history of using purslane seeds. All individuals used the same dose of metformin under the specialist supervision. Among these individuals, 16 were assigned at random to Purslane group and control group. The purslane group consumed 2.5 grams Purslane with lunch and along with 5 grams of purslane (Portulaca oleracea seeds 7.5 g daily) with dinner meals twice daily for 8 weeks. Blood sample was taken before and after 8 weeks, after 12 hours of fasting to 5 ml of the left brachial vein. RESULTS: After 8 weeks using purslane seeds in the experimental group, a significant increase was seen in glucagon-like peptide-1 concentrations (p<0.007), but there was no significant difference in the concentration of glucagon-like peptide-1 receptor (p <0.455). No significant relationship was found between changes in glucagon-like peptide-1 and its receptor. CONCLUSION: The use of purslane seeds improved Type II diabetes; therefore it can be effective in improving the health of women with diabetes. PMID- 26120387 TI - Application of Transtheoretical Model to Exercise in Office Staff. AB - BACKGROUND: Transtheoretical model is identified as a comprehensive model for behavior exercise. The aim of this study was to check the situation of stage of change in exercise behavior of office personnel of Yazd city using transtheoretical model. METHODS: In a cross-sectional study, 220 office personnel selected from administrative offices of Yazd through two-stage cluster-sampling method. The instrument for data collection was a questionnaire that included demographic variables and constructs of transtheoretical model. The reliability and validity of the instruments were examined and approved by experts. The data was analyzed using SPSS soft ware. RESULTS: 152 males (69.1%) and 68 females (30.9%) with an average age of 34+/-8.68 years were selected. Sixty percent of the subjects were in precontemplation and contemplation stages and only 7.3% were in action stages. Significant differences were found between TTM constructs and stages of change (P=0.000). The results also showed significant differences between components of decisional balance and behavioral process and cognitive process with the stages of change. We found that behavioral process of change and self efficacy were the most important variables for improving levels of exercise. CONCLUSION: Most of the participants were in the precontemplation and contemplation stages and most problems were related to behavioral process and self efficacy. Therefore, strategies and programs are needed to be taken into account to improve exercise among the staff. PMID- 26120388 TI - Determination of Job Stresses and Their Consequences in Drivers in Ilam. AB - BACKGROUND: Human factors cause 60-70 percent of automobile accidents. Everything related to people that is involved in and interacting with a system is considered to be a human factor. These factors can be psychological, biological, or social, and all of them can affect drivers' behaviors. Therefore, one of the negative and unfavorable effects of these factors is that they cause accidents. According to previous research, increases in the job stresses result in increases in the incidence of car accidents. Drivers who feel stressed often do not to observe the rules, and they may not even notice the warning signs. By measuring the job stress among drivers and its adverse effects, this research aimed to provide an appropriate managerial solution to reduce these problems. METHODS: The sample in this descriptive-analytical study consisted of 250 drivers who were selected and investigated. A job stress questionnaire was used as a means for collecting data. Health conditions were assessed by referring to clinical documents provided for the drivers. Accident data were included in the study using accident-related documentation. Two hundred and fifty drivers from Ilam, Iran participated and were analyzed in this study. This research is a cross-sectional study that was performed by dossiers and personal memoirs. Data were analyzed by SPSS16 and the chi-squared test. RESULTS: The study showed that the main factors that cause medium- to high-level stress are the physical environment, workload and ambiguity of duties. It also showed that the incidence and severity of accidents increased as stress levels increased. CONCLUSION: This study shows high prevalence of job stress amongst drivers in Ilam. The main causes of the prevalence of stress among drivers in Ilam City are physical environment, workload and ambiguity of duties, responsibility. PMID- 26120389 TI - Survey and comparison of sleep quality among fixed and changing shift staff in a steel factory in Tehran, Iran. AB - BACKGROUND: Given the hazardous nature of the work in steel factories and that the staff has to deal with hazardous equipment and machines, improper sleep quality and drowsiness among the works tackles performance and boosts rate of job accidents. This study is aimed to survey the quality of sleep and sleepiness status and the pertinent factors among the workers in a rolling mill and a steel production company in Tehran, Iran. METHODS: In a Cross-Sectional study 2011, 180 workers were selected randomly from a rolling mill and a steel production company in Tehran. A questionnaire was designed to collect demographic data and variables of work condition. Pitersborg's sleep quality questionnaire was used to survey quality and problems of Participants' sleep. Epworth Sleepiness questionnaire was used to deals with sleepiness during work, studying, watching TV, or during time spent in public. RESULTS: Average score of sleep quality for the fixed shift staff and changing shift staff were 7.5+/-2.82 and 8.49+/-2.95 respectively. Surveys of sleep quality for the two groups of the participants based on T-test showed a significant difference between the two groups so that the changing shift staff group suffered poorer sleep quality (p=0.03). Comparison of average drowsiness scores between the two groups of participants based on Mann-Whitney test showed no significant difference (p>0.005). Chi square test showed a significant difference between severity of drowsiness and type of working shift (p =0.028 and 0.009). CONCLUSION: Staff in revolving shifts suffers poor sleep quality comparing with staff with fixed working shift. Moreover, type of working shift greatly affects severity of drowsiness as staff at different work shift experienced different level of sleepiness. It is essential to survey sleep disorder of the staff in the industry and pay more emphasis on sleep disorder epidemic in other fields of industry. PMID- 26120390 TI - Prevalence and patterns of physical activity among medical students in Bangalore, India. AB - BACKGROUND: Physical activity is one of the leading health indicators. The objective was to study the prevalence and patterns of physical activity among young adults. METHODS: 259 Medical students (Men: Women = 116:143) in the age group of 18-22 yrs were interviewed using the official English long version of the International Physical Activity Questionnaire (IPAQ). The total level of physical activity and activity in each of the 4 life domains - work, transport, domestic and gardening and leisure-time were estimated and was expressed as metabolic equivalent-hours per week (MET-hour/week). RESULTS: 41.3 % showed high levels of physical activity, 43.2% and 15.4 % of students showed moderate level and low level of physical activity respectively. 84.6 % (n=219) were engaged in work related activity and 80.7% (n= 209) showed transport related activity. Domestic and gardening physical activity represented 63.7 % (n=165) of individuals total activity and 67.2% of students showed leisure time activity. The average time spent in sitting was 7.06 hrs/day. The median of the total physical activity for the whole sample was 39.13 MET/hour/week and 18.10 for work, 4.40 for transportation, 2.60 for domestic and gardening and 4 for leisure time activity. There was significant gender difference observed with women having low physical activity. CONCLUSION: This study provides baseline information about the physical activity levels and patterns including sitting hours among Indian young adults using IPAQ that can used for comparison of data across different parts of world. PMID- 26120391 TI - Investigation of Occupational Stress and its Relationship with the Demographic Characteristics of Workers in Ilam, Iran. AB - BACKGROUND: Workers are more susceptible to stress disorder for several reasons. The aim of this study was to investigate occupational stress among workers and other personnel at the ZardjinBaft Workshop in Ilam, Iran, and to examine the relationship between occupational stress and several parameters, such as age, gender, marital status, educational level, work experience, tobacco use, body mass index (BMI), and the type of work. METHOD: This was a descriptive, cross sectional study that was performed in June 2010. The sample population that was studied consisted of all of the workers and other personnel (130 people) at ZardjinBaft Workshop in Ilam, Iran. They were studied using Cooper's standard questionnaire for stress in the work environment, and we examined the relationship between stress, as the dependent variable, and the eight independent variables mentioned in the Abstract. RESULTS: In the sample population that was studied, severe stress was not observed in most of the sections of the workshop. In addition, using the analysis of variance test (ANOVA), no significant relationship was observed between the average degree of stress and the average demographic characteristics. However, the average stress level had significant relationships with the level of education, work experience, and the type of work, suggesting that stress increases as the level of education increases. In addition, in the beginning and early years of employment, medium levels of stress were observed, and the prevalence of stress decreased after the first 10 years of employment. In addition, workers in the ventilation section of the factory had the highest stress levels. The fear of losing their jobs was the main factor that caused stress among the workers at ZardjinBaft Workshop in Ilam. CONCLUSION: We suggest that managers consider the high importance of stress in the work environment. They should be able to recognize when workers are stressed and offer them assistance and training. They also can eliminate the factors that cause stress in the work environment by taking preventive action. In parallel, workers should try to interact well with their managers and talk to her or him about the conditions of their jobs. PMID- 26120392 TI - The effect of the use of NP305 masks in improving respiratory symptoms in workers exposed to sulfuric acid mists in plating and pickling units. AB - BACKGROUND: Plating and pickling processes are the most effective ways for increasing the strength of metal structures, and workers in these units are exposed to various contaminants, including acid mists. The aim of this study was to investigate the effect of protective masks in decreasing the respiratory symptoms and the aerobic capacity of workers that are exposed sulfuric acid mist. METHODS: This interventional study was based on National Institute for Occupational Safety and Health (NIOSH) standard 7903 in which silica gel tubes are used for sampling the air in plating and pickling units for eight hours. After the samples were acquired and prepared, they were analyzed by ion chromatography and were compared with the American Conference of Governmental Industrial Hygienists (ACGIH) exposure limits. Respiratory symptoms were evaluated among two sets of test subjects, i.e., those who used NP305 masks in the workplace and those who did not use the mask. RESULTS: The results showed that the concentration of sulfuric acid mist in the plating units was greater than the exposure limits, and concentrations at this level can cause an increase in symptoms related to irritation of the airway and a slight decrease in respiratory capacity. In this study, smoking had no significant effect on the severity of pulmonary dysfunction. CONCLUSION: The results indicated that the use of an NP305 mask is effective for decreasing symptoms resulting from exposure to sulfuric acid mist and improving respiratory capacity. PMID- 26120393 TI - Effect of six-week aerobic exercise on Chemerin and Resistin concentration in hypertensive postmenopausal women. AB - BACKGROUND: Physical activity reduces symptoms of cardiovascular diseases. The aim of this study was to examine the effect of six-week aerobic exercise upon Chemerin and Resistin concentration in women with menopause who had hypertension. METHODS: The population of this quasi-experimental study included postmenopausal women diagnosed with hypertension. They were 50 to 55 years old and lived in Amol, a city in north part of Iran. Twenty volunteers were filled the personal consent and Health Questionnaire. They were randomly assigned to Experimental and control groups equally (n=10 per group). The experimental group conducted a 6 week aerobic training program from 8-10am every day. RESULTS: Endurance exercise decreased Chemerin (t=10.41, P<0.000) and Resistin (t=2.42, P<0.051); indicating the decline of inflammation and cardiovascular disease. CONCLUSION: Considering anti-inflammatory effects of exercise, training plays an important role in reducing inflammatory indices in human; and endurance training can be a good strategy to deal with inflammation and cardiac- vascular risk factors. PMID- 26120395 TI - Short Report About the Inpatient Health Services Standards in Electronic Health Records. PMID- 26120394 TI - Application of WHO model for evaluating Patient Safety Friendly Hospital Initiatives (PSFHI) in an Eye hospital in Tehran, Iran. AB - BACKGROUND: Patient safety is one of the major issues concerning the medical community and the World Health Organization (WHO) in most countries. This study aimed to evaluate the patient safety status in an Eye Hospital in Tehran, using the WHO model for Patient Safety Friendly Hospital Initiatives (PSFHI) in 2012. METHODS: This Cross-Sectional study was done in an Eye Hospital in Tehran. Measurement tool was a checklist related to the PSFHI, including 140 standards in three groups of critical, core and developmental. It was covering five domains of: a) Leadership and management, b) Patient and public involvement, c) Safe evidence-based clinical practices, d) Safe environment, and e) Lifelong learning. RESULTS: Compliance with critical, core and developmental standards were 77.78%, 75.29%, and 21.42% respectively. The Rates of Meeting Standards in the leadership and management, patient and public involvement, safe evidence-based clinical practices, secure environment and for lifelong learning were 66.89%, 42.85%, 75.68%, 73.68%, and 63.63% respectively. CONCLUSIONS: The PSFHI standards play important role in improving patient safety using leadership, safety practices and creating good working conditions and environment for the staff. So focus on these standards is essential in improving the patient safety in hospitals in Iran. PMID- 26120396 TI - Analysis of Amygdala Nucleus in the Rat Brain: A review study. AB - Amygdale is one of the limbic related sub-cortical nuclei lying in the depth of temporal lobe and rostral of the inferior horn of lateral ventricle. In fact, amygdale is a nucleus complex that plays an important role in the emotional response, anger, fear, regulation of cardiovascular system, memory processes and learning and in pathophysiology of many diseases such as epilepsy, schizophrenia, Alzheimer, anxiety and depression. With regard to important of the amygdala in many critical functions, the cerebral disease and because of ethical problems most studies were done on animal models especially rats. Hence, in this review paper we tried to investigate different aspects of the rat amygdala complex including cyto, myelo and receptoarchitectonic. PMID- 26120398 TI - Application of information technology may increase the efficacy of Confidential Unit Exclusion (CUE) in blood donors. AB - Confidential Unit Exclusion (CUE) refers to a procedure by which a blood donor designates confidentially whether his or her blood might not be safe for transfusion. It applies to situations in which an individual who is not eligible for blood donation in terms of blood safety feel pressured by others to donate his or her blood. A potential problem in the CUE system is misunderstanding of the procedure and its significance by blood donors as well as the lack of their confidence regarding the confidentiality of their private information. Since the Information and Communication Technology (ICT) provides a secure and confidential atmosphere, it is expected the application of ICT have a positive impact on the efficacy of CUE system. PMID- 26120397 TI - Assessment of the prevalence of occupational accidents and their influential actors in an electricity distribution company during a five-year period. AB - BACKGROUND: Occupational accidents have been considered as one of the most important crippling factors contributing to disabilities and life-threatening situations in many countries. This study was conducted to survey the prevalence of occupational accidents and the factors of that lead to injuries in an Electricity Distribution Company during a five-year period. METHODS: In this descriptive study, the accident report form included items asking about the season of the year when the accident occurred, the ages and the average age of those injured, the type of employment, work experience, nature of the injuries that occurred, parts of the body affected, treatments that were applied, average number of days lost per accident, the levels of education of those involved, and their marital status. Data was analyzed using SPSS. RESULTS: A total of 66 Electricity Distribution Company workers were determined to be suffering from injuries due to accidents. The accidents mostly occurred in the summer (33%). Most of the injured workers (16.7%) belonged to the age groups of 25 to 29 and 40 to 44; there were no accidents reported for workers who were less than 20. About 48% of the accident victims had to be hospitalized. Furthermore, 35% of the accident victims were treated in outpatient clinics, and 7.4% of the accident victims died. We demonstrated that there were significant relationships between: 1) marital status and accidental injuries (P<0.001); 2) the average age of those injured among both permanent and temporary workers (P<0.001), 3) the level of education and the consequences of the accidents (P<0.001), and 4) the average of days lost per accident in both the permanent and temporary workers (P<0.001). In this study, no significant relationships were found between the accident occurrence and age (P>0.05) or work experience and the distribution of the accidents (P>0.05). CONCLUSION: This study indicated that most of the injuries in these accidents were related to the nature of employment, marital status, and level of education. The results showed the necessity for providing appropriate safety training for the workers. PMID- 26120399 TI - Management of Mallet Fracture by Closed Extension-Block Pinning - A case based review of a novel technique. AB - Close reduction by extension-block K-wire fixation for acute mallet fracture is a relatively novel mode of treatment which is based on two sound orthopedic principles - stable arc splinting and early protected motion. Distal interphalangeal joint splinting is still the technique commonly used for mallet fractures with significant morbidity and only moderate functional outcome. We have demonstrated here Ishiguro's technique in a partially treated 2 weeks old mallet fracture with the flexion deformity at distal interphalangeal (DIP) joint after proper preoperative assessment. Peroperatively, proper anatomical localization of mallet fragment was done under fluoroscopy. Reduction of the avulsion fracture was done by extension block K-wire and intra-articular K-wire was inserted subsequently to hold the reduction in place and DIP joint in extension. Later on K-wires were removed at the end of 6 weeks follow up. Patient was subjected to the physiotherapy during the course of the treatment. Excellent functional outcome was noted at the end of three months. PMID- 26120400 TI - Prevalence of HBc-Ab among HBs-Ag negative healthy blood donors in south of Iran. AB - BACKGROUND: The risk of infection with transfusion-transmitted viruses, such as Hepatitis B virus (HBV), has been reduced markedly. However, a zero-risk blood supply remains a popular goal. Anti-hepatitis B core antigen (anti-HBc) is considered to be an effective marker for occult HBV infection, and it has served a significant role in improving blood safety. The purpose of this study was to determine the seroprevalence of anti-HBc antibodies among blood donors. METHODS: During a period of six months in 2012, 1000 blood donors in Bandar Abbas were investigated for the presence of HBV infection markers. We used ELISA for the detection of HBsAg and chemiluminescence for the detection of HBsAb and anti-HBc antibodies. RESULTS: The prevalence of positive anti-HBc among the 1000 donors was 8.3%. Almost 2.3% of the donors were reactive for anti-HBc and negative for HBsAg. CONCLUSIONS: The study showed that more than 2% of healthy blood donors in Bandar Abbas already have been exposed to HBV, although their HBsAg tests were negative. We suggest screening for anti-HBc to improve the safety of the blood supply. PMID- 26120401 TI - Assessment of patient safety culture among personnel in the hospitals associated with Islamic Azad University in Tehran in 2013. AB - BACKGROUND: Patient safety is an essential element in the quality of healthcare, and a clear knowledge of its culture in healthcare organizations will lead to both improved healthcare and patient safety. The aim of this study was to assess the patient safety culture at Islamic Azad University hospitals in Tehran, Iran, in 2013. METHODS: This cross-sectional study was conducted on clinical and diagnostic staff in all Islamic Azad University hospitals in Tehran in June 2013. The international "Hospital Survey on Patient Safety Culture" questionnaire was used as the measurement tool. RESULTS: In these hospitals, the overall positive score of patient safety culture was 35%. "Teamwork within units" (48% positive) was evaluated as reflecting the most knowledge of the aspects of patient safety culture, and "non-punitive response to error" (12% positive) was evaluated as reflecting the least knowledge of the aspects of patient safety culture. CONCLUSION: The patient safety culture in the hospitals that were studied should be improved. This goal could be achieved by reinforcing the basics of patient safety culture by teaching the staff members about the aspects of a positive patient safety culture and encouraging them to incorporate these aspects in their day-to-day activities. PMID- 26120403 TI - New corruption detected: Bogus impact factors compiled by fake organizations. PMID- 26120402 TI - Prevalence of and Factors Associated with Migraine in Medical Students at BandarAbbas, Southern Iran, in 2012. AB - BACKGROUND: Migraine is one of the most common etiologies for headache. This very common neurological disorder has a significant impact on patients' quality of life. The aim of the current study is to evaluate the prevalence of migraine among medical students in the Hormozgan University of Medical Sciences (HUMS). METHODS: A total of 350 medical students were enrolled in our descriptive study. Data were collected using the standard questionnaire of the International Headache Association. The data were analyzed by SPSS 20.0 software using descriptive statistics, Chi-Square, and Independent Samples T-Test. A P-value of >=0.05 was considered statistically significant, since most public health professionals use this value as a standard. RESULTS: Among the medical students in our study, 24.6% had experienced frequent, severe headaches. The underlying causes of the headaches were diagnosed in 19.8% of the students. The prevalence of migraine in our study was 16.3% (mean age=21.28+/-2.71years). The prevalence varied by gender, and it was greater among male students. CONCLUSION: Our findings indicated that there was a high prevalence of migraine among the medical students in our study, and these findings were consistent with those of previous studies in Iran and other countries. PMID- 26120404 TI - Lifestyle factors and dietary intake of Iranian postgraduate students in Universiti Putra Malaysia (UPM). AB - BACKGROUND: A student's lifestyle can change notably in a foreign country. The objective of this study was to determine factors associated with the body weight status of Iranian postgraduate students in Universiti Putra Malaysia (UPM) 2009. METHODS: A self-administered questionnaire was administered to 210 Iranian postgraduate students at UPM. Anthropometric factors also were measured using standard procedures. Body mass index (BMI) and waist-to-hip ratio (WHR) also were calculated. The chi-squared test, Spearman's rho, and the Pearson product-moment correlation coefficient were used to determine the associations between the variables that were studied. Multiple linear regression analysis was used to measure the amount of influence a predictor variable had on a outcome variable. RESULTS: There was no significant correlation between nutritional knowledge (P > 0.05), weight-management knowledge (P > 0.05), and smoking (P > 0.05) and BMI. There were statistically significant correlations between gender (P < 0.01), physical activity (P < 0.05), protein (P < 0.01), carbohydrate (P < 0.01), fat (P < 0.01), fiber (P < 0.01), vitamin C (P < 0.05), calcium (P < 0.01), and iron (P < 0.01) and BMI. There were also relationships between body fat (P < 0.01), waist circumference (P < 0.01), hip circumference (P < 0.01) and WHR (P < 0.01) and BMI. CONCLUSION: Our findings showed the need for a nutrition promotion program for the Iranian students to help them change their negative food habits and improve their lifestyles. PMID- 26120405 TI - Review the number of accidents in Tehran over a two-year period and prediction of the number of events based on a time-series model. AB - BACKGROUND: One of the significant dangers that threaten people's lives is the increased risk of accidents. Annually, more than 1.3 million people die around the world as a result of accidents, and it has been estimated that approximately 300 deaths occur daily due to traffic accidents in the world with more than 50% of that number being people who were not even passengers in the cars. The aim of this study was to examine traffic accidents in Tehran and forecast the number of future accidents using a time-series model. METHODS: The study was a cross sectional study that was conducted in 2011. The sample population was all traffic accidents that caused death and physical injuries in Tehran in 2010 and 2011, as registered in the Tehran Emergency ward. The present study used Minitab 15 software to provide a description of accidents in Tehran for the specified time period as well as those that occurred during April 2012. RESULTS: The results indicated that the average number of daily traffic accidents in Tehran in 2010 was 187 with a standard deviation of 83.6. In 2011, there was an average of 180 daily traffic accidents with a standard deviation of 39.5. One-way analysis of variance indicated that the average number of accidents in the city was different for different months of the year (P < 0.05). Most of the accidents occurred in March, July, August, and September. Thus, more accidents occurred in the summer than in the other seasons. The number of accidents was predicted based on an auto regressive, moving average (ARMA) for April 2012. The number of accidents displayed a seasonal trend. The prediction of the number of accidents in the city during April of 2012 indicated that a total of 4,459 accidents would occur with mean of 149 accidents per day during these three months. CONCLUSION: The number of accidents in Tehran displayed a seasonal trend, and the number of accidents was different for different seasons of the year. PMID- 26120406 TI - Effects of Nanoparticles on the Environment and Outdoor Workplaces. AB - Today, most parts of different nanotechnologies are growing and developing without any special rules and regulations. This could result in undesirable changes in the environment and affect workers in indoor and outdoor workplaces. Carbon-based nanoparticles, such as fullerenes, nanotubes, the oxides of metals such as iron and titanium, and natural inorganic compounds, including asbestos and quartz, can have biological effects on the environment and human health. The risk assessment of such nanoparticles requires evaluation of their mobility, reactivity, environmental toxicity, and stability. With the increasing use of nanoparticles for commercial and industrial purposes, the debate becomes whether the numerous benefits of nanoparticles can overcome the economic costs, environmental impacts, and unknown risks resulting from their use. To date, few studies have been conducted on the toxic and environmental effects that result from direct and indirect exposure to nanoparticles, and there are no clear standards to determine their effects. Lack of technical information in this regard has provided an appropriate context for supporters and opponents of nanoparticles to present contradictory and ill-considered results. Such an uncertain atmosphere has caused increased concerns about the effects of nanoparticles. Therefore, adequate studies to determine the exact, real risks of the use of nanoparticles are required. The information resulting from these studies can be useful in minimizing the environmental hazards that could arise from the use of nanoparticles. Thus, this paper briefly explains the classification of environmental nanoparticles and how to deal with their formation, diffusion, environmental fate and impacts, and our exposure to them. PMID- 26120408 TI - A second chance for authors of hijacked journals to publish in legitimate journals. AB - This article proposes the republication of articles that have previously been published in counterfeit websites of hijacked journals. The paper also discusses the technical and ethical aspects of republishing such articles. PMID- 26120407 TI - Misoprostol versus High Dose Oxytocin and Laminaria in Termination of Pregnancy in Second Trimester Pregnancies. AB - BACKGROUND: In 2 recent decades, found drug regimen to induce abortion that are more effective than surgery. Prostaglandins especially misoprostol, oxytocin and osmotic dilators such as laminaria use for termination but the best method is unknown. Therefore we aimed to assess the comparison between the Misoprostol regimen and the highly concentrated oxytocin with laminaria regimen in second trimester of pregnancy termination. METHODS: In this randomized clinical trial, 100 women with gestational age 14 to 24 week coming to hospital due to termination of pregnancy in the absence of uterine contractions and items of exclusion criteria enrolled to study and randomly assign to 2 groups and received misoprostol (group 1) or oxytocin (group 2). Data collected with use of observation, examination and demographic checklist. In group 1, in admission time and then every 6 hour patients received 200 ugr misoprostol until start the pain or vaginal bleeding or abortion in 48 hr. in group 2, patients first received laminaria in cervix with duration of 6 hr and then oxytocin 50 unit in 500 cc normal saline in 3 hr. after 1 hr rest, oxytocin dosage elevated as multiple into 2 and continue until termination or maximum dose of 300 u in 500 cc normal saline. Data entered to SPSS software version 16 and analyzed with use of descriptive methods and also Chi-square and T-test. RESULTS: In each group enrolled 50 women that approximately no different in baseline characteristic. Number of abortion in misoprostol group was more than oxytocin group (P<0.001) and duration of abortion also was shorter than oxytocin in misoprostol group (P<0.001). Side effects in 23 (46%) women in misoprostol group were seen but no side effect seen in oxytocin group. Complementally interventions was seen in 31 women (60%) in misoprostol group versus 32 women (62%) in oxytocin group but this difference was not significant (P>0.05). CONCLUSION: This study demonstrated that misoprostol is effective than oxytocin in termination of pregnancy but with attention to limitation of this study include of limited abortion causes due to legal laws, additional studies on different doses of misoprostol and oxytocin due to achieve to suitable regimen with lower side effects recommended. PMID- 26120409 TI - Comparative evaluation of eosinophils in normal mucosa, dysplastic mucosa and oral squamous cell carcinoma with hematoxylin-eosin, Congo red, and EMR1 immunohistochemical staining techniques. AB - BACKGROUND: Oral squamous cell carcinoma is the most common malignant lesion of the oral cavity, and it involves various molecular mechanisms. The development of oral squamous cell carcinoma is influenced by the host immune cells, such as eosinophils. The present study was conducted to compare the presence of eosinophils in normal mucosa, dysplastic mucosa, and oral squamous cell carcinoma by -hematoxylin- eosin staining, Congo red staining, and epidermal growth factor like (EGF-like) module containing a mucin-like hormone receptor1 (EMR1) immunohistochemical marker. METHODS: In this cross-sectional study, 60 paraffinized samples were selected, consisting of 20 normal mucosae, 20 dysplastic mucosae, and 20 squamous cell carcinoma samples. After confirmation of the diagnosis, the mean number of eosinophils was evaluated by hematoxylin-eosin, Congo red, and immunohystochemical staining techniques. The data were analyzed by SPSS-10 software using the Kruskal-Wallis and Friedman tests. RESULTS: The results showed that the number of eosinophils in dysplastic mucosa was significantly higher than the number in normal mucosa, and the number of eosinophils in squamous cell carcinoma was significantly higher than the number in dysplastic mucosa in all staining techniques (p<0.001). Moreover, the comparison of staining techniques showed a significantly higher number of eosinophils in EMR1immunohistochemicalmarker than were observed when Congo red and hematoxylin - eosin (H&E) staining techniques were used (p<0.001). CONCLUSION: It can be argued that eosinophil contributes to the identification of lesions that have a higher potential of malignant transformation. Moreover, eosinophil can be suggested as an indicator in the differentiation of oral lesions in cases with borderline diagnosis and in targeted molecular therapy. PMID- 26120410 TI - Parkinsonism: a rare manifestation of craniopharyngioma. AB - Craniopharyngioma is a non-glial, non-malignant intracranial tumor of ectodermal origin, which arises from a remnant of Rathke's pouch. This tumor accounts for 5.6 to 13% of intracranial tumors in children. This paper discusses a case of craniopharyngioma in a five-year-old boy. An MRI scan of his brain showed a huge sella and supra sella cystic-solid lesion that had invaded the prepontine and interpeduncular cisterns, filling of 3rd ventricle and hydrocephalus. The patient operated via interhemispheric subfrontal through lamina terminalis and the tumor dissected from all part of brain stem and total resection achieved. After surgery Parkinsonism was worse for 3 days and levodopa started for 3 days. Parkinsonism was gone and after one week levodopa discontinued. This case practically implied that decompression of mass effect of tumor on brain stem and short-term management with levodopa can improve Parkinsonism due to midline compressive brain tumors without basal ganglia involvement. PMID- 26120411 TI - Regional lymph node radiotherapy in breast cancer: single anterior supraclavicular field vs. two anterior and posterior opposed supraclavicular fields. AB - BACKGROUND: The treatment of lymph nodes engaged in breast cancer with radiotherapy leads to improved locoregional control and enhanced survival rates in patients after surgery. The aim of this study was to compare two treatment techniques, namely single anterior posterior (AP) supraclavicular field with plan depth and two anterior and posterior opposed (AP/PA) supraclavicular fields. In the study, we also examined the relationships between the depth of supraclavicular lymph nodes (SCLNs) and the diameter of the wall of the chest and body mass index (BMI). METHODS: Forty patients with breast cancer were analyzed using computed tomography (CT) scans. In planning target volume (PTV), the SCLNs and axillary lymph nodes (AXLNs) were contoured, and, with the attention to PTV, supraclavicular (SC) depth was measured. The dosage that reached the aforementioned lymph nodes and the level of hot spots were investigated using two treatment methods, i.e., 1) AP/PA and 2) AP with three-dimensional (3D) planning. Each of these methods was analyzed using the program Isogray for the 6 MV compact accelerator, and the diameter of the wall of the chest was measured using the CT scan at the center of the SC field. RESULTS: Placing the plan such that 95% of the target volume with 95% or greater of the prescribed dose of 50 Gy (V95) had >=95% concordance in both treatment techniques. According to the PTV, the depth of SCLNs and the diameter of the wall of the chest were 3-7 and 12-21cm, respectively. Regression analysis showed that the mean SC depth (the mean Plan depth) and the mean diameter of the wall of the chest were related directly to BMI (p<0.0001, adjusted R(2)=0.67) and (p<0.0001, adjusted R(2)=0.71), respectively. CONCLUSION: The AP/PA treatment technique was a more suitable choice of treatment than the AP field, especially for overweight and obese breast cancer patients. However, in the AP/PA technique, the use of a single-photon, low energy (6 MV) caused more hot spots than usual. PMID- 26120412 TI - Comparing the quality of preconception care provided in healthcare centers in Mashhad in 2012. AB - BACKGROUND: Improving the quality of healthcare services is considered as the main strategy to improve maternal and neonatal health outcomes. Providing appropriate healthcare for mothers and their newborn children is facilitated significantly by considering the mothers' health and welfare before pregnancy occurs. Therefore, the aim of this study was to compare the quality of preconception care provided to women of reproductive age provided by five health centers in Mashhad in 2012 and 2013. METHODS: Multi-stage sampling was used to select the participants in this descriptive study. As a result, 360 women of reproductive age and 39 healthcare providers from 24 healthcare centers in Mashhad were selected to participate. The data gathering tool was a checklist based on the Donabedian model that includes the three dimensions of structure, process, and outcome. The data were analyzed by SPSS software (version 11.5), Kruskal-Wallis tests, ANOVA, and Spearman rank correlation. RESULTS: The results showed that preconception care at the 24 healthcare centers had essentially the same conditions. But in the process and outcome components, the quality of the preconception care at five of the health centers was significantly different (p=0.008). The highest quality of care processes was identified at health center number 3. The difference in the component of outcomes being followed up by the healthcare providers at five of the health centers was statistically significant (p=0.000); however, there were no significant differences found among the satisfaction and awareness of the women who participated at the five health centers. CONCLUSION: The results showed that the performance of health personnel in providing preconception care and providing follow-up care was not satisfactory. PMID- 26120413 TI - Nausea and vomiting in Iranian Traditional Medicine based on Avicenna's viewpoint. AB - BACKGROUND: Nausea and vomiting decrease one's quality of life significantly, and, despite various treatments, they are still uncontrollable, especially in acute illness. Perhaps it would be useful to search for new concepts and therapies for dealing with these issues at other medical schools. The aim of this research was to elucidate the causes of nausea and vomiting in Iranian Traditional Medicine (ITM) based on Avicenna's viewpoint in The Book of "Canon of medicine". METHODS: We reviewed the Canon of Medicine and other reference textbooks of ITM to get the experts' viewpoints, such as Kamel-al-Sanaeh, Al Havi, and Zakhireh-kharazmshahi, and we searched PubMed, Scopus, Embase, ISI and Science Iranian Database (SID) in November and December 2014 using keywords. RESULTS: Basic terms associated with nausea and vomiting in ITM are Gha'y (vomiting), Tahavo'a (retching), Gathayan (nausea), and Taghallob-al-nafs (continuous nausea). Different factors can induce these problems with direct or indirect change in the quantity/quality of humors in the body's systems or the stomach. Treatments are based on the correction of humors and modifications of lifestyle. ITM has recommended medicinal herbs for severe nausea and vomiting. For example, they may be effective in treating chemotherapy-induced nausea and vomiting (CINV). CONCLUSION: ITM suggests that almost the nausea and vomiting associated with almost all major diseases originate from abnormalities in either the quantity/quality of humors. The gold standard for managing nausea and vomiting is lifestyle modifications with attention to responsible humors. Some therapeutic protocols in ITM may be applicable today. Perhaps redefining the diseases and updating the expression of these concepts and approaches can lead to the development of complementary and alternative treatments for nausea and vomiting. PMID- 26120414 TI - Factors associated with prostate cancer screening behavior among men over 50 in Fasa, Iran, based on the PRECEDE model. AB - BACKGROUND: Prostate cancer is one of the most common and lethal cancers in the world. The incidence of prostate cancer has been increasing in recent years. The purpose of this study was to investigate factors associated with prostate cancer screening behaviors among men over 50 in Fasa, Iran, based on the PRECEDE model. METHODS: In this cross-sectional study, 400 men over 50 were studied in Fasa, Iran. Data were collected via a questionnaire on demographic characteristics, such as age, number of children, occupation, education, marital status, smoking, and prostate cancer screening behaviors. Data were analyzed using SPSS software, version 16. Independent samples t-test and the Pearson Product Moment correlation coefficient were used for the statistical analyses. RESULTS: Men in the study had little knowledge (34.11+/-8.22) and attitude (28.23+/-7.23) about prostate cancer and screening behavior. Their mean scores about prostate cancer, screening behavior, quality of life, and general health were moderate. The subjects had low self-efficacy and perceived social support. Their mean scores of enabling factors and screening behaviors were at a low level. Pearson correlation scores showed a significant correlation between cancer prostate screening behavior and demographic variables, such as age (p=0.04, r=0.136), occupation (p=0.01, r=0.121), educational level (p=0.02, r=0.211), and marital status of the subjects (p=0.01, r=0.112), but there were not significant correlations with the number of children (p=0.12, r=0.092) and smoking (p=0.09, r=0.002). The T-test results showed significant relationships between age, occupation, and education of the subjects, and the PRECEDE model structures were significant for predisposing factors, enabling factors, and reinforcing factors (p<0.05). CONCLUSION: The prostate cancer screening behaviors in men over 50 in Fasa, Iran, were at a low level. Due to predisposing factors, such as the knowledge, attitudes, and beliefs of individuals, reinforcing factors can have an important role in the behaviors related to prostate screening, such as their families and health staffs as well as enabling factors, such as health financing, access to medicines and learning self-care. Educational interventions to improve these behaviors and the quality of life of these people seem essential. PMID- 26120416 TI - The story of fake impact factor companies and how we detected them. AB - Beginning about three years ago, the world of academic publishing has become infected by fake impact factors and misleading metrics that are launched by bogus companies. The misleading metrics and fake impact factors have damaged the prestige and reliability of scientific research and scholarly journals. This article presents the in-depth story of some of the main bogus impact factors, how they approached the academic world, and how the author identified them. Some names that they use are Universal Impact Factor (UIF), Global Impact Factor (GIF), and Citefactor, and there even is a fake Thomson Reuters Company. PMID- 26120415 TI - Assessment of unhealthy days among Iranian reproductive age women in 2012. AB - BACKGROUND: Unhealthy days are defined as the number of days during the past 30 days that a woman has not had a feeling of wellbeing. Wellbeing includes the woman's judgments about the level of satisfaction and quality in her life. Assessment of a woman's perception of unhealthy days can be used to help her determine the extent of the burdens associated with mental and physical feelings that things are not going well in her life, job and relationship. This study was conducted to measure unhealthy days and the general health status in Iranian women of reproductive age based on their own perceptions. METHODS: The participants of this study were women of reproductive age who were referred to health centers in Mashhad, Iran, in 2012. With the stratified random sampling method, 220 women were included in the study. The health-related quality of life 4 (HRQOL-4) questionnaire was used to assess the women's self-perceived unhealthy days. The data that were collected were analyzed by Kruskal-Wallis, chi-squared, Pearson correlation, and logistic linear regression tests with SPSS 11.5. RESULTS: The mean age of the participants was 32.6 years, and the median number of the self-perceived unhealthy days was 7.1 days (per month). In the domains of physical, mental, and disability unhealthy days, the data indicated 2 days, 2.1 days, and 0.1 day in a month, respectively. Also, nearly half of the participants reported that their general health status was poor to fair. The Kruskal-Wallis test showed that there was a significant difference between unhealthy days in the different age groups (p=0.01) as well as for the physical (p=0.02) and mental domains (p=0.4). The results of the regression analysis showed that the number of physical unhealthy days increased with age, number of children, and education. The number of mental unhealthy days increased with age, and the number of disability days increased as the age at which they were married decreased (p<0.05). A significant inverse relationship was observed between physical unhealthy days and education, with the number of physical unhealthy days decreasing as the years of education increased (r=-0.19, p=0.005). CONCLUSION: Women with less education who were older than 40, who married at an early age, and had more children reported more unhealthy days. These results emphasize the importance of preventive and educational health interventions in these vulnerable groups based on their physical and mental needs. PMID- 26120417 TI - Presenting a model for dynamic facial expression changes in detecting drivers' drowsiness. AB - Drowsiness while driving is a major cause of accidents. A driver fatigue detection system that is designed to sound an alarm, when appropriate, can prevent many accidents that sometime leads to the loss of life and property. In this paper, we classify drowsiness detection sensors and their strong and weak points. A compound model is proposed that uses image processing techniques to study the dynamic changes of the face to recognize drowsiness during driving. PMID- 26120418 TI - Effects of family-centered care on the satisfaction of parents of children hospitalized in pediatric wards in a pediatric ward in Chaloos in 2012. AB - BACKGROUND: Family-centered care (FCC) involves holistic care and requires cooperation with the family in planning, intervention, and the evolution of the care that is being provided. Many previous studies have provided results that indicate the importance of the family's involvement in pediatric care, but there is still resistance in doing so within the organizational culture of the hospitals in Iran. The aim of this study was to determine the effects of FCC on the satisfaction of parents of children hospitalized in 2012 in the pediatric ward at Razi Hospital in Chaloos, Iran. METHODS: This Quasi-experimental study was conducted in 2012 in the pediatric ward at Razi Hospital in Chaloos, Iran. Seventy hospitalized children between the ages of 1 and 3 who suffered from diarrhea, vomiting, or pneumonia were selected through convenience sampling. They were divided randomly into two equal groups, a control group (routine care) and an experimental group (family-centered care). SPSS Statistics 14 software was used to analyze the data, and p<0.05 was considered to be significant. RESULTS: In the FCC group, the mean score of satisfaction among the parents of the children was 20 out of 90 before the intervention, but, after the FCC method was used, it increased to 83.2 out of 90. In addition, a significant difference was found between the scores of satisfaction for the control and experimental groups (p<0.001), and all parents of children in the experimental group expressed high satisfaction. CONCLUSION: Our findings showed that the practice of FCC in caring for the sick children can increase the satisfaction of their parents significantly. The role of the family's involvement is critical in every component of the intervention efforts, as shown by the constructs of participatory support, educational support, and psychological support. Thus, a notable implication here is that FCC may lead to increased quality of care and should be included in the educational programs of the nursing staff in pediatric ward. PMID- 26120419 TI - Comparing the effect of volar plate fixators and external fixators on outcome of patients with intra-articular distal radius fractures: A clinical trial. AB - BACKGROUND: Distal radius fractures (DRFs) are much more prone to malunion than unstable extra-articular fractures. There is no clear consensus concerning what the proper treatment should be, and the best approach to use for displaced DRFs remains challenging. OBJECTIVE: To compare the effect of two different therapeutic surgical methods, i.e., volar plate fixators and external fixators, on outcomes of patients with intra-articular distal radius fractures. METHODS: From May 2010 to November 2014, 76 subjects who had experienced intra-articular fractures of the distal radius were enrolled in this double-blind, randomized, controlled trial in Imam Ali Hospital in Bojnourd, Iran. The patients were divided into two groups, i.e., 1) patients who were treated with internal fixation using the volar plate (group A) and 2) patients who were treated with external fixators (group B). The primary outcome was a composite measure of the patient's quality of life using three different scores, i.e., 1) the MAYO score, 2) Disabilities of the Arm, Shoulder, and Hand (DASH (score, and 3) the Short Form (36) (SF-36) Health Survey score. RESULTS: A total of 76 patients were allocated randomly to groups A and B. The mean ages for external fixator cases and volar plate cases were 51.7 and 46.3, respectively. No significant age distribution was seen between the two groups (p=0.348). Gender distribution between the two groups was not significantly different (p=0.022). Grip power was significantly different between the two groups, but no significant differences were detected in range of motion (p=0.008, p=0.367, respectively). The MAYO score was significantly higher in the open reduction and internal fixation (ORIF) group, and, according to the SF-36 test, the ORIF group also a higher level of general mental and physical health, social functioning, and personal physical functioning than the other group. However, postoperatively, the mental discomfort and physical discomfort were more prevalent in the external fixator group. The DASH score was not significantly different between the two groups (p=0.124). CONCLUSIONS: ORIF and its subtitle, volar plate fixation, is a more preferred surgical procedure than the external fixator for the treatment of intra-articular distal radius fractures. This conclusion is important when one considers cost effectiveness and an earlier return to work. TRIAL REGISTRATION: The trial is registered at the Thai Clinical Trial Registry (clinicaltrials.in.th) with the TCR identification number TCTR20150609002. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 26120420 TI - Mapping hypersensitivity/allergic diseases in the International Classification of Diseases (ICD)-11: cross-linking terms and unmet needs. AB - BACKGROUND: With the aim of actively contributing to the ongoing 11(th) International Classification of Diseases (ICD) revision, an international collaboration led by the European Academy of Allergy and Clinical Immunology (EAACI) has decided to revise the classification of hypersensitivity/allergic diseases and to validate it for ICD-11 by crowdsourcing the allergist community. However, understanding that the construction of a classification was necessary but not sufficient, we developed a mapping strategy in the attempt to better fit it to the ICD-11 linearization structure. METHODS: The cross-linking terms process has been constructed based on an algorithm in which we prioritized the pre-coordination, followed by the post-coordination when the first step was not possible. If the above strategies failed to identify the entries, the conditions were ruled as "non specific terms", "no code fit properly" or "missing terms". RESULTS: Amongst the 652 terms distributed in 5 main groups of the Hypersensitivity/Allergic Diseases classification, 169 terms fit directly the codes listed in the ICD-11 beta draft (October 2014 version), 26 were considered as "nonspecific term", 21 were linked to the Foundation by Index, 7 were recorded as inclusions and 2 were cited just in the definition of the condition. The post coordination was possible for 97 terms, mainly for drug hypersensitivity conditions. We noticed a considerable number of allergen references missing. CONCLUSION: The proposed strategy of cross-linking terms and the results of this process can actively contribute to updating the hypersensitivity and allergic conditions classification in the ICD-11 beta revision and underlines the need for either a new chapter in ICD-11 possibly entitled Hypersensitivity / Allergic Disorders or at the very least the aggregation of all such diseases under the "Diseases of Immune System" chapter in order for the overlaps to be double parented to the appropriate 'system' chapters. PMID- 26120421 TI - Dispersal depends on body condition and predation risk in the semi-aquatic insect, Notonecta undulata. AB - Dispersal is the movement of organisms across space, which has important implications for ecological and evolutionary processes, including community composition and gene flow. Previous studies have demonstrated that dispersal is influenced by body condition; however, few studies have been able to separate the effects of body condition from correlated variables such as body size. Moreover, the results of these studies have been inconsistent with respect to the direction of the relationship between condition and dispersal. We examined whether body condition influences dispersal in backswimmers (Notonecta undulata). We also tested whether an interaction between body condition and predation risk (another proximate factor that influences dispersal) could contribute to the previously observed inconsistent relationship between condition and dispersal. We imposed diet treatments on backswimmers in the laboratory, and measured the effects of food availability on body condition and dispersal in the field. We found that dispersal was a positive function of body condition, which may have important consequences for population characteristics such as the rate of gene flow and population growth. However, the effects of body condition and predation risk were additive, not interactive, and therefore, our data do not support the hypothesis that the interaction between condition and predation risk contributes to the inconsistency in the results of previous condition-dependent dispersal studies. PMID- 26120423 TI - Plant-soil feedbacks from 30-year family-specific soil cultures: phylogeny, soil chemistry and plant life stage. AB - Intraspecific negative feedback effects, where performance is reduced on soils conditioned by conspecifics, are widely documented in plant communities. However, interspecific feedbacks are less well studied, and their direction, strength, causes, and consequences are poorly understood. If more closely related species share pathogens, or have similar soil resource requirements, plants may perform better on soils conditioned by more distant phylogenetic relatives. There have been few empirical tests of this prediction across plant life stages, and none of which attempt to account for soil chemistry. Here, we test the utility of phylogeny for predicting soil feedback effects on plant survival and performance (germination, seedling survival, growth rate, biomass). We implement a full factorial experiment growing species representing five families on five plant family-specific soil sources. Our experiments exploit soils that have been cultured for over 30 years in plant family-specific beds at Oxford University Botanic Gardens. Plant responses to soil source were idiosyncratic, and species did not perform better on soils cultured by phylogenetically more distant relatives. The magnitude and sign of feedback effects could, however, be explained by differences in the chemical properties of "home" and "away" soils. Furthermore, the direction of soil chemistry-related plant-soil feedbacks was dependent on plant life stage, with the effects of soil chemistry on germination success and accumulation of biomass inversely related. Our results (1) suggest that the phylogenetic distance between plant families cannot predict plant-soil feedbacks across multiple life stages, and (2) highlight the need to consider changes in soil chemistry as an important driver of population responses. The contrasting responses at plant life stages suggest that studies focusing on brief phases in plant demography (e.g., germination success) may not give a full picture of plant-soil feedback effects. PMID- 26120422 TI - Population genetics of four heavily exploited shark species around the Arabian Peninsula. AB - The northwestern Indian Ocean harbors a number of larger marine vertebrate taxa that warrant the investigation of genetic population structure given remarkable spatial heterogeneity in biological characteristics such as distribution, behavior, and morphology. Here, we investigate the genetic population structure of four commercially exploited shark species with different biological characteristics (Carcharhinus limbatus, Carcharhinus sorrah, Rhizoprionodon acutus, and Sphyrna lewini) between the Red Sea and all other water bodies surrounding the Arabian Peninsula. To assess intraspecific patterns of connectivity, we constructed statistical parsimony networks among haplotypes and estimated (1) population structure; and (2) time of most recent population expansion, based on mitochondrial control region DNA and a total of 20 microsatellites. Our analysis indicates that, even in smaller, less vagile shark species, there are no contemporary barriers to gene flow across the study region, while historical events, for example, Pleistocene glacial cycles, may have affected connectivity in C. sorrah and R. acutus. A parsimony network analysis provided evidence that Arabian S. lewini may represent a population segment that is distinct from other known stocks in the Indian Ocean, raising a new layer of conservation concern. Our results call for urgent regional cooperation to ensure the sustainable exploitation of sharks in the Arabian region. PMID- 26120424 TI - Climate change creates rapid species turnover in montane communities. AB - Recent decades have seen substantial changes in patterns of biodiversity worldwide. Simultaneously, climate change is producing a widespread pattern of species' range shifts to higher latitudes and higher elevations, potentially creating novel assemblages as species shift at different rates. However, the direct link between species' turnover as a result of climate-induced range shifts has not yet been empirically evaluated. We measured rates of species turnover associated with species' range shifts in relatively undisturbed montane areas in Asia, Europe, North America, South America, and the Indo-Pacific. We show that species turnover is rapidly creating novel assemblages, and this can be explained by variable changes in species' range limits following warming. Across all the areas we analyzed, mean species' turnover was 12% per decade, which was nearly balanced between the loss of existing co-occurrences and the gain of novel co occurrences. Turnover appears to be more rapid among ectothermic assemblages, and some evidence suggests tropical assemblages may be responding at more rapid rates than temperate assemblages. PMID- 26120425 TI - Sex-specific foraging behavior in response to fishing activities in a threatened seabird. AB - Some seabird species have learnt to efficiently exploit fishing discards from trawling activities. However, a discard ban has been proposed as necessary in Europe to ensure the sustainability of the seas. It is of crucial importance for the management and conservation purposes to study the potential consequences of a discard ban on the foraging ecology of threatened seabirds. We assessed the influence of fishing activities on the feeding habits of 22 male and 15 female Audouin's gulls (Larus audouinii) from the Ebro Delta (Mediterranean Sea) during the breeding period using GPS loggers together with Stable Isotope Analysis (SIA), which provided new insights into their foraging behavior and trophic ecology, respectively. GPS data revealed different sex-specific foraging patterns between workdays and weekends. Females were highly consistent in that they foraged at sea throughout the week even though discarding stops at weekends. In contrast, males switched from foraging at sea during the week (when discards are produced) to an increased use of rice field habitats at weekends (when fishermen do not work). This sex-specific foraging behavior could be related to specific nutritional requirements associated with previous egg production, an energetically demanding period for females. However, on a broader time scale integrated by the SIA, both sexes showed a high degree of individual specialization in their trophic ecology. The need to obtain detailed information on the dependence and response of seabirds to fishing activities is crucial in conservation sciences. In this regard, sex-specific foraging behavior in relation to fisheries has been overlooked, despite the ecological and conservation implications. For instance, this situation may lead to sex differentiation in bycatch mortality in longlines when trawlers do not operate. Moreover, any new fisheries policy will need to be implemented gradually to facilitate the adaptation of a specialized species to a discard ban scenario. PMID- 26120426 TI - An approach to consider behavioral plasticity as a source of uncertainty when forecasting species' response to climate change. AB - The rapid ecological shifts that are occurring due to climate change present major challenges for managers and policymakers and, therefore, are one of the main concerns for environmental modelers and evolutionary biologists. Species distribution models (SDM) are appropriate tools for assessing the relationship between species distribution and environmental conditions, so being customarily used to forecast the biogeographical response of species to climate change. A serious limitation of species distribution models when forecasting the effects of climate change is that they normally assume that species behavior and climatic tolerances will remain constant through time. In this study, we propose a new methodology, based on fuzzy logic, useful for incorporating the potential capacity of species to adapt to new conditions into species distribution models. Our results demonstrate that it is possible to include different behavioral responses of species when predicting the effects of climate change on species distribution. Favorability models offered in this study show two extremes: one considering that the species will not modify its present behavior, and another assuming that the species will take full advantage of the possibilities offered by an increase in environmental favorability. This methodology may mean a more realistic approach to the assessment of the consequences of global change on species' distribution and conservation. Overlooking the potential of species' phenotypical plasticity may under- or overestimate the predicted response of species to changes in environmental drivers and its effects on species distribution. Using this approach, we could reinforce the science behind conservation planning in the current situation of rapid climate change. PMID- 26120427 TI - Cryptic or pseudocryptic: can morphological methods inform copepod taxonomy? An analysis of publications and a case study of the Eurytemora affinis species complex. AB - Interest in cryptic species has increased significantly with current progress in genetic methods. The large number of cryptic species suggests that the resolution of traditional morphological techniques may be insufficient for taxonomical research. However, some species now considered to be cryptic may, in fact, be designated pseudocryptic after close morphological examination. Thus the "cryptic or pseudocryptic" dilemma speaks to the resolution of morphological analysis and its utility for identifying species. We address this dilemma first by systematically reviewing data published from 1980 to 2013 on cryptic species of Copepoda and then by performing an in-depth morphological study of the former Eurytemora affinis complex of cryptic species. Analyzing the published data showed that, in 5 of 24 revisions eligible for systematic review, cryptic species assignment was based solely on the genetic variation of forms without detailed morphological analysis to confirm the assignment. Therefore, some newly described cryptic species might be designated pseudocryptic under more detailed morphological analysis as happened with Eurytemora affinis complex. Recent genetic analyses of the complex found high levels of heterogeneity without morphological differences; it is argued to be cryptic. However, next detailed morphological analyses allowed to describe a number of valid species. Our study, using deep statistical analyses usually not applied for new species describing, of this species complex confirmed considerable differences between former cryptic species. In particular, fluctuating asymmetry (FA), the random variation of left and right structures, was significantly different between forms and provided independent information about their status. Our work showed that multivariate statistical approaches, such as principal component analysis, can be powerful techniques for the morphological discrimination of cryptic taxons. Despite increasing cryptic species designations, morphological techniques have great potential in determining copepod taxonomy. PMID- 26120428 TI - Ecosystem recharge by volcanic dust drives broad-scale variation in bird abundance. AB - Across the globe, deserts and volcanic eruptions produce large volumes of atmospheric dust, and the amount of dust is predicted to increase with global warming. The effects of long-distance airborne dust inputs on ecosystem productivity are potentially far-reaching but have primarily been measured in soil and plants. Airborne dust could also drive distribution and abundance at higher trophic levels, but opportunities to explore these relationships are rare. Here we use Iceland's steep dust deposition gradients to assess the influence of dust on the distribution and abundance of internationally important ground nesting bird populations. Surveys of the abundance of breeding birds at 729 locations throughout lowland Iceland were used to explore the influence of dust deposition on bird abundance in agricultural, dry, and wet habitats. Dust deposition had a strong positive effect on bird abundance across Iceland in dry and wet habitats, but not in agricultural land where nutrient levels are managed. The abundance of breeding waders, the dominant group of terrestrial birds in Iceland, tripled on average between the lowest and highest dust deposition classes in both wet and dry habitats. The deposition and redistribution of volcanic materials can have powerful impacts in terrestrial ecosystems and can be a major driver of the abundance of higher trophic-level organisms at broad spatial scales. The impacts of volcanic ash deposition during eruptions and subsequent redistribution of unstable volcanic materials are strong enough to override effects of underlying variation in organic matter and clay content on ecosystem fertility. Global rates of atmospheric dust deposition are likely to increase with increasing desertification and glacier retreat, and this study demonstrates that the effects on ecosystems are likely to be far-reaching, both in terms of spatial scales and ecosystem components. PMID- 26120429 TI - Maternal effects and maternal selection arising from variation in allocation of free amino acid to eggs. AB - Maternal provisioning can have profound effects on offspring phenotypes, or maternal effects, especially early in life. One ubiquitous form of provisioning is in the makeup of egg. However, only a few studies examine the role of specific egg constituents in maternal effects, especially as they relate to maternal selection (a standardized selection gradient reflecting the covariance between maternal traits and offspring fitness). Here, we report on the evolutionary consequences of differences in maternal acquisition and allocation of amino acids to eggs. We manipulated acquisition by varying maternal diet (milkweed or sunflower) in the large milkweed bug, Oncopeltus fasciatus. Variation in allocation was detected by examining two source populations with different evolutionary histories and life-history response to sunflower as food. We measured amino acids composition in eggs in this 2 * 2 design and found significant effects of source population and maternal diet on egg and nymph mass and of source population, maternal diet, and their interaction on amino acid composition of eggs. We measured significant linear and quadratic maternal selection on offspring mass associated with variation in amino acid allocation. Visualizing the performance surface along the major axes of nonlinear selection and plotting the mean amino acid profile of eggs from each treatment onto the surface revealed a saddle-shaped fitness surface. While maternal selection appears to have influenced how females allocate amino acids, this maternal effect did not evolve equally in the two populations. Furthermore, none of the population means coincided with peak performance. Thus, we found that the composition of free amino acids in eggs was due to variation in both acquisition and allocation, which had significant fitness effects and created selection. However, although there can be an evolutionary response to novel food resources, females may be constrained from reaching phenotypic optima with regard to allocation of free amino acids. PMID- 26120430 TI - Invasive plants may promote predator-mediated feedback that inhibits further invasion. AB - Understanding the impacts of invasive species requires placing invasion within a full community context. Plant invaders are often considered in the context of herbivores that may drive invasion by avoiding invaders while consuming natives (enemy escape), or inhibit invasion by consuming invaders (biotic resistance). However, predators that attack those herbivores are rarely considered as major players in invasion. Invasive plants often promote predators, generally by providing improved habitat. Here, we show that predator-promoting invaders may initiate a negative feedback loop that inhibits invasion. By enabling top-down control of herbivores, predator-promoting invaders lose any advantage gained through enemy escape, indirectly favoring natives. In cases where palatable invaders encounter biotic resistance, predator promotion may allow an invader to persist, but not dominate. Overall, results indicate that placing invaders in a full community context may reveal reduced impacts of invaders compared to expectations based on simple plant-plant or plant-herbivore subsystems. PMID- 26120431 TI - Variation in the population structure between a natural and a human-modified forest for a pioneer tropical tree species not restricted to large gaps. AB - The distribution of tree species in tropical forests is generally related to the occurrence of disturbances and shifts in the local environmental conditions such as light, temperature, and biotic factors. Thus, the distribution of pioneer tree species is expected to vary according to the gap characteristics and with human disturbances. We asked whether there was variation in the distribution of a pioneer species under different environmental conditions generated by natural disturbances, and between two forests with contrasting levels of human disturbance. To answer this question, we studied the distribution patterns and population persistence of the pioneer tree species Croton floribundus in the size and age gap range of a primary Brazilian forest. Additionally, we compared the plant density of two size-classes between a primary and an early successional human-disturbed forest. Croton floribundus was found to be widespread and equally distributed along the gap-size gradient in the primary forest. Overall density did not vary with gap size or age (F-ratio = 0.062, P = 0.941), and while juveniles were found to have a higher density in the early successional forest (P = 0.021), tree density was found to be similar between forests (P = 0.058). Our results indicate that the population structure of a pioneer tree species with long life span and a broad gap-size niche preference varied between natural and human-disturbed forests, but not with the level of natural disturbance. We believe this can be explained by the extreme environmental changes that occur after human disturbance. The ecological processes that affect the distribution of pioneer species in natural and human-modified forests may be similar, but our results suggest they act differently under the contrasting environmental conditions generated by natural and human disturbances. PMID- 26120432 TI - Black liquor and the hangover effect: fish assemblage recovery dynamics following a pulse disturbance. AB - Anthropogenic perturbations impact aquatic systems causing wide-ranging responses, from assemblage restructuring to assemblage recovery. Previous studies indicate the duration and intensity of disturbances play a role in the dynamics of assemblage recovery. In August 2011, the Pearl River, United States, was subjected to a weak black liquor spill from a paper mill which resulted in substantial loss of fish in a large stretch of the main channel. We quantified resilience and recovery of fish assemblage structure in the impacted area following the event. We compared downstream (impacted) assemblages to upstream (unimpacted) assemblages to determine initial impacts on structure. Additionally, we incorporated historic fish collections (1988-2011) to examine impacts on assemblage structure across broad temporal scales. Based on NMDS, upstream and downstream sites generally showed similar assemblage structure across sample periods with the exception of the 2 months postdischarge, where upstream and downstream sites visually differed. Multivariate analysis of variance (PERMANOVA) indicated significant seasonal variation among samples, but found no significant interaction between impacted and unimpacted assemblages following the discharge event. However, multivariate dispersion (MVDISP) showed greater variance among assemblage structure following the discharge event. These results suggest that 2 months following the disturbance represent a time period of stochasticity in regard to assemblage structure dynamics, and this was followed by rapid recovery. We term this dynamic the "hangover effect" as it represents the time frame from the cessation of the perturbation to the assemblage's return to predisturbance conditions. The availability and proximity of tributaries and upstream refugia, which were not affected by the disturbance, as well as the rapid recovery of abiotic parameters likely played a substantial role in assemblage recovery. This study not only demonstrates rapid recovery in an aquatic system, but further demonstrates the value of continuous, long-term, data collections which enhance our understanding of assemblage dynamics. PMID- 26120433 TI - Long-term livestock exclusion facilitates native woody plant encroachment in a sandy semiarid rangeland. AB - The role of livestock grazing in regulating woody cover and biomass in grass dominant systems is well recognized. However, the way in which woody plant populations in respond when livestock are removed from grazing in the absence of other disturbances, such as fire, remains unclear.We conducted a 10-year, replicated fencing experiment in a sandy semiarid rangeland in northern China (which has a mean annual rainfall of 365 mm), where fires have been actively suppressed for decades.Fencing dramatically influenced the growth and age structure of the native tree species, Ulmus pumila, which is the sole dominant tree in the area. After a decade, the density of the U. pumila tree population in the fencing plots increased doubly and canopy cover increased triply. The proportion of both saplings (U 2 ) and young trees (U 3 ) increased in fencing plots but decreased in grazing plots after the 10-year treatment period. The effects of fencing on U. pumila trees varied by age class, with potential implications for the future structure of the U. pumila tree community. Decadal fencing led to approximately 80-fold increase in recruitment and a nearly 2.5 fold decrease in the mortality of both U 2 and U 3 . Further, livestock grazing generated a "browsing trap" to the recruitment of both U 2 and U 3 , and had a small impact on the mortality of old trees. A long-term, fencing-driven shift in woody species composition was mediated via its effects on both recruitment and mortality rates.Synthesis and applications. Our results demonstrate that in the long-term absence of both fire and livestock, native woody plant encroachment tends to occur in sandy rangelands, transforming the woody plant demography in the process. The feasibility of full livestock exclusion in sandy rangelands requires further discussion. A balanced amount of livestock grazing may provide critical ecosystem services by regulating woody cover and mediating woody plant encroachment. PMID- 26120434 TI - A joint individual-based model coupling growth and mortality reveals that tree vigor is a key component of tropical forest dynamics. AB - Tree vigor is often used as a covariate when tree mortality is predicted from tree growth in tropical forest dynamic models, but it is rarely explicitly accounted for in a coherent modeling framework. We quantify tree vigor at the individual tree level, based on the difference between expected and observed growth. The available methods to join nonlinear tree growth and mortality processes are not commonly used by forest ecologists so that we develop an inference methodology based on an MCMC approach, allowing us to sample the parameters of the growth and mortality model according to their posterior distribution using the joint model likelihood. We apply our framework to a set of data on the 20-year dynamics of a forest in Paracou, French Guiana, taking advantage of functional trait-based growth and mortality models already developed independently. Our results showed that growth and mortality are intimately linked and that the vigor estimator is an essential predictor of mortality, highlighting that trees growing more than expected have a far lower probability of dying. Our joint model methodology is sufficiently generic to be used to join two longitudinal and punctual linked processes and thus may be applied to a wide range of growth and mortality models. In the context of global changes, such joint models are urgently needed in tropical forests to analyze, and then predict, the effects of the ongoing changes on the tree dynamics in hyperdiverse tropical forests. PMID- 26120435 TI - Interactions between density, home range behaviors, and contact rates in the Channel Island fox (Urocyon littoralis). AB - Many of the mechanisms underlying density-dependent regulation of populations, including contest competition and disease spread, depend on contact among neighboring animals. Understanding how variation in population density influences the frequency of contact among neighboring animals is therefore an important aspect to understanding the mechanisms underlying, and ecological consequences of, density-dependent regulation. However, contact rates are difficult to measure in the field and may be influenced by density through multiple pathways. This study explored how local density affects contact rates among Channel Island foxes (Urocyon littoralis) through two pathways: changes in home range size and changes in home range overlap. We tracked 40 radio-collared foxes at four sites on San Clemente Island, California. Fox densities at the four sites ranged from 2.8 +/- 1.28 to 42.8 +/- 9.43 foxes/km(2). Higher fox densities were correlated with smaller home ranges (R (2) = 0.526, F 1,38 = 42.19, P < 0.001). Thirty foxes wore collars that also contained proximity loggers, which recorded the time and duration of occasions when collared foxes were within 5 m of one another. Contact rates between neighboring fox dyads were positively correlated with home range overlap (R (2) = 0.341, P = 0.008), but not fox density (R (2) = 0.012, P = 0.976). Individuals at high densities had more collared neighbors with overlapping home ranges (R (2) = 0.123, P = 0.026) but not an increase in the amount of contact between individual neighbors. This study was the first time contact rates were directly measured and compared to density and home range overlap. Results suggest that foxes exhibit a threshold in their degree of tolerance for neighbors, overlap is a reliable index of the amount of direct contact between island foxes, and disease transmission rates will likely scale with fox density. PMID- 26120436 TI - Grazing intensifies degradation of a Tibetan Plateau alpine meadow through plant pest interaction. AB - Understanding the plant-pest interaction under warming with grazing conditions is critical to predict the response of alpine meadow to future climate change. We investigated the effects of experimental warming and grazing on the interaction between plants and the grassland caterpillar Gynaephora menyuanensis in an alpine meadow on the Tibetan Plateau in 2010 and 2011. Our results showed that grazing significantly increased nitrogen concentration in graminoids and sward openness with a lower sward height, sward coverage, and plant litter mass in the community. Grazing significantly increased G. menyuanensis body size and potential fecundity in 2010. The increases in female body size were about twofold greater than in males. In addition, grazing significantly increased G. menyuanensis density and its negative effects on aboveground biomass and graminoid coverage in 2011. We found that G. menyuanensis body size was significantly positively correlated with nitrogen concentration in graminoids but negatively correlated with plant litter mass. Even though warming did not significantly increased G. menyuanensis performance and the negative effects of G. menyuanensis on alpine meadow, the increases in G. menyuanensis growth rate and its negative effect on aboveground biomass under the warming with grazing treatment were significantly higher than those under the no warming with grazing treatment. The positive effects of grazing on G. menyuanensis performance and its damage were exacerbated by the warming treatment. Our results suggest that the fitness of G. menyuanensis would increase under future warming with grazing conditions, thereby posing a greater risk to alpine meadow and livestock production. PMID- 26097682 TI - Reliability and reproducibility of spectral and time domain optical coherence tomography images before and after correction for patients with age-related macular degeneration. AB - PURPOSE: To evaluate the reproducibility and reliability of optical coherence tomography scans obtained using the time domain (TD-OCT) Stratus (TM) OCT, and the Spectral Domain (SD-OCT) Spectralis (TM) and Cirrus (TM) OCT devices before and after manual correction in eyes with either Neovascular (NV-AMD) or Non Neovascular (NNV-AMD) age-related macular degeneration. DESIGN: Prospective observational study. METHODS: SETTING: University-based retina practice. PATIENTS: Thirty-six patients (50 eyes) with NV-AMD or NNV-AMD. PROCEDURE: OCT scans were taken simultaneously using one TD-OCT and two SD-OCT devices. MAIN OUTCOME MEASURES: Macular thickness measurements were assessed before and after correction of the algorithm by constructing Bland-Altman plots for agreement and calculating intraclass correlation coefficients (ICCs) and coefficients of repeatability (COR) to evaluate intraclass repeatability. RESULTS: Spectralis had the highest number of images needing manual correction. All machines had high ICCs, with Spectralis having the highest. Also, Bland-Altman plots indicated that there was low agreement between CirrusTM and StratusTM, SpectralisTM and StratusTM, while there was good agreement between the CirrusTM and SpectralisTM. The CORs were lowest for Spectralis (TM) and similar and higher for Cirrus (TM) and Stratus (TM). Agreement, CORs, and ICCs generally improved after manual correction, but only minimally. CONCLUSION: Agreement is low between devices, except between both SD-OCT machines. Manual correction tends to improve results. PMID- 26120439 TI - The chronic kalaemia conundrum. PMID- 26120441 TI - Eculizumab and drug-induced haemolytic-uraemic syndrome. AB - The monoclonal anti-C5 antibody eculizumab has been successfully tested in atypical haemolytic-uraemic syndrome (aHUS), with or without mutations in the regulatory proteins of the alternative pathway of the complement, and less convincingly in enterohaemorrhagic Escherichia coli-associated HUS. Here, we report a patient with mitomycin-C-induced HUS unresponsive to plasma exchanges. Eculizumab infusion was followed by a dramatic improvement of haematological parameters and renal function, suggesting a role of complement blockade in the management of refractory, drug-related HUS. PMID- 26120440 TI - Mineralocorticoid receptor blockade-a novel approach to fight hyperkalaemia in chronic kidney disease. AB - Hyperkalaemia continues to be a major hazard of mineralocorticoid receptor blockade in an effort to retard the progression of chronic kidney disease (CKD). In cardiac patients on mineralocorticoid receptor blockade, RLY-5016 which captures K(+) in the colon has been effective in reducing the risk of hyperkalaemia. This compound might be useful in CKD as well. PMID- 26120442 TI - Extramedullary hematopoiesis in renal allograft. AB - Extramedullary hematopoiesis (EMH), defined as the presence of hematopoietic elements outside of the medullary cavity of bone, has been reported in patients with various hematopoietic neoplasms including myelofibrosis. EMH commonly occurs in the liver and spleen (resulting in hepatosplenomegaly) and uncommonly involves the kidney. EMH involving the allograft kidney has not been reported in English literature. Herein, we report the first case of EMH in allograft kidney in a patient with myelofibrosis. The clinical and pathological findings are described. Through comparison of the medullary neoplastic infiltrate with the renal allograft infiltrate, we postulate the neoplastic nature of the infiltrate in the allograft kidney. PMID- 26120443 TI - Successful treatment of adult-onset collapsing focal segmental glomerulosclerosis with rituximab. AB - Collapsing focal segmental glomerulosclerosis (FSGS), or collapsing glomerulopathy (CG), responds poorly to commonly employed therapies, with a high proportion of patients progressing to end-stage renal disease. We report an adult in a nephrotic state, diagnosed with minimal-change disease on biopsy, who failed to respond to steroids, calcineurin inhibitors (CNIs), mycophenolate mofetil and cyclophosphamide. Repeat biopsy showed CG. Treatment with 4 weekly doses of rituximab led to sustained remission of his nephrotic state. This is the first report of adult-onset CG that has responded favourably to rituximab. Rituximab could be a treatment option for patients with this difficult-to-treat condition. PMID- 26120444 TI - Warfarin-related nephropathy in a patient with mild IgA nephropathy on dabigatran and aspirin. AB - Dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long-term anticoagulation. We describe a patient who developed acute kidney injury (AKI) in the setting of warfarin conversion to dabigatran, and a renal biopsy demonstrating acute tubular injury. Although the patient had undiagnosed IgA nephropathy that may have predisposed him to bleeding, AKI was due to heme associated tubular injury. We propose that severe hematuria in patients with underlying glomerular pathology treated with either dabigatran or warfarin may lead to toxic tubular injury through the accumulation of heme-proteins. PMID- 26120445 TI - Dialysis disequilibrium syndrome occurring during continuous renal replacement therapy. AB - The dialysis disequilibrium syndrome (DDS) is characterized by progressive neurological symptoms and signs attributable to cerebral edema that occurs due to fluid shifts into the brain following a relatively rapid decrease in serum osmolality during hemodialysis (HD). Since continuous renal replacement therapy (CRRT) is less efficient at solute clearance than intermittent HD, it seems logical that this mode of therapy is less likely to cause DDS. This entity has not been previously reported to occur with this modality. Here, we report two cases of DDS associated with CRRT that provide insights into its pathophysiological mechanisms and suggest strategies for its prevention. PMID- 26120446 TI - Curvilinear bodies in hydroxychloroquine-induced renal phospholipidosis resembling Fabry disease. AB - Inherited and acquired metabolic disorders are responsible for renal intracellular accumulation of phospholipids. Ultrastructural analysis revealing typical myeloid or zebra bodies was previously thought to be exclusive to Fabry disease. However, chloroquine/hydroxychloroquine toxicity can cause similar abnormalities. Recent studies have mentioned curvilinear bodies (CLB) in renal cells in such cases, never described in Fabry nephropathy. We report a 31-year old patient with systemic lupus erythematosus who was on long-term hydroxychloroquine treatment. The presence of zebra bodies on electron microscopy lead to initial interpretation of Fabry disease, but subsequent genetic analysis did not show a relevant mutation. Further evaluation revealed CLB in renal cells, supporting the diagnosis of hydroxycholoroquine-induced renal phospholipidosis. PMID- 26120447 TI - Variant thoracic venous drainage and its hazards with catheter for haemodialysis. PMID- 26120448 TI - Pure red cell aplasia after treatment of renal anaemia with epoetin theta. PMID- 26120449 TI - Perirenal fibrosis: make your diagnosis. PMID- 26120450 TI - A woman with ascites and oliguria. PMID- 26120451 TI - Page kidney phenomenon secondary to an atypical presentation of Erdheim-Chester disease. PMID- 26120452 TI - Angiosarcoma in vascular access after transplantation. PMID- 26120453 TI - Reverse autoperitoneal dialysis resulting in pseudo acute renal failure. PMID- 26120454 TI - Peritonitis from Rothia mucilaginosa in a chronic peritoneal dialysis patient. PMID- 26120455 TI - Dialysis practice from the English NHS to the orient. PMID- 26120456 TI - Peritoneal dialysis: from bench to bedside. AB - Peritoneal dialysis was first employed in patients with acute renal failure in the 1940s and since the 1960s for those with end-stage renal disease. Its popularity increased enormously after the introduction of continuous ambulatory peritoneal dialysis in the end of 1970s. This stimulated both clinical and basic research. In an ideal situation, this should lead to cross-fertilization between the two. The present review describes two examples of interactions: one where it worked out very well and another where basic science missed the link with clinical findings. Those on fluid transport are examples of how old physiological findings on absorption of saline and glucose solutions were adopted in peritoneal dialysis by the use of glucose as an osmotic agent. The mechanism behind this in patients was first solved mathematically by the assumption of ultrasmall intracellular pores allowing water transport only. At the same time, basic science discovered the water channel aquaporin-1 (AQP-1), and a few years later, studies in transgenic mice confirmed that AQP-1 was the ultrasmall pore. In clinical medicine, this led to its assessment in patients and the notion of its impairment. Drugs for treatment have been developed. Research on biocompatibility is not a success story. Basic science has focussed on dialysis solutions with a low pH and lactate, and effects of glucose degradation products, although the first is irrelevant in patients and effects of continuous exposure to high glucose concentrations were largely neglected. Industry believed the bench more than the bedside, resulting in 'biocompatible' dialysis solutions. These solutions have some beneficial effects, but are evidently not the final answer. PMID- 26120457 TI - Clinicopathological course of acute kidney injury following brown recluse (Loxoscles reclusa) envenomation. AB - We report a case of severe systemic loxoscelism in a previously healthy young man. This was associated with a Coombs-positive hemolytic anemia, striking leukomid reaction, renal failure, respiratory failure and cardiovascular collapse. This is the first documented case of a renal biopsy in a patient with renal failure after envenomation by the brown recluse spider. Associated systemic toxicity usually resolves but requires prompt recognition and supportive care in an intensive care setting. We also discuss the potential mechanism by which the venom of this small spider can lead to multiorgan failure and possibly death. PMID- 26120458 TI - Leukocyte chemotactic factor 2 (LECT2) amyloidosis presenting as pulmonary-renal syndrome: a case report and review of the literature. AB - Leukocyte chemotactic factor-2 (LECT2) amyloidosis has been described as being associated with kidney disease; however, no clinical manifestations outside of the kidney have been previously reported. We describe a patient presenting with pulmonary-renal syndrome found to have deposition of amyloidogenic LECT2 (ALECT2) within both the lung and the kidney. This case is unique in regard to both the patient's clinical presentation of pulmonary-renal syndrome in the setting of amyloidosis and the biopsy finding of ALECT2 deposition within the lung. It also emphasizes the importance of tissue diagnosis in such cases, given that amyloidosis was not initially considered in the differential diagnosis. PMID- 26120459 TI - Symptomatic lymphocele developing soon after acute renal allograft rejection: coincidental or causal connection? AB - A renal transplant patient developed a lymphocele soon after an episode of acute rejection (AR). The lymphocele rapidly increased in size causing transplant ureteric and venous obstruction, leading to acute graft dysfunction and swelling of the ipsilateral leg. We appraise the complex relationship that exists between AR, lymphangiogenesis and lymphocele formation to determine whether a case for a causal connection between AR and development of lymphocele can be made in our patient. PMID- 26120460 TI - Calciphylaxis. PMID- 26120461 TI - Cutaneous involvement in haemolytic uraemic syndrome. PMID- 26120462 TI - Azathioprine-induced Sweet syndrome in ANCA-associated vasculitis. PMID- 26120463 TI - Acute renal failure due to Dengue myositis: a rare cause of pigment cast nephropathy. PMID- 26120464 TI - Gross hematuria after kidney transplantation. PMID- 26120465 TI - Colchicine-induced rhabdomyolysis following a concomitant use of clarithromycin in a haemodialysis patient with familial Mediterranean fever. PMID- 26120466 TI - Renal amyloidosis secondary to hidradenitis suppurativa. PMID- 26120467 TI - Stability of biochemical analytes of end stage renal failure patients on renal replacement therapy for urea-kinetic modeling in the home dialysis setting. PMID- 26120469 TI - Erratum: Mineralocorticoid receptor blockade-a novel approach to fight hyperkalaemia in chronic kidney disease. PMID- 26120468 TI - Knuckle cracking: secondary hyperparathyroidism and what your mother did not tell you. AB - INTRODUCTION: Secondary hyperparathyroidism in end-stage renal disease patients has protean musculoskeletal manifestations. Some of our dialysis patients spontaneously vocalized that they had lost the ability to crack their knuckles and then experienced gratifying restoration after surgical parathyroidectomy. We propose that the physiology and mechanical basis of knuckle cracking would be affected by parathyroid-related mineral and bone disorders. METHODS AND RESULTS: We surveyed all of our chronic dialysis outpatients who had undergone surgical parathyroidectomy. Thirteen (~12% of the population) individuals were identified: eight males, age 37.7 +/- 12.5 years old, dialysis duration of 10.2 +/- 7.0 years and peak preoperative intact parathyroid hormone (PTH) levels of 2344 +/- 900 pg/mL. Seven patients had no recollection of knuckle cracking issues, with surgery as remote as decades. Six individuals were able to provide adequate histories: four had postoperative restoration of knuckle cracking and expressed great satisfaction from the emotional relief from what appeared to be habitual knuckle cracking. Two of these patients reported rapid return of cracking, occurring in less than ~2 weeks. CONCLUSIONS: This is the first report of loss of knuckle cracking due to hyperparathyroidism and its cure in 67% of patients, following surgical parathyroidectomy. We propose that parathyroid (e.g. calcific) changes in articular structures (tendons, ligaments) cause reduced elasticity, limited joint surface separation upon flexion, attenuation of cavitation and thus, loss of the audible crack upon vacuum collapse. The psychological 'release' from habitual knuckle cracking may be a motivator from some patients to adhere to complex parathyroid regimens or to pursue surgical intervention. PMID- 26120472 TI - Decline in non-smoking workers' urine cotinine levels after increased smoking regulation in Korea. AB - OBJECTIVES: To identify any association between implementing smoking regulation policies and workers' urine cotinine concentration levels in Korea. METHODS: From the first stage of the Korean National Environmental Health Survey conducted by the National Institute of Environmental Research from 2009 to 2011, 2,475 non smoking workers selected. We analyzed the trend in the changes of cotinine concentration in urine using the general linear model and linear regression, in various jobs as categorized by the National Center for Health Statistics (NCHS) and Korea Standard Classification of Occupations (KSCO). RESULTS: The urine cotinine concentration tended to decrease every year (2.91 ng/ml in 2009, 2.12 ng/ml in 2010, and 1.31 ng/ml in 2011), showing a decreasing trend (P < 0.001). The total subjects' decreased cotinine concentration in urine between 2009 and 2011 was 2.72 ng/ml (54.1 % relative decrease). The changes in each subgroup's urine cotinine concentration ranged from 1.59 to 6.03 ng/ml (33.2 to 77.5 %). All groups except for the managerial group (n = 49), which had a small sample size, had statistically significant negative regression coefficients (p < 0.05). The ranges of the decrease in urine cotinine were 2.75 ng/ml (53.6 %) for males and 2.72 ng/ml (54.9 %) for females. The negative slope in urine cotinine level was statistically significantly greater in men than women. The changes in urine cotinine by occupation as classified by the NCHS occupational categories ranged from 2.43 to 3.36 ng/ml (46.6 to 61.5 % relative decrease). The negative slopes in urine cotinine levels of the white-collar and farm workers were statistically significantly greater than those of the service workers and blue-collar workers. The change by occupation as classified by the KSCO ranged from 1.59 to 6.03 ng/ml (a 33.2 to 77.5 % relative decrease). The negative slopes in urine cotinine levels of the professionals and related workers and clerks were statistically significantly greater than those of the service workers and plant and machine operators and assemblers. CONCLUSIONS: The cotinine concentration in urine among non-smoking worker groups tended to decline from 2009 to 2011. Such a result may be an indirect indicator of the effectiveness of smoking regulation policies including the revision of the National Health Promotion Act. PMID- 26120470 TI - 16S rRNA gene-based profiling of the human infant gut microbiota is strongly influenced by sample processing and PCR primer choice. AB - BACKGROUND: Characterisation of the bacterial composition of the gut microbiota is increasingly carried out with a view to establish the role of different bacterial species in causation or prevention of disease. It is thus essential that the methods used to determine the microbial composition are robust. Here, several widely used molecular techniques were compared to establish the optimal methods to assess the bacterial composition in faecal samples from babies, before weaning. RESULTS: The bacterial community profile detected in the faeces of infants is highly dependent on the methodology used. Bifidobacteria were the most abundant bacteria detected at 6 weeks in faeces from two initially breast-fed babies using fluorescent in situ hybridisation (FISH), in agreement with data from previous culture-based studies. Using the 16S rRNA gene sequencing approach, however, we found that the detection of bifidobacteria in particular crucially depended on the optimisation of the DNA extraction method, and the choice of primers used to amplify the V1-V3 regions of 16S rRNA genes prior to subsequent sequence analysis. Bifidobacteria were only well represented among amplified 16S rRNA gene sequences when mechanical disruption (bead-beating) procedures for DNA extraction were employed together with optimised "universal" PCR primers. These primers incorporate degenerate bases at positions where mismatches to bifidobacteria and other bacterial taxa occur. The use of a DNA extraction kit with no bead-beating step resulted in a complete absence of bifidobacteria in the sequence data, even when using the optimised primers. CONCLUSIONS: This work emphasises the importance of sample processing methodology to downstream sequencing results and illustrates the value of employing multiple approaches for determining microbiota composition. PMID- 26120473 TI - Development of a novel approach to enhance the solubility of ftibamzone formulation. AB - Ftibamzone (FBZ) is known to be effective against herpes simplex virus that causes genital herpes but poor solubility of FBZ has reduced its therapeutic efficacy. We investigated water-soluble complexes of various nanoparticles with FBZ to improve its solubility as well as increase its absorption. Using phase solubility technique, we measured formation constant (K1:1 and K1:2) values at room temperature in pH 7 buffer. Solubility was determined by dissolving FBZ or FBZ-entrapped nanoparticles in phosphate buffers and pH adjusted to different pH range (2-12). The solutions were then equilibrated for 24 hours and then filtered and analyzed using HPCL. Nanoparticles were formulated using nanoprecipitation technique and cellular uptake of nanoparticle was determined by confocal microscope. No significant FBZ solubility was observed from pH 2 to 10 however we did notice a rapid increase in solubility from pH of 10 to 12 with FBZ solubility of 950 MUg/ml. Our log D against pH profile revealed that FBZ is characteristic of an acid drug since unionized group was dominant at low pH. FBZ interaction with methyl-beta-cyclodextrin (mbetaCD) complexation/nanoparticles showed a greater solubility of FBZ compared with FBZ alone while complexation constants were determined to be K1:1 and K1:2 were 7.06*10-3 and 8.98*10-8 mM-1 respectively. Only FBZ-chitosan nanoparticles were toxic against MDCK cells. Study demonstrates that FBZ-PLGA nanoparticles could significantly enhance the solubility and absorption of FBZ compared with FBZ alone and has the potential to be used as an effective delivery system for the treatment of genital herpes. PMID- 26120474 TI - Neuronal Activity, Mitogens, and mTOR: Overcoming the Hurdles for the Treatment of Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM) and other malignant gliomas are considered to be the most prevalent of primary malignant brain tumors. The incidence of these tumors per year is reported as 4.13 per 100,000 individuals per year. The median survival time following the diagnosis of GBM is approximately fifteen months in the setting of providing presently available treatments with surgical resection, radiation, and chemotherapy. Given these statistics, new strategies for the treatment of GBM and other aggressive tumors of the brain are warranted. PMID- 26120471 TI - Diagnostic and prognostic microRNAs in the serum of breast cancer patients measured by droplet digital PCR. AB - BACKGROUND: Breast cancer circulating biomarkers include carcinoembryonic antigen and carbohydrate antigen 15-3, which are used for patient follow-up. Since sensitivity and specificity are low, novel and more useful biomarkers are needed. The presence of stable circulating microRNAs (miRNAs) in serum or plasma suggested a promising role for these tiny RNAs as cancer biomarkers. To acquire an absolute concentration of circulating miRNAs and reduce the impact of preanalytical and analytical variables, we used the droplet digital PCR (ddPCR) technique. RESULTS: We investigated a panel of five miRNAs in the sera of two independent cohorts of breast cancer patients and disease-free controls. The study showed that miR-148b-3p and miR-652-3p levels were significantly lower in the serum of breast cancer patients than that in controls in both cohorts. For these two miRNAs, the stratification of breast cancer patients versus controls was confirmed by receiver operating characteristic curve analyses. In addition, we showed that higher levels of serum miR-10b-5p were associated with clinicobiological markers of poor prognosis. CONCLUSIONS: The study revealed the usefulness of the ddPCR approach for the quantification of circulating miRNAs. The use of the ddPCR quantitative approach revealed very good agreement between two independent cohorts in terms of comparable absolute miRNA concentrations and consistent trends of dysregulation in breast cancer patients versus controls. Overall, this study supports the use of the quantitative ddPCR approach for monitoring the absolute levels of diagnostic and prognostic tumor-specific circulating miRNAs. PMID- 26120475 TI - Mechanisms of morphogenetic disorders in the lower jaw under the influence of heavy metal salts on the body. AB - In the experiment on the 36 mature rats, the peculiarities of morphological disorders in the lower jaw of rats under the influence of salts of chromium, lead, zinc, iron, copper, and manganese are showed. Profound morphological changes in bone and cartilaginous tissues of lower jaw are followed by disorders of bone mineral content. The importance of the S100 protein in morphological changes in bone and cartilaginous tissues under the influence of heavy metal salts is shown. PMID- 26120476 TI - Cocaine use does not affect mean platelet volume. AB - Increased mean platelet volume (MPV) is a marker of platelet activation. Platelet activation with cocaine use is not well studied. We wanted to investigate MPV levels in patients with cocaine-associated chest pain (CACP) as a marker of platelet activation. Retrospectively, MPV of 82 consecutive patients with CACP (group 1) with positive urine drug screen (UDS), without acute myocardial infarction (AMI) (group 1A) and with AMI with elevated troponin (group 1B), were included in the study. The control group (group 2) consisted of 89 consecutive patients admitted during the same time period with acute chest pain (ACP) who had negative UDS and negative cardiac markers with a normal cardiac stress test or normal coronary angiogram. Analysis showed no statistically significant difference of MPV between group 1, 8.46 +/- 1.06 fL, versus group 2, 8.7 +/- 1.07 fL; p = 0.142; and between group 1A, 8.46 +/- 1.05 fL, and group 1B, 8.46 +/- 1.09 fL; p = 0.983. By multiple linear regression analysis, MPV was not influenced by cocaine abuse (R = 0.269, R (2) = 0.072, adjusted R (2) = -0.009, p = 0.562). MPV is not elevated in patients with cocaine use even when they had AMI. Further studies may be necessary to investigate the role of platelet activation in patients with cocaine use and chest pain. PMID- 26120477 TI - Effect of the timing of delivery on perinatal outcomes at gestational hypertension. AB - OBJECTIVE: We aimed to evaluate the perinatal outcomes of women diagnosed with gestational hypertension and no proteinuria according to the gestational weeks. METHODS: We included women diagnosed with gestational hypertension between 2010 and 2014 at our institution and excluded the patients with preeclampsia and chronic hypertension. Women with gestational hypertension were grouped according to the gestational weeks. One group consisted of the pregnancies between 37 and 38*6, whereas the other group included pregnancies between 39 and 41 weeks. Then the outcomes of these pregnancies were compared with healthy women who had delivery between the same weeks (37-38*6 weeks and 39-41 weeks). We analyzed the mode of delivery, birth weight, and neonatal outcomes of these pregnancies. RESULTS: First and fifth minute Apgar scores were significantly decreased in women with gestational hypertension who had delivery between 39 and 41 weeks compared to healthy subjects (respectively, p = 0.005 and p = 0.033). Perinatal outcomes were adversely affected if the time of delivery was beyond 39 weeks in pregnancies complicated with gestational hypertension. CONCLUSION: We concluded that perinatal outcomes were adversely affected if the time of delivery was beyond 39 weeks in pregnancies complicated with gestational hypertension, and outcomes of such pregnancies can be improved if time for delivery is <39 weeks. PMID- 26120478 TI - Pathogenetic mechanisms of heavy metals effect on proapoptotic and proliferative potential of breast cancer. AB - MATERIALS AND METHODS: Chemical composition was studied with the help of the scanning electron microscope with energy-dispersion spectrometer. Immunohistochemical reaction showed the p53 and Ki-67 receptors expression. The study of DNA fragmentation was performed in agarose gel. RESULTS: There was an interrelation between the accumulations of the trace elements with the degree of cancer malignancy. There were 85% of cases with positive reaction to Ki-67 and 40% cases with positive reaction to p53. We found a moderate correlation between the accumulation of microelements in the breast cancer tissue and the level of proliferative activity. We noted the combination of the increase of DNA fragmentation with the expression of p53 and Ki-67 receptors. CONCLUSIONS: The trace elements can cause the initiation and the progression of the tumorous growth, which is expressed in the increased proliferation of tumor cells. This leads to the destabilization of the genetic material which can be expressed in the synthesis of mutant p53 protein. Finally, it leads to the block of apoptosis and regulatory effects of cells. This can cause the tumor progression and the destabilization of the genome, which is reflected in the increased DNA fragmentation. PMID- 26120479 TI - The effects of urgent percutaneous coronary intervention on right ventricular systolic functions in non-ST-elevation acute coronary syndromes. AB - BACKGROUND: Although the importance of the right ventricle (RV) involvement has been known for many years in patients with ST-elevation myocardial infarction (STEMI), it is scarce in non-ST-elevation acute coronary syndrome (NSTE-ACS). OBJECTIVES: We aimed to investigate the effects of urgent percutaneous coronary intervention (PCI) on the RV systolic functions in patients with NSTE-ACS. MATERIALS AND METHODS: Ninety-five patients diagnosed with NSTE-ACS and who underwent urgent PCI were prospectively investigated. RV systolic functions were analyzed and compared before and after PCI in all patients by using RV index of myocardial performance (RIMP), tricuspid annular plane systolic excursion (TAPSE), two-dimensional (2D) RV fractional area change (FAC), and isovolumic acceleration (IVA) parameters with transthoracic echocardiography. RESULTS: Among 95 NSTE-ACS patients, 31 had impaired RIMP, 13 had impaired TAPSE, 8 had decreased 2D FAC, and 32 had impaired IVA values at baseline. There was a significant increase in 2D FAC and IVA values after PCI. CONCLUSIONS: The right ventricular functions may also be affected in patients with NSTE-ACS, and urgent PCI has a significant effect on the recovery of right ventricular systolic functions in patients with NSTE-ACS. PMID- 26120480 TI - Comparison of an essential-oil-based oral rinse and chlorhexidine as adjuncts to scaling and root planing in the treatment of periodontal inflammation. AB - OBJECTIVE: The aim of the present short-term follow-up study was to compare the effects of an essential oil (EO)-based oral rinse and chlorhexidine as adjuncts to scaling and root planing (SRP) in the treatment of periodontal inflammation. METHODS: In Group-1, SRP was performed and participants were instructed to rinse with EO-based oral rinse; in Group-2, SRP was performed and participants were instructed to rinse with chlorhexidine; and in Group-3, SRP was performed and participants were instructed to rinse with water. Periodontal parameters (plaque index [PI], bleeding-on-probing [BOP], and probing pocket depth [PPD] >= 4 mm) were assessed at baseline and after 7 and 30 days. RESULTS: In all groups, periodontal parameters (PI, BOP, and PPD >= 4 mm) were comparable at baseline. In Groups-1 and -2, there was a significant reduction in PI (P < 0.01), BOP (P < 0.01), and PD >= 4 mm after 7 days and 30 days of follow-up than baseline. In Group-3, there was a significant reduction in PI (P < 0.01) and BOP (P < 0.01) after 7 days of follow-up compared to baseline. There was no difference in periodontal parameters after 7 days and 30 days of follow-up in Groups-1 and -2. CONCLUSION: EO-based oral rinses and chlorhexidine digluconate (CHX) are acceptable adjuncts to SRP in the treatment of periodontal inflammation. PMID- 26120482 TI - Home Water Treatment Habits and Effectiveness in a Rural Arizona Community. AB - Drinking water quality in the United States (US) is among the safest in the world. However, many residents, often in rural areas, rely on unregulated private wells or small municipal utilities for water needs. These utilities may violate the Safe Drinking Water Act contaminant guidelines, often because they lack the required financial resources. Residents may use alternative water sources or install a home water treatment system. Despite increased home water treatment adoption, few studies have examined their use and effectiveness in the US. Our study addresses this knowledge gap by examining home water treatment in a rural Arizona community. Water samples were analyzed for metal(loid)s, and home treatment and demographic data were recorded in 31 homes. Approximately 42% of homes treated their water. Independent of source water quality, residents with higher income (OR = 1.25; 95%CI (1.00 - 1.64)) and education levels (OR = 1.49; 95%CI (1.12 - 2.12)) were more likely to treat their water. Some contaminant concentrations were effectively reduced with treatment, while some were not. We conclude that increased educational outreach on contaminant testing and treatment, especially to rural areas with endemic water contamination, would result in a greater public health impact while reducing rural health disparities. PMID- 26120481 TI - Horseshoe kidney transplantation. AB - Horseshoe kidney is a fusion anomaly found in approximately one in 400-600 people. Due to vascular and ureteral variations, transplantation with a horseshoe kidney presents a technical challenge. In our case, the isthmus connected the upper poles and contained parenchyma. It consisted of three renal arteries, five veins collected to the inferior vena cava, and two ureters and pyelons. It was implanted en bloc to the left side retroperitoneally. During the early period, cellular and humoral rejection was confirmed and treated. For a urine leak, double J catheters were implanted into both ureters. Later, the first catheter was removed. Subsequently, urinary sepsis developed, necessitating graftectomy. The uncommon anatomy of ureters and antibody-mediated rejection (AMR) may both be factors for a ureter tip necrosis led to an infected urinoma. After other Hungarian authors, we also report a horseshoe kidney transplantation that was technically successful. However, after an adequately treated but severe acute humoral rejection, the patient developed sepsis, and the kidney had to be removed. We conclude that transplantation with horseshoe kidney is technically feasible but may increase the risk for urinary complications and resultant infections. Careful consideration of risk and benefit is advised when a transplant professional is faced with this option. PMID- 26120483 TI - Computational Optimization of Bioanalytical Parameters for the Evaluation of the Toxicity of the Phytomarker 1,4 Napthoquinone and its Metabolite 1,2,4 trihydroxynapththalene. AB - OBJECTIVES: Lawsone (1,4 naphthoquinone) is a non redox cycling compound that can be catalyzed by DT diaphorase (DTD) into 1,2,4-trihydroxynaphthalene (THN), which can generate reactive oxygen species by auto oxidation. The purpose of this study was to evaluate the toxicity of the phytomarker 1,4 naphthoquinone and its metabolite THN by using the molecular docking program AutoDock 4. METHODS: The 3D structure of ligands such as hydrogen peroxide (H2O2), nitric oxide synthase (NOS), catalase (CAT), glutathione (GSH), glutathione reductase (GR), glucose 6 phosphate dehydrogenase (G6PDH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) were drawn using hyperchem drawing tools and minimizing the energy of all pdb files with the help of hyperchem by MM(+) followed by a semi empirical (PM3) method. The docking process was studied with ligand molecules to identify suitable dockings at protein binding sites through annealing and genetic simulation algorithms. The program auto dock tools (ADT) was released as an extension suite to the python molecular viewer used to prepare proteins and ligands. Grids centered on active sites were obtained with spacings of 54 * 55 * 56, and a grid spacing of 0.503 was calculated. Comparisons of Global and Local Search Methods in Drug Docking were adopted to determine parameters; a maximum number of 250,000 energy evaluations, a maximum number of generations of 27,000, and mutation and crossover rates of 0.02 and 0.8 were used. The number of docking runs was set to 10. RESULTS: Lawsone and THN can be considered to efficiently bind with NOS, CAT, GSH, GR, G6PDH and NADPH, which has been confirmed through hydrogen bond affinity with the respective amino acids. CONCLUSION: Naphthoquinone derivatives of lawsone, which can be metabolized into THN by a catalyst DTD, were examined. Lawsone and THN were found to be identically potent molecules for their affinities for selected proteins. PMID- 26120484 TI - The Anticancer Role of Capsaicin in Experimentallyinduced Lung Carcinogenesis. AB - OBJECTIVES: Capsaicin (CAP) is the chief pungent principle found in the hot red peppers and the chili peppers that have long been used as spices, food additives and drugs. This study investigated the anticancer potential of CAP through its ability to modify extracellular matrix components and proteases during mice lung carcinogenesis. METHODS: Swiss albino mice were treated with benzo(a) pyrene (50 mg/kg body weight dissolved in olive oil) orally twice a week for four successive weeks to induce lung cancer at the end of 14(th) week. CAP was administrated (10 mg/kg body weight dissolved in olive oil) intraperitoneally. Extracellular matrix components were assayed; Masson's trichome staining of lung tissues was performed. Western blot analyses of matrix metalloproteases 2 and 9 were also carried out. RESULTS: In comparison with the control animals, animals in which benzo(a)pyrene had induced lung cancer showed significant increases in extracellular matrix components such as collagen (hydroxy proline), elastin, uronic acid and hexosamine and in glycosaminoglycans such as hyaluronate, chondroitin sulfate, keratan sulfate and dermatan sulfate. The above alterations in extracellular matrix components were effectively counteracted in benzo(a)pyrene along with CAP supplemented animals when compared to benzo(a) pyrene alone supplemented animals. The results of Masson's trichome staining for collagen and of, immunoblotting analyses of matrix metalloproteases 2 and 9 further supported the biochemical findings. CONCLUSION: The apparent potential of CAP in modulating extracellular matrix components and proteases suggests that CAP plays a chemomodulatory and anti- cancer role working against experimentally induced lung carcinogenesis. PMID- 26120485 TI - Association of a Methanol Extract of Rheum undulatum L. Mediated Cell Death in AGS Cells with an Intrinsic Apoptotic Pathway. AB - OBJECTIVES: Rheum undulatum L. has traditionally been used for the treatment of many diseases in Asia. However, its anti-proliferative activity in cancer has still not been studied. In the present study, we investigated the anti-cancer effects of methanol extract of Rheum undulatum L. (MERL) on human adenocarcinoma gastric cell lines (AGS). METHODS: To investigate the anti-cancer effect of MERL on AGS cells, we treated the AGS cells with varying con!centrations of MERL and performed 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Cell cycle analyses, measurements of the mitochondrial membrane potential (MMP), caspase activity assays and Western blots were conducted to determine whether AGS cell death occurred by apoptosis. RESULTS: Treatment with MERL significantly inhibited growth of AGS cells in a concentration dependent manner. MERL treatment in AGS cells leaded to increased accumulation of apoptotic sub G1 phase cells in a concentration dependent manner. In control cultures, 5.38% of the cells were in the sub G1 phase. In MERL treated cells, however, this percentage was significantly increased (9.95% at 70 MUg/mL, 15.94% at 140 MUg/mL, 26.56% at 210 MUg/mL and 38.08% at 280 MUg/mL). MERL treatment induced the decreased expression of pro-caspase-8 and -9 in a concentration dependent manner, whereas the expression of the active form of caspase-3 was increased. A subsequent Western blot analysis revealed increased cleaved levels of poly (ADP ribose) polymerase (PARP) protein. Also, treatment with MERL increased the activities of caspase-3 and -9 compared with the control. MERL treatment increased the levels of the pro-apoptotic truncated Bid (tBid) and Bcl2 Antagonist X (Bax) proteins and decreased the levels of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein, whose is the stabilization of mitochondria. However, inhibitions of p38, extracellular signal regulated kinases (ERKs) and C-Jun N terminal kinases (JNK) by MERL treatment did not affect cell death. CONCLUSION: These results suggest that MERL mediated cell death is associated with an intrinsic apoptotic pathway in AGS cells. PMID- 26120486 TI - The Effects of Sa-am Acupuncture Simpo-jeongkyeok Treatment on the Blood Pressure, Pulse Rate, and Body Temperature. AB - OBJECTIVES: The present study evaluated the effects of sa-am acupuncture (SAA) simpo-jeongkyeok (SPJK) treatment on the blood pressure (BP), pulse rate (PR), and body temperature (BT) of patients with hwa byung (HB). METHODS: This patient assessor blind, randomized, placebo controlled trial included 50 volunteers, divided randomly into two groups. The treatment group underwent SPJK (PC9, LR1, PC3, KI10) while the control (sham) group received minimal needle insertion at non acupoints. The BP in both arms, PR, and BT at several acupoints were measured before and after treatment at the 1(st), 2(nd), 3(rd), and 4(th) visits and before treatment at the follow-up visit. We analyzed data by using the repeated measured analysis of variance (RM ANOVA), Mann-Whitney U, and wilcoxon signed rank tests; differences at P < 0.05 were considered significant. RESULTS: No significant differences in the systolic blood pressure (SBP), diastolic blood pressure (DBP) and PR between the treatment and control group were observed at each visit. However, the decrease in the SBP for the treatment group before and after each visit was significantly higher than it was in the control group. The SBP in both arms in the treatment group was decreased between visits 1 and 2, 1 and 3, 1 and 4, and 1 and follow-up. The DBP in both arms and in the right arm between visits 1 and 3 in the treatment group showed decreases. A minimal BT increase for treatment at CV06 and CV12 and a minimal BT decrease for treatment at CV17 and (Ex) Yintang were found. Patients in the treatment group who visited more frequently experienced a greater decrease in the PR, but that effect was not maintained. CONCLUSION: The results suggest that SAA SPJK treatment has instant positive effects on the BP, PR, and BT in patients with HB, but the effects on the BP and PR are not maintained. PMID- 26120487 TI - Single-dose Intravenous Toxicology Testing of Daebohwalryeok Pharmcopuncture in Sprague-Dawley Rats. AB - OBJECTIVES: The aims of the study were to test the single-dose intravenous toxicity of Daebohwalryeok pharmacopuncture (DHRP) in Sprague-Dawley (SD) rats and to estimate the crude lethal dose. METHODS: The experiments were conducted at Biotoxtech Co., a Good Laboratory Practice (GLP) laboratory, according to the GLP regulation and were approved by the Institutional Animal Care and Use Committee of Biotoxtech Co. (Approval no: 110156). The rats were divided into three groups: DHRP was injected into the rats in the two test groups at doses of 10 mL/kg and 20 mL/kg, respectively, and normal saline solution was injected into the rats in the control group. Single doses of DHRP were injected intravenously into 6 week old SD rats (5 male and 5 female rats per group). General symptoms were observed and weights were measured during the 14 day observation period after the injection. After the observation period, necropsies were done. Then, histopathological tests were performed. Weight data were analyzed with a one-way analysis of variance (ANOVA) by using statistical analysis system (SAS, version 9.2). RESULTS: No deaths and no statistical significant weight changes were observed for either male or female SD rats in either the control or the test groups during the observation period. In addition, no treatment related general symptoms or necropsy abnormalities were observed. Histopathological results showed no DHRP related effects in the 20 mL/kg DHRP group for either male or female rats. CONCLUSION: Under the conditions of this study, the results from single-dose intravenous injections of DHRP showed that estimated lethal doses for both male and female rats were above 20 mL/kg. PMID- 26120488 TI - A Pilot Study on Single-dose Toxicity Testing of Hominis placenta Pharmacopuncture in Sprague-Dawley Rats. AB - OBJECTIVES: This study was performed to analyze the toxicity and to find the lethal dose of the test substance Hominis placenta pharmacopuncture when used as a single-dose in 6 week old, male and female Sprague-Dawley (SD) rats. METHODS: All experiments were conducted at Biotoxtech (Chungwon, Korea), an institution authorized to perform non clinical studies, under the regulations of Good Laboratory Practice (GLP). SD rats were chosen for the pilot study. Doses of Hominis placenta pharmacopuncture extracts, 0.125, 0.25 and 0.5 mL, were administered to the experimental group, and 0.5 mL doses of normal saline solution were administered to the control group. This study was conducted under the approval of the Institutional Animal Ethics Committee. RESULTS: No deaths or abnormalities occurred in any of the groups. Also, no significant changes in body weights were observed among the groups, and no significant differences in hematology/biochemistry, necropsy, and histopathology results were noted. Hematologically, some changes in the male rats in two experimental groups were observed, but those changes had no clinical or toxicological meaning because they were not dose dependent. Histopathological tests on the injected parts showed cell infiltration in the male rats in one of the experimental groups; however, that result was due to spontaneous generation and had no toxicological meaning. Therefore, this study showed that Hominis placenta pharmacopuncture had no effect on the injected parts in terms of clinical signs, body weight, hematology, clinical chemistry, and necropsy. CONCLUSION: As a result of single-dose tests of the test substance Hominis placenta pharmacopuncture in 4 groups of rats, the lethal dose for both males and females exceeded 0.5 mL/animal. Therefore, the above findings suggest that treatment with Hominis placenta pharmacopuncture is relatively safe. Further studies on this subject are needed. PMID- 26120489 TI - Toxicity of Single-dose Intramuscular Injection of Samjeong Pharmacopuncture in Sprague-Dawley Rats. AB - OBJECTIVES: This study was carried out in order to find both the single-dose intramuscular injection toxicity and the approximate lethal dose of samjeong pharmacopuncture (SP) in Sprague-Dawley (SD) rats. METHODS: The SD rats in this study were divided into four groups, one control group (1.0 mL/animal, normal saline) and three experimental groups (0.25, 0.5, and 1.0 mL/animal, SP). All groups consisted of five male and five female rats. SP was injected as a single dose intramuscularly at the thigh. After the injection, general symptoms and weight were observed for 14 days. After the observations had ended, hematologic and serum biochemical examinations, necropsy and a local tolerance test at the injection site were performed. The experiments were carried out at the Good Laboratory Practice firm, Biotoxtech Co. (Cheongwon, Chungbuk). Animal experiments were approved by the Ethics Committee (Approval Number: 130379). RESULTS: No deaths occurred in any of the three experimental groups. The injection of SP had no effects on the general symptoms, body weights, results of the hematologic, and serum biochemical examinations, and necropsy findings. In local tolerance tests at the injection sites, mild inflammation was observed in the experimental group, but it did not appear to be a treatment related effect. CONCLUSION: Under the conditions of this test, the results from the injection of SP suggest that the approximate lethal dose of SP is above 1.0 mL/animal for both male and female SD rats. Therefore, the clinical use of SP is thought to be safe. PMID- 26120490 TI - Single-dose Toxicity of ShinYangHur Herbal Acupuncture. AB - OBJECTIVES: This study was carried out to analyze the single-dose toxicity of ShinYangHur (SYH) herbal acupuncture injected into the muscles of Sprague-Dawley (SD) rats. METHODS: The SYH herbal acupuncture was made in a clean room at the Korean Pharmacopuncture Institute (KPI, Korea-Good Manufacturing Practice, K GMP). After the mixing process with sterile distilled water, the pH was controlled to between 7.0 and 7.5. Then, NaCl was added to make a 0.9% isotonic solution by using sterilized equipment. All experiments were conducted at Biotoxtech, an institution authorized to perform non clinical studies under the regulations of Good Laboratory Practice (GLP). SD rats were chosen for the pilot study. Doses of SYH herbal acupuncture, 0.25, 0.5, and 1.0 mL, were administered to the experimental groups, and a dose of normal saline solution, 1.0 mL, was administered to the control group. This study was conducted under the approval of the Institutional Animal Ethics Committee. RESULTS: No deaths or abnormalities occurred in any of the four groups. No significant changes in weight, hematological parameters or clinical chemistry between the control group and the experimental groups were observed. To check for abnormalities in organs and tissues, we used microscopy was used to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs or tissues. CONCLUSION: The above outcomes suggest that treatment with SYH herbal acupuncture is relatively safe. Further studies on this subject are needed to yield more concrete evidence. PMID- 26120491 TI - Single-dose Toxicity of Water-soluble Ginseng Pharmacopuncture Injected Intramuscularly in Rats. AB - OBJECTIVES: Radix Ginseng has been traditionally used as an adaptogen that acts on the adrenal cortex and stimulates or relaxes the nervous system to restore emotional and physical balance and to improve well-being in cases of degenerative disease and/or old age. Radix Ginseng has been used for a long time, but the safety of ginseng pharmacopuncture needs testing. This study was done to analyze the single-dose toxicity of water-soluble ginseng pharmacopuncture (GP) intramuscular injections in rats. METHODS: All experiments were performed at Biotoxtech, an institution authorized to perform non clinical studies under the regulations of Good Laboratory Practice (GLP). Each group contained 10 Sprague Dawley rats, 5 males and 5 females. GP was prepared in a sterile room at the Korean Pharmacopuncture Institute under regulations of Good Manufacturing Practice (GMP). GP dosages were 0.1, 0.5 and 1.0 mL for the experimental groups; normal saline was administered to the control group. The animals general condition was examined daily for 14 days, and the rats were weighed on the starting day and at 3, 7 and 14 days after administration of the pharmacopuncture. Hematological and biochemistry tests and autopsies were done to test the toxicological effect of GP after 14 days. This study was performed with approval from the Institutional Animal Ethics Committee of Biotextech. RESULTS: No deaths were found in this single-dose toxicity test of intramuscular injections of GP, and no significant changes in the general conditions, body weights, hematological and biochemistry tests, and autopsies were observed. The local injection site showed no changes. Based on these results, the lethal dose was assumed to be over 1.0 mL/animal in both sexes. CONCLUSION: These results suggest that GP is relatively safe. Further studies, including a repeated toxicity test, are needed to provide more concrete evidence for the safety of GP. PMID- 26120492 TI - Erratum: Ethanolic Extract of Marsdenia condurango Ameliorates Benzo[a]pyrene induced Lung Cancer of Rats: Condurango Ameliorates BaP-induced Lung Cancer in Rats. AB - [This corrects the article DOI: 10.3831/KPI.2014.17.011.]. PMID- 26120494 TI - Social Media and Mentoring in Biomedical Research Faculty Development. AB - PURPOSE: To determine how effective and collegial mentoring in biomedical research faculty development may be implemented and facilitated through social media. METHOD: The authors reviewed the literature for objectives, concerns, and limitations of career development for junior research faculty. They tabularized these as developmental goals, and aligned them with relevant social media strengths and capabilities facilitated through traditional and/or peer mentoring. RESULTS: The authors derived a model in which social media is leveraged to achieve developmental goals reflected in independent and shared projects, and in the creation and expansion of support and research networks. CONCLUSIONS: Social media may be successfully leveraged and applied in achieving developmental goals for biomedical research faculty, and potentially for those in other fields and disciplines. PMID- 26120493 TI - Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model. AB - Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2alpha (HIF2alpha), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation. PMID- 26120495 TI - Development of a Nationally Coordinated Evaluation Plan for the Ghana National Strategy for Key Populations. AB - OBJECTIVE: Just as HIV prevention programs need to be tailored to the local epidemic, so should evaluations be country-owned and country-led to ensure use of those results in decision making and policy. The objective of this paper is to describe the process undertaken in Ghana to develop a national evaluation plan for the Ghana national strategy for key populations. METHODS: This was a participatory process that involved meetings between the Ghana AIDS Commission (GAC), other partners in Ghana working to prevent HIV among key populations, and MEASURE Evaluation. The process included three two-day, highly structured yet participatory meetings over the course of 12 months during which participants shared information about on-going and planned data and identified research questions and methods. RESULTS: An evaluation plan was prepared to inform stakeholders about which data collection activities need to be prioritized for funding, who would implement the study, the timing of data collection, the research question the data will help answer, and the analysis methods. The plan discusses various methods that can be used including the recommendation for the study design using multiple data sources. It has an evaluation conceptual model, proposed analyses, proposed definition of independent variables, estimated costs for filling data gaps, roles and responsibilities of stakeholders to carry out the plan, and considerations for ethics, data sharing and authorship. CONCLUSION: The experience demonstrates that it is possible to design an evaluation responsive to national strategies and priorities with country leadership, regardless of stakeholders' experiences with evaluations. This process may be replicable elsewhere, where stakeholders want to plan and implement an evaluation of a large-scale program at the national or subnational level that is responsive to national priorities and part of a comprehensive monitoring and evaluation system. PMID- 26120496 TI - Tapping Underserved Students to Reshape the Biomedical Workforce. AB - Low-income and underrepresented minority students remain a largely untapped source of new professionals that are increasingly needed to diversify and strengthen the biomedical workforce. Precollege enrichment programs offer a promising strategy to stop the "leak" in the biomedical pipeline. However, in the era of highly competitive science education funding, there is a lack of consensus about the elements that predict the long-term viability of such programs. In this commentary, the authors review the critical elements that contribute to the long term viability of university-based precollege biomedical pipeline programs. Successful programs are built on a foundation of responding to local community workforce needs, have access to local universities that provide an organizational home, and offer a direct pipeline to strong undergraduate science training and support for graduate or professional training. Such programs have shown that there are substantial pools of diverse students who can thrive academically when given enrichment opportunities. Replication of pipeline programs with long-term viability will be instrumental in reaching the large numbers of talented underserved students who are needed to diversify and strengthen the biomedical workforce over the coming decades. PMID- 26120497 TI - Self-Reporting Degradable Fluorescent Grafted Copolymer Micelles Derived from Biorenewable Resources. AB - A series of hydrolytically degradable fluorescent poly(ferulic acid-co-tyrosine) g-mPEG graft copolymers were synthesized and shown to undergo self-assembly in aqueous media to yield fluorescent micelles. The polymers and their micellar assemblies exhibited greater fluorescence emission intensity than did their small molecular building blocks, which provides a self-reporting character that has potential for monitoring the polymer integrity and also for performing in theranostics applications. The amphiphilic graft-copolymers were synthesized by Cu-assisted azide-alkyne "click" addition of azido-functionalized mPEG polymers onto fluorescent degradable hydrophobic copolymers displaying randomly distributed alkyne side-chain groups along their biorenewably derived poly(ferulic acid-co-tyrosine) backbones. The morphologies and photophysical properties of the supramolecular assemblies generated in aqueous solutions were evaluated by DLS, TEM, AFM, and steady-state optical spectroscopies. The 15-30 nm sized micelles behaved as broad-band emitters in the 350-600 nm range, which highlights their potential as self-reporting nanomaterials for in vitro studies. PMID- 26120498 TI - Long term efficacy and safety of Fludarabine, Cyclophosphamide and Rituximab regimen followed by (90)Y-ibritumomab tiuxetan consolidation for the treatment of relapsed grades 1 and 2 follicular lymphoma. AB - BACKGROUND: In this retrospective study, we investigated the efficacy and safety of radioimmunotherapy with (90)Yttrium- ibritumomab tiuxetan ((90)Y-RIT) in 9 patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete (CR) or partial remission (PR) with Fludarabine, Cyclophosphamide and Rituximab (FCR). METHODS: The median age was 63 years (range 46-77). All patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m(2)x 3 days), C (1 gr/m(2) day 1) and R (375 mg/m(2) day 4) for 4 cycles. Those who achieved at least a PR with <25 % bone marrow involvement were treated with (90)Y-RIT 11.1 or 14.8 MBq/Kg, at 3 months after completing FCR. Patients underwent a further restaging at 12 weeks after (90)Y-RIT with a total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy. RESULTS: Nine patients completed the treatment: FCR followed by (90)Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR, 7 patients obtained CR and 2 PR; after (90)Y RIT 2 patients in PR converted to CR 12 weeks later. With a median follow up of 95 months (range 20-114) since FCR and 88 months (range 13-104) since (90)Y-RIT 3 deaths were not related to lymphoma; all 3 deceased patients obtained CR before (90)Y-RIT and died still in CR. The median overall (OS) and progression free survival (PFS) have not been reached, in this analysis both OS or PFS are 67 % at 7.5 year. The most common grade 3 or 4 adverse events were hematologic. CONCLUSIONS: These results confirm the long term efficacy and safety of 4 cycles of FCR followed by (90)Y-RIT in relapsed grades 1 and 2 FL and suggest that this regimen could be a therapeutic option for this setting of patients, specially at age of 60-75 with no unexpected toxicities. PMID- 26120500 TI - Local Health Department Provision of WIC Services Relative to Local "Need"- Examining 3 States and 5 Years. AB - Great variation exists in the nature of LHD service delivery and it varies, in part, relative to jurisdiction population size. Larger LHD jurisdictions may achieve an economy of scale in WIC service delivery that is not matched in smaller areas. Overall, we found that WIC service provision appears relatively consistent across study states and in the presence of increasing need, with greater responsiveness to need in urban areas. As demand for some preventive services increases LHDs in rural areas may need greater support than LHDs in large jurisdictions for meeting local demand. Unlike WIC, LHD-provided services that have less consistently maintained service-delivery guidelines may have a harder time responding to increasing need. The relative consistency of a federally-funded program such as WIC may serve as a good baseline for further study of less consistently delivered programs among LHDs. LHD service statistics can serve as useful data sources in measuring volume of service delivery relative to need. PMID- 26120501 TI - Methods for measuring diffusion of a social media-based health intervention. AB - This study evaluated the feasibility of measuring diffusion from a social networking community-level intervention. One year after completion of a randomized controlled HIV prevention trial on Facebook, 112 minority men who have sex with men (MSM) were asked to refer African-American and/or Latino sex partners to complete a survey. Results suggest that, compared to non-referrers, referrers spent more time online, controlling for age, race, education, and condition. Over 60% of referrals reported hearing about the intervention, and over half reported that the referrer talked to them about changing health behaviors. Results provide support and initial feasibility of using social networking for diffusing community-based HIV interventions. PMID- 26120499 TI - Kidney Regeneration: Lessons from Development. AB - A number of genes involved in kidney development are reactivated in the adult after acute kidney injury (AKI). This has led to the belief that tissue repair mechanisms recapitulate pathways involved in embryonic development after AKI. We will discuss evidence to support this hypothesis by comparing the mechanisms of development with common pathways known to regulate post-AKI repair, or that we identified as cell-specific candidates based on public datasets from recent AKI translational profiling studies. We will argue that while many of these developmental pathways are reactivated after AKI, this is not associated with general cellular reprogramming to an embryonic state. We will show that reactivation of these developmental genes is often associated with expression in cells that are not normally involved in mediating parallel responses in the embryo, and that depending on the cellular context, these responses can have beneficial or detrimental effects on injury and repair after AKI. PMID- 26120502 TI - Differentiation of extranodal non-Hodgkins lymphoma from squamous cell carcinoma of the maxillary sinus: a multimodality imaging approach. AB - This study aimed to assess the efficacy of a multimodality imaging approach for differentiating between primary extranodal non-Hodgkin's lymphoma (NHL) and squamous cell carcinoma (SCC) of the maxillary sinus. Twelve NHLs and 29 SCCs of the maxillary sinus were included. CT findings, MR signal intensities, apparent diffusion coefficients (ADCs), and maximum standardized uptake values (SUVmax) were correlated with two pathologies. On CT, permeative growth frequency was greater among NHLs than among SCCs (50 % vs. 10 %; p < 0.01), whereas destructive growth frequency was greater among SCCs than among NHLs (83 % vs. 33 %; p < 0.01). On CT, remaining sinus wall within the tumor was more frequent with NHLs than with SCCs (92 % vs. 34 %; p < 0.01), whereas intratumoral necrosis was more frequent with SCCs than with NHLs (86 % vs. 17 %; p < 0.01). ADCs were lower for NHLs than for SCCs (0.61 vs. 0.95 * 10(-3) mm(2)/s; p < 0.01). No significant differences in MR signal intensities and SUVmax were observed. Tumor growth pattern, remaining sinus wall within the tumor, and intratumoral necrosis were useful CT findings for differentiating between NHLs and SCCs. ADC measurements could assist the differentiation of NHL from SCC. PMID- 26120503 TI - Beneficial effect of phosphatidylcholine supplementation in alleviation of hypomania and insomnia in a Chinese bipolar hypomanic boy and a possible explanation to the effect at the genetic level. AB - INTRODUCTION: Recent studies indicated that supplementation of phosphatidylcholine has been found to be beneficial for psychiatric diseases and Diacylglycerol Kinase, Eta (DGKH) protein was involved in regulating the metabolism of phosphatidic acid and diacylglycerol. This study reported a case of a 16-year-old Chinese boy with bipolar hypomania symptoms receiving supplementation of phosphatidylcholine, and a genetic study of a risk variant of DGKH gene was performed in an attempt to provide an explanation for the potential beneficial effect of phosphatidylcholine supplementation. CASE DESCRIPTION: We described a case of a 16-year-old boy with bipolar disorder, who suffered from monthly episodes of insomnia accompanied by hypomania for 5 months despite adherence to medication. After supplementation of phosphatidylcholine, he returned to a normal sleeping pattern and recovered from hypomania symptoms for approximately 14 months. Furthermore, genotyping results showed that this boy carries the risk genotype (G/C) in DGKH variant rs77072822 (adjusted p-value = 0.025 after 2000 permutation tests). DISCUSSION AND EVALUATION: The 16-year-old boy appears to have benefited from the supplementation with phosphatidylcholine and recovered from hypomania symptoms. He carries a risk genotype in rs77072822 which lies in the first intron of DGKH gene that was mostly reported to be associated with bipolar disorder. Thus, this finding is consistent with the hypothesis that alleviating the phosphatidylcholine deficiencies might accompany with the risk variants of DGKH gene, which might improve the efficacies of such supplementation and design new treatment strategies for bipolar disorder. CONCLUSIONS: This study illustrated that a 16-year-old boy with hypomania symptoms responded well to supplementation of phosphatidylcholine and the boy carries a risk genotype in DGKH gene for bipolar disorder, which provides a possible explanation for the boy's beneficial effect at the genetic level. PMID- 26120504 TI - Impediments in foreign collaboration and conducting a high throughput molecular epidemiology research in India, an assessment from a feasibility study. AB - BACKGROUND: Esophageal cancer is one of the world's top ten cancers. Its incidence, especially in the form of squamous cell carcinoma, is very high in some Asian regions including Kashmir. Jammu Kashmir and Ladakh are three provinces of Jammu and Kashmir, the northern most state of India. The three regions represent ethnically diverse socio-cultural populations with different incidences of esophageal squamous cell carcinoma (ESCC), a suitable setting for epidemiological studies. Hence, comparing the lifestyle, dietary habits and gene pools between the three regions will help in elucidation of ESCC etiology further. Therefore, to assess the possibility of conducting a larger case control study, we carried out a feasibility study to identify the collaborators as well as to explore patient referral systems and available research facilities in the state. FINDINGS: We found conducting good cancer molecular epidemiology studies is difficult due to lack of proper research facilities and favourable administrative guidelines. The appropriate storage, transportation and analyses facilities of biological specimens for genome-wide association study and assessment of nutrition and exposure markers are unavailable or not sufficiently developed. Guidelines that can encourage scientific collaborations within the country seem unavailable. However, the administrative guidelines available under which the export of biological specimens out of India for analysis seems impossible. Consequently, Indian researchers are unable to collaborate with foreign scientists and render state of art research facilities inaccessible to them. Scientists in other parts of India may also confront with most of these impediments. CONCLUSION: The study found that for conducting conclusive molecular epidemiological studies in India, referral system in hospitals is not systematic, scientific research facilities are inadequate as well as the guidelines for foreign collaboration are not favourable. PMID- 26120505 TI - A parallel algorithm for motion estimation in video coding using the bilinear transformation. AB - Accurate motion estimation between frames is important for drastically reducing data redundancy in video coding. However, advanced motion estimation methods are computationally intensive and their execution in real time usually requires a parallel implementation. In this paper, we investigate the parallel implementation of such a motion estimation technique. Specifically, we present a parallel algorithm for motion estimation based on the bilinear transformation on the well-known parallel model of the hypercube network and formally prove the time and the space complexity of the proposed algorithm. We also show that the parallel algorithm can also run on other hypercubic networks, such as butterfly, cube-connected-cycles, shuffle-exchange or de Bruijn network with only constant slowdown. PMID- 26120506 TI - A cross-sectional study of Colombian University students' self-perceived lifestyle. AB - BACKGROUND: The Fantastic Lifestyle Questionnaire was designed for enabling staff working in health sciences and physical activity (PA) areas to measure lifestyles (LS) in the general population. The aim of this study was to assess the lifestyle in a sample of university students. METHOD: This was a cross-sectional, descriptive, observational study involving 5,921 subjects' aged 18- to 30-years old (3,471 females) from three Colombian cities. Was applied "Fantastic" instrument (that consists of 25 closed items on the lifestyle), translated to Spanish in versions of three and five answers. RESULTS: Having a "good LS" was perceived by 57.4% of the females and 58.5% of the males; 14.0% of the females rating their LS as being "excellent" and males 19.3% (p < 0.001); 20.3% of the females and 36.6% of the males stated that they spent more than 20 min/day on PA (involving four or more times per week). Negative correlations between FANTASTIC score and weight (r = -0.113; p < 0.01), body mass index (BMI) (r = -0.152; p < 0.01) and waist circumference (r = -0.178, p < 0.01) were observed regarding females, whilst the correlation concerning males was (r = -0.143, p < 0.05) between Fantastic score and weight, (r = -0.167 for BMI, p < 0.01) and (r = 0.175, p < 0.01 for diastolic blood pressure). In spite of the students being evaluated referring to themselves as having a healthy LS (i.e. giving a self perceived view of their LS), stated behaviour involving a health risk was observed in the domains concerning nutrition, PA and smoking. CONCLUSION: Specific diffusion, education and intervention action is thus suggested for motivating the adoption of healthy LS. PMID- 26120507 TI - Visceral to total obesity ratio and severe hydronephrosis are independently associated with prolonged pneumoperitoneum operative time in patients undergoing laparoscopic radical nephroureterectomy for upper tract urothelial carcinoma. AB - BACKGROUND: Our aim was to evaluate the effect of visceral obesity and impact of severe hydronephrosis on surgical complexity in patients undergoing laparoscopic radical nephroureterectomy (LRNU). METHODS: From January 2000 to December 2013, 169 patients underwent radical nephroureterectomy at our institution. We retrospectively reviewed the medical records of 70 patients who underwent LRNU. We measured total fat area (TFA) and visceral fat area (VFA) at the level of the umbilicus using computed tomography. We defined accumulated visceral fat distribution as a VFA/TFA ratio >=0.45. Ipsilateral hydronephrosis was graded from 0 to 4 by two uro-radiologists blinded to the clinical outcomes. RESULTS: Among the 70 patients, VFA/TFA ratio was >=0.45 in 40 patients (57.1%) and 28 (40.0%) had severe hydronephrosis (grade 3 or greater). Patients with a VFA/TFA ratio >=0.45 had significantly longer pneumoperitoneum and total operation times compared to their counterparts (p = 0.047 and p = 0.002, respectively). Patients with severe hydronephrosis had significantly longer pneumoperitoneum and total operative times compared to their counterparts (p = 0.006 and p = 0.002, respectively). Multivariate logistic regression analysis showed that a high VFA/TFA and severe hydronephrosis were independent predictive factors for prolonged pneumoperitoneum (p = 0.048, HR = 2.90; p = 0.015, HR = 3.82, respectively) and total operative times (p < 0.001, HR = 18.7; p = 0.003, HR = 10.7; respectively). Other pre-clinical factors such as age, gender, BMI, clinical stage, tumor size, location, laterality, degree of perinephric stranding, and surgical procedure did not affect the operation times. CONCLUSION: The present data indicated that the visceral type of adipose accumulation and presence of severe hydronephrosis could provide preoperative information on the degree of technical difficulty associated with LRNU. PMID- 26120508 TI - Signal parameter estimation using fourth order statistics: multiplicative and additive noise environment. AB - Parameter estimation of various multi-component stationary and non-stationary signals in multiplicative and additive noise is considered in this paper. It is demonstrated that the parameters of complex sinusoidal signal, complex frequency modulated (FM) sinusoidal signal and complex linear chirp signal in presence of additive and multiplicative noise can be estimated using a new definition of the fourth order cumulant (FOC), and the computed accumulated FOC (AFOC). Analytical expressions for the FOC/AFOC of the above signals are derived. The concept of accumulated cumulant is introduced to handle the case of a non-stationary signal, for which the fourth order cumulant may be a function of both time and lag. Simulation study is carried out for all the three signals. In case of complex sinusoidal signals, the resul ts of parameter estimation show that the proposed method based on the new definition of fourth order cumulant performs better than an existing method based on fourth order statistics. The proposed method can be employed for parameter estimation of non-stationary signals also as mentioned above. For comparison purpose, the Cramer-Rao (CR) bound expressions are derived for all the signals considered for parameter estimation. The simulation results for non-stationary signals are compared with the CR bounds. PMID- 26120509 TI - Analysis of the substrate inhibition of complete and partial types. AB - A simple graphical method was described for determining the kinetic parameters of substrate inhibition of complete and partial types. The method consists of plotting experimental data as [Formula: see text] versus the reciprocals of the substrate concentrations, where V max represents the maximal velocity. The reaction rate constant of enzyme-substrate-inhibitor complex [Formula: see text] can be calculated from the ordinate intercept of the linear relationship between [Formula: see text] and the reciprocal of the substrate concentrations at the higher and inhibitory concentrations of the substrate: partial type [Formula: see text] of the substrate inhibition gives straight lines intersecting with the ordinate at [Formula: see text], whereas complete substrate inhibition [Formula: see text] yields straight lines converging on the origin. The [Formula: see text] value also can be calculated from the slope by using the [Formula: see text] value determined. Validity of the method was confirmed by analyzing the substrate inhibition of phosphofructokinase II from E. coli. The present method provides a simple way for determining kinetic parameters of the substrate inhibition irrespective of complete and partial types. PMID- 26120510 TI - The Biofilm Community-Rebels with a Cause. AB - Oral Biofilms are one of the most complex and diverse ecosystem developed by successive colonization of more than 600 bacterial taxa. Development starts with the attachment of early colonizers such as Actinomyces species and oral streptococci on the acquired pellicle and tooth enamel. These bacteria not only adhere to tooth surface but also interact with each other and lay foundation for attachment of bridging colonizer such as Fusobacterium nucleatum followed by late colonizers including the red complex species: Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola-the founders of periodontal disease. As the biofilm progresses from supragingival sites to subgingival sites, the environment changes from aerobic to anaerobic thus favoring the growth of mainly Gram-negative obligate anaerobes while restricting the growth of the early Gram positive facultative aerobes. Microbes present at supragingival level are mainly related to gingivitis and root-caries whereas subgingival species advance the destruction of teeth supporting tissues and thus causing periodontitis. This review summarizes our present understanding and recent developments on the characteristic features of supra- and subgingival biofilms, interaction between different genera and species of bacteria constituting these biofilms and draws our attention to the role of some of the recently discovered members of the oral community. PMID- 26120511 TI - Of Mice and Men: Protective and Pathogenic Immune Responses to West Nile virus Infection. AB - West Nile virus, a mosquito-borne flavivirus, first emerged in the Western Hemisphere in 1999. Although the majority of infections are asymptomatic, WNV causes significant morbidity and mortality in a minority of individuals who develop neuroinvasive disease, in particular the elderly and immunocompromised. Research in animal models has demonstrated interactions between WNV and the innate and adaptive immune system, some of which protect the host and others which are deleterious. Studies of disease pathogenesis in humans are less numerous, largely due to the complexities of WNV epidemiology. Human studies that have been done support the notion that innate and adaptive immune responses are delicately balanced and may help or harm the host. Further human investigations are needed to characterize beneficial responses to WNV with the goal of such research leading to therapeutics and effective vaccines in order to control this emerging viral disease. PMID- 26120512 TI - Update on Antifungal Drug Resistance. AB - Invasive fungal infections remain a major source of global morbidity and mortality, especially among patients with underlying immune suppression. Successful patient management requires antifungal therapy. Yet, treatment choices are restricted due to limited classes of antifungal agents and the emergence of antifungal drug resistance. In some settings, the evolution of multidrug resistant strains insensitive to several classes of antifungal agents is a major concern. The resistance mechanisms responsible for acquired resistance are well characterized and include changes in drug target affinity and abundance, and reduction in the intracellular level of drug by biofilms and efflux pumps. The development of high-level and multidrug resistance occurs through a stepwise evolution of diverse mechanisms. The genetic factors that influence these mechanisms are emerging and they form a complex symphony of cellular interactions that enable the cell to adapt and/or overcome drug-induced stress. Drivers of resistance involve a complex blend of host and microbial factors. Understanding these mechanisms will facilitate development of better diagnostics and therapeutic strategies to overcome and prevent antifungal resistance. PMID- 26120513 TI - Food allergies resulting from immunological cross-reactivity with inhalant allergens: Guidelines from the German Society for Allergology and Clinical Immunology (DGAKI), the German Dermatology Society (DDG), the Association of German Allergologists (AeDA) and the Society for Pediatric Allergology and Environmental Medicine (GPA). AB - A large proportion of immunoglobulin E (IgE)-mediated food allergies in older children, adolescents and adults are caused by cross-reactive allergenic structures. Primary sensitization is most commonly to inhalant allergens (e.g. Bet v 1, the major birch pollen allergen). IgE can be activated by various cross reactive allergens and lead to a variety of clinical manifestations. In general, local and mild - in rare cases also severe and systemic - reactions occur directly after consumption of the food containing the cross-reactive allergen (e. g. plant-derived foods containing proteins of the Bet v 1 family). In clinical practice, sensitization to the primary responsible inhalant and/or food allergen can be detected by skin prick tests and/or in vitro detection of specific IgE. Component-based diagnostic methods can support clinical diagnosis. For individual allergens, these methods may be helpful to estimate the risk of systemic reactions. Confirmation of sensitization by oral provocation testing is important particulary in the case of unclear case history. New, as yet unrecognized allergens can also cause cross-reactions. The therapeutic potential of specific immunotherapy (SIT) with inhalant allergens and their effect on pollen-associated food allergies is currently unclear: results vary and placebo-controlled trials will be necessary in the future. Pollen allergies are very common. Altogether allergic sensitization to pollen and cross-reactive food allergens are very common in our latitudes. The actual relevance has to be assessed on an individual basis using the clinical information. Cite this as Worm M, Jappe U, Kleine-Tebbe J, Schafer C, Reese I, Saloga J, Treudler R, Zuberbier T, Wassmann A, Fuchs T, Dolle S, Raithel M, Ballmer-Weber B, Niggemann B, Werfel T. Food allergies resulting from immunological cross-reactivity with inhalant allergens. Allergo J Int 2014; 23: 1-16 DOI 10.1007/s40629-014-0004-6. PMID- 26120514 TI - Climate change and air pollution: Effects on pollen allergy and other allergic respiratory diseases. AB - The observational evidence indicates that recent regional changes in climate, particularly temperature increases, have already affected a diverse set of physical and biological systems in many parts of the world. Allergens patterns are also changing in response to climate change and air pollution can modify the allergenic potential of pollen grains especially in the presence of specific weather conditions. Although genetic factors are important in the development of asthma and allergic diseases, their rising trend can be explained only by changes occurring in the environment and urban air pollution by motor vehicles has been indicated as one of the major risk factors responsible for this increase. Despite some differences in the air pollution profile and decreasing trends of some key air pollutants, air quality is an important concern for public health in the cities throughout the world. Due to climate change, air pollution patterns are changing in several urbanized areas of the world with a significant effect on respiratory health. The underlying mechanisms of all these interactions are not well known yet. The consequences on health vary from decreases in lung function to allergic diseases, new onset of diseases, and exacerbation of chronic respiratory diseases. In addition, it is important to recall that an individual's response to pollution exposure depends on the source and components of air pollution, as well as meteorological conditions. Indeed, some air pollution related incidents with asthma aggravation do not depend only on the increased production of air pollution, but rather on atmospheric factors that favor the accumulation of air pollutants at ground level. Associations between thunderstorms and asthma morbidity of pollinosis-affected people have also been identified in multiple locations around the world (Fig.1). Cite this as D'Amato G, Bergmann KC, Cecchi L, Annesi-Maesano I, Sanduzzi A, Liccardi G, Vitale C, Stanziola A, D'Amato M. Climate change and air pollution - Effects on pollen allergy and other allergic respiratory diseases. Allergo J Int 2014; 23: 17-23 DOI 10.1007/s40629-014-0003-7 A factor clouding the problem is that laboratory evaluations do not reflect what happens during natural exposition. Considering these aspects, governments worldwide, international organizations, and cooperations such as the World Health Organization (WHO) and the European Health Policy of the European Union (EU) are facing a growing problem of the respiratory effects induced by gaseous and particulate pollutants arising from motor vehicle emissions. PMID- 26120515 TI - Sphingosine-1-phosphate as signaling molecule in the skin: Relevance in atopic dermatitis. AB - Sphingolipids are essential molecules of the mammalian epidermis. Keratinocytes generate and secrete huge amounts of ceramide-precursors to the extracellular domain of the stratum corneum, where they are further metabolized to specific ceramide species. The arrangement of ceramides to well-organized lipid lamellae is essential to form the epidermal barrier. Besides their role as structural components sphingolipids are also critical molecules involved in the modulation of epidermal cells. Sphingosine-1-phosphate (S1P) has been identified as a prominent signaling molecule which regulates fundamental functions of keratinocytes and skin dendritic cells. Thus, S1P inhibits proliferation of keratinocytes and induces their differentiation. Moreover, antigen uptake, migration and cytokine production of dendritic cells are under the control of this sphingolipid. A dysregulation of the sphingolipid metabolism has been discussed in inflammatory skin disorders like atopic dermatitis. Animal models of contact dermatitis provide evidence that topical treatment with S1P is connected with an anti-inflammatory action suggesting a novel approach for the treatment of atopic dermatitis. PMID- 26120516 TI - Human heart as a shock organ in anaphylaxis. AB - Anaphylaxis is a potentially fatal, immediate hypersensitivity reaction. Mast cells and basophils, by elaborating vasoactive mediators and cytokines, are the main primary effector cells of anaphylaxis. Mast cells have been identified in human heart between myocardial fibers, perivascularly, in the adventitia, and in the arterial intima. Mast cells isolated from human heart tissue (HHMC) of patients undergoing cardiac transplantation express high affinity immunglobulin E (IgE) receptors (FcepsilonRI), C3a, C5a, and kit receptors (KIT). Anti-IgE, anti FcepsilonRI, and immunoglobulin superallergens induce in vitro secretion of preformed mediators (histamine, tryptase, chymase, and renin) and the de novo synthesis of cysteinyl leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) from HHMC. Complement is activated and anaphylatoxin forms during anaphylaxis. C5a and C3a cause the in vitro release of histamine and tryptase from HHMC. Therapeutic (general anesthetics, protamine, etc.) and diagnostic agents (radio contrast media, etc.), which can cause anaphylactoid reactions, activate HHMC in vitro. Low concentrations of histamine and cysteinyl leukotrienes given to subjects undergoing diagnostic catheterisation caused significant systemic and coronary hemodynamic effects. These data indicate that human heart mast cells and their mediators play a role in severe anaphylactic reactions. PMID- 26120517 TI - Modern diagnosis of celiac disease and relevant differential diagnoses in the case of cereal intolerance. AB - At an incidence of 1:500, celiac disease (formerly sprue) is an important differential diagnosis in patients with malabsorption, abdominal discomfort, diarrhea and food intolerances. Celiac disease can induce a broad spectrum of both gastrointestinal and extraintestinal symptoms, e.g. dermatitis herpetiformis (Duhring's disease). A variety of oligo- and asymptomatic courses (e.g. anemia, osteoporosis, depression) through to refractory collagenic celiac disease are seen. In HLA-DQ2 and -8 predisposed individuals, celiac disease is provoked by contact with wheat gliadin fractions through a predominantly Th1 immune response and an accompanying Th2 response, which can eventually lead to villous atrophy. Using appropriate serological tests (IgA antibodies against tissue transglutaminase, endomysium and deamidated gliadin peptides) under sufficient gluten ingestion, the diagnosis can be made more reliably today than previously. The same IgG-based serological tests should be used in the case of IgA deficiency. Diagnosis can either be made in children and adolescents with anti transglutaminase titers exceeding ten times the standard for two of the above mentioned serological markers and HLA conformity or it is made by endoscopy and histological Marsh classification in adults and in cases of inconclusive serology. If clinically tolerated, gluten challenges are indicated in patients that already have reduced gluten intake, in borderline serological results, discordance between serological and histological results or in suspected food allergy. The diagnosis of celiac disease needs to be definitive and robust before establishing a gluten-free diet, since lifelong abstention from gluten (gliadin < 20 mg/kg foodstuffs), cereal products (wheat, rye, barley and spelt) as well as from preparations and beverages containing gluten, is necessary. With effective elimination of gluten, the prognosis regarding complete resolution of small bowel inflammation is good. Refractory courses are seen only in rare cases, accompanied by enteropathy-associated T-cell lymphoma. PMID- 26120518 TI - Ash pollen allergy: reliable detection of sensitization on the basis of IgE to Ole e 1. AB - Background: Alongside hazel, alder and birch pollen allergies, ash pollen allergy is a relevant cause of hay fever during spring in the European region. For some considerable time, ash pollen allergy was not routinely investigated and its clinical relevance may well have been underestimated, particularly since ash and birch tree pollination times are largely the same. Ash pollen extracts are not yet well standardized and diagnosis is therefore sometimes unreliable. Olive pollen, on the other hand, is strongly cross-reactive with ash pollen and is apparently better standardized. Therefore, the main allergen of olive pollen, Ole e 1, has been postulated as a reliable alternative for the detection of ash pollen sensitization. Methods: To determine to what extent specific IgE against Ole e 1 in patients with ash pollen allergy is relevant, we included 183 subjects with ash pollen allergy displaying typical symptoms in March/April and positive skin prick test specific IgE against Ole e 1 (t224) and ash pollen (t25) and various birch allergens (Bet v 1, Bet v 2/v 4) in a retrospective study. Results: A significant correlation was seen between specific IgE against Ole e 1 and ash pollen, but also to a slightly lesser extent between IgE against Ole e 1 and skin prick test with ash pollen, the latter being even higher than IgE and skin prick test both with ash pollen. No relevant correlation was found with birch pollen allergens, demonstrating the very limited cross-reactivity between ash and birch pollen. Conclusion: It appears appropriate to determine specific IgE against Ole e 1 instead of IgE against ash pollen to detect persons with ash pollen allergy. Our findings may also support the idea of using possibly better standardized or more widely available olive pollen extracts instead of ash pollen extract for allergen-specific immunotherapy. PMID- 26120519 TI - Chlorhexidine allergy. PMID- 26120520 TI - Rupatadine: efficacy and safety of a non-sedating antihistamine with PAF antagonist effects. AB - Rupatadine is a modern non-sedating H1-antihistamine that also haswith additional antagonist effects on platelet-activating factor (PAF). Under the tradenames Rupafin(r) and Urtimed(r), Rrupatadine is approvedregistered in Germany for the treatment of allergic rhinitis and urticaria infor adults and children aged over 12 years. In this review, the available literature available to date onregarding the pharmacological profile and clinical application of Rrupatadine is reviewed and compared to other conventional histamines. In conclusionFinally, the side effects, safety and interaction profileincompatibility of Rrupatadine are discussed. Due to CYP p450 metabolism, Rrupatadine should not be given together with Eerythromycin, Kketoconazole or grapefruit juice. Rupatadine has been found to be effective and safe Iin a variety of randomized clinical trials both in both seasonal and perennial allergic rhinitis, as well as inbut also chronic urticaria Rupatadine has been found as effective and safe. PMID- 26120522 TI - Bronchitis and asthma in the setting of vitamin D deficiency. PMID- 26120521 TI - Guideline for acute therapy and management of anaphylaxis: S2 Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Austrian Society for Allergology and Immunology (OGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psychosomatic Medicine (DGPM), the German Working Group of Anaphylaxis Training and Education (AGATE) and the patient organization German Allergy and Asthma Association (DAAB). PMID- 26120523 TI - Acupuncture in allergic rhinitis: A Mini-Review. AB - Acupuncture is a therapy method known for millennia with apparently polygenetic roots. It is traditionally practiced in East Asian countries. During the recent fifty years, it has found wide applications in Europe as well. Today acupuncture is one of the most important parts of modern complementary medicine. Questions concerning the mechanism of action and efficacy of acupuncture, among others in the treatment of allergic rhinitis, still lead to many scientific discussions. This review summarizes the modern understanding of possible mechanisms of acupuncture as well as it presents the current state of clinical studies relating to the efficacy of acupuncture in the treatment of allergic rhinitis. Further investigations are necessary to confirm acupuncture as an effective therapy of allergic rhinitis. PMID- 26120524 TI - Mould allergens: Where do we stand with molecular allergy diagnostics?: Part 13 of the series Molecular Allergology. AB - The official WHO/IUIS database (www.allergen.org) currently lists 77 mould allergens from a variety of protein families. To date, only eight recombinant single allergens from three mould species are available for molecular allergy diagnosis of mould sensitization. These include rAlt a 1, the major allergen in Alternaria alternata-sensitized individuals, and enolase rAlt a 6 with it potential cross-reactivity to mould, food and natural latex allergens. rAsp f 1, 2, 3, 4 and 6 from Aspergillus fumigatus are available for diagnostic purposes; specific IgE to rAsp f 2, 4 and 6 is often positive in allergic bronchopulmonary aspergillosis (ABPA). The dehydrogenase rCla h 8 is considered a major allergen of Cladosporium herbarum with possible cross-reactivity to other dehydrogenase allergens. The narrow range of commercially available individual mould allergens should be expanded to include marker allergens typical for mould (e.g., serine proteases). In addition, standardization of total extracts needs to be improved in the future to guarantee valid mould products with defined allergen content for diagnostic and therapeutic purposes. PMID- 26120525 TI - Author guidelines: Allergo Journal International. PMID- 26120526 TI - Molecular sIgE profile in infants and young children with peanut sensitization and eczema. AB - BACKGROUND: Many children develop a sensitization to peanut in early infancy, even before peanut is introduced in their diet. Sensitization is particularly common in young children with eczema. There have been scant data available to date on the sensitization pattern for specific peanut allergens in this patient group. The aim of this study was to investigate the allergen profile of infants and young children with peanut sensitization and eczema. METHODS: Sera from 53 children aged <= 20 months with eczema and sensitization to peanut but who had not yet consumed products containing peanuts were included in the analysis. Sera were analyzed using microarray immunoassay (ImmunoCAP ISAC). RESULTS: In total, 63 % of peanut-sensitized children showed specific immunoglobulin E (sIgE) against at least one peanut allergen on the microarray. Specific IgE to the 7S globulin Ara h 1 was detected in 40 % of the children, to the 2S albumin Ara h 2 in 30 % and to the 11S globulin Ara h 3 in 23 %. Only one child had sIgE to Arah 8, the homologoue of Bet-v-1. Data on clinical relevance were available for 24 of 53 children: 14 of 24 patients had objective allergic reactions to peanut, while 10 children were peanut-tolerant. The seed storage protein Ara h 2 was not detected on microarray in 43 % (6 of 14) of children with peanut allergy. Two of these six children were mono-sensitized to Ara h 1 and two to Ara h 3, while in three children none of these seed storage proteins was detected. DISCUSSION: It could be shown that infants and young children with eczema and sensitization to peanut recognize predominantly seed storage proteins from peanut, even before the introduction of peanut into their diet. Sensitization to pollen-related food allergens seems to be rare at this age. At this age not only Ara h 2, but also Ara h 1 seems to be related to clinical relevance. PMID- 26120527 TI - Benefits and limitations of molecular diagnostics in peanut allergy: Part 14 of the series Molecular Allergology. AB - Allergic reactions to peanut (Arachis hypogaea, Ara h) are caused by immunoglobulin E (IgE)-mediated sensitizations to various proteins. The stability and relative proportion of these proteins in peanut determine the risk of hazardous reactions. Hazardous sensitization to seed storage proteins [S2 albumins (Ara h 2, 6 and 7) > other seed storage proteins (Ara 1 and 3) > oleosins (Ara h 10 and 11)] are distinct from sensitizations to lipid transfer protein (Ara h 9) with moderate risk or cross-sensitizations to Bet v 1 homologous PR-10 protein (Ara h 8) and to profilin (Ara h 5) with low risk. A specific IgE test, e.g. to Ara h 2 in the case of suspected systemic reaction, or where this should be ruled out, can facilitate easier risk assessment. Results, however, are only relevant in the presence of corresponding clinical symptoms. IgE sensitization to peanut extract without hazardous reactions is often caused in this part of the world by Bet v 1-related cross reactions (in birch pollen allergy sufferers), cross-reactive carbohydrate determinants (CCD) or profilin sensitizations. In the case of doubt, clinical relevance can only be established by means of oral challenge, particularly since not all peanut allergens (e. g., oleosins) are available as yet for diagnostic purposes. PMID- 26120528 TI - Cellular in vitro diagnosis of adverse drug reactions. AB - Adverse drug reactions can manifest clinically in a variety of ways. Whilst the majority can be explained by dose-dependent side effects, there is group of unpredictable immunological or non-immunological intolerances that represent a particular diagnostic challenge. Skin tests are frequently negative, whilst challenge tests are time-consuming and often hazardous. Against this backdrop, cellular in vitro tests play a particularly important role in the identification of the causative drug. Whilst basophil tests can be used in the case of immunoglobulin E (IgE)- as well as non-IgE-mediated hypersensitivity reactions, T cellular test methods assist in the diagnosis of drug eruptions. The reliability of individual tests can be affected by a variety of parameters, such as the pathomechanism underlying the drug reaction, the causative medication, or the point in time of testing. Not only is a sound knowledge of the basic principles of the individual assays an essential prerequisite for correctly indicating and interpreting this test method, but also an awareness of these additional factors. PMID- 26120529 TI - Clinical and diagnostic challenges of metal implant allergy using the example of orthopaedic surgical implants: Part 15 of the Series Molecular Allergology. AB - The focus of this review are allergic reactions to orthopaedic-surgical metal implants. The spectrum of metal implant associated potential allergic reactions encompasses eczema, impaired wound and fracture healing, infection-mimicking reactions, effusions, pain and loosening. Nickel, cobalt and chromium seem to be the predominant eliciting allergens. Despite the growing number of respective publications the topic "metal implant allergy" remains a diagnostic challenge. Initially, differential diagnoses should always be excluded in cooperation with surgery collegues. It is recommended to perform a combined evaluation of medical history, clinical findings, patch testing and histology. The lymphocyte transformation test (LTT) can indicate metal sensitization, but it needs careful interpretation. Allergists can provide a substantial contribution to this interdisciplinary topic. PMID- 26120532 TI - Abstracts, 9th German Allergy Congress, Wiesbaden, 2-4 October 2014. PMID- 26120531 TI - Author guidelines: Allergo Journal International. PMID- 26120530 TI - S3-Guideline on allergy prevention: 2014 update: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Society for Pediatric and Adolescent Medicine (DGKJ). AB - : The continued high prevalence of allergic diseases in Western industrialized nations combined with the limited options for causal therapy make evidence-based primary prevention necessary. The recommendations last published in the S3 guideline on allergy prevention in 2009 have been revised and a consensus reached on the basis of an up-to-date systematic literature search. Evidence was sought for the period between May 2008 and May 2013 in the Cochrane and MEDLINE electronic databases, as well as in the reference lists of recent review articles. In addition, experts were surveyed for their opinions. The relevance of retrieved literature was checked by means of two filter processes: firstly according to title and abstract, and secondly based on the full text of the articles. Included studies were given an evidence grade, and a bias potential (low/high) was specified for study quality. A formal consensus on the revised recommendations was reached by representatives of the relevant specialist societies and (self-help) organizations (nominal group process). Of 3,284 hits, 165 studies (one meta-analysis, 15 systematic reviews, 31 randomized controlled trials, 65 cohort studies, 12 case-control studies and 41 cross-sectional studies) were included and evaluated. Recommendations on the following remain largely unaltered: full breastfeeding for 4 months as a means of allergy prevention (hypoallergenic infant formula in the case of infants at risk); avoidance of overweight; fish consumption (during pregnancy/lactation and in the introduction of solid foods for infants); vaccination according to the recommendations of the German Standing Committee on Vaccination (Standige Impfkommission, STIKO); avoidance of air pollutants and tobacco exposure and avoidance of indoor conditions conducive to the development of mold. The assertion that a reduction in house-dust mite allergen content as a primary preventive measure is not recommended also remains unchanged. The introduction of solid foods into infant diet should not be delayed. In the case of children at risk cats should not be acquired as domestic pets. Keeping dogs is not associated with an increased risk of allergy. The updated guideline includes a new recommendation to consider the increased risk of asthma following delivery by cesarean section. Additional statements have been formulated on pre- and probiotic agents, psychosocial factors, medications, and various nutritional components. Revising the guideline by using an extensive evidence base has resulted not only in an endorsement of the existing recommendations, but also in modifications and in the addition of new recommendations. The updated guideline enables evidence-based and up-to-date recommendations to be made on allergy prevention. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available for this article at 10.1007/s40629-014-0022-4 and is accessible for authorized users. PMID- 26120533 TI - Lichenoid contact reaction to eugenol presenting as oral lichen planus. PMID- 26120534 TI - Bronchial asthma: is personalized therapy on the horizon? AB - In the last years there is an increasing trend towards personalized medicine for patients with asthma. This is due to the availability of novel specific therapies. These new compounds are supposed to be used in well-defined patient groups, which are likely to respond to these interventions. In addition to already used anti-IgE, novel monoclonal antibodies such as anti-IL-5 and anti-IL 13 are becoming available. Currently clinical trials are ongoing to identify which patient population will respond to these novel therapies. PMID- 26120536 TI - Immunodeficiency in adults a practical guide for the allergist. AB - Knowing the clinical warning signs of immunodeficiency (ID) in adulthood is crucial for early detection of the over 200 forms of primary ID known to date. Many of these congenital diseases with a genetic background already manifest in childhood. Antibody deficiency diseases represent an important exception, with common variable immunodeficiency (CVID) being the most common form of ID. The median age of onset of CVID is 24 years. Unfortunately, the delay in diagnosis is still in excess of 4 years. General practitioners as well as allergists play a particularly important role in early detection. ID patients who present primarily with signs of immune dysregulation pose an even greater diagnostic challenge. Thus, autoimmune cytopenia, inflammatory bowel diseases, or sarcoid-like granulomatous inflammation can be the first manifestation in up to 20 % of ID patients. Secondary forms of ID [e. g., due to long-term corticosteroid treatment, HIV-infection, leukemia, lymphoma, nephrotic syndrome, malabsorption syndrome] need to be differentiated from primary antibody deficiency. Considering the overlap with allergic symptoms [ID accompanied by a susceptibility to eczema, elevated total IgE, blood eosinophilia], the present article discusses, the clinical warning signs of ID, the first diagnostic steps required and the option of further diagnostic work up at specialist centers for complex cases, as well as the treatment options for such cases. PMID- 26120535 TI - Quality of life in the setting of anaphylaxis and food allergy. AB - The diagnosis of a food allergy generally has a considerable impact on patients. Not does it result in dietary restrictions, it is often also associated with a constant threat scenario, given the risk of sudden allergic reactions, including life-threatening anaphylaxis. It is essential for patients to receive training on how to deal with emergency situations and make the correct decision regarding the use of emergency medication. Severe allergic reactions occur only rarely if patients are well informed. However, the fear of allergic reactions results in a significant impairment in quality of life (QoL). In recent years, numerous studies have been carried out on QoL in food-allergy and anaphylaxis patients. These studies provide insight into patient behaviour in everyday life. More importantly, by means of targeted and specific counselling, they also make it possible to reduce adverse effects on QoL and improve avoidance behaviour and compliance in terms of the requisite emergency measures. The present article summarizes the available data and formulates recommendations aimed at improving the care of food-allergy patients in terms of QoL and compliance. PMID- 26120537 TI - Glucoamylase: a current allergen in the baking industry. AB - BACKGROUND: Over a 10 year period a decline in the rate of sensitizations to alpha-amylase (Aspergillus oryzae) was observed in bakers investigated for allergic obstructive airway disease. At the same time, glucoamylase (Aspergillus niger) was identified as the currently the most relevant allergen in sensitizations to enzymes in the baking industry. The aim of the present study was to investigate whether, over a period of 10 years and in the case of new onset disease, there had been any change in sensitization and exposure rates to enzymes used in the baking industry. METHODS: Total immunoglobulin-E (IgE) levels and specific IgE to baking enzymes were determined in 433 bakers investigated in the Baker's Asthma prevention program (Backerasthma Praventionsprogramm, BAP) of the German Social Accident Insurance Institution for the foodstuffs and catering industry (Berufsgenossenschaft Nahrungsmittel und Gastgewerbe, BGN). At the same time personal dust exposure, including assessment of the level of alpha-amylase exposure in the area of exposure, was recorded. RESULTS AND CONCLUSIONS: Serological investigations revealed a significant decline in the rate of sensitization to alpha-amylase from 26 % to 13 %. At 28 %, the rate of sensitization to the baking enzyme glucoamylase was significantly higher than to cellulase (16 %) and alpha-amylase among subjects in 2010. Multiple sensitizations to all three baking agents are common. In total, 30 % of affected bakers are currently sensitized to at least one of the baking enzymes investigated. Data from individual dust measurements revealed a decline in alpha amylase exposure while overall dust exposure remained almost unchanged. Today, 11 % fewer bakers are exposed to alpha-amylase compared with ten years previously and, at the same time, enzyme concentrations in exposed bakers have dropped significantly. The high sensitization rate to glucoamylase in affected bakers gives cause to investigate exposure levels in bakeries and to assess sensitizations in the context of occupational disease proceedings. PMID- 26120538 TI - Marker allergens of weed pollen - basic considerations and diagnostic benefits in the clinical routine: Part 16 of the Series Molecular Allergology. AB - The term weed is referring to plants used as culinary herbs and medicinal plants as well as ecologically adaptive and invasive segetal plants. In Europe, pollen of ragweed, mugwort, English plantain and pellitory are the main elicitors of weed pollen allergies. Presently, 35 weed pollen allergens have been identified. The most relevant belong to the protein families of pectate lyases, defensin-like proteins, non-specific lipid transfer proteins, and Ole e 1-like proteins. The sensitization frequency depends on geographic regions and might affect more than 50 % of pollen allergic patients in distinct regions. Due to overlapping flowering seasons, similar habitats, polysensitizations and cross-reactive (pan) allergens, it is difficult to diagnose genuine weed pollen sensitization using pollen extracts. Marker allergens for component-resolved diagnostics are available for the important weed pollen. These are Amb a 1 (ragweed), Art v 1 (mugwort), Pla l 1 (English plantain) and Par j 2 (pellitory). Molecule-based approaches can be used to identify the primary sensitizer and thus enable selection of the appropriate weed pollen extracts for allergen immunotherapy. PMID- 26120540 TI - House dust mites known to be an allergen source for 50 years: Der p 1 still detectable in the original sample. PMID- 26120541 TI - Th22 cells in allergic disease. AB - During the last decade, the field of T cell immunology started to confuse the scientific community. More and more subtypes of T helper cells and their counterparts in the innate immune system are described. We are just at the beginning to understand which specific function the distinct subtypes fulfill. Th22 cells are terminally differentiated and very specialized T helper cells characterized by the secretion of their signature cytokine IL-22 and lack of IL 4, IL-17 and IFN-gamma. The main function of Th22 cells is to protect epithelial barrier organs such as skin and lung, but also to modulate inflamed and injured tissue. This review summarizes our current knowledge on Th22 cells and their function in allergic disease. Cite this as Eyerich K, Eyerich S. Th22 cells in allergic disease. Allergo J Int 2015;24:1-7 DOI: 10.1007/s40629-015-0039-3. PMID- 26120542 TI - Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis. AB - The activation of naive CD4+ and CD8+ T cells in response to antigen and their subsequent proliferation and differentiation into effectors are important features of a cell-mediated immune response. CD4+ T cells (also known as T helper cells, Th) differentiate into several subpopulations including Th1, Th2, Th9, Th17, Tfh and Treg cells, characterized by specific cytokine profiles and effector functions. However, recent evidence indicates that CD8+ T cells (termed cytotoxic T lymphocytes, CTLs or Tc cells) can differentiate into subpopulations with similar characteristics denoted as Tc2, Tc9, Tc17 and CD8+ Treg cells in addition to CTLs. Although these subpopulations accomplish important protective functions, their uncontrolled responses cause immunopathology including allergy and autoimmunity. Our recent findings indicate a change of paradigm: during these pathologic responses, CD8+ T cell subpopulations act as strong helpers for the activity of CD4+ T cells rather than being cytotoxic. In this review, we focus on the role of Th2, Th9, Th17 as well as Tc9 and Tc17 cells in asthma and autoimmune encephalomyelitis and on their interaction during these immunopathologic responses. Cite this as Huber M, Lohoff M. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis. Allergo J Int 2015;24:8-15 DOI: 10.1007/s40629-015-0038-4. PMID- 26120544 TI - Guideline for authors: Allergo Journal International. PMID- 26120543 TI - Autoallergy in atopic dermatitis. AB - The term autoallergy denotes autoimmunity accompanying an atopic disease, with antigen-specific IgE as a hallmark. This phenomenon is discussed to contribute to a chronification of the disease and to shape the immune response in chronic atopic dermatitis (AD). In this review, we highlight recent insights into the autoallergic inflammation in AD. Different mechanisms underlying the allergenicity of autoallergens are discussed at the moment: intrinsic functions modulating the immune system as well as molecular mimicry may influence the allergenic potential of these proteins. Finally, the role of specific T cells is discussed. Cite this as: Hradetzky S, Werfel T, Roesner LM. Autoallergy in atopic dermatitis. Allergo J Int 2015; 24:16-22 DOI: 10.1007/s40629-015-0037-5. PMID- 26120539 TI - Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (OGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- Rhino Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). AB - The present guideline (S2k) on allergen-specific immunotherapy (AIT) was established by the German, Austrian and Swiss professional associations for allergy in consensus with the scientific specialist societies and professional associations in the fields of otolaryngology, dermatology and venereology, pediatric and adolescent medicine, pneumology as well as a German patient organization (German Allergy and Asthma Association; Deutscher Allergie- und Asthmabund, DAAB) according to the criteria of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). AIT is a therapy with disease-modifying effects. By administering allergen extracts, specific blocking antibodies, toler ance-inducing cells and mediators are activated. These prevent further exacerbation of the allergen-triggered immune response, block the specific immune response and attenuate the inflammatory response in tissue. Products for SCIT or SLIT cannot be compared at present due to their heterogeneous composition, nor can allergen concentrations given by different manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients. Non-modified allergens are used for SCIT in the form of aqueous or physically adsorbed (depot) extracts, as well as chemically modified allergens (allergoids) as depot extracts. Allergen extracts for SLIT are used in the form of aqueous solutions or tablets. The clinical efficacy of AIT is measured using various scores as primary and secondary study endpoints. The EMA stipulates combined symptom and medication scores as primary endpoint. A harmonization of clinical endpoints, e. g., by using the combined symptom and medication scores (CSMS) recommended by the EAACI, is desirable in the future in order to permit the comparison of results from different studies. The current CONSORT recommendations from the ARIA/GA2LEN group specify standards for the evaluation, presentation and publication of study results. According to the Therapy allergen ordinance (TAV), preparations containing common allergen sources (pollen from grasses, birch, alder, hazel, house dust mites, as well as bee and wasp venom) need a marketing authorization in Germany. During the marketing authorization process, these preparations are examined regarding quality, safety and efficacy. In the opinion of the authors, authorized allergen preparations with documented efficacy and safety, or preparations tradeable under the TAV for which efficacy and safety have already been documented in clinical trials meeting WAO or EMA standards, should be preferentially used. Individual formulations (NPP) enable the prescription of rare allergen sources (e.g., pollen from ash, mugwort or ambrosia, mold Alternaria, animal allergens) for specific immunotherapy. Mixing these allergens with TAV allergens is not permitted. Allergic rhinitis and its associated co-morbidities (e. g., bronchial asthma) generate substantial direct and indirect costs. Treatment options, in particular AIT, are therefore evaluated using cost-benefit and cost-effectiveness analyses. From a long-term perspective, AIT is considered to be significantly more cost effective in allergic rhinitis and allergic asthma than pharmacotherapy, but is heavily dependent on patient compliance. Meta-analyses provide unequivocal evidence of the efficacy of SCIT and SLIT for certain allergen sources and age groups. Data from controlled studies differ in terms of scope, quality and dosing regimens and require product specific evaluation. Therefore, evaluating individual preparations according to clearly defined criteria is recommended. A broad transfer of the efficacy of certain preparations to all preparations administered in the same way is not endorsed. The website of the German Society for Allergology and Clinical Immunology (www.dgaki.de/leitlinien/s2k-leitlinie-sit; DGAKI: Deutsche Gesellschaft fur Allergologie und klinische Immunologie) provides tables with specific information on available products for AIT in Germany, Switzerland and Austria. The tables contain the number of clinical studies per product in adults and children, the year of market authorization, underlying scoring systems, number of randomized and analyzed subjects and the method of evaluation (ITT, FAS, PP), separately given for grass pollen, birch pollen and house dust mite allergens, and the status of approval for the conduct of clinical studies with these products. Strong evidence of the efficacy of SCIT in pollen allergy-induced allergic rhinoconjunctivitis in adulthood is well-documented in numerous trials and, in childhood and adolescence, in a few trials. Efficacy in house dust mite allergy is documented by a number of controlled trials in adults and few controlled trials in children. Only a few controlled trials, independent of age, are available for mold allergy (in particular Alternaria). With regard to animal dander allergies (primarily to cat allergens), only small studies, some with methodological deficiencies are available. Only a moderate and inconsistent therapeutic effect in atopic dermatitis has been observed in the quite heterogeneous studies conducted to date. SCIT has been well investigated for individual preparations in controlled bronchial asthma as defined by the Global Initiative for Asthma (GINA) 2007 and intermittent and mild persistent asthma (GINA 2005) and it is recommended as a treatment option, in addition to allergen avoidance and pharmacotherapy, provided there is a clear causal link between respiratory symptoms and the relevant allergen. The efficacy of SLIT in grass pollen-induced allergic rhinoconjunctivitis is extensively documented in adults and children, whilst its efficacy in tree pollen allergy has only been shown in adults. New controlled trials (some with high patient numbers) on house dust mite allergy provide evidence of efficacy of SLIT in adults. Compared with allergic rhinoconjunctivitis, there are only few studies on the efficacy of SLIT in allergic asthma. In this context, newer studies show an efficacy for SLIT on asthma symptoms in the subgroup of grass pollen allergic children, adolescents and adults with asthma and efficacy in primary house dust mite allergy-induced asthma in adolescents aged from 14 years and in adults. Aspects of secondary prevention, in particular the reduction of new sensitizations and reduced asthma risk, are important rationales for choosing to initiate treatment early in childhood and adolescence. In this context, those products for which the appropriate effects have been demonstrated should be considered. SCIT or SLIT with pollen or mite allergens can be performed in patients with allergic rhinoconjunctivitis using allergen extracts that have been proven to be effective in at least one double-blind placebo-controlled (DBPC) study. At present, clinical trials are underway for the indication in asthma due to house dust mite allergy, some of the results of which have already been published, whilst others are still awaited (see the DGAKI table "Approved/potentially completed studies" via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit (according to www.clinicaltrialsregister.eu)). When establishing the indication for AIT, factors that favour clinical efficacy should be taken into consideration. Differences between SCIT and SLIT are to be considered primarily in terms of contraindications. In individual cases, AIT may be justifiably indicated despite the presence of contraindications. SCIT injections and the initiation of SLIT are performed by a physician experienced in this type of treatment and who is able to administer emergency treatment in the case of an allergic reaction. Patients must be fully informed about the procedure and risks of possible adverse events, and the details of this process must be documented (see "Treatment information sheet"; available as a handout via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). Treatment should be performed according to the manufacturer's product information leaflet. In cases where AIT is to be performed or continued by a different physician to the one who established the indication, close cooperation is required in order to ensure that treatment is implemented consistently and at low risk. In general, it is recommended that SCIT and SLIT should only be performed using preparations for which adequate proof of efficacy is available from clinical trials. Treatment adherence among AIT patients is lower than assumed by physicians, irrespective of the form of administration. Clearly, adherence is of vital importance for treatment success. Improving AIT adherence is one of the most important future goals, in order to ensure efficacy of the therapy. Severe, potentially life-threatening systemic reactions during SCIT are possible, but - providing all safety measures are adhered to - these events are very rare. Most adverse events are mild to moderate and can be treated well. Dose-dependent adverse local reactions occur frequently in the mouth and throat in SLIT. Systemic reactions have been described in SLIT, but are seen far less often than with SCIT. In terms of anaphylaxis and other severe systemic reactions, SLIT has a better safety profile than SCIT. The risk and effects of adverse systemic reactions in the setting of AIT can be effectively reduced by training of personnel, adhering to safety standards and prompt use of emergency measures, including early administration of i. m. epinephrine. Details on the acute management of anaphylactic reactions can be found in the current S2 guideline on anaphylaxis issued by the AWMF (S2-AWMF-LL Registry Number 061-025). AIT is undergoing some innovative developments in many areas (e. g., allergen characterization, new administration routes, adjuvants, faster and safer dose escalation protocols), some of which are already being investigated in clinical trials. Cite this as Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, Friedrichs F, Fuchs T, Hamelmann E, Hartwig-Bade D, Hering T, Huttegger I, Jung K, Klimek L, Kopp MV, Merk H, Rabe U, Saloga J, Schmid-Grendelmeier P, Schuster A, Schwerk N, Sitter H, Umpfenbach U, Wedi B, Wohrl S, Worm M, Kleine-Tebbe J. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases - S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (OGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int 2014;23:282-319. PMID- 26120545 TI - Correspondence to the "Guideline for acute therapy and management of anaphylaxis". PMID- 26120546 TI - Reply to the correspondence to the "Guideline for acute therapy and management of anaphylaxis". PMID- 26120547 TI - Occupational allergy to beta-lactam antibiotics. PMID- 26120548 TI - Hypersensitivity reactions to modern antiplatelet and anticoagulant drugs. AB - Anticoagulation and antiplatelet drugs are among the most commonly used medical drugs. In addition to the long-established heparins, hirudins, coumarins and antiplatelet drugs such as acetylsalicylic acid, numerous novel and predominantly synthetic pharmacologic agents have come onto the market in recent years. These new agents act at various sites in coagulation and have significantly broadened treatment options. Whilst immunological hypersensitivity reactions are on the whole rare, they have a considerable impact on patient management when they do occur. The present overview discusses the currently known hypersensitivity reactions to anticoagulant and antiplatelet agents, with particular attention to the newer substance classes including P2Y12 inhibitors, glycoprotein IIb/IIIb receptor antagonists, direct factor Xa inhibitors and direct thrombin inhibitors. PMID- 26120549 TI - Mites and other indoor allergens - from exposure to sensitization and treatment. AB - House dust mites, cats and dogs are amongst the most frequent sources of indoor allergens in Europe. The fact that the allergens of house dust mites cause allergic disease through inhalation of house dust was discovered in 1964. The diagnosis of mite allergy is regularly complicated by its often nonspecific symptoms, which frequently develop insidiously and by no means always include attacks of paroxysmal sneezing and itching. Antibody-based immunological detection methods can be used to measure exposure to mite allergens. The structure and function of more than 20 allergens from Dermatophagoides pteronyssinus and D. farina are known. Other relevant indoor allergens come from mammals kept in households. Here again, allergens have been described and diagnostic as well as exposure-measurement tools are available. It is important to remember indoor pests and other "unwelcome lodgers" as a possible cause in the case of unexplained symptoms experienced indoors. This short overview summarizes the current key points on the subject of "mites and other indoor allergens". The present article provides an overview of several articles published in a special issue of the German journal Allergologie [February 2015; 38(2)] on the subject of "Mites and other indoor allergens". PMID- 26120550 TI - Mammalian meat allergy: a diagnostic challenge. PMID- 26120551 TI - Authorised allergen products for intracutaneous testing may no longer be available in Germany: Allergy textbooks have to be re-written. AB - BACKGROUND: Beside the skin prick test, the intracutaneous test represents the most important skin test method for detecting type-1 allergies. With the incorporation of European directives into national law, test allergens used for allergy diagnosis are deemed medicinal products within the meaning of the German Medicinal Products Act (Arzneimittelgesetz) and therefore require marketing authorisation for distribution in Germany. The high costs of acquiring and maintaining these authorisations have lead to no new finished intracutaneous test products being authorized in Germany for more than 20 years. Instead, most manufacturers have voluntarily withdrawn their existing marketing authorisations for intracutaneous test extracts. The last manufacturer to offer approved finished allergen products for intracutaneous tests recently announced that it would now cease production and distribution of these solutions. METHODS: Research on the current European and German legislation; selective literature search in Medline, including national and international guidelines and Cochrane meta analyses; licensing information on the Paul-Ehrlich-Institute homepage (www.pei.de) as well as in the Bundesanzeiger (Federal Gazette). RESULTS: According to information on www.pei.de, marketing authorisations still existed as of 31.01.2015 for intracutaneous test solutions of six grass/cereal/herbal pollens, seven tree pollens, ten food allergens, twelve moulds and yeasts as well as two fungal mixtures, five house dust and storage mites and five animal epithelia/danders, all held by only one company in Germany. These marketing authorisations were granted between 16th March 1987 and 17th January 1992; more recent marketing authorisations do not exist. CONCLUSIONS: European legislation and the associated increase in production and licensing costs have already lead to numerous suppliers withdrawing their marketing authorisation for diagnostic test allergens - marketing authorisations for 443 diagnostic allergens were voluntarily withdrawn by manufacturers in 2013 alone. If the announced restrictions on the allergen portfolio go ahead, considerable problems in the management of allergy patients in Germany due to the discontinuation of the intracutaneous test are likely to be encountered. Moreover, the fact that a diagnostic procedure that has been established for decades seems set to disappear quite simply because all the requisite substances vanish from the market in one fell swoop may well be without parallel in modern medicine. The situation for skin prick test allergens is less dramatic, although, here again, the available range is becoming increasingly limited. PMID- 26120552 TI - Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (OGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM). AB - Drug hypersensitivity reactions are unpredictable adverse drug reactions. They manifest either within 1-6 h following drug intake (immediate reactions) with mild to life-threatening symptoms of anaphylaxis, or several hours to days later (delayed reactions), primarily as exanthematous eruptions. It is not always possible to detect involvement of the immune system (allergy). Waiving diagnostic tests can result in severe reactions on renewed exposure on the one hand, and to unjustified treatment restrictions on the other. With this guideline, experts from various specialist societies and institutions have formulated recommendations and an algorithm for the diagnosis of allergies. The key principles of diagnosing allergic/hypersensitivity drug reactions are presented. Where possible, the objective is to perform allergy diagnostics within 4 weeks-6 months following the reaction. A clinical classification of symptoms based on the morphology and time course of the reaction is required in order to plan a diagnostic work-up. In the case of typical symptoms of a drug hypersensitivity reaction and unequivocal findings from validated skin and/or laboratory tests, a reaction can be attributed to a trigger with sufficient confidence. However, skin and laboratory tests are often negative or insufficiently reliable. In such cases, controlled provocation testing is required to clarify drug reactions. This method is reliable and safe when attention is paid to indications and contraindications and performed under appropriate medical supervision. The results of the overall assessment are discussed with the patient and documented in an "allergy passport" in order to ensure targeted avoidance in the future and allow the use of alternative drugs where possible. PMID- 26120553 TI - Sleep, Performance, and Memory in Flies. AB - Drosophila has proven to be a powerful model to identify genes and circuits that impact sleep. While the majority of studies have primarily been interested in identifying manipulations that alter sleep time, a growing body of work has begun to focus on how changing sleep influences functional outcomes such as cognitive performance, structural plasticity, and metabolism to name a few. Evaluating sleep time provides an appropriate entry point into elucidating sleep function. However, it is not possible to fully understand how a manipulation has impacted sleep regulation without first establishing how it has affected the animals' well being. Synaptic plasticity and memory are important functional outcomes that can be used to asses an animal's status. In this manuscript, we review recent advances in studies examining sleep, memory, and performance. We conclude that as Drosophila sleep researchers expand their analysis beyond sleep time, the opportunities to discover the function of sleep will be enhanced. PMID- 26120554 TI - Non-Coding RNAs in Transcriptional Regulation: The review for Current Molecular Biology Reports. AB - Transcriptional gene silencing guided by small RNAs is a process conserved from protozoa to mammals. Small RNAs loaded into Argonaute family proteins direct repressive histone modifications or DNA cytosine methylation to homologous regions of the genome. Small RNA-mediated transcriptional silencing is required for many biological processes, including repression of transposable elements, maintaining the genome stability/integrity, and epigenetic inheritance of gene expression. Here we will summarize the current knowledge about small RNA biogenesis and mechanisms of transcriptional regulation in plants, Drosophila, C. elegans and mice. Furthermore, a rapidly growing number long non-coding RNAs (lncRNAs) have been implicated as important players in transcription regulation. We will discuss current models for long non-coding RNA-mediated gene regulation. PMID- 26120556 TI - Economic Inequality and Intergenerational Transfers: Evidence from Mexico. AB - Recent evidence of the National Transfer Accounts (NTA) of Mexico reveals that asset-based reallocations play a significant role in the financing of the expenditures by elderly Mexicans, whereas private and public transfers are used to support most of the expenditures for children. What that evidence does not consider, however, is the fact that differences in socioeconomic status (SES) may seriously distort the reallocation of intergenerational flows. Mexico has long been a country permeated by high levels of inequality, it is then necessary to include its effects in the analysis of intergenerational transfers. Furthermore, age reallocations of economic flows do change over time and such changes might also involve greater economic inequality. In this paper, I assess the effects of SES inequality on the reallocation of intergenerational flows using NTA estimates for two particular years, 1994 and 2004. I show that the reallocation of economic resources, mainly to children and the elderly, by SES changed substantially within this period. The main intergenerational effects associated with SES inequality are: a) equalizing effects of labor income and remittances, b) higher progressivity of public cash and educational transfers, and c) crowding-out effects between private and public transfers among the elderly. PMID- 26120555 TI - Sequencing of the TBX6 Gene in Families with Familial Idiopathic Scoliosis. AB - STUDY DESIGN: A hypothesis-driven study was conducted in a familial cohort to determine the potential association between variants within the TBX6 gene and Familial Idiopathic Scoliosis (FIS). OBJECTIVE: To determine if variants within exons of the TBX6 gene segregate with the FIS phenotype within a sample of families with FIS. SUMMARY OF BACKGROUND DATA: Idiopathic Scoliosis (IS) is a structural curvature of the spine whose underlying genetic etiology has not been established. IS has been reported to occur at a higher rate than expected in family members of individuals with congenital scoliosis (CS), suggesting that the two diseases might have a shared etiology. The TBX6 gene on chromosome 16p, essential to somite development, has been associated with CS in a Chinese population. Previous studies have identified linkage to this locus in families with FIS, and specifically with rs8060511, located in an intron of the TBX6 gene. METHODS: Parent-offspring trios from 11 families (13 trios, 42 individuals) with FIS were selected for Sanger sequencing of the TBX6 gene. Trios were selected from a large population of families with FIS in which a genome-wide scan had resulted in linkage to 16p. RESULTS: Sequencing analyses of the subset of families resulted in the identification of five coding variants. Three of the five variants were novel; the remaining two variants were previously characterized and account for 90% of the observed variants in these trios. In all cases, there was no correlation between transmission of the TBX6 variant allele and FIS phenotype. However, an analysis of regulatory markers in osteoblasts showed that rs8060511 is in a putative enhancer element. CONCLUSIONS: Although this study did not identify any TBX6 coding variants that segregate with FIS, we identified a variant that is located in a potential TBX6 enhancer element. Therefore, further investigation of the region is needed. PMID- 26120557 TI - Global Gene Expression Changes in Liver Following Hepatocyte Nuclear Factor 4 alpha deletion in Adult Mice. AB - Hepatocyte nuclear factor 4 alpha (HNF4alpha) is known as the master regulator of hepatic differentiation, which regulates over 60% of the hepatocyte specific genes. Recent studies including this (Walesky et al. Am J Physiol Gastrointest Liver Physiol. 304:G26-37, 2013) demonstrated that HNF4alpha also inhibits hepatocyte proliferation via repression of pro-mitogenic genes. In this study hepatocyte specific HNF4alpha knockout mice were generated using 2-3 month old HNF4alpha-floxed mice treated with Cre recombinase under Major Urinary Protein promoter delivered in AAV8 vector (MUP-iCre-AAV8). Control mice were treated with MUP-EGFP-AAV8. Livers were isolated from control and KO mice one week after AAV8 administration and used for gene array analysis. These data revealed several new negative target genes of HNF4alpha, majority of which are pro-mitogeneic genes inhibited by HNF4alpha in adult hepatocytes. PMID- 26120558 TI - Interactions between psychological and environmental characteristics and their impacts on walking. AB - Due to walking's benefits to physical and mental health as well as to environmental and economic sustainability, numerous studies have examined psychological and environmental characteristics on their impacts on walking. However, understanding of how the interactions between psychological and environmental characteristics influence walking remains limited. Recently, both competitive mechanism and synergetic mechanism have been proposed, and a number of empirical studies have examined the interactions between psychological and environmental characteristics, but the results were inconsistent. We reviewed 11 recent studies and discussed their difference in terms of studies population, outcomes, environmental characteristics, and psychological characteristics. We propose a framework that integrate both mechanisms and provides an explanation to the inconsistency. More important, the framework may stimulate further empirical researches and provide implications for policy intervention to promote walking. PMID- 26120559 TI - Physiological Competition of Brain Phenylalanine Accretion: Initial Pharmacokinetic Analyses of Aminoisobutyric and Methylaminoisobutyric Acids in Pahenu2-/- Mice. AB - OBJECTIVE: Initial studies on the use of non-physiological amino acids (NPAAs) to block the accretion of Phe in the brain Pahenu2-/- mice revealed that 2 aminoisobutyrate (AIB) and N-methyl-2-aminoisobutyrate (MAIB) were promising lead compounds whose pharmacokinetic parameters warranted investigation. METHODS: Control and Pahenu2-/- mice received intraperitoneal NPAA treatments as test compounds (150, 300 and 500 mg/kg, 1 or 7 days;) followed by collection of sera, liver and brain. LC-MS analysis was developed to quantify both AIB and MAIB in all matrices, and pharmacokinetic parameters for distribution, partitioning, accumulation and MAIB demethylation were determined. RESULTS: MAIB was partially converted to AIB in vivo. AIB and MAIB partitioned similarly from sera to brain and liver, with an approximate 10-fold higher accumulation in liver compared to brain. In comparison to MAIB, AIB accumulated to approximately 3 to 7-fold higher concentration in brain. Analysis of brain and liver revealed a trend toward decreased Phe with increased MAIB sera concentration. CONCLUSIONS: Our data support further pharmacokinetic characterization of MAIB and AIB in preparation for further preclinical safety, toxicity and tolerability studies of both AIB and MAIB. PMID- 26120560 TI - Clinical and pathological complete remission in a patient with metastatic renal cell carcinoma (mRCC) treated with sunitinib: Is mRCC curable with targeted therapy? AB - We report a patient with metastatic clear-cell renal cell carcinoma (mRCC) who presented with primary tumor in situ in the left kidney and metastases to bone, liver, lungs, and brain. After over 5 years of sunitinib therapy and subsequent cytoreductive left nephrectomy, the patient achieved radiographic complete response (CR) and had pathologic CR in the nephrectomy specimen. Durable clinical and pathological CRs are possible with targeted agents, even with primary tumor in situ and widely disseminated metastases. Ongoing research will define the optimal duration of systemic therapy in exceptional responders and identify the molecular determinants of response and resistance. PMID- 26120561 TI - The molecular ticks of the Drosophila circadian clock. AB - Drosophila is a powerful model to understand the mechanisms underlying circadian rhythms. The Drosophila molecular clock is comprised of transcriptional feedback loops. The expressions of the critical transcriptional activator CLK and its repressors PER and TIM are under tight transcriptional control. However, posttranslational modification of these proteins and regulation of their stability are critical to their function and to the generation of 24-hr period rhythms. We review here recent progress made in our understanding of PER, TIM and CLK posttranslational control. We also review recent studies that are uncovering the importance of novel regulatory mechanisms that affect mRNA stability and translation of circadian pacemaker proteins and their output. PMID- 26120562 TI - Heating and cooling the Drosophila melanogaster clock. AB - Most biological phenomena are under control of a circuit known as the 'molecular circadian clock.' Over the past forty years of research in Drosophila melanogaster, studies have made significant advances in our understanding of the molecular timing mechanism of this circuit, which is determined by a core inhibitory feedback loop. While the timing mechanism of the molecular circadian clock is endogenous, it is well established that exogenous cues such as light and temperature modulate its timing. In the following article, we summarize our current understanding of how temperature interacts with the molecular circadian clock in adult Drosophila. PMID- 26120564 TI - Female economic activity in Rural Malawi. AB - This study investigates economic activities and their determinants for women in households of rural Malawi, one of the poorest countries in Sub-Saharan Africa (SSA). Three waves of household panel data for years 2006, 2008 and 2010 from the Malawi Longitudinal Study of Families and Health (MLSFH) are used to examine female labor market participation. This study includes certain important characteristics of Malawian households i.e., polygamy, ethnicity, religion and self reported health status. The study reports five different labor market outcomes for women's participation i.e., agriculture related work, market & sales activities, cottage industry, other economic activities and out of the labor market. The study finds significant relationships between these five different labor market outcomes and age cohorts, ethnicity and marriage (monogamous or polygamous). PMID- 26120565 TI - Interdisciplinary Researches in Iran III: (Multi-Dimensional) Medical Signal Analysis Softwares. PMID- 26120563 TI - Disruption of dengue virus transmission by mosquitoes. AB - Current control efforts for mosquito-borne arboviruses focus on mosquito control involving insecticide applications, which are becoming increasingly ineffective and unsustainable in urban areas. Mosquito population replacement is an alternative arbovirus control concept aiming at replacing virus-competent vector populations with laboratory-engineered incompetent vectors. A prerequisite for this strategy is the design of robust anti-pathogen effectors that can ultimately be genetically driven through a wild-type population. Several anti-pathogen effector concepts have been developed that target the RNA genomes of arboviruses such as dengue virus in a highly sequence-specific manner. Design principles are based on long inverted-repeat RNA triggered RNA interference, catalytic hammerhead ribozymes, and trans-splicing Group I Introns that are able to induce apoptosis in virus-infected cells following splicing with target viral RNA. PMID- 26120566 TI - Comprehensive Performance Study of Magneto Cantilevers as a Candidate Model for Biological Sensors used in Lab-on-a-Chip Applications. AB - In recent years, demand for biological sensors which are capable of fast and accurate detection of minor amounts of pathogens in real-time form has been intensified. Acoustic wave (AW) devices whose performance is determined by mass sensitivity parameters and quality factor are used in biological sensors as platforms with high quality. Yet, current AW devices are facing many challenges such as the low value of their quality factor in practical applications and also their difficulty to use in liquids. The main focus of this article is to study on the magnetostrictive sensors which include milli/microcantilever (MSMC) type. In comparison with AW devices, MSMC has a lot of advantages; (1) its actuation and sensing unit is wirelessly controlled. (2) Its fabrication process is easy. (3) It works well in liquids. (4) It has a high-quality factor (in the air > 500). Simulation results demonstrate that the amount of quality factor depends on environment properties (density and viscosity), MSMC geometry, and its resonant behavior of harmonic modes. PMID- 26120567 TI - Biomarker Discovery Based on Hybrid Optimization Algorithm and Artificial Neural Networks on Microarray Data for Cancer Classification. AB - The improvement of high-through-put gene profiling based microarrays technology has provided monitoring the expression value of thousands of genes simultaneously. Detailed examination of changes in expression levels of genes can help physicians to have efficient diagnosing, classification of tumors and cancer's types as well as effective treatments. Finding genes that can classify the group of cancers correctly based on hybrid optimization algorithms is the main purpose of this paper. In this paper, a hybrid particle swarm optimization and genetic algorithm method are used for gene selection and also artificial neural network (ANN) is adopted as the classifier. In this work, we have improved the ability of the algorithm for the classification problem by finding small group of biomarkers and also best parameters of the classifier. The proposed approach is tested on three benchmark gene expression data sets: Blood (acute myeloid leukemia, acute lymphoblastic leukemia), colon and breast datasets. We used 10-fold cross-validation to achieve accuracy and also decision tree algorithm to find the relation between the biomarkers for biological point of view. To test the ability of the trained ANN models to categorize the cancers, we analyzed additional blinded samples that were not previously used for the training procedure. Experimental results show that the proposed method can reduce the dimension of the data set and confirm the most informative gene subset and improve classification accuracy with best parameters based on datasets. PMID- 26120568 TI - Longitudinal Impedance Tomography for Blood Pressure Characterization of Valve Deformation. AB - Aorta is formed in a dynamic environment which gives rise to imbalances between many forces that tend to extend the diameter and length. Furthermore, internal forces tend to resist this extension. Impedance tomography can show this imbalance to stimulate the stenosis of aortic valve, growth of the elastic, collagen and to effectively reduce the stresses in the underlying tissue. In blood flow, auscultation noises occurred and in the echocardiography decrease in left ventricular ejection speed can be observed. In this paper, we have modeled an aorta based on anatomical studies to simulate natural, 20% and 30% stenosis as usual heart disease to early diagnosis. Valve deformation causes different impedance tomography in 3D mesh of aorta as blood pressure. Remodeling of aorta and its flow is found when a cylindrical slice of the fully retracted blood aorta is cut longitudinally through the wall. PMID- 26120569 TI - Evaluation on Geant4 Hadronic Models for Pion Minus, Pion Plus and Neutron Particles as Major Antiproton Annihilation Products. AB - Geant4 is an open source simulation toolkit based on C++, which its advantages progressively lead to applications in research domains especially modeling the biological effects of ionizing radiation at the sub-cellular scale. However, it was shown that Geant4 does not give a reasonable result in the prediction of antiproton dose especially in Bragg peak. One of the reasons could be lack of reliable physic model to predict the final states of annihilation products like pions. Considering the fact that most of the antiproton deposited dose is resulted from high-LET nuclear fragments following pion interaction in surrounding nucleons, we reproduced depth dose curves of most probable energy range of pions and neutron particle using Geant4. We consider this work one of the steps to understand the origin of the error and finally verification of Geant4 for antiproton tracking. Geant4 toolkit version 9.4.6.p01 and Fluka version 2006.3 were used to reproduce the depth dose curves of 220 MeV pions (both negative and positive) and 70 MeV neutrons. The geometry applied in the simulations consist a 20 * 20 * 20 cm(3) water tank, similar to that used in CERN for antiproton relative dose measurements. Different physic lists including Quark Gluon String Precompound (QGSP)_Binary Cascade (BIC)_HP, the recommended setting for hadron therapy, were used. In the case of pions, Geant4 resulted in at least 5% dose discrepancy between different physic lists at depth close to the entrance point. Even up to 15% discrepancy was found in some cases like QBBC compared to QGSP_BIC_HP. A significant difference was observed in dose profiles of different Geant4 physic list at small depths for a beam of pions. In the case of neutrons, large dose discrepancy was observed when LHEP or LHEP_EMV lists were applied. The magnitude of this dose discrepancy could be even 50% greater than the dose calculated by LHEP (or LHEP_EMV) at larger depths. We found that effect different Geant4 physic list in reproducing depth dose profile of the beam of pions was not negligible. Because the discrepancies were pronounced in smaller depth and also regarding the contribution of pions in deposited dose of a beam of antiproton, further investigation on choosing most suitable and accurate physic list for this purpose should be done. Furthermore, this study showed careful attention must be paid to choose the appropriate Geant4 physic list for neutron tracking depending to the applications criteria. We failed to find any agreement between results from Geant4 and Fluka to reproduce depth dose profile of pion with the energy range used in this study. PMID- 26120570 TI - Designing and Dosimetry of a Shield for Photon Fields of Radiation Therapy in Oral Cavity Cancer. AB - The cancer of oral cavity is related to lesions of mucous membrane of tongue and gum that can be treated with radiation therapy. A lateral photon field can be used to treat this kind of tumor, which has a side-effect on normal tissue in the opposite side of the oral cavity. In this study the dosimetric effect of the various shields in oral cavity is evaluated. In this study, a special phantom similar to the structure of oral cavity with capability of film dosimetry was designed and constructed. The various shield slabs were made of five materials: Lead, Plexiglas, Acrylic resin, Silicon and Plaster. For irradiation, Cobalt 60 (60Co) and 6 MV photon beams were used. The film dosimetry before and after the shield was performed using GAFCHROMIC EBT2 films. The film before the shield measures the magnitude of backscattering radiation from the shield. The prescribed dose was 150 cGy. Results showed that 3 cm of the lead in both energies had the maximum absorption of radiation. The absorbed dose to opposite side of shield for 6 MV photon beams and 60Co were 21 and 32 cGy, respectively. The minimum attenuation on radiation was observed in silicon shield for which the dose of opposite side were 116 and 147 cGy for 6 MV and 60Co respectively. The maximum backscattered dose was measured 177 cGy and 219 cGy using 3 cm thickness of lead, which was quite considerable. The minimum backscattering where for acrylic resin 101 and 118 cGy for 6 MV and cobalt. In this study, it was concluded that the amount of backscattering for 3 cm Lead shield is quite considerable and increases the dose significantly. A composite layer of shield with 1-2 cm lead and 1 cm acrylic resin can have the protective effect and low backscattering radiation at the same time. PMID- 26120571 TI - Developing a Commercial Air Ultrasonic Ceramic Transducer to Transdermal Insulin Delivery. AB - The application of low-frequency ultrasound for transdermal delivery of insulin is of particular public interest due to the increasing problem of diabetes. The purpose of this research was to develop an air ultrasonic ceramic transducer for transdermal insulin delivery and evaluate the possibility of applying a new portable and low-cost device for transdermal insulin delivery. Twenty-four rats were divided into four groups with six rats in each group: one control group and three experimental groups. Control group (C) did not receive any ultrasound exposure or insulin (untreated group). The second group (T1) was treated with subcutaneous insulin (Humulin((r)) R, rDNA U-100, Eli Lilly and Co., Indianapolis, IN) injection (0.25 U/Kg). The third group (T2) topically received insulin, and the fourth group (T3) received insulin with ultrasound waves. All the rats were anesthetized by intraperitoneal injection of ketamin hydrochloride and xylazine hydrochloride. Blood samples were collected after anesthesia to obtain a baseline glucose level. Additional blood samples were taken every 15 min in the whole 90 min experiment. In order for comparison the changes in blood glucose levels" to " In order to compare the changes in blood glucose levels. The statistical multiple comparison (two-sided Tukey) test showed a significant difference between transdermal insulin delivery group (T2) and subcutaneous insulin injection group (T1) during 90 min experiment (P = 0.018). In addition, the difference between transdermal insulin delivery group (T2) and ultrasonic transdermal insulin delivery group (T3) was significant (P = 0.001). Results of this study demonstrated that the produced low-frequency ultrasound from this device enhanced the transdermal delivery of insulin across hairless rat skin. PMID- 26120572 TI - Validation of a Prototype Optical Computed Tomography System. AB - In radiation cancer treatments, the most of the side effects could be minimized using a proper dosimeter. Gel dosimeter is the only three-dimensional dosimeter and magnetic resonance imaging (MRI) is the gold standard method for gel dosimeter readout. Because of hard accessibility and high cost of sample reading by MRI systems, some other alternative methods were developed. The optical computed tomography (OCT) method could be considered as the most promising alternative method that has been studied widely. In the current study, gel dosimeter scanning using a prototype optical scanner and validation of this optical scanner was performed. Optical absorbance of the irradiated gel samples was determined by both of conventional spectrophotometer and the fabricated OCT system at 632 nm. Furthermore, these irradiated vials were scanned by a 1.5 T MRI. The slope of the curves was extracted as the dose-response sensitivity. The R2-dose sensitivity measured by MRI method was 0.1904 and 0.113 for NIPAM and PAGAT gels, respectively. The optical dose sensitivity obtained by conventional spectrophotometer and the fabricated optical scanner was 0.0453 and 0.0442 for NIPAM gels and 0.0244 and 0.0242 for PAGAT gels, respectively. The scanning results of the absorbed dose values showed that the new OCT and conventional spectrophotometer were in fair agreement. From the results, it could be concluded that the fabricated system is able to quantize the absorbed dose values in polymer gel samples with acceptable accuracy. PMID- 26120573 TI - Prevalence and Genotypic Characterization of Extended-Spectrum Beta-Lactamases Produced by Gram Negative Bacilli at a Tertiary Care Hospital in Rural South Western Uganda. AB - AIM: To determine the prevalence and genotypic characterisation of extended spectrum beta-lactamases produced by gram negative bacilli isolated at Mbarara Regional Referral Hospital (MRRH). SAMPLES: Gram negative clinical isolates. STUDY DESIGN: Laboratory-based descriptive cross-sectional study. PLACE AND DURATION OF THE STUDY: MRRH, June and August 2012. METHODS: Gram negative clinical isolates were sub cultured, and identified using biochemical tests. They were screened for ESBL by using oxyimino-cephalosporins and confirmed by double disc synergy Genotyping was performed using the PCR for TEM, SHV and CTX-M. Susceptibility pattern for the extended spectrum beta-lactamases, (ESBL) - positive isolates to other antibiotic classes was performed by the Kirby Bauer Technique. RESULTS: A total of 484 isolates were included in the study. The commonest ESBL producers were Escherichia coli (34%), followed by unidentified coliforms (19.3%) and Klebsiella spp. (12.7%). Phenotypically, 88/484 were ESBL producers while genotypically 213/ 484 possessed ESBL genes. The ESBL genes were blaCTX-M (146; 70%), blaSHV (72; 34%) and blaTEM (100; 47%). 87of 213 isolates expressed more than one ESBL gene. Of these 36 (7.4%) produced blaCTX-M/blaSHV, 28 (5.8%) blaCTX-M /blaTEM, 4 (0.8%) blaSHV/ blaTEM and 19 (3.9%) blaCTX M/blaSHV/blaTEM. Sixty two (16%) were phenotypically and genotypically positive, 12 (3%) of the isolates were phenotypically positive but genotypically negative and 140 (37%) isolates were phenotypically negative but genotypically positive. The ESBL producers were highly susceptible to imipenem (95%), nitrofurantoin (66%) but less susceptible to ampicillin (4%) and ticarcillin (7%). CONCLUSION: ESBL production among the Gram-negative clinical isolates at MRRH is very high with several isolates possessing multiple genes. The ESBL producers are highly susceptible to imipenem, but very resistant to ciprofloxacin. PMID- 26120574 TI - In vitro Antibacterial Activity of Ocimum suave Essential Oils against Uropathogens Isolated from Patients in Selected Hospitals in Bushenyi District, Uganda. AB - AIMS: To determine antibacterial activity of Ocimum suave essential oils against bacterial uropathogens. STUDY DESIGN: A cross sectional and experimental study. PLACE AND DURATION OF STUDY: Six selected hospitals in Bushenyi District, Uganda between June 2012 and July 2013. METHODOLOGY: Clean catch midstream urine samples were collected and inoculated on Cystine Lysine Electrolyte Deficient (CLED) agar. The plates were incubated at 37 degrees C for 24hrs to 48hrs. The O. suave essential oils were extracted by hydrodistillation of leaves for 4hrs using a Clevenger apparatus. The oil was collected and dried over anhydrous sodium sulphate (Na2SO4) and kept at 4 degrees C till further use. The antimicrobial activity of O. suave essential oils against isolates was determined by agar well method. The MIC of O. suave essential oil extract was carried out by microbroth dilution method. RESULTS: Of the three hundred (300) midstream urine samples collected, 67(22.33%) had significant bacterial growth. Escherichia coli is the most common isolate (61.19%, n = 41). The essential oil from O. suave showed activity against isolates of E. coli, K. pneumoniae, S. aureus, E. feacalis, M. morganii, Citrobacter species, Enterobacter species and P. aeruginosa with mean zone of inhibition (ZI) ranging from 10-22 mm. The essential oils had no inhibitory activity on Acinetobacter species. The minimum inhibitory concentration (MIC) for O. suave essential oils ranged from 0.78 to 22 MUg/ml. This study showed that O. suave essential oils had MIC value of 0.78 MUg/ml against S. aureus and MIC values ranging from 3 to 22 MUg/ml against the other tested isolates. CONCLUSION: The most common uropathogen was E. coli (61.19% n = 41). O. suave essential oils exhibited antibacterial activity against majority of the uropathogens, except Acinetobacter species, mean ZI of 10-22 mm and MIC of 0.78 - 22 MUg/ml. PMID- 26120575 TI - Clinical and financial outcomes of switching insulin glargine to insulin detemir in a veteran population with type 2 diabetes. AB - BACKGROUND: Although glargine and detemir are both FDA-approved in the U.S. as long-acting insulin analogues, inherent differences in the insulins may lead to varying outcomes. This study examined changes in clinical measures and associated costs for veterans with type 2 diabetes on insulin therapy converted from insulin glargine to insulin detemir. METHODS: A retrospective before-and-after comparison study was performed at a single-site medical center located in the southwestern U.S., comprising 133 Veterans diagnosed with type 2 diabetes receiving insulin therapy with glargine and converted to insulin detemir using a 1:1 unit dosage ratio. Patients' A1c, weight, body mass index, total daily dose, and estimated monthly insulin costs during and after conversion were compared employing Wilcoxon signed-rank tests. These measures were similarly assessed in patients at A1c goal (<7 %) prior to conversion. RESULTS: When switched from insulin glargine to insulin detemir, an increase in A1c (median of 7.7 % to 8.3 %, p < 0.01) and total daily dose (TDD: 40 to 46 units/day, p < 0.01) resulted. Monthly insulin costs decreased 19 % ($47 to $38, p < 0.01), or roughly a one-year savings of $110 per patient. An increase in A1c was similarly observed for patients at-goal prior to conversion but remained at-goal post-conversion (6.5 % to 6.7 %, p = 0.02). CONCLUSION: The increase in A1c and TDD following conversion from insulin glargine to insulin detemir suggests that glargine requires a smaller amount of units to reach the same glycemic-lowering ability compared to detemir. Despite the observed insulin cost savings associated with detemir, future studies should also determine overall costs (including indirect) and benefits associated with switching from glargine to detemir among Veteran with Type 2 diabetes. PMID- 26120577 TI - Hypokalemia Associated with Colonic Pseudo-Obstruction (Ogilvie's Syndrome). AB - We report a case of hypokalemia resulting from colonic pseudo-obstruction or Ogilvie's syndrome. Colonic pseudo-obstruction is characterized by profuse watery diarrhea that has a low sodium and high potassium concentration. It is seen in a variety of medical and surgical conditions, but its exact cause remains unknown. It is thought to result from an imbalance of sympathetic and parasympathetic input in the distal colon. The diarrhea is secretory and driven by potassium secretion rather than the inhibition of sodium reabsorption or chloride secretion, which are the most common pathophysiologic mechanisms of secretory diarrhea. Affected patients often lose >100 mmol of potassium daily. Colonic pseudo-obstruction is associated with a dramatic upregulation of the maxiK or BK potassium channel. This channel plays a prominent role in flow-mediated potassium secretion in the connecting tubule and collecting duct and is also upregulated in the distal colon in patients with advanced chronic kidney disease and end-stage renal disease. In vitro studies show that the channel is regulated by catecholamine binding to the beta receptor and cyclic AMP upregulation, somatostatin and aldosterone, insights that can be used to help guide pharmacologic therapy. Nephrologists should be aware of colonic pseudo obstruction as a cause of extrarenal potassium loss. PMID- 26120576 TI - ANCA-Associated Vasculitis in a Patient with Systematic Sclerosis and Sjogren's Syndrome: A Case Report. AB - A 65-year-old woman with a limited form of systematic sclerosis (SSc) and Sjogren's syndrome (SS) was admitted to our hospital for the evaluation of renal dysfunction. Her serum creatinine was 1.6 mg/dl, proteinuria was 1.6 g/day, and the urine sediment contained 20-29 erythrocytes/high-power field. Myeloperoxidase anti-neutrophil cytoplasmic antibodies, anti-SS-A/SS-B antibodies and anti centromere antibodies were positive. A renal biopsy showed focal necrotizing glomerulonephritis with focal interstitial lymphoplasmacytic infiltration. A diagnosis of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) was made. A steroid therapy was initiated and AAV subsided. This is a rare case of AAV in a patient with anti-centromere-positive limited SSc and SS. PMID- 26120578 TI - Antineutrophil Cytoplasmic Antibodies-Negative Pauci-Immune Crescentic Glomerulonephritis Associated with Multiple Myeloma. AB - Pauci-immune crescentic glomerulonephritis (PICGN) is most commonly associated with antineutrophil cytoplasmic antibodies (ANCA). We report a case of chronic, sclerosing ANCA-negative PICGN discovered when a patient presented with multiple myeloma. A 57-year-old woman presented with complaints of nausea, emesis and weakness. She was found to be in renal failure with a serum creatinine of 9.4 mg/dl, mild hyperkalemia and acidosis. She was noted to have normochromic, normocytic anemia with normal platelet and white cell counts, normal plasma proteins and serum protein electrophoresis. Further studies revealed increased concentrations of kappa and lambda light chains in a ratio of 34.89; a bone marrow biopsy found 12% plasma cells. Serum protein electrophoresis revealed no spike. ANCA, anti-glomerular basement membrane, antineutrophil antibody, hepatitis panel and serum complements were normal. A kidney biopsy result showed chronic sclerosing PICGN plus tubular necrosis, severe tubular atrophy, interstitial fibrosis and severe arteriosclerosis. Congo red stains were negative and electron microscopy showed no intraglomerular deposits. The patient was subsequently treated for myeloma with bortezomib and dexamethasone with good hematologic response but never recovered renal function. She remains on outpatient hemodialysis. Renal manifestations of myeloma often involve glomerular deposition disease, tubulointerstitial disease, with characteristic proteinaceous casts, or both. In contrast, our patient demonstrated neither of these findings but had chronic sclerosing PICGN. Crescentic glomerulonephritis occurring in patients with plasma cell dyscrasias has been previously reported, but the association remains extremely rare. PMID- 26120579 TI - CK2 Secreted by Leishmania braziliensis Mediates Macrophage Association Invasion: A Comparative Study between Virulent and Avirulent Promastigotes. AB - CK2 is a protein kinase distributed in different compartments of Leishmania braziliensis: an externally oriented ecto-CK2, an intracellular CK2, and a secreted CK2. This latter form is constitutively secreted from the parasite (CsCK2), but such secretion may be highly enhanced by the association of specific molecules, including enzyme substrates, which lead to a higher enzymatic activity, called inductively secreted CK2 (IsCK2). Here, we examined the influence of secreted CK2 (sCK2) activity on the infectivity of a virulent L. braziliensis strain. The virulent strain presented 121-fold higher total CK2 activity than those found in an avirulent strain. The use of specific CK2 inhibitors (TBB, DRB, or heparin) inhibited virulent parasite growth, whereas no effect was observed in the avirulent parasites. When these inhibitors were added to the interaction assays between the virulent L. braziliensis strain and macrophages, association index was drastically inhibited. Polyamines enhanced sCK2 activity and increased the association index between parasites and macrophages. Finally, sCK2 and the supernatant of the virulent strain increased the association index between the avirulent strain and macrophages, which was inhibited by TBB. Thus, the kinase enzyme CK2 seems to be important to invasion mechanisms of L. braziliensis. PMID- 26120580 TI - Development of In Vitro-In Vivo Correlation/Relationship Modeling Approaches for Immediate Release Formulations Using Compartmental Dynamic Dissolution Data from "Golem": A Novel Apparatus. AB - Different batches of atorvastatin, represented by two immediate release formulation designs, were studied using a novel dynamic dissolution apparatus, simulating stomach and small intestine. A universal dissolution method was employed which simulated the physiology of human gastrointestinal tract, including the precise chyme transit behavior and biorelevant conditions. The multicompartmental dissolution data allowed direct observation and qualitative discrimination of the differences resulting from highly pH dependent dissolution behavior of the tested batches. Further evaluation of results was performed using IVIVC/IVIVR development. While satisfactory correlation could not be achieved using a conventional deconvolution based-model, promising results were obtained through the use of a nonconventional approach exploiting the complex compartmental dissolution data. PMID- 26120581 TI - Potential Peripartum Markers of Infectious-Inflammatory Complications in Spontaneous Preterm Birth. AB - Spontaneous preterm birth significantly contributes to the overall neonatal morbidity associated with preterm deliveries. Nearly 50% of cases are associated with microbial invasion of the amniotic cavity followed by an inflammatory response. Robust diagnostic tools for neonates jeopardized by infection and inflammation may thus decrease the overall neonatal morbidity substantially. Amniotic fluid retrieved during labor retains fetal and pregnancy-related protein fingerprint and its sampling does not place any unwanted stress on women. Using exploratory and targeted methods we analyzed proteomes of amniotic fluid sampled at the end of spontaneous preterm labor prior to delivery from women with and without infection and inflammation. Exploratory data indicated several amniotic fluid proteins to be associated with infectious-inflammatory complications in spontaneous preterm birth. LC-SRM analysis subsequently verified statistically significant changes in lipocalin-1 (P = 0.047 and AUC = 0.67, P = 0.046), glycodelin (P = 0.013 and AUC = 0.73, P = 0.013), and nicotinamide phosphoribosyltransferase (P = 0.018 and AUC = 0.71, P = 0.01). PMID- 26120583 TI - Proteomic Analysis of Estrogen-Mediated Signal Transduction in Osteoclasts Formation. AB - Estrogen plays an important role in inhibiting osteoclast differentiation and protecting against bone loss from osteoporosis, especially in postmenopausal women. However, the precise mechanisms underlying the effect of estrogen on osteoclasts are not well known. In the present study, we performed proteomics analysis and bioinformatics analysis to comprehensively compare the differential expression of proteins in receptor activator of nuclear factor-kappaB ligand RANKL-induced osteoclasts in the presence and absence of estrogen. We identified 6403 proteins, of which 124 were upregulated and 231 were downregulated by estrogen. Bioinformatics analysis showed that estrogen treatment interfered with 77 intracellular pathways, including both confirmed canonical and unconfirmed pathways of osteoclast formation. Our findings validate the inhibitory effect of estrogen on osteoclasts via the promotion of apoptosis and suppression of differentiation and polarization and suggest that estrogen might inhibit osteoclast formation via other pathways, which requires further investigation and verification. PMID- 26120582 TI - Strategies of Intracellular Pathogens for Obtaining Iron from the Environment. AB - Most microorganisms are destroyed by the host tissues through processes that usually involve phagocytosis and lysosomal disruption. However, some organisms, called intracellular pathogens, are capable of avoiding destruction by growing inside macrophages or other cells. During infection with intracellular pathogenic microorganisms, the element iron is required by both the host cell and the pathogen that inhabits the host cell. This minireview focuses on how intracellular pathogens use multiple strategies to obtain nutritional iron from the intracellular environment in order to use this element for replication. Additionally, the implications of these mechanisms for iron acquisition in the pathogen-host relationship are discussed. PMID- 26120585 TI - Correlation between Gastric Mucosal Morphologic Patterns and Histopathological Severity of Helicobacter pylori Associated Gastritis Using Conventional Narrow Band Imaging Gastroscopy. AB - BACKGROUND AND AIM: Identifying specific gastric mucosal morphologic patterns useful for detecting Helicobacter pylori associated gastritis and correlation with histopathological severity. METHODS: The endoscopists classified the C-NBI gastroscopic findings into 5 gastric mucosal morphologic patterns as follows: type 1: regular arrangement of collecting venules, type 2: cone-shaped gastric pits, type 3: rod-shaped gastric pits with prominent sulci, type 4: ground glass like morphology, and type 5: dark brown patches with bluish margin and irregular border. Biopsies of all of the cases were then evaluated by 5 pathologists for definitive Helicobacter pylori diagnosis. RESULT: Type 1 and type 2 patterns were statistically significant in predicting Helicobacter pylori negative status (58/60, P < 0.01). Type 3, type 4, and type 5 patterns were statistically significant in predicting Helicobacter pylori positive status (132/140, P < 0.01). Furthermore, the sensitivity, specificity, and positive and negative predictive values of type 3, 4, or 5 morphologies for predicting Helicobacter pylori positive were 94.28%, 96.66%, 98.50%, and 87.87%, respectively, correlated well with inflammation grading according to the Sydney classification (P < 0.01). CONCLUSION: Our study suggests that gastric mucosal morphologic patterns in the Helicobacter pylori infected gastric mucosa can be reliably identified using C NBI gastroscopy with good correlation with inflammation grading. PMID- 26120584 TI - The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism. AB - Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease with ever growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH), which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment. PMID- 26120586 TI - Altered Expression Levels of MMP1, MMP9, MMP12, TIMP1, and IL-1beta as a Risk Factor for the Elevated IOP and Optic Nerve Head Damage in the Primary Open-Angle Glaucoma Patients. AB - The aim of presented work was to analyze the impact of particular polymorphic changes in the promoter regions of the -1607 1G/2G MMP1, -1562 C/T MMP9, -82 A/G MMP12, -511 C/T IL-1beta, and 372 T/C TIMP1 genes on their expression level in POAG patients. Blood and aqueous humor samples acquired from 50 patients with POAG and 50 control subjects were used for QPCR and protein levels analysis by ELISA. In vivo promoter activity assays were carried on HTM cells using dual luciferase assay. All studied subjects underwent ophthalmic examination, including BCVA, intraocular pressure, slit-lamp examination, gonioscopy, HRT, and OCT scans. Patients with POAG are characterized by an increased mRNA expression of MMP1, MMP9, MMP12, and IL-1beta genes as compared to the control group (P < 0.001). Aqueous humor acquired from patients with POAG displayed increased protein expression of MMP1, MMP9, MMP12, and IL-1beta compared to the control group (P < 0.001). Allele -1607 1G of MMP1 gene possesses only 42,91% of the 1607 2G allele transcriptional activity and allele -1562 C of MMP9 gene possesses only 21,86% of the -1562 T allele. Increased expression levels of metalloproteinases can be considered as a risk factor for the development of POAG. PMID- 26120587 TI - Nonalcoholic Fatty Liver Disease Relationship with Metabolic Syndrome in Class III Obesity Individuals. AB - INTRODUCTION: Obesity is represented mainly by abdominal obesity and insulin resistance (IR), both present in most individuals diagnosed with metabolic syndrome (MS). IR is the key risk factor in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Objective. To relate NAFLD to MS in class III obese individuals. METHODOLOGY: A descriptive cross-sectional study with class III obese individuals, aged >= 20-60 years. Blood pressure measurement, weight, height, body mass index (BMI), waist circumference (WC) and blood glucose, insulin, high-density lipoprotein cholesterol (HDL-c), and triglycerides data were obtained. HOMA-IR (homeostatic model assessment insulin resistance) calculation was carried out with a cutoff value of 2.71 for IR evaluation. The diagnosis of NAFLD was performed by liver biopsy and the diagnosis of MS was performed in accordance with the National Cholesterol Education Program/Adult Treatment Panel III (NCEPATP III). RESULTS: Of the 50 individuals evaluated, 86% were women and BMI means were 45.4 +/- 3.6 Kg/m(2). The overall individuals had NAFLD, 70% steatosis, and 30% steatohepatitis. The diagnosis of MS occurred in 56% but showed no significant association with NAFLD (P = 0.254). Triglycerides (178 +/- 65.5 mg/dL) and insulin (28.2 +/- 22.6 mcU/mL) mean values were significantly higher in steatohepatitis (P = 0.002 and P = 0.042, resp.) compared to individuals with steatosis. IR was confirmed in 76% and showed a relationship with NAFLD severity. CONCLUSION: NAFLD was not related to MS; however, MS components, evaluated in isolation, as well as IR, were related to the presence and severity of NAFLD. PMID- 26120588 TI - Five-Photon Absorption and Selective Enhancement of Multiphoton Absorption Processes. AB - We study one-, two-, three-, four-, and five-photon absorption of three centrosymmetric molecules using density functional theory. These calculations are the first ab initio calculations of five-photon absorption. Even- and odd-order absorption processes show different trends in the absorption cross sections. The behavior of all even- and odd-photon absorption properties shows a semiquantitative similarity, which can be explained using few-state models. This analysis shows that odd-photon absorption processes are largely determined by the one-photon absorption strength, whereas all even-photon absorption strengths are largely dominated by the two-photon absorption strength, in both cases modulated by powers of the polarizability of the final excited state. We demonstrate how to selectively enhance a specific multiphoton absorption process. PMID- 26120589 TI - Perceptions of Primary Care Among Breast Cancer Survivors: The Effects of Weight Status. AB - BACKGROUND: Obese breast cancer survivors (BCSs) are impacted by diminished quality of life (QOL), multiple comorbid conditions, and poor disease outcomes. Despite national guidelines recommending a healthy weight to improve QOL and outcomes posttreatment, support and education are not routinely provided to BCSs in primary care. To fill this gap, we assessed perceptions of primary care received among BCSs by weight status. METHODS: Cross-sectional surveys were administered to early-stage BCSs (N = 188) from 2 New Jersey cancer centers between May 2012 and July 2013. Sociodemographics, medical history, functional health status, perceived satisfaction with one's primary care provider (PCP), and PCP involvement in follow-up care were assessed. RESULTS: In total, 82% of overweight BCSs and 30% of obese BCSs reported not being told by their doctor that they were overweight or obese, despite these conditions being highly prevalent (35% and 35%, respectively). Obese BCSs were more likely than healthy weight BCSs to be African American, have a higher comorbidity score, poorer functional health, and greater satisfaction with their PCPs. CONCLUSION: The PCP patient encounter may represent an opportunity for PCPs to correct misperceptions and promote weight reduction efforts among BCSs, thus improving QOL and disease outcomes. PMID- 26120590 TI - Nutrient Excess in AMPK Downregulation and Insulin Resistance. AB - It is well established that chronic exposure to excess nutrients leads to insulin resistance (IR) in skeletal muscle. Since skeletal muscle is responsible for 70 80% of insulin-stimulated glucose uptake, skeletal muscle IR is a key pathological component of type 2 diabetes (T2D). Recent evidence suggests that inhibition of the nutrient-sensing enzyme AMP-activated protein kinase (AMPK) is an early event in the development of IR in response to high glucose, branched chain amino acids (BCAA), or fatty acids (FA). Whether the decrease in AMPK activity is causal to the events leading to insulin resistance (increased mTOR/p70S6K signaling) remains to be determined. Interestingly, pharmacological activation of AMPK can prevent activation of mTOR/p70S6K and insulin resistance, while inhibition of mTOR with rapamycin prevents insulin resistance, but not AMPK downregulation. AMPK can be inhibited by increased energy state (reduced AMP/ATP ratio), decreased phosphorylation of its activation site (alphaThr172) (by decreased upstream kinase activity or increased phosphatase activity), increased inhibitory phosphorylation at alphaSer485/491, changes in redox state or hormone levels, or other yet to be identified mechanisms. Excess nutrients also lead to an accumulation of the toxic lipid intermediates diacylglycerol (DAG) and ceramides, both of which can activate various protein kinase C (PKC) isoforms, and contribute to IR. The mechanism responsible for the initial downregulation of AMPK in response to excess nutrients, and whether glucose, BCAA, and FA act through similar or different pathways requires further study. Identification of this mechanism and the relative importance of other events would be beneficial for designing novel pharmacological interventions to prevent and/or reverse IR. This review will focus on the some of the mechanisms responsible for AMPK downregulation and the relative sequence and importance of these events. PMID- 26120591 TI - Abnormal hippocampal-thalamic white matter tract development and positive symptom course in individuals at ultra-high risk for psychosis. AB - BACKGROUND/OBJECTIVES: Abnormal development of the hippocampus has been reported in adolescents at ultra-high risk (UHR) for psychosis and thalamic abnormalities have been found. However, the white matter connections between the hippocampus and the thalamus have not been studied. The connections between these regions are of key importance to our understanding of the pathophysiology of psychosis. METHODS: Twenty-six UHR and 21 healthy age-matched controls were tested at a baseline assessment and 12 months later. Symptoms were assessed at both the time points and all the participants underwent diffusion tensor imaging scans. We used tractography to trace the white matter connections in each individual between the thalamus and hippocampus and then extracted fractional anisotropy (FA) to assess white matter structural integrity. RESULTS: There was a significant group by time interaction indicating that FA decreased in UHR, and increased in controls over 12 months. Across both groups, baseline FA of the thalamic-hippocampal tract was predictive of positive symptoms at 12-month follow-up. Critically, this pattern remained significant in UHR individual group alone. At baseline, those with higher FA, indicative of abnormal white matter development, show higher positive symptoms 1 year later. CONCLUSIONS: Here, we provide evidence to indicate that there are differences in white matter development in hippocampal-thalamic connections, both of which are important nodes in networks associated with schizophrenia. Furthermore, abnormal developmental patterns in UHR individuals are associated with positive symptom course. PMID- 26120592 TI - Portable robot for autonomous venipuncture using 3D near infrared image guidance. AB - Venipuncture is pivotal to a wide range of clinical interventions and is consequently the leading cause of medical injury in the U.S. Complications associated with venipuncture are exacerbated in difficult settings, where the rate of success depends heavily on the patient's physiology and the practitioner's experience. In this paper, we describe a device that improves the accuracy and safety of the procedure by autonomously establishing a peripheral line for blood draws and IV's. The device combines a near-infrared imaging system, computer vision software, and a robotically driven needle within a portable shell. The device operates by imaging and mapping in real-time the 3D spatial coordinates of subcutaneous veins in order to direct the needle into a designated vein. We demonstrate proof of concept by assessing imaging performance in humans and cannulation accuracy on an advanced phlebotomy training model. PMID- 26120594 TI - The Spear and Shield intervention to increase the availability and acceptability of voluntary medical male circumcision in Zambia: a cluster randomised controlled trial. AB - BACKGROUND: Widespread voluntary medical male circumcision in Africa could avert an estimated 3.436 million HIV infections and 300,000 deaths over the next 10 years. Most Zambian men have expressed little interest in the procedure. We tested the effect of the Spear and Shield intervention designed to increase demand for voluntary medical male circumcision among these hard-to-reach men. METHODS: This cluster randomised controlled trial was done between Feb 1, 2012, and Oct 31, 2014, in Lusaka, Zambia, where HIV prevalence is 20.8%. 13 community health centres were stratified by HIV voluntary counselling and testing rates and patient census, and randomly assigned (5:5:3) to experimental (the intervention), control, or observation-only conditions. Community health centre health-care providers at all 13 sites received training in voluntary medical male circumcision. Eligible participants were aged at least 18 years, HIV-negative, uncircumcised, and had not proactively requested or planned for voluntary medical male circumcision at the time of enrolment. Trial statisticians did not participate in randomisation. After voluntary counselling and HIV testing, participants were recruited; female partners were invited to participate. The primary outcomes at the individual level were the likelihood of voluntary medical male circumcision by 12 months post-intervention, and condom use after voluntary medical male circumcision among participants receiving the intervention. The trial is registered with ClinicalTrials.gov, number NCT01688167. FINDINGS: 800 uncircumcised HIV-negative men (400 in the experimental group, 400 in the control group) were enrolled. 161 participants in the experimental group and 96 in the control group had voluntary medical male circumcision (adjusted odds ratio 2.45, 95% CI 1.24-4.90; p=0.02). Condom use was examined in participants who had voluntary medical male circumcision and reported sexual activity within 1 month of a post-circumcision assessment (88 in the experimental group and 64 in the control group). Condom use over time increased in the experimental group (p=0.03) but not in the control group (p=0.2). One patient died in each group; no adverse events related to study participation were reported. INTERPRETATION: Comprehensive HIV prevention programmes can increase the demand for and uptake of voluntary medical male circumcision services. FUNDING: US National Institutes of Health/National Institute of Mental Health (R01MH095539). PMID- 26120595 TI - Accumulation of N-Acylphosphatidylserines and N-Acylserines in the Frontal Cortex in Schizophrenia. AB - BACKGROUND: While schizophrenia is generally considered a neurodevelopment disorder, our basic understanding of the biochemical processes involved in disease etiology and/or progression is limited. One class of biochemical mediators that has been suggested to play a role in the development of schizophrenia is N-acyl ethanolamine metabolites of N acylphosphatidylethanolamines. However, no investigations of N acylphosphatidylserines or their N-acylserine metabolites have been published. METHODS: We undertook a targeted postmortem lipidomics analysis of N acylphosphatidylserines (NAPS) and N-acylserines (NAS) in gray matter of the frontal cortex of schizophrenia subjects. RESULTS: Our data are the first to demonstrate that NAPS and NAS are present in human brain. Furthermore, NAPS and their bioactive metabolites, N-acylserines (NAS), were found to be significantly elevated in the frontal cortex of schizophrenia subjects. CONCLUSIONS: Elevated levels of NAPS lipid pools in schizophrenia may result in complex alterations in the structural function of neuronal membranes while increases in NAS may alter signal transduction pathways. PMID- 26120596 TI - Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes. AB - A genome-wide association study (GWAS) and subsequent replication studies in diverse ethnic groups indicate that common Niemann-Pick C1 gene (NPC1) polymorphisms are associated with morbid-adult obesity or diabetes independent of body weight. The objectives for this prospective cross-sectional study were to determine allele frequencies for NPC1 polymorphisms (644A>G, 1926C>G, 2572A>G, and 3797G>A) and association with metabolic disease phenotypes in an ethnically diverse New Mexican obstetric population. Allele frequencies for 1926C>G, 2572A>G, and 3797G>A were significantly different between race/ethnic groups (non Hispanic white, Hispanic, and Native American). The results also indicated a significant pairwise linkage-disequilibrium between each of the four NPC1 polymorphisms in race/ethnic groups. Moreover, the derived and major allele for 1926C>G was associated (OR 2.11, 95% CI 1.10-3.96, P = 0.022) with increased risk for maternal prepregnancy overweight (BMI 25.0-29.9kg/m2) while the ancestral and major allele for 2572A>G was associated (OR 4.68, 95% CI 1.23-17.8, P = 0.024) with increased risk for gestational diabetes in non-Hispanic whites, but not Hispanics or Native Americans. In summary, this is the first transferability study to investigate common NPC1 polymorphisms in a multiethnic population and demonstrate a differential association with increased risk for maternal prepregnancy overweight and gestational diabetes. PMID- 26120597 TI - Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together? AB - Autism spectrum disorders (ASD) are prevalent neurodevelopmental conditions, affecting 1 in 68 children in the United States alone. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. One of the most well studied mechanisms related to ASD and insomnia is dysregulation of the melatonin pathway, which has been observed in many individuals with ASD compared to typically developing controls. Furthermore, variation in genes whose products regulate endogenous melatonin modify sleep patterns in humans and have also been implicated in some cases of ASD. However, the relationship between comorbid insomnia, melatonin processing, and genes that regulate endogenous melatonin levels in ASD is complex and requires further study to fully elucidate. The aim of this review is to provide an overview of the current findings related to the effects of genetic variation in the melatonergic pathway on risk for expression of sleep disorders in children with ASD. In addition, functional findings related to endogenous levels of melatonin and pharmacokinetic profiles in this patient population are evaluated. PMID- 26120598 TI - Suppression of experimental arthritis through AMP-activated protein kinase activation and autophagy modulation. AB - Autophagy plays a central role in various disease processes. However, its contribution to inflammatory arthritides such as rheumatoid arthritis (RA) is unclear. We observed that autophagy is engaged in the K/BxN serum transfer model of RA but autophagic flux is severely impaired. Metformin is an anti-diabetic drug that has been shown to stimulate autophagy. Induction of autophagic flux, through metformin-mediated AMP-activated protein kinase (AMPK) activation and interruption of mammalian target of rapamycin (mTOR) signaling mitigated the inflammation in experimental arthritis. Further investigation into the effects of metformin suggest that the drug directly activates AMPK and dose-dependently suppressed the release of TNF-alpha, IL-6, and MCP-1 by macrophages while enhancing the release of IL-10 in vitro. In vivo, metformin treatment significantly suppressed clinical arthritis and inflammatory cytokine production. Mechanistic studies suggest that metformin exerts its anti-inflammatory effects by correcting the impaired autophagic flux observed in the K/BxN arthritis model and suppressing NF-kappaB-mediated signaling through selective degradation of IkappaB kinase (IKK). These findings establish a central role for autophagy in inflammatory arthritis and argue that autophagy modulators such as metformin may represent potential therapeutic agents for the treatment of RA. PMID- 26120599 TI - Protective Effect of Topiramate on Hyperglycemia-Induced Cerebral Oxidative Stress, Pericyte Loss and Learning Behavior in Diabetic Mice. AB - Diabetes mellitus-associated damage to the microvasculature of the brain is caused by hyperglycemia-induced oxidative stress, which results in pericyte loss, blood-brain barrier disruption, and impaired cognitive function. Oxidative stress, in diabetes, is caused by reactive oxygen species produced during accelerated respiration (mitochondrial oxidative metabolism of glucose). The rate of respiration is regulated by mitochondrial carbonic anhydrases (CAs). Inhibition of these enzymes protects the brain from diabetic damage. Previously, we reported that topiramate, a mitochondrial CA inhibitor, at a dose of 50 mg/kg/day protects the brain in diabetes by reducing oxidative stress and restoring pericyte numbers. Topiramate has high affinity for both mitochondrial CAs; therefore, it is conceivable that a much lower dose may inhibit these enzymes and thus protect the brain from hyperglycemia-induced oxidative damage. Therefore, in an effort to reduce the toxicity associated with higher doses of topiramate, the current study was designed to investigate the effect of 1.0 mg/kg topiramate on reducing oxidative stress, restoring pericyte numbers in the brain, and improving the impaired learning behavior in diabetic mouse. Diabetes was induced by a one-time injection of streptozotocin and topiramate was administered daily for 12 weeks. Levels of oxidative stress, reduced glutathione (GSH) and 4 hydroxy-2-trans-nonenal (HNE) were measured in the brain and pericyte/endothelial cell ratios in isolated brain microvessels. Learning behavior was assessed by T maze foot shock avoidance test. A significant decrease in GSH (control, 12.2 +/- 0.4 vs. diabetic, 10.8 +/- 0.4 vs. diabetic + topiramate, 12.6 +/- 0.6, p<0.05) and an increase in HNE (control, 100 +/- 4.2, vs. diabetic, 127.3 +/- 8.8 vs. diabetic + topiramate, 93.9 +/- 8.4 p<0.05) in diabetic mice were corrected by topiramate treatment. Topiramate treatment also resulted in restoration of pericyte numbers in diabetic mice (control, 25.89 +/- 0.85 vs. diabetic, 18.14 +/ 0.66 vs. diabetic + topiramate, 24.35 +/- 0.53, p<0.001) and improvement in learning behavior. In conclusion, these data clearly demonstrate that topiramate at 1.0 mg/kg protects the mouse brain from diabetic damage. A 1.0 mg/kg topiramate in the mouse translates to a 5.0 mg daily dose in a 60 kg human, which may help slow the onset and progression of diabetic complications in the human brain. PMID- 26120600 TI - The Presence of Histamine and a Histamine Receptor in the Bivalve Mollusc, Crassostrea virginica. AB - Histamine, a biogenic amine, is a neurotransmitter in neurons and sensory receptors in invertebrates. Histamine has rarely been reported in bivalves. We used HPLC with pre-column derivatization using 2,3-naphthalenedicarboxaldehyde (NDA) as a fluorescent labeling agent to measure histamine in ganglia, and peripheral tissues of the oyster Crassostrea virginica. We also used Western Blot technique to look for the presence of a histamine receptor in the mantle rim. HPLC results found histamine present in ng amounts in both the cerebral and visceral ganglia, as well as the mantle rim and other peripheral tissues of C. virginica. The study confirms and quantifies histamine as an endogenous biogenic amine in C. virginica in the nervous system and innervated organs. Western Blot technique also identified a histamine H2-like receptor present in sensory tissue of the oyster's mantle rim. PMID- 26120601 TI - Multiplexed femtomolar quantitation of human cytokines in a fluoropolymer microcapillary film. AB - Sensitive quantitation of multiple cytokines can provide important diagnostic information during infection, inflammation and immunopathology. In this study sensitive immunoassay detection of human cytokines IL-1beta, IL-6, IL-12p70 and TNFalpha is shown for singleplex and multiplex formats using a novel miniaturized ELISA platform. The platform uses a disposable plastic multi-syringe aspirator (MSA) integrating 8 disposable fluoropolymer microfluidic test strips, each containing an array of ten 200 MUm mean i.d. microcapillaries coated with a set of monoclonal antibodies. Each MSA device thus performs 10 tests on 8 samples, delivering 80 measurements. Unprecedented levels of sensitivity were obtained with the novel fluoropolymer microfluidic material and simple colorimetric detection in a flatbed scanner. The limit of detection for singleplex detection ranged from 2.0 to 15.0 pg ml(-1), i.e. 35 and 713 femtomolar for singleplex cytokine detection, and the intra- and inter-assay coefficient of variation (CV) remained within 10%. In addition, a triplex immunoassay was developed for measuring IL-1beta, IL-12p70 and TNFalpha simultaneously from a given sample in the pg ml(-1) range. These assays permit high sensitivity measurement with rapid <15 min assay or detection from undiluted blood serum. The portability, speed and low-cost of this system are highly suited to point-of-care testing and field diagnostics applications. PMID- 26120602 TI - Investigating the relationship between changes in collagen fiber orientation during skin aging and collagen/water interactions by polarized-FTIR microimaging. AB - Upon chronological aging, human skin undergoes structural and molecular modifications, especially at the level of type I collagen. This macromolecule is one of the main dermal structural proteins and presents several age-related alterations. It exhibits a triple helical structure and assembles itself to form fibrils and fibers. In addition, water plays an important role in stabilizing the collagen triple helix by forming hydrogen-bonds between collagen residues. However, the influence of water on changes of dermal collagen fiber orientation with age has not been yet understood. Polarized-Fourier Transform Infrared (P FTIR) imaging is an interesting biophotonic approach to determine in situ the orientation of type I collagen fibers, as we have recently shown by comparing skin samples of different ages. In this work, P-FTIR spectral imaging was performed on skin samples from two age groups (35- and 38-year-old on the one hand, 60- and 66-year-old on the other hand), and our analyses were focused on the effect of H2O/D2O substitution. Spectral data were processed with fuzzy C means (FCM) clustering in order to distinguish different orientations of collagen fibers. We demonstrated that the orientation was altered with aging, and that D2O treatment, affecting primarily highly bound water molecules, is more marked for the youngest skin samples. Collagen-bound water-related spectral markers were also highlighted. Our results suggest a weakening of water/collagen interactions with age. This non-destructive and label-free methodology allows us to understand better the importance of bound water in collagen fiber orientation alterations occurring with skin aging. Obtaining such structural information could find benefits in dermatology as well as in cosmetics. PMID- 26120603 TI - Oxides in silver-graphene nanocomposites: electrochemical signatures and electrocatalytic implications. AB - Herein we report an electrochemical approach to establish the presence of silver oxides in silver-reduced graphene oxide (Ag-rGO) nanocomposites synthesised under alkaline conditions. The recorded electrochemical signatures, further supported and validated by UV-Vis spectroscopy, XRD and TEM analysis, clearly establish the presence of an oxide phase of silver in the nanodimensional silver present in Ag rGO. The Ag-rGO was tested for its electrocatalytic and electrosensing activity for hydroquinone (H2Q) and ascorbic acid (AA). The presented results establish that the electrocatalytic and electrosensing potential of the Ag-rGO for H2Q and AA can be enhanced through electroreduction of the oxide phase of silver in these nanocomposites. Our results prove that the electrocatalytic and electroanalytic activities of electroreduced Ag-rGO for AA are better than most of the electrode materials reported so far in the literature. PMID- 26120604 TI - Detecting miRNA by producing RNA: a sensitive assay that combines rolling-circle DNA polymerization and rolling circle transcription. AB - Target miRNA was detected by producing RNA: rolling circle polymerization (RCP) and rolling circle transcription (RCT) were interlinked to provide dual amplification, producing multiplied malachite green (MG) aptamers, and a signal was generated by the SERS (surface-enhanced Raman scattering) quantification of the MG molecules that were bound to the transcripts. PMID- 26120605 TI - Two-step energy transfer enables use of phenylalanine in action-EET for distance constraint determination in gaseous biomolecules. AB - Two-step energy transfer is potentially useful for exploring macromolecular structure, but it has not been observed previously in the gas-phase. Single step excitation energy transfer (EET) has been recently documented for tyrosine and tryptophan containing peptides, but not for phenylalanine. Herein, we report sequential energy transfer from phenylalanine to tyrosine to a disulfide, resulting in homolytic cleavage of a sulfur-sulfur bond. Interestingly, energy transfer from phenylalanine is only observed in the presence of tyrosine and only occurs within certain distance constraints. Isolated, electronically excited phenylalanine is known to have an extremely long lifetime in the gas phase, potentially suggesting quicker relaxation occurs via energy transfer to tyrosine. Alternatively, the direct overlap of states between phenylalanine and disulfide bonds is predicted to be poor, in which case tyrosine would serve to bridge the gap. In either case, the distance constraints imposed by this two-step EET are shown to be useful for evaluation and determination of gaseous biomolecular structure. PMID- 26120606 TI - Achieving high power efficiency and low roll-off OLEDs based on energy transfer from thermally activated delayed excitons to fluorescent dopants. AB - Achieving high power efficiencies at high-brightness levels is still an important issue for organic light-emitting diodes (OLEDs) based on the thermally activated delayed fluorescence (TADF) mechanism. Herein, enhanced electroluminescence efficiencies were achieved in fluorescent OLEDs using a TADF molecule, (4s,6s) 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN), as a host and quinacridone derivatives (QA) as fluorescent dopants. PMID- 26120607 TI - A computational study of the quantum transport properties of a Cu-CNT composite. AB - The quantum transport properties of a Cu-CNT composite are studied using a non equilibrium Green's function approach combined with the self-consistent-charge density-functional tight-binding method. The results show that the electrical conductance of the composite depends strongly on CNT density and alignment but more weakly on chirality. Alignment with the applied bias is preferred and the conductance of the composite increases as its mass density increases. PMID- 26120608 TI - Optical properties of prodigiosin and obatoclax: action spectroscopy and theoretical calculations. AB - Prodiginine molecules (prodigiosin and obatoclax) are well-known pH-chromic dyes with promising anti-tumor properties. They present multiple tautomeric and rotameric forms. The protonation state and the structure of such flexible ligands in interaction with a protein are crucial to understand and to model the protein's biological activities. The determination of the protonation state via UV/vis absorption is possible if the ligand spectra of the neutral and protonated states are sufficiently different, and also if we can eliminate other factors potentially impacting the spectrum. Upon measuring the absorption spectra of the ligand in solution, varying solvents and pH values, we have determined that the optical properties of prodigiosin and obatoclax depend on the protonation state and not on the solvent permittivity constant. In parallel, action spectroscopy (using tunable lasers coupled to ion traps) in the gas phase of protonated and sodiated prodigiosin and obatoclax molecules has been performed to evaluate the sensitivity of the charge and the conformational state to their optical properties free of solvent. The spectra are interpreted using computational simulations of molecular structures and electronic excitations. The excitation energies are only slightly sensitive to various isomerizations, and may be used to distinguish between protonated and deprotonated states, even in the presence of a sodium counter-ion. PMID- 26120609 TI - Study of photophysical properties of 5-deazaalloxazine and 1,3-dimethyl-5 deazaalloxazine in dependence of pH using different spectral techniques. AB - The photophysical properties of 5-deazaalloxazine and 1,3-dimethyl-5 deazalloxazine at different pH values were characterized using absorption spectra, fluorescence emission spectra, fluorescence excitation spectra, synchronous fluorescence spectra and total fluorescence spectra. Their ionised and/or neutral forms were discussed in comparison with those obtained for other derivatives of 5-deazaalloxazine and/or 5-deazaisoalloxazine. Steady-state and time-resolved techniques were used to study the protonation/deprotonation equilibria between cationic and neutral forms of both compounds and between neutral and monoanionic forms of 5-deazalloxazine, as well as between monoanionic forms of this compound and its dianion. We estimated pKa values for these equilibria both in the ground and excited states. Our steady-state and time resolved measurements indicate that the cation of 5-deazaalloxazine in its isoalloxazinic form exhibits fluorescence that is quenched by protons in a dynamic process. Contrary to that, the cation of 1,3-dimethyl-5-deazaalloxazine has almost no fluorescence. Additionally, we found that the neutral forms of 5 deazalloxazine and 1,3-methyl-5-deazalloxazine are also quenched in acidic conditions by protons. In basic conditions, 5-deazaalloxazine forms two structurally different anions, namely the alloxazinic monoanion and the isoalloxazinic monoanion; both simultaneously dissociate into the isoalloxazinic dianion at even higher pH values. The synchronous fluorescence spectra and total fluorescence spectra demonstrated their suitability to characterize and differentiate different fluorescent forms of 5-deazalloxazine, namely: the cation, the neutral form, two monoanions, and the dianion, in a wide pH range. PMID- 26120610 TI - Nanoparticles in ionic liquids: interactions and organization. AB - Ionic liquids (ILs), defined as low-melting organic salts, are a novel class of compounds with unique properties and a combinatorially great chemical diversity. Ionic liquids are utilized as synthesis and dispersion media for nanoparticles as well as for surface functionalization. Ionic liquid and nanoparticle hybrid systems are governed by a combined effect of several intermolecular interactions between their constituents. For each interaction, including van der Waals, electrostatic, structural, solvophobic, steric, and hydrogen bonding, the characterization and quantitative calculation methods together with factors affecting these interactions are reviewed here. Various self-organized structures based on nanoparticles in ionic liquids are generated as a result of a balance of these intermolecular interactions. These structures, including colloidal glasses and gels, lyotropic liquid crystals, nanoparticle-stabilized ionic liquid containing emulsions, ionic liquid surface-functionalized nanoparticles, and nanoscale ionic materials, possess properties of both ionic liquids and nanoparticles, which render them useful as novel materials especially in electrochemical and catalysis applications. This review of the interactions within nanoparticle dispersions in ionic liquids and of the structure of nanoparticle and ionic liquid hybrids provides guidance on the rational design of novel ionic liquid-based materials, enabling applications in broad areas. PMID- 26120611 TI - Difference in TiO2 photocatalytic mechanism between rutile and anatase studied by the detection of active oxygen and surface species in water. AB - Various kinds of TiO2 photocatalysts have been practically applied in various fields. Knowing the exact surface properties is a prerequisite to develop further and efficient applications. However, the cause of the essential difference in the activities of the two polymorphs of TiO2, rutile and anatase, has not been clearly elucidated yet. We tried to clarify the cause in terms of active oxygen species (OH, O2(-), and H2O2) photogenerated on the surfaces, which are considered practically involved in the photocatalytic reactions. It was revealed that for anatase the rate of OH generation was high, but it decreased in the presence of H2O2. On the other hand, for rutile, OH generation was very low but it increased in the presence of H2O2. The formation rate of O2(-) for rutile was higher than that for anatase, suggesting that the photoinduced reduction process should not be accountable for the higher photocatalytic activity of anatase. Since the Ti-Ti distance on a rutile surface is smaller than that for anatase, rutile is capable of forming a surface structure such as Ti-OO-Ti, leading to readily form O2. The mechanism of fast coupling of two photoinduced conduction band holes to form Ti-OO-Ti was proposed, which is accountable for the lower reactivity of rutile. This mechanism was verified by the analysis of surface species with ATR-IR spectroscopy. PMID- 26120612 TI - Wolff-Parkinson-White syndrome: comprehensive electrophysiologic assessment with the help of a single PVC. PMID- 26120613 TI - Obituary. PMID- 26120614 TI - ["As a physician one stands on thin ice"]. PMID- 26120615 TI - [Leprosy - a neglected disease]. PMID- 26120616 TI - [In Memoriam--Jean Mouchet (1920-2014). A great figure of tropical medical entomology]. PMID- 26120617 TI - IN MEMORIAM. PMID- 26120618 TI - Response. PMID- 26120619 TI - Response. PMID- 26120620 TI - Response. PMID- 26120621 TI - Response. PMID- 26120622 TI - Response. PMID- 26120623 TI - Re: Correspondence to 'Cancer risk in adult residents near nuclear power plants in Korea - a cohort study of 1992-2010' (1) & subsequent debate (2, 3). PMID- 26120624 TI - Protein binder woes. PMID- 26120625 TI - THE AUTHOR FILE: Erin Margaret Schuman. PMID- 26120626 TI - POINTS OF SIGNIFICANCE: Bayesian statistics. PMID- 26120627 TI - RNA structure served in vivo. PMID- 26120629 TI - SPLITTING Cas9. PMID- 26120628 TI - Deep views into living mice. PMID- 26120630 TI - Shape-shifting MRI probes. PMID- 26120631 TI - Protein dynamics for the masses. PMID- 26120632 TI - Neurons pick up the heat. PMID- 26120633 TI - Solving XFEL's image problem. PMID- 26120634 TI - We are pleased to present this Special Issue on New Frontiers in Tendon Research. PMID- 26120635 TI - The Past, Present, and Future of the Wellness Movement: An Interview with Dr. Bill Hettler. PMID- 26120636 TI - Interconnectedness, Quantum Physics, and Awe. PMID- 26120637 TI - How Culture Interacts with the Concept of Wellness: The Role Wellness Plays in a Global Environment. PMID- 26120638 TI - The Multi-Dimensions of Wellness: The Vital Role of Terms and Meanings. PMID- 26120639 TI - Is Wellness Going Back to the Future? PMID- 26120640 TI - Making Something Great! The 25th Annual Art and Science of Health Promotion Conference. PMID- 26120641 TI - REPLY BY THE AUTHORS. PMID- 26120642 TI - Neoplastic plasma cells mimic mature neutrophils in plasma cell myeloma with t(11;14)(q13;q32). PMID- 26120643 TI - Canadian Association of Emergency Physicians position statement on acute ischemic stroke. AB - The CAEP Stroke Practice Committee was convened in the spring of 2013 to revisit the 2001 policy statement on the use of thrombolytic therapy in acute ischemic stroke. The terms of reference of the panel were developed to include national representation from urban academic centres as well as community and rural centres from all regions of the country. Membership was determined by attracting recognized stroke leaders from across the country who agreed to volunteer their time towards the development of revised guidance on the topic. The guideline panel elected to adopt the GRADE language to communicate guidance after review of existing systematic reviews and international clinical practice guidelines. Stroke neurologists from across Canada were engaged to work alongside panel members to develop guidance as a dyad-based consensus when possible. There was no unique systematic review performed to support this guidance, rather existing efficacy data was relied upon. After a series of teleconferences and face to face meetings, a draft guideline was developed and presented to the CAEP board in June of 2014. The panel noted the development of significant new evidence to inform a number of clinical questions related to acute stroke management. In general terms the recommendations issued by the CAEP Stroke Practice Committee are supportive of the use of thrombolytic therapy when treatment can be administered within 3 hours of symptom onset. The committee is also supportive of system-level changes including pre-hospital interventions, the transport of patients to dedicated stroke centers when possible and tele-health measures to support thrombolytic therapy in a timely window. Of note, after careful deliberation, the panel elected to issue a conditional recommendation against the use of thrombolytic therapy in the 3-4.5 hour window. The view of the committee was that as a result of a narrow risk benefit balance, one that is considerably narrower than the same considerations under 3 hours, a significant number of informed patients and families would opt against the risk of early intracranial hemorrhage and the possibility of increased 90-day mortality that is not seen for more timely treatment. Furthermore, the frequently impaired nature of patients suffering an acute stroke and the difficulties in asking families to make life and death decisions in a highly time-sensitive context led the panel to restrict a strong endorsement of thrombolytic to the 3 hour outermost limit. The committee noted as well that Health Canada has not approved a thrombolytic agent beyond a three hour window in acute ischemic stroke. PMID- 26120644 TI - Response. PMID- 26120645 TI - Response. PMID- 26120646 TI - Atlantoaxial instability and Chiari malformation--response. PMID- 26120647 TI - The psychometric properties of the dash and quickdash--response. PMID- 26120648 TI - Retraction: C terminus L-type Ca2+ channel calmodulin-binding domains are 'auto agonist' ligands in rabbit ventricular myocytes. PMID- 26120649 TI - Retraction: Cytoskeletal disrupting agents prevent calmodulin kinase, IQ domain and voltage-dependent facilitation of L-type Ca2+ channels. PMID- 26120650 TI - Retraction: Calmodulin kinase and a calmodulin-binding 'IQ' domain facilitate L type Ca2+ current in rabbit ventricular myocytes by a common mechanism. PMID- 26120651 TI - [Oligoprogression]. PMID- 26120652 TI - [Cognitive deficits following hematopoietic stem cell transplantation in childhood]. PMID- 26120653 TI - [Recommended duration of androgen suppression of localized pancreatic cancer before radiotherapy is still uncertain]. PMID- 26120654 TI - [Therapeutic approach in persistent diabetic macular edema]. AB - Terminology of persistent diabetic macular edema has been initially reserved to cases unresponsive to conventional laser photocoagulation according to ETDRS criteria. While knowledge about pathophysiology of macular edema evolved and new drugs became available, the terminology of persistent diabetic macular edema expanded to include resistance to most current therapies. The purpose of this paper is to review medical and surgical options in the treatment of such difficult cases according to literature data and personal experience. PMID- 26120655 TI - [Macular serpiginous choroiditis complicated by macular hole]. AB - Macular serpiginouschoroiditis is a rare variant of serpiginous choroiditis characterized by a severe recurrent inflammation of both central choroid and retinal pigment epithelium. Visual prognosis is severe due to subsequent distruction of retinal structures. Permanent central visual loss is the consequence of retinal pigment epithelium hyper or hypoplasia and/or subretinal neovascularization leading to fibrous scarring. This article reports the unusual case of rapid development of a macular hole soon after the onset of characteristic clinical features. Despite anti-inflammatory treatment and successful macular hole surgery the visual function remained significantly impaired by secondary central retinal pigment epithelium changes. PMID- 26120656 TI - Can Separate Be Equal? Ending the Segregation of Mental Health. PMID- 26120657 TI - Studies on South-east Asian fireflies: Abscondita, a new genus with details of life history, flashing patterns and behaviour of Abs. chinensis (L.) and Abs. terminalis (Olivier) (Coleoptera: Lampyridae: Luciolinae). AB - Abscondita, a new genus of fireflies from South-east Asia, is described from males and females of Abs. anceyi (Olivier 1883), Abs. cerata (Olivier 1911), Abs. chinensis (L. 1767), Abs. perplexa (Walker 1858), Abs. promelaena (Walker 1858) and Abs. terminalis (Olivier 1883), all transferred from Luciola Laporte. Both L. dubia Olivier 1903 and L. dejeani Gemminger 1870 are synonymised with Luciola perplexa (Walker), and L. aegrota Olivier 1891 and L. melaspis Bourgeois 1909 with L. promelaena Walker. Females are characterised by their bursa plates. Larvae are associated and described for Abs. anceyi (Olivier), Abs. chinensis (L.) and Abs. terminalis (Olivier). Taxonomic issues regarding the identification of species with very similar colouration of pale dorsum and black tipped elytra are addressed and in some cases resolved. A neotype for Luciola chinensis (L.) is erected and Luciola praeusta (Kiesenwetter 1874) is synonymised with L. chinensis (L.). Descriptions of life histories, biology and flashing patterns of populations of Abs. chinensis and Abs. terminalis from central China are included. A bs. terminalis is the first Asian firefly known to possess multiple flash trains where males are documented to display with repeating flash trains. PMID- 26120659 TI - A new species of the genus Basidissus (Coleoptera: Anthribidae) from east Madagascar, with a key to species.. AB - A new species, Basidissus bendai Tryzna & Baiat sp. nov. (Anthribidae: Anthribinae: Platyrhinini), from east Madagascar is described, female genitalia are studied and illustrated, and the mobility of the stylus of the toothed plate is discussed. Colour photographs as well as a key to Madagascan species of the genus Basidissus are provided. PMID- 26120658 TI - The genus Cyphoderopsis Carpenter (Collembola: Paronellidae) in Thailand and a faunal transition at the Isthmus of Kra in Troglopedetinae. AB - The genus Cyphoderopsis Carpenter is recorded for the first time from continental Southeast Asia, with four new species described from Peninsular Thailand. New characters of taxonomic importance are introduced. The new species herein described are distinguished from other species of the genus by the following combination of characters: dens with two rows of spines, absence of eyes and pigment, and claw with inner teeth. They differ among them in the number of inner teeth on claw, morphology of tenent hairs (pointed versus clavate), number of dental spines and number of central macrochaetae on Th.II (3+3 versus 4+4). The genus Cyphoderopsis in Thailand is shown to be restricted to the South of the Isthmus of Kra, while the closely related genus, Troglopedetes Absolon, replaces it further north, providing new evidence that the Isthmus of Kra is an important biogeographical boundary in Southeast Asia. A checklist and a key to world species of the genus are given. PMID- 26120660 TI - A new genus and species of ambush bugs from South Africa (Hemiptera: Heteroptera: Reduviidae: Phymatinae). AB - Doesburgella gen. nov. and its type species D. dilatata sp.nov (Hemiptera, Heteroptera: Reduviidac, Phymatinae; Macrocephalini) are described from South Africa. PMID- 26120662 TI - Descriptions of the final stadium larva and female adult of Coeliccia mingxiensis Xu (Odonata: Zygoptera: Platycnemididae). AB - The final stadium larva of Coeliccia mingxiensis Xu is described and illustrated. The female adult is also described for the first time. The larva can be easily separated from all known Coeliccia larvae by the following distinct morphological characters: (1) prementum longest in all known Coeliccia larvae; median lobe with 4 pairs of premental setae and palpal lobe with 6 palpal setae; (2) caudal gills shortest of all known Coeliccia larvae when compared with body length; median gill rounded at apex and lateral gill with a small median projection at apex. The female is similar to the male in many respects, differing chiefly in several respects as follows: the transverse yellow band on vertex of head broader and straighter than in male; antehumeral stripe on mesepisternum somewhat incurved basally, not forming a strong hook, which is present in male; distal abdomen with obviously different colour pattern; anal appendages brownish-black, shorter than S10; vulvar scales robust, brownish-yellow, projecting well beyond end of abdomen. PMID- 26120661 TI - Revision of the ocellatus species-group of the genus Plumarius Philippi 1873 (Hymenoptera, Chrysidoidea, Plumariidae), with description of three new species from Argentina. AB - This contribution presents the study of species-group of Plumarius Philippi 1873, as the result of a survey of the morphological variation in males. The group is characterized by the large ocelli and transverse head. It consists of the following three new species: P. culminatus Diez, Fidalgo & Roig-Alsina, sp. nov., P. ocellatus Diez, Fidalgo & Roig-Alsina, sp. nov., and P. stangei Diez, Fidalgo & Roig-Alsina, sp. nov. A characterization of the group, descriptions, and illustrations are provided. PMID- 26120663 TI - Description of the larva of Neuraeschna claviforcipata Martin, 1909 (Insecta: Odonata: Aeshnidae). AB - The ultimate stadium larva of Neuraeschna claviforcipata is described and illustrated based on an F-0 exuvia of a reared female from northern Amazonas State, Brazil. This larva differs from the other two known larvae of the genus in lacking the spiny lateral prominence of the mandible, and in having only a short spine each side of the median cleft of the prementum; labium is shorter and cercus longer. Noteworthy is the presence of a hair brush on each occipital lobe behind mesal angle of compound eye. The larva was found in a small blackwater pool with abundant leaf litter in an open, "campina"-type habitat, with sandy soil and low, bushy vegetation. PMID- 26120664 TI - Phytoseiidae in European grape (Vitis vinifera L.): bio-ecological aspects and keys to species (Acari: Mesostigmata). AB - The family Phytoseiidae includes many species of predators involved in the control of mite pests of crops all over the world. In European vineyards, these natural enemies play a key role in plant protection as their presence usually makes the use of acaricides unnecessary. Each species has its specific biological features. It is thus of great interest to identify the species reported on grape, Vitis vinifera. The present paper, based on a world database of the family Phytoseiidae and on an analysis of more than 250 publications, presents the 54 species of Phytoseiidae belonging to 15 genera reported on V. vinifera in Europe, and identification keys to species. Online versions of the key (dichotomous and polytomous) with illustrations are available at http://wwwl.montpellier.inra.fr/CBGP/phytoseiidae/sitewebvineyards2/index.htm. An analysis of the biogeographic distribution of these species and their prey has also been carried out. Most species reported on V. vinifera in Europe are rare; only five species are frequently observed: Kampimodromus aberrans, Typhlodromus (Typhlodromus) pyri, Typhlodromus (Typhlodromus) exhilaratus, Euseius finlandicus and Phytoseius finitimus. The 12 countries where Phytoseiidae have been reported from grapes have been unevenly surveyed, the most well-known faunas being from Italy, Greece and France. These species are reported to prey upon the main species of mite pests of grapes. PMID- 26120665 TI - New genera of Dicrepidiina from the Neotropical Region (Coleoptera, Elateridae, Elaterinae, Ampedini). AB - Two genera of Dicrepidiina, Paranoplischius gen. nov. and Paratractosomus gen. nov., and three species, Paranoplischius modestus sp. nov., P. nigellus sp. nov. and Paratractosomus sulciventris sp. nov., from South America, are described and illustrated. A provisional key to the genera of Dicrepidiina is also included. PMID- 26120666 TI - The fossil pulmonate snails of Sandelzhausen (Early/Middle Miocene, Germany): Succineidae, Testacelloidea and Helicoidea. AB - Sandelzhausen is an Early/Middle Miocene (Mammal Neogene zone MN5) fossil site near Mainburg, S Germany, and despite its small size it harbors a rich fossil record. Hundreds of fossil continental mollusks, almost exclusively pulmonates snails, were recovered during the excavations, but never received due attention by researchers. Here, the second part of a formal taxonomical treatment of the fossil pulmonates from Sandelzhausen is presented, dealing with the superfamilies Succineoidea, Testacelloidea and Helicoidea, and including the description of a new hygromiid species. The following species were found in the material: Succinea minima (Succineidae); Palaeoglandina sp. (Spiraxidae); Testacella zellii (Testacellidae); Klikia cf. coarctata (Elonidae); Cepaea cf. eversa, Cepaea cf. sylvestrina and Tropidomphalus cf. incrassatus (Helicidae); ?Helicodonta sp. and Helicodontidae indet. (Helicodontidae); Leucochroopsis kleinii and Urticicola perchtae sp. nov. (Hygromiidae). PMID- 26120667 TI - Revalidation of Saguinus ursula Hoffmannsegg (Primates: Cebidae: Callitrichinae). AB - In this study, we review the taxonomy of Saguinus niger (E. Geoffroy) and revalidate Saguinus ursula Hoffmannsegg as a distinct species. The revalidation is based on pelage coloration, and the pattern of morphological divergence is corroborated by molecular data. Samples from the east bank of the Tocantins River (S. ursulus) were distinct from specimens of S. niger from the west bank in having mid-dorsal hair with an wide (5.0-55 mm) intermediary band of bright and golden buffy color; long (ca. 23-26 mm) dorsal hair at the inter-scapular region; and naked (not noticeably haired) face, hands and fingers. Saguinus ursulus and S. niger are allopatric, and Tocantins River is putatively acting as an effective barrier for gene flow. A lectotype to S. ursulus from syntypes was designated. PMID- 26120668 TI - Nesticus dimensis new species, a new troglobitic spider from Turkey (Araneae, Nesticidae), with comments on its phylogenetic relationships. AB - A new troglobitic spider species, Nesticus dimensis n. sp. (felmale male), inhabiting the Dim Cave of Alanya (Antalya Prov., Turkey) is diagnosed and described. The new species belongs to the Eastern Mediterranean Nesticus Group, which includes N. eremita and N. speluncarum as the most common and widespread species along with N. arenstorffi and N. henderickxi. Evolutionary relationships of the taxa belonging to this group of species are discussed on the basis of morphological and molecular data (using cox1, rrnL and H3 gene sequence data). PMID- 26120669 TI - A new species of Apocellus Erichson, 1839 (Coleoptera: Staphylinidae) from Argentina with ecological notes. AB - Apocellus andinus sp. nov. from Argentina is described and illustrated, detailed information on its ecology is provided, and a key to species of Apocellus from southwestern South America is given. This species was collected in riparian areas of a mountain dam at 1355 m elevation, and it was found in an unstable wetland environment in association with species tolerant to human perturbations. Lectotypes are designated for Apocellus argentinus Bernhauer, 1908 and Apocellus opacus Bernhauer, 1908. PMID- 26120670 TI - Annotated checklist and keys for cumaceans (Crustacea: Peracarida) from the Tropical Eastern Pacific, with six new species from the Southern Mexican Pacific. AB - In the Tropical Eastern Pacific (TEP) 23 species of cumaceans are known, however none of these species has been previously registered in the southern Pacific coast of Mexico. The examination of 378 specimens resulted in six new species, belonging to two families and five genera, Coricuma zurai sp. nov., Cyclaspis boquillensis sp. nov., Cyclaspis hyalinus sp. nov., Cumella (Cumewingia) carmeinae sp. nov., Elassocumella krakeri sp. nov. and Nannastacus corallinus sp. nov. The genus Coricuma Watling & Breedy, 1988, increases its geographical range from Costa Rica to Mexico, and a second species is described. Recorded for the first time in the Eastern Pacific are the genera Elassocumella Watling, 1991 and Nannastacus Bate, 1865. An annotated checklist and illustrated key to all species of cumaceans recognised from the Tropical Eastern Pacific are included. PMID- 26120671 TI - New species of scaly crickets (Orthoptera: Mogoplistinae) from Bukit Fraser, Malay Peninsula. AB - Two new species of Mogoplistinae from Bukit Fraser, Pahang of Malay Peninsula are described: Micrornebius malaya sp. n. and Ornebius albalatus sp. n. PMID- 26120672 TI - Caught in speciation? A new host for Conchodytes meleagrinae Peters, 1852 (Decapoda, Caridea, Palaemonidae). AB - During fieldwork in 2009 at Ternate, Indonesia, a pair of a pontoniine shrimp species belonging to the genus Conchodytes was collected from a bivalve mollusk of the genus Spondylus. This constitutes the first record of a species of the genus Conchodytes associated with a spondylid host. The specimens can be distinguished from other known Conchodytes species based on both morphology and colour pattern. Its COI barcode however, strongly resembles those obtained from three specimens of C. meleagrinae and is nested in the C. meleagrinae clade of the reconstructed phylogeny. Based on morphology and colouration only the specimens associated with the Spondylus bivalve would have been described as a species new to science. The modest conflicting molecular data have lead the authors to fully describe and figure the Spondylus associated specimens and compare them with the Pinctada associated specimens. Based on the present information it is decided not to give the Spondylus associated specimens the status as a distinct species but regard them as host-related (colour)morph of Conchodytes meleagrinae. PMID- 26120673 TI - Chauliodites niedzwiedzkii sp. n. (Grylloblattida: Chaulioditidae) from Triassic sediments of Poland. AB - A new representative of the family Chaulioditidae (Insecta, Grylloblattida), Chauliodites niedzwiedzkii sp. n., is described from the Upper Olenekian-Lower Anisian sediments of Palegi in Holy Cross Mountains, Poland. This is the first formal description of any fossil insect from Palegi area. PMID- 26120674 TI - A new species of Tyrannomyrmex (Hymenoptera: Formicidae) from Sri Lanka. AB - Tyrannomyrmex legatus sp. nov. is described based on a single worker collected from leaf litter in dipterocarp forest in southern Sri Lanka. A key is presented to separate the three known species of Tyrannomyrmex. A probable male specimen of the genus from the Philippines is noted. Tyrannomyrmex is placed within the tribe Solenopsidini and close to the genus Monomorium. PMID- 26120675 TI - Paracloeodes caldensis (Ephemeroptera: Baetidae), an atypical new species from the Colombian Andes. AB - In the present work, an atypical new species of Paracloeodes Day (Ephemeroptera: Baetidae) is described based on nymphs collected in the Caldas Department, Central Cordillera of Colombia. This represents the first report of the genus from Colombia. The main characteristics that distinguish the new species from congeners are: abundant setae on femora, antennae length twice the width of the head capsule, maxilla with palp twice the length of the galea-lacinia, segment II of the labial palp with a rounded projection and 2.5 times the width of segment III, tarsal claws half the length of their respective tarsi and the abdominal color pattern. The concepts of the genera Paracloeodes, Varipes and Rivudiva are discussed in light of the discovery of P. caldensis n. sp. PMID- 26120676 TI - New species of the genus Ontholestes Ganglbauer, 1895 (Coleoptera: Staphylinidae: Staphylininae) from Yakutia. PMID- 26120677 TI - New replacement name for the genus Longitergus Pham, Bai, Heiss & Cai, 2013 (Hemiptera: Heteroptera: Aradidae). PMID- 26120678 TI - Ontogenetic development and redescription of Tribolonychus collyerae (Acari: Tetranychidae). AB - Tribolonychus collyerae Zhang & Martin is redescribed based on the larva, protonymph, deutonymph and adult male and female specimens from New Zealand. The ontogenetic development of chaetotaxy in Tribolonychus and the number and position of solenidia on tibia I are discussed. Patterns of setal addition on leg III and IV from larva to adult in Trilobonychus are different from the basic pattern of the Tetranychinae and allied genus Neonidulus. PMID- 26120679 TI - A new species of the genus Sonotetranychus (Acari: Tetranychidae) from New Zealand. AB - The genus Sonotetranychus consisted of seven species prior to this study. Sonotetranychus menziesii sp. nov., collected on Nothofagus menziesii and N. fusca from New Zealand, is described based on females, protonymphs, deutonymphs and a male. An updated key to the species of Sonotetranychus is provided. PMID- 26120680 TI - Cossyphodini (Coleoptera: Tenebrionidae: Pimeliinae) in South Africa, Namibia and adjacent regions: New species and records, key to genera, and Old World species catalogue. AB - Cossyphodini Wasmann, 1899 (Tenebrionidae: Pimeliinae) from South Africa, Namibia and adjacent regions are revised, and newly collected material is presented. All species are figured, including as much as possible type specimens of African taxa for comparison. New species are described: Cossyphodes andreaei sp. n. and Cossyphodes caecus sp. n. (both South Africa), Cossyphodes naukluftensis sp. n. (Namibia). New synonyms include: Cossyphodes freudei Basilewsky, 1957 (Cossyphodes uhligi Ferrer, 2004 syn. n.), Cossyphodes wasmanni Reichensperger, 1915 (Cossyphodes brincki Andreae, 1961 syn. n., Cossyphodes reichenspergeri Andreae, 1961 syn. n.). Lectotypes are designated for Cossyphodes arnoldi Brauns, 1925 and Cossyphodes wasmanni Reichensperger, 1915. The aedeagus is of lesser value for species separation. Keys to the four genera in South Africa and adjacent regions, as well as species of Cossyphodes in South Africa are presented. A catalogue of all Cossyphodini from the Old World including full references is added. PMID- 26120681 TI - The taxonomic value of the structures for the insertion of the stylet muscles in the Eutardigrada, and description of a new genus. AB - The new genus Dastychius has been instituted for the species Isohypsibius improvisus Dastych, 1984. It has claws of the Isohypsibius type, rigid buccal tube without ventral lamina and with ridge-shaped apophyses for the insertion of the stylet muscles; peribuccal lamellae absent; peribuccal papulae seem to be present but the datum should be confirmed; pharyngeal bulb with apophyses and placoids, lunules present in the known species; smooth eggs laid in the exuvium. The apophyses for the insertion of the stylet muscles have some peculiarities that justify the institution of a new genus. They are long, uninterrupted ridges tailing off caudally almost reaching the stylet supports; at almost a quarter of their length they have an incision and a septum never noted in other genera of Eutardigrada. In the author's opinion it is possible to hypothesize that all the structures for the insertion of the stylet muscles recognizable in the Eutardigrada may be derived from long ridge-shaped apophyses (but without incision and septum). The comparison of the shape of the apophyses for the insertion of the stylet muscles in the Eutardigrada seems to indicate that this character has taxonomic value at level of genus but not at family level. PMID- 26120682 TI - Crenicichla taikyra (Teleostei: Cichlidae), a new species of pike cichlid from the middle rio Parana, Argentina. AB - Crenicichla taikyra, new species, is described from the middle rio Parana, Argentina. Crenicichla taikyra is distinguished from the other species of the genus by the following combination of characters: lower pharyngeal tooth plate stout, bearing molariform teeth, ascending arm of premaxilla longer than the dentigerous arm, posterior edge of preoperculum serrated, a well developed suborbital stripe, and absence of scattered dark dots on flanks. Molariform teeth on pharyngeal jaws is a derived character among Crenicichla species, however this character state has appeared several times in unrelated species. PMID- 26120683 TI - A new species of Neosclerocalyptus Paula Couto (Mammalia: Xenarthra: Cingulata): the oldest record of the genus and morphological and phylogenetic aspects. AB - Among South American Quaternary Glyptodontidae (Mammalia, Cingulata), Neosclerocalyptus Paula Couto represents one of the best known genera. Prior to this contribution, four species were recognized. N. pseudornatus (Ameghino) and N. ornatus (Owen) (Ensenadan Age/Stage, early-middle Pleistocene); N. gouldi Zurita (Bonaerian Age/Stage, middle Pleistocene-late Pleistocene), and N. paskoensis (Zurita) (Lujanian Age/Stage, late Pleistocene-early Holocene). One of the most notable characters of the species of the genus is a modified area located in the distal part of the nasals, recently interpreted as a neomorphic structure derived from the ossification of the nasal cartilages. In this contribution, a new species of Neosclerocalyptus (N. castellanosi sp. nov.), which in turn represents the oldest record of the genus, is presented and described. In addition, a cladistic analysis is carried out to test the monophyly of Neosclerocalyptus and the phylogenetic position of this new species. The material comes from Vorohuean (late Pliocene) levels in the surroundings of Mar del Plata, Buenos Aires Province, Argentina. Among other morphological characters, this new species has ossified nasal cartilages restricted to the latero-dorsal area of the nasals, whereas in the remaining species these structures are more expanded and both sides contact in the midline of the skull. In turn, the phylogenetic analysis confirmed the monophyly of Neosclerocalyptus, whereas N. castellanosi sp. nov. appears closely related to N. pseudornatus, being N. ornatus the sister taxa of this clade. On the other hand, N. gouldi + N. paskoensis constitute the other clade. The clade constituted by Hoplophorus euphractus Lund + Panochthus intermedius Lydekker constitutes the sister taxa of Neosclerocalyptus. PMID- 26120684 TI - Correction and addition to "Contribution to the knowledge of the Polia praecipua (Staudinger, 1895) species complex with description of a new species from China (Lepidoptera, Noctuidae, Noctuinae, Hadenini)". PMID- 26120685 TI - Checklist of Turkish Opiinae (Hymenoptera, Braconidae). AB - The Opiinae (Hymenoptera: Braconidae) species recorded from Turkey until the end of 2011 are listed, the present total number being 182. Changes with respect to the previous Turkish fauna are briefly annotated and the distributions for all the species in each of the 68 biogeographical provinces of Turkey are presented. After the publication of our previous fauna, 174 species have been recorded as new to Turkey. Of these, 105 species are distributed only in Asian Turkey and ten species are distributed only in European Turkey, while 73 species occur in both. The presented checklist covers synonyms, zoogeographical region(s), hosts, host plants of the host species and parasitoid data for the species. In total, 182 species belonging to ten genera are reported for Turkey. The number of species of each genus is represented by: Atormus van Achterberg, 1997: one; Biosteres Foerster, 1862: 17; Bitomus Szepligeti, 1910: three; Diachasma Foerster, 1862: one; Diachasmimorpha Viereck, 1913: one; Eurytenes Foerster, 1862: three; Indiopius Fischer, 1966: three; Opius Wesmael, 1835: 151, Psyttalia Walker, 1860: one; Sternaulopius Fischer, 1965: one. PMID- 26120686 TI - A new giant Atractus (Serpentes: Dipsadidae) from Ecuador, with notes on some other large Amazonian congeners. AB - We describe a new species of Atractus from Cordillera de los Guacamayos in the Andes of Ecuador. This new species is the largest known species of Atractus, reaching almost 120 cm in total length with a robust habitus. We also use multivariate statistical analyses of morphometric data to look into the taxonomic confusion involving other large, banded/blotched, species of Atractus in Western Amazonia. We show that A. snethlageae has a widespread distribution in Amazonia and has been repeatedly confused with A. major in Ecuador owing to its color polymorphism. Our multivariate statistical analyses support previous suggestions to recognize A. snethlageae as a distinct species relative to A. flammigerus. Taxonomic accounts are provided for both A. major and A. snethlageae including detailed color pattern descriptions. We also find that there are no valid morphological differences to support recognizing A. arangoi as a separate species from A. major; consequently we synonymize the former name with the latter. PMID- 26120687 TI - Namalycastis occulta n. sp. and a new record of N. borealis (Polychaeta: Nereididae: Namanereidinae) from the Northwestern Caribbean Sea. AB - The nereidid polychaete genus Namalycastis Hartman, 1959 has been recorded almost exclusively in non-marine environments. This genus includes species having four pairs of tentacular cirri, and its species mainly differ by the relative size of dorsal cirri in posterior chaetigers. Namalycastis occulta n. sp. is described based upon non-mature and mature specimens collected in the intertidal from Chetumal Bay, Quintana Roo, Mexico. Its distinctive features are the lack of notopodial spinigers, eyes, and teeth in the mandibles. Namalycastis borealis Glasby was found in Tamalcab Island, Chetumal Bay and it is the first record for Mexico. Analyses of the intraspecific variability, a key to the known species in the Grand Caribbean region, and commentaries about some taxonomic topics are also included. PMID- 26120688 TI - Comparative description of larvae of the European species of Distoleon Banks: D. annulatus (Klug, 1834) and D. tetragrammicus (Fabricius, 1798) (Neuroptera, Myrmeleontidae). AB - The third instar larva of Distoleon annulatus (Klug, 1834) is described for the first time and compared with the larva of the other known species of the genus in Europe: D. tetragrammicus (Fabricius, 1798). Diagnostic characters of the larvae of the genus Distoleon, as well as the interspecific differences, are provided and illustrated. Larvae of Distoleon appear to be morphologically conservative and they are mainly recognized by means of the pigmentation pattern. PMID- 26120689 TI - A new species of Dexoris (Coleoptera: Lycidae) and parallel evolution of brachyptery in the soft-bodied elateroid beetles. AB - Dexoris chome sp. nov. is described from South Pare mountains, Tanzania, based on a male specimen. This is the only Dexoris with shortened elytra, rudimentary hind wings and large, larviform abdomen. Unlike males of other species in the genus, D. chome sp. nov. has a modified number of palpomeres and remarkably short, robust legs and antennae. Such modifications are similar to those in the neotenic female of Omalisus fontisbellaquei Fourcroy, 1785 (Omalisidae), suggesting analogous morphological changes in unrelated lineages supposedly caused by similar modifications of their metamorphosis. The distribution of all 11 known species of African Dexoris closely overlap with the location of the hypothesized centres for evolution of new species in the Afrotropical region. PMID- 26120690 TI - Revision of the plant bug genus Cylapocoris Carvalho (Hemiptera: Heteroptera: Miridae: Cylapinae), with descriptions of seven new species from Costa Rica, Brazil, Ecuador, and Venezuela. AB - The plant bug genus Cylapocoris Carvalho, 1954 is revised. Seven new species: Cylapocoris costaricaensis sp. nov., C. cucullatus sp. nov., C. fulvus sp. nov., C. laevigatus sp. nov., C. marmoreus sp. nov., C. plectipennis sp. nov., and C. simplex sp. nov. are described from Costa Rica, Brazil, Ecuador, and Venezuela. The genus Adcylapocoris Carvalho, 1989 is synonymized with Cylapocoris. Five species: C. castaneus (Carvalho, 1989), C. funebris (Distant, 1883), C. pilosus Carvalho, 1954, C. sulinus Carvalho & Gomes 1971, and C. tiquiensis Carvalho, 1954 are redescribed. Illustrations of the male genitalia, color photographs of dorsal and lateral views of the adult of most species, scanning electron micrographs of selected structures of C. simplex, and keys to species of the genus Cylapocoris are provided. PMID- 26120691 TI - New species and records of Scolytodes (Coleoptera, Curculionidae: Scolytinae) from South America. AB - Seventeen new species of Scolytodes Ferrari are described from Venezuela, Ecuador, Peru, Bolivia and Argentina: Scolytodes cenchros, S. concavifrons, S. conpunctus, S. fraterniatratus, S. frontocarinatus, S. solarius and S. trigonus from Cecropia leafstalks; S. pascopomus from a fruit husk; S. obovatus, S. clusiaphilus, S. clusiapraelatus and S. uniseriatus from Clusia litter sifting; S. grossepunctatus and S. fulvus from general litter sifting; and S. inusitatus, S. sagittarius and S. sus collected by flight intercept traps. The synonymy of S. imitans and S. nitidissimus is confirmed. Additional South American records are given for S. chapuisi (Ecuador), S. interpunctatus (Peru), S. maurus (Ecuador), and S. suspectus (Ecuador), all taken from Cecropia leafstalks, and S. similis (Peru) and S. unipunctatus (Bolivia). PMID- 26120692 TI - The structure and musculature of male terminalia in the tribe Xanthorhoini Pierce and related tribes (Lepidoptera: Geometridae: Larentiinae), with particular reference to the Palaearctic and Australian regions. AB - The musculature of the male genitalia was reviewed for the tribe Xanthorhoini and related tribes (Lepidoptera, Geometridae, Larentiinae). The genitalia morphology of males of 11 species was discussed and illustrated, and nine paired and unpaired genital muscles identified. Muscles m1, m2(10), m5(7), m6(5), m7(6), m8(3) and m21 have similar position in all species considered in the paper. Comparative morphology of the male terminalia and position of extensors of the valvae m3(2) and flexors m4 confirmed the previously uncertain separation of Euphyiini and Scotopterygini. Cataclysmini share musculature characters with the tribe Xanthorhoini. The generic affiliation of Xanthorhoe biriviata (Borkhausen) is questionable considering an unusual location of muscles m4. Generally, the places of attachment of the muscles m3(2) and m4 to the sclerites afford valuable characters for the higher classification of this group. PMID- 26120693 TI - Taxonomy and biology of a new species of Pincushion Millipede of the genus Monographis (Diplopoda: Polyxenidae) from Australia. AB - Monographis queenslandicus n. sp. is described from Brisbane, Queensland, Australia. The genus Monographis may be divided into two groups based on the arrangement of sensilla on the 6th antennal article. Species with a crescent shape arrangement are M. kraepelini, M. annandalei, M. baihualingensis, M. demangei and M. mirus; species with a triangular arrangement are M. tamoyensis, M. yunnanensis and M. queenslandicus n. sp. PMID- 26120694 TI - Nesting biology of Paravespa rex (von Schulthess 1924) (Hymenoptera: Vespidae: Eumeninae) in the Crimea, Ukraine. AB - Paravespa rex is the only species of the wasp genus Paravespa that occurs in Europe. Females of this species nest in clay loam soil of proluvial terraces and deluvial aprons of badlands. The nests are vertical burrows 10-12 cm deep, surmounted by turrets of two distinct architectural forms: funnel-shaped and curved. The nests contain 1-3 vertical cells (mean-1.9) not different from the other parts of nest burrow. An egg is laid onto the bottom of the cell without attaching; it stands vertically via the moist adhesive surface of the bottom and then with the help of the position of the first prey, which is laid around the egg. The species is univoltine; prepupae hibernate in the cocoon for one or several years. Females hunt for caterpillars of two species of the noctuid genus Heliotis; 3-7 caterpillars (mean-3.7) are stored per cell. Adult feeding is recorded on flowers of Thymus tauricus. Males look for females at their water collecting sites. Only a third of the cells are successful; the other ones are damaged by rain and the gold wasp, Chrysis valesiana, parasitizing in the nests. Nest-building and hunting activity of the species is described with the duration of certain nesting acts. Nesting biology of Paravespa species, rarity of P. rex, turret function, egg position, and measures for species conservation are discussed. PMID- 26120695 TI - New species of Drymopsalta Heath Cicadas (Cicadidae: Cicadettinae: Cicadettini) from Queensland and Northern Territory, Australia, with overview of genus. AB - Three new species are described in the genus Drymopsalta Ewart, previously known only from D. crepitum Ewart and D. daemeli Distant. The three new species occur in Southern Queensland and Northern Territory. D. wallumi sp. nov. occurs along coastal S.E. Queensland, whereas D. hobsoni sp. nov. is restricted to the Bringalily State Forest, near Inglewood, southern inland Queensland. D. acrotela sp. nov. is found in the Litchfield National Park and other locations near Jabaluka, Cahills Crossing, E. Alligator River and Nourlangie, all across the northern Northern Territory. D. crepitum occurs on the Cape York Peninsular extending into the southern Gulf, while D. daemeli occurs in two localised regions in central coastal N.S.W. Each of the species inhabits heath vegetation, often spilling-over into adjacent tree foliage. The species of Drymopsalta are small and inconspicuous cicadas (< 15 mm body length) with relatively high frequency songs (~15 to 22 kHz). The temporal structures of the normal calling songs follow a similar pattern in each species, consisting of the emission of short chirps (comprising 2-16 ticks). Between the chirps are emitted one (D. wallumi, D. hobsoni, D. acrotela), two (D. daemeli) or 1-9 (D. crepitum) intervening single ticks. The species can be distinguished by the timing and the number of these single ticks relative to the adjacent chirps with the notable exception of D. hobsoni and D. acrotela. The calling songs of these two allopatric species are indistinguishable, an unusual feature in Australian cicadas. Two additional song variants are described, a more unstructured chirping song without intervening single ticks observed in each of the species except D. crepitum, and periodic extended buzzing echemes emitted within the calling songs (excepting the D. wallumi song). PMID- 26120696 TI - Serina Gredler (Gastropoda, Stylommatophora: Enidae), the continuous-peristomed mountain snails endemic to the eastern slope of the Qinghai-Xizang Plateau. AB - In this paper we initiate a taxonomic review of the genus Serina Gredler, endemic to the eastern slope of the Qinghai-Xizang Plateau, namely S Gansu, SW Sichuan, SE Xizang Autonomous Region and N Yunnan of China. We describe the genital anatomy for some species and the shell morphology for all known species: Serina belae (Hilber), S. cathaica Gredler, S. egressa Sturany, S. prostoma (Ancey), S. ser Gredler, S. subser Gredler, S. soluta (Mollendorff) and S. vincentii (Gredler). Based on the re-evaluation of both shell and genitalian differentiations we prefer to classify the taxon egressa as a separate species rather than a subspecies of S. ser. In our study we come to the conclusion that S. soluta inflata Yen and S. soluta stenochila (Mollendorff) should be regarded as synonyms of S. soluta due to the insufficient differentiation among them. Buliminus (Holcauchen) tubios Annandale, Bulimus prostoma leucochila Ancey and Serina deqenensis Chen, Zhou and Luo were conspecific with Serina prostoma and that Serina sobrina (Preston) was conspecific with Clausiliopsis szechenyi (Bottger). We propose a new species Serina denticulata n. sp. from the Southern Gansu Plateau. Furthermore we discuss the phylogenetic relationship among the genera Serina, Clausiliopsis Mollendorff, Pupopsis Gredler, and Pupinidius Mo1lendorff based on the morphological data from twelve relevant species. PMID- 26120697 TI - Revision of species of the genus Tephritis Latreille 1804 (Diptera: Tephritidae) with entire apical spot. AB - Eleven species of the genus Tephritis with an uncommon banded wing pattern and/or solid apical crossband/spot instead of apical fork, mainly from the Palaearctic Middle East, are described and keyed, including Tephritis afrostriata new species, T. cameo new species, T gladius new species, T. ochroptera new species, and T. robusta new species. The following synonymy is established: Tephritis admissa Hering 1961 = T. conflata Dirlbek & Dirlbek 1995 new synonym. Lectotypes for T. angulatofasciata Portschinsky 1892 and T. tatarica Portschinsky 1892 are designated. New distribution records are reported. Tephritis tatarica is recorded to be reared Alfredia nivea Kar. et Kir.; T. admissa, T. cameo, T. gladius, and T. ochroptera were swept from Cousinia spp., which very probably are their host plants. PMID- 26120698 TI - A review of the anglerfish genus Chaunax (Lophiiformes: Chaunacidae) from New Zealand and adjacent waters, with descriptions of four new species. AB - Species of the anglerfish genus Chaunax Lowe, 1846 from the New Zealand region are taxonomically reviewed with six species recognized and described: Chaunax penicillatus McCulloch; C. nudiventer Ho & Shao, a new record for New Zealand; and four species new to science. Chaunax flavomaculatus sp. nov. distinguished by having its skin covered with a mix of numerous bifurcated and simple spinules, large yellow spots on dorsal surface of fresh specimens, and brownish coloured escal cirri; Chaunax mulleus sp. nov. by having a uniformly pink body with a deep red colour on ventral surfaces of the outer pectoral-fin and pelvic-fin, and lower part of caudal fin; Chaunax reticulatus sp. nov. by having cirri on the dorsal surface of head, and a pale reticulate colour pattern on a greyish background dorsally; and Chaunax russatus sp. nov. by its very wide illicial trough that is usually as wide or wider than the diameter of the pupil, and uniformly deep red body colour with creamy white to fuzzy greyish spots or patches on its dorsal surface. A key to species recognized from the study area is given. PMID- 26120699 TI - Lost and found: One of the world's most elusive amphibians, Pseudophilautus stellatus (Kelaart 1853) rediscovered. AB - Pseudophilautus stellatus (Kelaart 1853) has been rediscovered from the Peak Wilderness, Central Hills of Sri Lanka. The species, till now known only from its lost holotype, was the first shrub frog described from Sri Lanka, and had not been reported since then. It was thought to have become extinct for nearly 157 years, being the amphibian species "lost" for the longest amount of time. Here we designate a neotype from the material collected at what we consider its type locality, having considered characters of the lost holotype and provide a complete description. We have conducted a molecular phylogenetic analysis, on which basis the species is well differentiated from all other Pseudophilautus sequenced so far, and placed in a clade together with P. femoralis, P. frankenbergi, P. mooreorum, and P. poppiae. PMID- 26120700 TI - Biology and systematics of gall-inducing triozids (Hemiptera: Psylloidea) associated with Psidium spp. (Myrtaceae). AB - Psidium myrtoides (Myrtaceae) shelters the gall inducer Nothotrioza myrtoidis gen. et sp. n. (Hemiptera: Psylloidea) which is described and illustrated here. Nothotrioza belongs to the family Triozidae and is probably most closely related to Neolithus, a monotypic Neotropical genus associated with Sapiun (Euphorbiaceae). Three species are recognized within Nothotrioza: the type species N. myrtoidis sp. n. associated with Psidium myrtoides, N. cattleiani sp. n. (misidentified by Butignol & Pedrosa-Macedo as Neotrioza tavaresi) with Psidium cattleianum, and N. tavaresi (Crawford) comb. n. (from Neotrioza) with an unidentified species of Malpighiaceae, respectively. A lectotype is designated here for Neotrioza tavaresi. Also, the diversity of insect galls associated with P. myrtoides and the biology of N. myrtoidis were examined. N. myrtoidis presents five instars and an annual life cycle synchronised with the phenology of P. myrtoides. Gall size was proportional to the insect developmental stages, and rates of parasitism and mortality were 15.7 % and 29.8 %, respectively. The red colour is an important macroscopic diagnostic feature of the gall that could be associated with parasite-free condition of the galling insect. The biological features presented by the system Psidium myrtoides--Nothotrioza myrtoidis are in accordance with other systems involving sucking galling insects, however, it is exceptional by its univoltine life cycle associated with a perennial plant in the Neotropics. The galls induced by the three known Nothotrioza spp. are morphologically similar, i.e. closed, globoid and unilocular, as well as the opening mechanism for releasing the adults. PMID- 26120701 TI - Morphometric and bioacoustic data on three species of Pseudopaludicola Miranda Ribeiro, 1926 (Anura: Leptodactylidae: Leiuperinae) described from Chapada dos Guimaraes, Mato Grosso, Brazil, with the revalidation of Pseudopaludicola ameghini (Cope, 1887). AB - Due to minute size, overall morphological similarities, scarcity of diagnostic characters after preservation, and usual sympatric or even syntopic occurrence of two or more species of Pseudopaludicola, the taxonomy of the genus is not yet a matter of consensus. Three species in the genus Pseudopaludicola Miranda-Ribeiro, 1926 were described by Cope in 1887, based on material obtained at Chapada dos Guimaraes, mid-western state of Mato Grosso, Brazil. One of these species, Pseudopaludicola ameghini, was subsequently synonymized to P. mystacalis. In this paper we present morphological and bioacoustic evidences supporting a full specific status for the three sympatric species of Pseudopaludicola described from Chapada dos Guimaraes, including Pseudopaludicola ameghini Cope, 1887. PMID- 26120702 TI - A new species of Andean poison frog, Andinobates (Anura: Dendrobatidae), from the northwestern Andes of Colombia. AB - The poison frogs of the Colombian Andes, Pacific lowlands and Panama have been recently recognized as a new, monophyletic and well-supported genus: Andinobates. The species richness and distribution within Andinobates remain poorly understood due to the paucity of geographic, genetic and phenotypic data. Here we use a combination of molecular, bioacoustic and morphometric evidence to describe a new species of Andean poison frog: Andinobates cassidyhornae sp. nov. from the high elevation cloud forests of the Colombian Cordillera Occidental, in the northwestern Andes. The new species is associated to the bombetes group and characterized by a unique combination of ventral and dorsal color patterns. Data on 1119 bp from two mitochondrial markers allowed us to reject the null hypotheses that A. cassidyhornae sp. nov. is part of the phenotypically similar and geographically less distant species: A. opisthomelas, A. virolinensis or A. bombetes. The best available phylogenetic trees and the genetic distance to other Andinobates species further support this decision. Altogether, the advertisement call parameters unambiguously separated A. cassidyhornae sp. nov. calls from the calls of the three closest species. The new species adds to a poorly known and highly endangered genus of poison frogs that requires further studies and urgent conservation measures. PMID- 26120703 TI - A new species of salamander (Caudata: Plethodontidae, Bolitoglossa) from Sierra Nevada de Merida, Venezuela. AB - In this article, a new species of salamander of the genus Bolitoglossa (Eladinea) from the cloud forest near La Mucuy in Sierra Nevada de Merida, Venezuelan Andes, is described. Bolitoglossa mucuyensis sp. nov. differs from all Venezuelan salamanders, except B. orestes, by a larger SVL/TL ratio, and from La Culata salamander B. orestes by a reduced webbing extension of the front and hind limbs. Additionally, B. mucuyensis sp. nov. and B. orestes diverge 3.12% in terms of the nucleotide sequence of the 16S rRNA gene, as previously reported, and in 8.1% for the cytb gene as shown in this study. PMID- 26120704 TI - Two new species of Distaplia (Tunicata: Ascidiacea) from the SW Atlantic, Argentina. AB - The ascidian fauna from the Southwestern Atlantic (Argentine Sea) have scarcely been studied and have rarely been sampled. The existing scanty ascidian records are from specimens collected by dredging many decades ago. During samplings in the San Matias Gulf (Rio Negro, Patagonia), two new Distaplia species were found. Distaplia naufragii sp. nov. was collected in the subtidal zone attached to a shipwreck, while the other species, Distaplia fortuita sp. nov. was found released by the tides in the sandy intertidal zone. These two new species differ deeply from each other in the size and morphology of their zooids. They represent one third of the known species belonging to the family Holozoidae in the SW Atlantic. These results reinforce the importance of new studies in this extensive but little explored area that is, in addition, susceptible to invasion by non native species. PMID- 26120705 TI - Chewing lice of genus Myrsidea (Phthiraptera: Menoponidae) from Turdidae (Passeriformes) of Costa Rica, with descriptions of seven new species. AB - A total of 166 individuals from 10 bird species belonging to the family Turdidae were examined for chewing lice in Costa Rica during 2004, 2009 and 2010. A total of 12 species of the louse genus Myrsidea were collected from 54 birds, including four previously named, seven new undescribed species, and one identified as Myrsidea sp. Names, descriptions and illustrations are given for the seven new species of Myrsidea. They and their type hosts are: Myrsidea assimilis sp. nov. ex Turdus assimilis (Cabanis, 1850), M. cerrodelamuertensis sp. nov. ex Catharus gracilirostris (Salvin, 1865). M. hrabaki sp. nov. ex Myadestes melanops (Salvin, 1865), M. obsoleti sp. nov. ex Turdus obsoletus (Lawrence, 1862), M. quinchoi sp. nov. ex Catharus frantzii (Cabanis, 1861), M. tapanti sp. nov. ex Catharus fuscater (Lafresnaye, 1845), and M. tapetapersi sp. nov. ex Turdus nigrescens (Cabanis, 1861). Records of four named and one unidentified species of Myrsidea from other Costa Rican thrushes are also given and discussed. PMID- 26120706 TI - Descriptions of the final instar larvae of seven Chinese Chlorogomphidae species, with taxonomic notes on adults (Odonata: Anisoptera). AB - The larvae of seven species of Chlorogomphidae from South China are described based on reared larvae, i.e. Chlorogomphus kitawakii Karube, C. nasutus nasutus Needham, C. papilio Ris, C. shanicus Wilson, C. usudai Ishida, C. yokoii Karube and Chloropetalia soarer Wilson. The adult female of C. kitawakii is first described. Biological information on Chlorogomphidae is provided and a diagnosis of the family proposed. PMID- 26120707 TI - A lost species or the loss of stripes? The case of Contomastix lizards from Cabo Polonio, Uruguay, with observations on C. lacertoides (Dumeril & Bibron) and Cnemidophorus grandensis Cope (Squamata, Teiidae). AB - The main goal of this manuscript is the reevaluation of the taxonomic status of the teiid lizard Contomastix charrua, known only from Cabo Polonio, a small coastal rocky outcrop in southeastern Uruguay. This species was erected on the basis of the presence of a second pair of ceratobranchials and longer cornua in the hyoid bone, in addition to a reduced expression of the pattern of coloration as compared with C. lacertoides. Nevertheless, we found that both species have indistinguishable hyoid morphology, bearing C. lacertoides a noticeable second pair of ceratobranchials. Besides, we realized that the pattern of coloration in this species is more variable than previously considered. As a result of the present work, C. charrua is included in the synonymy of C. lacertoides. In addition, we provide some observations on the holotype of Cnemidophorus grandensis, a junior synonym of C. lacertoides. PMID- 26120708 TI - The complete mitochondrial genome of a tessaratomid bug, Eusthenes cupreus (Hemiptera: Heteroptera: Pentatomomorpha: Tessaratomidae). AB - The 16,299 bp long mitochondrial genome (mitogenome) of a tessaratomid bug, Eusthenes cupreus (Westwood), is reported and analyzed. The mitogenome represents the first sequenced complete mitogenome of the heteropteran family Tessaratomidae. The mitogenome of E. cuopreus is a typical circular DNA molecule with a total AT content of 74.1%, and contains 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, two ribosomal RNA (rRNA) genes, and a control region. The gene arrangement is identical with the most common type in insects. Most PCGs start with the typical ATN codon, except that the initiation codon for COI is TTG. All tRNAs possess the typical clover-leaf structure, except tRNASer(AGN), in which the dihydrouridine (DHU) arm forms a simple loop. Six domains with 45 helices and three domains with 27 helices are predicted in the secondary structures of rrnL and rrnS, respectively. The control region is located between rrnS and tRNA(Ile), including some short microsatellite repeat sequences. In addition, three different repetitive sequences are found in the control region and the tRNA(Ile)-tRNA(Gln)-tRNA(Met)-ND2 gene cluster. One of the unusual features of this mitogenome is the presence of one tRNA(Gln)-like sequence in the control region. This extra tRNA(Gln)-like sequence is 73 bp long, and the anticodon arm is identical to that of the regular tRNA(Gln). PMID- 26120709 TI - Redescription of Parapercis macrophthalma (Pietschmann, 1911) and description of a new species of Parapercis (Pisces: Pinguipedidae) from Taiwan. AB - Parapercis macrophthalina is confirmed as a valid species and redescribed on the basis of the holotype and other specimens collected from the type locality, Taiwan, and Japan. It is morphologically similar to P. muronis Tanaka, 1918, but differs in having five vertical transverse bars that extend well below the lateral line versus five oblique transverse bars, with the third to fifth bars ending on or above the lateral line. A new species is also described on the basis of a specimen collected from southwestern Taiwan. It is distinct in having numerous pores interconnected by canals on the head, forming 10 vertical or oblique rows on the cheek and opercular apparatus, predorsal scales extending to the level of the posterior margin of the eye, four dorsal-fin spines, six oblique bars laterally on the body, and a combination of other characters. A key to species of Parapercis with narrow transverse bars on the upper body is provided. PMID- 26120710 TI - Two new species of Protimesius from northern Brazil (Opiliones: Laniatores: Stygnidae). AB - Two new species of Protimesius Roewer, 1913 (Stygnidae), are described from northern Brazil. Protimesius regalo sp. nov. is described from Lageado, state of Tocantins. This is a large species and can be easily distinguished from the already described species of Protimesius by the presence of four apical mesal acute tubercles on tibia IV and two dorsal rows of tubercles on male patella IV. Protimesius jirau sp. nov. is described from Porto Velho, state of Rond6nia. This species is similar to P. cirio in having a large, pointed, dorso-apical apophysis on the male trochanter IV. However, it can be distinguished from P. cirio by the absence of a ventral row of tubercles on the male femur IV, as well as the presence of a ventral row of tubercles and two postero-distal apophyses on the male tibia IV. A new cladistic analysis for the genus is presented, and a key is given for the 18 species of Protimesius for which males are known. PMID- 26120711 TI - A new fossil caridean shrimp (Crustacea: Decapoda) from the Cretaceous (Albian) of the Romualdo Formation, Araripe Basin, northeastern Brazil. AB - A new fossil caridean shrimp, Kellnerius jamacaruensis n. gen. n. sp., of the early Cretaceous (Albian) from the Romualdo Formation, Araripe Basin, northeastern Brazil is described and illustrated. The new species is compared to known fossil palaemonids found in Brazil. Kellnerius jamacaruensis n. gen. n. sp. is easily differentiated from the other palaemonids by a rostrum with 5 spines, an enlarged scaphocerite that is longer than the rostrum, and a third somite with a distinct groove in the tergite that does not extend to the pleurite. PMID- 26120713 TI - The Cholevinae of Romania (exclusive of Leptodirini) (Coleoptera, Leiodidae) with special reference to the hypogeal records. AB - The first catalogue of the Romanian Cholevinae (excluding Leptodirini) is presented, based on revised and new records. The overall distribution and distribution in Romania are documented for every species, with particular reference to subterranean environment (caves and subterranean superficial environment). Epigeal and hypogeal records are listed separately. Thirty two of forty nine species group taxa recorded in the Romanian fauna occur both in the epigeal and subterranean environment, 14 of them frequently recorded in the latter. Many species, dependant on the subterranean environment during certain stages of their life cycle, are considered troglophilic or subtroglophilic: Choleva cisteloides dacica Jeannel 1922, Ch. glauca Britten, 1918, Catops picipes Fabricius, 1792, C. longulus Kellner, 1846 and C. tristis Panzer, 1874. The Romanian fauna of Cholevinae is more similar to that of the Central Europe than the Balkan Peninsula. PMID- 26120715 TI - Contribution to the knowledge of Chinese Phasmatodea I: A review of Neohiraseini (Phasmatodea: Phasmatidae: Lonchodinae) from Hainan Province, China, with descriptions of one new genus, five new species and three new subspecies, and redescriptions of Pseudocentema Chen, He & Li and Qiongphasma Chen, He & Li. AB - This study deals with three genera, seven species and four subspecies of the tribe Neohiraseini Hennemann & Conle, 2008 from Hainan Province, China. The genera Pseudocententa Chen, He & Li, 2002 and Qiongphasma Chen, He & Li, 2002 are revised and redescribed, including descriptions of four new species, P. liui spec. nov., Q. bispinosus spec. nov., Q. huishanensis spec. nov. and Q. wuzhishanense spec. nov., and three new subspecies, Q. bispinosus bispinosus subspec. nov., Q. b. minor subspec. nov. and Q. jianfengense obtusicristata subspec. nov. First descriptions are given for the male and egg of Pseudocentema bispinatum Chen & He, 2002 and for the female of Q. jianfengense jianfengense Chen & He, 2002 sen. str. A new genus, Neoqiongphasma gen. nov., is established for N. diaoluoshanensis spec. nov., distinguished from Pseudocentema by its spinose thorax and from Qiongphasma by its unarmed head. PMID- 26120714 TI - Symphurus orientalis (Bleeker) redefined based on morphological and molecular characters (Pleuronectiformes: Cynoglossidae). AB - Aphoristia (= Symphurus) orientalis Bleeker 1879, collected from an unspecified depth and location in Japanese waters, is the first described species of symphurine tonguefish from Indo-Pacific waters. The original description with accompanying illustration is based on the unique holotype specimen and provides limited diagnostic characters for this taxon. Subsequent to its description, the holotype of A. orientalis has been lost. Limited diagnostic information and loss of the holotype have caused considerable confusion to subsequent systematic studies regarding the identity of this and similar tonguefish species occurring in the Indo-West Pacific region. Several, often-cited, taxonomic accounts purportedly redescribing S. orientalis are erroneous because they include more than one species in these redescriptions. These erroneous redescriptions not only confused the species concept of S. orientalis (Bleeker), but also confounded the systematics of similar Indo-West Pacific tonguefishes. Symphurus novemfasciatus Shen and Lin, described on two specimens collected in southern Taiwan, shares many morphological and pigmentation features similar to those of S. orientalis. Morphological data from a large series of tonguefishes collected in Taiwanese and Japanese waters, as well as molecular data from a smaller number of specimens from these locations, including the type locality of S. novemfasciatus, confirm the presence of only one species, S. orientalis (Bleeker), among these specimens. Symphurus novemfasciatus Shen and Lin is therefore regarded as ajunior subjective synonym of S. orientalis. Symphurus orientalis is redefined based on a large series of specimens identified by a consistent set of morphological criteria, and a neotype is designated to stabilize nomenclature and systematics of this species. Symphurus orientalis differs from congeners by its combination of: a predominant 1-2-2-2-2 pattern of interdigitation of proximal dorsal-fin pterygiophores and neural spines, 12 caudal-fin rays, 9 abdominal and 52-55 total vertebrae, four hypurals, 96-101 dorsal-fin rays, 82-89 anal-fin rays, 87-99 longitudinal scale rows, 37-42 transverse scales, 5-11 (usually) distinct, complete or incomplete, blackish-brown crossbands on the ocular side, uniformly white blind side, and conspicuous bluish-black peritoneum. Documenting morphological variation for S. orientalis represents the most important step towards clarification of the identity of this and other symphurine tonguefish species from this region. Reliable identification of specimens of S. orientalis also provides the foundation for evaluating the status of several other, poorly known, nominal species of Indo-West Pacific tonguefishes that have features similar to those of S. orientalis. Improved identifications will lead to better knowledge on the geographic distribution of S. orientalis and these other species, as well as to improve estimates of biodiversity and the biogeography of Indo-West Pacific symphurine tonguefishes. PMID- 26120712 TI - Taxonomy of the super-cryptic Hyperolius nasutus group of long reed frogs of Africa (Anura: Hyperoliidae), with descriptions of six new species. AB - Specimens from across the range of the Hyperolius nasutus species group were sequenced for two mitochondrial genes and one nuclear gene. Advertisement calls were recorded from the same specimens where possible, and morphological characters were compared. Bayesian inference and maximum likelihood produced a tree indicating 16 clades. The clades show little or no overlap in combinations of 16S sequence difference, shared tyr haplotypes, advertisement call parameters, snout profiles and webbing. On the basis of these data we recognise H. acuticeps, H. adspersus, H. benguellensis, H. dartevellei, H. igbettensis, H. nasutus, H. nasicus, H. poweri, H. viridis and describe six new species: Hyperolius friedemanni sp. nov. Mercurio & Rodel, Hyperolius howelli sp. nov. Du Preez & Channing, Hyperolius inyangae sp. nov. Channing, Hyperolious jacobseni sp. nov. Channing, Hyperolius rwandae sp. nov. Dehling, Sinsch, R6del & Channing, and Hyperolius lupiroensis sp. nov. Channing. Hyperolius lamottei is confirmed to be outside the H. nasutus group clade. Hyperolius granulatus, H. oxyrhynchus, H. punctulatus and H. sagitta are assigned as junior synonyms. As our results are based on a small number of specimens, these hypotheses await testing with larger sample sizes and more characters. A species distribution model suggests where outlier populations might be found. PMID- 26120716 TI - Revision of the Indian Microplitis Foerster (Hymenoptera: Braconidae: Microgastrinae), with description of one new species. AB - The Indian fauna of the genus Microplitis Foerster, 1862 is revised. An illustrated key to eight species including the description of one new species, M. murkyi sp. nov., is provided. Six previously described species, namely: M. ajmerensis Rao & Kurian, M. demolitor Wilkinson, M. indicus Marsh, M. manilae Ashmead, M. prodeniae Rao & Kurian, and M. spodopterae Rao & Kurian are elaborated with taxonomical variations and extended distribution. Two species, M. bageshri Sathe, Inamdar & Dawale and M. dipika (Bhatnagar) are considered incertae sedis. A new combination is suggested for Snellenius maculipennis (Szepligeti) which is placed into synonymy with Microplitis. Information on taxonomic history of the genus, diagnostic characters of all the included species, distribution and host relationships are provided. PMID- 26120717 TI - Review of the bamboo-feeding species of tribe Evacanthini (Hemiptera: Cicadellidae) with description of two new species from China. AB - The bamboo-feeding species of tribe Evacanthini are reviewed. They include 9 genera and 13 species: Angustella leucostriata Li & Wang, 1991, Boundarus nigronotus Zhang, Zhang & Wei, 2010a, Carinata kelloggii (Baker, 1923), C. nigrofasciata Li & Wang, 1994a, Convexana fleura Chen, Yang & Li, 2012, Evacanthus repexus Distant, 1908, Onukia guttata Li & Wang, 1991, O. nigra Li & Wang, 1991, Parapythatnus suiyangensis Li & Li, 2011, Taperus fasciatus Li & Wang, 1994b, T. luchunensis Zhang, Zhang & Wei, 2010b and the two new species, Bundera bambusana sp. nov. and Paraonukia wangnioensis sp. nov. The new species are described and all the species are photographed and illustrated. A key to these 13 species is also given. PMID- 26120718 TI - Orchidophaga gastrodiacola Kato, 2006, is Chyliza vittata Meigen, 1826 (Diptera: Psilidae): discussion on its taxonomy and biology. AB - Morphological features of a Japanese fly that developes in orchids, Orchidophaga gastrodiacola Kato, 2006, assigned to the family Scathophagidae, are reviewed and this species is proposed as a junior synonym of Chyliza vittata Meigen, 1826, of the family Psilidae. Morphological features of specimens from Japan correspond well with those from European. Japanese specimens of this transpalaearctic species utilize buds and stems of the achlorophyllous mycoheterotrophic Gastrodia elata Blume. This association is an exceptional habitat in comparisons to other congeners and European specimens of the same species. PMID- 26120719 TI - A new synonym of Sericothrips from China and Japan (Thysanoptera: Thripidae). AB - Nine species are listed in the genus Sericothrips (Thripidae: Sericothripinae) (Mound 2013), and all of these species have the abdominal tergites completely covered with microtrichia medially (Mound & Tree 2009). S. marginalis Kud6 was described from Japan on a large number of specimens, including a micropterous holotype and macropterous females and micropterous males. These specimens were collected from plants in the families Poaceae and Fabaceae (Kudo 1991). Specimens from Japan were examined by the first author (including one paratype in SCAU), and three paratypes were also checked by the second author and compared with Chinese specimens of S. houji (Chou & Feng 1990). We were not able to find any character differences between these two species, and therefore place S. marginalis in synonymy with S. houji. PMID- 26120720 TI - A review of the ecology and distribution of Protoribates (Oribatida, Oripodoidea, Haplozetidae) in Alberta, Canada, with the description of a new species. AB - The oribatid mite genus Protoribates Berlese (Haplozetidae) is reviewed for North America and the genus diagnosis is revised to account for the North American species, Protoribates robustior (Jacot, 1937) is redescribed and newly reported from western North America and a new species from Alberta is described. Protoribates haughlandae sp. n. is bisexual, heterotridactylous, and lives primarily in the peat soils of fens and bogs. Protoribates robustior is all female, monodactylous, and occurs primarily in dry forests or in dry, treeless sites dominated by grasses, sedges, and shrubs. Both species feed on fungal hyphae and spores, but P. haughlandae also is an opportunistic predator and/or necrophage of small arthropods and P. robustior gut contents often include material that resembles plant cell walls. Examination of type specimens confirms that Protoribates prionotus (Woolley, 1968) is a junior synonym of the widespread Protoribates lophotrichus (Berlese, 1904). A key to differentiate Lagenobates from Protoribates and to identify the 7 species of the latter that are known or reported from North America is provided. PMID- 26120721 TI - The Protohermes dichrous species group (Megaloptera: Corydalidae), with description of two new species from eastern Malaysia. AB - A dobsonfly species group, the Protohermes dichrous group, endemic to Borneo, is characterized by the straight directed male ninth gonostylus with a narrow base and the elongate male ectoproct. Protohermes goodgeri sp. nov. and P. karubei sp. nov. from northern Borneo (eastern Malaysia) are herein described as new species placed in the P. dichrous group. PMID- 26120722 TI - Three new species of Kerria (Hemiptera: Sternorrhyncha: Coccoidea: Tachardiidae), a redesciption of K. yunnanensis Ou & Hong, and a revised key to species of Kerria. AB - Three new species of lac insect, Kerria Targioni-Tozzetti viz., Kerria manipurensis Ahmad & Ramamurthy sp. nov., Kerria maduraiensis Ahmad & Ramamurthy sp. nov., and Kerria thrissurensis Ahmad & Ramamurthy sp. nov. are described and illustrated. Kerria yunnanensis Ou & Hong is illustrated and redescribed, and a key to the known species of Kerria is provided. The usefulness of star pores as a diagnostic character in the subgeneric divisions of Kerria is also discussed. PMID- 26120723 TI - Two new species of Xenysmoderodes from China (Coleoptera: Curculionidae: Ceutorhynchinae). AB - Xenysmoderodes Yoshitake, 2007, belonging to the tribe Mecysmoderini, was described as a monotypic genus from Japan, including the species X. sasajii Yoshitake. Two new species, X. concavius sp. nov. and X. flos sp. nov., are described here from China, providing a new country record for this genus. We revise the description of the genus based on three species and present an updated key to the species. PMID- 26120724 TI - Review of the genus Cassidinoma Hincks (Coleoptera: Chrysomelidae: Cassidinae: Omocerini). AB - The Neotropical genus Cassidinoma Hincks is revised. A new synonymy is proposed: Cassidinoma denticulata (Boheman) = Cassidinoma monstrosa (Boheman) syn. n. The diagnosis, description, distribution, and biology are reviewed, and new distribution records are included. Illustrations of the habitus of adult and morphological structures are also added. PMID- 26120725 TI - Revision of the genus Acallopistus Schoenherr (Coleoptera, Curculionidae, Curculioninae, Nerthopini). . AB - The genus Acallopistus (Curculioninae, Nerthopini) is revised. Eight species are recognized as valid: A. vellicosus Schoenherr, A. abutilonis Marshall, A. fallax Boheman, A. guttatus Boheman, A. crassirostris Hustache and three new species, A. dissimilis, A. hibisci and A. dentirostris. The following new synonymies are proposed: A. maculithorax Hustache and A. senegalensis Hustache = A. vellicosus Schoenherr, A. pardalis Gyllenhal = A. guttatus Boheman. Lectotypes are designated for A. vellicosus Schoenherr, A. abutilonis Marshall, A. guttatus Boheman, A. crassirostris Hustache and A. malvae Boheman; one neotype is designated for A. fallax Boheman. The species A. malvae Boheman is excluded from the genus Acallopistus. A key to species, diagnosis of each species, together with habitus photographs and line illustrations of male and female genitalia are provided. PMID- 26120726 TI - Two new species of Halictophagus (Strepsiptera, Halictophagidae) from the Dominican Republic. AB - Halictophagus trigonodontos Cook, n. sp. and Halictophagus dominicus Cook, n. sp. are described from the Dominican Republic. The stout and heavily-sclerotized mandibles of H. trigonodontos are unusual for the genus. The genus Halictophagus and the subfamily Halictophaginae have previously been characterized as having non-sclerotized mandibles. However, H. trigonodontos and H. dominicus have sclerotized mandibles, as do other previously describes Halictophagus species. The subfamily Halictophaginae, including genera Halictophagus and Stenocranophilus, can still be separated from Coriophaginae by not having a head capsule with sulci and sutures as is found in Coriophaginae. PMID- 26120727 TI - Three new bathyal raphitomine gastropods (Mollusca: Conoidea) from the Indo Pacific region. AB - Three new species of Conoidea are described from Red Sea, Gulf of Aden and Philippines. Awheaturris lozoueti sp. nov., from Philippines, is the first representative in the recent Indo-Pacific molluscan fauna of a hitherto Miocene fossil genus. Taranis adenensis sp. nov., from Gulf of Aden, is the first species certainly referable to genus Taranis Jeffreys, 1870 reported in the Gulf of Aden and the smallest described member of this genus in the Indo-Pacific region. Mioawateria vivens sp. nov. represents the first member of the genus Mioawateria Vella, 1954 reported in the Red Sea. The status of Mioawateria is discussed and photographs of its type species, Awateria (Mioawateria) personata Powell, 1942, from the Pliocene of New Zealand, are presented for the first time. PMID- 26120728 TI - Larva of Nothotrichia shasta Harris & Armitage (Trichoptera: Hydroptilidae) from California, USA, with its phylogenetic and taxonomic implications. AB - Nothotrichia Flint 1967 is a small genus of infrequently collected microcaddisflies known from Chile and Brazil in South America, Costa Rica in Central America, and the United States in North America. Previously known only from adult specimens, we provide the first description and illustration of a larva in the genus, the larva of N. shasta from California, USA. We provide characters to separate Nothotrichia from other similar genera and an updated key to larval Hydroptilidae modified from that of Wiggins (1996). Larval characters provide additional evidence for the phylogeny and classification of the genus, which we now place tentatively in tribe Ochrotrichiini (subfamily Hydroptilinae). PMID- 26120729 TI - A new species of the genus Prethopalpus from Hainan Island, China (Araneae: Oonopidae). PMID- 26120730 TI - Emergence and Spread of New Races of Wheat Stem Rust Fungus: Continued Threat to Food Security and Prospects of Genetic Control. AB - Race Ug99 (TTKSK) of Puccinia graminis f. sp. tritici, detected in Uganda in 1998, has been recognized as a serious threat to food security because it possesses combined virulence to a large number of resistance genes found in current widely grown wheat (Triticum aestivum) varieties and germplasm, leading to its potential for rapid spread and evolution. Since its initial detection, variants of the Ug99 lineage of stem rust have been discovered in Eastern and Southern African countries, Yemen, Iran, and Egypt. To date, eight races belonging to the Ug99 lineage are known. Increased pathogen monitoring activities have led to the identification of other races in Africa and Asia with additional virulence to commercially important resistance genes. This has led to localized but severe stem rust epidemics becoming common once again in East Africa due to the breakdown of race-specific resistance gene SrTmp, which was deployed recently in the 'Digalu' and 'Robin' varieties in Ethiopia and Kenya, respectively. Enhanced research in the last decade under the umbrella of the Borlaug Global Rust Initiative has identified various race-specific resistance genes that can be utilized, preferably in combinations, to develop resistant varieties. Research and development of improved wheat germplasm with complex adult plant resistance (APR) based on multiple slow-rusting genes has also progressed. Once only the Sr2 gene was known to confer slow rusting APR; now, four more genes-Sr55, Sr56, Sr57, and Sr58-have been characterized and additional quantitative trait loci identified. Cloning of some rust resistance genes opens new perspectives on rust control in the future through the development of multiple resistance gene cassettes. However, at present, disease-surveillance-based chemical control, large-scale deployment of new varieties with multiple race-specific genes or adequate levels of APR, and reducing the cultivation of susceptible varieties in rust hot-spot areas remains the best stem rust management strategy. PMID- 26120732 TI - 4,5-Substituted 3-Isoxazolols with Insecticidal Activity Act as Competitive Antagonists of Housefly GABA Receptors. AB - The insect GABA receptor (GABAR), which is composed of five RDL subunits, represents an important target for insecticides. A series of 4,5-disubstituted 3 isoxazolols, including muscimol analogues, were synthesized and examined for their activities against four splice variants (ac, ad, bc, and bd) of housefly GABARs expressed in Xenopus oocytes. Muscimol was a more potent agonist than GABA in all four splice variants, whereas synthesized analogues did not exhibit agonism but rather antagonism in housefly GABARs. The introduction of bicyclic aromatic groups at the 4-position of muscimol and the simultaneous replacement of the aminomethyl group with a carbamoyl group at the 5-position to afford six 4 aryl-5-carbamoyl-3-isoxazolols resulted in compounds that exhibited significantly enhanced antagonism with IC50 values in the low micromolar range in the ac variant. The inhibition of GABA-induced currents by 100 MUM analogues was approximately 1.5-4-fold greater in the ac and bc variants than in the ad and bd variants. 4-(3-Biphenylyl)-5-carbamoyl-3-isoxazolol displayed competitive antagonism, with IC50 values of 30, 34, 107, and 96 MUM in the ac, bc, ad, and bd variants, respectively, and exhibited moderate insecticidal activity against houseflies, with an LD50 value of 5.6 nmol/fly. These findings suggest that these 3-isoxazolol analogues are novel lead compounds for the design and development of insecticides that target the orthosteric site of housefly GABARs. PMID- 26120731 TI - B cell autophagy mediates TLR7-dependent autoimmunity and inflammation. AB - Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, defined by loss of B cell self-tolerance that results in production of antinuclear antibodies (ANA) and chronic inflammation. While the initiating events in lupus development are not well defined, overexpression of the RNA-recognizing toll-like receptor (TLR)7 has been linked to SLE in humans and mice. We postulated that autophagy plays an essential role in TLR7 activation of B cells for the induction of SLE by delivering RNA ligands to the endosomes, where this innate immune receptor resides. To test this hypothesis, we compared SLE development in Tlr7 transgenic (Tg) mice with or without B cell-specific ablation of autophagy (Cd19 Cre Atg5(f/f)). We observed that in the absence of B cell autophagy the 2 hallmarks of SLE, ANA and inflammation, were eliminated, thus curing these mice of lupus. This was also evident in the significantly extended survival of the autophagy-deficient mice compared to Tlr7.1 Tg mice. Furthermore, glomerulonephritis was ameliorated, and the serum levels of inflammatory cytokines in the knockout (KO) mice were indistinguishable from those of control mice. These data provide direct evidence that B cells require TLR7-dependent priming through an autophagy-dependent mechanism before autoimmunity is induced, thereafter involving many cell types. Surprisingly, hyper-IgM production persisted in Tlr7.1 Tg mice in the absence of autophagy, likely involving a different activation pathway than the production of autoantibodies. Furthermore, these mice still presented with anemia, but responded with a striking increase in extramedullary hematopoiesis (EMH), possibly due to the absence of pro inflammatory cytokines. PMID- 26120734 TI - Self-Assembling Nano-Architectures Created from a Protein Nano-Building Block Using an Intermolecularly Folded Dimeric de Novo Protein. AB - The design of novel proteins that self-assemble into supramolecular complexes is an important step in the development of synthetic biology and nanotechnology. Recently, we described the three-dimensional structure of WA20, a de novo protein that forms an intermolecularly folded dimeric 4-helix bundle (PDB code 3VJF ). To harness the unusual intertwined structure of WA20 for the self-assembly of supramolecular nanostructures, we created a protein nanobuilding block (PN Block), called WA20-foldon, by fusing the dimeric structure of WA20 to the trimeric foldon domain of fibritin from bacteriophage T4. The WA20-foldon fusion protein was expressed in the soluble fraction in Escherichia coli, purified, and shown to form several homooligomeric forms. The stable oligomeric forms were further purified and characterized by a range of biophysical techniques. Size exclusion chromatography, multiangle light scattering, analytical ultracentrifugation, and small-angle X-ray scattering (SAXS) analyses indicate that the small (S form), middle (M form), and large (L form) forms of the WA20 foldon oligomers exist as hexamer (6-mer), dodecamer (12-mer), and octadecamer (18-mer), respectively. These findings suggest that the oligomers in multiples of 6-mer are stably formed by fusing the interdigitated dimer of WA20 with the trimer of foldon domain. Pair-distance distribution functions obtained from the Fourier inversion of the SAXS data suggest that the S and M forms have barrel- and tetrahedron-like shapes, respectively. These results demonstrate that the de novo WA20-foldon is an effective building block for the creation of self assembling artificial nanoarchitectures. PMID- 26120733 TI - 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. AB - We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability. PMID- 26120735 TI - Robotic-Assisted Procedures in Pediatric Surgery: A Critical Appraisal of the Current Best Evidence in Comparison to Conventional Minimally Invasive Surgery. AB - INTRODUCTION: In recent years, the use of robotic-assisted surgery (RAS) has expanded within pediatric surgery. Although increasing numbers of pediatric RAS case-series have been published, the level of evidence remains unclear, with authors mainly focusing on the comparison with open surgery rather than the corresponding laparoscopic approach. The aim of this study was to critically appraise the published literature comparing pediatric RAS with conventional minimally invasive surgery (MIS) in order to evaluate the current best level of evidence. MATERIALS AND METHODS: A systematic literature-based search for studies comparing pediatric RAS with corresponding MIS procedures was performed using multiple electronic databases and sources. The level of evidence was determined using the Oxford Centre for Evidence-based Medicine (OCEBM) criteria. RESULTS: A total of 20 studies met defined inclusion criteria, reporting on five different procedures: fundoplication (n=8), pyeloplasty (n=8), nephrectomy (n=2), gastric banding (n=1), and sleeve gastrectomy (n=1). Included publications comprised 5 systematic reviews and 15 cohort/case-control studies (OCEBM Level 3 and 4, respectively). No studies of OCEBM Level 1 or 2 were identified. Limited evidence indicated reduced operative time (pyeloplasty) and shorter hospital stay (fundoplication) for pediatric RAS, whereas disadvantages were longer operative time (fundoplication, nephrectomy, gastric banding, and sleeve gastrectomy) and higher total costs (fundoplication and sleeve gastrectomy). There were no differences reported for complications, success rates, or short-term outcomes between pediatric RAS and conventional MIS in these procedures. Inconsistency was found in study design and follow-up with large clinical heterogeneity. CONCLUSIONS: The best available evidence for pediatric RAS is currently OCEBM Level 3, relating only to fundoplication and pyeloplasty. Therefore, higher quality studies and comparative data for other RAS procedures in pediatric surgery are required. PMID- 26120736 TI - Triterpenoids from the barks of Terminalia chebula. AB - Two new triterpenoids, termichebuloside A (1), an unusual dimeric triterpenoid saponin, and termichebulolide (2), an oleanolic acid-type lactone, along with 11 known triterpenoids, were isolated from MeOH extract of the barks of Terminalia chebula. The structures of 1 and 2 were elucidated to be arjunglucoside I-(3-O 19',23-O-19')-18,19-seco-19-hydroxyarjunglucoside I (1) and 2alpha,3beta,23 trihydroxyolean-11,13(18)-dien-28,19beta-olide (2), respectively, on the basis of spectroscopic evidences and biogenetic consideration. PMID- 26120737 TI - Commentary on Stiers and colleagues' guidelines for competency development and measurement in rehabilitation psychology postdoctoral training. AB - Comments on the article, "Guidelines for competency development and measurement in rehabilitation psychology postdoctoral training," by Stiers et al. (see record 2014-55195-001). Stiers and colleagues have provided a thorough and well conceived set of guidelines that lay out the competencies expected for graduates of postdoctoral residencies in rehabilitation psychology, accompanied by a set of more specific, observable indicators of the residents' competence level. This work is an important aspect of the broader project of the Rehabilitation Psychology Specialty Council (APA Division 22, the American Board of Rehabilitation Psychology, the Foundation for Rehabilitation Psychology, the Academy of Rehabilitation Psychology, and the Council of Rehabilitation Psychology Postdocotral Training Programs) to develop overall guidelines for programs providing postdoctoral training in this field (Stiers et al., 2012). PMID- 26120738 TI - Defining the treatment targets and active ingredients of rehabilitation: Implications for rehabilitation psychology. AB - PURPOSE: Rehabilitation is a complex field incorporating many disciplines, settings, interventions, and populations, with patient goals ranging from improvement in function to enhanced participation in societal roles. Although there has been progress in measuring the inputs to the rehabilitation process, such as patient characteristics, and the outputs (i.e., outcomes) of the process, little attention has been devoted to specifying and measuring the process itself: the treatment. In this article, the authors describe a framework by which rehabilitation interventions, including those delivered by rehabilitation psychologists, may be defined according to the treatment theories underlying them. RESULTS: The tripartite structure of a treatment theory-the targets, active ingredients, and mechanisms of action-may be specified, often in hypothesized form, for each treatment component used to effect desired changes for each patient. Targets are specific, measurable aspects of patient functioning in which change is desired; active ingredients are specific, measurable actions performed by a clinician to effect these changes; and mechanisms of action are the often invisible and inferred ways in which ingredients work to cause the desired effects. To illustrate these concepts, the authors present how they might be applied in 2 areas of treatment that frequently involve rehabilitation psychologists: management of memory disorders and interventions for chronic pain. CONCLUSIONS/IMPLICATIONS: This type of systematic approach to defining and, ultimately, measuring the quality and quantity (dose) of specific treatments stands to enhance research, practice, and training in rehabilitation as well as communication across the treatment team and other stakeholders in the process and outcomes of rehabilitation. PMID- 26120739 TI - Comments on defining the targets, mechanisms, and active ingredients of rehabilitation. AB - Hart and Ehde (2015) provide a cogent framework for conceptualizing rehabilitation psychology interventions, within a broader classification of rehabilitation treatments. The tripartite structure of treatment seems simple and straightforward but, with further consideration, reveals a depth of complexity and richness. PMID- 26120740 TI - Key dimensions of impairment, self-report, and environmental supports in persons with traumatic brain injury. AB - PURPOSE/OBJECTIVES: To determine key dimensions relevant to recovery in the postacute period for persons with traumatic brain injury (TBI) and to determine the ability of scores on these dimensions to predict participation outcomes for persons with TBI. RESEARCH METHOD/DESIGN: This was a prospective cohort, observational study of 504 persons with medically documented TBI. Participants completed a comprehensive battery of measures including cognitive tests; questionnaires assessing self-report of physical, cognitive, and emotional symptoms and strengths; environmental supports; and a measure of participation outcome. RESULTS: Participants were a predominantly male, ethnically/racially diverse sample of persons with complicated mild, moderate, and severe TBI. Variable cluster analysis identified 12 key dimensions of cognitive function, neurobehavioral complaints, personal strengths, physical symptoms and function, environmental supports, and performance validity. In unadjusted analyses, all 12 dimensions were predictive of participation outcome. In multivariable regression analysis with adjustment of all predictors for all other predictors, dimensions measuring memory, independence and self-esteem, resilience, emotional distress, physical functioning, and economic and family support made unique contributions to predicting participation outcome. CONCLUSIONS/IMPLICATIONS: Findings add to our understanding of key aspects of functioning and self-perception for persons with TBI. Knowledge of the profile of an individual patient on these 12 dimensions may assist with development of a treatment approach for the person with TBI. (PsycINFO Database Record PMID- 26120741 TI - The association of negative attributions with irritation and anger after brain injury. AB - OBJECTIVES: Study objectives were to examine associations of irritation and anger with negative attributions, and associations of negative attributions with trait aggression in participants with traumatic brain injury (TBI). PARTICIPANTS: Forty eight participants with moderate to severe TBI participated in this study. Participants were primarily male (68.8%), and on average, approximately 5 years postinjury. DESIGN: Prospective study using a quasi-experimental design. MAIN MEASURES: Participants were presented with 21 vignettes that hypothetically led to negative consequences for the participant. Stories portrayed characters' actions as benign, ambiguous, or hostile. After each vignette, participants rated how irritated and angry they would be, and how intentional, hostile, and blameworthy they perceived the characters' actions. Participants' trait aggression was evaluated with the aggression questionnaire. RESULTS: Irritation and anger ratings were strongly correlated with intent, hostility, and blame ratings of the character (p < .001). Trait aggression was significantly associated with attributions of intent, hostility, and blame (p < .001). CONCLUSION: These preliminary findings suggest that irritation and anger after TBI may be linked to the negative attributions they make about others' behaviors. Findings further indicate a relationship between negative attributions and trait aggression. Thus, individuals with TBI who have higher trait aggression may have a tendency to make more negative attributions about others' behaviors, and in turn, have stronger feelings of irritation and anger as a response. Future studies with healthy controls and larger sample sizes are needed to build upon this clinically relevant topic. PMID- 26120742 TI - Integrating the ICF with positive psychology: Factors predicting role participation for mothers with multiple sclerosis. AB - OBJECTIVE: Being a mother has become a realizable life role for women with disabilities and chronic illnesses, including multiple sclerosis (MS). Identifying psychosocial factors that facilitate participation in important life roles-including motherhood-is essential to help women have fuller lives despite the challenge of their illness. By integrating the International Classification of Functioning, Disability, and Health (ICF) and a positive psychology perspective, this study examined how environmental social factors and positive personal factors contribute to daily role participation and satisfaction with parental participation. METHOD: One hundred and 11 community-dwelling mothers with MS completed Ryff's Psychological Well-Being Scales, the Medical Outcome Study Social Support Survey, the Short Form-36, and the Parental Participation Scale. Hierarchical regression analyses examined associations between social support and positive personal factors (environmental mastery, self-acceptance, purpose in life) with daily role participation (physical and emotional) and satisfaction with parental participation. One-way ANOVAs tested synergistic combinations of social support and positive personal factors. RESULTS: Social support predicted daily role participation (fewer limitations) and greater satisfaction with parental participation. Positive personal factors contributed additional unique variance. Positive personal factors and social support synergistically predicted better function and greater satisfaction than either alone. CONCLUSION: Integrating components of the ICF and positive psychology provides a useful model for understanding how mothers with MS can thrive despite challenge or impairment. Both positive personal factors and environmental social factors were important contributors to positive role functioning. Incorporating these paradigms into treatment may help mothers with MS participate more fully in meaningful life roles. PMID- 26120743 TI - Illness perceptions and adherence to exercise therapy in cardiac rehabilitation participants. AB - PURPOSE/OBJECTIVE: Two complementary frameworks, the common sense model, and social-cognitive theory, were used. The first purpose of this study was to compare 2 groups varying in their illness perceptions (strong vs. weak) on baseline differences in theory-based exercise cognitions (self-regulatory efficacy and outcome expectations), and health-related quality of life (HRQL). The second purpose was to examine illness perception group differences in cardiac rehabilitation exercise participation following 3 months of exercise therapy. RESEARCH METHOD/DESIGN: Newly enrolled cardiac rehabilitation participants (N = 49) completed baseline measures of illness perceptions, self-regulatory efficacy, outcome expectations, and HRQL. Cardiac rehabilitation exercise minutes were measured at baseline (after 2 weeks of participation) and following 3 months of cardiac rehabilitation. RESULTS: Individuals were successfully classified into strong and weak illness perception groups using cluster analysis. Analyses of variance indicated significant group differences on negative outcome expectations (p < .05), where the strong illness perception group reported greater negative outcome expectations. The strong illness perception group also reported significantly lower physical and mental HRQL as compared to their weak illness perception counterparts (p < .01). Parallel differences in cardiac rehabilitation exercise participation at 3 months were also observed (p < .05). CONCLUSIONS/IMPLICATIONS: This study was a first attempt to utilize the common sense model and social-cognitive theory to examine individuals engaged in rehabilitation to reduce cardiac risk. The findings suggest that complementary use of these 2 frameworks to study individual illness perception differences relative to psychological beliefs and adherence to exercise therapy may aid understanding of correlates of exercise adherence among cardiac rehabilitation participants. PMID- 26120744 TI - Clinical utility of the LANSE-A in adolescents with traumatic brain injury. AB - OBJECTIVE: To investigate the clinical utility of a brief cognitive screening instrument, the Lebby-Asbell Neurocognitive Screening Examination for Adolescents (LANSE-A) in 12-17 year-old adolescents with traumatic brain injury in an inpatient rehabilitation setting. METHOD: Retrospective study of 56 referred patients, evaluated at a median of 32 days postinjury. Regression analysis was used to determine the contribution of the LANSE-A to prediction of discharge status, as assessed with the Functional Independence Measure for Children (WeeFIM). RESULTS: After controlling for premorbid complicating factors, parental education, duration to follow commands, and WeeFIM Cognition score obtained upon admission, the LANSE-A Visual Memory and Verbal Association subtests accounted for a statistically significant amount of unique variance in the WeeFIM Cognition score obtained at discharge. CONCLUSIONS/IMPLICATIONS: The LANSE-A improves prediction of acute rehabilitation outcomes of adolescents with traumatic brain injury. PMID- 26120745 TI - A brief cognitive-behavioral intervention for sleep in individuals with chronic noncancer pain: A randomized controlled trial. AB - PURPOSE/OBJECTIVE: Chronic pain has a significant negative impact on the quality of life, including sleep disruption. There is compelling evidence that cognitive behavioral therapy can be effective in treating sleep disorders. To our knowledge, no research has been carried out on brief cognitive-behavioral educational interventions in individuals with chronic pain. This study was conducted to determine whether a brief education session that incorporates sleep hygiene and cognitive-behavioral strategies would help improve the sleep of individuals with chronic pain. RESEARCH METHOD/DESIGN: Eighty-five patients from a tertiary care Multidisciplinary Pain Centre completed all aspects of the study. This sample was randomized into 2 groups: a treatment group who received a brief cognitive-behavioral educational session, and a control group who did not. All participants completed a daily sleep diary for 28 days. Measures on sleep quality, beliefs and attitudes about sleep, pain, disability, and mood were recorded at baseline. RESULTS: No significant differences were found between groups on demographic, pain, disability, mood measures, or sleep quality at baseline. Overall, 42% of the individuals who completed this study had depression scores above the clinical cutoff. This sample reported a high level of pain related disability. Individuals in the treatment group had significantly reduced sleep onset latency compared to controls. No significant differences between groups on the number of times waking or hours slept. CONCLUSIONS/IMPLICATIONS: Our findings suggest that there is potential for a brief educational intervention to have a positive impact on some aspects of sleep in the chronic pain population. PMID- 26120746 TI - Recognizing encephalopathy and delirium in the cardiopulmonary rehabilitation setting. AB - OBJECTIVE: This article reviews the prevalence, underlying mechanisms, and challenges of treating encephalopathy and delirium in the postsurgical and medically compromised cardiopulmonary patient receiving services on an acute inpatient rehabilitation unit. Additionally, pertinent information is provided on conducting an evaluation to assess for neurocognitive sequelae of the above mentioned conditions to help achieve better treatment outcomes. METHOD: Review of the medical and neuropsychology literature is provided along with 2 case reports to illustrate evaluation of a persisting toxic-metabolic encephalopathy and a resolving delirium and the treatment team's effectiveness in producing a more optimal treatment outcome. The unique role of the rehabilitation psychologist, special treatment considerations, and the importance of integrated follow-up neurorehabilitation services for the cardiopulmonary patient and caregivers also are emphasized. RESULTS: Encephalopathy and delirium are 2 related, but somewhat different, conditions that can emerge postoperatively, any time during acute care hospitalization, and often enough, during impatient or subacute-care rehabilitation. Their association with long-term harm and poor outcome warrant early identification and immediate medical intervention. IMPLICATIONS: Encephalopathy and delirium can significantly affect rehabilitation outcomes and, as such, rehabilitation psychologists are encouraged to systematically screen for the presence of delirium and encephalopathy in the cardiopulmonary rehabilitation setting so to enhance treatment efficacy and quality of life in affected individuals. PMID- 26120747 TI - Measurement characteristics and clinical utility of the Patient Health Questionnaire-9 among individuals with spinal cord injury. AB - This Rehabilitation Measures Database summary provides a review of the psychometric properties of the PHQ-9 individuals with SCI. A full review of the PHQ-9 as well as reviews of over 300 other instruments can be found at www.rehabmeasures.org. PMID- 26120748 TI - Intrinsic Optical Activity and Large-Amplitude Displacement: Conformational Flexibility in (R)-Glycidyl Methyl Ether. AB - The dispersive optical activity of (R)-(-)-glycidyl methyl ether (R-GME) has been interrogated under ambient vapor-phase and solution-phase conditions, with quantum-chemical analyses built on density functional (B3LYP and CAM-B3LYP) and coupled-cluster (CCSD) implementations of linear-response theory exploited to interpret experimental findings. Inherent flexibility of the heavy atom skeleton leads to nine low-lying structural isomers that possess distinct chiroptical and physicochemical properties, as evinced by marked changes in the magnitude and the sign of rotatory powers observed in various media. These species are interconverted by independent motion along two large-amplitude torsional coordinates and are stabilized differentially by interaction with the surroundings, thereby reapportioning their relative contributions to the collective response evoked from a thermally equilibrated ensemble. The intrinsic behavior exhibited by isolated (vapor-phase) R-GME molecules was calculated through use of both conformer-averaging and restricted vibrational-averaging procedures, the former affording moderately good agreement with measurements of optical rotatory dispersion (ORD) and the latter providing strong evidence for sizable effects arising from vibrational degrees of freedom. A similar conformer averaging ansatz based on the polarizable-continuum model (PCM) for implicit solvation was deployed to elucidate R-GME specific-rotation parameters acquired for six dilute solutions. This approach gave reasonable predictions for sodium D line (589.3 nm) experiments performed in the extremes of solvent polarity represented by cyclohexane and acetonitrile but failed to reproduce the overall shape of ORD profiles and suggested more complex processes might be involved in the case of an aromatic medium. PMID- 26120749 TI - Middle East Respiratory Syndrome. PMID- 26120750 TI - [Gender and physical activity in Mexican women with experience of migration to the USA]. AB - OBJECTIVE: To analyze the influence of gender on the practice of physical activity, in women with experiences of migration to the U.S.A. METHODS: Qualitative design with methods based on grounded theory. The information was obtained through in-depth interviews of 19 women living in rural localities in the central zone of Mexico. RESULTS: Through this analysis, a core category arose: social criticism of physical exercise. The results show that married women do not perform physical exercise because, due social norms, it is socially frowned upon and men are responsible for making the decision to permit it. Gender, female identity, women's role as subordinates to men, and social criticism are elements that contribute to understanding the lack of physical activity among these women. CONCLUSION: We suggest that healthcare programs be designed to promote physical activity among adult women in rural areas, taking gender perspective and the population's context into account. PMID- 26120751 TI - [Human papilloma virus vaccination in teenage girls: a focus group evaluation]. AB - OBJECTIVE: The low immunization coverage levels for the human papilloma virus vaccine has led to a need to analyze the causes that affect the decision to vaccinate, as expressed by those directly involved in making this decision teenage girls. METHODOLOGY: Therefore, we proposed an assessment with a focus group methodology. An evaluation with a pilot group and four focal groups was carried out in Tirant lo Blanc of Gandia secondary school. The girls that made up the groups belonged to different populations within the health department, including vaccinated, non-vaccinated, and incorrectly vaccinated teenage girls. RESULTS: The girls talked about their experiences, knowledge and opinions with respect to HPV vaccination, which could be summarized as showing a large knowledge gap and the existence of erroneous ideas. CONCLUSION: A change in direction, involving the development of educational campaigns that empowers girls and their families to make suitable decisions, is necessary. PMID- 26120752 TI - [Sexual and reproductive health in university students at an institution of higher learning in Colombia]. AB - OBJECTIVE: To investigate the state of sexual and reproductive health in students at a public university in the Colombian Caribbean, with an emphasis on sexually transmitted diseases (STDs), fertility, sexuality, pregnancy and violence. METHODS: Cross-sectional survey study. University students, enrolled in the second semester of 2010 and who completed a self-administered survey based on the Reproductive Health survey of the Pan American Health Organization, were selected. Qualitative data was tabulated and graphed using measures of central tendency for quantitative variables. RESULTS: The age of population studied was around 20 years old, came from the urban area (57.9 %; IC95 %=54.7-61.1), was predominantly heterosexual (89.7 %), with an age of initiation of sexual activity of less than 18 years old, 11.8 % promiscuity, mainly using the condom as a Family Planning Method (FPM) (55 %). Although they had prior information on sexual health, STDs and FPMs, they did not behave according to this due to low education about HIV transmission routes, low incidence of serological tests for STDs, and high risk behavior (sex/alcohol/drugs). It was observed that 12.3 % had a history of pregnancy, physical violence (21.6 %) and sexual violence (4.6 %) with a predominant silence from the victims of sexual abuse (61.8 %). CONCLUSION: The sample reflects the student population in this region of Colombia. We plan to organize a health program with medical and psychological support to reduce the rates of STDs and unplanned pregnancies, preparing the adolescent for this important step in their life and serving as a model for other Latin American universities. PMID- 26120753 TI - [Direct costs involved in providing medical attention associated with traffic accidents in Bogota]. AB - OBJECTIVE: To determine the cost of medical attention associated with traffic accidents in Bogota, Colombia. METHODS: Prospective observational study with data from adult patients attended to in the emergency centers of 6 hospitals. RESULTS: Average total cost per patient was $1'112.000 COP. Average daily cost of hospitalized patients was $1'200.000 COP. Average cost of ambulatory treated patients ascended to $247.400 COP. Cost per accident calculated was $2'333.700 COP. In the whole city during study period, total medical costs were around $2.301'028.200 COP. All data was expressed in 2011 Colombian pesos. CONCLUSION: The medical cost of transit accidents is a significant economic burden. PMID- 26120754 TI - [Suicide attempts treated at public health units of Fortaleza-Ceara, Brazil]. AB - OBJECTIVE: This study aimed to describe the main characteristics of victims of suicide attempts treated at public health units of Fortaleza-Ceara, Brazil. METHODS: With a quantitative approach, we used a questionnaire with structured questions and the Beck Scale for depression. We worked with a convenience sample of 360 victims in Psychosocial Care Centers (General/Alcohol-Drug/Infant to Teen), Doutor Jose Frota Hospital, and the Apoio a Vida Project . RESULTS: In the statistical analysis, the dependent variable of more than one suicide attempt was used, associated to the independent variables. Multivariate analysis, with more than one attempt and significance (p<0.05), maintained association: male OR=2,1 (IC95 %: 1,2-3,6), p=0,005; feeling rejected, RC=2,4, (IC95 %:1,4-3,9), p=0,001; admission to psychiatric hospital, RC=3,4 (IC95 %:2,0-5,7), p=0,000; believing to have disappointed someone, RC=2,4 (IC95 %:1,3-4,4), p=0,005; depression, RC=1,0 (IC95 %: 1,0-1,0), p=0,001. CONCLUSION: The data shows the need for greater attention to this population, in the sense of promoting differentiated service support, either psychological or psychiatric, to improve people's lives. PMID- 26120756 TI - [Variables involved in the individual and collective practice of healthy habits]. AB - OBJECTIVE: To conduct a descriptive review of the concepts related to the practice of healthy habits by identifying the main variables associated with their managment in terms of health promotion actions. METHODOLOGY: In consultation with groups working in health promotion in the city of performed by consulting databases and documentary sources. The strategy and criteria for the selection of documents was previously defined. Finally, we proceeded to organizing and structuring the information. RESULTS: It was established that, to promote healthy habits, four groups of behavior are involved: a) consumption, b) phyisical activity and hygiene, c) safety, and d) social participation. All of these are reviewed in order to point out the main concepts contained in each. CONCLUSION: The promotion of healthy habits must involve not only the transmission of behaviors associated with them. It must also involve understanding and adapting these habits to the environments of life in which people operate, with consideration for the different roles that they perform and the psychological and cultural demands that each space implies. PMID- 26120755 TI - [Knowledge of human papilloma virus (HPV) and acceptance of vaginal self-sampling among Mexican woman]. AB - OBJECTIVE: To analyze the relationship between the level of knowledge about human papilloma virus and the acceptance of vaginal self-sampling as a cervical cancer diagnostic test among Mexican women who have already experienced vaginal self sampling at home. METHODS: A structured questionnaire consisting of 22 questions was applied to 690 women in the state of Morelos who had taken a vaginal self sample at home. The aspects explored were the level of knowledge about transmission of the human papilloma virus, identification of the virus as a necessary cause of cervical cancer, and clinical manifestations of infection and treatment. A knowledge index was constructed, identifying the relationship between the index and the women's acceptance of self-sampling, and their degree of trust in the procedure. The statistical analysis included a logistic regression with estimates of measures of association and their respective 95% confidence intervals. RESULTS: The level of knowledge about human papillomavirus showed a positive association with the degree of acceptance of vaginal self sampling (OR 2.9; 95% CI 1.0-5.01) and the women's level of confidence (OR 2.9; 95% CI 1.8-4.67). The level of knowledge increased with level of education and was higher in younger women. CONCLUSIONS: In order for women with an increased risk of cervical cancer to continue participating in vaginal self-sampling, they must be well informed about the virus. This is especially true for older women, those with lower levels of education, and those in lower socioeconomic levels. PMID- 26120757 TI - [The process of eliminating neonatal Tetanus in Colombia, 1989-2005]. AB - OBJECTIVE: To describe the country's progress in eliminating neonatal tetanus based on the information obtained from epidemiologic surveillance. MATERIAL AND METHODS: A retrospective descriptive study of the epidemiological surveillance of neonatal tetanus in Colombia in the period ranging from 1989 to 2005. Available information was consulted regarding confirmations of this event of interest for Public Health. RESULTS: During the study period, a total of 830 cases of neonatal tetanus were reported. In 1989, the rate of neonatal tetanus in Colombia was 0.22 per 1000 live births. In 2005, this value was reduced to 0.01 cases per 1000 live births; a reduction of nearly 94 %. CONCLUSIONS: Given the information provided by epidemiological surveillance, Colombia has achieved the goal of maintaining a rate<1 case per 1000 live births. Nevertheless, even one case anywhere in the country should be considered a failure of the healthcare system. PMID- 26120758 TI - [Estimate equation of body composition of the elderly male]. AB - OBJECTIVES: This study aims to develop and validate a predictive body composition equation in elderly men. METHODOLOGY: Correlational study using a sample of 85 men with 69.5+/-5,8 years from Vitoria, Brazil. The sample was divided in two groups: the regression group (n=54) was used to develop the predictive equation and a validation group (n=31). The following measurements: skinfolds (S), bone diameter (BD) and body circumferences (BC), body fat percent (%BF) measure by DXA. The predictive equations were developed using multiple linear regressions and validated through the stepwise method. Equations were compared using Student's T test for paired samples. Residual scores were analyzed using the Blant and Altman method. RESULTS: The regression group had 68.5+/-4,5 years, 78,5+/-14,4 kg; 1,6+/-0,6 m, and % BF 30.4+/-6,8. The validation group had 71.2+/ 7.4 years, body weight 75.2+/-11 kg, height 1.6+/-0.5 m, and % BF 29.4+/-7.7. The resulting predictive equation is % body fat =23.371+0.337 (BC abdomen)-1.464 (BC left arm)+0.501 (S calf)+0.175 (body weight)-0.741 (BD acromial)-0.415 (BC biiliocristal)+0.374 (Cleft tight) + 0.370 (BC neck). The best-fit plot was significant due to the correlation coefficient r=0.8. The r2 was 0.8, meaning that the independent variables are able to explain 87 % of the estimate. The EPE was 2.6 %. CONCLUSION: In light of the current results, the equation was considered adequate to estimate body composition in elderly men. The equation can be a simple and accurate alternative to estimate body fat in this population. PMID- 26120759 TI - [Evaluation of the BD MGITTM technique for identifying the Mycobacterium tuberculosis complex]. AB - OBJECTIVES: To evaluate BD MGITTM TBc(r) technique for identifying the Mycobacterium tuberculosis complex using isolates obtained in liquid and solid media. METHODS: A descriptive study was conducted in which 117 isolates were analyzed by the immune-chromatography technique obtained from solid and liquid cultures to identify the Mycobacterium tuberculosis complex. The kappa coefficient was calculated to determine the degree of agreement between the two methods .When there were different results, they were confirmed with a conventional test. The tool used to analyze the data was Epidat 3.1 RESULTS: The BD MGITTM TBc(r) methodology performed in solid and liquid culture isolates, showed an excellent degree of agreement with a kappa coefficient 0.84. CONCLUSION: The BD MGITTM TBc(r) technique using solid media culture isolates for the identification of the Mycobacterium tuberculosis complex has a good correlation compared to results obtained from liquid media culture isolates. The Reference National Laboratory recommends the use of this technique for the identification of species in solid media culture isolates. PMID- 26120760 TI - [Efficacy and safety of medication use for the cessation of tobacco addiction: A review of Clinical Practice Guidelines]. AB - OBJECTIVE: To review the efficacy and safety of pharmacotherapy for smoking cessation in the context of clinical practice guidelines (CPG). METHODS: A systematic review of CPGs was conducted, aimed at adapting recommendations for Colombia following the ADAPTE methodology. Outcomes comprised 6-months or higher smoking cessation rates and intervention safety. CPGs were peer-assessed based on DELBI. Results from aggregative studies included in selected CPGs were obtained. RESULTS: Pharmacotherapy doubles smoking cessation rates as compared with placebos (rates @25% and up to 27 % when combined with counseling). The highest efficacy was observed for ansyolitic and antidepressive drugs (8.7 % to 19.4 %), and the lowest for nicotine replacement therapy -NRT- (5.2 % to 12.9 %). Nortriptiline shows an efficacy similar to that of bupropion (@10%). With limited exceptions, combined pharmacotherapy for smoking cessation has shown no significant increase in cessation rates. CONCLUSIONS: NRT, varenicline, bupropion and nortriptiline are effective treatments for smoking cessation. Combination of drugs deserves further clinical evidence and should be restricted to highly dependent smokers or initial therapeutic failure. Cost-effectiveness analyses might help to introduce smoking cessation programs in low and middle income countries. PMID- 26120761 TI - [Factors that influence comorbidity from panic disorder and PTSD after earthquakes]. AB - OBJECTIVE: After the earthquake and tsunami in Chile (F-27), we studied the effect of socio-demographic factors, exposure to the event, and state aid received on comorbidity from panic disorder (PD) and posttraumatic stress disorder (PTSD). METHOD: Surveys that include the administration of the Davidson Trauma Scale (DTS) to 246 inhabitants. RESULTS: 19.1 % comorbidity was found (r=.583, R2=.340, p<.01). Females homeowners have a higher risk of PD and PTSD. State aid is associated with more cases of PD. CONCLUSIONS: We designed risk/resistance profilesagainst earthquakes/tsunamis and an instrument to detect cases at risk of PTSD. We suggest guidelines so that the government can improve its role after disasters. PMID- 26120762 TI - [Social determinants of health and the occurrence of oral cancer: a systematic literature review]. AB - OBJECTIVE: The aim of this article is to review the literature on the social determinants of health and its association with the development of oral cancer METHODS: A systematic search was performed in Pubmed database to access relevant, available articles published up until 2012. Reference lists of selected articles were examined to identify additional articles. Twenty-one articles were included in the study RESULTS: Despite the difficulties in making comparisons between the articles, due to lack of uniformity in the definition of social determinants of health and the small number of publications on the subject, the results showed a strong association between oral cancer and social deprivation; socioeconomic status and income; education and occupation Conclusion It is important that further work be conducted to study more in depth this association, to better understand the occurrence of oral cancer and it prevention. In addition, the development of social policies aimed at improving people's living conditions is required, since the results show that better living conditions constitute a protective factor for oral cancer. PMID- 26120763 TI - Behavioral science priorities in residency education: The perspective of practicing family physicians. AB - INTRODUCTION: The family medicine residency behavioral science curriculum is more effective if prioritized to match what is needed in practice after graduation. Two prior studies (Kendall, Marvel, & Cruickshank, 2003; Marvel & Major, 1999) identified physician priorities for behavioral science education. The present study extends this research to include topics from more recent curriculum guidelines and examines the extent to which size of community and perceived competence correlate with prioritization of Washington state family physicians. METHOD: Practicing family physicians in Washington state (N = 2,270) were invited to complete the survey. Respondents provided demographic and practice information. Respondents then rated, on a scale from 1 to 4, 35 behavioral science topics on 2 different scales including (a) priority to be given in residency education and (b) perceived level of competence. RESULTS: A total of 486 responded and 430 completed both priority and competence scales for a response rate of 19%. The top half of 35 topics of the present study included the top 13 topics found in the 2 prior studies. Priority and competence scales were moderately correlated (r = .48, n = 430, p = .001). There was a small significant correlation with size of community and priority ratings (r = .13, n = 435, p = .006). DISCUSSION: Family physicians in Washington state prioritize behavioral science topics in residency education similar to Colorado and Mississippi. The results of this study support recent ACGME guidelines, in that training should focus on common psychiatric illnesses, including depression and anxiety, and interpersonal processes. (PsycINFO Database Record PMID- 26120764 TI - Growing up with an ill parent: An examination of family characteristics and parental illness features. AB - INTRODUCTION: Existing literature suggests that the children of ill parents are vulnerable to a variety of psychosocial difficulties such as depression and anxiety. The purpose of the current study is to investigate the impact of family characteristics (parental involvement, familial support, stress experienced as a result of parental illness) and parental illness features (severity, duration, recovery status, frequency of symptoms, course) on the psychosocial functioning (depression, anxiety, life satisfaction) of late adolescents who have grown up with an ill parent but no longer live with their parents. METHOD: Participants were 71 college students with a parent who experienced a chronic medical condition while they were growing up. Participants provided information regarding family characteristics, parental illness features, and the impact of parental illness. Impact of parental illness was assessed using the Impact of Illness Scale. Participants also completed measures of depression, anxiety, and life satisfaction. RESULTS: Participants' reported impact of parent illness was positively correlated with participant depression and anxiety. Several family characteristics and parental illness features were significantly associated with participant psychosocial functioning. In particular, lower parental involvement was correlated with greater participant depression and anxiety, as well as lower life satisfaction. DISCUSSION: These findings extend our understanding of the impact of parental illness on late adolescents' psychosocial functioning. Results could have clinical applications for psychosocial interventions in children and families coping with chronic illness. (PsycINFO Database Record PMID- 26120765 TI - Fatal Outcome of Multiple Clinical Presentations of Human Herpesvirus 8-related Disease After Solid Organ Transplantation. AB - Kaposi sarcoma is the most common human herpesvirus 8 (HHV-8)-related disease described after solid organ transplantation. Multicentric Castleman disease and hemophagocytic syndrome are other potential HHV-8-induced entities but are less frequently reported. We describe the case of a liver transplant recipient who presented with an acute febrile illness 1 year after transplantation with a rapidly fatal outcome. Autopsy revealed 3 distinct HHV-8-related entities: Kaposi sarcoma, HHV-8-associated multicentric Castleman disease with microlymphomas and a severe hemophagocytic syndrome. Retrospective serologic tests suggested that HHV-8 was likely transmitted by the seropositive donor at the time of transplantation. To our knowledge, this is the first case of copresentation of 3 clinical presentations of HHV-8-mediated human disease in the post-transplant setting. Considering the absence of systematic screening of organ donors/recipients for HHV-8 infection, HHV-8-related illness should be suspected in transplant recipients who present with acute febrile illness, systemic symptoms, lymphadenopathies, and/or multiorgan failure to rapidly document the diagnosis and provide timely an adequate treatment. PMID- 26120767 TI - Photoredox-Catalyzed Intramolecular Aminodifluoromethylation of Unactivated Alkenes. AB - A photoredox catalyzed aminodifluoromethylation of unactivated alkenes has been developed in which HCF2SO2Cl is used as the HCF2 radical source. Sulfonamides were active nucleophiles in the final step of a tandem addition/oxidation/cyclization process to form pyrrolidines, and esters were found to cyclize to form lactones. Thus, a variety of pyrrolidines and lactones were obtained in moderate to excellent yield. In order for the cyclization reactions to be efficient, a combination of a copper catalyst (Cu(dap)2Cl) and silver carbonate was crucial to suppressing a competing chloro, difluoroalkylation process. PMID- 26120766 TI - Disturbed Flow Induces Autophagy, but Impairs Autophagic Flux to Perturb Mitochondrial Homeostasis. AB - AIM: Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. Autophagy is tightly regulated in intracellular bulk degradation/recycling system for maintaining cellular homeostasis. We postulated that disturbed flow modulates autophagy with an implication in mitochondrial superoxide (mtO2(*-)) production. RESULTS: In the disturbed flow or oscillatory shear stress (OSS)-exposed aortic arch, we observed prominent staining of p62, a reverse marker of autophagic flux, whereas in the pulsatile shear stress (PSS) exposed descending aorta, p62 was attenuated. OSS significantly increased (i) microtubule-associated protein light chain 3 (LC3) II to I ratios in human aortic endothelial cells, (ii) autophagosome formation as quantified by green fluorescent protein (GFP)-LC3 dots per cell, and (iii) p62 protein levels, whereas manganese superoxide dismutase (MnSOD) overexpression by recombinant adenovirus, N-acetyl cysteine treatment, or c-Jun N-terminal kinase (JNK) inhibition reduced OSS-mediated LC3-II/LC3-I ratios and mitochondrial DNA damage. Introducing bafilomycin to Earle's balanced salt solution or to OSS condition incrementally increased both LC3-II/LC3-I ratios and p62 levels, implicating impaired autophagic flux. In the OSS-exposed aortic arch, both anti-phospho-JNK and anti-8-hydroxy-2'-deoxyguanosine (8-OHdG) staining for DNA damage were prominent, whereas in the PSS-exposed descending aorta, the staining was nearly absent. Knockdown of ATG5 with siRNA increased OSS-mediated mtO2(*-), whereas starvation or rapamycin-induced autophagy reduced OSS-mediated mtO2(*-), mitochondrial respiration, and complex II activity. INNOVATION: Disturbed flow mediated oxidative stress and JNK activation induce autophagy. CONCLUSION: OSS impairs autophagic flux to interfere with mitochondrial homeostasis. Antioxid. Redox Signal. 23, 1207-1219. PMID- 26120769 TI - Intraoperative protective mechanical ventilation for prevention of postoperative pulmonary complications: a comprehensive review of the role of tidal volume, positive end-expiratory pressure, and lung recruitment maneuvers. AB - Postoperative pulmonary complications are associated with increased morbidity, length of hospital stay, and mortality after major surgery. Intraoperative lung protective mechanical ventilation has the potential to reduce the incidence of postoperative pulmonary complications. This review discusses the relevant literature on definition and methods to predict the occurrence of postoperative pulmonary complication, the pathophysiology of ventilator-induced lung injury with emphasis on the noninjured lung, and protective ventilation strategies, including the respective roles of tidal volumes, positive end-expiratory pressure, and recruitment maneuvers. The authors propose an algorithm for protective intraoperative mechanical ventilation based on evidence from recent randomized controlled trials. PMID- 26120771 TI - Use of the Modified Emotional Stroop Task to Detect Suicidality in College Population. AB - This cross-sectional study investigated the usefulness of the emotional Stroop task (EST) as a behavioral marker for suicidal behaviors in a college population. Eight hundred twenty college students were asked to perform on the EST and to respond to suicide-related self-report measures. The results indicated that past suicide attempters were slower in responding to the word "suicide" as compared to nonattempters, and female past attempters showed more delayed response when their most recent attempt was made in the past 12 months. We did not find evidence that the EST could outperform the traditional self-report measures. PMID- 26120770 TI - Halothane modulates the type i interferon response to influenza and minimizes the risk of secondary bacterial pneumonia through maintenance of neutrophil recruitment in an animal model. AB - BACKGROUND: To minimize the risk of pneumonia, many anesthesiologists delay anesthesia-requiring procedures when patients exhibit signs of viral upper respiratory tract infection. Postinfluenza secondary bacterial pneumonias (SBPs) are a major cause of morbidity and mortality. An increased host susceptibility to SBP postinfluenza has been attributed to physical damage to the pulmonary epithelium, but flu-induced effects on the immune system are being shown to also play an important role. The authors demonstrate that halothane mitigates the risk of SBP postflu through modulation of the effects of type I interferon (IFN). METHODS: Mice (n = 6 to 15) were exposed to halothane or ketamine and treated with influenza and Streptococcus pneumoniae. Bronchoalveolar lavage and lung homogenate were procured for the measurement of inflammatory cells, cytokines, chemokines, albumin, myeloperoxidase, and bacterial load. RESULTS: Halothane exposure resulted in decreased bacterial burden (7.9 +/- 3.9 * 10 vs. 3.4 +/- 1.6 * 10 colony-forming units, P < 0.01), clinical score (0.6 +/- 0.2 vs. 2.3 +/- 0.2, P < 0.0001), and lung injury (as measured by bronchoalveolar lavage albumin, 1.5 +/- 0.7 vs. 6.8 +/- 1.6 mg/ml, P < 0.01) in CD-1 mice infected with flu for 7 days and challenged with S. pneumoniae on day 6 postflu. IFN receptor A1 knockout mice similarly infected with flu and S. pneumoniae, but not exposed to halothane, demonstrated a reduction of lung bacterial burden equivalent to that achieved in halothane-exposed wild-type mice. CONCLUSION: These findings indicate that the use of halogenated volatile anesthetics modulates the type I IFN response to influenza and enhance postinfection antibacterial immunity. PMID- 26120772 TI - When higher working memory capacity hinders insight. AB - Higher working memory capacity (WMC) improves performance on a range of cognitive and academic tasks. However, a greater ability to control attention sometimes leads individuals with higher WMC to persist in using complex, attention demanding approaches that are suboptimal for a given task. We examined whether higher WMC would hinder insight problem solving, which is thought to rely on associative processes that operate largely outside of close attentional control. In addition, we examined whether characteristics of the insight problems influence whether this negative relationship will be revealed. In Experiment 1, participants completed matchstick arithmetic problems, which require a similar initial problem representation for all problems. Higher WMC was associated with less accurate insight problem solving. In Experiment 2, participants completed insight word problems, which require substantially different representations for each problem. Higher WMC was again negatively associated with insight, but only after statistically controlling for shared variance between insight and incremental problem-solving accuracy. These findings suggest that WMC may benefit performance on fundamental processes common to both incremental and insight problem solving (e.g., initial problem representation), but hinder performance on the processes that are unique to insight (e.g., solution and restructuring). By considering the WMC of the individual, and the nature of the insight task, we may better understand the process of insight and how to best support it. (PsycINFO Database Record PMID- 26120773 TI - Bridging gaps in common ground: Speakers design their gestures for their listeners. AB - Communication is shaped both by what we are trying to say and by whom we are saying it to. We examined whether and how shared information influences the gestures speakers produce along with their speech. Unlike prior work examining effects of common ground on speech and gesture, we examined a situation in which some speakers have the same amount of mutually shared experience with their listener but the relevance of the information from shared experience is different for listeners in different conditions. Additionally, speakers and listeners in all conditions shared a visual perspective. Speakers and listeners solved a version of the Tower of Hanoi task together. Speakers then solved a second version of the task without the listener present with the manner of disk movement manipulated; the manner was either the same as or different from the version that had been solved with the listener present. Thus, speakers' knowledge of the relevance of shared knowledge was manipulated. We measured the content of speech along with the physical form and content of the accompanying hand gesture. Although speakers did not modulate their spoken language, speakers who knew their listeners had not previously experienced the appropriate manner of completion gestured higher in space, highlighting manner information, but without altering the physical gesture trajectory. Thus, gesture can be sensitive to the knowledge of listeners even when speech is not. Speakers' gestures can play an independent role in reflecting common ground between speakers and listeners, perhaps by simultaneously incorporating both speaker and listener perspectives. (PsycINFO Database Record PMID- 26120774 TI - Carving executive control at its joints: Working memory capacity predicts stimulus-stimulus, but not stimulus-response, conflict. AB - Three experiments examined the relation between working memory capacity (WMC) and 2 different forms of cognitive conflict: stimulus-stimulus (S-S) and stimulus response (S-R) interference. Our goal was to test whether WMC's relation to conflict-task performance is mediated by stimulus-identification processes (captured by S-S conflict), response-selection processes (captured by S-R conflict), or both. In Experiment 1, subjects completed a single task presenting both S-S and S-R conflict trials, plus trials that combined the 2 conflict types. We limited ostensible goal-maintenance contributions to performance by requiring the same goal for all trial types and by presenting frequent conflict trials that reinforced the goal. WMC predicted resolution of S-S conflict as expected: Higher WMC subjects showed reduced response time interference. Although WMC also predicted S-R interference, here, higher WMC subjects showed increased error interference. Experiment 2A replicated these results in a version of the conflict task without combined S-S/S-R trials. Experiment 2B increased the proportion of congruent (nonconflict) trials to promote reliance on goal-maintenance processes. Here, higher WMC subjects resolved both S-S and S-R conflict more successfully than did lower WMC subjects. The results were consistent with Kane and Engle's (2003) 2-factor theory of cognitive control, according to which WMC predicts executive-task performance through goal-maintenance and conflict-resolution processes. However, the present results add specificity to the account by suggesting that higher WMC subjects better resolve cognitive conflict because they more efficiently select relevant stimulus features against irrelevant, distracting ones. PMID- 26120776 TI - Flavin-Protein Complexes: Aromatic Stacking Assisted by a Hydrogen Bond. AB - Enzyme-catalyzed reactions often rely on a noncovalently bound cofactor whose reactivity is tuned by its immediate environment. Flavin cofactors, the most versatile catalyst encountered in biology, are often maintained within the protein throughout numbers of complex ionic and aromatic interactions. Here, we have investigated the role of pi-pi stacking and hydrogen bond interactions between a tyrosine and the isoalloxazine moiety of the flavin adenine dinucleotide (FAD) in an FAD-dependent RNA methyltransferase. Combining several static and time-resolved spectroscopies as well as biochemical approaches, we showed that aromatic stacking is assisted by a hydrogen bond between the phenol group and the amide of an adjacent active site loop. A mechanism of recognition and binding of the redox cofactor is proposed. PMID- 26120777 TI - Erratum. PMID- 26120775 TI - beta-Guanidinopropionic acid extends the lifespan of Drosophila melanogaster via an AMP-activated protein kinase-dependent increase in autophagy. AB - Previous studies have demonstrated that AMP-activated protein kinase (AMPK) controls autophagy through the mammalian target of rapamycin (mTOR) and Unc-51 like kinase 1 (ULK1/Atg1) signaling, which augments the quality of cellular housekeeping, and that beta-guanidinopropionic acid (beta-GPA), a creatine analog, leads to a chronic activation of AMPK. However, the relationship between beta-GPA and aging remains elusive. In this study, we hypothesized that feeding beta-GPA to adult Drosophila produces the lifespan extension via activation of AMPK-dependent autophagy. It was found that dietary administration of beta-GPA at a concentration higher than 900 mm induced a significant extension of the lifespan of Drosophila melanogaster in repeated experiments. Furthermore, we found that Atg8 protein, the homolog of microtubule-associated protein 1A/1B light chain 3 (LC3) and a biomarker of autophagy in Drosophila, was significantly upregulated by beta-GPA treatment, indicating that autophagic activity plays a role in the effect of beta-GPA. On the other hand, when the expression of Atg5 protein, an essential protein for autophagy, was reduced by RNA interference (RNAi), the effect of beta-GPA on lifespan extension was abolished. Moreover, we found that AMPK was also involved in this process. beta-GPA treatment significantly elevated the expression of phospho-T172-AMPK levels, while inhibition of AMPK by either AMPK-RNAi or compound C significantly attenuated the expression of autophagy-related proteins and lifespan extension in Drosophila. Taken together, our results suggest that beta-GPA can induce an extension of the lifespan of Drosophila via AMPK-Atg1-autophagy signaling pathway. PMID- 26120778 TI - Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. AB - ISSUES: There have been reviews on the association between density of alcohol outlets and harm including studies published up to December 2008. Since then the number of publications has increased dramatically. The study reviews the more recent studies with regard to their utility to inform policy. APPROACH: A systematic review found more than 160 relevant studies (published between January 2009 and October 2014). The review focused on: (i) outlet density and assaultive or intimate partner violence; (ii) studies including individual level data; or (iii) 'natural experiments'. KEY FINDINGS: Despite overall evidence for an association between density and harm, there is little evidence on causal direction (i.e. whether demand leads to more supply or increased availability increases alcohol use and harm). When outlet types (e.g. bars, supermarkets) are analysed separately, studies are too methodologically diverse and partly contradictory to permit firm conclusions besides those pertaining to high outlet densities in areas such as entertainment districts. Outlet density commonly had little effect on individual-level alcohol use, and the few 'natural experiments' on restricting densities showed little or no effects. IMPLICATIONS AND CONCLUSIONS: Although outlet densities are likely to be positively related to alcohol use and harm, few policy recommendations can be given as effects vary across study areas, outlet types and outlet cluster size. Future studies should examine in detail outlet types, compare different outcomes associated with different strengths of association with alcohol, analyse non-linear effects and compare different methodologies. Purely aggregate-level studies examining total outlet density only should be abandoned. [Gmel G, Holmes J, Studer J. Are alcohol outlet densities strongly associated with alcohol-related outcomes? A critical review of recent evidence. Drug Alcohol Rev 2015]. PMID- 26120779 TI - Long-term outcome of infliximab in severe chronic and refractory systemic sarcoidosis: a report of 16 cases. AB - OBJECTIVES: Infliximab (IFX) appears to be effective in refractory sarcoidosis. However, data are lacking regarding its efficacy in severe sarcoidosis (i.e. with cardiac and/or neurological involvement). METHODS: Retrospective single-centre study including 16 unselected consecutive patients with biopsy proven, severe, and resistant sarcoidosis, who were treated by infliximab (3 or 5 mg /kg at 0, 2 and 6 weeks, then every 8 weeks) between 2005 and 2013. RESULTS: Following IFX therapy we observed an improvement in 92% of cases, with a marked decrease of the severity score [median score 6 (3-12) vs. 2 (1-8), p<0.0001] and trend toward steroid sparing effect [12.5 (0-40) vs. 8.5 mg/d (0-30), p=0.11] between baseline and the end of follow-up, respectively. Regarding the index organ response, we observed a remission of cardiac and central nervous system involvements in 4 out of 4 and 11 out 12 cases, respectively. Thirty-eight percent of patients experienced a relapse. After a median follow-up of 57 months (2 to 91), we observed 7 (44%) infectious complications, 1 paradoxical cutaneous granuloma and 1 leucoencephalopathy. Infectious complications were mostly observed in male [6/7 (86%), p=0.06], with a longer duration of steroids (108 vs. 39 months, p=0.11) and immunosuppressant use prior IFX (42 vs. 24 months, p=0.08) compared to their negative counterpart, respectively. CONCLUSIONS: IFX was efficient in severe and refractory sarcoidosis. Infectious complications were frequent and occurred mainly in male patients with longer duration of steroids and immunosuppressant use prior to IFX. PMID- 26120780 TI - Chemiresistive sensing behavior of SnO2 (n)-Cu2O (p) core-shell nanowires. AB - We report the synthesis of SnO2-Cu2O n-p core-shell nanowires (C-S NWs) and their use as chemiresistive sensors for detecting trace amounts of gas. The n-p C-S NWs were synthesized by a two-step process, in which the core SnO2 nanowires were prepared by the vapor growth technique and subsequently the Cu2O shell layers were deposited by atomic layer deposition. A systematic investigation of the sensing capabilities of the n-p C-S NWs, particularly as a function of shell thickness, revealed the underlying sensing mechanism. The radial modulation of the hole-accumulation layer is intensified under shells thinner than the Debye length. On the other hand, the contribution of volume fraction to resistance modulation is weakened. By the combination of these two effects, an optimal sensing performance for reducing gases is obtained for a critical p-shell thickness. In contrast, the formation of p-shell layers deteriorates the NO2 sensing performance by blocking the expansion of the hole-accumulation layer due to the presence of p-n heterointerface. PMID- 26120781 TI - Comment on "Improved Calibration of Voltammetric Sensors for Studying Pharmacological Effects on Dopamine Transporter Kinetics in Vivo". PMID- 26120783 TI - Approaching the limit of Cu(II)/Cu(I) mixed valency in a Cu(I)Br2-N methylquinoxalinium hybrid compound. AB - A novel 1D hybrid salt (MQ)[CuBr2]infinity (MQ = N-methylquinoxalinium) is reported. Structural, spectroscopic and magnetic investigations reveal a minimal Cu(II) doping of less than 0.1%. However it is not possible to distinguish Cu(I) and Cu(II). The unusually close packing of the organic moieties and the dark brown colour of the crystals suggest a defect electronic structure. PMID- 26120782 TI - A comparison of location of acute symptomatic vs. 'silent' small vessel lesions. AB - BACKGROUND: Acute lacunar ischaemic stroke, white matter hyperintensities, and lacunes are all features of cerebral small vessel disease. It is unclear why some small vessel disease lesions present with acute stroke symptoms, whereas others typically do not. AIM: To test if lesion location could be one reason why some small vessel disease lesions present with acute stroke, whereas others accumulate covertly. METHODS: We identified prospectively patients who presented with acute lacunar stroke symptoms with a recent small subcortical infarct confirmed on magnetic resonance diffusion imaging. We compared the distribution of the acute infarcts with that of white matter hyperintensity and lacunes using computational image mapping methods. RESULTS: In 188 patients, mean age 67 +/- standard deviation 12 years, the lesions that presented with acute lacunar ischaemic stroke were located in or near the main motor and sensory tracts in (descending order): posterior limb of the internal capsule (probability density 0.2/mm(3)), centrum semiovale (probability density = 0.15/mm(3)), medial lentiform nucleus/lateral thalamus (probability density = 0.09/mm(3)), and pons (probability density = 0.02/mm(3)). Most lacunes were in the lentiform nucleus (probability density = 0.01-0.04/mm(3) ) or external capsule (probability density = 0.05/mm(3)). Most white matter hyperintensities were in centrum semiovale (except for the area affected by the acute symptomatic infarcts), external capsules, basal ganglia, and brainstem, with little overlap with the acute symptomatic infarcts (analysis of variance, P < 0.01). CONCLUSIONS: Lesions that present with acute lacunar ischaemic stroke symptoms may be more likely noticed by the patient through affecting the main motor and sensory tracts, whereas white matter hyperintensity and asymptomatic lacunes mainly affect other areas. Brain location could at least partly explain the symptomatic vs. covert development of small vessel disease. PMID- 26120784 TI - Ionic Liquid Facilitates the Conjugative Transfer of Antibiotic Resistance Genes Mediated by Plasmid RP4. AB - The dissemination and propagation of antibiotic resistance genes (ARGs) is an emerging global health concern. In our previous study, the ionic liquid (IL) 1 butyl-3-methylimidazolium hexafluorophosphate ([BMIm][PF6]) had been proven to facilitate the dissemination of ARGs via horizontal gene transfer. In this study, we further confirm that this compound facilitates the horizontal transfer of plasmid RP4 through a conjugation mechanism and not by natural transformation. The mechanisms for [BMIm][PF6] promoting conjugative transfer are attributable to enhancing the mRNA expression levels of conjugative and global regulatory genes, as well as by inhibiting the genes that are responsible for the vertical transfer of cell growth. [BMIm][PF6] significantly enhanced the expression of the outer membrane porin proteins (OMPs) OmpC and OmpA and the corresponding mRNA expression levels of ompC and ompA genes in recipient bacteria, which contributed to pore formation and increased cell membrane permeability. The increased expression of pilin and pili allowed the donor pilus to attach to and access the recipient cells, thereby assisting cell-to-cell contact to facilitate the conjugative transfer of plasmid RP4. To the best of our knowledge, this is the first insightful exploration of [BMIm][PF6] facilitating the conjugative transfer of ARGs mediated by plasmid RP4 and of several other ILs with different cations or anions that are capable of promoting plasmid transfer. It is therefore suggested that the application of some ILs in industrial processes should be carefully evaluated before their bulk emission into the environment. PMID- 26120786 TI - Polymer@MOF@MOF: "grafting from" atom transfer radical polymerization for the synthesis of hybrid porous solids. AB - The application of a core-shell architecture allows the formation of a polymer coated metal-organic framework (MOF) maintaining high surface area (2289-2857 m(2) g(-1)). The growth of a MOF shell from a MOF core was used to spatially localize initiators by post-synthetic modification. The confinement of initiators ensures that polymerization is restricted to the outer shell of the MOF. PMID- 26120785 TI - Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge. AB - Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand alpha-galactosylceramide (alphaGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities. PMID- 26120787 TI - Abdominal Fat Distribution and Cardiovascular Risk in Men and Women With Different Levels of Glucose Tolerance. AB - CONTEXT: Regional fat distribution rather than overall obesity has been recognized as important to understanding the link between obesity and cardiovascular disease. OBJECTIVE: We examined the associations of abdominal visceral adipose tissue (VAT) and abdominal subcutaneous adipose tissue (SAT) with cardiovascular risk factors in a Caucasian population of men and women with normal glucose tolerance, prediabetes, or screen-detected diabetes. DESIGN, SETTING, AND PARTICIPANTS: The study was based on cross-sectional analysis of data from 1412 adults age 45-80 years. VAT and SAT were assessed by ultrasound. The associations of VAT and SAT with blood pressure and lipids were examined by linear regression analysis adjusted for age, sex, smoking, alcohol, physical activity, glucose tolerance status (GTS), medication use, and body mass index. Effect modification by GTS and sex was examined, and stratified analyses performed. RESULTS: Independent of SAT and overall obesity, VAT was associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels in both men and women and additionally associated with higher total cholesterol in men. SAT was independently associated with higher total cholesterol and low-density lipoprotein cholesterol levels in both sexes, and SAT was additionally associated with higher triglyceride and lower HDL cholesterol levels in women and with higher blood pressure in participants with diabetes. CONCLUSION: Both abdominal VAT and SAT are independent of overall obesity associated with cardiovascular risk in a population of men and women at low to high risk of diabetes or with screen-detected diabetes. PMID- 26120788 TI - ApoE4 Determines the Reduction in LDL-C After GH Replacement Therapy in Children With an Idiopathic GH Deficiency. AB - CONTEXT: GH activates the expression of low-density lipoprotein (LDL) receptors, leading to decreased LDL-cholesterol (LDL-C). Apolipoprotein (apo) E4 carriers suppress LDL receptor expression, rendering high LDL-C concentrations. OBJECTIVES: We examined whether GH-deficient children carrying apoE4 exhibited a greater reduction in LDL-C after GH replacement therapy. DESIGN AND SETTING: We determined lipoprotein profiles after 0, 4, and 12 months of GH treatment in children with an idiopathic GH deficiency. We compared the effects of GH treatment on LDL-C by apoE phenotype. SUBJECTS: In total, 66 children with idiopathic GH deficiency and 89 healthy children were classified into subgroups according to apoE phenotype. INTERVENTION: The intervention included GH replacement therapy for 12 months. MAIN OUTCOME MEASURES: The relationship between apoE phenotype and reduced LDL-C induced by GH treatment was measured. RESULTS: Concentrations of LDL-C and apoB were highest in the apoE4/3 group (n = 13), second highest in the apoE3/3 group (n = 46), and lowest in the apoE3/2 group (n = 7), whereas apoE concentrations were highest in the apoE3/2 group and lowest in the apoE4/3 group. The apoE4/3 group had significantly reduced LDL-C and apoB concentrations at months 4 and 12, whereas the apoE3/3 and apoE3/2 groups showed no changes. LDL-C concentrations did not differ among the three groups after 12 months. The trend in apoE concentration did not change among the groups. CONCLUSIONS: Children with a GH deficiency carrying apoE4 had higher baseline LDL-C concentrations and experienced a greater reduction in LDL-C after GH replacement therapy than those without apoE4. PMID- 26120789 TI - Mean Platelet Volume Is Closely Associated With Serum Glucose Level but Not With Arterial Stiffness and Carotid Atherosclerosis in Patients With Type 2 Diabetes. AB - CONTEXT: Mean platelet volume (MPV) has been suggested as a predictive biomarker for cardiovascular disease. OBJECTIVE: This study investigated the association between MPV and subclinical atherosclerosis in Korean patients with type 2 diabetes. METHODS: This cross-sectional study involved 1205 patients with type 2 diabetes mellitus. Both brachial-ankle pulse wave velocity measurements and an ultrasound assessment of carotid atherosclerosis were done. Subclinical atherosclerosis was assessed by the presence of high brachial-ankle pulse wave velocity (>1743 cm/sec), carotid atherosclerosis (intima-media thickness > 0.8 mm or the presence of plaques), and carotid stenosis (>=50% of luminal narrowing). The subjects were stratified into quartiles according to MPV, and the relationship between MPV and subclinical atherosclerosis was analyzed. RESULTS: High MPV quartiles were linearly associated with fasting glucose and glycated hemoglobin but not with diabetic duration or insulin resistance. The prevalence of high pulse wave velocity, carotid atherosclerosis, and carotid stenosis did not differ between the quartiles in men and women. Multivariate logistic regression analyses revealed no association between MPV and high pulse wave velocity, carotid atherosclerosis, and carotid stenosis. CONCLUSIONS: MPV was strongly associated with the severity of glycemic control but not significantly associated with the early and late stages of atherosclerotic vascular changes in type 2 diabetes mellitus patients. Our results suggest that MPV is not a reliable marker for subclinical atherosclerosis in a diabetic population. This is possibly confounded by the close association of MPV with poor glycemic control. Further research is needed to broaden and validate the results. PMID- 26120790 TI - Serum Testosterone (T) Level Variability in T Gel-Treated Older Hypogonadal Men: Treatment Monitoring Implications. AB - CONTEXT: The optimal frequency for on-treatment serum T measurement used for dose adjustment after transdermal T gel application is unknown, especially in older men with thinner skin and slower metabolic clearance. OBJECTIVES: The objectives of the study was to determine the variability of postgel application serum T concentrations and assess whether single levels are reflective of average serum T concentrations over 24 hours (Cavg0-24). DESIGN: This was a double-blinded, placebo-controlled randomized trial. SETTING: The study was conducted at five academic centers. PARTICIPANTS: Forty-seven symptomatic men 65 years old or older with an average of two morning T concentration less than 275 ng/dL participated in the study. INTERVENTION(S): Transdermal T or placebo gel was applied for 120 +/- 14 days. Monthly dose adjustments were made if necessary to target serum T between 400 and 500 to 800 ng/dL. MAIN OUTCOME MEASURES: Variability of serum T 2 hours after the gel application on two outpatient visits and at multiple time points over 24 hours during the inpatient day was measured. RESULTS: On-treatment T levels varied substantially on the 2 ambulatory days and over 24 hours during the inpatient day. Ambulatory 2-hour postapplication T levels did not correlate significantly with either 2-hour postapplication serum T or Cavg0-24 measured during the inpatient day. Only 22.2% of men receiving T had a Cavg0-24 within the target range of 500-800 ng/dL; 81.5% had a Cavg0-24 within the broader 300-1000 ng/dL range. CONCLUSION: Large within-individual variations in serum T after T gel application render ambulatory 2-hour postapplication T level a poor indicator of average serum T on another day. Our data point out the limitations of dose adjustments based on a single postapplication serum T measurement. PMID- 26120791 TI - Lipoprotein-Free Mitotane Exerts High Cytotoxic Activity in Adrenocortical Carcinoma. AB - CONTEXT: Mitotane (o,p'-DDD), the only approved drug for advanced adrenocortical carcinoma (ACC), is a lipophilic agent that accumulates into circulating lipoprotein fractions and high-lipid-containing tissues. OBJECTIVE: The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The effect of lipoprotein-bound or lipoprotein-free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of patients with ACC treated or not with statins was also performed. RESULTS: o,p'-DDD distribution among very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and LP-F fractions obtained after plasma ultracentrifugation of 23 of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL, but also LP-F compartment. Intratumor o,p'-DDD concentrations in five ACC samples of mitotane-treated patients were found to be independent of cholesterol transporter expression, scavenger receptors, and LDL receptors. In vitro studies showed significant higher antiproliferative and proapoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control. CONCLUSIONS: Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of LP-F mitotane. Patients with ACC may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction. PMID- 26120792 TI - Recent Changes in the Clinical Outcome of Papillary Thyroid Carcinoma With Cervical Lymph Node Metastasis. AB - CONTEXT: The prognosis of papillary thyroid cancer (PTC) with cervical lymph node (LN) metastasis has changed with increased detection of subclinical metastatic LNs. The number and size of metastatic LNs were proposed as new prognostic factors in PTC with cervical LN metastasis (N1). OBJECTIVE: The objective of the study was to evaluate changes in N1 PTC characteristics and clinical outcome over time and to confirm the prognostic value of the number and size of metastatic LNs. DESIGN AND PATIENTS: This study included 1815 N1 PTC patients diagnosed between 1997 and 2011. Patients were classified into three risk groups according to the number and size of metastatic LNs: very low risk, five or fewer and 0.2 cm or less; low risk, five or fewer and 0.2 cm or greater; and high risk, more than five. MAIN OUTCOME MEASURES: Response to initial therapy and disease-free survival (DFS) was measured. RESULTS: Metastatic LNs became smaller, and the ratio of metastatic LNs, which represents the extent of LN involvement and the completeness of surgery, decreased significantly over time. The proportion of patients with excellent response significantly increased from 33% to 67% over time (P < .001). These improvements were more evident in the low- and high-risk groups than in the very low-risk group. The DFS 5 years after initial surgery was also significantly increased from 73% to 91% over time (P < .001). The new LN classification was strongly associated with outcome. Patients in the very low risk group had longer DFS than those in the low- and high-risk groups during the study period. CONCLUSIONS: The clinical outcome of N1 PTC has significantly changed over time with the earlier detection of thyroid cancers with less extensive LN involvement. More complete surgical neck dissection also might be responsible for these changes. The number and size of metastatic LNs are important prognostic factors of recurrence in N1 PTC. PMID- 26120793 TI - Seasonal Variability in Vitamin D Levels No Longer Detectable in Primary Hyperparathyroidism. AB - CONTEXT: Seasonal variability in 25-hydroxyvitamin D [25(OH)D] and PTH levels in the general population has been associated with differences in bone turnover markers, bone density, and fracture risk. Seasonal variability in 25(OH)D and PTH levels has also been reported in primary hyperparathyroidism (PHPT). OBJECTIVE: Given the widespread use of vitamin D supplements, we sought to determine whether patients with PHPT still demonstrated seasonal variation in 25(OH)D levels. DESIGN AND SETTING: This cross-sectional study was conducted at a university medical center at a Northeastern U.S. latitude (New York, NY). PATIENTS: One hundred patients with PHPT participated in the study. OUTCOME MEASURES: We assessed vitamin D supplement use and seasonal variation in serum 25(OH)D. RESULTS: Patients had PHPT ([mean +/- SD] calcium, 10.8 +/- 1.0 mg/dL; PTH, 85 +/ 48 pg/mL) with a mean 25(OH)D level of 29 +/- 10 ng/mL. Although only one fifth of participants had vitamin D deficiency (19% < 20 ng/mL), more than half were either deficient or insufficient (54% < 30 ng/mL). Sun exposure varied by season, but there were no seasonal differences in levels of 25(OH)D, PTH, bone markers, or bone mineral density, or in the prevalence of 25(OH)D less than 20 or less than 30 ng/mL. Most of the participants (65%) took supplemental vitamin D (dose among users: mean, 1643 +/- 1496 IU; median, 1000 IU daily), and supplement users had markedly better vitamin D status than nonusers (25(OH)D < 20 ng/mL: 8 vs 40%; P < .0001; < 30 ng/mL: 40 vs 80%; P = .0001; >= 30 ng/mL: 60 vs 20%; P = .0001). CONCLUSIONS: We found no evidence of seasonal variation in 25(OH)D levels or PHPT disease severity in the Northeastern United States. This change is likely due to widespread high vitamin D supplement intake, which has resulted in better vitamin D status among supplement users and can mask the effect of season on serum 25(OH)D levels. PMID- 26120794 TI - 25-Hydroxyvitamin D Can Interfere With a Common Assay for 1,25-Dihydroxyvitamin D in Vitamin D Intoxication. AB - CONTEXT: Vitamin D intoxication is characterized by elevated serum 25 hydroxyvitamin D (25(OH)D) and suppressed serum 1,25-dihydroxvitamin D (1,25(OH)2D). We evaluated two adolescents with hypercalcemia due to vitamin D intoxication; both had elevated serum 1,25(OH)2D by Diasorin RIA, but normal serum 1,25(OH)2D concentrations by liquid chromatography-tandem mass spectrometry (LC-MS/MS). OBJECTIVE: This study aimed to determine the effect of 25(OH)D2 and 25(OH)D3 on 1,25(OH)2D concentration determined using RIA and LC-MS/MS. METHODS: Pools of normal serum and an artificial serum matrix were prepared and aliquots were spiked with >99% pure 25(OH)D2 or 25(OH)D3 (50-700 ng/mL). Samples were maintained at 4 degrees C or heated to 56 degrees C, and the concentrations of vitamin D metabolites were measured by LC-MS/MS and Diasorin RIA. RESULTS: Median 1,25(OH)2D increased by 114% with RIA and 21% with LC-MS/MS with addition of 100 ng/mL 25(OH)D3, and 349% (RIA) and 117% (LC-MS/MS) with 700 ng/mL of 25(OH)D3. Each 1-ng/mL increase in 25(OH)D3 increased 1,25(OH)2D by 0.231 pg/mL (RIA) and 0.121 pg/mL (LC-MS/MS). Spiking with 25(OH)D2 led to similar changes. Heat inactivation of serum, and using an artificial serum matrix, were associated with similar effects of 25(OH)D on 1,25(OH)2D assays. CONCLUSIONS: Vitamin D intoxication with high serum levels of 25(OH)D2 or 25(OH)D3 can be associated with elevated levels of 1,25(OH)2D due to interference in a commonly used RIA. A similar but attenuated effect also occurs when 1,25(OH)2D is measured using LC MS/MS but does not seem to be clinically significant. The basis for this effect on the LC-MS/MS assay is presently uncertain. PMID- 26120797 TI - Transvenous Approach to Intracranial Arteriovenous Malformations: Challenging the Axioms of Arteriovenous Malformation Therapy? AB - : A compartmental conceptualization of intracranial arteriovenous malformations (AVMs) allows recognition of feeding arteries, an intervening plexiform nidus, and draining veins. AVM therapy involves eliminating the nidus, which is the source of hemorrhage, without compromising normal arterial and venous drainage of the brain. Traditional methods of AVM therapy through microsurgery and endovascular embolization involve arterial devascularization, with preservation of AVM venous drainage, until the nidus is excluded. The transvenous approach in treating vascular malformations was popularized by successful treatment models for dural arteriovenous fistulas. More recently, high-flow intracranial AVMs are being managed with transvenous endovascular approaches, although this novel technique has its challenges and perils. We review the current literature on transvenous AVM therapy and highlight its role for AVM therapy in the present day. PMID- 26120796 TI - Structural basis of enzymatic benzene ring reduction. AB - In chemical synthesis, the widely used Birch reduction of aromatic compounds to cyclic dienes requires alkali metals in ammonia as extremely low-potential electron donors. An analogous reaction is catalyzed by benzoyl-coenzyme A reductases (BCRs) that have a key role in the globally important bacterial degradation of aromatic compounds at anoxic sites. Because of the lack of structural information, the catalytic mechanism of enzymatic benzene ring reduction remained obscure. Here, we present the structural characterization of a dearomatizing BCR containing an unprecedented tungsten cofactor that transfers electrons to the benzene ring in an aprotic cavity. Substrate binding induces proton transfer from the bulk solvent to the active site by expelling a Zn(2+) that is crucial for active site encapsulation. Our results shed light on the structural basis of an electron transfer process at the negative redox potential limit in biology. They open the door for biological or biomimetic alternatives to a basic chemical synthetic tool. PMID- 26120798 TI - New Protocol for Skin Landmark Registration in Image-Guided Neurosurgery: Technical Note. AB - BACKGROUND: Newer versions of the commercial Medtronic StealthStation allow the use of only 8 landmark pairs for patient-to-image registration as opposed to 9 landmarks in older systems. The choice of which landmark pair to drop in these newer systems can have an effect on the quality of the patient-to-image registration. OBJECTIVE: To investigate 4 landmark registration protocols based on 8 landmark pairs and compare the resulting registration accuracy with a 9 landmark protocol. METHODS: Four different protocols were tested on both phantoms and patients. Two of the protocols involved using 4 ear landmarks and 4 facial landmarks and the other 2 involved using 3 ear landmarks and 5 facial landmarks. Both the fiducial registration error and target registration error were evaluated for each of the different protocols to determine any difference between them and the 9-landmark protocol. RESULTS: No difference in fiducial registration error was found between any of the 8-landmark protocols and the 9-landmark protocol. A significant decrease (P < .05) in target registration error was found when using a protocol based on 4 ear landmarks and 4 facial landmarks compared with the other protocols based on 3 ear landmarks. CONCLUSION: When using 8 landmarks to perform the patient-to-image registration, the protocol using 4 ear landmarks and 4 facial landmarks greatly outperformed the other 8-landmark protocols and 9 landmark protocol, resulting in the lowest target registration error. PMID- 26120799 TI - Can Preoperative Imaging Predict Tumor Involvement of the Anterior Clinoid in Clinoid Region Meningiomas? AB - BACKGROUND: Anterior clinoid region meningiomas may infiltrate the bone over which they arise, therefore requiring an anterior clinoidectomy to achieve a Simpson grade 1 resection. A clinoidectomy, however, is not without risks. OBJECTIVE: We performed a study of diagnostic accuracy investigating whether preoperative imaging could predict tumor involvement of the clinoid, and thereby tailor the degree of bony removal. METHODS: Patients having undergone resection of a clinoid region meningioma between 2001 and 2011 were identified. Included in further analysis were those patients in whom a clinoidectomy was performed with subsequent pathologically confirmed presence or absence of tumor in the clinoid process on decalcified specimens. Two neuroradiologists, blinded to pathology results, independently reviewed available preoperative imaging and stated whether or not they anticipated the clinoid to be involved by tumor. Interobserver agreement and the ability to accurately predict tumor involvement of the clinoid were then analyzed. RESULTS: Sixty-two patients were included in the final analysis. Interobserver agreement was 100%. Sensitivity and specificity of preoperative imaging to predict tumor involvement was 89% and 52%, respectively, with positive and negative likelihood ratios of 1.85 and 0.20. Positive and negative predictive values were 73% and 76%, respectively. CONCLUSION: Preoperative imaging of clinoid region meningiomas can accurately predict the presence or absence of tumor involvement of the clinoid in only approximately 75% of cases. In light of the fact that a quarter of patients with radiographically negative clinoids will have tumor present on pathological analysis, we recommend a clinoidectomy for all clinoid region meningiomas. PMID- 26120801 TI - Hepatitis C Virus Treatment and Injection Drug Users: It Is Time to Separate Fact From Fiction. PMID- 26120800 TI - Resective Epilepsy Surgery for Tuberous Sclerosis in Children: Determining Predictors of Seizure Outcomes in a Multicenter Retrospective Cohort Study. AB - BACKGROUND: There are no established variables that predict the success of curative resective epilepsy surgery in children with tuberous sclerosis complex (TSC). OBJECTIVE: We performed a multicenter observational study to identify preoperative factors associated with seizure outcome in children with TSC undergoing resective epilepsy surgery. METHODS: A retrospective chart review was performed in eligible children at New York Medical Center, Miami Children's Hospital, Cleveland Clinic Foundation, BC Children's Hospital, Hospital for Sick Children, and Sainte-Justine Hospital between January 2005 and December 2013. A time-to-event analysis was performed. The "event" was defined as seizures after resective epilepsy surgery. RESULTS: Seventy-four patients (41 male) were included. The median age of the patients at the time of surgery was 120 months (range, 3-216 months). The median time to seizure recurrence was 24.0 +/- 12.7 months. Engel Class I outcome was achieved in 48 (65%) and 37 (50%) patients at 1 and 2-year follow-up, respectively. On univariate analyses, younger age at seizure onset (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.03-4.00, P = .04), larger size of predominant tuber (HR: 1.03, 95% CI: 0.99-1.06, P = .12), and resection larger than a tuberectomy (HR: 1.86, 95% CI: 0.92-3.74, P = .084) were associated with a longer duration of seizure freedom. In multivariate analyses, resection larger than a tuberectomy (HR: 2.90, 95% CI: 1.17-7.18, P = .022) was independently associated with a longer duration of seizure freedom. CONCLUSION: In this large consecutive cohort of children with TSC and medically intractable epilepsy, a greater extent of resection (more than just the tuber) is associated with a greater probability of seizure freedom. This suggests that the epileptogenic zone may include the cortex surrounding the presumed offending tuber. PMID- 26120802 TI - Phenotypic variation in epidermolytic ichthyosis: clinical and functional evaluation of the novel p.(Met339Lys) mutation in the L12 domain of KRT1. PMID- 26120803 TI - Doping of Graphene by Low-Energy Ion Beam Implantation: Structural, Electronic, and Transport Properties. AB - We investigate the structural, electronic, and transport properties of substitutional defects in SiC-graphene by means of scanning tunneling microscopy and magnetotransport experiments. Using ion incorporation via ultralow energy ion implantation, the influence of different ion species (boron, nitrogen, and carbon) can directly be compared. While boron and nitrogen atoms lead to an effective doping of the graphene sheet and can reduce or raise the position of the Fermi level, respectively, (12)C(+) carbon ions are used to study possible defect creation by the bombardment. For low-temperature transport, the implantation leads to an increase in resistance and a decrease in mobility in contrast to undoped samples. For undoped samples, we observe in high magnetic fields a positive magnetoresistance that changes to negative for the doped samples, especially for (11)B(+)- and (12)C(+)-ions. We conclude that the conductivity of the graphene sheet is lowered by impurity atoms and especially by lattice defects, because they result in weak localization effects at low temperatures. PMID- 26120804 TI - Nonsteroidal anti-inflammatory drugs (NSAIDs) and non-opioids for acute renal colic. AB - BACKGROUND: Renal colic is acute pain caused by urinary stones. The prevalence of urinary stones is between 10% and 15% in the United States, making renal colic one of the common reasons for urgent urological care. The pain is usually severe and the first step in the management is adequate analgesia. Many different classes of medications have been used in this regard including non-steroidal anti inflammatory drugs and narcotics. OBJECTIVES: The aim of this review was to assess benefits and harms of different NSAIDs and non-opioids in the treatment of adult patients with acute renal colic and if possible to determine which medication (or class of medications) are more appropriate for this purpose. Clinically relevant outcomes such as efficacy of pain relief, time to pain relief, recurrence of pain, need for rescue medication and side effects were explored. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register (to 27 November 2014) through contact with the Trials' Search Co ordinator using search terms relevant to this review. SELECTION CRITERIA: Only randomised or quasi randomised studies were included. Other inclusion criteria included adult patients with a clinical diagnosis of renal colic due to urolithiasis, at least one treatment arm included a non-narcotic analgesic compared to placebo or another non-narcotic drug, and reporting of pain outcome or medication adverse effect. Patient-rated pain by a validated tool, time to relief, need for rescue medication and pain recurrence constituted the outcomes of interest. Any adverse effects (minor or major) reported in the studies were included. DATA COLLECTION AND ANALYSIS: Abstracts were reviewed by at least two authors independently. Papers meeting the inclusion criteria were fully reviewed and relevant data were recorded in a standardized Cochrane Renal Group data collection form. For dichotomous outcomes relative risks and 95% confidence intervals were calculated. For continuous outcomes the weighted mean difference was estimated. Both fixed and random models were used for meta-analysis. We assessed the analgesic effects using four different outcome variables: patient reported pain relief using a visual analogue scale (VAS); proportion of patients with at least 50% reduction in pain; need for rescue medication; and pain recurrence. Heterogeneity was assessed using the I2 test. MAIN RESULTS: A total of 50 studies (5734 participants) were included in this review and 37 studies (4483 participants) contributed to our meta-analyses. Selection bias was low in 34% of the studies or unclear in 66%; performance bias was low in 74%, high in 14% and unclear in 12%; attrition bias was low in 82% and high in 18%; selective reporting bias low in 92% of the studies; and other biases (industry funding) was high in 4%, unclear in 18% and low in 78%.Patient-reported pain (VAS) results varied widely with high heterogeneity observed. For those comparisons which could be pooled we observed the following: NSAIDs significantly reduced pain compared to antispasmodics (5 studies, 303 participants: MD -12.97, 95% CI -21.80 to - 4.14; I2 = 74%) and combination therapy of NSAIDs plus antispasmodics was significantly more effective in pain control than NSAID alone (2 studies, 310 participants: MD -1.99, 95% CI -2.58 to -1.40; I2 = 0%).NSAIDs were significantly more effective than placebo in reducing pain by 50% within the first hour (3 studies, 197 participants: RR 2.28, 95% CI 1.47 to 3.51; I2 = 15%). Indomethacin was found to be less effective than other NSAIDs (4 studies, 412 participants: RR 1.27, 95% CI 1.01 to 1.60; I2 = 55%). NSAIDs were significantly more effective than hyoscine in pain reduction (5 comparisons, 196 participants: RR 2.44, 95% CI 1.61 to 3.70; I2 = 28%). The combination of NSAIDs and antispasmodics was not superior to NSAIDs only (9 comparisons, 906 participants: RR 1.00, 95% CI 0.89 to 1.13; I2 = 59%). The results were mixed when NSAIDs were compared to other non opioid medications.When the need for rescue medication was evaluated, Patients receiving NSAIDs were significantly less likely to require rescue medicine than those receiving placebo (4 comparisons, 180 participants: RR 0.35, 95% CI 0.20 to 0.60; I2 = 24%) and NSAIDs were more effective than antispasmodics (4 studies, 299 participants: RR 0.34, 95% CI 0.14 to 0.84; I2 = 65%). Combination of NSAIDs and antispasmodics was not superior to NSAIDs (7 comparisons, 589 participants: RR 0.99, 95% CI 0.62 to 1.57; I2 = 10%). Indomethacin was less effective than other NSAIDs (4 studies, 517 participants: RR 1.36, 95% CI 0.96 to 1.94; I2 = 14%) except for lysine acetyl salicylate (RR 0.15, 95% CI 0.04 to 0.65).Pain recurrence was reported by only three studies which could not be pooled: a higher proportion of patients treated with 75 mg diclofenac (IM) showed pain recurrence in the first 24 hours of follow-up compared to those treated with 40 mg piroxicam (IM) (60 participants: RR 0.05, 95% CI 0.00 to 0.81); no significant difference in pain recurrence at 72 hours was observed between piroxicam plus phloroglucinol and piroxicam plus placebo groups (253 participants: RR 2.52, 95% CI 0.15 to12.75); and there was no significant difference in pain recurrence within 72 hours of discharge between IM piroxicam and IV paracetamol (82 participants: RR 1.00, 95% CI 0.65 to 1.54).Side effects were presented inconsistently, but no major events were reported. AUTHORS' CONCLUSIONS: Although due to variability in studies (inclusion criteria, outcome variables and interventions) and the evidence is not of highest quality, we still believe that NSAIDs are an effective treatment for renal colic when compared to placebo or antispasmodics. The addition of antispasmodics to NSAIDS does not result in better pain control. Data on other types of non-opioid, non-NSAID medication was scarce.Major adverse effects are not reported in the literature for the use of NSAIDs for treatment of renal colic. PMID- 26120805 TI - Ag nanocluster-based label-free catalytic and molecular beacons for amplified biosensing. AB - By employing DNAzyme as a recognition group and amplifier, and DNA-stabilized silver nanoclusters (DNA/AgNCs) as signal reporters, we reported for the first time a label-free catalytic and molecular beacon as an amplified biosensing platform for highly selective detection of cofactors such as Pb(2+) and L histidine. PMID- 26120806 TI - Altered one-carbon metabolism in posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased morbidity and mortality through somatic conditions, particularly cardiovascular disease. The one-carbon metabolism in connection with the hypothalamic-pituitary adrenal (HPA)-axis may be an important mediator of this increased cardiovascular risk. METHODS: In a mixed-gender sample of 49 PTSD patients and 45 healthy controls we therefore investigated: (1) alterations in the one-carbon metabolism as reflected in fasting plasma concentrations of homocysteine, folate, vitamins B6 and B12, and (2) associations of these one-carbon metabolites with the HPA axis hormones cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S). RESULTS: After correction for confounders, PTSD patients had significantly elevated homocysteine (z = 2.963, p = .003) compared to controls, but normal levels of folate, vitamin B6 and B12. Comorbid depression did not explain the observed higher homocysteine levels. Patients showed increased risk for moderate hyperhomocysteinemia (OR = 7.0, chi(2) = 7.436, p = .006). Additionally, homocysteine was associated with PTSD severity (z = 2.281, p = .005). Moreover, all HPA-axis hormones were associated with folate in both patients and controls (all p's <= .011), while DHEA-S influenced folate in patients (z = 2.089, p = .037). LIMITATIONS: Our clinical sample is relatively small and therefore small sized effects may have remained undetected. CONCLUSIONS: Our study indicates that: (1) the one-carbon metabolism is altered in PTSD patients, (2) earlier findings of higher homocysteine in male PTSD patients are generalized to female patients, (3) homocysteine is negatively associated with PTSD severity, and (4) HPA-axis alterations are associated with the one-carbon metabolism. Longitudinal studies are needed to determine whether elevated homocysteine levels reflect preexisting risk factors and/or consequences of psychological trauma. PMID- 26120807 TI - Suicidality-based prediction of suicide attempts in a community-dwelling elderly population: Results from the Osan Mental Health Survey. AB - BACKGROUND: Data on outcomes of suicidality in the community-dwelling elderly are scarce. We investigated the association of suicidality with the suicide attempts in a community-dwelling elderly cohort. METHODS: In the Osan Mental Health Survey, 848 randomly sampled elderly Koreans participated in the baseline evaluation, 623 completed 2-year follow-up evaluation and 32 died during the follow-up period. The survey was conducted between February 2010 and January 2013. We evaluated suicidality using the Mini-International Neuropsychiatric Interview suicidality module that includes both suicidal ideation and attempts. RESULTS: The incidences of suicidality and suicide attempts were 70.7 and 13.1 per 1000 persons per year, respectively. Suicidality was associated with increased risk of suicide attempts (odds ratio (OR) = 3.84, 95% CI = 1.06-13.87). Two men with suicidality committed suicide by self-poisoning. Moderate to high intensity daily exercise decreased the risk of suicidality to become persistent or recurrent (OR = 0.32, 95% CI = 0.12-0.81). Low education level (OR = 2.41, 95% CI = 1.21-4.77) and depression (OR = 3.02, 95% CI = 1.65-5.53) were associated with risk of incident suicidality. LIMITATIONS: Study sample was enrolled from a single city of Korea, and the size of the study sample was small. CONCLUSIONS: We may reduce suicide attempts by screening for suicidality and implementing exercise programs in community-dwelling elderly people. PMID- 26120808 TI - Glucose metabolism alterations in patients with bipolar disorder. AB - Patients with bipolar disorder (BD) are more frequently affected by metabolic syndrome (MetS) than the general population, but the neurobiological correlates underlying such association are still not clarified and few studies in BD have evaluated the role of regulators of lipid and glucose metabolism. The present study was aimed to investigate putative alterations in markers linked to metabolic dysfunctions as C-peptide, Ghrelin, GIP, GLP-1, Glucagon, Insulin, Leptin, PAI-1 (total), Resistin and Visfatin in a sample of BD patients compared to controls. Furthermore, associations between changes of metabolic markers and relevant clinical features, such as severity of symptomatology, number and type of past mood episodes, drug treatments and presence/absence of metabolic alterations (MetS, diabetes and cardiovascular disease) were analyzed. A total of 57 patients with BD and 49 healthy controls were recruited. The main results showed lower serum levels of Glucagon, GLP-1, Ghrelin, and higher levels of GIP in BD patients as compared to controls (p = 0.018 for Ghrelin; p < 0.0001 for Glucagon; p < 0.0001 for GLP-1; p < 0.0001 for GIP). Further, Glucagon and GLP-1 levels were significantly associated with the number of past mood episodes. These findings support the hypothesis that alterations in Glucagon, GLP-1, GIP and Ghrelin might be involved in BD pathogenesis and might represent useful biomarkers for the development of preventive and personalized therapies in this disorder. PMID- 26120809 TI - Loudness dependence of auditory evoked potentials (LDAEP) in clinical monitoring of suicidal patients with major depression in comparison with non-suicidal depressed patients and healthy volunteers: A follow-up-study. AB - Differences in central serotonergic function due to affective disorders and due to extraordinary situations like suicidality may be visualized using the loudness dependence of auditory evoked potentials (LDAEP). Twenty patients (mean age 43.25 +/- 10.85, age range 20-61, 11 male) suffering from a major depressive episode who had either acutely attempted suicide or who had suicidal plans and behavior, which are reflected by item 3 of Hamilton Depression Rating Scale >= 3 (suicidality), were included in the study. Furthermore, we intended to compare their LDAEP to those of non-suicidal depressed patients as well as to healthy volunteers, each matched according to age and gender. LDAEP measurement and psychometric tests took place about 2, 5, 9, 16 and 30 days after acute suicidal action or suicide attempts. In contrast to previous results, significant differences in LDAEP could not have been shown in between the suicidal group, or by comparing results of suicidal patients to non-suicidal depressed patients or to healthy volunteers. However, when the LDAEP of non-suicidal depressed patients were compared to healthy volunteers, there was a trend for a higher LDAEP in the healthy volunteers. Further studies are necessary to detect and describe further influences on serotonergic function and confounding factors like medication, smoking, age, gender, comorbidities and methods of suicidal attempts. PMID- 26120810 TI - Novel signal amplification strategy for ultrasensitive sandwich-type electrochemical immunosensor employing Pd-Fe3O4-GS as the matrix and SiO2 as the label. AB - An ultrasensitive sandwich-type electrochemical immunosensor based on a novel signal amplification strategy was developed for the quantitative determination of human immunoglobulin G (IgG). Pd nanocubes functionalized magnetic graphene sheet (Pd-Fe3O4-GS) was employed as the matrix to immobilize the primary antibodies (Ab1). Owing to the synergetic effect between Pd nanocubes and magnetic graphene sheet (Fe3O4-GS), Pd-Fe3O4-GS can provide an obviously increasing electrochemical signal by electrochemical catalysis towards hydrogen peroxide (H2O2). Silicon dioxide (SiO2) was functionalized as the label to conjugate with the secondary antibodies (Ab2). Due to the larger steric hindrance of the obtained conjugate (SiO2@Ab2), the sensitive decrease of the electrochemical signal can be achieved after the specific recognition between antibodies and antigens. In this sense, this proposed immunosensor can achieve a high sensitivity, especially in the presence of low concentrations of IgG. Under optimum conditions, the proposed immunosensor offered an ultrasensitive and specific determination of IgG down to 3.2 fg/mL. This immunoassay method would open up a new promising platform to detect various tumor markers at ultralow levels for early diagnoses of different cancers. PMID- 26120811 TI - Exonuclease III-based target recycling for ultrasensitive homogeneous monitoring of HIV DNA using Ag(+)-coordinated hairpin probe. AB - A new homogeneous electrochemical sensing strategy based on exonuclease III assisted target recycling amplification was utilized for simple, rapid and highly sensitive detection of human immunodeficiency virus (HIV) DNA on an immobilization-free Ag(I)-assisted hairpin DNA through the cytosine-Ag(+) cytosine coordination chemistry. The assay involved target-induced strand displacement reaction accompanying dissociation of the chelated Ag(+) in the hairpins and exonuclease III-triggered target recycling. Initially, the added target DNA hybridized with hairpin DNA to disrupt the Ag(I)-coordinated hairpin probe and releases the coordinated Ag(+) ion. Then, the newly formed DNA double stranded DNA could be cleaved by exonuclease III, and released target HIV DNA, which retriggered the strand-displacement reaction with the hairpin for target recycling, thereby resulting in formation of numerous free Ag(+) ions in the detection cell. The released Ag(+) ions can be readily captured by the negatively charged electrode, and subsequent anodic-stripping voltammetric detection of the captured Ag(+) ions are conducted to form the anodic current for the production of the electronic signal within the applied potential. Under optimal conditions, the exonuclease III-based sensing system exhibited good electrochemical responses for the detection of HIV DNA at a concentration as low as 23 fM. PMID- 26120812 TI - Highly exposed Pt nanoparticles supported on porous graphene for electrochemical detection of hydrogen peroxide in living cells. AB - In this study, we developed a novel biosensor based on highly exposed Pt nanoparticles (Pt NPs) decorated porous graphene (PG) for the reliable detection of extracellular hydrogen peroxide (H2O2) released from living cells. The commercially available low-cost hydrophilic CaCO3 spheres were used as template for preparing PG. The porous structure provided larger surface area and more active sites. Due to the porous structure of PG, the Pt NPs supported on PG were not secluded by aggregated graphene layers and were highly exposed to target molecules. Ultrafine Pt NPs were well dispersed and loaded on PG by a method of microwave assistance. Electrochemical performances of the Pt/PG nanocomposites modified glassy carbon electrode (GCE) were investigated. The electrocatalytic reduction of H2O2 showed a wide linear range from 1 to 1477 MUM, with a high sensitivity of 341.14 MUA mM(-1) cm(-2) and a limit of detection (LOD) as low as 0.50 MUM. Moreover, the Pt/PG/GCE exhibited excellent anti-interference property, reproducibility and long-term storage stability. Because of these remarkable analytical advantages, the constructed sensor was used to determine H2O2 released from living cells with satisfactory results. The superior catalytic activity makes Pt/PG nanocomposites a promising candidate for electrochemical sensors and biosensors design. PMID- 26120813 TI - Triple functional DNA-protein conjugates: Signal probes for Pb(2+) using evanescent wave-induced emission. AB - We describe here a Pb(2+)-dependent DNAzyme-based evanescent wave-induced emission (EWIE) biosensing platform using triple functional DNA-protein conjugates as signal probes for Pb(2+) detection. Upon reaction with Pb(2+), the substrate strand is cleaved, releasing an invasion fragment, which is then hybridized with the complementary DNA strand immobilized on magnetic beads, while dissociating of the original hybridized signal probes. The signal probes, consisting of a streptavidin moiety and a Cy5.5 labeled DNA moiety, act simultaneously as signal conversion, signal recognition and signal report elements. Detection of the signal probes is accomplished by first adsorbing to the desthiobiotin-modified optical fiber, followed by fluorescence emission induced by an evanescent field. A linear calibration was obtained from 20 nM to 800 nM with a detection limit of 1 nM. The optical fiber system is robust enough for 250 sensing cycles and can be stored at room temperature over one month. These results demonstrate that application of DNA-streptavidin conjugates has been extended to DNAzyme-based biosensors, maintaining activity, specificity, regeneration and long-term storage ability. PMID- 26120814 TI - A high-performance nonenzymatic piezoelectric sensor based on molecularly imprinted transparent TiO2 film for detection of urea. AB - Transparent photocatalytic surfaces are of ever increasing importance for the enhancement of the photocatalytic efficiency. Here, the highly ordered transparent TiO2 nanotube arrays were prepared by the anodization and thermal annealing of titanium layer deposited onto the glass substrate, and a novel nonenzymatic piezoelectric sensor was developed for urea detection based on the modification of molecularly imprinted TiO2 thin film onto transparent TiO2 nanotube arrays. The performance of the fabricated sensor was evaluated and the results indicated that the sensor exhibited high sensitivity in urea detection, with a linear range from 0.04 to 120 MUM and a limit of detection of 0.01 MUM. Moreover, the sensor presented outstanding selectivity while used in coexisting systems containing various interferents with high concentration. The analytical application of the urea sensor confirmed the feasibility of urea detection in urine sample. PMID- 26120815 TI - A new fluorescent nitrogen-doped carbon dot system modified by the fluorophore labeled ssDNA for the analysis of 6-mercaptopurine and Hg (II). AB - A simple, environmentally friendly hydrothermal method was used to prepare strongly luminescent, nitrogen-doped carbon dots (NCDs) with the use of Chinese yams as a source of carbon and nitrogen. Such NCDs have an average size of 2.7+/ 1.4 nm; they emit blue light at 420 nm and have a quantum yield of up to 9.3%. Thus, carboxyfluorescein (FAM)-DNA macro-molecules were assembled on the surfaces of the NCDs, and stabilised by strong pi-pi stacking; the so formed hybrid nano sensors were found to have an ultra-sensitive response to 6-mercaptopurine (6 MP). A strong emission and enhancement of yellow radiation was observed from FAM. Furthermore, due to the specific interactions between DNA and Hg(2+), which resulted in the formation of the T-Hg(2+)-T (T: thymine base) complex - a large, conjugated system, which formed between NCDs, DNA and 6-MP, was broken up. Thus, the fluorescence from FAM was quenched. The detection limits for 6-MP and Hg(2+) were 0.67 and 1.26 nM, respectively. The proposed method was applied for the determination of 6-MP in human serum and Hg(2+) in water samples with satisfactory results. PMID- 26120816 TI - G-quadruplex DNAzyme-based electrochemiluminescence biosensing strategy for VEGF165 detection: Combination of aptamer-target recognition and T7 exonuclease assisted cycling signal amplification. AB - The expression profile of vascular endothelial growth factor (VEGF) is highly correlated with the occurrence and development of cancer. This work reports an electrochemiluminescence (ECL) approach for highly sensitive detection of VEGF165. This approach comprises aptamer-target recognition, T7 exonuclease (T7 Exo)-assisted cycling signal amplification and efficient quenching of ECL of CdS:Eu nanocrystals (NCs) by using DNAzyme. In this assay, CdS:Eu NCs were used as the ECL substrate, A guanine (G)-rich single-stranded DNA (ssDNA) sequence and VEGF165 aptamer were co-immobilized on the surface of the CdS:Eu NCs modified glassy carbon electrode. After recognition and binding to VEGF165, the aptamer moved away from the electrode surface and induced the proposed cyclic cleavage of the target DNA with T7 Exo. A large amount of G-rich ssDNA was released on the CdS:Eu film and folded into G-quadruplex/hemin DNAzyme in the presence of hemin and K(+), consequently decreasing the ECL intensity of CdS:Eu. A good linearity was obtained for VEGF165 detection within the range of 1 pM to 20 nM with a detection limit of 0.2 pM. This assay could be a universal and promising protocol for detection of various biomarkers for early clinical diagnosis. PMID- 26120817 TI - A label-free electrochemiluminescence immunosensor based on KNbO3-Au nanoparticles@Bi2S3 for the detection of prostate specific antigen. AB - A high sensitive label-free electrochemiluminescence (ECL) immunosensor was fabricated for the detection of prostate specific antigen (PSA) based on potassium niobate-Au nanoparticles@bismuth sulfide (KNbO3-Au NPs@Bi2S3) modified glassy carbon electrode (GCE). The prepared Bi2S3 nanosheets exhibited strong and stable cathodic ECL activity. The synthesized KNbO3-Au NPs was firstly used to fabricate ECL modified electrodes and Bi2S3 nanosheets worked as luminophores for the first time in ECL sensors. Au NPs were used to combine with Bi2S3 and anti PSA via the Au-S covalent bond and Au-NH2 covalent bond without the usage of crosslinking agents respectively, further enhancing the sensitivity and stability of immunosensor. Under the optimum experimental conditions, the ECL signal of KNbO3-Au NPs@Bi2S3 linearly decreased with the increase of PSA concentration in the range of 0.005-5 ng/mL with a detection limit of 3 pg/mL. The preparated label-free ECL immunosensor exhibited high sensitivity and selectivity, good repeatability and long-term stability. The applicability of the proposed ECL immunosensor was also evaluated by detecting PSA in real samples. PMID- 26120818 TI - Asymmetry in the Collision Judgments of People With Homonymous Field Defects and Left Hemispatial Neglect. AB - PURPOSE: Although the impact of homonymous visual field defects (HFDs) on mobility has been investigated previously, the emphasis has been on obstacle detection. Relatively little is known about HFD patients' ability to judge collisions once an obstacle is detected. We investigated this using a walking simulator. METHODS: Patients with HFDs (n = 29) and subjects with normal vision (NV; n = 21) were seated in front of a large screen on which a visual simulation of walking was displayed. They made collision judgments for a human figure that appeared for 1 second at lateral offsets from the virtual walking path. A perceived-collision threshold was calculated for right and left sides. RESULTS: Symmetrical collision thresholds (same on left and right sides) were measured for participants with NV (n = 21), and right (n = 9) and left (n = 7) HFD without hemispatial neglect. Participants with left neglect (n = 10) showed significant asymmetry with thresholds smaller (compared to the NV group and other HFD groups) on the blind (P < 0.001) and larger on the seeing (P = 0.05) sides. Despite the asymmetry, the overall width of the zone of perceived collision risk was not different, suggesting a relatively uniform rightward deviation in judgments of the left neglect group. CONCLUSIONS: Left neglect was associated with rightward asymmetry in collision judgments, which may cause collisions on the left side even when an obstacle is detected. These behaviors may represent the spatial misperceptions in body midline described previously in patients with left neglect. PMID- 26120819 TI - Genome-Wide Analysis of Ocular Adnexal Lymphoproliferative Disorders Using High Resolution Single Nucleotide Polymorphism Array. AB - PURPOSE: We identified the genomic signature of ocular adnexal lymphoproliferative disorders (LPDs), especially ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma, IgG4-related ophthalmic disease (IgG4-ROD), reactive lymphoid hyperplasia (RLH), and diffuse large B-cell lymphoma (DLBCL). METHODS: We included 52 subjects with ocular adnexal LPDs (13 orbital MALT lymphomas, 16 conjunctival MALT lymphomas, 13 IgG4-RODs, 4 RLHs, and 6 DLBCLs) who had been treated at the Tokyo Medical University Hospital from 2008 to 2012. Genomic DNA was extracted from the tumor tissues and subjected to high-resolution single nucleotide polymorphism array (SNP-A) karyotyping using GeneChip Human Mapping 250K SNP arrays. The array data were investigated using Copy Number Analysis for GeneChips (CNAG) software. RESULTS: In ocular adnexal MALT lymphomas, the most frequent copy number (CN) gain region was trisomy 3 detected in 31% (9/29), followed by trisomy 18 in 17% (5/29), and 6p and 21q in 14% (4/29). The most frequent CN loss regions were 6q and 9p, detected in 7% (2/29). Uniparental disomy was detected on 6q in 14% (4/29), followed by 3q in 10% (3/29). Copy number variations (CNVs) were not detected in IgG4-RODs and RLHs. Conversely, CNVs were more frequent in DLBCLs than in ocular adnexal MALT lymphomas. Copy number variations were detected in 77% (10/13) of orbital MALT lymphomas and in 67% (11/16) of conjunctival MALT lymphomas. CONCLUSIONS: High resolution single nucleotide polymorphism array is a useful method for discriminating ocular adnexal lymphomas from benign LPDs. The differences in the chromosomal abnormality patterns may reflect the activity of ocular adnexal LPDs. PMID- 26120820 TI - Electrospun Collagen Fibers with Spatial Patterning of SDF1alpha for the Guidance of Neural Stem Cells. AB - Producing gradients of biological cues into nerve conduits is crucial for nerve guidance and regeneration. Herein, the fabrication of gradients of stromal cell derived factor-1alpha (SDF1alpha) on electrospun collagen mats is reported using an electrohydrodynamic jet printing technique. The fabrication of various SDF1alpha gradated patterns on collagen fibrous mats is successfully demonstrated including shallow continuous gradient, steep continuous gradient, and step gradient by controlling the processing parameters. The SDF1alpha graded collagen scaffolds show a long-term stable gradient, as SDF1alpha is fused with a unique peptide of collagen binding domain (CBD), and CBD-SDF1alpha can specifically bind to the collagen mat. Such graded scaffolds exhibit sustained release of SDF1alpha. Further examination of neural stem cell (NSC) response to the CBD SDF1alpha gradients with various patterns show that the NSCs can sense the CBD SDF1alpha gradients, display a polarized morphology, and tend to migrate toward the region with a higher CBD-SDF1alpha content. The collagen mats with CBD SDF1alpha gradients guide gradual distribution of NSCs, and NSC-differentiated neurons and astrocytes after seeding for 1 and 7 d. This new class of CBD SDF1alpha gradient scaffolds can potentially be employed for guided nerve regeneration. PMID- 26120821 TI - Enhanced dipicolinic acid production during the stationary phase in Bacillus subtilis by blocking acetoin synthesis. AB - Bacterial bio-production during the stationary phase is expected to lead to a high target yield because the cells do not consume the substrate for growth. Bacillus subtilis is widely used for bio-production, but little is known about the metabolism during the stationary phase. In this study, we focused on the dipicolinic acid (DPA) production by B. subtilis and investigated the metabolism. We found that DPA production competes with acetoin synthesis and that acetoin synthesis genes (alsSD) deletion increases DPA productivity by 1.4-fold. The mutant showed interesting features where the glucose uptake was inhibited, whereas the cell density increased by approximately 50%, resulting in similar volumetric glucose consumption to that of the parental strain. The metabolic profiles revealed accumulation of pyruvate, acetyl-CoA, and the TCA cycle intermediates in the alsSD mutant. Our results indicate that alsSD-deleted B. subtilis has potential as an effective host for stationary-phase production of compounds synthesized from these intermediates. PMID- 26120822 TI - Hydrogen-sulfide-mediated vasodilatory effect of nucleoside 5' monophosphorothioates in perivascular adipose tissue. AB - Hydrogen sulfide (H2S) is synthesized in perivascular adipose tissue (PVAT) and induces vasorelaxation. We examined whether the sulfur-containing AMP and GMP analogs AMPS and GMPS can serve as the H2S donors in PVAT. H2S production by isolated rat periaortic adipose tissue (PAT) was measured with a polarographic sensor. In addition, phenylephrine-induced contractility of aortic rings with (+) or without (-) PAT was examined. Isolated PAT produced H2S from AMPS or GMPS in the presence of the P2X7 receptor agonist BzATP. Phenylephrine-induced contractility of PAT(+) rings was lower than of PAT(-) rings. AMPS or GMPS had no effect on the contractility of PAT(-) rings, but used together with BzATP reduced the contractility of PAT(+) rings when endogenous H2S production was inhibited with propargylglycine. A high-fat diet reduced endogenous H2S production by PAT. Interestingly, AMPS and GMPS were converted to H2S by PAT of obese rats, and reduced contractility of PAT(+) aortic rings isolated from these animals even in the absence of BzATP. We conclude that (i) AMPS and GMPS can be hydrolyzed to H2S by PAT when P2X7 receptors are activated, (ii) a high-fat diet impairs endogenous H2S production by PAT, (iii) AMPS and GMPS restore the anticontractile effects of PAT in obese animals without P2X7 stimulation. PMID- 26120823 TI - Focal mass-like autoimmune pancreatitis complicated by obviously elevated CA19-9: Efficacy of follow-up imaging. PMID- 26120825 TI - Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. OBJECTIVE: To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. DATA SOURCES: Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. STUDY SELECTION: Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. DATA EXTRACTION AND SYNTHESIS: Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. MAIN OUTCOMES AND MEASURES: The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. RESULTS: Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, -0.28; 95% CI, -0.37 to -0.19; P < .001) and in the medication score (SMD, 0.24; 95% CI, -0.31 to -0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. CONCLUSIONS AND RELEVANCE: Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT. PMID- 26120826 TI - Efficient and reproducible CH3NH3PbI(3-x)(SCN)x perovskite based planar solar cells. AB - We report the addition of a small amount of Pb(SCN)2 into PbI2 in a two-step solution method. The resulting CH3NH3PbI(3-x)(SCN)x perovskite films present larger-sized crystals and fewer traps than CH3NH3PbI3. Their planar solar cells exhibit a maximum power conversion efficiency of 11.07% with remarkably high reproducibility and good stability. PMID- 26120824 TI - Validation of the 'drinking expectancy questionnaire for men who have sex with men' in Peru. AB - INTRODUCTION AND AIMS: Alcohol use disorders are highly prevalent among men who have sex with men (MSM) in Peru, where the HIV epidemic is concentrated 100-fold greater among MSM than in the general population. Drinking expectancies have been associated with the intent to drink and engage in high-risk behaviours. Assessing them in this population may uncover attractive intervention targets that in turn can be used to reduce problematic drinking and risky sexual behaviours. The drinking expectancy questionnaire for MSM (DEQ-MSM) was developed to accurately measure drinking expectancies, specifically among MSM. This study aimed to validate this instrument for the first time in Spanish, in South America and among MSM in Peru. DESIGN AND METHODS: To validate the DEQ-MSM among Spanish speaking MSM in Peru, we used exploratory and confirmatory factor analysis in a sample of 5148 MSM, including 700 transgender women (TGW). RESULTS: Exploratory factor analysis showed a two-factor structure to the Spanish version of the DEQ MSM (DEQ-MSM-S), which was similar for MSM and TGW. The reliability of the translated DEQ-MSM was excellent (alpha = 0.91). DISCUSSION AND CONCLUSIONS: The DEQ-MSM-S was shown to be highly reliable in a large population of Peruvian MSM and TGW. This short instrument can be effectively integrated into research or clinical practice, in order to identify alcohol-consuming, high-risk MSM, who can then be directed for further screening and/or intervention. Future research should aim to associate the Spanish version of the DEQ-MSM with risky sexual behaviours among this population, in order to identify potential intervention targets. [Vagenas P, Wickersham JA, Calabrese SK, Lama JR, Benites CM, Pun M, Sanchez J, Altice FL. Validation of the 'drinking expectancy questionnaire for men who have sex with men' in Peru. Drug Alcohol Rev 2015;34:559-66]. PMID- 26120827 TI - Design, Synthesis, and Biological Evaluation of Dabigatran Etexilate Mimics, a Novel Class of Thrombin Inhibitors. AB - Human alpha-thrombin is a particularly promising target for anticoagulant therapy, and identification of oral small-molecular inhibitors of thrombin remains a research focus. On the basis of the X-ray crystal structure of human alpha-thrombin and its inhibitor dabigatran, we designed and synthesized a series of dabigatran etexilate mimics containing a novel tricyclic fused scaffold. The biological evaluations reveal that all of the compounds possess moderate activity of antiplatelet aggregation induced by thrombin in vitro. Moreover, compound I-8, which contains 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP), a cleavable moiety with antiplatelet activity, shows the best anticoagulant effect among the tested compounds in vivo. Those synthesized compounds that have better in vitro activity were subjected to bleeding complication tests, and the results demonstrate that the novel compounds are less likely to have bleeding risk than dabigatran etexilate. PMID- 26120828 TI - Vitamin D Levels Decline with Rising Number of Cardiometabolic Risk Factors in Healthy Adults: Association with Adipokines, Inflammation, Oxidative Stress and Advanced Glycation Markers. AB - INTRODUCTION: Hypovitaminosis D associates with obesity, insulin resistance, hypertension, and dyslipoproteinemia. We asked whether the presence of multiple cardiometabolic risk factors, and which particular combination, exerts additive negative effects on 25(OH)D3 levels; and whether 25(OH)D3 levels associate with markers of inflammation and oxidative stress. SUBJECTS AND METHODS: In non diabetic medication-free adults central obesity (waist-to-height ratio > 0.5); elevated blood pressure (systolic BP>=130 mm Hg and/or diastolic BP >=85 mm Hg); increased atherogenic risk (log(TAG/HDL) >= 0.11); and insulin resistance (QUICKI < 0.322) were considered as cardiometabolic risk factors. 25(OH)D3 status was classified as deficiency (25(OH)D3 <=20 ng/ml); insufficiency (levels between 20 to-30 ng/ml), or as satisfactory (>30 ng/ml). Plasma adipokines, inflammatory and oxidative stress markers, advanced glycation end-products, and their soluble receptor were determined. RESULTS: 162 subjects were cardiometabolic risk factors free, 162 presented increased (i.e. 1 or 2), and 87 high number (i.e. 3 or 4) of cardiometabolic risk factors. Mean 25(OH)D3 decreased with rising number of manifested risk factors (36 +/- 14 ng/ml, 33 +/- 14 ng/ml, and 31 +/- 15 ng/ml, respectively; pANOVA: 0.010), while prevalence of hypovitaminosis D did not differ significantly. Elevated blood pressure and insulin resistance appeared as significant determinants of hypovitaminosis D. Subjects presenting these risk factors concurrently displayed the lowest 25(OH)D3 levels (29 +/- 15 ng/ml). Plasma adipokines, inflammatory and oxidative stress markers, advanced glycation end-products, and their soluble receptor generally differed significantly between the groups, but only advanced oxidation protein products and advanced glycation end-products associated fluorescence of plasma showed significant independent association with 25(OH)D3 levels. CONCLUSION: In apparently healthy adults increasing number of cardiometabolic risk factors associates with poorer 25(OH)D3 status, while the association between 25(OH)D3 status and inflammatory or oxidative stress markers remains equivocal. PMID- 26120830 TI - Expression of Concern: RNAi-Dependent and Independent Control of LINE1 Accumulation and Mobility in Mouse Embryonic Stem Cells. PMID- 26120829 TI - [18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs. AB - OBJECTIVE: Inflammation is an important contributor to atherosclerosis progression. A glucose analogue 18F-fluorodeoxyglucose ([18F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [18F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [18F]FDG to various stages of coronary plaques in a pig model. METHODS: First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual gated cardiac PET/CT to measure [18F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG). RESULTS: Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7+/-0.7 times higher [18F]FDG accumulation in the intimal thickening and 4.1+/-2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6+/-1.2 vs. 1.3+/-0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1+/-0.5) and either intimal thickening (1.2+/-0.4, P = 1.0) or atheroma (1.6+/-0.6, P = 0.4). CONCLUSIONS: We found increased uptake of [18F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [18F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques. PMID- 26120831 TI - Expression of Five Endopolygalacturonase Genes and Demonstration that MfPG1 Overexpression Diminishes Virulence in the Brown Rot Pathogen Monilinia fructicola. AB - Monilinia fructicola is a devastating pathogen on stone fruits, causing blossom blight and fruit rot. Little is known about pathogenic mechanisms in M. fructicola and related Monilinia species. In this study, five endopolygalacturonase (endo-PG) genes were cloned and functionally characterized in M. fructicola. Quantitative reverse-transcriptase PCR (qRT-PCR) revealed that the five MfPG genes are differentially expressed during pathogenesis and in culture under various pH regimes and carbon and nitrogen sources. MfPG1 encodes the major endo-PG and is expressed to significantly higher levels compared to the other four MfPGs in culture and in planta. MfPG1 function during pathogenesis was evaluated by examining the disease phenotypes and gene expression patterns in M. fructicola MfPG1-overexpressing strains and in strains carrying the beta glucuronidase (GUS) reporter gene fused with MfPG1 (MfPG1-GUS). The MFPG1-GUS reporter was expressed in situ in conidia and hyphae following inoculation of flower petals, and qRT-PCR analysis confirmed MfPG1 expression during pathogenesis. MfPG1-overexpressing strains produced smaller lesions and higher levels of reactive oxygen species (ROS) on the petals of peach and rose flowers than the wild-type strain, suggesting that MfPG1 affecting fungal virulence might be in part resulted from the increase of ROS in the Prunus-M. fructicola interactions. PMID- 26120832 TI - A Critical Role of the mTOR/eIF2alpha Pathway in Hypoxia-Induced Pulmonary Hypertension. AB - Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2alpha (eIF2alpha) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2alpha were used in loss-of-function studies. The expression and activation of eIF2alpha, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2alpha signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2alpha activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2alpha by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2alphapathway in hypoxic vascular remodeling and PASMCs proliferation of HPH. PMID- 26120833 TI - Action Mechanism of Fibroblast Growth Factor-2 (FGF-2) in the Promotion of Periodontal Regeneration in Beagle Dogs. AB - Fibroblast growth factor-2 (FGF-2) enhances the formation of new alveolar bone, cementum, and periodontal ligament (PDL) in periodontal defect models. However, the mechanism through which FGF-2 acts in periodontal regeneration in vivo has not been fully clarified yet. To reveal the action mechanism, the formation of regenerated tissue and gene expression at the early phase were analyzed in a beagle dog 3-wall periodontal defect model. FGF-2 (0.3%) or the vehicle (hydroxypropyl cellulose) only were topically applied to the defect in FGF-2 and control groups, respectively. Then, the amount of regenerated tissues and the number of proliferating cells at 3, 7, 14, and 28 days and the number of blood vessels at 7 days were quantitated histologically. Additionally, the expression of osteogenic genes in the regenerated tissue was evaluated by real-time PCR at 7 and 14 days. Compared with the control, cell proliferation around the existing bone and PDL, connective tissue formation on the root surface, and new bone formation in the defect at 7 days were significantly promoted by FGF-2. Additionally, the number of blood vessels at 7 days was increased by FGF-2 treatment. At 28 days, new cementum and PDL were extended by FGF-2. Moreover, FGF 2 increased the expression of bone morphogenetic protein 2 (BMP-2) and osteoblast differentiation markers (osterix, alkaline phosphatase, and osteocalcin) in the regenerated tissue. We revealed the facilitatory mechanisms of FGF-2 in periodontal regeneration in vivo. First, the proliferation of fibroblastic cells derived from bone marrow and PDL was accelerated and enhanced by FGF-2. Second, angiogenesis was enhanced by FGF-2 treatment. Finally, osteoblastic differentiation and bone formation, at least in part due to BMP-2 production, were rapidly induced by FGF-2. Therefore, these multifaceted effects of FGF-2 promote new tissue formation at the early regeneration phase, leading to enhanced formation of new bone, cementum, and PDL. PMID- 26120834 TI - Targeting Homologous Recombination in Notch-Driven C. elegans Stem Cell and Human Tumors. AB - Mammalian NOTCH1-4 receptors are all associated with human malignancy, although exact roles remain enigmatic. Here we employ glp-1(ar202), a temperature sensitive gain-of-function C. elegans NOTCH mutant, to delineate NOTCH-driven tumor responses to radiotherapy. At <=20 degrees C, glp-1(ar202) is wild-type, whereas at 25 degrees C it forms a germline stem cell/progenitor cell tumor reminiscent of human cancer. We identify a NOTCH tumor phenotype in which all tumor cells traffic rapidly to G2/M post-irradiation, attempt to repair DNA strand breaks exclusively via homology-driven repair, and when this fails die by mitotic death. Homology-driven repair inactivation is dramatically radiosensitizing. We show that these concepts translate directly to human cancer models. PMID- 26120835 TI - Formation of a Trimeric Xpo1-Ran[GTP]-Ded1 Exportin Complex Modulates ATPase and Helicase Activities of Ded1. AB - The DEAD-box RNA helicase Ded1, which is essential in yeast and known as DDX3 in humans, shuttles between the nucleus and cytoplasm and takes part in several basic processes including RNA processing and translation. A key interacting partner of Ded1 is the exportin Xpo1, which together with the GTP-bound state of the small GTPase Ran, facilitates unidirectional transport of Ded1 out of the nucleus. Here we demonstrate that Xpo1 and Ran[GTP] together reduce the RNA stimulated ATPase and helicase activities of Ded1. Binding and inhibition of Ded1 by Xpo1 depend on the affinity of the Ded1 nuclear export sequence (NES) for Xpo1 and the presence of Ran[GTP]. Association with Xpo1/Ran[GTP] reduces RNA stimulated ATPase activity of Ded1 by increasing the apparent KM for the RNA substrate. Despite the increased KM, the Ded1:Xpo1:Ran[GTP] ternary complex retains the ability to bind single stranded RNA, suggesting that Xpo1/Ran[GTP] may modulate the substrate specificity of Ded1. These results demonstrate that, in addition to transport, exportins such as Xpo1 also have the capability to alter enzymatic activities of their cargo. PMID- 26120836 TI - Correction: Colostrum of Healthy Slovenian Mothers: Microbiota Composition and Bacteriocin Gene Prevalence. PMID- 26120837 TI - Hyaluronic Acid: Perspectives in Upper Aero-Digestive Tract. A Systematic Review. AB - BACKGROUND: To date, topical therapies guarantee a better delivery of high concentrations of pharmacologic agents to the mucosa of the upper aerodigestive tract (UADT). The use of topical drugs, which are able to reduce mucosal inflammation and to improve healing tissues, can represent a relevant therapeutic advance. Topical sodium hyaluronate (SH) has recently been recognized as adjuvant treatment in the chronic inflammatory disease of the UADT. AIMS: The aim of our work was to review the published literature regarding all the potential therapeutic effects of SH in the chronic inflammatory disease of UADT. METHODS: Relevant published studies were searched in Pubmed, Google Scholar, Ovid using keywords ("sodium hyaluronate" and "upper airways") or Medical Subject Headings. RESULTS: At the end of our selection process, sixteen publications have been included. Six of them in the post-operative period of nasal-sinus surgery, 2 of them in pediatric patients affected by recurrent upper respiratory tract infections, 4 of them in reducing symptoms and preventing exacerbations of chronic upper airways in adult population, 4 of them in patients with chronic inflammatory disease of UADT, including gastro-esophageal reflux disease (GERD). CONCLUSIONS: Topical administration of SH plays a pivotkey role in the postoperative phase of patients undergoing FESS and nasal surgery, and positive results are generally observed in all the patients suffering from UADT chronic inflammatory disease. PMID- 26120839 TI - Blinded Outcome Assessment Was Infrequently Used and Poorly Reported in Open Trials. AB - OBJECTIVE: Unblinded outcome assessment can lead to biased estimates of treatment effect in randomised trials. We reviewed published trials to assess how often blinded assessment is used, and whether its use varies according to the type of outcome or assessor. DESIGN AND SETTING: A review of parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. MAIN OUTCOME MEASURES: Whether assessment of the primary outcome was blinded, and whether this differed according to outcome or assessor type. RESULTS: We identified 258 eligible trials. Of these, 106 (41%) were reported as double-blind, and 152 (59%) as partially or fully open-label (that is, they included some groups who were unblinded, such as patients, those delivering the intervention, or those in charge of medical care). Of the 152 open trials, 125 required outcome assessment. Of these 125 trials, only 26% stated that outcome assessment was blinded; 51% gave no information on whether assessment was blinded or not. Furthermore, 18% of trials did not state who performed the assessment. The choice of outcome type (e.g. instrument measured, rated, or naturally occurring event) did not appear to influence whether blinded assessment was performed (range 24-32% for the most common outcome types). However, the choice of outcome assessor did influence blinding; independent assessors were blinded much more frequently (71%) than participant (5%) or physician (24%) assessors. Despite this, open trials did not use independent assessors any more frequently than double-blind trials (17% vs. 18% respectively). CONCLUSIONS: Blinding of outcome assessors is infrequently used and poorly reported. Increased use of independent assessors could increase the frequency of blinded assessment. PMID- 26120838 TI - Placental Features of Late-Onset Adverse Pregnancy Outcome. AB - OBJECTIVE: Currently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement. METHODS: Following third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium). RESULTS: Placentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10-12) vessels/mm2 vs. normal outcome 13 (12-15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19-50) nM vs. 12 (6-24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11-50) vs. 55 (24-102) mIU/mg, p = 0.007) and human placental lactogen (11 (6-14) vs. 27 (9-50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13-29) vs. 5 (2 15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue. CONCLUSION: These data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction. PMID- 26120840 TI - Analysis of Prostate Deformation during a Course of Radiation Therapy for Prostate Cancer. AB - PURPOSE: Accurate analysis of the correlation between deformation of the prostate and displacement of its center of gravity (CoG) is important for efficient radiation therapy for prostate cancer. In this study, we addressed this problem by introducing a new analysis approach. METHOD: A planning computed tomography (CT) scan and 7 repeat cone-beam CT scans during the course of treatment were obtained for 19 prostate cancer patients who underwent three-dimensional conformal radiation therapy. A single observer contoured the prostate gland only. To evaluate the local deformation of the prostate, it was divided into 12 manually defined segments. Prostate deformation was calculated using in-house developed software. The correlation between the displacement of the CoG and the local deformation of the prostate was evaluated using multiple regression analysis. RESULTS: The mean value and standard deviation (SD) of the prostate deformation were 0.6 mm and 1.7 mm, respectively. For the majority of the patients, the local SD of the deformation was slightly lager in the superior and inferior segments. Multiple regression analysis revealed that the anterior posterior displacement of the CoG of the prostate had a highly significant correlation with the deformations in the middle-anterior (p < 0.01) and middle posterior (p < 0.01) segments of the prostate surface (R2 = 0.84). However, there was no significant correlation between the displacement of the CoG and the deformation of the prostate surface in other segments. CONCLUSION: Anterior posterior displacement of the CoG of the prostate is highly correlated with deformation in its middle-anterior and posterior segments. In the radiation therapy for prostate cancer, it is necessary to optimize the internal margin for every position of the prostate measured using image-guided radiation therapy. PMID- 26120841 TI - Allogeneic Bone Marrow Transplant from MRL/MpJ Super-Healer Mice Does Not Improve Articular Cartilage Repair in the C57Bl/6 Strain. AB - BACKGROUND: Articular cartilage has been the focus of multiple strategies to improve its regenerative/ repair capacity. The Murphy Roths Large (MRL/MpJ) "super-healer" mouse demonstrates an unusual enhanced regenerative capacity in many tissues and provides an opportunity to further study endogenous cartilage repair. The objective of this study was to test whether the super-healer phenotype could be transferred from MRL/MpJ to non-healer C57Bl/6 mice by allogeneic bone marrow transplant. METHODOLOGY: The healing of 2mm ear punches and full thickness cartilage defects was measured 4 and 8 weeks after injury in control C57Bl/6 and MRL/MpJ "super-healer" mice, and in radiation chimeras reconstituted with bone marrow from the other mouse strain. Healing was assessed using ear hole diameter measurement, a 14 point histological scoring scale for the cartilage defect and an adapted version of the Osteoarthritis Research Society International scale for assessment of osteoarthritis in mouse knee joints. PRINCIPAL FINDINGS: Normal and chimeric MRL mice showed significantly better healing of articular cartilage and ear wounds along with less severe signs of osteoarthritis after cartilage injury than the control strain. Contrary to our hypothesis, however, bone marrow transplant from MRL mice did not confer improved healing on the C57Bl/6 chimeras, either in regards to ear wound healing or cartilage repair. CONCLUSION AND SIGNIFICANCE: The elusive cellular basis for the MRL regenerative phenotype still requires additional study and may possibly be dependent on additional cell types external to the bone marrow. PMID- 26120842 TI - Cardiorespiratory Fitness, Sedentary Behaviour and Physical Activity Are Independently Associated with the Metabolic Syndrome, Results from the SCAPIS Pilot Study. AB - BACKGROUND: Previous studies on the relation between lifestyle and the metabolic syndrome lack one or several aspects of the physical activity pattern in the analyses or cardiorespiratory fitness. Likewise, both uni- and triaxial accelerometry have been used, though, the predictive validity of these two modes has not been compared. OBJECTIVES: The aims of the present study were firstly to investigate the independent relation between cardiorespiratory fitness and physical activity pattern to the metabolic syndrome (MetS) and secondly to examine the predictive validity of uni- and triaxial accelerometry, respectively. METHODS: Data was extracted from the SCAPIS pilot study (n=930, mean age 57.7 yrs). Physical activity pattern was assessed by accelerometry. Cardiorespiratory fitness was estimated using cycle ergometry. MetS was defined per the Adult Treatment Panel III from the National Cholesterol Education Program definition. RESULTS: Time spent sedentary (OR: 2.38, 95% CI: 1.54-4.24 for T3 vs T1), in light intensity (OR: 0.50, 95% CI: 0.28-0.90) and in moderate-to-vigorous activity (OR: 0.33, 95% CI: 0.18-0.61), as well as cardiorespiratory fitness (OR: 0.24, 95% CI:0.12-0.48), were all independently related to the prevalence of MetS after adjustment for potential confounders, fitness and/or the other aspects of the physical activity pattern. In addition, we found that triaxial analyses were more discriminant, with ORs farther away from the reference group and additional significant ORs. CONCLUSION: The finding that several aspects of the physical activity pattern reveal independent relations to the MetS makes new possible targets for behaviour change of interest, focusing on both exercise and everyday life. When assessing the risk status of a patient, it is advised that triaxial accelerometry is used. PMID- 26120843 TI - Factors Associated with Reduced Quality of Life in Polio Survivors in Korea. AB - The purpose of this study is to assess health-related quality of life in polio survivors (PS) compared with that in the general population in Korea. Polio survivors (n = 120) from outpatient clinics at two hospitals, healthy controls (HC, n = 121) and members of the general population with activity limitations (AL, n = 121) recruited through a proportional-allocation, systematic sampling strategy from the Fourth Korean National Health and Nutrition Examination Survey were surveyed with self-rated health-related quality of life (Euro QoL five dimensions). The proportion of participants who reported problems in mobility, usual activity, and symptoms of anxiety/depression were higher in the PS group compared with the HC and AL groups. There was no significant difference in the self-care dimension across the groups. Polio-specific questionnaire, pain, depression, fatigue, Modified Barthel Index (K-MBI) and Short Physical Performance Battery (SPPB) were assessed in the PS group. Those with post poliomyelitis syndrome had greater problems in mobility, usual activity, and depression/anxiety. Polio survivors, especially those with more pain and fatigue symptoms, and those who did not have access to medical services had poorer health related quality of life. These findings afford useful information for potential intervention improving quality of life in polio survivors. PMID- 26120844 TI - Contrasting Lesion Dynamics of White Syndrome among the scleractinian corals Porites spp. AB - White syndrome (WS) is currently the most prevalent disease of scleractinian corals in the Indo-Pacific region, with an ability to exist in both epizootic and enzootic states. Here, we present results of an examination of WS lesion dynamics and show that potentially associated traits of host morphology (i.e., branching vs. massive), lesion size, and tissue deposition rate influence disease severity and recovery. Lesion healing rate was positively correlated with initial lesion size in both morphologies, but the rate at which lesions healed differed between morphologies. New lesions in branching Porites cylindrica appeared less frequently, were smaller and healed more quickly, but were more abundant than in closely-related massive Porites sp(p). The positive association between lesion size and healing rate was partly explained by geometry; branching limited lesion maximum size, and larger lesion margins contained more polyps producing new tissue, resulting in faster healing. However, massive colonies deposited tissue more slowly than branching colonies, resulting in slower recovery and more persistent lesions. Corallite size and density did not differ between species and did not, therefore, influence healing rate. We demonstrated multiple modes of pathogen transmission, which may be influenced by the greater potential for pathogen entrainment in branching vs. massive morphologies. We suggest that attributes such as colony morphology and species-specific growth rates require consideration as we expand our understanding of disease dynamics in colonial organisms such as coral. PMID- 26120845 TI - Clinical and Angioarchitectural Risk Factors Associated with Intracranial Hemorrhage in Dural Arteriovenous Fistulas: A Single-Center Retrospective Study. AB - PURPOSE: To investigate which clinical and angioarchitectural features were associated with the occurrence of intracranial hemorrhage in patients with intracranial dural arteriovenous fistulas (DAVFs). MATERIALS AND METHODS: We retrospectively reviewed the clinical and angioarchitectural features of 236 consecutive patients diagnosed with DAVF in our department from April 2009 to November 2013. Two groups of patients, with or without intracranial hemorrhage as clinical presentation at the initial diagnosis, were analysed to identify the differences in clinical and angioarchitectural features in univariate analysis. A multivariate logistic regression model was also developed to assess the independent contribution of the potential risk factors. Associations were considered significant for p<0.05. RESULTS: Fifty-six patients (23.7%) presented with intracranial hemorrhage at the initial diagnosis of DAVF. In univariate analysis, male patients (p = 0.002), patients with medical history of smoking (p<0.001) or alcohol consumption (p = 0.022), and DAVFs located at the tentorium (p = 0.010), frontalbasal (p = 0.007), foramen magnum (p = 0.043) or cerebral convexity (p<0.001) were associated with an increased risk of intracranial hemorrhage. A higher risk of hemorrhagic occurrence was also observed in DAVFs with superficial cortical venous drainage (p<0.001), deep venous drainage (p = 0.003), occluded venous sinus (p<0.032), or higher Borden type (p<0.001). A multivariate logistic regression model showed that intracranial hemorrhage in patients with DAVFs was correlated with higher Borden classification (OR 5.880; 95% CI, 3.370-10.257; p<0.001). CONCLUSION: Venous drainage pattern was the only independent risk factor of intracranial hemorrhage in our patients with intracranial DAVF. The other potential risk factors may be confounding factors in predicting intracranial hemorrhage. PMID- 26120846 TI - Determinants and Experiences of Repeat Pregnancy among HIV-Positive Kenyan Women- A Mixed-Methods Analysis. AB - OBJECTIVE: To identify factors associated with repeat pregnancy subsequent to an index pregnancy among women living with HIV (WLWH) in western Kenya who were enrolled in a 24-month phase-II clinical trial of triple-ART prophylaxis for prevention of mother-to-child transmission, and to contextualize social and cultural influences on WLWH's reproductive decision making. METHODS: A mixed methods approach was used to examine repeat pregnancy within a 24 month period after birth. Counselor-administered questionnaires were collected from 500 WLWH. Forty women (22 with a repeat pregnancy; 18 with no repeat pregnancy) were purposively selected for a qualitative interview (QI). Simple and multiple logistic regression analyses were performed for quantitative data. Thematic coding and saliency analysis were undertaken for qualitative data. RESULTS: Eighty-eight (17.6%) women had a repeat pregnancy. Median maternal age was 23 years (range 15-43 years) and median gestational age at enrollment was 34 weeks. In multiple logistic regression analyses, living in the same compound with a husband (adjusted odds ratio (AOR): 2.33; 95% confidence interval (CI): 1.14, 4.75) was associated with increased odds of repeat pregnancy (p <= 0.05). Being in the 30-43 age group (AOR: 0.25; 95% CI: 0.07, 0.87), having talked to a partner about family planning (FP) use (AOR: 0.53; 95% CI: 0.29, 0.98), and prior usage of FP (AOR: 0.45; 95% CI: 0.25, 0.82) were associated with a decrease in odds of repeat pregnancy. QI findings centered on concerns about modern contraception methods (side effects and views that they 'ruined the womb') and a desire to have the right number of children. Religious leaders, family, and the broader community were viewed as reinforcing cultural expectations for married women to have children. Repeat pregnancy was commonly attributed to contraception failure or to lack of knowledge about post-delivery fertility. CONCLUSIONS: In addition to cultural context, reproductive health programs for WLWH may need to address issues related to living circumstances and the possibility that reproductive-decision making may extend beyond the woman and her partner. PMID- 26120847 TI - Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence. AB - Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility. PMID- 26120848 TI - Bi-Directional Tuning of Amygdala Sensitivity in Combat Veterans Investigated with fMRI. AB - OBJECTIVES: Combat stress can be followed by persistent emotional consequences. It is thought that these emotional consequences are caused in part by increased amygdala reactivity. It is also thought that amygdala hyper-reactivity results from decreased inhibition from portions of the anterior cingulate cortex (ACC) in which activity is negatively correlated with activity in the amygdala. However, experimental support for these proposals has been inconsistent. METHODS: We showed movies of combat and civilian scenes during a functional magnetic resonance imaging (fMRI) session to 50 veterans of recent combat. We collected skin conductance responses (SCRs) as measures of emotional arousal. We examined the relation of blood oxygenation-level dependent (BOLD) signal in the amygdala and ACC to symptom measures and to SCRs. RESULTS: Emotional arousal, as measured with SCR, was greater during the combat movie than during the civilian movie and did not depend on symptom severity. As expected, amygdala signal during the less arousing movie increased with increasing symptom severity. Surprisingly, during the more-arousing movie amygdala signal decreased with increasing symptom severity. These differences led to the unexpected result that amygdala signal in highly symptomatic subjects was lower during the more-arousing movie than during the less-arousing movie. Also unexpectedly, we found no significant inverse correlation between any portions of the amygdala and ACC. Rather, signal throughout more than 80% of the ACC showed a strong positive correlation with signal throughout more than 90% of the amygdala. CONCLUSIONS: Amygdala reactivity can be tuned bi-directionally, either up or down, in the same person depending on the stimulus and the degree of post-traumatic symptoms. The exclusively positive correlations in BOLD activity between the amygdala and ACC contrast with findings that have been cited as evidence for inhibitory control of the amygdala by the ACC. The conceptualization of post-traumatic changes in neural function should be reconsidered. PMID- 26120849 TI - The Nucleotide-Free State of the Multidrug Resistance ABC Transporter LmrA: Sulfhydryl Cross-Linking Supports a Constant Contact, Head-to-Tail Configuration of the Nucleotide-Binding Domains. AB - ABC transporters are integral membrane pumps that are responsible for the import or export of a diverse range of molecules across cell membranes. ABC transporters have been implicated in many phenomena of medical importance, including cystic fibrosis and multidrug resistance in humans. The molecular architecture of ABC transporters comprises two transmembrane domains and two ATP-binding cassettes, or nucleotide-binding domains (NBDs), which are highly conserved and contain motifs that are crucial to ATP binding and hydrolysis. Despite the improved clarity of recent structural, biophysical, and biochemical data, the seemingly simple process of ATP binding and hydrolysis remains controversial, with a major unresolved issue being whether the NBD protomers separate during the catalytic cycle. Here chemical cross-linking data is presented for the bacterial ABC multidrug resistance (MDR) transporter LmrA. These indicate that in the absence of nucleotide or substrate, the NBDs come into contact to a significant extent, even at 4 degrees C, where ATPase activity is abrogated. The data are clearly not in accord with an inward-closed conformation akin to that observed in a crystal structure of V. cholerae MsbA. Rather, they suggest a head-to-tail configuration 'sandwich' dimer similar to that observed in crystal structures of nucleotide bound ABC NBDs. We argue the data are more readily reconciled with the notion that the NBDs are in proximity while undergoing intra-domain motions, than with an NBD 'Switch' mechanism in which the NBD monomers separate in between ATP hydrolysis cycles. PMID- 26120850 TI - Truncating Homozygous Mutation of Carboxypeptidase E (CPE) in a Morbidly Obese Female with Type 2 Diabetes Mellitus, Intellectual Disability and Hypogonadotrophic Hypogonadism. AB - Carboxypeptidase E is a peptide processing enzyme, involved in cleaving numerous peptide precursors, including neuropeptides and hormones involved in appetite control and glucose metabolism. Exome sequencing of a morbidly obese female from a consanguineous family revealed homozygosity for a truncating mutation of the CPE gene (c.76_98del; p.E26RfsX68). Analysis detected no CPE expression in whole blood-derived RNA from the proband, consistent with nonsense-mediated decay. The morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotrophic hypogonadism seen in this individual recapitulates phenotypes in the previously described fat/fat and Cpe knockout mouse models, evidencing the importance of this peptide/hormone-processing enzyme in regulating body weight, metabolism, and brain and reproductive function in humans. PMID- 26120851 TI - Policing behaviors, safe injection self-efficacy, and intervening on injection risks: Moderated mediation results from a randomized trial. AB - OBJECTIVE: We aim to use conditional or moderated mediation to simultaneously test how and for whom an injection risk intervention was efficacious at reducing receptive needle sharing among female sex workers who inject drugs (FSWs-IDUs) in Mexico. METHODS: Secondary analysis of data from a randomized trial. A total of 300 FSW-IDUs participated in Mujer Mas Segura in Ciudad Juarez, Mexico, and were randomized to an interactive injection risk intervention or a didactic injection risk intervention. We measured safe injection self-efficacy as the hypothesized mediator and policing behaviors (being arrested and syringe confiscation) as hypothesized moderators. In total, 213 women provided complete data for the current analyses. RESULTS: Conditional (moderated) mediation showed that the intervention affected receptive needle sharing through safe injection self efficacy among women who experienced syringe confiscation. On average, police syringe confiscation was associated with lower safe injection self-efficacy (p = .04). Among those who experienced syringe confiscation, those who received the interactive (vs. didactic) intervention reported higher self-efficacy, which in turn predicted lower receptive needle sharing (p = .04). CONCLUSIONS: Whereas syringe confiscation by the police negatively affected safe injection self efficacy and ultimately injection risk behavior, our interactive intervention helped to "buffer" this negative impact of police behavior on risky injection practices. The theory-based, active skills building elements included in the interactive condition, which were absent from the didactic condition, helped participants' self-efficacy for safer injection in the face of syringe confiscation. PMID- 26120852 TI - [Impact of a health education program on the elderly's knowledge about cardiovascular diseases]. AB - OBJECTIVE: To verify the impact of a health education program on elderly patients' knowledge of cardiovascular diseases. METHODS: A qualitative study with a participatory approach. The population was composed of seven elderly patients who took part in eight educational interventions on issues related to cardiovascular health. The data was analyzed with thematic content analysis. RESULTS: The content analysis showed that participatory interventions promoted knowledge expansion and that, after intervention, subjects were more self confident about the most appropriate preventive measures to avoid cardiovascular risks. It was found also that health education with a participatory approach positively impacted the formation of more critical subjects who were able to argue and make healthier choices. CONCLUSION: The study showed that the participatory approach is an effective strategy when the intention is to increase significant knowledge to minimize health risks. PMID- 26120853 TI - [The knowledge acquired during and adherence to a postgraduate course concerned with mental health aimed at school counselors]. AB - OBJECTIVE: To evaluate the academic performance in, and adherence to, a postgraduate course focused on promotion, prevention, identification, and early intervention with regard to the different mental problems and pathologies affecting children and adolescents. MATERIALS AND METHODS: This was a before-and after intervention study involving a postgraduate course. The population of school counselors from the Colombian regions of Boyaca and Cundinamarca were invited to participate in a postgraduate course that addressed mental health. Their knowledge was evaluated before and after having received it. RESULTS: The school counselors performed well on the academic test, with 48.5 % of the population obtaining a score of 4.0/5.0 before the intervention. After the course, 61.2 % achieved the same score. It was thus considered that the course functioned as a tool for improving knowledge about promotion, prevention, recognition, and early intervention with regard to mental health in educational institutions. There was a 90.6 % adherence to the 120-hour-long postgraduate course. CONCLUSION: The postgraduate course seemed to have a positive impact in terms of the knowledge acquired about mental health, and there was good adherence to the course. PMID- 26120854 TI - [Exposure to VOCs in furniture factories in two populations in northern Colombia]. AB - OBJECTIVES: Assess the exposure to volatile organic compounds (VOCs)in furniture handicraft factories workers in two populations of Sucre (Sincelejo and Sampues), North of Colombia.Identify possible signs and/or symptoms related to exposure to these contaminants. METHODS: This was an analytical cross sectional study (2011), using a questionnaire. Study population consisted of 66 individuals, 41 exposed and 25 controls. Personal samples were collected for concentration quantifying of benzene, toluene, ethylbenzene and xylenes (both groups) and contrasting them with health effects possible attributed to these contaminants. RESULTS: The concentrations of benzene, toluene and m/p-xylene were higher in the exposed group (9.5 mg/m(3), 8.1 mg/m(3) and 12.1 mg/m(3))compared with the control group (0.2 mg/m(3), 0.3 mg/m(3) and 0.03 mg/m(3)). Muscular pain 82.9 % (PR=3.8; CI95%:1.2-11.8) and somnolence 65.9 % (PR=4.9; CI95%:1.7-14.7)were associated with a higher exposure.Factor such as mixtures of solvents (thinner) in the work and vehicles' traffic can contribute to these results. CONCLUSIONS: Several sources contribute to increases personal exposure of VOCs in furniture handicraft factories workers North of Colombia. Additionally, excessive use of these compounds may be generating adverse effects on the health of workers. PMID- 26120855 TI - [Serological Profiles of Hepatitis-B HBcAb-Positive Blood donors ]. AB - OBJECTIVE: To assess the serological profiles for HBV in blood donors that were anti-HBc reactive and non-reactive to HBsAg in four Colombian cities. MATERIALS AND METHODS: A prospective transversal study was conducted during 17 months, applying a complete serological profile for HBV in samples from blood donors that were anti-HBc reactive and non-reactive to HBsAg, results were analyzed employing descriptive statistics using Microsoft Excel and Epiinfo V. 3.5.1. RESULTS: From donors reactive to anti-HBc, 75.0 % shown some additional infection marker for HBV. 1.3 % of blood donors had serological markers for chronical infection with hepatitis B, and a case had reactivity only for hepatitis B surface antigen (HBsAg). 6.1 % of donors showed a vaccination serological profile, only with reactivity to anti-HBsAg antibodies. CONCLUSIONS: With this study, anti-HBc blood screening importance was confirmed. PMID- 26120856 TI - [Intestinal Parasitism in Terena Indigenous People of the Province of Mato Grosso do Sul, Brazil]. AB - OBJECTIVE: Considering that intestinal protozoans and helminths infect more than half of the world population, with high prevalence in the poorest regions, the objective of this study was to conduct parasitological research among indigenous Terena people established in the state of MatoGrosso do Sul. An inquiry was performed to find the incidence of parasitism in these communities. METHODOLOGY: 134 aliquots of feces from individuals of the indigenous community were examined. Samples were conserved in Merthiolate-iodine-formol solution (MIF). The laboratory exams were carried out using the techniques of Hoffman, Pons and Janer; Willis and Kinyoun. RESULTS: We identified infections of nematode helminths of the species Ascaris lumbricoides, Ancylostomidae, Enterobius vermicularis, Strongyloides stercoralis, and Trichuris trichiura; and cestodes of the species Hymenolepis nana and Taenia spp. Also found were the protozoan species: Cryptosporidium spp., Giardia lamblia, Endolimax nana, Entamoeba coli, and Entamoeba histolytica. 23.1 % of the samples studied were negative. Of the 76.9 % of samples with parasites, there were non-statistically significant differences in parasitism between men and women examined between 1 and 33 years of-age. There were also no significant differences between monospecific parasitism and with concurrent species. In terms of parasitic diversity, seven species of nematode and cestodes helminths were found along with five species of Archamoebae protozoa: flagellates and enterozoans. CONCLUSIONS: These results were the basis for orientation and appropriate drug intervention and reveal the need for the implementation governmental, social and educational measures to improve the living conditions of that community. PMID- 26120857 TI - [Satisfaction of patients accessing the primary level of care (outpatient) in Bogota]. AB - OBJECTIVE: To assess outpatients'? perceptions of medical care. METHODOLOGY: A telephone survey was administered to patients treated in two different months in 2012 with a focus on socio-demographic variables, access to care, physician patient relationships, and on the process of medical care. RESULTS: 804 patients were surveyed. The average time of access to care was 9.6 days. 78 % reported having been able to tell the doctor everything that they felt, 60 % reported that the doctor explained what they had, and one in four patients said that the doctor asked about their families. 30 % felt complete relief after medical care. The average rating of care was 7.9 (SD +/-1.7). Variables related to the highest ratings were: having been able to tell that doctor everything that they felt (OR 7.5 CI 95 % 1.8-31), having been examined (OR 7.5 CI95 % 1.5-38.5), that the doctor explained what they had (OR 5.2 CI 95 % 1.8-15), that the doctor asked about the family (OR 5.8 CI95 % 2.1-16.1), and if doctor had treated them formerly (OR 3.5 CI95 % 1.4-8.6). CONCLUSIONS: Extensive communication with the patient is as important as dealing with the disease in the medical act. PMID- 26120858 TI - [Construction and validation of TQWL-42: a quality of work life measurement instrument]. AB - OBJECTIVE: The objective of this study was to build an instrument that evaluates quality of working life (QW:) in a comprehensive way that is in line with the WHOQOL instruments and is based on QWL's classic theoretical models, directed toward contemporary Brazilian society. METHODS: The content validation was performed through analysis by researchers in the area of QWL, and the verification of internal consistency was performed with Cronbach's alpha. The instrument was administered to 143 individuals. RESULTS: The final version of the instrument consists of 47 questions, with five for sampling knowledge and the remaining 42 divided into five spheres that take into account the dimensions of QWL.. Cronbach's alpha obtained from the administration of the instrument was 0.8568. A SPSS syntax and a tool in Microsoft Excel that performs the automated calculation after data tabulation was developed to calculate the results. CONCLUSIONS: We conclude that the goal of validating a comprehensive instrument with satisfactory psychometrical characteristics for the evaluation of QWL based on contemporary Brazilian culture was reached. This tool may be used without a need for SPSS utilization. PMID- 26120859 TI - [Evaluation of the mercury accumulating capacity of pepper (Capsicum annuum)]. AB - OBJECTIVE: To assess the mercury accumulating capacity in contaminated soils from the community of Mina Santa Cruz, in the south of the department of Bolivar, Colombia, of the pepper plant (Capsicum annuum), in order to establish the risk to the health of the consuming population. MATERIALS AND METHODS: Samples were taken from tissues (roots, stems, and leaves) of pepper plants grown in two soils contaminated with mercury and a control soil during the first five months of growth to determine total mercury through cold vapor atomic absorption spectrometry. Total mercury was determined in the samples of pepper plant fruits consumed in Mina Santa Cruz. RESULTS: The mean concentrations of total mercury in the roots were higher than in stems and leaves. Accumulation in tissues was influenced by mercury levels in soil and the growth time of the plants. Mercury concentrations in fruits of pepper plant were lower than tolerable weekly intake provided by WHO. CONCLUSION: Percent of translocation of mercury to aerial parts of the plant were low in both control and contaminated soils. Despite low levels of mercury in this food, it is necessary to minimize the consumption of food contaminated with this metal. PMID- 26120860 TI - [Diabetes mellitus: Contribution to changes in the life expectancy in Mexico 1990, 2000, and 2010]. AB - OBJECTIVE: To analyze the level and trend of diabetes mellitus (DM) in Mexico, and its contribution to the changes in temporary life expectancy between 20 and 100 years of age, in the period 1990-2010. MATERIALS AND METHODS: Data comes from National Mortality Vital Statistics and from the Population Census from the Mexican National Institute of Geography and Statistics (INEGI). We calculated standardized mortality rates. To analyze the impact of DM on the temporary life expectancy (80e20) we used Pollard?s method. RESULTS: Between 1990 and 2010, the standardized mortality rate for people 20 years and older increased by 224 %. The contribution of DM for men to the change in life expectancy during 1990-2000 was a reduction of 0.31 years; for women was a reduction of 0.32 years; in the period 2000-2010 the reduction continued for both men and women (0.34 and 0.12 years respectively). CONCLUSIONS: Mortality from DM continues to increase, especially for men, but for women a modest reduction was observed. It is essential to apply health services and programs aimed at reducing mortality from this cause, focused on prevention, early detection and timely treatment, with concrete actions on vulnerable groups. PMID- 26120861 TI - [Structural determinants in countries with decreased prevalence of HIV/AIDS infection between 2001 and 2011]. AB - OBJECTIVE: The present study aims analyze and compare structural features in order to establish a model about the decline in HIV/AIDS infection (greater than or equal to 25 %) in twenty-two countries between 2001 and 2011. METHODS: Retrospective cohort focused on social determinants of health perspective. The methodology was mainly documentary (epidemic behavior) and quantitative (simple linear regression model for economic and health variables). RESULTS: The major indicators that influence the decrease in the prevalence of HIV are: GDP per capita, health expenditure per capita and the Gini index CONCLUSIONS: Structural determinants, as well as inequities, may or not influence the decrease in prevalence of HIV. This hypothesis could be applied to other public health issues. PMID- 26120862 TI - [Systematic Review of Factors Associated with the Presence of Cytoplasmic Droplets in Boars]. AB - OBJECTIVE: To determine the factors associated with the presence of cytoplasmic droplets in boars. METHODS: A systematic review was carried out in which 133 articles were found, 70 were eliminated due to duplication, and 65 were finally selected: 57 in Cab Abstract, 39 in Pub Med, 20 in Agricola, and 17 in Science Direct. Forty-seven articles were found with an available full text. Data was tabulated in EpiData Entry and transferred to the Stata version 12.0 program. RESULTS: Factors Associated with cytoplasmic droplets are: Climatic and environmental variables; ejaculation frequency with intervals of less than three weeks; spermatic morphologic alterations in tail (coiled and distal reflex); DNA fragmentation; and enzymatic factors related to seminal biochemistry. Work carried out in equatorial climate regions or that focused on the analysis of the implications of CDs in artificial insemination centers was not found. CONCLUSIONS: The information is characterized by a wide heterogeneity and diversity studies. A contribution was made to Veterinary Public Health in Colombia on the importance of CGs as factors that limit reproductive processes in swine. It was not possible to determine the temporal relationship between the cause and effect of CDs. PMID- 26120863 TI - [Mercury in ASGM and its impact on water resources used for domestic water supply]. AB - In regions affected by artisanal and small-scale gold mining (ASGM), the inhalation of mercury vapor and the ingestion of fish contaminated with this metal constitute the main sources of mercury contamination that affect human health. Nevertheless, according to the World Health Organization, another source of contamination is polluted water. Although mercury in freshwater is usually found in very low concentrations because it is swiftly consumed by aquatic microorganisms, evidence shows that under specific circumstances its concentration in water can reach high levels, even surpassing the 2.0 MUg/L stipulated by Colombian legislation for use as a domestic water supply. Mercury concentrations above 3.0 MUg/L have been found in some Colombian municipalities, and above 8.0 MUg/L in other regions around the world. Even though mercury consumption via water is a minor concern, along with other alimentary sources this low mercury concentration contributes to the total burden that affects human health. PMID- 26120864 TI - Coxiella burnetii infection in a patient from a rural area of Monteria, Colombia. AB - Q fever is a zoonosis caused by Coxiella burnetii. In Colombia, there have been very few human cases reported to date. This report describes the case of a 56 year-old patient with a background in agriculture and livestock handling. An indirect immunofluorescence assay (IFA) showed high titers of IgG for C. burnetii anti-phase I (1: 256) and anti-phase II (1:1024). For the next six months the patient's IgG antibody titers remained high, and after treatment with doxycycline, the IgG antibody titers decreased to 50% (anti-phase I 1:128 and anti-phase II 1:512); this profile suggests an infection of C. burnetii. PMID- 26120865 TI - The Effect of a Meditative Movement Intervention on Quality of Sleep in the Elderly: A Systematic Review and Meta-Analysis. AB - BACKGROUND/OBJECTIVES: Sleep disorders are one of the most common difficulties facing older people. Meditative movement interventions (MMIs), a new category of exercise integrating physical activity and meditation (e.g., t'ai chi, yoga, and qigong), may benefit older people with sleep problems. This systematic review synthesized the evidence on the effect of MMIs on older people's quality of sleep. METHODS: PubMed, EMBASE, CINAHL, PsycINFO, Scopus, the Cochrane Library, the China Science and Technology Journal Database (CSTJ) and the China National Knowledge Infrastructure (CNKI) were searched-from 1950 to March 2014-for randomized controlled trials. Articles were screened and selected by two researchers. Data were extracted from the included studies using specified forms. The same researchers independently evaluated the quality of each article. A meta analysis was conducted to examine the pooled effect of MMI on sleep quality compared with the control groups. RESULTS: Fourteen of 1049 studies were included, involving 1225 participants. Interventions included t'ai chi, yoga, qigong, and multicomponent MMI and lasted 12-24 weeks. Ten studies had a low risk of bias. The interventions resulted in significantly better sleep quality scores than either active therapy or usual care/wait-list controls (standardized mean difference, -0.70;95% confidence interval, -0.96 to -0.43). Subgroup analyses revealed that the effect of MMI on sleep quality was not influenced by the type or duration of the intervention. However, pooled results of studies with intervention frequency of fewer than 3 times per week did not show a positive effect on sleep quality. Lower-quality studies had larger effect sizes than high quality studies. No adverse events were reported. CONCLUSION: The current review demonstrated that MMI had a moderate effect on improving the quality of sleep for older people with sleep complaints. However, the evidence is inconclusive because of the varying study quality and MMI modalities. This study highlights the need for higher-quality randomized, controlled trials and more sufficient fidelity of intervention implementation to confirm the results. It also highlights the need for comparing the effectiveness of MMI on different subgroups of the elderly population. PMID- 26120866 TI - Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature. AB - OBJECTIVES: AA amyloidosis is the most serious potential complication of chronic inflammatory disorders. The main aim of treatment is to suppress inflammation thereby inhibiting serum amyloid A protein (SAA), which is the precursor of AA amyloid fibrils, to prevent or halt amyloid deposition. Interleukin (IL)-6 blockade is frequently effective in inflammatory conditions, however, there are few published data on its use in AA amyloidosis or the systemic autoinflammatory diseases (SAIDs) or chronic inflammatory conditions. We assessed clinical and serological responses and adverse events associated with tocilizumab (TCZ) use in 20 adult patients with inflammatory disorders refractory to other treatments, including 70% with AA amyloidosis and four with renal transplants. METHODS: In addition to routine haematology and biochemistry (including SAA) blood panels, patients with AA amyloidosis underwent SAP scintigraphy to quantify amyloid load. Those with SAIDs underwent genetic analysis to identify mutations/variants in known associated genes. Quality of life (QoL) was surveyed using SF-36v2(r). RESULTS: Whole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days of the first dose; this response has been maintained over an on-treatment follow-up period of 23 months (p<0.0001). AA amyloid deposits either regressed or remained stable. QoL improved in several domains. Infections were the predominant adverse effect experienced, but none resulted in permanent discontinuation of therapy. CONCLUSIONS: This small series shows that in patients with treatment refractory chronic inflammatory conditions TCZ can be effective in suppressing inflammation, and in those with AA amyloidosis, can lead to regression of amyloid deposits. Longer follow-up is required to determined long-term safety and efficacy in these conditions. PMID- 26120867 TI - Experimental Inoculation of Egyptian Rousette Bats (Rousettus aegyptiacus) with Viruses of the Ebolavirus and Marburgvirus Genera. AB - The Egyptian rousette bat (Rousettus aegyptiacus) is a natural reservoir for marburgviruses and a consistent source of virus spillover to humans. Cumulative evidence suggests various bat species may also transmit ebolaviruses. We investigated the susceptibility of Egyptian rousettes to each of the five known ebolaviruses (Sudan, Ebola, Bundibugyo, Tai Forest, and Reston), and compared findings with Marburg virus. In a pilot study, groups of four juvenile bats were inoculated with one of the ebolaviruses or Marburg virus. In ebolavirus groups, viral RNA tissue distribution was limited, and no bat became viremic. Sudan viral RNA was slightly more widespread, spurring a second, 15-day Sudan virus serial euthanasia study. Low levels of Sudan viral RNA disseminated to multiple tissues at early time points, but there was no viremia or shedding. In contrast, Marburg virus RNA was widely disseminated, with viremia, oral and rectal shedding, and antigen in spleen and liver. This is the first experimental infection study comparing tissue tropism, viral shedding, and clinical and pathologic effects of six different filoviruses in the Egyptian rousette, a known marburgvirus reservoir. Our results suggest Egyptian rousettes are unlikely sources for ebolaviruses in nature, and support a possible single filovirus-single reservoir host relationship. PMID- 26120868 TI - Quantification of SAHA-Dependent Changes in Histone Modifications Using Data Independent Acquisition Mass Spectrometry. AB - Histone post-translational modifications (PTMs) are important regulators of chromatin structure and gene expression. Quantitative analysis of histone PTMs by mass spectrometry remains extremely challenging due to the complex and combinatorial nature of histone PTMs. The most commonly used mass spectrometry based method for high-throughput histone PTM analysis is data-dependent acquisition (DDA). However, stochastic precursor selection and dependence on MS1 ions for quantification impede comprehensive interrogation of histone PTM states using DDA methods. To overcome these limitations, we utilized a data-independent acquisition (DIA) workflow that provides superior run-to-run consistency and postacquisition flexibility in comparison to DDA methods. In addition, we developed a novel DIA-based methodology to quantify isobaric, co-eluting histone peptides that lack unique MS2 transitions. Our method enabled deconvolution and quantification of histone PTMs that are otherwise refractory to quantitation, including the heavily acetylated tail of histone H4. Using this workflow, we investigated the effects of the histone deacetylase inhibitor SAHA (suberoylanilide hydroxamic acid) on the global histone PTM state of human breast cancer MCF7 cells. A total of 62 unique histone PTMs were quantified, revealing novel SAHA-induced changes in acetylation and methylation of histones H3 and H4. PMID- 26120869 TI - Protective Role of Ternatin Anthocyanins and Quercetin Glycosides from Butterfly Pea (Clitoria ternatea Leguminosae) Blue Flower Petals against Lipopolysaccharide (LPS)-Induced Inflammation in Macrophage Cells. AB - Twelve phenolic metabolites (nine ternatin anthocyanins and three glycosylated quercetins) were identified from the blue flowers of Clitoria ternatea by high performance liquid chromatography diode array detection and electrospray ionization/mass spectrometry (HPLC-DAD-ESI/MS(n)). Three anthocyanins not reported in this species before show fragmentation pattern of the ternatin class. Extracts were fractionated in fractions containing flavonols (F3) and ternatin anthocyanins (F4). In general, C. ternatea polyphenols showed anti-inflammatory properties in lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophage cells with distinct molecular targets. Flavonols (F3) showed strong inhibition of COX-2 activity and partial ROS suppression. On the other hand, the ternatin anthocyanins (F4) inhibited nuclear NF-kappaB translocation, iNOS protein expression, and NO production through a non-ROS suppression mechanism. Accordingly, quercetin glycosides and ternatin anthocyanins from the blue flower petals of C. ternatea may be useful in developing drugs or nutraceuticals for protection against chronic inflammatory diseases by suppressing the excessive production of pro-inflammatory mediators from macrophage cells. PMID- 26120870 TI - Luciferin Amides Enable in Vivo Bioluminescence Detection of Endogenous Fatty Acid Amide Hydrolase Activity. AB - Firefly luciferase is homologous to fatty acyl-CoA synthetases. We hypothesized that the firefly luciferase substrate d-luciferin and its analogs are fatty acid mimics that are ideally suited to probe the chemistry of enzymes that release fatty acid products. Here, we synthesized luciferin amides and found that these molecules are hydrolyzed to substrates for firefly luciferase by the enzyme fatty acid amide hydrolase (FAAH). In the presence of luciferase, these molecules enable highly sensitive and selective bioluminescent detection of FAAH activity in vitro, in live cells, and in vivo. The potency and tissue distribution of FAAH inhibitors can be imaged in live mice, and luciferin amides serve as exemplary reagents for greatly improved bioluminescence imaging in FAAH-expressing tissues such as the brain. PMID- 26120871 TI - High through-plane thermal conduction of graphene nanoflake filled polymer composites melt-processed in an L-shape kinked tube. AB - Design of materials to be heat-conductive in a preferred direction is a crucial issue for efficient heat dissipation in systems using stacked devices. Here, we demonstrate a facile route to fabricate polymer composites with directional thermal conduction. Our method is based on control of the orientation of fillers with anisotropic heat conduction. Melt-compression of solution-cast poly(vinylidene fluoride) (PVDF) and graphene nanoflake (GNF) films in an L-shape kinked tube yielded a lightweight polymer composite with the surface normal of GNF preferentially aligned perpendicular to the melt-flow direction, giving rise to a directional thermal conductivity of approximately 10 W/mK at 25 vol % with an anisotropic thermal conduction ratio greater than six. The high directional thermal conduction was attributed to the two-dimensional planar shape of GNFs readily adaptable to the molten polymer flow, compared with highly entangled carbon nanotubes and three-dimensional graphite fillers. Furthermore, our composite with its density of approximately 1.5 g/cm(3) was mechanically stable, and its thermal performance was successfully preserved above 100 degrees C even after multiple heating and cooling cycles. The results indicate that the methodology using an L-shape kinked tube is a new way to achieve polymer composites with highly anisotropic thermal conduction. PMID- 26120873 TI - Support Morphology-Dependent Catalytic Activity of Pd/CeO2 for Formaldehyde Oxidation. AB - To eliminate indoor formaldehyde (HCHO) pollution, Pd/CeO2 catalysts with different morphologies of ceria support were employed. The palladium nanoparticles loaded on {100}-faceted CeO2 nanocubes exhibited much higher activity than those loaded on {111}-faceted ceria nanooctahedrons and nanorods (enclosed by {100} and {111} facets). The HCHO could be fully converted into CO2 over the Pd/CeO2 nanocubes at a GHSV of 10,000 h(-1) and a HCHO inlet concentration of 600 ppm at ambient temperature. The prepared catalysts were characterized by a series of techniques. The HRTEM, ICP-MS and XRD results confirmed the exposed facets of the ceria and the sizes (1-2 nm) of the palladium nanoparticles with loading amounts close to 1%. According to the Pd 3d XPS and H2 TPR results, the status of the Pd-species was dependent on the morphologies of the supports. The {100} facets of ceria could maintain the metallic Pd species rather than the {111} facets, which promoted HCHO catalytic combustion. The Raman and O 1s XPS results revealed that the nanorods with more defect sites and oxygen vacancies were responsible for the easy oxidation of the Pd-species and low catalytic activity. PMID- 26120872 TI - G Protein-Coupled Receptor Kinase 2 (GRK2) and 5 (GRK5) Exhibit Selective Phosphorylation of the Neurotensin Receptor in Vitro. AB - G protein-coupled receptor kinases (GRKs) play an important role in the desensitization of G protein-mediated signaling of G protein-coupled receptors (GPCRs). The level of interest in mapping their phosphorylation sites has increased because recent studies suggest that the differential pattern of receptor phosphorylation has distinct biological consequences. In vitro phosphorylation experiments using well-controlled systems are useful for deciphering the complexity of these physiological reactions and understanding the targeted event. Here, we report on the phosphorylation of the class A GPCR neurotensin receptor 1 (NTSR1) by GRKs under defined experimental conditions afforded by nanodisc technology. Phosphorylation of NTSR1 by GRK2 was agonist dependent, whereas phosphorylation by GRK5 occurred in an activation-independent manner. In addition, the negatively charged lipids in the immediate vicinity of NTSR1 directly affect phosphorylation by GRKs. Identification of phosphorylation sites in agonist-activated NTSR1 revealed that GRK2 and GRK5 target different residues located on the intracellular receptor elements. GRK2 phosphorylates only the C-terminal Ser residues, whereas GRK5 phosphorylates Ser and Thr residues located in intracellular loop 3 and the C-terminus. Interestingly, phosphorylation assays using a series of NTSR1 mutants show that GRK2 does not require acidic residues upstream of the phospho-acceptors for site-specific phosphorylation, in contrast to the beta2-adrenergic and MU-opioid receptors. Differential phosphorylation of GPCRs by GRKs is thought to encode a particular signaling outcome, and our in vitro study revealed NTSR1 differential phosphorylation by GRK2 and GRK5. PMID- 26120874 TI - Pb17O8Cl18: A Promising IR Nonlinear Optical Material with Large Laser Damage Threshold Synthesized in an Open System. AB - Mid-IR nonlinear optical (NLO) materials are of great importance in modern laser frequency conversion technology and optical parametric oscillator processes. However, the commercially available IR NLO crystals (e.g., AgGaQ2 (Q = S, Se) and ZnGeP2) suffer from two obstacles, low laser damage thresholds (LDTs) and the difficulty of obtaining high-quality crystals, both of which seriously hinder their applications. The introduction of Cl, an element with a large electronegativity, and Pb, a relatively heavy element to promote the optical properties, affords an oxide-based IR NLO material, Pb17O8Cl18 (POC). High quality POC single crystals with sizes of up to 7 mm * 2 mm * 2 mm have been grown in an open system. Additionally, POC exhibits a large LDT of 408 MW/cm(2), 12.8 times that of AgGaS2. POC also exhibits an excellent second harmonic generation response: 2 times that of AgGaS2, the benchmark IR NLO crystal at 2090 nm, and 4 times that of KDP, the standard UV NLO crystal at 1064 nm. Thus, we believe that POC is a promising IR NLO material. PMID- 26120875 TI - Asteltoxins from the Entomopathogenic Fungus Pochonia bulbillosa 8-H-28. AB - New asteltoxins C (3) and D (4) were found in the extract of the entomopathogenic fungus Pochonia bulbillosa 8-H-28. Compound 2, which was spectroscopically identical with the known asteltoxin B, was isolated, and structural analysis led to a revision of the structure of asteltoxin B. Compounds 2 and 4 have a novel tricyclic ring system connected to a dienyl alpha-pyrone structure. Compound 3 has a 2,8-dioxabicyclo[3.3.0]octane ring similar to that of asteltoxin (1). Compound 3 showed potent antiproliferative activity against NIAS-SL64 cells derived from the fat body of Spodoptera litura larvae, while 2 and 4 were inactive. PMID- 26120877 TI - Direct On-Chip Optical Plasmon Detection with an Atomically Thin Semiconductor. AB - The determination to develop fast, efficient devices has led to vast studies on photonic circuits but it is difficult to shrink these circuits below the diffraction limit of light. However, the coupling between surface plasmon polaritons and nanostructures in the near-field shows promise in developing next generation integrated circuitry. In this work, we demonstrate the potential for integrating nanoplasmonic-based light guides with atomically thin materials for on-chip near-field plasmon detection. Specifically, we show near-field electrical detection of silver nanowire plasmons with the atomically thin semiconductor molybdenum disulfide. Unlike graphene, atomically thin semiconductors such as molybdenum disulfide exhibit a bandgap that lends itself for the excitation and detection of plasmons. Our fully integrated plasmon detector exhibits plasmon responsivities of ~255 mA/W that corresponds to highly efficient plasmon detection (~0.5 electrons per plasmon). PMID- 26120878 TI - An examination of the leftward cradling bias among typically developing adults high on autistic traits. AB - The leftward cradling bias is the tendency to cradle infants on the left side of the body and it has been linked with hemispheric asymmetry for emotional processing. This study examines this phenomenon using a real-size infant doll in typically developing adults who score high in the Reading the Mind in the Eyes, the Autistic Spectrum Quotient and the Empathy Quotient, measures that assess autistic traits among typically developing individuals. Results revealed that this group showed a reduced tendency to cradle on the left compared to participants who score within the normal range on the above measurements. This study provides further support for the justification of the leftward cradling bias upon brain lateralization on emotional processing. Study limitations and suggestions for future research are discussed. PMID- 26120876 TI - Serotonin (5-HT) 5-HT2A Receptor (5-HT2AR):5-HT2CR Imbalance in Medial Prefrontal Cortex Associates with Motor Impulsivity. AB - A feature of multiple neuropsychiatric disorders is motor impulsivity. Recent studies have implicated serotonin (5-HT) systems in medial prefrontal cortex (mPFC) in mediating individual differences in motor impulsivity, notably the 5 HT2AR receptor (5-HT2AR) and 5-HT2CR. We investigated the hypothesis that differences in the ratio of 5-HT2AR:5-HT2CR protein expression in mPFC would predict the individual level of motor impulsivity and that the engineered loss of the 5-HT2CR would result in high motor impulsivity concomitant with elevated 5 HT2AR expression and pharmacological sensitivity to the selective 5-HT2AR antagonist M100907. High and low impulsive rats were identified in a 1-choice serial reaction time task. Native protein levels of the 5-HT2AR and the 5-HT2CR predicted the intensity of motor impulsivity and the 5-HT2AR:5-HT2CR ratio in mPFC positively correlated with levels of premature responses in individual outbred rats. The possibility that the 5-HT2AR and 5-HT2CR act in concert to control motor impulsivity is supported by the observation that high phenotypic motor impulsivity associated with a diminished mPFC synaptosomal 5-HT2AR:5-HT2CR protein:protein interaction. Knockdown of mPFC 5-HT2CR resulted in increased motor impulsivity and triggered a functional disruption of the local 5-HT2AR:5 HT2CR balance as evidenced by a compensatory upregulation of 5-HT2AR protein expression and a leftward shift in the potency of M100907 to suppress impulsive behavior. We infer that there is an interactive relationship between the mPFC 5 HT2AR and 5-HT2CR, and that a 5-HT2AR:5-HT2CR imbalance may be a functionally relevant mechanism underlying motor impulsivity. PMID- 26120879 TI - Development and function of follicular helper T cells. AB - Most currently available vaccines rely on the induction of long-lasting protective humoral immune responses by memory B cells and plasma cells. Antibody responses against most antigens require interactions between antigen-specific B cells and CD4(+) T cells. Follicular helper T cells (TFH cells) are specialized subset of T cells that provide help to B cells and are essential for germinal center formation, affinity maturation, and the development of high-affinity antibodies. TFH-cell differentiation is a multistage process involving B-cell lymphoma 6 and other transcription factors, cytokines, and costimulation through inducible costimulator (ICOS) and several other molecules. This article reviews recent advances in our understanding of TFH cell biology, including their differentiation, transcriptional regulation, and function. PMID- 26120880 TI - Social Participation and Disability among Children from Underserved Immigrant and Nonimmigrant Households. AB - The population of immigrant children in the United States has increased dramatically. Little is known about how immigrant children, especially those with disabilities, fare on outcomes relevant to occupational therapy such as participation in home, school, and community activities. Using secondary data from the Making Connections survey, we compared social participation outcomes and predictors for children with/without disabilities from underserved immigrant and nonimmigrant households in a sample of 2,295 children aged 3 to 17 years. We found that social participation rates differed significantly for children based on their disability and immigrant status and were lowest for immigrant children with disabilities. Several contextual factors were found to be associated with social participation of immigrant children, such as health insurance coverage, household education, household connectedness with the neighborhood, and access to computers and the Internet. Implications of these findings for occupational therapy practice and research are discussed. PMID- 26120881 TI - Should We Give Routine Postoperative Intravenous Fluids After Cleft Surgery? AB - OBJECTIVE: In 2012, the James Lind Alliance, together with the Craniofacial Society of Great Britain and Ireland and the Cleft Lip and Palate Association, set priorities for unanswered questions in cleft management. One of these priorities included postoperative fluid management. The authors' postoperative regimen does not include intravenous fluids unless the child fails to achieve adequate oral intake by the first evening postoperatively. This audit evaluated whether this is appropriate and safe practice. METHODS: All patients undergoing cleft-related surgery by a single surgeon in a single center during August 2011 to August 2012 were included. Patient age, weight, and surgery type were recorded together with fluid requirement, length of stay, and any returns to theater or readmissions. RESULTS: Of the 79 patients included, none required readmission or return to theater, and the mean length of stay was 1.72 days. Nineteen patients (24%) required intravenous fluids, but these tended to be the older children in the group (P value .034). In the youngest patients undergoing primary lip repair, only 1 of 20 required intravenous fluids. CONCLUSIONS: This study demonstrates that, especially in the younger patients, omitting intravenous fluids as a postoperative routine is associated with a shorter length of stay without an increased complication rate. The authors advocate early postoperative feeding and the return to physiological fluid balance. PMID- 26120882 TI - Transoral Robotic Cleft Palate Surgery. AB - Objective This study aimed to assess the safety and feasibility of transoral robotic surgery for the reconstruction of soft palatal clefts. Design The application of transoral robotic surgery for soft palate muscle reconstruction was investigated. The da Vinci Surgical Robot was first used on a cadaver to assess the optimal positioning of the patient and the robot. The robot was then used for the dissection and reconstruction of palatal muscles in 10 consecutive patients with palatal clefts. The procedures were documented using video and still photography. A group of 30 control patients were subjected to surgery with manual instruments. Surgical and clinical outcomes were evaluated with at least 6 months of follow-up (8 +/- 1 months). Results The use of the surgical robot on a cadaver provided great dexterity and excellent 3D depth perception. The transoral access was efficient and safe for the precise dissection, reorientation, and suturing of palatal muscles. In our series, the surgical duration was longer for the robotic approach than for the manual approach (87 +/- 6 minutes versus 122 +/- 8 minutes, P < .0001). No intraoperative or postoperative complications occurred in either group. CONCLUSIONS: A robotic surgical approach can be used safely for palatal surgery. We believe that the precise dissection of the palatal muscles provided by the robotic system might reduce damage to the vascularization and innervation of these muscles, as well as damage to the mucosal surfaces that could cause fistula formation. In addition, this technique might improve palatal function and Eustachian tube function in cleft palate patients. PMID- 26120883 TI - Speech, Language, and Reading in 10-Year-Olds With Cleft: Associations With Teasing, Satisfaction With Speech, and Psychological Adjustment. AB - BACKGROUND: Despite the use of multidisciplinary services, little research has addressed issues involved in the care of those with cleft lip and/or palate across disciplines. The aim was to investigate associations between speech, language, reading, and reports of teasing, subjective satisfaction with speech, and psychological adjustment. DESIGN: Cross-sectional data collected during routine, multidisciplinary assessments in a centralized treatment setting, including speech and language therapists and clinical psychologists. PARTICIPANTS: Children with cleft with palatal involvement aged 10 years from three birth cohorts (N = 170) and their parents. OUTCOME MEASURES: Speech: SVANTE N. Language: Language 6-16 (sentence recall, serial recall, vocabulary, and phonological awareness). Reading: Word Chain Test and Reading Comprehension Test. Psychological measures: Strengths and Difficulties Questionnaire and extracts from the Satisfaction With Appearance Scale and Child Experience Questionnaire. RESULTS: Reading skills were associated with self- and parent-reported psychological adjustment in the child. Subjective satisfaction with speech was associated with psychological adjustment, while not being consistently associated with speech therapists' assessments. Parent-reported teasing was found to be associated with lower levels of reading skills. Having a medical and/or psychological condition in addition to the cleft was found to affect speech, language, and reading significantly. CONCLUSIONS: Cleft teams need to be aware of speech, language, and/or reading problems as potential indicators of psychological risk in children with cleft. This study highlights the importance of multiple reports (self, parent, and specialist) and a multidisciplinary approach to cleft care and research. PMID- 26120884 TI - Serial Presurgical Orthopedics for Eye Repositioning and Optimization of Soft Tissue Repair in an Infant With Tessier No. 4 Cleft. AB - OBJECTIVE: A male patient with Tessier No. 4 cleft (unilateral left) presented at 20 days of age. The cleft defect beginning between the cupid bow and oral commissure extended to the ipsilateral orbital floor, skirting the nose and lacrimal duct while passing through the cheek medial to the infraorbital nerve. With the lesser segment disposed 16 mm transversely, the wide gap included an absence of orbital floor and lower eyelid. A deficient midfacial platform caused a severe inferior globe dystopia, superiorly displaced left ala base, and severe vertical shortening between ala-canthus and ala-globe. INTERVENTION: A modified Latham device applied directional orthopedics to contract the cleft gap and with an eye part added to elevate the dystopic globe. Two different Latham devices used in succession were each applied for 4 weeks. Lastly, a removable plate further repositioned the eye. Each appliance was designed to differentially move the noncleft and cleft segments of the maxilla. Presurgical orthopedics began at 3 weeks lasted 14 weeks. Intraoperatively at 17 weeks, the inferior globe dystopia was effectively reduced, and the cleft gaps were nearly closed and aligned at the orbital floor, cheek, and the alveolus. Respecting the aesthetic units of face became possible with the soft-tissue repair yet were tight enough in the malar region to retract the lower lid. CONCLUSION: The presurgical directional orthopedic and eye-globe mechanics were sufficient to enable medial canthal repositioning, sustainable correction of orbital distopia, and optimized primary soft-tissue repair. Early result suggests that surgery with presurgical orthopedics is superior to surgery alone. PMID- 26120885 TI - Social Interactions of School-Aged Children With Craniofacial Anomalies: Mothers' Perspectives and Advice. PMID- 26120886 TI - Congenital Ulcerated Lip Hemangioma Treated With a Cleft Lip Technique. AB - A neonate presented to our clinic for evaluation of unusual congenital cleft lip. The clinical follow-up showed at first an ulceration of the lesion and then a stable result after propanolol systemic therapy. After 18 months of clinical follow-up, surgical treatment was performed, which consisted of double unilimb Z plasty according to Mulliken's microform cleft lip repair. Knowing the existence of these strange vascular anomalies of the lip will allow us to improve the differential diagnosis and treatment plan. PMID- 26120887 TI - An Assessment of 30-Day Complications in Primary Cleft Palate Repair: A Review of the 2012 ACS NSQIP Pediatric. AB - OBJECTIVE: This study uses the American College of Surgeons Pediatric National Surgical Quality Improvement Program (ACS NSQIP Pediatric), a multicenter database, to identify risk factors for complications after cleft palate repair. DESIGN: Patients undergoing Current Procedural Terminology (CPT) codes 42200 and 42205 were extracted from the 2012 ACS NSQIP Pediatric. Patients older than 36 months or those who had undergone an additional surgery that altered the risk were excluded. Outcome variables were combined to create a complication variable. Fisher's exact, Pearson chi-square, and Wilcoxon rank-sum tests were used for analysis. RESULTS: Eligibility criteria were met by 751 patients. Of these, 192 (25.6%) had unilateral clefts, 146 (19.4%) bilateral, and 413 (55.0%) were unspecified. The average age at time of surgery for those without and with complications was 421.1 +/- 184.8 and 433.6 +/- 168.0 days, respectively (P = .76). Of the 21 (2.8%) patients with complications, respiratory complications were the most common. Risk factors associated with complications included American Society of Anesthesiologists classification of 3 (P = .003), nutritional support (P = .013), esophageal/gastric/intestinal disease (P = .016), oxygen support (P = .003), structural pulmonary/airway abnormality (P = .011), and impaired cognitive status (P = .009). Patients undergoing concurrent laryngoscopy (P = .048) or other surgeries (P = .047) were also found to be associated with increased complications. The 30-day fistula rate was 0.5%, and the readmission rate was 1.9%. CONCLUSION: Perioperative complications for primary palatoplasty were 2.8% according to the ACS NSQIP Pediatric. Preoperative patient-related factors as well as concurrent surgeries may affect 30-day complication rates. These results help target those at greater risk for complications and allow for appropriate interventions to mitigate risks. PMID- 26120889 TI - Generalised EPG treatment effect in a cochlear implant user maintained after 2 years. AB - PURPOSE: The aim of this study was to evaluate speech therapy using electropalatography (EPG) in home training of persistent articulation errors in a cochlear implant user with hearing impairment. There was a particular focus on aspects of maintenance of training effects and possible transfer to connected speech. METHOD: The participant was a young woman, deaf from early childhood and a cochlear implant user from pre-school age. Treatment effects were evaluated using a single-subject design with multiple measures. RESULT: Instrumental and perceptual outcome measures showed a clear improvement in the production of the treatment target /g/ in single words and sentences after 4 months of therapy (17 hours). The results were maintained at 3, 6 and 24 months after intervention. Also, /g/ in connected speech, consisting of text reading and spontaneous speech, showed a significant difference between before and after treatment and at long term follow-up. CONCLUSION: The results show that EPG used in home training can be an efficient method for treating persistent speech disorders associated with hearing impairment and that the treatment effect appears to maintain. PMID- 26120888 TI - SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. AB - Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 MUM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3(H248Y)) lacking deacetylase activity lost the capacity to suppress Cd induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial derived O2(*-) production and suppressed the autophagy induced by 10 MUM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatonin-mediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2(*-) stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway. PMID- 26120890 TI - Correlation of Internet Use for Health Care Engagement Purposes and HIV Clinical Outcomes Among HIV-Positive Individuals Using Online Social Media. AB - The authors aimed to describe cell phone and Internet use and assess the correlation of Internet use for health care engagement purposes and HIV clinical outcomes among HIV-positive individuals. The authors conducted a national survey using online social media to examine cell phone and Internet use, self-reported HIV viral load (detectable vs. undetectable), and antiretroviral adherence rating (excellent vs. less than excellent). Participants (N = 1,494) were asked about their Internet use for health care engagement purposes (including e-mailing health care providers, refilling medications online, and making medical appointments online). Approximately 95% of participants accessed the Internet nearly daily or daily in the past month (mean hours on Internet use per day = 5.2) and 55.5% used the Internet for health care engagement purposes. Those who used the Internet for any health care engagement purposes had a 1.52-fold odds of reporting an undetectable viral load (p = .009) and a 1.49-fold odds of reporting excellent adherence (p = .001). Although Internet access and use were similar across racial/ethnic, educational, and socioeconomic groups, disparities existed with the use of the Internet for health care engagement purposes among racial/ethnic minorities, those with low to moderate financial stability, lower education, and history of incarceration. The authors' data reveal that among HIV positive users of online social media, use of the Internet for health care engagement purposes is associated with better self-reported virologic and adherence outcomes. PMID- 26120891 TI - Antidepressant-like effect of simvastatin in diabetic rats. AB - Diabetes mellitus is accompanied by hormonal and neurochemical changes that can be associated with anxiety and depression. I investigated the antidepressant effect of simvastatin (SMV) on diabetic rats. Rats were divided into control (CTR) and streptozotocin-induced diabetic (STZ) groups and were orally administered 0, 5, or 10 mg/kg of SMV daily for 14 days, then exposed to the forced swimming test (FST). Our results showed that diabetic rats had higher immobility duration than the CTR rats, and SMV decreased this depressive-like behavior in the diabetic rats. However, clomipramine lowered the immobility time in the CTR and STZ rats. STZ decreased serotonin concentration in the hippocampus, which was reversed by SMV and clomipramine. The dopamine concentration in the hippocampus decreased in the STZ groups compared with the CTR groups. However, SMV and clomipramine had no significant effect on the dopamine levels in either the CTR or STZ groups. Corticosterone levels were increased in the untreated STZ group; SMV and clomipramine significantly decreased corticosterone levels in the STZ groups, but had no effect on the CTR groups. In conclusion, SMV exerts an antidepressant-like effect on diabetic rats that are submitted to the FST. The antidepressant-like effect of SMV in the FST appears to be mediated, at least in part, by the biochemical changes to the blood levels of corticosterone and of serotonin concentration in the hippocampus. PMID- 26120892 TI - Acute Kidney Injury Requiring Dialysis in Severe Sepsis. AB - RATIONALE: Understanding the changing incidence and impact of acute kidney injury requiring dialysis in patients with severe sepsis will allow better risk stratification, design of clinical trials, and guide resource allocation. OBJECTIVES: To assess the longitudinal incidence of acute kidney injury requiring dialysis and its impact on mortality in patients with severe sepsis. METHODS: Retrospective cohort study of adults (>=20 yr) hospitalized with severe sepsis from 2000 to 2009 in the United States using a nationally representative database. MEASUREMENTS AND MAIN RESULTS: We calculated the incidences of acute kidney injury requiring dialysis and mortality over time. We used linear regression to assess temporal trends. We used logistic regression to estimate the odds of acute kidney injury requiring dialysis and mortality. Of the estimated 5,257,907 hospitalizations with severe sepsis, 6.1% had acute kidney injury requiring dialysis. The odds of acquiring acute kidney injury requiring dialysis increased by 14% in 2009 compared with 2000. Mortality in patients with acute kidney injury requiring dialysis was higher (43.6% vs. 24.9%; P < 0.001). After multivariable adjustment, odds of mortality declined 61% by the year 2009. Acute kidney injury requiring dialysis remained an independent predictor of mortality in patients with severe sepsis, although its influence on mortality declined with time. CONCLUSIONS: Incidence of acute kidney injury requiring dialysis in patients with severe sepsis has increased over time; conversely, associated mortality has declined. The likelihood of demise from acute kidney injury requiring dialysis in patients with severe sepsis has also declined. PMID- 26120893 TI - Medical legal partnership and health informatics impacting child health: Interprofessional innovations. AB - Dramatic differences in health are closely related to degrees of social and economic disadvantage. Poverty-induced hardships such as food insecurity, utility shut-offs, and substandard housing, all have the potential to negatively impact the health of families. In an effort to better address social determinants of health in pediatric primary health care settings using the Medical Legal Partnership (MLP) model of health care delivery, an interprofessional team of investigators came together to design an innovative process for using computerized clinical decision support to identify health-harming legal and social needs, improve the delivery of appropriate physician counseling, and streamline access to legal and social service professionals when non-medical remedies are required. This article describes the interprofessional nature of the MLP model itself, illustrates the work that was done to craft this innovative health informatics approach to implementing MLP, and demonstrates how pediatricians, social workers and attorneys may work together to improve child health outcomes. PMID- 26120894 TI - E-Learning with virtual teammates: A novel approach to interprofessional education. AB - The Institute of Medicine identified interprofessional education (IPE) as a key innovation for achieving the triple aim of better care, better outcomes, and reduced healthcare costs. Yet, a shortage of qualified faculty and difficulty with aligning learners' schedules often prevent sustainable and scalable IPE. A virtual IPE intervention was developed to circumvent these barriers and compared to a blended-learning IPE intervention. We used a pre-test and post-test design with two comparison interventions to test the effects of these IPE interventions on changes in teamwork knowledge, skills, and attitudes. The interventions were delivered to pre-licensure learners at a large, metropolitan medical and a nursing school. We used one-sample and independent-sample t-tests to analyze data from 220 learners who received the blended-learning intervention in 2011 and 540 learners who received the virtual learning intervention in 2012. The students in the blended-learning intervention did not significantly (p < 0.05) outperform the students in the virtual learning intervention for any of the measured outcomes, except for medical students' attitudes around team value. Virtual IPE learning is an effective, scalable, and sustainable solution for imparting foundational teamwork knowledge in health profession students. PMID- 26120895 TI - Partnership to promote interprofessional education and practice for population and public health informatics: A case study. AB - Team-based healthcare delivery models, which emphasize care coordination, patient engagement, and utilization of health information technology, are emerging. To achieve these models, expertise in interprofessional education, collaborative practice across professions, and informatics is essential. This case study from informatics programs in the Academic Health Center (AHC) at the University of Minnesota and the Office of Health Information Technology (OHIT) at the Minnesota Department of Health presents an academic-practice partnership, which focuses on both interprofessionalism and informatics. Outcomes include the Minnesota Framework for Interprofessional Biomedical Health Informatics, comprising collaborative curriculum development, teaching and research, practicums to promote competencies, service to advance biomedical health informatics, and collaborative environments to facilitate a learning health system. Details on these Framework categories are presented. Partnership success is due to interprofessional connections created with emphasis on informatics and to committed leadership across partners. A limitation of this collaboration is the need for formal agreements outlining resources and roles, which are vital for sustainability. This partnership addresses a recommendation on the future of interprofessionalism: that both education and practice sectors be attuned to each other's expectations and evolving trends. Success strategies and lessons learned from collaborations, such as that of the AHC-OHIT that promote both interprofessionalism and informatics, need to be shared. PMID- 26120896 TI - Increasing medical students' understanding of the role of occupational therapists. AB - Understanding the roles and responsibilities of different healthcare professionals allows for collaborative care to occur. This article describes the evaluation of a student-designed, case-based educational module about the roles and responsibilities of occupational therapists (OTs) designed to increase the knowledge of occupational therapy among medical students. The study used a quasi experimental, pre-/post-test design. Independent paired t-tests showed medical students' mean score on the OT Awareness Education Module at post-test was significantly greater than their mean score at pre-test. Results demonstrated how using an evidence-based approach to design an educational strategy can increase the knowledge of one member of the healthcare team about the role of another within a short period. This study documented an effective approach for educating future physicians about the roles and responsibilities of occupational therapy as they prepare to make decisions affecting patient care outcomes. PMID- 26120897 TI - Antioxidant Capacity: Experimental Determination by EPR Spectroscopy and Mathematical Modeling. AB - A new method of determining antioxidant capacity based on a mathematical model is presented in this paper. The model was fitted to 1000 data points of electron paramagnetic resonance (EPR) spectroscopy measurements of various food product samples such as tea, wine, juice, and herbs with Trolox equivalent antioxidant capacity (TEAC) values from 20 to 2000 MUmol TE/100 mL. The proposed mathematical equation allows for a determination of TEAC of food products based on a single EPR spectroscopy measurement. The model was tested on the basis of 80 EPR spectroscopy measurements of herbs, tea, coffee, and juice samples. The proposed model works for both strong and weak antioxidants (TEAC values from 21 to 2347 MUmol TE/100 mL). The determination coefficient between TEAC values obtained experimentally and TEAC values calculated with proposed mathematical equation was found to be R(2) = 0.98. Therefore, the proposed new method of TEAC determination based on a mathematical model is a good alternative to the standard EPR method due to its being fast, accurate, inexpensive, and simple to perform. PMID- 26120898 TI - Trans-Carotid Placement of Balloon Expandable Covered Stent for Unplanned Left Carotid Coverage during Endovascular Repair of Distal Arch Aneurysm. AB - We present a technique for endovascular management of unplanned coverage of the left common carotid artery during endovascular repair of a distal aortic arch aneurysm. A balloon expandable covered stent was placed into the proximal left common carotid artery by neck incision. PMID- 26120899 TI - Minimally Invasive Implantation of the EDWARDS INTUITY Rapid Deployment Aortic Valve Via a Right Minithoracotomy. AB - During the past decade, many surgeons have focused their interest on the development and improvement of minimally invasive techniques for aortic valve replacement. Although the minimally invasive approaches for the treatment of mitral valve disease have been standardized, the preferred route for aortic valve replacement remains a matter of debate. Access through a right minithoracotomy avoids opening the sternum; however, it requires a greater surgical ability and a learning period, even for experienced surgeons. This enhances the role of sutureless prostheses because these devices are associated with easier placement, excellent hemodynamic performance, and acceptable rates of pacemaker implantation and paravalvular leak. Herein, we report a series of 10 consecutive patients who received an EDWARDS INTUITY rapid deployment valve (Edwards Lifesciences, Irvine, CA USA) by a right minithoracotomy. PMID- 26120900 TI - Interaction of methamphetamine abuse, tobacco abuse, and gender in the brain. PMID- 26120901 TI - Caveat Emptor on Sublingual Immunotherapy. PMID- 26120902 TI - Combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator for emergent revascularization in acute ischemic stroke (CLOTBUST-ER): design and methodology of a multinational phase 3 trial. AB - BACKGROUND: We designed a Phase 3 clinical trial to determine the safety and efficacy of adding transcranial ultrasound using an operator-independent headframe to recombinant tissue-plasminogen-activator for the treatment of acute ischemic stroke. METHODS: Combined lysis of thrombus with ultrasound and systemic tissue-plasminogen-activator for emergent revascularization in acute ischemic stroke is a randomized, double-blind, placebo-controlled clinical trial that will enroll subjects with the following main inclusion criteria: less than 4.5 hours from symptom onset (three-hours in US and Canada), age 18-80 years, baseline National Institutes of Health Stroke Scale score >= 10, and premorbid modified Rankin-score of 0-1, eligibility for full dose recombinant tissue-plasminogen activator. Subjects will receive two-hours of 2-MHz pulsed wave transcranial ultrasound (target group) or sham ultrasound (control group). The projected sample size is approximately 824 subjects. RESULTS: The primary endpoint, based on intention-to-treat criteria of patients enrolled within three-hours of symptom onset is the comparison between target and control groups of modified-Rankin score scores at day 90 poststroke assessed using the proportional odds method. The study will have two planned interim analyses after approximately one-third and two-thirds of subjects have reached the 90-day modified-Rankin-score evaluation. Safety outcomes are symptomatic intracranial hemorrhage within 24 h and an overall analysis of adverse events. CONCLUSIONS: Since intravenous recombinant tissue-plasminogen-activator remains the only medical therapy to reverse ischemic stroke applicable in the emergency department, our trial will determine if the additional use of transcranial ultrasound improves functional outcomes in patients with severe acute ischemic stroke (NCT#01098981). PMID- 26120903 TI - New Insights into the Functions of Transcription Factors that Bind the RNA Polymerase Secondary Channel. AB - Transcription elongation is regulated at several different levels, including control by various accessory transcription elongation factors. A distinct group of these factors interacts with the RNA polymerase secondary channel, an opening at the enzyme surface that leads to its active center. Despite investigation for several years, the activities and in vivo roles of some of these factors remain obscure. Here, we review the recent progress in understanding the functions of the secondary channel binding factors in bacteria. In particular, we highlight the surprising role of global regulator DksA in fidelity of RNA synthesis and the resolution of RNA polymerase traffic jams by the Gre factor. These findings indicate a potential link between transcription fidelity and collisions of the transcription and replication machineries. PMID- 26120905 TI - Acute in vivo toxicity mitigation of PEI-coated maghemite nanoparticles using controlled oxidation and surface modifications toward siRNA delivery. AB - A ceric ammonium nitrate (CAN)-based doping step was used for the fabrication of core maghemite nanoparticles (NPs) that enabled the obtainment of colloid particles with a view to a high-level nanoparticle (NP) surface doping by Ce(III/IV). Such doping of Ce(III/IV) cations enables one to exploit their quite rich coordination chemistry for ligand coordinative binding. In fact, they were shown to act as powerful Lewis acid centers for attaching any organic (Lewis base) ligand such as a 25 kDa branched PEI polymer. Resulting conPEI25-CAN-gamma Fe2O3 NPs have been fully characterized before a successful implementation of siRNA loading and cell delivery/gene silencing using a well-known dual luciferase system. This attractive result emphasized their significant potential as an NP platform technology toward additional MRI and/or drug delivery (peptide)-relating end applications. However, due to their high positive charge, PEI polymers can cause severe in vivo toxicity due to their interaction with negatively charged red blood cells (RBC), resulting in RBC aggregation and lysis, leading to thrombosis and, finally, to animal death. In order to mitigate these acute toxic effects, two different types of surface modifications were performed. One modification included the controlled oxidation of 0.1-5% of the PEI amines before or after conjugation to the NPs, using hydrogen peroxide or potassium persulfate. The other type of modification was the addition of a second biocompatible polyanionic polymer to the PEI grafted NPs, based on the concept of a layer-by layer (LbL) technique. This modification is based on the coordination of another polyanionic polymer on the NPs surface in order to create a combined hybrid PEI and polyanionic polymer nanosystem. In both cases, the surface modification successfully mitigated the NP acute in vivo toxicity, without compromising the silencing efficiency. PMID- 26120904 TI - Synthetic Proteins and Peptides for the Direct Interrogation of alpha-Synuclein Posttranslational Modifications. AB - alpha-Synuclein is the aggregation-prone protein associated with Parkinson's disease (PD) and related neurodegenerative diseases. Complicating both its biological functions and toxic aggregation are a variety of posttranslational modifications. These modifications have the potential to either positively or negatively affect alpha-synuclein aggregation, raising the possibility that the enzymes that add or remove these modifications could be therapeutic targets in PD. Synthetic protein chemistry is uniquely positioned to generate site specifically and homogeneously modified proteins for biochemical study. Here, we review the application of synthetic peptides and proteins towards understanding the effects of alpha-synuclein posttranslational modifications. PMID- 26120906 TI - Impact of musculoskeletal ultrasound on clinical practice in paediatric rheumatology. AB - OBJECTIVES: Musculoskeletal ultrasound (MSUS) is an imaging technique increasingly used in paediatric rheumatology. The aim of our study was to evaluate the extent to which MSUS may influence the diagnosis and management decisions in daily clinical practice in paediatric rheumatology. METHODS: All child patients attending our PR unit over a 3-month period were included. A consultant rheumatologist assessed juvenile patients and weighted the need for MSUS assessment under a Likert scale from 0 (not necessary) to 5 (very necessary) with scanning performed when the Likert score was greater than 0. The rheumatologist completed a questionnaire used to report previous and current diagnosis, therapeutic decisions and disease activity. An assistant rheumatologist who was blinded to the questionnaire carried out the MSUS scanning of selected joints. After MSUS examination, a second questionnaire was completed by the consultant rheumatologist reporting changes in diagnosis and systemic and local treatment, if applicable. RESULTS: We included 111 patients [73 (65.8%) female]. Fifteen (13.5%) were new patients and 96 (86.5%) follow-up patients. Fifty-one (45.9%) patients were diagnosed with JIA. 65 (58.6%) patients qualified for MSUS. A total of 108 joints from 65 patients were clinically assessed with 93 (86.1%) joints deemed to require complementary MSUS assessment (mean assessed joints 1.4 per patient). Of the 65 patients undergoing MSUS, 38 (58.5%) patients there was a change in diagnosis, therapeutic decisions or both following the MSUS information. CONCLUSIONS: MSUS may play a significant role in local diagnosis and therapeutic decisions among follow-up JIA patients and could help in the management of rheumatic diseases in children. Further longitudinal studies are needed to confirm the impact of MSUS in paediatric rheumatology. PMID- 26120908 TI - Reference-dependent risk sensitivity as rational inference. AB - Existing explanations of reference-dependent risk sensitivity attribute it to cognitive imperfections and heuristic choice processes. This article shows that behavior consistent with an S-shaped value function could be an implication of rational inferences about the expected values of alternatives. Theoretically, I demonstrate that even a risk-neutral Bayesian decision maker, who is uncertain about the reliability of observations, should use variability in observed outcomes as a predictor of low expected value for outcomes above a reference level, and as a predictor of high expected value for outcomes below a reference level. Empirically, I show that combining past outcomes using an S-shaped value function leads to accurate predictions about future values. The theory also offers a rationale for why risk sensitivity consistent with an inverse S-shaped value function should occur in experiments on decisions from experience with binary payoff distributions. PMID- 26120907 TI - Separating decision and encoding noise in signal detection tasks. AB - In this article we develop an extension to the signal detection theory framework to separately estimate internal noise arising from representational and decision processes. Our approach constrains signal detection theory models with decision noise by combining a multipass external noise paradigm with confidence rating responses. In a simulation study we present evidence that representation and decision noise can be separately estimated over a range of representative underlying representational and decision noise level configurations. These results also hold across a number of decision rules and show resilience to rule miss-specification. The new theoretical framework is applied to a visual detection confidence-rating task with 3 and 5 response categories. This study compliments and extends the recent efforts of researchers (Benjamin, Diaz, & Wee, 2009; Mueller & Weidemann, 2008; Rosner & Kochanski, 2009; Kellen, Klauer, & Singmann, 2012) to separate and quantify underlying sources of response variability in signal detection tasks. PMID- 26120909 TI - Affixation in semantic space: Modeling morpheme meanings with compositional distributional semantics. AB - The present work proposes a computational model of morpheme combination at the meaning level. The model moves from the tenets of distributional semantics, and assumes that word meanings can be effectively represented by vectors recording their co-occurrence with other words in a large text corpus. Given this assumption, affixes are modeled as functions (matrices) mapping stems onto derived forms. Derived-form meanings can be thought of as the result of a combinatorial procedure that transforms the stem vector on the basis of the affix matrix (e.g., the meaning of nameless is obtained by multiplying the vector of name with the matrix of -less). We show that this architecture accounts for the remarkable human capacity of generating new words that denote novel meanings, correctly predicting semantic intuitions about novel derived forms. Moreover, the proposed compositional approach, once paired with a whole-word route, provides a new interpretative framework for semantic transparency, which is here partially explained in terms of ease of the combinatorial procedure and strength of the transformation brought about by the affix. Model-based predictions are in line with the modulation of semantic transparency on explicit intuitions about existing words, response times in lexical decision, and morphological priming. In conclusion, we introduce a computational model to account for morpheme combination at the meaning level. The model is data-driven, theoretically sound, and empirically supported, and it makes predictions that open new research avenues in the domain of semantic processing. (PsycINFO Database Record PMID- 26120910 TI - Signal detection and threshold modeling of confidence-rating ROCs: A critical test with minimal assumptions. AB - An ongoing discussion in the recognition-memory literature concerns the question of whether recognition judgments reflect a direct mapping of graded memory representations (a notion that is instantiated by signal detection theory) or whether they are mediated by a discrete-state representation with the possibility of complete information loss (a notion that is instantiated by threshold models). These 2 accounts are usually evaluated by comparing their (penalized) fits to receiver operating characteristic data, a procedure that is predicated on substantial auxiliary assumptions, which if violated can invalidate results. We show that the 2 accounts can be compared on the basis of critical tests that invoke only minimal assumptions. Using previously published receiver operating characteristic data, we show that confidence-rating judgments are consistent with a discrete-state account. (PsycINFO Database Record PMID- 26120911 TI - Hidden processes in structural representations: A reply to Abbott, Austerweil, and Griffiths (2015). AB - In recent work exploring the semantic fluency task, we found evidence indicative of optimal foraging policies in memory search that mirror search in physical environments. We determined that a 2-stage cue-switching model applied to a memory representation from a semantic space model best explained the human data. Abbott, Austerweil, and Griffiths demonstrate how these patterns could also emerge from a random walk applied to a network representation of memory based on human free-association norms. However, a major representational issue limits any conclusions that can be drawn about the process model comparison: Our process model operated on a memory space constructed from a learning model, whereas their model used human behavioral data from a task that is quite similar to the behavior they attempt to explain. Predicting semantic fluency (e.g., how likely it is to say cat after dog in a sequence of animals) from free association (how likely it is to say cat when given dog as a cue) should be possible with a relatively simple retrieval mechanism. The 2 tasks both tap memory, but they also share a common process of retrieval. Assuming that semantic memory is a network from free-association behavior embeds variance due to the shared retrieval process directly into the representation. A simple process mechanism is then sufficient to simulate semantic fluency because much of the requisite process complexity may already be hidden in the representation. (PsycINFO Database Record PMID- 26120912 TI - Decreased SAPK/JNK signalling affects cytokine release and STAT3 activation in psoriatic fibroblasts. PMID- 26120914 TI - Suicide Disclosure in Suicide Attempt Survivors: Does Family Reaction Moderate or Mediate Disclosure's Effect on Depression? AB - Existing literature has found a link between disclosure of a stigmatized identity and improved mental health; however, research on the impact of suicide disclosure to family members is scarce. Suicide attempt survivors (n = 74) in the United States were examined to assess whether family reaction moderates or mediates the relationship between suicide disclosure and subsequent depression symptoms. Family reaction did not moderate but did mediate the relationship between disclosure and depression symptoms while controlling for time since most recent attempt. Higher rates of disclosure predicted more positive family reactions, which in turn predicted less severe depression symptoms. Findings indicate that family members can play an essential role in the recovery process after an attempt occurs, which has important implications for both researchers and clinicians who seek to decrease stigma for attempt survivors while simultaneously decreasing the likelihood of future attempts. PMID- 26120915 TI - Test or toy? Materiality and the measurement of infant intelligence. AB - Adopting a material culture perspective, this article interrogates the composition of the copy of the Cattell Infant Intelligence Scale housed at the University of Toronto Scientific Instruments Collection. As a deliberately assembled collection of toys, the Cattell Scale makes clear the indefinite boundary between test and toy in 20th-century American psychology. Consideration of the current condition of some of the material constituents of this particular Cattell Scale provides valuable insight into some of the elusive practices of intelligence testers in situ and highlights the dynamic nature of the testing process. At the same time, attending to the materiality of this intelligence test reveals some of the more general assumptions about the nature of intelligence inherent in tests for young children. The scale and others like it, I argue, exposes psychologists' often-uncritical equation of childhood intelligence with appropriate play undertaken with an appropriate toy, an approach complicit in, and fostered by, midcentury efforts to cultivate particular forms of selfhood. This analysis serves as an example of the kind of work that may be done on the history of intelligence testing when the material objects that were (and are) inherently a part of the testing process are included in historical scholarship. PMID- 26120916 TI - Freeman's transorbital lobotomy as an anomaly: A material culture examination of surgical instruments and operative spaces. AB - In 1946, Walter Freeman introduced the transorbital ice pick lobotomy. Touted as a procedure that could be learned and subsequently performed by psychiatrists outside of the operating room, the technique was quickly criticized by neurosurgeons. In this article, we take a material culture approach to consider 2 grounds upon which neurosurgeons based their objections-surgical instruments and operative spaces. On both counts, Freeman was in contravention of established normative neurosurgical practices and, ultimately, his technique was exposed as an anomaly by neurosurgeons. Despite its rejection, the transorbital lobotomy became entrenched in contemporary memory and remains the emblematic procedure of the psychosurgery era. PMID- 26120917 TI - The Utica crib: Biography of an unknown barbarous object. AB - During the latter half of the 19th century, a device known popularly as the "Utica crib" became widely used in asylums and state hospitals across North America. The design varied to an extent between institutions but generally consisted of an enclosed, rectangular box made from combinations of wood slats or metal screening, with a hinged lid that could be latched closed on one side. The box was large enough to allow a person to lie straight inside with the lid closed. It has generally been described as no more than a restraint device used to confine patients in a recumbent position. In this article, I resituate the Utica crib in its broader historical context, focusing on the key role it played in the boundary debates faced by North American alienists. Particular attention is paid to the challenge from British alienists with regard to the nonrestraint movement and the attack from neurologists concerning the purported expertise of alienists. PMID- 26120918 TI - Neglect of the foreign invisible: Historiography and the navigation of conflicting sensibilities. AB - This essay is intended first as a contribution to historiography, and only second as a contribution to the history of developmental psychology. It is therefore a discussion--primarily--of the doing of the history of psychology, rather than of its content. Briefly put: American psychology, including its associated approaches to the history of psychology, is not adequately equipped to benefit fully from the contributions of foreign scholars. To make the resulting argument clear, two archive-driven microhistories are reviewed, contrasted, augmented with new archival research, and synthesized: Yeh Hsueh's (2004) examination of the nomination process at Harvard University that led to the awarding of an honorary doctorate to Jean Piaget in 1936, and Marc Ratcliff and Paloma Borella's (2013) examination-just recently published in French-of a similar process that resulted in Piaget's hiring at Geneva in 1929 and his eventual promotion in 1940. Comparing the authors' different approaches to similar content then affords this article's larger argument: we need to broaden our sensibilities so we can see high-quality foreign contributions for what they are. Several interesting insights result if we do. Among them: although Piaget's theory is today mistakenly criticized for being asocial, and this serves as justification for countering his early works with Vygotsky's posthumous critique, it emerges from these archival studies that Piaget may have in fact chosen to present himself and his work as nonsociological (when this was not the case) for reasons unrelated to his intellectual project. Such examples then broaden the discussion of "neglect of the foreign invisible" to include suppression--even censorship (by self or other)--which in turn reflects the primary problem afforded by internationalization: by what standards are we to judge the contributions of "foreigners" into "our" discipline? PMID- 26120919 TI - Florence Goodenough and child study: The question of mothers as researchers. AB - This article examines the views of early developmental psychologist Florence Goodenough, summarizing her contributions to the field, her complex viewpoints on science and gender issues, and her arguments for maternal record-keeping as a valuable scientific strategy, as drawn from her writings in textbooks, popular magazine articles, and private correspondence. During the 1920s, 1930s, and 1940s, when Goodenough enjoyed a high professional profile as a research scientist, the field of child psychology shifted from focus on producing applied knowledge to benefit parents and educators to a preference for laboratory controlled basic science approaches to understanding development. Goodenough championed observation and other descriptive methods, including use of mothers as data collectors in the home, even while these approaches were increasingly discredited by prominent peers in the United States. I argue that Goodenough's allegiance to maternal record-keeping highlights a forgotten strand of context sensitive, descriptive work that survived despite its general disparagement among proponents of a narrower version of strictly experimental developmental science emerging in the 1920s. PMID- 26120920 TI - Searching for the structure of early American psychology: Networking Psychological Review, 1909-1923. AB - This study continues a previous investigation of the intellectual structure of early American psychology by presenting and analyzing 3 networks that collectively include every substantive article published in Psychological Review during the 15-year period from 1909 to 1923. The networks were laid out such that articles (represented by the network's nodes) that possessed strongly correlated vocabularies were positioned closer to each other spatially than articles with weakly correlated vocabularies. We identified distinct research communities within the networks by locating and interpreting the clusters of lexically similar articles. We found that the Psychological Review was in some turmoil during this period compared with its first 15 years attributable, first, to Baldwin's unexpected departure in 1910; second, to the pressures placed on the discipline by United States entry into World War I; and, third, to the emergence of specialty psychology journals catering to research communities that had once published in the Review. The journal emerged from these challenges, however, with a better-defined mission: to serve as the chief repository of theoretical psychology in the United States. PMID- 26120921 TI - The origins and professionalization of cognitive psychotherapy in Argentina. AB - The growing popularity of cognitive-behavioral therapy (CBT) has helped reshape the mental health scene in the city of Buenos Aires, historically the stronghold of psychoanalysis. In the early 1980s, CBT was infrequently used and sometimes overtly resisted in the field of mental health. Almost 3 decades later, the impact of CBT has increased dramatically in Argentina, not only in independent practice but also in the health system and in everyday life. This article aims to describe the process by which Argentine psychotherapists first adopted this new theoretical framework. PMID- 26120922 TI - Research report on a new volume on the crises in Italian psychology. PMID- 26120924 TI - Creating a new problem: The use of baclofen in the management of alcohol use disorder. PMID- 26120925 TI - Statins and subarachnoid hemorrhage in Medicare patients with unruptured cerebral aneurysms. AB - BACKGROUND: Statins have been shown to decrease aneurysm progression and rupture in two experimental settings: animals with cerebral aneurysm and humans with abdominal aortic aneurysms. AIMS: To investigate statin use and outcomes in humans with unruptured cerebral aneurysms through Medicare administrative data. METHODS: We used a 40% random sample Medicare denominator file and corresponding inpatient, outpatient (2003-2011), and prescription (2006-2011) claims to conduct a retrospective cohort study of patients diagnosed with unruptured cerebral aneurysms, between 2003 and 2011. We used propensity score-adjusted models to investigate the association between statin use and risk of subarachnoid hemorrhage. Secondary analyses repeated the main models stratified on tobacco use status and separately assessed other composite outcomes. RESULTS: We identified 28 931 patients with unruptured cerebral aneurysms (average age 72.0 years, 72.6% female); mean follow-up was 30.0 months; 41.3% used statins. Overall, 593 patients developed subarachnoid hemorrhage, and 703 underwent treatment before subarachnoid hemorrhage. Current or recent statin use was not associated with a difference in subarachnoid hemorrhage risk (odds ratio, 1.03; 95% conflict of interest 0.86-1.23); models stratified on tobacco use status were nearly identical. No association was observed between statin use and the composite outcome of subarachnoid hemorrhage or aneurysm treatment (odds ratio, 0.94; 95% conflict of interest, 0.84-1.06). The risk of subarachnoid hemorrhage or out-of hospital death was lower among statin users (odds ratio, 0.69; 95% conflict of interest, 0.64-0.74). CONCLUSIONS: Statin use by patients with unruptured cerebral aneurysms was not associated with subarachnoid hemorrhage risk. Given the prior animal experimental studies demonstrating a protective effect, further prospective studies are needed to investigate the potential relationship. PMID- 26120927 TI - Visible Light Photorelease of Carboxylic Acids via Charge-Transfer Excitation of N-Methylpyridinium Iodide Esters. AB - Iodide contrast sensitization to direct irradiation of charge transfer salts incurs carboxylic acid release via visible light absorption. The photochemical reduction of N-methyl-4-pyridinium iodide esters to release carboxylic acids is examined using (1)H NMR analysis. Photolysis reactions are carried out under mild, biphasic solvent conditions using a household LED lamp. Carboxylic acid release is reported in high yields, and the viability of this method for synthetic chemistry is demonstrated through a macroscale reaction. PMID- 26120926 TI - Paradoxical Elevation of High Density Lipoprotein Cholesterol in Association with Lacunar-Type Cerebral Infarction. AB - BACKGROUND: The aim of this study was to evaluate the association between high density lipoprotein cholesterol (HDLC) levels and the risk of lacunar infarction (LI) in a retrospective cohort study in China. MATERIAL AND METHODS: We recruited 229 patients with obsolete brain infarctions single side (SOBI), 218 with obsolete brain infarctions bilateral sides (BOBI), 193 with both acute stroke and obsolete lacunar infarctions single side (AI&SOBI), 113 with both acute stroke and obsolete lacunar infarctions bilateral sides (AI&BOBI), and 203 without any infarctions (Control). RESULTS: 1) The plasma levels of HDLC in group BOBI, AI&SOBI, and AI&BOBI were higher than in the control group, and lower in group SOBI than in the control group (p<0.01). 2) The plasma levels of HDLC in group AI&SOBI were significantly higher than in group SOBI (p<0.01). 3) The plasma levels of HLDL were similar between group AI&SOBI and AI&BOBI. 4) There were significant relationships between HDLC and acute lacunar stroke, even after adjusting for these factors such as age, sex, triglyceride, total cholesterol, low-density lipoprotein cholesterol, and history of diabetes (p=0.001). 4) Compared with the controls, the calculation of odds ratios indicated relative risk estimates of higher HDLC for acute lacunar stroke with obsolete lacunar infarction. CONCLUSIONS: Elevated HDLC may be an independent predictor of recurrent stroke with obsolete lacunar infarctions single side in Chinese people, justifying clinical trials for secondary prevention of stroke by generally increasing HLDL level. According to the difference between single and bilateral side multiple silent lacunar infarcts, it is inferred that HDLC may increase the risk of atherothrombotic infarction but reduce the risk of cardioembolic infarction in the general Chinese population. PMID- 26120928 TI - Influences on the drinking of heavier drinkers: Interactional realities in seeking to 'change drinking cultures'. AB - INTRODUCTION AND AIMS: 'Changing drinking culture' is a prominent goal in the Australian state of Victoria's current alcohol strategy-seeking a shift so that 'excessive drinking isn't seen as the norm'. As a social activity, there is a strong collective aspect to drinking and associated behaviour: customs within the drinking group and at the level of social worlds of drinking operate both to increase and to control drinking patterns and associated behaviours. The paper considers how risky drinkers and those in social worlds of heavy drinking experience others' expectations about drinking. DESIGN AND METHODS: Using Victorian population survey responses (n = 2092 adults who had consumed alcohol in previous year) to identify those in a social world of group drinking, and a subcategory who are also risky drinkers, the paper explores pressures on those in these categories both to drink more and to drink less, whether from family members, from work colleagues, or from friends. RESULTS: Those who are both risky and social drinkers are much more likely than other drinkers to report pressures to drink more from friends and workmates, and even from family members, although they more often report pressures from family members to drink less than to drink more. DISCUSSION AND CONCLUSIONS: Efforts to change a drinking culture, it is argued, must take account of the collective nature of drinking and of the interplay of influences at interpersonal and subcultural levels if they are to be effective in reducing rates of heavy drinking and alcohol problems. [Room R, Callinan S, Dietze P. Influences on the drinking of heavier drinkers: Interactional realities in seeking to 'change drinking cultures'. Drug Alcohol Rev 2015]. PMID- 26120929 TI - Glucosamine-Anchored Graphene Oxide Nanosheets: Fabrication, Ultraviolet Irradiation, and Electrochemical Properties. AB - A biofunctionalized graphene oxide (GO) nanosheet with improved physicochemical properties is useful for electrocatalysis and sensor development. Herein, a new class of functionalized GO with a chemically anchored biomolecule glucosamine is developed. Structural and chemical analyses confirm the glucosamine anchoring. Ultraviolet irradiation transforms the surface chemistry of GO. Glucosamine anchored GO nanosheets exhibit improved cyclic voltammetric and amperometric sensing activity toward the model redox probe, ruthenium(II) and N acetylneuraminic acid, respectively. The biomolecular anchoring and ultraviolet irradiation helped to tune and enhance the properties of GO, which may find multiple applications in optimizing sensor platforms. PMID- 26120930 TI - Redox-Sensitive PEG-Polypeptide Nanoporous Particles for Survivin Silencing in Prostate Cancer Cells. AB - We report the engineering of intracellular redox-responsive nanoporous poly(ethylene glycol)-poly(l-lysine) particles (NPEG-PLLs). The obtained particles exhibit no toxicity while maintaining the capability to deliver a small interfering RNA sequence (siRNA) targeting the anti-apoptotic factor, survivin, in prostate cancer cells. The redox-mediated cleavage of the disulfide bonds stabilizing the NPEG-PLL-siRNA complex results in the release of bioactive siRNA into the cytosol of prostate cancer PC-3 cells, which, in turn, leads to the effective silencing (~59 +/- 8%) of the target gene. These findings, obtained under optimal conditions, indicate that NPEG-PLLs may protect the therapeutic nucleic acid in the extracellular and intracellular environments, thus preventing the occurrence of competitive interactions with serum and cytosolic proteins as well as degradation by RNase. The intracellular trafficking and final fate of the NPEG-PLLs were investigated by a combination of deconvolution microscopy, fluorescence lifetime imaging microscopy, and super-resolution structured illumination microscopy. A significant impairment of cell survival was observed in cells concomitantly exposed to paclitaxel and siRNA-loaded NPEG-PLLs. Overall, our findings indicate that NPEG-PLLs represent a highly loaded depot for the delivery of therapeutic nucleic acids to cancer cells. PMID- 26120931 TI - Qualification and Verification of Serological Biomarker Candidates for Lung Adenocarcinoma by Targeted Mass Spectrometry. AB - Lung cancer is the leading cause of cancer mortality worldwide. Although many biomarkers have been identified for lung cancer, their low specificity and sensitivity present an urgent need for the identification of more candidate biomarkers. In this study, we conducted MRM-based targeted analysis to evaluate the potential utility of a list of candidate proteins for lung cancer diagnosis. A total of 1249 transitions of 420 peptides representing 102 candidate proteins from our previous study and the literature were first screened by MRM analysis in pooled plasma samples, resulting in 78 proteins remaining in the list. Relative quantification of these 78 proteins was further performed in 60 individual plasma samples from lung adenocarcinoma patients in stages I-III and matched healthy control subjects. Ultimately, nine proteins were found to be able to distinguish patients from controls. Further combinations of five, three, and two candidate marker proteins improved the sensitivity to discriminate patients from controls and resulted in a merged AUC value of nearly 1.00 in stages I-III patients versus controls. Our results highlighted several possible markers for lung adenocarcinoma, and the proposed protein panels require further validation in a larger cohort to evaluate their potential use in clinical applications or development of therapeutics. PMID- 26120932 TI - Enantiopure Peptide-Functionalized Metal-Organic Frameworks. AB - We present herein the first example of metal-organic frameworks postfunctionalized with peptides. Our microwave-assisted postsynthetic modification method yields enantiopure peptides anchored inside MOF cavities. Al MIL-101-NH2, In-MIL-68-NH2, and Zr-UiO-66-NH2 were chosen as starting platforms. A single amino acid and various oligopeptides are grafted with yields up to 60% after a 30 min microwave-assisted coupling-deprotection sequence. This allows efficient preparation of a library of functional hybrid solids for molecular recognition applications such as sensing, separation, or asymmetric catalysis, as demonstrated here for the chiral aldol reaction. PMID- 26120933 TI - Redox-Active Sites in Auricularia auricula-judae Dye-Decolorizing Peroxidase and Several Directed Variants: A Multifrequency EPR Study. AB - Peroxide-activated Auricularia auricula-judae dye-decolorizing peroxidase (DyP) forms a mixed Trp377 and Tyr337 radical, the former being responsible for oxidation of the typical DyP substrates (Linde et al. Biochem. J., 2015, 466, 253 262); however, a pure tryptophanyl radical EPR signal is detected at pH 7 (where the enzyme is inactive), in contrast with the mixed signal observed at pH for optimum activity, pH 3. On the contrary, the presence of a second tyrosine radical (at Tyr147) is deduced by a multifrequency EPR study of a variety of simple and double-directed variants (including substitution of the above and other tryptophan and tyrosine residues) at different freezing times after their activation by H2O2 (at pH 3). This points out that subsidiary long-range electron transfer pathways enter into operation when the main pathway(s) is removed by directed mutagenesis, with catalytic efficiencies progressively decreasing. Finally, self-reduction of the Trp377 neutral radical is observed when reaction time (before freezing) is increased in the absence of reducing substrates (from 10 to 60 s). Interestingly, the tryptophanyl radical is stable in the Y147S/Y337S variant, indicating that these two tyrosine residues are involved in the self reduction reaction. PMID- 26120934 TI - Label-Free Electrical Immunosensor for Highly Sensitive and Specific Detection of Microcystin-LR in Water Samples. AB - Microcystin-LR (MCLR) is one of the most commonly detected and toxic cyclic heptapeptide cyanotoxins released by cyanobacterial blooms in surface waters, for which sensitive and specific detection methods are necessary to carry out its recognition and quantification. Here, we present a single-walled carbon nanotube (SWCNTs)-based label-free chemiresistive immunosensor for highly sensitive and specific detection of MCLR in different source waters. MCLR was initially immobilized on SWCNTs modified interdigitated electrode, followed by incubation with monoclonal anti-MCLR antibody. The competitive binding of MCLR in sample solutions induced departure of the antibody from the antibody-antigen complexes formed on SWCNTs, resulting in change in the conductivity between source and drain of the sensor. The displacement assay greatly improved the sensitivity of the sensor compared with direct immunoassay on the same device. The immunosensor exhibited a wide linear response to log value of MCLR concentration ranging from 1 to 1000 ng/L, with a detection limit of 0.6 ng/L. This method showed good reproducibility, stability and recovery. The proposed method provides a powerful tool for rapid and sensitive monitoring of MCLR in environmental samples. PMID- 26120936 TI - Multiple context mere exposure: Examining the limits of liking. AB - Recent evidence suggests that increased liking of exposed stimuli-a phenomenon known as the mere exposure effect-is dependent on experiencing the stimuli in the same context at exposure and test. Three experiments extended this work by examining the effect of presenting target stimuli in single and multiple exposure contexts. Target face stimuli were repeatedly paired with nonsense words, which took the role of contexts, across exposure. On test, the mere exposure effect was found only when the target face stimuli were presented with nonsense word cues (contexts) with which they had been repeatedly paired. The mere exposure effect was eliminated when exposure to target face stimuli with the nonsense word cues (contexts) was minimal, despite the overall number of exposures to the target face being equated across single- and multiple-context exposure conditions. The results suggest that familiarity of the relationship between stimuli and their context, not simply familiarity of the stimuli themselves, leads to liking. The finding supports a broader framework, which suggests that liking is partly a function of the consistency between past and present experiences with a target stimulus. PMID- 26120935 TI - PI3K Phosphorylation Is Linked to Improved Electrical Excitability in an In Vitro Engineered Heart Tissue Disease Model System. AB - Myocardial infarction, a prevalent cardiovascular disease, is associated with cardiomyocyte cell death, and eventually heart failure. Cardiac tissue engineering has provided hopes for alternative treatment options, and high fidelity tissue models for drug discovery. The signal transduction mechanisms relayed in response to mechanoelectrical (physical) stimulation or biochemical stimulation (hormones, cytokines, or drugs) in engineered heart tissues (EHTs) are poorly understood. In this study, an EHT model was used to elucidate the signaling mechanisms involved when insulin was applied in the presence of electrical stimulation, a stimulus that mimics functional heart tissue environment in vitro. EHTs were insulin treated, electrically stimulated, or applied in combination (insulin and electrical stimulation). Electrical excitability parameters (excitation threshold and maximum capture rate) were measured. Protein kinase B (AKT) and phosphatidylinositol-3-kinase (PI3K) phosphorylation revealed that insulin and electrical stimulation relayed electrical excitability through two separate signaling cascades, while there was a negative crosstalk between sustained activation of AKT and PI3K. PMID- 26120937 TI - H-phosphonate-mediated sulfonylation of heteroaromatic N-oxides: a mild and metal free one-pot synthesis of 2-sulfonyl quinolines/pyridines. AB - A smart H-phosphonate-mediated synthetic strategy for the sulfonylation of heteroaromatic N-oxides has been developed, by which a large variety of 2 sulfonyl quinolines/pyridines were synthesized starting from easily available sulfonyl chlorides, diisopropyl H-phosphonate and pyridine/quinoline N-oxides in one pot under metal-free conditions at room temperature. PMID- 26120938 TI - Tissue-specificity of heparan sulfate biosynthetic machinery in cancer. AB - Heparan sulfate (HS) proteoglycans are key components of cell microenvironment and fine structure of their polysaccharide HS chains plays an important role in cell-cell interactions, adhesion, migration and signaling. It is formed on non template basis, so, structure and functional activity of HS biosynthetic machinery is crucial for correct HS biosynthesis and post-synthetic modification. To reveal cancer-related changes in transcriptional pattern of HS biosynthetic system, the expression of HS metabolism-involved genes (EXT1/2, NDST1/2, GLCE, 3OST1/HS3ST1, SULF1/2, HPSE) in human normal (fibroblasts, PNT2) and cancer (MCF7, LNCaP, PC3, DU145, H157, H647, A549, U2020, U87, HT116, KRC/Y) cell lines and breast, prostate, colon tumors was studied. Real-time RT-PCR and Western-blot analyses revealed specific transcriptional patterns and expression levels of HS biosynthetic system both in different cell lines in vitro and cancers in vivo. Balance between transcriptional activities of elongation- and post-synthetic modification- involved genes was suggested as most informative parameter for HS biosynthetic machinery characterization. Normal human fibroblasts showed elongation-oriented HS biosynthesis, while PNT2 prostate epithelial cells had modification-oriented one. However, cancer epithelial cells demonstrated common tendency to acquire fibroblast-like elongation-oriented mode of HS biosynthetic system. Surprisingly, aggressive metastatic cancer cells (U2020, DU145, KRC/Y) retained modification-oriented HS biosynthesis similar to normal PNT2 cells, possibly enabling the cells to keep like-to-normal cell surface glycosylation pattern to escape antimetastatic control. The obtained results show the cell type specific changes of HS-biosynthetic machinery in cancer cells in vitro and tissue specific changes in different cancers in vivo, supporting a close involvement of HS biosynthetic system in carcinogenesis. PMID- 26120939 TI - The Coagulant Factor Xa Induces Protease-Activated Receptor-1 and Annexin A2 Dependent Airway Smooth Muscle Cytokine Production and Cell Proliferation. AB - During asthma exacerbation, plasma circulating coagulant factor X (FX) enters the inflamed airways and is activated (FXa). FXa may have an important role in asthma, being involved in thrombin activation and an agonist of protease activated receptor-1 (PAR-1). Extracellular annexin A2 and integrins are also implicated in PAR-1 signaling. In this study, the potential role of PAR-1 in mediating the effects of FXa on human airway smooth muscle (ASM) cell cytokine production and proliferation was investigated. FXa (5-50 nM), but not FX, stimulated increases in ASM IL-6 production and cell number after 24- and 48-hour incubation, respectively (P < 0.05; n = 5). FXa (15 nM) also stimulated increases in the levels of mRNA for cytokines (IL-6), cell cycle-related protein (cyclin D1), and proremodeling proteins (FGF-2, PDGF-B, CTGF, SM22, and PAI-1) after 3 hour incubation (P < 0.05; n = 4). The actions of FXa were insensitive to inhibition by hirudin (1 U/ml), a selective thrombin inhibitor, but were attenuated by SCH79797 (100 nM), a PAR-1 antagonist, or Cpd 22 (1 MUM), an inhibitor of integrin-linked kinase. The selective targeting of PAR-1, annexin A2, or beta1-integrin by small interfering RNA and/or by functional blocking antibodies also attenuated FXa-evoked responses. In contrast, the targeting of annexin A2 did not inhibit thrombin-stimulated ASM function. In airway biopsies of patients with asthma, FXa and annexin A2 were detected in the ASM bundle by immunohistochemistry. These findings establish FXa as a potentially important asthma mediator, stimulating ASM function through actions requiring PAR-1 and annexin A2 and involving integrin coactivation. PMID- 26120940 TI - Do Prescription Drug Ads Tell Consumers Enough About Benefits and Side Effects? Results From the Health Information National Trends Survey, Fourth Administration. AB - Direct-to-consumer prescription drug advertising (DTCA) is a major source of consumer information about prescription drugs. The present study updates 2002 U.S. Food and Drug Administration phone survey questions that found that 44% and 61% of consumers thought that DTCA did not include enough information about benefits and risks, respectively. The present study was administered by mail using a nationally representative sample, and provides a more in-depth understanding of how these beliefs relate to demographic and health characteristics. Data collected from 3,959 respondents to the National Cancer Institute's 2011 Health Information National Trends Survey find results similar to the 2002 survey: 46% and 52% of respondents thought that DCTA did not include enough information about benefits and risks, respectively. Respondents fell into four groups: 23% agreed that DTCA tells enough about drug benefits and risks, 41% disagreed, 18% expressed no opinion, and 18% had discordant beliefs. DTCA attitudes were negatively associated with education, income, and whether respondents purchase prescription drugs; attitudes were positively associated with whether respondents understand prescription drug information. This study confirms that a plurality of Americans believe that DTCA does not include enough information about benefits and risks, suggesting that the educational effect of DTCA could be improved. PMID- 26120942 TI - Palladium-catalysed decarboxylative nitrile insertion via C-H activation or self coupling of indole-2-carboxylic acids: a new route to indolocarbolines and triindoles. AB - Palladium catalysed-reaction of indole carboxylic acids with nitriles in the presence of Ag2CO3 proceeds via decarboxylative dual C-H activation leading to the nitrile insertion products, triazaindeno-fluorenes (indolocarbolines); in the absence of nitrile, diindolocarbazoles (heptacyclic triindoles or triazatruxenes) are formed. PMID- 26120943 TI - Tuning the depth of bowl-shaped phosphine hosts: capsule and pseudo-cage architectures in host-guest complexes with C60 fullerene. AB - Bowl-shaped phosphine molecules, whose bowl geometry can be controlled by a variation of the axial substituent, were synthesized, and used as host molecules to encapsulate C60. Host molecules with relatively shallow bowls formed a chiral capsule, while hosts with deeper bowls formed an achiral pseudo-cage. PMID- 26120944 TI - Drug-Induced Systemic Hypersensitivity Reaction Associated With Ziprasidone: An Atypical Occurrence. PMID- 26120945 TI - Perphenazine-Associated Hyperosmolar Hyperglycemic State. PMID- 26120946 TI - Sortase A-mediated multi-functionalization of protein nanoparticles. AB - We report here a new strategy to enable fast, covalent, and site-directed functionalization of protein nanoparticles using Sortase A-mediated ligation using functional proteins ranging from monomeric to large tetrameric structures. Easy purification of the modified E2 nanoparticles is achieved by functionalization with a thermo-responsive elastin-like-peptide. The resulting protein nanoparticles remained intact and active even after repeated phase transitions, suggesting their use in biocatalysis, biosensing, and imaging applications. PMID- 26120948 TI - Assessing Single Upconverting Nanoparticle Luminescence by Optical Tweezers. AB - We report on stable, long-term immobilization and localization of a single colloidal Er(3+)/Yb(3+) codoped upconverting fluorescent nanoparticle (UCNP) by optical trapping with a single infrared laser beam. Contrary to expectations, the single UCNP emission differs from that generated by an assembly of UCNPs. The experimental data reveal that the differences can be explained in terms of modulations caused by radiation-trapping, a phenomenon not considered before but that this work reveals to be of great relevance. PMID- 26120949 TI - [In Process Citation]. PMID- 26120950 TI - [Care-Dependency in Parkinson's Disease: More Frequent than Assumed?]. AB - AIMS: Parkinson's disease (PD) increases the risk of care-dependency (CDP). While motor functions worsen continuously, the assignment of patients to CDP occurs categorically. It is unknown how many patients are already sufficiently severely impaired to be categorised as CDP yet do not have an officially acknowledged level of CDP. METHODS: A random sample of 1,449 PD outpatients was clinically characterised by office-based neurologists, including impairments of activities of daily living (ADL with the Unified Parkinson's Disease Rating scale (UPDRS subscale II) as well as regarding the presence of dementia according to DSM-IV criteria and the Mini-Mental State Exam (MMSE). Depression was screened for with the Montgomery-Asberg Depression Rating Scale (MADRS). For each patient the officially acknowledged level of CDP was documented; for patients without official CDP level, the clinician appraised whether the patient was care dependent anyhow. RESULTS: 266 patients (18.3%) were officially acknowledged as care-dependent, while n=121 patients (8.5%) were not, yet were appraised to be care-dependent according to the clinician. Compared to non-CDP patients, they differed on every measure considered. Compared to patients with an official CDP, their PD duration was significantly shorter (6.0 vs. 8.0 years, p<0.01) and they were less severely impaired in ADL (13.3 vs. 15.5, p<0.01). They did not differ regarding the rates of dementia (52.9 vs. 44.9%, p=0.203) or depression according to the MADRS (13.1 vs. 13.1, p=0.989). CONCLUSIONS: ADL impairments are the most important predictor for CDP while dementia and depression are not considered despite the impairments that are additionally caused by them. PMID- 26120951 TI - Three-Dimensional Cell Culture Assays: Are They More Predictive of In Vivo Efficacy than 2D Monolayer Cell-Based Assays? PMID- 26120952 TI - The Satisfaction with Daily Occupations (SDO-13) Scale: Psychometric Properties among Clients in Primary Care in Sweden. AB - This article describes the results to expand and develop the use of the Satisfaction with Daily Occupations (SDO-13) Scale. Data were collected in primary care before (I) and after intervention (II) among clients with stress related disorders and musculoskeletal pain. The Cronbach's alpha values of the SDO-13 Scale were 0.80 and 0.88. Convergent validity was assessed against global occupational satisfaction and general health, resulting in rs = -0.65 (p < 0.001) and rs = -0.46 (p < 0.001). The SDO-13 Scale could not discriminate between the primary care sample and a psychiatric sample (p = 0.15), whereas number of current occupations could (p < 0.001). The SDO-13 was not sensitive to change (p = 0.92). Future studies need to explore criterion and construct validity based on more dissimilar samples and more standardized interventions. Applications of these results to practice are discussed. PMID- 26120953 TI - Semicrystalline Structure-Dielectric Property Relationship and Electrical Conduction in a Biaxially Oriented Poly(vinylidene fluoride) Film under High Electric Fields and High Temperatures. AB - Poly(vinylidene fluoride) (PVDF)-based homopolymers and copolymers are attractive for a broad range of electroactive applications because of their high dielectric constants. Especially, biaxially oriented PVDF (BOPVDF) films exhibit a DC breakdown strength as high as that for biaxially oriented polypropylene films. In this work, we revealed the molecular origin of the high dielectric constant via study of a commercial BOPVDF film. By determination of the dielectric constant for the amorphous phase in BOPVDF, a high value of ca. 21-22 at 25 degrees C was obtained, and a three-phase (i.e., lamellar crystal/oriented interphase/amorphous region) semicrystalline model was proposed to explain this result. Meanwhile, electronic conduction mechanisms in BOPVDF under high electric fields and elevated temperatures were investigated by thermally stimulated depolarization current (TSDC) spectroscopy and leakage current studies. Space charge injection from metal electrodes was identified as a major factor for electronic conduction when BOPVDF was poled above 75 degrees C and 20 MV/m. In addition, when silver or aluminum were used as electrodes, new ions were generated from electrochemical reactions under high fields. Due to the electrochemical reactions between PVDF and the metal electrode, a question is raised for practical electrical applications using PVDF and its copolymers under high-field and high-temperature conditions. A potential method to prevent electrochemical degradation of PVDF is proposed in this study. PMID- 26120954 TI - Impact of initial symptom for accurate diagnosis of vertebral artery dissection. AB - BACKGROUND: It has been recognized that spontaneous vertebral artery dissection without neurological symptoms is not rare and easily misdiagnosed. Clinical clue for diagnosis of vertebral artery dissection includes initial symptoms such as headache, neck pain, or dizziness. AIM: To assess the role of initial symptoms for diagnosis of spontaneous vertebral artery dissection. METHODS: Between September 2007 and January 2014, we retrospectively reviewed clinical records of 83 patients with unilateral vertebral artery dissection without consciousness disturbance at admission. Based on the diagnostic criteria of the Spontaneous Cervicocephalic Arterial Dissections Study, the patients were divided into three groups: possible, probable, and definite cases of vertebral artery dissection. Initial symptoms were collected at the time of diagnosis from medical record for the presence or absence of headache, neck pain, tinnitus and vertigo, as well as the area of pain and its characteristics. RESULTS: The numbers of definite, probable, and possible vertebral artery dissection were 39, 26, and 18, respectively. Out of 83 cases, unilateral or bilateral headache was the most commonly seen (in 60 cases), followed by neck pain (in 41 cases) and vertigo (in 20 cases). Statistically, unilateral headache and/or neck pain was more common in cases with definite vertebral artery dissection group compared with other classification of the Spontaneous Cervicocephalic Arterial Dissections Study (P = 0.040). Vertigo was also associated with the stratification of Spontaneous Cervicocephalic Arterial Dissections Study criteria (P = 0.012). CONCLUSIONS: In our study, headache and/or neck pain, especially unilateral presentation, and vertigo were symptoms associated with the stratification of Spontaneous Cervicocephalic Arterial Dissections Study criteria. Physicians should carefully obtain clinical history for the presence of a unilateral headache and/or neck pain and vertigo when vertebral artery dissection is suspected in patients with or without objective neurological signs. PMID- 26120955 TI - Diastolic Stunning as a Marker of Severe Coronary Artery Stenosis: Analysis by Speckle Tracking Radial Strain in the Resting Echocardiogram. AB - BACKGROUND: Two-dimensional speckle tracking (2DST) stress echocardiography detects postischemic myocardial diastolic stunning. However, the use of 2DST at rest for detecting diastolic stunning in ischemia is unclear. RESULTS: Thirty nine patients (age = 65 +/- 12 years; male/female = 34/5) with effort angina pectoris that was confirmed by stress myocardial perfusion scintigraphy were enrolled. Ischemic area (I) was determined in the middle LV short axial view using stress myocardial scintigraphy. The area opposite to it was defined as nonischemic area (non-I). Midventricular parasternal short-axis (SAX) radial strains were estimated using 2DST at rest on the following day. LV diastolic function was evaluated using diastolic index (DI, changes in the regional LV radial strain during diastole) and radial strain rate (SR) during early diastolic period. These parameters were compared between I and non-I before and 1 month after percutaneous coronary intervention (PCI) in the I of 3 coronary vessels. For the I, the DI was lower (38 +/- 27 vs. 55 +/- 27; P = 0.003) and SR was higher (-1.6 +/- 0.6 vs. -1.9 +/- 0.8; P = 0.007) than in non-I before PCI. One month after PCI, the DI and SR recovered to 53 +/- 27 (P = 0.008) and -2.1 +/- 0.8 (P = 0.006), respectively. Furthermore, the DI of the LAD and LCX significantly improved (P = 0.0004 and 0.002, respectively); the RCA area showed tendency to improve (P = 0.092), and the SR also improved (P < 0.05) in all areas after PCI. CONCLUSION: Diastolic stunning in ischemic areas can be detected using 2DST at rest and recover 1 month after PCI. PMID- 26120956 TI - IL-33 induces Egr-1-dependent TSLP expression via the MAPK pathways in human keratinocytes. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease in which T-helper type 2 (Th2)-type immune responses are dominant. Th2 cytokine, interleukin (IL) 33 and thymic stromal lymphopoietin (TSLP) have been suggested to have an important role in AD. IL-33 is highly expressed in AD, but its role in AD has not yet been fully understood. To further identify the role of IL-33 in AD, we investigated the expression of TSLP induced by IL-33 in keratinocytes. This study revealed that IL-33 induced TSLP expression in human keratinocytes. Early growth response protein 1 (Egr)-1, which is an inflammatory transcriptional factor, is induced by IL-33. IL-33-mediated TSLP induction in keratinocytes was suppressed by treatment with mitogen-activated protein kinase (MAPK) inhibitors or small interfering RNA against Egr-1. Chromatin immunoprecipitation (ChIP) assay indicated the direct involvement of Egr-1 in IL-33-mediated TSLP induction. Taken together, these findings indicate that IL-33 may increase TSLP expression through an Egr-1-dependent mechanism via ERK1/2, JNK and p38 activation in keratinocytes. These data suggest that the IL-33-ERK/JNK/p38/Egr-1/TSLP axis is involved in allergic skin Th2 inflammation, and it may be a novel therapeutic target. PMID- 26120957 TI - Serum Brain Natriuretic Peptide Concentration 60 Days After Surgery as a Predictor of Long-Term Prognosis in Patients Implanted With a Left Ventricular Assist Device. AB - Mechanical circulatory support by a left ventricular assist device (LVAD) is used to bridge patients with advanced heart failure to transplant or as a definitive treatment. We retrospectively sought predictors of long-term outcome in a cohort of 83 patients who had undergone LVAD treatment. We subjected perioperative clinical data of patients to statistical analysis to establish parameters associated with all-cause mortality, and the cutoff values, sensitivity, and specificity of those that had a statistically significant relation with survival. Mean follow-up was 717 days (standard deviation, 334 days; range, 17-1,592 days). Fourteen patients (16.8%) died, but nine (10.8%) were weaned from support. Serum brain natriuretic peptide (BNP) concentration measured 60 days after implantation was significantly associated with all-cause mortality. The optimal BNP cutoff value to predict death during LVAD support was 322 pg/ml, with a sensitivity of 71.4% and specificity of 79.8%. Two-year survival was 92.0% in those with 60 days serum BNP concentration <322 pg/ml compared with 70.5% in those in whom it was >=322 pg/ml (p = 0.003). The relation between BNP and survival likely reflects recovery of native myocardial function and improvements in global health and should assist clinicians in the on-going management of long-term LVAD therapy. PMID- 26120958 TI - In Vitro Study of a Medical Device to Enhance Arteriovenous Fistula Eligibility and Maturation. AB - The arteriovenous fistula eligibility (AFE) system (Flow Forward Medical, Olathe, KS) is a small, temporary, wearable rotary blood pump system designed to rapidly dilate peripheral veins in hemodialysis patients and improve outcomes after arteriovenous fistula (AVF) creation. A benchtop pulsatile mock circulatory loop was developed to model forearm circulation and to compare the hemodynamics of the AFE system with those of a conventional radiocephalic AVF. The AFE system maintained a mean wall shear stress (mWSS) within the 2.5-7.5 Pa target range for cephalic outflow veins of 2-6 mm diameter, which when applied clinically will provide better control of mWSS during the outflow vein maturation process when compared with a conventional AVF. These results support further study to determine whether or not vein preconditioning with the AFE system under controlled levels of mWSS will promote improved AVF outcomes. PMID- 26120959 TI - Dejerine Hand Phenomenon. PMID- 26120960 TI - Amyloid myopathy masquerading as polymyositis. PMID- 26120961 TI - Different immune cells mediate mechanical pain hypersensitivity in male and female mice. AB - A large and rapidly increasing body of evidence indicates that microglia-to neuron signaling is essential for chronic pain hypersensitivity. Using multiple approaches, we found that microglia are not required for mechanical pain hypersensitivity in female mice; female mice achieved similar levels of pain hypersensitivity using adaptive immune cells, likely T lymphocytes. This sexual dimorphism suggests that male mice cannot be used as proxies for females in pain research. PMID- 26120962 TI - Human representation of visuo-motor uncertainty as mixtures of orthogonal basis distributions. AB - In many laboratory visuo-motor decision tasks, subjects compensate for their own visuo-motor error, earning close to the maximum reward possible. To do so, they must combine information about the distribution of possible error with values associated with different movement outcomes. The optimal solution is a potentially difficult computation that presupposes knowledge of the probability density function (pdf) of visuo-motor error associated with each possible planned movement. It is unclear how the brain represents such pdfs or computes with them. In three experiments, we used a forced-choice method to reveal subjects' internal representations of their spatial visuo-motor error in a speeded reaching movement. Although subjects' objective distributions were unimodal, close to Gaussian, their estimated internal pdfs were typically multimodal and were better described as mixtures of a small number of distributions differing only in location and scale. Mixtures of a small number of uniform distributions outperformed other mixture distributions, including mixtures of Gaussians. PMID- 26120963 TI - Nuclear pore complex remodeling by p75(NTR) cleavage controls TGF-beta signaling and astrocyte functions. AB - Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75(NTR)) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-beta signaling. Cleaved p75(NTR) interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75(NTR) controls astrocyte-neuronal communication in response to profibrotic factors. PMID- 26120964 TI - The medial entorhinal cortex is necessary for temporal organization of hippocampal neuronal activity. AB - The superficial layers of the medial entorhinal cortex (MEC) are a major input to the hippocampus. The high proportion of spatially modulated cells, including grid cells and border cells, in these layers suggests that MEC inputs are critical for the representation of space in the hippocampus. However, selective manipulations of the MEC do not completely abolish hippocampal spatial firing. To determine whether other hippocampal firing characteristics depend more critically on MEC inputs, we recorded from hippocampal CA1 cells in rats with MEC lesions. Theta phase precession was substantially disrupted, even during periods of stable spatial firing. Our findings indicate that MEC inputs to the hippocampus are required for the temporal organization of hippocampal firing patterns and suggest that cognitive functions that depend on precise neuronal sequences in the hippocampal theta cycle are particularly dependent on the MEC. PMID- 26120965 TI - Common circuit design in fly and mammalian motion vision. AB - Motion-sensitive neurons have long been studied in both the mammalian retina and the insect optic lobe, yet striking similarities have become obvious only recently. Detailed studies at the circuit level revealed that, in both systems, (i) motion information is extracted from primary visual information in parallel ON and OFF pathways; (ii) in each pathway, the process of elementary motion detection involves the correlation of signals with different temporal dynamics; and (iii) primary motion information from both pathways converges at the next synapse, resulting in four groups of ON-OFF neurons, selective for the four cardinal directions. Given that the last common ancestor of insects and mammals lived about 550 million years ago, this general strategy seems to be a robust solution for how to compute the direction of visual motion with neural hardware. PMID- 26120966 TI - Impaired recollection of visual scene details in adults with autism spectrum conditions. AB - Subtle memory deficits observed in autism spectrum conditions (ASC) have often been characterized as reflecting impaired recollection and it has been proposed that a relational binding deficit may underlie the recollection impairment. However, subjective recollection and relational binding have not been measured within the same task in ASC to date and it is unclear whether a relational binding deficit can provide a full account of recollection impairments in ASC. Relational memory has also not been compared with item memory when the demands of the 2 tasks are comparable. To assess recollection, relational memory, and item memory within a single task in ASC, 24 adults with ASC and 24 typically developed adults undertook a change detection memory task that assessed recollection of item-specific and spatial details. Participants studied rendered indoor and outdoor scenes and, in a subsequent recognition memory test, distinguished scenes that had not changed from those that had either undergone an item change (a different item exemplar) or a relational (spatial) change, which was followed by a subjective recollection judgment. The ASC group identified fewer item changes and spatial changes, to a similar degree, which was attributable to a specific reduction in recollection-based recognition relative to the control group. These findings provide evidence that recollection deficits in ASC may not be driven entirely by a relational binding deficit. PMID- 26120967 TI - Cytokine and Adipokine Levels in Patients with Premalignant Oral Lesions or in Patients with Oral Cancer Who Did or Did Not Receive 1alpha,25-Dihydroxyvitamin D3 Treatment upon Cancer Diagnosis. AB - Differences in levels of inflammation-modulating cytokines and adipokines in patients with premalignant oral lesions versus in patients that develop squamous cell carcinoma of the head and neck (HNSCC) were assessed. Also assessed was the impact of treating HNSCC patients with the immune regulatory mediator, 1alpha,25 dihydroxyvitamin D3 [1,25(OH)2D3], on modulators of inflammation. Compared to healthy controls, patients with premalignant oral lesions had increases in their systemic levels of the inflammatory cytokines IL-6 and IL-17, and increases in the adipokine, leptin. However, levels of these pro-inflammatory cytokines and adipokine were reduced in patients with HNSCC. Treatment of HNSCC patients with 1,25(OH)2D3 increased levels of each of the measured immune mediators. Levels of the anti-inflammatory adipokine, adiponectin, were shifted inversely with the levels of the pro-inflammatory cytokines and with leptin. These studies demonstrate heightened immune reactivity in patients with premalignant lesions, which wanes in patients with HNSCC, but which is restored by treatment with 1,25(OH)2D3. PMID- 26120968 TI - High-level expression and phosphorylation of phytochrome B modulates flowering time in Arabidopsis. AB - Optimal timing of flowering in higher plants is crucial for successful reproduction and is coordinated by external and internal factors, including light and the circadian clock. In Arabidopsis, light-dependent stabilization of the rhythmically expressed CONSTANS (CO) is required for the activation of FLOWERING LOCUS T (FT), resulting in the initiation of flowering. Phytochrome A and cryptochrome photoreceptors stabilize CO in the evening by attenuating the activity of the CONSTITUTIVE PHOTOMORPHOGENIC 1-SUPPRESSOR OF PHYA-105 1 (COP1 SPA1) ubiquitin ligase complex, which promotes turnover of CO. In contrast, phytochrome B (phyB) facilitates degradation of CO in the morning and delays flowering. Accordingly, flowering is accelerated in phyB mutants. Paradoxically, plants overexpressing phyB also show early flowering, which may arise from an early phase of rhythmic CO expression. Here we demonstrate that overexpression of phyB induces FT transcription at dusk and in the night without affecting the phase or level of CO transcription. This response depends on the light-activated Pfr form of phyB that inhibits the function of the COP1-SPA1 complex by direct interactions. Our data suggest that attenuation of COP1 activity results in the accumulation of CO protein and subsequent induction of FT. We show that phosphorylation of Ser-86 inhibits this function of phyB by accelerating dark reversion and thus depletion of Pfr forms in the night. Our results explain the early flowering phenotype of phyB overexpression and reveal additional features of the molecular machinery by which photoreceptors mediate photoperiodism. PMID- 26120969 TI - Restrictions for Medicaid Reimbursement of Sofosbuvir for the Treatment of Hepatitis C Virus Infection in the United States. AB - The aim of this study was to systematically evaluate state Medicaid policies for the treatment of hepatitis C virus (HCV) infection with sofosbuvir in the United States. Medicaid reimbursement criteria for sofosbuvir were evaluated in all 50 states and the District of Columbia. The authors searched state Medicaid Web sites between 23 June and 7 December 2014 and extracted data in duplicate. Any differences were resolved by consensus. Data were extracted on whether sofosbuvir was covered and the criteria for coverage based on the following categories: liver disease stage, HIV co-infection, prescriber type, and drug or alcohol use. Of the 42 states with known Medicaid reimbursement criteria for sofosbuvir, 74% limit sofosbuvir access to persons with advanced fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis [METAVIR] fibrosis stage F3) or cirrhosis (F4). One quarter of states require persons co-infected with HCV and HIV to be receiving antiretroviral therapy or to have suppressed HIV RNA levels. Two thirds of states have restrictions based on prescriber type, and 88% include drug or alcohol use in their sofosbuvir eligibility criteria, with 50% requiring a period of abstinence and 64% requiring urine drug screening. Heterogeneity is present in Medicaid reimbursement criteria for sofosbuvir with respect to liver disease staging, HIV co-infection, prescriber type, and drug or alcohol use across the United States. Restrictions do not seem to conform with recommendations from professional organizations, such as the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases. Current restrictions seem to violate federal Medicaid law, which requires states to cover drugs consistent with their U.S. Food and Drug Administration labels. PMID- 26120970 TI - miR-30c and miR-193 are a part of the TGF-beta-dependent regulatory network controlling extracellular matrix genes in liver fibrosis. AB - OBJECTIVE: MicroRNAs (miRNAs) have recently emerged as novel regulators in liver fibrosis. miR-30c and miR-193 are involved in fibrotic remodeling processes and cancer development, respectively. This study aimed to explore the role of miR-30c and miR-193 in liver fibrosis. METHODS: The regulation of miRNAs in carbon tetrachloride-induced liver fibrosis was analyzed by microarray. Expression patterns of miR-193 and miR-30c were further confirmed in fibrotic liver samples obtained from two murine models of hepatic fibrosis and human tissues. On a functional level, miRNA levels were analyzed in the context of transforming growth factor (TGF-beta) mediated activation of hepatic stellate cells (HSCs). Finally, predicted targets were assessed for their roles in fibrosis by transfecting murine HSCs with miRNA mimics. RESULTS: Microarray analysis in murine fibrotic livers revealed a panel of 44 dysregulated miRNAs. In addition to previously established miRNAs known to be regulated in liver fibrosis in a TGF beta-dependent manner (e.g., miR-29, miR-133), miR-193 and miR-30c were observed to be specifically downregulated not only in experimental hepatofibrogenesis but also in human liver fibrosis, while they showed a reciprocal expression pattern after recovery from liver fibrosis. Functional experiments confirmed the TGF-beta dependent downregulation of these respective new miRNAs in HSCs. Finally, we identified TGF-beta2 and SNAIL1, important regulators of extracellular matrix, as potential target genes of miR-193 and miR-30 in liver fibrosis. CONCLUSION: These results suggest that miR-30 and miR-193 are members of a network of miRNAs modifying the TGF-beta-dependent regulation of extracellular matrix-related genes in HSCs in the manifestation and resolution of liver fibrosis. PMID- 26120971 TI - Risk for Type 2 Diabetes Mellitus: Person, Place, and Precision Prevention. PMID- 26120972 TI - Self-supported fibrous porous aromatic membranes for efficient CO2/N2 separations. AB - In this paper, we describe a new synthesis protocol for the preparation of self supported hollow fiber membranes composed of porous aromatic framework PAF-56P and PSF. PAF-56P was facilely prepared by the cross-coupling reaction of triangle shaped cyanuric chloride and linear p-terophenyl monomers. The prepared PAF-56P material possesses an extended conjugated network, the structure of which is confirmed by nuclear magnetic resonance and infrared characterizations, as well as a permanent porosity with a BET surface area of 553.4 m(2) g(-1) and a pore size of 1.2 nm. PAF-56P was subsequently integrated with PSF matrix into PAF 56P/PSF asymmetric hollow fiber membranes via the dry jet-wet quench method employing PAF-56P/PSF suspensions. Scanning electron microscopy studies show that PAF-56P particles are embedded in the PSF matrix to form continuous membranes. Fabricated PAF-56P/PSF membranes were further exploited for CO2 capture, which was exemplified by gas separations of CO2/N2 mixtures. The PAF-56P/PSF membranes show a high selectivity of CO2 over N2 with a separation factor of 38.9 due to the abundant nitrogen groups in the PAF-56P framework. A preferred permeance for CO2 in the binary CO2/N2 gas mixture is obtained in the range of 93-141 GPU due to the large CO2 adsorption capacity and a large pore size of PAF-56P. Additionally, PAF-56P/PSF membranes exhibit excellent thermal and mechanical stabilities, which were examined by thermal analysis and gas separation tests with the dependencies of temperatures and pressures. The merits of high selectivity for CO2, good stability, and easy scale up make PAF-56P/PSF hollow fiber membranes of great interest for the industrial separations of CO2 from the gas exhausts. PMID- 26120974 TI - [Modern pathogenetic aspects of development of cerebral chronic ischemia]. AB - Key mechanisms of the development of cerebral blood circulation insufficiency are presented. The following initial patters are analyzed: primary cytokine response, endothelial dysfunction and functioning of neurovascular units. Current conceptions on the development of pathological apoptosis and neuroplasticity are considered. PMID- 26120973 TI - A systematic review of behavioural interventions to reduce preoperative alcohol use. AB - ISSUES: Preoperative alcohol use is associated with an increase in postoperative morbidity and mortality. Short-term abstinence prior to elective surgery has been shown to reduce postoperative risks. Therefore, behavioural intervention (BI) targeting risky drinking may have significant utility in preventing surgical complications. APPROACH: The literature was systematically reviewed to identify the scope and outcomes of BIs aiming to reduce alcohol use in risky drinkers before they underwent surgery. Five databases were searched using PRISMA criteria. Of 1243 studies identified, four met pre-established inclusion criteria: (i) implementation of a BI prior to an elective surgery; (ii) the BI targeted alcohol use among risky drinkers; and (iii) printed in English. KEY FINDINGS: Two studies indicated significant reductions in alcohol use at follow ups, and one study demonstrated reductions in postoperative risks. These findings are encouraging, but in light of methodological limitations, the efficacy of preoperative BIs for risky drinking could not be determined. IMPLICATIONS: Future efforts to screen and implement BIs addressing alcohol use in preoperative patients should carefully define risky drinking, allow ample time for recruitment prior to surgery, implement empirically supported interventions, examine the impact of relevant covariates, and consider the statistical power needed to detect change in postoperative complications. CONCLUSION: Given the strong link between preoperative alcohol use and postoperative risks, additional research on preoperative BIs is critically needed. Existing research suggests several promising directions for research that may enhance future intervention efforts with this high-risk population. [Fernandez AC, Claborn KR, Borsari B. A systematic review of behavioural interventions to reduce preoperative alcohol use. Drug Alcohol Rev 2015;34:508-20]. PMID- 26120975 TI - [Neck pain and headache as the only manifestation of cervical artery dissection]. AB - OBJECTIVE: To analyze clinical and neuroimaging data in patients with neck pain and headache as the only manifestation of the internal carotid artery (ICA) dissection (ICAD) and vertebral artery (VA) dissection (VAD). MATERIAL AND METHODS: One hundred and sixty-one patients (mean age - 37.4+/-4,99 years, 84 women, 52%) with cervical artery dissection (CAD) verified by magnetic resonance imaging (MRI) were enrolled. Neck pain and headache were the only CAD manifestation in 33 patients (mean age 37,3+/-7,4 yars, 28 women, 85%). RESULTS: The localization of the dissections in these patients was the following: one VA (15 patients), two VA (9), one ICA (7), two ICA (1), one ICA + two VA (1). The whole number of dissected arteries was 45: extracranial localization - 38, extra intracranial - 6, intracranial - 1. Dissection led to stenosis of the arterial lumen in 41 arteries, to occlusion - in 2 and to dual lumen in 2 arteries. Small aneurism was found in 4 arteries. Combination of headache and the neck pain was observed in 26 out of 33 patients (79%), the only headache in 4 patients, the only neck pain in 3 patients. Along with this, 9 out of 24 VAD patients had the shoulder and/or arm pain. Headache in VAD patients was located more often in the occipital region (18 out of 24) that had never been observed in ICAD patients (p=0.0009). Fronto-temporal pain was observed more often in ICAD patients (5 out of 8 patients) than in VAD (2 out of 24 patients) (p=0.003). Neck pain in all VAD patients in comparison with 3 out ofI8 [CAD patients had posterior localization (p=0,007). Anterolateral neck pain was observed in 4 out ofI8 ICAD patients and in no patients with VAD (p=0.0009). The pain appearance was abrupt in all ICAD patients and most of the VAD patients. In 8 VAD patients the pain has been increasing during several hours. The pain intensity was severe in 19 patients, moderate in 12 and mild in 2. The characteristics of the pain were as following: constrictive/dull (26 patients), throbbing (1 patient) or combined (6 patients). Pain was increasing in a stepwise manner during the first days in 14 out of 24 VAD patients and in no one of ICAD patients (p=0.008). The mean pain duration period was 31 8 +/- 15,7 days. Pain relief drugs were ineffective or had a short effect in 97% of patient. CONCLUSION: Isolated pain is more characteristic for women with VAD. Usually pain is presented as a combination of headache and neck pain. Pain localization, mode of appearance and the course are different in VAD and ICAD. The rarity of occlusion among patients with <> manifestation let to suggest that the intramural hematoma in this group of patients spreads to the adventitia that can reflect media weakness. Arterial wall changes underlying its weakness seem to be sex-hormone dependent taking into consideration the high predominace of women in cad manifested by isolated pain. PMID- 26120976 TI - [Cerebrospinal fluid in clinical aspects of tuberculosis of the central nervous system]. AB - OBJECTIVE: To identify clinical features of tuberculosis of the meninges and central nervous system (TM) with detailed characterization of changes in the composition of cerebrospinal fluid (CSF) in the initial period of the disease. MATERIAL AND METHODS: We analyzed the results of the examination of 42 patients, aged from 17 to 49 years, who were hospitalized in 2005-2014. RESULTS AND CONCLUSION: Most of the patients were admitted in the hospital in early acute disease onset. Along with the description of inflectional and cerebral symptoms, meningeal signs, disorders of consciousness and focal symptoms, we presented cell count values, protein and glucose concentrations at initial examination of CSF as well as the results of additional examination and specific therapy issues. The importance of combining treatment standards and individualization of therapy of TM patients is emphasized. PMID- 26120977 TI - [Play behavior in people with various degrees of pathological gambling risk]. AB - OBJECTIVE: We studied play behavior of customers of betting offices. MATERIAL AND METHODS: A study included 216 people who were surveyed using the Canadian problem gambling index. According to the results of the test, we stratified the sample by the risk of pathological gambling. RESULTS AND CONCLUSION: The high prevalence of people with medium and high risk of pathological gambling was identified. Significant differences in the characteristics of gambling behavior were found. We described the qualitative and quantitative indicators of gaming activity that proved the appearance of the addicted dominant in the high-risk group (changes in the motivational sphere, financial loss, using alternative forms of the game, the regular play activity and low level of the reflection of problems caused by the game). PMID- 26120978 TI - [Sleep disorders and circadian rhythms in diseases of the cardiovascular system]. AB - OBJECTIVE: To study disturbances of sleep and circadian rhythms in patients with cardiovascular diseases taking into account the level of melatonin secretion and to optimize a complex approach to their treatment. MATERIALS AND METHODS: The study included patients with cardiovascular diseases with- (n=121) and without (n=105) cerebrovascular diseases (CVD). All patients received melaxen in dose 3 mg daily 30-40 min before sleep. Examination of patients included assessment of neurological status, psychometric scales, the definition of circadian rhythm of the heart and blood pressure, determination of 6-SOMT in daily urine. RESULTS: Pathological changes in circadian rhythms affected sleep disturbances, emotional and cognitive disorders and were associated with a reduction in the level of 6 SOMT in the urine. These changes were most pronounced in patients with CVD and stroke. The inclusion of melaxen in the comprehensive regimen of treatment improved sleep, reduced mood disorders and normalized the circadian heart rate profile and blood pressure. CONCLUSION: The data obtained allowed to consider melaxen as an effective tool in the complex therapy of patients with CVD. PMID- 26120979 TI - [Experience of botulinum toxin in treatment of writer's cramp]. AB - OBJECTIVE: To evaluate the efficacy and safety of botulinum toxin type A (BTA) injections in patients with writer's cramp (WC). MATERIAL AND METHODS: We treated 29 patients, in general, 49 BTA injections were performed. To determine points for the injections, we used ultrasound examination of the forearm including the time of writing. RESULTS: Patients reported subjective improvement in 75.9% after the first injection. Positive results as assessed with the WCRS were seen in 82.7% of the patients. We observed muscle weakness in the hands of 17.2% of the patients. Most of the patients were satisfied with the result of the injection and agreed on the need to re-injection when clinical effect of BTA had decreased. CONCLUSION: To determine the indications for BTA injections in PS, an individual approach to the development of schemes of injections and calculation of dose is needed. Treatment of BTA should be used in severe forms of WC with social significance to the patients. PMID- 26120980 TI - [Efficacy of baclosan in combined therapy of muscular-tonic pain syndrome in the early postoperative period in patients after microdiscectomy]. AB - OBJECTIVE: A comparative analysis of the efficacy of baclosan in adjuvant therapy of muscular-tonic pain syndromes in the early postoperative period after microdiscectomy. MATERIAL AND METHODS: One hundred and three patients (65 men and 38 women, mean age 42+/-5,0 years) were divided into two sex- and age-matched groups depending on the treatment. Patients of group 1 received baclosan in the combination with standard therapy, patients of group 2 received standard therapy. Patients were assessed before treatment, at 3 and 10 days of treatment. RESULTS AND CONCLUSION: Treatment effect (maximum relief of pain and anxiety-depressive syndromes) was achieved earlier in group 1 compared to group 2. The questions of substantiation of pathogenetic action of baclosan effect in the complex therapy of muscular-tonic pain syndromes in patients after microdiscectomy are considered. PMID- 26120981 TI - [The effect of the succinic acid preparation on the dynamics of neurological and emotional disturbances in patients with dorsopathy]. AB - OBJECTIVE: To study the dynamics of neurological and emotional disturbances in patients with dorsopathy treated with cytoflavin. MATERIAL AND METHODS: We examined 120 patients aged from 21 to 55 years, mean age 38+/-9 years. All patients received nonsteroid anti-inflammatory drugs, myorelaxants, vitamins. The main group comprised 67 patients who received cytoflavin (10ml of the solution in one injection once a day in 200 ml of isotonic solution of sodium chloride intravenously in drops in the morning during 10 days) in addition to standard treatment. The comparison group included 53 patients who received standard treatment during 10 days. RESULTS AND CONCLUSION: The use of cytoflavin allowed earlier arresting of the pain syndrome, restored the disturbed sensitivity, improved emotional status and decreased the severity of a neuropathic pain component. PMID- 26120982 TI - [Lipid spectrum changes and ECG in patients with paranoid schizophrenia in the course of therapy with atypical antipsychotics]. AB - OBJECTIVE: To study correlations between parameters of lipid metabolism and ECG in patients with schizophrenia in light of therapy with atypical antipsychotics. MATERIAL AND METHODS: We examined 42 patients with paranoid schizophrenia. All patients received atypical neuroleptics - seroquel, zyprexa, and rispolept. A group of controls included 25 healthy people. RESULTS: There was a significant increase (p=0.0002) in body mass (in average by 1.5 kg) in 88% patients. A significant increase in the concentration of serum triglycerides was identified as well. The concentration of VLDL in the patients with schizophrenia was 2 times higher compared to controls. After treatment, VLDL concentration increased even more considerably An increase in atherogenic index (AI) was up to 3.1 in patients with schizophrenia compared to 2.2 in controls. After treatment, Al increased up to 4 that demonstrated the high risk of development of atherosclerosis. A significant increase in QT interval in the ECG and heart rate (p=0.03) was revealed only in patients receiving rispolept. In patients receiving zyprexa and seroquel only heart rate was increased. CONCLUSION: The antipsychotics studied increase the risk of development of cardiovascular pathology. PMID- 26120983 TI - [Computerized method of objectification of dizziness and vertigo and differential diagnostic of vestibulopathies]. AB - OBJECTIVE: To create a complex computerized method of objectification of dizziness and vertigo, and differentiation of vestibulopathies of various geneses using electrooculography approach that allows to record and analyze spontaneous, vestibular- and visually-induced eye movements, with the following classification (discriminant) analysis of the results obtained. MATERIAL AND METHODS: The study involved 69 patients of different sex and age complained of dizziness, vertigo and disequilibrium, and 64 healthy men. Based on the results of clinical examination, patients were divided into three groups: patients with peripheral vestibulopathy, patients with central vestibulopathy and patients with psychogenic vestibulopathy. Electrooculography was performed using the hardware software complex (HSC) "OCULOSTIM-CM". RESULTS AND CONCLUSION: Significant diagnostic parameters based on the recognition and analysis of spontaneous, vestibular- and visually-induced eye movements were coefficients of efficacy and increased frequency of fixation saccades and smooth pursuit with- and without retinal optokinetic stimulation. We developed the algorithm and complex computerized method for differentiation of different types of vestibulopathy. PMID- 26120984 TI - [Inflammatory mechanisms of fatigue syndrome in Parkinson's disease]. AB - OBJECTIVE: To study clinical characteristics of fatigue syndrome in patients with Parkinson's disease (PD) and a role of inflammation in its development. MATERIAL AND METHODS: We examined 98 patients with confirmed diagnosis of PD and 18 healthy people. Clinical examination included an analysis of anamnesis and objective somatic symptoms. The unified Parkinson's disease rating scale, The Hoehn and Yahr scale, the Multidimensional Fatigue Inventory (MFI-20) scale, the Modified Fatigue Impact Scale (MFIS), the Hospital Anxiety and Depression Scale (HADS), The Epworth Sleepiness Scale (ESS), Vein's Autonomic Symptoms Questionnaire (VASQ) were used for quantitative assessment. Serum concentrations of IL-6 were measured in 65 patients and 18 controls using ELISA. RESULTS AND CONCLUSION: In PD patients, fatigue assessed with MFI-20 was recorded in 46 (47%) cases and fatigue as assessed with MFIS in 45 (46%) of cases. High frequency and severity of fatigue syndrome were observed. The most prominent components in the structure of fatigue were physical fatigue, reduced motivation and decreased activity. Signs of fatigue increased with disease progression. Correlation between fatigue and axial motor symptoms of PD is of interest. Patients had higher serum IL-6 levels compared to the controls. Concentrations of IL-6 were correlated with fatigue severity and its main components (general and physical fatigue, decreased activity) and with depression level. PMID- 26120986 TI - [The peculiarities of the support therapy and adherence to the treatment in psychiatric outpatients]. AB - OBJECTIVE: To study peculiarities of the support therapy and factors hampering the compliance in psychiatric outpatients. MATERIAL AND METHODS: We questioned 1042 patients with mental diseases and 580 persons in their close social environment using the method of anonymous social questionnaire. RESULTS: The most of the respondents (78.2%) received "classic" psychotropic drugs, 21.8% - the drugs of new generations. One third of the patients (37.56%) did not take the prescribed medicine. The reasons for refusal were: polypragmasia (74.39%), poor drug tolerance (38.17%), the complex scheme of drug dosage regimen, the negative experience of the previous therapy (35.62%) and the lack of information about peculiarities of the disease (59.73%). CONCLUSION: Introduction of methods of psychosocial rehabilitation, in particular, psychoeducational and multiprofessional treatment programs, is required for psychiatric practice to improve the quality of outpatient care. PMID- 26120987 TI - [Factors of psychiatric treatment satisfaction in inpatients with neurotic and depressive disorders]. AB - OBJECTIVE: Factors of patients' satisfaction with medical care vary depending on the level of care and medical specialty. Patient's satisfaction with psychiatric care is understudied. An aim of the present study is to find out the factors of satisfaction with psychiatric care in inpatients with neurotic and depressive disorders. MATERIAL AND METHODS: The sample included 356 inpatients suffering from neurotic or depressive disorders. The patients were questioned using PAPI questionnaire designed for this study. Statistical analysis was performed using multiple regression. RESULTS AND CONCLUSION: Key factors of satisfaction with medical care included quality of work of nurses and psychiatrists, hospital ward comfort, the number and quality of psychotherapeutic sessions, psychiatrists' empathy and aptitude to provide the patient with information about the disease and treatment. Multiple regression equation explained 81% of the variance of patients' satisfaction. PMID- 26120985 TI - [Pharmacokinetic and pharmacodynamic synergism between neuropeptides and lithium in the neurotrophic and neuroprotective action of cerebrolysin]. AB - OBJECTIVE: To study the synergism between neuropeptides and lithium ions. MATERIAL AND METHODS: An experimental model of stroke (chronic bilateral occlusion of the common carotid arteries in rats), neuronal culture studies, histomorphological analyses, determination of micronutrient profile of brain substrates were used. RESULTS: A complex of experimental studies revealed that the effect of cerebrolysin is influenced by the synergism between lithium ions and the neuropeptide contentof this drug. Pharmacokinetic synergism promotes the accumulation of lithium in brain tissues during cerebrolysin treatment. The existence of the pharmacokinetic synergism is evident from the potentiation of neuroprotective effects of the drug under the action of lithium ions established in the model of stroke. CONCLUSION: Lithium ions potentiate neuroprotective effects of cerebrolysin. PMID- 26120988 TI - [The effect of vasonit on the structural/functional state of erythrocyte cytoplasmic membrane in patients with ischemic stroke]. AB - OBJECTIVE: To study the effect of vasonit on the structural/functional state of erythrocyte cytoplasmic membrane in patients with ischemic stroke (11) using atomic-power microscopy in vitro. MATERIAL AND METHODS: We examined 45 patients with II. Patients of the main group (n=30) received vasonit and standard treatment, 15 patients of the comparison group received only standard treatment. To assess the severity of patient's condition, we used the NIH stroke scale, modified Rankin scale, the Barthel index and the Rivermead Mobility index. Dried erythrocyte preparations were made to study erythrocyte cytoplasmic membrane. Scanning was performed using an atomic-power microscope manufactured by "SOLVER P47-Pro" (NT-MDT, Russia). RESULTS AND CONCLUSION: A statistically significant positive dynamics of neurological deficit and patient's functional state was found in the 14" day of the study. A significant decrease in Young's modulus value was identified in the main group that suggested the increase in the elasticity of erythrocyte cytoplasmic membrane. PMID- 26120989 TI - [Febrile children's convulsions]. AB - The data of the world literature on treatment children's febrile convulsions were generalized. Regimens of immediate treatment and intermittent prophylaxis of febrile convulsions were instituted. PMID- 26120990 TI - [Modern classification and clinical psychiatry]. PMID- 26120991 TI - [Neurovisualisation predictors of malignant cerebral infarction and hemorrhagic transformation]. AB - Neuroimaging plays a central role in the assessment of patients with acute ischemic stroke. Within a few minutes, modern multimodal imaging protocols can provide one with comprehensive information about prognosis, management, and outcome of the disease, and may detect changes in the intracranial structures reflecting severity of the ischemic injury depicted by four Ps: parenchyma (of the brain), pipes (i.e., the cerebral blood vessels), penumbra, and permeability (of the blood brain barrier). In this article, we have reviewed neuroradiological predictors of malignant middle cerebral artery infarction and hemorrhagic transformation in light of the aforementioned four Ps. PMID- 26120992 TI - [Tactics of antihypertensive therapy in patients with hypertonic crisis complicated with hemorrhagic stroke]. AB - OBJECTIVE: To determine an optimal tactics of antihypertensive therapy in patients with hypertonic crisis complicated with hemorrhagic stroke. MATERIAL AND METHODS: We examined 86 inpatients, 42 men and 44 women, aged 46-87 years, with hypertonic crisis complicated with hemorrhagic stroke. The severity of neurological deficit, parameters of cardiac output and Kaplan-Meier survival curve based on the level of arterial pressure (AP) were assessed. RESULTS: The best survival rate of the patients with systolic blood pressure >162 mm Hg to the 20th min from the beginning of treatment with the greater rate of its increase was established. The efficacy of antihypertensive therapy did not depend on the baseline neurological deficit. The remote survival rate did not depend on such factors as sex, age, baseline AP level, AP, frequency of heart contractions, hematoma's volume. PMID- 26120993 TI - [Dislocation syndrome in patients with severe massive ischemic stroke]. AB - OBJECTIVE: To compare the severity of brain dislocation, the rate of its progression according to CT results and clinical signs of dislocation syndrome (DS) in patients with unfavorable form of massive ischemic stroke (MII). MATERIAL AND METHODS: We analyzed the results of examination and treatment of 114 patients with unfavorable course of MII. Patients were stratified by the type of DS course into two groups: group 1 with unfavorable course (91 patients) and group 2 with favorable course (23 patients). Patients were compared by disease course and outcome as well as by progression rate and severity of brain dislocation. Twenty seven patients of group 1 underwent decompressive craniectomy (DC). RESULTS: All patients of group 1 had DS decompensation and, therefore DS course was assessed as unfavorable. All patients of group 1, who received only conservative treatment, died from brain dislocation. In patients treated with DC in addition to conservative treatment, the fatality rate was 48%. In this group, we singled out 3 variants of DS course: fulminant, progressive and delayed. In patients of group 2, the fatality rate was 52%. The patients died from non-cranial complications and DS course in this group was regarded as favorable. CONCLUSION: In patients with unfavorable course of MII, the risk of fatal outcome from temporal-tentorial impaction is determined both by the severity and progression rate of transverse dislocation of the middle brain structures. DS in patients with unfavorable course of MII can have favorable or unfavorable course. The unfavorable course is characterized by fulminant, progressive or delayed DS progression rate. The unfavorable course of DS is an absolute indication of administration of DC. PMID- 26120994 TI - [Characteristics of microcirculation in patients with acute ischemic stroke and chronic cerebral ischemia]. AB - OBJECTIVE: To study microcirculation in patients with acute ischemic stroke (IS) using the method of laser Doppler fluorimetry (LDF). MATERIAL AND METHODS: We examined 19 patients with acute carotid IS, including 12 patients who received thrombolytic therapy. The reference group included 22 patients with chronic cerebral ischemia without a history of IS. Computed and magnetic resonance tomography of the brain, ultrasound diagnosis of head and neck vessels, the study of the changes in neurological status, emotional sphere, cognitive functions and laboratory methods were used. RESULTS: An index of total blood flow in the microcirculatory bed on the side of stroke was lower compared to that in patients with chronic cerebral ischemia. The study of parameters of microcirculatory bed regulation revealed an increase of blood inflow into the microcirculatory bed with the augmentation of the myogenic activity of arterioles and primarily the nutritional regimen of microhemocirculation. A decrease in the myogenic activity in the microcirculation system and nutritional direction of microhemodynamics were noted in patients with large IS. In some cases, non-nutritional regimen and/or venule congestion were observed. CONCLUSION: The study of the microcirculation system with the LDF method can be used as the method of early diagnosis of unfavorable variants of cerebral microcirculation that is necessary for outcome prognosis and its correction. PMID- 26120995 TI - [Prevention of venous thromboembolism in the acute stroke]. AB - OBJECTIVE: To assess the effectiveness of preventive measures to reduce VTE rates among patients with severe stroke in intensive care unit (ICU). MATERIAL AND METHODS: The efficacy and safety of previously developed protocol for VTE prevention was assessed in 378 stroke patients in the ICU who received different levels of preventive measures. Subjects were distributed into three groups. We assessed neurological status of all patients on admission and in the course of stroke, and performed ultrasound scanning of lower limb veins for groups II and III. RESULTS: The rate of VTE events remained high regardless of the level of preventive measures. However, we observed a changing nature of PE from massive to nonmassive without increasing the rate of hemorrhagic complications while the strict protocol of VTE prevention with mandatory use of low molecular weight heparins was applied, including patients with hemorrhagic stroke. CONCLUSION: The use of the proposed protocol of VTE prevention in routine care for patients with stroke in ICU is safe and may significantly reduce the incidence of fatal pulmonary embolism. PMID- 26120996 TI - [Insomnia and sleep-related breathing disturbances are the new risk factors for ischemic stroke]. AB - Sleep disorders have an extremely negative impact on human vital functioning, encompassing both mental and somatic sphere. A large number of clinical trials have shown an increased risk of cardiovascular diseases and their complications, including the risk of ischemic stroke, in patients suffering from insomnia or sleep-related breathing disturbances. These types of sleep disorders are the most common in the structure of all violations of sleep. Obstructive sleep apnea syndrome is the most clinically significant type of sleep-related breathing disturbances. A number of pathophysiological mechanisms that may be responsible for the negative impact of sleep disorders was identified. In order to treat insomnia, behavioral techniques, including the normalization of sleep hygiene, behavioral and cognitive therapy, medication treatment, are used. Continuous Positive Airway Pressure (CPAP) therapy is currently the method of choice in the treatment of obstructive sleep apnea syndrome of any etiology. PMID- 26120997 TI - [Surgical treatment of putamen hematomas]. AB - We present the current data on surgical treatment of putamen hematomas and describe clinical presentation of this disease and its diagnosis including radiologic diagnosis. The results of most prominent publications devoted to the study of surgical treatment efficacy are presented. Indications to surgical treatment of the disease are discussed. PMID- 26120998 TI - [An expert assessment of medical care quality in patients with acute disturbances of cerebral blood flow at prehospital stage]. AB - OBJECTIVE: To study the criteria of expert assessment of medical care quality in patients with acute disturbances of cerebral blood flow at prehospital stage in the Smolensk region. MATERIAL AND METHODS: We analyzed the adequacy of medical care to regulation documents of the Russian Federation and worked out several assessment criteria. Based on these criteria, we selected and analyzed 190 ambulance care records over 1 month. RESULTS AND CONCLUSION: The quality of ambulance care was estimated on a three-level scale: satisfactory, satisfactory with minor deficiencies, unsatisfactory. In the Smolensk region, it is characterized by relatively low estimates. These criteria allow to fairly assess the quality of medical care for patients with acute disturbances of cerebral blood flow at prehospital stage. PMID- 26120999 TI - [Prognosis of morbidity of stroke in the Dagestan Republic]. AB - A prognosis of morbidity and mortality of stroke in the Republic of Dagestan is presented. Using the data of stroke register of the Republic of Dagestan for the period 2009-2011, logistic regression models for predicting the development of the situation with stroke within the next 7 years were built. PMID- 26121000 TI - [Etiology of stroke in children]. AB - The lecture contains information on terminology, etiology and pathogenesis of stroke in children. The current statistics on the incidence of stroke in the pediatric population, prognosis and principles of early diagnosis are presented. Different states, complicating stroke in children are described. PMID- 26121001 TI - [Neurorehabilitation of patients after stroke and brain injury]. AB - Cerebral vascular diseases, traumatic brain injuries are frequent causes of fatality and severe disability. A complex of measures seems to be perspective to restore the brain functions impaired due to the focal brain lesion. Main stages of the formation of neurorehabilitation as independent discipline are considered. The progress in this field and the problems that need to be resolved are analyzed. The contribution of Russian scientists (neurologists, neurosurgeons, psychologists) to the development of neurorehabilitation is highlighted. PMID- 26121002 TI - [The use of mexidol in the intensive treatment of acute severe ischemic stroke]. AB - OBJECTIVE: To study the efficacy and safety of early use of mexidol in the acute stage of severe ischemic stroke (IS). MATERIAL AND METHODS: A study included 112 patients, aged from 35 to 85 years, with a severe IS. Patients were stratified into two age and sex- matched groups. The main group (n=59) received mexidol in dose of 500 mg daily intravenously during 10 days in addition to standard treatment. The comparison group (n=53) received standard treatment only. RESULTS: In the main group, the percentage of good outcomes, assessed by the Rankin scale, was higher in earlier as well in delayed treatment and the fatality was lower compared to the comparison group. CONCLUSION: Mexidol increased the efficacy of treatment and may be recommended for treatment of patients with severe carotid IS. PMID- 26121003 TI - CHIVA method for the treatment of chronic venous insufficiency. AB - BACKGROUND: Many surgical approaches are available to treat varicose veins secondary to chronic venous insufficiency. One of the least invasive techniques is the ambulatory conservative hemodynamic correction of venous insufficiency method (cure conservatrice et hemodynamique de l'insuffisance veineuse en ambulatoire (CHIVA)), an approach based on venous hemodynamics with deliberate preservation of the superficial venous system. This is an update of the review first published in 2013. OBJECTIVES: To compare the efficacy and safety of the CHIVA method with alternative therapeutic techniques to treat varicose veins. SEARCH METHODS: The Trials Search Co-ordinator of the Cochrane Peripheral Vascular Diseases Group searched the Specialised Register (April 2015), the Cochrane Register of Studies (2015, Issue 3) and clinical trials databases. The review authors searched PubMed (April 2015). There was no language restriction. We contacted study authors to obtain more information when necessary. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the CHIVA method versus any other treatments. Two review authors independently selected and evaluated the studies. One review author extracted data and performed the quantitative analysis. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data from the selected papers. We calculated the risk ratio (RR), mean difference (MD), the number of people needed to treat for an additional beneficial outcome (NNTB), and the number of people needed to treat for an additional harmful outcome (NNTH), with 95% confidence intervals (CI) using Review Manager 5. MAIN RESULTS: No new studies were identified for this update. We included four RCTs with 796 participants (70.5% women). Three RCTs compared the CHIVA method with vein stripping, and one RCT compared the CHIVA method with compression dressings in people with venous ulcers. We judged the quality of the evidence of the included studies as low to moderate due to imprecision caused by the low number of events and because the studies were open. The overall risk of bias across studies was high because neither participants nor outcome assessors were blinded to the interventions. The primary endpoint, clinical recurrence, pooled between studies over a follow-up of 3 to 10 years, showed more favorable results for the CHIVA method than for vein stripping (721 people; RR 0.63; 95% CI 0.51 to 0.78; I(2) = 0%, NNTB 6; 95% CI 4 to 10) or compression dressings (47 people; RR 0.23; 95% CI 0.06 to 0.96; NNTB 3; 95% CI 2 to 17). Only one study reported data on quality of life (presented graphically) and these results significantly favored the CHIVA method.The vein stripping group had a higher risk of side effects than the CHIVA group; specifically, the RR for bruising was 0.63 (95% CI 0.53 to 0.76; NNTH 4; 95% CI 3 to 6) and the RR for nerve damage was 0.05 (95% CI 0.01 to 0.38; I(2) = 0%; NNTH 12; 95% CI 9 to 20). There were no statistically significant differences between groups regarding the incidence of limb infection and superficial vein thrombosis. AUTHORS' CONCLUSIONS: The CHIVA method reduces recurrence of varicose veins and produces fewer side effects than vein stripping. However, we based these conclusions on a small number of trials with a high risk of bias as the effects of surgery could not be concealed and the results were imprecise due to low number of events. New RCTs are needed to confirm these results and to compare CHIVA with approaches other than open surgery. PMID- 26121004 TI - Dichloroacetate and Trichloroacetate Toxicity in AML12 Cells: Role of Oxidative Stress. AB - The toxicity of the drinking water disinfection by products dichloroacetate (DCA) and trichloroacetate (TCA) was studied in the alpha mouse liver (AML12) cells at concentrations ranging between 770 and 4100 ppm and at incubation times ranging from 24 to 72 h. Cellular viability, superoxide anion (SA) and lipid peroxidation (LP) production, as well as superoxide dismutase (SOD) activity were determined. DCA and TCA resulted in time- and concentration-dependent decreases in cellular viability, and also in significant increases in SA and LP production, and in SOD activity at specific concentrations and time points. The effective toxic concentrations of the compounds in these cells were found to be 10-fold higher than those producing similar effects in the mouse liver. It has been concluded that the AML12 is a good screening system to identify toxic concentrations of the halaocetates present in the drinking water that may need further in vivo testing. PMID- 26121005 TI - Environmental Benefits and Burdens of Phosphorus Recovery from Municipal Wastewater. AB - The environmental benefits and burdens of phosphorus recovery in four centralized and two decentralized municipal wastewater systems were compared using life cycle assessment (LCA). In centralized systems, phosphorus recovered as struvite from the solids dewatering liquid resulted in an environmental benefit except for the terrestrial ecotoxicity and freshwater eutrophication impact categories, with power and chemical use offset by operational savings and avoided fertilizer production. Chemical-based phosphorus recovery, however, generally required more resources than were offset by avoided fertilizers, resulting in a net environmental burden. In decentralized systems, phosphorus recovery via urine source separation reduced the global warming and ozone depletion potentials but increased terrestrial ecotoxicity and salinization potentials due to application of untreated urine to land. Overall, mineral depletion and eutrophication are well-documented arguments for phosphorus recovery; however, phosphorus recovery does not necessarily present a net environmental benefit. While avoided fertilizer production does reduce potential impacts, phosphorus recovery does not necessarily offset the resources consumed in the process. LCA results indicate that selection of an appropriate phosphorus recovery method should consider both local conditions and other environmental impacts, including global warming, ozone depletion, toxicity, and salinization, in addition to eutrophication and mineral depletion impacts. PMID- 26121006 TI - Two-Photon Spectroscopy as a New Sensitive Method for Determining the DNA Binding Mode of Fluorescent Nuclear Dyes. AB - A new optical strategy to determine the binding modes (intercalation vs groove binding) of small fluorescent organic molecules with calf thymus DNA was developed using two-photon absorption (TPA) spectroscopy. Two-photon excited emission was utilized to investigate a series of fluorescent nuclear dyes. The results show that TPA cross-sections are able to differentiate the fine details between the DNA binding modes. Groove binding molecules exhibit an enhanced TPA cross-section due to the DNA electric field induced enhancement of the transition dipole moment, while intercalative binding molecules exhibit a decrease in the TPA cross-section. Remarkably, the TPA cross-section of 4,6-bis(4-(4 methylpiperazin-1-yl)phenyl) pyrimidine is significantly enhanced (13.6-fold) upon binding with DNA. The sensitivity of our TPA methodology is compared to circular dichroism spectroscopy. TPA demonstrates superior sensitivity by more than an order of magnitude at low DNA concentrations. This methodology can be utilized to probe DNA interactions with other external molecules such as proteins, enzymes, and drugs. PMID- 26121007 TI - Enhancement of the 1-Octanol/Water Partition Coefficient of the Anti-Inflammatory Indomethacin in the Presence of Lidocaine and Other Local Anesthetics. AB - Side effects and excessive potentiation of drug efficacy caused by polypharmacy are becoming important social issues. The apparent partition coefficient of indomethacin (log P'IND) increases in the presence of lidocaine, and this is used as a physicochemical model for investigating polypharmacy. We examined the changes in log P'IND caused by clinically used local anesthetics-lidocaine, tetracaine, mepivacaine, bupivacaine, and dibucaine-and by structurally similar basic drugs-procainamide, imipramine, and diltiazem. The quantitative structure activity relationship study of log P'IND showed that the partition coefficient values (log PLA) and the structural entropic terms (DeltaSobs, log f) of the additives affect log P'IND. These results indicate that the local anesthetics and structurally similar drugs function as phase-transfer catalysts, increasing the membrane permeability of indomethacin via heterogeneous intermolecular association. Therefore, we expect that the potency of indomethacin, an acidic nonsteroidal anti-inflammatory drug, will be increased by concurrent administration of the other drugs. PMID- 26121008 TI - Rapid Electrochemical Detection of New Delhi Metallo-beta-lactamase Genes To Enable Point-of-Care Testing of Carbapenem-Resistant Enterobacteriaceae. AB - The alarming rate at which antibiotic resistance is occurring in human pathogens causes a pressing need for improved diagnostic technologies aimed at rapid detection and point-of-care testing to support quick decision making regarding antibiotic therapy and patient management. Here, we report the successful development of an electrochemical biosensor to detect bla(NDM), the gene encoding the emerging New Delhi metallo-beta-lactamase, using label-free electrochemical impedance spectroscopy (EIS). The presence of this gene is of critical concern because organisms harboring bla(NDM) tend to be multiresistant, leaving very few treatment options. For the EIS assay, we used a bla(NDM)-specific PNA probe that was designed by applying a new approach that combines in silico probe design and fluorescence-based DNA microarray validation with electrochemical testing on gold screen-printed electrodes. The assay was successfully demonstrated for synthetic targets (LOD = 10 nM), PCR products (LOD = 100 pM), and direct, amplification free detection from a bla(NDM)-harboring plasmid. The biosensor's specificity, preanalytical requirements, and performance under ambient conditions were demonstrated and successfully proved its suitability for further point-of-care test development. PMID- 26121009 TI - Correction to "Supramolecular Autoregulation". PMID- 26121011 TI - Increasing the effective energy barrier promoted by the change of a counteranion in a Zn-Dy-Zn SMM: slow relaxation via the second excited state. AB - The trinuclear complex [ZnCl(MU-L)Dy(MU-L)ClZn]PF6 exhibits a single-molecule magnetic behaviour under zero field with a relatively large effective energy barrier of 186 cm(-1). Ab initio calculations reveal that the relaxation of the magnetization is symmetry-driven (the Dy(III) ion possesses a C2 symmetry) and occurs via the second excited state. PMID- 26121010 TI - Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells. AB - BACKGROUND INFORMATION: Previous studies have revealed that leptin may be involved in epithelial-mesenchymal transition (EMT), a crucial initiator of cancer progression to facilitate metastatic cascade, increase tumor recurrence, and ultimately cause poor prognosis. However, the underlying mechanism remains unclear. The aim of our present study was to investigate the effect of leptin on EMT of breast cancer cells and the underlying mechanism. RESULTS: Our data demonstrated that leptin significantly increased the phosphorylation of STAT3, Akt, and ERK1/2, elevated the expression of IL-8, and induced breast cancer cells to undergo EMT. The effect of leptin on IL-8 could visibly abolished by the inhibitor of PI3K LY294002. In addition, leptin-induced EMT of breast cancer cells was blocked by anti-IL-8 antibodies. Examination of the expression of ObR, leptin, IL-8 and EMT-related biomarkers in patient specimens demonstrated that malignant breast carcinoma with lymph node metastases (LNM), which represents poor prognosis, expressed higher levels of ObR, leptin, IL-8 than other types of breast cancer, and displayed more obvious EMT transversion. In vivo xenograft experiment revealed that leptin signally promoted tumor growth and metastasis and increased the expressions of IL-8 and EMT-related biomarkers. CONCLUSIONS: Our results support that leptin-induced EMT in breast cancer cells requires IL-8 activation via the PI3K/Akt signal pathway. PMID- 26121012 TI - Physical activity in adolescents who later developed schizophrenia: A prospective case-control study from the Young-HUNT. AB - BACKGROUND: Adults suffering from schizophrenia and other psychiatric disorders report low levels of physical activity. In addition, these patients have an increased risk of overweight and poor nutritional habits. Less is known about patterns and levels of physical activity before the onset of disease. AIMS: The purpose of the study was to investigate whether there were specific patterns of physical activity in the premorbid phase of schizophrenia and whether these participants differed from those with bipolar disorder (BD). A group of healthy controls (HC) was also included. METHODS: The study was a prospective, longitudinal, comparative cohort design in which 15 adolescents who later developed schizophrenia and 18 with later BD were compared with HC. Data were analysed using non-parametric statistical tests. RESULTS: Patients with a diagnosis of schizophrenia were less physically active with fewer days per week (p < 0.05) and fewer hours per week (p < 0.05) in the premorbid phase than both BD and HC. They also participated less in team sports than HC (p < 0.05). CONCLUSION: Our results suggest that individuals who develop schizophrenia in their teens may be at risk of establishing a lifestyle harmful to health. From a preventive perspective it is important to gain more knowledge about the connections between health habits and later development of disease. PMID- 26121013 TI - Lactation and the Marijuana-Using Mother. PMID- 26121014 TI - Quantification of vancomycin-resistant enterococci and corresponding resistance genes in a sewage treatment plant. AB - This study aimed to analyze vancomycin-resistant enterococci (VRE) and their resistance genes, vanA and vanB, to examine their presence in sewage treatment systems. Water samples were collected from primary sedimentation tank inlet, aeration tank, final sedimentation tank overflow outlet, and disinfection tank. Enterococcal strains were determined their vancomycin susceptibility by the minimum inhibitory concentration (MIC) test. Vancomycin-resistance genes (vanA and vanB) were quantified by real-time PCR. The sewage treatment process indeed decreased the number of most enterococci contained in the entering sewage, with a removal rate of >= 5 log. The MIC test showed that two enterococcal strains resistant to a high concentration of vancomycin (>128 MUg mL(-1)). However, most of the enterococcal strains exhibited sensitivity to vancomycin, indicating that VRE were virtually absent in the sewage treatment systems. On the other hand, vancomycin-resistance genes were detected in all the sewage samples, including those collected from the chlorination disinfection tank. The highest copy numbers of vanA (1.5 * 10(3) copies mL(-1)) and vanB (1.0 * 10(3) copies mL(-1)) were detected from the water sample of effluent water and chlorinated water, respectively. Therefore, antibiotic resistance genes remain in the sewage treatment plant and might discharged into water environments such as rivers and coastal areas. PMID- 26121015 TI - Biotechnologically obtained nanocomposites: A practical application for photodegradation of Safranin-T under UV-Vis and solar light. AB - This research was undertaken to determine the potential of biologically obtained ZnS-TiO2 nanocomposites to be used as catalysts in the photodegradation of organic pollutants, namely, Safranin-T. The photocatalysts were prepared by modifying the surface of commercial TiO2 particles with naturally produced ZnS, using sulfide species produced by sulfate-reducing bacteria and metal contaminated wastewaters. Comparative studies using powder X-ray diffraction (XRD) and scanning electron microscopy (SEM), prior and after photodegradation, were carried out in order to monitor possible structural and morphological changes on the particles. Adsorption properties and specific areas were determined by the Brunauer-Emmet-Teller (BET) method. The final solutions were characterized by UV-Vis and chemical oxygen demand (COD) content in order to determine Safranin-T concentration and toxicity. The influence of the catalyst amount, initial pH and dye concentration was also evaluated. Finally, the efficiency of the precipitates as catalysts in sunlight-mediated photodegradation was investigated, performing two scale experiments by using different volumes of dye-contaminated water (150 mL and 10 L). All tested composites showed potential to be used as photocatalysts for the degradation of Safranin-T, although the ZnS TiO2_0.06 composite (0.06 g of TiO2 per 50 mL of the zinc solution) was the most effective. This substantiates the applicability of these biologically obtained materials as efficient photocatalysts for the degradation of organic pollutants, in laboratorial conditions and under direct sunlight. PMID- 26121016 TI - Sulfamethoxazole in poultry wastewater: Identification, treatability and degradation pathway determination in a membrane-photocatalytic slurry reactor. AB - The presence of sulfamethoxazole (SMX) in a real-time poultry wastewater was identified via HPLC analysis. Subsequently, SMX removal from the poultry wastewater was investigated using a continuous-mode membrane-photocatalytic slurry reactor (MPSR). The real-time poultry wastewater was found to have an SMX concentration of 0-2.3 mg L(-1). A granular activated carbon supported TiO2 (GAC TiO2) was synthesized, characterized and used in MPSR experiments. The optimal MPSR condition, i.e., HRT ~ 125 min and catalyst dosage 529.3 mg L(-1), for complete SMX removal was found out using unconstrained optimization technique. Under the optimized condition, the effect of SMX concentration on MPSR performance was investigated by synthetic addition of SMX (i.e., 1, 25, 50, 75 and 100 mg L(-1)) into the wastewater. Interestingly, complete removals of total volatile solids (TVS), biochemical oxygen demand (BOD) and SMX were observed under all SMX concentrations investigated. However, a decline in SMX removal rate and proportionate increase in transmembrane-pressure (TMP) were observed when the SMX concentration was increased to higher levels. In the MPSR, the SMX mineralization was through one of the following degradation pathways: (i) fragmentation of the isoxazole ring and (ii) the elimination of methyl and amide moieties followed by the formation of phenyl sulfinate ion. These results show that the continuous-mode MPSR has great potential in the removal for SMX contaminated real-time poultry wastewater and similar organic micropollutants from wastewater. PMID- 26121017 TI - Plumage color and reproductive output of eastern bluebirds (Sialia sialis) nesting near a mercury-contaminated river. AB - Despite the growing evidence of mercury's impact on ecosystems, few studies have looked at the environmental impact of mercury pollution on terrestrial songbirds and the complex ways through which mercury might influence their fitness. In 2007 2008 eastern bluebirds (Sialia sialis) were monitored on mercury contaminated and reference sites for blood and feather mercury, reproductive success and plumage coloration. Higher tissue mercury accumulation was associated with plumage that was overall brighter and shifted towards the UV portion of the spectrum. In females, long-term mercury exposure, as indicated by feather mercury, was associated with smaller clutches of eggs. In males, recent mercury exposure, as indicated by blood mercury, was associated with a reduction in the proportion of hatchlings that fledged, potentially through reduced male provisioning of offspring. Reproductive success and plumage color are closely linked in bluebirds through mate choice, and our findings indicate that mercury contamination is associated with reproductive success directly and possibly indirectly, through coloration of bluebirds. PMID- 26121018 TI - Dietary exposure to, and internal organ transfer of, selected halogenated organic compounds in birds eating fish from the Southern Baltic. AB - The aim of this study was to assess the effect of a marine diet on the accumulation, magnification, maternal transfer and detoxification of chlorinated organic pollutants on the highest trophic level in the Baltic Sea. Results showed that birds eating whole herring received the highest doses of herbicides > pesticides > fungicides > polychlorinated dibenzofurans (PCDFs) > polychlorinated dibenzo-para-dioxins (PCDDs). The toxicity of PCDD/Fs in a penguin's 24-h alimentary exposure was estimated at 7.77 ng TEQ-WHO2005. Among pesticides, the highest concentrations--both in fish and penguin tissue--were those of the pp-DDE isomer. In terms of herbicides, simazine and terbutrine were predominant. The majority of Persistent Organic Pollutants (POPs) underwent accumulation and magnification, and these factors were observed to increase with the birds' age. Guano was found to be an effective means of elimination for all of the studied xenobiotics. Maternal transfer of PCDD/Fs into eggs from internal tissues was most prominent for highly chlorinated dioxins and low chlorinated furans. PMID- 26121019 TI - Evaluation of semidecentralized emergency drinking water treatment. AB - This study evaluates the potential for a novel semidecentralized approach that uses coagulant disinfectant products (CDPs) for humanitarian water treatment, by testing two commercially available products (CDP-W and CDP-T). Their performances were evaluated against the relevant water quality treatment objectives (The Sphere Project) under laboratory conditions, using a standardized testing protocol with both synthetic and natural surface test waters. Tests indicated a satisfactory performance by one of the products (CDP-W) with respect to humanitarian water quality objectives, (i.e., free chlorine residual, pH, and turbidity) that was dependent on initial water quality characteristics. Adequate bacterial inactivation (final thermotolerant coliform concentration of < 1 cfu/100 mL) was always attained and log reductions of up to 5 were achieved. The other product (CDP-T) did not exhibit any measurable coagulation and disinfection properties, indicating the variability of product quality and the need to conduct evaluations such as the ones presented in this study. Such results are of relevance to relief agencies delivering water supply interventions. PMID- 26121020 TI - Biocatalytic spectrophotometric method to detect paracetamol in water samples. AB - A biocatalytic methodology based on the quantification of the laccase inhibition during the oxidation of a standard substrate ABTS (2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) for the indirect determination of paracetamol in drinking water has been developed. The method displayed a fast response time (20 s), and high selectivity to paracetamol in presence of interfering substances such as naproxen, estradiol, ketoprofen, sulfamethoxazole, and diclofenac. The limit of detection (LOD) and limit of quantification (LOQ) were noticed to be 0.55 uM and 8.3 uM, respectively. By comparing the catalytic constants value KM and kcat for ABTS oxidation in the absence and presence of various concentrations of paracetamol, a competitive-type inhibition was disclosed. On the other hand, the close value between Ki and KM indicates similar binding affinity of the enzyme to ABTS and paracetamol corroborated by docking studies. The methodology was successfully applied to real water samples, presenting an interesting potential for further development of a biosensor to paracetamol detection. PMID- 26121021 TI - Removal of cationic dye methylene blue by zero-valent iron: Effects of pH and dissolved oxygen on removal mechanisms. AB - Effects of pH and dissolved oxygen on mechanisms for decolorization and total organic carbon (TOC) removal of cationic dye methylene blue (MB) by zero-valent iron (ZVI) were systematically examined. Decolorization and TOC removal of MB by ZVI are attributed to the four potential mechanisms, i.e. reduction, degradation, precipitation and adsorption. The contributions of four mechanisms were quantified at pH 3.0, 6.0 and 10.0 in the oxic and anoxic systems. The maximum efficiencies of decolorization and TOC removal of MB were found at pH 6.0. The TOC removal efficiencies at pH 3.0 and 10.0 were 11.0 and 17.0%, respectively which were considerably lower as compared with 68.1% at pH 6.0. The adsorption, which was favorable at higher pH but was depressed by the passive layer formed on the ZVI surface at alkaline conditions, characterized the effects of pH on decolorization and TOC removal of MB. The efficiencies of decolorization and TOC removal at pH 6.0 under the anoxic condition were 73.0 and 59.0%, respectively, which were comparable to 79.9 and 55.5% obtained under the oxic condition. In the oxic and anoxic conditions, however, the contributions of removal mechanisms were quite different. Although the adsorption dominated the decolorization and TOC removal under the oxic condition, the contribution of precipitation was largely superior to that of adsorption under the anoxic condition. PMID- 26121023 TI - The quality of reporting of randomized controlled trials. PMID- 26121022 TI - A novel cellulose-dioctyl phthate-baker's yeast biosorbent for removal of Co(II), Cu(II), Cd(II), Hg(II) and Pb(II). AB - In this work, dioctyl phthalate (Dop) was used as a highly plasticizing material to coat and link the surface of basic cellulose (Cel) with baker's yeast for the formation of a novel modified cellulose biosorbent (Cel-Dop-Yst). Characterization was accomplished by Fourier Transform Infrared Spectroscopy (FT IR), Thermogravimetric analysis (TGA) and Scanning Electron Microscope (SEM) measurements. The feasibility of using Cel-Dop-Yst biosorbent as an efficient material for removal of Co(II), Cu(II), Cd(II), Hg(II) and Pb(II) ions was explored using the batch equilibrium technique along with various experimental controlling parameters. The optimum pH values for removal of these metal ions were characterized in the range of 5.0-7.0. Cel-Dop-Yst was identified as a highly selective biosorbent for removal of the selected divalent metal ions. The Cel-Dop-Yst biosorbent was successfully implemented in treatment and removal of these divalent metal ions from industrial wastewater, sea water and drinking water samples using a multistage microcolumn technique. PMID- 26121024 TI - Noninvasive Diagnosis of Fetal Gender: Utility of Combining DYS14 and SRY. AB - OBJECTIVE: Diagnosis of fetal gender early in pregnancy is very useful as it would prevent invasive fetal sampling in almost half the cases at risk of inheriting X-linked disorders or those affecting sexual differentiation. Noninvasive prenatal diagnosis (NIPD) using circulating cell-free fetal (cff) DNA from maternal circulation has emerged as a useful alternative to existing methods for prenatal diagnosis of gender. NIPD eliminates the risk of miscarriage from invasive prenatal diagnosis and the necessity of possessing specialized obstetric skills for fetal tissue sampling. The aim of this study was to compare two Y chromosome markers-SRY and DYS14-for their utility in the diagnosis of fetal gender. SUBJECTS AND METHODS: Forty-eight plasma samples from pregnant women between 9 and 25 weeks of gestation were analyzed. Real-time polymerase chain reaction was performed on cff DNA extracted from maternal plasma to detect fetal Y chromosome with SRY (n=27) and DYS14 (n=48) markers. RESULTS: We observed 100% sensitivity and 85.6% specificity in noninvasive Y chromosome detection with the combined use of DYS14 and SRY markers (n=27) compared with the results obtained on using DYS14 (n=48 sensitivity 94%; specificity 71.4%) and SRY (n=27, sensitivity 84%; specificity 92.8%) markers alone. CONCLUSION: Our results show that the test performance improved with the employment of two Y-amplification assays. PMID- 26121025 TI - Does Tramadol Increase the Severity of Nicotine Dependence? A Study in an Egyptian Sample. AB - In Egypt, tramadol abuse is increasing, especially among youths and the middle- aged. Tobacco smoking is a worldwide health problem responsible for more deaths and disease than any other noninfectious cause. To investigate if there is a relationship between tramadol and nicotine dependence. 48 tramadol addicts completed a demographic sheet, drug use questionnaire, and the Fagerstrom Test for Nicotine Dependence (FTND). Numbers of cigarettes smoked were recorded every week or two weeks at follow-up or by phone calls, and the FTND was completed again five weeks after abstinence. All participants underwent full psychiatric assessment, plus a urine toxicology screening at first visit, and once again during follow-ups. All subjects of the study were cigarette smokers. The mean numbers of cigarettes smoked per day were 13, 31.8, 20.2, and 14.3 during the phase before tramadol taking, addiction phase, two weeks and five weeks after stopping tramadol. The mean FTND score dropped from 6.67 during the tramadol addiction phase to 4.31 only five weeks after stopping tramadol. Tramadol increases the severity of nicotine dependence. The relation seems to be bi directional, so increased cigarette smoking also increases tramadol intake. PMID- 26121026 TI - Association of Hearing Loss and Tinnitus with Health-Related Quality of Life: The Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: Hearing loss and tinnitus are global public health concerns. There have been some studies suggesting a relationship between hearing loss and tinnitus and impaired health-related quality of life (HRQoL), but there have been no large cross-sectional epidemiologic studies of a representative sample of the entire country population investigating this possible association. OBJECTIVE: The aim of this study was to investigate the relationship between hearing loss and tinnitus and HRQoL in South Korea using data from the Korea National Health and Nutrition Examination Surveys during 2010-2012. METHODS: Cross-sectional data of 11,266 adults who completed the Korea National Health and Nutrition Examination Surveys were analyzed. Subjects were divided into four groups as follows: normal hearing without tinnitus, normal hearing with tinnitus, hearing loss without tinnitus, and hearing loss with tinnitus. RESULTS: Among the population that was >=19 years of age, the prevalence of unilateral hearing loss was 9.69% and that of tinnitus in the prior 12 months was 32.76%. The hearing loss with tinnitus group had the highest percentage of subjects who responded "some or extreme problems" in all five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) of HRQoL. After adjustment for age, gender, body mass index, smoking status, alcohol intake, regular exercise, house income, education level, diabetes, hypertension, and stress level, the HRQoL odds ratios (OR) were 1.47 (95% confidence interval [CI], 1.07-2.02) for mobility, 1.59 (95% CI, 1.07-2.37) for usual activity, and 1.84 (95% CI, 1.25-2.70) for anxiety/depression in the hearing loss with tinnitus group, compared with the normal hearing without tinnitus group. The ORs for the normal hearing with tinnitus group compared with the hearing loss without tinnitus group was increased in all five dimensions of HRQoL after adjustment for confounders. CONCLUSION: Hearing loss with tinnitus has a considerable impact on HRQoL in the Korean population. In our study, the hearing loss without tinnitus group showed better a HRQoL than the normal hearing with tinnitus group. PMID- 26121027 TI - Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses. AB - Resident immune cells (e.g., macrophages [MPhis]) and airway mucus clearance both contribute to a healthy lung environment. To investigate interactions between pulmonary MPhi function and defective mucus clearance, a genetic model of lysozyme M (LysM) promoter-mediated MPhi depletion was generated, characterized, and crossed with the sodium channel beta subunit transgenic (Scnn1b-Tg) mouse model of defective mucus clearance. Diphtheria toxin A-mediated depletion of LysM(+) pulmonary MPhis in wild-type mice with normal mucus clearance resulted in lethal pneumonia in 24% of neonates. The pneumonias were dominated by Pasteurella pneumotropica and accompanied by emaciation, neutrophilic inflammation, and elevated Th1 cytokines. The incidence of emaciation and pneumonia reached 51% when LysM(+) MPhi depletion was superimposed on the airway mucus clearance defect of Scnn1b-Tg mice. In LysM(+) MPhi-depleted Scnn1b-Tg mice, pneumonias were associated with a broader spectrum of bacterial species and a significant reduction in airway mucus plugging. Bacterial burden (CFUs) was comparable between Scnn1b-Tg and nonpneumonic LysM(+) MPhi-depleted Scnn1b-Tg mice. However, the nonpneumonic LysM(+) MPhi-depleted Scnn1b-Tg mice exhibited increased airway inflammation, the presence of neutrophilic infiltration, and increased levels of inflammatory cytokines in bronchoalveolar lavage fluid compared with Scnn1b-Tg mice. Collectively, these data identify key MPhi-mucus clearance interactions with respect to both infectious and inflammatory components of muco-obstructive lung disease. PMID- 26121029 TI - Novel Functions and Regulation of Cryptic Cellobiose Operons in Escherichia coli. AB - Presence of cellobiose as a sole carbon source induces mutations in the chb and asc operons of Escherichia coli and allows it to grow on cellobiose. We previously engineered these two operons with synthetic constitutive promoters and achieved efficient cellobiose metabolism through adaptive evolution. In this study, we characterized two mutations observed in the efficient cellobiose metabolizing strain: duplication of RBS of ascB gene, (beta-glucosidase of asc operon) and nonsense mutation in yebK, (an uncharacterized transcription factor). Mutations in yebK play a dominant role by modulating the length of lag phase, relative to the growth rate of the strain when transferred from a rich medium to minimal cellobiose medium. Mutations in ascB, on the other hand, are specific for cellobiose and help in enhancing the specific growth rate. Taken together, our results show that ascB of the asc operon is controlled by an internal putative promoter in addition to the native cryptic promoter, and the transcription factor yebK helps to remodel the host physiology for cellobiose metabolism. While previous studies characterized the stress-induced mutations that allowed growth on cellobiose, here, we characterize the adaptation-induced mutations that help in enhancing cellobiose metabolic ability. This study will shed new light on the regulatory changes and factors that are needed for the functional coupling of the host physiology to the activated cryptic cellobiose metabolism. PMID- 26121028 TI - miR-155 Controls Lymphoproliferation in LAT Mutant Mice by Restraining T-Cell Apoptosis via SHIP-1/mTOR and PAK1/FOXO3/BIM Pathways. AB - Linker for Activation of T cells (LAT) is an adapter protein that is essential for T cell function. Knock-in mice with a LAT mutation impairing calcium flux develop a fatal CD4+ lymphoproliferative disease. miR-155 is a microRNA that is correlated with hyperproliferation in a number of cancers including lymphomas and leukemias and is overexpressed in mutant LAT T cells. To test whether miR-155 was merely indicative of T cell activation or whether it contributes to lymphoproliferative disease in mutant LAT mice, we interbred LAT mutant and miR 155-deficient mice. miR-155 deficiency markedly inhibited lymphoproliferative disease by stimulating BIM-dependent CD4+ T cell apoptosis, even though ERK activation and T cell proliferation were increased in double mutant CD4+ T cells. Bim/Bcl2l11 expression is activated by the forkhead transcription factor FOXO3. Using miR-155-deficient, LAT mutant T cells as a discovery tool, we found two connected pathways that impact the nuclear translocation and activation of FOXO3 in T cells. One pathway is mediated by the inositide phosphatase SHIP-1 and the serine/threonine kinases AKT and PDK1. The other pathway involves PAK1 and JNK kinase activation. We define crosstalk between the two pathways via the kinase mTOR, which stabilizes PAK1. This study establishes a role for PAK1 in T cell apoptosis, which contrasts to its previously identified role in T cell proliferation. Furthermore, miR-155 regulates the delicate balance between PAK1 mediated proliferation and apoptosis in T cells impacting lymphoid organ size and function. PMID- 26121031 TI - Correction: Examining the Predictive Validity of NIH Peer Review Scores. PMID- 26121030 TI - Patterns of MHC-G-Like and MHC-B Diversification in New World Monkeys. AB - The MHC class I (MHC-I) region in New World monkeys (Platyrrhini) has remained relatively understudied. To evaluate the diversification patterns and transcription behavior of MHC-I in Platyrrhini, we first analyzed public genomic sequences from the MHC-G-like subregion in Saimiri boliviensis, Ateles geoffroyi and Callicebus moloch, and from the MHC-B subregion in Saimiri boliviensis. While S. boliviensis showed multiple copies of both MHC-G-like (10) and -B (15) loci, A. geoffroyi and C. moloch had only three and four MHC-G-like genes, respectively, indicating that not all Platyrrhini species have expanded their MHC I loci. We then sequenced MHC-G-like and -B cDNAs from nine Platyrrhini species, recovering two to five unique cDNAs per individual for both loci classes. In two Saguinus species, however, no MHC-B cDNAs were found. In phylogenetic trees, MHC G-like cDNAs formed genus-specific clusters whereas the MHC-B cDNAs grouped by Platyrrhini families, suggesting a more rapid diversification of the former. Furthermore, cDNA sequencing in 12 capuchin monkeys showed that they transcribe at least four MHC-G-like and five MHC-B polymorphic genes, showing haplotypic diversity for gene copy number and signatures of positive natural selection at the peptide binding region. Finally, a quantitative index for MHC:KIR affinity was proposed and tested to predict putative interacting pairs. Altogether, our data indicate that i) MHC-I genes has expanded differentially among Platyrrhini species, ii) Callitrichinae (tamarins and marmosets) MHC-B loci have limited or tissue-specific expression, iii) MHC-G-like genes have diversified more rapidly than MHC-B genes, and iv) the MHC-I diversity is generated mainly by genetic polymorphism and gene copy number variation, likely promoted by natural selection for ligand binding. PMID- 26121032 TI - Technical Study of a Standalone Photovoltaic-Wind Energy Based Hybrid Power Supply Systems for Island Electrification in Malaysia. AB - Energy is one of the most important factors in the socioeconomic development of a country. In a developing country like Malaysia, the development of islands is mostly related to the availability of electric power. Power generated by renewable energy sources has recently become one of the most promising solutions for the electrification of islands and remote rural areas. But high dependency on weather conditions and the unpredictable nature of these renewable energy sources are the main drawbacks. To overcome this weakness, different green energy sources and power electronic converters need to be integrated with each other. This study presents a battery storage hybrid standalone photovoltaic-wind energy power supply system. In the proposed standalone hybrid system, a DC-DC buck-boost bidirectional converter controller is used to accumulates the surplus hybrid power in the battery bank and supplies this power to the load during the hybrid power shortage by maintaining the constant dc-link voltage. A three-phase voltage source inverter complex vector control scheme is used to control the load side voltage in terms of the voltage amplitude and frequency. Based on the simulation results obtained from MATLAB/Simulink, it has been found that the overall hybrid framework is capable of working under variable weather and load conditions. PMID- 26121033 TI - Genetic Polymorphisms Associated with Hearing Threshold Shift in Subjects during First Encounter with Occupational Impulse Noise. AB - Noise-induced hearing loss (NIHL) is the most significant occupational health issue worldwide. We conducted a genome-wide association study to identify single nucleotide polymorphisms (SNPs) associated with hearing threshold shift in young males undergoing their first encounter with occupational impulse noise. We report a significant association of SNP rs7598759 (p < 5 x 10(-7); p = 0.01 after permutation and correction; Odds Ratio = 12.75) in the gene coding for nucleolin, a multifunctional phosphoprotein involved in the control of senescence and protection against apoptosis. Interestingly, nucleolin has been shown to mediate the anti-apoptotic effect of HSP70, a protein found to prevent ototoxicity and whose polymorphisms have been associated with susceptibility to NIHL. Increase in nucleolin expression has also been associated with the prevention of apoptosis in cells undergoing oxidative stress, a well-known metabolic sequela of noise exposure. To assess the potential role of nucleolin in hearing loss, we tested down-regulation of nucleolin in cochlear sensory cells HEI-OC1 under oxidative stress conditions and report increased sensitivity to cisplatin, a chemotherapeutic drug with ototoxic side effects. Additional SNPs were found with suggestive association (p < 5 x 10(-4)), of which 7 SNPs were located in genes previously reported to be related to NIHL and 43 of them were observed in 36 other genes previously not reported to be associated with NIHL. Taken together, our GWAS data and in vitro studies reported herein suggest that nucleolin is a potential candidate associated with NIHL in this population. PMID- 26121034 TI - Combinatorial Effects of Fatty Acid Elongase Enzymes on Nervonic Acid Production in Camelina sativa. AB - Very long chain fatty acids (VLCFAs) with chain lengths of 20 carbons and longer provide feedstocks for various applications; therefore, improvement of VLCFA contents in seeds has become an important goal for oilseed enhancement. VLCFA biosynthesis is controlled by a multi-enzyme protein complex referred to as fatty acid elongase, which is composed of beta-ketoacyl-CoA synthase (KCS), beta ketoacyl-CoA reductase (KCR), beta-hydroxyacyl-CoA dehydratase (HCD) and enoyl reductase (ECR). KCS has been identified as the rate-limiting enzyme, but little is known about the involvement of other three enzymes in VLCFA production. Here, the combinatorial effects of fatty acid elongase enzymes on VLCFA production were assessed by evaluating the changes in nervonic acid content. A KCS gene from Lunaria annua (LaKCS) and the other three elongase genes from Arabidopsis thaliana were used for the assessment. Five seed-specific expressing constructs, including LaKCS alone, LaKCS with AtKCR, LaKCS with AtHCD, LaKCS with AtECR, and LaKCS with AtKCR and AtHCD, were transformed into Camelina sativa. The nervonic acid content in seed oil increased from null in wild type camelina to 6-12% in LaKCS-expressing lines. However, compared with that from the LaKCS-expressing lines, nervonic acid content in mature seeds from the co-expressing lines with one or two extra elongase genes did not show further increases. Nervonic acid content from LaKCS, AtKCR and AtHCD co-expressing line was significantly higher than that in LaKCS-expressing line during early seed development stage, while the ultimate nervonic acid content was not significantly altered. The results from this study thus provide useful information for future engineering of oilseed crops for higher VLCFA production. PMID- 26121035 TI - Sex Differences in Biological Markers of Health in the Study of Stress, Aging and Health in Russia. AB - BACKGROUND: The apparent contradiction that women live longer but have worse health than men, the so called male-female health-survival paradox, is very pronounced in Russia. The present study investigates whether men in Moscow are healthier than women at the level of biomarkers, and whether the associations between biomarkers and subjective health have sex-specific patterns. MATERIALS: Previously collected data in the study of Stress, Aging, and Health in Russia (SAHR, n = 1800) were used to examine sex differences in biomarkers and their associations with physical functioning and self-rated health. RESULTS: The present study found mixed directions and magnitudes for sex differences in biomarkers. Women were significantly disadvantaged with regard to obesity and waist circumference, whereas men had a tendency toward higher prevalence of electrocardiographic abnormalities. No sex differences were indicated in the prevalence of immunological biomarkers, and mixed patterns were found for lipid profiles. Many biomarkers were associated with physical functioning and general health. Obesity and waist circumference were related to lower physical functioning among females only, while major Q-wave abnormalities with high probabilities of myocardial infarction and atrial fibrillation or atrial flutter were associated with physical functioning and self-rated health among males only. CONCLUSION: No clear patterns of sex differences in prevalence of high-risk levels of biomarkers suggest that the male-female health-survival paradox is weaker at the level of health biomarkers. We found some evidence that certain biomarkers reflecting pathophysiological changes in the organism that do not possess acute health risks, but over many years may lead to physical disability, are associated with physical functioning and self-rated health in women, whereas others reflecting more serious life-threatening pathophysiological changes are associated with physical functioning and self-rated health in men. PMID- 26121036 TI - Elevated Intracranial Pressure and Cerebral Edema following Permanent MCA Occlusion in an Ovine Model. AB - INTRODUCTION: Malignant middle cerebral artery (MCA) stroke has a disproportionately high mortality due to the rapid development of refractory space-occupying cerebral edema. Animal models are essential in developing successful anti-edema therapies; however to date poor clinical translation has been associated with the predominately used rodent models. As such, large animal gyrencephalic models of stroke are urgently needed. The aim of the study was to characterize the intracranial pressure (ICP) response to MCA occlusion in our recently developed ovine stroke model. MATERIALS AND METHODS: 30 adult female Merino sheep (n = 8-12/gp) were randomized to sham surgery, temporary or permanent proximal MCA occlusion. ICP and brain tissue oxygen were monitored for 24 hours under general anesthesia. MRI, infarct volume with triphenyltetrazolium chloride (TTC) staining and histology were performed. RESULTS: No increase in ICP, radiological evidence of ischemia within the MCA territory but without space occupying edema, and TTC infarct volumes of 7.9+/-5.1% were seen with temporary MCAO. Permanent MCAO resulted in significantly elevated ICP, accompanied by 30% mortality, radiological evidence of space-occupying cerebral edema and TTC infarct volumes of 27.4+/-6.4%. CONCLUSIONS: Permanent proximal MCAO in the sheep results in space-occupying cerebral edema, raised ICP and mortality similar to human malignant MCA stroke. This animal model may prove useful for pre-clinical testing of anti-edema therapies that have shown promise in rodent studies. PMID- 26121038 TI - Considering the Spatial Layout Information of Bag of Features (BoF) Framework for Image Classification. AB - The spatial pooling method such as spatial pyramid matching (SPM) is very crucial in the bag of features model used in image classification. SPM partitions the image into a set of regular grids and assumes that the spatial layout of all visual words obey the uniform distribution over these regular grids. However, in practice, we consider that different visual words should obey different spatial layout distributions. To improve SPM, we develop a novel spatial pooling method, namely spatial distribution pooling (SDP). The proposed SDP method uses an extension model of Gauss mixture model to estimate the spatial layout distributions of the visual vocabulary. For each visual word type, SDP can generate a set of flexible grids rather than the regular grids from the traditional SPM. Furthermore, we can compute the grid weights for visual word tokens according to their spatial coordinates. The experimental results demonstrate that SDP outperforms the traditional spatial pooling methods, and is competitive with the state-of-the-art classification accuracy on several challenging image datasets. PMID- 26121037 TI - Combined Serum Biomarkers in Non-Invasive Diagnosis of Non-Alcoholic Steatohepatitis. AB - BACKGROUND: Non-alcoholic steatoheaptitis (NASH), the critical stage of non alcoholic fatty liver disease (NAFLD), is of chronic progression and can develop cirrhosis even hepatocellular carcinoma (HCC). However, non-invasive biomarkers for NASH diagnosis remain poorly applied in clinical practice. Our study aims at testing the accuracy of the combination of cytokeratin-18 M30 fragment (CK-18 M30), fibroblast growth factor 21 (FGF-21), interleukin 1 receptor antagonist (IL 1Ra), pigment epithelium-derived factor (PEDF) and osteoprotegerin (OPG) in diagnosing NAFLD and NASH. METHODS: 179 patients with biopsy-proven NAFLD were enrolled as training group, 91 age- and gender-matched healthy subjects were recruited at the same time as controls. 63 other NAFLD patients were separately collected as validation group. 45 alcoholic fatty liver disease (AFLD) patients, 50 hepatitis B virus (HBV) patients, 52 hepatitis C virus (HCV) patients were also included. Serum biomarker levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum levels of CK-18-M30, FGF-21, IL-1Ra and PEDF increased, while OPG decreased in a stepwise fashion in controls, non-NASH NAFLD patients and NASH patients (P < 0.01). The area under receiver-operating characteristics curve to diagnose NASH was 0.86 for CK-18-M30, 0.89 for FGF-21, 0.89 for IL-1Ra, 0.89 for PEDF and 0.89 for OPG. CK-18-M30 had 70% negative predictive value (NPV) and 79% positive predictive value (PPV) to diagnose NASH. A 5-step approach measuring CK-18-M30 followed by FGF21, IL-1Ra, PEDF and OPG gradually improved the NPV to 76% and PPV to 85%, which reached 80% and 76% respectively in the validation cohort. CONCLUSION: Compared to single biomarker, stepwise combination of CK-18-M30, FGF-21, IL-1Ra, PEDF and OPG can further improve the accuracy in diagnosing NASH. PMID- 26121039 TI - Structural Basis for the Specificity of Human NUDT16 and Its Regulation by Inosine Monophosphate. AB - Human NUDT16 is a member of the NUDIX hydrolase superfamily. After having been initially described as an mRNA decapping enzyme, recent studies conferred it a role as an "housecleaning" enzyme specialized in the removal of hazardous (deoxy)inosine diphosphate from the nucleotide pool. Here we present the crystal structure of human NUDT16 both in its apo-form and in complex with its product inosine monophosphate (IMP). NUDT16 appears as a dimer whose formation generates a positively charged trench to accommodate substrate-binding. Complementation of the structural data with detailed enzymatic and biophysical studies revealed the determinants of substrate recognition and particularly the importance of the substituents in position 2 and 6 on the purine ring. The affinity for the IMP product, harboring a carbonyl in position 6 on the base, compared to purine monophosphates lacking a H-bond acceptor in this position, implies a catalytic cycle whose rate is primarily regulated by the product-release step. Finally, we have also characterized a phenomenon of inhibition by the product of the reaction, IMP, which might exclude non-deleterious nucleotides from NUDT16 mediated hydrolysis regardless of their cellular concentration. Taken together, this study details structural and regulatory mechanisms explaining how substrates are selected for hydrolysis by human NUDT16. PMID- 26121040 TI - Native Electrophoresis-Coupled Activity Assays Reveal Catalytically-Active Protein Aggregates of Escherichia coli beta-Glucuronidase. AB - beta-glucuronidase is found as a functional homotetramer in a variety of organisms, including humans and other animals, as well as a number of bacteria. This enzyme is important in these organisms, catalyzing the hydrolytic removal of a glucuronide moiety from substrate molecules. This process serves to break down sugar conjugates in animals and provide sugars for metabolism in bacteria. While beta-glucuronidase is primarily found as a homotetramer, previous studies have indicated that the human form of the protein is also catalytically active as a dimer. Here we present evidence for not only an active dimer of the E. coli form of the protein, but also for several larger active complexes, including an octomer and a 16-mer. Additionally, we propose a model for the structures of these large complexes, based on computationally-derived molecular modeling studies. These structures may have application in the study of human disease, as several diseases have been associated with the aggregation of proteins. PMID- 26121041 TI - Identification of Burkholderia pseudomallei Near-Neighbor Species in the Northern Territory of Australia. AB - Identification and characterization of near-neighbor species are critical to the development of robust molecular diagnostic tools for biothreat agents. One such agent, Burkholderia pseudomallei, a soil bacterium and the causative agent of melioidosis, is lacking in this area because of its genomic diversity and widespread geographic distribution. The Burkholderia genus contains over 60 species and occupies a large range of environments including soil, plants, rhizospheres, water, animals and humans. The identification of novel species in new locations necessitates the need to identify the true global distribution of Burkholderia species, especially the members that are closely related to B. pseudomallei. In our current study, we used the Burkholderia-specific recA sequencing assay to analyze environmental samples from the Darwin region in the Northern Territory of Australia where melioidosis is endemic. Burkholderia recA PCR negative samples were further characterized using 16s rRNA sequencing for species identification. Phylogenetic analysis demonstrated that over 70% of the bacterial isolates were identified as B. ubonensis indicating that this species is common in the soil where B. pseudomallei is endemic. Bayesian phylogenetic analysis reveals many novel branches within the B. cepacia complex, one novel B. oklahomensis-like species, and one novel branch containing one isolate that is distinct from all other samples on the phylogenetic tree. During the analysis with recA sequencing, we discovered 2 single nucleotide polymorphisms in the reverse priming region of B. oklahomensis. A degenerate primer was developed and is proposed for future use. We conclude that the recA sequencing technique is an effective tool to classify Burkholderia and identify soil organisms in a melioidosis endemic area. PMID- 26121043 TI - Resibufogenin Induces G1-Phase Arrest through the Proteasomal Degradation of Cyclin D1 in Human Malignant Tumor Cells. AB - Huachansu, a traditional Chinese medicine prepared from the dried toad skin, has been used in clinical studies for various cancers in China. Resibufogenin is a component of huachansu and classified as bufadienolides. Resibufogenin has been shown to exhibit the anti-proliferative effect against cancer cells. However, the molecular mechanism of resibufogenin remains unknown. Here we report that resibufogenin induces G1-phase arrest with hypophosphorylation of retinoblastoma (RB) protein and down-regulation of cyclin D1 expression in human colon cancer HT 29 cells. Since the down-regulation of cyclin D1 was completely blocked by a proteasome inhibitor MG132, the suppression of cyclin D1 expression by resibufogenin was considered to be in a proteasome-dependent manner. It is known that glycogen synthase kinase-3beta (GSK-3beta) induces the proteasomal degradation of cyclin D1. The addition of GSK-3beta inhibitor SB216763 inhibited the reduction of cyclin D1 caused by resibufogenin. These effects on cyclin D1 by resibufogenin were also observed in human lung cancer A549 cells. These findings suggest that the anti-proliferative effect of resibufogenin may be attributed to the degradation of cyclin D1 caused by the activation of GSK-3beta. PMID- 26121044 TI - Comparisons and Uncertainty in Fat and Adipose Tissue Estimation Techniques: The Northern Elephant Seal as a Case Study. AB - Fat mass and body condition are important metrics in bioenergetics and physiological studies. They can also link foraging success with demographic rates, making them key components of models that predict population-level outcomes of environmental change. Therefore, it is important to incorporate uncertainty in physiological indicators if results will lead to species management decisions. Maternal fat mass in elephant seals (Mirounga spp) can predict reproductive rate and pup survival, but no one has quantified or identified the sources of uncertainty for the two fat mass estimation techniques (labeled-water and truncated cones). The current cones method can provide estimates of proportion adipose tissue in adult females and proportion fat of juveniles in northern elephant seals (M. angustirostris) comparable to labeled water methods, but it does not work for all cases or species. We reviewed components and assumptions of the technique via measurements of seven early-molt and seven late-molt adult females. We show that seals are elliptical on land, rather than the assumed circular shape, and skin may account for a high proportion of what is often defined as blubber. Also, blubber extends past the neck-to-pelvis region, and comparisons of new and old ultrasound instrumentation indicate previous measurements of sculp thickness may be biased low. Accounting for such differences, and incorporating new measurements of blubber density and proportion of fat in blubber, we propose a modified cones method that can isolate blubber from non-blubber adipose tissue and separate fat into skin, blubber, and core compartments. Lastly, we found that adipose tissue and fat estimates using tritiated water may be biased high during the early molt. Both the tritiated water and modified cones methods had high, but reducible, uncertainty. The improved cones method for estimating body condition allows for more accurate quantification of the various tissue masses and may also be transferrable to other species. PMID- 26121047 TI - Natural Occurrence of Alternaria Toxins in Wheat-Based Products and Their Dietary Exposure in China. AB - A total of 181 wheat flour and 142 wheat-based foods including dried noodle, steamed bread and bread collected in China were analyzed for alternariol (AOH), alternariol monomethyl ether (AME), tentoxin (TEN) and tenuazonic acid (TeA) by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. TeA was the predominant toxin found in 99.4% wheat flour samples at levels ranging from 1.76 MUg/kg to 520 MUg/kg. TEN was another Alternaria toxin frequently detected in wheat flour samples (97.2%) at levels between 2.72 MUg/kg and 129 MUg/kg. AOH and AME were detected in 11 (6.1%) samples at levels ranging from 16.0 MUg/kg to 98.7 MUg/kg (AOH) and in 165 (91.2%) samples with a range between 0.320 MUg/kg and 61.8 MUg/kg (AME). AOH was quantified at higher levels than AME with the ratio of AOH/AME ranging from 1.0 to 3.7. Significant linear regressions of correlation in toxin concentrations were observed between AOH and AME, AME and TeA, TEN and TeA, AOH+AME and TeA. At an average and 95th percentile, dietary exposure to AOH and AME in the Chinese general population and different age subgroups exceeded the relevant threshold value of toxicological concern (TTC), with the highest exposure found in children which deserves human health concern. TEN and TeA seem unlikely to be health concerns for the Chinese via wheat-based products but attention should be paid to synergistic or additive effects of TeA with AOH, AME, TEN and a further assessment will be performed once more data on toxicity-guided fractionation of the four toxins are available. It is necessary to conduct a systemic surveillance of Alternaria toxins in raw and processed foods in order to provide the scientific basis for making regulations on these toxins in China. PMID- 26121046 TI - Altered Interactions between the Gut Microbiome and Colonic Mucosa Precede Polyposis in APCMin/+ Mice. AB - Mutation of the adenomatous polyposis coli (APC gene), an early event in the adenoma-carcinoma sequence, is present in 70-80% of sporadic human colorectal adenomas and carcinomas. To test the hypothesis that mutation of the APC gene alters microbial interactions with host intestinal mucosa prior to the development of polyposis, culture-independent methods (targeted qPCR assays and Illumina sequencing of the 16S rRNA gene V1V2 hypervariable region) were used to compare the intestinal microbial composition of 30 six-week old C57BL/6 APCMin/+ and 30 congenic wild type (WT) mice. The results demonstrate that similar to 12 14 week old APCMin/+ mice with intestinal neoplasia, 6 week old APCMin/+ mice with no detectable neoplasia, exhibit an increased relative abundance of Bacteroidetes spp in the colon. Parallel mouse RNA sequence analysis, conducted on a subset of proximal colonic RNA samples (6 APCMin/+, 6 WT) revealed 130 differentially expressed genes (DEGs, fold change >= 2, FDR <0.05). Hierarchical clustering of the DEGs was carried out by using 1-r dissimilarity measurement, where r stands for the Pearson correlation, and Ward minimum variance linkage, in order to reduce the number of input variables. When the cluster centroids (medians) were included along with APC genotype as input variables in a negative binomial (NB) regression model, four of seven mouse gene clusters, in addition to APC genotype, were significantly associated with the increased relative abundance of Bacteroidetes spp. Three of the four clusters include several downregulated genes encoding immunoglobulin variable regions and non-protein coding RNAs. These results support the concept that mutation of the APC gene alters colonic microbial interactions prior to polyposis. It remains to be determined whether interventions directed at ameliorating dysbiosis in APCMin/+mice, such as through probiotics, prebiotics or antibiotics, could reduce tumor formation. PMID- 26121049 TI - Selective targeting of Mycobacterium smegmatis with trehalose-functionalized nanoparticles. AB - Silica and iron oxide nanoparticles with sizes ranging from 6 to 40 nm were functionalized with trehalose. The trehalose-conjugated nanoparticles showed strong interactions with Mycobacterium smegmatis (M. smegmatis) and minimal interactions with macrophage (RAW 264.7) or A549 cells. In addition, trehalose conjugated silica nanoparticles selectively interacted with M. smegmatis on M. smegmatis-treated A549 cells, demonstrating high potential of trehalose in developing targeted therapy for treating mycobacterial infection. PMID- 26121050 TI - Structured Ni catalysts on porous anodic alumina membranes for methane dry reforming: NiAl2O4 formation and characterization. AB - This communication presents the successful design of a structured catalyst based on porous anodic alumina membranes for methane dry reforming. The catalyst with a strong Ni-NiAl2O4 interaction shows both excellent activity and stability. PMID- 26121048 TI - Modelling the Abundances of Two Major Culicoides (Diptera: Ceratopogonidae) Species in the Niayes Area of Senegal. AB - In Senegal, considerable mortality in the equine population and hence major economic losses were caused by the African horse sickness (AHS) epizootic in 2007. Culicoides oxystoma and Culicoides imicola, known or suspected of being vectors of bluetongue and AHS viruses are two predominant species in the vicinity of horses and are present all year-round in Niayes area, Senegal. The aim of this study was to better understand the environmental and climatic drivers of the dynamics of these two species. Culicoides collections were obtained using OVI (Onderstepoort Veterinary Institute) light traps at each of the 5 sites for three nights of consecutive collection per month over one year. Cross Correlation Map analysis was performed to determine the time-lags for which environmental variables and abundance data were the most correlated. C. oxystoma and C. imicola count data were highly variable and overdispersed. Despite modelling large Culicoides counts (over 220,000 Culicoides captured in 354 night-traps), using on site climate measures, overdispersion persisted in Poisson, negative binomial, Poisson regression mixed-effect with random effect at the site of capture models. The only model able to take into account overdispersion was the Poisson regression mixed-effect model with nested random effects at the site and date of capture levels. According to this model, meteorological variables that contribute to explaining the dynamics of C. oxystoma and C. imicola abundances were: mean temperature and relative humidity of the capture day, mean humidity between 21 and 19 days prior a capture event, density of ruminants, percentage cover of water bodies within a 2 km radius and interaction between temperature and humidity for C. oxystoma; mean rainfall and NDVI of the capture day and percentage cover of water bodies for C. imicola. Other variables such as soil moisture, wind speed, degree days, land cover or landscape metrics could be tested to improve the models. Further work should also assess whether other trapping methods such as host-baited traps help reduce overdispersion. PMID- 26121052 TI - Nursing Staff Develop a Video to Prevent Falls: A Quality Improvement Project. AB - Many fall prevention strategies exist with some degree of effectiveness. Evidence to support 1 unique bundling of strategies is limited. The purpose of this article is to describe a staff-driven quality improvement initiative to develop a video in partnership with patients and families to prevent falls when hospitalized. Since the video's release, the fall rate has decreased by 29.4%. PMID- 26121051 TI - Late Sodium Current in Human Atrial Cardiomyocytes from Patients in Sinus Rhythm and Atrial Fibrillation. AB - Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (DeltaKPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 MUM) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27+/-0.06 pA/pF in ventricular cardiomyocytes from DeltaKPQ mice, and amounted to 0.04+/ 0.01 pA/pF and 0.09+/-0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 MUM) reduced INa,late by 0.02+/-0.02 pA/pF in SR and 0.09+/-0.02 pA/pF in AF cells. At physiological temperature (37 degrees C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated. PMID- 26121053 TI - Measuring Unfinished Nursing Care: What to Consider When Choosing and Scoring Surveys. AB - Unfinished nursing care is common in the inpatient setting and is associated with negative patient outcomes. This indicator is being assessed with increasing frequency to determine the quality of nursing services. Measurement bias was identified in this comparison of unfinished care surveys. Potential sources of bias should be considered when selecting and scoring unfinished nursing care surveys for quality assessment. PMID- 26121054 TI - Hospital Culture of Transitions in Care: Survey Development. AB - Understanding hospital culture is important to effectively manage patient flow. The purpose of this study was to develop a survey instrument that can assess a hospital's culture related to in-hospital transitions in care. Key transition themes were identified using a multidisciplinary team of experts from 3 health care systems. Candidate items were rigorously evaluated using a modified Delphi technique. Findings indicate 8 themes associated with hospital culture-mediating transitions. Forty-four items reflect the themes. PMID- 26121055 TI - Missed Nursing Care and Unit-Level Nurse Workload in the Acute and Post-Acute Settings. AB - This study replicates previous research on the nature and causes of missed nursing care and adds an explanatory variable: unit-level nurse workload (patient turnover percentage). The study was conducted in California, which legally mandates nurse staffing ratios. Findings demonstrated no significant relationship between patient turnover and missed nursing care. PMID- 26121056 TI - Facility Characteristics and Risk of Developing Pressure Ulcers in US Nursing Homes. AB - This research studied 12,507 residents in 1174 nursing homes from the 2004 National Nursing Home Survey. A multinomial logistic regression model was used to predict risk-adjusted probabilities of pressure ulcers with 4 stages. A medical director or a director of nursing on board reduced the odds of ulcers. Facilities offering clusters of beds for rehabilitation and special care programs for hospice care or behavior problems reduced the odds of stage IV ulcers. PMID- 26121057 TI - Ameliorating Effects of Biochar Derived from Poultry Manure and White Clover Residues on Soil Nutrient Status and Plant growth Promotion--Greenhouse Experiments. AB - Biochar application to agricultural soils is rapidly emerging as a new management strategy for its potential role in carbon sequestration, soil quality improvements, and plant growth promotion. The aim of our study was to investigate the effects of biochars derived from white clover residues and poultry manure on soil quality characteristics, growth and N accumulation in maize (Zea mays L.) and wheat (Triticum aestivum L.) grown in a loam soil under greenhouse conditions. Treatments comprised of: untreated control; mineral N fertilizer (urea N, UN) at the rate of 200, and 100 mg N kg(-1), white clover residues biochar (WCRB), poultry manure biochar (PMB) at 30 Mg ha(-1), and the possible combinations of WCRB+PMB (50:50), UN+WCRB (50:50), UN+PMB (50:50), and UN+WCRB+PMB (50:25:25). The treatments were arranged in a completely randomized design with three replications. Results indicated a significant increase in the growth and biomass production of maize and wheat supplemented with biochars alone or mixed with N fertilizer. Biochars treatments showed varying impact on plant growth depended upon the type of the biochar, and in general plant growth under PMB was significantly higher than that recorded under WCRB. The growth characteristics in the combined treatments (half biochar+half N) were either higher or equivalent to that recorded under full fertilizer N treatment (N200). The biochar treatments WCRB, PMB, and WCRB+PMB (50:50) increased maize shoot N by 18, 26 and 21%, respectively compared to the control while wheat shoot N did not show positive response. The N-uptake by maize treated with WCRB, PMB, and WCRB+PMB (50:50) was 54, 116, and 90 mg g(-1) compared to the 33 mg g(-1) in the control while the N-uptake by wheat was 41, 60, and 53 mg g(-1) compared to 24 mg g(-1) in the control. The mixed treatments (half biochar+half N) increased N uptake by 2.3 folds in maize and 1.7 to 2.5 folds in wheat compared to the N100 showing increasing effect of biochar on N use efficiency of applied N. Post harvest soil analysis indicated a significant increase in pH, organic matter, organic C, total N, C:N, and porosity (% pore space) by the added biochars while bulk density (BD) was significantly decreased. The organic matter content in the soil amended with biochars ranged between 19.5 and 23.2 g kg(-1) compared to 11.7 and 10.2 g kg(-1) in the control and N fertilizer treatments while the BD of biochars amended soils (WCRB, PMB, and WCRB+PMB) was 1.07, 1.17, and 1.11 g cm( 3) compared to 1.28 g cm(-1) in the control. In summary, the results of present study highlight the agronomic benefits of biochars in improving the quality of the soil, and promoting growth, yield and N accumulation of both maize and wheat with a consequent benefit to agriculture. PMID- 26121058 TI - Spectroscopic analysis and in vitro imaging applications of a pH responsive AIE sensor with a two-input inhibit function. AB - A novel terpyridine derivative formed stable aggregates in aqueous media (DMSO/H2O = 1/99) with dramatically enhanced fluorescence compared to its organic solution. Moreover, the ultra-violet absorption spectra also demonstrated specific responses to the incorporation of water. The yellow emission at 557 nm changed to a solution with intense greenish luminescence only in the presence of protons and it conformed to a molecular logic gate with a two-input INHIBIT function. This molecular-based material could permeate into live cells and remain undissociated in the cytoplasm. The new aggregation induced emission (AIE) pH type bio-probe permitted easy collection of yellow luminescence images on a fluorescent microscope. As designed, it displayed striking green emission in organelles at low internal pH. This feature enabled the self-assembled structure to have a whole new function for the pH detection within the field of cell imaging. PMID- 26121059 TI - Transcutaneous Peripheral Nerve Stimulation for Occipitalis Nerve Block. PMID- 26121060 TI - Nocturnal Glucose Metabolism in Type 1 Diabetes: A Study Comparing Single Versus Dual Tracer Approaches. AB - BACKGROUND: Understanding the effect size, variability, and underlying physiology of the dawn phenomenon is important for next-generation closed-loop control algorithms for type 1 diabetes (T1D). SUBJECTS AND METHODS: We used an iterative protocol design to study 16 subjects with T1D on individualized insulin pump therapy for two successive nights. Endogenous glucose production (EGP) rates at 3 a.m. and 7 a.m. were measured with [6,6-(2)H(2)]glucose as a single tracer, infused from midnight to 7 a.m. in all subjects. To explore possibility of tracer recycling due to prolonged [6,6-(2)H(2)]glucose infusion, which was highly probable after preplanned interim data analyses, we infused a second tracer, [6 (3)H]glucose, from 4 a.m. to 7 a.m. in the last seven subjects to measure EGP at 7 a.m. RESULTS: Cortisol concentrations increased during both nights, but changes in glucagon and insulin concentration were inconsistent. Although the plasma glucose concentrations rose from midnight to 7 a.m. during both nights, EGP measured with [6,6-(2)H(2)]glucose between 3 a.m. and 7 a.m. did not differ during Night 1 but fell in Night 2. However, EGP measured with [6-(3)H]glucose at 7 a.m. was higher than that measured with [6,6-(2)H(2)]glucose during both nights, thereby suggesting tracer recycling probably underestimating EGP calculated at 7 a.m. with [6,6-(2)H(2)]glucose. Likewise, EGP was higher at 7 a.m. with [6-(3)H]glucose than at 3 a.m. with [6,6-(2)H(2)]glucose during both nights. CONCLUSIONS: The data demonstrate a consistent overnight rise in glucose concentrations through increased EGP, mediated likely by rising cortisol concentrations. The observations with the dual tracer approach imply significant tracer recycling leading to underestimation of EGP measured by longer-duration tracer infusion. PMID- 26121061 TI - Health resource use and costs of vilazodone and other selective serotonin re uptake inhibitors in treating major depressive disorder. AB - OBJECTIVE: Selective serotonin re-uptake inhibitors (SSRIs) are widely prescribed antidepressants. This claims database study compared healthcare resource use and costs among patients with major depressive disorder (MDD) treated with vilazodone vs other SSRIs. METHODS: Adults with an MDD diagnosis and >= 1 prescription fill for vilazodone, citalopram, escitalopram, fluoxetine, paroxetine, or sertraline were identified from administrative claims data (2010-2012). Patients who concomitantly used adjunctive medication, either a second-generation antidepressant or antipsychotic, were excluded. All-cause and MDD-related healthcare resource use and costs (in 2012 USD) were compared between patients treated with vilazodone vs other SSRIs over a 6-month follow-up period using unadjusted and multivariable analyses. RESULTS: The study cohort included 49 861 patients (mean age = 44.0 years; 70% female). Compared with the vilazodone cohort (n = 3527), patients in the citalopram (n = 12 187), escitalopram (n = 8275), fluoxetine (n = 10 142), paroxetine (n = 3146), and sertraline (n = 12 584) cohorts had significantly more all-cause inpatient hospital visits, longer hospital stays and more frequent emergency department visits, following the index date, after adjusting for baseline characteristics. All-cause medical service costs (inpatient + outpatient + emergency department visits) were significantly higher across all other SSRI cohorts vs vilazodone by $758-$1165 (p < 0.05). Similarly, all-cause total costs, were significantly or numerically (non significantly) higher across all SSRI cohorts vs vilazodone by $351-$780. LIMITATIONS: The was no clinical measurement of disease severity, partial coverage of the Medicare-eligible population, and short follow-up. CONCLUSION: MDD treatment with vilazodone was associated with significantly lower rates of inpatient and emergency services, and with significantly lower all-cause medical service costs and numerically (non-significantly) lower total costs to payers than with the other SSRIs included in this study. PMID- 26121063 TI - Customised 3D Printing: An Innovative Training Tool for the Next Generation of Orbital Surgeons. AB - Additive manufacturing or 3D printing is the process by which three dimensional data fields are translated into real-life physical representations. 3D printers create physical printouts using heated plastics in a layered fashion resulting in a three-dimensional object. We present a technique for creating customised, inexpensive 3D orbit models for use in orbital surgical training using 3D printing technology. These models allow trainee surgeons to perform 'wet-lab' orbital decompressions and simulate upcoming surgeries on orbital models that replicate a patient's bony anatomy. We believe this represents an innovative training tool for the next generation of orbital surgeons. PMID- 26121062 TI - Probing DNA Stiffness through Optical Fluctuation Analysis of Plasmon Rulers. AB - The distance-dependent plasmon coupling between biopolymer tethered gold or silver nanoparticles forms the foundation for the so-called plasmon rulers. While conventional plasmon ruler applications focus on the detection of singular events in the far-field spectrum, we perform in this Letter a ratiometric analysis of the continuous spectral fluctuations arising from thermal interparticle separation variations in plasmon rulers confined to fluid lipid membranes. We characterized plasmon rulers with different DNA tethers and demonstrate the ability to detect and quantify differences in the plasmon ruler potential and tether stiffness. The influence of the nature of the tether (single-stranded versus double-stranded DNA) and the length of the tether is analyzed. The characterization of the continuous variation of the interparticle separation in individual plasmon rulers through optical fluctuation analysis provides additional information about the conformational flexibility of the tether molecule(s) located in the confinement of the deeply subdiffraction limit interparticle gap and enhances the versatility of plasmon rulers as a tool in Biophysics and Nanotechnology. PMID- 26121065 TI - Drug Discovery Goes Three-Dimensional: Goodbye to Flat High-Throughput Screening? AB - Immortalized cells, generated from two-dimensional cell culture techniques, are widely used in compound screening, lead optimization, and drug candidate selection. However, such cells lack many characteristics of cells in vivo. This could account for the high failure rates of lead candidates in clinical evaluation. New approaches from cell biology, materials science, and bioengineering are increasing the utility of three-dimensional (3D) culture. These approaches have become more compatible with automation and, thus, provide more physiologically relevant cells for high-throughput/high-content screening, notably in oncology drug discovery. Techniques range from simple 3D spheroids, comprising one or more cell types, to complex multitissue organoids cultured in extracellular matrix gels or microfabricated chips. Furthermore, each approach can be applied to stem cells, such as induced pluripotent stem cells, thereby providing additional phenotypic relevance and the exciting potential to enable screening in disease-specific cell types. PMID- 26121064 TI - A double-tuned (1) H/(23) Na resonator allows (1) H-guided (23) Na-MRI in ischemic stroke patients in one session. AB - BACKGROUND: Established imaging methods are still not confident in the determination of stroke onset. Sodium imaging in animal models and lately in humans implicates that the sodium signal intensity within the ischemic lesion increases in a time-dependent fashion. Sodium imaging usually requires a time consuming change of resonators or magnetic resonance imaging systems. To avoid this, we used a double-tuned (1) H/(23) Na birdcage head coil in combination with a protocol minimizing T1 - and T2 *-weighting effects for measurement of sodium intensity in acute stroke patients. METHODS: Multinuclear (1) H/(23) Na data sets were obtained from 16 stroke patients [75 +/- 9.9 (standard deviation) years old] 4-130 h after symptom onset. The protocol was acquired on a clinical 3T magnetic resonance imaging site using a double-tuned (1) H/(23) Na birdcage head coil. Sodium signal intensity within the lesion and homologous contralateral side was measured and compared. RESULTS: With an acquisition time of the complete magnetic resonance imaging protocol of 22 min, a nonlinear sodium signal intensity increase within the lesion over time after stroke onset was acknowledged. Onset time within six-hours showed an increase of only 8% or less, whereas onset time beyond 8.5 h demonstrated increases of 36% or more reaching a maximum of 170% > 120 h. In addition, some patients showed a difference in sodium signal intensity compared with diffusion weighted imaging lesion. CONCLUSIONS: The use of a double tuned (1) H/(23) Na birdcage head coil in a clinical setting 'allowed sodium intensity measurements' in a justifiable time also for acute stroke patients, and heterogenous sodium signal intensity in the diffusion weighted imaging lesion might represent differences in tissue damage or repair. PMID- 26121066 TI - Enhanced red upconversion emission, magnetoluminescent behavior, and bioimaging application of NaSc0.75Er0.02Yb0.18Gd0.05F4@AuNPs nanoparticles. AB - The present study reports significant enhancement in the red upconversion emission of Er(3+) in NaSc0.8Er0.02Yb0.18F4 upconversion nanoparticles (UCNPs), via a two step process, (i) codoping of Gd(3+) ion at Sc(3+) site and (ii) attaching gold nanoparticles (AuNPs) at the surface of these codoped nanostructures, and further probes the use of these Gd:UCNPs@AuNPs for bioimaging application. The Gd(3+) codoping tailors the particle size (reduces) of UCNPs and bring out Er(3+)-Yb(3+) ion pair in close proximity, which promotes the cross relaxation mechanism and boosts the population in red emitting level (4)F9/2. Further, attachment of AuNPs on the surface of UCNPs gives 2-fold advantages, that is, reduction in green band (through resonance energy transfer with efficiency 31.54%) and enhancement in red band (through plasmonic effect). It gives red to green (R/G) ratio nearly 20:1 (almost single band red UC), which is quite promising for imaging application. In addition to this, codoping of Gd(3+) enhances the magnetic moment appreciably and the obtained magnetic moment for NaSc0.75Er0.02Yb0.18Gd0.05F4 UCNPs (~1.7 emu/g) is close to the reported values for bioseparation in case of NPs. This shows the potential of the material for multimodal (optical and magnetic both) imaging application. These magnetoluminescence particles were found safe up to 1 mg/mL dose as assessed by cytotoxicity measurement in human cervical cancer (HeLa) and lung cancer (A549) cells. Ultrafine nanoparticles, transparent, and stable colloidal solution and the unique red UC emission endow these NPs as optical probe for imaging applications. PMID- 26121067 TI - 8-methoxypsoralen plus UVA (PUVA) therapy normalizes signalling of phosphorylated component of mTOR pathway in psoriatic skin of K5.hTGFbeta1 transgenic mice. PMID- 26121068 TI - Deficiency of the parathyroid hormone-related peptide nuclear localization and carboxyl terminal sequences leads to premature skin ageing partially mediated by the upregulation of p27. AB - We previously reported that deficiency of the PTHrP nuclear localization sequence (NLS) and C-terminus in PTHrP knockin (PTHrP KI) mice resulted in premature ageing of skin. P27, a cyclin-dependent kinase inhibitor, was upregulated in PTHrP KI mice and acted as a downstream target of the PTHrP NLS to regulate the proliferation of vascular smooth muscle cells. To determine the effects of p27 deficiency on premature skin ageing of PTHrP KI mice, we compared the skin phenotypes of PTHrP KI mice to those of p27 knockout (p27(-/-) ) mice and to those of double homozygous p27-deficient and PTHrP KI (p27(-/-) PTHrP KI) mice at 2 weeks age. Compared with wild-type littermates, PTHrP KI mice displayed thinner skin and decreased subcutaneous fat and collagen fibres, decreased skin cell proliferation and increased apoptosis, higher expression of p27, p19 and p53 and lower expression of cyclin E and CDK2, and increased reactive oxygen species levels and decreased antioxidant capacity. Deficiency of p27 in the PTHrP KI mice at least in part corrected the skin premature ageing phenotype resulting in thicker skin and increased subcutaneous fat and collagen. These alternations were associated with higher expression of CDK2 and cyclin E, lower expression of p19 and p53, and enhanced antioxidant capacity with increased skin cell proliferation and inhibition of apoptosis. Our results indicate that the NLS and C-terminus of PTHrP play a critical role in preventing skin from premature ageing that is partially mediated by p27. PMID- 26121069 TI - Progress in Neonatal Neurology with a Focus on Neuroimaging in the Preterm Infant. AB - There have been tremendous changes in the methods used to evaluate brain injury in the preterm infant in the past 30 years. In particular, major improvements have been made in how we use neuroimaging techniques and now magnetic resonance imaging (MRI) is used more often and considered complimentary to routine and sequential cranial ultrasound. The focus has shifted from severe lesions such as large intraventricular and parenchymal hemorrhages and cystic periventricular leukomalacia to assessing and understanding the etiology of more subtle noncystic white matter injury, punctate hemorrhage, and cerebellar lesions. The more severe lesions that dominated the early period of preterm neonatal brain imaging occur less frequently but are still associated with major disabilities, such as, cerebral palsy, while subtle white matter injury and cerebellar lesions are more often associated with cognitive and behavioral problems, which have become the most prevalent issues among the survivors of extremely preterm birth. PMID- 26121070 TI - Circulating Histones Are Major Mediators of Cardiac Injury in Patients With Sepsis. AB - OBJECTIVE: To investigate the impact of circulating histones on cardiac injury and dysfunction in a murine model and patients with sepsis. DESIGN: Prospective, observational clinical study with in vivo and ex vivo translational laboratory investigations. SETTING: General ICU and university research laboratory. SUBJECTS: Sixty-five septic patients and 27 healthy volunteers. Twelve-week-old male C57BL/6N mice. INTERVENTIONS: Serial blood samples from 65 patients with sepsis were analyzed, and left ventricular function was assessed by echocardiography. Patients' sera were incubated with cultured cardiomyocytes in the presence or absence of antihistone antibody, and cellular viability was assessed. Murine sepsis was initiated by intraperitoneal Escherichia coli injection (10(8) colony-forming unit/mouse) in 12-week-old male C57BL/6N mice, and the effect of antihistone antibody (10 mg/kg) was studied. Murine blood samples were collected serially, and left ventricular function was assessed by intraventricular catheters and electrocardiography. MEASUREMENTS AND MAIN RESULTS: Circulating histones and cardiac troponins in human and murine plasma were quantified. In 65 patients with sepsis, circulating histones were significantly elevated compared with healthy controls (n = 27) and linearly correlated with cardiac troponin T levels (rs = 0.650; p < 0.001), noradrenaline doses required to achieve hemodynamic stability (rs = 0.608; p < 0.001), Sequential Organ Failure Assessment scores (p = 0.028), and mortality (p = 0.008). In a subset of 36 septic patients without prior cardiac disease, high histone levels were significantly associated with new-onset left ventricular dysfunction (p = 0.001) and arrhythmias (p = 0.01). Left ventricular dysfunction only predicted adverse outcomes when combined with elevated histones or cardiac troponin levels. Furthermore, patients' sera directly induced histone-specific cardiomyocyte death ex vivo, which was abrogated by antihistone antibodies. In vivo studies on septic mice confirmed the cause-effect relationship between circulating histones and the development of cardiac injury, arrhythmias, and left ventricular dysfunction. CONCLUSION: Circulating histones are novel and important mediators of septic cardiomyopathy, which can potentially be utilized for prognostic and therapeutic purposes. PMID- 26121071 TI - Time to Appropriate Antibiotic Therapy Is an Independent Determinant of Postinfection ICU and Hospital Lengths of Stay in Patients With Sepsis. AB - OBJECTIVE: To assess the timing of appropriate antibiotic therapy as a determinant of postinfection hospital and ICU lengths of stay in patients with sepsis. DESIGN: Single-center retrospective cohort study (January 2008-December 2012). SETTING: One thousand two hundred fifty-bed academic hospital. PATIENTS: One thousand fifty-eight consecutive blood culture positive patients. INTERVENTIONS: We retrospectively identified adult patients with severe sepsis or septic shock. Timing of appropriate antibiotic therapy was determined from blood culture collection time to the administration of the first dose of antibiotic therapy with documented in vitro susceptibility against the identified pathogen. We constructed generalized linear models to examine the determinants of attributable lengths of stay. MEASUREMENTS AND MAIN RESULTS: The median (interquartile range) time from blood culture collection to the administration of appropriate antibiotic therapy was 6.7 hours (0.0-23.3 hr). Linear regression analysis adjusting for severity of illness and comorbid conditions identified time to appropriate antibiotic therapy to be an independent determinant of postinfection ICU length of stay (0.095-d increase per hr of time to deliver appropriate antibiotic therapy; 95% CI, 0.057-0.132 d; p < 0.001) and postinfection hospital length of stay (0.134-d increase per hr of time to deliver appropriate antibiotic therapy; 95% CI, 0.074-0.194 d; p < 0.001). Other independent determinants associated with increasing ICU length of stay and hospital length of stay were mechanical ventilation (both ICU and hospital lengths of stay) and incremental peak WBC counts (hospital length of stay only). Incremental changes in severity of illness assessed by Acute Physiology and Chronic Health Evaluation II scores and comorbidity burden assessed by the Charlson comorbidity score were independently associated with decreases in ICU length of stay and hospital length of stay. CONCLUSIONS: We identified time to appropriate antibiotic therapy in patients with sepsis to be an independent determinant of postinfection ICU and hospital lengths of stay. Clinicians should implement local strategies aimed at timely delivery of appropriate antibiotic therapy to improve outcomes and reduce length of stay. PMID- 26121072 TI - Variations in the Operational Process of Withdrawal of Life-Sustaining Therapy. AB - OBJECTIVE: The process of withdrawal of life-sustaining therapy remains poorly described in the current literature despite its importance for patient comfort and optimal end-of-life care. We conducted a structured review of the published literature to summarize patterns of withdrawal of life-sustaining therapy processes in adult ICUs. DATA SOURCES: Electronic journal databases were searched from date of first issue until April 2014. STUDY SELECTION: Original research articles describing processes of life-support therapy withdrawal in North American, European, and Australian ICUs were included. DATA EXTRACTION: From each article, we extracted definitions of withdrawal of life-sustaining therapy, descriptions and order of interventions withdrawn, drugs administered, and timing from withdrawal of life-sustaining therapy until death. DATA SYNTHESIS: Fifteen articles met inclusion criteria. Definitions of withdrawal of life-sustaining therapy varied and focused on withdrawal of mechanical ventilation; two studies did not present operational definitions. All studies described different aspects of process of life-support therapy withdrawal and measured different time periods prior to death. Staggered patterns of withdrawal of life-support therapy were reported in all studies describing order of interventions withdrawn, with vasoactive drugs withdrawn first followed by gradual withdrawal of mechanical ventilation. Processes of withdrawal of life-sustaining therapy did not seem to influence time to death. CONCLUSIONS: Further description of the operational processes of life-sustaining therapy withdrawal in a more structured manner with standardized definitions and regular inclusion of measures of patient comfort and family satisfaction with care is needed to identify which patterns and processes are associated with greatest perceived patient comfort and family satisfaction with care. PMID- 26121073 TI - The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: We sought to systematically review and meta-analyze the available data on the association between timing of antibiotic administration and mortality in severe sepsis and septic shock. DATA SOURCES: A comprehensive search criteria was performed using a predefined protocol. STUDY SELECTION: INCLUSION CRITERIA: adult patients with severe sepsis or septic shock, reported time to antibiotic administration in relation to emergency department triage and/or shock recognition, and mortality. EXCLUSION CRITERIA: immunosuppressed populations, review article, editorial, or nonhuman studies. DATA EXTRACTION: Two reviewers screened abstracts with a third reviewer arbitrating. The effect of time to antibiotic administration on mortality was based on current guideline recommendations: 1) administration within 3 hours of emergency department triage and 2) administration within 1 hour of severe sepsis/septic shock recognition. Odds ratios were calculated using a random effect model. The primary outcome was mortality. DATA SYNTHESIS: A total of 1,123 publications were identified and 11 were included in the analysis. Among the 11 included studies, 16,178 patients were evaluable for antibiotic administration from emergency department triage. Patients who received antibiotics more than 3 hours after emergency department triage (< 3 hr reference) had a pooled odds ratio for mortality of 1.16 (0.92 1.46; p = 0.21). A total of 11,017 patients were evaluable for antibiotic administration from severe sepsis/septic shock recognition. Patients who received antibiotics more than 1 hour after severe sepsis/shock recognition (< 1 hr reference) had a pooled odds ratio for mortality of 1.46 (0.89-2.40; p = 0.13). There was no increased mortality in the pooled odds ratios for each hourly delay from less than 1 to more than 5 hours in antibiotic administration from severe sepsis/shock recognition. CONCLUSION: Using the available pooled data, we found no significant mortality benefit of administering antibiotics within 3 hours of emergency department triage or within 1 hour of shock recognition in severe sepsis and septic shock. These results suggest that currently recommended timing metrics as measures of quality of care are not supported by the available evidence. PMID- 26121074 TI - Mannitol Improves Brain Tissue Oxygenation in a Model of Diffuse Traumatic Brain Injury. AB - OBJECTIVES: Based on evidence supporting a potential relation between posttraumatic brain hypoxia and microcirculatory derangements with cell edema, we investigated the effects of the antiedematous agent mannitol on brain tissue oxygenation in a model of diffuse traumatic brain injury. DESIGN: Experimental study. SETTING: Neurosciences and physiology laboratories. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were IV administered with either a saline solution (traumatic brain injury-saline group) or 20% mannitol (1 g/kg) (traumatic brain injury-mannitol group). Sham-saline and sham-mannitol groups received no insult. MEASUREMENTS AND MAIN RESULTS: Two series of experiments were conducted 2 hours after traumatic brain injury (or equivalent) to investigate 1) the effect of mannitol on brain edema and oxygenation, using a multiparametric magnetic resonance-based approach (n = 10 rats per group) to measure the apparent diffusion coefficient, tissue oxygen saturation, mean transit time, and blood volume fraction in the cortex and caudoputamen; 2) the effect of mannitol on brain tissue PO2 and on venous oxygen saturation of the superior sagittal sinus (n = 5 rats per group); and 3) the cortical ultrastructural changes after treatment (n = 1 per group, taken from the first experiment). Compared with the sham-saline group, the traumatic brain injury-saline group had significantly lower tissue oxygen saturation, brain tissue PO2, and venous oxygen saturation of the superior sagittal sinus values concomitant with diffuse brain edema. These effects were associated with microcirculatory collapse due to astrocyte swelling. Treatment with mannitol after traumatic brain injury reversed all these effects. In the absence of traumatic brain injury, mannitol had no effect on brain oxygenation. Mean transit time and blood volume fraction were comparable between the four groups of rats. CONCLUSION: The development of posttraumatic brain edema can limit the oxygen utilization by brain tissue without evidence of brain ischemia. Our findings indicate that an antiedematous agent such as mannitol can improve brain tissue oxygenation, possibly by limiting astrocyte swelling and restoring capillary perfusion. PMID- 26121075 TI - Characteristics, Outcomes, and Predictability of Critically Ill Obstetric Patients: A Multicenter Prospective Cohort Study. AB - OBJECTIVE: To evaluate pregnant/postpartum patients requiring ICUs admission in Argentina, describe characteristics of mothers and outcomes for mothers/babies, evaluate risk factors for maternal-fetal-neonatal mortality; and compare outcomes between patients admitted to public and private health sectors. DESIGN: Multicenter, prospective, national cohort study. SETTING: Twenty ICUs in Argentina (public, 8 and private, 12). PATIENTS: Pregnant/postpartum (< 42 d) patients admitted to ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred sixty-two patients were recruited, 51% from the public health sector and 49% from the private. Acute Physiology and Chronic Health Evaluation II was 8 (4-12); predicted/observed mortality, 7.6%/3.6%; hospital length of stay, 7 days (5-13 d); and fetal-neonatal losses, 17%. Public versus private health sector patients: years of education, 9 +/- 3 versus 15 +/- 3; transferred from another hospital, 43% versus 12%; Acute Physiology and Chronic Health Evaluation II, 9 (5-13.75) versus 7 (4-9); hospital length of stay, 10 days (6-17 d) versus 6 days (4-9 d); prenatal care, 75% versus 99.4%; fetal-neonatal losses, 25% versus 9% (p = 0.000 for all); and mortality, 5.4% versus 1.7% (p = 0.09). Complications in ICU were multiple-organ dysfunction syndrome (34%), shock (28%), renal dysfunction (25%), and acute respiratory distress syndrome (20%); all predominated in the public sector. Sequential Organ Failure Assessment (during first 24 hr of admission) score of at least 6.5 presented the best discriminative power for maternal mortality. Independent predictors of maternal-fetal-neonatal mortality were Acute Physiology and Chronic Health Evaluation II, education level, prenatal care, and admission to tertiary hospitals. CONCLUSIONS: Patients spent a median of 7 days in hospital; 3.6% died. Maternal-fetal-neonatal mortality was determined not only by acuteness of illness but to social and healthcare aspects like education, prenatal control, and being cared in specialized hospitals. Sequential Organ Failure Assessment (during first 24 hr of admission), easier to calculate than Acute Physiology and Chronic Health Evaluation II, was a better predictor of maternal outcome. Evident health disparities existed between patients admitted to public versus private hospitals: the former received less prenatal care, were less educated, were more frequently transferred from other hospitals, were sicker at admission, and developed more complications; maternal and fetal-neonatal mortality were higher. These findings point to the need of redesigning healthcare services to account for these inequities. PMID- 26121076 TI - Comparison of Needle Insertion and Guidewire Placement Techniques During Internal Jugular Vein Catheterization: The Thin-Wall Introducer Needle Technique Versus the Cannula-Over-Needle Technique. AB - OBJECTIVES: For needle insertion and guidewire placement during central venous catheterization, a thin-wall introducer needle technique and a cannula-over needle technique have been used. This study compared these two techniques regarding the success rates and complications during internal jugular vein catheterization. DESIGN: Prospective, randomized, controlled study. SETTING: A university-affiliated hospital. PATIENTS: Two hundred sixty-six patients scheduled for thoracic surgery, gynecologic surgery, or major abdominal surgery, who required central venous catheterization. INTERVENTIONS: Patients were randomly assigned to either the thin-wall introducer needle group (n = 134) or the cannula-over-needle group (n = 132). Central venous catheterization was performed on the right internal jugular vein under assistance with real-time ultrasonography. Needle insertion and guidewire placement were performed using a thin-wall introducer needle technique in the thin-wall introducer needle group and a cannula-over-needle technique in the cannula-over-needle group. MEASUREMENTS AND MAIN RESULTS: The guidewire placement on the first skin puncture was regarded as a successful guidewire insertion on the first attempt. The number of puncture attempts for internal jugular vein catheterization was recorded. Internal jugular vein was assessed by ultrasonography to identify complications. The rate of successful guidewire insertion on the first attempt was higher in the thin-wall introducer needle group compared with the cannula-over-needle group (87.3% vs 77.3%; p = 0.037). There were fewer puncture attempts in the thin-wall introducer needle group than in the cannula-over-needle group (1.1 +/- 0.4 vs 1.3 +/- 0.6; p = 0.026). There was no significant difference in complications of internal jugular vein catheterization between the two groups. CONCLUSIONS: The thin-wall introducer needle technique showed a superior success rate for first attempt of needle and guidewire insertion and required fewer puncture attempts during internal jugular vein catheterization. PMID- 26121077 TI - Addressing the gender gap: Prolonged exposure for PTSD in veterans. AB - As the proportion of women serving in the United States military continues to increase, more female veterans are being treated for posttraumatic stress disorder (PTSD) in Department of Veterans Affairs (VA) health care settings. Prolonged Exposure (PE) therapy is an evidence-based treatment for PTSD and is often used in VA settings. However, only a few studies have investigated the effectiveness of PE specifically for female veterans with appropriate power. Results of these studies have varied, with similar effects between female and male veterans on par with civilian effects, and more recently, better outcomes for female veterans receiving PE compared with male veterans. The current study contextualizes the evidence from those studies and considers new data regarding clinical outcomes pre- and posttreatment for a large (N = 325) sample of male and female veterans treated with PE in a PTSD specialty clinic. Results indicate a large statistically significant decrease in PTSD as measured by PTSD Checklist (PCL) scores for both male and female veterans treated with PE (d = 1.33). No difference in effectiveness and no difference in treatment completion rates were found between male and female veterans. Our findings support the effectiveness of PE for the treatment of PTSD in female as well as male veterans. Results are compared and contrasted to previous findings in the literature taking into account heterogeneity in methodological and ecological factors among the studies. Emphasis is placed on context of care issues to further the empirical conversation regarding meeting the mental health needs of female veterans. (PsycINFO Database Record PMID- 26121078 TI - Stable radicals and biochemical compounds in embryos and endosperm of wheat grains differentiating sensitive and tolerant genotypes--EPR and Raman studies. AB - The aim of this study was to uncover the specific species in grains that might differentiate the wheat genotypes according to their tolerance to oxidative stress. Measurements by EPR and Raman spectroscopy techniques were used to examine whole grains and their parts (embryo, endosperm, seed coat) originating from four wheat genotypes with differing tolerance to drought stress. Raman spectra showed that, in spite of the similar amounts of proteins in whole grains from tolerant and sensitive genotypes, in tolerant ones they were accumulated mainly in embryos. Moreover, in embryos from these grains, a higher content of unsaturated fatty acids was observed. Endosperm of grains from the tolerant genotype, richer with starch than that of sensitive one, exhibited higher content of amylopectin. Detailed analysis of EPR signals and simulation procedures of the spectra allowed the estimation of the nature of interactions of Fe(III) and Mn(II) with organic and inorganic structures of grains and the character of organic stable radicals. Three types of these radicals: carbohydrate, semiquinone and phenoxyl, were identified. The amounts of these radicals were higher in grains of sensitive genotypes, mostly because of differences in carbohydrate radical content in endosperm. Taking into account the level of radical concentration and greater capacity for radical formation in grains from plants of lower tolerance to stress, the content of radicals, especially of a carbohydrate nature, was considered as a marker of the plant resistance to stress conditions. PMID- 26121079 TI - Spermine and lutein quench chlorophyll fluorescence in isolated PSII antenna complexes. AB - Non photochemical quenching is a spontaneous mechanism that protects plants and algae from photodamage. In the last two decades, carotenoids through the xanthophylls cycle have been proposed to play a key role in quenching of chlorophyll. More recently, the involvement of endogenous polyamines in energy dependent component of non photochemical quenching has been suggested by several research groups. In the present contribution, the combined effect of spermine and the xanthophylls, zeaxanthin and lutein on the fluorescence of antenna complexes of photosystem II was tested in vitro. Lutein caused significant quenching on trimeric and monomeric antenna complexes, whereas zeaxanthin under our experimental conditions had negligible effect. Spermine has been shown to allow fluorescence quenching to be induced in isolated antenna in the absence of DeltapH and to accelerate quenching formation. The simultaneous treatment of spermine and lutein maximizes quenching even at relatively low concentrations. PMID- 26121080 TI - Sample size planning for the noninferiority or equivalence of a linear contrast with cost considerations. AB - Tests of equivalence have been used by psychological and social researchers to demonstrate the equivalence of 2 group means. However, there is a need for better methods of sample size planning if there are more than 2 groups and the aim is to carry out a linear contrast of population means, especially if cost constraints and variance heterogeneity among groups are considered. Therefore, this study presents an iterative procedure of sample size estimation for testing the linear contrast of noninferiority/superiority and equivalence, respectively, by using the proposed group size allocation ratios, especially if some group sizes are fixed at certain values. The proposed method has the advantages of minimizing total cost at the designated power or maximizing the statistical power if the total budget has a limit. Three illustrative examples show the key points of the proposed approach the effectiveness of determining sample sizes is demonstrated in terms of empirical Type I errors and power of computer simulation. Because software or applets to determine the sample size for equivalence and noninferiority/superiority testing are not widely available, the authors provide R programs for ease of use. They conclude by emphasizing the need for systematic thinking on sample size planning with regard to the related research and evaluation frameworks, and some directions for further research are also discussed. PMID- 26121082 TI - Convergence of regenerative medicine and synthetic biology to develop standardized and validated models of human diseases with clinical relevance. AB - In order to progress beyond currently available medical devices and implants, the concept of tissue engineering has moved into the centre of biomedical research worldwide. The aim of this approach is not to replace damaged tissue with an implant or device but rather to prompt the patient's own tissue to enact a regenerative response by using a tissue-engineered construct to assemble new functional and healthy tissue. More recently, it has been suggested that the combination of Synthetic Biology and translational tissue-engineering techniques could enhance the field of personalized medicine, not only from a regenerative medicine perspective, but also to provide frontier technologies for building and transforming the research landscape in the field of in vitro and in vivo disease models. PMID- 26121083 TI - Increased messenger RNA levels of the mesenchymal cadherin-11 in the peripheral blood of systemic sclerosis patients correlate with diffuse skin involvement. AB - OBJECTIVES: Cadherin-11 is a cell-cell adhesion molecule also involved in cellular migration and invasion. Experimental studies implicated this molecule in inflammatory arthritis and fibrosing conditions. Moreover, cadherin-11 protein is hyper-expressed on fibroblasts and macrophages in the skin of systemic sclerosis (SSc) patients, whereas the respective mRNA levels correlate with skin thickness. Herein, we searched for possible cadherin-11 expression also in cells that circulate in SSc peripheral blood. METHODS: Cadherin-11 mRNA was quantified by real-time reverse transcription-polymerase chain reaction in 3 ml blood samples obtained from 71 SSc patients (aged 53+/-2 years, 65 women) and 35 control non SSc patients with Raynaud's phenomenon. RESULTS: Cadherin-11 mRNA transcripts were detected in blood samples from 39% of patients with diffuse SSc, versus 16% of those with limited SSc, versus 6% and 16% of patients with idiopathic or associated with other connective tissue diseases Raynaud's phenomenon, respectively (p=0.049). Cadherin-11 mRNA levels in SSc patients were increased by 3.74-fold comparing to controls (p=0.036). By multivariate logistic regression analysis we found that diffuse skin involvement correlated, independently of age, gender, disease duration, lung involvement, digital ulcers, inflammatory indices or anti-Scl-70 autoantibody presence, with cadherin-11 mRNA positivity (p=0.028), but also with increased cadherin-11 mRNA levels (>=3-fold of non-SSc levels, p=0.011). CONCLUSIONS: Cadherin-11 may be hyper-expressed in the peripheral blood of diffuse SSc patients. Studies on the origin and possible pathogenic function of these circulating cells may shed light into the complex disease pathogenesis and further support the notion that cadherin-11 is a potential therapeutic target in SSc. PMID- 26121084 TI - Synthesis of Carbohydrate Capped Silicon Nanoparticles and their Reduced Cytotoxicity, In Vivo Toxicity, and Cellular Uptake. AB - The development of smart targeted nanoparticles (NPs) that can identify and deliver drugs at a sustained rate directly to cancer cells may provide better efficacy and lower toxicity for treating primary and advanced metastatic tumors. Obtaining knowledge of the diseases at the molecular level can facilitate the identification of biological targets. In particular, carbohydrate-mediated molecular recognitions using nano-vehicles are likely to increasingly affect cancer treatment methods, opening a new area in biomedical applications. Here, silicon NPs (SiNPs) capped with carbohydrates including galactose, glucose, mannose, and lactose are successfully synthesized from amine terminated SiNPs. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] analysis shows an extensive reduction in toxicity of SiNPs by functionalizing with carbohydrate moiety both in vitro and in vivo. Cellular uptake is investigated with flow cytometry and confocal fluorescence microscope. The results show the carbohydrate capped SiNPs can be internalized in the cells within 24 h of incubation, and can be taken up more readily by cancer cells than noncancerous cells. Moreover, these results reinforce the use of carbohydrates for the internalization of a variety of similar compounds into cancer cells. PMID- 26121081 TI - Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study. AB - IMPORTANCE: Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE: To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task dependent functional MRI, and plasma amyloid-beta (Abeta) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional measures of structural and functional MRI and plasma Abeta assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellin, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES: All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Abeta1-42 concentrations and Abeta1-42:Abeta1-40 ratios, memory encoding dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS: Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Abeta1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Abeta1-42:Abeta1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons). CONCLUSIONS AND RELEVANCE: Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Abeta1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD. PMID- 26121085 TI - Rare A2ML1 variants confer susceptibility to otitis media. AB - A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis prone European-American and Hispanic-American children but is absent in non otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media. PMID- 26121086 TI - Mutational dynamics between primary and relapse neuroblastomas. AB - Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma. PMID- 26121089 TI - Selection BIAS: Stereotypes and discrimination related to having a history of cancer. AB - Although great strides have been made in increasing equality and inclusion in organizations, a number of stigmatized groups are overlooked by diversity initiatives, including people with a history of cancer. To examine the workplace experiences of these individuals in selection contexts, we conducted 3 complementary studies that assess the extent to which cancer is disclosed, the stereotypes associated with cancer in the workplace, and discrimination resulting from these stereotypes. In a pilot study, we surveyed 196 individuals with a history of cancer (across 2 samples) about their workplace disclosure habits. In Study 1, we explored stereotypes related to employees with a history of cancer using the framework outlined by the stereotype content model. In Study 2, we used a field study to assess the experiences of job applicants who indicated they were "cancer survivors" (vs. not) with both formal and interpersonal forms of discrimination. This research shows that cancer is disclosed at relatively high rates (pilot study), those with a history of cancer are stereotyped as being higher in warmth than competence (Study 1), and the stereotypes associated with those who have had cancer result in actual discrimination toward them (Study 2). We discuss the theory behind these findings and aim to inform both science and practice with respect to this growing workplace population. PMID- 26121088 TI - The support of human genetic evidence for approved drug indications. AB - Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs. PMID- 26121087 TI - Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. AB - The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease. PMID- 26121090 TI - Accumulative job demands and support for strength use: Fine-tuning the job demands-resources model using conservation of resources theory. AB - Absenteeism associated with accumulated job demands is a ubiquitous problem. We build on prior research on the benefits of counteracting job demands with resources by focusing on a still untapped resource for buffering job demands-that of strengths use. We test the idea that employees who are actively encouraged to utilize their personal strengths on the job are better positioned to cope with job demands. Based on conservation of resources (COR) theory, we hypothesized that job demands can accumulate and together have an exacerbating effect on company registered absenteeism. In addition, using job demands-resources theory, we hypothesized that perceived organizational support for strengths use can buffer the impact of separate and combined job demands (workload and emotional demands) on absenteeism. Our sample consisted of 832 employees from 96 departments (response rate = 40.3%) of a Dutch mental health care organization. Results of multilevel analyses indicated that high levels of workload strengthen the positive relationship between emotional demands and absenteeism and that support for strength use interacted with workload and emotional job demands in the predicted way. Moreover, workload, emotional job demands, and strengths use interacted to predict absenteeism. Strengths use support reduced the level of absenteeism of employees who experienced both high workload and high emotional demands. We conclude that providing strengths use support to employees offers organizations a tool to reduce absenteeism, even when it is difficult to redesign job demands. PMID- 26121091 TI - Catching rudeness is like catching a cold: The contagion effects of low-intensity negative behaviors. AB - In this article we offer a new perspective to the study of negative behavioral contagion in organizations. In 3 studies, we investigate the contagion effect of rudeness and the cognitive mechanism that explains this effect. Study 1 results show that low-intensity negative behaviors like rudeness can be contagious, and that this contagion effect can occur based on single episodes, that anybody can be a carrier, and that this contagion effect has second-order consequences for future interaction partners. In Studies 2 and 3 we explore in the laboratory the cognitive mechanism that underlies the negative behavioral contagion effect observed in Study 1. Specifically, we show that rudeness activates a semantic network of related concepts in individuals' minds, and that this activation influences individual's hostile behaviors. In sum, in these 3 studies we show that just like the common cold, common negative behaviors can spread easily and have significant consequences for people in organizations. PMID- 26121092 TI - Constituent attachment and voluntary turnover in low-wage/low-skill service work. AB - This paper draws on life stage theory, ethnographic research conducted in the service sector, and evidence for secondary segmentation within the low-wage/low skill labor force to offer evidence that social bond development with coworkers can help reduce the high rate of turnover observed in low-wage/low-skill service work. Contrary to the belief that these employees will leave before social ties can develop, constituent attachment was found to be the only significant predictor of turnover in 2 samples of front-line service workers in a casual dining, national restaurant chain after controlling for other aspects of work that can create a sense of attachment to a job, and other job attitudes, such as satisfaction and commitment. However, the effect was dependent on developmental life stage. Constituent attachment reduced turnover among workers classified as emerging adults, whereas constituent attachment did little to affect turnover among nonemerging adults. Implications of the results are discussed with respect to the value of considering segmentation in future research on turnover in the service sector and the use of life stage theory for understanding the leaving behavior of workers in different stages of adulthood. PMID- 26121093 TI - Regulation of Unperturbed DNA Replication by Ubiquitylation. AB - Posttranslational modification of proteins by means of attachment of a small globular protein ubiquitin (i.e., ubiquitylation) represents one of the most abundant and versatile mechanisms of protein regulation employed by eukaryotic cells. Ubiquitylation influences almost every cellular process and its key role in coordination of the DNA damage response is well established. In this review we focus, however, on the ways ubiquitylation controls the process of unperturbed DNA replication. We summarise the accumulated knowledge showing the leading role of ubiquitin driven protein degradation in setting up conditions favourable for replication origin licensing and S-phase entry. Importantly, we also present the emerging major role of ubiquitylation in coordination of the active DNA replication process: preventing re-replication, regulating the progression of DNA replication forks, chromatin re-establishment and disassembly of the replisome at the termination of replication forks. PMID- 26121094 TI - OsARID3, an AT-rich Interaction Domain-containing protein, is required for shoot meristem development in rice. AB - The shoot apical meristem (SAM) produces all of the plant's aerial organs. The SAM is established either during embryogenesis or experimentally in in vitro tissue culture. Although several factors including the Class I KNOTTED1-LIKE HOMEOBOX (KNOXI) proteins, auxin, and cytokinin are known to play essential roles in SAM development, the underlying mechanisms of SAM formation and maintenance are still largely not understood. Herein we demonstrate that OsARID3, a member of the rice (Oryza sativa) AT-rich Interaction Domain (ARID) family, is required for SAM development. Disruption of OsARID3 leads to a defective SAM, early seedling lethality, and impaired capacity of in vitro shoot regeneration. We show that the expression levels of several KNOXI genes and the biosynthetic genes for auxin and cytokinin are significantly altered in the Osarid3 mutant calli. Moreover, we determine that auxin concentrations are increased, whereas cytokinin levels are decreased, in Osarid3 calli. Furthermore, chromatin immunoprecipitation results demonstrate that OsARID3 binds directly to the KNOXI gene OSH71, the auxin biosynthetic genes OsYUC1 and OsYUC6, and the cytokinin biosynthetic genes OsIPT2 and OsIPT7. We also show through electrophoretic mobility shift assays that OsARID3 specifically binds to the AT-rich DNA sequences of the identified target genes. We conclude that OsARID3 is an AT-rich specific DNA-binding protein and that it plays a major role in SAM development in rice. PMID- 26121095 TI - Limited Access to New Hepatitis C Virus Treatment Under State Medicaid Programs. PMID- 26121096 TI - Effects of Excessive Antibiotic Use in Nursing Homes. PMID- 26121098 TI - Neuroimaging, Pain Sensitivity, and Neuropsychological Functioning in School-Age Neonatal Extracorporeal Membrane Oxygenation Survivors Exposed to Opioids and Sedatives. AB - OBJECTIVES: Animal studies found negative long-term effects of exposure to sedatives and opioids in early life, especially when administered in the absence of pain. Around the world, children who require extracorporeal membrane oxygenation receive opioids and sedatives for extended periods, generally in the absence of major pain as extracorporeal membrane oxygenation cannulation is considered minor surgery. Therefore, our objective was to determine the long-term effects of extracorporeal membrane oxygenation treatment with respect to pain sensitivity, brain functioning during pain, brain morphology, and neuropsychological functioning in humans. DESIGN: Prospective follow-up study. SETTING: Level III university hospital. SUBJECTS: Thirty-six extracorporeal membrane oxygenation survivors (8.1-15.5 yr) and 64 healthy controls (8.2-15.3 yr). MEASUREMENTS AND MAIN RESULTS: We measured detection and pain thresholds, brain activity during pain (functional MRI), brain morphology (high-resolution structural MRI), and neuropsychological functioning and collected information regarding the subject's experience of chronic pain. We found a significant difference in the detection threshold for cold measured in a reaction time dependent fashion (extracorporeal membrane oxygenation group, 29.9 degrees C [SD, 1.4]; control group, 30.6 degrees C [SD, 0.8]; p < 0.01), but no differences in other modalities or in pain sensitivity between groups. Furthermore, no differences in brain activation during pain, brain morphology, or in the occurrence of chronic pain were observed. However, extracorporeal membrane oxygenation survivors performed significantly worse on a verbal memory test compared with controls (p = 0.001). CONCLUSIONS: While the most critically ill newborns receive extracorporeal membrane oxygenation and, relatedly, large doses of opioids and sedatives for extended periods, global measures of pain sensitivity and neurobiological and neuropsychological development appear to have minor long-term consequences. Possible memory deficits in extracorporeal membrane oxygenation survivors require additional study, but neonatal extracorporeal membrane oxygenation treatment and associated exposure to opioids and sedatives seem less harmful to humans than expected from animal studies. PMID- 26121097 TI - Detection of Multiple Respiratory Viruses Associated With Mortality and Severity of Illness in Children. AB - OBJECTIVE: Respiratory viral infection is a common source of morbidity and mortality in children. Coinfection with multiple viruses occurs frequently; however, the clinical significance of concomitant viral pathogens is unclear. We hypothesized that presence of more than one respiratory virus is associated with increased morbidity and mortality when compared with children with a single respiratory virus. DESIGN: Retrospective cohort study. SETTING: A tertiary care hospital. PATIENTS: All children at Duke Children's Hospital over a 2-year period with isolation of a virus on an extended viral respiratory panel result. Demographic data, comorbidities, and details of hospital encounter were recorded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred thirty-five hospital encounters demonstrated positive extended viral respiratory panels. Immunocompromised status (37%) and respiratory comorbidities (23%) were common. Twenty-eight patients (12%) tested positive for multiple viruses, with adenovirus (23/28) and respiratory syncytial virus (15/28) most prevalent in patients with multiple viruses. Viral codetection was associated with increased use of noninvasive ventilation (p = 0.02), extracorporeal membrane oxygenation (p = 0.02), increased likelihood of moderate or severe illness (p = 0.005), and increased mortality (p = 0.01). Subgroup analysis demonstrated that this mortality association persisted for children with normal immune function (p = 0.003) and children with no comorbidities (p = 0.007). CONCLUSIONS: Children with multiple respiratory viruses may be at increased risk of moderate or severe illness and mortality, with previously healthy children potentially being at greatest risk. Further studies are indicated to determine the significance and generalizability of this finding and to better understand the pathophysiology of viral coinfection. PMID- 26121099 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin Predicts Renal Injury Following Extracorporeal Membrane Oxygenation. AB - OBJECTIVE: To evaluate the course of urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule-1 levels in young children during extracorporeal membrane oxygenation and concomitant continuous hemofiltration. Furthermore, to evaluate whether these levels predict outcome. DESIGN: Prospective observational cohort study from July 2010 to July 2013. SETTING: ICU of a level III university children's hospital. PATIENTS: Thirty-one extracorporeal membrane oxygenation-treated children up to 1 year were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were weaned from extracorporeal membrane oxygenation after a median of 162 hours (interquartile range, 83-304). Throughout the study, 58% of the patients met the criteria for acute kidney injury (i.e., Risk Injury Failure Loss End-Stage Renal Disease-Risk or higher defined as an increase in serum creatinine corresponding to >= 150% when compared with age-specific reference values). Levels of both biomarker patterns changed significantly throughout extracorporeal membrane oxygenation (urinary neutrophil gelatinase-associated lipocalin, p < 0.001 and urinary kidney injury molecule-1, p = 0.005, linear mixed model analyses). Urinary neutrophil gelatinase-associated lipocalin levels were already high before extracorporeal membrane oxygenation, whereas urinary kidney injury molecule-1 levels increased throughout the first extracorporeal membrane oxygenation day and peaked at 12-24 hours. Also, urinary neutrophil gelatinase-associated lipocalin levels at 12-24 hours of extracorporeal membrane oxygenation therapy were higher among patients with acute kidney injury post extracorporeal membrane oxygenation (p = 0.002, Mann-Whitney U test). Biomarker levels did not differ between survivors and nonsurvivors. CONCLUSIONS: The increased urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule-1 levels confirm that renal tubular damage occurs in critically ill infants in need of extracorporeal membrane oxygenation. The fact that the maximal urinary neutrophil gelatinase-associated lipocalin levels were measured 24 hours earlier than urinary kidney injury molecule-1 supports the use of biomarker combinations rather than a single biomarker to identify patients at risk of acute kidney injury. Finally, since urinary neutrophil gelatinase-associated lipocalin levels at 12-24 hours of extracorporeal membrane oxygenation therapy were associated with acute kidney injury post extracorporeal membrane oxygenation, this marker may facilitate more timely adjustment of therapeutic interventions. PMID- 26121100 TI - Evidence-Based Pediatric Outcome Predictors to Guide the Allocation of Critical Care Resources in a Mass Casualty Event. AB - OBJECTIVE: ICU resources may be overwhelmed by a mass casualty event, triggering a conversion to Crisis Standards of Care in which critical care support is diverted away from patients least likely to benefit, with the goal of improving population survival. We aimed to devise a Crisis Standards of Care triage allocation scheme specifically for children. DESIGN: A triage scheme is proposed in which patients would be divided into those requiring mechanical ventilation at PICU presentation and those not, and then each group would be evaluated for probability of death and for predicted duration of resource consumption, specifically, duration of PICU length of stay and mechanical ventilation. Children will be excluded from PICU admission if their mortality or resource utilization is predicted to exceed predetermined levels ("high risk"), or if they have a low likelihood of requiring ICU support ("low risk"). Children entered into the Virtual PICU Performance Systems database were employed to develop prediction equations to assign children to the exclusion categories using logistic and linear regression. Machine Learning provided an alternative strategy to develop a triage scheme independent from this process. SETTING: One hundred ten American PICUs SUBJECTS: : One hundred fifty thousand records from the Virtual PICU database. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The prediction equations for probability of death had an area under the receiver operating characteristic curve more than 0.87. The prediction equation for belonging to the low-risk category had lower discrimination. R for the prediction equations for PICU length of stay and days of mechanical ventilation ranged from 0.10 to 0.18. Machine learning recommended initially dividing children into those mechanically ventilated versus those not and had strong predictive power for mortality, thus independently verifying the triage sequence and broadly verifying the algorithm. CONCLUSION: An evidence-based predictive tool for children is presented to guide resource allocation during Crisis Standards of Care, potentially improving population outcomes by selecting patients likely to benefit from short-duration ICU interventions. PMID- 26121101 TI - Pilot Randomized Trials in Pediatric Critical Care: A Systematic Review. AB - OBJECTIVES: Pilot trials are smaller randomized controlled trials conducted to inform the design and assess the feasibility of a large-scale trials. The objectives of this systematic review were to describe pilot trials in pediatric critical care, their conclusions about the clinical implications of the results, and the need for future research and to determine the frequency of large follow up trials. DATA SOURCES: The Evidence in Pediatric Intensive Care database (http://epicc.mcmaster.ca), a comprehensive repository of published pediatric critical care randomized controlled trials and the World Health Organization's Clinical Trials Registry Platform. STUDY SELECTION: Randomized controlled trials described in the publication as "pilot," "feasibility," "proof-of-concept," "exploratory," "phase 2," "vanguard," or "preliminary." DATA EXTRACTION: Pairs of reviewers screened studies for eligibility and abstracted data independently. DATA SYNTHESIS: We found 32 pilot trials (12.2% of all pediatric critical care randomized controlled trials) published before July 2014, varying in size from 6 to 165 children. Pilot trials were significantly smaller than those not described as pilots, but other key characteristics were not significantly different. The authors of 16 publications (48.4%) included explicit and specific conclusions about the design or feasibility of larger trials based on the results of the pilot trial. In 20 publications (64.5%), the authors made conclusions about clinical efficacy based on results of the pilot trial. Four of the 32 pilot trials (12.9%) led to larger trials, two of which have been published. CONCLUSIONS: Published pilot trials in pediatric critical care often focus on clinical outcomes. They uncommonly report explicit feasibility outcomes, criteria for success, or rationale for the pilot sample size. These pilot trials infrequently lead to larger trials. Understanding and addressing the reasons for this are key to the success of pediatric critical care research. PMID- 26121102 TI - Comparison of hepatic arterial infusion chemotherapy versus sorafenib monotherapy in patients with advanced hepatocellular carcinoma. AB - OBJECTIVES: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and those refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). The application of sorafenib has been approved by the Japanese Government-sponsored Medicare for unresectable HCC. In this retrospective cohort study we aimed to compare various aspects of HAIC with sorafenib in the treatment of Child-Pugh A patients with advanced HCC who were otherwise free of extrahepatic metastasis. METHODS: Altogether 177 patients with advanced HCC at Child-Pugh class A who were free of extrahepatic metastasis were retrospectively enrolled. The patients were divided into the HAIC group (n = 136) and the sorafenib group (n = 41), and were followed up until their death or withdrawal of therapy. Responses to treatment and overall survival were determined and compared between the two groups. RESULTS: The proportion of patients with complete response, partial response, stable disease and progressive disease were 5.9%, 25.0%, 40.4% and 21.3% in the HAIC and 2.4%, 2.4%, 43.9% and 41.5% in the sorafenib group, respectively. The response rate was higher in the HAIC group than in the sorafenib group (30.9% vs 4.8%). The median survival time was 10 months in both HAIC and sorafenib groups. In patients with macroscopic vascular invasion (MVI) by the case-control method, the response rate was higher in the HAIC group than in the sorafenib group. Overall survival was longer in the HAIC group than in the sorafenib group (14 months vs 7 months, P = 0.005). Multivariate analysis identified MVI (hazard ratio 2.4, P = 0.018) as an independent prognostic factor of survival in the sorafenib group. CONCLUSIONS: Response rate to HAIC was higher than that to sorafenib monotherapy. Prognosis was favorable in HAIC responders despite MVI. HAIC might be a potential treatment option for advanced HCC without extrahepatic metastasis. PMID- 26121104 TI - Polysiloxane-based block copolymers with marine bacterial anti-adhesion properties. AB - Di- and triblock copolymers based on tert-butyldimethylsilyl methacrylate (MASi) and poly(dimethylsiloxane) (PDMS) macro-RAFT agents were synthesized resulting in copolymers with predictable molar masses and low dispersities (D < 1.2). The block copolymers exhibited two glass transition temperatures, corresponding to the PDMS- and poly(tert-butyldimethylsilyl methacrylate) (PMASi)-enriched phases, respectively. Contact angle measurements revealed the influence of the copolymer composition on their surface free energy, with block copolymers exhibiting surface free energies as low as 15.0 mJ m(-2). A laboratory assay using 96-well plates was used to assess the activity of the block copolymers against two marine bacteria (Pseudoalteromonas sp. and Shewanella sp.) isolated from the Mediterranean Sea. Coatings based on PDMS-based block copolymers demonstrated anti-adhesive performances against the two strains better than that of the coating containing only PMASi-based polymers. Coatings based on diblock copolymers demonstrated antifouling performances in the field that were better than those of the corresponding coatings containing triblock copolymers. Results of both lab and field assays showed that the antifouling properties were related to coatings possessing the highest receding water contact angle. PMID- 26121103 TI - Design of Environmentally Responsive Fluorescent Polymer Probes for Cellular Imaging. AB - We report the development of environmentally responsive fluorescent polymers. The reversible temperature-induced phase transition of copolymers composed of N isopropylacrylamide and a fluorescent monomer based on the fluorescein (FL), coumarin (CO), rhodamine (RH), or dansyl (DA) skeleton was used as a molecular switch to control the fluorescence intensity. The poly(N-isopropylacrylamide) (PNIPAAm) chain showed an expanded coil conformation below the lower critical solution temperature (LCST) due to hydration, but it changed to a globular form above the LCST due to dehydration. Through the combination of a polarity sensitive fluorophore with PNIPAAm, the synthetic fluorescent polymer displayed a response to external temperature, with the fluorescence strength dramatically changing close to the LCST. Additionally, the P(NIPAAm-co-FL) and P(NIPAAm-co-CO) polymers, containing fluorescein and coumarin groups, respectively, exhibited pH responsiveness. The environmental responsiveness of the reported polymers is derived directly from the PNIPAAm and fluorophore structures, thus allowing for the cellular uptake of the fluorescence copolymer by RAW264.7 cells to be temperature-controlled. Cellular uptake was suppressed below the LCST but enhanced above the LCST. Furthermore, the cellular uptake of both P(NIPAAm-co-CO) and P(NIPAAm-co-RH) conjugated with a fusogenic lipid, namely, l-alpha phosphatidylethanolamine, dioleoyl (DOPE), was enhanced. Such lipid-conjugated fluorescence probes are expected to be useful as physiological indicators for intracellular imaging. PMID- 26121105 TI - Why the 'last drinking occasion' approach to measuring alcohol consumption should be avoided. AB - INTRODUCTION AND AIMS: There has been debate about which type of measurement instrument gives the best alcohol consumption estimates. This study used alcohol consumption data for a simulated population to compare the last drinking occasion (LDO) method against the true alcohol consumption. The LDO method requires respondents to indicate the quantity consumed at the LDO, and this information is used to calculate population estimates. DESIGN AND METHODS: We simulated three hypothetical distributions of alcohol consumption, each with different underlying drinking patterns and each representing an idealised example of the distribution of alcohol consumption in Norway, Russia and France under specified conditions. We investigated the level of agreement between LDO consumption and the within person average consumption, and the expected bias that arises when parameters of interest such as means, percentiles, exceedance proportions, differences in group means, correlation and regression coefficients, attributable fractions, and estimated disease risk functions, are calculated from LDO consumption. RESULTS: Severe bias was found when LDO consumption was used to calculate common parameters of interest in alcohol and health research. The bias is caused by poor agreement between consumption at the LDO and the within-person 'true' or average consumption. The asymptotically expected bias is particularly problematic because it is unpredictable in terms of direction and magnitude, it varies across groups and populations, and it is probably impossible to adjust for. DISCUSSION AND CONCLUSION: Future data collections should avoid relying on the LDO method as a measure of typical alcohol consumption, despite its ease of administration. [Osthus S, Brunborg GS. Why the 'last drinking occasion' approach to measuring alcohol consumption should be avoided. Drug Alcohol Rev 2015;34:549-58]. PMID- 26121106 TI - Second allogeneic hematopoietic stem cell transplantation in children with severe aplastic anemia. AB - The outcome of 55 children with severe aplastic anemia (SAA) who received a second hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed using the registration data of the Japanese Society for Hematopoietic Cell Transplantation. The 5-year overall survival (OS) and failure-free survival (FFS) after the second transplantation were 82.9% (95% confidence interval (CI), 69.7-90.8)) and 81.2% (95% CI, 67.8-89.4), respectively. FFS was significantly better when the interval between the first and second transplantation was >60 days (88.9%; 95% CI, 73.0-95.7) than when it was ?60 days (61.4%; 95% CI, 33.3 80.5; P=0.026). All 12 patients who were conditioned with regimens containing fludarabine and melphalan were alive with hematopoietic recovery. These findings justify the recommendation of a second HSCT for children with SAA who have experienced graft failure after first HSCT. PMID- 26121107 TI - Autologous hematopoietic stem cell transplant induces the molecular aging of T cells in multiple myeloma. PMID- 26121108 TI - Salvage bortezomib-dexamethasone and high-dose melphalan (HDM) and autologous stem cell support (ASCT) in myeloma patients at first relapse after HDM with ASCT. A phase-2 trial. AB - Until recently, only retrospective studies had been published on salvage high dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naive patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naive patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment. PMID- 26121109 TI - Outcomes of patients with therapy-related AML/myelodysplastic syndrome (t AML/MDS) following hematopoietic cell transplantation. AB - We studied outcomes of 65 consecutive patients with therapy-related AML/myelodyplastic syndrome (t-AML/MDS) who underwent allogeneic hematopoietic cell transplantation (HCT). Previously published scores of HCT-CI, CIBMTR, EBMT and Comorbidity-age index were also evaluated. Median follow-up of survivors was 72 months (range 16-204). At 2 years, overall survival (OS) was 34% (95% confidence interval (CI) 23-45). Nineteen patients (29%) had monosomal karyotype (MK). Patients with MK had an OS of 21% (95% CI 7-41) at 2 years. Abnormal adverse cytogenetics, unrelated donor, bone marrow graft and CIBMTR score were significant risk factors for OS on univariate analysis. On multivariate analysis, abnormal adverse cytogenetics (hazard ratio (HR) 2.7; 95% CI 1.02-7.2; P value=0.02) and unrelated donor (HR 2.7; 95% CI 1.5-5.0; P-value=0.0013) were independent factors for survival. Non-relapse mortality (NRM) at 2 years was 31% (95% CI 15-47). Donor type was the only factor that was significant for NRM with matched related donors having an NRM of 20% (95% CI 0-42) whereas unrelated donors had NRM of 60% (95% CI 40-80; P-value=0.0007). In conclusion, patients with t-AML/MDS have poor OS. Unrelated donor is a significant risk factor for both higher NRM and decreased OS. Cytogenetics are predictive for OS. PMID- 26121110 TI - Successful management of cutaneous BCG dissemination in a child affected by SCID and receiving allogeneic hematopoietic stem cell transplant. PMID- 26121111 TI - Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation. AB - In vivo T-cell depletion with anti-thymocyte globulin (ATG) can attenuate GvHD but may increase infection and relapse risks. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg was standard GvHD prophylaxis in unrelated donor hematopoietic stem cell transplantation (HSCT) at our institution. We changed to an incremental reduced dose regimen of 35 mg/kg and extended ATG prophylaxis to include older matched related donor transplants considered to be at higher risk of GvHD. A total of 265 adults with hematological malignancies receiving a first allogeneic HSCT after myeloablative conditioning between 2009 and 2014 were analyzed in this cohort study. Patients had either received higher dose (n=32) or lower dose ATG-F (n=88) or no ATG (n=145). ATG-F was associated with slower engraftment and less chronic GvHD, whereas no effect was noted on acute grade II-IV GvHD and relapse incidence. Transplant-related mortality (TRM) was lower and survival higher with lower dose, but not with higher dose ATG-F. Both ATG-F groups were associated with more viral reactivation, viral disease and bacterial blood stream infection, but not invasive fungal infection, and with slower immune reconstitution. The recently adopted strategy of using lower doses of ATG-F in unrelated and older age-related donor HSCT appears to reduce TRM without increasing disease relapse, leading to slightly enhanced survival. PMID- 26121112 TI - Human herpesvirus 6B reactivation and delirium are frequent and associated events after cord blood transplantation. AB - Human herpesvirus 6B (HHV-6B) frequently reactivates after cord blood transplantation (CBT). We previously reported an association between HHV-6B reactivation and delirium after hematopoietic cell transplantation. In this prospective study, 35 CBT recipients underwent twice-weekly plasma PCR testing for HHV-6 and thrice-weekly delirium assessment until day 84. There was a quantitative association between HHV-6B reactivation and delirium in univariable (odds ratio, 2.88; 95% confidence interval (CI), 0.97-8.59) and bivariable models. In addition, intensified prophylaxis with high-dose valacyclovir mitigated HHV-6B reactivation (adjusted hazard ratio, 0.39; 95% CI, 0.14-1.08). Larger trials are needed to explore the utility of HHV-6B prophylaxis after CBT. PMID- 26121113 TI - 3D-Printed Artificial Microfish. AB - Hydrogel microfish featuring biomimetic structures, locomotive capabilities, and functionalized nanoparticles are engineered using a rapid 3D printing platform: microscale continuous -optical printing (MUCOP). The 3D-printed -microfish exhibit chemically powered and magnetically guided propulsion, as well as highly efficient detoxification capabilities that highlight the technical versatility of this platform for engineering advanced functional microswimmers for diverse biomedical applications. PMID- 26121114 TI - Development of Prediction Models for the Reactivity of Organic Compounds with Ozone in Aqueous Solution by Quantum Chemical Calculations: The Role of Delocalized and Localized Molecular Orbitals. AB - Second-order rate constants (kO3) for the reaction of ozone with micropollutants are essential parameters for the assessment of micropollutant elimination efficiency during ozonation in water and wastewater treatment. Prediction models for kO3 were developed for aromatic compounds, olefins, and amines by quantum chemical molecular orbital calculations employing ab initio Hartree-Fock (HF) and density functional theory (B3LYP) methods. The kO3 values for aromatic compounds correlated well with the energy of a delocalized molecular orbital first appearing on an aromatic ring (i.e., the highest occupied molecular orbital (HOMO) or HOMO-n (n >= 0) when the HOMO is not located on the aromatic ring); the number of compounds tested (N) was 112, and the correlation coefficient (R(2)) values were 0.82-1.00. The kO3 values for olefins and amines correlated well with the energy of a localized molecular orbital (i.e., the natural bond orbital (NBO)) energy of the carbon-carbon pi bond of olefins (N = 45, R(2) values of 0.82-0.85) and the NBO energy of the nitrogen lone-pair electrons of amines (N = 59, R(2) values of 0.81-0.83), respectively. Considering the performance of the kO3 prediction model and the computational costs, the HF/6-31G method is recommended for all aromatic groups and olefins investigated herein, whereas the HF/MIDI!, HF/6-31G*, or HF/6-311++G** methods are recommended for amines. Based on their mean absolute errors, the above models could predict kO3 within a factor of 4, on average, relative to the experimentally determined values. Overall, good correlations were also observed (R(2) values of 0.77-0.96) between kO3 predictions by quantum molecular orbital descriptors in this study and by the Hammett (sigma) and Taft (sigma*) constants from previously developed quantitative structure-activity relationship (QSAR) models. Hence, the quantum molecular orbital descriptors are an alternative to sigma and sigma*-values in QSAR applications and can also be utilized to estimate unknown sigma or sigma* values. . PMID- 26121115 TI - Dressings and topical agents for arterial leg ulcers. AB - BACKGROUND: It is estimated that people in industrialised countries have a 1% chance of suffering from a leg ulcer at some time in their life. The majority of leg ulcers are associated with circulation problems; poor blood return in the veins causes venous ulcers (around 70% of ulcers) and poor blood supply to the legs causes arterial ulcers (around 22% of ulcers). Treatment of arterial leg ulcers is directed towards correcting the poor arterial blood supply, for example by correcting arterial blockages (either surgically or pharmaceutically). If the blood supply has been restored, these arterial ulcers can heal following principles of good wound care. Dressings and topical agents make up a part of good wound care for arterial ulcers but there are many products available and it is unclear what impact these have on ulcer healing. This is an update of a review first published in 2003. OBJECTIVES: To determine whether topical agents and wound dressings affect healing in arterial ulcers. To compare healing rates, patient-centred outcomes and costs between wound dressings and topical agents. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2014) and The Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library) (2014, Issue 10). SELECTION CRITERIA: Randomised controlled trials (RCTs), or controlled clinical trials (CCTs) evaluating dressings and topical agents in the treatment of arterial leg ulcers were eligible for inclusion. The participants had to have ulcers that were described as arterial, and the time to healing, proportion completely healed, or rate of reduction in ulcer area had to be reported. All wound dressings and topical agents were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The two review authors independently extracted information on the participants' characteristics, the interventions, and outcomes using a standardised data extraction form. Disagreements between the review authors were resolved through discussion. MAIN RESULTS: One trial met the inclusion criteria, which was a small trial that compared 2% ketanserin ointment in polyethylene glycol (PEG) with vehicle alone (PEG) control, changed twice a day in 40 participants with arterial leg ulcers. The overall quality of the evidence was low with a single small included study which showed inadequate reporting of the results and had too short a follow-up time (eight weeks) to be able to capture sufficient healing events to allow comparisons to be made. In addition, the study was of low methodological quality. The majority of the 'risk of bias' domains received an 'unclear' risk rating as very little information was provided in the text on the methods of the study. The trial demonstrated increased wound healing in the ketanserin group, compared with the control group, but the trial was too small and had too short a follow-up period (eight weeks) to be able to determine whether there was any difference in healing rates. It should also be noted that ketanserin is not licensed in all countries for use in humans. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether the choice of topical agent or dressing affects the healing of arterial leg ulcers. PMID- 26121116 TI - Positional Isomers of Tetramethoxypyrene-based Mono- and Biradicals. AB - The positional isomers of tert-butylnitroxide (NO) substituted 4,5,9,10 tetramethoxypyrene-based mono- and biradical are synthesized. While the biradical 2,7-TMPNO in which two NO radical moieties are attached at the nodal plane of pyrene adopts a semiquinoid structure, the 1,6- and 1,8-isomers of the same exist in biradical form. The tuning of the antiferromagnetic exchange interactions is achieved by synthesizing the positional isomers of the biradical while maintaining the same radical moiety as well as the pi spacer. PMID- 26121117 TI - Inactivation of Human Nevus Tissue Using High Hydrostatic Pressure for Autologous Skin Reconstruction: A Novel Treatment for Giant Congenital Melanocytic Nevi. AB - Giant congenital melanocytic nevi are intractable lesions associated with a risk of melanoma. High hydrostatic pressure (HHP) technology is a safe physical method for producing decellularized tissues without chemicals. We have reported that HHP can inactivate cells present in various tissues without damaging the native extracellular matrix (ECM). The objectives of this study were to inactivate human nevus tissue using HHP and to explore the possibility of reconstructing skin using inactivated nevus in combination with cultured epidermis (CE). Human nevus specimens 8 mm in diameter were pressurized by HHP at 100, 200, 500, and 1000 MPa for 10 min. The viability of specimens just after HHP, outgrowth of cells, and viability after cultivation were evaluated to confirm the inactivation by HHP. Histological evaluation using hematoxylin-eosin staining and immunohistochemical staining for type IV collagen was performed to detect damage to the ECM of the nevus. The pressurized nevus was implanted into the subcutis of nude mice for 6 months to evaluate the retention of human cells. Then, human CE was applied on the pressurized nevus and implanted into the subcutis of nude mice. The viability of pressurized nevus was not detected just after HHP and after cultivation, and outgrowth of fibroblasts was not observed in the 200, 500, and 1000 MPa groups. Human cells were not observed after 6 months of implantation in these groups. No apparent damage to the ECM was detected in all groups; however, CE took on nevus in the 200 and 500 MPa groups, but not in the 1000 MPa group. These results indicate that human nevus tissue was inactivated by HHP at more than 200 MPa; however, HHP at 1000 MPa might cause damage that prevents the take of CE. In conclusion, all cells in nevus specimens were inactivated after HHP at more than 200 MPa and this inactivated nevus could be used as autologous dermis for covering full-thickness skin defects after nevus removal. HHP between 200 and 500 MPa will be optimal to reconstruct skin in combination with cultured epidermal autograft without damage to the ECM. PMID- 26121118 TI - Localized Excitation of Ti(3+) Ions in the Photoabsorption and Photocatalytic Activity of Reduced Rutile TiO2. AB - In reduced TiO2, electronic transitions originating from the Ti(3+)-induced states in the band gap are known to contribute to the photoabsorption, being in fact responsible for the material's blue color, but the excited states accessed by these transitions have not been characterized in detail. In this work we investigate the excited state electronic structure of the prototypical rutile TiO2(110) surface using two-photon photoemission spectroscopy (2PPE) and density functional theory (DFT) calculations. Using 2PPE, an excited resonant state derived from Ti(3+) species is identified at 2.5 +/- 0.2 eV above the Fermi level (EF) on both the reduced and hydroxylated surfaces. DFT calculations reveal that this excited state is closely related to the gap state at ~1.0 eV below EF, as they both result from the Jahn-Teller induced splitting of the 3d orbitals of Ti(3+) ions in reduced TiO2. Localized excitation of Ti(3+) ions via 3d -> 3d transitions from the gap state to this empty resonant state significantly increases the TiO2 photoabsorption and extends the absorbance to the visible region, consistent with the observed enhancement of the visible light induced photocatalytic activity of TiO2 through Ti(3+) self-doping. Our work reveals the physical origin of the Ti(3+) related photoabsorption and visible light photocatalytic activity in prototypical TiO2 and also paves the way for the investigation of the electronic structure and photoabsorption of other metal oxides. PMID- 26121119 TI - Looking into Living Cell Systems: Planar Waveguide Microfluidic NMR Detector for in Vitro Metabolomics of Tumor Spheroids. AB - The complex cell metabolism and its link to oncogenic signaling pathways have received huge interest within the last few years. But the lack of advanced analytical tools for the investigation of living cell metabolism is still a challenge to be faced. Therefore, we designed and fabricated a novel miniaturized microslot NMR detector with on-board heater integrated with a microfluidic device as NMR sample holder. For the first time, a tumor spheroid of 500 MUm diameter and consisting of 9000 cells has been studied noninvasively and online for 24 h. The dynamic processes of production and degradation of 23 intra- and extracellular metabolites were monitored. Remarkably high concentrations of lactate and alanine were observed, being an indicator for a shift from oxidative to glycolytic metabolism. In summary, this methodical development has proven to be a successful analytical tool for the elucidation of cellular functions and their corresponding biochemical pathways. Additionally, the planar geometry of the microslot NMR detector allows the hyphenation with versatile lab-on-a chip (LOC) technology. This opens a new window for metabolomics studies on living cells and can be implemented into new application fields in biotechnology and life sciences. PMID- 26121120 TI - The highly sensitive and facile colorimetric detection of the glycidyl azide polymer based on propargylamine functionalized gold nanoparticles using click chemistry. AB - A highly sensitive and facile colorimetric sensor for the glycidyl azide polymer explosive was developed based on propargylamine functionalized gold nanoparticles using click chemistry. PMID- 26121121 TI - Hepatic Steatosis: Assessment with Acoustic Structure Quantification of US Imaging. AB - PURPOSE: To investigate the diagnostic performance of acoustic structure quantification (ASQ) for the assessment of hepatic steatosis by using hydrogen 1 ((1)H) magnetic resonance (MR) spectroscopy as the reference standard and to compare ASQ with hepatorenal ratio. MATERIALS AND METHODS: This prospective study was approved by an institutional review board, and informed written consent was obtained from all participants. ASQ and MR spectroscopy were performed in 89 participants (mean age, 41.48 years +/- 14.16; 35 men, 54 women) without history of chronic liver disease. Obtained were focal disturbance (FD) ratio by using ASQ, hepatic fat fraction (HFF) by using MR spectroscopy, and hepatorenal ratio by using a histogram. Correlation coefficient, intraclass correlation coefficient, and receiver operating curve analyses were performed. RESULTS: FD ratio measured with ASQ had a strong linear correlation with HFF measured with MR spectroscopy after logarithmic transformation of both variables (r = -0.87; P < .001). By using HFF of 5.79% as a cutoff value of 10% hepatic steatosis, 29 of 89 participants (32.6%) were categorized into the group with hepatic steatosis of 10% or greater (mean HFF, 13.18% +/- 4.89). The area under curve of the FD ratio for diagnosing hepatic steatosis 10% or greater was 0.959 (95% confidence interval: 0.895, 0.990) with sensitivity of 86.2% (95% confidence interval: 68.3%, 96.0%) and specificity of 100% (95% confidence interval: 94.0%, 100.0%) by using a cutoff value of 0.1; the area under curve and specificity of the FD ratio were significantly higher than those of the hepatorenal ratio (respectively, 0.772 and 73.3%; respective P values, .001 and <.001). CONCLUSION: This pilot study in a cohort of patients with hepatic steatosis without other parenchymal disease suggested ASQ may be valuable for the quantification of hepatic steatosis and detection of hepatic steatosis 10% or greater in living liver donors. PMID- 26121122 TI - Beta-blocker use in severe sepsis and septic shock: a systematic review. AB - OBJECTIVE: Recent growing evidence suggests that beta-blocker treatment could improve cardiovascular dynamics and possibly the outcome of patients admitted to intensive care with severe sepsis or septic shock. DESIGN: Systematic review. DATA SOURCES: MEDLINE and EMBASE healthcare databases. REVIEW METHODS: To investigate this topic, we conducted a systematic review of the above databases up to 31 May 2015. Due to the clinical novelty of the subject, we also included non-randomized clinical studies. We focused on the impact of beta-blocker treatment on mortality, also investigating its effects on cardiovascular, immune and metabolic function. Evidence from experimental studies was reviewed as well. RESULTS: From the initial search we selected 10 relevant clinical studies. Five prospective studies (two randomized) assessed the hemodynamic effects of the beta1-blocker esmolol. Heart rate decreased significantly in all, but the impact on other parameters differed. The imbalance between prospective studies' size (10 to 144 patients) and the differences in their design disfavor a meta-analysis. One retrospective study showed improved hemodynamics combining metoprolol and milrinone in septic patients, and another retrospective study found no association between beta-blocker administration and mortality. We also found three case series. Twenty-one experimental studies evaluated the hemodynamic, immune and/or metabolic effects of selective and/or non-selective beta-blockers in animal models of sepsis (dogs, mice, pigs, rats, sheep), yielding conflicting results. CONCLUSIONS: Whilst there is not enough prospective data to conduct a meta-analysis, the available clinical data are promising. We discuss the ability of beta blockade to modulate sepsis-induced alterations at cardiovascular, metabolic, immunologic and coagulation levels. PMID- 26121123 TI - Dysphonia in extremely preterm children: A longitudinal observation. AB - INTRODUCTION: Dysphonia is a potential long-term complication of preterm birth. Childhood voice disorders caused by vocal hyperfunction resolve with pubertal changes to the vocal mechanism in many cases. In extremely preterm children, whose voice quality is affected by supraglottic hyperfunction adapted secondary to underlying structural laryngeal pathology sustained during neonatal intubation, the prognosis is unknown. METHODS: A pilot study was conducted to assess the incidence and severity of dysphonia in children born at < 25 weeks' gestation. Ten individuals, aged between 9.67 and 17.08 years, presented for repeat assessment in a replication and extension of the original study. The mean period between assessments was 2.85 (SD 0.38) years. The primary outcome measure was the severity score on the Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V), with the Acoustic Voice Quality Index score as the secondary outcome measure. Scores on the Pediatric Voice Handicap Index were also compared. RESULTS: Perceptual dysphonia severity scores were significantly lower on repeat assessment, but no differences were observed in objective or quality of life scores. Individual variation was observed: the difference in CAPE-V scores ranged from -36 to + 1. No participant presented with normal voice quality on repeat assessment. DISCUSSION: Analysis of group data masked individual variability in this series. Mechanisms underlying such individual variation are currently unknown. These data suggest that dysphonia is persistent in extremely preterm children. CONCLUSION: Further investigation is warranted to elucidate the progression of voice disorders in extremely preterm children, to inform prognostic predictors and treatment decisions. PMID- 26121124 TI - Response to Jansson et al. PMID- 26121125 TI - Race, Employment Disadvantages, and Heavy Drinking: A Multilevel Model. AB - We intended to determine (1) whether stress from employment disadvantages led to increased frequency of heavy drinking and (2) whether race had a role in the relationship between such disadvantages and heavy drinking. Study data came from the National Longitudinal Survey of Youth, a prospective study that has followed a representative sample of youth since 1979. Our study employed data from 11 particular years, during which the survey included items measuring respondents' heavy drinking. Our final sample numbered 10,171 respondents, which generated 75,394 person-waves for data analysis. Both of our hypotheses were supported by results from multilevel mixed-effects linear regression capturing the time varying nature of three employment disadvantages and of the heavy-drinking outcome. Results show that more-frequent heavy drinking was associated with employment disadvantages, and that disadvantages' effects on drinking were stronger for Blacks and Hispanics than for Whites. That worsening employment disadvantages have worse effects on minority groups' heavy drinking (compared to Whites) probably contributes to the racial health disparities in our nation. Policies and programs addressing such disparities are especially important during economic downturns. PMID- 26121126 TI - Contribution of Fetal, but Not Adult, Pulmonary Mesothelium to Mesenchymal Lineages in Lung Homeostasis and Fibrosis. AB - The lung is enveloped by a layer of specialized epithelium, the pulmonary mesothelium. In other organs, mesothelial cells undergo epithelial-mesenchymal transition and contribute to organ stromal cells. The contribution of pulmonary mesothelial cells (PMCs) to the developing lung has been evaluated with differing conclusions. PMCs have also been indirectly implicated in lung fibrosis in the progressive, fatal lung disease idiopathic pulmonary fibrosis. We used fetal or postnatal genetic pulse labeling of PMCs to assess their fate in murine development, normal lung homeostasis, and models of pulmonary fibrosis. We found that most fetal PMC-derived mesenchymal cells (PMCDCs) expressed markers of pericytes and fibroblasts, only a small minority expressed smooth muscle markers, and none expressed endothelial cell markers. Postnatal PMCs did not contribute to lung mesenchyme during normal lung homeostasis or in models of lung fibrosis. However, fetal PMCDCs were abundant and actively proliferating within fibrotic regions in lung fibrosis models, suggesting that they actively participate in the fibrotic process. These data clarify the role of fetal and postnatal PMCDCs in lung development and disease. PMID- 26121127 TI - "Who Doesn't?"--The Impact of Descriptive Norms on Corruption. AB - Corruption poses one of the major societal challenges of our time. Considerable advances have been made in understanding corruption on a macro level, yet the psychological antecedents of corrupt behavior remain largely unknown. In order to explain why some people engage in corruption while others do not, we explored the impact of descriptive social norms on corrupt behavior by using a novel behavioral measure of corruption. We conducted three studies to test whether perceived descriptive norms of corruption (i.e. the belief about the prevalence of corruption in a specific context) influence corrupt behavior. The results indicated that descriptive norms highly correlate with corrupt behavior--both when measured before (Study 1) or after (Study 2) the behavioral measure of corruption. Finally, we adopted an experimental design to investigate the causal effect of descriptive norms on corruption (Study 3). Corrupt behavior in the corruption game significantly drops when participants receive short anti corruption descriptive norm primes prior to the game. These findings indicate that perceived descriptive norms can impact corrupt behavior and, possibly, could offer an explanation for inter-personal and inter-cultural variation in corrupt behavior in the real world. We discuss implications of these findings and draw avenues for future research. PMID- 26121128 TI - Full-Genome Sequencing as a Basis for Molecular Epidemiology Studies of Bluetongue Virus in India. AB - Since 1998 there have been significant changes in the global distribution of bluetongue virus (BTV). Ten previously exotic BTV serotypes have been detected in Europe, causing severe disease outbreaks in naive ruminant populations. Previously exotic BTV serotypes were also identified in the USA, Israel, Australia and India. BTV is transmitted by biting midges (Culicoides spp.) and changes in the distribution of vector species, climate change, increased international travel and trade are thought to have contributed to these events. Thirteen BTV serotypes have been isolated in India since first reports of the disease in the country during 1964. Efficient methods for preparation of viral dsRNA and cDNA synthesis, have facilitated full-genome sequencing of BTV strains from the region. These studies introduce a new approach for BTV characterization, based on full-genome sequencing and phylogenetic analyses, facilitating the identification of BTV serotype, topotype and reassortant strains. Phylogenetic analyses show that most of the equivalent genome-segments of Indian BTV strains are closely related, clustering within a major eastern BTV 'topotype'. However, genome-segment 5 (Seg-5) encoding NS1, from multiple post 1982 Indian isolates, originated from a western BTV topotype. All ten genome-segments of BTV-2 isolates (IND2003/01, IND2003/02 and IND2003/03) are closely related (>99% identity) to a South African BTV-2 vaccine-strain (western topotype). Similarly BTV-10 isolates (IND2003/06; IND2005/04) show >99% identity in all genome segments, to the prototype BTV-10 (CA-8) strain from the USA. These data suggest repeated introductions of western BTV field and/or vaccine-strains into India, potentially linked to animal or vector-insect movements, or unauthorised use of 'live' South African or American BTV-vaccines in the country. The data presented will help improve nucleic acid based diagnostics for Indian serotypes/topotypes, as part of control strategies. PMID- 26121129 TI - The Effects of Methylene Blue on Autophagy and Apoptosis in MRI-Defined Normal Tissue, Ischemic Penumbra and Ischemic Core. AB - Methylene blue (MB) USP, which has energy-enhancing and antioxidant properties, is currently used to treat methemoglobinemia and cyanide poisoning in humans. We recently showed that MB administration reduces infarct volume and behavioral deficits in rat models of ischemic stroke and traumatic brain injury. This study reports the underlying molecular mechanisms of MB neuroprotection following transient ischemic stroke in rats. Rats were subjected to transient (60-mins) ischemic stroke. Multimodal MRI during the acute phase and at 24 hrs were used to define three regions of interest (ROIs): i) the perfusion-diffusion mismatch salvaged by reperfusion, ii) the perfusion-diffusion mismatch not salvaged by reperfusion, and iii) the ischemic core. The tissues from these ROIs were extracted for western blot analyses of autophagic and apoptotic markers. The major findings were: 1) MB treatment reduced infarct volume and behavioral deficits, 2) MB improved cerebral blood flow to the perfusion-diffusion mismatch tissue after reperfusion and minimized harmful hyperperfusion 24 hrs after stroke, 3) MB inhibited apoptosis and enhanced autophagy in the perfusion diffusion mismatch, 4) MB inhibited apoptotic signaling cascades (p53-Bax-Bcl2 Caspase3), and 5) MB enhanced autophagic signaling cascades (p53-AMPK-TSC2-mTOR). MB induced neuroprotection, at least in part, by enhancing autophagy and reducing apoptosis in the perfusion-diffusion mismatch tissue following ischemic stroke. PMID- 26121130 TI - SIRT3 & SIRT7: Potential Novel Biomarkers for Determining Outcome in Pancreatic Cancer Patients. AB - PURPOSE: The sirtuin gene family has been linked with tumourigenesis, in both a tumour promoter and suppressor capacity. Information regarding the function of sirtuins in pancreatic cancer is sparse and equivocal. We undertook a novel study investigating SIRT1-7 protein expression in a cohort of pancreatic tumours. The aim of this study was to establish a protein expression profile for SIRT1-7 in pancreatic ductal adenocarcinomas (PDAC) and to determine if there were associations between SIRT1-7 expression, clinico-pathological parameters and patient outcome. MATERIAL AND METHODS: Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in a tissue micro-array comprising 77 resected PDACs. Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome. RESULTS: Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome. Low level SIRT3 expression in the tumour cytoplasm correlated with more aggressive tumours, and a shorter time to relapse and death, in the absence of chemotherapeutic intervention. Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis. CONCLUSIONS: Our data suggests that SIRT3 and SIRT7 possess tumour suppressor properties in the context of pancreatic cancer. SIRT3 may also represent a novel predictive biomarker to determine which patients may or may not respond to chemotherapy. This study opens up an interesting avenue of investigation to potentially identify predictive biomarkers and novel therapeutic targets for pancreatic cancer, a disease that has seen no significant improvement in survival over the past 40 years. PMID- 26121131 TI - Out of Lust or Jealousy: The Effects of Mate-Related Motives on Study-Time Allocation to Faces Varying in Attractiveness. AB - Although a growing number of empirical studies have revealed that activating mate related motives might exert a specific set of consequences for human cognition and behaviors, such as attention and memory, little is known about whether mate related motives affect self-regulated learning. The present study examined the effects of mate-related motives (mate-search and mate-guarding) on study-time allocation to faces varying in attractiveness. In two experiments, participants in mate-related priming conditions (Experiment 1: mate-search; Experiment 2: mate guarding) or control conditions studied 20 female faces (10 highly attractive, 10 less attractive) during a self-paced study task, and then were given a yes/no face recognition task. The finding of Experiment 1 showed that activating a mate search motive led the male participants to allocate more time to highly attractive female faces (i.e., perceived potential mates) than to less attractive ones. In Experiment 2, female participants in the mate-guarding priming condition spent more time studying highly attractive female faces (i.e., perceived potential rivals) than less attractive ones, compared to participants in the control condition. These findings illustrate the highly specific consequences of mate-related motives on study-time allocation, and highlight the value of exploring human cognition and motivation within evolutionary and self-regulated learning frameworks. PMID- 26121132 TI - Evaluation of Dewatering Performance and Fractal Characteristics of Alum Sludge. AB - The dewatering performance and fractal characteristics of alum sludge from a drinking-water treatment plant were investigated in this study. Variations in residual turbidity of supernatant, dry solid content (DS), specific resistance to filtration (SRF), floc size, fractal dimension, and zeta potential were analyzed. Sludge dewatering efficiency was evaluated by measuring both DS and SRF. Results showed that the optimum sludge dewatering efficiency was achieved at 16 mg?L(-1) flocculant dosage and pH 7. Under these conditions, the maximum DS was 54.6%, and the minimum SRF was 0.61 * 10(10) m?kg(-1). Floc-size measurements demonstrated that high flocculant dosage significantly improved floc size. Correlation analysis further revealed a strong correlation between fractal dimension and floc size after flocculation. A strong correlation also existed between floc size and zeta potential, and flocculants with a higher cationic degree had a larger correlation coefficient between floc size and zeta potential. In the flocculation process, the main flocculation mechanisms involved adsorption bridging under an acidic condition, and a combination between charge neutralization and adsorption bridging interaction under neutral and alkaline conditions. PMID- 26121133 TI - Integrating Crop Growth Models with Whole Genome Prediction through Approximate Bayesian Computation. AB - Genomic selection, enabled by whole genome prediction (WGP) methods, is revolutionizing plant breeding. Existing WGP methods have been shown to deliver accurate predictions in the most common settings, such as prediction of across environment performance for traits with additive gene effects. However, prediction of traits with non-additive gene effects and prediction of genotype by environment interaction (G*E), continues to be challenging. Previous attempts to increase prediction accuracy for these particularly difficult tasks employed prediction methods that are purely statistical in nature. Augmenting the statistical methods with biological knowledge has been largely overlooked thus far. Crop growth models (CGMs) attempt to represent the impact of functional relationships between plant physiology and the environment in the formation of yield and similar output traits of interest. Thus, they can explain the impact of G*E and certain types of non-additive gene effects on the expressed phenotype. Approximate Bayesian computation (ABC), a novel and powerful computational procedure, allows the incorporation of CGMs directly into the estimation of whole genome marker effects in WGP. Here we provide a proof of concept study for this novel approach and demonstrate its use with synthetic data sets. We show that this novel approach can be considerably more accurate than the benchmark WGP method GBLUP in predicting performance in environments represented in the estimation set as well as in previously unobserved environments for traits determined by non-additive gene effects. We conclude that this proof of concept demonstrates that using ABC for incorporating biological knowledge in the form of CGMs into WGP is a very promising and novel approach to improving prediction accuracy for some of the most challenging scenarios in plant breeding and applied genetics. PMID- 26121134 TI - Molecular Mechanisms Mediating the Adaptive Regulation of Intestinal Riboflavin Uptake Process. AB - The intestinal absorption process of vitamin B2 (riboflavin, RF) is carrier mediated, and all three known human RF transporters, i.e., hRFVT-1, -2, and -3 (products of the SLC52A1, 2 & 3 genes, respectively) are expressed in the gut. We have previously shown that the intestinal RF uptake process is adaptively regulated by substrate level, but little is known about the molecular mechanism(s) involved. Using human intestinal epithelial NCM460 cells maintained under RF deficient and over-supplemented (OS) conditions, we now show that the induction in RF uptake in RF deficiency is associated with an increase in expression of the hRFVT-2 & -3 (but not hRFVT-1) at the protein and mRNA levels. Focusing on hRFVT-3, the predominant transporter in the intestine, we also observed an increase in the level of expression of its hnRNA and activity of its promoter in the RF deficiency state. An increase in the level of expression of the nuclear factor Sp1 (which is important for activity of the SLC52A3 promoter) was observed in RF deficiency, while mutating the Sp1/GC site in the SLC52A3 promoter drastically decreased the level of induction in SLC52A3 promoter activity in RF deficiency. We also observed specific epigenetic changes in the SLC52A3 promoter in RF deficiency. Finally, an increase in hRFVT-3 protein expression at the cell surface was observed in RF deficiency. Results of these investigations show, for the first time, that transcriptional and post transcriptional mechanisms are involved in the adaptive regulation of intestinal RF uptake by the prevailing substrate level. PMID- 26121135 TI - Dual Action of Myricetin on Porphyromonas gingivalis and the Inflammatory Response of Host Cells: A Promising Therapeutic Molecule for Periodontal Diseases. AB - Periodontitis that affects the underlying structures of the periodontium, including the alveolar bone, is a multifactorial disease, whose etiology involves interactions between specific bacterial species of the subgingival biofilm and the host immune components. In the present study, we investigated the effects of myricetin, a flavonol largely distributed in fruits and vegetables, on growth and virulence properties of Porphyromonas gingivalis as well as on the P. gingivalis induced inflammatory response in host cells. Minimal inhibitory concentration values of myricetin against P. gingivalis were in the range of 62.5 to 125 MUg/ml. The iron-chelating activity of myricetin may contribute to the antibacterial activity of this flavonol. Myricetin was found to attenuate the virulence of P. gingivalis by reducing the expression of genes coding for important virulence factors, including proteinases (rgpA, rgpB, and kgp) and adhesins (fimA, hagA, and hagB). Myricetin dose-dependently prevented NF-kappaB activation in a monocyte model. Moreover, it inhibited the secretion of IL-6, IL 8 and MMP-3 by P. gingivalis-stimulated gingival fibroblasts. In conclusion, our study brought clear evidence that the flavonol myricetin exhibits a dual action on the periodontopathogenic bacterium P. gingivalis and the inflammatory response of host cells. Therefore, myricetin holds promise as a therapeutic agent for the treatment/prevention of periodontitis. PMID- 26121136 TI - Nanohybrids from nanotubular J-aggregates and transparent silica nanoshells. AB - Organic-inorganic nanohybrids have been synthesized by in situ coating supramolecular nanotubular J-aggregates with helically wound silica ribbons, reflecting the J-aggregates' superstructure. The J-aggregates retain their morphology and optical properties in the nanohybrids, and display improved stability against elevated temperatures, chemical ambient and photo-bleaching. PMID- 26121137 TI - Amblyomma americanum as a Bridging Vector for Human Infection with Francisella tularensis. AB - The gamma-proteobacterium Francisella tularensis causes seasonal tick-transmitted tularemia outbreaks in natural rabbit hosts and incidental infections in humans in the south-central United States. Although Dermacentor variabilis is considered a primary vector for F. tularensis, Amblyomma americanum is the most abundant tick species in this endemic region. A systematic study of F. tularensis colonization of A. americanum was undertaken to better understand its potential to serve as an overwintering reservoir for F. tularensis and as a bridging vector for human infections. Colony-reared A. americanum were artificially fed F. tularensis subspecies holarctica strain LVS via glass capillaries and colonization levels determined. Capillary-fed larva and nymph were initially infected with 10(4) CFU/tick which declined prior to molting for both stages, but rebounded post-molting in nymphs and persisted in 53% at 10(3) to 10(8) CFU/nymph at 168 days post-capillary feeding (longest sampling time in the study). In contrast, only 18% of adults molted from colonized nymphs maintained LVS colonization at 10(1) to 10(5) CFU/adult at 168 days post-capillary feeding (longest sampling time). For adults, LVS initially colonized the gut and disseminated to salivary glands by 24 h and had an ID50 of <5CFU in mice. Francisella tularensis infected the ovaries of gravid females, but transmission to eggs was infrequent and transovarial transmission to hatched larvae was not observed. The prolonged persistence of F. tularensis in A. americanum nymphs supports A. americanum as an overwintering reservoir for F. tularensis from which seasonal epizootics may originate; however, although the rapid dissemination of F. tularensis from gut to salivary glands in adults A. americanum is compatible with intermittent feeding adult males acting as bridging vectors for incidental F. tularensis infections of humans, acquisition of F. tularensis by adults may be unlikely based on adult feeding preference for larger mammals which are not involved in maintenance of sylvatic tularemia. PMID- 26121138 TI - Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity. AB - Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS) in 1,256 pigs from Laiwu, Erhualian and Duroc * (Landrace * Yorkshire) populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC) for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc * Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption. PMID- 26121140 TI - Synthesis of dendritic Pt-Ni-P alloy nanoparticles with enhanced electrocatalytic properties. AB - Dendritic Pt-Ni-P alloy NPs with different chemical compositions were successfully synthesized via a facile wet-chemical route. Owing to the unique dendritic nanostructures and synergistic electronic effects of P, Ni, and Pt atoms, the as-prepared dendritic Pt-Ni-P alloy NPs exhibit a higher electrocatalytic activity than dendritic Pt-Ni alloy NPs and commercial Pt/C. PMID- 26121139 TI - Channel Activity of Cardiac Ryanodine Receptors (RyR2) Determines Potency and Efficacy of Flecainide and R-Propafenone against Arrhythmogenic Calcium Waves in Ventricular Cardiomyocytes. AB - Flecainide blocks ryanodine receptor type 2 (RyR2) channels in the open state, suppresses arrhythmogenic Ca2+ waves and prevents catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice and humans. We hypothesized that differences in RyR2 activity induced by CPVT mutations determines the potency of open-state RyR2 blockers like flecainide (FLEC) and R-propafenone (RPROP) against Ca2+ waves in cardiomyocytes. Using confocal microscopy, we studied Ca2+ sparks and waves in isolated saponin-permeabilized ventricular myocytes from two CPVT mouse models (Casq2-/-, RyR2-R4496C+/-), wild-type (c57bl/6, WT) mice, and WT rabbits (New Zealand white rabbits). Consistent with increased RyR2 activity, Ca2+ spark and wave frequencies were significantly higher in CPVT compared to WT mouse myocytes. We next obtained concentration-response curves of Ca2+ wave inhibition for FLEC, RPROP (another open-state RyR2 blocker), and tetracaine (TET) (a state-independent RyR2 blocker). Both FLEC and RPROP inhibited Ca2+ waves with significantly higher potency (lower IC50) and efficacy in CPVT compared to WT. In contrast, TET had similar potency in all groups studied. Increasing RyR2 activity of permeabilized WT myocytes by exposure to caffeine (150 uM) increased the potency of FLEC and RPROP but not of TET. RPROP and FLEC were also significantly more potent in rabbit ventricular myocytes that intrinsically exhibit higher Ca2+ spark rates than WT mouse ventricular myocytes. In conclusion, RyR2 activity determines the potency of open-state blockers FLEC and RPROP for suppressing arrhythmogenic Ca2+ waves in cardiomyocytes, a mechanism likely relevant to antiarrhythmic drug efficacy in CPVT. PMID- 26121141 TI - Shared Segment Analysis and Next-Generation Sequencing Implicates the Retinoic Acid Signaling Pathway in Total Anomalous Pulmonary Venous Return (TAPVR). AB - Most isolated congenital heart defects are thought to be sporadic and are often ascribed to multifactorial mechanisms with poorly understood genetics. Total Anomalous Pulmonary Venous Return (TAPVR) occurs in 1 in 15,000 live-born infants and occurs either in isolation or as part of a syndrome involving aberrant left right development. Previously, we reported causative links between TAVPR and the PDGFRA gene. TAPVR has also been linked to the ANKRD1/CARP genes. However, these genes only explain a small fraction of the heritability of the condition. By examination of phased single nucleotide polymorphism genotype data from 5 distantly related TAPVR patients we identified a single 25 cM shared, Identical by Descent genomic segment on the short arm of chromosome 12 shared by 3 of the patients and their obligate-carrier parents. Whole genome sequence (WGS) analysis identified a non-synonymous variant within the shared segment in the retinol binding protein 5 (RBP5) gene. The RBP5 variant is predicted to be deleterious and is overrepresented in the TAPVR population. Gene expression and functional analysis of the zebrafish orthologue, rbp7, supports the notion that RBP5 is a TAPVR susceptibility gene. Additional sequence analysis also uncovered deleterious variants in genes associated with retinoic acid signaling, including NODAL and retinol dehydrogenase 10. These data indicate that genetic variation in the retinoic acid signaling pathway confers, in part, susceptibility to TAPVR. PMID- 26121142 TI - A Comparative Analysis on Assessment of Land Carrying Capacity with Ecological Footprint Analysis and Index System Method. AB - Land carrying capacity (LCC) explains whether the local land resources are effectively used to support economic activities and/or human population. LCC can be evaluated commonly with two approaches, namely ecological footprint analysis (EFA) and the index system method (ISM). EFA is helpful to investigate the effects of different land categories whereas ISM can be used to evaluate the contributions of social, environmental, and economic factors. Here we compared the two LCC-evaluation approaches with data collected from Xiamen City, a typical region where rapid economic growth and urbanization are found in China. The results show that LCC assessments with EFA and ISM not only complement each other but also are mutually supportive. Both assessments suggest that decreases in arable land and increasingly high energy consumption have major negative effects on LCC and threaten sustainable development for Xiamen City. It is important for the local policy makers, planners and designers to reduce ecological deficits by controlling fossil energy consumption, protecting arable land and forest land from converting into other land types, and slowing down the speed of urbanization, and to promote sustainability by controlling rural-to-urban immigration, increasing hazard-free treatment rate of household garbage, and raising energy consumption per unit industrial added value. Although EFA seems more appropriate for estimating LCC for a resource-output or self-sufficient region and ISM is more suitable for a resource-input region, both approaches should be employed when perform LCC assessment in any places around the world. PMID- 26121144 TI - Origin of the facet dependence in the hydrogenation catalysis of olefins: experiment and theory. AB - Shape-controlled Pd nanocrystals are used as model catalysts to demonstrate facet dependent catalysis in the hydrogenation of olefins. The close packed Pd{111} shows high catalytic activity for styrene but not for trans-stilbene. However, the open Pd{100} facets hydrogenate both olefins. DFT calculations reveal that the hydrogenation reactivity critically depends on the stability of half hydrogenated intermediates. PMID- 26121143 TI - Proteomics and Transcriptomics of BJAB Cells Expressing the Epstein-Barr Virus Noncoding RNAs EBER1 and EBER2. AB - In Epstein-Barr virus (EBV) latent infection, the EBV-encoded RNAs EBER1 and EBER2 accumulate in the host cell nucleus to ~10(6) copies. While the expression of EBERs in cell lines is associated with transformation, a mechanistic explanation of their roles in EBV latency remains elusive. To identify EBER specific gene expression features, we compared the proteome and mRNA transcriptome from BJAB cells (an EBV-negative B lymphoma cell line) stably transfected with an empty plasmid or with one carrying both EBER genes. We identified ~1800 proteins with at least 2 SILAC pair measurements, of which only 8 and 12 were up- and downregulated >= 2-fold, respectively. One upregulated protein was PIK3AP1, a B-cell specific protein adapter known to activate the PI3K AKT signaling pathway, which regulates alternative splicing and translation in addition to its pro-survival effects. In the mRNA-seq data, the mRNA levels for some of the proteins changing in the SILAC data did not change. We instead observed isoform switch events. We validated the most relevant findings with biochemical assays. These corroborated the upregulation of PIK3AP1 and AKT activation in BJAB cells expressing high levels of both EBERs and EBNA1 (a surrogate of Burkitt's lymphoma EBV latency I) relative to those expressing only EBNA1. The mRNA-seq data in these cells showed multiple upregulated oncogenes whose mRNAs are enriched for 3'-UTR AU-rich elements (AREs), such as ccl3, ccr7, il10, vegfa and zeb1. The CCL3, CCR7, IL10 and VEGFA proteins promote cell proliferation and are associated with EBV-mediated lymphomas. In EBV latency, ZEB1 represses the transcription of ZEBRA, an EBV lytic phase activation factor. We previously found that EBER1 interacts with AUF1 in vivo and proposed stabilization of ARE-containing mRNAs. Thus, the ~10(6) copies of EBER1 may promote not only cell proliferation due to an increase in the levels of ARE containing genes like ccl3, ccr7, il10, and vegfa, but also the maintenance of latency, through higher levels of zeb1. PMID- 26121145 TI - Finger Flexor Force Influences Performance in Senior Male Air Pistol Olympic Shooting. AB - The ability to stabilize the gun is crucial for performance in Olympic pistol shooting and is thought to be related to the shooters muscular strength. The present study examines the relation between performance and finger flexor force as well as shoulder abduction isometric force in senior male air pistol shooting. 46 Spanish national level shooters served as test subjects of the study. Two maximal force tests were carried out recording handgrip and deltoid force data under competition conditions, during the official training time at national Spanish championships. Performance was measured as the total score of 60 shots at competition. Linear regressions were calculated to examine the relations between performance and peak and average finger flexor forces, peak and average finger flexor forces relative to the BMI, peak and average shoulder abduction isometric forces, peak shoulder abduction isometric force relative to the BMI. The connection between performance and other variables such as age, weight, height, BMI, experience in years and training hours per week was also analyzed. Significant correlations were found between performance at competition and average and peak finger flexor forces. For the rest of the force variables no significant correlations were found. Significant correlations were also found between performance at competition and experience as well as training hours. No significant correlations were found between performance and age, weight, height or BMI. The study concludes that hand grip strength training programs are necessary for performance in air pistol shooting. PMID- 26121146 TI - Investigation of Ground-Level Ozone and High-Pollution Episodes in a Megacity of Eastern China. AB - Differential Optical Absorption Spectroscopy (DOAS) was used for the long-term observation of ground-level ozone (O3) from March 2010 to March 2013 over Shanghai, China. The 1-hour average concentration of O3 was 27.2 +/- 17.0 ppbv. O3 level increased during spring, reached the peak in late spring and early summer, and then decreased in autumn and finally dropped to the bottom in winter. The highest monthly average O3 concentration in June (41.1 ppbv) was nearly three times as high as the lowest level recorded in December (15.2 ppbv). In terms of pollution episodes, 56 hourly samples (on 14 separate days) in 2010 exceeded the 1-hour ozone limit of 200 MUg/m3 specified by the Grade II of the Chinese Ambient Air Quality Standards (CAAQS, revised GB 3095-2012). Utilizing the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model, the primary contribution to high ozone days (HODs) was identified as the regional transportation of volatile organic compounds (VOC) and high concentrations of O3 from the chemical industrial zone in the Jinshan district of Shanghai. HODs showed higher concentrations of HONO and NO2 than non-episode conditions, implying that HONO at high concentration during HODs was capable of increasing the O3 concentration. The photolysis rate of HONO was estimated, suggesting that the larger number of OH radicals resulting from high concentrations of HONO have a considerable impact on ozone concentrations. PMID- 26121147 TI - Structural and Biochemical Characterization of the Francisella tularensis Pathogenicity Regulator, Macrophage Locus Protein A (MglA). AB - Francisella tularensis is one of the most infectious bacteria known and is the etiologic agent of tularemia. Francisella virulence arises from a 33 kilobase (Kb) pathogenicity island (FPI) that is regulated by the macrophage locus protein A (MglA) and the stringent starvation protein A (SspA). These proteins interact with both RNA polymerase (RNAP) and the pathogenicity island gene regulator (PigR) to activate FPI transcription. However, the molecular mechanisms involved are not well understood. Indeed, while most bacterial SspA proteins function as homodimers to activate transcription, F. tularensis SspA forms a heterodimer with the MglA protein, which is unique to F. tularensis. To gain insight into MglA function, we performed structural and biochemical studies. The MglA structure revealed that it contains a fold similar to the SspA protein family. Unexpectedly, MglA also formed a homodimer in the crystal. Chemical crosslinking and size exclusion chromatography (SEC) studies showed that MglA is able to self associate in solution to form a dimer but that it preferentially heterodimerizes with SspA. Finally, the MglA structure revealed malate, which was used in crystallization, bound in an open pocket formed by the dimer, suggesting the possibility that this cleft could function in small molecule ligand binding. The location of this binding region relative to recently mapped PigR and RNAP interacting sites suggest possible roles for small molecule binding in MglA and SspA*MglA function. PMID- 26121148 TI - Improving Negative Emotion Recognition in Young Offenders Reduces Subsequent Crime. AB - BACKGROUND: Children with antisocial behaviour show deficits in the perception of emotional expressions in others that may contribute to the development and persistence of antisocial and aggressive behaviour. Current treatments for antisocial youngsters are limited in effectiveness. It has been argued that more attention should be devoted to interventions that target neuropsychological correlates of antisocial behaviour. This study examined the effect of emotion recognition training on criminal behaviour. METHODS: Emotion recognition and crime levels were studied in 50 juvenile offenders. Whilst all young offenders received their statutory interventions as the study was conducted, a subgroup of twenty-four offenders also took part in a facial affect training aimed at improving emotion recognition. Offenders in the training and control groups were matched for age, SES, IQ and lifetime crime level. All offenders were tested twice for emotion recognition performance, and recent crime data were collected after the testing had been completed. RESULTS: Before the training there were no differences between the groups in emotion recognition, with both groups displaying poor fear, sadness and anger recognition. After the training fear, sadness and anger recognition improved significantly in juvenile offenders in the training group. Although crime rates dropped in all offenders in the 6 months following emotion testing, only the group of offenders who had received the emotion training showed a significant reduction in the severity of the crimes they committed. CONCLUSIONS: The study indicates that emotion recognition can be relatively easily improved in youths who engage in serious antisocial and criminal behavior. The results suggest that improved emotion recognition has the potential to reduce the severity of reoffending. PMID- 26121150 TI - Suicide Is Still With Us. PMID- 26121149 TI - Gene Expression Profiling of H9c2 Myoblast Differentiation towards a Cardiac-Like Phenotype. AB - H9c2 myoblasts are a cell model used as an alternative for cardiomyocytes. H9c2 cells have the ability to differentiate towards a cardiac phenotype when the media serum is reduced in the presence of all-trans-retinoic acid (RA), creating multinucleated cells with low proliferative capacity. In the present study, we performed for the first time a transcriptional analysis of the H9c2 cell line in two differentiation states, i.e. embryonic cells and differentiated cardiac-like cells. The results show that RA-induced H9c2 differentiation increased the expression of genes encoding for cardiac sarcomeric proteins such as troponin T, or calcium transporters and associated machinery, including SERCA2, ryanodine receptor and phospholamban as well as genes associated with mitochondrial energy production including respiratory chain complexes subunits, mitochondrial creatine kinase, carnitine palmitoyltransferase I and uncoupling proteins. Undifferentiated myoblasts showed increased gene expression of pro-survival proteins such as Bcl-2 as well as cell cycle-regulating proteins. The results indicate that the differentiation of H9c2 cells lead to an increase of transcripts and protein levels involved in calcium handling, glycolytic and mitochondrial metabolism, confirming that H9c2 cell differentiation induced by RA towards a more cardiac-like phenotype involves remodeled mitochondrial function. PI3K, PDK1 and p-CREB also appear to be involved on H9c2 differentiation. Furthermore, complex analysis of differently expressed transcripts revealed significant up-regulation of gene expression related to cardiac muscle contraction, dilated cardiomyopathy and other pathways specific for the cardiac tissue. Metabolic and gene expression remodeling impacts cell responses to different stimuli and determine how these cells are used for biochemical assays. PMID- 26121151 TI - Metacognitive Deficits in Schizophrenia: Presence and Associations With Psychosocial Outcomes. AB - Early formulations of schizophrenia suggested that the disorder involves a loss of ability to form integrated ideas about oneself, others, and the world, resulting in reductions in complex goal-directed behaviors. Exploring this position, the current review describes evidence that persons with schizophrenia experience decrements in their ability to form complex ideas about themselves and to ultimately use that knowledge to respond to psychological and social challenges. Studies are detailed that find greater levels of these impairments, defined as metacognitive deficits, in persons with schizophrenia in both early and later phases of illness as compared with other clinical and community groups. Furthermore, studies linking metacognitive deficits with poorer psychosocial functioning and other variables closely linked to outcomes are summarized. Clinical implications are also discussed. PMID- 26121152 TI - An Examination of Executive Functioning in Young Adults Exhibiting Body-Focused Repetitive Behaviors. AB - Body-focused repetitive behaviors (BFRBs), including hair pulling, nail biting, and skin picking are repetitive, habitual, and compulsive in nature. Although characteristic of disorders such as trichotillomania and skin picking disorder, BFRBs are associated with other psychiatric conditions as well. To date, research has failed to examine neurocognitive risk factors, particularly executive functioning, implicated in BFRBs utilizing a transdiagnostic approach. The present study recruited 53 participants (n = 27 demonstrating BFRBs and n = 26 randomly selected controls) from a larger sample of young adults. Participants completed an automated neurocognitive test battery including tasks of cognitive flexibility, working memory, and planning and organization. Results revealed that participants in the BFRB group demonstrated significantly poorer cognitive flexibility (d = 0.63) than controls. No differences were noted in other neurocognitive domains. However, planning and organization demonstrated a significant relationship with various BFRB severity measures. Implications, limitations, and avenues for further research are discussed. PMID- 26121153 TI - Housing First and the Risk of Failure: A Comment on Westermeyer and Lee (2013). AB - Over the last 5 years, community policies in response to homelessness have shifted toward offering permanent housing accompanied by treatment supports, without requiring treatment success as a precondition. The US Department of Veterans Affairs (VA) has embraced this "Housing First" approach. A 2013 report sounds a contrarian note. In a 16-person quasi-experimental study, 8 veterans who entered VA's permanent supportive housing did poorly, whereas 8 veterans who remained in more traditional treatment did well. In this commentary, we suggest that the report was problematic in the conceptualization of the matters it sought to address and in its science. Nonetheless, it highlights challenges that must not be ignored. From this report and other research, we now know that even more attention is required to support clinical recovery for Housing First clients. Successful implementation of Housing First requires guidance from agency leaders, and their support for clinical staff when individual clients fare poorly. PMID- 26121154 TI - Housing First/HUD-VASH: Importance, Flaws, and Potential for Transformation: Response to Commentary. AB - This paper consists of responses to issues raised in the accompanying Commentary. Our response is organized under three topics: (1) reasons regarding the importance of issues, (2) the need for a comprehensive framework in housing placement, and (3) conceptualization and scientific design (with details on contemporary methods for investigating unanticipated consequences when randomization is no longer feasible). Recurrences to substance use disorder in the American Society of Addiction Medicine (ASAM) housing placement condition are noted within hours or days, with rapid implementation of planned contingencies, and avoidance of enabling. Recurrences in the Housing First/HUD-VASH (HF/H-V) condition escape notice for weeks to months, and continued use is accepted as a core principle of the program. HF/H-V contingencies occur later for major disruptions, leading to discharge. For patients recruited from our clinic, HF/H-V performed poorly when compared to a long-accepted standard of care, the ASAM placement criteria. PMID- 26121156 TI - VERO stable cell lines expressing full-length human epidermal growth factor receptors 2 and 3: platforms for subtractive phage display. AB - Cross-talk between human epidermal growth factor receptor 2 and 3 (HER2 and HER3) may potentially contribute to therapeutic resistance in human breast cancer. Subtractive phage display allows highly specific selection for antibody fragments directed against cells surface HER2 and HER3. The strategies to select conformation- and activation-specific antibodies against HER2 and HER3 require tightly regulated HER2 and HER3 expressing cells that allow controlled activation/inactivation of these receptors during panning procedures. To achieve this, first, we found that the VERO cell line is an appropriate cell line for heterogeneous expression of HER2 and HER3, and then we established a panel of VERO stable cell lines expressing high levels of HER2 and HER3 alone and in combination. We also showed that HER2 and HER3 expressed in VERO cells were biologically active and could form heterodimer following neuregulin1 treatment. The cell line established here not only provided platforms for phage display based methods but also could be used in any HER-related studies. PMID- 26121155 TI - Symptoms of Eating Disorders and Depression in Emerging Adults with Early-Onset, Long-Duration Type 1 Diabetes and Their Association with Metabolic Control. AB - BACKGROUND: This study analyzed the prevalence of and association between symptoms of eating disorders and depression in female and male emerging adults with early-onset, long-duration type 1 diabetes and investigated how these symptoms are associated with metabolic control. METHODS: In a nationwide population-based survey, 211 type 1 diabetes patients aged 18-21 years completed standardized questionnaires, including the SCOFF questionnaire for eating disorder symptoms and the Patient Health Questionnaire (PHQ-9) for symptoms of depression and severity of depressive symptoms (PHQ-9 score). Multiple linear and logistic regression models were used to analyze the association between eating disorder and depressive symptoms and their associations with HbA1c. RESULTS: A total of 30.2% of the women and 9.5% of the men were screening positive for eating disorders. The mean PHQ-9 score (standard deviation) was 5.3 (4.4) among women and 3.9 (3.6) among men. Screening positive for an eating disorder was associated with more severe depressive symptoms among women (betawomen 3.8, p<0.001). However, neither eating disorder symptoms nor severity of depressive symptoms were associated with HbA1c among women, while HbA1c increased with the severity of depressive symptoms among men (betamen 0.14, p=0.006). CONCLUSIONS: Because of the high prevalence of eating disorder and depressive symptoms, their interrelationship, and their associations with metabolic control, particularly among men, regular mental health screening is recommended for young adults with type 1 diabetes. PMID- 26121157 TI - A Golgi-localized two-photon probe for imaging zinc ions. AB - We report a two-photon fluorescent probe which shows a strong two photon excited fluorescence enhancement in response to Zn(2+), easy loading into the cells, Golgi-localizing ability, low cytotoxicity, and high photostability. Two-photon microscopy imaging revealed that this probe allows for real-time monitoring of the changes in Golgi Zn(2+) as well as their 3D distributions in live cells and tissues. PMID- 26121158 TI - Structural Stability and Flexibility Direct the Selection of Activating Mutations in Epidermal Growth Factor Receptor Kinase. AB - Herein we investigate the potential of novel methods of molecular dynamics analysis to provide information on the key factors that underlie the preferential localization and the effects of mutations modulating protein activities. Epidermal growth factor receptor (EGFR) kinases are selected as a test case. The combined analysis of protein energetics and internal dynamics indicates a clear polarization in the native protein, whereby a highly stable and ordered scaffold in one domain, namely the C-lobe, is combined to a flexible and loosely stabilized domain, the N-lobe. The subdivision in two portions with different properties directs the presence of point mutations mainly to the N-lobe. This allows modulating protein flexibility so that the protein can more efficiently sample the conformations necessary for substrate recognition, while leaving the stability of the protein unperturbed. In this context, comparative simulations of EGFR in the wild type sequence and in the presence of the activating oncogenic mutation G719S reveal flexibility changes in several key regions, involving in particular the part of the kinase devoted to the regulation of substrate recognition (regulatory core) and an increase in the number of stabilizing interactions in the N-lobe for the activated mutant. Our approaches represent a promising and simple strategy toward rationalizing the effects of mutations in modulating enzymatic activities. PMID- 26121159 TI - Re: Cost-effectiveness of continuous subcutaneous apomorphine in the treatment of Parkinson's Disease in the UK and Germany. PMID- 26121160 TI - Healthcare costs of pregnancy in systemic lupus erythematosus: retrospective observational analysis from a US health claims database. AB - OBJECTIVE: Systemic lupus erythematosus is a complex autoimmune disease, most frequently affecting women of childbearing age. Women with lupus are at increased risk of pregnancy complications that are exacerbated by active disease. Despite this, their use of medications and hospital resources has not been extensively studied. METHODS: Retrospective analyses of the Truven Health MarketScan database (2006-2012) aimed to quantify drug and resource utilization in pregnant women with lupus, as well as the incidence of pregnancy complications in these patients. Records of women aged 12-54 were reviewed and both lupus patients and pregnancies identified. Pregnant women with lupus were matched 1:5 with either pregnant women without lupus, or non-pregnant women with lupus. RESULTS: Pregnancies with lupus were associated with increased complications when compared to pregnancies without lupus. During pregnancy, the use of immunosuppressants decreased in pregnant women with lupus, as did rheumatologist visits, while the number of women not treated with any immunosuppressant increased. Pregnant women with lupus showed higher overall treatment costs than controls. However, compared to non-pregnant women with lupus, medication costs actually dropped, possibly due to the withdrawal of medications from these patients or women becoming pregnant while disease activity was low. CONCLUSIONS: The large database analyses reported here revealed that pregnancies in women with lupus were associated with a higher risk of complications, higher healthcare costs, and fewer prescribed medications, including immunosuppressants, than the control groups. The increased risk of complications and decreased immunosuppressant use suggest that patients require additional guidance from physicians to give them the best chance of experiencing a safe pregnancy. Indeed, despite the recognized role active lupus plays in increasing pregnancy complications, women with lupus had fewer rheumatology visits during pregnancy, although their visits to their general practitioner/primary healthcare provider increased, highlighting the need for team-based co-ordination care between OBGYN physicians and rheumatologists. PMID- 26121161 TI - Impact of initiation of asenapine on patterns of utilization and cost of healthcare resources associated with the treatment of bipolar I disorder. AB - OBJECTIVE: To assess the impact of initiation of asenapine on "real-world" levels of utilization and cost of healthcare services for the treatment of bipolar I disorder (BPD) in the US. METHODS: Using two large US healthcare claims databases that collectively included commercially insured patients aged < 65 years and Medicare enrollees, this study identified all adults (>= 18 years) with evidence of BPD who began therapy with asenapine between 2009-2012. The date of the earliest claim for asenapine during this period was deemed the 'index date', and patients without continuous enrollment for the 6-month periods before and after this date were excluded ('pre-index' and 'post-index', respectively). Healthcare claims with a BPD diagnosis, plus psychiatric medications and the costs thereof (2012 dollars) were deemed 'BPD-related'. Differences in BPD-related utilization and cost of healthcare services were compared between the pre- and post-index periods. RESULTS: A total of 1403 patients met all selection criteria; the mean age was 42.8 years and 70.6% were women. Relative to pre-index, significant decreases were noted in post-index use of BPD-related healthcare services, most notably admissions (from 24.0% to 12.3% during the post-index period) and emergency department visits (from 4.6% to 2.6%) (both p < 0.05). While pharmacy costs increased, mean total post-index BPD-related healthcare costs were $979 lower than pre-index ($5002 vs $5981; p < 0.05), primarily due to the decrease in BPD-related admissions. CONCLUSIONS: Relative to the 6-month period beforehand, levels of utilization of BPD-related healthcare services and costs decreased during the 6-month period immediately following initiation of asenapine therapy. PMID- 26121162 TI - A Case of Unilateral Hypnic Headache: Rapid Response to Ramelteon, a Selective Melatonin MT1/MT2 Receptor Agonist. PMID- 26121163 TI - Effects of "Reduced" and "Business-As-Usual" CO2 Emission Scenarios on the Algal Territories of the Damselfish Pomacentrus wardi (Pomacentridae). AB - Turf algae are a very important component of coral reefs, featuring high growth and turnover rates, whilst covering large areas of substrate. As food for many organisms, turf algae have an important role in the ecosystem. Farming damselfish can modify the species composition and productivity of such algal assemblages, while defending them against intruders. Like all organisms however, turf algae and damselfishes have the potential to be affected by future changes in seawater (SW) temperature and pCO2. In this study, algal assemblages, in the presence and absence of farming Pomacentrus wardi were exposed to two combinations of SW temperature and pCO2 levels projected for the austral spring of 2100 (the B1 "reduced" and the A1FI "business-as-usual" CO2 emission scenarios) at Heron Island (GBR, Australia). These assemblages were dominated by the presence of red algae and non-epiphytic cyanobacteria, i.e. cyanobacteria that grow attached to the substrate rather than on filamentous algae. The endpoint algal composition was mostly controlled by the presence/absence of farming damselfish, despite a large variability found between the algal assemblages of individual fish. Different scenarios appeared to be responsible for a mild, species specific change in community composition, observable in some brown and green algae, but only in the absence of farming fish. Farming fish appeared unaffected by the conditions to which they were exposed. Algal biomass reductions were found under "reduced" CO2 emission, but not "business-as-usual" scenarios. This suggests that action taken to limit CO2 emissions may, if the majority of algae behave similarly across all seasons, reduce the potential for phase shifts that lead to algal dominated communities. At the same time the availability of food resources to damselfish and other herbivores would be smaller under "reduced" emission scenarios. PMID- 26121164 TI - Conduction Mechanisms in CVD-Grown Monolayer MoS2 Transistors: From Variable Range Hopping to Velocity Saturation. AB - We fabricate transistors from chemical vapor deposition-grown monolayer MoS2 crystals and demonstrate excellent current saturation at large drain voltages (Vd). The low-field characteristics of these devices indicate that the electron mobility is likely limited by scattering from charged impurities. The current voltage characteristics exhibit variable range hopping at low Vd and evidence of velocity saturation at higher Vd. This work confirms the excellent potential of MoS2 as a possible channel-replacement material and highlights the role of multiple transport phenomena in governing its transistor action. PMID- 26121166 TI - P63 Positive Mucoepidermoid Tumor of the Lacrimal Sac with Associated Papilloma. AB - We report a case of a 44-year-old man who presented with a left medial canthal mass and epiphora. Imaging was suggestive of a mass continuous with the nasolacrimal sac. Subsequent surgical exploration revealed a mass adherent to bone with invasion of the lacrimal system. Histological examination revealed a squamous/transitional cell papilloma overlying a low-grade mucoepidermoid carcinoma (MEC). Complete surgical resection was completed and pathology confirmed the diagnosis. This is the first case in which a MEC has been reported concurrently with an overlying papilloma, providing support for the hypothesis that MECs arise from papillomas in the lacrimal sac. Additionally, the tissue stained positive for p63, which is congruent with MEC immunoreactivity in the salivary gland. The description of these unique histopathological findings may assist in definitive diagnosis and improve our understanding of the pathophysiology underlying lacrimal sac MEC tumors. PMID- 26121165 TI - Bacterial Exposures and Associations with Atopy and Asthma in Children. AB - BACKGROUND: The increase in prevalence of asthma and atopic diseases in Western countries has been linked to aspects of microbial exposure patterns of people. It remains unclear which microbial aspects contribute to the protective farm effect. OBJECTIVE: The objective of this study was to identify bacterial groups associated with prevalence of asthma and atopy, and to quantify indoor exposure to some of these bacterial groups. METHODS: A DNA fingerprinting technique, denaturing gradient gel electrophoresis (DGGE), was applied to mattress dust samples of farm children and control children in the context of the GABRIEL Advanced study. Associations between signals in DGGE and atopy, asthma and other allergic health outcomes were analyzed. Quantitative DNA based assays (qPCR) for four bacterial groups were applied on the dust samples to seek quantitative confirmation of associations indicated in DNA fingerprinting. RESULTS: Several statistically significant associations between individual bacterial signals and also bacterial diversity in DGGE and health outcomes in children were observed. The majority of these associations showed inverse relationships with atopy, less so with asthma. Also, in a subsequent confirmation study using a quantitative method (qPCR), higher mattress levels of specifically targeted bacterial groups - Mycobacterium spp., Bifidobacteriaceae spp. and two different clusters of Clostridium spp. - were associated with a lower prevalence of atopy. CONCLUSION: DNA fingerprinting proved useful in identifying bacterial signals that were associated with atopy in particular. These findings were quantitatively confirmed for selected bacterial groups with a second method. High correlations between the different bacterial exposures impede a clear attribution of protective effects to one specific bacterial group. More diverse bacterial flora in mattress dust may link to microbial exposure patterns that protect against development of atopic diseases. PMID- 26121167 TI - A Phase 1 exercise dose escalation study for stroke survivors with impaired walking. AB - BACKGROUND: Targeted exercise and increased practice can improve the mobility of stroke survivors. However, many stroke survivors continue to have reduced physical work capacity and impaired walking, and experience frequent falls after participating in physical rehabilitation programs. AIM: In this Phase 1 study, we used a dose escalation method, common in pharmaceutical trials, to determine the maximum tolerable dose of multimodal exercise in community-dwelling stroke survivors with mobility impairment. METHODS: Stroke survivors 14-59 months poststroke participated in a 12-week (36 sessions) multimodal exercise program implemented using a cumulative 3 + 3 dose escalation design (featuring increasing doses in successive cohorts of three participants), with set dose-limiting tolerance criteria. The exercise intervention included challenging balance activities, strength, and endurance training. The program was individualized and focused on task-specific requirements for walking in the community. RESULTS: Six survivors participated before escalation was ceased. Four participants were able to tolerate up to 10.5 h/week of exercise, which included 283 min of endurance, 182 min of task practice, 138 min of strengthening, and 28 min resting. The program led to increased walking distance (Six-Minute Walk Test) and faster mobility (4 Square Step Test, Timed Up and Go Test), with pre-postimprovements averaging 23-41%. CONCLUSIONS: This is the first multimodal exercise dose escalation study in stroke. The maximal dose of exercise identified was dramatically higher than the dose typically delivered to stroke survivors in current trials. We now plan to confirm safety and feasibility of this program in a larger Phase II trial. PMID- 26121168 TI - Morphometric correlates of dysarthric deficit in amyotrophic lateral sclerosis. AB - Our objective was to investigate the volumetric correlates of speech in amyotrophic lateral sclerosis (ALS). Twenty-three ALS patients had a structural 3D MRI scan, neuropsychological, linguistic and speech assessments. Twenty-three healthy adults of comparable age, education, white-matter hyperintensity load and intracranial volumes were also recruited. Between-group differences in grey matter and white matter (WM) were examined to characterize ALS patients accurately. The association between residual speech and volumetric maps was studied in these patients. Results demonstrated that ALS patients showed a pattern of WM reduction, which was located in peri-cortical motor/premotor fibres bilaterally, and in a large volume extending from the pons/midbrain to the cerebellum. A speech composite score was computed, and this was positively associated with premotor/supplementary-motor WM bilaterally, and right cerebellar WM. Since premotor associations were found in volumes where ALS patients showed WM reduction, this region is believed to be directly involved in speech execution in this group. Since cerebellar associations were instead found in volumes free from shrinkage, this region is interpreted as playing a modulatory role, compensating for the impact of ALS pathology. PMID- 26121169 TI - Predictors of impaired communication in amyotrophic lateral sclerosis patients with tracheostomy-invasive ventilation. AB - Predictors of communication impairment in patients with amyotrophic lateral sclerosis (ALS) using tracheostomy-invasive ventilation (TIV) were investigated. Seventy-six ALS patients using TIV were enrolled and classified into three subgroups of communication ability: patients who could communicate with communication devices (Stage I), patients who had difficulty with communication (Stage II, III, or IV), and patients who could not communicate by any means (Stage V). Predictors of communication impairment were analysed by the Cox proportional hazard model. Results demonstrated that there were no significant differences in disease duration between subgroups. Within 24 months after disease onset, patients who needed TIV and tube feeding, developed oculomotor impairment or became totally quadriplegic and progressed from Stage I to II and V significantly earlier. Multivariate analyses revealed that within 24 months from onset, the need for TIV and progression to total quadriplegia were significant events in patients who progressed to Stage II, whereas the development of oculomotor limitation was significant in patients who progressed to Stage V. In conclusion, TIV, impaired oculomotor movement and total quadriplegia are predictors of severe communication impairment. Rapid disease progression might indicate future communication impairment after the use of TIV. We highly recommend early detection of impaired communication and identification of the best methods of communication. PMID- 26121170 TI - A revision of the El Escorial criteria - 2015. PMID- 26121171 TI - Associations between executive functions and long-term stress reactions after extreme trauma: A two-year follow-up of the Utoya survivors. AB - Terror attacks cause variation in everyday functioning across several domains. This paper focuses on the individual long-term costs in terms of clinical symptoms and cognitive (e.g., shifting, inhibition, and spatial working memory) difficulties associated with these symptoms in 24 survivors of a terror attack in Norway. Another 24 controls were included for comparison purposes. Participants were administered a battery of clinical and neurocognitive tests. Results showed that all clinical variables differed as a function of group, ps <= .001, eta2 >= .64, but no significant differences were revealed for the neurocognitive measures. In the survivor group, shifting capacity and its interaction with gender predicted intrusion symptoms, p = .045, etap2 = .338, and symptoms of avoidance, p = .008, etap2 = .453. We discuss the findings in relation to theoretical models and therapeutic interventions. PMID- 26121172 TI - Predicting professional quality of life among professional and volunteer caregivers. AB - This study is one of the few that has compared volunteers' professional quality of life (PQL), which includes secondary traumatic stress (STS), burnout, and compassion satisfaction (CS), to those of professional caregivers. In addition, the research compared the ethical behavior of volunteers with that of professional therapists and examined the connection between years of experience, ethical behavior, and PQL. One hundred eighty-three volunteers and professional caregivers filled out a sociodemographic questionnaire, an Ethical Behavior Questionnaire and the Professional Quality of Life (ProQOL) questionnaire. The results indicated that professional caregivers report lower levels of STS and burnout, and higher levels of CS and ethical behavior compared with volunteer caregivers. Moreover, the findings suggest that ethical behavior correlates with STS, burnout, and CS. Ethical behavior has a protective value for mental health caregivers. The discussion emphasizes the value of a professional code of ethics and ethical training for professional and volunteering caregivers. PMID- 26121173 TI - Early PTSD symptom sub-clusters predicting chronic posttraumatic stress following sexual assault. AB - Contemporary models of PTSD disaggregate this disorder into sub-clusters that differentially impact functioning. Severity of different types of PTSD symptoms in the acute posttrauma period may be predictive of the course of PTSD over time. Few research studies, however, have examined the predictive utility of PTSD sub clusters. This study sought to determine the relative predictive validity of 4 sub-clusters, namely reexperiencing, strategic avoidance, emotional numbing, and hyperarousal, assessed within 1 month of a sexual assault. Women (N=120) who had been sexually assaulted completed self-report measures at 1 and 4 months postassault. Linear regression analyses revealed that early reexperiencing and emotional numbing sub-clusters uniquely contributed to the prediction of PTSD symptoms at month 4 (strategic avoidance and hyperarousal did not). To help explain and contextualize these findings, we explored the extent to which posttraumatic cognitions mediated the relationship between acute reexperiencing and emotional numbing and later PTSD symptoms. Simultaneous multiple mediation analyses revealed that general negative cognitions about the self significantly mediated the relationship between both reexperiencing and emotional numbing and month 4 PTSD symptoms. These findings have significant clinical implications, pointing to the importance of targeting posttraumatic cognitions in the acute posttrauma phase. PMID- 26121174 TI - Hypervigilance in college students: Associations with betrayal and dissociation and psychometric properties in a Brief Hypervigilance Scale. AB - Betrayal trauma theory (Freyd, 1994, 1996) proposes that traumas high in social betrayal are expected to lead to psychological outcomes of dissociation, amnesia, and/or shame because these responses are adaptive to a survivor trying to preserve a necessary relationship in the face of mistreatment. Within the field of trauma studies more generally, there is substantial support for the proposition that traumas that cause intense fear should lead to posttraumatic anxiety and hypervigilance. Despite ample evidence for both theorized causal pathways, very few studies have tested associations between betrayal exposure, hypervigilance, and dissociation. The current study had 2 aims: first, as no self report measure of hypervigilance had been developed for nonveteran populations, we sought to identify a subset of Hypervigilance Questionnaire (Knight, 1993) items that validly and reliably measure hypervigilance within college undergraduates (n = 489; 62.6% female, 69.9% Caucasian) with and without elevated levels of posttraumatic stress. Second, we tested the associations among trauma history, hypervigilance, and dissociation. Psychometric analyses revealed 5 hypervigilance items we introduce as the Brief Hypervigilance Scale. Partial correlations revealed that each posttraumatic response was not related to a history of low betrayal trauma (i.e. non-interpersonal trauma) controlling for betrayal trauma (i.e. interpersonal trauma), but was related to betrayal trauma controlling for low betrayal trauma. These associations remained significant after controlling for the other posttraumatic response (i.e. hypervigilance or dissociation). Follow-up analyses revealed that hypervigilance was independently associated with adult, but not child high betrayal trauma, and the opposite was true for dissociation. Implications for theory, research, and clinical practice are discussed. PMID- 26121175 TI - Treatment initiation and dropout from prolonged exposure and cognitive processing therapy in a VA outpatient clinic. AB - Emerging data suggest that few veterans are initiating prolonged exposure (PE) and cognitive processing therapy (CPT) and dropout levels are high among those who do start the therapies. The goal of this study was to use a large sample of veterans seen in routine clinical care to 1) report the percent of eligible and referred veterans who (a) initiated PE/CPT, (b) dropped out of PE/CPT, (c) were early PE/CPT dropouts, 2) examine predictors of PE/CPT initiation, and 3) examine predictors of early and late PE/CPT dropout. We extracted data from the medical records of 427 veterans who were offered PE/CPT following an intake at a Veterans Health Administration (VHA) PTSD Clinical Team. Eighty-two percent (n = 351) of veterans initiated treatment by attending Session 1 of PE/CPT; among those veterans, 38.5% (n = 135) dropped out of treatment. About one quarter of veterans who dropped out were categorized as early dropouts (dropout before Session 3). No significant predictors of initiation were identified. Age was a significant predictor of treatment dropout; younger veterans were more likely to drop out of treatment than older veterans. Therapy type was also a significant predictor of dropout; veterans receiving PE were more likely to drop out late than veterans receiving CPT. Findings demonstrate that dropout from PE/CPT is a serious problem and highlight the need for additional research that can guide the development of interventions to improve PE/CPT engagement and adherence. PMID- 26121176 TI - Correlates of improvement in substance abuse among dually diagnosed veterans with post-traumatic stress disorder in specialized intensive VA treatment. AB - Substantial rates of substance use comorbidity have been observed among veterans with Post-Traumatic Stress Disorder (PTSD), highlighting the need to identify patient and program characteristics associated with improved outcomes for substance abuse. Data were drawn from 12,270 dually diagnosed veterans who sought treatment from specialized intensive Veterans Health Administration PTSD programs between 1993 and 2011. The magnitude of the improvement in Addiction Severity Index (ASI) alcohol and drug use composite scores from baseline was moderate, with effect sizes (ES) of -.269 and -.287, respectively. Multivariate analyses revealed that treatment in longer-term programs, being prescribed psychiatric medication, and planned participation in reunions were all associated with slightly improved outcomes. Reductions in substance use measures were associated with robust improvements in PTSD symptoms and violent behavior. These findings suggest not only synergistic treatment effects linking improvement in PTSD symptoms with substance use disorders among dually diagnosed veterans with PTSD, but also to reductions in violent behavior. Furthermore, the findings indicate that proper discharge planning in addition to intensity and duration of treatment for dually diagnosed veterans with severe PTSD may result in better outcomes. Further dissemination of evidence-based substance abuse treatment may benefit this population. PMID- 26121177 TI - CD1d knockout mice exhibit aggravated contact hypersensitivity responses due to reduced interleukin-10 production predominantly by regulatory B cells. AB - Conflicting observations have been reported concerning the role of CD1d-dependent natural killer T (NKT) cells in contact hypersensitivity (CHS), supporting either a disease-promoting or downregulatory function. We studied the role of NKT cells in CHS by comparing the immune response in CD1d knockout (CD1d KO) and wild-type (Wt) mice after contact allergen exposure. For induction of CHS, C57BL/6 CD1d KO mice (n = 6) and C57BL/6 Wt mice (n = 6) were sensitised with 1% (w/v) dinitrochlorobenzene (DNCB) or vehicle for three consecutive days and subsequently challenged with a single dose of 0.5% DNCB (w/v) on the ears fifteen days later. We demonstrate that CD1d KO mice, as compared with Wt littermates, have more pronounced infiltration of mononuclear cells in the skin (29.1% increase; P < 0.001), lower frequencies of interleukin-10(+) B cells (B(regs) ) in the spleen (53.2% decrease; P < 0.05) and peritoneal cavity (80.8% decrease; P < 0.05) and increased production of interferon-gamma (3-fold; P < 0.05) after DNCB sensitisation and challenge, which suggests an important regulatory and protective role of CD1d-dependent NKT cells in CHS in our model, at least in part via regulation of IL-10 producing B(regs) . PMID- 26121178 TI - Improve First-Cycle Efficiency and Rate Performance of Layered-Layered Li1.2Mn0.6Ni0.2O2 Using Oxygen Stabilizing Dopant. AB - The poor first-cycle Coulombic efficiency and rate performance of the Li-rich layered-layered oxides are associated with oxygen gas generation in the first activation charging and sluggish charge transportation along the layers. In this work, we report that barium doping improves the first-cycle efficiency of Li-rich layered-layered Li1.2Mn0.6Ni0.2O2 via suppression of the oxidation of O(2-) ions in the first charging. This effect can be attributed to the stabilizing effect of the barium cations on the oxygen radical intermediates generated during the oxidation of O(2-). Meanwhile, because the stabilized oxygen radicals likely facilitate the charge transportation in the layered-layered structure, the barium doped Li1.2Mn0.6Ni0.2O2 exhibits significant improvement in rate performance. Stabilizing the oxygen radicals could be a promising strategy to improve the electrochemical performance of Li-rich layered-layered oxides. PMID- 26121179 TI - Room for Death--International museum-visitors' preferences regarding the end of their life. AB - Just as pain medications aim to relieve physical suffering, supportive surrounding for death and dying may facilitate well-being and comfort. However, little has been written of the experience of or preferences for the surroundings in which death and dying take place. In this study, we aim to complement our research from perspectives of patients, family members and staff, with perspectives from an international sample of the general public. Data derives from a project teaming artists and craftspeople together to create prototypes of space for difficult conversations in end-of-life (EoL) settings. These prototypes were presented in a museum exhibition, "Room for Death", in Stockholm in 2012. As project consultants, palliative care researchers contributed a question to the public viewing the exhibition, to explore their reflections: "How would you like it to be around you when you are dying?" Five-hundred and twelve responses were obtained from visitors from 46 countries. While preliminary analysis pointed to many similarities in responses across countries, continued analysis with a phenomenographic approach allowed us to distinguish different foci related to how preferences for surroundings for EoL were conceptualized. Responses were categorized in the following inductively-derived categories: The familiar death, The 'larger-than life' death, The lone death, The mediated death, The calm and peaceful death, The sensuous death, The 'green' death, and The distanced death. The responses could relate to a single category or be composites uniting different categories in individual combinations, and provide insight into different facets of contemporary reflections about death and dying. Despite the selective sample, these data give reason to consider how underlying assumptions and care provision in established forms for end-of-life care may differ from people's preferences. This project can be seen as an example of innovative endeavors to promote public awareness of issues related to death and dying, within the framework of health-promoting palliative care. PMID- 26121180 TI - Quality of Life in Head and Neck Cancer Patient-Caregiver Dyads: A Systematic Review. AB - BACKGROUND: As we learn about patient experiences with head and neck cancer, it is also important to consider caregivers so that family-centered care can be improved. OBJECTIVES: The purpose of this systematic review was to (a) identify the research questions, methods, and measures that have been examined in quality of-life studies with head and neck cancer patients and their caregivers (dyads) and (b) identify gaps and future directions for research and practice. METHODS: We conducted a systematic search of electronic databases using keywords (head and neck cancer, caregiver, quality of life) and included studies that assessed quality of life-related constructs in both patients and caregivers. A dyadic quality-of-life conceptual model guided the summary of observations. RESULTS: Thirteen studies met eligibility criteria. The most common research questions included comparing patient and caregiver quality of life, examining relationships between personal and clinical factors in 1 dyad member and a quality-of-life outcome in the other, and exploring relationships between interpersonal processes and quality of life. Psychological quality-of-life constructs were most commonly studied. There was substantial variability in study findings, in part due to differences in study questions and samples. CONCLUSIONS: Future research is needed to examine longitudinal interpersonal processes in head and neck cancer. Unique caregiving tasks should be inventoried, and dyadic data analysis techniques should be used. IMPLICATIONS FOR PRACTICE: Head and neck cancer dramatically affects quality of life in patients and caregivers, and quality clinical care requires a dyadic focus. Oncology nurses have a unique opportunity to develop and implement dyadic illness management models for head and neck cancer. PMID- 26121181 TI - Epithelial deletion of podoplanin is dispensable for re-epithelialization of skin wounds. AB - The mucin-like transmembrane protein podoplanin (PDPN) is prominently represented in tumor-associated gene expression signatures of numerous types of cancer including squamous cell carcinoma, and gain-of-function and knockdown approaches in tissue culture strongly suggested an important role of PDPN in cell proliferation, migration and adhesion. PDPN is absent during epidermal homeostasis but is highly expressed in basal keratinocytes during cutaneous wound healing. Enhanced motility of immortalized keratinocytes upon ectopic PDPN overexpression argues for wound healing defects upon podoplanin deficiency in keratinocytes; however, in vivo data that unequivocally define the impact of PDPN by functional studies in a physiologically relevant system are still missing. Here, we have applied an in vivo loss-of-function approach by generating a novel transgenic mouse line with keratinocyte-specific podoplanin deficiency. Performing cutaneous full-thickness excisional wounds to examine re epithelialization capacity, unexpectedly, no defects were observed in wound healing properties of mutant mice. Similarly, PDPN-deficient primary keratinocytes showed no impairment in migration, adhesion or proliferation. Thus, PDPN function is not rate-limiting for re-epithelialization but may be functionally compensated by an as yet unknown protein. Our data also call for in vivo functional studies on PDPN in settings of skin tumor development and progression to clarify PDPN's role in skin pathology. PMID- 26121182 TI - The Importance of Lesbian, Gay, Bisexual, and Transgender Health in Neurology: What's in a Name? PMID- 26121183 TI - The PCA learning effect: An emerging correlate of face memory during childhood. AB - Human adults implicitly learn the prototype and the principal components of the variability distinguishing faces (Gao & Wilson, 2014). Here we measured the implicit learning effect in adults and 9-year-olds, and with a modified child friendly procedure, in 7-year-olds. All age groups showed the implicit learning effect by falsely recognizing the average (the prototype effect) and the principal component faces as having been seen (the PCA learning effect). The PCA learning effect, but not the prototype effect increased between 9years of age and adulthood and at both ages was the better predictor of memory for the actually studied faces. In contrast, for the 7-year-olds, the better predictor of face memory was the prototype effect. The pattern suggests that there may be a developmental change between ages 7 and 9 in the mechanism underlying memory for faces. We provide the first evidence that children as young as age 7 can extract the most important dimensions of variation represented by principal components among individual faces, a key ability that grows stronger with age and comes to underlie memory for faces. PMID- 26121184 TI - The impact of abatacept treatment on the vasculature in patients with rheumatoid arthritis. PMID- 26121185 TI - Generalized social anxiety disorder: A still-neglected anxiety disorder 3 decades since Liebowitz's review. AB - In the 3 decades since Liebowitz's review of 'a neglected anxiety disorder,' controversy and challenges have remained in the study of social anxiety disorder (SAD). This review examines evidence around the classification and subtyping of SAD, focusing on generalized SAD. Substantial discrepancies and variation in definition, epidemiology, assessment, and treatment of generalized SAD exist as the international literature on it has grown. In East Asian cultures in particular, study of taijin kyofusho has been important to a broadened conceptualization of SAD into generalized SAD. Despite important progress with biological and other studies, many challenges in the understanding of generalized SAD will remain in the years to come. PMID- 26121186 TI - A Weibull statistics-based lignocellulose saccharification model and a built-in parameter accurately predict lignocellulose hydrolysis performance. AB - Renewable energy from lignocellulosic biomass has been deemed an alternative to depleting fossil fuels. In order to improve this technology, we aim to develop robust mathematical models for the enzymatic lignocellulose degradation process. By analyzing 96 groups of previously published and newly obtained lignocellulose saccharification results and fitting them to Weibull distribution, we discovered Weibull statistics can accurately predict lignocellulose saccharification data, regardless of the type of substrates, enzymes and saccharification conditions. A mathematical model for enzymatic lignocellulose degradation was subsequently constructed based on Weibull statistics. Further analysis of the mathematical structure of the model and experimental saccharification data showed the significance of the two parameters in this model. In particular, the lambda value, defined the characteristic time, represents the overall performance of the saccharification system. This suggestion was further supported by statistical analysis of experimental saccharification data and analysis of the glucose production levels when lambda and n values change. In conclusion, the constructed Weibull statistics-based model can accurately predict lignocellulose hydrolysis behavior and we can use the lambda parameter to assess the overall performance of enzymatic lignocellulose degradation. Advantages and potential applications of the model and the lambda value in saccharification performance assessment were discussed. PMID- 26121187 TI - Alphalpha 2a-Adrenoceptor Gene Expression and Early Life Stress-Mediated Propensity to Alcohol Drinking in Outbred Rats. AB - Stressful events early in life, later high alcohol consumption and vulnerability to alcohol use disorder (AUD) are tightly linked. Norepinephrine is highly involved in the stress response and the alpha2A-adrenoceptor, which is an important regulator of norepinephrine signalling, is a putative target in pharmacotherapy of AUD. The aim of the present study was to investigate the effects of early-life stress and adult voluntary alcohol drinking on the alpha2A adrenoceptor. The relative expression and promoter DNA methylation of the Adra2a gene were measured in the hypothalamus, a key brain region in stress regulation. A well-characterized animal model of early-life stress was used in combination with an episodic voluntary drinking in adulthood. Alcohol drinking rats with a history of early-life stress had lower Adra2a expression than drinking rats not exposed to stress. Alcohol intake and Adra2a gene expression were negatively correlated in high-drinking animals, which were predominantly rats subjected to early-life stress. The results provide support for a link between early-life stress, susceptibility for high alcohol consumption, and low Adra2a expression in the hypothalamus. These findings can increase our understanding of the neurobiological basis for vulnerability to initiate risk alcohol consumption and individual differences in the response to alpha2A-adrenoceptor agonists. PMID- 26121188 TI - Forecasting and Analyzing the Disease Burden of Aged Population in China, Based on the 2010 Global Burden of Disease Study. AB - BACKGROUND: Forecasting the disease burden of the elderly will contribute to make a comprehensive assessment about physical and mental status of the elderly in China and provide a basis for reducing the negative consequences of aging society to a minimum. METHODS: This study collected data from a public database online provided by Global Burden of Disease Study 2010. Grey model GM (1, 1) was used to forecast all-cause and disease-specific rates of disability adjusted life years (DALYs) in 2015 and 2020. RESULTS: After cross-sectional and longitudinal analysis, we found that non-communicable diseases (NCDs) were still the greatest threats in the elderly, followed by injuries. As for 136 predicted causes, more than half of NCDs increased obviously with age, less than a quarter of communicable, material, neonatal, and nutritional disorders or injuries had uptrend. CONCLUSIONS: The findings display the health condition of the Chinese elderly in the future, which will provide critical information for scientific and sociological researches on preventing and reducing the risks of aging society. PMID- 26121189 TI - Physical Activity and Snus: Is There a Link? AB - The study aimed at assessing the link between physical activity (PA), sports activity and snus use among young men in Switzerland. Data from the Cohort Study on Substance Use Risk Factors (C-SURF) were used to measure PA with the International Physical Activity Questionnaire and sports activity with a single item. Multivariate logistic regression analysis was conducted to measure the association between snus use, PA and sports activity. Similar models were run for smoking and snuff use. Snus use increased in a dose-response association with PA (high level: OR = 1.72; 95% CI 1.16-2.55) and with individuals exercising once a week or more often (OR = 1.65; 95% CI 1.26-2.16; p < 0.001) or almost every day (OR = 2.27; 95% CI 1.72-3.01; p < 0.001) in separate models. Entered simultaneously, only sports and exercise maintained a basically unchanged significant dose-response relationship, whereas PA became non-significant. A non significant dose-response relation was found for cigarette smoking and snuff use, indicating that the association with sport is specific to snus and not to tobacco use in general or smokeless tobacco in particular. This study showed that the association between snus use and sports is not specific to Nordic countries. PMID- 26121190 TI - Cardiovascular mortality associated with 5 leading risk factors: national and state preventable fractions estimated from survey data. AB - BACKGROUND: Impressive decreases in cardiovascular mortality have been achieved through risk factor reduction and clinical intervention, yet cardiovascular disease remains a leading cause of death nationally. OBJECTIVE: To estimate up-to date preventable fractions of cardiovascular mortality associated with elimination and reduction of 5 leading risk factors nationally and by state in the United States. DESIGN: Cross-sectional and cohort studies. SETTING: Nationally representative and state-representative samples of the U.S. population. PARTICIPANTS: Adults aged 45 to 79 years. MEASUREMENTS: Self-reported risk factor status in the BRFSS (Behavioral Risk Factor Surveillance System) 2009 2010 was corrected to approximate clinical definitions. The relative hazards of cardiovascular death (International Classification of Diseases, 10th Revision, codes I00 to I99) associated with risk factors were estimated using data from NHANES (National Health and Nutrition Examination Survey) (1988-1994 and 1999 2004, followed through 2006). RESULTS: The preventable fraction of cardiovascular mortality associated with complete elimination of elevated cholesterol levels, diabetes, hypertension, obesity, and smoking was 54.0% for men and 49.6% for women in 2009 to 2010. When the more feasible target of reducing risk factors to the best achieved levels in the states was considered, diabetes (1.7% and 4.1%), hypertension (3.8% and 7.3%), and smoking (5.1% and 4.4%) were independently associated with the largest preventable fractions among men and women, respectively. With both targets, southern states had the largest preventable fractions, and western states had the smallest. LIMITATION: Self-reported state data; mortality hazards relied on baseline risk factor status. CONCLUSION: Major modifiable cardiovascular risk factors collectively accounted for half of cardiovascular deaths in U.S. adults aged 45 to 79 years in 2009 to 2010. Fewer than 10% of cardiovascular deaths nationally could be prevented if all states were to achieve risk factor levels observed in the best-performing states. PRIMARY FUNDING SOURCE: Robert Wood Johnson Foundation. PMID- 26121191 TI - Computed Tomography Radiation Dose in Patients With Suspected Urolithiasis. PMID- 26121192 TI - A gut feeling about immunity. PMID- 26121045 TI - Application of DNA Barcodes in Asian Tropical Trees--A Case Study from Xishuangbanna Nature Reserve, Southwest China. AB - BACKGROUND: Within a regional floristic context, DNA barcoding is more useful to manage plant diversity inventories on a large scale and develop valuable conservation strategies. However, there are no DNA barcode studies from tropical areas of China, which represents one of the biodiversity hotspots around the world. METHODOLOGY AND PRINCIPAL FINDINGS: A DNA barcoding database of an Asian tropical trees with high diversity was established at Xishuangbanna Nature Reserve, Yunnan, southwest China using rbcL and matK as standard barcodes, as well as trnH-psbA and ITS as supplementary barcodes. The performance of tree species identification success was assessed using 2,052 accessions from four plots belonging to two vegetation types in the region by three methods: Neighbor Joining, Maximum-Likelihood and BLAST. We corrected morphological field identification errors (9.6%) for the three plots using rbcL and matK based on Neighbor-Joining tree. The best barcode region for PCR and sequencing was rbcL (97.6%, 90.8%), followed by trnH-psbA (93.6%, 85.6%), while matK and ITS obtained relative low PCR and sequencing success rates. However, ITS performed best for both species (44.6-58.1%) and genus (72.8-76.2%) identification. With trnH-psbA slightly less effective for species identification. The two standard barcode rbcL and matK gave poor results for species identification (24.7-28.5% and 31.6 35.3%). Compared with other studies from comparable tropical forests (e.g. Cameroon, the Amazon and India), the overall performance of the four barcodes for species identification was lower for the Xishuangbanna Nature Reserve, possibly because of species/genus ratios and species composition between these tropical areas. CONCLUSIONS/SIGNIFICANCE: Although the core barcodes rbcL and matK were not suitable for species identification of tropical trees from Xishuangbanna Nature Reserve, they could still help with identification at the family and genus level. Considering the relative sequence recovery and the species identification performance, we recommend the use of trnH-psbA and ITS in combination as the preferred barcodes for tropical tree species identification in China. PMID- 26121193 TI - Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. AB - Recent advances in genome-wide association studies (GWAS) across autoimmune and immune-mediated diseases have augmented our understanding of pathogenic mechanisms underlying these diseases. This has further highlighted their heterogeneous nature, both within and between diseases. Furthermore, varying responses to therapy have also served to underline the importance of this heterogeneity in the manner in which these diseases are diagnosed and treated. Here we discuss our current understanding of the shared pathways of autoimmunity, including the tumor necrosis factor (TNF), major histocompatibility complex (MHC), interleukin 23 receptor (IL23R) and protein tyrosine phosphatase non receptor type 22 (PTPN22) pathways. In addition, we summarize effective specific therapies tested across major autoimmune diseases, highlighting the insight they have provided into disease mechanisms and their implications for potential future improvements. PMID- 26121194 TI - Influence of nutrient-derived metabolites on lymphocyte immunity. AB - Organisms need to protect themselves against potential dangers from their surroundings, yet they require constant and intimate interactions with the same environment for their survival. The immune system is instrumental for protection against invading organisms and their toxins. The immune system consists of many cell types and is highly integrated within other tissues. Immune activity is particularly enriched at surfaces that separate the host from its environment, such as the skin and the gastrointestinal tract. This enables protection at sites directly at risk but also enables environmental factors to influence the maturation and function of immune structures and cells. Recent work has indicated that the diet in particular is able to influence the immune system and thus affect the development of inflammatory disease. This review aims to highlight recent work on how external factors, with a focus on those derived from the diet such as vitamin A, can have a direct or indirect deterministic influence on the activity and function of immunity. PMID- 26121195 TI - The emerging role of resident memory T cells in protective immunity and inflammatory disease. AB - Over the past decade, it has become clear that there is an important subset of memory T cells that resides in tissues-tissue-resident memory T (TRM) cells. There is an emerging understanding that TRM cells have a role in human tissue specific immune and inflammatory diseases. Furthermore, the nature of the molecular signals that maintain TRM cells in tissues is the subject of much investigation. In addition, whereas it is logical for TRM cells to be located in barrier tissues at interfaces with the environment, these cells have also been found in brain, kidney, joint and other non-barrier tissues in humans and mice. Given the biology and behavior of these cells, it is likely that they have a role in chronic relapsing and remitting diseases of both barrier and non-barrier tissues. In this Review we discuss recent insights into the biology of TRM cells with a particular focus on their roles in disease, both proven and putative. PMID- 26121196 TI - IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune mediated inflammatory diseases. AB - The cytokine interleukin-12 (IL-12) was thought to have a central role in T cell mediated responses in inflammation for more than a decade after it was first identified. Discovery of the cytokine IL-23, which shares a common p40 subunit with IL-12, prompted efforts to clarify the relative contribution of these two cytokines in immune regulation. Ustekinumab, a therapeutic agent targeting both cytokines, was recently approved to treat psoriasis and psoriatic arthritis, and related agents are in clinical testing for a variety of inflammatory disorders. Here we discuss the therapeutic rationale for targeting these cytokines, the unintended consequences for host defense and tumor surveillance and potential ways in which these therapies can be applied to treat additional immune disorders. PMID- 26121199 TI - Feasibility of Routinely Offering Early Combined Antiretroviral Therapy to HIV infected Infants in a Resource-limited Country: The ANRS-PediaCAM Study in Cameroon. AB - BACKGROUND: Early diagnosis of HIV is increasingly available for infants in resource-limited settings. We assessed the timing of events until combined antiretroviral therapy (cART) initiation in infants diagnosed before 7 months of age in Cameroon. METHODS: The ANRS-PediaCAM cohort included HIV-infected infants followed from birth associated with prevention of mother-to-child transmission activities (group 1) or diagnosed for any other reason before 7 months of age (group 2). All infants were offered free cART early after diagnosis. Frequency and factors associated with no or delayed cART initiation, were studied using univariable and multivariable logistic regressions. RESULTS: Between 2007 and 2011, 210 HIV-infected infants (group 1: 69; group 2: 141) were included. Fewer group 1 (14.3%) than group 2 (59.1%) infants were symptomatic (World Health Organization stage 3 or 4). Overall, 5.7% (n = 12) died before receiving any cART. Of the remaining 198 infants, 3.0% (n = 6) were not treated. The median age at initiating cART was 4.1 months [interquartile range (IQR): 3.2-5.6]. The median time until cART initiation after HIV testing was 6.2 weeks (IQR: 4.4-9.4) in group 1 and 5.1 weeks (IQR: 2.9-9.4) in group 2. No or delayed cART, observed for 37.9% (75 of 198) of the infants, was associated with clinical site [adjusted odds ratio (aOR): 4.8; 95% confidence interval: (2.1-11.2)], late diagnosis [aOR: 2.0 (0.9-4.1)], and delayed pretherapeutic biological assessment [aOR: 3.7 (1.4 10.0)]. CONCLUSIONS: Although most children included were treated before age 7 months, the initiation of therapy was delayed for more than 1 in 3. The period around HIV diagnosis is critical and should be better managed to reduce delays before cART initiation. PMID- 26121197 TI - Inflammasomes: mechanism of action, role in disease, and therapeutics. AB - The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. They have been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research. PMID- 26121201 TI - Risk Factors for Bloodstream Infection After Living-donor Liver Transplantation in Children. AB - BACKGROUND: Postoperative bloodstream infection (BSI) is the most important determinant of recipient morbidity and mortality after liver transplantation (LT). Children who underwent LT are at the highest risk of developing BSI because of the significant surgical intervention, use of multiple devices, and administration of immunosuppressive agents. However, information regarding the risk factors for BSI in children after LT is limited. METHODS: We retrospectively reviewed 210 children who underwent living-donor LT at the largest pediatric LT center in Japan. Patients' characteristics, blood culture results and clinical outcomes were extracted from electronic medical records. Univariate and multivariate analyses were performed to identify the risk factors for BSI. RESULTS: Among the 210 LT recipients, 53 (25%) recipients experienced 86 episodes of BSI during the observational period. The source of the BSI was identified only in 38%: catheter-related BSI (27%) peritonitis (7%), urinary tract infection (2%), pneumonia (1%) and infectious endocarditis (1%). A multivariate analysis demonstrated that body weight (P = 0.03), volume of blood loss during LT (P < 0.001) and cytomegalovirus (CMV) antigenemia positivity (P = 0.04) were independently associated with the development of BSI. The risk factors for BSI differed when we analyzed the subjects according to age (<=24 months and >24 months), blood loss and pediatric end-stage liver disease/model for end-stage liver disease versus positive CMV antigenemia. CONCLUSIONS: The volume of blood loss, postoperative CMV antigenemia positivity and body weight were associated with the development of BSI after LT in pediatric living-donor recipients. To identify the age-specific predictors of BSI in children who underwent LT, age specific analyses are crucial. PMID- 26121200 TI - Immunogenicity and Safety of a 13-Valent Pneumococcal Conjugate Vaccine Given With DTaP Vaccine in Healthy Infants in Japan. AB - BACKGROUND: 13-Valent pneumococcal conjugate vaccine (PCV13) provides broader protection against pneumococcal disease than 7-valent pneumococcal conjugate vaccine (PCV7). This study performed in Japan compared the safety and immunogenicity of PCV13 with PCV7. METHODS: Healthy Japanese infants received PCV13 and diphtheria, tetanus and acellular pertussis vaccine (DTaP), PCV7 and DTaP or DTaP alone subcutaneously as a 3-dose infant series, with a fourth dose at 12 months of age. Antigen-specific immunoglobulin G (IgG) serum concentrations and opsonophagocytic activity and DTaP antibodies were measured 1 month after doses 3 and 4. RESULTS: After 3 and 4 doses, the proportion of subjects in the PCV13 + DTaP group achieving IgG concentrations >=0.35 MUg/mL to the 7 serotypes common to PCV13 and PCV7 was noninferior to that of the PCV7 + DTaP group. IgG geometric mean concentrations (GMCs) in the PCV13 + DTaP group were lower than but noninferior to the PCV7 + DTaP group GMCs. For the 6 additional pneumococcal serotypes, the proportion of PCV13 + DTaP group responders achieving IgG concentrations >=0.35 MUg/mL and IgG GMCs (except serotype 3 after dose 4) was noninferior to the lowest PCV7 + DTaP group pneumococcal response in PCV7 recipients, and responses to the 6 additional antigens were significantly higher. The majority of the subjects achieved prespecified antibody levels to DTaP antigens. GMCs to DTaP antigens were comparable among groups, except filamentous hemagglutinin (numerically higher in the DTaP alone group after dose 4). CONCLUSIONS: PCV13 + DTaP was as immunogenic as PCV7 for the 7 common pneumococcal antigens and elicited significantly higher responses to the 6 additional antigens. DTaP responses were comparable across groups. PCV13 given with DTaP was safe and well tolerated. PMID- 26121198 TI - Innate lymphoid cells in the initiation, regulation and resolution of inflammation. AB - A previously unappreciated cell type of the innate immune system, termed innate lymphoid cells (ILCs), has been characterized in mice and humans and found to influence the induction, regulation and resolution of inflammation. ILCs have an important role in these processes in mouse models of infection, inflammation and tissue repair. Further, disease-association studies in defined patient populations have identified significant alterations in ILC responses, suggesting a potential role for these cell populations in human health and disease. In this review we discuss the emerging family of ILCs, the role of ILCs in inflammation, and how current or novel therapeutic strategies could be used to selectively modulate ILC responses and limit chronic inflammatory diseases. PMID- 26121202 TI - Risk Factors for Measles in HIV-infected Children and Adolescents in Botswana. AB - We conducted a matched case-control study of 566 HIV-infected children in Botswana during a 2009-2010 measles outbreak to identify the risk factors for measles. Children in the oldest age quartile (>=13.1 years) were 4-fold more likely to acquire measles than those in the youngest quartile (<7.1 years). HIV infected older children and adolescents may benefit from additional measles vaccination. PMID- 26121203 TI - Correlation of a Vancomycin Pharmacokinetic Model and Trough Serum Concentrations in Pediatric Patients. AB - BACKGROUND: Vancomycin trough concentrations specific to pediatric patients have yet to be validated that achieve an area under the curve (AUC) over 24 hours to minimum inhibitory concentration (MIC) ratio >=400. The primary objective of this study was to validate a pharmacokinetic model in a pediatric hospital and determine the correlation between a calculated AUC/MIC ratio and measured trough vancomycin concentration. METHODS: A retrospective evaluation of patients aged 3 months to 18 years prescribed vancomycin at a pediatric hospital between January 2012 and June 2013. The correlation between patient-specific AUC/MIC and measured vancomycin trough concentration was assessed. RESULTS: Forty pediatric patients with 40 vancomycin trough concentrations and documented Staphylococcus aureus cultures were included in the study. Median age was 8.5 (interquartile range, 2 14.3) years, median weight 28.7 (range, 14-50.2) kg, and mean baseline serum creatinine 0.51 +/- 0.3 mg/dL. The mean daily dose of vancomycin prescribed was 58 +/- 13.8 mg/kg/d. The mean vancomycin trough concentration was 11 +/- 5.5 mcg/mL, and the mean AUC/MIC was 534 +/- 373. No correlation was found between trough concentration and AUC/MIC (r = 0.082, p = 0.07). CONCLUSIONS: This study validates the clinical applicability of a pharmacokinetic model for calculating vancomycin clearance to determine patient-specific AUC over 24 hours in pediatrics. Trough concentrations associated with proposed therapeutic AUC/MIC ratios were lower than reported in the adult population. Further research is needed to determine if AUC/MIC, trough concentration, or both is best for monitoring therapeutic efficacy of vancomycin in pediatrics. PMID- 26121204 TI - Clinical Endpoints for Respiratory Syncytial Virus Prophylaxis Trials in Infants and Children in High-income and Middle-income Countries. AB - Respiratory syncytial virus (RSV) continues to cause significant clinical and economic burden around the world. Historically, RSV-associated hospitalization was used as a primary endpoint for RSV prophylaxis trials in infants. However, because of the changing epidemiology and healthcare system landscape, this endpoint has become a critical bottleneck on the pathway to licensure for new therapeutics. A panel of 7 RSV experts was convened (Chicago, IL, May 22, 2014) to evaluate the challenges of defining RSV prevention endpoints for clinical trials and to develop endpoints that are clinically meaningful while minimizing subjectivity and bias to achieve sufficient consistency of response for regulatory approval. Particular consideration was given to the ability to collect data systematically and consistently in countries with different healthcare practices and systems, while capturing the greatest proportion of disease impact. The group consensus was that a clinically meaningful primary endpoint could include medically attended RSV illness in settings beyond RSV-associated hospitalizations alone, in particular, a composite reduction in hospitalization, emergency room or urgent care center visits because of an RSV respiratory infection. Relevant secondary endpoints included reductions in RSV lower respiratory tract infection, RSV-related intensive care unit rates, subsequent recurrent wheezing or asthma and direct and indirect costs. PMID- 26121206 TI - Adipose-derived stem cells: A candidate for liver regeneration. AB - The scarcity of donor livers and the impracticality of hepatocyte transplantation represent the biggest obstacles for the treatment of liver failure. Adipose derived stem cells, with their ability to differentiate into the hepatic lineage, provide a reliable alternative cell source with clear ethical and practical advantages. Moreover, adipose-derived stem cells can effectively repair liver damage by the dominant indirect pattern and increase the number of hepatocytes by the secondary direct pattern. In recent years, the development of the indirect pattern, which mainly includes immunomodulatory and trophic effects, has become a hot topic in the field of cell engineering. Therefore, adipose-derived stem cells are considered to be ideal therapeutic stem cells for human liver regeneration. In this article, we reviewed the advantages of adipose-derived stem cells in liver regeneration, and explore their underlying mechanisms. PMID- 26121205 TI - Respiratory Viral Detections During Symptomatic and Asymptomatic Periods in Young Andean Children. AB - BACKGROUND: Viruses are commonly detected in children with acute respiratory illnesses (ARIs) and in asymptomatic children. Longitudinal studies of viral detections during asymptomatic periods surrounding ARI could facilitate interpretation of viral detections but are currently scant. METHODS: We used reverse transcription polymerase chain reaction to analyze respiratory samples from young Andean children for viruses during asymptomatic periods within 8-120 days of index ARI (cough or fever). We compared viral detections over time within children and explored reverse transcription polymerase chain reaction cycle thresholds (CTs) as surrogates for viral loads. RESULTS: At least 1 respiratory virus was detected in 367 (43%) of 859 samples collected during asymptomatic periods, with more frequent detections in periods with rhinorrhea (49%) than those without (34%, P < 0.001). Relative to index ARI with human rhinovirus (HRV), adenovirus (AdV), respiratory syncytial virus (RSV) and parainfluenza virus detected, the same viruses were also detected during 32, 22, 10 and 3% of asymptomatic periods, respectively. RSV was only detected 8-30 days after index RSV ARI, whereas HRV and AdV were detected throughout asymptomatic periods. Human metapneumovirus and influenza were rarely detected during asymptomatic periods (<3%). No significant differences were observed in the CT for HRV or AdV during asymptomatic periods relative to ARI. For RSV, CTs were significantly lower during ARI relative to the asymptomatic period (P = 0.03). CONCLUSIONS: These findings indicate that influenza, human metapneumovirus, parainfluenza virus and RSV detections in children with an ARI usually indicate a causal relationship. When HRV or AdV is detected during ARI, the causal relationship is less certain. PMID- 26121207 TI - LbL Assembly of Albumin on Nitric Oxide-Releasing Silica Nanoparticles Using Suramin, a Polyanion Drug, as an Interlayer Linker. AB - Preformed protein corona of nanoparticles can be utilized as a promising formulation strategy for improving nano drug delivery. Nitric oxide (NO) is a labile molecule with extensive therapeutic implications. In this study, we test whether preformation of protein coatings can enhance the performance of NO delivering nanoparticles. S-Nitroso (SNO) silica nanoparticles (SNO-SiNPs) were prepared using a nanoprecipitation method. For the first time, bovine serum albumin (BSA) was used to coat NO-releasing nanoparticles, facilitated by a polyanionic drug, suramin, under a layer-by-layer (LbL) scheme. Bare and coated nanoparticles were characterized by zeta-potential, size, and spectroscopic measurements. We demonstrate that albumin/suramin-surface coassembly has advantages in preventing particle aggregation during lyophilization, controlling NO release and exerting an enhanced anticancer effect. PMID- 26121208 TI - High-performance multilayer composite membranes with mussel-inspired polydopamine as a versatile molecular bridge for CO2 separation. AB - It is desirable to develop high-performance composite membranes for efficient CO2 separation in CO2 capture process. Introduction of a highly permeable polydimethylsiloxane (PDMS) intermediate layer between a selective layer and a porous support has been considered as a simple but efficient way to enhance gas permeance while maintaining high gas selectivity, because the introduced intermediate layer could benefit the formation of an ultrathin defect-free selective layer owing to the circumvention of pore penetration phenomenon. However, the selection of selective layer materials is unfavorably restricted because of the low surface energy of PDMS. Various highly hydrophilic membrane materials such as amino group-rich polyvinylamine (PVAm), a representative facilitated transport membrane material for CO2 separation, could not be facilely coated over the surface of the hydrophobic PDMS intermediate layer uniformly. Inspired by the hydrophilic nature and strong adhesive ability of polydopamine (PDA), PDA was therefore selected as a versatile molecular bridge between hydrophobic PDMS and hydrophilic PVAm. The PDA coating endows a highly compatible interface between both components with a large surface energy difference via multiple-site cooperative interactions. The resulting multilayer composite membrane with a thin facilitated transport PVAm selective layer exhibits a notably enhanced CO2 permeance (1887 GPU) combined with a slightly improved CO2/N2 selectivity (83), as well as superior structural stability. Similarly, the multilayer composite membrane with a hydrophilic CO2-philic Pebax 1657 selective layer was also developed for enhanced CO2 separation performance. PMID- 26121209 TI - Prevalence of cognitive enhancer use among New Zealand tertiary students. AB - INTRODUCTION AND AIMS: Cognitive enhancers (CE) such as methylphenidate, amphetamines and modafinil are becoming more commonly used in non-medical situations. This study explored the prevalence and motivations for CE use in a New Zealand university. DESIGN AND METHODS: Students from the Schools of Pharmacy, Nursing, Medicine, Law and Accounting at a university in New Zealand were invited to complete a paper-based questionnaire that elicited their views on the prevalence, reasons for use and attitudes towards use of CEs. Questionnaires were distributed at the end of a third-year lecture (August-October 2012). Reasons for use and attitudes towards use was measured using a 7-point Likert scale from strongly agree (1) to strongly disagree (7). Descriptive and prevalence statistics were calculated. Inferential statistics were generated to explore the overall associations between CE use and how the respondents had first learnt about CEs, and to investigate reasons for CE use. RESULTS: The response fraction was 88.6 % (442/499) and the prevalence of CE use was 6.6% (95% confidence interval 4.5-9.0). Commonly cited reasons for use were to get high [M = 4.43, standard deviation (SD) 2.36], experimentation (M = 4.17, SD 2.36), increase alertness (M = 3.55, SD 2.48), to help concentrate (M = 3.48, SD 2.42), to help stay awake (M = 3.20, SD 2.33), to help study (M = 3.10, SD 2.47) and to concentrate better while studying (M = 3.00, SD 2.43). DISCUSSION AND CONCLUSIONS: Use of CEs was uncommon in contrast to the prevalence reported in the USA. The reasons for use also varied depending on which CE was used. Students who use CEs have differing attitudes towards their acceptability, which warrants further research about how these attitudes influence their use and attitudes towards academic performance. [Ram S(S), Hussainy S, Henning M, Jensen M, Russell B. Prevalence of cognitive enhancer use among New Zealand tertiary students. Drug Alcohol Rev 2016;35:245-351]. PMID- 26121210 TI - Predicting the Risk of a Second Basal Cell Carcinoma. AB - A third of basal cell carcinoma (BCC) patients will develop subsequent BCCs. We aimed to develop a simple model to predict the absolute risk of a second BCC. We observed 14,628 participants of Northern European ancestry from a prospective population-based cohort study. BCCs were identified using a linkage with the Dutch Pathology Registry (Pathological Anatomy National Automated Archive). Predictors for a second BCC included 13 phenotypic, lifestyle, and tumor-specific characteristics. The prediction model was based on the Fine and Gray regression model to account for the competing risk of death from other causes. Among 1,077 participants with at least one BCC, 293 developed a second BCC at a median of 3 years. Several well-known risk factors for a first BCC were not prognostic for a second BCC, whereas having more than one initial BCC was the strongest predictor. Discriminative ability at 3 years was reasonable (bootstrap validated c index=0.65). Three groups were created, with 7, 12, and 28% risk of a second BCC within 3 years. We conclude that a combination of readily available clinical characteristics can reasonably identify patients at high risk of a second BCC. External validation and extension with stronger predictors is desirable to further improve risk prediction. PMID- 26121211 TI - Cathelicidin LL-37 Induces Semaphorin 3A Expression in Human Epidermal Keratinocytes: Implications for Possible Application to Pruritus. PMID- 26121212 TI - Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13-Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation. AB - Many biochemical pathways involved in hair and skin development have not been investigated. Here, we reported on the lesions and investigated the mechanism underlying hair and skin abnormalities in Zdhhc13(skc4) mice with a deficiency in DHHC13, a palmitoyl-acyl transferase encoded by Zdhhc13. Homozygous affected mice showed ragged and dilapidated cuticle of the hair shaft (CUH, a hair anchoring structure), poor hair anchoring ability, and premature hair loss at early telogen phase of the hair cycle, resulting in cyclic alopecia. Furthermore, the homozygous affected mice exhibited hyperproliferation of the epidermis, disturbed cornification, fragile cornified envelope (CE, a skin barrier structure), and impaired skin barrier function. Biochemical investigations revealed that cornifelin, which contains five palmitoylation sites at cysteine residues (C58, C59, C60, C95, and C101), was a specific substrate of DHHC13 and that it was absent in the CUH and CE structures of the affected mice. Furthermore, cornifelin levels were markedly reduced when two palmitoylated cysteines were replaced with serine (C95S and C101S). Taken together, our results suggest that DHHC13 is important for hair anchoring and skin barrier function and that cornifelin deficiency contributes to cyclic alopecia and skin abnormalities in Zdhhc13(skc4) mice. PMID- 26121215 TI - Stabilization of Boiling Nuclei by Insoluble Gas: Can a Nanobubble Cloud Exist? AB - Liquid boiling that starts off with an insoluble gas bubble is thermodynamically analyzed. This case is an idealization of very low gas solubility and very slow diffusion of this gas in the boiling liquid. The analysis is made for a spherical, freely suspended bubble as well as for a bubble attached to a solid surface. The results predict the spontaneous formation of a stable, critical bubble at pressures higher than the saturation pressure. Stable critical radii are also predicted for pressures lower than the saturation pressure but in addition to unstable, larger critical bubbles. These bubbles are affected by the presence and nature of a solid surface. The present analysis provides a basis for a feasible explanation of the long-debated, long-time stability of nanobubbles. PMID- 26121213 TI - The Androgen Receptor Antagonizes Wnt/beta-Catenin Signaling in Epidermal Stem Cells. AB - Activation of Wnt/beta-catenin signaling in adult mouse epidermis leads to expansion of the stem cell compartment and redirects keratinocytes in the interfollicular epidermis and sebaceous glands (SGs) to differentiate along the hair follicle (HF) lineages. Here we demonstrate that during epidermal development and homeostasis there is reciprocal activation of the androgen receptor (AR) and beta-catenin in cells of the HF bulb. AR activation reduced beta-catenin-dependent transcription, blocked beta-catenin-induced induction of HF growth, and prevented beta-catenin-mediated conversion of SGs into HFs. Conversely, AR inhibition enhanced the effects of beta-catenin activation, promoting HF proliferation and differentiation, culminating in the formation of benign HF tumors and a complete loss of SG identity. We conclude that AR signaling has a key role in epidermal stem cell fate selection by modulating responses to beta-catenin in adult mouse skin. PMID- 26121214 TI - Impaired gp100-Specific CD8(+) T-Cell Responses in the Presence of Myeloid Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model. AB - Murine tumor models that closely reflect human diseases are important tools to investigate carcinogenesis and tumor immunity. The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in the percentages of CD4(+) T cells including regulatory T cells (Tregs) in CD45(+) leukocytes present in tumor tissue and draining lymph nodes (LNs). In contrast, the percentages of CD8(+) T cells were unchanged, and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein 100 (gp100)-specific CD8(+) T cells were not deleted during tumor development, as revealed by pentamer staining in the skin and draining LNs. They, however, were unresponsive to ex vivo gp100-peptide stimulation in late-stage tumor mice. Interestingly, immunosuppressive myeloid-derived suppressor cells (MDSCs) were recruited to tumor tissue with a preferential accumulation of granulocytic MDSC (grMDSCs) over monocytic MDSC (moMDSCs). Both subsets produced Arginase-1, inducible nitric oxide synthase (iNOS), and transforming growth factor-beta and suppressed T-cell proliferation in vitro. In this work, we describe the immune status of a spontaneous melanoma mouse model that provides an interesting tool to develop future immunotherapeutical strategies. PMID- 26121216 TI - Facile interchange of 3d and 4f ions in single-molecule magnets: stepwise assembly of [Mn4 ], [Mn3Ln] and [Mn2Ln2 ] cages within calix[4]arene scaffolds. AB - The central Mn(II) ions in a series of calix[4]arene-stabilised butterflies can be sequentially replaced with Ln(III) ions, maintaining the structural integrity of the molecule but transforming its magnetic properties. The replacement of Mn(II) for Gd(III) allows for the examination of the transferability of spin Hamiltonian parameters within the family as well as permitting their reliable determination. The introduction of the 4f ions results in weaker intramolecular magnetic exchange, an increase in the number of low-lying excited states, and an increase in magnetisation relaxation, highlighting the importance of exchange over single-ion anisotropy for the observation of SMM behaviour in this family of complexes. The presence of the [TM(II/III) (TBC[4])(OH)(solvent)] metalloligand (TM=transition metal, TBC=p-tBu-calix[4]arene) suggests that magnetic calix[n]arene building blocks can be employed to encapsulate a range of different "guests" within structurally robust "hosts". PMID- 26121217 TI - Nickel Cobaltite Nanostructures for Photoelectric and Catalytic Applications. AB - Bimetallic oxide nickel cobaltite (NiCo2 O4 ) shows extensive potential for innovative photoelectronic and energetic materials owing to their distinctive physical and chemical properties. In this review, representative fabrications and applications of NiCo2 O4 nanostructures are outlined for photoelectronic conversion, catalysis, and energy storage, aiming to promote the development of NiCo2 O4 nanomaterials in these fields through an analysis and comparison of their diverse nanostructures. Firstly, a brief introduction of the spinel structures, properties, and morphologies of NiCo2 O4 nanomaterials are presented. Then, the advanced progress of NiCo2 O4 nanomaterials for both photoelectronic conversion and energy fields is summarized including such examples as solar cells, electrocatalysis, and lithium ion batteries. Finally, further prospects and promising developments of NiCo2 O4 nanomaterials in these significant fields are proposed. PMID- 26121218 TI - Novel Two- and Three-Dimensional Organometallic-Organic Hybrid Materials Based on Polyphosphorus Complexes. AB - The reaction of the silver salt Ag[Al{OC(CF3)3}4] (1) with the P2 ligand complex [Cp2Mo2(CO)4(eta(2)-P2)] (2) and the organic ditopic linker trans-1,2-di(pyridine 4-yl)ethene (dpe) results in the formation of four novel organometallic-organic hybrid compounds. Depending on the reaction conditions, the two-dimensional networks [{Cp2Mo2(CO)4(MU4,eta(1:1:2:2)-P2)}(MU,eta(1:1) C12H10N2)Ag]n[Al{OC(CF3)3}4]n.0.075nCH2Cl2.1.425nC6H6 (3) and [{Cp2Mo2(CO)4(MU3,eta(2:2:2)-P2)}2(MU,eta(1:1) C12H10N2)3Ag2]n[Al{OC(CF3)3}4]2n.2nC7H8 (4) are accessible. The latter shows a two-dimensional (2D) -> 2D interpenetration structure. Furthermore, the formation of a unique three-dimensional polymer [{Cp2Mo2(CO)4(MU4,eta(1:1:2:2) P2)}(MU,eta(1:1)-C12H10N2)Ag]n[Al{OC(CF3)3}4]n.0.3nCH2Cl2 (5b) together with another 2D polymer [{Cp2Mo2(CO)4(MU4,eta(1:1:2:2)-P2)}(MU,eta(1:1) C12H10N2)3Ag2]n[Al{OC(CF3)3}4]2n.0.75CH2Cl2.0.5C7H8 (5a) was observed. In three of these polymers, unprecedented organometallic nodes were realized including one, two, or even four silver cations. All products were characterized by X-ray structural analysis and classified by the structural characteristics in three different network topologies. PMID- 26121219 TI - Correction to In Situ Formation of Carbon Nanotubes Encapsulated within Boron Nitride Nanotubes via Electron Irradiation. PMID- 26121221 TI - DNA with Parallel Strand Orientation: A Nanometer Distance Study with Spin Labels in the Watson-Crick and the Reverse Watson-Crick Double Helix. AB - Parallel-stranded (ps) DNA characterized by its sugar-phosphate backbones pointing in the same direction represents an alternative pairing system to antiparallel-stranded (aps) DNA with the potential to inhibit transcription and translation. 25-mer oligonucleotides were selected containing only dA.dT base pairs to compare spin-labeled nucleobase distances over a range of 10 or 15 base pairs in ps DNA with those in aps DNA. By means of the copper(I)-catalyzed Huisgen-Meldal-Sharpless alkyne-azide cycloaddition, the spin label 4-azido 2,2,6,6-tetramethylpiperidine-1-oxyl was clicked to 7-ethynyl-7-deaza-2' deoxyadenosine or 5-ethynyl-2'-deoxyuridine to yield 25-mer oligonucleotides incorporating two spin labels. The interspin distances between spin labeled residues were determined by pulse EPR spectroscopy. The results reveal that in ps DNA these distances are between 5 and 10% longer than in aps DNA when the labeled DNA segment is located near the center of the double helix. The interspin distance in ps DNA becomes shorter compared with aps DNA when one of the spin labels occupies a position near the end of the double helix. PMID- 26121222 TI - Rapid and Automated Quantification of Microalgal Lipids on a Spinning Disc. AB - We have developed a fully integrated centrifugal microfluidic device for rapid on site quantification of lipids from microalgal samples. The fully automated serial process involving cell sedimentation and lysis, liquid-liquid extraction, and colorimetric detection of lipid contents was accomplished within 13 min using a lab-on-a-disc. The presented organic solvent-tolerable (for n-hexane, ethanol) microfluidic disc was newly fabricated by combining thermal fusion bonding and carbon dot-based valving techniques. It is expected that this novel platform will possibly contribute toward sustainable biofuel applications by providing a practical solution for on-site monitoring of lipid accumulation in microalgal samples, thus providing imperative contribution toward energy and environmental purposes of centrifugal microfluidic technology. PMID- 26121223 TI - Catalytic Asymmetric Arylation of alpha-Aryl-alpha-diazoacetates with Aniline Derivatives. AB - The asymmetric arylation of diazo compounds with aniline derivatives cooperatively catalyzed by an achiral dirhodium complex and a chiral spiro phosphoric acid is reported. The reaction provides a new method for the facile synthesis of alpha-diarylacetates, versatile building blocks with a diaryl tertiary chiral center, in good yields (up to 95%) with high enantioselectivities (up to 97% ee). Preliminary mechanistic studies suggest that the arylation reaction proceeds via a stepwise process, in which the enantioselectivity is controlled by a chiral spiro phosphoric acid-promoted proton shift in a zwitterionic intermediate. This work represents the first asymmetric intermolecular C(sp(2))-H bond insertion reaction with arenes. PMID- 26121224 TI - N-Heterocyclic carbene-catalyzed [3+3] cyclocondensation of bromoenals with aldimines: highly enantioselective synthesis of dihydropyridinones. AB - The N-heterocyclic carbene-catalyzed [3+3] cyclocondensation of bromoenals and aldimines was developed to give the corresponding dihydropyridinones in good yields with excellent enantioselectivities. PMID- 26121225 TI - SR-FTIR Coupled with Principal Component Analysis Shows Evidence for the Cellular Bystander Effect. AB - Synchrotron radiation-Fourier transform infrared (SR-FTIR) microscopy coupled with multivariate data analysis was used as an independent modality to monitor the cellular bystander effect. Single, living prostate cancer PC-3 cells were irradiated with various numbers of protons, ranging from 50-2,000, with an energy of either 1 or 2 MeV using a proton microprobe. SR-FTIR spectra of cells, fixed after exposure to protons and nonirradiated neighboring cells (bystander cells), were recorded. Spectral differences were observed in both the directly targeted and bystander cells and included changes in the DNA backbone and nucleic bases, along with changes in the protein secondary structure. Principal component analysis (PCA) was used to investigate the variance in the entire data set. The percentage of bystander cells relative to the applied number of protons with two different energies was calculated. Of all the applied quantities, the dose of 400 protons at 2 MeV was found to be the most effective for causing significant macromolecular perturbation in bystander PC-3 cells. PMID- 26121226 TI - Defining Blood Processing Parameters for Optimal Detection of gamma-H2AX Foci: A Small Blood Volume Method. AB - Biodosimetric methods used to measure the effects of radiation are critical for estimating the health risks to irradiated individuals or populations. The direct measurement of radiation-induced gamma-H2AX foci in peripheral blood lymphocytes is one approach that provides a useful end point for triage. Despite the documented advantages of the gamma-H2AX assay, there is considerable variation among laboratories regarding foci formation in the same exposure conditions and cell lines. Taking this into account, the goal of our study was to evaluate the influence of different blood processing parameters on the frequency of gamma-H2AX foci and optimize a small blood volume protocol for the gamma-H2AX assay, which simulates the finger prick blood collection method. We found that the type of fixative, temperature and blood processing time markedly affect the results of the gamma-H2AX assay. In addition, we propose a protocol for the gamma-H2AX assay that may serve as a potential guideline in the event of large-scale radiation incidents. PMID- 26121227 TI - Variation in RBE for Survival of V79-4 Cells as a Function of Alpha-Particle (Helium Ion) Energy. AB - High linear energy transfer (LET) alpha particles are important with respect to the carcinogenic risk associated with human exposure to ionizing radiation, most notably to radon and its progeny. Additionally, the potential use of alpha particle-emitting radionuclides in radiotherapy is increasingly being explored. Within the body the emitted alpha particles slow down, traversing a number of cells with a range of energies and therefore with varying efficiencies at inducing biological response. The LET of the particle typically rises from between ~70-90 keV MUm(-1) at the start of the track (depending on initial energy) to a peak of ~237 keV MUm(-1) towards the end of the track, before falling again at the very end of its range. To investigate the variation in biological response with incident energy, a plutonium-238 alpha-particle irradiator was calibrated to enable studies with incident energies ranging from 4.0 MeV down to 1.1 MeV. The variation in clonogenic survival of V79-4 cells was determined as a function of incident energy, along with the relative variation in the initial yields of DNA double-strand breaks (DSB) measured using the FAR assay. The clonogenic survival data also extends previously published data obtained at the Medical Research Council (MRC), Harwell using the same cells irradiated with helium ions, with energies ranging from 34.9 MeV to 5.85 MeV. These studies were performed in conjunction with cell morphology measurements on live cells enabling the determination of absorbed dose and calculation of the average LET in the cell. The results show an increase in relative biological effectiveness (RBE) for cell inactivation with decreasing helium ion energy (increasing LET), reaching a maximum for incident energies of ~3.2 MeV and corresponding average LET of 131 keV MUm(-1), above which the RBE is observed to fall at lower energies (higher LETs). The effectiveness of single alpha-particle traversals (relevant to low-dose exposure) at inducing cell inactivation was observed to increase with decreasing energy to a peak of ~68% survival probability for incident energies of ~1.8 MeV (average LET of 190 keV MUm(-1)) producing ~0.39 lethal lesions per track. However, the efficiency of a single traversal will also vary significantly with cell morphology and angle of incidence, as well as cell type. PMID- 26121228 TI - Solid Cancer Incidence in the Techa River Incidence Cohort: 1956-2007. AB - Previously reported studies of the Techa River Cohort have established associations between radiation dose and the occurrence of solid cancers and leukemia (non-CLL) that appear to be linear in dose response. These analyses include 17,435 cohort members alive and not known to have had cancer prior to January 1, 1956 who lived in areas near the river or Chelyabinsk City at some time between 1956 and the end of 2007, utilized individualized dose estimates computed using the Techa River Dosimetry System 2009 and included five more years of follow-up. The median and mean dose estimates based on these doses are consistently higher than those based on earlier Techa River Dosimetry System 2000 dose estimates. This article includes new site-specific cancer risk estimates and risk estimates adjusted for available information on smoking. There is a statistically significant (P = 0.02) linear trend in the smoking-adjusted all solid cancer incidence risks with an excess relative risk (ERR) after exposure to 100 mGy of 0.077 with a 95% confidence interval of 0.013-0.15. Examination of site-specific risks revealed statistically significant radiation dose effects only for cancers of the esophagus and uterus with an ERR per 100 mGy estimates in excess of 0.10. Esophageal cancer risk estimates were modified by ethnicity and sex, but not smoking. While the solid cancer rates are attenuated when esophageal cancer is removed (ERR = 0.063 per 100 mGy), a dose-response relationship is present and it remains likely that radiation exposure has increased the risks for most solid cancers in the cohort despite the lack of power to detect statistically significant risks for specific sites. PMID- 26121229 TI - Subject-Based versus Population-Based Care after Radiation Exposure. AB - In a mass casualty radiation event situation, individualized therapy may overwhelm available resources and feasibility issues suggest a need for the development of population-based strategies. To investigate the efficacy of a population-based strategy, Chinese macaques (n = 46) underwent total-body irradiation and received preemptive antibiotics, IV hydration on predetermined postirradiation days and were then compared to macaques (n = 48) that received subject-based care in which blood transfusions, IV hydration, nutritional supplementation and antibiotic supportive measures were provided. Estimated radiation doses for LD30/60, LD50/60 and LD70/60 of animals with subject-based care: 6.83 Gy (6.21, 7.59), 7.44 Gy (6.99, 7.88) and 8.05 Gy (7.46, 8.64), respectively, and for population-based care: 5.61 Gy (5.28, 6.17), 6.62 Gy (6.13, 7.18) and 7.63 Gy (7.21, 8.20), respectively. Analysis of four time periods, 0-9, 10-15, 16-25 and 26-60 days postirradiation, identified significant mortality differences during the period of 10-15 days. A subset analysis of higher radiation doses (6.75-7.20 Gy, n = 32) indicated hydration, nutrition and septic status were not significantly different between treatments. Whole blood transfusion treatment, administered only in subject-supportive care, was associated with significantly higher platelet and absolute neutrophil counts. Median platelet counts greater than 5,670 cells/MUl and absolute neutrophil counts greater than 26 cells/MUl during this period correlated with survival. We observed that the population-based treatment increased the LD50/60 compared to nontreatment (6.62 Gy vs. 4.92 Gy) and may be further optimized during days 10 15, where strategic blood transfusions or other strategies to achieve increases in neutrophil and platelet counts may further increase survival rates in subjects exposed to high doses of radiation. PMID- 26121230 TI - Metal ion interactions with mAbs: Part 1. AB - Fragmentation in the hinge region of an IgG1 monoclonal antibody (mAb) can affect product stability, potentially causing changes in potency and efficacy. Metals ions, such as Cu(2+), can bind to the mAb and undergo hydrolysis or oxidation, which can lead to cleavage of the molecule. To better understand the mechanism of Cu(2+)-mediated mAb fragmentation, hinge region cleavage products and their rates of formation were studied as a function of pH with and without Cu(2+). More detailed analysis of the chemical changes was investigated using model linear and cyclic peptides (with the sequence of SCDKTHTC) derived from the upper hinge region of the mAb. Cu(2+) mediated fragmentation was determined to be predominantly via a hydrolytic pathway in solution. The sites and products of hydrolytic cleavage are pH and strain dependent. In more acidic environments, rates of Cu(2+) induced hinge fragmentation are significantly slower than at higher pH. Although the degradation reaction rates between the linear and cyclic peptides are not significantly different, the products of degradation vary. mAb fragmentation can be reduced by modifying His, which is a potential metal binding site and a known ligand in other metalloproteins. These results suggest that a charge may contribute to stabilization of a specific molecular structure involved in hydrolysis, leading to the possible formation of a copper binding pocket that causes increased susceptibility of the hinge region to degradation. PMID- 26121231 TI - Adherence to denosumab in the treatment of osteoporosis and its utilization in the Czech Republic. AB - OBJECTIVES: The objective was to analyze adherence and current trends in utilization and prescription practice patterns of the anti-RANKL monoclonal antibody denosumab in the treatment of postmenopausal osteoporosis (OP). METHODS: The prescription-based database of the General Health Insurance Company of the Czech Republic that covers approximately 60% of the Czech population (6 million) was used as the data source. Medication possession ratio (MPR) and persistence were calculated for all patients (both OP medication-naive and medication experienced) with postmenopausal OP from the start of their therapy with denosumab 60 mg per ml subcutaneous injection within a period between September 2011, i.e. first denosumab availability, and May 2014. Clinical data such as fractures, co-morbidities and co-medication were not analyzed. RESULTS: A total of 7904 women treated with denosumab were analyzed; 93.8% of patients were identified as compliant (MPR >=0.8) while 6.2% were non-compliant (MPR < 0.8). Persistence (base case, i.e. refill gap <=30 days) was 59.1% after 12 months and 34.8% after 24 months. By 2013, i.e. within 2 years, denosumab became the second most utilized and most costly drug after oral bisphosphonates. CONCLUSIONS: Despite relatively high MPR and persistence rate observed in denosumab treatment, adherence enhancing strategies, focused on persistence in particular, are still needed. The uptake of denosumab has been rapid, its utilization keeps rising swiftly, and denosumab already represents a significant part of the osteoporosis therapy budget. PMID- 26121232 TI - Phytoremediation of domestic wastewaters in free water surface constructed wetlands using Azolla pinnata. AB - Two constructed wetlands, one with Azolla pinnata plant (CW1) and the other without (CW2) for treating domestic wastewaters were developed. Fifteen water parameters which include: Dissolved Oxygen (DO), Biochemical Oxygen Demand (BOD5), Chemical Oxygen Demand (COD), Total Suspended Solid (TSS), Total Phosphorus (TP), Total Nitrogen (TN), Ammoniacal Nitrogen (NH3N), Turbidity, pH, Electrical Conductivity (EC), Iron (Fe), Magnesium (Mg), Manganese (Mn), and heavy metals such as Lead (Pb) and Zinc (Zn) were analyzed using standard laboratory procedures. The experiments were conducted in two (dry and wet) seasons simultaneously. Results showed considerable reductions in all parameters and metals including Zn in CW1 compared with CW2 in the two seasons considered while Pb and Mn were not detected throughout the study. Zn concentration levels reduced significantly in both seasons just as removal efficiencies of 70.03% and 64.51% were recorded for CW1 while 35.17% and 33.45% were recorded for CW2 in both seasons. There were no significant differences in the removal efficiencies of Fe in both seasons as 99.55%, 59.09%, 88.89%, and 53.56% were recorded in CW1 and CW2 respectively. Azolla pinnata has proved effective in domestic wastewater phytoremediation studies. PMID- 26121233 TI - Bone Morphogenic Protein 4 Mediates NOX1-Dependent eNOS Uncoupling, Endothelial Dysfunction, and COX2 Induction in Type 2 Diabetes Mellitus. AB - We have recently shown that angiotensin II-mediated uncoupling of endothelial nitric oxide synthase (eNOS) contributes to endothelial dysfunction in streptozotocin-induced type 1 diabetes mellitus. However, it has remained unclear whether and how eNOS uncoupling occurs in type 2 diabetes mellitus (T2DM) and the consequences of such in regulating vascular function. Here we investigated a role of bone morphogenic protein (BMP)-4 in mediating eNOS uncoupling, endothelial dysfunction, and inflammation in db/db mice. Circulating levels of BMP4 were markedly elevated in db/db mice but not in mice with type 1 diabetes mellitus, in which angiotensin II levels were significantly increased. Infusion of BMP4 antagonist noggin into db/db mice (15 MUg/kg/day, 4 weeks) abolished eNOS uncoupling activity while restoring tetrahydrobiopterin (H(4)B) bioavailability. The impaired endothelium-dependent vasorelaxation in db/db aortas was significantly improved by noggin infusion. Exposure of aortic endothelial cells to BMP4 (50 ng/mL, 24 hours) resulted in eNOS uncoupling, which was attenuated by H(4)B precursor sepiapterin or small interfering RNA silencing nicotinamide adenine dinucleotide phosphate oxidase isoform 1 (NOX1). Interestingly, BMP4 dependent NOX1 up-regulation was abrogated by sepiapterin, implicating a NOX1 uncoupled eNOS-NOX1 feed-forward loop. BMP4 induction of cyclooxygenase 2 (COX2) expression and vascular cell adhesion protein 1 was found in db/db mice. Consistently, COX2 was up-regulated by BMP4 in endothelial cells, which was attenuated by sepiapterin, implicating an upstream role of eNOS uncoupling in COX2-mediated inflammatory activation. Taken together, our data for the first time reveal a novel role of BMP4 in inducing NOX1-dependent eNOS uncoupling in T2DM, which may promote development of novel therapeutics restoring endothelial function in T2DM. PMID- 26121234 TI - Role of Nongenomic Signaling Pathways Activated by Aldosterone During Cardiac Reperfusion Injury. AB - Aldosterone (Aldo) activates both genomic and nongenomic signaling pathways in the cardiovascular system. Activation of genomic signaling pathways contributes to the adverse cardiac actions of Aldo during reperfusion injury; however, the extent nongenomic signaling pathways contribute has been difficult to identify due to lack of a specific ligand that activates only nongenomic signaling pathways. Using a pegylated aldosterone analog, aldosterone-3 carboxymethoxylamine-TFP ester conjugated to methoxypegylated amine (Aldo-PEG), we are able for the first time to distinguish between nongenomic and genomic cardiac actions of Aldo. We confirm Aldo-PEG activates phosphorylation of ERK1/2 in rat cardiomyocyte H9c2 cells similar to Aldo and G protein-coupled receptor 30 (GPR30 or GPER) agonist G1. GPER antagonist, G36, but not mineralocorticoid receptor (MR) antagonist spironolactone, prevented ERK1/2 phosphorylation by Aldo, Aldo-PEG, and G1. The selective nongenomic actions of Aldo-PEG are confirmed, with Aldo-PEG increasing superoxide production in H9c2 cells to similar levels as Aldo but having no effect on subcellular localization of MR. Striatin serves as a scaffold for GPER and MR, with GPER antagonist G36, but not spironolactone, restoring MR-striatin complexes. Aldo-PEG had no effect on MR dependent transcriptional activation, whereas Aldo increased transcript levels of serum-regulated kinase 1 and plasminogen activator inhibitor-1. Using our ex vivo experimental rat model of myocardial infarction, we found aggravated infarct size and apoptosis by Aldo but not Aldo-PEG. Our studies confirm that in the heart, activation of nongenomic signaling pathways alone are not sufficient to trigger the deleterious effects of aldosterone during myocardial reperfusion injury. PMID- 26121235 TI - Minireview: Spatial Programming of G Protein-Coupled Receptor Activity: Decoding Signaling in Health and Disease. AB - Probing the multiplicity of hormone signaling via G protein-coupled receptors (GPCRs) has demonstrated the complex signal pathways that underlie the multiple functions these receptors play in vivo. This is highly pertinent for the GPCRs key in reproduction and pregnancy that are exposed to cyclical and dynamic changes in their extracellular milieu. How such functional pleiotropy in GPCR signaling is translated to specific downstream cellular responses, however, is largely unknown. Emerging data strongly support mechanisms for a central role of receptor location in signal regulation via membrane trafficking. In this review, we discuss current progress in our understanding of the role membrane trafficking plays in location control of GPCR signaling, from organized plasma membrane signaling microdomains, potentially provided by both distinct endocytic and exocytic pathways, to more recent evidence for spatial control within the endomembrane system. Application of these emerging mechanisms in their relevance to GPCR activity in physiological and pathophysiological conditions will also be discussed, and in improving therapeutic strategies that exploits these mechanisms in order to program highly regulated and distinct signaling profiles. PMID- 26121237 TI - Autophagy governs erythroid differentiation both in vitro and in vivo. AB - OBJECTIVES: Although the importance of autophagy in determination of cell fate has been much explored in recent years, its definite role in regulating erythroid differentiation remains unclear. METHODS: In this study, human erythroleukemic cell line K562 was employed as a cell model for studying erythroid differentiation in vitro. Starvation and rapamycin were used to induce autophagy, whereas Baf-A1 and CRISPR/Cas9/Atg7 were used to inhibit late and early phase of autophagy, respectively. The mice model of autophagy activation and autophagy deletion were established, and red blood cell counts and flow cytometry were used to analyze erythroid differentiation in vivo. RESULTS: The results showed that the transcriptional levels of alpha-globin and gamma-globin, and the ratio of hemoglobin-positive cells all significantly increased in K562 cells with starvation and rapamycin treatment, which were blocked by autophagy inhibitor, Baf-A1 or Atg7 gene knockout. In the autophagy-enhanced mouse model, the number of mature erythrocytes significantly increased, while in Atg7-deleted mouse model, erythroid differentiation was severely blocked. CONCLUSION: It is concluded that autophagy is indispensible in the development, maturation, and homeostasis of erythroid cells both in vitro and in vivo. Our findings support the potential strategy for erythroleukemia treatment and production of erythroblasts in vitro by modulating autophagy. PMID- 26121238 TI - Tailoring flavins for visible light photocatalysis: organocatalytic [2+2] cycloadditions mediated by a flavin derivative and visible light. AB - A new application of flavin derivatives in visible light photocatalysis was found. 1-Butyl-7,8-dimethoxy-3-methylalloxazine, when irradiated by visible light, was shown to allow an efficient cyclobutane ring formation via an intramolecular [2+2] cycloaddition of both styrene dienes, considered as electron rich substrates, and electron-poor bis(arylenones), presumably proceeding via an energy transfer mechanism. PMID- 26121236 TI - Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a restrictive lung disease that is associated with high morbidity and mortality. Current medical therapies are not fully effective at limiting mortality in patients with IPF, and new therapies are urgently needed. Matrix metalloproteinases (MMPs) are proteinases that, together, can degrade all components of the extracellular matrix and numerous nonmatrix proteins. MMPs and their inhibitors, tissue inhibitors of MMPs (TIMPs), have been implicated in the pathogenesis of IPF based upon the results of clinical studies reporting elevated levels of MMPs (including MMP-1, MMP-7, MMP-8, and MMP-9) in IPF blood and/or lung samples. Surprisingly, studies of gene-targeted mice in murine models of pulmonary fibrosis (PF) have demonstrated that most MMPs promote (rather than inhibit) the development of PF and have identified diverse mechanisms involved. These mechanisms include MMPs: (1) promoting epithelial-to mesenchymal transition (MMP-3 and MMP-7); (2) increasing lung levels or activity of profibrotic mediators or reducing lung levels of antifibrotic mediators (MMP 3, MMP-7, and MMP-8); (3) promoting abnormal epithelial cell migration and other aberrant repair processes (MMP-3 and MMP-9); (4) inducing the switching of lung macrophage phenotypes from M1 to M2 types (MMP-10 and MMP-28); and (5) promoting fibrocyte migration (MMP-8). Two MMPs, MMP-13 and MMP-19, have antifibrotic activities in murine models of PF, and two MMPs, MMP-1 and MMP-10, have the potential to limit fibrotic responses to injury. Herein, we review what is known about the contributions of MMPs and TIMPs to the pathogenesis of IPF and discuss their potential as therapeutic targets for IPF. PMID- 26121239 TI - Vitamin D Receptor Gene Ablation in the Conceptus Has Limited Effects on Placental Morphology, Function and Pregnancy Outcome. AB - Vitamin D deficiency has been implicated in the pathogenesis of several pregnancy complications attributed to impaired or abnormal placental function, but there are few clues indicating the mechanistic role of vitamin D in their pathogenesis. To further understand the role of vitamin D receptor (VDR)-mediated activity in placental function, we used heterozygous Vdr ablated C57Bl6 mice to assess fetal growth, morphological parameters and global gene expression in Vdr null placentae. Twelve Vdr+/- dams were mated at 10-12 weeks of age with Vdr+/- males. At day 18.5 of the 19.5 day gestation in our colony, females were euthanised and placental and fetal samples were collected, weighed and subsequently genotyped as either Vdr+/+, Vdr+/- or Vdr-/-. Morphological assessment of placentae using immunohistochemistry was performed and RNA was extracted and subject to microarray analysis. This revealed 25 genes that were significantly differentially expressed between Vdr+/+ and Vdr-/- placentae. The greatest difference was a 6.47-fold change in expression of Cyp24a1 which was significantly lower in the Vdr-/- placentae (P<0.01). Other differentially expressed genes in Vdr-/- placentae included those involved in RNA modification (Snord123), autophagy (Atg4b), cytoskeletal modification (Shroom4), cell signalling (Plscr1, Pex5) and mammalian target of rapamycin (mTOR) signalling (Deptor and Prr5). Interrogation of the upstream sequence of differentially expressed genes identified that many contain putative vitamin D receptor elements (VDREs). Despite the gene expression differences, this did not contribute to any differences in overall placental morphology, nor was function affected as there was no difference in fetal growth as determined by fetal weight near term. Given our dams still expressed a functional VDR gene, our results suggest that cross talk between the maternal decidua and the placenta, as well as maternal vitamin D status, may be more important in determining pregnancy outcome than conceptus expression of VDR. PMID- 26121240 TI - Direct Gamete Sequencing Reveals No Evidence for Segregation Distortion in House Mouse Hybrids. AB - Understanding the molecular basis of species formation is an important goal in evolutionary genetics, and Dobzhansky-Muller incompatibilities are thought to be a common source of postzygotic reproductive isolation between closely related lineages. However, the evolutionary forces that lead to the accumulation of such incompatibilities between diverging taxa are poorly understood. Segregation distorters are believed to be an important source of Dobzhansky-Muller incompatibilities between hybridizing species of Drosophila as well as hybridizing crop plants, but it remains unclear if these selfish genetic elements contribute to reproductive isolation in other taxa. Here, we collected viable sperm from first-generation hybrid male progeny of Mus musculus castaneus and M. m. domesticus, two subspecies of rodent in the earliest stages of speciation. We then genotyped millions of single nucleotide polymorphisms in these gamete pools and tested for a skew in the frequency of parental alleles across the genome. We show that segregation distorters are not measurable contributors to observed infertility in these hybrid males, despite sufficient statistical power to detect even weak segregation distortion with our novel method. Thus, reduced hybrid male fertility in crosses between these nascent species is attributable to other evolutionary forces. PMID- 26121241 TI - Substitution in Amino Acid 70 of Hepatitis C Virus Core Protein Changes the Adipokine Profile via Toll-Like Receptor 2/4 Signaling. AB - BACKGROUND & AIMS: It has been suggested that amino acid (aa) substitution at position 70 from arginine (70R) to glutamine (70Q) in the genotype 1b hepatitis C virus (HCV) core protein is associated with insulin resistance and worse prognosis. However, the precise mechanism is still unclear. The aim of this study was to investigate the impact of the substitution at position 70 in HCV core protein on adipokine production by murine and human adipocytes. METHODS: The influence of treatment with HCV core protein (70R or 70Q) on adipokine production by both 3T3-L1 and human adipocytes were examined with real-time PCR and enzyme linked immunosorbent assay (ELISA), and triglyceride content was also analyzed. The effects of toll-like receptor (TLR)2/4 inhibition on IL-6 production by 3T3 L1 induced by HCV core protein were examined. RESULTS: IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes. IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%. CONCLUSIONS: Our study suggests that extracellular HCV core protein with substitution at position 70 enhanced IL-6 production and reduced adiponectin production from visceral adipose tissue, which can cause insulin resistance, hepatic steatosis, and ultimately development of HCC. PMID- 26121242 TI - Specificity and Strain-Typing Capabilities of Nanorod Array-Surface Enhanced Raman Spectroscopy for Mycoplasma pneumoniae Detection. AB - Mycoplasma pneumoniae is a cell wall-less bacterial pathogen of the human respiratory tract that accounts for > 20% of all community-acquired pneumonia (CAP). At present the most effective means for detection and strain-typing is quantitative polymerase chain reaction (qPCR), which can exhibit excellent sensitivity and specificity but requires separate tests for detection and genotyping, lacks standardization between available tests and between labs, and has limited practicality for widespread, point-of-care use. We have developed and previously described a silver nanorod array-surface enhanced Raman Spectroscopy (NA-SERS) biosensing platform capable of detecting M. pneumoniae with statistically significant specificity and sensitivity in simulated and true clinical throat swab samples, and the ability to distinguish between reference strains of the two main genotypes of M. pneumoniae. Furthermore, we have established a qualitative lower endpoint of detection for NA-SERS of < 1 genome equivalent (cell/MUl) and a quantitative multivariate detection limit of 5.3 +/- 1 cells/MUl. Here we demonstrate using partial least squares- discriminatory analysis (PLS-DA) of sample spectra that NA-SERS correctly identified M. pneumoniae clinical isolates from globally diverse origins and distinguished these from a panel of 12 other human commensal and pathogenic mycoplasma species with 100% cross-validated statistical accuracy. Furthermore, PLS-DA correctly classified by strain type all 30 clinical isolates with 96% cross-validated accuracy for type 1 strains, 98% cross-validated accuracy for type 2 strains, and 90% cross-validated accuracy for type 2V strains. PMID- 26121243 TI - Innovative use of the taxol binding peptide overcomes key challenges of stable and high drug loading in polymeric nanomicelles. AB - Despite widespread clinical use, delivery of taxane chemotherapeutics remains a challenge due to poor solubility and lack of selectively. Polymeric nanomicelle strategies have been pursued to overcome these issues; however current formulations are often limited by low drug loading and poor serum stability. To achieve a drug delivery system that addresses these issues, poly(D,L-lactide-co-2 methyl-2-carboxytrimethylene carbonate)-g-poly(ethylene glycol) was covalently modified with the taxol binding peptide - a peptide from the beta-tubulin-taxane binding site. This modification resulted in drug loadings five times higher than unmodified polymers, which is significantly higher than typical hydrophobic modifications, including with benzyl and docetaxel functionalization. Unlike many formulations with high drug loading, these nanomicelles were stable in serum for up to 24 h and maintained docetaxel cytotoxicity. By incorporating the taxane binding peptide into the polymer chemistry, a new twist was applied to an old problem, which is broadly applicable to other polymeric micelle systems and drug peptide combinations in general. PMID- 26121244 TI - Correction: Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer's Disease. PMID- 26121245 TI - A short GC rich DNA derived from microbial origin targets tubulin/microtubules and induces apoptotic death of cancer cells. AB - A short GC rich DNA derived from microbial origin interacts with tubulin/microtubules activates p53 over expression and induces apoptotic death of human breast cancer (MCF-7) cells. PMID- 26121246 TI - Construct Validity of the Chinese Version of the Activities of Daily Living Rating Scale III in Patients with Schizophrenia. AB - BACKGROUND: The Chinese version of the Activities of Daily Living Rating Scale III (ADLRS-III), which has 10 domains, is commonly used for assessing activities of daily living (ADL) in patients with schizophrenia. However, construct validity (i.e., unidimensionality) for each domain of the ADLRS-III is unknown, limiting the explanations of the test results. PURPOSE: This main purpose of this study was to examine unidimensionality of each domain in the ADLRS-III. We also examined internal consistency and ceiling/floor effects in patients with schizophrenia. METHODS: From occupational therapy records, we obtained 304 self report data of the ADLRS-III. Confirmatory factor analysis (CFA) was conducted to examine the 10 one-factor structures. If a domain showed an insufficient model fit, exploratory factor analysis (EFA) was performed to investigate the factor structure and choose one factor representing the original construct. Internal consistency was examined using Cronbach's alpha (alpha). Ceiling and floor effects were determined by the percentage of patients with the maximum and minimum scores in each domain, respectively. RESULTS: CFA analyses showed that 4 domains (i.e., leisure, picture recognition, literacy ability, communication tools use) had sufficient model fits. These 4 domains had acceptable internal consistency (alpha = 0.79-0.87) and no ceiling/floor effects, except the leisure domain which had a ceiling effect. The other 6 domains showed insufficient model fits. The EFA results showed that these 6 domains were two-factor structures. CONCLUSION: The results supported unidimensional constructs of the leisure, picture recognition, literacy ability, and communication tool uses domains. The sum scores of these 4 domains can be used to represent their respective domain specific functions. Regarding the 6 domains with insufficient model fits, we have explained the two factors of each domain and chosen one factor to represent its original construct. Future users may use the items from the chosen factors to assess domain-specific functions in patients with schizophrenia. PMID- 26121247 TI - Comprehensive Analysis and Characterization of Linear Antigenic Domains on HN Protein from Genotype VII Newcastle Disease Virus Using Yeast Surface Display System. AB - Circulation of genotype VII Newcastle disease virus (NDV) has posed a great threat for the poultry industry worldwide. Antibodies against Hemagglutinin neuraminidase (HN), a membrane protein of NDV with critical roles in NDV infection, have been reported to provide chickens protection from NDV infection. In this study, we comprehensively analyzed the in vivo antibody responses against the linear antigenic domains of the HN protein from genotype VII NDV using a yeast surface display system. The results revealed four distinct regions of HN, P1 (1-52aa), P2 (53-192aa), P3 (193-302aa) and P4 (303-571aa), respectively, according to their antigenic potency. Analysis by FACS and ELISA assay indicated P2 to be the dominant linear antigenic domain, with the immunogenic potency to protect the majority of chickens from NDV challenge. In contrast, the P1, P3 and P4 domains showed weak antigenicity in vivo and could not protect chickens from NDV challenge. These results provide important insight into the characteristic of humoral immune responses elicited by HN of NDV in vivo. PMID- 26121248 TI - High Intensity Interval Training (HIIT) Induces Specific Changes in Respiration and Electron Leakage in the Mitochondria of Different Rat Skeletal Muscles. AB - High intensity interval training (HIIT) is characterized by vigorous exercise with short rest intervals. Hydrogen peroxide (H2O2) plays a key role in muscle adaptation. This study aimed to evaluate whether HIIT promotes similar H2O2 formation via O2 consumption (electron leakage) in three skeletal muscles with different twitch characteristics. Rats were assigned to two groups: sedentary (n=10) and HIIT (n=10, swimming training). We collected the tibialis anterior (TA fast), gastrocnemius (GAST-fast/slow) and soleus (SOL-slow) muscles. The fibers were analyzed for mitochondrial respiration, H2O2 production and citrate synthase (CS) activity. A multi-substrate (glycerol phosphate (G3P), pyruvate, malate, glutamate and succinate) approach was used to analyze the mitochondria in permeabilized fibers. Compared to the control group, oxygen flow coupled to ATP synthesis, complex I and complex II was higher in the TA of the HIIT group by 1.5 , 3.0- and 2.7-fold, respectively. In contrast, oxygen consumed by mitochondrial glycerol phosphate dehydrogenase (mGPdH) was 30% lower. Surprisingly, the oxygen flow coupled to ATP synthesis was 42% lower after HIIT in the SOL. Moreover, oxygen flow coupled to ATP synthesis and complex II was higher by 1.4- and 2.7 fold in the GAST of the HIIT group. After HIIT, CS activity increased 1.3-fold in the TA, and H2O2 production was 1.3-fold higher in the TA at sites containing mGPdH. No significant differences in H2O2 production were detected in the SOL. Surprisingly, HIIT increased H2O2 production in the GAST via complex II, phosphorylation, oligomycin and antimycin by 1.6-, 1.8-, 2.2-, and 2.2-fold, respectively. Electron leakage was 3.3-fold higher in the TA with G3P and 1.8 fold higher in the GAST with multiple substrates. Unexpectedly, the HIIT protocol induced different respiration and electron leakage responses in different types of muscle. PMID- 26121249 TI - Changes in Antioxidant Defense Capability and Lipid Profile after 12-Week Low- Intensity Continuous Training in Both Cigarette and Hookah Smokers: A Follow-Up Study. AB - To examine the impact of low-intensity continuous training program on antioxidant defense capability and lipid profile in male cigarette or hookah smokers. Forty three male adults participated in a 12-week continuous training program at an intensity of 40% of VO2max. All subjects were subjected to anthropometric, physical and biochemical tests before and after the training program. The increase of Glutathione reductase (GR) and Superoxide dismutase (SOD) is significant only for cigarette smokers (CS) and hookah smokers (HS) groups. The Malondialdehyde (MDA) decrease and alpha-tocopherol increase are significant only for HS group. GPx was increased in NS, CS and HS by 2.6% (p< 0.01), 2% (p< 0.05) and 1.7% (p< 0.05) respectively. Likewise, significant improvements of high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C) and TC/HDL-C ratio were observed in three groups. En contrast no significant changes were recorded in triglycerides (TG). Also, significant reduction of total cholesterol (TC) for CS group (p< 0.01) and HS groups (p< 0.05). This continuous training program appears to have an important role in lipid levels improving and oxidative stress attenuation. PMID- 26121250 TI - Bisexual Behaviors, HIV Knowledge, and Stigmatizing/Discriminatory Attitudes among Men Who Have Sex with Men. AB - OBJECTIVE: To assess the correlates for bisexual behaviors, HIV knowledge, and HIV/AIDS-related stigmatizing/discriminatory attitudes among men who have sex with men (MSM). METHODS: A cross-sectional survey among MSM was conducted in 2011 to provide demographics, sexual behaviors, HIV knowledge, HIV/AIDS-related stigmatizing/discriminatory attitudes, and services in Jinan, Qingdao, and Yantai of Shandong Province of China. RESULTS: Of 1230 participants, 82.8% were single, 85.7% aged <35 years, and 47.2% received college or higher education. There were 28.6% MSM who reported to be married or cohabitating or ever had sex with woman in the past 6 months (P6M). 74.5% had >=6 HIV-related knowledge score. The average total score of stigmatizing/discriminatory attitude was 37.4+/ 4.4(standard deviation). Bisexual behavior was independently associated with higher levels of HIV/AIDS-related stigma/discrimination(AOR = 1.1, 95% CI:1.0 1.1), older age(AOR = 1.2, 95%CI:1.1-1.2), and lower HIV-related knowledge score(AOR = 1.6, 95%CI:1.2-2.2). HIV knowledge score >=6 was independently associated with lower levels of HIV/AIDS-related stigma/discrimination(AOR = 1.3, 95%CI:1.2-1.3), less bisexual behaviors(AOR = 0.6, 95%CI:0.5-0.9), ever received a test for HIV in the past 12 months (P12M)(AOR = 3.2, 95%CI:2.3-4.5), college or higher level education(AOR = 1.9, 95%CI:1.4-2.6), consistent condom use with men in P6M(AOR=6.9, 95%CI:4.6-10.6), recruited from internet or HIV testing sites(AOR = 11.2, 95%CI:8.0-16.1) and bars, night clubs, or tea houses(AOR = 2.5, 95%CI:1.7 4.8). Expressing higher levels of HIV/AIDS-related stigmatizing/discriminatory attitudes was independently associated with bisexual behaviors(Abeta = 0.9, 95%CI:0.4-1.4), lower HIV-related knowledge score(Abeta = 3.6, 95%CI:3.0-4.1), the number of male sex partners in the past week >=2(Abeta = 1.4, 95%CI:1.0-1.9), unprotected male anal sex in P6M(Abeta = 1.0, 95%CI:0.5-1.6), and inversely associated with ever received HIV test(Abeta = 1.4, 95%CI:0.8-2.0) and peer education in P12M(Abeta = 1.4, 95%CI:0.9-1.9). CONCLUSION: HIV/AIDS-related stigmatizing/discriminatory attitudes were associated with bisexual behaviors, low HIV testing rate, lower HIV-related knowledge and risk behaviors. This study called for innovative programs that would reduce HIV/AIDS-related stigmatizing/discriminatory attitudes and bisexual behaviors and improve the uptake of prevention service among MSM. PMID- 26121252 TI - Quantitative Evaluation of the Environmental Impact Quotient (EIQ) for Comparing Herbicides. AB - Various indicators of pesticide environmental risk have been proposed, and one of the most widely known and used is the environmental impact quotient (EIQ). The EIQ has been criticized by others in the past, but it continues to be used regularly in the weed science literature. The EIQ is typically considered an improvement over simply comparing the amount of herbicides applied by weight. Herbicides are treated differently compared to other pesticide groups when calculating the EIQ, and therefore, it is important to understand how different risk factors affect the EIQ for herbicides. The purpose of this work was to evaluate the suitability of the EIQ as an environmental indicator for herbicides. Simulation analysis was conducted to quantify relative sensitivity of the EIQ to changes in risk factors, and actual herbicide EIQ values were used to quantify the impact of herbicide application rate on the EIQ Field Use Rating. Herbicide use rate was highly correlated with the EIQ Field Use Rating (Spearman's rho >0.96, P-value <0.001) for two herbicide datasets. Two important risk factors for herbicides, leaching and surface runoff potential, are included in the EIQ calculation but explain less than 1% of total variation in the EIQ. Plant surface half-life was the risk factor with the greatest relative influence on herbicide EIQ, explaining 26 to 28% of the total variation in EIQ for actual and simulated EIQ values, respectively. For herbicides, the plant surface half-life risk factor is assigned values without any supporting quantitative data, and can result in EIQ estimates that are contrary to quantitative risk estimates for some herbicides. In its current form, the EIQ is a poor measure of herbicide environmental impact. PMID- 26121251 TI - A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most difficult to treat malignancies per se. In almost 90% of all GBM alterations in the PI3K/Akt/mTOR have been found, making this survival cascade a promising therapeutic target, particular for combination therapy that combines an apoptosis sensitizer, such as a pharmacological inhibitor of PI3K, with an apoptosis inducer, such as radio- or chemotherapy. However, while in vitro data focusing mainly on established cell lines has appeared rather promising, this has not translated well to a clinical setting. In this study, we analyze the effects of the dual kinase inhibitor PI-103, which blocks PI3K and mTOR activity, on three matched pairs of GBM stem cells/differentiated cells. While blocking PI3K mediated signaling has a profound effect on cellular proliferation, in contrast to data presented on two GBM cell lines (A172 and U87) PI-103 actually counteracts the effect of chemotherapy. While we found no indications for a potential role of the PI3K signaling cascade in differentiation, we saw a clear and strong contribution to cellular motility and, by extension, invasion. While blocking PI3K-mediated signaling concurrently with application of chemotherapy does not appear to be a valid treatment option, pharmacological inhibitors, such as PI-103, nevertheless have an important place in future therapeutic approaches. PMID- 26121253 TI - Sleep-disordered breathing decreases after opioid withdrawal: results of a prospective controlled trial. AB - An increased cardiovascular event rate in elderly patients under opioid medications was recently reported. One reason for this increase could be the occurrence of nocturnal apnea and hypoxia, as a consequence of sleep-disordered breathing (SDB). Using a controlled study, we prospectively analyzed SDB using polysomnography in a total of 18 patients before and after opioid withdrawal (opioid withdrawal group [OG]) and 14 patients before and after comprehensive pain management (without any strong-acting opioids) who served as the control group (CG). To analyze the differences, unpaired/paired t tests and Mann-Whitney U tests/Wilcoxon rank tests were used. At baseline, the OG presented more nocturnal apneas/hypopneas than the CG with an apnea-hypopnea index (AHI) of 41.4 +/- 27.8 vs 21.8 +/- 15.9 (P = 0.018). After treatment, the AHI decreased significantly only in the withdrawal group (OG: 16.7 +/- 8.9; CG: 20.1 +/- 12.9) (P < 0.01). Before treatment, none of the CG but half of the OG patients showed central apnea, which disappeared afterwards. A mean O2 saturation during rapid eye movement sleep lower than 90% was found in 27.5% of the OG patients before opioid withdrawal and in none of the patients after withdrawal (P < 0.01). The AHI was not significantly affected by body mass index, age, or sex. Obviously, nocturnal apnea and O2 desaturation occurred more frequently, as was clinically expected in patients with opioid intake; these findings may explain the opioid associated cardiovascular morbidity. Thus, SDB may be a risk at lower opioid doses than hitherto described, and particular caution should be exercised in patients with comorbidities that might make them vulnerable to the consequences of SDB. PMID- 26121254 TI - Nerve growth factor-induced synapse-like structures in contralateral sensory ganglia contribute to chronic mirror-image pain. AB - Elevated nerve growth factor (NGF) in the contralateral dorsal root ganglion (DRG) mediates mirror-image pain after peripheral nerve injury, but the underlying mechanism remains unclear. Using intrathecal injection of NGF antibodies, we found that NGF is required for the development of intra-DRG synapse-like structures made by neurite sprouts of calcitonin gene-related peptide (CGRP(+)) nociceptors and sympathetic axons onto neurite sprouts of Kv4.3(+) nociceptors. These synapse-like structures are formed near NGF-releasing satellite glia surrounding large DRG neurons. Downregulation of the postsynaptic protein PSD95 with a specific shRNA largely eliminates these synapse-like structures, suppresses activities of Kv4.3(+) but not CGRP(+) nociceptors, and attenuates mirror-image pain. Furthermore, neutralizing the neurotransmitter norepinephrine or CGRP in the synapse-like structures by antibodies has similar analgesic effect. Thus, elevated NGF after peripheral nerve injury induces neurite sprouting and the formation of synapse-like structures within the contralateral DRG, leading to the development of chronic mirror-image pain. PMID- 26121256 TI - Long-acting reversible contraception: Findings from the Understanding Fertility Management in Contemporary Australia survey. PMID- 26121255 TI - Neuropathic pain as part of chronic widespread pain: environmental and genetic influences. AB - Chronic widespread pain (CWP) has complex aetiology and forms part of the fibromyalgia syndrome. Recent evidence suggests a higher frequency of neuropathic pain features in those with CWP than previously thought. The aim of this study was to determine the prevalence of neuropathic pain features in individuals with CWP and to estimate the influence of genetic and environmental factors on neuropathic pain in CWP. Validated questionnaires (the London Fibromyalgia Screening Study questionnaire and PainDETECT questionnaire) were used to classify twins as having CWP and neuropathic pain, respectively. The prevalence of CWP was 14.7% (n = 4324), and of the 1357 twins invited to complete neuropathic pain screening, 15.9% of those having CWP demonstrated features of neuropathic pain. Neuropathic pain was found to be heritable (A = 37%; 95% confidence interval [CI]: 23%-50%) with unique environmental factors accounting for 63% (95% CI: 49% 79%) of the variance. Heritability of neuropathic pain and CWP were found to be correlated, 0.54 (95% CI: 0.42-0.65). Increasing age, raised body mass index, female gender, and smoking were all risk factors for neuropathic pain (P < 0.05), and CWP (P < 0.05). High socioeconomic status showed negative correlation with neuropathic pain (P = 0.003) and CWP (P = 0.001). Bivariate analysis of the 2 pain traits revealed that genetic predisposition to neuropathic pain is shared with that for CWP. This is the first study to provide formal heritability estimates for neuropathic pain in CWP. The findings suggest that at least some of the genetic factors underlying the development of neuropathic pain and CWP are the same. PMID- 26121258 TI - Tool for Rapid & Easy Identification of High Risk Diabetic Foot: Validation & Clinical Pilot of the Simplified 60 Second Diabetic Foot Screening Tool. AB - BACKGROUND: Most diabetic foot amputations are caused by ulcers on the skin of the foot i.e. diabetic foot ulcers. Early identification of patients at high risk for diabetic foot ulcers is crucial. The 'Simplified 60-Second Diabetic Foot Screening Tool' has been designed to rapidly detect high risk diabetic feet, allowing for timely identification and referral of patients needing treatment. This study aimed to determine the clinical performance and inter-rater reliability of 'Simplified 60 Second Diabetic Foot Screening Tool' in order to evaluate its applicability for routine screening. METHODS AND FINDINGS: The tool was independently tested by n=12 assessors with n=18 Guyanese patients with diabetes. Inter-rater reliability was assessed by calculating Cronbach's alpha for each of the assessment items. A minimum value of 0.60 was considered acceptable. Reliability scores of the screening tool assessment items were: 'monofilament test' 0.98; 'active ulcer' 0.97; 'previous amputation' 0.97; 'previous ulcer' 0.97; 'fixed ankle' 0.91; 'deformity' 0.87; 'callus' 0.87; 'absent pulses' 0.87; 'fixed toe' 0.80; 'blisters' 0.77; 'ingrown nail' 0.72; and 'fissures' 0.55. The item 'stiffness in the toe or ankle' was removed as it was observed in only 1.3% of patients. The item 'fissures' was also removed due to low inter-rater reliability. Clinical performance was assessed via a pilot study utilizing the screening tool on n=1,266 patients in an acute care setting in Georgetown, Guyana. In total, 48% of patients either had existing diabetic foot ulcers or were found to be at high risk for developing ulcers. CONCLUSIONS: Clinicians in low and middle income countries such as Guyana can use the Simplified 60-Second Diabetic Screening Tool to facilitate early detection and appropriate treatment of diabetic foot ulcers. Implementation of this screening tool has the potential to decrease diabetes related disability and mortality. PMID- 26121257 TI - Pericentriolar Targeting of the Mouse Mammary Tumor Virus GAG Protein. AB - The Gag protein of the mouse mammary tumor virus (MMTV) is the chief determinant of subcellular targeting. Electron microscopy studies show that MMTV Gag forms capsids within the cytoplasm and assembles as immature particles with MMTV RNA and the Y box binding protein-1, required for centrosome maturation. Other betaretroviruses, such as Mason-Pfizer monkey retrovirus (M-PMV), assemble adjacent to the pericentriolar region because of a cytoplasmic targeting and retention signal in the Matrix protein. Previous studies suggest that the MMTV Matrix protein may also harbor a similar cytoplasmic targeting and retention signal. Herein, we show that a substantial fraction of MMTV Gag localizes to the pericentriolar region. This was observed in HEK293T, HeLa human cell lines and the mouse derived NMuMG mammary gland cells. Moreover, MMTV capsids were observed adjacent to centrioles when expressed from plasmids encoding either MMTV Gag alone, Gag-Pro-Pol or full-length virus. We found that the cytoplasmic targeting and retention signal in the MMTV Matrix protein was sufficient for pericentriolar targeting, whereas mutation of the glutamine to alanine at position 56 (D56/A) resulted in plasma membrane localization, similar to previous observations from mutational studies of M-PMV Gag. Furthermore, transmission electron microscopy studies showed that MMTV capsids accumulate around centrioles suggesting that, similar to M-PMV, the pericentriolar region may be a site for MMTV assembly. Together, the data imply that MMTV Gag targets the pericentriolar region as a result of the MMTV cytoplasmic targeting and retention signal, possibly aided by the Y box protein-1 required for the assembly of centrosomal microtubules. PMID- 26121259 TI - The recyclable synthesis of hierarchical zeolite SAPO-34 with excellent MTO catalytic performance. AB - A facile and green route has been developed for the synthesis of hierarchical zeolite catalysts by recycling of waste mother-liquors. After three recycles of mother-liquors, the obtained hierarchical SAPO-34 zeolites retain high crystallinity, texture properties, and acidity, as well as excellent MTO catalytic performance as compared to the initially prepared catalysts. PMID- 26121260 TI - A FOXM1 Dependent Mesenchymal-Epithelial Transition in Retinal Pigment Epithelium Cells. AB - The integrity of the epithelium is maintained by a complex but regulated interplay of processes that allow conversion of a proliferative state into a stably differentiated state. In this study, using human embryonic stem cell (hESC) derived Retinal Pigment Epithelium (RPE) cells as a model; we have investigated the molecular mechanisms that affect attainment of the epithelial phenotype. We demonstrate that RPE undergo a Mesenchymal-Epithelial Transition in culture before acquiring an epithelial phenotype in a FOXM1 dependent manner. We show that FOXM1 directly regulates proliferation of RPE through transcriptional control of cell cycle associated genes. Additionally, FOXM1 modulates expression of the signaling ligands BMP7 and Wnt5B which act reciprocally to enable epithelialization. This data uncovers a novel effect of FOXM1 dependent activities in contributing towards epithelial fate acquisition and furthers our understanding of the molecular regulators of a cell type that is currently being evaluated as a cell therapy. PMID- 26121261 TI - Longevity of Mycobacterium bovis in Raw and Traditional Souring Milk as a Function of Storage Temperature and Dose. AB - BACKGROUND: Unpasteurised fresh and souring dairy products form an essential component of household diets throughout many rural communities in southern Africa. The presence of milk-borne zoonotic pathogens such as Mycobacterium bovis (M. bovis), the causative agent of bovine tuberculosis and zoonotic tuberculosis in humans, constitute a public health threat, especially in remote areas with poor disease surveillance in livestock and highly compromised human health due to HIV/AIDS. METHODS: In this study we used culture to determine the longevity of M. bovis in experimentally inoculated fresh and naturally souring milk obtained from communal cattle in the KwaZulu-Natal province of South Africa. The effect of bacterial load and storage temperature on the survival of M. bovis was evaluated by spiking mixtures of fresh milk and starter soured milk (aMasi) culture with three concentrations of bacteria (10(2), 10(4), 10(7) colony forming units/ml), followed by incubation under controlled laboratory conditions that mimicked ambient indoor (20 degrees C) and outdoor (33 degrees C) temperatures and periodic sampling and testing over time (0-56 days). RESULTS: M. bovis cultured from samples of the fresh and souring milk was identified by PCR analysis. At the highest spiking concentration (10(7) cfu/ml), M. bovis survived for at least 2 weeks at 20 degrees C; but, at all concentrations in the 33 degrees C treatment, M. bovis was absent by three days after inoculation. Logistic regression analysis was used to assess the effects of bacterial concentration and time since inoculation, as well as determine the potential half-life of M. bovis in raw souring milk. Given the most favourable tested conditions for bacterial survival (20 degrees C), approximately 25% of mycobacteria were alive after one day of storage (95% CI: 9-53%), giving an estimated half-life of M. bovis in raw souring milk of approximately 12 hours (95% CI: 7-27 hours). CONCLUSIONS: This study demonstrates that M. bovis may survive in fresh and souring milk for periods of time that represent a risk of exposure to people consuming these products, as well as domestic or wild animal populations that have reported opportunities to consume homemade unpasteurised dairy products. The temperature at which the milk is soured and stored substantially affects the survival time of M. bovis. PMID- 26121262 TI - Relating Essential Proteins to Drug Side-Effects Using Canonical Component Analysis: A Structure-Based Approach. AB - The molecular mechanism of many drug side-effects is unknown and difficult to predict. Previous methods for explaining side-effects have focused on known drug targets and their pathways. However, low affinity binding to proteins that are not usually considered drug targets may also drive side-effects. In order to assess these alternative targets, we used the 3D structures of 563 essential human proteins systematically to predict binding to 216 drugs. We first benchmarked our affinity predictions with available experimental data. We then combined singular value decomposition and canonical component analysis (SVD-CCA) to predict side-effects based on these novel target profiles. Our method predicts side-effects with good accuracy (average AUC: 0.82 for side effects present in <50% of drug labels). We also noted that side-effect frequency is the most important feature for prediction and can confound efforts at elucidating mechanism; our method allows us to remove the contribution of frequency and isolate novel biological signals. In particular, our analysis produces 2768 triplet associations between 50 essential proteins, 99 drugs, and 77 side effects. Although experimental validation is difficult because many of our essential proteins do not have validated assays, we nevertheless attempted to validate a subset of these associations using experimental assay data. Our focus on essential proteins allows us to find potential associations that would likely be missed if we used recognized drug targets. Our associations provide novel insights about the molecular mechanisms of drug side-effects and highlight the need for expanded experimental efforts to investigate drug binding to proteins more broadly. PMID- 26121264 TI - Tightly-Coupled Plant-Soil Nitrogen Cycling: Comparison of Organic Farms across an Agricultural Landscape. AB - How farming systems supply sufficient nitrogen (N) for high yields but with reduced N losses is a central challenge for reducing the tradeoffs often associated with N cycling in agriculture. Variability in soil organic matter and management of organic farms across an agricultural landscape may yield insights for improving N cycling and for evaluating novel indicators of N availability. We assessed yields, plant-soil N cycling, and root expression of N metabolism genes across a representative set of organic fields growing Roma-type tomatoes (Solanum lycopersicum L.) in an intensively-managed agricultural landscape in California, USA. The fields spanned a three-fold range of soil carbon (C) and N but had similar soil types, texture, and pH. Organic tomato yields ranged from 22.9 to 120.1 Mg ha-1 with a mean similar to the county average (86.1 Mg ha-1), which included mostly conventionally-grown tomatoes. Substantial variability in soil inorganic N concentrations, tomato N, and root gene expression indicated a range of possible tradeoffs between yields and potential for N losses across the fields. Fields showing evidence of tightly-coupled plant-soil N cycling, a desirable scenario in which high crop yields are supported by adequate N availability but low potential for N loss, had the highest total and labile soil C and N and received organic matter inputs with a range of N availability. In these fields, elevated expression of a key gene involved in root N assimilation, cytosolic glutamine synthetase GS1, confirmed that plant N assimilation was high even when inorganic N pools were low. Thus tightly-coupled N cycling occurred on several working organic farms. Novel combinations of N cycling indicators (i.e. inorganic N along with soil microbial activity and root gene expression for N assimilation) would support adaptive management for improved N cycling on organic as well as conventional farms, especially when plant-soil N cycling is rapid. PMID- 26121265 TI - Assessment of Sublethal and Transgenerational Effects of Pirimicarb on the Wheat Aphids Rhopalosiphum padi and Sitobion avenae. AB - The wheat aphids, Rhopalosiphum padi (Linnaeus) and Sitobion avenae (Fabricius), are key pests on wheat crops worldwide. Management practices rely primarily on insecticides. The pirimicarb (carbamate) is used extensively as an effective insecticide to control these two aphids. In addition to the mortality caused by pirimicarb, various sublethal effects may occur in aphids when exposed to low lethal or sublethal doses. Understanding the general effect of pirimicarb on aphids could help increasing rational use of this insecticide. Under laboratory conditions, we assessed the sublethal effects of a low lethal concentration of pirimicarb (LC25) on biological traits and acetylcholinesterase (AChE) activity of R. padi and S. avenae. Both direct and transgenerational effects, i.e. on parent and the F1 generations were assessed, respectively. We found that R. padi and S. avenae responded differentially to the LC25 of pirimicarb. The parent generation of R. padi showed a 39% decrease in fecundity and multiple transgenerational effects were observed in the F1 generation; overall juvenile development, reproductive period, adult longevity and lifespan were longer than those of the control group. By contrast, LC25 of pirimicarb showed almost no effects on S. avenae biological traits in both the parent and F1 generations; only the pre-reproductive duration was reduced in F1 generations. Demographic parameter estimates (e.g. rm) showed similar trend, i.e. significant negative effect on R. padi population growth and no effect on S. avenae. However, AChE activity decreased in both R. padi and S. avenae treated by the LC25 of pirimicarb. We demonstrated sublethal and transgenerational effects of pirimicarb in the two wheat aphid species; it hinted at the importance of considering sublethal effects (including hormesis) of pirimicarb for optimizing Integrated Pest Management (IPM) of wheat aphids. PMID- 26121266 TI - Emergence of Ciprofloxacin-Resistant Salmonella enterica Serovar Typhi in Italy. AB - In developed countries, typhoid fever is often associated with persons who travel to endemic areas or immigrate from them. Typhoid fever is a systemic infection caused by Salmonella enterica serovar Typhi. Because of the emergence of antimicrobial resistance to standard first-line drugs, fluoroquinolones are the drugs of choice. Resistance to ciprofloxacin by this Salmonella serovar represents an emerging public health issue. Two S. enterica ser. Typhi strains resistant to ciprofloxacin (CIP) were reported to the Italian surveillance system for foodborne and waterborne diseases (EnterNet-Italia) in 2013. The strains were isolated from two Italian tourists upon their arrival from India. A retrospective analysis of 17 other S. enterica ser. Typhi strains isolated in Italy during 2011 2013 was performed to determine their resistance to CIP. For this purpose, we assayed for susceptibility to antimicrobial agents and conducted PCR and nucleotide sequence analyses. Moreover, all strains were typed using pulsed-field gel electrophoresis to evaluate possible clonal relationships. Sixty-eight percent of the S. enterica ser. Typhi strains were resistant to CIP (MICs, 0.125 16 mg/L), and all isolates were negative for determinants of plasmid-mediated quinolone resistance. Analysis of sequences encoding DNA gyrase and topoisomerase IV subunits revealed mutations in gyrA, gyrB, and parC. Thirteen different clonal groups were detected, and the two CIP-resistant strains isolated from the individuals who visited India exhibited the same PFGE pattern. Because of these findings, the emergence of CIP-resistant S. enterica ser. Typhi isolates in Italy deserves attention, and monitoring antibiotic susceptibility is important for efficiently managing cases of typhoid fever. PMID- 26121267 TI - Headache and Alcohol. AB - BACKGROUND: The notion that alcohol intake may trigger headache is well known. Historical data as well as clinical experience indicate that this may be the case for headache patients as well persons without known headache disorders. This monograph reviews the medical literature about alcohol as a headache trigger, what headache types are triggered, and why. METHODS: Literature search primarily using the terms "alcohol and headache," "migraine and alcohol," "cluster headache and alcohol," and "alcohol hangover headache," as well as combined search, was performed, limiting the search to the last decade. Relevant articles were picked. RESULTS: The search "alcohol and headache" yielded 918 hits for the decade 2004 2014. Combined search gave substantially less, and 30 papers were reviewed, of which 25 are included in this review. DISCUSSION: Epidemiological studies find some correlations between alcohol intake and mainly primary headache disorders, such as migraine and cluster headache. Cultural differences in alcohol consumption are probably reflected in some of the results and conclusions. Both migraine and cluster headaches may be triggered by alcohol; however, which type of alcoholic beverage triggers these headaches is not clear. There is no single mechanism that explains the pathophysiology of alcohol-induced headache, other that hangover headache in some may be triggered by inactive alcohol dehydrogenase 2. Alcohol-induced headache may be diagnosed as a secondary headache, while in patients with migraine or cluster headache alcohol intake may act as a trigger for these primary headaches. CONCLUSIONS AND RECOMMENDATIONS: Based on the literature, there is no reason to tell headache patients in general to abstain from alcohol. Individual dispositions as well as cultural factors may play a role in alcohol-induced headache. PMID- 26121268 TI - Structuring Light by Concentric-Ring Patterned Magnetic Metamaterial Cavities. AB - Ultracompact and tunable beam converters pose a significant potential for modern optical technologies ranging from classical and quantum communication to optical manipulation. Here we design and demonstrate concentric-ring patterned structures of magnetic metamaterial cavities capable of tailoring both polarization and phase of light by converting circularly polarized light into a vector beam with an orbital angular momentum. We experimentally illustrate the realization of both radially and azimuthally polarized vortex beams using such concentric-ring patterned magnetic metamaterials. These results contribute to the advanced complex light manipulation with optical metamaterials, making it one step closer to realizing the simultaneous control of polarization and orbital angular momentum of light on a chip. PMID- 26121263 TI - Accessibility to Reperfusion Therapy Among Women with Acute Myocardial Infarction: Impact on Hospital Mortality. AB - BACKGROUND: The available evidence about the effect of gender and/or sex on mortality differences is contradictory. Our aim is to assess the impact of gender on the access to reperfusion therapy in patients with acute coronary syndrome with ST-segment elevation (STEMI), and secondly, to analyze the effect of delay on the differences with regard to hospital mortality. METHODS: A retrospective cohort study was conducted among consecutive patients with STEMI included in the ARIAM-SEMICYUC registry (2010-2013). RESULTS: A total of 4816 patients were included (22.09% women). Women were older, presented with longer patient delay (90 vs. 75 minutes, p=0.0066), higher risk profile (GRACE>140: 75.1% vs. 56.05%, p<0.0001), and received less reperfusion therapy (68.8% vs. 74.7%, p<0.0001) with longer total reperfusion time (307 vs. 240 minutes, p<0.0001). Women received less thrombolysis (24.53% vs. 29.98%, p<0.0001) and longer door-to-needle time (85 vs. 70 minutes, p 0.0023). We found no differences regarding primary percutaneous coronary intervention or door-to-balloon time. Women also had higher hospital mortality (crude odds ratio 2.54, 95% confidence interval 1.99-3.26, p<0.0001), which persisted after controlling the effect of patient delay, age, risk (GRACE), and reperfusion (adjusted odds ratio 1.43, 95% confidence interval 1.0-2.06, p=0.0492). Using TIMI or Killip risk scores as risk estimates yielded nonsignificant results. CONCLUSIONS: Compared with men, women with STEMI have worse access to reperfusion and higher hospital mortality. The impact of the differences in accessibility on mortality gap remains uncertain. PMID- 26121271 TI - Giant Blue Nevus: A New Association to Nevus of Ota. AB - Nevus of Ota, also known as oculodermal melanocytosis, is a congenital pigmentary condition that can affect structures in the distribution of the ophthalmic and maxillary divisions of the trigeminal cranial nerve. Malignant transformation, although rare, may occur within nevus of Ota and result in uveal, cutaneous, orbital or even dural melanoma. We present a new association of Nevus of Ota complicated with a giant orbital Blue Nevus in a young white male and the management of this tumor. PMID- 26121269 TI - The miRNA Profile of Platelets Stored in a Blood Bank and Its Relation to Cellular Damage from Storage. AB - Millions of blood products are transfused each year, and many lives are directly affected by transfusion. Platelet concentrate (PC) is one of the main products derived from blood. Even under good storage conditions, PC is likely to suffer cell damage. The shape of platelets changes after 5 to 7 days of storage at 22 degrees C. Taking into consideration that some platelet proteins undergo changes in their shape and functionality during PC storage. Sixteen PC bags were collected and each PC bag tube was cut into six equal pieces to perform experiments with platelets from six different days of storage. Thus, on the first day of storage, 1/6 of the tube was used for miRNA extraction, and the remaining 5/6 was stored under the same conditions until extraction of miRNAs on each the following five days. Samples were sequenced on an Illumina Platform to demonstrate the most highly expressed miRNAs. Three miRNAs, mir127, mir191 and mir320a were validated by real-time quantitative PCR (RQ-PCR) in 100 PC bags tubes. Our method suggests, the use of the miRNAs mir127 and mir320a as biomarkers to assess the "validity period" of PC bags stored in blood banks for long periods. Thus, bags can be tested on the 5th day of storage for the relative expression levels of mir127 and mir320a. Thus, we highlight candidate miRNAs as biomarkers of storage damage that can be used as tools to evaluate the quality of stored PC. The use of miRNAs as biomarkers of damage is unprecedented and will contribute to improved quality of blood products for transfusions. PMID- 26121272 TI - High levels of von Willebrand factor and low levels of its cleaving protease, ADAMTS13, are associated with stroke in young HIV-infected patients. AB - BACKGROUND: Stroke associated with human immunodeficiency virus infection may occur through a variety of mechanisms. Von Willebrand factor is a marker of endothelial dysfunction, and is elevated in human immunodeficiency virus infection. High levels of von Willebrand factor, a protein involved in platelet adhesion and aggregation, and low levels of ADAMTS13, a metalloproteinase that cleaves von Willebrand factor, have been associated with an increased risk of thrombosis. AIM: To investigate the role of von Willebrand factor and ADAMTS13 in the pathogenesis of human immunodeficiency virus-related stroke in young patients. METHODS: A case-control study (n = 100) comprising three participant groups: human immunodeficiency virus-positive antiretroviral therapy-naive young strokes (n = 20), human immunodeficiency virus-negative young strokes (n = 40), and human immunodeficiency virus-positive antiretroviral therapy-naive nonstroke controls (n = 40). von Willebrand factor and ADAMTS13 levels were measured in plasma samples collected five- to seven-days poststroke. RESULTS: Human immunodeficiency virus-positive stroke participants had higher von Willebrand factor levels than human immunodeficiency virus-negative strokes (173.5% vs. 135%, P = 0.032). They tended to have higher levels of von Willebrand factor than human immunodeficiency virus-positive nonstroke controls (173.5% vs. 129%, P = 0.061). Human immunodeficiency virus-positive stroke participants had lower levels of ADAMTS13 than human immunodeficiency virus-positive nonstroke controls (0% vs. 23.5% P = 0.018) most likely due to the effect of the acute stroke. However, in the nonstroke group, these levels were significantly reduced compared with population norms. von Willebrand factor levels in all human immunodeficiency virus-positive participants were negatively correlated with CD4 counts. CONCLUSIONS: Stroke in human immunodeficiency virus infection is associated with a prothrombotic state, characterized by elevated von Willebrand factor and low ADAMTS13 levels. PMID- 26121270 TI - High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort. AB - RAS and BRAF mutations impact treatment and prognosis of metastatic colorectal cancer patients (mCRC), but the knowledge is based on trial patients usually not representative for the general cancer population. Patient characteristics, treatment and efficacy according to KRAS, BRAF and MSI status were analyzed in a prospectively collected unselected population-based cohort of 798 non-resectable mCRC patients. The cohort contained many patients with poor performance status (39% PS 2-4) and elderly (37% age>75), groups usually not included in clinical trials. Patients without available tissue micro array (TMA) (42%) had worse prognostic factors and inferior survival (all patients; 7m vs 11m, chemotherapy treated;12m vs 17m). The 92 patients (21%) with BRAF mutation had a poor prognosis regardless of microsatellite instability, but receipt of 1-2nd chemotherapy was similar to wildtype BRAF patients. Median survival in this cohort varied from 1 month in BRAF mutated patients not given chemotherapy to 26 months in wildtype KRAS/BRAF patients <75 years in good PS. TMA availability, BRAF mutation and KRAS mutation were all independent prognostic factors for survival. The observed 21% BRAF mutation incidence is higher than the previously and repeatedly reported incidence of 5-12% in mCRC. Screening for BRAF mutations before selection of treatment is relevant for many patients, especially outside clinical trials. A BRAF mutation only partly explained the very poor prognosis of many mCRC patients. Survival in unselected metastatic colorectal cancer patients is extremely variable and subgroups have an extremely short survival compared to trial patients. Patients without available TMA had worse prognostic factors and shorter survival, which questions the total generalizability of present TMA studies and implies that we lack information on the biologically worst mCRC cases. Lack of available tissue is an important underexposed issue which introduces sample bias, and this should be recognized more clearly when conclusions are made from translational mCRC studies. PMID- 26121273 TI - The serum lipid profiles of amyotrophic lateral sclerosis patients: A study from south-west China and a meta-analysis. AB - Associations between the fasting levels of serum lipid and amyotrophic lateral sclerosis (ALS) in Chinese populations remain largely unknown. Our objective was to analyse data from a cohort of ALS patients to determine these associations. Four hundred and thirteen ALS patients and 400 age- and gender-matched healthy controls were included. Fasting serum lipid concentration of all subjects, including total cholesterol, low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglyceride (TG), were measured at the time of first visit. The revised ALS Functional Rating Scale (ALSFRS-R) was used to assess the severity of ALS. Systems Analysis by Review Manager 5 was used to evaluate differences in dyslipidaemia between ALS patients and controls. Results showed that ALS patients with higher triglyceride levels had longer survival time compared to patients with lower triglyceride levels (p < 0.05). We found a median prolonged life expectancy of 5.8 months for patients with serum triglyceride levels above the median of 127.5 mg/dl. Cox regression analysis indicated that disease duration and age were positively correlated with death, and triglyceride was positively correlated with survival. A meta-analysis indicated that there were no significant differences in mean total cholesterol, TG, LDL or the LDL/HDL ratio between patients and controls. In conclusion, high serum TG might be a protective factor for the survival of patients with ALS. PMID- 26121274 TI - The longitudinal cerebrospinal fluid metabolomic profile of amyotrophic lateral sclerosis. AB - Neurochemical biomarkers are urgently sought in ALS. Metabolomic analysis of cerebrospinal fluid (CSF) using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy is a highly sensitive method capable of revealing nervous system cellular pathology. The (1)H-NMR CSF metabolomic signature of ALS was sought in a longitudinal cohort. Six-monthly serial collection was performed in ALS patients across a range of clinical sub-types (n = 41) for up to two years, and in healthy controls at a single time-point (n = 14). A multivariate statistical approach, partial least squares discriminant analysis, was used to determine differences between the NMR spectra from patients and controls. Significantly predictive models were found using those patients with at least one year's interval between recruitment and the second sample. Glucose, lactate, citric acid and, unexpectedly, ethanol were the discriminating metabolites elevated in ALS. It is concluded that (1)H-NMR captured the CSF metabolomic signature associated with derangements in cellular energy utilization connected with ALS, and was most prominent in comparisons using patients with longer disease duration. The specific metabolites identified support the concept of a hypercatabolic state, possibly involving mitochondrial dysfunction specifically. Endogenous ethanol in the CSF may be an unrecognized novel marker of neuronal tissue injury in ALS. PMID- 26121275 TI - Asymmetry in the discrimination of quantity: The role of stimulus generalization. AB - In order to evaluate 1 account for the asymmetry that has been found with discriminations based on stimulus magnitude, in 5 autoshaping experiments, 2 groups of pigeons received a discrimination between 5 and 20 squares presented on a TV screen. One group received a 20+/5- discrimination, with food signaled by 20 squares but not 5 squares; the other group received the opposite discrimination, 5+/20-. The 20+/5- discrimination was acquired more readily than 5+/20- in Experiments 1, 3a, 3b, and 4. For Experiment 1, the screen was white for the intertrial interval (ITI) and the stimuli were black squares on a white background; for Experiment 3a, the screen was black for the ITI and the stimuli were black squares on a white background; and for Experiments 3b and 4, the screen was white for the ITI and the stimuli were white squares on a black background. In Experiment 2, the stimuli were black squares on a white background, but they were separated by an ITI in which 288 black squares were presented against a white background. The 20+/5- discrimination was now acquired more slowly than the 5+/20- discrimination. The asymmetry in the acquisition of the magnitude discriminations in each experiment is attributed to inhibition being associated with the stimuli present during the ITI. The generalization of this inhibition, along a dimension related to the number of squares on the screen, is then assumed to disrupt the acquisition of 1 discrimination to a greater extent than the other. PMID- 26121277 TI - Klk8 is required for microabscess formation in a mouse imiquimod model of psoriasis. PMID- 26121276 TI - Immunological Response to Single Pathogen Challenge with Agents of the Bovine Respiratory Disease Complex: An RNA-Sequence Analysis of the Bronchial Lymph Node Transcriptome. AB - Susceptibility to bovine respiratory disease (BRD) is multi-factorial and is influenced by stress in conjunction with infection by both bacterial and viral pathogens. While vaccination is broadly used in an effort to prevent BRD, it is far from being fully protective and cases diagnosed from a combination of observed clinical signs without any attempt at identifying the causal pathogens are usually treated with antibiotics. Dairy and beef cattle losses from BRD are profound worldwide and genetic studies have now been initiated to elucidate host loci which underlie susceptibility with the objective of enabling molecular breeding to reduce disease prevalence. In this study, we employed RNA sequencing to examine the bronchial lymph node transcriptomes of controls and beef cattle which had individually been experimentally challenged with bovine respiratory syncytial virus, infectious bovine rhinotracheitis, bovine viral diarrhea virus, Pasteurella multocida, Mannheimia haemolytica or Mycoplasma bovis to identify the genes that are involved in the bovine immune response to infection. We found that 142 differentially expressed genes were located in previously described quantitative trait locus regions associated with risk of BRD. Mutations affecting the expression or amino acid composition of these genes may affect disease susceptibility and could be incorporated into molecular breeding programs. Genes involved in innate immunity were generally found to be differentially expressed between the control and pathogen-challenged animals suggesting that variation in these genes may lead to a heritability of susceptibility that is pathogen independent. However, we also found pathogen-specific expression profiles which suggest that host genetic variation for BRD susceptibility is pathogen dependent. PMID- 26121278 TI - Efficient electrochemical CO2 conversion powered by renewable energy. AB - The catalytic conversion of CO2 into industrially relevant chemicals is one strategy for mitigating greenhouse gas emissions. Along these lines, electrochemical CO2 conversion technologies are attractive because they can operate with high reaction rates at ambient conditions. However, electrochemical systems require electricity, and CO2 conversion processes must integrate with carbon-free, renewable-energy sources to be viable on larger scales. We utilize Au25 nanoclusters as renewably powered CO2 conversion electrocatalysts with CO2 > CO reaction rates between 400 and 800 L of CO2 per gram of catalytic metal per hour and product selectivities between 80 and 95%. These performance metrics correspond to conversion rates approaching 0.8-1.6 kg of CO2 per gram of catalytic metal per hour. We also present data showing CO2 conversion rates and product selectivity strongly depend on catalyst loading. Optimized systems demonstrate stable operation and reaction turnover numbers (TONs) approaching 6 * 10(6) molCO2 molcatalyst(-1) during a multiday (36 h total hours) CO2 electrolysis experiment containing multiple start/stop cycles. TONs between 1 * 10(6) and 4 * 10(6) molCO2 molcatalyst(-1) were obtained when our system was powered by consumer-grade renewable-energy sources. Daytime photovoltaic-powered CO2 conversion was demonstrated for 12 h and we mimicked low-light or nighttime operation for 24 h with a solar-rechargeable battery. This proof-of-principle study provides some of the initial performance data necessary for assessing the scalability and technical viability of electrochemical CO2 conversion technologies. Specifically, we show the following: (1) all electrochemical CO2 conversion systems will produce a net increase in CO2 emissions if they do not integrate with renewable-energy sources, (2) catalyst loading vs activity trends can be used to tune process rates and product distributions, and (3) state-of-the art renewable-energy technologies are sufficient to power larger-scale, tonne per day CO2 conversion systems. PMID- 26121279 TI - Perinatal dioxin exposure and psychosocial and behavioral development in school aged children. AB - OBJECTIVE: The aim of this study was to elucidate the association between psychosocial and behavioral problems in children at school age and dioxin level in breast milk or estimated dioxin exposure (EDE) through breastfeeding in the general Japanese population. METHODS: Dioxin level of breast milk at 1month of age and breastfeeding ratio through the first year of life were used to calculate the EDE of infants born in 1998-2005 in Japan. The Japanese Social Difficulties Questionnaire (SDQ) for the assessment of children's behavior was sent by mail to mothers whose breast milk underwent the dioxin survey, at the time when their infants were aged 6-13 years. RESULTS: The study subjects were 175 pairs of mothers and their first infants (79 boys, 96 girls). The mean total dioxin levels of breast milk were 18.3 and 19.8 (pgTEQ/g fat) and EDEs were 16.4 and 19.6 (ngTEQ/kg/year) in boys and girls, respectively. In linear multiple regression analyses after adjusting for age at SDQ, maternal age, birth weight and maternal smoking habit, dioxin level in breast milk was not significantly related to the total difficulties score (TDS) of SDQ in boys, B=2.29 (95% CI -7.60-12.18), or in girls, B=-1.04 (95% CI -9.24-7.15). EDE correlated to the TDS in neither boys, B= 0.99 (95% CI -4.14-2.15), nor girls, B=1.08 (95% CI -2.69-4.85). CONCLUSION: No evidence was found of a correlation between perinatal dioxin exposure and behavioral and psychosocial problems of children measured by SDQ. These results support the benefits of recommending breastfeeding. PMID- 26121280 TI - Postnatal changes in skin water content in preterm infants. AB - BACKGROUND: Preterm infants have immature skin, which contributes to skin problems. Very little is known about postnatal changes in the skin, despite the clinical importance of this issue. AIM: To assess temporal changes in skin water content in preterm infants. STUDY DESIGN: A prospective observational study. SUBJECTS: Infants admitted to the neonatal intensive care unit were included in this study. OUTCOME MEASURES: Skin water content was measured at five different skin regions using dielectric methods at a depth of 1.5mm. Skin water content was measured on postnatal day 1 in 101 infants, and the correlation between skin water content and gestational week was analyzed. Measurements were also made on postnatal days 2, 3, and 7, and every 7days thereafter until the corrected age of 37weeks in 87 of the 101 infants. Temporal changes were statistically analyzed after dividing participants into seven groups by gestational age. RESULTS: On postnatal day 1, skin water content correlated inversely with gestational age at all skin regions. Skin water content decreased significantly over time, converging to the level of term infants by the corrected age of 32-35weeks. CONCLUSIONS: Skin water content at a depth of 1.5mm was related to corrected age and reached the level of term infants by the corrected age of approximately 32 35weeks. PMID- 26121282 TI - Pineal Melatonin in a Sub-chronic Tryptophan Depletion Female Rat Model of Treatment-resistant Depression. PMID- 26121281 TI - Monosodium Glutamate Dietary Consumption Decreases Pancreatic beta-Cell Mass in Adult Wistar Rats. AB - BACKGROUND: The amount of dietary monosodium glutamate (MSG) is increasing worldwide, in parallel with the epidemics of metabolic syndrome. Parenteral administration of MSG to rodents induces obesity, hyperglycemia, hyperlipidemia, insulin resistance, and type 2 diabetes. However, the impact of dietary MSG is still being debated. We investigated the morphological and functional effects of prolonged MSG consumption on rat glucose metabolism and on pancreatic islet histology. METHODS: Eighty adult male Wistar rats were randomly subdivided into 4 groups, and test rats in each group were supplemented with MSG for a different duration (1, 3, 6, or 9 months, n=20 for each group). All rats were fed ad libitum with a standard rat chow and water. Ten test rats in each group were provided MSG 2 mg/g body weight/day in drinking water and the 10 remaining rats in each group served as non-MSG treated controls. Oral glucose tolerance tests (OGTT) were performed and serum insulin measured at 9 months. Animals were sacrificed at 1, 3, 6, or 9 months to examine the histopathology of pancreatic islets. RESULTS: MSG-treated rats had significantly lower pancreatic beta-cell mass at 1, 6 and 9 months of study. Islet hemorrhages increased with age in all groups and fibrosis was significantly more frequent in MSG-treated rats at 1 and 3 months. Serum insulin levels and glucose tolerance in MSG-treated and untreated rats were similar at all time points we investigated. CONCLUSION: Daily MSG dietary consumption was associated with reduced pancreatic beta-cell mass and enhanced hemorrhages and fibrosis, but did not affect glucose homeostasis. We speculate that high dietary MSG intake may exert a negative effect on the pancreas and such effect might become functionally significant in the presence or susceptibility to diabetes or NaCl; future experiments will take these crucial cofactors into account. PMID- 26121283 TI - Pericytes in wound healing: friend or foe? PMID- 26121284 TI - Personality, self-perceptions, and daily variability in perceived usefulness among older adults. AB - Age-based self-stereotyping is associated with a variety of long-term physical health and psychological well-being outcomes for older people. However, little is known about how older individuals' day-to-day experiences of functional limitations may be related to concurrent self-appraisals on dimensions representing negative age stereotypes. We examined how distal personality traits and global self-perceptions of aging at baseline affect processing of daily experiences relevant to age-based self-stereotyping over time. Data from the 100 day Internet-based Personal Understanding of Life and Social Experiences (PULSE) study (N = 98, age = 52 - 88) were used to examine the link between personality and self-perceptions of aging to differences in 2 age stereotype-relevant daily experiences: cognitive limitations and variation in usefulness. Multilevel random coefficient models suggested that personality and self-perceptions of aging were associated with the level of usefulness and the frequency of reporting trouble concentrating during the study period. Daily experiences of trouble concentrating were significantly associated with lower perceived usefulness on that day, and conscientiousness moderated this relationship. By linking personality and global self-perceptions to daily experiences, our findings contribute toward understanding self-stereotyping processes by which personality and perceptions may affect long-term outcomes. PMID- 26121285 TI - Global perceived stress predicts cognitive change among older adults. AB - Research on stress and cognitive aging has primarily focused on examining the effects of biological and psychosocial indicators of stress, with little attention provided to examining the association between perceived stress and cognitive aging. We examined the longitudinal association between global perceived stress (GPS) and cognitive change among 116 older adults (M(age) = 80, SD = 6.40, range = 67-96) in a repeated measurement burst design. Bursts of 6 daily cognitive assessments were repeated every 6 months over a 2-year period, with self-reported GPS assessed at the start of every burst. Using a double exponential learning model, 2 parameters were estimated: (a) asymptotic level (peak performance), and (b) asymptotic change (the rate at which peak performance changed across bursts). We hypothesized that greater GPS would predict slowed performance in tasks of attention, working memory, and speed of processing and that increases in GPS across time would predict cognitive slowing. Results from latent growth curve analyses were consistent with our first hypothesis and indicated that level of GPS predicted cognitive slowing across time. Changes in GPS did not predict cognitive slowing. This study extends previous findings by demonstrating a prospective association between level of GPS and cognitive slowing across a 2-year period, highlighting the role of psychological stress as a risk factor for poor cognitive function. PMID- 26121286 TI - Cerebrovascular function associated with fluid, not crystallized, abilities in older adults: A transcranial Doppler study. AB - The brain is dependent on the cerebrovascular system, particularly microvasculature, for a consistent blood supply; however, age-related changes in this system affect neuronal and therefore cognitive function. Structural vascular markers and vascular disease appear to preferentially affect fluid cognitive abilities, sparing crystallized abilities. We sought to investigate the relationships between cerebrovascular function and cognitive domains. Fifty individuals between 60 and 75 years of age (31 women, 19 men) underwent cognitive testing: Wechsler Vocabulary and Matrix Reasoning subtests (crystallized and fluid ability measures, respectively Wechsler, 2011), and the Addenbrooke's Cognitive Examination-Revised (ACE-R; general cognitive ability; Mioshi, Dawson, Mitchell, Arnold, & Hodges, 2006). Transcranial Doppler (TCD) measures were also collected at rest and during a cognitive word-generation task, from which a lateralization index was calculated. Lower pulsatility index at rest, and greater left lateralization during the TCD cognitive task were associated with better performance on the Matrix Reasoning but not the Vocabulary test; these effects were independent from each other and from any vascular comorbidity burden. These functional findings confirm previous structural studies, which revealed that fluid abilities are more vulnerable to cerebrovascular dysfunction than crystallized abilities, and identify two (likely related) mechanisms: degraded cerebrovascular integrity (indexed by pulsatility index) and a delateralization of function. Cerebrovascular dysfunction is a key contributor to cognitive aging that deserves further attention, particularly in relation to early diagnostic markers of impairment and monitoring of vascular (e.g., physical activity) interventions. PMID- 26121287 TI - Age-related differences in inhibitory control predict audiovisual speech perception. AB - Audiovisual (AV) speech perception is the process by which auditory and visual sensory signals are integrated and used to understand what a talker is saying during face-to-face communication. This form of communication is markedly superior to speech perception in either sensory modality alone. However, there are additional lexical factors that are affected by age-related cognitive changes that may contribute to differences in AV perception. In the current study, we extended an existing model of spoken word identification to the AV domain, and examined the cognitive factors that contribute to age-related and individual differences in AV perception of words varying in lexical difficulty (i.e., on the basis of competing items). Young (n = 49) and older adults (n = 50) completed a series of cognitive inhibition tasks and a spoken word identification task. The words were presented in auditory-only, visual-only, and AV conditions, and were equally divided into lexically hard (words with many competitors) and lexically easy (words with few competitors). Overall, young adults demonstrated better inhibitory abilities and higher identification performance than older adults. However, whereas no relationship was observed between inhibitory abilities and AV word identification performance in young adults, there was a significant relationship between Stroop interference and AV identification of lexically hard words in older adults. These results are interpreted within the framework of existing models of spoken-word recognition with implications for how cognitive deficits in older adults contribute to speech perception. PMID- 26121288 TI - Happiness and age in European adults: The moderating role of gross domestic product per capita. AB - Studies of happiness levels across the life span have found support for two rival hypotheses. The positivity effect states that as people get older, they increasingly attend to positive information, which implies that happiness remains stable or increases with age, whereas the U-shaped hypothesis posits a curvilinear shape resulting from a dip during midlife. Both have been presented as potentially universal hypotheses that relate to cognitive and/or biological causes. The current study examined the happiness-age relationship across 29 European nations (N = 46,301) to explore whether it is moderated by national wealth, as indexed by Gross Domestic Product (GDP) per capita. It was found that eudaimonic and hedonic happiness remained relatively stable across the life span only in the most affluent nations; in poorer nations, there was either a fluctuating or steady age-associated decline. These findings challenge the cultural universality of the happiness-age relationship and suggest that models of how age relates to happiness should include the socioeconomic level of analysis. PMID- 26121289 TI - Emotional well-being and interactions with older adults' close social partners: Daily variation in social context matters. AB - Close social partners may contribute to or detract from older adults' health and well-being, in part because daily emotions are closely coupled with the quality of daily social interactions. This study examines variation in this sensitivity to interactions with social partners across the contexts of emotional closeness, interactions with others, and experienced relationship satisfaction across the study period. Using data from the 100-day web-based personal understanding of life and social experiences (PULSE) study, the authors examined the unique contribution of older adults' closest and other social partners to daily experiences of positive and negative affect and considered transitory state-like aspects of sensitivity that vary within individuals across the context of social interactions on that day. Participants in this microlongitudinal study (N = 99, M(age) = 62.3) identified their 5 closest social partners and then reported daily contact satisfaction with those partners as well as positive and negative affect. Multivariate multilevel analysis showed sensitivity of positive and negative affect to the quality of social interactions to vary across participant-defined hierarchies of closeness. Sensitivity to interactions with the closest partner also varied within individuals depending on the quality of interactions with others on that day and also across individual differences in the level of experienced relationship satisfaction during the study period. Together, the findings suggest that emotional responses to social interactions vary according to the context of daily social experiences, as well as accumulated social experiences over time. PMID- 26121290 TI - When and why do old adults outsource control to the environment? AB - Old adults' tendency to rely on information present in the environment rather than internal representations has been frequently noted, but is not well understood. The fade-out paradigm provides a useful model situation to study this internal-to-external shift across the life span: Subjects need to transition from an initial, cued task-switching phase to a fade-out phase where only 1 task remains relevant. Old adults exhibit large response-time "fade-out costs," mainly because they continue to consult the task cues. Here we show that age differences in fade-out costs remain very large even when we insert between the task switching and the fade-out phase 20 single-task trials without task cues (during which even old adults' performance becomes highly fluent; Experiment 1), but costs in old adults are eliminated when presenting an on-screen instruction to focus on the 1 remaining task at the transition point between the task-switching and fade-out phase (Experiment 2). Furthermore, old adults, but not young adults, also exhibited "fade-in costs" when they were instructed to perform an initial single-task phase that would be followed by the cued task-switching phase (Experiment 3). Combined, these results show that old adults' tendency to overutilize external support is not a problem of perseverating earlier-relevant control settings. Instead, old adults seem less likely to initiate the necessary reconfiguration process when transitioning from 1 phase to the next because they use underspecified task models that lack the higher-level distinction between those contexts that do and that do not require external support. PMID- 26121291 TI - Prevalence of Childhood Exposure to Violence, Crime, and Abuse: Results From the National Survey of Children's Exposure to Violence. AB - IMPORTANCE: It is important to estimate the burden of and trends for violence, crime, and abuse in the lives of children. OBJECTIVE: To provide health care professionals, policy makers, and parents with current estimates of exposure to violence, crime, and abuse across childhood and at different developmental stages. DESIGN, SETTING, AND PARTICIPANTS: The National Survey of Children's Exposure to Violence (NatSCEV) includes a representative sample of US telephone numbers from August 28, 2013, to April 30, 2014. Via telephone interviews, information was obtained on 4000 children 0 to 17 years old, with information about exposure to violence, crime, and abuse provided by youth 10 to 17 years old and by caregivers for children 0 to 9 years old. MAIN OUTCOME AND MEASURE: Exposure to violence, crime, and abuse using the Juvenile Victimization Questionnaire. RESULTS: In total, 37.3% of youth experienced a physical assault in the study year, and 9.3% of youth experienced an assault-related injury. Two percent of girls experienced sexual assault or sexual abuse in the study year, while the rate was 4.6% for girls 14 to 17 years old. Overall, 15.2% of children and youth experienced maltreatment by a caregiver, including 5.0% who experienced physical abuse. In total, 5.8% witnessed an assault between parents. Only 2 significant rate changes could be detected compared with the last survey in 2011, namely, declines in past-year exposure to dating violence and lifetime exposure to household theft. CONCLUSIONS AND RELEVANCE: Children and youth are exposed to violence, abuse, and crime in varied and extensive ways, which justifies continued monitoring and prevention efforts. PMID- 26121292 TI - Temporal trends in bisphenol A exposure in the United States from 2003-2012 and factors associated with BPA exposure: Spot samples and urine dilution complicate data interpretation. AB - Nationally representative data on urinary levels of BPA and its metabolites in the United States from the 2003-2004 to 2011-2012 National Health and Nutrition Examination Surveys (NHANES) were used to estimate daily BPA intakes and examine temporal trends. Additionally, NHANES data on lifestyle/demographic/dietary factors previously reported to be associated with BPA exposures were examined to assess the resiliency of the reported associations (whether the association is maintained across the five surveys). Finally, various approaches for addressing issues with the use of BPA concentration data from spot urine samples were examined for their effect on trends and associations. Three approaches were assessed here: (i) use of generic literature-based 24-h urine excretion volumes, (ii) use of creatinine adjustments, and (iii) use of individual urine flow rate data from NHANES. Based on 2011-2012 NHANES urinary BPA data and assumptions described in this paper, the median daily intake for the overall population is approximately 25 ng/kg day; median intake estimates were approximately two to three orders of magnitude below current health-based guidance values. Estimates of daily BPA intake have decreased significantly compared to those from the 2003 2004 NHANES. Estimates of associations between lifestyle/demographic/dietary factors and BPA exposure revealed inconsistencies related to both NHANES survey year and the three approaches listed above; these results demonstrate the difficulties in interpreting urinary BPA data, despite efforts to account for urine dilution and translation of spot sample data to 24-h data. The results further underscore the importance of continued research on how to best utilize urinary measures of environmental chemicals in exposure research. Until a consensus is achieved regarding the best biomonitoring approaches for assessing exposures to short-lived chemicals using urine samples, research on factors associated with BPA exposures should include - and report results from - assessments using both volume-based urinary BPA and creatinine-adjusted urinary BPA data. PMID- 26121293 TI - Zinc compound air releases from Toxics Release Inventory facilities and cardiovascular disease mortality rates. AB - BACKGROUND: Inhaled zinc has been found in association with cardiopulmonary toxicity. However, limited human epidemiologic studies are available. This study analyzed the association between covariate-adjusted cardiovascular (CVD) mortality rates and zinc compound air releases in the United States. METHODS: We conducted an ecological analysis on the association between zinc compound air releases for 1991-2000 using the Toxics Release Inventory database and average age-adjusted CVD mortality for 2006-2010, adjusting for race/ethnicity composition and several health and socioeconomic factors. Models were estimated for males and females and for metropolitan and nonmetropolitan counties. RESULTS: Zinc compound air releases were positively associated with increased adjusted CVD mortality rates in all four models (beta=0.0085, p<0.0001 for males in nonmetropolitan counties; beta=0.0093, p<0.0001 for males in metropolitan counties; beta=0.0145, p<0.0001 for females in nonmetropolitan counties; and beta=0.0098, p<0.0001 for females in metropolitan counties). Results were largely robust to various sensitivity analyses. CONCLUSION: This study provides epidemiological evidence for possible CVD health impacts of inhaled zinc in the United States. Although the strongest effect was found for females in nonmetropolitan counties, the associations were consistent in nonmetropolitan or metropolitan counties for both genders. PMID- 26121294 TI - Is health workforce planning recognising the dynamic interplay between health literacy at an individual, organisation and system level? AB - The growing demands on the health system to adapt to constant change has led to investment in health workforce planning agencies and approaches. Health workforce planning approaches focusing on identifying, predicting and modelling workforce supply and demand are criticised as being simplistic and not contributing to system-level resiliency. Alternative evidence- and needs-based health workforce planning approaches are being suggested. However, to contribute to system-level resiliency, workforce planning approaches need to also adopt system-based approaches. The increased complexity and fragmentation of the healthcare system, especially for patients with complex and chronic conditions, has also led to a focus on health literacy not simply as an individual trait, but also as a dynamic product of the interaction between individual (patients, workforce)-, organisational- and system-level health literacy. Although it is absolutely essential that patients have a level of health literacy that enables them to navigate and make decisions, so too the health workforce, organisations and indeed the system also needs to be health literate. Herein we explore whether health workforce planning is recognising the dynamic interplay between health literacy at an individual, organisation and system level, and the potential for strengthening resiliency across all those levels. PMID- 26121295 TI - The potential of random forest and neural networks for biomass and recombinant protein modeling in Escherichia coli fed-batch fermentations. AB - Product quality assurance strategies in production of biopharmaceuticals currently undergo a transformation from empirical "quality by testing" to rational, knowledge-based "quality by design" approaches. The major challenges in this context are the fragmentary understanding of bioprocesses and the severely limited real-time access to process variables related to product quality and quantity. Data driven modeling of process variables in combination with model predictive process control concepts represent a potential solution to these problems. The selection of statistical techniques best qualified for bioprocess data analysis and modeling is a key criterion. In this work a series of recombinant Escherichia coli fed-batch production processes with varying cultivation conditions employing a comprehensive on- and offline process monitoring platform was conducted. The applicability of two machine learning methods, random forest and neural networks, for the prediction of cell dry mass and recombinant protein based on online available process parameters and two dimensional multi-wavelength fluorescence spectroscopy is investigated. Models solely based on routinely measured process variables give a satisfying prediction accuracy of about +/- 4% for the cell dry mass, while additional spectroscopic information allows for an estimation of the protein concentration within +/- 12%. The results clearly argue for a combined approach: neural networks as modeling technique and random forest as variable selection tool. PMID- 26121296 TI - Road traffic injuries in northern Laos: trends and risk factors of an underreported public health problem. AB - OBJECTIVES: Road traffic injuries (RTI) have become a leading cause for admissions at Luang Namtha Provincial Hospital (LNPH) in rapidly developing northern Laos. Objectives were to investigate trends, risk factors and better estimates of RTI. METHODS: Repeated annual surveys were conducted with structured questionnaires among all RTI patients at LNPH from 2007 to 2011. Hospital and police data were combined by capture-recapture method. RESULTS: The majority of 1074 patients were young [median 22 years (1-88)], male (68%), motorcyclists (76%), drove without licence (85%) and without insurance (95%). Most accidents occurred during evenings and Lao New Year. Serious motorbike injuries were associated with young age (1-15 years), male sex (OR 2.2, 95% CI 1.1-4.6) and drivers (OR 2.1, 95% CI 1.1-4.3); more serious head injuries with alcohol consumption (OR 2.5, 95% CI 1.7-3.7), male sex (OR 2.3, 95% CI 1.4-3.7) and no helmet use (OR 2.0, 95% CI 1.2-3.4). No helmet use was associated with young age, time period, pillion passengers (OR 2.7, 95% CI 1.6-4.7), alcohol (OR 1.9, 95% CI 1.2-2.8) and no driver license (OR 2.0; 95% CI 1.1-3.4). Main reasons not to wear helmets were not possessing one, and being pillion passenger. Capture-recapture analysis showed four times higher RTI estimates than officially reported. Mortality rate was 11.6/100.000 population (95% CI 5.1-18.1/100.000). CONCLUSIONS: RTI were substantially underestimated. Combining hospital with police data can provide better estimates in resource-limited settings. Preventive programmes and law enforcement have to target male drivers, alcohol, licensing and helmet use, especially among children and pillion passengers. Increased efforts are needed during evening time and special festivals. PMID- 26121297 TI - Shewanella sp. O23S as a Driving Agent of a System Utilizing Dissimilatory Arsenate-Reducing Bacteria Responsible for Self-Cleaning of Water Contaminated with Arsenic. AB - The purpose of this study was a detailed characterization of Shewanella sp. O23S, a strain involved in arsenic transformation in ancient gold mine waters contaminated with arsenic and other heavy metals. Physiological analysis of Shewanella sp. O23S showed that it is a facultative anaerobe, capable of growth using arsenate, thiosulfate, nitrate, iron or manganite as a terminal electron acceptor, and lactate or citrate as an electron donor. The strain can grow under anaerobic conditions and utilize arsenate in the respiratory process in a broad range of temperatures (10-37 degrees C), pH (4-8), salinity (0%-2%), and the presence of heavy metals (Cd, Co, Cr, Cu, Mn, Mo, Se, V and Zn). Under reductive conditions this strain can simultaneously use arsenate and thiosulfate as electron acceptors and produce yellow arsenic (III) sulfide (As2S3) precipitate. Simulation of As-removal from water containing arsenate (2.5 mM) and thiosulfate (5 mM) showed 82.5% efficiency after 21 days of incubation at room temperature. Based on the obtained results, we have proposed a model of a microbially mediated system for self-cleaning of mine waters contaminated with arsenic, in which Shewanella sp. O23S is the main driving agent. PMID- 26121298 TI - Systemic Lupus Erythematosus Patients Exhibit Reduced Expression of CLEC16A Isoforms in Peripheral Leukocytes. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with multiple etiological factors. The SLE susceptibility locus on chromosome 16p13 encodes a novel gene CLEC16A and its functional relationship with SLE is unclear. This study aimed to investigate the expression correlation of the two major CLEC16A spliced transcripts with SLE development. Expressions of the long (V1) and short (V2) CLEC16A isoforms in the peripheral blood mononuclear cells (PBMCs) were assayed by quantitative real time PCR and compared between healthy individuals and SLE patients. Correlation of CLEC16A isoform expression levels with SLE susceptibility, disease severity and twelve clinical parameters were also evaluated. Full length transcripts of CLEC16A V1 and V2 isoforms were readily amplified from PBMCs of healthy controls and patients at varying abundance. Compared with healthy controls (n = 86), expression levels of V1 and V2 were significantly reduced by ~two- and four-fold respectively in SLE patients (n = 181). The relative V2/V1 ratio was also significantly reduced by approximately two-fold. With regard to SLE disease parameters, only a weak positive correlation was found between CLEC16A V1 expression levels and SLE disease activity index (SLEDAI) score. Taken together, CLEC16A was found to be a susceptibility factor for SLE, with possible contribution to the development of the disease. PMID- 26121299 TI - Proteomic Identification of Target Proteins of Thiodigalactoside in White Adipose Tissue from Diet-Induced Obese Rats. AB - Previously, galectin-1 (GAL1) was found to be up-regulated in obesity-prone subjects, suggesting that use of a GAL1 inhibitor could be a novel therapeutic approach for treatment of obesity. We evaluated thiodigalactoside (TDG) as a potent inhibitor of GAL1 and identified target proteins of TDG by performing comparative proteome analysis of white adipose tissue (WAT) from control and TDG treated rats fed a high fat diet (HFD) using two dimensional gel electrophoresis (2-DE) combined with MALDI-TOF-MS. Thirty-two spots from a total of 356 matched spots showed differential expression between control and TDG-treated rats, as identified by peptide mass fingerprinting. These proteins were categorized into groups such as carbohydrate metabolism, tricarboxylic acid (TCA) cycle, signal transduction, cytoskeletal, and mitochondrial proteins based on functional analysis using Protein Annotation Through Evolutionary Relationship (PANTHER) and Database for Annotation, Visualization, Integrated Discovery (DAVID) classification. One of the most striking findings of this study was significant changes in Carbonic anhydrase 3 (CA3), Voltage-dependent anion channel 1 (VDAC1), phosphatidylethanolamine-binding protein 1 (PEBP1), annexin A2 (ANXA2) and lactate dehydrogenase A chain (LDHA) protein levels between WAT from control and TDG-treated groups. In addition, we confirmed increased expression of thermogenic proteins as well as reduced expression of lipogenic proteins in response to TDG treatment. These results suggest that TDG may effectively prevent obesity, and TDG-responsive proteins can be used as novel target proteins for obesity treatment. PMID- 26121300 TI - Evaluation of the Interactions between Water Extractable Soil Organic Matter and Metal Cations (Cu(II), Eu(III)) Using Excitation-Emission Matrix Combined with Parallel Factor Analysis. AB - The objectives of this study were to evaluate the binding behavior of Cu(II) and Eu(III) with water extractable organic matter (WEOM) in soil, and assess the competitive effect of the cations. Excitation-emission matrix (EEM) fluorescence spectrometry was used in combination with parallel factor analysis (PARAFAC) to obtain four WEOM components: fulvic-like, humic-like, microbial degraded humic like, and protein-like substances. Fluorescence titration experiments were performed to obtain the binding parameters of PARAFAC-derived components with Cu(II) and Eu(III). The conditional complexation stability constants (logKM) of Cu(II) with the four components ranged from 5.49 to 5.94, and the Eu(III) logKM values were between 5.26 to 5.81. The component-specific binding parameters obtained from competitive binding experiments revealed that Cu(II) and Eu(III) competed for the same binding sites on the WEOM components. These results would help understand the molecular binding mechanisms of Cu(II) and Eu(III) with WEOM in soil environment. PMID- 26121301 TI - Do the Effects of Secondary Prevention of Cardiovascular Events in PAD Patients Differ from Other Atherosclerotic Disease? AB - Atherosclerosis is considered a generalized disease. Similar or identical etiopathogenetic mechanisms and risk factors are involved in various atherosclerotic diseases, and the positive effects of preventive measures on atherogenesis in different parts of the arterial system were shown. However, until know, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease (CHD), while less attention has been devoted to the management of peripheral arterial disease (PAD), despite its significant morbidity and mortality. Data on the efficacy of preventive measures in PAD patients have mostly been gained from subgroup analyses from studies devoted primarily to the management of coronary patients. These data have shown that treatment of risk factors for atherosclerosis with drugs can reduce cardiovascular events also in patients with PAD. The effects of some preventive procedures in PAD patients differ from coronary patients. Aspirin as a basic antiplatelet drug has been shown to be less effective in PAD patients than in coronary patients. The latest Antithrombotic Trialists' Collaboration (ATC) meta analysis demonstrates no benefit of aspirin in reducing cardiovascular events in PAD. Statins reduce cardiovascular events in all three of the most frequently presented cardiovascular diseases, including PAD to a comparable extent. Recent studies indicate that in PAD patients, in addition to a reduction in cardiovascular events, statins may have some hemodynamic effects. They prolong walking distance and improve quality of life. Similarly, angiotensin enzyme inhibitors are also effective in the prevention of cardiovascular events in coronary, cerebrovascular, as well as PAD patients and show positive effects on the walking capacity of patients with intermittent claudication. In PAD patients, the treatment of hypertension and diabetes also effectively prevents cardiovascular morbidity and mortality. As PAD patients are at a highest risk of cardiovascular complications, the risk factors of atherosclerosis should be treated intensively in this group of patients. Most of the preventive measures, including the drugs used for prevention of CHD, are also effective in PAD patients. PMID- 26121302 TI - Cloning and Characterization of Surface-Localized alpha-Enolase of Streptococcus iniae, an Effective Protective Antigen in Mice. AB - Streptococcus iniae is a major fish pathogen that can also cause human bacteremia, cellulitis and meningitis. Screening for and identification of protective antigens plays an important role in developing therapies against S. iniae infections. In this study, we indicated that the alpha-enolase of S. iniae was not only distributed in the cytoplasm and associated to cell walls, but was also secreted to the bacterial cell surface. The functional identity of the purified recombinant alpha-enolase protein was verified by its ability to catalyze the conversion of 2-phosphoglycerate (2-PGE) to phosphoenolpyruvate (PEP), and both the recombinant and native proteins interacted with human plasminogen. The rabbit anti-rENO serum blockade assay shows that alpha-enolase participates in S. iniae adhesion to and invasion of BHK-21 cells. In addition, the recombinant alpha-enolase can confer effective protection against S. iniae infection in mice, which suggests that alpha-enolase has potential as a vaccine candidate in mammals. We conclude that S. iniae alpha-enolase is a moonlighting protein that also associates with the bacterial outer surface and functions as a protective antigen in mice. PMID- 26121303 TI - The trajectory of fidelity in a multiyear trial of the family check-up predicts change in child problem behavior. AB - OBJECTIVE: Therapist fidelity to evidence-based family interventions has consistently been linked to child and family outcomes. However, few studies have evaluated the potential ebb and flow of fidelity of therapists over time. We examined therapist drift in fidelity over 4 years in the context of a Family Check-Up prevention services in early childhood (ages 2-5 years). METHOD: At age 2, families engaging in Women, Infants, and Children Nutritional Supplement Program services were randomized and offered annual Family Check-Ups. Seventy nine families with a child in the clinical range of problem behaviors at age 2 years were included in this analysis. RESULTS: Latent growth modeling revealed a significant linear decline in fidelity over time (M = -0.35, SD = 0.35) and that steeper declines were related to less improvement in caregiver-reported problem behaviors assessed at ages 7.5/8.5 years (b = -.69, p = .003; beta = -.95, 95% CI [-2.11, -0.22]). CONCLUSION: These findings add to the literature concerning the need to continually monitor therapist fidelity to an evidence-based practice over time to optimize family benefits. Limitations and directions for future research are discussed. PMID- 26121305 TI - Contemporary Nationwide Patterns of Active Surveillance Use for Prostate Cancer. PMID- 26121304 TI - Underascertainment of acute hepatitis C virus infections in the U.S. surveillance system: a case series and chart review. AB - BACKGROUND: In 2010, the incidence of hepatitis C virus (HCV) infection in the United States was estimated to be 17 000 cases annually, based on 850 acute HCV cases reported to the Centers for Disease Control and Prevention by local public health authorities. Absence of symptomatic disease and lack of a specific laboratory test for acute infection complicates diagnosis and surveillance. OBJECTIVE: To validate estimates of the incidence of acute HCV infection by determining the reporting rate of clinical diagnoses of acute infection to the Massachusetts Department of Public Health (MDPH) and Centers for Disease Control and Prevention. DESIGN: Case series and chart review. SETTING: Two hospitals and the state correctional health care system in Massachusetts. PATIENTS: 183 patients clinically diagnosed with acute HCV infection from 2001 to 2011 and participating in a research study. MEASUREMENTS: Rate of electronic case reporting of acute HCV infection to the MDPH and rate of subsequent confirmation according to national case definitions. RESULTS: 149 of 183 (81.4%) clinical cases of acute HCV infection were reported to the MDPH for surveillance classification. The MDPH investigated 43 of these reports as potential acute cases of HCV infection based on their surveillance requirements; ultimately, only 1 met the national case definition and was counted in nationwide statistics published by the Centers for Disease Control and Prevention. Discordance in clinical and surveillance classification was often related to missing clinical or laboratory data at the MDPH as well as restrictive definitions, including requirements for negative hepatitis A and B laboratory results. LIMITATION: Findings may not apply to other jurisdictions because of differences in resources for surveillance. CONCLUSION: Clinical diagnoses of acute HCV infection were grossly underascertained by formal surveillance reporting. Incomplete clinician reporting, problematic case definitions, limitations of diagnostic testing, and imperfect data capture remain major limitations to accurate case ascertainment despite automated electronic laboratory reporting. These findings may have implications for national estimates of the incidence of HCV infection. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 26121306 TI - In situ study of the initiation of hydrogen bubbles at the aluminium metal/oxide interface. AB - The presence of excess hydrogen at the interface between a metal substrate and a protective oxide can cause blistering and spallation of the scale. However, it remains unclear how nanoscale bubbles manage to reach the critical size in the first place. Here, we perform in situ environmental transmission electron microscopy experiments of the aluminium metal/oxide interface under hydrogen exposure. It is found that once the interface is weakened by hydrogen segregation, surface diffusion of Al atoms initiates the formation of faceted cavities on the metal side, driven by Wulff reconstruction. The morphology and growth rate of these cavities are highly sensitive to the crystallographic orientation of the aluminium substrate. Once the cavities grow to a critical size, the internal gas pressure can become great enough to blister the oxide layer. Our findings have implications for understanding hydrogen damage of interfaces. PMID- 26121307 TI - VITREOMACULAR TRACTION AFTER DEXAMETHASONE INTRAVITREAL IMPLANT (OZURDEX) INJECTION: THE EFFECT OF ANOMALOUS POSTERIOR VITREOUS DETACHMENT. AB - PURPOSE: To describe an unusual macular complication after dexamethasone intravitreal implant (Ozurdex) injection. METHODS: Case history and macular optical coherence tomography findings are described. The report describes a patient with proliferative diabetic retinopathy and vitreoschisis who received Ozurdex treatment for diabetic macular edema. RESULTS: After Ozurdex injection, visual acuity worsened because of newly formed vitreomacular traction that was demonstrated on optical coherence tomography imaging. A mechanism is proposed by which the medication might have contributed to this outcome. CONCLUSION: In this patient with vitreoschisis, a thickened posterior hyaloid membrane and traction developed after Ozurdex injection. The authors recommend careful evaluation of the macula before injection, particularly in diabetic patients with vitreoschisis. PMID- 26121308 TI - Serum Albumin-Alginate Microparticles Prepared by Transacylation: Relationship between Physicochemical, Structural and Functional Properties. AB - Our laboratory develops a method of microencapsulation using a transacylation reaction in a water-in-oil (W/O) emulsion. The method is based on the creation of amide bonds between free amine functions of a protein (human serum albumin (HSA)) and ester groups of propylene glycol alginate (PGA) in the inner aqueous phase after alkalization. The aim of this work is to study the influence of physicochemical properties of HSA-PGA mixtures on microparticle characteristics. Microparticles were prepared varying the concentrations of PGA and HSA, then characterized (inner structure, size, swelling rate, release kinetics). PGA and each polymer mixture used in the microencapsulation procedure were examined in order to elucidate the mechanism of microstructure formation. It was found that the morphology and functional properties of HSA-alginate microparticles were related to the two polymer concentrations in the aqueous solution. Actually, the polymer concentration variations led to physicochemical changes, which affected the microparticle structure and functional properties. PMID- 26121309 TI - Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by in Silico Target Fishing. AB - In silico target fishing is an emerging tool in drug discovery, which is mostly used for primary target or off-target prediction and drug repositioning. In this work, we developed an in silico target fishing protocol to identify the primary target of GV2-20, a false-positive hit highlighted in a cell-based screen for 14 3-3 modulators. Although GV2-20 does not bind to 14-3-3 proteins, it showed remarkable antiproliferative effects in CML cells, thus raising interest toward the identification of its primary target. Six potential targets of GV2-20 were prioritized in silico and tested in vitro. Our results show that the molecule is a potent inhibitor of carbonic anhydrase 2 (CA2), thus confirming the predictive capability of our protocol. Most notably, GV2-20 experienced a remarkable selectivity for CA2, CA7, CA9, and CA12, and its scaffold was never explored before as a chemotype for CA inhibition, thus becoming an interesting lead candidate for further development. PMID- 26121310 TI - Alcohol outlet density and violence: A geographically weighted regression approach. AB - INTRODUCTION AND AIMS: We investigate the relationship between outlet density (of different types) and violence (as measured by police activity) across the North Island of New Zealand, specifically looking at whether the relationships vary spatially. DESIGN AND METHODS: We use New Zealand data at the census area unit (approximately suburb) level, on police-attended violent incidents and outlet density (by type of outlet), controlling for population density and local social deprivation. We employed geographically weighted regression to obtain both global average and locally specific estimates of the relationships between alcohol outlet density and violence. RESULT: We find that bar and night club density, and licensed club density (e.g. sports clubs) have statistically significant and positive relationships with violence, with an additional bar or night club is associated with nearly 5.3 additional violent events per year, and an additional licensed club associated with 0.8 additional violent events per year. These relationships do not show significant spatial variation. In contrast, the effects of off-licence density and restaurant/cafe density do exhibit significant spatial variation. However, the non-varying effects of bar and night club density are larger than the locally specific effects of other outlet types. DISCUSSION AND CONCLUSION: The relationships between outlet density and violence vary significantly across space for off-licences and restaurants/cafes. These results suggest that in order to minimise alcohol-related harms, such as violence, locally specific policy interventions are likely to be necessary. [Cameron MP, Cochrane W, Gordon C, Livingston M. Alcohol outlet density and violence: A geographically weighted regression approach. Drug Alcohol Rev 2016;35:280-288]. PMID- 26121312 TI - Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium-Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates. AB - The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium-catalyzed aminocarbonylation reaction of the corresponding alpha fluoroalkyl o-iodobenzylamines. A base-mediated anti beta-hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine-tuning the pKa of the base. PMID- 26121311 TI - Nanoplex-Mediated Codelivery of Fibroblast Growth Factor and Bone Morphogenetic Protein Genes Promotes Osteogenesis in Human Adipocyte-Derived Mesenchymal Stem Cells. AB - This study highlights the importance of transfection mediated coordinated bone morphogenetic protein 2 (BMP-2) and fibroblast growth factor 2 (FGF-2) signaling in promoting osteogenesis. We employed plasmids independently encoding BMP-2 and FGF-2 complexed with polyethylenimine (PEI) to transfect human adipose derived mesenchymal stem cells (hADMSCs) in vitro. The nanoplexes were characterized for size, surface charge, in vitro cytotoxicity, and transfection ability in hADMSCs. A significant enhancement in BMP-2 protein secretion was observed on day 7 post transfection of hADMSCs with PEI nanoplexes loaded with both pFGF-2 and pBMP-2 (PEI/(pFGF-2+pBMP-2)) versus transfection with PEI nanoplexes of either pFGF-2 alone or pBMP-2 alone. Osteogenic differentiation of transfected hADMSCs was determined by measuring osteocalcin and Runx-2 gene expression using real time polymerase chain reactions. A significant increase in the expression of Runx-2 and osteocalcin was observed on day 3 and day 7 post-transfection, respectively, by cells transfected with PEI/(pFGF-2+pBMP-2) compared to cells transfected with nanoplexes containing pFGF-2 or pBMP-2 alone. Alizarin Red staining and atomic absorption spectroscopy revealed elevated levels of calcium deposition in hADMSC cultures on day 14 and day 30 post-transfection with PEI/(pFGF-2+pBMP-2) compared to other treatments. We have shown that codelivery of pFGF-2 and pBMP-2 results in a significant enhancement in osteogenic protein synthesis, osteogenic marker expression, and subsequent mineralization. This research points to a new clinically translatable strategy for achieving efficient bone regeneration. PMID- 26121313 TI - Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors. AB - Renal prostaglandin (PG) E2 regulates salt and water transport, and affects disease processes via EP1-4 receptors, but its role in the proximal tubule (PT) is unknown. Our study investigates the effects of PGE2 on mouse PT fluid reabsorption, and its role in growth, sodium transporter expression, fibrosis, and oxidative stress in a mouse PT cell line (MCT). To determine which PGE2 EP receptors are expressed in MCT, qPCR for EP1-4 was performed on cells stimulated for 24 h with PGE2 or transforming growth factor beta (TGFbeta), a known mediator of PT injury in kidney disease. EP1 and EP4 were detected in MCT, but EP2 and EP3 are not expressed. EP1 was increased by PGE2 and TGFbeta, but EP4 was unchanged. To confirm the involvement of EP1 and EP4, sulprostone (SLP, EP1/3 agonist), ONO8711 (EP1 antagonist), and EP1 and EP4 siRNA were used. We first show that PGE2, SLP, and TGFbeta reduced H(3)-thymidine and H(3)-leucine incorporation. The effects on cell-cycle regulators were examined by western blot. PGE2 increased p27 via EP1 and EP4, but TGFbeta increased p21; PGE2-induced p27 was attenuated by TGFbeta. PGE2 and SLP reduced cyclinE, while TGFbeta increased cyclinD1, an effect attenuated by PGE2 administration. Na-K-ATPase alpha1 (NaK) was increased by PGE2 via EP1 and EP4. TGFbeta had no effect on NaK. Additionally, PGE2 and TGFbeta increased fibronectin levels, reaching 12-fold upon co-stimulation. EP1 siRNA abrogated PGE2-fibronectin. PGE2 also increased ROS generation, and ONO 8711 blocked PGE2-ROS. Finally, PGE2 significantly increased fluid reabsorption by 31 and 46% in isolated perfused mouse PT from C57BL/6 and FVB mice, respectively, and this was attenuated in FVB-EP1 null mice. Altogether PGE2 acting on EP1 and EP4 receptors may prove to be important mediators of PT injury, and salt and water transport. PMID- 26121314 TI - Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing. AB - Benign fibrous histiocytomas (FH) can be subdivided into several morphological and clinical subgroups. Recently, gene fusions involving either one of two protein kinase C genes (PRKCB and PRKCD) or the ALK gene were described in FH. We here wanted to evaluate the frequency of PRKCB and PRKCD gene fusions in FH. Using interphase fluorescence in situ hybridization on sections from formalin fixed paraffin-embedded (FFPE) tumors, 36 cases could be analyzed. PRKCB or PRKCD rearrangements were seen in five tumors: 1/7 regular, 0/3 aneurysmal, 0/6 cellular, 2/7 epithelioid, 0/1 atypical, 2/10 deep, and 0/2 metastatic lesions. We also evaluated the status of the ALK gene in selected cases, finding rearrangements in 3/7 epithelioid and 0/1 atypical lesions. To assess the gene fusion status of FH further, deep sequencing of RNA (RNA-Seq) was performed on FFPE tissue from eight cases with unknown gene fusion status, as well as on two FH and six soft tissue sarcomas with known gene fusions; of the latter eight positive controls, the expected fusion transcript was found in all but one, while 2/8 FH with unknown genetic status showed fusion transcripts, including a novel KIRREL/PRKCA chimera. Thus, also a third member of the PRKC family is involved in FH tumorigenesis. We conclude that gene fusions involving PRKC genes occur in several morphological (regular, cellular, aneurysmal, epithelioid) and clinical (cutaneous, deep) subsets of FH, but they seem to account for only a minority of the cases. In epithelioid lesions, however, rearrangements of PRKC or ALK were seen, as mutually exclusive events, in the majority (5/7) of cases. Finally, the study also shows that RNA-Seq is a promising tool for identifying gene fusions in FFPE tissues. PMID- 26121315 TI - Vascular endothelial growth factor receptor-3 is a novel target to improve net ultrafiltration in methylglyoxal-induced peritoneal injury. AB - Appropriate fluid balance is important for good clinical outcomes and survival in patients on peritoneal dialysis. We recently reported that lymphangiogenesis associated with fibrosis developed in the peritoneal cavity via the transforming growth factor-beta1-vascular endothelial growth factor-C (VEGF-C) pathway. We investigated whether VEGF receptor-3 (VEGFR-3), the receptor for VEGF-C and -D, might be a new target to improve net ultrafiltration by using adenovirus expressing soluble VEGFR-3 (Adeno-sVEGFR-3) in rodent models of peritoneal injury induced by methylglyoxal (MGO). We demonstrated that lymphangiogenesis developed in these MGO models, especially in the diaphragm, indicating that lymphangiogenesis is a common feature in the peritoneal cavity with inflammation and fibrosis. In MGO models, VEGF-D was significantly increased in the diaphragm; however, VEGF-C was not significantly upregulated. Adeno-sVEGFR-3, which was detected on day 50 after administration via tail vein injections, successfully suppressed lymphangiogenesis in the diaphragm and parietal peritoneum in mouse MGO models without significant effects on fibrosis, inflammation, or neoangiogenesis. Drained volume in the peritoneal equilibration test using a 7.5% icodextrin peritoneal dialysis solution (the 7.5% icodextrin peritoneal equilibration test) was improved by Adeno-sVEGFR-3 on day 22 (P<0.05) and day 50 after reduction of inflammation (P<0.01), indicating that the 7.5% icodextrin peritoneal equilibration test identifies changes in lymphangiogenesis. The solute transport rate was not affected by suppression of lymphangiogenesis. In human peritoneal dialysis patients, the dialysate to plasma ratio of creatinine positively correlated with the dialysate VEGF-D concentration (P<0.001). VEGF-D mRNA was significantly higher in the peritoneal membranes of patients with ultrafiltration failure, indicating that VEGF-D is involved in the development of lymphangiogenesis in peritoneal dialysis patients. These results indicate that VEGFR-3 is a new target to improve net ultrafiltration by suppressing lymphatic absorption and that the 7.5% icodextrin peritoneal equilibration test is useful for estimation of lymphatic absorption. PMID- 26121316 TI - Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors. AB - Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR 182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments. PMID- 26121319 TI - Overexpression of SULT2B1b is an independent prognostic indicator and promotes cell growth and invasion in colorectal carcinoma. AB - Aberrant expression of cytosolic sulfotransferase 2B1b (SULT2B1b) has been reported in several human malignancies. However, the expression pattern and clinical significance of SULT2B1b in colorectal carcinoma (CRC) remains unknown. Real-time quantitative PCR, western blot, and immunohistochemistry analyses were used to determine SULT2B1b expression in CRC clinical samples and CRC-derived cell lines. Kaplan-Meier and Cox proportional regression analyses were used to evaluate the association between SULT2B1b expression and patient survival in two independent cohorts of 485 patients with CRC. Gain- and loss-of-function approaches were employed to investigate the role of SULT2B1b in regulation of CRC cell growth and invasion. We found that SULT2B1b expression was frequently upregulated in CRC clinical samples and CRC-derived cell lines and was significantly correlated with lymph node metastasis and TNM stage in both the training and validation cohorts. Patients with higher intratumoral SULT2B1b expression had a significantly shorter disease-specific survival (DSS) and disease-free survival (DFS) than those with lower expression. Importantly, increased expression of SULT2B1b significantly predicted poor DSS and DFS and was an independent unfavorable prognostic indicator for stage II patients in both cohorts. Functional studies revealed that overexpression of SULT2B1b promoted CRC cell growth and invasion in vitro. Conversely, knockdown of SULT2B1b inhibited these processes. In conclusion, our findings suggest that SULT2B1b expression correlates with disease progression and metastasis and may serve as a novel prognostic biomarker and potential therapeutic target for patients with CRC. PMID- 26121320 TI - Sialic acid supplementation ameliorates puromycin aminonucleoside nephrosis in rats. AB - Defects in sialylation are known to have serious consequences on podocyte function leading to collapse of the glomerular filtration barrier and the development of proteinuria. However, the cellular processes underlying aberrant sialylation in renal disease are inadequately defined. We have shown in cultured human podocytes that puromycin aminonucleoside (PAN) downregulates enzymes involved in sialic acid metabolism and redox homeostasis and these can be rescued by co-treatment with free sialic acid. The aim of the current study was to ascertain whether sialic acid supplementation could improve renal function and attenuate desialylation in an in vivo model of proteinuria (PAN nephrosis) and to delineate the possible mechanisms involved. PAN nephrotic rats were supplemented with free sialic acid, its precursor N-acetyl mannosamine or the NADPH oxidase inhibitor apocynin. Glomeruli, urine, and sera were examined for evidence of kidney injury and therapeutic efficacy. Of the three treatment regimens, sialic acid had the broadest efficacy in attenuating PAN-induced injury. Proteinuria and urinary nephrin loss were reduced. Transmission electron microscopy revealed that podocyte ultrastructure, exhibited less severe foot process effacement. PAN induced oxidative stress was ameliorated as evidenced by a reduction in glomerular NOX4 expression and a downregulation of urine xanthine oxidase levels. Sialylation dysfunction was improved as indicated by reduced urinary concentrations of free sialic acid, restored electrophoretic mobility of podocalyxin, and improved expression of a sialyltransferase. These data indicate that PAN induces alterations in the expression of enzymes involved in redox control and sialoglycoprotein metabolism, which can be ameliorated by sialic acid supplementation possibly via its properties as both an antioxidant and a substrate for sialylation. PMID- 26121317 TI - Clinical significance of the integrin alpha6beta4 in human malignancies. AB - Integrin alpha6beta4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin alpha6beta4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK, and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor-promoting transcription factors such as the NFATs and NF-kappaB. Expression of integrin alpha6beta4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin alpha6beta4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin alpha6beta4 that contribute to tumor progression. PMID- 26121322 TI - Powerful Bis-facially Pyrazolate-Bridged Dinuclear Ruthenium Epoxidation Catalyst. AB - A new bis-facial dinuclear ruthenium complex, {[Ru(II)(bpy)]2(MU-bimp)(MU Cl)}(2+), 2(2+), containing a hexadentate pyrazolate-bridging ligand (Hbimp) and bpy as auxiliary ligands has been synthesized and fully characterized in solution by spectrometric, spectroscopic, and electrochemical techniques. The new compound has been tested with regard to its capacity to oxidize water and alkenes. The in situ generated bis-aqua complex, {[Ru(II)(bpy)(H2O)]2(MU-bimp)}(3+), 3(3+), is an excellent catalyst for the epoxidation of a wide range of alkenes. High turnover numbers (TN), up to 1900, and turnover frequencies (TOF), up to 73 min(-1), are achieved using PhIO as oxidant. Moreover, 3(3+) presents an outstanding stereospecificity for both cis and trans olefins toward the formation of their corresponding epoxides due to specific interactions transmitted by its ligand scaffold. A mechanistic analysis of the epoxidation process has been performed based on density functional theory (DFT) calculations in order to better understand the putative cooperative effects within this dinuclear catalyst. PMID- 26121321 TI - Development of a High-Throughput Functional Screen Using Nanowell-Assisted Cell Patterning. AB - Living-cell-based screens can facilitate lead discovery of functional therapeutics of interest. A versatile and scalable method is reported that uses dense arrays of nanowells for imparting defined patterns on monolayers of cells. It is shown that this approach can coordinate a multi-component biological assay by designing and implementing a high-throughput, functional nanoliter-scale neutralization assay to identify neutralizing antibodies against HIV. PMID- 26121318 TI - MicroRNAs in the pathobiology of sarcomas. AB - Sarcomas are a rare and heterogeneous group of tumors. The last decade has witnessed extensive efforts to understand the pathobiology of many aggressive sarcoma types. In parallel, we have also begun to unravel the complex gene regulation processes mediated by microRNAs (miRNAs) in sarcomas and other cancers, discovering that microRNAs have critical roles in the majority of both oncogenic and tumor suppressor signaling networks. Expression profiles and a greater understanding of the biologic roles of microRNAs and other noncoding RNAs have considerably expanded our current knowledge and provided key pathobiological insights into many sarcomas, and helped identify novel therapeutic targets. The limited number of sarcoma patients in each sarcoma type and their heterogeneity pose distinct challenges in translating this knowledge into the clinic. It will be critical to prioritize these novel targets and choose those that have a broad applicability. A small group of microRNAs have conserved roles across many types of sarcomas and other cancers. Therapies that target these key microRNA-gene signaling and regulatory networks, in combination with standard of care treatment, may be the pivotal component in significantly improving treatment outcomes in patients with sarcoma or other cancers. PMID- 26121323 TI - Picosecond Solvation and Rotational Dynamics: An Attempt to Reinvestigate the Mystery of Alcohol-Water Binary Mixtures. AB - In this article, we have investigated the anomalous behavior of two alcohol-water (tert-butyl alcohol (TBA)-water and ethanol-water) binary mixtures using femtosecond fluorescence upconversion technique. Recently, Gupta and Patey (Gupta, R.; Patey, G. N. J. Chem. Phys. 2012, 137, 034509(1)-034509(12)) have used four force fields to simulate TBA-water binary mixtures. Surprisingly, two of them do not identify any aggregation of TBA molecules. We have calculated average solvation time of Coumarin 480 (C480) using two different methods. Our results indicate slowdown in solvation time in the mole fraction ranges XT = 0.09 0.15, XT = 0.40-0.46 and XE = 0.06-0.08, XE = 0.20-0.25 for TBA-water and ethanol water binary mixtures, respectively. Additionally, we have detected another anomalous region at XT ~ 0.03. Slow solvation responses in the ranges XT = 0.40 0.46 and XE = 0.20-0.25 are probably due to the higher shear viscosity of the medium. However, XT = 0.09-0.15 and XE = 0.06-0.08 are the manifestation of aggregation induced structural transition of alcohol molecules. Hindered rotation of C480 in the ranges XT = 0.04-0.09 and XE = 0.03-0.07 corroborates our solvation dynamics results. From temperature dependent anisotropy measurements, we have shown that aggregation of alcohol molecules increases with increase in temperature. PMID- 26121324 TI - The secondary release of mercury in coal fly ash-based flue-gas mercury removal technology. AB - The secondary release of mercury from coal fly ash is a negative by-product from coal-fired power plants, and requires effective control to reduce environmental pollution. Analysing particle size distribution and composition of the coal fly ash produced by different mercury removing technologies indicates that the particles are generally less than 0.5 mm in size and are composed mainly of SiO2, Al2O3, and Fe2O3. The relationships between mercury concentration in the coal fly ash, its particle size, and loss of ignition were studied using different mercury removing approaches. The research indicates that the coal fly ash's mercury levels are significantly higher after injecting activated carbon or brominating activated carbon when compared to regular cooperating-pollution control technology. This is particularly true for particle size ranges of >0.125, 0.075 0.125, and 0.05-0.075 mm. Leaching experiments revealed the secondary release of mercury in discarded coal fly ash. The concentration of mercury in the coal fly ash increases as the quantity of injecting activated carbon or brominating activated carbon increases. The leached concentrations of mercury increase as the particle size of the coal fly ash increases. Therefore, the secondary release of mercury can be controlled by adding suitable activated carbon or brominating activated carbon when disposing of coal fly ash. Adding CaBr2 before coal combustion in the boiler also helps control the secondary release of mercury, by increasing the Hg(2+) concentration in the leachate. This work provides a theoretical foundation for controlling and removing mercury in coal fly ash disposal. PMID- 26121325 TI - GLP-1 Receptor Mediated Targeting of a Fluorescent Zn(2+) Sensor to Beta Cell Surface for Imaging Insulin/Zn(2+) Release. AB - The pancreatic islet beta cell plays an essential role in maintaining the normal blood glucose level by releasing insulin. Loss of functional beta cell mass leads to diabetes-a disease affecting ~9% of the population worldwide. There has been great interest and intense effort in developing imaging probes for monitoring islet beta cells, and glucagon-like peptide-1 receptor (GLP-1R) has emerged as a valuable biomarker for targeting beta cells. However, efforts thus far in GLP-1R mediated beta cell labeling and imaging has largely, if not exclusively, focused on developing imaging probes for monitoring beta cell mass, and few studies have investigated imaging beta cell function (insulin release) through GLP-1R. We now report the design and synthesis of a bioconjugate, ZIMIR-Ex4(9-39), that consists of a fluorescent Zn(2+) sensor and a truncated exendin 4 peptide for imaging insulin/Zn(2+) release in islet beta cells. In vitro, the conjugate bound to Zn(2+) with high affinity and displayed a robust fluorescence enhancement upon Zn(2+) chelation. When added to beta cells at submicromolar concentration, ZIMIR Ex4(9-39) rapidly labeled cell surface in minutes to report the dynamics of insulin/Zn(2+) release with high spatiotemporal resolution. Future explorations of this approach may lead to probes for tracking beta cell function using different imaging modalities. PMID- 26121326 TI - Imidazolium salt-modified porous hypercrosslinked polymers for synergistic CO2 capture and conversion. AB - A new type of imidazolium salt-modified porous hypercrosslinked polymer (BET surface area up to 926 m(2) g(-1)) was reported. These porous materials exhibited good CO2 capture capacities (14.5 wt%) and catalytic activities for the conversion of CO2 into various cyclic carbonates under metal-free conditions. The synergistic effect of CO2 capture and conversion was observed. PMID- 26121327 TI - Centenarian Rates and Life Expectancy Related to the Death Rates of Multiple Sclerosis, Asthma, and Rheumatoid Arthritis and the Incidence of Type 1 Diabetes in Children. AB - The autoimmune diseases are among the 10 leading causes of death for women and the number two cause of chronic illness in America as well as a predisposing factor for cardiovascular diseases and cancer. Patients of some autoimmune diseases have shown a shorter life span and are a model of accelerated immunosenescence. Conversely, centenarians are used as a model of successful aging and have shown several immune parameters that are better preserved and lower levels of autoantibodies. The study reported here focused on clarifying the connection between longevity and some autoimmune and allergic diseases in 29 developed Organisation for Economic Co-operation and Development (OECD) countries, because multidisciplinary analyses of the accelerated or delayed aging data could show a distinct relationship pattern, help to identify common factors, and determine new important factors that contribute to longevity and healthy aging. The relationships between the mortality rates data of multiple sclerosis (MS), rheumatoid arthritis (RA), asthma, the incidence of type 1 diabetes (T1D) from one side and centenarian rates (two sets) as well as life expectancy data from the other side were assessed using regression models and Pearson correlation coefficients. The data obtained correspond to an inverse linear correlation with different degrees of linearity. This is the first observation of a clear tendency of diminishing centenarian rates or life expectancy in countries having higher death rates of asthma, MS, and RA and a higher incidence of T1D in children. The conclusion is that most probably there are common mechanistic pathways and factors affecting the above diseases and at the same time but in the opposite direction the processes of longevity. Further study, comparing genetic data, mechanistic pathways, and other factors connected to autoimmune diseases with those of longevity could clarify the processes involved, so as to promote longevity and limit the expansion of those diseases in the younger and older population. PMID- 26121329 TI - Leucanthemum vulgare Lam. crude oil phytoremediation. AB - Sites with crude oil pollution have been successfully treated using phytoremediation, but expanding the range of plants that can be used and understanding how exposure impacts the plants are two areas of study that are important to continue. Leucanthemum vulgare has been shown to grow well under a variety of stressful conditions. To examine L. vulgare's ability to both survive crude oil exposure and to reduce crude oil concentrations in soil, plants were placed in soil containing 0, 2.5%, 5%, 7.5% or 10% w/w crude oil. Total Petroleum Hydrocarbons (TPH) concentration, peroxidase and catalase activity, proline and phenol content in roots and leaves were determined at the start of planting and every 2 months for six months. L. vulgare roots were successfully colonized with mycorrhizae under all conditions. Results showed positive correlation between antioxidant compound concentration and crude oil contamination. Also, a significant reduction occurred in TPH content of soil over time in planted pots as compared to controls. The lowest TPH content was recorded after 6 months under all treatments. Results showed L. vulgare could survive crude oil exposure and enhance reducing of crude oil from soil. PMID- 26121328 TI - Osteoporotic fractures and associated hospitalizations among patients treated with teriparatide compared to a matched cohort of patients not treated with teriparatide. AB - OBJECTIVE: To compare fractures and fracture-related resource utilization (RU) among patients with a recent fracture and treated with teriparatide (TPTD) to a matched cohort of patients not treated with TPTD (non-TPTD). RESEARCH DESIGN AND METHODS: Women aged 50 years or older initiating TPTD (N = 5314; index date between 1 January 2007 and 31 December 2012) were identified in an insurance claims database. Patients with fragility fracture (hip, pelvis, clavicle, humerus, wrist, leg or spine) during the 12 months prior to the index date (N = 1164) were selected to control for unmeasured confounding due to absence of bone mineral density test levels. TPTD patients were matched to the non-TPTD cohort using propensity score and exact matching (N = 912). Relative risk (RR) of fracture and fracture-related RU were estimated by Cox proportional hazard modeling, adjusted for potential fracture risk factors. RESULTS: Fractures were observed in 4.6%, 8.6%, 10.3%, and 11.3% of TPTD patients and in 9.2%, 15.2%, 19.2% and 21.7% of non-TPTD patients over 6, 12, 18, and 24 months, respectively. The adjusted RR reduction in TPTD was 36% (RR = 0.64, 95% CI: 0.44-0.94) during 6 months, 27% (RR = 0.73, 95% CI: 0.54-0.97) during 12 months, 28% (RR = 0.72, 95% CI: 0.55-0.93) during 18 months, and 28% (RR = 0.72, 95% CI: 0.56-0.92) during 24 months versus matched non-TPTD patients. Fracture-related RU followed a similar trend to that observed for fracture risk. CONCLUSIONS: This real-world study found TPTD to be more effective in reducing risk of fragility fractures as early as 6 months with continuous treatment benefit up to 24 months compared to a matched non-TPTD cohort. TPTD patients experienced lower rates of fracture related RU than non-TPTD patients. Key study limitations include the inability to confirm reported diagnostic and procedural codes and the absence of uninsured and individually insured patients in the claims database. PMID- 26121330 TI - Polycaprolactone-based in situ implant containing curcumin-PLGA nanoparticles prepared using the multivariate technique. AB - Studies on the effect of curcumin/PLGA ratio (CPR), stabilizer (PVA) concentration, homogenization speed, homogenization time, and sonication time on mean particle size (MPS) and percentage drug encapsulation (PDE) were performed using the multivariate technique. MPS and PDE were found to be more dependent on the interaction of sonication time with the other variables. Curcumin was released in a sustained manner from curcumin-PLGA nanoparticles (CPN). CPN improved the survival rate of Ehrlich ascites carcinoma (EAC)-bearing mice and controlled the EAC-induced change in hematological parameters. Histopathology of vital organs showed that the formulation was safe. Polycaprolactone was used in preparing an in situ implant containing CPN. PMID- 26121331 TI - Analysis of Selenium Levels in Osteosarcoma Patients and the Effects of Se Methylselenocysteine on Osteosarcoma Cells In Vitro. AB - The form of selenium appears to be important for preventing cancer in humans. Here, we evaluated selenium levels in the serum and bone tissue samples from osteosarcoma patients using atomic absorption spectrometry. The in vitro effects of Se-methylselenocysteine (Se-MSC) on growth, cell cycle status, and apoptosis of osteosarcoma cells were assessed using the WST-1 assay, Hoechst 33342/propidium iodide staining, and flow cytometry, respectively. In osteosarcoma cases, the mean serum selenium levels in osteosarcoma tissue and normal bone were 0.08 mg/kg and 0.03 mg/kg, respectively (P < 0.05). Serum selenium levels in osteosarcoma and non-osteosarcoma cases were 0.09 mg/L and 0.08 mg/L, respectively (P > 0.05). Se-MSC-treated MG63 cells showed altered cellular morphology, decreased viability in a time- and dose-dependent manner, and an increase in the sub-G1 cell population. Se-MSC also downregulated Bcl-2 expression and upregulated Bax. Se-MSC inhibited the proliferation of the drug resistant osteosarcoma cell line Saos-2/MTX300 and enhanced the inhibitory effect of pirarubicin on MG63 cells. Our data demonstrate that selenium levels are significantly higher in osteosarcoma tissue than normal bone tissue in osteosarcoma patients. The results also support the anticancer effects of Se-MSC in osteosarcoma. Further development of Se-MSC as an ancillary chemotherapy agent in osteosarcoma is warranted. PMID- 26121332 TI - alpha-Aminoisobutyric acid incorporation induces cell permeability and antiviral activity of HIV-1 major homology region fragments. AB - The design of a cell penetrating antiviral peptide, which is derived from the major homology region of HIV-1 capsid protein and includes the non-coded alpha aminoisobutyric acid, provides functional evidence for the role of the conserved region in the HIV assembly process and demonstrates the correlation between conformational stability and cellular permeability. PMID- 26121333 TI - A platinum shell for ultraslow ligand exchange: unmodified DNA adsorbing more stably on platinum than thiol and dithiol on gold. AB - Due to the ultraslow ligand exchange rate on Pt, non-thiolated DNA is adsorbed on platinum nanoparticles (PtNPs) more stably than thiolated and even dithiolated DNA on AuNPs. Adsorption kinetics, capacity and stability are systematically compared as a function of DNA sequence. The Pt conjugates can tolerate extreme pH, salt, and thiol molecules. Taking advantage of the optical properties of AuNPs and the extreme stability of DNA on PtNPs, DNA-functionalized Au@Pt NPs are prepared using a cost-effective and more stable bioconjugation method. The DNA directed assembly of non-thiolated DNA conjugates is also demonstrated. PMID- 26121334 TI - Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats. AB - OBJECTIVE: Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-alpha (PFT, an inhibitor of p53 activity). METHODS AND RESULTS: PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 MUM PFT. CONCLUSIONS: Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis. PMID- 26121335 TI - Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats. AB - Cognitive function can be affected by the estrous cycle. However, the effect of the estrous cycle on synaptic functions is poorly understood. Here we show that in female rats, inhibitory-avoidance (IA) task (hippocampus-dependent contextual fear-learning task) drives GluA2-lacking Ca2+-permeable AMPA receptors (CP AMPARs) into the hippocampal CA3-CA1 synapses during all periods of the estrous cycle except the proestrous period, when estrogen levels are high. In addition, IA task failed to drive CP-AMPARs into the CA3-CA1 synapses of ovariectomized rats only when estrogen was present. Thus, changes in the stoichiometry of AMPA receptors during learning depend on estrogen levels. Furthermore, the induction of long-term potentiation (LTP) after IA task was prevented during the proestrous period, while intact LTP is still expressed after IA task during other period of the estrous cycle. Consistent with this finding, rats conditioned by IA training failed to acquire hippocampus-dependent Y-maze task during the proestrous period. On the other hand, during other estrous period, rats were able to learn Y-maze task after IA conditioning. These results suggest that high estrogen levels prevent the IA learning-induced delivery of CP-AMPARs into hippocampal CA3-CA1 synapses and limit synaptic plasticity after IA task, thus preventing the acquisition of additional learning. PMID- 26121337 TI - Wavelength-switchable photocurrent in a hybrid TiO2-Ag nanocluster photoelectrode. AB - A hybrid TiO2-Ag nanocluster (NC) photoelectrode demonstrates unique wavelength switchable photocurrent. By simply tuning the light wavelength from ultraviolet (UV) to visible light, the photocurrent generated on a single electrode can be switched from anodic to cathodic current, in which the Ag NCs behave like a new type of visible light active photocatalyst. PMID- 26121336 TI - Safety and Efficacy of Thermal Ablation for Small Renal Masses in Solitary Kidney: Evidence from Meta-Analysis of Comparative Studies. AB - OBJECTIVE: To evaluate comparative renal functional preservation, perioperative and oncologic outcomes, and complications of thermal ablation (TA) versus partial nephrectomy (PN) in management of Small renal masses (SRMs) in solitary kidney. METHODS AND FINDINGS: Medline, Embase, Web of Science and the Cochrane Library were systematically searched. A meta-analysis for comparative studies comparing TA with PN was performed. According to predefined inclusion criteria, seven datasets were identified from 8 observational studies including a total of 628 patients. Cumulated data showed the changes of creatinine (p=0.02) and estimated glomerular filtration rate (eGFR) (p<0.0001) in TA arm were significantly less than these in PN arm. Significantly less new-set chronic kidney disease (CKD) was observed in TA group (p=0.04). In terms of postoperative dialysis rate, the difference favoring TA was also noted, though there is no statistical significance (p=0.09). With regard to perioperative outcomes, our data demonstrated that patients who underwent TA had significantly shorter operation time (p=0.002), less blood loss (p<0.0001), shorter length of stay (p<0.00001), and less transfusion rate (p=0.01) than those underwent PN. In addition, patients underwent TA suffered less intra- and postoperative complications (p=0.007, p<0.00001; respectively). With regard to oncologic outcomes, disease-free survival (DFS) (p<0.00001) and cancer-specific survival (CSS) (p=0.01) in the PN arm were significantly better than these of the TA arm. But, TA yielded a comparable overall survival to PN (p=0.40). Sensitivity analyses led to very similar results with overall results, and confirmed its stability. CONCLUSIONS: Our analysis indicates that PN have advantage in controlling cancer recurrence. However, TA is associated with significantly better renal functional preservation and perioperative outcomes, and less complications without increasing overall death. Our data suggest that indication for TA may be extended to select younger, healthier patients who desire a much less invasive therapeutic option. PMID- 26121338 TI - Mortality following Stroke, the Weekend Effect and Related Factors: Record Linkage Study. AB - BACKGROUND: Increased mortality following hospitalisation for stroke has been reported from many but not all studies that have investigated a 'weekend effect' for stroke. However, it is not known whether the weekend effect is affected by factors including hospital size, season and patient distance from hospital. OBJECTIVE: To assess changes over time in mortality following hospitalisation for stroke and how any increased mortality for admissions on weekends is related to factors including the size of the hospital, seasonal factors and distance from hospital. METHODS: A population study using person linked inpatient, mortality and primary care data for stroke from 2004 to 2012. The outcome measures were, firstly, mortality at seven days and secondly, mortality at 30 days and one year. RESULTS: Overall mortality for 37 888 people hospitalised following stroke was 11.6% at seven days, 21.4% at 30 days and 37.7% at one year. Mortality at seven and 30 days fell significantly by 1.7% and 3.1% per annum respectively from 2004 to 2012. When compared with week days, mortality at seven days was increased significantly by 19% for admissions on weekends, although the admission rate was 21% lower on weekends. Although not significant, there were indications of increased mortality at seven days for weekend admissions during winter months (31%), in community (81%) rather than large hospitals (8%) and for patients resident furthest from hospital (32% for distances of >20 kilometres). The weekend effect was significantly increased (by 39%) for strokes of 'unspecified' subtype. CONCLUSIONS: Mortality following stroke has fallen over time. Mortality was increased for admissions at weekends, when compared with normal week days, but may be influenced by a higher stroke severity threshold for admission on weekends. Other than for unspecified strokes, we found no significant variation in the weekend effect for hospital size, season and distance from hospital. PMID- 26121339 TI - Correction: Selective Targeting of CTNNB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs. PMID- 26121340 TI - Two New Genera of Planktonic Ciliates and Insights into the Evolution of the Family Strombidiidae (Protista, Ciliophora, Oligotrichia). AB - Oligotrich ciliates are common marine microplankters, but their biodiversity and evolutionary relationships have not been well-documented. Morphological descriptions and small subunit rRNA gene sequences of two new species representing two new strombidiid genera, Sinistrostrombidium cupiformum gen. nov., sp. nov. and Antestrombidium agathae gen. nov., sp. nov. are presented, and their taxonomy and molecular phylogeny are analyzed. Sinistrostrombidium gen. nov. is characterized by a sinistrally spiraled girdle kinety and a longitudinal ventral kinety. Antestrombidium gen. nov. is distinguished by tripartite somatic kineties (circular and ventral kineties plus dextrally spiraled girdle kinety). Sinistrostrombidium and Antestrombidium branched separately from one another in phylogenetic trees, clustering with different clades of strombidiids. The new genera added to the diversities of ciliary patterns and small subunit rRNA gene sequences in strombidiids leads to presentation of a new hypothesis about evolution of the 12 known strombidiid genera, based on ciliary pattern and partly supported by molecular evidence. In addition, our new morphological and molecular analyses support establishment of a new order Lynnellida ord. nov., characterized by an open adoral zone of membranelles without differentiation of anterior and ventral membranelles, for Lynnella, but we remain unable to assign the genus to a subclass with confidence. PMID- 26121341 TI - The Wnt Co-Receptor Lrp5 Is Required for Cranial Neural Crest Cell Migration in Zebrafish. AB - During vertebrate neurulation, cranial neural crest cells (CNCCs) undergo epithelial to mesenchymal transition (EMT), delaminate from the neural plate border, and migrate as separate streams into different cranial regions. There, they differentiate into distinct parts of the craniofacial skeleton. Canonical Wnt signaling has been shown to be essential for this process at different levels but the involved receptors remained unclear. Here we show that the frizzled co receptor low-density-lipoprotein (LDL) receptor-related protein 5 (Lrp5) plays a crucial role in CNCC migration and morphogenesis of the cranial skeleton. Early during induction and migration of CNCCs, lrp5 is expressed ubiquitously but later gets restricted to CNCC derivatives in the ventral head region besides different regions in the CNS. A knock-down of lrp5 does not interfere with induction of CNCCs but leads to reduced proliferation of premigratory CNCCs. In addition, cell migration is disrupted as CNCCs are found in clusters at ectopic positions in the dorsomedial neuroepithelium after lrp5 knock-down and transient CRISPR/Cas9 gene editing. These migratory defects consequently result in malformations of the craniofacial skeleton. To date, Lrp5 has mainly been associated with bone homeostasis in mammals. Here we show that in zebrafish, lrp5 also controls cell migration during early morphogenetic processes and contributes to shaping the craniofacial skeleton. PMID- 26121343 TI - Ghrelin Supresses Sympathetic Hyperexcitation in Acute Heart Failure in Male Rats: Assessing Centrally and Peripherally Mediated Pathways. AB - The hormone ghrelin prevents a dangerous increase in cardiac sympathetic nerve activity (SNA) after acute myocardial infarction (MI), although the underlying mechanisms remain unknown. This study aimed to determine whether ghrelin's sympathoinhibitory properties stem either from directly within the central nervous system, or via modulation of specific cardiac vagal inhibitory afferents. Cardiac SNA was recorded in urethane-anesthetized rats for 3 hours after the ligation of the left anterior descending coronary artery (ie, MI). Rats received ghrelin either sc (150 MUg/kg) or intracerebroventricularly (5 MUg/kg) immediately after the MI. In another two groups, the cervical vagi were denervated prior to the MI, followed by sc injection of either ghrelin or placebo. Acute MI induced a 188% increase in cardiac SNA, which was significantly attenuated in ghrelin-treated rats for both sc or intracerebroventricularly administration (36% and 76% increase, respectively). Consequently, mortality (47%) and the incidence of arrhythmic episodes (12 per 2 h) were improved with both routes of ghrelin administration (<13% and less than five per 2 h, respectively). Bilateral vagotomy significantly attenuated the cardiac SNA response to acute MI (99% increase). Ghrelin further attenuated the sympathetic response to MI in vagotomized rats so that the SNA response was comparable between vagotomized and vagal-intact MI rats treated with ghrelin. These results suggest that ghrelin may act primarily via a central pathway within the brain to suppress SNA after MI, although peripheral vagal afferent pathways may also contribute in part. The exact region(s) within the central nervous system whereby ghrelin inhibits SNA remains to be fully elucidated. PMID- 26121344 TI - Journal of Pediatric Gastroenterology and Nutrition. Introduction. PMID- 26121342 TI - Rapid Glucocorticoid Feedback Inhibition of ACTH Secretion Involves Ligand Dependent Membrane Association of Glucocorticoid Receptors. AB - The hypothesis that rapid glucocorticoid inhibition of pituitary ACTH secretion mediates a feedforward/feedback mechanism responsible for the hourly glucocorticoid pulsatility was tested in cultured pituitary cells. Perifusion with 30 pM CRH caused sustained the elevation of ACTH secretion. Superimposed corticosterone pulses inhibited CRH-stimulated ACTH release, depending on prior glucocorticoid clearance. When CRH perifusion started after 2 hours of glucocorticoid-free medium, corticosterone levels in the stress range (1 MUM) caused a delayed (25 min) and prolonged inhibition of CRH-stimulated ACTH secretion, up to 60 minutes after corticosterone withdrawal. In contrast, after 6 hours of glucocorticoid-free medium, basal corticosterone levels inhibited CRH stimulated ACTH within 5 minutes, after rapid recovery 5 minutes after corticosterone withdrawal. The latter effect was insensitive to actinomycin D but was prevented by the glucocorticoid receptor antagonist, RU486, suggesting nongenomic effects of the classical glucocorticoid receptor. In hypothalamic derived 4B cells, 10 nM corticosterone increased immunoreactive glucocorticoid receptor content in membrane fractions, with association and clearance rates paralleling the effects on ACTH secretion from corticotrophs. Corticosterone did not affect CRH-stimulated calcium influx, but in AtT-20 cells, it had biphasic effects on CRH-stimulated Src phosphorylation, with early inhibition and late stimulation, suggesting a role for Src phosphorylation on the rapid glucocorticoid feedback. The data suggest that the nongenomic/membrane effects of classical GR mediate rapid and reversible glucocorticoid feedback inhibition at the pituitary corticotrophs downstream of calcium influx. The sensitivity and kinetics of these effects is consistent with the hypothesis that pituitary glucocorticoid feedback is part of the mechanism for adrenocortical ultradian pulse generation. PMID- 26121345 TI - Safety and Tolerability of Esomeprazole in Children With Gastroesophageal Reflux Disease. AB - OBJECTIVES: To evaluate safety, tolerability, and symptom improvement with once daily esomeprazole in children with endoscopically proven gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this 8-week, multicenter, randomized, uncontrolled, double-blind study, children ages 1 to 11 years were stratified by weight to receive esomeprazole 5 or 10 mg (children < 20 kg) or 10 or 20 mg (children >= 20 kg) once daily. Safety and tolerability was assessed by evaluating adverse events (AEs; both treatment- and non-treatment-related AEs) and changes from baseline in medical history, physical examinations, and clinical laboratory tests. Investigators scored symptom severity every 2 weeks using the Physician's Global Assessment (PGA). Patients' parents rated GERD symptoms of heartburn, acid regurgitation, and epigastric pain (none to severe, 0-3) at baseline (based on past 72 hours) and daily (from past 24 hours). RESULTS: Of 109 patients randomized, 108 had safety data. AEs were experienced by 68.0% and 65.2% of children < 20 kg receiving esomeprazole 5 and 10 mg, respectively, and 83.9% and 82.8% of children >= 20 kg receiving esomeprazole 10 and 20 mg, respectively, regardless of causality. Overall, only 9.3% of patients reported 13 treatment related AEs; the most common were diarrhea (2.8% [3/108]), headache (1.9% [2/108]), and somnolence (1.9% [2/108]). Vomiting, a serious AE in 2 patients, was not judged by the investigator to be related to treatment. At the final visit, PGA scores improved significantly from baseline (P < 0.001). Of 58 patients with moderate to severe baseline PGA symptom scores, 91.4% had lower scores by the final visit. GERD symptom scores were significantly improved from baseline to the final week of the study in all of the treatment groups (P < 0.01) CONCLUSIONS: In children ages 1 to 11 years with endoscopically proven GERD, esomeprazole (at daily doses of 5, 10, or 20 mg) was generally well tolerated. The frequency and severity of GERD-related symptoms were significantly reduced during the active treatment period. PMID- 26121346 TI - Pharmacokinetics and Acid-suppressive Effects of Esomeprazole in Infants 1-24 Months Old With Symptoms of Gastroesophageal Reflux Disease. AB - OBJECTIVES: To evaluate the pharmacokinetics and acid-suppressive effects of esomeprazole in infants with gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: In this single-blind, randomized, parallel-group study, 50 infants 1 to 24 months old with symptoms of GERD, and >= 5% of time with intraesophageal pH <4 during 24-hour dual pH monitoring, received oral esomeprazole 0.25 mg/kg (n = 26) or 1 mg/kg (n = 24) once daily for 1 week. Intraesophageal and intragastric pH were recorded at 1 week, and blood samples were taken for pharmacokinetic analysis. RESULTS: At baseline, mean percentages of time with intragastric pH > 4 and intraesophageal pH < 4 were 30.5% and 11.6%, respectively, in the esomeprazole 0.25 mg/kg group and 28.6% and 12.5% in the esomeprazole 1 mg/kg group. After 1 week of treatment, times with intragastric pH >4 were 47.9% and 69.3% in the esomeprazole 0.25 mg/kg and 1 mg/kg groups, respectively (P < 0.001 vs baseline), and times with intraesophageal pH < 4 were 8.4% (P < 0.05 vs baseline) and 5.5% (P < 0.001 vs. baseline), respectively. The mean number of acid reflux episodes of > 5 minutes duration decreased from 6 at baseline to 3 and 2 with esomeprazole 0.25 mg/kg and 1 mg/kg, respectively. The geometric mean AUC0-t of esomeprazole were 0.24 and 1.79 MUmol . h/L for the 0.25 mg/kg and 1 mg/kg dosages of esomeprazole, respectively. Both esomeprazole dosages were well tolerated. CONCLUSIONS: Oral treatment with esomeprazole 0.25 mg/kg and 1 mg/kg was well tolerated and provided dose-related acid suppression, dose-related exposure to esomeprazole, and decreased esophageal acid exposure in infants 1-24 months old with GERD. PMID- 26121347 TI - Esomeprazole for the Treatment of Erosive Esophagitis in Children: An International, Multicenter, Randomized, Parallel-Group, Double-Blind (for Dose) Study. AB - BACKGROUND: Acid suppression with a proton pump inhibitor is standard treatment for gastroesophageal reflux disease and erosive esophagitis in adults and increasingly is becoming first-line therapy for children aged 1-17 years. We evaluated endoscopic healing of erosive esophagitis with esomeprazole in young children with gastroesophageal reflux disease and described esophageal histology. METHODS: Children aged 1-11 years with endoscopically or histologically confirmed gastroesophageal reflux disease were randomized to esomeprazole 5 or 10 mg daily (< 20 kg) or 10 or 20 mg daily (>= 20 kg) for 8 weeks. Patients with erosive esophagitis underwent an endoscopy after 8 weeks to assess healing of erosions. RESULTS: Of 109 patients, 49% had erosive esophagitis and 51% had histologic evidence of reflux esophagitis without erosive esophagitis. Of the 45 patients who had erosive esophagitis and underwent follow-up endoscopy, 89% experienced erosion resolution. Dilation of intercellular space was reported in 24% of patients with histologic examination. CONCLUSIONS: Esomeprazole (0.2-1.0 mg/kg) effectively heals macroscopic and microscopic erosive esophagitis in this pediatric population with gastroesophageal reflux disease. Dilation of intercellular space may be an important histologic marker of erosive esophagitis in children. PMID- 26121348 TI - Healing of Erosive Esophagitis and Improvement of Symptoms of Gastroesophageal Reflux Disease After Esomeprazole Treatment in Children 12 to 36 Months Old. AB - OBJECTIVES: The aim of the study was to evaluate erosive esophagitis healing and symptom improvement with once-daily esomeprazole in children ages 12 to 36 months with endoscopically or histologically proven gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: Data from children ages 12 to 36 months were included in a post-hoc analysis of an 8-week, multicenter, randomized, and double blind by dose strata study of patients ages 1 to 11 years with endoscopically or histologically confirmed GERD. Children were randomized to receive esomeprazole 5 or 10 mg once daily. Patients underwent endoscopy and, if required, mucosal biopsy at baseline. Patients who had erosive esophagitis (graded using the Los Angeles classification system) at baseline underwent a follow-up endoscopy at final study visit to assess healing of erosive esophagitis. Investigators scored severity of GERD symptoms at baseline and every 2 weeks using the Physician Global Assessment. RESULTS: Thirty-one of 109 primary study patients ages 12 to 36 months were included in the post hoc analysis. At baseline, 15 patients (48.4%) had erosive esophagitis, underwent follow-up endoscopy, and were healed after 8 weeks of esomeprazole treatment. Of the 19 patients with moderate-to severe baseline Physician Global Assessment symptom scores, 84.2% had lower scores by the final visit. Following esomeprazole treatment, GERD symptoms were significantly improved from baseline to final visit (P <= 0.0018). CONCLUSIONS: Esomeprazole 5 or 10 mg may be used to successfully treat erosive esophagitis and symptoms of GERD in children as young as 1 year. Moreover, although not yet validated in pediatric patients, the Los Angeles classification system was useful in grading erosive esophagitis in children ages 12 to 36 months. PMID- 26121349 TI - Esomeprazole for the Treatment of GERD in Infants Ages 1-11 Months. AB - OBJECTIVES: Gastroesophageal reflux disease (GERD) is present in pediatric patients when reflux of gastric contents causes troublesome symptoms and/ or complications. The present study evaluates the efficacy and safety of esomeprazole in infants ages 1 to 11 months with GERD. METHODS: In this multicenter randomized, double-blind, placebo-controlled, parallel-group, treatment-withdrawal study, infants received open-label, weight-adjusted doses of esomeprazole (2.5-10 mg) once daily for 2 weeks. Infants with symptom improvement were randomized to esomeprazole (weight-adjusted doses [2.5-10 mg]) or placebo for 4 weeks. The primary endpoint was time to discontinuation owing to symptom worsening based on global assessments by the parent/guardian and physician. Adverse events were recorded. RESULTS: Of the 98 patients enrolled, 81 (82.7%) experienced symptom improvement determined by physician global assessment (PGA) during open-label esomeprazole treatment; 80 entered the double-blind phase. During this phase, discontinuation rates owing to symptom worsening were 48.8% (20/41) for placebo-treated versus 38.5% (15/39) for esomeprazole-treated patients (hazard ratio 0.69; P = 0.28). Posthoc analysis of infants with symptomatic GERD (ie, no diagnostic procedure performed) revealed that time to discontinuation was significantly longer with esomeprazole than placebo (hazard ratio 0.24; P = 0.01); the complementary subgroup difference was not significant (hazard ratio 1.39; P = 0.48). Esomeprazole was well tolerated. CONCLUSIONS: The discontinuation rate owing to symptom worsening did not differ significantly between infants receiving esomeprazole versus those receiving placebo. Improved diagnostic criteria in this age group are needed to identify infants with GERD who may benefit from acid suppression therapy. PMID- 26121350 TI - "Give, but Give until It Hurts": The Modulatory Role of Trait Emotional Intelligence on the Motivation to Help. AB - Two studies investigated the effect of trait Emotional Intelligence (trait EI) on people's motivation to help. In Study 1, we developed a new computer-based paradigm that tested participants' motivation to help by measuring their performance on a task in which they could gain a hypothetical amount of money to help children in need. Crucially, we manipulated participants' perceived efficacy by informing them that they had been either able to save the children (positive feedback) or unable to save the children (negative feedback). We measured trait EI using the Trait Emotional Intelligence Questionnaire-Short Form (TEIQue-SF) and assessed participants' affective reactions during the experiment using the PANAS-X. Results showed that high and low trait EI participants performed differently after the presentation of feedback on their ineffectiveness in helping others in need. Both groups showed increasing negative affective states during the experiment when the feedback was negative; however, high trait EI participants better managed their affective reactions, modulating the impact of their emotions on performance and maintaining a high level of motivation to help. In Study 2, we used a similar computerized task and tested a control situation to explore the effect of trait EI on participants' behavior when facing failure or success in a scenario unrelated to helping others in need. No effect of feedback emerged on participants' emotional states in the second study. Taken together our results show that trait EI influences the impact of success and failure on behavior only in affect-rich situation like those in which people are asked to help others in need. PMID- 26121351 TI - An Au(I)-catalyzed rearrangement/cyclization cascade toward the synthesis of 2 substituted-1,4,5,6-tetrahydrocyclopenta[b]pyrrole. AB - An Au(I)-catalyzed tandem reaction for the synthesis of 2-phenyl-1,4,5,6 tetrahydrocyclopenta[b]pyrrole derivatives from 1-(1-hydroxy-3-phenylprop-2-yn-1 yl)cyclobutanol and primary amines or NH4OAc has been developed to afford a series of polysubstituted pyrroles in moderate to good yields. PMID- 26121353 TI - Topographic and Bioclimatic Determinants of the Occurrence of Forest and Grassland in Tropical Montane Forest-Grassland Mosaics of the Western Ghats, India. AB - The objective of this analysis was to identify topographic and bioclimatic factors that predict occurrence of forest and grassland patches within tropical montane forest-grassland mosaics. We further investigated whether interactions between topography and bioclimate are important in determining vegetation pattern, and assessed the role of spatial scale in determining the relative importance of specific topographic features. Finally, we assessed the role of elevation in determining the relative importance of diverse explanatory factors. The study area consists of the central and southern regions of the Western Ghats of Southern India, a global biodiversity hotspot. Random forests were used to assess prediction accuracy and predictor importance. Conditional inference classification trees were used to interpret predictor effects and examine potential interactions between predictors. GLMs were used to confirm predictor importance and assess the strength of interaction terms. Overall, topographic and bioclimatic predictors classified vegetation pattern with approximately 70% accuracy. Prediction accuracy was higher for grassland than forest, and for mosaics at higher elevations. Elevation was the most important predictor, with mosaics above 2000 m dominated largely by grassland. Relative topographic position measured at a local scale (within a 300 m neighbourhood) was another important predictor of vegetation pattern. In high elevation mosaics, northness and concave land surface curvature were important predictors of forest occurrence. Important bioclimatic predictors were: dry quarter precipitation, annual temperature range and the interaction between the two. The results indicate complex interactions between topography and bioclimate and among topographic variables. Elevation and topography have a strong influence on vegetation pattern in these mosaics. There were marked regional differences in the roles of various topographic and bioclimatic predictors across the range of study mosaics, indicating that the same pattern of grass and forest seems to be generated by different sets of mechanisms across the region, depending on spatial scale and elevation. PMID- 26121352 TI - Molecular Details of Olfactomedin Domains Provide Pathway to Structure-Function Studies. AB - Olfactomedin (OLF) domains are found within extracellular, multidomain proteins in numerous tissues of multicellular organisms. Even though these proteins have been implicated in human disorders ranging from cancers to attention deficit disorder to glaucoma, little is known about their structure(s) and function(s). Here we biophysically, biochemically, and structurally characterize OLF domains from H. sapiens olfactomedin-1 (npoh-OLF, also called noelin, pancortin, OLFM1, and hOlfA), and M. musculus gliomedin (glio-OLF, also called collomin, collmin, and CRG-L2), and compare them with available structures of myocilin (myoc-OLF) recently reported by us and R. norvegicus glio-OLF and M. musculus latrophilin-3 (lat3-OLF) by others. Although the five-bladed beta-propeller architecture remains unchanged, numerous physicochemical characteristics differ among these OLF domains. First, npoh-OLF and glio-OLF exhibit prominent, yet distinct, positive surface charges and copurify with polynucleotides. Second, whereas npoh OLF and myoc-OLF exhibit thermal stabilities typical of human proteins near 55 degrees C, and most myoc-OLF variants are destabilized and highly prone to aggregation, glio-OLF is nearly 20 degrees C more stable and significantly more resistant to chemical denaturation. Phylogenetically, glio-OLF is most similar to primitive OLFs, and structurally, glio-OLF is missing distinguishing features seen in OLFs such as the disulfide bond formed by N- and C- terminal cysteines, the sequestered Ca2+ ion within the propeller central hydrophilic cavity, and a key loop-stabilizing cation-pi interaction on the top face of npoh-OLF and myoc OLF. While deciphering the explicit biological functions, ligands, and binding partners for OLF domains will likely continue to be a challenging long-term experimental pursuit, we used structural insights gained here to generate a new antibody selective for myoc-OLF over npoh-OLF and glio-OLF as a first step in overcoming the impasse in detailed functional characterization of these biomedically important protein domains. PMID- 26121354 TI - Tissue-Specific Evolution of Protein Coding Genes in Human and Mouse. AB - Protein-coding genes evolve at different rates, and the influence of different parameters, from gene size to expression level, has been extensively studied. While in yeast gene expression level is the major causal factor of gene evolutionary rate, the situation is more complex in animals. Here we investigate these relations further, especially taking in account gene expression in different organs as well as indirect correlations between parameters. We used RNA seq data from two large datasets, covering 22 mouse tissues and 27 human tissues. Over all tissues, evolutionary rate only correlates weakly with levels and breadth of expression. The strongest explanatory factors of purifying selection are GC content, expression in many developmental stages, and expression in brain tissues. While the main component of evolutionary rate is purifying selection, we also find tissue-specific patterns for sites under neutral evolution and for positive selection. We observe fast evolution of genes expressed in testis, but also in other tissues, notably liver, which are explained by weak purifying selection rather than by positive selection. PMID- 26121355 TI - Work Content and Serious Mental Illness among Middle-Aged Men: Results from a 6 Year Longitudinal Study in Japan. AB - OBJECTIVE: The present study aimed to determine prospective associations between work content after a working life of more than 20 years and serious mental illness among Japanese men aged 50 to 59 years, using a nationwide population based survey. METHODS: Data were extracted from a national longitudinal survey of middle-aged and elderly persons previously conducted by the Ministry of Health, Labour and Welfare in Japan. We analyzed data across 10 work content categories for Japanese men who had been working in the same job type or industry for over 20 years. As part pf the survey, participants completed the Kessler (K)6 scale each year to determine their level of psychological distress (with scores >=13 indicating serious mental illness). Cox discrete time proposal hazard regression analysis was used to examine potential associations between work content and serious mental illness from 2005 to 2010. Further adjustments were made for other sociodemographic characteristics and lifestyle factors. RESULTS: The current study involved a total of 11,942 participants with a mean (+/- standard deviation [SD]) of follow-up was 3.4 (+/- 2.0) years, during which time 892 participants (7.5%) had been classified as having a new-onset serious mental illness. Men who had worked in service jobs and in manufacturing jobs at baseline were more likely to develop serious mental illness than those in managerial jobs (hazard ratio 1.37, 1.30, 95% confidence intervals 1.04-1.80, 1.02-1.65) after adjustment for confounding variables. CONCLUSION: These findings suggest that Japanese men aged 50 to 59 years who have worked in service and manufacturing jobs after a working life of over 20 years have an increased risk of serious mental illness during follow-up. Identifying the most at-risk work content category after a working life of over 20 years would be an essential part of providing more effective interventions for psychological distress among Japanese men in this age group. PMID- 26121356 TI - Search, Memory, and Choice Error: An Experiment. AB - Multiple attribute search is a central feature of economic life: we consider much more than price when purchasing a home, and more than wage when choosing a job. An experiment is conducted in order to explore the effects of cognitive limitations on choice in these rich settings, in accordance with the predictions of a new model of search memory load. In each task, subjects are made to search the same information in one of two orders, which differ in predicted memory load. Despite standard models of choice treating such variations in order of acquisition as irrelevant, lower predicted memory load search orders are found to lead to substantially fewer choice errors. An implication of the result for search behavior, more generally, is that in order to reduce memory load (thus choice error) a limited memory searcher ought to deviate from the search path of an unlimited memory searcher in predictable ways-a mechanism that can explain the systematic deviations from optimal sequential search that have recently been discovered in peoples' behavior. Further, as cognitive load is induced endogenously (within the task), and found to affect choice behavior, this result contributes to the cognitive load literature (in which load is induced exogenously), as well as the cognitive ability literature (in which cognitive ability is measured in a separate task). In addition, while the information overload literature has focused on the detrimental effects of the quantity of information on choice, this result suggests that, holding quantity constant, the order that information is observed in is an essential determinant of choice failure. PMID- 26121357 TI - Relationship among Medical Student Resilience, Educational Environment and Quality of Life. AB - CONTEXT: Resilience is a capacity to face and overcome adversities, with personal transformation and growth. In medical education, it is critical to understand the determinants of a positive, developmental reaction in the face of stressful, emotionally demanding situations. We studied the association among resilience, quality of life (QoL) and educational environment perceptions in medical students. METHODS: We evaluated data from a random sample of 1,350 medical students from 22 Brazilian medical schools. Information from participants included the Wagnild and Young's resilience scale (RS-14), the Dundee Ready Educational Environment Measure (DREEM), the World Health Organization Quality of Life questionnaire - short form (WHOQOL-BREF), the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). RESULTS: Full multiple linear regression models were adjusted for sex, age, year of medical course, presence of a BDI score >= 14 and STAI state or anxiety scores >= 50. Compared to those with very high resilience levels, individuals with very low resilience had worse QoL, measured by overall (beta=-0.89; 95% confidence interval =-1.21 to -0.56) and medical-school related (beta=-0.85; 95%CI=-1.25 to -0.45) QoL scores, environment (beta=-6.48; 95%CI=-10.01 to -2.95), psychological (beta=-22.89; 95%CI=-25.70 to 20.07), social relationships (beta=-14.28; 95%CI=-19.07 to -9.49), and physical health (beta=-10.74; 95%CI=-14.07 to -7.42) WHOQOL-BREF domain scores. They also had a worse educational environment perception, measured by global DREEM score (beta=-31.42; 95%CI=-37.86 to -24.98), learning (beta=-7.32; 95%CI=-9.23 to 5.41), teachers (beta=-5.37; 95%CI=-7.16 to -3.58), academic self-perception (beta=-7.33; 95%CI=-8.53 to -6.12), atmosphere (beta=-8.29; 95%CI=-10.13 to 6.44) and social self-perception (beta=-3.12; 95%CI=-4.11 to -2.12) DREEM domain scores. We also observed a dose-response pattern across resilience level groups for most measurements. CONCLUSIONS: Medical students with higher resilience levels had a better quality of life and a better perception of educational environment. Developing resilience may become an important strategy to minimize emotional distress and enhance medical training. PMID- 26121359 TI - Correction: Surface Vulnerability of Cerebral Cortex to Major Depressive Disorder. PMID- 26121358 TI - Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees. AB - The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee's susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions. PMID- 26121360 TI - Correction: Rough-Fuzzy Clustering and Unsupervised Feature Selection for Wavelet Based MR Image Segmentation. PMID- 26121361 TI - Comparison of the Efficacy of Entecavir and Tenofovir in Nucleos(T)ide Analogue Experienced Chronic Hepatitis B Patients. AB - The efficacy of entecavir (ETV) and tenofovir (TDF) for the treatment of nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients has been little studied. Here, we compare the efficacy of both ETV and TDF in NA experienced CHB patients without detectable genotypic resistance. This retrospective cohort study included consecutive NA-experienced patients who had neither current nor previous genotypic resistance and had received ETV or TDF for at least 6 months. Overall, 202 patients (146 patients in the ETV group and 56 in the TDF group) were analyzed. The cumulative probabilities of complete virologic suppression (CVS) at month 12 were 76.1% in the ETV group and 95.0% in the TDF group (P<0.001), respectively. The TDF-treated group achieved CVS more rapidly than the ETV group for both Hepatitis B e antigen (HBeAg)-negative and -positive patients (P = 0.006 and < 0.001, respectively), and for those with both low (< 2,000 IU/mL) and high (>= 2,000 IU/mL) HBV DNA levels (P = 0.01 and 0.002, respectively). TDF group had an increased probability of achieving CVS (hazard ratio, 2.242; 95% confidence interval, 1.587-3.165; P = 0.001), after adjustment for HBV DNA level, the presence of HBeAg, and a history of CVS during prior treatment. During the treatment period, 23 patients (15.8%) in the ETV group developed virologic breakthrough, compared to none in the TDF group. The cumulative probabilities of developing virologic breakthrough and ETV-resistance at month 24 were 9.7% and 5.3%, respectively. In conclusion, TDF is preferable to ETV for achieving CVS in NA-experienced CHB patients without genotypic resistance. PMID- 26121362 TI - Positive Effect of Large Birth Intervals on Early Childhood Hemoglobin Levels in Africa Is Limited to Girls: Cross-Sectional DHS Study. AB - BACKGROUND: Short birth intervals are independently associated with increased risk of adverse maternal, perinatal, infant and child outcomes. Anemia in children, which is highly prevalent in Africa, is associated with an increased risk of morbidity and mortality. Birth spacing is advocated as a tool to reduce anemia in preschool African children, but the role of gender differences and contextual factors has been neglected. The present study aims to determine to what extent the length of preceding birth interval influences the hemoglobin levels of African preschool children in general, as well as for boys and girls separately, and which contextual factors thereby play a crucial role. METHODS AND FINDINGS: This cross-sectional study uses data from Demographic and Health Surveys (DHS) conducted between 2003 and 2011 in 20 African countries. All preschool children aged 6-59 months with a valid hemoglobin measurement and a preceding birth interval of 7-72 months as well as their corresponding multigravida mothers aged 21-49 years were included in the study. Hemoglobin levels of children and mothers were measured in g/l, while birth intervals were calculated as months difference between consecutive births. Multivariate analyses were done to examine the relationship between length of preceding birth interval and child hemoglobin levels, adjusted for factors at the individual, household, community, district, and country level. A positive linear relationship was observed between birth interval and the 49,260 included children's hemoglobin level, whereby age and sex of the child, hemoglobin level of the mother, household wealth, mother's education and urbanization of place of residence also showed positive associations. In the interaction models, the effect of a month increase in birth interval is associated with an average increase of 0.025 g/l in hemoglobin level (P = 0.001) in girls, while for boys the effect was not significant. In addition, for girls, the effect of length of preceding birth interval was highest in young mothers and mothers with higher hemoglobin levels, while for boys, the highest effect was noticed for those living in more highly educated regions. Finally, significantly higher hemoglobin levels of girls compared to boys were observed at birth but with increasing age, the sex difference in hemoglobin level gradually becomes smaller. CONCLUSIONS: A longer birth interval has a modest positive effect on early childhood hemoglobin levels of girls, and this effect is strongest when their mothers are in their early twenties and have a high hemoglobin level. Remarkably, although the physiological iron requirement is higher for boys than girls, birth spacing has little influence on hemoglobin levels of preschool boys. We speculate that the preference for male offspring in large parts of Africa significantly influences nutritional patterns of African preschool boys and girls, and as such also determines the different effect of birth spacing. Finally, gender aspects should be considered in intervention programs that aim to improve anemia in African children. PMID- 26121363 TI - The Negative Correlation between Fiber Color and Quality Traits Revealed by QTL Analysis. AB - Naturally existing colored cotton was far from perfection due to having genetic factors for lower yield, poor fiber quality and monotonous color. These factors posed a challenge to colored cotton breeding and innovation. To identify novel quantitative trait loci (QTL) for fiber color along with understanding of correlation between fiber color and quality in colored cotton, a RIL and two F2 populations were generated from crosses among Zong128 (Brown fiber cotton) and two white fiber cotton lines which were then analyzed in four environments. Two stable and major QTLs (qLC-7-1, qFC-7-1) for fiber lint and fuzz color were detected accounting for 16.01%-59.85% of the phenotypic variation across multiple generations and environments. Meanwhile, some minor QTLs were also identified on chromosomes 5, 14, 21 and 24 providing low phenotypic variation (<5%) from only F2 populations, not from the RILs population. Especially, a multiple-effect locus for fiber color and quality has been detected between flanking markers NAU1043 and NAU3654 on chromosome 7 (A genome) over multiple environments. Of which, qLC 7-1, qFC-7-1 were responsible for positive effects and improved fiber color in offsprings. Meanwhile, the QTLs (qFL-7-1, qFU-7-1, qFF-7-1, qFE-7-1, and qFS-7-1) for fiber quality had negative effects and explained 2.19%-8.78% of the phenotypic variation. This multiple-effect locus for fiber color and quality may reveal the negative correlation between the two types of above traits, so paving the way towards cotton genetic improvement. PMID- 26121364 TI - Obsessions and Compulsions in Postpartum Women Without Obsessive Compulsive Disorder. AB - BACKGROUND: To describe the prevalence of obsessions and compulsions and the specific symptoms present in postpartum women without obsessive compulsive disorder (OCD). METHODS: In this prospective cohort, women were screened with the Yale Brown Obsessive Compulsive Scale at 2 weeks postpartum. Demographics and comorbid psychiatric symptoms were compared between women with screen-positive OCD, screen-negative OCD but with some endorsed symptoms (subclinical OCD), and no OCD symptoms. The prevalence of each specific set of obsessive and compulsive symptoms and the rate of impairment from those symptoms were compared. RESULTS: Of the 461 women included, 52 (11.2%) screened positive for OCD, while 173 (37.5%) reported experiencing subclinical obsessions or compulsions. This subclinical OCD was associated with an increased rate of depression (24%) and state-trait anxiety (8%) compared with women who did not endorse experiencing any obsessions or compulsions. Aggressive, religious, and somatic obsessions as well as obsessions with symmetry, when present, were most likely to result in OCD screen positivity. CONCLUSIONS: Nearly half of all women who screen negative for OCD experienced obsessions or compulsions that did not result in OCD screen positivity. However, the presence of these subclinical obsessions and compulsions is associated with an increased rate of depression or anxiety. PMID- 26121366 TI - Pasteur's Experiment Performed at the Nanoscale: Manual Separation of Chiral Molecules, One by One. AB - Understanding the principles of molecular recognition is a difficult task and calls for investigation of appropriate model systems. Using the manipulation capabilities of scanning tunneling microscopy (STM) we analyzed the chiral recognition in self-assembled dimers of helical hydrocarbons at the single molecule level. After manual separation of the two molecules of a dimer with a molecule-terminated STM tip on a Cu(111) surface, their handedness was subsequently determined with a metal atom-terminated tip. We find that these molecules strongly prefer to form heterochiral pairs. Our study shows that single molecule manipulation is a valuable tool to understand intermolecular recognition at surfaces. PMID- 26121365 TI - A Biofilm Pocket Model to Evaluate Different Non-Surgical Periodontal Treatment Modalities in Terms of Biofilm Removal and Reformation, Surface Alterations and Attachment of Periodontal Ligament Fibroblasts. AB - BACKGROUND AND AIM: There is a lack of suitable in vitro models to evaluate various treatment modalities intending to remove subgingival bacterial biofilm. Consequently, the aims of this in vitro-study were: a) to establish a pocket model enabling mechanical removal of biofilm and b) to evaluate repeated non surgical periodontal treatment with respect to biofilm removal and reformation, surface alterations, tooth hard-substance-loss, and attachment of periodontal ligament (PDL) fibroblasts. MATERIAL AND METHODS: Standardized human dentin specimens were colonized by multi-species biofilms for 3.5 days and subsequently placed into artificially created pockets. Non-surgical periodontal treatment was performed as follows: a) hand-instrumentation with curettes (CUR), b) ultrasonication (US), c) subgingival air-polishing using erythritol (EAP) and d) subgingival air-polishing using erythritol combined with chlorhexidine digluconate (EAP-CHX). The reduction and recolonization of bacterial counts, surface roughness (Ra and Rz), the caused tooth substance-loss (thickness) as well as the attachment of PDL fibroblasts were evaluated and statistically analyzed by means of ANOVA with Post-Hoc LSD. RESULTS: After 5 treatments, bacterial reduction in biofilms was highest when applying EAP-CHX (4 log10). The lowest reduction was found after CUR (2 log10). Additionally, substance-loss was the highest when using CUR (128+/-40 um) in comparison with US (14+/-12 um), EAP (6+/-7 um) and EAP-CHX (11+/-10) um). Surface was roughened when using CUR and US. Surfaces exposed to US and to EAP attracted the highest numbers of PDL fibroblasts. CONCLUSION: The established biofilm model simulating a periodontal pocket combined with interchangeable placements of test specimens with multi species biofilms enables the evaluation of different non-surgical treatment modalities on biofilm removal and surface alterations. Compared to hand instrumentation the application of ultrasonication and of air-polishing with erythritol prevents from substance-loss and results in a smooth surface with nearly no residual biofilm that promotes the reattachment of PDL fibroblasts. PMID- 26121367 TI - Phomopsis Stem Canker: A Reemerging Threat to Sunflower (Helianthus annuus) in the United States. AB - Phomopsis stem canker causes yield reductions on sunflower (Helianthus annuus L.) on several continents, including Australia, Europe, and North America. In the United States, Phomopsis stem canker incidence has increased 16-fold in the Northern Great Plains between 2001 and 2012. Although Diaporthe helianthi was assumed to be the sole causal agent in the United States, a newly described species, D. gulyae, was found to be the primary cause of Phomopsis stem canker in Australia. To determine the identity of Diaporthe spp. causing Phomopsis stem canker in the Northern Great Plains, 275 infected stems were collected between 2010 and 2012. Phylogenetic analyses of sequences of the ribosomal DNA internal transcribed spacer region, elongation factor subunit 1-alpha, and actin gene regions of representative isolates, in comparison with those of type specimens, confirmed two species (D. helianthi and D. gulyae) in the United States. Differences in aggressiveness between the two species were determined using the stem-wound method in the greenhouse; overall, D. helianthi and D. gulyae did not vary significantly (P<=0.05) in their aggressiveness at 10 and 14 days after inoculation. These findings indicate that both Diaporthe spp. have emerged as sunflower pathogens in the United States, and have implications on the management of this disease. PMID- 26121368 TI - Strategies to promote peripheral nerve regeneration: electrical stimulation and/or exercise. AB - Enhancing the regeneration of axons is often considered to be a therapeutic target for improving functional recovery after peripheral nerve injury. In this review, the evidence for the efficacy of electrical stimulation (ES), daily exercise and their combination in promoting nerve regeneration after peripheral nerve injuries in both animal models and in human patients is explored. The rationale, effectiveness and molecular basis of ES and exercise in accelerating axon outgrowth are reviewed. In comparing the effects of ES and exercise in enhancing axon regeneration, increased neural activity, neurotrophins and androgens are considered to be common requirements. Similarly, there are sex specific requirements for exercise to enhance axon regeneration in the periphery and for sustaining synaptic inputs onto injured motoneurons. ES promotes nerve regeneration after delayed nerve repair in humans and rats. The effectiveness of exercise is less clear. Although ES, but not exercise, results in a significant misdirection of regenerating motor axons to reinnervate different muscle targets, the loss of neuromuscular specificity encountered has only a very small impact on resulting functional recovery. Both ES and exercise are promising experimental treatments for peripheral nerve injury that seem to be ready to be translated to clinical use. PMID- 26121369 TI - Metabolism of Multiple Aromatic Compounds in Corn Stover Hydrolysate by Rhodopseudomonas palustris. AB - Lignocellulosic biomass hydrolysates hold great potential as a feedstock for microbial biofuel production, due to their high concentration of fermentable sugars. Present at lower concentrations are a suite of aromatic compounds that can inhibit fermentation by biofuel-producing microbes. We have developed a microbial-mediated strategy for removing these aromatic compounds, using the purple nonsulfur bacterium Rhodopseudomonas palustris. When grown photoheterotrophically in an anaerobic environment, R. palustris removes most of the aromatics from ammonia fiber expansion (AFEX) treated corn stover hydrolysate (ACSH), while leaving the sugars mostly intact. We show that R. palustris can metabolize a host of aromatic substrates in ACSH that have either been previously described as unable to support growth, such as methoxylated aromatics, and those that have not yet been tested, such as aromatic amides. Removing the aromatics from ACSH with R. palustris, allowed growth of a second microbe that could not grow in the untreated ACSH. By using defined mutants, we show that most of these aromatic compounds are metabolized by the benzoyl-CoA pathway. We also show that loss of enzymes in the benzoyl-CoA pathway prevents total degradation of the aromatics in the hydrolysate, and instead allows for biological transformation of this suite of aromatics into selected aromatic compounds potentially recoverable as an additional bioproduct. PMID- 26121370 TI - Hemicyanine dyes derived from 2,3,3-trimethyl-3H-indolium as candidates for non covalent protein probes. AB - Non-covalent interaction of hemicyanine dyes, derivatives of 2,3,3-trimethyl-3H indolium with bovine serum albumin has been studied by spectral method. For this purpose, three hemicyanine dyes containing N-(2-carboxyethyl)-2,3,3-trimethyl-3H indolium moiety were synthesized and their UV/Vis and fluorescence spectra, aggregation, photostability and association with bovine serum albumin were studied. The hemicyanine dyes with 2-ethylcarboxylic group was found to interact with bovine serum albumin, which is probably due to negative charge on the dye molecule at the expense of the carboxylic group and the ability to form hydrogen bonds with albumin. PMID- 26121371 TI - Dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection. AB - BACKGROUND: We prospectively investigated temporal and spatial evolution of intramural hematomas in patients with acute spontaneous internal carotid artery dissection using repeated magnetic resonance imaging over six-months. AIM: The aim of the present study was to assess dynamic changes of intramural hematoma in patients with acute spontaneous internal carotid artery dissection at multiple follow-up time-points with T1w, PD/T2w, and magnetic resonance angiography. METHODS: We performed serial multiparametric magnetic resonance imaging in 10 patients with spontaneous internal carotid artery dissection on admission, at days 1, 3, 7-14 and at months 1.5, 3, and 6. We calculated the volume and extension of the hyperintense intramural hematoma using T1w and PD/T2w fat suppressed sequences and assessed the degree of stenosis due to the hematoma using magnetic resonance angiography. RESULTS: Mean interval from symptom onset to first magnetic resonance imaging was two-days (SD 2.7). Two patients presented with ischemic stroke, three with transient ischemic attacks, and five with pain and local symptoms only. Nine patients had a transient increase of the intramural hematoma volume, mainly up to day 10 after symptom onset. Fifty percent had a transient increase in the degree of the internal carotid artery stenosis on MRA, one resulting in a temporary occlusion. Lesions older than one-week were predominantly characterized by a shift from iso- to hyperintese signal on T2w images. At three-month follow-up, intramural hematoma was no longer detectable in 80% of patients and had completely resolved in all patients after six-months. CONCLUSIONS: Spatial and temporal dynamics of intramural hematomas after spontaneous internal carotid artery dissection showed an early volume increase with concomitant progression of the internal carotid artery stenosis in 5 of 10 patients. Although spontaneous internal carotid artery dissection overall carries a good prognosis with spontaneous hematoma resorption in all our patients, early follow-up imaging may be considered, especially in case of new clinical symptoms. PMID- 26121372 TI - The impact of traffic light color-coding on food health perceptions and choice. AB - Government regulators and consumer packaged goods companies around the world struggle with methods to help consumers make better nutritional decisions. In this research we find that, depending on the consumer, a traffic light color coding (TLC) approach to product labeling can have a substantial impact on perceptions of foods' health quality and food choice. Across 3 lab experiments and a field experiment, we find that TLC labels provide nondieters with an information processing cue that directly influences evaluations in a manner that is consistent with the "stop" and "go" logic behind the traffic light labels. In contrast, we find that dieters do not simply adopt the red, yellow, and green cues into their health quality evaluations. Instead, regardless of the color, the TLC approach increases the depth at which dieters process label information. Dieters tend to focus on the costs of consumption and, as a result, lower their health quality evaluations. In a field study, measuring actual behavior in a grocery store, health quality evaluations predicted consumption and consistent with the color coding of the labels nondieters consumed the most when they were presented with a predominantly green label. PMID- 26121373 TI - Violent video games: The effects of narrative context and reward structure on in game and postgame aggression. AB - The potential influence of video game violence on real-world aggression has generated considerable public and scientific interest. Some previous research suggests that playing violent video games can increase postgame aggression. The generalized aggression model (GAM) attributes this to the generalized activation of aggressive schemata. However, it is unclear whether game mechanics that contextualize and encourage or inhibit in-game violence moderate this relationship. Thus, we examined the effects of reward structures and narrative context in a violent video game on in-game and postgame aggression. Contrary to GAM-based predictions, our manipulations differentially affected in-game and postgame aggression. Reward structures selectively affected in-game aggression, whereas narrative context selectively affected postgame aggression. Players who enacted in-game violence through a heroic character exhibited less postgame aggression than players who enacted comparable levels of in-game violence through an antiheroic character. Effects were not attributable to self-activation or character-identification mechanisms, but were consistent with social-cognitive context effects on the interpretation of behavior. These results contradict the GAM's assertion that violent video games affect aggression through a generalized activation mechanism. From an applied perspective, consumer choices may be aided by considering not just game content, but the context in which content is portrayed. PMID- 26121374 TI - Evaluating the accuracy of size perception on screen-based displays: Displayed objects appear smaller than real objects. AB - Accurate perception of the size of objects in computer-generated imagery is important for a growing number of applications that rely on absolute scale, such as medical visualization and architecture. Addressing this problem requires both the development of effective evaluation methods and an understanding of what visual information might contribute to differences between virtual displays and the real world. In the current study, we use 2 affordance judgments--perceived graspability of an object or reaching through an aperture--to compare size perception in high-fidelity graphical models presented on a large screen display to the real world. Our goals were to establish the use of perceived affordances within spaces near to the observer for evaluating computer graphics and to assess whether the graphical displays were perceived similarly to the real world. We varied the nature of the affordance task and whether or not the display enabled stereo presentation. We found that judgments of grasping and reaching through can be made effectively with screen-based displays. The affordance judgments revealed that sizes were perceived as smaller than in the real world. However, this difference was reduced when stereo viewing was enabled or when the virtual display was viewed before the real world. PMID- 26121375 TI - Enhancing the energy density of asymmetric stretchable supercapacitor based on wrinkled CNT@MnO2 cathode and CNT@polypyrrole anode. AB - With the advantages of high stickiness and stretchability of the hydrogel electrolyte as well as the resilient properties of film electrodes, the facile "prestrain-stick-release" strategy can be utilized for the assembly of a stretchable supercapacitor. Two major issues of concern are the relatively low mechanical strength of the hydrogel electrolyte and the low energy density of the assembled device. Herein, vinyl group grafted silica (CH2?CH-SiO2) nanoparticles were used as a nanoparticle cross-linker for polyacrylamide (PAAM), enhancing the tensile strength of 844 kPa at the strain of 3400% for the KCl-CH2?CH-SiO2/PAAM hydrogel electrolyte. Besides, carbon nanotube supported polypyrrole (CNT@PPy) and manganese dioxide (CNT@MnO2) film electrodes are prepared to assemble the stretchable asymmetric CNT@MnO2//KCl-CH2?CH-SiO2/PAAM//CNT@PPy supercapacitor, significantly enhancing the potential window to 0-2.0 V and achieving a high energy density of 40 Wh kg(-1) at the power density of 519 kW kg(-1) with the strain of 100%, which is the best known for the reported stretchable supercapacitors. PMID- 26121376 TI - Impact of immunosuppressive therapy on hepatitis B vaccination in inflammatory bowel diseases. AB - BACKGROUND AND AIMS: The vaccination rate against hepatitis B virus (HBV) is low in inflammatory bowel disease (IBD) patients. The Consensus from the European Crohn's and Colitis Organisation on opportunistic infections recommends testing all IBD patients for HBV at diagnosis and vaccinating all HBV-negative patients. We compared the efficacy of HBV vaccine between IBD patients and healthy controls and investigated the impact of immunosuppressive therapy on vaccine response in IBD patients. MATERIALS AND METHODS: IBD patients and healthy adult workers were vaccinated against HBV following a standard protocol (at 0, 1, and 6 months; Engerix B). The efficacy of vaccination was evaluated at 8 months by a titer of antibodies against hepatitis B surface antigen (anti-HBs). RESULTS: Among 164 participants (96 with IBD and 68 healthy workers), the level of anti-HBs was greater than 10 IU/l in 80.2 and 94.1% (P=0.0115) of IBD patients and healthy controls, respectively, and anti-HBs levels greater than 100 IU/l were seen in 45.8 versus 77.9% (P<0.0001) of IBD patients and healthy controls, respectively. The median level of anti-HBs was significantly higher in healthy controls (497.0+/-386.2) than in IBD patients (253.9+/-34.5) (P<0.0001). None of the baseline characteristics of IBD patients, including immunomodulators and antitumor necrosis factor therapy, influenced the vaccine response. In the multivariate analysis, ileal disease was the only factor associated with a lower response to the vaccine (odds ratio=3.2; 95% confidence interval=1.0-9.7; P=0.049). CONCLUSION: The response rate to HBV vaccination is significantly lower in IBD patients than in the general population. Immunosuppressive therapy for IBD did not influence the vaccine response. PMID- 26121377 TI - Chronic kidney disease. AB - INTRODUCTION: Continued progression of kidney disease will lead to renal function too low to sustain healthy life. In developed countries, such people will be offered renal replacement therapy in the form of dialysis or renal transplantation. Requirement for dialysis or transplantation is termed end-stage renal disease (ESRD). METHODS AND OUTCOMES: We conducted a systematic review, aiming to answer the following clinical questions: What are the effects of a low sodium diet to reduce progression rate of chronic kidney disease? What are the effects of a low-protein diet to reduce progression rate of chronic kidney disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: We found seven studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic overview we present information relating to the effectiveness and safety of the following interventions: low-protein diet versus control, different low-protein diets versus each other (low-protein diet versus very low-protein diet), low-sodium diet versus control, different low-sodium diets versus each other. PMID- 26121378 TI - Transfemoral versus Transapical Aortic Implantation for Aortic Stenosis Based on No Significant Difference in Logistic EuroSCORE: A Meta-Analysis. AB - Background Transcatheter aortic valve implantation (TAVI) has gained increasing acceptance for patients with severe aortic stenosis (AS). The present meta analysis was performed to assess if the transapical (TA) approach has any benefit in reduction of mortality and complications relative to the transfemoral (TF) approach for patients with AS. Methods All relevant studies comparing TF-TAVI and TA-TAVI from January 2002 to November 2013 were retrieved from Medline and Embase databases. The relative risk (RR) and 95% confidence interval (CI) were used to evaluate the difference between two groups. Heterogeneity assumption was assessed by an I (2) test. The random-effect model or fixed-effect model was used to estimate summary effect based on I (2) test. Results Nine studies conformed to the predefined criteria, including 666 patients in the TF-TAVI group and 457 patients in the TA-TAVI group. No difference was found in all-cause mortality at 30 days and beyond 1 year between the two groups (30 days: 9.2% versus 11.4%; RR, 0.72; 95% CI, 0.47 to 1.11; p = 0.14 and beyond 1 year: RR, 0.96; 95% CI, 0.59 to 1.56; p = 0.86). There was a trend toward increased incidence of stroke in patients in the TF-TAVI group (4.7% versus 2.6%; RR, 1.64; 95% CI, 0.75 to 3.58; p = 0.21), and the incidence of vascular complication and postoperative heart block were significantly increased in patients having TF-TAVI (vascular complications: 14.7% versus 7.1%; RR, 2.04; 95% CI, 1.15 to 3.61; p = 0.01 and heart block: 13.4% versus 4.6%; RR, 2.53; 95% CI, 1.10 to 5.83; p = 0.03). Additionally, more patients in the TF-TAVI group required permanent pacemaker relative to the TA-TAVI group (10.8% versus 3.4%; RR, 2.74; 95% CI, 1.41 to 5.32; p = 0.003). Conclusions Among patients with AS with no significant difference in logistic EuroSCORE, TA-TAVI has a lower risk of vascular complication and postoperative heart block but a similar incidence of stroke and mortality compared with TF-TAVI. Accordingly, TA approach is a promising and feasible option for the patients with severe AS. PMID- 26121379 TI - Subclinical Hypothyroidism Might Increase the Risk of Postoperative Atrial Fibrillation after Aortic Valve Replacement. AB - Background To evaluate the influence of subclinical hypothyroidism (SCH) on the development of postoperative atrial fibrillation (AF) in patients undergoing aortic valve replacement surgery with extracorporeal circulation. Methods A prospective study in a tertiary hospital between July 2005 and December 2013 in which all patients undergoing aortic valve replacement with no other valve surgery were consecutively included. Patients who were in preoperative sinus rhythm were selected and they underwent thyroxine (T4) and thyroid-stimulating hormone determination in the month before surgery. Postoperative AF was defined as the development of AF during hospital admittance. Descriptive analysis and binary logistic regression were performed for the target variable. Results A total of 467 patients were studied, with 35 cases of SCH. The incidence of postoperative AF was 57% in the group with SCH versus 30.3% (p = 0.001) in the group without hypothyroidism, without significant differences in other postoperative complications. In the logistic regression analysis, the independent predictors of postoperative AF were SCH, age, and aortic clamping time. SCH multiplies the odds ratio of postoperative AF by 3.14 (95% confidence interval: 1.24-7.96). Conclusion SCH behaves like a risk factor for the development of postoperative AF in patients undergoing aortic valve replacement with extracorporeal circulation. Other studies are needed to determine whether preoperative T4 replacement therapy and/or more aggressive AF prophylaxis can prevent this complication in patients undergoing aortic valve replacement. PMID- 26121380 TI - Prolonged Activated Clotting Time after Protamine Administration Does Not Indicate Residual Heparinization after Cardiopulmonary Bypass in Pediatric Open Heart Surgery. AB - BACKGROUND: In open heart surgery, heparinization is commonly neutralized using an empirical heparin:protamine ratio ranging between 1:1 and 1:1.5. However, these ratios may result in protamine overdose that should be avoided for its negative side effects on the coagulation system. This study aimed to indicate the appropriate treatment for prolonged activated clotting time (ACT) after protamine administration following cardiopulmonary bypass (CPB) in pediatric open heart surgery by investigating the underlying reasons for it. METHODS: Twenty-seven children (<10 kg) undergoing open heart surgery were included. Heparin was administered only before CPB (400 IU/kg) and in the pump priming volume for CPB (2,000 IU) and was neutralized by 1:1 protamine after CPB. The blood heparin concentration was measured using anti-Xa assay. ACT and blood concentrations of heparin, coagulation factors, thrombin-antithrombin complex, and prothrombin fragment 1 + 2 were assessed. A rotational thromboelastometry (ROTEM; Tem International GmbH, Munchen, Bayern, Germany) was used to confirm the coagulation status and residual heparin after protamine administration. RESULTS: Anti-Xa assay showed that there is no residual heparin in the blood after 1:1 protamine administration. Nevertheless, ACT (128.89 +/- 3.09 seconds before heparin administration) remained prolonged (177.14 +/- 5.43 seconds at 10 minutes after protamine, 182.00 +/- 5.90 seconds at 30 minutes after protamine). The blood concentrations of coagulation factors were significantly lower than those before heparin administration (p < 0.01). The low FIBTEM MCF of ROTEM (4.43 +/- 0.32 mm) at 10 minutes after protamine indicated low fibrinogen concentration. CONCLUSION: Prolonged ACT after heparin neutralization by 1:1 protamine administration does not necessarily indicate residual heparin, but low blood concentrations of coagulation factors should be considered as a reason as well. Accordingly, supply of coagulation factors instead of additional protamine should be considered. PMID- 26121381 TI - Attention-deficit/hyperactivity disorder (ADHD) symptoms, anxiety symptoms, and executive functioning in emerging adults. AB - The current study examined attention-deficit/hyperactivity disorder (ADHD) and anxiety symptoms in relation to self-reported executive functioning deficits in emerging adults. College students (N = 421; ages 17-25; 73.1% female) completed self-reports of ADHD, anxiety, and executive functioning in a laboratory setting. Structural equation modeling analyses revealed that self-reported executive functioning deficits were significantly related to all 3 symptom domains. Executive functioning deficits were most strongly related to inattention followed by hyperactivity/impulsivity and anxiety. Analyses based on clinical groups revealed that groups with ADHD and comorbid anxiety showed greater deficits on self-regulation of emotion and self-organization/problem solving than those with ADHD only or anxiety only. Groups with ADHD showed greater deficits with self motivation and self-restraint than those with anxiety only. All clinical groups differed from a control group on executive functioning deficits. Overall, anxiety symptoms appear to be associated with college students' self-reported executive functioning deficits above and beyond relationships with ADHD symptomatology. Further, those with ADHD and anxiety appear to show increased difficulties with self-regulation of emotion and self-organization/problem solving, a domain which appears to overlap substantially with working memory. Future studies should seek to replicate our findings with a clinical population, utilize both report-based and laboratory task measures of executive functioning, and integrate both state and trait anxiety indices into study designs. Finally, future studies should seek to determine how executive functioning deficits can be best ameliorated in emerging adults with ADHD and anxiety. (PsycINFO Database Record PMID- 26121382 TI - Measurement invariance of the Schizotypal Personality Questionnaire in Asian, Pacific Islander, White, and multiethnic populations. AB - The Schizotypal Personality Questionnaire (SPQ; Raine, 1991) is one of the most commonly used self-report measures of schizotypal personality traits. Previous work has found that the SPQ has a 3- or 4-factor structure, but most of this work was with White participants. Little is known about the psychometric properties of the scale in Pacific Islander populations, and some evidence suggests scores may differ between White and Asian participants. The current study included 398 Asian, 293 White, 159 Pacific Islander, and 308 multiethnic nonclinical participants. A 4-factor model fit the data well, and this factor structure displayed configural and metric invariance, suggesting that the factor structure is the same across these diverse groups. However, results provided mixed evidence for scalar invariance, suggesting the scale may lack scalar invariance in these populations. Follow-up analyses revealed that the questionable scalar invariance was related to the intercepts of the Ideas of Reference and Suspiciousness subscales in the White sample. This suggests that mean comparisons among ethnic groups involving the Ideas of Reference and Suspiciousness subscales are not appropriate. PMID- 26121383 TI - Does response distortion statistically affect the relations between self-report psychopathy measures and external criteria? AB - Given that psychopathy is associated with narcissism, lack of insight, and pathological lying, the assumption that the validity of self-report psychopathy measures is compromised by response distortion has been widespread. We examined the statistical effects (moderation, suppression) of response distortion on the validity of self-report psychopathy measures in the statistical prediction of theoretically relevant external criteria (i.e., interview measures, laboratory tasks) in a large sample of offenders (N = 1,661). We conducted 378 moderation and 378 suppression analyses to examine the response distortion hypothesis. The substantial majority of analyses (97% moderation, 83% suppression) offered no support for this hypothesis. Nevertheless, suppression analyses revealed consistent evidence that controlling for response distortion slightly increased the relations between the fearless dominance and coldheartedness features of psychopathy and maladaptive outcomes. Our findings are largely inconsistent with the popular notion that the validity of self-report psychopathy measures is markedly diminished by response distortion. Further research is necessary to determine whether these findings generalize to other populations or contexts. PMID- 26121384 TI - Compliance on neuropsychological performance validity testing in patients with borderline personality disorder. AB - Complaints of cognitive dysfunction are common in patients with borderline personality disorder (BPD), and they are often accompanied by deficits on neuropsychological testing. Prior studies of BPD, however, did not evaluate compliance on neuropsychological performance validity testing, which could partially account for cognitive deficits observed in patients. The aims of the current study were to evaluate the frequency at which patients with BPD show less than adequate compliance on performance validity testing, and whether patients showing less compliance perform lower on standardized neuropsychological measures. Fifty outpatients with BPD completed the Victoria Symptom Validity Test, a 2-alternative, forced-choice recognition test as part of a larger neuropsychological test battery for research on cognitive functioning in BPD. As a group, patients with BPD made more errors and had longer response latencies on seemingly difficult items as compared to healthy individuals. Based on established guidelines for interpretation of performances on the Victoria Symptom Validity Test, 2% of the sample was classified as probably not compliant, 10% questionably compliant, and 88% compliant. Patients with questionably or probably not compliant performances had lower estimated premorbid intellectual functioning and displayed poorer response control on neuropsychological testing than compliant patients. These findings highlight the value of incorporating performance validity testing in neuropsychological studies of patients with BPD and suggest that prior research on the disorder should be interpreted with caution because the results may not be based on valid performances. PMID- 26121385 TI - Psychometric properties of Glasgow Sleep Effort Scale in Portuguese language. AB - Sleep effort is generally defined as the attempt to force and induce sleep in a voluntary manner. This study aimed to document the psychometric properties of a brief measure of sleep effort--the Glasgow Sleep Effort Scale--in its European (Portuguese) version using a large sample (N = 2,995). The results supported the good internal consistency of the overall scale scores (alpha = .79). Potential construct validity was evaluated with various methods, including criterion validity. There was also a convergent validity indicator. Principal components analysis revealed a 1-dimensional structure that accounted for 45% of the total variance. This preliminary study suggests that this Portuguese version of the Glasgow Sleep Effort Scale is a measure of sleep behavior suitable for research and clinical purposes. However, more studies are needed, particularly with clinical groups. PMID- 26121386 TI - Positive and negative item wording and its influence on the assessment of callous unemotional traits. AB - This study examined the item functioning of the Inventory of Callous-Unemotional Traits (ICU) in an ethnically diverse sample 1,190 of first-time justice-involved adolescents (mean age = 15.28 years, SD = 1.29). On elimination of 2 items, the total ICU score provided a reliable (internally consistent and stable) and valid (correlated with and predictive of measures of empathy, school conduct problems, delinquency, and aggression) continuous measure of callous and unemotional (CU) traits. A shortened, 10-item version of the total scale, developed from item response theory (IRT) analyses, appeared to show psychometric properties similar to those of the full ICU and, thus, could be used as an abbreviated measure of CU traits. Finally, item analyses and tests of validity suggested that the factor structure of the ICU reported in a large number of past studies could reflect method variance related to the ICU, including equal numbers of positively and negatively worded items. Specifically, positively worded items (i.e., items for which higher ratings are indicative of higher levels of CU traits) were more likely to be rated in the lower response categories, showed higher difficulty levels in IRT analyses (i.e., discriminated best at higher levels of CU traits), and were more highly correlated with measures of antisocial and aggressive behavior. On the basis of these findings, we recommend using the total ICU as a continuous measure of CU traits and do not recommend continued use of the subscale structure that has been reported in multiple past studies. PMID- 26121387 TI - Recovery Assessment Scale: Testing validity with Portuguese community-based mental health organization users. AB - The aim of the present study was to develop the Portuguese version of the Recovery Assessment Scale (RAS-P), and to assess the validity of the findings using the revised test, with 213 users from 5 nonprofit community-based mental health organizations. Participants in the assessment completed a self-reported survey investigating their sense of personal recovery, personal empowerment, capabilities achievement, psychiatric symptoms' frequency, and demographic data. Evidence from exploratory and confirmatory factor analyses using the 24-item version of the test, validated a 4-factor structure for the RAS-P model based on the dimensions of Personal Goals and Hope, Managing Help Needs, Supportive Interpersonal Relationships, and Life Beyond Symptoms, consistent with components of the recovery process. Convergent and discriminant validity was also achieved using bivariate correlation coefficients among the 4 subscales' scores, between the overall scale and the subscales, and in relation to external variables. Findings allowed for the interpretation that the RAS-P is measuring a particular psychological construct, which is different from symptoms of the mental illness. A hypothesized significant association with personal empowerment and with capabilities achievement was demonstrated. Positive association was also found between participants' use of recovery-oriented services such as independent housing or supported employment programs. The RAS-P scores also revealed excellent internal consistency for the overall scale (alpha = .90), and good consistency for the subscales (>.75), which attest to its precision in measurement. In conclusion, the study proved the RAS-P a reliable and useful tool in the context of the community mental health practice. PMID- 26121388 TI - Measuring executive function in early childhood: A case for formative measurement. AB - This study tested whether individual executive function (EF) tasks were better characterized as formative or reflective indicators of the latent construct of EF. EF data that were collected as part of the Family Life Project (FLP), a prospective longitudinal study of families who were recruited at the birth of a new child (N = 1,292), when children were 3, 4, and 5 years old. Vanishing tetrad tests were used to test the relative fit of models in which EF tasks were used as either formative or reflective indicators of the latent construct of EF in the prediction of intellectual ability (at Age 3), attention-deficit hyperactivity disorder symptoms (at Ages 3 to 5 years), and academic achievement (at kindergarten). Results consistently indicated that EF tasks were better represented as formative indicators of the latent construct of EF. Next, individual tasks were combined to form an overall measure of EF ability in ways generally consistent with formative (i.e., creating a composite mean score) and reflective (i.e., creating an EF factor score) measurement. The test-retest reliability and developmental trajectories of EF differed substantially, depending on which overall measure of EF ability was used. In general, the across time stability of EF was markedly higher when represented as a factor score versus composite score. Results are discussed with respect to the ways in which the statistical representation of EF tasks can exert a large impact on inferences regarding the developmental causes, course, and consequences of EF. PMID- 26121390 TI - Measuring the Performance of Health Insurance Marketplaces. PMID- 26121389 TI - Antigen-Specific versus Non-Antigen-Specific Immunoadsorption in ABO-Incompatible Renal Transplantation. AB - INTRODUCTION: ABO-incompatible (ABOi) renal transplantation (RTx) from living donors is an established procedure to expand the donor pool for patients with end stage renal disease. Immunoadsorption (IA) is a standard procedure for the removal of preformed antibodies against the allograft. In this study, antigen specific and non-antigen-specific IA in ABOi RTx were compared. PATIENTS AND METHODS: 10 patients underwent antigen-specific IA (Glycosorb group) and 13 patients non-antigen-specific IA (Immunosorba group). The effects of both procedures regarding antibody reduction, number of treatments, complications, costs, as well as the allograft function and patient survival were compared between both groups. RESULTS: Although the IgG levels were reduced equally by both procedures (p=0.82), the reduction of the IgM level was more effective in the Glycosorb group (p=0.0172). Patients in both groups required a median number of 6 IA before ABOi RTx. Allograft function at one year after AB0i RTx was similar in both groups (estimated glomerular filtration rate: 66 vs. 64 ml/min/1.73m2 respectively), with a death-censored graft survival of 90.0% and 92.3% respectively. Complication rates did not differ between procedures. Due to the reuse of non-antigen-specific Immunosorba columns, costs were considerably lower in this group; however, the use of the Immunosorba-based IA was less time efficient. CONCLUSION: Considering upcoming alternatives as simultaneous performance of dialysis and IA or a possible reuse of Glycosorb columns, this might become less relevant in the future. PMID- 26121391 TI - COX inhibition enhances inflammatory immune cell infiltration in UV-irradiated human skin: implications for the treatment of sunburn. PMID- 26121392 TI - South Asians and Anglo Australians with heart disease in Australia. AB - OBJECTIVES: The aim of the present study was to determine cardiovascular disease (CVD) risk tactors and compare presentation and severity of ischaemic heart disease (IHD) among South Asians (SAs) and Anglo Australians (AAs). METHODS: A retrospective clinical case audit was conducted at a public tertiary hospital. The study population included SA and AA patients hospitalised for IHD. Baseline characteristics, evidence of diabetes and other CVD risk factors were recorded. Angiography data were also included to determine severity, and these were assessed using a modified Gensini score. RESULTS: SAs had lower mean (+/- s.d.) age of IHD presentation that AAs (52 +/- 9 vs 55 +/- 9 years, respectively; P = 0.02), as well as a lower average body mass index (BMI; 26 +/- 4 vs 29 +/- 6 kg/m2, respectively; P = 0.005), but a higher prevalence of type 2 diabetes (57% vs 31%, respectively; P = 0.00 1). No significant differences were found in coronary angiography parameters. There were no significant differences in the median (interquartile range) Gensini score between SAs and AAs (43.5 (27-75) vs 44 (26.5-68.5), respectively), median vessel score (1 (1-2) vs 2 (1-3), respectively) or multivessel score (37% (33/89) vs 54% (22/41), respectively). CONCLUSIONS: The findings show that in those with established IHD, cardiovascular risk factors, such as age at onset and BMI, differ between SAs and AAs and these differences should be considered in the prevention and management of IHD. PMID- 26121393 TI - Post-harvest light treatment increases expression levels of recombinant proteins in transformed plastids of potato tubers. AB - Plastid genetic engineering represents an attractive system for the production of foreign proteins in plants. Although high expression levels can be achieved in leaf chloroplasts, the results for non-photosynthetic plastids are generally discouraging. Here, we report the expression of two thioredoxin genes (trx f and trx m) from the potato plastid genome to study transgene expression in amyloplasts. As expected, the highest transgene expression was detected in the leaf (up to 4.2% of TSP). The Trx protein content in the tuber was approximately two to three orders of magnitude lower than in the leaf. However, we demonstrate that a simple post-harvest light treatment of microtubers developed in vitro or soil-grown tubers induces up to 55 times higher accumulation of the recombinant protein in just seven to ten days. After the applied treatment, the Trx f levels in microtubers and soil-grown tubers increased to 0.14% and 0.11% of TSP, respectively. Moreover, tubers stored for eight months maintained the capacity of increasing the foreign protein levels after the light treatment. Post-harvest cold induction (up to five times) at 4 degrees C was also detected in microtubers. We conclude that plastid transformation and post-harvest light treatment could be an interesting approach for the production of foreign proteins in potato. PMID- 26121394 TI - Lactobacillus kunkeei YB38 from honeybee products enhances IgA production in healthy adults. AB - AIMS: To identify lactic acid bacterial isolates, which promote immunoglobulin A (IgA) production in honeybee products and honeybees (Apis mellifera). METHODS AND RESULTS: Pyrosequencing analysis of the microbiota of honeybee products and honeybees revealed the predominance of Lactobacillus kunkeei in honey, bee pollen, bee bread and royal jelly. Lactobacillus kunkeei was isolated from bee pollen, bee bread and honey stomach, and its effect on IgA production was evaluated in vitro. Heat-killed YB38 and YB83 isolates from bee pollen promoted IgA production in mouse Peyer's Patch cells and had little mitogenic activity or effect on IL-2 production in mouse spleen cells in comparison with Listeria monocytogenes, which does exhibit mitogen activity. A pilot study in 11 healthy adults showed that 4-week intake of 1000 mg day(-1) heat-killed YB38 increased secretory IgA (SIgA) concentrations and secretion in saliva with no adverse effects. CONCLUSION: Heat-killed Lact. kunkeei YB38 from bee pollen increases IgA production and may safely improve immune responsiveness. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of microbiota analysis of royal jelly and the immune efficacy of Lact. kunkeei from honeybee products in humans. PMID- 26121395 TI - Iridium-Catalysed ortho-Directed Deuterium Labelling of Aromatic Esters--An Experimental and Theoretical Study on Directing Group Chemoselectivity. AB - Herein we report a combined experimental and theoretical study on the deuterium labelling of benzoate ester derivatives, utilizing our developed iridium N heterocyclic carbene/phosphine catalysts. A range of benzoate esters were screened, including derivatives with electron-donating and -withdrawing groups in the para- position. The substrate scope, in terms of the alkoxy group, was studied and the nature of the catalyst counter-ion was shown to have a profound effect on the efficiency of isotope exchange. Finally, the observed chemoselectivity was rationalized by rate studies and theoretical calculations, and this insight was applied to the selective labelling of benzoate esters bearing a second directing group. PMID- 26121396 TI - Redox-Active Profile Characterization of Remirea maritima Extracts and Its Cytotoxic Effect in Mouse Fibroblasts (L929) and Melanoma (B16F10) Cells. AB - Remirea maritima is a tropical plant with a reticulated root system belonging to the family Cyperaceae, also known to have biologically active secondary metabolites. However, very few data on R. maritima's biological actions are available and there are no reports regarding the redox-active profile of this plant. In this study, we examined the total phenolic content of Remirea maritima hydroalcoholic (RMHA) extracts, redox properties against different reactive species generated in vitro and their cytotoxic effect against fibroblasts (L929) and melanoma (B16F10) cells. Total reactive antioxidant potential index (TRAP) and total antioxidant reactivity (TAR) results revealed that RMHA at all concentrations tested showed significant antioxidant capacity. RMHA was also effective against hydroxyl radical formation, reduction of Fe3+ to Fe2+ and in scavenging nitric oxide (NO) radicals. In vitro, the level of lipid peroxidation was reduced by RMHA extract and the data showed significant oxidative damage protection. The RMHA cytotoxicity was evaluated by a neutral red assay in fibroblast (L929) and melanome (B16F10) cells. The obtained results showed that the RMHA (40 and 80 ug/mL, respectively) reduced 70% of the viable cells. In conclusion, this study represents the first report regarding the antioxidant and anti-proliferative potential of R. maritima against B16F10 melanoma cells. PMID- 26121397 TI - Transport of Twelve Coumarins from Angelicae Pubescentis Radix across a MDCK pHaMDR Cell Monolayer-An in Vitro Model for Blood-Brain Barrier Permeability. AB - Angelicae Pubescentis Radix (APR), a widely used traditional Chinese medicine, is reported to have central nervous system activities. The purpose of this study was to characterize the blood-brain barrier permeability of twelve coumarins from APR including umbelliferone (1), osthol (2), scopoletin (3), peucedanol (4), ulopterol (5), angepubebisin (6), psoralen (7), xanthotoxin (8), bergapten (9), isoimperatorin (10), columbianadin (11), and columbianetin acetate (12) with an in vitro model using a MDCK-pHaMDR cell monolayer. The cell monolayer was validated to be suitable for the permeation experiments. The samples' transports were analyzed by high performance liquid chromatography and their apparent permeability coefficients (Papp) were calculated. According to the Papp value, most coumarins could be characterized as well-absorbed compounds except for 4, 10 and 11 which were moderately absorbed ones, in concentration-dependent and time dependent manners. The results of P-glycoprotein (P-gp) inhibitor (verapamil) experiments showed that the transport of coumarin 4 was affected by the transport protein P-gp. Sigmoid functions between permeability log(Papp AP-BL*MW0.5) and log D (at pH 7.4) were established to analyze the structure-activity relationship of coumarins. The results provide useful information for discovering the substance basis for the central nervous system activities of APR, and predicting the permeability of other coumarins through BBB. PMID- 26121398 TI - The Emergence of Quinone Methides in Asymmetric Organocatalysis. AB - Quinone methides (QMs) are highly reactive compounds that have been defined as "elusive" intermediates, or even as a "synthetic enigma" in organic chemistry. Indeed, there were just a handful of examples of their utilization in catalytic asymmetric settings until some years ago. This review collects organocatalytic asymmetric reactions that employ QMs as substrates and intermediates, from the early examples, mostly based on stabilized QMs bearing specific substitution patterns, to more recent contributions, which have dramatically expanded the scope of QM chemistry. In fact, it was only very recently that the generation of QMs in situ through strategies compatible with organocatalytic methodologies has been realized. This tactic has finally opened the gate to the full exploitation of these unstable intermediates, leading to a series of remarkable disclosures. Several types of synthetically powerful asymmetric addition and cycloaddition reactions, applicable to a broad range of QMs, are now available. PMID- 26121399 TI - Overexpression of Rat Neurons Nitric Oxide Synthase in Rice Enhances Drought and Salt Tolerance. AB - Nitric oxide (NO) has been shown to play an important role in the plant response to biotic and abiotic stresses in Arabidopsis mutants with lower or higher levels of endogenous NO. The exogenous application of NO donors or scavengers has also suggested an important role for NO in plant defense against environmental stress. In this study, rice plants under drought and high salinity conditions showed increased nitric oxide synthase (NOS) activity and NO levels. Overexpression of rat neuronal NO synthase (nNOS) in rice increased both NOS activity and NO accumulation, resulting in improved tolerance of the transgenic plants to both drought and salt stresses. nNOS-overexpressing plants exhibited stronger water holding capability, higher proline accumulation, less lipid peroxidation and reduced electrolyte leakage under drought and salt conditions than wild rice. Moreover, nNOS-overexpressing plants accumulated less H2O2, due to the observed up-regulation of OsCATA, OsCATB and OsPOX1. In agreement, the activities of CAT and POX were higher in transgenic rice than wild type. Additionally, the expression of six tested stress-responsive genes including OsDREB2A, OsDREB2B, OsSNAC1, OsSNAC2, OsLEA3 and OsRD29A, in nNOS-overexpressing plants was higher than that in the wild type under drought and high salinity conditions. Taken together, our results suggest that nNOS overexpression suppresses the stress enhanced electrolyte leakage, lipid peroxidation and H2O2 accumulation, and promotes proline accumulation and the expression of stress-responsive genes under stress conditions, thereby promoting increased tolerance to drought and salt stresses. PMID- 26121400 TI - A detection advantage for facial threat in the absence of anger. AB - Quickly and accurately perceiving the potential for aggression in others is adaptive and beneficial for self-protection. Superior detection of facial threat is demonstrated by studies in which transient threat indices (i.e., angry expressions) are identified more efficiently than are transient approach indices (i.e., happy expressions). Not all signs of facial threat are temporary, however: Persistent, biologically based craniofacial attributes (e.g., low eyebrow ridge) are also associated with a perceived propensity for aggression. It remains unclear whether such static properties of the face elicit comparable attentional biases. We used a novel visual search task of faces for the present study that lacked explicit displays of emotion, but varied on perceived threat via manipulated craniofacial structure. A search advantage for threatening facial elements surfaced, suggesting that efficient detection of threat is not limited to the perception of anger, but rather extends to more latent facial signals of aggressive potential. Although all stimuli were primarily identified as emotionally neutral, thus confirming that the effect does not require emotional content, individual variation in the perception of structurally threatening faces as angry was associated with a greater detection advantage. These results indicate that attributing anger to objectively emotionless faces may serve as a mechanism for their heightened salience and influence important facets of social perception and interaction. PMID- 26121401 TI - The integration of care for mental health, substance abuse, and other behavioral health conditions into primary care: executive summary of an American College of Physicians position paper. AB - Behavioral health care includes care for patients around mental health and substance abuse conditions, health behavior change, life stresses and crises, and stress-related physical symptoms. Mental and substance use disorders alone are estimated to surpass all physical diseases as a major cause of worldwide disability by 2020. The literature recognizes the importance of the health care system effectively addressing behavioral health conditions. Recently, there has been a call for the use of the primary care delivery platform and the related patient-centered medical home model to effectively address these conditions. This position paper focuses on the issue of better integration of behavioral health into the primary care setting. It provides an environmental scan of the current state of conditions included in the concept of behavioral health and examines the arguments for and barriers to increased integration into primary care. It also examines various approaches of integrated care delivery and offers a series of policy recommendations that are based on the reviewed information and evidence to inform the actions of the American College of Physicians and its members regarding advocacy, research, and practice. PMID- 26121402 TI - Longitudinal Associations Between Neighborhood Physical and Social Environments and Incident Type 2 Diabetes Mellitus: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - IMPORTANCE: Neighborhood environments may influence the risk for developing type 2 diabetes mellitus (T2DM), but, to our knowledge, no longitudinal study has evaluated specific neighborhood exposures. OBJECTIVE: To determine whether long term exposures to neighborhood physical and social environments, including the availability of healthy food and physical activity resources and levels of social cohesion and safety, are associated with incident T2DM during a 10-year period. DESIGN, SETTING, AND PARTICIPANTS: We used data from the Multi-Ethnic Study of Atherosclerosis, a population-based cohort study of adults aged 45 to 84 years at baseline (July 17, 2000, through August 29, 2002). A total of 5124 participants free of T2DM at baseline underwent 5 clinical follow-up examinations from July 17, 2000, through February 4, 2012. Time-varying measurements of neighborhood healthy food and physical activity resources and social environments were linked to individual participant addresses. Neighborhood environments were measured using geographic information system (GIS)- and survey-based methods and combined into a summary score. We estimated hazard ratios (HRs) of incident T2DM associated with cumulative exposure to neighborhood resources using Cox proportional hazards regression models adjusted for age, sex, income, educational level, race/ethnicity, alcohol use, and cigarette smoking. Data were analyzed from December 15, 2013, through September 22, 2014. MAIN OUTCOMES AND MEASURES: Incident T2DM defined as a fasting glucose level of at least 126 mg/dL or use of insulin or oral antihyperglycemics. RESULTS: During a median follow-up of 8.9 years (37,394 person-years), 616 of 5124 participants (12.0%) developed T2DM (crude incidence rate, 16.47 [95% CI, 15.22-17.83] per 1000 person-years). In adjusted models, a lower risk for developing T2DM was associated with greater cumulative exposure to indicators of neighborhood healthy food (12%; HR per interquartile range [IQR] increase in summary score, 0.88 [95% CI, 0.79-0.98]) and physical activity resources (21%; HR per IQR increase in summary score, 0.79 [95% CI, 0.71-0.88]), with associations driven primarily by the survey exposure measures. Neighborhood social environment was not associated with incident T2DM (HR per IQR increase in summary score, 0.96 [95% CI, 0.88-1.07]). CONCLUSIONS AND RELEVANCE: Long-term exposure to residential environments with greater resources to support physical activity and, to a lesser extent, healthy diets was associated with a lower incidence of T2DM, although results varied by measurement method. Modifying neighborhood environments may represent a complementary, population-based approach to prevention of T2DM, although further intervention studies are needed. PMID- 26121403 TI - Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. AB - N(6)-methyladenosine (m6A) is the most abundant modified base in eukaryotic mRNA and has been linked to diverse effects on mRNA fate. Current mapping approaches localize m6A residues to transcript regions 100-200 nt long but cannot identify precise m6A positions on a transcriptome-wide level. Here we developed m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) and used it to demonstrate that antibodies to m6A can induce specific mutational signatures at m6A residues after ultraviolet light-induced antibody-RNA cross linking and reverse transcription. We found that these antibodies similarly induced mutational signatures at N(6),2'-O-dimethyladenosine (m6Am), a modification found at the first nucleotide of certain mRNAs. Using these signatures, we mapped m6A and m6Am at single-nucleotide resolution in human and mouse mRNA and identified small nucleolar RNAs (snoRNAs) as a new class of m6A containing non-coding RNAs (ncRNAs). PMID- 26121407 TI - ASSOCIATION BETWEEN AQUEOUS HUMOR CXC MOTIF CHEMOKINE LIGAND 13 LEVELS AND SUBFOVEAL CHOROIDAL THICKNESS IN NORMAL OLDER SUBJECTS. AB - PURPOSE: To investigate the association of subfoveal choroidal thickness with intraocular inflammatory cytokines and chemokines. METHODS: The subjects consisted of 76 eyes of consecutive cataract patients at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between September 2010 and August 2012. In addition, two autopsy eyes from elderly males were used for immunohistochemical study. Subfoveal choroidal thickness was measured using spectral domain optical coherence tomography before cataract surgery. At the beginning of cataract surgery, a sample of undiluted aqueous humor was manually aspirated and the concentrations of the following cytokines were determined using a multiplex cytokine assay: IP-10, MCP-1, MMP-9, IL-6, IL-10, CXCL1, CXCL12, CXCL13, and CCL11. The association of subfoveal choroidal thickness with intraocular cytokine concentration was analyzed. Expression of CXCL13 was examined in autopsy eyes. RESULTS: Among these factors, higher concentration of CXCL13 was associated with thicker choroid. In particular, multiple regression analysis showed that the concentration of CXCL13 was associated with subfoveal choroidal thickness (P = 0.001), independently of axial length (P = 0.049). By immunostaining, CXCL13 was clearly detected in choroidal endothelial cells. CONCLUSION: Aqueous humor concentration of CXCL13 is correlated with subfoveal choroidal thickness in normal subjects. PMID- 26121404 TI - Assembly and diploid architecture of an individual human genome via single molecule technologies. AB - We present the first comprehensive analysis of a diploid human genome that combines single-molecule sequencing with single-molecule genome maps. Our hybrid assembly markedly improves upon the contiguity observed from traditional shotgun sequencing approaches, with scaffold N50 values approaching 30 Mb, and we identified complex structural variants (SVs) missed by other high-throughput approaches. Furthermore, by combining Illumina short-read data with long reads, we phased both single-nucleotide variants and SVs, generating haplotypes with over 99% consistency with previous trio-based studies. Our work shows that it is now possible to integrate single-molecule and high-throughput sequence data to generate de novo assembled genomes that approach reference quality. PMID- 26121406 TI - Protein structure determination by combining sparse NMR data with evolutionary couplings. AB - Accurate determination of protein structure by NMR spectroscopy is challenging for larger proteins, for which experimental data are often incomplete and ambiguous. Evolutionary sequence information together with advances in maximum entropy statistical methods provide a rich complementary source of structural constraints. We have developed a hybrid approach (evolutionary coupling-NMR spectroscopy; EC-NMR) combining sparse NMR data with evolutionary residue-residue couplings and demonstrate accurate structure determination for several proteins 6 41 kDa in size. PMID- 26121405 TI - Assessment of a method to characterize antibody selectivity and specificity for use in immunoprecipitation. AB - Antibodies are used in multiple cell biology applications, but there are no standardized methods to assess antibody quality-an absence that risks data integrity and reproducibility. We describe a mass spectrometry-based standard operating procedure for scoring immunoprecipitation antibody quality. We quantified the abundance of all the proteins in immunoprecipitates of 1,124 new recombinant antibodies for 152 chromatin-related human proteins by comparing normalized spectral abundance factors from the target antigen with those of all other proteins. We validated the performance of the standard operating procedure in blinded studies in five independent laboratories. Antibodies for which the target antigen or a member of its known protein complex was the most abundant protein were classified as 'IP gold standard'. This method generates quantitative outputs that can be stored and archived in public databases, and it represents a step toward a platform for community benchmarking of antibody quality. PMID- 26121408 TI - Correspondence. PMID- 26121410 TI - Mimicking enzymatic active sites on surfaces for energy conversion chemistry. AB - Metal-organic supramolecular chemistry on surfaces has matured to a point where its underlying growth mechanisms are well understood and structures of defined coordination environments of metal atoms can be synthesized in a controlled and reproducible procedure. With surface-confined molecular self-assembly, scientists have a tool box at hand which can be used to prepare structures with desired properties, as for example a defined oxidation number and spin state of the transition metal atoms within the organic matrix. From a structural point of view, these coordination sites in the supramolecular structure resemble the catalytically active sites of metallo-enzymes, both characterized by metal centers coordinated to organic ligands. Several chemical reactions take place at these embedded metal ions in enzymes and the question arises whether these reactions also take place using metal-organic networks as catalysts. Mimicking the active site of metal atoms and organic ligands of enzymes in artificial systems is the key to understanding the selectivity and efficiency of enzymatic reactions. Their catalytic activity depends on various parameters including the charge and spin configuration in the metal ion, but also on the organic environment, which can stabilize intermediate reaction products, inhibits catalytic deactivation, and serves mostly as a transport channel for the reactants and products and therefore ensures the selectivity of the enzyme. Charge and spin on the transition metal in enzymes depend on the one hand on the specific metal element, and on the other hand on its organic coordination environment. These two parameters can carefully be adjusted in surface confined metal-organic networks, which can be synthesized by virtue of combinatorial mixing of building synthons. Different organic ligands with varying functional groups can be combined with several transition metals and spontaneously assemble into ordered networks. The catalytically active metal centers are adequately separated by the linking molecules and constitute promising candiates for heterogeneous catalysts. Recent advances in synthesis, characterization, and catalytic performance of metal-organic networks are highlighted in this Account. Experimental results like structure determination of the networks, charge and spin distribution in the metal centers, and catalytic mechanisms for electrochemical reactions are presented. In particular, we describe the activity of two networks for the oxygen reduction reaction in a combined scanning tunneling microscopy and electrochemical study. The similarities and differences of the networks compared to metallo-enzymes will be discussed, such as the metal surface that operates as a geometric template and concomitantly functions as an electron reservoir, and how this leads to a new class of bioinspired catalysts. The possibility to create functional two-dimensional coordination complexes at surfaces taking inspiration from nature opens up a new route for the design of potent nanocatalyst materials for energy conversion. PMID- 26121409 TI - Green solvents in carbohydrate chemistry: from raw materials to fine chemicals. PMID- 26121411 TI - Failing to 'carry the people along'. PMID- 26121412 TI - Amino Acid Chirality and Ferrocene Conformation Guided Self-Assembly and Gelation of Ferrocene-Peptide Conjugates. AB - The self-assembly and gelation behavior of a series of mono- and disubstituted ferrocene (Fc)-peptide conjugates as a function of ferrocene conformation and amino acid chirality are described. The results reveal that ferrocene-peptide conjugates self-assemble into organogels by controlling the conformation of the central ferrocene core, through inter- versus intramolecular hydrogen bonding in the attached peptide chain(s). The chirality controlled assembling studies showed that two monosubstituted Fc conjugates FcCO-LFLFLA-OMe and FcCO-LFLFDA-OMe form gels with nanofibrillar network structures, whereas the other two diastereomers FcCO-DFLFLA-OMe and FcCO-LFDFLA-OMe exclusively produced straight nanorods and non-interconnected small fibers, respectively. This suggests the potential tuning of gelation behavior and nanoscale morphology by altering the chirality of constituted amino acids. The current study confirms the profound effect of diastereomerism and no influence of enantiomers on gelation. Correspondingly, the diastereomeric and enantiomeric Fc[CO-FFA-OMe]2 were constructed for the study of chirality-organized structures. PMID- 26121414 TI - Flexible guide-RNA design for CRISPR applications using Protospacer Workbench. PMID- 26121415 TI - Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. AB - CRISPR-Cas-mediated genome editing relies on guide RNAs that direct site-specific DNA cleavage facilitated by the Cas endonuclease. Here we report that chemical alterations to synthesized single guide RNAs (sgRNAs) enhance genome editing efficiency in human primary T cells and CD34(+) hematopoietic stem and progenitor cells. Co-delivering chemically modified sgRNAs with Cas9 mRNA or protein is an efficient RNA- or ribonucleoprotein (RNP)-based delivery method for the CRISPR Cas system, without the toxicity associated with DNA delivery. This approach is a simple and effective way to streamline the development of genome editing with the potential to accelerate a wide array of biotechnological and therapeutic applications of the CRISPR-Cas technology. PMID- 26121417 TI - Detection of Defect-Induced Magnetism in Low-Dimensional ZnO Structures by Magnetophotocurrent. AB - The detection of defect-induced magnetic order in single low-dimensional oxide structures is in general difficult because of the relatively small yield of magnetically ordered regions. In this work, the effect of an external magnetic field on the transient photocurrent measured after light irradiation on different ZnO samples at room temperature is studied. It has been found that a magnetic field produces a change in the relaxation rate of the transient photocurrent only in magnetically ordered ZnO samples. This rate can decrease or increase with field, depending on whether the magnetically ordered region is in the bulk or only at the surface of the ZnO sample. The phenomenon reported here is of importance for the development of magneto-optical low-dimensional oxides devices and provides a new guideline for the detection of magnetic order in low dimensional magnetic semiconductors. PMID- 26121416 TI - Macromolecular Crystallography for Synthetic Abiological Molecules: Combining xMDFF and PHENIX for Structure Determination of Cyanostar Macrocycles. AB - Crystal structure determination has long provided insight into structure and bonding of small molecules. When those same small molecules are designed to come together in multimolecular assemblies, such as in coordination cages, supramolecular architectures and organic-based frameworks, their crystallographic characteristics closely resemble biological macromolecules. This resemblance suggests that biomacromolecular refinement approaches be used for structure determination of abiological molecular complexes that arise in an aggregate state. Following this suggestion we investigated the crystal structure of a pentagonal macrocycle, cyanostar, by means of biological structure analysis methods and compared results to traditional small molecule methods. Cyanostar presents difficulties seen in supramolecular crystallography including whole molecule disorder and highly flexible solvent molecules sitting in macrocyclic and intermolecule void spaces. We used the force-field assisted refinement method, molecular dynamics flexible fitting algorithm for X-ray crystallography (xMDFF), along with tools from the macromolecular structure determination suite PHENIX. We found that a standard implementation of PHENIX, namely one without xMDFF, either fails to produce a solution by molecular replacement alone or produces an inaccurate structure when using generic geometry restraints, even at a very high diffraction data resolution of 0.84 A. The problems disappear when taking advantage of xMDFF, which applies an optimized force field to realign molecular models during phasing by providing accurate restraints. The structure determination for this model system shows excellent agreement with the small molecule methods. Therefore, the joint xMDFF-PHENIX refinement protocol provides a new strategy that uses macromolecule methods for structure determination of small molecules and their assemblies. PMID- 26121418 TI - Synthesis and Properties of the Heterospin (S1 = S2 = (1)/2) Radical-Ion Salt Bis(mesitylene)molybdenum(I) [1,2,5]Thiadiazolo[3,4-c][1,2,5]thiadiazolidyl. AB - Low-temperature interaction of [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazole (1) with MoMes2 (Mes = mesitylene/1,3,5-trimethylbenzene) in tetrahydrofuran gave the heterospin (S1 = S2 = (1)/2) radical-ion salt [MoMes2](+)[1](-) (2) whose structure was confirmed by single-crystal X-ray diffraction (XRD). The structure revealed alternating layers of the cations and anions with the Mes ligands perpendicular, and the anions tilted by 45 degrees , to the layer plane. At 300 K the effective magnetic moment of 2 is equal to 2.40 MUB (theoretically expected 2.45 MUB) and monotonically decreases with lowering of the temperature. In the temperature range 2-300 K, the molar magnetic susceptibility of 2 is well described by the Curie-Weiss law with parameters C and theta equal to 0.78 cm(3) K mol(-1) and -31.2 K, respectively. Overall, the magnetic behavior of 2 is similar to that of [CrTol2](+)[1](-) and [CrCp*2](+)[1](-), i.e., changing the cation [MAr2](+) 3d atom M = Cr (Z = 24) with weak spin-orbit coupling (SOC) to a 4d atom M = Mo (Z = 42) with stronger SOC does not affect macroscopic magnetic properties of the salts. For the XRD structure of salt 2, parameters of the Heisenberg spin-Hamiltonian were calculated using the broken-symmetry DFT and CASSCF approaches, and the complex 3D magnetic structure with both the ferromagnetic (FM) and antiferromagnetic (AF) exchange interactions was revealed with the latter as dominating. Salt 2 is thermally unstable and slowly loses the Mes ligands upon storage at ambient temperature. Under the same reaction conditions, interaction of 1 with MoTol2 (Tol = toluene) proceeded with partial loss of the Tol ligands to afford diamagnetic product. PMID- 26121419 TI - The Online Big Blue Test for Promoting Exercise: Health, Self-Efficacy, and Social Support. AB - BACKGROUND: Recent articles have documented the influence of self-efficacy and social support on exercising. Simultaneously, insulin use is also related to the perception of self-efficacy and social support in patients with diabetes. We combine these two ideas through the Big Blue Test experience in a social networking site and propose to analyze whether a change in blood sugar levels after completion of the Big Blue Test and insulin use are related to the perception of self-efficacy and social support in patients with diabetes. MATERIALS AND METHODS: To undergo the Big Blue Test, 3,926 participants voluntarily joined the Diabetes Hands Foundation. Responses were analyzed using descriptive analysis. RESULTS: The participants who reduced their blood glucose after exercise the least were those with lower self-efficacy and also with lower perceived social support. There seems to have been no relationship between changes in blood sugar level and the explicit intention of doing exercise in the future. Insulin-dependent participants demonstrated a lower perception of self efficacy and social support than non-insulin-dependent participants. CONCLUSIONS: Change in blood glucose level or being insulin-dependent or not do not explain completely a health behavior such as exercise. Hence, self-efficacy and social support have an impact on behavioral change such as exercise to become a habit in people with diabetes, and this experience through a social networking site is an important tool for this behavioral change. For exercise to become a habit in people with diabetes, it is necessary to consider not only the crucial physiological variables, but also those psychological variables that clearly have an impact on behavioral change. PMID- 26121420 TI - Acetylcholinesterase-Fc Fusion Protein (AChE-Fc): A Novel Potential Organophosphate Bioscavenger with Extended Plasma Half-Life. AB - Acetylcholinesterase (AChE) is the physiological target of organophosphate nerve agent compounds. Currently, the development of a formulation for prophylactic administration of cholinesterases as bioscavengers in established risk situations of exposure to nerve agents is the incentive for many efforts. While cholinesterase bioscavengers were found to be highly effective in conferring protection against nerve agent exposure in animal models, their therapeutic use is complicated by short circulatory residence time. To create a bioscavenger with prolonged plasma half-life, compatible with biotechnological production and purification, a chimeric recombinant molecule of HuAChE coupled to the Fc region of human IgG1 was designed. The novel fusion protein, expressed in cultured cells under optimized conditions, maintains its full enzymatic activity, at levels similar to those of the recombinant AChE enzyme. Thus, this novel fusion product retained its binding affinity toward BW284c5 and propidium, and its bioscavenging reactivity toward the organophosphate-AChE inhibitors sarin and VX. Furthermore, when administered to mice, AChE-Fc exhibits exceptional circulatory residence longevity (MRT of 6000 min), superior to any other known cholinesterase-based recombinant bioscavengers. Owing to its optimized pharmacokinetic performance, high reactivity toward nerve agents, and ease of production, AChE-Fc emerges as a promising next-generation organophosphate bioscavenger. PMID- 26121421 TI - Cu(II)-Dy(III) and Co(III)-Dy(III) based single molecule magnets with multiple slow magnetic relaxation processes in the Cu(II)-Dy(III) complex. AB - Two dinuclear Schiff-base complexes [Cu(II)Dy(III)] and [Co(III)Dy(III)] have been synthesized and structurally characterized. The AC susceptibility measurements taken at BDC = 0.2 T show a slow magnetic relaxation typical for single-molecule magnets. Unusual is the presence of three relaxation branches in [Cu(II)Dy(III)]; the slowest (low-frequency) process possesses the barrier to spin reversal of U/kB = 2.8 K and an extrapolated relaxation time as slow as tau0 = 0.11 s. The intermediate-frequency process is typical for SMM of this class with U/kB = 122 K and tau0 = 9.9 * 10(-7) s; an onset of the high-frequency process is evidenced and this is the fastest. In contrast, the [Co(III)Dy(III)] complex free of exchange coupling exhibits only a single relaxation path with SMM parameters U/kB = 113 K and tau0 = 7.0 * 10(-9) s. PMID- 26121422 TI - Knockdown of Brm and Baf170, Components of Chromatin Remodeling Complex, Facilitates Reprogramming of Somatic Cells. AB - The SWI/SNF (SWItch/Sucrose NonFermentable or BAF, Brg/Brahma-associated factors) complexes are epigenetic modifiers of chromatin structure and undergo progressive changes in subunit composition during cellular differentiation. For example, in embryonic stem cells, esBAF contains Brg1 and Baf155, while their homologs, Brm and Baf170, are present in BAF of somatic cells. In this study, we sought to determine whether Brm and Baf170 play any roles in induced pluripotent stem cell (iPSC) reprogramming by using shRNA-mediated knockdown studies in the mouse model. We found that knocking down Brm during early, mid, and late stages (days 3, 6, and 9 after initial iPSC induction) and knocking down Baf170 during late stage (day 9) reprogramming improve the numbers of iPSC colonies formed. We further showed that inhibition of these somatic BAF components also promotes complete reprogramming of partially reprogrammed somatic cells (pre-iPSCs). Finally, we found that the expression of Brm and Baf170 during reprogramming was regulated by Jak/Stat3 activity. Taken together, these data suggest that inhibiting somatic BAF improves complete reprogramming by facilitating the activation of the pluripotency circuitry. PMID- 26121423 TI - Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis. AB - OBJECTIVE: There is a need to identify effective switch therapies for patients with relapsing-remitting multiple sclerosis (RRMS) who experience high disease activity despite receiving disease-modifying therapy (DMT). The objective of this study was to assess the efficacy of fingolimod versus placebo in patients with RRMS who had experienced high disease activity despite previously receiving DMT, using post hoc analyses of two phase 3 trials: FREEDOMS (NCT00289978) and FREEDOMS II (NCT00355134). RESEARCH DESIGN AND METHODS: Clinical and magnetic resonance imaging outcomes over 24 months were analyzed in patients from FREEDOMS and FREEDOMS II who had received treatment in the previous year and had: (1) >=1 relapse in the previous year and either >=1 gadolinium (Gd) enhancing T1 lesion or >=9 T2 lesions at baseline and/or (2) as many or more relapses in the year before baseline as in the previous year (as per fingolimod's EU label). MAIN OUTCOME MEASURES: The inclusion criteria were fulfilled by 249 and 257 patients in the fingolimod and placebo groups, respectively. Annualized relapse rates were reduced by 48% for fingolimod versus placebo (p < 0.001). Fingolimod reduced the risk of 3 month and 6 month confirmed disability progression by 34% (p = 0.031) and 45% (p = 0.016), respectively, versus placebo. Brain volume loss was reduced by 46% for fingolimod versus placebo (p < 0.001). The reduction in Gd-enhancing T1 lesion counts for fingolimod versus placebo was 65% (p < 0.001). Furthermore, fingolimod reduced the number of new or newly enlarged T2 lesions by 69% relative to placebo (p < 0.001). LIMITATION: The analyses are post hoc, but the population is specified by the European Medicines Agency in the label for fingolimod. CONCLUSIONS: Fingolimod demonstrated efficacy across all four key RRMS disease measures analyzed in patients with high disease activity despite previous DMT. PMID- 26121424 TI - Group II intron lariat: Structural insights into the spliceosome. AB - Group II introns are self-splicing catalytic RNAs found in bacteria and the organelles of fungi and plants. They are thought to share a common ancestor with the spliceosome, which catalyzes the removal of nuclear introns from pre-mRNAs in eukaryotes. Recent structural and biochemical evidence supports the hypothesis that the spliceosome has a catalytic RNA core homologous to that found in group II introns. The crystal structure of a eukaryotic group IIB intron was recently determined and reveals the architecture of a branched lariat RNA that is also formed by the spliceosome. Here we describe the active site components of this intron and propose a model for RNA splicing involving dynamic base triples in the catalytic triad. Based on this structure, we draw analogies to the U2/U6 snRNA pairing and RNA-protein interactions that form in the active site of the spliceosome. PMID- 26121425 TI - Calcifying pseudoneoplasm of the foramen magnum--Case report and review of the literature. AB - We present a case of a 29-year-old male with a calcifying pseudoneoplasm of the neuraxis (CAPNON) located in the region of the foramen magnum, treated successfully by complete resection. After a 2-year follow-up the patient remains recurrence free. Clinical and histopathological characterization of CAPNON is provided with special emphasis on the intraoperative and neuroradiological features of the lesion. PMID- 26121426 TI - Blood coagulation factor XIII-A subunit Val34Leu polymorphisms and intracerebral hemorrhage risk: A meta-analysis of case-control studies. AB - BACKGROUND: Previous studies investigating the association between factor XIII-A subunit (FXIII-A) Val34Leu polymorphisms and intracerebral hemorrhage (ICH) had provided inconsistent results and no large systematic review or meta-analysis had been conducted regarding this issue. METHODS: We conducted a meta-analysis to confirm whether the FXIII-A Val34Leu polymorphisms increased the risk of ICH. Relevant studies were identified from the Pubmed, Medline, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine Databases published up to September 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for FXIII-A Val34Leu polymorphisms and ICH were calculated in a fixed-effects model or a random-effects model when appropriate. We also carried out the stratified analyses and sensitivity analyses by region, source of control group, and sample size. RESULTS: Eight eligible studies were reviewed. As FXIII Val34Leu was absent or had a very low prevalence among East Asians, only six studies in Caucasians were analyzed, involving 564 cases and 1276 controls. Overall, the Leu allele of FXIII gene had a trend to slightly increased odds of having ICH, but there is no statistic significance (OR1.23, 95% CI 0.94-1.61, P = 0.13). The OR of genotypes Leu+(Leu/Leu or Leu/Val) for the risk of ICH was 1.21, 95% CI 0.98-1.50, P = 0.08. And the OR of recessive model genotypes was 1.53, 95% CI 0.81-2.88, P = 0.19. There was no difference of the association between the Leu allele of FXIII gene and risk of ICH in stratified analysis. CONCLUSIONS: Our meta-analysis suggests that there is no evidence for strong association between FXIII Val34Leu polymorphisms and ICH, but Leu allele of FXIII gene might slightly increase the risk of ICH in Caucasians. Since limited studies and subjects were included, larger scale association studies exploring the gene-gene interactions and gene environment interactions are necessary to further validate the association. PMID- 26121427 TI - Impact of hydrocarbons from a diesel fuel on the germination and early growth of subantarctic plants. AB - Special Antarctic Blend (SAB) is a diesel fuel dominated by aliphatic hydrocarbons that is commonly used in Antarctic and subantarctic regions. The past and present use of SAB fuel at Australia's scientific research stations has resulted in multiple spills, contaminating soils in these pristine areas. Despite this, no soil quality guidelines or remediation targets have been developed for the region, primarily due to the lack of established indigenous test species and subsequent biological effects data. In this study, twelve plant species native to subantarctic regions were collected from Macquarie Island and evaluated to determine their suitably for use in laboratory-based toxicity testing, using germination success and seedling growth (shoot and root length) as endpoints. Two soil types (low and high organic carbon (OC)) were investigated to reflect the variable OC content found in soils on Macquarie Island. These soils were spiked with SAB fuel and aged for 14 days to generate a concentration series of SAB contaminated soils. Exposure doses were quantified as the concentration of total petroleum hydrocarbons (TPH, nC9-nC18) on a soil dry mass basis. Seven species successfully germinated on control soils under laboratory conditions, and four of these species (Colobanthus muscoides Hook.f., Deschampsia chapmanii Petrie, Epilobium pendunculare A.Cunn. and Luzula crinita Hook.f.) showed a dose dependent inhibition of germination when exposed to SAB-contaminated soils. Contaminated soils with low OC were generally more toxic to plants than high organic carbon soils. Increasing soil-TPH concentrations significantly inhibited shoot and root growth, and root length was identified as the most sensitive endpoint. Although the test species were tolerant to SAB-contaminated soils in germination assays, development of early life stages (up to 28 days) were generally more sensitive indicator of exposure effects, and may be more useful endpoints for future testing. PMID- 26121428 TI - A switch-on MRI contrast agent for noninvasive visualization of methylmercury. AB - This communication presents the first Gd(III)-based T1 MRI contrast agent, o MeHgGad, for noninvasive visualization of CH3Hg(+). o-MeHgGad showed a relaxivity enhancement of 62% in the presence of 1 equiv. of CH3Hg(+). Moreover, a noticeable contrast enhancement was recorded in the liver, kidney, and intestine of mice exposed to CH3Hg(+). Thus, the newly designed contrast agent has the potential to be used for in vivo bio-imaging of CH3Hg(+) and could be useful for biomedical applications. PMID- 26121429 TI - Palladium-catalyzed oxalyl amide assisted direct ortho-alkynylation of arylalkylamine derivatives at delta and epsilon positions. AB - Palladium-catalyzed oxalyl amide directed ortho-alkynylation of arylalkylamine derivatives is reported for the first time. A wide variety of beta-arylethamine and gamma-arylpropamine derivatives are compatible with this protocol. This method provides a general means to synthesize substituted alkynylarylalkylamine derivatives, highlighting the ability of oxalyl amide in promoting C-H functionalization at unique delta and epsilon positions. PMID- 26121430 TI - A facile Pt catalyst regeneration process significantly improves the catalytic activity of Pt-organic composites for the O2 reduction reaction. AB - Combination of the "nano-size" effect and Cl(-) complexation ability causes massive electrodissolution of Pt under acidic conditions to promote the regeneration of Pt-organic composites and to significantly improve the catalytic performance of the O2 reduction reaction. PMID- 26121431 TI - Acute Effects of Deep Tissue Foam Rolling and Dynamic Stretching on Muscular Strength, Power, and Flexibility in Division I Linemen. AB - Behara, B and Jacobson, BH. Acute effects of deep tissue foam rolling and dynamic stretching on muscular strength, power, and flexibility in Division I linemen. J Strength Cond Res 31(4): 888-892, 2017-A recent strategy to increase sports performance is a self-massage technique called myofascial release using foam rollers. Myofascial restrictions are believed to be brought on by injuries, muscle imbalances, overrecruitment, and/or inflammation, all of which can decrease sports performance. The purpose of this study was to compare the acute effects of a single-bout of lower extremity self-myofascial release using a custom deep tissue roller (DTR) and a dynamic stretch protocol. Subjects consisted of NCAA Division 1 offensive linemen (n = 14) at a Midwestern university. All players were briefed on the objectives of the study and subsequently signed an approved IRB consent document. A randomized crossover design was used to assess each dependent variable (vertical jump [VJ] power and velocity, knee isometric torque, and hip range of motion was assessed before and after: [a] no treatment, [b] deep tissue foam rolling, and [c] dynamic stretching). Results of repeated-measures analysis of variance yielded no pretest to posttest significant differences (p > 0.05) among the groups for VJ peak power (p = 0.45), VJ average power (p = 0.16), VJ peak velocity (p = 0.25), VJ average velocity (p = 0.23), peak knee extension torque (p = 0.63), average knee extension torque (p = 0.11), peak knee flexion torque (p = 0.63), or average knee flexion torque (p = 0.22). However, hip flexibility was statistically significant when tested after both dynamic stretching and foam rolling (p = 0.0001). Although no changes in strength or power was evident, increased flexibility after DTR may be used interchangeably with traditional stretching exercises. PMID- 26121432 TI - Velocity Drives Greater Power Observed During Back Squat Using Cluster Sets. AB - This investigation compared the kinetics and kinematics of cluster sets (CLU) and traditional sets (TRD) during back squat in trained (RT) and untrained (UT) men. Twenty-four participants (RT = 12, 25 +/- 1 year, 179.1 +/- 2.2 cm, 84.6 +/- 2.1 kg; UT = 12, 25 +/- 1 year, 180.1 +/- 1.8 cm, 85.4 +/- 3.8 kg) performed TRD (4 * 10, 120-second rest) and CLU (4 * (2 * 5) 30 seconds between clusters; 90 seconds between sets) with 70% one repetition maximum, randomly. Kinematics and kinetics were sampled through force plate and linear position transducers. Resistance trained produced greater overall force, velocity, and power; however, similar patterns were observed in all variables when comparing conditions. Cluster sets produced significantly greater force in isolated repetitions in sets 1-3, while consistently producing greater force due to a required reduction in load during set 4 resulting in greater total volume load (CLU, 3302.4 +/- 102.7 kg; TRD, 3274.8 +/- 102.8 kg). Velocity loss was lessened in CLU resulting in significantly higher velocities in sets 2 through 4. Furthermore, higher velocities were produced by CLU during later repetitions of each set. Cluster sets produced greater power output for an increasing number of repetitions in each set (set 1, 5 repetitions; sets 2 and 3, 6 repetitions; set 4, 8 repetitions), and the difference between conditions increased over subsequent sets. Time under tension increased over each set and was greater in TRD. This study demonstrates greater power output is driven by greater velocity when back squatting during CLU; therefore, velocity may be a useful measure by which to assess power. PMID- 26121433 TI - ALTERED CIRCULATING LEVELS OF RETINOL BINDING PROTEIN 4 AND TRANSTHYRETIN IN RELATION TO INSULIN RESISTANCE, OBESITY, AND GLUCOSE INTOLERANCE IN ASIAN INDIANS. AB - OBJECTIVE: Retinol binding protein 4 (RBP4) has been implicated in metabolic disorders including type 2 diabetes mellitus (T2DM), but few studies have looked at transthyretin (TTR) with which RBP4 is normally bound to in the circulation. We report on the systemic levels of RBP4 and TTR and their associations with insulin resistance, obesity, prediabetes, and T2DM in Asian Indians. METHODS: Age matched individuals with normal glucose tolerance (NGT, n = 90), impaired glucose tolerance (IGT, n = 70) and T2DM (n = 90) were recruited from the Chennai Urban Rural Epidemiology Study (CURES). Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). RBP4 and TTR levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Circulatory RBP4 and TTR levels (in MUg/mL) were highest in T2DM (RBP4: 13 +/- 3.9, TTR: 832 +/- 310) followed by IGT (RBP4: 10.5 +/- 3.2; TTR: 720 +/- 214) compared to NGT (RBP4: 8.7 +/- 2.5; TTR: 551 +/- 185; P<.001). Compared to nonobese NGT individuals, obese NGT, nonobese T2DM, and obese T2DM had higher RBP4 (8.1 vs. 10.6, 12.1, and 13.2 MUg/mL, P<.01) and TTR levels (478 vs. 737, 777, and 900 MUg/mL, P<.01). RBP4 but not TTR was significantly (P<.001) correlated with insulin resistance even among NGT subjects. In regression analysis, RBP4 and TTR showed significant associations with T2DM after adjusting for confounders (RBP4 odds ratio [OR]: 1.107, 95% confidence interval [CI]: 1.008-1.216; TTR OR: 1.342, 95% CI: 1.165-1.547). CONCLUSION: Circulatory levels of RBP4 and TTR showed a significant associations with glucose intolerance, obesity, T2DM and RBP4 additionally, with insulin resistance. PMID- 26121434 TI - SIGNIFICANT ELEVATION OF GROWTH HORMONE LEVEL IMPACTS SURGICAL OUTCOMES IN ACROMEGALY. AB - OBJECTIVE: Transsphenoidal adenomectomy (TSA) is first-line treatment for acromegaly. Our aim was to determine the impact of pre-operative biochemical parameters on the outcomes of surgery. METHODS: Retrospective case series of 79 consecutive acromegalics operated between 1994 and 2013. Inclusion criteria were: first TSA, pathology-confirmed growth hormone (GH) adenoma, and follow-up >3 months. Biochemical remission was defined as normal insulin-like growth factor 1 (IGF-1) without adjuvant therapy during follow-up. RESULTS: Median follow-up was 35.4 months (range, 3 to 187 months). Logistic regression analysis showed that the best model to predict long-term remission included the following pre operative markers: GH, tumor diameter, and cavernous sinus invasion (CSI) (area under the curve, 0.933). A threshold GH of 40 ng/mL was associated with long-term remission (sensitivity, 97%; specificity, 42%). Group A (GH >40 ng/mL) comprised 19 patients (9 men); age, 43 +/- 13 years; tumor diameter, 2.7 +/- 1.0 cm; 73.7% with CSI; and pre-operative median GH, 77.8 ng/mL (interquartile range [IQR], 66.7 to 107.0 ng/mL). Three patients (15%) in group A achieved remission at 3 months, but 2 patients recurred during follow-up. Group B (GH <=40 ng/mL) comprised 60 patients (25 men); age, 47 +/- 13 years; tumor diameter, 1.6 +/- 1.0 cm; 35% with CSI, preoperative median GH, 6.9 ng/mL (IQR, 3.4 to 16.9 ng/mL). Thirty-five patients (58%) in group B achieved remission at 3 months without recurrence during follow-up. Group A had larger tumors and a higher proportion of tumors with CSI (P<.05). CONCLUSION: Both GH and IGF-1 should be measured pre operatively, as highly elevated GH levels negatively impact long-term surgical remission. This strategy allows early identification of patients who require adjuvant therapy and may decrease time to biochemical control. PMID- 26121435 TI - PITUITARY MRI FINDINGS IN PATIENTS WITH PITUITARY AND ECTOPIC ACTH-DEPENDENT CUSHING SYNDROME: DOES A 6-MM PITUITARY TUMOR SIZE CUT-OFF VALUE EXCLUDE ECTOPIC ACTH SYNDROME? AB - OBJECTIVE: Expert opinion and a consensus statement on Cushing syndrome (CS) indicate that in a patient with a clinical presentation and biochemical studies consistent with a pituitary etiology, the presence of a pituitary tumor >=6 mm is highly suggestive of Cushing disease (CD). The purpose of the present study was to determine the optimal pituitary tumor size that can differentiate between patients with CD and ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) and obviate the need for inferior petrosal sinus sampling (IPSS). METHODS: We performed a retrospective study of 130 patients seen between 2000 and 2012 including 104 patients with CD and 26 patients with EAS. RESULTS: A pituitary lesion was reported in 6/26 (23%) patients with EAS and 71/104 (68.3%) patients with CD, with median (range) sizes of 5 mm (3-14) and 8 mm (2-31), respectively. All tumors in the EAS group measured <=6 mm except for 1 that measured 14 mm. The presence of a pituitary tumor >6 mm in size had 40% sensitivity and 96% specificity for the diagnosis of CD. ACTH levels >209 pg/mL and serum potassium <2.7 mmol/L were found in patients with EAS. All patients with EAS had a 24-hour urine free cortisol (UFC) >3.4 times the upper limit of normal (*ULN) Conclusion: Pituitary incidentalomas as large as 14 mm in size can be seen in patients with EAS. However, the 6-mm tumor size cut-off value provided 96% specificity and may be a reasonable threshold to proceed with surgery without the need for IPSS when the biochemical data support a pituitary etiology. PMID- 26121436 TI - GUIDELINES TO IMPROVE PERIOPERATIVE MANAGEMENT OF DIABETES MELLITUS: ASSESSMENT OF THE IMPACT OF CHANGE ACROSS TIME. AB - OBJECTIVE: Assess the impact of guidelines on the care of patients with diabetes undergoing elective surgery. METHODS: A multidisciplinary team developed perioperative guidelines. Overall changes in key measures were evaluated after guidelines were introduced and compared with a historical cohort. RESULTS: The historical cohort included 254 surgical procedures, and the post-guidelines implementation cohort comprised 1,387. Glucose monitoring was performed preoperatively in 93% of cases in the post-guidelines implementation cohort and in 88% in the historical cohort (P<.01), but the percentage of cases with measurements decreased over 12 months (from 95% to 91%, P = .044). Glucose was intraoperatively monitored in 67% of cases after guidelines were introduced and in 29% historically (P<.01); the post-guidelines implementation percentage decreased over 12 months from 67% to 55% (P<.01). The performance of glucose monitoring in the postanesthesia care unit (PACU) did not differ (86% vs. 87%, P = .57), but it decreased over 12 months, from 91% to 84% (P<.01). After introduction of the guidelines, insulin use increased in the preoperative, intraoperative, and PACU areas (all P<=.01) but decreased by the end of 12 months (all P<.01). Mean preoperative and PACU glucose levels in the post- guidelines implementation cohort were significantly lower than in the historical cohort (P<.01). CONCLUSION: Multidisciplinary management guidelines for diabetes patients undergoing surgery can improve the performance of key measures of care. Although adherence to recommendations generally remained higher after guideline implementation than in the historical period, the improvement in several measures began to decline over time. PMID- 26121437 TI - NORMOMAGNESEMIC GITELMAN SYNDROME PATIENTS EXHIBIT A STRONGER REACTION TO THIAZIDE THAN HYPOMAGNESEMIC PATIENTS. AB - OBJECTIVE: In recent decades, the thiazide test has been introduced to aid the diagnosis of Gitelman syndrome (GS), but the effect of thiazide in normomagnesemic GS patients is currently unknown. This study was conducted to compare the thiazide test results of normomagnesemic and hypomagnesemic GS patients. METHODS: Seventeen GS patients with SLC12A3 gene mutations were enrolled, five of whom did not have a history of hypomagnesemia. The clinical data were documented, and SLC12A3 gene screening was performed. The thiazide test was performed in all of the patients and 20 healthy controls. A receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the thiazide test in the diagnosis of GS. RESULTS: A 7-fold increase in sodium and chloride excretion was observed after thiazide application in healthy controls, and an approximately 2-fold increase was found in the 5 normomagnesemic GS patients; however, there was no change in the 12 hypomagnesemic GS patients. A weaker reaction to thiazide was observed in hypomagnesemic compared with normomagnesemic GS patients. The clearance of chloride in 1 patient was overestimated because of chronic renal function insufficiency (CRI). When a reasonable cutoff value for chloride fractional excretion was selected, the thiazide test was 95% sensitive and 94.1% specific for the diagnosis of GS. CONCLUSION: Hypomagnesemic GS patients exhibited greater sodium-chloride cotransporter dysfunction than normomagnesemic GS patients. When CRI occurs, the chloride and sodium clearance rates, rather than the fractional excretion, should be used in the evaluation of the thiazide test results. PMID- 26121438 TI - DIABETES AND PREDIABETES ARE SIGNIFICANTLY HIGHER IN MORBIDLY OBESE CHILDREN COMPARED WITH OBESE CHILDREN. AB - OBJECTIVE: The objective of this study was to examine the prevalence and characteristics of comorbidities in obese and morbidly obese children with a comparison between the 2 sets of children. METHODS: This was a retrospective electronic chart review of obese and morbidly obese children and adolescents as defined by body mass index. We evaluated medical history of comorbid conditions, medication use, and cardiovascular risk markers, including blood pressure, lipid profile, and glycosylated hemoglobin. RESULTS: There were 1,111 subjects (African American = 635; non-Hispanic white = 364; Hispanic = 36; others = 86), of which 274 were obese and 837 were morbidly obese children with a mean age of 12.7 +/- 3.37 years. Morbidly obese children had a higher prevalence of prediabetes (19.5% of obese versus 27.3% of morbidly obese; P<.0001) and type 2 diabetes (39.8% of obese versus 52.4% of morbidly obese; P<.0001). Use of medications for treatment of asthma was significantly higher in the morbidly obese group compared with the obese group (21% versus 14%; P = .01). CONCLUSION: Morbidly obese children have a higher prevalence of diabetes, prediabetes, and use of asthma medications compared with obese children. PMID- 26121439 TI - HRPT2- (CDC73) RELATED HEREDITARY HYPERPARATHYROIDISM: A CASE SERIES FROM WESTERN INDIA. AB - OBJECTIVE: To describe a case series of HRPT2- (CDC73) related hereditary primary hyperparathyroidism (PHPT) from western India. METHODS: We present a case series of 4 families (7 patients) with PHPT caused by CDC73 gene mutations. RESULTS: The mean age of presentation of the 4 index cases was 27.25 +/- 9.8 years. Two family members were identified through biochemical screening (Cases 1b and 2b), while 1 mutation-positive family member did not manifest any features of PHPT or hyperparathyroidism jaw tumor syndrome (HPT-JT) syndrome (Case 2c). Biochemistry showed increased serum calcium (mean: 13.21 +/- 1.24 mg/dL), low serum phosphorus (mean: 1.78 +/- 0.44 mg/dL), and high parathyroid hormone (PTH, mean: 936 +/- 586.9 pg/mL). All patients had a uniglandular presentation and underwent single adenoma excision initially except Cases 2a and 2b, who underwent subtotal parathyroidectomy at baseline. Two cases experienced PHPT recurrence (Cases 3 and 4), while 1 remained uncured due to parathyroid carcinoma (Case 1a). Other associated syndromic features like ossifying jaw fibromas were present in 2 patients, renal cysts in 3 patients, and uterine involvement in 2 patients. Two families had novel germline CDC73 mutations (Families 1 and 3), while the other 2 had reported mutations. Family 2 had familial isolated PHPT without any other features of HPT-JT syndrome. CONCLUSION: Our findings reaffirm the need for genetic analysis of patients with PHPT, especially those with younger age of disease onset; recurrent disease; and associated features like polycystic kidneys, endometrial involvement, ossifying jaw tumors, or parathyroid carcinoma. PMID- 26121440 TI - HISTORICAL AND CURRENT PERSPECTIVE IN THE USE OF THYROID EXTRACTS FOR THE TREATMENT OF HYPOTHYROIDISM. AB - OBJECTIVE: To describe the history, refinements, implementation, physiology, and clinical outcomes achieved over the past several centuries of thyroid hormone replacement strategies. METHODS: A Medline search was initiated using the following search terms: bioidentical thyroid hormone, thyroid hormone extract, combination thyroxine (T4) and tri-iodothyronine (T3) therapy, homeopathic thyroid hormone therapy, and thyroid hormone replacement. Pertinent articles of interest were identified by title (and where available abstract) for further review. Additional references were identified during a review of the identified literature. RESULTS: A rich history of physician intervention in thyroid dysfunction was identified dating back more than 2 millennia. Although not precisely documented, thyroid ingestion from animal sources had been used for centuries but was finally scientifically described and documented in Europe over 130 years ago. Since the reports by Bettencourt and Murray, there has been a continuous documentation of outcomes, refinement of hormone preparation production, and updating of recommendations for the most effective and safe use of these hormones for relieving the symptoms of hypothyroidism. As the thyroid extract preparations contain both levothyroxine (LT4) and liothyronine (LT3), current guidelines do not endorse their use as controlled studies do not clearly document enhanced objective outcomes compared with LT4 monotherapy. Among current issues cited, the optimum ratio of LT4 to LT3 has yet to be determined, and the U.S. Food and Drug Administration (FDA) does not appear to be monitoring the thyroid hormone ratios or content in extract preparations on the market. Taken together, these limitations are important detriments to the use of thyroid extract products. CONCLUSION: The evolution of thyroid hormone therapies has been significant over the extended period of time they have been in use to treat hypothyroidism. Although numerous websites continue to advocate the use of thyroid hormone extracts as a superior therapy for hypothyroidism, none of the most recent guidelines of major endocrine societies recommend thyroid extract use for hypothyroidism. PMID- 26121441 TI - CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF PATIENTS WITH ECTOPIC ACTH SYNDROME DUE TO BRONCHIAL CARCINOID TUMORS: A ONE-CENTER EXPERIENCE. AB - OBJECTIVE: To describe the diagnostic features and long-term outcome of patients with bronchial carcinoid tumors with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), treated in our department. METHODS: We studied 10 cases with EAS and histologically confirmed bronchial carcinoid tumors, diagnosed from 1992 until 2006. Diagnosis was based upon blood, urine, radiologic, and interventional tests. Disease status at the time of the last follow-up was the primary outcome measure. RESULTS: Clinical manifestations included Cushingoid features (100%), psychiatric symptoms (90%), hypertension (70%), diabetes/impaired glucose tolerance (40%), osteoporosis (10%), and hypokalemia (10%). The average time from the onset of symptoms until diagnosis was 14.2 +/- 17.0 months. None of the patients exhibited a positive cortisol or ACTH response to corticotropin releasing hormone (CRH) test, and none showed a positive gradient on bilateral inferior petrosal sinus sampling (BIPSS). All tumors were identified by computed tomography and by octreotide scintigraphy in 8 patients. All patients underwent surgical resection of the tumor, and 2 patients had adjuvant radiation therapy. The mean follow-up was 126.6 +/- 63.3 months. At latest follow-up, 8 patients were in remission and 2 had recurrence of the EAS; both had a multifocal tumor. The 2 patients submitted to adjuvant radiation therapy were in remission at their latest follow-up, despite local invasion and lymph node metastases. CONCLUSION: CRH test and BIPSS are the most useful methods in diagnosing EAS. For localization, repeated imaging studies are necessary. Surgical treatment is effective in most cases. Adjunctive radiotherapy may be useful in patients with lymph node metastases. Patients with multifocal disease should be monitored for potential recurrence. PMID- 26121442 TI - EVALUATION OF PARA- AND PERIRENAL FAT THICKNESS AND ITS ASSOCIATION WITH METABOLIC DISORDERS IN POLYCYSTIC OVARY SYNDROME. AB - OBJECTIVE: The aim of this study was to compare para- and perirenal fat (PFT) and subcutaneous abdominal fat (SFT) measurements between patients with polycystic ovary syndrome (PCOS) and control subjects and to assess the possible relation with metabolic disorders. METHODS: This study included 68 patients with PCOS and 40 age- and body mass index (BMI)-matched healthy controls. We evaluated anthropometric, hormonal, and metabolic parameters, and abdominal ultrasonography was performed to measure PFT and SFT. RESULTS: The mean PFT values were 6.1 +/- 2.9 mm in patients with PCOS and 4.3 +/- 2.3 mm in healthy controls (P = .002). SFT values were also higher in the patient group (9.6 +/- 5 mm) compared to healthy subjects (3.5 +/- 0.5 mm) (P = .017). A significant positive correlation was found between PFT and BMI (r = 0.368), waist circumference (WC) (r = 0.441), Ferriman-Gallwey (FG) score (r = 0.313), blood pressure (systolic, SBP, r = 0.213; diastolic, DBP, r = 0.215), plasma glucose (r = 0.195), homeostasis model assessment-insulin resistance (HOMA-IR, r = 0.273), SFT (r = 0.555). Conversely, negative correlations were found between PFT and estradiol (r = -0.218) and sex hormone-binding globulin (SHBG, r = -0.304). Nonobese PCOS patients (6.1 +/- 3.07 mm) had higher PFT values than nonobese controls (3.47 +/- 1.5 mm); however, SFT measurements did not differ (P = .086). In multiple linear regression analysis, SFT (P = .006) was a significant and independent predictor for PFT, along with WC (P = .023). In a stepwise model, SFT was the predictor of PFT (P = .001). CONCLUSION: PFT values were higher particularly in nonobese PCOS patients compared to nonobese control subjects. There was a significant interaction between PCOS and obesity on PFT. PMID- 26121444 TI - Visual Vignette. PMID- 26121443 TI - SERUM THYROTROPIN CONCENTRATIONS ARE NOT PREDICTIVE OF AGGRESSIVE BREAST CANCER BIOLOGY IN EUTHYROID INDIVIDUALS. AB - OBJECTIVE: The potential influence of hypothyroidism on breast cancer remains incompletely understood. The objective of this study was to investigate the relationship between serum thyrotropin (thyroid-stimulating hormone, TSH) concentration and markers of aggressive breast cancer biology as defined by receptor expression profile, tumor grade, and American Joint Committee on Cancer (AJCC) stage characteristics. METHODS: This was a retrospective cohort study of patients from 2002 to 2014. All breast cancer patients who had complete receptor (estrogen receptor, ER; progesterone receptor, PR; and human epidermal growth factor receptor 2, Her2/neu) and prediagnosis serum TSH data (n = 437) were included. All patients had 1 of 6 receptor profiles: ER+ PR+ Her2/neu-, ER+ PR- Her2/neu-, ER+ PR+ Her2/neu+, ER+ PR- Her2/neu+, ER- PR- Her2/neu+, or ER- PR- Her2/neu-. Log-transformed serum TSH concentrations were analyzed using multinomial and logistic regressions to identify potential relationships with markers of breast cancer aggressiveness. RESULTS: Increasing serum TSH concentration was associated with a lower probability of having the receptor expression profile ER+ PR+ Her2/neu+ compared to patients with the ER+ PR+ Her2/neu- profile (odds ratio [OR] = 0.52, P = .0045). No significant associations between other receptor expression profiles and serum TSH concentration were found. All time-weighted and unweighted median serum TSH concentrations were within normal limits. No significant associations between serum TSH concentration and tumor grade, overall AJCC stage, tumor size (T), lymph node positivity (N), or presence of metastasis (M) were observed. CONCLUSIONS: Serum TSH was not associated with markers of breast cancer aggressiveness in our cohort. PMID- 26121445 TI - SELECTIVE HYPOALDOSTERONISM: A REVIEW. AB - OBJECTIVE: Selective hypoaldosteronism (SH) is a condition manifested by hyperkalemia due to low aldosterone secretion with normal cortisol. One of the obstacles in diagnosis is the awareness of the condition itself. The objective of this review is to highlight what is known about the epidemiology, pathophysiology, etiology, presentation, diagnosis, and treatment of SH. METHODS: Literature search was performed on PubMed and Ovid Medline for articles which contained hypoaldosteronism as a major topic. RESULTS: The recent literature on this topic is surprisingly limited. Few recent review articles were found, none of which were in English and less than 5 years old. Case reports and genetic literature were also included in this review, as they contain the most recent reports of SH in the literature. CONCLUSION: Awareness about SH will hopefully help physicians to identify patients at risk as well as decide on treatment if any therapy is required. PMID- 26121446 TI - THE ABSENCE OF THYROID DISEASE IN AN AUSTRALIAN HEPATITIS C COHORT TREATED WITH TRIPLE COMBINATION THERAPY: A PARADIGM SHIFT. AB - OBJECTIVE: To assess the prevalence of thyroid disease in triple combination therapy with interferon (IFN)-alpha, ribavirin (RBV), and protease inhibitors (boceprevir and telaprevir) for the treatment of chronic hepatitis C virus (HCV) infection in an Australian hepatitis C cohort. Also, to compare with those who received dual RBV and IFN in the past. METHODS: A preliminary, retrospective, and nested case control study of thyroid disease in patients who underwent triple combination therapy for chronic HCV infection compared with dual therapy at a major tertiary referral hospital center. Fifty-nine patients were treated with such therapy at the Hunter New England Area Hepatitis C Treatment Center. Of these, 38 were treated with boceprevir and 21 with telaprevir. All had genotype 1 HCV infection. The main outcome measures included (1) the prevalence of thyroid disease (TD), including hyperthyroidism and hypothyroidism, and (2) thyroid outcome comparison with patients who had received dual therapy. RESULTS: There was no case of TD detected for the entire duration of therapy with triple anti HCV therapy. There was a significant absence of TD in the protease inhibitor treated group. CONCLUSION: No case of TD was detected during the treatment of HCV patients with protease inhibitor-based triple therapy. The reasons for this are unclear. Larger studies are necessary to confirm this finding. PMID- 26121447 TI - ASSOCIATION BETWEEN MIFEPRISTONE DOSE, EFFICACY, AND TOLERABILITY IN PATIENTS WITH CUSHING SYNDROME. AB - OBJECTIVE: To examine the relationship between dose, clinical response (based on independent evaluation of metabolic, physical, neurologic, and social assessments), and safety of mifepristone treatment in patients with endogenous Cushing syndrome (CS). METHODS: This post hoc analysis included 40 clinical responders and 50 participants who received a dose of mifepristone (safety population) in the 24-week phase 3 SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. The dose of mifepristone at the initial clinical response was analyzed, and the rate of serious adverse events (SAEs) and AEs reported in >=20% of patients were compared to average mifepristone doses over time. RESULTS: Among the clinical responders, 85% and 35% had their initial clinical responses at mifepristone doses >=600 and >=900 mg/day, respectively. The SAE rate did not increase with a higher dose over time. The AE rates for fatigue, headache, nausea, and peripheral edema declined significantly at weeks 16 to 24 (all P<.05 vs. weeks 1-2) as the study progressed and mifepristone doses were increased. Other AEs such as hypokalemia, vomiting, and decreased appetite did not significantly increase from weeks 1 to 2 as mifepristone doses were increased. CONCLUSIONS: The majority of clinical responders in the SEISMIC trial received mifepristone doses >=600 mg/day suggesting that higher doses were required to achieve optimal clinical benefit in patients with endogenous CS. Notably, mifepristone dose escalations did not result in any significant or concordant increase in the rates of SAEs and common AEs. PMID- 26121449 TI - RETROSPECTIVE STUDY OF GLYCEMIC CONTROL FOLLOWING TRANSITION FROM THE INTENSIVE CARE UNIT IN A NATIONAL SAMPLE OF U.S. HOSPITALS. AB - OBJECTIVE: Retrospective study to evaluate glycemic control outcomes after transition from the intensive care unit (ICU) to a non-ICU area in a national sample of U.S. hospitals. METHODS: Mean point-of-care blood glucose (POC-BG) data were assessed overall and at 24 hours before and up to 72 hours after the transition. Comparisons in glucose variability (standard deviation of POC-BG data) were assessed. Impact on glycemic control was evaluated after accounting for hospital characteristics through logistic regression analysis. RESULTS: POC BG data were obtained from 576 hospitals. Overall mean (SD) POC-BG values in ICU versus non-ICU areas were 176 (24) versus 169 (21) mg/dL (P<.01). Mean (SD) of the ICU POC-BG data were 76 (16) versus 73 (16) mg/dL in the non-ICU data (P<.01). However, when comparing values of POC-BG in the last 24-hour ICU period with those from up to 72 hours posttransition, we found no differences, indicative of overall stable glycemic control and variability after transition. Any deterioration of glucose control following the transition was significantly associated with hospital size (P<.01): the smallest hospitals had the highest percentage of these cases. In addition, geographic region showed significant variability (P = .04), with hospitals in the Midwest and West having the highest proportion of cases in which glycemic control worsened following the transition. CONCLUSION: Glycemic control and variability did not change after transition from the ICU, but outcomes may depend on certain hospital characteristics. Inpatient glycemic control assessment should move beyond just cross-sectional studies and consider the impact of transitioning across inpatient areas. Other statistical approaches to studying this question should be evaluated. PMID- 26121448 TI - VITAMIN D-BINDING PROTEIN IN HEALTHY PRE- AND POSTMENOPAUSAL WOMEN: RELATIONSHIP WITH ESTRADIOL CONCENTRATIONS. AB - OBJECTIVE: To examine the relationship between endogenous serum estradiol and vitamin D-binding protein (DBP) and total, free, and bioavailable 25 hydroxyvitamin D (25OHD) concentrations in pre- and postmenopausal women. METHODS: In 165 healthy women (ages, 26 to 75 years) not taking any form of exogenous estrogen, the serum concentrations of estradiol, 25OHD, DBP, parathyroid hormone, and albumin were measured. Free and bioavailable 25OHD (free + albumin-bound) levels were calculated from total 25OHD, DBP, and serum albumin levels. RESULTS: Premenopausal women had higher serum 25OHD (31.5 +/- 7.9 ng/mL), DBP (45.3 +/- 6.2 mg/dL), and estradiol (52.8 +/- 35.0 pg/mL) levels than postmenopausal women (26.5 +/- 4.9 ng/mL, 41.7 +/- 5.7 mg/dL, and 12.9 +/- 4.9 pg/mL), respectively. In addition, the calculated free and bioavailable 25OHD levels were higher in pre- than postmenopausal women (P<.05). Serum estradiol correlated with DBP (r = 0.22; P<.01) and total 25OHD (r = 0.27; P<.01). In multivariate regression models (with or without serum 25OHD), estradiol was independently associated with DBP (P<.05). CONCLUSION: Lower estradiol level is one of the factors that contribute to lower DBP levels in older women. Our data indicate that besides well-known factors such as age, gender, and race, serum estradiol concentrations are also a physiologic predictor of DBP concentration. PMID- 26121450 TI - EFFECTIVENESS OF INPATIENT INSULIN ORDER SETS USING HUMAN INSULINS IN NONCRITICALLY ILL PATIENTS IN A RURAL HOSPITAL. AB - OBJECTIVE: Recent guidelines recommend a physiologic approach to non-intensive care unit (ICU) inpatient glucose management utilizing basal-bolus with correctional (BBC) insulin over traditional sliding-scale insulin monotherapy. Unfortunately, few studies exist using a BBC approach restricted to human insulins (regular and neutral protamine Hagedorn [NPH]). This study evaluated changes in provider prescribing patterns, effects on blood glucose, and safety with implementation of hospital order sets for BBC using human insulins. METHODS: Order sets were developed for non-ICU inpatients, consisting of basal, prandial, and correctional insulin using NPH and regular human insulins. Evaluation compared a 4-month period before (admissions, n = 274) with a 4-month period after order set availability (n = 302). Primary outcome was change in insulin prescribing patterns. Secondary outcomes included use of nonpreferred diabetes treatments, hemoglobin A1c testing, mean daily blood glucose, and incidence of hypoglycemia. RESULTS: Use of BBC insulin regimen increased from 10.6 to 27.5% after order set implementation (P<.001). Use of oral antihyperglycemic agents decreased from 24.1 to 14.9% after implementation (P = .006). Hemoglobin A1c testing rose from 50.0 to 62.3% after (P = .003). Mean daily blood glucose improved, with an estimated mean difference of 14.4 mg/dL (95% confidence interval, 2.2 to 26.5 mg/dL) over hospital days 3 through 9 (P = .02). There was no significant change in the incidence of moderate or severe hypoglycemia. CONCLUSION: Implementation of hospital-wide human insulin order sets led to improvements in prescribing practices and blood glucose control, without increasing the incidence of hypoglycemia. These order sets may be useful for facilities limited by formulary and cost considerations to the use of older human insulins. PMID- 26121451 TI - PATIENTS ACHIEVING GOOD GLYCEMIC CONTROL (HBA1c <7%) EXPERIENCE A LOWER RATE OF HYPOGLYCEMIA WITH INSULIN DEGLUDEC THAN WITH INSULIN GLARGINE: A META-ANALYSIS OF PHASE 3A TRIALS. AB - OBJECTIVE: Meta-analysis to compare hypoglycemia rates of basal insulin degludec (IDeg) with insulin glargine (IGlar) in patients with diabetes achieving good glycemic control (hemoglobin A1c [HbA1c] <7% at end of trial). METHODS: In a preplanned meta-analysis, patient data from 7 randomized, treat-to-target, 26- or 52-week trials in patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) who administered IDeg (n = 2,899) or IGlar (n = 1,431) once daily were analyzed. Using a negative binomial regression model, this meta analysis compared hypoglycemia rates in patients achieving HbA1c <7% at end of trial with IDeg (n = 1,347) and IGlar (n = 697). RESULTS: In all trials, IDeg was noninferior to IGlar in HbA1c reduction from baseline. At end of trial, 2,044 patients (T2DM, n = 1,661; T1DM, n = 383) achieved HbA1c <7%. The overall confirmed hypoglycemia rate, defined as plasma glucose <56 mg/dL or severe hypoglycemia if requiring assistance, was significantly lower with IDeg versus IGlar (estimated rate ratio [ERR] IDeg:IGlar, 0.86; 95% confidence interval [CI], 0.76 to 0.98). The nocturnal confirmed hypoglycemia rate, defined as occurring between midnight and 6:00 am, was significantly lower with IDeg (ERR, 0.63; 95% CI, 0.52 to 0.77). In the maintenance period (16 weeks onward when average insulin dose and glycemic levels stabilized), the overall confirmed hypoglycemia rate was significantly lower (ERR, 0.79; 95% CI, 0.68 to 0.92) and the nocturnal confirmed hypoglycemia rate was significantly lower (ERR, 0.57; 95% CI, 0.45 to 0.72) with IDeg versus IGlar. CONCLUSION: Patients with T1DM and T2DM achieved HbA1c <7% with significantly lower rates of overall and nocturnal confirmed hypoglycemia with IDeg versus IGlar. The lower hypoglycemia rate with IDeg was more pronounced in the maintenance period. PMID- 26121452 TI - THE EFFECT OF PHLEBOTOMY-INDUCED HEMOLYSIS ON INSULIN LEVEL DETERMINATION. AB - OBJECTIVE: To examine the effect of phlebotomy-induced hemolysis on serum insulin and C-peptide measurement by an immunochemiluminometric assay. METHODS: As part of a study designed to evaluate beta-cell function in a group of adults with newly diagnosed type 2 diabetes, we tested insulin and C-peptide levels in 1,048 samples. In order to evaluate the effect of phlebotomy-induced hemolysis, we determined insulin and C-peptide levels simultaneously in hemolyzed and nonhemolyzed samples. RESULTS: Forty-seven (4.5%) of the 1,048 samples were affected by hemolysis. In 26 cases, we had paired hemolyzed and nonhemolyzed serum samples that allowed a simultaneous comparison. We found that all degrees of hemolysis led to a significant decrease in insulin level. In hemolyzed serum, the median (interquartile range) of the insulin was 5.6 (1.8 to 24.3) mIU/L, versus 21.3 (11.4 to 48.5) mIU/L in nonhemolyzed serum, representing a 25 to 98% loss. This phenomenon was not found for C-peptide levels. CONCLUSION: Clinicians have to be aware that even a mild degree of phlebotomy-induced hemolysis has a significant effect on serum insulin level determination, which can lead to misinterpretation of test results. This finding has important implications, especially in the evaluation of suspected cases of hyperinsulinemic hypoglycemia. PMID- 26121453 TI - CLINICAL OUTCOMES IN ADRENAL INCIDENTALOMA: EXPERIENCE FROM ONE CENTER. AB - OBJECTIVE: To investigate the outcome in patients with adrenal incidentaloma (AI). METHODS: A retrospective evaluation of 637 patients with AI referred to a tertiary center over 8 years. Radiologic and hormonal evaluations were performed at baseline. Follow-up imaging was carried out if necessary, and hormonal evaluation was performed at 24 months according to national guidelines. RESULTS: The mean age was 62.7 +/- 11.6 years, and the mean AI size was 25.3 +/- 17.0 mm at presentation. Hormonal evaluation revealed that 85.4% of all tumors were nonfunctioning adenomas, 4.1% subclinical Cushing syndrome (SCS), 1.4% pheochromocytoma, 1.4% primary hyperaldosteronism, 0.8% Cushing syndrome, 0.6% adrenocortical carcinoma, 0.3% congenital adrenal hyperplasia, 2.2% metastasis to adrenals, and 3.8% other lesions of benign origin. Bilateral tumors were found in 11%, and compared to unilateral tumors, SCS was more prevalent. Only 2 cases were reclassified during follow-up, both as SCS, but neither had had a dexamethasone suppression test performed at initial work-up. In patients diagnosed with an adrenal metastasis, 92.9% were deceased within 2 years. Excluding those with malignant tumors, 12.9% of patients died during the study period of up to 11 years due to other causes than adrenal. CONCLUSION: Most AIs were benign, but a small fraction of tumors were functional and malignant. The prognosis of patients with adrenal metastasis was extremely poor, but otherwise, the mortality rate was similar to that for the general population. Follow-up of AIs <4 cm with an initial nonfunctional profile and benign radiologic appearance appears unwarranted, but screening for congenital adrenal hyperplasia should be considered. PMID- 26121454 TI - MORNING SERUM CORTISOL LEVEL AFTER TRANSSPHENOIDAL SURGERY FOR PITUITARY ADENOMA PREDICTS HYPOTHALAMIC-PITUITARY-ADRENAL FUNCTION DESPITE INTRAOPERATIVE DEXAMETHASONE USE. AB - OBJECTIVE: Perioperative glucocorticoid (GC) is rarely needed in patients undergoing transsphenoidal surgery (TSS). We instituted a steroid-sparing protocol in the settings of intraoperative dexamethasone use. We evaluated the safety of using a cut off cortisol level of 14 MUg/dL on postoperative day (POD) 1 and -6 after dexamethasone use during the surgery. We also analyzed the efficacy of serial morning cortisol levels for weaning GC replacement. METHODS: The charts of 48 adult patients who received dexamethasone 4 mg intraoperatively were reviewed. Morning cortisol levels were measured on POD-1. Patients with cortisol >=14 MUg/dL were discharged without CG replacement. Morning cortisol level was checked routinely on POD-6, and GC replacement was initiated when the level was <14 MUg/dL. Serial cortisol levels were measured in patients requiring GC after the first postoperative week. RESULTS: Overall, 67% patients had POD-1 cortisol >=14 MUg/dL and did not require GC on discharge. After POD-6, 83% of patients were not on GC replacement. A cosyntropin stimulation testing (CST) was only performed in 3 patients. There were no hospital admissions for adrenal crisis during the postoperative period. CONCLUSION: A steroid-sparing protocol with POD-1 and -6 morning cortisol levels can be safely and effectively used in the settings of intraoperative dexamethasone administration. It leads to avoidance of GC in more than two-thirds of patients on discharge and more than 80% of patients after the first postoperative week. We found that dynamic adrenal testing could be omitted in the majority of patients by using serial morning cortisol levels to assess the hypothalamic-pituitary-adrenal (HPA) axis. PMID- 26121455 TI - A COMPARATIVE STUDY OF REAL-TIME AND STATIC ULTRASONOGRAPHY DIAGNOSES FOR THE INCIDENTAL DETECTION OF DIFFUSE THYROID DISEASE. AB - OBJECTIVE: The aim of this study was to compare the diagnostic accuracy of real time and static ultrasonography (US) for the incidental detection of diffuse thyroid disease (DTD). METHODS: In 118 consecutive patients, a single radiologist performed real-time US before thyroidectomy. For static US, the same radiologist retrospectively investigated the sonographic findings on a picture-archiving and communication system after 3 months. The diagnostic categories of both real-time and static US diagnoses were determined based on the number of abnormal findings, and the diagnostic indices were calculated by a receiver operating characteristic (ROC) curve analysis using the histopathologic results as the reference standard. RESULTS: Histopathologic results included normal thyroid (n = 77), Hashimoto thyroiditis (n = 11), non-Hashimoto lymphocytic thyroiditis (n = 29), and diffuse hyperplasia (n = 1). Normal thyroid and DTD showed significant differences in echogenicity, echotexture, glandular margin, and vascularity on both real-time and static US. There was a positive correlation between US categories and histopathologic results in both real-time and static US. The highest diagnostic indices were obtained when the cutoff criteria of real-time and static US diagnoses were chosen as indeterminate and suspicious for DTD, respectively. The ROC curve analysis showed that real-time US was superior to static US in diagnostic accuracy. CONCLUSION: Both real-time and static US may be helpful for the detection of incidental DTD, but real-time US is superior to static US for detecting incidental DTD. PMID- 26121456 TI - DAILY INPATIENT GLYCEMIC SURVEY (DINGS): A PROCESS TO REMOTELY IDENTIFY AND ASSIST IN THE MANAGEMENT OF HOSPITALIZED PATIENTS WITH DIABETES AND HYPERGLYCEMIA. AB - OBJECTIVE: Hyperglycemia, hypoglycemia, and glycemic variability have been associated with increased morbidity, mortality, and overall costs of care in hospitalized patients. At the Stratton VA Medical Center in Albany, New York, a process aimed to improve inpatient glycemic control by remotely assisting primary care teams in the management of hyperglycemia and diabetes was designed. METHODS: An electronic query comprised of hospitalized patients with glucose values <70 mg/dL or >350 mg/dL is generated daily. Electronic medical records (EMRs) are individually reviewed by diabetes specialist providers, and management recommendations are sent to primary care teams when applicable. Glucose data was retrospectively examined before and after the establishment of the daily inpatient glycemic survey (DINGS) process, and rates of hyperglycemia and hypoglycemia were compared. RESULTS: Patient-day mean glucose slightly but significantly decreased from 177.6 +/- 64.4 to 173.2 +/- 59.4 mg/dL (P<.001). The percentage of patient-days with any value >350 mg/dL also decreased from 9.69 to 7.36% (P<.001), while the percentage of patient-days with mean glucose values in the range of 90 to 180 mg/dL increased from 58.1 to 61.4% (P<.001). Glycemic variability, assessed by the SD of glucose, significantly decreased from 53.9 to 49.8 mg/dL (P<.001). Moreover, rates of hypoglycemia (<70 mg/dL) decreased significantly by 41% (P<.001). CONCLUSION: Quality metrics of inpatient glycemic control improved significantly after the establishment of the DINGS process within our facility. Prospective controlled studies are needed to confirm a causal association. PMID- 26121457 TI - HLA DQ2 HAPLOTYPE, EARLY ONSET OF GRAVES DISEASE, AND POSITIVE FAMILY HISTORY OF AUTOIMMUNE DISORDERS ARE RISK FACTORS FOR DEVELOPING CELIAC DISEASE IN PATIENTS WITH GRAVES DISEASE. AB - OBJECTIVE: The diagnosis of celiac disease (CD) in patients with different autoimmune diseases including Graves disease (GD) remains a challenge. The aims of our study were to: (1) assess the prevalence of CD in Polish patients with GD and (2) evaluate the prevalence of CD in the subgroups of patients with GD divided on the basis of clinical and human leukocyte antigen (HLA) typing criteria. METHODS: The prospective study was conducted at an academic referral center. The study groups consisted of consecutive, euthyroid patients with GD (n = 232) and healthy volunteers without autoimmune thyroid diseases (n = 122). The diagnosis of CD was based on elevated immunoglobulin A autoantibodies to the enzyme tissue transglutaminase (IgA-TTG) and small intestine biopsy findings. RESULTS: CD was diagnosed in 8 patients with GD (3.4%) and 1 healthy volunteer (0.8%). The development of CD in patients with GD was strongly associated with HLA-DQ2 haplotype (as predicted from linkage disequilibria, 14.6% vs. 1.5%, P = .009; odds ratio [OR] = 11.3; 95% confidence interval [CI] 1.3-252.7): 6 patients with CD carried HLA-DRB1(*)03, 1 carried an HLA-DRB1(*)04 allele, and 1 had an HLA-DRB1(*)07/(*)11 genotype. Multivariate analysis showed independent associations between CD and early GD onset (P = .014, OR = 9.6), autoimmunity in family (P = .029, OR = 6.3) and gastroenterologic symptoms (P = .031, OR = 8.1). CONCLUSIONS: The results of our study suggest that serologic screening for CD may be considered in GD patients (1) with the HLA alleles typical for CD, (2) with an early onset of GD, or (3) a family history of autoimmunity. Moreover, the diagnosis of CD should be explored in euthyroid GD patients with nonspecific gastrointestinal symptoms. PMID- 26121458 TI - Visual Vignette. PMID- 26121459 TI - HEALTH-RELATED QUALITY OF LIFE AFTER PERCUTANEOUS RADIOFREQUENCY ABLATION OF COLD, SOLID, BENIGN THYROID NODULES: A 2-YEAR FOLLOW-UP STUDY IN 40 PATIENTS. AB - OBJECTIVE: We studied the impact of radiofrequency ablation (RFA) on health related quality of life (HRQL) in patients with benign thyroid nodules (TN) in a 2-year follow-up. METHODS: Forty patients (35 women and 5 men; age, 54.9 +/- 14.3 years) with cold thyroid solitary nodules or a dominant nodule within a normofunctioning multi-nodular goiter (volume range, 6.5 to 90.0 mL) underwent RFA of thyroid nodular tissue under ultrasound real-time assistance. RESULTS: Data are mean and standard deviation. Energy delivered was 37,154 +/- 18,092 joules, with an output power of 37.4 +/- 8.8 watts. Two years after RFA, nodule volume decreased from 30.0 +/- 18.2 mL to 7.9 +/- 9.8 mL (-80.1 +/- 16.1% of initial volume; P<.0001). Thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels remained stable. Symptom score measured on a 0- to 10-cm visual analogue scale (VAS) declined from 5.6 +/- 3.1 cm to 1.9 +/- 1.3 cm (P<.0001). Cosmetic score (VAS 0-10 cm) declined from 5.7 +/- 3.2 cm to 1.9 +/- 1.5 cm (P<.0001). Two patients became anti-thyroglobulin antibody-positive. Physical Component Summary (PCS)-12 improved from 50.4 +/- 8.9 to 54.5 +/- 5.3, and the Mental Component Summary (MCS)-12 improved from 36.0 +/- 13.3 to 50.3 +/- 6.3 (P<.0001 for both score changes). CONCLUSION: Our 2-year follow-up study confirms that RFA of benign TNs is effective in reducing nodular volume and compressive and cosmetic symptoms, without causing thyroid dysfunction or life threatening complications. Our data indicate that the achievement of these secondary endpoints is associated with HRQL improvement, measured both as PCS and MCS. PMID- 26121460 TI - BASAL-BOLUS REGIMEN WITH INSULIN ANALOGUES VERSUS HUMAN INSULIN IN MEDICAL PATIENTS WITH TYPE 2 DIABETES: A RANDOMIZED CONTROLLED TRIAL IN LATIN AMERICA. AB - OBJECTIVE: Few randomized studies have focused on the optimal management of non intensive care unit patients with type 2 diabetes in Latin America. We compared the safety and efficacy of a basal-bolus regimen with analogues and human insulins in general medicine patients admitted to a University Hospital in Asuncion, Paraguay. METHODS: In a prospective, open-label trial, we randomized 134 nonsurgical patients with blood glucose (BG) between 140 and 400 mg/dL to a basal-bolus regimen with glargine once daily and glulisine before meals (n = 66) or Neutral Protamine Hagedorn (NPH) twice daily and regular insulin before meals (n = 68). Major outcomes included differences in daily BG levels and frequency of hypoglycemic events between treatment groups. RESULTS: There were no differences in the mean daily BG (157 +/- 37 mg/dL versus 158 +/- 44 mg/dL; P = .90) or in the number of BG readings within target <140 mg/dL before meals (76% versus 74%) between the glargine/glulisine and NPH/regular regimens. The mean insulin dose in the glargine/glulisine group was 0.76 +/- 0.3 units/kg/day (glargine, 22 +/- 9 units/day; glulisine, 31 +/- 12 units/day) and was not different compared with NPH/regular group (0.75 +/- 0.3 units/kg/day [NPH, 28 +/- 12 units/day; regular, 23 +/- 9 units/day]). The overall prevalence of hypoglycemia (<70 mg/dL) was similar between patients treated with NPH/regular and glargine/glulisine (38% versus 35%; P = .68), but more patients treated with human insulin had severe (<40 mg/dL) hypoglycemia (7.6% versus 25%; P = .08). There were no differences in length of hospital stay or mortality between groups. CONCLUSION: The basal-bolus regimen with insulin analogues resulted in equivalent glycemic control and frequency of hypoglycemia compared to treatment with human insulin in hospitalized patients with diabetes. PMID- 26121461 TI - HYPERGLYCEMIA AND HOSPITAL TRANSITIONS: STILL A LONG ROAD AHEAD. PMID- 26121462 TI - PITUITARY DYSFUNCTION IN DEVELOPMENTAL DELAY: MEDICAL AND ETHICAL CONCERNS. PMID- 26121463 TI - PHYSICIANS' SELF-PERCEPTIONS OF CARE FOR EMERGING ADULTS WITH TYPE 1 DIABETES. AB - OBJECTIVE: Establishing care with adult providers is essential for emerging adults with type 1 diabetes (T1D) transitioning from pediatric care. Although research evaluating the transition from pediatric to adult care has been focused primarily on patients' perceptions, little is known about the adult providers' perspectives. We sought to ascertain adult providers' perspectives of caring for the medical and psychosocial needs of this patient population. METHODS: We developed and mailed a survey to 79 regional adult endocrinologists and 186 primary care physicians (PCPs) identified through 2 regional insurance plans. Questions addressed perceived aptitude in clinical aspects of diabetes management, importance and availability of diabetes team members, and opinions regarding recommended transition methods. RESULTS: The response rate was 43% for endocrinologists and 13% for PCPs. Endocrinologists reported higher aptitude in insulin management (P<.01). PCPs reported greater aptitude in screening and treating depression (P<0.01). Although endocrinologists and PCPs did not differ in their views of the importance of care by a comprehensive team, endocrinologists reported better access to diabetes educators and dieticians than PCPs (P<.01). Recommended transition methods were described as useful. CONCLUSION: These preliminary results suggest that endocrinologists are better prepared to assume diabetes care of emerging adults, whereas PCPs may be better prepared to screen and treat associated depression. Future studies are needed to determine if a medical home model with cooperative management improves care for emerging adults with T1D. PMID- 26121464 TI - ABSENCE OF A THYROID PHENOTYPE IN SORTILIN-DEFICIENT MICE. AB - OBJECTIVE: The Vps10p family member sortilin is expressed in thyroid epithelial cells where it contributes to recycling of the thyroid hormone precursor thyroglobulin (Tg), a process that is thought to render hormone release more effective. Here we investigated the functional impact of sortilin in the thyroid gland using sortilin-deficient mice. METHODS: We measured free T4, thyroid stimulating hormone (TSH) and Tg serum levels and studied thyroid morphology in 14 sortilin-deficient (Sort1)(-/-)and 12 wildtype (WT) mice. RESULTS: Serum free T4 levels did not differ between Sort1(-/-)and WT females but were significantly lower in Sort1(-/-)males compared with WT (P = .0424). Neither serum TSH nor Tg levels differed between Sort1(-/-)and WT mice, regardless of sex. On the same line, no thyroid histology differences were observed. CONCLUSION: Our findings seem to exclude a role of sortilin in thyroid hormone secretion, although it is possible that the absence of sortilin may result in a thyroid phenotype if combined with other molecular defects of thyroid hormone synthesis and secretion or under iodine deficiency. PMID- 26121466 TI - Hydrologic-Process-Based Soil Texture Classifications for Improved Visualization of Landscape Function. AB - Soils lie at the interface between the atmosphere and the subsurface and are a key component that control ecosystem services, food production, and many other processes at the Earth's surface. There is a long-established convention for identifying and mapping soils by texture. These readily available, georeferenced soil maps and databases are used widely in environmental sciences. Here, we show that these traditional soil classifications can be inappropriate, contributing to bias and uncertainty in applications from slope stability to water resource management. We suggest a new approach to soil classification, with a detailed example from the science of hydrology. Hydrologic simulations based on common meteorological conditions were performed using HYDRUS-1D, spanning textures identified by the United States Department of Agriculture soil texture triangle. We consider these common conditions to be: drainage from saturation, infiltration onto a drained soil, and combined infiltration and drainage events. Using a k means clustering algorithm, we created soil classifications based on the modeled hydrologic responses of these soils. The hydrologic-process-based classifications were compared to those based on soil texture and a single hydraulic property, Ks. Differences in classifications based on hydrologic response versus soil texture demonstrate that traditional soil texture classification is a poor predictor of hydrologic response. We then developed a QGIS plugin to construct soil maps combining a classification with georeferenced soil data from the Natural Resource Conservation Service. The spatial patterns of hydrologic response were more immediately informative, much simpler, and less ambiguous, for use in applications ranging from trafficability to irrigation management to flood control. The ease with which hydrologic-process-based classifications can be made, along with the improved quantitative predictions of soil responses and visualization of landscape function, suggest that hydrologic-process-based classifications should be incorporated into environmental process models and can be used to define application-specific maps of hydrologic function. PMID- 26121465 TI - Economic Evaluation alongside Multinational Studies: A Systematic Review of Empirical Studies. AB - PURPOSE OF THE STUDY: This study seeks to explore methods for conducting economic evaluations alongside multinational trials by conducting a systematic review of the methods used in practice and the challenges that are typically faced by the researchers who conducted the economic evaluations. METHODS: A review was conducted for the period 2002 to 2012, with potentially relevant articles identified by searching the Medline, Embase and NHS EED databases. Studies were included if they were full economic evaluations conducted alongside a multinational trial. RESULTS: A total of 44 studies out of a possible 2667 met the inclusion criteria. Methods used for the analyses varied between studies, indicating a lack of consensus on how economic evaluation alongside multinational studies should be carried out. The most common challenge appeared to be related to addressing differences between countries, which potentially hinders the generalisability and transferability of results. Other challenges reported included inadequate sample sizes and choosing cost-effectiveness thresholds. CONCLUSIONS: It is recommended that additional guidelines be developed to aid researchers in this area and that these be based on an understanding of the challenges associated with multinational trials and the strengths and limitations of alternative approaches. Guidelines should focus on ensuring that results will aid decision makers in their individual countries. PMID- 26121467 TI - Metal-organic framework-derived porous carbon polyhedra for highly efficient capacitive deionization. AB - Porous carbon polyhedra (PCP) were prepared through direct carbonization of zeolitic imidazolate framework-8 and used as an electrode material for capacitive deionization. The results show that PCP treated at 1200 degrees C exhibit the highest electrosorption capacity of 13.86 mg g(-1) when the initial NaCl concentration is 500 mg l(-1), due to their high accessible surface area and low charge transfer resistance. PMID- 26121468 TI - Three-Dimensional Surface Parameters and Multi-Fractal Spectrum of Corroded Steel. AB - To study multi-fractal behavior of corroded steel surface, a range of fractal surfaces of corroded surfaces of Q235 steel were constructed by using the Weierstrass-Mandelbrot method under a high total accuracy. The multi-fractal spectrum of fractal surface of corroded steel was calculated to study the multi fractal characteristics of the W-M corroded surface. Based on the shape feature of the multi-fractal spectrum of corroded steel surface, the least squares method was applied to the quadratic fitting of the multi-fractal spectrum of corroded surface. The fitting function was quantitatively analyzed to simplify the calculation of multi-fractal characteristics of corroded surface. The results showed that the multi-fractal spectrum of corroded surface was fitted well with the method using quadratic curve fitting, and the evolution rules and trends were forecasted accurately. The findings can be applied to research on the mechanisms of corroded surface formation of steel and provide a new approach for the establishment of corrosion damage constitutive models of steel. PMID- 26121469 TI - Research on the Effect of Electrical Signals on Growth of Sansevieria under Light Emitting Diode (LED) Lighting Environment. AB - The plant electrical signal has some features, e.g. weak, low-frequency and time varying. To detect changes in plant electrical signals, LED light source was used to create a controllable light environment in this study. The electrical signal data were collected from Sansevieria leaves under the different illumination conditions, and the data was analyzed in time domain, frequency domain and time frequency domain, respectively. These analyses are helpful to explore the relationship between changes in the light environment and electrical signals in Sansevieria leaves. The changes in the plant electrical signal reflected the changes in the intensity of photosynthesis. In this study, we proposed a new method to express plant photosynthetic intensity as a function of the electrical signal. That is, the plant electrical signal can be used to describe the state of plant growth. PMID- 26121470 TI - t-Darpp Promotes Enhanced EGFR Activation and New Drug Synergies in Her2-Positive Breast Cancer Cells. AB - Trastuzumab has led to improved survival rates of HER2+ breast cancer patients. However, acquired resistance remains a problem in the majority of cases. t-Darpp is over-expressed in trastuzumab-resistant cell lines and its over-expression is sufficient for conferring the resistance phenotype. Although its mechanism of action is unknown, t-Darpp has been shown to increase cellular proliferation and inhibit apoptosis. We have reported that trastuzumab-resistant BT.HerR cells that over-express endogenous t-Darpp are sensitized to EGFR inhibition in the presence (but not the absence) of trastuzumab. The purpose of the current study was to determine if t-Darpp might modulate sensitivity to EGFR inhibitors in trastuzumab resistant cells. Using EGFR tyrosine kinase inhibitors AG1478, gefitinib and erlotinib, we found that trastuzumab-resistant SK.HerR cells were sensitized to EGFR inhibition, compared to SK-Br-3 controls, even in the absence of trastuzumab. t-Darpp knock-down in SK.HerR cells reversed their sensitivity to EGFR inhibition. Increased EGFR sensitivity was also noted in SK.tDp cells that stably over-express t-Darpp. High levels of synergy between trastuzumab and the EGFR inhibitors were observed in all cell lines with high t-Darpp expression. These cells also demonstrated more robust activation of EGFR signaling and showed greater EGFR stability than parental cells. The T75A phosphorylation mutant of t Darpp did not confer sensitivity to EGFR inhibition nor activation of EGFR signaling. The over-expression of t-Darpp might facilitate enhanced EGFR signaling as part of the trastuzumab resistance phenotype. This study suggests that the presence of t-Darpp in HER2+ cancers might predict the enhanced response to dual HER2/EGFR targeting. PMID- 26121471 TI - Immunization with an ApoB-100 Related Peptide Vaccine Attenuates Angiotensin-II Induced Hypertension and Renal Fibrosis in Mice. AB - Recent studies suggest the potential involvement of CD8+ T cells in the pathogenesis of murine hypertension. We recently reported that immunization with apoB-100 related peptide, p210, modified CD8+ T cell function in angiotensin II (AngII)-infused apoE (-/-) mice. In this study, we hypothesized that p210 vaccine modulates blood pressure in AngII-infused apoE (-/-) mice. Male apoE (-/-) mice were immunized with p210 vaccine and compared to unimmunized controls. At 10 weeks of age, mice were subcutaneously implanted with an osmotic pump which released AngII for 4 weeks. At 13 weeks of age, p210 immunized mice showed significantly lower blood pressure response to AngII compared to controls. CD8+ T cells from p210 immunized mice displayed a different phenotype compared to CD8+ T cells from unimmunized controls. Serum creatinine and urine albumin to creatinine ratio were significantly decreased in p210 immunized mice suggesting that p210 vaccine had renal protective effect. At euthanasia, inflammatory genes IL-6, TNF alpha, and MCP-1 in renal tissue were down-regulated by p210 vaccine. Renal fibrosis and pro-fibrotic gene expression were also significantly reduced in p210 immunized mice. To assess the role of CD8+ T cells in these beneficial effects of p210 vaccine, CD8+ T cells were depleted by CD8 depleting antibody in p210 immunized mice. p210 immunized mice with CD8+ T cell depletion developed higher blood pressure compared to mice receiving isotype control. Depletion of CD8+ T cells also increased renal fibrotic gene expression compared to controls. We conclude that immunization with p210 vaccine attenuated AngII-induced hypertension and renal fibrosis. CD8+ T cells modulated by p210 vaccine could play an important role in the anti-hypertensive, anti-fibrotic and renal protective effect of p210 vaccine. PMID- 26121472 TI - Upregulation of TMEM16A Protein in Bronchial Epithelial Cells by Bacterial Pyocyanin. AB - Induction of mucus hypersecretion in the airway epithelium by Th2 cytokines is associated with the expression of TMEM16A, a Ca2+-activated Cl- channel. We asked whether exposure of airway epithelial cells to bacterial components, a condition that mimics the highly infected environment occurring in cystic fibrosis (CF), also results in a similar response. In cultured human bronchial epithelial cells, treatment with pyocyanin or with a P. aeruginosa culture supernatant caused a significant increase in TMEM16A function. The Ca2+-dependent Cl- secretion, triggered by stimulation with UTP, was particularly enhanced by pyocyanin in cells from CF patients. Increased expression of TMEM16A protein and of MUC5AC mucin by bacterial components was demonstrated by immunofluorescence in CF and non-CF cells. We also investigated TMEM16A expression in human bronchi by immunocytochemistry. We found increased TMEM16A staining in the airways of CF patients. The strongest signal was observed in CF submucosal glands. Our results suggest that TMEM16A expression/function is upregulated in CF lung disease, possibly as a response towards the presence of bacteria in the airways. PMID- 26121473 TI - De novo Transcriptome Assemblies of Rana (Lithobates) catesbeiana and Xenopus laevis Tadpole Livers for Comparative Genomics without Reference Genomes. AB - In this work we studied the liver transcriptomes of two frog species, the American bullfrog (Rana (Lithobates) catesbeiana) and the African clawed frog (Xenopus laevis). We used high throughput RNA sequencing (RNA-seq) data to assemble and annotate these transcriptomes, and compared how their baseline expression profiles change when tadpoles of the two species are exposed to thyroid hormone. We generated more than 1.5 billion RNA-seq reads in total for the two species under two conditions as treatment/control pairs. We de novo assembled these reads using Trans-ABySS to reconstruct reference transcriptomes, obtaining over 350,000 and 130,000 putative transcripts for R. catesbeiana and X. laevis, respectively. Using available genomics resources for X. laevis, we annotated over 97% of our X. laevis transcriptome contigs, demonstrating the utility and efficacy of our methodology. Leveraging this validated analysis pipeline, we also annotated the assembled R. catesbeiana transcriptome. We used the expression profiles of the annotated genes of the two species to examine the similarities and differences between the tadpole liver transcriptomes. We also compared the gene ontology terms of expressed genes to measure how the animals react to a challenge by thyroid hormone. Our study reports three main conclusions. First, de novo assembly of RNA-seq data is a powerful method for annotating and establishing transcriptomes of non-model organisms. Second, the liver transcriptomes of the two frog species, R. catesbeiana and X. laevis, show many common features, and the distribution of their gene ontology profiles are statistically indistinguishable. Third, although they broadly respond the same way to the presence of thyroid hormone in their environment, their receptor/signal transduction pathways display marked differences. PMID- 26121474 TI - Visible Light Induces Melanogenesis in Human Skin through a Photoadaptive Response. AB - Visible light (400-700 nm) lies outside of the spectral range of what photobiologists define as deleterious radiation and as a result few studies have studied the effects of visible light range of wavelengths on skin. This oversight is important considering that during outdoors activities skin is exposed to the full solar spectrum, including visible light, and to multiple exposures at different times and doses. Although the contribution of the UV component of sunlight to skin damage has been established, few studies have examined the effects of non-UV solar radiation on skin physiology in terms of inflammation, and limited information is available regarding the role of visible light on pigmentation. The purpose of this study was to determine the effect of visible light on the pro-pigmentation pathways and melanin formation in skin. Exposure to visible light in ex-vivo and clinical studies demonstrated an induction of pigmentation in skin by visible light. Results showed that a single exposure to visible light induced very little pigmentation whereas multiple exposures with visible light resulted in darker and sustained pigmentation. These findings have potential implications on the management of photo-aggravated pigmentary disorders, the proper use of sunscreens, and the treatment of depigmented lesions. PMID- 26121475 TI - What Explains Child Malnutrition of Indigenous People of Northeast India? AB - Household risk factors affecting child health, particularly malnutrition, are mainly basic amenities like drinking water, toilet facility, housing and fuel used for cooking. This paper considered the collective impact of basic amenities measured by an index specially constructed as the contextual factor of child malnutrition. The contextual factor operates at both the macro and micro levels namely the state level and the household level. The importance of local contextual factors is especially important when studying the nutritional status of children of indigenous people living in remote and inaccessible regions. This study has shown the contextual factors as potential factors of malnutrition among children in northeast India, which is home to the largest number of tribes in the country. In terms of macro level contextual factor it has been found that 8.9 per cent, 3.7 per cent and 3.6 per cent of children in high, medium and low risk households respectively, are severely wasted. Lower micro level household health risks, literate household heads, and scheduled tribe households have a negating effect on child malnutrition. Children who received colostrum feeding at the time of birth and those who were vaccinated against measles are also less subject to wasting compared to other children, and these differences are statistically significant. PMID- 26121476 TI - Decoy Receptor 3 Improves Survival in Experimental Sepsis by Suppressing the Inflammatory Response and Lymphocyte Apoptosis. AB - PURPOSE: Unbalanced inflammatory response and lymphocyte apoptosis is associated with high mortality in septic patients. Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is an anti-inflammatory and anti apoptotic factor. Recently, DcR3 expression was found to be increased in septic patients. This study evaluated the therapeutic effect and mechanisms of DcR3 on cecal ligation and puncture (CLP)-induced sepsis in mice. METHODS: C57BL/6 mice were subjected to CLP-induced polymicrobial sepsis. DcR3 Fc was intravenously injected 30 min before and 6 h after CLP. Bacterial clearance, cytokine production, histology, lymphocyte apoptosis and survival were evaluated. Furthermore, we investigated the systemic effects of DcR3 in in vitro lymphocyte apoptosis regulation. RESULTS: Our results demonstrated that DcR3 protein treatments significantly improved survival in septic mice (p <0.05). Treatment with DcR3 protein significantly reduced the inflammatory response and decreased lymphocyte apoptosis in the thymus and spleen. Histopathological findings of the lung and liver showed milder impairment after DcR3 administration. In vitro experiments showed that DcR3 Fc inhibited Fas-FasL mediated lymphocyte apoptosis. CONCLUSIONS: Treatment with the DcR3 protein protects mice from sepsis by suppressing the inflammatory response and lymphocyte apoptosis. DcR3 protein may be useful in treatment of sepsis. PMID- 26121477 TI - Titanium Dioxide Nanoparticles Induce Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death via Mitochondria-Associated Endoplasmic Reticulum Membrane Disruption in Normal Lung Cells. AB - Nanomaterials are used in diverse fields including food, cosmetic, and medical industries. Titanium dioxide nanoparticles (TiO2-NP) are widely used, but their effects on biological systems and mechanism of toxicity have not been elucidated fully. Here, we report the toxicological mechanism of TiO2-NP in cell organelles. Human bronchial epithelial cells (16HBE14o-) were exposed to 50 and 100 MUg/mL TiO2-NP for 24 and 48 h. Our results showed that TiO2-NP induced endoplasmic reticulum (ER) stress in the cells and disrupted the mitochondria-associated endoplasmic reticulum membranes (MAMs) and calcium ion balance, thereby increasing autophagy. In contrast, an inhibitor of ER stress, tauroursodeoxycholic acid (TUDCA), mitigated the cellular toxic response, suggesting that TiO2-NP promoted toxicity via ER stress. This novel mechanism of TiO2-NP toxicity in human bronchial epithelial cells suggests that further exhaustive research on the harmful effects of these nanoparticles in relevant organisms is needed for their safe application. PMID- 26121478 TI - The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis. AB - AIMS: To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus. METHODS: Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo) in adults with type 2 diabetes and a mean body mass index >= 25 kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator. RESULTS: In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg), exenatide 20 MUg: -1.37 kg (95% CI: -222 kg, -0.52 kg), liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg) and liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss. CONCLUSIONS: This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed. PMID- 26121479 TI - Warming-Induced Decline of Picea crassifolia Growth in the Qilian Mountains in Recent Decades. AB - Warming-induced drought has widely affected forest dynamics in most places of the northern hemisphere. In this study, we assessed how climate warming has affected Picea crassifolia (Qinghai spruce) forests using tree growth-climate relationships and the normalized difference vegetation index (NDVI) along the Qilian Mountains, northeastern Tibet Plateau (the main range of Picea crassifolia). Based on the analysis on trees radial growth data from the upper tree line and the regional NDVI data, we identified a pervasive growth decline in recent decades, most likely caused by warming-induced droughts. The drought stress on Picea crassifolia radial growth were expanding from northeast to southwest and the favorable moisture conditions for tree growth were retreating along the identical direction in the study area over the last half century. Compared to the historical drought stress on tree radial growth in the 1920s, recent warming-induced droughts display a longer-lasting stress with a broader spatial distribution on regional forest growth. If the recent warming continues without the effective moisture increasing, then a notable challenge is developed for Picea crassifolia in the Qilian Mountains. Elaborate forest management is necessary to counteract the future risk of climate change effects in this region. PMID- 26121480 TI - A Comparison of Entecavir and Lamivudine for the Prophylaxis of Hepatitis B Virus Reactivation in Solid Tumor Patients Undergoing Systemic Cytotoxic Chemotherapy. AB - BACKGROUND: Nucleos(t)ide analogues reduce the incidence of hepatitis B virus (HBV) reactivation in cancer patients undergoing systemic cytotoxic chemotherapy but the experience of solid tumors remains limited. Aims. The aim of this study was to compare the efficacy of entecavir and lamivudine in the prophylaxis of HBV reactivation in solid tumor patients undergoing systemic cytotoxic chemotherapy. METHODS: HBsAg seropositive patients undergoing systemic cytotoxic chemotherapy for solid tumors with prophylactic entecavir and lamivudine between January 2006 and June 2013 were retrospectively investigated. The incidence of HBV reactivation and outcome of the patients were analyzed. The risk factors of HBV reactivation were examined. RESULTS: A total of 213 patients (entecavir group, 70 patients; lamivudine group, 143 patients) were evaluated. Less incidence of HBV reactivation was noticed in entecavir group than in lamivudine group (0% vs. 7.0%, P = 0.02). No HBV reactivation was noticed in the patients with a baseline HBV DNA level < 2000 IU/mL. A baseline HBV DNA level >= 2000 IU/mL, HBeAg, and lamivudine were significantly associated with HBV reactivation. Subgroup analysis of the patients with a baseline HBV DNA level >= 2000 IU/mL found that lamivudine was significantly associated with HBV reactivation. Most of the reactivation events were properly managed by using tenofovir disoproxil fumarate. The incidence of hepatitis during chemotherapy and disruption of chemotherapy was similar between patients using entecavir and lamivudine with a baseline HBV DNA level >= or < 2000 IU/mL. CONCLUSIONS: A baseline HBV DNA level >= 2000 IU/mL, HBeAg, and lamivudine were the risk factors of HBV reactivation during systemic cytotoxic chemotherapy in solid tumor patients. Entecavir was superior to lamivudine in terms of less incidence of reactivation in the patients with a baseline HBV DNA level >= 2000 IU/mL. Both agents were equally efficacious in the patients with HBV DNA levels < 2000 IU/mL. PMID- 26121481 TI - Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase gamma. AB - A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kgamma were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kgamma selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described. PMID- 26121482 TI - Correction: A Maize Jasmonate Zim-Domain Protein, ZmJAZ14, Associates with the JA, ABA, and GA Signaling Pathways in Transgenic Arabidopsis. PMID- 26121483 TI - Correction: EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer. PMID- 26121484 TI - Assessment of Hemostasis after Plasma Exchange Using Rotational Thrombelastometry (ROTEM). AB - BACKGROUND: Therapeutic plasma exchange (TPE)-based protocols immediately before cadaveric donor kidney transplantation have been extensively used in highly sensitized recipients. Plasma is generally preferred over human albumin as replacement fluid to avoid depletion of coagulation factors and perioperative bleeding. The aim of this study was to estimate bleeding risk after TPE replaced with albumin using rotational thromboelastography (ROTEM). METHODOLOGY: Ten patients without overt coagulation abnormalities underwent TPE. Standard laboratory coagulation tests (thromboplastin time, activated partial thromboplastin time (aPTT), international normalized ratio (INR), thrombin clotting time, fibrinogen levels and antithrombin activity) were compared with thrombelastometry analysis (EXTEM and INTEM tests) before and after TPE. PRINCIPAL FINDINGS: TPE significantly reduced fibrinogen levels (482 +/- 182 vs. 223 +/- 122 mg/dL), antithrombin activity (103 +/- 11 vs. 54 +/- 11 %), and prolonged aPTT (28 +/- 3 vs. 45 +/- 8 s), thromboplastin time (108 +/- 11 vs. 68 +/- 11 %), INR (0.95 +/- 0.06 vs. 1.25 +/- 0.16), and thrombin clotting time (18 +/- 2 vs. 20 +/- 3 s). INTEM and EXTEM analyses revealed significantly prolonged clot-formation time and reduced maximum clot firmness. CONCLUSIONS/SIGNIFICANCE: TPE replaced with albumin induces significant changes in global hemostasis parameters thus potentially increasing bleeding risk. Therefore, pretransplant TPE should be considered carefully in indicated patients before kidney transplantation. The role of the ROTEM point-of-care test to estimate the risk of bleeding in renal transplantation needs to be evaluated in further studies. PMID- 26121485 TI - Mammography Screening in a Large Health System Following the U.S. Preventive Services Task Force Recommendations and the Affordable Care Act. AB - BACKGROUND: Practice recommendations for mammography screening were issued by the U.S. Preventive Services Task Force in 2009 and expansion of insurance coverage was provided under the Patient Protection and Affordable Care Act soon thereafter, yet the influence of these changes on screening practices in the United States is not known. METHODS: To determine changes in mammography screening and their associations with new practice recommendations and the Affordable Care Act, we examined patient-level data from 249,803 screening mammograms from January 1, 2008 through December 31, 2012 in a large community based health system in the northwestern United States. Associations were determined by an intervention analysis of time-series data method. RESULTS: Among women screened, 64% were age 50-74 years; 84% self-identified as white race; 62% had commercial insurance; and 70% were seen in facilities located in metropolitan areas. Practice recommendations were associated with decreased screening volumes among women age <40 (-37.4 mammograms/month; -39.4% change; P<0.001), 40-49 ( 106.0 mammograms/month; -11.2% change; P<0.001), and >=75 (-54.7 mammograms/month; -10.0% change; P<0.001), but not women age 50-74. Implementation of the Affordable Care Act was associated with increased screening among women age 50-74 (+184.3 mammograms/month; +7.2% change; P=0.001), but not women <40 or >=75; increases for age 40-49 were of borderline statistical significance (+56.9 mammograms/month; +6% change; P=0.06). Practice recommendations were also associated with decreased screening for women with commercial insurance, while the Affordable Care Act was associated with increased screening for women with Medicare, Medicaid, or other noncommercial sources of payment. CONCLUSIONS: Mammography screening volumes in a large community health system decreased among women age <50 and >=75 in association with new U.S. Preventive Services Task Force practice recommendations, while insurance coverage changes under the Affordable Care Act were associated with increased screening volumes among women age 50-74. PMID- 26121486 TI - Diabetes Mellitus and the Risk of Depressive and Anxiety Disorders in Australian Women: A Longitudinal Study. AB - BACKGROUND: Longitudinal studies examining the risk of depressive and anxiety disorders associated with diabetes are limited. This study examined the association between diabetes and the risk of depressive and anxiety disorders in Australian women using longitudinal data. METHODS: Data were from a sample of women who were part of an Australian pregnancy and birth cohort study. Data comprised self-reported diabetes mellitus and the subsequent reporting of depressive and anxiety disorders. Mood disorders were assessed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, obtained from participants using Composite International Diagnostic Interview (CIDI)-Auto (WHO WMH-CIDI CAPI, version 21.1.3). Multiple regression models with adjustment for important covariates were used. RESULTS: Women with diabetes had a higher lifetime prevalence of any depressive and/or anxiety disorder than women without diabetes. About 3 in 10 women with diabetes experienced a lifetime event of any depressive disorder, while 1 in 2 women with diabetes experienced a lifetime event of any anxiety disorder. In prospective analyses, diabetes was only significantly associated with a 30-day episode of any anxiety disorder (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.09-2.15). In the case of lifetime disorders, diabetes was significantly associated with any depressive disorder (OR 1.37, 95% CI 1.03-1.84), major depressive disorder (OR 1.36, 95% CI 1.01-1.85), and posttraumatic stress disorder (OR 1.42, 95% CI 1.01-2.02). CONCLUSIONS: The findings suggest that the presence of diabetes is a significant risk factor for women experiencing current anxiety disorders. However, in the case of depression, the association with diabetes only held for women who had experienced past episodes, there was no association with current depression. This suggests that the evidence is not strong enough to support a direct effect of diabetes as a cause of mood disorders. PMID- 26121487 TI - Graphene Near-Degenerate Four-Wave Mixing for Phase Characterization of Broadband Pulses in Ultrafast Microscopy. AB - We investigate near-degenerate four-wave mixing in graphene using femtosecond laser pulse shaping microscopy. Intense near-degenerate four-wave mixing signals on either side of the exciting laser spectrum are controlled by amplitude and phase shaping. Quantitative signal modeling for the input pulse parameters shows a spectrally flat phase response of the near-degenerate four-wave mixing due to the linear dispersion of the massless Dirac Fermions in graphene. Exploiting these properties we demonstrate that graphene is uniquely suited for the intrafocus phase characterization and compression of broadband laser pulses, circumventing disadvantages of common methods utilizing second or third harmonic light. PMID- 26121488 TI - Mitochondrial dysfunction and Parkinson disease: a Parkin-AMPK alliance in neuroprotection. AB - Although a subject of intense research, the etiology of Parkinson disease (PD) remains poorly understood. However, a wide range of studies conducted over the past few decades have collectively implicated aberrant mitochondrial homeostasis as a key contributor to the development of PD. Particularly strong support for this came from the recent demonstration that parkin, a familial PD-linked gene, is a critical regulator of mitochondrial quality control. Indeed, Parkin appears to be involved in all stages of the mitochondrial life cycle (i.e., from biogenesis to its exit from the cell (via mitophagy). Interestingly, the role of Parkin in the biogenesis and clearance of mitochondria is akin to that performed by the energy sensor AMP-activated protein kinase (AMPK), suggesting that the two proteins might act in a functionally converging manner to maintain the quality of cellular mitochondria. In this review, we discuss the contribution of mitochondrial dysfunction to PD pathogenesis and the role of Parkin and AMPK in preserving neuronal mitochondrial homeostasis. Alongside this, we will also articulate our thoughts on the potential alliance between Parkin and AMPK in offering neuroprotection through their ability to maintain energy balance in the brain. PMID- 26121489 TI - The immunomodulatory properties of adult skin-derived precursor Schwann cells: implications for peripheral nerve injury therapy. AB - Skin-derived precursor Schwann cell (SKPSC) therapy has been identified as a potentially beneficial treatment for peripheral nerve injuries. One hypothesised mechanism by which SKPSCs enhance recovery is via the modulation of macrophages. In the present study, we investigated the immunomodulatory properties of adult rat SKPSCs, and demonstrated that these cells expressed a battery of cytokines, including interferon-gamma (IFN-gamma), interleukin (IL)-1beta, and, most abundantly, IL-6. Whereas macrophages exposed to depleted or fibroblast conditioned medium secreted minimal amounts of tumor necrosis factor-alpha (TNF alpha), in the presence of SKPSC-conditioned medium, macrophages secreted > 500 pg/mL TNF-alpha. Following the transplantation of SKPSCs into injured rat sciatic nerves, we observed an SKPSC density-dependent increase in the number of macrophages (Pearson's r = 0.66) and an SKPSC density-dependent decrease in myelin debris (Pearson's r = -0.68). To determine the effect of IL-6 in a proinflammatory context, macrophage cultures were primed with either lipopolysaccharide (LPS)/IFN-gamma/IL-1beta or LPS/IFN-gamma/IL-1beta + IL-6, and this showed a 212% and 301% increase in the number of inducible nitric oxide synthase (iNOS)-positive proinflammatory macrophages respectively. In contrast to neurons exposed to conditioned medium from unprimed macrophages, neurons treated with conditioned medium from proinflammatory-primed macrophages showed a 13-26% reduction in neurite outgrowth. Anti-IL-6 antibody combined with SKPSC transplant therapy following nerve injury did not alter macrophage numbers or debris clearance, but instead reduced iNOS expression as compared with SKPSC + IgG treated rats. SKPSC + anti-IL-6 treatment also resulted in a two-fold increase in gastrocnemius compound muscle action potential amplitudes as compared with SKPSC + IgG treatment. Understanding the mechanisms underlying immunomodulatory aspects of SKPSC therapy and developing approaches to manipulate these responses are important for advancing Schwann cell-based therapies. PMID- 26121490 TI - A molecular biomarker to diagnose community-acquired pneumonia on intensive care unit admission. AB - RATIONALE: Community-acquired pneumonia (CAP) accounts for a major proportion of intensive care unit (ICU) admissions for respiratory failure and sepsis. Diagnostic uncertainty complicates case management, which may delay appropriate cause-specific treatment. OBJECTIVES: To characterize the blood genomic response in patients with suspected CAP and identify a candidate biomarker for the rapid diagnosis of CAP on ICU admission. METHODS: The study comprised two cohorts of consecutively enrolled patients treated for suspected CAP on ICU admission. Patients were designated CAP (cases) and no-CAP patients (control subjects) by post hoc assessment. The first (discovery) cohort (101 CAP and 33 no-CAP patients) was enrolled between January 2011 and July 2012; the second (validation) cohort (70 CAP and 30 no-CAP patients) between July 2012 and June 2013. Blood was collected within 24 hours of ICU admission. MEASUREMENTS AND MAIN RESULTS: Blood microarray analysis of CAP and no-CAP patients revealed shared and distinct gene expression patterns. A 78-gene signature was defined for CAP, from which a FAIM3:PLAC8 gene expression ratio was derived with area under curve of 0.845 (95% confidence interval, 0.764-0.917) and positive and negative predictive values of 83% and 81%, respectively. Robustness of the FAIM3:PLAC8 ratio was ascertained by quantitative polymerase chain reaction in the validation cohort. The FAIM3:PLAC8 ratio outperformed plasma procalcitonin and IL-8 and IL-6 in discriminating between CAP and no-CAP patients. CONCLUSIONS: CAP and no-CAP patients presented shared and distinct blood genomic responses. We propose the FAIM3:PLAC8 ratio as a candidate biomarker to assist in the rapid diagnosis of CAP on ICU admission. Clinical trial registered with www.clinicaltrials.gov (NCT 01905033). PMID- 26121491 TI - HIV-1 Genetic Diversity and Its Impact on Baseline CD4+T Cells and Viral Loads among Recently Infected Men Who Have Sex with Men in Shanghai, China. AB - The HIV-1 epidemic among men who have sex with men (MSM) has been spreading throughout China. Shanghai, a central gathering place for MSM, is facing a continuously increasing incidence of HIV-1 infection. In order to better understand the dynamics of HIV-1 diversity and its influence on patient's immune status at baseline on diagnosis, 1265 newly HIV-1-infected MSM collected from January 2009 to December 2013 in Shanghai were retrospectively analyzed for genetic subtyping, CD4+T cell counts, and viral loads. HIV-1 phylogenetic analysis revealed a broad viral diversity including CRF01_AE (62.13%), CRF07_BC (24.51%), subtype B (8.06%), CRF55_01B (3.24%), CER67_01B (0.95%), CRF68_01B (0.4%), CRF08_BC (0.08%) and CRF59_01B (0.08%). Twenty-four unique recombination forms (URFs) (1.98%) were identified as well. Bayesian inference analysis indicated that the introduction of CRF01_AE strain (1997) was earlier than CRF07_BC strain (2001) into MSM population in Shanghai based on the time of the most recent common ancestor (tMRCA). Three epidemic clusters and five sub clusters were found in CRF01_AE. Significantly lower CD4+T cell count was found in individuals infected with CRF01_AE than in those infected with CRF07_BC infection (P<0.01), whereas viral load was significantly higher those infected with CRF01_AE than with CRF07_BC (P<0.01). In addition, the patients with >45 years of age were found to have lower CD4+T cell counts and higher viral loads than the patients with <25 years of age (P<0.05). This study reveals the presence of HIV-1 subtype diversity in Shanghai and its remarkable influence on clinical outcome. A real-time surveillance of HIV-1 viral diversity and phylodynamics of epidemic cluster, patient's baseline CD4+T cell count and viral load would be of great value to monitoring of disease progression, intervention for transmission, improvement of antiretroviral therapy strategy and design of vaccines. PMID- 26121492 TI - Single Exposure to near Roadway Particulate Matter Leads to Confined Inflammatory and Defense Responses: Possible Role of Metals. AB - Inhalation of traffic-associated atmospheric particulate matter (PM2.5) is recognized as a significant health risk. In this study, we focused on a single ("subclinical response") exposure to water-soluble extracts from PM collected at a roadside site in a major European city to elucidate potential components that drive pulmonary inflammatory, oxidative, and defense mechanisms and their systemic impacts. Intratracheal instillation (IT) of the aqueous extracts induced a 24 h inflammatory response characterized by increased broncho-alveolar lavage fluid (BALF) cells and cytokines (IL-6 and TNF-alpha), increased reactive oxygen species production, but insignificant lipids and proteins oxidation adducts in mouse lungs. This local response was largely self-resolved by 48 h, suggesting that it could represent a subclinical response to everyday-level exposure. Removal of soluble metals by chelation markedly diminished the pulmonary PM mediated response. An artificial metal solution (MS) recapitulated the PM extract response. The self-resolving nature of the response is associated with activating defense mechanisms (increased levels of catalase and glutathione peroxidase expression), observed with both PM extract and MS. In conclusion, metals present in PM collected near roadways are largely responsible for the observed transient local pulmonary inflammation and oxidative stress. Simultaneous activation of the antioxidant defense response may protect against oxidative damage. PMID- 26121494 TI - Prognostic importance of weight change on short-term functional outcome in acute ischemic stroke. AB - BACKGROUND: Controversy exists regarding the question of whether weight change decreases or increases the risk of mortality. AIM: The aim of this study was to evaluate the prognostic importance of weight change on short-term outcomes in acute ischemic stroke patients. METHODS: A total of 654 patients with acute ischemic stroke were enrolled in this study from March 2010 to May 2013. We assessed the weight change of each participant between admission and discharge from the Department of Neurology. Weight change was defined as change >=0.05 kg/baseline body mass index unit. We evaluated the short-term outcomes using a modified Rankin Scale at three-months after the onset of a stroke. RESULTS: Among the 654 patients, 35.2% were included in the weight-change group. Weight loss occurred in 24.6% of the participants during the hospital stay following the stroke, which lasted an average of nine-days. Compared with the weight-stable group, the pronounced weight-loss group had a higher risk of unfavorable outcomes (odds ratio 2.43; 95% confidence interval 1.12-5.25). CONCLUSIONS: Short-term weight loss after stroke appears to be more common than we expected, and our results suggest that it is associated with unfavorable functional outcomes. Therefore, clinical nutrition should be considered as a component of medical treatment and weight loss should be monitored as an indicator of malnutrition. PMID- 26121495 TI - Extinction learning as a moderator of d-cycloserine efficacy for enhancing exposure therapy in posttraumatic stress disorder. AB - Augmentation of exposure therapy with d-cycloserine (DCS) has proven efficacious across anxiety disorders, although results in PTSD have been mixed. Work in animals and anxiety-disordered patients suggest that the potentiating effects of DCS are dependent on the level of extinction learning during extinction training and exposure treatment, respectively. The aim of the current study was to replicate and extend previous work by examining the association between the degree of extinction learning and DCS efficacy in our randomized clinical trial on DCS (50 mg) versus placebo enhancement of exposure therapy in a chronic mixed trauma PTSD sample (N=67; de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012). The decline in subjective units of distress ratings collected during and across the exposure sessions were evaluated as indices of extinction learning. First, we examined whether extinction learning during an exposure session moderated DCS effects on self-reported PTSD symptoms at the next session. Second, we examined whether averaged extinction learning over the course of treatment interacted with group assignment to predict change over time and post treatment outcome. We did not find evidence that DCS effects were moderated by the degree of extinction learning, although, extinction learning was related to outcome regardless of group assignment. In PTSD, not one extinction-learning index has been consistently linked to DCS enhanced exposure treatment outcome. More (experimental) work needs to been done to unravel the complex interplay between extinction learning and DCS enhancement, especially in PTSD patients. PMID- 26121493 TI - Inhibition of the Inositol Kinase Itpkb Augments Calcium Signaling in Lymphocytes and Reveals a Novel Strategy to Treat Autoimmune Disease. AB - Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease. PMID- 26121496 TI - Anxiety sensitivity and post-traumatic stress reactions: Evidence for intrusions and physiological arousal as mediating and moderating mechanisms. AB - A growing body of research has implicated anxiety sensitivity (AS) and its dimensions in the development of post-traumatic stress disorder (PTSD). However, the mechanism(s) that may account for the association between AS and PTSD remains unclear. Using the "trauma film paradigm," which provides a prospective experimental tool for investigating analog intrusion development, the present study examines the extent to which intrusions mediate the association between AS and the development of posttraumatic stress reactions. After completing a measure of AS and state mood, unselected participants (n = 45) viewed a 10 min film of graphic scenes of fatal traffic accidents and then completed a second assessment of state mood. Participants then kept a daily diary to record intrusions about the film for a one-week period. Post-traumatic stress reactions about the film were then assessed after the one-week period. The results showed that general AS and physical and cognitive concerns AS predicted greater post-traumatic stress reactions about the film a week later. Furthermore, the number of intrusions the day after viewing the traumatic film, but not fear and disgust in response to the trauma film, mediated the association between general AS (and AS specifically for physical and cognitive concerns) and post-traumatic stress reactions a week later. Subsequent analysis also showed that physiological arousal during initial exposure to the traumatic film moderated the association between general AS and the number of intrusions reported the day after viewing the film. The implications of these analog findings for conceptualizing the mechanism(s) that may interact to explain the role of AS in the development of PTSD and its effective treatment are discussed. PMID- 26121497 TI - Fast perception of binocular disparity. AB - Is depth perception from binocular disparities-stereopsis-slow or fast? Many of the temporal properties of stereopsis are known. For example, rapidly changing disparities are perceptually difficult to track, which suggests that stereopsis is generally slow. But, remarkably, this basic question has not yet been addressed. We compared speed-accuracy trade-off functions between 2 forced-choice discriminations: 1 based on stereoscopic depth and 1 based on luminance. Unexpectedly, both speed-accuracy trade-off functions deviated from chance levels of accuracy at the same response time-approximately 200 ms-with stereo accuracy increasing, on average, more slowly than luminance accuracy after this initial delay. Thus, the initial processing of disparity for perceived depth took no longer than the initial processing of luminance for perceived brightness. This finding, that binocular disparities are available early during visual processing, means that depth is perceived quickly, and, intriguingly, that disparities may be more important for everyday visual function than previously thought. PMID- 26121498 TI - The attentional cost of receiving a cell phone notification. AB - It is well documented that interacting with a mobile phone is associated with poorer performance on concurrently performed tasks because limited attentional resources must be shared between tasks. However, mobile phones generate auditory or tactile notifications to alert users of incoming calls and messages. Although these notifications are generally short in duration, they can prompt task irrelevant thoughts, or mind wandering, which has been shown to damage task performance. We found that cellular phone notifications alone significantly disrupted performance on an attention-demanding task, even when participants did not directly interact with a mobile device during the task. The magnitude of observed distraction effects was comparable in magnitude to those seen when users actively used a mobile phone, either for voice calls or text messaging. PMID- 26121499 TI - A deficit perceiving slow motion after brain damage and a parallel deficit induced by crowding. AB - Motion perception is known to involve at least 2 kinds of mechanisms-lower level signal detectors and higher level algorithms for comparing object positions over time. When stimulus motion is modal (continuously visible), it is generally assumed that processing via lower level mechanisms is sufficient to make accurate motion judgments. We investigated the possibility that higher level mechanisms may also be involved in the processing of slow motion, even when it is smooth and continuous. This possibility was suggested by results from a brain-damaged patient, JKI, who showed left visual field deficits in both the explicit representation of object position and judgments concerning the direction of slow, but not fast, smooth motion. We investigated the possibility further by using crowding to induce a behaviorally similar motion-perception deficit in healthy observers. Crowding, which is known to impair object-position representation, impaired direction judgments for slow, but not for faster, smooth motion. The results suggest an everyday role for higher level mechanisms in the perception of slow motion, and they reinforce the taxonomy of motion perception in terms of underlying processing mechanisms as opposed to stimulus properties. PMID- 26121500 TI - Syntactic processing in the absence of awareness and semantics. AB - The classical view that multistep rule-based operations require consciousness has recently been challenged by findings that both multiword semantic processing and multistep arithmetic equations can be processed unconsciously. It remains unclear, however, whether pure rule-based cognitive processes can occur unconsciously in the absence of semantics. Here, after presenting 2 words consciously, we suppressed the third with continuous flash suppression. First, we showed that the third word in the subject-verb-verb format (syntactically incongruent) broke suppression significantly faster than the third word in the subject-verb-object format (syntactically congruent). Crucially, the same effect was observed even with sentences composed of pseudowords (pseudo subject-verb adjective vs. pseudo subject-verb-object) without any semantic information. This is the first study to show that syntactic congruency can be processed unconsciously in the complete absence of semantics. Our findings illustrate how abstract rule-based processing (e.g., syntactic categories) can occur in the absence of visual awareness, even when deprived of semantics. PMID- 26121501 TI - ZnxGe1-xO 3D micronano structures with excellent performance as anode material in lithium ion battery. AB - As anode material used in power storage device, lithium ion battery (LIB) for example, ZnO has not been recognized as a promising candidate, although which shows advantages like environmental benign, low cost, and large reservation. Several problems, such as volume expansion, pulverization, and active substance detachment because of the particular lithiation kinetics, which result in very high irreversible capacity and following fading, can account for the present situation. Here in this work, we report the self-assembly of ZnxGe1-xO three dimensional (3D) micronano structures and achieve enormous improvement on both recyclability and rate performance. After the 100th cycle, the capacity remains ~690 mAh/g at the rate of 100 and ~510 mA/g at the rate of 500 mAh/g. The capacity recovered rapidly even the rates alternating repeatedly between 50 mA/g and 3.5A/g. Ex situ observation reveals that substance detachment and nanoparticle agglomeration were avoided, benefiting from the firm 3D space configuration. As the Li(+) insertion, the 3D architectures fracture hierarchically with releasing the volume-expansion produced strain. Stable and smooth Li(+)/electrons path would form in these nanoparticles integrated microfragments, which act as the working unit free of further detachment. These facts demonstrate that ZnO based anode materials are anticipant to be good candidate in LIB device through rational design of advanced mirco-nano structures without introduction of carbon coating. PMID- 26121502 TI - Revisiting the analysis of impedance data for double layer capacitance. AB - A method was developed to extract double layer capacitance (C(dl)) from data displaying time constant dispersion at a frequency where the phase angle reached its maximum (f1). This method was implemented in a set of synthetic data and the Kramers-Kronig (K-K) transformable experimental data for mild steel in an acidic solution. The double layer capacitance values were compared with ones extracted from the constant phase element (CPE) parameters, Y(o) and alpha, at a frequency where the imaginary part of the impedance reached its maximum (f2). A significant closeness of the results was reached for two different frequencies. PMID- 26121503 TI - Vietnam Veterans--Thank Them for Their Service. PMID- 26121505 TI - Caring for Vietnam Veterans. AB - Veterans of the Vietnam era are now the largest group of United States Veterans, and are at or approaching Social Security and Medicare eligibility. As a result, it is likely that home care clinicians will be caring for many patients who are Vietnam Veterans. The purpose of this article is to increase awareness of the unique healthcare needs of Vietnam Veterans. Having an understanding of military and Veteran culture can help inform home healthcare clinicians in ways to manage the unique healthcare needs of Veterans and engage previously learned behaviors and attitudes from military service. In addition, knowing the types of exposures and health risks specific to this era could be beneficial in identifying potential problems that may have not yet been addressed. PMID- 26121507 TI - Best Practices for Managing Medical Equipment and Supplies Stored in a Vehicle. AB - Home care clinicians often have to transport supplies to patients' homes, and remove and transport items from the home after care is provided. This article will provide guidelines and best practices for the proper methods of managing and storing infection prevention and control supplies and regulated medical waste in a home care clinician's personal vehicle. PMID- 26121509 TI - Smoking Cessation Strategies for Patients with COPD. AB - Smoking cessation remains the priority intervention for patients suffering from chronic obstructive pulmonary disease (COPD) to slow progression of lung tissue damage, decrease symptoms, and enhance quality of life. This article highlights ways home healthcare clinicians can incorporate Prochaska's stages of change to individualize smoking cessation interventions for COPD patients. By assessing patients' readiness-to-quit and implementing evidence-based teaching techniques, including motivational interviewing, home healthcare clinicians can identify specific strategies to promote smoking cessation and enhance the health and quality of life for this population. PMID- 26121510 TI - Dyspnea Management of Hospice Patients. AB - Up to 70% of hospice patients are reported to experience dyspnea at end of life. Despite the high prevalence of this burdensome symptom, there is little in the literature to guide effective treatment. Assessment of subjective symptoms and objective signs as well as physical, psychospiritual, sociocultural, or environmental barriers is critical to an effective plan of care. The purpose of the article is to review the current literature on assessment and management of dyspnea in hospice patients and provide implications for hospice clinicians. PMID- 26121511 TI - Welcoming Home the Patient with a New Ostomy. AB - The 5-day average inpatient hospital length-of-stay postostomy limits opportunities for patients and family members to master self-care of the new ostomy prior to discharge. The literature suggests premature discharge, poor care coordination, lack of symptom reporting and follow-up as the primary factors supporting causes of readmissions. Home care nurses are faced with failed handoffs, limited resources, poor care coordination, payor restrictions, and knowledge and skill deficits that negatively impact safe and effective discharge practices of patients with a new ostomy. This article describes an evolving community standard related to nursing care of the patient with a new ostomy as identified by the Baltimore Wound, Ostomy, Continence (WOC) Nursing Affiliate. Case managers, discharge planners, intake team members, and home care nurses benefit from ongoing education from WOC nurse experts to master the skills needed to care for patients with ostomies. PMID- 26121512 TI - Implementation of Transition in Care and Relationship Based Care to Reduce Preventable Rehospitalizations. AB - Home healthcare agencies are accountable for preventing rehospitalization, yet many struggle to make progress with this metric. The purpose of this article is to share how our organization turned to two frameworks, Transitions in Care and Relationship-Based Care, to prevent unnecessary rehospitalizations. Appreciative inquiry, motivational interviewing, and action plans are used by our Transitional Care Nurses to engage and motivate patients to manage chronic diseases and achieve desirable health outcomes. Implementation of a Transitional Care Program has led our organization to improve the health of our patients and to decrease rehospitalization rates. PMID- 26121513 TI - Type 2 Diabetes and Bariatric Surgery. PMID- 26121514 TI - Oral Syringes: A Crucial and Economical Risk-Reduction Strategy That Has Not Been Fully Utilized. PMID- 26121515 TI - A Day in the Life of a Nursing Student During a Hospice Rotation. PMID- 26121516 TI - Common Questions About Pacemakers and Implantable Cardioverter Defibrillators. PMID- 26121517 TI - Quality Measures in Home Care: How Can We Prepare? PMID- 26121518 TI - Human Touch Trumps Technology. PMID- 26121519 TI - [The Anterior "Triple-/Quadruple" Technique for C1/C2 Trauma in the Elderly: First Experience with 16 Patients]. AB - INTRODUCTION: In geriatric patients the management of odontoid type II fractures is complicated by osteoporosis and atlantoaxial arthritis (spondylarthritis C1/C2) with an increased lever arm. Furthermore, a few of the odontoid fractures are accompanied by an atlas fracture resulting in the "atlantoaxial unhappy triad". Posterior C1/C2 spondylodesis with bilateral Magerl screws and C1 hooks is a strong biomechanical construct, however, the posterior approach is associated with several drawbacks such as increased risk of infection and increased blood loss. In contrast, the anterior bilateral C1/C2 transarticular screw fixation with additional odontoid screw fixation is also a known technique. Advantages of the anterior approach are shorter surgery time, lower intraoperative blood loss and lower risk of infection. MATERIALS AND METHODS: In this retrospective study, all geriatric patients with an atlantoaxial arthritis and odontoid or combined atlantoaxial fracture treated at our institution between 01/2012 and 12/2014 with an anterior screw fixation were included. Following closed reduction, the surgical management was performed over a standard right anterior approach. At the end of surgery, operation time and blood loss were documented. During the hospital stay radiological follow-up of the upper cervical spine were performed to analyse the screw position. We also report the length of stay on intensive care unit, the hospital course and demographic data of the patients. Follow-up was planned after 6 weeks, 6, 12 and 18 months. During follow up COMI evaluation and X-rays of the cervical spine were made. RESULTS AND CONCLUSION: This study included 16 patients who underwent surgery for C1-C2 lesions. There were 9 females and 7 males. Median age at the time of operation was 76 years. At the time of surgery, fractures were classified as follows: 8 patients showed an "atlantoaxial unhappy triad", 8 patients had a type II odontoid fracture complicated by osteoporosis and atlantoaxial arthritis (spondylarthritis C1/C2). Average time for operative treatment was 100 +/- 36.35 minutes with a median intraoperative fluoroscopy time of 161 seconds. The intraoperative blood loss was minimal (45 +/- 22.80 ml). Length of stay was documented with 10 (+/- 4.60) days whereby the patients spent on average 0.8 days in the intensive care unit postoperatively. No serious morbidities, such as esophageal perforation, carotid artery laceration, neurological deterioration, and airway obstruction were reported. All cases of transient dysphagia resolved gradually and spontaneously without therapy. In 4 cases (25 %) we detected a penetration of the atlantooccipital joint without functional impairment. In one case we have seen an implant failure. The technique of anterior screw fixation of odontoid and bilateral transarticular C1-C2 anterior screw fixation provides a fast surgery without higher morbidity. Based on our findings, this technique and its feasibility is an alternative to known posterior C1/C2 spondylodesis in the elderly. PMID- 26121520 TI - [The Biological Knife II - Fracture Healing and Pharmacological Interactions]. AB - The reasons for delayed fracture healing or non-union formation are multifactorial. Mechanical factors are well known to influence the process of fracture healing. However, there is a lack of knowledge about the biological conditions that have to be achieved for adequate bone healing. Treatment of non unions is still demanding and we have only poor options to stimulate the bone healing process. Therefore, it is important to optimise the biological conditions to avoid non-union formation. Beside patient-related factors, pharmacological drugs are able to impede or stimulate fracture healing. Especially geriatric patients show a pre-existing drug medication due to different co-morbidities. However, also younger patients are frequently treated with different drugs for infection prophylaxis, analgesia or thrombosis prophylaxis. The aim of the current review article is to give an overview about the influence of different pharmacological agents on the process of fracture healing. A deeper understanding of a drug-related influence on fracture healing could help the medical practitioner to optimise the general conditions for adequate fracture healing, i.e., by avoiding specific pharmacological agents. Vice versa some drugs could be used to stimulate fracture healing in the future. PMID- 26121521 TI - [The Biological Knife I--Fracture Healing and Patient-Dependent Influencing Factors]. AB - Despite our growing knowledge about the mechanisms of fracture healing, about 5 to 10 % of all fractures show impaired healing or non-union formation. We have learned about the biomechanical requirements for adequate fracture healing, leading to sophisticated osteosynthesis techniques and specific implant systems. A poor "biology" is often made responsible for the failure of bone healing. However, the underlying "biological" mechanisms are multifactorial and poorly understood. There is a lack of knowledge and clinical evidence about specific biological factors which influence fracture healing. However, it is the responsibility of the medical practitioner to address all factors that could negatively influence fracture healing, while respecting general principles of conservative or operative fracture management. The current review aims to summarise patient-related factors that influence fracture healing including co morbidities of the patient just as well as life style-related factors such as smoking, nutrition and alcohol consumption. It is hardly possible to prove a significant influence for each of these factors in clinical studies, because homogeneous cohorts and very high patient numbers would be needed. Nevertheless, a deeper knowledge about these factors potentially influencing fracture healing could help us to improve fracture healing and decrease the number of non-unions in our patients. Just as well as the surgeons performs precise incisions with a knife, a precise analysis and improvement of the "biology" are possible and recommended. PMID- 26121522 TI - A comparison between general rheumatologists and scleroderma experts with respect to following systemic sclerosis guidelines. AB - OBJECTIVES: To determine if there are differences between expert and non-expert rheumatologists in systemic sclerosis (SSc) management. METHODS: Information relating to demographics, complications, investigations, and treatment of SSc patients was obtained from an online survey to members of the Canadian Rheumatology Association (CRA), and selected chart audits. Results were compared to data from a SSc database ('experts', Canadian Scleroderma Research Group- CSRG). RESULTS: The online survey (61/300 respondents; 20% response rate) found that most agreed with the EULAR SSc guidelines. Some exceptions were only 47% said they ordered annual echocardiograms and 45% pulmonary function tests. Chart audits of 70 SSc patients from 7 community rheumatology practices revealed no significant differences in their treatment from SSc guidelines, but some investigations differed compared to the CSRG. There was site variability among community practices relating to investigations, and treatment. Patients receiving an echocardiogram within the previous year varied from 10-90%, and PA pressure was reported in 30-100% of SSc patients among sites. Overall, 91% of SSc patients on chart audit had ever received an echocardiogram, but in 30% of cases there was no PA pressure recorded vs. only 19% in CSRG (p=0.001). CONCLUSIONS: Compared to SSc experts, general rheumatologists did not differ in their practices for many SSc guidelines despite the fact that they do not see many SSc patients when compared to SSc experts, but there was site variability. An apparent difference is that although echocardiograms are being ordered, PA pressures are missing which could lead to late detection of PAH. PMID- 26121523 TI - The ascent of man: Theoretical and empirical evidence for blatant dehumanization. AB - Dehumanization is a central concept in the study of intergroup relations. Yet although theoretical and methodological advances in subtle, "everyday" dehumanization have progressed rapidly, blatant dehumanization remains understudied. The present research attempts to refocus theoretical and empirical attention on blatant dehumanization, examining when and why it provides explanatory power beyond subtle dehumanization. To accomplish this, we introduce and validate a blatant measure of dehumanization based on the popular depiction of evolutionary progress in the "Ascent of Man." We compare blatant dehumanization to established conceptualizations of subtle and implicit dehumanization, including infrahumanization, perceptions of human nature and human uniqueness, and implicit associations between ingroup-outgroup and human animal concepts. Across 7 studies conducted in 3 countries, we demonstrate that blatant dehumanization is (a) more strongly associated with individual differences in support for hierarchy than subtle or implicit dehumanization, (b) uniquely predictive of numerous consequential attitudes and behaviors toward multiple outgroup targets, (c) predictive above prejudice, and (d) reliable over time. Finally, we show that blatant-but not subtle-dehumanization spikes immediately after incidents of real intergroup violence and strongly predicts support for aggressive actions like torture and retaliatory violence (after the Boston Marathon bombings and Woolwich attacks in England). This research extends theory on the role of dehumanization in intergroup relations and intergroup conflict and provides an intuitive, validated empirical tool to reliably measure blatant dehumanization. PMID- 26121524 TI - Close relationships and self-regulation: How relationship satisfaction facilitates momentary goal pursuit. AB - In the new millennium, scholars have built a robust intersection between close relationships research and self-regulation research. However, virtually no work has investigated how the most basic and broad indicator of relationship quality, relationship satisfaction, affects self-regulation and vice versa. In the present research, we show that higher relationship satisfaction promotes a motivational mind-set that is conducive for effective self-regulation, and thus for goal progress and performance. In Study 1-a large-scale, intensive experience sampling project of 115 couples (total N = 230)-we closely tracked fluctuations in state relationship satisfaction (SRS) and 4 parameters of effective self-regulation according to our conceptual model. Dyadic process analyses showed that individuals experiencing higher SRS than they typically do exhibited higher levels of (a) perceived control, (b) goal focus, (c) perceived partner support, and (d) positive affect during goal pursuit than they typically exhibit. Together, these 4 self-regulation-relevant variables translated into higher rates of daily progress on specific, idiographic goals. In Study 2 (N = 195), we employed a novel experimental manipulation of SRS, replicating the link between SRS and parameters of effective self-regulation. Taken together, these findings suggest that momentary increases in relationship satisfaction may benefit everyday goal pursuit through a combination of cognitive and affective mechanisms, thus further integrating relationship research with social-cognitive research on goal pursuit. PMID- 26121526 TI - Extracting Time-Accurate Acceleration Vectors From Nontrivial Accelerometer Arrangements. AB - Sports-related concussions are of significant concern in many impact sports, and their detection relies on accurate measurements of the head kinematics during impact. Among the most prevalent recording technologies are videography, and more recently, the use of single-axis accelerometers mounted in a helmet, such as the HIT system. Successful extraction of the linear and angular impact accelerations depends on an accurate analysis methodology governed by the equations of motion. Current algorithms are able to estimate the magnitude of acceleration and hit location, but make assumptions about the hit orientation and are often limited in the position and/or orientation of the accelerometers. The newly formulated algorithm presented in this manuscript accurately extracts the full linear and rotational acceleration vectors from a broad arrangement of six single-axis accelerometers directly from the governing set of kinematic equations. The new formulation linearizes the nonlinear centripetal acceleration term with a finite difference approximation and provides a fast and accurate solution for all six components of acceleration over long time periods (>250 ms). The approximation of the nonlinear centripetal acceleration term provides an accurate computation of the rotational velocity as a function of time and allows for reconstruction of a multiple-impact signal. Furthermore, the algorithm determines the impact location and orientation and can distinguish between glancing, high rotational velocity impacts, or direct impacts through the center of mass. Results are shown for ten simulated impact locations on a headform geometry computed with three different accelerometer configurations in varying degrees of signal noise. Since the algorithm does not require simplifications of the actual impacted geometry, the impact vector, or a specific arrangement of accelerometer orientations, it can be easily applied to many impact investigations in which accurate kinematics need to be extracted from single-axis accelerometer data. PMID- 26121525 TI - Wanting to maximize the positive and minimize the negative: implications for mixed affective experience in American and Chinese contexts. AB - Previous studies have demonstrated that European Americans have fewer mixed affective experiences (i.e., are less likely to experience the bad with the good) compared with Chinese. In this article, we argue that these cultural differences are due to "ideal affect," or how people ideally want to feel. Specifically, we predict that people from individualistic cultures want to maximize positive and minimize negative affect more than people from collectivistic cultures, and as a result, they are less likely to actually experience mixed emotions (reflected by a more negative within-person correlation between actual positive and negative affect). We find support for this prediction in 2 experience sampling studies conducted in the United States and China (Studies 1 and 2). In addition, we demonstrate that ideal affect is a distinct construct from dialectical view of the self, which has also been related to mixed affective experience (Study 3). Finally, in Study 4, we demonstrate that experimentally manipulating the desire to maximize the positive and minimize the negative alters participants' actual experience of mixed emotions during a pleasant (but not unpleasant or combined pleasant and unpleasant) TV clip in the United States and Hong Kong. Together, these findings suggest that across cultures, how people want to feel shapes how they actually feel, particularly people's experiences of mixed affect. PMID- 26121527 TI - Autosomal-dominant cutis laxa resulting from an intronic mutation in ELN. PMID- 26121528 TI - Situational Context and Perceived Threat Modulate Approachability Judgements to Emotional Faces. AB - Facial expressions of emotion play a key role in guiding social judgements, including deciding whether or not to approach another person. However, no research has examined how situational context modulates approachability judgements assigned to emotional faces, or the relationship between perceived threat and approachability judgements. Fifty-two participants provided approachability judgements to angry, disgusted, fearful, happy, neutral, and sad faces across three situational contexts: no context, when giving help, and when receiving help. Participants also rated the emotional faces for level of perceived threat and labelled the facial expressions. Results indicated that context modulated approachability judgements to faces depicting negative emotions. Specifically, faces depicting distress-related emotions (i.e., sadness and fear) were considered more approachable in the giving help context than both the receiving help and neutral context. Furthermore, higher ratings of threat were associated with the assessment of angry, happy and neutral faces as less approachable. These findings are the first to demonstrate the significant role that context plays in the evaluation of an individual's approachability and illustrate the important relationship between perceived threat and the evaluation of approachability. PMID- 26121529 TI - Cellular basis of detrusor smooth muscle contraction. PMID- 26121530 TI - A Traditional Diet Is Associated with a Reduced Risk of Eczema and Wheeze in Colombian Children. AB - BACKGROUND: Diet might influence the risk of allergic diseases. Evidence from developing countries with high prevalence of childhood asthma is scant. METHODS: Information on wheeze, rhinitis, and eczema was collected from 3209 children aged 6-7 years in 2005, who were taking part in the International Study on Asthma and Allergy in Children (ISAAC) in Colombia. Intake frequency of twelve food groups was assessed. Associations between each food group and current wheeze, rhino conjunctivitis, and eczema were investigated with multiple logistic regressions, adjusting for potential confounders. Simes' procedure was used to test for multiple comparisons. RESULTS: 14.9% of children reported wheeze in the last 12 months, 16% rhino-conjunctivitis, and 22% eczema. Eczema was negatively associated with consumption of fresh fruits and pulses three or more times per week (adjusted Odds ratio (aOR): 0.64; 95% Confidence Interval (CI): 0.49 to 0.83; p value = 0.004; and aOR: 0.62, 95% CI: 0.47 to 0.80; p value < 0.001, respectively). Current wheeze was negatively associated with intake of potatoes (aOR: 0.44, 95% CI: 0.31 to 0.62, p value = 0.005), whilst this outcome was positively associated with consumption of fast food (aOR: 1.76, 95% CI: 1.32 to 2.35, p value = 0.001). These associations remained statistically significant after controlling for multiple comparisons. CONCLUSIONS: A traditional diet might have a protective effect against eczema and wheeze in Colombian children, whilst intake of fast foods increases this risk. PMID- 26121532 TI - Trajectories of fathers' psychological distress across the early parenting period: Implications for parenting. AB - Fathers' parenting behavior is a likely key mechanism underlying the consistent associations between paternal mental health difficulties and poor emotional behavioral outcomes for children. This study investigates the association between fathers' mental health trajectories and key parenting behaviors (warmth, hostility, consistency) spanning the first 8-9 years postpartum. Secondary analyses of 5 waves of data from 2,662 fathers participating in the Longitudinal Study of Australian Children were conducted. Latent growth class analysis was used to identify distinct trajectories of fathers' distress (Kessler-6; Kessler et al., 2003), and latent growth models estimated parenting warmth, hostility, and consistency. Multiple group analyses were conducted to describe and compare the course of parenting behaviors for fathers assigned to the distress trajectories identified. Two distinct classes of fathers were identified based on the trajectories of distress: minimal distress (92%) and persistent and increasing distress (8%). The latter group reported significantly lower parenting warmth when their children were 8-9 years and lower consistency and higher hostility across all study intervals. The postnatal and early parenting period is a critical time for the development of parenting behaviors that are important for children's development. Engagement and support for fathers around well-being and parenting is vital for promoting optimal family and child developmental outcomes. PMID- 26121531 TI - Factors Affecting 25-Hydroxyvitamin D Concentration in Response to Vitamin D Supplementation. AB - Sun exposure is the main source of vitamin D. Due to many lifestyle risk factors vitamin D deficiency/insufficiency is becoming a worldwide health problem. Low 25(OH)D concentration is associated with adverse musculoskeletal and non musculoskeletal health outcomes. Vitamin D supplementation is currently the best approach to treat deficiency and to maintain adequacy. In response to a given dose of vitamin D, the effect on 25(OH)D concentration differs between individuals, and it is imperative that factors affecting this response be identified. For this review, a comprehensive literature search was conducted to identify those factors and to explore their significance in relation to circulating 25(OH)D response to vitamin D supplementation. The effect of several demographic/biological factors such as baseline 25(OH)D, aging, body mass index(BMI)/body fat percentage, ethnicity, calcium intake, genetics, oestrogen use, dietary fat content and composition, and some diseases and medications has been addressed. Furthermore, strategies employed by researchers or health care providers (type, dose and duration of vitamin D supplementation) and environment (season) are other contributing factors. With the exception of baseline 25(OH)D, BMI/body fat percentage, dose and type of vitamin D, the relative importance of other factors and the mechanisms by which these factors may affect the response remains to be determined. PMID- 26121533 TI - Neurophysiological Correlates of Children's Processing of Interparental Conflict Cues. AB - This study builds on the literature on child exposure to marital conflict by testing whether mother-reported marital conflict exposure predicts a child's P3 event-related potential (ERP) components generated in response to viewing quasi marital conflict photos. We collected ERP data from 23 children (9-11 years of age) while presenting photos of actors pretending to be a couple depicting interpersonal anger, happiness, and neutrality. To elicit the P3 ERP, stimuli were presented using an oddball paradigm, with angry and happy photos presented on 20% of trials each and neutral photos presented on the remaining 60% of trials. Angry photos were the target in 1 block, and happy photos were the target in the other block. In the angry block, children from high-conflict homes had shorter reaction times (RTs) on happy trials than on neutral trials, and children from low-conflict homes had shorter RTs on angry trials than on happy trials. Also within the angry block, children generated larger P3s on angry trials than on happy trials, regardless of exposure to conflict. Further, children from high conflict homes generated larger P3s on angry trials and on happy trials compared with neutral trials, but children from low-conflict homes did not. Results are discussed in terms of implications for children's processing of displays of interpersonal emotion. PMID- 26121534 TI - Relationship stigma and relationship outcomes in interracial and same-sex relationships: Examination of sources and buffers. AB - Interracial and same-sex romantic relationships are more common and socially accepted in the United States than ever before; yet, stigmatization of these relationships persists, with consequences for relationship dynamics. We conducted an online survey study with adults living in the United States in interracial and same-sex relationships to examine associations of relationship stigma from family, friends, and public with several relationship outcomes (i.e., investment, satisfaction, intimate partner aggression victimization and perpetration, commitment, intimacy, trust, passion, love, sexual communication, and sexual satisfaction), as well as the potential buffering roles of egalitarianism and dyadic coping. Regression analyses with 480 participants support that above and beyond individually experienced discrimination and other well-known predictors of relationship outcomes, relationship stigma from friends in particular was associated with lower relationship commitment, trust, love, and sexual communication, as well as greater odds of intimate partner aggression victimization. Egalitarianism and dyadic coping moderated some of the associations of relationship stigma from family, friends, and public with relationship outcomes, supporting their potential roles as buffers. These findings suggest many avenues for future research and implications for clinicians working with interracial and same-sex couples, individuals in those couples, and their families. Given increasing prevalence of interracial and same-sex relationships and marriages, more work should continue to explore these couples' experiences and how best to support them. PMID- 26121535 TI - Effectiveness and moderators of the preventive intervention kids in divorce situations: A randomized controlled trial. AB - Children of divorced parents have an increased risk of a variety of problems in comparison to children from intact families. Therefore, several intervention programs have been developed directed at children of divorced parents. Yet, empirical data on the effectiveness of these interventions are limited. This study evaluated the school-based, child-directed prevention program Kids In Divorce Situations (KIDS) using a randomized controlled trial. The sample consisted of 156 children randomly assigned at the school level into an experimental (80 children) and control condition (76 children). In addition, 131 mothers and 76 fathers participated in the study. Four assessments took place: a pretest, a posttest, and two follow-up assessments conducted 6 months and 1 year after finishing KIDS. Latent growth analyses demonstrated that the intervention significantly reduced child-reported emotional problems and enhanced child reported communication with the father and mother-reported communication with the child. The effect sizes ranged from .30-.63. Few moderation effects of gender, time since divorce, or perceived parental conflict on the intervention effects were found. After parental divorce, a limited school-based intervention for children can be efficacious in promoting children's emotional well-being and parent-child communication. PMID- 26121536 TI - How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society. PMID- 26121537 TI - Variability in Antibiotic Use Across Nursing Homes and the Risk of Antibiotic Related Adverse Outcomes for Individual Residents. AB - IMPORTANCE: Antibiotics are frequently and often inappropriately prescribed to patients in nursing homes. These antibiotics pose direct risks to recipients and indirect risks to others residing in the home. OBJECTIVE: To examine whether living in a nursing home with high antibiotic use is associated with an increased risk of antibiotic-related adverse outcomes for individual residents. DESIGN, SETTING, AND PARTICIPANTS: In this longitudinal open-cohort study performed from January 1, 2010, through December 31, 2011, we studied 110,656 older adults residing in 607 nursing homes in Ontario, Canada. EXPOSURES: Nursing home-level antibiotic use was defined as use-days per 1000 resident-days, and facilities were classified as high, medium, and low use according to tertile of use. Multivariable logistic regression modeling was performed to assess the effect of nursing home-level antibiotic use on the individual risk of antibiotic-related adverse outcomes. MAIN OUTCOMES AND MEASURES: Antibiotic-related harms included Clostridium difficile, diarrhea or gastroenteritis, antibiotic-resistant organisms (which can directly affect recipients and indirectly affect nonrecipients), allergic reactions, and general medication adverse events (which can affect only recipients). RESULTS: Antibiotics were provided on 2,783,000 of 50,953,000 resident-days in nursing homes (55 antibiotic-days per 1000 resident days). Antibiotic use was highly variable across homes, ranging from 20.4 to 192.9 antibiotic-days per 1000 resident-days. Antibiotic-related adverse events were more common (13.3%) in residents of high-use homes than among residents of medium-use (12.4%) or low-use homes (11.4%) (P < .001); this trend persisted even among the residents who did not receive antibiotic treatments. The primary analysis indicated that residence in a high-use nursing home was associated with an increased risk of a resident experiencing an antibiotic-related adverse event (adjusted odds ratio, 1.24; 95% CI, 1.07-1.42; P = .003). A sensitivity analysis examining nursing home-level antibiotic use as a continuous variable confirmed an increased risk of resident-level antibiotic-related harms (adjusted odds ratio, 1.004 per additional day of nursing home antibiotic use; 95% CI, 1.001-1.006; P = .01). CONCLUSIONS AND RELEVANCE: Antibiotic use is highly variable across nursing homes; residents of high-use homes are exposed to an increased risk of antibiotic related harms even if they have not directly received these agents. Antibiotic stewardship is needed to improve the safety of all nursing home residents. PMID- 26121538 TI - Direct measurement on the geometric phase of a double quantum dot qubit via quantum point contact device. AB - We propose a direct measurement scheme to read out the geometric phase of a coupled double quantum dot system via a quantum point contact(QPC) device. An effective expression of the geometric phase has been derived, which relates the geometric phase of the double quantum dot qubit to the current through QPC device. All the parameters in our expression are measurable or tunable in experiment. Moreover, since the measurement process affects the state of the qubit slightly, the geometric phase can be protected. The feasibility of the scheme has been analyzed. Further, as an example, we simulate the geometrical phase of a qubit when the QPC device is replaced by a single electron transistor(SET). PMID- 26121539 TI - A Case-matched Comparative Study of Laparoscopic Versus Open Distal Pancreatectomy. AB - INTRODUCTION: Although the laparoscopic approach to distal pancreatectomy for benign and malignant diseases is largely replacing open surgery in some centers, well-designed studies comparing these approaches are limited. We present a case matched study that compares the outcomes of laparoscopic distal pancreatectomy (LDP) to open distal pancreatectomy (ODP). METHODS: Of 112 patients (51 female) who underwent surgery between January 2002 and December 2011, 44 patients were matched on a 1:1 basis (22 LDP, 22 ODP) according to age, sex, and tumor size. Outcomes were compared on an intention-to-treat basis. Data shown represent median where appropriate. RESULTS: The laparoscopic and open groups were comparable for age (57 vs. 59.9 y, P=0.980), sex distribution (P=1.000), tumor size (3 vs. 4 cm, P=0.904), and the frequency of benign versus malignant disease (P=0.920). LDP was associated with significantly lower blood loss (100 vs. 500 mL, P=0.001), higher spleen preservation rate (45% vs. 18%, P=0.029), as well as shorter high dependency unit stay (1 vs. 5 d, P=0.001) and postoperative hospital stay (5 vs. 14 d, P=0.017). There was no significant difference in operating time (245 vs. 240 min, P=0.602) and postoperative morbidity (13.6% vs. 27.2%, P=0.431). In patients with malignant disease, there were no differences in R0 resection margin status (90% vs. 85.7%, P=0.88), the numbers of lymph nodes retrieved (12.7 vs. 14.1, P=0.82), the 1- and 2-year survival rates (89% vs. 81%, P=0.54 and 74.2% vs. 71.5%, P=0.63, respectively), and the mean duration of survival (45 vs. 31 mo, P=0.157). CONCLUSIONS: The laparoscopic approach to distal pancreatectomy offers advantages over open surgery in terms of reductions in operative trauma and duration of postoperative recovery without compromising the oncologic resection. PMID- 26121540 TI - Totally Percutaneous Endovascular Aneurysm Repair Using the Preclosing Technique: Towards the Least Invasive Therapeutic Alternative. AB - Endovascular aneurysm repair (EVAR) offers a minimally invasive approach for the treatment of abdominal aortic aneurysms, whereas arterial closure devices have made totally percutaneous EVAR feasible. This is a retrospective analysis of patients undergoing EVAR in a single institution, between May 2011 and October 2014 using surgical or percutaneous access. Hemostasis after percutaneous access was achieved with 2 Perclose ProGlide suture-mediated devices and a preclosing technique. Technical success, local complications, procedural times, length of hospitalization, and need for analgesics are recorded and compared between groups. Among 82 patients/164 groins, 120/164 (73%) groins underwent percutaneous and 44/146 (27%) surgical access. An average 2.2 devices per access site was used. Technical success was 95% (114/120). Local complications (3.3% vs. 11.4%, P=0.05), procedural times (90 vs. 112 min, P=0.05), hospitalization (2 vs. 5 d, P<0.001), and postoperative analgesics (0.7 vs. 4.4 g IV paracetamol, P=0.01) were significantly reduced after percutaneous access which overall seems safe and effective to perform EVAR. PMID- 26121541 TI - Harness Traction Technique (HARNESS): Novel Method for Controlling the Transection Plane During Laparoscopic Hepatectomy. AB - We present our experience using a novel method for controlling the transection plane, which we termed as the Harness Traction Technique (HARNESS) and evaluate its usefulness. From May 2009 to March 2012, laparoscopic hepatectomies using HARNESS were performed on 35 patients. After the superficial hepatic parenchyma on the line was transected at 1 to 2 cm depth, 5 mm tape was placed along the groove of the line and tied to prevent it from slipping off. Tape was tied and pulled using a forceps toward the best direction for minimizing the bleeding, moving the transection point to the appropriate position and creating good tension for parenchymal transection at the transection point. There were no conversions to laparotomy or intraoperative complications. HARNESS is useful for controlling the dissection line during laparoscopic hepatectomy, leading to precise and safe laparoscopic liver parenchymal dissection. PMID- 26121542 TI - BiClamp-Fracture Method in Pure Laparoscopic Hepatectomy: Verifying its Efficacy Irrespective of Liver Stiffness. AB - BACKGROUND: Transecting cirrhotic liver in pure laparoscopic hepatectomy (PLH) is generally considered technically demanding. We have preferentially used BiClamp in PLH by fracturing liver parenchyma using this device. The aim of the current study was to retrospectively verify the efficacy of BiClamp-fracture method in transecting cirrhotic parenchyma. METHODS: The medical records of 21 patients who underwent PLH using BiClamp-fracture method between April 2011 and September 2014 were examined. The patients were divided into the Nonstiff group (F0-F2, n=11) and the Stiff group (F3 and F4, n=10) and various surgical factors were compared between the groups. RESULTS: The mean operation time, the mean intraoperative blood loss, and the mean postoperative hospital stay in the Stiff group were comparable with those in the Nonstiff group. There were no postoperative complications in both groups. CONCLUSION: BiClamp-fracture method was effective in transecting liver parenchyma irrespective of liver stiffness in PLH. PMID- 26121543 TI - Laparoscopic Left Hemihepatectomy for Left-sided Hepatolithiasis. AB - INTRODUCTION: Hepatolithiasis is a prevalent disease in the southeastern coastal regions of China. Partial hepatectomy is the most definitive treatment for hepatolithiasis. This study evaluated the safety and efficacy of the laparoscopic left hemihepatectomy (LLH) for left-sided hepatolithiasis. METHODS: The clinical data of 37 consecutive patients who underwent pure LLH for left-sided hepatolithiasis at Yinzhou Second Hospital between March 2009 and December 2013 were reviewed retrospectively. RESULTS: Pure LLH was performed successfully in 36 patients. Because of severe adhesions from previous choledochotomy, 1 patient was converted to open procedure. The mean operative time was 257.9 minutes (range, 188 to 396 min). The mean duration of postoperative hospital stay was 11.7 days (range, 8 to 21 d). There were 2 (5.4 %) cases of postoperative bile leakage, 2 (5.4%) cases of intra-abdominal fluid collection, and 1 (2.7%) case of incisional infection, which were successfully managed conservatively. Residual stones were observed in 2 (5.4%) patients. The residual stones were located in the common bile duct in these cases and were removed through the T-tube tract by choledochoscopy. During a mean follow-up of 31.3 months (range, 6 to 63 mo), recurrent stones were detected in 2 (5.4%) patients and were successfully treated with endoscopic sphincterotomy. CONCLUSIONS: LLH for left-sided hepatolithiasis is feasible and safe in selected patients. PMID- 26121544 TI - Results of Immediate Discharge From Postanesthesia Care Unit to Home After Laparoscopic Appendectomy for Acute Nonperforated Appendicitis. AB - BACKGROUND: This study examines the efficacy and safety of immediate discharge from the postanesthesia care unit after laparoscopic appendectomy for patients with acute nonperforated appendicitis. METHODS: A retrospective study of 114 laparoscopic appendectomy cases was performed. Seventy-four patients met inclusion criteria of having uncomplicated acute appendicitis. Patient demographics, operative times, length of postoperative stay, and complication rates were analyzed. RESULTS: Only 3 of the 74 patients failed to be discharged immediately. Mean postoperative discharge time was 130.5 minutes with 86% of patients leaving within 3 hours. Delay in voiding was the most common cause of stays longer than 4 hours. Six of the 74 patients (8%) returned to the emergency room without need for readmission. There were no complications associated with the early discharge. CONCLUSIONS: Immediate discharge from the postanesthesia care unit for patients with acute nonperforated appendicitis appears safe and effective in the community hospital setting. PMID- 26121545 TI - Muscle Relaxation in Laparoscopic Surgery: What is the Evidence for Improved Operating Conditions and Patient Outcome? A Brief Review of the Literature. AB - When neuromuscular blocking agents (NMBA) were introduced into clinical practice in 1942, the event was called the "second revolution in anesthesia." Despite some significant side effects, NMBAs have remained in the anesthetists' repertoire, not at least because muscle relaxation has been claimed to allow or facilitate many surgical procedures. Aim of this literature review was to investigate the evidence for the use of NMBA as well as the optimum depth of neuromuscular blockade during laparoscopic surgery. Muscle relaxation may optimize laparoscopic operating conditions by preventing patient movement and achieving more intra abdominal space for a given intra-abdominal insufflation pressure. In this context, deeper than normally maintained levels of neuromuscular blockade appear to be superior. However, the decision to utilize deeper than standard muscle relaxation should currently be based on a risk-benefit analysis for each individual patient. Thus good communication between surgeon and anesthetist remains crucial to achieve best outcomes. PMID- 26121546 TI - Xylitol Gum Chewing to Achieve Early Postoperative Restoration of Bowel Motility After Laparoscopic Surgery. AB - Our objective was to evaluate the effects of postoperative xylitol gum chewing on gastrointestinal functional recovery after laparoscopy. Altogether, 120 patients undergoing elective gynecologic laparoscopy were randomly divided into 2 groups of 60 each (final numbers: 53 controls, 56 patients). Controls underwent a routine postoperative regimen. Starting 6 hour after surgery, study patients chewed mint-flavored, sugarless xylitol gum until flatus occurred thrice a day. Other postoperative management was routine. First bowel sounds, first flatus, first bowel movement, and discharge times were recorded. Symptoms included abdominal distension, nausea, and vomiting. First flatus and first bowel sounds occurred significantly (P<0.001) earlier in the study patients. No significant differences were found for first defecation time, hospitalization duration, or mild/severe intestinal obstruction (all P>0.05). Thus, xylitol gum chewing after laparoscopy can effectively shorten the time to first flatus and helps with postoperative gastrointestinal functional recovery. It is simple, convenient, and well tolerated. PMID- 26121547 TI - Economic Implications of Providing Emergency Cholecystectomy for All Patients With Biliary Pathology: A Retrospective Analysis. AB - INTRODUCTION: This study assessed the safety and efficacy of acute laparoscopic cholecystectomy (ALC) in patients presenting with biliary pathology. The potential savings plus income generation for the hospital were calculated. METHODS: All patients undergoing emergency cholecystectomy were identified from computerized and hand-written theater records to ensure complete capture. Length of stay, procedure time, patient demographics, and postoperative complications were recorded. Tariffs for conservative versus acute management were calculated. Total admissions and readmissions with biliary pathology (acute cholecystitis, biliary colic, gallstone pancreatitis, and obstructive jaundice) over a 12-month period were recorded. RESULTS: Eighty-four patients undergoing ALC were identified. There was only 1 major complication (1 postoperative bleed managed laparoscopically). ALC for all admissions would result in savings of L 695,918 over 12 months. The implementation of ALC for all patients would result in a small loss in revenue when compared with elective laparoscopic cholecystectomy (L 15,495) provided that all operations could be accommodated on established operating lists. Implementing ALC on all appropriate biliary admissions could generate up to 3 cholecystectomies daily for a population base of 1 million. CONCLUSIONS: ALC is cost-effective and safe. It can be offered to all patients with biliary pathology provided they are fit enough for surgery. PMID- 26121548 TI - Surgical Outcomes of Laparoscopic Liver Resection in Elderly Patients: A Comparative Study From a Single Center. AB - The life expectancy continues to gradually increase worldwide. Laparoscopic liver resection (LLR) was recently reported to be a relatively safe procedure for treatment of liver disease because of the development of new techniques and instruments. The aim of this study was to evaluate the surgical outcomes of elderly patients who underwent LLR. Of these 61 patients who underwent LLR in our institute from January 2010 through April 2014, 21 were aged 75 years and above (group E), and 40 were aged below 75 years (group NE). Patient characteristics were retrospectively analyzed between the 2 groups. The results showed that patient characteristics were similar between the 2 groups, although the incidence of hypertension was significantly greater among patients in group E. There were no significant differences in the incidence of postoperative complications or length of hospital stay between the 2 groups. In conclusion, LLR for elderly patients was a feasible procedure compared with nonelderly patients. PMID- 26121549 TI - Strategic Approach to the Splenic Artery in Laparoscopic Spleen-preserving Distal Pancreatectomy. AB - BACKGROUND: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) is an ideal procedure in selected patients with benign or low-grade malignant tumors in the body/tail of the pancreas. We describe our procedure and experience with splenic vessel-preserving LSPDP (SVP-LSPDP) in a retrospective case series. METHODS: Six consecutive patients underwent SVP-LSPDP from January 2011 to September 2013. We evaluated the courses of the splenic artery by preoperative computed tomography and applied an individualized approach (the superior approach or inferior approach) to the splenic artery. RESULTS: All of the operations were successful. The median surgical duration was 249 minutes. The median blood loss was 0 mL. Pathologic examination revealed 4 cases of insulinoma, 1 case of solid pseudopapillary tumor, and 1 case of pancreatic metastasis from renal carcinoma. CONCLUSIONS: In performing SVP-LSPDP, it is effective to make a strategic choice between 2 different approaches according to the course of splenic artery. PMID- 26121550 TI - Molecular metal phosphonates. PMID- 26121552 TI - Electronic doping and redox-potential tuning in colloidal semiconductor nanocrystals. AB - Electronic doping is one of the most important experimental capabilities in all of semiconductor research and technology. Through electronic doping, insulating materials can be made conductive, opening doors to the formation of p-n junctions and other workhorses of modern semiconductor electronics. Recent interest in exploiting the unique physical and photophysical properties of colloidal semiconductor nanocrystals for revolutionary new device technologies has stimulated efforts to prepare electronically doped colloidal semiconductor nanocrystals with the same control as available in the corresponding bulk materials. Despite the impact that success in this endeavor would have, the development of general and reliable methods for electronic doping of colloidal semiconductor nanocrystals remains a long-standing challenge. In this Account, we review recent progress in the development and characterization of electronically doped colloidal semiconductor nanocrystals. Several successful methods for introducing excess band-like charge carriers are illustrated and discussed, including photodoping, outer-sphere electron transfer, defect doping, and electrochemical oxidation or reduction. A distinction is made between methods that yield excess band-like carriers at thermal equilibrium and those that inject excess charge carriers under thermal nonequilibrium conditions (steady state). Spectroscopic signatures of such excess carriers, accessible by both equilibrium and nonequilibrium methods, are reviewed and illustrated. A distinction is also proposed between the phenomena of electronic doping and redox-potential shifting. Electronically doped semiconductor nanocrystals possess excess band-like charge carriers at thermal equilibrium, whereas redox-potential shifting affects the potentials at which charge carriers are injected under nonequilibrium conditions, without necessarily introducing band-like charge carriers at equilibrium. Detection of the key spectroscopic signatures of band-like carriers allows distinction between these two regimes. Both electronic doping and redox-potential shifting can be powerful tools for tuning the performance of nanocrystals in electronic devices. Finally, key chemical challenges associated with nanocrystal electronic doping are briefly discussed. These challenges are centered largely on the availability of charge-carrier reservoirs with suitable redox potentials and on the relatively poor control over nanocrystal surface traps. In most cases, the Fermi levels of colloidal nanocrystals are defined by the redox properties of their surface traps. Control over nanocrystal surface chemistries is therefore essential to the development of general and reliable strategies for electronically doping colloidal semiconductor nanocrystals. Overall, recent progress in this area portends exciting future advances in controlling nanocrystal compositions, surface chemistries, redox potentials, and charge states to yield new classes of electronic nanomaterials with attractive physical properties and the potential to stimulate unprecedented new semiconductor technologies. PMID- 26121553 TI - Alcohol, ageing and Australia. PMID- 26121551 TI - Inter-Individual Differences in the Oral Bacteriome Are Greater than Intra-Day Fluctuations in Individuals. AB - Given the advent of massively parallel DNA sequencing, human microbiome is analyzed comprehensively by metagenomic approaches. However, the inter- and intra individual variability and stability of the human microbiome remain poorly characterized, particularly at the intra-day level. This issue is of crucial importance for studies examining the effects of microbiome on human health. Here, we focused on bacteriome of oral plaques, for which repeated, time-controlled sampling is feasible. Eighty-one supragingival plaque subjects were collected from healthy individuals, examining multiple sites within the mouth at three time points (forenoon, evening, and night) over the course of 3 days. Bacterial composition was estimated by 16S rRNA sequencing and species-level profiling, resulting in identification of a total of 162 known bacterial species. We found that species compositions and their relative abundances were similar within individuals, and not between sampling time or tooth type. This suggests that species-level oral bacterial composition differs significantly between individuals, although the number of subjects is limited and the intra-individual variation also occurs. The majority of detected bacterial species (98.2%; 159/162), however, did not fluctuate over the course of the day, implying a largely stable oral microbiome on an intra-day time scale. In fact, the stability of this data set enabled us to estimate potential interactions between rare bacteria, with 40 co-occurrences supported by the existing literature. In summary, the present study provides a valuable basis for studies of the human microbiome, with significant implications in terms of biological and clinical outcomes. PMID- 26121554 TI - MgI2 -mediated chemoselective cleavage of protecting groups: an alternative to conventional deprotection methodologies. AB - The scope of MgI2 as a valuable tool for quantitative and mild chemoselective cleavage of protecting groups is described here. This novel synthetic approach expands the use of protecting groups, widens the concept of orthogonality in synthetic processes, and offers a facile opportunity to release compounds from solid supports. PMID- 26121556 TI - Metallophilic Contacts in 2-C6F4PPh2 Bridged Heterobinuclear Complexes: A Crystallographic and Computational Study. AB - Treatment of the bis(chelate) complex trans-[Pd(kappa(2)-2-C6F4PPh2)2] (7) with PMe3 gave trans-[Pd(kappaC-2-C6F4PPh2)2(PMe3)2] (13) as a mixture of syn- and anti-isomers. Reaction of 13 with CuCl, AgCl, or [AuCl(tht)] (tht = tetrahydrothiophene) gave the heterobinuclear complexes [(Me3P)2Pd(MU-2 C6F4PPh2)2MCl] [M = Cu (14), Ag (15), Au (16)], from which the corresponding salts [(Me3P)2Pd(MU-2-C6F4PPh2)2M]PF6 [M = Cu (17), Ag (18), Au (19)] could be prepared by abstraction of the chloro ligand with TlPF6; 18, as well as its triflato (20) and trifluoroacetato (21) analogues, were also prepared directly from 13 and the appropriate silver salt. Reaction of 13 with [AuCl(PMe3)] gave the zwitterionic complex [(Me3P)PdCl(MU-2-C6F4PPh2)2Au] (24) in which the 2 C6F4PPh2 ligands are in a head-to-head arrangement. In contrast, the analogous reaction with [AuCl(PPh3)] gave [(Ph3P)PdCl(MU-2-C6F4PPh2)2Au] (25) with a head to-tail ligand arrangement. Single crystal X-ray diffraction studies of complexes 14-21 show short metal-metal separations [2.7707(11)-2.9423(3) A] suggestive of attractive noncovalent (dispersion) interactions, a conclusion that is supported by theoretical calculations of the electron localization function and the noncovalent interactions descriptor. PMID- 26121557 TI - A Theoretical Study of Phosphoryl Transfers of Tyrosyl-DNA Phosphodiesterase I (Tdp1) and the Possibility of a "Dead-End" Phosphohistidine Intermediate. AB - Tyrosyl-DNA phosphodiesterase I (Tdp1) is a DNA repair enzyme conserved across eukaryotes that catalyzes the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3'-phosphate of DNA. Atomic level details of the mechanism of Tdp1 are proposed and analyzed using a fully quantum mechanical, geometrically constrained model. The structural basis for the computational model is the vanadate-inhibited crystal structure of human Tdp1 (hTdp1, Protein Data Bank entry 1RFF ). Density functional theory computations are used to acquire thermodynamic and kinetic data along the catalytic pathway, including the phosphoryl transfer and subsequent hydrolysis. Located transition states and intermediates along the reaction coordinate suggest an associative phosphoryl transfer mechanism with five-coordinate phosphorane intermediates. Similar to both theoretical and experimental results for phospholipase D, the proposed mechanism for hTdp1 also includes the thermodynamically favorable possibility of a four-coordinate phosphohistidine "dead-end" product. PMID- 26121555 TI - Integration of actin dynamics and cell adhesion by a three-dimensional, mechanosensitive molecular clutch. AB - During cell migration, the forces generated in the actin cytoskeleton are transmitted across transmembrane receptors to the extracellular matrix or other cells through a series of mechanosensitive, regulable protein-protein interactions termed the molecular clutch. In integrin-based focal adhesions, the proteins forming this linkage are organized into a conserved three-dimensional nano-architecture. Here we discuss how the physical interactions between the actin cytoskeleton and focal-adhesion-associated molecules mediate force transmission from the molecular clutch to the extracellular matrix. PMID- 26121558 TI - Photofragmentation Mechanisms of Chlorosulfonyl Isocyanate, ClSO2NCO, Excited with Synchrotron Radiation between 12 and 550 eV. AB - The unimolecular photofragmentation mechanisms of chlorosulfonyl isocyanate, ClSO2NCO, excited with tunable synchrotron radiation between 12 and 550 eV, were investigated by means of time-of-flight (TOF) coincidence techniques. The main fragmentation mechanism after single ionization, produced by irradiation of an effusive beam of the sample with synchrotron light in the valence electron region, occurs through the breaking of the Cl-S single bond, giving a chloride radical and a SO2NCO(+) fragment. This mechanism contrasts with the one observed for the related FSO2NCO, in which the rupture of the S-N bond originates the FSO2(+) fragment. The energies of the shallow- (S 2p, Cl 2p, and S 2s) and core shell (C 1s, N 1s, and O 1s) electrons were determined by X-ray absorption. Transitions between these shallow and core electrons to unoccupied molecular orbitals were also observed in the total ion yield (TIY) spectra. Fourteen different fragmentation mechanisms of the doubly charged parent ion, ClSO2NCO(2+), were inferred from the bidimensional photoelectron-photoion photoion-coincidence (PEPIPICO) spectra. The rupture of the S-N bond can evolve to form NCO(+)/SO2(*+), NCO(+)/SO(*+), or S(*+)/NCO(+) pairs of ions. The Cl-S bond breaking originates different mechanisms, Cl(+)/SO(*+), Cl(+)/S(*+), CO(*+)/S(*+), O(*+)/SO(*+), O(*+)/Cl(+), O(*+)/S(*+), C(*+)/S(*+), and C(*+)/O(*+) pairs being detected in coincidence as the final species. Another three coincidence islands can only be explained with an initial atomic rearrangement forming ClNCO(2+), ONCO(2+), and ClCO(2+), as precursors of CO(*+)/Cl(+), O(*+)/CO(*+), and C(*+)/Cl(+) pairs, respectively. The formation of Cl(*) radical is deduced from several mechanisms. PMID- 26121559 TI - Metal loading of lanthanidopolymers driven by positive cooperativity. AB - This work demonstrates how the thermodynamic loading of monodisperse polymeric single-stranded multi-tridentate receptors of variable lengths is controlled by the nature of the metallic carrier Ln(hfac)3 (Ln is La, Eu or Y, and hfac is hexafluoroacetylacetonate). Whereas the intrinsic affinity of the tridentate binding site is maximum for medium-sized Eu(3+) and decreases for Y(3+), the contraction of the hydrodynamic radius of the polymer upon metal loading induces positive allosteric cooperativity for the smaller cations. The origin of this behaviour is rationalized within the frame of intermetallic dipole-dipole interactions modulated by the solvation potential of dipolar solutes in dielectric materials. Positive cooperativity produces local high-density of metal ions along the ligand strands (metal clustering) with potential interest in energy migration and sensing processes. PMID- 26121560 TI - Betahistine plus piracetam dual therapy versus betahistine monotherapy for peripheral vestibular vertigo: a confounder-corrected subanalysis of the OSVaLD study. AB - INTRODUCTION: This subanalysis compared the efficacy of betahistine plus piracetam dual therapy versus betahistine monotherapy using data from OSVaLD, a 3 month, open-label, observational study conducted in 2272 patients with peripheral vestibular vertigo. Of the 1898 patients included in the original efficacy population, 1076 were from countries where betahistine plus piracetam dual therapy was prescribed to >1 patient; 114 of these 1076 patients (11%) received the dual therapy and 567 (53%) were treated with betahistine monotherapy; these patients were selected for analysis. METHODS: Efficacy was assessed using the Dizziness Handicap Inventory (DHI) total and subscale scores. Propensity-score matching was used to correct potential differences in patient baseline characteristics between treatment groups. In addition, a subgroup analysis evaluated 103 patients treated with betahistine because of insufficient efficacy with their existing treatment. RESULTS: In the propensity-score matched, total population evaluation, improvements in the DHI total and subscale scores were numerically greater in the betahistine plus piracetam group (n = 88) versus the betahistine group (n = 89) (DHI total, -42.9 vs. -37.6, respectively; DHI physical, -12.1 vs. -10.4; DHI emotional, -13.5 vs. -13.2) and statistically significant for the DHI functional score (-17.3 vs. -14.0, respectively, p = 0.01). The percentage of patients with no impairment at final visit was 27% with betahistine and 47% with betahistine plus piracetam; odds ratio: 2.3, 95% confidence interval: 1.3-2.4 (p = 0.007). Similar results were obtained in the subgroup analyses for patients whose current vertigo treatment was insufficient. The overall incidence of adverse events was low and similar in both groups, and there were no discontinuations due to drug-related adverse events. CONCLUSIONS: By using propensity-score matching, which controls for potential heterogeneity in patient baseline characteristics and small patient numbers, the results of this analysis suggest that combined betahistine and piracetam may be more effective than betahistine alone in patients with peripheral vestibular vertigo. PMID- 26121561 TI - The efficacy and safety of canagliflozin across racial groups in patients with type 2 diabetes mellitus. AB - OBJECTIVE: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, enhances urinary glucose excretion through an insulin-independent mode of action, and improves glycemic control in patients with type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of canagliflozin across racial groups. METHODS: The efficacy of canagliflozin 100 mg and 300 mg was evaluated by racial group using data pooled from four placebo-controlled phase 3 studies and two placebo-controlled sub-studies of a population of patients with inadequately controlled T2DM (N = 4158). Least-squares mean changes from baseline were calculated for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), body weight (BW), cholesterol, and triglycerides. Safety/tolerability evaluation included reporting of general and prespecified adverse events (AEs). RESULTS: A total of 75% of patients were White, 13% were Asian, 4% were Black/African American, and 8% were 'Other' (American Indian, Alaskan Native, mixed race, Native Hawaiian or other Pacific Islander, not reported, and unknown). Baseline demographics were similar for these groups. Dose-related reductions in HbA1c, BW, and SBP were observed with both canagliflozin doses in all racial groups. Canagliflozin was generally safe and well tolerated. Treatment with canagliflozin was associated with an increased rate of genital mycotic infections (GMIs) and urinary tract infections (UTIs) in all racial groups. GMIs were observed more often in Black/African American males and males from the 'Other' racial group, whereas UTIs and osmotic diuresis-related AEs were less common in Asians. Key study limitations include the high proportion of White patients compared with other racial groups and the fact that included studies were not powered to evaluate racial differences. CONCLUSION: Canagliflozin was generally well tolerated and consistently associated with reductions in HbA1c, BW, and SBP in patients with T2DM independent of racial background. (ClinicalTrials.gov numbers: NCT01081834; NCT01106677; NCT01106625; NCT01106690; and NCT01032629.). PMID- 26121563 TI - Passenger strand loading in overexpression experiments using microRNA mimics. AB - MicroRNAs (miRNAs) are important regulators of gene function and manipulation of miRNAs is a central component of basic research. Modulation of gene expression by miRNA gain-of-function can be based on different approaches including transfection with miRNA mimics; artificial, chemically modified miRNA-like small RNAs. These molecules are intended to mimic the function of a miRNA guide strand while bypassing the maturation steps of endogenous miRNAs. Due to easy accessibility through commercial providers this approach has gained popularity, and accuracy is often assumed without prior independent testing. Our in silico analysis of over-represented sequence motifs in microarray expression data and sequencing of AGO-associated small RNAs indicate, however, that miRNA mimics may be associated with considerable side-effects due to the unwanted activity of the miRNA mimic complementary strand. PMID- 26121562 TI - Prevalence of Compliance with a New Physical Activity Guideline for Preschool-Age Children. AB - BACKGROUND: Four expert panels from Australia, Canada, the United Kingdom, and the United States issued physical activity (PA) recommendations for young children that are quite similar. The aim of this study was to determine compliance with the new PA guideline (defined as >=15 min/hr of total PA) in two independent samples of preschool children. METHODS: We conducted a cross sectional study of children attending preschools in Columbia, South Carolina. A total of 286 children in one sample and 337 children in a second sample participated. The main outcome of interest was total PA (sum of light, moderate, and vigorous intensity activity) measured by accelerometry. Compliance with the PA guideline was determined for both samples. Separately for each sample, mixed logistic models were used to determine whether there were differences in compliance with the PA guideline between groups based on sex, race/ethnicity, parent education, and weight status, controlling for preschool. RESULTS: Total PA was 14.5 and 15.2 min/hr in the first and second samples, respectively. The prevalence of meeting the PA guideline was 41.6% and 50.2% in the first and second samples, respectively. In both samples, more males than females met the guideline (53.5% vs. 33.5% and 57.6% vs. 45.9%) in the first and second samples, respectively (p<0.05). CONCLUSIONS: Approximately one half of children in two independent samples met the guideline for PA in young children. Policies and practices designed to increase PA among preschool children are needed, given that most children are not meeting this PA guideline. PMID- 26121564 TI - Getting PrEPared for HIV Prevention Navigation: Young Black Gay Men Talk About HIV Prevention in the Biomedical Era. AB - Biomedical HIV prevention strategies, such as pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), represent new opportunities to reduce critically high HIV infection rates among young black men who have sex with men (YBMSM). We report results of 24 dyadic qualitative interviews (N=48), conducted in Los Angeles, CA, exploring how YBMSM and their friends view PrEP and PEP. Interviews were analyzed using a grounded theory approach. Participants had widely divergent levels of knowledge about these prevention methods. Misconceptions and mistrust regarding PrEP were common, and concerns were expressed about PrEP-related stigma and the potential for gossip among peers who might assume a person on PrEP was HIV-positive. Yet participants also framed PrEP and PEP as valuable new options within an expanded "tool kit" of HIV prevention strategies that created possibilities for preventing new HIV infections, dating men with a different HIV status, and decreased anxiety about exposure to HIV. We organized themes around four main areas: (1) information and misinformation about biomedical HIV prevention; (2) expectations about PrEP, sexual behavior, and stigma; (3) gossip, disclosure, and "spreading the word" about PrEP and PEP; and (4) the roles of PrEP and PEP in an expanded HIV prevention tool kit. The findings suggest a need for guidance in navigating the increasingly complex array of HIV-prevention options available to YBMSM. Such "prevention navigation" could counter misconceptions and address barriers, such as stigma and mistrust, while helping YBMSM make informed selections from among expanded HIV prevention options. PMID- 26121565 TI - Further comparisons of ABR response amplitudes, test time, and estimation of hearing threshold using frequency-specific chirp and tone pip stimuli in newborns: Findings at 0.5 and 2 kHz. AB - OBJECTIVE: To compare auditory brainstem response (ABR) amplitudes evoked by 0.5 and 2 kHz tone pip and narrowband chirp (NB CE-Chirp) stimuli when testing post screening newborns. To determine the difference in 'estimated hearing level' correction values. DESIGN: Tests were performed with tone pips and NB CE-Chirps at 0.5 or 2 kHz and the ABR threshold for each stimulus defined. Response amplitude, response quality (Fmp), and residual noise were compared for both stimuli. STUDY SAMPLE: Thirty-nine babies (42 ears) who passed our ABR discharge criterion at 4 kHz following referral from their newborn hearing screen. RESULTS: NB CE-Chirp responses were, on average, 31% larger than the tone pip responses at 0.5 kHz and were 52% larger at 2 kHz. Fmp was significantly higher for NB CE Chirps. CONCLUSIONS: The advantages of NB CE-Chirps over tone pips we previously identified at 4 and 1 kHz extends to 0.5 and 2 kHz, which supports the use of NB CE-Chirps when testing newborns. We propose that ABR nHL threshold to eHL corrections for NB CE-Chirps should be approximately 5 dB less than corrections for tone pips at 0.5 and 2 kHz, mirroring our recommendation at 4 and 1 kHz. PMID- 26121566 TI - The isomeric effect of mercaptobenzoic acids on the preparation and fluorescence properties of copper nanoclusters. AB - A one-pot approach has been developed to synthesize copper nanocluster (Cu NC) aggregates from copper nitrate and mercaptobenzoic acid (MBA). Cu NCs prepared separately in the three isomers of MBA exhibit different physical and optical properties. PMID- 26121567 TI - Supramolecular inclusion-based molecular integral rigidity: a feasible strategy for controlling the structural connectivity of uranyl polyrotaxane networks. AB - The assembly of two-dimensional (2D) large channel uranyl-organic polyrotaxane networks as well as structural regulation of uranyl-bearing units using jointed cucurbit[6]uril-based pseudorotaxanes with integral rigidity based on supramolecular inclusion is presented for the first time. This construction strategy concerning controlling molecular integral rigidity based on supramolecular inclusion may afford an entirely new methodology for coordination chemistry. PMID- 26121568 TI - A Rare Subglottic Capillary Hemangioma. PMID- 26121569 TI - Two new flavonoids from Morus notabilis. AB - Phytochemical investigation of the twigs of Morus notabilis led to the isolation and characterization of two new flavonoids, notabilisin F (1) and notabilisin G (2). Their structures were elucidated on the basis of extensive spectroscopic analysis. PMID- 26121570 TI - Mesoporous crystalline-amorphous oxide nanocomposite network for high-performance lithium storage. AB - Mesoporous nanocomposites composed of crystalline and amorphous oxides network were successfully synthesized by a continuous aerosol spray process; electrodes made from such nanocomposites with a thin-layer of protective oxide coating exhibit high capacity and long cycling life for lithium storage. PMID- 26121571 TI - Organogels formed by substituent-free pyrene-appended oligo(m-phenylene ethynylene)s. AB - A new class of pyrene-appended m-phenylene ethynylene oligomers, which bear no alkyl chains or heteroatoms, have been demonstrated to gelate organic solvents, and one of them forms chiral twisted gels in cyclohexane. PMID- 26121572 TI - ARID3B Directly Regulates Ovarian Cancer Promoting Genes. AB - The DNA-binding protein AT-Rich Interactive Domain 3B (ARID3B) is elevated in ovarian cancer and increases tumor growth in a xenograft model of ovarian cancer. However, relatively little is known about ARID3B's function. In this study we perform the first genome wide screen for ARID3B direct target genes and ARID3B regulated pathways. We identified and confirmed numerous ARID3B target genes by chromatin immunoprecipitation (ChIP) followed by microarray and quantitative RT PCR. Using motif-finding algorithms, we characterized a binding site for ARID3B, which is similar to the previously known site for the ARID3B paralogue ARID3A. Functionality of this predicted site was demonstrated by ChIP analysis. We next demonstrated that ARID3B induces expression of its targets in ovarian cancer cell lines. We validated that ARID3B binds to an epidermal growth factor receptor (EGFR) enhancer and increases mRNA expression. ARID3B also binds to the promoter of Wnt5A and its receptor FZD5. FZD5 is highly expressed in ovarian cancer cell lines, and is upregulated by exogenous ARID3B. Both ARID3B and FZD5 expression increase adhesion to extracellular matrix (ECM) components including collagen IV, fibronectin and vitronectin. ARID3B-increased adhesion to collagens II and IV require FZD5. This study directly demonstrates that ARID3B binds target genes in a sequence-specific manner, resulting in increased gene expression. Furthermore, our data indicate that ARID3B regulation of direct target genes in the Wnt pathway promotes adhesion of ovarian cancer cells. PMID- 26121573 TI - Spatiotemporal Dynamics of Hand-Foot-Mouth Disease and Its Relationship with Meteorological Factors in Jiangsu Province, China. AB - Hand, foot and mouth disease (HFMD) is an important public health issue in mainland China, including Jiangsu Province. The main purpose of this study was to depict the epidemiological characteristics of HFMD and evaluate the effects of meteorological variables on its dynamics via spatiotemporal analytic methods, which is essential for formulating scientific and effective prevention and control strategies and measures. In total, 497,910 cases of HFMD occurred in the 2009-2013 period, with an average annual incidence of 126.3 per 100,000 in Jiangsu. Out of these, 87.7% were under 5 years old with a male-to-female incidence ratio of 1.4. The dominant pathogens of the laboratory-confirmed cases were EV71 and CoxA16, accounting for 44.8% and 30.6% of all cases, respectively. Two incidence peaks were observed in each year, the higher occurring between April and June, the lower between November and December. The incidence ranged between 16.8 and 233.5 per 100,000 at the county level. The incidence in the South of the province was generally higher than that in the northern regions. The most likely spatiotemporal cluster detected by space-time scan analysis occurred in May-June of 2012 in the southern region. Average temperature and rainfall were positively correlated with HFMD incidence, while the number of days with rainfall >= 0.1mm, low temperature, high temperature and hours of sunshine were negatively related. Particularly, relative humidity had no relationship. In conclusion, the prevalence of HFMD in Jiangsu Province has an obvious feature of seasonality. The etiological composition changed dynamically and might be a latent driving force for the temporal variation of the incidence of HFMD. A moderately warm environment promotes the transmission of the HFMD viruses, while particularly cold and hot climate conditions restrain their transmission. PMID- 26121574 TI - Elderly Peritoneal Dialysis Compared with Elderly Hemodialysis Patients and Younger Peritoneal Dialysis Patients: Competing Risk Analysis of a Korean Prospective Cohort Study. AB - The outcomes of peritoneal dialysis (PD) in elderly patients have not been thoroughly investigated. We aimed to investigate the clinical outcomes and risk factors associated with PD in elderly patients. We conducted a prospective observational nationwide adult end-stage renal disease (ESRD) cohort study in Korea from August 2008 to March 2013. Among incident patients (n = 830), patient and technical survival rate, quality of life, and Beck's Depression Inventory (BDI) scores of elderly PD patients (>=65 years, n = 95) were compared with those of PD patients aged <=49 years (n = 205) and 50~64 years (n = 192); and elderly hemodialysis (HD) patients (n = 315). The patient death and technical failure were analyzed by cumulative incidence function. Competing risk regressions were used to assess the risk factors for survival. The patient survival rate of elderly PD patients was inferior to that of younger PD patients (P<0.001). However, the technical survival rate was similar (P = 0.097). Compared with elderly HD patients, the patient survival rate did not differ according to dialysis modality (P = 0.987). Elderly PD patients showed significant improvement in the BDI scores, as compared with the PD patients aged <=49 years (P = 0.003). Low albumin, diabetes and low residual renal function were significant risk factors for the PD patient survival; and peritonitis was a significant risk factor for technical survival. Furthermore, low albumin and hospitalization were significant risk factors of patient survival among the elderly. The overall outcomes were similar between elderly PD and HD patients. PD showed the benefit in BDI and quality of life in the elderly. Additionally, the technical survival rate of elderly PD patients was similar to that of younger PD patients. Taken together, PD may be a comparable modality for elderly ESRD patients. PMID- 26121576 TI - Comment on: HMGB1-dependent and -independent autophagy. AB - HMGB1 (high mobility group box 1), a ubiquitously expressed DNA-binding nucleoprotein, has not only been attributed with important functions in the regulation of gene expression but is thought to function as an important damage associated molecular pattern in the extracellular space. Recently, conditional Hmgb1 deletion strategies have been employed to overcome the perinatal mortality of global Hmgb1 deletion and to understand HMGB1 functions under disease conditions. From these studies, it has become evident that HMGB1 is not required for normal organ function. However, the different conditional ablation strategies have yielded contradictory results in some disease models. With nearly complete recombination in all transgenic mouse models, the main reason for opposite results is likely to lie within different targeting strategies. In summary, different targeting strategies need to be taken into account when interpreting HMGB1 functions, and further efforts need to be undertaken to compare these models side by side. PMID- 26121575 TI - Predictors of Adherence to Multiple Clinical Preventive Recommendations among Adults with Diabetes in Spain. AB - OBJECTIVE: This study aims to describe adherence to seven clinical preventive services among Spanish adults with diabetes, to compare adherence with people without diabetes and to identify predictor of adherence to multiple practices among adults with diabetes. DESIGN: Cross-sectional study based on data obtained from the European Health Survey for Spain 2009 and the Spanish National Health Survey 2011. We analyzed those aged 40-69 years (n= 20,948). Diabetes status was self-reported. The study variables included adherence to blood pressure (BP) checkup, cholesterol measurement, influenza vaccination, dental examination, fecal occult blood test (FOBT), mammography and cytology. Independent variables included socio-demographic characteristics, variables related to health status and lifestyle factors. RESULTS: The study sample included 1,647 subjects with diabetes and 19,301 without. Over 90% had measured their BP and cholesterol in the last year, 44.4% received influenza immunization, 36.4% had a dental checkup within the year and only 8.1% underwent a FOBT. Among diabetic women 75.4% had received a mammography and 52.4% a cytology in the recommended periods. The adherence to BP and cholesterol measurements and influenza vaccination was significantly higher among those suffering diabetes and cytology and dental checkup were lower. Only 63.4% of people with diabetes had fulfilled half or more of the recommended practices. Female sex, higher educational level, being married or cohabiting, higher number of chronic conditions and number of physician visits increased the adherence to multiple preventive practices. For each unhealthy lifestyle reported the probability of having a higher adherence level decreased. CONCLUSIONS: Acceptable adherence is found for BP and cholesterol checkups and mammography. Unacceptably low rates were found for influenza vaccine, dental care, cytology and FOBT. Moreover, preventive services are provided neither equitably nor efficiently so future research needs to identify individual and organizational factors that allow interventions to reach these subjects with diabetes. PMID- 26121577 TI - Correction: Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease. PMID- 26121578 TI - Design and Performance of a New Severity Score for Intermediate Care. AB - BACKGROUND: Application of illness-severity scores in Intermediate Care Units (ImCU) shows conflicting results. The aim of the study is to design a severity-of illness score for patients admitted to an ImCU. METHODS: We performed a retrospective observational study in a single academic medical centre in Pamplona, Spain. Demographics, past medical history, reasons for admission, physiological parameters at admission and during the first 24 hours of ImCU stay, laboratory variables and survival to hospital discharge were recorded. Logistic regression analysis was performed to identify variables for mortality prediction. RESULTS: A total of 743 patients were included. The final multivariable model (derivation cohort = 554 patients) contained only 9 variables obtained at admission to the ImCU: previous length of stay 7 days (6 points), health-care related infection (11), metastatic cancer (9), immunosuppressive therapy (6), Glasgow comma scale 12 (10), need of non-invasive ventilation (14), platelets 50000/mcL (9), urea 0.6 g/L (10) and bilirubin 4 mg/dL (9). The ImCU severity score (ImCUSS) is generated by summing the individual point values, and the formula for determining the expected in-hospital mortality risk is: e(ImCUSS points*0.099 - 4,111)/(1 + e(ImCUSS points*0.099 - 4,11)1). The model showed adequate calibration and discrimination. Performance of ImCUSS (validation cohort = 189 patients) was comparable to that of SAPS II and 3. Hosmer-Lemeshow goodness of-fit C test was chi2 8.078 (p=0.326) and the area under receiver operating curve 0.802. CONCLUSIONS: ImCUSS, specially designed for intermediate care, is based on easy to obtain variables at admission to ImCU. Additionally, it shows a notable performance in terms of calibration and mortality discrimination. PMID- 26121579 TI - Body Mass Index and Risk of Parkinson's Disease: A Dose-Response Meta-Analysis of Prospective Studies. AB - BACKGROUND: A number of epidemiologic studies examining the relationship between body mass index (BMI) and the future occurrence of Parkinson's disease (PD) reported largely inconsistent findings. We conducted a dose-response meta analysis of prospective studies to clarify this association. METHODS: Eligible prospective studies were identified by a search of PubMed and by checking the references of related publications. The generalized least squares trend estimation was employed to compute study-specific relative risks (RR) and 95% confidence intervals (CI) for an increase in BMI of 5 kg/m2, and the random effects model was used to compute summary RR and 95% CI. RESULTS: A total of 10 prospective studies were included in the final analysis. An increase in BMI of 5 kg/m2 was not associated with PD risk, with a summary RR of 1.00 (95% CI = 0.89 1.12). Results of subgroup analysis found similar results except for a week positive association in studies that adjusted for alcohol consumption (RR = 1.13, 95% CI = 0.99-1.29), and a week inverse association in studies that did not (RR = 0.90, 95% CI = 0.78-1.04). In a separate meta-analysis, no significant association between overweight (25 kg/m2 <= BMI <=29.9 kg/m2), obesity (BMI>=30 kg/m2) or excess weight (BMI>=25 kg/m2) and PD risk was observed. CONCLUSION: This meta-analysis does not support the notion that higher BMI materially increases PD risk. However, a week positive BMI-PD association that may be masked by confounders still cannot be excluded, and future prospective studies with a good control for potential confounding factors are needed. PMID- 26121581 TI - Influence of Fire Mosaics, Habitat Characteristics and Cattle Disturbance on Mammals in Fire-Prone Savanna Landscapes of the Northern Kimberley. AB - Patch mosaic burning, in which fire is used to produce a mosaic of habitat patches representative of a range of fire histories ('pyrodiversity'), has been widely advocated to promote greater biodiversity. However, the details of desired fire mosaics for prescribed burning programs are often unspecified. Threatened small to medium-sized mammals (35 g to 5.5 kg) in the fire-prone tropical savannas of Australia appear to be particularly fire-sensitive. Consequently, a clear understanding of which properties of fire mosaics are most instrumental in influencing savanna mammal populations is critical. Here we use mammal capture data, remotely sensed fire information (i.e. time since last fire, fire frequency, frequency of late dry season fires, diversity of post-fire ages in 3 km radius, and spatial extent of recently burnt, intermediate and long unburnt habitat) and structural habitat attributes (including an index of cattle disturbance) to examine which characteristics of fire mosaics most influence mammals in the north-west Kimberley. We used general linear models to examine the relationship between fire mosaic and habitat attributes on total mammal abundance and richness, and the abundance of the most commonly detected species. Strong negative associations of mammal abundance and richness with frequency of late dry season fires, the spatial extent of recently burnt habitat (post-fire age <1 year within 3 km radius) and level of cattle disturbance were observed. Shrub cover was positively related to both mammal abundance and richness, and availability of rock crevices, ground vegetation cover and spatial extent of >=4 years unburnt habitat were all positively associated with at least some of the mammal species modelled. We found little support for diversity of post-fire age classes in the models. Our results indicate that both a high frequency of intense late dry season fires and extensive, recently burnt vegetation are likely to be detrimental to mammals in the north Kimberley. A managed fire mosaic that reduces large scale and intense fires, including the retention of >=4 years unburnt patches, will clearly benefit savanna mammals. We also highlighted the importance of fire mosaics that retain sufficient shelter for mammals. Along with fire, it is clear that grazing by introduced herbivores also needs to be reduced so that habitat quality is maintained. PMID- 26121580 TI - Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice. AB - Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE2 to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE2 T26A administered alone to anesthetized rats dose dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE2 over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE2 induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE2. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension. PMID- 26121582 TI - Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice. AB - OBJECTIVE: Sodium-glucose cotransporter 1 (SGLT1) is thought to be expressed in the heart as the dominant isoform of cardiac SGLT, although more information is required to delineate the subtypes of SGLTs in human hearts. Moreover, the functional role of SGLTs in the heart remains to be fully elucidated. We herein investigated whether SGLT1 is expressed in human hearts and whether SGLTs significantly contribute to cardiac energy metabolism during ischemia-reperfusion injury (IRI) via enhanced glucose utilization in mice. METHODS AND RESULTS: We determined that SGLT1 was highly expressed in both human autopsied hearts and murine perfused hearts, as assessed by immunostaining and immunoblotting with membrane fractionation. To test the functional significance of the substantial expression of SGLTs in the heart, we studied the effects of a non-selective SGLT inhibitor, phlorizin, on the baseline cardiac function and its response to ischemia-reperfusion using the murine Langendorff model. Although phlorizin perfusion did not affect baseline cardiac function, its administration during IRI significantly impaired the recovery in left ventricular contractions and rate pressure product, associated with an increased infarct size, as demonstrated by triphenyltetrazolium chloride staining and creatine phosphokinase activity released into the perfusate. The onset of ischemic contracture, which indicates the initiation of ATP depletion in myocardium, was earlier with phlorizin. Consistent with this finding, there was a significant decrease in the tissue ATP content associated with reductions in glucose uptake, as well as lactate output (indicating glycolytic flux), during ischemia-reperfusion in the phlorizin perfused hearts. CONCLUSIONS: Cardiac SGLTs, possibly SGLT1 in particular, appear to provide an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhancing availability of glucose. The present findings provide new insight into the significant role of SGLTs in optimizing cardiac energy metabolism, at least during the acute phase of IRI. PMID- 26121583 TI - Angiographic Lesion Complexity Score and In-Hospital Outcomes after Percutaneous Coronary Intervention. AB - OBJECTIVE: We devised a percutaneous coronary intervention (PCI) scoring system based on angiographic lesion complexity and assessed its association with in hospital complications. BACKGROUND: Although PCI is finding increasing application in patients with coronary artery disease, lesion complexity can lead to in-hospital complications. METHODS: Data from 3692 PCI patients were scored based on lesion complexity, defined by bifurcation, chronic total occlusion, type C, and left main lesion, along with acute thrombus in the presence of ST-segment elevation myocardial infarction (1 point assigned for each variable). RESULTS: The patients' mean age was 67.5 +/- 10.8 years; 79.8% were male. About half of the patients (50.3%) presented with an acute coronary syndrome, and 2218 (60.1%) underwent PCI for at least one complex lesion. The patients in the higher-risk score groups were older (p < 0.001) and had present or previous heart failure (p = 0.02 and p = 0.01, respectively). Higher-risk score groups had significantly higher in-hospital event rates for death, heart failure, and cardiogenic shock (from 0 to 4 risk score; 1.7%, 4.5%, 6.3%, 7.1%, 40%, p < 0.001); bleeding with a hemoglobin decrease of >3.0 g/dL (3.1%, 11.0%, 13.1%, 10.3%, 28.6%, p < 0.001); and postoperative myocardial infarction (1.5%, 3.1%, 3.8%, 3.8%, 10%, p = 0.004), respectively. The association with adverse outcomes persisted after adjustment for known clinical predictors (odds ratio 1.72, p < 0.001). CONCLUSION: The complexity score was cumulatively associated with in-hospital mortality and complication rate and could be used for event prediction in PCI patients. PMID- 26121585 TI - High-Resolution Correlative Microscopy: Bridging the Gap between Single Molecule Localization Microscopy and Atomic Force Microscopy. AB - Nanoscale characterization of living samples has become essential for modern biology. Atomic force microscopy (AFM) creates topological images of fragile biological structures from biomolecules to living cells in aqueous environments. However, correlating nanoscale structure to biological function of specific proteins can be challenging. To this end we have built and characterized a correlated single molecule localization microscope (SMLM)/AFM that allows localizing specific, labeled proteins within high-resolution AFM images in a biologically relevant context. Using direct stochastic optical reconstruction microscopy (dSTORM)/AFM, we directly correlate and quantify the density of localizations with the 3D topography using both imaging modalities along (F )actin cytoskeletal filaments. In addition, using photo activated light microscopy (PALM)/AFM, we provide correlative images of bacterial cells in aqueous conditions. Moreover, we report the first correlated AFM/PALM imaging of live mammalian cells. The complementary information provided by the two techniques opens a new dimension for structural and functional nanoscale biology. PMID- 26121584 TI - Low Completeness of Bacteraemia Registration in the Danish National Patient Registry. AB - Bacteraemia is associated with significant morbidity and mortality and timely access to relia-ble information is essential for health care administrators. Therefore, we investigated the complete-ness of bacteraemia registration in the Danish National Patient Registry (DNPR) containing hospital discharge diagnoses and surgical procedures for all non-psychiatric patients. As gold standard we identified bacteraemia patients in three defined areas of Denmark (~2.3 million inhabitants) from 2000 through 2011 by use of blood culture data retrieved from electronic microbiology databases. Diagnoses coded according to the International Classification of Diseases, version 10, and surgical procedure codes were retrieved from the DNPR. The codes were categorized into seven groups, ranked a priori according to the likelihood of bacteraemia. Completeness was analysed by contin-gency tables, for all patients and subgroups. We identified 58,139 bacteraemic episodes in 48,450 patients; 37,740 episodes (64.9%) were covered by one or more discharge diagnoses within the sev-en diagnosis/surgery groups and 18,786 episodes (32.3%) had a code within the highest priority group. Completeness varied substantially according to speciality (from 17.9% for surgical to 36.4% for medical), place of acquisition (from 26.0% for nosocomial to 36.2% for community), and mi-croorganism (from 19.5% for anaerobic Gram negative bacteria to 36.8% for haemolytic strepto-cocci). The completeness increased from 25.1% in 2000 to 35.1% in 2011. In conclusion, one third of the bacteraemic episodes did not have a relevant diagnosis in the Danish administrative registry recording all non-psychiatric contacts. This source of information should be used cautiously to iden-tify patients with bacteraemia. PMID- 26121586 TI - Serendipitous SAD Solution for DMSO-Soaked SOCS2-ElonginC-ElonginB Crystals Using Covalently Incorporated Dimethylarsenic: Insights into Substrate Receptor Conformational Flexibility in Cullin RING Ligases. AB - Suppressor of cytokine signalling 2 (SOCS2) is the substrate-binding component of a Cullin-RING E3 ubiquitin ligase (CRL) complex that targets phosphorylated hormone receptors for degradation by the ubiquitin-proteasome system. As a key regulator of the transcriptional response to growth signals, SOCS2 and its protein complex partners are potential targets for small molecule development. We found that crystals of SOCS2 in complex with its adaptor proteins, Elongin C and Elongin B, underwent a change in crystallographic parameters when treated with dimethyl sulfoxide during soaking experiments. To solve the phase problem for the new crystal form we identified the presence of arsenic atoms in the crystals, a result of covalent modification of cysteines by cacodylate, and successfully extracted anomalous signal from these atoms for experimental phasing. The resulting structure provides a means for solving future structures where the crystals must be treated with DMSO for ligand soaking approaches. Additionally, the conformational changes induced in this structure reveal flexibility within SOCS2 that match those postulated by previous molecular dynamics simulations. This conformational flexibility illustrates how SOCS2 can orient its substrates for successful ubiquitination by other elements of the CRL complex. PMID- 26121587 TI - Does EBV alter the pathogenesis of malaria? AB - Plasmodium falciparum infections have been implicated in immune deficiencies resulting in ineffective control of Epstein-Barr virus, thereby increasing the risk of endemic Burkitt lymphoma in children. However, the impact of Epstein-Barr virus infections on the development of immunity to P. falciparum has not been studied in depth. In this review, we examine novel findings from animal co infection models and human immuno-epidemiologic studies to speculate on the impact of acute gammaherpesvirus co-infection on malarial disease severity. Children are often concurrently or sequentially infected with multiple pathogens, and this has implications for understanding the development of protective immunity as well as in the evaluation of vaccine efficacy. PMID- 26121589 TI - Correction: Environmental Control on Fish and Macrocrustacean Spring Community Structure, on an Intertidal Sandy Beach. PMID- 26121588 TI - Cultivation-Based and Molecular Assessment of Bacterial Diversity in the Rhizosheath of Wheat under Different Crop Rotations. AB - A field study was conducted to compare the formationand bacterial communities of rhizosheaths of wheat grown under wheat-cotton and wheat-rice rotation and to study the effects of bacterial inoculation on plant growth. Inoculation of Azospirillum sp. WS-1 and Bacillus sp. T-34 to wheat plants increased root length, root and shoot dry weight and dry weight of rhizosheathsoil when compared to non-inoculated control plants, and under both crop rotations. Comparing both crop rotations, root length, root and shoot dry weight and dry weight of soil attached with roots were higher under wheat-cotton rotation. Organic acids (citric acid, malic acid, acetic acid and oxalic acid) were detected in rhizosheaths from both rotations, with malic acid being most abundant with 24.8+/ 2 and 21.3+/-1.5 MUg g(-1) dry soil in wheat-cotton and wheat-rice rotation, respectively. Two sugars (sucrose, glucose) were detected in wheat rhizosheath under both rotations, with highest concentrations of sucrose (4.08+/-0.5 MUg g( 1) and 7.36+/-1.0 MUg g(-1)) and glucose (3.12+/-0.5 MUg g(-1) and 3.01+/- MUg g( 1)) being detected in rhizosheaths of non-inoculated control plants under both rotations. Diversity of rhizosheath-associated bacteria was evaluated by cultivation, as well as by 454-pyrosequencing of PCR-tagged 16S rRNA gene amplicons. A total of 14 and 12 bacterial isolates predominantly belonging to the genera Arthrobacter, Azospirillum, Bacillus, Enterobacter and Pseudomonaswere obtained from the rhizosheath of wheat grown under wheat-cotton and wheat-rice rotation, respectively. Analysis of pyrosequencing data revealed Proteobacteria, Bacteriodetes and Verrucomicrobia as the most abundant phyla in wheat-rice rotation, whereas Actinobacteria, Firmicutes, Chloroflexi, Acidobacteria, Planctomycetes and Cyanobacteria were predominant in wheat-cotton rotation. From a total of 46,971 sequences, 10.9% showed >=97% similarity with 16S rRNA genes of 32 genera previously shown to include isolates with plant growth promoting activity (nitrogen fixation, phosphate-solubilization, IAA production). Among these, the most predominant genera were Arthrobacter, Azoarcus, Azospirillum, Bacillus, Cyanobacterium, Paenibacillus, Pseudomonas and Rhizobium. PMID- 26121590 TI - Low 25-Hydroxyvitamin D Levels Are Associated with Infections and Mortality in Patients with Cirrhosis. AB - BACKGROUND & AIMS: Vitamin D, best known to regulate bone mineralization, has numerous additional roles including regulation inflammatory pathways. Recently, an increased incidence of 25-hydroxyvitamin D3 (25(OH)D3) deficiency has been found in subjects suffering from liver diseases. We here investigated if low vitamin D levels might be associated with prognosis, inflammation and infectious complications in patients with cirrhosis. METHODS: We performed a prospective cohort study investigating the relation between 25(OH)D3 levels and stages of cirrhosis, mortality and complications of cirrhosis, including infections. RESULTS: 251 patients with cirrhosis were enrolled into the present prospective cohort study. 25(OH)D3 levels were quantified by radioimmunoassay from serum samples obtained at study inclusion. The mean follow-up time was 411 +/- 397 days with a range of 1-1382 days. 30 (12.0%) patients underwent liver transplantation and 85 (33.8%) individuals died within the study. The mean serum 25(OH)D3 concentration was 8.93 +/- 7.1 ng/ml with a range of 1.0 to 46.0 ng/ml. 25(OH)D3 levels differed significantly between Child Pugh scores and showed a negative correlation with the model of end stage liver disease (MELD) score. Patients with decompensated cirrhosis and infectious complications, had significantly lower 25(OH)D3 levels compared to subjects without complications. Low 25(OH)D3 was associated with mortality in uni- as well as multivariate Cox regression models. CONCLUSIONS: 25(OH)D3 deficiency is associated with advanced liver disease and low 25(OH)D3 levels are an indicator for a poor outcome and are associated with infectious complications. PMID- 26121591 TI - Direction of Biological Motion Affects Early Brain Activation: A Link with Social Cognition. AB - A number of EEG studies have investigated the time course of brain activation for biological movement over this last decade, however the temporal dynamics of processing are still debated. Moreover, the role of direction of movement has not received much attention even though it is an essential component allowing us to determine the intentions of the moving agent, and thus permitting the anticipation of potential social interactions. In this study, we examined event related responses (ERPs) in 15 healthy human participants to light point walkers and their scrambled counterparts, whose movements occurred either in the radial or in the lateral plane. Compared to scrambled motion (SM), biological motion (BM) showed an enhanced negativity between 210 and 360ms. A source localization algorithm (sLORETA) revealed that this was due to an increase in superior and middle temporal lobe activity. Regarding direction, we found that radial BM produced an enhanced P1 compared to lateral BM, lateral SM and radial SM. This heightened P1 was due to an increase in activity in extrastriate regions, as well as in superior temporal, medial parietal and medial prefrontal areas. This network is known to be involved in decoding the underlying intentionality of the movement and in the attribution of mental states. The social meaning signaled by the direction of biological motion therefore appears to trigger an early response in brain activity. PMID- 26121592 TI - Fetal and Childhood Exposure to Phthalate Diesters and Cognitive Function in Children Up to 12 Years of Age: Taiwanese Maternal and Infant Cohort Study. AB - Few studies have examined the association between environmental phthalate exposure and children's neurocognitive development. This longitudinal study examined cognitive function in relation to pre-and postnatal phthalate exposure in children 2-12 years old. We recruited 430 pregnant women in their third trimester in Taichung, Taiwan from 2001-2002. A total of 110, 79, 76, and 73 children were followed up at ages 2, 5, 8, and 11, respectively. We evaluated the children's cognitive function at four different time points using the Bayley and Wechsler tests for assessing neurocognitive functions and intelligence (IQ). Urine samples were collected from mothers during pregnancy and from children at each follow-up visit. They were analyzed for seven metabolite concentrations of widely used phthalate esters. These esters included monomethyl phthalate, monoethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, and three metabolites of di(2-ethylhexyl) phthalate, namely, mono-2-ethylhexyl phthalate, mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. We constructed a linear mixed model to examine the relationships between the phthalate metabolite concentrations and the Bayley and IQ scores. We found significant inverse associations between the children's levels of urinary mono(2 ethyl-5-oxohexyl) phthalate and the sum of the three metabolites of di(2 ethylhexyl) phthalate and their IQ scores (beta = -1.818; 95% CI: -3.061, -0.574, p = 0.004 for mono(2-ethyl-5-oxohexyl) phthalate; beta = -1.575; 95% CI: -3.037, 0.113, p = 0.035 for the sum of the three metabolites) after controlling for maternal phthalate levels and potential confounders. We did not observe significant associations between maternal phthalate exposure and the children's IQ scores. Children's but not prenatal phthalate exposure was associated with decreased cognitive development in the young children. Large-scale prospective cohort studies are needed to confirm these findings in the future. PMID- 26121593 TI - Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer. AB - BACKGROUND: To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. METHODS: This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). RESULTS: By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. CONCLUSIONS: CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer. PMID- 26121595 TI - Distribution System Water Quality Affects Responses of Opportunistic Pathogen Gene Markers in Household Water Heaters. AB - Illustrative distribution system operation and management practices shaped the occurrence and persistence of Legionella spp., nontuberculous mycobacteria (NTM), Pseudomonas aeruginosa, and two amoebae host (Acanthamoeba spp., Vermamoeba vermiformis) gene markers in the effluent of standardized simulated household water heaters (SWHs). The interplay between disinfectant type (chlorine or chloramine), water age (2.3-5.7 days) and materials (polyvinyl chloride (PVC), cement or iron) in upstream simulated distribution systems (SDSs) profoundly influenced levels of pathogen gene markers in corresponding SWH bulk waters. For example, Legionella spp. were 3-4 log higher in SWHs receiving water from chloraminated vs chlorinated SDSs, because of disinfectant decay from nitrification. By contrast, SWHs fed with chlorinated PVC SDS water not only harbored the lowest levels of all pathogen markers, but effluent from the chlorinated SWHs were even lower than influent levels in several instances (e.g., 2 log less Legionella spp. and NTM for PVC and 3-5 log less P. aeruginosa for cement). However, pathogen gene marker influent levels correlated positively to effluent levels in the SWHs (P < 0.05). Likewise, microbial community structures were similar between SWHs and the corresponding SDS feed waters. This study highlights the importance and challenges of distribution system management/operation to help control opportunistic pathogens. PMID- 26121594 TI - Hippocampal interplay with the nucleus accumbens is critical for decisions about time. AB - Human cognition depends upon the capacity to make decisions in the present that bear upon outcomes in the future. The nucleus accumbens, a recipient of direct projections from both the hippocampus and orbitofrontal cortex, is known to contribute to these aspects of decision-making. Here we demonstrate that interaction of the nucleus accumbens with the hippocampus, but not the orbitofrontal cortex, is critical in shaping decisions that involve time trade offs. Compared with controls, rats with a disrupted hippocampal-accumbens interaction were strongly biased toward choosing stimuli that led to small and immediate food rewards over large and delayed ones. We show that this pattern of behavior cannot be ascribed to the impaired representation of stimulus value, the incapacity to wait, or a general disruption of decision-making. These results identify a hippocampal-accumbens circuit that may underlie a range of problems in which daily decisions are marked by a shift toward immediate gratification. PMID- 26121596 TI - Canadian Stroke Best Practice Recommendations: Mood, Cognition and Fatigue Following Stroke practice guidelines, update 2015. AB - Every year, approximately 62 000 people with stroke and transient ischemic attack are treated in Canadian hospitals, and the evidence suggests one-third or more will experience vascular-cognitive impairment, and/or intractable fatigue, either alone or in combination. The 2015 update of the Canadian Stroke Best Practice Recommendations: Mood, Cognition and Fatigue Module guideline is a comprehensive summary of current evidence-based recommendations for clinicians in a range of settings, who provide care to patients following stroke. The three consequences of stroke that are the focus of the this guideline (poststroke depression, vascular cognitive impairment, and fatigue) have high incidence rates and significant impact on the lives of people who have had a stroke, impede recovery, and result in worse long-term outcomes. Significant practice variations and gaps in the research evidence have been reported for initial screening and in-depth assessment of stroke patients for these conditions. Also of concern, an increased number of family members and informal caregivers may also experience depressive symptoms in the poststroke recovery phase which further impact patient recovery. These factors emphasize the need for a system of care that ensures screening occurs as a standard and consistent component of clinical practice across settings as stroke patients transition from acute care to active rehabilitation and reintegration into their community. Additionally, building system capacity to ensure access to appropriate specialists for treatment and ongoing management of stroke survivors with these conditions is another great challenge. PMID- 26121598 TI - A Study on Serum Antithyroglobulin Antibodies Interference in Thyroglobulin Measurement in Fine-Needle Aspiration for Diagnosing Lymph Node Metastasis in Postoperative Patients. AB - PURPOSE: Thyroglobulin measurement in fine-needle aspiration washout fluid (FNA Tg) is widely used for detection of lymph node metastasis (LNM) in patients with papillary thyroid cancer (PTC). Recent studies suggested that serum anti thyroglobulin antibodies (TgAbs) could interfere with FNA-Tg. We evaluated whether TgAbs can affect FNA-Tg when diagnosing LNM in postoperative patients with PTC. METHODS: From November 2006 to June 2011, a total of 239 LNs from 201 patients who underwent bilateral thyroidectomy and radioactive iodine ablation therapy were included. The interactions between FNA-Tgs and serum TgAbs, and diagnostic performances between FNA with additional FNA-Tg and FNA alone according to the presence of serum TgAbs were evaluated using the generalized linear mixed model and the bootstrap method. RESULTS: From 106 (44.4%) malignant and 133 (55.6%) benign LNs, there were 32 (13.4%) LNs with detectable serum TgAb levels and 207 (86.6%) LNs with undetectable serum TgAb levels. In logistic regression analysis, a significant negative interaction was observed between FNA Tgs and serum TgAbs (p = 0.031). In the absence of serum TgAbs, the diagnostic performances were superior in the FNA with FNA-Tg than in the FNA only. However, in the presence of serum TgAbs, the diagnostic performances of the FNA with FNA Tg were not significantly different from the FNA only, even with a different cutoff value of FNA-Tg. CONCLUSIONS: Serum TgAbs may interfere with FNA-Tg studies and caution is advised while analyzing FNA-Tg for detection of LNM in patients with PTC. PMID- 26121599 TI - Analysis of metformin, sitagliptin and creatinine in human dried blood spots. AB - For analysis of the anti-diabetic drugs metformin and sitagliptin and the renal clearance marker creatinine in the same human dried blood spot (DBS) extract two liquid chromatography methods employing HPLC/UV and LC-ESI-MS/MS have been developed and validated. An accurate volume of 40MUL blood was spotted on a sampling paper which was extracted using 90% acetonitrile with 10% formic acid. The new methods were shown to be selective, accurate and precise. The validated ranges were 0.2-5MUg/mL for metformin, 1.5-15MUg/mL for creatinine and 3-500ng/mL for sitagliptin. Since drug analysis in DBS determines whole blood concentrations as opposed to the typically used plasma levels the partition ratios between human plasma and blood cells, c(P)/c(BC), were elucidated in vitro to gain insight into the significance of blood cells as compartment of distribution for both compounds. The c(P)/c(BC) was found to be 4.65+/-0.73 for metformin and 5.58+/ 0.98 for sitagliptin. While an accumulation of metformin in erythrocytes was already known we now present the first evidence that sitagliptin distributes into human blood cells. The analytical methods were also successfully applied to authentic capillary blood samples from two diabetic patients regularly taking a combination of metformin and sitagliptin. Both samples revealed analyte trough concentrations well above the lower limit of quantification of the respective compounds. Therefore, the present study offers a methodological basis for the DBS analysis of metformin and sitagliptin in relation to the patients' creatinine concentration. PMID- 26121600 TI - Spinal cord stimulation for cancer-related pain in adults. AB - BACKGROUND: This is an update of a review first published in The Cochrane Library in Issue 3, 2013. Cancer-related pain places a heavy burden on public health with related high expenditure. Severe pain is associated with a decreased quality of life in patients with cancer. A significant proportion of patients with cancer related pain are under-treated. There is a need for more effective control of cancer-related pain. Spinal cord stimulation (SCS) may have a role in pain management. The effectiveness and safety of SCS for patients with cancer-related pain is currently unknown. OBJECTIVES: This systematic review evaluated the effectiveness of SCS for cancer-related pain compared with standard care using conventional analgesic medication. We also appraised risk and potential adverse events associated with the use of SCS. SEARCH METHODS: This is an update of a review first published in The Cochrane Library in Issue 3, 2013. The search strategy for the update was the same as in the original review. We searched the following bibliographic databases in order to identify relevant studies: the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library; MEDLINE; EMBASE; and CBM (Chinese Biomedical Database) in October 2014. We also handsearched relevant journals. There were no language restrictions. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) that directly compared SCS with other interventions with regards to the effectiveness of pain management. We also planned to include cross-over trials that compared SCS with another treatment. We planned to identify non-randomised controlled trials but these would only be included if no RCTs could be found. DATA COLLECTION AND ANALYSIS: The literature search for the update of this review found 121 potentially eligible articles. The initial search strategy yielded 430 articles. By scrutinising titles and abstracts, we found 412 articles irrelevant to the analytical purpose of this systematic review due to different scopes of diseases or different methods of intervention (intrathecal infusion system; oral medication) or aims other than pain control (spinal cord function monitoring, bladder function restoration or amelioration of organ metabolism). The remaining 18 trials were reviewed as full manuscripts. No RCTs were identified. Fourteen sporadic case reports and review articles were excluded and four before-and-after case series studies (92 participants) were included. Two review authors independently selected the studies to be included in the review according to the prespecified eligibility criteria. A checklist for methodological quality of non randomised controlled trials was used (STROBE checklist) and all review authors discussed and agreed on the inclusion of trials and the results of the quality assessment. MAIN RESULTS: No new studies were identified for inclusion in this update of the review. Four before-and-after case series studies (a total of 92 participants) met our criteria for inclusion in the previous version of the review. All included trials adopted a visual analogue scale (VAS) to evaluate pain relief. Heterogeneity existed in terms of baseline characteristics, electrode and stimulator parameters, level of implantation and route of implantation; each trial reported data differently. In two trials, pain relief was achieved in 76% (48/63) of participants at the end of the follow-up period. In the third trial, pre-procedure VAS was 6 to 9 (mean 7.43 ); the one-month post implant VAS was 2 to 4 (mean 3.07); the 12-month post-implant VAS was 1 to 3 (mean 2.67). In the fourth trial, the pre-procedure VAS was 6 to 9 (mean 7.07); 1 to 4 (mean 2.67) at one-month; 1 to 4 (mean 1.87) at 12 months. Analgesic use was largely reduced. The main adverse events were infection of sites of implantation, cerebrospinal fluid (CSF) leakage, pain at the sites of electrodes, dislodgement of the electrodes, and system failure; however, the incidence in participants with cancer could not be calculated. Since all trials were small, non-randomised controlled trials, they carried high or unclear risk of all types of bias. AUTHORS' CONCLUSIONS: Since the first publication of this review, no new studies were identified. Current evidence is insufficient to establish the role of SCS in treating refractory cancer-related pain. Future randomised studies should focus on the implantation of SCS in participants with cancer-related pain. PMID- 26121597 TI - Tethering of Epidermal Growth Factor (EGF) to Beta Tricalcium Phosphate (betaTCP) via Fusion to a High Affinity, Multimeric betaTCP-Binding Peptide: Effects on Human Multipotent Stromal Cells/Connective Tissue Progenitors. AB - Transplantation of freshly-aspirated autologous bone marrow, together with a scaffold, is a promising clinical alternative to harvest and transplantation of autologous bone for treatment of large defects. However, survival proliferation, and osteogenic differentiation of the marrow-resident stem and progenitor cells with osteogenic potential can be limited in large defects by the inflammatory microenvironment. Previous studies using EGF tethered to synthetic polymer substrates have demonstrated that surface-tethered EGF can protect human bone marrow-derived osteogenic stem and progenitor cells from pro-death inflammatory cues and enhance their proliferation without detriment to subsequent osteogenic differentiation. The objective of this study was to identify a facile means of tethering EGF to clinically-relevant betaTCP scaffolds and to demonstrate the bioactivity of EGF tethered to betaTCP using stimulation of the proliferative response of human bone-marrow derived mesenchymal stem cells (hBMSC) as a phenotypic metric. We used a phage display library and panned against betaTCP and composites of betaTCP with a degradable polyester biomaterial, together with orthogonal blocking schemes, to identify a 12-amino acid consensus binding peptide sequence, LLADTTHHRPWT, with high affinity for betaTCP. When a single copy of this betaTCP-binding peptide sequence was fused to EGF via a flexible peptide tether domain and expressed recombinantly in E. coli together with a maltose-binding domain to aid purification, the resulting fusion protein exhibited modest affinity for betaTCP. However, a fusion protein containing a linear concatamer containing 10 repeats of the binding motif the resulting fusion protein showed high affinity stable binding to betaTCP, with only 25% of the protein released after 7 days at 37oC. The fusion protein was bioactive, as assessed by its abilities to activate kinase signaling pathways downstream of the EGF receptor when presented in soluble form, and to enhance the proliferation of hBMSC when presented in tethered form on commercial betaTCP bone regeneration scaffolds. PMID- 26121601 TI - Numerical Methodology to Evaluate the Effects of Bone Density and Cement Augmentation on Fixation Stiffness of Bone-Anchoring Devices. AB - Bone quality is one of the reported factors influencing the success of bone anchors in arthroscopic repairs of torn rotator cuffs at the shoulder. This work was aimed at developing refined numerical methods to investigate how bone quality can influence the fixation stiffness of bone anchors. To do that bone biopsies were scanned at 26-MUm resolution with a high-resolution microcomputer tomography (micro-CT) scanner and their images were processed for virtual implantation of a typical design of bone anchor. These were converted to microfinite element (MUFE) and homogenized classical FE models, and analyses were performed to simulate pulling on the bone anchor with and without cement augmentation. Quantification of structural stiffness for each implanted specimen was then computed, as well as stress distributions within the bone structures, and related to the bone volume fraction of the specimens. Results show that the classical method is excellently correlated to structural predictions of the more refined MUFE method, despite the qualitative differences in local stresses in the bone surrounding the implant. Predictions from additional loading cases suggest that structural fixation stiffness in various directions is related to apparent bone density of the surrounding bone. Augmentation of anchoring with bone cement stiffens the fixation and alters these relations. This work showed the usability of homogenized FE (hFE) in the evaluation of bone anchor fixation and will be used to develop new methodologies for virtual investigations leading to optimized repairs of rotator cuff and glenoid Bankart lesions. PMID- 26121603 TI - A comparative analysis on the in vivo toxicity of copper nanoparticles in three species of freshwater fish. AB - Copper nanoparticles (CuNPs) are used extensively in a wide range of products and the potential for toxicological impacts in the aquatic environment is of high concern. In this study, the fate and the acute toxicity of spherical 50nm copper nanoparticles was assessed in juvenile rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas) and zebrafish (Danio rerio) for in vivo aqueous exposures following standardized OECD 203 guideline tests. The fate of the CuNPs in the aqueous media was temperature dependent. At the higher study temperature (26+/-1 degrees C), there was both an enhanced particle aggregation and higher rate of dissolution compared with that at the lower study temperature (15+/-1 degrees C). 96h LC50s of the CuNPs were 0.68+/-0.15, 0.28+/-0.04 and 0.22+/-0.08mg Cu/L for rainbow trout, fathead minnow and zebrafish, respectively. The 96h lowest-observed-effect concentration (LOEC) for the CuNPs were 0.17, 0.023 and <0.023mg/L for rainbow trout, fathead minnow, and zebrafish respectively, and are below the predicted environmental concentration of CuNPs for some aquatic environments suggesting a possible ecotoxicological risk to fish. Soluble copper was one of main drivers for the acute toxicity of the copper nanoparticles suspensions. Both CuNPs suspension and copper nitrate caused damage to gill filaments and gill pavement cells, with differences in sensitivity for these effects between the fish species studied. We show therefore common toxicological effects of CuNPs in different fish species but with differences in sensitivity with implications for hazard extrapolation between fish species. PMID- 26121604 TI - Increased acute toxicity to fish caused by pharmaceuticals in hospital effluents in a pharmaceutical mixture and after solar irradiation. AB - Hospital effluents are an important source of residual drugs and other classes of pharmaceuticals in aquatic environments. The raw wastewater from the studied hospital exhibited acute toxicity to vertebrate organisms, and Cyprinus carpio was the most sensitive organism tested. A mixture of 19 commonly used pharmaceuticals caused acute toxicity to C. carpio with an LC50 value of 60.68mgL(-1) after 96h. This study demonstrated that irradiation for 1-5days significantly increased the acute toxicity of the pharmaceuticals to fish, leading to increased mortality after a 2-h exposure and approximately 40% of the surviving fish died within 28days. The pre-irradiated pharmaceutical mixture also induced strange behaviors in the fish that survived the test. The synergistic increase in toxicity caused by the photolysis and mixing of pharmaceuticals cannot be ignored and warrants further examination. PMID- 26121602 TI - MicroRNAs (miRNAs) in the control of HF development and cycling: the next frontiers in hair research. AB - Hair follicle development and its postnatal regeneration are characterized by dramatic changes in its microanatomy and cellular activity, which are controlled by multiple signalling pathways, transcription factors and epigenetic regulators, including microRNAs (miRNAs). miRNAs and their targets form remarkably diverse regulatory networks, playing a key role in the execution of gene expression programmes in the different cell lineages of the hair follicle. This review summarizes the roles of miRNAs in the control of hair follicle development, cycling and hair pigmentation, emphasizes the remaining problems/unanswered questions, and provides future directions in this rapidly growing and exciting area of research. PMID- 26121605 TI - Galleria mellonella as a novel in vivo model for assessment of the toxicity of 1 alkyl-3-methylimidazolium chloride ionic liquids. AB - The larval form of the Greater Wax Moth (Galleria mellonella) was evaluated as a model system for the study of the acute in vivo toxicity of 1-alkyl-3 methylimidazolium chloride ionic liquids. 24-h median lethal dose (LD50) values for nine of these ionic liquids bearing alkyl chain substituents ranging from 2 to 18 carbon atoms were determined. The in vivo toxicity of the ionic liquids was found to correlate directly with the length of the alkyl chain substituent, and the pattern of toxicity observed was in accordance with previous studies of ionic liquid toxicity in other living systems, including a characteristic toxicity 'cut off' effect. However, G. mellonella appeared to be more susceptible to the toxic effects of the ionic liquids tested, possibly as a result of their high body fat content. The results obtained in this study indicate that G. mellonella represents a sensitive, reliable and robust in vivo model organism for the evaluation of ionic liquid toxicity. PMID- 26121606 TI - N-doped carbon-coated tungsten oxynitride nanowire arrays for highly efficient electrochemical hydrogen evolution. AB - It is highly desired but still challenging to develop active nonprecious metal hydrogen evolution reaction (HER) electrocatalysts operating under all pH conditions. Herein, the development of three-dimensional N-doped carbon-coated tungsten oxynitride nanowire arrays on carbon cloth as a highly efficient and durable HER cathode was explored. The material delivers current densities of 10 and 100 mA cm(-2) at overpotentials of 106 and 172 mV, respectively, in acidic medium, and it also performs well in neutral and basic electrolytes. PMID- 26121607 TI - Age-dependent decline in fin regenerative capacity in the short-lived fish Nothobranchius furzeri. AB - The potential to regenerate declines with age in a wide range of organisms. A popular model system to study the mechanisms of regeneration is the fin of teleost fish, which has the ability to fully regrow upon amputation. Here, we used the short-lived killifish Nothobranchius furzeri to analyse the impact of aging on fin regeneration in more detail. We observed that young fish were able to nearly completely (98%) regenerate their amputated caudal fins within 4 weeks, whereas middle-aged fish reached 78%, old fish 57% and very old fish 46% of their original fin size. The difference in growth rate between young and old fish was already significant at 3 days post amputation (dpa) and increased with time. We therefore hypothesized that early events are crucial for the age-related differences in regenerative capacity. Indeed, we could observe a higher percentage of proliferating cells in early regenerating fin tissue of young fish compared with aged fish and larger fractions of apoptotic cells in aged fish. Furthermore, young fish showed peak upregulation of several genes involved in fgf and wnt/beta-catenin signalling at an earlier time point than old fish. Our findings suggest that regenerative processes are initiated earlier and that regeneration overall is more efficient in younger fish. PMID- 26121608 TI - Vision and Control for UAVs: A Survey of General Methods and of Inexpensive Platforms for Infrastructure Inspection. AB - Unmanned aerial vehicles (UAVs) have gained significant attention in recent years. Low-cost platforms using inexpensive sensor payloads have been shown to provide satisfactory flight and navigation capabilities. In this report, we survey vision and control methods that can be applied to low-cost UAVs, and we list some popular inexpensive platforms and application fields where they are useful. We also highlight the sensor suites used where this information is available. We overview, among others, feature detection and tracking, optical flow and visual servoing, low-level stabilization and high-level planning methods. We then list popular low-cost UAVs, selecting mainly quadrotors. We discuss applications, restricting our focus to the field of infrastructure inspection. Finally, as an example, we formulate two use-cases for railway inspection, a less explored application field, and illustrate the usage of the vision and control techniques reviewed by selecting appropriate ones to tackle these use-cases. To select vision methods, we run a thorough set of experimental evaluations. PMID- 26121609 TI - Low-Light Image Enhancement Using Adaptive Digital Pixel Binning. AB - This paper presents an image enhancement algorithm for low-light scenes in an environment with insufficient illumination. Simple amplification of intensity exhibits various undesired artifacts: noise amplification, intensity saturation, and loss of resolution. In order to enhance low-light images without undesired artifacts, a novel digital binning algorithm is proposed that considers brightness, context, noise level, and anti-saturation of a local region in the image. The proposed algorithm does not require any modification of the image sensor or additional frame-memory; it needs only two line-memories in the image signal processor (ISP). Since the proposed algorithm does not use an iterative computation, it can be easily embedded in an existing digital camera ISP pipeline containing a high-resolution image sensor. PMID- 26121610 TI - MEMS Microphone Array Sensor for Air-Coupled Impact-Echo. AB - Impact-Echo (IE) is a nondestructive testing technique for plate like concrete structures. We propose a new sensor concept for air-coupled IE measurements. By using an array of MEMS (micro-electro-mechanical system) microphones, instead of a single receiver, several operational advantages compared to conventional sensing strategies in IE are achieved. The MEMS microphone array sensor is cost effective, less sensitive to undesired effects like acoustic noise and has an optimized sensitivity for signals that need to be extracted for IE data interpretation. The proposed sensing strategy is justified with findings from numerical simulations, showing that the IE resonance in plate like structures causes coherent surface displacements on the specimen under test in an area around the impact location. Therefore, by placing several MEMS microphones on a sensor array board, the IE resonance is easier to be identified in the recorded spectra than with single point microphones or contact type transducers. A comparative measurement between the array sensor, a conventional accelerometer and a measurement microphone clearly shows the suitability of MEMS type microphones and the advantages of using these microphones in an array arrangement for IE. The MEMS microphone array will make air-coupled IE measurements faster and more reliable. PMID- 26121611 TI - Eco Assist Techniques through Real-time Monitoring of BEV Energy Usage Efficiency. AB - Energy efficiency enhancement has become an increasingly important issue for battery electric vehicles. Even if it can be improved in many ways, the driver's driving pattern strongly influences the battery energy consumption of a vehicle. In this paper, eco assist techniques to simply implement an energy-efficient driving assistant system are introduced, including eco guide, eco control and eco monitoring methods. The eco guide is provided to control the vehicle speed and accelerator pedal stroke, and eco control is suggested to limit the output power of the battery. For eco monitoring, the eco indicator and eco report are suggested to teach eco-friendly driving habits. The vehicle test, which is done in four ways, consists of federal test procedure (FTP)-75, new european driving cycle (NEDC), city and highway cycles, and visual feedback with audible warnings is provided to attract the driver's voluntary participation. The vehicle test result shows that the energy usage efficiency can be increased up to 19.41%. PMID- 26121612 TI - Efficient and Secure Temporal Credential-Based Authenticated Key Agreement Using Extended Chaotic Maps for Wireless Sensor Networks. AB - A secure temporal credential-based authenticated key agreement scheme for Wireless Sensor Networks (WSNs) enables a user, a sensor node and a gateway node to realize mutual authentication using temporal credentials. The user and the sensor node then negotiate a common secret key with the help of the gateway node, and establish a secure and authenticated channel using this common secret key. To increase efficiency, recent temporal credential-based authenticated key agreement schemes for WSNs have been designed to involve few computational operations, such as hash and exclusive-or operations. However, these schemes cannot protect the privacy of users and withstand possible attacks. This work develops a novel temporal credential-based authenticated key agreement scheme for WSNs using extended chaotic maps, in which operations are more efficient than modular exponential computations and scalar multiplications on an elliptic curve. The proposed scheme not only provides higher security and efficiency than related schemes, but also resolves their weaknesses. PMID- 26121613 TI - Observed Thermal Impacts of Wind Farms Over Northern Illinois. AB - This paper assesses impacts of three wind farms in northern Illinois using land surface temperature (LST) data from the Moderate Resolution Imaging Spectroradiometer (MODIS) instruments onboard the Terra and Aqua satellites for the period 2003-2013. Changes in LST between two periods (before and after construction of the wind turbines) and between wind farm pixels and nearby non wind-farm pixels are quantified. An areal mean increase in LST by 0.18-0.39 degrees C is observed at nighttime over the wind farms, with the geographic distribution of this warming effect generally spatially coupled with the layout of the wind turbines (referred to as the spatial coupling), while there is no apparent impact on daytime LST. The nighttime LST warming effect varies with seasons, with the strongest warming in winter months of December-February, and the tightest spatial coupling in summer months of June-August. Analysis of seasonal variations in wind speed and direction from weather balloon sounding data and Automated Surface Observing System hourly observations from nearby stations suggest stronger winds correspond to seasons with greater warming and larger downwind impacts. The early morning soundings in Illinois are representative of the nighttime boundary layer and exhibit strong temperature inversions across all seasons. The strong and relatively shallow inversion in summer leaves warm air readily available to be mixed down and spatially well coupled with the turbine. Although the warming effect is strongest in winter, the spatial coupling is more erratic and spread out than in summer. These results suggest that the observed warming signal at nighttime is likely due to the net downward transport of heat from warmer air aloft to the surface, caused by the turbulent mixing in the wakes of the spinning turbine rotor blades. PMID- 26121614 TI - Optimal Parameter Design of Coarse Alignment for Fiber Optic Gyro Inertial Navigation System. AB - Two different coarse alignment algorithms for Fiber Optic Gyro (FOG) Inertial Navigation System (INS) based on inertial reference frame are discussed in this paper. Both of them are based on gravity vector integration, therefore, the performance of these algorithms is determined by integration time. In previous works, integration time is selected by experience. In order to give a criterion for the selection process, and make the selection of the integration time more accurate, optimal parameter design of these algorithms for FOG INS is performed in this paper. The design process is accomplished based on the analysis of the error characteristics of these two coarse alignment algorithms. Moreover, this analysis and optimal parameter design allow us to make an adequate selection of the most accurate algorithm for FOG INS according to the actual operational conditions. The analysis and simulation results show that the parameter provided by this work is the optimal value, and indicate that in different operational conditions, the coarse alignment algorithms adopted for FOG INS are different in order to achieve better performance. Lastly, the experiment results validate the effectiveness of the proposed algorithm. PMID- 26121615 TI - In Opposition to Liberty: We Need a "Sovereign" to Govern Drug Claims. PMID- 26121616 TI - Long-Term Follow-Up of De Novo Use of mTOR and Calcineurin Inhibitors After Kidney Transplantation. AB - BACKGROUND: Long-term efficacy and safety of de novo use of the mammalian target of rapamycin inhibitors (mTORi) have been evaluated primarily using registry data. METHODS: This was a pooled retrospective analysis of data obtained from 10 prospective randomized trials in de novo kidney transplant recipients (n = 581) receiving calcineurin inhibitors (CNIs) combined with sirolimus (n = 329), everolimus (n = 128), or antimetabolites (n = 124). RESULTS: There were no differences in patient (84.5 versus 80.9 versus 89.7%, P = 0.996), graft (65.4 versus 59.5 versus 73.1%, P = 0.868), and biopsy-confirmed acute rejection-free (78.1 versus 77.3 versus 79.0%, P = 0.976) survivals, respectively. The incidence of cytomegalovirus infection was lower (6 versus 3 versus 11%, P = 0.024) but treatment discontinuation was higher among patients receiving mTORi (66.0 versus 47.7 versus 31.5%, P < 0.001), respectively. At 5 years, median estimated glomerular filtration rate (49.6 versus 43.9 versus 53.2 mL/min, P = 0.006) was lower and the proportion of patients with proteinuria (53 versus 40 versus 23%, P < 0.001) was higher among patients receiving mTORi, respectively. CONCLUSIONS: The efficacy of de novo use of mTORi is comparable with that of antimetabolites in kidney transplant recipients receiving calcineurin inhibitor. Apart from the lower cytomegalovirus infection rate, the safety profile is unfavorable, showing higher treatment discontinuation rates and higher incidence of proteinuria. PMID- 26121617 TI - Transfer of mRNA Encoding Invariant NKT Cell Receptors Imparts Glycolipid Specific Responses to T Cells and gammadeltaT Cells. AB - Cell-based therapies using genetically engineered lymphocytes expressing antigen specific T cell receptors (TCRs) hold promise for the treatment of several types of cancers. Almost all studies using this modality have focused on transfer of TCR from CD8 cytotoxic T lymphocytes (CTLs). The transfer of TCR from innate lymphocytes to other lymphocytes has not been studied. In the current study, innate and adaptive lymphocytes were transfected with the human NKT cell-derived TCRalpha and beta chain mRNA (the Valpha24 and Vbeta11 TCR chains). When primary T cells transfected with NKT cell-derived TCR were subsequently stimulated with the NKT ligand, alpha-galactosylceramide (alpha-GalCer), they secreted IFN-gamma in a ligand-specific manner. Furthermore when gammadeltaT cells were transfected with NKT cell-derived TCR mRNA, they demonstrated enhanced proliferation, IFN gamma production and antitumor effects after alpha-GalCer stimulation as compared to parental gammadeltaT cells. Importantly, NKT cell TCR-transfected gammadeltaT cells responded to both NKT cell and gammadeltaT cell ligands, rendering them bi potential innate lymphocytes. Because NKT cell receptors are unique and universal invariant receptors in humans, the TCR chains do not yield mispaired receptors with endogenous TCR alpha and beta chains after the transfection. The transfection of NKT cell TCR has the potential to be a new approach to tumor immunotherapy in patients with various types of cancer. PMID- 26121618 TI - Nickel-Catalyzed Insertion of Alkynes and Electron-Deficient Olefins into Unactivated sp(3) C-H Bonds. AB - Insertion of unsaturated systems such as alkynes and olefins into unactivated sp(3) C-H bonds remains an unexplored problem. We herein address this issue by successfully incorporating a wide variety of functionalized alkynes and electron deficient olefins into the unactivated sp(3) C-H bond of pivalic acid derivatives with excellent syn- and linear- selectivity. A strongly chelating 8 aminoquinoline directing group proved beneficial for these insertion reactions, while an air-stable and inexpensive Ni(II) salt has been employed as the active catalyst. PMID- 26121619 TI - Experimental Evidence for Phonemic Contrasts in a Nonhuman Vocal System. AB - The ability to generate new meaning by rearranging combinations of meaningless sounds is a fundamental component of language. Although animal vocalizations often comprise combinations of meaningless acoustic elements, evidence that rearranging such combinations generates functionally distinct meaning is lacking. Here, we provide evidence for this basic ability in calls of the chestnut-crowned babbler (Pomatostomus ruficeps), a highly cooperative bird of the Australian arid zone. Using acoustic analyses, natural observations, and a series of controlled playback experiments, we demonstrate that this species uses the same acoustic elements (A and B) in different arrangements (AB or BAB) to create two functionally distinct vocalizations. Specifically, the addition or omission of a contextually meaningless acoustic element at a single position generates a phoneme-like contrast that is sufficient to distinguish the meaning between the two calls. Our results indicate that the capacity to rearrange meaningless sounds in order to create new signals occurs outside of humans. We suggest that phonemic contrasts represent a rudimentary form of phoneme structure and a potential early step towards the generative phonemic system of human language. PMID- 26121620 TI - The Cellular Proteins Grb2 and DDX3 Are Increased upon Human Cytomegalovirus Infection and Act in a Proviral Fashion. AB - While it is well established that human cytomegalovirus (HCMV) upregulates many cellular proteins and incorporates several of them into its virion, little is known about the functional relevance of such virus-host interactions. Two cellular proteins, Grb2 and DDX3, gained our interest as they appeared enriched in virion particles and this incorporation depended on the viral tegument protein pp65, suggesting a functional relevance. We therefore tested whether the level of these proteins is altered upon HCMV infection and whether they support viral replication. Immunoblotting analyses of cellular fractions showed increased levels of both proteins in infected cells with a maximum at 2 d p.i. and a reduction of the soluble Grb2 fraction. Knockdown of either gene by transfection of siRNAs reduced viral spread not only of the cell culture adapted HCMV strain TB40/E but also of recent clinical isolates. Apparently, Grb2 and DDX3 are proviral cellular factors that are upregulated in infected cells. PMID- 26121622 TI - [Pals don't evaluate pals...: or do they?]. PMID- 26121621 TI - Individual, school-related and family characteristics distinguish co-occurrence of drinking and depressive symptoms in very young adolescents. AB - INTRODUCTION AND AIMS: Alcohol misuse and depressed mood are common during early adolescence, and comorbidity of these conditions in adulthood is associated with poorer health and social outcomes, yet little research has examined the co occurrence of these problems at early adolescence. This study assessed risky and protective characteristics of pre-teens with concurrent depressed mood/early alcohol use in a large school-based sample. DESIGN AND METHODS: School children aged 10-14 years (n = 7289) from late primary and early secondary school classes in government, Catholic and independent sectors participated with parental consent in the cross-sectional Healthy Neighbourhoods Study. Key measures included depressed mood, recent alcohol use, school mobility, family relationship quality, school engagement and coping style. Multinomial logistic regression analyses were used to identify school and family-related factors that distinguished those with co-occurring drinking and depressive symptoms from those with either single condition. Gender and school-level interactions for each factor were evaluated. RESULTS: Co-occurring conditions were reported by 5.7% of students [confidence interval (CI)95 5.19, 6.19]. Recent drinkers were more likely than non-drinkers to have symptoms consistent with depression (odds ratio 1.80; CI95 1.58, 2.03). Low school commitment was associated with co-occurring drinking/depressive symptoms (odds ratio 2.86; CI95 2.25, 3.65 compared with null condition). This association appeared to be weaker in the presence of adaptive stress-coping skills (odds ratio 0.18; CI95 0.14, 0.23). CONCLUSIONS: We have identified factors that distinguish pre-teens with very early co-occurrence of drinking and depressed mood, and protective factors with potential utility for school-based prevention programmes targeting these conditions. [Salom CL, Kelly AB, Alati R, Williams GM, Patton GC, Williams JW. Individual, school-related and family characteristics distinguish co-occurrence of drinking and depressive symptoms in very young adolescents. Drug Alcohol Rev 2016;35:387-396]. PMID- 26121623 TI - [Controversial Issues in Economic Evaluation (II): health Outcomes of Health Care Interventions]. AB - In this second article of a series of three, we will discuss using the Metaplan technique on controversial issues of health outcomes in economic evaluation of health care interventions. The four-discussion areas focus on: choice of health outcomes measures, where any outcome measure is superior to another; extrapolation and transferability of health outcomes measures, which should not be assumed the results of an EEIS of one country to another without making certain adjustments; appropriate instruments to measure quality of life in Spain, where the EQ-5D was indicated as convenient due to its widespread international use; and, indirect comparisons, where the combination of both comparisons, direct and indirect, it would be advisable if the test for indirect estimates is consistent and has been validated. Finally, research lines to try to overcome the identified discrepancies were identified in each of these areas, some of those are: doing studies of correlation between scores of specific and generic instruments measuring quality of life; update or create a database of economic evaluations in Spain; estimating utilities for the Spanish population by existing generic and specific instruments; or, establish a common way to show the results of a meta-analysis network. PMID- 26121624 TI - [Geographic Patterns of Mortality and Socioeconomic Inequalities in Mortality in Spain]. AB - BACKGROUND: Estimates of socioeconomic inequalities in mortality coming from individual data sources were only available from Madrid, the Basque Country and the city of Barcelona. The aim of this study was to show the geographical pattern of mortality in different socio-economic groups, as well as that of inequalities in mortality in the whole Spanish territory. METHODS: All people aged 25 and older in the 2001 census were followed for seven years and two months to determine their vital status (196 470 401 person-years at risk and 2,379,558 deaths). The socioeconomic variable was educational level. Age-adjusted mortality rate was estimated for women and men in every province and in each category of educational level. Inequalities in mortality in each province have been estimated by the ratio of mortality in subjects with primary or lower level of education compared to subjects with university education. RESULTS: In women, the lowest rate ratios -between 1.06 and 1.16- are observed in Palencia, Segovia, Guadalajara, Avila and Castellon and the highest -between 1.53 and 1,75- in Malaga, Las Palmas, Ceuta, Melilla and Toledo. In men, the lowest rate ratios between 1.00 and 1.12- are observed in Guadalajara, Teruel, Cuenca, La Rioja and Avila and the highest -between 1.47 and 1,73- in Las Palmas, Cantabria, Murcia, Melilla and Ceuta. CONCLUSIONS: The geographical pattern of mortality rates in Spain varies by educational level. Inequalities in mortality by education have the lowest magnitude in central peninsular provinces. PMID- 26121625 TI - [Comparative Effectiveness of Remote Monitoring of People with Cardiac Pacemaker versus Conventional: quality of Life at the 6 Months]. AB - BACKGROUND: The use of remote follow-up (RF) of people with pacemakers (PM) is limited in comparison to the hospital modality (HS), being still poor the scientific evidence that shows their comparative effectiveness. The aim of this study was to compare the quality of life in individuals with different modalities of follow-up. METHODS: Controlled, not randomized nor masked clinical trial, with data collection at pre and post-implantation of pacemakers during the 6 months follow-up. All patients over 18 years-old who were implanted a PM during the study period were selected (n = 83), and they were assigned to RF (n = 30) or HF (n = 53) groups according to their personal characteristics and patient's preferences. Baseline characteristics and number of visits to the hospital were analysed, the EuroQol-5D (EQ5D) questionnaire was administered to evaluate the health-related quality of life, and Duke Activity Status Index (DASI) to assess the functional capacity. RESULTS: There were no significant differences between both groups in relation to the baseline analysis, EQ5D (RF:0.7299; HF:0.6769) and DASI (RF:21.41; HF:19.99). At 6 months the quality of life was improved in both groups (EQ5D RF:0.8613; HF:0.8175; p = 0,439) still without significant differences between them. DASI score was similar to baseline (20.51 vs 21.80). RF group performed less transmissions/visits per patient (1.57) than hospital group (1.96; relative reduction 31%; p = 0.015). CONCLUSIONS: Remote follow-up of people with pacemakers might be considered as an equivalent option to the hospital follow-up in relation to the quality of life and it reduces the number of hospital visits. PMID- 26121626 TI - [Clinical-Epidemiological Profile of Patients Initiating Intensive Statin Therapy for the Secondary Prevention of Vascular Disease in Spain]. AB - BACKGROUND: The new recommendations regarding the utilization of high potency statins (intensive therapy) for the treatment of cardiovascular disease have been based on the extrapolation of data coming from clinical trials. The objective is to describe the clinical-epidemiological profile of statin therapy users for the secondary prevention of cardiovascular disease in Spain and to examine the predictors for intensive therapy initiation. METHODS: Cross-sectional study from a sample of 88,751 patients aged >=45 years-old with previous cardiovascular disease which initiated statin therapy between 1st January 2007 to 31st December 2011. Dose treatments >40 mg simvastatin daily (or equivalent dose if different statin) were considered intensive therapy treatment. Multivariable logistic regression models were built for dependent summary variables to examine the association between and the intensive therapy utilization (vs low-moderate intensity therapy). RESULTS: 16,857 adult patients receiving a first prescription of statin for the secondary prevention of cardiovascular diseases were identified. Predictors for intensive therapy initiation were year of statin prescription, male gender (adjusted OR: 1.70; 95% CI: 1.44-2.00), age >75 years old (1.39; 1.15-1.69), previous history of coronary artery disease (1.71; 1.44 2.04), previous history of transient ischemic attack (1.24; 0,97-1.59), smoking (1.62; 1.34-1.95), hypertension (1.41; 1.20-1.65) and recent use of fibrates (2.32; 1.27-4.26). CONCLUSIONS: The onset of intensive therapy with statins in secondary was determined by the type of vascular event and age (>75 years-old in which the risk benefit balance could be controversial). No statistically significant differences were found according to the LDL-c levels. PMID- 26121627 TI - [Validation of the Spanish Version of Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS)]. AB - BACKGROUND: At the international level PREMIS -"Physician Readiness to Manage Intimate Partner Violence Survey"- is amongst the most comprehensive instruments to evaluate primary health care professionals' readiness. The aim of this study is to assess the reliability, internal consistency and construct validity of the Spanish version of this questionnaire. METHODS: After translation, back translation and assessment of content validity of the questionnaire, 200 questionnaires were distributed to medical doctors and nurses working in 15 primary health care centres located in 4 autonomous regions (Comunidad Valenciana, Castilla Leon, Murcia, Cantabria), in 2013. Cronbach's alpha, intraclass correlation and rho Spearman coefficients were calculated. RESULTS: the Spanish version of PREMIS encompasses 64 items. Cronbach's alpha coefficient was greater than or close to 0.7 in most of indices. Intraclass correlation coefficient of 0.87 and Spearman coefficient of 0.67 showed a high reliability. All correlations for the scale of Opinions, which is the only one that was considered factorial structure of the questionnaire PREMIS, were higher than 0.30. CONCLUSIONS: the Spanish version of PREMIS obtained good internal validity, high reliability and predictive self-reported capacity of medical practitioners and nurses in Intimate Partner Violence cases in PHC centers. PMID- 26121628 TI - [Duration of the Reimbursement Process in Spain for Innovative Drugs Approved by the European Medicines Agency during the Period 2008-2013]. AB - BACKGROUND: In Spain, the decision of Price and Reimbursement (P&R) of a new drug must be taken between 180-270 days. The objective of this study was to assess the reimbursement timing in Spain for innovative drugs approved by the European Medicines Agency (EMA) between January 2008 and December 2013 and to explore the potential impact of drug's price on this time. METHODS: Drugs approved were extracted from EMA's website, authorization dates in Spain from the Spanish Agency (AEMPS) and, P&R dates and prices from Nomenclator and BotPlus. Depending on days from approval to reimbursement, drugs were quick (<180), on time (180 270) and delayed (>270). Depending on posology: chronic or acute. Depending on dispensing conditions: retail or hospital drugs. It was calculated: median, maximum, minimum, first, and third quartiles of time until reimbursement. RESULTS: 431 drugs were approved by EMA; 285 were innovative, from them 147 were approved by the AEMPS and reimbursed: 103 chronic and 44 acute. Median price/day was ?2.44 for chronic and ?21 for acute. From 2008-2011, 80% of drugs were reimbursed, in 2012 21% and in 2013 17%. Time from approval to reimbursement move from 230 days in 2009 to 431 days in 2013. From the 139 drugs with reimbursement date 33 were quick, 44 on time and 62 delayed. CONCLUSIONS: The median time from approval by the EMA of innovative drugs since the reimbursement in Spain in 2013 is double that of 2008. The main driver of delays in the process of P&R seems to be the budget impact of the drug instead of its unit price. PMID- 26121629 TI - [Sociodemographic and Clinical Factors Associated with Informal Care in Hematologic Malignancy Patients: a Study Based on Different Phases of the Treatment, Spain]. AB - BACKGROUND: There is little information on factors related to use of to informal care in cancer patients. Our objective is to study sociodemographic and clinical factors associated with use of informal care in patients with hematologic malignancy and analyze how these changes throughout different phases of the treatment. METHODS: 139 patients diagnosed with hematologic malignancy who received an haematopoietic stem cell transplantation between 2006-2011 in two Spanish hospitals completed the developed postal questionnaire. A binary logistic regression model was used to analyse the factors associated with use of informal care each of four phases of the treatment (pretransplant, first year, second and third year, and from the fouth to sixth year postransplant). Dependent variable was receive vs. not receive informal care. RESULTS: Patients diagnosed with acute leukemia had higher probability of receiving informal care during pretransplant period (OR = 6.394) and during the second and third year postransplantation (OR = 42.212). In the long-term (4-6 years), multiple myeloma patients were the ones who required more informal care (OR = 15.977). Health status was statistically significant during all phases. Being male (OR = 0.263), having partner (OR = 0.137) and being employed (OR = 0.110) were associated with lower likelihood of receiving informal care in the long-term. CONCLUSIONS: Over 75% of patients diagnosed with hematologic malignancy received informal care during pretrasplant and first year postransplant. Type of diagnosis and health status are decisive factors in the probability of receiving informal care at all phases, while the type of transplantation is not. Sociodemografic factors are relevant in the long term. PMID- 26121630 TI - [Impact of Teriparatide on Quality of Life in Osteoporotic Patients]. AB - BACKGROUND: Lost bone in osteoporotic patients increases the risk of fractures and back pain, and decreases quality of life. The aim of this study was to analyse the effect of teriparatide (TPTD) in osteoporotic patients with vertebral pain. METHODS: A prospective observational study between April 2006 and February 2014 was done with 77 patients treated with teriparatide in the Pain Unit of Hospital Obispo Polanco of Teruel (Spain). Treatment duration was 18 or 24 months. Pain was assessed by the Visual Analogue Scale (VAS). Health-related quality of life was measured using the European Quality of Life Questionnaire (EuroQol-5D) in order to obtain the social tariff (ST). Pre and post-treatment values were collected respectively. A descriptive and regression analysis was done. RESULTS: Improvement in pain was observed (80%) and in health-related quality of life (65%). The mean VAS improved (from 5.42 to 3.47 points) and the mean health status value too (from 0.36 to 0.58 points). The regression indicated an improvement of VAS in 0.441 for each initial VAS point, and of ST in 0.0528 points for each 0.1 initial ST point. The probability of VAS reduction in 3 points (OR = 2.021) was greater than in 2 points (OR = 1.695). CONCLUSIONS: TPTD reduces pain and improves quality of life of osteoporotic patients. The worse the baseline situation, the more patients' health improved, so it could be used as criteria for therapeutic decisions and health management. PMID- 26121631 TI - [Incidence of Bartonella Henselae Infection during the period 2009-2012 in the Valencian Community, Spain]. AB - BACKGROUND: Bartonella henselae is the causative agent of the disease caused by cat scratches and it has a worldwide distribution. The objective of the study was to investigate its incidence in the Valencian Community during the period 2009 2012. METHODS: A study of the chosen microbiological tests for B. henselae during four years was carried out. Pacients with serology (IgM and IgG), culture, or PCR positive were considered case studies. Data from the Red de Vigilancia Microbiologica Valenciana (RedMIVA) depending on the "General Direction of Public Health" (Direccion General de Salud Publica) was used as the source of information. RESULTS: During the studied period, 14 cases were detected. The incidence rates were: 0,07 per 10(5) inhabitants and year of the Valencian Community, 0,10 per 10(5) inhabitants/year in the province of Alicante, with marked differences in relation to Valencia of 0,06 per 105 inhabitants/year and Castellon (with no cases). The temporal distribution of the cases were: 4 in 2009, 4 in 2010, 3 in 2011, and 3 in 2012. 64% of the cases were women and 36% men. The median age was 21 years (range 1-65 years). Predominant age groups arose between 1-10 years (42%) and 31-40 years (28%). CONCLUSIONS: The incidence of B. henselae in the Valencian Community is low. The data obtained suggest that its distribution varies depending on the geographical area in the Community. There is a predominance of young people. PMID- 26121632 TI - Unimolecular micelles of amphiphilic cyclodextrin-core star-like block copolymers for anticancer drug delivery. AB - Well-defined star-like amphiphilic polymers composed of a beta-cyclodextrin core, from which 21 hydrophobic poly(lactic acid) arms and hydrophilic poly(ethylene glycol) arms are grafted sequentially, form robust and uniform unimolecular micelles that are biocompatible and efficient in the delivery of anticancer drugs. PMID- 26121633 TI - PVDF-HFP/ether-modified polysiloxane membranes obtained via airbrush spraying as active separators for application in lithium ion batteries. AB - Improved hybrid polymer electrolyte membranes are introduced based on ether modified polysiloxanes and poly(vinylidene fluoride-co-hexafluoropropylene) yielding a safe separator membrane, which is able to be sprayed directly onto lithium ion battery active materials, with an active role for enhanced ion transport. PMID- 26121634 TI - o-Carborane functionalized pentacenes: synthesis, molecular packing and ambipolar organic thin-film transistors. AB - New 6,13-bis[1'-(C=C)-2'-R-1',2'-C2B10H10]pentacenes (R = H, Me, Et, n-Bu) are synthesized and fully characterized. The results show that the alkyl substituents on the second cage carbon have a significant impact on the molecular packing, and the incorporation of the o-carboranyl moiety into a pi conjugated system can lower both LUMO and HOMO energy levels, converting a typical p-type semiconductor into an ambipolar one. PMID- 26121635 TI - A high-yield ionic liquid-promoted synthesis of boron nitride nanosheets by direct exfoliation. AB - Boron nitride nanosheets (BNNSs) with micron-sized edges were prepared in high yields by direct exfoliation of bulk hexagonal boron nitrides using ionic liquids (ILs). The ILs strongly attached onto BNNS surfaces, and dramatically enhanced the exfoliation, giving highly concentrated BNNS dispersions (~1.9 mg mL(-1)) and yields reaching ~50%. PMID- 26121636 TI - Local and Regional Determinants of an Uncommon Functional Group in Freshwater Lakes and Ponds. AB - A combination of local and regional factors and stochastic forces is expected to determine the occurrence of species and the structure of communities. However, in most cases, our understanding is incomplete, with large amounts of unexplained variation. Using functional groups rather than individual species may help explain the relationship between community composition and conditions. In this study, I used survey data from freshwater lakes and ponds to understand factors that determine the presence of the floating plant functional group in the northeast United States. Of the 176 water bodies surveyed, 104 (59.1%) did not contain any floating plant species. The occurrence of this functional group was largely determined by local abiotic conditions, which were spatially autocorrelated across the region. A model predicting the presence of the floating plant functional group performed similarly to the best species-specific models. Using a permutation test, I also found that the observed prevalence of floating plants is no different than expected by random assembly from a species pool of its size. These results suggest that the size of the species pool interacts with local conditions in determining the presence of a functional group. Nevertheless, a large amount of unexplained variation remains, attributable to either stochastic species occurrence or incomplete predictive models. The simple permutation approach in this study can be extended to test alternative models of community assembly. PMID- 26121637 TI - Genome-Wide Computational Analysis of Musa Microsatellites: Classification, Cross Taxon Transferability, Functional Annotation, Association with Transposons & miRNAs, and Genetic Marker Potential. AB - The development of organized, informative, robust, user-friendly, and freely accessible molecular markers is imperative to the Musa marker assisted breeding program. Although several hundred SSR markers have already been developed, the number of informative, robust, and freely accessible Musa markers remains inadequate for some breeding applications. In view of this issue, we surveyed SSRs in four different data sets, developed large-scale non-redundant highly informative therapeutic SSR markers, and classified them according to their attributes, as well as analyzed their cross-taxon transferability and utility for the genetic study of Musa and its relatives. A high SSR frequency (177 per Mbp) was found in the Musa genome. AT-rich dinucleotide repeats are predominant, and trinucleotide repeats are the most abundant in transcribed regions. A significant number of Musa SSRs are associated with pre-miRNAs, and 83% of these SSRs are promising candidates for the development of therapeutic SSR markers. Overall, 74% of the SSR markers were polymorphic, and 94% were transferable to at least one Musa spp. Two hundred forty-three markers generated a total of 1047 alleles, with 2-8 alleles each and an average of 4.38 alleles per locus. The PIC values ranged from 0.31 to 0.89 and averaged 0.71. We report the largest set of non-redundant, polymorphic, new SSR markers to be developed in Musa. These additional markers could be a valuable resource for marker-assisted breeding, genetic diversity and genomic studies of Musa and related species. PMID- 26121638 TI - Molecular Genetic Analysis and Evolution of Segment 7 in Rice Black-Streaked Dwarf Virus in China. AB - Rice black-streaked dwarf virus (RBSDV) causes maize rough dwarf disease or rice black-streaked dwarf disease and can lead to severe yield losses in maize and rice. To analyse RBSDV evolution, codon usage bias and genetic structure were investigated in 111 maize and rice RBSDV isolates from eight geographic locations in 2013 and 2014. The linear dsRNA S7 is A+U rich, with overall codon usage biased toward codons ending with A (A3s, S7-1: 32.64%, S7-2: 29.95%) or U (U3s, S7-1: 44.18%, S7-2: 46.06%). Effective number of codons (Nc) values of 45.63 in S7-1 (the first open reading frame of S7) and 39.96 in S7-2 (the second open reading frame of S7) indicate low degrees of RBSDV-S7 codon usage bias, likely driven by mutational bias regardless of year, host, or geographical origin. Twelve optimal codons were detected in S7. The nucleotide diversity (pi) of S7 sequences in 2013 isolates (0.0307) was significantly higher than in 2014 isolates (0.0244, P = 0.0226). The nucleotide diversity (pi) of S7 sequences in isolates from Jinan (0.0391) was higher than that from the other seven locations (P < 0.01). Only one S7 recombinant was detected in Baoding. RBSDV isolates could be phylogenetically classified into two groups according to S7 sequences, and further classified into two subgroups. S7-1 and S7-2 were under negative and purifying selection, with respective Ka/Ks ratios of 0.0179 and 0.0537. These RBSDV populations were expanding (P < 0.01) as indicated by negative values for Tajima's D, Fu and Li's D, and Fu and Li's F. Genetic differentiation was detected in six RBSDV subpopulations (P < 0.05). Absolute Fst (0.0790) and Nm (65.12) between 2013 and 2014, absolute Fst (0.1720) and Nm (38.49) between maize and rice, and absolute Fst values of 0.0085-0.3069 and Nm values of 0.56-29.61 among these eight geographic locations revealed frequent gene flow between subpopulations. Gene flow between 2013 and 2014 was the most frequent. PMID- 26121639 TI - Circulating IgM Requires Plasma Membrane Disruption to Bind Apoptotic and Non Apoptotic Nucleated Cells and Erythrocytes. AB - Autoimmunity is associated with defective phagocytic clearance of apoptotic cells. IgM deficient mice exhibit an autoimmune phenotype consistent with a role for circulating IgM antibodies in apoptotic cell clearance. We have extensively characterised IgM binding to non-apoptotic and apoptotic mouse thymocytes and human Jurkat cells using flow cytometry, confocal imaging and electron microscopy. We demonstrate strong specific IgM binding to a subset of Annexin-V (AnnV)+PI (Propidium Iodide)+ apoptotic cells with disrupted cell membranes. Electron microscopy studies indicated that IgM+AnnV+PI+ apoptotic cells exhibited morphologically advanced apoptosis with marked plasma membrane disruption compared to IgM-AnnV+PI+ apoptotic cells, suggesting that access to intracellular epitopes is required for IgM to bind. Strong and comparable binding of IgM to permeabilised non-apoptotic and apoptotic cells suggests that IgM bound epitopes are 'apoptosis independent' such that IgM may bind any cell with profound disruption of cell plasma membrane integrity. In addition, permeabilised erythrocytes exhibited significant IgM binding thus supporting the importance of cell membrane epitopes. These data suggest that IgM may recognize and tag damaged nucleated cells or erythrocytes that exhibit significant cell membrane disruption. The role of IgM in vivo in conditions characterized by severe cell damage such as ischemic injury, sepsis and thrombotic microangiopathies merits further exploration. PMID- 26121640 TI - Salivary MicroRNA in Pancreatic Cancer Patients. AB - BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in Western countries, with the lowest 1-year survival rate among commonly diagnosed cancers. Reliable biomarkers for pancreatic cancer diagnosis are lacking and are urgently needed to allow for curative surgery. As microRNA (miRNA) recently emerged as candidate biomarkers for this disease, we explored in the present pilot study the differences in salivary microRNA profiles between patients with pancreatic tumors that are not eligible for surgery, precancerous lesions, inflammatory disease or cancer-free patients as a potential early diagnostic tool. METHODS: Whole saliva samples from patients with pancreatic cancer (n = 7), pancreatitis (n = 4), IPMN (n = 2), or healthy controls (n = 4) were obtained during endoscopic examination. After total RNA isolation, expression of 94 candidate miRNAs was screened by q(RT)PCR using Biomark Fluidgm. Human-derived pancreatic cancer cells were xenografted in athymic mice as an experimental model of pancreatic cancer. RESULTS: We identified hsa-miR-21, hsa-miR-23a, hsa-miR-23b and miR-29c as being significantly upregulated in saliva of pancreatic cancer patients compared to control, showing sensitivities of 71.4%, 85.7%, 85,7% and 57%, respectively and excellent specificity (100%). Interestingly, hsa-miR-23a and hsa-miR23b are overexpressed in the saliva of patients with pancreatic cancer precursor lesions. We found that hsa-miR-210 and let-7c are overexpressed in the saliva of patients with pancreatitis as compared to the control group, with sensitivity of 100% and 75%, and specificity of 100% and 80%, respectively. Last hsa-miR-216 was upregulated in cancer patients as compared to patients diagnosed with pancreatitis, with sensitivity of 50% and specificity of 100%. In experimental models of PDAC, salivary microRNA detection precedes systemic detection of cancer cells markers. CONCLUSIONS: Our novel findings indicate that salivary miRNA are discriminatory in pancreatic cancer patients that are not eligible for surgery. In addition, we demonstrate in experimental models that salivary miRNA detection precedes systemic detection of cancer cells markers. This study stems for the use of salivary miRNA as biomarker for the early diagnosis of patients with unresectable pancreatic cancer. PMID- 26121641 TI - Complement-Opsonized HIV-1 Overcomes Restriction in Dendritic Cells. AB - DCs express intrinsic cellular defense mechanisms to specifically inhibit HIV-1 replication. Thus, DCs are productively infected only at very low levels with HIV 1, and this non-permissiveness of DCs is suggested to go along with viral evasion. We now illustrate that complement-opsonized HIV-1 (HIV-C) efficiently bypasses SAMHD1 restriction and productively infects DCs including BDCA-1 DCs. Efficient DC infection by HIV-C was also observed using single-cycle HIV-C, and correlated with a remarkable elevated SAMHD1 T592 phosphorylation but not SAMHD1 degradation. If SAMHD1 phosphorylation was blocked using a CDK2-inhibitor HIV-C induced DC infection was also significantly abrogated. Additionally, we found a higher maturation and co-stimulatory potential, aberrant type I interferon expression and signaling as well as a stronger induction of cellular immune responses in HIV-C-treated DCs. Collectively, our data highlight a novel protective mechanism mediated by complement opsonization of HIV to effectively promote DC immune functions, which might be in the future exploited to tackle HIV infection. PMID- 26121642 TI - CD103+ CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis. AB - Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+ CD11b- DCs and increased CD103- CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1beta, IL-6, IL-17, TNFalpha, and IFNgamma combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon. CD103+ CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103- CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+ CD11b+ DCs inducing IL-17 producing T cells being a key feature of extensively spread colitis. PMID- 26121643 TI - Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration Resistant Prostate Cancer Cells. AB - Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. PMID- 26121644 TI - Doxorubicin Activates Hepatitis B Virus Replication by Elevation of p21 (Waf1/Cip1) and C/EBPalpha Expression. AB - Hepatitis B virus reactivation is an important medical issue in cancer patients who undergo systemic chemotherapy. Up to half of CHB carriers receiving chemotherapy develop hepatitis and among these cases a notable proportion are associated with HBV reactivation. However, the molecular mechanism(s) through which various chemotherapeutic agents induce HBV reactivation is not yet fully understood. In this study, we investigated the role of the cell cycle regulator p21 (Waf1/Cip1) in the modulation of HBV replication when a common chemotherapeutic agent, doxorubicin, is present. We showed that p21 expression was increased by doxorubicin treatment. This elevation in p21 expression enhanced the expression of CCAAT/enhancer-binding protein alpha (C/EBPalpha); such an increase is likely to promote the binding of C/EBPalpha to the HBV promoter, which will contribute to the activation of HBV replication. Our current study thus reveals the mechanism underlying doxorubicin modulation of HBV replication and provides an increased understanding of HBV reactivation in CHB patients who are receiving systemic chemotherapy. PMID- 26121645 TI - Several N-Glycans on the HIV Envelope Glycoprotein gp120 Preferentially Locate Near Disulphide Bridges and Are Required for Efficient Infectivity and Virus Transmission. AB - The HIV envelope glycoprotein gp120 contains nine disulphide bridges and is highly glycosylated, carrying on average 24 N-linked glycans. Using a probability calculation, we here demonstrate that there is a co-localization of disulphide bridges and N-linked glycans in HIV-1 gp120, with a predominance of N-linked glycans in close proximity to disulphide bridges, at the C-terminal side of the involved cysteines. Also, N-glycans are frequently found immediately adjacent to disulphide bridges in gp120 at the N-terminal side of the involved cysteines. In contrast, N-glycans at positions close to, but not immediately neighboring disulphide bridges seem to be disfavored at the N-terminal side of the involved cysteines. Such a pronounced co-localization of disulphide bridges and N-glycans was also found for the N-glycans on glycoprotein E1 of the hepatitis C virus (HCV) but not for other heavily glycosylated proteins such as E2 from HCV and the surface GP from Ebola virus. The potential functional role of the presence of N glycans near disulphide bridges in HIV-1 gp120 was studied using site-directed mutagenesis, either by deleting conserved N-glycans or by inserting new N glycosylation sites near disulphide bridges. The generated HIV-1NL4.3 mutants were subjected to an array of assays, determining the envelope glycoprotein levels in mutant viral particles, their infectivity and the capture and transmission efficiencies of mutant virus particles by DC-SIGN. Three N-glycans located nearby disulphide bridges were found to be crucial for the preservation of several of these functions of gp120. In addition, introduction of new N glycans upstream of several disulphide bridges, at locations where there was a significant absence of N-glycans in a broad variety of virus strains, was found to result in a complete loss of viral infectivity. It was shown that the N-glycan environment around well-defined disulphide bridges of gp120 is highly critical to allow efficient viral infection and transmission. PMID- 26121646 TI - A Meta-Analysis of Randomized Controlled Trials to Compare Long-Term Outcomes of Nissen and Toupet Fundoplication for Gastroesophageal Reflux Disease. AB - AIM: In recent years, several studies with large sample sizes and recent follow up data have been published comparing outcomes between laparoscopic Nissen fundoplication and laparoscopic Toupet fundoplication. It is now timely to be re evaluated and synthesized long-term efficacy and adverse events of both total and partial posterior fundoplication. MATERIALS AND METHODS: Electronic searches for RCTs comparing the outcome after laparoscopic Nissen fundoplication and laparoscopic Toupet fundoplication were performed in the databases of MEDLINE, EMBASE, and the Cochrane Center Register of Controlled Trials. The data of evaluation in positive and adverse results of laparoscopic Nissen fundoplication and laparoscopic Nissen fundoplication were extracted and compared using meta analysis. RESULTS: 13 RCTs were ultimately identified involving 814 (52.05%) and 750 (47.95%) patients who underwent laparoscopic Nissen fundoplication and laparoscopic Toupet fundoplication, respectively. The operative time, perioperative complications, postoperative satisfaction, recurrence, and the rates of medication adoption or re-operation due to recurrence were not significantly different between two groups. The two types of fundoplication both reinforced the anti-reflux barrier and elevated the lower esophageal sphincter pressure. However, rates of adverse results involving dysphasia, gas-bloat syndrome, inability to belch and re-operation due to severe dysphasia were significantly higher after LNF. In the subgroup analysis of wrap length<=2 cm, laparoscopic Nissen fundoplication was associated with a significantly higher incidence of postoperative dysphagia. However, in the subgroup wrap length>2 cm, the difference was not statistically significant. CONCLUSION: Laparoscopic Toupet fundoplication might be the better surgery approach for gastroesophageal reflux disease with a lower rate of postoperative adverse results and equal effectiveness as Laparoscopic Nissen fundoplication. PMID- 26121647 TI - Mortality and Length of Stay of Very Low Birth Weight and Very Preterm Infants: A EuroHOPE Study. AB - The objective of this paper was to compare health outcomes and hospital care use of very low birth weight (VLBW), and very preterm (VLGA) infants in seven European countries. Analysis was performed on linkable patient-level registry data from seven European countries between 2006 and 2008 (Finland, Hungary, Italy (the Province of Rome), the Netherlands, Norway, Scotland, and Sweden). Mortality and length of stay (LoS) were adjusted for differences in gestational age (GA), sex, intrauterine growth, Apgar score at five minutes, parity and multiple births. The analysis included 16,087 infants. Both the 30-day and one-year adjusted mortality rates were lowest in the Nordic countries (Finland, Sweden and Norway) and Scotland and highest in Hungary and the Netherlands. For survivors, the adjusted average LoS during the first year of life ranged from 56 days in the Netherlands and Scotland to 81 days in Hungary. There were large differences between European countries in mortality rates and LoS in VLBW and VLGA infants. Substantial data linkage problems were observed in most countries due to inadequate identification procedures at birth, which limit data validity and should be addressed by policy makers across Europe. PMID- 26121648 TI - Identification of a Conserved Linear B-Cell Epitope of Streptococcus dysgalactiae GapC Protein by Screening Phage-Displayed Random Peptide Library. AB - The GapC of Streptococcus dysgalactiae (S. dysgalactiae) is a highly conserved surface protein that can induce protective humoral immune response in animals. However, B-cell epitopes on the S. dysgalactiae GapC have not been well identified. In this study, a monoclonal antibody (mAb5B7) against the GapC1-150 protein was prepared. After passive transfer, mAb5B7 could partially protect mice against S. dysgalactiae infection. Eleven positive phage clones recognized by mAb5B7 were identified by screening phage-displayed random 12-peptide library, most of which matched the consensus motif DTTQGRFD. The motif sequence exactly matches amino acids 48-55 of the S. dysgalactiae GapC protein. In addition, the motif 48DTTQGRFD55 shows high homology among various streptococcus species. Site directed mutagenic analysis further confirmed that residues D48, T50, Q51, G52 and F54 formed the core motif of 48DTTQGRFD55. This motif was the minimal determinant of the B-cell epitope recognized by the mAb5B7. As expected, epitope peptide evoked protective immune response against S. dysgalactiae infection in immunized mice. Taken together, this identified conserved B-cell epitope within S. dysgalactiae GapC could provide very valuable insights for vaccine design against S. dysgalactiae infection. PMID- 26121649 TI - Morphology and molecular phylogeny of an Indian population of Cyrtohymena citrina (Ciliophora, Hypotricha), including remarks on ontogenesis of Urosomoida Notohymena-Cyrtohymena group. AB - The oxytrichid ciliate Cyrtohymena citrina, isolated from a soil sample from India, is moderately flexible, measures about 105 * 35 MUm in life and possesses citrine cortical granules, mainly arranged around cirri and dorsal cilia. Morphology and ontogenesis was investigated using live observation and protargol impregnation, and 18S rDNA was sequenced. Ontogenesis of an Indian population of Urosomoida agilis was also investigated. All three genera included in the Urosomoida-Notohymena-Cyrtohymena group have long been characterized by the ontogenetic feature that "anlagen V and VI of proter originate de novo". This ontogenetic feature has been considered as the sole synapomorphy and an important diagnostic feature of the group. Based on current observations on ontogenesis of C. citrina and U. agilis, and previous observations of C. shii, Notohymena saprai and N. australis, the aforesaid ontogenetic feature is no longer true for the group. Indian population of C. citrina clusters with C. muscorum, Paraurosomoida, Urosomoida, Notohymena and Paraurostyla, and is placed away from Oxytricha granulifera; all oxytrichids in the cluster show deviation(s) from any of the typical oxytrichid features like Oxytricha pattern undulating membrane, 18 frontoventral transverse cirri and fragmentation of dorsal kinety 3. Phylogenetic analyses supported non-monophyly of Cyrtohymena and other flexible-bodied oxytrichids. PMID- 26121650 TI - Diarrheal Illness and Healthcare Seeking Behavior among a Population at High Risk for Diarrhea in Dhaka, Bangladesh. AB - Diarrhea remains one of the major causes of death in Bangladesh. We studied diarrheal disease risk and healthcare seeking behavior among populations at high risk for diarrhea in Dhaka, Bangladesh. Data were obtained from a cross-sectional survey conducted during April and September 2010. The prevalence of diarrhea was calculated by age-group and sex. A generalized estimating equation with logit link function was used to predict diarrheal disease risk and seeking care from a professional healthcare provider. Of 316,766 individuals, 10% were young children (<5 years). The prevalence of diarrhea was 16 per 1000 persons among all ages; young children accounted for 44 per 1000 persons. Prevalence of diarrhea was significantly higher (p=.003) among younger males (<15 years) compared to that among younger females. In contrast, prevalence of diarrhea was significantly higher (p<.0001) among older females (>=15 years) compared to that among older males. An increased risk for diarrhea was observed in young children, males, and those staying in rented houses, lower family members in the house, using non sanitary toilets, living in the area for short times, living in a community with less educated persons, living in a community with less use of safe water source for drinking, or living close to the hospital. About 80% of those with diarrhea sought care initially from a non-professional healthcare provider. Choice of the professional healthcare provider was driven by age of the patient, educational status of the household head, and hygienic practices by the household. The study reaffirms that young children are at greater risk for diarrhea. Like other developing countries most people in this impoverished setting of Dhaka are less likely to seek care from a professional healthcare provider than from a non professional healthcare provider, which could be attributed to a higher number of diarrheal deaths among young children in Bangladesh. Dissemination of information on health education, increasing the supply of skilled healthcare providers, and low-cost and quality healthcare services may encourage more people to seek care from professional healthcare providers, thus may help reduce child mortality in the country. Further studies are warranted to validate the results. PMID- 26121652 TI - Correction: Repeated Exposure of Adult Rats to Transient Oxidative Stress Induces Various Long-Lasting Alterations in Cognitive and Behavioral Functions. PMID- 26121651 TI - Polymorphonuclear Cell Functional Impairment in Relapsing Remitting Multiple Sclerosis Patients: Preliminary Data. AB - Multiple Sclerosis patients run an increased risk of microbial infections, which leads to high rates of hospitalization and infection-related mortality. Although immunotherapy may increase infection risk in some cases, data as to the relationship among microbial factors, immunotherapy and alterations in the innate immunity of these patients are still scanty. On these grounds, this interdisciplinary study aims at investigating the role the functional activity of polymorphonuclear cells (PMNs) play in relapsing remitting multiple sclerosis at different stages. The in vitro ability of PMNs from patients, either untreated or treated with immunosuppressant or immunomodulatory drugs to kill Klebsiella pneumonia or Candida albicans, were investigated and compared to PMNs from healthy subjects. The release of various cytokines was also assessed, as was the production of reactive oxygen species and their ability to regulate apoptosis after microbial stimulation. Our results indicate that although patients have a normal number of PMNs, they have a statistically significant (p<0.05) reduction in intracellular killing activity. Although variations are strongly related to the therapeutic management of patients, they are independent from their disease stage. As no statistically significant differences were observed between patients and controls in cytokine release values, reactive oxygen species production or apoptosis, we came to the conclusion that other factors may be involved. Supportive validation of these results from further studies might well help in identifying a subset of patients at high risk of infection who could benefit from a closer follow-up and/or antibiotic prophylaxis. PMID- 26121653 TI - Impaired Neonatal Outcome after Emergency Cerclage Adds Controversy to Prolongation of Pregnancy. AB - OBJECTIVE: Emergency cervical cerclage is one of the treatment options for the reduction of preterm birth. The aim of this study is to assess neonatal outcome after cerclage with special focus on adverse effects in very low birth weight infants. STUDY DESIGN: Retrospective cohort study. Classification of cerclages in history-indicated (HIC, n = 38), ultrasound-indicated (UIC, n = 29) and emergency/ physical examination-indicated (PEIC, n = 33) cerclage. Descriptive analysis of pregnancy and neonatal outcome (admission to NICU, duration of hospitalization, respiratory outcome (intubation, CPAP, FiO2max), neonatal complications (ROP, IVH)). Statistical comparison of perinatal parameters and outcome of neonates <1500 g after cerclage with a birth weight matched control group. RESULTS: Neonates <1500 g after PEIC show significantly impaired outcome, i.e. prolonged respiratory support (total ventilation in days, CPAP, FiO2max) and higher rates of neonatal complications (IVH >= II, ROP >= 2). Placental pathologic evaluation revealed a significantly higher rate of chorioamnionitis (CAM) after PEIC. Neonates <1500 g after UIC or HIC show no significant difference in neonatal complications or CAM. CONCLUSIONS: In our study PEIC is associated with adverse neonatal outcome in infants <1500 g. The high incidence of CAM indicates a potential inflammatory factor in the pathogenesis. Large well designed RCTs are required to give conclusive answers to the question whether to prolong or to deliver. PMID- 26121654 TI - National Cohort Study of Suicidality and Violent Criminality among Danish Immigrants. AB - BACKGROUND: Immigrant populations in western societies have grown in their size and diversity yet evidence is incomplete for their risks of suicidality and criminal violence. We examined these correlated harmful behaviours in a national cohort. AIMS: (i) Compare absolute risk between first and second generation immigrants, foreign-born adoptees and native Danes by plotting cumulative incidence curves to onset of early middle age; (ii) estimate sex-specific relative risks for these immigrant type subgroups vs. native Danes; (iii) examine effect modification by higher vs. lower socio-economic status. METHODS: In a cohort of over two million persons, attempted suicides and violent crimes were investigated using data from multiple interlinked registers. We plotted sex specific cumulative incidence curves and estimated incidence rate ratios. RESULTS: In the whole study cohort, 1414 people died by suicide, 46,943 attempted suicide, and 51,344 were convicted of committing a violent crime. Among all immigrant subgroups combined, compared with native Danes, relative risk of attempted suicide was greater in female immigrants (incidence rate ratio, 1.59; 95% confidence interval: CI 1.54-1.64) than in male immigrants (1.26; CI 1.20 1.32), and vice versa for relative risk of violent offending in male immigrants (2.36; CI 2.31-2.42) than in female immigrants (1.74; CI 1.62-1.87). Risk for both adverse outcomes was significantly elevated in virtually every gender specific immigrant type subgroup examined. Violent crime risk was markedly raised in first generation immigrant males and in the Danish born male children of two immigrant parents. However, male immigrants of lower social status had lower risk of attempted suicide than their native Danish peers. CONCLUSION: Young immigrants of both first and second generation status face serious challenges and vulnerabilities that western societies need to urgently address. Relative risk patterns for these adverse outcomes vary greatly between the genders and also by socioeconomic status. This high degree of heterogeneity points to the existence of modifiable factors that are amenable to positive change and a potential for effective intervention. PMID- 26121655 TI - Optimization of Mutation Pressure in Relation to Properties of Protein-Coding Sequences in Bacterial Genomes. AB - Most mutations are deleterious and require energetically costly repairs. Therefore, it seems that any minimization of mutation rate is beneficial. On the other hand, mutations generate genetic diversity indispensable for evolution and adaptation of organisms to changing environmental conditions. Thus, it is expected that a spontaneous mutational pressure should be an optimal compromise between these two extremes. In order to study the optimization of the pressure, we compared mutational transition probability matrices from bacterial genomes with artificial matrices fulfilling the same general features as the real ones, e.g., the stationary distribution and the speed of convergence to the stationarity. The artificial matrices were optimized on real protein-coding sequences based on Evolutionary Strategies approach to minimize or maximize the probability of non-synonymous substitutions and costs of amino acid replacements depending on their physicochemical properties. The results show that the empirical matrices have a tendency to minimize the effects of mutations rather than maximize their costs on the amino acid level. They were also similar to the optimized artificial matrices in the nucleotide substitution pattern, especially the high transitions/transversions ratio. We observed no substantial differences between the effects of mutational matrices on protein-coding sequences in genomes under study in respect of differently replicated DNA strands, mutational cost types and properties of the referenced artificial matrices. The findings indicate that the empirical mutational matrices are rather adapted to minimize mutational costs in the studied organisms in comparison to other matrices with similar mathematical constraints. PMID- 26121656 TI - From virotherapy to oncolytic immunotherapy: where are we now? AB - Viruses have been suggested to be useful as anti-cancer agents since the early 20th century, although following the advent of chemotherapy and radiotherapy work largely stopped until the 1990s when a number of groups began to explore the use of engineered viruses. This overview summarizes the development of the field from the 1990s to the present day, an era when oncolytic viruses have now demonstrated clear clinical benefit to patients. The hurdles and challenges which needed to be overcome are discussed, and in particular the importance of the immune component in achieving a therapeutic effect is highlighted. Today, oncolytic therapy is generally thought of as an immunotherapy, the term 'oncolytic immunotherapy' having been widely adopted. With the advent of immuno-oncology drugs based on immune checkpoint blockade, a clear rationale for synergy between the two approaches, and initial pre-clinical and clinical data suggesting this to be the case, it might be expected that oncolytic immunotherapy combined with checkpoint blockade will provide a cornerstone of future cancer treatment. PMID- 26121657 TI - De Novo Assembly and Characterization of Fruit Transcriptome in Black Pepper (Piper nigrum). AB - Black pepper is one of the most popular and oldest spices in the world and valued for its pungent constituent alkaloids. Pinerine is the main bioactive compound in pepper alkaloids, which perform unique physiological functions. However, the mechanisms of piperine synthesis are poorly understood. This study is the first to describe the fruit transcriptome of black pepper by sequencing on Illumina HiSeq 2000 platform. A total of 56,281,710 raw reads were obtained and assembled. From these raw reads, 44,061 unigenes with an average length of 1,345 nt were generated. During functional annotation, 40,537 unigenes were annotated in Gene Ontology categories, Kyoto Encyclopedia of Genes and Genomes pathways, Swiss-Prot database, and Nucleotide Collection (NR/NT) database. In addition, 8,196 simple sequence repeats (SSRs) were detected. In a detailed analysis of the transcriptome, housekeeping genes for quantitative polymerase chain reaction internal control, polymorphic SSRs, and lysine/ornithine metabolism-related genes were identified. These results validated the availability of our database. Our study could provide useful data for further research on piperine synthesis in black pepper. PMID- 26121659 TI - Routine ultrasound in late pregnancy (after 24 weeks' gestation). AB - BACKGROUND: Diagnostic ultrasound is used selectively in late pregnancy where there are specific clinical indications. However, the value of routine late pregnancy ultrasound screening in unselected populations is controversial. The rationale for such screening would be the detection of clinical conditions which place the fetus or mother at high risk, which would not necessarily have been detected by other means such as clinical examination, and for which subsequent management would improve perinatal outcome. OBJECTIVES: To assess the effects on obstetric practice and pregnancy outcome of routine late pregnancy ultrasound, defined as greater than 24 weeks' gestation, in women with either unselected or low-risk pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All acceptably controlled trials of routine ultrasound in late pregnancy (defined as after 24 weeks). DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Thirteen trials recruiting 34,980 women were included in the systematic review. Risk of bias was low for allocation concealment and selective reporting, unclear for random sequence generation and incomplete outcome data and high for blinding of both outcome assessment and participants and personnel. There was no difference in antenatal, obstetric and neonatal outcome or morbidity in screened versus control groups. Routine late pregnancy ultrasound was not associated with improvements in overall perinatal mortality. There is little information on long term substantive outcomes such as neurodevelopment. There is a lack of data on maternal psychological effects.Overall, the evidence for the primary outcomes of perinatal mortality, preterm birth less than 37 weeks, induction of labour and caesarean section were assessed to be of moderate or high quality with GRADE software. There was no association between ultrasound in late pregnancy and perinatal mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.67 to 1.54; participants = 30,675; studies = eight; I2 = 29%), preterm birth less than 37 weeks (RR 0.96, 95% CI 0.85 to 1.08; participants = 17,151; studies = two; I2 = 0%), induction of labour (RR 0.93, 95% CI 0.81 to 1.07; participants = 22,663; studies = six; I2 = 78%), or caesarean section (RR 1.03, 95% CI 0.92 to 1.15; participants = 27,461; studies = six; I2 = 54%). Three additional primary outcomes chosen for the 'Summary of findings' table were preterm birth less than 34 weeks, maternal psychological effects and neurodevelopment at age two. Because none of the included studies reported these outcomes, they were not assessed for quality with GRADE software. AUTHORS' CONCLUSIONS: Based on existing evidence, routine late pregnancy ultrasound in low-risk or unselected populations does not confer benefit on mother or baby. There was no difference in the primary outcomes of perinatal mortality, preterm birth less than 37 weeks, caesarean section rates, and induction of labour rates if ultrasound in late pregnancy was performed routinely versus not performed routinely. Meanwhile, data were lacking for the other primary outcomes: preterm birth less than 34 weeks, maternal psychological effects, and neurodevelopment at age two, reflecting a paucity of research covering these outcomes. These outcomes may warrant future research. PMID- 26121661 TI - Capping in situ with activated carbon in Trondheim harbor (Norway) reduces bioaccumulation of PCBs and PAHs in marine sediment fauna. AB - Three types of thin-layer caps with activated carbon (AC) were tested in situ in experimental plots (10 * 10 m) in Trondheim harbor, Norway, using AC + clay, AC only or AC + sand. One year after capping, intact sediment cores were collected from the amended plots for ex situ surveys of the capping efficiency in reducing the PAH and PCB aqueous concentrations and bioaccumulation by the polychaete Hediste diversicolor and the clam Abra nitida. Reduced pore water concentrations were observed in all AC treatments. The capping efficiency was in general AC + clay > AC-only > AC + sand. AC + clay reduced bioaccumulation of PAH and PCB congeners between 40% and 87% in the worms and between 67% and 97% in the clams. Sediment capped with AC-only also led to reduced bioaccumulation of PCBs, while AC + sand showed no reduction in bioaccumulation. Thus the best thin-layer capping method in this study was AC mixed with clay. PMID- 26121660 TI - Identification of Cyclobutane Pyrimidine Dimer-Responsive Genes Using UVB Irradiated Human Keratinocytes Transfected with In Vitro-Synthesized Photolyase mRNA. AB - Major biological effects of UVB are attributed to cyclobutane pyrimidine dimers (CPDs), the most common photolesions formed on DNA. To investigate the contribution of CPDs to UVB-induced changes of gene expression, a model system was established by transfecting keratinocytes with pseudouridine-modified mRNA (Psi-mRNA) encoding CPD-photolyase. Microarray analyses of this model system demonstrated that more than 50% of the gene expression altered by UVB was mediated by CPD photolesions. Functional classification of the gene targets revealed strong effects of CPDs on the regulation of the cell cycle and transcriptional machineries. To confirm the microarray data, cell cycle regulatory genes, CCNE1 and CDKN2B that were induced exclusively by CPDs were selected for further investigation. Following UVB irradiation, expression of these genes increased significantly at both mRNA and protein levels, but not in cells transfected with CPD-photolyase Psi-mRNA and exposed to photoreactivating light. Treatment of cells with inhibitors of c-Jun N-terminal kinase (JNK) blocked the UVB-dependent upregulation of both genes suggesting a role for JNK in relaying the signal of UVB-induced CPDs into transcriptional responses. Thus, photolyase mRNA-based experimental platform demonstrates CPD-dependent and independent events of UVB-induced cellular responses, and, as such, has the potential to identify novel molecular targets for treatment of UVB-mediated skin diseases. PMID- 26121663 TI - Local Dynamic Joint Stability During Human Treadmill Walking in Response to Lower Limb Segmental Loading Perturbations. AB - Our purpose was to quantify changes in local dynamic stability (LDS) of the lumbar spine, hip, knee, and ankle in response to changes in lower limb segment mass, as well as to quantify temporal adaptations to segment loading during treadmill walking. Results demonstrate that increased mass distal to a joint yields either the maintenance of, or increased stabilization of, that particular joint relative to the unloaded condition. Increased mass proximal to a particular joint resulted in joint destabilization. The hip and ankle LDS were observed to change temporally, independent of segment loading condition, suggesting adaptation to walking on a treadmill interface. PMID- 26121662 TI - Fabrication of 3D Scaffolds with Precisely Controlled Substrate Modulus and Pore Size by Templated-Fused Deposition Modeling to Direct Osteogenic Differentiation. AB - Scaffolds with tunable mechanical and topological properties fabricated by templated-fused deposition modeling promote increased osteogenic differentiation of bone marrow stem cells with increasing substrate modulus and decreasing pore size. These findings guide the rational design of cell-responsive scaffolds that recapitulate the bone microenvironment for repair of bone damaged by trauma or disease. PMID- 26121664 TI - A Well-Defined Aluminum-Based Lewis Acid as an Effective Catalyst for Diels-Alder Transformations. AB - A catalytically active aluminum-based system for Diels-Alder transformations is reported. The system was generated by mixing a beta-diketiminate-stabilized aluminum bistriflate compound with Na[BAr(Cl) 4 (Ar(Cl) =3,5-Cl2 C6 H3). Solid state analysis of the catalytic system reveals a unique structure incorporating a two-dimensional coordination polymer. According to the experimental results obtained from several Diels-Alder transformations, the aluminum-based system appears to be a more practical and more robust alternative to the recently reported compounds based on carbon and silicon cations. PMID- 26121665 TI - mypub.org, a customizable URL shortener for the NCBI My Bibliography. PMID- 26121666 TI - Slow Cone Reflectance Changes during Bleaching Determined by Adaptive Optics Scanning Laser Ophthalmoscope in Living Human Eyes. AB - To investigate the changes in the reflectance of human cone photoreceptors by an adaptive optics scanning laser ophthalmoscope (AO-SLO) during photobleaching. A custom-built AO-SLO with an observation light of 840-nm was used to measure the cone densities and the reflectance changes during bleaching by 630 nm red light emitting diodes. Measurements were made at 1 degrees and 3 degrees temporal to the fovea within an area of 1 degrees * 1 degrees in 8 eyes of 8 normal subjects. After dark-adaptation, images of the cone mosaics were recorded continuously for 5-min before, 5-min during, and after 5-min of light stimulation with a sampling rate of 5-Hz. The first positive peak (P1) was observed at 72.2 +/- 15.0-s and a second positive peak (P2) at 257.5 +/- 34.5-s at 1 degrees . The increase of the reflectance of P1 was significantly larger at 1 degrees (34.4 +/ 13.9%) than at 3 degrees (26.0 +/- 10.5%; P = 0.03, Wilcoxon's signed rank test). The average cone density at 1 degrees (51123.13 +/- 1401.23 cells/mm2) was significantly larger than that at 3 degrees (30876.13 +/- 1459.28 cells/mm2; P <0.001, Wilcoxon's signed rank test). The changes in the reflectance of the cones during bleaching by red light had two peaks. The two peaks may be caused by regeneration of cone photopigment during bleaching. PMID- 26121667 TI - Drosophila Lipophorin Receptors Recruit the Lipoprotein LTP to the Plasma Membrane to Mediate Lipid Uptake. AB - Lipophorin, the main Drosophila lipoprotein, circulates in the hemolymph transporting lipids between organs following routes that must adapt to changing physiological requirements. Lipophorin receptors expressed in developmentally dynamic patterns in tissues such as imaginal discs, oenocytes and ovaries control the timing and tissular distribution of lipid uptake. Using an affinity purification strategy, we identified a novel ligand for the lipophorin receptors, the circulating lipoprotein Lipid Transfer Particle (LTP). We show that specific isoforms of the lipophorin receptors mediate the extracellular accumulation of LTP in imaginal discs and ovaries. The interaction requires the LA-1 module in the lipophorin receptors and is strengthened by a contiguous region of 16 conserved amino acids. Lipophorin receptor variants that do not interact with LTP cannot mediate lipid uptake, revealing an essential role of LTP in the process. In addition, we show that lipophorin associates with the lipophorin receptors and with the extracellular matrix through weak interactions. However, during lipophorin receptor-mediated lipid uptake, LTP is required for a transient stabilization of lipophorin in the basolateral plasma membrane of imaginal disc cells. Together, our data suggests a molecular mechanism by which the lipophorin receptors tether LTP to the plasma membrane in lipid acceptor tissues. LTP would interact with lipophorin particles adsorbed to the extracellular matrix and with the plasma membrane, catalyzing the exchange of lipids between them. PMID- 26121668 TI - Seasonal Dynamics of Marine Microbial Community in the South Sea of Korea. AB - High-resolution 16S rRNA tag pyrosequencing was used to obtain seasonal snapshots of the bacterial diversity and community structure at two locations in Gosung Bay (South Sea, Korea) over a one year period. Seasonal sampling from the water column at each site revealed highly diverse bacterial communities containing up to 900 estimated Operational Taxonomic Units (OTUs). The Alphaproteobacteria and Gammaproteobacteria were the most abundant groups, and the most frequently recorded OTUs were members of Pelagibacter and Glaciecola. In particular, it was observed that Arcobacter, a genus of the Epsilonproteobacteria, dominated during summer. In addition, Psedoalteromonadaceae, Vibrionaceae and SAR11-1 were predominant members of the OTUs found in all sampling seasons. Environmental factors significantly influenced the bacterial community structure among season, with the phosphate and nitrate concentrations contributing strongly to the spatial distribution of the Alphaproteobacteria; the Gammaproteobacteria, Flavobacteria, and Actinobacteria all showed marked negative correlations with all measured nutrients, particularly silicon dioxide and chlorophyll-a. The results suggest that seasonal changes in environmental variables contribute to the dynamic structure of the bacterial community in the study area. PMID- 26121669 TI - Kinetoplastid Specific RNA-Protein Interactions in Trypanosoma cruzi Ribosome Biogenesis. AB - RNA binding proteins (RBP) play essential roles in the highly conserved and coordinated process of ribosome biogenesis. Our laboratory has previously characterized two essential and abundant RBPs, P34 and P37, in Trypanosoma brucei which are required for several critical steps in ribosome biogenesis. The genes for these proteins have only been identified in kinetoplastid organisms but not in the host genome. We have identified a homolog of the TbP34 and TbP37 in a T. cruzi strain (termed TcP37/NRBD). Although the N-terminal APK-rich domain and RNA recognition motifs are conserved, the C-terminal region which contains putative nuclear and nucleolar localization signals in TbP34 and TbP37 is almost entirely missing from TcP37/NRBD. We have shown that TcP37/NRBD is expressed in T. cruzi epimastigotes at the level of mature mRNA and protein. Despite the loss of the C terminal domain, TcP37/NRBD is present in the nucleus, including the nucleolus, and the cytoplasm. TcP37/NRBD interacts directly with Tc 5S rRNA, but does not associate with polyadenylated RNA. TcP37/NRBD also associates in vivo and in vitro with large ribosomal protein TcL5 and, unlike the case of T. brucei, this association is strongly enhanced by the presence of 5S rRNA, suggesting that the loss of the C-terminal domain of TcP37/NRBD may alter the interactions within the complex. These results indicate that the unique preribosomal complex comprised of L5, 5S rRNA, and the trypanosome-specific TcP37/NRBD or TbP34 and TbP37 is functionally conserved in trypanosomes despite the differences in the C-termini of the trypanosome-specific protein components. PMID- 26121670 TI - Factors Associated with the Perception of Speed among Recreational Skiers. AB - BACKGROUND: Skiers have to differ between slow to moderate and fast skiing speed to determine their skiing style according to the ISO 11088 standard for setting binding release values. Despite existing evidence that males ski significantly faster than females, no sex-specific factor was inserted into the ISO 11088 standard. OBJECTIVE: To evaluate factors potentially associated with the perception of individual skiing speed among recreational skiers. METHODS: Skiing speeds of 416 adult skiers (62% males,) were measured with a radar speed gun. Skiers were interviewed about their age, sex, skill level, risk taking behaviour and helmet use. Finally, skiers had to rate their perceived speed on one out of three speed categories (fast, moderate, slow). RESULTS: The measured mean speed of this cohort was 48.2+/-14.3 km/h (30.0+/-8.9 mph). A total of 32%, 52%, and 16% of skiers perceived their actual speed as fast, moderate and slow, respectively. Mean speed differed significantly between the 3 speed categories with a mean of about 53.5+/-13.7 km/h (33.2+/-8.5 mph) for fast, 47.6+/-14.0 km/h (29.6+/-8.7 mph) for moderate, and 39.4+/-12.2 km/h (24.5+/-7.6 mph) for slow skiing, respectively. Sex (eta2 = .074), skill level (eta2 = .035) and risk taking behavior (eta2 = .033) showed significant differences of skiing speeds with regard to the 3 categories of speed perception (all p < .001) while age groups and ski helmet use did not. Males, more skilled skiers and risky skiers perceived their actual speed as fast, moderate and slow, when skiing up to 10 km/h (6 mph) faster compared to females, less skilled and cautious skiers. CONCLUSION: The perception of skiing speed as fast, moderate or slow depends on sex, skill level, and risk taking behaviour. These findings should be considered when discussing the introduction of a sex factor into the ISO 11088 standard for setting binding release values. PMID- 26121671 TI - Executioner Caspase-3 and 7 Deficiency Reduces Myocyte Number in the Developing Mouse Heart. AB - Executioner caspase-3 and -7 are proteases promoting cell death but non-apoptotic roles are being discovered. The heart expresses caspases only during development, suggesting they contribute to the organ maturation process. Therefore, we aimed at identifying novel functions of caspases in heart development. We induced simultaneous deletion of executioner caspase-3 and -7 in the mouse myocardium and studied its effects. Caspase knockout hearts are hypoplastic at birth, reaching normal weight progressively through myocyte hypertrophy. To identify the molecular pathways involved in these effects, we used microarray-based transcriptomics and multiplexed quantitative proteomics to compare wild type and executioner caspase-deficient myocardium at different developmental stages. Transcriptomics showed reduced expression of genes promoting DNA replication and cell cycle progression in the neonatal caspase-deficient heart suggesting reduced myocyte proliferation, and expression of non-cardiac isoforms of structural proteins in the adult null myocardium. Proteomics showed reduced abundance of proteins involved in oxidative phosphorylation accompanied by increased abundance of glycolytic enzymes underscoring retarded metabolic maturation of the caspase null myocardium. Correlation between mRNA expression and protein abundance of relevant genes was confirmed, but transcriptomics and proteomics indentified complementary molecular pathways influenced by caspases in the developing heart. Forced expression of wild type or proteolytically inactive caspases in cultured cardiomyocytes induced expression of genes promoting cell division. The results reveal that executioner caspases can modulate heart's cellularity and maturation during development, contributing novel information about caspase biology and heart development. PMID- 26121672 TI - Viruses and the nuclear envelope. AB - Viruses encounter and manipulate almost all aspects of cell structure and metabolism. The nuclear envelope (NE), with central roles in cell structure and genome function, acts and is usurped in diverse ways by different viruses. It can act as a physical barrier to infection that must be overcome, as a functional barrier that restricts infection by various mechanisms and must be counteracted or indeed as a positive niche, important or even essential for virus infection or production of progeny virions. This review summarizes virus-host interactions at the NE, highlighting progress in understanding the replication of viruses including HIV-1, Influenza, Herpes Simplex, Adenovirus and Ebola, and molecular insights into hitherto unknown functional pathways at the NE. PMID- 26121673 TI - Immediate versus Delayed Sequential Bilateral Cataract Surgery: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Immediately sequential bilateral cataract surgery (ISBCS), the cataract surgery that is performed in both eyes simultaneously, is gaining popularity worldwide compared to the traditional treatment paradigm: delayed sequential bilateral cataract surgery (DSBCS), the surgery that is performed in each eye on a different day as a completely separate operation. ISBCS provides advantages to patients and patients' families in the form of fewer hospital visits. Additionally, patients enjoy rapid rehabilitation, lack of anisometropia potentially reducing accidents and falls, and avoid suboptimal visual function in daily life. The hospital may benefit due to lower cost. OBJECTIVE: To perform a systematic review and meta-analysis to evaluate ISBCS and DSBCS. DATA SOURCES: Databases including MEDLINE, EMBASE, BIOSIS, CINAHL, Health Economic Evaluations Database (HEED), ISI Web of Science (Thomson-Reuters) and the Cochrane Library were searched. PARTICIPANTS: Not applicable. METHODS: Literature was systematically reviewed using EPPI-Reviewer 4 gateway. Meta-analysis was conducted using STATA v. 13.0. Standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated and heterogeneity was assessed using I2 statistics. Fixed-effect and random-effect models were computed based on heterogeneity. Meta-analysis was done by instrument used to calculate utility score. RESULTS: In total, 9,133 records were retrieved from multiple databases and an additional 128 records were identified through grey literature search. Eleven articles with 3,657 subjects were included for analysis. Our meta-analysis results indicated significant improvement in post-operative utility score using TTO, EQ5D, HUI3, VF-7, and VF-14 and a non-significant improvement using Catquest questionnaire for both surgeries. For ISBCS versus DSBCS, utility-specific fixed effect model provided an overall SMD of the utility score using the TTO method as 0.12 (95% CI: -0.15, 0.40), EQ5D as 0.14 (95% CI: -0.14, 0.41), HUI3 as 0.12 (95% CI: -0.15, 0.40), VF-7 as -0.02 (95% CI: -0.15, 0.10), and Catquest Questionnaire as 1.45 (95% CI: -0.88, 2.01). The results for utility score, which were measured using various instruments, indicated non-significant improvement in the utility due to DSBCS compared to ISBCS. However, a significant improvement in post operative utility score was seen using Catquest questionnaire for ISBCS compared to DSBCS. The included studies using VF-14 instrument were highly heterogeneous (I2 = 97.1%). Results provided SMD of -0.25 (95% CI:-1.06, 0.57) using VF-14 indicating non-significant improvement in the utility due to DSBCS compared to ISBCS surgery. Best corrected visual acuity (BCVA) significantly improved after both surgeries (overall SMD of BCVA due to ISBCS was -1.79 (95% CI: -2.45, -1.14) and due to DSBCS was -1.53 (95% CI: -2.25, -0.81)). A non-significant improvement was seen in BCVA due to ISBCS when compared to DSBCS (SMD = -0.18; 95% CI: -0.37, 0.01). CONCLUSION: Both surgeries, ISBCS and DSBCS significantly improve patients' quality of life and visual acuity. Further, ISBCS may deliver certain additional benefits at the individual and societal levels as well. PMID- 26121674 TI - BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-beta Responses. AB - The innate immune system pattern recognition receptors (PRR) are the first line of host defenses recognizing the various pathogen- or danger-associated molecular patterns and eliciting defenses by regulating the production of pro-inflammatory cytokines such as IL-1beta, IL-18 or interferon beta (IFN-beta). NOD-like receptors (NLRs) and AIM2-like receptors (ALRs) are cytoplasmic inflammasome sensors of foreign molecules, including DNA. IFI16, a sequence-independent nuclear innate sensor ALR, recognizes episomal dsDNA genomes of herpes viruses such as KSHV, EBV, and HSV-1 in the infected cell nuclei, forms an inflammasome complex with ASC and procaspase1, and relocates into the cytoplasm leading into Caspase-1 and IL-1beta generation. IFI16 also induces IFN-beta during HSV-1 infection via the cytoplasmic STING-TBK1-IRF3 pathway. Thus far, whether IFI16 recognizes foreign DNA directly or utilizes other host protein(s) is unknown. Here, we demonstrate that BRCA1, a DNA damage repair sensor and transcription regulator, is in complex with IFI16 in the host cell nucleus, and their association increases in the presence of nuclear viral genomes during de novo KSHV, EBV and HSV-1 infection, and in latent KSHV or EBV infection, but not by DNA damage responses (DDR) induced by bleomycin and vaccinia virus cytoplasmic dsDNA. BRCA1 is a constituent of the triggered IFI16-inflammasome and is translocated into the cytoplasm after genome recognition along with the IFI16 inflammasome. The absence of BRCA1 abrogated IFI16-viral genome association, inflammasome assembly, IFI16 cytoplasmic localization, and Caspase-1 and IL-1beta production. The absence of BRCA1 also abolished the cytoplasmic IFI16-STING interaction, downstream IRF3 phosphorylation, nuclear translocation of pIRF3 and IFN-beta production during de novo KSHV and HSV-1 infection. These findings highlight that BRCA1 plays a hitherto unidentified innate immunomodulatory role by facilitating nuclear foreign DNA sensing by IFI16, subsequent assembly and cytoplasmic distribution of IFI16-inflammasomes leading into IL-1beta formation and the induction of IFN-beta via cytoplasmic signaling through IFI16-STING, TBK1 and IRF3. PMID- 26121675 TI - Maternal Serum Meteorin Levels and the Risk of Preeclampsia. AB - BACKGROUND: Meteorin (METRN) is a recently described neutrophic factor with angiogenic properties. This is a nested case-control study in a longitudinal cohort study that describes the serum profile of METRN during different periods of gestation in healthy and preeclamptic pregnant women. Moreover, we explore the possible application of METRN as a biomarker. METHODS AND FINDINGS: Serum METRN was measured by ELISA in a longitudinal prospective cohort study in 37 healthy pregnant women, 16 mild preeclamptic women, and 20 healthy non-pregnant women during the menstrual cycle with the aim of assessing serum METRN levels and its correlations with other metabolic parameters. Immunostaining for METRN protein was performed in placenta. A multivariate logistic regression model was proposed and a classifier model was formulated for predicting preeclampsia in early and middle pregnancy. The performance in classification was evaluated using measures such as sensitivity, specificity, and the receiver operating characteristic (ROC) curve. In healthy pregnant women, serum METRN levels were significantly elevated in early pregnancy compared to middle and late pregnancy. METRN levels are significantly lower only in early pregnancy in preeclamptic women when compared to healthy pregnant women. Decision trees that did not include METRN levels in the first trimester had a reduced sensitivity of 56% in the detection of preeclamptic women, compared to a sensitivity of 69% when METRN was included. CONCLUSIONS: The joint measurements of circulating METRN levels in the first trimester and systolic blood pressure and weight in the second trimester significantly increase the probabilities of predicting preeclampsia. PMID- 26121676 TI - Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol. AB - BACKGROUND: Results from the recent CROSS trial showed that neoadjuvant chemoradiotherapy (nCRT) significantly increased survival as compared to surgery alone in patients with potentially curable esophageal cancer. Furthermore, in the nCRT arm 49% of patients with a squamous cell carcinoma (SCC) and 23% of patients with an adenocarcinoma (AC) had a pathologically complete response in the resection specimen. These results provide a rationale to reconsider and study the timing and necessity of esophagectomy in (all) patients after application of the CROSS regimen. OBJECTIVE: We propose a "surgery as needed" approach after completion of nCRT. In this approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom residual disease or a locoregional recurrence is highly suspected or proven. However, before a surgery as needed approach in oesophageal cancer patients (SANO) can be tested in a randomized controlled trial, we aim to determine the accuracy of detecting the presence or absence of residual disease after nCRT (preSANO trial). METHODS: This study is set up as a prospective, single arm, multicenter, diagnostic trial. Operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction will be included. Approximately 4-6 weeks after completion of nCRT all included patients will undergo a first clinical response evaluation (CRE-I) including endoscopy with (random) conventional mucosal biopsies of the primary tumor site and of any other suspected lesions in the esophagus and radial endo-ultrasonography (EUS) for measurement of tumor thickness and area. Patients in whom no locoregional or disseminated disease can be proven by cytohistology will be offered a postponed surgical resection 6-8 weeks after CRE-I (ie, approximately 12-14 weeks after completion of nCRT). In the week preceding the postponed surgical resection, a second clinical response evaluation (CRE-II) will be planned that will include a whole body PET-CT, followed again by endoscopy with (random) conventional mucosal biopsies of the primary tumor site and any other suspected lesions in the esophagus, radial EUS for measurement of tumor thickness and area, and linear EUS plus fine needle aspiration of PET-positive lesions and/or suspected lymph nodes. The main study parameter is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen. RESULTS: The first patient was enrolled on July 23, 2013, and results are expected in January 2016. CONCLUSIONS: If this preSANO trial shows that the presence or absence of residual tumor can be predicted reliably 6 or 12 weeks after completion of nCRT, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus "surgery as needed" will be conducted (SANO trial). TRIAL REGISTRATION: Netherlands Trial Register: NTR4834; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4834 (archived by Webcite at http://www.webcitation.org/6Ze7mn67B). PMID- 26121677 TI - Modelling the Health Impact of an English Sugary Drinks Duty at National and Local Levels. AB - BACKGROUND: Increasing evidence associates excess refined sugar intakes with obesity, Type 2 diabetes and heart disease. Worryingly, the estimated volume of sugary drinks purchased in the UK has more than doubled between 1975 and 2007, from 510 ml to 1140 ml per person per week. We aimed to estimate the potential impact of a duty on sugar sweetened beverages (SSBs) at a local level in England, hypothesising that a duty could reduce obesity and related diseases. METHODS AND FINDINGS: We modelled the potential impact of a 20% sugary drinks duty on local authorities in England between 2010 and 2030. We synthesised data obtained from the British National Diet and Nutrition Survey (NDNS), drinks manufacturers, Office for National Statistics, and from previous studies. This produced a modelled population of 41 million adults in 326 lower tier local authorities in England. This analysis suggests that a 20% SSB duty could result in approximately 2,400 fewer diabetes cases, 1,700 fewer stroke and coronary heart disease cases, 400 fewer cancer cases, and gain some 41,000 Quality Adjusted Life Years (QALYs) per year across England. The duty might have the biggest impact in urban areas with young populations. CONCLUSIONS: This study adds to the growing body of evidence suggesting health benefits for a duty on sugary drinks. It might also usefully provide results at an area level to inform local price interventions in England. PMID- 26121678 TI - Association of Oxytocin Receptor Gene (OXTR) rs53576 Polymorphism with Sociality: A Meta-Analysis. AB - A common variant in the oxytocin receptor gene (OXTR), rs53576, has been broadly linked to socially related personality traits and behaviors. However, the pattern of published results is inconsistent. Here, we performed a meta-analysis to comprehensively evaluate the association. The literature was searched for relevant studies and effect sizes between individuals homozygous for the G allele (GG) and individuals with A allele carriers (AA/AG). Specifically, two indices of sociality were evaluated independently: i) general sociality (24 samples, n = 4955), i.e., how an individual responds to other people in general; and ii) close relationships (15 samples, n = 5262), i.e., how an individual responds to individuals with closed connections (parent-child or romantic relationship). We found positive association between the rs53576 polymorphism and general sociality (Cohen's d = 0.11, p = .02); G allele homozygotes had higher general sociality than the A allele carriers. However, the meta-analyses did not detect significant genetic association between rs53576 and close relationships (Cohen's d = 0.01, p = .64). In conclusion, genetic variation in the rs53576 influences general sociality, which further implies that it is worthy to systematically examine whether the rs53576 is a valid genetic marker for socially related psychiatric disorders. PMID- 26121679 TI - HIV-DNA Given with or without Intradermal Electroporation Is Safe and Highly Immunogenic in Healthy Swedish HIV-1 DNA/MVA Vaccinees: A Phase I Randomized Trial. AB - BACKGROUND: We compared safety and immunogenicity of intradermal (ID) vaccination with and without electroporation (EP) in a phase I randomized placebo-controlled trial of an HIV-DNA prime HIV-MVA boost vaccine in healthy Swedish volunteers. METHODS: HIV-DNA plasmids encoding HIV-1 genes gp160 subtypes A, B and C; Rev B; Gag A and B and RTmut B were given ID at weeks 0, 6 and 12 in a dose of 0.6 mg. Twenty-five volunteers received vaccine using a needle-free device (ZetaJet) with (n=16) or without (n=9) ID EP (Dermavax). Five volunteers were placebo recipients. Boosting with recombinant MVA-CMDR expressing HIV-1 Env, Gag, Pol of CRF01_AE (HIV-MVA) or placebo was performed at weeks 24 and 40. Nine of the vaccinees received a subtype C CN54 gp140 protein boost together with HIV-MVA. RESULTS: The ID/EP delivery was very well tolerated. After three HIV-DNA immunizations, no statistically significant difference was seen in the IFN-gamma ELISpot response rate to Gag between HIV-DNA ID/EP recipients (5/15, 33%) and HIV DNA ID recipients (1/7, 14%, p=0.6158). The first HIV-MVA or HIV-MVA+gp140 vaccination increased the IFN-gamma ELISpot response rate to 18/19 (95%). CD4+ and/or CD8+ T cell responses to Gag or Env were demonstrable in 94% of vaccinees. A balanced CD4+ and CD8+ T cell response was noted, with 78% and 71% responders, respectively. IFN-gamma and IL-2 dominated the CD4+ T cell response to Gag and Env. The CD8+ response to Gag was broader with expression of IFN-gamma, IL-2, MIP 1beta and/or CD107. No differences were seen between DNA vaccine groups. Binding antibodies were induced after the second HIV-MVA+/-gp140 in 93% of vaccinees to subtype C Env, with the highest titers among EP/gp140 recipients. CONCLUSION: Intradermal electroporation of HIV-DNA was well tolerated. Strong cell- and antibody-mediated immune responses were elicited by the HIV-DNA prime and HIV-MVA boosting regimen, with or without intradermal electroporation use. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) 60284968. PMID- 26121680 TI - Glycation of H1 Histone by 3-Deoxyglucosone: Effects on Protein Structure and Generation of Different Advanced Glycation End Products. AB - Advanced glycation end products (AGEs) culminate from the non-enzymatic reaction between a free carbonyl group of a reducing sugar and free amino group of proteins. 3-deoxyglucosone (3-DG) is one of the dicarbonyl species that rapidly forms several protein-AGE complexes that are believed to be involved in the pathogenesis of several diseases, particularly diabetic complications. In this study, the generation of AGEs (Nepsilon-carboxymethyl lysine and pentosidine) by 3-DG in H1 histone protein was characterized by evaluating extent of side chain modification (lysine and arginine) and formation of Amadori products as well as carbonyl contents using several physicochemical techniques. Results strongly suggested that 3-DG is a potent glycating agent that forms various intermediates and AGEs during glycation reactions and affects the secondary structure of the H1 protein. Structural changes and AGE formation may influence the function of H1 histone and compromise chromatin structures in cases of secondary diabetic complications. PMID- 26121681 TI - Disruption of Rhino Demography by Poachers May Lead to Population Declines in Kruger National Park, South Africa. AB - The onslaught on the World's rhinoceroses continues despite numerous initiatives aimed at curbing it. When losses due to poaching exceed birth rates, declining rhino populations result. We used previously published estimates and growth rates for black rhinos (2008) and white rhinos (2010) together with known poaching trends at the time to predict population sizes and poaching rates in Kruger National Park, South Africa for 2013. Kruger is a stronghold for the south eastern black rhino and southern white rhino. Counting rhinos on 878 blocks 3x3 km in size using helicopters, estimating availability bias and collating observer and detectability biases allowed estimates using the Jolly's estimator. The exponential escalation in number of rhinos poached per day appears to have slowed. The black rhino estimate of 414 individuals (95% confidence interval: 343 487) was lower than the predicted 835 individuals (95% CI: 754-956). The white rhino estimate of 8,968 individuals (95% CI: 8,394-9,564) overlapped with the predicted 9,417 individuals (95% CI: 7,698-11,183). Density- and rainfall dependent responses in birth- and death rates of white rhinos provide opportunities to offset anticipated poaching effects through removals of rhinos from high density areas to increase birth and survival rates. Biological management of rhinos, however, need complimentary management of the poaching threat as present poaching trends predict detectable declines in white rhino abundances by 2018. Strategic responses such as anti-poaching that protect supply from illegal harvesting, reducing demand, and increasing supply commonly require crime network disruption as a first step complimented by providing options for alternative economies in areas abutting protected areas. PMID- 26121682 TI - Early Risk Factors of Overweight Developmental Trajectories during Middle Childhood. AB - BACKGROUND: Research is needed to identify early life risk factors associated with different developmental paths leading to overweight by adolescence. OBJECTIVES: To model heterogeneity in overweight development during middle childhood and identify factors associated with differing overweight trajectories. METHODS: Data was drawn from the Quebec Longitudinal Study of Child Development (QLSCD; 1998-2010). Trained research assistants measured height and weight according to a standardized protocol and conducted yearly home interviews with the child's caregiver (mother in 98% of cases). Information on several putative early life risk factors for the development of overweight were obtained, including factors related to the child's perinatal, early behavioral family and social environment. Group-based trajectories of the probability of overweight (6 12 years) were identified with a semiparametric method (n=1678). Logistic regression analyses were used to identify early risk factors (5 months- 5 years) associated with each trajectory. RESULTS: Three trajectories of overweight were identified: "early-onset overweight" (11.0 %), "late-onset overweight" (16.6%) and "never overweight" (72.5%). Multinomial analyses indicated that children in the early and late-onset group, compared to the never overweight group, had 3 common types of risk factors: parental overweight, preschool overweight history, and large size for gestational age. Maternal overprotection (OR= 1.12, CI: 1.01 1.25), short nighttime sleep duration (OR=1.66, CI: 1.07-2.57), and immigrant status (OR=2.01, CI: 1.05-3.84) were factors specific to the early-onset group. Finally, family food insufficiency (OR=1.81, CI: 1.00-3.28) was weakly associated with membership in the late-onset trajectory group. CONCLUSIONS: The development of overweight in childhood follows two different trajectories, which have common and distinct risk factors that could be the target of early preventive interventions. PMID- 26121683 TI - Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis. AB - Various studies have evaluated the significance of Notch1 expression in breast cancer, but the results have ever been disputed. By using 21 studies involving 3867 patients, this meta-analysis revealed that the expression of Notch1 was significantly higher in breast cancer than in normal tissues (OR=7.21; 95%CI, 4.7 11.07) and that higher Notch1 expression was associated with transition from ductal carcinoma in situ (DCIS) to invasive cancer (OR=3.75; 95% CI, 1.8-7.78). Higher Notch1 activity was observed in the basal subtype of breast cancer (OR=2.53; 95% CI, 1.18-5.43). Moreover, patients with Notch1 overexpression exhibited significantly worse overall and recurrence-free survival. Our meta analysis suggests that Notch inhibitors may be useful in blocking the early progression of DCIS and that the outcomes of clinical trials for Notch1-targeting therapeutics could be improved by the molecular stratification of breast cancer patients. PMID- 26121685 TI - Outcomes and Treatment of Lumbosacral Spinal Tuberculosis: A Retrospective Study of 53 Patients. AB - STUDY STRATEGY: A retrospective clinic study. PURPOSE: To evaluate the efficacy of conservative and surgical treatment for lumbosacral tuberculosis. METHODS: This study retrospectively reviewed 53 patients with lumbosacral tuberculosis who were treated in our institution between January 2005 and January 2011. There were 29 males and 24 females with average ages of 37.53 +/- 17.28 years (range 6-72 years). 11 patients were given only anti-TB drugs; the remainder underwent anterior debridement, interbody fusion with and without instrumentation, or one stage anterior debridement combined with posterior instrumentation. Outcome data for these patients included neurologic status, lumbosacral angle, erythrocyte sedimentation rate value(ESR) and C-reactive protein value(CRP) were assessed before and after treatment. RESULTS: The mean lumbosacral angles were 23.00 degrees +/- 2.90 degrees in the conservatively treated patients and 22.36 degrees +/- 3.92o in the surgically treated patients. At the final follow-up, this had improved to 24.10o +/- 2.96 degrees in the conservatively treated patients and 28.13 degrees +/- 1.93 degrees in the surgically treated patients (all P < 0.05). There were statistically significant differences before and after treatment in terms of ESR and CRP (all P < 0.05). All patients achieved bone fusion. The mean follow-up period was 32.34 +/- 8.13 months (range 18 to 55 months). The neurological deficit did not worsen in any of the patients. CONCLUSIONS: It has been proven that conservative and surgical treatments are safe and effective and produce good clinical outcomes for patients with lumbosacral tuberculosis. The advantages of operation include thoroughness of debridement, decompression of the spinal cord, and adequate spinal stabilization. PMID- 26121684 TI - Current progress in nanotechnology applications for diagnosis and treatment of kidney diseases. AB - Significant progress has been made in nanomedicine, primarily in the form of nanoparticles, for theranostic applications to various diseases. A variety of materials, both organic and inorganic, have been used to develop nanoparticles with promise to achieve improved efficacy in medical applications as well as reduced systemic side effects compared to current standard of care medical practices. In particular, this article highlights the recent development and application of nanoparticles for diagnosing and treating nephropathologies. PMID- 26121687 TI - Correction: Lateralized Readiness Potentials Reveal Properties of a Neural Mechanism for Implementing a Decision Threshold. PMID- 26121686 TI - Pleiotropic Effects of Bitter Taste Receptors on [Ca2+]i Mobilization, Hyperpolarization, and Relaxation of Human Airway Smooth Muscle Cells. AB - Asthma is characterized by airway inflammation and airflow obstruction from human airway smooth muscle (HASM) constriction due to increased local bronchoconstrictive substances. We have recently found bitter taste receptors (TAS2Rs) on HASM, which increase [Ca2+]i and relax the muscle. We report here that some, but not all, TAS2R agonists decrease [Ca2+]i and relax HASM contracted by G-protein coupled receptors (GPCRs) that stimulate [Ca2+]i. This suggests both a second pathway by which TAS2Rs relax, and, a heterogeneity of the response phenotype. We utilized eight TAS2R agonists and five procontractile GPCR agonists in cultured HASM cells. We find that heterogeneity in the inhibitory response hinges on which procontractile GPCR is activated. For example, chloroquine inhibits [Ca2+]i increases from histamine, but failed to inhibit [Ca2+]i increases from endothelin-1. Conversely, aristolochic acid inhibited [Ca2+]i increases from endothelin-1 but not histamine. Other dichotomous responses were found when [Ca2+]i was stimulated by bradykinin, angiotensin, and acetylcholine. There was no association between [Ca2+]i inhibition and TAS2R subtype, nor whether [Ca2+]i was increased by Gq- or Gi-coupled GPCRs. Selected studies revealed a correlation between [Ca2+]i inhibition and HASM cell-membrane hyperpolarization. To demonstrate physiologic correlates, ferromagnetic beads were attached to HASM cells and cell stiffness measured by magnetic twisting cytometry. Consistent with the [Ca2+]i inhibition results, chloroquine abolished the cell stiffening response (contraction) evoked by histamine but not by endothelin-1, while aristolochic acid inhibited cell stiffening from endothelin 1, but not from histamine. In studies using intact human bronchi, these same differential responses were found. Those TAS2R agonists that decreased [Ca2+]i, promoted hyperpolarization, and decreased HASM stiffness, caused relaxation of human airways. Thus TAS2Rs relax HASM in two ways: a low-efficiency de novo [Ca2+]i stimulation, and, a high-efficiency inhibition of GPCR-stimulated [Ca2+]i. Furthermore, there is an interaction between TAS2Rs and some GPCRs that facilitates this [Ca2+]i inhibition limb. PMID- 26121688 TI - The Taxonomic Status of Mazama bricenii and the Significance of the Tachira Depression for Mammalian Endemism in the Cordillera de Merida, Venezuela. AB - We studied the taxonomy and biogeography of Mazama bricenii, a brocket deer classified as Vulnerable by the IUCN, drawing on qualitative and quantitative morphology and sequences of the mitochondrial cytochrome-b gene. We used Ecological Niche Modeling (ENM) to evaluate the hypothesis that M. bricenii of the Venezuelan Cordillera de Merida (CM) might have become isolated from populations of its putative sister species, Mazama rufina, in the Colombian Cordillera Oriental (CO). This hypothesis assumes that warm, dry climatic conditions in the Tachira Depression were unsuitable for the species. Our analyses did not reveal morphological differences between specimens geographically attributable to M. bricenii and M. rufina, and phylogenetic analyses of molecular data recovered M. bricenii nested within the diversity of M. rufina. These results indicate that M. bricenii should be regarded as a junior synonym of M. rufina. ENM analyses revealed the existence of suitable climatic conditions for M. rufina in the Tachira Depression during the last glacial maximum and even at present, suggesting that gene flow between populations in the CO and CM may have occurred until at least the beginning of the current interglacial period and may continue today. Because this pattern might characterize other mammals currently considered endemic to the CM, we examined which of these species match two criteria that we propose herein to estimate if they can be regarded as endemic to the CM with confidence: (1) that morphological or molecular evidence exists indicating that the putative endemic taxon is distinctive from congeneric populations in the CO; and (2) that the putative endemic taxon is restricted to either cloud forest or paramo, or both. Only Aepeomys reigi, Cryptotis meridensis, and Nasuella meridensis matched both criteria; hence, additional research is necessary to assess the true taxonomic status and distribution of the remaining species thought to be CM endemics. PMID- 26121689 TI - Enhancing Interferon Regulatory Factor 7 Mediated Antiviral Responses and Decreasing Nuclear Factor Kappa B Expression Limit HIV-1 Replication in Cervical Tissues. AB - Establishment of a productive HIV-1 infection in the female reproductive tract likely depends on the balance between anti-viral and pro-inflammatory responses leading to activation and proliferation of HIV target cells. Immune modulators that boost anti-viral and depress pro-inflammatory immune responses may decrease HIV-1 infection or replication. Polyinosinic:polycytidylic [Poly (I:C)] has been reported to down-regulate HIV-1 replication in immune cell subsets and lymphoid tissues, yet the scope and mechanisms of poly (I:C) regulation of HIV-1 replication in the cervicovaginal mucosa, the main portal of viral entry in women remain unknown. Using a relevant, underexplored ex vivo cervical tissue model, we demonstrated that poly (I:C) enhanced Interferon Regulatory Factor (IRF)7 mediated antiviral responses and decreased tissue Nuclear Factor Kappa B (NFkappaB) RNA expression. This pattern of cellular transcription factor expression correlated with decreased HIV-1 transcription and viral release. Reducing IRF7 expression up-regulated HIV-1 and NFkappaB transcription, providing proof of concept for the critical involvement of IRF7 in cervical tissues. By combining poly (I:C) with a suboptimal concentration of tenofovir, the leading anti-HIV prophylactic microbicide candidate, we demonstrated an earlier and greater decrease in HIV replication in poly (I:C)/tenofovir treated tissues compared with tissues treated with tenofovir alone, indicating overall improved efficacy. Poly (I:C) decreases HIV-1 replication by stimulating IRF7 mediated antiviral responses while reducing NFkappaB expression. Early during the infection, poly (I:C) improved the anti-HIV-1 activity of suboptimal concentrations of tenofovir likely to be present during periods of poor adherence i.e. inconsistent or inadequate drug use. Understanding interactions between anti viral and pro-inflammatory immune responses in the genital mucosa will provide crucial insights for the identification of targets that can be harnessed to develop preventative combination strategies to improve the efficacy of topical or systemic antiviral prophylactic agents and protect women from HIV-1 and other sexually transmitted infections. PMID- 26121690 TI - NLRP7, Involved in Hydatidiform Molar Pregnancy (HYDM1), Interacts with the Transcriptional Repressor ZBTB16. AB - Mutations in the maternal effect gene NLRP7 cause biparental hydatidiform mole (HYDM1). HYDM1 is characterized by abnormal growth of placenta and lack of proper embryonic development. The molar tissues are characterized by abnormal methylation patterns at differentially methylated regions (DMRs) of imprinted genes. It is not known whether this occurs before or after fertilization, but the high specificity of this defect to the maternal allele indicates a possible maternal germ line-specific effect. To better understand the unknown molecular mechanism leading to HYDM1, we performed a yeast two-hybrid screen against an ovarian library using NLRP7 as bait. We identified the transcriptional repressor ZBTB16 as an interacting protein of NLRP7 and verified this interaction in mammalian cells by immunoprecipitation and confocal microscopy. Native protein analysis detected NLRP7 and ZBTB16 in a 480kD protein complex and both proteins co-localize in the cytoplasm in juxtanuclear aggregates. HYDM1-causing mutations in NLRP7 did not show altered patterns of interaction with ZBTB16. Hence, the biological significance of the NLRP7-ZBTB16 interaction remains to be revealed. However, a clear effect of harvesting ZBTB16 to the cytoplasm when the NLRP7 protein is overexpressed may be linked to the pathology of the molar pregnancy disease. PMID- 26121691 TI - SIRT3 Enhances Glycolysis and Proliferation in SIRT3-Expressing Gastric Cancer Cells. AB - SIRT3 is a key NAD+-dependent protein deacetylase in the mitochondria of mammalian cells, functioning to prevent cell aging and transformation via regulation of mitochondrial metabolic homeostasis. However, SIRT3 is also found to express in some human tumors; its role in these SIRT3-expressing tumor cells needs to be elucidated. This study demonstrated that the expression of SIRT3 was elevated in a group of gastric cancer cells compared to normal gastric epithelial cells. Although SIRT3 expression levels were increased in the gastric tumor tissues compared to the adjacent non-tumor tissues, SIRT3 positive cancer cells were more frequently detected in the intestinal type gastric cancers than the diffuse type gastric cancers, indicating that SIRT3 is linked with subtypes of gastric cancer. Overexpression of SIRT3 promoted cell proliferation and enhanced ATP generation, glucose uptake, glycogen formation, MnSOD activity and lactate production, which were inhibited by SIRT3 knockdown, indicating that SIRT3 plays a role in reprogramming the bioenergetics in gastric tumor cells. Further analysis revealed that SIRT3 interacted with and deacetylated the lactate dehydrogenase A (LDHA), a key protein in regulating anaerobic glycolysis, enhancing LDHA activity. In consistence, a cluster of glycolysis-associated genes was upregulated in the SIRT3-overexpressing gastric tumor cells. Thus, in addition to the well-documented SIRT3-mediated mitochondrial homeostasis in normal cells, SIRT3 may enhance glycolysis and cell proliferation in SIRT3 expressing cancer cells. PMID- 26121692 TI - Genetic Polymorphisms in Endothelin-1 as Predictors for Long-Term Survival and the Cardiac Index in Patients Undergoing On-Pump Cardiac Surgery. AB - Genetic variants within the endothelin-1 gene (EDN1) have been associated with several cardiovascular diseases and may act as genetic prognostic markers. Here, we explored the overall relevance of EDN1 polymorphisms for long-term survival in patients undergoing on-pump cardiac surgery. A prospectively collected cohort of 455 Caucasian patients who underwent cardiac surgery with cardiopulmonary bypass was followed up for 5 years. The obtained genotypes and inferred haplotypes were analyzed for their associations with the five-year mortality rate (primary endpoint). The EDN1 T-1370G and K198N genotype distributions did not deviate from Hardy-Weinberg equilibrium and the major allele frequencies were 83% and 77%, respectively. The cardiovascular risk factors were equally distributed in terms of the different genotypes and haplotypes associated with the two polymorphisms. The five-year mortality rate did not differ among the different EDN1 T-1370G and K198N genotypes and haplotypes. Haplotype analysis revealed that carriers of the G-T (compound EDN1 T-1370G G/K198N T) haplotype had a higher cardiac index than did non-carriers (p = 0.0008); however, this difference did not reach significance after adjusting for multiple testing. The results indicate that common variations in EDN1 do not act as prognostic markers for long-term survival in patients undergoing on-pump cardiac surgery. PMID- 26121693 TI - Interpopulational Variations in Sexual Chemical Signals of Iberian Wall Lizards May Allow Maximizing Signal Efficiency under Different Climatic Conditions. AB - Sexual signals used in intraspecific communication are expected to evolve to maximize efficacy under a given climatic condition. Thus, chemical secretions of lizards might evolve in the evolutionary time to ensure that signals are perfectly tuned to local humidity and temperature conditions affecting their volatility and therefore their persistence and transmission through the environment. We tested experimentally whether interpopulational altitudinal differences in chemical composition of femoral gland secretions of male Iberian wall lizards (Podarcis hispanicus) have evolved to maximize efficacy of chemical signals in different environmental conditions. Chemical analyses first showed that the characteristics of chemical signals of male lizards differed between two populations inhabiting environments with different climatic conditions in spite of the fact that these two populations are closely related genetically. We also examined experimentally whether the temporal attenuation of the chemical stimuli depended on simulated climatic conditions. Thus, we used tongue-flick essays to test whether female lizards were able to detect male scent marks maintained under different conditions of temperature and humidity by chemosensory cues alone. Chemosensory tests showed that chemical signals of males had a lower efficacy (i.e. detectability and persistence) when temperature and dryness increase, but that these effects were more detrimental for signals of the highest elevation population, which occupies naturally colder and more humid environments. We suggest that the abiotic environment may cause a selective pressure on the form and expression of sexual chemical signals. Therefore, interpopulational differences in chemical profiles of femoral secretions of male P. hispanicus lizards may reflect adaptation to maximize the efficacy of the chemical signal in different climates. PMID- 26121694 TI - Ohr Protects Corynebacterium glutamicum against Organic Hydroperoxide Induced Oxidative Stress. AB - Ohr, a bacterial protein encoded by the Organic Hydroperoxide Resistance (ohr) gene, plays a critical role in resistance to organic hydroperoxides. In the present study, we show that the Cys-based thiol-dependent Ohr of Corynebacterium glutamicum decomposes organic hydroperoxides more efficiently than hydrogen peroxide. Replacement of either of the two Cys residues of Ohr by a Ser residue resulted in drastic loss of activity. The electron donors supporting regeneration of the peroxidase activity of the oxidized Ohr of C. glutamicum were principally lipoylated proteins (LpdA and Lpd/SucB). A Deltaohr mutant exhibited significantly decreased resistance to organic hydroperoxides and marked accumulation of reactive oxygen species (ROS) in vivo; protein carbonylation was also enhanced notably. The resistance to hydrogen peroxide also decreased, but protein carbonylation did not rise to any great extent. Together, the results unequivocally show that Ohr is essential for mediation of organic hydroperoxide resistance by C. glutamicum. PMID- 26121695 TI - Modeling Zinc Intake for Intervention and Scenario Analysis. AB - BACKGROUND: A large number of illnesses, afflicting one-third of the world's population, have been attributed to zinc deficiency. Inadequate dietary intake of bioavailable forms of zinc is considered the most frequent cause of zinc deficiency, which is most common in arid regions of developing countries. OBJECTIVE: To employ a modeling approach in a test population to analyze how best to eliminate zinc deficiency using different plausible dietary scenarios. METHODS: A comprehensive database was built upon food consumption patterns of two population groups residing in a village and a suburb in semiarid central Iran near Isfahan city. A database was created on zinc and phytic acid concentrations of different foods and ingredients consumed by the study populations. A zinc intake model was constructed and parameterized accounting for bioavailability and model input uncertainties. RESULTS: The zinc intake of about one-third of both study populations, which did not differ significantly in their rates of zinc deficiency, was below the Estimated Average Requirement (EAR) for zinc. Scenario analyses predicted that at the current rate of food consumption, it would take up to 60 years for 97.5% of the population to meet their zinc EARs. Fortification of wheat flour and biofortification of wheat grains would result in 93% and 88% of the population, respectively, achieving their EARs in 15 years. CONCLUSIONS: The modeled results suggest that fortification and biofortification are the most effective and sustainable strategies to combat zinc deficiency. The methodology developed in this study is general and is shown to be a useful tool for the analysis of possible future trends and intervention scenarios. PMID- 26121696 TI - Acceptability of Two Ready-to-Use Therapeutic Foods by HIV-Positive Patients in Vietnam. AB - BACKGROUND: Ready-to-use therapeutic food (RUTF) has been found effective in treating severe acute malnutrition. Vietnam's National Institute of Nutrition (NIN), the Institut de Recherche pour le Developpement (IRD), and UNICEF collaborated to formulate a local RUTF called High-Energy Bar for Integrated Management of Acute Malnutrition (HEBI). RUTF might be useful to address malnutrition in HIV patients. OBJECTIVE: To compare the acceptability of the local RUTF and an imported RUTF among malnourished people with HIV in Vietnam Methods: The acceptability of HEBI and Plumpy'Nut was studied among 80 HIV positive children and 80 HIV-positive adults. In a crossover design, participants were randomly assigned to receive either Plumpy'Nut or HEBI for 2 weeks and were switched to the other product for the subsequent 2 weeks. A third (control) group of about 40 HIV-positive participants in each study was randomly assigned to receive no RUTF. Nurses took anthropometric measurements weekly, and the subjects or their caregivers monitored daily RUTF intake. RESULTS: Children consumed 69% of HEBI and 65% of Plumpy'Nut (p = .13). Adults consumed 91% of HEBI and 81% of Plumpy'Nut (p = .059). Both children (p = .058) and adults (p <= .0001) preferred HEBI. Significant gains were observed in percent weight (p = .035), weight-for age (p = .014), and body mass index (BMI)-for-age (p = .036) in children who received RUTF and in percent weight (p = .017) and BMI (p = .0048) in adults who received RUTF compared with the control groups. CONCLUSIONS: In this study in Vietnam, both HEBI and Plumpy'Nut were found acceptable by people with HIV. PMID- 26121697 TI - Prediction of Serum Zinc Levels in Mexican Children at 2 Years of Age Using a Food Frequency Questionnaire and Different Zinc Bioavailability Criteria. AB - BACKGROUND: The 2006 Mexican National Health and Nutrition Survey documented a prevalence of zinc deficiency of almost 30% in children under 2 years of age. OBJECTIVE: We sought to validate a food frequency questionnaire (FFQ) for quantifying dietary bioavailable zinc intake in 2-year-old Mexican children accounting for phytic acid intake and using serum zinc as a reference. METHODS: This cross-sectional study was nested within a longitudinal birth cohort of 333 young children in Mexico City. Nonfasting serum zinc concentration was measured and dietary zinc intake was calculated on the basis of a semiquantitative FFQ administered to their mothers. The relationship between dietary zinc intake and serum zinc was assessed using linear regression, adjusting for phytic acid intake, and analyzed according to two distinct international criteria to estimate bioavailable zinc. Models were stratified by zinc deficiency status. RESULTS: Dietary zinc, adjusted for phytic acid intake, explained the greatest proportion of the variance of serum zinc. For each milligram of dietary zinc intake, serum zinc increased on average by 0.95 MUg/dL (0.15 MUmol/L) (p = .06). When stratified by zinc status, this increase was 0.74 MUg/dL (p = .12) for each milligram of zinc consumed among children with adequate serum zinc (n = 276), whereas among those children with zinc deficiency (n = 57), serum zinc increased by only 0.11 MUg/dL (p = .82). CONCLUSIONS: A semiquantitative FFQ can be used for predicting serum zinc in relation to dietary intake in young children, particularly among those who are zinc-replete, and when phytic acid or phytate intake is considered. Future studies should be conducted accounting for both zinc status and dietary zinc inhibitors to further elucidate and validate these findings. PMID- 26121698 TI - Integration of Nutrition Into Extension and Advisory Services: A Synthesis of Experiences, Lessons, and Recommendations. AB - BACKGROUND: The need for nutrition-sensitive agriculture is well recognized and of growing interest to global development players. Extension and advisory services (EAS), with their established infrastructure, provide a unique opportunity for nutrition interventions to be implemented at scale with significant reach. OBJECTIVE: To assess current integration of nutrition in EAS, document training provided to EAS agents, and identify challenges and opportunities for the integration of nutrition. METHODS: A mixed methodology was used, which included a systematic literature review covering the following databases: PubMed, ISI Web of Science, Agris, Google Scholar, Econlit, and IBSS. In addition, online surveys and semistructured key informant interviews with stakeholders were performed. Data were collected between December 2012 and June 2013. RESULTS: Based on this study, the most common integration of nutrition into EAS is through efforts to increase the availability of nutritious food. The nutrition training of extension agents is often inadequate, particularly in the realm beyond technical agricultural skill. Additionally, a lack of career opportunities discourages EAS agents form engaging with nutrition integration. The major challenges to integrating nutrition into EAS centered on lack of training for agents, unclear organizational mandates, lack of female inclusion, lack of mobility, and systemic challenges between agriculture and nutrition sectors. Key opportunities for integration efforts are engaging communities, creating a demand for nutrition, and use of innovative communications. CONCLUSIONS: This study demonstrates a large degree of variability across programs in the integration and implementation of nutrition activities into EAS, providing differing opinions on the feasibility of integration. Although the need for nutrition-sensitive agriculture is known, and there is agreement that EAS would provide a positive framework, there are still challenges impeding a simple integration of nutrition into EAS as a delivery platform. PMID- 26121699 TI - Identifying the Sociocultural Barriers and Facilitating Factors to Nutrition related Behavior Change: Formative Research for a Stunting Prevention Program in Ntchisi, Malawi. AB - BACKGROUND: As the Scaling Up Nutrition (SUN) movement gains momentum globally, more attention and resources are being given to integrated nutrition interventions. In 2013, the Government of Malawi, with support from the World Food Programme and partners, initiated such an intervention in Ntchisi District. Aimed to reduce the prevalence of stunting, the intervention has several components, including the provision of a small-quantity, lipid-based nutrient supplement (SQ-LNS) for children aged 6 to 23 months. OBJECTIVE: This paper describes formative research findings derived from a Rapid Assessment Procedures (RAP) approach to inform the integrated nutrition intervention. METHODS: With a three-phase, emergent research design, this study utilized ethnographic methods including in-depth interviews, direct meal observations, and full-day child observations. Free lists and pile sorts were conducted to define food and illness domains through cultural domain analysis. Participants included community leaders, caregivers, health surveillance assistants, and children aged 6 to 23 months. RESULTS: Community members felt that nutrition-related illnesses were less salient and threatening than other illnesses, and food quality was less important than food quantity. Household food allocation occurred in predictable patterns and varied by type of household member and season. Considered an energy giving food, the SQ-LNS was accepted, but health education and communications tailored to local understanding of nutrition and health are necessary to ensure its appropriate utilization. CONCLUSIONS: Tailoring a communications strategy to Ntchisi, Malawi could only be done through formative research to understand the sociocultural factors influencing nutrition-related behaviors. A RAP approach allowed for a comprehensive understanding of this local environment. PMID- 26121700 TI - Landscape Analysis of Nutrition-sensitive Agriculture Policy Development in Senegal. AB - BACKGROUND: Unlocking the agricultural potential of Africa offers a genuine opportunity to address malnutrition and drive development of the continent. OBJECTIVE: Using Senegal as a case study, to identify gaps and opportunities to strengthen agricultural policies with nutrition-sensitive approaches. METHODS: We carried out a systematic analysis of 13 policy documents that related to food production, agriculture, food security, or nutrition. Next, we collected data during a participatory analysis with 32 national stakeholders and in-depth interviews with 15 national experts of technical directorates of the different ministries that deal with agriculture and food production. RESULTS: The current agricultural context has various elements that are considered to enhance its nutrition sensitivity. On average, 8.3 of the 17 Food and Agriculture Organization guiding principles for agriculture programming for nutrition were included in the policies reviewed. Ensuring food security and increasing dietary diversity were considered to be the principal objectives of agricultural policies. Although there was considerable agreement that agriculture can contribute to nutrition, current agricultural programs generally do not target communities on the basis of their nutritional vulnerability. Agricultural programs were reported to have specific components to target female beneficiaries but were generally not used as delivery platforms for nutritional interventions. CONCLUSIONS: The findings of this study indicate the need for a coherent policy environment across the food system that aligns recommendations at the national level with local action on the ground. In addition, specific activities are needed to develop a shared understanding of nutrition and public health nutrition within the agricultural community in Senegal. PMID- 26121701 TI - Measuring the Food Access Dimension of Food Security: A Critical Review and Mapping of Indicators. AB - BACKGROUND: With food security now a top priority for many governments and for the global development community, there is heightened awareness of the need to improve our understanding and measurement of food security. OBJECTIVE: To bring clarity in the assessment of the food access dimension of food security at the household and individual level. METHODS: For the most commonly used indicators, we reviewed their original purpose and construction, at what levels (household or individual) they were designed to be used, what components (quality, quantity, safety, and cultural acceptability) they were intended to reflect, and whether or not they have been tested for validity and comparability across contexts. RESULTS: We identified nine indicators and grouped them in three broad categories: experience-based, coping strategies, and dietary diversity. The indicators only capture the quantity and quality components of food access; none of the indicators capture information on safety or cultural acceptability of food access. Household Dietary Diversity (HDDS) and Food Consumption Score (FCS) are often considered indicators of both quantity and quality, but they have not been validated for the latter. CONCLUSIONS: We recommend the use of experience-based indicators, HDDS, or FCS to assess household access to energy; experience-based indicators to assess household access to diet quality (defined qualitatively as not having to adopt practices that favor acquiring cheaper, less appealing, and less micronutrient-dense foods); and individual dietary diversity scores for women or children to assess individual access to diet quality, defined as micronutrient adequacy. PMID- 26121702 TI - Food for Survival: Diagnosing Crop Patterns to Secure Lower Threshold Food Security Levels in Farm Households of Burundi. AB - BACKGROUND: Burundi is one of the world's poorest countries, coming last in the Global Food Index (2013). Yet, a large majority of its population depends on agriculture. Most smallholder families do not produce enough to support their own families. OBJECTIVE: To estimate the optimal crop mix and resources needed to provide the family with food containing sufficient energy, fat, and protein. METHODS: This study uses mathematical programming to obtain the optimal crop mix that could maximize output given the constraints on production factor endowments and the need to feed the household. The model is calibrated with household-level data collected in 2010 in Ngozi Province in northern Burundi. Four models are developed, each representing a different farm type. The typology is based on 2007 data. Model predictions are compared with data collected during a revisit of the area in 2012. RESULTS: By producing a smaller number of crops and concentrating on those in which they have a comparative advantage, and trading produce and input with other farms, large and medium-sized farms can improve their productivity and hire extra workers to supplement family labor. Predictions of crops to be planted coincided to a high degree with those that farmers planted 2 years after our survey on newly acquired plots. CONCLUSIONS: Despite land scarcity, it is still possible for households that own land to find optimal crop combinations that can meet their minimal food security requirements while generating a certain level of income. Nearly landless households would benefit from the increased off-farm employment opportunities. With only 0.05 ha of land per capita, the annotation Nearly Landless is used to highlight the limited access to land observed in this farm category. PMID- 26121703 TI - Comparison of a Household Consumption and Expenditures Survey with Nationally Representative Food Frequency Questionnaire and 24-hour Dietary Recall Data for Assessing Consumption of Fortifiable Foods by Women and Young Children in Cameroon. AB - BACKGROUND: Household Consumption and Expenditures Surveys (HCES) are potential sources of data on dietary patterns for planning fortification programs, but they rarely have been compared with individual-level dietary assessment methods. OBJECTIVE: To compare apparent consumption of fortifiable foods estimated from the Third Cameroon Household Survey (ECAM3) with the results of a national dietary survey using food frequency questionnaire (FFQ) and 24-hour recall (24HR) methods among women aged 15 to 49 years and children aged 12 to 59 months. METHODS: We estimated coverage and frequency of consumption in the previous week (ECAM3 and FFQ) and coverage and amount consumed on the previous day (ECAM3 and 24HR) of refined vegetable oil, wheat flour, sugar, and bouillon cubes. RESULTS: Coverage in the past week as measured by the ECAM3 and FFQ, respectively, was 64% vs. 54% for oil, 60% vs. 92% for flour, 69% vs. 78% for sugar, and 85% vs. 96% for bouillon cubes. The different methods identified similar patterns of coverage among subgroups for oil, but patterns for other foods were variable. Frequency of consumption and previous-day coverage were lower with the ECAM3 than with the FFQ and 24HR, likely reflecting infrequent acquisition relative to intake. For women, the mean amounts consumed on the previous day (among consumers) were 43 vs. 29 g of oil, 71 vs. 83 g of flour, 42 vs. 32 g of sugar, and 5.0 vs. 2.4 g of bouillon cubes (ECAM and 24HR, respectively). CONCLUSIONS: HCES provide useful information on patterns of food access but inadequate information on individual consumption amounts to estimate appropriate food fortification levels. PMID- 26121704 TI - Is There an Enabling Environment for Nutrition-Sensitive Agriculture in South Asia? Stakeholder Perspectives from India, Bangladesh, and Pakistan. AB - BACKGROUND: Almost half of all children in South Asia are stunted. Although agriculture has the potential to be a strong driver of undernutrition reduction and serves as the main source of livelihood for over half of South Asia's population, its potential to reduce undernutrition is currently not being realized. OBJECTIVE: The Leveraging Agriculture for Nutrition in South Asia (LANSA) research consortium seeks to understand how agriculture and agrifood systems can be better designed to improve nutrition in South Asia. In 2013 and 2014, LANSA carried out interviews with stakeholders influential in, and/or knowledgeable of, agriculture-nutrition policy in India, Pakistan, and Bangladesh, to gain a better understanding of the institutional and political factors surrounding the nutrition sensitivity of agriculture in the region. METHODS: Semistructured interviews were carried out in India, Bangladesh, and Pakistan with a total of 56 stakeholders representing international organizations, research, government, civil society, donors, and the private sector. RESULTS: The findings point to mixed perspectives on countries' policy sensitivity toward nutrition. There was consensus among stakeholders on the importance of political commitment to nutrition, improving nutrition literacy, strengthening capacities, and improving the use of financial resources. CONCLUSIONS: Although there are different ways in which South Asian agriculture can improve its impact on nutrition, sensitizing key influencers to the importance of nutrition for the health of a country's population appears as a critical issue. This should in turn serve as the premise for political commitment, intersectoral coordination to implement nutrition-relevant policies, adequately resourced nutrition-specific and nutrition-sensitive programs, and sufficient capacities at all levels. PMID- 26121705 TI - Dr. Ricardo Bressani, Former Associate Editor of the Food and Nutrition Bulletin : 1926-2015. PMID- 26121706 TI - A Meta-Analysis of Randomized Controlled Trials of Conventional Stenting Versus Direct Stenting in Patients With Acute Myocardial Infarction. AB - BACKGROUND: Direct stenting (DS) is commonly used during percutaneous coronary intervention for acute myocardial infarction (AMI) to prevent distal embolization; however, no guideline recommendations exist regarding DS. We sought to compare DS with conventional stenting (CS) in patients presenting with AMI in a meta-analysis of randomized controlled trials. METHODS: Studies were identified from EMBASE, MEDLINE, and Cochrane databases. To be included, randomized controlled trials must have compared DS with CS in patients with AMI. Data were extracted and articles were critically appraised by two authors. A fixed effects model was used, with Peto odds ratios (ORs). The primary endpoint was death from cardiovascular causes. RESULTS: Five trials (n = 754) met the eligibility criteria. ST-segment resolution occurred in 68.9% (146/212) in the DS group vs 60.2% (127/211) in the CS group (OR, 1.51; 95% CI, 1.00-2.27; P=.05; I2=52%). No reflow occurred in 6.6% in the DS group compared with 6.9% in the CS group (OR, 0.78; 95% CI, 0.39-1.55; P=.48; I2=0%). DS was associated with a significant reduction in the risk of in-hospital cardiovascular death (OR, 0.21; 95% CI, 0.06 0.77; P=.02; I2=0%). No significant differences were observed in myocardial infarction (OR, 0.38; 95% CI, 0.09-1.51; P=.17; I2=7%) or target lesion revascularization (OR, 1.20; 95% CI, 0.36-3.97; P=.76; I2=0%). CONCLUSION: Small trials suggest a potential benefit to DS in AMI. Further large-scale randomized trials are warranted to confirm the benefit of this approach. PMID- 26121707 TI - Transradial Approach for Cardiac Catheterization in Patients With Negative Allen's Test. AB - AIMS: To assess the efficacy and safety of transradial approach regardless of the Allen's test results for coronary angiography and angioplasty. METHODS AND RESULTS: Prospective data collection of 1035 consecutive patients who underwent coronary angiography with or without ad hoc angioplasty through the radial approach was conducted. Baseline demographic and procedural data were recorded. Allen's test was evaluated in all subjects before the procedure and catheterization was performed from the radial approach irrespective of the results. Radial artery patency was evaluated at discharge clinically, or by Doppler examination if pulse was not palpable. A total of 256 patients (24.7%) were found to have a negative Allen's test and 779 patients (75.3%) had a positive test. The baseline and procedural characteristics were similar in both groups. No significant differences in complications were reported. Radial artery thrombosis was observed in 6.2% of the negative Allen's test group and 4.8% of the positive Allen's test group (P=.85), but this was clinically silent even in the negative Allen's test group. CONCLUSION: Transradial approach for coronary angiography and ad hoc angioplasty can be performed with similar efficacy and safety regardless of the Allen's test results before the procedure. PMID- 26121717 TI - Child Protection During Disasters. PMID- 26121708 TI - Coronary Artery Bypass Surgery Compared With Percutaneous Coronary Intervention for Proximal Left Anterior Descending Artery Treatment in Patients With Acute Coronary Syndrome: Analysis From the ACUITY Trial. AB - BACKGROUND: The optimal revascularization strategy in patients with acute coronary syndrome (ACS) and proximal left anterior descending (pLAD) coronary artery lesions is not well defined. The aim of this study was to compare the outcomes of ACS patients with pLAD culprit lesions receiving percutaneous coronary intervention (PCI) vs coronary artery bypass graft (CABG). METHODS: The ACUITY trial was a multicenter, prospective trial of patients with ACS treated with an early invasive strategy. Major adverse cardiac event (MACE; defined as death, myocardial infarction [MI], and repeat revascularization) and stroke were compared at 30 days and 1 year between PCI and CABG in patients with significant stenosis of the pLAD undergoing revascularization. Postprocedural major bleeding was evaluated at 30 days. RESULTS: Among patients with a significant pLAD stenosis (n = 842), a total of 562 (66.7%) underwent PCI and 280 (33.3%) underwent CABG. Baseline characteristics, including age, sex, diabetes, and TIMI risk score, were well matched between groups; however, patients undergoing PCI were more likely to have had previous CABG (21.9% vs 6.4%; P<.001). Death, MI, MACE, and stroke rates did not differ between groups at 1 year. PCI patients had lower bleeding rates (8.1% vs 52.4%; P<.001) and blood product transfusion at 30 days (4.5% vs 41.3%; P<.001), but higher rates of unplanned revascularization at 1 year (12.7% vs 5.2%; P<.01). These results were consistent in patients with single vs multivessel disease and in diabetics vs non-diabetics. CONCLUSIONS: Among ACS patients with pLAD culprit lesions, an initial revascularization strategy of PCI compared with CABG yields similar 1-year death, MI, and MACE rates, although unplanned revascularization is more common after PCI. PMID- 26121718 TI - Undesirable Effects of Media on Children: Why Limitation is Necessary? AB - Pervasive media environment is a social problem shared by most of the countries around the world. Several studies have been performed to highlight the undesired effects of media on children. Some of these studies have focused on the time spent by children watching television, playing with computers or using mobile media devices while some others have tried to explain the associations between the obesity, postural abnormalities or psychological problems of children, and their media use. This article discusses the recent approaches to curb influence of media on children, and the importance of family media literacy education programs with particular relevance to developing countries. PMID- 26121719 TI - Biomarkers for Diagnosis of Kawasaki Disease. PMID- 26121720 TI - Duchenne Muscular Dystrophy: Advances in Molecular Genetics and Changing Strategies in Diagnosis, Prevention and Therapeutics. PMID- 26121721 TI - Blood N-terminal Pro-brain Natriuretic Peptide and Interleukin-17 for Distinguishing Incomplete Kawasaki Disease from Infectious Diseases. AB - OBJECTIVE: To explore the diagnostic value of blood N-terminal pro-brain natriuretic peptide (NT-proBNP) and interleukin-17(IL-17) for incomplete Kawasaki disease. METHODS: Patients with Kawasaki disease, Incomplete Kawasaki disease and unclear infectious fever were included in this retrospective study. Their clinical features, and laboratory test results of blood NT-proBNP and IL-17 were collected and compared. RESULTS: 766 patients with complete clinical information were recruited, consisting of 291 cases of Kawasaki disease, 74 cases of incomplete Kawasaki disease, and 401 cases of unclear infectious diseases. When the consistency with indicator 2 and 3 in Kawasaki disease diagnosis criteria was assessed with blood IL-17 ?11.55 pg/mL and blood NT-proBNP ? 225.5 pg/dL as the criteria, the sensitivity and specificity for distinguishing incomplete Kawasaki disease and infectious diseases reached 86.5% and 94.8%, respectively. When we chose the consistency with indicator 1 and 2 in Kawasaki disease diagnosis criteria, the appearance of decrustation and/or the BCG erythema, blood IL-17 ?11.55 pg/mL and blood NT-Pro BNP ?225.5 pg/dL as the criteria, the sensitivity and specificity for distinguishing incomplete Kawasaki disease and infectious diseases was 43.2% and 100%, respectively. CONCLUSIONS: Blood NT-proBNP and IL-17 are useful laboratory indicators for distinguishing incomplete Kawasaki disease and infectious diseases at the early stage. PMID- 26121722 TI - Genetic and Clinical Profile of Patients of Duchenne Muscular Dystrophy: Experience from a Tertiary Care Center in Eastern India. AB - OBJECTIVE: To study the genetic pattern, clinical profile and to find any correlation between them in patients of Duchenne muscular dystrophy. METHODS: Patients were selected from Neurogenetic clinic on the basis of clinical features, elevated serum CPK level and electromyographic features. After history and clinical examination, molecular genetic testing was performed by Polymerase Chain Reaction (PCR) technique. RESULTS: Among 100 patients, 73 patients had genetically confirmed disease while 8 cases were proven by biopsy, and thus a total 81 cases were further taken up for the study. Mean age of onset of clinical symptoms was 3.9 yrs; Valley sign and calf hypertrophy were most consistent features, while about 51% had facial weakness. Out of 73 genetically confirmed cases 53 (72.6%) showed deletion in distal exons and 12 (16.4%) showed deletion in both proximal and distal exons while 8 (10.9%) had only proximal deletion. There was no correlation between genetic pattern and clinical features. CONCLUSIONS: The positivity of PCR- based diagnosis is higher in our study possibly related to highly selective group of patients. Phenotype and genotype correlation was not seen. PMID- 26121723 TI - Impact of System Factors and Modifiable ICU Interventions on the Outcome of Cardio-pulmonary Resuscitation in PICU. AB - OBJECTIVE: To assess the impact of system factors and modifiable interventions on outcome of cardiac arrest in a pediatric intensive care unit. DESIGN: Retrospective medical record review. SETTING: Pediatric intensive care unit of a hospital in China. PARTICIPANTS: Children (age<14 yrs) who had cardiac arrest within our PICU over a period of two years. RESULTS: Sixty-one of the 94 cardiac arrest events were successfully resuscitated. There was no significant association between personal and unit factors with immediate outcomes in our unit. The rate of unsuccessful resuscitation in sedated patients and those without sedation was 26% and 50%, respectively. Unsuccessful resuscitation occurred in 19% of patients who were on positive pressure ventilation as compared with 74% for those without positive pressure ventilation. Arrests which had resuscitation attempts that lasted more than 30 min had 135-fold higher odds of unsuccessful outcome. 78% of patients who received base supplement at the time of arrest had unsuccessful resuscitation compared with 21% for those without base supplement. CONCLUSION: Our data shows no impact of system factors on the outcome of cardio-pulmonary resuscitation in our PICU. Pre-arrest sedation in pediatric critical ill patients might be beneficial to the outcome of cardiac arrests. PMID- 26121724 TI - Energy and Protein Intake During Pregnancy in Relation to Preterm Birth: A Case Control Study. AB - OBJECTIVE: To find the association of maternal energy and protein intake with preterm birth. DESIGN: Case-control study. SETTING: Two hospitals at Lucknow in Northern India. PARTICIPANTS: Cases (n=350) were defined as mothers (age 18-40 y) of singleton live preterm (<37 wks) neonates. Controls (n=350) were mothers who delivered a singleton neonate, consecutive to enrolled case, after completing 37 weeks of gestation. RESULTS: There was a statistically significant lower mean (SD) energy intake [cases 1624 (249) Kcal vs. controls 1911 (341) Kcal; P<0.001] and protein intake [cases 32.1 (6.1) vs. controls 37.2 (7.0); P<0.001] among women who delivered preterm neonates. Maternal energy and protein intake had significant positive correlation with neonatal weight, length, foot length, head circumference and chest circumference. CONCLUSION: Lower energy and protein intake during pregnancy is possibly associated with preterm birth. PMID- 26121725 TI - Oral Sucrose for Pain in Neonates During Echocardiography: A Randomized Controlled Trial. AB - OBJECTIVE: To test the efficacy of oral sucrose in reducing pain/stress during echocardiography as estimated by Premature Infant Pain Profile score. DESIGN: Double-blind, parallel-group, randomized control trial. SETTING: Tertiary-care neonatal care unit located in Western India. PARTICIPANTS: Neonates with established enteral feeding, not on any respiratory support and with gestational age between 32 and 42 weeks requiring echocardiography. INTERVENTIONS: Neonates in intervention group received oral sucrose prior to echocardiography. MAIN OUTCOME MEASURES: Assessment was done using Premature Infant Pain Profile score. RESULTS: There were 104 examinations; 52 in each group. Baseline characteristics like mean gestational age (37.6 vs. 37.1), birth weight (2.20 vs. 2.08), and feeding status (Breastfeeding- 59.6% vs. 44.2%, paladai feeding- 13.5% vs. 13.5%, and gavage feeding- 26.9% vs. 42.3%) were comparable. The mean (SD) premature infant pain profile score was significantly higher in control group [(7.4 (3.78) vs. 5.2 (1.92), P <0.001]. CONCLUSION: Oral sucrose significantly reduces pain, and is safe to administer to neonates. PMID- 26121726 TI - Long-term Complications of Congenital Esophageal Atresia, Single Institution Experience. AB - OBJECTIVE: To evaluate general health condition of children operated for esophageal atresia, including complications from gastrointestinal tract and skeletal defects. METHODS: Between 1990 and 2005, 77 patients were operated for esophageal atresia in the Polish Mothers Health Memorial Hospital. The study was based on retrospective analysis of medical case records of all children with esophageal atresia. All living patients (n=51) were invited for follow-up studies. RESULTS: Pathological gastroesophageal reflux was found in 46.7% of children. Scoliosis was diagnosed in 20 patients. Chest deformations were observed in 43.3% children. CONCLUSION: The absence of clinical symptoms does not exclude the presence of gastroesophageal reflux in children operated for esophageal atresia. Children operated for esophageal atresia should be followed up regularly by a multispecialistic medical team. PMID- 26121727 TI - Cryptococcal Meningoencephalitis, A Tale of 50 Years. PMID- 26121728 TI - IAP Position Paper on Burden of Mumps in India and Vaccination Strategies. AB - JUSTIFICATION: Mumps, despite being a widely prevalent disease in the country, is considered as an insignificant public health problem mainly because of poor documentation of clinical cases and lack of published studies. In the absence of adequate published data on disease burden, Government of India has recently decided to introduce measles-rubella (MR) vaccine in its National Immunization Program and neglected mumps component. PROCESS: Following an IAP ACVIP meeting on December 6 and 7, 2014, a detailed review of burden of mumps in India along with vaccination strategies to control the disease was prepared. The draft was circulated amongst the members of the committee for review and approval. Revised final draft was later approved by IAP executive board in January 2015. OBJECTIVES: To provide a review of community burden of mumps in India; and to discuss the vaccination strategies to impress upon policymakers to include mumps vaccination in National immunization program. RECOMMENDATIONS: A total of 14 studies and two media reports on mumps outbreak were retrieved. The outbreaks were reported from all the regions of the country. Mumps meningoencephalitis was responsible for 2.3% to 14.6% of all investigated hospitalized acute encephalitis syndrome or viral encephalitis cases in different studies. Data from Infectious Disease Surveillance (ID Surv) portal of IAP and Integrated Disease Surveillance Program (IDSP) of Government of India (GoI) were also reviewed. While a total of 1052 cases were reported by the IDSurv, IDSP had investigated 72 outbreaks with 1564 cases in 14 states during different time periods. Genotypes G (subtype G2) and C were found to be main genotypes of the mumps virus circulating in the country. Three studies studied serological status of young children and adolescents against mumps, and found susceptibility rates ranging from 32% to 80% in different age groups. CONCLUSIONS: Mumps poses a significant disease burden in India. This calls for inclusion of mumps vaccine in the National immunization program. PMID- 26121729 TI - Does Supplementation With Vitamin B12 and or Folic Acid Improve Growth ? PMID- 26121732 TI - Familial Hypomagnesemia with Secondary Hypocalcemia Mimicking Neurodegenerative Disorder. AB - BACKGROUND: Familial hypomagnesemia with secondary hypocalcemia is a genetic disorder of magnesium metabolism that presents with refractory seizures in infancy. CASE CHARACTERISTICS: We herein report an infant with familial hypomagnesemia who presented as medically-refractory seizures and had cerebral atrophy on neuroimaging. Interestingly he had lost previous two siblings because of lack of correct diagnosis. INTERVENTION: Child was given oral magnesium supplementation and the seizures got controlled. MESSAGE: Familial hypomagnesemia should be considered in any child with recurrent or refractory hypocalcemic seizures. PMID- 26121733 TI - Acute Kidney Injury Following Plastic Bronchitis Associated with Influenza B Virus in a Child with Nephrotic Syndrome. AB - BACKGROUND: Plastic bronchitis is a rare but life-threatening disorder and is usually associated with congenital heart disease or pulmonary disease. CASE CHARACTERISTICS: A 5-year-old boy with minimal change nephrotic syndrome who developed a relapse along with cough, fever and dyspnea. OBSERVATION: Chest X-ray showed atelectasis of right upper lobe of lung, and nasal swab was positive for influenza B virus. His respiratory condition worsened, and required ventilation; bronchoscopy revealed bronchial casts. This was followed by acute kidney injury which was successfully managed with hemodialysis. MESSAGE: Children with nephrotic syndrome on immunosuppressive agents can develop plastic bronchitis and acute kidney injury, following influenza virus infection. PMID- 26121734 TI - Appendicular Perforation in a Neonate Masquerading as Testicular Torsion. AB - BACKGROUND: Neonatal appendicitis is difficult to diagnose, and is associated with high mortality. CASE CHARACTERISTICS: A preterm (33 wk) neonate developed abdominal distension feeding intolerance and erythema of left inguinal region on day 4 of life. OBSERVATION: Testicular torsion was suspected but inguinal exploration revealed normal testis with feco-purulent fluid draining into processus vaginalis from peritoneal cavity. Laparotomy revealed inflamed and perforated appendix. Appendectomy and intravenous antibiotics led to a recovery. MESSAGE: Appendicitis in a neonate can rarely present with inguinal symptoms, masquerading as testicular torsion. PMID- 26121735 TI - Mid upper Arm Circumference for Detection of Severe Acute Malnutrition in Infants Aged Between One and Six Months. AB - This study conducted among 302 infants aimed to determine the most suitable mid upper arm circumference cutoff to diagnose severe acute malnutrition (weight-for length <-3 SD) in infants aged between 1 and 6 months. The cut off of 11.0 cm had the best performance (Youden index 0.63, sensitivity 82.5%, specificity 80.3%). PMID- 26121736 TI - Vitamin D Deficiency Among Women in Labor and Cord Blood of Newborns. AB - 25-hydroxy Vitamin D levels of 106 maternal blood samples and cord blood levels of their newborns were studied. Maternal mean (SD) vitamin D level was 16.3 (10.3) ng/mL, and mean (SD) cord blood level was 12.8 (8.5) ng/mL. Seventy-five (70.7% mothers (70.7%) and 88 (83%) newborns had hypovitaminosis- D. Seventy (93.3%) newborns of mothers with hypovitaminosis-D had low vitamin D levels. There was a strong correlation between maternal and newborn Vitamin D levels (r=0.6; P<0.001). There is a high prevalence of hypovitaminosis D in women in labor and their newborns. PMID- 26121737 TI - Continuous Ambulatory Peritoneal Dialysis in Children, Experience from Eastern India. PMID- 26121738 TI - Macroamylasemia: A Benign Cause for High Serum Amylase. PMID- 26121739 TI - Acute Demyelinating Encephalomyelitis in a Neonate Secondary to Dengue Infection. PMID- 26121740 TI - Spontaneous Migration of Airway Foreign Body to the Gastrointestinal Tract. PMID- 26121741 TI - Single Magnet Ingestion- Individualizing the Algorithm. PMID- 26121742 TI - CDKL5 Encephalopathy: A Rare Cause of Infantile Epileptic Encephalopathy. PMID- 26121743 TI - Hair Thread Tourniquet Syndrome of Penis Causing Urethral Fistula. PMID- 26121744 TI - Mirizzi Syndrome - An Uncommon Cause of Obstructive Jaundice in a Child. PMID- 26121745 TI - Chitinase 3-like-1 and its receptors in Hermansky-Pudlak syndrome-associated lung disease. AB - Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3 like-1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Ralpha2 as a consequence of dysfunctional BLOC-3-dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1 dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS. PMID- 26121746 TI - Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. AB - Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism. PMID- 26121747 TI - MicroRNA-132 enhances transition from inflammation to proliferation during wound healing. AB - Wound healing is a complex process that is characterized by an initial inflammatory phase followed by a proliferative phase. This transition is a critical regulatory point; however, the factors that mediate this process are not fully understood. Here, we evaluated microRNAs (miRs) in skin wound healing and characterized the dynamic change of the miRNome in human skin wounds. miR-132 was highly upregulated during the inflammatory phase of wound repair, predominantly expressed in epidermal keratinocytes, and peaked in the subsequent proliferative phase. TGF-beta1 and TGF-beta2 induced miR-132 expression in keratinocytes, and transcriptome analysis of these cells revealed that miR-132 regulates a large number of immune response- and cell cycle-related genes. In keratinocytes, miR 132 decreased the production of chemokines and the capability to attract leukocytes by suppressing the NF-kappaB pathway. Conversely, miR-132 increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth. Silencing of the miR-132 target heparin-binding EGF-like growth factor (HB-EGF) phenocopied miR-132 overexpression in keratinocytes. Using mouse and human ex vivo wound models, we found that miR-132 blockade delayed healing, which was accompanied by severe inflammation and deficient keratinocyte proliferation. Together, our results indicate that miR-132 is a critical regulator of skin wound healing that facilitates the transition from the inflammatory to the proliferative phase. PMID- 26121748 TI - High IFN-gamma and low SLPI mark severe asthma in mice and humans. AB - Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-gamma (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra-/- mice, although airway inflammation was lower. Computer assisted pathway analysis tools linked IFN-gamma to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-gamma inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-gamma/SLPI axis that affects lung function. PMID- 26121749 TI - IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease. AB - Macrophages (Mo) are integral in ischemia/reperfusion injury-incited (I/R incited) acute kidney injury (AKI) that leads to fibrosis and chronic kidney disease (CKD). IL-34 and CSF-1 share a receptor (c-FMS), and both cytokines mediate Mo survival and proliferation but also have distinct features. CSF-1 is central to kidney repair and destruction. We tested the hypothesis that IL-34 dependent, Mo-mediated mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD. In renal I/R, the time-related magnitude of Mo-mediated AKI and subsequent CKD were markedly reduced in IL-34-deficient mice compared with controls. IL-34, c-FMS, and a second IL-34 receptor, protein-tyrosine phosphatase zeta (PTP-zeta) were upregulated in the kidney after I/R. IL-34 was generated by tubular epithelial cells (TECs) and promoted Mo-mediated TEC destruction during AKI that worsened subsequent CKD via 2 distinct mechanisms: enhanced intrarenal Mo proliferation and elevated BM myeloid cell proliferation, which increases circulating monocytes that are drawn into the kidney by chemokines. CSF-1 expression in TECs did not compensate for IL-34 deficiency. In patients, kidney transplants subject to I/R expressed IL-34, c-FMS, and PTP-zeta in TECs during AKI that increased with advancing injury. Moreover, IL-34 expression increased, along with more enduring ischemia in donor kidneys. In conclusion, IL-34-dependent, Mo-mediated, CSF-1 nonredundant mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD. PMID- 26121752 TI - Evidence-Based Practice: Be a Champion! PMID- 26121750 TI - Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity. AB - Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. Reduced mTORC1 signaling is associated with life span extension and improved metabolic homeostasis, yet the downstream targets that mediate these benefits are unclear. Here, we demonstrated that enhanced 4E-BP1 activity in mouse skeletal muscle protects against age- and diet-induced insulin resistance and metabolic rate decline. Transgenic animals displayed increased energy expenditure; altered adipose tissue distribution, including reduced white adipose accumulation and preserved brown adipose mass; and were protected from hepatic steatosis. Skeletal muscle-specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) and enhanced respiratory function. Non-cell autonomous protection was through preservation of brown adipose tissue metabolism, which was increased in 4E-BP1 transgenic animals during normal aging and in a response to diet-induced type 2 diabetes. Adipose phenotypes may derive from enhanced skeletal muscle expression and secretion of the known myokine FGF21. Unlike skeletal muscle, enhanced adipose-specific 4E-BP1 activity was not protective but instead was deleterious in response to the same challenges. These findings indicate that regulation of 4E-BP1 in skeletal muscle may serve as an important conduit through which mTORC1 controls metabolism. PMID- 26121753 TI - Should Water Birth Be Offered as an Option for Childbearing Women? PMID- 26121754 TI - Lymphatic Filariasis in Children in Haiti. AB - Using available evidence and astute assessment skills, nurses and advanced practice nurses, as members of an inter-professional team, were able to assess, diagnose, and initiate treatment for a child with lymphatic filariasis within a global health practice setting. The lessons learned during health outreach trips to an underserved commune of Port-au-Prince, Haiti can promote an understanding of appropriate nursing practice related to this parasitic infection. They can also assist nursing students, nurse practitioner students, and faculties as members of a medical outreach team to promote sustainability which is a benchmark of nursing leadership in global health. PMID- 26121751 TI - Flow-dependent expression of ectonucleotide tri(di)phosphohydrolase-1 and suppression of atherosclerosis. AB - The ability of cells to detect and respond to nucleotide signals in the local microenvironment is essential for vascular homeostasis. The enzyme ectonucleotide tri(di)phosphohydrolase-1 (ENTPD1, also known as CD39) on the surface of leukocytes and endothelial cells metabolizes locally released, intravascular ATP and ADP, thereby eliminating these prothrombotic and proinflammatory stimuli. Here, we evaluated the contribution of CD39 to atherogenesis in the apolipoprotein E-deficient (ApoE-deficient) mouse model of atherosclerosis. Compared with control ApoE-deficient animals, plaque burden was markedly increased along with circulating markers of platelet activation in Cd39+/-Apoe-/- mice fed a high-fat diet. Plaque analysis revealed stark regionalization of endothelial CD39 expression and function in Apoe-/- mice, with CD39 prominently expressed in atheroprotective, stable flow regions and diminished in atheroprone areas subject to disturbed flow. In mice, disturbed flow as the result of partial carotid artery ligation rapidly suppressed endothelial CD39 expression. Moreover, unidirectional laminar shear stress induced atheroprotective CD39 expression in human endothelial cells. CD39 induction was dependent upon the vascular transcription factor Kruppel-like factor 2 (KLF2) binding near the transcriptional start site of CD39. Together, these data establish CD39 as a regionalized regulator of atherogenesis that is driven by shear stress. PMID- 26121755 TI - Discovering Self: Childbearing Adolescents' Maternal Identity. AB - PURPOSE: Adolescent pregnancy and motherhood have long been a topic of interest for many healthcare professionals. However, there are limited data on how childbearing adolescents incorporate motherhood identity into their sense of self. The purpose of this study was to explore how childbearing adolescents perceive motherhood as becoming part of their personal identity. STUDY DESIGN: This qualitative study using ethnographic data collection involved 7 months of observation, interaction, and interviews. METHODS: Data were collected from nine expectant adolescents during in-depth interviews. All participants were patients at a teen mother and child clinic staffed by certified nurse midwives and a pediatrician. RESULTS: Narrative content analysis revealed the overall theme of discovering self, with three major themes: confirming the pregnancy, the loss of my body, and imagining my child in my arms. CLINICAL IMPLICATIONS: Adolescent mothers may need assistance to construct their maternal identity in order to strengthen self-perceptions and improve maternal/child outcomes. PMID- 26121756 TI - Implementing Skin-to-Skin Care in the Operating Room After Cesarean Birth. AB - BACKGROUND: After vaginal birth, newborns who have been skin-to-skin (STS) with their mother have greater temperature and glucose stability and higher exclusive breastfeeding rates at discharge. There are minimal data about STS in the operating room (OR) after cesarean birth. Although implementing STS in the OR can be challenging, it may promote positive maternal and infant outcomes. PURPOSE: The purpose of this quality improvement project was to evaluate maternal satisfaction and maternal perception of pain when babies were placed STS immediately after cesarean birth in the OR. STUDY DESIGN AND METHODS: This quality improvement project was conducted at Baylor All Saints Medical Center Andrews Women's Hospital, an urban, nonprofit, private hospital with an average of 5,000 births per year. Over a 90-day period, all women having cesarean birth were evaluated for two outcomes, maternal birth experience and pain perception during surgery. Following scheduled repeat cesarean, satisfaction of the birth experience was compared to the previous birth experience. Pain control during surgery of women having cesarean birth with and without STS was evaluated. Postpartum interviews with the new mothers and review of their anesthesia records were used to determine project findings. RESULTS: Maternal satisfaction was higher and maternal perception of pain was lower for women who experienced STS in the OR when compared to women where STS was not performed. CLINICAL IMPLICATIONS: Babies can be placed STS in the OR with positive implications for mothers' satisfaction with the birth experience and their perception of pain during the surgical procedure. Infant safety should be supported by a nurse with the mother and baby during the STS process. PMID- 26121757 TI - Postpartum Depression Among Asian Indian Mothers. AB - PURPOSE: To explore Asian Indian mothers' perspectives of postpartum depression (PPD) and mental health help-seeking behavior. STUDY DESIGN: Qualitative exploratory design. METHODS: Using convenience sampling, postpartum mothers were recruited through flyers posted in public places and on social media sites. Postpartum depression risk was assessed with the Edinburgh Postnatal Depression Scale (EPDS) prior to qualitative interviews. Content analysis methods were used to extract themes from participant narratives. RESULTS: Twelve self-identified, married, Asian Indian mothers, aged between 29 and 40 years, living in Northern California, who gave birth to a healthy infant within the last 12 months, took part in this study. Scores on the EPDS indicated two participants were at an increased risk for developing PPD. Content analysis revealed two emerging themes: (1) Culture-specific postpartum practices and ceremonies and their role in maternal-infant postpartum recovery; and (2) Maternal mental health help-seeking behavior. CLINICAL IMPLICATIONS: Nurses taking care of women during the extended prenatal and postpartum period have the unique opportunity to build rapport with their patients which can offer a window of opportunity to educate and help dispel myths about PPD symptoms and treatment. To promote successful maternal-infant outcomes, PPD education should be initiated at the first prenatal appointment, continue during the pregnancy, and be incorporated into well-baby visits through the first postpartum year. Education should include signs and symptoms of PPD as well as importance of timely mental-health help-seeking. PMID- 26121758 TI - Cardiac Arrest in Pregnancy. PMID- 26121759 TI - The Social Nature of Eating. PMID- 26121760 TI - Exploring Massive Open Online Courses for Nurses. PMID- 26121761 TI - Family-Centered Care and Preterm Babies. PMID- 26121763 TI - Newborn Safety in the Hospital. PMID- 26121767 TI - Index of countries/areas. Index, volume 20, 2015, Nos.1-26. PMID- 26121766 TI - [Response]. PMID- 26121768 TI - Yellow fever in Africa and the Americas, 2014. PMID- 26121769 TI - Monthly report on dracunculiasis cases, January-May 2015. PMID- 26121770 TI - Provision of Early Intervention and Special Education Services to Eligible DoD Dependents. Final rule. AB - This rule reissues the current regulations and: Establishes policy, assigns responsibilities, and implements the non-funding and non-reporting provisions in DoD for: Provision of early intervention services (EIS) to infants and toddlers with disabilities and their families, as well as special education and related services to children with disabilities entitled under this part to receive education services from the DoD; implementation of a comprehensive, multidisciplinary program of EIS for infants and toddlers with disabilities and their families who, but for age, are eligible to be enrolled in DoD schools; provision of a free appropriate public education (FAPE), including special education and related services, for children with disabilities, as specified in their individualized education programs (IEP), who are eligible to enroll in DoD schools; and monitoring of DoD programs providing EIS, and special education and related services for compliance with this part. This rule also establishes a DoD Coordinating Committee to recommend policies and provide compliance oversight for early intervention and special education. PMID- 26121771 TI - Evidence-Based Review and Discussion Points. PMID- 26121772 TI - Reply by Author. PMID- 26121773 TI - Reply by Author. PMID- 26121774 TI - The authors respond. PMID- 26121775 TI - Animal welfare: a bigger issue. PMID- 26121776 TI - Standards for detecting bacteria in chicken. PMID- 26121777 TI - Adopting dogs. PMID- 26121778 TI - Looking for alternatives for feral cats. PMID- 26121779 TI - [Learn from the Sea]. PMID- 26121780 TI - [Future and Current Status of Monitored Anesthesia Care (MAC) in Japan: Preface and Comments]. AB - American Society of Anesthesiologists defines that monitored anesthesia care (MAC) is a specific anesthesia service for a diagnostic or therapeutic procedure. Indications for monitored anesthesia care include the nature of the procedure, the patient's clinical condition and/or the potential need to convert to a general or regional anesthetic. In the USA, MAC is popular as an anesthesiologist service provided for an individual patient. MAC is also becoming increasingly popular in Japan. However, most Japanese anesthesiologists are not involved in MAC, and instead, physicians belonging to other departments such as internal medicine and pediatrics are in charge for MAC. Several guidelines for MAC during MRI in children and endoscopy in adults have recently been published in Japan. In the featured articles, we are dealing with the future and current status of MAC in Japan. Through the featured articles, I hope readers would know what to do next for us anesthesiologists in order to provide safe and useful MAC in Japan. PMID- 26121781 TI - [Sedation as a Part of Monitored Anesthesia Care (MAC) and Its Introduction to Japanese Clinical Practice]. AB - To relieve or eliminate distress caused by invasive medical procedures, sedation is often used in routine clinical practice. Monitored anesthesia care (MAC) is needed in patients who receive increased doses of sedatives and/or analgesics, which may suppress the respiratory, cardiac, and/or vascular systems. Deep sedation, in particular, suppreses the nomal protective reflexes. It requires careful monitoring and intervention for patients. In Japan, sedation is performed in a large number of cases. It is unreasonable that only anesthesiologists administer MAC. In fact, sedation is often performed by non-anesthesiologists. In these circumstances, education and training for non-anesthesiologists are important PMID- 26121782 TI - [Monitoring Required for Monitored Anesthesia Care (MAC) and Specific MAC Methodologies]. AB - Many physicians responsible for monitored anesthesia care (MAC) are not anesthesiologists and are not acquainted with treatment in response to sudden changes in patient condition. In particular, rapid response and early detection are essential for respiratory depression. Physicians engaged in MAC require pharmacological knowledge regarding sedative and analgesic medications, need to be able to accurately evaluate physiological responses to sedative and anesthetic levels, and need to be acquainted with emergency procedures such as basic life support (BLS) and advanced cardiovascular life support (ACLS). Patient management focusing on both ventilation and oxygenation, through the use of capnography and continuous respiratory monitoring, in addition to oxygenation monitoring using a pulse oximeter, and measuring ECGs and blood pressure in the management of sedated patients, is also important. PMID- 26121783 TI - [The Monitored Anesthesia Care in Gastrointestinal Endoscopy--Current Situation in Japan]. AB - Monitored Anesthesia Care (MAC) in gastrointestinal endoscopy-treatment has been introduced in Japanese clinical situations recently. Nonetheless, MAC in gastrointestinal endoscopy-examination is not so popular unlike the North American situation because of the lack of trained sedation providers. However, Japan Gastroenterological Endoscopy Society created the "Guidelines for sedation in endoscopic practice"in 2013 under the cooperation of the Japanese Society of Anesthesiologists. These guidelines for sedation in endoscopic practice made MAC more popular for pain relief of the patient, and the establishment of safe sedation system should be provided eventually. In this review article, the guidelines are introduced and discussed for the current clinical practice and for the future. PMID- 26121784 TI - [MAC for Pediatric Examinations]. AB - MAC is often required for pediatric examinations outside of operating room. It is difficult to conduct MAC for pediatric population safely. In Japan, most MAC for pediatric examinations are not conducted by anesthesiologists but pediatricians. Following practices in other countries, Japan Pediatric Society, Japanese Society of Pediatric Anesthesiology and Japanese Society of Pediatric Radiology collaborated to establish the first Japanese guideline for pediatric sedation: Proposals about sedation for MRI examinations in 2013. This proposal consists of six parts; 1. informed consent 2. pre-sedation patient assessment, 3. back-up team for emergency, 4. pre-sedation NPO, 5. patient monitoring, and 6. post sedation care. Anesthesiologists are expected to play supervisor roles of sedation operation to make the sedation environment safe, even though they can not conduct sedation by themselves. PMID- 26121785 TI - [Monitored Anesthesia Care for Respiratory Endoscopy]. AB - Sedation and/or analgesia are required during respiratory endoscopy procedure to reduce the patient's anxiety, unpleasantness and pain. At present most of diagnostic respiratory endoscopy cases are carried out outside the operating room without the involvement of anesthesiologists in Japan. Inadequate anesthesia/sedation may cause patient's discomfort and/or serious injury. Anesthesiologists are expected to play a part in the sedation and analgesia education/training for nonanesthesiologists to ameliorate patient satisfaction and safety. Interventional endoscopy procedures are more invasive and painful than simple diagnostic ones for patients, and sometimes result in a crisis such as respiratory tract bleeding and airway obstruction. Since the number of interventional cases and high-risk patients will increase with the society aging, peri-procedure management by anesthesiologists or monitored anesthesia care will become popular in the future. PMID- 26121786 TI - [Current Status and Issues of Sedation and Anesthesia in Cardiovascular Medicine]. AB - Sedation or anesthesia is necessary in most of the patients undergoing catheter ablation of atrial fibrillation (AF) because of longer procedure time and interventions causing pain and discomfort such as cardioversion, administration of adenosine or RF applications to the posterior left atrium. In the United States, AF ablation is performed under general anesthesia by anesthesiologists or anesthesia nurses in half of the patients and other half is under conscious sedation by cardiologists or nurses. In Japan, however, a nationwide survey revealed more than 95% of patients underwent AF ablation under conscious or deep sedation and most of them are performed by cardiologists who also have other responsibility. Current problems include a difficulty in management of respiration in patients with sleep apnea that often coincide with AF. Continuous positive airway pressure combined with nasal or oral airway and jaw elevation device is often used. Frequencies of monitoring of SP(O2), arterial blood pressure, BIS, and Et(CO)2 were 99%, 79%, 13.2% and 2% of patients, respectively, which suggests monitoring of consciousness level and ventilation may be insufficient Japanese Heart Rhythm Society started educational activities for safe sedation by themselves. PMID- 26121787 TI - [Monitored Anesthesia Care for Deep Brain Stimulation and Embolization of Brain Arteriovenous Malformation]. AB - The aim of monitored anesthesia care (MAC) in neurosurgery and interventional neuroradiology is to provide optimal surgical conditions including patient immobility and comfort, facilitate intraoperative neuromonitoring, and rapidly treat any complication. The anesthetist has a crucial role in facilitating procedures, and this requires an understanding of specific procedures, their potential complications, and their management. Choice of anesthetic technique varies between centers with little data to support any specific technique. Dexmedetomidine is useful as a sedative and hypnotic for patients undergoing procedures without the need for tracheal intubation. We usually use dexmedetomidine in MAC. PMID- 26121788 TI - [Effect of Oral Rehydration Therapy before General Anesthesia on Satisfaction, Stress Response, and Hemodynamics in Surgical Patients for Laparoscopic Colectomy]. AB - BACKGROUND: The recommended intake of clear liquids until 2 hours before surgery is reportedly safe and effective. We investigated whether oral rehydration therapy before surgery had improved satisfaction, stress response, and hemodynamics in patients during perioperative period. METHODS: Patients scheduled to undergo laparoscopic colectomy were enrolled and randomly divided into 2 groups. The oral rehydration therapy (ORT) group (29 cases) was allowed to drink clear liquids until 2 hours before anesthesia induction and the control group (29 cases) fasted from 21 : 00 the night before surgery. All patients entered the operating room at 8: 40. Patient satisfaction was examined after admission to the operating room. The volume and pH of gastric fluid were measured after anesthetic induction. The serum concentrations of cortisol and catecholamine were measured as stress response indicators after anesthetic induction and at the completion of surgery. Intraoperative hemodynamics was also recorded. RESULTS: There were no differences in patient satisfaction, stress response, and hemodynamics between the 2 groups. Intraoperative urine volume was significantly larger in the ORT group. Vomiting and aspiration were not observed in any patient CONCLUSIONS: Oral rehydration therapy until 2 hours before surgery seemed safe but did not improve satisfaction, stress response, and hemodynamics in perioperative patients. PMID- 26121789 TI - [Hypotonic Versus Isotonic Electrolyte Solution for Perioperative Fluid Therapy in Infants]. AB - BACKGROUND: This study was designed to evaluate the effects of perioperative administration of an isotonic electrolyte solution with 1% glucose (IT) on blood sodium (Na+) and blood glucose (BG) concentrations in pediatric patients < 1-year old undergoing plastic surgery in comparison with a conventional hypotonic electrolyte solution with 2.6% glucose (HT). METHODS: Fifty Patients were randomly allocated to HT group and IT group. Na+ and BG were measured at induction of anesthesia (Tind), the end of surgery (Tend), and 4 hours after surgery (T4h). RESULTS: Patient characteristics were similar for the 2 groups. In the HT group, Na+ at Tend insignificantly dropped compared with that at Tind, whereas in the IT group Na+ was significantly elevated. Na+ at T4h significantly increased compared with that at Tend in each group. No cases developed new dysnatremia or dysglycemia in IT group. The incidence of hyponatremia at Tend was significantly lower in the IT group. A positive correlation between intraoperative Na+ concentration changes and the infusion duration was observed in the IT group. CONCLUSIONS: Isotonic solution with 1% glucose is suggested to be safe in infants during and after surgery. PMID- 26121790 TI - [Postoperative Management and Cost-effectiveness of Epidural Anesthesia in Patients undergoing Abdominal Aortic Replacement Surgery]. AB - BACKGROUND: The use of epidural anesthesia for ablominal aortic replacement surgery may be problematic because of the amount of heparin used during the procedure, which places the patient at increased risk of epidural hematoma. We evaluated its benefits, risks, postoperative outcomes and costs. METHODS: We retrospectively collected data on 93 patients who underwent Y-graft infra-renal abdominal aortic replacement at our institution between 2008 and 2010. All patients were admitted to the intensive care unit (ICU) for postoperative care. We compared the mortality rate, the time until extubation, length of ICU and postoperative hospital stay, and ICU cost of those who received epidural anesthesia comparing with those who did not. RESULTS: Thirty-two of the 93 patients (34.4%) received epidural anesthesia, which was used for 2-5 (mean +/- SD ; 3.2 +/- 0.8) postoperative days. Postoperative mortality during the 2-year period was 3.3% in the group that did not receive epidural anesthesia (two patients) compared with 3.1% (one patient) in the epidural group (P = 1.00). Postoperative respiratory disorders were recorded in 1.6% of patients who did not receive an epidural (one patient) compared with 6.3% (two patients) in those that did (P = 0.27). There were no reports of epidural hemorrhage, hematoma or infection. Patients with epidurals were extubated earlier than those in the non epidural group (mean +/- standard deviation 5.5 +/- 7.2 hours versus 11.6 +/- 7.9 hours, respectively P < 0.001), but there were no significant differences between the two groups in terms of ICU cost or length of ICU and postoperative hospital stay. CONCLUSIONS: Epidural anesthesia during abdominal aortic replacement facilitated more rapid extubation, but did not appear to influence other aspects of patient recovery or ICU costs. PMID- 26121791 TI - [Use of the i-gel for Tracheostomy in a Patient with Neck Deformity and Tracheal Stenosis]. AB - We report a successful use of the i-gel for tracheostomy in a patient with severe neck deformity and tracheal stenosis. A 20-year-old man, 142 cm, 22 kg, was scheduled for tracheotomy. He had tracheal stenosis with hypoxemia, due to the pressure from the brachiocephalic artery, associated with severe progression of symptomatic scoliosis and thoracic deformity. Using a fiberoptic bronchoscope, we confirmed that there was no upper airway obstruction. After induction of anesthesia, facemask ventilation was easy. The i-gel was easily inserted, and fiberscope-aided tracheal intubation through the i-gel was attempted, but decided not to intubate the trachea, due to the degree of stenosis. Tracheostomy was performed, while a clear airway was maintained by the i-gel. We consider that the i-gel has a potential role for tracheostomy in a patient with neck deformity and tracheal stenosis. PMID- 26121792 TI - [Successful Awake Nasal Endotracheal Intubation with the McGrath Videolaryngoscope and a Soft-tipped Extra Firm Exchange Catheter in a Patient with a Necrotic Mandible]. AB - Here we report a case of successful awake nasal intubation with the McGrath videolaryngscope (McGrath) in conjunction with a soft-tipped extra firm exchange catheter in a patient with a necrotic mandible developing a hole. An 81-year-old woman underwent partial tongue resection and cervical lymph node dissection. After additional radiation therapy, she developed a necrotic mandible with a hole from the oral cavity to the neck region. She was scheduled for resection of the necrotic mandible under general anesthesia. Upon sedation with dexmedetomidine 1.0 MUg xkg-(1 )-xhr-(1 )and applying topical anesthesia with lido-aine, we inserted the McGrath orally and the soft- ipped extra firm tube exchange catheter (TE) nasally. Under the guide of the McGrath's monitor, we inserted the TE, using Magill forceps, into her trachea. A 6.0 mm internal diameter spiral tracheal tube was inserted via the TE uneventfully. PMID- 26121793 TI - [Monitoring of Somatosensory Evoked Potentials during Foramen Magnum Decompression of Chiari Malformation Type I Complicated with Syringomyelia: A Report of Two Cases]. AB - Few reports exist on anesthetic management for foramen magnum decompression (FMD) of Chiari malformation type I (CM I) complicated with syringomyelia. In two such cases we monitored somatosensory evoked potentials (SEP). Case 1 : A 40-year-old woman presented with occipital headache and nuchal pain for 2 months; numbness and muscular weakness of bilateral upper limbs for a month. Magnetic resonance imaging (MRI) scan showed CM I complicated with syringomyelia. Case 2 : A 32-year old man presented with numbness and muscular weakness of bilateral upper limbs for 5 months; numbness and muscular weakness of lower limbs for 2 months. MRI scan showed CM I complicated with syringomyelia. They underwent FMD. In both cases, general anesthesia was induced with remifentanil, propofol and rocuronium, and was maintained with oxygen, air, remifentanil and propofol. Moreover, we monitored SEP. Their operative courses were uneventful. In case 1, SEP latency became shorter after FMD. Her preoperative neurologic symptoms disappeared on first postoperative day. In contrast there was no change of SEP latency after FMD in case 2. His preoperative neurologic symptoms showed no change on fifth postoperative day. SEP monitoring may be a useful index for prediction of early recovery of neurologic symptoms after FMD. PMID- 26121794 TI - [Bispectral Index Electrodes May Induce Skin Lesions]. AB - Bispectral index (BIS) monitoring has been used since the 1990 s, and many studies on BIS monitoring have demonstrated its usefulness and safety. Currently, BIS monitoring has become indispensable for observation of patients under general anesthesia. However, we observed the development of postoperative skin lesions in 13 patients (11 female and 2 male; age range, 14-76 years) resulting from contact with the BIS electrodes between May 2012 and April 2013. None of the patients had a history of allergies or skin diseases prior to surgery. During the surgery, nine patients were placed in the supine position and four in the prone position. The duration of anesthesia ranged from 2 hr 7 min to 13 hr. The overall incidence of skin lesions was approximately 0.27% (13/4,900), and that in patients in the prone position was 3.1% (4/129). The skin lesions resolved within 1 week without scaring following the application of a steroid-containing ointment. Although the occurrence of such skin complications is rare, some patients may experience postoperative anxiety because skin lesions caused by BIS electrodes are noticeable. Therefore, both the usefulness of BIS monitoring and the potential skin complications should be explained to patients preoperatively prior to obtaining patient consent. PMID- 26121795 TI - [Anesthetic Management of an Infant with Rapidly Developed Hyponatremia due to Bowel Perforation during Enema Reduction Using Diluted Contrast Medium]. AB - A 7-kg 8-month-old boy was transferred to our institution after failed enema reduction of intussusception elsewhere. During the redo intervention using a 6 fold-diluted solution of Gastrografin with water as contrast medium, the bowel was perforated. Urgent surgical repair was planned and preoperative examination revealed serum sodium of 137 mEq x l(-1). On arrival in the operating room, the patient presented abdominal distension, drowsiness and tachypnea. His trachea was intubated and anesthesia was maintained with sevoflurane. Arterial blood examination immediately before the surgery (approximate by 80 minutes after the previous blood test) showed the following findings: pH 7.27, base excess -8.5 mEq x l(-1) and sodium 122 mEq x l(-1). Watery ascites estimated at 450 ml was evacuated upon a peritoneal incision. At termination of anesthesia, serum sodium recovered to 133 mEq x l(-1), resulting from replenishment of electrolytes and sodium bicarbonate administration. The patient became fully awake and his trachea was extubated in the operating room. Gastrografin has osmolarity of 1,900 mOsm x l(-1), containing sodium of 158 mEq x l(-1). Massive intraperitoneal accumulation of diluted Gastrografin is a rational explanation for the rapidly developed hyponatremia, which can lead to hyponatremic encephalopathy, especially in infants. Prompt surgical intervention is therefore essential for successful management of such cases. PMID- 26121796 TI - [Successful Subarachnoid Phenol Block Therapy in a Patient with Pelvic Tumor related Rectal Tenesmus]. AB - We report a successful case of subarachnoid phenol block therapy in a patient with refractory rectal tenesmus caused by metastatic breast cancer. A 50-year-old woman with pelvic metastasis of breast cancer had the constant desire for defecation and anal discomfort, although analgesics including opioids relieved her from low abdominal and anal pain. Computed tomography revealed rectal invasion of metastatic breast cancer and the diagnosis of tumor-related rectal tenesmus was made. Symptoms of rectal tenesmus were severe and drug-resistant. Subarachnoid phenol block in the sitting position, which was neurolytic saddle block and expected to inhibit rectal reflex, was performed and her symptom was dramatically relieved. The effect of the block continued until she died 19 days after. To our knowledge, we first report subarachnoid phenol block therapy for a patient with pelvic-tumor related rectal tenesmus. PMID- 26121797 TI - [Comparison of the Intracuff Pressure Increase by Upper Gastrointestinal Endoscope Insertion in TaperGuard Cuffed Tube and High-volume Low Pressure Cuffed Tracheal Tube: A Porcine Larynx Model Study]. AB - BACKGROUND: The purpose of this study was to compare the upper gastrointestinal endoscope (UGE) insertion-mediated cuff pressure increase between a tracheal tube with a tapered cuff (Taper) and or conventional high volume low pressure cuff (HVLP) utilizing a porcine larynx model. METHODS: The automated cuff pressure was adjusted to 10, 20, and 30 cmH2O. The Taper and HVLP cuff pressure increases by UGE insertion were measured. RESULTS: Significant cuff pressure increase was observed by UGE insertion regardless of initial cuff pressure. The cuff pressure of the Taper was significantly lower than that of the HVLP by UGE insertion. CONCLUSIONS: These findings suggest that the Taper may be more effective than the HVLP in preventing tracheal tube cuff increase by UGE insertion. PMID- 26121798 TI - [Preoperative Spirometry Leads Latent COPD Patients to be Discovered and Treated]. AB - BACKGROUND AND METHODS: We have noticed the possibility that preoperative spirometry may discover latent COPD patients. When COPD is discovered before operation, we can start to treat COPD promptly. Consequently, the better perioperative care is given to COPD patients. On discharge, patients are referred to their family doctors, so that they can receive COPD treatment. RESULTS: There activities were started in July 2012. During the initial twelve months, 90 patients of COPD II x III were discovered and treated before admission. FEV1.0 was significantly improved (1.54 l vs. 1.71 l in average) on repeated spirometry on admission. There was no adverse event in COPD treatment All patients have shown good clinical courses. CONCLUSIONS: Latent COPD patients can be discovered by preoperative spirometry. PMID- 26121799 TI - [Minor Anesthesia for Minor Surgery]. PMID- 26121800 TI - [The Effect of Remifentanil on the Estimated Target Effect-site Concentration (esTEC) of Propofol during Total Intravenous Anesthesia]. AB - BACKGROUND: Using an algorithm by which the effect-site concentration of propofol (esTEC) necessary for BIS level set from information input from BIS monitor and TCI pump is estimated, the effect of remifentanil on esTEC was investigated. METHODS: In 14 abdominal/thoracic surgical patients managed under total intravenous anesthesia with propofol and remifetanil, the distribution of relation between the effect-site concentration of remifetanil and remifentanil esTEC was analyzed in a retrospective manner. RESULTS: While the propofol esTEC decreased in accordance with the increase of the effect-site concentration of remifetanil, the effect-site concentration of propofol esTEC45 for maintaining BIS 45 became within a certain range and with less dispersion when the concentration of remifetanil exceeded 10 ng x ml(-1). CONCLUSIONS: A mutual interaction was observed between propofol esTEC and remifetanil. For anesthetic management with less variation in BIS levels, it was considered that 10 ng x ml( 1) or higher of the effect-site concentration of remifetanil would be necessary. PMID- 26121801 TI - [Effect of Preoperative Oral Rehydration on Onset Time and Recovery Time of Rocuronium]. AB - BACKGROUND: Preoperative oral rehydration solution (ORS) prevents hypovolemia. The aim of this study was to compare the effect of intubating dose of rocuronium in patients taking and those not taking preoperative ORS. METHODS: Twenty patients, ASA I aged 20-50 years scheduled for elective surgery, were investigated and randomly assigned to two groups: drinking 1,500 ml ORS 6 to 2 hours before anesthesia (ORS group) and nothing by mouth from 6 hours before anesthesia (control group). Anesthesia was maintained with propofol and remifentanil, and rocuronium 0.6 mg x kg(-1) was administrated. To evaluate the effect of rocuronium, acceleromyography at the adductor pollicis was performed using 0.1 Hz stimulation. Cardiac index (CI) and stroke volume variation (SVV) from FloTra/Vigileo, times to 95% twitch depression as onset time (OT), and times to first twitch re-detection (TR) were recorded. RESULTS: SVV was significantly lower in ORS group (P = 0.03), and CI showed no difference. In ORS group, TR was significantly shorter than that of control group (P=0.002), and OT tended to be prolonged (99.0 +/- 36.3 s vs. 84.0 +/- 37.5 s), but not significantly. CONCLUSIONS: Preoperative oral rehydration possibly increases circulating blood volume, and shortens the duration of rocuronium effect. PMID- 26121802 TI - [General Anesthesia for the Thoracoscopic Lung Resection Surgery in 12 Very Elderly Patients above 85 Years of Age]. AB - We investigated perioperative management and clinical outcome of 12 patients who were 85 years old or older and received video-assisted thoracic surgery under general anesthesia. Although all the patients had preoperative respiratory complications or cardiovascular complications, they were discharged without any additional respiratory assistance such as home oxygen therapy. Our observation suggests that it is important to evaluate the indication of anesthesia from their daily activities and pulmonary function test even if they are oldest-old. If the patient demonstrates good physical function, he or she should not be excluded from anesthesia. PMID- 26121803 TI - [The Use of Thromboelastometry and Tranexamic Acid Reduces Blood Loss and Transfusion Requirements in Cardiac Surgery under Cardiopulmonary Bypass]. AB - BACKGROUND: We evaluated whether using thromboelastometry and tranexamic acid influenced blood loss and transfusion requirements in cardiac surgery requiring cardiopulmonary bypass. METHODS: We perfomed a retrospective analysis examining perioperative coagulation results, and the transfusion requirements of concentrated red cells (CRCs), fresh frozen plasma (FFP) and platelet administration between 12 months before and 10 months after thromboelastometry and tranexamic acid had been introduced in our institution. We also recorded patients' demographic details, the surgery performed and patient outcomes. RESULTS: After the introduction of thromboelastometry and tranexamic acid, fewer units of CRC were transfused during surgery, and fewer patients required postoperative CRC transfusion. Intra- and postoperative FFP requirements were also reduced. Intraoperative blood loss, blood loss in the first 24 hr after surgery, and length of hospital stay were also reduced. CONCLUSIONS: The use of ROTEM and tranexamic acid can potentially reduce blood loss and transfusion requirements in cardiac surgery. PMID- 26121804 TI - [Outcome of the Pediatric Patients Who Required Repeated Cardiopulmonary Bypass during the Repair of Congenital Heart Disease]. AB - BACKGROUND: We occasionally encounter clinical deterioration after discontinuation of cardiopulmonary bypass (CPB) and are forced to reinstitute CPB during cardiac surgery. Some reports describe such cases occurring in adults, but few in infants and children. We retrospectively investigated the causes and outcomes of children requiring repeated CPB during the repair of congenital heart anomalies. METHODS: Patients who required repeated CPB during the repair of congenital heart anomalies in our institution from 2007 to 2012 were recruited into the study. Patient's background, diagnosis, surgical procedures, durations of total CPB and aortic cross-clamping, indications for re-CPB, procedures or treatment added after reinstitution of CPB and outcomes were collected. RESULTS: Out of 600 pediatric patients who underwent the repair of congenital heart disease during the study period, 34 required repeated CPB and were enrolled into the study. Mean age was 2 years and mean body weight was 9.9 kg. Twenty-six patients of 34 were weaned from the CPB after additional surgical repair with re bypass, one of whom died in the ICU. The remaining 8 patients were weaned from the CPB after medical treatment. One of 8 patients died in the ICU and 2 died after discharge from ICU. CONCLUSIONS: In cardiac surgery of congenital heart disease, pediatric patients who required repeated CPB showed high mortality but patients who received additional surgical repair to be weaned from CPB had better outcome compared with those who received medical treatment. PMID- 26121805 TI - [Changes in Electrolytic Concentration Resulting from Perioperative Amino Acid Fluid Administration]. AB - BACKGROUND: Amino acid infusion is frequently selected to avoid hypothermia during surgery. However, changes in electrolytic concentration resulting from its use are unclear. The aim of this study was to identify the effect of amino acid on body temperature and changes in electrolytic concentrations. METHODS: Thirty women undergoing breast cancer surgery under general anesthesia were divided into the following three groups: no amino acid administration, low-dose administration (2 ml x kg(-1) x hr(-1)), and high-dose administration (4 ml x kg(-1) x hr(-1)). Esophageal temperature was recorded every ten minutes and arterial blood samples were obtained before and after surgery. Body temperatures at each time point and arterial blood gas data, including blood gases, electrodes, serum glucose, and hematocrit were compared between the three groups. RESULTS: Body temperature started to increase significantly 40 minutes after starting general anesthesia in the high-dose group, 90 minutes after starting general anesthesia in the low-dose group compared with the no amino acid group. Body temperature was maintained until surgery was completed. The concentration of sodium ion decreased significantly (2.4 mmol x l(-1)) in the high-dose group compared with the other two groups. The concentration of other electrolytes, including potassium, chloride, and calcium, did not change significantly. CONCLUSIONS: Perioperative amino acid administration was effective in maintaining a stable body temperature during surgery under general anesthesia. However, sodium ion concentration might decrease after amino acid administration of 4 ml x kg(-1) x hr(-1) or greater. PMID- 26121806 TI - [Effectiveness of Sacral Intervertebral Epidural Block for Umbilical Hernia Repair in Children]. AB - BACKGROUND: Effectiveness of sacral intervertebral epidural block (S 2-3 block) for umbilical hernia repair has not been clarified. METHOD: We investigate 24 children, undergoing umbilical hernia repair; mean age of 3 years (age range: 20 65 months). Under general anesthesia, epidural block was performed at S 2-3 interspace with 1 ml x kg(-1) ropivacaine (0.2%) at injecting rate of 1 ml x sec( 1) followed by 0.25 ml x kg(-1) normal saline. RESULTS: In all cases, neither systolic blood pressure nor heart rate increased > 15% from those just before the block. Postoperative analgesics were given in 6 patients (25%) rectally. Mean time between the block and the administration of analgesic was 10.5 hours. CONCLUSIONS: S 2-3 block can be effective for postoperative pain in umbilical hernia repair. PMID- 26121807 TI - [Airway Management Using McGrath MAC in a Pediatric Patient with a Laryngeal Saccular Cyst]. AB - An 18-month-old female infant was scheduled for resection of a laryngeal saccular cyst inducing narrow airway. Since the cyst protruded from the left side of the epiglottis and the vocal cord was compressed to the right side, a difficult airway was anticipated. In addition, there was a risk of tracheal occlusion by rupture of the cyst Awake intubation was considered to be dangerous. Slow induction with sevoflurane and neuromusclar blockade was attempted, preparing reversal of the neuromusclar blockade. Fortunately, mask ventilation was achieved without difficulty. It was necessary to insert a tracheal tube avoiding the cyst We used McGrath MAC (Aircraft Medical Co., UK), which enabled us to manipulate the tracheal tube. A tracheal tube was successfully inserted under McGrath monitor guidance. PMID- 26121808 TI - [Anesthetic Management of a Patient with Corrected Transposition of Great Arteries for Cesarean Section]. AB - A 30-year-old woman with corrected transposition of great arteries (c-TGA) was scheduled for elective cesarean section at 37 weeks of gestation. At previous cesarean section, she received general anesthesia for dyspnea and lower cardiac function by severe mitral regurgitation, with a pulmonary catheter inserted. In the current pregnancy, she had tricuspid regurgitation, but she had no signs of heart failure. Cardiac index (CI) and stroke volume variation (SVV) were monitored by the FloTrack, before induction of anesthesia. Because the CI was 3.6 l x min(-1) x m(-2), and the SVV was 18%, we decided to perform combined spinal epidural anesthesia. Epidural anesthesia was performed at L1-2, and spinal anesthesia was performed at L3-4. Hyperbaric 0.5% bupivacaine 2.0 ml with fentanyl 10 MUg was given to the subarachnoid space. The total dose of phenylephrine administered was 150 MUg, and the CI as well as the SVV were stable during surgery. Her postpartum couse was uneventful. Anesthetic management of c TGA is discussed, and we should select anesthetic method carefully. PMID- 26121809 TI - [Anesthetic Management for Endoscopic Sinus Surgery in a Patient with Transplanted Heart--A Case Report]. AB - A 19-year-old male patient with transplanted heart received endoscopic sinus surgery. He was with X-linked dilated cardiomyopathy, and was one year after the transplantation. Preanesthetic study showed lactate dehydrogenase elevation estimated to have derived from striated muscle. Heart function was normal, and other abnormal findings were not revealed. Total intravenous anesthesia was performed with propofol target controlled infusion and remifentanil. Rocuronium was administered only for oro-tracheal ntubation. After the operation, train-of four ratio was 95%, and he awoke from anesthesia smoothly. We did not use atropine, neostigmine or sugammadex to reverse neuromuscular blockade. No inotropic agent was administered. He was discharged from the hospital 5 days after the operation without any complications. We used usual anesthetic management but we had to be careful about both denervated heart and myopathy. PMID- 26121810 TI - [Anesthetic Management of Laparoscopic Nephrectomy for a Renal Cancer Patient with Distal Myopathy of Rimmed Vacuole]. AB - A 56-year-old male with distal myopathy of rimmed vacuoles underwent laparoscopic nephrectomy. Anesthesia was induced with propofol, remifentanil and ketamine. Tracheal intubation using McGRATH was uneventful without using muscle relaxants. Then ultrasound-guided right thoracic paravertebral (TPVB) block was performed using 20 ml 0.75% ropivacaine with 10 ml 2% lidocaine by 3 injections of 10 ml each at T9 to T11. General anesthesia was maintained with propofol, remifentanil and ketamine monitoring bispectral index. Good surgical condition and pneumoperitoneum were maintained without using muscle relaxants. His postoperative course was smooth and uneventful, even though a small amount of fentanyl was administrated to relieve wound pain. This case suggests that McGRATH and ultrasound-guided TPVB can be one of the options to avoid using muscle relaxants in patient with neuromuscular disease. PMID- 26121811 TI - [Management of Pulmonary Blood Flow for a Patient with Congenital Pulmonary Vein Stenosis Undergoing Pulmonary Venous Obstruction Release and Pulmonary Artery Banding]. AB - Congenital pulmonary vein stenosis (CPVS) is a rare fetal congenital heart disease with a prevalence of 1.7 per 100,000 children younger than two years of age. Because of the difficulty of maintaining the pulmonary blood flow, CPVS is associated with a 50% survival rate within five years of diagnosis. We describe a successful management of pulmonary blood flow for a 4-month-old-girl with CPVS, combined with atrial septal defect and ventricular septal defect, undergoing pulmonary vein obstruction release (PVOR). In this case, CPVS was the only cause for pulmonary hypertension because there was no significant pressure gradient between each pulmonary capillary wedge pressure and the paired pulmonary vein pressure, indicating the normal pulmonary vascular structure prior to pulmonary vein stenosis. As pulmonary blood flow was estimated to be high after PVOR, pulmonary artery banding was also performed. Management of pulmonary blood flow is the most important issue for anesthesia of this surgery, especially in postcardiopulmonary bypass period, when the pulmonary vasoconstriction is induced by endothelial dysfuncion. PMID- 26121812 TI - [Perioperative Management of Emergency Gastrointestinal Surgery in a Patient with Left Ventricular Non-compaction]. AB - Left ventricular non-compaction (LVNC) is a rare congenital cardiomyopathy characterized by heart failure, arrhythmia, and embolic events. A 65-year-old man, previously diagnosed as LVNC, was admitted to the emergency department with severe abdominal pain. He was diagnosed as appendicitis and treated conservatively with antibiotics. The echocardiogram examination showed left ventricular ejection fraction of less than 25%, and his B-type natriuretic peptide assay was > 5,000 pg x ml(-1) on admission. Ten days after admission, he underwent emergency surgery for suspected perforation of vermiform appendix. Transesophageal echocardiography (TEE) was used for real-time evaluation of cardiac function and restrictive fluid management during surgery. He was transferred to intensive care unit (ICU) for postoperative care, and extubated 16 hours after surgery. On the third postoperative day, he was discharged from ICU without any complications. We consider that perioperative hemodynamic management with TEE may be useful for gastrointestinal tract surgeries in patients with severe cardiac disease, such as LVNC. PMID- 26121813 TI - [Extracorporeal Membrane Oxygenation for Anesthesia Induction in a Patient with Severe Cardiorespiratory Impairment due to Mediastinal Angiosarcoma]. AB - BACKGROUND: Mediastinal angiosarcoma is a rare intrathoracic tumor that can cause severe pleural and pericardial fibrosis. CASE REPORT: We report the anesthetic management for pericardiectomy and pleurolysis in a 33-year-old patient with a mediastinal angiosarcoma. He presented with severe restrictive ventilatory impairment and heart failure due to fibrosis of the pleura and pericardium. Spirometry indicated a forced vital capacity of 0.66 l, while arterial blood gas analysis under noninvasive positive pressure ventilation indicated hypercapnia (pH 7.44; Pa(CO2) 59.2 mmHg). His cardiac index was 1.36 l x min(-1) x m(-2). Anesthesia induction and positive pressure ventilation are associated with an extremely high cardiorespiratory risk; therefore, veno-arterial-extracorporeal membrane oxygenation (VA-ECMO) with femoral cannulation was started prior to anesthesia induction. After achieving a stable circulation and adequate gas exchange, anesthesia was induced, and mechanical ventilation with intratracheal intubation was initiated. With ECMO and inotropic support stable hemodynamics was maintained throughout anesthesia induction and the operation was performed uneventfully under cardiopulmonary bypass. The patient was extubated on the first postoperative day and discharged one month after the operation. CONCLUSION: ECMO is a useful option to secure adequate gas exchange and circulation during anesthesia induction in patients with severe cardiopulmonary problems due to mediastinal tumors. PMID- 26121814 TI - [Emergency Tracheal Intubation Using Airwayscope in a Patient with Hematoma after Thyroidectomy]. AB - We report a case of emergency awake intubation using Airwayscope (AWS) in a patient with difficulty of the ventilation combined with severe neck swelling due to hematoma after thyroidectomy. A 28-year-old woman with thyroid tumor received, general anesthesia induced, easily with facemask ventilation and tracheal intubation. Her trachea was extubated after she had become awake. Several minutes later, sudden swelling of the neck was observed, and she lost her consciousness. Despite attempts at facemask ventilation, hypoxia with bradycardia was observed. We judged that insertion of the supraglottic airway or the needle cannulation of the cricothyroid membrane would be difficult reducing the chance of re intubation. While we asked surgeons to prepare for emergency surgical tracheotomy, we attempted to intubate the trachea using the AWS under sedation. Despite difficulty in opening the mouth and swelling of the tongue, we managed to intubate the trachea. We consider that knowledge of difficult airway management (DAM) is necessary, but we must be flexible to judge which method should be used in each patient In addition we conclude that the AWS is useful for awake intubation. PMID- 26121815 TI - [Successful Tracheal Intubation Using Videolaryngoscope in an Infant with Massive Tongue Swelling]. AB - We report use of videolaryngoscope for difficult airway management in an infant with severe tongue swelling after laceration repair. A 3-month-old male infant was transferred to our hospital for respiratory difficulty. He could not open his mouth sufficiently, and the examination revealed massive swelling of the left side of the tongue. Emergent surgical repair of the tongue was scheduled, anticipating a difficult airway. The venous line was kept patent preoperatively, and 8% sevoflurane was administered maintaining spontaneous ventilation. We then inserted the Pentax Airway Scope with an infant-sized Intlock (AWS-I) from the right side of the mouth and obtained a good view at laryngoscopy. A 3.5-mm tracheal tube was passed uneventfully under the view of AWS-I. The AWS-I is useful for difficult airway management in infants, preserving spontaneous ventilation. PMID- 26121816 TI - [A Case of Emergency Cesarean Section and Craniotomy in a 26 Week Pregnant Woman]. AB - Intracranial hemorrhage is a rare complication during the pregnancy but carries a poor prognosis. We experienced a case of emergency cesarean section and craniotomy for removal of hematoma due to arteriovenous malformation (AVM) rupture. A 33-year-old woman at 26 weeks of pregnancy suffered a sudden onset of headache and disturbance of consciousness. She was diagnosed with left cerebral hemorrhage due to AVM rupture. Emergency cesarean section was followed by the surgical removal of the hematoma under general anesthesia. Postoperative courses of both mother and baby were satisfactory. The severity of illness of the mother strongly influences her fetus and vise versa. When performing cesarean section before craniotomy, anesthesia should be managed to prevent recurrence of intracranial hemorrhage during the cesarean section and atonic bleeding during the craniotomy. Anesthetist should have adequate knowledge and communicate adequately with obstetrician and pediatrician to achieve better prognosis for the intracranial hemorrhage during pregnancy. PMID- 26121817 TI - [Implantable Cardioverter Defibrillator and Perioperative Magnet Application: A Case Report]. AB - An implantable cardioverter defibrillator (ICD) can falsely recognize noise by monopolar electrocautery as tachyarrhythmia and deliver inappropriate antitachycardia therapy. Application of a clinical magnet on an ICD suspends antitachycardia therapy, but it has not been widely used for this purpose. A 67 year-old male underwent laryngopharyngectomy, cervical esophagectomy, right neck dissection, tracheostomy and reconstruction with free jejunal transplant for recurrent hypopharyngeal cancer. He had an ICD (PARADYM DR8550, Sorin) implanted below the left clavicle for ventricular tachycardia and prolonged QT syndrome. During the operation, a clinical magnet was left on the ICD to disable antitachycardia therapy. The magnet mode of the ICD provided asynchronous AAI pacing at 96 beats x min(-1). The surgery proceeded uneventfully. No episode of ventricular tachyarrythmia or pacing inhibition by electromagnetic interference was observed on electrocardiogram. This case illustrated the potential role of a clinical magnet as an alternative to reprogramming of an ICD by a programmer in the perioperative management of a patient with an ICD when a technical expert to operate a programmer is not available. PMID- 26121818 TI - [Bupivacaine-induced Anaphylaxis in a Parturient Undergoing Cesarean Section]. AB - We describe a case of anaphylaxis that occurred in a 33-year-old gravida 1, para 1 term woman scheduled for cesarean delivery for breech presentation. Her past history was unremarkable except for orciprenaline allergy. Spinal anesthesia was performed at L3-4 using 2.5 ml of 0.5% hyperbaric bupivacaine and 0.1 mg morphine. Seven minutes after spinal anesthesia, she complained of hoarseness and difficulty in breathing and 3 minutes later, blood pressure decreased to 76/51 mmHg, and oxygen saturation to 87% with supplemental oxygen. Skin flushing was noted in the face and trunk of the body and anaphylaxis was diagnosed. She was treated with a rapid intravenous infusion and iv administration of phenylephrine (total dose 0.4 mg), ephedrine (total dose 25 mg), hydrocortisone and famotidine. Cesarean section was started 23 minutes after spinal anesthesia when blood pressure and oxygen saturation recovered. A male infant was delivered (18 minutes after the onset of anaphylactic event) with Apgar scores of 2 and 5 at 1 and 5 min, respectively and resuscitated with mask ventilation. Umbilical artery blood gas analysis revealed pH 6.85, base excess -20.3 mmol x l (-1) and lactate 109 mg x dl (-1). The mother was discharged from the hospital on the 6th postoperative day. The baby's electroencephalogram, however, demonstrated a pattern consistent with mild hypoxic-ischemic encephalopathy. Lymphocyte stimulation test revealed that she was allergic to bupivacaine. If maternal hypotension persists, i.m. or i.v. adrenaline should be administered immediately because maternal hypotension and hypoxemia may cause significant fetal morbidity and mortality and prompt cesarean section should be considered. PMID- 26121819 TI - [The Distance between the Sciatic Nerve Bifurcation and Popliteal Fossa in Japanese]. AB - BACKGROUND: The bifurcation into tibial nerve and common peroneal nerve is generally targeted for sciatic nerve block at popliteal approach. However, it is sometimes difficult to determine the exact bifurcation point in clinical situation. The mean distance between the popliteal fossa and division of sciatic nerve (DPDSN) was reported approximately 6 cm +/- 2.5 cm in Caucasian cadaver study. We also studied DPDSN in Japanese cadaver to find ethnic difference. METHODS: We dissected and recorded DPDSN and distance from gluteal fold to heel (foot length : FL) in 15 cadavers. RESULTS: Mean DPDSN was 2.46 +/- 2.00 cm (range: 0 to 8.8 cm). The DPDSN and FL were not correlated. CONCLUSIONS: DPDSN of Japanese cadaver is shorter than the previously reported data in Caucasian cadaver. Since the DPDSN has inter-individual and intra-individual differences, we should estimate the DPDSN carefully in each leg using ultrasonography and nerve stimulator. PMID- 26121820 TI - [Postoperative Analgesia in Peritonectomy for Patients with Peritoneal Surface Malignancy]. AB - BACKGROUND: We investigated the efficacy of postoperative analgesia in peritonectomy for patients with peritoneal surface malignancy, by comparing peripheral nerve block (PNB) with intravenous patient controlled analgesia (iv PCA) group to patient controlled epidural analgesia (PCEA) group. METHODS: Forty one patients of PNB+iv-PCA group received ultrasound guided rectus sheath block (using 0.25% levobupivacaine 20 ml bilaterally) and posterior transversus abdominis plane block (30 ml bilaterally) after induction of anesthesia. Then, iv PCA with fentanyl was commenced before skin incision and 10 mg morphine was given 1 hr before the end of surgery. Fifty eight patients of PCEA group received 5-6 mg morphine epidural block at T6-7 or T7-8 before induction of anesthesia, and PCEA of 4-5 mg morphine and 200 ml normal saline was commenced before skin incision. When PCA showed inadequate effect for post- operative pain, flurbiprofen was used for all patients. RESULTS: The rate of administration of flurbiprofen during the first 24 hr after surgery was significantly lower in PNB+iv-PCA group. The duration of the first administration of flurbiprofen after extubation was significantly longer in PNB+iv-PCA group. Levobupivacaine (0.25%) 100 ml for PNB was safe to use without complications. CONCLUSIONS: PNB+iv-PCA decreased the rate of administration of flurbiprofen as compared to PCEA for postoperative pain after peritonectomy. PMID- 26121821 TI - [Investigation of a Novel Intravenous Catheter "Safe Wing Cath"]. AB - BACKGROUND: A Safe Wing Cath (SWC) is a novel intravenous catheter which has a unique needlestick injury safety mechanism. METHODS: We investigated the success rate of intravenous catheterization using SWC by questionnaire. Anesthesiologists were recruited who had no previous experience of using SWC. Two or three consecutive trials were subjected for investigation. RESULTS: During four months in 2012, 8 anesthesiologists were asked to do the job 23 times. The success rate was 62.5% at first use by each anesthesiologist 87.5% at second use, and 100% at third use. CONCLUSIONS: Experienced anesthesiologists can learn the technique of SWC on its second or third use. PMID- 26121822 TI - [Nitrous Oxide Exposure-mediated Increases in Cuff Pressure: A Comparison of Disposable Type and Re-use Type air-Q Devices]. AB - BaCKGROUND: The present study aimed to compare nitrous oxide-mediated increases in cuff pressure between the disposable type air-Q (air-Q-DT) and re-use type air Q (air-Q-RU) in a simulated adult airway model. METHODS: Automated cuff pressure was adjusted to 10, 20, and 30 cmH2O. The air-Q-DT and air-Q-RU were exposed to 80% nitrous oxide and cuff pressure was measured 15 and 30 minutes later. RESULTS: Cuff pressure of the air-Q-DT was significantly lower than that of the air-Q-RU after 15 and 30 minutes, regardless of the initial pressure. CONCLUSIONS: The polyvinyl chloride-based air-Q-DT may be more effective than the silicon-based air-Q-RU in preventing hyperinflation of the tracheal tube cuff in response to nitrous oxide exposure. PMID- 26121823 TI - [Efficacy of softband Ponto in young children with bilateral congenital microtia with aural atresia]. AB - OBJECTIVE: To evaluate auditory developments and the effectiveness of children with congenital bilateral aural atresia after using softband Ponto and to compare them with children with normal hearing. METHOD: Twenty patients (age ranging from 3 months to 21 months ) with bilateral aural atresia were studied. The air and bone auditory thresholds were assessed by auditory brain stem response (ABR). The infant-todder meaning auditory integration scale (IT-MAIS) was used to evaluate the auditory development at three time levels: baseline, 3 months and 6 months. RESULT: The average unaided bone conduction hearing thresholds of patients is (17.5 +/- 5.9)dB nHL,and the average air conduction hearing thresholds is (72.5 +/- 9.3)dB nHL. The average VRA hearing thresholds of 5 patients is (30.5 +/- 5.9) dB HL. The IT-MAIS total, detection and perception scores are improved specifically after wearing softband Ponto and approaching the normal level. CONCLUSION: Softband Ponto is suitable for infants with bilateral atresia. Results from these auditory development testing are encouraging. Softband Ponto should be used as a bridge for surgical implantations when temporal bone is thick enough. PMID- 26121824 TI - [Efficacy of cochlear implantation for bilateral severe Meniere's disease]. AB - OBJECTIVE: To investigate the effecacy of cochlear implantation (CI) improving hearing of Lermoyez's syndrome, we retrospectively analyzed a case of Lermoyez's syndrome whose left ear was extremely severe sensorineural deafness and right ear was severe sensorineural deafness. METHOD: The patient had completed preoperative audiological examination , vestibular function and imaging examination, then was carried out bilateral endolymphatic sac decompression and left side CI. Follow up after the surgery. RESULT: The vertigo could be controlled very well after the bilateral endolymphatic sac decompression surgery, but the hearing loss couldn't be control, so CI was carried out to improve hearing and speech recognition rate. The contralateral hearing also improved significantly after the operation. CONCLUSION: Endolymphatic sac decompression can effectively control. Meniere's disease in patients with vertigo attacks. CI can improve patients' hearing, and speech recognition rate and, also could improve the quality of life. CI was the first choice for the patient of 4 stage Meniere's disease. PMID- 26121825 TI - [Study of ceiling effect of commonly used Chinese recognition materials in post lingual deafened patients with cochlear implant]. AB - OBJECTIVE: To evaluate and compare outcomes effects of Chinese recognition materials in post-lingually deafened patients with cochlear implant. METHOD: Thirty-two post-lingually deafened cochlear implant users participated in the study. Each one of them was given a series of speech recognition tests including the speech recognition score of monosyllable words, spondee words, Chinese BKB sentences and MHINT in quiet, as well as speech recognition threshold of HOPE corpus in babble noise. Speech recognition scores and thresholds were compared among these test materials using histograms , scatter diagrams and statistical methods. RESULT: Recognition scores for spondee words, Chinese BKB sentences and MHINT were affected by ceiling effects, with 1,14 and 4 cases scored 100% respectivelty. Meanwhile, 17, 26 and 14 cases scored more than 85% correspondingly. On the other hand, speech recognition scores for monosyllable words in quiet and speech recognition threshold for HOPE corpus in babble noise were not affected. CONCLUSION: For a considerable part of post-lingually deafened patients using cochlear implant, some Chinese speech recognition materials have demonstrated different degrees of ceiling effects. While speech recognition scores for monosyllable words in quiet and recognition threshold for HOPE corpus in noise can evaluate the performance of speech recognition abilitymore objectively. PMID- 26121826 TI - [The effect of improving the physical and mental health on different rehabilitation programs for post-linguistic cochlear implantees]. AB - OBJECTIVE: To evaluate the physical and mental health status of post-linguistic cochlear implantees, and then to explore the effectiveness on of different rehabilitation programs. METHOD: Mandarin hearing in noise test (MHINT), personal report of communication apprehension (PRCA-24) and Nijmegen cochlear implant questionnaire (NCIQ) were used to measure the hearing ability, mental health degree and the health related life quality in 36 post-linguistic cochlear implant users, respectively. The improvement of subjects' physical and mental health levels was compared with among different rehabilitation programs, including family training program, auditory habilitation program and psychological intervention program. RESULT: (1) Family training program only can improve the subject's hearing ability (P < 0.05), but failed to ease the communication apprehension; ((2) Auditory habilitation program can both significantly improve the subjects' hearing ability (P < 0.01) and ease the fear of talking face to face (P < 0.01); (3) Psychological intervention program can significantly increase the auditory abilities (P < 0.01), reduce the communication apprehension (P < 0.01) and improve the quality of life. CONCLUSION: Post-linguistic cochlear implantees had obvious mental symptoms. It was very important to design an effective rehabilitation program to improvement the living quality of hearing loss people. PMID- 26121827 TI - [Meta-analysis on effectiveness of prelingually deaf patients at different ages following cochlear implantation]. AB - OBJECTIVE: To assess the clinical effeetiveness of prelingually deaf children after cochlear implantation at different ages so as to provide reasonable expectations for the patients and guidance for the clinical treatment. METHOD: Electronic databases PubMed, YZ365. COM, WANFANG DATA, CMJD, CHKD, CNKI were searched using relevant keywords. Extracted data included author, year of publication, diagnosis, et al. Reported treatment outcomes were clustered into speech discrimination and hearing abilities. Meta-analyses were performed on studies with numerical results using random or fixed effects model. RESULT: There were eight randomized control studies including 442 patients. Comparing speech perception of prelingually deaf children after cochlear implantation younger than three years old (experimental group) and 3-6 years old (control group), three and six months after operation showed that experimental group performed significantly worse than control group; 12 months after operation showed that experimental group performed significantly better than control group. Comparing hearing abilities, three and six months after operation showed that experimental group performed significantly worse than control group; 12 months after operation showed showed that experimental group performed significantly better than control group. Comparing speech perception of younger or older than 4. 5 years old children showed that after 1.5-2 years of operation children implanted younger than 4.5 years of age performed significantly better than children implanted older than 4.5 years old. Comparing speech perception of 7-12 years old children showed that after 3, 6, 12 months of operation patients of 7-12 years old performed significantly better than those children older than 12 years old. Comparing speech perception of implantation younger or older than 18 years old (7 14 yeas old was group A, > 14-18 yeas old was group B, older than 18 yeas old was group C) showed that after one and four years of operation A > B > C, and there were significant differences among them. Comparing warble tone threshold average (WTA) showed that after one year of operation A < B < C, and there were significant differences among them. However, after four years of operation, there was no significant difference among them. CONCLUSION: Prelinguistically deafened patients younger than three years old with cochlear implantation, insisting on scienctific rehabilitation training for a long period of time can receive the optimal recovery effect. The older patients are suggested as early as possible receiving cochlear implantation. The longer they are implanted, the better results they will receive. Moreover, the younger age they are implanted, the faster postoperative language progress they will receive. Further controlled studies with longer follow-up periods and more person included may make the effectiveness of cochlear implantaion more reliable. PMID- 26121828 TI - [The effects of newborn genetic screening for GJB2 and hearing follow-ups]. AB - OBJECTIVE: To determine the prevalence of GJB2 mutations in newborns and provide clinical experience for newborn genetic screening. METHOD: Blood samples of 23 836 newborns in Beijing from March 2012 to December 2013 were screened for hot spot mutations of GJB2 associated with hearing loss. The genetic screening results were comprehensively analyzed with hearing results in genetic counseling. RESULT: One or two pathogenic mutations of GJB2 were spotted in 622(2. 61%) individuals. Among them, numbers of newborns with 1 mutation of c. 35deiG,c. 176191 del16,c. 235delC and c. 299300 delAT were 3,26,467 and 120. One compound heterozygote, and 5 homozygotes were also identified. Five hundred and fifty(88. 6%)newborns were followed up by telephones and SMS (short message service) and 325 newborns visit our genetic clinic regularly which were regarded as the research object. In the hearing screening, the referral rate for hearing loss in the first-step screening was 13.8% (45/325), and became 9.2% (30/325) upon retesting. Nine newborns (2. 8%) were diagnosed as hearing loss of different degrees as early as 3 months old,including 6 homozygous/compound heterozygote and 3 heterozygotes. CONCLUSION: Patients with GJB2 mutations have various phenotype. Newborns with homozygous/compound heterozygous GJB2 mutations may pass the hearing screening at first. Carriers of GJB2 may also have hearing problems. The combination of genetic and audiological screening can play an important role in deafness detections of infants before key period of speech development. PMID- 26121829 TI - [Mutation analysis of 16 mutation spots related to children patients with non syndromic sensorineural hearing loss]. AB - OBJECTIVE: To explore the clinical signification of screening 16 target deafness mutations in GJB2, GJB3, SLC26A4, WFS1 and mitochondrial DNA 12S rRNA in 135 children patients with non-syndromic sensorineural hearing loss (NSHL) in Zibo City, Shandong province. METHOD: Peripheral blood samples of 135 subjects in the study diagnosed as NSHL were collected; Polymerase chain reaction (PCR) and direct sequencing were used to analyze the 16 mutation spots. RESULT: Sixty-two cases of 135 patients (45.9%, 62/135) were found out to be carries of at least one pathogenic gene mutation. Among them, 24 cases (17.8%, 24/135) had two mutated alleles (homozygote and compound heterozygote), and 38 cases (28.1%, 38/135) were single mutant carriers. Among all the children patients, 30 cases (22. 2%, 30/135) had SLC26A4 mutations, and 19 cases (14.1%, 19/135) had GJB2 mutations. In the study 86 Mutant alleles were detected, and the allele frequency of SLC26A4 c. 766_2A > G and GJB2 c. 235delC was 11.11% (30/270) and 8.5% (23/270) respectively. The allele frequency of SLC26A4 c. 2168A > G and WFS1 c. 2158A > G is 2.6% (7/270). CONCLUSION: SLC26A4 mutation is the primary cause of the patients with NSHL in this study, and GJB2 mutation is the secondary. The most common mutant form is c. 766_2A of SLC26A4, and the second is c. 235delC of GJB2. GJB3 and WFS1 mutations were detected, whereas mtDNA mutations were not found out in this study. PMID- 26121830 TI - [Analysis the treatment of sudden sensorineural hearing loss with steroid from different administration routes]. AB - OBJECTIVE: To explore the treatment of sudden sensorineural hearing loss with steroid from different administration routes. METHOD: One hundred and eighty eight patients with diagnosis of sudden sensorineural hearing loss were selected, in accordance with the random number table, and all patients were divided into three groups. With different administration routes, they were devided into systemic steroid therapy group, intratympanic steroid therapy group and postauricular steroid therapy group,and the curative effects were collected and analyzed. RESULT: The total effective rate was 78.26% in systemic steroid therapy group, 80.70% in intratympanic steroid therapy group and 80.65% in postauricularsteroid therapy group,and no statistical difference was detected among these three groups (P > 0.05). CONCLUSION: The treatment of sudden sensorineural hearing loss with steroid from different adminsthation routes all can achieve a relatively favorable prognosis, and there were no obvious different among those different treatments. PMID- 26121831 TI - [Study on correlation between otitis media with effusion and tracheal intubation]. AB - OBJECTIVE: To explore the factors related to the occurrence of otitis media with effusion (OME) in patients with long-term tracheal intubation. METHOD: This retrospective study included 47 cases with endotracheal intubation more than 7 days (endotracheal intubation group) and 20 cases without mechanically ventilated in the same period(control group). The relationships between secretory otitis media with age, gender, intubation method,duration of intubation, breathing patterns, consciousness, gastric tube position were analysed. RESULT: The study showed 27 out of 47 patients in endotracheal intubation group had OME, 9 cases had negative pressure in the middle ear and 11 patients were normal. No OME was found in control group, and 2 cases with negative pressure in bilateral middle ear were detected. The incidence of OME was significantly increased in patients with the application of ventilator in PEEP mode or nasotracheal tube, and with conscious disturbance or tracheal intubation using for more than 10 days. The presence of OME had a significantly higher rate in patients with nasal intake subjects than the oral intake subjects. The incidence of OME decreased significantly in patients using glucocorticoid. CONCLUSION: The incidence of OME increased in patients applied with tracheal intubation for more than 7 days. Ventilator in PEEP mode, nasotracheal tube, and conscious disturbance were closely related with OME. Application of glucocorticoids reduced the incidence of OME. PMID- 26121832 TI - [The clinical efficacy of composite acoustic therapy in patients of sudden deafness with tinnitus]. AB - OBJECTIVE: To determine whether the composite acoustic therapy is effective to treat tinnitus in patients with sudden deafness and to explore the mechanisms. METHOD: Ninety-six cases (96 ears) were divided into experimental group and control group, and all the patients underwent drug treatment. The patients in experimental group were given personalized composite acoustic therapy in the first 30 days, music therapy in next 31-90 days, however, the patients in control group were not given sound therapy. Additionally, pure tone audiogram, tinnitus pitch and loudness as well as questionnaires (including THI, VAS, and SAS) were conducted for each patient before treatment, at day 30 and day 90 posttreatment. RESULT: Eighty-nine patients (n = 47 for experimental group and n = 42 for control group) completed the trial. The results of day 30 posttreatment showed there were no significant differences in VAS and hearing recovery rate between these two groups, but THI and SAS showed significant differences. The results of day 90 posttreatment showed significant differences in VAS (P < 0.05), THI (P < 0.01) and SAS (P < 0.01), and no significant difference of hearing recovery rate was detected. The most significant changes of VAS appeared in the first 30 days of treatment. The hearing and tinnitus recovery in experimental group were better for the first 30 days of treatment than for the next 31-90 days, and similar results were obtaind in control group. (P < 0.01). CONCLUSION: Composite acoustic treatment combined with drug therapy can improve the tinnitus and anxiety symptoms of patients with sudden deafness, and the effect on hearing recovery still need to be confirmed in further studies. PMID- 26121833 TI - [The options of surgery and laryngeal preservation for hypopharyngeal cancer patients more than 65 years old]. AB - OBJECTIVE: To study the effectiveness of preserving laryngeal function for senile hypopharyngeal cancer patientsolder than 65. METHOD: The clinical data of 58 surgery cases of senile hypopharyngeal cancer patients more than 65 years old were colleted and analyzed. Thirty-one cases preserved the laryngeal function, while the rest did not. Perfect preoperative preparation was done before surgery. Surgical resection specimens were sent to frozen-section examination. When the negative incisal margin was confirmed, the defect was repaired by the appilication of local stitching, ribbon muscle flap, major myocutaneous flaps, split thickness skin and replacement of esophagus by stomach. Radical radiotherapy was used after surgery. Survival rate was calculated by the Kaplan Meier method. Chi-square test was used to compare complications of the two groups. RESULT: The 3 years and 5 years survival rate for all cases were 48.3% (28/58) and 27.6% (16/58), respectively. For patients with laryngeal function preservation, the 3 years and 5 years survival rate were 51.6% (16/31), 29.0% (9/31), respectively. For cases without laryngeal function preservation, the 3 years survival rate and 5 years survival rate were 44.4% (12/ 27), 25.9% (7/27), respectively. The result showed no obvious difference in survival rate between two groups (P > 0.05). Surgery complication rate were 45.2% (14/31) and 40.7% (11/27), without obvious differences between the two groups (P > 0.05). CONCLUSION: It is feasible for senile hypopharyngeal cancer patients to choose suitable operation based on their physical conditions and the tumor extension. The key issues include well perioperative treatment management, correct indications grasp, and intraoperative repair skills improvement. PMID- 26121834 TI - [The microsurgical anatomic research of the internal auditory canal area on the retrosigmold approach]. AB - OBJECTIVE: To evaluate the safety of the circular round window and discus anatomic landmarks of posterior wall of internal auditory canal by investigating the microscopic anatomy of internal auditory canal area of the retrosigmold approach, which can provide the anatomical basis for acoustic neutrinomas surgery. METHOD: Fifteen adult cadaver heads (30 sides) fixed with formalin were used in the study. The retrosigmold approach operations were imitated to dissect the blood vessels and nerves in internal auditory canal area by opening round bony window and removing posterior wall of internal auditory canal. RESULT: Fifteen specimens of 30 sides circular bone window were opened without injury with transverse sinus and sigmoid sinus. The vertical distance between the highest point of bone window margo superior and the lowest point of transverse sinus margo inferior was (4.02 +/- 0.32) mm. The vertical distance from the most anterior point of bone window leading edge to the most posterior point of sigmoid sinus trailing edge was (6.31 +/- 0.43) mm. The internal auditory canal tubercle located in the anterior superior position of internal auditory canal. The vertical distance from the highest point of internal auditory canal tubercle to the upper margin of internal auditory canal was (2.31 +/- 0.32) mm. To expose the whole internal auditory canal, the length and width of the internal auditory canal posterior wall removal was (7.29 +/- 0.32) mm, (4.12 +/- 0.29) mm. Within this removal range, no case of cochlea, semicircular canal or venous was injured in 30 specimens. CONCLUSION: The method of opening round window through retrosigmold approach is simple, practial and convenient. With little variation and easiness of location, the sinternal auditory canal tubercle can be used in the identification of the internal auditory canal. When exposing the whole internal auditory canal, the removal scope of the posterior wall should be paid more attention to, in order to avoid the damage of cochlea, semicircular canal and jugular bulb. PMID- 26121835 TI - [Adenoid cystic carcinoma of external auditory canal: 8 cases report]. AB - OBJECTIVE: To observe the clinical and pathological features of adenoid cystic carcinoma(ACC) of external auditory canal (EAC, and analyze the possible factors related to prognosis. METHOD: One out of 8 patients with ACC of EAC underwent tumor open biopsy. 5 patients underwent the extensive tumor resection, and 2 patients underwent the modified lateral temporal bone resection (1 of the 2 subjoined a total parotidectomy). Five patients received the postoperative radiotherapy. RESULT: The time of follow up was 5-97 months. Two patients were loss to follow-up, 5 patients with disease free survival, and 1 patient survival with tumor. CONCLUSION: In this study, ACC of EAC is more often observed in female. The most common clinical manifestations are otalgia and neoplasm which grows slowly. The disease has high misdiagnosis rate. Surgical treatment is effective for it. PMID- 26121836 TI - [Exploration of the role of cisplatin on transformation of larvngeal tumor cells to stem-like cancer cells]. AB - OBJECTIVE: To explore the possibility mechanism of non-side population cells (NSP) of Hep-2 be induced into stem-like cancer cells by chemotherapy drug- cisplatin. METHOD: Hep-2 cell lines were sorted by fluorescence-actived cell sorting. The acquired NSP cells in trail group were co-cultured with cisplatin for more than 48 hours,while the control group with normal saline(NS). Then identified the percentage of the side population (SP) cells by flow cytometer. The beta-catenin, notch-1 mRNA in trial and control group were detected using quantitative realtime PCR, and the beta-catenin, notch-1 protein in two groups were compared by Western blot. RESULT: The percentage of side population cells in two groups were (17.16 +/- 0.18)%, (10.05 +/- 1.20)%, respectively. There was significant difference between two groups (t = 5.844, P < 0.01). The expression of beta-catenin, notch-1 was higher in trail group by qRT-PCR; the protein levels of beta- catenin, notch-1 was found to inceased in the trail group by Western blot (t = 5.155, P = 0.031; t = 5.977, P = 0.004). Statistical analysis showed significant difference between two groups (P < 0.05). CONCLUSION: NSP cells can be differentiated into stem-like cancer cells after being treating with cisplatin. The supposed mechanism is maybe through wnt/beta-catenin, notch signaling transduction pathway abnormalities. PMID- 26121837 TI - [Combined inhibition of Stat3 and HIF-1alpha for enhancement of radio- and chemo sensitivity in laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To investigate the influence of signal transducer and activator of transcription 3 (Stat3) and hypoxia-inducible factor-lalpha (HIF-1alpha) on the resistance effect of laryngeal squamous cell carcinoma to radiation therapy and chemotherapy under the hypoxia circumstances. METHOD: Western blot was used to test the expression of p-Stat3 and HIF-1alpha in the Hep-2 cells under the hypoxia conditions. MTT assay was used to test the proliferation of Hep-2 cells after radiation therapy and chemotherapy; the Hep-2 cells were suppressed expression of Stat3 and/or HIF-1alpha. RESULT: (1) AG490 induced significant proliferation inhibition on Hep-2 cells and Hep-2HIF-1alpha-/- cells in vitro underthe hypoxia environments (P < 0.05); (2) Suppressing expression of Stat3 reduced the expression of HIF-1alpha protein (P < 0.05); (3) Combined inhibition of Stat3 and HIF-1alpha enhanced radio- and chemo-sensitivity in laryngeal squamous carcinoma cells under hypoxia. CONCLUSION: Combined inhibition of Stat3 and HIF-1alpha can further enhance radio- and chemo-sensitivity in laryngeal squamous carcinoma cells under hypixia compare than inhibiting Stat3 or HIF 1alpha alone. Effectively blocking of HIF-1alpha pathway and suppressing the expression of Stat3, would be an effective method to enhance radio- and chemo sensitivity in laryngeal squamous carcinoma cells, which provides a new thought to reduce the resistance to treatment. PMID- 26121838 TI - [Modified technique of endoscopic myringoplasty for repairing big perforation located at the rear of tympanic membrane]. PMID- 26121839 TI - [Study of the curative effect for middle and high frequency sudden sensorineural hearing loss by opisthotic dose way]. PMID- 26121840 TI - [Clinical effects of treatment in large perforation of tympanic membrane with the tragus cartilage perichondrium]. PMID- 26121841 TI - [External auditory canal cholesteatoma surgery]. PMID- 26121842 TI - [The analysis of hearing screening results with 18,000 subjects]. PMID- 26121843 TI - [The report of 26 cases on esophageal barium imaging positive misdiagnosed as esophageal foreign body]. PMID- 26121844 TI - [Laryngeal obstruction caused by giant thyroglossal duct cyst: one case report]. AB - Thyroglossal duct cyst is the most common congenital malformation of the neck. It is generally with non-specific symptoms. In our hospital, one case of laryngeal obstruction caused by giant thyroglossal duct cyst was cured, and this case was reported for reference. PMID- 26121845 TI - [One case report of nasal vestibule aggressive fibromatosis]. AB - The patient had found local uplift on the left nasal vestibule area for 3 years. An 2.0 cm x 1.0 cm mass was found on the left nasal vestibule area, which had tough texture, clear boundaries and no tenderness. In the operation, the tumor was found located between the left maxilla and major alar cartilage with no capsule and unclear boundary. The tumor is aggressive fibromatosis, which has invasive growth in adjacent muscle tissue. Immunohistochemical results: Ki-67, Vimentin(+), SMA(+), CD31(+), CD34(+), CK(-), Desmin (-), S-100(-), LCA(-). DIAGNOSIS: Aggressive fibromatosis. PMID- 26121846 TI - [One case of nasal Kaposiform hemangioendothelioma]. AB - Female patients, 41 years old, with the left nasal cavity bleeding intermittently and left nasal congestion 20 days as the chief complaint to the hospital. Physical examinationindicated dark red mass was at the front-end of left nasal cavity, which has not smooth surface with blood vessels and hemorrhagic secretions, and back up to the middle turbinate. Sinus enhancement 3D-CT showed soft tissue density can be found in the left nasal cavity,Scan CT value is 37-47 HU, and enhanced and delay is about 69-78 HU. Nasal septum,middle turbinate and inferior turbinate bonewas visible damage. The pathologic biopsy of left nasal cavity lesions results conform to the Kaposiform hemangioendothelioma. PMID- 26121847 TI - [Two cases of synovial sarcoma in the head and neck]. AB - Synovial sarcoma is a malignant soft tissue with unknown origin. Although head and neck region is the second common site of involvement, rare cases have been reported in Para nasal sinus and larynx. We presented two cases of synovial sarcoma, one of which arised from maxillary sinus and the other from laryx, and re- view the literature to sum up the diagnosis and treatment strategies. The conclusion is that synovial sarcoma in the head and neck still raises diagnostic and therapeutic issues. Surgical excision with wide margins is essential and necessary, usually associated radiotherapy. The effect of chemotherapy remains to explored. PMID- 26121848 TI - [The clinical significance of the Delphian lymph node metastasis in papillary thyroid carcinoma]. AB - Thyroid cancer is one of the commonest head and neck cancer. According to the recent research, VI lymph nodes (also called the front area, including thyrocricoid lymph nodes, tracheal surrounding lymph nodes, thyroid surrounding lymph node,recurrent laryngeal nerve lymph nodes, retropharyngeal lymph nodes) is the most common site of involvement in the differentiated thyroid carcinoma. Thyrocricoid lymph nodes known as the Delphian lymph node(DLN) is located between the thyroid cartilage and the cricoid cartilage. The DLN is one of the most accurate predictor. This paper reviewed the clinical significance of the DLN, the role of DLN metastasis in papillary thyroid cancer, and the relationship between tumor size, multicentricity and DLN metastasis. We also discussed the association between DLN metastasis and additional central compartment metastasis, as well as lateral compartment metastasis. PMID- 26121849 TI - [The research progress of relationship between the obstructive sleep apnea hypopnea syndrome and asthma]. AB - Obstructive sleep apnea hypopnea syndrome (OSAHS) is characterized by repeated episodes of upper airway obstruction that results in brief periods of breathing cessation (apnea) or a marked reduction in airflow (hypopnea) during sleep. Asthma is a chronic inflammatory disease of the airways characterized by revesible air-flow obstruction and bronchial hyperresponsiveness. This article reviewed related reseaches progress of relationship between the obstructive sleep apnea hypopnea syndrom and asthma in the vascular endothelial growth factor, systemic inflammation, leptin, obesity, gastroesophageal reflux disease and upper airway diseases, excessive daytime sleepiness and asthma control. PMID- 26121850 TI - [Effect of Pulsed Electromagnetic Fields on Osteogenic Differentiation and Wnt/beta-catenin Signaling Pathway in Rat Bone Marrow Mesenchymal Stem Cells]. AB - OBJECTIVE: To investigate the effect of pulsed electromagnetic tields (FEMFs) on osteogemc differentiation and Wnt/beta-catenin signaling pathway in rat bone marrow mesenchymal stem cells (BMSCs). METHODS: Rat BMSCs were isolated and the passage 3 cells were divided into 3 groups. Cells were cultured in LG-DMEM complete medium for 1 d to ensure fully adherent. Then, change the medium. Cells were maintained in complete medium (Control group) or in osteo-induction medium (OM group). The cells in PEMFs group were cultured in complete medium and exposed to 8 Hz, 3. 8 mT PEMF stimulation for 40 min/d. The intervention lasted for 21 d. Cell proliferation activity was determined by using MTT. The effects of PEMF onosteogenic differentiation were assessed by ALP and Alizarin Red S staining. Various osteoblast-relevant genes and genes of Wnt/beta-catenin signaling were analyzed by quantitative real-time RT-PCR. RESULTS: We. found that OM could significantly promote the proliferation of BMSC at 7 d, 14 d, 21 d (P<0. 05), but the effect was not obviously found in PEMFs group. For osteogenic differentiation, the positive rates of ALP or Alizarin Red S staining were detected higher in PEMFs/ OM group (P < 0. 05). Quantitative RT-PCR revealed PEMFs or OM could increase mRNA levels of Wnt1, Wnt3a, LRP5, beta-catenin, BMP-2, Runx2, ALP, OC at special time point (P<0. 05). Compared to OM group, PEMFs have a lower expression in each detection, but the trends were consistent. CONCLUSION: PEMFs (8 Hz, 3. 8 mT) could induce the osteogenic differentiation of rat BMSCs via activating Wnt/beta-catenin signaling pathway. PMID- 26121851 TI - [The New Bacteria Expressing Recombinant Multi-epitope Vaccine against Helicobacter pylori and Its Microbiological Characteristics]. AB - OJECTIVE: To construct the engineering bacteria with recombinant plasmid expressing the multi-epitope vaccine which composed of Helicobacter pylori urea membrane channel protein (UreI), Helicobacter pylori urease B subunit (UreB) and cholera toxin B subunit (CTB), and then to study it's microbiological characteristics. METHODS: The sequence contains some dominant epitopes of Helicobacter pylori UreI and UreB was designed, and ctB was added at the N terminal, all the sequence were linked by flexible linkers. Codon optimization was done according to Escherichia coli (E. coli) BL21 (DE3) bias, the optimized sequence was designated BIB. BIB sequence was synthesized and cloned into plasmid pET28a(+). The recombinant plasmid was confirmed by restriction enzyme digestion and DNA sequencing. The recombinant protein BIB was expressed in E. coli BL21 (DE3) and analyzed by Western blot. RESULTS: The plasmid of pET28a(+)/BIB was constructed successfully, confirmed by restriction enzyme digestion and DNA sequencing. The recombinant protein BIB with relative molecular mass about 33 x 10(3) could be produced by E. coli BL21 (DE3) and was detected by Western blot. The relative molecular mass and N-terminal amino acid sequence of BIB were 100% identity with the design. CONCLUTION: The engineering bacteria with recombinant plasmid expressing the multi-epitope vaccine against Helicobacter pylori was constructed successfully. The recombinant protein BIB can be identified by anti Sydney strain 1 of Helicobacter pylori (H. pylori SS1) polyclonal antibody and anti-CTB monoclonal antibody, which demonstrated that BIB has the expected antigenicity. PMID- 26121852 TI - [Prokaryotic Expression of Rv0757 Gene in Mycobacterium tuberculosis and the Effect of Its Coding Protein on the Function of Macrophage]. AB - OBJECTIVE: To construct recombinant plasmid pET28a-Rv0757 with Mycobacterium tuberculosis (Mtb) Rv0757 gene, and to determine the effect of the protein of Rv0757 gene on ANA-1 cells. METHODS: We recombined the amplified Rv0757 gene into theprokaryotic plasmid pET28a (+). The expressed product was identified by SDS PAGE and Western blot. Murine macrophages were treated with purified protein PhoP. Survived cells, lactic dehydrogenase (LDH), nitric oxide (NO), and cell apoptosis were detected after the treatment. RESULTS: We successfully constructed the recombinant plasmid pET28a-Rv0757. The target protein was confirmed by SDS PAGE and Western blot. The protein had no significant effect on cell numbers and LDH activities in the culture supernatant, but it inhibited the release of NO and apoptosis of ANA-1 cells. CONCLUSION: pET28a-Rv0757 plasmid with prokaryotic expression was successfully constructed. The targetprotein has no toxicity on macrophages, but it can inhibit NO release and cell apoptosis of ANA-1. PMID- 26121853 TI - [Construction of BAD Lentivirus Vector and Its Effect on Proliferation in A549 Cell Lines]. AB - OBJECTIVE: To construct the recombinant lentivirus expressing vector BAD (Bcl-2 associated death protein) gene and to study its effect on A549 cell proliferation. METHODS: The BAD gene was amplified from plasmid pAV-MCMV-BAD-GFP by PCR. The purified BAD gene fragment was inserted into a lentivirus vector (pLVX-IRES-ZsGreen 1), and the insertion was identified by PCR, restriction endonuclease analysis and DNA sequencing. A549 cells were then transfected with the packaged recombinant lentivirus, and resistant cell clones were selected with flow cytometry. The expression of BAD in A549 cell lines stably transduction with a lentivirus was examined using Western blot. The effect of BAD overexpression on proliferation of A549 cells was evaluated by using CCK-8 kit. RESULTS: Restriction enzyme digestion and DNA sequencing showed that the full-length BAD gene (507 bp) had been successfully subcloned into the lentiviral vector to result in the recombinant vector pLVX-IRES-ZsGreen 1. Monoclonal cell lines BAD A549 was produced after transfection with the recombinant lentivirus and selected with flow cytometry. Stable expression of BAD protein was verified by Western blot. In vitro, the OD value in BAD group was significantly lower than that of control groups from 120-144 h (P<0. 05). CONCLUSION: A549 cell lines stably transduced with a lentivirus expressing the BAD gene had been successfully generated. In vitro, BAD overexpression significantly inhibited A549 cells proliferation. PMID- 26121854 TI - [Sodium Ferulate Attenuates Oxidative Stress Induced Inflammation via Suppressing NALP3 and NF-kappaB Signal Pathway]. AB - OBJECTIVE: To study the effects of sodium ferulate on inflammation in human lung epithelial cells (A549) under oxidative stress and itsinfluence onthe expression of inflammasome NACHT-PYD-containing protein 3 (NALP3) and nuclear factor kappa B (NF-kappaB). METHODS: Human lung epithelial cells A549 cultured in vitro were divided into 4 groups, including control group, H2O2 (100umol/L) stress group, NF kappaB blockers group (PDTC 100 umol/L+ H2O2 100 umol/L), sodium ferulate (SF) intervention group (SF 400ug/mL+ H2O2 10umol/L). The expression of NALP3,IkappaBalpha protein were evaluated by Western blot, while mRNA levels of NALP3, NF-kappaB (P65) were measured by qRT-PCR. The level of interleukin-1beta (ILbeta1) were detected by ELISA. RESULTS: H2O2 not only increased the mRNA and protein expression levels of NALP3, but also enhanced the secretion of ILbeta1p in human lung epithelial cells A549 (P<0. 05) when compared with control group. NF-kappaB blockers PDTC and sodium ferulateresisted the effects of H2O2 on A549 cells, that decreased the mRNA and protein expression of NALP3 and the mRNA expression of NF-kappaB (P65), reduced the degeneration of IkappaBalpha and the secretion of IL-1beta (P<0. 05) when compared to H2O2 stress group. CONCLUSION: SF may reduce the expression of NALP3 and IL-1beta by inhibiting NF-kappaB, so as to reduce the inflammation caused by oxidative stress. PMID- 26121855 TI - [Effect of Chlorogenic Acid on Hepatic Stellate Cell Proliferation, Generation and Degradation of Extracelluar Matrix]. AB - OBJECTIVE: To investigate the effects of chlorogenic acid (CGA) on hepatic stellate cell proliferation and the expression and secretion of Collagen I, Collagen III, tissue inhibitors of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase-2 (MMP-2). METHODS: An immortalized rat hepatic stellate cell (HSC) line was cultured in vitro. The cells were divided into 5 groups: control group; platelet-derived growth factor (PDGF) (10 ng/mL), PDGF+CGA (12.5 ug/mL), PDGF+CGA (25 ug/mL), PDGF+CGA (50 ug/mL) and CGA (50 ug/mL) group. After 24 hours treatment, the proliferation of HSC was detected by MTT method. The mRNA expression of Collagen I, Collagen III, TIMP-1 and MMP-2 were detected by RT-PCR. The protein levels of Collagen I, Collagen III, TIMP-1 and MMP-2 in the culture supernatant of HSC were measured by ELISA. RESULTS: PDGF increased the hepatic stellate cell proliferation, the mRNA expression and the protein levels of Collagen I, Collagen III and TIMP-1. (P < 0.05), which were significantly decreased by CGA (P < 0. 05). However, CGA had no significant influence on the expression of MMP-2. CONCLUSION: The antifibrotic effect of CGA may be related with the inhibition of hepatic stellate cell proliferation and generation of extracelluar matrix and promotion of extracelluar matrix degradation. PMID- 26121856 TI - [Effect of Phellinus Polysaccharide on Canonical Wnt Signaling in Synovium in Rats with Rheumatoid Arthritis]. AB - OBJECTIVE: To investigate the role of Phellinus Polysaccharide (FPS) in activating canonical Wnt signaling in rats with rheumatoid arthritis (RA). METHODS: Male SD rats were randomly divided into three groups (normal group, RA model group and PPS treated RA group), each with 10 rats. The RA model rats were prepared through intradermal injection of 0. 1 mL complete Freund's adjuvant into the right rear toes of the rats. The PPS treated RA rats were given 50 mg/kg PPS by gavage eight days after the introduction of RA. All rats were evaluated with arthritis score and paw swelling score at day 16, 20, 24, 28, 32. At day 28, the expressions of fibronectin gene, Wnt signal pathway negative regulation gene SFRP1,2 and Wnt key gene beta-catenin, C-myc, and ccndl were detected by real time qPCR. RESULTS: PPS significantly reduced the arthritis score and paw swelling score of RA model rats. Lower levels of expression of SFRP1, 2 and higher levels of expression of beta-catenin, C-myc, ccndl and fibronectin were found in the RA model rats compared with the normal controls. PPS increased the expression of SFRP1, 2 and decreased the expression of beta-catenin, C-myc, ccndl and fibronectin in the RA rats. CONCLUSION: PPS has significant therapeutic effect on RA model rats through inhibiting canonical Wnt signaling. PMID- 26121857 TI - [The Role of 5-Aza-CdR on Methylation of Promoter in RASSF1A Gene in Endometrial Carcinoma]. AB - OBJECTIVE: To explore the effect of demethylating drug 5-Aza-2'-deoxycytidine (5 Aza-CdR) on methtylation status of the Ras-association domain familylA gene (RASSF1A) in human endometrial carcinoma. METHODS: Randomly'assign the human endometrial carcinoma cell line HEC-1-B into groups and use demethylating drug 5 Aza-CdR of different concentration to treat them. Then Methylation-specific polymerase chain reaction (MSP), real-time PCR, Western blot, TUNEL technology were used to analyze methylation status of RASSF1A promoter CpG islands, RASSF1A mRNA expression, RASSF1A protein expression and apoptosis of HEC-1-B cell. RESULTS: High DNA methylation in RASSF1A gene promoter region, low RASSF1A mRNA level and protein expression and out of control of human endometrial carcinoma cell HEC-1-B apoptosis were observed. 5-Aza-CdR of different concentration could reverse RASSF1A gene's methylation status, recover the expression of mRNA and protein, and control the growth of HEC-1-B by inducing apoptosis. CONCLUSION: Aberrant methylation of RASSF1A in endometrial cancer as a therapeutic target, demethylating agent 5-Aza-CdR could be an effective way of gene therapy. PMID- 26121858 TI - [S-Adenosylmethionine Inhibits Expression of Vascular Endothelial Growth Factor-C Protein and Cellular Proliferation in Gastric Cancer]. AB - OBJECTIVE: To explore inhibitory effects of S-adenosylmethionine on vascular endothelial growth factor-C (VEGF-C) protein and cellular proliferation in gastric cancer by regulating methylation status of VEGF-C promoter. METHODS: MTT analyses and nude mice model were employed to examine the effects of S- adenosylmethionine on inhibiting gastric cancer growth in vitro and in vivo. The protein expression of VEGF-C in gastric cancer cells was assessed by Western blot. The methylation status of VEGF-C promoter was assessed by bisulfite genomic DNA sequencing analysis. RESULTS: VEGF-C promoter was hypomethylated in MGC803 and SGC7901. The treatment of S-adenosylmethionine resulted in a heavy hypermethylation of VEGF-C promoter, which consequently down regulated protein level of VEGF-C. S-adenosylmethionine effectively inhibited the growth of gastric cancer cells in vitro and in vivo (P<0. 05). CONCLUSION: S-adenosylmethionine can effectively reverse DNA hypomethylation on VEGF-C promoter which down-regulates VEGF-C protein expression and inhibit gastric cancer growth. PMID- 26121859 TI - [Effects of 18beta-glycyrrhetinic Acid on the Expression of CCL11, AQP1 and EOS in Nasal Mucosa of Allergic Rhinitis Rats]. AB - OBJECTIVE: To investigate the effects of 18beta-glycyrrhetinic acid (GA) on the expression of eotaxin 1 (CCL11), aquaporin protein 1 (AQP1) and eosinophil (EOS) in nasal mucosa of allergic rhinitis (AR) rats. METHODS: Seventy six Wistar rats were randomly divided into 4 groups, normal control (NC) group, AR model (AR) group, loratadine (LOA) group and 18beta-GA group. All the mice in AR, LOA and 18beta-GA groups were sensitized intraperitoneally with OVA and AL(OH), from day 1-14, then induced by intranasal administration with OVA from day 14-21, while the mice in NC group were sensitized with saline. The mice in both LOA and 18beta GA group were given LOA and 18beta-GA once a day respectively from the 21 d, while the mice in AR and NC groups were administrated with saline. At the end of 1 week, 2 weeks and 3 weeks, the behavioral changes of mice were observed and recorded, the level of CCL11 mRNA was measured by RT-QPCR, and AQP1 expression was investiaged by SP staing. EOS in nasal mucosa was studied with the methods of HE staining. RESULTS: Compared with NC group, AR group showed typical AR symptoms. With the treatments, AR symptom scores and the expression levels of CCL11, AQP1 and EOS in nasal mucosa were improved significantly (P<0. 05). When compared with AR group, the above statistics in LOA group were down-regulated evidently at different points in time (P<. 05). At the end of 1 week, the above detection results in 18beta-GA group were lower than those in AR group (P<0. 05). At the end of 2 weeks, those parameters approached to the levels of LOA and NC group significantly. CONCLUSION: 18beta-GA administration could down-regulate the expression levels of CCL11, AQP1 and EOS in nasal mucosa of allergic rhinitis rats and cast effects on inhibiting the progress of AR. PMID- 26121860 TI - [Cariporide Pretreatment Attenuates Lung Ischemia-Reperfusion Injury in Rabbits]. AB - OBJECTIVE: To explore the effects of selective Na+/H+ exchanger antagonist Cariporide on ischemia-reperfusion induced lung injury. METHODS: Twenty four New Zealand White rabbits with lung ischemia-reperfusion model were established and randomly divided into four groups (n=6 per group) including sham group (S group), ischemia-reperfusion group (IR group), low potassium dextran group (LPD group) and Cariporide group (HOE group). Blood and lung tissue samples were obtained for blood gas, biochemical analyses and histologic examination. RESULTS: Systemic administration of HOE increased oxygenation index (arterial oxygen tension/fraction of inspire oxygen, PaO2/FiO2) and superoxide dismutase (SOD) activities, while decreased malondialdehyde (MDA) contents, proinflammatory cytokines and natrium hydrogen exchanger-1 (NHEI) expressions, along with the reduction of lung water content (LWC) except for histologic evaluation scores (P< 0. 05, versus IR group and LPD group). CONCLUSION: Systemic administration of Cariporide before ischemia could protects the lung from ischemia-reperfusion injury via decreasing NHE1 expression. The protective effect seems to be closely related to regulating intracellular calcium overload, oxidative damage and antioxidant enzyme activities and neutrophil infiltration. PMID- 26121861 TI - [Protective Effect of Activated Nrf2 against Hyperoxia-induced Lung Injury in Neonatal Rats]. AB - OBJECTIVE: To observe the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) agonist on the apoptosis of alveolar cell induced by hyperoxia and to explore whether Nrf2 activation could protect neonatal rats from hyperoxia induced lung injury. METHODS: 90 neonatal Sprague-Dawley rats were randomized into room air group (FiO2 =21%, N group), hyperoxia group (0 group) and Nrf2 group (n=30 each). Neonatal rats in the 0 group and Nrf2 group received saline 0. 2 mL and Nrf2 agonist 30 mg/kg respectively at the first and second day after birth, and were exposed in high concentration oxygen (95%) for 4 d. N group rats were fed in room air. The apoptotic index (AI) and Nrf2 expression of lung tissue were detected by TUNEL and immunohistochemistry staining respectively. RESULTS: Compared with 0 group (28. 8% +/- 3. 0%), the AI of alveolar. cell was lower in N group (0. 7%+/-0. 6%) and Nrf2 group (7. 2% +/- 0. 8%) (P<0. 01). The expression of Nrf2 was significantly higher in 0 group (926. 80 +/- 130. 51) and Nrf2 group (1038. 40+/-151. 12) than that in N group (30. 03+/-9. 99) (P<0. 01). CONCLUSION: Nrf2 activation could reduce the alveolar cellular apoptosis and protect neonatal rats from hyperoxia induced lung injury. PMID- 26121862 TI - [Genetic Polymorphisms in Wnt Signaling Pathway and Acute Leukemia]. AB - OBJECTIVE: To determine the impacts of Wnt signaling pathway products polymorphisms of rs4135385, rs11079571 and rs7832767 located in beta-catenin gene (CTNNB1), Axin gene (AXIN2), and secreted frizzled-related protein gene (SFRP1) on the risk and treatment outcomes of acute leukemia. METHODS: Bone marrows (volume 1-1. 5 mL) were collected from 372 untreated patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), and peripheral blood samples (2. 0 mL) were obtained from 401 healthy controls for the purpose of total DNA extraction. Polymorphisms of rs4135385, rs11079571 and rs7832767 located in CTNNB1, AXIN2 and SFRP1 were genotyped with high-resolution melting method (HRM). Chi-square analyses were performed to compare the genotype and allele distributions of the three single nucleotides (SNPs) between the leukemia patients and healthy controls. Single factor variance tests were performed to compare the differences in clinical features among different genotype groups. Complete remission (CR) rates after induction chemotherapy were also compared between different genotype groups using Chi-square tests. RESULTS: No significant differences were found beiween the leukemia patients and healthy controls in the frequencies of alleles and genotypes of CTNNB1 rs4135385, SFRP1 rs7832767 polymorphisms. Those with A allele in AXIN2 rs11079571 polymorphism was less likely to have acute myelomonocytic/monocytic leukemia than those with G allele (P = 0. 016, OR=0. 677, 95%CI:0. 439-0. 930). Acute bead monocyte/mononuclear cell leukemia (AML-M4/5)patients with AA genotype presented higher platelet count (P = 0. 040), and higher complete remission rate after chemotherapy (P = 0. 040), compared with the patients with AG and GG genotypes. CONCLUSION: AML-M4/5 patients have less frequency of A allele in AXIN2 rs11079571 polymorphism than healthy controls. Patients carrying A allele have higher platelet counts and higher sensitivity to chemotherapy. PMID- 26121863 TI - [The Methylation of p16 Gene Promoter in Carcinogenesis and Development of Breast Cancer]. AB - OBJECTIVE: To investigate the protein expression of the p16 gene and the methylation of its promoter in breast cancer, and to analyze the correlation between the p16 DNA methylation and the clinicopathological features. METHODS: Immuno-histochemistry technique (SP method) and methylation-specific-PCR (MSP) were used to detect p16 protein expression and the methylation of the p16 promoter in 47 breast cancer samples as well as in 20 hyperplasia samples of mammary glands. Results The p16 protein expression in breast cancer samples significantly lower when compared with those of hyperplasia samples (48. 9% vs. 70. 0%) and p16 methylation was more frequent in breast-tumor tissues when compared with those of hyperplasia samples (38. 3% vs. 20. 0%), but the statistical significance wasn't found (P> 0. 05). Down-regulation of p16 protein was negatively correlation with p16 gene hypermethylation (r= -0. 33, P =0. 02). Meanwhile, p16 methylation in breast cancer tissues correlated with histological type, lymph node metastasis, but not correlated with the age, tumor diameter, TNM stage, expression of estrogen receptor (ER) and progesterone receptor (PR) gene status. CONCLUSION: The downregulation of p16 protein induced by promoter methylation of p16 gene may not contribute to early cancinogenesis, but may contribute to progression of breast cancer. PMID- 26121864 TI - [Expression of USP9X in Non-small Cell Lung Cancer and Its Clinical Significance]. AB - OBJECTIVE: To investigate the expression and clinical significance of ubiquitin specific protease 9X (USP9X) protein in non-small cell lung cancer (NSCLC). METHODS: USP9X proteins were detected in 71 cases of NSCLC and 20 cases of benign pulmonary tissues by immunohistochemical staining. The correlation between USP9X expression and 51 NSCLC clinicopathological parameters as well as survival rates were indicated. RESULTS: Higher rate [69. 0% (49/71)] of the expression of USP9X was observed in NSCLC samples, compared with 20. 0% (4/20) in benign pulmonary tissues (P<0. 001). Furthermore, the expression of USP9X proteins was positively associated with both histological types and lymph node metastasis (P<0. 05). The survival analysis showed that the survival rate was lower in patients with positive expressions of USP9X than in patients with negative expressions (P< 0. 05). USP9X expression, together with histological types and TNM stage was an independent predictor for overall survival in the multivariate Cox regression model (P < 0. 05). CONCLUSION: Up-regulation of USP9X plays an important role in the invasion and progression of NSCLC and could be considered as a prognostic predictor for NSCLC. PMID- 26121865 TI - [The Antimicrobial Resistance Analysis of 73 Strains of Streptococcus pneumoniae Isolated from Infant Respiratory Tract]. AB - OBJECTIVE: To preliminary study of the resistance mechanisms of S. pneumoniae (S. pn) by determining the resistance rates and gene of S. pn isolated from the lower respiratory tract infection infants. METHODS: Drug susceptibility test with disk diffusion and broth micro-dilution was conducted to evaluate the resistance rates of 73 strains of S. pn isolated from the lower respiratory tract infection infants to penicillin, levofloxacin and other 10 antibiotics. PCR method was used to analysis the antimicrobial resistant genes tet M, mef A, erm A, erm B and int Tn of the isolates. RESULTS: The antibiotic resistance rates of the S. pn isolates to erythromycin, clindamycin and tetracycline were 95. 9%, 94. 5%, 87. 7% and 0% to vancomycin when tested with disk diffusion method. The antibiotic resistance rates of these isolates to penicillin, cefotaxime and ceftriaxone were 45. 2%, 47. 9% and 46. 6% respectively when tested with broth micro-dilution method. The carrier frequencies of tet M, mef A, erm A, erm B, int Tn genes in the 73 isolates were 91. 8%, 63. 0%, 58. 9%, 39. 7% and 61. 6% respectively. CONCLUSION: The S. pn strains isolated from infant respiratory tract in Chengdu perform a serious drug resistance problem, especially to routine antibiotics like erythromycin, clindamycin and tetracycline and cephalosporin, the resistance rate to levofloxacin, chloramphenicol remained at a low level; the resistance to tetracycline was closely related with the tet M gene fragment, the resistance to macrolide was mainly decided by active efflux pump and secondarily by the alternation of gene targeting, int Tn had close relation with tet M, erm B. PMID- 26121866 TI - [Relationship of Human Papillomavirus Subtypes and Multiple Infection with Different Cervical Precancerous Diseases in Sichuan Province]. AB - OBJECTIVE: To investigate the relationship of human papillomavirus (HPV) subtypes and multiple infections with different cervical precancerous diseases. METHODS: Retrospective study was done to review 1 226 patients with different cervical lesions who were pathologically diagnosed and scanned for HPV 23 subtypes with positive results from June 2006 to May 2012. These patients were divided into the following groups, chronic cervicitis, cervical condyloma, cervical intraepithelium neoplasia grade I (CIN I), grade II (CIN II), grade III (CINIII). RESULTS: There were significant differences in the proportion of HPV low risk types and high risk types between cervicitis, condyloma, CIN I group and CIN II + III groups (P<0. 05). HPV low risk types in condyloma group were mainly 6 and 11 subtype, while the other four groups were 42 and 43 subtype. The four most prevalence high risk types were 58, 16, 52,18 subtype. The infection rates of HPV16 were significant different in cervicitis (11. 0%), CIN II (20. 3%), and CIN III (20. 2%)(P<0. 01), and the infection rates of HPV58 was quite different between cervicitis (15. 9%) and CIN II (21. 4%) (P<0. 05). HPV multiple infection rate in condyloma (68. 8%) was significant different from that of cervicitis (23. 1%), CINI (26. 1%), CIN II (27. 8%) and CIN III (27. 1%) (P<0. 01); while the rest four groups were not significantly different (P>0. 05). CONCLUSION: There is a unique epidemiologic characteristic of HPV infection in Sichuan Province. The HPV low risk types were mainly 42 and 43, and high risk types were mainly 58, 16, 52, 18. It seems that HPV multiple infection is not the leading cause of progression of cervical disease. PMID- 26121867 TI - [Vestibular Dysfunction in Patients with Sudden Sensorineural Hearing Loss without Vertigo]. AB - OBJECTIVE: To observe the vestibular dysfunction in sudden sensorineural hearing loss (SSHL) patients without vertigo. METHODS: Forty-two cases of unilateral SSHL without vertigo were enrolled in the study from May 2012 to May 2014. All patients underwent air conducted sound elicited oVEMP and cVEMP respectively. Some of them also received caloric test. Sixty-two SSHL patients with vertigo and twenty-five age-and gender-matched normal subjects were recruited as controls to analyze the vestibular dysfunction in SSHL patients without. vertigo. RESULTS: Abnormal oVEMP was observed in 54. 8% affected ears without vertigo (23/42), 64. 5% ears with vertigo (40/62), and 26. 0% normal ears (13/50). Abnormal cVEMP was observed in 52. 4% affected ears without vertigo (22/42), 48. 4% ears with vertigo (30/62), and 14. 0% normal ears (7/50). Caloric test was operated in 21 SSHL patients without vertigo and 29 patients with vertigo. Abnormal caloric test was observed in 52.4% (11/21) SSHL patients without vertigo and 75. 9% (22/29) SSHL patients with vertigo respectively. Statistical significance was found in oVEMP and cVEMP rates between SSHL without vertigo and normal group (P<0. 01). However, no significant statistical difference was found in oVEMP, cVEMP rates and caloric test between SSHL without vertigo and SSHL with vertigo group (P>0. 05). CONCLUSION: Vestibular function could be damaged in SSHL patients without vertigo. The abnormal rates of oVEMP, cVEMP and caloric test in SSHL patients without vertigo were similar to that of SSHL patients with vertigo. The appearance of vertigo might be irrelevant to the range and extent of vestibular dysfunction. PMID- 26121868 TI - [The Cross-sectional Study on the Influence Factors for Encrustation of Double J Stent in Patients with Urolithiasis]. AB - OBJECTIVE: To study the influence factors for encrustation of double J stent in patients with urolithiasis. METHODS: In this study, there were 84 urolithiasis patients with double J stent included from February to July 2014 in our hospital. The encrustation on double J stent was evaluated by a PC stereo microscope. The nterrelated clinical data were obtained, then the factors which may affect the encrustation were studied by logistic regression analysis. RESULTS: The mean indwelling time was (17. 0+/-6. 0) d, and a thin encrustation formed on the stents for most cases [67/84(79. 8%)]. Compared with the cases who did not form a thin encrustation, those having a thin encrustation formation on the stent were younger [(44. 9+/-11. 5) vs. (54. 4+/-12. 6), P=0. 004]; The patients with proteinuria got a higher rate of encrustation [62/73(84. 9%) vs. 5/11 (45. 5%), P=0. 002]. The patients with urinary tract infection had a higher rate of encrustation [26/28(92. 9%) vs. 41/56(73. 2%), P 3. 035]. The patients with hematuriaalso got a higher rate of encrustation [67/80(83. 8%) vs. 0/4, P=0. 001]. Different sex, retention time,serum calcium,inorganic phosphorus, uric acid, urine pH,lithiasis component had no effects on encrustation (P>0. 05). Logistic regression analysis showed that age and proteinuria was retained as idependent correlated factors with encrustation (P<0. 05), while hematuria and urinary tract infections had a low ntensity correlation with encrustation (P>0. 05). CONCLUSION: For encrustation of double J stentin patients with urolithiasis, younger age, increased urinary protein, hematuria and infections are important risk-factors. PMID- 26121869 TI - [Childhood Overweight and Socioeconomic Status: Evidence from China]. AB - OBJECTIVE: To determine the prevalence of childhood overweight and its association with family socio-economic status (SES). METHODS: Data of children aged 7-18 years were extracted from the 1991-2009 China Health and Nutrition Survey. Childhood overweight was defined using criteria proposed by the China and International Obesity Task Force (IOTF). SES was measured with average household income per capita. The associations between SES and childhood body mass index (BMI) and overweight were analyzed by a multivariate linear regression model and a logistic regression model, respectively. RESULTS: A triple increase in household income and prevalence of childhood overweight was found during the period from 1991 to 2009. Increased household income was associated with increased childhood BMI. Children living in a low-income family were less likely to be overweight than those living in a high-income family [odds ratio (OR) = 0. 490, 95% confidence interval (CI): 0. 266, 0. 904]. CONCLUSION: Childhood overweight is associated with household income. Family intervention can help control childhood overweight problem in China. PMID- 26121870 TI - [Prevalence and Risk Factors of Major Depression Disorders in Local Teachers Three Months after Lushan Earthquake]. AB - OBJECTIVE: To determine the prevalence and risk factors of major depression disorder (MDD) in local teachers at an early stage post Lushan earthquake. METHODS: A prospective cohort study was undertaken, with 319 local teachers receiving diagnostic MDD assessment using MINI 14-22 d and 85-95 d after the earthquake, respectively. Possible predictive factors were identified using a self-developed questionnaire. Univariate and multivariate logistic regression analyses were performed to determine the predictors of MDD. RESULTS: Fifteen (4. 70%) local teachers were diagnosed with MDD. Those who had an injured direct relative [odds ratio (OR) = 6. 26], with inhabitable house (OR=4. 26), and felt easy to get sad 14-20 d weeks post earthquake (OR= 11. 45) were more likely to suffer from MDD than others. An anxious emotion 14-20 d post earthquake was a protective factor (OR=0. 14) of MDD. CONCLUSION: Post earthquake MDD in local teachers deserves concerns, especially for those who have injured relatives, with an inhabitable house, and who feel easy to get sad 14-20 d post earthquake. PMID- 26121871 TI - [A Survey of Maternal Dietary Behavior Based on Theory of Reasoned Action]. AB - OBJECTIVE: To detect the diet behavior and influencing factors of related behavior at different stages among pregnant women. METHODS: Based on the Theory of Reasoned Action (TRA), literature review, expert evaluation and preliminary investigation, we designed and finalized three questionnaires. Diet behaviors among women in early term, medium term and late term were investigated by using the questionnaires. RESULTS: 624 early term, 619 medium term and 738 late term valid questionnaires were returned. Participants ranged from 18 to 45 years of age. 74% pregnancy body mass index (BMI) was within the normal range. More than 43% care taking was provided by the mother, followed by the husband. The participants had a good eating behavior on the whole. At 3 stages, carbohydrate intake, protein intake and fat intake were no significant difference when compared with that of recommended value (P> 0. 05). The pregnant women intaked insufficient cereal, beans, dairy and aquatic products, while fruit and nuts were more than needed (P<0. 05). Subjective norms influenced their eating behavior indirectly through influencing their behavior attitude and behavioral intention. The attitude could influence behavior directly without involving the intention. CONCLUSION: The participants had relatively good diet behavior, but still had problems on food choice and a reasonable combination of a variety of food. Subjective norms influenced their behavior attitude and behavioral intention. The mother had the strongest influence on the pregnant woman's diet attitude and behavioral intention among all those had direct contact with the pregnant woman. PMID- 26121872 TI - [Affinity Detection and Quantification of Receptors of TRAIL Based on Their Thermostability]. AB - OBJECTIVE: To develop a way for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors quantification in cancer via its' thermostability. METHODS: Endougenous alkaline phosphatase (AP) activity and denaturation temperature of pancreatic cancer cell lines AsPC-1 and Capan-2 were detected. Boiling treated recombinant protein death receptor 5 (DR5), named DR5 AP, as well as pancreatic cancer cells lines AsPC-1 and Capan-2 were incubated with AP-tagged TRAIL (AP-TRAIL), and then reacted with Reagent A and Reagent S, the substrate of AP, to quantitive and in site detection of the receptor. RESULTS: The endougenous AP activity of pancreatic cancer cells lines AsPC-1 and Capan-2 could not be totally inactivated by incubated at 65 degrees C, thus inhibited the detection of TRAIL receptor, but the activity was dramatically decreased after treated with boiling water, whereas the DR5-AP was thermal stable. The surface receptor of AsPC-1 and Capan-2 could be recognized and bound by AP-TRAIL after treated at 100 degrees C, the readings were 2. 210+/-0. 393 and 2. 027+/-0. 019. CONCLUSION: The TRAIL receptors are thermostable and this may provide a better diagnosis and prognosis of cancer as well as personalize cancer therapy. PMID- 26121873 TI - [3D Reconstruction of PCL Based on MRI and CT Image Fusion]. AB - OBJECTIVE: To reconstruct three-dimensional (3D) image of posterior cruciate ligament (PCL) based on MRI and CT image fusion. METHODS: CT and MRI scans were performed on 12 knees of young men. The Dicom data were extracted and unified. The outline of PCL on MRI imaging was drew and plugged into the CT data. Finally, the visible 3D image of PCL with adjacent bones was reconstructed. The imaging anatomical measurements were examined and compared with those in published literature. RESULTS: Two cases were excluded from this study because of data deviations. The 3D visible reconstruction of PCL was proved to be feasible on the other ten cases. CONCLUSION: Three-dimensional visible reconstruction of PCL based on CT and MRI image fusion is feasible, which can provide support for individualized treatment of PCL injuries. Further simplification with increased accuracy may be needed. PMID- 26121874 TI - [Improving Threshold Segmentation in 3D Reconstruction of Mandible CT Image]. AB - OBJECTIVE: To develop a new threshold segmentation method for mandible image segmentation. METHODS: CT data of 12 volunteers were exported into Mimics 10. 01. An improved method usinga narrowed threshold range (the maximum threshold range that can segment mandible without manual efforts) was developed in 3D reconstruction, and compared with the traditional method. We used dilation operations to make up the information loss of image borders, by which we obtained an approxinate segment result. A precise segment resultwas eventually arrived with the help of logical operations and region growing. We compared mean time consumptions of the two methods, as well as their 3D reconstruction results using Geomagic Studio 11. 0. RESULTS: The new method generated a success rate of 91. 67% (11/12), with a mean time consumption of (319. 7+/-125. 3) s. The traditional method took much longer time [(1,261. 3+/-427. 3) s, P<0. 05] than the new method. Compared with the reconstruction results of traditional method, the new method had an outward deviation of (0. 066+/-0. 011) mm and an inward deviation of (0. 070+/-0. 008) mm. Such deviations were less than the minimum distance that a naked eye can discern. The lower limit of the widest threshold range which mandible could be isolated was (507. 72+/- 100. 31) HU, while the upper limit was (1,133. 33+/-47. 57) HU. CONCLUSION: The new method we proposed can improve the efficiency of threshold segmentation of mandible. PMID- 26121875 TI - [Comparison of Quantification of Myocardial Infarct Size by One Breath Hold Single Shot PSIR Sequence and Segmented FLASH-PSIR Sequence at 3. 0 Tesla MR]. AB - OBJECTIVE: To compare the two sequences [single shot true-FISP-PSIR (single shot PSIR) and segmented-turbo-FLASH-PSIR (segmented-PSIR)] in the value of quantification for myocardial infarct size at 3. 0 tesla MRI. METHODS: 38 patients with clinical confirmed myocardial infarction were served a comprehensive gadonilium cardiac MRI at 3. 0 tesla MRI system (Trio, Siemens). Myocardial delayed enhancement (MDE) were performed by single shot-PSIR and segmented-PSIR sequences separatedly in 12-20 min followed gadopentetate dimeglumine injection (0. 15 mmol/kg). The quality of MDE images were analysed by experienced physicians. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) between the two techniques were compared. Myocardial infarct size was quantified by a dedicated software automatically (Q-mass, Medis). RESULTS: All objectives were scanned on the 3. 0T MR successfully. No significant difference was found in SNR and CNR of the image quality between the two sequences (P>0. 05), as well as the total myocardial volume, between two sequences (P>0. 05). Furthermore, there were still no difference in the infarct size [single shot-PSIR (30. 87 +/- 15. 72) mL, segmented-PSIR (29. 26+/-14. 07) ml], ratio [single shot PSIR (22. 94%+/-10. 94%), segmented-PSIR (20. 75% +/- 8. 78%)] between the two sequences (P>0. 05). However, the average aquisition time of single shot-PSIR (21. 4 s) was less than that of the latter (380 s). CONCLUSION: Single shot-PSIR is equal to segmented-PSIR in detecting the myocardial infarct size with less acquisition time, which is valuable in the clinic application and further research. PMID- 26121876 TI - [Perinatal Management for Monochorionic Twin Reversed Arterial Perfusion Sequence]. AB - OBJECTIVE: To evaluate the perinatal managementof monochorionic twin pregnancies complicated by twin reversed arterial perfusion (TRAP) sequence. METHODS: A retrospectively study was performed on the management and perinatal outcome of monochorionic multiple pregnanciescomplicated by TRAP sequence at West China Second University Hospital from May 2010 to May 2014. RESULTS: Thirteen cases of TRAP sequence were identified during the study period, included 4 monochorionicmonoamniotic (MCMA) twins, 7 monochorionic diamniotic(MCDA) twins,1 monochorionic-triamniotic (MCTA) triplet pregnancy and 1 MCDA triplet pregnancy. Gestational age at diagnosis of TRAP sequence was from 11+5 to 31+6 gestational weeks in 12 cases. TRAP sequence was diagnosed by post-mortem examination in the case of MCDA triplet pregnancy transferred to our hospital with inevitable abortion at 21+3 weeks. 9 cases underwent conservative management. In the conservative management group, intrauterine death of the pump twin occurred in two MCMA twins and 7 cases delivered a healthy pump twin between 31+3 and 39+5 weeks of gestation. 2 cases were treated with bipolar cord coagulation of acardiac twin and delivered a healthy pump twin at 32+1 and 33+5 weeks of gestation. CONCLUSION: Early antenatal diagnosis of TRAP sequence is very important. Consultation with the parents is recommended as to the options of conservative management or intervention. Conservative management with close monitoring may be a safe option for TRAP sequence with a small acardiac twin. Bipolar cord coagulation of acardiac twin is a relatively safe and effective procedure in TRAP sequence with indications to intervention. PMID- 26121877 TI - [Two Methods of Internal Iliac Artery Exclusion in Endovascular Aorta Repair: a Middle-long Term Follow-up Study]. AB - OBJECTIVE: To compare the middle and long term results of two internal iliac artery exclusionmethods (with or without coils) in endovascular aorta repair (EVAR). METHODS: Clinical data of patients who underwent EVAR from January 2006 to December 2013 were analyzed retrospectively. The participants were divided into two group: coils were not used in Group A, but were used in Group B. The patients were followed up from June 2006 to June 2014. RESULTS: A total of 137 patients (74 in Group A, 63 in Group B) were included in this study, with a mean age of 71. 6 years. The majority (124) of participants were men. Postoperative 30 day mortality of the participants was 0. 73%. None of the participants developed pelvic and spinal ischemia. Claudication appeared in 9 patients (3 in Group A and 6 in Group B). Ischemia in lower extremity happened in 5 patients (2 in Group A and 3 in Group B). Gluteal sore was reported by 5 patients (1 in Group A and 4 in Group B). One patient from Group B developed gluteal skin necrosis. No statistical difference in ischemia and stent occlusion was found between the two groups (P=0. 301, P=0. 108). However, patients in Group B stayed in hospitals longer (P<0. 001) than those in group A. One patient in Group B developed severe ischemic complication: skin and gluteus necrosis. CONCLUSION: Internal iliac artery exclusions with and without coilsresult in similar middle and long term outcomes measured by ischemic complications. PMID- 26121878 TI - [Efficacy and Safety of Tiotropium Bromide in the Treatment of Chronic Obstructive Pulmonary Disease--a Multi-center Randomized Clinical Trial]. AB - OBJECTIVE: To investigate the efficacy and safety of domestic tiotropium inhalation capsule in patients with chronic obstructive pulmonary disease (COPD) with multi-center randomized clinical trial. METHODS: Patients with stable slight to moderate COPD were randomized into trial group (n=109) with tiotropium 18 pg Qd or control group (n =111) with ipratropium 40 ug Qid for a treatment of four weeks. The spirometry and scoring questionaire were recorded at different visits during the treatment. Rescue medication consumption and adverse events were recorded. Results Forced expiratory volume in 1 s (FEV1) of both groups increased obviously 30 min and 3 h after first dosing. After four weeks treatments, FEV, and forced vital capacity (FVC) in both groups were improved obviously, and the improvement in tiotropium group was significantly higher than that ipratropium group. COPD symptom scores were significantly reduced in both groups, and the improvement in tiotropium group was significantly better than that in ipratropium group. There was no significant difference in rescue medication consumption between the two groups. The ratios of adverse events were 22. 02% and 15. 32% in tiotropium and ipratropium group, respectively (P=0. 23). CONCLUSION: Domestic tiotropium inhalation capsule is efficient and safe in the treatment of COPD. PMID- 26121879 TI - [Learning versus teaching. The new role of schools]. PMID- 26121880 TI - [DECREASE OF DEHISCENCE AND OTHER COMPLICATIONS IN THE USE OF PERIPHERAL VENOUS LINES IN POST-OPERATIVE HEPATO-BILIARY AND VASCULAR SURGERY THROUGH THE USE OF NOBECUTAN(r) AEROSOL]. AB - Peripheral venous canalization, its surveillance and maintenance is realized by nurses with a diagnostic or therapeutic purpose. In the surgery unit was observed frequent appearances of phlebitis, extravasations or dehiscence in the point puncture. In order to increase the quality cares and patient safety, it was searched for new guidelines for preventing or minimizing applications using Nobecutan(r) aerosol as a new technical and material to fix. It was selected by its characteristics: adhesive layer (helps to fix), elastic, transparent (allows to visualize insertion point), permeable and sealing material. It was intended to open up a new field to realize new studies and to implement new procedures by means of a randomized cross-sectorial descriptive study. The objectives were: reduce catheter changes, avoid dehiscence, reduce phlebitis, get a better fixation and determine Nobecutan(r) effectiveness to prevent complications. With obtained data, a data base was designed and analyzed by statistical software SPSS version 19.0 for Windows. According to obtained results and after discussion, it was concluded to apply Nobecutan(r) to decrease dehiscence in the insertion point and the numbers of intravenous lines changes during admittance. It wasn't found beneficial influence to phlebitis. PMID- 26121881 TI - [WOMEN AND RETIREMENT: KNOWLEDGE OF THE TRANSITION OF RETIREMENT OF WOMEN]. AB - OBJECTIVE: To describe the transition involved in the retirement process for women who have worked in the Barcelona work context. DESIGN: Methodology qualitative, exploratory study. LOCATION: The study was carried out in Barcelona, between the years 2008-2011. PARTICIPANTS: Users of health centers that serve two profiles by type of work activity developed as managers and technical, or professional activity with little or no autonomy. MAIN INTERVENTTON: A technique discussion group was used until narratives did not add significantly to the information available. Transcription, analysis, coding, categorization, and content analysis to obtain the results. RESULTS: The results reflected differences between these profiles involved in the sample when analyzing data related to the meaning of their working lives, expectations of retirement, the motives which determine it, their health during the initial period and their adaptation to retirement. There were many similarities and few differences when analyzing family responsibilities/ workloads before and after retirement. CONCLUSIONS: These were based on the results described of the two distinct typologies of transition to retirement among women involved in the study in accordance with their profile of working life (the description used concepts and elements which model the Meleis Transition Theories as its basis). Some aspects of their experiences and needs are also stressed which, from a nursing perspective, lead to the identification of ambits, means of intervention which enable them to prepare and address this transition in a healthy way. PMID- 26121882 TI - [CONTROL OF FETAL WELL-BEING: BIOPHYSICS ANTEPARTUM MONITORING]. AB - This article provides an update on the control of antepartum fetal well-being, including the biophysical monitoring with non-stressful and stressful test and its evaluation. The fetal heart rate--base line, variability and transitional increases in fetal heart rate--are described based on fetal movements, its clinical meaning and actions derived from it. PMID- 26121884 TI - [CROHN'S DISEASE PATIENTS' SATISFACTION WITH COLONOSCOPY VERSUS ENTERO MAGNETIC RESONANCE IMAGING (MRI)]. AB - OBJECTIVES: To evaluate satisfaction and preferences in Crohn's disease patients who have undergone a colonoscopy (CL) and a MRI colonography (MRI). As well as evaluate the effectiveness of the information system to collect the data. METHOD: A sectional pilot study conducted through a satisfaction survey questionnaire for patients diagnosed with Crohn's disease (CD). Study patients were selected from the Gastroenterology Department in the Principe de Asturias University Hospital, where both the colonoscopy and the entero magnetic resonance imaging tests were done from the 1st of January to the 30th of June 2012. Surveys were conducted during July and August 2012. RESULTS: A total of 48 patients with Crohn's disease participated. Out of these, 24 were women and 24 were men. The mean age was 43 years (SD: 13.8). The worst score was obtained at the time of preparation for both procedures. If patients could choose they would prefer CL 23, 16 MRI and 9 were indifferent. CONCLUSIONS: The patients' preference for CL could be due to the administration of sedatives prior to the procedure. A procedure such as the CL which initially may result unpleasant for the patient is tolerated much better as a result of the sedation. In both tests, the preparations prior to the procedures are perceived as unpleasant. We will think about how to improve patients' tolerance to these preparations, maybe by giving more information as patients, because we don't know often how to do it properly, which could magnify this unpleasant perception. PMID- 26121883 TI - [DESCRIPTIVE STUDY OF DRUGS OF ABUSE IN THE COMPLEJO HOSPITALARIO DE JAEN]. AB - Drugs is, according to the World Health Organization (WHO), any substance introduced into a living organism by any route is capable of acting on the central nervous system. For decades, drug abuse has increased in the population of our country but not all drugs are an illegal drug. OBJECTIVES: The overall objective is the description of testing for drugs of abuse, and their distribution, as they were made in the Hospital Medico-Quirurgico (HMQ) and Neurotraumatologico (HNT) of the Hospital of Jaen, in 2012. Secondary objectives analyzed the differences in the tests as variables: sex, months of the year and age of the subject (patient). METHODOLOGY: We carry a description of differences by type of drug and associations of two, three, four or five drugs at once and finally, we study differences detected by drug or therapeutic use is illegal (of abuse). RESULTS: The results indicate a positive per 300 inhabitants, mostly men, adults and Hospital Neurotraumatologico. The most commonly detected drugs are benzodiazepines, alone or in association with cannabis. PMID- 26121885 TI - [SYSTEMATIZATION, ORDER AND SECURITY AS A RESULT OF THE NURSE ASSESSMENT IN PAEDIATRIC EMERGENCY: A METAMORPHOSIS PROCESS]. AB - OBJECTIVE: To determine from the health care professionals perspective the impact on clinical practice of incorporating an assessment tool for primary care paediatric emergency. METHOD: Qualitative study based on the collection of written documents. Twenty-four wide and detailed documents were collected. Thematic analysis was used. RESULTS: Participants were 9 nurses and 7 paediatricians, all with experience in the Paediatric Emergency Department. The results are grouped into three areas: perception of previous situation; benefits perceived; difficulties of the change process related to the triage instrument. The benefits perceived include the achievement of the objectives related to triage as well as collateral benefits for the organization and distribution of structural resources, adequacy of human resources, self-assessment and professional recognition, improvement of team communication and users service perception. The difficulties identified are related to the feasibility of using this instrument when patient flow is high and to the need of specialized training. CONCLUSIONS: All participants perceived more benefits than disadvantages, and both nurses and paediatricians experienced the process as a positive experience. The introduction of the assessment tool had a broader impact than expected. PMID- 26121886 TI - [COMMUNICATION WITH TERMINALLY ILL PATIENT]. AB - The communication is a essential therapeutic instrument in every process of relationship in the team patient-family, and mainly in the transmission of bad news. The communication is not just a simple transmission of information. It is a process whose goal is to enable the adaptation of the patient and family to their actual situation and where the "what", "how" and "how much do you want to know", are belonged to the own patient. Along this article, we will expose some thoughts that the team has to take into account when informing the patient. We are going to explain the SPIKES protocol, or its Spanish version EPICEE. 6-step protocol, based on those recommended by the experts to deliver bad news procedures. And finally we'll talk about the conspiracy of silence, one of the most common and difficult situations to handle in day to day due to paternalism by professionals and families, in which they prefer to hide the situation to the patient, thinking it's the best for him. PMID- 26121887 TI - [Diet and nutrition in the palliative care patient]. PMID- 26121888 TI - "ROUTINE" PREOXYGENATION. PMID- 26121889 TI - THE IMPACT OF ENDOTRACHEAL TUBE VS. LARYNGEAL MASK AIRWAY ON THE INCIDENCE OF POSTOPERATIVE NAUSEA AND VOMITING: A SYSTEMIC REVIEW AND META-ANALYSIS. AB - OBJECTIVE: To investigate the impact of Endotracheal tube (ETT) vs. Laryngeal Mask Airway (LMA) on postoperative nausea and vomiting (PONV) in patients undergoing surgery with general anesthesia. METHODS: Key words searching from databases such as Medline, Embase, and Cochrane library provided 14 studies focusing on the use of EET vs. LMA for general anesthesia. Pooled estimate of relative risk with 95% confidence interval using random effect model was conducted. RESULTS: 14 studies were selected for meta-analysis with a total of 1866 patients. 9 studies focused on the outcome of PONV in adult patients. It showed incidence of PONV with of LMA and ETT in adult of about 204/690 (30%) and 145/725 (20%) respectively with [Odds Ratio (OR) = 1.69, 95% CI, 0.76-3.75, P = 0.20]. Heterogeneity was high (I2 = 87%). Five studies focused on the outcome of PONV in pediatric patients with PONV in LMA and ETT group of 85/229 (37%) and 72/222 (32%) respectively with (OR = 1.30, 95% CI, 0.61-2.76, P = 0.50). Heterogeneity was moderate at (I2 = 53%). When all patients were combined heterogeneity was high at 81% with OR = 1.56, 95% CI, 0.87-2.79, P = 0.14. CONCLUSION: Risk of PONV shows an increase trend toward the use of LMA. Larger randomized trials are needed to assess the impact of airway devices on PONV. PMID- 26121890 TI - RENAL PROTECTION IN THE CARDIAC SURGERY PATIENT: PERI-OPERATIVE SODIUM BICARBONATE INFUSION (POSBI) OR NOT? AB - BACKGROUND: Acute renal failure following cardiac surgery is not uncommon and carries a high level of morbidity and mortality. The aim of our study was to determine whether perioperative sodium bicarbonate infusion (POSBI) would decrease acute kidney injury in cardiac surgery patients and improve post operative outcomes. METHODS: A retrospective analysis of 318 cardiac surgery patients from 2008-2011 was performed. Clinical parameters were compared in patients receiving POSBI versus sodium chloride. Serum creatinine levels were measured in the first five post-operative days. The primary outcome measured was the number of patients developing post-operative renal injury. Secondary outcomes included three-month mortality, intensive care unit and hospital length of stay. RESULTS: Patients given POSBI showed no significant differences compared to the normal saline cohort in regards to increases in serum creatinine [< 25% rise in Cr: 93% vs 94%; > 25% rise in Cr: 6% vs 6%; > 50% rise in Cr: 1% vs 1%; > 100% rise in Cr: 1% vs 0%, all with p-value > 0.99]. There were fewer patients with AKIN stage 1 renal failure receiving POSBI [8% vs 28%, p = 0.02] however there was no difference between POSBI and sodium chloride cohorts in AKIN stages 2 and 3 renal failure. Mortality, duration of hospitalization and ICU stay were not statistically significant. CONCLUSIONS: POSBI resulted in fewer patients developing AKIN stage 1 renal failure. Despite this, there appears to be little benefit in the prevention of acute kidney injury after 48 hours or mortality reduction in cardiac surgery patients. PMID- 26121891 TI - EFFECT OF ULTRASOUND-GUIDED SUBSARTORIAL APPROACH FOR SAPHENOUS NERVE BLOCK IN CASES WITH SAPHENOUS NERVE ENTRAPMENT IN ADDUCTOR CANAL FOR CONTROLLING CHRONIC KNEE PAIN. AB - BACKGROUND: Saphenous nerve neuropathy is one of the causes of chronic pain of the knee. Blockade of saphenous nerve under sonographich guide has been used for controlling pain in recent years. The goal of this study was to evaluate the effect of saphenous nerve block for controlling pain in patients with chronic knee pain. METHOD: Thirty five patients with chronic knee pain referred to Amir Alam hospital during June 2012-June 2013 were enrolled in this study. Under sonographic approach, subsartorial blockade of saphenous nerve conducted and patients were followed up for 3 months after treatment. Demographic data, ASA (American Society of Anesthesiologists) category, weight, height, complications of intervention and pain scores were recorded. RESULTS: In 54%, the NRS was zero 30 minutes after intervention. In one patient (2.8%) all NRSs were 0 after intervention. We observed no sensory dysfunction in enrolled cases. CONCLUSION: The result of current study showed that ultrasound guided subsartorial approach is moderately effective in blockade of saphenous nerve in cases with saphenous nerve entrapment in adductor canal for controlling chronic knee pain. PMID- 26121892 TI - COMPARISON OF THE EFFECTS OF ORAL VS. PERITONSILLAR INFILTRATION OF KETAMINE IN PAIN REDUCTION AFTER TONSILLECTOMY: A RANDOMIZED CLINICAL TRIAL. AB - BACKGROUND: Although oral ketamine has been used in some cases to reduce pain in children, the use of this drug to reduce pain after tonsillectomy has not been studied yet. METHODS: This double-blind clinical trial was conducted in 2009 in 92 children who were aged three to nine years old, met ASA I or II criteria, and were candidate for tonsillectomy. Patients were divided randomly into two groups. Half an hour before general anesthesia, 5 mg/kg ketamine mixed in 2 cc/kg apple juice was given to the children in oral ketamine group and 2 cc/kg of apple juice alone was given to the children in the peritonsillar group. After general anesthesia and three minutes before surgery 1 cc of 0.9% normal saline in the oral group and 1cc of ketamine (0.5 mg/kg) in the peritonsillar group was injected to the tonsil bed of patients. RESULTS: There was no difference between the two groups in terms of sex, age, and weight. Duration of surgery was significantly shorter in the peritonsillar group (P < 0.001) and the severity of postoperative bleeding was significantly higher in peritonsillar group (P = 0.022). However, postoperative bleeding recurred in 25 patients (27%) and there was no statistically significant difference between the two groups. The level of pain in children six hours after surgery according to CHEOPS criteria was significantly lower in the peritonsillar group (0.9 +/- 0.8) than in the oral group (2.6 +/- 1) (P < 0.001). CONCLUSIONS: The finding of this study showed that, compared with the peritonsillar infiltration of ketamine, the use of oral ketamine before general anesthesia was less effective in reducing postoperative pain of tonsillectomy in children. PMID- 26121893 TI - THE IMPACT OF ANESTHETIC TECHNIQUES ON COGNITIVE FUNCTIONS AFTER UROLOGICAL SURGERY. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a well-recognized complication of cardiac and noncardiac surgery. However, contradictory results concerning postoperative mental function have been reported. The aim is to determine the effect of anesthetic techniques (general or spinal) on cognitive functions using more sensitive neuropsychological tests in patients undergoing urological surgery. MATERIAL AND METHODS: A total of thirty patients were enrolled in the study and assigned to receive either general (n = 15) or spinal (n = 15) anesthesia. A battery of neuropsychological tests including Wisconsin Card Sorting Test, Iowa Gambling Task, Stroop Color-Word Test, N-back Task and Continuous Performance Test was performed preoperatively and three days later. RESULTS: The two experimental groups were similar at baseline assessment of cognitive function. Although there were no statistically significant differences between general and spinal anesthetic groups with respect to Wisconsin Card Sorting Test and Iowa Gambling Task, a significant intergroup difference between pre-and postoperative N-back scores was detected in the general anesthesia group (p = 0.001 & p = 0.004). In addition, patients within this group had significantly higher error rates on the Stroop Color-Word (p = 0.019) and Continuous Performance Tests (p = 0.045). In contrast, patients receiving spinal anesthesia exhibited little change or marginal improvement on all subscales of the battery. CONCLUSIONS: Our findings indicate significant decline in specific aspects of mental function among patients who were administered general anesthesia compared with the other technique. It seems that spinal anesthesia contributes to lower disturbance after surgery. PMID- 26121894 TI - COMPARISON BETWEEN C-MAC VIDEO-LARYNGOSCOPE AND MACINTOSH DIRECT LARYNGOSCOPE DURING CERVICAL SPINE IMMOBILIZATION. AB - BACKGROUND: Video-laryngoscopes have gained popularity in the recent years and have shown definite advantages over the conventional Macintosh direct laryngoscopes. However, there is still insufficient evidence comparing the C-MAC with the Macintosh for patients during manual inline stabilization (MILS). METHODS: This prospective, randomized, single blind study was carried out to compare tracheal intubation using the C-MAC video-laryngoscope and Macintosh laryngoscope in patients during MILS. Ninety consented patients, without features of difficult airway, who required general anesthesia and tracheal intubation were recruited. Intubation was performed with either the C-MAC video-laryngoscope or the Macintosh laryngoscope by one single investigator experienced with both devices. Various parameters which included Cormack and Lehane score, time to intubate, intubation attempts, optimization maneuvers, complications and hemodynamic changes were recorded over the initial period of 5 minutes. RESULTS: C-MAC video-laryngoscope performed significantly better with lower Cormack and Lehane grades, shorter time to intubate of 32.7 +/- 6.8 vs. 38.8 +/- 8.9 seconds (p = 0.001) and needed less optimization maneuvers. There were no significant differences seen in the intubation attempts, complications or hemodynamic status of the patients with either device. CONCLUSION: The C-MAC video-laryngoscope was superior to the Macintosh laryngoscope for patients requiring intubation when manual inline neck stabilization was applied. PMID- 26121895 TI - EFFECTS OF MEMANTINE ON PAIN IN PATIENTS WITH COMPLEX REGIONAL PAIN SYNDROME--A RETROSPECTIVE STUDY. AB - INTRODUCTION: Memantine was discovered in 1968 and is used as a treatment for Alzheimer's disease. We evaluated the use of memantine to treat complex regional pain syndrome in this retrospective study. PATIENTS AND METHODS: 56 patients with CRPS, who were treated with trial of memantine for at least two months with 40mg QHS from 2007 until 2009. RESULTS: 34 females and 22 male patients. Age-46.0 +/- 9.7 years. Number of years with CRPS-9.24 +/- 5.7 years. Mean age-46.0 +/- 9.7 years. Memantine was started at 5 or 10 mg QHS, before being increased by 5 or 10mg every 4-7 days, as tolerated, to a maximumdose of 40 mg - 60 mg, as tolerated. In all, 13 patients showed complete remission from CRPS with VAS 0 and the disappearance of allodynea for at least nine months after the use of memantine. In addition, 18 patients showed partial improvement of VAS and allodynea. Eight patients showed no improvement even after continuous use of memantine at a dose of 40 mg QHS for two months. Seven patients could not take more than 5 mg of memantine per day and had to stop it due to side effects. In terms of subjective improvement in short-term memory, nine patients showed much improvement, 14 patients showed some improvement, three patients showed no changes and one patient did not answer the questionnaire. Regarding subjective feelings of a having better quality of life, 17 patient answered yes, three did not feel any changes, six could not give an answer and two did not fill out the questionnaire. CONCLUSIONS: Memantine is a promising option for the treatment of CRPS. A randomised controlled study is needed to evaluate its efficacy. PMID- 26121896 TI - EFFECTS OF DEXAMETHASONE AND PHENIRAMINE MALEATE ON HEMODYNAMIC AND RESPIRATORY PARAMETERS AFTER CEMENTATION IN CEMENTED PARTIAL HIP PROSTHESIS. AB - PURPOSE: To prevent hemodynamic and respiratory changes that are likely to occur during cementation in partial hip prosthesis by prophylactic use of pheniramine maleate and dexamethasone. METHODS AND MATERIALS: The study included 40 patients aged between 60 and 85 years with an American Society ofAnesthesiologists (ASA) grade of II-III who underwent partial hip prosthesis. Just after spinal anesthesia, 4 mL normal saline was pushed in patients in Group S, whereas 45.5 mg pheniramine maleate and 8 mg dexamethasone mixture was pushed intravenously in a total volume of 4 mL in patients in Group PD. RESULTS: Amounts of atropine and adrenaline administered after cementation were significantly higher in Group S than in Group PD (P < 0.05). There was a significant difference between SpO2 values before and after cementation in Group S; SpO2 value was lower after cementation (P < 0.05) except for 1. min after cementation. SpO2 value increased 1 min after cementation (P = 0.031) CONCLUSION: Prophylactic use of pheniramine maleate and dexamethasone in partial hip prosthesis led to an increase in SpO2 value and a decrease in the utilization of adrenaline and atropine after cementation. PMID- 26121897 TI - EFFECT OF PREOPERATIVE ORAL PREGABALIN ON POSTOPERATIVE PAIN AFTER MASTECTOMY. AB - BACKGROUND: This was a randomized, double-blinded clinical trial to study the effects of a single oral dose of pregabalin 150 mg in postoperative pain management after mastectomy. METHODS: DESIGN: forty nine patients ASA I or II, aged between 20-60 years, scheduled for mastectomy with or without axillary lymph nodes dissection (ALND) were recruited into this study. They were randomized into two groups, placebo (n = 24) or pregabalin (n = 25) receiving either oral pregabalin 150 mg or placebo when called to operation theatre (OT). The assessment of pain score were performed at recovery, 2, 4, 6 and 24 hours postoperatively at rest and on movement, using the verbal numeral rating score (VNRS). RESULTS: VNRS scores for pain at rest were lower in the pregabalin group at 2 (p = 0.024), 4 (p = 0.006) and 6 (p = 0.003) hours postoperatively, and also at 4 (p = 0.005) and 6 (p = 0.016) hours postoperatively on movement compared to the placebo group. Incidences. of dizziness were common, however, side effects such as nausea and vomiting, headache, somnolence and visual disturbance were low and comparable in both groups. CONCLUSION: A single dose of 150 mg pregabalin given preoperatively compared to placebo significantly reduced postoperative pain scores after mastectomy. PMID- 26121898 TI - CONSUMPTION TRENDS OF RESCUE ANTI-PSYCHOTICS FOR DELIRIUM IN INTENSIVE CARE UNITS (ICU DELIRIUM) SHOW INFLUENCE OF CORRESPONDING LUNAR PHASE CYCLES: A RETROSPECTIVE AUDIT STUDY FROM ACADEMIC UNIVERSITY HOSPITAL IN THE UNITED STATES. AB - BACKGROUND: The etiology of delirium in intensive care units (ICU) is usually multi-factorial. There is common "myth" that lunar phases affect human body especially human brains (and minds). OBJECTIVE: In the absence of any pre existing studies in ICU patients, the current retrospective study was planned to investigate whether lunar phases play any role in ICU delirium by assessing if lunar phases correlate with prevalence of ICU delirium as judged by the corresponding consumptions of rescue anti-psychotics used for delirium in ICU. MATERIALS AND METHODS: After institutional review board approval with waived consent, the daily census of ICU patients from the administrative records was accessed at an academic university's Non-Cancer Hospital in a Metropolitan City of United States. Thereafter, the ICU pharmacy's electronic database was accessed to obtain data on the use of haloperidol and quetiapine over the two time periods for patients aged 18 years or above. Subsequently the data was analyzed for whether the consumption of haloperidol or quetiapine followed any trends corresponding to the lunar phase cycles. RESULTS: A total of 5382 pharmacy records of haloperidol equivalent administrations were analyzed for this study. The cumulative prevalence of incidents of haloperidol equivalent administrations peaked around the full moon period and troughed around the new moon period. As compared to male patients, female patients followed much more uniform trends of haloperidol equivalent administrations' incidents which peaked around the full moon period and troughed around the new moon period. Further sub-analysis of 70 lunar cycles across the various solar months of the total 68-month study period revealed that haloperidol equivalent administrations' incidents peaked around the full moon periods during the months of November-December and around the new moon periods during the month of July which all are interestingly the major holiday months (a potential confounding factor) in the United States. CONCLUSION: Consumption trends of rescue anti-psychotics for ICU delirium revealed an influence by lunar phase cycles particularly that of full moon periods on female patients in the ICU. PMID- 26121899 TI - THE USE OF PARAVERTEBRAL BLOCKADE FOR ANALGESIA AFTER ANTERIOR-APPROACH TOTAL HIP ARTHROPLASTY. AB - BACKGROUND: Anterior approaches for total hip arthroplasty (ATHA) are becoming increasingly popular. We postulated that the use of PVB of the T12, L1, and L2 roots would provide adequate analgesia for ATHA while allowing motor sparing. METHODS: The medical records of 20 patients undergoing primary ATHA were reviewed. T12, L1 and L2 paravertebral blockade was accomplished with 3-4 ml of 1% ropivacaine with epinephrine 1:200,000 and 0.5 mg/ml of preservative-free dexamethasone per level. Primary outcomes were mean opioid consumption in intravenous morphine equivalents and worst recorded visual analog scale (VAS) pain scores during postoperative days 0 to 2 (POD 0 to 2). RESULTS: Mean opioid consumption was 8.4 mg on POD0, 16.6 mg on POD1, and 9.8 mg on POD2. Median worst VAS scores were 2 for all time intervals except POD 0, which had a median value of 0. All patients had full hip motor strength the evening of POD0.19 patients were able to ambulate the afternoon of POD1. CONCLUSION: T12-L2 PVB, when utilized as part of a multimodal analgesic regimen, results in moderate opioid consumption, low VAS scores, preservation of hip motor function, and may be an effective regional anesthesia technique for ATHA. PMID- 26121900 TI - SUBTENON BUPIVACAINE INJECTION FOR POSTOPERATIVE PAIN RELIEF FOLLOWING PEDIATRIC STRABISMUS SURGERY: A RANDOMIZED CONTROLLED DOUBLE BLIND TRIAL. AB - BACKGROUND: Strabismus surgery in children is often associated with undesirable intraoperative and postoperative side effects including pain, postoperative nausea and vomiting (PONV), and occulocardiac reflex (OCR). Systemic analgesics have side effects and are contraindicated in some cases. We hypothesized that the preoperative subtenon injection of bupivacaine would reduce postoperative pain and the incidence of side effects adverse effects. METHODS: Sixty children (2 to 6 years of age, ASA status I to II) were randomized to receive either subtenon bupivacaine 0.5% or a saline injection before the beginning of surgery in a double-blind manner. Pain scores using the Face, Legs, Cry, Activity, and Consolability (FLACC) scale, incidence of OCR and PONV, requirement of additional systemic analgesia, and time to discharge from the recovery room were compared. RESULTS: The pain scores were significantly lower in the subtenon bupivacaine group at 0 min (p = 0.0056) and at 30 min (p = 0.013). There was no significant difference between the two groups at the other time intervals. There was a significant reduction in the incidence of occulocardiac reflex and the incidence of vomiting in the subtenon bupivacaine group. Eight of the 27 patients in the subtenon bupivacaine group required additional systemic analgesia compared to 19 of 29 controls. The time to discharge from recovery room was lower in the subtenon bupivacaine group. CONCLUSION: These data provide some evidence that a preoperative subtenon block with bupivacaine combined with general anesthesia allows efficient control of postoperative pain as well as a reduction in the incidence of OCR and PONV in young children undergoing strabismus surgery. PMID- 26121901 TI - STRAIGHT TO VIDEO: TONSILLAR INJURY DURING ELECTIVE GLIDESCOPE(o)-ASSISTED PEDIATRIC INTUBATION. AB - Airway management in pediatric patients presenting for tonsillectomy and adenoidectomy may prove challenging given the enlarged upper airway structures. Video Laryngoscopy (VL) can be very helpful but it does not come without risks. In this case report, we report an unfavorable outcome of VL in a pediatric patient with adenotonsillar hypertrophy. PMID- 26121902 TI - PERCUTANEOUS BALLOON COMPRESSION OF GASSERIAN GANGLION FOR THE TREATMENT OF TRIGEMINAL NEURALGIA: AN EXPERIENCE FROM INDIA. AB - Trigeminal neuralgia (TN) is characterized by unilateral, lancinating, paroxysmal pain in the dermatomal distribution area of trigeminal nerve. Percutaneous balloon compression (PBC) of Gasserian ganglion is an effective, comparatively cheaper and simple therapeutic modality for treatment of TN. Compression secondary to PBC selectively injures the large myelinated A-alfa (afferent) fibers that mediate light touch and does not affect A-delta and C-fibres, which carry pain sensation. Balloon compression reduces the sensory neuronal input, thus turning off the trigger to the neuropathic trigeminal pain. In this current case series, we are sharing our experience with PBC of Gasserian Ganglion for the treatment of idiopathic TN in our patients at an academic university-based medical institution in India. During the period of August 2012 to October 2013, a total of twelve PBCs of Gasserian Ganglion were performed in eleven patients suffering from idiopathic TN. There were nine female patients and two male patients with the age range of 35-70 years (median age: 54 years). In all patients cannulation of foramen ovale was done successfully in the first attempt. In eight out of eleven (72.7%) patients ideal 'Pear-shaped' balloon visualization could be achieved. In the remaining three patients (27.3%), inflated balloon was 'Bullet-shaped'. In one patient final placement of Fogarty balloon was not satisfactory and it ruptured during inflation. This case was deferred for one week when it was completed successfully with 'Pear-shaped' balloon inflation. During the follow up period of 1-13 months, there have been no recurrences of TN. Eight out of eleven patients (72.7%) are completely off medicines (carbamazepine and baclofen) and other two patients are stable on very low doses of carbamazepine. All patients have reported marked improvement in quality of life. This case series shows that percutaneous balloon compression is a useful minimally invasive intervention for the treatment of trigeminal neuralgia. PMID- 26121903 TI - BEDSIDE RETAINED RADIAL ARTERY CATHETER REMOVAL IN A HEMODYNAMICALLY UNSTABLE NEUROCRITICALLY-ILL PATIENT: A CASE REPORT. . AB - Radial artery insertion is a common procedure in intensive care units. We describe a case of a critically-ill 73-year-old man in the neurocritical care unit with a subarachnoid hemorrhage whose radial arterial catheter tip was transected from the main line and was successfully managed with bedside retrieval of the catheter. PMID- 26121904 TI - ESOPHAGEAL PERFORATION FOLLOWING OROGASTRIC SUCTION CATHETER INSERTION IN AN ELDERLY PATIENT. AB - Esophageal rupture has been described following iatrogenic manipulation. In this report, we present an elderly lady admitted to the operative theater for laparoscopic cholecystectomy. Multiple intra-operative attempts to place a flexible orogastric tube were unsuccessful because of failure to advance. Post operatively, the patient developed sepsis and a right pleural effusion. She was transferred to the Intensive Care Unit and she was treated with antibiotics. Radiologic evaluation confirmed an esophago-pleural fistula. Surgical repair was urgently performed for closure of fistula and lung decortication. The patient recovered and was discharged home. PMID- 26121905 TI - PEDIATRIC ENDOTRACHEAL INTUBATION. PMID- 26121906 TI - Models of lipid droplets growth and fission in adipocyte cells. AB - Lipid droplets (LD) are spherical cellular inclusion devoted to lipids storage. It is well known that excessive accumulation of lipids leads to several human worldwide diseases like obesity, type 2 diabetes, hepatic steatosis and atherosclerosis. LDs' size range from fraction to one hundred of micrometers in adipocytes and is related to the lipid content, but their growth is still a puzzling question. It has been suggested that LDs can grow in size due to the fusion process by which a larger LD is obtained by the merging of two smaller LDs, but these events seems to be rare and difficult to be observed. Many other processes are thought to be involved in the number and growth of LDs, like the de novo formation and the growth through additional neutral lipid deposition in pre existing droplets. Moreover the number and size of LDs are influenced by the catabolism and the absorption or interaction with other organelles. The comprehension of these processes could help in the confinement of the pathologies related to lipid accumulation. In this study the LDs' size distribution, number and the total volume of immature (n=12), mature (n=12, 10-days differentiated) and lipolytic (n=12) 3T3-L1 adipocytes were considered. More than 11,000 LDs were measured in the 36 cells after Oil Red O staining. In a previous work Monte Carlo simulations were used to mimic the fusion process alone between LDs. We found that, considering the fusion as the only process acting on the LDs, the size distribution in mature adipocytes can be obtained with numerical simulation starting from the size distribution in immature cells provided a very high rate of fusion events. In this paper Monte Carlo simulations were developed to mimic the interaction between LDs taking into account many other processes in addition to fusion (de novo formation and the growth through additional neutral lipid deposition in pre-existing droplets) in order to reproduce the LDs growth and we also simulated the catabolism (fission and the decrease through neutral lipid exit from pre-existing droplets) to reproduce their size reduction observed in lipolytic conditions. The results suggest that each single process, considered alone, can not be considered the only responsible for the size variation observed, but more than one of them, playing together, can quite well reproduce the experimental data. PMID- 26121907 TI - Scaly Erythematous Patches in a Patient With Down Syndrome. PMID- 26121908 TI - The Effect of pH and Temperature on Cabbage Volatiles During Storage. AB - During storage of shredded cabbage, characteristic sulfurous volatile compounds are formed affecting cabbage aroma both negatively and positively. Selected ion flow tube-mass spectrometry (SIFT-MS) was used to measure the concentration of cabbage volatiles during storage. The volatile levels of cabbage samples were measured at pH 3.3 to 7.4 at 4 degrees C for 14 d, and pH 3.3 at 25 degrees C for 5 d in order to determine the effect of pH and temperature. Aroma intensity, best aroma, freshness, and off odor were evaluated in a sensory test of the samples at 4 degrees C. The desirable volatile allyl isothiocyanate was lower in high pH samples (pH 7.4 and 6.4), whereas higher concentrations were detected in low pH samples (pH 3.3 and 4.6). Lipoxygenase volatiles, which produce a fresh green and leafy aroma in cabbage, were generated in very low amounts at any pH value. High pH samples generated significantly higher concentrations of off odors such as dimethyl sulfide, dimethyl disulfide, dimethyl trisulfide, and methanethiol. Sensory tests showed that higher pH samples had significantly stronger off odor and lower desirable cabbage aroma than lower pH samples. Thus, sensory results matched the volatile results in that samples at higher pH levels formed the highest amount of undesirable volatiles and the least amount of desirable volatiles. Storage at 25 degrees C produced similar concentrations of allyl isothiocyanate, but significantly higher levels of off odors, than at 4 degrees C. Shredded cabbage products should be stored in low pH dressings to minimize formation of off odors and maximize formation of characteristic, desirable cabbage odor. PMID- 26121909 TI - Antenatal screening for hepatitis C: Universal or risk factor based? AB - BACKGROUND: There is no clear consensus on whether antenatal screening for hepatitis C (HCV) should be universal, or based on an assessment of risk factors. AIM: To report the HCV status and risk factors for HCV amongst women delivering at a tertiary metropolitan hospital in order to better understand the implications of changing from universal to risk factor based HCV screening. MATERIALS AND METHODS: An audit of practice was performed at Mater Mothers' Hospitals (Brisbane) using routinely collected data from 2007 to 2013 (n = 57,659). The demographic and clinical characteristics of HCV-positive women (n = 281) were compared with those with a negative result (n = 57,378), and compared for the presence or absence of risk factors for HCV. RESULTS: From a cohort of 57,659 women, 281 (0.5%) women were HCV positive. HCV-positive women were more likely to have received blood products (10.0 vs 3.1%; P < 0.001), have a history of illicit drug use (72.2 vs 9.8%; P < 0.001), and have at least one risk factor for HCV infection (92 vs 17%; P < 0.001). Of the HCV-positive women, only seven of the 281 (2.5%) had no identifiable risk factor, whilst most (83%) HCV-negative women did not have any documented risk factor for HCV infection. CONCLUSION: Most women testing positive for HCV antibodies have identifiable risk factors; however, a small number will not be detected if a risk factor based screening approach is adopted. The benefits of universal screening must be weighed against the potential cost savings of a risk factor based screening program. PMID- 26121910 TI - Chronic hypoxia facilitates Alzheimer's disease through demethylation of gamma secretase by downregulating DNA methyltransferase 3b. AB - INTRODUCTION: Environmental factors and epigenetic mechanisms are believed to contribute to Alzheimer's disease (AD). We previously documented that prenatal hypoxia aggravated the cognitive impairment and neuropathology in offspring mice. Here, we investigate the chronic hypoxia-induced epigenetic modifications in AD. METHODS: The 3-month-old APP(swe)/PS1(dE9) mice were exposed to hypoxic environment 6 hour/day for 30 days, followed by learning and memory tests and biochemical and neuropathology measurement at the age of 4, 6, and 9 months. RESULTS: We found hypoxia exaggerated the neuropathology and cognitive impairment in AD mice. Chronic hypoxia induced demethylation on genomic DNA and decreased the expression of DNA methyltransferase 3b (DNMT3b) in vivo. We further found that DNMTs inhibition elevated the protein levels of amyloid precursor protein, beta- and gamma-secretases, whereas overexpression of DNMT3b suppressed the levels of them in vitro. DISCUSSION: Our study suggests chronic hypoxia can aggravate AD progression through demethylation of genes encoding gamma-secretase components by downregulation of DNMT3b. PMID- 26121911 TI - Enhanced osteoconductivity of polyethersulphone nanofibres loaded with bioactive glass nanoparticles in in vitro and in vivo models. AB - OBJECTIVES: There is growing need for new scaffold constructions for synthetic bone graft substitutes to repair large bone lesions. A very promising and important class of new implants for tissue engineering is based on three dimensional scaffolds and bioceramics. MATERIALS AND METHODS: In this study, after investigation of mechanical properties of polyethersulphone (PES) nanofibres, fabricated by electrospinning methodology and coated with bioactive glass (BG), cells of the MG-63 line were cultured on surfaces of these scaffolds. Their capacity to support MG-63 proliferation was also investigated in vitro by MTT assay. Osteoconductivity on these scaffolds was investigated by the common osteogenic markers alkaline phosphatase (ALP) activity, calcium mineral deposition and bone-related gene activation. Next, a bone reconstruction of rat critical-size defects model was evaluated using radiographic imaging analysis (digital mammography), computed tomography and histological examination. RESULTS: In vitro results indicated that biocompatibility and osteogenic markers of MG-63 cells were significantly enhanced after coating PES with BG. Based on in vivo results, new bone formation in the defect site was enhanced in implanted rats in comparison with a control group. The highest reconstruction was observed in animals implanted with BG-coated nanofibres. CONCLUSIONS: Osteoconductivity of PES nanofibres was markedly enhanced after coating them with BG, and introduction of this construct as new bone-graft substitute for bone loss and defects is indicated. PMID- 26121912 TI - Effects of Selenium Supplementation on Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice. AB - BACKGROUND: Recent clinical studies have demonstrated the suppressive effect of selenium (Se) treatment on serum thyroid-specific antibody titers in patients with autoimmune thyroiditis (AIT), but the mechanism underlying this process is not clear. The aim of the present study was to investigate the effects of selenium on the incidence and severity of AIT, titers of thyroid autoantibodies, and selenoprotein expression in thyroid in a spontaneous autoimmune thyroiditis (SAT) model. METHODS: NOD.H-2(h4) mice at four weeks of age were randomly divided into control, iodine supplement (SAT), and selenium supplement groups (SAT+Se). Mice were given 0.005% sodium iodide water for eight weeks to induce SAT and then 0.3 mg/L sodium selenite in drinking water for 8 weeks and 16 weeks. The severity of lymphocytic infiltration in the thyroid, serum thyroglobulin antibody (TgAb) titers, serum selenium concentration, expression of glutathione peroxidase-1 (GPx1), thioredoxin reductase-1 (Txnrd1), and peroxiredoxin 5 were measured. RESULTS: Serum selenium concentration significantly increased after selenium supplementation. Serum TgAb levels were significantly lower in the selenium group compared with the SAT group (p<0.05). The prevalence of thyroiditis and the degree of infiltration of lymphocytes decreased gradually over time in the group provided with selenium supplementation. The expression of GPx1 and Txnrd1 by Western blotting were found to be significantly higher in the SAT+Se group than in other groups (p<0.05). CONCLUSIONS: These results indicate that selenium treatment can increase the function of antioxidation by upregulating the expression of selenoproteins in the thyroid and have an inhibitory effect on TgAb titers, which may have an impact on AIT. PMID- 26121913 TI - Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. AB - OBJECTIVE: Human papillomavirus (HPV) vaccines can potentially control cervical cancer and help to reduce other HPV-related cancers. We aimed to estimate the relative contribution (RC) of the nine types (HPVs 16/18/31/33/45/52/58/6/11) included in the recently approved 9-valent HPV vaccine in female anogenital cancers and precancerous lesions (cervix, vulva, vagina and anus). METHODS: Estimations were based on an international study designed and coordinated at the Catalan Institute of Oncology (Barcelona-Spain), including information on 10,575 invasive cervical cancer (ICC), 1709 vulvar, 408 vaginal and 329 female anal cancer cases and 587 Vulvar Intraepitelial Neoplasia grade 2/3 (VIN2/3), 189 Vaginal Intraepitelial Neoplasia grade 2/3 (VaIN2/3) and 29 Anal Intraepitelial Neoplasia grade 2/3 (AIN2/3) lesions. Consecutive histologically confirmed paraffin-embedded cases were obtained from hospital pathology archives from 48 countries worldwide. HPV DNA-detection and typing was performed by SPF10-DEIA LiPA25 system and RC was expressed as the proportion of type-specific cases among HPV positive samples. Multiple infections were added to single infections using a proportional weighting attribution. RESULTS: HPV DNA prevalence was 84.9%, 28.6%, 74.3% and 90.0% for ICC, vulvar, vaginal and anal cancers, respectively, and 86.7%, 95.8% and 100% for VIN2/3, VaIN2/3 and AIN2/3, respectively. RC of the combined nine HPV types was 89.5% (95% confidence interval (CI): 88.8-90.1)-ICC, 87.1% (83.8-89.9)-vulvar, 85.5% (81.0-89.2)-vaginal, 95.9% (93.0-97.9)-female anal cancer, 94.1% (91.7-96.0)-VIN2/3, 78.7% (71.7-84.2)-VaIN2/3 and 86.2% (68.3 96.1)-AIN2/3. HPV16 was the most frequent type in all lesions. Variations in the RC of HPVs 31/33/45/52/58 by cancer site were observed, ranging from 7.8% (5.0 11.4)-female anal cancer to 20.5% (16.1-25.4)-vaginal cancer. CONCLUSIONS: The addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines (HPV16/18) could prevent almost 90% of HPV positive female anogenital lesions worldwide. Taking into account that most HPV-related cancers are ICC ones, the 9 valent HPV vaccine could potentially avoid almost 88% of all female anogenital cancers. PMID- 26121915 TI - Spontaneous generation of functional osteoclasts from synovial fluid mononuclear cells as a model of inflammatory osteoclastogenesis. AB - In osteoimmunology, osteoclastogenesis is understood in the context of the immune system. Today, the in vitro model for osteoclastogenesis necessitates the addition of recombinant human receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The peripheral joints of patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) are characterized by an immune-mediated inflammation that can lead to bone destruction. Here, we evaluate spontaneous in vitro osteoclastogenesis in cultures of synovial fluid mononuclear cells (SFMCs) activated only in vivo. SFMCs were isolated and cultured for 21 days at 0.5-1.0 * 10(6) cells/mL in culture medium. SFMCs and healthy control peripheral blood monocytes were cultured with RANKL and M-CSF as controls. Tartrate-resistant acid phosphatase (TRAP) positive multinucleated cells were found in the SFMC cultures after 21 days. These cells expressed the osteoclast genes calcitonin receptor, cathepsin K, and integrin beta3, formed lacunae on dentin plates and secreted matrix metalloproteinase 9 (MMP9) and TRAP. Adding RANKL and M-CSF potentiated this secretion. In conclusion, we show that SFMCs from inflamed peripheral joints can spontaneously develop into functionally active osteoclasts ex vivo. Our study provides a simple in vitro model for studying inflammatory osteoclastogenesis. PMID- 26121916 TI - A novel recombinant lineage's contribution to the outbreak of coxsackievirus A6 associated hand, foot and mouth disease in Shanghai, China, 2012-2013. AB - Since late 2012, coxsackievirus A6 (CVA6) has gradually become the predominant pathogen responsible for hand-foot-mouth disease (HFMD) in several provinces of China. A total of 626 patients diagnosed with HFMD in Shanghai, China from January 2012 to September 2013 were enrolled in this study. Of these, 292 CVA6 infected cases were subjected to clinical analyses. Whole-genome sequencing, recombination and phylogenetic analyses were also performed. A recombinant CVA6 monophyletic lineage was found during an outbreak of CVA6-associated HFMDs in Shanghai, China in November 2012, and accounted for 21.9% (64/292) of the CVA6 strains during the study period. Recombination analyses showed that the 2C gene of the novel CVA6 virus was probably derived from a coxsackievirus A4 (CVA4) strain circulating in the population. Clinical observation showed that this recombinant CVA6 virus led to a more generalized rash than did the non recombinant CVA6 virus. This newly emerged CVA6 lineage was associated with a considerable proportion of HFMD cases from 2012 to 2013 in Shanghai, and poses a potential threat to public health. PMID- 26121917 TI - Controlled non-heart beating donor lung transplantation: initial experience in Spain. AB - Although the number of lung transplants in Spain is increasing annually, more organs are required to ease waiting lists. Controlled non-heart beating donors (NHBD) (Maastricht III) are a reality at international level, and contribute significantly to increasing donor numbers. In this study, we present our NHBD protocol and the initial experience in Spain using lung grafts from this type of donor. Three bilateral lung transplants were performed between January 2012 and December 2014. Preservation was by ex-vivo lung perfusion in 2 cases and by traditional cold ischemia in the other. None of the patients developed grade 3 primary graft dysfunction, no in-hospital mortality was recorded and 1-year survival was 100%. These initial results, and international experience, should help to develop similar protocols to encourage the use of controlled non-heart beating donors. PMID- 26121918 TI - Metazoan parasites of blue jack mackerel Trachurus picturatus (Perciformes: Carangidae) from Portuguese mainland waters. AB - Blue jack mackerel, Trachurus picturatus, is a carangid fish which constitutes an important commercial resource in the north-east Atlantic. Its metazoan parasite community from Portuguese mainland waters was investigated here for the first time. Nine parasite taxa were found, most of which are common parasites of Trachurus spp. The parasite community was broadly similar to that of the Atlantic horse mackerel, T. trachurus, from the same region, but two digenean species were detected in blue jack mackerel, Monascus filiformis and Tergestia sp., which did not occur in horse mackerel from this region. A comparison with the two previous studies of T. picturatus parasite communities shows that continental-shelf regions are characterized by higher prevalences of digenean trematodes and an absence of trypanorhynch cestodes, in contrast with oceanic regions. PMID- 26121919 TI - Vaginal reconstruction with pedicled vertical deep inferior epigastric perforator flap (diep) after pelvic exenteration. A consecutive case series. AB - Vaginal reconstruction after pelvic exenteration (PE) represents a challenge for the oncologic surgeon. Since the introduction of perforator flaps, using pedicled vertical DIEP (deep inferior epigastric perforator) flap allows to reduce the donor site complication rate. From November 2012 to December 2014, 27 PEs were performed in our institution. 13 patients who underwent PE with vaginal reconstruction and programmed DIEP procedure for gynecologic malignancies were registered. Nine patients underwent PE for recurrent disease and four for primary treatment. Six of the 13 patients have a preoperative fistula. Anterior PE was performed in 10 patients, and total PE in 3 patients. A vertical DIEP flap was performed in 10 patients using one or two medial perforators. The reasons for abortion of vertical DIEP flap procedure were: failure to localizing perforator vessels in two cases, and unavailability of plastic surgeon in one case. A vertical fascia-sparring rectus abdominis myocutaneous flap was then harvested. Median length of surgery was 335min, and 60min for DIEP harvesting and vaginal reconstruction. No flap necrosis occurred. One patient in the VRAM (vertical rectus abdominis myocutaneous) group experienced a late incisional hernia and one patient in the DIEP flap group required revision for vaginal stenosis. In our experience, DIEP flap represents our preferred choice of flap for circumferential vaginal reconstruction after PE. To achieve a high reproducibility, the technically demanding pedicled vertical DIEP flap has to be harvested by a trained surgeon, after strict evaluation of the preoperative imaging with identification and localization of perforator vessels. PMID- 26121920 TI - Altered circulating endothelial progenitor cells in patients with keloid. AB - Evidence has suggested that vascular endothelial growth factor (VEGF), a crucial growth factor in regulating endothelial progenitor cells (EPCs), plays a central role in keloid formation. However, the levels of circulating EPCs in patients with keloid have not yet been explored. The aim of this study was to determine the number of circulating EPCs in patients with keloid. Circulating EPCs (defined as CD45- CD34+CD133+VEGFR2+cells) and VEGF levels from 39 patients with keloid and 22 healthy controls (HCs) were assessed by flow cytometry and ELISA, respectively. EPCs were detectable in the peripheral blood of patients with keloid. The number of circulating EPCs and the levels of plasma VEGF were significantly higher in patients with keloid than in HCs. However, no correlation was found between the number of circulating EPCs and the serum VEGF levels. This study provides the first evidence that EPCs are increased in the peripheral blood of patients with keloid. Understanding the roles of EPCs in keloid fromation may lead to the development of novel therapeutic strategies for keloid. PMID- 26121921 TI - Bisphenol A: Human exposure and neurobehavior. AB - The effect of bisphenol A (BPA) exposure on human brain and behavior is a relatively new issue, and particular concerns have been raised about its potential impact on children. The primary objective of this review was to analyze the current state of knowledge on the association of environmental BPA exposure during pregnancy and/or childhood with child cognitive and/or behavior outcomes. All scientific publications until March 2015 that include examination of this relationship have been reviewed using the MEDLINE/PubMed database. Although research on this issue has not been abundant, an association with altered neurobehavior was reported by eight out of the twelve available articles, including aggressive behavior, attention deficit, hyperactivity disorder, depression and anxiety impairments, mostly in children exposed in utero, indicating disruption of the brain during this critical window of development. Despite the reduced number of studies and their heterogeneity, the results suggest that prenatal BPA exposure may have a negative impact on neurobehavioral functioning in children and that the effects may be sex-dependent. It is therefore necessary to be vigilant towards the potential adverse effects of ubiquitous low-level BPA exposure, although more studies in humans are required to convincingly confirm or rule out the association between BPA exposure and health. Meanwhile, it is desirable to inform women planning or undergoing pregnancy about measures to reduce or avoid exposure to BPA. We discuss some key aspects of the relationship between exposure and neurobehavioral outcomes. PMID- 26121923 TI - Corrigendum: evidence for photogenerated intermediate hole polarons in ZnO. PMID- 26121922 TI - Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study. AB - INTRODUCTION: Olfactory dysfunction has been identified as an early warning sign for Alzheimer's disease, Parkinson's disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone. METHODS: Olfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE). RESULTS: The average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD=5.7) years. Mean tibia lead was 16.3 (SD=12.0) MUg/g bone, mean patella lead was 22.4 (SD=14.4)MUg/g bone, and mean UPSIT score was 26.9 out of 40 (SD=7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15 MUg/g tibia lead: beta=-1.57; 95% CI: -2.93, -0.22; p=0.02) in models adjusted for smoking and age. Additional adjustment for education did not significantly change results. Of all the genes explored, only the presence of one or more HFE variant alleles was significantly associated with olfaction recognition (HFE beta=2.26; 95% CI: 0.09, 4.43; p=0.04). In a model containing the HFE term and a lead term, the tibia lead parameter estimate dropped by 21% (per 15 MUg/g tibia lead: beta=-1.25; 95% CI: -2.64, 0.14; p=0.08) while the HFE term dropped 15% (beta=1.91; 95% CI: -0.28, 4.10; p=0.09). None of the other gene terms were associated with olfactory recognition in this cohort, nor were any gene-lead interaction terms significant. Additional sensitivity analysis in men with MMSE scores of 25 or higher (n=149) showed a similar but slightly attenuated association between lead and olfactory recognition (per 15 MUg/g tibia lead beta= 1.39; 95% CI: -3.00, 0.22; p=0.09). CONCLUSION: Cumulative exposure to lead is associated with reduced olfactory recognition in a cohort of elderly men. The association was similar but not significant in men with better cognitive function as measured by the MMSE. Iron metabolism gene status may also affect olfactory function. PMID- 26121924 TI - Antiallergic effects of peiminine through the regulation of inflammatory mediators in HMC-1 cells. AB - Peiminine is the main biologically active component derived from Fritillaria ussuriensis. Peiminine was investigated in various pulmonary diseases, but its antiallergic effect and the related mechanism have not been reported yet. The present study aimed to evaluate the effect of peiminine on mast cell-mediated allergic inflammation in HMC-1 cells. The pro-inflammatory cytokine production was measured using ELISA, reverse transcription-polymerase chain reaction and nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinases (MAPKs) pathway activation, as determined by Western blot analysis. Peiminine inhibits the production of the pro-inflammatory cytokine, such as interleukin (IL)-6, IL 8, tumor necrosis factor-alpha (TNF-alpha) and IL-1beta (IL-1beta). It was shown to have inhibitory effects on MAPKs phosphorylation and NF-B expression in human mast cells (HMC)-1 using Western blot. HMC-1 cells were observed for confirmation of histamine release. Passive cutaneous anaphylaxis (PCA) reactions were evaluated using an animal model and peiminine demonstrated inhibitory effects on IgE-dependent anaphylaxis. These results suggest that peiminine has regulatory potential for allergic inflammatory reactions mediated by HMC-1 cells. PMID- 26121925 TI - Rehabilitation needs of the survivors of the 2013 Ya'an earthquake in China. AB - OBJECTIVE: To determine the physical, functional and psychosocial rehabilitation needs of the injured survivors of the 2013 earthquake in Ya'an, China. DESIGN: Cross-sectional survey. METHODS: A total of 143 injured survivors (80 males, 63 females, mean age 41.4 years (standard deviation (SD) 20.2)) were recruited for the study. A questionnaire was designed to collect their demographic and environmental information. Manual muscle testing and active range of motion (AROM) were used to assess physical function. The Modified Barthel Index was used to assess activities of daily living (ADL) and the Post-Traumatic Stress Disorder - Self Rating Scale was used to assess psychological status. The rehabilitation needs of the injured survivors were identified based on the assessment results. RESULTS: Physical problems of the back and lower limbs were more severe than those of the upper limbs, as measured by MMT and AROM. Various degrees of dependence in ADL were measured in 74.2% of subjects, and psychological distress was present in more than 50% of subjects. Rehabilitation training prescribed by local therapists included functional training (74.8%), exercises (49.0%), provision of splints (44.8%), etc. Psychological interventions were re-commended to most of the patients. There were high levels of need for assistive devices, and home and community modifications. CONCLUSION: There is a high level of need for early rehabilitation in hospital, followed by continued home and community rehabilitation services, particularly for injured survivors who are returning to villages with very limited resources. PMID- 26121926 TI - Inflammation-adapted liver stiffness values for improved fibrosis staging in patients with hepatitis C virus and alcoholic liver disease. AB - BACKGROUND & AIMS: It is well known that inflammation increases liver stiffness (LS) in patients with chronic hepatitis C (HCV) and alcoholic liver disease (ALD) independent of fibrosis stage, but no inflammation-adapted cut-off values have been settled so far. An early identification of rapid fibrosers, however, is essential to decide whom to treat first with the novel but expensive antiviral drugs. METHODS: Liver stiffness, biopsy-proven fibrosis stages F0-F4 (METAVIR or Kleiner score) and routine laboratory parameters were studied in 2068 patients with HCV (n = 1391) and ALD (n = 677). RESULTS: Among the routine parameters for liver damage, AST correlated best with LS (HCV: r = 0.54, P < 0.0001 and ALD: r = 0.34, P < 0.0001). In the absence of elevated transaminases, cut-off values were almost identical between HCV and ALD for F1-2, F3 and F4 (HCV: 5.1, 9.0 and 11.9 kPa vs ALD: 4.9, 8.1 and 10.5 kPa). These cut-off values increased exponentially as a function of median AST level. The impact of AST on LS was higher in lobular pronounced ALD as compared to portal tract-localized HCV. Most notably, Cohen's weighted Kappa displayed an improved agreement of the novel AST-dependent cut-off values with histological fibrosis stage both for HCV (0.68 vs 0.65) and ALD (0.80 vs 0.76). CONCLUSIONS: The novel AST-adapted cut-off values improve non-invasive fibrosis staging in HCV and ALD and may be also applied to other liver diseases. Especially in HCV, they could help to decide whom to treat first with the novel but expensive antiviral drugs. PMID- 26121927 TI - Sexual risk at first coitus: Does alcohol make a difference? AB - This study examines whether use of alcohol at first coitus is associated with increased sexual risk for young women. First coitus is the focus of the investigation because it is a memorable, formative experience that has implications for subsequent sexual health. A community sample of young women ages 18-19 years (N = 227) completed retrospective interviews. Characteristics and perceptions of the first coital event were examined using chi squares and one-way multivariate analysis of variance (MANOVA) to determine if there were differences based on alcohol-involvement. Alcohol-involved first coitus events occurred in social settings with risky partners, were rated less positively, and were non consensual relative to those that did not involve alcohol. Alcohol use was not related to condom use. Alcohol-involvement was associated with subsequent pairing of alcohol with sex and incapacitated rape. Adolescent alcohol use occurs in contexts that increases young women's sexual risk through exposure to risky partners. PMID- 26121928 TI - Diagnostic accuracy of (18)F-FDG PET/CT compared with that of contrast-enhanced MRI of the breast at 3 T. AB - PURPOSE: To compare the diagnostic accuracy of prone (18)F-FDG PET/CT with that of contrast-enhanced MRI (CE-MRI) at 3 T in suspicious breast lesions. To evaluate the influence of tumour size on diagnostic accuracy and the use of maximum standardized uptake value (SUVMAX) thresholds to differentiate malignant from benign breast lesions. METHODS: A total of 172 consecutive patients with an imaging abnormality were included in this IRB-approved prospective study. All patients underwent (18)F-FDG PET/CT and CE-MRI of the breast at 3 T in the prone position. Two reader teams independently evaluated the likelihood of malignancy as determined by (18)F-FDG PET/CT and CE-MRI independently. (18)F-FDG PET/CT data were qualitatively evaluated by visual interpretation. Quantitative assessment was performed by calculation of SUVMAX. Sensitivity, specificity, diagnostic accuracy, area under the curve and interreader agreement were calculated for all lesions and for lesions <10 mm. Histopathology was used as the standard of reference. RESULTS: There were 132 malignant and 40 benign lesions; 23 lesions (13.4%) were <10 mm. Both (18)F-FDG PET/CT and CE-MRI achieved an overall diagnostic accuracy of 93%. There were no significant differences in sensitivity (p = 0.125), specificity (p = 0.344) or diagnostic accuracy (p = 1). For lesions <10 mm, diagnostic accuracy deteriorated to 91% with both (18)F-FDG PET/CT and CE MRI. Although no significant difference was found for lesions <10 mm, CE-MRI at 3 T seemed to be more sensitive but less specific than (18)F-FDG PET/CT. Interreader agreement was excellent (kappa = 0.85 and kappa = 0.92). SUVMAX threshold was not helpful in differentiating benign from malignant lesions. CONCLUSION: (18)F-FDG PET/CT and CE-MRI at 3 T showed equal diagnostic accuracies in breast cancer diagnosis. For lesions <10 mm, diagnostic accuracy deteriorated, but was equal for (18)F-FDG PET/CT and CE-MRI at 3 T. For lesions <10 mm, CE-MRI at 3 T seemed to be more sensitive but less specific than (18)F-FDG PET/CT. Quantitative assessment using an SUVMAX threshold for differentiating benign from malignant lesions was not helpful in breast cancer diagnosis. PMID- 26121929 TI - Validation of pixel-wise parametric mapping of myocardial blood flow with 13NH3 PET in patients with hypertrophic cardiomyopathy. AB - PURPOSE: Transmural abnormalities in myocardial blood flow (MBF) are important causes of ischaemia in patients with left ventricular (LV) hypertrophy. The study aimed to test whether pixel-wise parametric mapping of (13)NH3 MBF can reveal transmural abnormalities in patients with hypertrophic cardiomyopathy (HCM). METHODS: We submitted 11 HCM patients and 9 age-matched controls with physiological LV hypertrophy to rest and stress (dipyridamole) (13)NH3 PET. We measured MBF using a compartmental model, and obtained rest and stress parametric maps. Pixel MBF values were reorganized to obtain subendocardial and subepicardial MBF of LV segments. RESULTS: MBF at rest was higher in the subendocardial than in the subepicardial layer: 0.78 +/- 0.19 vs. 0.60 +/- 0.18 mL/min/g in HCM patients; 0.92 +/- 0.24 vs. 0.75 +/- 0.24 mL/min/g in controls (both p < 0.0001). Transmural perfusion gradient (TPG = subendocardial MBF/subepicardial MBF) at rest was similar: 1.35 +/- 0.31 in HCM patients; 1.28 +/- 0.27 in controls (NS). During stress, controls maintained higher subendocardial MBF: 2.44 +/- 0.54 vs. 1.96 +/- 0.67 mL/min/g tissue (p < 0.0001), with a TPG of 1.33 +/- 0.35 (NS vs. rest). In HCM patients, the difference between subendocardial and subepicardial MBF was reduced (1.46 +/- 0.48 vs. 1.36 +/- 0.48 mL/min/g tissue, p < 0.01) and TPG decreased to 1.11 +/- 0.34 (p < 0.0001 vs. rest and vs. controls). In HCM patients 8 of 176 segments had subendocardial MBF less than -2 * SD of the mean, versus none of 144 segments in controls (p < 0.01). CONCLUSION: Pixel-wise parametric mapping of (13)NH3 MBF enables the identification of transmural abnormalities in patients with HCM. PMID- 26121931 TI - ClpB/Hsp100 proteins and heat stress tolerance in plants. AB - High-temperature stress can disrupt cellular proteostasis, resulting in the accumulation of insoluble protein aggregates. For survival under stressful conditions, it is important for cells to maintain a pool of native soluble proteins by preventing and/or dissociating these aggregates. Chaperones such as GroEL/GroES (Hsp60/Hsp10) and DnaK/DnaJ/GrpE (Hsp70/Hsp40/nucleotide exchange factor) help cells minimize protein aggregation. Protein disaggregation is accomplished by chaperones belonging to the Caseinolytic Protease (Clp) family of proteins. ClpB/Hsp100 proteins are strikingly ubiquitous and are found in bacteria, yeast and multi-cellular plants. The expression of these proteins is regulated by heat stress (HS) and developmental cues. Bacteria and yeast contain one and two forms of ClpB proteins, respectively. Plants possess multiple forms of these proteins that are localized to different cellular compartments (i.e. cytoplasm/nucleus, chloroplast or mitochondria). Overwhelming evidence suggests that ClpB/Hsp100 proteins play decisive roles in cell adaptation to HS. Mutant bacteria and yeast cells lacking active ClpB/Hsp100 proteins are critically sensitive to high-temperature stress. Likewise, Arabidopsis, maize and rice mutants lacking cytoplasmic ClpB proteins are very sensitive to heat. In this study, we present the structural and functional attributes of plant ClpB forms. PMID- 26121930 TI - (18)F-Alfatide II PET/CT in healthy human volunteers and patients with brain metastases. AB - PURPOSE: We report the biodistribution and radiation dosimetry of an integrin alphavbeta3 specific PET tracer (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) (denoted as (18)F-Alfatide II). We also assessed the value of (18)F-Alfatide II in patients with brain metastases. METHODS: A series of torso (from the skull to the thigh) static images were acquired in five healthy volunteers (3 M, 2 F) at 5, 10, 15, 30, 45, and 60 min after injection of (18)F-Alfatide II (257 +/- 48 MBq). Regions of interest (ROIs) were drawn manually, and the time-activity curves (TACs) were obtained for major organs. Nine patients with brain metastases were examined by static PET imaging with (18)F-FDG (5.55 MBq/kg) and (18)F-Alfatide II. RESULTS: Injection of (18)F-Alfatide II was well tolerated in all healthy volunteers, with no serious tracer-related adverse events found. (18)F-Alfatide II showed rapid clearance from the blood pool and kidneys. The total effective dose equivalent (EDE) and effective dose (ED) were 0.0277 +/- 0.003 mSv/MBq and 0.0198 +/- 0.002 mSv/MBq, respectively. The organs with the highest absorbed dose were the kidneys and the spleen. Nine patients with 20 brain metastatic lesions identified by MRI and/or CT were enrolled in this study. All 20 brain lesions were visualized by (18)F-Alfatide II PET, while only ten lesions were visualized by (18)F-FDG, and 13 by CT. CONCLUSION: F-Alfatide II is a safe PET tracer with a favorable dosimetry profile. The observed ED suggests that (18)F-Alfatide II is feasible for human studies. (18)F-Alfatide II has potential value in finding brain metastases of different cancers as a biomarker of angiogenesis. PMID- 26121932 TI - Enzymatic kinetic resolution of racemic ibuprofen: past, present and future. AB - This review is a journey concerning the investigations of the kinetic resolution of racemic ibuprofen for the last 20 years. The relevancy of the pharmacological uses of the S( + ) enantiomer along with its higher cost compared with racemic profen are the driving forces of a variety of scientific research studies addressing the enzymatic resolution of ibuprofen through enantiomeric esterification using lipases as biocatalysts. Lipases of fungal sources such as Candida rugosa, Rhizomucor miehei and the lipase B of Candida antarctica have been extensively studied both in homogeneous and heterogeneous (immobilized on solid supports) processes. In this context, the various alcohols and organic co solvents frequently used in the esterification of racemic ibuprofen are summarized and discussed in this review. Moreover, recent investigations using membranes as reactors coupled with the separation of the desired product and microfluidic devices are presented. Finally, some guidelines about future perspectives regarding the technology of the kinetic resolution of profens and research niches are given. PMID- 26121933 TI - The 'price signal' for health care is loud and clear: A cross-sectional study of self-reported access to health care by disadvantaged Australians. AB - OBJECTIVE: To describe self-reported inability to access health care and factors associated with lack of access among a socioeconomically disadvantaged group. METHOD: A cross-sectional survey with 906 adult clients of a large community welfare agency in New South Wales. Clients attending the service for emergency assistance completed a touchscreen survey. RESULTS: Inability to access health care in the prior year was reported by more than one-third of the sample (38%), compared to the 5% found for the general population. Dentists (47%), specialists (43%) or GPs (29%) were the least accessible types of health care. The main reason for inability to access health care was cost, accounting for 60% of responses. Almost half (47%) the sample reported delayed or non-use of medicines due to cost. Increasing financial stress was associated with increased inability to access GP or specialist care, medicines and imaging. Higher anxiety scores were associated with inability to access health care, and with cost-related inability to access medicines and imaging. CONCLUSION: For disadvantaged groups, cost-related barriers to accessing care are prominent and are disproportionately high - particularly regarding dentistry, specialist and GP care. IMPLICATIONS: Improvements in health outcomes for disadvantaged groups are likely to require strategies to reduce cost-related barriers to health care. PMID- 26121936 TI - Theoretical exploration of the nanoscale host-guest interactions between [n]cycloparaphenylenes (n = 10, 8 and 9) and fullerene C60: from single- to three potential well. AB - The nanoscale host-guest interactions between [n]cycloparaphenylene ([n]CPP; n = 10, 8 and 9) nano-ring and fullerene C60 were explored theoretically. It is found that relatively small variations in the sizes of the [n]CPP host lead to very significant changes in encapsulation property toward the fullerene C60 guest. Expectedly, one stable inclusion-configuration of [10]CPP?C60 and one floating configuration of [8]CPP?C60 are located on the potential surfaces of the two complexes, respectively. Unexpectedly, besides a floating-configuration (F [9]CPP?C60), another stable inclusion-configuration (I-[9]CPP?C60) is also located on the potential surface of [9]CPP?C60 host-guest complex. Interaction energies and natural steric analysis show that these complexes are stabilized by balancing concave-convex pi-pi attractive and steric repulsive host-guest interactions. In contrast, the steric repulsive energy (Es) between host and guest of I-[9]CPP?C60 is as high as 233.12 kJ mol(-1), which is much larger than those in other complexes. The movements of C60 guest through the cavities of [n]CPP host (n = 10, 8 and 9) are simulated by calculating the energy profile, and the results interestingly reveal that the encapsulation of C60 by [10]CPP is in the manner of a single-potential well, by [8]CPP in the manner of a double potential well, and by [9]CPP in the special manner of a three-potential well. We predict that the movement of C60 guest through the cavity of [9]CPP host should be experimentally observable owing to the relatively low energy barrier (<50 kJ mol(-1), M06-2X/6-31G(d)). Charge population analysis shows that an obvious charge transfer between host and guest takes place during the formation of I [9]CPP?C60, which is different from those during the formation of [8]CPP?C60, [10]CPP?C60 and F-[9]CPP?C60. Additionally, the host-guest interaction regions were detected and visualized in real space based on the electron density and reduced density gradient. PMID- 26121935 TI - Effects of preceding endoscopic mucosal resection on the efficacy and safety of radiofrequency ablation for treatment of Barrett's esophagus: results from the United States Radiofrequency Ablation Registry. AB - The effects of preceding endoscopic mucosal resection (EMR) on the efficacy and safety of radiofrequency ablation (RFA) for treatment of nodular Barrett's esophagus (BE) is poorly understood. Prior studies have been limited to case series from individual tertiary care centers. We report the results of a large, multicenter registry. We assessed the effects of preceding EMR on the efficacy and safety of RFA for nodular BE with advanced neoplasia (high-grade dysplasia or intramucosal carcinoma) using the US RFA Registry, a nationwide study of BE patients treated with RFA at 148 institutions. Safety outcomes included stricture, gastrointestinal bleeding, and hospitalization. Efficacy outcomes included complete eradication of intestinal metaplasia (CEIM), complete eradication of dysplasia (CED), and number of RFA treatments needed to achieve CEIM. Analyses comparing patients with EMR before RFA to patients undergoing RFA alone were performed with Student's t-test, Chi-square test, logistic regression, and Kaplan-Meier analysis. Four hundred six patients were treated with EMR before RFA for nodular BE, and 857 patients were treated with RFA only for non-nodular BE. The total complication rates were 8.4% in the EMR-before-RFA group and 7.2% in the RFA-only group (P = 0.48). Rates of stricture, bleeding, and hospitalization were not significantly different between patients treated with EMR before RFA and patients treated with RFA alone. CEIM was achieved in 84% of patients treated with EMR before RFA, and 84% of patients treated with RFA only (P = 0.96). CED was achieved in 94% and 92% of patients in EMR-before-RFA and RFA only group, respectively (P = 0.17). Durability of eradication did not differ between the groups. EMR-before-RFA for nodular BE with advanced neoplasia is effective and safe. The preceding EMR neither diminished the efficacy nor increased complication rate of RFA treatment compared to patients with advanced neoplasia who had RFA with no preceding EMR. Preceding EMR is not associated with poorer outcomes in RFA. PMID- 26121937 TI - A national follow-up survey of UK graduates opinion of undergraduate oral surgery teaching. AB - INTRODUCTION: A national follow-up survey was undertaken to determine whether dental graduates from 2009 perceived that their undergraduate oral surgery education had equipped them for general dental practice 4 years after graduating. MATERIALS AND METHODS: Graduates from the same 13 United Kingdom dental schools who had taken part in the original survey were invited to take part in this follow-up online survey. Their contact details were identified via the general dental council register, social media and alumni groups. RESULTS: In total, 161 responded (2009b) which represents 16% of the graduates of the original survey in 2009a. A similar percentage of these respondents perceived that the teaching in oral surgery had given them sufficient knowledge to undertake independent practice (83% and 79% in 2009a and 2009b, respectively). Most respondents (99% in both years) reported confidence in undertaking simple forceps exodontia. Confidence in surgical exodontia was poor in both surveys, but one area that appeared improved in the follow-up related to the sectioning of teeth (84% in 2009b compared with 49% in 2009a). Areas of weakness identified in 2009 were reported to be improved in the follow-up. CONCLUSION: This follow-up survey supports the findings of the original survey. Future longitudinal studies would allow institutions to identify possible weaknesses in their curriculum and to track the career development of their graduates and facilitate robust data collection. PMID- 26121938 TI - Human Papillomavirus-related tumours of the oropharynx display a lower tumour hypoxia signature. AB - OBJECTIVES: Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) patients have improved prognosis compared to other head and neck (HNSCC) cancers. Since poor prognosis is associated with tumour hypoxia, we studied whether the hypoxic response is different in HPV-related cells and tumours. MATERIAL AND METHODS: HPV-positive and -negative cells were incubated in hypoxia and analyzed by qRTPCR, western blotting and cell proliferation assays. Tumours formed by xenografting these cells in nude mice were studied by IHC. HNSCC patient samples were analyzed by unsupervised clustering of hypoxia-related gene expression, quantitative real-time PCR (qRTPCR) and immunohistochemical (IHC) detection of neo-blood vessels. RESULTS AND CONCLUSION: HPV-positive and negative cells responded differently to hypoxia, in terms of gene expression (HIF 1alpha, PHD-3, GLUT-1 and VEGF-A) and cell survival. Tumour xenografts formed by HPV-positive cells had fewer hypoxic areas than those formed by HPV-negative cells. HPV related tumours were less hypoxic, expressed lower levels of hypoxia responsive genes, and had a higher density of neo-blood vessels. HPV-related OSCC display lower tumour hypoxia, which could be linked to the distinct intrinsic abilities of HPV-positive tumour cells to adapt to hypoxia and to their better prognosis. PMID- 26121939 TI - BH3-mimetic small molecule inhibits the growth and recurrence of adenoid cystic carcinoma. AB - OBJECTIVES: To evaluate the anti-tumor effect of BM-1197, a new potent and highly specific small molecule inhibitor of Bcl-2/Bcl-xL, in preclinical models of human adenoid cystic carcinoma (ACC). METHODS: Low passage primary human adenoid cystic carcinoma cells (UM-HACC-2A,-2B,-5,-6) and patient-derived xenograft (PDX) models (UM-PDX-HACC) were developed from surgical specimens obtained from 4 patients. The effect of BM-1197 on cell viability and cell cycle were evaluated in vitro using this panel of low passage ACC cells. The effect of BM-1197 on tumor growth, recurrence and tumor cell apoptosis in vivo was evaluated with the PDX model of ACC (UM-PDX-HACC-5). RESULTS: Exposure of low passage primary human ACC cells to BM-1197 mediated an IC50 of 0.92-2.82 MUM. This correlated with an increase in the fraction of apoptotic cells (p<0.0001) and an increase in caspase-3 activity (p<0.0001), but no noticeable differences in cell cycle (p>0.05). In vivo, BM 1197 inhibited tumor growth (p=0.0256) and induced tumor cell apoptosis (p=0.0165) without causing significant systemic toxicities, as determined by mouse weight over time. Surprisingly, weekly BM-1197 decreased the incidence of tumor recurrence (p=0.0297), as determined by Kaplan-Meier analysis. CONCLUSION: These data demonstrated that single agent BM-1197 induces apoptosis and inhibits tumor growth in preclinical models of adenoid cystic carcinoma. Notably, single agent BM-1197 inhibited tumor recurrence, which is considered a major clinical challenge in the clinical management of adenoid cystic carcinoma. Collectively, these results suggest that patients with adenoid cystic carcinoma might benefit from therapy with a BH3-mimetic small molecule. PMID- 26121940 TI - MoS2 Heterojunctions by Thickness Modulation. AB - In this work, we report lateral heterojunction formation in as-exfoliated MoS2 flakes by thickness modulation. Kelvin probe force microscopy is used to map the surface potential at the monolayer-multilayer heterojunction, and consequently the conduction band offset is extracted. Scanning photocurrent microscopy is performed to investigate the spatial photocurrent response along the length of the device including the source and the drain contacts as well as the monolayer multilayer junction. The peak photocurrent is measured at the monolayer multilayer interface, which is attributed to the formation of a type-I heterojunction. The work presents experimental and theoretical understanding of the band alignment and photoresponse of thickness modulated MoS2 junctions with important implications for exploring novel optoelectronic devices. PMID- 26121941 TI - Optical tracking with two markers for robust prospective motion correction for brain imaging. AB - OBJECTIVE: Prospective motion correction (PMC) during brain imaging using camera based tracking of a skin-attached marker may suffer from problems including loss of marker visibility due to the coil and false correction due to non-rigid-body facial motion, such as frowning or squinting. A modified PMC system is introduced to mitigate these problems and increase the robustness of motion correction. MATERIALS AND METHODS: The method relies on simultaneously tracking two markers, each providing six degrees of freedom, that are placed on the forehead. This allows us to track head motion when one marker is obscured and detect skin movements to prevent false corrections. Experiments were performed to compare the performance of the two-marker motion correction technique to the previous single marker approach. RESULTS: Experiments validate the theory developed for adaptive marker tracking and skin movement detection, and demonstrate improved image quality during obstruction of the line-of-sight of one marker when subjects squint or when subjects squint and move simultaneously. CONCLUSION: The proposed methods eliminate two common failure modes of PMC and substantially improve the robustness of PMC, and they can be applied to other optical tracking systems capable of tracking multiple markers. The methods presented can be adapted to the use of more than two markers. PMID- 26121942 TI - Pseudoceramide stimulates peroxisome proliferator-activated receptor-alpha expression in a murine model of atopic dermatitis: molecular basis underlying the anti-inflammatory effect and the preventive effect against steroid-induced barrier impairment. AB - Topical pseudoceramides are successfully used in skin barrier repair therapy for atopic dermatitis (AD) and demonstrated to reduce the adverse effects of topical glucocorticoids (GC). However, the molecular mechanisms involved are not fully understood. We investigated whether PC-9S (myristoyl/palmitoyloxostearamide/arachamide MEA, Neopharm, Daejeon, Korea), one of the synthetic pseudoceramides, could stimulate peroxisome proliferator activated receptor (PPAR)alpha expression in a hapten [oxazolone (oxa)]-induced AD murine model (oxa-AD mice) and subsequently improved permeability barrier, reduced inflammation, and increased antimicrobial peptides (AMPs) expression. Normal hairless mice and oxa-AD mice were topically treated twice daily with either PC-9S-containing physiologic lipid mixture (PLM), vehicle (PLM), or PPARalpha agonist for 4 days. Topical PC-9S significantly increased PPARalpha expression in mouse epidermis in vivo and in oxa-AD mice skin comparable with PPARalpha agonist. Topical PC-9S-containing PLM significantly reduced basal trans epidermal water loss (TEWL), surface pH, and mast cell infiltrates and prevented the decline of AMPs expression in oxa-AD mice, which were abrogated by PPARalpha antagonist. Then, oxa-AD mice were treated with super-potent topical GC twice daily for 4 days with or without PC-9S co-applications. Co-treatment with PC-9S containing PLM suppressed GC-induced increase in basal TEWL, epidermal thinning, reduced loricrin expression, and impaired barrier recovery and these effects were attenuated by PPARalpha antagonist. Collectively, our findings suggest that pseudoceramide PC-9S-induced stimulation of PPARalpha expression provides a new mechanism by which pseudoceramides show anti-inflammatory property, improve the permeability and antimicrobial barrier function, and prevent the negative effects of topical GC. PMID- 26121943 TI - Influence of psoriasis on circulatory system function assessed in echocardiography. AB - Psoriasis vulgaris is a chronic disease with a multifactorial pathogenesis. It affects about 2-4 % of the population all over the world. In course of psoriatic arthritis, joints' damages are observed. In patients with psoriasis vulgaris and psoriatic arthritis, there is increased morbidity and mortality caused by cardiovascular diseases observed. The aim of the study is to analyze the echocardiography of patients with psoriasis vulgaris and psoriatic arthritis on the basis of the literature available in PubMed database. Abnormalities found in echocardiography of patients with psoriasis include valvular defects (40.7 % of the patients), left ventricle diastolic dysfunction (27.8 %), and left ventricle hypertrophy (11.1 %). Left ventricle's systolic disorders, increased aorta stiffness index and increased pulmonary artery blood pressure were also observed in this group of patients. PMID- 26121944 TI - Reply to "Misconceptions in the assessment of cough peak flow measurements for extubation or decanulation protocols". PMID- 26121945 TI - Enzymatic conversion of lignin into renewable chemicals. AB - The aromatic heteropolymer lignin is a major component of plant cell walls, and is produced industrially from paper/pulp manufacture and cellulosic bioethanol production. Conversion of lignin into renewable chemicals is a major unsolved problem in the development of a biomass-based biorefinery. The review describes recent developments in the understanding of bacterial enzymes for lignin breakdown, such as DyP peroxidases, bacterial laccases, and beta-etherase enzymes. The use of pathway engineering methods to construct genetically modified microbes to convert lignin to renewable chemicals (e.g. vanillin, adipic acid) via fermentation is discussed, and the search for novel applications for lignin (e.g. carbon fibre). PMID- 26121947 TI - LivestockPlus: Forages, sustainable intensification, and food security in the tropics. AB - The increased use of grain-based feed for livestock during the last two decades has contributed, along with other factors, to a rise in grain prices that has reduced human food security. This circumstance argues for feeding more forages to livestock, particularly in the tropics where many livestock are reared on small farms. Efforts to accomplish this end, referred to as the 'LivestockPlus' approach, intensify in sustainable ways the management of grasses, shrubs, trees, and animals. By decoupling the human food and livestock feed systems, these efforts would increase the resilience of the global food system. Effective LivestockPlus approaches take one of two forms: (1) simple improvements such as new forage varieties and animal management practices that spread from farmer to farmer by word of mouth, or (2) complex sets of new practices that integrate forage production more closely into farms' other agricultural activities and agro ecologies. PMID- 26121946 TI - Restoration of middle-ear input in fluid-filled middle ears by controlled introduction of air or a novel air-filled implant. AB - The effect of small amounts of air on sound-induced umbo velocity in an otherwise saline-filled middle ear (ME) was investigated to examine the efficacy of a novel balloon-like air-filled ME implant suitable for patients with chronically non aerated MEs. In this study, air bubbles or air-filled implants were introduced into saline-filled human cadaveric MEs. Umbo velocity, a convenient measure of ME response, served as an indicator of hearing sensitivity. Filling the ME with saline reduced umbo velocity by 25-30 dB at low frequencies and more at high frequencies, consistent with earlier work (Ravicz et al., Hear. Res. 195: 103-130 (2004)). Small amounts of air (~30 MUl) in the otherwise saline-filled ME increased umbo velocity substantially, to levels only 10-15 dB lower than in the dry ME, in a frequency- and location-dependent manner: air in contact with the tympanic membrane (TM) increased umbo velocity at all frequencies, while air located away from the TM increased umbo velocity only below about 500 Hz. The air filled implant also affected umbo velocity in a manner similar to an air bubble of equivalent compliance. Inserting additional implants into the ME had the same effect as increasing air volume. These results suggest these middle-ear implants would significantly reduce conductive hearing loss in patients with chronically fluid-filled MEs. PMID- 26121948 TI - Waterfowl foraging in winter-flooded ricefields: Any agronomic benefits for farmers? AB - Winter-flooding of ricefields provides foraging habitat to waterfowl, which in return may bring agronomic benefits to farmers. Our study experimentally tested the effect of mallards (Anas platyrhynchos) on the standing stalks and weed seed bank in the Camargue (France), both of which present major challenges for farmers. Three duck densities were tested: (D1) 5 ducks ha(-1) (historical nocturnal density), (D2) 23 ducks ha(-1) (present nocturnal density), and (D3) 300 ducks ha(-1) (Asian rice-duck farming density). The ducks reduced the stalks significantly: -27 % (D1), -52 % (D2), and -91 % (D3). Conversely, they decreased the number of seeds by only 3 % (D3) and the seed mass by about 21 % (D1 and D3), which was not significant. Besides they had no effect on seed species richness. This study clearly demonstrates that the winter-flooding effect on straw decomposition can be enhanced by waterfowl foraging, hence showing an agronomic benefit from ducks to farmers. However, there was no clear effect in terms of seed bank reduction. PMID- 26121949 TI - Addendum to the Special Issue Entitled Genetic Influences on Peer and Family Relationships Across Development. PMID- 26121951 TI - Against Genetic Tests for Athletic Talent: The Primacy of the Phenotype. AB - New insights into the genetics of sport performance lead to new areas of application. One area is the use of genetic tests to identify athletic talent. Athletic performances involve a high number of complex phenotypical traits. Based on the ACCE model (review of Analytic and Clinical validity, Clinical utility, and Ethical, legal and social implications), a critique is offered of the lack of validity and predictive power of genetic tests for talent. Based on the ideal of children's right to an open future, a moral argument is given against such tests on children and young athletes. A possible role of genetic tests in sport is proposed in terms of identifying predisposition for injury. In meeting ACCE requirements, such tests could improve individualised injury prevention and increase athlete health. More generally, limitations of science are discussed in the identification of talent and in the understanding of complex human performance phenotypes. An alternative approach to talent identification is proposed in terms of ethically sensitive, systematic and evidence-based holistic observation over time of relevant phenotypical traits by experienced observers. Talent identification in sport should be based on the primacy of the phenotype. PMID- 26121950 TI - Current Methodologies and Implications of Phase Identification of the Vertical Jump: A Systematic Review and Meta-analysis. AB - BACKGROUND: The vertical jump (VJ) is considered a key indicator of lower limb explosive strength. Previous research has established that rate of force development and time to peak force are linked closely to athletic ability and hence the ability to extract these accurately is of significance. OBJECTIVES: The objectives of this study were to (1) review the literature to ascertain what methods are currently used to extract jump phases from the force platform data and (2) compare identified methods on neutral data. METHODS: In Part 1, an electronic search was conducted using PubMed, Central, and EBSCO host (January 1965 to April 2014). Articles were included if they (1) detailed how VJ phases from the force platform data were identified and (2) used only force platform data in the analysis. Additionally, study design and quality was independently examined. In Part 2, the three common methodologies identified were used to analyze a neutral pool of data to determine if any variance existed. RESULTS: For Part 1, a total of 19 studies met the inclusion criteria. Meta-analysis determined three methods of phase identification used in the literature from which to extract force-time variables. In Part 2, a one-way analysis of variance and Scheffe's post-hoc tests showed significant differences (p < 0.01) for force time variables (eccentric phase time, concentric phase time, time to peak force, rate of force development) between methods. CONCLUSION: The results demonstrate that three common methods exist for determination of the VJ phases from force platform data. Consequently, each produce different values for force-time variables when used on a neutral data pool. There is a clear need for a robust agreed method for VJ analysis. PMID- 26121952 TI - Effect of tamoxifen on fatty degeneration and atrophy of rotator cuff muscles in chronic rotator cuff tear: An animal model study. AB - Fatty degeneration of the rotator cuff muscles is an irreversible change resulting from chronic rotator cuff tear and is associated with poor clinical outcomes following rotator cuff repair. We evaluated the effect of Tamoxifen, a competitive estrogen receptor inhibitor, on fatty degeneration using a mouse model for chronic rotator cuff tear. Sixteen adult mice were divided into two diet groups (Tamoxifen vs. Regular) and subjected to surgical creation of a large rotator cuff tear and suprascapular nerve transection in their left shoulder with the right shoulder serving as a control. The rotator cuff muscles were harvested at 16 weeks and subjected to histology and RT-PCR for adipogenic and myogenic markers. Histology showed substantially decreased atrophy and endomysial inflammation in Tamoxifen group, but no significant differences in the amount of intramuscular adipocytes and lipid droplets compared to the Regular group. With RT-PCR, the operated shoulders showed significant upregulation of myogenin and PPAR-gamma, and downregulation of myostatin compared to the nonsurgical shoulder. No significant differences of gene expression were found between the two diet groups. Our study demonstrated that tamoxifen diet leads to decreased muscle atrophy and inflammatory changes following chronic rotator cuff tear, but has no apparent effect on adipogenesis. PMID- 26121953 TI - Isolation of mesenchymal stromal/stem cells from small-volume umbilical cord blood units that do not qualify for the banking system. AB - The clinical application of mesenchymal stromal/stem cells (MSCs) has been extensively explored. In this study, we examined the availability of freshly donated umbilical cord blood (UCB) units that do not qualify for the Japanese banking system for transplantation because of their small volume as a source of MSCs. Forty-five UCB units were used. The median volume of each UCB unit and number of nucleated cells per unit were 40 mL and 5.39 * 10(8), respectively. MSCs were successfully isolated from 18 of 45 units (40 %). The MSC isolation rate was not affected by cell processing method or the interval between delivery and cell processing. The volume of the UCB unit and the mononuclear cell count were predictive factors of the MSC isolation rate. MSCs were effectively isolated by selecting UCB units with a volume of >=54 mL and containing >=1.28 * 10(8) mononuclear cells, yielding a MSC isolation rate of >70 %. UCB-derived MSCs were similar to bone marrow-derived MSCs in terms of their morphology, surface marker expression, and differentiation potential, apart from adipogenesis. Our data indicate that UCB units that are currently discarded due to inadequate volume should be reconsidered as a source of MSCs using the well-established UCB banking system. PMID- 26121954 TI - The efficacy of prophylactic azithromycin on bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. AB - The aim of this study was to determine whether prophylactic azithromycin treatment prevents bronchiolitis obliterans syndrome (BOS) after hematopoietic stem cell transplantation (HCT). A series of 1187 patients who underwent HCT between December 1993 and November 2013 at our tertiary referral center in South Korea were enrolled. The median age of these patients was 39.0 years, and 668 (56.3 %) were men. Acute leukemia was the most common indication for HCT. During a median follow-up of 30.7 months after HCT, BOS was diagnosed in 82 patients (6.9 %) at a median of 12.3 months after HCT. One hundred patients received prophylactic azithromycin, of whom 12 developed BOS. BOS was significantly more frequent in patients who were treated with than without prophylactic azithromycin (12.0 versus 6.4 %, P = 0.036). Multivariate analysis revealed that a busulfan based conditioning regimen (HR 2.73, 95 % CI 1.66-6.45) was the only independent predictor of BOS. The prophylactic use of azithromycin was not associated with the development of BOS by multivariate analysis. Although the present study had some limitations such as its non-randomized retrospective design, differences in baseline patient characteristics between the two groups, and the preference for azithromycin use at our hospital, our findings suggest that prophylactic azithromycin seems to not prevent the development of BOS in HCT recipients. PMID- 26121955 TI - The use of hyperbaric oxygen therapy in the treatment of hemorrhagic cystitis after allogeneic stem cell transplantation from an unrelated donor. AB - Hemorrhagic cystitis (HC) is a diffuse inflammation of the bladder of an infectious or non-infectious etiology, causing bleeding of the bladder mucosa. There are no explicit guidelines defining the appropriate treatment of HC. Hyperbaric oxygen therapy (HBO) is a non-invasive method involving the use of 100 % oxygen under increased pressure, which penetrates to poorly perfused areas. The most appropriate group for treatment with HBO is patients with BK virus associated HC after allogenic human stem cell transplantation (alloHSCT). In this report, we present five patients after alloHSCT from a matched unrelated donor with symptoms of HC successfully treated with HBO. All patients received therapy with 100 % oxygen in a hyperbaric chamber at 2.5 atmospheres for 60 min, delivered 5 days per week. Complete response with resolution of pain and hematuria, as well as eradication of viral load, was achieved by all the patients after a mean of 13 sessions (range 11-30) of HBO. These data indicate that HBO therapy is sufficient and effective in the treatment of HC, and represents a well tolerated procedure with good clinical and laboratory results after ineffective primary treatment. PMID- 26121956 TI - Functional abnormalities and changes in gene expression in fibroblasts and macrophages from the bone marrow of patients with acute myeloid leukemia. AB - In bone marrow malignancies, little is known about the fate of stromal cells after replacement of normal cells by neoplastic hematopoietic ones. In this study, fibroblasts from patients with acute myeloid leukemia or myelodysplastic syndromes exhibited a significantly lower ability to support hematopoiesis originating from co-cultured allogeneic CD34-positive cells than did fibroblasts from healthy marrow. Conversely, macrophages from acute myeloid leukemia marrow significantly enhanced the production of blood cells compared with control macrophages. Aberrant function was associated with consistent changes in the expression of genes involved in hematopoietic stem cell control, such as cytokines and regulators of the Wnt signaling pathway. PMID- 26121957 TI - Psychophysics and the anisotropy of time. AB - In psychophysics, experimental control over the presented stimuli is an important prerequisite. Due to the anisotropy of time, this prerequisite is not given in psychophysical experiments on time perception. Many important factors (e.g., the direction of perceived time flow) cannot be manipulated in timing experiments. The anisotropy of time is a peculiarity, which distinguishes the time dimension from other perceptual qualities. Here I summarize the anisotropy-related differences between the perception of time and the perception of other qualities. It is discussed to what extent these differences might affect results and interpretations in psychophysical experiments. In conclusion, I argue for a 'view from nowhen' on the psychophysical study of time perception. PMID- 26121958 TI - Modulations of the experience of self and time. AB - Empirical findings in the Cognitive Sciences on the relationship between feeling states and subjective time have led to the assumption that time perception entails emotional and interoceptive states. The perception of time would thereafter be embodied; the bodily self, the continuous input from the body is the functional anchor of phenomenal experience and the mental self. Subjective time emerges through the existence of the self across time as an enduring and embodied entity. This relation is prominently disclosed in studies on altered states of consciousness such as in meditative states, under the influence of hallucinogens as well as in many psychiatric and neurological conditions. An increased awareness of oneself coincides with an increased awareness of time. Conversely, a decreased awareness of the self is associated with diminished awareness of time. The body of empirical work within different conceptual frameworks on the intricate relationship between self and time is presented and discussed. PMID- 26121959 TI - Lipidomic and proteomic analysis of Caenorhabditis elegans lipid droplets and identification of ACS-4 as a lipid droplet-associated protein. AB - Lipid droplets are cytoplasmic organelles that store neutral lipids for membrane synthesis and energy reserves. In this study, we characterized the lipid and protein composition of purified Caenorhabditis elegans lipid droplets. These lipid droplets are composed mainly of triacylglycerols, surrounded by a phospholipid monolayer composed primarily of phosphatidylcholine and phosphatidylethanolamine. The fatty acid composition of the triacylglycerols is rich in fatty acid species obtained from the dietary Escherichia coli, including cyclopropane fatty acids and cis-vaccenic acid. Unlike other organisms, C. elegans lipid droplets contain very little cholesterol or cholesterol esters. Comparison of the lipid droplet proteomes of wild type and high-fat daf-2 mutant strains shows a very similar proteome in both strains, except that the most abundant protein in the C. elegans lipid droplet proteome, MDT-28, is relatively less abundant in lipid droplets isolated from daf-2 mutants. Functional analysis of lipid droplet proteins identified in our proteomic studies indicated an enrichment of proteins required for growth and fat homeostasis in C. elegans. Finally, we confirmed the localization of one of the newly identified lipid droplet proteins, ACS-4. We found that ACS-4 localizes to the surface of lipid droplets in the C. elegans intestine and skin. This study bolsters C. elegans as a model to study the dynamics and functions of lipid droplets in a multicellular organism. PMID- 26121960 TI - Diet quality across early childhood and adiposity at 6 years: the Southampton Women's Survey. AB - BACKGROUND: Poor diet quality in early childhood is inconsistently linked to obesity risk. Understanding may be limited by the use of cross-sectional data and the use of body mass index (BMI) to define adiposity in childhood. OBJECTIVE: The objective of this study is to examine the effects of continued exposure to diets of varying quality across early childhood in relation to adiposity at 6 years. METHODS: One thousand and eighteen children from a prospective UK birth cohort were studied. Diet was assessed using food frequency questionnaires when the children were aged 6 and 12 months, and 3 and 6 years; diet quality was determined according to scores for a principal component analysis-defined dietary pattern at each age (characterized by frequent consumption of fruits, vegetables and fish). At each age, children were allocated a value of 0/1/2 according to third of the distribution (bottom/middle/top) their diet quality score was in; values were summed to calculate an overall diet quality index (DQI) for early childhood (range 0-8). Obesity outcomes considered at 6 years were dual-energy X ray absorptiometry-assessed fat mass and BMI. RESULTS: One hundred and seven (11%) children had a DQI=0, indicating a consistently low diet quality, 339 (33%) had a DQI=1-3, 378 (37%) had a DQI=4-6 and 194 (19%) had a DQI=7-8. There was a strong association between lower DQI and higher fat mass z-score at 6 years that was robust to adjustment for confounders (fat mass s.d. per 1-unit DQI increase: beta=-0.05 (95% confidence interval (CI): -0.09, -0.01), P=0.01). In comparison with children who had the highest diet quality (DQI=7-8), this amounted to a difference in fat mass of 14% (95% CI: 2%, 28%) at 6 years for children with the poorest diets (DQI=0). In contrast, no independent associations were observed between DQI and BMI. CONCLUSIONS: Continued exposure to diets of low quality across early childhood is linked to adiposity at the age of 6 years. PMID- 26121961 TI - Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes. AB - BACKGROUND/OBJECTIVES: Insulin therapy is required for many patients with the obesity-related disorder type 2 diabetes, but is also associated with weight gain. The specific location of adipose tissue location matters to cardiovascular disease (CVD) risk. We investigated effects of exogenous insulin on fat distribution in the high-fat/high-sucrose fed rat treated with streptozotocin (HF/HS-STZ) rat model of type 2 diabetes. We also examined effects of insulin therapy on circulating CVD markers, including adiponectin, triglycerides (TGs), total cholesterol and high-density lipoprotein. SUBJECTS/METHODS: Male SD rats were HF/HS fed for 5 weeks followed by STZ treatment to mimic the hallmarks of human obesity-associated insulin resistance followed by hyperglycemia. Magnetic resonance imaging and computed tomography were used to determine total fat, abdominal fat distribution and liver fat before and after insulin therapy in HF/HS-STZ rats. HbA1c%, TGs, cholesterol, high-density lipoprotein and adiponectin were analyzed by conventional methods adapted for rats. RESULTS: Insulin therapy lowered HbA1c (P<0.001), increased body weight (P<0.001), increased lean mass (P<0.001) and led to a near doubling of total fat mass (P<0.001), with the highest increase in subcutaneous adipose tissue as compared with visceral adipose tissue (P<0.001). No changes in liver fat were observed after insulin therapy, whereas plasma TG and cholesterol levels were decreased (P<0.001, P<0.01), while high-density lipoprotein (HDL) and adiponectin levels were elevated (P<0.01, P<0.001). CONCLUSIONS: Using the HF/HS-STZ rat as an animal model for type 2 diabetes, we find that insulin therapy modulates fat distribution. Specifically, our data show that insulin has a relatively positive effect on CVD-associated parameters, including abdominal fat distribution, lean body mass, adiponectin, TGs and HDL in HF/HS-STZ rats, despite a modest gain in weight. PMID- 26121962 TI - 'I don't feel trapped anymore...I feel like a bird': People with Learning Disabilities' Experience of Psychological Therapy. AB - BACKGROUND: There are very few studies that investigate the qualitative experiences of people with a learning disability who have engaged in psychological therapy. Indeed, having a learning disability has traditionally been an exclusion criterion for good quality research about psychological treatments (Psychotherapy and Learning Disability. Council Report CR116. London: Royal College of Psychiatrists, 2004; Journal of Applied Research in Intellectual Disabilities, 19, 2005 and 5). The current research was developed in response to a clinical psychology service recognizing the need to evaluate their psychological service and, as part of this evaluation, the importance of consulting with service users about their experience of psychological therapies. The overall aim of gaining this feedback would be to improve the service offered and to ensure that people receive the best psychological care. METHODS: Six service users with a learning disability were interviewed about their experience of individual psychological therapy. The interviews were analysed using interpretative phenomenological analysis. RESULTS: Themes were generated from the interviews which highlighted both positive and negative feedback on the psychological therapy process. The feedback covered areas such as access to therapy, feelings about therapy, preparing for therapy, skill development and collaborative working, accessibility and making therapy fun, challenges to confidentiality, positive feelings towards the therapist, aspects of the therapeutic relationship, therapy being challenging but helpful, and positive outcomes. CONCLUSIONS: These results have contributed to the evidence base that people with a learning disability are able to meaningfully engage in research and provide essential feedback on the services that they receive. No longer can people be excluded from individual psychological therapy or research just because of their label. PMID- 26121963 TI - Cognitive function in chronic rhinosinusitis: a controlled clinical study. AB - BACKGROUND: Cognitive dysfunction in patients with chronic rhinosinusitis (CRS) has previously received little attention. Cognitive data generally includes only subjective measures and lack appropriate controls when cognition is considered. The purpose of this study was to characterize dimensions of cognitive function that are affected in patients with CRS compared to a control sample using subjective and objective measures of cognitive function. METHODS: Patients fulfilling diagnostic criteria for CRS and non-CRS controls were recruited from the same clinical reference population. Patient-reported cognitive dysfunction was assessed using the Cognitive Failures Questionnaire (CFQ) and fatigue via the Fatigue Severity Scale (FSS). Objective cognitive function was assessed using a battery of tests from the Automated Neuropsychological Assessment Metrics (ANAM) computerized platform. RESULTS: A total of 100 subjects were enrolled, including 50 patients with active CRS and 50 control subjects. Patients with CRS scored significantly worse in subjective cognition as measured by total CFQ scores (38.3 +/- 16.5 vs 30.9 +/- 12.5; p = 0.009) and the FSS (4.2 +/- 1.6 vs 3.0 +/- 1.5; p = 0.001). Patients with CRS were also found to have worse simple reaction time scores compared to controls without CRS (162.4 +/- 56.2 vs 193.0 +/- 44.6; p = 0.003). These differences persisted regardless of polyp status. Performance differences for FSS and SRT measures remained significant after controlling for age, gender, race/ethnicity, education, allergic rhinitis, asthma, obstructive sleep apnea, depression, and antihistamine usage. CONCLUSION: Patients with CRS report significantly more cognitive dysfunction and fatigue on validated instruments and had worse reaction times on computerized testing. Further study is necessary to determine whether available treatments impact these measures. PMID- 26121964 TI - Evaluating Intervention Programs Targeting Parents to Manage Childhood Overweight and Obesity: A Systematic Review Using the RE-AIM Framework. AB - Intervention programs targeting parents to manage childhood overweight and obesity have emerged based on parents influence on the health behaviors of their children. The purpose of this review was to systematically evaluate intervention programs targeting parents to manage childhood overweight and obesity using the Reach, Efficacy, Adopt, Implementation, and Maintenance (RE-AIM) framework. There was a moderate risk of bias across all studies. The overall proportion of studies (n=7) reporting on each dimension of the RE-AIM framework ranged from 78.6% (reach) to 23.8% (maintenance). The majority of intervention programs demonstrated improvement in child BMI. However intervention programs did not reach families of diverse race/ethnicity, were provided by highly trained professionals, and demonstrated high attrition, thus limiting generalizability. PMID- 26121965 TI - Reply. PMID- 26121966 TI - Acceleration of protein folding by four orders of magnitude through a single amino acid substitution. AB - Cis prolyl peptide bonds are conserved structural elements in numerous protein families, although their formation is energetically unfavorable, intrinsically slow and often rate-limiting for folding. Here we investigate the reasons underlying the conservation of the cis proline that is diagnostic for the fold of thioredoxin-like thiol-disulfide oxidoreductases. We show that replacement of the conserved cis proline in thioredoxin by alanine can accelerate spontaneous folding to the native, thermodynamically most stable state by more than four orders of magnitude. However, the resulting trans alanine bond leads to small structural rearrangements around the active site that impair the function of thioredoxin as catalyst of electron transfer reactions by more than 100-fold. Our data provide evidence for the absence of a strong evolutionary pressure to achieve intrinsically fast folding rates, which is most likely a consequence of proline isomerases and molecular chaperones that guarantee high in vivo folding rates and yields. PMID- 26121967 TI - Interaction of enamel matrix proteins with human periodontal ligament cells. AB - OBJECTIVES: It has recently been shown that enamel matrix derivative (EMD) components (Fraction C, containing <6 kDa peptides (mainly a 5.3 kDa tyrosine rich amelogenin peptide (TRAP)), and Fraction A, containing a mixture of >6 kDa peptides (including a leucine-rich amelogenin peptide (LRAP))) differentially regulate osteogenic differentiation of periodontal ligament (PDL) cells. The present study examined whether EMD and the EMD Fractions (i) bind and internalize into PDL cells and (ii) precipitate and form insoluble complexes on PDL cells. MATERIALS AND METHODS: Biotin-labelled EMD/EMD Fractions were incubated with PDL cells under various different culture conditions and confocal and electron microscopies were carried out to examine the binding and intracellular trafficking of these proteins. RESULTS: The results reported here show, for the first time, that at least some components in Fraction A and the TRAP peptide in Fraction C can bind and be internalized by human PDL cells via receptor-mediated endocytosis. In addition, Fraction A was found to form insoluble aggregate-like structures on PDL cells, whereas Fraction C was soluble in culture media. CONCLUSION: Soluble amelogenin isoform TRAP appears to be internalizing into a subset of PDL cells. Moreover, TRAP uptake is most likely controlled by receptor mediated endocytosis. CLINICAL RELEVANCE: Information on interaction between PDL cells and EMD/TRAP might prove useful in designing targeted interventions (i.e. use of chemically prepared soluble amelogenin peptides) to repair/regenerate periodontal tissues. Such interventions can also (i) avoid the use of rather crude animal-derived enamel matrix protein (EMP)/EMD preparation and (ii) preparation of cost-effective and more controlled chemically synthesized amelogenin peptides for the clinical use. PMID- 26121968 TI - Consensus report of the European Federation of Conservative Dentistry: erosive tooth wear--diagnosis and management. AB - OBJECTIVE: Due to an increased focus on erosive tooth wear (ETW), the European Federation of Conservative Dentistry (EFCD) considered ETW as a relevant topic for generating this consensus report. MATERIALS AND METHODS: This report is based on a compilation of the scientific literature, an expert conference, and the approval by the General Assembly of EFCD. RESULTS: ETW is a chemical-mechanical process resulting in a cumulative loss of hard dental tissue not caused by bacteria, and it is characterized by loss of the natural surface morphology and contour of the teeth. A suitable index for classification of ETW is the basic erosive wear examination (BEWE). Regarding the etiology, patient-related factors include the pre-disposition to erosion, reflux, vomiting, drinking and eating habits, as well as medications and dietary supplements. Nutritional factors relate to the composition of foods and beverages, e.g., with low pH and high buffer capacity (major risk factors), and calcium concentration (major protective factor). Occupational factors are exposition of workers to acidic liquids or vapors. Preventive management of ETW aims at reducing or stopping the progression of the lesions. Restorative management aims at reducing symptoms of pain and dentine hypersensitivity, or to restore esthetic and function, but it should only be used in conjunction with preventive strategies. CONCLUSIONS: Effective management of ETW includes screening for early signs of ETW and evaluating all etiological factors. CLINICAL RELEVANCE: ETW is a clinical condition, which calls for the increased attention of the dental community and is a challenge for the cooperation with other medical specialities. PMID- 26121969 TI - New: consensus reports of the European Federation of Conservative Dentistry. PMID- 26121970 TI - Fit of 4-unit FDPs from CoCr and zirconia after conventional and digital impressions. AB - OBJECTIVES: To evaluate the marginal and internal fit of CAD/CAM-generated frameworks for 4-unit, fixed dental prostheses (FDPs) from zirconia (Z) and cobalt-chromium alloy (C) made with conventional (CI) and digital impressions (DI). MATERIALS AND METHODS: A titanium model was digitized with an intraoral scanner (DI, LAVATM C.O.S.; 3M ESPE; Seefeld, Germany; n = 12). Additionally, 12 conventional impressions were taken, and referring plaster casts were digitized by a laboratory-scanner (CI, LAVATM Scan ST; 3M ESPE; n = 12). Frameworks were fabricated (3M ESPE) from cobalt-chromium (DI-C, n = 12; CI-C, n = 12) and zirconia (DI-Z, n = 12; CI-Z, n = 12) from the same datasets. A replica technique was applied to measure the accuracy. The Mann-Whitney U statistical test was applied to detect statistical differences between each material and methodology groups in terms of fit. RESULTS: Frameworks from DI-C (median 19.07 MUm) showed significantly better marginal fit than CI-C (median 64.64 MUm, p < 0.001). Frameworks from DI-Z (median 52.50 MUm) showed significantly better marginal fit than CI-Z (median 72.94 MUm, p = 0.001). Additionally, frameworks from DI-C showed a significantly better marginal fit than DI-Z (p < 0.001). CONCLUSIONS: CI and DI led to a clinically acceptable marginal fit of 4-unit FDPs from cobalt chromium and zirconia. DI leads to better marginal fit of the cobalt-chromium frameworks; however, no effect on zirconia was found. CLINICAL RELEVANCE: The results indicate that DI is suitable for fabricating 4-unit, cobalt-chromium and zirconia frameworks with regard to fit requirements. PMID- 26121971 TI - Three-dimensional culture of dental pulp stem cells in direct contact to tricalcium silicate cements. AB - OBJECTIVES: Calcium silicate cements are biocompatible dental materials applicable in contact with vital tissue. The novel tricalcium silicate cement BiodentineTM offers properties superior to commonly used mineral trioxide aggregate (MTA). Objective of this study was to evaluate its cytocompatibility and ability to induce differentiation and mineralization in three-dimensional cultures of dental pulp stem cells after direct contact with the material. MATERIALS AND METHODS: Test materials included a new tricalcium silicate (BiodentineTM, Septodont, Saint-Maur-des-Fosses, France), MTA (ProRoot(r) MTA, DENSPLY Tulsa Dental Specialities, Johnson City, TN, USA), glass ionomer (KetacTM Molar AplicapTM, 3M ESPE, Seefeld, Germany), human dentin disks and polystyrene. Magnetic activated cell sorting for to the surface antigen STRO-1 was performed to gain a fraction enriched with mesenchymal stem cells. Samples were allowed to set and dental pulp stem cells in collagen carriers were placed on top. Scanning electron microscopy of tricalcium silicate cement surfaces with and without cells was conducted. Cell viability was measured for 14 days by MTT assay. Alkaline phosphatase activity was evaluated (days 3, 7, and 14) and expression of mineralization-associated genes (COL1A1, ALP, DSPP, and RUNX2) was quantified by real-time quantitative PCR. Nonparametric statistical analysis for cell viability and alkaline phosphatase data was performed to compare different materials as well as time points (Mann-Whitney U test, alpha = 0.05). RESULTS: Cell viability was highest on tricalcium silicate cement, followed by MTA. Viability on glass ionomer cement and dentin disks was significantly lower. Alkaline phosphatase activity was lower in cells on new tricalcium silicate cement compared to MTA, whereas expression patterns of marker genes were alike. CONCLUSIONS: Increased cell viability and similar levels of mineralization-associated gene expression in three-dimensional cell cultures on the novel tricalcium silicate cement and mineral trioxide aggregate indicate that the material is cytocompatible and bioactive. CLINICAL RELEVANCE: The tested new tricalcium silicate cement confirms its suitability as an alternative to MTA in vital pulp therapy. PMID- 26121972 TI - Periodontal pathogens and tetracycline resistance genes in subgingival biofilm of periodontally healthy and diseased Dominican adults. AB - OBJECTIVE: The objective of this study was to compare the periodontopathogen prevalence and tetracycline resistance genes in Dominican patients with different periodontal conditions. METHODS: Seventy-seven samples were collected from healthy, gingivitis, chronic (CP) and aggressive (AgP) periodontitis patients. Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Prevotella intermedia, Parvimonas micra, Eikenella corrodens and Dialister pneumosintes and 11 resistance genes were studied by PCR. P. gingivalis fimA genotype was determined. RESULTS: In healthy patients, P. micra and P. intermedia were the most and least frequently detected, respectively. T. forsythia and E. corrodens appeared in 100% of gingivitis patients. Red complex, D. pneumosintes and E. corrodens were significantly more prevalent in CP compared to healthy patients. F. nucleatum and T. denticola were detected more frequently in AgP. A. actinomycetemcomitans was the most rarely observed in all groups. The fimA II genotype was the most prevalent in periodontitis patients. Seven tetracycline resistant genes were detected. tet(Q), tet(32) and tet(W) showed the greatest prevalence. tet(32) was significantly more prevalent in CP than in healthy patients. CONCLUSIONS: Red complex bacteria and D. pneumosintes were significantly the most prevalent species among periodontitis patients. T. forsythia was the most frequently detected in this population. To our knowledge, this is the first study describing the tet(32) gene in subgingival biofilm from healthy and periodontally diseased subjects. CLINICAL RELEVANCE: This study contributes to the knowledge on the subgingival microbiota and its resistance genes of a scarcely studied world region. Knowing the prevalence of resistance genes could impact on their clinical prescription and could raise awareness to the appropriate use of antibiotics. PMID- 26121974 TI - Nebulized bronchodilators instead of metered-dose inhalers for obstructive pulmonary symptoms. PMID- 26121975 TI - Belgian experience with triple therapy with boceprevir and telaprevir in genotype 1 infected patients who inject drugs. AB - No data have been reported yet on treatment outcome in persons who inject drugs (PWID) infected with hepatitis C virus treated with boceprevir or telaprevir in combination with peginterferon (Peg IFN) and ribavirin (RBV). Additionally, there are concerns about the safety of boceprevir and telaprevir in some subgroups of patients with hepatitis C (HCV). In a cohort of HCV patients infected with genotype 1 in Belgium, treatment outcome of patients infected due to IV drug use was analyzed and compared with patients who have no history of substance use. The study population consisted of 179 patients: 78 PWID and 101 controls treated with boceprevir (n = 79) or telaprevir (n = 100) additional to Peg IFN and RBV; 53 (30%) had advanced disease (F3, F4) and 79 (44%) had an antiviral therapy previously. There were no significant differences in the baseline characteristics between both groups, except that PWID patients were more frequently infected with genotype 1a (67% vs 21%), were younger and were predominantly male. Psychiatric complaints during follow-up occurred more frequently in the PWID patients: 24% versus 11% (P = .02). Treatment failure for other reasons than absence of viral response was 70% and 64% in PWID and non-PWID respectively. The sustained viral response (SVR) rates were similar in both groups (71% in PWID vs 72% in non PWID); with a non-inferiority test with -5% margin there is a difference of -1% (95% CI [-15%, 13%]) and P = 0.30. There are no reasons to exclude PWID from treatment with boceprevir, telaprevir and novel antiviral therapies. PMID- 26121973 TI - Infection as cause of immobility and occurrence of venous thromboembolism: analysis of 1635 medical cases from the RIETE registry. AB - Several risk assessment models include infection and immobility among the items to be considered for venous thromboembolism (VTE) prevention. However, information on patients with infection leading to immobility and developing VTE are limited, as well as on the role of specific types of infection. Data were collected from the worldwide RIETE registry, including patients with symptomatic objectively confirmed VTE, and followed-up for at least 3 months. The overall population of RIETE at June 2013 (n = 47,390) was considered. Acute infection leading to immobility was reported in 3.9 % of non-surgical patients. Compared with patients immobilized due to dementia, patients with infection had a shorter duration of immobilization prior to VTE (less than 4 weeks in 94.2 vs. 25.9 % of cases; p < 0.001). During the 3-month follow-up, VTE patients with infection versus those with dementia had a lower rate of fatal bleeding (0.5 vs. 1.1 %; p < 0.05) or fatal PE (1.7 vs. 3.5 %; p < 0.01). Patients with respiratory tract infections had more likely PE as initial VTE presentation than other types of infection (62.3 vs. 37.7 %; p < 0.001). Significantly more patients with pneumonia than those with other respiratory infections had received VTE prophylaxis (50.2 vs. 30.6 %; p < 0.001). Following VTE, patients with sepsis showed a significantly higher risk of fatal bleeding. Based on our real-world data, infection seems to contribute to the pathogenesis of VTE by accelerating the effects of immobility. Its role as VTE risk factor probably deserves further attention and specific assessment in order to optimize VTE prophylaxis and treatment. PMID- 26121976 TI - Anticancer drug sensitivity prediction in cell lines from baseline gene expression through recursive feature selection. AB - BACKGROUND: An enduring challenge in personalized medicine is to select right drug for individual patients. Testing drugs on patients in large clinical trials is one way to assess their efficacy and toxicity, but it is impractical to test hundreds of drugs currently under development. Therefore the preclinical prediction model is highly expected as it enables prediction of drug response to hundreds of cell lines in parallel. METHODS: Recently, two large-scale pharmacogenomic studies screened multiple anticancer drugs on over 1000 cell lines in an effort to elucidate the response mechanism of anticancer drugs. To this aim, we here used gene expression features and drug sensitivity data in Cancer Cell Line Encyclopedia (CCLE) to build a predictor based on Support Vector Machine (SVM) and a recursive feature selection tool. Robustness of our model was validated by cross-validation and an independent dataset, the Cancer Genome Project (CGP). RESULTS: Our model achieved good cross validation performance for most drugs in the Cancer Cell Line Encyclopedia (>=80% accuracy for 10 drugs, >=75% accuracy for 19 drugs). Independent tests on eleven common drugs between CCLE and CGP achieved satisfactory performance for three of them, i.e., AZD6244, Erlotinib and PD-0325901, using expression levels of only twelve, six and seven genes, respectively. CONCLUSIONS: These results suggest that drug response could be effectively predicted from genomic features. Our model could be applied to predict drug response for some certain drugs and potentially play a complementary role in personalized medicine. PMID- 26121977 TI - Lipopolysaccharide significantly influences the hepatic triglyceride metabolism in growing pigs. AB - BACKGROUND: In the practical commercial pig farms, inflammation is a perennial problem, yet most of studies on inflammation are focused on immune response. Actually, inflammation can induce body metabolism disorder which will finally influence animals' growth. In this study, we investigated the effect of acute inflammation on the triglyceride (TG) metabolism in the liver of growing pigs and the possible underlying mechanisms. METHODS: Twelve male growing pigs were randomly divided into two groups, a control group (received saline) and a LPS group (intramuscular injected with 15 MUg/kg LPS). Six hours after LPS injection, the pigs were euthanized and sampled. Biochemical indexes, inflammation factors, lipid metabolism related parameters and mitochondrial function were evaluated. The relationship between glucocorticoid receptor (GR) and the key enzymes of de novo lipogenesis were also investigated by chromatin immunoprecipitation assay (ChIP). RESULTS: LPS induced a serious inflammation in the liver of growing pigs proved by liver morphologic changes, the up-regulated plasma cortisol, tumor necrosis factor-alpha (TNF-alpha) content and gene expression of inflammation related genes in liver. For de novo lipogenesis, LPS significantly decreased the gene expression of fatty acid synthase (FAS), Acetyl-CoA carboxylase-1 (ACC-1) and Stearoyl-CoA desaturase-1 (SCD-1), and the protein expression of ACC-1 and SCD-1. For lipolysis, only the gene expression of adipose triglyceride lipase (ATGL) was decreased. LPS did nothing to the gene expression of hormone-sensitive lipase (HSL) and the lipolytic enzymes activities. For beta-oxidation, LPS significantly increased the protein expression of CPT-1alpha, but the gene expression of mitochondrial DNA-encoded genes and the activities of mitochondrial complex IV and V demonstrated no obviously changes. Furthermore, ChIP results showed that LPS significantly decreased the level of GR binding to ACC-1 promoter. CONCLUSION: LPS infection has a profound impact on hepatic TG metabolism. This impact is mainly demonstrated by the significantly deceased de novo lipogenesis, and GR may involve in its regulation. PMID- 26121978 TI - Abdominal fascia closure following elective midline laparotomy: a surgical experience at a tertiary care hospital in Tanzania. AB - BACKGROUND: The optimal strategy of abdominal wall closure after midline laparotomy has remained an issue of ongoing debate. This study was undertaken to describe our own experiences with abdominal fascial closure following elective midline laparotomy and compare with what is described in literature. METHODS: This was a descriptive prospective study of patients who underwent elective midline laparotomy at Bugando Medical Centre between March 2009 and February 2014. RESULTS: A total of 872 patients (M:F = 2.8:1) were studied. The median age was 38 years. The fascia closure was performed with a continuous and interrupted sutures in 804 (92.2%) and 68 (7.8%) patients, respectively. Mass closure and layered closure were performed in 842 (96.6%) and 30 (3.4%) patients, respectively. Monofilament sutures were applied for fascia closure in 366 (42.0%) patients, multifilament sutures in 506 (58.0%) patients. Non-absorbable sutures were chosen in 304 (34.9%) patients, slowly absorbable sutures in 506 (58.0%), and moderately absorbable sutures in 62 (7.1%) patients. Sutures used for fascial closure were vicryl 464 (53.2%), nylon 250 (28.7%), prolene 62 (7.1%), PDSII 54 (6.2%) and silk 42 (4.8%). Sutures with the strength of 0 were used in 214 (24.4%) patients, with strength of 1 in 524 (60.1%) patients, and with strength of 2 in 134 (15.4%) patients. The mean time required for massive closure of the midline incision was 8.20 +/- 6.12 min whereas in layered closure, the mean time required for closure was 12.22 +/- 7.11 min and this was statistically significant (p = 0.002). Mass closure was significantly associated with low incidence of wound dehiscence and incisional hernia (p < 0.001). Continuous suture was significantly associated with low incidence of wound dehiscence and incisional hernia as compared to interrupted suture (p < 0.001). Non-absorbable sutures were significantly associated with increased incidence of persistent wound pain and stitch sinus as compared to absorbable sutures (p < 0.001). The use of monofilament sutures was insignificantly associated with low incidence of surgical site infection as compared to multifilament sutures (p = 0.051). Prolene was significantly associated with persistent wound pain as compared to vicryl (p = 0.017). CONCLUSION: Continuous mass closure with vicryl is commonly used for abdominal fascial closure following elective midline laparotomy in our setting and gives satisfactory results. PMID- 26121979 TI - The prevalence and pattern of deciduous molar hypomineralization and molar incisor hypomineralization in children from a suburban population in Nigeria. AB - BACKGROUND: Molar Incisor Hypoplasia (MIH) and Deciduous Molar Hypoplasia (DMH) have significant impact on the quality of life of affected individuals. The objective of the study was to determine the prevalence, pattern and clinical presentation of MIH and DMH in children resident in Ile-Ife, Nigeria, and their association with sex and socioeconomic status of the children. METHODS: Information on age, sex and socioeconomic status was collected from 563 children aged 3 to 5 years and 8 to 10 years using a structured questionnaire through a household survey. Clinical examination was conducted to assess for the presence of DMH and MIH. The prevalence of DMH and MIH were determined. Tests of association between sex, socioeconomic status, prevalence, and pattern of presentation of both DMH and MIH were conducted using Pearson's Chi-squared test Fisher's exact test. RESULT: Fifteen (4.6%) of the 327 children aged 3 to 5 years and 23 (9.7%) of the 237 children aged 8 to 10 years had DMH and MIH respectively. There were no significant association between DMH, sex (p = 0.49) and socioeconomic status (p = 0.32). There were also no significant association between MIH, sex (p = 0.31) and socioeconomic status (p = 0.41). MIH/DMH co morbidity was observed in eight (34.8%) of the 23 children with MIH. The mandible and maxilla were affected equally. Antimere was not observed. CONCLUSION: The prevalence of DMH and the prevalence of MIH in the study population were high. DMH and MIH were not associated with sex and socioeconomic status. There was no specific pattern identified in the presentation of DMH and MIH. The prevalence of DMH/MIH co-morbidity is also high. Patients with DMH should be screened for MIH. PMID- 26121981 TI - DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. AB - Upregulation of microRNA-21 (miR-21) is known to be strongly associated with the proliferation, invasion, and radio-resistance of glioma cells. However, the regulatory mechanism that governs the biogenesis of miR-21 in glioma is still unclear. Here, we demonstrate that the DEAD-box RNA helicase, DDX23, promotes miR 21 biogenesis at the post-transcriptional level. The expression of DDX23 was enhanced in glioma tissues compared to normal brain, and expression level of DDX23 was highly associated with poor survival of glioma patients. Specific knockdown of DDX23 expression suppressed glioma cell proliferation and invasion in vitro and in vivo, which is similar to the function of miR-21. We found that DDX23 increased the level of miR-21 by promoting primary-to-precursor processing of miR-21 through an interaction with the Drosha microprocessor. Mutagenesis experiments critically demonstrated that the helicase activity of DDX23 was essential for the processing (cropping) of miR-21, and we further found that ivermectin, a RNA helicase inhibitor, decreased miR-21 levels by potentially inhibiting DDX23 activity and blocked invasion and cell proliferation. Moreover, treatment of ivermectin decreased glioma growth in mouse xenografts. Taken together, these results suggest that DDX23 plays an essential role in glioma progression, and might thus be a potential novel target for the therapeutic treatment of glioma. PMID- 26121980 TI - Genome-wide association analysis identified splicing single nucleotide polymorphism in CFLAR predictive of triptolide chemo-sensitivity. AB - BACKGROUND: Triptolide is a therapeutic diterpenoid derived from the Chinese herb Tripterygium wilfordii Hook f. Triptolide has been shown to induce apoptosis by activation of pro-apoptotic proteins, inhibiting NFkB and c-KIT pathways, suppressing the Jak2 transcription, activating MAPK8/JNK signaling and modulating the heat shock responses. RESULTS: In the present study, we used lymphoblast cell lines (LCLs) derived from 55 unrelated Caucasian subjects to identify genetic markers predictive of cellular sensitivity to triptolide using genome wide association study. Our results identified SNPs on chromosome 2 associated with triptolide IC50 (p < 0.0001). This region included biologically interesting genes as CFLAR, PPIl3, Caspase 8/10, NFkB and STAT6. Identification of a splicing-SNP rs10190751, which regulates CFLAR alternatively spliced isoforms predictive of the triptolide cytotoxicity suggests its role in triptolides action. Our results from functional studies in Panc-1 cell lines further demonstrate potential role of CFLAR in triptolide toxicity. Analysis of gene-expression with cytotoxicity identified JAK1 expression to be a significant predictor of triptolide sensitivity. CONCLUSIONS: Overall out results identified genetic factors associated with triptolide chemo-sensitivity thereby opening up opportunities to better understand its mechanism of action as well as utilize these biomarkers to predict therapeutic response in patients. PMID- 26121982 TI - Structure-Function Basis of Attenuated Inverse Agonism of Angiotensin II Type 1 Receptor Blockers for Active-State Angiotensin II Type 1 Receptor. AB - Ligand-independent signaling by the angiotensin II type 1 receptor (AT1R) can be activated in clinical settings by mechanical stretch and autoantibodies as well as receptor mutations. Transition of the AT1R to the activated state is known to lower inverse agonistic efficacy of clinically used AT1R blockers (ARBs). The structure-function basis for reduced efficacy of inverse agonists is a fundamental aspect that has been understudied not only in relation to the AT1R but also regarding other homologous receptors. Here, we demonstrate that the active-state transition in the AT1R indeed attenuates an inverse agonistic effect of four biphenyl-tetrazole ARBs through changes in specific ligand-receptor interactions. In the ground state, tight interactions of four ARBs with a set of residues (Ser109(TM3), Phe182(ECL2), Gln257(TM6), Tyr292(TM7), and Asn295(TM7)) results in potent inverse agonism. In the activated state, the ARB-AT1R interactions shift to a different set of residues (Val108(TM3), Ser109(TM3), Ala163(TM4), Phe182(ECL2), Lys199(TM5), Tyr292(TM7), and Asn295(TM7)), resulting in attenuated inverse agonism. Interestingly, V108I, A163T, N295A, and F182A mutations in the activated state of the AT1R shift the functional response to the ARB binding toward agonism, but in the ground state the same mutations cause inverse agonism. Our data show that the second extracellular loop is an important regulator of the functional states of the AT1R. Our findings suggest that the quest for discovering novel ARBs, and improving current ARBs, fundamentally depends on the knowledge of the unique sets of residues that mediate inverse agonistic potency in the two states of the AT1R. PMID- 26121983 TI - Airway and Respiration Parameters Improve Following Vocal Fold Medialization: A Prospective Study. AB - OBJECTIVES/HYPOTHESIS: Laryngeal medialization procedures such as injection laryngoplasty (IL) and thyroplasty type 1 (TT1) are standard techniques for the treatment of glottic insufficiency related to unilateral vocal fold paralysis (UVFP). These procedures reliably improve the voice and may also improve swallowing function. Despite the association of laryngeal paralysis with airway regulation, there is little published on the effect of UVFP and its surgical treatment on respiration. The aim of this prospective study was to evaluate the aerodynamic outcomes of UVFP patients before and after vocal fold medialization, either by IL or TT1. METHODS: Consecutive patients with dysphonia due to UVFP were included in this prospective study between 2012 and 2014. Nineteen patients were investigated (5 females, 14 males) with a mean age of 37.05 +/- 17.8 years. Eight patients were treated by IL while 11 patients received TT1. The patients were subjected to Modified Medical Research Council (MMRC) and Borg dyspnea scales, maximum phonation time (MPT) measurement, spirometry, and cycle ergometry, pre- and postoperatively at 2 months. RESULTS: There was a statistically significant increase in MPT from 5.5 +/- 3 seconds to 11.2 +/- 4.9 seconds postoperatively (P < .001). The MMRC and Borg dyspnea scales also showed significant improvement postoperatively (P < .001, P = .006, respectively). The change in spirometric parameters (peak expiratory flow, forced expiratory volume in 1 second, forced vital capacity, and peak inspiratory flow) were nonsignificant, while there was a significant improvement in cycle ergometry test postoperatively (P = .018). CONCLUSION: Laryngeal medialization procedures such as IL and TT1 improve UVFP patients' respiration-related quality of life and aerodynamic performance with no significant changes in spirometry. PMID- 26121984 TI - HIV-associated lymphoma in the era of combination antiretroviral therapy: shifting the immunological landscape. AB - HIV infection increases the risk of many types of cancer, including lymphoma. Combination antiretroviral therapy (cART) has reduced, but not eliminated, the risk of HIV-associated lymphoma. There has been a substantial shift in the subtypes of lymphoma observed in HIV-infected patients treated with cART. In this review, we will first outline these changes based on epidemiological studies and describe the impact of cART on lymphoma risk and mortality. Then, we will discuss some immunological factors that may contribute to the increased risk of lymphoma persisting after the administration of cART, including immunological non-response to therapy, chronic B-cell activation and dysfunction, T follicular helper cells, natural killer cells and altered lymphopoiesis. A better understanding of the pathophysiologic mechanisms of HIV-associated lymphoma under effective cART will inform future treatment strategies. PMID- 26121985 TI - Cross-cultural verification of the EORTC QLQ-C15-PAL questionnaire in mainland China. AB - BACKGROUND: Simplified by European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30), EORTC Quality-of Life Questionnaire Core 15 Palliative Care (QLQ-C15-PAL) is specifically applied to evaluating palliative care patients' quality of life. AIM: This study examined cross-cultural adaptability and validity of QLQ-C15-PAL for evaluating quality of life of palliative care patients with advanced cancer in mainland China. PARTICIPANTS AND DESIGN: From May to October 2013, 243 palliative care patients in Tianjin Cancer Hospital completed the EORTC QLQ-C30. We extracted QLQ-C15-PAL data for analysis. Physicians completed the Eastern Cooperative Oncology Group Performance Status score and mental state assessment for each patient. RESULTS: A total of 243 patients completed the study. The compliance rate was high, with missing rate for each item ranging from 0% to 2.1%. In addition to emotional function, the remaining dimensions demonstrated a high reliability (Cronbach's alpha > 0.7). Whether we divided patients into two groups according to their Eastern Cooperative Oncology Group Performance Status or divided patients into three groups according to mental status, both sets of results showed significant differences in QLQ-C15-PAL subscale scores (p < 0.05), indicating that the QLQ C15-PAL scale could be used to distinguish between the aforementioned subgroups. Overall quality of life was moderately correlated with fatigue (r = -0.406) but weakly correlated with other subscales. The proportion of variance (R(2)) ranged from 0.848 to 0.903, which showed that QLQ-C15-PAL subscale scores explained between 84.8% and 90.3% of the original QLQ-C30 score distribution. CONCLUSION: The Chinese version of the EORTC QLQ-C15-PAL questionnaire has high reliability and validity and is therefore suitable for clinical use in China to determine health-related quality of life in Chinese patients with advanced cancer. PMID- 26121986 TI - A "client-centred activities of daily living" intervention for persons with stroke: One-year follow-up of a randomized controlled trial. AB - OBJECTIVE: To compare changes regarding perceived participation, independence in activities of daily living (ADL) and life satisfaction between 3, 6 and 12 months after inclusion in a study of a client-centred ADL intervention and usual ADL intervention after stroke. DESIGN: A multicentre randomized controlled trial. METHODS: Sixteen rehabilitation units were randomly assigned to provide client centred ADL intervention or usual ADL intervention. Eligible participants were persons <= 3 months after stroke who had been treated in a stroke unit, were dependent in two ADL domains, had not been diagnosed with dementia, and were able to understand instructions. Data collection was performed by blinded assessors. The primary outcome, perceived participation, was assessed with the Stroke Impact Scale 3.0, domain 8. The secondary outcomes, participation, independence in ADL, and life satisfaction, were assessed with validated instruments. For statistical power, 280 participants were required. Statistical analyses were performed on an intention-to-treat basis. RESULTS: There were no differences between the groups regarding changes in perceived participation, independence in ADL, or life satisfaction during the first 12 months. There was a trend towards a clinically meaningful positive change in perceived participation that favoured client centred ADL intervention. CONCLUSION: Further research is required to understand the benefits of client-centred interventions. PMID- 26121987 TI - A prospective study of insulin-like growth factor 1, its binding protein 3, and risk of endometriosis. AB - Several retrospective case-control studies suggested that insulin-like growth factor 1 (IGF-1) or insulin-like growth factor binding protein 3 (IGFBP-3) was associated with endometriosis. However, results are inconsistent and no prospective study exists. We prospectively evaluated associations between plasma levels of IGF-1 and IGFBP-3 and laparoscopically confirmed endometriosis in a case-control study nested within the Nurses' Health Study II. Between blood collections in 1996-1999 and 2007, we ascertained 310 premenopausal women with incident endometriosis and 615 matched controls. We estimated incidence rate ratios and 95% confidence intervals using multivariable conditional logistic regression. We observed no statistically significant associations between endometriosis and IGF-1 (incidence rate ratio (IRR) = 0.88, 95% confidence interval (CI): 0.61, 1.27; Ptrend = 0.48), IGFBP-3 (IRR = 1.12, 95% CI: 0.80, 1.57; Ptrend = 0.51), and the IGF-1:IGFBP-3 molar ratio (IRR = 0.94, 95% CI: 0.66, 1.34; Ptrend = 0.64), comparing the top with the bottom tertile. IGF-1, IGFBP-3, and the molar ratio appeared to be positively associated with endometriosis risk among women aged <40 years at blood draw (IGF-1: IRR = 1.60, 95% CI: 0.86, 2.98; IGFBP-3: IRR = 1.85, 95% CI: 1.08, 3.16; IGF-1:IGFBP-3: IRR = 1.57, 95% CI: 0.85, 2.88) but not among women aged >=40 years at blood draw (all Pheterogeneity <= 0.05). Overall, these data suggest that, if IGF-1 or IGFBP-3 plays a role in the etiology of endometriosis, it is minimal and perhaps only among younger women. PMID- 26121988 TI - The association between traumatic brain injury and suicide: are kids at risk? AB - Traumatic brain injury (TBI) in late adolescence and adulthood is associated with a higher risk of suicide; however, it is unknown whether this association is also present in people who sustained a TBI during childhood. The purpose of the present study was to determine whether experiencing a TBI during childhood is a risk factor for suicide later in life and to examine whether the risk of suicide differs by sex or injury severity. A cohort of 135,703 children aged 0-17 years was identified from the Quebec population-based physician reimbursement database in 1987, and follow-up was conducted until 2008. Of the children in this cohort, 21,047 had sustained a TBI. Using a survival analysis with time-dependent indicators of TBI, we found a higher risk of suicide for people who sustained a TBI during childhood (hazard ratio (HR) = 1.49, 95% confidence interval (CI): 1.04, 2.14), adolescence (HR = 1.57, 95% CI: 1.09, 2.26), and adulthood (HR = 2.53, 95% CI: 1.79, 3.59). When compared with less severe injuries, such as concussions and cranial fractures, more severe injuries, such as intracranial hemorrhages, were associated with a higher risk of suicide (HR = 2.18 vs. 2.77, respectively). Repeated injuries were associated with higher risks of suicide in all age groups. PMID- 26121990 TI - Children mix direct and indirect speech: evidence from pronoun comprehension. AB - This study investigates children's acquisition of the distinction between direct speech (Elephant said, "I get the football") and indirect speech (Elephant said that he gets the football), by measuring children's interpretation of first, second, and third person pronouns. Based on evidence from various linguistic sources, we hypothesize that the direct-indirect distinction is acquired relatively late. We also predict more mistakes for third person pronouns compared to first and second person pronouns. We tested 136 Dutch-speaking children between four and twelve in a referent selection task and found that children interpret pronouns in direct speech predominantly as in indirect speech, supporting our hypothesis about a late acquisition of the direct-indirect distinction. In addition, we found differences between I, you, and he that deviate from a simple first and second vs. third person split. We discuss our results in the light of cross-linguistic findings of direct-indirect mixing. PMID- 26121989 TI - Associations Between Residential Proximity to Power Plants and Adverse Birth Outcomes. AB - Few studies have assessed the associations between residential proximity to power plants and adverse birth outcomes including preterm delivery (PTD), very preterm delivery (VPTD), and term low birth weight (LBW). We geocoded 423,719 singleton Florida births born from 2004 to 2005 and all active power plants and determined residential proximity to the nearest power plant for each birth. Prenatal exposure to particulate matter less than 2.5 um in diameter for women living near different types of power plants was also determined by using National Environmental Public Health Tracking Network data. Logistic regression models were used to test the hypothesized associations. Women who lived closer to coal and solid waste power plants were exposed to higher levels of particulate matter less than 2.5 um in diameter compared with other types. We observed a 1.8% (95% confidence interval (CI): 1.3, 2.3) increased odds for PTD, 2.2% (95% CI: 1.0, 3.4) for VPTD, and 1.1% (95% CI: 0.2, 2.0) for term LBW for each 5 km closer to any power plant. When stratifying by different fuel type, we found that only solid waste had an association with term LBW, whereas oil, gas, and solid waste all had an association with PTD and VPTD. Results were consistent when exposure was categorized by number of power plants. Our study found evidence of increasing odds of adverse birth outcomes among infants born to pregnant women living closer to power plants. More research is warranted to better understand the causal relationship. PMID- 26121991 TI - Foaming Properties of Whey Protein Isolate and lambda-Carrageenan Mixed Systems. AB - Heating protein with polysaccharide under neutral or near neutral pH can induce the formation of soluble complex with improved functional properties. The objective of our research was to investigate the effects of lambda-carrageenan (lambdaC) concentrations and pH on foaming properties of heated whey protein isolate (WPI) and lambdaC soluble complex (h-cpx) in comparison to heated WPI with added lambdaC (pWPI-lambdaC), and unheated WPI with lambdaC (WPI-lambdaC). In all 3 WPI-lambdaC systems at pH 7, increasing lambdaC concentration led to improved foamability until a certain concentration before it decreased. Despite their higher viscosity, both heated systems (pWPI-lambdaC and h-cpx) showed significantly better foamability and foam stability compared to WPI-lambdaC. Rheological results of foams with 0.25% lambdaC suggested that higher elasticity and viscous films were produced in h-cpx and pWPI-lambdaC systems corresponding to better foam stability. Foam microstructure images indicated that foams produced from h-cpx had thicker film and consisted of smaller initial bubble area and more uniform bubble size. Results from the effect of pH (6.2, 6.5, and 7.0) further confirmed that stronger interactions between WPI and lambdaC during heating contributed to the improved foaming properties. Foam stability was higher in h-cpx system at all 3 pH levels, especially under pH 6.2 where there were strongest interactions between the biopolymers. PMID- 26121992 TI - Functional capacity in idiopathic pulmonary fibrosis: Looking beyond the lungs. PMID- 26121993 TI - Dose-dependency of clonidine's effects in ascitic cirrhotic rats: comparison with alpha1-adrenergic agonist midodrine. AB - BACKGROUND & AIMS: Sympathetic nervous system (SNS) activation decreases response to diuretics, but both alpha1-adrenoceptor agonists and sympatholytic alpha2 adrenoceptor agonists are recommended in the management of ascitic cirrhosis. We intend to compare the effects of increasing doses of clonidine (alpha2-agonist) vs. midodrine (alpha1-agonist) in advanced cirrhosis. METHODS: Renal function, mean arterial pressure (MAP), and hormonal status were measured in rats with ascitic cirrhosis due to 13-week CCl(4) administration (groups G1-G5), in control rats (Gc), and in rats with ascitic cirrhosis untreated (G6) or treated with daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K(+) -canrenoate during the 11(th) -13(th) weeks of CCl(4)) (G7). G1-G5 cirrhotic rats received daily, during the 11(th)-13(th) CCl(4) weeks: clonidine 0.3 MUg only (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3) or 1 MUg (G4), and diuretics + midodrine 1 mg/kg b.w. (G5). RESULTS: Cirrhotic rats in G1 or G2 had higher glomerular filtration rate, renal plasma flow and natriuresis than cirrhotic rats treated with diuretics (G7) (all P < 0.05). The addition of clonidine 0.2 MUg to diuretics (G2 vs. G7) reduced serum norepinephrine (169 +/- 71 ng/L vs. 523 +/- 88 ng/L) and plasma renin activity (12 +/- 3 ng/ml/h vs. 25 +/- 5 ng/ml/h) (all P < 0.05). Midodrine did not improve the renal performance in ascitic rats treated with diuretics. In comparison to absolute cirrhotic controls (G6), MAP was lower in G4 and higher in G5 (all P < 0.05). CONCLUSION: Low-dose alpha2-agonists improve natriuresis and reduce SNS function and hyper-aldosteronism without affecting arterial pressure in experimental ascitic cirrhosis treated with diuretics. PMID- 26121994 TI - A three-dimensional in vitro culture model of Hailey-Hailey disease. PMID- 26121995 TI - A systems approach to reducing maternal obesity: The Health in Preconception, Pregnancy and Postbirth (HIPPP) Collaborative. AB - Obesity in our childbearing population has increased to epidemic proportions in developed countries; efforts to address this issue need to focus on prevention. The Health in Preconception, Pregnancy and Postbirth (HIPPP) Collaborative - a group of researchers, practitioners, policymakers and end-users - was formed to take up the challenge to address this issue as a partnership. Application of systems thinking, participatory systems modelling and group model building was used to establish research questions aiming to optimise periconception lifestyle, weight and health. Our goal was to reduce the burden of maternal obesity through systems change. PMID- 26121996 TI - Dietary protein intake may reduce hospitalisation due to infection in Maori of advanced age: LiLACS NZ. AB - OBJECTIVE: To investigate factors related to hospital admission for infection, specifically examining nutrient intakes of Maori in advanced age (80+ years). METHOD: Face-to-face interviews with 200 Maori (85 men) to obtain demographic, social and health information. Diagnoses were validated against medical records. Detailed nutritional assessment using the 24-hour multiple-pass recall method was collected on two separate days. FOODfiles was used to analyse nutrient intake. National Health Index (NHI) numbers were matched to hospitalisations over a two year period (12 months prior and 12 months following dietary assessment). Selected International Classification of Disease (ICD) codes were used to identify admissions related to infection. RESULTS: A total of 18% of participants were hospitalised due to infection, most commonly lower respiratory tract infection. Controlling for age, gender, NZ deprivation index, diabetes, CVD and chronic lung disease, a lower energy-adjusted protein intake was independently associated with hospitalisation due to infection: OR (95%CI) 1.14 (1.00-1.29), p=0.046. CONCLUSIONS: Protein intake may have a protective effect on the nutrition-related morbidity of older Maori. Improving dietary protein intake is a simple strategy for dietary modification aiming to decrease the risk of infections that lead to hospitalisation and other morbidities. PMID- 26121997 TI - A central approach to splenorenal shunt in pediatric living donor liver transplantation. AB - The management of LSRS is a crucial problem to ensure a sufficient PV flow during pediatric LT. Although several techniques have been indicated to solve this problem, a more appropriate approach to LSRS is still needed in pediatric LT. We herein present a modified surgical approach to the ligation of LSRS via the left side of the IVC for a nine-month-old boy with severe portal hypertension and a history of Kasai portoenterostomy. LSRS was identified and exposed through the left side of the IVC and the dorsal surface of the pancreas from the superior side of the body of the pancreas. The post-operative course was uneventful with an excellent PV flow. The central approach for the ligation of LSRS is worth considering as an alternative procedure for a patient with collateral vessels and a history of multiple laparotomies. PMID- 26121998 TI - A telephone-delivered multiple health behaviour change intervention for colorectal cancer survivors: making the case for cost-effective healthcare. AB - In patients with colorectal cancer, a trial of a telephone-delivered multiple health behaviour change intervention, using acceptance commitment therapy strategies, found benefits for health and psychosocial outcomes including increased physical activity, improved dietary habits and lower body mass index. Our aim was to address the health economic outcomes by assessing the health system cost and health utility impacts of the intervention. A cost-consequences analysis was performed using data from a two-group randomised controlled intervention trial (n = 410). Outcomes included health-related quality of life (HRQoL), health utility and health system costs. At 12 months, clinically meaningful improvements were found for SF-6D over time but no significant differences were found between groups (P = 0.95). The cost of delivering the 6 month intervention was on average ?280 per person and made up 21% of overall healthcare costs for participants during the intervention period. Excluding intervention costs, costs were similar for health professional visits and medications across groups. Despite significant positive intervention effects on health behaviours, health utility and HRQoL scores were similar across groups. On the basis that intervention costs were small and physical activity, diet and weight management improved, on balance the intervention is potentially a worthwhile investment in healthcare funds. TRIAL REGISTRATION: ACTRN12608000399392. PMID- 26121999 TI - Epitaxial B-Graphene: Large-Scale Growth and Atomic Structure. AB - Embedding foreign atoms or molecules in graphene has become the key approach in its functionalization and is intensively used for tuning its structural and electronic properties. Here, we present an efficient method based on chemical vapor deposition for large scale growth of boron-doped graphene (B-graphene) on Ni(111) and Co(0001) substrates using carborane molecules as the precursor. It is shown that up to 19 at. % of boron can be embedded in the graphene matrix and that a planar C-B sp(2) network is formed. It is resistant to air exposure and widely retains the electronic structure of graphene on metals. The large-scale and local structure of this material has been explored depending on boron content and substrate. By resolving individual impurities with scanning tunneling microscopy we have demonstrated the possibility for preferential substitution of carbon with boron in one of the graphene sublattices (unbalanced sublattice doping) at low doping level on the Ni(111) substrate. At high boron content the honeycomb lattice of B-graphene is strongly distorted, and therefore, it demonstrates no unballanced sublattice doping. PMID- 26122000 TI - Microscopic Positive Margins in Differentiated Thyroid Cancer Is Not an Independent Predictor of Local Failure. AB - BACKGROUND: In contrast to other head and neck cancers, the impact of histological thyroid specimen margin status in differentiated thyroid cancer (DTC) is not well understood. The aim of this study was to investigate the prognostic value of margin status on local recurrence in DTC. METHOD: The records of 3664 consecutive patients treated surgically for DTC between 1986 and 2010 were identified from an institutional database. Patients with less than total thyroidectomy, unresectable or gross residual disease, or M1 disease at presentation and those with unknown pathological margin status were excluded from analysis. In total, 2616 patients were included in the study; 2348 patients (90%) had negative margins and 268 patients (10%) had positive margins. Microscopic positive margin status was defined as tumor present at the specimen's edge on pathological analysis. Patient, tumor, and treatment characteristics were compared by Pearson's chi-squared test. Local recurrence free survival (LRFS) was calculated for each group using the Kaplan Meier method. RESULTS: The median age of the cohort was 48 years (range 7-91 years) and the median follow-up was 50 months (range 1-330 months). Age, sex, and histology types were similar between groups. As expected, patients who had positive margins were more likely to have larger tumors (p<0.001), extrathyroidal extension (ETE) (p<0.001), multicentric disease (p<0.001), or nodal disease (p<0.001) and were more likely to receive adjuvant radioactive iodine therapy (p<0.001) as well as external beam radiotherapy (p<0.001). The LRFS at 5 years for patients with positive margins status was slightly poorer compared with patients with negative margins (98.9% vs. 99.5%, p=0.018). Twelve patients developed local recurrence-8/2348 (0.34%) patients with negative margins and 4/263 (1.52%) patients with positive margins. Univariate predictors of LRFS were sex (p=0.006), gross ETE (<0.001), and positive margins (p=0.018). However, when controlling for presence of gross ETE on multivariate analysis, microscopic positive margin status was not an independent predictor of LRFS (p=0.193). CONCLUSION: Patients with resectable, M0 disease that undergo total thyroidectomy have an excellent five year LRFS of 99.4%. Microscopic positive margin status was not a significant predictor for local failure after adjusting for ETE or pathological tumor (pT) stage. PMID- 26122002 TI - Antibiotic prophylaxis to prevent postoperative infectious morbidity in low-risk elective cesarean deliveries: a prospective randomized clinical trial. AB - OBJECTIVE: To determine the effectiveness and cost of antibiotic chemoprophylaxis in reducing infectious morbidity in low-risk women undergoing elective cesarean delivery. METHODS: A prospective randomized clinical trial was performed at a single tertiary care center in Jinan, China between November 2012 and December 2013. Women were randomized to receive either antibiotic prophylaxis or no antibiotics prior to elective cesarean delivery at term. The infectious morbidity (fever, surgical site infection - SSI, endometritis and urinary tract infection), routine blood tests and hospital costs were measured. RESULTS: Total of 414 women were enrolled into the study; and 202 women received antibiotic chemoprophylaxis and 212 women received no antibiotics. Demographic and clinical characteristics were similar between the two groups. Total of one case in the treatment group and four case in the non-treatment group developed endometritis, giving the postoperative infection rate of 1.2%, which was not statistically significant between the two groups (chi(2) = 1.679, p = 0.195). The secondary outcomes were also not different between the two groups, except the costs of hospitalization, which was significantly higher in the treatment group (p < 0.001). CONCLUSIONS: In low-risk women undergoing elective cesarean delivery at term, prophylactic antibiotics did not reduce the risk of postoperative infection, but significantly increased the cost of hospitalization. PMID- 26122003 TI - Temporal dynamics of anxiety phenotypes in a dental pulp injury model. AB - BACKGROUND: Accumulating clinical and preclinical evidence indicates that chronic pain is often comorbid with persistent low mood and anxiety. However, the mechanisms underlying pain-induced anxiety, such as its causality, temporal progression, and relevant neural networks are poorly understood, impeding the development of efficacious therapeutic approaches. RESULTS: Here, we have identified the sequential emergence of anxiety phenotypes in mice subjected to dental pulp injury (DPI), a prototypical model of orofacial pain that correlates with human toothache. Compared with sham controls, mice subjected to DPI by mechanically exposing the pulp to the oral environment exhibited significant signs of anxiogenic effects, specifically, altered behaviors on the elevated plus maze (EPM), novelty-suppressed feeding (NSF) tests at 1 but not 3 days after the surgery. Notably, at 7 and 14 days, the DPI mice again avoided the open arm, center area, and novelty environment in the EPM, open field, and NSF tests, respectively. In particular, DPI-induced social phobia and increased repetitive grooming did not occur until 14 days after surgery, suggesting that DPI-induced social anxiety requires a long time. Moreover, oral administration of an anti inflammatory drug, ibuprofen, or an analgesic agent, ProTx-II, which is a selective inhibitor of NaV1.7 sodium channels, both significantly alleviated DPI induced avoidance in mice. Finally, to investigate the underlying central mechanisms, we pharmacologically blocked a popular form of synaptic plasticity with a GluA2-derived peptide, long-term depression, as that treatment significantly prevented the development of anxiety phenotype upon DPI. CONCLUSIONS: Together, these results suggest a temporally progressive causal relationship between orofacial pain and anxiety, calling for more in-depth mechanistic studies on concomitant pain and anxiety disorders. PMID- 26122004 TI - Distribution of cervical intraepithelial neoplasia on the cervix in Chinese women: pooled analysis of 19 population based screening studies. AB - BACKGROUND: Controversy remains whether a pattern of cervical intraepithelial neoplasia exists on the cervix. Our study aims at determining if the prevalence of histologically proven lesions differs by cervical four-quadrant location or by 12 o'clock surface locations of diagnosis. METHODS: We conducted a retrospective, histopathological study of 19 different population based cervical cancer screening studies from 1999 to 2010 by Cancer Hospital of Chinese Academy of Medical Sciences. The Institutional Review Board for human research subjects at CHCAMS approved all of the studies. During the colposcopy procedure, participant received either 4-quadrant biopsy or directed biopsy with/without endocervical curettage. Data of all samples were stratified by the methods of sampling. Kruskal-Wallis test was used to determine overall distribution of normal/CIN1, CIN2 and CIN3+ on the cervix. RESULTS: In total, 53,088 cervical samples were included in distribution analysis. 66.9% samples were obtained by random biopsy, 16.1% were by directed biopsy, and 17.0% were by endocervical curettage. 95.9%of the biopsied samples were diagnosed as normal/CIN1, 2.0% were CIN2, and 2.1% were CIN3+. CIN2 and CIN3+ were most often found in quadrants 2 and 3 (chiKW2=46.6540, p<0.0001) and at the 4- and 7-o'clock positions by directed biopsy (ORCIN2=2.572, 1.689, ORCIN3+=3.481, 1.678, respectively), and at the 5-, 6-, 7-, 9- and 12 o'clock positions by random biopsy. CIN3+ was least often found at the 11-o'clock position by directed biopsy (OR=0.608). CONCLUSIONS: Our results suggest a predisposition of specific locations on the cervix to CIN occurrence. Quadrants 2 and 3, especially the 4- and 7-o'clock positions should be preferentially targeted during biopsy. The decision for random biopsy should be reconsidered in future studies. PMID- 26122005 TI - Development and cognitive testing of the Nottwil Environmental Factors Inventory in Canada, Switzerland and the USA. AB - OBJECTIVE: To develop and pre-test the Nottwil Environmental Factors Inventory (NEFI), a questionnaire assessing the perceived impact of environmental factors on specific areas of participation (productive life, social life, and community life) experienced by people with spinal cord injury. SUBJECTS/PATIENTS: Thirty seven participants with spinal cord injury in Canada, Switzerland and the USA. METHODS: A first draft of the NEFI was developed based on a new theoretical model, the International Classification of Functioning, Disability and Health (ICF) Core Sets for spinal cord injury, and expert consultation. Three rounds of cognitive testing were conducted to examine participants' comprehension of the conceptual framework and items, to identify challenges in cross-cultural measurement, and iteratively to refine the questionnaire. RESULTS: Participants were able to differentiate well between environmental factors influencing productive life and those influencing social life or community life, but not between environmental factors influencing social life and community life. Items intended to capture avoidance of participation due to barriers or overcoming of obstacles were generally well understood. CONCLUSION: For people with spinal cord injury, the NEFI may help to identify limiting and helpful environmental factors, while considering avoiding and overcoming behaviours. Quantitative validation and exploration of the possible use of the NEFI in other diagnostic groups is recommended. PMID- 26122006 TI - Down Syndrome Cell Adhesion Molecule , Mother of Innovations. PMID- 26122007 TI - Evidence that histone H1 is dispensable for proper meiotic recombination in budding yeast. AB - BACKGROUND: Histone H1, referred to as the linker histone, associates with the nucleosome core particle. While there is indication that the budding yeast version of histone H1 (Hho1) contributes to regulation of chromatin structure and certain chromatin-related processes, such as DNA double-strand break repair, cells lacking Hho1 are healthy and display subtle phenotypes. A recent report has revealed that Hho1 is required for optimal sporulation. The studies described here were conducted to determine whether Hho1 influences meiotic recombination, an event that occurs during sporulation, involves generation and repair of DNA double-strand breaks, and is critical for spore viability. FINDINGS: Through tetrad analysis, cells with or without Hho1 were compared for meiotic reciprocal recombination events within several chromosome XV intervals. Parameters investigated included crossover frequency (genetic map distance) and crossover interference. No significant differences were detected between the two cell types. In agreement with earlier studies, spore viability was not affected by Hho1 absence. CONCLUSION: These data suggest that complete absence of Hho1 from chromatin does not affect reciprocal recombination between homologous chromosomes during meiosis. Therefore, the basal level of Hho1 that remains after its reported depletion early in meiosis is unlikely to be important for regulating recombination. Furthermore, the subsequent accumulation of Hho1 as the haploid products mature does not appear to be crucial for spore viability. PMID- 26122008 TI - Erratum: Computational identification of multi-omic correlates of anticancer therapeutic response. PMID- 26122009 TI - Sputum matrix metalloproteinase-8 and -9 and tissue inhibitor of metalloproteinase-1 in bronchiectasis: clinical correlates and prognostic implications. AB - BACKGROUND AND OBJECTIVE: The triplet of airway infection, inflammation and bronchial wall destruction associated with excessive matrix metalloproteinases (MMP) release and imbalance of tissue inhibitor metalloproteinase-1 (TIMP-1) is implicated in bronchiectasis. We sought to determine the associations between sputum MMP (MMP-8, MMP-9) and TIMP-1 and the severity of bronchiectasis; the utility of MMP in predicting risks of future bronchiectasis exacerbations (BE); and the changes in MMP levels during BE. METHODS: We recruited 102 patients with stable bronchiectasis and 22 healthy subjects. For bronchiectasis patients, baseline measurements consisted of sputum inflammation and MMP measurements, bacterial culture, spirometry and chest high-resolution computed tomography (HRCT). Bronchiectasis patients were followed up for 1 year to determine the frequency of BE. Changes in MMP levels during BE were assessed in 36 bronchiectasis patients. RESULTS: Sputum MMP-8, MMP-9 and MMP-9/TIMP-1 ratio in bronchiectasis patients were significantly increased compared with healthy subjects. MMP-8 and MMP-9 levels, but not TIMP-1, were positively correlated with clinical measures, including HRCT scores, spirometry and Bronchiectasis Severity Index. Seventy-nine bronchiectasis patients were included in survival analyses of BE. Lower levels of baseline MMP-9 were associated with reduced risks of and a longer time to the first BE during follow-up. MMP-8 and MMP-9, but not TIMP-1 or MMP-9/TIMP-1 ratio, were significantly heightened during BE. CONCLUSIONS: Sputum MMP might be useful biomarkers for the assessment of bronchiectasis severity and the prediction of future risks of BE. Our results provide the rationales for the future clinical application of MMP inhibitors. PMID- 26122010 TI - Cervical epidural blood patch--A literature review. AB - OBJECTIVE: Epidural blood patches (EBP) are rarely performed at the cervical levels, primarily due to fear of neurological complications such as spinal cord compression. We reviewed the literature to provide an evidence-based review of performance of cervical EBPs, with a specific focus on indication, technique, safety, and efficacy. DESIGN: A comprehensive electronic literature search was done to include studies that reported on performance of cervical EBPs in patients with CSF leak at the cervical level. Data regarding indication, level of CSF leak, level of cervical EBP, volume of blood used, efficacy, and complications were collected. RESULTS: A total of 15 studies, reporting on 19 patients were included. All patients presented with a headache that increased in the standing position, and improved in the supine position. All patients were identified to have a CSF leak at the cervical level. Eight patients first underwent a lumbar EBP, without complete, long-term relief. All these patients, along with 11 patients who did not undergo a lumbar EPB prior to cervical EBP, reported complete, long-term pain relief. EBPs were mostly done in the prone position, using imaging guidance. An average of 5-8 mL of autologous blood was injected in the epidural space. No major neurological complications were reported in any patient. CONCLUSION: The review suggests that cervical EBP can be performed for cervical CSF leaks associated with positional headache without a significant risk of serious adverse events. CLASSIFICATION OF EVIDENCE: Our review provides Class II level of evidence that cervical EBPs are safe and effective in reliving positional headache due to CSF leak. PMID- 26122011 TI - Association of microRNA 146a polymorphism rs2910164 and the risk of melanoma in an Italian population. PMID- 26122012 TI - Association of cord blood vitamin D at delivery with postpartum depression in Australian women. AB - BACKGROUND: Observational studies have implicated low serum vitamin D (25 hydroxyvitamin D (25(OH)D)) levels in the development of mood disorders. Postpartum depression (PPD) is an important public health issue, although little is known about its association with serum 25(OH)D. AIMS: To determine the association between 25(OH)D at delivery and the subsequent risk of PPD at six weeks and six months postpartum in a large cohort of Australian women. MATERIALS AND METHODS: Cord blood samples from 1040 women participating in the docosahexaenoic acid (DHA) to Optimise Maternal Infant Outcome randomised controlled trial were analysed for 25(OH)D by mass spectroscopy. Maternal PPD was assessed using the Edinburgh Postnatal Depression Scale at six weeks and six months postpartum. The association between standardised 25(OH)D and PPD was assessed, taking into account DHA treatment, social and demographic variables. RESULTS: There was no association between cord blood 25(OH)D concentration at delivery and PPD at either six weeks or six months postpartum. Cord blood 25(OH)D 25-50 and >50 nmol/L at delivery was associated with decreased risk of PPD at six weeks postpartum compared with 25(OH)D <25 nmol/L in the control group, but not the DHA group. There was no association between cord blood 25(OH)D <25 nmol/L at delivery and PPD at six months postpartum. CONCLUSIONS: This largest study to date of 25(OH)D levels at delivery and PPD did not reveal a consistent link with PPD. PMID- 26122013 TI - The impact of migration on deaths and hospital admissions from work-related injuries in Australia. AB - OBJECTIVE: The shift from an industrial to a service-based economy has seen a decline in work-related injuries (WRIs) and mortality. How this relates to migrant workers, who traditionally held high-risk jobs is unknown. This study examined deaths and hospital admissions from WRI, among foreign and Australian born workers. METHODS: Tabulated population data from the 1991 to 2011 censuses, national deaths 1991-2002 and hospital admission for 2001-10. Direct age standardised mortality and hospital admission rates (DSRs) and rate ratios (RRs) were derived to examine differences in work-related mortality/hospital admissions by gender, country of birth, employment skill level and years of residence in Australia. RESULTS: DSRs and RRs were generally lower or no different between Australian and foreign-born workers. Among men, mortality DSRs were lower for nine of 16 country of birth groups, and hospital admissions DSRs for 14 groups. An exception was New Zealand-born men, with 9% (95%CI 9-13) excess mortality and 24% (95%CI 22-26) excess hospital admissions. CONCLUSIONS: Four decades ago, foreign-born workers were generally at higher risk of WRI than Australian-born. This pattern has reversed. The local-born comprise 75% of the population and a pro-active approach to health and safety regulation could achieve large benefits. PMID- 26122015 TI - Corrigendum: Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations. PMID- 26122014 TI - Inhibitors of Protein Translocation Across the ER Membrane. AB - Protein translocation into the endoplasmic reticulum (ER) constitutes the first step of protein secretion. ER protein import is essential in all eukaryotic cells and is particularly critical in fast-growing tumour cells. Thus, the process can serve as target both for potential cancer drugs and for bacterial virulence factors. Inhibitors of protein transport across the ER membrane range from broad spectrum to highly substrate-specific and can interfere with virtually any stage of this multistep process, and even with transport of endocytosed antigens into the cytosol for cross-presentation. PMID- 26122016 TI - Defining attributes of patient safety through a concept analysis. AB - AIM: The aim of this study was to report an analysis of the concept of patient safety. BACKGROUND: Despite recent increase in the number of work being done to clarify the concept and standardize measurement of patient safety, there are still huge variations in how the term is conceptualized and how to measure patient safety data across various healthcare settings and in research. DESIGN: Concept analysis. DATA SOURCES: A literature search was conducted through PubMed and Cumulative Index to Nursing and Allied Health Literature, Plus using the terms 'patient safety' in the title and 'concept analysis,' 'attributes' or 'definition' in the title and or abstract. All English language literature published between 2002-2014 were considered for the review. METHODS: Walker and Avant's method guided this analysis. RESULTS: The defining attributes of patient safety include prevention of medical errors and avoidable adverse events, protection of patients from harm or injury and collaborative efforts by individual healthcare providers and a strong, well-integrated healthcare system. The application of Collaborative Alliance of Nursing Outcomes indicators as empirical referents would facilitate the measurement of patient safety. CONCLUSION: With the knowledge gained from this analysis, nurses may improve patient surveillance efforts that identify potential hazards before they become adverse events and have a stronger voice in health policy decision-making that influence implementation efforts aimed at promoting patient safety, worldwide. Further studies are needed on development of a conceptual model and framework that can aid with collection and measurement of standardized patient safety data. PMID- 26122017 TI - Guidelines for safe practice of stereotactic body (ablative) radiation therapy. AB - The uptake of stereotactic ablative body radiation therapy (SABR)/stereotactic body radiation therapy (SBRT) worldwide has been rapid. The Australian and New Zealand Faculty of Radiation Oncology (FRO) assembled an expert panel of radiation oncologists, radiation oncology medical physicists and radiation therapists to establish guidelines for safe practice of SABR. Draft guidelines were reviewed by a number of international experts in the field and then distributed through the membership of the FRO. Members of the Australian Institute of Radiography and the Australasian College of Physical Scientists and Engineers in Medicine were also asked to comment on the draft. Evidence-based recommendations (where applicable) address aspects of departmental staffing, procedures and equipment, quality assurance measures, as well as organisational considerations for delivery of SABR treatments. Central to the guidelines is a set of key recommendations for departments undertaking SABR. These guidelines were developed collaboratively to provide an educational guide and reference for radiation therapy service providers to ensure appropriate care of patients receiving SABR. PMID- 26122018 TI - Photothermal ablation of bone metastasis of breast cancer using PEGylated multi walled carbon nanotubes. AB - This study investigates therapeutic efficacy of photothermal therapy (PTT) in an orthotropic xenograft model of bone metastasis of breast cancer. The near infrared (NIR) irradiation on Multi-Walled Carbon Nanotubes (MWNTs) resulted in a rapid heat generation which increased with the MWNTs concentration up to 100 MUg/ml. MWNTs alone exhibited no toxicity, but inclusion of MWNTs dramatically decreased cell viability when combined with laser irradiation. Thermographic observation revealed that treatment with 10 MUg MWNTs followed by NIR laser irradiation resulted in a rapid increase in temperature up to 73.4+/-11.98 degrees C in an intraosseous model of bone metastasis of breast cancer. In addition, MWNTs plus NIR laser irradiation caused a remarkably greater suppression of tumor growth compared with treatment with either MWNTs injection or NIR irradiation alone, significantly reducing the amount of tumor-induced bone destruction. All these demonstrate the efficacy of PTT with MWNTs for bone metastasis of breast cancer. PMID- 26122019 TI - CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy. AB - We aimed to explore the possible influence of CYP2C9 (*2, *3 and IVS8-109 A>T), CYP2C19 (*2, *3 and *17) and ABCB1 (1236C>T, 2677G>A/T and 3435C>T) on phenytoin (PHT) plasma concentrations in 64 Mexican Mestizo (MM) patients with epilepsy currently treated with PHT in mono- (n=25) and polytherapy (n=39). Genotype and allele frequencies of these variants were also estimated in 300 MM healthy volunteers. Linear regression models were used to assess associations between the dependent variables (PHT plasma concentration and dose-corrected PHT concentration) with independent variables (CYP2C9, CYP2C19 and ABCB1 genotypes, ABCB1 haplotypes, age, sex, weight, and polytherapy). In multivariate models, CYP2C9 IVS8-109 T was significantly associated with higher PHT plasma concentrations (t(64)=2.27; P=0.03). Moreover, this allele was more frequent in the supratherapeutic group as compared with the subtherapeutic group (0.13 versus 0.03, respectively; P=0.05, Fisher's exact test). Results suggest that CYP2C9 IVS8-109 T allele may decrease CYP2C9 enzymatic activity on PHT. More research is needed to confirm findings. PMID- 26122022 TI - Hypertension: Benefit of pharmacists prescribing antihypertensive medication. PMID- 26122020 TI - Network analysis of gene expression in mice provides new evidence of involvement of the mTOR pathway in antipsychotic-induced extrapyramidal symptoms. AB - To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP induced EPS and offers new and valuable markers for pharmacogenetic studies. PMID- 26122021 TI - Germline and somatic genetic predictors of pathological response in neoadjuvant settings of rectal and esophageal cancers: systematic review and meta-analysis. AB - Oncologists have pointed out an urgent need for biomarkers that can be useful for clinical application to predict the susceptibility of patients to preoperative therapy. This review collects, evaluates and combines data on the influence of reported somatic and germline genetic variations on histological tumor regression in neoadjuvant settings of rectal and esophageal cancers. Five hundred and twenty seven articles were identified, 204 retrieved and 61 studies included. Among 24 and 14 genetic markers reported for rectal and esophageal cancers, respectively, significant associations in meta-analyses were demonstrated for the following markers. In rectal cancer, major response was more frequent in carriers of the TYMS genotype 2 R/2 R-2 R/3 R (rs34743033), MTHFR genotype 677C/C (rs1801133), wild-type TP53 and KRAS genes. In esophageal cancer, successful therapy appeared to correlate with wild-type TP53. These results may be useful for future research directions to translate reported data into practical clinical use. PMID- 26122023 TI - Cardiac resuscitation: Improving outcomes after out-of-hospital cardiac arrest. PMID- 26122024 TI - Gene therapy: Can SDF-1 improve cardiac function? PMID- 26122025 TI - Clinicopathological features and prognosis of triple-negative breast cancer: a comparison between younger (<60) and elderly (>=60) patients. AB - Triple-negative breast cancer (TNBC) has attracted more attention both clinically and experimentally because of its high-risk biological characteristics and lacking of effective treatment method. The tumour characteristics, patterns of recurrence and metastasis, therapy methods and prognosis in younger TNBC patients have been widely formulated, but the relevant data of the elderly people are lacking. We conducted this retrospective study to compare and analyse the above related characteristics between the younger and elderly patients with TNBC to estimate the relevance for the elderly TNBC patients. A total of 1489 female patients with primary breast cancer were diagnosed and treated at the department of General Surgery, the Chinese PLA General Hospital, China, from January 2004 to December 2008. In the 1489 patients, 302 patients (20.28%) with TNBC histopathologically confirmed were retrospectively analysed. The 302 TNBC patients were divided into two groups: the younger (<60 years) group and the elderly (>=60 years) group. The relevant characteristics of the two groups were compared. There were no statistically significant differences between the two groups in common clinical data of the patients, clinicopathological features of tumour and the features of local recurrences and metastases of tumour, and the 5 year disease-free survival and overall survival were all significantly higher in the elderly group than those in the younger group, although the elderly group patients accepted significantly less radiotherapy and chemotherapy than the younger group patients. The elderly and younger TNBC patients may belong to different subtypes of TNBC and we probably could take a more conservative and cautious attitude in choosing the post-operative adjuvant treatment for the elderly patients with TNBC. PMID- 26122026 TI - Self-Biased Hybrid Piezoelectric-Photoelectrochemical Cell with Photocatalytic Functionalities. AB - Utilizing solar energy for environmental and energy remediations based on photocatalytic hydrogen (H2) generation and water cleaning poses great challenges due to inadequate visible-light power conversion, high recombination rate, and intermittent availability of solar energy. Here, we report an energy-harvesting technology that utilizes multiple energy sources for development of sustainable operation of dual photocatalytic reactions. The fabricated hybrid cell combines energy harvesting from light and vibration to run a power-free photocatalytic process that exploits novel metal-semiconductor branched heterostructure (BHS) of its visible light absorption, high charge-separation efficiency, and piezoelectric properties to overcome the aforementioned challenges. The desirable characteristics of conductive flexible piezoelectrode in conjunction with pronounced light scattering of hierarchical structure originate intrinsically from the elaborate design yet facile synthesis of BHS. This self-powered photocatalysis system could potentially be used as H2 generator and water treatment system to produce clean energy and water resources. PMID- 26122027 TI - Skin manifestations of chromosome 18q deletion syndrome. PMID- 26122031 TI - Withdrawn: Standard first-line immunosuppression for acquired severe aplastic anemia in adults. AB - Withdrawn by the publisher. PMID- 26122028 TI - Obesity reduces the pro-angiogenic potential of adipose tissue stem cell-derived extracellular vesicles (EVs) by impairing miR-126 content: impact on clinical applications. AB - BACKGROUND/OBJECTIVES: Soluble factors and cell-derived extracellular vesicles (EVs) are crucial tissue repair mediators in cell-based therapy. In the present study, we investigate the therapeutic impact of EVs released by adipose tissue derived stem cells (ASCs) recovered from obese subjects' visceral and subcutaneous tissues. METHODS: ASCs were recovered from 10 obese (oASCs) and 6 non-obese (nASCs) participants and characterized. In selected experiments, nASCs and oASCs were cultured with palmitic acid (PA) or high glucose (HG), respectively. EVs from obese (oEVs) and non-obese (nEVs) subjects' visceral and subcutaneous ASCs were collected after ultracentrifugation and analyzed for their cargo: microRNA-126 (miR-126), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2 (MMP-2), and for their biological effects on endothelial cells (ECs). Western blotting analysis and loss- and gain-of function experiments were performed. RESULTS: oEVs show impaired angiogenic potential compared with nEVs. This effect depends on EV cargo: reduced content of VEGF, MMP 2 and, more importantly, miR-126. We demonstrate, using gain- and loss-of function experiments, that this reduced miR-126 content leads to Spred1 upregulation and the inhibition of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway in ECs. We also show that PA treatment of nASCs translates into the release of EVs that recapitulate oEV cargo. Moreover, HG treatment of oASCs further reduces miR-126 EV content and EV mediated in vitro angiogenesis. Finally, impaired pro-angiogenic potential is also detected in EVs released from obese subcutaneous adipose tissue-derived ASCs. CONCLUSIONS: These results indicate that obesity impacts on EV pro angiogenic potential and may raise concerns about the use of adipose tissue derived EVs in cell-based therapy in the obese setting. PMID- 26122029 TI - Sarcopenic obesity and risk of new onset depressive symptoms in older adults: English Longitudinal Study of Ageing. AB - BACKGROUND: We examined the role of sarcopenic obesity as a risk factor for new onset depressive symptoms over 6-year follow-up in a large sample of older adults. METHODS: The sample comprised 3862 community dwelling participants (1779 men, 2083 women; mean age 64.6+/-8.3 years) without depressive symptoms at baseline, recruited from the English Longitudinal Study of Ageing. At baseline and 4-year follow-up, handgrip strength (kg) of the dominant hand was assessed using a hand-held dynamometer, as a measure of sarcopenia. The outcome was new onset depressive symptoms at 6-year follow-up, defined as a score of ?4 on the 8 item Centre of Epidemiological Studies Depression scale. Sarcopenic obesity was defined as obese individuals (body mass index ?30 kg m(-)(2)) in the lowest tertile of sex-specific grip strength (<35.3 kg men; <19.6 kg women). RESULTS: Using a multivariable logistic regression model, the risk of depressive symptoms was greatest in obese adults in the lowest tertile of handgrip strength (odds ratio (OR), 1.79, 95% confidence interval (CI), 1.10, 2.89) compared with non obese individuals with high handgrip strength. Participants who were obese at baseline and had a decrease of more than 1 s.d. in grip strength over 4-year follow-up were at greatest risk of depressive symptoms (OR=1.97, 95% CI, 1.22, 3.17) compared with non-obese with stable grip strength. CONCLUSIONS: A reduction in grip strength was associated with higher risk of depressive symptoms in obese participants only, suggesting that sarcopenic obesity is a risk factor for depressive symptoms. PMID- 26122032 TI - Epigenetic Regulation of Myocardial Homeostasis, Self-Regeneration and Senescence. AB - The adult myocardium has limited capacity to preserve, renew or rejuvenate itself. The local microenvironment may induce epigenetic changes affecting the survival, proliferation, function and senescence of cardiac cells at rest and following the exposure to different stressors. The cellular response to microenvironment is characterized by the release of ions, oxygen free radicals, auto/paracrine factors and RNAs that drive the magnitude of gene reprogramming through the interaction with specific promoters. The epigenetic alterations may act at transcriptional and post-transcriptional level and change cardiac physiological traits. The abnormal DNA methylation underlies the progressive decay of contractile function and the angiogenic ability; while, the histone acetylation promotes the survival, function and proliferation of cardiac cells in the presence of ischemic microenvironment. At least, the expression and secretion of microRNAs and long noncoding RNAs may regulate the threshold to stress tolerance of adult cardiac cells and induce the matrix turnover as well. Natural or synthetic active compounds effectively modulate the epigenetic state of cardiac cells. Plant foods contain many active compounds with epigenetic properties and might assume a clinical significance as natural cardiac regenerators or rejuvenators. Our review describes novel epigenetic mechanisms that underpin myocardial remodeling, repair/ regeneration or senescence in order to support the development of most effective and reproducible rescue therapy of adult heart. PMID- 26122033 TI - Wnt Signaling in Rhabdomyosarcoma - A Potential Targeted Therapy Option. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in the pediatric population and recapitulates many of the phenotypic and biological features of embryonic skeletal muscle. RMS is pathologically characterized by myogenic differentiation arrest. Dysregulation of pathways essential for myogenesis like contribute to the tumorigenesis of RMS. The Wnt signaling pathway is one of the major pathways required for normal myogenesis. Aberrant Wnt signaling has also been demonstrated in many types of cancer. The role of Wnt pathway in the pathogenesis of RMS is beginning to be appreciated. This review will go over current knowledge on biological roles of Wnt pathway in RMS and potential translational application in therapeutics. PMID- 26122034 TI - SIRT1 as a Promising Novel Therapeutic Target for Myocardial Ischemia Reperfusion Injury and Cardiometabolic Disease. AB - BACKGROUND: Cardiovascular diseases, especially ischemic heart disease and cardiometabolic disease, remain to be the leading cause of morbidity and mortality worldwide. Despite recent progress in diagnostic and therapeutic approaches, the incidence of cardiovascular disease is still rising. Therefore, alternative favorable treatment is urgently needed to rescue the fast growing numbers of patients. OBJECTIVE: Herein we aimed to review the relevant role and explore the possibility of SIRT1 as a promising target for protection of heart from ischemia/reperfusion injury and cardiometabolic diseases. RESULTS: The activation of SIRT1 participates in a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance in heart ischemia injury and cardiometabolic disease. CONCLUSION: Current medication targeting SIRT1 may represent a new therapeutic trend for the prevention of cardiovascular disease that is related to energy balance and metabolism. PMID- 26122035 TI - Release of Soluble Ligands for the Activating NKG2D Receptor: One More Immune Evasion Strategy Evolved by HIV-1 ? AB - Increasing lines of evidence indicate that NKG2D, an activating receptor of natural killer (NK) and CD8(+) T cells, plays an important role in immune responses against HIV-1. Through its ability to recognize a diverse array of ligands (NKG2DLs) induced by cell 'stress' such as viral infection, NKG2D delivers activating and co-stimulatory signals resulting in cytotoxicity and release of cytokines. Therefore, HIV-1 and other viruses have evolved clever mechanisms to counteract NKG2D-dependent immune responses. While, on one hand, the HIV-1 Vpr protein up-regulates NKG2DLs expression by activating the DNA damage response (DDR) pathway, other viral proteins (Nef and Vif) have developed the capacity to reduce NKG2DLs expression levels. In addition, recent evidences suggest that HIV-1-infected CD4(+) T cells may release NKG2DLs, particularly MICA, in soluble form, a phenomenon that has the potential to down-modulate NKG2D on circulating lymphocytes and allow evasion of NKG2D-mediated immune responses. Indeed, despite controversial, lower NKG2D expression was found on both NK and CD8(+) T cells in HIV-1-infected patients. This review discusses recent advances in the understanding of how HIV-1 affects the NKG2D/NKG2DLs system, with a special focus on virus-induced release of soluble NKG2DLs and its functional implications for the immune surveillance of the infected host. PMID- 26122036 TI - Does a short-term increase in testosterone affect the intensity or persistence of territorial aggression? - An approach using an individual's hormonal reactive scope to study hormonal effects on behavior. AB - In this study, we describe an approach based on an individual's hormonal reactive scope to study short-term effects of hormones on behavior. The control of territorial aggression has been traditionally linked to testosterone. Males of some vertebrate species show an increase in testosterone during territorial interactions and implantation studies suggest that such an increase in testosterone enhances the intensity and persistence of aggression. Here, we tested whether a short-term maximum release of testosterone - based on an individual's hormonal reactive scope - affects the intensity or persistence of territorial aggression in male black redstarts, a bird species in which testosterone does not increase during territorial encounters. An injection with gonadotropin-releasing-hormone (GnRH) induced a physiological peak in plasma testosterone that was specific for each individual (=individual reactive scope). However, such short-term surges in an individual's testosterone concentration did not affect the intensity or persistence of aggression. In conclusion, this study demonstrated (1) that a species that naturally does not increase testosterone during male-male encounters would not benefit from such an increase in terms of being more aggressive, (2) that behavioral studies using GnRH-injections represent a promising approach to study species differences in androgen responsiveness, and (3) that injections of releasing or tropic hormones in general may be a suitable approach to study short-term influences of hormones on behavior. These injections effectively mimic the potential short-term changes in hormones that can occur in the real life of individuals and enable us to study the effects of hormonal changes on behavior or other traits within an ecological and evolutionary framework. PMID- 26122037 TI - Investigating the contribution of short wavelengths in the alerting effect of bright light. AB - INTRODUCTION: Short-wavelengths can have an acute impact on alertness, which is allegedly due to their action on intrinsically photosensitive retinal ganglion cells. Classical photoreceptors cannot, however, be excluded at this point in time as contributors to the alerting effect of light. The objective of this study was to compare the alerting effect at night of a white LED light source while wearing blue-blockers or not, in order to establish the contribution of short wavelengths. MATERIALS AND METHODS: 20 participants stayed awake under dim light (< 5 lx) from 23:00 h to 04:00 h on two consecutive nights. On the second night, participants were randomly assigned to one light condition for 30 min starting at 3:00 h. Group A (5M/5F) was exposed to 500 MUW/cm(2) of unfiltered LED light, while group B (4M/6F) was required to wear blue-blocking glasses, while exposed to 1500 MUW/cm(2) from the same light device in order to achieve 500 MUW/cm(2) at eye level (as measured behind the glasses). Subjective alertness, energy, mood and anxiety were assessed for both nights at 23:30 h, 01:30 h and 03:30 h using a visual analog scale (VAS). Subjective sleepiness was assessed with the Stanford Sleepiness Scale (SSS). Subjects also performed the Conners' Continuous Performance Test II (CPT-II) in order to assess objective alertness. Mixed model analysis was used to compare VAS, SSS and CPT-II parameters. RESULTS: No difference between group A and group B was observed for subjective alertness, energy, mood, anxiety and sleepiness, as well as CPT-II parameters. Subjective alertness (p < 0.001), energy (p < 0.001) and sleepiness (p < 0.05) were, however improved after light exposure on the second night independently of the light condition. CONCLUSIONS: The current study shows that when sleepiness is high, the alerting effect of light can still be triggered at night in the absence of short wavelengths with a 30 minute light pulse of 500 MUW/cm(2). This suggests that the underlying mechanism by which a brief polychromatic light exposure improves alertness is not solely due to short-wavelengths through intrinsically photosensitive retinal ganglion cells. PMID- 26122039 TI - Cognitive behavioural therapy for depression: systematic review of imaging studies. AB - OBJECTIVE: Although cognitive behavioural therapy (CBT) has been shown to be an effective treatment for depression, the biological mechanisms underpinning it are less clear. This review examines if it is associated with changes identifiable with current brain imaging technologies. METHODS: To better understand the mechanisms by which CBT exerts its effects, we undertook a systematic review of studies examining brain imaging changes associated with CBT treatment of depression. RESULTS: Ten studies were identified, five applying functional magnetic resonance imaging, three positron emission tomography, one single photon emission computer tomography, and one magnetic resonance spectroscopy. No studies used structural MRI. Eight studies included a comparator group; in only one of these studies was there randomised allocation to another treatment. CBT associated changes were most commonly observed in the anterior cingulate cortex (ACC), posterior cingulate, ventromedial prefrontal cortex/orbitofrontal cortex (VMPFC/OFC) and amygdala/hippocampus. DISCUSSION: The evidence, such as it is, suggests resting state activity in the dorsal ACC is decreased by CBT. It has previously been suggested that treatment with CBT may result in increased efficiency of a putative 'dorsal cognitive circuit', important in cognitive control and effortful regulation of emotion. It is speculated this results in an increased capacity for 'top-down' emotion regulation, which is employed when skills taught in CBT are engaged. Though changes in activity of the dorsal ACC could be seen as in-keeping with this model, the data are currently insufficient to make definitive statements about how CBT exerts its effects. Data do support the contention that CBT is associated with biological brain changes detectable with current imaging technologies. PMID- 26122040 TI - Estrogen receptor alpha enhances the transcriptional activity of ETS-1 and promotes the proliferation, migration and invasion of neuroblastoma cell in a ligand dependent manner. AB - BACKGROUND: It is well known that estrogen receptor alpha (ERalpha) participates in the pathogenic progress of breast cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma. In neuroblastoma cells and related cancer clinical specimens, moreover, the ectopic expression of ERalpha has been identified. However, the detailed function of ERalpha in the proliferation of neuroblastoma cell is yet unclear. METHODS: The transcriptional activity of ETS-1 (E26 transformation specific sequence 1) was measured by luciferase analysis. Western blot assays and Real-time RT-PCR were used to examine the expression of ERalpha, ETS-1 and its targeted genes. The protein-protein interaction between ERalpha and ETS-1 was determined by co-IP and GST-Pull down assays. The accumulation of ETS-1 in nuclear was detected by western blot assays, and the recruitment of ETS-1 to its targeted gene's promoter was tested by ChIP assays. Moreover, SH-SY5Y cells' proliferation, anchor-independent growth, migration and invasion were quantified using the MTT, soft agar or Trans-well assay, respectively. RESULTS: The transcriptional activity of ETS-1 was significantly increased following estrogen treatment, and this effect was related to ligand mediated activation of ERalpha. The interaction between the ERalpha and ETS-1 was identified, and enhancement of ERalpha activation would up-regulate the ETS-1 transcription factor activity via modulating its cytoplasm/nucleus translocation and the recruitment of ETS-1 to its target gene's promoter. Furthermore, treatment of estrogen increased proliferation, migration and invasion of neuroblastoma cells, whereas the antagonist of ERalpha reduced those effects. CONCLUSIONS: In this study, we provided evidences that activation of ERalpha promoted neuroblastoma cells proliferation and up-regulated the transcriptional activity of ETS-1. By investigating the role of ERalpha in the ETS-1 activity regulation, we demonstrated that ERalpha may be a novel ETS-1 co-activator and thus a potential therapeutic target in human neuroblastoma treatment. PMID- 26122041 TI - Health state utilities associated with major clinical events in the context of secondary hyperparathyroidism and chronic kidney disease requiring dialysis. AB - BACKGROUND: Patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) who require dialysis are at increased risk for cardiovascular events and bone fractures. To assist in economic evaluations, this study aimed to estimate the disutility of these events beyond the impact of CKD and SHPT. METHODS: A basic one-year health state was developed describing CKD and SHPT requiring dialysis. Further health states added acute events (cardiovascular events, fractures, and surgical procedures) or chronic post-event effects. Acute health states described a year including an event, and chronic health states described a year subsequent to an event. General population participants in Canada completed time trade-off interviews from which utilities were derived. Pairwise comparisons were made between the basic state and event, and between comparable health states. RESULTS: A total of 199 participants (54.8% female; mean age = 46.3 years) completed interviews. Each health state had >=130 valuations. The mean (SD) utility of the basic health state was 0.60 (0.34). For acute events, mean utility differences versus the basic state were: myocardial infarction, -0.06; unstable angina, -0.05; peripheral vascular disease (PVD) with amputation, -0.33; PVD without amputation, -0.11; heart failure, -0.14; stroke, 0.30; hip fracture, -0.14; arm fracture, -0.04; parathyroidectomy, +0.02; kidney transplant, +0.06. Disutilities for chronic health states were: stable angina, 0.09; stroke, -0.27; PVD with amputation, -0.30; PVD without amputation, -0.12; heart failure, -0.14. CONCLUSIONS: Cardiovascular events and fractures were associated with lower utility scores, suggesting a perceived decrease in quality of life beyond the impact of CKD and SHPT. PMID- 26122042 TI - Lutein dietary supplementation attenuates streptozotocin-induced testicular damage and oxidative stress in diabetic rats. AB - BACKGROUND: Diabetes mellitus with the successive generation of reactive oxygen species signifies a major risk factor for testicular dysfunction. Antioxidant supplements are one of the best options to prevent such disorder. In the present study, lutein as dietary supplement has been used to explore its potential protective effects against diabetes-induced oxidative stress in testicular cells. METHODS: Diabetes was induced using a single i.p. injection of streptozotocin (STZ). Lutein was mixed with rat chow powder and supplemented to diabetic rats for 5 weeks. Serum testosterone levels were estimated. In testicular cells, thiobarbituric acid reactive substances (TBARS), total sulfhydryl groups (T-GSH), non-protein sulfhydryl groups (NP-SH), superoxide dismutase (SOD) and catalase (CAT) activities were measured. Pro-inflammatory mediators like tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) were measured in the testis. Nucleic acids and total protein (TP) levels were also estimated in testicular cells. Histopathological changes were evaluated in testis. RESULTS: Serum testosterone level was significantly decreased in diabetic animals compared to controls. Diabetes markedly reduced T-GSH, NP-SH, CAT and SOD, while TBARS, TNF-alpha and IL-1beta levels were increased in the diabetic testis compared to non-diabetic controls. Lutein supplementation, significantly and dose dependently increased the serum testosterone level. The elevated TBARS levels were significantly decreased compared to diabetic group, while the decreased levels of T-GSH and NP-SH and activities of CAT and SOD were found increased by lutein treatments in dose dependent manner. Lutein pretreatment also inhibited the TNF alpha and IL-1beta levels compared to diabetic group. The decreased values of nucleic acids and total protein in diabetic group were also significantly increased in lutein supplemented groups. The histopathological evaluation revealed protection the damaged testicular cells in the diabetic rats by lutein supplementation. CONCLUSION: These findings showed that lutein has potential beneficial effects in diabetes-induced testicular damage, probably through its antioxidant and anti-inflammatory properties. PMID- 26122043 TI - Extrahepatic metastases as initial manifestations of hepatocellular carcinoma: an Egyptian experience. AB - BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in Egypt has markedly increased in the recent years, mainly due to the high incidence of hepatitis C virus (HCV) infection. Consequently, the frequency of metastatic HCC has also increased. The current study presents a series of 47 patients who were initially diagnosed as metastatic HCC. METHODS: Forty seven patients with the diagnosis of extrahepatic metastases of HCC at initial presentation were included in the study. The sites of metastases were bones (17), lymph nodes (9), soft tissue (7), omentum (7), maxillary sinus (2), adrenal gland (2), brain (2) and skin (1). The diagnosis of metastatic HCC was confirmed by immunohistochemistry. RESULTS: The patients included in the study were 38 males and 9 females, ranging from 40 to 80 years (median 60 years). All patients were HCV-positive and 36 were cirrhotic. The diagnosis of primary HCC was confirmed in all cases, based on the typical hypervascular radiological features and/or high serum alpha-fetoprotein concentration, or histologic examination of liver biopsy. CONCLUSION: Metastasis of HCC should be put into consideration when evaluating metastatic carcinoma with unknown primary. This is of particular importance in the Egyptian population who has the highest prevalence of HCV infection in the world. PMID- 26122044 TI - Clinical audit for occupational therapy intervention for children with autism spectrum disorder: sampling steps and sample size calculation. AB - A priori sample size calculations are used to determine the adequate sample size to estimate the prevalence of the target population with good precision. However, published audits rarely report a priori calculations for their sample size. This article discusses a process in health services delivery mapping to generate a comprehensive sampling frame, which was used to calculate an a priori sample size for a targeted clinical record audit. We describe how we approached methodological and definitional issues in the following steps: (1) target population definition, (2) sampling frame construction, and (3) a priori sample size calculation. We recommend this process for clinicians, researchers, or policy makers when detailed information on a reference population is unavailable. PMID- 26122045 TI - The Streptomyces leeuwenhoekii genome: de novo sequencing and assembly in single contigs of the chromosome, circular plasmid pSLE1 and linear plasmid pSLE2. AB - BACKGROUND: Next Generation DNA Sequencing (NGS) and genome mining of actinomycetes and other microorganisms is currently one of the most promising strategies for the discovery of novel bioactive natural products, potentially revealing novel chemistry and enzymology involved in their biosynthesis. This approach also allows rapid insights into the biosynthetic potential of microorganisms isolated from unexploited habitats and ecosystems, which in many cases may prove difficult to culture and manipulate in the laboratory. Streptomyces leeuwenhoekii (formerly Streptomyces sp. strain C34) was isolated from the hyper-arid high-altitude Atacama Desert in Chile and shown to produce novel polyketide antibiotics. RESULTS: Here we present the de novo sequencing of the S. leeuwenhoekii linear chromosome (8 Mb) and two extrachromosomal replicons, the circular pSLE1 (86 kb) and the linear pSLE2 (132 kb), all in single contigs, obtained by combining Pacific Biosciences SMRT (PacBio) and Illumina MiSeq technologies. We identified the biosynthetic gene clusters for chaxamycin, chaxalactin, hygromycin A and desferrioxamine E, metabolites all previously shown to be produced by this strain (J Nat Prod, 2011, 74:1965) and an additional 31 putative gene clusters for specialised metabolites. As well as gene clusters for polyketides and non-ribosomal peptides, we also identified three gene clusters encoding novel lasso-peptides. CONCLUSIONS: The S. leeuwenhoekii genome contains 35 gene clusters apparently encoding the biosynthesis of specialised metabolites, most of them completely novel and uncharacterised. This project has served to evaluate the current state of NGS for efficient and effective genome mining of high GC actinomycetes. The PacBio technology now permits the assembly of actinomycete replicons into single contigs with >99 % accuracy. The assembled Illumina sequence permitted not only the correction of omissions found in GC homopolymers in the PacBio assembly (exacerbated by the high GC content of actinomycete DNA) but it also allowed us to obtain the sequences of the termini of the chromosome and of a linear plasmid that were not assembled by PacBio. We propose an experimental pipeline that uses the Illumina assembled contigs, in addition to just the reads, to complement the current limitations of the PacBio sequencing technology and assembly software. PMID- 26122046 TI - Association between intraoperative ventilator settings and plasma levels of soluble receptor for advanced glycation end-products in patients without pre existing lung injury. AB - BACKGROUND AND OBJECTIVE: The soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated and correlated with severity in patients with acute respiratory distress syndrome (ARDS). The impact of ventilator settings on plasma levels of sRAGE, in patients with or without pre-existing lung injury, remains under-investigated to date. Our objective was to assess the effects of a lung-protective ventilation strategy (combining low tidal volume, positive end expiratory pressure and recruitment maneuvers), as compared with a non-protective approach (with high tidal volume and zero end-expiratory pressure), on plasma levels of sRAGE in patients without lung injury undergoing major abdominal surgery. METHODS: Plasma samples were obtained from 95 patients enrolled in a large randomized controlled trial of lung-protective ventilation for major abdominal surgery. Plasma levels of sRAGE were measured in duplicate with an enzyme-linked immunoassay on day 1, immediately after surgery, and on postoperative days 1, 3 and 7. RESULTS: Early postoperative plasma levels of sRAGE were significantly lower in the lung-protective ventilation group (n = 47) than in the non-protective ventilation group (n = 48) (mean (standard deviation), 1782 (836) vs 2171 (1678) pg/mL, respectively, P = 0.03). Intraoperative changes in plasma sRAGE were associated with postoperative hypoxemia and ARDS. CONCLUSIONS: A lung-protective ventilation strategy decreased plasma sRAGE in patients without lung injury undergoing major abdominal surgery compared with the patients with non-protective ventilation. This intraoperative decrease could reflect a lesser degree of epithelial injury. PMID- 26122047 TI - Expression and function of the LIM-homeodomain transcription factor Islet-1 in the developing and mature vertebrate retina. AB - The LIM-homeodomain transcription factor Islet-1 (Isl1) has been widely used as a marker of different subtypes of neurons in the developing and mature retina of vertebrates. During retinal neurogenesis, early Isl1 expression is detected in the nuclei of neuroblasts that give rise to ganglion, amacrine, bipolar, and horizontal cells. In the mature retina, Isl1 expression is restricted to the nuclei of ganglion cells, cholinergic amacrine cells, ON-bipolar cells, and subpopulations of horizontal cells. Recent studies have explored the functional mechanisms of Isl1 during specification and differentiation of these retinal cell types. Thus, conditional inactivation of Isl1 in the developing mouse retina disrupts retinal function, and also results in optic nerve hypoplasia, marked reductions in mature ganglion, amacrine, and bipolar cells, and a substantial increase in horizontal cells. Furthermore, conditional knockout shows delayed ganglion cell axon growth, ganglion cell axon guidance error, and ganglion cell nerve fiber defasciculation. These data together suggest a possible role for Isl1 in the early differentiation and maintenance of different vertebrate retinal cell types. This review examines whether the expression pattern of Isl1 during vertebrate retinal development is conserved across vertebrate species, and discusses current understanding of the developmental functions of Isl1 in retinogenesis. PMID- 26122048 TI - Angiography reveals novel features of the retinal vasculature in healthy and diabetic mice. AB - The mouse retina is a commonly used animal model for the study of pathogenesis and treatment of blinding retinal vascular diseases such as diabetic retinopathy. In this study, we aimed to characterize normal and pathological variations in vascular anatomy in the mouse retina using fluorescein angiography visualized with scanning laser ophthalmoscopy and optical coherence tomography (SLO-OCT). We examined eyes from C57BL/6J wild type mice as well as the Ins2(Akita) and Akimba mouse models of diabetic retinopathy using the Heidelberg Retinal Angiography (HRA) and OCT system. Angiography was performed on three focal planes to examine distinct vascular layers. For comparison with angiographic data, ex vivo analyses, including Indian ink angiography, histology and 3D confocal scanning laser microscopy were performed in parallel. All layers of the mouse retinal vasculature could be readily visualized during fluorescein angiography by SLO OCT. Blood vessel density was increased in the deep vascular plexus (DVP) compared with the superficial vascular plexus (SVP). Arteriolar and venular typologies were established and structural differences were observed between venular types. Unexpectedly, the hyaloid artery was found to persist in 15% of C57BL/6 mice, forming anastomoses with peripheral retinal capillaries. Fluorescein leakage was easily detected in Akimba retinae by angiography, but was not observed in Ins2(Akita) mice. Blood vessel density was increased in the DVP of 6 month old Ins2(Akita) mice, while the SVP displayed reduced branching in precapillary arterioles. In summary, we present the first comprehensive characterization of the mouse retinal vasculature by SLO-OCT fluorescein angiography. Using this clinical imaging technique, we report previously unrecognized variations in C57BL/6J vascular anatomy and novel features of vascular retinopathy in the Ins2(Akita) mouse model of diabetes. PMID- 26122049 TI - Distribution of galanin receptors in the human eye. AB - The neuropeptide galanin (GAL) is widely distributed within intrinsic and extrinsic sources supplying the eye. It is involved in regulation of the vascular tone, thus important for ocular homeostasis. Since the presence/distribution of its receptors is unknown, we here screen for the presence of the various GAL receptors in the human eye. Meeting the Helsinki-Declaration, human eyes (n = 6; 45-83 years of age, of both sex, post mortem time 10-19 h) were obtained from the cornea bank and prepared for immunohistochemistry against GAL receptors 1-3 (GALR1-GALR3). Over-expressing cell assays served as positive controls and confocal laser-scanning microscopy was used for documentation. Cell assays reliably detected immunoreactivity for GALR1-3 and cross-reactions between antibodies used were not observed. In the cornea, GALR1-3 were detected in basal layers of the epithelium, stroma, endothelium, as well as in adjacent conjunctiva. In the iris, GALR1-3 were detected in iris sphincter and dilator, while iris vessels displayed immunoreactivity for GALR1 and GALR3. In the ciliary body, GALR1 was exclusively found in the non-pigmented epithelium while GALR3 was detected in the ciliary muscle and vessels. In the retina, GALR1 was present in fibers of the IPL, OPL, NFL, many cells of the INL and few cells of the ONL. GALR2 and GALR3 were present in few neurons of the INL, while GALR2 was also found surrounding retinal vessels. RPE displayed weak immunoreactivity for GALR2 but intense immunoreactivity for GALR3. In the choroid, GALR1-3 were detectable in intrinsic choroidal neurons and nerve fibers of the choroidal stroma, and all three receptors were detected surrounding choroidal blood vessels, while the choriocapillaris was immunoreactive for GALR3 only. This is the first report of the various GALRs in the human eye. While the presence of GALRs in cornea and conjunctiva might be relevant for wound healing or inflammatory processes, the detection in iris vessels (GALR1, 2) and choroidal vessels (GALR1-3) highlights the role of GAL in vessel dynamics. Presence of GALR1 in ciliary body epithelium and GALR3 in ciliary vessels indicates involvement in aqueous humor production, whereas retinal GALR distribution might contribute to signal transduction. PMID- 26122050 TI - MicroRNA-7a regulates Muller glia differentiation by attenuating Notch3 expression. AB - miRNA-7a plays critical roles in various biological aspects in health and disease. We aimed to reveal roles of miR-7a in mouse retinal development by loss- and gain-of-function analyses of miR-7a. Plasmids encoding miR-7a or miR-7a-decoy (anti-sense miR-7a) were introduced into mouse retina at P0, and the retina was cultured as explant. Then, proliferation of retinal progenitors and differentiation of retinal subtypes were examined by immunostaining. miR-7a had no apparent effect on the proliferation of retinal progenitor cells. However, the expression of Muller glia marker, cyclin D3, was reduced by miR-7a overexpression and up-regulated by miR-7a decoy, suggesting that miR-7a negatively regulates differentiation of Muller glia. Targets of miR-7a, which were predicted by using a public program miRNA.org, and Notch3 was suggested to be one of candidate genes of miR-7a target. Notch3 3' UTR appeared to contain complementary sequence to the seed sequence of miR-7a. A reporter assay in NIH3T3 cells using a plasmid containing multiple repeats of potential target sequence of 3' Notch UTR showed that miR-7a suppress expression of reporter EGFP through 3'UTR region. Expression of sh-Notch3 and over-expression of NICD3 in retina suggested that miR-7a regulates Muller glia differentiation through attenuation of Notch3 expression. Taken together, we revealed that the miR-7a regulates the differentiation of Muller glia through the suppression of Notch3 expression. PMID- 26122051 TI - The G7 and global health: inaction or incisive leadership? PMID- 26122052 TI - Managing the tide of childhood obesity. PMID- 26122053 TI - Child poverty in France: alarming trends. PMID- 26122054 TI - Capacity for science in sub-Saharan Africa. PMID- 26122056 TI - Planning for US Precision Medicine Initiative underway. PMID- 26122057 TI - Trans-Pacific trade pact triggers fears over drug prices. PMID- 26122061 TI - Making us as cruel as dogs: plague in 16th and 17th century England. PMID- 26122060 TI - Jean-Jacques Muyembe-Tamfum: Africa's veteran Ebola hunter. PMID- 26122062 TI - Ciaran Bernard John Woodman. PMID- 26122063 TI - Promotion of sports, physical activity, and a healthy lifestyle in Russia. PMID- 26122064 TI - Causes of child death: comparison of MCEE and GBD 2013 estimates. PMID- 26122065 TI - Causes of child death: comparison of MCEE and GBD 2013 estimates - Authors' reply. PMID- 26122066 TI - Department of Error. PMID- 26122067 TI - Eosinophilic myocarditis: a paraneoplastic event. PMID- 26122068 TI - Implementation of a two-group likelihood time-to-event continual reassessment method using SAS. AB - BACKGROUND AND OBJECTIVES: Dose finding trials using model-based methods have the ability to handle the increasingly complex landscape being seen in clinical trials. Issues such as patient heterogeneity in trial populations are important to address in the designing of a trial in addition to the inclusion/exclusion criteria. Designs accommodating patient heterogeneity have been described using the continual reassessment method (CRM) and time-to-event CRM (TITE-CRM), yet, the implementation of these trials in practice have been limited. These methods and other model-based methods generally need statisticians to help design and conduct these trials. However, the statistical programs which facilitate the use of these methods, currently available focus on estimation in the one-sample case. METHODS: A SAS program to accommodate two groups using the TITE-CRM and likelihood estimation has been developed. The program consists of macros that assist with the planning and implementation of a trial accounting for patient heterogeneity. RESULTS: Description of the program is given as well as examples using the programs. For planning purposes, an example will be provided showing how the program can be used to guide sample size estimates for the trial. CONCLUSIONS: This program provides researchers with a valuable tool for designing dose-finding studies to account for the presence of patient heterogeneity and conduct a trial using a hypothetical example. PMID- 26122069 TI - Probing changes in corticospinal excitability following theta burst stimulation of the human primary motor cortex. AB - OBJECTIVE: To determine whether the intensity of transcranial magnetic stimulation (TMS) used to probe changes in corticospinal excitability influences the measured plasticity response to theta burst stimulation (TBS) of the human primary motor cortex. METHODS: Motor evoked potential (MEP) input/output (I/O) curves were recorded before and following continuous TBS (cTBS) (Experiment 1; n=18) and intermittent TBS (iTBS) (Experiment 2; n=18). RESULTS: The magnitude and consistency of MEP depression induced by cTBS was greatest when probed using stimulus intensities at or above 150% of resting motor threshold (RMT). In contrast, facilitation of MEPs following iTBS was strongest and most consistent at 110% of RMT. CONCLUSIONS: The plasticity response to both cTBS and iTBS is influenced by the stimulus intensity used to probe the induced changes in corticospinal excitability. SIGNIFICANCE: The results highlight the importance of the test stimulus intensity used to assess TBS-induced changes in corticospinal excitability when interpreting neuroplasticity data, and suggest that a number of test intensities may be required to reliably probe the plasticity response. PMID- 26122070 TI - Analysis of infant cortical synchrony is constrained by the number of recording electrodes and the recording montage. AB - OBJECTIVE: To assess how the recording montage in the neonatal EEG influences the detection of cortical source signals and their phase interactions. METHODS: Scalp EEG was simulated by forward modeling 20-200 simultaneously active sources covering the cortical surface of a realistic neonatal head model. We assessed systematically how the number of scalp electrodes (11-85), analysis montage, or the size of cortical sources affect the detection of cortical phase synchrony. Statistical metrics were developed for quantifying the resolution and reliability of the montages. RESULTS: The findings converge to show that an increase in the number of recording electrodes leads to a systematic improvement in the detection of true cortical phase synchrony. While there is always a ceiling effect with respect to discernible cortical details, we show that the average and Laplacian montages exhibit superior specificity and sensitivity as compared to other conventional montages. CONCLUSIONS: Reliability in assessing true neonatal cortical synchrony is directly related to the choice of EEG recording and analysis configurations. Because of the high conductivity of the neonatal skull, the conventional neonatal EEG recordings are spatially far too sparse for pertinent studies, and this loss of information cannot be recovered by re montaging during analysis. SIGNIFICANCE: Future neonatal EEG studies will need prospective planning of recording configuration to allow analysis of spatial details required by each study question. Our findings also advice about the level of details in brain synchrony that can be studied with existing datasets or by using conventional EEG recordings. PMID- 26122071 TI - Atypical EEG abnormalities in genetic generalized epilepsies. AB - OBJECTIVE: Bilateral, symmetric and synchronous generalized epileptiform activity is considered to be the typical electroencephalographic (EEG) abnormality in genetic generalized epilepsy (GGE). We sought to study atypical EEG abnormalities in a systematic way based on 24-h ambulatory EEG recordings. METHODS: The diagnosis of GGE was validated and classified into syndromes according to the International League against Epilepsy criteria. All participants underwent 24-h ambulatory EEG recording. Epileptiform discharges were counted and detailed information was entered into an electronic database. Amplitude asymmetry, focal onset/offset of paroxysms, focal discharges, atypical morphology and generalized paroxysmal fast rhythm were defined as atypical abnormalities. RESULTS: Of the total of 120 patients, 107 had abnormal EEGs, of which 66.4% had at least one atypical epileptiform abnormality on EEG. Atypical morphology was the most frequent abnormality in 93.4% of patients, followed by amplitude asymmetry (28.0%), focal discharges (21.5%), focal onset of paroxysms (13.1%), focal offset of paroxysms (8.2%) and generalized paroxysmal fast rhythm (1.9%). The analysis of individual discharges revealed that 76% of paroxysms were of atypical morphology. Significant associations were found between (a) amplitude asymmetry and state of arousal (p<0.001) as well as seizure-free duration (p 0.013); (b) atypical morphology and state of arousal (p<0.001). CONCLUSION: In GGE, there are both common and rare atypical epileptiform EEG abnormalities that may vary according to the state of arousal and seizure-free duration. SIGNIFICANCE: Awareness of these variations is important to avoid misdiagnosis. PMID- 26122072 TI - Convergence of flexor reflex and corticospinal inputs on tibialis anterior network in humans. AB - OBJECTIVE: Integration between descending and ascending inputs at supraspinal and spinal levels is a key characteristic of neural control of movement. In this study, we characterized convergence of the flexor reflex and corticospinal inputs on the tibialis anterior (TA) network in healthy human subjects. Specifically, we characterized the modulation profiles of the spinal TA flexor reflex following subthreshold and suprathreshold transcranial magnetic stimulation (TMS). We also characterized the modulation profiles of the TA motor evoked potentials (MEPs) following medial arch foot stimulation at sensory and above reflex threshold. METHODS: TA flexor reflexes were evoked following stimulation of the medial arch of the foot with a 30 ms pulse train at innocuous intensities. TA MEPs were evoked following TMS of the leg motor cortex area. RESULTS: TMS at 0.7 and at 1.2 MEP resting threshold increased the TA flexor reflex when TMS was delivered 40 100 ms after foot stimulation, and decreased the TA flexor reflex when TMS was delivered 25-110 ms before foot stimulation. Foot stimulation at sensory and above flexor reflex threshold induced a similar time-dependent modulation in resting TA MEPs, that were facilitated when foot stimulation was delivered 40-100 ms before TMS. The flexor reflex and MEPs recorded from the medial hamstring muscle were modulated in a similar manner to that observed for the TA flexor reflex and MEP. CONCLUSION: Cutaneomuscular afferents from the distal foot can increase the output of the leg motor cortex area. Descending motor volleys that directly or indirectly depolarize flexor motoneurons increase the output of the spinal FRA interneuronal network. The parallel facilitation of flexor MEPs and flexor reflexes is likely cortical in origin. SIGNIFICANCE: Afferent mediated facilitation of corticospinal excitability can be utilized to strengthen motor cortex output in neurological disorders. PMID- 26122074 TI - Quality of evidence of rehabilitation interventions in long-term care for people with severe disorders of consciousness after brain injury: A systematic review. AB - OBJECTIVE: To characterize existing rehabilitation interventions for patients with disorders of consciousness in long-term care and to evaluate the quality of evidence of these interventions. DATA SOURCES: Databases MEDLINE, Embase, CINAHL, the Cochrane Library, CareLit and SoLit from January 2003 until July 2013. STUDY SELECTION: Studies were selected that focused on rehabilitation interventions for patients in a coma, vegetative state or minimally conscious state who were living in a long-term care setting. Interventions related to rehabilitation nursing, physical therapy, occupational therapy, and speech therapy were described. A total of 53 publications was included. DATA EXTRACTION: Two authors independently extracted the data and assessed the quality of reporting using the National Service Framework (NSF) for Long Term Neurological Conditions (LTNC). DATA SYNTHESIS: Out of all extracted rehabilitation interventions 12 categories were generated and described. Out of 53 publications 28 (52.8%) contained expert-based evidence and 25 (47.2%) presented research-based evidence. CONCLUSION: There are a multitude of different rehabilitation interventions for individuals with disorders of consciousness, which are established in clinical practice and supported by expert opinion. However, evidence regarding these interventions is weak and recommendations are strictly limited. The findings of this review may represent a basis for further research. PMID- 26122073 TI - A novel system for visualizing alphavirus assembly. AB - Alphaviruses are small, enveloped RNA viruses that form infectious particles by budding through the cellular plasma membrane. To help visualize and understand the intracellular assembly of alphavirus virions we have developed a bimolecular fluorescence complementation-based system (BiFC) that allows visualization of capsid and E2 subcellular localization and association in live cells. In this system, N- or C-terminal Venus fluorescent protein fragments (VN- and VC-) are fused to the N-terminus of the capsid protein on the Sindbis virus structural polyprotein, which results in the formation of fluorescent capsid-like structures in the absence of viral genomes that associate with the plasma membrane of cells. Mutation of the capsid autoprotease active site blocks structural polyprotein processing and alters the subcellular distribution of capsid fluorescence. Incorporating mCherry into the extracellular domain of the E2 glycoprotein allows the visualization of E2 glycoprotein localization and showed a close association of the E2 and capsid proteins at the plasma membrane as expected. These results suggest that this system is a useful new tool to study alphavirus assembly in live cells and may be useful in identifying molecules that inhibit alphavirus virion formation. PMID- 26122075 TI - Antigenic composition and immunoreactivity differences between HEV recombinant capsid proteins generated from different genotypes. AB - Appreciable variability has been observed in hepatitis E virus (HEV) serological diagnostics. Four recombinant proteins (p166s) were generated from position 452 to 617 aa of ORF2 of different HEV genotypes and used in an indirect ELISA to detect anti-HEV IgMs and IgGs in serially diluted sera of patients infected with different HEV genotypes (genotype 1, n=15; genotype 3, n=12; genotype 4, n=17). To evaluate the differences at a conformational level, 3D-structure models of p166s were predicted, and different bioinformatics tools were used to analyze the antigenic composition. With both anti-HEV IgMs and IgGs antibodies, there was a considerable variability between the four antigens immunoreactivities. In silico results revealed the region 483-533 aa with the highest antigenic potential and contains six key aa at positions 488, 489, 512, 533, 483 and 530. This immunoreactivity variation could affect diagnosis results and seroprevalence estimations and the identification in silico of a region highly antigenic would guide the development of efficient serological assays and epitope-based vaccines. PMID- 26122077 TI - An analytical approach to test and design upper limb prosthesis. AB - In this work the signal acquiring technique, the analysis models and the design protocols of the prosthesis are discussed. The different methods to estimate the motion intended by the amputee from surface electromyogram (SEMG) signals based on time and frequency domain parameters are presented. The experiment proposed that the used techniques can help significantly in discriminating the amputee's motions among four independent activities using dual channel set-up. Further, based on experimental results, the design and working of an artificial arm have been covered under two constituents--the electronics design and the mechanical assembly. Finally, the developed hand prosthesis allows the amputated persons to perform daily routine activities easily. PMID- 26122076 TI - Comparison between rapid and mixed maxillary expansion through an assessment of arch changes on dental casts. AB - BACKGROUND: Aim of this retrospective observational study was to compare upper and lower dental changes in patients treated with Rapid Maxillary Expansion (RME) and Mixed Maxillary Expansion (MME), assessed by dental cast analysis. METHODS: Treatment groups consisted of 42 patients: the RME group (n = 21) consisted of 13 female and 8 male subjects with the mean age of 8.8 years +/- 1.37 at T0 and 9.6 years +/- 1.45 at T1; the MME group (n = 21) consisted of 12 female and 9 male patients with a mean age of 8.9 years +/- 2.34 at T0 and 10.5 years +/- 2.08 at T1. The upper and lower arch analysis was performed on four dental bilateral landmarks, on upper and lower casts; also upper and lower arch depths were measured. The groups were compared using independent sample t-test to estimate dental changes in upper and lower arches. RESULTS: Before expansion treatment (T0), the groups were similar for all examined variables (p>0.05). In both RME and MME group, significant increments in all the variables for maxillary and mandibular arch widths were observed after treatment. No significant differences in maxillary and mandibular arch depths were observed at the end of treatment in both groups. An evaluation of the changes after RME and MME (T1) showed statistically significant differences in mandibular arch depth (p<0.001) and maxillary intercanine widths (p<0.05). Differences in maxillary arch depth and arch width measurements were not significant. CONCLUSIONS: RME and MME can be considered two effective treatment options to improve transverse arch dimensions and gain space in the dental arches. A greater lower arch expansion was observed in the MME group, which might be attributed to the "lip bumper effects" observed in the MME protocol. PMID- 26122078 TI - Helping cancer patients quit smoking by increasing their risk perception: a study protocol of a cluster randomized controlled trial. AB - BACKGROUND: Despite smoking cessation can largely improve cancer prognosis and quality of life, many patients continued smoking after the diagnosis of cancer. This study aims to test the effectiveness of a smoking cessation intervention using risk communication approach to help cancer patients quit smoking, and to improve their health related quality of life. METHODS: A cluster randomized controlled trial will be employed. Cancer patients who continued smoking after the diagnosis of cancer and have medical follow-up at the out-patient clinics of the five acute hospitals in Hong Kong will be invited to participate. Subjects in the experimental group will receive (1) health warnings of smoking based on a special designed leaflet; and (2) a patient-centred counseling from nurse counselors with emphasis on risk perceptions of smoking to cancer prognosis. Additionally, they will receive two more telephone counseling at 1-week and 1 month. Control group receive standard care and a generic self-help smoking cessation booklet. Outcomes measure include (a) self-reported and the biochemically validated quit rate, (b) patient's smoking reduction by at least 50% compared to baseline, (c) quit attempt(s), (d) change in the intention to quit, (e) change in risk perceptions of smoking, and (f) change in health related quality of life. DISCUSSION: This study will make an important contribution to evidence-based practice by testing the effectiveness of a tailored smoking cessation intervention for cancer patients. The results will support the development of clinical practice guidelines to promote smoking cessation in cancer patients to improve their prognosis and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT01685723. Registered 9 November 2012. PMID- 26122080 TI - Reliability and validity of a vertical numerical rating scale supplemented with a faces rating scale in measuring fatigue after stroke. AB - BACKGROUND: Poststroke fatigue is a persistent and distressing symptom among stroke survivors. In this study, we investigated the reliability and validity of a vertical numerical rating scale supplemented with a faces rating scale (NRS FRS) in measuring poststroke fatigue. METHODS: The fatigue intensity of 106 individuals with stroke was measured twice, 1 week apart, using a vertical NRS FRS to measure test-retest reliability. The intraclass correlation coefficient, a relative reliability index, was calculated to examine the degree of consistency and agreement between the two test occasions. Absolute reliability indices, including the standard error of measurement, minimal detectable change, and Bland Altman limits of agreement, were used to quantify measurement errors and determine systematic biases of the two test occasions. We also administered the vertical NRS concurrently as a comparator measure for assessing fatigue in 50 consecutive patients with stroke who were recruited later in the study period. The Spearman rank correlation coefficient (rho) was used to examine the concurrent validity of the NRS-FRS. Discriminant validity was assessed by means of receiver operating characteristic curves, sensitivity, and specificity. RESULTS: The intraclass correlation coefficient was 0.95 for the NRS-FRS. The standard error of measurement and the minimal detectable change at the 95 % confidence interval of the NRS-FRS were 0.50 and 1.39, respectively. The Bland Altman analyses showed no significant systematic bias between the repeated measurements. A narrow range of the limits of agreement was shown on the Bland Altman plot, indicating the NRS-FRS had high stability and low variation between the two test occasions. The correlations between the NRS-FRS and NRS were good at test (rho = 0.85) and retest (rho = 0.84). Compared with the NRS cutoff value of >=1, sensitivity with the NRS-FRS at test and retest was 94 and 92 % and specificity was 79 and 90 %, respectively. CONCLUSIONS: This study provides further evidence of the reliability and validity of the NRS-FRS in measuring fatigue intensity in patients with stroke. The NRS-FRS had high sensitivity and specificity. The NRS-FRS may be a reliable and valid measure for clinicians and researchers to assess fatigue and determine whether a real change has occurred in groups and at the individual level of patients with stroke. PMID- 26122081 TI - Care of patients in emergency department waiting rooms--an integrative review. AB - AIM: To conduct an integrative review of primary research examining patient care roles introduced into emergency department waiting rooms. BACKGROUND: Internationally, emergency departments are under pressure to meet increasing patient demand with limited resources. Several initiatives have been developed that incorporate a healthcare role in waiting rooms, to assess and initiate early interventions to decrease waiting times, detect patient deterioration and improve communication. The literature reporting these roles has not been systematically evaluated. DESIGN: Integrative review. DATA SOURCES: Published English-language peer reviewed articles in CINAHL, Scopus, Medline and Web of Knowledge between 2003-2014. REVIEW METHODS: Identified literature was evaluated using an integrative review framework, incorporating methodological critique and narrative synthesis of findings. RESULTS: Six papers were included, with three waiting room roles identified internationally - clinical initiative nurse, Physician-Nurse Supplementary Assessment Team and clinical assistants. All roles varied in terms of definitions, scope, responsibilities and skill sets of individuals in the position. There was limited evidence that the roles decreased waiting times or improved patient care, especially during busy periods. Of note, staff members performing these roles require high-level therapeutic relationship and effective interpersonal skills with patients, family and staff. The role requires support from other staff, particularly during periods of high workload, for optimal functioning and effective patient care. CONCLUSION: Generalisations and practice recommendations are limited due to the lack of available literature. Further research is required to evaluate the impact emergency department waiting room roles have on patient outcomes and staff perspectives. PMID- 26122079 TI - Preclinical Development of New Therapy for Glycogen Storage Diseases. AB - Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of beta2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available. PMID- 26122082 TI - Ciliated hepatic foregut cyst: a report of 6 cases and a review of the English literature. AB - BACKGROUND: Ciliated hepatic foregut cyst (CHFC) is a rare cystic lesion most commonly identified in segment 4 of the liver that arises from the embryonic foregut. The classic histologic pattern is comprised of 4 distinct layers (inner ciliated epithelial lining, smooth muscle, loose connective tissue, fibrous capsule). Although rare, cases of metaplastic and malignant epithelial lining have been described in CHFC. METHODS: We report 6 additional cases of CHFC, one of which had gastric metaplasia of the cyst lining, and review all reported cases of CHFC in the English literature. We describe the clinicopathologic analysis of 6 cases, with selective immunohistochemical analysis on 1 case with gastric metaplasia. RESULTS: Cases occurred in 4 women and 2 men (average age 55 years, range 42 to 67 years). Cysts ranged in size from 0.7 to 17 cm (average 7.2 cm) and were grossly tan-pink to white with blood-filled contents. The majority were located in segment 4 of the liver, however 2 were located in the porta hepatis. Tumor serologies (CA19-9 and/or CEA) were performed in 3 cases; 1 case demonstrated elevated CA19-9, and 2 cases had laboratory values within normal limits. All cases showed the classic histologic findings, however one case additionally had extensive gastric metaplasia. CONCLUSIONS: In conclusion, CHFC is a rare diagnostic entity that should be considered in the differential diagnosis for cystic hepatic lesions, particularly those located in segment 4 of the liver. Metaplasia and squamous carcinoma can occur, therefore complete surgical excision is the recommended treatment. PMID- 26122083 TI - Caffeic acid phenethyl ester attenuates ionize radiation-induced intestinal injury through modulation of oxidative stress, apoptosis and p38MAPK in rats. AB - Caffeic acid phenyl ester (CAPE) is a potent anti-inflammatory agent and it can eliminate the free radicals. This study aimed to investigate the radioprotective effects of CAPE on X-ray irradiation induced intestinal injury in rats. Rats were intragastrically administered with 10 MUmol/kg/d CAPE for 7 consecutive days before exposing them to a single dose of X-ray irradiation (9Gy) to abdomen. Rats were sacrificed 72 h after exposure to radiation. We found that pretreatment with CAPE effectively attenuated intestinal pathology changes, apoptosis, oxidative stress, bacterial translocation, the content of nitric oxide and myeloperoxidase as well as the concentration of plasma tumor necrosis factor-alpha. Pretreatment with CAPE also reversed the activation of p38MAPK and the increased expression of intercellular cell adhesion molecule-1 induced by radiation in intestinal mucosa. Taken together, these results suggest that pretreatment with CAPE could be a promising candidate for treating radiation-induced intestinal injury. PMID- 26122084 TI - Automobile diesel exhaust particles induce lipid droplet formation in macrophages in vitro. AB - Exposure to diesel exhaust particles (DEP) has been associated with adverse cardiopulmonary health effects, which may be related to dysregulation of lipid metabolism and formation of macrophage foam cells. In this study, THP-1 derived macrophages were exposed to an automobile generated DEP (A-DEP) for 24h to study lipid droplet formation and possible mechanisms. The results show that A-DEP did not induce cytotoxicity. The production of reactive oxygen species was only significantly increased after exposure for 3h, but not 24h. Intracellular level of reduced glutathione was increased after 24h exposure. These results combined indicate an adaptive response to oxidative stress. Exposure to A-DEP was associated with significantly increased formation of lipid droplets, as well as changes in lysosomal function, assessed as reduced LysoTracker staining. In conclusion, these results indicated that exposure to A-DEP may induce formation of lipid droplets in macrophages in vitro possibly via lysosomal dysfunction. PMID- 26122085 TI - Cultural influences on palliative family caregiving: service recommendations specific to the Vietnamese in Canada. AB - BACKGROUND: Much of what is known about family caregiving at end-of-life in Canada has been studied within the context of various disease categories or across different care settings, rather than in relation to specific ethnic/cultural identities. Such homogeneity belies the impact of cultural and social factors on the experiences and outcomes of palliative and end-of-life (P/EOL) care. We know little about the end-of-life experiences of Vietnamese Canadian families. Consequently, there is a lack of understanding around how to best meet the needs of Vietnamese care recipients, caregivers, and their families via the health service system, whose services of which we know they have limited access. RESULTS: To determine a set of service recommendations for health care settings (including the home) specific to caring for Vietnamese (P/EOL) care recipients, caregivers and their families, a qualitative instrumental case-study design was employed. The perspectives of 18 adult Vietnamese family caregivers (FCGs) were obtained. In addition, seven semi-structured key informant interviews were implemented with a range of personnel from community service providers to front-line health care professionals. The ways in which caregiving was perceived and expressed were reflected in three thematic findings: (1) Natural: identity and care work; (2) Intentional: whole person care; and (3) Intensive: standards, struggle, and the context of care. Ten main recommendations have been vetted with service provider leaders and confirmed as being appropriate for uptake. CONCLUSIONS: The ten service recommendations for health care settings (including the home), if implemented, would contribute to improved P/EOL services for the Vietnamese population. Further research involves the evaluation of these policy and programs. PMID- 26122086 TI - A user-friendly workflow for analysis of Illumina gene expression bead array data available at the arrayanalysis.org portal. AB - BACKGROUND: Illumina whole-genome expression bead arrays are a widely used platform for transcriptomics. Most of the tools available for the analysis of the resulting data are not easily applicable by less experienced users. ArrayAnalysis.org provides researchers with an easy-to-use and comprehensive interface to the functionality of R and Bioconductor packages for microarray data analysis. As a modular open source project, it allows developers to contribute modules that provide support for additional types of data or extend workflows. RESULTS: To enable data analysis of Illumina bead arrays for a broad user community, we have developed a module for ArrayAnalysis.org that provides a free and user-friendly web interface for quality control and pre-processing for these arrays. This module can be used together with existing modules for statistical and pathway analysis to provide a full workflow for Illumina gene expression data analysis. The module accepts data exported from Illumina's GenomeStudio, and provides the user with quality control plots and normalized data. The outputs are directly linked to the existing statistics module of ArrayAnalysis.org, but can also be downloaded for further downstream analysis in third-party tools. CONCLUSIONS: The Illumina bead arrays analysis module is available at http://www.arrayanalysis.org . A user guide, a tutorial demonstrating the analysis of an example dataset, and R scripts are available. The module can be used as a starting point for statistical evaluation and pathway analysis provided on the website or to generate processed input data for a broad range of applications in life sciences research. PMID- 26122087 TI - Is the effect of smoking on rosacea still somewhat of a mystery? AB - CONTEXT: Rosacea is an inflammatory skin disease with a chronic course. In the past, the association between rosacea and smoking was examined only in a few studies. OBJECTIVE: The objective of this study is to investigate the prevalence and the influence of smoking in rosacea patients. MATERIALS AND METHODS: This prospective cross-sectional study includes 200 rosacea patients and 200 age- and gender-matched rosacea-free controls. Using National Rosacea Society Expert Committee classification, we divided patients into three subgroups as having erythematotelangiectatic (ETR), papulopustular (PPR), and phymatous rosacea (PhR). Demographic data, risk factors, and smoking habits were recorded. RESULTS: In multivariate analysis, the prevalence of smoking was significantly higher (66%) among patients compared with controls. ETR subtype (43.5%) was found to be significantly higher among active smokers (p < 0.001). Considering the risk factors, caffeine intake and alcohol consumption could not be evaluated because of their never or rarely intake. Whereas rates of photosensitive skin type and positive family history were significantly prominent in ETR patients (p < 0.001). While PhR was mostly detected in men who are very old, a significant tendency was found to develop ETR in women. CONCLUSION: While a significantly increased risk of developing rosacea among smokers was observed in this study, ETR seems to be the disease of active smokers. Further studies are required for better understanding of the association between rosacea and smoking. PMID- 26122088 TI - Passive movement and active exercise for very young infants with congenital heart disease: a study protocol for a randomized controlled trial. AB - BACKGROUND: Delayed motor development is reported in patients with congenital heart disease (CHD). Exercise is widely used to facilitate motor development and improve motor ability. Exercise for adolescents and adults with CHD has been extensively studied. However, the evidence of exercise for infants with CHD is sparse. This study aims to identify the effect of passive movement and active exercise on motor development within very young CHD infants with cardiac catheterization. METHODS/DESIGN: A prospective and randomized controlled trial will be conducted in very young CHD infants with cardiac catheterization. A total of 147 infants with CHD will be randomized by a 1:1:1 allocation ratio by computer to an exercise intervention group, a home-based intervention group and a control group. The exercise intervention group will receive passive movement and active exercise from experienced physiotherapists in pediatrics three times a week for 12 weeks. The home-based intervention group will receive passive movement and active exercise from their parents or caregivers at home three times a week for 12 weeks. The control group will receive follow up only. The follow-up duration is 20 months. The primary outcome measures are the motor quotient measured by the Peabody Developmental Motor Scales-II. The secondary outcome measures are the Ross score, ventricular function, bone quality, body length, weight, head circumference, upper arm circumference, and adverse events. DISCUSSION: This study has several important features, including the randomization process, the long follow-up duration, the control group, and the large sample size. The aim of this study is to determine whether 12-week passive movement and active exercise promotes motor development and produces other beneficial effects for very young CHD infants with cardiac catheterization. Therefore, this study will contribute new knowledge regarding the rehabilitation program in very young CHD infants with cardiac catheterization. TRIAL REGISTRATION: Current Controlled Trials ChiCTR-IOR-15005909 (January 31, 2015). PMID- 26122089 TI - High genetic diversity declines towards the geographic range periphery of Adonis vernalis, a Eurasian dry grassland plant. AB - Genetic diversity is important for species' fitness and evolutionary processes but our knowledge on how it varies across a species' distribution range is limited. The abundant centre hypothesis (ACH) predicts that populations become smaller and more isolated towards the geographic range periphery - a pattern that in turn should be associated with decreasing genetic diversity and increasing genetic differentiation. We tested this hypothesis in Adonis vernalis, a dry grassland plant with an extensive Eurasian distribution. Its life-history traits and distribution characteristics suggest a low genetic diversity that decreases and a high genetic differentiation that increases towards the range edge. We analysed AFLP fingerprints in 28 populations along a 4698-km transect from the geographic range core in Russia to the western range periphery in Central and Western Europe. Contrary to our expectation, our analysis revealed high genetic diversity (range of proportion of polymorphic bands = 56-81%, He = 0.168-0.238) and low genetic differentiation across populations (Phi(ST) = 0.18). However, in congruence with the genetic predictions of the ACH, genetic diversity decreased and genetic differentiation increased towards the range periphery. Spanish populations were genetically distinct, suggesting a divergent post-glacial history in this region. The high genetic diversity and low genetic differentiation in the remaining A. vernalis populations is surprising given the species' life-history traits and points to the possibility that the species has been widely distributed in the studied region or that it has migrated from a diverse source in an East-West direction, in the past. PMID- 26122090 TI - Influence of different morphology of three-dimensional Cu(x)O with mixed facets modified air-cathodes on microbial fuel cell. AB - Three kinds of three-dimensional (3D) CuxO catalysts were prepared to modify activated carbon air-cathode using a facile electrochemical method with addition of surfactants. The maximum power density of MFC using SC-Cu air cathode (added sodium citrate into the electrolyte solution in electrodeposition process) was 1550+/-47 mW m(-2), almost 77% higher than AC cathode. Specifically, the charge transfer resistance significantly decreased by 89% from 9.3980 Omega to 1.0640 Omega compared to the control. Lumphy and mutually embedded filmy sheet structure were observed in SEM, which provided sufficient active sites for oxygen adsorption and diffusion. In XRD and TEM result, CuxO with mixed facets showed special structure which had a better performance. Crystallization condition of electrodeposited materials played a significant role in their nature electrochemical properties, morphology controlled by surfactant of CuxO exhibited high properties on the air-cathode MFC. PMID- 26122091 TI - Bioelectronic platforms for optimal bio-anode of bio-electrochemical systems: From nano- to macro scopes. AB - The current trend of bio-electrochemical systems is to improve strategies related to their applicability and potential for scaling-up. To date, literature has suggested strategies, but the proposal of correlations between each research field remains insufficient. This review paper provides a correlation based on platform techniques, referred to as bio-electronics platforms (BEPs). These BEPs consist of three platforms divided by scope scale: nano-, micro-, and macro-BEPs. In the nano-BEP, several types of electron transfer mechanisms used by electrochemically active bacteria are discussed. In the micro-BEP, factors affecting the formation of conductive biofilms and transport of electrons in the conductive biofilm are investigated. In the macro-BEP, electrodes and separators in bio-anode are debated in terms of real applications, and a scale-up strategy is discussed. Overall, the challenges of each BEP are highlighted, and potential solutions are suggested. In addition, future research directions are provided and research ideas proposed to develop research interest. PMID- 26122093 TI - Regression analysis of longitudinal data with correlated censoring and observation times. AB - Longitudinal data occur in many fields such as the medical follow-up studies that involve repeated measurements. For their analysis, most existing approaches assume that the observation or follow-up times are independent of the response process either completely or given some covariates. In practice, it is apparent that this may not be true. In this paper, we present a joint analysis approach that allows the possible mutual correlations that can be characterized by time dependent random effects. Estimating equations are developed for the parameter estimation and the resulted estimators are shown to be consistent and asymptotically normal. The finite sample performance of the proposed estimators is assessed through a simulation study and an illustrative example from a skin cancer study is provided. PMID- 26122094 TI - Endorsement of addendae to common obstetric procedures, information pamphlets and a management guideline by AOFOG Maternal Fetal Medicine Committee. PMID- 26122092 TI - A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-kappaB, oxidative stress and metalloproteinases. AB - BACKGROUND: Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema. METHODS: Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2alpha and p65-NF-kappaB in the fixed tissues as well as to evaluate cytokine levels and p65-NF-kappaB protein expression. RESULTS: In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-alpha, IL-1beta and M-CSF in the BALF as well as the levels of NF kappaB and 8-iso-PGF-2alpha in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function. CONCLUSION: These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema. PMID- 26122095 TI - Weight loss interventions and progression of diabetic kidney disease. AB - Progressive renal impairment (diabetic kidney disease (DKD)) occurs in upwards of 40 % of patients with obesity and type 2 diabetes mellitus (T2DM) and is a cause of significant morbidity and mortality. Means of attenuating the progression of DKD focus on amelioration of risk factors. Visceral obesity is implicated as a causative agent in impaired metabolic and cardiovascular control in T2DM, and various approaches primarily targeting weight have been examined for their impact on markers of renal injury and dysfunction in DKD. The current report summarises the evidence base for the impact of surgical, lifestyle and pharmacological approaches to weight loss on renal end points in DKD. The potential for a threshold of weight loss more readily achievable by surgical intervention to be a prerequisite for renal improvement is highlighted. Comparing efficacious non surgical weight loss strategies with surgical strategies in appropriately powered and controlled prospective studies is a priority for the field. PMID- 26122096 TI - The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPARalpha-tr, autonomously regulates proliferative and pro-inflammatory genes. AB - BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARalpha) controls lipid/energy homeostasis and inflammatory responses. The truncated splice variant PPARalpha-tr was suggested to exert a dominant negative function despite being unable to bind consensus PPARalpha DNA response elements. METHODS: The distribution and variability factor of each PPARalpha variant were assessed in the well-characterized cohort of human liver samples (N = 150) on the mRNA and protein levels. Specific siRNA-mediated downregulation of each transcript as well as specific overexpression with subsequent qRT-PCR analysis of downstream genes was used for investigation of specific functional roles of PPARalpha-wt and PPARalpha-tr forms in primary human hepatocytes. RESULTS: Bioinformatic analyses of genome-wide liver expression profiling data suggested a possible role of PPARalpha-tr in downregulating proliferative and pro-inflammatory genes. Specific gene silencing of both forms in primary human hepatocytes showed that induction of metabolic PPARalpha-target genes by agonist WY14,643 was prevented by PPARalpha-wt knock-down but neither prevented nor augmented by PPARalpha-tr knock down. WY14,643 treatment did not induce proliferative genes including MYC, CDK1, and PCNA, and knock-down of PPARalpha-wt had no effect, while PPARalpha-tr knock down caused up to 3-fold induction of these genes. Similarly, induction of pro inflammatory genes IL1B, PTGS2, and CCL2 by IL-6 was augmented by knock-down of PPARalpha-tr but not of PPARalpha-wt. In contrast to human proliferative genes, orthologous mouse genes were readily inducible by WY14,643 in PPARalpha-tr non expressing AML12 mouse hepatocytes. Induction was augmented by overexpression of PPARalpha-wt and attenuated by overexpression of PPARalpha-tr. Pro-inflammatory genes including IL-1beta, CCL2 and TNFalpha were induced by WY14,643 in mouse and human cells and both PPARalpha forms attenuated induction. As potential mechanism of PPARalpha-tr inhibitory action we suggest crosstalk with WNT/beta-catenin pathway. Finally, treatment with WY14,643 in the presence of PPARalpha-tr resulted in the significant reduction of cell viability of AML12 and human ovarian cancer cell line, SKOV3. CONCLUSIONS: Our data suggest that the truncated PPARalpha splice variant functions as an endogenous inhibitor of proliferative and pro-inflammatory genes in human cells and that its absence in mouse may explain species-specific differences in fibrate-induced hepatocarcinogenesis. PMID- 26122098 TI - A Simple High Efficiency Intra-Islet Transduction Protocol Using Lentiviral Vectors. AB - Successful normalization of blood glucose in patients transplanted with pancreatic islets isolated from cadaveric donors established the proof-of-concept that Type 1 Diabetes Mellitus is a curable disease. Nonetheless, major caveats to the widespread use of this cell therapy approach have been the shortage of islets combined with the low viability and functional rates subsequent to transplantation. Gene therapy targeted to enhance survival and performance prior to transplantation could offer a feasible approach to circumvent these issues and sustain a durable functional beta-cell mass in vivo. However, efficient and safe delivery of nucleic acids to intact islet remains a challenging task. Here we describe a simple and easy-to-use lentiviral transduction protocol that allows the transduction of approximately 80 % of mouse and human islet cells while preserving islet architecture, metabolic function and glucose-dependent stimulation of insulin secretion. Our protocol will facilitate to fully determine the potential of gene expression modulation of therapeutically promising targets in entire pancreatic islets for xenotransplantation purposes. PMID- 26122099 TI - Pluripotent Stem Cells for Gene Therapy of Degenerative Muscle Diseases. AB - Human pluripotent stem cells represent a unique source for cell-based therapies and regenerative medicine. The intrinsic features of these cells such as their easy accessibility and their capacity to be expanded indefinitely overcome some limitations of conventional adult stem cells. Furthermore, the possibility to derive patient-specific induced pluripotent stem (iPS) cells in combination with the current development of gene modification methods could be used for autologous cell therapies of some genetic diseases. In particular, muscular dystrophies are considered to be a good candidate due to the lack of efficacious therapeutic treatments for patients to date, and in view of the encouraging results arising from recent preclinical studies. Some hurdles, including possible genetic instability and their efficient differentiation into muscle progenitors through vector/transgene-free methods have still to be overcome or need further optimization. Additionally, engraftment and functional contribution to muscle regeneration in pre-clinical models need to be carefully assessed before clinical translation. This review offers a summary of the advanced methods recently developed to derive muscle progenitors from pluripotent stem cells, as well as gene therapy by gene addition and gene editing methods using ZFNs, TALENs or CRISPR/Cas9. We have also discussed the main issues that need to be addressed for successful clinical translation of genetically corrected patient-specific pluripotent stem cells in autologous transplantation trials for skeletal muscle disorders. PMID- 26122097 TI - The Skeletal Muscle Environment and Its Role in Immunity and Tolerance to AAV Vector-Mediated Gene Transfer. AB - Since the early days of gene therapy, muscle has been one the most studied tissue targets for the correction of enzyme deficiencies and myopathies. Several preclinical and clinical studies have been conducted using adeno-associated virus (AAV) vectors. Exciting progress has been made in the gene delivery technologies, from the identification of novel AAV serotypes to the development of novel vector delivery techniques. In parallel, significant knowledge has been generated on the host immune system and its interaction with both the vector and the transgene at the muscle level. In particular, the role of underlying muscle inflammation, characteristic of several diseases affecting the muscle, has been defined in terms of its potential detrimental impact on gene transfer with AAV vectors. At the same time, feedback immunomodulatory mechanisms peculiar of skeletal muscle involving resident regulatory T cells have been identified, which seem to play an important role in maintaining, at least to some extent, muscle homeostasis during inflammation and regenerative processes. Devising strategies to tip this balance towards unresponsiveness may represent an avenue to improve the safety and efficacy of muscle gene transfer with AAV vectors. PMID- 26122100 TI - Adult Stem Cells and Skeletal Muscle Regeneration. AB - Satellite cells are unipotent stem cells involved in muscle regeneration. However, the skeletal muscle microenvironment exerts a dominant influence over stem cell function. The cell intrinsic complexity of the skeletal muscle niche located within the connective tissue between fibers includes motor neurons, tendons, blood vessels, immune response mediators and interstitial cells. All these cell types modulate the trafficking of stimuli responsible of muscle fiber regeneration. In addition, several stem cell types have been discovered in skeletal muscle tissue, mainly located in the interstitium. The majority of these stem cells appears to directly contribute to myogenic differentiation, although some of them are mainly implicated in paracrine effects. This review focuses on adult stem cells, which have been used for therapeutic purposes, mainly in animal models of chronic muscle degeneration. Emerging literature identifies other myogenic progenitors generated from pluripotent stem cells as potential candidates for the treatment of skeletal muscle degeneration. However, adult stem cells still represent the gold standard for future comparative studies. PMID- 26122101 TI - Therapeutic Approaches for Dominant Muscle Diseases: Highlight on Myotonic Dystrophy. AB - Myotonic Dystrophy (DM), one of the most common neuromuscular disorders in adults, comprises two genetically distinct forms triggered by unstable expanded repeats in non-coding regions. The most common DM1 is caused by expanded CTG repeats in the 3'UTR of the DMPK gene, whereas DM2 is due to large expanded CCTG repeats in the first intron of the CNBP gene. Both mutations induce a pathogenic RNA gain-of-function mechanism. Mutant RNAs containing CUG or CCUG expanded repeats, which are retained in the nuclei as aggregates alter activities of alternative splicing regulators such as MBNL proteins and CELF1. As a consequence, alternative splicing misregulations of several pre-mRNAs are associated with DM clinical symptoms. Currently, there is no available cure for this dominant neuromuscular disease. Nevertheless, promising therapeutic strategies have been developed in the last decade. Preclinical progress in DM research prompted the first DM1 clinical trial based on antisense oligonucleotides promoting a RNase-H-mediated degradation of the expanded CUG transcripts. The ongoing Phase 1/2a clinical trial will hopefully give further insights into the quest to find a bona fide cure for DM1. In this review, we will provide an overview of the different strategies that were developed to neutralize the RNA toxicity in DM1. Different approaches including antisense oligonucleotide technologies, gene therapies or small molecules have been tested and validated in cellular and animal models. Remaining challenges and additional avenues to explore will be discussed. PMID- 26122102 TI - Antibacterial and antibiotic resistance modifying activity of the extracts from Allanblackia gabonensis, Combretum molle and Gladiolus quartinianus against Gram negative bacteria including multi-drug resistant phenotypes. AB - BACKGROUND: Bacterial resistance to antibiotics is becoming a serious problem worldwide. The discovery of new and effective antimicrobials and/or resistance modulators is necessary to tackle the spread of resistance or to reverse the multi-drug resistance. We investigated the antibacterial and antibiotic resistance modifying activities of the methanol extracts from Allanblackia gabonensis, Gladiolus quartinianus and Combretum molle against 29 Gram-negative bacteria including multi-drug resistant (MDR) phenotypes. METHODS: The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of the samples meanwhile the standard phytochemical methods were used for the preliminary phytochemical screening of the plant extracts. RESULTS: Phytochemical analysis showed the presence of alkaloids, flavonoids, phenols and tannins in all studied extracts. Other chemical classes of secondary metabolites were selectively presents. Extracts from A. gabonensis and C. molle displayed a broad spectrum of activity with MICs varying from 16 to 1024 MUg/mL against about 72.41% of the tested bacteria. The extract from the fruits of A. gabonensis had the best activity, with MIC values below 100 MUg/mL on 37.9% of tested bacteria. Percentages of antibiotic-modulating effects ranging from 67 to 100% were observed against tested MDR bacteria when combining the leaves extract from C. molle (at MIC/2 and MIC/4) with chloramphenicol, kanamycin, streptomycin and tetracycline. CONCLUSION: The overall results of the present study provide information for the possible use of the studied plant, especially Allanblackia gabonensis and Combretum molle in the control of Gram-negative bacterial infections including MDR species as antibacterials as well as resistance modulators. PMID- 26122103 TI - Explaining the resurgent popularity of the wild: motivations for wild plant gathering in the Biosphere Reserve Grosses Walsertal, Austria. AB - BACKGROUND: Wild plant gathering becomes again a popular and fashionable activity in Europe after gathering practices have been increasingly abandoned over the last decades. Recent ethnobotanical research documented a diversity of gathering practices from people of diverse socio-economic and cultural backgrounds who gather in urban and rural areas. Few efforts were though made to study the motivations for gathering wild plants and to understand the resurgent popularity of wild plant gathering. This paper addresses the following research questions: (1) which motivations activate wild plant gatherers? (2) which motivation-types of gatherers exist in the Grosses Walsertal? (3) how do the motivations for gathering relate to the socio-demographic background of gatherers? METHODS: Field research was conducted in the Grosses Walsertal, Austria in the years 2008 and 2009 in two field research periods. Thirty-six local farmers were first interviewed with semi-structured interviews. The motivations identified in these interviews were then included in a structured questionnaire, which was used to interview 353 residents of the valley. Pupils of local schools participated in the data collection as interviewers. Principal Component Analysis was used to categorize the motivations and to identify motivation-types of wild plant gatherers. Generalized Linear Models were calculated to identify relations between motivations and the socio-demographic background of gatherers. RESULTS: The respondents listed 13 different motivations for gathering wild plants and four motivations for not gathering. These 17 motivations were grouped in five motivation-types of wild plant gatherers, which are in decreasing importance: product quality, fun, tradition, not-gathering, income. Women, older respondents and homegardeners gather wild plants more often for fun; older respondents gather more often for maintaining traditions; non-homegardeners more frequently mention motivations for not gathering. CONCLUSIONS: The resurgent popularity of wild plant gathering comes along with an internalization of motivations: the main motivations for wild plant gathering changed from the external extrinsic motivation of gathering because of necessity towards the internalized extrinsic motivation of gathering for the highly esteemed product quality and the intrinsic motivation of gathering for the pleasure of the activity itself. This internalization of motivations supports the persistence of wild plant gathering, a positive self-perception of gatherers and good quality of engagement with wild plant gathering. PMID- 26122104 TI - Factors associated with the exposure of vaccines to adverse temperature conditions: the case of North West region, Cameroon. AB - BACKGROUND: Adverse temperature recording in vaccine's cold chain is a major issue worldwide and this condition is known to compromise the quality of vaccines very rapidly. In Cameroon, with tropical climate, vaccines exposure to abnormal temperatures is very common. This study was conducted to identify factors associated to abnormal temperature recording in cold chain in the North West region. RESULTS: A total of 65 vaccinating health facilities were visited for the study from eight health districts. Concerning type of health facility, 48 (73.8%) of the health facilities were governmental facilities. About 50 (76.0%) of the facilities had a functional thermometer. Among the 50 health facilities with functional thermometer, abnormal temperatures were registered in 10 (20%) health facilities during data collection and 12 (24%) in the 2 months preceding collection. Factor significantly associated with abnormal temperature recording was the absence of an alternative power source (OR = 6.5, p = 0.03). CONCLUSION: The absence of an alternative source of power was significantly associated with abnormal temperature exposure in the 2 months preceding data collection. To improve on the quality of vaccines administered in North West region, each vaccinating health facility must have at least two sources of power supply. PMID- 26122106 TI - Does the Medicare 3-Day Rule Increase Length of Stay? AB - Medicare will only cover a stay in a skilled nursing facility (SNF) after TKA if the patient stays for at least 3 days at the inpatient hospital. The 3-day stay rule was instituted in 1965, to prevent over utilization of Medicare. We retrospectively reviewed 800 consecutive TKA, identifying patients that were discharged to rehab after surgery. 322 patients were discharged to SNF after surgery (209 Medicare, 113 private insurances). The LOS was 2.3 days for privately insured patients and 3.02 for Medicare recipients (P<0.05). No difference was found with regard to age, BMI, and ASA score. The Medicare 3-day rule independently increased the LOS in patients who required inpatient rehab, leading to increased cost. We suggest that this rule must be revised. PMID- 26122107 TI - The 24th annual meeting of the American Association of Hip and Knee Surgeons. PMID- 26122105 TI - The Neisseria gonorrhoeae Obg protein is an essential ribosome-associated GTPase and a potential drug target. AB - BACKGROUND: Neisseria gonorrhoeae (GC) is a Gram-negative pathogen that most commonly infects mucosal surfaces, causing sexually transmitted urethritis in men and endocervicitis in women. Serious complications associated with these infections are frequent and include pelvic inflammatory disease, ectopic pregnancy, and infertility. The incidence of gonorrhea cases remains high globally while antibiotic treatment options, the sole counter measures against gonorrhea, are declining due to the remarkable ability of GC to acquire resistance. Evaluating of potential drug targets is essential to provide opportunities for developing antimicrobials with new mechanisms of action. We propose the GC Obg protein, belonging to the Obg/CgtA GTPase subfamily, as a potential target for the development of therapeutic interventions against gonorrhea, and in this study perform its initial functional and biochemical characterization. RESULTS: We report that NGO1990 encodes Obg protein, which is an essential factor for GC viability, associates predominantly with the large 50S ribosomal subunit, and is stably expressed under conditions relevant to infection of the human host. The anti-Obg antisera cross-reacts with a panel of contemporary GC clinical isolates, demonstrating the ubiquitous nature of Obg. The cellular levels of Obg reach a maximum in the early logarithmic phase and remain constant throughout bacterial growth. The in vitro binding and hydrolysis of the fluorescent guanine nucleotide analogs mant-GTP and mant-GDP by recombinant wild type and T192AT193A mutated variants of Obg are also assessed. CONCLUSIONS: Characterization of the GC Obg at the molecular and functional levels presented herein may facilitate the future targeting of this protein with small molecule inhibitors and the evaluation of identified lead compounds for bactericidal activity against GC and other drug-resistant bacteria. PMID- 26122108 TI - Midterm Results of Delta Ceramic-on-Ceramic Total Hip Arthroplasty. AB - This study reports mid-term results of Delta ceramic on ceramic (COC) in total hip arthroplasty (THA). Subjects received Delta COC THA in a prospective multi center study with either 28 mm (n=177) or 36 mm (n=168) articulations. Annual clinical and radiographic evaluations were performed, and patients were asked about hip noises. At mean 5.3-year follow-up there were 3 (0.9%) post-operative liner fractures. Nine revisions were performed (2 liner fracture, 4 stem loosening, 3 deep infection). Kaplan-Meier survivorship at 6 years was 96.9% (94.0-98.4). Twenty-six (7.5%) subjects reported squeaking, of whom none were revised. One (0.3%) subject could reproduce a sound in clinic. More patients reported squeaking with a 36 mm bearing (28 mm: 7/177, 36 mm: 19/168, P=0.013). PMID- 26122109 TI - MRI Findings Associated with Recalled Modular Femoral Neck Rejuvenate and ABG Implants. AB - MARS-MRI is suggested for the diagnosis of adverse local tissue reactions (ALTR) in patients with recalled femoral stems with modular necks, but there has been no major study looking at MARS-MRI findings in this population. A retrospective review was performed on 312 patients who received a modular neck hip implant between October 2007 and February 2012. 62% of patients had intra-articular effusions, with 27% containing debris. Extra-capsular effusions were present in 35% of hips. 54% had synovitis and 5.4% had osteolysis. Tendinopathy and tendon disruption was present in the gluteus medius (58%/12%), hamstring (56%/12%), gluteus minimus (38%/7.7%) and iliopsoas (7.1%/4.8%). Abnormal MARS-MRI findings are associated with modular neck femoral components and can suggest underlying ALTR. MARS-MRI abnormalities merit serious consideration in this population. PMID- 26122110 TI - Are Financial Conflicts of Interest for the Surgeon A Source of Concern for the Patient? AB - We surveyed 269 consecutive patients (81% response rate) with an anonymous questionnaire to assess their attitudes toward conflicts-of-interest (COIs) resulting from three financial relationships between orthopedic surgeons and orthopedic industry: (1) being paid as a consultant; (2) receiving research funding; (3) receiving product design royalties. The majority perceived these relationships favorably, with 75% agreeing that surgeons in such relationships are top experts in the field and two-thirds agreeing that surgeons engage in such relationships to serve patients better. Patients viewed surgeons who designed products more favorably than those who are consultants (P=0.03). The majority (74%) agreed that these COIs should be disclosed to patients. Given patients' desires for disclosure and their favorable perceptions of these relationships, open discussions about financial COIs is appropriate. PMID- 26122111 TI - Total Joint Arthroplasty in Patients with Chronic Renal Disease: Is It Worth the Risk? AB - 26-27% of patients with end stage hip and knee arthritis requiring TJR have chronic renal disease. A multi-center, prospective clinical registry was queried for TJA's from 2006 to 2012, and 74,300 cases were analyzed. Renal impairment was quantified using estimated glomerular filtration rate (eGFR) to stratify each patient by stage of CRD (1-5). There was a significantly greater rate of overall complications in patients with moderate to severe CRD (6.1% vs. 7.6%, P<0.001). In those with CRD (Stage 3-5), mortality was twice as high (0.26% vs. 0.48%, P<0.001). Patients with Stage 4 and 5 CRD had a 213% increased risk of any complication (OR 2.13, 95% CI: 1.73-2.62). Surgeons may use these findings to discuss the risk-benefit ratio of elective TJR in patients with CRD. PMID- 26122112 TI - Development of a Modern Knee Society Radiographic Evaluation System and Methodology for Total Knee Arthroplasty. AB - To accompany the new clinical Knee Society Score, a committee was formed to develop an updated radiographic assessment and evaluation system. The purpose is to accumulate radiographic data in a standardized manner to facilitate more accurate interpretation, documentation and clinical correlation. We systematically reviewed the TKA radiographic evaluation literature as well as the original Knee Society Radiographic Evaluation and Scoring System. A modern system was developed, approved by the Knee Society membership, which ensured proper radiographic documentation of coronal and sagittal implant alignment, fixation interface integrity with respect to radiolucent lines and osteolysis, and a zonal classification system to document precise deficiency locations. It is hoped that data may be accumulated in a standardized manner with eventual formulation of implant risk "criteria" or "scores'. PMID- 26122114 TI - Gynaecological laparoscopy deaths in Australia. AB - AIM: To determine the incidence and clinical features of laparoscopic gynaecological deaths in Australia. MATERIALS AND METHODS: Gynaecological laparoscopic mortality data were obtained from the National Coronial Information Systems (NCIS) and Australian State Coroners Courts, for the period July 1 2000 to December 31 2012. RESULTS: Eighteen deaths were identified, providing a mortality rate of approximately 1 per 70,000 laparoscopic procedures. The commonest cause of death was from bowel perforation, most of which were unrecognised during the operation. CONCLUSION: Gynaecologists should be trained to recognise and manage the rare event of laparoscopic perforation of a viscus or a blood vessel. PMID- 26122113 TI - Requirement of POL3 and POL4 on non-homologous and microhomology-mediated end joining in rad50/xrs2 mutants of Saccharomyces cerevisiae. AB - Non-homologous end joining (NHEJ) directly joins two broken DNA ends without sequence homology. A distinct pathway called microhomology-mediated end joining (MMEJ) relies on a few base pairs of homology between the recombined DNA. The majority of DNA double-strand breaks caused by endogenous oxygen species or ionizing radiation contain damaged bases that hinder direct religation. End processing is required to remove mismatched nucleotides and fill in gaps during end joining of incompatible ends. POL3 in Saccharomyces cerevisiae encodes polymerase delta that is required for DNA replication and other DNA repair processes. Our previous results have shown that POL3 is involved in gap filling at 3' overhangs in POL4-independent NHEJ. Here, we studied the epistatic interaction between POL3, RAD50, XRS2 and POL4 in NHEJ using a plasmid-based endjoining assay in yeast. We demonstrated that either rad50 or xrs2 mutation is epistatic for end joining of compatible ends in the rad50 pol3-t or xrs2 pol3-t double mutants. However, the pol3-t and rad50 or pol3-t and xrs2 mutants caused an additive decrease in the end-joining efficiency of incompatible ends, suggesting that POL3 and RAD50 or POL3 and XRS2 exhibit independent functions in NHEJ. In the rad50 pol4 mutant, end joining of incompatible ends was not detected. In the rad50 or xrs2 mutants, NHEJ events did not contain any microhomology at the rejoined junctions. The pol3-t mutation restored MMEJ in the rad50 or xrs2 mutant backgrounds. Moreover, we demonstrated that NHEJ of incompatible ends required RAD50 and POL4 more than POL3. In conclusion, POL3 and POL4 have differential functions in NHEJ, independent of the RAD50-mediated repair pathway. PMID- 26122116 TI - Radiation Oncology Training Program Curriculum developments in Australia and New Zealand: Design, implementation and evaluation--What next? AB - INTRODUCTION: The Australian and New Zealand Radiation Oncology Training Program has undergone major changes to align with pedagogical principles and best evidence practice. The curriculum was designed around the Canadian Medical Education Directives for Specialists framework and involved structural programme changes and new in-training assessment. This paper summarises the work of programme design and implementation and presents key findings from an evaluation of the revised programme. METHODS: An independent team conducted the evaluation during the last year of the first 5-year curriculum cycle. Opinions were sought from trainees, supervisors and directors of training (DoTs) through online surveys, focused interviews and group consultations. One hundred nineteen participated in surveys; 211 participated in consultations. All training networks were represented. RESULTS: The new curriculum was viewed favourably by most participants with over 90% responding that it 'provided direction in attaining competencies'. Most (87/107; 81%) said it 'promotes regular, productive interaction between trainees and supervisors'. Adequacy of feedback to trainees was rated as only 'average' by trainees/trainers in one-third of cases. Consultations revealed this was more common where trainers were less familiar with curriculum tools. Half of DoTs/supervisors felt better supported. Nearly two third of all responders (58/92; 63%) stated that clinical service requirements could be met during training; 17/92 (18.5%) felt otherwise. When asked about 'work-readiness', 59/90 (66%) respondents, including trainees, felt this was improved. CONCLUSION: Findings suggest that the 'new' curriculum has achieved many of its aims, and implementation has largely been successful. Outcomes focus future work on better supporting trainers in using curriculum tools and providing useful feedback to trainees. PMID- 26122117 TI - Protective effect of epigallocatechin gallate, a major constituent of green tea, against renal ischemia-reperfusion injury in rats. AB - BACKGROUND: Renal ischemia-reperfusion (I/R) injury plays an important role in the acute kidney injury. The pathogenetic mechanisms potential I/R injury is involved in apoptosis and inflammation. Epigallocatechin gallate (EGCG), a major constituent of green tea, has been shown to have anti-inflammatory and anti apoptotic activities. This study aimed to explore the underlying effects and mechanisms of EGCG on renal I/R injury in a rat model. MATERIALS AND METHODS: We induced renal I/R injury in SD rats by clamping the left renal artery for 45 min followed by 24-h reperfusion, along with a contralateral nephrectomy. We randomly allocated 30 rats to three groups (n = 10): sham group, IRI group, and EGCG group. We preconditioned rats intraperitoneally with EGCG (50 mg/kg) or vehicle (50 mg/kg) 45 min before inducing renal ischemia. We collected serum and kidneys at 24 h after reperfusion. Renal function and histologic damage were assessed. We also determined markers of inflammation and apoptosis in kidneys or serum. RESULTS: EGCG pretreatment can significantly reduce renal dysfunction, histologic change and the expression of tumor necrosis factor-alpha, IL-1beta, IL-6, Bax and cleavage caspase 3 induced by I/R injury and increase the expression of Bax and caspase 3. Moreover, EGCG pretreatment can further induce the activation of p38 mitogen-activated protein kinase in kidney, with no influence on the expression of p38. CONCLUSIONS: EGCG treatment can decrease renal ischemia-reperfusion injury by suppressing inflammation and cell apoptosis. Thus, EGCG may represent a potential strategy to reduce renal I/R injury. PMID- 26122118 TI - Effect of medical expulsive therapy on the health-related quality of life of patients with ureteral stones: a critical evaluation. AB - PURPOSE: To evaluate the possible effects of medical expulsive therapy (MET) on the health-related quality of life (HRQOL) of the patients under watchful waiting for ureteral stones. PATIENTS AND METHODS: A total 120 patients with ureteral stones were included into this study program. Patients were divided into two subgroups. While patients in group 1 received medical therapy only for colic pain if needed, patients in group 2 received MET (tamsulosin 0.4 mg/once daily) in addition to medical therapy. All cases were evaluated weekly during 1-month period, and the patients with persistent stones after this period in both groups were evaluated with respect to the analgesic requirement, number of renal colic attacks as well as emergency department (ED) visits along with the QOL scores. RESULTS: Mean values of patient age and stone burden were 37.14 +/- 2.46 years and 42.04 +/- 2.03 mm(2), respectively. Evaluation of the cases with residing stones after 4 weeks (28 cases in group 1 and 27 cases in group 2) with or without MET revealed following findings; renal colic, total amount of analgesic required and the mean number of ED visits were significantly lower in cases receiving MET. Evaluation of the mean HRQOL in terms of EQ-5D index and EQ-5D VAS values in both groups again demonstrated higher mean values in patients undergoing MET (p < 0.05). CONCLUSION: Our findings indicated that MET for ureteral calculi during watchful waiting period could increase the HRQOL scores by lowering the number of both renal colic attacks and ED visits resulting in decreased analgesic need. PMID- 26122119 TI - Correlation between the androgen receptor status of the appendix testis and the efficacy of human chorionic gonadotropin treatment in undescended testis. AB - PURPOSE: To compare the androgen receptor (AR) status of the appendix testis (AT) in congenital undescended and retractile testes. MATERIALS AND METHODS: Twenty four appendix testes (AT) were removed from 21 boys to detect AR expression by immunohistochemistry and immunofluorescence staining. Group 1 (n = 3) includes ATs from three patients with unilateral and group 2 (n = 6) with bilateral congenital undescended testis. All patients with bilateral form had been previously treated with human chorionic gonadotropin (hCG) without an acceptable effect. Group 3 (n = 12) includes ATs collected from 12 boys with acquired undescended testis or retractile testicle. Group 4 (n = 3) includes ATs from three young adults who received hCG treatment for undescended testis in their childhood and underwent open testicular biopsy to investigate infertility. Further seven ATs were collected to detect AR mRNA using RT-PCR analysis. RESULTS: Both immunohistochemistry and immunofluorescence staining of ATs showed AR expression in 100 % of the cases in groups 3 and 4 (12/12 and 3/3), but there was no visible AR expression in groups 1 and 2 (0/3 and 0/6); however, RT-PCR analysis revealed mRNA expression of AR both in congenital undescended and in retractile testicles. CONCLUSIONS: The presence of AR in the epithelial cells of AT in patients with retractile testicle and its absence in patients with congenital undescended testis can be a possible cause of the effectiveness of hormonal treatment in retractile testis and its inefficacy in patients with congenital undescended testis. PMID- 26122120 TI - A novel rat model of catheter-associated urinary tract infection. AB - PURPOSE: The authors aimed to establish a rat model of catheter-associated UTIs using a complete urethral catheter. Bacterial growth in biofilms on urethral catheters was analyzed using standard culture methods to validate this model. METHODS: A total of 15 rats were divided into the following three groups according to the duration of indwelling catheter placement: a 2-week group (n = 5, group 1), a 4-week group (n = 5, group 2), and a 6-week group (n = 5, group 3). A urethral catheter was inserted with the distal end buried just beneath the urethra, and it was fixed inside of the urethra with a single suture starting at the vagina so that the suture knot was hidden inside of the vagina, preventing the rats from biting it off. A standard culture method was used to analyze bacterial growth in the biofilms. RESULTS: All 15 urethral catheters were intact at the end of the experiment. Pseudomonas aeruginosa, Escherichia coli, Enterococcus spp., Enterococcus faecalis, and Corynebacterium spp. were identified in the biofilms on the urethral catheters. CONCLUSION: Our rat UTI model consisting of a complete urinary catheter is feasible. Our study may provide fundamental data for future biofilm studies incorporating molecular techniques, and even clinical studies. PMID- 26122122 TI - Differential Effects of Oxytocin on Agency and Communion for Anxiously and Avoidantly Attached Individuals. AB - Oxytocin promotes prosocial behavior, especially in those individuals who are low in affiliation (e.g., avoidantly attached individuals), but can exacerbate interpersonal insecurities in those preoccupied with closeness (e.g., anxiously attached individuals). One explanation for these opposing observations is that oxytocin induces a communal, other-orientation. Becoming more other oriented should help those people who focus on the self to the exclusion of others, but could be detrimental to those who are other focused but have little sense of an agentic self. Using a within-subjects design, we administered intranasal oxytocin and placebo to 40 males and measured their agency (self-orientation) and communion (other-orientation). Oxytocin produced a slight increase in communion for the average participant; however, as predicted, avoidantly attached individuals were especially likely to perceive themselves as more communal ("kind," "warm," "gentle," etc.) after receiving oxytocin than after receiving the placebo. There was no main effect of oxytocin on agency for the average participant; however, anxiously attached individuals showed a selective decrease in agency ("independent," "self-confident," etc.) following administration of oxytocin. These data help explain the complex social effects of oxytocin. PMID- 26122121 TI - Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission. AB - Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis. PMID- 26122123 TI - Organochlorine pesticide levels in maternal blood and placental tissue with reference to preterm birth: a recent trend in North Indian population. AB - Organochlorine pesticides (OCPs) have been widely used in public health and agriculture programs in developed as well as developing countries, including India. Being xenoestrogenic in nature, OCPs may act as endocrine disruptors leading to preterm birth (PTB) through disturbance of normal estrogen progesterone ratio. PTB is the leading cause of neonatal deaths worldwide. Therefore, the present study is aimed to determine the extent to which persistent environmental chemicals may accumulate in pregnant women and placenta and ascertain possible associations between exposure level and period of gestation (POG), baby weight, and/or placental weight in PTB cases. Maternal blood and placenta samples of PTB cases (n = 50) and subjects of term delivery as controls (n = 50) were collected. OCP residue levels were estimated by the gas chromatography system equipped with an electron capture detector. Significantly higher levels of alpha-hexachlorocyclohexane (alpha-HCH), beta hexachlorocyclohexane (beta-HCH), dichlorodiphenyldichloroethane (DDD), and dichlorodiphenyldichloroethylene (DDE) were found in maternal blood of PTB cases as compared to control. Significantly higher levels of DDE and dichlorodiphenyltrichloroethane (DDT) were also found in placental tissue of PTB cases as compared to control group. There was a statistically significant negative correlation between maternal blood level of alpha-HCH and birth-weight (r = -0.299) and POG (r = -0.234). gamma-Hexachlorocyclohexane (gamma-HCH) and dieldrin had a negative correlation with placental weight (r = -0.401 and -0.256, respectively), and DDE and beta-HCH had a negative correlation with POG (r = 0.251 and -0.229, respectively). The presence of OCPs in maternal blood and placental tissue represents prenatal exposure hazard for fetuses due to chronic bioaccumulation and poor elimination with possible deleterious effect on health. PMID- 26122124 TI - Response of micro- and mesozooplankton in the southwestern Bay of Bengal to a cyclonic eddy during the winter monsoon, 2005. AB - A cyclonic eddy (CE) in the southwestern Bay of Bengal (SWBoB; 10-15 degrees N; 81-87 degrees E) during winter monsoon 2005 and associated changes in the open ocean hydrography and productivity patterns were studied using satellite observations and in situ measurements. Analysis of the satellite-derived sea surface height anomaly (SSHA) indicated the existence of a large eddy (10-15 degrees N; 81-87 degrees E) from November to January, with its core centered at 13 degrees N and 82 degrees E. The large positive wind stress curl (~1.8 * 10( 7) N m(-2)) and resultant Ekman pumping (~3 * 10(-2) cm s(-1)) were identified as the prominent forcing mechanisms. In addition, the cyclonic storms and depressions experienced in the region during the study period seem to have served to maintain the strength of the CE through associated Ekman pumping. The cold (~26.6 degrees C), nutrient-enriched (NO3 > 2 MUM, PO4 > 0.73 MUM and SiO4 > 3 MUM) upwelled waters in the upper layers of the CE enhanced the biological production (chl. a > 0.56 mg m(-3)). Dissolved oxygen in the surface waters was > 200 MUM. The phytoplankton and zooplankton biomass recorded during the season was comparable or perhaps higher than the peak values reported from the northeastern Arabian Sea (chlorophyll a concentrations of 0.2 to 0.4 mg m(-3) and zooplankton biovolume 0.6 ml m(-3)) during winter. Occurrence of a higher mesozooplankton biovolume (0.8 ml m(-3)) and relatively low abundance of microzooplankton indicates the prevalence of a short food chain. In conclusion, high biological production, both at primary as well as secondary level, suggests the prevalence of an efficient food web as a result of physical forcing and subsequent ecological interactions evident up to tertiary level in an oligotrophic basin like BoB. PMID- 26122125 TI - Distribution of polycyclic aromatic hydrocarbons in sediments of Akaki River, Lake Awassa, and Lake Ziway, Ethiopia. AB - The quantification of 14 polycyclic aromatic hydrocarbons (PAHs) was carried out in sediment samples collected from Akaki River, Lake Awassa, and Lake Ziway, Ethiopia. The concentration of PAHs in the samples was determined using gas chromatography-mass spectrometry (GC-MS) in selected ion monitoring (SIM) mode, after microwave-assisted extraction (MAE), using acetone/n-hexane (1:1, v/v) mixture. The accuracy of the method was determined by extracting and analyzing New York/New Jersey waterway sediment standard reference material (SRM 1944). The measured concentrations of PAHs in SRM 1944 agreed well with the certified values. In samples from Akaki River, Lake Awassa, and Lake Ziway, the total content of PAHs determined ranged from 0 to 3070 ng/g (average 534 ng/g), 24.9 to 413 ng/g (average 169 ng/g), and 15.0 to 305 ng/g (average 175 ng/g), respectively. Source ratios indicated that the PAHs were mainly from petrogenic origin. Sediments from all sampling sites indicated negligible levels of toxicity with no risk of adverse biological effects. PMID- 26122126 TI - Microbial and chemical contamination of water, sediment and soil in the Nakivubo wetland area in Kampala, Uganda. AB - The reuse of domestic and industrial wastewater in urban settings of the developing world may harm the health of people through direct contact or via contaminated urban agricultural products and drinking water. We assessed chemical and microbial pollutants in 23 sentinel sites along the wastewater and faecal sludge management and reuse chain of Kampala, Uganda. Water samples were examined for bacteria (thermotolerant coliforms (TTCs), Escherichia coli and Salmonella spp.) and helminth eggs. Physico-chemical parameters were determined. Water, sediment and soil samples and edible plants (yams and sugar cane) were tested for heavy metals. Water samples derived from the Nakivubo wetland showed mean concentrations of TTCs of 2.9 * 10(5) colony-forming units (CFU)/100 mL. Mean E. coli was 9.9 * 10(4) CFU/100 mL. Hookworm eggs were found in 13.5% of the water samples. Mean concentrations of iron (Fe), copper (Cu) and cadmium (Cd) were 21.5, 3.3 and 0.14 mg/L, respectively. In soil samples, we found a mean lead (Pb) concentration of 132.7 mg/L. In yams, concentrations of Cd, chromium (Cr) and Pb were 4.4, 4.0 and 0.2 mg/L, while the respective concentrations in sugar cane were 8.4, 4.3 and 0.2 mg/L. TTCs and E. coli in the water, Pb in soil, and Cd, Cr and Pb in the plants were above national thresholds. We conclude that there is considerable environmental pollution in the Nakivubo wetland and the Lake Victoria ecosystem in Kampala. Our findings have important public health implications, and we suggest that a system of sentinel surveillance is being implemented that, in turn, can guide adequate responses. PMID- 26122127 TI - Could the presence of larger fractions of non-cyanobacterial species be used as a predictor of microcystin production under variable nutrient regimes? AB - The occurrence of cyanobacteria and microcystin is highly dynamic in natural environments and poses one of the biggest challenges to water resource management. While a number of drivers are known to be responsible for the occurrence of cyanobacterial blooms, the drivers of microcystin production are not adequately known. This study aims to quantify the effects of the changes in the structures of phytoplankton and cyanobacterial communities on the dynamics of microcystin production under highly variable nutrient concentration. In our study, nutrient variability could explain 64% of the variability in microcystin production. When changes in the fractions of non-cyanobacteria versus cyanobacteria genera were additionally included, 80% of the variability in microcystin production could be explained; under high nutrient concentrations, non-cyanobacterial phytoplankton groups were dominant over cyanobacteria and cyanobacteria produced more toxins. In contrast, changes in the cyanobacterial community structures could only explain a further 4% of the dynamics of microcystin production. As such, the dominance of non-cyanobacterial groups appears to be a useful factor to explain microcystin occurrence in addition to traditionally used factors such as absolute cyanobacterial cell numbers, especially when the nutrient regime is taken into account. This information could help to further refine the risk assessment frameworks which are currently used to manage the risk posed by cyanobacterial blooms. PMID- 26122128 TI - Assessing environmental risks for high intensity agriculture using the material flow analysis method--a case study of the Dongting Lake basin in South Central China. AB - This study primarily examined the assessment of environmental risk in high intensity agricultural areas. Dongting Lake basin was taken as a case study, which is one of the major grain producing areas in China. Using data obtained from 1989 to 2012, we applied Material Flow Analysis (MFA) to show the material consumption, pollutant output and production storage in the agricultural environmental system and assessed the environmental risk index on the basis of the MFA results. The results predicted that the status of the environmental quality of the Dongting Lake area is unsatisfactory for the foreseeable future. The direct material input (DMI) declined by 13.9%, the domestic processed output (DPO) increased by 28.21%, the intensity of material consumption (IMC) decreased by 36.7%, the intensity of material discharge (IMD) increased by 10%, the material productivity (MP) increased by 27 times, the environmental efficiency (EE) increased by 15.31 times, and the material storage (PAS) increased by 0.23%. The DMI and DPO was higher at rural places on the edge of cities, whereas the risk of urban agriculture has arisen due to the higher increasing rate of DMI and DPO in cities compared with the counties. The composite environmental risk index increased from 0.33 to 0.96, indicating that the total environmental risk changed gradually but seriously during the 24 years assessed. The driving factors that affect environmental risk in high intensity agriculture can be divided into five classes: social, economic, human, natural and disruptive incidents. This study discussed a number of effective measures for protecting the environment while ensuring food production yields. Additional research in other areas and certain improvements of this method in future studies may be necessary to develop a more effective method of managing and controlling agricultural-environmental interactions. PMID- 26122129 TI - Traumatic injuries of the thoracic aorta: The role of imaging in diagnosis and treatment. AB - Traumatic injury of the thoracic aorta remains the leading cause of death in multiple trauma patients and it requires urgent management. Computed tomography has a key diagnostic role and allows the clinician to choose an appropriate treatment strategy. The development of new classifications, based on a better understanding of the mechanisms of these injuries, has clarified the indications for treatment. Advances in techniques, especially in endovascular management, have contributed to improving prognosis for patients. Interventional radiology, which usually consists of endovascular placement of a covered stent, now constitutes the gold standard treatment in these injuries. Due to the potentially grave prognosis of these patients, it is crucial to know how to detect these injuries and to describe the imaging signs of serious damage. PMID- 26122131 TI - NMR based biomarkers to study age-related changes in the human quadriceps. AB - Age-related sarcopenia is a major health issue. To improve elderly person quality of life, it is important to characterize age-associated structural changes within the skeletal muscle. NMR imaging offers quantitative tools to monitor these changes. We scanned 93 subjects: 33 young adults aged between 19 and 27 years old and 60 older adults between 69 and 80 years old. Their physical activity was assessed using a tri-axial accelerometer and they were classified either as active or sedentary. A standard multi-slice multi-echo (MSME) sequence was run and water T2 maps were extracted using a tri-exponential fit. Fat fraction was quantified using three-point Dixon technique. Each quadriceps muscle was characterized by: water T2 mean value, water T2 heterogeneity and the mean fat fraction. Statistical analysis (ANOVA) showed that water T2 mean values and its heterogeneity indices as well as fat fraction were significantly higher in the elderly group (p<0.05). Only fat fraction was significantly lower in the active group compared to the sedentary one (p<0.05). Linear regression confirmed the significant impact of age on these NMR parameters whereas physical activity impact was not systematic. NMR imaging provided a comprehensive assessment of the aging process impact on skeletal muscle composition. Water T2 increase might be related to changes in fiber typology while increased T2 heterogeneities might correlate with some degree of tissue disorganization, like the development of interstitial fibrosis. Fat fraction and water T2 heterogeneity increase was partly slowed down by physical activity. These changes were not gender dependent. PMID- 26122130 TI - Sustained dual drug delivery of anti-inhibitory molecules for treatment of spinal cord injury. AB - Myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) are major contributors to axon growth inhibition following spinal cord injury and limit functional recovery. The NEP1-40 peptide competitively binds the Nogo receptor and partially blocks inhibition from MAIs, while chondroitinase ABC (ChABC) enzymatically digests CSPGs, which are upregulated at the site of injury. In vitro studies showed that the combination of ChABC and NEP1-40 increased neurite extension compared to either treatment alone when dissociated embryonic dorsal root ganglia were seeded onto inhibitory substrates containing both MAIs and CSPGs. Furthermore, the ability to provide sustained delivery of biologically active ChABC and NEP1-40 from biomaterial scaffolds was achieved by loading ChABC into lipid microtubes and NEP1-40 into poly (lactic-co-glycolic acid) (PLGA) microspheres, obviating the need for invasive intrathecal pumps or catheters. Fibrin scaffolds embedded with the drug delivery systems (PLGA microspheres and lipid microtubes) were capable of releasing active ChABC for up to one week and active NEP1-40 for over two weeks in vitro. In addition, the loaded drug delivery systems in fibrin scaffolds decreased CSPG deposition and development of a glial scar, while also increasing axon growth after spinal cord injury in vivo. Therefore, the sustained, local delivery of ChABC and NEP1-40 within the injured spinal cord may block both myelin and CSPG-associated inhibition and allow for improved axon growth. PMID- 26122132 TI - Vitamin B12 deficiency in the institutionalized elderly: A regional study. AB - The prevalence of vitamin B12 deficiency increases with age and is suggested to be even higher in the elderly living in institutions. This retrospective study evaluated the vitamin B12 and folate status of 1996 institutionalized elderly residents aged over 65years. Among them, 34.9% had vitamin B12 deficiency (serum vitamin B12 <150pmol/L), 11.8% had folate deficiency (serum folate <6.8nmol/L), and 4.9% had both. The majority of vitamin B12 deficient residents (68%) had serum vitamin B12 between 100pmol/L and 149pmol/L. Macrocytosis was found in 24.2% of vitamin B12 deficient residents. A significant increase in macrocytosis was associated with a decrease in serum vitamin B12 below 100pmol/L. Macrocytosis was most common in those with vitamin B12 ?69pmol/L (50.9%). Overall, vitamin B12 deficiency is common in the institutionalized elderly, however macrocytosis cannot predict deficiency. More liberal testing for vitamin B12 status in the institutionalized elderly may be warranted. PMID- 26122133 TI - Does fat get you skinny? PMID- 26122134 TI - Sappanone A exhibits anti-inflammatory effects via modulation of Nrf2 and NF kappaB. AB - Homoisoflavonoids constitute a small class of natural products. In the present study, we investigated the anti-inflammatory effect of sappanone A (SPNA), a homoisoflavanone that is isolated from the heartwood of Caesalpinia sappan (Leguminosae), in murine macrophages. SPNA inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-6 (IL-6) as well as the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, SPNA protected C57BL/6 mice from LPS-induced mortality. Treatment of RAW264.7 cells with SPNA induced heme oxygenase (HO)-1 protein and mRNA expression and increased nuclear translocation of the nuclear factor-E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes such as NAD(P)H: quinone oxidoreductase 1 (NQO1). Knockdown of Nrf2 by siRNA blocked SPNA-mediated HO-1 induction. SB203580, p38 mitogen-activated protein kinase (MAPK) inhibitor, blocked SPNA induced HO-1 expression and nuclear translocation of Nrf2, suggesting that SPNA induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti-inflammatory properties, inhibiting HO-1 significantly abrogated the anti-inflammatory effects of SPNA in LPS-stimulated RAW264.7 cells. Moreover, SPNA suppressed LPS-induced nuclear factor kappaB (NF-kappaB) activation via inhibiting Ser 536 phosphorylation and transcriptional activity of RelA/p65 subunit of NF-kappaB. Taken together, these findings suggest that SPNA exerts its anti-inflammatory effect by modulating the Nrf2 and NF-kappaB pathways, and may be a valuable compound to prevent or treat inflammatory diseases. PMID- 26122135 TI - Effect of novel PKCtheta selective inhibitor AS2521780 on acute rejection in rat and non-human primate models of transplantation. AB - Selective inhibition of protein kinase Ctheta (PKCtheta) may be useful in inducing T cell-specific immunosuppression with a reduced rate of side effects. To our knowledge, however, no reports have been published regarding the selective inhibition of PKCtheta by small-molecule compounds in animal models of allograft rejection. Here, we investigated the effect of the newly synthesized PKCtheta selective inhibitor AS2521780 in mono- and combination therapies on acute rejection in ACI-to-Lewis rat cardiac and non-human primate (NHP) renal transplantation models. In the rat cardiac transplantation model, AS2521780 significantly prolonged graft survival to 14days at 10mg/kg twice daily (b.i.d.) and to 20days at 30mg/kg b.i.d. In contrast, acute rejection occurred in all recipients in the non-treated group by Days 5 or 6 post-transplantation. Significant improvements (P<0.001) in graft survival were observed following treatment with a combination of AS2521780 at 3mg/kg b.i.d. and a suboptimal dose of tacrolimus (0.02mg/kg) or mycophenolate mofetil (15mg/kg). In the NHP renal transplantation model, AS2521780 at 3mg/kg b.i.d. and tacrolimus at 1mg/kg (suboptimal dose) significantly improved graft survival compared to tacrolimus alone (P<0.05). The present study of AS2521780 in rat cardiac and NHP renal transplantation models demonstrates the potential of PKCtheta as a novel drug target for organ transplantation. As AS2521780 was well tolerated and the dose of tacrolimus or mycophenolate mofetil can be reduced when used in combination with this drug, immunosuppressive regimens containing selective inhibitors of PKCtheta might have good safety profiles. PMID- 26122136 TI - Ginsenoside Rg1 improves lipopolysaccharide-induced acute lung injury by inhibiting inflammatory responses and modulating infiltration of M2 macrophages. AB - Ginsenoside Rg1 (Rg1), the major effective component of ginseng, has been reported to have potent anti-inflammatory properties. However, the effect of ginsenoside Rg1 on lipopolysaccharide (LPS) -induced acute lung injury (ALI) in mice was unknown. The present study was designed to investigate the protective role of Rg1 on LPS-induced ALI and explore the potential mechanisms. The mice were divided randomly into four groups: the sham group, the LPS group and the LPS+Rg1 (40 mg/kg or 200mg/kg) pretreatment groups. All mice received Rg1 or an equivalent volume of phosphate buffer saline (PBS) intraperitoneally 1h before LPS administration. Edema quantification, histology, and apoptosis were detected 6h after LPS administration. The number of inflammatory cells, the percentage of alternative activated (M2) macrophages and the exudate quantification in bronchoalveolar lavage fluid (BALF) were evaluated. The caspase 3 expression, and the levels of phosphorylated IkappaB-alpha and p65 were tested. The results showed that the Rg1 pretreatment group markedly improved lung damage, modulated the infiltration of neutrophils and M2 macrophages, prevented the production of protein and proinflammatory cytokines in BALF, and inhibited apoptosis in lung. We also found that Rg1 suppressed NF-kappaB and caspase 3 activation. These data suggest that Rg1 plays a protective role against LPS-induced ALI by ameliorating inflammatory responses, regulating the infiltration of M2 macrophages, and inhibiting pulmonary cell apoptosis. PMID- 26122137 TI - Prostaglandin E2 blockade enhances the pulmonary anti-Cryptococcus neoformans immune reaction via the induction of TLR-4. AB - The present study aimed to explore whether the inhibition of prostaglandin E2 enhances pulmonary anti-Cryptococcus neoformans immunity. Lung colony forming unit (CFU) assays demonstrated that the cryptococcal infection was dramatically depressed in mice given EP2 and EP4 or single EP antagonist treatment compared to the untreated wild type mice (p<0.05), leading to the increased survival of the infected mice by 8-9 days or 2-4 days, respectively. RT-PCR and flow cytometry assays showed that the expression of IFN-gamma, IL-17, IL-22 in M1 macrophages and IL-10 in M2 macrophages increased significantly at 1 week post-infection in mice with either EP2 or EP4 blockade (p<0.05). The polarization of alveolar macrophages showed that, at 1 week post infection, the alveolar macrophages in untreated wild type mice, TLR4(-/-) mice and TLR4(-/-) mice with EP2 and EP4 blockade were strongly M2 polarized, whereas the alveolar macrophages in wild type mice with EP2 and EP4 blockade were M1 polarized. In conclusion, the blockade of EP2 and EP4 promotes mouse survival after cryptococcus infection by promoting the production of cytokines via TLR4, as well as the enhanced M1 polarization of alveolar macrophages. PMID- 26122138 TI - Cortical microinfarcts on 7 T MRI in patients with spontaneous intracerebral hemorrhage. PMID- 26122140 TI - Mano a Mano for health professions students in Chile: a pilot HIV prevention program. PMID- 26122141 TI - Reflections on Mentorship on the Occasion of Dr Kurt J. Isselbacher's 90th Birthday. PMID- 26122139 TI - Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. AB - BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults. METHODS: We estimated the association between serum 25 hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts. RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09). CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies. PMID- 26122142 TI - Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas. AB - Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9(V90M) had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments. PMID- 26122143 TI - Physician Non-adherence to Colonoscopy Interval Guidelines in the Veterans Affairs Healthcare System. AB - BACKGROUND & AIMS: Colonoscopy can decrease colorectal cancer (CRC) mortality, although performing this procedure more frequently than recommended could increase costs and risks to patients. We aimed to determine rates and correlates of physician non-adherence to guidelines for repeat colonoscopy screening and polyp surveillance intervals. METHODS: We performed a multi-center, retrospective, observational study using administrative claims, physician databases, and electronic medical records (EMR) from 1455 patients (50-64 y old) who underwent colonoscopy in the Veterans Affairs healthcare system in fiscal year 2008. Patients had no prior diagnosis of CRC or inflammatory bowel disease, and had not undergone colonoscopy examinations in the previous 10 years. We compared EMR-documented, endoscopist-recommended intervals for colonoscopies with intervals recommended by the 2008 Multi-Society Task Force guidelines. RESULTS: The overall rate of non-adherence to guideline recommendations was 36% and ranged from 3% to 80% among facilities. Non-adherence was 28% for patients who underwent normal colonoscopies, but 45%-52% after colonoscopies that identified hyperplastic or adenomatous polyps. Most of all recommendations that were not followed recommended a shorter surveillance interval. In adjusted analyses, non adherence was significantly higher for patients whose colonoscopies identified hyperplastic (odds ratio [OR] = 3.1; 95% CI, 1.7-5.5) or high-risk adenomatous polyps (OR = 3.0; 95% CI, 1.2-8.0), compared to patients with normal colonoscopy examinations, but not for patients with low-risk adenomatous polyps (OR = 1.8; 95% CI, 0.9-3.7). Nonadherence was also associated with bowel preparation quality, geographic region, Charlson comorbidity score, and colonoscopy indication. CONCLUSIONS: In a managed care setting with salaried physicians, endoscopists recommend repeat colonoscopy sooner than guidelines for more than one third of patients. Factors associated with non-adherence to guideline recommendations were colonoscopy findings, quality of bowel preparation, and geographic region. Targeting endoscopist about non-adherence to colonoscopy guidelines could reduce overuse of colonoscopy and associated healthcare costs. PMID- 26122144 TI - Sustainable equality--a goal to aspire to. PMID- 26122145 TI - Reforming public and global health in Germany. PMID- 26122146 TI - Mental health in China: what will be achieved by 2020? PMID- 26122149 TI - Canada lacks national suicide prevention strategy. PMID- 26122147 TI - Japan's vision for health care in 2035. PMID- 26122150 TI - Mounting cancer burden tests Africa's health resources. PMID- 26122151 TI - Constructing Scientific Communities: Citizen Science. PMID- 26122152 TI - Medical periodicals: mining the past. PMID- 26122153 TI - HPV vaccination crisis in Japan. PMID- 26122154 TI - Anti-inflammatory therapies in myocardial infarction. PMID- 26122155 TI - A 21st-century medical school. PMID- 26122156 TI - A 21st-century medical school - Authors' reply. PMID- 26122157 TI - Responses to the Chief Medical Officer's report 2013. PMID- 26122158 TI - Department of Error. PMID- 26122160 TI - Department of Error. PMID- 26122159 TI - Department of Error. PMID- 26122161 TI - Department of Error. PMID- 26122162 TI - Responses to the Chief Medical Officer's report 2013. PMID- 26122163 TI - Donovanosis causing lymphadenitis, mastoiditis, and meningitis in a child. PMID- 26122164 TI - Lgr5 positive stem cells sorted from small intestines of diabetic mice differentiate into higher proportion of absorptive cells and Paneth cells in vitro. AB - Intestinal epithelial stem cells (IESCs) can differentiate into all types of intestinal epithelial cells (IECs) and Leucine-rich repeat-containing G protein coupled receptor 5 (Lgr5) is a marker for IESC. Previous studies reported enhanced proliferation of IECs in diabetic mice. In this study, the in vitro differentiation of Lgr5 positive IESCs sorted from diabetic mice was further investigated. The diabetic mouse model was induced by streptozotocin (STZ), and crypt IECs were isolated from small intestines. Subsequently, Lgr5 positive IESCs were detected by flow cytometry (FCM) and sorted by magnetic activated cell sorting (MACS). Differentiation of the sorted IESCs was investigated by detecting the IEC markers in the diabetic mice using immunostaining, quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), and Western blot analysis, which was compared with normal mice. We found that the proportion of Lgr5 positive cells in the crypt IECs of diabetic mice was higher than that of control mice (P < 0.05). Lgr5 positive IESCs could be significantly enriched in Lgr5 positive cell fraction sorted by MACS. Furthermore, the absorptive cell marker sucrase-isomaltase (SI) and the Paneth cell marker lysozyme 1 (Lyz1) were more highly expressed in the differentiated cells derived from Lgr5 positive IESCs of diabetic mice in vitro (P < 0.05). We demonstrate that the number of Lgr5 positive IESCs is significantly increased in the small intestines of STZ induced diabetic mice. Lgr5 positive IESCs sorted from the diabetic mice can differentiate into a higher proportion of absorptive cells and Paneth cells in vitro. We characterized the expression of Lgr5 in the small intestine of diabetic mice, and sorted Lgr5 positive intestinal epithelial stem cells (IESCs) for investigating their differentiation in vitro. We proved that the quantity of Lgr5 positive IESCs was significantly increased in the small intestines of diabetic mice. IESCs sorted from the diabetic mice can differentiate into a higher proportion of absorptive cells and Paneth cells in vitro. PMID- 26122165 TI - sb203580 preconditioning recharges matrix-expanded human adult stem cells for chondrogenesis in an inflammatory environment - A feasible approach for autologous stem cell based osteoarthritic cartilage repair. AB - Autologous stem cells are a promising cell source for cartilage regeneration; however, cell replicative senescence and joint posttraumatic inflammation provide challenges in bringing this treatment modality to fruition. In this study, we hypothesized that preconditioning with p38 MAPK inhibitor (sb203580) would recharge decellularized extracellular matrix (dECM) expanded human synovium derived stem cell (hSDSC) chondrogenesis in an inflammatory environment. We found that preconditioning with sb203580 greatly enhanced dECM expanded hSDSC proliferation and chondrogenic potential while supplementation with sb203580 in an induction medium dramatically retarded hSDSC chondrogenic differentiation, even for dECM expanded cells. We also found that sb203580 preconditioning enhanced matrix-expanded hSDSC chondrogenic capacity even in an interleukin-1 (IL 1) induced inflammatory environment. Non-detectable expression of HLA-DR in the hSDSCs grown on allogeneic dECM indicates the feasibility of commercial preparation of these dECMs from healthy, young donors for patients who need autologous transplantation. Our study indicated that p38 MAPK inhibitor has a distinctive priming effect on dECM mediated stem cell cartilage regeneration. Combined rejuvenation with sb203580 and dECM expansion can precondition hSDSCs' resurfacing capacity for osteoarthritic patients with cartilage defects. PMID- 26122166 TI - Population genetic dynamics of an invasion reconstructed from the sediment egg bank. AB - Biological invasions are a global issue with far-reaching consequences for single species, communities and whole ecosystems. Our understanding of modes and mechanisms of biological invasions requires knowledge of the genetic processes associated with successful invasions. In many instances, this information is particularly difficult to obtain as the initial phases of the invasion process often pass unnoticed and we rely on inferences from contemporary population genetic data. Here, we combined historic information with the genetic analysis of resting eggs to reconstruct the invasion of Daphnia pulicaria into Lower Lake Constance (LLC) in the 1970s from the resting egg bank in the sediments. We identified the invader as 'European D. pulicaria' originating from meso- and eutrophic lowland lakes and ponds in Central Europe. The founding population was characterized by extremely low genetic variation in the resting egg bank that increased considerably over time. Furthermore, strong evidence for selfing and/or biparental inbreeding was found during the initial phase of the invasion, followed by a drop of selfing rate to low levels in subsequent decades. Moreover, the increase in genetic variation was most pronounced during early stages of the invasion, suggesting additional introductions during this period. Our study highlights that genetic data covering the entire invasion process from its beginning can be crucial to accurately reconstruct the invasion history of a species. We show that propagule banks can preserve such information enabling the study of population genetic dynamics and sources of genetic variation in successful invasive populations. PMID- 26122167 TI - Human REM sleep: influence on feeding behaviour, with clinical implications. AB - Rapid eye movement (REM) sleep shares many underlying mechanisms with wakefulness, to a much greater extent than does non-REM, especially those relating to feeding behaviours, appetite, curiosity, exploratory (locomotor) activities, as well as aspects of emotions, particularly 'fear extinction'. REM is most evident in infancy, thereafter declining in what seems to be a dispensable manner that largely reciprocates increasing wakefulness. However, human adults retain more REM than do other mammals, where for us it is most abundant during our usual final REM period (fREMP) of the night, nearing wakefulness. The case is made that our REM is unusual, and that (i) fREMP retains this 'dispensability', acting as a proxy for wakefulness, able to be forfeited (without REM rebound) and substituted by physical activity (locomotion) when pressures of wakefulness increase; (ii) REM's atonia (inhibited motor output) may be a proxy for this locomotion; (iii) our nocturnal sleep typically develops into a physiological fast, especially during fREMP, which is also an appetite suppressant; (iv) REM may have 'anti-obesity' properties, and that the loss of fREMP may well enhance appetite and contribute to weight gain ('overeating') in habitually short sleepers; (v) as we also select foods for their hedonic (emotional) values, REM may be integral to developing food preferences and dislikes; and (vii) REM seems to have wider influences in regulating energy balance in terms of exercise 'substitution' and energy (body heat) retention. Avenues for further research are proposed, linking REM with feeding behaviours, including eating disorders, and effects of REM-suppressant medications. PMID- 26122169 TI - Internal morphology of the nonsyndromic prematurely fused sagittal suture in the human skull--A preliminary micro-CT study. AB - Although nonsyndromic craniosynostosis (NSC) of the sagittal suture is a well known type of craniosynostosis, little is currently known about the internal morphology of this prematurely fused suture in modern humans. Recently, micro computed tomography (micro-CT) has been applied as a new tool for the quantitative evaluation of cranial suture morphology. However, so far there are only a small number of reports concerning studies of the internal morphology of prematurely fused sagittal suture in humans using micro-CT. The primary aim of this study was to examine the internal morphology of a completely obliterated sagittal suture in NSC. Two modern human skulls were used in this study: a skull of a child (aged 10 +/- 2.5 years) displaying NSC of the sagittal suture and a skull of an adult showing non-prematurely completely obliterated sagittal suture. Quantitative variables of the sagittal sutures were assessed using method proposed by the authors. Porosity, and relative thickness of three bone layers in two examined skulls (inner cortical, diploe and outer cortical) were analysed using micro-CT in three equal sections of the sagittal suture. In the case of the prematurely fused suture, there were statistically significant differences mainly in the mean values of the porosity, thickness and relative thickness of the diploe between the anterior part and the two other parts (central and posterior) of this suture. Significant differences were also observed in some of the analysed variables between the sections of the sagittal suture of the skull with NSC and the normal skull. PMID- 26122168 TI - Microneedles: an innovative platform for gene delivery. AB - The advent of microneedle (MN) technology has provided a revolutionary platform for the delivery of therapeutic agents, particularly in the field of gene therapy. For over 20 years, the area of gene therapy has undergone intense innovation and progression which has seen advancement of the technology from an experimental concept to a widely acknowledged strategy for the treatment and prevention of numerous disease states. However, the true potential of gene therapy has yet to be achieved due to limitations in formulation and delivery technologies beyond parenteral injection of the DNA. Microneedle-mediated delivery provides a unique platform for the delivery of DNA therapeutics clinically. It provides a means to overcome the skin barriers to gene delivery and deposit the DNA directly into the dermal layers, a key site for delivery of therapeutics to treat a wide range of skin and cutaneous diseases. Additionally, the skin is a tissue rich in immune sentinels, an ideal target for the delivery of a DNA vaccine directly to the desired target cell populations. This review details the advancement of MN-mediated DNA delivery from proof-of-concept to the delivery of DNA encoding clinically relevant proteins and antigens and examines the key considerations for the improvement of the technology and progress into a clinically applicable delivery system. PMID- 26122170 TI - Maraviroc Clinical Test (MCT) as an alternative tool to decide CCR5-antagonists prescription in naive HIV-infected patients. AB - Our aim was to analyze the virological response to a combined antiretroviral therapy started after Maraviroc Clinical Test (MCT) in naive HIV-infected patients. Forty-one patients were exposed to MCT, based on an 8-day MVC monotherapy. If undetectability or a viral load reduction >1 log10 HIV-RNA copies/ml was achieved, a MVC-containing cART was prescribed. Forty patients showed a positive MCT; undetectability after 48weeks on cART was achieved in 34/41 (82.9%) patients. The result of MCT was compared with a genotypic tropism method and with Trofile(r), showing 10.7% and 18.75% discordance rates, respectively. MCT is a reliable tool to decide CCR5-antagonists prescription, also in the naive scenario where most patients show a virological response to MVC independently the tropism result reported by genotypic or phenotypic methods. PMID- 26122172 TI - Immunotherapies and immune biomarkers in Type 1 diabetes: A partnership for success. AB - The standard of care (SoC) for Type 1 diabetes (T1D) today is much the same as it was in the early 1920s, simply with more insulin options-fast-acting, slow acting, injectable, and inhalable insulins. However, these well-tolerated treatments only manage the symptoms and complications, but do nothing to halt the underlying immune response. There is an unmet need for better treatment options for T1D that address all aspects of the disease. For decades, we have successfully treated T1D in preclinical animal models with immune-modifying therapies that have not demonstrated comparable efficacy in humans. The path to bringing such options to the clinic will depend on the implementation and standard inclusion of biomarkers of immune and therapeutic efficacy in T1D clinical trials, and dictate if we can create a new SoC that treats the underlying autoimmunity as well as the symptoms it causes. PMID- 26122171 TI - Biomarkers for antigen immunotherapy in allergy and type 1 diabetes. AB - Allergy and type 1 diabetes are immune mediated diseases that, despite being etiologically distinct, each have inappropriate activation and effector function of antigen-specific T cells in the pathogenic process. Understanding changes in the frequency and phenotype of these cells is critical to improve assessment of disease diagnosis and prognosis and effectively assess immunological response to therapy. In the setting of antigen-specific therapy in allergy and type 1 diabetes, assays to monitor the immunological mechanisms of disease have been improving in recent years, and we are getting closer to an accurate understanding of how the cellular immune response is modulated during treatment. In this review, we summarize the current state of cell-based immune monitoring of antigen therapy trials. We then discuss emerging advances in antigen-specific biomarkers that are transforming our knowledge about allergy and that have the potential to dramatically impact our understanding of T cell-mediated autoimmune diseases, such as type 1 diabetes. PMID- 26122173 TI - Effects of enzyme replacement therapy on immune function in ADA deficiency patient. PMID- 26122174 TI - The bacterial microbiota in inflammatory lung diseases. AB - Numerous lines of evidence, ranging from recent studies back to those in the 1920s, have demonstrated that the lungs are NOT bacteria-free during health. We have recently proposed that the entire respiratory tract should be considered a single ecosystem extending from the nasal and oral cavities to the alveoli, which includes gradients and niches that modulate microbiome dispersion, retention, survival and proliferation. Bacterial exposure and colonization of the lungs during health is most likely constant and transient, respectively. Host microanatomy, cell biology and innate defenses are altered during chronic lung disease, which in turn, alters the dynamics of bacterial turnover in the lungs and can lead to longer term bacterial colonization, as well as blooms of well recognized respiratory bacterial pathogens. A few new respiratory colonizers have been identified by culture-independent methods, such as Pseudomonas fluorescens; however, the role of these bacteria in respiratory disease remains to be determined. PMID- 26122177 TI - The Raman optical activity of beta-D-xylose: where experiment and computation meet. AB - Besides its applications in bioenergy and biosynthesis, beta-d-xylose is a very simple monosaccharide that exhibits relatively high rigidity. As such, it provides the best basis to study the impact of different solvation shell radii on the computation of its Raman optical activity (ROA) spectrum. Indeed, this chiroptical spectroscopic technique provides exquisite sensitivity to stereochemistry, and benefits much from theoretical support for interpretation. Our simulation approach combines density functional theory (DFT) and molecular dynamics (MD) in order to efficiently account for the crucial hydration effects in the simulation of carbohydrates and their spectroscopic response predictions. Excellent agreement between the simulated spectrum and the experiment was obtained with a solvation radius of 10 A. Vibrational bands have been resolved from the computed ROA data, and compared with previous results on different monosaccharides in order to identify specific structure-spectrum relationships and to investigate the effect of the solvation environment on the conformational dynamics of small sugars. From the comparison with ROA analytical results, a shortcoming of the classical force field used for the MD simulations has been identified and overcome, again highlighting the complementary role of experiment and theory in the structural characterisation of complex biomolecules. Indeed, due to unphysical puckering, a spurious ring conformation initially led to erroneous conformer ratios, which are used as weights for the averaging of the spectral average, and only by removing this contribution was near perfect comparison between theory and experiment achieved. PMID- 26122176 TI - Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance and progression-free survival in serous epithelial ovarian cancers. AB - BACKGROUND: Platinum-based combination therapy is the standard first-line treatment for women with advanced serous epithelial ovarian carcinoma (EOC). However, about 20 % will not respond and are considered clinically resistant. The availability of biomarkers to predict responses to the initial therapy would provide a practical approach to identify women who would benefit from a more appropriate first-line treatment. Ascites is an attractive inflammatory fluid for biomarker discovery as it is easy and minimally invasive to obtain. The aim of this study was to evaluate whether six selected inflammation-regulating factors in ascites could serve as diagnostic or drug resistance biomarkers in patients with advanced serous EOC. METHODS: A total of 53 women with stage III/IV serous EOC and 10 women with benign conditions were enrolled in this study. Eleven of the 53 women with serous EOC were considered clinically resistant to treatment with progression-free survival<6 months. Ascites were collected at the time of the debulking surgery and the levels of cytokines were measured by ELISA. The six selected cytokines were evaluated for their ability to discriminate serous EOC from benign controls, and to discriminate platinum resistant from platinum sensitive patients. RESULTS: Median ascites levels of IL-6, IL-10 and osteoprotegerin (OPG) were significantly higher in women with advanced serous EOC than in controls (P<=0.012). There were no significant difference in the median ascites levels of leptin, soluble urokinase plasminogen activator receptor (suPAR) and CCL18 among serous EOC women and controls. In Receiver Operator curve (ROC) analysis, IL-6, IL-10 and OPG had a high area under the curve value of 0.905, 0.832 and 0.825 respectively for distinguishing EOC from benign controls. ROC analysis of individual cytokines revealed low discriminating potential to stratify patients according to their sensitivity to first-line treatment. The combination of biomarkers with the highest discriminating potential was with CA125 and leptin (AUC=0.936, 95% CI: 0.894-0.978). CONCLUSION: IL-6 was found to be strongly associated with advanced serous EOC and could be used in combination with serum CA125 to discriminate benign and EOC. Furthermore, the combination of serum CA125 and ascites leptin was a strong predictor of clinical resistance to first-line therapy. PMID- 26122178 TI - Retracted: Adsorption Features of Flavonoids on Macroporous Adsorption Resins Functionalized with Ionic Liquids. PMID- 26122175 TI - Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders. AB - Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways. PMID- 26122179 TI - Whole genome amplification with SurePlex results in better copy number alteration detection using sequencing data compared to the MALBAC method. AB - Current whole genome amplification (WGA) methods lead to amplification bias resulting in over- and under-represented regions in the genome. Nevertheless, certain WGA methods, such as SurePlex and subsequent arrayCGH analysis, make it possible to detect copy number alterations (CNAs) at a 10 Mb resolution. A more uniform WGA combined with massive parallel sequencing (MPS), however, could allow detection at higher resolution and lower cost. Recently, MALBAC, a new WGA method, claims unparalleled performance. Here, we compared the well-established SurePlex and MALBAC WGA for their ability to detect CNAs in MPS generated data and, in addition, compared PCR-free MPS library preparation with the standard enrichment PCR library preparation. Results showed that SurePlex amplification led to more uniformity across the genome, allowing for a better CNA detection with less false positives compared to MALBAC amplified samples. An even more uniform coverage was observed in samples following a PCR-free library preparation. In general, the combination of SurePlex and MPS led to the same chromosomal profile compared to a reference arrayCGH from unamplified genomic DNA, underlining the large potential of MPS techniques in CNA detection from a limited number of DNA material. PMID- 26122180 TI - Bundap Marram Durn Durn: Engagement with Aboriginal women experiencing comorbid chronic physical and mental health conditions. AB - OBJECTIVE: To explore antecedents of health service engagement and experience among urban Aboriginal people with comorbid physical and mental health conditions. METHODS: Focus groups and interviews were conducted with Aboriginal people who had comorbid health conditions and were accessing Aboriginal and/or mainstream services. RESULTS: Nineteen participants, all women, were recruited. Participants' personal histories and prior experience of health services affected effective service utilisation. Participants' service experiences were characterised by long waiting times in the public health system and high healthcare staff turnover. Trusted professionals were able to act as brokers to other clinically and culturally competent practitioners. CONCLUSIONS: Many urban Aboriginal women attended health services with multiple comorbid conditions including chronic disease and mental health issues. Several barriers and enablers were identified concerning the capacity of services to engage and effectively manage Aboriginal patients' conditions. IMPLICATIONS: Results indicate the need to explore strategies to improve health care utilisation by urban Aboriginal women. PMID- 26122182 TI - Gynaecological cancer: ADAMTS mutations predict sensitivity to chemotherapy in ovarian cancer. PMID- 26122181 TI - ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. AB - Approximately 70% of breast cancers are oestrogen receptor alpha (ER) positive, and are, therefore, treated with endocrine therapies. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. Despite the magnitude of this clinical challenge, the mechanisms underlying the development of resistance remain largely unknown. In the past 2 years, several studies unveiled gain-of function mutations in ESR1, the gene encoding the ER, in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies, such as tamoxifen and aromatase inhibitors. These mutations are clustered in a 'hotspot' within the ligand-binding domain (LBD) of the ER and lead to ligand independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity; thus, ER LBD mutations might account for a mechanism of acquired endocrine resistance in a substantial fraction of patients with metastatic disease. In general, the absence of detectable ESR1 mutations in patients with treatment-naive disease, and the correlation between the frequency of patients with tumours harbouring these mutations and the number of endocrine treatments received suggest that, under selective treatment pressure, clonal expansion of rare mutant clones occurs, leading to resistance. Preclinical and clinical development of rationale-based novel therapeutic strategies that inhibit these ER mutants has the potential to substantially improve treatment outcomes. We discuss the contribution of ESR1 mutations to the development of acquired resistance to endocrine therapy, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes. PMID- 26122184 TI - Breast cancer: PALOMA-3 confirms that CDK4/6 is a key therapeutic target. PMID- 26122183 TI - Inflammation and cancer: advances and new agents. AB - Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response. PMID- 26122186 TI - Lung cancer: Squiring immunotherapy to CheckMate. PMID- 26122188 TI - Association of measles and mumps with cardiovascular disease: The Japan Collaborative Cohort (JACC) study. AB - OBJECTIVE: Although it has been suggested that exposure to infections during childhood could decrease risk of atherosclerotic cardiovascular disease (CVD), the evidence is scarce. We investigated the association of measles and mumps with CVD. METHODS: 43,689 men and 60,147 women aged 40-79 years at baseline (1988 1990) completed a lifestyle questionnaire, including their history of measles and mumps, and were followed until 2009. Histories of infections were categorized as having no infection (reference), measles only, mumps only, or both infections. Hazard ratios (HR) for mortality from CVD across histories of infections were calculated. RESULTS: Men with measles only had multivariable HR (95% confidence interval) of 0.92 (0.85-0.99) for total CVD, those with mumps only had 0.52 (0.28 0.94) for total stroke and 0.21 (0.05-0.86) for hemorrhagic stroke, and those with both infections had 0.80 (0.71-0.90) for total CVD, 0.71 (0.53-0.93) for myocardial infarction, and 0.83 (0.69-0.98) for total stroke. Women with both infections had 0.83 (0.74-0.92) for total CVD and 0.84 (0.71-0.99) for total stroke. We also compared subjects with measles only or mumps only (reference) and those with both infections. Men with both infections had 0.88 (0.78-0.99) for total CVD. Women with both infections had 0.85 (0.76-0.94) for total CVD, 0.79 (0.67-0.93) for total stroke, 0.78 (0.62-0.98) for ischemic stroke and 0.78 (0.62 0.98) for hemorrhagic stroke. CONCLUSIONS: Measles and mumps, especially in case of both infections, were associated with lower risks of mortality from atherosclerotic CVD. PMID- 26122189 TI - Co-existence of vascular disease in different arterial beds: Peripheral artery disease and carotid artery stenosis--Data from Life Line Screening((r)). AB - BACKGROUND: Atherosclerosis is a systemic vascular disorder, involving multiple arterial territories. This project sought to investigate the relationship between lower extremity peripheral artery disease (PAD) and carotid artery stenosis (CAS) in a large self-referred population. METHODS: Data from the ankle brachial index (ABI) and carotid duplex ultrasound were analyzed from 3.67 million US subjects in the Life Line Screening program between 2004 and 2008. PAD was defined by ABI<0.9 and CAS was defined by greater than 50% stenosis. Multivariate logistic regression analysis was used to estimate odds of CAS by PAD status and severity. RESULTS: Mean age of the population was 63.7 +/- 10.6 years and 64% were women. The prevalence of PAD and CAS was 4.1% and 3.9%, respectively. Subjects with PAD had a higher prevalence of CAS than those without PAD (18.8% vs. 3.3%, P < 0.0001). In multivariate analysis, PAD was associated with greater odds of CAS (OR 3.28, 95% CI 3.22-3.34). Both symptomatic (OR 3.66, 95% CI 3.58-3.75) and asymptomatic PAD (OR 2.91, 95% CI 2.84-2.98) was associated with CAS. Increasing severity of PAD was associated with greater odds of CAS (OR 2.32, 3.61, 4.19, 5.14, and 7.59 for ABI categories 0.81-0.90, 0.71-0.80, 0.61-0.70, 0.41-0.60, <=0.40, respectively). CONCLUSION: Presence and severity of PAD was associated with prevalence of CAS in the large self-referred and self-paying Life Line cohort, regardless of lower extremity symptoms. PMID- 26122191 TI - Corrigendum: Generation of the SCN1A epilepsy mutation in hiPS cells using the TALEN technique. PMID- 26122185 TI - Opportunities and challenges of radiotherapy for treating cancer. AB - The past 20 years have seen dramatic changes in the delivery of radiation therapy, but the impact of radiobiology on the clinic has been far less substantial. A major consideration in the use of radiotherapy has been on how best to exploit differences between the tumour and host tissue characteristics, which in the past has been achieved empirically by radiation-dose fractionation. New advances are uncovering some of the mechanistic processes that underlie this success story. In this Review, we focus on how these processes might be targeted to improve the outcome of radiotherapy at the individual patient level. This approach would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour. PMID- 26122192 TI - Rational Design and Tuning of Functional RNA Switch to Control an Allosteric Intermolecular Interaction. AB - Conformational transitions of biomolecules in response to specific stimuli control many biological processes. In natural functional RNA switches, often called riboswitches, a particular RNA structure that has a suppressive or facilitative effect on gene expression transitions to an alternative structure with the opposite effect upon binding of a specific metabolite to the aptamer region. Stability of RNA secondary structure (-DeltaG degrees ) can be predicted based on thermodynamic parameters and is easily tuned by changes in nucleobases. We envisioned that tuning of a functional RNA switch that causes an allosteric interaction between an RNA and a peptide would be possible based on a predicted switching energy (DeltaDeltaG degrees ) that corresponds to the energy difference between the RNA secondary structure before (-DeltaG degrees before) and after ( DeltaG degrees after) the RNA conformational transition. We first selected functional RNA switches responsive to neomycin with predicted DeltaDeltaG degrees values ranging from 5.6 to 12.2 kcal mol(-1). We then demonstrated a simple strategy to rationally convert the functional RNA switch to switches responsive to natural metabolites thiamine pyrophosphate, S-adenosyl methionine, and adenine based on the predicted DeltaDeltaG degrees values. The DeltaDeltaG degrees values of the designed RNA switches proportionally correlated with interaction energy (DeltaG degrees interaction) between the RNA and peptide, and we were able to tune the sensitivity of the RNA switches for the trigger molecule. The strategy demonstrated here will be generally applicable for construction of functional RNA switches and biosensors in which mechanisms are based on conformational transition of nucleic acids. PMID- 26122193 TI - Serious outbreak of human metapneumovirus in patients with hematologic malignancies. AB - Human metapneumovirus (hMPV) is an important cause of lower respiratory tract infection. In healthy subjects infections are usually mild and rarely necessitate hospitalization. However, more serious outcomes have been described for allogeneic stem cell transplant recipients. This study reports an outbreak of hMPV A2 infection in severely immunocompromised adult hematologic cancer patients in a tertiary care unit. HMPV RNA was detected in bronchoalveolar lavage or produced sputum from patients presenting with typical clinical features. A total of 15 patients were diagnosed in a period of 7 weeks. Molecular subtyping revealed infection with genotype A2a virus, implicating nosocomial transmission. Eleven patients (73%) were treated with intravenous immunoglobulins and ribavirin. Ten patients (65%) presented with severe dyspnea, five (33%) required mechanical ventilation. Four patients (26.6%) died from hMPV-associated pneumonia and consequent multi-organ failure. Thus, hMPV is a critical pathogen for patients with hematologic cancers warranting early detection. PMID- 26122194 TI - Minimal residual disease of leukemia and the quality of cryopreserved human ovarian tissue in vitro. AB - Auto-transplant of cryopreserved ovarian tissue in leukemia patients carries a risk to reintroduce malignant cells. Maturation of ovarian follicles in vitro is a promising strategy to overcome the leukemic cell contamination. The follicle development and survival in 14 cryopreserved ovarian tissues with leukemia specific PCR marker was evaluated after 7 or 14 days culture. Minimal residual disease (MRD) quantification was assessed by real-time quantitative PCR in order to identify the MRD positive (n = 6) and negative (n = 8) samples and to monitor levels of MRD before and after culture. The morphology of ovarian follicles were studied by light microscopy. After culture, no statistical significant differences were detected in follicle densities between MRD positive- and negative samples. Ovarian MRD either decreased below undetectable or fluctuated near the baseline level after 7 and 14 days in culture. This study provides quantitative in vitro evidence that leukemia contamination does not affect the follicle survival in cryopreserved ovarian tissue. PMID- 26122195 TI - Metabolic profile and psychological variables after bariatric surgery: association with weight outcomes. AB - PURPOSE: This study aims to examine associations between metabolic profile and psychological variables in post-bariatric patients and to investigate if metabolic and psychological variables, namely high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), glycated hemoglobin (HbA 1c), impulsivity, psychological distress, depressive and eating disorder symptoms are independently associated with percentage of excess weight loss (%EWL) after bariatric surgery. METHODS: One hundred and fifty bariatric patients (BMI = 33.04 +/- 5.8 kg/m(2)) who underwent to bariatric surgery for more than 28.63 +/- 4.9 months were assessed through a clinical interview, a set of self-report measures and venous blood samples. Pearson's correlations were used to assess correlations between %EWL, metabolic and psychological variables. Multiple linear regression was conducted to investigate which metabolic and psychological variables were independently associated with %EWL, while controlling for type of surgery. RESULTS: Higher TG blood levels were associated with higher disordered eating, psychological distress and depression scores. HDL-C was associated with higher depression scores. Both metabolic and psychological variables were associated with %EWL. Regression analyses showed that, controlling for type of surgery, higher % EWL is significantly and independently associated with less disordered eating symptoms and lower TG and HbA_1c blood concentrations (R (2) aj = 0.383, F (4, 82) = 14.34, p < 0.000). CONCLUSION: An association between metabolic and psychological variables, particularly concerning TG blood levels, disordered eating and psychological distress/depression was found. Only higher levels of disordered eating, TG and HbA_1c showed and independent correlation with less weight loss. Targeting maladaptive eating behaviors may be a reasonable strategy to avoid weight regain and optimize health status post-operatively. PMID- 26122196 TI - Rotary scanning acquisition in ultra-low-field MRI. AB - PURPOSE: To develop a method of achieving large field of view (FOV) imaging with a smaller amount of data in ultra-low-field (ULF) MRI. THEORY: In rotary scanning acquisition (RSA), data from the imaging object is acquired at multiple angles by rotating the object or the scanner. RSA is similar to radial-trajectory acquisition but simplifies the measurement and image reconstruction when concomitant fields are nonnegligible. METHODS: RSA was implemented to achieve large FOV with only three localized superconductive quantum interference device (SQUID) sensors at the ULF-MRI field of 50 MUT. RESULTS: Simulations suggest benefits of RSA, including reduced concomitant field artifacts, large FOV imaging, and SNR improvement. Experimental data demonstrate the feasibility of reconstructing large FOV images using only three SQUID sensors with 33% of the amount of data collected using a Cartesian trajectory. CONCLUSION: RSA can be useful in low-field, low-weight, or portable MRI to generate large FOV images with only a few sensors. Magn Reson Med 75:2255-2264, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26122197 TI - Percutaneous recanalization for combined-type Budd-Chiari syndrome: strategy and long-term outcome. AB - PURPOSE: To investigate the feasibility, strategy, and long-term outcome of percutaneous recanalization for combined-type Budd-Chiari syndrome (BCS). METHODS: From December 2007 to August 2014, consecutive symptomatic combined-type BCS patients were treated by percutaneous recanalization in our centers. Inferior vena cava (IVC) recanalization was the first-stage treatment for all patients. Recanalization of one hepatic vein (HV) was the second-stage treatment for the selected patients. If the patient had the compensatory and patent accessory HV (AHV), we observed this patient for 7 days after IVC recanalization. If the symptoms of portal hypertension improved, HV recanalization was not needed. Otherwise, HV recanalization was performed. If the patient had no patent AHV, HV recanalization was performed 3 days after IVC recanalization. Data on technical success, clinical success, and follow-up were analyzed, respectively. RESULTS: Sixty-two symptomatic combined-type BCS patients were enrolled. Technical success of percutaneous recanalization was achieved in 60 patients. Among them, 52 patients had the patent AHV and underwent single IVC recanalization, and 8 patients had no patent AHV and underwent combined IVC and HV recanalization. Clinical success was achieved in all of the 60 patients. Three patients died during the follow-up. The cumulative 1-, 2-, and 4-year survival rates were 98.3%, 96.5%, and 92.7%, respectively. CONCLUSION: Percutaneous recanalization is suitable for most combined-type BCS patients. Treatment strategy can be made according to the situation of AHV. If the patient has the patent AHV, single IVC recanalization is enough. Otherwise, combined IVC and HV recanalization should be performed. PMID- 26122198 TI - Scaling behavior can be tricky: Comment on "Universal scaling for the dilemma strength in evolutionary games" by Z. Wang et al. PMID- 26122199 TI - The law of cooperation: Comment on "Universal scaling for the dilemma strength in evolutionary games" by Z. Wang et al. PMID- 26122200 TI - [Neuroleptic malignant syndrome : Rare cause of fever of unknown origin]. AB - Neuroleptic malignant syndrome (NMS) is a possible cause of fever of unknown origin (FUO) and is a potentially fatal adverse effect of various drugs, especially of neuroleptics. First generation antipsychotics, such as received by the patient described in this article, are more likely to cause NMS than second generation antipsychotics. The key symptoms are the development of severe muscle rigidity and elevated temperature associated with the use of neuroleptic medication. Malignant catatonia (MC) is an important differential diagnosis of NMS. While neuroleptics can trigger NMS and must be immediately discontinued if NMS occurs, neuroleptic therapy represents the first line treatment for MC. This article describes the case of a patient with schizoaffective disorder where initially the diagnosis of NMS was not clear. Eventually, fever and a markedly elevated serum creatine kinase (CK) led to the correct diagnosis and the appropriate therapy with dantrolene, bromocriptine and amantadine. Furthermore, a thorough review of the currently available literature on NMS is provided. PMID- 26122201 TI - Characterization of CCTalpha and evaluating its expression in the mud crab Scylla paramamosain when challenged by low temperatures alone and in combination with high and low salinity. AB - Chaperonin containing the T-complex polypeptide-1 (CCT), which is known to be involved in intracellular assembly and folding of proteins, is a class of chaperonin omnipresent in all forms of life. Previous studies showed that CCT played a vital role in cold hardiness of various animals. In order to understand the response of the polypeptide complex to low temperature challenge and other environmental stresses, a subunit of CCT (CCTalpha) was cloned from the mud crab Scylla paramamosain by expressed sequence tag (EST) analysis and rapid amplification of cDNA ends (RACE). The full-length cDNA SpCCTalpha was of 1972 bp and contained a 1668 bp open reading frame (ORF) encoding a polypeptide of 555 amino acids with four conserved motifs. The messenger ribonucleic acid (mRNA) levels of SpCCTalpha in ten tissues of adult S. paramamosain was subsequently examined and the highest expression was found in muscle, followed by gill, hepatopancreas, thoracic ganglion, hemocyte, heart, cerebral ganglion, stomach, eyestalk ganglion, and epidermis. The expressions of SpCCTalpha in the muscle of sub-adult crabs (pre-acclimated to 28 degrees C) subjected to the challenges of both lower temperatures (25, 20, 15, and 10 degrees C) alone and low temperatures (15 and 10 degrees C) in combination with salinity of 35 and 10 were further investigated by fluorescent quantitative real-time PCR (qPCR). It was revealed that when exposed to lower temperatures alone, the mRNA transcripts of the SpCCTalpha gene in the muscle were generally induced for significant higher expression at 10 degrees C treatment than the 25, 20, and 15 degrees C treatments; meanwhile, exposure to 15 degrees C also frequently led to significantly higher expression than those at 20 and 25 degrees C. This finding indicated that the up-regulation of SpCCTalpha was closely related to the cold hardiness of S. paramamosain. The results of an additional experiment challenging the sub-adult crabs with various combinations of low temperatures with different salinity conditions generally demonstrated that at both 10 and 15 degrees C, the expression of SpCCTalpha under the high salinity of 35 was significantly lower than that at low salinity of 10, implying that the damages caused by low temperatures with high salinity were less than that under low salinity. PMID- 26122202 TI - Comorbidity and correlates of disruptive mood dysregulation disorder in 6-8-year old children with ADHD. AB - This study aimed to characterize the nature and impact of disruptive mood dysregulation disorder (DMDD) in children with attention-deficit/hyperactivity disorder (ADHD) including its co-occurrence with other comorbidities and its independent influence on daily functioning. Children with ADHD (6-8 years) were recruited through 43 Melbourne schools, using a 2-stage screening (parent and teacher Conners 3 ADHD index) and case-confirmation (Diagnostic Interview Schedule for Children, Version IV; [DISC-IV]) procedure. Proxy DMDD diagnosis was confirmed via items from the oppositional defiant disorder (ODD) and major depressive disorder modules of the DISC-IV. Outcome domains included comorbid mental health disorders, academic functioning, social functioning, child and family quality of life, parent mental health, and parenting behaviors. Unadjusted and adjusted linear and logistic regression were used to compare children with comorbid ADHD and DMDD and children with ADHD without DMDD. Thirty-nine out of 179 children (21.8 %) with ADHD had comorbid DMDD. Children with ADHD and DMDD had a high prevalence of ODD (89.7 %) and any anxiety disorder (41.0 %). Children with ADHD and DMDD had poorer self-control and elevated bullying behaviors than children with ADHD without DMDD. Children with ADHD and DMDD were similar to children with ADHD in the other domains measured when taking into account other comorbidities including ODD. One in five children with ADHD in their second year of formal schooling met criteria for DMDD. There was a very high diagnostic overlap with ODD; however, the use of a proxy DMDD diagnosis containing items from the ODD module of the DISC-IV may have artificially inflated the comorbidity rates. DMDD added to the burden of ADHD particularly in the area of social functioning. PMID- 26122203 TI - Chronic lymphocytic leukemia of the oropharyngeal cavity and paranasal sinuses: a case series and literature review. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is an indolent B-lineage neoplasm responsible for 30% of all leukemias. The median age of onset is 67 years with a male predominance of 2:1. Localized infiltration in the oropharynx and paranasal sinuses is exceptionally rare. The aims of this study were (1) to add an additional case series of CLL with involvement of the oropharynx and paranasal sinuses to the literature and (2) to determine incidence and demographic data. METHODS: Retrospective chart review from 1990 to 2014. RESULTS: Five cases were found in our case series, representing 0.74% of the total number of cases analyzed (5/680). Sixteen additional cases were identified through literature review, resulting in a total of 21 cases of CLL (13 men, 8 women) with involvement of the oropharynx (n = 15) and paranasal sinuses (n = 6). The average age of patients with CLL in the oropharynx was 62 years whereas in the paranasal sinuses it was 52 years (p = 0.16). The average age of female cases was 62 years and the average age of male cases was 58 years (p = 0.63). Almost 85% (84.6%) of men had oropharynx invasion vs 50% of females (p = 0.15), which suggests a nonsignificant trend. CONCLUSION: The results of our study indicate that CLL infiltrates the oropharynx or paranasal sinuses in less than 1% of CLL cases. Although there seems to be no age bias between invasion in the oropharynx and the paranasal sinuses, there is a trend whereby women appear more likely to experience invasion of the paranasal sinuses. PMID- 26122204 TI - Water extract of brewers' rice induces apoptosis in human colorectal cancer cells via activation of caspase-3 and caspase-8 and downregulates the Wnt/beta-catenin downstream signaling pathway in brewers' rice-treated rats with azoxymethane induced colon carcinogenesis. AB - BACKGROUND: Brewers' rice, is locally known as temukut, is a mixture of broken rice, rice bran, and rice germ. The current study is an extension of our previous work, which demonstrated that water extract of brewers' rice (WBR) induced apoptosis in human colorectal cancer (HT-29) cells. We also identified that brewers' rice was effective in reducing the tumor incidence and multiplicity in azoxymethane (AOM)-injected colon cancer rats. Our present study was designed to identify whether WBR confers an inhibitory effect via the regulation of upstream components in the Wnt signaling pathway in HT-29 cells. To further determine whether the in vitro mechanisms of action observed in the HT-29 cells inhibit the downstream signaling target of the Wnt/beta-catenin pathway, we evaluated the mechanistic action of brewers' rice in regulating the expressions and key protein markers during colon carcinogenesis in male Sprague-Dawley rats. METHODS: The mRNA levels of several upstream-related genes in the Wnt signaling pathway in HT 29 cells treated with WBR were determined by quantitative real-time PCR analyses. Caspase-3 and -8 were evaluated using a colorimetric assay. Male Sprague-Dawley rats were administered two intraperitoneal injections of AOM in saline (15 mg/kg body weight) over a two-week period and received with 10, 20, and 40% (w/w) brewers' rice. The expressions and protein levels of cyclin D1 and c-myc were evaluated by immunohistochemical staining and western blotting, respectively. RESULTS: The overall analyses revealed that the treatment of HT-29 cells with WBR inhibited Wnt signaling activity through upregulation of the casein kinase 1 (CK1) and adenomatous polyposis coli (APC) mRNA levels. We discovered that the treatment of HT-29 cells with WBR resulted in the induction of apoptosis by the significant activation of caspase-3 and -8 activities compared with the control (P < 0.05). In vivo analyses indicated that brewers' rice diminished the beta catenin, cyclin D1, and c-myc protein levels. CONCLUSIONS: We provide evidence that brewers' rice can induce apoptosis and inhibit the proliferation of HT-29 cells through regulation of caspase-dependent pathways and inhibit the Wnt/beta catenin downstream signaling pathway in vivo. We suggest that brewers' rice may be a useful dietary agent for colorectal cancer. PMID- 26122205 TI - Urbanization, Grassland, and Diet Influence Coyote (Canis latrans) Parasitism Structure. AB - Land use change can alter the ecological mechanisms that influence infectious disease exposure in animal populations. However, few studies have empirically integrated the environmental, spatial, and dietary patterns of wildlife epidemiology. We investigate how urbanization, habitat type, and dietary behavior are associated with coyote (Canis latrans) parasitism structure along a gradient of rural to urban land cover using multivariate redundancy analyses. Coyote fecal samples were collected in eight urban and six rural sites in Calgary, Alberta, Canada. Parasite and diet components were identified using common flotation procedures and fecal dietary analysis, respectively. Redundancy analysis was used to identify the best land cover, connectivity, and dietary predictors. We tested for significance using multiple permutation tests and ANOVAs. Significant factors affecting enteric parasite prevalence included dietary and land cover factors (R (2) = 0.4130, P < 0.05). Variation in dietary behavior was observed between urban and rural sites (R (2) = 0.4712, P < 0.05), as anthropogenic diet items (i.e., garbage, crabapples) were strongly influenced by urbanization. Our research supports that developed habitat, grassland cover, and dietary choice interact to possibly influence the exposure of coyote hosts to enteric parasites and pioneers future investigation of disease ecology for natural populations in anthropogenic landscapes. PMID- 26122207 TI - [Low birth weight and obesity: causal or casual association?]. AB - OBJECTIVE: To present the conceptual foundations that explain how events occurring during intrauterine life may influence body development, emphasizing the interrelation between low birth weight and risk of obesity throughout life. DATA SOURCES: Google Scholar, Library Scientific Electronic Online (SciELO), EBSCO, Scopus, and PubMed were the databases. "Catch-up growth", "life course health", "disease", "child", "development", "early life", "perinatal programming", "epigenetics", "breastfeeding", "small baby syndrome", "phenotype", "micronutrients", "maternal nutrition", "obesity", and "adolescence" were isolated or associated keywords for locating reviews and epidemiological, intervention and experimental studies published between 1934 and 2014, with complete texts in Portuguese and English. Duplicate articles, editorials and reviews were excluded, as well as approaches of diseases different from obesity. DATA SYNTHESIS: Within 47 selected articles among 538 eligible ones, the thrifty phenotype hypothesis, the epigenetic mechanisms and the development plasticity were identified as fundamental factors to explain the mechanisms involved in health and disease throughout life. They admit the possibility that both cardiometabolic events and obesity originate from intrauterine nutritional deficiency, which, associated with a food supply that is excessive to the metabolic needs of the organism in early life stages, causes endocrine changes. However, there may be phenotypic reprogramming for low birth weight newborns from adequate nutritional supply, thus overcoming a restrictive intrauterine environment. Therefore, catch-up growth may indicate recovery from intrauterine constraint, which is associated with short-term benefits or harms in adulthood. CONCLUSIONS: Depending on the nutritional adequacy in the first years of life, developmental plasticity may lead to phenotype reprogramming and reduce the risk of obesity. PMID- 26122206 TI - Cultural and Economic Motivation of Pig Raising Practices in Bangladesh. AB - The interactions that pig raisers in Bangladesh have with their pigs could increase the risk of zoonotic disease transmission. Since raising pigs is a cultural taboo to Muslims, we aimed at understanding the motivation for raising pigs and resulting practices that could pose the risk of transmitting disease from pigs to humans in Bangladesh, a predominantly Muslim country. These understandings could help identify acceptable strategies to reduce the risk of disease transmission from pigs to people. To achieve this objective, we conducted 34 in-depth interviews among pig herders and backyard pig raisers in eight districts of Bangladesh. Informants explained that pig raising is an old tradition, embedded in cultural and religious beliefs and practices, the primary livelihood of pig herders, and a supplemental income of backyard pig raisers. To secure additional income, pig raisers sell feces, liver, bile, and other pig parts often used as traditional medicine. Pig raisers have limited economic ability to change the current practices that may put them at risk of exposure to diseases from their pigs. An intervention that improves their financial situation and reduces the risk of zoonotic disease may be of interest to pig raisers. PMID- 26122209 TI - The novel strategy of glucocorticoid drug development via targeting nongenomic mechanisms. AB - Glucocorticoids (GCs) are widely used in clinical practice as potent anti inflammatory and immunosuppressive agents. Unfortunately, they can also produce numerous and potentially serious side effects that limit their usage. This problem represents the driving force for the intensive search for novel GCs with a better benefit-risk ratio compared to conventional GCs. GCs are believed to take effects mainly through classical genomic mechanisms, which are also largely responsible for GCs' side effects. However, in addition to these genomic effects, GCs also demonstrate rapid genomic-independent activities. It has become increasingly evident that some of the anti-inflammatory, immunosuppressive, anti allergic and anti-shock effects of GCs could be mediated through nongenomic mechanisms. Thus, theoretically, trying to use nongenomic mechanisms of GCs more intensively may represent a novel strategy for development of GCs with low side effect profile. The new GCs' drugs will take clinical effects mainly via nongenomic mechanisms and do not execute the classical genomic mechanism to reduce side effects. PMID- 26122208 TI - [Diet quality of preschool children aged 2 to 5 years living in the urban area of Pelotas, Brazil]. AB - OBJECTIVE: To assess the dietary quality of preschool children in the urban area of Pelotas, Rio Grande do Sul, southern Brazil. METHODS: Dietary quality was measured according to the Healthy Eating Index (HEI), adapted to Brazil. Food consumption was obtained using the Food Frequency Questionnaire (FFQ). The index score was obtained by a score, ranging from 0 to 100, distributed in 13 food groups that characterize different components of a healthy diet. The better the quality of the diet, the closer the score is to 100. RESULTS: Dietary was evaluated in 556 preschoolers. The mean HEI score value was 74.4 points, indicating that diets need improvement. The mean scores were significantly higher among girls and in children from families with income between one and less than three minimum wages. CONCLUSIONS: The children showed vegetable consumption below the recommended level, while the food group of oils and fats, as well as the group of sugars, candies, chocolates and snacks were consumed in excess. It is important to reinforce guidelines to promote healthier eating habits, which may persist later in life. PMID- 26122210 TI - AzaHx, a novel fluorescent, DNA minor groove and G.C recognition element: Synthesis and DNA binding properties of a p-anisyl-4-aza-benzimidazole-pyrrole imidazole (azaHx-PI) polyamide. AB - The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza benzimidazole-pyrrole-imidazole (5) are described. AzaHx, 2-(p-anisyl)-4-aza benzimidazole-5-carboxamide, is a novel, fluorescent DNA recognition element, derived from Hoechst 33258 to recognize G.C base pairs. Supported by theoretical data, the results from DNase I footprinting, CD, DeltaT(M), and SPR studies provided evidence that an azaHx/IP pairing, formed from antiparallel stacking of two azaHx-PI molecules in a side-by-side manner in the minor groove, selectively recognized a C-G doublet. AzaHx-PI was found to target 5'-ACGCGT-3', the Mlu1 Cell Cycle Box (MCB) promoter sequence with specificity and significant affinity (K(eq) 4.0+/-0.2*10(7) M(-1)). PMID- 26122211 TI - Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate. AB - A novel series of terminal and internal phosphonate esters based on our previously developed aryl carboxylate-type tryptase selective inhibitor 1 was synthesized. The potency of these synthesized compounds was assessed in vitro with an enzyme inhibition assay using three available serine proteases, that is, tryptase, trypsin, and thrombin. The internal phosphonate derivative 6 showed potent thrombin inhibitory activity with an IC50 value of 1.0 MUM, whereas it exhibited no or only weak tryptase and trypsin inhibition at 10 MUM. The Lineweaver-Burk plot analysis indicates that the inhibition pattern of thrombin with 6 is non-competitive in spite of the fact that the lead carboxylate compound 1 is competitive inhibitor. Therefore, the skeletal conversion of the carboxylate into a phosphonate alters the mode of molecular recognition of these inhibitors by thrombin. PMID- 26122212 TI - Antimicrobial activity of customary medicinal plants of the Yaegl Aboriginal community of northern New South Wales, Australia: a preliminary study. AB - BACKGROUND: This study is a collaboration between Macquarie University researchers and the Yaegl Aboriginal Community of northern NSW, Australia to investigate the antimicrobial potential of plants used in the topical treatment of wounds, sores and skin infections. Based on previously documented medicinal applications, aqueous and aqueous ethanolic extracts of Alocasia brisbanensis, Canavalia rosea, Corymbia intermedia, Hibbertia scandens, Ipomoea brasiliensis, Lophostemon suaveolens and Syncarpia glomulifera and the aqueous extracts of Smilax australis and Smilax glyciphylla were tested against common wound pathogens, including antibiotic resistant bacterial strains. METHODS: Plant material was prepared as aqueous extractions modelled on customary preparations and using 80% aqueous ethanol. Extracts were assayed against a selection of clinically relevant Gram positive (Streptococcus pyogenes and sensitive and resistant strains of Staphylococcus aureus) and Gram negative (Pseudomonas aeruginosa, Escherichia coli and Salmonella typhimurium) bacteria and a fungus (Candida albicans) using disc diffusion and MTT microdilution methods. Viability of treated microorganisms was determined by subculturing from microdilution assays. RESULTS: The extracts of Corymbia intermedia, Lophostemon suaveolens and Syncarpia glomulifera had promising levels of antimicrobial activity (MIC 31 1,000 ug/mL) against both antibiotic sensitive and resistant Staphylococcus aureus as well as the fungus Candida albicans (clinical isolate). CONCLUSION: Aqueous and 80% aqueous ethanolic extracts of Lophostemon suaveolens, Corymbia intermedia and Syncarpia glomulifera exhibited promising levels of antimicrobial activity against a range of both antibiotic sensitive and resistant strains of microorganisms. This is the first report of antimicrobial activities for C. intermedia and L. suaveolens and the leaves of S. glomulifera. This study demonstrates the value of customary knowledge in the identification of new sources of antimicrobial treatments. PMID- 26122213 TI - DYSMICROBISM, INFLAMMATORY BOWEL DISEASE AND THYROIDITIS: ANALYSIS OF THE LITERATURE. AB - The human body is colonized by a large number of microbes that are collectively referred to as the microbiota. They interact with the hosting organism and some do contribute to the physiological maintenance of the general good health thru regulation of some metabolic processes while some others are essential for the synthesis of vitamins and short-chain fatty acids. The abnormal variation, in the quality and/or quantity of individual bacterial species residing in the gastro intestinal tract, is called ?dysmicrobism?. The immune system of the host will respond to these changes at the intestinal mucosa level which could lead to Inflammatory Bowel Diseases (IBD). This inflammatory immune response could subsequently extend to other organs and systems outside the digestive tract such as the thyroid, culminating in thyroiditis. The goal of the present study is to review and analyze data reported in the literature about thyroiditis associated with inflammatory bowel diseases such as Ulcerative Colitis (UC) and Crohn?s Disease (CD). It was reported that similarities of some molecular bacterial components with molecular components of the host are considered among the factors causing IBD through an autoimmune reaction which could involve other non-immune cell types. The axis dysmicrobism-IBD-autoimmune reaction will be investigated as a possible etiopathogenic mechanism to Autoimmune Thyroiditis. If such is the case, then the employment of specific probiotic strains may represent a useful approach to moderate the immune system. PMID- 26122214 TI - PERIODONTAL DISEASE AND BONE PATHOGENESIS: THE CROSSTALK BETWEEN CYTOKINES AND PORPHYROMONAS GINGIVALIS. AB - Periodontal disease is the most frequent cause of tooth loss among adults. It is defined as a plaque-induced inflammation of the periodontal tissues that results in a loss of support of the affected teeth. This process is characterized by destruction of the periodontal attachment apparatus, increased bone resorption with loss of crestal alveolar bone, apical migration of the epithelial attachment, and formation of periodontal pockets. Although the presence of periodontal pathogens such as Porphyromonas gingivalis is a prerequisite, the progression of periodontal disease is dependent on the host response to pathogenic bacteria that colonize the tooth surface. Nowadays, a growing body of literature has accumulated to investigate the association between bone diseases, periodontal pathogens and periodontal diseases. The integration of pathogen associated molecular patterns from microorganisms with their surface receptors in the immune cells, induces the production of several cytokines and chemokines that present either a pro- and/or anti-inflammatory role and the activation of mechanisms of controlling this and the related disease, such as osteoporosis and rheumatoid arthritis. This review focuses on the evidence and significance of bone host cell invasion by Porphyromonas gingivalis in the pathogenesis of bone disorders, as well as the different lines of evidence supporting the role of cytokines in bone diseases. PMID- 26122215 TI - CROSSTALK BETWEEN VITAMIN B AND IMMUNITY. AB - Vitamin B1 (thiamin) is considered to be the oldest vitamin and in 1936 R.R. Williams and colleagues determined its chemical structure and were able to synthesize this vitamin. Vitamin B1 influences pro-apoptotic proteins, mitochondrial membrane potential, cytochrome C release, protein kinases, p38 MAPK, suppresses oxidative stress-induced NF-kappaB and has anti-inflammatory properties. Deficiency of vitamin B1 may cause beriberi, dysfunction of the nervous system, neuroinflammation, T cell infiltration, chemokine CCL2 activation, over expression of proinflammatory cytokines, such as IL-1, TNF, IL 6, and arachidonic acid products, and induces expression of CD40 by the microglia and CD40L by astrocytes which provoke the death of neurons. Here we report the relationship between vitamin B complex and immunity. PMID- 26122216 TI - THE INFLUENCE OF CARBON MONOXIDE ON THE SECRETION OF MELATONIN BY PINEALOCYTES MEASURED IN VITRO. AB - Photoperiod is considered the most important factor entraining the circannual physiological rhythms through changing circadian patterns of melatonin (MEL) secretion from the pineal gland. The pineal gland of mammals does not respond directly to light but is controlled by light via neuronal phototransduction originating in the retina. In accordance with humoral phototransduction hypothesis, the aim of this study was to determine whether an increased concentration of CO, as a carrier of a light signal in pineal cell culture, affects the synthesis of melatonin. This study demonstrates that a commonly used carbon monoxide donor (CORM-2) markedly stimulated melatonin release from pineal cells incubated in vitro in a time-dependent manner, but the mechanism whereby CO modulates MEL release needs to be further explored. PMID- 26122217 TI - INHIBITORY EFFECT OF TETRAMETHYLPYRAZINE ON HEPATOCELLULAR CARCINOMA: POSSIBLE ROLE OF APOPTOSIS AND CELL CYCLE ARREST. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer. An important approach to control HCC is chemoprevention. This study aims at investigating the antitumor effect of Tetramethylpyrazine (TMP). Rats were injected with N Nitrosodiethylamine (DEN) to establish HCC. Tumor development was observed. Liver function was evaluated. Apoptosis and cell cycle arrest-related makers and signaling cascades were determined by Western blot, RT-PCR and flow cytometric analysis. The administration of TMP could significantly inhibit tumor development in DEN-induced HCC rats, shown by reduced incidence of tumor, decreased number of tumor nodules and reduced maximal size of tumor. DEN-induced increase of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and alkaline phosphatase activities were significantly inhibited by TMP. TMP exhibited inhibitory effect on HCC through induction of apoptosis and cell cycle arrest in rats. TMP induced apoptosis through increasing Bax, decreasing Bcl-2, increasing the release of cytochrome c, and activating caspase, which consisted of the mitochondrial apoptotic pathway. TMP induced G2/M cell cycle arrest through down-regulation of cyclin B1/cdc2. In addition, inhibition of Akt and ERK signaling and the antioxidant activities of TMP may also contribute to its antitumor effect. These data provide new insight into the mechanisms underlying the antitumor effect of TMP. PMID- 26122219 TI - FLOW CYTOMETRIC DETECTION OF SUBHAPLOID NUCLEI IN HUMAN SPERM AS A MEASURE OF DNA FRAGMENTATION AND APOPTOSIS. AB - The use of assisted reproductive technologies (ARTs) is increasing worldwide. In order to predict the rate of pregnancy after ART the DNA fragmentation index (DFI) of ejaculated spermatocytes may be a better marker than conventional semen quality parameters. Spermatocytes with fragmented DNA are associated with apoptotic stages and are characterized by a low DNA content. The subhaploid nuclei of DNA-damaged spermatocytes can be easily detected by flow cytometry. We here analyzed the percentage of subhaploid nuclei of semen samples from 163 patients aged 26 to 74 years who consulted one of the ten centres for reproductive medicine which routinely send sperm samples to our laboratory in order to determine special sperm parameters. The percentage of subhaploid nuclei indicating the DFI of spermatocytes did not correlate with age and sperm volume, but inversely correlated with sperm concentration and the percentage of motile spermatocytes. This is in concordance with previous studies which demonstrated that DNA damage of spermatozoa correlates with conventional semen quality parameters. Since DNA-damaged spermatocytes are associated with an impaired outcome of assisted conception technologies, this method could help to monitor sperm quality of subfertile men after measures to increase sperm quality and to improve selection criteria of cryopreserved sperm samples in assisted reproduction medicine. PMID- 26122218 TI - KNOCKDOWN OF CASEIN KINASE 1e INHIBITS CELL PROLIFERATION AND INVASION OF COLORECTAL CANCER CELLS VIA INHIBITION OF THE Wnt/beta-CATENIN SIGNALING. AB - Deregulation of casein kinase 1 epsilon (CK1epsilon) is involved in the development of multiple pathological disorders such as cancer, however the function and molecular mechanism of CK1epsilonin cancer are still unclear. In the present study, we aimed to investigate the role of CK1epsilon in human colorectal cancer (CRC). The expression of CK1epsilon was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was performed to observe the effects of lentivirus-mediated CK1epsilon shRNA (Lv shCK1epsilon) on cell proliferation and invasive potential by MTT and Transwell assays in CRC cell line (SW480). As a result, we found that the expression of CK1epsilon protein was significantly increased in CRC tissues compared with that in adjacent non-cancerous tissues (ANCT) (68.9% vs 42.2%, P=0.017) and was correlated with the Duke?s staging and depth of invasion in CRC patients (P=0.012; P=0.015). Knockdown of CK1epsilon reduced cell proliferation and invasion of CRC cells followed by the downregulation of wnt3alpha, beta-catenin, PCNA and MMP-9. In conclusion, our findings show that high expression of CK1epsilon is positively associated with the Duke?s staging and depth of invasion in CRC patients, and knockdown of CK1epsilon suppresses the growth and invasion of CRC cells through inhibition of the wnt/beta-catenin signaling, suggesting that CK1epsilon may serve as a promising therapeutic target for the treatment of CRC. PMID- 26122220 TI - MELATONIN ALLEVIATES BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN MICE. AB - Pulmonary fibrosis occurs as a common end-stage sequela of a number of acute and chronic lung diseases. Eicosanoids exert crucial roles in inflammatory processes pertinent to fibrogenesis induction, however, the role of cyclooxygenase 2 (COX 2) is not fully elucidated in most pulmonary fibrosis related-disorders. Recently, melatonin (MLN) has been introduced as an effective immuno-modulator and anti-oxidant agent. The present study aimed to investigate the effect of MLN on COX-2 expression in idiopathic pulmonary fibrosis (IPF). Animals were divided into five groups, including: 1) saline control, 2) 1% ethanol control, 3) MLN control, 4) bleomycin (BLM), in which mice were injected with BLM (15 mg/kg, i.p.) two times per week for four weeks, and 5) BLM+MLN, in which MLN was given to mice (10 mg/kg, i.p.) 30 minutes prior to BLM injections for four weeks. MLN administration significantly reduced body weight loss (P<0.05), the rate of mortality, edema formation, lung injury, COX-2 expression (P>0.05), interstitial tissue percentage volume (P<0.05), and also increased the alveolar space percentage volume. MLN attenuated the BLM-induced lung injury responses such as collagen accumulation and airway dysfunction in mice. Finally, histological evidence supported the ability of MLN to inhibit COX-2 expression. Thus, it may serve as a novel potential therapeutic agent for IPF. PMID- 26122221 TI - THE EFFECT OF DIHYDROARTEMISININ ON THE PROLIFERATION, METASTASIS AND APOPTOSIS OF HUMAN OSTEOSARCOMA CELLS AND ITS MECHANISM. AB - This study aims to research the effect of dihydroartemisinin on the proliferation, metastasis and apoptosis in human osteosarcoma cells 143B and the underlying mechanism. This study designed five groups for experiment and control, using dimethylsulfoxide (DMSO), and docosahexaenoic acid (DHA) at concentrations of 15, 25, 35 MUmol.L-1 respectively. Experiments including methyl thiazolyl tetrazolium (MTT) assay, clone formation assay, Hoechst 33258 staining assay, luciferase reporter plasmid assay, Western blot and scratch test were carried out. In addition, SPSS 18.0 software from IBM was used for statistical analysis and all the data obtained from the experiments were expressed as mean +/- SD, and variance was used to compare the difference between the groups. DHA is proved to be able to inhibit the proliferation and metastasis of osteosarcoma cells, as well as leaving a positive effect on apoptosis in the cytomorphosis. It achieves regulation over the human osteosarcoma cells by keeping the expression of related protein under control. PMID- 26122222 TI - 4(alpha-L-RHAMNOSYLOXY)-BENZYL ISOTHIOCYANATE, A BIOACTIVE PHYTOCHEMICAL THAT DEFENDS CEREBRAL TISSUE AND PREVENTS SEVERE DAMAGE INDUCED BY FOCAL ISCHEMIA/REPERFUSION. AB - Natural compounds are a promising source to treat several pathologies. The present study shows the in vivo pharmacological beneficial effect of 4(alpha-L rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG-ITC) obtained from glucomoringin (GMG; 4(alpha;-L-rhamnosyloxy)- benzyl glucosinolate), purified from Moringa oleifera seeds and hydrolyzed by myrosinase enzyme (β-thioglucoside glucohydrolase; E.C. 3.2.1.147). Cerebral ischemia/reperfusion (CIR) was induced in rats according to a classic model of carotid artery occlusion for a time period of 1 h and the reperfusion time was prolonged for seven days. GMG-ITC (3.5 mg GMG/ml plus 30 MUl enzyme/rat; one ml i.p./rat) was administered 15 min after the beginning of ischemia and daily. The results clearly show that GMG-ITC possesses the capability to counteract the CIR induced damage reducing TNF-alpha release, IkappaB-alpha cytosolic degradation/NFkappaBp65 nuclear translocation, as well as several other direct or indirect markers of inflammation (phospho-ERK p42/44, p-selectin) and oxidative stress (inducible Nitric Oxide Synthase (iNOS), MMP-9). GMG-ITC was shown to exert neuroprotective properties in preventing CIR-induced damage and the related cascade of inflammatory and oxidative mediators that exacerbate the progression of this disease in an experimental rat model. Our results clearly show that the tested phytochemical GMG-ITC possesses the capability to counteract CIR-induced damage. PMID- 26122223 TI - ANTIPSYCHOTICS REVERSE P-GLYCOPROTEIN-MEDIATED DOXORUBICIN RESISTANCE IN HUMAN UTERINE SARCOMA MES-SA/Dx5 CELLS: A NOVEL APPROACH TO CANCER CHEMOTHERAPY. AB - Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains one of the major obstacles to effective cancer chemotherapy. Several chemosensitizers have been used in vivo and in vitro to reverse MDR but have exhibited several unwanted side effects. Antipsychotics are often administered to treat psychiatric disorders such as delirium, anxiety and sleep disorders in cancer patients during chemotherapy. The present in vitro study, examined the effects of two common antipsychotic compounds, haloperidol and risperidone, and a natural compound such as theobromine on reversing MDR Pgp-mediated, to evaluate their potential use as chemosensitizing agents. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp (100-fold), were treated with the antipsychotic alone (1, 10 and 20 MUM) or in combination with different concentrations of doxo (2, 4 and 8 MUM). The accumulation and cytotoxicity of doxo (MTT assay) and cellular GSH content (GSH assay) in comparison with verapamil, a well-known Pgp inhibitor, used as reference molecule were examined. It was found that the three compounds significantly enhanced the intracellular accumulation of doxo in resistant cancer cells, when compared with cells receiving doxo alone (p<0.05). Furthermore, compounds showed strong potency to increase doxo cytotoxicity toward resistant MES-SA/Dx5 cells, when compared with untreated control cells. The antipsychotic compounds also significantly increased GSH content at all concentrations (> 30%) in resistant cells, when compared to untreated control cells (p<0.05). These findings suggest that the antipsychotics or their derivatives might represent a novel class of reversal agents for overcoming MDR in cancer therapy, in particular theobromine showed to be an effective Pgp inhibitor with the lowest toxicity. PMID- 26122224 TI - INFLUENCE OF miR-373 ON THE INVASION AND MIGRATION OF BREAST CANCER AND THE EXPRESSION LEVEL OF TARGET GENES TXNIP. AB - An increasing number of people die from breast cancer every year. Consequently, more research has been concentrated on the study of this type of tumour, and miR 373 resulted as an important gene for treating breast cancer. To explore the influence of miR-373 on the invasion and migration of breast cancer and the expression level of target gene TXNIP, a set of therapeutic methods were designed based on miR-373. The transfection was performed using miR-373 inhibitor; the concentration of miR-373 was controlled by inhibitor, and it was transfected into MCF-7 cell by lipofectin. Fluorescent quantitative polymerase chain reaction was used to detect the expression level of miR-373 in cells after transfection as well as that of Caspase-3 and Caspase-8. MTT assay was used to detect the influence of miR-373 inhibitor on MCF-7 cells. The expression quantity of miR-373 in cell and tissue of breast cancer with high-low invasion and migration ability was detected by qRT-PCR (quantitative real-time polymerase chain reaction), thus the influence of the expression quantity of miR-373 on the invasion and migration of cell was determined. The expression of miR-373, EMT and TXNIP was determined by Western blot. Through the identification of proteomics and bioinformatics, it was finally found that TXNIP was regulated by miR-373. The protein expression level of TXNIP was negatively correlated with the level of miR-373. Thus it was concluded that miR-373 could promote the invasion and migration of breast cancer. In addition, in the tissue and cell of breast cancer with different invasion and migration abilities, the expression level of TXNIP was negatively correlated with the level of miR-373. PMID- 26122225 TI - HOW EXPRESSIONS OF CLAUDIN-1 AND MMP-2 IN RETINOBLASTOMA CORRELATE WITH HISTOLOGICAL DIFFERENTIATION AND OPTIC NERVE INVASION. AB - Retinoblastoma is a commonly seen and dangerous intraocular malignant tumor in infants. Studies have found that Claudin-1 and MMP-2, whose expressions may be connected, play roles in tissues of retinoblastoma. In this study we analyze and discuss changes of Claudin-1 and MMP-2 expressions, and the correlation between the expressions and retinoblastoma histological differentiation and optic nerve invasion. MaxVisionTM was applied to detect expressions of Claudin-1 and MMP-2 in 45 samples of retinoblastoma and 15 paraffin-embedded samples of normal retina. The correlation between Claudin-1 expression and MMP-2 expression was analyzed based on chi-squared test and Spearman?s correlation test. Positive expressions of Claudin-1 in retinoblastoma were fewer than those in retina; higher positive expressions were found in differentiated tissues than in undifferentiated tissues; while compared to expressions in invasive optic nerves, Claudin-1 expressed more positively in optic nerves without invasion. As for MMP-2, its expressions were higher in retinoblastoma than in normal retina; undifferentiated tissues had higher positive expressions than differentiated tissues, which were not statistically significant; higher positive expressions were detected in invasive optic nerves. Thus, it could be concluded that the correlation between Claudin-1 expression and MMP-2 expression in retinoblastoma was negative. Expressions of Claudin-1 were positively related to histological differentiation and optic nerve invasion of retinoblastoma; while MMp-2 expression had negative correlation with histological differentiation and optic nerve invasion of retinoblastoma. Claudin-1 and MMP-2 played a negative role in the optic nerve invasion and tumor development of retinoblastoma. PMID- 26122226 TI - SIDE EFFECTS OF TUBERCULOSIS TREATMENT WITH FIXED-DOSE COMBINATIONS. AB - This paper aimed to explore the therapeutic effect and safety of Fixed-dose Combinations (FDCs) on tuberculosis. A computer search was carried out to review the literature related to clinical randomized controlled trials (RCTs) and clinical controlled trails (CCTs) on the curative effect and safety of treating pulmonary tuberculosis with FDCs. The results demonstrated that, in the 22 studies examined, comparison of sputum negative conservation rate of treating smear-positive pulmonary tuberculosis with FDCs and single drug, the relative risk (RR) value and 95% confidence interval (CI) were 1.02 (1.01, 1.03) and 1.01 (1.00, 1.02), respectively, at the end of the 2nd month and 6th month (P<0.05), while comparison of the relapse rate within six months showed that RR value and 95% CI was 1.72 (0.98, 3.02) (P>0.05). No statistically significant differences were found between the two groups in total occurrence of the rates of side effects pertaining to skin reaction, gastrointestinal tract side reaction, occurrence rate of liver and gall side reaction or occurrence rate of drug withdrawal because of side effects (P>0.05). After sensitivity analysis, it was found that occurrence rate of gastrointestinal tract side effects and occurrence rate of liver and gall side effects were unstable. All the findings suggest that the curative effect of treating tuberculosis with FDCs is better than that of a single drug. More reliable evidence is required since the safety evaluation results are not stable. PMID- 26122227 TI - THE INFLUENCE OF POSTERIOR APPROACH CERVICAL INTRASPINAL TUMOR RESECTION ON THE STABILITY OF CERVICAL VERTEBRA. AB - This paper discusses the influence of posterior approach cervical intraspinal tumor resection on the stability of cervical vertebra. A total of 32 patients with cervical intraspinal tumor were included and divided into a group undergoing posterior approach bilateral vertebral lamina resection (group A) (n=16) and a group undergoing posterior approach semi-laminectomy (group B) (n=16). It was found, through follow-up visits, that the incidence rate of cervical instability of the patients was 25% and the incidence rate of cervical curvature deterioration of the patients was 37.5% in group A, whereas the two incidence rates of group B were 6.25% and 12.5% respectively; the incidence rates of cervical curvature deterioration and instability were significantly increased compared to group B (P< 0.05). It is concluded that, both regular posterior approach vertebral lamina resection and semi-laminectomy influence the biomechanical change of cervical vertebra, but the influence of the latter is less. Also, it is found that, applying titanium connectors and titanium nails for rigid internal fixation maintains the completeness and stability of the structure of the cervical vertebra. PMID- 26122228 TI - BERBERIS VULGARIS FRUIT CRUDE EXTRACT AS A NOVEL ANTI-LEUKAEMIC AGENT. AB - Tumor protein p53 encoded by the TP53 gene in humans is known as a cancer biomarker in patients diagnosed with cancer, and it plays an essential role in apoptosis, genomic stability, and inhibition of angiogenesis. Cancer therapies with common chemotherapy methods are effective, as known, but have some side effects. Berberis vulgaris is traditionally administrated as a cancer drug. The current research aims to evaluate p53 as a biomarker in WEHI-3 cell line and to demonstrate the Berberis vulgaris fruit crude extract (BVFCE) as a new anticancer drug. For this purpose, we evaluated the effect of BVFCE in different concentrations against WEHI-3cell line in vitro and determined the quantitative level of p53 gene in the treated WEHI-3 cells. The results demonstrated that even at only 1 mg/ml concentration of Berberis vulgaris crude extract, there was a low level of p53 biomarker expression on WEHI-3 cells in comparison with doxorubicin. Therefore, the current study suggests BVFCE as a reliable anti-leukaemic drug and candidate for anticancer therapy. However, further investigation need be carried out to confirm its efficiency in vivo. PMID- 26122229 TI - EFFECT OF PREGNANE XENOBIOTIC RECEPTOR ACTIVATION ON INFLAMMATORY BOWEL DISEASE TREATED WITH RIFAXIMIN. AB - The causes and pathogenesis of Inflammatory Bowel Disease (IBD) are still not clearly understood. This study aims to prove the important role of rifaximin played in inflammatory reaction caused by abnormity of the intestinal mucosal immune system. Intestinal microflora can greatly promote and maintain the inflammatory reaction of IBD, therefore, antibiotics can be used to treat IBD. Rifaximin is a medicine usually used for local intestinal infection. Many clinical and basic studies have shown that both a single application of rifaximin and the joint application with other medicines could achieve a good efficacy. This paper studied the activation of Pregnane Xenobiotic Receptor (PXR) in treating IBD with rifaximin and analyzed its efficacy in IBD when PXR was involved in the transport of medicine and metabolism. The results prove that rifaximin can not only serve as an anti-microbial drug, but can activate PXR and actually weaken the reaction of IBD. Thus it is safe to say that rifaximin has great potential in treating IBD. PMID- 26122230 TI - CLINICAL DIAGNOSIS OF CAROTID ATHEROSCLEROSTIC PLAQUE IN HYPERTENSIVE PATIENTS WITH HIGH RESOLUTION MAGNETIC RESONANCE ANGIOGRAPHY. AB - As the incidence of ischemic cerebrovascular disease increases continuously over the years, carotid atherosclerosis as an important dangerous factor has drawn a lot of attention from many experts and scholars. To explore the clinical significance of high resolution magnetic resonance angiography (MRA) in carotid atherosclerosis and ischemic cerebrovascular disease, a group contrasting method was adopted. One hundred patients with ischemic cerebrovascular disease and 100 patients without ischemic cerebrovascular disease were taken as observation group and control group, respectively. High resolution MRA was used for examining and observing the development of carotid atherosclerostic plaque in patients in the two groups. We found that the proportion of carotid atherosclerostic plaque in the experimental group and control group had statistical difference (P<0.05); and the proportion of carotid atherosclerostic plaque in patients over 60 years of age was higher than in patients under 60 years, and the difference was statistically significant (P<0.05). The proportion of carotid atherosclerostic plaque in patients with high blood pressure was also higher than in patients without high blood pressure, and the difference was statistically significant (P<0.05). Moreover, the proportion of carotid atherosclerostic plaque in patients with hyperlipidemia was higher than in patients without hyperlipidemia, and the differences were statistically significant (P<0.05). We can therefrore draw a conclusion that the development of carotid atherosclerostic plaque affects the occurrence of ischemic cerebrovascular disease, which is related to patient?s age, level of blood pressure and blood lipids. In addition, high resolution MRA is helpful to early discovery of the formation of carotid atherosclerostic plaque. PMID- 26122231 TI - Alpha case of multiple bilateral testicular capsule mast cell tumours in a dog. AB - A 5-year-old intact male German Shepherd dog was referred with a diagnosis of leishmaniasis. Several testicular masses were palpated during the physical examination, while the diagnostic screening yielded no remarkable findings. Fine needle aspiration cytology of the masses revealed the presence of intermediately differentiated mast cell tumours. Scrotal ablation and orchiectomy were performed as a definitive treatment option. The pathological examination of the surgical specimens confirmed the diagnosis of grade II mast cell tumours and showed that they were all confined to the testicular capsule. At 7 months post-admission, the dog exhibited neither postsurgical complications nor metastatic foci and was, therefore, given a favourable prognosis. Despite their exceptionally rare occurrence, mast cell tumours should be considered for the differential diagnosis of testicular tumours. PMID- 26122232 TI - EXPRESSION MECHANISM AND CLINICAL SIGNIFICANCE OF NOB1 IN GASTRIC CANCER TISSUE AND ADJACENT NORMAL TISSUE. AB - This paper studies the effect and relationship of NOB1 in the development of gastric cancer, based on an analysis of NOB1expression in gastric cancer tissue and adjacent tissue. Thirty gastric cancer tissue samples taken during surgery with complete pathological data and their related adjacent normal tissue were examined in this study. NOB1 protein expression in gastric cancer tissue and adjacent normal tissue was detected by immunohistochemistry (IHC). Real-time PCR was used to detect NOB1 mRNA expression, which provided a basis on which to explore the clinical pathological characteristics for patients with gastric cancer. Results show that NOB1 protein in gastric cancer tissue and adjacent normal tissue were diffusely expressed both in the cytoplasm and nucleus. The positive expression rate in gastric cancer tissue was 73%, higher than that in adjacent normal tissue (47%). Both the reference NAPDH and NOB1 amplification are reflected in the amplification curve in standard S-shape and the unimodal solubility curve which was not altered by non-specific amplification and primer dimer. NOB1 mRNA relative expression in cancer tissue was 4.899∓1.412. NOB1 expression had no direct relationship with the patients? age, gender, tumor differentiation or infiltration degree, lymphatic metastasis, distant metastasis nor pTNM periodization, but was directly related to the size of the tumor. All the findings in this paper suggest that NOB1 can be one of the focuses for diagnosing and treating gastric cancer and that its protein expression is likely to increase with the growth of tumor, thus playing a great role in the incidence and development of gastric cancer. PMID- 26122233 TI - EXPRESSION AND CLINICAL SIGNIFICANCE OF APOPTOSIS-ASSOCIATED PROTEINS SURVIVIN AND LIVIN IN CONDYLOMA ACUMINATUM. AB - The objective of the present study was to explore the expression and significance of survivin and Livin in lesions of Condyloma acuminatum (CA). Streptavidin peroxidase (SP) immunohistochemistry method was used to measure the expression of survivin, Livin and Ki-67 in 48 cases of CA and 25 cases of normal foreskin tissues. The positive expression rates of survivin, Livin and Ki-67 were 72.91% (35/48), 77.08% (37/48) and 85.42% (41/48) in CA tissues, and 4% (1/25), 4% (5/25) and 60% (15/25) in the control group, respectively. The expression intensity of survivin, Livin and Ki-67 in CA tissues (++ ~ +++) was significantly higher than that in the normal control group (- ~ ++). There were significant differences (P <0.05) both in the positive rates and the expression intensity of survivin, Livin and Ki-67 between the two groups. There was positive correlation between the expression of survivin and Livin in CA group (P < 0.01); the expressions of survivin and Ki-67 were positively correlated with each other (P < 0.01); Livin and Ki-67 expressions were positively correlated with each other (P < 0.01). There were over-expressions and excessive proliferations of survivin and Livin in CA tissues, and apoptosis suppressors survivin and Livin were correlated with CA. PMID- 26122234 TI - EFFECT OF RELATIVE GENE EXPRESSION ON PLAQUE VULNERABILITY IN PATIENTS WITH STABLE ANGINA AND PATIENTS WITH ACUTE CORONARY SYNDROME. AB - This study was conducted to investigate the effect of relative gene expression on plaque vulnerability in patients with either stable angina or acute coronary syndrome (ACS). A total of 30 patients with ACS, 28 patients with stable angina and 17 healthy volunteers were selected. High resolution ultrasound was used to detect carotid arterial intima-media thickness (IMT) and plaque score, Sandwich enzyme linked immunoassay to determine the change of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1. The three groups had no statistically significant difference in age, gender, total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. MMP-9, TIMP-1, MMP-9/TIMP-1 and IMT, total plaque score, soft plaque score and hard plaque score of patients? acute coronary syndrome were obviously higher than those with stable angina and normal people. It was also found that MMP-9 was in a positive correlation with IMT, total and soft plaques score, TIMP-1 was positively correlated with IMT as was MMP-9/TIMP-1. Regardless of age, IMT was in a positive correlation with MMP-9, TIMP-1 and MMP-9/TIMP-1 in partial correlation analysis. All these findings suggest that ACS patients have remarkably higher MMP-9, 1TIMP-1, MMP- 9/TIMP-1, IMT, total plaque score, soft plaque score and hard plaque score compared to patients with stable angina pectoris and healthy subjects (P<0.05) and there are positive correlations between MMP- 9, TIMP-1, 1MMP-8/TIMP-1, total plaque and soft plaque score. PMID- 26122235 TI - EVALUATION OF ANTIVIRAL THERAPY TREATMENT FOR LIVER CIRRHOSIS CAUSED BY CHRONIC HEPATITIS C AND HEPATITIS C BY 31P-MRS, BASED ON METABOLITE DETECTION. AB - This study discusses the application of magnetic resonance spectrum (MRS) to evaluate the efficacy of antiviral therapy in the treatment of liver cirrhosis caused by chronic hepatitis C and hepatitis C, based on metabolite detection. A total of 54 patients with liver cirrhosis caused by chronic hepatitis C and hepatitis C were selected and divided into treatment group and control group. 31P MRS imaging was carried out on patients in the two groups both before receiving antiviral treatment and 6 months after treatment to compare the change of metabolite ratio (PE+PC)/(GPE+GPC). It was revealed that no statistically significant difference was found in the comparison of (PC+PE)/(GPC+GPE) ratio in the two groups before treatment, but the difference was found 6 months after treatment; ratio of (PC+PE)/ (GPC+GPE) in the treatment group distinctly decreased 6 months after treatment compared to before treatment, with a statistically significant difference, while the control group had no remarkable change or statistical significance. Moreover, 32 patients were found with sustained virus response to antiviral therapy. Of these, 25 patients possessed a decreased ratio of (PC+PE)/ (GPC+GPE), 4 remained without change and 3 had a slightly increased ratio after antiviral treatment. Of 12 patients with no response, 1 had a decreased ratio of (PC+PE)/ (GPC+GPE), 2 remained without change and 9 had a slightly increased ratio. The differences were all statistically significant in comparison of the two groups. 31P-MRS is thought to be effective for evaluating the efficacy of antiviral therapy through non invasive detection of liver energy metabolism. PMID- 26122236 TI - META-ANALYSIS OF HIGH RISK FACTORS OF RESIDUE OR RELAPSE OF CERVICAL INTRAEPITHELIAL NEOPLASIA AFTER CONIZATION. AB - This study assesses the high risk factors of residue or relapse after conization of cervical intraepithelial neoplasia. Literature on high risk factors of residue or relapse after conization of cervical intraepithelial neoplasia from January 2006 to June 2011 were selected from the Pubmed Database, Elsevier Database, Chinese Biomedicine Database and Chinese Journal Full-text Database of China National Knowledge Internet (CNKI). Software RevMan 4. 2 provided by Cochrane collaboration network was used in the statistical analysis of the data. According to the inclusion criteria, 10 essays were retrieved, including 348 cases in case groups and 1,608 cases in control groups. Information about residue or relapse after conization, incisal edge, HIV infection after six months of surgery, age, menopause status was obtained through the above method. Meta-analysis showed that positive surgical margin groups had a higher residual or recurrence rate than negative surgical margin groups after conization; groups where glands were involved had a higher residual or recurrence rate than non-involved glands groups after conization; positive HR-HPV infection after six months of conization groups had higher residual or recurrence rates than negative HR-HPV infection groups; 50 years or older groups had higher residual or recurrence rate than under 50 year old groups after conization; postmenopausal groups had higher residual or recurrence rate than premenopausal groups. Menopause, 50 years old or older, gland involvement, positive surgical margin and HR-HPV infection after six months are high risk factors of residue or relapse after alpha - beta conization of CIN. PMID- 26122237 TI - PROTEIN EXPRESSION OF METADHERIN AND SENSIBILITY OF BREAST CANCER MDA-MB-231 CELLS TO TREATMENT BEFORE AND AFTER TRANSFECTION. AB - Breast cancer tends to have an increasing mortality, severely threatening the health of females. The invasion and metastasis of breast cancer are the leading causes of death. It has been reported that breast cancer is caused by the activation of a series of proto-oncogenes and inactivation of anti-oncogenes. In the present study, Real-time PCR and Western blot were used to detect the protein expression level of metadherin before and after transfecting MDA-MB-231 cells to identify the effect, while the sensitivity of MDA-MB-231 cells to 1 mg/L doxorubicin and 8mg/L taxol was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT). The results demonstrated that mRNA and protein expression level of metadherin both improved after transfection. The inhibition effect of 1 mg/L doxorubicin and 8 mg/L taxol on breast cancer cells decreased after transfection. Detected by flow cytometry, the apoptosis rate of breast cancer cells was 39.68+/ 0.42%, 20.64+/-0.55%, respectively, under the effect of 1 mg/L doxorubicin; while under the effect of 8 mg/L taxol, the rate was 24.89+/-0.41% and 13.8+/-0.63%, respectively. Thus the inhibition effects of 1 mg/L doxorubicin and 8mg/L taxol to breast cancer cells and their effects on apoptosis were different, and the differences were statistically significant (P<0.05). Based on the statistics on the expression level of metadherin after transfecting breast cancer cells MDA-MB 231 and the exploration of the sensitivity of the cells to treatment, the effect of metadherin on breast cancer MDA-MB-232 cells was proved. PMID- 26122238 TI - EFFICACY OF DIFFERENT RESECTIONS ON NON-MUSCLE-INVASIVE BLADDER CANCER AND ANALYSIS OF THE OPTIMAL SURGICAL METHOD. AB - This study aimed to analyze the clinical efficacy of different resections in treating non-muscle-invasive bladder cancer (NMIBC), including partial cystectomy, transurethral resection of bladder tumor (TURBT) and holmium laser resection of bladder tumor. Two hundred and sixteen patients were recruited with NMIBC who were available for follow-up visits in hospital, including 62 cases treated with partial cystectomy, 90 cases treated with TURBT and 64 cases with holmium laser resection. Analysis was made on the cases with tumor relapse in the two years, on operation time, blood loss, time for indwelling urinary catheter, hospital stay and complications after operation. Results were compared to the clinical efficacy of these operation patterns. It was found that the two-year relapse rate for TURBT group, partial cystectomy group and Holmium laser resection group was 41%, 31%, and 33% respectively, and the difference had no statistical significance (p>0.05). Both the TURBT group and holmium laser resection group had shorter operation time, hospital stay and time for indwelling urinary catheter as well as much less blood loss when compared with the partial cystectomy group; the difference had statistical significance (p<0.001). In terms of complications, the TURBT group was likely to induce obturator nerve reflex and bladder perforation while the partial cystectomy group was likely to induce bladder spasm. Therefore, this study presumes that holmium laser resection and TURBT are much safer and quicker for recovery and obviously superior to the partial cystectomy. PMID- 26122239 TI - CORRELATION BETWEEN C-erbB-2 WITH GASTRIC MUCOSAL ATYPICAL HYPERPLASIA AND GASTRIC CARCINOMA. AB - C-erbB-2 is a cancer gene originating from cells. The high-expression and amplification of C-erbB-2 and its protein products (P185) are found in a wide variety of tumors. The abnormal expression of C-erbB-2 has great influence on the occurrence and development of gastric carcinoma. This paper aimed to analyze the expression of C-erbB-2 in the tissues of gastric carcinoma, gastric mucosal atypical hyperplasia and gastritis, and discuss its role in the occurrence and development of gastric carcinoma. The morphological differences and connections among simple intestinal metaplasia (SIM), atypical intestinal metaplasia (AIM) and dysplasia in intestinal metaplasia through hematoxylin and eosin (HE) staining were studied. Three groups were set to detect the expression condition of C-erbB-2 by immunohistochemical method (IHC). The result showed that C-erbB-2 had no significant difference in AIM and gastric carcinoma, that is, AIM was closely related to gastric carcinoma. The positive expression was demonstrated of C-erbB-2 products (P185) in medium and gastric mucosa dysplasia tissues and was 29.41% and 66.67%, respectively, while it was 25%, 50% and 77.78% in high, medium and low differentiation of gastric carcinoma. It can be seen that there was a significant difference between them (P<0.05), and the expression degree was significantly enhanced (P<0.05); the expression degree in high differentiation gastric cancer tissue was significantly higher than the middle and low differentiation gastric cancer tissue. It was concluded that C-erbB-2 played an important role in the pathogenic mechanism of gastric carcinoma, and it might act on the later period of the gastric carcinoma, which provides objective reference index for the diagnosis and prognosis of gastric carcinoma and meanwhile provides instructional theoretical reference for the application of targeted drugs in the clinical treatment of gastric carcinoma. PMID- 26122240 TI - THIN-LAYER CHROMATOGRAPHY IDENTIFICATION FOR RHUBARB AND PHELLODENDRI AMURENSIS CORTEX IN SHUANG-BAI CATAPLASM AND STUDY OF SKIN IRRITATION ASSAY. AB - This paper aimed to raise a thin-layer chromatography (TLC) identification method for rhubarb and Phellodendri Amurensis Cortex and inspected skin irritation induced by them. It applied the TLC identification for Rhubarb and Phellodendri Amurensis Cortex in Shuang-bai cataplasm prescription. In this study six rabbits were divided into two groups to observe the skin irritation from Shuang-bai cataplasm on intact and defected skin. Another 36 were randomly divided into 6 groups to observe the acute toxicity from Shuang-bai cataplasm on intact and defected skin. Also 30 guinea pigs were divided into 3 groups to observe skin allergy to Shuang-bai cataplasm. The results showed that the average weight of the group of intact-skin rabbits was 2.026+/-0.10 kg and 2.427+/-0.023 kg after medication; the average weight of the group of defected-skin rabbits was 2.170+/ 0.05 kg and 2.540+/-0.15 kg after medication; Shuang-bai cataplasm produced no irritation on intact or defected rabbit skin, no acute toxicity in rabbits and no allergy on the skin of guinea pigs. The skin allergy rate on guinea pigs of the medication group was 0 at each time quantum. Therefore, it can be concluded that this preparation produces no extreme skin irritation for rabbits, guinea pigs or human beings, and it can be safely put into practice. PMID- 26122241 TI - THE INFLUENCE AND REGULATORY MECHANISM OF Y-BOX BINDING PROTEIN 1 IN OSTEOSARCOMA AND ITS SIGNIFICANCE. AB - This study quantified the expression of Y-box binding protein 1 (YB-1) by the immunohistochemical method based on pathological paraffin block specimens of aspiration biopsy from patients with osteosarcoma to explore the influence and regulatory mechanism of YB-1 in osteosarcoma and its significance. Patients were divided into two groups with high and low expressed YB-1, and results showed that 7 cases (13.7%) and 18 cases (26.1%) were in level III, and 44 cases (86.3%) and 51 cases (76.9%) were in level IV respectively, and patients with high YB-1 expression quantity had higher malignant tumor degree (p=0.03). Moreover, the tumor necrosis rate induced by chemotherapy in the two groups were 21 cases (41.2%) and 38 cases (51.8%), respectively. By survival analysis, it was found that a 5-year overall survival rate of patients with high YB-1 expression and low YB-1 expression were 61.2% and 76.6%, respectively (p = 0.054), and 5-year event free survival rates were 52.5% and 72.4%, respectively (p = 0.033). Furthermore, metastasis rate of high YB-1 expression and low YB-1 expression were 41.8% and 22.7%, respectively (p = 0.036), indicating that patients with high YB-1 expression had higher pulmonary metastasis rate. Through further study, we discovered that possibly miR-382 plays a regulatory role in YB-1 gene in osteosarcoma. PMID- 26122242 TI - GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY. AB - It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine -> arginine substitution at 192 (Q192R) and a leucine -> methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease. PMID- 26122243 TI - QUALITY OF LIFE FOLLOWING SURGICAL TREATMENT OF LOWER LIMB METASTASES IN LONG BONE. AB - Pathological fractures have a high incidence in musculo-skeletal oncology, and localization in long bone causes severe pain, disability and poor quality of life. The aim of this retrospective case series is to evaluate the clinical results, in particular regarding the quality of life, in patients affected by lower long bone pathological fractures surgically treated. We analyzed 93 patients with pathological fractures of tibia and femur surgically treated in our Orthopaedic Department and followed up for at least 3 years or until their death. Intramedullary nailing or endoprosthetic reconstruction for pathologic fractures located in the metadiaphyseal and diaphyseal or proximal regions in advanced stage cancer patients are suitable methods for a stable fixation or reconstruction. These approaches guarantee a good mechanical stability, a faster mobilization, a better control of pain with an overall improvement in quality of life in all patients, confirmed also by the trend of the ECOG performance status and QOL-ACD. PMID- 26122244 TI - POTENTIAL USE OF MELATONIN IN PROCEDURAL ANXIETY AND PAIN IN CHILDREN UNDERGOING BLOOD WITHDRAWAL. AB - The recognition of the value of pain, especially in the pediatric population, has increased over the last decade. It is known that pain-related anxiety can increase perceived pain intensity. There are several different approaches to the treatment of pre-procedural anxiety and procedural pain in children. Melatonin, a neurohormone with the profile of a novel hypnotic-anaesthetic agent, plays an important role in anxiolysis and analgesia. This study investigated the effects of oral melatonin premedication to reduce anxiety and pain in children having blood samples taken. The investigations were carried out on 60 children, aged 1 14 years, divided into 2 equal groups. Using a computer-generated randomization schedule, patients were given either melatonin orally (0.5 mg/kg BW, max 5 mg) or placebo 30 min before blood draw. Pre-procedural anxiety was assessed using the scale from the Children?s Anxiety and Pain Scales, while procedural pain used the Face, Legs, Activity, Cry and Consolability assessment tool for children under the age of 3 years, Faces Pain Scale-Revised for children aged 3-8 years and Numeric Rating Scale for children over the age of 8 years. Oral administration of melatonin before the blood withdrawal procedure significantly reduced both anxiety (p<0.0005) and pain levels than placebo (p<0.0002 for children under 3 years and p<0.0039 for children over 3 years). These data support the use of melatonin for taking blood samples due to its anxiolytic and analgesic properties. Further studies are needed to support the routine use of melatonin to alleviate anxiety and pain in pediatric patients having blood samples taken. PMID- 26122245 TI - MIXED DENTITION SPACE ANALYSIS OF A SOUTHERN ITALIAN POPULATION: NEW REGRESSION EQUATIONS FOR UNERUPTED TEETH. AB - Mixed dentition analysis forms a critical aspect of early orthodontic treatment. In fact an accurate space analysis is one of the important criteria in determining whether the treatment plan may involve serial extraction, guidance of eruption, space maintenance, space regaining or just periodic observation of the patients. The aim of the present study was to calculate linear regression equations in mixed dentition space analysis, measuring 230 dental casts mesiodistal tooth widths, obtained from southern Italian patients (118 females, 112 males, mean age 15+/-3 years). Student?s t-test or Wilcoxon test for independent and paired samples were used to determine right/left side and male/female differences. On the basis of the sum of the mesiodistal diameters of the 4 mandibular incisors as predictors for the sum of the widths of the canines and premolars in the mandibular mixed dentition, a new linear regression equation was found: y = 0.613x+7.294 (r= 0.701) for both genders in a southern Italian population. To better estimate the size of leeway space, a new regression equation was found to calculate the mesiodistal size of the second premolar using the sum of the four mandibular incisors, canine and first premolar as a predictor. The equation is y = 0.241x+1.224 (r= 0.732). In conclusion, new regression equations were derived for a southern Italian population. PMID- 26122246 TI - Use of Imaging Techniques in Inflammatory Bowel Diseases That Minimize Radiation Exposure. AB - The use of imaging in the management of inflammatory bowel disease (IBD) has grown exponentially in the last few years. This has raised concerns about the risk of high cumulative level of radiation exposure from medical imaging in IBD patients during their lifetime, especially when the disease begins in pediatric age. Physicians caring for IBD children should be aware of the malignant potential of ionizing radiation and of the availability of alternative radiation free techniques such as magnetic resonance imaging (MRI) and ultrasonography (US), in order to use them whenever possible. This review will focus on the value of US and MRI in pediatric IBD. PMID- 26122248 TI - Screening and Prophylaxis for Varices in Children with Liver Disease. AB - Esophageal varices in children with portal hypertension are quite common. Bleeding from these varices frequently occurs. Prophylactic measures to prevent such bleeding can be undertaken either before ("primary," prompted by a screening endoscopy) or after ("secondary") an initial variceal bleed. There are no clear pediatric guidelines for primary or secondary prophylaxis of esophageal varices. Adult studies clearly support the use of pharmacologic (beta blockers) and endoscopic (endoscopic band ligation, EBL) management for both primary and secondary prophylaxis of esophageal varices in patients with portal hypertension. Pediatric studies are limited. There are inadequate data to recommend use of beta blockers to prevent variceal bleeding or rebleeding in children with portal hypertension. There is very limited support for EBL for primary prophylaxis in children and more compelling support for EBL for secondary prophylaxis. Further randomized controlled studies are needed but are difficult to implement in this vulnerable population. PMID- 26122247 TI - Clinical Utility of Biomarkers in IBD. AB - There is no gold standard for the diagnosis and monitoring of inflammatory bowel diseases (IBD). Biomarkers are useful tools for the management of patients suffering from IBD. However, they should be used only when their additional information is useful for clinical decision-making. In principal, four situations during the management of an individual IBD patient can be discriminated from a clinical standpoint in which biomarkers provide useful information. First, biomarkers may be helpful when the diagnosis of IBD is established and aid in the discrimination between ulcerative colitis (UC) and Crohn's disease (CD) is necessary. Second, biomarkers may be helpful in the prognostic evaluation of IBD severity or disease behavior and for early decisions on the best treatment. The third situation in which biomarkers are useful is the evaluation of disease activity during the disease course, for monitoring and for guidance of ongoing treatment. Finally, the fourth typical situation when biomarkers are of value is after surgery to predict or diagnose a relapse of the disease. From a clinical point of view, it may be more useful to discuss specific biomarkers and their individual value and impact in these four prototypic situations than to sum up advantages and disadvantages for each biomarker isolated from the clinical situation. Therefore, this overview is structured in chapters reflecting those four typical situations during the disease course of IBD patents to critically evaluate the potential and value of each of the biomarkers in the specific situation. PMID- 26122249 TI - PPI-Refractory GERD: an Intriguing, Probably Overestimated, Phenomenon. PMID- 26122250 TI - Erratum to: Gestational Weight Gain and Health Outcomes 18 Years Later in Urban Black Women. PMID- 26122251 TI - From Theory to Measurement: Recommended State MCH Life Course Indicators. AB - PURPOSE: In May 2012, the Association of Maternal and Child Health (MCH) Programs initiated a project to develop indicators for use at a state or community level to assess, monitor, and evaluate the application of life course principles to public health. DESCRIPTION: Using a developmental framework established by a national expert panel, teams of program leaders, epidemiologists, and academicians from seven states proposed indicators for initial consideration. More than 400 indicators were initially proposed, 102 were selected for full assessment and review, and 59 were selected for final recommendation as Maternal and Child Health (MCH) life course indicators. ASSESSMENT: Each indicator was assessed on five core features of a life course approach: equity, resource realignment, impact, intergenerational wellness, and life course evidence. Indicators were also assessed on three data criteria: quality, availability, and simplicity. CONCLUSION: These indicators represent a major step toward the translation of the life course perspective from theory to application. MCH programs implementing program and policy changes guided by the life course framework can use these initial measures to assess and influence their approaches. PMID- 26122252 TI - Determinants of Skilled Delivery Assistance in a Rural Population: Findings from an HDSS Site of Rural West Bengal, India. AB - OBJECTIVE: This study examines the determinants of utilisation of skilled birth attendants (SBAs) amongst 2886 rural women in the state of West Bengal, India, using data from a survey of 2012-2013 conducted by the Birbhum Health and Demographic Surveillance System. METHOD: Multilevel logit regression models were estimated and qualitative investigations conducted to understand the determinants of utilisation of SBAs in rural West Bengal. RESULTS: Among women who delivered their last child during the 3 years preceding the survey, 69.1 % of deliveries were assisted by SBAs, while 30.9 % were home deliveries without any SBA assistance. Multivariate analysis revealed that apart from socio-demographic and economic factors (such as household affluence, women's education, birth order, uptake of comprehensive ANC check-ups, advice regarding danger signs of pregnancy and household's socio-religious affiliation), supply side factors, such as availability of skilled birth attendants in the village and all-weather roads, have significant effect on seeking skilled assistance. Our findings also show that unobserved factors at village level independently influence uptake of SBA assisted delivery. CONCLUSIONS FOR PRACTICE: The present findings emphasise that both demand and supply side intervention strategies are essential prerequisites to enhance skilled birth attendance. Ample communication is observed at the individual level, but improving community level outreach and advocacy activities could generate further demand. SBAs can be better integrated by accommodating the socio-religious needs of local communities, such as providing female doctors and doctors with similar socio-religious backgrounds. PMID- 26122253 TI - The Effects of Prepregnancy Body Mass Index and Gestational Weight Gain on Fetal Macrosomia Among American Indian/Alaska Native Women. AB - OBJECTIVES: The American Indian/Alaska Native (AI/AN) population is a high-risk group across many health indicators, including fetal macrosomia. We aimed to investigate the effects of prepregnancy body mass index (BMI) and gestational weight gain (GWG) on macrosomia and explore possible racial and geographical variations among AI/AN women. METHODS: This retrospective cohort study was conducted from the Pregnancy Risk Assessment Monitoring System in eight states (2004-2011) among live, singleton, term births to AI/AN women 20 years or older. Prevalence of macrosomia (birth weight >= 4000 g) by select characteristics were estimated; differences were assessed with Chi-squares. Multivariable logistic regression was conducted to calculate adjusted odds ratios (aOR) for effects on macrosomia of BMI and GWG (enumerating the pounds women deviated from the Institute of Medicine guidelines for GWG) controlling for other factors in the total sample and stratified by race and state of residence. RESULTS: The prevalence of macrosomia was 14 %, ranging from 8 to 21 % (Utah-Alaska). Among AI/AN women, 30 % were obese prepregnancy and 50 % had excess GWG. Significant independent effects were found for macrosomia of prepregnancy overweight (aOR 1.27; 95 % Confidence Interval 1.01-1.59), obesity (aOR 1.63; 1.29-2.07), and excess GWG (aOR 1.16; 1.13-1.20 per five pounds gained beyond appropriate). Adjusted estimates varied between race and state. CONCLUSIONS: Prepregnancy BMI and GWG are independent factors for macrosomia among AI/AN women. Future research should prioritize development, testing, and implementation of weight management programs, which account for variations among AI/AN women, both before and during pregnancy for BMI regulation and GWG control. PMID- 26122254 TI - The Relationship Between Maternal Education and Child Health Outcomes in Urban Australian Children in the First 12 Months of Life. AB - OBJECTIVES: To describe the relationship between maternal education and child health outcomes at 12 months of age in a cohort of children in urban Australia, and to determine whether this relationship could be explained by the intermediate factors of maternal health behaviour and the social environmental context. METHODS: Data were derived from The Environments for Health Living Griffith Birth Cohort Study. Women attending their third trimester antenatal appointment at one of three public hospitals were recruited between 2006 and 2010 and invited to complete a 48-item, baseline self-administered questionnaire. Twelve months following the birth of their baby, a follow-up questionnaire consisting of 63 items was distributed. RESULTS: Women for whom complete follow-up data were not available were different from women who did complete follow-up data. The children of women with follow-up data-whom at the time of their pregnancy had not completed school or whose highest level of education was secondary school or a trade-had respectively a 59 and 57 % increased chance of having had a respiratory/infectious disease or injury in the first year of life (according to parent proxy-reports), compared to children of women with a tertiary education. When maternal behavioural and social environmental factors during pregnancy were included in the model (n=1914), the effect of secondary education was still evident but with a reduced odds ratio of 1.35 (95 % CI 1.07-1.72) and 1.19 (95 % CI 0.87-1.64), respectively. The effect of not having completed school was no longer significant. CONCLUSIONS: Results indicate that the relationship between maternal education and child outcomes may be mediated by maternal social environmental and behavioural factors. Results are likely an underestimation of the effect size, given the under representation in our cohort of participants with maternal characteristics associated with elevated risk of infant morbidity. PMID- 26122255 TI - Birth Outcomes in a Disaster Recovery Environment: New Orleans Women After Katrina. AB - OBJECTIVES: To examine how the recovery following Hurricane Katrina affected pregnancy outcomes. METHODS: 308 New Orleans area pregnant women were interviewed 5-7 years after Hurricane Katrina about their exposure to the disaster (danger, damage, and injury); current disruption; and perceptions of recovery. Birthweight, gestational age, birth length, and head circumference were examined in linear models, and low birthweight (<2500 g) and preterm birth (<37 weeks) in logistic models, with adjustment for confounders. RESULTS: Associations were found between experiencing damage during Katrina and birthweight (adjusted beta for high exposure = -158 g) and between injury and gestational age (adjusted beta = -0.5 days). Of the indicators of recovery experience, most consistently associated with worsened birth outcomes was worry that another hurricane would hit the region (adjusted beta for birthweight: -112 g, p = 0.08; gestational age: -3.2 days, p = 0.02; birth length: -0.65 cm, p = 0.06). CONCLUSIONS: Natural disaster may have long-term effects on pregnancy outcomes. Alternately, women who are most vulnerable to disaster may be also vulnerable to poor pregnancy outcome. PMID- 26122256 TI - The Role of Health Information Sources in Decision-Making Among Hispanic Mothers During Their Children's First 1000 Days of Life. AB - OBJECTIVES: This qualitative research aimed to explore how health information sources inform decision-making among Hispanic mothers during their children's first 1000 days of life (conception-age 24 months), and to generate appropriate health information sources and communication strategies for future interventions. METHODS: We conducted seven focus groups with 49 Hispanic women who were pregnant or had children <2 years old. Domains included interpersonal and media sources, source trustworthiness, dealing with contradictory information, and how information affects decision-making. We used immersion/crystallization process for analysis. RESULTS: Trusted health information sources included health care providers, female and male family members, BabyCenter.com and other Internet sources, selected social media, and television. Some immigrant women reported preferring the Internet citing less established local support networks. Women highlighted the importance of validating health information through checking multiple sources for consistency and resolving contradictory information. Mothers expressed interest in receiving reliable website links from healthcare professionals and outreach to extended family. CONCLUSIONS FOR PRACTICE: Cultural factors, including immigration status, are important in understanding the use of health information sources and their role in decision-making about pregnancy and child health among Hispanic mothers. Healthcare providers and public health professionals should consider Hispanic mothers health information environment and provide culturally-relevant communication strategies and interventions during this high information-seeking time period. PMID- 26122257 TI - Acute and Chronic Risk Preceding Suicidal Crises Among Middle-Aged Men Without Known Mental Health and/or Substance Abuse Problems: An Exploratory Mixed-Methods Analysis. AB - BACKGROUND: Suicides among men aged 35-64 years increased by 27% between 1999 and 2013, yet little research exists to examine the nature of the suicide risk within this population. Many men do not seek help if they have mental health problems and suicides may occur in reaction to stressful circumstances. AIMS: We examined the precipitating circumstances of 600 suicides without known mental health or substance abuse (MH/SA) problems and with a recent crisis. Whether these suicides occurred within the context of an acute crisis only or in the context of chronic circumstances was observed. METHOD: Using data from the National Violent Death Reporting System and employing mixed-methods analysis, we examined the circumstances and context of a census of middle-aged male suicides (n = 600) in seven states between 2005 and 2010. RESULTS: Precipitating circumstances among this group involved intimate partner problems (IPP; 58.3%), criminal/legal problems (50.7%), job/financial problems (22.5%), and health problems (13.5%). Men with IPP and criminal/legal issues were more likely than men with health and/or job/financial issues to experience suicide in the context of an acute crisis only. CONCLUSION: Suicides occurring in reaction to an acute crisis only or in the context of acute and chronic circumstances lend themselves to opportunities for intervention. Further implications are discussed. PMID- 26122258 TI - Crisis Phones - Suicide Prevention Versus Suggestion/Contagion Effects. AB - BACKGROUND: There has been no systematic work on the short- or long-term impact of the installation of crisis phones on suicides from bridges. The present study addresses this issue. METHOD: Data refer to 219 suicides from 1954 through 2013 on the Skyway Bridge in St. Petersburg, Florida. Six crisis phones with signs were installed in July 1999. RESULTS: In the first decade after installation, the phones were used by 27 suicidal persons and credited with preventing 26 or 2.6 suicides a year. However, the net suicide count increased from 48 in the 13 years before installation of phones to 106 the following 13 years or by 4.5 additional suicides/year (t =3.512, p < .001). CONCLUSION: Although the phones prevented some suicides, there was a net increase after installation. The findings are interpreted with reference to suggestion/contagion effects including the emergence of a controversial bridge suicide blog. PMID- 26122259 TI - Is Case Management Effective for Long-Lasting Suicide Prevention? AB - BACKGROUND: Case management services have been implemented in suicide prevention programs. AIMS: To investigate whether case management is an effective strategy for reducing the risks of repeated suicide attempts and completed suicides in a city with high suicide rates in northern Taiwan. METHOD: The Suicide Prevention Center of Keelung City (KSPC) was established in April 2005. Subjects included a consecutive sample of individuals (N = 2,496) registered in KSPC databases between January 1, 2006, and December 31, 2011, with at least one episode of nonfatal self-harm. Subjects were tracked for the duration of the study. RESULTS: Of all the subjects, 1,013 (40.6%) received case management services; 416 (16.7%) had at least one other deliberate self-harm episode and 52 (2.1%) eventually died by suicide. No significant differences were found in the risks of repeated self harm and completed suicides between suicide survivors who received case management and those who refused the services. However, a significant reduction in suicide rates was found after KSPC was established. CONCLUSION: Findings suggest that case management services might not reduce the risks of suicide repetition among suicide survivors during long-term follow-up. Future investigation is warranted to determine factors impacting the downward trend of suicide rates. PMID- 26122260 TI - Lack of Trust in the Health-Care System After Losing a Child to Suicide. AB - BACKGROUND: Lack of trust in the health-care system after losing a child to suicide may prevent bereaved parents from seeking professional treatment when needed, thus diminishing their chances of recovery. AIMS: This is the first large study to aim at evaluating the incidence of lack of trust in the health-care system and associated variables in suicide-bereaved parents. METHOD: This nationwide population-based survey included 569 parents who lost a child to suicide 2-5 years earlier and a matched comparison group of 326 nonbereaved parents. Using a study-specific questionnaire, we asked bereaved and nonbereaved parents if they trusted the health-care system and measured psychological and background variables. RESULTS: Prevalence of lack of trust in the health-care system differed between the bereaved (46.5%) and the nonbereaved parents (18.3%), giving a relative risk of 2.5 (95% CI = 2.0-3.3). After multivariable modeling, high scores of depression, living in big cities, and being single were identified as variables associated with lack of trust in suicide-bereaved parents. CONCLUSION: Suicide-bereaved parents show lack of trust in the health-care system. We present possible effect modifiers that may be considered in professional interventions aiming at influencing suicide-bereaved parents' level of trust. PMID- 26122261 TI - Plasma glial cell line-derived neurotrophic factor in patients with major depressive disorder: a preliminary study. AB - BACKGROUND: Some clinical studies have reported reduced peripheral glial cell line-derived neurotrophic factor (GDNF) level in elderly patients with major depressive disorder (MDD). We verified whether a reduction in plasma GDNF level was associated with MDD. METHOD: Plasma GDNF level was measured in 23 healthy control subjects and 23 MDD patients before and after 6 weeks of treatment. RESULTS: Plasma GDNF level in MDD patients at baseline did not differ from that in healthy controls. Plasma GDNF in MDD patients did not differ significantly from baseline to the end of treatment. GDNF level was significantly lower in recurrent-episode MDD patients than in first-episode patients before and after treatment. CONCLUSIONS: Our findings revealed significantly lower plasma GDNF level in recurrent-episode MDD patients, although plasma GDNF levels in MDD patients and healthy controls did not differ significantly. The discrepancy between our study and previous studies might arise from differences in the recurrence of depression or the ages of the MDD patients. PMID- 26122263 TI - Forensic ancestry analysis with two capillary electrophoresis ancestry informative marker (AIM) panels: Results of a collaborative EDNAP exercise. AB - There is increasing interest in forensic ancestry tests, which are part of a growing number of DNA analyses that can enhance routine profiling by obtaining additional genetic information about unidentified DNA donors. Nearly all ancestry tests use single nucleotide polymorphisms (SNPs), but these currently rely on SNaPshot single base extension chemistry that can fail to detect mixed DNA. Insertion-deletion polymorphism (Indel) tests have been developed using dye labeled primers that allow direct capillary electrophoresis detection of PCR products (PCR-to-CE). PCR-to-CE maintains the direct relationship between input DNA and signal strength as each marker is detected with a single dye, so mixed DNA is more reliably detected. We report the results of a collaborative inter laboratory exercise of 19 participants (15 from the EDNAP European DNA Profiling group) that assessed a 34-plex SNP test using SNaPshot and a 46-plex Indel test using PCR-to-CE. Laboratories were asked to type five samples with different ancestries and detect an additional mixed DNA sample. Statistical inference of ancestry was made by participants using the Snipper online Bayes analysis portal plus an optional PCA module that analyzes the genotype data alongside calculation of Bayes likelihood ratios. Exercise results indicated consistent genotyping performance from both tests, reaching a particularly high level of reliability for the Indel test. SNP genotyping gave 93.5% concordance (compared to the organizing laboratory's data) that rose to 97.3% excluding one laboratory with a large number of miscalled genotypes. Indel genotyping gave a higher concordance rate of 99.8% and a reduced no-call rate compared to SNP analysis. All participants detected the mixture from their Indel peak height data and successfully assigned the correct ancestry to the other samples using Snipper, with the exception of one laboratory with SNP miscalls that incorrectly assigned ancestry of two samples and did not obtain informative likelihood ratios for a third. Therefore, successful ancestry assignments were achieved by participants in 92 of 95 Snipper analyses. This exercise demonstrates that ancestry inference tests based on binary marker sets can be readily adopted by laboratories that already have well-established CE regimes in place. The Indel test proved to be easy to use and allowed all exercise participants to detect the DNA mixture as well as achieving complete and concordant profiles in nearly all cases. Lastly, two participants successfully ran parallel next-generation sequencing analyses (each using different systems) and achieved high levels of genotyping concordance using the exercise PCR primer mixes unmodified. PMID- 26122264 TI - Therapy and differential diagnosis of posterior reversible encephalopathy syndrome (PRES) during pregnancy and postpartum. AB - PURPOSE: Posterior reversible encephalopathy syndrome (PRES) is an usually reversible neuro-radiological clinical entity characterized by headache, confusion, visual disturbances or blindness and seizures. It rarely occurs without seizures. METHODS: We conducted a literature review in MEDLINE about PRES during post partum and pregnancy, focusing on differential diagnosis and therapy. We reviewed 28 articles (case reports, original articles and reviews) describing PRES as well as a case of a severe, immediate postpartum HELLP syndrome (haemolysis, elevated liver enzyme levels, low platelet count) with PRES without generalized seizure. RESULTS: The development of PRES after delivery is unusual. Magnetic resonance imaging represents the gold standard for the diagnosis of this condition. White matter oedema in the posterior cerebral hemispheres is typical on neuroimaging. PRES is reversible when early diagnosis is established and appropriate treatment is started without delay. The pathogenesis of PRES is discussed and the importance of a prompt diagnosis is emphasized, as the crucial role of rapid blood press reduction. CONCLUSION: MRI is the diagnostic gold standard and it may be useful in the differential diagnosis. The goal of the therapy is to control elevated blood pressure and to prevent seizures or promptly manage it. PMID- 26122265 TI - Accuracy of information on medication use and adverse drug reactions recorded in pregnancy hand-held records. AB - BACKGROUND: Pregnancy hand-held records (PHR) are a personally controlled health record utilised in the promotion of continuity of care across pregnancy by providing a single resource for the recording of pregnancy-related health information. AIMS: To determine the accuracy of the PHR in relation to information on medications and adverse drug reactions (ADRs) and to examine the frequency and nature of any identified discrepancies. MATERIALS AND METHODS: A 12 week prospective clinical audit of 300 women admitted to either the antenatal or postnatal ward at a tertiary-level maternity hospital. A detailed medication history was completed for each woman by a pharmacist, with women interviewed about medication use prior to and during their pregnancy as well as any ADRs. The medication history and PHR were compared to identify discrepancies. RESULTS: Medication discrepancies were extremely common, with 254 (84.7%; 95% CI 80.6 88.8%) women having at least one or more medication-related discrepancy involving 686 (55%; 95% CI 52.2-57.8%) prescription and nonprescription medications. Most common reasons for prescription medication discrepancies included the medication details being incomplete (44%), missing (29%) or incorrect (17%). ADRs and allergy discrepancies were also common, identified among 59 (20%; 95% CI 15.5 24.5%) women. CONCLUSIONS: The PHR is of low accuracy in relation to the recording of medications and ADRs. This warrants further research to examine the impact of these discrepancies on patient care and outcomes. The identification of strategies for improving the recording of information on medications and ADRs in the PHR is also required. PMID- 26122266 TI - Isoprene emission by poplar is not important for the feeding behaviour of poplar leaf beetles. AB - BACKGROUND: Chrysomela populi (poplar leaf beetle) is a common herbivore in poplar plantations whose infestation causes major economic losses. Because plant volatiles act as infochemicals, we tested whether isoprene, the main volatile organic compound (VOC) produced by poplars (Populus x canescens), affects the performance of C. populi employing isoprene emitting (IE) and transgenic isoprene non-emitting (NE) plants. Our hypothesis was that isoprene is sensed and affects beetle orientation or that the lack of isoprene affects plant VOC profiles and metabolome with consequences for C. populi feeding. RESULTS: Electroantennographic analysis revealed that C. populi can detect higher terpenes, but not isoprene. In accordance to the inability to detect isoprene, C. populi showed no clear preference for IE or NE poplar genotypes in the choice experiments, however, the beetles consumed a little bit less leaf mass and laid fewer eggs on NE poplar trees in field experiments. Slight differences in the profiles of volatile terpenoids between IE and NE genotypes were detected by gas chromatography - mass spectrometry. Non-targeted metabolomics analysis by Fourier Transform Ion Cyclotron Resonance Mass Spectrometer revealed genotype-, time- and herbivore feeding-dependent metabolic changes both in the infested and adjacent undamaged leaves under field conditions. CONCLUSIONS: We show for the first time that C. populi is unable to sense isoprene. The detected minor differences in insect feeding in choice experiments and field bioassays may be related to the revealed changes in leaf volatile emission and metabolite composition between the IE and NE poplars. Overall our results indicate that lacking isoprene emission is of minor importance for C. populi herbivory under natural conditions, and that the lack of isoprene is not expected to change the economic losses in poplar plantations caused by C. populi infestation. PMID- 26122268 TI - We specialize in change leadership: A call for hospitalists to lead the quest for workforce gender equity. PMID- 26122267 TI - Osteogenic changes in kidneys of hyperoxaluric rats. AB - Many calcium oxalate (CaOx) kidney stones develop attached to renal papillary sub epithelial deposits of calcium phosphate (CaP), called Randall's plaque (RP). Pathogenesis of the plaques is not fully understood. We hypothesize that abnormal urinary environment in stone forming kidneys leads to epithelial cells losing their identity and becoming osteogenic. To test our hypothesis male rats were made hyperoxaluric by administration of hydroxy-l-proline (HLP). After 28days, rat kidneys were extracted. We performed genome wide analyses of differentially expressed genes and determined changes consistent with dedifferentiation of epithelial cells into osteogenic phenotype. Selected molecules were further analyzed using quantitative-PCR and immunohistochemistry. Genes for runt related transcription factors (RUNX1 and 2), zinc finger protein Osterix, bone morphogenetic proteins (BMP2 and 7), bone morphogenetic protein receptor (BMPR2), collagen, osteocalcin, osteonectin, osteopontin (OPN), matrix-gla-protein (MGP), osteoprotegrin (OPG), cadherins, fibronectin (FN) and vimentin (VIM) were upregulated while those for alkaline phosphatase (ALP) and cytokeratins 10 and 18 were downregulated. In conclusion, epithelial cells of hyperoxaluric kidneys acquire a number of osteoblastic features but without CaP deposition, perhaps a result of downregulation of ALP and upregulation of OPN and MGP. Plaque formation may additionally require localized increases in calcium and phosphate and decrease in mineralization inhibitory potential. PMID- 26122269 TI - Systematic review with meta-analysis of the impact of surgical fellowship training on patient outcomes. AB - BACKGROUND: The number of surgeons entering fellowship training before independent practice is increasing. This may have a negative impact on surgeons in training. The impact of fellowship training on patient outcomes is not yet known. This review aimed to investigate the impact of fellowship training in surgery on patient outcomes. METHODS: A systematic review of the literature was conducted to identify studies exploring the structural and surgeon-specific characteristics of fellowship training on patient outcomes. Data from these studies were extracted, synthesized and reported qualitatively, or quantitatively through meta-analysis. RESULTS: Twenty-three studies were included. The mortality rate for patients in centres with an affiliated fellowship programme was lower than that for centres without (odds ratio 0.86, 95 per cent c.i. 0.84 to 0.88), as was the rate of complications (odds ratio 0.90, 0.78 to 1.02). Surgeons without fellowship training converted more laparoscopic operations to open surgery than those with fellowship training (risk ratio (RR) 1.04, 95 per cent c.i. 1.03 to 1.05). Comparison of outcomes for senior surgeons versus current fellows showed no differences in rates of mortality (RR 1.00, 1.00 to 1.01), complications (RR 1.03, 0.98 to 1.08) or conversion to open surgery (RR 1.01, 1.00 to 1.01). CONCLUSION: Fellowship training appears to have a positive impact on patient outcomes. PMID- 26122271 TI - Genomic diagnosis by whole genome sequencing in a Korean family with atypical progeroid syndrome. AB - Clinical genomic diagnosis is unfamiliar to many dermatologists. Limited knowledge of bioinformatics has limited the use of the next generation sequencing method in dermatological clinics. We evaluated the usefulness of whole genome sequencing as a diagnostic approach to inherited dermatological disease. Here, we present our experience with two female siblings with atypical familial generalized lipodystrophy with diabetes mellitus and dyslipidemia. Whole genome sequencing was performed to diagnose the inherited disease. We compared control genomic databases using the Exome Aggregation Consortium, and filtered false positive calls with the segmental duplication, non-flagged single nucleotide variants and COSMIC mutation databases, and applied the prediction tools of SIFT and PolyPhen2. The two siblings who presented with generalized lipodystrophy were diagnosed with an atypical progeroid syndrome with a p.D136H mutation in the LMNA gene (NM_005572). We diagnosed a familial atypical progeroid syndrome using whole genome sequencing. In this paper, we present our experience with whole genome sequencing and demonstrate that it can provide useful information for clinical genomic diagnosis of inherited diseases with atypical clinical features, such as atypical progeroid syndrome. PMID- 26122270 TI - Medical professionalism: what the study of literature can contribute to the conversation. AB - Medical school curricula, although traditionally and historically dominated by science, have generally accepted, appreciated, and welcomed the inclusion of literature over the past several decades. Recent concerns about medical professional formation have led to discussions about the specific role and contribution of literature and stories. In this article, we demonstrate how professionalism and the study of literature can be brought into relationship through critical and interrogative interactions based in the literary skill of close reading. Literature in medicine can question the meaning of "professionalism" itself (as well as its virtues), thereby resisting standardization in favor of diversity method and of outcome. Literature can also actively engage learners with questions about the human condition, providing a larger context within which to consider professional identity formation. Our fundamental contention is that, within a medical education framework, literature is highly suited to assist learners in questioning conventional thinking and assumptions about various dimensions of professionalism. PMID- 26122272 TI - Grazing-induced changes in muscle microRNA-206 and -208b expression in association with myogenic gene expression in cattle. AB - To investigate the roles of microRNAs (miRNAs) in muscle type conversion, the effects of 4 months of grazing on the expression levels of miRNAs and mRNAs associated with skeletal muscle development were analyzed by quantitative RT-PCR using the Biceps femoris muscle of Japanese Shorthorn cattle. After 4 months of grazing, the expression of muscle fiber type-associated miR-208b was higher in the grazed cattle than in the housed. In concordance with the pattern in miR-208b expression, the expression of MyoD, a myogenic regulatory factor associated with the shifting of muscle property to the fast type, was lower in the grazed cattle after 4 months of grazing than in the housed cattle. In addition, the expression of MyHC-2x (a fast type) was higher in the housed cattle than in the grazed, after 4 months of grazing. During the grazing period, miR-206 expression decreased in the housed cattle, whereas expression in the grazed cattle did not change, but rather remained higher than that of the housed cattle even at 3 months after the grazing ended. These miRNAs including miR-206 persisting with muscles of grazed cattle may be associated with regulation of muscle gene expression during skeletal muscle adaptation to grazing. PMID- 26122274 TI - Tele-intensivists can instruct non-physicians to acquire high-quality ultrasound images. AB - PURPOSE: Intensive care unit telemedicine (tele-ICU) uses audiovisual systems to remotely monitor and manage patients. Intensive care unit ultrasound can augment an otherwise limited bedside evaluation. To date, no studies have utilized tele ICU technology to assess the quality and clinical use of real-time ultrasound images. We assessed whether tele-intensivists can instruct nonphysicians to obtain high-quality, clinically useful ultrasound images. METHODS: This prospective pilot evaluated the effectiveness of a brief educational session of nonphysician "ultrasonographers" on their ability to obtain ultrasound images (right internal jugular vein, bilateral lung apices and bases, cardiac subxiphoid view, bladder) with real-time tele-intensivist guidance. All ultrasound screen images were simultaneously photographed with a 2-way camera and saved on the ultrasound machine. The tele-intensivist assessed image quality, and an independent ultrasound expert rated their use in guiding clinical decisions. RESULTS: The intensivist rated the tele-ICU camera images as high quality (70/77, 91%) and suitable for guiding clinical decisions (74/77, 96%). Only bilateral lung apices demonstrated differences in quality and clinical use. All other images were rated noninferior and clinically useful. CONCLUSION: Tele intensivists can guide minimally trained nonphysicians to obtain high-quality, clinically useful ultrasound images. For most anatomic sites, tele-ICU images are of similar quality to those acquired directly by ultrasound. PMID- 26122273 TI - 4'-modified nucleoside analogs: potent inhibitors active against entecavir resistant hepatitis B virus. AB - Certain nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more-potent agents that offer profound viral suppression. Here, we report that 4'-C-cyano-2-amino-2'-deoxyadenosine (CAdA) is a novel, highly potent inhibitor of both HBV (half maximal inhibitory concentration [IC50 ] = 0.4 nM) and HIV-1 (IC50 = 0.4 nM). In contrast, the approved anti-HBV NRTI, entecavir (ETV), potently inhibits HBV (IC50 = 0.7 nM), but is much less active against HIV-1 (IC50 = 1,000 nM). Similarly, the highly potent HIV-1 inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA; IC50 = 0.3 nM) is less active against HBV (IC50 = 160 nM). Southern analysis using Huh-7 cells transfected with HBV-containing plasmids demonstrated that CAdA was potent against both wild type (IC50 = 7.2 nM) and ETV-resistant HBV (IC50 = 69.6 nM for HBVETV RL180M/S202G/M204V), whereas ETV failed to reduce HBVETV-RL180M/S202G/M204V DNA even at 1 MUM. Once-daily peroral administration of CAdA reduced HBVETV RL180M/S202G/M204V viremia (P = 0.0005) in human-liver-chimeric/ HBVETV RL180M/S202G/M204V-infected mice, whereas ETV completely failed to reduce HBVETV RL180M/S202G/M204V viremia. None of the mice had significant drug-related body weight or serum human-albumin concentration changes. Molecular modeling suggests that a shallower HBV-RT hydrophobic pocket at the polymerase active site can better accommodate the slightly shorter 4'-cyano of CAdA-triphosphate (TP), but not the longer 4'-ethynyl of EFdA-TP. In contrast, the deeper HIV-1-RT pocket can efficiently accommodate the 4'-substitutions of both NRTIs. The ETV-TP's cyclopentyl ring can bind more efficiently at the shallow HBV-RT binding pocket. CONCLUSION: These data provide insights on the structural and functional associations of HBV- and HIV-1-RTs and show that CAdA may offer new therapeutic options for HBV patients. PMID- 26122275 TI - The Efficacy of Tolvaptan in Congestive Heart Failure Patients with and Without Hypoalbuminemia: A Pilot Study. AB - BACKGROUND: Heart failure (HF) with hypoalbuminemia is associated with poor response to conventional therapy. We investigated whether tolvaptan, a potent aquaretic agent, might be of benefit in HF patients with hypoalbuminemia. METHODS: We prospectively enrolled 40 patients hospitalized for HF. Patients received conventional therapy including loop diuretics. We subsequently added tolvaptan in the range of 3.75-15 mg daily and it was discontinued after improvement of HF symptoms. We compared clinical and laboratory data in HF patients with and without hypoalbuminemia (defined as serum albumin <3.0 g/dL). RESULTS: Tolvaptan was administered in 18 HF patients with hypoalbuminemia (Group A) and 22 HF patients without hypoalbuminemia (Group B). The mean serum albumin was 2.63 +/- 0.27 and 3.46 +/- 0.25 g/dL, respectively. The average urine output on tolvaptan increased significantly in both groups (1644.4 +/- 797.6-3011.6 +/- 1453.8 mL/day, P = 0.004; 1459 +/- 612.7-2112.2 +/- 724.5 mL/day, P = 0.008; respectively). In addition, we observed higher urine output on therapy in Group A than in Group B (P = 0.015). There was a moderate negative correlation between serum albumin and average urine output on tolvaptan (r = -0.42, P = 0.007). CONCLUSIONS: The addition of tolvaptan to low dose loop diuretics might be an effective strategy for treatment of HF patients with hypoalbuminemia. PMID- 26122276 TI - Fathers' and mothers' attachment representations as predictors of preadolescents' attachment security: A ten-year follow-up of Finnish families. AB - The question of how mothers' and fathers' representations of attachment correlate ten years later with children's perceptions of attachment relationships was examined in a longitudinal study on Finnish families (N = 42). The parents completed the Adult Attachment Interview (AAI) during the child's first year of life. At 11 years, the children filled out three scales on how secure they perceive the relationship with each parent. Parents' AAI classifications and AAI dimensions based on continuous scales were used as predictors of the preadolescents' attachment security. Regression analyses demonstrated that fathers' but not mothers' State-of-Mind and Experience dimensions predicted preadolescents' security of attachment to father. The discussion focuses on the predictive validity of the classical categorical versus the recently proposed continuous approach and the different roles of parents in transmitting security from one generation to another. PMID- 26122277 TI - Local and regional chromatin silencing in Candida glabrata: consequences for adhesion and the response to stress. AB - Candida glabrata is a fungal pathogen frequently found as a commensal in humans. To colonize and disseminate successfully in the mammalian host, C. glabrata must detect signals within the host and reprogram gene expression to respond appropriately to hostile environmental conditions. One of the layers of regulation of expression of many virulence-related genes (adhesin-encoding genes, genes involved in response to oxidative stress and xenobiotics) is achieved through epigenetic mechanisms. Local and regional silencing is mediated by the activity of two NAD(+)-dependent histone deacetylases, Hst1 and Sir2, respectively, repressing many virulence genes. Hst1 and Sir2 interact with different repressor complexes to achieve regional or local silencing. Sir2 can associate with Sir4, which is then recruited to the telomere by Rap1 and yKu. Deacetylation of the histone tails creates high affinity binding sites for new molecules of the Sir complex, thereby spreading the silent domain over >20 kb. Many of the adhesin-encoding EPA genes are subject to this regulation. Hst1 in turn associates with the Sum1-Rfm1 complex. Sum1 is a DNA-binding protein, which recognizes specific sites at individual promoters, recruiting Hst1 to specific genes involved in the response to oxidative stress and xenobiotics, which results in their repression. PMID- 26122278 TI - Molecular cloning and characterization of the ATP citrate lyase from carotenogenic yeast Phaffia rhodozyma. AB - ATP citrate lyase (ACL), is a key cytosolic source of acetyl-CoA for fatty acid and sterol biosynthesis and appear to be involved in carotenoid biosynthesis in yeasts. Three homologous DNA sequences encoding ACLs in Phaffia rhodozyma were isolated i.e two genes and one cDNA. The two genes were multi-intronic, with 3450 bp-coding sequences and both genes, as the cDNA, encoded identical 120.1-kDa polypeptides. Full-length amino acid sequences of these ACLs showed the two multidomains, PLN02235 and PLN02522, which are necessary for activity. The ACLs showed 82-87% similarity to putative ACLs from other basidiomycetes and 71% similarity to human ACL. The acl cDNA was used to express the heterologous ACL 6XHis-tagged which was identified using MALDI-TOF-MS. The sequenced peptides with 42.2% coverage showed 100% identity to the amino acid sequence generated in silico. The recombinant ACL purified to homogeneity showed an activity of 2 U. This is the first study to characterize a recombinant ACL from a carotenogenic yeast. The present study provides a key foundation for future studies to assess (a) the possible occurrence of alternative splicing, (b) identify the promoter(s) sequence(s) and (c) the involvement of ACL in the differential regulation of fatty acid and carotenoid biosynthesis in yeasts. PMID- 26122279 TI - Effects of a Dissostichus mawsoni-CaM recombinant proteins feed additive on the juvenile orange-spotted grouper (Epinephelus coioides) under the acute low temperature challenge. AB - The effects of Dissostichus mawsoni-Calmodulin (Dm-CaM) on growth performance, enzyme activities, respiratory burst, MDA level and immune-related gene expressions of the orange-spotted grouper (Epinephelus coioides) exposed to the acute low temperature stress were evaluated. The commercial diet supplemented with Dm-CaM protein was fed to the groupers for 6 weeks. No significant difference was observed in the specific growth rates, weight gains and survivals. After the feeding trial, the groupers were exposed to acute low temperature challenge. The groupers fed with Dm-CaM additive diet showed a significant decrease in the respiratory burst activity, while the blood cell number increased significantly at 25 degrees C by comparing with the control and additive control group. The enzymatic activity of SOD, ACP and ALP increased significantly in Dm CaM additive group, while MDA level maintained stable with the lowest value. qRT PCR analysis indicated that the up-regulated transcript expressions of CaM, C3, SOD2, LysC and HSPA4 were observed in Dm-CaM additive group. These results indicated that Dm-CaM additive diet may regulate the grouper immune response to the acute low temperature challenge. PMID- 26122280 TI - Extracellular ATP enhances radiation-induced brain injury through microglial activation and paracrine signaling via P2X7 receptor. AB - Activation of purinergic receptors by extracellular ATP (eATP) released from injured cells has been implicated in the pathogenesis of many neuronal disorders. The P2X7 receptor (P2X7R), an ion-selective purinergic receptor, is associated with microglial activation and paracrine signaling. However, whether ATP and P2X7R are involved in radiation-induced brain injury (RBI) remains to be determined. Here, we found that the eATP level was elevated in the cerebrospinal fluid (CSF) of RBI patients and was associated with the clinical severity of the disorder. In our experimental model, radiation treatment increased the level of eATP in the supernatant of primary cultures of neurons and glial cells and in the CSF of irradiated mice. In addition, ATP administration activated microglia, induced the release of the inflammatory mediators such as cyclooxygenase-2, tumor necrosis factor alpha and interleukin 6, and promoted neuronal apoptosis. Furthermore, blockade of ATP-P2X7R interaction using P2X7 antagonist Brilliant Blue G or P2X7 knockdown suppressed radiation-induced microglial activation and proliferation in the hippocampus, and restored the spatial memory of irradiated mice. Finally, we found that the PI3K/AKT and nuclear factor kappaB mediated pathways were downstream of ATP-P2X7R signaling in RBI. Taken together, our results unveiled the critical role of ATP-P2X7R in brain damage in RBI, suggesting that inhibition of ATP-P2X7R axis might be a potential strategy for the treatment of patients with RBI. PMID- 26122281 TI - Efficacy of feed enzymes in pig and poultry diets containing distillers dried grains with solubles: a review. AB - Distiller's dried grains with solubles (DDGS), a coproduct of the ethanol industry, are often used as feed material in livestock and poultry nutrition. Results of many experiments have indicated, however, that a high dietary level of DDGS can negatively affect the digestibility of nutrients and the performance of monogastric animals due to their high content of non-starch polysaccharides (NSP). Nevertheless, using high levels of DDGS as a protein source in livestock diets can be still economically justifiable in view of the rising prices of soya bean meal and other protein sources. The aim of some recent experiments with poultry and pigs was to improve the nutritional efficacy of high-NSP diets through the addition of feed enzymes. As presented and discussed in this review article, the efficacy of feed enzymes added to poultry and pig diets containing DDGS is not consistent and depends on many factors. However, NSP-hydrolysing enzymes generally seemed to be more efficient than phytases in terms of the digestibility of nutrients and the growth performance of poultry and pigs fed high-DDGS diets. For this reason, supplementation with NSP-hydrolysing enzymes could be an efficient way to enable the use of increased levels of DDGS in poultry and pig diets. PMID- 26122283 TI - Advances in the management of rheumatoid arthritis. AB - Modern early rheumatoid arthritis strategies are usually based upon a number of important overarching principles: 1. early diagnosis facilitates early commencement of disease modifying anti-rheumatic therapy; 2. early commencement of treatment reduces the long-term risk of erosive damage and functional decline; 3. composite disease activity measures should be used to quantify global rheumatoid arthritis disease activity; and 4. therapy should be intensified until a predefined disease activity target has been achieved. A substantial minority of rheumatoid arthritis patients (approximately 40%) will experience an adequate response to methotrexate monotherapy; however, the remainder may require disease modifying anti-rheumatic combination therapy, and/or biologic therapy, to achieve disease activity targets. Importantly, short term trials of methotrexate monotherapy do not appear to disadvantage outcomes provided treatment continues to be intensified if disease activity targets are not achieved. PMID- 26122282 TI - Validity of energy intake estimated by digital photography plus recall in overweight and obese young adults. AB - BACKGROUND: Recent reports have questioned the adequacy of self-report measures of dietary intake as the basis for scientific conclusions regarding the associations of dietary intake and health, and reports have recommended the development and evaluation of better methods for the assessment of dietary intake in free-living individuals. We developed a procedure that used pre- and post-meal digital photographs in combination with dietary recalls (DP+R) to assess energy intake during ad libitum eating in a cafeteria setting. OBJECTIVE: To compare mean daily energy intake of overweight and obese young adults assessed by a DP+R method with mean total daily energy expenditure assessed by doubly labeled water (TDEE(DLW)). METHODS: Energy intake was assessed using the DP+R method in 91 overweight and obese young adults (age = 22.9+/-3.2 years, body mass index [BMI; calculated as kg/m(2)]=31.2+/-5.6, female=49%) over 7 days of ad libitum eating in a university cafeteria. Foods consumed outside the cafeteria (ie, snacks, non cafeteria meals) were assessed using multiple-pass recall procedures, using food models and standardized, neutral probing questions. TDEE(DLW) was assessed in all participants over the 14-day period. RESULTS: The mean energy intakes estimated by DP+R and TDEE(DLW) were not significantly different (DP+R=2912+/-661 kcal/d; TDEE(DLW)=2849+/-748 kcal/d, P=0.42). The DP+R method overestimated TDEE(DLW) by 63+/-750 kcal/d (6.8+/-28%). CONCLUSION: Results suggest that the DP+R method provides estimates of energy intake comparable to those obtained by TDEE(DLW). PMID- 26122284 TI - Ablation of B7-H3 but Not B7-H4 Results in Highly Increased Tumor Burden in a Murine Model of Spontaneous Prostate Cancer. AB - The costimulatory molecules B7-H3 and B7-H4 are overexpressed in a variety of human tumors and have been hypothesized as possible biomarkers and immunotherapeutic targets. Despite this potential, the predominating uncertainty about their functional implication in tumor-host interaction hampers their evaluation as a target for cancer therapy. By means of a highly physiologic, spontaneous tumor model in mice, we establish a causal link between B7-H3 and host tumor control and found B7-H4 to be redundant. PMID- 26122285 TI - Risk factors associated with falls in elderly patients with type 2 diabetes. AB - AIMS: This study investigated risk factors of falls in elderly patients with type 2 diabetes mellitus. METHODS: A total of 211 patients aged ?60years (168 diabetic patients and 43 non-diabetic control subjects) were studied. Factors associated with falls in the past year were retrospectively examined using multiple logistic regression analysis. RESULTS: The prevalence of patients who had a history of falls in the past year was twice as high as in diabetic patients compared in control subjects (36.9% vs. 18.6%, P<0.05). When diabetic patients were exclusively analyzed, the presence of any level of hypoglycemia and the Timed Up and Go test (TUG) scores correlated with patients' falls. The presence of hypoglycemia (OR 3.62, 95% CI: 1.242-10.534, P=0.018), cognitive impairment (OR 3.63, 95% CI: 1.227-10.727, P=0.020), and high Fall Risk Index scores (OR 1.2, 95% CI: 1.010-1.425, P=0.039) was independently correlated with the presence of multiple falls. When the diabetic patients were divided into three groups according to the frequency of hypoglycemia episodes, the prevalence of falls increased as the frequency of hypoglycemia increased. CONCLUSION: Hypoglycemia was a risk factor of falls in elderly type 2 diabetic patients. PMID- 26122286 TI - Hyperlactatemia in type 2 diabetes: Can physical training help? AB - Type 2 diabetic patients often exhibit hyperlactatemia in association with a reduced aerobic-oxidative capacity and a restricted lactate transport. Studies suggest a link between increased lactate levels and the manifestation and progression of insulin resistance. However, the specificities of molecular mechanisms remain unclear, and it is not entirely clear whether elevated lactate levels are a cause or consequence of type 2 diabetes. This review focuses on lactate as a key molecule in diabetes and provides an overview of how regular physical activity can be helpful in normalizing elevated lactate levels in type 2 diabetic patients. Physical training may reduce lactate production and reinforce lactate transport and clearance among this particular patient group. We emphasize the crucial role physical training plays in the therapy of type 2 diabetes due to evidence that pharmacological treatment with metformin, which is commonly used in the first-line therapy of type 2 diabetes, does not help reducing lactate levels. PMID- 26122288 TI - Estradiol rapidly modulates spinogenesis in hippocampal dentate gyrus: Involvement of kinase networks. AB - This article is part of a Special Issue "Estradiol and cognition". Estradiol (E2) is locally synthesized within the hippocampus and the gonads. Rapid modulation of hippocampal synaptic plasticity by E2 is essential for synaptic regulation. The molecular mechanisms of modulation through the synaptic estrogen receptor (ER) and its downstream signaling, however, are largely unknown in the dentate gyrus (DG). We investigated the E2-induced modulation of dendritic spines in male adult rat hippocampal slices by imaging Lucifer Yellow-injected DG granule cells. Treatments with 1 nM E2 increased the density of spines by approximately 1.4-fold within 2h. Spine head diameter analysis showed that the density of middle-head spines (0.4-0.5 MUm) was significantly increased. The E2-induced spine density increase was suppressed by blocking Erk MAPK, PKA, PKC and LIMK. These suppressive effects by kinase inhibitors are not non-specific ones because the GSK-3beta antagonist did not inhibit E2-induced spine increase. The ER antagonist ICI 182,780 also blocked the E2-induced spine increase. Taken together, these results suggest that E2 rapidly increases the density of spines through kinase networks that are driven by synaptic ER. PMID- 26122287 TI - Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats. AB - This article is part of a Special Issue "Parental Care". Since the first report of maternal care effects on DNA methylation in rats, epigenetic modifications of the genome in response to life experience have become the subject of intense focus across many disciplines. Oxytocin receptor expression varies in response to early experience, and both oxytocin signaling and methylation status of the oxytocin receptor gene (Oxtr) in blood have been related to disordered social behavior. It is unknown whether Oxtr DNA methylation varies in response to early life experience, and whether currently employed peripheral measures of Oxtr methylation reflect variation in the brain. We examined the effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus). Rats reared by "high" licking-grooming (HL) and "low" licking-grooming (LL) rat dams exhibited differences across study outcomes: LL offspring were more active in behavioral arenas, exhibited lower body mass in adulthood, and showed reduced corticosterone responsivity to a stressor. Oxtr DNA methylation was significantly lower at multiple CpGs in the blood of LL versus HL males, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region. Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in DNA methylation relative to these global patterns was not consistent across tissues. These results suggest that blood Oxtr DNA methylation may reflect early experience of maternal care, and that Oxtr methylation across tissues is highly concordant for specific CpGs, but that inferences across tissues are not supported for individual variation in Oxtr methylation. PMID- 26122289 TI - Estrogen involvement in social behavior in rodents: Rapid and long-term actions. AB - This article is part of a Special Issue ("Estradiol and cognition"). Estrogens have repeatedly been shown to influence a wide array of social behaviors, which in rodents are predominantly olfactory-mediated. Estrogens are involved in social behavior at multiple levels of processing, from the detection and integration of socially relevant olfactory information to more complex social behaviors, including social preferences, aggression and dominance, and learning and memory for social stimuli (e.g. social recognition and social learning). Three estrogen receptors (ERs), ERalpha, ERbeta, and the G protein-coupled ER 1 (GPER1), differently affect these behaviors. Social recognition, territorial aggression, and sexual preferences and mate choice, all requiring the integration of socially related olfactory information, seem to primarily involve ERalpha, with ERbeta playing a lesser, modulatory role. In contrast, social learning consistently responds differently to estrogen manipulations than other social behaviors. This suggests differential ER involvement in brain regions important for specific social behaviors, such as the ventromedial and medial preoptic nuclei of the hypothalamus in social preferences and aggression, the medial amygdala and hippocampus in social recognition, and the prefrontal cortex and hippocampus in social learning. While the long-term effects of ERalpha and ERbeta on social behavior have been extensively investigated, our knowledge of the rapid, non genomic, effects of estrogens is more limited and suggests that they may mediate some social behaviors (e.g. social learning) differently from long-term effects. Further research is required to compare ER involvement in regulating social behavior in male and female animals, and to further elucidate the roles of the more recently described G protein-coupled ERs, both the GPER1 and the Gq-mER. PMID- 26122290 TI - Neuropeptide Y administration reverses tricyclic antidepressant treatment resistant depression induced by ACTH in mice. AB - Depression is one of the most common mental disorders and a primary cause of disability. To better treat patients suffering this illness, elucidation of the underlying psychopathological and neurobiological mechanisms is urgently needed. Based on the above-mentioned evidence, we sought to investigate the effects of neuropeptide Y (NPY) treatment in tricyclic antidepressant treatment-resistant depression induced by adrenocorticotropic hormone (ACTH) administration. Mice were treated with NPY (5.84, 11.7 or 23.4mmol/MUl) intracerebroventricularly (i.c.v.) for one or five days. The levels of serum corticosterone, tryptophan (TRP), kynurenine (KYN), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and indoleamine 2,3-dioxygenase (IDO) activity in the hippocampus were analyzed. The behavioral parameters (depressive-like and locomotor activity) were also verified. This study demonstrated that ACTH administration increased serum corticosterone levels, KYN, 5-HIAA levels, IDO activity (hippocampus), immobility in the forced swimming test (FST) and the latency to feed in the novelty suppressed feeding test (NSFT). In addition, ACTH administration decreased the BDNF and NGF levels in the hippocampus of mice. NPY treatment was effective in preventing these hormonal, neurochemical and behavioral alterations. It is suggested that the main target of NPY is the modulation of corticosterone and neuronal plasticity protein levels, which may be closely linked with pharmacological action in a model of tricyclic antidepressant treatment-resistant depression. Thus, this study demonstrated a protective effect of NPY on the alterations induced by ACTH administration in mice, indicating that it could be useful as a therapy for the treatment of tricyclic antidepressant treatment resistant depression. PMID- 26122291 TI - The impact of luteinizing hormone and testosterone on beta amyloid (Abeta) accumulation: Animal and human clinical studies. AB - This article is part of a Special Issue "SBN 2014". Hormonal changes associated with ageing have been implicated in the pathogenesis of Alzheimer's disease (AD), the most common form of dementia. Reductions in serum testosterone and increases in luteinizing hormone (LH) are established AD risk factors for dementia in men and have important roles in modulating AD pathogenesis. One of the defining features of AD is the accumulation of amyloid-beta (Abeta) in the brain, which has a key role in the neurodegenerative cascade. Both testosterone and LH have been shown to modulate CNS Abeta accumulation in animal studies, and associations with cerebral amyloid load in human studies have supported this. The underlying mechanisms by which these hormones modulate Abeta accumulation and contribute to neurodegeneration are not completely understood, however they have been shown to regulate Abeta metabolism, enhance its clearance and alter the processing of its parent molecule, the amyloid precursor protein. This review will discuss underlying mechanisms by which testosterone and LH modulate Abeta and provide an update on therapeutic approaches targeting these hormones. PMID- 26122292 TI - Mice that are resistant to diet-induced weight loss have greater food anticipatory activity and altered melanocortin-3 receptor (MC3R) and dopamine receptor 2 (D2) gene expression. AB - Diet-induced weight loss varies considerably between individuals, but the mechanisms driving these individual differences remain largely unknown. Here we investigated whether key neuropeptides involved in the regulation of energy balance or reward systems were differentially expressed in mice that were prone or resistant to caloric restriction (CR) induced weight loss. Mice (n=30 males and n=34 females) were fed 70% of their own baseline ad libitum intake for 25days, after which their brains were collected and expression of various neuropeptides were investigated and compared between the 10 male and 10 female mice that showed the greatest (high weight loss, HWL) or lowest weight loss (LWL) (n=40 in total). HWL mice showed a differential neuropeptide profile to LWL in both sexes, characterised by increased expression of neuropeptide Y (NPY), agouti related peptide (AgRP), leptin receptor (ObRb), and melanocortin 3 receptor (MC3R) in the arcuate nucleus. No changes in the expression of fat mass and obesity related gene (FTO) or suppressor of cytokine signalling 3 (Socs3) were observed. Levels of dopamine D2 receptor were decreased in the nucleus accumbens in HWL compared to LWL mice. HWL mice showed a stronger increase in food anticipatory activity (FAA) in response to CR than LWL mice. These results indicate that the mice prone to diet-induced weight loss experienced greater hunger, potentially driving their elevated FAA. PMID- 26122293 TI - Fathering in rodents: Neurobiological substrates and consequences for offspring. AB - This article is part of a Special Issue "Parental Care". Paternal care, though rare among mammals, is routinely displayed by several species of rodents. Here we review the neuroanatomical and hormonal bases of paternal behavior, as well as the behavioral and neuroendocrine consequences of paternal behavior for offspring. Fathering behavior is subserved by many of the same neural substrates which are also involved in maternal behavior (for example, the medial preoptic area of the hypothalamus). While gonadal hormones such as testosterone, estrogen, and progesterone, as well as hypothalamic neuropeptides such as oxytocin and vasopressin, and the pituitary hormone prolactin, are implicated in the activation of paternal behavior, there are significant gaps in our knowledge of their actions, as well as pronounced differences between species. Removal of the father in biparental species has long-lasting effects on behavior, as well as on these same neuroendocrine systems, in offspring. Finally, individual differences in paternal behavior can have similarly long-lasting, if more subtle, effects on offspring behavior. Future studies should examine similar outcome measures in multiple species, including both biparental species and closely related uniparental species. Careful phylogenetic analyses of the neuroendocrine systems presumably important to male parenting, as well as their patterns of gene expression, will also be important in establishing the next generation of hypotheses regarding the regulation of male parenting behavior. PMID- 26122295 TI - A friend in need: Time-dependent effects of stress on social discounting in men. AB - Stress is often associated with a tend-and-befriend response, a putative coping mechanism where people behave generously towards others in order to invest in social relationships to seek comfort and mutual protection. However, this increase in generosity is expected to be directed only towards a delimited number of socially close, but not distant individuals, because it would be maladaptive to befriend everyone alike. In addition, the endocrinological stress response follows a distinct temporal pattern, and it is believed that tend-and-befriend tendencies can be observed mainly under acute stress. By contrast, the aftermath (>1h after) of stress is associated with endocrinological regulatory processes that are proposed to cause increased executive control and reduced emotional reactivity, possibly eliminating the need to tend-and-befriend. In the present experiment, we set out to investigate how these changes immediately and >1h after a stressful experience affect social-distance-dependent generosity levels, a phenomenon called social discounting. We hypothesized that stress has a time dependent effect on social discounting, with decisions made shortly after (20min), but not 90min after stress showing increased generosity particularly to close others. We found that men tested 20min after stressor onset indeed showed increased generosity towards close but not distant others compared to non stressed men or men tested 90min after stressor onset. These findings contribute to our understanding on how stress affects prosocial behavior by highlighting the importance of social closeness and the timing of stress relative to the decision as modulating factors in this type of decision making in men. PMID- 26122296 TI - Oral contraceptives and cognition: A role for ethinyl estradiol. AB - This article is part of a Special Issue "Estradiol and cognition". Estrogens have been seen to play a role in human cognitive abilities, but questions remain about the cognitive impact of ethinyl estradiol, which is contained in many oral contraceptives (OCs). Inconsistencies in past studies likely reflect small samples and heterogeneous groups of OC users. The aims of the present work were to examine OC effects on sex-typed spatial and verbal abilities by (a) comparing mental rotations and expressional fluency in normally-cycling (NC) women and men to OC users considered as a heterogeneous group and then to homogeneous groups of OC users created by classifying pills according to their active constituents, and (b) determining the relation between synthetic hormone doses in OCs and mental rotations and expressional fluency. Participants were 136 men, 93 NC women, and 148 OC users, including homogeneous monophasic (n = 55) and triphasic (n = 43) OC groups, aged 18 to 30 years. Significant effects of OC use were seen in homogeneous group comparisons but not when OC users were considered as a heterogeneous group. On mental rotations, men outperformed women, and monophasic OC users outperformed NC women. The latter difference may be attributable to estradiol, as ethinyl estradiol was inversely related to spatial ability among OC users and was lower in monophasic than in triphasic users. On expressional fluency, NC women and monophasic OC users outperformed men, and monophasic users outperformed triphasic users. Thus, results show the importance of ethinyl estradiol and of considering pill constituents when studying the cognitive effects of OCs. PMID- 26122294 TI - Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females. AB - This article is part of a Special Issue "Estradiol and cognition". Over the past 30 years, research has demonstrated that estrogens not only are important for female reproduction, but also play a role in a diverse array of cognitive functions. Originally, estrogens were thought to have only one receptor, localized exclusively to the cytoplasm and nucleus of cells. However, it is now known that there are at least three estrogen receptors (ERs): ERalpha, ERbeta and G-protein coupled ER1 (GPER1). In addition to being localized to nuclei, ERalpha and ERbeta are localized to the cell membrane, and GPER1 is also observed at the cell membrane. The mechanism through which ERs are associated with the membrane remains unclear, but palmitoylation of receptors and associations between ERs and caveolin are implicated in membrane association. ERalpha and ERbeta are mostly observed in the nucleus using light microscopy unless they are particularly abundant. However, electron microscopy has revealed that ERs are also found at the membrane in complimentary distributions in multiple brain regions, many of which are innervated by dopamine inputs and were previously thought to contain few ERs. In particular, membrane-associated ERs are observed in the prefrontal cortex, dorsal striatum, nucleus accumbens, and hippocampus, all of which are involved in learning and memory. These findings provide a mechanism for the rapid effects of estrogens in these regions. The effects of estrogens on dopamine dependent cognition likely result from binding at both nuclear and membrane associated ERs, so elucidating the localization of membrane-associated ERs helps provide a more complete understanding of the cognitive effects of these hormones. PMID- 26122298 TI - Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) and emotional processing - A behavioral and electrophysiological approach. AB - Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS) may have mood enhancement effects: higher DHEAS concentrations and DHEA/cortisol ratio have been related to lower depression scores and controlled trials of DHEA administration have reported significant antidepressant effects. The balance between DHEAS and DHEA has been suggested to influence brain functioning. We explored DHEAS, DHEA, cortisol, DHEA/cortisol and DHEAS/DHEA ratios relations to the processing of negative emotional stimuli at behavioral and brain levels by recording the electroencephalogram of 21 young women while performing a visual task with implicit neutral or negative emotional content in an audio-visual oddball paradigm. For each condition, salivary DHEA, DHEAS and cortisol were measured before performing the task and at 30 and 60min intervals. DHEA increased after task performance, independent of the implicit emotional content. With implicit negative emotion, higher DHEAS/DHEA and DHEA/cortisol ratios before task performance were related to shorter visual P300 latencies suggesting faster brain processing under a negative emotional context. In addition, higher DHEAS/DHEA ratios were related to reduced visual P300 amplitudes, indicating less processing of the negative emotional stimuli. With this study, we could show that at the electrophysiological level, higher DHEAS/DHEA and DHEA/cortisol ratios were related to shorter stimulus evaluation times suggesting less interference of the implicit negative content of the stimuli with the task. Furthermore, higher DHEAS/DHEA ratios were related to reduced processing of negative emotional stimuli which may eventually constitute a protective mechanism against negative information overload. PMID- 26122299 TI - Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults. AB - This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus. PMID- 26122297 TI - Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it? AB - This article is part of a Special Issue "Estradiol and cognition". Estrogens impact the organization and activation of the mammalian brain in both sexes, with sex-specific critical windows. Throughout the female lifespan estrogens activate brain substrates previously organized by estrogens, and estrogens can induce non transient brain and behavior changes into adulthood. Therefore, from early life through the transition to reproductive senescence and beyond, estrogens are potent modulators of the brain and behavior. Organizational, reorganizational, and activational hormone events likely impact the trajectory of brain profiles during aging. A "brain profile," or quantitative brain measurement for research purposes, is typically a snapshot in time, but in life a brain profile is anything but static--it is in flux, variable, and dynamic. Akin to this, the only thing continuous and consistent about hormone exposures across a female's lifespan is that they are noncontinuous and inconsistent, building and rebuilding on past exposures to create a present brain and behavioral landscape. Thus, hormone variation is especially rich in females, and is likely the destiny for maximal responsiveness in the female brain. The magnitude and direction of estrogenic effects on the brain and its functions depend on a myriad of factors; a "Goldilocks" phenomenon exists for estrogens, whereby if the timing, dose, and regimen for an individual are just right, markedly efficacious effects present. Data indicate that exogenously-administered estrogens can bestow beneficial cognitive effects in some circumstances, especially when initiated in a window of opportunity such as the menopause transition. Could it be that the age-related reduction in efficacy of estrogens reflects the closure of a late-in-life critical window occurring around the menopause transition? Information from classic and contemporary works studying organizational/activational estrogen actions, in combination with acknowledging the tendency for maximal responsiveness to cyclicity, will elucidate ways to extend sensitivity and efficacy into post-menopause. PMID- 26122300 TI - The importance of neural aromatization in the acquisition, recall, and integration of song and spatial memories in passerines. AB - This article is part of a Special Issue "Estradiol and cognition". In addition to their well-studied and crucial effects on brain development and aging, an increasing number of investigations across vertebrate species indicate that estrogens like 17beta-estradiol (E2) have pronounced and rapid effects on cognitive function. The incidence and regulation of the E2-synthesizing enzyme aromatase at the synapse in regions of the brain responsible for learning, memory, social communication and other complex cognitive processes suggest that local E2 production and action affect the acute and chronic activity of individual neurons and circuits. Songbirds in particular are excellent models for the study of this "synaptocrine" hormone provision given that aromatase is abundantly expressed in neuronal soma, dendrites, and at the synapse across many brain regions in both sexes. Additionally, songbirds readily acquire and recall memories in laboratory settings, and their stereotyped behaviors may be manipulated and measured with relative ease. This leads to a rather unparalleled advantage in the use of these animals in studies of the role of neural aromatization in cognition. In this review we describe the results of a number of experiments in songbird species with a focus on the influence of synaptic E2 provision on two cognitive processes: auditory discrimination reliant on the caudomedial nidopallium (NCM), a telencephalic region likely homologous to the auditory cortex in mammals, and spatial memory dependent on the hippocampus. Data from these studies are providing evidence that the local and acute provision of E2 modulates the hormonal, electrical, and cognitive outputs of the vertebrate brain and aids in memory acquisition, retention, and perhaps the confluence of memory systems. PMID- 26122302 TI - Neuroplasticity in the maternal hippocampus: Relation to cognition and effects of repeated stress. AB - This article is part of a Special Issue "Parental Care". It is becoming clear that the female brain has an inherent plasticity that is expressed during reproduction. The changes that occur benefit the offspring, which in turn secures the survival of the mother's genetic legacy. Thus, the onset of maternal motivation involves basic mechanisms from genetic expression profiles, to hormone release, to hormone-neuron interactions, all of which fundamentally change the neural architecture - and for a period of time that extends, interestingly, beyond the reproductive life of the female. Although multiple brain areas involved in maternal responses are discussed, this review focuses primarily on plasticity in the maternal hippocampus during pregnancy, the postpartum period and well into aging as it pertains to changes in cognition. In addition, the effects of prolonged and repeated stress on these dynamic responses are considered. The maternal brain is a marvel of directed change, extending into behaviors both obvious (infant-directed) and less obvious (predation, cognition). In sum, the far-reaching effects of reproduction on the female nervous system provide an opportunity to investigate neuroplasticity and behavioral flexibility in a natural mammalian model. PMID- 26122303 TI - Intermittent dosing of rapamycin maintains antiepileptogenic effects in a mouse model of tuberous sclerosis complex. AB - OBJECTIVE: Inhibitors of the mechanistic target of rapamycin (mTOR) pathway have antiepileptogenic effects in preventing epilepsy and pathologic and molecular mechanisms of epileptogenesis in mouse models of tuberous sclerosis complex (TSC). However, long-term treatment with mTOR inhibitors may be required to maintain efficacy and potentially has chronic side effects, such as immunosuppression. Attempts to minimize drug exposure will facilitate translational efforts to develop mTOR inhibitors as antiepileptogenic agents for patients with TSC. In this study, we tested intermittent dosing paradigms of mTOR inhibitors for antiepileptogenic properties in a TSC mouse model. METHODS: Western blot analysis of phosphorylation of S6 protein was used to assess the dose- and time-dependence of mTOR inhibition by rapamycin in control mice and conditional knockout mice with inactivation of the Tsc1 gene in glial fibrillary acidic protein (GFAP)-expressing cells (Tsc1(GFAP)CKO mice). Based on the Western blot studies, different dosing paradigms of rapamycin starting at postnatal day 21 were tested for their ability to prevent epilepsy or pathologic abnormalities in Tsc1(GFAP)CKO mice: 4 days of rapamycin only (4-infinity), 4 days on-24 days off (4-24), and 4 days on-10 days off (4-10). RESULTS: mTOR activity was inhibited by rapamycin in a dose-dependent fashion and recovered to baseline by about 10 days after the last rapamycin dose. The 4-10 and 4-24 dosing paradigms almost completely prevented epilepsy and the 4-10 paradigm inhibited glial proliferation and megalencephaly in Tsc1(GFAP)CKO mice. SIGNIFICANCE: Intermittent dosing of rapamycin, with drug holidays of more than 3 weeks, maintains significant antiepileptogenic properties in mouse models of TSC. These findings have important translational applications in developing mTOR inhibitors as antiepileptogenic agents in TSC patients by minimizing drug exposure and potential side effects. PMID- 26122304 TI - The influence of areas of worklife fit and work-life interference on burnout and turnover intentions among new graduate nurses. AB - AIM: To examine the relationships among the overall person-job match in the six areas of worklife, work-life interference, new nurses' experiences of burnout and intentions to leave their jobs. BACKGROUND: As a large cohort of nurses approaches retirement, it is important to understand the aspects of the nurses work-life that are related to turnover among new graduate nurses to address the nursing workforce shortage. METHODS: Secondary analysis of data collected in a cross-sectional survey of 215 registered nurses working in Ontario acute hospitals was conducted using structural equation modelling. RESULTS: The fit indices suggested a reasonably adequate fit of the data to the hypothesised model [chi(2) = 247, d.f. = 122, P = 0.001, chi(2) /d.f. = 2.32, Incremental Fit Index (IFI) = 0.954, Comparative Fit Index (CFI) = 0.953, Root Mean Square Error of Approximation (RMSEA) = 0.06]. Person-job match in six areas of worklife had a direct negative effect on burnout (emotional exhaustion and cynicism), which in turn had a direct positive effect on turnover intentions. Work-life interference also influenced turnover intentions indirectly through burnout. CONCLUSION: The study findings demonstrate that new graduate nurses' turnover intentions are a recurring problem, which could be reduced by improving nurses' working conditions. Retention of new graduate nurses could be enhanced by creating supportive working environments to reduce the susceptibility to workplace burnout, and ultimately, lower turnover intentions. IMPLICATIONS FOR NURSING MANAGEMENT: Managers must employ strategies to enhance workplace conditions that promote a person-job fit and work-life balance to improve retention of new graduate nurses, and, thereby, lessen the nursing shortage. PMID- 26122305 TI - The role of endoscopic ultrasonography in endoscopic debridement of walled-off pancreatic necrosis--A single center experience. AB - BACKGROUND: In recent years the significance of endoscopic ultrasonography (EUS) has increased. In our center we have also performed EUS-guided cystostomy since 2011. Earlier we had performed this procedure without EUS. Introduction of EUS in our hospital has inspired us to perform a retrospective analysis of the influence of EUS use on the risk of complications and the effectiveness of endoscopic treatment of patients with WOPN. METHODS: Between years 2001 and 2013 176 patients with symptomatic WOPN underwent endoscopic treatment in the Department of Gastroenterology and Hepatology of Medical University of Gdansk. The results and complications of treatment in relation to the use of EUS during drainage/debridement were compared retrospectively. RESULTS: 64 patients underwent EUS-guided drainage/debridement of WOPN (group 1). In the case of 112 patients endoscopic drainage/debridement was performed without EUS control (group 2). In group 1 therapeutic success was achieved in 60/64 (93.75%) patients in comparison to 104/112 (92.9%) patients in group 2 (P = 0.870). The mean duration of drainage/debridement in both groups was 25 days - 4-173 days in group 1 and 4 112 days in group 2 (P = 0.519). The complications of endotherapy occurred in 9/64 (14.06%) patients from group 1 in comparison to 29/112 (25.9%) patients from group 2 (P = 0.047). CONCLUSIONS: In our study the use of EUS during endoscopic drainage/debridement of WOPN significantly reduced the number of procedure related complications, mainly gastrointestinal bleeding. However, it had no influence on the duration of treatment or the effectiveness of therapy. PMID- 26122306 TI - Minnelide, a novel drug for pancreatic and liver cancer. AB - BACKGROUND: Pancreatic cancer is the 10th leading cause of all new cancer cases for men and the fourth leading cause of death across genders, having very poor prognosis and survival rates. The current standard of care Gemcitabine fails to add any survival benefit for this disease (www.cancer.gov). Though the incidence of pancreatic cancer is found to be higher in developed countries, the aggressive biology of the cancer, its high rate of recurrence and chemo-resistance make it a formidable disease in all parts of the globe. Hepatocellular carcinoma (HCC) or liver cancer, on the other hand affects almost 750,000 people world wide with 84% of the cases coming from underdeveloped or developing countries RESULTS: Our studies show that Minnelide, a water soluble pro-drug of triptolide (active compound from a chinese herb) is very effective against a number of malignant diseases. CONCLUSION: The current study discusses the efficacy of this compound in pancreatic and liver cancer. PMID- 26122301 TI - Common and divergent psychobiological mechanisms underlying maternal behaviors in non-human and human mammals. AB - Maternal interactions with young occupy most of the reproductive period for female mammals and are absolutely essential for offspring survival and development. The hormonal, sensory, reward-related, emotional, cognitive and neurobiological regulators of maternal caregiving behaviors have been well studied in numerous subprimate mammalian species, and some of the importance of this body of work is thought to be its relevance for understanding similar controls in humans. We here review many of the important biopsychological influences on maternal behaviors in the two best studied non-human animals, laboratory rats and sheep, and directly examine how the conceptual framework established by some of the major discoveries in these animal "models" do or do not hold for our understanding of human mothering. We also explore some of the limits for extrapolating from non-human animals to humans. We conclude that there are many similarities between non-human and human mothers in the biological and psychological factors influencing their early maternal behavior and that many of the differences are due to species-characteristic features related to the role of hormones, the relative importance of each sensory system, flexibility in what behaviors are exhibited, the presence or absence of language, and the complexity of cortical function influencing caregiving behaviors. PMID- 26122308 TI - Management of hypertrophic nonunion with failure of internal fixation by distraction osteogenesis. AB - INTRODUCTION AND AIM: Distraction osteogenesis is employed in the management of hypertrophic nonunion associated with angular deformity and shortening. This study was aimed at evaluating the outcomes of Ilizarov apparatus without bone graft or open osteotomy in cases of hypertrophic nonunion not responding to treatment with internal fixation. METHODS: We retrospectively reviewed the data of 12 patients (mean age, 46.5 years) treated for hypertrophic nonunion at our institution. All patients had two-plane angular deformities (mean, 19 degrees and 23.5 degrees in sagittal and frontal plane, respectively) and limb-length discrepancy (mean, 3.8cm). The Ilizarov apparatus was used to simultaneously treat the nonunion, malalignment, and limb-length discrepancy. RESULTS: The mean follow-up duration after the removal of the apparatus was 42 months. In all cases, bone union had been achieved within an average of 8 months after a single surgery, without the need for any additional procedure. Additionally, none of the patients had recurrence of limb-length discrepancy or malalignment during the follow-up period. Complications of superficial pin-tract infections and mild Achilles tendon contracture were observed, but they resolved over time. All patients were satisfied with the outcome of the surgery. CONCLUSION: Patients with hypertrophic nonunion associated with internal fixation failure can be treated by using the Ilizarov apparatus, thereby eliminating the need for bone graft or open osteotomy. Distraction osteogenesis appears to be effective as a minimally invasive percutaneous procedure in the treatment of hypertrophic nonunion with deformity and shortening. PMID- 26122307 TI - Health-related quality of life in young adults with congenital central hypoventilation syndrome due to PHOX2B mutations: a cross-sectional study. AB - BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disease due to PHOX2B mutations. CCHS patients suffer from many autonomic disorders, dominated clinically by defective ventilatory automatisms. From birth, the life of CCHS patients depends on ventilatory support during sleep, involving a high burden of care. Whether or not this impairs the quality of life of these patients during adulthood remains unknown. METHODS: We applied the medical outcome study short form-36 (SF-36) to 12 CCHS patients aged 15-33 (9 women) at the time of their passage from pediatric to adult care. Scores for the SF-36 dimensions were compared to the age- and gender-matched French reference population after transformation into standardized Z-scores. The SF-36 physical component summary score (PCS) and mental component summary score (MCS) were compared to American reference values. RESULTS: Median Z-scores were significantly different from zero for PF (physical functioning, p = 0.020) and GH (general health perception, p = 0.0342) and for PCS (p = 0.020). The other physical dimensions (RP, role limitation due to physical function; BP, bodily pain) and the mental dimensions (VT, vitality; SF, social functioning; RE, role limitation due to emotional function; MH, mental health) and MCS were not altered. CONCLUSIONS: We conclude that, despite the physical constraints imposed by CCHS and its anxiogenic nature, this disease is associated with an impairment of health-related quality of life in young adults that remains moderate. Whatever the underlying explanations, these results convey hope to parents with a child diagnosed with CCHS and for patients themselves. PMID- 26122309 TI - Codon-optimized fluorescent mTFP and mCherry for microscopic visualization and genetic counterselection of streptococci and enterococci. AB - Despite the powerful potential of fluorescent proteins for labeling bacteria, their use has been limited in multi-species oral biofilm models. Fermentative metabolism by streptococcal species that initiate biofilm colonization results in an acidic, reduced microenvironment that may limit the activities of some fluorescent proteins which are influenced by pH and oxygen availability. The need to reliably distinguish morphologically similar strains within biofilms was the impetus for this work. Teal fluorescent protein (mTFP1) and red fluorescent protein (mCherry) were chosen because their fluorescent properties made them promising candidates. Since tRNA availability has been implicated in efficient translation of sufficient quantities of protein for maximum fluorescence, a streptococcal codon optimization approach was used. DNA was synthesized to encode either protein using codons most frequently used in streptococci; each coding region was preceded by an engineered ribosomal binding site and restriction sites for cloning a promoter. Plasmids carrying this synthesized DNA under control of the Streptococcus mutans lactate dehydrogenase promoter conferred fluorescence to nine representative streptococcal and two Enterococcus faecalis strains. Further characterization in Streptococcus gordonii showed that mTFP1 and mCherry expressions could be detected in cells grown planktonically, in biofilms, or in colonies on agar when expressed on an extrachromosomal plasmid or in single copy integrated into the chromosome. This latter property facilitated counterselection of chromosomal mutations demonstrating value for bacterial strain construction. Fluorescent and non-fluorescent bacteria were distinguishable at acidic pH. These codon-optimized versions of mTFP1 and mCherry have promising potential for use in multiple experimental applications. PMID- 26122310 TI - A novel nucleic lateral flow assay for screening of PHA-producing haloarchaea. AB - Polyhydroxyalkanoates (PHAs) are important for biodegradable plastic production, and prokaryotes play a very important role in PHA production. PHA synthase is a key enzyme for the polymerization of PHAs. There are four classes of PHA synthase. The phaC gene is necessary for the production of all classes of PHA synthase, whereas the phaE gene is necessary for the production of class III PHA synthase. This gene is a biomarker for microorganisms that contain class III PHA synthase, such as haloarchaea. Standard techniques for screening of PHA-producing haloarchaea require time for culturing and have poor specificity and sensitivity. Thus, the phaE biosensor was developed to overcome these issues. PCR and DNA lateral flow biosensor techniques were combined for construction of the phaE biosensor. The phaE biosensor has a high specificity for PHA-producing haloarchaea. The lowest amount of genomic DNA of Haloquadratum walsbyi DSM 16854 that the phaE gene could be detected by the biosensor was approximately 250 fg. The phaE biosensor can be applied for screening of PHA-producing haloarchaea from environmental samples. The phaE biosensor is easy to handle and dispose. For screening PHA-producing haloarchaea, the phaE biosensor requires less time and costs less than the standard methods. PMID- 26122311 TI - Effect of mevalonic acid on cholesterol synthesis in bovine intramuscular and subcutaneous adipocytes. AB - Mevalonic acid (MVA) is a key material in the synthesis of cholesterol; indeed, intracellular cholesterol synthesis is also called the mevalonic acid pathway. 3 Hydroxy-3-methylglutaryl-CoA reductase (HMGR) is an essential enzyme in cholesterol biosynthesis. This study suggests that MVA may play an important role in the differentiation of bovine adipose tissue in vivo. We investigated differential mRNA expression in bovine intramuscular preadipocytes (BIPs) and bovine subcutaneous preadipocytes (BSPs) by culturing cells from the longissimus dorsi muscle and subcutaneous fat tissues of Luxi yellow cattle. The morphology of lipid accumulation of bovine preadipocytes was detected by Oil Red O staining, and total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), and high density lipoprotein cholesterol (HDLC) levels were measured. Temporospatial expression of HMGR was investigated by real-time quantitative polymerase chain reaction (PCR). The TC, LDLC, and HDLC content did not significantly differ over time but increased slowly with increasing MVA concentration. HMGR expression increased over time and with increasing concentrations of MVA. MVA increased adipose cell proliferation in a dose-dependent and time-dependent manner. MVA stimulated HMGR expression in two cell types and its influence on adipocyte differentiation. PMID- 26122312 TI - Dietary metal toxicity to the marine sea hare, Aplysia californica. AB - Metal pollution from anthropogenic inputs is a concern in many marine environments. Metals accumulate in tissue and in excess cause toxicity in marine organisms. This study investigated the accumulation and effects of dietary metals in a macroinvertebrate. The green seaweed, Ulva lactuca and the red seaweed, Agardhiella subulata were each concurrently exposed to two concentrations (100 or 1000 MUg/L) of five metals (Cu, Ni, Pb, Cd, and Zn). Additionally, U. lactuca was exposed to 10 MUg/L of the metal mixture as well as 10 or 100 MUg/L of each metal individually for 48 h. The seaweeds were then used as food for the sea hare, Aplysia californica for two to three weeks depending on the exposure concentration. Body mass of A. californica was measured weekly, and at the end of the exposure duration, metal concentrations were quantified in dissected organs (mouth, esophagus, crop, gizzard, ovotestis, heart, hepatopancreas, gill, and the carcass). Metal distribution and accumulation in the organs of A. californica varied with the metal. A. californica fed the metal-exposed diets had significantly reduced body weight by the end of the exposure periods, as compared to controls; however, differences were observed in the extent of growth reductions, dependent on exposure concentration, duration, and exposure regime (metal mixture versus individual metal-exposed diet). Metal mixture diets decreased A. californica growth more so than comparable individual metal diets, despite more metal accumulating in the individual metal diets. Additionally, Zn- and Cu-contaminated algal diets decreased control-normalized growth of A. californica significantly more than comparable Cd-, Pb-, or Ni-contaminated diets. The seaweed diets in this study contained environmentally relevant tissue metal burdens. Therefore, these results have implications for metals in marine systems. PMID- 26122313 TI - Metal and metallothionein distribution in different tissues of the Mediterranean clam Venerupis philippinarum during copper treatment and detoxification. AB - Filter feeding animals can accumulate large amount of contaminants in their body through particles filtered from seawater. In particular, copper is interesting since it plays important roles as co-factor of numerous proteins but its toxicity is well established, also because it can readily generate free radicals or oxidize cellular components through their redox activity. Its availability is tightly regulated within cells: it is immediately transferred to metallothionein (MT) that in turn provides efficient and specific mechanisms for its intracellular storage and transport. The aim of this study was to evaluate the acute effect of sublethal copper concentrations in Venerupis philippinarum, by studying the kinetics of copper, zinc (for its interactions at the sites of intake or elimination with the accumulation of other essential and not essential trace metals) and metallothionein accumulation under laboratory conditions. The time-course of metal accumulation/elimination is similar in digestive gland and gills and importantly it is dose-dependent. Both copper and zinc increase slowly within cells, reaching a maximum concentration at the end of the exposure period. During the detoxification period, the metal levels in digestive gland and gills rapidly decrease, with different kinetics in the two tissues. Positive correlations between metallothionein accumulation and copper or zinc concentrations have been verified in both treated groups. The obtained data demonstrated the involvement of MTs in detoxification strategies after a recovery period in clean seawater. PMID- 26122314 TI - Unmet Health Care Service Needs of Children With Disabilities in Penang, Malaysia. AB - Information on unmet health care needs reveal problems that are related to unavailability and inaccessibility of services. The study objectives were to determine the prevalence, and the reasons for unmet service needs among children with disabilities in the state of Penang, Malaysia. Caregivers of children with disabilities aged 0 to 12 years registered with the Penang Social Welfare Department in 2012 answered a self-administered mailed questionnaire. A total of 305 questionnaires were available for analysis (response rate 37.9%). Services that were very much needed and yet highly unmet were dental services (49.6% needed, 59.9% unmet), dietary advice (30.9% needed, 63.3% unmet), speech therapy (56.9% needed, 56.8% unmet), psychology services (25.5% needed, 63.3% unmet), and communication aids (33.0% needed, 79.2% unmet). Access problems were mainly due to logistic issues and caregivers not knowing where to obtain services. Findings from this study can be used to inform strategies for service delivery and advocacy for children with disabilities in Penang, Malaysia. PMID- 26122315 TI - Carbene insertion into a P-H bond: parent phosphinidene-carbene adducts from PH3 and bis(phosphinidene)mercury complexes. AB - PH3 reacts with the in situ generated N-heterocyclic carbene DippNHC* (DippNHC* = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene) to give the phosphanyl imidazolidine [(Dipp)NHC*-H]-[PH2]. Upon treatment with an ortho-quinone, [(Dipp)NHC*-H]-[PH2] is dehydrogenated to give the parent phosphinidene-carbene adduct (Dipp)NHC*[double bond, length as m-dash]PH. Alternative routes to [(Dipp)NHC*-H]-[PH2] and (Dipp)NHC*[double bond, length as m-dash]PH employ NaPH2 and (TMS)3P7 (TMS = trimethylsilyl), respectively, as phosphorus sources. The adduct (Dipp)NHC*[double bond, length as m-dash]PH and the related adduct (Dipp)NHC[double bond, length as m-dash]PH ((Dipp)NHC = bis(2,6 diisopropylphenyl)imidazol-2-ylidene) possessing an unsaturated NHC backbone both react with HgCl2 to give the bis(carbene-phosphinidenyl) complexes [((Dipp)NHC*[double bond, length as m-dash]P)2Hg] and [((Dipp)NHC[double bond, length as m-dash]P)2Hg]. PMID- 26122316 TI - Optimizing Eating Performance for Older Adults With Dementia Living in Long-term Care: A Systematic Review. AB - BACKGROUND: Review of research to date has been focusing on maintaining weight and nutrition with little attention on optimizing eating performance. OBJECTIVE: To evaluate the effectiveness of interventions on eating performance for older adults with dementia in long-term care (LTC). METHODS: A systematic review was performed. Five databases including Pubmed, Medline (OVID), EBM Reviews (OVID), PsychINFO (OVID), and CINAHL (EBSCOHost) were searched between January 1980 and June 2014. Keywords included dementia, Alzheimer, feed(ing), eat(ing), mealtime(s), oral intake, autonomy, and intervention. Intervention studies that optimize eating performance and evaluate change of self-feeding or eating performance among older adults (>=65 years) with dementia in LTC were eligible. Studies were screened by title and abstract, and full texts were reviewed for eligibility. Eligible studies were classified by intervention type. Study quality was accessed using the Quality Assessment Tool for Quantitative Studies, and level of evidence using the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence. RESULTS: Eleven intervention studies (five randomized controlled trials [RCTs]) were identified, and classified into four types: training program, mealtime assistance, environmental modification, and multicomponent intervention. The quality of the 11 studies was generally moderate (four studies were rated as strong, four moderate, and three weak in quality), with the main threats as weak designs, lack of blinding and control for confounders, and inadequate psychometric evidence for measures. Training programs targeting older adults (Montessori methods and spaced retrieval) demonstrated good evidence in decreasing feeding difficulty. Mealtime assistance offered by nursing staff (e.g., verbal prompts and cues, positive reinforcement, appropriate praise and encouragement) also showed effectiveness in improving eating performance. LINKING EVIDENCE TO ACTION: This review provided preliminary support for using training and mealtime assistance to optimize eating performance for older adults with dementia in LTC. Future effectiveness studies may focus on training nursing caregivers as interventionists, lengthening intervention duration, and including residents with varying levels of cognitive impairment in diverse cultures. The effectiveness of training combined with mealtime assistance may also be tested to achieve better resident outcomes in eating performance. PMID- 26122317 TI - Investigating the costs of major and minor cycling crashes in Tasmania, Australia. AB - OBJECTIVE: A pilot study to estimate the societal costs of cycling crashes in Tasmania. METHODS: A telephone-based questionnaire collected information on demographics, cycling habits and details of major and minor crashes. Costs were estimated from medical resource consumption, lost work and leisure time. RESULTS: The survey was completed by 136 cyclists. Participants reported 59 major crashes in five years preceding the interview and 27 minor crashes in 12 months. Mean (standard deviation) costs/major crash were $12,499 ($14,301), including direct medical costs $2,569 ($4,523), direct non-medical costs $372 ($728), indirect costs of $6,027 ($10,092) and costs of lost leisure time $3,531 ($7,062). Costs/minor crashes were $632 ($795), including direct non-medical costs of $225 ($601), productivity losses of $117 ($210) and costs of lost leisure time $290 (622). Total annual costs of major cycling crashes in Tasmania were $4,239,097 ($4,850,255). CONCLUSIONS: Indirect costs and costs due to lost leisure time are major contributors to the total societal costs. The comprehensive quantification of costs of crashes will inform decision makers formulating policies that improve the safety of cyclists leading to reductions in the economic burden on society. PMID- 26122318 TI - An Interfacial Europium Complex on SiO2 Nanoparticles: Reduction-Induced Blue Emission System. AB - In this study, Eu-coated SiO2 nanoparticles have been prepared, consisting of an interfacial complex of Eu and 1,10-phenanthroline (phen) at the solid surfaces of the SiO2/Eu nanostructures. The as-prepared SiO2/Eu/phen nanoparticles exhibits sharp red emission via energy transfer from the phen to the Eu(III). After sintering at 200 degrees C in air, the emission is tuned from red to blue. The blue emission is originated from Eu(II). This reduction-induced emissive phenomenon resulted from the electron-donating environment created by the surrounding phen and SiO2, which is the first reported fabrication of a stable Eu(II)-based emissive material using mild conditions (reaction in air and at low temperature) and an organic-inorganic hybrid nanostructure. The existence of two different stable oxidation states with characteristic emissions, blue emissive Eu(II) and red emissive Eu(III), suggests significant potential applications as novel luminescent materials with inorganic-organic hybrid structures. PMID- 26122320 TI - Parathyroid function: Key role for dicer-dependent miRNAs. PMID- 26122321 TI - Closing the NET on impaired wound healing in diabetes mellitus. PMID- 26122322 TI - Paracetamol-induced endocrine disruption in human fetal testes. PMID- 26122319 TI - Cognitive and autonomic determinants of energy homeostasis in obesity. AB - Obesity ensues from an imbalance between energy intake and expenditure that results from gene-environment interactions, which favour a positive energy balance. A society that promotes unhealthy food and encourages sedentary lifestyle (that is, an obesogenic environment) has become a major contributory factor in excess fat deposition in individuals predisposed to obesity. Energy homeostasis relies upon control of energy intake as well as expenditure, which is in part determined by the themogenesis of brown adipose tissue and mediated by the sympathetic nervous system. Several areas of the brain that constitute cognitive and autonomic brain systems, which in turn form networks involved in the control of appetite and thermogenesis, also contribute to energy homeostasis. These networks include the dopamine mesolimbic circuit, as well as the opioid, endocannabinoid and melanocortin systems. The activity of these networks is modulated by peripheral factors such as hormones derived from adipose tissue and the gut, which access the brain via the circulation and neuronal signalling pathways to inform the central nervous system about energy balance and nutritional status. In this Review, I focus on the determinants of energy homeostasis that have emerged as prominent factors relevant to obesity. PMID- 26122323 TI - The course of dry eye after phacoemulsification surgery. AB - BACKGROUND: The aim of this retrospective study was to evaluate the course of dry eye syndrome after phacoemulsification surgery. METHODS: One hundred and ninety two eyes of 96 patients (30 males, 66 females) with chronic dry eye syndrome and cataract, who had undergone phacoemulsification surgery were enrolled in this study. RESULTS: Their mean age was 68.46 +/- 8.14 standard deviation (SD) (range 56-83) years . Thirty of them (31 %) were males and 66 (69 %) were females. Ocular Surface Disease Index (OSDI) questionnaire scores increased postoperatively, but arrived preoperative levels at the end of 3rd month following the surgery. Fluorescein staining patterns according to Oxford Schema got worse postoperatively, however after postoperative 3rd month they got better and resembled preoperative patterns. The mean postoperative 1st day, 1st week and 1st month Break-up Time (BUT) values were significantly lower than preoperative BUT value (P < 0.001, P < 0.001, P < 0.001), however 3rd month, 6th month, 1st year and 2nd year values were not significantly different from preoperative value (P = 0.441, P = 0.078, P = 0.145, P = 0.125). The mean postoperative 1st day, 1st week and 1st month Schirmer Test 1 (ST1) values were significantly lower than preoperative ST1 value (P < 0.001, P < 0.001, P < 0.001), however 3rd month, 6th month, 1st year and 2nd year values were not significantly different from preoperative value (P = 0.748, P = 0.439, P = 0.091, P = 0.214). CONCLUSION: Phacoemulsification surgery may aggravate the signs and symptoms of dry eye and affect dry eye test values in chronic dry eye patients in short-term. However, in long-term, signs and symptoms of dry eye decrease and dry eye test values return to preoperative values. PMID- 26122324 TI - Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm. AB - A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral artery (PCA) aneurysm. This aneurysm was successfully treated by endovascular coil sacrifice of the affected segment of the PCA. The patient made an excellent recovery with no significant residual neurologic deficit. PMID- 26122325 TI - Transvenous sclerotherapy of a large symptomatic orbital venous varix using a microcatheter balloon and bleomycin. AB - An orbital venous varix is rare and can present with diplopia, proptosis, or hemorrhage. Treatment can be challenging, especially if the varix is in a posterior location within the orbit, since surgical exposure becomes difficult. A few case reports have been published describing transcatheter embolization of an orbital varix with coils, direct percutaneous injection of n-butyl cyanoacrylate glue, and the percutaneous injection of bleomycin. We present a case of a symptomatic orbital venous varix of the left inferior ophthalmic vein successfully treated with transvenous endovascular sclerotherapy using a microcatheter balloon and bleomycin. PMID- 26122326 TI - Covered stents for exclusion of iatrogenic common carotid artery-internal jugular vein fistula and brachiocephalic artery pseudoaneurysm. AB - Covered stents have rarely been used in neuroendovascular procedures. We report the case of a 74-year-old woman with a complex iatrogenic vascular injury from attempted insertion of a hemodialysis catheter: concurrent brachiocephalic artery pseudoaneurysm and common carotid artery to internal jugular vein fistula. Both lesions were excluded successfully by using two balloon-expandable covered stents with a satisfactory short-term clinical and angiographic outcome. PMID- 26122328 TI - Revision on Renal Sympathetic Ablation in the Treatment of Resistant Hypertension. AB - INTRODUCTION: Hypertension is one of the most prevalent diseases in the world, with about 1 billion people affected and a possible increase to 1.5 billion by 2025. Despite advances in treatment, a proportion of patients remain resistant to conventional treatment and uncontrolled, and this can adversely affect future cardiovascular events and mortality. This alarming growth is already reflected in an important public health problem and one of the largest economic burdens of health, requiring new approaches and development of different strategies to fight this problem. OBJECTIVES: This review will focus on the definition of resistant hypertension and its etiology, as well as in contemporary evidence supporting the usefulness of renal sympathetic denervation while addressing current and emerging devices, potential treatment indications in the future and unresolved issues that need to be addressed before renal sympathetic denervation can be adopted not only as a last resort exclusively for resistant hypertension. Finally an evaluation algorithm for patients with resistant hypertension which should be implemented before the execution of this technique will be proposed. RESULTS: Renal sympathetic denervation is a technique that possibly could have future implications in the population with hypertension, especially those with true resistant hypertension. This technique aims to reduce the renal sympathetic activation (a component in the pathophysiology of hypertension) through the destruction of the renal sympathetic nerves located in the adventitia of the renal arteries. There are several catheters that can be used; each with its specifications and therefore their selection should be made individually depending on the profile of the patient. However, a detailed pre-procedure evaluation is extremely important to exclude the large percentage of individuals with uncontrolled hypertension due to several factors that make it impossible to control blood pressure, but are likely to be corrected and as such should be treated first. CONCLUSION: Several studies have demonstrated the efficacy and safety both in resistant hypertension as in other co-morbidities. However, there is no marker to evaluate the effectiveness of this technique, neither a robust predictor of a stronger response in certain patients. Additionally there are several factors that seem to influence various parameters related to this technique. Therefore there is a need for additional studies to consolidate the data existing on the renal sympathetic denervation. PMID- 26122329 TI - Vascular Endothelial Primary Cilia: Mechanosensation and Hypertension. AB - Primary cilia are sensory organelles that extend from the cell surface and sense extracellular signals. Endothelial primary cilia protruding from the inner surface of blood vessel walls sense changes in blood flow and convert this mechanosensation into an intracellular biochemical/molecular signal, which triggers a cellular response. Primary endothelial cilia dysfunction may contribute to the impairment of this response and thus be directly implicated in the development of vascular abnormalities such as hypertension and aneurysms. Using both in vitro techniques as well as in vivo animal models, we and others have investigated fluid flow mechanosensory functions of endothelial cilia in cultured cells, animal models and autosomal dominant polycystic kidney disease (ADPKD) patients. More in-depth studies directed at identification of the mechanisms of fluid flow sensing will further enhance our knowledge of cilia dependent vascular pathology. Although the current treatments aimed at treating the cardiovascular symptoms in ADPKD patients successfully slowed the progression of cyst growth, there is growing evidence which suggests that drugs which interfere with primary cilia function or structure could reduce cardiovascular complications in ADPKD. This review is to summarize the most recent studies on primary endothelial cilia function in the vascular system and to present primary cilia as a novel therapeutic target for vascular hypertension. PMID- 26122330 TI - Corrigendum: Role of Ran-regulated nuclear-cytoplasmic trafficking of pVHL in the regulation of microtubular stability-mediated HIF-1alpha in hypoxic cardiomyocytes. PMID- 26122331 TI - High-speed, high-resolution, multielemental laser ablation-inductively coupled plasma-time-of-flight mass spectrometry imaging: part I. Instrumentation and two dimensional imaging of geological samples. AB - Low-dispersion laser ablation (LA) has been combined with inductively coupled plasma-time-of-flight mass spectrometry (ICP-TOFMS) to provide full-spectrum elemental imaging at high lateral resolution and fast image-acquisition speeds. The low-dispersion LA cell reported here is capable of delivering 99% of the total LA signal within 9 ms, and the prototype TOFMS instrument enables simultaneous and representative determination of all elemental ions from these fast-transient ablation events. This fast ablated-aerosol transport eliminates the effects of pulse-to-pulse mixing at laser-pulse repetition rates up to 100 Hz. Additionally, by boosting the instantaneous concentration of LA aerosol into the ICP with the use of a low-dispersion ablation cell, signal-to-noise (S/N) ratios, and thus limits of detection (LODs), are improved for all measured isotopes; the lowest LODs are in the single digit parts per million for single shot LA signal from a 10-MUm diameter laser spot. Significantly, high sensitivity, multielemental and single-shot-resolved detection enables the use of small LA spot sizes to improve lateral resolution and the development of single shot quantitative imaging, while also maintaining fast image-acquisition speeds. Here, we demonstrate simultaneous elemental imaging of major and minor constituents in an Opalinus clay-rock sample at a 1.5 MUm laser-spot diameter and quantitative imaging of a multidomain Pallasite meteorite at a 10 MUm LA-spot size. PMID- 26122332 TI - The complete plastid genome of Bunge's pine Pinus bungeana (Pinaceae). AB - The complete nucleotide sequence of Bunge's pine Pinus bungeana Zucc. ex Endl. chloroplast genome (cp DNA) was determined in this study. The cpDNA was 117 861 bp in length, containing a pair of 475 bp inverted repeat regions (IRa and IRb), which were separated by large and small single copy regions (LSC and SSC) of 65 373 and 51 538 bp, respectively. The cpDNA contained 111 genes, including 71 protein-coding genes (71 PCG species), 4 ribosomal RNA genes (4 rRNA species) and 36 tRNA genes (32 tRNA species). In these genes, 13 harbored a single intron and 1 (ycf3) contained a couple of introns. The overall AT content of Bunge's pine cpDNA is 61.2%, while the corresponding values of the LSC, SSC and IR regions are 61.9%, 60.2% and 62.5%, respectively. A phylogenetic reconstruction based on the maximum parsimony analysis suggested that all the sampled Pinus species clustered a monophyletic clade and have a high bootstrap support, and the cpDNA of P. bungeana is closely related to that of congeneric P. gerardiana. PMID- 26122333 TI - Complete mitogenome of a variegated racerunner, Eremias vermiculata, from north of Tianshan Mountains, Xinjiang, China. AB - The complete mitochondrial genome was determined from a variegated racerunner, Eremias vermiculata, which was collected from north of Tianshan Mountains, Xinjiang, China. The mitogenome sequence was 19,494 bp in size, containing 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a control region (D-loop), which is similar to the typical mtDNA of vertebrates. All the protein-coding genes in E. vermiculata were distributed on the H-strand, except the ND6 gene and eight tRNA genes, which were encoded on the L-strand. The mitogenome sequence herein will provide fundamental data for further investigating the phylogeographical pattern of E. vermiculata, along with testing the barrier effect of the Tianshan Mountains to gene flow. A preliminary phylogenetic inference has been implemented with five racerunner species and several other related lacertid species. PMID- 26122334 TI - The phylogenetic position of the roughskin skate Dipturus trachyderma (Krefft & Stehmann, 1975) (Rajiformes, Rajidae) inferred from the mitochondrial genome. AB - The complete mitochondrial genome of the roughskin skate Dipturus trachyderma is described from 1 455 724 sequences obtained using Illumina NGS technology. Total length of the mitogenome was 16 909 base pairs, comprising 2 rRNAs, 13 protein coding genes, 22 tRNAs and 2 non-coding regions. Phylogenetic analysis based on mtDNA revealed low genetic divergence among longnose skates, in particular, those dwelling the continental shelf and slope off the coasts of Chile and Argentina. PMID- 26122335 TI - The complete mitochondrial genome of the hybrid of Pagrus major (?) * Acanthopagrus schlegelii (?). AB - The complete mitochondrial sequence of the hybrid from red bream (Pagrus major ?) * black porgy (Acanthopagrus schlegelii ?) was firstly determined by using the PCR-based method. The total length of the mitogenome genes of the hybrid was 17 028 bp in accordance with red bream, and it contained 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and one control regions. Compared with the complete mitochondrial genome of its parents, the results showed that the hybrid of P. major (?) * A. schlegelii (?) was consistent with a maternal inheritance. All protein initiation codons are ATG, except for COX1 that begins with GTG. The complete mitogenome of the hybrid of P. major (?) * A. schlegelii (?) provides an important data set for the exploration of mitochondrial inheritance mechanism. PMID- 26122336 TI - The complete mitochondrial genome of Galeruca daurica (Joannis) (Coleoptera: Chrysomelidae). AB - Galeruca daurica (Joannis) (Coleoptera: Chrysomelidae) is one of important pests in the Inner Mongolia grasslands. The complete mitochondrial genome was sequenced. The genome is 16 615 bp long, with an AT content of 78.1%, containing 37 typical animal mitochondrial genes and an AT-rich region. All 13 PCGs share the start codon ATN, and the usual termination codons (TAA and TAG) are found from 13 protein-coding genes, except for COI, COII, and ND4 (T). All the 22 typical animal tRNA genes are found in G. daurica mt-genome, and most of the tRNAs could be folded into the classic cloverleaf secondary structure except for tRNA-Ser (AGN), which lacks the dihydrouracil (DHU) stem. The sizes of the large ribosomal RNA genes are 1276 bp long and small ribosomal RNA genes are 747 bp long. The AT content of the AT-rich region is 79.0%. Phylogenetic analysis supports that the coleopteran insects from the same family cluster in the same group, and Chrysomelidae and Tenebrionidae are basal to the Cerambycidae. Galeruca daurica has a closest relationship with Diabrotica barberi and Diabrotica virgifera. PMID- 26122337 TI - Complete mitochondrial genomes for Icelus spatula, Aspidophoroides olrikii and Leptoclinus maculatus: pan-Arctic marine fishes from Canadian waters. AB - Three Arctic marine fishes Icelus spatula, Aspidophoroides olrikii and Leptoclinus maculatus have been identified as target species for investigating the effects of ocean warming on population patterns in high-latitude marine habitats around Canada. In preparation for this research, we have resolved whole mitochondrial genome sequences of 16 384, 17 200 and 16 384 bp for each species, respectively. GC content for each species was 47.5%, 44.2% and 45.3%, respectively. Mitogenome gene composition included 13 protein-encoding genes, 2 rRNA and 22 tRNA genes, for I. spatula and L. maculatus, consistent with other teleosts. Only 20 tRNA genes were annotated for A. olrikii, because tRNA-Pro and tRNA-Thr are poorly characterized and aberrantly located in this species. PMID- 26122338 TI - Complete mitochondrial genome of the Common redpoll (Carduelis flammea). AB - The Common redpoll (Carduelis flammea) is one species of family Fringillidae. In the present study, we determined the complete mitochondrial DNA sequences of this species. The mitochondrial genome of Common redpoll is a circular molecule of 16 820 bp in size and contains 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region. The total base composition is 31.35% for C, 14.14% for G, 30.57% for A and 23.94% for T, respectively. The phylogenetic tree of Common redpoll and 12 other closely related Fringillidae species was built. These data will be useful for studying the genetic diversity within the species of Common redpoll and phylogenetic relationships among different Fringillidae species. PMID- 26122339 TI - Complete mitochondrial genome of the hybrid of Acipenser schrenckii (?) * Huso dauricus (?). AB - The complete mitochondrial genome sequence of the hybrid of Acipenser schrenckii (?) * Huso dauricus (?) (A * H) was first determined by a PCR-based sequencing method in this study. The mitochondrial was 16 687 bp in length, including 13 protein genes, two ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and one control region. All genes were encoded on the heavy strain except for ND6 and eight tRNA genes. Base composition of the heavy strain was A (29.80%), T (24.42%), C (28.94%), G (16.82%), and with A + T bias of 54.26%. Compared with the complete mitochondrial genome of the parents, results showed the hybrid sturgeon was consistent with a maternal inheritance; however, we also found ND6 and tRNA-Glu which were species-specific for the male parent H. dauricus. The complete mitochondrial genome sequence of the A * H provided an important data set for further study in mitochondrial inheritance mechanism. PMID- 26122340 TI - Complete mitochondrial genome of the endemic South Korean species Odontobutis interrupta (Perciformes, Odontobutidae). AB - The complete mitochondrial genome of Odontobutis interrupta (Perciformes, Odontobutidae), a species endemic to South Korea, is reported here for the first time. The O. interrupta mitogenome is 16 802 base pairs in total length and includes 13 PCGs, small and large rRNAs, a control region and 22 tRNAs. Nine genes are encoded on the light strand and 29 on the heavy strand. The O. interrupta mitochondrial genome has a conserved gene order compared to four other Odontobutis species and Micropercops swinhonis, a closely related species. The data will provide useful molecular information for phylogenetic studies concerning Odontobutidae and its related species. PMID- 26122341 TI - DNA barcoding of two solitary ascidians, Herdmania momus Savigny, 1816 and Microcosmus squamiger Michaelsen, 1927 from Thoothukudi coast, India. AB - Morphology-based taxonomical studies of ascidians in India are meagre due to lack of ascidian taxonomist and limitations inherent in conventional system-based identification. The use of short fragment of mitochondrial DNA sequence is proving highly useful in identifying species in a situation where, the traditional morphology-based identification is difficult. In the present study, two adult solitary ascidians collected from the Thoothukudi coast were morphologically identified as Herdmania momus Savigny, 1816 and Microcosmus squamiger Michaelsen, 1927. The genomic DNA of these ascidians was isolated, COI gene was amplified, sequenced and submitted to the GenBank under the accession numbers KM058116, KM411616 and KJ944390. Homology search result using BLAST showed that H. momus showed 100% matched with other H. momus, while M. squamiger showed similarity with Pyura herdmani, a member of the same family Pyuridae. The phylogenetic and genetic distance was maximum in interspecies than in intraspecies. These COI sequences will allow the identification of the species through DNA barcoding technique. Here, we report for the first time the COI gene of H. momus, Savigny 1816 from the Indian coast. PMID- 26122342 TI - The complete mitochondrial genome sequence of Plotosus japonicus (Siluriformes: Plotosidae) and phylogenetic studies of Siluriformes. AB - In this study, we first determined and described the complete mitogenome sequence of Plotosus japonicus, which is a kind of marine fish widely distributed in Northwest Pacific. The complete mitogenome sequence is 16 472 bp in length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, a putative control region (CR) and a light-strand replication origin (OL). The overall base composition is 31.9% A, 24.7% T, 27.7% C, 15.7% G, with a slight AT bias (56.6%), similar to other vertebrate mitochondrial genomes. All the protein-coding genes use the initiation codon ATG except COI uses GTG. Most of them have TAA or TAG as the stop codon, while COII and ND4 use AGA, COIII and Cytb use an incomplete stop codon TA or T. Maximum Likelihood (ML) tree and Bayesian analyses based on concatenated nucleotide sequences of 12 mitochondrial protein-coding genes were constructed and both yielded identical topologies. These results are expected to provide useful molecular data for species identification and further phylogenetic studies of Siluriformes. PMID- 26122343 TI - The complete mitochondrial genome of Perca schrenkii (Perciformes: Percidae). AB - The complete mitochondrial genome of Perca schrenkii was obtained in the present study. The total length of the mitogenome was 16 536 bp in accordance with other teleost fish. It consisted of 37 genes (13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes) and 2 main non-coding regions (the control region and the origin of the light strand replication). All protein-coding genes started with ATG except for COX1, which began with GTG. However, the termination codons of 13 protein-coding genes were varied with TAA, TA, T or TAG. The overall base composition in descending order was T 27.9%, C 27.7%, A 27.1% and G 17.4%, with a slight A + T bias. The complete mitochondrial genome sequence may provide important information for phylogenetic analysis and studies on the population genetics of P. schrenkii. PMID- 26122344 TI - Complete genome sequence and SNPs of Raja pulchra (Rajiformes, Rajidae) mitochondria. AB - Mitochondrial genomes were sequenced from five Raja pulchra individuals, and single-nucleotide polymorphisms (SNPs) were identified by comparing previously announced sequences in this study. Total 117 SNPs were detected and they were present in 2 rRNA genes, 9 tRNA genes, 13 protein coding genes and non-coding region. One deleted polymorphic site, which was located in 16S rRNA gene, was observed in two individuals. Six polymorphic sites were non-synonymous SNPs, which were distributed in ND1, ND2, ATP6 and ND4 gene. Phylogenic analysis validated current taxa. The genome sequences of R. pulchra mitochondria could be comparable information for understanding species divergence and genomic variation among the populations. PMID- 26122345 TI - Cost-effectiveness of first-line induction and maintenance treatment sequences in non-squamous non-small cell lung cancer (NSCLC) in the U.S. AB - OBJECTIVES: Due to the lack of direct head-to-head trials, there are limited data regarding the comparative effectiveness of induction-maintenance sequences. The objective of this study was to develop a cost-effectiveness model to compare induction-maintenance sequences in the US for the treatment of advanced non squamous NSCLC. MATERIALS AND METHODS: Decision analytic modelling was used to synthesize the treatment effect and baseline risk estimates for nine induction and maintenance treatment sequences, reflecting treatments used in the US. The model was structured using an area-under-the-curve approach and sensitivity analyses were conducted. Model validation was conducted by an independent third party. RESULTS: All active maintenance therapy-containing regimens, with the exception of gemcitabine+cisplatin (first-line)->erlotinib (maintenance), were more costly than induction-only regimens. Concerning treatments that may be cost effective, the incremental costs per life-year gained were $121,425, $148,994, and $191,270 for gemcitabine+cisplatin->erlotinib versus gemcitabine+cisplatin >best supportive care (BSC), pemetrexed+cisplatin->BSC versus gemcitabine+cisplatin->erlotinib, and for pemetrexed+cisplatin->pemetrexed versus pemetrexed+cisplatin->BSC, respectively. All other regimens were found to be dominated (carboplatin+paclitaxel->BSC; carboplatin+paclitaxel->erlotinib; carboplatin+paclitaxel->pemetrexed; bevacizumab+carboplatin+paclitaxel >bevacizumab) or extendedly dominated (cisplatin+gemcitabine->pemetrexed). Sensitivity analyses demonstrated stability. CONCLUSIONS: Depending on the specific cost-effectiveness threshold used by a decision maker, the most cost effective treatment sequence may include the referent comparator gemcitabine+cisplatin and the studied regimens of gemcitabine+cisplatin >erlotinib, pemetrexed+cisplatin->BSC, or pemetrexed+cisplatin->pemetrexed. PMID- 26122346 TI - Variant of BCL3 gene is strongly associated with five-year survival of non-small cell lung cancer patients. AB - OBJECTIVES: BCL3, a known atypical IkappaB family member, has been documented to be upregulated in hematological malignancies and in some solid tumors, functioning as a crucial player in tumor development. Recently, rs8100239, a tag Single Nucleotide Polymorphism (SNP) in BCL3 (T>A) has been identified, but there are no data regarding its involvement in non-small-cell lung cancer (NSCLC) initiation and progression. MATERIALS AND METHODS: To study the possible association of BCL3 with NSCLC, 268 patients and 279 healthy controls were genotyped for rs8100239. Moreover, BCL3 protein expression was also investigated in 112 NSCLC cases through an immunohistochemical analysis. RESULTS: NSCLC patients with AA genotype displayed significantly worse prognosis compared to T allele carriers (P<0.001), who had less frequent intermediate nuclear BCL3 expression (P=0.042). In addition, overexpression of BCL3 was detected in tumor specimens, compared to normal tissue (P<0.001). Furthermore, BCL3 protein levels were associated with five-year survival (P=0.039), maximum diameter of lesion (P=0.012), grade (P=0.002) and relapse frequency (P=0.041). CONCLUSIONS: The present study is the first to show a relationship between the genetic variation rs8100239 of BCL3 and cancer patients' survival. It also represents the first quantitative evaluation of BCL3 expression in NSCLC. Our findings indicate that rs8100239 may be considered as a novel prognostic indicator, demonstrating also the overexpression of BCL3 protein in NSCLC and implicating this pivotal molecule in the pathogenesis of NSCLC. PMID- 26122347 TI - Perceived Educational Needs of the Integrated Care Psychiatric Consultant. AB - OBJECTIVE: With the increased implementation of models that integrate behavioral health with other medical care, there is a need for a workforce of integrated care providers, including psychiatrists, who are trained to deliver mental health care in new ways and meet the needs of a primary care population. However, little is known about the educational needs of psychiatrists in practice delivering integrated care to inform the development of integrated care training experiences. METHOD: The educational needs of the integrated care team were assessed by surveying psychiatric consultants who work in integrated care. RESULTS: A convenience sample of 52 psychiatrists working in integrated care responded to the survey. The majority of the topics included in the survey were considered educational priorities (>50% of the psychiatrists rated them as essential) for the psychiatric consultant role. Psychiatrists' perspectives on educational priorities for behavioral health providers (BHPs) and primary care providers (PCPs) were also identified. Almost all psychiatrists reported that they provide educational support for PCPs and BHPs (for PCP 92%; for BHP 96%). CONCLUSIONS: The information provided in this report suggests likely educational needs of the integrated care psychiatric consultant and provides insight into the learning needs of other integrated care team members. Defining clear priorities related to the three roles of the integrated care psychiatric consultant (clinical consultant, clinical educator, and clinical team leader) will be helpful to inform residency training programs to prepare psychiatrists for work in this emerging field of psychiatry. PMID- 26122348 TI - Both Feet In: Maintaining an Academic Focus During the Transition from Residency to a First Military Assignment. AB - OBJECTIVE: Maintenance of an academic focus is difficult for military residents transitioning into their first duty assignment. METHOD: Building upon previous work on this subject, the authors present an updated and expanded junior faculty development model organized around seven overlapping domains: mentorship, scholarship, research, career planning, openness to experience, networking with other disciplines, and responsibility seeking. Using these seven domains as a platform for discussion, the authors focus on challenges facing early-career military psychiatrists and provide guidance based upon personal experience and limited applicable research. RESULTS: The authors believe that highly successful early-career psychiatrists wishing to maintain an academic focus possess a proactive attitude, obtain skillful mentoring, work well with others, and are able to adapt to new environments. CONCLUSION: Through conscious planning and goal setting, they are able to capitalize on opportunities as they become available. PMID- 26122349 TI - Social Media Use in Psychiatric Graduate Medical Education: Where We Are and the Places We Could Go. AB - This commentary discusses the use of social media in psychiatric graduate medical education (GME) based on a systematic search of the literature. The authors conclude that research on social media use in psychiatric GME is in its infancy. For the most part, the few articles that have been published on this topic caution against the use of social media in psychiatric training. However, reports from other specialties, in which social media use in medical education has been more extensively studied, suggest that there may be significant benefits to incorporating social media into medical education. Although additional challenges may exist in implementing these tools in psychiatric education, the authors suggest that this is an emerging field of scholarship that merits further investigation. PMID- 26122350 TI - Resident Evaluation of a Required Telepsychiatry Clinical Experience. AB - OBJECTIVE: The authors explored resident experiences of telepsychiatry clinical training. This paper describes an analysis of evaluation forms completed by psychiatry residents following a required training experience in telepsychiatry. METHODS: Retrospective numeric and narrative data were collected from 2005 to 2012. Using a five-point Likert-type scale (1 = strongly disagree and 5 = strongly agree), residents ranked the session based on the following characteristics: the overall experience, interest in participating in telepsychiatry in the future, understanding service provision to underserved areas, telepsychiatry as mode of service delivery, and the unique aspects of telepsychiatry work. The authors also conducted a content analysis of narrative comments in response to open-ended questions about the positive and negative aspects of the training experience. RESULTS: In all, 88% of residents completed (n = 335) an anonymous evaluation following their participation in telepsychiatry consultation sessions. Numeric results were mostly positive and indicated that the experience was interesting and enjoyable, enhanced interest in participating in telepsychiatry in the future, and increased understanding of providing psychiatric services to underserved communities. Narrative data demonstrated that the most valuable aspects of training included the knowledge acquired in terms of establishing rapport and engaging with patients, using the technology, working collaboratively, identifying different approaches used, and awareness of the complexity of cases. Resident desire for more training of this nature was prevalent, specifically a wish for more detail, additional time for discussion and debriefing, and further explanation of the unique aspects of telepsychiatry as mode of delivery. CONCLUSIONS: More evaluation of telepsychiatry training, elective or required, is needed. The context of this training offered potential side benefits of learning about interprofessional and collaborative care for the underserved. PMID- 26122351 TI - A "Middle Way": Introducing a Flexible Year-Long Program to Prepare for Certification in Addiction Medicine. PMID- 26122352 TI - Problem-Solving Skills and Suicidal Ideation Among Malaysian College Students: the Mediating Role of Hopelessness. AB - OBJECTIVE: Recent evidence suggests that suicidal ideation has increased among Malaysian college students over the past two decades; therefore, it is essential to increase our knowledge concerning the etiology of suicidal ideation among Malaysian college students. This study was conducted to examine the relationships between problem-solving skills, hopelessness, and suicidal ideation among Malaysian college students. METHODS: The participants included 500 undergraduate students from two Malaysian public universities who completed the self-report questionnaires. RESULTS: Structural equation modeling estimated that college students with poor problem-solving confidence, external personal control of emotion, and avoiding style were more likely to report suicidal ideation. Hopelessness partially mediated the relationship between problem-solving skills and suicidal ideation. CONCLUSION: These findings reinforce the importance of poor problem-solving skills and hopelessness as risk factors for suicidal ideation among college students. PMID- 26122353 TI - The Transcultural Psychiatry Reading Group: a Learner-Led Approach to Cultural Psychiatry. PMID- 26122354 TI - The Effect of Teaching Clinics on Prescribing Practices. AB - OBJECTIVE: The objective of this study was to investigate the effect of lack of continuity in a teaching clinic and to ascertain the role of supervisory attending in treatment decisions in a teaching psychiatric clinic. METHODS: A retrospective evaluation of paired consecutive visits of patients attending an education clinic was performed. RESULTS: Medication changes occurred in 56.3% of all visit pairs. Visit pairs in which the resident was unchanged had significantly more medication changes than visit pairs in which the attending was unchanged. When the resident stays the same, the number of medication changes is high and does not change significantly even if the attending is the same or different. Similarly, when the resident is different, the number of medication changes is low and does not change significantly if the attending is the same or different. CONCLUSION: Residents, not the attending physicians, are more instrumental in medication changes in patients attending an education clinic. PMID- 26122355 TI - Psychiatry Resident Quality of Life. AB - OBJECTIVE: The objective of this study was to evaluate psychiatry resident physician quality of life. METHODS: A voluntary, anonymous, 10-min survey was e mailed to residents from all 14 Accreditation Council for Graduate Medical Education (ACGME)-accredited programs in Pennsylvania, New Jersey, and Delaware. Included in the survey was the Multi-Cultural Quality of Life Inventory (MQLI). RESULTS: Response rate was 112 (34.1%). Internal consistency of the MQLI was high (Cronbach's alpha 0.92), and follow-up exploratory factor analysis extracted only one underlying factor (60.1% variance among all 10 items). Average total MQLI score was 80.6. No significant difference in MQLI total was found for therapy status, sex, or race. Post-graduate year (PGY) 4 residents scored higher on total MQLI score (86.7) (F = 2.80, p = 0.04) and ranked occupational functioning and community and services support subscales significantly higher (occupation F = 2.73, p = 0.048, community F = 3.11, p = 0.030). Total MQLI score for residents over the age of 40 (n = 3) was significantly lower (F = 3.45, p = 0.019). CONCLUSION: Despite the stresses of residency training, residents from a variety of programs in one geographic area report an encouraging quality of life on the MQLI. Psychiatry resident quality of life is similar to that reported in other populations of mental health professionals. PMID- 26122356 TI - On contrast mechanisms in p-space imaging. AB - PURPOSE: The effects of microstructure on susceptibility mapping have recently received increasing attention. In this work, the capability of p-space imaging to resolve subvoxel structure and susceptibility is assessed. METHODS: In a simulation study, the p-space contrast of axon bundles comprised of hollow cylinders is investigated. Various axon and susceptibility distributions are considered and compared with the corresponding case of a voxel with homogeneous substructure of the order of the voxel size. RESULTS: MR signal behavior for p space imaging of a voxel containing axon bundles and a voxel containing homogeneous substructure are nearly identical. CONCLUSION: p-Space imaging resolves subvoxel structure of the order of the voxel size. Due to dephasing effects, strong susceptibility variations alter p-space contrast. However, p space contrast is not directly linked to the susceptibility of the axon compartment. Magn Reson Med 75:2526-2533, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26122358 TI - Expansion of myeloid-derived suppressor cells in chronic obstructive pulmonary disease and lung cancer: potential link between inflammation and cancer. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer (LC). Myeloid-derived suppressor cells (MDSCs) down-regulate the T cell receptor zeta chain (TCR zeta) through L-arginine deprivation and lead to T cell dysfunction and deficient antitumor immunity. We hypothesized that abnormally high levels of MDSCs in COPD patients may alter tumor immunosurveillance. METHODS: We compared the proportion of circulating MDSCs (Lin HLA-DR-/CD33+/CD11b+) (by flow cytometry), arginase I (ARG I) serum levels (by ELISA), and expression levels of TCR zeta on circulating lymphocytes (by flow cytometry) in 28 patients with LC, 62 subjects with COPD, 41 patients with both LC and COPD, 40 smokers with normal spirometry and 33 non-smoking controls. T cell proliferation assays were performed in a subgroup of participants (CFSE dilution protocol). RESULTS: We found that: (1) circulating MDSCs were up regulated in COPD and LC patients (with and without COPD); (2) MDSCs expansion was associated with TCR zeta down-regulation in the three groups; (3) in LC patients, these findings were independent of COPD and tobacco smoking exposure; (4) TCR zeta down-regulation correlates with T cell hyporesponsiveness in COPD and LC patients. CONCLUSIONS: These results suggest that tumor immunosurveillance might be impaired in COPD and may contribute to the increased risk of LC reported in these patients. PMID- 26122357 TI - Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. AB - Regulatory T cell (Treg)-mediated immunosuppression is considered a major obstacle for successful cancer immunotherapy. The association between clinical outcome and Tregs is being studied extensively in clinical trials, but unfortunately, no consensus has been reached about (a) the markers and (b) the gating strategy required to define human Tregs in this context, making it difficult to draw final conclusions. Therefore, we have organized an international workshop on the detection and functional testing of Tregs with leading experts in the field, and 40 participants discussing different analyses and the importance of different markers and context in which Tregs were analyzed. This resulted in a rationally composed ranking list of "Treg markers". Subsequently, the proposed Treg markers were tested to get insight into the overlap/differences between the most frequently used Treg definitions and their utility for Treg detection in various human tissues. Here, we conclude that the CD3, CD4, CD25, CD127, and FoxP3 markers are the minimally required markers to define human Treg cells. Staining for Ki67 and CD45RA showed to provide additional information on the activation status of Tregs. The use of markers was validated in a series of PBMC from healthy donors and cancer patients, as well as in tumor-draining lymph nodes and freshly isolated tumors. In conclusion, we propose an essential marker set comprising antibodies to CD3, CD4, CD25, CD127, Foxp3, Ki67, and CD45RA and a corresponding robust gating strategy for the context-dependent analysis of Tregs by flow cytometry. PMID- 26122359 TI - Severe sleep apnea-hypopnea syndrome is related to left ventricle dysfunction and hypertrophy in acromegalic patients. AB - OBJECTIVE: To assess whether sleep apnea-hypopnea syndrome (SAHS) is a risk factor for development of acromegalic cardiomyopathy. METHODS: A descriptive, cross-sectional study of 32 patients with acromegaly (15 categorized as non controlled-NCA and 17 as controlled-CA) compared to 20 matched controls (by sex, age, and BMI) referred to the pulmonology department for suspected SAHS. Polysomnography, echocardiography (M-mode, 2-dimensional, and Doppler), and 12 lead electrocardiography were performed in all participants. Development of cardiac morbidity (ischemia heart disease or heart failure) was evaluated after 7 years. RESULTS: SAHS was diagnosed in 81.3% of patients with acromegaly and 85% of controls. Mild SAHS was more common in CA than in NCA patients (31.3% vs. 0%, p=0.048). There was a trend to greater prevalence of left ventricular diastolic dysfunction (LVDD) in acromegalic patients as compared to controls (58.1% vs. 30%, p=0.05). Presence of severe SAHS in patients with acromegaly was related to greater risk of LVDD (90.9% vs. 40%, p=0.008; OR 2.3 [1.3-4.0]), LV hypertrophy (55.6% vs. 10.5%, p=0.02; OR 5.3 [1.3-22.2]), and cardiac events (87.5% vs. 35.6%; p=0.01; OR 7.53 [1.07-53.24]). CONCLUSION: SAHS is highly prevalent in patients with acromegaly. Only in these patients was severe SAHS associated to hypertrophy, LV diastolic dysfunction, and cardiac events. PMID- 26122360 TI - Can we cure breast cancer? PMID- 26122362 TI - [Not Available]. PMID- 26122361 TI - Pancreaticoduodenectomy hospital resource utilization in octogenarians. AB - BACKGROUND: Although pancreaticoduodenectomy (PD) is feasible in patients greater than or equal to 80 years, little is known about the potential strain on resource utilization. METHODS: Outcomes and inpatient charges were compared across age cohorts (I: <=70, II: 71 to 79, III: >=80 years) in 99 patients who underwent PD (2005 to 2013) at our institution. The generalized linear modeling approach was used to estimate the impact of age. RESULTS: Perioperative complications were equivalent among cohorts. Increasing age was associated with intensive care unit use, increased length of stay (LOS), and the likelihood of discharge to a skilled facility. After controlling for covariates, hospital charges were significantly higher in Cohort III (P = .006) and Cohort II (P = .035) when compared with Cohort I. However, hospital charges between Cohorts II and III were equivalent (P = .374). Complications (P = .005) and LOS (P < .001) were associated with higher hospital charges. CONCLUSIONS: Increasing age was associated with increased intensive care unit, LOS, and discharge to skilled facilities. However, octogenarians had equivalent PD charges and outcome measures when compared with septuagenarians and future studies should validate these findings in larger national studies. PMID- 26122363 TI - [Improving health literacy among older adults: Findings based on the IROHLA project]. AB - Health literacy has been defined as the degree to which people are able to access, understand, appraise, and communicate information to make informed decisions about their health. It is therefore essential to be able to engage with the demands of different health contexts and to stay healthy. The topic of health literacy is thus receiving growing political and scientific attention and is becoming increasingly important in Germany too. Results of a survey on health literacy in Germany that were published by the AOK's scientific research institute, WidO, in 2014, stress the need for health literacy improvement. These results are briefly summarized. At a European level, the IROHLA (Intervention Research on Health Literacy among Ageing population) project was started in December 2012. IROHLA is aimed at introducing evidence-based guidelines for policy and practice to improve health literacy among the ageing population in the member states of the European Union (EU). The project consortium is led by the University Medical Center Groningen (UMCG) and consists of 22 partners from nine EU member states. German partners in the project are the Federal Centre for Health Education (Bundeszentrale fur gesundheitliche Aufklarung-BZgA), the Federal Association of the AOK (AOK-Bundesverband), liveonline coaching, and Jacobs University Bremen. The purpose of this article is to present the major findings of the IROHLA project and to point out approaches to improving health literacy among older adults. A key aspect within IROHLA is the comprehensive approach, which targets multiple groups, i.e., individuals and their social environment, in addition to professionals and the health system. PMID- 26122364 TI - Transformation and characterization of an arsenic gene operon from urease positive thermophilic Campylobacter (UPTC) in Escherichia coli. AB - An arsenate susceptibility test was performed with transformed and cultured Escherichia coli DH5alpha cells, which carried recombinant DNA of full-length arsenic (ars) operon, namely a putative membrane permease, ArsP; a transcriptional repressor, ArsR; an arsenate reductase, ArsC; and an arsenical resistance membrane transporter, Acr3, from the Japanese urease-positive thermophilic Campylobacter lari (UPTC) CF89-12. The E. coli DH5alpha transformant showed reduced susceptibility to arsenate (~1536 MUg/mL), compared to the control. Thus, these ars four-genes from the UPTC CF89-12 strain cells could confer a reduced susceptibility to arsenate in the transformed and E. coli DH5alpha cells. E. coli transformants with truncated ars operons, acr3 (acr3) and arsC-acr3 (?arsC-acr3), of the ars operon, showed an MIC value of 384 MUg/mL (~384 MUg/mL), similar to the E. coli cells which carried the pGEM-T vector (control). Reverse transcription PCR confirmed in vivo transcription of recombinant full-length ars operon and deletion variants (?acr3 and ?arsC-acr3) in the transformed E. coli cells. PMID- 26122365 TI - A two-dimensional protein map of Pleurotus ostreatus microsomes-proteome dynamics. AB - Recent studies documented that several processes in filamentous fungi are connected with microsomal enzyme activities. In this work, microsomal subproteomes of Pleurotus ostreatus were analyzed by two-dimensional (2-D) polyacrylamide gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis. To assess proteome dynamics, microsomal proteins were isolated from fungal cultures after 7 and 12 days of cultivation. Additionally, 10 mg/L of 17alpha-ethinylestradiol (EE2) was treated with the cultures during 2 days. Despite the EE2 degradation by the fungus reached 97 and 76.3 % in 7- and 12-day-old cultures, respectively, only a minor effect on the composition of microsomal proteins was observed. The changes in protein maps related to ageing prevailed over those induced by EE2. Epoxide hydrolase, known to metabolize EE2, was detected in 12-day-old cultures only which suggests differences in EE2 degradation pathways utilized by fungal cultures of different age. The majority (32 %) of identified microsomal proteins were parts of mitochondrial energy metabolism. PMID- 26122366 TI - Improved mortality of the Formosan subterranean termite by fungi, when amended with cuticle-degrading enzymes or eicosanoid biosynthesis inhibitors. AB - Formosan subterranean termites (FST) were exposed to strains of Beauveria pseudobassiana (Bpb) and Isaria fumosorosea (Ifr) to determine virulence of the fungi. Once lethality was determined, sublethal doses of Bpb were combined with enzymes capable of degrading the insect cuticle to measure the potential to enhance fungal infection. Bpb applied to FST in combination with proteinases and a chitinase caused increased mortality over the fungus alone. Mortality was enhanced when Ifr was applied to FST in combination with a chitinase isolated from Serratia marcesans. A lipase isolated from Pseudomonas cepacia, when combined with Ifr, also resulted in greater mortality than all control treatments. FST were also exposed to the eicosanoid biosynthesis inhibitors (EBIs) dexamethasone (DEX), ibuprofen (IBU), and ibuprofen sodium salt (IBUNA), in combination with Ifr. Combining Ifr with IBUNA caused significantly increased mortality on days 6, 7, and 9. Cuticle-degrading enzymes and EBIs may have potential to enhance the pathogenic effect of a fungal control agent against the Formosan subterranean termite. PMID- 26122367 TI - ERG and FLI1 are useful immunohistochemical markers in phosphaturic mesenchymal tumors. AB - Phosphaturic mesenchymal tumors (PMT) are the most common cause of tumor-induced osteomalacia (TIO) related to mesenchymal neoplasms. The lineage of differentiation of PMTs has not been elucidated in existing literature. Fourteen cases of PMT were analyzed for this study to elucidate its lineage. We used vascular and/or lymphatic endothelial markers for the immunohistochemical analysis, which included CD31, CD34, factor VIII-related antigen, podoplanin, Freund's leukemia integration site 1 (FLI1), and avian v-ets erythroblastosis virus E26 oncogene homolog (ERG). FLI1 and ERG were stained in all cases with proportion of immunopositive tumor cells largely more than 50 %; staining intensity was moderate or strong for both FLI1 and ERG. The tumor cells were stained with CD31 and/or CD34, with significantly less staining than observed for FLI1 and ERG. The tumor cells were completely immunonegative for factor VIII related antigen and podoplanin. FLI1 and ERG are known to have considerable specificity to endothelial cells; ERG is more widely equipped in surgical pathology laboratories than FLI1. We concluded that ERG (or FLI1 if available) is useful marker for the diagnosis of PMT, and that PMTs may have an endothelial cell lineage. PMID- 26122368 TI - The negative influence of sperm cryopreservation on the quality and development of the embryo depends on the morphology of the oocyte. AB - The present case-control study aimed to identify the effect of sperm cryopreservation on the quality of the embryo and on the probability of blastocyst formation when oocytes free of dimorphisms are injected and when at least one dymorphism is present. The study included 22 186 zygotes, obtained from 2802 patients undergoing intracytoplasmic sperm injection cycles, in a private assisted reproduction center, using either fresh or cryopreserved sperm. The effect of sperm cryopreservation on the embryo quality on cleavage stage and blastocyst formation chance were evaluated when oocytes free of dimorphisms are injected and when at least one dymorphism is present. The quality of the embryo on cleavage stage as well as the chance for blastocyst formation was not influenced by the origin of the spermatozoa when the quality of the oocyte was not considered. When at least one oocyte defect was present, a negative influence of sperm cryopreservation on cleavage stage embryo quality and the chance for blastocyst formation was noted. In oocytes with extra-cytoplasmic dimorphisms, the injection of cryopreserved sperm did not affect the quality of the embryo during the cleavage stage, but did affect the chance for blastocyst formation. Conversely, in oocytes with intracytoplasmic defects, the quality of the embryos on cleavage stage and the chance of blastocyst formation were negatively influenced by the injection of cryopreserved sperm. The results suggest an oocyte quality-dependent negative effect of sperm cryopreservation on embryo quality and on the probability of blastocyst formation. PMID- 26122369 TI - Non-metastatic Pancreatic Cancer: Resectable, Borderline Resectable, and Locally Advanced-Definitions of Increasing Importance for the Optimal Delivery of Multimodality Therapy. PMID- 26122371 TI - Attitudes and Perceptions of Surgical Oncology Fellows on ACGME Accreditation and the Complex General Surgical Oncology Certification. AB - BACKGROUND: With the first qualifying examination administered September 15, 2014, complex general surgical oncology (CGSO) is now a board-certified specialty. We aimed to assess the attitudes and perceptions of current and future surgical oncology fellows regarding the recently instituted Accreditation Council for Graduate Medical Education (ACGME) accreditation. METHODS: A 29-question anonymous survey was distributed to fellows in surgical oncology fellowship programs and applicants interviewing at our fellowship program. RESULTS: There were 110 responses (79 fellows and 31 candidates). The response rate for the first- and second-year fellows was 66 %. Ninety-percent of the respondents were aware that completing an ACGME-accredited fellowship leads to board eligibility in CGSO. However, the majority (80 %) of the respondents stated that their decision to specialize in surgical oncology was not influenced by the ACGME accreditation. The fellows in training were concerned about the cost of the exam (90 %) and expressed anxiety in preparing for another board exam (83 %). However, the majority of the respondents believed that CGSO board certification will be helpful (79 %) in obtaining their future career goals. Interestingly, candidate fellows appeared more focused on a career in general complex surgical oncology (p = 0.004), highlighting the impact that fellowship training may have on organ specific subspecialization. CONCLUSIONS: The majority of the surveyed surgical oncology fellows and candidates believe that obtaining board certification in CGSO is important and will help them pursue their career goals. However, the decision to specialize in surgical oncology does not appear to be motivated by ACGME accreditation or the new board certification. PMID- 26122370 TI - Percutaneous Preoperative Biliary Drainage for Resectable Perihilar Cholangiocarcinoma: No Association with Survival and No Increase in Seeding Metastases. AB - BACKGROUND: Endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) are both used to resolve jaundice before surgery for perihilar cholangiocarcinoma (PHC). PTBD has been associated with seeding metastases. The aim of this study was to compare overall survival (OS) and the incidence of initial seeding metastases that potentially influence survival in patients with preoperative PTBD versus EBD. METHODS: Between 1991 and 2012, a total of 278 patients underwent preoperative biliary drainage and resection of PHC at 2 institutions in the Netherlands and the United States. Of these, 33 patients were excluded for postoperative mortality. Among the 245 included patients, 88 patients who underwent preoperative PTBD (with or without previous EBD) were compared to 157 patients who underwent EBD only. Survival analysis was done with Kaplan-Meier and Cox regression with propensity score adjustment. RESULTS: Unadjusted median OS was comparable between the PTBD group (35 months) and EBD-only group (41 months; P = 0.26). After adjustment for propensity score, OS between the PTBD group and EBD-only group was similar (hazard ratio, 1.05; 95 % confidence interval, 0.74-1.49; P = 0.80). Seeding metastases in the laparotomy scar occurred as initial recurrence in 7 patients, including 3 patients (3.4 %) in the PTBD group and 4 patients (2.7 %) in the EBD-only group (P = 0.71). No patient had an initial recurrence in percutaneous catheter tracts. CONCLUSIONS: The present study found no effect of PTBD on survival compared to patients with EBD and no increase in seeding metastases that developed as initial recurrence. These data suggest that PTBD can safely be used in preoperative management of PHC. PMID- 26122372 TI - Preoperative Contrast-Enhanced CT Versus 18F-FDG PET/CT Evaluation and the Prognostic Value of Extranodal Extension for Surgical Patients with Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND: Extranodal extension (ENE) is a poor prognostic indicator for patients with head and neck squamous cell carcinoma (HNSCC), but pretreatment detection assists with proper treatment planning. This study evaluated whether the ENE of HNSCC is accurately detected by computed tomography (CT) versus fluorine 18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT and whether it has any impact on patient prognosis. METHODS: In this study, 186 HNSCC patients were preoperatively evaluated using contrast-enhanced CT and (18)F FDG PET/CT. The histopathologic findings for the neck dissection samples served as a standard reference. McNemar's test and logistic regression using the generalized estimating equations were used to compare the diagnostic value of CT versus (18)F-FDG PET/CT, and Cox proportional hazard regression was used to assess the prognostic value of ENE. RESULTS: Among the 186 study patients, 113 (60.8 %) had a neck metastasis, 44 (23.7 %) had pathologic ENE, and 37 (19.9 %) had macroscopic ENE. Radiologic ENE (rENE) on CT was documented for 48 patients (25.8 %) and 52 neck sides (19.8 %). Using 4.9 as the cutoff value for nodal maximum standardized uptake, (18)F-FDG PET/CT documented rENE for 44 patients (23.7 %) and 48 neck sides (18.3 %). Compared with (18)F-FDG PET/CT, CT detected ENE, with a specificity of 92.1 versus 74.4 % (p < 0.001) and an accuracy of 88.6 versus 75.3 % (p < 0.001). However, rENE was not a significant predictor of recurrence or survival (p > 0.05). CONCLUSION: The findings showed that ENE of HNSCC is more accurately detected by using CT than by using (18)F-FDG PET/CT. The accurate pretreatment detection of ENE may help in the planning for HNSCC treatments. PMID- 26122373 TI - Reduced Expression of Adherens Junctions Associated Protein 1 Predicts Recurrence of Hepatocellular Carcinoma After Curative Hepatectomy. AB - BACKGROUND: Hepatocellular carcinoma (HCC) frequently recurs after curative resection. Therefore, the availability of sensitive biomarkers for progression and recurrence is essential for managing patients' clinical course. Adherens junctions associated protein 1 (AJAP1) may serve this purpose, because it mediates activities of tumor cells. METHODS: AJAP1 mRNA levels and those of genes encoding potential interacting proteins, such as SRC in HCC cell lines, and 144 pairs of resected liver tissues were determined as well as the methylation status of the AJAP1 promoter and copy number changes at AJAP1 locus. The expression pattern of AJAP1 protein was evaluated using immunohistochemistry. RESULTS: AJAP1 mRNA levels varied among nine HCC cell lines, and AJAP1 expression was reactivated after demethylation of its promoter. AJAP1 mRNA levels correlated inversely with those of SRC in HCC cell lines and tissues. AJAP1 mRNA levels were suppressed in HCC tissues. The expression pattern of AJAP1 correlated significantly with that of AJAP1 mRNA. Low levels of AJAP1 mRNA in patients with HCC associated significantly with elevated levels of tumor markers, larger tumor size, serosal infiltration, vascular invasion, hypermethylation of the AJAP1 promoter, and copy number loss at AJAP1 locus. Patients with low levels of AJAP1 expression were more likely to experience shorter disease-free survival (DFS), and multivariate analysis identified low AJAP1 expression as an independent factor for predicting DFS. CONCLUSIONS: AJAP1 may function as a key regulatory molecule associated with the recurrence of HCC. Hypermethylation of the AJAP1 promoter is a key regulatory mechanism controlling AJAP1 expression. PMID- 26122374 TI - Development and Validation of a Disease-Specific Instrument to Measure Diet Targeted Quality of Life for Postoperative Patients with Esophagogastric Cancer. AB - BACKGROUND: Patients who have undergone esophagectomy or gastrectomy have certain dietary limitations because of changes to the alimentary tract. This study attempted to develop a psychometric scale, named "Esophago-Gastric surgery and Quality of Dietary life (EGQ-D)," for assessment of impact of upper gastrointestinal surgery on diet-targeted quality of life. METHODS: Using qualitative methods, the study team interviewed both patients and surgeons involved in esophagogastric cancer surgery, and we prepared an item pool and a draft scale. To evaluate the scale's psychometric reliability and validity, a survey involving a large number of patients was conducted. Items for the final scale were selected by factor analysis and item response theory. Cronbach's alpha was used for assessment of reliability, and correlations with the short form (SF) 12, esophagus and stomach surgery symptom scale (ES(4)), and nutritional indicators were analyzed to assess the criterion-related validity. RESULTS: Through multifaceted discussion and the pilot study, a draft questionnaire comprising 14 items was prepared, and a total of 316 patients were enrolled. On the basis of factor analysis and item response theory, six items were excluded, and the remaining eight items demonstrated strong unidimensionality for the final scale. Cronbach's alpha was 0.895. There were significant associations with all the subscale scores for SF-12, ES(4), and nutritional indicators. CONCLUSIONS: The EGQ-D scale has good contents and psychometric validity and can be used to evaluate disease-specific instrument to measure diet-targeted quality of life for postoperative patients with esophagogastric cancer. PMID- 26122375 TI - Liposuction for Advanced Lymphedema: A Multidisciplinary Approach for Complete Reduction of Arm and Leg Swelling. AB - PURPOSE: This research describes and evaluates a liposuction surgery and multidisciplinary rehabilitation approach for advanced lymphedema of the upper and lower extremities. METHODS: A prospective clinical study was conducted at an Advanced Lymphedema Assessment Clinic (ALAC) comprised of specialists in plastic surgery, rehabilitation, imaging, oncology, and allied health, at Macquarie University, Australia. Between May 2012 and 31 May 2014, a total of 104 patients attended the ALAC. Eligibility criteria for liposuction included (i) unilateral, non-pitting, International Society of Lymphology stage II/III lymphedema; (ii) limb volume difference greater than 25 %; and (iii) previously ineffective conservative therapies. Of 55 eligible patients, 21 underwent liposuction (15 arm, 6 leg) and had at least 3 months postsurgical follow-up (85.7 % cancer related lymphedema). Liposuction was performed under general anesthesia using a published technique, and compression garments were applied intraoperatively and advised to be worn continuously thereafter. Limb volume differences, bioimpedance spectroscopy (L-Dex), and symptom and functional measurements (using the Patient Specific Functional Scale) were taken presurgery and 4 weeks postsurgery, and then at 3, 6, 9, and 12 months postsurgery. RESULTS: Mean presurgical limb volume difference was 45.1 % (arm 44.2 %; leg 47.3 %). This difference reduced to 3.8 % (arm 3.6 %; leg 4.3 %) by 6 months postsurgery, a mean percentage volume reduction of 89.6 % (arm 90.2 %; leg 88.2 %) [p < 0.001]. All patients had improved symptoms and function. Bioimpedance spectroscopy showed reduced but ongoing extracellular fluid, consistent with the underlying lymphatic pathology. CONCLUSIONS: Liposuction is a safe and effective option for carefully selected patients with advanced lymphedema. Assessment, treatment, and follow-up by a multidisciplinary team is essential. PMID- 26122376 TI - A Comparison of Radiocolloid and Indocyanine Green Fluorescence Imaging, Sentinel Lymph Node Mapping in Patients with Cervical Cancer Undergoing Laparoscopic Surgery. AB - BACKGROUND AND PURPOSE: (99)TC combined with blue-dye mapping is considered the best sentinel lymph node (SLN) mapping technique in cervical cancer. Indocyanine green (ICG) with near infrared fluorescence imaging has been introduced as a new methodology for SLN mapping. The aim of this study was to compare these two techniques in the laparoscopic treatment of cervical cancer. METHODS: Medical records of patients undergoing laparoscopic SLN mapping for cervical cancer with either (99)Tc and patent blue dye (Group 1) or ICG (Group 2) from April 2008 until August 2012 were reviewed. Sensitivity, specificity, and overall and bilateral detection rates were calculated and compared. RESULTS: Fifty-eight patients were included in the study-36 patients in Group 1 and 22 patients in Group 2. Median tumor diameter was 25 and 29 mm, and mean SLN count was 2.1 and 3.7, for Groups 1 and 2, respectively. Mean non-SLN (NSLN) count was 39 for both groups. SLNs were ninefold more likely to be affected by metastatic disease compared with NSLNs (p < 0.005). Sensitivity and specificity were both 100 %. Overall detection rates were 83 and 95.5 % (p = nonsignificant), and bilateral detection rates were 61 and 95.5 % (p < 0.005), for Groups 1 and 2, respectively. In 75 % of cases, SLNs were located along the external or internal iliac nodal basins. CONCLUSIONS: ICG SLN mapping in cervical cancer provides high overall and bilateral detection rates that compare favorably with the current standard of care. PMID- 26122377 TI - Does the adhesive strategy influence the post-operative sensitivity in adult patients with posterior resin composite restorations?: A systematic review and meta-analysis. AB - OBJECTIVES: A systematic review and meta-analysis were performed on the risk and intensity of postoperative sensitivity (POS) in posterior resin composite restorations bonded with self-etch (SE) and etch-and-rinse (ER) adhesives. SOURCE: A comprehensive search was performed in the MEDLINE via PubMeb, Scopus, Web of Science, LILACS, BBO and Cochrane Library and SIGLE without restrictions. The abstracts of the annual conference of the IADR (1990-2014), unpublished and ongoing trials registry were also searched. Dissertations and theses were searched using the ProQuest Dissertations and Periodicos Capes Theses databases. STUDY SELECTION: We included randomized clinical trials that compared the clinical effectiveness of SE and ER used for direct resin composite restorations in permanent dentition of adult patients. The risk/intensity of POS was the primary outcome. The risk of bias tool of the Cochrane Collaboration was used. The meta-analysis was performed on the studies considered 'low' risk of bias. DATA: After duplicates removal, 2600 articles were identified but only 29 remained in the qualitative synthesis. Five were considered to be 'high' risk of bias and eleven were considered to be 'unclear' in the key domains, yielding 13 studies for meta-analysis. The overall relative risk of the spontaneous POS was 0.63 (95% CI 0.35 to 1.15), while the stimuli-induced POS was 0.99 (95% CI 0.63 to 1.56). The overall standardized mean difference was 0.08 (95%CI -0.19 to 0.35). No overall effect was revealed in the meta-analyses, meaning that no influence of the ER or SE strategy on POS. SIGNIFICANCE: The type of adhesive strategy (ER or SE) for posterior resin composite restorations does not influence the risk and intensity of POS. CRD42014006617. PMID- 26122378 TI - Xia-yu-xue decoction (XYXD) reduces carbon tetrachloride (CCl4)-induced liver fibrosis through inhibition hepatic stellate cell activation by targeting NF kappaB and TGF-beta1 signaling pathways. AB - BACKGROUND: Hepatic stellate cell (HSC) activation is activated mainly by endotoxin and transforming growth factor (TGF-beta1) in chronic liver injury, consequently, can be important therapeutic targets. Xia-yu-xue decoction (XYXD), a classical recipe used in China to treat liver fibrosis, and has been revealed to inhibit hepatic fibrosis in animal models, the mechanism of action of XYXD remains elusive. In the present study, we evaluated whether XYXD reduced endotoxin and pro-fibrogenic pathways induced by lipopolysaccharide (LPS) and TGF beta1 in HSCs. METHODS: The in vivo effect of XYXD on fibrosis progression was assessed in mice model induced by carbon tetrachloride (CCl4), The in vitro effect of XYXD on mice GFP-Col-HSC cells was evaluated using LPS and TGF-beta1 stimulation. RESULTS: XYXD treatment reduced CCl4-induced liver fibrosis and decreased hepatic hydroxyproline (Hyp) content, the mRNA levels of smooth muscle actin (alpha-SMA) and Col 1(alpha1) in fibrotic liver. XYXD suppressed nuclear factor-kappaB (NF-kappaB) activation induced by LPS and TGF-beta1 assessed by using NF-kappaB-luciferase reporter. The expression of NF-kappaB target genes, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 2 (CXCL2) induced by LPS was suppressed after XYXD treatment. The expression of TGF beta1 targets genes, Col1(alpha1) and tissue inhibitor of metalloproteinases (TIMP1) induced by TGF-beta1 was inhibit after XYXD treatment. CONCLUSION: XYXD treatment attenuates liver fibrosis by inhibiting HSC activation via inhibition of NF-kappaB and TGF-beta1 signaling pathway, thereby blocking the synthesis of Col1 (alpha1) and TIMP-1. These findings from present study suggest that XYXD may be a therapeutic decoction for liver fibrosis in which NF-kappaB and TGF-beta1 are thought to take part. PMID- 26122379 TI - Minimally invasive redo discectomy for recurrent lumbar disc herniations. AB - The purpose of this systematic review is to investigate which minimally invasive techniques have been used for discectomy in recurrent lumbar disc herniation (LDH), to present the success and complication rates and to evaluate the advantages and limitations of each technique. Discectomy for recurrent LDH is accompanied by a higher morbidity rate compared with primary LDH. Because of the limited operating field, the majority of surgeons have been discouraged from utilising a minimally invasive approach for revision surgery. Minimally invasive techniques have gained ground in the treatment of primary LDH and an increasing number of patients are expressing interest in such techniques for the treatment of recurrent LDH. Microendoscopic discectomy (MED), endoscopic transforaminal and interlaminar discectomy (ETD and EID) have been used for treatment of recurrent LDH. The reported success rate is 60-95%. Full endoscopic techniques, especially ETD, showed favourable results concerning dural tear rates but have a demanding learning curve. The limitations of ETD include dislocated disc fragments or concomitant lateral recess stenosis, and MED is more effective in these instances. All three techniques have a low delayed instability rate. MED, ETD and EID are safe and efficient treatment options for surgical management of recurrent LDH with good success and low complication rates. At the same time, they offer the advantages of minimally invasive access. PMID- 26122380 TI - Intrasphenoidal Rathke's cleft cyst. AB - We report a rare patient with an intrasphenoidal Rathke's cleft cyst (RCC) and review the literature. RCC are benign epithelium lined cysts containing mucoid material, which typically occur in a location that is either entirely intrasellar, or intrasellar with suprasellar extension (intra-suprasellar). RCC in a completely extrasellar location are uncommon. An intrasphenoidal RCC is extremely rare with only two patients reported in the literature to date. Preoperative diagnosis is difficult due to the uncommon location and absence of any characteristic radiological features. However, it remains of utmost clinical relevance because it may limit the operative management to biopsy sampling of the cyst wall and drainage of the contents via the transsphenoidal route. PMID- 26122381 TI - Patient and treatment factors associated with survival among adult glioblastoma patients: A USA population-based study from 2000-2010. AB - In this study, we utilized the USA surveillance, epidemiology, and end results (SEER) database to examine factors influencing survival of glioblastoma multiforme (GBM) patients. GBM is the most common primary malignant brain tumor in adults and despite advances in treatment, prognosis remains poor. Using the SEER database, we defined a cohort of adult patients for the years 2000-2009 with confirmed GBM and minimum follow-up of 12 months. A total of 14,675 patients with GBM met the inclusion criteria. Demographic, clinical, and treatment variables were examined. Death was the primary outcome. Median survival time was 11 months. Patients had increasingly longer survival over the decade span. We found, on multivariate analysis, that significantly worse survival was associated with age >75 years, male sex, unmarried status, and non-Hispanic Caucasian race/ethnicity. Patients in the Northeast had a significantly lower risk of mortality. Patients with tumors that were non-lateralized and >3 cm fared worse. Patients who did not receive adjuvant radiation also had worse outcomes. Gross total resection imparted a survival advantage for patients compared to biopsy or partial resection. Thus, this report adds to the growing body of literature supporting the positive role of maximal resection on patient survival. PMID- 26122382 TI - Cervicomedullary neurocysticercosis causing obstructive hydrocephalus. AB - We present a 45-year-old man with tussive headache and blurred vision found to have obstructive hydrocephalus from a neurocysticercal cyst at the cervicomedullary junction who underwent surgical removal of the cyst. We performed a suboccipital craniectomy to remove the cervicomedullary cyst en bloc. Cyst removal successfully treated the patient's headaches without necessitating permanent cerebrospinal fluid diversion. Neurocysticercosis is the most common parasite infection of the central nervous system causing seizures and, less commonly, hydrocephalus. Intraventricular cysts or arachnoiditis usually cause hydrocephalus in neurocysticercosis but craniocervical junction cysts causing obstructive hydrocephalus are rare. Neurocysticercosis at the craniocervical junction may cause Chiari-like symptoms. In the absence of arachnoiditis and leptomeningeal enhancement, surgical removal of the intact cyst can lead to favorable outcomes. PMID- 26122383 TI - Deep brain stimulation for chronic pain. AB - Deep brain stimulation (DBS) is a neurosurgical intervention popularised in movement disorders such as Parkinson's disease, and also reported to improve symptoms of epilepsy, Tourette's syndrome, obsessive compulsive disorders and cluster headache. Since the 1950s, DBS has been used as a treatment to relieve intractable pain of several aetiologies including post stroke pain, phantom limb pain, facial pain and brachial plexus avulsion. Several patient series have shown benefits in stimulating various brain areas, including the sensory thalamus (ventral posterior lateral and medial), the periaqueductal and periventricular grey, or, more recently, the anterior cingulate cortex. However, this technique remains "off label" in the USA as it does not have Federal Drug Administration approval. Consequently, only a small number of surgeons report DBS for pain using current technology and techniques and few regions approve it. Randomised, blinded and controlled clinical trials that may use novel trial methodologies are desirable to evaluate the efficacy of DBS in patients who are refractory to other therapies. New imaging techniques, including tractography, may help optimise electrode placement and clinical outcome. PMID- 26122384 TI - Risk of anterior cruciate ligament fatigue failure is increased by limited internal femoral rotation during in vitro repeated pivot landings. AB - BACKGROUND: A reduced range of hip internal rotation is associated with increased peak anterior cruciate ligament (ACL) strain and risk for injury. It is unknown, however, whether limiting the available range of internal femoral rotation increases the susceptibility of the ACL to fatigue failure. HYPOTHESIS: Risk of ACL failure is significantly greater in female knee specimens with a limited range of internal femoral rotation, smaller femoral-ACL attachment angle, and smaller tibial eminence volume during repeated in vitro simulated single-leg pivot landings. STUDY DESIGN: Controlled laboratory study. METHODS: A custom built testing apparatus was used to simulate repeated single-leg pivot landings with a 4*-body weight impulsive load that induces knee compression, knee flexion, and internal tibial torque in 32 paired human knee specimens from 8 male and 8 female donors. These test loads were applied to each pair of specimens, in one knee with limited internal femoral rotation and in the contralateral knee with femoral rotation resisted by 2 springs to simulate the active hip rotator muscles' resistance to stretch. The landings were repeated until ACL failure occurred or until a minimum of 100 trials were executed. The angle at which the ACL originates from the femur and the tibial eminence volume were measured on magnetic resonance images. RESULTS: The final Cox regression model (P = .024) revealed that range of internal femoral rotation and sex of donor were significant factors in determining risk of ACL fatigue failure. The specimens with limited range of internal femoral rotation had a failure risk 17.1 times higher than did the specimens with free rotation (P = .016). The female knee specimens had a risk of ACL failure 26.9 times higher than the male specimens (P = .055). CONCLUSION: Limiting the range of internal femoral rotation during repetitive pivot landings increases the risk of an ACL fatigue failure in comparison with free rotation in a cadaveric model. CLINICAL RELEVANCE: Screening for restricted internal rotation at the hip in ACL injury prevention programs as well as in individuals with ACL injuries and/or reconstructions is warranted. PMID- 26122385 TI - Utility of the Instability Severity Index Score in Predicting Failure After Arthroscopic Anterior Stabilization of the Shoulder. AB - BACKGROUND: The redislocation rate after arthroscopic stabilization for anterior glenohumeral instability is up to 30%. The Instability Severity Index Score (ISIS) was developed to preoperatively rationalize the risk of failure, but it has not yet been validated by an independent group. PURPOSE: To assess the utility of the ISIS in predicting failure of arthroscopic anterior shoulder stabilization and to identify other preoperative factors for failure. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A case-control study was performed on 141 consecutive patients, comparing those who suffered failure of arthroscopic stabilization with those who had successful arthroscopic stabilization. The mean follow-up time was 47 months (range, 24-132 months). The ISIS was applied retrospectively, and an analysis was performed to establish independent risk factors for failure. A receiver operator coefficient curve was constructed to set a threshold ISIS for considering alternative surgery. RESULTS: Of 141 patients, 19 (13.5%) suffered recurrent instability. The mean ISIS of the failed stabilization group was higher than that of the successful stabilization group (5.1 vs 1.7; P < .001). Independent risk factors for failure were Hill Sachs lesion (P < .001), glenoid bone loss (P < .001), age <21 years at the time of surgery (P < .001), age at first dislocation (P = .01), competitive-level participation in sports (P < .001), and participation in contact or overhead sports (P = .03). The presence of glenoid bone loss carried the highest risk of failure (70%). There was a 70% risk of failure if the ISIS was >=4, as opposed to a 4% risk of failure if the ISIS was <4. CONCLUSION: This is the first completely independent study to confirm that the ISIS is a useful preoperative tool. It is recommended that surgeons consider alternative forms of stabilization if the ISIS is >=4. PMID- 26122386 TI - Factors associated with failure of nonoperative treatment in lateral epicondylitis. AB - BACKGROUND: Lateral epicondylitis is a common cause of elbow pain that is treated with a variety of nonoperative measures and often improves with time. Minimal research is available on patients in whom these nonoperative treatments fail. PURPOSE: To identify baseline patient and disease factors associated with the failure of nonoperative treatment of lateral epicondylitis, defined as surgery after a period of nonoperative treatment. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: A total of 580 patients treated for lateral epicondylitis at a tertiary center between 2007 and 2012 were analyzed. Disease specific and patient demographic characteristics were compared between patient groups (nonoperative vs surgical treatment). A multivariable logistic regression model was created based on preliminary univariate testing to determine which characteristics were associated with failure of nonoperative treatment. RESULTS: Of the 580 patients, 92 (16%) underwent surgical treatment at a mean of 6 months (range, 0-31 months) from their initial visit. Univariate analysis demonstrated a potential association (P < .10) between operative management and the following factors at initial diagnosis: increased age, body mass index, duration of symptoms, presence of radial tunnel syndrome, prior injection, physical therapy, splinting, smoking, workers' compensation, a labor occupation, use of narcotics, use of antidepressant medications, and previous orthopaedic surgery. In the final multivariable model, a workers' compensation claim (odds ratio [OR], 8.1), prior injection (OR, 5.6), the presence of radial tunnel syndrome (OR, 3.1), previous orthopaedic surgery (OR, 3.2), and duration of symptoms >12 months (OR, 2.5) remained significant independent predictors of surgical treatment. CONCLUSION: This study identifies risk factors for surgical treatment for lateral epicondylitis. While these findings do not provide information regarding causal factors associated with surgery, these patient and disease-specific considerations may be helpful when counseling patients regarding treatment options and the likelihood of the success of continued nonoperative treatment. PMID- 26122387 TI - Development and verification of a protocol to quantify hip joint kinematics: an evaluation of ice hockey goaltender pads on hip motion. AB - BACKGROUND: The butterfly save technique is commonly used by ice hockey goaltenders and has recently been identified as a potential mechanism for hip joint injuries due to the extreme body positions involved. Unfortunately, commonly used kinematic marker sets that determine these body positions are heavily influenced by skin motion artifact and are obscured by protective equipment, making it difficult to obtain reliable measures of hip motion. PURPOSE: To create a new kinematic protocol that could be used when protective equipment prevents typical marker placements and to use this protocol to quantify hip kinematics and butterfly performance in 4 different goalie pad conditions. STUDY DESIGN: Controlled laboratory study. METHODS: A new marker set consisting of marker clusters attached to the lateral thigh and posterior leg was developed. This marker set was verified by evaluating the root mean square (RMS) difference between the developed testing marker set and the calibrated anatomic systems technique marker set during passive range of motion (ROM) tests. The testing marker set was then used in a repeated-measures study in which 12 junior goaltenders performed 5 butterfly movements on synthetic ice, in 4 different goalie pad conditions (control, flexible-wide leg channel, flexible-tight leg channel, and stiff-wide leg channel). RESULTS: The grouped RMS differences and SDs calculated during verification were 1.43 degrees +/- 0.41 degrees , 1.0 degrees +/- 0.39 degrees , and 3.32 degrees +/- 1.32 degrees for hip flexion extension, abduction-adduction, and internal-external rotation, respectively. There was no significant main effect of goal pad condition on the peak amount of hip internal rotation; however, there was a significant main effect of goal pad condition on the butterfly width (P = .022). Post hoc comparisons revealed that the butterfly width was significantly smaller in the control pad condition compared with the flexible-tight pad condition (P = .03). CONCLUSION: The new marker set enabled measurements of hip joint kinematics while subjects are wearing protective equipment that are not possible with other marker sets. Interindividual variations in performance of the butterfly technique influenced the amount of hip internal rotation achieved; however, on average, goaltenders exceeded their active internal ROM during butterfly movements. CLINICAL RELEVANCE: Exceeding internal rotation range of hip motion may make goaltenders susceptible to hip injuries such as femoral acetabular impingement. PMID- 26122388 TI - Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update. AB - Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder, characterized by peripheral blood monocytosis and overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs). Clonal cytogenetic changes are seen in up to 30 % patients, while approximately 90 % have detectable molecular abnormalities. Most patients are diagnosed in the seventh decade of life. Gene mutations in ten-eleven translocation (TET) oncogene family member 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), and RAS (20-30 %) are frequent, with only frame shift and nonsense ASXL1 mutations negatively impacting overall survival. With the lack of formal guidelines, management and response criteria are often extrapolated from MDS and MPN. Contemporary molecularly integrated CMML-specific prognostic models include the Groupe Francais des Myelodysplasies (GFM) model and the Molecular Mayo Model, both incorporating ASXL1 mutational status. Hypomethylating agents and allogeneic stem cell transplant remain the two most commonly used treatment strategies, with suboptimal results. Clinical trials exploiting epigenetic and signal pathway abnormalities, frequent in CMML, offer hope and promise. PMID- 26122389 TI - Is There a Role for Flow Cytometry in the Evaluation of Patients With Myelodysplastic Syndromes? AB - This review focuses on the most recent literature concerning flow cytometry (FCM) application for diagnosis of myelodysplastic syndrome (MDS). Aberrant FCM results have been defined as abnormalities in at least three tested features comprising at least two bone marrow (BM) cell compartments. FCM results should be interpreted together with the BM smear cytology, the morphological assessment of BM biopsy, and cytogenetic results. Including FCM in the pre-treatment assessment may provide not only diagnostic but also prognostic information. Further studies are needed to evaluate the role of FCM in individual risk assessment for MDS patients and in therapy choice and/or follow-up. PMID- 26122390 TI - Dietary Restriction Behaviors and Binge Eating in Anorexia Nervosa, Bulimia Nervosa and Binge Eating Disorder: Trans-diagnostic Examination of the Restraint Model. AB - OBJECTIVE: To compare dietary restriction behaviors among adults with eating disorders involving binge eating, including anorexia nervosa-binge/purge subtype (AN-BE/P), bulimia nervosa (BN), and binge eating disorder (BED), and to examine whether dietary restriction behaviors impact binge eating frequency across diagnoses. METHOD: Participants included 845 treatment seeking adults (M=30.42+10.76years) who met criteria for DSM-5 AN-BE/P (7.3%;n=62), BN (59.7%;n=504), and BED (33.0%;n=279). All participants self-reported their past and current eating disorder symptoms on the Eating Disorder Questionnaire. RESULTS: Adults with AN-BE/P and BN reported significantly more dietary restriction behaviors (e.g. eating fewer meals per day, higher frequency of fasting, consuming small and low calorie meals) in comparison to adults with BED. Adults with AN-BE/P and BN who reported restricting food intake via eating fewer meals per day had more frequent binge eating episodes. However, adults with BN who reported restricting food intake via eating small meals and low calorie meals had less frequent binge eating episodes. DISCUSSION: This study provides mixed support for the restraint model by suggesting that not all dietary restriction behaviors are associated with higher levels of binge eating. It may be that adults with BN who report a higher frequency of eating small and low calorie meals display more control over their eating in general, and therefore also have lower frequency of binge eating. Clinicians should assess for dietary restriction behaviors at the start of treatment prior to assuming that all forms of strict dieting and weight control behaviors similarly impact binge eating. PMID- 26122391 TI - SF-1 (NR5A1) expression is stimulated by the PKA pathway and is essential for the PKA-induced activation of LIPE expression in Y-1 cells. AB - In the adrenal cortex, corticotropin induces the expression of several genes encoding proteins involved in the synthesis and intracellular transport of steroid hormones via the protein kinase A (PKA) signalling pathway, and this process is mediated by steroidogenic factor-1 (SF-1). This study was designed to elucidate the influence of the PKA and PKC pathways on the expression of the SF-1 gene in mouse adrenocortical cells, line Y-1. It has also been attempted to answer the question whether or not SF-1 plays a role in the PKA-induced expression of LIPE gene encoding hormone-sensitive lipase/cholesteryl esterase, which supplies cholesterol for steroid hormone synthesis. In this study, we found that stimulation of the PKA pathway caused a significant increase in SF-1 expression, and that this effect was abolished by the PKA inhibitor, H89. Decreased SF-1 gene transcript levels were seen with the simultaneous activation of PKA and PKC, suggesting a possible interaction between the PKA and PKC pathways. It was also observed that SF-1 increased the transcriptional activity of the LIPE gene by interacting with the SF-1 response element located in promoter A. Moreover, transient silencing of SF-1 expression with specific siRNAs abolished PKA-stimulated transcription of the LIPE gene, indicating that SF-1 is an important regulator of LIPE expression in Y-1 cells and thus could play a role in the regulation of the cholesterol supply for adrenal steroidogenesis. PMID- 26122392 TI - Identification of functional leptin receptors expressed in ventricular mitochondria. AB - Leptin is a 16 kDa pro-satiety peptide produced primarily not only by white adipocytes but also by numerous other tissues including the heart. Circulating leptin exerts its effect through specific receptors, although its principle actions are dependent on the activation of the long form of the leptin receptor, termed OBRb. As leptin is also produced within the cardiomyocyte, we hypothesized that the peptide can also exert effects by targeting intracellular sites. Accordingly, we determined whether cardiac mitochondria express functional leptin receptors. The presence of mitochondrial OBRb was identified through Western blotting of isolated mitochondria, immunofluorescence as well as immunogold labeling with electron microscopy. Although leptin had no direct effect on mitochondrial integrity, it profoundly enhanced the ability of calcium to induce mitochondrial swelling, an effect partially reversed by an OBR antagonist. 24 h exposure to leptin (50 ng/ml) was without effect on mitochondria in cultured neonatal rat ventricular myocytes in contrast to leptin tagged with a 10 amino acid membrane translocation sequence which significantly induced mitochondrial permeability transition pore opening, whereas both leptins produced a hypertrophic response. Our results therefore show that mitochondria express functional OBR which may be of importance toward understanding the role of intracellularly derived leptin in cardiac physiology and pathology. PMID- 26122393 TI - Autophagy regulates hyperoxia-induced intracellular accumulation of surfactant protein C in alveolar type II cells. AB - Surfactant protein C (SP-C) deficiency is a risk factor for hyperoxia-induced bronchopulmonary dysplasia in newborn infants. However, the role of SP-C deficiency in the process is unclear. Here, using neonatal rat BPD model and MLE 12, mouse alveolar epithelial type II cell, we examined the changes of SP-C levels during hyperoxia. Immunohistochemistry, immunofluorescence, and ELISA analysis showed SP-C accumulation in alveolar epithelial type II cells. Electron microscopy further demonstrated the accumulation of lamellar bodies and the co localization of lamellar bodies with autophagosomes in the cytoplasm of alveolar epithelial type II cells. The inhibition of autophagy with 3-Methyladenine and knockdown of Atg7 abolished hyperoxia-induced SP-C accumulation in the cytoplasm. Furthermore, inhibition of JNK signaling with SP600125 suppressed hyperoxia induced Atg7 expression and SP-C accumulation. These findings suggest that hyperoxia triggers autophagy via JNK signaling-mediated Atg7 expression, which promotes the accumulation of SP-C within alveolar epithelial type II cells. Our data provide a potential approach for hyperoxic lung injury therapy by targeted pharmacological inhibition of autophagic pathway. PMID- 26122394 TI - Multistate outbreak of listeriosis caused by imported cheese and evidence of cross-contamination of other cheeses, USA, 2012. AB - Listeria monocytogenes is a foodborne pathogen that can cause bacteraemia, meningitis, and complications during pregnancy. In July 2012, molecular subtyping identified indistinguishable L. monocytogenes isolates from six patients and two samples of different cut and repackaged cheeses. A multistate outbreak investigation was initiated. Initial analyses identified an association between eating soft cheese and outbreak-related illness (odds ratio 17.3, 95% confidence interval 2.0-825.7) but no common brand. Cheese inventory data from locations where patients bought cheese and an additional location where repackaged cheese yielded the outbreak strain were compared to identify cheeses for microbiological sampling. Intact packages of imported ricotta salata yielded the outbreak strain. Fourteen jurisdictions reported 22 cases from March-October 2012, including four deaths and a fetal loss. Six patients ultimately reported eating ricotta salata; another reported eating cheese likely cut with equipment also used for contaminated ricotta salata, and nine more reported eating other cheeses that might also have been cross-contaminated. An FDA import alert and US and international recalls followed. Epidemiology-directed microbiological testing of suspect cheeses helped identify the outbreak source. Cross-contamination of cheese highlights the importance of using validated disinfectant protocols and routine cleaning and sanitizing after cutting each block or wheel. PMID- 26122397 TI - Increased expression of integrin alpha6beta4 in the basement membrane zone lining the sebaceous glands in hidradenitis suppurativa. PMID- 26122398 TI - Small access postaural parotidectomy: an analysis of techniques, feasibility and safety. AB - For cosmetic consideration of parotidectomy, the surgical approaches have evolved from Blair incision through modified facelift incision to postaural-hairline incision. The present study aims at evaluating the feasibility and safety of the new technique of postaural approach. Parotidectomy was performed with a 4-5 cm incision in the postaural sulcus. There were 69 patients who were assessed pre operatively feasible for consideration of the postaural parotidectomy. There were 56 (81 %) patients who could have the postaural parotidectomy successfully without complications. The minimally invasive postaural approach is a further step in cosmetic consideration of parotidectomy. It is a feasible and safe approach for most small to medium size benign parotid tumors located in the mid and lower pole regions of the parotid gland. PMID- 26122400 TI - A matter of priorities? Exploring the persistent gender pay gap in hospital medicine. AB - BACKGROUND: Gender earnings disparities among physicians exist even after considering differences in specialty, part-time status, and practice type. Little is known about the role of job satisfaction priorities on earnings differences. OBJECTIVE: To examine gender differences in work characteristics and job satisfaction priorities, and their relationship with gender earnings disparities among hospitalists. DESIGN: Observational cross-sectional survey study. PARTICIPANTS: US hospitalists in 2010. MEASUREMENTS: Self-reported income, work characteristics, and priorities among job satisfaction domains. RESULTS: On average, women compared to men hospitalists were younger, less likely to be leaders, worked fewer full-time equivalents, worked more nights, reported fewer daily billable encounters, more were pediatricians, worked in university settings, worked in the Western United States, and were divorced. More hospitalists of both genders prioritized optimal workload among the satisfaction domains. However, substantial pay ranked second in prevalence by men and fourth by women. Women hospitalists earned $14,581 less than their male peers in an analysis adjusting for these differences. CONCLUSIONS: The gender earnings gap persists among hospitalists. A portion of the disparity is explained by the fewer women hospitalists compared to men who prioritize pay. PMID- 26122401 TI - Risk of new-onset type II diabetes after appendicectomy. AB - BACKGROUND: Altered immune function after appendicectomy has been associated with autoimmune disease, even though the mechanisms are not clearly elucidated. This study aimed to investigate whether the frequency of new-onset type II diabetes was increased after appendicectomy in a case-control study. METHODS: This was a retrospective cohort study from the Taiwan Longitudinal Health Insurance Database 2000. The relative risk was compared with that in the general population using population-based data. Each patient was tracked for a 3-year interval to identify those who developed type II diabetes. Cox proportional hazard regression analysis was used to assess the risk of type II diabetes during follow-up. RESULTS: A total of 31,512 patients were included in the study, of whom 5252 had an appendicectomy (study cohort) and 26,260 were matched for comparison. Some 714 patients (2.3 per cent) developed type II diabetes during the 3-year follow-up, 161 in the study cohort (3.1 per cent) and 553 in the comparison cohort (2.1 per cent). The adjusted hazard ratio (HR) for type II diabetes in the study cohort was 1.45 (95 per cent c.i. 1.22 to 1.74). This increased risk was most pronounced in men (adjusted HR 1.47, 1.16 to 1.88) and in those with a perforated appendix (adjusted HR 2.28, 1.71 to 3.03), and applied only to patients younger than 65 years of age. CONCLUSION: An increased risk of new-onset type II diabetes within 3 years after appendicectomy was found in patients aged less than 65 years. The risk was highest in men and in those with complicated appendicitis. PMID- 26122399 TI - The redox biology network in cancer pathophysiology and therapeutics. AB - The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1) and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic), greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular heterogeneity and the hypoxia map in the tumor niche, along with the adjoining and systemic effects of oxidative stress-based therapies. PMID- 26122402 TI - An ultrasonographic scoring method for transabdominal monitoring of ascarid burdens in foals. AB - REASONS FOR PERFORMING STUDY: Parascaris spp. infections can lead to life threatening small intestinal impactions in foals. Currently available diagnostic techniques cannot estimate the magnitude of an ascarid burden, and hence identify foals potentially at risk of developing impactions. OBJECTIVES: To describe and evaluate an ultrasonographic transabdominal scoring technique for monitoring of ascarid burdens in foals and to perform a cost-benefit analysis of the application of this technique. STUDY DESIGN: A transabdominal ultrasonographic technique was validated against ascarid worm counts from 10 foals aged 162-294 days. In a treatment trial, 15 foals were randomly allocated to 3 treatment groups: ivermectin, oxibendazole and no treatment. Blinded ultrasound examinations were performed daily for 5 consecutive days following treatment. Foals were examined ultrasonographically twice by the same investigator, and by different investigators for intra- and interobserver agreement evaluation. Cost benefit analyses identified threshold values for the probability of ascarid impactions above which the screening method becomes cost-effective. METHODS: The ultrasound technique used 3 locations along the ventral midline. An ascarid scoring system was established that assessed the magnitude of ascarid burden ranging from 1-4. The method was validated against worm burdens of 10 worms and above with calculation of diagnostic specificity, sensitivity, and predictive values. Treatment trial data were evaluated statistically using mixed model analysis. Kappa values were generated for intra- and interobserver agreement. RESULTS: Two consecutive examinations were found to detect worm burdens >10 ascarids reliably. Ascarid scores declined in response to both anthelmintic treatments, although differences were not statistically significant. Kappa values indicated fair to moderate intra- and interobserver agreements. The majority of cost-benefit analyses indicated that ultrasound examinations are cost effective when the probability of ascarid impactions is above a range of 0.0001-0.0082 (i.e. 1 in 10,000 to 8 in 1000 foals). CONCLUSIONS: The ultrasonographic screening techniques can be a useful tool for monitoring ascarid burdens in foals. PMID- 26122403 TI - Estimation of the optimum standardized ileal digestible total sulfur amino acid to lysine ratio in late finishing gilts fed low protein diets supplemented with crystalline amino acids. AB - A total of 90 gilts were used to investigate the effects of various standard ileal digestible (SID) total sulfur amino acid (TSAA) to lysine (Lys) ratios on the performance and carcass characteristics of late finishing gilts receiving low crude protein (CP) diets supplemented with crystalline amino acids (CAA). Graded levels of crystalline methionine (Met) (0, 0.3, 0.5, 0.8 or 1.1 g/kg) were added to the basal diet to produce diets providing SID TSAA to Lys ratios of 0.48, 0.53, 0.58, 0.63 or 0.68. At the termination of the experiment, 30 gilts (one pig per pen) with an average body weight (BW) of 120 kg were killed to evaluate carcass traits. Increasing the SID TSAA to Lys ratio increased average daily gain (ADG) (linear and quadratic effect, P < 0.05), improved feed conversion ratio (FCR) (linear and quadratic effect, P < 0.05) and decreased serum urea nitrogen (SUN) concentration (linear and quadratic effect, P < 0.05) of finishing gilts. No effects were obtained for carcass traits. The optimum SID TSAA to Lys ratios to maximize ADG as well as to minimize FCR and SUN levels were 0.57, 0.58 and 0.53 using a linear-break point model and 0.64, 0.62 and 0.61 using a quadratic model. PMID- 26122405 TI - Bile acids and nonalcoholic fatty liver disease: An intriguing relationship. PMID- 26122404 TI - Genome-wide Identification and Expression Analysis of the CDPK Gene Family in Grape, Vitis spp. AB - BACKGROUND: Calcium-dependent protein kinases (CDPKs) play vital roles in plant growth and development, biotic and abiotic stress responses, and hormone signaling. Little is known about the CDPK gene family in grapevine. RESULTS: In this study, we performed a genome-wide analysis of the 12X grape genome (Vitis vinifera) and identified nineteen CDPK genes. Comparison of the structures of grape CDPK genes allowed us to examine their functional conservation and differentiation. Segmentally duplicated grape CDPK genes showed high structural conservation and contributed to gene family expansion. Additional comparisons between grape and Arabidopsis thaliana demonstrated that several grape CDPK genes occured in the corresponding syntenic blocks of Arabidopsis, suggesting that these genes arose before the divergence of grapevine and Arabidopsis. Phylogenetic analysis divided the grape CDPK genes into four groups. Furthermore, we examined the expression of the corresponding nineteen homologous CDPK genes in the Chinese wild grape (Vitis pseudoreticulata) under various conditions, including biotic stress, abiotic stress, and hormone treatments. The expression profiles derived from reverse transcription and quantitative PCR suggested that a large number of VpCDPKs responded to various stimuli on the transcriptional level, indicating their versatile roles in the responses to biotic and abiotic stresses. Moreover, we examined the subcellular localization of VpCDPKs by transiently expressing six VpCDPK-GFP fusion proteins in Arabidopsis mesophyll protoplasts; this revealed high variability consistent with potential functional differences. CONCLUSIONS: Taken as a whole, our data provide significant insights into the evolution and function of grape CDPKs and a framework for future investigation of grape CDPK genes. PMID- 26122406 TI - Focal Cerebral Arteriopathy: The Face With Many Names. AB - OBJECTIVE: Focal cerebral arteriopathy is a term used to describe unilateral intracranial arteriopathy involving the distal internal carotid artery and proximal segments of the middle and anterior cerebral artery. We describe the disease course of 10 pediatric arterial ischemic stroke patients with focal cerebral arteriopathy from a single quaternary-care center. METHODS: We retrospectively reviewed pediatric stroke patients with focal cerebral arteriopathy without lenticulostriate collaterals treated at our institution between 2005 and 2014. Angiography was reviewed by a child neurologist and a pediatric neuroradiologist, and chart reviews were performed. RESULTS: Ten individuals with focal cerebral arteriopathy were identified. At the time of stroke presentation, four patients were diagnosed with arterial dissection, two with moyamoya disease, one with embolic occlusion, one with hemorrhagic stroke, and two with arterial dissection or vasculitis. At last follow-up, six patients had a change in diagnosis: four were diagnosed with transient cerebral arteriopathy, two with arterial dissection, and four with moyamoya disease. Four children experienced stroke recurrence. All were administered aspirin, one was administered heparin, two were administered intravenous tissue plasminogen activator, and five underwent surgical revascularization. CONCLUSIONS: Among pediatric stroke patients with a similar angiographic appearance, there is variable concordance between diagnosis, prognosis and treatment choice. Improved consensus-based diagnostic criteria and further research is needed to identify disease biomarkers and predictors of arterial progression. PMID- 26122407 TI - Longitudinal relationships between gratitude, deliberate rumination, and posttraumatic growth in adolescents following the Wenchuan earthquake in China. AB - To examine the longitudinal relationship between gratitude, deliberate rumination and posttraumatic growth (PTG) in the adolescent survivors after the Wenchuan earthquake, 217 adolescent survivors were randomly selected from several primary and secondary schools in the county of Wenchuan, and were assessed by questionnaires at three and a half years (T1), four and a half years (T2), five and a half years (T3) after the Wenchuan earthquake, respectively. The results found that there was a one-way predictive relationship of gratitude onto PTG from T1 to T3, and gratitude predicted deliberate rumination from T1 to T2 but not T2 to T3. Deliberate rumination only had a significant positive effect on PTG from T2 to T3, and PTG only predicted deliberate rumination from T1 to T2. These results indicated that gratitude could be a stable predictive factor for the development of PTG, and gratitude could also affect PTG by deliberate rumination. In addition, the predictive effect between deliberate rumination and PTG is unstable with time change. PMID- 26122408 TI - Correlates of public support toward federal funding for harm reduction strategies. AB - BACKGROUND: Historically, US federal policy has not supported harm reduction interventions, such as safe injection facilities (SIFs) and needle and syringe programs (NSPs), which can reduce the burden associated with injection drug use. Given recent increases in abuse of both legal and illegal opioids, there has been a renewed debate about effective ways to address this problem. The current study (1) assessed participants' support for SIFs and NSPs, and (2) evaluated several demographic factors (e.g., age, gender, race, education, political ideology, and religiosity) and individual differences in stigmatizing beliefs about people who inject drugs (PWID) that might relate to support for these interventions. METHODS: U.S. adults (N = 899) completed a web-based study that assessed self reported support for NSPs and SIFs, and stigma about PWID. RESULTS: The majority of participants were at least somewhat supportive of both NSPs and SIFs. Regression analyses indicated greater support for NSPs and SIFs was predicted by more liberal political ideology, more agreement that PWID deserve help rather than punishment, older age, and male gender. Also, participants who endorsed lower stigma about PWID were more supportive of NSPs and SIFs. Race, religiosity, and education did not predict support for NSPs and SIFs. CONCLUSIONS: Most participants tended to report support for harm reduction strategies. Age, political ideology, and individual differences in stigmatizing beliefs about PWID were significantly associated with support. Given the potential malleability of stigmatizing beliefs, efforts that seek to shift stigma about PWID could have important implications for public policy towards harm reduction strategies for PWID. PMID- 26122409 TI - Local manifold learning for multiatlas segmentation: application to hippocampal segmentation in healthy population and Alzheimer's disease. AB - AIMS: Automated hippocampal segmentation is an important issue in many neuroscience studies. METHODS: We presented and evaluated a novel segmentation method that utilized a manifold learning technique under the multiatlas-based segmentation scenario. A manifold representation of local patches for each voxel was achieved by applying an Isomap algorithm, which can then be used to obtain spatially local weights of atlases for label fusion. The obtained atlas weights potentially depended on all pairwise similarities of the population, which is in contrast to most existing label fusion methods that only rely on similarities between the target image and the atlases. The performance of the proposed method was evaluated for hippocampal segmentation and compared with two representative local weighted label fusion methods, that is, local majority voting and local weighted inverse distance voting, on an in-house dataset of 28 healthy adolescents (age range: 10-17 years) and two ADNI datasets of 100 participants (age range: 60-89 years). We also implemented hippocampal volumetric analysis and evaluated segmentation performance using atlases from a different dataset. RESULTS: The median Dice similarities obtained by our proposed method were approximately 0.90 for healthy subjects and above 0.88 for two mixed diagnostic groups of ADNI subjects. CONCLUSION: The experimental results demonstrated that the proposed method could obtain consistent and significant improvements over label fusion strategies that are implemented in the original space. PMID- 26122410 TI - Subclavian Vein Stent Fracture and Venous Motion. AB - Primary subclavian vein stents are not recommended for venous thoracic outlet syndrome before surgical decompression by first rib resection due to a high risk of fracture because they are compressed between the clavicle and first rib. After rib removal, however, stent insertion has been advocated for venous restenosis, and it is felt that stent fracture is unlikely to occur. We present a case suggesting that repetitive differential vein movement during respiration may be one of the causative factors for stent fractures occurring in this anatomic region. PMID- 26122411 TI - Endovascular Repair of a False Aneurysm Developing from IgG4-Related Periaortitis during Corticosteroid Therapy. AB - Immunoglobulin G4 (IgG4)-related disease is a systemic autoimmune disease that can affect various organs. Corticosteroid therapy is generally an effective treatment; however, IgG4-related aortic lesions pose a risk of aortic rupture related to corticosteroid use. Here, we report a case of IgG4-related periaortitis complicated with a false aneurysm during corticosteroid therapy. Although endovascular repair was successfully performed, autoimmune pancreatitis and sclerosing cholangitis emerged after surgery. The multiple lesions associated with IgG4-related disease were resolved through continuous corticosteroid therapy. Our case suggests that both appropriate surgical intervention and continuous corticosteroid therapy are essential for the treatment of IgG4-related periaortitis. PMID- 26122412 TI - Endovascular Repair of Descending Thoracic Aorta in Loeys-Dietz II Syndrome. AB - Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder that is predominantly characterized by involvement of the aorta, manifesting as aneurysmal dilatation or aortic dissection. Patients with LDS manifest with spontaneous aneurysms and dissections of central and peripheral arterial beds. We present 2 cases of young male patients with Loeys-Dietz II aortopathy, who manifested with spontaneous intimal tear of descending thoracic aorta and contained aortic rupture. Both patients were managed by endovascular repair, with collaborative efforts of teams comprising interventional cardiologists and radiologists, and a vascular surgeon. PMID- 26122413 TI - Usefulness of Endovascular Therapy for Penile Gangrene Secondary to Calciphylaxis: A Case Report. AB - We here report a case of successful endovascular therapy for penile gangrene in a patient with calciphylaxis and a long history of diabetes mellitus and end-stage renal disease on dialysis. The internal iliac artery, with 75% stenosis, was treated with balloon-expandable bare metal stent implantation, whereas the inferior gluteal artery, 75% stenosis, was treated with balloon dilatation. After endovascular therapy, the intractable penile pain immediately resolved, and penile salvage with complete wound healing was achieved 6 months after the procedure. PMID- 26122414 TI - The Antegrade Approach Using Transbrachial Access Improves Technical Success Rate of Endovascular Recanalization of TASC C-D Aortoiliac Occlusion in Case of Failed Femoral Access. AB - BACKGROUND: Technical success rates of endovascular recanalizations for Trans Atlantic Inter-Society Consensus (TASC) C-D chronic occlusions are highly variable and depend on the characteristics and sites of the lesions as well as on the operator experience. We hypothesized that an antegrade approach via transbrachial access could improve the technical success rate of endovascular treatment of TASC C-D occlusions in case of failed femoral access. METHODS: From January 2010 to December 2012, all patients with symptomatic chronic TASC C-D aortoiliac occlusion were treated with an endovascular-first approach. Recanalization was first attempted using a femoral access. In case of failure, an antegrade approach using a transbrachial access was performed. Patient characteristics, anatomic details, procedural data, and immediate outcomes were prospectively recorded. RESULTS: During the study period, 73 patients (99 arteries) were included. Twenty-seven (37%) patients had TASC C occlusions including 11 bilateral common iliac artery occlusions and 16 external iliac artery (EIA) occlusions involving the common femoral or the internal iliac arteries. Forty-six (63%) patients had TASC D occlusions including 10 aortoiliac occlusions, 31 unilateral occlusions of both common and EIAs, and 5 bilateral EIA occlusions. Technical success with femoral access has been obtained in 53 arteries. An antegrade approach via transbrachial access allowed technical success in the other arteries, except in 7 arteries. Overall technical success rate was 93%, and 2 complications were related to the brachial accesses including 1 thrombosis and 1 pseudoaneurysm both requiring a reintervention. CONCLUSIONS: Brachial access for TASC C-D aortoiliac chronic occlusion improves the technical success rate without the need for reentry devices. PMID- 26122415 TI - Vertebral Artery Transection in Nonpenetrating Trauma: A Series of 4 Patients. AB - Blunt cerebrovascular injury is a common and potentially devastating consequence of nonpenetrating trauma to the head and neck. The degree of injury ranges from minimal intimal disruption to complete transection with free extravasation. Although blunt carotid transection has been well characterized in clinical reports and radiologic studies, the computed tomographic angiography (CTA) features of blunt vertebral artery transection have not been well described. We report a series of 4 patients presenting to our level I trauma center with blunt vertebral artery transection, with an emphasis on their CTA imaging findings at presentation and their respective clinical courses. A brief review of the pertinent literature is provided. PMID- 26122416 TI - Use of Physician-Modified Endografts to Repair Unilateral or Bilateral Aortoiliac Aneurysms. AB - BACKGROUND: This article presents an endovascular approach to repair a unilateral or bilateral aortoiliac aneurysm with a bifurcated iliac limb that can maintain perfusion to the internal iliac artery (IIA) bilaterally through a brachial access. METHODS: A standard infrarenal aortic aneurysm repair is performed followed by iliac aneurysm exclusion. To obtain exclusion in the common iliac artery aneurysm, a bifurcated Endurant iliac limb is modified to compartmentalize iliac flow 2-3 cm above the internal iliac ostia. Then, a balloon-expandable covered stent graft is used to achieve sealing in the IIA and external iliac artery (EIA). The IIA is stented from the arm and the EIA is stented from the groin. RESULTS: There was no in-hospital or 30-day mortality. The procedural design was followed in each of the patients who received treatment. Technical success was 100%, short-term clinical success was 92%, and midterm clinical success was 83%. Average dosage of contrast medium was 116 mL (range, 55-193 mL), and average fluoroscopy time was 42.1 min (range, 20.8-91.6 min). Average length of hospital stay was 2.6 days (range, 1-9 days). There was 1 recorded endoleak. No reports of gluteal claudication, sexual dysfunction, or bowel or spinal claudication have been found. CONCLUSIONS: The technique described here does not require an up-and-over approach, allowing simplified bilateral repair. Although this is a promising technique, long-term durability needs to be evaluated in a controlled prospective study. PMID- 26122417 TI - Open Surgical Treatment of a Severe Case of Obstructive Calcifying Aortic Disease. AB - The obstructive calcifying aortic disease refers to severe calcifications of the descending aorta that obstruct or slow blood flow. Here, we report the case of a 65-year-old woman with recent onset of a very tight intermittent claudication and concomitant severe and uncontrolled hypertension, treated with a bypass graft between the proximal descending thoracic aorta and the supravisceral abdominal aorta. PMID- 26122418 TI - Salvage of Early-Failing Radiocephalic Fistulae with Techniques that Minimize Venous Dissection. AB - Although radiocephalic fistulae are the preferred hemodialysis access, juxta anastomotic stenosis is often responsible for early fistula failure. We hypothesized that wall ischemia from surgical manipulation leads to early juxta anastomotic neointimal hyperplasia and failure of maturation and that minimal venous dissection will improve surgical salvage, increasing fistula maturation rates. For failing-to-mature radiocephalic fistulae that develop early juxta anastomotic stenosis, we describe 3 variations to perform a new proximal anastomosis with a minimal dissection technique on the forearm cephalic vein: (1) side-to-side anastomosis, (2) radial artery deviation and reimplantation, or (3) radial artery deviation and loop reimplantation. Minimal dissection of the cephalic vein achieves fistula salvage without needing a more proximal site for access. PMID- 26122419 TI - Inferior Vena Cava Stent-Graft Sepsis. AB - We present the case of a patient with a complicated medical history, which included stent grafting as a life-saving measure for an iatrogenic inferior vena cava (IVC) injury. For persistent sepsis secondary to stent-graft infection, the patient underwent extraction of 2 IVC stent grafts, primary repair of a duodenal caval fistula, and repair of the IVC with an allograft vein patch. Discussion of this case sought to shed light on the intricacies involved in medical decision making in an era of advanced medical technology. PMID- 26122420 TI - Immediate and Late Open Conversion after Ovation Endograft. AB - The risk of intraoperative open conversion during endovascular aortic repair (EVAR) still remains a main issue, albeit in a small percentage of cases. Open conversion can be extremely demanding and risky in relation to the type of the stent graft implanted and can be somehow challenging even for the most experienced vascular surgeons. We discuss a case of immediate conversion and 1 case of late conversion in patients previously treated with EVAR using the Ovation stent graft. The design of the endograft and its proximal sealing allowed the partial preservation of the graft and its use for proximal and distal anastomosis with a Dacron graft in both presented cases. PMID- 26122422 TI - Successful Surgical Pulmonary Embolectomy for Massive Perinatal Embolism after Emergency Cesarean Section. AB - Pregnant women are exposed to an increased risk for developing pulmonary embolism (PE), a main cause for maternal mortality. Surgical pulmonary embolectomy is one important therapeutic and potential life-saving armamentarium, considering pregnancy as a relative contraindication for thrombolysis. We present a case of a 36-year-old woman with massive bilateral PE after emergent caesarean delivery, requiring reanimation by external heart massage. The onset of massive intrauterine bleeding contraindicated thrombolysis and emergency surgical pulmonary embolectomy, followed by a hysterectomy, were preformed successfully. Acute surgical pulmonary embolectomy may be an option in critically diseased high risk patients, requiring a multiteam approach, and should be part of the therapeutic armamentarium of the attending cardiac surgeon. PMID- 26122421 TI - The First Case of a Nellix Sac-Anchoring Endoprosthesis Removal for Aortoenteric Fistula. AB - The Nellix device (Endologix, Irvine, CA), has been designed with a brand new concept to seal the abdominal aortic aneurysms, minimizing endoleaks and reducing reinterventions. We present the first open conversion of a Nellix endograft due to aortoduodenal fistula of a 74-year-old male patient treated for an abdominal aortic aneurysms of 62-mm diameter. PMID- 26122423 TI - Unusual Case of Parkes Weber Syndrome with Aneurysm of the Left Common Iliac Vein and Thrombus in Inferior Vena Cava. AB - We report an unusual case of aneurysm of the left common iliac vein and thrombus formation in inferior vena cava associated with Parkes Weber syndrome (PWS). In addition to many already known clinical signs which determine PWS, common iliac vein aneurysm formation together with inferior vena cava thrombus present a new clinical feature and new challenges in treatment strategy of these patients. PMID- 26122424 TI - Life Saver: Aortic Wrapping. AB - Reoperative aortic root reconstruction remains a formidable surgical challenge. Thereof, the wrapping of Dacron graft using remnants of native aorta may be reasonable to avoid complications such as bleeding and infection. Our case that had a modified Bentall procedure at our institute was reoperated because of discontinuity between left ventricular outflow and valved aortic conduit. During reoperation, proximal portion of the valved conduit was partially separated from its attachment in the left ventricular outflow tract. The residual native aorta that was wrapped around the Dacron graft was like in a shape of sac. This technique may play a major role in preventing rupture of the ascending aorta in case of separation of valved conduit from left ventricular outflow. PMID- 26122425 TI - A Comparison of 1,470-nm Endovenous Laser Ablation and Radiofrequency Ablation in the Treatment of Great Saphenous Veins 10 mm or More in Size. AB - BACKGROUND: To compare 1,470-nm endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) in the treatment of patients with great saphenous vein diameters of 10 mm or more. METHODS: One hundred twenty consecutive patients presenting to the cardiovascular surgery department with a great saphenous vein diameter exceeding 10 mm at the saphenofemoral junction between January and December 2013 were included in the study. The first randomly selected 60 patients (group 1) received 1,470-nm EVLA and the other 60 patients (group 2) received RFA. Patients were assessed on the second day, the first week, and the first, third, and sixth months. Major and minor complications were recorded. RESULTS: Minor complications in EVLA and RFA were hyperemia at 20% and 30% (P = 0.50), ecchymosis at 16.7% and 48.3% (P = 0.02), and edema at 40.0% and 65.5% (P < 0.08), respectively. No major complication was observed in any patient. Recanalization developed during monitoring in 3 patients in the RFA group, a rate of 5%. No recanalization was observed in the EVLA group. Success rates in the EVLA and RFA groups were 100% and 95%, respectively. Mean time to return to daily activity was 0.7 days in the EVLA group and 1.4 days in the RFA group (P < 0.006), whereas mean time to return to work was 1.8 days in the EVLA group and 2.2 days in the RFA group (P < 0.07). There was no statistically significant difference between the groups in terms of pain during the procedure or postoperatively. Less pain was reported in the EVLA during both (P < 0.02). CONCLUSIONS: EVLA using a 1,470-nm radial fiber is superior to RFA in the treatment of saphenous veins larger than 10 mm in diameter. PMID- 26122426 TI - Reproductive performance of layer chickens reared on deep litter system with or without access to grass or legume pasture. AB - Despite several studies carried out to investigate the effects of access to pasture on poultry performance, there is a dearth of information on the comparative benefit of grass and legumes. This study investigated the effects of rearing systems [deep litter system (DL), deep litter with access to legumes (LP) or grass (GP) pastures] on the performance of ISA Brown layers. Two hundred and forty 12-week-old pullets were housed for this study. They were reared until 60 weeks of age. Eighty birds were assigned to each treatment; each treatment had four replicates of 20 birds each. Two birds per replicate were slaughtered at weeks 20, 35 and 58 for determination of the weights of liver, ovary, oviduct and the number of follicles. Daily egg production records were kept from the day of first egg to 42 weeks in lay. Body weights were recorded weekly. Results indicated that at 20 weeks of age, the hens kept in the LP had higher (p < 0.05) ovary weight (g) (34.98 +/- 1.4), oviduct weight (52.55 +/- 2.28) and oviduct length (cm) (49.73 +/- 11.34), and higher number of large yellow follicles (3.75 +/- 1.31) and small yellow follicles (12.75 +/- 5.17) than those in the GP (0.83 +/- 0.02, 1.68 +/- 0.19, 16.38 +/- 1.14, 0.00 and 0.00), and DL (1.03 +/- 0.11, 1.48 +/- 0.48, 14.43 +/- 0.58, 0.00 and 0.00) respectively. The age (days) at first oviposition was earlier (p < 0.05) in the LP (139.25 +/- 0.85) than that in the GP (146.75 +/- 0.48) and DL (146.75 +/- 0.48). The hen-day egg production was lower (p < 0.05) in GP (74.19 +/- 1.25) than that in the DL (78.82 +/- 0.78) and LP (79.93 +/- 1.13) at mid-laying phase. Concentrate feed intake was lower (p < 0.05) in LP and GP than DL suggesting economic benefit. It was concluded that access to LP enhanced the performance of layers than DL and GP as indicated by the parameters measured. PMID- 26122427 TI - Current status of invasive mosquito surveillance in the UK. AB - BACKGROUND: Non-native invasive mosquitoes have for many years made incursions into Europe, and are now established in many European countries. The continued European importation of potential vectors and their expansion within Europe increases their potential for importation and establishment in the UK. Coupled with increasing numbers of returning dengue and chikungunya infected travellers, the potential exists for transmission of vector borne disease in new regions. METHODS: To ensure a cost-effective risk assessment and preparedness strategy the UK employs a multi-faceted approach to surveillance for non-native Aedes mosquitoes, including passive and active surveillance strategies at a local, regional, and national level. Passive surveillance, including a national mosquito recording scheme and local authority nuisance biting reporting, are combined with targeted active surveillance at seaports, airports, used tyre importers, and motorway service stations. RESULTS: There is no evidence to date that any invasive Aedes species (e.g., Aedes albopictus, Aedes japonicus, Aedes aegypti) occur in the UK despite sharing many of the same routes that have been found to have facilitated their entry into other countries. CONCLUSIONS: This paper sets in context the UK approaches with other European countries and those recommended by the ECDC. It also highlights future UK strategies to enhance surveillance for non-native mosquitoes to help ensure that incursions can be managed, and these mosquitoes do not establish and public health is protected. Focus will be given to increasing the number of submissions of mosquitoes to passive surveillance schemes and maintaining active surveillance efforts at key routes of potential importation. PMID- 26122429 TI - Safety of graded challenge in allergic patients. PMID- 26122428 TI - Comparison of Somatostatin Receptor 2-Targeting PET Tracers in the Detection of Mouse Atherosclerotic Plaques. AB - PURPOSE: Rupture-prone atherosclerotic plaques are characterized by accumulation of macrophages, which have shown to express somatostatin type 2 receptors. We aimed to investigate whether somatostatin receptor-targeting positron emission tomography (PET) tracers, [(68)Ga]DOTANOC, [(18)F]FDR-NOC, and [(68)Ga]DOTATATE, can detect inflamed atherosclerotic plaques. PROCEDURES: Atherosclerotic IGF II/LDLR(-/-)ApoB(100/100) mice were studied in vivo and ex vivo for tracer uptake into atherosclerotic plaques. Furthermore, [(68)Ga]DOTANOC and [(68)Ga]DOTATATE were compared in a head-to-head setting for in vivo PET/X-ray computed tomography (CT) imaging characteristics. RESULTS: Ex vivo uptake of [(68)Ga]DOTANOC and [(68)Ga]DOTATATE in the aorta was higher in atherosclerotic mice compared to control C57Bl/6N mice, while the aortic uptake of [(18)F]FDR-NOC showed no genotype difference. Unlike [(18)F]FDR-NOC, [(68)Ga]DOTANOC and [(68)Ga]DOTATATE showed preferential binding to atherosclerotic plaques with plaque-to-wall ratio of 1.7 +/- 0.3 and 2.1 +/- 0.5, respectively. However, the aortic uptake and aorta-to-blood ratio of [(68)Ga]DOTANOC were higher compared to [(68)Ga]DOTATATE in in vivo PET/CT imaging. CONCLUSION: Our results demonstrate superior applicability for [(68)Ga]DOTANOC and [(68)Ga]DOTATATE in the detection of atherosclerotic plaques compared to [(18)F]FDR-NOC. PMID- 26122430 TI - OCT1 and imatinib transport in CML: is it clinically relevant? AB - Imatinib is a highly effective therapy for chronic phase-chronic myeloid leukaemia (CP-CML) patients; however, responses to frontline imatinib are variable. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter involved in imatinib uptake into CML cells. Furthermore, variation in the efficiency of imatinib influx via OCT1 has been demonstrated to result in the inter-patient variation observed in primary response to imatinib. Although studies have questioned the role of OCT1 in imatinib influx, these have been largely performed in non-clinical settings. Measuring both OCT1 mRNA levels and the functional activity of OCT1 in primary leukaemic cells has been demonstrated to predict molecular response and outcome in imatinib-treated CP-CML patients in several independent studies. Here, the role of OCT1 and OCT1 genetic variants in imatinib uptake and response prediction is summarised and data generated from model systems assessing the role of OCT1 in imatinib transport is discussed. PMID- 26122431 TI - Motility, Chemotaxis and Aerotaxis Contribute to Competitiveness during Bacterial Pellicle Biofilm Development. AB - Biofilm formation is a complex process involving various signaling pathways and changes in gene expression. Many of the sensory mechanisms and regulatory cascades involved have been defined for biofilms formed by diverse organisms attached to solid surfaces. By comparison, our knowledge on the basic mechanisms underlying the formation of biofilms at air-liquid interfaces, that is, pellicles, is much less complete. In particular, the roles of flagella have been studied in multiple solid-surface biofilm models but remain largely undefined for pellicles. In this work, we characterize the contributions of flagellum-based motility, chemotaxis and oxygen sensing to pellicle formation in the Gram positive Bacillus subtilis. We confirm that flagellum-based motility is involved in, but is not absolutely essential for, B. subtilis pellicle formation. Further, we show that flagellum-based motility, chemotaxis and oxygen sensing are important for successful competition during B. subtilis pellicle formation. We report that flagellum-based motility similarly contributes to pellicle formation and fitness in competition assays in the Gram-negative Pseudomonas aeruginosa. Time-lapse imaging of static liquid cultures demonstrates that, in both B. subtilis and P. aeruginosa, a turbulent flow forms in the tube and a zone of clearing appears below the air-liquid interface just before the formation of the pellicle but only in strains that have flagella. PMID- 26122433 TI - Crossing the minefield of disease names. PMID- 26122434 TI - Schistosomiasis reaches Europe. PMID- 26122435 TI - Antimicrobial resistance: what's needed. PMID- 26122432 TI - C-Terminal Threonine Reduces Abeta43 Amyloidogenicity Compared with Abeta42. AB - Abeta43, a product of the proteolysis of the amyloid precursor protein APP, is related to Abeta42 by an additional Thr residue at the C-terminus. Abeta43 is typically generated at low levels compared with the predominant Abeta42 and Abeta40 forms, but it has been suggested that this longer peptide might have an impact on amyloid-beta aggregation and Alzheimer's disease that is out of proportion to its brain content. Here, we report that both Abeta42 and Abeta43 spontaneously aggregate into mature amyloid fibrils via sequential appearance of the same series of oligomeric and protofibrillar intermediates, the earliest of which appears to lack beta-structure. In spite of the additional beta-branched amino acid at the C-terminus, Abeta43 fibrils have fewer strong backbone H-bonds than Abeta42 fibrils, some of which are lost at the C-terminus. In contrast to previous reports, we found that Abeta43 spontaneously aggregates more slowly than Abeta42. In addition, Abeta43 fibrils are very inefficient at seeding Abeta42 amyloid formation, even though Abeta42 fibrils efficiently seed amyloid formation by Abeta43 monomers. Finally, mixtures of Abeta42 and Abeta43 aggregate more slowly than Abeta42 alone. Both in this Abeta42/Abeta43 co-aggregation reaction and in cross-seeding by Abeta42 fibrils, the structure of the Abeta43 in the product fibrils is influenced by the presence of Abeta42. The results provide new details of amyloid structure and assembly pathways, an example of structural plasticity in prion-like replication, and data showing that low levels of Abeta43 in the brain are unlikely to favorably impact the aggregation of Abeta42. PMID- 26122436 TI - Online future of The Lancet Infectious Diseases review papers. PMID- 26122437 TI - Correction. AB - ENCORE1 Study Group. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non inferiority ENCORE1 study. Lancet Infect Dis 2015; published online April 13. http://dx.doi.org/10.1016/S1473- 3099(15)70060-5-In this Article, the numbers of patients in the 96-week adverse events analysis were incorrect. PMID- 26122438 TI - Corrections. AB - Griffi n MR, Grijalva CG. Restraining the pneumococcus. Lancet Infect Dis 2015; 15: 491-92-This linked Comment should have been accessible as Gold Open Access (CC BY) since March 19, 2015. This correction has been made to the online version as of May 22, 2015. PMID- 26122439 TI - Corrections. AB - Lai Y-S, Biedermann P, Ekpo UF, et al. Spatial distribution of schistosomiasis and treatment needs in sub-Saharan Africa: a systematic review and geostatistical analysis. Lancet Infect Dis 2015; published online May 22. http://dx.doi.org/10.1016/S1473-3099(15)00066-3-Figure 1 of this Article should have contained a box stating '100 references added' with an arrow pointing inwards, rather than a box stating '199 records excluded', and an asterisk should have been added after '1473 records extracted into GNTD'. Additionally, the positioning of the 'S and '?' footnotes has been corrected in table 1. These corrections have been made to the online version as of June 4, 2015. PMID- 26122440 TI - Corrections. AB - Bourliere M, Bronowicki J-P, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015; 15: 397-404-In the second paragraph of the Randomisation and Masking section the sentence describing study drug assignment should have read: "Patients were assigned in a 1:1 ratio. In the ledipasvir-sofosbuvir plus ribavirin group..." [see text] PMID- 26122441 TI - Stepped-wedge trial design to evaluate Ebola treatments. PMID- 26122442 TI - Are all Staphylococcus aureus equal? PMID- 26122443 TI - Health-care-associated infections. PMID- 26122444 TI - Role of co-trimoxazole for urinary tract infections in developing countries. PMID- 26122445 TI - Health-care-associated infections--Authors' reply. PMID- 26122446 TI - Dengue transmission during the 2014 FIFA World Cup in Brazil. PMID- 26122447 TI - Anti-vaxxing: a privilege of the fortunate. PMID- 26122448 TI - Cover illustration. PMID- 26122449 TI - Cover illustration--Editor's reply. PMID- 26122450 TI - Rubella is eliminated from the Americas. PMID- 26122451 TI - Risk of infection after the Nepal earthquake. PMID- 26122456 TI - The HIV care continuum in Latin America: challenges and opportunities. AB - Combination antiretroviral therapy (ART), also known as highly active antiretroviral therapy, provides clinical and immunological benefits for people living with HIV and is an effective strategy to prevent HIV transmission at the individual level. Early initiation of ART as part of a test and treat approach might decrease HIV transmission at the population level, but to do so the HIV continuum of care, from diagnosis to viral suppression, should be optimised. Access to ART has improved greatly in Latin America, and about 600,000 people are on treatment. However, health-care systems are deficient in different stages of the HIV continuum of care, and in some cases only a small proportion of individuals achieve the desired outcome of virological suppression. At present, data for most Latin American countries are not sufficient to build reliable metrics. Available data and estimates show that many people living with HIV in Latin America are unaware of their status, are diagnosed late, and enter into care late. Stigma, administrative barriers, and economic limitations seem to be important determinants of late diagnosis and failure to be linked to and retained in care. Policy makers need reliable data to optimise the HIV care continuum and improve individual-based and population-based outcomes of ART in Latin America. PMID- 26122457 TI - A Critical Examination of the "Bad Luck" Explanation of Cancer Risk. AB - Tomasetti and Vogelstein (1) argue that lifetime cancer risk for particular tissues is mostly determined by the total number of stem cell (SC) divisions within the tissue, whereby most cancers arise due to "bad luck"-mutations occurring during DNA replication. We argue that the poorly substantiated estimations of SC division parameters and assumptions that oversimplify somatic evolution prevent such a conclusion from being drawn. PMID- 26122459 TI - Under pressure to treat? PMID- 26122458 TI - First estimates of the potential cost and cost saving of protecting childhood hearing from damage caused by congenital CMV infection. AB - BACKGROUND: Congenital cytomegalovirus (cCMV) is an important cause of childhood deafness, which is modifiable if diagnosed within the first month of life. Targeted screening of infants who do not pass their newborn hearing screening tests in England is a feasible approach to identify and treat cases to improve hearing outcome. AIMS: To conduct a cost analysis of targeted screening and subsequent treatment for cCMV-related sensorineural hearing loss (SNHL) in an, otherwise, asymptomatic infant, from the perspective of the UK National Health Service (NHS). METHODS: Using data from the newborn hearing screening programme (NHSP) in England and a recent study of targeted screening for cCMV using salivary swabs within the NHSP, we estimate the cost (in UK pounds (L)) to the NHS. The cost of screening (time, swabs and PCR), assessing, treating and following up cases is calculated. The cost per case of preventing hearing deterioration secondary to cCMV with targeted screening is calculated. RESULTS: The cost of identifying, assessing and treating a case of cCMV-related SNHL through targeted cCMV screening is estimated to be L6683. The cost of improving hearing outcome for an infant with cCMV-related SNHL through targeted screening and treatment is estimated at L14 202. CONCLUSIONS: The costs of targeted screening for cCMV using salivary swabs integrated within NHSP resulted in an estimate of cost per case that compares favourably with other screening programmes. This could be used in future studies to estimate the full economic value in terms of incremental costs and incremental health benefits. PMID- 26122460 TI - PACES in epilepsy: Results of a self-management randomized controlled trial. AB - OBJECTIVE: Self-management challenges facing adults with epilepsy include limited understanding of the condition and treatment, associated psychosocial issues, and lack of community integration. Self-management interventions improve patients' medical, life role, and emotional management. Previous interventions, developed from expert opinion, indicated issues with participant engagement/retention, and limited follow-up periods. PACES in Epilepsy addressed methodologic concerns by utilizing patient needs assessment data (n = 165) to derive self-management content and program features for evaluation via randomized controlled trial (RCT). METHODS: Participants were adults with chronic epilepsy (n = 83), without serious mental illness or substantive intellectual impairment, who were recruited from two epilepsy centers. Participants were assigned randomly to intervention or treatment-as-usual groups. Outcomes included the Epilepsy Self-Management Scale (ESMS), Epilepsy Self-Efficacy Scale (ESES), Quality of Life in Epilepsy-31 (QOLIE-31), Patient Health Questionnaire-9 (PHQ-9), and the Generalized Anxiety Disorder-7 (GAD-7), administered at baseline, postintervention (8 weeks), and 6 months postintervention. The intervention was an 8-week group of 6-8 adults co led by a psychologist and trained peer with epilepsy that met one evening per week at a hospital for 75 min. Topics included medical, psychosocial, cognitive, and self-management aspects of epilepsy, in addition to community integration and optimizing epilepsy-related communication. The treatment group provided satisfaction ratings regarding program features. RESULTS: PACES participants (n = 38) improved relative to controls (n = 40) on the ESMS (p < 0.001) and subscales [Information (p < 0.001); Lifestyle (p < 0.002)]; ESES (p < 0.001); and QOLIE-31 (p = 0.002). At 6-month follow up, PACES participants remained improved on the ESMS (p = 0.004) and Information subscale (p = 0.009); and Energy/Fatigue (p = 0.032) and Medication Effects (p = 0.005) of the QOLIE-31. Attrition in both groups was low (8% in each group) and all program satisfaction ratings exceeded 4.0/5.0, with leadership (4.76), topics (4.53), and location (4.30) as the most highly rated aspects. SIGNIFICANCE: A consumer generated epilepsy self-management program appears to be a promising intervention from multiple perspectives, particularly in relation to disability management. PMID- 26122461 TI - The blood pressure response to acute and chronic aerobic exercise: A meta analysis of candidate gene association studies. AB - OBJECTIVES: To meta-analyze candidate gene association studies on the change in blood pressure beyond the immediate post-exercise phase after versus before aerobic exercise. DESIGN: Meta-analysis. METHODS: A systematic search was conducted. Studies retrieved included acute (short-term or postexercise hypotension) or chronic (long-term or training) aerobic exercise interventions; and blood pressure measured before and after aerobic exercise training, or before and after exercise or control under ambulatory conditions by genotype. Effect sizes were determined for genotype and adjusted for sample features. RESULTS: Qualifying studies (k=17, n=3524) on average included middle-aged, overweight men (44.2%) and women (55.8%) with prehypertension (134.9+/-11.7/78.6+/-9.5mmHg). Training interventions (k=12) were performed at 60.4+/-12.9% of maximum oxygen consumption (VO2max) for 41.9+/-12.5minsession(-1), 3.6+/-1.2daysweek(-1) for 15.7+/-7.6week; and post-exercise hypotension interventions (k=5) were performed at 53.5+/-14.4% VO2max for 38.5+/-5.4minsession(-1). Sample characteristics explained 54.2-59.0% of the variability in the blood pressure change after versus before acute exercise or control under ambulatory conditions, and 57.4-67.1% of the variability in the blood pressure change after versus before training (p<0.001). Only angiotensinogen M235T (rs699) associated with the change in diastolic blood pressure after versus before training (R(2)=0.1%, p=0.05), but this association did not remain statistically significant after adjustment for multiple comparisons. CONCLUSIONS: Sample characteristics explained most of the variability in the change of BP beyond the immediate post-exercise phase after versus before acute and chronic aerobic exercise. Angiotensinogen M235T (rs699) was the only genetic variant that associated with the change in diastolic blood pressure after versus before training, accounting for <1% of the variance. PMID- 26122463 TI - Species-specific lipophilicity of morphine antagonists. AB - Complete sets of microscopic acid-base and partition equilibrium constants were experimentally determined for therapeutically important morphine derivatives, including the widely used antagonists naloxone and naltrexone. The acid-base microequilibria were characterized by combining pH-potentiometry and deductive methods using synthesized auxiliary compounds. Microscopic protonation equilibria show that approximately three times as many zwitterionic microspecies than non charged ones exist in oxymorphone and naltrexone solutions. On the other hand, the non-charged microspecies is the dominant one in the case of naloxone, although its concentration is only 1.34 times higher than that of its zwitterionic protonation isomer. Partition coefficients of the individual microspecies were determined by a combination of experimentally measured distribution constants and deductive methods. The contribution ratio of the non charged versus zwitterionic species to the overall lipophilicity is quantified and depicted in terms of species-specific lipophilicities over the entire pH range for each compound. Our lipophilicity values allowed the molecular interpretation of the classical pharmacologic observation that naloxone has a faster onset for antagonist activity, and a concomitant shorter duration of action. PMID- 26122464 TI - Intrapartum mean platelet volume is not a useful predictor of new-onset delayed postpartum pre-eclampsia. AB - OBJECTIVE: To determine whether intrapartum mean platelet volume (MPV) can predict new-onset delayed postpartum pre-eclampsia. METHODS: In a retrospective study, data were obtained for women with delayed postpartum pre-eclampsia (>=48 hours after delivery) who attended the Detroit Medical Center, Detroit, MI, USA, between January 2002 and July 2010. Patients were divided into two subgroups: new onset delayed postpartum pre-eclampsia (no history of hypertensive disorder before 48 hours after delivery) and other late-onset/delayed postpartum pre eclampsia (history of hypertensive disorders). Cases with no hypertensive disorders paired by delivery date were selected as controls. Receiver operating characteristic (ROC) curves were used to determine whether MPV could distinguish between cases and controls. RESULTS: Data for 130 cases of new-onset delayed postpartum pre-eclampsia, 71 cases of other late-onset/delayed postpartum pre eclampsia, and 405 controls were collected. MPV was significantly different between the pre-eclampsia subgroups (P=0.007). ROC curves showed that MPV significantly distinguished new-onset delayed postpartum pre-eclampsia cases (area under the curve 0.6, 95% confidence interval 0.5-0.6; P=0.02), with a sensitivity and specificity of 58.1% and 55.4%, respectively. CONCLUSION: Although MPV was significantly lower in women who went on to develop new-onset delayed postpartum pre-eclampsia than among controls, it is not a useful predictor. The low MPV suggests a different mechanism for the development of new onset delayed postpartum pre-eclampsia. PMID- 26122466 TI - Diagnoses have the greatest impact on variation in sick-leave certification rate among primary-care patients in Sweden: A multilevel analysis including patient, physician and primary health-care centre levels. AB - AIMS: The aims of this study were to determine and evaluate simultaneously the importance of factors known to influence sick-leave certification such as the sick leave-related diagnoses, the patients' socio-economic status, and characteristics of the physicians. METHODS: Computerised medical records from 24 public primary health-care centres (PHCC) were used in a multilevel logistic regression analysis at three levels: patients (n=64,354; sex, age, socio-economic status, workplace factors and diagnoses), physicians (n=574; sex and level of experience) and PHCC (n=24). The variation of sick-leave certification at each level was the outcome. RESULTS: Most of the variation was attributed to the patient level and only 3.5% to the physician and 1.2% to the PHCC levels. Among the patient characteristics, psychiatric diagnoses (mostly acute stress) had the highest odds ratio (OR) for sick leave (OR=16.0; 95% confidence interval [CI] 15 17.2), followed by musculoskeletal diagnoses (OR=6.1; 95% CI 5.8-6.5). Other factors with increased OR were low education (OR=1.7; 95% CI 1.6-1.8), use of social allowance (OR=1.4; 95% CI 1.2-1.7) and certain workplaces (manufacture and health and social care). Being older was not associated with increased certified sick leave. CONCLUSIONS: The greatest variation in sick-leave certification rate was seen at the patient level, specifically psychiatric diagnoses. Socio-economic factors increasing the risk for sick-leave certification were education, social allowance and occupations in manufacture and caregiving. Understanding the impact of the different factors that influence certified sick leave is important both for targeted interventions in order to facilitate patients' return to work. PMID- 26122467 TI - Estimation of the prevalence of autism spectrum disorder in South Korea, revisited. AB - Two-phase designs in epidemiological studies of autism prevalence introduce methodological complications that can severely limit the precision of resulting estimates. If the assumptions used to derive the prevalence estimate are invalid or if the uncertainty surrounding these assumptions is not properly accounted for in the statistical inference procedure, then the point estimate may be inaccurate and the confidence interval may not be a true reflection of the precision of the estimate. We examine these potential pitfalls in the context of a recent high profile finding by Kim et al. (2011, Prevalence of autism spectrum disorders in a total population sample. American Journal of Psychiatry 168: 904-912), who estimated that autism spectrum disorder affects 2.64% of children in a South Korean community. We reconstructed the study's methodology and used Monte Carlo simulations to analyze whether their point estimate and 95% confidence interval (1.91%, 3.37%) were reasonable, given what was known about their screening instrument and sample. We find the original point estimate to be highly assumption-dependent, and after accounting for sources of uncertainty unaccounted for in the original article, we demonstrate that a more reasonable confidence interval would be approximately twice as large as originally reported. We argue that future studies should give serious consideration to the additional sources of uncertainty introduced by a two-phase design, which may easily outstrip any expected gains in efficiency. PMID- 26122468 TI - Parity effect of bipolar quantum Hall edge transport around graphene antidots. AB - Parity effect, which means that even-odd property of an integer physical parameter results in an essential difference, ubiquitously appears and enables us to grasp its physical essence as the microscopic mechanism is less significant in coarse graining. Here we report a new parity effect of quantum Hall edge transport in graphene antidot devices with pn junctions (PNJs). We found and experimentally verified that the bipolar quantum Hall edge transport is drastically affected by the parity of the number of PNJs. This parity effect is universal in bipolar quantum Hall edge transport of not only graphene but also massless Dirac electron systems. These results offer a promising way to design electron interferometers in graphene. PMID- 26122469 TI - The match between common antibiotics packaging and guidelines for their use in Australia. AB - OBJECTIVES: To determine the potential for a source of surplus antibiotics in the community to come from the mismatch between the recommended duration of antibiotic treatment for common indications in primary care and that dictated by default pharmaceutical industry packaging. METHODS: Analysis of existing published information of: 1) the most common antibiotics prescribed in primary care in Australia; 2) their most common indications; 3) the guideline recommendations for their duration; and 4) the duration dictated by antibiotic packaging. RESULTS: Of 32 common antibiotic prescribing scenarios, 10 had doses left over in surplus and 18 had a shortfall, leaving only four in which the packaging size matched the duration recommended by electronic Therapeutic Guidelines. Where there was a shortfall, this was only exactly accommodated by a repeat prescription in two cases. CONCLUSIONS: Mismatch contributes to a shortfall or excess of doses compared to recommended antibiotic treatment protocols and probably exaggerates redundant doses in the community from prescribed antibiotics dispensed and not consumed. IMPLICATIONS: Prescribers need to be aware that the mismatch between antibiotic pack sizes and guideline recommendations for their duration is contributing to antibiotic resistance in the community. PMID- 26122470 TI - Differential utilisation of ceramide during replication of the flaviviruses West Nile and dengue virus. AB - It is well established that +ssRNA viruses manipulate cellular lipid homoeostasis and distribution to facilitate efficient replication. Here, we show that the cellular lipid ceramide is redistributed to the West Nile virus strain Kunjin virus (WNVKUN) replication complex (RC) but not to the dengue virus serotype 2 strain New Guinea C (DENVNGC) RC. We show that prolonged chemical inhibition of serine palmitoyltransferase with myriocin had a significant deleterious effect on WNVKUN replication but enhanced DENVNGC replication. Additionally, inhibition of ceramide synthase with Fumonisin B1 had a detrimental effect on WNVKUN replication and release of infectious virus particles but contrastingly an enhancing effect on DENVNGC replication and virus production. These observations suggest that ceramide production via the de novo and salvage pathway is a requirement for WNVKUN replication but inhibitory for DENVNGC replication. Thus, although these two viruses are from the same genus, they have a differential ceramide requirement for replication. PMID- 26122471 TI - The AT-hook DNA binding ability of the Epstein Barr virus EBNA1 protein is necessary for the maintenance of viral genomes in latently infected cells. AB - Epstein Barr Virus (EBV) is a human tumor virus that is causally linked to malignancies such as Burkitt's lymphoma, and gastric and nasopharyngeal carcinomas. Tethering of EBV genomes to cellular chromosomes is required for the synthesis and persistence of viral plasmids in tumor cells. However, it is not established how EBV genomes are tethered to cellular chromosomes. We test the hypothesis that the viral protein EBNA1 tethers EBV genomes to chromosomes specifically through its N-terminal AT-hook DNA-binding domains by using a small molecule, netropsin, that has been shown to inhibit the AT-hook DNA-binding of EBNA1 in vitro. We show that netropsin forces the loss of EBV genomes from epithelial and lymphoid cells in an AT-hook dependent manner and that EBV positive lymphoma cells are significantly more inhibited in their growth by netropsin than are corresponding EBV-negative cells. PMID- 26122472 TI - Development of a reverse genetics system to generate a recombinant Ebola virus Makona expressing a green fluorescent protein. AB - Previous studies have demonstrated the potential application of reverse genetics technology in studying a broad range of aspects of viral biology, including gene regulation, protein function, cell entry, and pathogenesis. Here, we describe a highly efficient reverse genetics system used to generate recombinant Ebola virus (EBOV) based on a recent isolate from a human patient infected during the 2014 2015 outbreak in Western Africa. We also rescued a recombinant EBOV expressing a fluorescent reporter protein from a cleaved VP40 protein fusion. Using this virus and an inexpensive method to quantitate the expression of the foreign gene, we demonstrate its potential usefulness as a tool for screening antiviral compounds and measuring neutralizing antibodies. PMID- 26122474 TI - Pancreatitis: MPTP pore opening proves crucial for experimental pancreatitis. PMID- 26122473 TI - The spectrum of noncoeliac gluten sensitivity. AB - The past 5 years have seen an increase in the use of a gluten-free diet outside a diagnosis of coeliac disease or IgE-mediated wheat allergy. This trend has led to the identification of a new clinical entity termed noncoeliac gluten sensitivity (NCGS). In this Review, we discuss the evidence for NCGS as demonstrated by the results of double-blind, placebo-controlled dietary rechallenge studies. Furthermore, the characteristic phenotype of individuals with NCGS is described as well as the symptom manifestations commonly reported after gluten exposure, which include intestinal symptoms consistent with IBS, and extraintestinal symptoms such as neurological dysfunction, psychological disturbances, fibromyalgia and skin rash. Moreover, emerging evidence suggests that NCGS can be associated with organic gastrointestinal pathologies, such as IBD, in which its presence might be a reflection of severe or stricturing disease. However, NCGS is not without its controversies and uncertainties, in particular pertaining to whether it is gluten or nongluten components of the grain evoking symptoms; evidence suggests that fermentable carbohydrates, amylase trypsin inhibitors and wheat-germ agglutinin can also be responsible culprits. Finally, we discuss the novel techniques that might help diagnose NCGS in the future. PMID- 26122476 TI - NAFLD: Cardiovascular complications of NAFLD--they do matter. PMID- 26122475 TI - Modelling hepatitis C therapy--predicting effects of treatment. AB - Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). There also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response. PMID- 26122477 TI - Diagnosis: A step closer to screening for curable pancreatic cancer? PMID- 26122479 TI - Corrigendum: Label-Free Characterization of Emerging Human Neuronal Networks. PMID- 26122480 TI - Sensor Based on Aptamer Folding to Detect Low-Molecular Weight Analytes. AB - Aptamers have emerged as promising biorecognition elements in the development of biosensors. The present work focuses on the application of quartz crystal microbalance with dissipation monitoring (QCM-D) for the enantioselective detection of a low molecular weight target molecule (less than 200 Da) by aptamer based sensors. While QCM-D is a powerful technique for label-free, real-time characterization and quantification of molecular interactions at interfaces, the detection of small molecules interacting with immobilized receptors still remains a challenge. In the present study, we take advantage of the aptamer conformational changes upon the target binding that induces displacement of water acoustically coupled to the sensing layer. As a consequence, this phenomenon leads to a significant enhancement of the detection signal. The methodology is exemplified with the enantioselective recognition of a low molecular weight model compound, L-tyrosinamide (L-Tym). QCM-D monitoring of L-Tym interaction with the aptamer monolayer leads to an appreciable signal that can be further exploited for analytical purposes or thermodynamics studies. Furthermore, in situ combination of QCM-D with spectroscopic ellipsometry unambiguously demonstrates that the conformational change induces a nanometric decrease of the aptamer monolayer thickness. Since QCM-D is sensitive to the whole mass of the sensing layer including water that is acoustically coupled, a decrease in thickness of the highly hydrated aptamer layer induces a sizable release of water that can be easily detected by QCM-D. PMID- 26122478 TI - Secretory diarrhoea: mechanisms and emerging therapies. AB - Diarrhoeal disease remains a major health burden worldwide. Secretory diarrhoeas are caused by certain bacterial and viral infections, inflammatory processes, drugs and genetic disorders. Fluid secretion across the intestinal epithelium in secretory diarrhoeas involves multiple ion and solute transporters, as well as activation of cyclic nucleotide and Ca(2+) signalling pathways. In many secretory diarrhoeas, activation of Cl(-) channels in the apical membrane of enterocytes, including the cystic fibrosis transmembrane conductance regulator and Ca(2+) activated Cl(-) channels, increases fluid secretion, while inhibition of Na(+) transport reduces fluid absorption. Current treatment of diarrhoea includes replacement of fluid and electrolyte losses using oral rehydration solutions, and drugs targeting intestinal motility or fluid secretion. Therapeutics in the development pipeline target intestinal ion channels and transporters, regulatory proteins and cell surface receptors. This Review describes pathogenic mechanisms of secretory diarrhoea, current and emerging therapeutics, and the challenges in developing antidiarrhoeal therapeutics. PMID- 26122481 TI - Beneficial Effects of Early mTORC1 Inhibition after Traumatic Brain Injury. AB - The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway mediates many aspects of cell growth and regeneration and is upregulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signaling event for recovery of brain function is presently unclear. We analyzed the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI) and identified an early neuronal peak of activity that occurs within a few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin 1 h after CCI and showed that this acute treatment significantly diminishes the extent of neuronal death, astrogliosis, and cognitive impairment 1-3 days after injury. Our findings suggest that the early neuronal peak of mTORC1 activity after TBI is deleterious to brain function, and that acute, early intervention with mTORC1 inhibitors after injury may represent an effective form of treatment to improve recovery in human patients. PMID- 26122482 TI - Visual signs and symptoms in patients with the visual variant of Alzheimer disease. AB - BACKGROUND: Prominent visual symptoms can present in the visual variant of Alzheimer's disease (VVAD). Ophthalmologists have a significant role to play in the early diagnosis of VVAD. METHODS: We retrospectively reviewed the files of ten consecutive patients diagnosed with VVAD. All patients had a full neuro ophthalmologic examination, a formal neurological and neuro-psychological testing, and cerebral MRI to confirm diagnosis. In addition, functional neuroimaging was obtained in seven patients. RESULTS: The common primary symptom at presentation with all patients was difficulty with near vision (reading difficulty n = 8, "visual blur" in near vision n = 2), and difficulty writing (n = 3). Following assessment, impaired reading and writing skills were evident in 9/10 and 8/10 patients respectively. Median distance visual acuity was 20/25 and at near the median visual acuity was J6. Partial homonymous visual field defect was detected in 80 % (8/10) of the patients. Color vision was impaired in all patients when tested with Ishihara pseudoisochromatic plates, but simple color naming was normal in 8/9 tested patients. Simultanagnosia was present in 8/10 patients. Vision dysfunction corresponded with cerebral MRI findings where parieto-occipital cortical atrophy was observed in all patients. PET scan (5 patients) or SPECT (2 patients) revealed parieto-occipital dysfunction (hypometabolism or hypoperfusion) in all 7 tested patients CONCLUSIONS: Visual difficulties are prominent in VVAD. Dyslexia, incomplete homonymous hemianopia, preserved color identification with abnormal color vision on Ishihara, and simultanagnosia were all symptoms observed frequently in this patient series. Ophthalmologists should be aware of the possibility of neurodegenerative disorders such as VVAD in patients with unexplained visual complaints, in particular reading difficulties. PMID- 26122483 TI - Spatial sorting promotes the spread of maladaptive hybridization. AB - Invasive hybridization is causing loss of biodiversity worldwide. The spread of such introgression can occur even when hybrids have reduced Darwinian fitness, which decreases the frequency of hybrids due to low survival or reproduction through time. This paradox can be partially explained by spatial sorting, where genotypes associated with dispersal increase in frequency at the edge of expansion, fueling further expansion and allowing invasive hybrids to increase in frequency through space rather than time. Furthermore, because all progeny of a hybrid will be hybrids (i.e., will possess genes from both parental taxa), nonnative admixture in invaded populations can increase even when most hybrid progeny do not survive. Broader understanding of spatial sorting is needed to protect native biodiversity. PMID- 26122484 TI - Fitness of multidimensional phenotypes in dynamic adaptive landscapes. AB - Phenotypic traits influence species distributions, but ecology lacks established links between multidimensional phenotypes and fitness for predicting species responses to environmental change. The common focus on single traits rather than multiple trait combinations limits our understanding of their adaptive value, and intraspecific trait covariation has been neglected in ecology despite its importance in evolutionary theory and its likely impact on species distributions. Here, we extend the adaptive landscape framework to ecological sorting of multidimensional phenotypes across environments and discuss how two analytical approaches can be used to quantify fitness as a function of the interaction between the phenotype and the environment. We encourage ecologists to consider how phenotypic integration will constrain species responses to environmental change. PMID- 26122485 TI - D-Aspartic acid stimulates steroidogenesis through the delay of LH receptor internalization in a mammalian Leydig cell line. AB - PURPOSE: Recent experimental evidence on non-mammalian animal models showed that D-Aspartic acid (d-Asp) administration increases testosterone levels through upregulation of StAR in Leydig cells. In this study, we aimed to investigate in vitro the signaling pathway associated with d-Asp stimulation in MA-10 murine Leydig cells. METHODS: MA-10 cells were stimulated with different concentrations of d-Asp, in presence or absence of hCG. Then total testosterone (T) levels in the culture medium were evaluated by electrochemiluminescence immunoassay, and StAR and LHR protein expressions were quantified by the means of Western blotting. LHR cellular localization after hormonal stimulation was assessed by immunofluorescence. RESULTS: Stimulation with the sole d-Asp did not induce any relevant increase of T release from cultured cells. On the other hand, stimulation with hCG induced significant increase of T (P = 0.045). Concomitant stimulation with hCG and d-Asp, at the concentration of 0.1 and 1 nM, induced additional and significant increase of released T (P = 0.03 and P = 0.04, respectively). StAR protein levels increased after concomitant stimulation with hCG and d-Asp 0.1 nM, compared with stimulation with the sole hCG (P = 0.02), whereas no variation in LHR protein expression was observed. Finally, d-Asp attenuated displacement of LHR staining, from cell membrane to cytoplasm, subsequent to hCG stimulation. CONCLUSIONS: In this study, we confirmed a steroidogenic role for d-Asp, in concert with hCG, on murine Leydig cells, which is mediated by an increase in StAR protein levels. In addition, we showed that the possible mechanism subtending the effect of d-Asp could rely on the modulation of LHR exposure on the cell membrane. PMID- 26122486 TI - Sleep apnea syndrome in endocrine clinics. AB - Obstructive sleep apnea syndrome (OSAS) is a chronic condition with a high prevalence (up to 7 % of the general population) characterized by frequent episodes of upper airway collapse while sleeping. Left untreated, OSAS can cause severe complications, including systemic hypertension, cardiovascular disease, stroke, and abnormal glucose metabolism. This review aims to summarize the close links between OSAS, endocrinology, and metabolism. In patients with metabolic syndrome, OSAS is an independent risk factor for the onset of type 2 diabetes and a worsening glycemic control. The accumulation of adipose tissue in the neck and limited chest wall dynamics, hypoxia, and local micro-inflammation link visceral obesity closely with OSAS. There is now an abundance of convincing data indicating that promoting lifestyle changes, improving sleep hygiene, and adjusting diet can ameliorate both metabolic syndrome and OSAS, especially in obese patients. The incidence of OSAS in acromegaly is high, though GH treatments seem to be unrelated to the onset of apnea in GH-deficient individuals. Prospective studies have suggested an association between hypertension and OSAS because intermittent nocturnal hypoxia prompts an increase in sympathetic tone, endothelial dysfunction, and vascular inflammation: aldosterone excess may have a pathophysiological role, and some authors have reported that treating OSAS leads to a modest, but significant, reduction in blood pressure. PMID- 26122488 TI - An efficient case finding strategy to diagnose osteoporosis in a developing society with low treatment frequency. AB - OBJECTIVES: Osteoporosis is a debilitating condition with rising frequency of fragility fractures with advancing age. Life expectancy increases in developing societies with the emergence of osteoporosis. There is a need for a simple protocol to diagnose fractures that merit treatment for osteoporosis. METHODS: Evaluation of all consecutive lateral chest radiographs performed at the National Hospital in the capital city in Greenland over a 3-month period for vertebral body heights at the anterior, middle and posterior regions. Use of anti osteoporotic drug was evaluated from records of dispensed drugs from Greenland National Pharmacy. RESULTS: 1869 vertebrae were evaluated on radiographs from 203 subjects. On average 9.2 vertebrae (range 5-13) qualified for evaluation in each individual. Median (range) age was 55 (30-82) years. Any vertebral deformity above 25 (20) % was seen in 28.6 (50.2) %. More than one fracture was seen in 10.3 (27.1) %. Fractures occurred in 18.5 (36.9) % of patients from the General Medicine Clinic and in 33.3 (56.5) % of inpatients (p = 0.029). The occurrence of vertebral fractures increased with age (p < 0.001) and hosting more than one vertebral fracture was markedly more frequent after the age of 60 years [OR, 95 % CI 9.6, 3.1-30 (5.7, 2.9-11); p < 0.001] after correction for gender in logistic regressions. The National Pharmacy handed out anti-osteoporotic drugs equal to the treatment of 36 individuals. CONCLUSIONS: Vertebral fractures that merit treatment can be readily diagnosed from lateral chest radiographs taken in routine clinical work-up. They are common in Greenland as demonstrated by this simple protocol to improve diagnosis and treatment of osteoporosis in a developing society. PMID- 26122489 TI - Inversion group (IG) fitting: A new T1 mapping method for modified look-locker inversion recovery (MOLLI) that allows arbitrary inversion groupings and rest periods (including no rest period). AB - PURPOSE: The Modified Look-Locker Inversion Recovery (MOLLI) technique is used for T1 mapping in the heart. However, a drawback of this technique is that it requires lengthy rest periods in between inversion groupings to allow for complete magnetization recovery. In this work, a new MOLLI fitting algorithm (inversion group [IG] fitting) is presented that allows for arbitrary combinations of inversion groupings and rest periods (including no rest period). THEORY AND METHODS: Conventional MOLLI algorithms use a three parameter fitting model. In IG fitting, the number of parameters is two plus the number of inversion groupings. This increased number of parameters permits any inversion grouping/rest period combination. Validation was performed through simulation, phantom, and in vivo experiments. RESULTS: IG fitting provided T1 values with less than 1% discrepancy across a range of inversion grouping/rest period combinations. By comparison, conventional three parameter fits exhibited up to 30% discrepancy for some combinations. The one drawback with IG fitting was a loss of precision-approximately 30% worse than the three parameter fits. CONCLUSION: IG fitting permits arbitrary inversion grouping/rest period combinations (including no rest period). The cost of the algorithm is a loss of precision relative to conventional three parameter fits. Magn Reson Med 75:2332 2340, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26122487 TI - Phosphodiesterase type 5 inhibitors: back and forward from cardiac indications. AB - PDE5 inhibitors (PDE5i) are widely known as treatment for erectile dysfunction (ED). This favorable action has emerged as a "side effect" from pioneering studies when PDE5i have been originally proposed as treatment for coronary artery disease (CAD). PDE5i showed marginal benefits for CAD treatment; although disappointing for that indication, they improved systemic and pulmonary vasodilation and ameliorated general endothelial function. Therefore, PDE5i have been approved and licensed also for pulmonary artery hypertension (PAH), besides ED. Nowadays, fine-tuned biomolecular mechanisms of PDE5i are well recognized to be beneficial onto myocardial contractility and geometry, to reduce tissue fibrosis, hypertrophy and apoptosis. PDE5i consistently exert benefits on heart failure, infarct, cardiomyopathy. The concept that PDE5i likely blunt Th1-driven inflammatory processes, which shift the homeostatic balance from health to disease, has emerged; PDE5i seem to decrease the release of active biomolecules from cells to tissues interested by inflammation. In this view, following clinical and basic research progresses, PDE5i can be undoubtedly "re-allocated" for cardiac indications and, hopefully, they could be approved as therapeutic tools to treat and prevent heart disease. This review aims to summarize PDE5i different clinical applications, from past to present and future, focusing on their potential power as treatment for cardiac diseases. PMID- 26122490 TI - Andreas Vesalius' five hundreth anniversary: initiation of the rotator cuff concept. AB - PURPOSE: The rotator cuff concept refers to the four scapulohumeral muscles that stabilize and rotate the humerus relative to the scapula. To date, the first description of the rotator cuff remained unidentified. METHOD: In light of the 500th birthday of Andreas Vesalius (1515-1564) we searched his 1543 masterwork "Fabrica Corporis Humani Libri Septem" for references to the morphology and function of the rotator cuff muscles. RESULT: Even though he distinguished three rather than four scapulohumeral muscles, Vesalius recognized the need for structures that prevent dislocation of the shoulder inherent to the morphology of the humeral caput and scapular socket. He recorded "three strong ligaments" and the "three muscles that rotate the arm" of which the tendons completely "embrace the ligaments of the joint" as such structures. CONCLUSION: Vesalius defined the rotator cuff concept avant la lettre. PMID- 26122491 TI - [Treatment options of distal intestinal obstruction syndrome: And if the enemas fail?]. PMID- 26122492 TI - [Hepatic hemangiomas: Spectacular response to treatment with propranolol]. PMID- 26122493 TI - Should we use CT or MRI for detection and characterization of benign adrenal lesions? AB - OBJECTIVES: Computed tomography (CT) and magnetic resonance imaging (MRI) are the main imaging modalities used for analysis of adrenal lesions. We compared the ability of CT and MRI to detect and characterize benign adrenal lesions. PATIENTS AND METHODS: Unenhanced abdominal CT and MRI were performed in 16 patients (age range 39-77), and reviewed by a radiologist with 6years of experience in abdominal imaging. The presence, number, size and structure of each mass were analyzed and compared between the two modalities. RESULTS: There were 18 adrenal masses in 11 patients, four patients had adrenal hyperplasia (AH), whereas one patient had left-sided AH and right-sided adenoma. Ten masses were>=2cm in diameter, and were perfectly depicted using CT and all MRI techniques. There were nine masses with diameter<2cm detected by CT, three of them were missed using MRI. AH was detected in five patients using CT, but its mild form was missed in one patient using MRI. Four masses with attenuation values of>10Hounsfield units could not be characterized using unenhanced CT, but three of them were characterized using MRI. CONCLUSION: CT has higher sensitivity for detection of small adrenal tumours and adrenal hyperplasia than MRI. MRI is an important tool in characterization of adrenal masses that could not be characterized using unenhanced CT. PMID- 26122494 TI - Panhypopituitarism revealing sellar tuberculoma. PMID- 26122495 TI - Biological and radiological exploration and management of non-functioning pituitary adenoma. AB - Non-functioning pituitary adenoma may be totally asymptomatic and discovered "incidentally" during radiological examination for some other indication, or else induce tumoral signs with compression of the optic chiasm and pituitary dysfunction. Non-functioning adenomas are mainly gonadotroph, but may also be "silent". Treatment strategy depends on initial clinical, biological, ophthalmological and radiological findings. The present French Society of Endocrinology Consensus work-group sought to update the pitfalls associated with hormone assay and outline a hormonal exploration strategy for diagnosis and follow-up, without overlooking the particularities of silent adenoma. We also drew up basic rules for initial exploration and radiological follow-up of both operated and non-operated pituitary adenomas. PMID- 26122496 TI - [Dyspnea in left-sided heart disease]. AB - Shortness of breath (dyspnea) is a common symptom in left-sided heart disease but clinically, patient symptoms show a high variability. Echocardiography is the mainstay for evaluating whether left-sided heart disease is the cause of dyspnea. If left-sided heart failure is diagnosed, this symptom complex must then be subjected to further etiological evaluation. Hypertensive, ischemic and valvular heart diseases are common, as well as atrial fibrillation. If the patient does not have angina pectoris, testing for ischemic heart disease should be done non invasively by coronary computed tomography or testing for regional myocardial ischemia. Coronary revascularization is indicated only when a prognostically relevant ischemia of more than 10 % of the left ventricle is diagnosed. Diuretics are important for the relief of dyspnea but do not improve the prognosis of patients. In patients with reduced left ventricular function, combination therapy with angiotensin-converting enzyme (ACE) inhibitors, beta blockers and aldosterone antagonists improve the symptoms and prognosis. For treatment of heart failure with preserved ejection fraction evidence-based measures are still lacking. In this case the recommended therapy consists of optimal treatment of comorbidities, regulation of heart rate and blood pressure and participation in structured exercise programs. Angiotensin receptor blockers and aldosterone antagonists can be given in patients with more severe symptoms even though the available data are very sparse. PMID- 26122498 TI - An Update of the Brazilian Regulatory Bioequivalence Recommendations for Approval of Generic Topical Dermatological Drug Products. AB - This note aims to clarify the Brazilian regulatory bioequivalence recommendations for approval of generic topical dermatological drug products, since the legal framework of the "Brazilian Health Surveillance Agency" (ANVISA) is only available in Portuguese. According to Resolutions RE n. 1170 (December 19th 2006) and RDC n. 37 (August 3rd 2011) in Brazil, only in vitro studies are required for registration of generic topical dermatological drug products. Current Regulatory Agenda of ANVISA, which contains possible future resolutions to be revised over 2015-2016, includes a discussion on biowaiver requirements and on possible in vitro and in vivo comparability tests for these products. PMID- 26122497 TI - Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization. AB - A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG750) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG750. PolyQPA-mPEG750 was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39 mg/ml, 0.107 mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50 nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by (1)H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG750 underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG750 polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation. PMID- 26122499 TI - Inflammatory Biomarkers in Peripheral Artery Disease: Diagnosis, Prognosis, and Therapeutic Challenges. AB - Peripheral artery disease (PAD) is an inflammatory disease caused by atherosclerosis. It has been demonstrated that PAD is related to chronic inflammation. While conventional risk factors lead to the pathogenesis and progression of PAD, the role of novel inflammatory biomarkers in relation to PAD is being increasingly recognized. The novel biomarkers for PAD may allow for earlier screening and detection, suppression of disease progression, and development of new therapeutic approaches. In this review, inflammatory biomarkers that should be contributory to diagnosis, prognosis, and avenues for therapeutic challenges in PAD are summarized. PMID- 26122500 TI - Novel Inflammatory Indices in Aortic Disease. AB - Inflammation plays a critical role in the atherosclerotic process in various vascular beds, starting from endothelial dysfunction and counting all stages of plaque development. The significant contribution of inflammation in the initiation and progression of atherosclerosis has been documented over many years but its contribution to the development of other cardiovascular disease remains unclear. Inflammatory process constitutes a basic part of pathogenic cascade of aortic diseases including those of aortic valve stenosis and aortic aneurysms. Thus, both of these entities are related with high rates of morbidity and mortality. Therefore, the need to detect and investigate indices representative of inflammation that will be easily measured and may reflect the process of these diseases, is mandatory. However, such biomarkers for aortic diseases that could have a significant prognostic value on survival via the early identification of high risk patients, in general, remain few. Therefore, the illumination of role of such biomarkers, will facilitate the understanding of the mechanisms in molecular and/or cellular level that are responsible for the creation of aortic disease. Such an approach may provide a pathophysiological basis for early diagnosis. PMID- 26122501 TI - More Effective Strategies are Needed for Elderly Asthmatics in Real-World Practice. PMID- 26122502 TI - Chronic Rhinosinusitis and the Coagulation System. AB - Chronic rhinosinusitis (CRS) is one of the most common chronic diseases in adults and severely affects quality of life in patients. Although various etiologic and pathogenic mechanisms of CRS have been proposed, the causes of CRS remain uncertain. Abnormalities in the coagulation cascade may play an etiologic role in many diseases, such as asthma and other inflammatory conditions. While studies on the relationship between asthma and dysregulated coagulation have been reported, the role of the coagulation system in the pathogenesis of CRS has only been considered following recent reports. Excessive fibrin deposition is seen in nasal polyp (NP) tissue from patients with chronic rhinosinusitis with nasal polyp (CRSwNP) and is associated with activation of thrombin, reduction of tissue plasminogen activator (t-PA) and upregulation of coagulation factor XIII-A (FXIII A), all events that can contribute to fibrin deposition and crosslinking. These findings were reproduced in a murine model of NP that was recently established. Elucidation of the mechanisms of fibrin deposition may enhance our understanding of tissue remodeling in the pathophysiology of NP and provide new targets for the treatment of CRSwNP. PMID- 26122504 TI - Addition of Montelukast to Low-Dose Inhaled Corticosteroid Leads to Fewer Exacerbations in Older Patients Than Medium-Dose Inhaled Corticosteroid Monotherapy. AB - PURPOSE: There have been few reports regarding the efficacy of antiasthmatics in older patients. To compare the efficacy of the addition of montelukast to low dose inhaled budesonide (MON-400BUD) versus increasing the dose of inhaled steroid (800BUD) on asthma control in older asthmatics. METHODS: A randomized, open-label, parallel-designed trial was conducted for 12 weeks. The primary endpoint was the rate of patients who reached "well-controlled asthma status" after the 12-week treatment period. Additionally, asthma exacerbations, sputum inflammatory cells, asthma control test (ACT) and physical functioning scale (PFS), and adverse reactions were monitored. RESULTS: Twenty-four (36.9%) and 22 (34.9%) subjects in the MON-400BUD (n=65) and 800BUD (n=63) groups had well controlled asthma at the end of the study, respectively. The numbers of asthma exacerbations requiring oral corticosteroid treatment (20 vs 9, respectively, P=0.036) and the development of sore throat (22 vs 11, respectively, P=0.045) were significantly higher in the 800BUD group than in the MON-400BUD group. Body mass index and changes in ACT, FEV1%, 6-min walk distance and PFS from baseline were all significant determinants for distinguishing subjects with well controlled and partly controlled asthma from those with uncontrolled asthma (P<0.05) at the end of the study. CONCLUSIONS: The efficacy of 12-week treatment with MON-400BUD in older asthmatics was comparable to that of 800BUD on asthma control but associated with reduced frequency of asthma exacerbations requiring oral steroids and sore throat events. Changes in ACT and PFS can be useful predictors of asthma control status in older patients. PMID- 26122503 TI - Challenges in the Management of Asthma in the Elderly. AB - Recent literature has emphasized the clinical and socio-epidemiological significance of asthma in the elderly. However, why the disease burden remains high in this group is unclear. Elderly subjects usually have multiple chronic illnesses, and the role played by comorbidities in the context of asthma has been underappreciated. This review aims to summarize the literature associations between comorbidities and asthma in elderly patients. In addition, we discuss patient management issues. PMID- 26122505 TI - Altered microRNA Expression Profiles of Extracellular Vesicles in Nasal Mucus From Patients With Allergic Rhinitis. AB - PURPOSE: Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. Exosomes or extracellular vesicles are nanosized vesicles of endosomal origin released from inflammatory and epithelial cells that have been implicated in allergic diseases. In this study, we characterized the microRNA (miRNA) content of exosomes in AR. METHODS: Extracellular vesicles were isolated from nasal mucus from healthy control subjects (n=10) and patients with severe AR (n=10). Vesicle RNA was analyzed by using a TaqMan microRNA assays Human Panel-Early Access kit (Applied Biosystems, Foster City, CA, USA) containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis for the differentially expressed miRNAs were performed using DIANA-mirPath. RESULTS: Twenty-one vesicle miRNAs were up regulated and 14 miRNAs were under-regulated significantly (P<0.05) in nasal mucus from AR patients when compared to healthy controls. Bioinformatic analysis by DIANA-mirPath demonstrated that 32 KEGG biological processes were significantly enriched (P<0.05, FDR corrected) among differentially expressed vesicle miRNA signatures. Among them, the B-cell receptor signaling pathway (P=3.709E-09), the natural killer cell-mediated cytotoxicity (P=8.466E-05), the T cell receptor signaling pathway (P=0.00075), the RIG-I-like receptor signaling pathway (P=0.00127), the Wnt signaling pathway (P=0.00130), endocytosis (P=0.00440), and salivary secretion (P=0.04660) were the most prominent pathways enriched in quantiles with differential vesicle miRNA patterns. Furthermore, miR 30-5p, miR-199b-3p, miR-874, miR-28-3p, miR-203, and miR-875-5p, involved in B cell receptor and salivary secretion signaling pathways, were selected for validation using independent samples from 44 AR patients and 20 healthy controls. MiR-30-5p and miR-199b-3p were significantly increased in extracellular vesicles from nasal mucus when compared to healthy controls, while miR-874 and miR-28-3p were significantly down-regulated. In addition, miRNA-203 was significantly increased in AR patients, while miRNA-875-5p was found to be significantly decreased in AR patients. CONCLUSIONS: This study demonstrated that vesicle miRNA may be a regulator for the development of AR. PMID- 26122506 TI - The Prevalence of Toxocariasis and Diagnostic Value of Serologic Tests in Asymptomatic Korean Adults. AB - PURPOSE: Toxocariasis is the most common cause of peripheral blood eosinophilia in Korea and produces eosinophilic infiltration in various organs, including the lung. However, the prevalence of toxocariasis in the general population is rarely reported. METHODS: We investigated the seroprevalence of Toxocara larval antibody among asymptomatic people who attended Samsung Medical Center for a health checkup, including low-dose chest computed tomography (CT) between March 2012 and December 2013. A total of 633 people (400 men and 233 women) were prospectively recruited. RESULTS: The Toxocara-seropositive rate was 51.2% using the current cutoff value based on Toxocara enzyme-linked immunosorbent assay (ELISA) (67.0% for men and 24.0% for women). In the multivariate-adjusted model, age (odds ratio [OR], 1.08; 95% confidence intervals [CI], 1.04-1.11), male sex (OR, 3.47; 95% CI, 2.26-5.33), rural residence (OR, 1.55; 95% CI, 1.05-2.30), and history of raw liver intake (OR, 8.52; 95% CI, 3.61-20.11) were significantly associated with Toxocara seropositivity. When subjects were divided into 3 groups using cutoff values base on weak positive and strong positive control optical densities (ODs), the ORs for peripheral blood eosinophilia and serum hyperIgEaemia were 0.31 (95% CI, 0.02-2.89) in the weakpositive group and 36.64 (95% CI, 11.73-111.42) in the strong positive group compared to the seronegative group. Similarly, ORs for the solid nodule with surrounding halo were 2.54 (95% CI, 0.60-10.84) in the weak positive group and 15.08 (95 CI 4.09-55.56) in the strong positive group compared to the seronegative group. CONCLUSIONS: The study indicated that the Toxocara seropositive rate obtained by using the current cutoff value based on ELISA was high in the asymptomatic population in Korea. The results of this study suggest that active toxocariasis may be more frequently seen in the Toxocara-strong positive group than in the Toxocara-weak positive group. PMID- 26122507 TI - Activation of the Intrinsic Coagulation Pathway in Patients With Chronic Urticaria. AB - PURPOSE: Although coagulation activation has been reported in chronic urticaria, data pertaining to detailed changes in coagulation factors and global coagulation status are lacking. The current study evaluated global coagulation status in patients with chronic urticaria using thrombin generation assay (TGA) and the levels of individual coagulation factors. METHODS: Patients with chronic urticaria (n=57) and 20 healthy controls were enrolled. TGA was performed under stimulation with 2 concentrations of tissue factor (TF). Coagulation factors and conventional coagulation assays were also analyzed. RESULTS: Although patients with chronic urticaria showed prolonged activated partial thromboplastin time, prothrombin time did not differ significantly between patients and controls. In both 1 pM and 5 pM TF-stimulated TGA, peak thrombin and endogenous thrombin potential (ETP) levels were markedly decreased in patients with chronic urticaria. As expected, intrinsic coagulation factors (VIII, IX, and XII), as well as coagulation factors of the common pathway (II, V, and X), were consistently decreased. Additionally, D-dimer was significantly increased in patients as compared to controls. In multivariate regression analysis, the presence of chronic urticaria was the only significant independent contributor to the low ETP value. CONCLUSIONS: Chronic urticaria is characterized by in vivo coagulation activation through the intrinsic coagulation pathway, which can be measured with sensitivity using TGA. PMID- 26122508 TI - Human Rhinovirus-induced Proinflammatory Cytokine and Interferon-beta Responses in Nasal Epithelial Cells From Chronic Rhinosinusitis Patients. AB - PURPOSE: Asthma exacerbation from human rhinovirus (HRV) infection is associated with deficient antiviral interferon (IFN) secretion. Although chronic rhinosinusitis (CRS), an inflammatory upper airway disease, is closely linked to asthma, IFN-beta responses to HRV infections in human nasal epithelial cells (HNECs) from CRS patients remain to be studied. We evaluated inflammatory and antiviral responses to HRV infection in HNECs from CRS patients. METHODS: HNECs, isolated from turbinate tissue of 13 patients with CRS and 14 non-CRS controls, were infected with HRV16 for 4 hours. The HRV titer, LDH activity, production of proinflammatory cytokines and IFN-beta proteins, and expression levels of RIG-I and MDA5 mRNA were assessed at 8, 24, and 48 hours after HRV16 infection. RESULTS: The reduction in viral titer was slightly delayed in the CRS group compared to the non-CRS control group. IL-6 and IL-8 were significantly increased to a similar extent in both groups after HRV infection. In the control group, IFN beta production and MDA5 mRNA expression were significantly increased at 8 and 24 hours after HRV16 infection, respectively. By contrast, in the CRS group, IFN beta was not induced by HRV infection; however, HRV-induced MDA5 mRNA expression was increased, but the increase was slightly delayed compared to the non-CRS control group. The RIG-I mRNA level was not significantly increased by HRV16 infection in either group. CONCLUSIONS: HRV-induced secretion of proinflammatory cytokines in CRS patients was not different from that in the non-CRS controls. However, reductions in viral titer, IFN-beta secretion, and MDA5 mRNA expression in response to HRV infection in CRS patients were slightly impaired compared to those in the controls, suggesting that HRV clearance in CRS patients might be slightly deficient. PMID- 26122509 TI - Enhanced Allergic Inflammation of Der p 2 Affected by Polymorphisms of MD-2 Promoter. AB - PURPOSE: Myeloid differentiation-2 (MD-2) has been associated with endotoxin and inflammatory disorders because it can recognize lipopolysaccharide (LPS) binding and attenuate Toll-like receptor 4 (TLR4)-mediated signaling. However, its role in allergic inflammation has yet to be clarified. We examined whether single nucleotide polymorphisms (SNPs) in MD-2 promoter can affect MD-2 expression and aimed to clarify the relationship between Der p 2 allergy and SNPs of MD-2 promoter. METHODS: The function of SNPs of MD-2 promoter and the effects of cytokines and immunoglobulin on the secretion and mRNA expression were investigated in 73 allergic subjects with different MD-2 gene promoter variants. Peripheral blood mononuclear cells were cultured with or without LPS in the presence of Dermatophagoides pteronyssinus group 2 allergen (Der p 2), followed by mRNA extraction and cytokine expression analysis. The culture supernatants were collected for cytokine measurement. RESULTS: Patients with the MD-2 promoter SNPs (rs1809441/rs1809442) had increased mRNA expressions of MD-2, epsilon heavy chain of IgE (Cepsilon), and interleukin (IL)-8; however, only MD-2 and IL-8 were further up-regulated after Der p 2 stimulation. Patients with SNPs of MD-2 promoter tended to have high levels of IL-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha after Der p 2 and LPS stimulation. Increased secretions of IL-6, IL-8, and IL-10 were found to be up-regulated by Der p 2 stimulation, and an increased secretion of IFN-gamma and decreased secretion of IL-4 were noted after LPS stimulation. CONCLUSIONS: The high levels of proinflammatory cytokines secreted by Der p 2 were predetermined by MD-2 promoter SNPs (rs1809441/rs1809442). Through cytokine secretion by Der p 2 and LPS, these SNPs may serve as an indicator of the pathological phenotype of Der p 2-induced allergic inflammation. PMID- 26122510 TI - Progress and Prospect: A Bibliometric Analysis of Research Papers by Korean Allergists Over Recent Five Years (2009-2013). AB - Since the establishment of the academic society in 1972, Korean allergists have made continuous efforts to elucidate pathogenic mechanisms and therapeutic advances for allergic diseases. The present study aimed to summarize recent progress and explore future prospects of research performance by Korean allergists. We performed a comprehensive bibliometric analysis for research papers published in the Science Citation Index (SCI) or SCI-expanded journals by Korean allergists between 2009 and 2013. Research performance was quantitatively analyzed for the numbers of papers by publication year, research type, and main topic. In addition, the performance was also examined for qualitative indices, such as impact factor and citation number. A total of 1,091 papers were identified. The number of publication increased continuously, with an annual increase rate of 12.3%. Clinical and basic studies were the most frequent types of research, and recently the number of epidemiological studies has increased. By research topic, asthma was the most commonly studied, accounting for 20.9% of the total number of publications. Notably, the amount of rhinitis/rhinosinusitis research has risen steeply in 2013. Qualitative analyses also indicated continuous progress; the median impact factor of published journals increased from 1.918 in 2009 to 2.746 in 2013, yielding an annual increase rate of 7.4%. In conclusion, the present analyses identified a continuous increase in the research performance of Korean allergists over a recent 5 year period (2009-2013), both quantitatively and qualitatively. A more significant contribution is expected in the forthcoming era. PMID- 26122512 TI - Current Approaches and Future Trends to Promote Tendon Repair. AB - Tendons are composed by extracellular collagen fibres arranged in regular arrays and are responsible to transmit tensile forces from a muscle to a bone. Due to their poor healing ability, in some cases tendons injuries are debilitating impairments that affect life quality among adult population worldwide. In the last years, attending to the social and economic concern associated to the high prevalence of tendons injuries and the limited success of the available current treatments, several scaffolds have been developed. Some of these scaffolds are intended to be used as graft-augmentation devices and others to fully replace a damaged tendon. The synthetic ones present superior mechanical characteristics compared to biological scaffolds. However, attending to the specific tendons physiology, even the synthetic scaffolds still don't present the ideal mechanical properties to accomplish a complete and long-term functional tissue repair. Therefore, to enhance tendogenesis when using a tendon engineering approach, several methodologies have been developed to associate with scaffolds, including surface modification and cell seeding. PMID- 26122511 TI - The long term follow-up of early stage follicular lymphoma treated with radiotherapy, chemotherapy or combined modality treatment. AB - Local (involved-field or recently involved-site) radiotherapy is the standard therapy in limited-stage follicular lymphoma (FL). We retrospectively analyzed the value of chemotherapy in 130 patients with limited-stage FL (46 treated with radiotherapy alone [RT group], 30 with radiotherapy plus chemotherapy [COMBINED group] and 43 with chemotherapy alone [CHEMO group], 11 were managed with observation). Ninety-six percent of patients responded (RT 98%, COMBINED 100%, CHEMO 91%, p=0.179), and 37% (40/107) of patients in complete response relapsed (RT 42%, COMBINED 27%, CHEMO 41%, p=0.371). Progression-free survival (PFS) and overall survival (OS) probabilities at 10 years were similar in RT, COMBINED and CHEMO patients (PFS 41%, 61% and 39% [p=0.167], and OS 77%, 81% and 72% [p=0.821], respectively), while the COMBINED group showed a trend to better time to-progression (TTP 43%, 72% and 47% [p=0.055]). On multivariate analysis, only a FLIPI score >=2 showed a trend to influence PFS (HR 2.1 [95% confidence interval 0.9-4.6], p=0.067), and OS (HR 2.4 [0.9-6.5], p=0.084), while patients treated with radiotherapy plus chemotherapy (COMBINED group) showed a significantly better TTP compared with those receiving only RT (HR 0.3 [0.1-0.8], p=0.024). In our study no benefit was observed in survival with the use of systemic therapy compared with local radiotherapy. PMID- 26122513 TI - Novel high-performance metagenome beta-galactosidases for lactose hydrolysis in the dairy industry. AB - The industrially utilised beta-galactosidases from Kluyveromyces spp. and Aspergillus spp. feature undesirable kinetic properties in praxis, such as an unsatisfactory lactose affinity (KM) and product inhibition (KI) by galactose. In this study, a metagenome library of about 1.3 million clones was investigated with a three-step activity-based screening strategy in order to find new beta galactosidases with more favourable kinetic properties. Six novel metagenome beta galactosidases (M1-M6) were found with an improved lactose hydrolysis performance in original milk when directly compared to the commercial beta-galactosidase from Kluyveromyces lactis (GODO-YNL2). The best metagenome candidate, called "M1", was recombinantly produced in Escherichia coli BL21(DE3) in a bioreactor (volume 35 L), resulting in a total beta-galactosidase M1 activity of about 1100 MUkatoNPGal,37 degrees C L(-1). Since milk is a sensitive and complex medium, it has to be processed at 5-10 degrees C in the dairy industry. Therefore, the beta galactosidase M1 was tested at 8 degrees C in milk and possessed a good stability (t1/2=21.8 d), a desirably low apparent KM,lactose,8 degrees C value of 3.8+/-0.7 mM and a high apparent KI,galactose,8 degrees C value of 196.6+/ 55.5 mM. A lactose hydrolysis process (milk, 40 nkatlactose mLmilk,8 degrees C( 1)) was conducted at a scale of 0.5L to compare the performance of M1 with the commercial beta-galactosidase from K. lactis (GODO-YNL2). Lactose was completely (>99.99%) hydrolysed by M1 and to 99.6% (w/v) by K. lactis beta-galactosidase after 25 h process time. Thus, M1 was able to achieve the limit of <100 mg lactose per litre milk, which is recommended for dairy products labelled as "lactose-free". PMID- 26122514 TI - Mass Spectrometric Imaging Using Laser Ablation and Solvent Capture by Aspiration (LASCA). AB - A novel interface for ambient, laser ablation-based mass spectrometric imaging (MSI) referred to as laser ablation and solvent capture by aspiration (LASCA) is presented and its performance demonstrated using selected, unaltered biological materials. LASCA employs a pulsed 2.94 MUm laser beam for specimen ablation. Ablated materials in the laser plumes are collected on a hanging solvent droplet with electric field-enhanced trapping, followed by aspiration of droplets and remaining plume material in the form of a coarse aerosol into a collection capillary. The gas and liquid phases are subsequently separated in a 10 MUL volume separatory funnel, and the solution is analyzed with electrospray ionization in a high mass resolution Q-ToF mass spectrometer. The LASCA system separates the sampling and ionization steps in MSI and combines high efficiencies of laser plume sampling and of electrospray ionization (ESI) with high mass resolution MS. Up to 2000 different compounds are detected from a single ablation spot (pixel). Using the LASCA platform, rapid (6 s per pixel), high sensitivity, high mass-resolution ambient imaging of "as-received" biological material is achieved routinely and reproducibly. PMID- 26122515 TI - Comparison of Ultraviolet Photodissociation and Collision Induced Dissociation of Adrenocorticotropic Hormone Peptides. AB - In an effort to better characterize the fragmentation pathways promoted by ultraviolet photoexcitation in comparison to collision induced dissociation (CID), six adrenocorticotropic hormone (ACTH) peptides in a range of charge states were subjected to 266 nm ultraviolet photodissociation (UVPD), 193 nm UVPD, and CID. Similar fragment ions and distributions were observed for 266 nm UVPD and 193 nm UVPD for all peptides investigated. While both UVPD and CID led to preferential cleavage of the Y-S bond for all ACTH peptides [except ACTH (1 39)], UVPD was far less dependent on charge state and location of basic sites for the production of C-terminal and N-terminal ions. For ACTH (1-16), ACTH (1-17), ACTH (1-24), and ACTH (1-39), changes in the distributions of fragment ion types (a, b, c, x, y, z, and collectively N-terminal ions versus C-terminal ions) showed only minor changes upon UVPD for all charge states. In contrast, CID displayed significant changes in the fragment ion type distributions as a function of charge state, an outcome consistent with the dependence on the number and location of mobile protons that is not prominent for UVPD. Sequence coverages obtained by UVPD showed less dependence on charge state than those determined by CID, with the latter showing a consistent decrease in coverage as charge state increased. PMID- 26122516 TI - EPOR-Based Purification and Analysis of Erythropoietin Mimetic Peptides from Human Urine by Cys-Specific Cleavage and LC/MS/MS. AB - The development of a new class of erythropoietin mimetic agents (EMA) for treating anemic conditions has been initiated with the discovery of oligopeptides capable of dimerizing the erythropoietin (EPO) receptor and thus stimulating erythropoiesis. The most promising amino acid sequences have been mounted on various different polymeric structures or carrier molecules to obtain highly active EPO-like drugs exhibiting beneficial and desirable pharmacokinetic profiles. Concomitant with creating new therapeutic options, erythropoietin mimetic peptide (EMP)-based drug candidates represent means to artificially enhance endurance performance and necessitate coverage by sports drug testing methods. Therefore, the aim of the present study was to develop a strategy for the comprehensive detection of EMPs in doping controls, which can be used complementary to existing protocols. Three model EMPs were used to provide proof of-concept data. Following EPO receptor-facilitated purification of target analytes from human urine, the common presence of the cysteine-flanked core structure of EMPs was exploited to generate diagnostic peptides with the aid of a nonenzymatic cleavage procedure. Sensitive detection was accomplished by targeted SIM/data-dependent MS(2) analysis. Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL). Additionally, first data for the identification of the erythropoietin mimetic peptides EMP1 and BB68 were generated, demonstrating the multi-analyte testing capability of the presented approach. PMID- 26122518 TI - The SEQUEST family tree. AB - Since its introduction in 1994, SEQUEST has gained many important new capabilities, and a host of successor algorithms have built upon its successes. This Account and Perspective maps the evolution of this important tool and charts the relationships among contributions to the SEQUEST legacy. Many of the changes represented improvements in computing speed by clusters and graphics cards. Mass spectrometry innovations in mass accuracy and activation methods led to shifts in fragment modeling and scoring strategies. These changes, as well as the movement of laboratories and lab members, have led to great diversity among the members of the SEQUEST family. Graphical Abstract ?. PMID- 26122519 TI - Investigations of Some Liquid Matrixes for Analyte Quantification by MALDI. AB - Sample inhomogeneity is one of the obstacles preventing the generation of reproducible mass spectra by MALDI and to their use for the purpose of analyte quantification. As a potential solution to this problem, we investigated MALDI with some liquid matrixes prepared by nonstoichiometric mixing of acids and bases. Out of 27 combinations of acids and bases, liquid matrixes could be produced from seven. When the overall spectral features were considered, two liquid matrixes using alpha-cyano-4-hydroxycinnamic acid as the acid and 3 aminoquinoline and N,N-diethylaniline as bases were the best choices. In our previous study of MALDI with solid matrixes, we found that three requirements had to be met for the generation of reproducible spectra and for analyte quantification: (1) controlling the temperature by fixing the total ion count, (2) plotting the analyte-to-matrix ion ratio versus the analyte concentration as the calibration curve, and (3) keeping the matrix suppression below a critical value. We found that the same requirements had to be met in MALDI with liquid matrixes as well. In particular, although the liquid matrixes tested here were homogeneous, they failed to display spot-to-spot spectral reproducibility unless the first requirement above was met. We also found that analyte-derived ions could not be produced efficiently by MALDI with the above liquid matrixes unless the analyte was sufficiently basic. In this sense, MALDI processes with solid and liquid matrixes should be regarded as complementary techniques rather than as competing ones. PMID- 26122520 TI - Utility of Ion Mobility Mass Spectrometry for Drug-to-Antibody Ratio Measurements in Antibody-Drug Conjugates. AB - Antibody-drug conjugates (ADCs) are emerging modalities in the pharmaceutical industry. Characterization of ADC's drug-to-antibody ratio (DAR) becomes a key assessment because of its importance in ADC efficacy and safety. DAR characterization by conventional intact protein MS analysis, however, is challenging because of high heterogeneity of ADC samples. The analysis often requires protein deglycosylation, disulfide-bond reduction, or partial fragmentation. In this study, we illustrate the practical utility of ion mobility mass spectrometry (IM-MS) in a routine LC/MS workflow for DAR measurements. This strategy allows analyte "cleanup" in the gas phase, providing significant improvement of signal-to-noise ratios of ADC intact mass spectra for accurate DAR measurements. In addition, protein drift time analysis offers a new dimension in monitoring the changes of DAR in lot-to-lot analysis. PMID- 26122521 TI - Novor: real-time peptide de novo sequencing software. AB - De novo sequencing software has been widely used in proteomics to sequence new peptides from tandem mass spectrometry data. This study presents a new software tool, Novor, to greatly improve both the speed and accuracy of today's peptide de novo sequencing analyses. To improve the accuracy, Novor's scoring functions are based on two large decision trees built from a peptide spectral library with more than 300,000 spectra with machine learning. Important knowledge about peptide fragmentation is extracted automatically from the library and incorporated into the scoring functions. The decision tree model also enables efficient score calculation and contributes to the speed improvement. To further improve the speed, a two-stage algorithmic approach, namely dynamic programming and refinement, is used. The software program was also carefully optimized. On the testing datasets, Novor sequenced 7%-37% more correct residues than the state-of the-art de novo sequencing tool, PEAKS, while being an order of magnitude faster. Novor can de novo sequence more than 300 MS/MS spectra per second on a laptop computer. The speed surpasses the acquisition speed of today's mass spectrometer and, therefore, opens a new possibility to de novo sequence in real time while the spectrometer is acquiring the spectral data. Graphical Abstract ?. PMID- 26122522 TI - Improving the Sensitivity of Matrix-Assisted Ionization (MAI) Mass Spectrometry Using Ammonium Salts. AB - In matrix-assisted ionization (MAI), analyte incorporated in a small molecule matrix is introduced into an aperture linking atmospheric pressure with the vacuum of a mass spectrometer. Gas-phase analyte ions are spontaneously produced without use of a laser or high voltage. Here we investigate analyte and background ion abundances upon addition of ammonium salts to various MAI matrix/analyte solutions. Regardless of the ammonium salt or matrix used, chemical background ions are suppressed and/or analyte ion abundance improved for basic small molecules, peptides, and proteins. Background ion abundances increase with increasing inlet temperature, but are suppressed with addition of any of a variety of ammonium salts without much effect on the total ion abundances of the analyte ions. However, at lower inlet temperature using the matrices 2-bromo-2 nitropropane-1,3-diol, 1,2-dicyanobenzene, and 3-nitrobenzonitrile (3-NBN), analyte ion abundance increases and any chemical background decreases upon addition of ammonium salt. The improvement in sensitivity using 3-NBN with ammonium salt allows full acquisition mass spectra consuming as little as 1 fmol of ubiquitin. More complete peptide coverage for 100 fmol of a BSA tryptic digest, and increased sensitivity of drugs spiked in urine and saliva were observed after ammonium salt addition to the 3-NBN matrix. PMID- 26122523 TI - Gas-Phase Amidation of Carboxylic Acids with Woodward's Reagent K Ions. AB - Gas-phase amidation of carboxylic acids in multiply-charged peptides is demonstrated via ion/ion reactions with Woodward's reagent K (wrk) in both positive and negative mode. Woodward's reagent K, N-ethyl-3-phenylisoxazolium-3' sulfonate, is a commonly used reagent that activates carboxylates to form amide bonds with amines in solution. Here, we demonstrate that the analogous gas-phase chemistry occurs upon reaction of the wrk ions and doubly protonated (or doubly deprotonated) peptide ions containing the carboxylic acid functionality. The reaction involves the formation of the enol ester intermediate in the electrostatic complex. Upon collisional activation, the ethyl amine on the reagent is transferred to the activated carbonyl carbon on the peptide, resulting in the formation of an ethyl amide (addition of 27 Da to the peptide) with loss of a neutral ketene derivative. Further collision-induced dissociation (CID) of the products and comparison with solution-phase amidation product confirms the structure of the ethyl amide. PMID- 26122525 TI - Information extraction from shadowed regions in images: an eye movement study. AB - Natural scenes often contain variations in local luminance as a result of cast shadows and illumination from different directions. When making judgments about such scenes, it may be hypothesized that darker regions (with lower relative contrast due to a lack of illumination) are avoided as they may provide less detailed information than well-illuminated areas. We here test this hypothesis, first by presenting participants images of faces that were digitally modified to simulate the effect of a shadow over half of the image, and second by presenting photographs of faces taken with side illumination, also resulting in the appearance of a shadow across half of the face. While participants viewed these images, they were asked to perform different tasks on the images, to allow for the presentation of the different versions of each image (left shadow, right shadow, no shadow), and to distract the observers from the contrast and illumination manipulations. The results confirm our hypothesis and demonstrate that observers fixate the better illuminated regions of the images. PMID- 26122524 TI - Neuroprotection and spatial memory enhancement of four herbal mixture extract in HT22 hippocampal cells and a mouse model of focal cerebral ischemia. AB - BACKGROUND: Four traditional Korean medicinal herbs which act in retarding the aging process, Polygonum multiflorum Thunb., Rehmannia glutinosa (Gaertn) Libosch., Polygala tenuifolia Willd., and Acorus gramineus Soland., were prepared by systematic investigation of Dongeuibogam (Treasured Mirror of Eastern Medicine), published in the early 17th century in Korea. This study was performed to evaluate beneficial effects of four herbal mixture extract (PMC-12) on hippocampal neuron and spatial memory. METHODS: High performance liquid chromatography (HPLC) analysis was performed for standardization of PMC-12. Cell viability, lactate dehydrogenase, flow cytometry, reactive oxygen species (ROS), and Western blot assays were performed in HT22 hippocampal cells and immunohistochemistry and behavioral tests were performed in a mouse model of focal cerebral ischemia in order to observe alterations of hippocampal cell survival and subsequent memory function. RESULTS: In the HPLC analysis, PMC-12 was standardized to contain 3.09% 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D glucoside, 0.35% 3',6-disinapoyl sucrose, and 0.79% catalpol. In HT22 cells, pretreatment with PMC-12 resulted in significantly reduced glutamate-induced apoptotic cell death. Pretreatment with PMC-12 also resulted in suppression of ROS accumulation in connection with cellular Ca(2+) level after exposure to glutamate. Expression levels of phosphorylated p38 mitogen-activated protein kinases (MAPK) and dephosphorylated phosphatidylinositol-3 kinase (PI3K) by glutamate exposure were recovered by pretreatment with either PMC-12 or anti oxidant N-acetyl-L-cysteine (NAC). Expression levels of mature brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (CREB) were significantly enhanced by treatment with either PMC-12 or NAC. Combination treatment with PMC-12, NAC, and intracellular Ca(2+) inhibitor BAPTA showed similar expression levels. In a mouse model of focal cerebral ischemia, we observed higher expression of mature BDNF and phosphorylation of CREB in the hippocampus and further confirmed improved spatial memory by treatment with PMC-12. CONCLUSIONS: Our results suggest that PMC-12 mainly exerted protective effects on hippocampal neurons through suppression of Ca(2+) related ROS accumulation and regulation of signaling pathways of p38 MAPK and PI3K associated with mature BDNF expression and CREB phosphorylation and subsequently enhanced spatial memory. PMID- 26122526 TI - Automatic de-identification of electronic medical records using token-level and character-level conditional random fields. AB - De-identification, identifying and removing all protected health information (PHI) present in clinical data including electronic medical records (EMRs), is a critical step in making clinical data publicly available. The 2014 i2b2 (Center of Informatics for Integrating Biology and Bedside) clinical natural language processing (NLP) challenge sets up a track for de-identification (track 1). In this study, we propose a hybrid system based on both machine learning and rule approaches for the de-identification track. In our system, PHI instances are first identified by two (token-level and character-level) conditional random fields (CRFs) and a rule-based classifier, and then are merged by some rules. Experiments conducted on the i2b2 corpus show that our system submitted for the challenge achieves the highest micro F-scores of 94.64%, 91.24% and 91.63% under the "token", "strict" and "relaxed" criteria respectively, which is among top ranked systems of the 2014 i2b2 challenge. After integrating some refined localization dictionaries, our system is further improved with F-scores of 94.83%, 91.57% and 91.95% under the "token", "strict" and "relaxed" criteria respectively. PMID- 26122527 TI - The role of fine-grained annotations in supervised recognition of risk factors for heart disease from EHRs. AB - This paper describes a supervised machine learning approach for identifying heart disease risk factors in clinical text, and assessing the impact of annotation granularity and quality on the system's ability to recognize these risk factors. We utilize a series of support vector machine models in conjunction with manually built lexicons to classify triggers specific to each risk factor. The features used for classification were quite simple, utilizing only lexical information and ignoring higher-level linguistic information such as syntax and semantics. Instead, we incorporated high-quality data to train the models by annotating additional information on top of a standard corpus. Despite the relative simplicity of the system, it achieves the highest scores (micro- and macro-F1, and micro- and macro-recall) out of the 20 participants in the 2014 i2b2/UTHealth Shared Task. This system obtains a micro- (macro-) precision of 0.8951 (0.8965), recall of 0.9625 (0.9611), and F1-measure of 0.9276 (0.9277). Additionally, we perform a series of experiments to assess the value of the annotated data we created. These experiments show how manually-labeled negative annotations can improve information extraction performance, demonstrating the importance of high quality, fine-grained natural language annotations. PMID- 26122528 TI - Detection of Multi-walled Carbon Nanotubes and Carbon Nanodiscs on Workplace Surfaces at a Small-Scale Producer. AB - BACKGROUND: The industrial use of novel-manufactured nanomaterials such as carbon nanotubes and carbon nanodiscs is increasing globally. Occupational exposure can occur during production, downstream use, and disposal. The health effects of many nanomaterials are not yet fully characterized and to handle nano-objects, their aggregates and agglomerates >100nm (NOAA), a high degree of control measures and personal protective equipment are required. The emission of airborne NOAA during production and handling can contaminate workplace surfaces with dust, which can be resuspended resulting in secondary inhalation exposures and dermal exposures. This study surveys the presence of carbon-based nanomaterials, such as multi walled carbon nanotubes (MWCNTs) and carbon nanodiscs, as surface contamination at a small-scale producer using a novel tape sampling method. METHODS: Eighteen different surfaces at a small-scale producer were sampled with an adhesive tape sampling method. The surfaces selected were associated with the production and handling of MWCNT powder in the near-field zone. Surfaces in the far-field zone were also sampled. In addition, tape stripping of the skin was performed on one worker. The tape samples were analysed with scanning electron microscopy to detect the carbon-based NOAA. Air sampling with a personal impactor was also performed on a worker who was producing MWCNTs the same day as the tape samples were collected. RESULTS: MWCNTs were detected in 50% of the collected tape samples and carbon nanodiscs in 17%. MWCNTs and carbon nanodiscs were identified in all parts of the workplace, thus, increasing the risk for secondary inhalation and dermal exposure of the workers. Both airborne MWCNTs and carbon nanodiscs were detected in the personal impactor samples. The tape-strip samples from the worker showed no presence of carbon-containing nanoparticles. CONCLUSIONS: Tape sampling is a functional method for detecting surface contamination of carbon based NOAA and for exposure control during production at potentially any workplace that produces or handles such manufactured nanomaterials. With the tape method, it is possible to monitor if a potential for secondary inhalation exposure or dermal exposure exists through resuspension of dust deposited on workplace surfaces. By means of air sampling, we could confirm that carbon nanodiscs were resuspended into the air at the workplace even though they were not handled during that particular work shift. MWCNTs were detected in the air samples, but can have been derived from either resuspension or from the work tasks with MWCNTs that were performed during the air sampling. Tape sampling is a complementary method to air sampling and together these two methods provide a better view of the hygienic situation in workplaces where NOAA can be emitted into work environments. PMID- 26122529 TI - Crude extract of Euphorbia formosana induces apoptosis of DU145 human prostate cancer cells acts through the caspase-dependent and independent signaling pathway. AB - Prostate cancer is the most frequently diagnosed malignancy in men and the second highest contributor of male cancer mortality. The crude extract of Euphorbia formosana (CEEF) has been used for treatment of different diseases but the cytotoxic effects of CEEF on human cancer cells have not been reported. The purpose of the present experiments was to determine effects of CEEF on cell cycle distribution and induction of apoptosis in DU145 human prostate cancer cells in vitro. Contrast-phase microscope was used for examining cell morphological changes. Flow cytometric assays were used for cell viability, cell cycle, apoptosis, reactive oxygen species, and Ca2+ production and mitochondria membrane potential (DeltaPsim ). Western blotting was used for examining protein expression of cell cycle and apoptosis associated proteins. Real-time PCR was used for examining mRNA levels of caspase-3, -8, and -9, AIF, and Endo G. Confocal laser microscope was used to examine the translocation of AIF, Endo G, and cytochrome in DU145 cells after CEEF exposure. CEEF-induced cell morphological changes, decreased the percentage of viable cells, and induced S phase arrest and apoptosis in DU145 cells. Furthermore, CEEF promoted RAS and Ca2+ production and reduced DeltaPsim levels. Real-time QPCR confirmed that CEEF promoted the mRNA expression of caspase-3 and -9, AIF and Endo G and we found that AIF and Endo G and cytochrome c were released from mitochondria. Taken together, CEEF-induced cytotoxic effects via ROS production, induced S phase arrest and induction of apoptosis through caspase-dependent and independent and mitochondria-dependent pathways in DU245 cancer cells. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1600-1611, 2016. PMID- 26122530 TI - A decisive step toward the origin of life. AB - Several hypotheses exist regarding how life emerged from the abiotic world, the most popular of which is the 'RNA World' hypothesis. Recent advances describe nonenzymatic polymerization of mononucleotides in a phospholipid liquid crystalline matrix, suggesting that a 'Lipid World' might have preceded the RNA World. PMID- 26122531 TI - Indwelling peritoneal catheters in patients with cirrhosis and refractory ascites. AB - BACKGROUND: The prevalence of spontaneous bacterial peritonitis (SBP) in hospitalised cirrhotics with ascites is 10-30%. Treatment for refractory ascites includes paracenteses, transjugular intrahepatic portosystemic shunt or drain placement; the latter is discouraged due to a perceived infection risk. AIM: This study aimed to evaluate the risk of bacterial peritonitis (BP) with peritoneal drains in patients with Child-Pugh class B or C cirrhosis and determine their impact on survival. METHODS: We conducted a retrospective review of end-stage liver disease (ESLD) patients with non-malignant, refractory ascites who had peritoneal drains placed for >=3 days at Loyola University between 1999 and 2009. Cell counts were performed at drain placement and within 72 h. BP was defined as ascitic polymorphonuclear neutrophils >250/mm(3) . Univariate analysis assessed the association between demographics, laboratory markers and development of BP. Kaplan-Meier curve estimates by infection were constructed and survival distributions were compared using log-rank statistic. RESULTS: There were 227 drain placements during the study period. Twenty-two per cent were diagnosed with BP (12% had SBP at drain placement; 10% developed BP within 72 h). There was no association between BP and baseline characteristics. Patients who developed BP within 72 h of drain placement had 50% mortality at 5 months compared with 50 months in those without infection (log-rank P <= 0.003). CONCLUSION: In ESLD patients who received an indwelling peritoneal catheter, there was 10% risk of developing BP and significant mortality increase. Though placing drains is not the mainstay of treatment for refractory ascites, we confirm the theoretical adverse risk of peritoneal drains on infection and survival in cirrhotics. PMID- 26122532 TI - Headache and Pain in Guillain-Barre Syndrome. AB - While moderate and severe back or extremity pain is frequent in Guillain-Barre syndrome (GBS), headache appears to be uncommon. Most of the reports of headache in GBS place it in the context of the posterior reversible encephalopathy syndrome (PRES) which is increasingly recognized as a likely dysautonomia-related GBS complication. There are also a few reports of headache in the setting of increased CSF pressure and papilledema and in association with the Miller Fisher GBS variant. In comparison, back and extremity pain is highly prevalent. Aching muscle pain and neuropathic pain are the two most common of several pain types. Pain may be a heralding feature and has been described in patients as long as 2 years after disease onset. Pain management is a major axis of treatment in GBS. Gabapentin is a reasonable first-line choice, and opioid medications can be added for more severe pain but there are few clinical trials to inform specific recommendations. While the understanding of pain pathophysiology in GBS is incomplete, its prevalence and clinical impact are increasingly recognized and studied. Pain should be considered a cardinal manifestation of GBS along with acute, mostly symmetric weakness and diminished reflexes. PMID- 26122533 TI - Sports-Related Concussion. AB - Sports-related concussions (SRC) are common in all ages and occur in all sports. The diagnosis based on clinical suspicion after more serious injury is ruled out. Symptoms of concussion are due to a temporary and reversible neurometabolic cascade resulting in blood flow changes, neuronal excitotoxicity, ionic shifts, and mitochondrial changes. Symptoms are nonspecific, and commonly include headache, cognitive complaints, photophobia, and phonophobia. Loss of consciousness is rare in SRC and has limited influence on recovery and prognosis. Imaging has a limited role in the management of concussion and should be used to evaluate for more serious intracranial pathology. Treatment is based on symptoms and an understanding of the typical, rapid (7-10 days) recovery. No athlete should return to play until their symptoms have resolved and they have completed a supervised, step-wise return to play protocol. The article covers the most recent literature on the diagnosis and management of SRC, including evidence based recommendations and expert-based consensus opinion. The article will also discuss issues regarding medical retirement, legislation, and future concepts in concussion diagnosis and management. PMID- 26122535 TI - Two kinds of autism: a comparison of distinct understandings of psychiatric disease. AB - In this article, I argue that the history and philosophy of autism need to account for two kinds of autism. Contemporary autism research and practice is structured, directed and connected by an 'ontological understanding of disease'. This implies that autism is understood as a disease like any other medical disease, existing independently of its particular manifestations in individual patients. In contrast, autism in the 1950s and 1960s was structured by a psychoanalytical framework and an 'individual understanding of disease'. This implied that autism was not a distinct disease but an idiosyncratic and meaningful response of the child to a disturbed development of the ego. These two kinds of autism are embedded in and reveal two very different 'styles of psychiatric thought'. PMID- 26122536 TI - The overriding of TRAIL resistance by the histone deacetylase inhibitor MS-275 involves c-myc up-regulation in cutaneous, uveal, and mucosal melanoma. AB - Malignant melanoma is a highly aggressive tumor which may occur in the skin, eye, and mucous membranes. The prognosis of melanoma remains poor in spite of therapeutic advances, emphasizing the importance of innovative treatment modalities. Currently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is showing promising clinical responses, however its use is hampered by intrinsic or acquired melanoma resistance to apoptosis. Recently, we showed that the combination of TRAIL with the class I-specific histone deacetylase inhibitor (HDACi) MS-275 was a privileged way to override TRAIL resistance through down regulation of cellular Fas-associated death domain (FADD)-like interleukin-1beta converting enzyme-inhibitory protein (c-FLIP). Here, we elucidated the underlying mechanism and provided evidence that a crucial step in the c-FLIP downregulation triggered by MS-275 implies the up-regulation of c-myc, a transcriptional repressor of c-FLIP. Notably, MS-275 caused H3 histone acetylation at the promoter of c-myc and increased its binding to the c-FLIP promoter, that in turn led to reduced c-FLIP gene transcription. Knockdown of c-myc prevented the MS-275 mediated downregulation of c-FLIP and hindered TRAIL-plus MS-275-induced apoptosis. Findings reported here provide additional knowledge tools for a more aware and effective molecular therapy of melanoma. PMID- 26122537 TI - Ovarian suppression in a marsupial following single treatment with a gonadotrophin-releasing hormone agonist in microspheres. AB - The effect of treatment with Lucrin Depot (1 month), a microsphere gonadotrophin releasing hormone agonist preparation, was investigated in the fat-tailed dunnart (Sminthopsis crassicaudata) as a potential strategy to synchronise cycling. The status of the ovaries (ovarian size, number and size of Graafian follicles and corpora lutea) and reproductive tract (weight, vascularity and muscularity) in twelve untreated females were assessed to establish the activity parameters for randomly selected cycling animals. Thirty-six females were treated with 1mgkg-1 (n=12), 10mgkg-1 (n=12) or 20mgkg-1 (n=12) Lucrin Depot. At 4, 6 and 8 weeks the reproductive tracts were assessed using the criteria developed in the untreated females. All of the females treated with 10mgkg-1 showed suppression at 4 weeks and 25% showed return of reproductive activity at 8 weeks. A dose of 1mgkg-1 did not appear to suppress reproductive activity and 20mgkg-1 gave equivocal results, with evidence of both suppression and activity. The results indicate that Lucrin Depot appears to be a promising agent to regulate and potentially synchronise breeding activity in the fat-tailed dunnart. PMID- 26122539 TI - Lichen Planus Possibly Induced by Acyclovir in a Child. PMID- 26122538 TI - The impact of heptavalent pneumococcal conjugate vaccine on the incidence of childhood community-acquired pneumonia and bacteriologically confirmed pneumococcal pneumonia in Japan. AB - Heptavalent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2010. We investigated the impact of PCV7 on childhood community-acquired pneumonia (CAP) and pneumococcal pneumonia (PP). Children aged <5 years living in Chiba city, Japan, who were admitted to hospitals were enrolled to estimate the incidence of CAP based on the mid-year population. PP was determined by the presence of Streptococcus pneumoniae in cultured blood and/or sputum samples of CAP patients. The incidence of CAP and S. pneumoniae isolated from PP patients was compared before (April 2008-March 2009) and after (April 2012-March 2013) the introduction of PCV7 immunization. The annual incidence of CAP was reduced [incidence rate ratio 0.81, 95% confidence interval (CI) 0.73-0.90]. When comparing post-vaccine with pre-vaccine periods, the odds ratio for PP incidence was 0.60 (95% CI 0.39-0.93, P = 0.024). PCV7-covered serotypes markedly decreased (66.6% in pre-vaccine vs. 15.6% in post-vaccine, P < 0.01), and serotypes 6C, 15A, 15C and 19A increased. Multidrug-resistant international clones in the pre vaccine period (Spain6B-2/ST90, Taiwan19F-14/ST236) decreased, while Sweden15A 25/ST63 was the dominant clone in the post-vaccine period. A significant reduction in the incidence of both CAP hospitalizations and culture-confirmed PP of vaccine serotypes was observed at 2 years after PCV7 vaccination. PMID- 26122540 TI - Neuro-ophthalmology and neuro-otology update. AB - This review summarizes topical papers from the fields of neuro-ophthalmology and neuro-otology published from August 2013 to February 2015. The main findings are: (1) diagnostic criteria for pseudotumor cerebri have been updated, and the Idiopathic Intracranial Hypertension Treatment Trial evaluated the efficacy of acetazolamide in patients with mild vision loss, (2) categorization of vestibular disorders through history and ocular motor examination is particularly important in the acute vestibular syndrome, where timely distinction between a central or peripheral localization is essential, (3) the newly described "sagging eye syndrome" provides a mechanical explanation for an isolated esodeviation that increases at distance in the aging population and (4) eye movement recordings better define how cerebellar dysfunction and/or sixth nerve palsy may play a role in other patients with esodeviations that increase at distance. PMID- 26122541 TI - Functional dizziness: diagnostic keys and differential diagnosis. PMID- 26122542 TI - Regional covariance of muscarinic acetylcholine receptors in Alzheimer's disease using (R, R) [(123)I]-QNB SPECT. AB - Alzheimer's disease (AD) is characterised by deficits in cholinergic neurotransmission and subsequent receptor changes. We investigated (123)I-iodo quinuclidinyl-benzilate (QNB) SPECT images using spatial covariance analysis (SCA), to detect an M1/M4 receptor spatial covariance pattern (SCP) that distinguished AD from controls. Furthermore, a corresponding regional cerebral blood flow (rCBF) SCP was also derived. Thirty-nine subjects (15 AD and 24 healthy elderly controls) underwent (123)I-QNB and (99m)Tc-exametazime SPECT. Voxel SCA was simultaneously applied to the set of smoothed/registered scans, generating a series of eigenimages representing common intercorrelated voxels across subjects. Linear regression identified individual M1/M4 and rCBF SCPs that discriminated AD from controls. The M1/M4 SCP showed concomitant decreased uptake in medial temporal, inferior frontal, basal forebrain and cingulate relative to concomitant increased uptake in frontal poles, occipital, pre-post central and precuneus/superior parietal regions (F1,37 = 85.7, p < 0.001). A largely different perfusion SCP was obtained showing concomitant decreased rCBF in medial and superior temporal, precuneus, inferior parietal and cingulate relative to concomitant increased rCBF in cerebellum, pre-post central, putamen, fusiform and brain stem/midbrain regions (F1,37 = 77.5, p < 0.001). The M1/M4 SCP expression correlated with the duration of cognitive symptoms (r = 0.90, p < 0.001), whereas the rCBF SCP expression negatively correlated with MMSE, CAMCOG and CAMCOGmemory (r >= |0.63|, p <= 0.006). (123)I-QNB SPECT revealed an M1/M4 basocortical covariance pattern, distinct from rCBF, reflecting the duration of disease rather than current clinical symptoms. This approach could be more sensitive than univariate methods in characterising the cholinergic/rCBF changes that underpin the clinical phenotype of AD. PMID- 26122544 TI - The effects of an individual, multistep intervention on adherence to treatment in hemodialysis patients. AB - PURPOSE: The present study was conducted to investigate the effect of individual, multistep intervention on adherence to treatment in hemodialysis patients referred to a hemodialysis center in Shahrekord, Iran. METHOD: In this interventional study, hemodialysis patients referring the center of the study were randomly assigned into two control and intervention groups (each 33). The control group received routine treatment, recommended dietary and fluid restrictions. The intervention group participated in eight individual interventional sessions accompanied routine treatment. At the beginning and the end of the study, routine laboratory tests and end-stage renal disease-adherence questionnaire were filled out for patients in both groups. The data were analyzed using Mann-Whitney and Wilcoxon tests. RESULTS: At the end of the study, the two groups showed a significant difference in all domains of adherence except adherence to diet and adherence was better in the intervention group (p < 0.05). In demographic characteristic, only age indicated a positive correlation with adherence to dialysis program (p = 0.04, r = 0.254). After intervention, serum phosphorus decreased significantly in the intervention group (p < 0.05). CONCLUSIONS: Adherence to treatment is one of the major problems in hemodialysis patients; however, comprehensive interventions are required in view of individual condition. Implications for Rehabilitation Adherence to treatment means that all patients' behaviors (diet, fluids and drugs intake) should be in line with the recommendations given by healthcare professionals. There is evidence on the association between adherence to treatment and decreased risk of hospitalization in dialysis patients. Individual structured programs are most likely to be successful in encouraging adherence to treatment. PMID- 26122543 TI - The diagnostic value of dopamine transporter imaging and olfactory testing in patients with parkinsonian syndromes. AB - The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinson's disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand (123)I-FP-CIT (DaTSCAN((r))) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75%) had visually predominant dopamine depletion in putamen, while most APS patients (56%) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately. PMID- 26122545 TI - What are the perceived barriers, facilitators and attitudes to exercise for women with rheumatoid arthritis? A qualitative study. AB - PURPOSE: This study qualitatively examined the attitudes and perceived barriers to exercise of women with rheumatoid arthritis (RA). We also explored the level of exercise that might be considered helpful or harmful, and whether walking would be an acceptable type of exercise. METHOD: Eight women with RA were interviewed via telephone using a semi-structured approach. Transcripts were coded for themes using the General Inductive Approach. These themes were used to develop a theoretical model of the effect of barriers and facilitators to exercise for women with RA. RESULTS: Two themes emerged (social connections and fear). Social connections could facilitate participation in exercise or prove to be a barrier. Fear had three distinct sub-themes: fear of the unknown (including a safe level of exercise), fear of the known and fear for safety. For most participants, walking 3-4 times a week was thought to be an acceptable programme for themselves or others with RA. CONCLUSION: Among those interviewed, walking was considered an acceptable form of exercise for people with RA. Many of the barriers to exercise identified by participants could be alleviated by detailed instructions on the type and duration of exercise recommended. These findings inform the development of walking interventions. Implications for Rehabilitation People with RA and various other chronic illnesses have previously been found to request more specific guidance for incorporating physical activity into their treatment. There was a willingness to participate in physical activity among our participants with RA. Activities such as walking appear to be feasible for people with RA but fears and social support can be barriers. Rehabilitation professionals are ideally placed to help people with RA overcome fears and social support barriers: providing encouragement to participate with others is recommended. PMID- 26122547 TI - The experiences of everyday activities post-stroke. AB - PURPOSE: Practitioners can use stroke survivors' lived experiences associated with everyday activities to understand and assess recovery from stroke, to plan interventions and to facilitate goal setting. This study explored the experiences associated with daily activities among community dwelling survivors of stroke to identify factors that influenced these experiences. METHOD: In this mixed method study, 23 stroke survivors completed the Daily Experiences of Pleasure, Productivity and Restoration Profile, a time use survey, on three separate, self chosen days within 1 week. Participants subsequently completed individual, semi structured interviews. RESULTS: Descriptive statistics and constant comparative analysis revealed that high levels of pleasure were associated with low-demand leisure activities, high levels of productivity were associated with home management activities and engaging in hobbies provided the highest combination of pleasure, productivity and restoration. The study also revealed that lived experiences of pleasure, productivity and restoration were influenced by the convergence of internal and external factors. CONCLUSIONS: Stroke survivors' lived experiences of pleasure, productivity and restoration in the context of everyday activities yields insight into the survivors' recovery and adjustment processes and into their quality of life. Practitioners should therefore incorporate stroke survivors' experiences as they facilitate goal setting and plan interventions. Implications for Rehabilitation Understanding stroke survivors' lived experiences provides practitioners valuable information to assist with goal setting and intervention planning. A sense of accomplishment may be gained outside of work in home management and high demand leisure activities for survivors with low self-efficacy. Practitioners should consider facilitating stroke survivors' participation in their hobbies as these activities were associated with high level of pleasure, productivity and restoration. Attending to stroke survivors' self-perceptions and self-expectations is critical as these internal factors influence their lived experience. PMID- 26122546 TI - Health-related quality of life improvements among women with chronic pain: comparison of two multidisciplinary interventions. AB - PURPOSE: To measure the effect of 4 weeks traditional multidisciplinary pain management program (TMP) versus neuroscience education and mindfulness-based cognitive therapy (NEM) on quality of life (HRQL) among women with chronic pain. METHOD: This observational longitudinal cohort study conducted in an Icelandic rehabilitation centre included 122 women who received TMP, 90 receiving NEM, and 57 waiting list controls. Pain intensity (visual analogue scale) and HRQL (Icelandic Quality of Life scale) were measured before and after interventions. ANOVA and linear regression were used for comparisons. RESULTS: Compared with controls we observed statistically significant changes in pain intensity (p < 0.001) and HRQL (p < 0.001) among women receiving both interventions, while NEM participants reported significant improvements in sleep (8.0 versus 4.4 in TMP; p = 0.008). Head to head comparison between study groups revealed that pain intensity improved more among TMP participants (21.8 versus 17.2 mm; p = 0.013 adjusted). Women with low HRQL at baseline improved more than those with higher HRQL (mean TMP = 13.4; NEM = 12.9 if HRQL <= 35 versus mean TMP = 6.6 and NEM = 7.8 if HQRL > 35). CONCLUSIONS: Our non-randomized study suggests that both NEM and TMP programs improve pain and HRQL among women with chronic pain. Sleep quality showed more improvements in NEM while pain intensity in TMP. Longer-term follow-ups are needed to address whether improvements sustain. IMPLICATIONS FOR REHABILITATION: Chronic pain is a debilitating condition affecting quality of life and restricting societal participation. Intensive multidisciplinary bio psycho-social rehabilitation is essential for this patient group. This study shows improvement in health-related quality of life and pain intensity following such rehabilitation. Emphasizing mindfulness based cognitive therapy and neuroscience patient education improves sleep to more extend than more traditional approach. PMID- 26122548 TI - [(68) Ga]-HP-DO3A-nitroimidazole: a promising agent for PET detection of tumor hypoxia. AB - The goal of this study is to evaluate a new (68) Ga-based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [(68) Ga]-HP-DO3A-nitroimidazole ([(68) Ga]-HP DO3A-NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance(r), HP-DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [(68) Ga]-HP-DO3A-NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O2 . The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 +/- 1.2 (n = 3) as measured by PET at 2 h post-injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [(68) Ga]-HP-DO3A-NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [(68) Ga]-HP-DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor-bearing mice breathing air versus 100% O2 . Given the commercial availability of cGMP (68) Ge/(68) Ga generators and the ease of (68) Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy. PMID- 26122549 TI - Effects of transport, fasting and anaesthesia on the faecal microbiota of healthy adult horses. AB - REASONS FOR PERFORMING STUDY: The intestinal microbiota is important for health and disease. Factors that disturb the equine intestinal microbiota need further investigation. OBJECTIVES: To determine the effects of transport, fasting and anaesthesia on the faecal microbiota of healthy adult horses using next generation sequencing. STUDY DESIGN: Experimental trial. METHODS: Faecal samples were taken from 8 horses at baseline, after transport, 12 h of fasting and 24, 48 and 72 h after a 6 h anaesthesia. Next generation sequencing of the V4 region of the 16S rRNA gene was used to assess the microbial composition of faeces. Alpha diversity, phylogenetic structures and beta diversity were assessed. RESULTS: There were significant changes in the relative abundances of phyla, classes, orders and families after transport, fasting and anaesthesia. Most notably horses had a significantly lower abundance of Clostridiales after transport compared with baseline (P = 0.03) and a decreased abundance of Rickettsiales after fasting (P = 0.024). Alpha diversity was not significantly different between time points (all P>0.21). When parsimony analysis was applied, anaesthesia had a significant effect on community membership and structure (Jaccard index and Yue and Clayton index both P = 0.02). CONCLUSIONS: There was some effect of transport, fasting and anaesthesia on the composition and structure of the microbiota of healthy horses. This indicates these are potentially stress factors for the equine intestinal microbiota. Further investigation is required to look at the potential impact of changes in the microbiota on the development of disease in the post anaesthetic period. PMID- 26122550 TI - Negative feedback regulation of bile acid metabolism: impact on liver metabolism and diseases. PMID- 26122551 TI - Transient memory impairment and transient global amnesia induced by photodynamic therapy. AB - Photodynamic therapy (PDT) is a commonly used and effective treatment option for nonmelanoma skin cancer. Apart from local side-effects such as pain, oedema and erythema, no major adverse events occur in the majority of cases. Here we report on five patients who developed memory deficits such as transient global amnesia immediately after PDT for actinic keratosis. All PDT treatments were performed according to standard therapy protocols. The reported patients had a memory gap for the entire procedure, as well as for the consecutive emergency medical care. Other common neurological causes such as stroke or epileptic seizures were excluded. No focal neurological deficits were detectable. The symptoms had a fairly rapid onset following red-light illumination and were reversible without sequelae within 1-24 h. No correlation of the condition and pain during the illumination could be revealed. Magnetic resonance imaging of the brain revealed punctuated lesions in the hippocampus as a potential morphological correlate in one patient. The association between amnestic syndromes and PDT is novel and has not previously been reported. Even though PDT is considered a safe treatment modality, the possibility of neurological adverse events, albeit rare, should be kept in mind. PMID- 26122552 TI - Ovarian function in captive owl monkeys (Aotus nancymaae and A. vociferans). AB - BACKGROUND: Ovarian function and morphology of owl monkeys (Aotus spp.) is inadequately known, but it is essential to describe this organ in detail to better understand reproductive patterns of the species. METHODS: This study reports the anatomical and histological features of the ovaries from 41 owl monkeys, considering their reproductive status and parity. RESULTS: The corpora lutea (CL) and reproductive state had a significant effect on ovarian volume. Follicles were observed in both pregnant and non-pregnant subjects. All females in the luteal phase and pregnant females showed at least one cyclic or pregnancy CL. Mean ovulation rate was 1.89 CL/female, and the mean ovum mortality was 37.5%. There were no significant differences in ovarian volume related to parity. CONCLUSIONS: These results contribute to the scarce information available on the reproductive biology of owl monkeys and can aid in the development of biotechnologies involved in assisted reproduction. PMID- 26122553 TI - Personalized peptide vaccination for cervical cancer patients who have received prior platinum-based chemotherapy. AB - A feasibility study was performed to evaluate the immunological efficacy and safety of a personalized peptide vaccine (PPV) for cervical cancer patients who have received platinum-based chemotherapy. A total of 24 patients with standard chemotherapy-resistant cervical cancer, including 18 recurrent cases, were enrolled in this study and received a maximum of 4 peptides based on HLA-A types and IgG levels to the vaccine candidate peptides in pre-vaccination plasma. The parental protein expression of most of the vaccine peptides was confirmed in the cervical cancer tissues. No vaccine-related systemic grade 3 or 4 adverse events were observed in any patients. Due to disease progression, 2 patients failed to complete the first cycle of vaccinations (sixth vaccination). Cytotoxic T lymphocyte (CTL) or IgG responses specific for the peptides used for vaccination were augmented in half of cases after the first cycle. The median overall survival was 8.3 months. The clinical responses of the evaluable 18 cases consisted of 1 case with a partial response and 17 cases with disease progression; the remaining 6 cases were not evaluable. Performance status, injection site skin reaction and circulating PD-1(+) CD4(+) T-cells were significantly prognostic of overall survival, and multivariate analysis also indicated that the performance status and circulating PD-1(+) CD4(+) T-cells were prognostic. Because of the safety and immunological efficacy of PPV and the possible prolongation of overall survival, further clinical trials of PPV at a larger scale in advanced or recurrent cervical cancer patients who have received prior platinum-based chemotherapy are recommended. PMID- 26122554 TI - Dual Antiplatelet Therapy of Clopidogrel and Aspirin in Secondary Prevention of Ischemic Stroke: Evidence and Indications. AB - Nowadays the dual antiplatelet therapy (DAPT) becomes more widely used in patients with ischemic stroke. Nevertheless, controversies exist for indications of DAPT. In view of evidence-based medicine analysis, patients with high-risk transient ischemic attack and minor stroke, severe symptomatic intracranial artery stenosis, symptomatic intracranial and extracranial artery stenosis causing artery-to-artery embolism, ischemic stroke attributed to aortic arch plaques, high-risk atrial fibrillation not suitable for oral anticoagulants, intracranial and extracranial stent implantation, and ischemic stroke with acute coronary syndrome may gain great benefit from DAPT of clopidogrel and aspirin. In clinical practice, individualized antiplatelet therapy strategies should be taken by weighing risks of ischemia and hemorrhage. PMID- 26122555 TI - Governing for the Common Good. AB - The proper object of global health governance (GHG) should be the common good, ensuring that all people have the opportunity to flourish. A well-organized global society that promotes the common good is to everyone's advantage. Enabling people to flourish includes enabling their ability to be healthy. Thus, we must assess health governance by its effectiveness in enhancing health capabilities. Current GHG fails to support human flourishing, diminishes health capabilities and thus does not serve the common good. The provincial globalism theory of health governance proposes a Global Health Constitution and an accompanying Global Institute of Health and Medicine that together propose to transform health governance. Multiple lines of empirical research suggest that these institutions would be effective, offering the most promising path to a healthier, more just world. PMID- 26122557 TI - Response to Letter to the Editor: Perineal burn care: French working group recommendations [Burns 2014 40:655-663]. PMID- 26122556 TI - Genetical genomics of Populus leaf shape variation. AB - BACKGROUND: Leaf morphology varies extensively among plant species and is under strong genetic control. Mutagenic screens in model systems have identified genes and established molecular mechanisms regulating leaf initiation, development, and shape. However, it is not known whether this diversity across plant species is related to naturally occurring variation at these genes. Quantitative trait locus (QTL) analysis has revealed a polygenic control for leaf shape variation in different species suggesting that loci discovered by mutagenesis may only explain part of the naturally occurring variation in leaf shape. Here we undertook a genetical genomics study in a poplar intersectional pseudo-backcross pedigree to identify genetic factors controlling leaf shape. The approach combined QTL discovery in a genetic linkage map anchored to the Populus trichocarpa reference genome sequence and transcriptome analysis. RESULTS: A major QTL for leaf lamina width and length:width ratio was identified in multiple experiments that confirmed its stability. A transcriptome analysis of expanding leaf tissue contrasted gene expression between individuals with alternative QTL alleles, and identified an ADP-ribosylation factor (ARF) GTPase (PtARF1) as a candidate gene for regulating leaf morphology in this pedigree. ARF GTPases are critical elements in the vesicular trafficking machinery. Disruption of the vesicular trafficking function of ARF by the pharmacological agent Brefeldin A (BFA) altered leaf lateral growth in the narrow-leaf P. trichocarpa suggesting a molecular mechanism of leaf shape determination. Inhibition of the vesicular trafficking processes by BFA interferes with cycling of PIN proteins and causes their accumulation in intercellular compartments abolishing polar localization and disrupting normal auxin flux with potential effects on leaf expansion. CONCLUSIONS: In other model systems, ARF proteins have been shown to control the localization of auxin efflux carriers, which function to establish auxin gradients and apical-basal cell polarity in developing plant organs. Our results support a model where PtARF1 transcript abundance changes the dynamics of endocytosis-mediated PIN localization in leaf cells, thus affecting lateral auxin flux and subsequently lamina leaf expansion. This suggests that evolution of differential cellular polarity plays a significant role in leaf morphological variation observed in subgenera of genus Populus. PMID- 26122558 TI - Pediatric burns research: A history or an evolution? AB - BACKGROUND/PURPOSE: Pediatric burns research has increasingly been recognized as a sub-specialty of its own. The aim of this study was to assess and analyze the publication patterns of the pediatric burns literature over the last six decades. METHODS: A search strategy for the Web of Science database was designed for pediatric burns publications, with output analyzed between two periods: 1945-1999 (period 1) and 2000-2013 (period 2). RESULTS: There were 1133 and 1194 publications for periods 1 (1945-1999) and 2 (2000-2013), respectively. The mean citation counts of the top 50 publications were 77 (range 45-278) and 49 (range 33-145) for periods 1 and 2, respectively. There were 26 and 20 authors with two or more publications in the top 50 list in periods 1 and 2, respectively. Of these there are two authors that have published 47 papers in both combined time periods. There were 29 and 9 journals that have published 50% of the publications for time-period 1 and 2 respectively. In period 2, there were two burns journals that have published 37.2% of the total articles. CONCLUSIONS: Pediatric burns research has evolved from an associated, dispersed entity into a consolidated sub specialty that has been successfully integrated into mainstream burns journals. PMID- 26122559 TI - Severe burns due to biofuel heater injury: A case series. AB - BACKGROUND: Biofuel heaters are a new form of flame heating for indoor and outdoor use. Fuelled by methylated spirits, they are simple structures with few safety features, and can be associated with severe burn. We report five cases of severe burns in adults that occurred when refilling these heaters. METHODS: We undertook a retrospective audit of all adults presenting to the Royal Brisbane and Women's Hospital (RBWH) with a biofuel heater-related burn between 20 and 30th June 2014. RESULTS: Five patients required admission for management of their burns. Three were admitted to ICU for greater than 3 weeks, and remained inpatients for up to 78 days. Two did not require ICU and were managed in the burns unit. Average total body surface area (TBSA) burned was 24.7%, and patients went to theatre up to seven times for debridement and skin grafting. Average length of stay was 41.8 days. CONCLUSIONS: Biofuel heaters are easily accessible yet there is no Australian Standard to ensure they are safe or perform in the way they were intended. As such, people using them are at undue risk of severe burn, even when following the operating instructions. These products should be removed from the market to prevent further harm and potential mortality. PMID- 26122560 TI - Examining the implementation of NICE guidance: cross-sectional survey of the use of NICE interventional procedures guidance by NHS Trusts. AB - BACKGROUND: In the UK, NHS hospitals receive large amounts of evidence-based recommendations for care delivery from the National Institute for Health and Care Excellence (NICE) and other organisations. Little is known about how NHS organisations implement such guidance and best practice for doing so. This study was therefore designed to examine the dissemination, decision-making, and monitoring processes for NICE interventional procedures (IP) guidance and to investigate the barriers and enablers to the implementation of such guidance. METHODS: A cross-sectional survey questionnaire was developed and distributed to individuals responsible for managing the processes around NICE guidance in all 181 acute NHS hospitals in England, Scotland, Wales and Northern Ireland. A review of acute NHS hospital policies for implementing NICE guidance was also undertaken using information available in the public domain and from organisations' websites. RESULTS: The response rate to the survey was 75 % with 135 completed surveys received. Additionally, policies from 25 % of acute NHS hospitals were identified and analysed. NHS acute hospitals typically had detailed processes in place to implement NICE guidance, although organisations recognised barriers to implementation including organisational process barriers, clinical engagement and poor targeting with a large number of guidance issued. Examples of enablers to, and good practice for, implementation of guidance were found, most notably the value of shared learning experiences between NHS hospitals. Implications for NICE were also identified. These included making improvements to the layout of guidance, signposting on the website and making better use of their shared learning platform. CONCLUSIONS: Most organisations have robust processes in place to deal with implementing guidance. However, resource limitations and the scope of guidance received by organisations create barriers relating to organisational processes, clinician engagement and financing of new procedures. Guidance implementation can be facilitated through encouragement of shared learning by organisations such as NICE and open knowledge transfer between organisations. PMID- 26122561 TI - Differential transcriptional responses underlie dietary induction of intestinal carbohydrase activities in house sparrow nestlings. AB - Many species show diet-induced flexibility of activity of intestinal enzymes; however, molecular and genetic mechanisms responsible for such modulation are less known, particularly in altricial birds. The goal of our study was to test whether a diet-induced increase in activity of intestinal maltase and sucrase in house sparrow nestlings is matched with an increase in maltase-glucoamylase (MG) and sucrase-isomaltase (SI) complex mRNAs respectively. Both enzyme activities were significantly higher in mid-intestine of nestlings fed a medium-starch (MS) diet compared to those fed a starch-free (SF) diet. In contrast to the similar pattern of dietary induction for both enzyme activities, diet MS elevated significantly only the level of MG mRNA, but not SI mRNA. The coordinated increase in activity of maltase and in MG mRNA is consistent with the hypothesis that dietary induction of this enzyme is under transcriptional control. In contrast, the lack of such coordination for changes in activity of sucrase and SI mRNA suggests that upregulation of this enzyme may be achieved by post translational factor(s). We conclude that genetic mechanisms responsible for diet induced flexibility of digestive enzymes in birds may differ from that observed in mammals. PMID- 26122562 TI - Prenatal exposure to lead in relation to risk of preterm low birth weight: A matched case-control study in China. AB - We investigated the association between prenatal exposure to lead (Pb) and the risk of preterm low birth weight (PLBW). Pb concentrations in maternal urine collected at birth from 408 subjects (102 cases and 306 matched controls) were analyzed and adjusted by creatinine. The median Pb concentration in the PLBW cases (10.60MUgPb/g creatinine) was higher than that of the controls (7.28MUgPb/g creatinine). An adjusted odds ratio (OR) of 2.96 (95% CI=1.49-5.87) for PLBW was observed when the highest tertile was compared to the lowest tertile of Pb levels. The association was more pronounced among female infants (adjusted OR=3.67 for the highest tertile; 95% CI=1.35-9.93) than male infants (adjusted OR=1.91 for the highest tertile; 95% CI=0.74-4.95). Our study suggests that prenatal exposure to levels of Pb encountered today in China is associated with an elevated risk of PLBW. PMID- 26122563 TI - Selenium species in the roots and shoots of chickpea plants treated with different concentrations of sodium selenite. AB - The trace element selenium has an essential role for human health. It is involved in redox center functions, and it is related to the immune system response. Legumes are among the main suppliers of selenium into the human food chain. Not only Se concentration as such but also more the chemical species of Se is of higher importance for successful Se supply to the human diet and its bioavailability. The current study was focused on the investigation of the Se species present in chickpea plants exposed to 0, 10, 25, 50, and 100 MUM selenite in short- and long-term treatment studies. The linear increase of total Se concentration could be linked to the increased concentrations of Se exposure. The selenium species (SeMet, SeCys, selenite, selenate, GPx) detected in varying concentrations in shoots and roots depend on the exposure's concentration and duration. The investigation showed that chickpea can accumulate Se in favorable concentrations and its transformation to bioavailable Se species may have positive impacts on human health and aid to implement Se into the diet. PMID- 26122564 TI - Influence of PAHs among other coastal environmental variables on total and PAH degrading bacterial communities. AB - We evaluated the relative impact of anthropogenic polycyclic aromatic hydrocarbons (PAHs) among biogeochemical variables on total, metabolically active, and PAH bacterial communities in summer and winter in surface microlayer (SML) and subsurface seawaters (SSW) across short transects along the NW Mediterranean coast from three harbors, one wastewater effluent, and one nearshore observatory reference site. At both seasons, significant correlations were found between dissolved total PAH concentrations and PAH-degrading bacteria that formed a gradient from the shore to nearshore waters. Accumulation of PAH degraders was particularly high in the SML, where PAHs accumulated. Harbors and wastewater outfalls influenced drastically and in a different way the total and active bacterial community structure, but they only impacted the communities from the nearshore zone (<2 km from the shore). By using direct multivariate statistical analysis, we confirmed the significant effect of PAH concentrations on the spatial and temporal dynamic of total and active communities in this area, but this effect was putted in perspective by the importance of other biogeochemical variables. PMID- 26122565 TI - Solar light (hv) and H2O2/hv photo-disinfection of natural alkaline water (pH 8.6) in a compound parabolic collector at different day periods in Sahelian region. AB - The photo-disinfection of natural alkaline surface water (pH 8.6 +/- 0.3) for drinking purposes was carried out under solar radiation treatments. The enteric bacteria studied were the wild total coliforms/Escherichia coli (10(4) CFU/ml) and Salmonella spp. (10(4) CFU/ml) naturally present in the water. The photo disinfection of a 25-l water sample was carried out in a solar compound parabolic collector (CPC) in the absence and in the presence of hydrogen peroxide (H2O2). The addition of H2O2 (10 mg/L) to the sample water was sufficient to enhance the photo-disinfection and ensure an irreversible lethal action on the wild enteric bacteria contents of the sample. The inactivation kinetic of the system was significantly enhanced compared to the one carried out without H2O2 addition. The effect of the solar radiation parameters on the efficiency of the photo disinfection were assessed. The pH has increased during the treatment in all the photo-disinfection processes (hv and H2O2/hv). The Salmonella spp strain has shown the best effective inactivate time in alkaline water than the one recorded under acidic or near-neutral conditions. The evolution of some physico-chemical parameters of the water (turbidity, NO2(-), NO3(-), NH4(+), HPO4(2-), and bicarbonate (HCO3(-))) was monitored during the treatment. Finally, the possible mechanistic process involved during the enteric bacteria inactivation was suggested. PMID- 26122566 TI - Metals other than uranium affected microbial community composition in a historical uranium-mining site. AB - To understand the links between the long-term impact of uranium and other metals on microbial community composition, ground- and surface water-influenced soils varying greatly in uranium and metal concentrations were investigated at the former uranium-mining district in Ronneburg, Germany. A soil-based 16S PhyloChip approach revealed 2358 bacterial and 35 archaeal operational taxonomic units (OTU) within diverse phylogenetic groups with higher OTU numbers than at other uranium-contaminated sites, e.g., at Oak Ridge. Iron- and sulfate-reducing bacteria (FeRB and SRB), which have the potential to attenuate uranium and other metals by the enzymatic and/or abiotic reduction of metal ions, were found at all sites. Although soil concentrations of solid-phase uranium were high, ranging from 5 to 1569 MUg.g (dry weight) soil(-1), redundancy analysis (RDA) and forward selection indicated that neither total nor bio-available uranium concentrations contributed significantly to the observed OTU distribution. Instead, microbial community composition appeared to be influenced more by redox potential. Bacterial communities were also influenced by bio-available manganese and total cobalt and cadmium concentrations. Bio-available cadmium impacted FeRB distribution while bio-available manganese and copper as well as solid-phase zinc concentrations in the soil affected SRB composition. Archaeal communities were influenced by the bio-available lead as well as total zinc and cobalt concentrations. These results suggest that (i) microbial richness was not impacted by heavy metals and radionuclides and that (ii) redox potential and secondary metal contaminants had the strongest effect on microbial community composition, as opposed to uranium, the primary source of contamination. PMID- 26122567 TI - Water quality changes in response to urban expansion: spatially varying relations and determinants. AB - Urban expansion is an important stressor to water bodies, and the spatial variations of their relations are increasingly highlighted by recent studies. What remain unclear, however, are the underlying drivers to the spatial variability. The paper was not limited to modeling spatially varying linkages but also drew attention to the local anthropogenic influential factors that shape land-water relations. We employed geographically weighted regression to examine the relationships between urban expansion (measured by land use change intensity) and water quality changes (focusing on six water quality indicators) in a recently fast-growing Chinese city, Lianyungang. Specifically, we analyzed how the local characteristics including urbanization level, environmental management, industrial zone expansion, and land use composition, attributed to the varying responses of water quality changes. Results showed that urbanization level significantly affects land-water linkages. Remarkable water quality improvement was accompanied by urbanization in highly developed watersheds, primarily due to strong influence from extensive water management practices (particularly for COD, BOD, NH3-N, and TP). By contrast, water qualities of less-urbanized watersheds were more sensitive and negatively responsive to land use changes. Clustering industrial activities acted as distinct contributor to Hg contamination, while boosted organic pollution control in highly urbanized areas. The approach proposed in the study can locate and further zoom into the hot-spots of human water interactions, thereby contributing to better solutions for mitigating undesirable impacts of urbanization on water environment. PMID- 26122568 TI - Functional and structural responses of soil N-cycling microbial communities to the herbicide mesotrione: a dose-effect microcosm approach. AB - Microbial communities driving the nitrogen cycle contribute to ecosystem services such as crop production and air, soil, and water quality. The responses to herbicide stress of ammonia-oxidizing and ammonia-denitrifying microbial communities were investigated by an analysis of changes in structure-function relationships. Their potential activities, abundances (quantitative PCR), and genetic structure (denaturing gradient gel electrophoresis) were assessed in a microcosm experiment. The application rate (1 * FR, 0.45 MUg g(-1) soil) of the mesotrione herbicide did not strongly affect soil N-nutrient dynamics or microbial community structure and abundances. Doses of the commercial product Callisto(r) (10 * FR and 100 * FR) or pure mesotrione (100 * FR) exceeding field rates induced short-term inhibition of nitrification and a lasting stimulation of denitrification. These effects could play a part in the increase in soil ammonium content and decrease in nitrate contents observed in treated soils. These functional impacts were mainly correlated with abundance shifts of ammonia oxidizing Bacteria (AOB) and Archaea (AOA) or denitrifying bacteria. The sustained restoration of nitrification activity, from day 42 in the 100 * FR treated soils, was likely promoted by changes in the community size and composition of AOB, which suggests a leading role, rather than AOA, for soil nitrification restoration after herbicide stress. This ecotoxicological community approach provides a nonesuch multiparameter assessment of responses of N-cycling microbial guilds to pesticide stress. PMID- 26122569 TI - Assessing the relative efficiency of water companies in the English and Welsh water industry: a metafrontier approach. AB - The assessment of relative efficiency of water companies is essential for managers and authorities. This is evident in the UK water sector where there are companies with different services such as water and sewerage companies (WaSCs) and water-only companies (WoCs). Therefore, it is a critical limitation to estimate a common production frontier for both types of companies, as it might lead to biased efficiency estimates. In this paper, a robust and reliable methodology, the metafrontier model, is applied to compare the efficiency of water companies providing different services. The results illustrate the superior performance of WaSCs compared to WoCs. It also confirms the presence of economies of scope in the UK water industry. The methodology and results of this study are of great interest for both regulators and water utility managers to make informed decisions. PMID- 26122570 TI - Insights into tetracycline adsorption onto kaolinite and montmorillonite: experiments and modeling. AB - Adsorption of tetracycline (TC) on kaolinite and montmorillonite was investigated using batch adsorption experiments with different pH, ionic strength, and surface coverage. As a result, pH and ionic strength-dependent adsorption of TC was observed for the two clay minerals. The adsorption of TC decreased with the increase of pH and ionic strength, and high initial TC concentration had high adsorption. In addition, a triple-layer model was used to predict the adsorption and surface speciation of TC on the two minerals. As a result, four complex species on kaolinite (=X(-)?H3TC(+), =X(-)?H2TC(+/-), =SOH(0)?H2TC(+/-), and =SOH(0)?HTC(-)) and three species on montmorillonite (=X(-)?H3TC(+), =X( )?H2TC(+/-), and =SOH(0)?HTC(-)) were structurally constrained by spectroscopy, and these species were also successfully fitted to the adsorption edges of TC. Three functional groups of TC were involved in these adsorption reactions, including the positively charged dimethylamino group, the C=O amide I group, and the C=O group at the C ring. Combining adsorption experiments and model in this study, the adsorption of TC on kaolinite and montmorillonite was mainly attributed to cation exchange on the surface sites (=X(-)) compared to surface complexation on the edge sites (=SOH) at natural soil pH condition. Moreover, the surface adsorption species, the corresponding adsorption modes, and the binding constants for the surface reactions were also estimated. PMID- 26122571 TI - Natural transformation of chlordecone into 5b-hydrochlordecone in French West Indies soils: statistical evidence for investigating long-term persistence of organic pollutants. AB - Chlordecone (CLD) was an organochlorine insecticide whose previous use resulted in an extensive pollution of the environment with severe health effects and social consequences. A closely related compound, 5b-hydrochlordecone (5b hydroCLD), has been searched for and often detected in environmental matrices from the geographical area where CLD was applied. The current consensus considered that its presence was not the result of a biotic or abiotic dechlorination of CLD in these matrices but rather the consequence of its presence as impurity (synthesis by-product) in the CLD released into the environment. The aim of the present study was to determine if and to what extent degradation of CLD into 5b-hydroCLD occurred in the field. To test this hypothesis, the ratios of 5b-hydroCLD and CLD concentrations in a dataset of 810 soils collected between 2006 and 2012 in Martinique were compared to the ratios measured in 3 samples of the CLD dust commercial formulations applied in the banana fields of French West Indies (FWI) and 1 sample of the technical-grade CLD corresponding to the active ingredient used in such formulations. Soil data were processed with a hierarchical Bayesian model to account for random measurement errors and data censoring. Any pathway of CLD transformation into 5b-hydroCLD occurring over the long term in FWI soils would indeed change the ratio of 5b hydroCLD/CLD compared to what it was in the initially applied formulations. Results showed a significant increase of the 5b-hydroCLD/CLD ratio in the soils 25 times greater in soil than in commercial formulations-which suggested that natural CLD transformation into 5b-hydroCLD over the long term occurred in these soils. Results from this study may impact future decisions for the remediation of the polluted areas. PMID- 26122572 TI - Cadmium toxicity in Maize (Zea mays L.): consequences on antioxidative systems, reactive oxygen species and cadmium accumulation. AB - Increased cadmium (Cd) accumulation in soils has led to tremendous environmental problems, with pronounced effects on agricultural productivity. Present study investigated the effects of Cd stress imposed at various concentrations (0, 75, 150, 225, 300, 375 MUM) on antioxidant activities, reactive oxygen species (ROS), Cd accumulation, and productivity of two maize (Zea mays L.) cultivars viz., Run Nong 35 and Wan Dan 13. Considerable variations in Cd accumulation and in behavior of antioxidants and ROS were observed under Cd stress in both maize cultivars, and such variations governed by Cd were concentration dependent. Exposure of plant to Cd stress considerably increased Cd concentration in all plant parts particularly in roots. Wan Dan 13 accumulated relatively higher Cd in root, stem, and leaves than Run Nong 35; however, in seeds, Run Nong 35 recorded higher Cd accumulation. All the Cd toxicity levels starting from 75 MUM enhanced H2O2 and MDA concentrations and triggered electrolyte leakage in leaves of both cultivars, and such an increment was more in Run Nong 35. The ROS were scavenged by the enhanced activities of superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, and glutathione peroxidase in response to Cd stress, and these antioxidant activities were higher in Wan Dan 13 compared with Run Nong 35 at all Cd toxicity levels. The grain yield of maize was considerably reduced particularly for Run Nong 35 under different Cd toxicity levels as compared with control. The Wan Dan 13 was better able to alleviate Cd-induced oxidative damage which was attributed to more Cd accumulation in roots and higher antioxidant activities in this cultivar, suggesting that manipulation of these antioxidants and enhancing Cd accumulation in roots may lead to improvement in Cd stress tolerance. PMID- 26122573 TI - Mixed messages from benthic microbial communities exposed to nanoparticulate and ionic silver: 3D structure picks up nano-specific effects, while EPS and traditional endpoints indicate a concentration-dependent impact of silver ions. AB - Silver nanoparticles (AgNP) are currently defined as emerging pollutants in surface water ecosystems. Whether the toxic effects of AgNP towards freshwater organisms are fully explainable by the release of ionic silver (Ag(+)) has not been conclusively elucidated. Long-term effects to benthic microbial communities (periphyton) that provide essential functions in stream ecosystems are unknown. The effects of exposure of periphyton to 2 and 20 MUg/L Ag(+) (AgNO3) and AgNP (polyvinylpyrrolidone stabilised) were investigated in artificial indoor streams. The extracellular polymeric substances (EPS) and 3D biofilm structure, biomass, algae species, Ag concentrations in the water phase and bioassociated Ag were analysed. A strong decrease in total Ag was observed within 4 days. Bioassociated Ag was proportional to dissolved Ag indicating a rate limitation by diffusion across the diffusive boundary layer. Two micrograms per liter of AgNO3 or AgNP did not induce significant effects despite detectable bioassociation of Ag. The 20-MUg/L AgNO3 affected green algae and diatom communities, biomass and the ratio of polysaccharides to proteins in EPS. The 20-MUg/L AgNO3 and AgNP decreased biofilm volume to about 50 %, while the decrease of biomass was lower in 20 MUg/L AgNP samples than the 20-MUg/L AgNO3 indicating a compaction of the NP-exposed biofilms. Roughness coefficients were lower in 20 MUg/L AgNP-treated samples. The more traditional endpoints (biomass and diversity) indicated silver ion concentration-dependent effects, while the newly introduced parameters (3D structure and EPS) indicated both silver ion concentration-dependent effects and effects related to the silver species applied. PMID- 26122574 TI - Combinational effects of sulfomethoxazole and copper on soil microbial community and function. AB - Sulfonamides and Cu are largely used feed additives in poultry farm. Subsequently, they are spread onto agricultural soils together with contaminated manure used as fertilizer. Both sulfonamides and Cu affect the soil microbial community. However, an interactive effect of sulfonamides and Cu on soil microorganisms is not well understood. Therefore, a short-time microcosm experiment was conducted to investigate the interaction of veterinary antibiotic sulfomethoxazole (SMX) and Cu on soil microbial structure composition and functions. To this end, selected concentrations of SMX (0, 5, and 50 mg kg(-1)) and Cu (0, 300, and 500 mg kg(-1)) were combined, respectively. Clear dose dependent effects of SMX on microbial biomass and basal respiration were determined, and these effects were amplified in the presence of additional Cu. For activities of soil enzymes including beta-glucosidase, urease, and protease, clear reducing effects were determined in soil samples containing 5 or 50 mg kg( 1) of SMX, and the interaction of SMX and Cu was significant, particularly in soil samples containing 50 mg kg(-1) SMX or 500 mg kg(-1) Cu. SMX amendments, particularly in combination with Cu, significantly reduced amounts of the total, bacterial, and fungal phospholipid fatty acids (PLFAs) in soil. Moreover, the derived ratio of bacteria to fungi decreased significantly with incremental SMX and Cu, and principal component analysis of the PLFAs showed that soil microbial composition was significantly affected by SMX interacted with Cu at 500 mg kg( 1). All of these results indicated that the interaction of SMX and Cu was synergistic to amplify the negative effect of SMX on soil microbial biomass, structural composition, and even the enzymatic function. PMID- 26122575 TI - Effects of drying on phosphorus uptake in re-flooded lake sediments. AB - Sediment drying associated with large water level fluctuations is an increasingly common feature of temporary streams and lakes worldwide. Drying-induced sediment aeration and re-flooding periodically alter redox conditions, and therefore stimulate redox-sensitive processes influencing phosphorus (P) binding forms. We experimentally tested the effects of drying on P binding forms, and the P sorption potential, by drying and re-flooding lake sediments in the laboratory. Wet and dried fine sediments were re-flooded in columns, and the overlying water was continuously re-stocked to a constant P concentration. We measured changes in P forms, P uptake rates, and the pore water dynamics in each column over 36 weeks. Drying decreased the fraction of stable P, stimulated the mineralization of organic P, and increased the proportion of labile and reductant-soluble forms. Drying of sediment furthermore reduced its P sorption affinity and capacity by up to 32% in batch equilibrium experiments, and led to a fourfold increase in sediment compaction which increased P uptake rates by a factor of 1.7 in sediment column experiments. Compaction due to drying also induced the development of a sharp gradient below which P was mobilized. These results indicate that in fine sediments, a single drying event can result in the transformation of P components into more labile forms which accumulate in the uppermost sediment layer, therefore raising the potential for a pulsed P release under reducing conditions. PMID- 26122576 TI - Environmental PCBs in Guanica Bay, Puerto Rico: implications for community health. AB - Guanica Bay, located in southwestern Puerto Rico, has suffered oil spills and other pollution discharges since the 1960s. Previous research showed elevated concentrations of polychlorinated biphenyls (PCBs) in coral reef and sediment. This research examined PCB concentrations in sediment and fish. Sediment and fish sampling in the bay was facilitated by community members. This study identified the second highest reported PCB level (129,300 ng/g) in sediment in the USA. Fish samples also showed elevated concentrations (1623 to 3768 ng/g), which were higher than the thresholds of safe levels of PCBs in fish for human consumption. The alarmingly high concentration of PCBs calls for proactive community engagement to bring awareness about contamination of the bay and more extensive sampling to test for the concentration of PCBs in seafood and the people of Guanica. This study also underscores the value of the involvement of local communities during sampling design aimed at identifying hot spots of contaminants. PMID- 26122577 TI - Biosynthesis, mosquitocidal and antibacterial properties of Toddalia asiatica synthesized silver nanoparticles: do they impact predation of guppy Poecilia reticulata against the filariasis mosquito Culex quinquefasciatus? AB - Mosquito-borne diseases represent a deadly threat for millions of people worldwide. Furthermore, pathogens and parasites polluting water also constitute a severe plague for populations of developing countries. In this study, silver nanoparticles (AgN) were biosynthesized a cheap aqueous extract of T. asiatica leaves as reducing and stabilizing agent. The formation of nanoparticle was confirmed by surface Plasmon resonance band illustrated in UV-vis spectrophotometer. AgN were characterized by FTIR, SEM, EDX, and XRD analyses. AgN were mostly spherical in shape, crystalline in nature, with face-centered cubic geometry, and their mean size was 25-30 nm. T. asiatica aqueous extract and green-synthesized AgN showed excellent larvicidal and pupicidal toxicity against the filariasis vector Culex quinqufasciatus, both in laboratory and field experiments. AgN LC50 ranged from 16.48 (I instar larvae) to 31.83 ppm (pupae). T. asiatica-synthesized were also highly effective in inhibiting growth of Bacillus subtilis, Klebsiella pneumoniae, and Salmonella typhi using the agar disk diffusion and minimum inhibitory concentration protocol. Lastly, we evaluated if sublethal doses of nanoparticles affect predation rates of fishes, Poecilia reticulata, against C. quinquefasciatus. In AgN-contaminated environment, predation of guppies against mosquito larvae was slightly higher over normal laboratory conditions. Overall, this study highlighted that T. asiatica-synthesized AgN are easy to produce, stable over time, and may be employed at low dosages to reduce populations of filariasis vectors, without detrimental effects on predation rates of mosquito natural enemies. PMID- 26122578 TI - Combining multivariate analysis and human risk indices for assessing heavy metal contents in muscle tissues of commercially fish from Southern Red Sea, Saudi Arabia. AB - Jizan fishers are the major fish source for more than 1.5 million populations in the southern region in Saudi Arabia. Despite the overgrowing of various man-made activities in Jizan City, no recent study on environmental monitoring was reported. In the current study, heavy metals were quantified in muscle tissues of 12 fish species, as the most edible, from Jizan fisheries. Electrothermal atomic absorption spectrophotometry was used for quantification after microwave wet digestion. Acceptable recovery values (83.46-97.48%) for spiked fish samples with standard solutions were obtained. The following wide ranges of heavy metal concentrations (MUg/g, wet weight) in studied fish species were recorded: V (0.004-0.561), Cr (0.013-0.477), Mn (0.073-0.128), As (0.002-0.935), Se (0.083 3.058), Sn (2.835-5.540), and Pb (0.150-0.386). Comparing with international permissible limits, lower levels were recorded in the current study. For total metal accumulation, the relationship between species was examined by cluster analysis, which showed that Epinephelinae was the farthest species from others. The principal component analysis shows one component indicating normal distribution of heavy metals in fish species. Different metal pollution indices (1.35-0.30), which shows the distribution of the total heavy metal concentrations in each species, were recorded. The hazard indices for muscle consumption were less than 1.0 for all studied metals at both ingestion rates except Sn which showed a marginal value of 28.9. PMID- 26122580 TI - Pediatric immunization-related safety incidents in primary care: A mixed methods analysis of a national database. AB - BACKGROUND: Children are scheduled to receive 18-20 immunizations before their 18th birthday in England and Wales; this approximates to 13 million vaccines administered per annum. Each immunization represents a potential opportunity for immunization-related error and effective immunization is imperative to maintain the public health benefit from immunization. Using data from a national reporting system, this study aimed to characterize pediatric immunization-related safety incident reports from primary care in England and Wales between 2002 and 2013. METHODS: A cross-sectional mixed methods study was undertaken. This comprised reading the free-text of incident reports and applying codes to describe incident type, potential contributory factors, harm severity, and incident outcomes. A subsequent thematic analysis was undertaken to interpret the most commonly occurring codes, such as those describing the incident, events leading up to it and reported contributory factors, within the contexts they were described. RESULTS: We identified 1745 reports and most (n=1077, 61.7%) described harm outcomes including three deaths, 67 reports of moderate harm and 1007 reports of low harm. Failure of timely vaccination was the potential cause of three child deaths from meningitis and pneumonia, and described in a further 113 reports. Vaccine administration incidents included the wrong number of doses (n=476, 27.3%), wrong timing (n=294, 16.8%), and wrong vaccine (n=249, 14.3%). Documentation failures were frequently implicated. Socially and medically vulnerable children were commonly described. CONCLUSION: This is the largest examination of reported contributory factors for immunization-related patient safety incidents in children. Our findings suggest investments in IT infrastructure to support data linkage and identification of risk predictors, development of consultation models that promote the role of parents in mitigating safety incidents, and improvement efforts to adapt and adopt best practices from elsewhere, are needed to mitigate future immunization-related patient safety incidents. These priorities are particularly pressing for vulnerable patient groups. PMID- 26122581 TI - Value of post-licensure data on benefits and risks of vaccination to inform vaccine policy: The example of rotavirus vaccines. AB - In 1999, the first rhesus-human reassortant rotavirus vaccine licensed in the United States was withdrawn within a year of its introduction after it was linked with intussusception at a rate of ~1 excess case per 10,000 vaccinated infants. While clinical trials of 60,000-70,000 infants of each of the two current live oral rotavirus vaccines, RotaTeq (RV5) and Rotarix (RV1), did not find an association with intussusception, post-licensure studies have documented a risk in several high and middle income countries, at a rate of ~1-6 excess cases per 100,000 vaccinated infants. However, considering this low risk against the large health benefits of vaccination that have been observed in many countries, including in countries with a documented vaccine-associated intussusception risk, policy makers and health organizations around the world continue to support the routine use of RV1 and RV5 in national infant immunization programs. Because the risk and benefit data from affluent settings may not be directly applicable to developing countries, further characterization of any associated intussusception risk following rotavirus vaccination as well as the health benefits of vaccination is desirable for low income settings. PMID- 26122579 TI - Cytotoxic and genotoxic effects of abamectin, chlorfenapyr, and imidacloprid on CHOK1 cells. AB - The cytotoxicity and genotoxicity of abamectin, chlorfenapyr, and imidacloprid have been evaluated on the Chinese hamster ovary (CHOK1) cells. Neutral red incorporation (NRI), total cellular protein content (TCP), and methyl tetrazolium (MTT) assays were followed to estimate the mid-point cytotoxicity values, NRI50, TCP50, and MTT50, respectively. The effects of the sublethal concentration (NRI25) on glutathione S-transferase (GST), glutathione reductase (GRD), glutathione peroxidase (GPX), and total glutathione content have been evaluated in the presence and absence of reduced glutathione (GSH), vitamin C, and vitamin E. The genotoxicity was evaluated using chromosomal aberrations (CA), micronucleus (MN) formation, and DNA fragmentation techniques in the presence and absence of the metabolic activation system, S9 mix. Abamectin was the most cytotoxic pesticide followed by chlorfenapyr, while imidacloprid was the least cytotoxic one. The glutathione redox cycle components were altered by the tested pesticides in the absence and presence of the tested antioxidants. The results of genotoxicity indicate that abamectin, chlorfenapyr, and imidacloprid have potential genotoxic effects on CHOK1 cells under the experimental conditions. PMID- 26122582 TI - Rescue of CD8+ T cell vaccine memory following sublethal gamma irradiation. AB - Sublethal gamma irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D(d)) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36gamma, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal gamma radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal gamma irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D(d) skin allograft rejection response was lost in mice exposed to sublethal gamma radiation, but infusion of allogeneic D(d) expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following gamma irradiation. PMID- 26122583 TI - Trials and tribulations on the path to developing a dengue vaccine. AB - Dengue is a rapidly expanding global health problem. Development of a safe and efficacious tetravalent vaccine along with strategic application of vector control activities represents a promising approach to reducing the global disease burden. Although many vaccine development challenges exist, numerous candidates are in clinical development and one has been tested in three clinical endpoint studies. The results of these studies have raised numerous questions about how we measure vaccine immunogenicity and how these readouts are associated with clinical outcomes in vaccine recipients who experience natural infection. In this review the authors discuss the dengue vaccine pipeline, development challenges, the dengue vaccine-immunologic profiling intersection, and research gaps. PMID- 26122584 TI - Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: possible differential markers of affective and impulsive pathways of risk for alcohol use disorder. AB - Prior work suggests that there may be two distinct pathways of alcohol use disorder (AUD) risk: one associated with positive emotion enhancement and behavioral impulsivity, and another associated with negative emotion relief and coping. We sought to map these two pathways onto individual differences in neural reward and threat processing assessed using blood-oxygen-level-dependent functional magnetic resonance imaging in a sample of 759 undergraduate students (426 women, mean age 19.65+/-1.24 years) participating in the Duke Neurogenetics Study. We demonstrate that problem drinking is highest in the context of stress and in those with one of two distinct neural phenotypes: (1) a combination of relatively low reward-related activity of the ventral striatum (VS) and high threat-related reactivity of the amygdala; or (2) a combination of relatively high VS activity and low amygdala reactivity. In addition, we demonstrate that the relationship between stress and problem alcohol use is mediated by impulsivity, as reflected in monetary delay discounting rates, for those with high VS-low amygdala reactivity, and by anxious/depressive symptomatology for those with the opposite neural risk phenotype. Across both neural phenotypes, we found that greater divergence between VS and amygdala reactivity predicted greater risk for problem drinking. Finally, for those individuals with the low VS high amygdala risk phenotype we found that stress not only predicted the presence of AUD diagnosis at the time of neuroimaging but also subsequent problem drinking reported 3 months following study completion. These results offer new insight into the neural basis of AUD risk and suggest novel biological targets for early individualized treatment or prevention. PMID- 26122585 TI - Neural signatures of human fear conditioning: an updated and extended meta analysis of fMRI studies. AB - Classical Pavlovian fear conditioning remains the most widely employed experimental model of fear and anxiety, and continues to inform contemporary pathophysiological accounts of clinical anxiety disorders. Despite its widespread application in human and animal studies, the neurobiological basis of fear conditioning remains only partially understood. Here we provide a comprehensive meta-analysis of human fear-conditioning studies carried out with functional magnetic resonance imaging (fMRI), yielding a pooled sample of 677 participants from 27 independent studies. As a distinguishing feature of this meta-analysis, original statistical brain maps were obtained from the authors of 13 of these studies. Our primary analyses demonstrate that human fear conditioning is associated with a consistent and robust pattern of neural activation across a hypothesized genuine network of brain regions resembling existing anatomical descriptions of the 'central autonomic-interoceptive network'. This finding is discussed with a particular emphasis on the neural substrates of conscious fear processing. Our associated meta-analysis of functional deactivations-a scarcely addressed dynamic in fMRI fear-conditioning studies-also suggests the existence of a coordinated brain response potentially underlying the 'safety signal' (that is, non-threat) processing. We attempt to provide an integrated summary on these findings with the view that they may inform ongoing studies of fear-conditioning processes both in healthy and clinical populations, as investigated with neuroimaging and other experimental approaches. PMID- 26122588 TI - No Need to Abandon Focused Unilateral Exploration for Primary Hyperparathyroidism with Intraoperative Monitoring of Intact Parathyroid Hormone. AB - BACKGROUND: We investigated the rate of persistent and recurrent hyperparathyroidism after focused unilateral exploration (UE) with intraoperative monitoring of intact parathyroid hormone (IOPTH). STUDY DESIGN: A prospective cohort of 915 patients with primary hyperparathyroidism (PHP) underwent parathyroid surgery by a single surgeon from January 2003 to September 2013. A total of 556 patients with at least a single positive preoperative localization by ultrasound (US) and/or sestamibi scan (STS) underwent UE with IOPTH. The criterion for completion of surgery was an IOPTH fall of 50% from the highest intraoperative level and into the normal range 5 to 10 minutes after resection of the localized gland. RESULTS: Fifteen patients had either persistent or recurrent PHP, yielding a 2.7% (95% CI 1.6% to 4.4%) overall recurrence rate based on the refined Wilson method with continuity correction. Four patients had persistent PHP. Three of these patients were cured with reoperation, and the fourth patient was followed nonoperatively. Eleven patients had recurrent PHP, with 5 corrected by surgery and 6 patients followed nonoperatively. The mean postoperative serum calcium (Ca) level was 9.4 mg/dL over a mean follow-up interval of 44.0 months. Preoperative localization rates by each localization study were: US 74.3% (n = 413), STS 86.9% (n = 483), and US and STS 71.4% (n = 397). There was no difference in the preoperative study that localized the hyperfunctional parathyroid gland in recurrent vs nonrecurrent patients by the Fisher's exact test (US, p =1.00; STS, p =0.65; US and STS, p =1.00). CONCLUSIONS: The low rate of recurrent PHP after focused unilateral exploration with IOPTH suggests that this procedure should not be abandoned. PMID- 26122587 TI - Polygenic dissection of major depression clinical heterogeneity. AB - The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression. PMID- 26122586 TI - Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group. AB - The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference= 1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ?21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d= 0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status. PMID- 26122589 TI - Collapsible Enteroatmospheric Fistula Isolation Device: A Novel, Simple Solution to a Complex Problem. PMID- 26122590 TI - Whipple's pancreaticoduodenectomy: Surgical technique and perioperative clinical outcomes in a single center. AB - INTRODUCTION: Pancreatic cancer is the fourth cause of death from cancer in Western countries. The radical surgical resection is the only curative option for this pathology. The prevalence of this disease increases with age in population. The causes of pancreatic cancer are unknown, but we consider risk factors like smoke and tobacco usage, alcohol consumption coffee, history of diabetes or chronic pancreatitis. In this study we report our experience in the treatment of resectable pancreatic cancer and periampullary neoplasms with particular attention to evaluate the evolution of surgical technique and the clinical postoperative outcomes. METHODS: In our Department between January 2010 and December 2014 we performed a total of 97 pancreaticoduodenectomy. We considered only resectable pancreatic cancer and periampullary neoplasms defined by absence of distant metastases, absence of local tumor extension to the celiac axis and hepatic artery as the lack of involvement of the superior mesenteric vasculature. None of these patients received neoadjuvant chemotherapy. RESULTS: The mean age of these patients was 64.5 years. Jaundice was the commonest presenting symptom associated to anorexia and weight loss. The mean operative time was 295 min (+/- 55 min). The mean blood loss was 450 ml and median blood transfusion was 1 units. 12.1% of patients had an intra-abdominal complication. The commonest complication was Delayed Gastric Emptying responsable of increased length of hospital stay and readmission rate. Postoperative pancreatic fistula of grade C occurred in 4 patients. 2 patients developed a postpancreatectomy hemorrhage. Perioperative mortality was 4.1%. CONCLUSION: Pancreaticoduodenectomy is a complex surgical technique and the associated high morbidity and mortality resulted in initial reluctance to adopt this surgery for the management of pancreatic and periampullary tumors. Surgical outcomes of pancreatic surgery are better at high volume experienced center reporting mortality rates below 5%. We perform an end to-side duct-to-mucosa pancreaticojejunostomy with routinely use of internal pancreatic stent. However no one technique has been shown to definitely be the solution to the problem of postoperative pancreatic fistula. At our center we have a reasonable volume and our data are comparable to literature data. PMID- 26122591 TI - Fixation probabilities on superstars, revisited and revised. AB - Population structures can be crucial determinants of evolutionary processes. For the Moran process on graphs certain structures suppress selective pressure, while others amplify it (Lieberman et al., 2005). Evolutionary amplifiers suppress random drift and enhance selection. Recently, some results for the most powerful known evolutionary amplifier, the superstar, have been invalidated by a counter example (Diaz et al., 2013). Here we correct the original proof and derive improved upper and lower bounds, which indicate that the fixation probability remains close to 1-1/(r(4)H) for population size N->infinity and structural parameter H?1. This correction resolves the differences between the two aforementioned papers. We also confirm that in the limit N,H->infinity superstars remain capable of eliminating random drift and hence of providing arbitrarily strong selective advantages to any beneficial mutation. In addition, we investigate the robustness of amplification in superstars and find that it appears to be a fragile phenomenon with respect to changes in the selection or mutation processes. PMID- 26122592 TI - Clinical assessment of the orthopaedic and trauma patient. PMID- 26122593 TI - Nursing in fast-track total hip and knee arthroplasty: A retrospective study. AB - AIM: To describe the increased activity in total hip arthroplasty (THA) and total knee arthroplasty (TKA) from 2002 to 2012 in a single orthopaedic department, the organisation of fast-track and its consequences for nursing care. METHODS: Retrospective, descriptive design. Data collection; from the hospital administrative database, local descriptions of fast-track, personal contact and discussion with staff. RESULTS: The number of operations increased threefold from 351 operations in 2002 to 1024 operations in 2012. In 2012, THA/TKA patients had a postoperative mean LOS of 2.6/2.8 days. Nurses had gained tasks from surgeons and physiotherapists and thus gained more responsibility, for example, for pain management and mobilisation. Staffing levels in the ward in 2002 and 2012 were almost unchanged; 16.0 and 15.8 respectively. Nurses were undertaking more complicated tasks. CONCLUSION: Nursing care must still focus on the individual patient. Nurses need to have enough education to manage the complex tasks and increased responsibility. To prevent undesirable outcomes in the future, there is a need to pay attention to the nursing quality in balance with the nursing budget. It may, therefore, be considered a worthwhile investment to employ expert/highly qualified professional nurses in fast-track THA and TKA units. PMID- 26122594 TI - The patient's experience of early discharge following total hip replacement. AB - BACKGROUND: Strategies within the public health system to curtail costs, increase efficiency and service utilisation have resulted in reduced hospital stays following elective orthopaedic procedures. Although there are advantages that support the concept of early discharge from hospital, very little is known about how patients manage the transition from hospital to home. AIM: The aim of this qualitative study was to describe the post-discharge experience of elderly patients following primary total hip replacement (THR). METHODS: Ten patients, six women and four men, provided descriptions of their experience. Data were collected by face-to-face interviews and the analysis process was based on Giorgi's phenomenological scientific methodology (Giorgi, 1994, 1997, 2000). RESULTS: The analysis of the data resulted in four themes, namely; an inadequate assessment of suitable adaptive aids and personal needs; personal frustration; coping with the physical and mobility and limited social interaction. CONCLUSION: Findings from this study demonstrated a need to review the discharge process and implement strategies to prepare patients for the stressors that the participants in this study encountered as a result of their early discharge. PMID- 26122595 TI - Identifying outcomes associated with co-managed care models for patients who have sustained a hip fracture: an integrative literature review. AB - AIMS AND OBJECTIVES: The aim of this integrative literature review is to identify themes associated with improved patient outcomes related to orthogeriatric co managed inpatient unit models of care for patients who had sustained a hip fracture. APPROACH: An integrative literature review was undertaken from 2002 July 2013 using electronic databases with specific search terms. METHODS: The theoretical framework of Whittemore and Knafl was used to guide the review. This framework was chosen as it allows for the inclusion of varied methodologies and has the capability to increase informed evidence-based nursing practice. RESULTS: Five distinct themes relating to outcomes emerged from the analysis, which were: time from admission to surgery; complications; length of stay; mortality and initiation of osteoporosis treatment. CONCLUSION: The analysis of this integrative literature review clearly indicates the need for national and international sets of agreed outcome measures to be adopted to facilitate the comparison of models of care. This would significantly improve the way in which outcomes and costs are reported, further enhancing international partnerships as the health care team strive to achieve overall improvements in the management of older people presenting to hospital with hip fracture. PMID- 26122596 TI - Assessment of chronic pain: A practice update. PMID- 26122597 TI - Clinical assessment in trauma and orthopaedic nursing. PMID- 26122599 TI - Obituary: Anne Footner OBE 1937-2015. PMID- 26122601 TI - Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. AB - Evidence-based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or "state of the art" interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video-EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short-term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short-term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long-term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits. PMID- 26122602 TI - Clinical Exercise Stress Testing in Adults (2014). AB - This position paper provide guidelines on the minimum requirements of both personnel and equipment for the safe performance of clinical exercise electrocardiography, and for the adequate interpretation and assessment of results. This document was originally developed by Professor Ben Freedman and members of the Rehabilitation, Exercise and Prevention Working Group in 1996. It has been recently reviewed by a Working Group chaired by Associate Professor David Colquhoun. The resulting, revised Statement was considered by the Continuing Education and Recertification Committee and ratified at the CSANZ Board meeting held on 1st August 2014. PMID- 26122604 TI - Facilitating student education and support using videoconference. PMID- 26122605 TI - Caring and healing in health care: The evidence base. PMID- 26122606 TI - Should I stay or should I go? Exploring the job preferences of allied health professionals working with people with disability in rural Australia. AB - INTRODUCTION: The uneven distribution of allied health professionals (AHPs) in rural and remote Australia and other countries is well documented. In Australia, like elsewhere, service delivery to rural and remote communities is complicated because relatively small numbers of clients are dispersed over large geographic areas. This uneven distribution of AHPs impacts significantly on the provision of services particularly in areas of special need such as mental health, aged care and disability services. OBJECTIVE: This study aimed to determine the relative importance that AHPs (physiotherapists, occupational therapists, speech pathologists and psychologists - "therapists") living in a rural area of Australia and working with people with disability, place on different job characteristics and how these may affect their retention. METHODS: A cross sectional survey was conducted using an online questionnaire distributed to AHPs working with people with disability in a rural area of Australia over a 3-month period. Information was sought about various aspects of the AHPs' current job, and their workforce preferences were explored using a best-worst scaling discrete choice experiment (BWSDCE). Conditional logistic and latent class regression models were used to determine AHPs' relative preferences for six different job attributes. RESULTS: One hundred ninety-nine AHPs completed the survey; response rate was 51 %. Of those, 165 completed the BWSDCE task. For this group of AHPs, "high autonomy of practice" is the most valued attribute level, followed by "travel BWSDCE arrangements: one or less nights away per month", "travel arrangements: two or three nights away per month" and "adequate access to professional development". On the other hand, the least valued attribute levels were "travel arrangements: four or more nights per month", "limited autonomy of practice" and "minimal access to professional development". Except for "some job flexibility", all other attributes had a statistical influence on AHPs' job preference. Preferences differed according to age, marital status and having dependent children. CONCLUSIONS: This study allowed the identification of factors that contribute to AHPs' employment decisions about staying and working in a rural area. This information can improve job designs in rural areas to increase retention. PMID- 26122607 TI - Consumer support for healthy food and drink vending machines in public places. AB - OBJECTIVE: To investigate the feasibility of introducing vending machines for healthier food into public places, and to examine the effectiveness of two front of-pack labelling systems in the vending machine context. METHODS: A survey was conducted with 120 students from a university and 120 employees, patients and visitors of a hospital in regional NSW, Australia. Questions explored vending machine use, attitudes towards healthier snack products and price, and the performance of front-of-pack labelling formats for vending machine products. RESULTS: Most participants viewed the current range of snacks and drinks as "too unhealthy" (snacks 87.5%; drinks 56.7%). Nuts and muesli bars were the most liked healthier vending machine snack. Higher proportions of participants were able to identify the healthier snack in three of the five product comparisons when products were accompanied with any type of front-of-pack label (all p<0.01); however, participants were less likely to be able to identify the healthier product in the drinks comparison when a front-of-pack guide was present. CONCLUSION: Respondents were interested in a range of healthier snacks for vending machines. Front-of-pack label formats on vending machines may assist consumers to identify healthier products. IMPLICATIONS: Public settings, such as universities and hospitals, should support consumers to make healthy dietary choices by improving food environments. PMID- 26122608 TI - Direct Reading of Bona Fide Barcode Assays for Diagnostics with Smartphone Apps. AB - The desire to develop new point-of-care (POC) diagnostic tools has led to the adaptation of smartphones to tackle limitations in state-of-the-art instrumentation and centralized laboratory facilities. Today's smartphones possess the computer-like ability to image and process data using mobile apps; barcode scanners are one such type of apps. We demonstrate herein that a diagnostic assay can be performed by patterning immunoassay strips in a bona fide barcode format such that after target binding and signal enhancement, the linear barcode can be read directly with a standard smartphone app. Quantitative analysis can then be performed based on the grayscale intensities with a customized mobile app. This novel diagnostic concept has been validated for a real-world application, i.e., the detection of human chorionic gonadotropin, a pregnancy hormone. With the possibility of multiplex detection, the barcode assay protocol promises to boost POC diagnosis research by the direct adaptation of mobile devices and apps. PMID- 26122609 TI - Yeast as a cell factory: current state and perspectives. AB - The yeast Saccharomyces cerevisiae is one of the oldest and most frequently used microorganisms in biotechnology with successful applications in the production of both bulk and fine chemicals. Yet, yeast researchers are faced with the challenge to further its transition from the old workhorse to a modern cell factory, fulfilling the requirements for next generation bioprocesses. Many of the principles and tools that are applied for this development originate from the field of synthetic biology and the engineered strains will indeed be synthetic organisms. We provide an overview of the most important aspects of this transition and highlight achievements in recent years as well as trends in which yeast currently lags behind. These aspects include: the enhancement of the substrate spectrum of yeast, with the focus on the efficient utilization of renewable feedstocks, the enhancement of the product spectrum through generation of independent circuits for the maintenance of redox balances and biosynthesis of common carbon building blocks, the requirement for accurate pathway control with improved genome editing and through orthogonal promoters, and improvement of the tolerance of yeast for specific stress conditions. The causative genetic elements for the required traits of the future yeast cell factories will be assembled into genetic modules for fast transfer between strains. These developments will benefit from progress in bio-computational methods, which allow for the integration of different kinds of data sets and algorithms, and from rapid advancement in genome editing, which will enable multiplexed targeted integration of whole heterologous pathways. The overall goal will be to provide a collection of modules and circuits that work independently and can be combined at will, depending on the individual conditions, and will result in an optimal synthetic host for a given production process. PMID- 26122617 TI - What do dental students know about trauma? AB - AIM: To assess the baseline knowledge, knowledge acquisition and retention of dental undergraduate students in dental trauma, and the impact of a lecture on their level of confidence in managing traumatic dental injuries. MATERIAL AND METHODS: A total of 145 dental undergraduate students from King's College London were invited to attend a lecture on dental trauma. The participants were asked to complete a questionnaire on dental trauma before (T0), immediately after (T1) and 6 months (T2) following a 1-h lecture. RESULTS: Seventy of the 145 students participated in the study. The level of knowledge at T0, T1 and T2 was 64.9%, 83.2% and 69.5%, respectively. The increase in score was statistically significant between T0 and T1, and between T0 and T2. A significant decrease in score was also found between T1 and T2. Sex, level of education and whether or not the participants received previous teaching in dental trauma were not significant in predicting a change in score. The level of confidence increased significantly from 2.14 at T0 to 3.13 at T2. Participants who received teaching in dental trauma previous to the lecture were significantly more confident at T0. CONCLUSIONS: Lectures are effective at improving the knowledge and retention of knowledge of dental undergraduate students in dental trauma. However, retention of the knowledge is time limited suggesting that education should be repeated after a certain period of time to ensure that a high level of knowledge is maintained. PMID- 26122615 TI - p53 in survival, death and metabolic health: a lifeguard with a licence to kill. AB - The function of p53 as a tumour suppressor has been attributed to its ability to promote cell death or permanently inhibit cell proliferation. However, in recent years, it has become clear that p53 can also contribute to cell survival. p53 regulates various metabolic pathways, helping to balance glycolysis and oxidative phosphorylation, limiting the production of reactive oxygen species, and contributing to the ability of cells to adapt to and survive mild metabolic stresses. Although these activities may be integrated into the tumour suppressive functions of p53, deregulation of some elements of the p53-induced response might also provide tumours with a survival advantage. PMID- 26122618 TI - Cultural Humility: A Concept Analysis. AB - Diversity is being increasingly recognized as an area of emphasis in health care. The term cultural humility is used frequently but society's understanding of the term is unclear. The aim of this article was to provide a concept analysis and a current definition for the term cultural humility. Cultural humility was used in a variety of contexts from individuals having ethnic and racial differences, to differences in sexual preference, social status, interprofessional roles, to health care provider/patient relationships. The attributes were openness, self awareness, egoless, supportive interactions, and self-reflection and critique. The antecedents were diversity and power imbalance. The consequences were mutual empowerment, partnerships, respect, optimal care, and lifelong learning. Cultural humility was described as a lifelong process. With a firm understanding of the term, individuals and communities will be better equipped to understand and accomplish an inclusive environment with mutual benefit and optimal care. PMID- 26122616 TI - Specifying and protecting germ cell fate. AB - Germ cells are the special cells in the body that undergo meiosis to generate gametes and subsequently entire new organisms after fertilization, a process that continues generation after generation. Recent studies have expanded our understanding of the factors and mechanisms that specify germ cell fate, including the partitioning of maternally supplied 'germ plasm', inheritance of epigenetic memory and expression of transcription factors crucial for primordial germ cell (PGC) development. Even after PGCs are specified, germline fate is labile and thus requires protective mechanisms, such as global transcriptional repression, chromatin state alteration and translation of only germline appropriate transcripts. Findings from diverse species continue to provide insights into the shared and divergent needs of these special reproductive cells. PMID- 26122619 TI - Corrigendum: Complex structures of different CaFe2As2 samples. PMID- 26122620 TI - Chemically Induced Changes to Membrane Permeability in Living Cells Probed with Nonlinear Light Scattering. AB - Second-harmonic light scattering (SHS) permits characterization of membrane specific molecular transport in living cells. Herein, we demonstrate the use of time-resolved SHS for quantifying chemically induced enhancements in membrane permeability. As proof of concept, we examine the enhanced permeability of the cytoplasmic membrane in living Escherichia coli following addition of extracellular adenosine triphosphate (ATPe). The transport rate of the hydrophobic cation, malachite green, increases nearly an order of magnitude following addition of 0.1 mM ATPe. The absence of an ATPe-enhanced permeability in liposomes strongly suggests the induced effect is protein-mediated. The utility of SHS for elucidating the mechanism of action of antimicrobials is discussed. PMID- 26122621 TI - Changes in rates of arthroscopy due to degenerative knee disease and traumatic meniscal tears in Finland and Sweden. AB - BACKGROUND AND PURPOSE: Knee arthroscopy is commonly performed to treat degenerative knee disease symptoms and traumatic meniscal tears. We evaluated whether the recent high-quality randomized control trials not favoring arthroscopic surgery for degenerative knee disease affected the procedure incidence and trends in Finland and Sweden. PATIENTS AND METHODS: We conducted a bi-national registry-based study including all adult (aged >=18 years) inpatient and outpatient arthroscopic surgeries performed for degenerative knee disease (osteoarthritis (OA) and degenerative meniscal tears) and traumatic meniscal tears in Finland between 1997 and 2012, and in Sweden between 2001 and 2012. RESULTS: In Finland, the annual number of operations was 16,389 in 1997, reached 20,432 in 2007, and declined to 15,018 in 2012. In Sweden, the number of operations was 9,944 in 2001, reached 11,711 in 2008, and declined to 8,114 in 2012. The knee arthroscopy incidence for OA was 124 per 10(5) person-years in 2012 in Finland and it was 51 in Sweden. The incidence of knee arthroscopies for meniscal tears coded as traumatic steadily increased in Finland from 64 per 10(5) person-years in 1997 to 97 per 10(5) person-years in 2012, but not in Sweden. INTERPRETATION: The incidence of arthroscopies for degenerative knee disease declined after 2008 in both countries. Remarkably, the incidence of arthroscopy for degenerative knee disease and traumatic meniscal tears is 2 to 4 times higher in Finland than in Sweden. Efficient implementation of new high-quality evidence in clinical practice could reduce the number of ineffective surgeries. PMID- 26122623 TI - Blood culture contamination rates. PMID- 26122622 TI - Evidence that a novel quaternary compound and its organic N-chloramine derivative do not select for resistant mutants of Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is well known for causing hospital-acquired infections that are often difficult to treat because of its high intrinsic and acquired resistance to antibiotics. Resistance-nodulation-division (RND) efflux pumps are the major contributors to the intrinsic multidrug resistance (MDR) in this organism. Various biocides used in hospital settings have been shown to select for RND-pump-overexpressing mutants of P. aeruginosa that show cross resistance to clinically relevant antibiotics. Therefore, finding biocides that do not select for multidrug-resistant mutants is important in controlling the spread of bacteria such as P. aeruginosa. AIM: To evaluate the potential of a novel quaternary ammonium compound and its N-chloramine derivative in selecting for MDR mutants of P. aeruginosa. METHODS: P. aeruginosa PA01 was cultured in the presence of increasing concentrations of the quaternary ammonium compound and its N-chloramine derivative respectively, and one mutant each selected. Susceptibility of the mutants to both compounds as well as antibiotics was tested. Susceptibility of P. aeruginosa strains with deletions in RND pumps was also tested for both compounds to determine whether they are a substrate of these pumps. Expression of mexB, mexD, and mexY genes in the mutants was analysed using quantitative reverse transcriptase-polymerase chain reaction to determine whether the compounds can select for pump-overexpressing mutants. FINDINGS: We show that whereas both compounds can be pumped by the MexCD-OprJ pump, they neither select for mutants that overexpress RND pumps nor for mutants that display cross resistance to antibiotics. CONCLUSION: These compounds are promising candidates to be used as disinfectants in hospital settings. PMID- 26122624 TI - Effects of fluoroquinolone restriction (from 2007 to 2012) on resistance in Enterobacteriaceae: interrupted time-series analysis. AB - BACKGROUND: Antibiotic stewardship is a key component in the effort to reduce healthcare-associated infections. AIM: To describe the implementation and analyse the impact of fluoroquinolone restriction on resistance in Enterobacteriaceae, focusing on urinary isolates of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, which were historically almost universally resistant to fluoroquinolones. METHODS: ESBL-producing E. coli hospital and community isolates, obtained between April 2009 and March 2012 from consecutive non duplicate urine samples, were included in an interrupted time-series analysis based on a Poisson distribution model. Periods before and after fluoroquinolone restriction were compared. The trend in fluoroquinolone resistance in all urinary isolates of Enterobacteriaceae (N ~ 20,000 per year) and blood culture isolates of E. coli (N ~ 350) between 2009 and 2013 were also analysed. FINDINGS: A large decline in the percentage of ciprofloxacin-resistant ESBL-producing urinary E. coli isolates was observed in both hospital (risk ratio: 0.473; 95% confidence interval: 0.315-0.712) and community settings (0.098; 0.062-0.157). The decline was also marked in all urinary isolates of Enterobacteriaceae and E. coli isolates from blood cultures. CONCLUSION: We conclude that reducing fluoroquinolone usage to a level of <=2 defined daily doses per 100 occupied bed days in hospital sufficiently removed selection pressure to allow resistant Enterobacteriaceae - specifically, the UK endemic strains of ESBL-producing E. coli - to revert back to fluoroquinolone susceptibility within a short span of four months. This was accompanied with a concomitant reduction in overall ESBL burden. PMID- 26122625 TI - How to isolate a patient with Cladophialophora bantiana infection? An opinion. PMID- 26122626 TI - The Pathobiochemistry of Gastrointestinal Symptoms in a Patient with Niemann-Pick Type C Disease. AB - The molecular basis of gastrointestinal intolerances in a severe case of Niemann Pick type C disease was analyzed in an intestinal biopsy specimen. The enzyme activities of intestinal sucrase-isomaltase and maltase-glucoamylase are reduced in the patient, while that of lactase is comparable to the control. The association of SI with lipid rafts is reduced in the patient's biopsy as a consequence of altered composition of membrane microdomains. As association with lipid rafts influences the intracellular transport and the enzyme activities of sucrase-isomaltase and maltase-glucoamylase, these data explain reduced carbohydrate digestion in the intestinal lumen and delineate the effect of deficient cholesterol and sphingolipid homeostasis in development of gastrointestinal symptoms in NPC patients. PMID- 26122627 TI - Vitamin E Improves Clinical Outcome of Patients Affected by Glycogen Storage Disease Type Ib. AB - BACKGROUND: It has been suggested, on a few GSD1b patients, that vitamin E improves neutrophil count and reduces frequency and severity of infections.The main objective of the present study was to investigate the efficacy of vitamin E on the neutropenia, neutrophil dysfunction and IBD in the entire Italian caseload of GSD1b patients. PATIENTS AND METHODS: Eighteen GSD1b patients, median age at the time of the study protocol 14.5 (range, 0.6-42 years), were enrolled from four Italian referral centres for metabolic diseases. For the evaluation of the efficacy of vitamin E, neutrophil count and function, frequency of infections needing hospitalization and inflammatory bowel activity were evaluated periodically all over one year before and during vitamin E therapy. RESULTS: Frequency (1.5 +/- 0.1 vs. 6.0 +/- 0.6, p = 0.003) and severity of infections (2.2 +/- 0.2 vs. 3.7 +/- 0.4, p = 0.003) were lower and mean value of neutrophil count (1,583 +/- 668 vs. 941 +/- 809, p = 0.03) higher during vitamin E supplementation. Neutrophil function results improved during vitamin supplementation. PCDAI showed a significant reduction in the inflammatory activity during vitamin E supplementation (9 +/- 1.4 vs. 13 +/- 1.2, p = 0.006). In seven patients G-CSF requirement decreased and the dose was reduced after the end of the study.In conclusion, our study demonstrated the efficacy of vitamin E supplementation. Vitamin E has evident advantages as compared to G-CSF, as it can be assumed orally, and it has not been associated with severe side effects. PMID- 26122628 TI - Urine Beta2-Microglobulin Is an Early Marker of Renal Involvement in LPI. AB - OBJECTIVE: Lysinuric protein intolerance (LPI) is a rare autosomal recessive disorder affecting the transport of cationic amino acids. It has previously been shown that approximately one third of the Finnish LPI patients have impaired renal function. The aim of this study was to analyse in detail urine beta2 microglobulin values, renal dysfunction, oral L-citrulline doses and plasma citrulline concentrations in Finnish LPI patients. METHODS AND RESULTS: Of the 41 Finnish LPI patients, 56% had proteinuria and 53% hematuria. Mean plasma creatinine concentration was elevated in 48%, serum cystatin C in 62%, and urine beta2-microglobulin in 90% of the patients. Seventeen per cent of the patients developed ESRD, and five of them received a kidney transplant. L-citrulline doses and fasting plasma citrulline concentrations were similar in adult LPI patients with decreased and normal GFR (mean +/- SD 79.5 +/- 29.2 vs. 82.4 +/- 21.9 mg/kg/day, P = 0.619, and 80.3 +/- 20.1 vs. 64.8 +/- 23.0 MUmol/l, P = 0.362, respectively). CONCLUSIONS: Urine beta2-microglobulin is a sensitive early marker of renal involvement, and it should be monitored regularly in LPI patients. Weight-based oral L-citrulline doses and plasma citrulline concentrations were not associated with renal function. LPI patients with ESRD were successfully treated with dialysis and kidney transplantation. PMID- 26122629 TI - Improvement of Diffusion Tensor Imaging (DTI) Parameters with Decoppering Treatment in Wilson's Disease. AB - OBJECTIVE: This study was undertaken to analyse serially the effects of decoppering therapy on the clinical features, disability and MRI brain including DTI metrics in patients with Wilson's disease. METHODS AND RESULTS: Thirty-five patients with clinically and serologically confirmed neuropsychiatric form of Wilson's disease (WD) on decoppering therapy were followed for a minimum duration of 1 year with serial assessment of their clinical features, disability status and serial MR imaging of the brain including DTI. The cohort included 18 treatment-naive patients and 17 patients already on decoppering therapy (M/F = 2.18:1). The mean age at which they underwent baseline assessment for this study was 18.6 +/- 7.6 years, and follow-up assessment was done after a mean duration of 23.5 +/- 8.8 months (range, 12 to 45 months). Along with the overall clinical improvement noted at follow-up, the disability assessed using Chu staging and MSEADL showed significant reduction in the number of patients with severe disability and the mean NSS reducing from 9.74 to 6.37 (p = 0.002). The mean MRI scores showed significantly reduced disease burden from a baseline score of 5.9 (+/-4.2) to 4.9 (+/-4.7) in follow-up scans (p < 0.05). Voxel-wise comparison of serial DTI metrics on TBSS (tract-based spatial statistics) analysis showed that the entire cohort had significant (p < 0.05) improvement in all the four parameters (MD, FA, DA and RD) indicated by a decrease in MD, DA and RD values and increase in FA values. Comparison of whole-brain white matter DTI measures between pre- and posttreatment did not show any significant difference (p < 0.05). CONCLUSION: Patients with Wilson's disease on decoppering therapy showed clinical improvement accompanied with improvement in DTI metrics. Quantitative DTI metrics may be used as surrogate markers of clinical status following initiation of medical therapy in Wilson's disease. PMID- 26122630 TI - Screening Mucopolysaccharidosis Type IX in Patients with Juvenile Idiopathic Arthritis. AB - Mucopolysaccharidosis is a group of lysosomal disorders of a deficiency of specific enzyme required for glycosaminoglycan degradation. Mucopolysaccharidosis type IX is the rarest form of mucopolysaccharidosis. To date, only four patients have been reported. The first reported patient had mild short stature and periarticular soft tissue masses; the other reported patients are clinically indistinguishable from juvenile idiopathic arthritis. In the present study, we screened mucopolysaccharidosis type IX among patients with juvenile idiopathic arthritis with hyaluronidase enzyme assay. One hundred and eight patients with JIA and 50 healthy age-matched control subjects were enrolled in the study. Among all patients, none had deficient hyaluronidase activity. Though serum Hyal-1 activity was significantly increased in JIA patients, compared with control subjects (p < 0.000), no correlation was found between CRP, ESR, and Hyal-1 activity (p = 0.187). In conclusion, the data reported in our study indicates that systemic metabolic investigation for hyaluronidase activity is not recommended in all patients with JIA. PMID- 26122631 TI - Opportunities and Challenges in the Design and Analysis of Biomass Supply Chains. AB - The biomass supply chain is one of the most critical elements of large-scale bioenergy production and in many cases a key barrier for procuring initial funding for new developments on specific energy crops. Most productions rely on complex transforming chains linked to feed and food markets. The term 'supply chain' covers various aspects from cultivation and harvesting of the biomass, to treatment, transportation, and storage. After energy conversion, the product must be delivered to final consumption, whether it is in the form of electricity, heat, or more tangible products, such as pellets and biofuels. Effective supply chains are of utmost importance for bioenergy production, as biomass tends to possess challenging seasonal production cycles and low mass, energy and bulk densities. Additionally, the demand for final products is often also dispersed, further complicating the supply chain. The goal of this paper is to introduce key components of biomass supply chains, examples of related modeling applications, and if/how they address aspects related to environmental metrics and management. The paper will introduce a concept of integrated supply systems for sustainable biomass trade and the factors influencing the bioenergy supply chain landscape, including models that can be used to investigate the factors. The paper will also cover various aspects of transportation logistics, ranging from alternative modal and multi-modal alternatives to introduction of support tools for transportation analysis. Finally gaps and challenges in supply chain research are identified and used to outline research recommendations for the future direction in this area of study. PMID- 26122632 TI - Future Forest Cover Change Scenarios with Implications for Landslide Risk: An Example from Buzau Subcarpathians, Romania. AB - This study focuses on future forest cover change in Buzau Subcarpathians, a landslide prone region in Romania. Past and current trends suggest that the area might expect a future increase in deforestation. We developed spatially explicit scenarios until 2040 to analyze the spatial pattern of future forest cover change and potential changes to landslide risk. First, we generated transition probability maps using the weights of evidence method, followed by a cellular automata allocation model. We performed expert interviews, to develop two future forest management scenarios. The Alternative scenario (ALT) was defined by 67% more deforestation than the Business as Usual scenario (BAU). We integrated the simulated scenarios with a landslide susceptibility map. In both scenarios, most of deforestation was projected in areas where landslides are less likely to occur. Still, 483 (ALT) and 276 (BAU) ha of deforestation were projected on areas with a high-landslide occurrence likelihood. Thus, deforestation could lead to a local-scale increase in landslide risk, in particular near or adjacent to forestry roads. The parallel process of near 10% forest expansion until 2040 was projected to occur mostly on areas with high-landslide susceptibility. On a regional scale, forest expansion could so result in improved slope stability. We modeled two additional scenarios with an implemented landslide risk policy, excluding high-risk zones. The reduction of deforestation on high-risk areas was achieved without a drastic decrease in the accessibility of the areas. Together with forest expansion, it could therefore be used as a risk reduction strategy. PMID- 26122633 TI - Significance of the width of keratinized mucosa on peri-implant health. AB - In implant therapy, the adequate state of peri-implant tissue health and soft tissue aesthetics is the essential criterion of restorative success. The need for keratinized mucosa for the maintenance of peri-implant health and soft-tissue integration remains a debated issue. The aim of this paper is to provide a narrative review of the current literature concerning the significance of keratinized mucosa with respect to the clinical parameters of monitoring oral hygiene practice and tissue status. The published studies revealed that there were conflicting results with regard to the influence of keratinized mucosa on plaque score and soft-tissue inflammation. Most studies showed that the amount of soft-tissue recession was significantly increased at implant sites with narrow keratinized mucosa, but the amount of keratinized mucosa had little effect on deepening of peri-implant pockets. The evidence related to the effect of keratinized mucosa on the changes of attachment or bone levels is limited, and conclusions could not be drawn at present. Further, this review found that a band of keratinized mucosa was not absolutely necessary for the maintenance of peri implant tissue, whereas lack of adequate keratinized mucosa around the implant might impede proper oral hygiene performance and compromise the aesthetic results. In conclusion, because there is a wide variety of clinical features in patients pursuing implant therapy, individual consideration of treatment strategies for the patient with minimal keratinized mucosa is recommended. PMID- 26122634 TI - The essential function of Rrs1 in ribosome biogenesis is conserved in budding and fission yeasts. AB - The Rrs1 protein plays an essential role in the biogenesis of 60S ribosomal subunits in budding yeast (Saccharomyces cerevisiae). Here, we examined whether the fission yeast (Schizosaccharomyces pombe) homologue of Rrs1 also plays a role in ribosome biogenesis. To this end, we constructed two temperature-sensitive fission yeast strains, rrs1-D14/22G and rrs1-L51P, which had amino acid substitutions corresponding to those of the previously characterized budding yeast rrs1-84 (D22/30G) and rrs1-124 (L61P) strains, respectively. The fission yeast mutants exhibited severe defects in growth and 60S ribosomal subunit biogenesis at high temperatures. In addition, expression of the Rrs1 protein of fission yeast suppressed the growth defects of the budding yeast rrs1 mutants at high temperatures. Yeast two-hybrid analyses revealed that the interactions of Rrs1 with the Rfp2 and Ebp2 proteins were conserved in budding and fission yeasts. These results suggest that the essential function of Rrs1 in ribosome biogenesis may be conserved in budding and fission yeasts. PMID- 26122635 TI - A Novel Risk Score to Predict Dysphagia After Cardiac Surgery Procedures. AB - BACKGROUND: Although the exact cause of dysphagia after cardiac operations is unknown, timely diagnosis is critical to avoid a devastating aspiration event. Accordingly, we sought to generate the risk of dysphagia in cardiac surgery (RODICS) score to identify patients at risk for its development after heart surgery. METHODS: All adult heart surgery patients at our institution between January 2011 and March 2012 were analyzed. A videofluoroscopic swallow study stratified patients into two groups based on the presence or absence of dysphagia. Covariates (p < 0.20) were included in a multivariable model to determine the strongest independent predictors of postoperative dysphagia. Based on the relative odds ratios of significant variables, the RODICS score was generated. Risk cohorts were then created based on easily applicable, whole integer score cutoffs. RESULTS: During the study period, 115 of 1,314 patients (8.8%) undergoing heart surgery were diagnosed with clinically significant dysphagia. The 38-point RODICS score comprises seven patient-specific characteristics and perioperative factors. The low risk (less than 4), intermediate risk (5 to 9), and high risk (more than 9) cohorts had postoperative dysphagia rates of 3.0%, 6.8%, and 21.6%, respectively (p < 0.001). The intermediate-risk cohort (odds ratio 2.3, 95% confidence interval: 1.33 to 4.27, p = 0.01) and high-risk cohort (odds ratio 8.9, 95% confidence interval: 5.22 to 15.32, p < 0.001) were at significantly higher risk of dysphagia developing. The RODICS score demonstrated excellent discriminatory ability (area under the curve 0.75). CONCLUSIONS: The incidence and impact of dysphagia after open cardiac operations is significant. This novel scoring system could lead to prompt identification of patients at high risk for postoperative dysphagia and potentially minimize the complications of aspiration. PMID- 26122636 TI - 1-year results of combined half-dose photodynamic therapy and ranibizumab for polypoidal choroidal vasculopathy. AB - BACKGROUND: To evaluate the efficacy and safety of half-dose photodynamic therapy (PDT combined with ranibizumab for polypoidal choroidal vasculopathy (PCV). PCV is commonly treated with a combination of anti-vascular endothelial growth factor and standard-dose photodynamic therapy (PDT). Choroidal ischemia and visual loss can be resulted from the standard-dose PDT. Half-dose PDT has proved to produce similar results and safety profile in treating central serous chorioretinopathy. Half-dose PDT may offer an alternative for PCV cases where the damage to choroidal vasculature maybe less. Here, we report the efficacy of treating PCV cases with combination of ranibizumab and half-dose PDT. METHODS: In this prospective, non-comparative, interventional case series, 19 treatment-naive eyes were treated with combined half-dose PDT and ranibizumab. All subjects were followed up for 12 months with measurement of best-corrected visual acuity (BCVA), central foveal thickness (CFT) by optical coherence tomography. Indocyanine green angiogram (ICG) was performed every 3-monthly, and subjects assessed in terms of polyp regression rates, changes in vision and central foveal thickness, need to repeat half-dose PDT. Subgroup analysis was performed based on ICG features. RESULTS: The mean logMAR BCVA improved from 0.64 at baseline to 0.41 at 12 months. The mean CFT improved from 459.6 mum at baseline to 384.2 mum at 12 months. The difference between baseline BCVA and CFT and that at 12 months were statistically significant (both P = 0.03). Polyp regression rate after one half-dose PDT was 42.1 %. This was 61.5 % in the polyp-only group, while that in the branching-vascular-network (BVN) group was 0 % (P = < 0.01). CONCLUSION: Half dose PDT combined with intravitreal ranibizumab was able to induce high polyp regression rate in PCV cases that had one single polyp. PMID- 26122637 TI - [New therapeutic strategies for remyelination in multiple sclerosis]. AB - Multiple sclerosis (MS) is characterized by oligodendrocyte death and myelin sheath destruction of the central nervous system (CNS) in response to autoinflammatory processes. Besides demyelination axonal degeneration constitutes the second histopathological hallmark of this disease. A large number of immunomodulatory and targeted immunosuppression treatments have been approved for relapsing remitting (RR) MS where they effectively reduce relapse rates; however, currently no treatment options exist to repair injured axonal tracts or myelin damage that accumulates over time particularly in progressive MS. In light of the growing available therapeutic repertoire of highly potent immunomodulatory medications there is an increasing interest in the development of therapies aimed at neutralizing neurodegenerative damage. Endogenous remyelination processes occur mainly as a result of oligodendrocyte precursor cell (OPC) activation, recruitment and maturation; however, this repair activity appears to be limited and increasingly fails during disease progression. Based on these observations OPCs are considered as promising targets for the regenerative treatment of all stages of MS. This article presents an overview of approved medications with a suggested role in regeneration, regenerative treatments that are currently being tested in clinical trials, as well as promising future therapeutic approaches derived from basic glial cell research aiming at the promotion of the endogenous repair activity of the brain. PMID- 26122638 TI - [Disulfiram in outpatient treatment of alcohol dependency]. AB - AIM: The alcohol deterrent drug disulfiram plays a minor role in the treatment of alcohol dependency in Germany. The study looks at the efficacy, tolerability and feasibility of a disulfiram outpatient treatment program in a German psychiatric hospital. METHOD: Data from 190 outpatients with alcohol dependency, who had participated in a disulfiram therapy program at the psychiatric outpatient department over a period of 10 years, were analyzed with respect to efficacy and tolerability. To test for predictors, independent variables and treatment success as a dependent variable a logistic regression was carried out. RESULTS: After 1 year 24.2 % of the patients maintained alcohol abstinence while 55 % had had an alcohol relapse despite being in the disulfiram program. No severe complications were observed under disulfiram treatment. Therapy success was largely related to participating in treatment-specific group therapy. CONCLUSION: Disulfiram proved to be a well-tolerated medication as part of multimodal therapy of alcohol dependency. The disulfiram program was easily integrated into other health service treatment. Approximately one quarter of patients who had had an unfavorable course before, achieved abstinence, while participation in group therapy was a major predictor of treatment success. Disulfiram is a medication, which in the context of a psychosocial treatment concept, should receive a wider distribution in Germany. PMID- 26122639 TI - [Assessment of quality indicators with routine data: Presentation of a feasibility test in ten specialist clinics for psychiatry and psychotherapy]. AB - BACKGROUND: Prior to nationwide implementation, the feasibility of newly developed quality indicators must be assessed. The aim of this multicenter feasibility test was an evaluation of the measurability of cross-sectoral quality indicators for depression and schizophrenia by means of routine data. METHODS: The feasibility of the quality indicators was assessed in ten specialist clinics for psychiatry and psychotherapy by means of retrospective analyses of anonymous routine data. The data were extracted from the routine clinical documentation of the hospital information systems and the data from the admission and discharge sheets of the basic documentation in psychiatry (BADO) were additionally used for some clinics. Analyses were conducted for all cases of adults diagnosed with depression or schizophrenia within predefined assessment periods. RESULTS: In total five indicators for depression and nine indicators for schizophrenia were assessed and evaluated as measurable or measurable to a limited extent, sometimes with slight adaptations in the operationalization of the indicator. Due to variations in documentation, some indicators could not be calculated for all clinics. Most indicators could be collated with the data from the BADO. CONCLUSION: An assessment of indicators that measure quality-relevant aspects of care in depression and schizophrenia, is partially feasible by means of current routine data documentation analysis from the participating clinics. However, differing documentation methodologies in the participating clinics impeded a uniform assessment; therefore, for the implementation of nationwide minimum standards for the quality assurance of mental healthcare, a uniform cross sectoral documentation methodology should be adapted to consensus and relevant quality indicators. The BADO appears to be a suitable instrument for this purpose. PMID- 26122640 TI - [Production of accentuated personality traits in baroque opera : Opera buffa Arcifanfano-Re dei matti (1749)]. AB - BACKGROUND: Madness served primarily as a form of amusement for the spectators in operas of the seventeenth century. This representation was far removed from clinical reality. This circumstance changed in the eighteenth century at the time when tragic madness emerged in numerous operas. MATERIAL AND METHODS: The opera buffa Arcifanfano-Re dei matti (Arcifanfano-King of fools, premiered in 1749 in Venice, text by Carlo Goldoni 1707-1793 and music by Baldassare Galuppi 1706 1785), which continuously enacts a realm of fools and is meant to appear amusing, is riddled with psychopathological abnormalities for which a retrospective diagnosis is methodologically rejected. However, the opera presents many subjects for working out a typology of fools based on outlasting personality traits of the protagonists. The libretto is investigated. A musical analysis is spared. RESULTS: The conceptualized typology of fools in the opera, which is oriented towards the seven main vices or deadly sins serves, in the tradition of moral satire, to critically hold up a mirror to the audience to reflect their own vices by an amusing characterization of the latter. Historically classified, the treatment of fools by means of isolation, custody, locking up in cages as well as authoritarian measures of submission reflects the custom in those days before humanizing the treatment of people with mental illness in the course of the Enlightenment and the French Revolution. CONCLUSION: The opera Arcifanfano is essentially characterized by continuous madness. A typology of the fools can be worked out from the precise depiction of the personalities. A mirror is held up to the spectators in terms of vices, in the tradition of the contemporary baroque opera. At the same time, the opera can be classified psychiatrically and historically as a seismograph of its time when in the seventeenth and eighteenth centuries people with mental illness were isolated and incarcerated. PMID- 26122641 TI - mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines. AB - Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte (CTL) responses, Toll-like receptor (TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3K, ERK, and mTOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates mTOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, mTOR plays a crucial role in c-fos expression, thereby modulating NFkappaB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, mTOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of mTOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which mTOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy. PMID- 26122642 TI - A respiratory syncytial virus persistent-infected cell line system reveals the involvement of SOCS1 in the innate antiviral response. AB - HEp-2 cells persistently infected with respiratory syncytial virus (RSV) are a heterogeneous mixture of viral antigen-positive and -negative variants; however, the mechanism through which viral replication becomes latent remains unclear. In this study, we investigated the potential mechanism by which RSV escapes from innate immune surveillance. Persistent-infected RSV HEp-2 cells were isolated and cell clones were passaged. The RSV-persistent cells produced viruses at a lower titer, resisted wild-type RSV re-infection, and secreted high levels of interferon-beta (IFN-beta), macrophage inflammatory protein-1alpha (Mip-1alpha), interleukin-8 (IL-8), and Rantes. Toll-like receptor 3 (TLR3), retinoic acid inducible gene-I (RIG-I), and suppressor of cytokine signaling 1 (SOCS1) levels were upregulated in these cells. The silencing of TLR3 mRNA decreased the expression of SOCS1 protein and the secretion of cytokines. RSV-persistent cells are in an inflammatory state; upregulation of SOCS1 is related to the TLR3 signaling pathway, which could be associated with the mechanism of viral persistence. PMID- 26122643 TI - Are developing countries prepared to face Ebola-like outbreaks? PMID- 26122644 TI - Infrared signature of micro-hydration in the organophosphate Sarin: an ab initio study. AB - The infrared (IR) spectra of micro-hydrated Sarin*(H2O)n clusters containing between one and four explicit waters have been studied using ab initio density functional theory (DFT) methods. The phosphate group P=O bond vibration region (~1270 to 1290 cm(-1)) revealed the largest frequency variation with hydration, with a frequency red shift reflecting the direct hydrogen bond formation between the P=O of Sarin and water. Small variations to the P-F stretch (~810 to 815 cm( 1)) and the C-O-P vibrational modes (~995 to 1004 cm(-1)) showed that the water interactions with these functional groups were minor, and that the structures of Sarin were not extensively perturbed in the hydrated complexes. Increasing the number of explicit hydration waters produced only small vibrational changes in the lowest free energy complexes. These minor changes were consistent with a single water-phosphate hydrogen bond being the dominant structure, though a second water-phosphate hydrogen bond was observed in some complexes and was identified by an additional red shift of the P=O bond vibration. The H2O*H2O vibrational modes (~3450 to 3660 cm(-1)) increased in complexity with higher hydration levels and reflect the extended hydrogen bonding networks formed between the explicit waters in the hydrated Sarin clusters. Graphical Abstract Ab initio studies of the infrared signature for micro-hydrated Sarin. PMID- 26122645 TI - Treatment of medication-overuse headache: A systematic review. AB - INTRODUCTION: The objective of this review is to provide an evidence-based discussion of different treatment strategies for medication-overuse headache (MOH). METHOD: We searched PubMed for articles discussing the treatment and prognosis of MOH published between 2004 and August 2014. Titles, abstract and articles were reviewed systematically. The level of evidence provided by each study of the included articles was determined according to the American Academy of Neurology Clinical practice guideline manual. We discuss the level of evidence to support the early discontinuation/withdrawal of overused medications, the level of evidence to support the use of preventive treatment, the short- and long term prognosis, and the outcome according to the class of drug overused in patients diagnosed with MOH. RESULTS: The initial search resulted in 1313 articles; 68 articles met our inclusion criteria and were discussed. The level of evidence to support early discontinuation of overused medications alone is low due to the absence of controlled studies. Adding preventive medication to early discontinuation led to a better outcome than early discontinuation alone. For patients with chronic migraine (CM) and medication overuse (MO), there are large randomized control trials supporting the use of onabotulinumtoxinA and topiramate without early discontinuation of overuse; however, the evidence is limited since data were obtained from post hoc analysis. CONCLUSION: Considering current available evidence and the systemic toxicity of overusing acute headache medication, we suggest discontinuation of the overused medication with the addition of preventive medication. Appropriately sized, randomized controlled trials evaluating the safety and long-term efficacy of preventive medication plus early discontinuation of overuse vs preventive medication alone vs early discontinuation of overuse alone are needed. PMID- 26122646 TI - Migraine diagnosis and treatment: A knowledge and needs assessment among primary care providers. AB - BACKGROUND: Studies reveal that migraine is often under-recognized, misdiagnosed and inadequately treated in the primary care setting. OBJECTIVE: The objective of this article is to assess primary care providers' (PCP) knowledge and needs regarding migraine diagnosis and management. METHODS: We held semi-structured group interviews and distributed a brief questionnaire to PCPs in our hospital network. Building on the information from the interviews, we developed a comprehensive survey assessing PCPs' knowledge about migraine. Descriptive analyses were performed. RESULTS: The initial interviews and brief questionnaires revealed that PCPs are aware of the prevalence of migraine but are uncertain about the details of management. Eighty-three of 120 physicians completed the comprehensive survey. Only 47% would order imaging for a new type of headache, 31% for worsening headache, and 35% for a headache unresponsive to treatment. Only 28% were familiar with the American Academy of Neurology guidelines on preventive treatment and 40% were familiar with the Choosing Wisely Campaign recommendations on migraine treatment. Just 34% were aware that opioids can cause medication-overuse headache. Non-pharmacologic treatment was not usually recommended. PCPs favored educational opportunities involving direct contact with headache physicians (56%). CONCLUSIONS: PCPs are not universally aware of the specific recommendations for managing migraine patients. Future work should focus on innovative ways to provide decision support and education for PCPs caring for migraineurs. PMID- 26122647 TI - Geographic variation in racial disparities in child maltreatment: The influence of county poverty and population density. AB - There are documented disparities in the rates at which black children come into contact with the child welfare system in the United States compared to white children. A great deal of research has proliferated aimed at understanding whether systematic biases or differential rates of risk among different groups drive these disparities (Drake et al., 2011). In the current study, county rates of maltreatment disparity are compared across the United States and examined in relation to rates of poverty disparity as well as population density. Specifically, using hierarchical linear modeling with a spatially lagged dependent variable, the current study examined data from the National Child Abuse and Neglect Data System (NCANDS) and found that poverty disparities were associated with rates of maltreatment disparities, and densely populated metropolitan counties tended to have the greatest levels of maltreatment disparity for both black and Hispanic children. A significant curvilinear relationship was also observed between these variables, such that in addition to the most densely populated counties, the most sparsely populated counties also tended to have higher rates of maltreatment disparity for black and Hispanic children. PMID- 26122648 TI - Sex Differences in HIV Prevalence, Behavioral Risks and Prevention Needs Among Anglophone and Francophone Sub-Saharan African Migrants Living in Rabat, Morocco. AB - Morocco has experienced a dramatic increase of migration from sub-Sahara Africa during the past decade. Recently included among the most vulnerable populations cited in the Morocco National Strategic Plans on HIV/TB for 2012-2016, sub Saharan Africa migrants living in an irregular administrative situation participated in a survey to provide baseline data about their socio-demographic, sexual and HIV testing behaviors and HIV and syphilis prevalence. Two surveys using respondent driven sampling were conducted in 2013 among males and females, >=18 years, originating from sub-Saharan African countries and living and/or working in an irregular administrative situation in Rabat and residing at least 3 months in Morocco. Analysis was conducted to evaluate differences between the two samples and between females and males within each sample using the successive sampling estimator in RDS Analyst. Roughly 3 % of francophone and anglophone migrants were infected with HIV, whereas a statistically significantly higher percentage of francophone (2.8 %), compared to anglophone (0.3 %), migrants were infected with syphilis. Females were found to have HIV infection rates three times higher and past year sexually transmitted infection signs and symptoms more than two times higher than their male counterparts. Female migrants also had statistically significantly higher percentages of ever testing for HIV and HIV testing and receiving results in the past year compared to males. We found distinct and important differences between migrants depending on whether they come from francophone versus anglophone countries and whether they were male or female. Future research should continue to explore these differences, while policies and programs should note these differences to best allocate resources in providing social and health services to these populations. PMID- 26122649 TI - HIV Testing and Awareness of Partner's HIV Status Among Chinese Men Who Have Sex with Men in Main Partnerships. AB - Many men who have sex with men (MSM) do not use condoms with their main partners, especially if both parties are of the same HIV status. However, significant proportions of MSM have never tested or recently tested and are unaware of their main partners' HIV status. A cross-sectional survey was conducted among 524 MSM in Jiangsu, China in 2013-2014. Time-location sampling and online convenience sampling were used to recruit participants. We compared awareness of HIV status and recent HIV testing between participants who had main partners versus those who did not, and identified factors associated with recent HIV testing among men in main partnerships. Participants in main partnerships were significantly more likely to report recent HIV testing and being HIV-negative instead of HIV-unknown compared to participants in casual partnerships only. Overall, 74.5 % of participants were aware of their main partners' HIV status. Among participants in main partnerships, those who had 2-5 male anal sex partners in the past 6 months and those who reported that their partners were HIV-negative had 2.36 (95 % CI 1.12, 4.97) and 4.20 (95 % CI 2.03, 8.70) fold greater odds of being tested in the past year compared to those who had main partners only and those whose partners were HIV-positive/unknown, respectively. Chinese MSM in main partnerships might be practicing serosorting and may be at lower risk for HIV infection due to increased awareness of main partners' HIV status and higher uptake of recent testing. PMID- 26122650 TI - Depressive Symptoms, Substance Use and Partner Violence Victimization Associated with HIV Disclosure Among Men Who have Sex with Men. AB - HIV continues to disproportionately affect men who have sex with men (MSM). Depression and substance use have been shown to be risk factors of partner violence among male same-sex couples. However, research exploring the risk factors for partner violence victimization after HIV disclosure among MSM is limited. The aim of this study was to determine the association between depressive symptoms, substance use, and disclosure-associated verbal and/or physical violence from a partner among MSM. Data were obtained from 340 HIV positive MSM. Multivariable logistic regression was used to determine the associations between Center for Epidemiologic Studies-Depression and substance use scores, and disclosure-associated partner violence. After adjusting for age and income, every one-unit increase in substance use scores resulted in a 9 % (OR 1.09; 95 % CI 1.01-1.16) increase in the odds of disclosure-associated partner violence. HIV disclosure interventions for MSM populations should address substance use and potential violence from partners after disclosure. PMID- 26122652 TI - Simple reaction time to the onset of time-varying sounds. AB - Although auditory simple reaction time (RT) is usually defined as the time elapsing between the onset of a stimulus and a recorded reaction, a sound cannot be specified by a single point in time. Therefore, the present work investigates how the period of time immediately after onset affects RT. By varying the stimulus duration between 10 and 500 msec, this critical duration was determined to fall between 32 and 40 milliseconds for a 1-kHz pure tone at 70 dB SPL. In a second experiment, the role of the buildup was further investigated by varying the rise time and its shape. The increment in RT for extending the rise time by a factor of ten was about 7 to 8 msec. There was no statistically significant difference in RT between a Gaussian and linear rise shape. A third experiment varied the modulation frequency and point of onset of amplitude-modulated tones, producing onsets at different initial levels with differently rapid increase or decrease immediately afterwards. The results of all three experiments results were explained very well by a straightforward extension of the parallel grains model (Miller and Ulrich Cogn. Psychol. 46, 101-151, 2003), a probabilistic race model employing many parallel channels. The extension of the model to time varying sounds made the activation of such a grain depend on intensity as a function of time rather than a constant level. A second approach by mechanisms known from loudness produced less accurate predictions. PMID- 26122651 TI - Development of target-specific liposomes for delivering small molecule drugs after reperfused myocardial infarction. AB - Although reperfusion is essential in restoring circulation to ischemic myocardium, it also leads to irreversible events including reperfusion injury, decreased cardiac function and ultimately scar formation. Various cell types are involved in the multi-phase repair process including inflammatory cells, vascular cells and cardiac fibroblasts. Therapies targeting these cell types in the infarct border zone can improve cardiac function but are limited by systemic side effects. The aim of this work was to develop liposomes with surface modifications to include peptides with affinity for cell types present in the post-infarct myocardium. To identify peptides specific for the infarct/border zone, we used in vivo phage display methods and an optical imaging approach: fluorescence molecular tomography (FMT). We identified peptides specific for cardiomyocytes, endothelial cells, myofibroblasts, and c-Kit + cells present in the border zone of the remodeling infarct. These peptides were then conjugated to liposomes and in vivo specificity and pharmacokinetics were determined. As a proof of concept, cardiomyocyte specific (I-1) liposomes were used to deliver a PARP-1 (poly [ADP ribose] polymerase 1) inhibitor: AZ7379. Using a targeted liposomal approach, we were able to increase AZ7379 availability in the infarct/border zone at 24h post injection as compared with free AZ7379. We observed ~3-fold higher efficiency of PARP-1 inhibition when all cell types were assessed using I-1 liposomes as compared with negative control peptide liposomes (NCP). When analyzed further, I 1 liposomes had 9-fold and 1.5-fold higher efficiencies in cardiomyocytes and macrophages, respectively, as compared with NCP liposomes. In conclusion, we have developed a modular drug delivery system that can be targeted to cell types of therapeutic interest in the infarct border zone. PMID- 26122653 TI - Tissue-Specific Methylation of Long Interspersed Nucleotide Element-1 of Homo Sapiens (L1Hs) During Human Embryogenesis and Roles in Neural Tube Defects. AB - Epigenetic regulation of long interspersed nucleotide element-1 (LINE-1) retrotransposition events plays crucial roles during early development. Previously we showed that LINE-1 hypomethylation in neuronal tissues is associated with pathogenesis of neural tube defect (NTD). Herein, we further evaluated LINE-1 Homo sapiens (L1Hs) methylation in tissues derived from three germ layers of stillborn NTD fetuses, to define patterns of tissue specific methylation and site-specific hypomethylation at CpG sites within an L1Hs promoter region. Stable, tissue-specific L1Hs methylation patterns throughout three germ layer lineages of the fetus, placenta, and maternal peripheral blood were observed. Samples from maternal peripheral blood exhibited the highest level of L1Hs methylation (64.95%) and that from placenta showed the lowest (26.82%). Between samples from NTDs and controls, decrease in L1Hs methylation was only significant in NTD-affected brain tissue at 7.35%, especially in females (8.98%). L1Hs hypomethylation in NTDs was also associated with a significant increase in expression level of an L1Hs-encoded transcript in females (r = -0.846, p = 0.004). This could be due to genomic DNA instability and alternation in chromatins accessibility resulted from abnormal L1Hs hypomethylation, as showed in this study with HCT-15 cells treated with methylation inhibitor 5-Aza. PMID- 26122654 TI - TNFR1 Regulates Ovarian Cancer Cell Tumorigenicity Through PIK3CB-p110Beta. AB - Studies have shown that TNFR1 is a key factor in the tumor microenvironment that is dependent on the TNF-alpha-initiated cascade for tumorigenesis. In this present study, we found that TNFR1 is over-expressed in ovarian cancer, which is relevant to both clinical survival and disease free status. Knockdown of TNFR1 dramatically attenuates malignant phenotypes, including proliferation and colony growth in soft agar, as well as glycolysis in ovarian cancer cells. Unexpectedly, knocking down TNFR1 blocks EGF-induced p-AKT and p-p70S6K expression and EGF induced cell transformation through PIK3-p110beta rather than p110alpha expression. Taken together, our data provide evidence that TNFR1 plays a critical role in ovarian cancer and show that the EGF induced signaling pathway is independent of the TNF-alpha triggering cascade signal. Therefore, TNFR1 may serve as a prognostic molecule in ovarian cancer. PMID- 26122655 TI - FoxQ1 is a Novel Molecular Target for Pancreatic Cancer and is Associated with Poor Prognosis. AB - FOXQ1 is an oncogene for a variety of tumors and encodes the forkhead boxrelated transcription factor FoxQ1. However, little is known about the role of FoxQ1 in pancreatic cancer (PC). In this study, we examined FoxQ1 expression in PC cell lines and human PC tissues by quantitative PCR and tissue microarray based immunohistochemical staining (IHC), and investigated the clinical correlation between FoxQ1 tissue levels and the clinicopathological characteristics of PC patients. We found that FoxQ1 mRNA expression was up-regulated both in PC cell lines and tumor tissues. IHC results revealed that FoxQ1 was mainly expressed in the cytoplasm, and to a lesser extent in the nucleus of PC cells. FoxQ1 protein levels were significantly higher in PC tissues when compared with matched non cancerous tissues, and associated positively with the degree of tumor differentiation. Univariate and multivariate survival analysis revealed that patients with high FoxQ1 expression and advanced TNM stage had poor prognosis (HR=1.856, 95%CI 1.065- 3.234, P=0.029; HR=2.091, 95%CI 1.181-3.705, P=0.01). These data indicate that FoxQ1 expression is negatively associated with the overall survival of PC patients, and that this protein may therefore represent a novel molecular target and new prognostic biomarker for PC. PMID- 26122656 TI - Prophylactic Admission of an In Vitro Reconstructed Complexes of Human Recombinant Heat Shock Proteins and Melanoma Antigenic Peptides Activates Anti Melanoma Responses in Mice. AB - Tumor-derived autologous antigenic peptides when bound to endogenous 70 kDa family heat shock proteins (HSP70) are able to induce effective T-cell responses against tumors. However, efficacy of HSPbased vaccines in clinical practical stand point still has a number of certain limitations including an activation of immune responses against alien non-human HSPs. In this study we reconstructed the complexes of human recombinant HSPs70 (human recombinant HSP70A1B and HSC70 mixture; hrHSPs70) with antigenic lowweight peptides derived from mice B16F10 melanoma cell lysate (PepMCL) in vitro and investigated the prophylactic potential of these complexes to activate anti-tumor immunity in melanoma mouse model. Our results demonstrate that the developed prophylactic vaccine elicits melanoma-specific immune responses and anti-tumor effects against melanoma. These results suggest that hrHSPs70 has capability to reconstitute complexes with peptides obtained from tumor cells lysates in vitro and, therefore, can be used for delivery of multiple antigenic peptides into antigen-presenting cells (APCs) to activate effectors cells. Designed in such a way hrHSPs70-based prophylactic vaccines induce immune responses resulting in a significant efficient prevention of tumor growth and metastases. PMID- 26122657 TI - Arraying Autoantibodies in SLE - Lessons Learned. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune connective tissue disease characterized by the production of a large number of autoantibodies, but the etiology is complex and poorly understood. A range of different platforms have served as screening methods for the determination of autoantibody specificities over the past few decades. Proteomic microarray is a relatively new high-throughput technology which is playing an increasingly important role in autoantibody diagnostics. In this article, we review different platforms for assaying autoantibodies in SLE, and highlight the use of autoantigen arrays as powerful tools for autoantibody exploration in SLE. PMID- 26122658 TI - Current Evidence and Potential Mechanisms of Therapeutic Action of PEDF in Cervical Cancer Treatment. AB - Cervical cancer is the second leading gynecological malignancy threat to the health of women in the world. However, few improvements in the efficacy of treatments of cervical cancer have been reported for the recurrent and metastasis patterns. As an endogenous antitumor agent, pigment epithelium derived factor (PEDF) has attracted wide attention, and its sensitivity to estrogen suggests a special role in female tumors, including cervical cancer. This review aims to summarize recent findings, the role of PEDF in cervical cancer treatment, and enhance the current understanding of the antitumor properties of PEDF such as inhibiting angiogenesis and metastasis, inducing tumor cell apoptosis and differentiation, and modulating cellular immunity against cervical cancer. The production and delivery of PEDF, as well as derived short peptides and their respective receptors will also be discussed. PMID- 26122659 TI - Taming Influenza Virus: Role of Antisense Technology. AB - Human Influenza A virus (IAV), a relatively newer threat to mankind, is becoming invincible due to non availability of proper antiviral drug or effective long lasting vaccine against it. All existing measures to control this virus are overpowered by the phenomena of genetic shift and drift shown by Influenza A virus (IAV). Throughout the world, researchers are exploring the therapeutic potential of antisense technology (AST) to fight against this genetically variable virus. Antisense technology refers to the laboratory manipulation and/or modification of DNA or RNA so that its components (nucleotides) hybridize with target nucleic acid or mRNA or protein itself to inhibit the protein finally encoded. RNA inhibitory (RNAi) mechanism (particularly siRNA) seems to be the most promising among the different agents of AST. However, other agents like oligonucleotides, ribozymes and DNAzymes also show great potential. Decoys and aptamers, alone or in conjunction with other agents, are also being explored to inhibit the replication of virus. Presently, most of these agents have passed initial level of in vitro and in vivo experiments, passing through various levels of clinical trials but none of them has been approved for human purpose till date. Present review consolidates the efforts of researchers worldwide in this particular field and discusses the future perspectives this technology holds, to tame this notorious virus. Day by day, various areas of this technology are being explored and the day is not far when this chemical entity will reach from "bench to bedside". PMID- 26122660 TI - The American Society of Clinical Oncology 51st Annual Meeting 2015: An overview and summary of selected abstracts. PMID- 26122661 TI - Therapeutic antiviral T cells noncytopathically clear persistently infected microglia after conversion into antigen-presenting cells. AB - Several viruses can infect the mammalian nervous system and induce neurological dysfunction. Adoptive immunotherapy is an approach that involves administration of antiviral T cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus (CMV), Epstein Barr virus (EBV), and adenovirus, among others. In contrast, clearance of neurotropic infections is particularly challenging because the central nervous system (CNS) is relatively intolerant of immunopathological reactions. Therefore, it is essential to develop and mechanistically understand therapies that noncytopathically eradicate pathogens from the CNS. Here, we used mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) to demonstrate that therapeutic antiviral T cells can completely purge the persistently infected brain without causing blood-brain barrier breakdown or tissue damage. Mechanistically, this is accomplished through a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T cells enlisted the support of nearly all brain-resident myeloid cells (microglia) by inducing proliferation and converting them into CD11c(+) antigen-presenting cells (APCs). Two-photon imaging experiments revealed that antiviral CD8(+) and CD4(+) T cells interacted directly with CD11c(+) microglia and induced STAT1 signaling but did not initiate programmed cell death. We propose that noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T cells reliant on restricted chemoattractant production and interactions with apoptosis-resistant microglia. PMID- 26122662 TI - Nuclear factor kappaB-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity. AB - The nuclear factor kappaB (NF-kappaB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. Whereas canonical NF-kappaB signaling is well studied, there is little information on the divergent noncanonical NF-kappaB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF kappaB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of beta cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-kappaB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-kappaB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-kappaB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. PMID- 26122663 TI - Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling beta-catenin signaling in cancer-initiating cells. AB - Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear beta-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of beta-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-beta-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis. PMID- 26122664 TI - Extrapolation of acenocoumarol pharmacogenetic algorithms. AB - INTRODUCTION: Acenocoumarol (ACN) has a narrow therapeutic range that is especially difficult to control at the start of its administration. Various dosing pharmacogenetic-guided dosing algorithms have been developed, but further work on their external validation is required. The aim of this study was to evaluate the extrapolation of pharmacogenetic algorithms for ACN as an alternative to the development of a specific algorithm for a given population. MATERIAL AND METHODS: The predictive performance, deviation, accuracy, and clinical significance of five pharmacogenetic algorithms (EU-PACT, Borobia, Rathore, Markatos, Krishna Kumar) were compared in 189 stable ACN patients representing all indications for anticoagulant treatment. RESULTS: The correlation between the dose predictions of the five pharmacogenetic models ranged from 7.7 to 70.6% and the percentage of patients with a correct prediction (deviation <=20% from actual ACN dose) ranged from 5.9 to 40.7%. EU-PACT and Borobia pharmacogenetic dosing algorithms were the most accurate in our setting and evidenced the best clinical performance. CONCLUSIONS: Among the five models studied, the EU-PACT and Borobia pharmacogenetic dosing algorithms demonstrated the best potential for extrapolation. PMID- 26122665 TI - Multiple functions of Maf in the regulation of cellular development and differentiation. AB - Cellular muscular aponeurotic fibrosarcoma (c-Maf) is a member of the large macrophage-activating factor family. C-Maf plays important roles in the morphogenetic processes and cellular differentiation of the lens, kidneys, liver, T cells and nervous system, and it is particularly important in pancreatic islet and erythroblastic island formation. However, the exact role of c-Maf remains to be elucidated. In this review, we summarize the research to clarify the functions of c-Maf in the cellular development and differentiation. The expression of c-Maf is higher in pancreatic duct cells than in pancreatic islet cells. Therefore, we suggest that pancreatic duct cells may be converted to the functional insulin secreting cells by regulating c-Maf. PMID- 26122666 TI - A suspected genetic form of bilateral osteochondritis dissecans of the knee in a Dutch family. AB - Osteochondritis dissecans (OCD) mostly has an idiopathic origin, but syndromic and familial forms have been reported. Mutations of the aggrecan (ACAN) and COL9A2 genes are associated with familial OCD, but these patients present with syndromic features. This article describes a mother and a daughter who both have bilateral OCD of the medial femoral condyles, and the monozygotic twin sister of the mother who has confirmed unilateral OCD (and possible bilateral OCD) of the medial femoral condyle. No short stature or any other syndromic features were present. None of the syndromic features associated with ACAN or COL9A2 mutations or any other known syndromes were present in this case. This case suggests a possible unknown genetic anomaly. PMID- 26122667 TI - Case series: Revision anterior cruciate ligament reconstructions using patellar tendon autografts. AB - BACKGROUND: Using intra-operative findings and clinical results, including return to play (RTP) at the pre-injury level, this study investigated the causes of primary graft failure after revision anterior cruciate ligament (ACL) reconstruction with bone-patellar-tendon-bone (BPTB) autografts. METHODS: A total of 54 patients were followed for a mean of 38.2 +/- 10.2 months post-surgery. Subjective and objective results were evaluated using single assessment numeric evaluation (SANE) scores, Lachman tests, KT-2000 arthrometer results, and pivot shift tests. The change in each patient's Tegner activity scale and RTP at the pre-injury level were also evaluated. RESULTS: Inappropriate positioning of the tunnels was the most important reason (54%) for primary graft failure. After revision surgery, anterior knee stability was significantly improved (1.2 (mean) +/- 1.2 (SD)mm vs 4.5(mean) +/- 1.9 (SD)mm; P < 0.01). Two (4%) patients sustained revision graft ruptures while two (4%) sustained contralateral knee ACL tears. The rate of RTP at the pre-injury level was 67% (36 patients), and mean SANE scores at the time of RTP were higher than before surgery (74.8 +/- 13.8 points vs 24.1 +/- 16.4; P<0.001). The average time from primary graft failure to revision surgery was shorter (12.2 (mean) +/- 4.0 (SD) vs 37.6 (mean) +/- 8.8 (SD)months; P < 0.01) and the ratio of major cartilage injury was lower (39% vs 83%; P < 0.05) in the RTP group than that in the non-RTP group. CONCLUSIONS: The time from primary graft failure to revision surgery and the extent of the cartilage injury are major factors in RTP after revision ACL reconstructions. PMID- 26122668 TI - Clinical and functional outcome after anterior cruciate ligament reconstruction using the LARSTM system at a minimum follow-up of 10 years. AB - BACKGROUND: Since the 1980's several artificial ligaments were used for reconstruction of the anterior cruciate ligament (ACL) serving different complications. The aim of this study was to assess the clinical and functional outcomes of primary ACL reconstruction using the Ligament Augmentation Reconstruction System (LARSTM) with a minimum follow-up of 10-years. The LARSTM presents a synthetic material consisting of non-absorbing polyethylene terephthalate fibres used for ligament reconstruction. METHODS: Outcomes of 18 patients who underwent arthroscopic ACL reconstruction using the LARSTM system between 2000 and 2004 with a minimum follow-up of 10 years were observed. The International Knee Documentation Committee score (IKDC), Visual Analog Scale (VAS), Lysholm score, and Tegner Activity Scale were assessed. Clinical assessment was performed by Lachman testing, assessment of side-to-side difference on KT-2000 testing and plain radiography evaluation of osteoarthritis. RESULTS: There were seven males and 11 females, mean age 29 years (range, 18 to 44 years) and a mean follow-up of 151.5 months. Five patients (27.8%) sustained a re-rupture of the LARSTM system and underwent revision surgery after a mean time of 23 months and four patients (22.2%) presented with a re-rupture. The average IKDC score was 76.60 +/- 18.18, the average Lysholm score was 88.00 +/- 10.07 and the average Tegner activity score was five at final follow-up. CONCLUSION: Our results indicate that the LARSTM system should currently not be suggested as a potential graft for primary reconstruction of the ACL. In special cases, however, the LARSTM system can serve as an alternative graft. PMID- 26122669 TI - Protective effect of advanced age on post-ERCP pancreatitis and unplanned hospitalisation. AB - BACKGROUND: As the median age of Australia's population rises, endoscopic retrograde cholangiopancreatography (ERCP) is becoming increasingly used in the elderly. However, ERCP remains associated with serious complications including post-ERCP pancreatitis (PEP), which often necessitate unplanned hospital admission. Although previous research has demonstrated a protective effect of age against PEP, inconsistencies have arisen in recent studies. In addition to age, post-ERCP complication rates have been previously shown to be affected by various factors including longer procedure duration and high-risk indications. AIM: The aim of this study was to investigate the rates of PEP and unplanned hospital admission or prolongation of hospital stay (UHAP) across age groups and their relation to procedure duration and indication. METHODS: Prospective analysis of 1284 consecutive ERCP on patients aged 20-101 years performed at a tertiary referral centre. RESULTS: Advanced age (>80 years) was associated with a significantly lower risk of both PEP (P = 0.02) and UHAP (P < 0.05) compared with patients aged 50-79 years. Rates of PEP and UHAP differed significantly according to indication (P < 0.01) and longer procedure duration similarly increased the risk of both complications (P < 0.01). However, there were no significant differences between age groups in terms of the proportion of patients with 'high risk' indications. Importantly, age remained a significant negative predictor of PEP even after adjusting for procedure duration (P = 0.04). CONCLUSIONS: The protective effect of age against PEP and UHAP is not due to confounding by high risk indications or increased procedure duration. ERCP may be a relatively safe option for our growing cohort of elderly patients. PMID- 26122670 TI - Topical application of Acheflan on rat skin injury accelerates wound healing: a histopathological, immunohistochemical and biochemical study. AB - BACKGROUND: Dermal wound healing involves a cascade of complex events including angiogenesis and extracellular matrix remodeling. Several groups have focused in the study of the skin wound healing activity of natural products. The phytomedicine Acheflan(r), and its main active constituent is the oil from Cordia verbenacea which has known anti-inflammatory, analgesic and antimicrobial activities. To our knowledge, no investigation has evaluated the effect of Acheflan(r) in an experimental model of skin wound healing. The present study has explored the wound healing property of Acheflan(r) and has compared it with topical effectiveness of collagenase and fibrinolysin by using Wistar rat cutaneous excision wound model. METHODS: Animals were divided into four groups: untreated animals are negative control (NC), wounds were treated topically every day with Collagenase ointment (TC), with Fibrinolysin ointment (TF) and with cream Acheflan (TAc). Skin samples were collected on zero, 8th and 15th days after wounding. The healing was assessed by hematoxylin-eosin (HE), picrosirius red, hydoxyproline content and immunohistochemical analysis of the vascular endothelial growth factor (VEGF) and matrix metalloprotease-9 (MMP-9). Statistical analysis was done by ANOVA and Student t-test (p < 0.05). RESULTS: The histological analysis HE of wound in the TAc group was more efficient because it was possible to observe the complete remodeling of the epidermis indicating the regression of lesions compared with the NC. The evaluation of picrosirius staining has demonstrated a significant increase of collagen distribution in the TC and TAc treatments compared with NC and TF groups. These results are corroborated with hydroxyproline content. Skin TC and TAc treated rats have showed an increase of VEGF and MMP-9 compared with NC and TF groups. All parameters were significant (P < 0.05). CONCLUSION: The phytomedicine Acheflan(r) (oil of Cordia verbenacea) and TC possess higher therapeutic properties for wound healing compared with TF. These ointments seem to accelerate wound healing, probably due to their involvement with the increase of angiogenesis and dermal remodeling. PMID- 26122673 TI - Near-infrared-responsive gold nanorod/liquid crystalline elastomer composites prepared by sequential thiol-click chemistry. AB - A novel NIR-responsive GNR/LCE composite fiber material was prepared by a three step sequential thiol-click chemistry approach. Taking advantage of GNRs' significant photo-thermal effect, a GNR/LCE composite material with a very low Au loading-level (0.09 wt%), under 808 nm NIR stimulus achieved the N-to-I transition and shrank dramatically in an ambient environment. PMID- 26122671 TI - Excessive daytime sleepiness in patients with ADHD--diagnostic and management strategies. AB - The links between attention-deficit hyperactivity disorder (ADHD) and sleep disorders remain unclear. Specific sleep disorders are a frequent comorbid condition associated with ADHD according to a categorical approach. However, sleep disorders can also induce ADHD-like symptoms according to a dimensional approach and are thought to be the consequence of excessive daytime sleepiness. It may thus be difficult for clinicians to differentiate the diagnosis of ADHD comorbid with a sleep disorder from sleep disorders with ADHD-like symptoms. This distinction could be important for the appropriate management of patients with dual complaints of trouble maintaining attention and daytime sleepiness. This paper summarizes the main sleep disorders associated with ADHD: sleep-related breathing disorders, sleep-related movement disorders, circadian rhythm sleep wake disorders, and central disorders of hypersomnolence (aka hypersomnias). The history of presenting symptoms should be taken into account since ADHD is a neurodevelopmental disorder whereas ADHD symptoms comorbid with sleep disorder are not. Finally, we propose a model to clarify the links between ADHD, ADHD symptoms, and excessive daytime sleepiness induced by sleep disorders. Clinicians should therefore routinely assess, monitor, and manage the sleep problems of patients with ADHD who have both comorbidities and should search for the presence of ADHD symptoms in subjects with sleep disorders. PMID- 26122674 TI - The emergence of plasmid mediated quinolone resistance qnrA2 in extended spectrum beta-lactamase producing Klebsiella pneumoniae in the Middle East. AB - BACKGROUND: Klebsiella pneumoniae is one of the most important opportunistic pathogens causing serious complications in patients in hospitals and community. The clinical significance of K. pneumoniae is mainly due to its ability to acquire multiple antibiotic resistance genes. In this study we report the findings of a survey of plasmid mediated quinolone resistance in Extended Spectrum beta-lactamase (ESBL)-producing K. pneumoniae in Kuwait. METHODS: Clinical samples were collected from the microbiology laboratories of three major hospitals. Isolates were confirmed as ESBL-producers by disc diffusion method and PCR for the presence of bla genes. Antimicrobial susceptibility testing and genetic analysis were performed to detect the presence of a number of genes conferring resistance to beta-lactam and fluoroquinolone antimicrobial agents including bla SHV, bla TEM, aac (6')-Ib-cr, qnrA, qnrB and qnrS. Pulsed-field gel electrophoresis (PFGE) was used for typing the isolates. RESULTS: In total 173 ESBL-producing K. pneumoniae were detected. qnr genes were identified in 27 (15.6 %) isolates and aac(6')-Ib Ib-cr gene in 26 (96 %). One (3.7 %) contained qnrA2, 21 harbored qnrB1 (78 %) and 5 (18.5 %) contained qnrS. Twenty one (78 %) isolates contained all three bla genes. PFGE showed diverse profiles. CONCLUSION: We identified for the first time the emergence of the mobile fluoroquinolone resistance qnrA2 in a clinical isolate in the middle east and also showed the dissemination of aac (6')-Ib-cr, qnrB, and qnrS genes among ESBL-producing K. pneumoniae in Kuwait. The abundance of plasmid mediated resistance to fluoroquinolones among ESBL-producing K. pneumoniae is alarming as it facilitates therapy failure. Preventing the spread of these isolates is crucial if we are to sustain the effectiveness of the limited choices we have left in antimicrobial therapy. PMID- 26122675 TI - Evolving epidemiology of Nipah virus infection in Bangladesh: evidence from outbreaks during 2010-2011. AB - Drinking raw date palm sap is the primary route of Nipah virus (NiV) transmission from bats to people in Bangladesh; subsequent person-to-person transmission is common. During December 2010 to March 2011, we investigated NiV epidemiology by interviewing cases using structured questionnaires, in-depth interviews, and group discussions to collect clinical and exposure histories. We conducted a case control study to identify risk factors for transmission. We identified 43 cases; 23 were laboratory-confirmed and 20 probable. Thirty-eight (88%) cases died. Drinking raw date palm sap and contact with an infected person were major risk factors; one healthcare worker was infected and for another case transmission apparently occurred through contact with a corpse. In absence of these risk factors, apparent routes of transmission included drinking fermented date palm sap. For the first time, a case was detected in eastern Bangladesh. Identification of new epidemiological characteristics emphasizes the importance of continued NiV surveillance and case investigation. PMID- 26122676 TI - Telehealth and Occupational Therapy: Integral to the Triple Aim of Health Care Reform. AB - Programs and concepts included in the Patient Protection and Affordable Care Act of 2010 are expected to transform health care in the United States from a volume based health system to a value-based health system with increased emphasis on prevention and health promotion. The Triple Aim, a framework set forth by the Institute for Healthcare Improvement, focuses on improving the health care experience, the health of populations, and the affordability of care. This article describes telehealth as an integral component in achieving the Triple Aim of health care and discusses implications for occupational therapy practitioners. PMID- 26122677 TI - Results of a School-Based Evidence-Based Practice Initiative. AB - OBJECTIVE: To investigate the effects of a 17-mo initiative designed to increase practitioners' knowledge and skills related to evidence-based practice (EBP) in the schools. METHOD: We evaluated participants' EBP knowledge and skills at pretest and posttest using the Adapted Fresno Test (AFT) and collected their perceptions through a survey. RESULTS: Participants demonstrated significant improvements in their EBP knowledge and skills after participating in this initiative as measured by changes in AFT scores. A significant difference was noted in scores between pretest (MU=43.9, SD=32.67) and posttest (MU=74.66, SD=33.99), t(28)=-5.645, p<.001. CONCLUSION: This initiative was influential in increasing school-based practitioners' EBP knowledge and skills. PMID- 26122678 TI - Effects of Stability Balls on Children's On-Task Behavior, Academic Achievement, and Discipline Referrals: A Randomized Controlled Trial. AB - OBJECTIVE: We used a randomized controlled design to investigate whether using stability balls during the school day was associated with higher levels of on task behavior and academic achievement and fewer discipline referrals. METHOD: Over 9 mo, students in 2 second-grade classrooms in a southeastern rural elementary school used stability balls as chairs while students in 2 control classrooms used chairs as usual. We collected measures of on-task behavior, standardized measures of literacy and mathematics achievement, and discipline referrals. RESULTS: We found similar levels of on-task behavior and achievement in treatment and control classrooms and a downward trend in disruptive behaviors in treatment classrooms. CONCLUSION: This study did not find use of stability balls for entire general education classrooms to be a practical use of resources for schools. More research with rigorous controlled designs is needed to support the use of stability balls for the general education population. PMID- 26122679 TI - Comprehensive Social Skills Taxonomy: Development and Application. AB - OBJECTIVE: We developed a comprehensive social skills taxonomy based on archived children's social skill goal sheets, and we applied the taxonomy to 6,897 goals of children in 6 diagnostic categories to explore patterns related to diagnosis. METHOD: We used a grounded theory approach to code and analyze social skill goals and develop the taxonomy. Multivariate analysis of variance and Tukey post hoc honestly significant difference test were used to analyze differences in social skill needs among diagnostic groups. RESULTS: We developed a taxonomy of 7 social skill constructs or categories, descriptions, and behavioral indicators. The 7 social skill categories were reflected across 6 diagnostic groups, and differences in social skill needs among groups were identified. CONCLUSION: This comprehensive taxonomy of social skills can be useful in developing research based individual, group, or institutional programming to improve social skills. PMID- 26122680 TI - Longitudinal Study of Occupational Therapy Students' Beliefs About Knowledge and Knowing. AB - Research has demonstrated the importance of beliefs about knowledge and knowing, or epistemic and ontological cognition (EOC), to learning and achievement; however, little research has examined occupational therapy students' EOC or determined whether occupational therapy programs promote its development. This study examined changes in EOC over 18 mo of didactic coursework in an occupational therapy program. Thirty-one students completed the Epistemic Beliefs Inventory at the beginning, middle, and end of 18 mo of didactic coursework. Results indicated no difference in ontological cognition. However, change occurred in epistemic cognition, with students demonstrating statistically significantly weaker beliefs in justification of knowledge by an omniscient authority by the end of the didactic portion of the program. Although causal inferences cannot be made from this small study of one cohort of occupational therapy students, it is possible that intensive study in the discipline of occupational therapy contributed to change in these students' epistemic cognition. PMID- 26122681 TI - Reduced Physical Fitness in Patients With Heart Failure as a Possible Risk Factor for Impaired Driving Performance. AB - OBJECTIVE: Reduced physical fitness secondary to heart failure (HF) may contribute to poor driving; reduced physical fitness is a known correlate of cognitive impairment and has been associated with decreased independence in driving. No study has examined the associations among physical fitness, cognition, and driving performance in people with HF. METHOD: Eighteen people with HF completed a physical fitness assessment, a cognitive test battery, and a validated driving simulator scenario. RESULTS: Partial correlations showed that poorer physical fitness was correlated with more collisions and stop signs missed and lower scores on a composite score of attention, executive function, and psychomotor speed. Cognitive dysfunction predicted reduced driving simulation performance. CONCLUSION: Reduced physical fitness in participants with HF was associated with worse simulated driving, possibly because of cognitive dysfunction. Larger studies using on-road testing are needed to confirm our findings and identify clinical interventions to maximize safe driving. PMID- 26122682 TI - Factors That Moderate Activity Limitation and Participation Restriction in People With Multiple Sclerosis. AB - We examined the variables most associated with activity limitation (i.e., cooking) and participation restriction (i.e., employment) in 72 people with multiple sclerosis (MS). Participants underwent a comprehensive neuropsychological test battery assessing memory, executive functions, visual perception, and processing speed and completed questionnaires assessing activity, participation, fatigue, and affective symptoms. Results showed that processing speed was the only variable consistently significantly related to both activity and participation. When examining specific aspects of activity and participation in isolation, employment status was significantly associated with education level, visual memory, fatigue, and processing speed. Cooking ability was associated with performance on tasks of working memory, verbal memory, and processing speed. These findings suggest that processing speed is a primary cognitive factor in MS influencing quality of both activity and participation in everyday life. PMID- 26122683 TI - "Don't Think Paralysis Takes Away Your Womanhood": Sexual Intimacy After Spinal Cord Injury. AB - Sexuality and intimacy are important components of health and well-being. Issues surrounding sexuality and intimacy are equally important for men and women living with physical disabilities, including spinal cord injury (SCI). Yet, women's sexuality after SCI remains largely unexamined. This article presents the findings from an in-depth qualitative investigation of the sexual and reproductive health experiences of 20 women with SCI in or around Detroit, MI. Findings echo existing literature documenting the sexual consequences of life after SCI and suggest new areas of inquiry important for better addressing sexual concerns across the lifespan. Specifically, findings suggest a need to consider the variable effects of SCI on sexual intimacy in relation to a person's developmental trajectory, the appropriate timing of sexual education, the need to expand conceptualizations of sexual intimacy, and the ways SCI may affect sexuality in later life. PMID- 26122684 TI - Effectiveness of a Clinical Decision Support System for Pointing Device Prescription. AB - OBJECTIVE: We present a novel, knowledge-driven approach to prescription of pointing devices that uses the Ontology-Supported Computerized Assistive Technology Recommender (OSCAR), a clinical decision support system (CDSS). METHOD: Fifty-five occupational therapists were divided into four groups: two assistive technology (AT) expert groups and two novice groups. Novice Group 1 used the OSCAR CDSS for the prescription process, and Novice Group 2 used the conventional method. OSCAR's effectiveness and its impact on users were evaluated. RESULTS: The ability of Novice Group 1 to make suitable pointing device prescriptions was similar to that of the two expert groups and was significantly better than that of Novice Group 2. The system positively affected Novice Group 1's learning of the prescription process. CONCLUSION: The structure and organized framework for clinical reasoning of the OSCAR CDSS appear to enable occupational therapy practitioners inexperienced in AT to achieve performance levels comparable to those of experts. PMID- 26122685 TI - Patients With Brain Tumors: Who Receives Postacute Occupational Therapy Services? AB - Data on the utilization of occupational therapy among patients with brain tumors have been limited to those with malignant tumors and small samples of patients outside North America in specialized palliative care settings. We built on this research by examining the characteristics of patients with brain tumors who received postacute occupational therapy services in Ontario, Canada, using health care administrative data. Between fiscal years 2004-2005 and 2008-2009, 3,199 patients with brain tumors received occupational therapy services in the home care setting after hospital discharge; 12.4% had benign brain tumors, 78.2% had malignant brain tumors, and 9.4% had unspecified brain tumors. However, patients with benign brain tumors were older (mean age=63.3 yr), and a higher percentage were female (65.2%). More than 90% of patients received in-home occupational therapy services. Additional research is needed to examine the significance of these differences and to identify factors that influence access to occupational therapy services in the home care setting. PMID- 26122687 TI - Clinical Reasoning Guideline for Home Modification Interventions. AB - OBJECTIVE: The objective of this study was to develop and validate a clinical reasoning tool to describe an occupational therapist's clinical reasoning process while delivering home modification interventions. METHOD: We used a two-phase, mixed-methods approach. In Phase 1, we developed a personal factors guideline to support clinical reasoning in home modification interventions based on in-depth interviews, a focus group, and field observations of 6 home modification experts. In Phase 2, the guideline was validated by a second group of 6 home modification experts. RESULTS: During analysis, 16 personal and environmental factors with a corresponding set of conditions and strategies for each factor emerged to form a clinical reasoning guideline, which was validated by a second group of experts. CONCLUSION: Unpacking the "black box" of the clinical reasoning process has yielded a useful clinical reasoning tool that will allow occupational therapists to deliver complex interventions with fidelity. PMID- 26122686 TI - Improving Quality of Life and Depression After Stroke Through Telerehabilitation. AB - OBJECTIVE: The aim of this study was to determine the effects of home-based robot assisted rehabilitation coupled with a home exercise program compared with a home exercise program alone on depression and quality of life in people after stroke. METHOD: A multisite randomized controlled clinical trial was completed with 99 people<6 mo after stroke who had limited access to formal therapy. Participants were randomized into one of two groups, (1) a home exercise program or (2) a robot-assisted therapy+home exercise program, and participated in an 8-wk home intervention. RESULTS: We observed statistically significant changes in all but one domain on the Stroke Impact Scale and the Center for Epidemiologic Studies Depression Scale for both groups. CONCLUSION: A robot-assisted intervention coupled with a home exercise program and a home exercise program alone administered using a telerehabilitation model may be valuable approaches to improving quality of life and depression in people after stroke. PMID- 26122688 TI - Taking Control: An Exploratory Study of the Use of Tilt-in-Space Wheelchairs in Residential Care. AB - Tilt-in-space (TIS) wheelchairs are common in residential care, but little empirical evidence exists regarding how they are used by residents and staff in these settings. As part of a larger study exploring the use of wheeled mobility in these facilities, we conducted a substudy to examine how TIS wheelchairs are used in practice and to explore the experiences of the residents who use them. We conducted a series of three participant observations and interviews with 6 residents or their family members and interviewed 10 staff. Our analysis identified taking control as the main overarching theme, subsuming two subthemes: promoting comfort and mobilizing to participate. Findings suggest that power TIS wheelchairs enable user control, whereas manual TIS wheelchairs promote staff control. These findings illustrate how TIS wheelchairs may enable or inhibit occupational engagement and suggest that vigilance is necessary to prevent their use as a restraint. PMID- 26122689 TI - Effectiveness of Use of Button-Operated Electronic Devices Among Persons With Balint Syndrome. AB - OBJECTIVE: Little is known about how visuospatial deficits affect the use of electronic devices operated by pressing spatially interspersed buttons. This study aimed to determine whether people with Balint syndrome can effectively use such devices. METHOD: We quantified the ability of 7 study participants with Balint syndrome to use button-operated electronic devices by measuring the time required to input digit sequences into three different types of devices. Control groups were 8 participants with amnesia and 8 healthy participants. RESULTS: Participants with Balint syndrome took longer to input a digit sequence on all three devices than did those in the two control groups. Although we found no significant differences with respect to type of device, 2 of 3 participants with severe Balint syndrome were able to input one- to five-digit sequences with the electronic calculator. CONCLUSION: Distinctive design features might positively affect the performance of people with Balint syndrome. PMID- 26122690 TI - Test-Retest Reliability of the Child Occupational Self-Assessment (COSA). AB - We examined the test-retest reliability of the Child Occupational Self-Assessment (COSA). Fifty-two children ages 6-12 yr completed the COSA on two separate occasions 7-14 days apart. Participant data were analyzed using intraclass correlation coefficients (ICCs). Test-retest reliability was good for total Competence and Value scores (ICC2,1=.72-.77) and poor to good across category scores (ICC2,1=.44-.78). These findings suggest that the children's perceptions of their abilities and the value they placed on their everyday activities as reflected in the test items were fairly consistent over a short period of time. PMID- 26122691 TI - Interrater Reliability of the Record of Driving Errors (RODE). AB - The Record of Driving Errors (RODE) is a novel standardized tool designed to quantitatively document the specific types of driving errors that occur during a standardized performance-based road test. The purpose of this study was to determine interrater reliability between two occupational therapy driver rehabilitation specialists who quantitatively scored specific driving errors using the RODE in a sample of older adults diagnosed with dementia (n=24). Intraclass correlation coefficients of major driving error and intervention categories indicated almost perfect agreement between raters. Using raters with adequate training and similar professional backgrounds, it is possible to have good interrater reliability using the RODE on a standardized road test. PMID- 26122692 TI - Transition Needs of Adolescents With Sickle Cell Disease. AB - OBJECTIVE: This article describes how adolescents with sickle cell disease (SCD) perceive their ability to perform everyday tasks required for transition to adult health care and independent living. METHOD: The Adolescent Autonomy Checklist (AAC) was adapted to include skills associated with managing SCD (AAC-SCD) and was administered to adolescents during clinic visits. Participants indicated "can do already" or "needs practice" for 100 activities in 12 categories. RESULTS: Of 122 patients, the percentage of adolescents who needed practice was greatest in living arrangements (38.7%), money management (35.8%), vocational skills (29.6%), and health care skills (25.5%). We found a significant effect of age and of cerebrovascular injury on the percentage of those who reported "needs practice" in multiple categories. We found no effect of gender and limited effect of hemoglobin phenotype on any skill category. CONCLUSION: Findings support the need for educational intervention to improve transition skills in adolescents with SCD. PMID- 26122693 TI - Creating Evidence for Practice Using Data-Driven Decision Making. AB - To realize the American Occupational Therapy Association's Centennial Vision, occupational therapy practitioners must embrace practices that are not only evidence based but also systematic, theoretically grounded, and driven by data related to outcomes. This article presents a framework, the Data-Driven Decision Making (DDDM) process, to guide clinicians' occupational therapy practice using systematic clinical reasoning with a focus on data. Examples are provided of DDDM in pediatrics and adult rehabilitation to guide practitioners in using data driven practices to create evidence for occupational therapy. PMID- 26122695 TI - Disseminated Mycobacterium chelonae Infection Identified by Repeated Skin Sampling and Molecular Methods in a Patient with Rheumatoid Arthritis. PMID- 26122697 TI - Current drugs in early development for treating hepatitis C virus-related hepatic fibrosis. AB - INTRODUCTION: More than 100 million people worldwide are infected with hepatitis C virus (HCV), which is responsible for chronic liver disease accompanied by progressive fibrosis of hepatic tissue, often leading to liver cirrhosis. Novel therapeutic options are able to clear the virus in almost all diagnosed patients. However, even after successful treatment, hepatic fibrosis may persist in many of them. There is no registered therapy specific for liver fibrosis, but numerous molecules are currently in development. AREAS COVERED: In this review, the authors look at drugs in early development for the treatment of HCV-related hepatic fibrosis. Their mechanism of action is based on the inhibition of hepatic inflammation, the modulation of cellular sources of extracellular matrix (ECM), the stimulation of ECM degradation and prevention of collagen crosslinking. Importantly, significant antifibrotic effects have been demonstrated with both IFN-based and IFN-free anti-HCV regimens. EXPERT OPINION: Successful future therapy is likely to be based on sequential administration of drugs leading initially to HCV clearance, followed by treatment for the possible reversal of liver fibrosis. The primary consideration with clinical trials carried out in patients with advanced liver disease is safety. Indeed, the evaluation of anti fibrotic therapy depends on reliable noninvasive techniques for quantification of liver fibrosis, such as transient or shear-wave elastography or serologic tests which are able to replace liver biopsy. PMID- 26122696 TI - Plasticity of the developmentally arrested staggerer cerebellum in response to exogenous RORalpha. AB - Retinoid-related orphan receptor alpha (RORalpha) is a critical master transcription factor that governs postnatal cerebellar development. An RORalpha deficient cerebellum has a persistent external granular layer (EGL), rudimentary Purkinje cell (PC) dendrites, grossly reduced numbers of immature parallel fiber (PF)-PC synapses, and multiple climbing fibers (CF) innervating PCs in mice after 3 weeks of age when these features have disappeared in wild-type mice. Functionally, metabotropic glutamate receptor (mGluR)-mediated signaling in PCs is completely abrogated. Here we examined whether these defects could be corrected by lentivirally providing the RORalpha gene to 3-week-old PCs of RORalpha-deficient homozygous staggerer (sg/sg) mice. RORalpha expression in sg/sg PCs significantly increased the numbers of PF-PC synapses, spines on PC dendritic branchlets, and internal granule cells, concomitant with regression of the EGL, suggesting enhanced proliferation in the EGL and migration of post mitotic progeny into the internal granular layer with augmented synaptogenesis between PFs and PC dendrites. However, the primary dendritic stems were only slightly extended, and mGluR signaling and the loss of redundant CF synapses in sg/sg PCs remained unrestored. These results suggest that the mitogenic and migratory potential of external granule cells in response to RORalpha was preserved in the >3-week-old sg/sg mouse cerebellum. Moreover, sg/sg PCs sprouted spines and formed synapses with PFs. However, lengthening of the primary dendritic stems, establishment of mGluR signaling, and removal of CF synapses in sg/sg PCs were regressed by 3 weeks of age. PMID- 26122698 TI - Hexacyclic lactam building blocks for highly efficient polymer solar cells. AB - Two hexacyclic lactam building blocks, TD1 and TD2, and four D-A copolymers have been developed. Compared with thiophene copolymers, selenophene analogues PSeTD1 and PSeTD2 possess medium optical bandgaps, better packing, higher hole mobilities, enhanced EQE, and higher J(sc). Inverted PSeTD2:PC71BM solar cells exhibited a decent PCE of 8.18%, which is a record for D-A copolymers using selenophene as the donor unit. PMID- 26122699 TI - Aortic and Mitral Calcification Is Marker of Significant Carotid and Limb Atherosclerosis in Patients with First Acute Coronary Syndrome. AB - PURPOSE: Atherosclerosis is a systemic disease and coronary artery disease is frequently associated with peripheral artery disease. As aortic and mitral valvular calcification (VC) share some etiopathogenetic mechanisms with atherosclerosis, we analyzed the risk profile and the echocardiographic characteristics of patients admitted for first acute coronary syndrome (ACS) to investigate whether the presence of VC could be a marker of asymptomatic hemodynamically significant peripheral atherosclerosis. METHODS: A total of 151 patients admitted for ACS without previous history of cardiovascular disease were consecutively enrolled. The presence of VC was identified by echocardiography; a carotid stenosis >=50% by ultrasound identified carotid artery disease (CarAD); an ankle-brachial index <=0.9 or >=1.4 identified lower extremity artery disease (LEAD). Significant peripheral atherosclerosis was defined by the presence of CarAD and/or LEAD. RESULTS: Peripheral atherosclerosis was diagnosed in 82 (54.3%) patients; isolated CarAD in 24, isolated LEAD in 20, both diseases in 38 patients. VC was present in 103 (68.2%) patients. By multivariate analysis, age (OR = 1.059, 95% CI 1.007-1.113, P = 0.025), diabetes mellitus (OR = 5.068, 95% CI 1.480-17.351, P = 0.010), VC (OR = 7.422, 95% CI 2.421-22.880, P < 0.001), and multivessel CAD (OR = 3.317, 95% CI 1.281-8.586, P = 0.013) were the only independent predictors of having peripheral atherosclerosis. C-statistic for VC was not inferior to that obtained by age (0.728, 95% CI 0.649-0.797 vs. 0.800, 95% CI 0.727-0.861, P = 0.101) and to that obtained by the combination of multivessel CAD with diabetes (0.750; 95% CI 0.673-0.817, P = 0.635), and, furthermore, it was higher than that obtained by diabetes alone (0.620, 95% CI 0.538-0.698, P = 0.036). CONCLUSION: Ruling out the presence of significant peripheral atherosclerosis should be routinely considered in patients with ACS showing VC at echocardiography. PMID- 26122700 TI - Length of time spent working on a commercial construction site and the associations with worker characteristics. AB - BACKGROUND: Construction workers move frequently from jobsite to jobsite, yet little is documented about length of stay on-site and associations with worker characteristics. METHOD: Using cross-sectional data, we investigated associations between worker characteristics (including trade and musculoskeletal pain) and length of stay on-site (dichotomized as < 1 month, n = 554, and >= 1 month, n = 435). RESULTS: Approximately, 56% of workers remained on the worksite for at least 1 month. Length of stay was significantly associated with workers' race/ethnicity, union status, title, trade, and musculoskeletal pain (P-values < 0.05). Trades associated with longer length of stay included pipefitters and plumbers. Trades associated with shorter length of stay included operators and piledrivers. Workers with single-location pain had 2.21 times (95%CI: 1.52, 3.19) the odds of being short-term versus long-term, adjusting for trade, title, and race/ethnicity. CONCLUSION: The length of stay and associated characteristics provide important insight into how workers come and go on construction sites and the methodological challenges associated with traditional intervention evaluations. PMID- 26122701 TI - Successful pharmaceutical-grade streptozotocin (STZ)-induced hyperglycemia in a conscious tethered baboon (Papio hamadryas) model. AB - BACKGROUND: Non-human primate (NHP) diabetic models using chemical ablation of beta-cells with STZ have been achieved by several research groups. Chemotherapeutic STZ could lead to serious adverse events including nephrotoxicity, hepatotoxicity, and mortality. METHODS: We implemented a comprehensive therapeutic strategy that included the tether system, permanent indwelling catheter implants, an aggressive hydration protocol, management for pain with IV nubain and anxiety with IV midazolam, moment-by-moment monitoring of glucose levels post-STZ administration, and continuous intravenous insulin therapy. RESULTS: A triphasic response in blood glucose after STZ administration was fully characterized. A dangerous hypoglycemic phase was also detected in all baboons. Other significant findings were hyperglycemia associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations. CONCLUSIONS: We successfully induced frank diabetes by IV administering a single dose of pharmaceutical-grade STZ safely and without adverse events in conscious tethered baboons. PMID- 26122702 TI - Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice. AB - Differentially regulated microRNA (miRNA) are associated with hepatic fibrosis; however, their potential usefulness for blocking hepatic fibrosis has not been exploited fully. We examined the expression of miRNA in the liver of a transgenic mouse model in which platelet-derived growth factor C (PDGF-C) is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis and steatosis and the eventual development of hepatocellular carcinoma (HCC). Robust induction of miR-214 correlated with fibrogenesis in the liver of Pdgf-c Tg mice, atherogenic high-fat diet-induced NASH mice, and patients with chronic hepatitis B or C. Pdgf-c Tg mice were injected with locked nucleic acid (LNA)-antimiR-214 via the tail vein using Invivofectamine 2.0 and the degree of hepatic fibrosis and tumor incidence were evaluated. Pdgf-c Tg mice treated with LNA-antimiR-214 showed a marked reduction in fibrosis and tumor incidence compared with saline or LNA-miR-control injected control mice. In vitro, LNA-antimiR-214 significantly ameliorated TGF beta1-induced pro-fibrotic gene expression in Lx-2 cells. MiR-214 targets a negative regulator of EGFR signaling, Mig-6. Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF-mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) in Huh-7 cells. Conversely, LNA-antimiR-214 repressed the expression of these genes. In conclusion, miR-214 appears to participate in the development of hepatic fibrosis by modulating the EGFR and TGF beta signaling pathways. LNA-antimiR-214 is a potential therapy for the prevention of hepatic fibrosis. PMID- 26122703 TI - Cytokine Responses to Specific Immunotherapy in House Dust Mite-Induced Allergic Rhinitis Patients. AB - Allergen-specific immunotherapy is the only immunomodulatory treatment that may alter the natural course of allergic disease. However, cytokine responses accompanying sublingual immunotherapy (SLIT) responder phenotypes have not been fully understood. Herein, we examined the level of crucial plasma cytokines during SLIT and evaluated whether their changes correlated to symptom scores. We observed that the levels of interleukin (IL)-17 and complement components C3a and C5a as well as IL-4 at year 3 of SLIT were significantly decreased than those at baseline. In contrast, there was no significant difference in the levels of IL-5, IL-13, and interferon (IFN)-gamma. Notably, a significant positive correlation was found between the levels of IL-17 and the symptom scores at year 3. These results suggest that IL-17 could be considered a potential biomarker for the therapeutic effect of SLIT in allergic rhinitis caused by house dust mite. PMID- 26122704 TI - A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease. AB - AIMS: To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects. METHODS: We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting. RESULTS: Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI 641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449. CONCLUSIONS: These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD. PMID- 26122705 TI - Digestive physiology, metabolism and methane production of captive Linne's two toed sloths (Choloepus didactylus). AB - Sloths are renowned for their low metabolic rate, low food intake and low defecation frequency. We investigated factors of digestive physiology and energy metabolism in four captive individuals (mean body mass 10.0 +/- SD 3.7 kg) of a hitherto mostly unstudied sloth species, Linne's two-toed sloth (Choloepus didactylus), in a 2-week digestion recording and 23-h respiration experiment on animals fed a standard zoo diet of vegetables and starchy components. Dry matter intake, defecation frequency and particle mean retention time (MRT) in the gastrointestinal tract (GIT) were 12 +/- 3 g/(kg(0.75) day), once every 5 days and >140 h in three individuals, but 53 g/(kg(0.75) day), daily and 82 h in one individual that was apparently compensating for a period of weight loss prior to the experiment. In all animals, solute marker was eliminated at a faster rate than the particle marker, indicating 'digesta washing' in the sloths' GIT. The overall metabolic rate calculated from oxygen consumption matched the metabolisable energy intake in three individuals [173 +/- 22 vs. 168 +/- 44 kJ/(kg(0.75) day)] but not in the fourth one [225 vs. 698 kJ/(kg(0.75) day)], supporting the interpretation that this animal was replenishing body stores. In spite of the low food intake and the low-fibre diet (209 +/- 26 g neutral detergent fibre/kg dry matter), methane production was rather high accounting for 9.4 +/- 0.8% of gross energy intake (2.7% in the fourth individual), which exceeded literature data for ruminants on forage-only diets. These results corroborate literature reports on low intake, low defecation frequency, low metabolic rate and long MRT in other sloth species. The long MRT is probably responsible for the comparatively high methane production, providing more opportunity for methanogenic archaea than in other non-ruminant mammals to produce significant amounts of methane. PMID- 26122706 TI - The calcineurin antagonist RCAN1-4 is induced by exhaustive exercise in rat skeletal muscle. AB - The aim of this work was to study the regulation of the calcineurin antagonist regulator of calcineurin 1 (RCAN1) in rat skeletal muscles after exhaustive physical exercise, which is a physiological modulator of oxidative stress. Three skeletal muscles, namely extensor digitorum longus (EDL), gastrocnemius, and soleus, were investigated. Exhaustive exercise increased RCAN1-4 protein levels in EDL and gastrocnemius, but not in soleus. Protein oxidation as an index of oxidative stress was increased in EDL and gastrocnemius, but remained unchanged in soleus. However, lipid peroxidation was increased in all three muscles. CuZnSOD and catalase protein levels were increased at 3 h postexercise in soleus, whereas they remained unchanged in EDL and gastrocnemius. Calcineurin enzymatic activity declined in EDL and gastrocnemius but not in soleus, and its protein expression was decreased in all three muscles. The level of PGC1-alpha protein remained unchanged, whereas the protein expression of the transcription factor NFATc4 was decreased in all three muscles. Adiponectin expression was increased in all three muscles. RCAN1-4 expression in EDL and gastrocnemius muscles was augmented by the oxidative stress generated from exhaustive exercise. We propose that increased RCAN1-4 expression and the signal transduction pathways it regulates represent important components of the physiological adaptation to exercise-induced oxidative stress. PMID- 26122707 TI - Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy. AB - Oxidative stress is closely associated with the pathophysiology of diabetic cardiomyopathy (DCM). The mitochondrial flavoenzyme monoamine oxidase A (MAO-A) is an important source of oxidative stress in the myocardium. We sought to determine whether MAO-A plays a major role in modulating DCM. Diabetes was induced in Wistar rats by single intraperitoneal injection of streptozotocin (STZ). To investigate the role of MAO-A in the development of pathophysiological features of DCM, hyperglycemic and age-matched control rats were treated with or without the MAO-A-specific inhibitor clorgyline (CLG) at 1 mg/kg/day for 8 weeks. Diabetes upregulated MAO-A activity; elevated markers of oxidative stress such as cardiac lipid peroxidation, superoxide dismutase activity, and UCP3 protein expression; enhanced apoptotic cell death; and increased fibrosis. All these parameters were significantly attenuated by CLG treatment. In addition, treatment with CLG substantially prevented diabetes-induced cardiac contractile dysfunction as evidenced by decreased QRS, QT, and corrected QT intervals, measured by ECG, and LV systolic and LV end-diastolic pressure measured by microtip pressure transducer. These beneficial effects of CLG were seen despite the persistent hyperglycemic and hyperlipidemic environments in STZ-induced experimental diabetes. In summary, this study provides strong evidence that MAO-A is an important source of oxidative stress in the heart and that MAO-A-derived reactive oxygen species contribute to DCM. PMID- 26122709 TI - Correlation of single nucleotide polymorphisms in the pregnancy-associated plasma protein-A gene with carotid plaques. AB - BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) is abundantly expressed in carotid plaques. This study investigated the association between single nucleotide polymorphisms (SNPs) of PAPP-A and the presence of carotid plaques. METHODS: A total of 408 patients with carotid plaques and 493 controls were included in the study. All subjects were Southern Chinese Han. Carotid plaques were analyzed by computer tomography angiography. PAPP-A SNPs were identified by ligase detection reaction-polymerase chain reaction analysis. The PAPP-A genotypes rs3747823, rs7020782, and rs13290387 were analyzed. RESULTS: The rs7020782 C allele genotype correlated with an increased risk of developing carotid plaques under the dominant, recessive, and additive models (adjusted odds ratios: 2.60, 2.36, and 3.48, respectively; P <= 0.001). Only C allele-carrying genotypes correlated with a significantly increased risk of carotid plaque based on studies stratified by age and sex under the dominant model. rs7020782 remained significantly associated with the risk of carotid plaque calcification after adjusting for age and potential confounders (adjusted odds ratio, 1.89; 95 % confidence interval, 1.17-3.08; P = 0.010). CONCLUSIONS: This study found, for the first time, that the A?C variation of rs7020782 might be an independent risk factor for carotid plaque development and calcification. The determination of such genotypes could provide a new tool for identifying individuals at high risk for carotid atherosclerosis. PMID- 26122711 TI - Evaluation of effect of body mass index and weight loss on survival of patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy. AB - BACKGROUND: Previous studies report body-mass index (BMI) and percent weight loss (WL) to have prognostic significance when treating patients with nasopharyngeal carcinoma (NPC). However, most of these investigations studied patients treated using different radiotherapeutic techniques. We evaluated the predictive effect of these two nutrition-related measurements on therapeutic outcome in NPC patients who only received intensity-modulated radiation therapy (IMRT) as part of their total treatment program. METHODS: We retrospectively studied NPC patients treated with IMRT from January 2006 to February 2012. Cox proportional hazards was used to test the association of pretreatment BMI (<23 kg/m(2) vs. >=23 kg/m(2)) and percent weight loss (>=5 % vs. <5 %) during therapy and related survival rates while controlling for various potential confounders. RESULTS: Eighty-one (34 %) of the 238 patients had BMIs >=23 kg/m(2) at pretreatment and 150 (63 %) had significant (>=5 %) weight loss. Median follow-up time was 41.71 months; median radiotherapy was 7.46 +/- 0.77 weeks. Those with BMIs >=23 kg/m(2) did not have a better 3-year overall survival (p = 0.672), 3-year disease specific survival (p = 0.341), 3-year locoregional free survival (p = 0.281), or 3-year distant metastatic free survival (p = 0.134). Those with significant WL (>=5 %) did not have worse 3-year clinical endpoints, even after stratifying magnitude of weight loss by BMI category. In sensitivity test, the adjusted hazard ratio remained statistically insignificant using different cutoffs for BMIs and percent weight loss. CONCLUSIONS: This study found no significant relationship between BMI and percent weight loss on survival of NPC patients receiving IMRT based therapy. Further studies might want to consider other nutrition related factors as prognostic indicators when studying the correlate between malnutrition and survival in this population. PMID- 26122710 TI - Sensorimotor and cognitive factors associated with the age-related increase of visual field dependence: a cross-sectional study. AB - Reliance on the visual frame of reference for spatial orientation (or visual field dependence) has been reported to increase with age. This has implications on old adults' daily living tasks as it affects stability, attention, and adaptation capacities. However, the nature and underlying mechanisms of this increase are not well defined. We investigated sensorimotor and cognitive factors possibly associated with increased visual field dependence in old age, by considering functions that are both known to degrade with age and important for spatial orientation and sensorimotor control: reliance on the (somatosensory based) egocentric frame of reference, visual fixation stability, and attentional processing of complex visual scenes (useful field of view, UFOV). Twenty young, 18 middle-aged, and 20 old adults completed a visual examination, three tests of visual field dependence (RFT, RDT, and GEFT), a test of egocentric dependence (subjective vertical estimation with the body erect and tilted at 70 degrees ), a visual fixation task, and a test of visual attentional processing (UFOV(r)). Increased visual field dependence with age was associated with reduced egocentric dependence, visual fixation stability, and visual attentional processing. In addition, visual fixation instability and reduced UFOV were correlated. Results of middle-aged adults fell between those of the young and old, revealing the progressive nature of the age effects we evaluated. We discuss results in terms of reference frame selection with respect to ageing as well as visual and non visual information processing. Inter-individual differences amongst old adults are highlighted and discussed with respect to the functionality of increased visual field dependence. PMID- 26122713 TI - Current surgical standards of care in Wilms tumor. AB - BACKGROUND: Wilms tumor (WT) is the second most common abdominal tumor in children. METHODS: This chapter discusses surgical considerations for the management of unilateral and bilateral WT. RESULTS: Currently, survival exceeds 90%, owing to multicenter studies under the auspices of the Children's Oncology Group and Societe Internationale d'Oncologie Pediatrique. Surgical excision remains the mainstay of oncologic control and is also crucial for proper staging of disease in order to direct adjuvant therapy and limit treatment-related morbidity. CONCLUSIONS: Careful attention must be paid to proper disease staging, upfront and adjuvant therapy, and surgical technique in order to optimize oncologic outcomes while minimizing short- and long-term morbidity. PMID- 26122714 TI - Assessing the clinical benefit of a nomogram to predict specimen-confined disease at radical prostatectomy in patients with high-risk prostate cancer: An external validation. AB - OBJECTIVE: The objective of the current study was to test generalizability and clinical value of a recently published nomogram to predict specimen-confined disease (SCD, pT2-pT3a+R0+pN0) at radical prostatectomy (RP) in patients with clinical high-risk prostate cancer (HRPCa). The nomogram allows improved decision making with curative intent within this heterogeneous patient cohort, which is important, as RP in patients with clinical HRPCa remains a topic of controversy. METHODS: We externally validated the nomogram in 1,669 men with clinical HRPCa who underwent RP and extended pelvic lymph node dissection between 1992 and 2011. A Kaplan-Meier analysis to estimate 5- and 10-year biochemical recurrence-free survival was performed. To investigate the SCD model's performance, the previously reported regression coefficients of the SCD nomogram were applied. Within loess calibration plots, the extent of overestimation or underestimation was graphically explored. Finally, decision curve analysis (DCA) to assess the clinical value of the SCD nomogram was performed. RESULTS: Overall, 49% of men showed SCD after RP. The 5- and 10-year biochemical recurrence rates for men with SCD were 66% and 56%, respectively, vs. 32% and 20%, respectively, for men without SCD (log-rank test P<0.001). External validation demonstrated comparable accuracy in relation to accuracy derived from internal validation (68.1% vs. 72.0%). Calibration was suboptimal, showing a tendency to underestimate SCD probability. In DCA, the nomogram's usage was associated with a clinical net benefit relative to both treating all and none. CONCLUSIONS: Within our cohort, the nomogram's use was associated with a clinical net benefit according to DCA. However, one-third of men were falsely classified as having SCD or non-SCD. Nevertheless, in the absence of superior tools, the SCD nomogram represents a useful clinical decision aid. PMID- 26122712 TI - Neoadjuvant chemotherapy administration and time to cystectomy for muscle invasive bladder cancer: An evaluation of transitions between academic and community settings. AB - OBJECTIVES: Neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). Many patients are referred to an academic medical center (AMC) for cystectomy but receive NAC in the community setting. This study examines if administration of NAC in the community is associated with differences in type of NAC received, pathologic response rate (pT0), and time to cystectomy as compared to NAC administered at an AMC. METHODS: We performed a retrospective study of patients with MIBC (cT2a-T4 Nx-M0) referred to a single AMC between 1/2012 and 1/2014 who received NAC. We analyzed chemotherapy received, time to cystectomy, pT0, and survival in patients who received NAC in our AMC compared to those treated in the community. RESULTS: In all, 47 patients were analyzed. A similar total dose of cisplatin (median: 280 mg/m(2) for both groups, P = 0.82) and pT0 rate (25% vs. 29%, P = 0.72) were seen in patients treated in our AMC and the community. However, administration of NAC in the community was associated with a prolonged time to cystectomy compared with that in our AMC (median number of days 162 vs. 128, P<0.01). This remained significant after adjusting for stage, comorbidity status, and distance to the AMC (P = 0.02). Disease-free survival and overall survival did not differ. CONCLUSION: Patients with MIBC treated with NAC in the community as compared to an AMC received similar chemotherapy and achieved comparable pT0 rates, indicating effective implementation of NAC in the community. However, NAC in the community was associated with longer time to cystectomy, suggesting a delay in the transition of care between settings. PMID- 26122717 TI - Effect of mesenchymal stromal cells for articular cartilage degeneration treatment: a meta-analysis. AB - BACKGROUND AIMS: Articular cartilage is an avascular tissue that has limited capacity for self-repair. Mesenchymal stromal cells have been considered as potential candidates for cartilage regeneration. However, clinical results of cartilage formation with the use of these cells need evaluation. We aimed to assess the effect of mesenchymal stromal cell treatment on articular cartilage defects. METHODS: We searched PubMed, Embase and the Cochrane Central Register of Controlled Trials with key words including "cartilage," "clinical trial," "mesenchymal," "stromal" and "stem cell" up to December 3, 2014. We selected the controlled trial that used treatment with mesenchymal stromal cells on cartilage injury compared with other treatment. We assessed the results of the meta analysis by means of the error matrix approach. The outcome measures were ranked as comprehensive evaluation index, highest relevance; unilateral evaluation index, medial relevance; and single evaluation index, lowest relevance. RESULTS: Eleven trials assessing 558 patients were included in the meta-analysis. Stem cell treatment significantly improved the American Orthopedic Foot and Ankle Society Scale (Standard Mean Difference, SMD, 0.91; 95% confidence interval [CI], 0.52 to 1.29). The Osteo-Arthritis Outcome Score was also significantly improved in stem cell treatment (SMD, 2.81; 95% CI, 2.02 to 3.60). Other comprehensive evaluation indexes, such as the American Knee Society Knee Score System (SMD 0.12, 95% CI, -1.02 to 0.78), the Hospital for Special Surgery Knee Rating Scale (SMD, 0.24, 95% CI, -0.56 to 1.05) and the International Knee Documentation Committee (SMD, -0.21; 95% CI, -0.77 to 0.34), appeared to have no significant differences by use of stem cell and other treatments. Overall, there was no obvious advantage regarding the application of stem cells to treat cartilage injury, compared with other treatments. CONCLUSIONS: In conclusion, assessment of the comprehensive evaluation index indicated that there were no significant differences after stem cell treatment. However, assessment of clinical symptoms and cartilage morphology showed significant improvement after stem cell treatment. PMID- 26122719 TI - Eosinophilia associated with disease exacerbations in a patient with pyostomatitis vegetans. PMID- 26122708 TI - Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. AB - Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates the basal and stress-inducible expression of a battery of genes encoding key components of the glutathione-based and thioredoxin-based antioxidant systems, as well as aldo-keto reductase, glutathione S-transferase, and NAD(P)H: quinone oxidoreductase-1 drug metabolizing isoenzymes along with multidrug-resistance-associated efflux pumps. It therefore plays a pivotal role in both intrinsic resistance and cellular adaptation to reactive oxygen species (ROS) and xenobiotics. Activation of Nrf2 can, however, serve as a double-edged sword because some of the genes it induces may contribute to chemical carcinogenesis by promoting futile redox cycling of polycyclic aromatic hydrocarbon metabolites or confer resistance to chemotherapeutic drugs by increasing the expression of efflux pumps, suggesting its cytoprotective effects will vary in a context-specific fashion. In addition to cytoprotection, Nrf2 also controls genes involved in intermediary metabolism, positively regulating those involved in NADPH generation, purine biosynthesis, and the beta-oxidation of fatty acids, while suppressing those involved in lipogenesis and gluconeogenesis. Nrf2 is subject to regulation at multiple levels. Its ability to orchestrate adaptation to oxidants and electrophiles is due principally to stress-stimulated modification of thiols within one of its repressors, the Kelch-like ECH-associated protein 1 (Keap1), which is present in the cullin-3 RING ubiquitin ligase (CRL) complex CRLKeap1. Thus modification of Cys residues in Keap1 blocks CRLKeap1 activity, allowing newly translated Nrf2 to accumulate rapidly and induce its target genes. The ability of Keap1 to repress Nrf2 can be attenuated by p62/sequestosome-1 in a mechanistic target of rapamycin complex 1 (mTORC1)-dependent manner, thereby allowing refeeding after fasting to increase Nrf2-target gene expression. In parallel with repression by Keap1, Nrf2 is also repressed by beta-transducin repeat-containing protein (beta-TrCP), present in the Skp1-cullin-1-F-box protein (SCF) ubiquitin ligase complex SCFbeta TrCP. The ability of SCFbeta-TrCP to suppress Nrf2 activity is itself enhanced by prior phosphorylation of the transcription factor by glycogen synthase kinase-3 (GSK-3) through formation of a DSGIS-containing phosphodegron. However, formation of the phosphodegron in Nrf2 by GSK-3 is inhibited by stimuli that activate protein kinase B (PKB)/Akt. In particular, PKB/Akt activity can be increased by phosphoinositide 3-kinase and mTORC2, thereby providing an explanation of why antioxidant-responsive element-driven genes are induced by growth factors and nutrients. Thus Nrf2 activity is tightly controlled via CRLKeap1 and SCFbeta-TrCP by oxidative stress and energy-based signals, allowing it to mediate adaptive responses that restore redox homeostasis and modulate intermediary metabolism. Based on the fact that Nrf2 influences multiple biochemical pathways in both positive and negative ways, it is likely its dose-response curve, in terms of susceptibility to certain degenerative disease, is U-shaped. Specifically, too little Nrf2 activity will lead to loss of cytoprotection, diminished antioxidant capacity, and lowered beta-oxidation of fatty acids, while conversely also exhibiting heightened sensitivity to ROS-based signaling that involves receptor tyrosine kinases and apoptosis signal-regulating kinase-1. By contrast, too much Nrf2 activity disturbs the homeostatic balance in favor of reduction, and so may have deleterious consequences including overproduction of reduced glutathione and NADPH, the blunting of ROS-based signal transduction, epithelial cell hyperplasia, and failure of certain cell types to differentiate correctly. We discuss the basis of a putative U-shaped Nrf2 dose-response curve in terms of potentially competing processes relevant to different stages of tumorigenesis. PMID- 26122718 TI - Mutations in KCNT1 cause a spectrum of focal epilepsies. AB - Autosomal dominant mutations in the sodium-gated potassium channel subunit gene KCNT1 have been associated with two distinct seizure syndromes, nocturnal frontal lobe epilepsy (NFLE) and malignant migrating focal seizures of infancy (MMFSI). To further explore the phenotypic spectrum associated with KCNT1, we examined individuals affected with focal epilepsy or an epileptic encephalopathy for mutations in the gene. We identified KCNT1 mutations in 12 previously unreported patients with focal epilepsy, multifocal epilepsy, cardiac arrhythmia, and in a family with sudden unexpected death in epilepsy (SUDEP), in addition to patients with NFLE and MMFSI. In contrast to the 100% penetrance so far reported for KCNT1 mutations, we observed incomplete penetrance. It is notable that we report that the one KCNT1 mutation, p.Arg398Gln, can lead to either of the two distinct phenotypes, ADNFLE or MMFSI, even within the same family. This indicates that genotype-phenotype relationships for KCNT1 mutations are not straightforward. We demonstrate that KCNT1 mutations are highly pleiotropic and are associated with phenotypes other than ADNFLE and MMFSI. KCNT1 mutations are now associated with Ohtahara syndrome, MMFSI, and nocturnal focal epilepsy. They may also be associated with multifocal epilepsy and cardiac disturbances. PMID- 26122720 TI - Effects of Anthropogenic Pollution on the Oxidative Phosphorylation Pathway of Hepatocytes from Natural Populations of Fundulus heteroclitus. AB - Persistent organic pollutants (POPs), including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs), potentially target mitochondria and cause toxicity. We compared the effects of POPs on mitochondrial respiration by measuring oxidative phosphorylation (OxPhos) metabolism in hepatocytes isolated from lab-depurated Fundulus heteroclitus from a Superfund site contaminated with PAHs (Elizabeth River VA, USA) relative to OxPhos metabolism in individuals from a relatively clean, reference population (King's Creek VA, USA). In individuals from the polluted Elizabeth River population, OxPhos metabolism displayed lower LEAK and lower activities in complex III, complex IV, and E State, but higher activity in complex I compared to individuals from the reference King's Creek population. To test the supposition that these differences were due to or related to the chronic PAH contamination history of the Elizabeth River population, we compared the OxPhos functions of undosed individuals from the polluted and reference populations to individuals from these populations dosed with a PAH {benzo [alpha] pyrene (BaP)} or a PCB {PCB126 (3,3',4,4',5-pentachlorobiphenyl)}, respectively. Exposure to PAH or PCB affected OxPhos in the reference King's Creek population but had no detectable effects on the polluted Elizabeth River population. Thus, PAH exposure significantly increased LEAK, and exposure to PCB126 significantly decreased State 3, E state and complex I activity in the reference King's Creek population. These data strongly implicate an evolved tolerance in the Elizabeth River fish where dosed fish are not affected by PAH exposure and undosed fish show decreased LEAK and increased State 3 and E state. PMID- 26122721 TI - Video-tracking of zebrafish (Danio rerio) as a biological early warning system using two distinct artificial neural networks: Probabilistic neural network (PNN) and self-organizing map (SOM). AB - Biological early warning systems (BEWS) are becoming very important tools in ecotoxicological studies because they can detect changes in the behavior of organisms exposed to toxic substances. In this work, a video tracking system was fully developed to detect the presence of commercial bleach (NaOCl) in water in three different concentrations (0.0005%; 0.0010% and 0.0020% (v/v)) during one hour of exposure. Zebrafish was selected as the test organism because it is widely used in many different areas and studies. Two distinct statistical models were developed, using probabilistic neural network (PNN) and correspondence analysis associated with self-organizing map (SOM-CA). The diagnosis was based only in the analysis of a few behavioral components of the fish, namely: mean angular velocity, mean linear velocity, spatial dispersion, mean value of the X coordinate and mean value of the Y coordinate. Both models showed good results in their diagnosis capabilities. However, the overall performance (accuracy) was always superior in the PNN model. The worst result was with the SOM-CA model, at the lowest concentration (0.0005% v/v), achieving only 65% of correct diagnosis. The best result was with the PNN model, at the highest concentration (0.0020% v/v), achieving 94% of correct diagnosis. PMID- 26122723 TI - Increasing quality and quantity of student placements in smaller rural health services: It can be done. AB - PROBLEM: Future rural nursing and midwifery workforce shortage and current shortage of placements for undergraduate nursing and midwifery students. DESIGN: Developmental evaluation. SETTING: Five small hospitals and a regional community health service. KEY MEASURES OF IMPROVEMENT: Increased number of placements available for students; sustainable, quality clinical placement system in place for the future. STRATEGIES FOR CHANGE: Clinical facilitators developed a clinical facilitation model and resources that increased quality and quantity of student placements, assisted clinicians to provide higher quality teaching to students, enabled students to develop skills in rural health care service provision and enhanced knowledge around future career options. EFFECTS OF CHANGE: Placement targets were met and all health services involved chose to continue the model of clinical facilitation developed after project funding ceased. The clinical education skills developed by staff under the project remain in the region to support future students. LESSONS LEARNT: It is possible to create a sustainable, high-quality, rural placement experience for larger numbers of nursing and midwifery students. Funding sources are available to continue the clinical facilitation model in to the future, but for it to work optimally, a steady supply of students across the year is required. PMID- 26122724 TI - Classification of occupational activity categories using accelerometry: NHANES 2003-2004. AB - BACKGROUND: An individual's occupational activity (OA) may contribute significantly to daily physical activity (PA) and sedentary behavior (SB). However, there is little consensus about which occupational categories involve high OA or low OA, and the majority of categories are unclassifiable with current methods. The purpose of this study was to present population estimates of accelerometer-derived PA and SB variables for adults (n = 1112, 20-60 years) working the 40 occupational categories collected during the 2003-2004 National Health and Nutrition Examination Survey (NHANES). METHODS: ActiGraph accelerometer-derived total activity counts/day (TAC), activity counts/minute, and proportion of wear time spent in moderate-to-vigorous PA [MVPA], lifestyle, and light PA organized by occupational category were ranked in ascending order and SB was ranked in descending order. Summing the ranks of the six accelerometer derived variables generated a summary score for each occupational category, which was re-ranked in ascending order. Higher rankings indicated higher levels of OA, lower rankings indicated lower levels of OA. Tertiles of the summary score were used to establish three mutually exclusive accelerometer-determined OA groupings: high OA, intermediate OA, and low OA. RESULTS: According to their summary score, 'farm and nursery workers' were classified as high OA and 'secretaries, stenographers, and typists' were classified as low OA. Consistent with previous research, some low OA occupational categories (e.g., 'engineers, architects, and scientists', 'technicians and related support occupations', 'management related occupations', 'executives, administrators, and managers', 'protective services', and 'writers, artists, entertainers, and athletes') associated with higher education and income had relatively greater amounts of MVPA compared to other low OA occupational categories, likely due to the greater percentage of men in those occupations and/or the influence of higher levels of leisure time PA. Men had more TAC, activity counts/minute and time in MVPA, but similar proportions of SB compared to women in all three OA groupings. CONCLUSIONS: Objectively measured PA allowed for a more precise estimate of the amount of PA and SB associated with different occupations and facilitated systematic classification of the 40 different occupational categories into three distinct OA groupings. This information provides new opportunities to explore the relationship between OA and health outcomes. PMID- 26122725 TI - Informing the public health management of typhoid and paratyphoid: the Australian context. AB - OBJECTIVE: To examine outcomes of public health management of notified enteric fever cases in South-East Queensland over the past five years. METHODS: Notification records of typhoid and paratyphoid infection in South-East Queensland 2008-2012 (inclusive) were reviewed to determine likelihood of cases and contacts adhering to present or previous recommendations for faecal clearance/screening, duration of infectiousness of cases and extent of local transmission to contacts. RESULTS: Sixty-nine of 85 cases and 218 of 265 contacts submitted at least one faecal specimen. Cases were 2.7 (95%CI 1.2-6.0) and contacts were 4.4 (95%CI 3.0-6.4) times more likely to complete recommended faecal clearance/screening under previous compared to present guidelines (requiring more specimens). In ten cases with positive post-treatment specimens, last recorded infectiousness was 19 days to six months after notification. The documented rate of local transmission of infection was 18/1,000 contacts submitting at least one faecal specimen (95%CI 6-48/1,000). CONCLUSIONS: Local transmission risk of enteric fever in South-East Queensland is low, although small numbers of cases may have prolonged bacilli excretion post-treatment. More complex clearance/screening regimens are associated with decreased compliance. IMPLICATIONS: Pursuing extensive faecal clearance/screening regimens is unlikely to be effective in terms of public health management of enteric fever in South East Queensland. We suggest a unified national approach focussing on cases/contacts at high risk of disease transmission. PMID- 26122726 TI - Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. AB - BACKGROUND: Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US licensed reference product, Neupogen((r)), in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC). PATIENTS AND METHODS: A total of 218 patients receiving 5 ug/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1. RESULTS: The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 +/- 1.11 (biosimilar, N = 101) and 1.20 +/- 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments. CONCLUSION: This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment. STUDY NUMBER: NCT01519700. PMID- 26122727 TI - Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis. AB - BACKGROUND: De-escalation of bone-targeted agents, such as bisphosphonates and denosumab, from 4- to 12-weekly dosing is an increasingly used strategy in patients with bone metastases from breast cancer. It is unclear whether there is sufficient evidence to support de-escalation as a standard of care. METHODS: A systematic review of randomized trials comparing standard 4-weekly administration of bone-targeted agents with de-escalated (Q12-weekly) dosing in breast cancer patients was carried out. Medline, PubMed and the Cochrane Register of Controlled Trials were searched from inception until November 2014 for relevant studies. Outcomes of interest included skeletal-related event (SRE) rates, bone pain, adverse events (AEs) and bone turnover biomarkers. Random-effects meta-analyses were carried out. RESULTS: A total of nine citations representing seven unique studies were eligible. One study is ongoing with no reported data. Six studies reported data for at least one outcome of interest. Data were available comparing standard versus de-escalated therapy for pamidronate (1 study, 38 patients), zoledronate (3 studies, 1117 patients) and denosumab (2 studies, 284 patients). Meta-analysis of five trials reporting data for on-study SRE rates between standard (61/443 patients) and de-escalated (49/392 patients) arms produced a summary risk ratio of 0.90 (95% confidence interval 0.63-1.29). Meta-analyses of data for AEs and bone turnover biomarkers also showed no statistically significant differences between standard and de-escalated arms, though only limited numbers of patients and events were present for most analyses. CONCLUSION: In this systematic review of studies of bisphosphonates and denosumab, there appears to be no difference in SREs or pain with de-escalated therapy. While a large, hopefully definitive study is ongoing, the data presented so far are consistent with de-escalation of bone-targeting agents becoming a standard of care for patients with bone metastases from breast cancer. PMID- 26122728 TI - Nanodomained Nickel Unite Nanocrystal Strength with Coarse-Grain Ductility. AB - Conventional metals are routinely hardened by grain refinement or by cold working with the expense of their ductility. Recent nanostructuring strategies have attempted to evade this strength versus ductility trade-off, but the paradox persists. It has never been possible to combine the strength reachable in nanocrystalline metals with the large uniform tensile elongation characteristic of coarse-grained metals. Here a defect engineering strategy on the nanoscale is architected to approach this ultimate combination. For Nickel, spread-out nanoscale domains (average 7 nm in diameter) were produced during electrodeposition, occupying only ~2.4% of the total volume. Yet the resulting Ni achieves a yield strength approaching 1.3 GPa, on par with the strength for nanocrystalline Ni with uniform grains. Simultaneously, the material exhibits a uniform elongation as large as ~30%, at the same level of ductile face-centered cubic metals. Electron microscopy observations and molecular dynamics simulations demonstrate that the nanoscale domains effectively block dislocations, akin to the role of precipitates for Orowan hardening. In the meantime, the abundant domain boundaries provide dislocation sources and trapping sites of running dislocations for dislocation multiplication, and the ample space in the grain interior allows dislocation storage; a pronounced strain-hardening rate is therefore sustained to enable large uniform elongation. PMID- 26122729 TI - Renal fibrosis: Kidney-specific deletion of Lkb1 perturbs intracellular metabolism and induces severe renal fibrosis. PMID- 26122730 TI - IgG4-related disease and the kidney. AB - IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent manifestations in the kidney-IgG4 related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4(+) T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches. PMID- 26122731 TI - Acute kidney injury: Steroids for prevention of AKI after cardiopulmonary bypass. PMID- 26122732 TI - Hypertension: A new therapeutic strategy for PAH. PMID- 26122733 TI - Synthesis, characterization and biocompatibility of silver nanoparticles synthesized from Nigella sativa leaf extract in comparison with chemical silver nanoparticles. AB - Despite the development potential in the field of nanotechnology, there is a concern about possible effects of nanoparticles on the environment and human health. In this study, silver nanoparticles (AgNPs) were synthesized by 'green' and 'chemical' methods. In the wet-chemistry method, sodium borohydrate, sodium citrate and silver nitrate were used as raw materials. Leaf extract of Nigella sativa was used as reducing as well as capping agent to reduce silver nitrate in the green synthesis method. In addition, toxic responses of both synthesized AgNPs were monitored on bone-building stem cells of mice as well as seed germination and seedling growth of six different plants (Lolium, wheat, bean and common vetch, lettuce and canola). In both synthesis methods, the colorless reaction mixtures turned brown and UV-visible spectra confirmed the presence of silver nanoparticles. Scanning electron microscope (SEM) observations revealed the predominance of silver nanosized crystallites and fourier transform infra-red spectroscopy (FTIR) indicated the role of different functional groups in the synthetic process. MTT assay showed cell viability of bone-building stem cells of mice was further in the green AgNPs synthesized using black cumin extract than chemical AgNPs. IC50 (inhibitory concentrations) values for seed germination, root and shoot length for 6 plants in green AgNPs exposures were higher than the chemical AgNPs. These results suggest that cytotoxicity and phytotoxicity of the green synthesized AgNPs were significantly less than wet-chemistry synthesized ones. This study indicated an economical, simple and efficient ecofriendly technique using leaves of N. sativa for synthesis of AgNPs and confirmed that green AgNPs are safer than chemically-synthesized AgNPs. PMID- 26122734 TI - Biodegradation of multiple microcystins and cylindrospermopsin in clarifier sludge and a drinking water source: Effects of particulate attached bacteria and phycocyanin. AB - The effects of particulate attached bacteria (PAB) and phycocyanin on the simultaneous biodegradation of a mixture of microcystin-LR, YR, LY, LW, LF and cylindrospermopsin (CYN) was assessed in clarifier sludge of a drinking water treatment plant (DWTP) and in a drinking water source. The biomass from lake water and clarifier sludge was able to degrade all microcystins (MCs) at initial concentrations of 10ugL(-1) with pseudo-first order reaction half-lives ranging from 2.3 to 8.8 days. CYN was degraded only in the sludge with a biodegradation rate of 1.0*10(-1)d(-1) and a half-life of 6.0 days. This is the first study reporting multiple MCs and CYN biodegradation in the coagulation-flocculation sludge of a DWTP. The removal of PAB from the lake water and the sludge prolonged the lag time substantially, such that no biodegradation of MCLY, LW and LF was observed within 24 days. Biodegradation rates were shown to increase in the presence of C-phycocyanin as a supplementary carbon source for indigenous bacteria, a cyanobacterial product that accompanies cyanotoxins during cyanobacteria blooms. MCs in mixtures degraded more slowly (or not at all) than if they were degraded individually, an important outcome as MCs in the environment are often present in mixtures. The results from this study showed that the majority of the bacterial biomass responsible for the biodegradation of cyanotoxins is associated with particles or biological flocs and there is a potential for extreme accumulation of cyanotoxins within the DWTP during a transient bloom. PMID- 26122735 TI - Aquatic risk assessment of a novel strobilurin fungicide: A microcosm study compared with the species sensitivity distribution approach. AB - The ecotoxicological effects of pyraoxystrobin, a novel strobilurin fungicide, were studied using outdoor freshwater microcosms and the species sensitivity distribution approach. The microcosms were treated with pyraoxystrobin at concentrations of 0, 1.0, 3.0, 10, 30 and 100ug/L. Species sensitivity distribution (SSD) curves were constructed by means of acute toxicity data using the BurrliOZ model for fourteen representatives of sensitive invertebrates, algae and fish and eleven taxa of invertebrates and algae, respectively. The responses of zooplankton, phytoplankton and physical and chemical endpoints in microcosms were studied. Zooplankton, especially Sinodiaptomus sarsi was the most sensitive to pyraoxystrobin exposure in the microcosms. Short-term toxic effects (<8 weeks) on zooplankton occurred in 1ug/L treatment group. The duration of toxic effects on S. sarsi could not be evaluated within the initial 56 days. Significant long term toxic effects were observed at 10, 30 and 100ug/L (>281 days) for S. sarsi and the zooplankton community. Based on the results obtained from the organisms in the microcosm system, 1ug/L was recommended as the NOEAEC (no observed ecologically adverse effect concentration). Also, 0.33ug/L was derived as the Regulatory Acceptable Concentration based on the ecological recovery option (ERO RAC) of pyraoxystrobin. For all fourteen tested species, the median HC5 (hazardous concentration affecting 5% of species) was 0.86ug/L, and the lower limit HC5 (LL-HC5) was 0.39ug/L. For the eleven taxa of invertebrates and algae tested, the median HC5 was 1.1ug/L, and the LL-HC5 was 0.26ug/L. The present study positively contributes to the suggestion of adequately using acute L(E)C50 based HC5/ LL-HC5 for deriving protective concentrations for strobilurin fungicides, and it should be valuable for full comprehension of the potential toxicity of pyraoxystrobin in aquatic ecosystems. PMID- 26122736 TI - Identification of enhanced hydrogen and ethanol Escherichia coli producer strains in a glycerol-based medium by screening in single-knock out mutant collections. AB - BACKGROUND: Earth's climate is warming as a result of anthropogenic emissions of greenhouse gases from fossil fuel combustion. Bioenergy, which includes biodiesel, biohydrogen and bioethanol, has emerged as a sustainable alternative fuel source. For this reason, in recent years biodiesel production has become widespread but this industry currently generates a huge amount of glycerol as a by-product, which has become an environmental problem in its own right. A feasible possibility to solve this problem is the use of waste glycerol as a carbon source for microbial transformation into biofuels such as hydrogen and ethanol. For instance, Escherichia coli is a microorganism that can synthesize these compounds under anaerobic conditions. RESULTS: In this work an experimental procedure was established for screening E. coli single mutants to identify strains with enhanced ethanol and/or H2 productions compared to the wild type strain. In an initial screening of 150 single mutants, 12 novel strains (gnd, tdcE, rpiA nanE, tdcB, deoB, sucB, cpsG, frmA, glgC, fumA and gadB) were found to provide enhanced yields for at least one of the target products. The mutations, that improve most significantly the parameters evaluated (gnd and tdcE genes), were combined with other mutations in three engineered E. coli mutant strains in order to further redirect carbon flux towards the desired products. CONCLUSIONS: This methodology can be a useful tool to disclose the metabolic pathways that are more susceptible to manipulation in order to obtain higher molar yields of hydrogen and ethanol using glycerol as main carbon source in multiple E. coli mutants. PMID- 26122738 TI - Clinical Long-Term Outcome and Reinterventional Rate After Uterine Fibroid Embolization with Nonspherical Versus Spherical Polyvinyl Alcohol Particles. AB - PURPOSE: This study was designed to evaluate the long-term clinical outcome and frequency of reinterventions in patients with uterine fibroids treated with embolization at a single center using polyvinyl alcohol microparticles. METHODS: The study included all patients with symptomatic uterine fibroids treated with uterine fibroid embolization (UFE) with spherical (s-PVA) and nonspherical (ns PVA) polyvinyl alcohol microparticles during the period January 2001 to January 2011. Clinical success and secondary interventions were examined. Hospital records were reviewed during follow-up, and symptom-specific questionnaires were sent to all patients. RESULTS: In total, 515 patients were treated with UFE and 350 patients (67 %) were available for long-term clinical follow-up. Median time of follow-up was 93 (range 76-120.2) months. Eighty-five patients (72 %) had no reinterventions during follow-up in the group embolized with ns-PVA compared with 134 patients (58 %) treated with s-PVA. Thirty-three patients (28 %) underwent secondary interventions in the ns-PVA group compared with 98 patients (42 %) in s PVA group (chi(2) test, p < 0.01). CONCLUSIONS: Spherical PVA particles 500-700 um showed high reintervention rate at long-term follow-up, and almost one quarter of the patients underwent secondary interventions, suggesting that this type of particle is inappropriate for UFE. PMID- 26122737 TI - Oncogenic mutations weaken the interactions that stabilize the p110alpha-p85alpha heterodimer in phosphatidylinositol 3-kinase alpha. AB - Phosphatidylinositol 3-kinase (PI3K) alpha is a heterodimeric lipid kinase that catalyzes the conversion of phosphoinositol-4,5-bisphosphate to phosphoinositol 3,4,5-trisphosphate. The PI3Kalpha signaling pathway plays an important role in cell growth, proliferation, and survival. This pathway is activated in numerous cancers, where the PI3KCA gene, which encodes for the p110alpha PI3Kalpha subunit, is mutated. Its mutation often results in gain of enzymatic activity; however, the mechanism of activation by oncogenic mutations remains unknown. Here, using computational methods, we show that oncogenic mutations that are far from the catalytic site and increase the enzymatic affinity destabilize the p110alpha-p85alpha dimer. By affecting the dynamics of the protein, these mutations favor the conformations that reduce the autoinhibitory effect of the p85alpha nSH2 domain. For example, we determined that, in all of the mutants, the nSH2 domain shows increased positional heterogeneity as compared with the wild type, as demonstrated by changes in the fluctuation profiles computed by normal mode analysis of coarse-grained elastic network models. Analysis of the interdomain interactions of the wild-type and mutants at the p110alpha-p85alpha interface obtained with molecular dynamics simulations suggest that all of the tumor-associated mutations effectively weaken the interactions between p110alpha and p85alpha by disrupting key stabilizing interactions. These findings have important implications for understanding how oncogenic mutations change the conformational multiplicity of PI3Kalpha and lead to increased enzymatic activity. This mechanism may apply to other enzymes and/or macromolecular complexes that play a key role in cell signaling. PMID- 26122739 TI - Feeding Arteries of Primary Tongue Cancers on Intra-arterial Infusion Chemotherapy. AB - PURPOSE: To evaluate the frequency and the predictive factor of each feeding artery on intra-arterial infusion chemotherapy (IAIC) in primary tongue cancer. MATERIALS AND METHODS: We retrospectively evaluated 20 patients who received IAIC for primary tongue cancer. The main and accompanying feeding arteries were identified on super-selective angiography of the branches of the external carotid artery. Tumor diameter, and extension to the contralateral side, tongue extrinsic muscles (TEMs), and lateral mesopharyngeal wall were determined based on magnetic resonance imaging or computed tomography findings. RESULTS: The main feeding artery was the ipsilateral lingual artery (LA) in 15 of the 20 examined tumors and the contralateral LA in the other 5. Ten cancers had only one feeding artery, and multiple feeding arteries were detected in the remaining 10. Tumors >4 cm (n = 9), those with extension to the contralateral side (n = 13), and those with extension to TEMs (n = 15) were supplied by significantly larger numbers of feeding arteries compared to tumors without these features (P = 0.01, 0.049, and 0.02, respectively). The frequency of feeding from the contralateral LA was 64 % (9/14) and 17 % (1/6) in tumors with and without extension to the contralateral side, respectively. Feeding from a facial artery (FA) was not detected in tumors <=4 cm, while 5 of the 9 (56 %) tumors >4 cm were supplied by a FA (P = 0.01). CONCLUSION: A careful search for feeding arteries is required, especially in large tumors with extension to the contralateral side or to TEMs. PMID- 26122740 TI - Perigraft Plug Embolization of the Internal Iliac Artery and Implantation of a Bifurcated Stentgraft: One Treatment Option for Insufficient Tubular Stentgraft Repair of a Common Iliac Artery Aneurysm. AB - We report an endovascular technique for the treatment of type Ia endoleak after a plain tubular stentgraft had been implanted for a large common iliac artery aneurysm with an insufficient proximal landing zone and without occlusion of the hypogastric in another hospital. CT follow-up showed an endoleak with continuous sac expansion over 12 months. This was classified as type Ia by means of dynamic contrast-enhanced MRI. Before a bifurcated stentgraft was implanted to relocate the landing zone more proximally, the still perfused ipsilateral hypogastric artery was embolized to prevent a type II endoleak. A guidewire was manipulated alongside the indwelling stentgraft. The internal iliac artery could then be selectively intubated followed by successful plug embolization of the vessel's orifice despite the stentgraft being in place. PMID- 26122741 TI - Large transport J(c) in Cu-sheathed Sr(0.6)K(0.4)Fe2As2 superconducting tape conductors. AB - Copper sheath is the first choice for manufacturing high-T(c) superconducting wires and tapes because of its high electrical and thermal conductivities, low cost and good mechanical properties. However, Cu can easily react with superconducting cores, such as BSCCO, MgB2 and pnictides, and therefore drastically decrease the transport J(c). Here, we report the fabrication of Cu sheathed Sr(1-x)K(x)Fe2As2 tapes with superior J(c) performance using a simple hot pressing method that is capable of eliminating the lengthy high-temperature sintering. We obtained high-quality Sr(1-x)K(x)Fe2As2 tapes with processing at 800 degrees C for 30 minutes and measured high T(c) and sharp transition. By this rapid fabrication, Cu sheath does not give rise to apparent reaction layer, and only slightly diffuses into Sr-122 core. As a consequence, we achieved high transport J(c) of 3.1 * 10(4) A/cm(2) in 10 T and 2.7 * 10(4) A/cm(2) in 14 T at 4.2 K. The in-field J(c) performance is by far the highest reported for Cu sheathed high-T(c) conductors. More importantly, Cu-sheathed Sr-122 tapes also showed a high J(e) value of 1.0 * 10(4) A/cm(2) in 10 T at 4.2 K, which has reached the widely accepted practical level for applications. These results demonstrate that Cu is a very promising sheath for the practical application of pnictide conductors. PMID- 26122742 TI - Management of cervical esophageal and hypopharyngeal perforations. AB - PURPOSE: Evidence is limited for outcomes of surgical versus conservative management for patients with cervical esophageal or hypopharyngeal perforations. METHODS: Patients with cervical esophageal or hypopharyngeal perforations treated between 1994 and 2014 were identified using an institutional database. Outcomes were compared between patients who underwent operative drainage and those who had conservative management with broad-spectrum antibiotics and withholding oral intake. RESULTS: Twenty-eight patients were identified with hypopharyngeal or cervical esophageal perforations, mostly due to iatrogenic (nasogastric tube placement, endoscopy, endotracheal intubation) injuries (68%). Fourteen were treated initially with conservative management and 14 with initial surgery. Six patients failed conservative treatment and two patients failed surgical treatment. Patients managed conservatively who had eaten between injury and diagnosis (p=0.003), those who had 24 hours or more between the time of injury and diagnosis (p=0.026), and those who showed signs of systemic toxicity (p=0.001) were significantly more likely to fail conservative treatment and require surgery. No variables were significant for treatment failure in the surgical group. Of the 20 patients who ultimately underwent a surgical procedure, two required a second procedure. CONCLUSION: Patients who have eaten between the time of perforation and diagnosis, have 24 hours or more between injury and diagnosis, and those that show signs of systemic toxicity are at higher risk of failing conservative management and surgical drainage should be considered. For patients without these risk factors, a trial of conservative management can be attempted. PMID- 26122743 TI - External osteotomy in rhinoplasty: Piezosurgery vs osteotome. AB - PURPOSE: To achieve the desired outcome in rhinoplasty depends on many factors. Osteotomy and surgical reshaping of nasal bones are important steps that require careful planning and execution. The availability of different tools raises the question of which one provides significant advantages for both technique and surgical outcome. Our prospective randomized pilot study compared the outcome of post-traumatic rhinoplasty performed with two different external techniques: ultrasound osteotomic cut using the Piezosurgery Medical Device (Mectron, Carasco, Italy) and traditional external osteotomy. MATERIAL AND METHODS: Forty four lateral osteotomies of the nasal wall were performed in twenty-two patients. In twelve patients the osteotomies were conducted with a 2-mm traditional osteotome (control group), while in the remaining ten patients these were done with the Piezosurgery Medical Device (experimental group). RESULTS: At the postoperative evaluation, significantly lower pain, edema and ecchymosis were noticed in the experimental group (p<0.05). Moreover, the endoscopic evaluation showed fewer mucosal injuries in the experimental group (p<0.05), whereas bleeding, symmetry of the pyramid and presence of external scars, were similar in the two groups. CONCLUSIONS: In the present study, Piezosurgery Medical Device allowed for safe lateral osteotomies in rhinoplasty preliminarily demonstrating the potential to reduce some of the most frequent complications of rhinoplasty. PMID- 26122744 TI - Can performance-based financing help reaching the poor with maternal and child health services? The experience of rural Rwanda. AB - More than 20 countries in Africa are scaling up performance-based financing (PBF), but its impact on equity in access to health services remains to be documented. This paper draws on evidence from Rwanda to examine the capacity of PBF to ensure equal access to key health interventions especially in rural areas where most of the poor live. Specifically, it focuses on maternal and child health services, distinguishing two wealth groups, and uses data from a rigorous impact evaluation. Difference-in-difference technique is used, and different model specifications are tested: control for unobserved heterogeneity and common random error using linear probability model, seemingly unrelated regression equations, and clustering and fixed effects. Results suggest that in Rwanda, PBF improved efficiency rather than equity for most health services. We find that PBF achieved efficiency gains by improving access to health services for those easier to reach, generally the relatively more affluent. It turns out to be less effective in reaching the poorest. Our results illustrate the advantages of rigorous randomized impact evaluation data as results published earlier using a nationally representative survey (Demographic and Health Survey) were not able to capture the pro-rich nature of the PBF scheme in Rwanda. Our paper advocates for building mechanisms targeting the vulnerable groups in PBF strategies. It also highlights the need to understand the impact of PBF together with the specific development of health insurance coverage and the organization of the health system. PMID- 26122745 TI - Re: 'Lenghtening temporalis myoplasty: Outcome and radiographic anatomical evaluation of length required'. PMID- 26122746 TI - [Surgical management for upper urinary tract transitional cell carcinoma]. PMID- 26122747 TI - Elevated Expression of CD109 in Esophageal Squamous Cell Carcinoma. PMID- 26122748 TI - Factors affecting cataract surgical coverage and outcomes: a retrospective cross sectional study of eye health systems in sub-Saharan Africa. AB - BACKGROUND: Recently there has been a great deal of new population based evidence on visual impairment generated in sub-Saharan Africa (SSA), thanks to the Rapid Assessment of Avoidable Blindness (RAAB) survey methodology. The survey provides information on the magnitude and causes of visual impairment for planning services and measuring their impact on eye health in administrative "districts" of 0.5-5 million people. The survey results describing the quantity and quality of cataract surgeries vary widely between study sites, often with no obvious explanation. The purpose of this study was to examine health system characteristics that may be associated with cataract surgical coverage and outcomes in SSA in order to better understand the determinants of reducing the burden of avoidable blindness due to cataract. METHODS: This was a descriptive study using secondary and primary data. The outcome variables were collected from existing surveys. Data on potential district level predictor variables were collected through a semi-structured tool using routine data and key informants where appropriate. Once collected the data were coded and analysed using statistical methods including t-tests, ANOVA and the Kruskal-Wallis analysis of variance test. RESULTS: Higher cataract surgical coverage was positively associated with having at least one fixed surgical facility in the area; availability of a dedicated operating theatre; the number of surgeons per million population; and having an eye department manager in the facility. Variables that were associated with better outcomes included having biometry and having an eye department manager in the facility. CONCLUSIONS: There are a number of health system factors at the district level that seem to be associated with both cataract surgical coverage and post-operative visual acuity outcomes. This study highlights the needs for better indicators and tools by which to measure and monitor the performance of eye health systems at the district level. It is unlikely that epidemiological data alone is sufficient for planning eye health services within a district and health managers and study coordinators need to consider collecting supplementary information in order to ensure appropriate planning can take place. PMID- 26122749 TI - Huxley's Model for Muscle Contraction Revisited: The Importance of Microscopic Reversibility. AB - Andrew Huxley's model for muscle contraction is the first mechanistic description of how an energy-providing chemical reaction, ATP hydrolysis, can be coupled by a molecule (myosin) to do work in the environment in a cyclic process. The model was originally used to fit experimentally obtained force vs velocity curves, and has served as a paradigm for understanding mechanochemical coupling ever since. Despite the remarkable success in fitting kinetic data, Huxley's model is thermodynamically inconsistent in several regards, most notably in its failure to include thermal noise in the description of the mechanical transitions by which motion occurs. This inconsistency has led subsequent workers to incorrect conclusions regarding the importance of mechanical transitions for determining the direction of motion, the efficiency of energy conversion, the ratio of forward to backward steps, and the applied force necessary to stop the motion of chemically driven molecular motors. In this chapter an extension of Huxley's model is described where the principle of microscopic reversibility provides a framework for developing a thermodynamically consistent description of a molecular machine. The results show clearly that mechanical strain and the so called "power stroke" are irrelevant for determining the directionality and thermodynamic properties of any chemically driven molecular motor. Instead these properties are controlled entirely by the chemical specificity that describes how the relative rates of the ATP hydrolysis reaction depend, by allosteric interactions, on the mechanical state of the molecule. This mechanism has been termed an "information ratchet" in the literature. In contrast to the results for chemical driving, a power stroke can be a key component for the operation of an optically driven motor, the transitions of which do not obey microscopic reversibility. PMID- 26122750 TI - Response to the Commentary on "Arsenic mobility in the arsenic-contaminated Yangzonghai Lake in China". AB - This is the response to "Commentary on 'Arsenic mobility in the arsenic contaminated Yangzonghai Lake in China' by Changliang Yang et al. [Ecotoxicology and Environmental Safety, 107(2014)321-327]" (by Jing Chen et al.). To doubts and questions raised by Chen et al., we give further explanations and provide more relevant evidences. The water temperature stratification existed in Lake Yangzonghai in summer, and affected by which arsenic concentration with water depth was uneven and peaked in the bottom layer in summer. In the case of adding carbon source (glucose) and maintaining anerobic state, enhanced microbial activity promoted the release of arsenic from sediment to water which was observed in the laboratory experiments. Errors might exist in sampling, determination and calculation, but they would not change the main conclusions of the article. PMID- 26122751 TI - Promoting "Healthy Futures" to Reduce Risk Behaviors in Urban Youth: A Randomized Controlled Trial. AB - There is increasing evidence of the interconnection between educational and health outcomes. Unfortunately wide disparities exist by both socioeconomic status and race/ethnicity in educational and vocational success. This study sought to promote urban youths' career readiness as a way to reduce involvement in risk behaviors. Two hundred primarily African-American youth (ages 14-21) were recruited from a pediatric primary care clinic. Youth randomized to the intervention received three motivational interviewing sessions focused around expectations and planning for the future. Baseline and 6-month follow-up assessments included measures of career readiness and risk behavior involvement (i.e., physical fighting, alcohol and marijuana use). At 6-months, youth randomized to the intervention condition showed increased confidence in their ability to perform the behaviors needed to reach their college/career goals. Additionally, youth randomized to the intervention arm showed decreased fighting behavior (adjusted rate ratio: .27) and marijuana use (adjusted rate ratio: .61). Assisting urban youth in thinking and planning about their future holds promise as a way to reduce their involvement in risk behaviors. This study also demonstrated that motivational interviewing could be used to promote positive behaviors (i.e., career readiness). PMID- 26122752 TI - Teaching children to like and eat vegetables. AB - Higher vegetable intake has been related to lower risks of diabetes, cardiovascular disease, several cancers and obesity. Yet children consume fewer than the recommended servings of fruits and vegetables set forth by the USDA. Exposure to vegetables has successfully improved children's liking for and consumption of vegetables particularly for children younger than two years. In contrast, associative conditioning seems necessary for older children, especially with bitter vegetables. We review studies using both exposure and associative conditioning to teach children to like vegetables, including flavor-flavor learning and flavor-calorie learning. Recognizing these different processes helps reconcile discrepant literature and may provide techniques for increasing preferences for vegetables in children. Associative conditioning and exposure can be used by parents and others to enhance children's liking for and consumption of vegetables. PMID- 26122754 TI - The effect of emotional state on taste perception. AB - Taste perception can be modulated by a variety of extraneously applied influences, such as the manipulation of emotion or the application of acute stress. To evaluate the effect of more commonplace day-to-day emotional variation on taste function, taste intensity ratings and hedonic evaluations were collected from approximately 550 attendees following men's hockey games spanning the 2013 2014 season, a period encompassing 4 wins, 3 losses, and 1 tie. Since different outcomes at competitive sporting events are shown to induce varying affective response, this field study presented a unique environment to evaluate the effect of real-life emotional manipulations on our perception of taste, where previous research focused more on extraneous manipulation within a laboratory environment. Analysis revealed that positive emotions correlated with enhanced sweet and diminished sour intensities while negative emotions associated with heightened sour and decreased sweet tastes. Theoretically, both an increase in sweet and a decrease in sour taste intensity would drive acceptance of a great number of foods. Indeed, hedonic ratings for samples that were less liked (and parenthetically mostly sweet and sour in nature), selectively increased as positive affect grew, possibly due to the perceived decrease in sourness and increase in sweetness. The results of this field study indicate that emotional manipulations in the form of pleasantly or unpleasantly perceived real-life events can influence the intensity perception of taste, driving hedonics for less acceptable foods. These results suggest that such modulation of taste perception could play a role in emotional eating. PMID- 26122753 TI - Low demanding parental feeding style is associated with low consumption of whole grains among children of recent immigrants. AB - We explored the influence of immigrant mothers feeding style on their children's fruit, vegetable and whole grain intake and how this relationship differed by mother's time in the U.S. Baseline data were collected on mother-child (3-12 yrs) dyads enrolled in Live Well (n = 313), a community-based, participatory, randomized controlled lifestyle intervention (2008-2013). Socio-demographics, years of residence in the U.S., behavioral data, and responses to the Caregiver's Feeding Styles Questionnaire (CFSQ) were obtained from the mother. Measured heights and weights were obtained for both mother and child. Child dietary intake was assessed using the Block Food Screener. Separate multiple linear regression models were run, adjusting for child and mother covariates. Interactions between feeding styles and years in the U.S. (<5 and >= 5 years), ethnicity, and child age were tested. Sixty-nine percent of mothers were overweight or obese, 46% of the children were overweight or obese. For mothers in the U.S. for<5 years, having a low demanding/high responsive style was associated with lower child intake of whole grains in adjusted models vs. a high demanding/high responsive style (p < 0.05). This was not seen for mothers in the U.S. for>=5 years. Thus, the influence of feeding style on dietary intake may change with length of time in the U.S. These hypotheses-generating findings call for future research to understand how broader socio-cultural factors influence the feeding dynamic among immigrants. PMID- 26122755 TI - Energy-dense snacks can have the same expected satiation as sugar-containing beverages. AB - Sugar-sweetened beverages (SSBs) are thought to be problematic for weight management because energy delivered in liquid form may be less effective at suppressing appetite than solid foods. However, little is known about the relative 'expected satiation' (anticipated fullness) of SSBs and solid foods. This is relevant because expected satiation is an important determinant of portion selection and energy intake. Here, we used a method of constant stimuli to assess the expected satiation of test meals that were presented in combination with different caloric and non-caloric beverages (500 ml) (Experiment 1 and 2), as well as with high-energy solid snack foods (Experiment 2). All energy containing beverages and snack foods were presented in 210 kcal portions. Both experiments found that expected satiation was greater for meals containing caloric versus non-caloric beverages (201.3 +/- 17.3 vs. 185.4 +/- 14.1 kcal in Experiment 2; p < 0.05). Further, Experiment 2 showed that this difference was greater in participants who were familiar with our test beverages, indicating a role for learning. Notably, we failed to observe a significant difference in expected satiation between any of the caloric beverages and snack foods in Experiment 2 (range: 192.5-205.2 kcal; p = 0.87). This finding suggests that it may be more appropriate to consider beverages and solid foods on the same continuum, recognizing that the expected satiation of some solid foods is as weak as some beverages. PMID- 26122756 TI - Training response inhibition to food is associated with weight loss and reduced energy intake. AB - The majority of adults in the UK and US are overweight or obese due to multiple factors including excess energy intake. Training people to inhibit simple motor responses (key presses) to high-energy density food pictures reduces intake in laboratory studies. We examined whether online response inhibition training reduced real-world food consumption and weight in a community sample of adults who were predominantly overweight or obese (N = 83). Participants were allocated in a randomised, double-blind design to receive four 10-min sessions of either active or control go/no-go training in which either high-energy density snack foods (active) or non-food stimuli (control) were associated with no-go signals. Participants' weight, energy intake (calculated from 24-h food diaries), daily snacking frequency and subjective food evaluations were measured for one week pre and post-intervention. Participants also provided self-reported weight and monthly snacking frequency at pre-intervention screening, and one month and six months after completing the study. Participants in the active relative to control condition showed significant weight loss, reductions in daily energy intake and a reduction in rated liking of high-energy density (no-go) foods from the pre-to post-intervention week. There were no changes in self-reported daily snacking frequency. At longer-term follow-up, the active group showed significant reductions in self-reported weight at six months, whilst both groups reported significantly less snacking at one- and six-months. Excellent rates of adherence (97%) and positive feedback about the training suggest that this intervention is acceptable and has the potential to improve public health by reducing energy intake and overweight. PMID- 26122757 TI - The speed of our mental soundtracks: Tracking the tempo of involuntary musical imagery in everyday life. AB - The study of spontaneous and everyday cognitions is an area of rapidly growing interest. One of the most ubiquitous forms of spontaneous cognition is involuntary musical imagery (INMI), the involuntarily retrieved and repetitive mental replay of music. The present study introduced a novel method for capturing temporal features of INMI within a naturalistic setting. This method allowed for the investigation of two questions of interest to INMI researchers in a more objective way than previously possible, concerning (1) the precision of memory representations within INMI and (2) the interactions between INMI and concurrent affective state. Over the course of 4 days, INMI tempo was measured by asking participants to tap to the beat of their INMI with a wrist-worn accelerometer. Participants documented additional details regarding their INMI in a diary. Overall, the tempo of music within INMI was recalled from long-term memory in a highly veridical form, although with a regression to the mean for recalled tempo that parallels previous findings on voluntary musical imagery. A significant positive relationship was found between INMI tempo and subjective arousal, suggesting that INMI interacts with concurrent mood in a similar manner to perceived music. The results suggest several parallels between INMI and voluntary imagery, music perceptual processes, and other types of involuntary memories. PMID- 26122758 TI - Assessment of Genetic Heterogeneity in Structured Plant Populations Using Multivariate Whole-Genome Regression Models. AB - Plant breeding populations exhibit varying levels of structure and admixture; these features are likely to induce heterogeneity of marker effects across subpopulations. Traditionally, structure has been dealt with as a potential confounder, and various methods exist to "correct" for population stratification. However, these methods induce a mean correction that does not account for heterogeneity of marker effects. The animal breeding literature offers a few recent studies that consider modeling genetic heterogeneity in multibreed data, using multivariate models. However, these methods have received little attention in plant breeding where population structure can have different forms. In this article we address the problem of analyzing data from heterogeneous plant breeding populations, using three approaches: (a) a model that ignores population structure [A-genome-based best linear unbiased prediction (A-GBLUP)], (b) a stratified (i.e., within-group) analysis (W-GBLUP), and (c) a multivariate approach that uses multigroup data and accounts for heterogeneity (MG-GBLUP). The performance of the three models was assessed on three different data sets: a diversity panel of rice (Oryza sativa), a maize (Zea mays L.) half-sib panel, and a wheat (Triticum aestivum L.) data set that originated from plant breeding programs. The estimated genomic correlations between subpopulations varied from null to moderate, depending on the genetic distance between subpopulations and traits. Our assessment of prediction accuracy features cases where ignoring population structure leads to a parsimonious more powerful model as well as others where the multivariate and stratified approaches have higher predictive power. In general, the multivariate approach appeared slightly more robust than either the A- or the W-GBLUP. PMID- 26122759 TI - Are Epstein-Barr Virus-positive and -negative Gastric Carcinomas, With Lymphoid Stroma, Single Entity or Different Entities? PMID- 26122760 TI - Pulling the Trigger on Pancreatic Cysts. PMID- 26122761 TI - Development and Validation of a Prediction Model for Admission After Endoscopic Retrograde Cholangiopancreatography. AB - BACKGROUND & AIMS: In outpatients undergoing endoscopic retrograde cholangiopancreatography (ERCP) with anesthesia, rates of and risk factors for admission are unclear. We aimed to develop a model that would allow physicians to predict hospitalization of patients during postanesthesia recovery. METHODS: We conducted a retrospective study of data from ERCPs performed on outpatients from May 2012 through October 2013 at the Indiana University School of Medicine. Medical records were abstracted for preanesthesia, intra-anesthesia, and early (within the first hour) postanesthesia characteristics potentially associated with admission. Significant factors associated with admission were incorporated into a logistic regression model to identify subgroups with low, moderate, or high probabilities for admission. The population was divided into training (first 12 months) and validation (last 6 months) sets to develop and test the model. RESULTS: We identified 3424 ERCPs during the study period; 10.7% of patients were admitted to the hospital, and 3.7% developed post-ERCP pancreatitis. Postanesthesia recovery times were significantly longer for patients requiring admission (362.6 +/- 213.0 minutes vs 218.4 +/- 71.8 minutes for patients not admitted; P < .0001). A higher proportion of admitted patients had high-risk indications. Admitted patients also had more severe comorbidities, higher baseline levels of pain, longer procedure times, performance of sphincter of Oddi manometry, higher pain during the first hour after anesthesia, and greater use of opiates or anxiolytics. A multivariate regression model identified patients who were admitted with a high level of accuracy in the training set (area under the curve, 0.83) and fair accuracy in the validation set (area under the curve, 0.78). On the basis of this model, nearly 50% of patients could be classified as low risk for admission. CONCLUSION: By using factors that can be assessed through the first hour after ERCP, we developed a model that accurately predicts which patients are likely to be admitted to the hospital. Rates of admission after outpatient ERCP are low, so a policy of prolonged observation might be unnecessary. PMID- 26122762 TI - Secondary Extramedullary Plasmablastic Myeloma of the Small Bowel. PMID- 26122763 TI - Comment on "Patients With Roux-en-Y Gastric Bypass Require Increased Sedation During Upper Endoscopy". PMID- 26122765 TI - Shifting Away From Fee-For-Service: Alternative Approaches to Payment in Gastroenterology. AB - Fee-for-service payments encourage high-volume services rather than high-quality care. Alternative payment models (APMs) aim to realign financing to support high value services. The 2 main components of gastroenterologic care, procedures and chronic care management, call for a range of APMs. The first step for gastroenterologists is to identify the most important conditions and opportunities to improve care and reduce waste that do not require financial support. We describe examples of delivery reforms and emerging APMs to accomplish these care improvements. A bundled payment for an episode of care, in which a provider is given a lump sum payment to cover the cost of services provided during the defined episode, can support better care for a discrete procedure such as a colonoscopy. Improved management of chronic conditions can be supported through a per-member, per-month (PMPM) payment to offer extended services and care coordination. For complex chronic conditions such as inflammatory bowel disease, in which the gastroenterologist is the principal care coordinator, the PMPM payment could be given to a gastroenterology medical home. For conditions in which the gastroenterologist acts primarily as a consultant for primary care, such as noncomplex gastroesophageal reflux or hepatitis C, a PMPM payment can support effective care coordination in a medical neighborhood delivery model. Each APM can be supplemented with a shared savings component. Gastroenterologists must engage with and be early leaders of these redesign discussions to be prepared for a time when APMs may be more prevalent and no longer voluntary. PMID- 26122764 TI - Analyses of the Post-reflux Swallow-induced Peristaltic Wave Index and Nocturnal Baseline Impedance Parameters Increase the Diagnostic Yield of Impedance-pH Monitoring of Patients With Reflux Disease. AB - BACKGROUND & AIMS: Analyses of impedance parameters such as the post-reflux swallow-induced peristaltic wave (PSPW) index and the mean nocturnal baseline impedance (MNBI) have been proposed to increase the accuracy of diagnosis of reflux disease. We assessed whether these improve the diagnostic yield of impedance pH monitoring of reflux disease. METHODS: We performed a prospective study of consecutive patients with proton pump inhibitor-responsive heartburn who underwent 24-hour impedance pH monitoring at hospitals in Italy from January 2011 through December 2013. Reviewers blindly analyzed off-therapy impedance pH tracings from 289 patients with proton pump inhibitor-responsive heartburn, 68 with erosive reflux disease and 221 with non-erosive reflux disease (NERD), along with 50 healthy individuals (controls). The PSPW index, the MNBI, the esophageal acid exposure time, the number of total refluxes, and the bolus exposure were calculated, as well as the symptom association probability (SAP) and the symptom index (SI). RESULTS: In receiver operating characteristic analysis, the area under curve of the PSPW index (0.977; 95% confidence interval, 0.961-0.993) was significantly greater than that of the other impedance pH parameters in identifying patients with reflux disease (P < .001). The PSPW index and the MNBI identified patients with erosive reflux disease with the highest level of sensitivity (100% and 91%, respectively), as well as the 118 pH-positive (99% and 86%) and 103 pH-negative (77% and 56%) cases of NERD. The PSPW index and the MNBI identified pH-negative NERD with the highest level of sensitivity; values were 82% and 52% for the 65 SAP-positive and/or SI-positive cases and 68% and 63% for the 38 SAP-negative and SI-negative cases. Diagnoses of NERD were confirmed by pH only criteria, including those that were positive on the basis of the SAP or SI, for 165 of 221 cases (75%) and by impedance pH criteria for 216 of 221 cases (98%) (P = .001). CONCLUSIONS: The PSPW index and the MNBI increase the diagnostic yield of impedance pH monitoring of patients with reflux disease. Analysis of impedance pH data by calculating the PSPW index and the MNBI can increase the accuracy of diagnosis of patients with reflux disease, compared with pH-only data. PMID- 26122766 TI - The Debate Continues Over the Best Method of Endoscopic Surveillance for Colorectal Cancer in Patients With Colitis. PMID- 26122768 TI - Coronary artery perforation at the level of two-overlapping bioresorbable vascular scaffolds: The importance of vessel sizing and scaffold thickness. AB - Everolimus-eluting bioresorbable vascular scaffolds (BVS) have emerged as an alternative to conventional metallic stents and have demonstrated favorable outcomes in simple coronary lesions. As the use of BVS increases and extends to more complex lesion subsets, intraprocedural complications are expected to occur. We describe for the first time the occurrence of a free coronary perforation localized at the exact point of overlap of two BVS. This case illustrates the importance of appropriate vessel sizing, especially when BVS overlapping is performed in a small vessel, and potential advantages of scaffold juxtaposition compared to overlapping when implanting BVS in series. PMID- 26122767 TI - Risk of Acute Liver Failure in Patients With Drug-Induced Liver Injury: Evaluation of Hy's Law and a New Prognostic Model. AB - BACKGROUND & AIMS: Few studies have evaluated the ability of laboratory tests to predict risk of acute liver failure (ALF) among patients with drug-induced liver injury (DILI). We aimed to develop a highly sensitive model to identify DILI patients at increased risk of ALF. We compared its performance with that of Hy's Law, which predicts severity of DILI based on levels of alanine aminotransferase or aspartate aminotransferase and total bilirubin, and validated the model in a separate sample. METHODS: We conducted a retrospective cohort study of 15,353 Kaiser Permanente Northern California members diagnosed with DILI from 2004 through 2010, liver aminotransferase levels above the upper limit of normal, and no pre-existing liver disease. Thirty ALF events were confirmed by medical record review. Logistic regression was used to develop prognostic models for ALF based on laboratory results measured at DILI diagnosis. External validation was performed in a sample of 76 patients with DILI at the University of Pennsylvania. RESULTS: Hy's Law identified patients that developed ALF with a high level of specificity (0.92) and negative predictive value (0.99), but low level of sensitivity (0.68) and positive predictive value (0.02). The model we developed, comprising data on platelet count and total bilirubin level, identified patients with ALF with a C statistic of 0.87 (95% confidence interval [CI], 0.76-0.96) and enabled calculation of a risk score (Drug-Induced Liver Toxicity ALF Score). We found a cut-off score that identified patients at high risk patients for ALF with a sensitivity value of 0.91 (95% CI, 0.71-0.99) and a specificity value of 0.76 (95% CI, 0.75-0.77). This cut-off score identified patients at high risk for ALF with a high level of sensitivity (0.89; 95% CI, 0.52-1.00) in the validation analysis. CONCLUSIONS: Hy's Law identifies patients with DILI at high risk for ALF with low sensitivity but high specificity. We developed a model (the Drug Induced Liver Toxicity ALF Score) based on platelet count and total bilirubin level that identifies patients at increased risk for ALF with high sensitivity. PMID- 26122769 TI - Structure Based Library Design (SBLD) for new 1,4-dihydropyrimidine scaffold as simultaneous COX-1/COX-2 and 5-LOX inhibitors. AB - The various scaffolds containing 1,4-dihydropyrimidine ring were designed by considering the environment of the active site of COX-1/COX-2 and 5-LOX enzymes. The structure-based library design approach, including the focused library design (Virtual Combinatorial Library Design) and virtual screening was used to select the 1,4-dihydropyrimidine scaffold for simultaneous inhibition of both enzyme pathways (COX-1/COX-2 and 5-LOX). The virtual library on each 1,4 dihydropyrimidine scaffold was enumerated in two alternative ways. In first way, the chemical reagents at R groups were filtered by docking of scaffold with single position substitution, that is, only at R1, or R2, or R3, ... Rn on COX-2 enzyme using Glide XP docking mode. The structures that do not dock well were removed and the library was enumerated with filtered chemical reagents. In second alternative way, the single position docking stage was bypassed, and the entire library was enumerated using all chemical reagents by docking on the COX-2 enzyme. The entire library of approximately 15,629 compounds obtained from both ways after screening for drug like properties, were further screened for their binding affinity against COX-1 and 5-LOX enzymes using Virtual Screening Workflow. Finally, 142 hits were obtained and divided into two groups based on their binding affinity for COX-1/COX-2 and for both enzyme pathways (COX-1/COX-2 and 5-LOX). The ten molecules were selected, synthesized and evaluated for their COX-1, COX-2 and 5-LOX inhibiting activity. PMID- 26122770 TI - Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines. AB - In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concentrations. Introduction of iodine at C7 resulted in significant enhancement of potency by reducing the IC50 into sub-micromolar levels, thereby suggesting the importance of a halogen at C7. This finding was further supported by an increased antiproliferative effect for 4 as compared to 3. Cell-cycle and apoptosis studies conducted on the two potent compounds 1 and 2 showed differences in their cytotoxic mechanisms in triple negative breast cancer MDA-MB 231 cells, wherein compound 1 induced cells to accumulate at the G2/M stage with little evidence of apoptotic death. In contrast, compound 2 robustly induced apoptosis with concomitant G2/M cell cycle arrest in this cell model. PMID- 26122771 TI - Discovery of a novel class anti-proliferative agents and potential inhibitors of EGFR tyrosine kinases based on 4-anilinotetrahydropyrido[4,3-d]pyrimidine scaffold: Design, synthesis and biological evaluations. AB - A novel series of 4-arylamino-6/7-substituted-5,6,7,8-tetrahydropyrido[4,3 d]pyrimidines were designed, synthesized and their biological activities as the potential anti-proliferative agents and EGFR kinase inhibitors were evaluated. Both of N-acrylamide fragment in THPPs and 4-aniline groups with substituents played key roles for their significant anti-proliferative activities against four cancer cell lines (HT29, A549, H460 and H1975). Especially inhibitory activity of Gefitinib-resistant H1975 were showed more favorable, which could be observed from compounds 13b, 13c, 13n, 13o, 13p, 13r, 13s, 13u and 24c obviously. By evaluation of inhibiting EGFR and HER2 kinases, seven compounds (13b, 13g, 13n, 13o, 13p, 13r and 13s) showed stronger EGFR potency with IC50 ? 18 nM, which could also be understood by preliminary docking study of 13b with EGFR kinase. In view of the primary SAR, bisarylaniline derivatives (13o, 13p, 13r and 13s) showed obvious improvements on HER2 inhibition, which indicated their being potential EGFR/HER2 dual kinase inhibitors. PMID- 26122772 TI - gamma-Benzylidene digoxin derivatives synthesis and molecular modeling: Evaluation of anticancer and the Na,K-ATPase activity effect. AB - Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with gamma-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase alpha1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with gamma-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives. PMID- 26122773 TI - Development of novel DIF-1 derivatives that selectively suppress innate immune responses. AB - The multiple pharmacological activities of differentiation-inducing factor-1 (DIF 1) of the cellular slime mold Dictyostelium discoideum led us to examine the use of DIF-1 as a 'drug template' to develop promising seed compounds for drug discovery. DIF-1 and its derivatives were synthesized and evaluated for their regulatory activities in innate immune responses. We found two new derivatives (4d and 5e) with highly selective inhibitory activities against production of the antimicrobial peptide attacin in Drosophila S2 cells and against production of interleukin-2 in Jurkat cells. PMID- 26122774 TI - Synthesis and biological evaluation of novel histone deacetylases inhibitors with nitric oxide releasing activity. AB - A novel series of histone deacetylases inhibitors (HDACIs) containing benzofuroxan pharmacophore as nitric oxide (NO) donor were designed based on the combination principle and 'multifunctional drugs' theory. As a novel study on embedding NO donor into the structure of HDACIs, all designed hybrid compounds, especially 19d and 24d, displayed remarkable HDACs inhibitory activity and outstanding antiproliferative activity on tumor cells. Besides, they could produce high levels of NO in HCT-116 cells; furthermore, their antiproliferative activity on HCT-116 cells could be diminished by pretreatment with hemoglobin, as the NO scavenger, in a dose-dependent manner. All in all, our designed compounds displayed great inhibitory activities and might offer a prospective avenue to discover novel anti-cancer drugs. PMID- 26122775 TI - Rapid response teams in adult hospitals: time for another look? AB - Rapid response teams (RRT), alternatively termed medical emergency teams, have become part of the clinical landscape in the majority of adult hospitals throughout Australia and New Zealand. These teams aim to bring critical care expertise to the bedside of clinically deteriorating patients residing in general hospital wards with the aim of preventing adverse outcomes, in particular death or cardiorespiratory arrests. While the concept of RRT has considerable face validity, there is little high quality evidence of their effectiveness and much uncertainty as to the optimal methods for identifying patients in need of RRT and calling the RRT (afferent limb) and how, and with whom, the RRT should then respond (efferent limb). Adverse unintended consequences of RRT systems and the opportunity costs involved in maintaining such systems have not been subject to study, amid concerns RRT may be compensating for other potentially remediable system of care failures. This article presents an overview of the current state of play of RRT in hospital practice as they pertain to the care of adult patients and identifies several issues around their implementation and evaluation that should be subject to further research. PMID- 26122777 TI - The Physiological Basis and Nutritional Function of Alpha-ketoglutarate. AB - Alpha-Ketoglutarate (AKG) is a biological substance that plays important roles in cell metabolism and physiology. AKG is synthesized from glucose or oxaloacetate plus pyruvate. As an intermediate of the tricarboxylic acid cycle, AKG is essential for the oxidation of fatty acids, amino acids, and glucose. Extracellular AKG is a significant source of energy for cells of the gastrointestinal tract. As a precursor for the synthesis of glutamate and glutamine in multiple tissues (including liver, skeletal muscle, heart, brain, and white adipose tissue), AKG bridges carbohydrate and nitrogen metabolism for both conservation of amino acids and ammonia detoxification. Additionally, emerging evidence shows that AKG is a regulator of gene expression and cell signaling pathways (including the mammalian target of rapamycin and AMPactivated protein kinase). Thus, AKG is an attractive dietary supplement in animal and human nutrition to improve cellular energy status, immunity, and health. PMID- 26122778 TI - Functions of Antimicrobial Peptides in Gut Homeostasis. AB - Antimicrobial peptides (AMPs), produced by several species including bacteria, insects, amphibians and mammals as well as by chemical synthesis and genetically engineered microorganisms, are of great importance in maintaining normal gut homeostasis. AMPs exhibit a broad spectrum of antimicrobial activity and inhibit microbial cells by interaction with their membranes or by other mechanisms, such as inhibition of cell-wall synthesis or suppression of nucleic acid or protein synthesis. In addition to their direct antimicrobial functions, they have multiple roles in the stabilization of epithelial barrier integrity and function as potent immune regulators. The fate of AMPs in vivo is poorly understood, prompting the need for studying AMPs pharmacokinetics. This review summarizes the current knowledge about the basic biology of AMPs and discusses the features of AMPs in gut homeostasis and their relative mechanisms of action. PMID- 26122779 TI - Interaction between Microbes and Host Intestinal Health: Modulation by Dietary Nutrients and Gut-Brain-Endocrine-Immune Axis. AB - The mammalian gut, the site of digestion and nutrients absorption, harbors diverse microbes that play an essential role in maintaining physiological homeostasis of the gastrointestinal system. These commensal microbes are important for the normal development of the host immune system and alteration of the microbiota of gastrointestinal system has been found to play an important role in the development of obesity, metabolic syndromes such as type 2 diabetes, and cardiovascular diseases. Several recent studies with mouse models and in humans have demonstrated that intestinal microbiota has important role in host metabolism by regulating energy absorption and modulating the endocrine functions. A variety of nutrients and metabolites derived from commensal bacteria have been proved to be important regulators in improving gut barrier functions and immune homeostasis. Here we review current literature on the interactions between microbes and host in the Gastrointestinal (GI) tract and based on these interactions we proposed a hypothesis in which the microbiota interacts with the host gastrointestine through a gut-brainendocrine- immune system. By understanding this system, we should be in better position to develop treatment for metabolic diseases and inflammation in human and animals. PMID- 26122780 TI - Crosstalk Between Bioactive Peptide and Intestinal Barrier in Gut Homeostasis. AB - The bioactive peptides are protein fragments which have a positive impact on the intestinal homeostasis. Intestinal homeostasis depends on the diverse functions of intestinal barrier including the microbiological, physical, chemical and immunological barriers. Defects in intestinal barrier function are associated with intestinal diseases. In this review, we will present current knowledge of the crosstalk between bioactive peptides and intestinal barrier during gut homeostasis. PMID- 26122781 TI - Soybean Antigen Proteins and their Intestinal Sensitization Activities. AB - Soybean is widely utilized in the food and feed industries. However, soybean contains many anti-nutritional factors that limit its extended application. The two most important antigenic proteins are glycinin and beta-conglycinin. When young animals are fed diets containing soybean protein, a small portion of undigested proteins enters the lymph and blood through gaps between the intestinal epithelial cells. These macromolecules have considerable antigenic activity and stimulate the immune system resulting in specific antigen-antibody reactions and T lymphoid cell-mediated delayed hypersensitivity. A current focus of research is to develop methods to decrease the immuno-reactivity of soybean proteins. Several strategies have been developed to prevent food allergies including those feed processing and plant breeding. The latest studies indicate that certain kinds of immuno-modulators, such as vitamin C and lipoic acid, may specifically block the IgE mediated anaphylaxis and these may provide new insight into the effective prevention of soybean-induced allergy and perhaps other food allergies. This review is divided into seven parts including (1) Allergenic proteins found in soybean; (2) Structure-function relationships of allergenic proteins in soybean; (3) Extraction, purification and detection of allergenic proteins in soybean; (4) Anaphylaxis induced by allergenic proteins in soybean; (5) The potential mechanism of soybean allergy; (6) Prevention and treatment of soybean allergy; (7) The effects of plant breeding on the antigenicity of allergen proteins in soybean. Being fully aware of the soy protein antigen and finding the methods to eliminate anaphylaxis induced by soybean proteins will help to significantly improve efficiency of soybean protein utilization. PMID- 26122782 TI - Crosstalk Between The Immune Receptors and Gut Microbiota. AB - The mucosal surfaces of the intestinal tract are constantly exposed to complex microbial communities that contain commensal microorganisms and potential pathogens. Therefore, hosts harbor multiple molecular mechanisms to modulate the gut innate immunity to achieve gut-microbe homeostasis. Pattern recognition receptors (PRRs), such as Toll-like receptor (TLR) and nucleotide oligomerization domain (NOD)-like receptor (NLR), play a key role in sensing pathogens and promoting the induction of innate effectors. Gut microbiota, through PRRs, can modulate the expression of genes involved in inflammatory responses and the production of antimicrobial peptides. In turn, the expression of PRRs affects the structure of gut microbiota in health or disease status. Deficiency in PRRs such as NOD2 and TLR5 can alter the gut microbiota composition in mice. The crosstalk between PRRs and microbiota connects the microbial action with the host response. This article outlines recent advances in the role of immune sensors in the gut microbiota balance and the related microbiota-host interaction. PMID- 26122783 TI - The Role of Autophagy in the Gut Pathogens Clearance and Evasion. AB - The mammalian intestine harbors a mass of microorganisms that is essential to maintain intestinal epithelium homeostasis and health. However, some microbes can damage the epithelial mucosal barrier to utilize nutrients for their survival and growth. Autophagy is a highly conserved cellular process that targets cytoplasmic damaged organelles and some cellular molecules to lysosome for degradation. Accumulating studies have demonstrated that autophagy plays an important role in the innate immune system in response to different gut pathogens. For instance, autophagy can be induced to mediate the process of pathogenic infection during pathogens invasion. In this review, we mainly discuss the steps of autophagy pathway mediated by microbes and the role of autophagy in the gut pathogens clearance and evasion. PMID- 26122784 TI - Metabolites of Dietary Protein and Peptides by Intestinal Microbes and their Impacts on Gut. AB - Dietary protein is a vital nutrient for humans and animals, which is primarily digested into peptides and free amino acids (FAAs) in the upper gastrointestine with the help of proteases. The products are absorbed by the enterocytes and are metabolized in different organs of body. Dietary protein, peptides and FAAs that escape digestion and absorption of the small intestine will enter the large intestine for further fermentation by the vast gut microbiota. Particularly, amino acid (AAs) metabolism by bacteria occurs via either deamination or decarboxylation reactions and generates short chain fatty acids (SCFAs) or amines, respectively. These metabolites elicit a wide range of biological functions via different receptors and mechanisms. This review discusses the interaction between protein metabolites and gastrointestine, illustrates regulation of intestinal motility and immune response by SCFAs and their receptors, and focuses on modulation of intestinal inflammation and signal transduction by biogenic amines (BAs) involving polyamines and monoamine neurotransmitters. PMID- 26122785 TI - Transcriptional Regulation of Antimicrobial Host Defense Peptides. AB - Host defense peptides (HDPs) are of either myeloid or epithelial origin with antimicrobial and immunomodulatory functions. Due to HDP's ability to physically disrupt bacterial cell membranes and profoundly regulate host innate and adaptive immunity, microbial resistance to these peptides is rare. As an important first line of defense, HDPs are mostly present in epithelial cells of the digestive, respiratory or urogenital tracts as well as in the granules of neutrophils, macrophages or intestinal secretory Paneth cells. HDPs are either directly released or inducibly expressed upon exposure to microbes or microbial products, although certain pathogens such as Shigella have evolved an ability to down regulate HDP synthesis as an immune invasion strategy. Even if a majority of HDPs are induced by infection and inflammation, it is undesirable to augment HDP synthesis and host immunity using pathogen-associated molecular patterns because of an excessive inflammation that is usually accompanied. Recently, several different classes of small-molecule compounds have been identified with the capacity to specifically induce HDP synthesis without triggering extensive inflammatory response. A few HDPinducing compounds even synergize with each other in HDP induction. In this review, we summarized the recent progresses on transcriptional regulation of HDPs by infection and inflammation and by small molecule compounds. We suggested the potential of dietary regulation of HDPs as a novel antibiotic-alternative strategy to antimicrobial therapy, as oral supplementation of HDP-inducing compounds has shown promise of preventing and controlling infections in humans and several animal species. PMID- 26122786 TI - They Must Hold Tight: Junction Proteins, Microbiota And Immunity In Intestinal Mucosa. AB - Homeostasis of the immune system depends on several factors. The gastrointestinal tract plays an important role in maintaining our immune system. With this aim, the intestinal immune system interacts with epithelial barrier molecules, especially tight junction proteins, that are key molecules involved in controlling paracellular permeability to increase the protection barrier against external antigens or possibly to respond to commensal microorganisms. During intestinal inflammatory diseases, the expression of innate immune receptors in intestinal epithelial cells and infiltration of immune cells are related, but it is still unclear how the immune system induces modulation of paracellular permeability. In this review, we provide an overview of the understanding of how the immune system modulates the expression of tight junctions to maintain the mucosal immune system. PMID- 26122787 TI - Experiences of a PAR Intervention in Care for Older People. AB - Participatory action research (PAR) is an approach for dealing with problematic areas in practice. Follow-up studies in which participants describe their participation in PAR in detail are rare. This follow-up study aimed to describe care providers' (CPs) experiences of having participated in a PAR intervention designed to assist them to constructively deal with troubled conscience. Twenty nine CPs who participated in a PAR intervention were interviewed 2 to 4 months post-intervention. Content analysis was used to analyze the data. The analysis revealed three main categories: the importance of having a communal and collaborative meeting place, perceived changes in daily life, and "It has been good, but it has not solved all of our problems." Using PAR to deal with troubled conscience might be an important organizational investment for the future that can help prevent ill health among CPs and maintain or improve the quality of care. PMID- 26122788 TI - The Presence of Symptoms With Comorbid Conditions in Individuals With Multiple Sclerosis (MS). AB - Individuals with multiple sclerosis (MS) may experience symptoms that impact comorbid conditions and quality of life (QOL). There is some evidence that symptom severity may vary in certain common health conditions in this population. We aimed to examine symptom severity in light of comorbid conditions commonly seen in individuals with MS (N = 339). Using a cross-sectional Internet survey, we found there was a significant increase in symptom severity of common symptoms of fatigue, imbalance, and weakness, specifically with presence or absence of certain comorbid conditions (depression, arthritis, migraine headaches, coronary artery disease [CAD]). These findings endorse the presence of more severe symptoms with certain comorbid conditions compared with individuals with MS who do not report having comorbid conditions. The findings support the importance of symptom management in individuals with MS who also have comorbid conditions. PMID- 26122789 TI - Finite element analysis of the residual thermal stresses on functionally gradated dental restorations. AB - The aim of this work was to study, using the finite element method (FEM), the distribution of thermal residual stresses arising in metal-ceramic dental restorations after cooling from the processing temperature. Three different interface configurations were studied: with conventional sharp transition; one with a 50% metal-50% ceramic interlayer; and one with a compositionally functionally gradated material (FGM) interlayer. The FE analysis was performed based on experimental data obtained from Dynamic Mechanical Analysis (DMA) and Dilatometry (DIL) studies of the monolithic materials and metal/ceramic composites. Results have shown significant benefits of using the 50% metal-50% ceramic interlayer and the FGM interlayer over the conventional sharp transition interface configuration in reduction of the thermal residual stress and improvement of stress profiles. Maximum stresses magnitudes were reduced by 10% for the crowns with 50% metal-50% ceramic interlayer and by 20% with FGM interlayer. The reduction in stress magnitude and smoothness of the stress distribution profile due to the gradated architectures might explain the improved behavior of these novel dental restorative systems relative to the conventional one, demonstrated by in-vitro studies already reported in literature. PMID- 26122790 TI - Functional and molecular structural analysis of dentine interfaces promoted by a Zn-doped self-etching adhesive and an in vitro load cycling model. AB - The aim of this study was to evaluate if mechanical cycling influences bioactivity and bond strength of resin-dentine interface after bonding with Zn doped self-etching adhesives. Sound dentine surfaces were bonded with Clearfil SE Bond (SEB), 10 wt% ZnO microparticles or 2 wt% ZnCl2 were added into the SEB primer (P) or bonding (Bd) for Zn-doping. Bonded interfaces were stored in simulated body fluid (24h), and then tested or submitted to mechanical loading. Microtensile bond strength testing was performed. Debonded dentine surfaces were studied by scanning electron microscopy. Remineralisation of the bonded interfaces was assessed by nano-indentation, Raman spectroscopy, and Masson's trichrome staining. Load cycling (LC) increased the percentage of adhesive failures in all groups. LC increased the Young's modulus (Ei) at the hybrid layer (HL) when SEB, SEB.P-ZnO and SEB.P-ZnCl2 were applied, but decreased when both ZnO and ZnCl2 were incorporated into the bonding. Ei was higher when Zn compounds were incorporated into the primer (SEB.P). ZnO promoted an increase, and ZnCl2 a decrease, of both the relative presence of minerals and crystallinity, after LC. LC increased collagen crosslinking with both SEB.P-ZnO and SEB.P-ZnCl2. The ratios which reflect the nature of collagen increased, in general, at both HL and BHL after LC, confirming recovery, better organisation, improved structural differences and collagen quality. After loading, trichrome staining reflected a deeper demineralised dentine fringe when Zn-doped compounds were incorporated into SEB.Bd. Multiple Zn-rich phosphate deposits and salt formations were detected. Mineral precipitates nucleated in multilayered platforms or globular formations on peritubular and intertubular dentine. PMID- 26122791 TI - Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): blocking 5HT3 receptors enhances release of serotonin, norepinephrine, and acetylcholine. AB - Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. 5HT3 receptor antagonism is one of these actions, and this leads to increased release of norepinephrine (NE), acetylcholine (ACh), and serotonin (5HT) within various brain circuits. PMID- 26122792 TI - Strategies from UW-Madison for rescuing biomedical research in the US. AB - A cross-campus, cross-career stage and cross-disciplinary series of discussions at a large public university has produced a series of recommendations for addressing the problems confronting the biomedical research community in the US. PMID- 26122793 TI - A Case of Noonan Syndrome with Multiple Subcutaneous Tumours with MAPK-ERK/p38 Activation. PMID- 26122794 TI - Transient 5-oxoprolinuria: unusually high anion gap acidosis in an infant. AB - Transient 5-oxoprolinuria is a phenomenon that is well recognised in adults. We illustrate an unusual paediatric case of transient 5-oxoprolinuria presenting during an episode of severe sepsis with concomitant paracetamol use. The 15-month old patient had an extremely high anion gap metabolic acidosis. Adequate resuscitation failed to correct the biochemical disturbance, and high levels of 5 oxoproline were identified. A combination of haemofiltration, replenishment of glutathione stores with N-acetylcysteine and cessation of paracetamol administration resulted in the resolution of the acidosis. Subsequent testing following treatment of the sepsis revealed no ongoing 5-oxoprolinuria. CONCLUSION: Transient 5-oxoprolinuria has been previously reported in the adult population during episodes of severe sepsis and various pharmaceutical interventions. This case illustrates that it is a phenomenon that should be considered in paediatric patients where a very high anion gap metabolic acidosis exists that cannot be explained by the biochemical indices. WHAT IS KNOWN: * 5 oxoprolinuria in the paediatric population is usually secondary to an inborn error of metabolism. * Transient 5-oxoprolinuria is well recognised in adults during episodes of severe glutathione depletion. WHAT IS NEW: * Transient 5 oxoprolinuria is a phenomenon rarely reported in the paediatric population. * It highlights the importance of investigating a high anion gap such that unusual diagnoses are not missed. PMID- 26122795 TI - In situ characterization of organo-modified and unmodified montmorillonite aqueous suspensions by UV-visible spectroscopy. AB - UV-visible (UV-Vis) spectroscopy (Tyndall spectra) was applied and tested for its ability to measure organo-modified and unmodified montmorillonite (MMT) clays in aqueous suspensions. A full factorial design of experiments was used to study the influence of pH, NaCl and clay concentrations on the average particle size of the clay agglomerates. The methodology was evaluated by observing results that were consistent with previous research about the unmodified clay's behavior in aqueous suspensions. The results from this evaluation corresponded to accepted theories about the unmodified clay's behavior, indicating that the methodology is precise enough to distinguish the effects of the studied factors on these clay suspensions. The effect of clay concentration was related to the amount of ions per clay particle for the unmodified clay, but was not significant for the organo modified MMT. The average particle size of the organo-modified MMT in suspension was significantly larger than that of the unmodified clay. Size of the organo modified MMT agglomerates in suspension decreased in the presence of NaCl and at both high and low pH; this behavior was opposite to that of the unmodified clay. These results demonstrate that the UV-Vis methodology is well-suited for characterizing clay particle size in aqueous suspensions. The technique also is simple, rapid, and low-cost. PMID- 26122796 TI - Rapid removal and decomposition of gaseous acetaldehyde by the thermo- and photo catalysis of gold nanoparticle-loaded anatase titanium(IV) oxide. AB - Gold nanoparticles (NPs) with a mean particle size ranging from 2.1 to 7.4 nm were loaded on anatase TiO2 particles (Au/TiO2) by the heating temperature-varied deposition precipitation technique. This study has shown that Au/TiO2 with Au particle size <3 nm and TiO2 surface area >50 m(2) g(-1) can be a promising environmental catalyst for the rapid removal and decomposition of gaseous acetaldehyde in a closed space. The Au loading on TiO2 causes a drastic enhancement of the acetaldehyde adsorption in the dark, and the adsorption amount increases as the Au particle size decreases. This result originates from the thermocatalytic activity of Au/TiO2 for the oxidation of acetaldehyde to acetic acid under ambient conditions. The resulting acetic acid spontaneously moves to the TiO2 surface due to the great adsorptivity for the carboxyl group. Consequently, the acetaldehyde adsorption amount strongly depends on the TiO2 surface area in addition to the Au particle size. UV-light irradiation of acetaldehyde (or acetate)-adsorbed Au/TiO2 leads to the complete decomposition to carbon dioxide by the high photocatalytic activity of anatase TiO2. PMID- 26122797 TI - Preparation and characterization of VO2(M)-SnO2 thermochromic films for application as energy-saving smart coatings. AB - Novel VO2(M)/SnO2 heterostructured nanorods are prepared by combining the conventional hydrothermal synthesis method and post annealing process. The results reveal that the nanosized SnO2 particles are not only successfully grown on the surface of the VO2 nanorods but also uniformly distribute on VO2 without aggregation. The existence of the SnO2 nanoparticles inhibits the aggregation during the annealing process and widens the band gap of the VO2 crystals from 0.75 to 1.7 eV. The two aspects can both improve the optical properties of the VO2(M)/SnO2 composite film. The visible transmittance is up to 35.7% and the IR modulation at 2500 nm is more than 56%, which were much higher than the pure VO2(M) film. In addition, the SnO2 layer could reduce the width of the hysteresis from 17.8 to 10.7 degrees C caused by Sn-doping and enhance the sensitivity. We believe that the VO2(M)/SnO2 heterostructured coating is a good candidate for smart windows. PMID- 26122798 TI - Study of volume swelling and interfacial tension of the polystyrene-carbon dioxide-dimethyl ether system. AB - We investigated the interaction of blended carbon dioxide (CO2) and dimethyl ether (DME) with polystyrene (PS) through volume swelling and interfacial tension. The experiments were carried out over a temperature range of 423-483 K, and the pressure was varied from 6.89 MPa to 20.68 MPa. With an incremental concentration of DME in the blend, the volume swelling increased while the interfacial tension between the PS/blend gas mixture and the blend gas decreased. The validity of the Simha-Somcynsky (SS) equation of state (EOS) for the ternary system was established by comparing experimentally measured volume swelling to that obtained via SS-EOS. PMID- 26122799 TI - Synthesis of mercaptopropyl-(phenylene)s-benzoates passivated gold nanoparticles: Implications for plasmonic photovoltaic cells. AB - The incorporation of gold nanoparticles in heterojunction solar cells is expected to increase the efficiency due to plasmon effects, but the literature studies are sometimes controversial. In this work, gold nanoparticles passivated with (Ph)n (CH2)3SH (n=1, 2, 3) have been synthesized by reduction of tetrachloroauric acid with sodium borohydride in two ways: (1) one-phase where both the thiol and the gold salt are solubilized in a mixture of methanol with acetic acid: Au-s-(Ph)n or (2), two-phase, using tetraoctylammonium bromide (TOAB) to transfer gold from water to toluene where the thiol is solubilized, Au(TOAB)-s-(Ph)n. The morphological, experimental and simulated optical properties were studied and analyzed as a function of the thiol and of the synthetic procedure in order to correlate them with the efficiency of plasmonic hybrid solar cells in the following configuration ITO/PEDOT:PSS/P3HT:PCBM-C60:Au-nanoparticles/Field's metal, where PEDOT: PSS is poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate), P3HT is poly(3-hexylthiophene-2,5-diyl) and PCBM-C60 is [6,6]-Phenyl C61 butyric acid methyl ester. Our findings indicate that the gold nanoparticles incorporation is affecting the electrical properties of the active layer giving a maximum efficiency for Au-s-(Ph)3. Moreover, TOAB, which is usually used in the synthesis of thiol passivated gold nanoparticles, has negative effects in both plasmonic and electrical properties. This result is important for optoelectronic applications of gold nanoparticles prepared with any procedures that involve TOAB. PMID- 26122800 TI - Pharmacogenetics in irritable bowel syndrome. AB - Irritable bowel syndrome (IBS) is a chronic disease characterized by complex interactions between genetic predisposition and the environment. Current treatments for IBS are characterized by a highly variable response. Gene variations may result from insertions or deletions, gene rearrangements, splice variants or copy number variants, or, more commonly, from substitutions in the DNA of one (single nucleotide polymorphism [SNPs]) or more than one nucleotide. The objective of this editorial is to review the potential importance of pharmacogenetics in the treatment of IBS based on current evidence. PMID- 26122802 TI - The Use of Telemedicine to Address Access and Physician Workforce Shortages. AB - The use of telemedicine technologies by primary care pediatricians, pediatric medical subspecialists, and pediatric surgical specialists (henceforth referred to as "pediatric physicians") has the potential to transform the practice of pediatrics. The purpose of this policy statement is to describe the expected and potential impact that telemedicine will have on pediatric physicians' efforts to improve access and physician workforce shortages. The policy statement also describes how the American Academy of Pediatrics can advocate for its members and their patients to best use telemedicine technologies to improve access to care, provide more patient- and family-centered care, increase efficiencies in practice, enhance the quality of care, and address projected shortages in the clinical workforce. As the use of telemedicine increases, it is likely to impact health care access, quality, and education and costs of care. Telemedicine technologies, applied to the medical home and its collaborating providers, have the potential to improve current models of care by increasing communication among clinicians, resulting in more efficient, higher quality, and less expensive care. Such a model can serve as a platform for providing more continuous care, linking primary and specialty care to support management of the needs of complex patients. In addition, telemedicine technologies can be used to efficiently provide pediatric physicians working in remote locations with ongoing medical education, increasing their ability to care for more complex patients in their community, reducing the burdens of travel on patients and families, and supporting the medical home. On the other hand, telemedicine technologies used for episodic care by nonmedical home providers have the potential to disrupt continuity of care and to create redundancy and imprudent use of health care resources. Fragmentation should be avoided, and telemedicine, like all primary and specialty services, should be coordinated through the medical home. PMID- 26122803 TI - Umbilical Cord Milking Versus Delayed Cord Clamping in Preterm Infants. AB - BACKGROUND AND OBJECTIVE: Delayed cord clamping (DCC) is recommended for premature infants to improve blood volume. Most preterm infants are born by cesarean delivery (CD), and placental transfusion may be less effective than in vaginal delivery (VD). We sought to determine whether infants <32 weeks born by CD who undergo umbilical cord milking (UCM) have higher measures of systemic blood flow than infants who undergo DCC. METHODS: This was a 2-center trial. Infants delivered by CD were randomly assigned to undergo UCM or DCC. Infants delivered by VD were also randomly assigned separately. UCM (4 strippings) or DCC (45-60 seconds) were performed. Continuous hemodynamic measurements and echocardiography were done at site 1. RESULTS: A total of 197 infants were enrolled (mean gestational age 28 +/- 2 weeks). Of the 154 infants delivered by CD, 75 were assigned to UCM and 79 to DCC. Of the infants delivered by CD, neonates randomly assigned to UCM had higher superior vena cava flow and right ventricular output in the first 12 hours of life. Neonates undergoing UCM also had higher hemoglobin, delivery room temperature, blood pressure over the first 15 hours, and urine output in the first 24 hours of life. There were no differences for the 43 infants delivered by VD. CONCLUSIONS: This is the first randomized controlled trial demonstrating higher systemic blood flow with UCM in preterm neonates compared with DCC. UCM may be a more efficient technique to improve blood volume in premature infants delivered by CD. PMID- 26122804 TI - BRAFV600E Mutation in Melanotic Neuroectodermal Tumor of Infancy: Toward Personalized Medicine? AB - The melanotic neuroectodermal tumor of infancy (MNTI) is a rare neoplasm that primarily affects the maxilla of infants during their first year of life. Complete resection is the conventional treatment and recurrence rates vary from 10% to 60%. The recurrent tumors grow more aggressively and can invade other anatomic structures, such as the nasal cavity, the orbit, and the skull base. The aggressive behavior of MNTIs may require radical resection, which may not be possible in some cases because of its rapid and invading growth together with invasion of vital structures. In these situations, adjunct radiotherapy or chemotherapy has been used. However, as there are no conclusive data regarding the molecular profile of this tumor, currently there is no targeted therapy that may be used in the treatment of selected aggressive cases. On the basis of MNTI similarities with melanomas, such as derivation from the neural crest cells and presence of large melanin-containing cells, we hypothesized that MNTIs also may harbor the BRAFV600E oncogenic mutation. We show for the first time that this important pediatric tumor may harbor the oncogenic BRAFV600E mutation, providing the first insights to their personalized treatment. PMID- 26122805 TI - Effects of Physician-Based Preventive Oral Health Services on Dental Caries. AB - BACKGROUND: Most Medicaid programs reimburse nondental providers for preventive dental services. We estimate the impact of comprehensive preventive oral health services (POHS) on dental caries among kindergarten students, hypothesizing improved oral health among students with medical visits with POHS. METHODS: We conducted a retrospective study in 29,173 kindergarten students by linking Medicaid claims (1999-2006) with public health surveillance data (2005-2006). Zero-inflated regression models estimated the association between number of visits with POHS and (1) decayed, missing, and filled primary teeth (dmft) and (2) untreated decayed teeth while adjusting for confounding. RESULTS: Kindergarten students with >=4 POHS visits averaged an adjusted 1.82 dmft (95% confidence interval: 1.55 to 2.09), which was significantly less than students with 0 visits (2.21 dmft; 95% confidence interval: 2.16 to 2.25). The mean number of untreated decayed teeth was not reduced for students with >=4 POHS visits compared with those with 0 visits. CONCLUSIONS: POHS provided by nondental providers in medical settings were associated with a reduction in caries experience in young children but were not associated with improvement in subsequent use of treatment services in dental settings. Efforts to promote oral health in medical settings should continue. Strategies to promote physician dentist collaborations are needed to improve continuity of care for children receiving dental services in medical settings. PMID- 26122806 TI - Family Experiences With Feeding Tubes in Neurologic Impairment: A Systematic Review. AB - BACKGROUND AND OBJECTIVE: Gastrostomy tubes (G-tubes) are frequently used to provide enteral nutrition for children who have neurologic impairment. Understanding the impact of G-tubes from the family's perspective will inform decision-making and improve support from health care providers. This study explored the experiences of families after G-tube placement in children with neurologic impairment. METHODS: We conducted a systematic review of English language qualitative primary research studies describing family experiences after G-tube placement. Six electronic databases were searched from inception to June 2014. Two authors independently screened and identified relevant studies, evaluated quality of reporting by using the Consolidated Criteria for Reporting Qualitative Research tool, and extracted data. Overarching concepts were developed by using thematic analysis. RESULTS: From 2674 screened abstracts, 84 texts were reviewed, and 13 studies met the inclusion criteria. G-tubes affect the lives of children, parents, and the family unit in many ways, both positive and negative. Improvements and challenges were described for children's health and happiness, for parental caregiving and stress, and for logistics and bonding within the family. G-tube feeding also changed relationships within the family, between the family and the medical system, and between the family and the outside world. Furthermore, experiences varied, with different families framing similar concepts as positive and negative. CONCLUSIONS: G-tube placement has diverse effects on daily life for children with neurologic impairment and their families. Clinicians may use the themes identified in this study to guide conversations with families about their values, experiences, and expectations before and after G-tube placement. PMID- 26122807 TI - De Novo Assessment of Pediatric Musculoskeletal Soft Tissue Tumors: Beyond Anatomic Imaging. AB - MRI plays a central role in the assessment of pediatric musculoskeletal soft tissue tumors. Although these neoplasms may initially be evaluated on other modalities, such as sonography, MRI is essential for accurately determining the extent of disease. Traditionally, MRI has been performed with sequences that provide excellent anatomic detail, with T1-weighted, fluid-sensitive, and static postcontrast T1-weighted sequences. However, with the introduction of noncontrast sequences such as diffusion-weighted imaging and magnetic resonance spectroscopy to the arsenal of available MRI techniques, functional and metabolic features of a neoplasm can now be examined noninvasively. These more recent MRI methods offer information for lesion characterization, the assessment of treatment response, and the distinction of postoperative scar from recurrence. Dynamic contrast enhanced perfusion imaging is another useful functional technique that can be acquired before conventional static postcontrast imaging, without requiring additional contrast material. This review presents recent advances in MRI methodology that enable a comprehensive clinical assessment of musculoskeletal tumors in the pediatric population. The roles and challenges of combining anatomic, functional, and metabolic MRI sequences will be discussed as they relate to newly discovered soft tissue tumors in children. PMID- 26122808 TI - Eliminating Rumination in Developmentally Disabled Children: A Case Report. AB - Rumination is the effortless regurgitation of food, with subsequent spitting out or rechewing and reswallowing. In developmentally delayed children, rumination is a pleasurable, self-stimulating habit. For 3 years, we evaluated and treated 2 nonambulatory, nonverbal 4-year-old children who ruminated frequently while awake. The social isolation caused by a child covered in regurgitated food prompted caregivers of these children to find a solution. We hypothesized that rumination would cease if the stomach stayed empty of food. We intervened by placing gastrojejunostomy tubes and then initiated continuous drip jejunal tube feedings over 12 waking hours to reduce hunger; the children's oral diet was also stopped. In both cases, these changes reduced episodes of rumination to 3 to 5 times daily. To eliminate rumination, unpleasant tasting substances (N acetylcysteine or cayenne pepper-based hot sauce) were given through the gastrostomy tube every 4 hours while the children were awake. Within 1 week of adding the unpalatable substances, rumination ceased. After 2 months of no rumination, 1 mother restarted oral feeding. There was no recurrence of rumination, and 3 months after gastrojejunal tube placement, the tube was removed. In 1 year of follow-up, rumination did not recur. The second mother was pleased with the outcome with jejunal feedings and chose not to resume oral feedings. These results showed that jejunal tube feeding in combination with insertion of unpalatable contents into the stomach eliminated rumination in these developmentally delayed children. PMID- 26122809 TI - Prenatal Risk Factors and Outcomes in Gastroschisis: A Meta-Analysis. AB - BACKGROUND AND OBJECTIVE: Gastroschisis is a congenital anomaly with increasing incidence, easy prenatal diagnosis and extremely variable postnatal outcomes. Our objective was to systematically review the evidence regarding the association between prenatal ultrasound signs (intraabdominal bowel dilatation [IABD], extraabdominal bowel dilatation, gastric dilatation [GD], bowel wall thickness, polyhydramnios, and small for gestational age) and perinatal outcomes in gastroschisis (bowel atresia, intra uterine death, neonatal death, time to full enteral feeding, length of total parenteral nutrition and length of in hospital stay). METHODS: Medline, Embase, and Cochrane databases were searched electronically. Studies exploring the association between antenatal ultrasound signs and outcomes in gastroschisis were considered suitable for inclusion. Two reviewers independently extracted relevant data regarding study characteristics and pregnancy outcome. All meta-analyses were computed using individual data random-effect logistic regression, with single study as the cluster unit. RESULTS: Twenty-six studies, including 2023 fetuses, were included. We found significant positive associations between IABD and bowel atresia (odds ratio [OR]: 5.48, 95% confidence interval [CI] 3.1-9.8), polyhydramnios and bowel atresia (OR: 3.76, 95% CI 1.7-8.3), and GD and neonatal death (OR: 5.58, 95% CI 1.3-24.1). No other ultrasound sign was significantly related to any other outcome. CONCLUSIONS: IABD, polyhydramnios, and GD can be used to an extent to identify a subgroup of neonates with a prenatal diagnosis of gastroschisis at higher risk to develop postnatal complications. Data are still inconclusive on the predictive ability of several signs combined, and large prospective studies are needed to improve the quality of prenatal counseling and the neonatal care for this condition. PMID- 26122810 TI - Persistent Pneumonia in an Infant. AB - A 4-month-old boy with past medical history of eczema presented with fever and cough; a chest radiograph showed lung consolidation, and he was initially treated with amoxicillin for presumed community-acquired pneumonia. After several days, his fever persisted. He was also profoundly anemic. Antibiotic coverage was broadened because of the concern for resistant organisms; he began to improve and was discharged from the hospital. However, at 5 months of age, his fever returned, and he continued to demonstrate lung consolidation on chest radiograph. Additionally, he had lost weight and continued to be anemic. Splenic cysts were noted on abdominal ultrasound. He was diagnosed with an unusual etiology for his pneumonia and improved with the appropriate therapy. An underlying immunodeficiency was suspected, but initial testing was nondiagnostic. At 12 months of age, he presented with another infection, and the final diagnosis was made. PMID- 26122811 TI - Optimizing Placental Transfusion for Preterm Infants. PMID- 26122812 TI - The Role of the Pediatrician in Primary Prevention of Obesity. AB - The adoption of healthful lifestyles by individuals and families can result in a reduction in many chronic diseases and conditions of which obesity is the most prevalent. Obesity prevention, in addition to treatment, is an important public health priority. This clinical report describes the rationale for pediatricians to be an integral part of the obesity-prevention effort. In addition, the 2012 Institute of Medicine report "Accelerating Progress in Obesity Prevention" includes health care providers as a crucial component of successful weight control. Research on obesity prevention in the pediatric care setting as well as evidence-informed practical approaches and targets for prevention are reviewed. Pediatricians should use a longitudinal, developmentally appropriate life-course approach to help identify children early on the path to obesity and base prevention efforts on family dynamics and reduction in high-risk dietary and activity behaviors. They should promote a diet free of sugar-sweetened beverages, of fewer foods with high caloric density, and of increased intake of fruits and vegetables. It is also important to promote a lifestyle with reduced sedentary behavior and with 60 minutes of daily moderate to vigorous physical activity. This report also identifies important gaps in evidence that need to be filled by future research. PMID- 26122814 TI - Carotid Ultrasound Maximum Plaque Height-A Sensitive Imaging Biomarker for the Assessment of Significant Coronary Artery Disease. AB - OBJECTIVES: We investigated the use of carotid intima-media thickness and carotid plaque in predicting significant angiographic coronary stenosis. METHODS: Three hundred eighteen consecutive outpatients underwent angiography and carotid ultrasound on the same day. The extent of coronary stenosis was determined using an established scoring system. Mean far distal carotid intima-media thickness of the common carotid artery, maximum plaque height, and total plaque area in the bulbs were measured by ultrasound. Cutoff values were identified using a receiver operating characteristic curve for predicting and ruling out coronary artery disease. RESULTS: The mean +/- SD carotid intima-media thickness (>=50% stenosis = 0.91 +/- 0.23 mm, <50% stenosis = 0.82 +/- 0.18 mm), maximum plaque height (>=50% stenosis = 2.64 +/- 0.85 mm, <50% stenosis = 1.72 +/- 1.04 mm), and total plaque area (>=50% stenosis = 39.1 +/- 27.7 mm(2) , <50% stenosis = 22.2 +/- 23.4 mm(2) ) were significantly higher in patients with coronary artery disease (P <= 0.001 for all three comparisons). Increased CIMT, plaque height, and area correlated with increased number of affected vessels. Plaque height had the best negative likelihood ratio for ruling out disease (0.15). The optimal threshold values for predicting coronary disease were 0.82 mm for carotid intima-media thickness, 1.54 mm for plaque height, and 25.6 mm(2) for total plaque area. CONCLUSION: Increased carotid intima-media thickness and plaque measurements are indicative of the presence of epicardial coronary stenosis. Plaque burden is a more sensitive imaging biomarker for ruling out significant coronary artery disease, including in younger individuals. PMID- 26122815 TI - Introduction to the collection on research to practice in the construction industry. PMID- 26122813 TI - Telemedicine: Pediatric Applications. AB - Telemedicine is a technological tool that is improving the health of children around the world. This report chronicles the use of telemedicine by pediatricians and pediatric medical and surgical specialists to deliver inpatient and outpatient care, educate physicians and patients, and conduct medical research. It also describes the importance of telemedicine in responding to emergencies and disasters and providing access to pediatric care to remote and underserved populations. Barriers to telemedicine expansion are explained, such as legal issues, inadequate payment for services, technology costs and sustainability, and the lack of technology infrastructure on a national scale. Although certain challenges have constrained more widespread implementation, telemedicine's current use bears testimony to its effectiveness and potential. Telemedicine's widespread adoption will be influenced by the implementation of key provisions of the Patient Protection and Affordable Care Act, technological advances, and growing patient demand for virtual visits. PMID- 26122816 TI - Systemic sodium metabisulfite allergy. PMID- 26122817 TI - Experiences of care by Australians with a diagnosis of borderline personality disorder. AB - Borderline personality disorder (BPD) is a complex and challenging mental health condition for the person and service providers who support them. This paper reports on the results of a survey of 153 people with a diagnosis of BPD about their experiences of attempting to receive support in managing this mental health condition. It provides their perceptions of a range of experiences not reported in the existing literature, including general practitioner roles, urban and rural differences, public and private hospital differences, and comparison of usefulness of support across multiple support types. People with a diagnosis of BPD continue to experience significant discrimination when attempting to get their needs met within both public and private health services. Further education for nurses and other health professionals is indicated to address pervasive negative attitudes towards people with a diagnosis of BPD. There is limited understanding of the experience of seeking and receiving treatment and care by people with a diagnosis of borderline personality disorder (BPD), their perceptions of barriers to care and the quality of services they receive. This study aimed to explore these experiences from the perspective of Australians with this diagnosis. An invitation to participate in an online survey was distributed across multiple consumer and carer organizations and mental health services, by the Private Mental Health Consumer Carer Network (Australia) in 2011. Responses from 153 people with a diagnosis of BPD showed that they experience significant challenges and discrimination when attempting to get their needs met within both public and private health services, including general practice. Seeking help from hospital emergency departments during crises was particularly challenging. Metropolitan and rural differences, and gender differences, were also apparent. Community supports were perceived as inadequate to meet their needs. This study provides data on a range of experiences not reported in existing literature, including general practitioner roles, urban and rural differences, public and private hospital differences, and comparison of usefulness of support across multiple support types. Its findings can help inform better training for health professionals and better care for this population. PMID- 26122819 TI - Climate Factors as Important Determinants of Dengue Incidence in Curacao. AB - Macro- and microclimates may have variable impact on dengue incidence in different settings. We estimated the short-term impact and delayed effects of climate variables on dengue morbidity in Curacao. Monthly dengue incidence data from 1999 to 2009 were included to estimate the short-term influences of climate variables by employing wavelet analysis, generalized additive models (GAM) and distributed lag nonlinear models (DLNM) on rainfall, temperature and relative humidity in relation to dengue incidence. Dengue incidence showed a significant irregular 4-year multi-annual cycle associated with climate variables. Based on GAM, temperature showed a U-shape, while humidity and rainfall exhibited a dome shaped association, suggesting that deviation from mean temperature increases and deviation from mean humidity and rainfall decreases dengue incidence, respectively. Rainfall was associated with an immediate increase in dengue incidence of 4.1% (95% CI: 2.2-8.1%) after a 10-mm increase, with a maximum increase of 6.5% (95% CI: 3.2-10.0%) after 1.5 month lag. A 1 degrees C decrease of mean temperature was associated with a RR of 17.4% (95% CI: 11.2-27.0%); the effect was inversed for a 1 degrees C increase of mean temperature (RR= 0.457, 95% CI: 0.278-0.752). Climate variables are important determinants of dengue incidence and provide insight into its short-term effects. An increase in mean temperature was associated with lower dengue incidence, whereas lower temperatures were associated with higher dengue incidence. PMID- 26122818 TI - Neuroprotective mechanism of losartan and its interaction with nimesulide against chronic fatigue stress. AB - Potential role of angiotensin-II and cyclooxygenase have been suggested in the pathophysiology of chronic fatigue stress. The present study has been designed to evaluate the neuroprotective effect of losartan and its interaction with nimesulide against chronic fatigue stress and related complications in mice. In the present study, male Laca mice (20-30 g) were subjected to running wheel activity test session (RWATS) for 6 min daily for 21 days. Losartan, nimesulide and their combinations were administered daily for 21 days, 45 min before being subjected to RWATS. Various behavioral and biochemical and neuroinflammatory mediators were assessed subsequently. 21 days RWATS treatment significantly decreased number of wheel rotations/6 min indicating fatigue stress like behaviors as compared to naive group. 21 days treatment with losartan (10 and 20 mg/kg, ip), nimesulide (5 and 10 mg/kg, po) and their combinations significantly improved behavior [increased number of wheel rotations, reversal of post-exercise fatigue, locomotor activity, antianxiety-like behavior (number of entries, latency to enter and time spent in mirror chamber), and memory performance (transfer latency in plus-maze performance task)], biochemical parameters (reduced serum corticosterone, brain lipid peroxidation, nitrite concentration, acetylcholinesterase activity, restored reduced glutathione levels and catalase activity) as compared to RWATS control. Besides, TNF-alpha, CRP levels were significantly attenuated by these drugs and their combinations as compared to control. The present study highlights the role of cyclooxygenase modulation in the neuroprotective effect of losartan against chronic fatigue stress-induced behavioral, biochemical and cellular alterations in mice. PMID- 26122821 TI - Effect of replacing corn with whole-grain paddy rice and brown rice in broiler diets on growth performance and intestinal morphology. AB - The present study was conducted to investigate replacing corn with whole-grain paddy rice (WPR) and whole-grain brown rice (BR) in broiler chicken diets and its effect on growth performance and histological structures of the intestinal villi. Marshall Chunky male chicks (14 days old) were divided into five groups with four replicates of four chicks each. In the dietary treatments, corn in the basal diet was replaced with WPR and BR. The chickens received five experimental diets consisting of corn, WPR and BR in ratios of 100:0:0 (Control), 50:0:50 (50Corn + 50BR), 50:25:25 (50Corn + 25WPR + 25BR), 25:50:25 (25Corn + 50WPR + 25BR) and 0:50:50 (50WPR + 50BR) respectively. Feed and water were provided ad libitum for 35 day. No significant differences were found in feed intake, body weight gain and feed efficiency among the treatment groups. The relative weights of the gizzard in the 50Corn + 25WPR + 25BR, 25Corn + 50WPR + 25BR and 50WPR + 50BR groups were significantly higher than that of the Control and 50Corn + 50BR groups (p < 0.05). The gizzard pH of the experimental groups was lower than those of Control (p < 0.05). The ileal crypt of birds on the Control diets was deeper (p < 0.05) than those observed in the experimental birds. Moreover, the ileal villus height: crypt depth ratio increased (p < 0.05) in the 50WPR + 50BR group (p < 0.05) compared with the Control group. No specific changes were observed in the epithelial cells on the duodenal apical surface among the groups except that the villus of the 25Corn + 50WPR + 25BR group had cell clusters. The jejunal and ileal villus apical surface of the experimental groups showed similar morphology to the Control group. These findings suggest that WPR and BR can totally replace corn in broiler diets without negatively affecting growth performance. PMID- 26122820 TI - KRAS and aneusomy of chromosomes 4, 10 and 12 in colorectal carcinomas. AB - AIMS: KRAS mutation status has predictive significance in EGFR-antibody treatment of colorectal adenocarcinoma. The aim of the study was the evaluation of KRAS mutation status in correlation to KRAS copy numbers and ploidy status. METHODS: Colorectal adenocarcinomas (n=52) were assembled into a TMA and analyzed by FISH. Probes for centromeres 4 and 10 were applied as surrogate markers for the ploidy status. In addition, a dual color FISH probe set for the centromere of chromosome 12 and the KRAS gene was applied to the TMA to analyze numerical alterations and KRAS gene copy numbers. Further we analyzed DNA sequence profiles of KRAS codons 12 and 13 to assess the allele status of the mutation within the tumor samples. RESULTS: KRAS mutation was confirmed in 24 cases, while 28 cases showed a wild type KRAS status. The majority of cases showed diploid FISH signals for chromosomes 4 and 10. Near triploid FISH signals were observed in only 2 cases, 12 cases were hypodiploid, and 8 cases were hyperdiploid. In 6 cases, trisomy 12 could be ascertained. In total, aneuploidy could be detected in 28 cases, including cases with trisomy 12 and hyposomy 10. Tumors with aneuploid chromosomal content had a worse prognosis compared to euploid tumors, however, without reaching statistical significance (p=0.231). Hypodiploid carcinomas carried the worst prognosis. Specifically, monosomy 10 was significantly associated with reduced survival (p=0.039). Increased FISH signals of KRAS did not correlate significantly with relapse (p=0.916). CONCLUSIONS: FISH analysis can be used as a surrogate marker for the ploidy status. Loss of chromosome 10 may serve as a potential adverse prognostic marker being indicative for tumor progression. PMID- 26122822 TI - Over-expression of neurotrophin 3 in human aortic valves affected by calcific disease induces the osteogenic responses via the Trk-Akt pathway. AB - Calcific aortic valve disease (CAVD) is a leading cardiovascular disorder in the elderly. While aortic valve interstitial cells (AVICs) are the main cells that express osteogenic mediators, the molecular mechanism that mediates AVIC osteogenic responses is incompletely understood. This study aims to identify pro osteogenic factors in human AVICs affected by CAVD. METHODS AND RESULTS: Microarray analysis identified 11 up-regulated genes in AVICs of diseased valves. Among these genes, mRNA levels of neurotrophin 3 (NT3) increased by 2 fold. Higher levels of NT3 protein in diseased aortic valves and diseased AVICs were confirmed by immunofluorescent staining and immunoblotting, respectively. An exposure of AVICs of normal valves to recombinant human NT3 (0.025-0.10MUg/mL) up regulated the production of Runx2, TGF-beta1 and BMP-2 in a dose-dependent fashion. NT3 also promotes calcium deposit formation. The pro-osteogenic effect of NT3 was not affected by neutralization of Toll-like receptor 2 or 4. Interestingly, mRNA encoding neural growth factor receptors (TrkA, TrkB, TrkC and p75 NTR) was detectable in human AVICs. Inhibition of Trk receptors markedly reduced the effects of NT3 on Runx2, TGF-beta1 and BMP-2 production, calcium deposit formation and Akt phosphorylation. Further, inhibition of Akt also reduced the pro-osteogenic effects of NT3. CONCLUSIONS: AVICs of diseased human aortic valves express higher levels of NT3. NT3 up-regulates the production of Runx2, TGF-beta1 and BMP-2, and promotes calcium deposit formation in human AVICs via the Trk-Akt pathway. Thus, NT3 is a novel pro-osteogenic factor in aortic valves and may play a role in valvular calcification. PMID- 26122823 TI - Special issue: Molecular basis of NCL. PMID- 26122824 TI - A Boundary Value Approach to Optimization with an Application to Salmonella Competition. AB - We develop a novel optimization framework to study strategies in ecological competition processes. The optimization method uses theory from dynamical systems describing the asymptotic behavior of a bistable system based on initial conditions, which we implement using a numerical boundary value problem. As an application of our method, we develop a model of the competition between Salmonella Typhimurium and the host's native microflora, which constantly and densely inhabit the intestinal lining of most mammals. S. Typhimurium invades the gut in two distinct phenotypic populations, one virulent and one avirulent, though the avirulent bacteria have the ability to activate a virulence factor and thereby "switch" into the virulent population. Counterintuitively, some studies have found that the combined population of S. Typhimurium gains an environmental advantage over the commensal microbiota after the virulent subpopulation provokes the body's inflammatory defenses. Our model represents the competition between the commensal microbiota, the avirulent salmonella, and the virulent salmonella populations and incorporates a simple representation of the immune response. We use our model to predict optimal strategies that would favor salmonella in its competition with the commensal bacteria. PMID- 26122825 TI - Oncolytic Treatment for Cancer Recommended for Approval. PMID- 26122828 TI - Macrophage-Derived IGF-1 Is a Potent Coordinator of Myogenesis and Inflammation in Regenerating Muscle. PMID- 26122829 TI - Shedding New Light on the Use of Imaging Technology for Glioblastoma Tumor Resection. PMID- 26122830 TI - Corrigendum to "Insulin-like Growth Factor-binding Protein-7 (IGFBP7): A Promising Gene Therapeutic for Hepatocellular Carcinoma (HCC)". PMID- 26122831 TI - Corrigendum to "Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy In Vivo". PMID- 26122832 TI - Relation of cholesterol metabolism to pediatric gallstone disease: a retrospective controlled study. AB - BACKGROUND: Cholesterol metabolism may be involved in pediatric gallstone disease. We aimed to reveal cholesterol metabolites and phytosterols and their relation to stone composition of sterols in children having black pigment and cholesterol stones. METHODS: We performed retrospective controlled clinical study, in which we examined parameters of cholesterol metabolism and liver function values in serum (n = 28) and gallstones (n = 46) of consecutively cholecystectomized children. Serum values of age-, body mass index- and sex matched children (n = 82) and adult gallstones (n = 187) served as controls. RESULTS: Surrogate markers of cholesterol synthesis in serum (squalene/cholesterol, cholestenol/cholesterol and lathosterol/cholesterol) were 26-52 % higher in both stone subclasses compared to controls (p < 0.05 for all). Respectively, cholestanol/cholesterol and plant sterols campesterol/cholesterol and sitosterol/cholesterol (cholesterol absorption markers) had decreasing order in serum: black pigment stone group > controls > cholesterol stone group (p < 0.05 for all). In black pigment stone group, stone cholestanol/cholesterol was associated with serum bile acids (r = 0.620, p = 0.018). In cholesterol stone group, surrogate markers of cholesterol synthesis in serum (e.g., lathosterol/cholesterol) inversely reflected those of absorption (r-range -0.633- 0.706, p-range 0.036-0.015). In cholesterol stone group, serum and stone lathosterol/cholesterol and cholestanol/cholesterol were positively interrelated (r-range 0.727-0.847, p < 0.05 for both). CONCLUSIONS: Gallstone subclasses shared enhanced cholesterol synthesis. Cholesterol stone children were low cholesterol absorbers with intact homeostasis of cholesterol metabolism. Black pigment stone group was characterized by deteriorated cholesterol metabolism, and accumulation of cholestanol, campesterol and sitosterol in serum and stones suggesting their participation in pathogenesis. PMID- 26122833 TI - Primum Non Nocere: Does Screening For Abdominal Aortic Aneurysm Do More Harm Than Good? PMID- 26122834 TI - Clinical Safety and Preliminary Efficacy of Plasmid pUDK-HGF Expressing Human Hepatocyte Growth Factor (HGF) in Patients with Critical Limb Ischemia. AB - OBJECTIVE: Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease and a major unmet public health care need. This phase I clinical study was performed to assess the safety and preliminary efficacy of naked plasmid DNA (pUDK-HGF) expressing human hepatocyte growth factor (HGF) in patients with critical limb ischemia (CLI). DESIGN: Twenty-one patients with CLI were enrolled and randomly divided into four dose groups (4-16 mg) to receive local injection of pUDK-HGF into ischemic calf and/or thigh muscles twice on days 1 and 15. Safety, including adverse events and physiological parameters, and preliminary efficacy, including pain severity score (VAS), ulcer size, transcutaneous oxygen pressure (TcPO2), and ankle brachial index (ABI), were evaluated throughout a 3 month follow up period. RESULTS: All doses of pUDK-HGF were well tolerated by the patients. None of the adverse effects was considered to be related to pUDK-HGF injection. Two significant clinical results were observed after pUDK-HGF administration. The mean VAS value of all patients decreased from 4.52 at baseline to 0.30 (p < .01), and pain had disappeared in 14 out of 17 evaluable patients by day 91. Two of four ulcers had completely healed, with the other two patients having more than 25% ulcer size reduction in the long axis diameter. Of five patients with gangrene, one gangrenous wound had healed completely and two patients showed marked size reduction by day 91. The mean hemodynamic parameters (ABI, TcPO2) were also improved. CONCLUSION: Intramuscular injection of pUDK-HGF is safe, and may provide symptomatic relief for CLI patients. A larger, randomized, double blinded phase II trial will provide more information on safety and efficacy. PMID- 26122835 TI - New insights into evolution of IgT genes coming from Antarctic teleosts. AB - Cloning and characterization of IgT heavy chain genes were performed in the Antarctic Notothenioid teleost Trematomus bernacchii and in a non-Antarctic Notothenioid species, Bovichtus diacanthus, belonging to a phyletically basal lineage of Notothenioids. Compared to IgT from other non-Antarctic teleost species, including B. diacanthus, T. bernacchii IgT lacked most of the second constant domain but maintained only a few amino acid residues, which could be aligned to B. diacanthus CH2 domain. By analyzing several cDNA clones from a single specimen, three differently sized IgT transcript variants, named Long, Short and Shortest, were identified. Genomic analysis of T. bernacchii and B. diacanthus IgH loci revealed that, in the case of T. bernacchii, within the intron between the exons coding for the entire first and second constant domains a reminiscence of the ancestral second exon was present. The Long and Short variants were found to be encoded by indel alleles, whereas the Shortest variant was generated by alternative splicing that led to the CH2 exonic remnant skipping. Through comparison between genomic and cDNA sequences we hypothesized the presence of three different copies of the IgT heavy chain gene, one of which being considered the functional gene since the corresponding transcripts were identified. Moreover, either Long or Short exonic variants were found to be used in IgT heavy chain membrane form in an unbiased manner, as seen for the secretory form. Phylogenetic analysis was performed on the constant region from all teleost IgT available to date, including IgT from another Antarctic Notothenioid species, Notothenia coriiceps, identified by searching the transcriptome. The loss of almost an entire domain together with the conservation of some amino acids such as proline, glycine and cysteine in the CH2 domain remnant, could be interpreted as another distinctive feature of the Antarctic fish genome evolution, providing also new insights into the structural variation of teleost immunoglobulin genes. PMID- 26122836 TI - Expressed sequence tag analyses of three leukocyte subpopulations in ayu Plecoglossus altivelis altivelis, separated by monoclonal antibodies. AB - Ayu Plecoglossus altivelis altivelis are one of the most economically important fish for freshwater aquaculture in Japan. We conducted expressed sequence tag analyses of three leukocyte subpopulations, thrombocytes, neutrophils, and B lymphocytes in ayu using a next generation sequencer. The sequencing and de novo assembly yielded 22,494, 22,733, and 16,505 contigs from the thrombocyte, neutrophil, and B lymphocyte cDNA libraries, respectively. Pathways involving endocytosis, phagosomes, and lysosomes, were found in all three cDNA libraries using pathway analysis. The thrombocyte cDNA library contained 2894 unique sequences, including CXC chemokine receptor 4 and MHC class II. Cytokine and cytokine receptor genes such as interleukin (IL)-1beta, IL-8, IL-1 receptor (IL 1R), IL-8RA, and IL-8RB were found among the 3056 unique sequences of the neutrophil cDNA library. Typical B lymphocyte related genes such as B cell linker protein, immunoglobulin (Ig) M, IgD and transforming growth factor beta were found in the 1590 unique sequences of the B lymphocyte cDNA library. In summary, a large number of immune-related genes were identified from the three leukocyte cDNA libraries. Our results represent a valuable sequence resource for understanding the immune system function in ayu. PMID- 26122837 TI - Can an increase in neuropeptide production in the soma lead to DCV circulation in axon terminals with type III en passant boutons? AB - Neuropeptides are synthesized in the neuron soma; they are packaged in dense core vesicles (DCVs) which undergo axonal transport toward nerve terminals. Published experimental results suggest that in terminals with type Ib boutons DCVs circulate in the terminal, undergoing repeated anterograde and retrograde transport, while in type III terminals DCVs do not circulate in the terminal. In this paper we developed a mathematical model that allowed us to investigate the effects of an increased rate of DCV production in the soma. We demonstrated that our model reproduces some important experimental results, in particular those concerning DCV circulation in type Ib and type III terminals. Our model makes testable predictions. Probably the most important prediction concerns the effect of an increased DCV production rate in the soma, which we anticipate leads to increased DCV circulation in type Ib boutons and to the appearance of DCV circulation in type III boutons. Other predictions concern various stages of development of DCV circulation in the terminals after they were depleted of DCVs due to neuropeptide release. PMID- 26122838 TI - Gene therapy for neurodegenerative diseases. AB - Gene therapy is, potentially, a powerful tool for treating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Parkinson's disease (PD) and Alzheimer's disease (AD). To date, clinical trials have failed to show any improvement in outcome beyond the placebo effect. Efforts to improve outcomes are focusing on three main areas: vector design and the identification of new vector serotypes, mode of delivery of gene therapies, and identification of new therapeutic targets. These advances are being tested both individually and together to improve efficacy. These improvements may finally make gene therapy successful for these disorders. PMID- 26122839 TI - Tackling Crizotinib Resistance: The Pathway from Drug Discovery to the Pediatric Clinic. AB - Neuroblastoma is a childhood malignancy that has not yet benefitted from the rapid progress in the development of small-molecule therapeutics for cancer. An opportunity to take advantage of pharmaceutical innovation in this area arose when the identification of ALK fusion proteins in non-small cell lung cancer (NSCLC) occurred in parallel to the discovery of point mutations of ALK in neuroblastomas. ALK is now known to be a marker of poor outcome in neuroblastoma, and therefore, urgent development of specific ALK inhibitors to treat this devastating disease is a necessity. However, the translation of small molecules from adult directly into pediatric practice has thus far been challenging, due to mutation-specific structural variances in the ALK kinase domain. We discuss how the most recent structural and biological characterizations of ALK are directing preclinical and clinical studies of ALK inhibitors for both NSCLC and neuroblastoma. PMID- 26122840 TI - Investigation of Optical Coherence Microelastography as a Method to Visualize Cancers in Human Breast Tissue. AB - An accurate intraoperative identification of malignant tissue is a challenge in the surgical management of breast cancer. Imaging techniques that help address this challenge could contribute to more complete and accurate tumor excision, and thereby help reduce the current high reexcision rates without resorting to the removal of excess healthy tissue. Optical coherence microelastography (OCME) is a three-dimensional, high-resolution imaging technique that is sensitive to microscale variations of the mechanical properties of tissue. As the tumor modifies the mechanical properties of breast tissue, OCME has the potential to identify, on the microscale, involved regions of fresh, unstained tissue. OCME is based on the use of optical coherence tomography (OCT) to measure tissue deformation in response to applied mechanical compression. In this feasibility study on 58 ex vivo samples from patients undergoing mastectomy or wide local excision, we demonstrate the performance of OCME as a means to visualize tissue microarchitecture in benign and malignant human breast tissues. Through a comparison with corresponding histology and OCT images, OCME is shown to enable ready visualization of features such as ducts, lobules, microcysts, blood vessels, and arterioles and to identify invasive tumor through distinctive patterns in OCME images, often with enhanced contrast compared with OCT. These results lay the foundation for future intraoperative studies. Cancer Res; 75(16); 3236-45. (c)2015 AACR. PMID- 26122842 TI - Discovery and Validation of Biomarkers That Distinguish Mucinous and Nonmucinous Pancreatic Cysts. AB - The use of advanced imaging technologies for the identification of pancreatic cysts has become widespread. However, accurate differential diagnosis between mucinous cysts (MC) and nonmucinous cysts (NMC) consisting of pseudocysts (NMC1) and nonmucinous neoplastic cysts (NMC2) remains a challenge. Thus, it is necessary to develop novel biomarkers for the differential diagnosis of pancreatic cysts. An integrated proteomics approach yielded differentially expressed proteins in MC that were verified subsequently in 99 pancreatic cysts (21 NMC1, 41 NMC2, and 37 MC) using a method termed GeLC-stable isotope dilution multiple reaction monitoring-mass spectrometry (GeLC-SID-MRM-MS) along with established immunoassay techniques. We identified 223 proteins by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC/MS-MS). Nine candidate biomarkers were identified, including polymeric immunoglobulin receptor (PIGR), lipocalin 2 (LCN2), Fc fragment of IgG-binding protein (FCGBP), lithostathine-1-alpha (REG1A), afamin (AFM), chymotrypsin C (caldecrin; CTRC), amylase, alpha 2B (pancreatic; AMY2B), lectin, galactoside-binding, soluble, 3 binding protein (LGALS3BP), and chymotrypsin-like elastase family, member 3A (CELA3A), which were established as biomarker candidates for MC. In particular, we have shown that a biomarker subset, including AFM, REG1A, PIGR, and LCN2, could differentiate MC not only from NMC (including NMC1) but also from NMC2. Overall, the MS-based comprehensive proteomics approach used in this study established a novel set of candidate biomarkers that address a gap in efforts to distinguish early pancreatic lesions at a time when more successful therapeutic interventions may be possible. PMID- 26122841 TI - Interleukin-6 Prevents the Initiation but Enhances the Progression of Lung Cancer. AB - Recent studies suggest that high expression of the proinflammatory cytokine IL6 is associated with poor survival of lung cancer patients. Accordingly, IL6 has been a target of great interest for lung cancer therapy. However, the role of IL6 in lung cancer has not been determined yet. Here, we demonstrate that IL6 plays opposite roles in the initiation and growth of lung cancer in a mouse model of lung cancer induced by the K-Ras oncogene. We find that compared with wild-type mice, IL6-deficient mice developed much more lung tumors after an activating mutant of K-Ras was induced in the lungs. However, lung tumors developed in IL6 deficient mice were significantly smaller. Notably, both the lung tumor suppressing and -promoting functions of IL6 involve its ability in activating the transcription factor STAT3. IL6/STAT3 signaling suppressed lung cancer initiation through maintaining lung homeostasis, regulating lung macrophages, and activating cytotoxic CD8 T cells under K-Ras oncogenic stress, whereas it promoted lung cancer cell growth through inducing the cell proliferation regulator cyclin D1. These studies reveal a previously unexplored role of IL6/STAT3 signaling in maintaining lung homeostasis and suppressing lung cancer induction. These studies also significantly improve our understanding of lung cancer and provide a molecular basis for designing IL6/STAT3-targeted therapies for this deadliest human cancer. PMID- 26122843 TI - Identification of Prognostic Groups in High-Grade Serous Ovarian Cancer Treated with Platinum-Taxane Chemotherapy. AB - Disseminated high-grade serous ovarian cancer (HGS-OvCa) is an aggressive disease treated with platinum and taxane combination therapy. While initial response can be favorable, the disease typically relapses and becomes resistant to treatment. As genomic alterations in HGS-OvCa are heterogeneous, identification of clinically meaningful molecular markers for outcome prediction is challenging. We developed a novel computational approach (PSFinder) that fuses transcriptomics and clinical data to identify HGS-OvCa prognostic subgroups for targeted treatment. Application of PSFinder to transcriptomics data from 180 HGS-OvCa patients treated with platinum-taxane therapy revealed 61 transcript isoforms that characterize two poor and one good survival-associated groups (P = 0.007). These groups were validated in eight independent data sets, including a prospectively collected ovarian cancer cohort. Two poor prognostic groups have distinct expression profiles and are characteristic by increased hypermethylation and stroma-related genes. Integration of the PSFinder signature and BRCA1/2 mutation status allowed even better stratification of HGS-OvCa patients' prognosis. The herein introduced novel and generally applicable computational approach can identify outcome-related subgroups and facilitate the development of precision medicine to overcome drug resistance. A limited set of biomarkers divides HGS-OvCa into three prognostic groups and predicts patients in need of targeted therapies. PMID- 26122844 TI - Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication. AB - The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid derived suppressor cells. Moreover, rapamycin completely abolished vaccine induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines. PMID- 26122845 TI - Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer. AB - Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is a hallmark of many types of cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) and whether specific mechanisms or genes could be linked to these phenotypes. The genomic instability syndrome Fanconi anemia is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since patients with Fanconi anemia have a high risk to develop HNSCC, we investigated whether and to which extent Fanconi anemia pathway inactivation underlies CIN in HNSCC of non-Fanconi anemia individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without Fanconi anemia. In addition, defective sister chromatid cohesion was observed in five HNSCC cell lines. Inactivation of FANCM was responsible for chromosomal breakage in one cell line, whereas in two other cell lines, somatic mutations in PDS5A or STAG2 resulted in inadequate sister chromatid cohesion. In addition, FANCF methylation was found in one cell line by screening an additional panel of 39 HNSCC cell lines. Our data demonstrate that CIN in terms of ICL-induced chromosomal breakage and defective chromatid cohesion is frequently observed in HNSCC. Inactivation of known Fanconi anemia and chromatid cohesion genes does explain CIN in the minority of cases. These findings point to phenotypes that may be highly relevant in treatment response of HNSCC. PMID- 26122847 TI - CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch Dependent Signaling. AB - Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancer-induced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurologic syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas; however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling, and GBM cell proliferation. We demonstrated that elevated CRMP5 promotes Notch receptor expression and Akt activation in human tumor cell lines, GBM stem cells, and primary tumor biopsies. We have shown that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in GBM that correlates with and may predict patient survival. PMID- 26122846 TI - Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors. AB - The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents. PMID- 26122848 TI - Diverse Targets of beta-Catenin during the Epithelial-Mesenchymal Transition Define Cancer Stem Cells and Predict Disease Relapse. AB - Wnt signaling contributes to the reprogramming and maintenance of cancer stem cell (CSC) states that are activated by epithelial-mesenchymal transition (EMT). However, the mechanistic relationship between EMT and the Wnt pathway in CSC is not entirely clear. Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) indicated that EMT induces a switch from the beta-catenin/E cadherin/Sox15 complex to the beta-catenin/Twist1/TCF4 complex, the latter of which then binds to CSC-related gene promoters. Tandem coimmunoprecipitation and re-ChIP experiments with epithelial-type cells further revealed that Sox15 associates with the beta-catenin/E-cadherin complex, which then binds to the proximal promoter region of CASP3. Through this mechanism, Twist1 cleavage is triggered to regulate a beta-catenin-elicited promotion of the CSC phenotype. During EMT, we documented that Twist1 binding to beta-catenin enhanced the transcriptional activity of the beta-catenin/TCF4 complex, including by binding to the proximal promoter region of ABCG2, a CSC marker. In terms of clinical application, our definition of a five-gene CSC signature (nuclear beta catenin(High)/nuclear Twist1(High)/E-cadherin(Low)/Sox15(Low)/CD133(High)) may provide a useful prognostic marker for human lung cancer. PMID- 26122850 TI - Complete remission after rituximab therapy in an HIV-positive patient with pemphigus vulgaris. PMID- 26122849 TI - Antiangiogenic VEGF-Ax: A New Participant in Tumor Angiogenesis. AB - The transcript of the angiogenic factor vascular endothelial growth factor A (VEGF-A) is subject to a multitude of stimulus-dependent, posttranscriptional regulatory events, consistent with its unusually long 3' untranslated region. We have recently reported translational readthrough of VEGFA mRNA whereby translating ribosomes traverse the canonical stop codon to a conserved, downstream stop codon, generating VEGF-Ax ("x" for extended), a novel, extended isoform with an additional 22 amino acids appended at the C-terminus. This event is the first vertebrate example of protein-regulated, programmed translational readthrough that generates a protein with a known function. Remarkably, VEGF-Ax exhibits potent antiangiogenic activity, both in vitro and in vivo, thus raising profound clinical implications, particularly with respect to cancer treatment. In this review, we discuss the potential of VEGF-Ax as a therapeutic agent and drug target, as well as its possible role in the failure of, or resistance to, conventional anti-VEGF therapies in many types of cancers. PMID- 26122852 TI - Retrospective analysis of cancer survival across South-Western Victoria in Australia. AB - OBJECTIVE: This paper aims to describe cancer survival and examine association between survival and socio-demographic characteristics across Barwon South Western region (BSWR) in Victoria, Australia. DESIGN: This study is based on the retrospective cohort database of patients accessing oncology services across BSWR. SETTING: Six rural and three urban hospital settings across the BSWR. PARTICIPANTS: The participants were patients who were diagnosed with cancer in 2009. MAIN OUTCOME MEASURES: Overall survival (OS) of participants was the main outcome measure. RESULTS: Total of 1778 eligible patients had four-year OS for all cancers combined of 59.7% (95% CI, 57.4-62.0). Improved OS was observed for patients in the upper socio-economic tertile (64.2%; 95% CI, 60.9-67.5) compared to the middle (59.3%; 95% CI, 55.5-63.1) and lowest tertiles (49.6%; 95% CI, 44.2 54.9) (P < 0.01). On multivariate analyses, higher socio-economic status remained a significant predictor of OS adjusting for gender, remoteness and age (HR [hazard ratio] 0.81; 95% CI 0.74-0.89; P < 0.01). Remoteness was significantly associated with improved OS after adjusting for age, gender and socio-economic status (HR 0.86; 95% CI, 0.77-0.97; P = 0.01). Older age >=70 years compared to <70 years conferred inferior OS (HR 3.08; 95% CI, 2.64-3.59; P < 0.01). CONCLUSIONS: Our study confirmed improved survival outcomes for patients of higher socio-economic status and younger age. Future research to explain the unexpected survival benefit in patients who lived in more remote areas should examine factors including the correlation between geographical residence and eventual treatment facility as well as compare the BSWR care model to other regions' approaches. PMID- 26122853 TI - Modulation of the neuronal network activity by P2X receptors and their involvement in neurological disorders. AB - ATP is a key energetic molecule, fundamental to cell function, which also has an important role in the extracellular milieu as a signaling molecule, acting as a chemoattractant for immune cells and as a neuro- and gliotransmitter. The ionotropic P2X receptors are members of an ATP-gated ion channels family. These ionotropic receptors are widely expressed through the body, with 7 subunits described in mammals, which are arranged in a trimeric configuration with a central pore permeable mainly to Ca(2+) and Na(+). All 7 subunits are expressed in different brain areas, being present in neurons and glia. ATP, through these ionotropic receptors, can act as a neuromodulator, facilitating the Ca(2+) dependent release of neurotransmitters, inducing the cross-inhibition between P2XR and GABA receptors, and exercising by this way a modulation of synaptic plasticity. Growing evidence shows that P2XR play an important role in neuronal disorders and neurodegenerative diseases, like Parkinson's and Alzheimer's disease; this role involves changes on P2XR expression levels, activation of key pathways like GSK3beta, APP processing, oxidative stress and inflammatory response. This review is focused on the neuromodulatory function of P2XR on pathophysiological conditions of the brain; the recent evidence could open a window to a new therapeutic target. PMID- 26122854 TI - Validated chiral high performance liquid chromatography separation method and simulation studies of dipeptides on amylose chiral column. AB - Chiral resolution of dl-alanine-dl-tyrosine and dl-leucine-dl-phenylalanine dipeptides was achieved on AmyCoat-RP column. The mobile phase used for dl alanine-dl-tyrosine was acetonitrile-ammonium acetate (10mM, pH 6.0) [50:50, v/v]. It was acetonitrile-methanol-ammonium acetate (10mM; pH adjusted to 4.5 with glacial acetic acid) [50:20:30, v/v] for dl-leucine-dl-phenylalanine. The flow rate of the mobile phases was 0.8mL/min with UV detection at 275nm. The values of retention factors for ll-, dd-, dl- and ld-stereomers of dl-alanine-dl tyrosine were 1.71, 2.86, 5.43 and 9.42, respectively. The values of separation and resolution factors were 1.67, 1.90 and 1.73 and 2.88, 6.43 and 7.90, respectively. Similarly, these values for dl-leucine-dl-phenylalanine stereomers were 1.50, 2.88, 3.50 and 4.07 (retention factors), 1.92, 1.22 and 1.62 (separation factors) and 2.67, 1.55 and 2.30 (resolution factors). The limits of detections and quantitation were ranged from 2.03 to 6.40 and 6.79 to 21.30MUg/mL, respectively. The modeling studies were in agreement with the elution orders. The mechanism of chiral recognition was established by modeling and chromatographic studies. It was observed that hydrogen bondings and pi-pi interactions are the major forces for chiral separation. PMID- 26122855 TI - Analysis of polybrominated diphenyl ethers and emerging halogenated and organophosphate flame retardants in human hair and nails. AB - A method for the digestion, extraction, fractionation, and analysis of three classes of flame retardants, including 36 polybrominated diphenyl ethers (PBDEs), 9 halogenated alternative flame retardants (AFRs), and 12 organophosphate esters (OPEs) in human hair and nail samples was developed. The method employed HNO3/H2O2 digestion, liquid-liquid extraction with (4:1 vol) hexane:dichloromethane, fractionation on a 6g column of 2.5% water deactivated Florisil, and analysis by gas chromatographic mass spectrometry. The accuracy and precision of the method was validated using spiked samples of 6 replicates for both hair and nail samples. The method validation results showed good accuracy and precision for all PBDEs except BDE-209, all AFRs except hexabromobenzene (HBB), and all of the 12 OPEs, with average recovery efficiencies>90% and relative standard deviations (RSDs)<10%. The average recovery efficiencies for HBB were between 60% and 86%, with RSDs<10%. BDE-209 had recovery efficiencies of 64% (RSD, 13%) for hair and 71% (RSD, 10%) for nail. This method was applied to analyze 5 human hair and 5 fingernail samples from the general student population at Indiana University Bloomington campus. BDE-47 and BDE-99 were the predominant PBDEs detected in both hair and nail samples, with a concentration range of 11 620 and 4.6-780ng/g (dry weight) in hair and 7.3-43 and 2.1-11ng/g in nails, respectively. Di-(2-ethylhexyl)-tetrabromophthalate (TBPH) and 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB) were detected in all the samples, with concentrations of 20-240 and 11-350ng/g in hair and <17-80 and <9.2-71ng/g in nails, respectively. Among the 12 OPEs analyzed, tris(2-chloroethyl)phosphate (TCEP), tris(1-chloro-2-propyl)phosphate (TCIPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), and triphenyl phosphate (TPHP) were most often detected. The concentrations of these OPEs (summed together) were 1100-3900 and 380-18,000ng/g in hair and nails, respectively. These levels exceed those of both the PBDEs and the AFRs. PMID- 26122856 TI - Magnetic solid phase extraction and gas chromatography-mass spectrometrical analysis of sixteen polycyclic aromatic hydrocarbons. AB - Fluorenyl functionalized superparamagnetic core/shell magnetic nanoparticles (MNPs, Fe3O4@SiO2@Flu) were prepared and characterized by transmission electron microscope, X-ray diffraction and infrared spectroscopy. The MNPs having an average diameter of 200nm were then used as solid-phase extraction sorbent for the determination of 16 priority pollutants polycyclic aromatic hydrocarbons (PAHs) in water samples designated by United States Environmental Protection Agency (U.S. EPA). The main influencing parameters, including sorbent amount, desorption solvent, sample volume and extraction time were optimized. Analyses were performed on gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM) mode. Method validation proved the feasibility of the developed sorbents for the quantitation of the investigated analytes at trace levels. Limit of detection ranging from 0.5 to 4.0ng/L were obtained. The repeatability was investigated by evaluating the intra- and inter-day precisions with relative standard deviations (RSDs) lower than 13.1%. Finally, the proposed method was successfully applied for the determination of PAHs in water samples with the recoveries in the range of 96.0-106.7%. PMID- 26122857 TI - Microfluidic device for sheathless particle focusing and separation using a viscoelastic fluid. AB - Continuous sheathless particle separation with high efficiency is essential for various applications such as biochemical analyses and clinical diagnosis. Here, a novel microfluidic device for highly efficient, sheathless particle separation using an elasticity-dominant non-Newtonian fluid is proposed. Our device consists of two stages: sheathless three-dimensional focusing (1 st stage) and separation (2nd stage). It is designed based on the principle of a viscoelasticity-induced particle lateral migration, which promises precise separation of particles in a microfluidic device. Particles of 5- and 10-MUm diameters were all focused at the centerline of a circular channel at the 1st stage and successfully separated at the 2nd stage with an efficiency of ~99.9% using size-based lateral migration of particles induced by the viscoelasticity of the medium. We also demonstrated the capability of our device for separation of blood cells into multiple fractions. The tunability of separable particle size could be achieved by changing the viscoelastic property of the medium and flow rate. PMID- 26122858 TI - Computational analysis and ratiometric comparison approaches aimed to assist column selection in hydrophilic interaction liquid chromatography-tandem mass spectrometry targeted metabolomics. AB - In the present work two different approaches, a semi-quantitative and a Derringer function approach, were developed to assist column selection for method development in targeted metabolomics. These approaches were applied in the performance assessment of three HILIC columns with different chemistries (an amide, a diol and a zwitterionic phase). This was the first step for the development of a HILIC UPLC-MS/MS method that should be capable to analyze a large number of polar metabolites. Two gradient elution profiles and two mobile phase pH values were tested for the analysis of multi-analyte mixtures. Acquired chromatographic data were firstly treated by a ratiometric, "semi-quantitative" approach which quantifies various overall analysis parameters (e.g. the percent of detected compounds, retentivity and resolved critical pairs). These parameters were used to assess chromatographic performance in a rather conventional/traditional and cumbersome/labor-intensive way. Secondly, a comprehensive and automated comparison of the three columns was performed by monitoring several well-known chromatographic parameters (peak width, resolution, tailing factor, etc.) using a lab-built programming script which calculates overall desirability utilizing Derringer functions. Derringer functions exhibit the advantage that column performance is ultimately expressed in an objective single and quantitative value which can be easily interpreted. In summary, results show that each column exhibits unique strengths in metabolic profiling of polar compounds. The applied methodology proved useful for the selection of the most effective chromatographic system during method development for LC-MS/MS targeted metabolomics, while it could further assist in the selection of chromatographic conditions for the development of multi-analyte methods. PMID- 26122860 TI - Neurodegenerative disease: Could fingolimod provide cognitive benefits in patients with Huntington disease? PMID- 26122859 TI - Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study. AB - OBJECTIVE: To investigate the incidence and characteristics of vitamin D deficiency rickets in New Zealand (NZ). METHODS: Prospective surveillance among paediatricians of Vitamin D Deficiency Rickets was conducted by the New Zealand Paediatric Surveillance Unit (NZPSU) for 36 months, from July 2010 to June 2013, inclusive. Inclusion criteria were: children and adolescents <15 years of age with vitamin D deficiency rickets (defined by low serum 25-hydroxyvitamin D and elevated alkaline phosphatase levels, and/or radiological rickets). RESULTS: Fifty-eight children with confirmed vitamin D deficiency rickets were identified. Median age was 1.4 (range 0.3-11) years, 47% were male, and 95% of the children were born in NZ; however, the majority of the mothers (68%) were born outside NZ. Overall annual incidence of rickets in children aged <15 years was 2.2/100,000 (95%CI 1.4-3.5); with incidence in those <3 years being 10.5/100,000 (95%CI 6.7 16.6). Skeletal abnormalities, poor growth and motor delay were the most common presenting features, with hypocalcaemic convulsion in 16% of children. Key risk factors identified were: darker skin pigment, Indian and African ethnicity, age <3 years, exclusive breast feeding, and southern latitude, particularly when combined with season (winter/spring). Of the patients reported, none had received appropriate vitamin D supplementation. CONCLUSIONS: Vitamin D deficiency rickets remains a problem for NZ children. Key risk factors remain similar to those identified in the international literature. Preventative targeted vitamin D supplementation, as per existing national guidelines, was lacking in all cases reported. IMPLICATIONS: Vitamin D deficiency rickets is the most significant manifestation of vitamin D deficiency in growing children. To reduce the incidence of this disease among those at high risk, increasing awareness and implementation of current public health policies for targeted maternal, infant and child supplementation are required. PMID- 26122861 TI - A Broadband Bessel Beam Launcher Using Metamaterial Lens. AB - An approach of generating broadband Bessel beams is presented. The broadband Bessel beams are produced by a gradient index (GRIN) metamaterial lens illuminated by broadband waveguide antenna. The metamaterial lens is constructed with multi-layered structure and each layer is composed of GRIN metamaterials. The metamaterials are designed as dielectric plates printed with metallic patterns in the center region and drilled by air holes near the edge, which operate in wide band. The metamaterial lens serves as a convertor which transforms the spherical beams emitted from feed into conical beams. The conical beams form quasi-Bessel beams in the near-field region. The aperture diameter of the GRIN lens is much larger than the operating wavelength to guarantee the transformation. In principle, this kind of metamaterial lens can produce Bessel beams at arbitrary distance by designing the refractive-index distribution. To verify the approach, we have designed, fabricated and tested a metamaterial lens. Full-wave simulation and experiment results have proved that the generated Bessel beams can be maintained in distance larger than 1 meter within a ranging from 12 GHz to 18 GHz. PMID- 26122862 TI - BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients. AB - We propose an extensive review of the literature about BDNF/TRKB/P75NTR polymorphisms and their consequences on antidepressant efficacy in depressed patients. Five genome-wide association studies and 30 association studies were included. Twenty seven studies focused on the Val66Met polymorphism (rs6265), the Met allele being associated with a higher antidepressant efficacy only in Asian patients. Other BDNF/TRKB/P75NTR polymorphisms (BDNF: rs7103411, rs7124442, rs908867, rs2049046, rs61888800, rs10501087, rs1491850; TRKB: rs10868223, rs11140778, rs1565445, rs1659412; P75NTR: rs2072446) were reported to be associated with antidepressant efficacy but these results were not replicated. Finally, there are 15 positive studies among 30 studies regarding BDNF/TRKB/P75NTR polymorphisms. The only SNP which benefits of at least three positive studies is the BDNF Val66Met polymorphism (rs6265). Consequently, with a lack of good and consistent studies, the clinical utility of BDNF in treatment selection is far from clear. We propose several recommendations for further studies. PMID- 26122863 TI - Misoprostol-induced fever and genetic polymorphisms in drug transporters SLCO1B1 and ABCC4 in women of Latin American and European ancestry. AB - AIM: Misoprostol, a prostaglandin analogue used for the treatment of postpartum hemorrhage and termination of pregnancy, can cause high fevers. Genetic susceptibility may play a role in misoprostol-induced fever. SUBJECTS & METHODS: Body temperature of women treated with misoprostol for termination of pregnancy in the UK (n = 107) and for postpartum hemorrhage in Ecuador (n = 50) was measured. Genotyping for 33 single nucleotide polymorphisms in 15 candidate genes was performed. Additionally, we investigated the transport of radiolabeled misoprostol acid across biological membranes in vitro. RESULTS: The ABCC4 single nucleotide polymorphism rs11568658 was associated with misoprostol-induced fever. Misoprostol acid was transported across a blood-brain barrier model by MRP4 and SLCO1B1. CONCLUSION: Genetic variability in ABCC4 may contribute to misoprostol induced fever in pregnant women. Original submitted 21 January 2015; Revision submitted 24 April 2015. PMID- 26122864 TI - Effect of gender and CYP2C9 and CYP2C8 polymorphisms on the pharmacokinetics of ibuprofen enantiomers. AB - AIM: To evaluate the effect of polymorphisms in CYP2C9 and CYP2C8 and gender on the pharmacokinetics of the enantiomeric forms of ibuprofen. MATERIALS & METHODS: 122 healthy volunteers were genotyped for polymorphisms in CY2C8 and CYP2C9 using real-time PCR. RESULTS: CYP2C8 polymorphisms affected neither R- nor S-ibuprofen. CYP2C9*3 and CYP2C9*2 carriers had a lower S-ibuprofen clearance and a higher S ibuprofen AUC and half-life. R-ibuprofen clearance was decreased in CYP2C9*3 carriers. Gender affected R-ibuprofen and S-ibuprofen pharmacokinetics. Multiple regression analysis showed that CYP2C9*2, CYP2C9*3 and gender were associated with S-ibuprofen clearance, but only CYP2C9*3 was associated with R-ibuprofen clearance. CONCLUSION: The pharmacokinetics of S-ibuprofen and R-ibuprofen is affected by CYP2C9 polymorphisms and gender. CYP2C8 polymorphisms do not have a significant role. Original submitted 6 February 2015; Revision submitted 1 April 2015. PMID- 26122865 TI - How close are we to a pharmacogenomic test for clozapine-induced agranulocytosis? PMID- 26122867 TI - Left ventricular remodeling in patients with sickle cell disease: determinants factors and impact on outcome. AB - Cardiovascular complications have been increasingly detected as a result of prolonged longevity of patients with sickle cell disease (SCD). Previous studies have focused especially on pulmonary hypertension and its consequences on the right-side heart chambers, whereas factors associated with morphological changes in left ventricle (LV) remain poorly understood. This study was designed to identify clinical, laboratorial, and echocardiographic parameters associated with LV remodeling and its impact on outcome in SCD. Ninety patients aged 28 +/- 7 years and 20 age- and gender-balanced healthy subjects were enrolled. Laboratory tests, electrocardiogram, and an echocardiogram with tissue Doppler imaging were performed in all patients. Patients with SCD had larger left and right heart chambers dimensions, LV mass, and tricuspid regurgitation (TR) velocity compared to health controls with similar demographic features. Despite chambers enlargement, systolic function of both ventricles was preserved. The mitral inflow velocities were higher in the patients than in controls, whereas septal and lateral annular motion velocities were normal, suggesting normal ventricular relaxation. SCD patients who were on hydroxyurea therapy and/or hypertransfusion had higher hemoglobin concentrations, but similar echocardiographic findings in comparison to those without treatment. Systolic blood pressure, ferritin concentration, TR velocity, and parameters of diastolic function were independently associated with increased LV mass. In addition, the predictors of adverse events were ferritin concentration, lactate dehydrogenase levels, and TR velocity. LV remodeling in SCD patients seems to be influenced by a combination of factors including blood pressure, ferritin concentration, TR velocity, and parameters of LV diastolic function, and was not associated with adverse outcomes. PMID- 26122866 TI - Bendamustine as first-line treatment in patients with advanced indolent non Hodgkin lymphoma and mantle cell lymphoma in German routine clinical practice. AB - Bendamustine has demonstrated clinical activity and a favorable safety profile as monotherapy or in combination with rituximab in lymphoid malignancies. As interventional trials do not always reflect clinical reality, we were interested in the treatment modalities and the outcome of bendamustine-based first-line therapy in patients with advanced indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL) in routine practice. Between April 2010 and October 2011, 324 patients were enrolled in a prospective non-interventional multicenter study. Choice of the bendamustine regimen was at the treating physician's discretion. Effectiveness was assessed by best response. Mean age at onset of therapy was 69 years. The majority (94 %) of the patients was treated with bendamustine in combination with rituximab at a median bendamustine dose of 177 mg/m(2) per cycle. Most often, bendamustine was administered on days 1 and 2 (87 %) at 4-week intervals over a median of 6 cycles. Two hundred eighty-one patients qualified for evaluation of response. The overall response rate was 86 % (complete response 43 %, partial response 43 %, stable disease 10 %, progressive disease 4 %). Side effects of all grades were documented for 161 of the 323 patients (50 %), most frequently affecting blood/bone marrow (35 %). Fifty-four (17 %) patients experienced side effects of grade 3 (15 %) or grade 4 (2 %), and two patients grade 5 toxicities. Bendamustine-based first-line treatment of patients with advanced indolent NHL and MCL in clinical routine practice was assessed as effective and well tolerated in our study. Response was comparable to results from interventional clinical trials. PMID- 26122868 TI - External bone marrow cytological examination quality assurance (EQAhem)--summary after 6 years in Poland. AB - Bone marrow macroscopic examination remains one of the most difficult and subjective laboratory assessments in hematology. Only a few external quality assurance programs in the field are present worldwide. We have developed an external quality assurance program EQAhem that allows assessment of the whole process of bone marrow examination. The program participants assess blood and bone marrow smears from the patient, identify selected cells from photographs provided to them, and interpret the microscopic results. In this article, the results of the EQAhem program in Poland from 6 years are summarized. During this time, 62 labs were assessed in total, and positive results were achieved by 89.25 % labs, taking into account all tests. Correct responses with respect to the percentage of cell count were provided by ca. 77.5 % labs. Slightly worse results were obtained when megakaryocyte count and cell identification from photographs were tested. The worst results were obtained in case of dysplasia assessment and clinical interpretation of microscopic examination (54.1 and 58.6 % correct responses, respectively). EQAhem delivers precise information about the quality of bone marrow examinations performed in Poland and has a substantial educational value. We believe that after 6 years, EQAhem has significantly improved the quality of bone marrow microscopic examinations performed in Poland. PMID- 26122869 TI - Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results. AB - The efficacy of danazol was assessed in 50 patients with myelofibrosis and anemia using the recently revised criteria of the International Working Group for Myelofibrosis Research and Treatment. According to them, anemia response (clinical improvement) is defined as transfusion cessation in transfusion dependent patients or an Hb increase >2 g/dl in patients without transfusion requirements, both maintained for at least 12 weeks. Median follow-up from danazol start was 36 months (interquartile range [IQR] 19.2-58.8). Anemia response was achieved in 15 patients (30 %), including 5 of the 27 with transfusion dependency (18.5 %) and 10 of the 23 without transfusion requirements (43.5 %). Median time to response was 5 months (IQR 4-7) and median duration of the response 14 months (IQR 10-21). Among responder patients, 5 discontinued therapy due to toxicity or personal decision and 1 died from spleen rupture while being in response. A trend for worse response was seen in transfusion-dependent patients (p = 0.055). A platelet increase >50 * 10(9)/l was observed in 3 of 13 thrombocytopenic patients, all of whom had moderate thrombocytopenia. Toxicity was usually moderate, leading to treatment withdrawal in only 4 patients. Danazol is effective in 30 % of patients with anemia-associated myelofibrosis. The responses are less frequent in patients with transfusion dependency. PMID- 26122870 TI - Two-Dimensional Pnictogen Honeycomb Lattice: Structure, On-Site Spin-Orbit Coupling and Spin Polarization. AB - Because of its novel physical properties, two-dimensional materials have attracted great attention. From first-principle calculations and vibration frequencies analysis, we predict a new family of two-dimensional materials based on the idea of octet stability: honeycomb lattices of pnictogens (N, P, As, Sb, Bi). The buckled structures of materials come from the sp(3) hybridization. These materials have indirect band gap ranging from 0.43 eV to 3.7 eV. From the analysis of projected density of states, we argue that the s and p orbitals together are sufficient to describe the electronic structure under tight-binding model, and the tight-binding parameters are obtained by fitting the band structures to first-principle results. Surprisingly large on-site spin-orbit coupling is found for all the pnictogen lattices except nitrogen. Investigation on the electronic structures of both zigzag and armchair nanoribbons reveals the possible existence of spin-polarized ferromagnetic edge states in some cases, which are rare in one-dimensional systems. These edge states and magnetism may exist under the condition of high vacuum and low temperature. This new family of materials would have promising applications in electronics, optics, sensors, and solar cells. PMID- 26122871 TI - Non-destructive monitoring of viability in an ex vivo organ culture model of osteochondral tissue. AB - Organ culture is an increasingly important tool in research, with advantages over monolayer cell culture due to the inherent natural environment of tissues. Successful organ cultures must retain cell viability. The aim of this study was to produce viable and non-viable osteochondral organ cultures, to assess the accumulation of soluble markers in the conditioned medium for predicting tissue viability. Porcine femoral osteochondral plugs were cultured for 20 days, with the addition of Triton X-100 on day 6 (to induce necrosis), camptothecin (to induce apoptosis) or no toxic additives. Tissue viability was assessed by the tissue destructive XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5 carboxyanilide tetrazolium salt) assay method and LIVE/DEAD(r) staining of the cartilage at days 0, 6 and 20. Tissue structure was assessed by histological evaluation using haematoxylin & eosin and safranin O. Conditioned medium was assessed every 3-4 days for glucose depletion, and levels of lactate dehydrogenase (LDH), alkaline phosphatase (AP), glycosaminoglycans (GAGs), and matrix metalloproteinase (MMP)-2 and MMP-9. Necrotic cultures immediately showed a reduction in glucose consumption, and an immediate increase in LDH, GAG, MMP-2 and MMP-9 levels. Apoptotic cultures showed a delayed reduction in glucose consumption and delayed increase in LDH, a small rise in MMP-2 and MMP-9, but no significant effect on GAGs released into the conditioned medium. The data showed that tissue viability could be monitored by assessing the conditioned medium for the aforementioned markers, negating the need for tissue destructive assays. Physiologically relevant whole- or part-joint organ culture models, necessary for research and pre-clinical assessment of therapies, could be monitored this way, reducing the need to sacrifice tissues to determine viability, and hence reducing the sample numbers necessary. PMID- 26122872 TI - Dynamics of Energy Transfer in a Conjugated Dendrimer Driven by Ultrafast Localization of Excitations. AB - Solar energy conversion starts with the harvest of light, and its efficacy depends on the spatial transfer of the light energy to where it can be transduced into other forms of energy. Harnessing solar power as a clean energy source requires the continuous development of new synthetic materials that can harvest photon energy and transport it without significant losses. With chemically controlled branched architectures, dendrimers are ideally suited for these initial steps, since they consist of arrays of chromophores with relative positioning and orientations to create energy gradients and to spatially focus excitation energies. The spatial localization of the energy delimits its efficacy and has been a point of intense research for synthetic light harvesters. We present the results of a combined theoretical experimental study elucidating ultrafast, unidirectional, electronic energy transfer on a complex molecule designed to spatially focus the initial excitation onto an energy sink. The study explores the complex interplay between atomic motions, excited-state populations, and localization/delocalization of excitations. Our findings show that the electronic energy-transfer mechanism involves the ultrafast collapse of the photoexcited wave function due to nonadiabatic electronic transitions. The localization of the wave function is driven by the efficient coupling to high frequency vibrational modes leading to ultrafast excited-state dynamics and unidirectional efficient energy funneling. This work provides a long-awaited consistent experiment-theoretical description of excited-state dynamics in organic conjugated dendrimers with atomistic resolution, a phenomenon expected to universally appear in a variety of synthetic conjugated materials. PMID- 26122873 TI - Improved hand hygiene compliance after eliminating mandatory glove use from contact precautions-Is less more? AB - BACKGROUND: Guidelines recommend that health care personnel (HCP) wear gloves for all interactions with patients on contact precautions. We aimed to assess hand hygiene (HH) compliance during contact precautions before and after eliminating mandatory glove use. METHODS: We assessed HH compliance of HCP in the care of patients on contact precautions in 50 series before (2009) and 6 months after (2012) eliminating mandatory glove use and compared these results with the hospital-wide HH compliance. RESULTS: We assessed 426 HH indications before and 492 indications after the policy change. Compared with 2009, we observed a significantly higher HH compliance in patients on contact precautions in 2012 (52%; 95% confidence interval [95% CI], 47-57) vs 85%; 95% CI, 82-88; P < .001). During the same period, hospital-wide HH compliance also increased from 63% (95% CI, 61-65) to 81% (95% CI 80-83) (P < .001). However, the relative improvement (RI) of HH compliance during contact precautions was significantly higher than the hospital-wide relative improvement (RI, 1.6; 95% CI, 1.49-1.81 vs 1.29; 95% CI, 1.25-1.34), with a relative improvement ratio of 1.27 (95% CI, 1.15-1.41). CONCLUSION: Eliminating mandatory glove use in the care of patients on contact precautions increased HH compliance in our institution, particularly before invasive procedures and before patient contacts. Further studies on the effect on pathogen transmission are needed before revisiting the current official guidelines on the topic. PMID- 26122874 TI - Corruption costs lives: a cross-country study using an IV approach. AB - This study quantitatively estimates the effects of corruption on five major health indicators by using recent cross-country panel data covering 119 countries for the period of 2005-2011. The corruption indicators provided by the World Bank and Transparency International are used, and both the two-way fixed effect and the two-stage least squares approaches are employed for our estimation. The estimation results show that, in general, corruption is negatively associated with a country's health outcomes. A lower level of corruption or a better control of corruption in a country can lead to longer life expectancy, a lower infant mortality rate and a lower under-five mortality rate for citizens. However, our estimation finds no significant association between corruption and individual diseases including human immunodeficiency virus prevalence and tuberculosis incidence. The findings suggest that corruption reduction itself is an effective method to promote health. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26122875 TI - Hyperinsulinemia and hyperglycemia: risk factors for recurrence of benign paroxysmal positional vertigo. AB - INTRODUCTION: Changes in carbohydrate metabolism may lead to recurrence of benign paroxysmal positional vertigo. OBJECTIVE: To evaluate the influence of the disturbance of carbohydrate metabolism in the recurrence of idiopathic BPPV. METHODS: A longitudinal prospective study of a cohort, with 41 months follow-up. We analyzed the results of 72 glucose-insulin curves in patients with recurrence of BPPV. The curves were classified into intolerance, hyperinsulinemia, hyperglycemia and normal. RESULTS: The RR for hyperinsulinism was 4.66 and p=0.0015. Existing hyperglycemia showed an RR=2.47, with p=0.0123. Glucose intolerance had a RR of 0.63, with p=0.096. When the examination was within normal limits, the result was RR=0.2225 and p=0.030. DISCUSSION: Metabolic changes can cause dizziness and vertigo and are very common in people who have cochleovestibular disorders. However, few studies discuss the relationship between idiopathic BPPV and alterations in carbohydrate metabolism. In the present study, we found that both hyperglycemia and hyperinsulinemia are risk factors for the recurrence of BPPV, whereas a normal test was considered a protective factor; all these were statistically significant. Glucose intolerance that was already present was not statistically significant in the group evaluated. CONCLUSION: Hyperinsulinemia and hyperglycemia are risk factors for the recurrence of idiopathic BPPV and a normal exam is considered a protective factor. PMID- 26122876 TI - Dissecting the Role of Oxytocin in the Formation and Loss of Social Relationships. AB - Current concepts of human sociality highlight a fundamental role of the hypothalamic peptide oxytocin (OXT) in the formation and maintenance of social relationships. However, emerging evidence indicates that OXT does not invariably facilitate social bonding but also produces nonprosocial effects that may have evolved to promote offspring survival. From a mechanistic perspective, we hypothesize that OXT modulates interoceptive signals and self-referential processing, which may result in various social outcomes depending on context- and person-dependent variables such as early-life adversity. Based on this theoretical framework, we discuss translational implications for clinical trials and identify open questions for future research. Specifically, we propose that disrupted OXT signaling due to the loss of affectionate bonds may contribute to emotional disequilibrium and confer elevated risk for the onset of stress-related disorders. PMID- 26122877 TI - p66Shc deletion or deficiency protects from obesity but not metabolic dysfunction in mice and humans. AB - AIMS/HYPOTHESIS: Oxygen radicals generated by p66Shc drive adipogenesis, but contradictory data exist on the role of p66Shc in the development of obesity and the metabolic syndrome. We herein explored the relationships among p66Shc, adipose tissue remodelling and glucose metabolism using mouse models and human adipose tissue samples. METHODS: In wild-type (WT), leptin-deficient (ob/ob), p66Shc(-/-) and p66Shc(-/-) ob/ob mice up to 30 weeks of age, we analysed body weight, subcutaneous and visceral adipose tissue histopathology, glucose tolerance and insulin sensitivity, and liver and muscle fat accumulation. A group of mice on a high fat diet (HFD) was also analysed. A parallel study was conducted on adipose tissue collected from patients undergoing elective surgery. RESULTS: We found that p66Shc(-/-) mice were slightly leaner than WT mice, and p66Shc(-/-) ob/ob mice became less obese than ob/ob mice. Despite their lower body weight, p66Shc(-/-) mice accumulated ectopic fat in the liver and muscles, and were glucose intolerant and insulin resistant. Features of adverse adipose tissue remodelling induced by obesity, including adipocyte enlargement, apoptosis, inflammation and perfusion were modestly and transiently improved by p66Shc (also known as Shc1) deletion. After 12 weeks of the HFD, p66Shc(-/-) mice were leaner than but equally glucose intolerant and insulin resistant compared with WT mice. In 77 patients, we found a direct correlation between BMI and p66Shc protein levels. Patients with low p66Shc levels were less obese, but were not protected from other metabolic syndrome features (diabetes, dyslipidaemia and hypertension). CONCLUSIONS/INTERPRETATION: In mice and humans, reduced p66Shc levels protect from obesity, but not from ectopic fat accumulation, glucose intolerance and insulin resistance. PMID- 26122878 TI - Management of nicotinamide N-methyltransferase overexpression: inhibit the enzyme or reduce nicotinamide intake? PMID- 26122879 TI - Prognostic value of the cadmium-zinc-telluride camera: A comparison with a conventional (Anger) camera. AB - BACKGROUND: New multipinhole cadmium-zinc-telluride (CZT) cameras allow for faster imaging and lower radiation doses for single photon emission computed tomography (SPECT) studies, but assessment of prognostic ability is necessary. METHODS AND RESULTS: We collected data from all myocardial SPECT perfusion studies performed over 15 months at our institution, using either a CZT or conventional Anger camera. A Cox proportional hazards model was used to assess the relationship between camera type, imaging results, and either death or myocardial infarction (MI). Clinical variables including age, sex, body mass index (BMI), and historical risk factors were used for population description and model adjustments. We had 2,088 patients with a total of 69 deaths and 65 MIs (122 events altogether). A 3% increase in DDB (difference defect burden) represented a 12% increase in the risk of death or MI, whereas a 3% increase in rest defect burden or stress defect burden represented an 8% increase; these risks were the same for both cameras (P > .24, interaction tests). CONCLUSIONS: The CZT camera has similar prognostic values for death and MI to conventional Anger cameras. This suggests that it may successfully be used to decrease patient dose. PMID- 26122880 TI - Clinical value of high duke treadmill score with myocardial perfusion SPECT. PMID- 26122882 TI - Incidental ectopic thyroid follicular adenoma on myocardial perfusion imaging. PMID- 26122883 TI - Cardiac (18)F-FDG uptake in chagas disease. PMID- 26122884 TI - Single-incision port-site herniation: meta-analysis vs. nationwide cohort study. PMID- 26122885 TI - Current Practices in the Treatment of Alzheimer Disease: Where is the Evidence After the Phase III Trials? AB - PURPOSE: The purpose of this systematic review was to review the current place in therapy of the 4 medications, donepezil, rivastigmine, galantamine, and memantine, approved for the treatment of Alzheimer disease (AD) since the publication of Phase III trials. METHODS: A systematic literature search of MEDLINE and EMBASE was conducted for articles published in the past 10 years. The search was performed using the following Medical Subject Headings and text key words: Alzheimer's disease, treatment, donepezil, galantamine, rivastigmine, memantine, dementia of the Alzheimer's type, and dementia. FINDINGS: Studies that evaluated new doses, indications, and dose formulations remain a large part of the current literature. Donepezil gained approval for the treatment of severe AD and became available in a 23-mg/d dose formulation. Rivastigmine became available in a patch formulation. Memantine became available as an extended-release capsule. Use of a combination product formulation was recently approved, memantine extended release/donepezil. Controversy among clinicians remains regarding when to initiate therapy, appropriate duration of therapy, and how and when to discontinue the treatment of AD. IMPLICATIONS: Only drugs that affect cholinergic function have shown consistent, but modest, clinical effects, even in late-phase trials. There is a need for a better appreciation of the various risk factors and drug targets for the treatment of AD. The wide range of targets makes it unlikely that affecting only 1 of those targets (eg, cholinergic function or N methyl-d-aspartate) will lead to a more than minimally effective treatment option, regardless of when a treatment is started and discontinued. There is substantial opportunity for the continued growth and development of drugs and clinical trial expansion for the treatment of AD. PMID- 26122886 TI - Jonesia luteola sp. nov., a bacterium isolated from Xinjiang Province, China. AB - A Gram-positive, facultative anaerobe microorganism, designated YIM 93067(T), was isolated from a salt lake in Xinjiang Province of China and subjected to a polyphasic taxonomic study. Strain YIM 93067(T) grew at 5-40 degrees C, 0-8.0 % (w/v) NaCl and pH 7.0-9.0. Phylogenetic analyses based on 16S rRNA gene sequences revealed that the organism belongs to the genus Jonesia and exhibited a sequence similarity of 98.8 % to the closely related type strain Jonesia quinghaiensis DSM 15701(T). The predominant menaquinone was MK-9 and the major fatty acids were anteiso-C15:0 and C16:0. The polar lipids consisted of diphosphatidylglycerol, glycolipid, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and one unidentified phospholipid. The G+C content of the genomic DNA was 57.4 mol%. Based on the results of phylogenetic, physiological and chemotaxonomic comparative analyses, the isolate is assigned to a novel species of the genus Jonesia, for which the name Jonesia luteola sp. nov. is proposed, with the type strain YIM 93067(T) (=DSM 21367(T) = CCTCC AB 2014350(T)). PMID- 26122887 TI - Paralcaligenes ginsengisoli sp. nov., isolated from ginseng cultivated soil. AB - A novel bacterial strain DCY104(T) isolated from soil of a ginseng field in Yeoncheon County, Republic of Korea is described in this study. Cells were short rod-shaped, motile by mean of one polar flagellum, strictly aerobic, Gramreaction negative, oxidase and catalase-positive. 16S rRNA gene sequence analysis showed that strain DCY104(T) shared highest similarity 98.2 % to Paralcaligenes ureilyticus GR24-5(T), and from 97.7 to 97.1 % with other type strains belong to the genera Candidimonas, Pusillimonas and Parapusillimonas Otherwise, phylogenetic trees analyses indicated that strain DCY104(T) belongs to a single group with P. ureilyticus GR24-5(T) that was distinct to other genera. The major polar lipids were phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, and diphosphatidylglycerol. The major cellular fatty acids consisted of C16:0, cyclo-C17:0, and summed feature 8 (comprising C18:1 omega7c and/or C18:1 omega6c). The predominant polyamine was putrescine. The ubiquinone was Q-8. The genomic DNA G+C content was 55.9 mol%. These data in combination with the presence of one polar flagellum and positive activity of urease confirmed the placement of strain DCY104(T) in the genus Paralcaligenes. DNA-DNA relatedness between strain DCY104(T) and P. ureilyticus KACC 13888(T) was 40 %. The differences in the profiles of polar lipids, fatty acids and phenotypic characteristics in combination with DNA-DNA relatedness delineated strain DCY104(T) and P. ureilyticus KACC 13888(T). In summary, taxonomic analyses in this study demonstrated that strain DCY104(T) represents a novel species within the genus Paralcaligenes, for which we propose the name Paralcaligenes ginsengisoli. The type strain is DCY104(T) (= KCTC 42406(T) = JCM 30746(T)). PMID- 26122888 TI - Skermanella rubra sp. nov., a bacterium isolated from the desert of Xinjiang, China. AB - A Gram-negative, pink-coloured, rod-shaped, motile bacterium, designated YIM 93097(T), was isolated from the desert soil collected from Xinjiang province of China. Strain YIM 93097(T) was found to grow at 20-45 degrees C (optimum 28-37 degrees C), pH 5.0-7.0 (optimum pH 7.0) and 0-8 % (w/v) NaCl (optimum 1 %, w/v). Based on 16S rRNA gene sequence similarity studies, it belongs to the genus Skermanella. The 16S rRNA gene sequence similarity was identified to be 98.7 % to Skermanella xinjiangensis CCTCC AB 207153(T) while the DNA-DNA hybridization value was found to be only 48.1 %. The predominant isoprenoid quinone was determined to be Q-10. The major fatty acids were identified to be C16:0, C18:1 omega7c and summed feature 4 (consisting of C17:1 anteiso B/iso I). The major polar lipids were identified as phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, two unidentified phospholipids and one unidentified aminolipid. The DNA G+C content was found to be 67.2 mol %. The analysis of the genotypic and phenotypic data indicated that strain YIM 93097(T) belongs to a novel species of the genus Skermanella, for which the name Skermanella rubra sp. nov. is proposed. The type strain is YIM 93097(T) (=DSM 21389(T)=CCTCC AB 2015161(T)). PMID- 26122889 TI - Assessment of endophytic yeast diversity in rice leaves by a culture-independent approach. AB - Endophytic microorganisms inhabit internal plant tissues in the host plant without causing any symptoms or negative effects. Although the diversity of endophytes has been evaluated by both culture-dependent and culture-independent methods, less information is available on yeast communities. Therefore, in this study a culture-independent method was used to examine endophytic yeasts associated with rice leaves based on the large subunit of ribosomal DNA using a semi-nested PCR technique. Sequence analysis indicated that the colonization frequency and the relative species frequency (RF) of endophytic yeast phylotypes were 0.41 and 0.06, respectively, and the majority of the yeast phylotypes were basidiomycetous yeasts. The phylotypes were designated as five known species (Cryptococcus victoriae, Debaryomyces hansenii, Debaryomyces vindobonensis, Meyerozyma guilliermondii and Pseudozyma antarctica), together with seventeen phylotypes closest to Candida metapsilosis, Cryp. foliicola, Cryp. laurentii, Pseudozyma abaconensis, Pseudozyma aphidis and Trichosporon asahii, among which some could be novel species. The most prevalent phylotypes were those closest to Cryp. foliicola (47.5 % RF) followed by D. hansenii (22.8 % RF) and P. antarctica (16.8 % RF). The presence of the phylotypes related to species known for their potential applications as biocontrol agents and plant growth promoting hormone producers suggests that they may have valuable applications. In addition, our findings revealed the occurrence of novel phylotypes at high frequency, which should encourage extensive studies to discover novel yeast species and to understand their roles in the rice leaves. PMID- 26122890 TI - Marinobacter adhaerens HP15 harbors two CzcCBA efflux pumps involved in zinc detoxification. AB - Several members of the ubiquitously found gamma-proteobacterial genus Marinobacter were described or assumed to inhabit marine environments naturally enriched in heavy metals. However, direct studies that describe the ability of this genus to occupy such environments have not been conducted. To cope with heavy metal stress, bacteria possess specific efflux pumps as tools for detoxification, among which the CzcCBA type efflux system is one representative. Previous studies showed that this system plays an important role in resistance towards cadmium, zinc, and cobalt. Up to now, no study had focused on characterization of Czc pumps in Marinobacter sp. or other marine prokaryotes. Herein, we elucidated the function of two CzcCBA pumps encoded by Marinobacter adhaerens HP15's genome during exposure to cadmium, zinc, and cobalt. Single and double knock-out mutants lacking the corresponding two czcCBA operons were generated and analyzed in terms of their resistance profiles. Both operons appeared to be important for zinc resistance but had no role in tolerance towards cadmium or cobalt. One of the mutations was genetically complemented thereby restoring the wild type phenotype. In accordance with the resistance pattern, expression of the genes coding for both CzcCBA pumps was induced by zinc but neither by cadmium nor cobalt. PMID- 26122891 TI - Frequency and change mechanisms of psychotherapy among depressed patients: study protocol for a multicenter randomized trial comparing twice-weekly versus once weekly sessions of CBT and IPT. AB - BACKGROUND: Cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) are among the most well established therapies for the treatment of depression. However, some major questions remain unanswered. First, it is unknown what session frequency results in the most optimal (cost) effectiveness in psychotherapy. Second, the debate as to what mechanisms underlie the effect of psychotherapy has not yet been resolved. Enhancing knowledge about the optimal session frequency and mechanisms of change seems crucial in order to optimize the (cost) effectiveness of psychotherapy for depression. This study aims to compare treatment outcome of twice-weekly versus once-weekly sessions of CBT and IPT. We expect twice-weekly sessions to be more effective and lead to more rapid recovery of depressive symptoms in comparison to once-weekly sessions. Both therapy specific and non-specific process measures will be included to unravel the mechanisms of change in psychotherapy for depression. Besides the use of self reports and behavioral observations, this study will also examine underlying biological processes by collecting blood samples. METHOD: In a multicenter randomized trial, two hundred depressed patients will be recruited from Dutch specialized mental healthcare centers and randomized into one of the following groups, all receiving a maximum of 20 sessions in different frequencies: a) twice weekly sessions at the start of CBT, b) twice-weekly sessions at the start of IPT, c) once-weekly sessions at the start of CBT, d) once-weekly sessions at the start of IPT. Primary outcome measures are depression severity, cost effectiveness and quality of life. Process measures include therapeutic alliance, recall, therapy-specific skills, motivation and compliance. Assessments will take place during baseline, monthly during treatment and follow-up at month 9, 12 and 24. In addition, at 12 and 24 months, the frequency of depressive episodes in the previous year will be assessed. Blood samples will be taken pre- and post treatment. The study has been ethically approved and registered. DISCUSSION: Finding that twice-weekly sessions are more effective or lead to more rapid recovery of depressive symptoms could lead to treatment adaptations that have the potential to reduce the personal and societal burden of depression. In addition, insight into the mechanisms of change and physiological processes in psychotherapy will enable us to optimize treatments and may help to understand human functioning beyond the context of treatment. TRIAL REGISTRATION: The study has been registered on October 21th, 2014 at the Netherlands Trial Register, part of the Dutch Cochrane Centre ( NTR4856 ). PMID- 26122892 TI - Voluntary exercise contributed to an amelioration of abnormal feeding behavior, locomotor activity and ghrelin production concomitantly with a weight reduction in high fat diet-induced obese rats. AB - In the present study, effects of voluntary exercise in an obese animal model were investigated in relation to the rhythm of daily activity and ghrelin production. Male Sprague-Dawley rats were fed either a high fat diet (HFD) or a chow diet (CD) from four to 16 weeks old. They were further subdivided into either an exercise group (HFD-Ex, CD-Ex) with a running wheel for three days of every other week or sedentary group (HFD-Se, CD-Se). At 16 weeks old, marked increases in body weight and visceral fat were observed in the HFD-Se group, together with disrupted rhythms of feeding and locomotor activity. The induction of voluntary exercise brought about an effective reduction of weight and fat, and ameliorated abnormal rhythms of activity and feeding in the HFD-Ex rats. Wheel counts as voluntary exercise was greater in HFD-Ex rats than those in CD-Ex rats. The HFD obese had exhibited a deterioration of ghrelin production, which was restored by the induction of voluntary exercise. These findings demonstrated that abnormal rhythms of feeding and locomotor activity in HFD-obese rats were restored by infrequent voluntary exercise with a concomitant amelioration of the ghrelin production and weight reduction. Because ghrelin is related to food anticipatory activity, it is plausible that ghrelin participates in the circadian rhythm of daily activity including eating behavior. A beneficial effect of voluntary exercise has now been confirmed in terms of the amelioration of the daily rhythms in eating behavior and physical activity in an animal model of obesity. PMID- 26122893 TI - Priming of hand and foot response: is spatial attention to the body site enough? AB - The purpose of the present study was to test whether we see evidence for body compatibility effects when viewing both familiar and unusual body postures. Specifically, in a task where colour targets have to be discriminated, we tested whether spatial orienting to a body site is sufficient for effects of body compatibility to emerge when viewing a task-irrelevant body or whether effects are dependent on whether or not we are able to adopt the viewed body posture. The results suggest that spatial orienting to a body site is insufficient; rather we argue that it is only postures that are familiar and we are easily able to adopt that can be processed fluently and influence target discrimination. This points to a key contribution of motor representations to body compatibility effects. PMID- 26122894 TI - Cross-language parafoveal semantic processing: Evidence from Korean-Chinese bilinguals. AB - In the present study, we aimed at testing cross-language cognate and semantic preview effects. We tested how native Korean readers who learned Chinese as a second language make use of the parafoveal information during the reading of Chinese sentences. There were 3 types of Korean preview words: cognate translations of the Chinese target words, semantically related noncognate words, and unrelated words. Together with a highly significant cognate preview effect, more critically, we also observed reliable facilitation in processing of the target word from the semantically related previews in all fixation measures. Results from the present study provide first evidence for semantic processing from parafoveally presented Korean words and for cross-language parafoveal semantic processing. PMID- 26122895 TI - Unaware yet reliant on attention: Experience sampling reveals that mind-wandering impedes implicit learning. AB - Although implicit learning has been widely studied, controversy remains regarding its reliance on attentional resources. A central issue in this controversy is the question of how best to manipulate attention. The usual approach of comparing implicit learning in a serial reaction time (SRT) task under single- versus dual task conditions is known to be problematic, because the secondary task may not only divert attention away from the primary task, but also interfere with the implicit-learning process itself. To address this confound, in the present study we used an experience-sampling instead of a dual-task approach. We assessed lapses of attention (mind-wandering) with experience-sampling thought probes during a standard implicit-learning SRT task. The results revealed a significant negative correlation between mind-wandering and implicit learning. Thus, greater task focus was associated with improved implicit sequence learning. This result suggests that, at least in the context of this SRT task, optimal implicit learning relies on attention. PMID- 26122897 TI - Should Cesarean Scar Defect Be Treated Laparoscopically? A Case Report and Review of the Literature. AB - Several obstetric complications due to inappropriately healed cesarean scar such as placenta accreta, scar dehiscence, and ectopic scar pregnancy are increasingly reported along with rising cesarean rates. Furthermore, many gynecologic conditions, including abnormal uterine bleeding, pelvic pain and infertility, are imputed to deficient cesarean scar healing. Hysteroscopy is the most commonly reported approach for the revision of cesarean scar defects (CSDs). Nevertheless, existing evidence is inadequate to conclude that either hysteroscopy or laparoscopy is effective or superior to each other. Although several management options have been suggested recently, the laparoscopic approach has not been thoroughly scrutinized. We present a case and reviewed the data related to the laparoscopic repair of CSDs and compared the hysteroscopic and laparoscopic management options based on the data from previously published articles. As a result of our analyses, the laparoscopic approach increases uterine wall thickness when compared with the hysteroscopic approach, and both surgical techniques seem to be effective for the resolution of gynecologic symptoms. Hysteroscopic treatment most likely corrects the scar defect but does not strengthen the uterine wall; thus, the potential risk of dehiscence or rupture in subsequent pregnancies does not seem to be improved. Because large uterine defects are known risk factors for scar dehiscence, the repair of the defect to reinforce the myometrial endurance seems to be an appropriate method of treatment. PMID- 26122896 TI - Underpowered samples, false negatives, and unconscious learning. AB - The scientific community has witnessed growing concern about the high rate of false positives and unreliable results within the psychological literature, but the harmful impact of false negatives has been largely ignored. False negatives are particularly concerning in research areas where demonstrating the absence of an effect is crucial, such as studies of unconscious or implicit processing. Research on implicit processes seeks evidence of above-chance performance on some implicit behavioral measure at the same time as chance-level performance (that is, a null result) on an explicit measure of awareness. A systematic review of 73 studies of contextual cuing, a popular implicit learning paradigm, involving 181 statistical analyses of awareness tests, reveals how underpowered studies can lead to failure to reject a false null hypothesis. Among the studies that reported sufficient information, the meta-analytic effect size across awareness tests was d z = 0.31 (95 % CI 0.24-0.37), showing that participants' learning in these experiments was conscious. The unusually large number of positive results in this literature cannot be explained by selective publication. Instead, our analyses demonstrate that these tests are typically insensitive and underpowered to detect medium to small, but true, effects in awareness tests. These findings challenge a widespread and theoretically important claim about the extent of unconscious human cognition. PMID- 26122898 TI - Combined Endometrial Ablation and Levonorgestrel Intrauterine System Use in Women With Dysmenorrhea and Heavy Menstrual Bleeding: Novel Approach for Challenging Cases. AB - STUDY OBJECTIVE: To evaluate the feasibility and impact of levonorgestrel intrauterine system (LNG-IUS) on treatment failure after endometrial ablation (EA) in women with heavy menstrual bleeding (HMB) and dysmenorrhea at 4 years. DESIGN: Cohort study (Canadian Task Force II-2). SETTING: An academic institution in the upper Midwest. PATIENTS: All women with HMB and dysmenorrhea who underwent EA with combined placement of LNG-IUS (EA/LNG-IUS cohort, 23 women) after 2005 and an historic reference group from women who had EA alone (EA cohort, 65 women) from 1998 through the end of 2005. INTERVENTION: Radiofrequency EA, thermal balloon ablation, and LNG-IUS. MEASUREMENTS AND MAIN RESULTS: The primary outcome was treatment failure defined as persistent pain, bleeding, and hysterectomy after EA at 4 years. The combined treatment failure outcome was documented in 2 patients (8.7%) in the EA/LNG-IUS group and 19 patients (29.2%) in the EA group with an unadjusted OR of .23 (95% CI, .05-1.08). After adjusting for known risk factors of failure, the adjusted OR was .19 (95% CI, .26-.88). None of the women who underwent EA/LNG-IUS had hysterectomy for treatment failure compared with 16 (24%) in the EA group (p = .009); postablation pelvic pain was documented in 1 woman (4.3%) in the EA/LNG-IUS group compared with 8 women (12.3%) in the EA group (p = .24). One woman in the EA/LNG-IUS group (4.3%) presented with persistent bleeding compared with 15 (23.1%) in the EA group (p = .059). Office removal of the intrauterine device was performed in 4 women with no complications. CONCLUSION: LNG-IUS insertion at the time of EA is feasible and can provide added benefit after EA in women with dysmenorrhea and HMB. PMID- 26122899 TI - Indocyanine Green Fluorescence Imaging in the Surgical Management of an Iatrogenic Lymphatic Fistula: Description of a Surgical Technique. AB - We present a case of laparoscopic surgical management of an iatrogenic lymphorrhea using indocyanine green (ICG). A case of a patient who developed recurrent symptomatic lymphorrhea after laparoscopic radical hysterectomy and bilateral pelvic lymphadenectomy for an early stage cervical cancer is presented. Intraoperative bipedal interdigital subcutaneous injection of ICG exactly localized the disrupted lymphatic duct on fluorescence imaging performed with a near-infrared laparoscopic fluorescent optic device, thus allowing a successful surgical repair. PMID- 26122900 TI - A metabolic chimera: Two defective genotypes make a normal phenotype. PMID- 26122901 TI - [Information security in health care]. AB - Doctors, nurses and other medical professionals are spending more and more time in front of the computer, using applications developed for general practitioners, specialized care, or perhaps an integrated hospital system. The data they handle during healing and patient care are mostly sensitive data and, therefore, their management is strictly regulated. Finding our way in the jungle of laws, regulations and policies is not simple. Notwithstanding, our lack of information does not waive our responsibility. This study summarizes the most important points of international recommendations, standards and legal regulations of the field, as well as giving practical advices for managing medical and patient data securely and in compliance with the current legal regulations. PMID- 26122902 TI - [Uterine anomalies in women with recurrent pregnancy loss]. AB - INTRODUCTION: One percent of couples trying to have children are affected by recurrent miscarriage. These pregnancy losses have different pathogenetic (genetic, endocrine, anatomic, immunologic, microbiologic, haematologic and andrologic) backgrounds, but recurrent miscarriage remains unexplained in more than half of the affected couples. AIM: To explore risk factors for recurrent pregnancy loss the authors studied the incidence of anatomic disorders of the uterine cavity occur in Hungarian women with recurrent miscarriage. METHOD: Medical records of 152 patients with recurrent miscarriage were analyzed retrospectively. In order to explore disorders of the uterine cavity hysteroscopy or 3-dimensional sonography in 132 women, hysterosalpingography in 16 and hysterosalpingo-sonography in 4 patients were used. RESULTS: Incidence of anomalies in the uterine cavity was found in women with recurrent miscarriage to be 15.8%. A variety of the uterine anomalies was found including uterine septum in 6.5%, endometrial polyp in 2.6%, arcuate and bicornuate uteri both in 2% and 2%, submucosal myoma in 1.3 %, and intrauterine synechiae in 1.3%. CONCLUSIONS: These findings suggest that morphologic disorder of the uterine cavity is frequent in Hungarian women with recurrent miscarriage. Therefore, assessment of the uterine anatomy is recommended in such patients. PMID- 26122903 TI - [Ultrasound-guided central venous access in patients with uncorrected coagulopathy]. AB - INTRODUCTION: Correction of coagulopathy prior to central venous catheterization is a standard practice. Before ultrasound-guided procedures, routine correction of coagulopathy is controversial as mechanical complications are rare. AIM: To evaluate the safety of ultrasound-guided central venous access in critically ill patients with coagulopathy. METHOD: In this retrospective study the authors included all ultrasound-guided central venous catheterizations performed in their Intensive Care Unit between February 2011 and January 2013. They defined coagulopathy as INR or APTT ratio above 1.5, platelet count below 100 G/l, and anticoagulation or clopidogrel therapy. Data obtained from ultrasound register and patient records were used. RESULTS: 310 ultrasound-guided central venous catheterizations were performed. Coagulopathy was observed in 134 cases (43.2%) and corrected in 10 cases prior to catheterization. There were no bleeding complications (complication rate in uncorrected coagulopathy: 0%, 95% confidence interval: 0-3.0%). CONCLUSIONS: Coagulopathy is common in critically ill patients, but its routine correction prior to ultrasound-guided central venous catheterization seems unnecessary. PMID- 26122904 TI - [Sleep disturbances in Parkinson's disease: characteristics, evaluation and therapeutic approaches]. AB - INTRODUCTION: Parkinson's disease is a well known representent of the movement disorder group of neurological disorders. The diagnosis of Parkinson's disease is based on specific symptoms and signs of movement abnormalities. In addition to classic motor symptoms, Parkinson's disease has characteristic non-motor features, and some of these emerges the classic signs. AIM: The authors discuss characteristics and therapeutic interventions in Parkinson's disease related sleep disturbances. METHOD: The authors reviewed and summarised literature data on sleep disorders in Parkinson's disease published in the PubMed database up to January 2015. RESULTS: Sleep problems are important non-motor complains (insomnia, hypersomnia, REM behaviour disorder, sleep apnea and restless legs syndrome). The neurodegenerative process of the brain-stem, the effect of symptoms of Parkinson's disease on sleep and concomitant sleep disorders constitute the background of the patient's complains. CONCLUSIONS: Appropriate diagnosis and therapy of the consequential or concomitant sleep disorders in Parkinson's disease will help to improve the patient's quality of life. PMID- 26122905 TI - [Fill it up...! Combined consumption of alcohol with energy drinks and its correlation with risk taking behaviour among young adults]. AB - INTRODUCTION: In Hungary and all around the world the incidence of consumption of energy drinks together with alcohol has increased among adolescents and young adults. AIM: The foremost aim of this survey was to find out whether alcohol mixed with energy drinks can enhance the appearance of other forms of risky behaviour among young adults. METHOD: In spring 2013 the authors carried out a quantitative sociological survey at three faculties of two major universities in Budapest, Hungary. RESULTS: The survey showed that 1) consumers, who mixed alcohol with energy drinks, were likely to drink more alcohol both at parties and on ordinary days, and they took part in binge drinking more frequently than those consuming only alcohol; 2) students drank significantly less alcohol when they mixed it with energy drink. CONCLUSIONS: The conflicts of the results showed that even at the starting point there was a clear distinction between the two groups, moreover, it is not yet clear what interactions the combined effect of caffeine and alcohol can trigger in the behaviour of the individual. PMID- 26122907 TI - Commentary on: Hegedus A. and Kozel B. (2014). Does adherence therapy improve medication adherence among patients with schizophrenia? A systematic review. International Journal of Mental Health Nursing, doi: 10.1111/inm.12089. PMID- 26122908 TI - Engineered Tissue Patch for Cardiac Cell Therapy. AB - OPINION STATEMENT: Cell therapy can be administered via injections delivered directly into the myocardium or as engineered cardiac tissue patches, which are the subject of this review. Engineered cardiac patches can be created from sheets of interconnected cells or by suspending the cells in a scaffold of material that is designed to mimic the native extracellular matrix. The sheet-based approach produces patches with well-aligned and electronically coupled cardiomyocytes, but cell-containing scaffolds are more readily vascularized by the host's circulatory system and, consequently, are currently more suitable for applications that require a thicker patch. Cell patches can also be modified for the co-delivery of peptides that may promote cell survival and activate endogenous repair mechanisms; nevertheless, techniques for controlling inflammation, limiting apoptosis, and improving vascular growth need continue to be developed to make it a therapeutic modality for patients with myocardial infarction. PMID- 26122909 TI - Telocytes in Liver. AB - Telocytes (TCs) are a newly identified interstitial cell type which are named after and characterized by specialized thin, long synaptic structures called telopodes (Tps). The existence of TCs has been reported in lots of tissues and organs. There are numerous on-going studies to explore the biological functions of TCs, including their involvement in human disease. TCs are generally considered as supporting cells that help maintain the micro-structure of tissues by forming a three-dimensional interstitial network via intercellular junctions. In addition, TCs have also been implicated in the regulation of stem cell activity and the stem cell niche microenvironment, thus contributing to tissue repair and renewal. In this review, the most recent findings concerning hepatic TCs are described. PMID- 26122910 TI - PPARgamma and Its Ligands: Potential Antitumor Agents in the Digestive System. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a versatile member of the ligand-activated nuclear hormone receptor superfamily of transcription factors, with expression in several different cell lines, especially in the digestive system. After being activated by its ligand, PPARgamma can suppress the growth of oral, esophageal, gastric, colorectal, liver, biliary, and pancreatic tumor cells, suggesting that PPARgamma ligand is a potential anticancer agent in PPARgamma-expressing tumors. This review highlights key advances in understanding the effects of PPARgamma ligands in the treatment of tumors in the digestive system. PMID- 26122911 TI - Genome-wide analysis of translational efficiency reveals distinct but overlapping functions of yeast DEAD-box RNA helicases Ded1 and eIF4A. AB - DEAD-box RNA helicases eIF4A and Ded1 are believed to promote translation initiation by resolving mRNA secondary structures that impede ribosome attachment at the mRNA 5' end or subsequent scanning of the 5' UTR, but whether they perform unique or overlapping functions in vivo is poorly understood. We compared the effects of mutations in Ded1 or eIF4A on global translational efficiencies (TEs) in budding yeast Saccharomyces cerevisiae by ribosome footprint profiling. Despite similar reductions in bulk translation, inactivation of a cold-sensitive Ded1 mutant substantially reduced the TEs of >600 mRNAs, whereas inactivation of a temperature-sensitive eIF4A variant encoded by tif1-A79V (in a strain lacking the ortholog TIF2) yielded <40 similarly impaired mRNAs. The broader requirement for Ded1 did not reflect more pervasive secondary structures at low temperature, as inactivation of temperature-sensitive and cold-sensitive ded1 mutants gave highly correlated results. Interestingly, Ded1-dependent mRNAs exhibit greater than average 5' UTR length and propensity for secondary structure, implicating Ded1 in scanning through structured 5' UTRs. Reporter assays confirmed that cap distal stem-loop insertions increase dependence on Ded1 but not eIF4A for efficient translation. While only a small fraction of mRNAs shows a heightened requirement for eIF4A, dependence on eIF4A is correlated with requirements for Ded1 and 5' UTR features characteristic of Ded1-dependent mRNAs. Our findings suggest that Ded1 is critically required to promote scanning through secondary structures within 5' UTRs, and while eIF4A cooperates with Ded1 in this function, it also promotes a step of initiation common to virtually all yeast mRNAs. PMID- 26122912 TI - Molecular Typing of Treponema pallidum in Denmark: A Nationwide Study of Syphilis. AB - The aim of this nationwide study is to determine the strain type diversity among patients diagnosed with syphilis by PCR during a 4-year period in Denmark. Epidemiological data, including HIV status, for all patients were obtained from the Danish national syphilis registration system. Molecular strain typing was based on characterization of 3 variable treponemal genes, arp, tpr and tp0548. A total of 278 specimens from 269 patients were included. Among the fully typeable specimens (n = 197), 22 strain types were identified, with 1 type, 14d/g, accounting for 54%. The majority (93%) of the patients reported acquiring syphilis in Denmark. Among patients with concurrent HIV, 9 full strain types were identified and no difference in strain type was found by HIV status (p = 0.197). In conclusion, the majority of patients were infected in Denmark and the HIV infected syphilis patients were diagnosed with a wide spectrum of different strain types of Treponema pallidum. PMID- 26122913 TI - Outcome of Intensive Cognitive Behaviour Therapy in a Residential Setting for People with Severe Obsessive Compulsive Disorder: A Large Open Case Series. AB - BACKGROUND: There is little data to inform the treatment of severe obsessive compulsive disorder (OCD) in an inpatient or residential setting. AIMS: This paper aimed to: a) describe treatment outcomes at a residential unit over 11 years; b) investigate whether treatment was successful for a subset of severe treatment refractory residents; c) compare an intensive treatment programme to a "standard" treatment programme; and d) find predictors of self or early discharge from the unit. METHOD: We compared treatment outcomes for (i) a minimum 12-week treatment (hereafter "standard") programme versus a 2-week intensive programme and (ii) for severe treatment refractory cases on the standard programme. We identified 472 residents with OCD admitted to the Anxiety Disorders Residential Unit at the Bethlem Royal Hospital between 2001 and 2012. Outcomes were measured with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Obsessive Compulsive Inventory (OCI), Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) obtained throughout treatment and up to one year after discharge. RESULTS: Although residents had very severe OCD on admission, sequential assessment with the Y-BOCS, OCI, BAI and BDI demonstrated that scores on all outcome measures significantly decreased from pre to posttreatment and were generally maintained at follow-up. There was no significant difference between those on the standard or the 2-week intensive programme. Sixty-nine per cent of residents with OCD made significant improvements, with at least a 25% reduction on the Y-BOCS. There were predictors of self or early discharge but none for outcome on the Y-BOCS. CONCLUSIONS: The data support the principle of stepped care for severe OCD. PMID- 26122915 TI - Inequality of Opportunity: The New Motherhood and Apple Pie? PMID- 26122914 TI - Proteomics-driven design of a multiplex bead-based platform to assess natural IgG antibodies to pneumococcal protein antigens in children. AB - Pneumococcal surface proteins are potential candidates for the development of protein-based vaccines and serological assays. The objective of the study was to develop a multiple bead-based immunoassay using Luminex xMAP(r) technology for the quantitation of natural antibodies against Streptococcus pneumoniae proteins and the characterization of the acute serum response following pneumococcal pneumonia in children. Sixty-four recombinantly produced pneumococcal proteins, which were selected based on their proteomic experimental identification by "shaving" live cells with trypsin followed by LC/MS/MS analysis, were coupled to fluorescent SeroMAP(r) beads and anti-pneumococcal specific IgG levels were determined in sera. Multiplex assay was validated through comparison of IgG levels to 14 randomly chosen pneumococcal antigens by using multiplex and singleplex assays. Acute serum IgG levels against RrgB were significantly lower in children <= 4 years old with pneumococcal pneumonia than those in controls. In addition, there was a small trend toward slightly lower antibody levels for PrsA, RrgC and RrgB in pneumonia patients of the all age group. PMID- 26122916 TI - Implementation of Ultramini Percutaneous Nephrolithotomy for Treatment of 2-3 cm Kidney Stones: A Preliminary Report. AB - BACKGROUND AND PURPOSE: Miniatured percutaneous nephrolithotomy (PCNL) techniques such as micro-PCNL (microperc) and ultramini-PCNL (UMP) are usually indicated for renal stones <2 cm. We present our preliminary report of treating patients with 2 to 3 cm renal stones using UMP in a semisupine combined lithotomy position associated with a retrograde ureteral access sheath (UAS). METHODS: From April 2013 to January 2014, we implemented 13F UMP for 22 patients with renal stones that were 2 to 3 cm with the patient positioned in a 45-degree semisupine combined lithotomy position. A retrograde 9.5/11.5F UAS was placed for maintaining low intrarenal pressure and debris drainage. Flexible ureteroscopy was used for stones inaccessible through the primary percutaneous tract in two patients. A 200-MU holmium laser was used for stone disintegration. Intrapelvic pressure was measured using an open end 5F ureteral catheter inserted through the UAS. RESULTS: All 22 cases were completed successfully. The mean preoperative stone size was 26.6 +/- 4.7 mm (range 21-32 mm), mean operative time was 85.7 +/- 18.0 minutes (range 47-112 min), and mean hemoglobin drop was 1.2 +/- 0.3 g/dL (range 0.5-2.2 g/dL). Intrapelvic pressure during the surgical procedure ranged 5 to 10 cm H2O. The mean hospital stay was 3.1 +/- 1.8 days (range 2-5 d). Complete stone clearance was 18/22 (81.8%) with solo UMP and 20/22 (90.9%) when associated with retrograde intrarenal surgery (RIRS). No major intra- or postoperative complications occurred. CONCLUSION: Implementation of UMP for the treatment of patients with renal stones 2-3 cm is feasible and safe. The procedure is less invasive and has a faster recovery period. Intraoperative retrograde UAS decreases intrarenal pressure, facilitates removal of stone fragments, and also allows simultaneous RIRS for stones in an inaccessible calix. PMID- 26122917 TI - Mechanisms, Capabilities, and Applications of High-Resolution Electrohydrodynamic Jet Printing. AB - This review gives an overview of techniques used for high-resolution jet printing that rely on electrohydrodynamically induced flows. Such methods enable the direct, additive patterning of materials with a resolution that can extend below 100 nm to provide unique opportunities not only in scientific studies but also in a range of applications that includes printed electronics, tissue engineering, and photonic and plasmonic devices. Following a brief historical perspective, this review presents descriptions of the underlying processes involved in the formation of liquid cones and jets to establish critical factors in the printing process. Different printing systems that share similar principles are then described, along with key advances that have been made in the last decade. Capabilities in terms of printable materials and levels of resolution are reviewed, with a strong emphasis on areas of potential application. PMID- 26122919 TI - Unveiling the mechanism of melatonin impacts on maize seedling growth: sugar metabolism as a case. AB - Melatonin regulates growth in many plants; however, the mechanism remains unclear. In this study, exogenous melatonin feeding resulted in both promotional (<=10 MUm) and inhibitory (>=100 MUm) effects on maize seedling growth. Initial analyses suggested positive correlations between the amount of melatonin and sucrose synthesis and hydrolysis-related gene expression, enzyme activities, and sucrose metabolites. However, assays of photosynthetic rate, hexokinase (HxK) activity, expression of photosynthetic marker genes, and HxK-related genes showed opposite effects under 10 MUm (positive) and 100 MUm (negative) melatonin treatments. Similarly, 10 MUm melatonin accelerated starch catabolism at night, whereas 100 MUm melatonin significantly decreased this process and led to starch accumulation in photosynthetic tissues. Furthermore, expression analysis of genes related to sucrose phloem loading resulted in a slight upregulation of sucrose transporters (SUT1 and SUT2) when seedlings were induced with 10 MUm melatonin, while treatment with 100 MUm melatonin resulted in significant downregulation of these sucrose transporter genes (SUT1 and SUT2), as well as tie-dyed2 (Tdy2) and sucrose export defective 1. Taken together, these results suggest that low doses of melatonin benefit maize seedling growth by promoting sugar metabolism, photosynthesis, and sucrose phloem loading. Conversely, high doses of melatonin inhibit seedling growth by inducing the excessive accumulation of sucrose, hexose and starch, suppressing photosynthesis and sucrose phloem loading. PMID- 26122920 TI - Disabling low back pain associated with night shift duration: sleep problems as a potentiator. AB - BACKGROUND: We investigated how night shift duration and sleep problems were jointly associated with disabling low back pain (LBP) among workers in different occupations. METHODS: An online-survey was conducted regarding work schedules, disabling LBP, sleep problems, and other relevant factors in 5,008 workers who were randomly selected from a market research panel. Multiple logistic regression analyses determined the joint associations of night shift duration (0 [permanent day shift], <8, 8-9.9, 10-15.9, >=16 hr) and sleep problems (no, yes) with disabling LBP adjusted for potential confounders. RESULTS: A night shift >=16 hr was associated with a significant increase in the likelihood of disabling LBP. The magnitude of this association was elevated when participants perceived sleep problems including both sleep duration and quality. CONCLUSION: Associations between extended night shifts and disabling LBP became stronger in the presence of short or poor quality sleep. PMID- 26122921 TI - Contact sensitization to 34 common contact allergens in university students in Beijing. PMID- 26122923 TI - A pilot test of the new Swiss regulatory procedure for categorizing clinical trials by risk: A randomized controlled trial. AB - BACKGROUND/AIMS: Several countries are working to adapt clinical trial regulations to align the approval process to the level of risk for trial participants. The optimal framework to categorize clinical trials according to risk remains unclear, however. Switzerland is the first European country to adopt a risk-based categorization procedure in January 2014. We assessed how accurately and consistently clinical trials are categorized using two different approaches: an approach using criteria set forth in the new law (concept) or an intuitive approach (ad hoc). METHODS: This was a randomized controlled trial with a method comparison study nested in each arm. We used clinical trial protocols from eight Swiss ethics committees approved between 2010 and 2011. Protocols were randomly assigned to be categorized in one of three risk categories using the concept or the ad hoc approach. Each protocol was independently categorized by the trial's sponsor, a group of experts and the approving ethics committee. The primary outcome was the difference in categorization agreement between the expert group and sponsors across arms. Linear weighted kappa was used to quantify agreements, with the difference between kappas being the primary effect measure. RESULTS: We included 142 of 231 protocols in the final analysis (concept=78; ad hoc=64). Raw agreement between the expert group and sponsors was 0.74 in the concept and 0.78 in the ad hoc arm. Chance-corrected agreement was higher in the ad hoc (kappa: 0.34 (95% confidence interval=0.10-0.58)) than in the concept arm (0.27 (0.06 0.50)), but the difference was not significant (p=0.67). LIMITATIONS: The main limitation was the large number of protocols excluded from the analysis mostly because they did not fit with the clinical trial definition of the new law. CONCLUSION: A structured risk categorization approach was not better than an ad hoc approach. Laws introducing risk-based approaches should provide guidelines, examples and templates to ensure correct application. PMID- 26122922 TI - Characteristics of participants consenting versus declining follow-up for up to 10 years in a randomized clinical trial. AB - BACKGROUND: With patients living a decade or longer post-procedure, long-term data are needed to assess the durability of carotid artery stenting versus carotid endarterectomy. Identifying characteristics of those consenting or declining to continue in long-term follow-up may suggest strategies to improve retention in clinical trials. PURPOSE: This report describes differences between patients choosing or declining to continue follow-up for up to 10 years in the Carotid Revascularization Endarterectomy versus Stenting Trial. METHODS: Following completion of the primary outcome, patients who were in active Carotid Revascularization Endarterectomy versus Stenting Trial follow-up were asked to continue beyond their original 4-year commitment for a maximum of 10 years. The characteristics of those who consented were compared with those who declined. Univariate and multivariable logistic regression were used for analysis, and backwards stepwise logistic regression (the most parsimonious model) was used to determine the factors associated with continuation. RESULTS: Of the 1921 active Carotid Revascularization Endarterectomy versus Stenting Trial participants for whom consent to extend follow-up was requested, 1695 (88%; mean age: 68.4) consented; 226 (12%; mean age: 69.6) declined. Of those who did not consent versus those who consented, 66% versus 48% were symptomatic at baseline (p<0.0001), at follow-up 28% versus 20% were smokers (p=0.009), 85% versus 90% were hypertensive (p=0.01), and 84% versus 94% were dyslipidemic (p<0.0001). Additional factors that differed between those who did not consent and those who consented included the mean number of years in the study at time of consent (4.8 years vs 3.7 years (p=<0.0001)) and patients from sites that enrolled <30 patients compared to sites randomizing 30 or more (70% vs 52% (p<0.0001)). Multivariable logistic regression indicated that those with lesser odds of consenting to the extended follow-up were older (odds ratio: 0.80; 95% confidence interval: 0.67, 0.96), more likely to be symptomatic (odds ratio: 0.58; 95% confidence interval: 0.42, 0.80), smokers (odds ratio: 0.48; 95% confidence interval: 0.34, 0.70), were in the study 5+ years versus <3 (odds ratio: 0.21; 95% confidence interval: 0.13, 0.34), and at a site that randomized <30 patients (odds ratio: 0.46; 95% confidence interval: 0.33, 0.63), while patients with dyslipidemia at follow-up had increased odds of consenting (odds ratio: 2.28 (1.47, 3.54)). CONCLUSION: Symptomatic status, increasing age, randomized at lower volume centers, and longer time in follow-up were associated with reduced odds of consenting to long-term follow-up. Identifying factors associated with reduced willingness to extend participation long-term can suggest targeted strategies to improve retention in future clinical trials. PMID- 26122924 TI - The influence of prison climate on the mental health of adult prisoners: a literature review. AB - ACCESSIBLE SUMMARY: Little is known about how the prison environment may impact upon the mental health of adult prisoners. This paper highlights that prisoners perceive that the prison environment has a negative influence upon their mental health. However, a small number regarded prison as a place of respite, which afforded structure and an opportunity to access health services. There is a need for more research in this area specifically relating to the impact the prison climate may have upon those from black and minority ethic groups. Nurses must recognize the aspects of the prison environment that may impact upon the mental health of prisoners and demonstrate innovation and imagination in their application of interventions. ABSTRACT: Little is known regarding how the prison environment may affect the mental health of adult prisoners. Consequently, there is a need to investigate how this setting may exacerbate mental distress among this community. This literature review explores how the prison climate influences the mental health of adult prisoners. A thematic synthesis approach was used to elicit data relating to the aspects of the prison climate, which influence the mental health of prisoners. Four primary themes emerged from the synthesis: social, emotional, organizational and physical aspects. Prisoners perceive the prison climate to have a negative influence upon their mental health. However, perceived positively, prison was regarded as a place of respite, which afforded structure and an opportunity to access health services. There is limited research available specifically exploring the potential impact of the prison climate upon those from black and ethnic minorities groups. Nurses must recognize the aspects of the prison environment that may impact upon the mental health of prisoners and demonstrate innovation and imagination in their application of interventions. Additionally nurses need to take an active role in influencing and structuring the political agenda, which governs the clinical setting. PMID- 26122925 TI - Vocal Tract Morphology in Inhaling Singing: An MRI-Based Study. AB - OBJECTIVES/HYPOTHESIS: Inhaling singing is a recently developed singing technique explored by the soprano singer Francoise Vanhecke. It is based on an inspiratory airflow instead of an expiratory airflow. This article describes the anatomical structural differences of the vocal tract between inhaling and exhaling singing. We hypothesize that the vocal tract alters significantly in inhaling singing, especially concerning the configuration of the anatomical structures in the oral cavity and the subglottal region. STUDY DESIGN: This is a prospective study. METHODS: A professional singer (F.V.) performed sustained tones from F5 chromatically rising up to Bb5 on the vowel /a/. Vocal tract anatomy is assessed by magnetic resonance imaging. RESULTS: Wilcoxon directional testing demonstrates (1) that the vocal tract volume above the glottal region does not differ statistically in contrast to the subglottal region and (2) significant changes in the configuration of the tongue, the upright position of the epiglottis, the length of the floor of mouth, and the distance between the teeth. CONCLUSIONS: The narrowing of the subglottis is considered to be secondary to suction forces used in the inhaling singing technique. The changes in the anatomical structures above the vocal folds possibly suggest a valve-like function controlling the air inlet together with the regulator function of the resonator capacities of the vocal tract. PMID- 26122926 TI - Disruption of Radiologist Workflow. AB - The effect of disruptions has been studied extensively in surgery and emergency medicine, and a number of solutions-such as preoperative checklists-have been implemented to enforce the integrity of critical safety-related workflows. Disruptions of the highly complex and cognitively demanding workflow of modern clinical radiology have only recently attracted attention as a potential safety hazard. In this article, we describe the variety of disruptions that arise in the reading room environment, review approaches that other specialties have taken to mitigate workflow disruption, and suggest possible solutions for workflow improvement in radiology. PMID- 26122927 TI - Imputation of genotypes in Danish purebred and two-way crossbred pigs using low density panels. AB - BACKGROUND: Genotype imputation is commonly used as an initial step in genomic selection since the accuracy of genomic selection does not decline if accurately imputed genotypes are used instead of actual genotypes but for a lower cost. Performance of imputation has rarely been investigated in crossbred animals and, in particular, in pigs. The extent and pattern of linkage disequilibrium differ in crossbred versus purebred animals, which may impact the performance of imputation. In this study, first we compared different scenarios of imputation from 5 K to 8 K single nucleotide polymorphisms (SNPs) in genotyped Danish Landrace and Yorkshire and crossbred Landrace-Yorkshire datasets and, second, we compared imputation from 8 K to 60 K SNPs in genotyped purebred and simulated crossbred datasets. All imputations were done using software Beagle version 3.3.2. Then, we investigated the reasons that could explain the differences observed. RESULTS: Genotype imputation performs as well in crossbred animals as in purebred animals when both parental breeds are included in the reference population. When the size of the reference population is very large, it is not necessary to use a reference population that combines the two breeds to impute the genotypes of purebred animals because a within-breed reference population can provide a very high level of imputation accuracy (correct rate >= 0.99, correlation >= 0.95). However, to ensure that similar imputation accuracies are obtained for crossbred animals, a reference population that combines both parental purebred animals is required. Imputation accuracies are higher when a larger proportion of haplotypes are shared between the reference population and the validation (imputed) populations. CONCLUSIONS: The results from both real data and pedigree-based simulated data demonstrate that genotype imputation from low-density panels to medium-density panels is highly accurate in both purebred and crossbred pigs. In crossbred pigs, combining the parental purebred animals in the reference population is necessary to obtain high imputation accuracy. PMID- 26122928 TI - Effect of calcium with and without probiotic, lactose, or both on organ and body weights, immune response and caecal microbiota in moulted laying hens. AB - A total of 72 laying hens were used to investigate the effect of probiotic and lactose on body weight loss, tibia ash, antibody production against sheep red blood cell (SRBC), heterophile-to-lymphocyte (H/L) ratio and gut microbiota in a common moulting method for 14 d. Hens were randomly allocated to 6 experimental groups consisting of (i) full feed (FF), (ii) feed withdrawal (FW), (iii) FW with calcium (Ca), (iv) FW with Ca and offering 7 g/lit lactose in drinking water (CaL), (v) FW with Ca and offering 1 g/lit probiotic in drinking water (CaP), and (vi) FW with Ca and offering a mixture of lactose and probiotic in drinking water (CaLP). The results showed body weight loss in all FW groups were more than 25% that was significantly higher than FF group (p < 0.05). The relative organ weights of hens in FW groups were lower than FF group; especially, it was significant for liver and ovary (p < 0.05). No significant difference was observed between all groups for tibia ash. The highest H/L ratio was related to FW group and offering Ca and lactose numerically and probiotic alone significantly resulted in decrease of this ratio (p < 0.05). The results also showed no significant difference for antibody production against SRBC among experimental groups. The highest coliform bacteria numeration observed in FW group and lactose could significantly reduce this population (p < 0.05). Lactic acid bacteria (LAB) numeration demonstrated a significant difference among treatments, so that FF hens had higher LAB than others (p < 0.05). In addition, FW moulted hens had significantly lower LAB compared to other moulted hens (p < 0.05), except for Ca group. In conclusion, probiotic and lactose was effective in maintaining caecal microbiota balance and improving immunity in hens exposed to moulting. PMID- 26122929 TI - Solubility and modeling acid-base properties of adrenaline in NaCl aqueous solutions at different ionic strengths and temperatures. AB - Solubility and acid-base properties of adrenaline were studied in NaCl aqueous solutions at different ionic strengths (0= 5 years) and 68 age- and sex-matched controls were evaluated for the following: (i) smoking, alcohol intake, BMI, blood pressure, fasting plasma glucose, HbA1c and lipid profile; (ii) microvascular complications; (iii) serum markers of ED (ICAM-1, VCAM-1 and E-selectin); (iv) AS, assessed as aortic pulse wave velocity (aPWV); and (v) Hp genotype. RESULTS: The prevalence of the 1/1, 2/1 and 2/2 Hp genotypes was 28.5%, 46.7% and 24.8% in patients with type 1 diabetes and 20.9%, 38.8% and 40.3% in controls, respectively. No differences were found in classical CV risk factors between patients homozygous for allele 2 and the remaining genotypes, both in patients with type 1 diabetes and controls. Patients with type 1 diabetes carrying the Hp2/2 genotype had higher concentrations of ICAM-1 (65.1 (56.7-76.0) ng/mL vs. 59.0 (51.7-69.3) ng/mL; P = 0.033) and sVCAM-1 (1133.1 (884.6-1458.6) ng/mL vs. 956.4 (738.5-1206.1) ng/mL; P = 0.040) than those without it. The Hp2/2 genotype remained independently associated with ED after adjusting for CV risk factors (P = 0.038). No significant differences were found for aPWV between Hp genotypes. CONCLUSIONS: Endothelial dysfunction may be influenced by Hp2/2 genotype in patients with type 1 diabetes with independence of classical CV risk factors. PMID- 26122943 TI - Generalized pruritus in primary sclerosing cholangitis: implications of histamine release by lysophosphatidic acid. PMID- 26122944 TI - Fanning the flames: inflammation in cardiovascular diseases. PMID- 26122946 TI - How do regional and rural general practitioners use the internet to gather patient information? PMID- 26122945 TI - A dual wavelength-activatable gold nanorod complex for synergistic cancer treatment. AB - A multifunctional gold nanorod (AuNR) complex is described with potential utility for theranostic anticancer treatment. The AuNR was functionalized with cyclodextrin for encapsulation of doxorubicin, with folic acid for targeting, and with a photo-responsive dextran-azo compound for intracellular controlled drug release. The interaction of a AuNR complex with HeLa cells was facilitated via a folic acid targeting ligand as displayed in the dark-field images of cells. Enhanced anticancer efficacy was demonstrated through the synergistic combination of promoted drug release upon ultraviolet (UV) light irradiation and photothermal therapy upon infrared (IR) irradiation. This multifunctional AuNR-based system represents a novel theranostic strategy for spatiotemporal delivery of anticancer therapeutics. PMID- 26122947 TI - The economic feasibility of price discounts to improve diet in Australian Aboriginal remote communities. AB - OBJECTIVE: To estimate the cost-effectiveness of fiscal measures applied in remote community food stores for Aboriginal Australians. METHODS: Six price discount strategies on fruit, vegetables, diet drinks and water were modelled. Baseline diet was measured as 12 months' actual food sales data in three remote Aboriginal communities. Discount-induced changes in food purchases were based on published price elasticity data while the weight of the daily diet was assumed constant. Dietary change was converted to change in sodium and energy intake, and body mass index (BMI) over a 12-month period. Improved lifetime health outcomes, modelled for the remote population of Aboriginal and Torres Strait Islanders, were converted to disability adjusted life years (DALYs) saved using a proportional multistate lifetable model populated with diet-related disease risks and Aboriginal and Torres Strait Islander rates of disease. RESULTS: While dietary change was small, five of the six price discount strategies were estimated as cost-effective, below a $50,000/DALY threshold. CONCLUSION: Stakeholders are committed to finding ways to reduce important inequalities in health status between Aboriginal and Torres Strait Islanders and non-Indigenous Australians. Price discounts offer potential to improve Aboriginal and Torres Strait Islander health. Verification of these results by trial-based research coupled with consideration of factors important to all stakeholders is needed. PMID- 26122950 TI - Rheumatoid arthritis: Predicting mortality in RA: the quest for useful information. AB - A new study suggests that rheumatoid arthritis does not increase cancer-related mortality in patients with cancer, particularly in those with advanced stage malignancies. Could the inclusion of quantitative measures of inflammation, physical function or socioeconomic status have changed these findings? PMID- 26122951 TI - The evolution of drug discovery in systemic lupus erythematosus. AB - Drug discovery in systemic lupus erythematosus (SLE) has lagged behind other rheumatic diseases, in large part because of difficulty in measuring change or improvement in a disorder that involves multiple organ systems to varying degrees at different times. The metrics currently used as primary endpoints are composite indices that rely mainly on disease assessment measures derived before the era of clinical trials of targeted therapies. Only one agent has been approved for the treatment of SLE since 1957. This monograph reviews the evolution of drug development for SLE, problems and pitfalls that have been encountered, and outlines the domains used to evaluate SLE in the clinic. Finally, several initiatives underway to improve clinical trial design are outlined. PMID- 26122952 TI - Current treatment of antiphospholipid syndrome: lights and shadows. AB - For patients with antiphospholipid syndrome (APS), the consensus is to treat those who develop thrombosis with long-term oral anticoagulation therapy and to prevent obstetric manifestations by use of aspirin and heparin. These recommendations are based on data from randomized controlled trials and observational studies. Despite this body of knowledge, areas of uncertainty regarding the management of APS exist where evidence is scarce or nonexistent. In other words, for a subset of patients the course of management is unclear. Some examples are patients with 'seronegative' APS, those who do not fulfil the formal (clinical or serological) classification criteria for definite APS, and those with recurrent thrombotic events despite optimal anticoagulation. Other challenges include the treatment of clinical manifestations not included in the classification criteria, such as haematologic manifestations (thrombocytopenia and haemolytic anaemia), neurologic manifestations (chorea, myelitis and multiple sclerosis-like lesions), and nephropathy and heart valve disease associated with antiphospholipid antibodies (aPL), as well as the possible withdrawal of anticoagulation treatment in selected cases of thrombotic APS in which assays for aPL become persistently negative. This Review focuses on the current recommendations for thrombotic and obstetric manifestations of APS, as well as the management of difficult cases. Some aspects of treatment, such as secondary prophylaxis of venous thrombosis, are based on strong evidence--the 'lights' of APS treatment. Conversely, other areas, such as the treatment of non-criteria manifestations of APS, are based only on expert consensus or common sense and remain the 'shadows' of APS therapy. PMID- 26122953 TI - Enzymatic measurement of phosphatidylglycerol and cardiolipin in cultured cells and mitochondria. AB - Phosphatidylglycerol (PG) and cardiolipin (CL) are synthesized in mitochondria and regulate numerous biological functions. In this study, a novel fluorometric method was developed for measuring PG and CL using combinations of specific enzymes and Amplex Red. This assay quantified the sum of PG and CL (PG + CL) regardless of the species of fatty acyl chain. The calibration curve for PG + CL measurement was linear, and the detection limit was 1 MUM (10 pmol in the reaction mixture). This new method was applied to the determinations of PG + CL content in HEK293 cells and CL content in purified mitochondria, because the mitochondrial content of PG is negligible compared with that of CL. We demonstrated that the PG+CL content was greater at low cell density than at high cell density. The overexpression of phosphatidylglycerophosphate synthase 1 (PGS1) increased the cellular contents of PG + CL and phosphatidylcholine (PC), and reduced that of phosphatidic acid. PGS1 overexpression also elevated the mitochondrial contents of CL and PC, but had no effect on the number of mitochondria per cell. In addition to the enzymatic measurements of other phospholipids, this simple, sensitive and high-throughput assay for measuring PG + CL can be used to understand cellular, physiological and pathological processes. PMID- 26122954 TI - Ultraviolet-C light inactivation of Escherichia coli O157:H7 and Listeria monocytogenes on organic fruit surfaces. AB - This study investigated UV-C light inactivation of Escherichia coli O157:H7 and Listeria monocytogenes on the surface of organic apples, pears, strawberries, red raspberries and cantaloupes. Fruit surfaces spot inoculated with cocktail strains of E. coli O157:H7 and L. monocytogenes were exposed to UV-C doses up to 11.9 kJ/m(2) at 23 degrees C. Fruit surface roughness, contact angle, and surface energy were determined and correlated with UV-C inactivation kinetics. Results demonstrate that bacterial pathogens on fruit surfaces respond differently to UV C light exposure. E. coli O157:H7 on apple and pear surfaces was reduced by 2.9 and 2.1 log CFU/g, respectively when treated with UV-C light at 0.92 kJ/m(2) (60s). For berries, the reduction of E. coli O157:H7 was lower with 2.0 (strawberry) and 1.1 log CFU/g (raspberry) achieved after UV-C treatment at 7.2 kJ/m(2) (8 min) and at 10.5 kJ/m(2) (12 min), respectively. Similarly, a higher reduction of L. monocytogenes was observed on apple (1.6 log CFU/g at 3.75 kJ/m(2)) and pear (1.7 log CFU/g at 11.9 kJ/m(2)) surfaces compared to cantaloupe and strawberry surfaces (both achieved 1.0 log CFU/g at 11.9 kJ/m(2)). L. monocytogenes shows more resistance than E. coli O157:H7. Inactivation rates were higher for less hydrophobic fruits with smoother surfaces (apples and pears) as compared to fruits with rougher surfaces (cantaloupe, strawberry and raspberry). Findings indicate that UV-C light can effectively reduce E. coli O157:H7 and L. monocytogenes populations on fruit and berry surfaces. However, surface characteristics influence the efficacy of UV-C light. PMID- 26122959 TI - Sinomenine hydrochloride-loaded dissolving microneedles enhanced its absorption in rabbits. AB - Sinomenine hydrochloride-loaded dissolving microneedles (SH-DM) were fabricated by maltose and poly-lactic-co-glycolic acid using a casting method. The mechanical strength of SH-DM was investigated by an insertion test. In vivo transdermal absorption experiment was performed to evaluate the percutaneous absorption of SH-DM, sinomenine hydrochloride gel (SH-G) was used as a control. The results demonstrated that prepared SH-DM was morphologically intact with sufficient mechanical strength after inserting into aluminum foil and rat skin. The value of area under curve obtained after administration of SH-DM through transdermal in rabbits showed a significantly rise and was 1.99 times higher than that of SH-G, and the relative bioavailability value was 199.21%. These results showed that SH-DM enhanced bioavailability and permeability of SH. PMID- 26122955 TI - The role of grandparents in childhood obesity in China - evidence from a mixed methods study. AB - BACKGROUND: The current literature on the influences of family environment on childhood obesity is predominantly based on western populations and has focused on the role of parents. This study examined the influence of grandparents on the development of obesity among Chinese primary school aged children. METHODS: A mixed methods study was conducted in four socioeconomically distinct primary school communities in two cities of southern China. The qualitative study (17 focus groups and four personal interviews) involved parents, grandparents, school staff, and food retailers in the vicinity of the schools (n = 99) and explored perceived causes of childhood obesity. The cross-sectional study examined the association between children's objectively measured weight status and reported health behaviours, and the presence and role of grandparents in the household. It included children from three randomly selected third grade (8 to 10 years) classes from each school (n = 497). RESULTS: Grandparents were commonly perceived to contribute to childhood obesity through inappropriate perception (e.g. fat children are healthy and well cared for), knowledge (e.g. obesity related diseases can only happen in adults; the higher the dietary energy/fat content, the more nutritious the food), and behaviour (e.g. overfeeding and indulging through excusing the children from household chores). Conflicting child care beliefs and practices between grandparents and parents, and between grandparents and school teachers, were felt to undermine efforts to promote healthy behaviours in children. In the cross-sectional study, children who were mainly cared for by their grandparents were more likely to be overweight/obese (adjusted OR = 2.03; 95 % CI = 1.19 to 3.47); and to consume more sugar-added drinks and unhealthy snacks (B = 2.13, 95 % CI = 0.87 to 3.40), than children who were mainly cared for by their parents or other adult. Children who lived with two or more grandparents in the household were more likely to be overweight/obese than children who did not live with any grandparent (adjusted OR = 1.72; 95 % CI = 1.00 to 2.94). CONCLUSIONS: Involvement of grandparents in childcare is an important factor contributing to childhood obesity in China. Future preventive interventions should include strategies that target grandparents. PMID- 26122956 TI - Cost consequences due to reduced ulcer healing times - analyses based on the Swedish Registry of Ulcer Treatment. AB - Resource use and costs for topical treatment of hard-to-heal ulcers based on data from the Swedish Registry of Ulcer Treatment (RUT) were analysed in patients recorded in RUT as having healed between 2009 and 2012, in order to estimate potential cost savings from reductions in frequency of dressing changes and healing times. RUT is used to capture areas of improvement in ulcer care and to enable structured wound management by registering patients with hard-to-heal leg, foot and pressure ulcers. Patients included in the registry are treated in primary care, community care, private care, and inpatient hospital care. Cost calculations were based on resource use data on healing time and frequency of dressing changes in Swedish patients with hard-to-heal ulcers who healed between 2009 and 2012. Per-patient treatment costs decreased from SEK38 223 in 2009 to SEK20 496 in 2012, mainly because of shorter healing times. Frequency of dressing changes was essentially the same during these years, varying from 1.4 to 1.6 per week. The total healing time was reduced by 38%. Treatment costs for the management of hard-to-heal ulcers can be reduced with well-developed treatment strategies resulting in shortened healing times as shown in RUT. PMID- 26122960 TI - NECTIN-4 increased the 5-FU resistance in colon cancer cells by inducing the PI3K AKT cascade. AB - PURPOSE: 5-Fluorouracil is the most commonly used drug for the treatment of colon cancer, yet clinical resistance to this drug is frequently observed in patients making this drug ineffective. Thus, identification of gene responsible for 5-FU resistance is of utmost importance. METHODS: Cellular cytotoxicity and expressions of different protein markers in colon cancer cells were measured by MTT assay and Western blotting, respectively. Cell cycle regulation, migration and colony formation ability were measured by FACS, wound-healing assay and clonogenic assay, respectively. RESULTS: Increased NECTIN-4 expression was observed in 5-FU-resistant (5-FU-R) and 5-FU-exposed HCT-116 cells. A significant increase in the cell proliferation, migration, colony formation, and resistant to 5-FU were noted in 5-FU-R cells, but reverse was observed after silencing of NECTIN-4. Apoptosis caused by 5-FU in 5-FU-R cells after NECTIN-4 knockdown indicates that NECTIN-4 is responsible for 5-FU resistance. Cell survival proteins were upregulated in 5-FU-R and NECTIN-4-over-expressed cells and downregulated in NECTIN-4 knockdown or LY294002-pretreated 5-FU-R cells. Drug combination of BCNU + Resveratrol decreased the cell survival and NECTIN-4 expressions in 5-FU-R cells and NECTIN-4-over-expressed cells. CONCLUSIONS: Our data suggest that NECTIN-4 is responsible for 5-FU resistance and BCNU + Resveratrol combination can be used to increase the 5-FU sensitivity. PMID- 26122961 TI - Pyridine-type alkaloid composition affects bacterial community composition of floral nectar. AB - Pyridine-type alkaloids are most common in Nicotiana species. To study the effect of alkaloid composition on bacterial community composition in floral nectar, we compared the nicotine-rich wild type (WT) N. attenuata, the nicotine biosynthesis silenced N. attenuata that was rich in anatabine and the anabasine-rich WT N. glauca plants. We found that the composition of these secondary metabolites in the floral nectar drastically affected the bacterial community richness, diversity and composition. Significant differences were found between the bacterial community compositions in the nectar of the three plants with a much greater species richness and diversity in the nectar from the transgenic plant. The highest community composition similarity index was detected between the two wild type plants. The different microbiome composition and diversity, caused by the different pyridine-type alkaloid composition, could modify the nutritional content of the nectar and consequently, may contribute to the change in the nectar consumption and visitation. These may indirectly have an effect on plant fitness. PMID- 26122962 TI - Expression of estrogen, estrogen related and androgen receptors in adrenal cortex of intact adult male and female rats. AB - INTRODUCTION: Adrenocortical activity in various species is sensitive to androgens and estrogens. They may affect adrenal cortex growth and functioning either via central pathways (CRH and ACTH) or directly, via specific receptors expressed in the cortex and/or by interfering with adrenocortical enzymes, among them those involved in steroidogenesis. Only limited data on expression of androgen and estrogen receptors in adrenal glands are available. Therefore the present study aimed to characterize, at the level of mRNA, expression of these receptors in specific components of adrenal cortex of intact adult male and female rats. MATERIAL AND METHODS: Studies were performed on adult male and female (estrus) Wistar rats. Total RNA was isolated from adrenal zona glomerulosa (ZG) and fasciculate/reticularis (ZF/R). Expression of genes were evaluated by means of Affymetrix(r) Rat Gene 1.1 ST Array Strip and QPCR. RESULTS: By means of Affymetrix(r) Rat Gene 1.1 ST Array we examined adrenocortical sex differences in the expression of nearly 30,000 genes. All data were analyzed in relation to the adrenals of the male rats. 32 genes were differentially expressed in ZG, and 233 genes in ZF/R. In the ZG expression levels of 24 genes were lower and 8 higher in female rats. The more distinct sex differences were observed in the ZF/R, in which expression levels of 146 genes were lower and 87 genes higher in female rats. Performed analyses did not reveal sex differences in the expression levels of both androgen (AR) and estrogen (ER) receptor genes in the adrenal cortex of male and female rats. Therefore matrix data were validated by QPCR. QPCR revealed higher expression levels of AR gene both in ZG and ZF/R of male than female rats. On the other hand, QPCR did not reveal sex-related differences in the expression levels of ERalpha, ERbeta and non-genomic GPR30 (GPER-1) receptor. Of those genes expression levels of ERalpha genes were the highest. In studied adrenal samples the relative expression of ERalpha mRNA was higher than ERbeta mRNA. In adrenals of adult male and female rats expression levels of estrogen-related receptors ERRalpha and ERRbeta were similar, and only in the ZF/R of female rats ERRgamma expression levels were significantly higher than in males. We also analyzed expression profile of three isoforms of steroid 5alpha-reductase (Srd5a1, Srd5a2 and Srd5a3) and aromatase (Cyp19a1) and expression levels of all these genes were similar in ZG and ZF/R of male and female rats. CONCLUSIONS: In contrast to Affymetrix microarray data QPCR revealed higher expression levels of AR gene in adrenal glands of the male rats. In adrenals of both sexes expression levels of ERa, ERb, non-genomic GPR30 (GPER-1), ERR alpha and ERRbeta receptors were comparable. The obtained results suggest that acute steroidogenic effect of estrogens on corticosteroid secretion may be mediated by non-genomic GPR30. PMID- 26122963 TI - Semisynthetic Lipopeptides Derived from Nisin Display Antibacterial Activity and Lipid II Binding on Par with That of the Parent Compound. AB - The lipid II-binding N-terminus of nisin, comprising the so-called A/B ring system, was synthetically modified to provide antibacterially active and proteolytically stable derivatives. A variety of lipids were coupled to the C terminus of the nisin A/B ring system to generate semisynthetic constructs that display potent inhibition of bacterial growth, with activities approaching that of nisin itself. Most notable was the activity observed against clinically relevant bacterial strains including MRSA and VRE. Experiments with membrane models indicate that these constructs operate via a lipid II-mediated mode of action without causing pore formation. A lipid II-dependent mechanism of action is further supported by antagonization assays wherein the addition of lipid II was found to effectively block the antibacterial activity of the nisin-derived lipopeptides. PMID- 26122964 TI - A literature review: polypharmacy protocol for primary care. AB - The purpose of this literature review is to critically evaluate published protocols on polypharmacy in adults ages 65 and older that are currently used in primary care settings that may potentially lead to fewer adverse drug events. A review of OVID, CINAHL, EBSCO, Cochrane Library, Medline, and PubMed databases was completed using the following key words: protocol, guideline, geriatrics, elderly, older adult, polypharmacy, and primary care. Inclusion criteria were: articles in medical, nursing, and pharmacology journals with an intervention, protocol, or guideline addressing polypharmacy that lead to fewer adverse drug events. Qualitative and quantitative studies were included. Exclusion criteria were: publications prior to the year 1992. A gap exists in the literature. No standardized protocol for addressing polypharmacy in the primary care setting was found. Mnemonics, algorithms, clinical practice guidelines, and clinical strategies for addressing polypharmacy in a variety of health care settings were found throughout the literature. Several screening instruments for use in primary care to assess potentially inappropriate prescription of medications in the elderly, such as the Beers Criteria and the STOPP screening tool, were identified. However, these screening instruments were not included in a standardized protocol to manage polypharmacy in primary care. Polypharmacy in the elderly is a critical problem that may result in adverse drug events such as falls, hospitalizations, and increased expenditures for both the patient and the health care system. No standardized protocols to address polypharmacy specific to the primary care setting were identified in this review of the literature. Given the growing population of elderly in this country and the high number of medications they consume, it is critical to focus on the utilization of a standardized protocol to address the potential harm of polypharmacy in the primary care setting and evaluate its effects on patient outcomes. PMID- 26122965 TI - A mass spectrometric study of the acid-catalysed d-fructose dehydration in the gas phase. AB - 5-hydroxymethylfuraldehyde (5-HMF) and simpler compounds, such as levulinic acid (LA) and glyceraldehyde, are platform molecules produced by the thermal acid catalyzed dehydration of carbohydrates coming from biomass. Understanding sugar degradation pathways on a molecular level is necessary to increase selectivity, reduce degradation by-products yields and optimize catalytic strategies, fundamental knowledge for the development of a sustainable renewable industry. In this work gaseous protonated d-fructose ions, generated in the ESI source of a triple quadrupole mass spectrometer, were allowed to undergo Collisionally Activated Decomposition (CAD) into the quadrupole collision cell. The ionic intermediates and products derived from protonated d-fructose dehydration were structurally characterized by their fragmentation patterns and the relative water loss dehydration energies measured by energy-resolved CAD mass spectra. The data were compared with those obtained from protonated d-glucose decomposition in the same experimental conditions. In the gas phase, d-fructose dehydration leads to the formation of a mixed population of isomeric [C6H6O3]H(+) ions, whose structures do not correspond exclusively to 5-hydroxymethyl-2-furaldehyde protonated at the more basic aldehydic group. PMID- 26122966 TI - Prevalence of atherosclerosis in patients with inactive rheumatoid arthritis. AB - Patients with rheumatoid arthritis (RA) exhibit higher cardiovascular morbidity and mortality than the general population. The common carotid artery intima-media thickness (CCA-IMT) measured by ultrasound is a validated surrogate marker of atherosclerosis. We studied the prevalence of subclinical atherosclerosis in patients with inactive RA. CCA-IMT was measured at the level of the carotid bifurcation in 35 patients with RA and 35 age- and sex-matched controls. CCA-IMT measurements more than two standard deviations above the mean measurement of the control group were defined as abnormal. Patients and controls with known cardiovascular risk factors were excluded from the study. The following data were taken into consideration for each patient: age, sex, duration of RA, and medication received by the patient. These variables were adjusted in data analysis. The patients were required to have had normal C-reactive protein levels for at least 1 year and no clinical signs or symptoms of active disease. An independent t test and chi-squared test were used for statistical analysis. Nine patients with RA (25.7 %) and two controls (5.7 %) had an abnormal IMT. Patients showed more carotid atherosclerotic plaques and a higher mean CCA-IMT than did controls (48.6 vs. 14.3 % and 0.705 +/- 0.140 vs. 0.580 +/- 0.125, respectively). An abnormal CCA-IMT was more prevalent in patients >50 years of age with >5 years of involvement (P = 0.001). These results support the theory that chronic inflammation in patients with inactive RA is associated with atherosclerosis and suggest the use of carotid ultrasonography as a useful tool with which to establish the risk of cardiovascular disease. PMID- 26122967 TI - Lethal male combats in Schizotetranychus brevisetosus (Acari: Tetranychidae) on blue Japanese oak (Quercus glauca). AB - Male spider mites (Acari: Tetranychidae) guard preimaginal quiescent females to reserve paternity. In a few species of Stigmaeopsis that make densely woven silky nests on the surface of host plants, mature males attack and even kill rivals to gain their rights to inseminate young females in the nest. Here we report that the adult males of Schizotetranychus brevisetosus (Acari: Tetranychidae), whose web nest construction behavior evolved independently from Stigmaeopsis spp., also exhibit highly aggressive behavior towards one another. Combat mortality was measured in an experimental design where two males in the treatment group were forced to live in a nest made by adult females on a leaf arena, while one male in the control group was allowed to live in a nest on another arena. We found that the 5-day mortality of males in the treatment group (56 and 37 % in two replicates) was significantly higher than in the control group (9 and 12 %) and that lethal combats frequently arose in the treatment group. However, we found no consistent trend for the length of the first legs, which is known to affect the outcome of battle in Tetranychus urticae and Stigmaeopsis miscanthi. This might be due to a relatively small number of measurable specimens, and the effects of body size should be explored in future studies. PMID- 26122968 TI - Laboratory development of Dermacentor marginatus ticks (Acari: Ixodidae) at two temperatures. AB - The influence of two temperatures on the development of Dermacentor marginatus evolutive cycle was studied. Tests performed under controlled laboratory conditions at 21 degrees C, 80 % RH and 27 degrees C, RH 80 %, on ten fully engorged female ticks collected from naturally infested goats, in Cluj County, Romania. Hatched larvae were fed on white mice and the nymphs and adults on guinea pigs. The following parameters were evaluated: egg incubation; pre feeding, feeding and pre-moulting for larvae and nymphs; pre-feeding, feeding, pre-oviposition and oviposition for females. Significant differences (p < 0.001) were observed in: egg incubation period (29.4 +/- 1.07 at 21 degrees C; 5.9 +/- 0.73 at 27 degrees C) and pre-moulting duration of larvae (18.9 +/- 1.02 at 21 degrees C; 6.1 +/- 0.58 at 27 degrees C) and nymphs (21.3 +/- 0.87 at 21 degrees C; 19.9 +/- 0.71 at 27 degrees C). The average duration of the developmental cycle was 133.9 days (range 122-154 days) at 21 degrees C, and 94.2 days (range 83-111 days) at 27 degrees C. PMID- 26122969 TI - In a rapidly changing world, can we truly predict the impact of liver graft quality 15 years from now? PMID- 26122970 TI - Large pleural effusion leading to cardiac tamponade. PMID- 26122971 TI - Effects of propofol on diaphragmatic electrical activity in mechanically ventilated pediatric patients. PMID- 26122972 TI - Apocynin attenuates cholesterol oxidation product-induced programmed cell death by suppressing NF-kappaB-mediated cell death process in differentiated PC12 cells. AB - Cholesterol oxidation products are suggested to be involved in neuronal degeneration. Apocynin has demonstrated to have anti-inflammatory and anti oxidant effects. We assessed the effect of apocynin on the cholesterol oxidation product-induced programmed cell death in neuronal cells using differentiated PC12 cells in relation to NF-kappaB-mediated cell death process. 7-Ketocholesterol and 25-hydroxycholesterol decreased the levels of Bid and Bcl-2, increased the levels of Bax and p53, and induced loss of the mitochondrial transmembrane potential, release of cytochrome c and activation of caspases (-8, -9 and -3). 7 Ketocholesterol caused an increase in the levels of cytosolic and nuclear NF kappaB p65, cytosolic NF-kappaB p50 and cytosolic phospho-IkappaB-alpha, which was inhibited by the addition of 0.5 MUM Bay11-7085 (an inhibitor of NF-kappaB activation). Apocynin attenuated the cholesterol oxidation product-induced changes in the programmed cell death-related protein levels, NF-kappaB activation, production of reactive oxygen species, and depletion of GSH. The results show that apocynin appears to attenuate the cholesterol oxidation product induced programmed cell death in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways that are mediated by NF-kappaB activation. The preventive effect appears to be associated with the inhibitory effect on the production of reactive oxygen species and depletion of GSH. PMID- 26122973 TI - On the antioxidant, neuroprotective and anti-inflammatory properties of S-allyl cysteine: An update. AB - Therapeutic approaches based on isolated compounds obtained from natural products to handle central and peripheral disorders involving oxidative stress and inflammation are more common nowadays. The validation of nutraceutics vs. pharmaceutics as tools to induce preventive and protective profiles in human health alterations is still far of complete acceptance, but the basis to start more solid experimental and clinical protocols with natural products has already begun. S-allyl cysteine (SAC) is a promising garlic-derived organosulfur compound exhibiting a considerable number of positive actions in cell models and living systems. An update, in the form of review, is needed from time to time to get access to the state-of-the-art on this topic. In this review we visited recent and refreshing evidence of new already proven and potential targets to explain the benefits of using SAC against toxic and pathological conditions. The broad spectrum of protective actions covered by this molecule comprises antioxidant, redox modulatory and anti-inflammatory activities, accompanied by anti-apoptotic, pro-energetic and signaling capacities. Herein, we detail the evidence on these aspects to provide the reader a more complete overview on the promising aspects of SAC in research. PMID- 26122974 TI - Neutron flux assessment of a neutron irradiation facility based on inertial electrostatic confinement fusion. AB - Neutron generators based on inertial electrostatic confinement fusion were considered for the design of a neutron irradiation facility for explanted organ Boron Neutron Capture Therapy (BNCT) that could be installed in a health care center as well as in research areas. The chosen facility configuration is "irradiation chamber", a ~20*20*40 cm(3) cavity near or in the center of the facility geometry where samples to be irradiated can be placed. Neutron flux calculations were performed to study different manners for improving scattering processes and, consequently, optimize neutron flux in the irradiation position. Flux distributions were assessed through numerical simulations of several models implemented in MCNP5 particle transport code. Simulation results provided a wide spectrum of combinations of net fluxes and energy spectrum distributions. Among them one can find a group that can provide thermal neutron fluxes per unit of production rate in a range from 4.1.10(-4) cm(-2) to 1.6.10(-3) cm(-2) with epithermal-to-thermal ratios between 0.3% and 13% and fast-to-thermal ratios between 0.01% to 8%. Neutron generators could be built to provide more than 10(10) n s(-1) and, consequently, with an arrangement of several generators appropriate enough neutron fluxes could be obtained that would be useful for several BNCT-related irradiations and, eventually, for clinical practice. PMID- 26122975 TI - Radiation-induced meningiomas after BNCT in patients with malignant glioma. AB - Of the 180 patients with malignant brain tumors whom we treated with boron neutron capture therapy (BNCT) since 1968, only one (0.56%) developed multiple radiation-induced meningiomas. The parasagittal meningioma that had received 42 Gy (w) for BNCT showed more rapid growth on Gd-enhanced MRI scans and more atypical features on histopathologic studies than the temporal convexity tumor that had received 20 Gy (w). Long-term follow up MRI studies are necessary in long-survivors of malignant brain tumors treated by BNCT. PMID- 26122976 TI - A new concept of a vacuum insulation tandem accelerator. AB - A tandem accelerator with vacuum insulation has been proposed and developed in the Budker Institute of Nuclear Physics. Negative hydrogen ions are accelerated by the positive 1 MV potential of the high voltage electrode, converted into protons in the gas stripping target inside the electrode, and then the protons are accelerated again by the same potential. The potential for high voltage and intermediate electrodes is supplied by the sectioned rectifier through a sectioned bushing insulator with a resistive divider. In this work, we propose a radical improvement of the accelerator concept. It is proposed to abandon the separate placement of the accelerator and the power supply and connect them through the bushing insulator. The source of high voltage is proposed to be located inside the accelerator insulator with high voltage and intermediate electrodes mounted on it. This will reduce the facility height from 7 m to 3m and make it really compact and attractive for placing in a clinic. This will significantly increase the stability of the accelerator because the potential for intermediate electrodes can be fed directly from the relevant sections of the rectifier. PMID- 26122977 TI - The perception of place and the 'origins of handedness' debate: towards a cognitive cartography of science in late-Victorian Dublin. AB - In 1884, a medical paper entitled 'Consideration of the Structural and Acquisitional Elements in Dextral Pre-Eminence' penned by the Dublin physician George Sigerson, appeared in the Proceedings of the Royal Irish Academy. A number of years later, the Journal of the Anthropological Institute of Great Britain and Ireland presented a similar piece by Dublin anatomist Daniel John Cunningham, on the topic of 'Right-Handedness and Left-Brainedness'. For the late nineteenth century scientific community, these articles represented two Dublin-based contributions to a long-running and wide-ranging debate on the origins of handedness. However, by building on the geographical premise that scientific knowledge bears the imprint of its location and that place matters in the way scientific claims come to be sanctioned, this paper probes, not merely an encounter with evolutionary science in the less well explored domain of fin de siecle Dublin, but more crucially, how these local reviews of manual dexterity were in part shaped by the scientists' differing perceptions of their city. By attending to the lives of Sigerson and Cunningham and focusing on the interplay between life-space, city-space and science, it underscores the critical role of place and space in the reception, circulation and mobilisation of scientific knowledge in the city. PMID- 26122978 TI - Efficient estimation of Weber's W. AB - Many studies rely on estimation of Weber ratios (W) in order to quantify the acuity an individual's approximate number system. This paper discusses several problems encountered in estimating W using the standard methods, most notably low power and inefficiency. Through simulation, this work shows that W can best be estimated in a Bayesian framework that uses an inverse (1/W) prior. This beneficially balances a bias/variance trade-off and, when used with MAP estimation is extremely simple to implement. Use of this scheme substantially improves statistical power in examining correlates of W. PMID- 26122979 TI - Predictors of photo naming: Dutch norms for 327 photos. AB - In the present study, we report naming latencies and norms for 327 photos of objects in Dutch. We provide norms for eight psycholinguistic variables: age of acquisition, familiarity, imageability, image agreement, objective and subjective visual complexity, word frequency, word length in syllables and letters, and name agreement. Furthermore, multiple regression analyses revealed that the significant predictors of photo-naming latencies were name agreement, word frequency, imageability, and image agreement. The naming latencies, norms, and stimuli are provided as supplemental materials. PMID- 26122980 TI - Analysis of reverse transcriptase and protease genes of HIV for antiretroviral drug resistance in treatment-exposed Jamaican pediatrics. AB - This study reports on the drug resistance profiles for HIV-infected pediatrics in Jamaica who have been exposed to antiretroviral therapy (ART). The genetic diversity of HIV-1 found in these patients was also determined using phylogenetic analysis. The protease-reverse transcriptase (Pro-RT) region of the genome was amplified from 40 samples, sequenced, and analyzed for the identification of antiretroviral resistance-associated mutations (RAMs). All isolates belonged to subtype B and 39 possessed multiple RAMs in the reverse transcriptase genes that would compromise the efficacy of drugs being used to treat these patients. Four isolates possessed RAMs in the protease genes. The overall frequency of HIV drug resistance was 95%. The high frequency of drug resistance is supported by epidemiological data that revealed an equally high frequency of treatment failure (98%) among the study participants. The results of this study indicate the urgent need for greater access to drug resistance testing in Jamaica. PMID- 26122981 TI - Liver toxicity and risk of discontinuation in HIV/hepatitis C virus-coinfected patients receiving an etravirine-containing antiretroviral regimen: influence of liver fibrosis. AB - OBJECTIVES: The aim of the study was to establish the risk of liver toxicity in HIV/hepatitis C virus (HCV)-coinfected patients receiving etravirine, according to the degree of liver fibrosis. METHODS: A prospective cohort study of 211 HIV infected patients initiating an etravirine-containing regimen was carried out. HCV coinfection was defined as a positive HCV RNA test, and baseline liver fibrosis was assessed by transient elastography. Hepatotoxicity was defined as clinical symptoms, or an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value > 5-fold higher than the upper limit of normal if baseline values were normal, or 3.5-fold higher if values were altered at baseline. RESULTS: Overall, 145 patients (69%) were HCV coinfected, with a lower nadir (165 versus 220 cells/MUL, respectively; p = 0.03) and baseline (374 versus 498 cells/MUL, respectively; p = 0.04) CD4 count than monoinfected patients. Etravirine was mainly used with two nucleoside reverse transcriptase inhibitors (129; 61%) or with a boosted protease inhibitor (PI) (28%), with no significant differences according to HCV serostatus. Transient elastography in 117 patients (81%) showed a median (range) stiffness value of 8.25 (3.5-69) kPa, with fibrosis stage 1 in 43 patients (37%) and fibrosis stage 4 in 28 patients (24%). During an accumulated follow-up time of 449.3 patient-years (median 548 days), only one patient with advanced fibrosis (50.8 kPa) had grade 3-4 liver toxicity (0.7%). Transaminases changed slightly, with no significant differences compared with baseline fibrosis, and nine and six patients had grade 1 and 2 transaminase increases, respectively. Also, HCV coinfection was not associated with a higher risk of discontinuation (25% discontinued versus 21% of monoinfected patients; p = 0.39, log-rank test) or virological failure (8% versus 12%, respectively; p = 0.4). CONCLUSIONS: Our data suggest that etravirine is a safe option for HIV/HCV coinfected patients, including those with significant liver fibrosis. PMID- 26122982 TI - Expanding care for perinatal women with depression (EXPONATE): study protocol for a randomized controlled trial of an intervention package for perinatal depression in primary care. AB - BACKGROUND: Depression is common among women during perinatal period and is associated with long-term adverse consequences for the mother and infant. In Nigeria, as in many other low- and-middle-income countries (LMIC), perinatal depression usually goes unrecognized and untreated. The aim of EXPONATE is to test the effectiveness and cost-effectiveness of an intervention package for perinatal depression delivered by community midwives in primary maternal care in which physician support and enhanced patient compliance are implemented using mobile phones. METHODS/STUDY DESIGN: A pragmatic two-arm parallel cluster randomized controlled trial was designed. The units of allocation are the primary maternal care clinics. Thirty eligible and consenting clinics were randomized but, due to problems with logistics, 29 eventually participated. Consenting pregnant women with a gestational age between 16 and 28 weeks who screened positive on the Edinburgh Postnatal Depression Scale (EPDS score >=12), absent psychosis or bipolar disorder, and not actively suicidal were recruited into the trial (N = 686). Midwives in the intervention arm were trained to deliver psychoeducation, problem solving treatment, and parenting skills. Eight weekly sessions were delivered following entry into the study. Further sessions during pregnancy and 6 weeks following childbirth were determined by level of depressive symptoms. Clinical support and supervision, delivered mainly by mobile phone, were provided by general physicians and psychiatrists. Automated text and voice messages, also delivered by mobile phones, were used to facilitate patient compliance with clinic appointments and 'homework' tasks. Patients in the control arm received care as usual enhanced by further training of the providers in that arm in the recognition and standard treatment of depression. Assessments are undertaken at baseline, 2 months following recruitment into the study and 3, 6, 9 and 12 months after childbirth. The primary outcome is recovery from depression (EPDS < 6) at 6 months. Secondary outcomes include measures of disability, parenting skills, maternal attitudes, health care utilization as well as infant physical and cognitive development comprehensively assessed using the Bayley's Scales. DISCUSSION: To the best of our knowledge, this is the largest randomized controlled trial of an intervention package delivered by community midwives in sub-Saharan Africa. TRIAL REGISTRATION: Trial is registered with the ISRTCN registry at isrtcn.com; Trial number ISRCTN60041127 . Date of registration is 15/05/2013. PMID- 26122984 TI - Evaluation of Mononuclear Cells in Lichen Planus Pemphigoides. PMID- 26122983 TI - Low wear rates seen in THAs with highly crosslinked polyethylene at 9 to 14 years in patients younger than age 50 years. AB - BACKGROUND: Patients 50 years or younger are at high risk for wear-related complications of their total hip arthroplasty (THA) because of their generally higher levels of activity. Highly crosslinked polyethylene (HXLPE) is believed to be more durable for this population than conventional polyethylene because of its improved wear; however, limited information is available on the wear of HXLPE in this population, particularly the wear of HXLPE when it articulates with alternative bearings like Oxinium (Smith & Nephew, Memphis, TN, USA). QUESTIONS/PURPOSES: The purpose of this study was to evaluate two questions relative to this population of patients undergoing THA. First, what was the linear and volumetric wear rate of HXLPE in patients 50 years or younger at a minimum followup of 9 years and was osteolysis observed in any of these hips? Given the potential for damage to the Oxinium femoral head surface, was the wear of HXLPE in the patients with this material similar to the other bearings or was there accelerated or runaway wear that was visible in any of the patients? METHODS: From November 1999 to April 2005, 105 THAs were performed in 95 patients 50 years of age or younger (mean, 42 years; range, 20-50 years). The mean body mass index was 30 kg/m(2) (range, 17-51 kg/m(2)).The mean followup was 12 years (range, 9-14 years). Two patients died, five patients (one bilateral) were lost to followup, and one hip was revised elsewhere for pain. The patients' information was not included in the study, which left 87 patients with 96 hips for analysis. Highly crosslinked polyethylene was the acetabular bearing for all of the hips. We analyzed the linear and volumetric wear of all of the hips using the Martell method. Eighty hips had the same diameter head (28 mm) allowing us to more accurately compare the different bearing materials. The type of femoral head used was related to our sequential use of materials beginning with cobalt chrome (14), ceramic (23) followed by Oxinium (43) in the hips with 28-mm heads. Although cobalt-chrome was used early in this study, our previous experience with ceramic on polyethylene encouraged us to use it as an alternative bearing. The Oxinium was used consecutively for the remaining hips. RESULTS: The mean wear of the HXLPE after 1 year of bedding-in (true linear wear)was 0.022 mm/year (95% confidence interval [CI], 0.015-0.030 mm/year). The mean volumetric wear of HXLPE after 1 year of bedding-in (true volumetric wear) was 9 mm(3)/year (95% CI, 4-14 mm(3)/year). None of the hip radiographs had evidence of loosening or osteolysis. Wear was not associated with femoral head material (p = 0.58 for linear wear/year versus head material and p = 0.52 for volumetric wear/year versus head material). CONCLUSIONS: In our study of patients 50 years of age or younger undergoing THA, the linear and volumetric wear rates of HXLPE were very low regardless of the bearing surface material. The laboratory concerns of Oxinium surface damage are serious but at this time we have not seen high wear of the HXLPE or osteolysis in this population. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26122985 TI - The importance of stories in understanding people's relationship to food: narrative inquiry methodology has much to offer the public health nutrition researcher and practitioner. AB - OBJECTIVE: Despite the usefulness of quantitative research, qualitative research methodologies are equally needed to allow researchers to better understand the important social and environmental factors affecting food choice and eating habits. The present paper contributes insights from narrative inquiry, a well established qualitative methodology, to a food-related doctoral research study. The connections between food shoppers and the producer, family, friends and others in the food system, between eaters and the earth, and how these connections affect people's meaning-making of food and pathways to food citizenship, were explored in the research. DESIGN: The research used narrative inquiry methodology and focus groups for data collection. SETTING: Five different food-ways in the Canberra region of Australia were selected for the present research; that is, community gardens, community-supported agriculture, farmers' markets, fresh food markets and supermarkets. SUBJECTS: Fifty-two people voluntarily attended eight focus groups with four to nine participants in each. RESULTS: From a practical perspective, the present paper offers a guide to the way in which narrative inquiry has been applied to one research project. The paper describes the application of narrative inquiry methodology, revealing the important place of narratives in generating new knowledge. The paper further outlines how phased narrative analysis can lead to a defensible and rigorous interpretive framework grounded in the data generated from people's stories and meaning-making. CONCLUSIONS: We argue that individual, social and system change will not be possible without further rigorous qualitative studies to inform and complement the empirical basis of public health nutrition practice. PMID- 26122986 TI - Thermodynamic and saccharification analysis of cloned GH12 endo-1,4-beta glucanase from Thermotoga petrophila in a mesophilic host. AB - The thermotolerant endo-1,4-beta-glucanase gene, of Thermotoga petrophila RKU-1, was cloned and over-expressed in E. coli strain BL21 CodonPlus. Enzyme was purified to homogeneity, producing a single band on SDS-PAGE corresponding to 38 kDa, by purification steps of heat treatment combined with ion-exchange column chromatography. The purified enzyme was optimally active, with specific activity of 530 Umg(-1) against carboxymethyl cellulose (CMC), at pH 6.0 and 95 degrees C and was also stable upto 8 h at 80 degrees C. The enzyme also showed activity against beta-glucan barley: 303 %, laminarin: 13.7 %, Whatman filter paper: 0.017 % with no activity against starch and Avicel. The recombinant enzyme exhibited Km, Vmax and Kcat of 12.5 mM, 735 umol mg-1min-1 and 2351.23 s-1, respectively against CMC as a substrate. The stable recombinant enzyme manifested half life (t1/2) of 6.6 min even at temperature as high as 97 degrees C, with free energy of denaturation (DeltaG*D), enthalpy of denaturation (DeltaH*D), and entropy of denaturation (DeltaS*D) of 98.2 kJ mol(-1), 528.9 kJ mol(-1), and 1.17 kJ mol( 1)K(-1), respectively at 97 degrees C. In addition, the enthalpy (DeltaH*), Gibbs free energy (DeltaG*) and entropy (DeltaS*) for hydrolysis of CMC substrate by endo-1,4-beta-glucanase were calculated at 95 degrees C as 48.2 kJ mol(-1), 54.6 kJ mol(-1) and -17.4 J mol(-1) K(-1), respectively. The recombinant enzyme saccharified pre-treated wheat straw and bagasse to 3.32 % and 3.2 %, respectively after 6 h incubation at 85 degrees C. Its thermostability, resistance to heavy metal ions and specific activity make this enzyme an interesting candidate for industrial applications. PMID- 26122988 TI - Equality of Opportunity, A Flexible Framework. PMID- 26122987 TI - Identification and Characterization of Novel Antioxidant Peptides Involved in Redox Homeostasis of Frog, Limnonectes fragilis. AB - Previous studies have proved that a novel antioxidant system composed of various antioxidant peptides (AOPs) exists in the skin of ranid frogs, keeping the redox homeostasis. However, only a small number of AOPs have been identified so far. Here, a total of 47 cDNA sequences encoding 21 different AOPs belonging to 11 families were cloned from the skin cDNA library of Limnonectes fragilis. Among them, fragilin-A1 (VKRRGQDCIHGFCSD) and fragilin-B1 (GQFNDKRWIPFG) were also purified from skin secretions. They were selected with odorranain-Q-Lf (APIRMWYMYRKLTDMEPKPVA), the newest sequence among all 21 AOPs, to evaluate the antioxidant activities by direct free radical scavenging and lipid peroxidation inhibition assay. Results demonstrated that all peptides possessed strong DPPH and ABTS(.+) scavenging activities, and effectively inhibited lipid peroxidation in linoleic acid emulsion system during a 7- day test. No cytotoxic and hemolytic activity against human erythrocytes was observed for the three AOPs. The homology modeling analysis revealed that they all adopt tertiary structures ideally suited for the key residues to come into contact with the radicals. Current results reveal the existence of antioxidant system constituted of AOPs in the skin of the L. fragilis, and furthermore provide excellent templates for the development of novel antioxidant agents. PMID- 26122989 TI - New finding of Trichinella britovi in a European beaver (Castor fiber) in Latvia. AB - We report the first finding of Trichinella britovi in a European beaver. In Latvia, beaver is a common game animal and frequently used in human diet. A high prevalence of Trichinella infections in Latvia is present in the most common hosts-carnivores and omnivores. In total, 182 European beaver muscle samples were tested for Trichinella larvae accordingly to the reference method of European Communities Commission Regulation (EC) No. 2075/2005 (2005). Trichinella britovi larvae were detected in one animal (prevalence 0.5%; intensity 5.92 larvae per gram of muscle). This finding suggests that the consumption of European beaver meat can be a risk to human health. Further studies are needed in order to determine if the present observation represents an isolated individual case or low prevalence of Trichinella infection in beavers. PMID- 26122990 TI - Meta-analysis of the diagnostic efficiency of the questionnaires screening for schistosomiasis. AB - Schistosomiasis is the second widespread tropical disease that affects the health of over 240 million people of 78 countries. Questionnaires have been commonly used to diagnose schistosomiasis, while no meta-analysis of their efficacy had been reported previously. This meta-analysis was conducted to assess their diagnostic accuracy of schistosomiasis. Studies published prior to December 1, 2014, that had used questionnaires as a diagnostic tool were searched in PubMed, Medline, EMBASE, and China National Knowledge Infrastructure (CNKI) database. A total of 32 studies with 72,812 cases were identified for the meta-analysis. The best diagnostic odds ratio (DOR) was obtained from Schistosoma haematobium (67.68, 95 % confidence interval (CI) = 31.48 to 145.54), followed by Schistosoma japonicum (11.74, 95 % CI = 4.59 to 30.05) then Schistosoma mansoni (2.98, 95 % CI = 1.95 to 4.54). Pooled sensitivity and specificity were respectively 0.82, 0.88, and 0.46, and 0.59, 0.86, and 0.81 for S. japonicum, S. haematobium, and S. mansoni. The multivariable subgroup analyses showed that the questionnaires which had been pretested and standardized had better diagnostic performance. The result suggested that questionnaires can be used to diagnose schistosomiasis with moderate sensitivity and specificity and the questionnaires for diagnosing S. haematobium performed best. PMID- 26122991 TI - Larval development of Angiostrongylus vasorum in the land snail Helix aspersa. AB - The metastrongyloid nematode Angiostrongylus vasorum affects the heart and pulmonary arteries of dogs and wild animals. Over the recent years, dog angiostrongylosis has gained great attention in the veterinary community for the expansion of its geographic range and for a rise in the number of clinical cases. Global warming, changes in phenology of mollusc intermediate hosts and movements of wild reservoirs have been evocated in the spreading of mollusc-borne parasites, including A. vasorum. The land snail Helix aspersa, a vector of other respiratory metastrongyloids, is endemic in most regions of the World, where it is a pest outside its native Mediterranean range. In the present study, the susceptibility and suitability of H. aspersa as an intermediate host of A. vasorum were investigated along with the characteristics of larval recovery and development following two different ways of inoculation, i.e. experimental (group A) vs natural infection (group B). After infections, the snails were kept at environmental conditions for 2 months. Five snails from groups A and B were randomly selected, digested and examined at 15-day intervals for 2 months. L1s, L2s and L3s were microscopically identified based on key morphological and morphometric characteristics and their identity was genetically confirmed. The results showed that A. vasorum may reach the infective stage in H. aspersa and that uptake of larvae and parasitic burden within the snails depend on the grazing capability of the molluscs. Biological and epidemiological implications are discussed. PMID- 26122992 TI - Mosquitocidal and antiplasmodial activity of Senna occidentalis (Cassiae) and Ocimum basilicum (Lamiaceae) from Maruthamalai hills against Anopheles stephensi and Plasmodium falciparum. AB - Each year, mosquito-borne diseases infect nearly 700 million people, resulting to more than 1 million deaths. In this study, we evaluated the larvicidal, pupicidal, and smoke toxicity of Senna occidentalis and Ocimum basilicum leaf extracts against the malaria vector Anopheles stephensi. Furthermore, the antiplasmodial activity of plant extracts was evaluated against chloroquine (CQ) resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum. In larvicidal and pupicidal experiments, S. occidentalis LC50 ranged from 31.05 (I instar larvae) to 75.15 ppm (pupae), and O. basilicum LC50 ranged from 29.69 (I instar larvae) to 69 ppm (pupae). Smoke toxicity experiments conducted against adults showed that S. occidentalis and O. basilicum coils evoked mortality rates comparable to the pyrethrin-based positive control (38, 52, and 42%, respectively). In antiplasmodial assays, Senna occidentalis 50% inhibitory concentration (IC50) were 48.80 MUg/ml (CQ-s) and 54.28 MUg/ml (CQ-r), while O. basilicum IC50 were 68.14 MUg/ml (CQ-s) and 67.27 MUg/ml (CQ-r). Overall, these botanicals could be considered as potential sources of metabolites to build newer and safer malaria control tools. PMID- 26122993 TI - Completion of the life cycle of Tylodelphys mashonense (Sudarikov, 1971) (Digenea: Diplostomidae) with DNA barcodes and rDNA sequences. AB - The life cycle of Tylodelphys mashonense (Digenea: Diplostomidae), whose metacercariae occur in the cranial cavity of the widely cultivated catfish Clarias gariepinus, was resolved by the application of molecular markers. Both COI barcodes and ITS sequences obtained from diplostomid-like cercariae infecting Bulinus spp. from Mindu Dam, Morogoro, matched those acquired from metacercariae from the catfish C. gariepinus, and those from adult T. mashonense from the grey heron Ardea cinerea and the white egret Egretta alba. The success in linking the life cycle stages of T. mashonense using molecular tools highlights the usefulness of this approach in resolving the complex life cycles of digeneans in the absence of experimental establishment. PMID- 26122994 TI - Ecology of the interaction between Ixodes loricatus (Acari: Ixodidae) and Akodon azarae (Rodentia: Criceridae). AB - The present study explores associations of different factors (i.e. host parameters, presence of other ectoparasites and [mainly biotic] environmental factors) with burdens of Ixodes loricatus immature stages in one of its main hosts in Argentina, the rodent Akodon azarae. For 2 years, rodents were trapped and sampled monthly at 16 points located in four different sites in the Parana River Delta region. Data were analysed with generalized linear mixed models with a negative binomial response (counts of larvae or nymphs). The independent variables assessed were (a) environmental: trapping year, presence of cattle, type of vegetation, rodent abundance; (b) host parameters: body length, sex, body condition, blood cell counts, natural antibody titers and (c) co-infestation with other ectoparasites. Two-way interaction terms deemed a priori as relevant were also included in the analysis. Most of the associations investigated were found significant, but in general, the direction and magnitude of the associations were context-dependent. An exception was the presence of cattle, which was consistently negatively associated with both larvae and nymphs independently of all other variables considered and had the strongest effect on tick burdens. Mites, fleas and Amblyomma triste were also significantly associated (mostly positively) with larval and nymph burdens, and in many cases, they influenced associations with environmental or host factors. Our findings strongly support that raising cattle may have a substantial impact on the dynamics of I. loricatus and that interactions within the ectoparasite community may be an important-but generally ignored-driver of tick dynamics. PMID- 26122995 TI - Human wound myiasis caused by Phormia regina and Sarcophaga haemorrhoidalis in Minia Governorate, Egypt. AB - Myiasis is the parasitic infestation of human by the larvae (maggots) of dipterous fly that grow within the host while feeding on its tissue. Cutaneous myiasis is the most considerably encountered clinical form. Moreover, wound (traumatic) myiasis is the main clinical manifestation of cutaneous myiasis. In this research, we aimed to study the type of infesting larvae that are responsible for wound myiasis in the patients in Minia city, Egypt. Three cases of wound myiasis have been noticed among 280 patients with wounds at different parts of bodies. Two of them were diabetic patients. The third one had a history of hypertension with right side hemiplegia 2 years ago. All of them were elderly. The larvae removed from cases 1 and 3 were identified macroscopically and microscopically as the third-stage larvae of Sarcophaga haemorrhoidalis. The larvae removed from case 2 were the third-stage larvae of Phormia regina, which is very rare worldwide. In addition to the open and obsolete wound, diabetes mellitus and low socio-economic circumstances were shown to be attributed as important predisposing risk factors that led to the occurrence of myiasis in these patients. PMID- 26122996 TI - Impact of gold nanoparticles on brain of mice infected with Schistosoma mansoni. AB - Schistosomiasis is a condition characterized by high rates of morbidity and cognitive impairment. It afflicts many people in tropical and sub-tropical countries. Our study aimed to investigate the protective role of gold nanoparticles (GNPs) on the brain of mice infected with Schistosoma mansoni. Characterizations of GNPs were determined by using high-resolution transmission electron microscopy. Three doses of GNPs (0.25, 0.5, and 1.0 mg/kg body weight) were used to treat animals after S. mansoni infection. The infection induced impairments in histological picture as a result of schistosome infection resulting in a disturbance in the content of the brain neurotransmitters, norepinephrine (NE), and dopamine (DA). Also, the infection induced significant reduction in glutathione level; oppositely, the levels of nitric oxide and malondialdehyde were increased significantly. In addition, S. mansoni was able to disregulate the infected mice brain Cacnb4, Cabp4, Vdac3, Glrb, and Adam23 messenger RNA (mRNA). On the other hand, treatment of mice with GNPs could alleviate the histological impairments, the changes in the content of NE and DA, and the brain oxidative damage. Also, GNPs could regulate the gene expression due to S. mansoni infection. Generally, GNPs could decrease the neurooxidative stress and regulated the gene expression in the brain of infected mice. Consequently, our results revealed an anti-neuroschistosomal effect of GNPs in mice infected with S. mansoni. PMID- 26122997 TI - Application of polymerase chain reaction on cerebrospinal fluid for diagnosis of cerebral coenurosis in small ruminants. AB - Sheep and goats serve as intermediate hosts for the canine tapeworm Taenia multiceps. The cysts produced by the intermediate stage of parasite are usually found in the cerebral hemispheres of small ruminants, and the resulting disease is commonly known as coenurosis. Coenurosis is clinically manifested in the form of various nervous symptoms, depending on the exact location of the cyst. The variety of neurological symptoms contributes to the complexity of clinical diagnosis and reinforces the need for a more specific and acceptable diagnostic approach. We demonstrated here, for the first time, that the T. multiceps DNA is present in the cerebrospinal fluid (CSF) of the infected sheep and goats. In addition, the molecular genetic marker of the mitochondrial DNA was applied phylogenetically to show that our isolates together with other T. multiceps strains comprised a monophyletic group that is a sister to Taenia krabbei. Pairwise comparison between the cox1 sequences of our study and other T. multiceps genotypes existing in the GenBank showed similarity ranging from 98 to 100%. Accordingly, the polymerase chain reaction (PCR) can be used for amplification of DNA of the parasite originated from the CSF and provides a valuable method for accurate identification of coenurosis cases. PMID- 26122998 TI - A comparison of mini-FLOTAC and FLOTAC with classic methods to diagnosing intestinal parasites of dogs from Brazil. AB - Dogs may be affected by different species of gastrointestinal parasites which present great importance in veterinary medicine and public health. Several techniques to diagnosing these parasites have been proposed, but different performances achieved by each method make difficult the choice of the best technique to be used. In this study, the performance of two classic methods (i.e., Willis and Hoffman techniques) and two recent techniques (i.e., FLOTAC and Mini-FLOTAC) to diagnosing gastrointestinal parasites of dogs was evaluated. Fecal samples (n = 127) of dogs divided in pools (n = 30) were collected and analyzed using four different techniques (see above). Eggs and/or oocysts of gastrointestinal parasites were detected in 93.3 % (28/30) of the samples. In particular, 20 % (6/30) were detected through the method of Hoffman, 53.3 % (16/30) by the Willis technique, and 63.3 % (19/30) and 90 % (27/30) by Mini FLOTAC and FLOTAC, respectively. Ancylostomatidae, Trichuris vulpis and Toxocara canis were the most frequent parasites herein detected. The FLOTAC and Mini FLOTAC techniques were the most efficient tools to detect eggs and/or oocysts of gastrointestinal parasites of dogs, therefore their use is recommended in the laboratorial routine of veterinary medicine. This study is the first report of the use of both techniques (i.e., FLOTAC and Mini-FLOTAC) to diagnosing parasites of dogs in Brazil. PMID- 26122999 TI - Label-free quantification reveals major proteomic changes in Pseudomonas putida F1 during the exponential growth phase. AB - The physiological adaptation to stationary growth by Pseudomonas putida F1, a model organism for the degradation of aromatic compounds, was investigated by proteome-wide label-free quantification.The data unveiled that entrance to the stationary phase did not involve an abrupt switch within the P. putida F1 proteome, but rather an ongoing adaptation that started already during the mid exponential growth phase. The proteomic adaptations involved a clear increase in amino acid degradation capabilities and a loss of transcriptional as well as translational capacity. The final entrance to the stationary phase was accompanied by increased oxidative stress protection, although the stress and stationary sigma factor RpoS increased in abundance already during mid exponential growth. The results show that it is important to consider significant sample variations when exponentially growing cultures are studied alone or compared across proteomic or transcriptomic literature. All MS data have been deposited in the ProteomeXchange with identifier PXD001219 (http://proteomecentral.proteomexchange.org/dataset/PXD001219). PMID- 26123000 TI - Common concepts in separate domains? Family physicians' ways of understanding teaching patients and trainees, a qualitative study. AB - BACKGROUND: Medical education is increasingly expanding into new community teaching settings and the need for clinical teachers is rising. Many physicians taking on this new role are already skilled patient educators. The purpose of this research was to explore how family physicians conceptualize teaching patients compared to the teaching of trainees. Our aim was to understand if there is any common ground between these two roles in order to support faculty development based on already existing skills. METHODS: Semi-structured interviews with twenty-five family physician preceptors were conducted in Vancouver, Canada and thematically analyzed. RESULTS: We identified four key areas of overlap between the two fields (being learner-centered; supporting the acquisition, application and integration of knowledge; role modeling and self-disclosure; and facilitating autonomy) and three areas of divergence (aim of teaching and setting the learning objectives; establishing rapport; and providing feedback). CONCLUSIONS: Finding common ground between these two teaching roles would support knowledge translation and inquiry between the domains of teaching patients and trainees. It would furthermore open up new avenues for improving training and practice for clinical teachers by better linking faculty development and continuing medical education (CME). PMID- 26123001 TI - Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes. AB - Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-gamma coactivator 1 alpha, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders. PMID- 26123004 TI - Trauma Center Based Youth Violence Prevention Programs: An Integrative Review. AB - OBJECTIVE: Youth violence recidivism remains a significant public health crisis in the United States. Violence prevention is a requirement of all trauma centers, yet little is known about the effectiveness of these programs. Therefore, this systematic review summarizes the effectiveness of trauma center-based youth violence prevention programs. METHODS: A systematic review of articles from MEDLINE, CINAHL, and PsychINFO databases was performed to identify eligible control trials or observational studies. Included studies were from 1970 to 2013, describing and evaluating an intervention, were trauma center based, and targeted youth injured by violence (tertiary prevention). The social ecological model provided the guiding framework, and findings are summarized qualitatively. RESULTS: Ten studies met eligibility requirements. Case management and brief intervention were the primary strategies, and 90% of the studies showed some improvement in one or more outcome measures. These results held across both social ecological level and setting: both emergency department and inpatient unit settings. CONCLUSIONS: Brief intervention and case management are frequent and potentially effective trauma center-based violence prevention interventions. Case management initiated as an inpatient and continued beyond discharge was the most frequently used intervention and was associated with reduced rearrest or reinjury rates. Further research is needed, specifically longitudinal studies using experimental designs with high program fidelity incorporating uniform direct outcome measures. However, this review provides initial evidence that trauma centers can intervene with the highest of risk patients and break the youth violence recidivism cycle. PMID- 26123005 TI - Factors influencing Saprolegnia spp. spore numbers in Norwegian salmon hatcheries. AB - A quantitative survey of Saprolegnia spp. in the water systems of Norwegian salmon hatcheries was performed. Water samples from 14 salmon hatcheries distributed along the Norwegian coastline were collected during final incubation in the hatcheries. Samples of inlet and effluent water were analyzed to estimate Saprolegnia propagule numbers. Saprolegnia spores were found in all samples at variable abundance. Number of spores retrieved varied from 50 to 3200 L(-1) in inlet water and from 30 to >5000 L(-1) in effluent water. A significant elevation of spore levels in effluent water compared to inlet water was detected. The estimated spore levels were related to recorded managerial and environmental parameters, and the number of spores in inlet water and temperature was the factor having most influence on the spore concentration in the incubation units (effluent water). Further, the relative impact of spore concentration on hatching rates was investigated by correlation analysis. From this was found that even high spore counts did not impact significantly on hatching success. PMID- 26123003 TI - A case-control study of airways obstruction among construction workers. AB - BACKGROUND: While smoking is the major cause of chronic obstructive pulmonary disease (COPD), occupational exposures to vapors, gases, dusts, and fumes (VGDF) increase COPD risk. This case-control study estimated the risk of COPD attributable to occupational exposures among construction workers. METHODS: The study population included 834 cases and 1243 controls participating in a national medical screening program for older construction workers between 1997 and 2013. Qualitative exposure indices were developed based on lifetime work and exposure histories. RESULTS: Approximately 18% (95% CI = 2-24%) of COPD risk can be attributed to construction-related exposures, which are additive to the risk contributed by smoking. A measure of all VGDF exposures combined was a strong predictor of COPD risk. CONCLUSIONS: Construction workers are at increased risk of COPD as a result of broad and complex effects of many exposures acting independently or interactively. Control methods should be implemented to prevent worker exposures, and smoking cessation should be promoted. PMID- 26123006 TI - The importance of caring to older persons' mental health nurses: a cross sectional study. PMID- 26123007 TI - Tracking social motivation systems deficits: the affective neuroscience view of autism. AB - Abnormal functioning of primary brain systems that express and modulate basic emotional drives are increasingly considered to underlie mental disorders including autism spectrum disorders. We hypothesized that ASD are characterized by disruptions in the primary systems involved in the motivation for social bonding. Twenty adults with ASD were compared to 20 neurotypical participants on the basis of self-reports and clinical assessments, including the Social Anhedonia Scale (SAS) and the Affective Neuroscience Personality Scales (ANPS). ASD diagnosis was related to SAS, as well as to positive (PLAYFULNESS) and negative (FEAR) ANPS-traits. In the overall sample, levels of autistic traits (AQ) were related to SAS and PLAYFULNESS. We argue that PLAYFULNESS could be at the root of social bonding impairments in ASD. PMID- 26123008 TI - Preschoolers with Autism Spectrum Disorder Followed for 2 Years: Those Who Gained and Those Who Lost the Most in Terms of Adaptive Functioning Outcome. AB - Clinical predictors of 2-year outcome in preschoolers with ASD were studied in a population-based group of very young children with ASD (n = 208). Children who gained the most (n = 30) and lost the most (n = 23), i.e., increased or decreased their adaptive functioning outcome according to the Vineland Composite Score between study entry (T1) and follow-up (T2), 2 years later were compared. Individual factors that differed significantly between the two outcome groups were cognitive level, age at referral, not passing expected milestones at 18 months, autistic type behavior problems and regression. However, logistic regression analysis showed that only cognitive level at T1 (dichotomized into IQ < 70 and IQ >= 70) made a unique statistically significant contribution to outcome prediction (p = <.001) with an odds ratio of 18.01. The findings have significant clinical implications in terms of information at diagnosis regarding clinical prognosis in ASD. PMID- 26123009 TI - The New DSM-5 Impairment Criterion: A Challenge to Early Autism Spectrum Disorder Diagnosis? AB - The possible effect of the DSM-5 impairment criterion on diagnosing autism spectrum disorder (ASD) in young children was examined in 127 children aged 20-47 months with a DSM-IV-TR clinical consensus diagnosis of ASD. The composite score of the Vineland Adaptive Behavior Scales (VABS) served as a proxy for the DSM-5 impairment criterion. When applying a mild level of impairment (cutoff: 1 SD below the mean on the VABS), 88 % of the cases fulfilled the impairment criterion. Sixty-nine percent fulfilled the impairment criterion at a moderate level (1.5 SDs) and 33 % at a severe level (2 SDs). Findings indicate that a strict application of the new DSM-5 impairment criterion might compromise early diagnosis of ASD. PMID- 26123010 TI - Autism Symptoms Across Adulthood in Men with Fragile X Syndrome: A Cross Sectional Analysis. AB - A cross-sectional analysis was used to examine age-related differences in ASD symptoms and corresponding differences in disruptive behavior and social skills in 281 adult men with fragile X syndrome. Four age groups were created: 18-21, 22 29, 30-39, and 40-49 years. The 18-21 year-old group was reported to have more impairments in verbal communication than the 22-29 year-old group and more restricted and repetitive behaviors than the 40-49 year-old group. There was not an age-group difference in the percentage of men who met criteria for an ASD diagnosis based on respondent-reported, current symptoms. There was a trend for an age-related difference in disruptive behavior. Findings add to understanding of the developmental trajectory of ASD symptoms in adulthood. PMID- 26123011 TI - Mechanical Dyssynchrony and Abnormal Regional Strain Promote Erroneous Measurement of Systolic Function in Pediatric Heart Transplantation. AB - BACKGROUND: Clinical experience suggests that measurement of left ventricular (LV) ejection fraction (EF) using two-dimensional echocardiography (2DE) is often at variance with results of three-dimensional echocardiography (3DE) in patients who have undergone heart transplantation (HT). The aim of this study was to test the hypothesis that LV mechanical dyssynchrony and abnormal regional strain are present in asymptomatic pediatric HT patients and that they promote errors in the measurement of LV function when 2DE is used. METHODS: HT subjects and normal volunteer children were prospectively enrolled. All had normal estimated right ventricular systolic pressure and function. LV EF, global and regional strain, and systolic dyssynchrony index (SDI) were quantified using real time 3DE. SDI was determined from volume-time curves of the 16 LV segments and expressed as the standard deviation of the heart rate-corrected time to reach minimal segmental systolic volume. Septal strain was defined as the average of five segments in the interventricular septum. In addition to 3DE, the Teichholz, biplane Simpson, and bullet (5/6 area-length) methods were used to measure EF using 2DE in each subject. Ninety-three examinations were done: 40 in the 40 normal control subjects (mean age, 14.6 +/- 10.6 years; 10 male) and 53 in 36 HT subjects (mean age, 10.3 +/- 6.2 years; 21 male). RESULTS: SDI was greater in HT patients (mean, 6.2 +/- 4.3%) than in normal controls (mean, 2.2 +/- 1.1%) (P < .0001). Global and septal strain was lower in HT patients than in normal controls. EF divergence (absolute difference between two- and three-dimensional EFs) was greater in HT patients (mean, 3.8 +/- 2.2%) than in normal controls (mean, 0.7 +/- 0.5%) (P < .0001). EF divergence had a strong positive correlation with SDI (adjusted r2 = 0.46, P < .001) and negative correlations with all measures of strain (range of adjusted r2 values, 0.13-0.32). SDI had no particular relation to LV mass or to QRS duration. CONCLUSIONS: Children after HT have abnormal LV mechanics characterized by greater dyssynchrony and lower strain. These features correlate with, and possibly contribute to differences between measurements by 2DE and 3DE. EF should be calculated using 3DE in this population and others with dyssynchrony and regional strain abnormalities. PMID- 26123012 TI - Abnormal Regulation of Microvascular Tone in a Murine Model of Sickle Cell Disease Assessed by Contrast Ultrasound. AB - BACKGROUND: Microvascular dysregulation, abnormal rheology, and vaso-occlusive events play a role in the pathophysiology of sickle cell disease (SCD). The aim of this study was to test the hypothesis that abnormalities in skeletal muscle perfusion in a murine model of SCD could be parametrically assessed by quantitative contrast-enhanced ultrasound perfusion imaging. METHODS: A murine model of moderate SCD without anemia produced by homozygous beta-globin deletion replaced by human betas-globin transgene (NY1DD-/-; n = 18), heterozygous transgene replacement (NY1DD+/-; n = 19), and C57Bl/6 control mice (n = 14) was studied. Quantitative contrast-enhanced ultrasound of the proximal hindlimb skeletal muscle was performed at rest and during contractile exercise (2 Hz). Time-intensity data were analyzed to measure microvascular blood volume (MBV), microvascular blood transit rate (beta), and microvascular blood flow. Erythrocyte deformability was measured by elongation at various rotational shears. RESULTS: At rest, muscle MBV was similar between strains, whereas beta was significantly (P = .0015, analysis of variance) reduced to a similar degree in NY1DD-/- and NY1DD+/- compared with wild-type mice (0.24 +/- 0.10, 0.16 +/- 0.07, and 0.34 +/- 0.14 sec(-1), respectively), resulting in a reduction in microvascular blood flow. During contractile exercise, there were no groupwise differences in beta (1.43 +/- 0.67, 1.09 +/- 0.42, and 1.36 +/- 0.49 sec(-1) for NY1DD-/-, NY1DD+/-, and wild-type mice, respectively) or in microvascular blood flow or MBV. Erythrocyte deformability at high shear stress (>=5 Pa) was mildly reduced in both transgenic groups, although it was not correlated with blood flow or beta. CONCLUSIONS: Contrast-enhanced ultrasound in skeletal muscle revealed a lower microvascular blood transit rate in the NY1DD model of SCD and sickle trait but no alterations in MBV. The abnormality in microvascular blood transit rate was likely due to vasomotor dysfunction, because it was abrogated by contractile exercise and at rest was only weakly related to erythrocyte deformability. PMID- 26123013 TI - [Fetal therapy and fetoscopy: A reality in clinical practice in 2015]. AB - Both the improvement of pathophysiological knowledge of major fetal anomalies and the development of therapeutic tools have allowed in some specific cases in utero therapy by foetoscopy. We discuss the state of art and recent advances for four major anomalies: twin-to-twin transfusion syndrome, congenital diaphragmatic hernia, myelomeningocele and lower urinary tract obstruction. Fetoscopic laser surgery for twin-to-twin transfusion syndrome has become the gold standard for treatment of TTS. In terms of fetal surgery, severe congenital diaphragmatic hernia and myelomeningocele are the two main indications, even if open fetal surgery is still the gold standard for management of myelomeningocele. New techniques using fetal cystoscopy are currently under development. Although the maternal morbidity associated with foetoscopy is low, preterm rupture of membranes and preterm delivery remain an important problem. Long-term evaluation of those neonates remains mandatory. PMID- 26123014 TI - [Risk of uterine rupture after cervical ripening with ballon catheter on uterus with previous cesarean section]. AB - OBJECTIVE: To evaluate the rate of uterine rupture after cervical ripening by mechanical methods using balloon catheter in patients with a previous cesarean section. MATERIALS AND METHODS: A literature search using the Medline database, Cochrane Library((r)) database. RESULTS: We identified 13 studies evaluating four types of ballon catheter. One thousand two hundred and seventy-eight patients underwent cervical ripening by balloon catheter and 8 (0.62%) cases of uterine rupture were reported. The vaginal delivery rate was 741/1278 (58%). CONCLUSION: The use of balloon catheters in case of previous cesarean section does not appear to be associated with an increased risk of uterine rupture compared with spontaneous labor. However, further studies are required to evaluate correctly this risk. PMID- 26123015 TI - [Odon device: A revolution in the field of assisted vaginal delivery?]. PMID- 26123016 TI - [Maternal knowledge of fetal movements in late pregnancy]. AB - OBJECTIVES: Evaluate knowledge of patients with late pregnancy on active foetal movements. PATIENTS AND METHOD: This prospective study has been carried out with volontary patients during the 41-week of gestation term consultation, with a questionnaire, at the obstetric gynecology departments of St-Etienne Hospital (CHU), Clermont-Ferrand Hospital (CHU), Roanne Hospital (CH) and Firminy Hospital (CH), from July 22nd, 2013 to September 14th, 2014. RESULTS: Few patients (17%) have been seen urgently by an obstetrician or a midwife in case of a decrease of the active foetal movements. Most patients (73.6%) wait 24hours to consult. More than 50% of women have not been informed on this topic before the birth. However, 86.84% of the patients are interested in being informed when they see their doctor. The easiest way would be to count the active foetal movements 3 times a day on a short period. CONCLUSION: There is still a lack of information on the active foetal movements. It remains a difficult topic because its definition is still subjective and the information has no protocol. PMID- 26123017 TI - The art of destruction: revealing the proteolytic capacity of bacterial caspase homologs. AB - Caspases are proteases that initiate and execute programmed cell death in animal tissues, thereby facilitating multicellular development and survival. While caspases are unique to metazoans and specifically cleave substrates at aspartic acid residues, homologs are found in protozoa, plants, algae, fungi, bacteria and archaea, and show specificity for basic residues. In this issue of Molecular Microbiology, Klemencic and colleagues present the first biochemical characterization of a bacterial caspase homolog, classified as an orthocaspase. By expressing the gene MaOC1 from the cyanobacterium Microcystis aeruginosa PCC 7806 in Escherichia coli, the authors discovered specificity for substrates with arginine in the P1 position. The protein requires autocatalytic processing to become active and is dependent on an intact histidine-cysteine dyad. These results significantly extend our knowledge of the specificities of bacterial caspase homologs, which are known to be highly diverse in protein domain architectures and active site mutations. Although bacterial programmed cell death is one possible area of action, the function of most bacterial caspase homologs remains unexplored. Cyanobacteria represent the best studied group in terms of prokaryotic caspase-like proteins both genomically and experimentally, and thereby provide a suitable platform for further investigations into activation, regulation and physiological roles of orthocaspases. PMID- 26123018 TI - Error correction and statistical analyses for intra-host comparisons of feline immunodeficiency virus diversity from high-throughput sequencing data. AB - BACKGROUND: Infection with feline immunodeficiency virus (FIV) causes an immunosuppressive disease whose consequences are less severe if cats are co infected with an attenuated FIV strain (PLV). We use virus diversity measurements, which reflect replication ability and the virus response to various conditions, to test whether diversity of virulent FIV in lymphoid tissues is altered in the presence of PLV. Our data consisted of the 3' half of the FIV genome from three tissues of animals infected with FIV alone, or with FIV and PLV, sequenced by 454 technology. RESULTS: Since rare variants dominate virus populations, we had to carefully distinguish sequence variation from errors due to experimental protocols and sequencing. We considered an exponential-normal convolution model used for background correction of microarray data, and modified it to formulate an error correction approach for minor allele frequencies derived from high-throughput sequencing. Similar to accounting for over-dispersion in counts, this accounts for error-inflated variability in frequencies - and quite effectively reproduces empirically observed distributions. After obtaining error corrected minor allele frequencies, we applied ANalysis Of VAriance (ANOVA) based on a linear mixed model and found that conserved sites and transition frequencies in FIV genes differ among tissues of dual and single infected cats. Furthermore, analysis of minor allele frequencies at individual FIV genome sites revealed 242 sites significantly affected by infection status (dual vs. single) or infection status by tissue interaction. All together, our results demonstrated a decrease in FIV diversity in bone marrow in the presence of PLV. Importantly, these effects were weakened or undetectable when error correction was performed with other approaches (thresholding of minor allele frequencies; probabilistic clustering of reads). We also queried the data for cytidine deaminase activity on the viral genome, which causes an asymmetric increase in G to A substitutions, but found no evidence for this host defense strategy. CONCLUSIONS: Our error correction approach for minor allele frequencies (more sensitive and computationally efficient than other algorithms) and our statistical treatment of variation (ANOVA) were critical for effective use of high-throughput sequencing data in understanding viral diversity. We found that co-infection with PLV shifts FIV diversity from bone marrow to lymph node and spleen. PMID- 26123019 TI - Can microcatheters be cleaned for reuse after NBCA embolization? Cleaning technique with gelatin sponge particles. AB - PURPOSE: To study a new technique for cleaning microcatheters for reuse after NBCA embolization ("NBCA"), and to evaluate the clinical reusability of microcatheters that were cleaned with gelatin sponge particles after NBCA. MATERIALS AND METHODS: Four cleaning solution flushes for microcatheters after NBCA injection-5 % glucose ("glucose") only, Lipiodol-glucose, gelatin sponge particles ("gelatin")-glucose, and Lipiodol-gelatin-glucose-were examined experimentally. These solutions were evaluated by performing three examinations: a microcatheter resistance test based on the time taken to pass water through the microcatheter, a microcatheter resistance test based on the ease of insertion of a microguidewire, and observations of the inner surfaces of the cylinders after NBCA. Microcatheters that had already been used in NBCA were cleaned using this new technique and then applied in 20 clinical sessions (19 patients). RESULTS: There was no significant difference in water passage time between the controls and the groups that received a gelatin flush. In the resistance test based on the insertion of a microguidewire, groups that received a gelatin flush showed significantly less resistance than the groups that did not receive a gelatin flush. Observations of the inner surfaces of the cylinders indicated that cleaning with gelatin can lead to inner surfaces that are almost indistinguishable from control surfaces in terms of cleanliness. All clinical procedures involving Lipiodol-gelatin-glucose flushes were performed without any technical difficulties or complications. CONCLUSIONS: Applying the new cleaning technique utilizing gelatin sponge particles to microcatheters after NBCA ensures that they are clean enough to be reused. PMID- 26123020 TI - T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. AB - The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2 induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities. PMID- 26123022 TI - Global-scale coherence modulation of radiation-belt electron loss from plasmaspheric hiss. AB - Over 40 years ago it was suggested that electron loss in the region of the radiation belts that overlaps with the region of high plasma density called the plasmasphere, within four to five Earth radii, arises largely from interaction with an electromagnetic plasma wave called plasmaspheric hiss. This interaction strongly influences the evolution of the radiation belts during a geomagnetic storm, and over the course of many hours to days helps to return the radiation belt structure to its 'quiet' pre-storm configuration. Observations have shown that the long-term electron-loss rate is consistent with this theory but the temporal and spatial dynamics of the loss process remain to be directly verified. Here we report simultaneous measurements of structured radiation-belt electron losses and the hiss phenomenon that causes the losses. Losses were observed in the form of bremsstrahlung X-rays generated by hiss-scattered electrons colliding with the Earth's atmosphere after removal from the radiation belts. Our results show that changes of up to an order of magnitude in the dynamics of electron loss arising from hiss occur on timescales as short as one to twenty minutes, in association with modulations in plasma density and magnetic field. Furthermore, these loss dynamics are coherent with hiss dynamics on spatial scales comparable to the size of the plasmasphere. This nearly global-scale coherence was not predicted and may affect the short-term evolution of the radiation belts during active times. PMID- 26123021 TI - Identification of cis-suppression of human disease mutations by comparative genomics. AB - Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity. PMID- 26123023 TI - A hemi-fission intermediate links two mechanistically distinct stages of membrane fission. AB - Fusion and fission drive all vesicular transport. Although topologically opposite, these reactions pass through the same hemi-fusion/fission intermediate, characterized by a 'stalk' in which only the outer membrane monolayers of the two compartments have merged to form a localized non-bilayer connection. Formation of the hemi-fission intermediate requires energy input from proteins catalysing membrane remodelling; however, the relationship between protein conformational rearrangements and hemi-fusion/fission remains obscure. Here we analysed how the GTPase cycle of human dynamin 1, the prototypical membrane fission catalyst, is directly coupled to membrane remodelling. We used intramolecular chemical crosslinking to stabilize dynamin in its GDP.AlF4(-)-bound transition state. In the absence of GTP this conformer produced stable hemi-fission, but failed to progress to complete fission, even in the presence of GTP. Further analysis revealed that the pleckstrin homology domain (PHD) locked in its membrane inserted state facilitated hemi-fission. A second mode of dynamin activity, fuelled by GTP hydrolysis, couples dynamin disassembly with cooperative diminishing of the PHD wedging, thus destabilizing the hemi-fission intermediate to complete fission. Molecular simulations corroborate the bimodal character of dynamin action and indicate radial and axial forces as dominant, although not independent, drivers of hemi-fission and fission transformations, respectively. Mirrored in the fusion reaction, the force bimodality might constitute a general paradigm for leakage-free membrane remodelling. PMID- 26123025 TI - Searching for biomarkers in feline chronic kidney disease: A new frontier. PMID- 26123026 TI - Tablet computer-based multimedia enhanced medical training improves performance in gastroenterology and endoscopy board style exam compared with traditional medical education. PMID- 26123024 TI - Molecular basis for 5-carboxycytosine recognition by RNA polymerase II elongation complex. AB - DNA methylation at selective cytosine residues (5-methylcytosine (5mC)) and their removal by TET-mediated DNA demethylation are critical for setting up pluripotent states in early embryonic development. TET enzymes successively convert 5mC to 5 hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), with 5fC and 5caC subject to removal by thymine DNA glycosylase (TDG) in conjunction with base excision repair. Early reports indicate that 5fC and 5caC could be stably detected on enhancers, promoters and gene bodies, with distinct effects on gene expression, but the mechanisms have remained elusive. Here we determined the X-ray crystal structure of yeast elongating RNA polymerase II (Pol II) in complex with a DNA template containing oxidized 5mCs, revealing specific hydrogen bonds between the 5-carboxyl group of 5caC and the conserved epi-DNA recognition loop in the polymerase. This causes a positional shift for incoming nucleoside 5'-triphosphate (NTP), thus compromising nucleotide addition. To test the implication of this structural insight in vivo, we determined the global effect of increased 5fC/5caC levels on transcription, finding that such DNA modifications indeed retarded Pol II elongation on gene bodies. These results demonstrate the functional impact of oxidized 5mCs on gene expression and suggest a novel role for Pol II as a specific and direct epigenetic sensor during transcription elongation. PMID- 26123027 TI - Anti-angiogenic effect of metformin in human liver carcinogenesis related to metabolic syndrome. PMID- 26123028 TI - GABAA receptor-mediated feedforward and feedback inhibition differentially modulate the gain and the neural code transformation in hippocampal CA1 pyramidal cells. AB - Diverse variety of hippocampal interneurons exists in the CA1 area, which provides either feedforward (FF) or feedback (FB) inhibition to CA1 pyramidal cell (PC). However, how the two different inhibitory network architectures modulate the computational mode of CA1 PC is unknown. By investigating the CA3 PC rate-driven input-output function of CA1 PC using in vitro electrophysiology, in vitro-simulation of inhibitory network, and in silico computational modeling, we demonstrated for the first time that GABAA receptor-mediated FF and FB inhibition differentially modulate the gain, the spike precision, the neural code transformation and the information capacity of CA1 PC. Recruitment of FF inhibition buffered the CA1 PC spikes to theta-frequency regardless of the input frequency, abolishing the gain and making CA1 PC insensitive to its inputs. Instead, temporal variability of the CA1 PC spikes was increased, promoting the rate-to-temporal code transformation to enhance the information capacity of CA1 PC. In contrast, the recruitment of FB inhibition sub-linearly transformed the input rate to spike output rate with high gain and low spike temporal variability, promoting the rate-to-rate code transformation. These results suggest that GABAA receptor-mediated FF and FB inhibitory circuits could serve as network mechanisms for differentially modulating the gain of CA1 PC, allowing CA1 PC to switch between different computational modes using rate and temporal codes ad hoc. Such switch will allow CA1 PC to efficiently respond to spatio-temporally dynamic inputs and expand its computational capacity during different behavioral and neuromodulatory states in vivo. PMID- 26123029 TI - Serum eye drop preparation in Australia: Current manufacturing practice. AB - Serum eye drops are used to treat diseases such as dry eye syndrome (keratoconjunctivitis sicca), a disease of the surface of the eye that results in an unstable tear film. Patients are referred to the Australian Red Cross Blood Service by ophthalmologists for autologous serum eye drops when other therapies such as artificial tears or topical immunosuppressive agents have failed. In order to manufacture autologous serum eye drops, whole blood is collected from the patients using standard blood collection procedures. The blood is then allowed to clot to produce serum and processed into 20% serum eye drops, which are then returned to the patient for their own use. The eye drops are packaged into a long length of tubing, which is then heat-sealed to produce single-use segments. The demand for serum eye drops in Australia is increasing every year, with a 30% increase in the past 12 months. PMID- 26123030 TI - The effect of sexually transmitted co-infections on HIV viral load amongst individuals on antiretroviral therapy: a systematic review and meta-analysis. AB - BACKGROUND: Antiretroviral therapy (ART) markedly reduces HIV transmission, and testing and treatment programs have been advocated as a method for decreasing transmission at the population level. Little is known, however, about the extent to which sexually transmitted infections (STIs), which increase the HIV infectiousness of untreated individuals, may decrease the effectiveness of treatment as prevention. METHODS: We searched major bibliographic databases to August 12(th), 2014 and identified studies reporting differences in HIV transmission rate or in viral load between individuals on ART who either were or were not co-infected with another STI. We used hierarchical Bayesian models to estimate viral load differences between individuals with and without STI co infections. RESULTS: The search strategy retrieved 1630 unique citations of which 14 studies (reporting on 4607 HIV viral load measurements from 2835 unique individuals) met the inclusion criteria. We did not find any suitable studies that estimated transmission rates directly in both groups. Our meta-analysis of HIV viral load measurements among treated individuals did not find a statistically significant effect of STI co-infection; viral loads were, on average, 0.11 log10 (95% CI -0.62 to 0.83) higher among co-infected versus non-co infected individuals. CONCLUSIONS: Direct evidence about the effects of STI co infection on transmission from individuals on ART is very limited. Available data suggests that the average effect of STI co-infection on HIV viral load in individuals on ART is less than 1 log10 difference, and thus unlikely to decrease the effectiveness of treatment as prevention. However, there is not enough data to rule out the possibility that particular STIs pose a larger threat. PMID- 26123032 TI - Oxidative addition of the C-I bond on aluminum nanoclusters. AB - Energetics and the in-depth reaction mechanism of the oxidative addition step of the cross-coupling reaction are studied in the framework of density functional theory (DFT) on aluminum nanoclusters. Aluminum metal in its bulk state is totally inactive towards carbon-halogen bond dissociation but selected Al nanoclusters (size ranging from 3 to 20 atoms) have shown a significantly lower activation barrier towards the oxidative addition reaction. The calculated energy barriers are lower than the gold clusters and within a comparable range with the conventional and most versatile Pd catalyst. Further investigations reveal that the activation energies and other reaction parameters are highly sensitive to the geometrical shapes and electronic structures of the clusters rather than their size, imposing the fact that comprehensive studies on aluminum clusters can be beneficial for nanoscience and nanotechnology. To understand the possible reaction mechanism in detail, the reaction pathway is investigated with the ab initio Born Oppenheimer Molecular Dynamics (BOMD) simulation and the Natural Bond Orbital (NBO) analysis. In short, our theoretical study highlights the thermodynamic and kinetic details of C-I bond dissociation on aluminum clusters for future endeavors in cluster chemistry. PMID- 26123031 TI - Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor. AB - BACKGROUND: INCB018424 is a novel, potent Janus kinase (JAK)1/JAK2 inhibitor that blocks signal transduction of multiple proinflammatory cytokines. OBJECTIVES: To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of topical INCB018424 phosphate cream in patients with plaque psoriasis. METHODS: Topical INCB018424 phosphate 1.0% or 1.5% cream was applied once daily (QD) or twice daily (BID) for 4 weeks to 2-20% body surface area in five sequential cohorts of five patients aged 18-65 years. Target lesions were scored on a scale of 0-4 for erythema, scaling and thickness. Additionally, the overall disease activity in each patient was measured using Physician's Global Assessment. INCB018424 concentrations were measured in plasma, and cytokine stimulated phosphorylated signal transducer and activator of transcription 3 phosphorylation (pSTAT3) levels in peripheral blood cells were evaluated. Pretreatment and post-treatment skin biopsies were compared with healthy skin, including evaluation of histopathology, immunohistochemistry and mRNA expression. RESULTS: Treatment with INCB018424 phosphate cream either 1.0% QD or 1.5% BID resulted in improvements in lesion scores. No significant inhibition of pSTAT3 in peripheral blood cells was observed following topical application, consistent with the generally low steady-state plasma concentrations of INCB018424 measured. Transcriptional markers of immune cell lineage/activation in lesional skin were reduced by topical INCB018424, with correlations observed between clinical improvement and decreases in markers of T helper 17 lymphocyte activation, dendritic-cell activation and epidermal hyperplasia. INCB018424 treatment reduced epidermal hyperplasia and dermal inflammation in most patient samples, with reductions in CD3, CD11c, Ki67 and keratin 16 observed by immunohistochemical analysis. CONCLUSIONS: Topical INCB018424 dosed for 28 days QD or BID is pharmacologically active in patients with active psoriasis and modulates proinflammatory cytokines in the pathogenesis of psoriatic lesions. PMID- 26123033 TI - European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG registry): Study Protocol for a Prospective Clinical Registry and Proposal of Classification of Postoperative Complications. AB - BACKGROUND: Clinical evidence in coronary surgery is usually derived from retrospective, single institutional series. This may introduce significant biases in the analysis of critical issues in the treatment of these patients. In order to avoid such methodological limitations, we planned a European multicenter, prospective study on coronary artery bypass grafting, the E-CABG registry. DESIGN: The E-CABG registry is a multicenter study and its data are prospectively collected from 13 centers of cardiac surgery in university and community hospitals located in six European countries (England, Italy, Finland, France, Germany, Sweden). Data on major and minor immediate postoperative adverse events will be collected. Data on late all-cause mortality, stroke, myocardial infarction and repeat revascularization will be collected during a 10-year follow up period. These investigators provided a score from 0 to 10 for any major postoperative adverse events and their rounded medians were used to stratify the severity of these complications in four grades. The sum of these scores for each complication/intervention occurring after coronary artery bypass grafting will be used as an additive score for further stratification of the prognostic importance of these events. DISCUSSION: The E-CABG registry is expected to provide valuable data for identification of risk factors and treatment strategies associated with suboptimal outcome. These information may improve the safety and durability of coronary artery bypass grafting. The proposed classification of postoperative complications may become a valuable research tool to stratify the impact of such complications on the outcome of these patients and evaluate the burden of resources needed for their treatment. CLINICAL TRIALS NUMBER: NCT02319083. PMID- 26123034 TI - Predictors of frequent emergency department visits among rural older adults in Ontario using the Resident Assessment Instrument-Home Care. AB - OBJECTIVE: To describe factors predicting frequent emergency department (ED) use among rural older adults receiving home care services in Ontario, Canada. DESIGN: A cross-sectional examination of Ontario hospital administrative data linked to provincial home care data compares frequent ED users (i.e. >4 visits/year) with regular users (i.e. 1-3 visits/year) and no ED use over a 1-year period. Multiple logistic regression analysis was performed using independent variables from home care health assessments. MAIN OUTCOME MEASURES: Predictors of frequent ED use among rural older adults receiving home care services using adjusted odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: Ontario's rural home care clients visited the ED an average of 4.9 times (SD = 11.9) over a year. Frequent ED users were observed in 170 cases per 1000 home care clients. Congestive heart failure was the most frequently cited reason for frequent ED use; however, it was not a main driver in the adjusted model. Frequent ED use was predicted by younger age (i.e. 60-74 years) (OR = 1.9; 95% CI, 1.7-2.2), a recent ED visit in the last 3 months (OR = 1.5; 95% CI, 1.4-1.7), regularly taking >9 medications (OR = 1.5; 95% CI, 1.3-1.6), and poor self-rated health (OR = 1.4; 95% CI, 1.2-1.5). CONCLUSION: Despite popular assumptions, the main drivers for frequent ED use among rural older adults in Ontario included a mix of sociodemographic and clinical characteristics, rather than disease diagnoses. PMID- 26123037 TI - The effect of nutrition education on nutrition-related health outcomes of Aboriginal and Torres Strait Islander people: a systematic review. AB - OBJECTIVE: To determine the effectiveness of nutrition education on improving nutrition-related health outcomes in Aboriginal and Torres Strait Islander people. METHODS: Databases Medline, Cinahl, Scopus, ProQuest and ATSI Health were searched in September 2013 to identify nutrition education intervention studies in Indigenous Australian populations. Peer-reviewed and grey literature with nutrition-related biochemical or anthropometrical health outcomes were included in a qualitative comparative analysis. RESULTS: Of 1,162 studies identified from the search, six met inclusion criteria. Three studies were from a remote setting and three from an urban setting. Four of the six education interventions were shown to improve body mass index (BMI) and/or nutritional biochemical indicators. Components of the nutrition education interventions showing greatest effect included cooking skills workshops, group education sessions and store interventions. Community involvement in the program design was most strongly associated with a positive effect on BMI. CONCLUSION: Nutrition education had some effect in reducing biochemical and anthropometric risk factors for chronic disease in Indigenous Australians. IMPLICATIONS: Nutrition education can be considered as part of a range of strategies to improve nutrition-related health for Aboriginal and Torres Strait Islander people. Further evidence is needed to strengthen this recommendation. PMID- 26123038 TI - Prostate cancer: Transdifferentiate to prevail. PMID- 26123039 TI - Kidney cancer: Single nucleotide polymorphisms in mRCC-is their time up? PMID- 26123040 TI - Genetics: Known prostate cancer risk loci-guilty by association? PMID- 26123041 TI - Kidney cancer: Tumour versus nephron gene expression yields survival score. PMID- 26123043 TI - Differential diagnosis of suspected deep tissue injury. AB - Deep tissue injury (DTI) can be difficult to diagnose because many other skin and wound problems can appear as purple skin or rapidly appearing eschar. The diagnosis of DTI begins with a thorough history to account for times of exposure to pressure, such as 'time down' at the scene or time during which the patient was flat and could not respond. Patients with light skin tones present with classic skin discolouration of purple or maroon tissue, a defined border around the area of injury, and often surrounding erythema is evident. Persistent erythema and hyperpigmentation, rather than blanching, should be used to determine pressure injury in dark skin tone patients. Differential diagnosis includes stage 2 pressure ulcers, incontinence-associated dermatitis, skin tears, bruising, haematoma, venous engorgement, arterial insufficiency, necrotising fasciitis and terminal skin ulcers. Many skin problems can also have a purple hue or rapidly developing eschar, and a working knowledge of dermatology is needed. PMID- 26123042 TI - Spinal muscular atrophy phenotype is ameliorated in human motor neurons by SMN increase via different novel RNA therapeutic approaches. AB - Spinal muscular atrophy (SMA) is a primary genetic cause of infant mortality due to mutations in the Survival Motor Neuron (SMN) 1 gene. No cure is available. Antisense oligonucleotides (ASOs) aimed at increasing SMN levels from the paralogous SMN2 gene represent a possible therapeutic strategy. Here, we tested in SMA human induced pluripotent stem cells (iPSCs) and iPSC-differentiated motor neurons, three different RNA approaches based on morpholino antisense targeting of the ISSN-1, exon-specific U1 small nuclear RNA (ExSpeU1), and Transcription Activator-Like Effector-Transcription Factor (TALE-TF). All strategies act modulating SMN2 RNA: ASO affects exon 7 splicing, TALE-TF increase SMN2 RNA acting on the promoter, while ExSpeU1 improves pre-mRNA processing. These approaches induced up-regulation of full-length SMN mRNA and differentially affected the Delta-7 isoform: ASO reduced this isoform, while ExSpeU1 and TALE-TF increased it. All approaches upregulate the SMN protein and significantly improve the in vitro SMA motor neurons survival. Thus, these findings demonstrate that therapeutic tools that act on SMN2 RNA are able to rescue the SMA disease phenotype. Our data confirm the feasibility of SMA iPSCs as in vitro disease models and we propose novel RNA approaches as potential therapeutic strategies for treating SMA and other genetic neurological disorders. PMID- 26123044 TI - Transmission of scrapie prions to primate after an extended silent incubation period. AB - Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10 year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie. PMID- 26123045 TI - Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy. AB - BACKGROUND: Recurrent chest pain in the absence of coronary artery disease is a common problem which sometimes leads to excess use of medical care. Although many studies have examined the causes of pain in these patients, few clinical trials have evaluated treatment. This is an update of a Cochrane review originally published in 2005 and last updated in 2010. The studies reviewed in this paper provide an insight into the effectiveness of psychological interventions for this group of patients. OBJECTIVES: To assess the effects of psychological interventions for chest pain, quality of life and psychological parameters in people with non-specific chest pain. SEARCH METHODS: We searched the Cochrane Library (CENTRAL, Issue 4 of 12, 2014 and DARE Issue 2 of 4, 2014), MEDLINE (OVID, 1966 to April week 4 2014), EMBASE (OVID, 1980 to week 18 2014), CINAHL (EBSCO, 1982 to April 2014), PsycINFO (OVID, 1887 to April week 5 2014) and BIOSIS Previews (Web of Knowledge, 1969 to 2 May 2014). We also searched citation lists and contacted study authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) with standardised outcome methodology that tested any form of psychotherapy for chest pain with normal anatomy. Diagnoses included non-specific chest pain (NSCP), atypical chest pain, syndrome X or chest pain with normal coronary anatomy (as either inpatients or outpatients). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data and assessed quality of studies. We contacted trial authors for further information about the included RCTs. MAIN RESULTS: We included two new papers, one of which was an update of a previously included study. Therefore, a total of 17 RCTs with 1006 randomised participants met the inclusion criteria, with the one new study contributing an additional 113 participants. There was a significant reduction in reports of chest pain in the first three months following the intervention: random-effects relative risk = 0.70 (95% CI 0.53 to 0.92). This was maintained from three to nine months afterwards: relative risk 0.59 (95% CI 0.45 to 0.76). There was also a significant increase in the number of chest pain-free days up to three months following the intervention: mean difference (MD) 3.00 (95% CI 0.23 to 5.77). This was associated with reduced chest pain frequency (random-effects MD -2.26, 95% CI -4.41 to -0.12) but there was no evidence of effect of treatment on chest pain frequency from three to twelve months (random-effects MD -0.81, 95% CI -2.35 to 0.74). There was no effect on severity (random-effects MD -4.64 (95% CI -12.18 to 2.89) up to three months after the intervention. Due to the nature of the main interventions of interest, it was impossible to blind the therapists as to whether the participant was in the intervention or control arm. In addition, in three studies the blinding of participants was expressly forbidden by the local ethics committee because of issues in obtaining fully informed consent . For this reason, all studies had a high risk of performance bias. In addition, three studies were thought to have a high risk of outcome bias. In general, there was a low risk of bias in the other domains. However, there was high heterogeneity and caution is required in interpreting these results. The wide variability in secondary outcome measures made it difficult to integrate findings from studies. AUTHORS' CONCLUSIONS: This Cochrane review suggests a modest to moderate benefit for psychological interventions, particularly those using a cognitive-behavioural framework, which was largely restricted to the first three months after the intervention. Hypnotherapy is also a possible alternative. However, these conclusions are limited by high heterogeneity in many of the results and low numbers of participants in individual studies. The evidence for other brief interventions was less clear. Further RCTs of psychological interventions for NSCP with follow-up periods of at least 12 months are needed. PMID- 26123046 TI - Extending the validity of the Feeding Practices and Structure Questionnaire. AB - BACKGROUND: Feeding practices are commonly examined as potentially modifiable determinants of children's eating behaviours and weight status. Although a variety of questionnaires exist to assess different feeding aspects, many lack thorough reliability and validity testing. The Feeding Practices and Structure Questionnaire (FPSQ) is a tool designed to measure early feeding practices related to non-responsive feeding and structure of the meal environment. Face validity, factorial validity, internal reliability and cross-sectional correlations with children's eating behaviours have been established in mothers with 2-year-old children. The aim of the present study was to further extend the validity of the FPSQ by examining factorial, construct and predictive validity, and stability. METHODS: Participants were from the NOURISH randomised controlled trial which evaluated an intervention with first-time mothers designed to promote protective feeding practices. Maternal feeding practices (FP) and child eating behaviours were assessed when children were aged 2 years and 3.7 years (n = 388). Confirmatory Factor analysis, group differences, predictive relationships, and stability were tested. RESULTS: The original 9-factor structure was confirmed when children were aged 3.7 +/- 0.3 years. Cronbach's alpha was above the recommended 0.70 cut-off for all factors except Structured Meal Timing, Over Restriction and Distrust in Appetite which were 0.58, 0.67 and 0.66 respectively. Allocated group differences reflected behaviour consistent with intervention content and all feeding practices were stable across both time points (range of r = 0.45-0.70). There was some evidence for the predictive validity of factors with 2 FP showing expected relationships, 2 FP showing expected and unexpected relationships and 5 FP showing no relationship. CONCLUSIONS: Reliability and validity was demonstrated for most subscales of the FPSQ. Future validation is warranted with culturally diverse samples and with fathers and other caregivers. The use of additional outcomes to further explore predictive validity is recommended as well as testing test-retest reliability of the questionnaire. PMID- 26123047 TI - Tree Nut consumption is associated with better adiposity measures and cardiovascular and metabolic syndrome health risk factors in U.S. Adults: NHANES 2005-2010. AB - INTRODUCTION: Previous research has shown inconsistencies in the association of tree nut consumption with risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS). OBJECTIVE: To determine the association of tree nut consumption with risk factors for CVD and for MetS in adults. METHODS: NHANES 2005-2010 data were used to examine the associations of tree nut consumption with health risks in adults 19+ years (n = 14,386; 51% males). Tree nuts were: almonds, Brazil nuts, cashews, filberts [hazelnuts], macadamias, pecans, pine nuts, pistachios, and walnuts. Group definitions were non-consumers < 1/4 ounce/day and consumers of >= 1/4 ounce/day tree nuts using data from 24-h dietary recalls. Means and ANOVA (covariate adjusted) were determined using appropriate sample weights. Using logistic regression, odds ratios of being overweight (OW)/obese (OB) (body mass index [BMI] >25/<30 and >=30, respectively) and having CVRF or MetS, were determined. RESULTS: Tree nut consumption was associated with lower BMI (p = 0.004), waist circumference (WC) (p = 0.008), systolic blood pressure (BP) (p = 0.001), Homeostatic Model Assessment-Insulin Resistance (p = 0.043), and higher high density lipoprotein-cholesterol (p = 0.022), compared with no consumption, and a lower likelihood of OB (-25%), OW/OB (-23%), and elevated WC (-21%). CONCLUSIONS: Tree nut consumption was associated with better weight status and some CVRF and MetS components. PMID- 26123049 TI - Anti-VEGF Anticancer Drugs: Mind the Hypertension. AB - The introduction of therapies that inhibit tumor angiogenesis and particularly target to vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) (VEGF inhibitors/VEGFi) have revolutionized the treatment of various cancer types. Although their clinical benefit can be optimal for cancer-affected patients, the safety of these targeted agents is of special concern especially for longer-term adjuvant or maintenance treatment. Importantly, VEGFi therapy has been significantly associated with hypertension (HTN) as an adverse effect and therefore the control of blood pressure (BP) after the administration of these drugs remains a challenging matter to be faced. The aim of this review is to summarize studies which investigate the association of VEGFi agents with HTN manifestation and the possible risks associated with this complication. Additionally, given that the optimal management of HTN caused by VEGFi remains obscure, this review will focus on prevention strategies including BP monitoring plans and propose potential therapeutic approaches. PMID- 26123048 TI - Quantitative T2 relaxation time and magnetic transfer ratio predict endplate biochemical content of intervertebral disc degeneration in a canine model. AB - BACKGROUND: Direct measurement of disc biochemical content is impossible in vivo. Therefore, magnetic resonance imaging (MRI) is used to evaluate disc health. Unfortunately, current clinical imaging techniques do not adequately assess degeneration, especially in the early stage of cartilage endplate, and subchondral bone zone (CEPZ). Therefore, this study aimed to investigate the sensitivity of quantitative MRI methods, namely T2 relaxation time and Magnetic Transfer Ratio (MTR), to identify early disc degeneration, especially for the CEPZ, using an experimental canine model of intervertebral disc injury and to investigate their sensitivity in depicting biochemically and histologically controlled degenerative changes in the disc. METHODS: Sixteen juvenile dogs underwent iatrogenic annular disruption via stab incisions. The animals underwent repeated 3.0 T MR imaging, and were sacrificed 4, 8, and 12 weeks post operatively. A continuous rectangle drawing method was used to select regions of interest for the intervertebral disc from the cephalic to caudal CEPZ including the vertebrae, nucleus pulposus (NP) and annulus fibrosus (AF), which resembled pixel measurement for imaging analysis. Presence of degenerative changes was controlled by biochemical and histological analyses. The correlations between histological score, biochemical content, and quantitative MRI signal intensities were also analyzed. RESULTS: Both T2 relaxation time and MTR values changed for CEPZ, NP, and AF tissues within 12 weeks. T2 relaxation time values decreased significantly in the NP, AF, and CEPZ separately at pre-operation, 4, 8, and 12 weeks when compared each time (P < 0.05). MTR values showed no significant differences for the CEPZ between 8 and 4 weeks or 12 weeks, or compared to pre operative values; there were significant differences for the AF. Biochemical and histological analysis showed changes consistent with quantitative MRI signal intensities for early stage degeneration. CONCLUSIONS: Early traumatic or degenerative changes are detectable with both T2 and MTR. T2 changes were more sensitive to the differences in disc status, especially for the CEPZ. Since T2 and MTR reflect different disc properties, performing both imaging under the same conditions would be helpful in the evaluation of disc degeneration. The continuous rectangle drawing can be a sensitive method to detect the changes of CEPZ. PMID- 26123050 TI - Biotransformation of Flavokawains A, B, and C, Chalcones from Kava (Piper methysticum), by Human Liver Microsomes. AB - The in vitro metabolism of flavokawains A, B, and C (FKA, FKB, FKC), methoxylated chalcones from Piper methysticum, was examined using human liver microsomes. Phase I metabolism and phase II metabolism (glucuronidation) as well as combined phase I+II metabolism were studied. For identification and structure elucidation of microsomal metabolites, LC-HRESIMS and NMR techniques were applied. Major phase I metabolites were generated by demethylation in position C-4 or C-4' and hydroxylation predominantly in position C-4, yielding FKC as phase I metabolite of FKA and FKB, helichrysetin as metabolite of FKA and FKC, and cardamonin as metabolite of FKC. To an even greater extent, flavokawains were metabolized in the presence of uridine diphosphate (UDP) glucuronic acid by microsomal UDP glucuronosyl transferases. For all flavokawains, monoglucuronides (FKA-2'-O glucuronide, FKB-2'-O-glucuronide, FKC-2'-O-glucuronide, FKC-4-O-glucuronide) were found as major phase II metabolites. The dominance of generated glucuronides suggests a role of conjugated chalcones as potential active compounds in vivo. PMID- 26123051 TI - Framing optional genetic testing in the context of mandatory newborn screening tests. AB - BACKGROUND: Parents are increasingly faced with decisions about optional newborn bloodspot screening (NBS) despite no consistent policy for communicating information about such testing. We examined whether framing optional NBS alongside mandatory NBS influenced intention to participate in optional NBS. METHODS: For this Internet-administered study, 2,991 adults read a hypothetical vignette in which optional NBS for Duchenne muscular dystrophy (DMD) was either presented by itself (in isolation), alongside a description including the total number of mandatory NBS tests ("bundled" mandatory context), or alongside a listing of each mandatory NBS test ("unbundled" mandatory context). We assessed associations with participants' intended participation using ordered logistic regression models, and associations with attitudes towards optional DMD NBS and subjective norms using Analysis of Variance. RESULTS: Participants were more likely to choose optional DMD NBS if they also read information about mandatory NBS (either bundled or unbundled) versus when DMD NBS was presented in isolation. Participants who read about optional DMD NBS in isolation also reported such testing to be less important and that they would worry more about the results than those who also saw mandatory NBS information. CONCLUSIONS: Future NBS programs should pay attention to the framing of optional testing communication, as it influences parental behavior. Predictors of NBS uptake will become increasingly important as NBS programs continue expanding. PMID- 26123052 TI - Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy. AB - INTRODUCTION: Beta-propeller protein associated neurodegeneration (BPAN) is associated with mutations in the WD repeat domain 45 (WDR45) gene on chromosome Xp11 resulting in reduced autophagic flux. This study describes the clinical and neuropathological features of a female 51 year old BPAN case. The clinical history includes learning disability and progressive gait abnormalities since childhood followed by progressive dystonic features in young adulthood. Brain imaging revealed generalised brain atrophy and bilateral mineralisation of the globus pallidus and substantia nigra. RESULTS: The major pathological findings were observed in the substantia nigra with excess iron deposition, gliosis, axonal swellings and severe neuronal loss. Iron deposition was also observed in the globus pallidus. There was extensive hyperphosphorylated-tau deposition in the form of neurofibrillary tangles, pre-tangles and neuropil threads. Furthermore, histological studies and immunoblotting confirmed a mixed Alzheimer type 3-and 4-repeat tau pathology. Microtubule-associated protein 1A/1B-light chain 3 (LC3) immunoblotting of brain homogenates indicated autophagic activity and may support the role of WDR45 in autophagy. CONCLUSIONS: The widespread Alzheimer-type tau pathology in this disease indicates that this should be considered as a tauopathy and adds further support to the proposal that impaired autophagy may have a role in tauopathies. PMID- 26123053 TI - Short communication: phylodynamics analysis of the human immunodeficiency virus type 1 envelope gene in mother and child pairs. AB - Characterizing the impact of HIV transmission routes on viral genetic diversity can improve the understanding of the mechanisms of virus evolution and adaptation. HIV vertical transmission can occur in utero, during delivery, or while breastfeeding. The present study investigated the phylodynamics of the HIV 1 env gene in mother-to-child transmission by analyzing one chronically infected pair from Brazil and three acutely infected pairs from Zambia, with three to five time points. Sequences from 25 clones from each sample were obtained and aligned using Clustal X. ML trees were constructed in PhyML using the best evolutionary model. Bayesian analyses testing the relaxed and strict molecular clock were performed using BEAST and a Bayesian Skyline Plot (BSP) was construed. The genetic variability of previously described epitopes was investigated and compared between each individual time point and between mother and child sequences. The relaxed molecular clock was the best-fitted model for all datasets. The tree topologies did not show differentiation in the evolutionary dynamics of the virus circulating in the mother from the viral population in the child. In the BSP, the effective population size was more constant in time in the chronically infected patients while in the acute patients it was possible to detect bottlenecks. The genetic variability within viral epitopes recognized by the human immune system was considerably higher among the chronically infected pair in comparison with acutely infected pairs. These results contribute to a better understanding of HIV-1 evolutionary dynamics in mother-to-child transmission. PMID- 26123055 TI - Fitness Cost of Methoxyfenozide and the Effects of Its Sublethal Doses on Development, Reproduction, and Survival of Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae). AB - In the present study, two experiments were designed to investigate the lethal and sublethal effects of methoxyfenozide on Spodoptera litura (F.). The first experiment was conducted to explore the fitness cost of methoxyfenozide resistance in a methoxyfenozide-resistant strain (selected with methoxyfenozide for 13 consecutive generations), leading to resistance ratio to methoxyfenozide 83.0- and 2359-fold higher when compared to the field and susceptible populations with a fitness cost of 0.17. In the second experiment, second instars of the susceptible strain were treated with sublethal doses of methoxyfenozide (LC30, LC20, and LC10) by diet incorporation for larval feeding for 3 days. It was observed that higher concentrations of methoxyfenozide significantly prolonged the larval and pupal development time of S. litura as compared to the control treatment. The number of eggs per female, egg hatching, sex ratio, and longevity of adults of methoxyfenozide-treated groups was greatly reduced as compared to untreated S. litura. Our data clearly indicated that fitness cost of methoxyfenozide and its sublethal effects on S. litura has an important impact on its population dynamics. PMID- 26123054 TI - Prediction of length and diameter of hamstring tendon autografts for knee ligament surgery in Caucasians. AB - PURPOSE: Prediction of hamstring tendon autograft size facilitates preoperative planning of knee ligament surgery and may reduce the need for allografts in complex knee reconstructions. The aim of this study was to analyse whether length and diameter of hamstring tendon autografts can be predicted preoperatively with anthropometric parameters and patient characteristics. METHODS: In this observational study, 725 consecutive Caucasian patients scheduled for ACL reconstruction were included. Preoperatively gender, age, height and weight were recorded. After harvest, tendon lengths of both gracilis and semitendinosus tendons were measured. Diameter of the final four-strand hamstring autograft was recorded. Relationship between length and diameter of tendon grafts and different anthropometric parameters were assed by linear and logistic regression analyses. RESULTS: Mean lengths of the semitendinosus and gracilis tendon autografts were 28.9 +/- 3.1 and 27.7 +/- 3.0 cm, respectively. Length of the gracilis and semitendinosus grafts was independently related to patient height. Female gender was correlated with smaller graft diameter. One in nine female patients had a diameter <8 mm. The ratio in men was 1 in 36. CONCLUSION: Hamstring autograft length and size can be predicted in Caucasians. Length of the gracilis and semitendinosus tendons was related to patient height. Smaller graft diameter was related to female gender. LEVEL OF EVIDENCE: II. PMID- 26123056 TI - Coccinellidae Parasitoids in Brazil: Neglected Species in a Mega-Diverse Country. AB - Current knowledge on coccinellids is primarily focused on their role as natural enemies of soft-bodied insects. However, there is a great diversity of coccinellid parasitoid species that are less studied. Here, we describe new records of coccinellid parasitoids with emphasis on new host-parasitoid interactions in 11 sample sites in Brazil. We collected 122 coccinellid individuals parasitized by six species of parasitoids in the Cerrado and in the Atlantic Rainforest biomes. New records of coccinellid parasitoids and host associations, expansion of habitat ranges and interactions are discussed focusing on the lack of basic information on these interactions in Brazil. PMID- 26123057 TI - Aggressive venous thromboembolism prophylaxis reduces VTE events in vascular surgery patients. AB - OBJECTIVE: Venous thromboembolism (VTE) is a potentially preventable complication following surgery. There is variation with regard to the most effective mode of prophylaxis. We sought to determine if an aggressive approach to VTE prophylaxis would reduce VTE rates on the inpatient vascular surgical service. METHODS: Vascular inpatients from a single institution from July 2010 to March 2013 were included in the analysis. A protocol for VTE prophylaxis was implemented on the inpatient vascular surgical service in November 2011. This included subcutaneous (SQ) heparin initiation within 24 h of admission unless deemed inappropriate by the attending, as well as intermittent compression devices (ICD) and compression stockings (CS). The rate of VTE was compared prior to and following the intervention. Patients were compared using AHRQ comorbidity categories, APR-DRG severity of illness, insurance status, and principle procedure. T-tests were used to compare continuous variables and chi-square analysis used to compare categorical variables. RESULTS: There were 1483 vascular patients in the pre intervention group and 1652 patients in the post-intervention group. The rate of pharmacologic prophylaxis was 52.57% pre-intervention compared to 69.33% post intervention (p < 0.001). The rate of pharmacologic or mechanical prophylaxis was 91.76% pre-intervention compared to 93.10% post-intervention (p = 0.54). The overall rate of VTE prior to the intervention was 1.49% compared to after intervention which was 0.38% (p = 0.033). The DVT rate prior to intervention was 1.09% vs 0.189% after intervention (p = 0.0214). The rate of pulmonary embolism trended towards a significant reduction with the intervention (0.681% vs 0.189%, p = 0.095). There were no statistically significant differences in patient groups based on gender, comorbidity category, severity of illness, or insurance type. CONCLUSIONS: The overall rate of VTE was reduced by 75% after the initiation of a standard protocol for pharmacologic VTE prophylaxis. These findings justify an aggressive approach to VTE prophylaxis in vascular surgery patients. PMID- 26123058 TI - A computational fluid-structure interaction model of the blood flow in the healthy and varicose saphenous vein. AB - OBJECTIVE: Varicose vein has become enlarged and twisted and, consequently, has lost its mechanical strength. As a result of the varicose saphenous vein (SV) mechanical alterations, the hemodynamic parameters of the blood flow, such as blood velocity as well as vein wall stress and strain, would change accordingly. However, little is known about stress and strain and there consequences under experimental conditions on blood flow and velocity within normal and varicose veins. In this study, a three-dimensional (3D) computational fluid-structure interaction (FSI) model of a human healthy and varicose SVs was established to determine the hemodynamic characterization of the blood flow as a function of vein wall mechanical properties, i.e. elastic and hyperelastic. METHODS: The mechanical properties of the human healthy and varicose SVs were experimentally measured and implemented into the computational model. The fully coupled fluid and structure models were solved using the explicit dynamics finite element code LS-DYNA. RESULTS: The results revealed that, regardless of healthy and varicose, the elastic walls reach to the ultimate strength of the vein wall, whereas the hyperelastic wall can tolerate more stress. The highest von Mises stress compared to the healthy ones was seen in the elastic and hyperelastic varicose SVs with 1.412 and 1.535 MPa, respectively. In addition, analysis of the resultant displacement in the vein wall indicated that the varicose SVs experienced a higher displacement compared to the healthy ones irrespective of elastic and hyperelastic material models. The highest blood velocity was also observed for the healthy hyperelastic SV wall. CONCLUSION: The findings of this study may have implications not only for determining the role of the vein wall mechanical properties in the hemodynamic alterations of the blood, but also for employing as a null information in balloon-angioplasty and bypass surgeries. PMID- 26123059 TI - TMFoldRec: a statistical potential-based transmembrane protein fold recognition tool. AB - BACKGROUND: Transmembrane proteins (TMPs) are the key components of signal transduction, cell-cell adhesion and energy and material transport into and out from the cells. For the deep understanding of these processes, structure determination of transmembrane proteins is indispensable. However, due to technical difficulties, only a few transmembrane protein structures have been determined experimentally. Large-scale genomic sequencing provides increasing amounts of sequence information on the proteins and whole proteomes of living organisms resulting in the challenge of bioinformatics; how the structural information should be gained from a sequence. RESULTS: Here, we present a novel method, TMFoldRec, for fold prediction of membrane segments in transmembrane proteins. TMFoldRec based on statistical potentials was tested on a benchmark set containing 124 TMP chains from the PDBTM database. Using a 10-fold jackknife method, the native folds were correctly identified in 77% of the cases. This accuracy overcomes the state-of-the-art methods. In addition, a key feature of TMFoldRec algorithm is the ability to estimate the reliability of the prediction and to decide with an accuracy of 70%, whether the obtained, lowest energy structure is the native one. CONCLUSION: These results imply that the membrane embedded parts of TMPs dictate the TM structures rather than the soluble parts. Moreover, predictions with reliability scores make in this way our algorithm applicable for proteome-wide analyses. AVAILABILITY: The program is available upon request for academic use. PMID- 26123060 TI - Factors associated with self-rated sexual function in Korean patients with schizophrenia receiving risperidone monotherapy. AB - OBJECTIVE: This study aims to investigate the factors associated with sexual function in Korean patients with schizophrenia. METHODS: This study evaluated 169 patients with schizophrenia who were receiving risperidone monotherapy. The Visual Analog Scale was used to assess sexual function in terms of sexual desire, sexual arousal, and sexual satisfaction. The Positive and Negative Syndrome Scale, the Beck Depression Inventory, the Korean version of the Subjective Well being under Neuroleptic Treatment-Brief Form (SWN-K) scale, and the Drug Attitude Inventory (DAI) were also administered. RESULTS: Sexual function was negatively associated with age, duration of illness, gender (female), marital status (single), the presence of tardive dyskinesia, and Beck Depression Inventory score, but positively associated with the SWN-K and DAI scores. A linear regression analysis revealed that being male and married had significant positive associations with sexual arousal, sexual satisfaction, and/or sexual desire, while the presence of tardive dyskinesia and a longer duration of illness were associated with poor sexual arousal and/or sexual desire. Additionally, sexual function was significantly associated with the SWN-K and DAI scores in multivariate analysis. CONCLUSIONS: The acknowledgement and management of sexual dysfunction in patients with schizophrenia by clinicians may be important for improvement of their quality of life and adherence to medication. PMID- 26123061 TI - Zero coronary calcium in the presence of three-vessel and left main coronary artery disease in a Hodgkin lymphoma survivor. AB - We describe a 45-year-old male survivor of Hodgkin lymphoma, treated with mediastinal radiation therapy, referred for single-photon emission computed tomography (SPECT) myocardial perfusion imaging in combination with coronary artery calcium (CAC) scoring. SPECT demonstrated a reversible moderate-sized lateral perfusion defect, and the CAC score was zero. A calcium score of zero markedly reduces the probability of having coronary artery disease (CAD) and is associated with a very low risk of future cardiovascular events. However, a CAC score of zero does not completely rule out obstructive CAD. In this case, invasive coronary angiography revealed three-vessel CAD with left main involvement. Whether mediastinal radiation therapy in general is associated with CAD without accompanying CAC is yet unclear. PMID- 26123062 TI - Genetic variation analysis in a Chinese Maffucci syndrome patient. AB - OBJECTIVE: To report on the molecular genetic analysis of a Chinese patient with Maffucci syndrome. METHODS: Using the genomic DNA extracted from the patient's hemangioma sample, the coding exons and exon/intron splice junctions of the IDH1 and IDH2 genes were amplified by polymerase chain reaction (PCR) and then sequenced. Genomic DNA was extracted from blood and a hemangioma sample from the patient, and also from her mother's blood, for chromosome microarray analysis (CMA) by Affymetrix CytoScan HD array. RESULTS: None of the known pathogenic mutations in the whole IDH1 or IDH2 genes was found in the patient's hemangioma sample. CMA detected 40 tumor-specific copy number variations (CNVs), and one copy number neutral loss of heterozygosity (LOH) region. Among the 73 known genes included in the 40 CNV regions, only 2 genes, CHEK2 (604373) located in 22q12.1 and EP300 (602700) located in 22q13.2, were found to be related to tumorigenesis. We did not find any CNVs at the IDH1 and IDH2 loci. CONCLUSIONS: This is the first molecular genetic analysis report on a Chinese patient with Maffucci syndrome and our data enrich the understanding of the genetic background of Maffucci syndrome in different ethnic groups. The relationship between CHEK2, EP300 and Maffucci syndrome needs to be further explored. PMID- 26123063 TI - Quantitative Chemical Mapping of InGaN Quantum Wells from Calibrated High-Angle Annular Dark Field Micrographs. AB - We present a simple and robust method to acquire quantitative maps of compositional fluctuations in nanostructures from low magnification high-angle annular dark field (HAADF) micrographs calibrated by energy-dispersive X-ray (EDX) spectroscopy in scanning transmission electron microscopy (STEM) mode. We show that a nonuniform background in HAADF-STEM micrographs can be eliminated, to a first approximation, by use of a suitable analytic function. The uncertainty in probe position when collecting an EDX spectrum renders the calibration of HAADF STEM micrographs indirect, and a statistical approach has been developed to determine the position with confidence. Our analysis procedure, presented in a flowchart to facilitate the successful implementation of the method by users, was applied to discontinuous InGaN/GaN quantum wells in order to obtain quantitative determinations of compositional fluctuations on the nanoscale. PMID- 26123064 TI - Identification of critical residues for transport activity of Acr3p, the Saccharomyces cerevisiae As(III)/H+ antiporter. AB - Acr3p is an As(III)/H(+) antiporter from Saccharomyces cerevisiae belonging to the bile/arsenite/riboflavin transporter superfamily. We have previously found that Cys151 located in the middle of the fourth transmembrane segment (TM4) is critical for antiport activity, suggesting that As(III) might interact with a thiol group during the translocation process. In order to identify functionally important residues involved in As(III)/H(+) exchange, we performed a systematic alanine-replacement analysis of charged/polar and aromatic residues that are conserved in the Acr3 family and located in putative transmembrane segments. Nine residues (Asn117, Trp130, Arg150, Trp158, Asn176, Arg230, Tyr290, Phe345, Asn351) were found to be critical for proper folding and trafficking of Acr3p to the plasma membrane. In addition, we found that replacement of highly conserved Phe266 (TM7), Phe352 (TM9), Glu353 (TM9) and Glu380 (TM10) with Ala abolished transport activity of Acr3p, while mutation of Ser349 (TM9) to Ala significantly reduced the As(III)/H(+) exchange, suggesting an important role of these residues in the transport mechanism. Detailed mutational analysis of Glu353 and Glu380 revealed that the negatively charged residues located in the middle of transmembrane segments TM9 and TM10 are crucial for antiport activity. We also discuss a hypothetical model of the Acr3p transport mechanism. PMID- 26123065 TI - A transdiagnostic minority stress treatment approach for gay and bisexual men's syndemic health conditions. AB - Developing and deploying separate treatments for separate conditions seems ill suited to intervening upon the co-occurring, and possibly functionally similar, psychosocial conditions facing gay and bisexual men. This article argues for the need to create transdiagnostic interventions that reduce multiple syndemic conditions facing gay and bisexual men at the level of their shared source in minority stress pathways. This article first reviews psychosocial syndemic conditions affecting gay and bisexual men, then suggests pathways that might link minority stress to psychosocial syndemics based on recent advancements in emotion science, psychiatric nosology, and cognitive-affective neuroscience, and finally suggests cross-cutting psychosocial treatment principles to reduce minority stress-syndemic pathways among gay and bisexual men. Because minority stress serves as a common basis of all psychosocial syndemic conditions reviewed here, locating the pathways through which minority stress generates psychosocial syndemics and employing overarching treatment principles capable of simultaneously alleviating these pathways will ultimately create a transdiagnostic approach to improving gay and bisexual men's health. Clinical research and training approaches are suggested to further validate the pathways suggested here, establish the efficacy of treatment approaches tied to those pathways, and generate effective methods for disseminating a transdiagnostic minority stress treatment approach for gay and bisexual men's psychosocial syndemic health. PMID- 26123067 TI - Do behavioral scientists really understand HIV-related sexual risk behavior? A systematic review of longitudinal and experimental studies predicting sexual behavior. AB - Behavioral interventions to reduce sexual risk behavior depend on strong health behavior theory. By identifying the psychosocial variables that lead causally to sexual risk, theories provide interventionists with a guide for how to change behavior. However, empirical research is critical to determining whether a particular theory adequately explains sexual risk behavior. A large body of cross sectional evidence, which has been reviewed elsewhere, supports the notion that certain theory-based constructs (e.g., self-efficacy) are correlates of sexual behavior. However, given the limitations of inferring causality from correlational research, it is essential that we review the evidence from more methodologically rigorous studies (i.e., longitudinal and experimental designs). This systematic review identified 44 longitudinal studies in which investigators attempted to predict sexual risk from psychosocial variables over time. We also found 134 experimental studies (i.e., randomized controlled trials of HIV interventions), but of these only 9 (6.7 %) report the results of mediation analyses that might provide evidence for the validity of health behavior theories in predicting sexual behavior. Results show little convergent support across both types of studies for most traditional, theoretical predictors of sexual behavior. This suggests that the field must expand the body of empirical work that utilizes the most rigorous study designs to test our theoretical assumptions. The inconsistent results of existing research would indicate that current theoretical models of sexual risk behavior are inadequate, and may require expansion or adaptation. PMID- 26123066 TI - Sexual health and socioeconomic-related factors among HIV-positive men who have sex with men in Puerto Rico. AB - Most of the research among HIV-positive populations has been approached from behavioral risk models. This is particularly true for those otherwise socially vulnerable groups like men who have sex with men (MSM). As a response to this pattern, we examined data from an ongoing health promotion research being conducted in Puerto Rico (PR). The study is limited to HIV-positive MSM and consists of the participation in a survey interview that includes domains used to assess indicators of socio-economic-related factors (age, educational level, employment, religion, and partnership status) and sexual health (sexual satisfaction, condom use, and sexual health knowledge(SHK)). Participants reported a relatively high level (75 %) of sexual satisfaction and inconsistent condom use (50.9 % reported always using a condom). A deficient (61 %) SHK was also reported. In multivariate analyses, a higher educational level was associated with higher sexual satisfaction (abeta = 3.223; 95 % CI 0.291-6.156) and higher levels of SHK (abeta = 1.328; 95 % CI 0.358-2.297), while unemployment was associated with less condom use (aOR 0.314; 95 % CI 0.122-0.810). Not having a primary sexual partner was associated with less sexual satisfaction (abeta = 3.871; 95 % CI -7.534-0.208) and more condom use (aOR 4.292; 95 % CI 1.310 14.068). Findings support the notion that men of a disadvantaged socioeconomic position may have a poorer sexual health status; with a lower level of education and unemployment leading this disparity. Findings also evidence that partnership status may have a role in the sexual health of HIV-positive MSM. To our knowledge, this is the first comprehensive analysis of sexual health and socioeconomic indicators among Hispanic/Latino HIV-positive MSM in PR and in the Caribbean. Findings provide valuable information to address the sexual health needs of an underserved population. PMID- 26123070 TI - Fluorescence cystoscopy: the end of biopsies for carcinoma in situ detection? PMID- 26123071 TI - Can we rely on lymphovascular invasion for determining the need for adjuvant chemotherapy in organ-confined bladder cancer? PMID- 26123068 TI - Pilot randomized controlled trial of an integrative intervention with methamphetamine-using men who have sex with men. AB - Contingency management (CM) is an evidence-based intervention that provides tangible rewards as positive reinforcement for biologically confirmed abstinence from substance use. Integrative approaches targeting positive affect regulation could boost the effectiveness of CM by sensitizing individuals to non-drug related sources of reward and assisting them with effectively managing symptoms of withdrawal. This pilot randomized controlled trial with 21 methamphetamine using men who have sex with men (MSM) examined the feasibility and acceptability of a 5-session, positive affect intervention delivered during CM-Affect Regulation Treatment to Enhance Methamphetamine Intervention Success (ARTEMIS). After completing 4 weeks of a 12-week CM program, participants were randomized to receive ARTEMIS+CM (n = 12) or CM-only (n = 9). Those randomized to receive the ARTEMIS positive affect intervention completed 98 % of sessions and reported marginally significant increases in positive affect over the five sessions. In exit interviews with ARTEMIS+CM participants, individuals noted that the positive affect regulation skills increased self-awareness and led to greater engagement in the recovery process. ARTEMIS+CM participants reported significant increases in positive affect and CM-only participants reported significant reductions in negative affect over a 2-month follow-up. These affective changes were not maintained, and no concurrent effects on stimulant use or sexual risk taking were observed over the 6-month follow-up. More definitive clinical research is necessary to examine the efficacy of ARTEMIS+CM with methamphetamine-using MSM. PMID- 26123072 TI - Towards a standardised training curriculum for robotic surgery. PMID- 26123073 TI - Scabies: an ancient global disease with a need for new therapies. AB - BACKGROUND: Scabies is an ancient disease (documented as far back as 2500 years ago). It affects about 300 million people annually worldwide, and the prevalence is as high as about 60% in Indigenous and Torres Strait Islander children in Australia. This is more than six times the rate seen in the rest of the developed world. Scabies is frequently complicated by bacterial infection leading to the development of skin sores and other more serious consequences such as septicaemia and chronic heart and kidney diseases. This causes a substantial social and economic burden especially in resource poor communities around the world. DISCUSSION: Very few treatment options are currently available for the management of scabies infection. In this manuscript we briefly discuss the clinical consequences of scabies and the problems found (studies conducted in Australia) with the currently used topical and oral treatments. Current scabies treatment options are fairly ineffective in preventing treatment relapse, inflammatory skin reactions and associated bacterial skin infections. None have ovicidal, antibacterial, anti-inflammatory and/or anti-pruritic properties. Treatments which are currently available for scabies can be problematic with adverse effects and perhaps of greater concern the risk of treatment failure. The development of new chemical entities is doubtful in the near future. Though there may be potential for immunological control, the development of a vaccine or other immunotherapy modalities may be decades away. The emergence of resistance among scabies mites to classical scabicides and ineffectiveness of current treatments (in reducing inflammatory skin reactions and secondary bacterial infections associated with scabies), raise serious concerns regarding current therapy. Treatment adherence difficulties, and safety and efficacy uncertainties in the young and elderly, all signal the need to identify new treatments for scabies. PMID- 26123074 TI - Investigation of the amount of transdermal exposure of newborn babies to phthalates in paper diapers and certification of the safety of paper diapers. AB - A risk assessment study of seven phthalates in paper diapers for newborn babies produced in Japan was performed. The diapers were purchased and the contents of the seven phthalates were determined and estimated amounts of exposure were calculated based on the eluted rate into artificial medium of urine or sweat, average weight of infants, and frequency of use. Di-2-ethylhexyl phthalate and di n-butyl phthalate were detected in the topsheets and determined to be 0.6 MUg/g and 0.2 MUg/g, respectively. The daily estimated exposure volume was calculated to be in the range of 1.86 * 10(-10)-2.98 * 10(-6) mg/kg/day as follows: content of seven phthalates in the topsheet (0.1-1 MUg/g) * eluted rate of phthalates into artificial sweat (0.0006-2.4%) * weight of the topsheet of a diaper (1.5 g) * the number of diapers used per day (12 sheets) * skin absorption rate (0.005 0.1)/average body weight (2.9 kg). For hazard assessment, we used 0.2-300 mg/kg/day for the seven phthalates based on the data available at international agencies. The margin of exposure to the seven phthalates was 6.71 * 10(4)-1.99 * 10(11), indicating that the risk of exposure to phthalates from the diapers produced in Japan was negligible. PMID- 26123076 TI - Fifteen-year experience with the Bicarbon heart valve prosthesis in a single center. AB - BACKGROUND: The purpose of this study was to evaluate retrospectively the clinical performance of the Bicarbon valve (Sorin Biomedica Cardio, Saluggia, Italy) implanted at our center in Japan. METHODS: Between January 1997 and December 2011, 415 patients in our institution were implanted with the Bicarbon valve. Nine of these recipients were excluded from the study because they had already undergone valve implantation and received a Bicarbon valve in a different position. The remaining patients were analyzed for evaluation of the postoperative clinical outcomes. Of the 406 patients (mean age 60.2 +/- 11.7 years), 179 underwent aortic valve replacement (AVR), 149 mitral valve replacement (MVR), and 78 both aortic and mitral valve replacement (DVR). RESULTS: There were 10 early deaths (2.5 %: 4 in the AVR group and 6 in the MVR group). Three hundred eighty-nine patients were followed up (95.8 % completeness of follow-up) with a mean follow-up of 6.6 +/- 4.2 years overall (AVR 6.8 +/- 4.2, MVR, 6.7 +/- 4.4, and DVR 5.7 +/- 3.4 years) and a cumulative follow-up of 2661 patient-years (1214, 1001, and 446 patient-years for AVR, MVR, and DVR, respectively). Ninety-nine patients died (3.7 % per patient-year: 22 valve related and 77 valve-unrelated deaths). Survival at 10 years was 74.1 +/- 4.0 % in the AVR group, 73.7 +/- 4.2 % in the MVR group, and 61.0 +/- 7.9 % in the DVR group. The linearized incidence of thromboembolic complications, bleeding complications, prosthetic valve endocarditis, paravalvular leaks, and sudden death in all patients was 0.5 %, 0.5 %, 0.2 %, 0.2 %, and 0.4 % per patient-year, respectively. The incidence of valve-related complications and reoperation was 1.6 % and 0.4 %, respectively. No other valve-related complications were observed. CONCLUSIONS: The Bicarbon prosthetic heart valve has shown excellent clinical results and is associated with a low incidence of valve-related complications. PMID- 26123078 TI - Distribution of haemic neoplasia of soft-shelled clams in Prince Edward Island: an examination of anthropogenic factors and effects of experimental fungicide exposure. AB - Haemic neoplasia was first considered a disease of concern for soft-shell clams in Prince Edward Island (PEI) when it was diagnosed as the cause of mass mortalities in 1999. The aetiology of the disease remains elusive, but has been associated with environmental degradation. In this study, a 2-year (2001-2002) geographic and seasonal survey was conducted for haemic neoplasia, using histology, in soft-shell clams from PEI. In addition, using geographic information system, the association between anthropogenic factors in the watersheds at sites affected by haemic neoplasia and the prevalence of the disease was investigated. Finally, histopathological changes were assessed in soft-shell clams experimentally exposed to four concentrations of chlorothalonil for 27 days. Haemic neoplasia could not be induced at any concentration of chlorothalonil. Clams exposed to a concentration of 1000 MUg L(-1) of the fungicide, however, exhibited an LC50 of 17 days. Although this information provides additional toxicity information (LC50) for soft-shell clams, further experiments are required to assess longer term exposure to the fungicide. The highest prevalences of haemic neoplasia in PEI were found in North River and Miscouche (28.3-50.9% and 33.0-77.8%, respectively). No clear seasonal patterns were found. There was a correlation between haemic neoplasia prevalence and watersheds with a high percentage of potato acreage and forest coverage (P = 0.026 and P = 0.045, respectively), suggesting a link between anthropogenic activity and the prevalence of the disease. PMID- 26123077 TI - Genipin suppresses NLRP3 inflammasome activation through uncoupling protein-2. AB - Incomplete clearance of apoptotic cells and reactive oxygen species (ROS) release are known to trigger inflammasome activation causing severe inflammation in acute lung injury and various metabolic and autoimmune diseases. Moreover, it has been reported that apoptotic cell clearance and ROS-mediated apoptosis critically depend on mitochondrial uncoupling protein-2 (UCP2). However, the relationship between UCP2 and inflammasome activation has not been studied. This report investigates the role of UCP2 in the expression and activation of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in human macrophages. We found that UCP2 overexpression significantly enhanced the expression levels of NLRP3. The NLRP3 expression levels were significantly suppressed in THP1 cells treated with genipin, a UCP2 inhibitor, compared to controls. In addition, genipin altered adenosine triphosphate (ATP)- and hydrogen peroxide (H2O2) mediated interleukin-1 beta (IL-1beta) secretion and significantly suppressed caspase-1 activity in inflammasome-activated human macrophages. Taken together, our results suggest that genipin modulates NLRP3 inflammasome activation and ATP- or H2O2-mediated IL-1beta release. PMID- 26123079 TI - Prophylaxis of HCV reinfection and direct-acting antiviral agents during liver transplantation. PMID- 26123080 TI - Association between the polymorphism of C861G (rs6296) in the serotonin 1B receptor gene and Tourette syndrome in Han Chinese people. AB - INTRODUCTION: Clinical, neuroimaging and other studies provided evidence that the dysfunction of the serotonin neurotransmitter system were found in Tourette syndrome (TS). This study is to explore the association between the polymorphism of C861G (rs6296) in HTR1B and TS in Han Chinese people. METHODS: Two hundred ninety-nine TS patients (260 TS trios and 39 TS patients) and 388 healthy controls were collected. The genotype of HTR1B C861G was detected using Taqman probes. The case-control study and family-based study was used separately to study association between HTR1B C861G and TS in Han Chinese people. RESULTS: In case-control study, no statistically significant difference was found in the distribution of HTR1B C861G polymorphism between TS patients and controls (for genotype: chi2 = 3.408, P = 0.182; for allele: chi2 = 0.395, P = 0.530, OR = 0.934, 95%CI: 0.754-1.156). In family-based study, we observed nonsignificant over-transmission of the G861 allele in HTR1B to TS offspring using the transmission disequilibrium test (TDT), haplotype relative risk (HRR) and haplotype-based HRR (HHRR) (TDT chi2 = 0.410, P = 0.560; HRR = 1.151, chi2 = 0.421, P = 0.517, 95% CI: 0.753-1.759; HHRR = 0.919, chi2 = 0.467, P = 0.495, 95%CI: 0.720-1.172). DISCUSSION: Our study suggested that the polymorphism of HTR1B C861G is not a risk factor for TS in Han Chinese population. However, the result should be replicated in larger sample and different population. PMID- 26123081 TI - Titmouse calling and foraging are affected by head and body orientation of cat predator models and possible experience with real cats. AB - Although anti-predator behavior systems have been studied in diverse taxa, less is known about how prey species detect and assess the immediate threat posed by a predator based on its behavior. In this study, we evaluated a potential cue that some species may utilize when assessing predation threat-the predator's body and head orientation. We tested the effect of this orientation cue on signaling and predation-risk-sensitive foraging of a prey species, tufted titmice (Baeolophus bicolor). Earlier work revealed sensitivity of titmice and related species to the presence of predator stimuli. Here, we manipulated cat models to face either toward or away from a food source preferred by titmice and then measured titmouse calling and seed-taking behavior. Titmice showed greater feeder avoidance when the cat predator models faced the feeder, compared to when the models faced away from the feeder or when titmice were exposed to control stimuli. Titmouse calling was also sensitive to predator head/body orientation, depending upon whether titmice were from sites where real cats had been observed or not. This study experimentally demonstrated that both calling and foraging of prey species can be affected by the head and body orientation of an important terrestrial predator. Prey species may therefore signal in strategic ways to conspecifics not just about predator presence, but also urgency of threat related to the more subtle cue of the head and body orientation of the predator. These findings hold potential implications for understanding animal cognition and learning processes. PMID- 26123082 TI - Some factors affecting performance of rats in the traveling salesman problem. AB - The traveling salesman problem (TSP) is used to measure the efficiency of spatial route selection. Among researchers in cognitive psychology and neuroscience, it has been utilized to examine the mechanisms of decision making, planning, and spatial navigation. While both human and non-human animals produce good solutions to the TSP, the solution strategies engaged by non-human species are not well understood. We conducted two experiments on the TSP using Long-Evans laboratory rats as subjects. The first experiment examined the role of arena walls in route selection. Rats tend to display thigmotaxis in testing conditions comparable to the TSP, which could produce results similar to a convex hull type strategy suggested for humans. The second experiment examined the role of turn angle between targets along the optimal route, to determine whether rats exhibit a preferential turning bias. Our results indicated that both thigmotaxis and preferential turn angles do affect performance in the TSP, but neither is sufficient as a predictor of route choice in this task. PMID- 26123083 TI - Purification and Identification of Two Antifungal Cyclic Peptides Produced by Bacillus amyloliquefaciens L-H15. AB - Bacillus amyloliquefaciens L-H15 with broad spectrum antifungal activity was used as a biocontrol agent to suppress Fusarium oxysporum and other soil-borne fungal plant pathogens. Two antifungal fractions were isolated by bioactivity-guided reversed-phase high-performance liquid chromatography. The two compounds were identified by tandem Q-TOF mass spectroscopy as C15 Iturin A (1) and a novel cyclic peptide with a molecular weight of 852.4 Da (2). Both compounds showed good inhibitory activities against three plant fungal pathogens in cylinder-plate diffusion assay. To our best knowledge, this is the first report on a cyclic antifungal peptide with a molecular weight of 852.4 Da. The strong antifungal activity suggests that the B. amyloliquefaciens L-H15 and its bioactive components might provide an alternative resource for the biocontrol of plant diseases and sustainable agriculture. PMID- 26123084 TI - Bioprocess Evaluation of Water Soaking-Based Microbiological Biodegradation with Exposure of Cellulosic Microfibers Relevant to Bioconversion Efficiency. AB - To verify the interconnective relationship between biodegradation efficiency and microfibril structure, recalcitrant rice straw (RS) was depolymerized using water soaking-based microbiological biodegradation (WSMB). This eco-friendly biosystem, which does not predominantly generate inhibitory metabolites, could increase both the hydrolytic accessibility and fermentation efficiency of RS. In detail, when swollen RS (with Fenton cascades) was simultaneously bio-treated with Phanerochaete chrysosporium for 12 days, the biodegradability was 65.0 % of the theoretical maximum at the stationary phase. This value was significantly higher than the 30.3 % measured from untreated RS. Similarly, the WSMB platform had an effect on the yield enhancement of ethanol productivity of 32.5 %. However, uniform exposure of fibril polymers appeared to have little impact on bioconversion yields. Additionally, the proteomic pools of the WSMB system were analyzed to understand either substrate-specific or nonspecific biocascades based on the change in microcomposite materials. Remarkably, regardless of modified microfibril chains, the significant pattern of 14 major proteins (|fold| > 2) was reasonably analogous in both systems, especially for lignocellulolysis-related targets. PMID- 26123085 TI - Defining the RNA-binding glycine-rich (RBG) gene superfamily: new insights into nomenclature, phylogeny, and evolutionary trends obtained by genome-wide comparative analysis of Arabidopsis, Chinese cabbage, rice and maize genomes. AB - RNA-binding glycine-rich (RBG) proteins play diverse roles in plant growth, development, protection and genome organization. An overly broad definition for class IV glycine-rich proteins (GRPs), namely RNA-binding activity and a glycine rich C-terminus, has resulted in many distantly related and/or non-related proteins being grouped into this class of RBGs. This definition has hampered the study of RBG evolution. In this study, we used a comparative genomic approach consisting of ortholog, homolog, synteny and phylogenetic analyses to legitimately exclude all distantly/non-related proteins from class IV GRPs and to identify 15, 22, 12 and 18 RBG proteins in Arabidopsis, Chinese cabbage, rice and maize genomes, respectively. All identified RBGs could be divided into three subclasses, namely RBGA, RBGB and RBGD, which may be derived from a common ancestor. We assigned RBGs excluded from class IV GRPs to a separate RBG superfamily. RBGs have evolved and diversified in different species via different mechanisms; segmental duplication and recombination have had major effects, with tandem duplication, intron addition/deletion and domain recombination/deletion playing minor roles. Loss and retention of duplicated RBGs after polyploidization has been species and subclass specific. For example, following recent whole genome duplication and triplication in maize and Chinese cabbage, respectively, most duplicated copies of RBGA have been lost in maize while RBGD duplicates have been retained; in Chinese cabbage, in contrast, RBGA duplicates have been retained while RBGD duplicates have been lost. Our findings reveal fundamental information and shed new light on the structural characteristics and evolutionary dynamics of RBGs. PMID- 26123086 TI - Phacomatosis Melanorosea: A Further Case of an Unusual Skin Disorder. PMID- 26123087 TI - Response to letter by Berger: The success of masking should be tested routinely and correctly. PMID- 26123088 TI - Rowing against the current. PMID- 26123089 TI - Not All Retina Is Created Equal: Metabolic Quantification of Ultra-Widefield Images. PMID- 26123090 TI - Serous Retinopathy Associated with Mitogen-Activated Protein Kinase Kinase Inhibition (Binimetinib) for Metastatic Cutaneous and Uveal Melanoma. AB - PURPOSE: To analyze the clinical characteristics of a serous retinopathy associated with mitogen-activated protein kinase kinase (MEK) inhibition with binimetinib treatment for metastatic cutaneous melanoma (CM) and uveal melanoma (UM), and to determine possible pathogenetic mechanisms that may lead to this retinopathy. DESIGN: Prospective observational, cohort-based, cross-sectional study. PARTICIPANTS: Thirty CM patients and 5 UM patients treated with the MEK inhibitor binimetinib (CM) or a combination of binimetinib and the protein kinase C inhibitor sotrastaurin (UM). METHODS: Extensive ophthalmic examination was performed, including Early Treatment of Diabetic Retinopathy Study best-corrected visual acuity, applanation tonometry, slit-lamp examination, indirect ophthalmoscopy, digital color fundus photography, and optical coherence tomography (OCT). In selected cases, additional examinations were performed, including visual field testing and electro-oculography (EOG). Blood samples were obtained from 3 CM patients and 3 UM patients to analyze the presence of autoantibodies against retinal and retinal pigment epithelium (RPE) proteins. MAIN OUTCOME MEASURES: Visual symptoms, visual acuity, fundus appearance, characteristics on OCT, fundus autofluorescence (FAF), and EOG. RESULTS: Six CM patients (20%) and 2 UM patients (40%) reported visual symptoms during the study. The median time to the onset of symptoms, which were all mild and transient, was 3.5 days (range, <1 hour to 3 weeks). On OCT, subretinal fluid (SRF) was detected in 77% of CM patients and 60% of UM patients. In the 26 patients with SRF, the fovea was affected in 85%. After the start of the medication, an EOG was performed in 19 eyes of 11 patients; 16 of these eyes (84%) developed SRF on OCT. Fifteen of these eyes (94%) showed an abnormal Arden ratio (<1.65). A broad pattern of anti-retinal antibodies was found in 3 CM patients and 2 UM patients tested, whereas anti-RPE antibodies were detected in all 6 tested patients. CONCLUSIONS: A time-dependent and reversible serous retinopathy can develop both in patients with metastatic CM and UM treated with binimetinib. A minority of patients develop visual symptoms, which are generally mild and transient. A cause of binimetinib-associated serous retinopathy may be toxicity of medication, but autoantibodies also may be involved. PMID- 26123091 TI - Topical Nonsteroidal Anti-inflammatory Drugs and Cataract Surgery: A Report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the available evidence on the effectiveness of prophylactic topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing vision loss resulting from cystoid macular edema (CME) after cataract surgery. METHODS: Literature searches of the PubMed and the Cochrane Library databases were last conducted on January 21, 2015, with no date restrictions. The searches retrieved 149 unique citations. The first author reviewed the abstracts of these articles and selected 27 articles of possible clinical relevance for full-text review. Of these 27 articles, 12 were deemed relevant to analyze in full. Two additional articles were identified from the reference list of the selected articles, and another article was identified from a national meeting. The panel methodologist assigned ratings of level of evidence to each of the selected citations. RESULTS: Nonsteroidal anti-inflammatory drug therapy was effective in reducing CME detected by angiography or optical coherence tomography (OCT) and may increase the speed of visual recovery after surgery when compared directly with placebo or topical corticosteroid formulations with limited intraocular penetration. However, the use of NSAIDs did not alter long-term (>=3 months) visual outcomes. Furthermore, there was no evidence that the benefits observed with NSAID therapy could not be obtained similarly with equivalent dosing of a corticosteroid. The reported impression that there is a pharmacologic drug synergy from the use of both an NSAID and a corticosteroid is not supported by the literature. There is no uniform method of reporting CME in the literature, which prevents accurate assessment of its incidence and response to anti-inflammatory therapies. CONCLUSIONS: Cystoid macular edema after cataract surgery has a tendency to resolve spontaneously. There is a lack of level I evidence that supports the long term benefit of NSAID therapy to prevent vision loss from CME at 3 months or more after cataract surgery. Although dosing of NSAIDs before surgery may hasten the speed of visual recovery in the first several weeks after cataract surgery, there is no evidence that this practice affects long-term visual outcomes. Standardized reporting of CME based on OCT may allow for more uniform quantitation of its incidence and more reliable assessment of treatment outcomes. PMID- 26123092 TI - Rapid evidence assessment: increasing the transparency of an emerging methodology. AB - RATIONALE, AIMS AND OBJECTIVES: Within the field of evidence-based practice, policy makers, health care professionals and consumers require timely reviews to inform decisions on efficacious health care and treatments. Rapid evidence assessment (REA), also known as rapid review, has emerged in recent years as a literature review methodology that fulfils this need. It highlights what is known in a clinical area to the target audience in a relatively short time frame. METHODS: This article discusses the lack of transparency and limited critical appraisal that can occur in REA, and goes on to propose general principles for conducting a REA. The approach that we describe is consistent with the principles underlying systematic review methodology, but also makes allowances for the rapid delivery of information as required while utilizing explicit and reproducible methods at each stage. RESULTS: Our method for conducting REA includes: developing an explicit research question in consultation with the end-users; clear definition of the components of the research question; development of a thorough and reproducible search strategy; development of explicit evidence selection criteria; and quality assessments and transparent decisions about the level of information to be obtained from each study. In addition, the REA may also include an assessment of the quality of the total body of evidence. CONCLUSIONS: Transparent reporting of REA methodologies will provide greater clarity to end-users about how the information is obtained and about the trade offs that are made between speed and rigour. PMID- 26123093 TI - Analysis of transtheoretical model of health behavioral changes in a nutrition intervention study--a continuous time Markov chain model with Bayesian approach. AB - Continuous time Markov chain (CTMC) models are often used to study the progression of chronic diseases in medical research but rarely applied to studies of the process of behavioral change. In studies of interventions to modify behaviors, a widely used psychosocial model is based on the transtheoretical model that often has more than three states (representing stages of change) and conceptually permits all possible instantaneous transitions. Very little attention is given to the study of the relationships between a CTMC model and associated covariates under the framework of transtheoretical model. We developed a Bayesian approach to evaluate the covariate effects on a CTMC model through a log-linear regression link. A simulation study of this approach showed that model parameters were accurately and precisely estimated. We analyzed an existing data set on stages of change in dietary intake from the Next Step Trial using the proposed method and the generalized multinomial logit model. We found that the generalized multinomial logit model was not suitable for these data because it ignores the unbalanced data structure and temporal correlation between successive measurements. Our analysis not only confirms that the nutrition intervention was effective but also provides information on how the intervention affected the transitions among the stages of change. We found that, compared with the control group, subjects in the intervention group, on average, spent substantively less time in the precontemplation stage and were more/less likely to move from an unhealthy/healthy state to a healthy/unhealthy state. PMID- 26123094 TI - Magnetic guidance versus manual control: comparison of radiofrequency lesion dimensions and evaluation of the effect of heart wall motion in a myocardial phantom. AB - BACKGROUND: Magnetic navigation system (MNS) ablation was suspected to be less effective and unstable in highly mobile cardiac regions compared to radiofrequency (RF) ablations with manual control (MC). The aim of the study was to compare the (1) lesion size and (2) stability of MNS versus MC during irrigated RF ablation with and without simulated mechanical heart wall motion. METHODS: In a previously validated myocardial phantom, the performance of Navistar RMT Thermocool catheter (Biosense Webster, CA, USA) guided with MNS was compared to manually controlled Navistar irrigated Thermocool catheter (Biosense Webster, CA, USA). The lesion dimensions were compared with the catheter in inferior and superior orientation, with and without 6-mm simulated wall motion. All ablations were performed with 40 W power and 30 ml/ min irrigation for 60 s. RESULTS: A total of 60 ablations were performed. The mean lesion volumes with MNS and MC were 57.5 +/- 7.1 and 58.1 +/- 7.1 mm(3), respectively, in the inferior catheter orientation (n = 23, p = 0.6), 62.8 +/- 9.9 and 64.6 +/- 7.6 mm(3), respectively, in the superior catheter orientation (n = 16, p = 0.9). With 6-mm simulated wall motion, the mean lesion volumes with MNS and MC were 60.2 +/- 2.7 and 42.8 +/- 8.4 mm(3), respectively, in the inferior catheter orientation (n = 11, p = <0.01*), 74.1 +/- 5.8 and 54.2 +/- 3.7 mm(3), respectively, in the superior catheter orientation (n = 10, p = <0.01*). During 6-mm simulated wall motion, the MC catheter and MNS catheter moved 5.2 +/- 0.1 and 0 mm, respectively, in inferior orientation and 5.5 +/- 0.1 and 0 mm, respectively, in the superior orientation on the ablation surface. CONCLUSIONS: The lesion dimensions were larger with MNS compared to MC in the presence of simulated wall motion, consistent with greater catheter stability. However, similar lesion dimensions were observed in the stationary model. PMID- 26123095 TI - Abundant epicardial adipose tissue surrounding the left atrium predicts early rather than late recurrence of atrial fibrillation after catheter ablation. AB - PURPOSE: Epicardial adipose tissue (EAT) surrounding the left atrium has been reported to have a pro-arrhythmic influence on atrial myocardium and to play an important role in the pathophysiology of atrial fibrillation (AF). The purpose of this study was to explore whether the abundance of EAT correlates with early and late recurrences of AF after ablation. METHODS: We included 53 consecutive patients with drug-refractory AF scheduled for ablation. Early and late recurrences were defined as atrial tachyarrhythmias within and after 3 months following the ablation procedure, respectively. The total and left atrial EAT volumes were obtained by 320-detector-row multislice computed tomography. RESULTS: During a follow-up period of 16 +/- 4 months, early and late recurrences occurred in 29 (55 %) and 12 (23 %) patients, respectively. The left atrial EAT volume was larger in patients with than without early recurrence (35.1 +/- 13.1 vs. 25.0 +/- 9.5 cm(3), p = 0.002); however, there was no difference in the total EAT volume between the two groups (98.5 +/- 45.7 vs. 94.5 +/- 35.2 cm(3), p = 0.72). A multivariate analysis revealed that a large left atrial EAT volume, persistent AF, and large left atrial volume were independent predictors of early recurrence. Conversely, there was no significant difference in left atrial (29.3 +/- 14.6 vs. 29.7 +/- 11.7 cm(3), p = 0.93) and total EAT (91.0 +/- 50.1 vs. 97.9 +/- 37.0 cm(3), p = 0.66) volumes between patients with and without late recurrence. CONCLUSIONS: The abundance of left atrial EAT independently predicted early recurrence after AF ablation; on the contrary, it did not have an impact on late recurrence. Left atrial EAT may have a pro-arrhythmic influence, especially in the early post-ablation phase. PMID- 26123096 TI - Impaired adaptation to left atrial pressure increase in patients with atrial fibrillation. AB - BACKGROUND OR PURPOSE: Episodes of left atrial (LA) pressure increase predispose to atrial fibrillation (AF). The adaptation of LA mechanical function and electrophysiology to pressure elevation in healthy adults, and in patients with AF, is largely unknown. METHODS: Eleven patients with left-sided accessory pathway (controls) and 16 patients with paroxysmal AF undergoing catheter ablation were studied. LA pressure (LAP) was recorded through transseptal catheterization, while speckle tracking-derived peak LA longitudinal strain (PALS) was measured using transthoracic echocardiography. Stiffness index (SI) was calculated as mean LAP/PALS. Effective refractory period (ERP) of the LA was determined during simultaneous atrioventricular (AV) pacing and during atrial pacing. RESULTS: At baseline, AF patients had higher LA pressure (mean LAP 8.3 +/ 4.7 vs. 5.1 +/- 3.1 mmHg, p = 0.048), reduced LA mechanical function (PALS 15.1 +/- 5.1 vs. 21.6 +/- 6.2 %, p = 0.006, SI 0.69 +/- 0.75 vs. 0.28 +/- 0.22, p = 0.015), and longer LA ERP (242.3 +/- 33.4 vs. 211.7 +/- 15.6 ms, p = 0.017). Mean LAP was increased to the same extent by AV pacing in controls and AF patients (mean change 12.6 +/- 7.4 vs. 12.6 +/- 7.5 mmHg, p = 0.980). At the same time PALS decreased (from 15.1 +/- 5.1 to 11.6 +/- 3.3 %, p = 0.008), SI increased (from 0.69 +/- 0.75 to 1.29 +/- 1.17, p < 0.001) and ERP shortened (from 242.3 +/ 33.4 to 215.9 +/- 26.3 ms, p = 0.003) in AF patients, while they remained unchanged in controls. CONCLUSIONS: The stiffened LA in patients with AF responds to acute pressure elevation with an exaggerated increase in wall tension and decrease in ERP, which is not seen in the normal LA. This may underlie the propensity for AF during episodes of atrial stretch in these patients. PMID- 26123097 TI - A review of causal mechanisms underlying the link between age-related hearing loss and cognitive decline. AB - Accumulating evidence points to a link between age-related hearing loss and cognitive decline, but their relationship is not clear. Does one cause the other, or does some third factor produce both? The answer has critical implications for prevention, rehabilitation, and health policy but has been difficult to establish for several reasons. First, determining a causal relationship in natural, correlational samples is problematic, and hearing and cognition are difficult to measure independently. Here, we critically review the evidence for a link between hearing loss and cognitive decline. We conclude that the evidence is convincing, but that the effects are small when hearing is measured audiometrically. We review four different directional hypotheses that have been offered as explanations for such a link, and conclude that no single hypothesis is sufficient. We introduce a framework that highlights that hearing and cognition rely on shared neurocognitive resources, and relate to each other in several different ways. We also discuss interventions for sensory and cognitive decline that may permit more causal inferences. PMID- 26123098 TI - Slow light response kinetics in rods points towards a perturbation of the normal cellular milieu. PMID- 26123099 TI - Reply from Nan Ge Jin, Alice Z. Chuang, Philippe J. Masson and Christophe P. Ribelayga. PMID- 26123100 TI - Melatonin regulates the transcription of betaAPP-cleaving secretases mediated through melatonin receptors in human neuroblastoma SH-SY5Y cells. AB - Melatonin is involved in the control of various physiological functions, such as sleep, cell growth and free radical scavenging. The ability of melatonin to behave as an antioxidant, together with the fact that the Alzheimer-related amyloid beta-peptide (Abeta) triggers oxidative stress through hydroxyl radical induced cell death, suggests that melatonin could reduce Alzheimer's pathology. Although the exact etiology of Alzheimer's disease (AD) remains to be established, excess Abeta is believed to be the primary contributor to the dysfunction and degeneration of neurons that occurs in AD. Abeta peptides are produced via the sequential cleavage of beta-secretase beta-site APP-cleaving enzyme 1 (BACE1) and gamma-secretase (PS1/PS2), while alpha-secretase (ADAM10) prevents the production of Abeta peptides. We hypothesized that melatonin could inhibit BACE1 and PS1/PS2 and enhance ADAM10 expression. Using the human neuronal SH-SY5Y cell line, we found that melatonin inhibited BACE1 and PS1 and activated ADAM10 mRNA level and protein expression in a concentration-dependent manner and mediated via melatonin G protein-coupled receptors. Melatonin inhibits BACE1 and PS1 protein expressions through the attenuation of nuclear factor-kappaB phosphorylation (pNF-kappaB). Moreover, melatonin reduced BACE1 promoter transactivation and consequently downregulated beta-secretase catalytic activity. The present data show that melatonin is not only a potential regulator of beta/gamma-secretase but also an activator of alpha-secretase expression through the activation of protein kinase C, thereby favoring the nonamyloidogenic pathway over the amyloidogenic pathway. Altogether, our findings suggest that melatonin may be a potential therapeutic agent for reducing the risk of AD in humans. PMID- 26123102 TI - The Effect of Early Postoperative Non-Steroidal Anti-Inflammatory Drugs on Pancreatic Fistula Following Pancreaticoduodenectomy. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used commonly for postoperative analgesia but can potentially impair healing. Their effect on pancreaticoduodenectomy (PD) outcomes is unknown. We sought to examine the impact of early postoperative NSAIDs on pancreatic fistula (PF) after PD. METHODS: We reviewed our prospective pancreatectomy database supplemented by medication administration records, including all PDs from 2002 to 2012. Primary outcome was occurrence of clinically significant (grade B-C) PF. Secondary outcomes included major morbidity (Clavien grade III-V) and 90-day mortality. Patients were compared based on early postoperative NSAID use (first 3 days following surgery) using univariate and multivariate analyses. Subgroup analyses were conducted based on NSAID type (COX-2 inhibitors and non-selective inhibitors). RESULTS: We included 251 PDs, of whom 127 (50.6%) patients received NSAIDs postoperatively (35.5% COX-2 inhibitors, 18.3% non-selective inhibitors, and 4.4% both). Use of any NSAIDs was associated with a non-significant increase in PF (16.5 vs 11.3%%; p = 0.23), and no difference in major morbidity and mortality. Use of non selective inhibitors was not associated with an increase in PF (8.7 vs 15.1%; p = 0.256). COX-2 inhibitors were associated with increased PF (20.2 vs 10.5 %; p = 0.033), but no difference in major morbidity or mortality. After adjusting for Charlson comorbidity and estimated blood loss, use of COX-2 inhibitors was independently associated with PF (odds ratio 2.12; p = 0.044). CONCLUSIONS: COX-2 inhibitors are associated with PF in the early postoperative period. While non selective inhibitors appear safe in this setting, caution is warranted with the use of COX-2 inhibitors. PMID- 26123103 TI - SMARCA4-deficient undifferentiated carcinoma of the ovary (small cell carcinoma, hypercalcemic type): clinicopathologic and immunohistochemical study of 3 cases. AB - Small cell carcinoma of the ovary, hypercalcemic type is a very rare aggressive neoplasm of unknown histogenesis, affecting mainly girls and young women. Recently, inactivating mutations in SMARCA4 (BRG1), a member of the switch/sucrose nonfermenting chromatin remodeling complex, has been identified as driver events in most cases. We herein describe 3 cases in 34, 34, and 37-year old women. Symptoms were mainly abdominal pain and mass. One patient was normocalcemic, and the other 2 had no preoperative serum calcium values available. All patients received radical hysterectomy with salpingo-oophorectomy, lymphadenectomy, and variable multimodality therapy. Two developed abdominal recurrences/metastases and died of disease at 4 and 12 months. One patient was alive without disease 17 months after surgery and radiochemotherapy. Histologic examination showed undifferentiated neoplasms composed of diffuse sheets, nests and cords of noncohesive monomorphic small blue/basaloid cells (classic variant, 1 case), and large undifferentiated/rhabdoid cells with abundant cytoplasm (large cell/rhabdoid variant, 2 case) admixed with minor small cell areas. One case contained rare isolated goblet cells, but true glandular component was absent. All tumors expressed vimentin and variably pancytokeratin and WT1. Nuclear SMARCB1 was intact in all cases (1 case showed small foci with mosaic loss). All tumors showed complete loss of SMARCA4. In conclusion, SMARCA4 immunohistochemistry represents a highly valuable emerging tool in identifying small cell carcinoma of the ovary, hypercalcemic type in routine practice. Distinguishing this aggressive neoplasm from juvenile granulosa cell tumor and other undifferentiated ovarian cancers is mandatory in selecting appropriate chemotherapeutic regimens and would allow better characterization of this entity, for which targeted molecular therapy still remains to be established. PMID- 26123105 TI - A new safety channel based on 17N detection in research reactors. AB - Tehran research reactor (TRR) is a representative of pool type research reactors using light water, as coolant and moderator. This reactor is chosen as a prototype to demonstrate and prove the feasibility of (17)N detection as a new redundant channel for reactor power measurement. In TRR, similar to other pool type reactors, neutron detectors are immersed in the pool around the core as the main power measuring devices. In the present article, a different approach, using out of water neutron detector, is employed to measure reactor power. This new method is based on (17)O (n,p) (17)N reaction taking place inside the core and subsequent measurement of delayed neutrons emitted due to (17)N disintegration. Count and measurement of neutrons around outlet water pipe provides a reliable redundant safety channel to measure reactor power. Results compared with other established channels indicate a good agreement and shows a linear interdependency with true thermal power. Safety of reactor operation is improved with installation & use of this new power measuring channel. The new approach may equally serve well as a redundant channel in all other types of reactors having coolant comprised of oxygen in its molecular constituents. Contrary to existing channels, this one is totally out of water and thus is an advantage over current instrumentations. It is proposed to employ the same idea on other reactors (nuclear power plants too) to improve safety criteria. PMID- 26123101 TI - The clearance effect of bovine anti-Helicobacter pylori antibody-containing milk in O blood group Helicobacter pylori-infected patients: a randomized double-blind clinical trial. AB - BACKGROUND: The failure in standard triple therapy has recently increased to high levels in China, primarily because of insufficient patient compliance, antimicrobial resistance, and high costs. Effective prevention and eradication of Helicobacter pylori (H. pylori) by artificial passive immunization with orally administered bovine antibodies in the milk has been demonstrated in many animal studies, but the clinical studies that are available have shown no H. pylori eradication. This study was to evaluate the efficacy and safety of orally administered bovine anti-H. pylori antibodies for the clearance of H. pylori infecting O blood group subpopulations. METHODS: Two local epidemic H. pylori strains that were prevalent locally were screened and then used to immunize dairy cows. After confirmation of the presence of anti-H. pylori polyclonal antibodies in the milk by enzyme-linked immunosorbent assay, the milk was subsequently defatted and processed into sterile milk by pasteurization. This study was designed as a double-blind placebo-controlled randomized clinical trial. Our 61 H. pylori-infected O blood group subjects were assigned to two groups; 31 subjects were treated with bovine milk containing antibodies and 30 subjects with the placebo. The medication-based study was continued for 28 days. Subjects were followed up for 56 days. The effect was assessed by the C-14 urea breath test (UBT). SPSS 17.0 software for Windows was used to analyze the data. RESULTS: Of the 61 subjects enrolled, 58 completed the protocol. One volunteer in the antibodies group and two volunteers in the control group dropped out. Of the 30 antibody-treated subjects, 13 became UBT negative, whereas none of the 30 of the placebo-treated subjects became UBT negative after the medication. Of 13 UBT negative patients, 3 became positive again at the end of the follow-up. Both intention to treat and per-protocol analysis indicated a significant difference in the clearance rate of infected patients between the groups treated with bovine antibody-containing milk and the placebo (P = 0.001, P < 0.05) and no significant difference in adverse effects (P > 0.05 all). CONCLUSIONS: Bovine antibody-based oral immunotherapy appears to be safe and has a significant clearance effect on intragastric H. pylori that infects O blood group adults. TRIAL REGISTRATION: ChiCTR-TRC-14005212. PMID- 26123104 TI - Status epilepticus induction has prolonged effects on the efficacy of antiepileptic drugs in the 6-Hz seizure model. AB - Several factors may influence the efficacy of antiepileptic drugs (AEDs) in patients with epilepsy, and treatment resistance could be related to genetics, neuronal network alterations, and modification of drug transporters or targets. Consequently, preclinical models used for the identification of potential new, more efficacious AEDs should reflect at least a few of these factors. Previous studies indicate that induction of status epilepticus (SE) may alter drug efficacy and that this effect could be long-lasting. In this context, we wanted to assess the protective effects of mechanistically diverse AEDs in mice subjected to pilocarpine-induced SE in another seizure model. We first determined seizure thresholds in mice subjected to pilocarpine-induced SE in the 6-Hz model, 2 weeks and 8 weeks following SE. We then evaluated the protective effects of mechanistically diverse AEDs in post-SE and control animals. No major differences in 6-Hz seizure susceptibility were observed between control groups, while the seizure threshold of pilocarpine mice at 8 weeks after SE was higher than at 2 weeks and higher than in control groups. Treatment with AEDs revealed major differences in drug response depending on their mechanism of action. Diazepam produced a dose-dependent protection against 6-Hz seizures in control and pilocarpine mice, both at 2 weeks and 8 weeks after SE, but with a more pronounced increase in potency in post-SE animals at 2 weeks. Levetiracetam induced a potent and dose-dependent protection in pilocarpine mice, 2 weeks after SE, while its protective effects were observed only at much higher doses in control mice. Its potency decreased in post-SE mice at 8 weeks and was very limited (30% protection at the highest tested dose) in the control group. Carbamazepine induced a dose-dependent protection at 2 weeks in control mice but only limited effect (50% at the highest tested dose) in pilocarpine mice. Its efficacy deeply decreased in post-SE mice at 8 weeks after SE. Perampanel and phenytoin showed almost comparable protective effects in all groups of mice. These experiments confirm that prior SE may have an impact on both potency and efficacy of AEDs and indicate that this effect may be dependent on the underlying epileptogenic processes. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26123106 TI - Development of a surrogate model for elemental analysis using a natural gamma ray spectroscopy tool. AB - A systematic computational method for obtaining accurate elemental standards efficiently for varying borehole conditions was developed based on Monte Carlo simulations, surrogate modeling, and data assimilation. Elemental standards are essential for spectral unfolding in formation evaluation applications commonly used for nuclear well logging tools. Typically, elemental standards are obtained by standardized measurements, but these experiments are expensive and lack the flexibility to address different logging conditions. In contrast, computer-based Monte Carlo simulations provide an accurate and more flexible approach to obtaining elemental standards for formation evaluation. The presented computational method recognizes that in contrast to typical neutron-photon simulations, where the source is typically artificial and well characterized (Galford, 2009), an accurate knowledge of the source is essential for matching the obtained Monte Carlo elemental standards with their experimental counterparts. Therefore, source distributions are adjusted to minimize the L2 difference of the Monte Carlo computed and experimental standards. Subsequently, an accurate surrogate model is developed accounting for different casing and cement thicknesses, and tool positions within the borehole. The adjusted source distributions are then utilized to generate and validate spectra for varying borehole conditions: tool position, casing and cement thickness. The effect of these conditions on the spectra are investigated and discussed in this work. Given that Monte Carlo modeling provides much lower cost and more flexibility, employing Monte Carlo could enhance the processing of nuclear tool logging data computed standards. PMID- 26123107 TI - Characterizations of BC501A and BC537 liquid scintillator detectors. AB - Two 2"*2" liquid scintillator detectors BC537 and BC501A have been characterized for their responses and efficiencies to gamma-ray detection. Light output resolution and response functions were derived by least-squares minimization of a simulated response function, fitted to experimental data. The gamma-ray response matrix and detection efficiency were simulated with Monte Carlo (MC) methods and validated. For photon energies below 2.4 MeVee, the resolution, as well as the efficiency, of BC501A is better than BC537 scintillator. The situation is reversed when the energy is higher than 2.4 MeVee. BC537 has higher gamma-ray detection efficiency than BC501A if the impinging photon energy is more than 2 MeV due to different ratios of C to H/D atoms. PMID- 26123109 TI - How cells coordinate waste removal through their major proteolytic pathways. AB - The eukaryotic cell uses two complex machineries to degrade unwanted proteins. The first is the ubiquitin-proteasome system and the second is autophagy. A new study contributes to our understanding of how the two systems interconnect to coordinate protein degradation. PMID- 26123110 TI - Rubicon swaps autophagy for LAP. AB - Phagocytic cells engulf their prey into vesicular structures called phagosomes, of which a certain proportion becomes demarcated for enhanced maturation by a process called LC3-associated phagocytosis (LAP). Light has now been shed on the molecular requirements of LAP, establishing a central role for the protein Rubicon in the immune response to Aspergillus fumigatus. PMID- 26123108 TI - Proteostasis control by the unfolded protein response. AB - Stress induced by accumulation of misfolded proteins in the endoplasmic reticulum is observed in many physiological and pathological conditions. To cope with endoplasmic reticulum stress, cells activate the unfolded protein response, a dynamic signalling network that orchestrates the recovery of homeostasis or triggers apoptosis, depending on the level of damage. Here we provide an overview of recent insights into the mechanisms that cells employ to maintain proteostasis and how the unfolded protein response determines cell fate under endoplasmic reticulum stress. PMID- 26123111 TI - Super-resolution links vinculin localization to function in focal adhesions. AB - Integrin-based focal adhesions integrate biochemical and biomechanical signals from the extracellular matrix and the actin cytoskeleton. The combination of three-dimensional super-resolution imaging and loss- or gain-of-function protein mutants now links the nanoscale dynamic localization of proteins to their activation and function within focal adhesions. PMID- 26123112 TI - Kinetochore components are required for central spindle assembly. PMID- 26123113 TI - MCUR1 is an essential component of mitochondrial Ca(2+) uptake that regulates cellular metabolism. PMID- 26123114 TI - The influence of dietary restriction on hepatic mononuclear cell numbers and functions in mice. AB - BACKGROUND: Surgical patients with gastrointestinal malignancies are at increased risk for malnutrition. However, the mechanism by which dietary restriction (DR), one form of malnutrition, impairs hepatic immunity remains to be clarified. The present study was designed to examine the influence of DR on hepatic mononuclear cell (MNC) numbers, subpopulations, and cytokine productions (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], and interleukin 10 [IL 10]) in response to lipopolysaccharide (LPS) in mice. Immunoglobulin (Ig) A levels in the gallbladder and histopathologic changes in the liver were also assessed. MATERIAL AND METHODS: Male Institute of Cancer Research mice were randomly assigned to three dietary groups: ad libitum (AD), mild restriction (MR), and severe restriction (SR). The AD, MR, and SR groups received daily mouse chow in amounts of 190, 133, and 76 g/kg, respectively, for 7 d. After the mice had been fed for 7 d, hepatic MNCs were isolated. Total hepatic MNCs were counted and subpopulations were determined by flow cytometry. Cytokine productions (TNF alpha, IFN-gamma, and IL-10) by hepatic MNCs in response to LPS were measured. Blood samples were analyzed for hepatobiliary biochemical parameters. IgA levels in gallbladder bile were measured with enzyme-linked immunosorbent assay. In addition, liver histologies were examined. RESULTS: Hepatic MNC numbers were significantly lower in the MR and SR groups than in the AD group, with no significant difference between the MR and SR groups. The percentage of B cells was significantly lower in the SR group than in the MR and AD groups, whereas the T-cell percentage was higher in the SR group than in the MR and AD groups. The percentage of Kupffer cells was significantly lower in the SR group than in the AD group, whereas that in the MR group was midway between those in the SR and AD groups. TNF-alpha and IL-10 levels in hepatic MNC culture supernatants were increased LPS-dose dependently in the AD group. However, the increase was slight in the MR group and absent in the SR group. The IgA levels in gallbladder bile were significantly lower in the SR and MR groups than in the AD group. On the basis of hematoxylin and eosin staining of hepatic sections, livers from the SR group showed atrophic hepatocytes and sinusoidal dilatation, whereas these changes were absent in the AD group. CONCLUSIONS: DR decreases hepatic MNC number with subpopulation changes, reduces IgA levels in gallbladder bile, blunts cytokine production by hepatic MNCs, and induces pathologic damage in the liver, which may be an important mechanism underlying the impaired host defense associated with malnutrition. PMID- 26123115 TI - Establishment of swine-penetrating craniocerebral gunshot wound model. AB - BACKGROUND: Bullet-induced brain wounds are common among military personnel in war zones and among civilians with gun accidents or crime-related gun injuries. The goal of this study was to develop a nonfatal porcine model of penetrating craniocerebral gunshot wound (PCGW) by firing a projectile in live swine to induce PCGW in such a realistic manner as to reconstruct their physical characteristics. MATERIALS AND METHODS: We established a nonfatal porcine model of PCGW based on a custom-designed experimental gun that emulates the shooting of a 5.56-mm NATO standard rifle at 800 m (317 m/s; 200.9 J). Commercial swine (n = 20) were subjected to a ballistic wound to the bilateral frontal lobe, and four swine were used as controls. Surviving swine were used in subsequent first-aid, management, and monitoring experiments for neurosurgeons. Various physiological variables were measured continuously. After computed tomography (CT) scanning and three-dimensional CT reconstructions, all pigs underwent primary lifesaving emergency interventions, including emergency decompressive craniotomies and hemorrhage control. RESULTS: In our nonfatal porcine model of PCGW, injuries were comparable in their morphology to real gunshot wounds, as evidenced by analysis of wound characteristics and CT scan images. The survival rates of the pigs were 100% within 2 h, 95% within 6 h, 85% within 12 h, and 85% within 24 h (P < 0.01). Hemodynamics, hematology, blood routine biochemistry, coagulation, and other physiological parameters also exhibited significant changes in the PCGW pigs. CONCLUSIONS: This model makes possible the laboratory reproduction of real ballistic wounds in a live large animal model that is close to humans. PMID- 26123116 TI - Radiotherapy: The tyranny of distance. PMID- 26123117 TI - Linking Precursor Alterations to Nanoscale Structure and Optical Transparency in Polymer Assisted Fast-Rate Dip-Coating of Vanadium Oxide Thin Films. AB - Solution processed metal oxide thin films are important for modern optoelectronic devices ranging from thin film transistors to photovoltaics and for functional optical coatings. Solution processed techniques such as dip-coating, allow thin films to be rapidly deposited over a large range of surfaces including curved, flexible or plastic substrates without extensive processing of comparative vapour or physical deposition methods. To increase the effectiveness and versatility of dip-coated thin films, alterations to commonly used precursors can be made that facilitate controlled thin film deposition. The effects of polymer assisted deposition and changes in solvent-alkoxide dilution on the morphology, structure, optoelectronic properties and crystallinity of vanadium pentoxide thin films was studied using a dip-coating method using a substrate withdrawal speed within the fast-rate draining regime. The formation of sub-100 nm thin films could be achieved rapidly from dilute alkoxide based precursor solutions with high optical transmission in the visible, linked to the phase and film structure. The effects of the polymer addition was shown to change the crystallized vanadium pentoxide thin films from a granular surface structure to a polycrystalline structure composed of a high density of smaller in-plane grains, resulting in a uniform surface morphology with lower thickness and roughness. PMID- 26123118 TI - Descriptive study of carers' support, encouragement and modelling of healthy lifestyle behaviours in residential out-of-home care. AB - OBJECTIVE: Given the high prevalence of overweight/obesity among young people in residential out-of-home care (OOHC), and as their carers are in loco parentis, this research aimed: 1) to examine the healthy lifestyle cognitions and behaviours of residential carers; and 2) to describe resources needed to improve diet and/or physical activity outcomes for residents. METHODS: Cross-sectional data were collected from 243 residential carers. Measures included: demographics; knowledge of dietary/physical activity recommendations; self-reported encouragement/importance of health behaviours; physical activity/screen time (at work); unit 'healthiness'; and necessary resources for creating a healthy environment. RESULTS: Staff placed importance on the residents eating well and being physically active. However, examination of carer knowledge found significant gaps in staff education. Three key priority areas were identified to help build a healthy food and activity environment in residential OOHC: funding, professional development and policy. CONCLUSION: Carer knowledge of healthy lifestyles can be improved and they need to be well resourced to ensure children in public care settings live in a healthy environment. IMPLICATIONS: These findings may inform the development of ongoing professional development to improve carers' health literacy, as well as policy to support dietary/activity guidelines for the OOHC sector. PMID- 26123119 TI - TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis. AB - Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS-F). Expression of TP53 was evaluated in BM core biopsy specimens using dual-colour CD34/TP53 immunohistochemistry with computer-assisted image analysis. Mutation analysis was performed using next generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47.1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0.0294). High levels of TP53 expression (3 + in >=10% cells) were associated with higher BM blast counts (P = 0.0149); alterations of chromosomes 5 (P = 0.0009) or 7 (P = 0.0141); complex karyotype (P = 0.0002); high- and very-high risk IPSS-R groups (P = 0.009); and TP53 mutations (P = 0.0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0.001). Expression of TP53 by CD34-positive cells was associated with shorter OS and leukaemia-free survival (P = 0.0428). TP53 overexpression is a predictor of poor outcome in patients with MDS-F. PMID- 26123120 TI - Which, when and why? Rational use of tissue-based molecular testing in localized prostate cancer. AB - An increased molecular understanding of localized prostate cancer and the improved ability for molecular testing of pathologic tissue has led to the development of multiple clinical assays. Here we review the relevant molecular biology of localized prostate cancer, currently available tissue-based tests and describe which is best supported for use in various clinical scenarios. Literature regarding testing of human prostate cancer tissue with Ki-67, PTEN (by immunohistochemistry (IHC) or fluroescence in situ hybridization (FISH)), ProMark, Prolaris, OncotypeDX Prostate and Decipher was reviewed to allow for generation of expert opinions. At diagnosis, evaluation of PTEN status, use of ProMark or OncotypeDX Prostate in men with Gleason 6 or 3+4=7 disease may help guide the use of active surveillance. For men with Gleason 7 or above disease considering watchful waiting, Ki-67 and Prolaris add independent prognostic information. For those men who have undergone prostatectomy and have adverse pathology, Decipher testing may aid in the decision to undergo adjuvant radiation. Newly available molecular tests bring opportunities to improve decision making for men with localized prostate cancer. A review of the currently available data suggests clinical scenarios for which each of these tests may have the greatest utility. PMID- 26123121 TI - Fabrication of SnO2-SnO nanocomposites with p-n heterojunctions for the low temperature sensing of NO2 gas. AB - In this report, the fabrication of a novel SnO2-SnO nanostructure with p-n heterojunctions has been achieved through a facile one-pot and low-cost hydrothermal process. The structure and properties of the nanocomposite were analyzed with X-ray techniques and electron microscopy. HRTEM characterization showed that the p-n heterojunctions were formed with small n-type SnO2 nanocrystals dispersed on the surface of large p-type SnO crystals. Compared to the single SnO2-based material, a gas sensor fabricated from the SnO2-SnO composite exhibited an enhanced sensing performance for NO2 gas detection, with a limit of detection and sensitivity of 0.1 ppm and 0.26 ppm(-1), respectively, at a relatively low operating temperature (50 degrees C). Moreover, the p-n heterojunctions exhibited high sensing selectivity for NO2. Such a high sensing sensitivity and a low operating temperature make the SnO2-SnO p-n nanomaterial a promising gas sensor for practical NO2 gas detection. The improved sensing response characteristics of the hybrid material could be attributed to the p-n junctions formed through the in situ growth of SnO2 nanocrystals on SnO nanoplates. The present study is helpful for the design of novel gas sensing materials and the development of NO2 gas sensors. PMID- 26123122 TI - Early versus delayed laparoscopic common bile duct exploration for common bile duct stone-related nonsevere acute cholangitis. AB - It is undetermined when and how laparoscopic common bile duct exploration (LCBDE) should be used in patients with common bile duct (CBD) stone-related nonsevere acute cholangitis. We aimed to evaluate the effect of LCBDE on the clinical outcome of those patients within (early) or beyond (delayed) 72 hours of emergent admission. Surgery-related complications, length of hospital stay (LOS), and total cost, as well as demographic and clinical parameters were compared between the two groups. Finally, 3 and 5 patients in early and delayed LCBDE group, respectively, had retained stones, which were removed by choledochoscopy before T tube was removed. Each group had 3 patients who developed biliary leak, which was conservatively cured by the drainage. Shorter LOS and less total cost were observed in early group compared to the late one (13.34 +/- 4.48 vs. 18.32 +/- 9.13, p < 0.05; 17712 +/- 5446.63 vs. 21776 +/- 7230.41 YRMB, p < 0.05). Improvement of cholangitis was achieved in all patients with LCBDE. None of the patients developed stricture of the CBD after LCBDE. To conclude, both early and delayed LCBDE are safe and effective for the treatment of CBD stone-related nonsevere acute cholangitis during emergent admissions. Early LCBDE may be superior to delayed procedure due to the shorter LOS and less cost. PMID- 26123123 TI - Needs and priorities of women with endometrial and cervical cancer. AB - INTRODUCTION: Rehabilitation after cancer is important, and efficient rehabilitation requires knowledge of patient's needs. This study aimed to identify short-term rehabilitation needs of women with endometrial and cervical cancer. METHODS: Ninety-six women (82.6%) were included in an exploratory questionnaire study from Odense University Hospital from September 2011 to March 2012. Needs were assessed pre-treatment and 3 months later using the three-levels of-needs questionnaire. Furthermore, 16 women participated in focus group interviews following the treatment. The interviews were audio-recorded, transcribed verbatim and analyzed thematically. RESULTS: Forty-four of the included women were diagnosed with cervical cancer (median age 45 years). Of these, 22 had FIGO-stage 1 disease (50%) and 23 received radiation therapy (52.3%). The remaining 52 women (median age 66.5 years) were diagnosed with endometrial cancer. Of these, 38 had FIGO-stage 1 disease (73.1%) and 25 were treated with laparoscopic surgery (48.1%). Emotional functioning was significantly worse prior to treatment in both the cancers (p < 0.001 cervical and p = 0.002 endometrial) and worry constituted an unmet need in 70.7% of cervical and 34.7% of endometrial cancer patients. Both the patient groups experienced significant lymphedema post-treatment [endometrial cancer (p = 0.006) and cervical cancer (p = 0.002)]. Further, urological problems were more prevalent post-treatment in endometrial cancer patients (p = 0.018), while sexual problems were of specific concern for cervical cancer patients (p = 0.029). However, in both cancer groups, the mean problem intensity scores were comparable to normative data, suggesting that the majority of patients will not require extensive rehabilitation. Qualitative analysis indicated that treatment modality and marital status severely impacted on coping, suggesting that irradiated and single women are at higher risk of developing rehabilitation needs. Additionally, women younger than 55 years more often requested help dealing with sexual and psychological complications. DISCUSSION: Women with endometrial and cervical cancer experience emotional problems prior to therapy and lymphedema, and urological and sexual problems following treatment. An awareness of these problems may facilitate early identification of women with unmet needs and enable individualized follow-up adjusted for such patient's needs. Interventions aimed at improving sexual and psychological functioning should be available. PMID- 26123124 TI - HLA-B*59:09, a novel allele identified by sequence-based typing in a cord blood donated by a Korean woman. AB - The new allele B*59:09 showed two nucleotide differences with B*59:01:01:01 in exon 3. PMID- 26123125 TI - The predominant cluster of CRF01_AE circulating among newly diagnosed HIV-1 positive people in Anhui Province, China. AB - CRF01_AE, which has led a new epidemic in many provinces in China and has displayed complex characteristics, has now evolved into multiple clusters in China. Some clusters often circulate in specific regions or among specific risk populations in China. To better determine the characteristics of CRF01_AE circulating in Anhui Province, we analyzed CRF01_AE based on gag and pol sequences. Our results showed that CRF01_AE circulating in Anhui Province was clearly divided into three clusters. Cluster 1 covered 90% of the sequences in all CRF01_AE. Among Cluster 1, the sequences from men who have sex with men (MSM) and heterosexuals were interwoven. It is suggested that MSM may play a bridge role in transmitting HIV-1 among the different risk groups. PMID- 26123127 TI - Reply to "Tuberculosis in infants less than 3 months of age of Risaralda, Colombia". PMID- 26123126 TI - Interventions for increasing the proportion of health professionals practising in rural and other underserved areas. AB - BACKGROUND: The inequitable distribution of health professionals, within countries, poses an important obstacle to the optimal functioning of health services. OBJECTIVES: To assess the effectiveness of interventions aimed at increasing the proportion of health professionals working in rural and other underserved areas. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, including specialised register of the Cochrane Effective Practice and Organisation of Care Group; March 2014), MEDLINE (1966 to March 2014), EMBASE (1988 to March 2014), CINAHL (1982 to March 2014), LILACS (February 2014), Science Citation Index and Social Sciences Citation Index (up to April 2014), Global Health (March 2014) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (June 2013). We also searched reference lists of all papers and relevant reviews identified, and contacted authors of relevant papers regarding any further published or unpublished work. SELECTION CRITERIA: Randomised trials, non-randomised trials, controlled before-and-after studies and interrupted time series studies evaluating the effects of various interventions (e.g. educational, financial, regulatory or support strategies) on the recruitment or retention, or both, of health professionals in underserved areas. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts and assessed full texts of potentially relevant studies for eligibility. Two review authors independently extracted data from eligible studies. MAIN RESULTS: For this first update of the original review, we screened 8945 records for eligibility. We retrieved and assessed the full text of 125 studies. Only one study met the inclusion criteria of the review. This interrupted time series study, conducted in Taiwan, found that the implementation of a National Health Insurance scheme in 1995 was associated with improved equity in the geographic distribution of physicians and dentists. We judged the certainty of the evidence provided by this one study very low. AUTHORS' CONCLUSIONS: There is currently limited reliable evidence regarding the effects of interventions aimed at addressing the inequitable distribution of health professionals. Well-designed studies are needed to confirm or refute findings of observational studies of educational, financial, regulatory and supportive interventions that might influence healthcare professionals' decisions to practice in underserved areas. Governments and medical schools should ensure that when interventions are implemented, their impacts are evaluated using scientifically rigorous methods to establish the true effects of these measures on healthcare professional recruitment and retention in rural and other underserved settings. PMID- 26123128 TI - Effects of eldecalcitol on cortical bone response to mechanical loading in rats. AB - BACKGROUND: Mechanical loading of bones activates modeling and suppresses remodeling by promoting bone formation. Eldecalcitol is approved for the treatment of osteoporosis in Japan and is often used in patients undergoing exercise therapy. However, the effects of eldecalcitol on bone formation during mechanical loading are unknown. The aim of this study was to clarify the influence of eldecalcitol administration on bone response to mechanical loading using a four-point bending device. METHODS: Forty six-month-old female Wistar rats were randomized into four groups based on eldecalcitol dose (vehicle administration (VEH), low dose (ED-L), medium dose (ED-M), and high dose (ED-H)). Loads of 38 N were applied in vivo to the right tibia for 36 cycles at 2 Hz, by four-point bending, 3 days per week for 3 weeks. After calcein double-labeling, rats were sacrificed and tibial cross sections were prepared from the region with maximal bending at the central diaphysis. Histomorphometry was performed on the entire periosteal and endocortical surface of the tibiae, dividing the periosteum into lateral and medial surfaces. RESULTS: The effects of external loading on bone formation parameters were significant at all three surfaces. Bone formation parameters were highest in the ED-H group, and the effects of eldecalcitol on bone formation rate were significant at the endocortical surface. In addition, the interaction between loading and eldecalcitol dose significantly affected bone formation rate at the endocortical surface. CONCLUSIONS: Eldecalcitol enhanced the cortical bone response to mechanical loading and a synergistic effect was observed in a rat model. PMID- 26123129 TI - Leukoencephalopathy with cerebral calcifications and cysts: clinical and pathological features in two adults. AB - Two adult patients diagnosed with Leukoencephalopathy with cerebral calcifications and cysts (LCC) were presented. Both patients had a long-term (8 10 years) following-up. Radiological findings of both patients revealed the characteristic signs of LCC: cerebral white matter abnormalities, calcifications, and cysts. In case 1, the initial CT scan showed a low-density area in the right frontal lobe and it had developed into a large cystic lesion after 8 years. Histopathological determination revealed that the cyst wall was associated with hemorrhage, angiomatous formation, and some Rosenthal fibers. In case 2, a major cystic lesion was located at the left parietal lobe which was resected and an old hematoma was found inside the cyst. Nine years later, the follow-up neuroimaging of case 2 showed a remarkable improvement of white matter abnormalities and cystic lesions. Hemorrhagic fluid was observed inside the cysts. Additionally, follow-up CT and MR scans showed a rapid enlargement of cystic lesions accompanied with hemorrhagic fluid levels after a year. Then, a major cyst was surgically removed to relieve pressure symptoms. Pathology of the resected cyst exhibited an organized hemorrhage inside the cyst and a large amount of hemosiderin surrounding the cyst wall. In conclusion, our two cases demonstrated that angiomatous changes subsequent with hemorrhage may be the major mechanism of cyst formation and development. PMID- 26123130 TI - Therapeutic administration of atomoxetine combined with rTMS and occupational therapy for upper limb hemiparesis after stroke: a case series study of three patients. AB - Atomoxetine, a selective noradrenaline reuptake inhibitor, has been reported to enhance brain plasticity, but has not yet been used in stroke patients. We reported the feasibility and clinical benefits on motor functional recovery of the combination of repetitive transcranial magnetic stimulation (rTMS) and intensive occupational therapy (OT) in stroke patients. This pilot study was designed to evaluate the additive effects of oral atomoxetine to rTMS/OT in post stroke hemiparetic patients. The study included three post-stroke patients with upper limb hemiparesis. Treatment with 40 mg/day atomoxetine commenced 2 weeks before admission. After confirming tolerance, the dose was increased to 120 mg/day. Low-frequency rTMS/OT was provided daily for 15 days during continued atomoxetine therapy. Motor function of the affected upper limb was evaluated with the Fugl-Meyer Assessment and Wolf Motor Function test. All patients completed the protocol and showed motor improvement up to 4 weeks after the treatment. No atomoxetine-related side effects were noted. Our protocol of triple therapy of atomoxetine, low-frequency rTMS, and OT is safe and feasible intervention for upper limb hemiparesis after stroke. PMID- 26123131 TI - Segmentation of white blood cells and comparison of cell morphology by linear and naive Bayes classifiers. AB - BACKGROUND: Blood smear microscopic images are routinely investigated by haematologists to diagnose most blood diseases. However, the task is quite tedious and time consuming. An automatic detection and classification of white blood cells within such images can accelerate the process tremendously. In this paper we propose a system to locate white blood cells within microscopic blood smear images, segment them into nucleus and cytoplasm regions, extract suitable features and finally, classify them into five types: basophil, eosinophil, neutrophil, lymphocyte and monocyte. DATASET: Two sets of blood smear images were used in this study's experiments. Dataset 1, collected from Rangsit University, were normal peripheral blood slides under light microscope with 100* magnification; 555 images with 601 white blood cells were captured by a Nikon DS Fi2 high-definition color camera and saved in JPG format of size 960 * 1,280 pixels at 15 pixels per 1 MUm resolution. In dataset 2, 477 cropped white blood cell images were downloaded from CellaVision.com. They are in JPG format of size 360 * 363 pixels. The resolution is estimated to be 10 pixels per 1 MUm. METHODS: The proposed system comprises a pre-processing step, nucleus segmentation, cell segmentation, feature extraction, feature selection and classification. The main concept of the segmentation algorithm employed uses white blood cell's morphological properties and the calibrated size of a real cell relative to image resolution. The segmentation process combined thresholding, morphological operation and ellipse curve fitting. Consequently, several features were extracted from the segmented nucleus and cytoplasm regions. Prominent features were then chosen by a greedy search algorithm called sequential forward selection. Finally, with a set of selected prominent features, both linear and naive Bayes classifiers were applied for performance comparison. This system was tested on normal peripheral blood smear slide images from two datasets. RESULTS: Two sets of comparison were performed: segmentation and classification. The automatically segmented results were compared to the ones obtained manually by a haematologist. It was found that the proposed method is consistent and coherent in both datasets, with dice similarity of 98.9 and 91.6% for average segmented nucleus and cell regions, respectively. Furthermore, the overall correction rate in the classification phase is about 98 and 94% for linear and naive Bayes models, respectively. CONCLUSIONS: The proposed system, based on normal white blood cell morphology and its characteristics, was applied to two different datasets. The results of the calibrated segmentation process on both datasets are fast, robust, efficient and coherent. Meanwhile, the classification of normal white blood cells into five types shows high sensitivity in both linear and naive Bayes models, with slightly better results in the linear classifier. PMID- 26123132 TI - Pluripotent stem cell-derived radial glia-like cells as stable intermediate for efficient generation of human oligodendrocytes. AB - Neural precursor cells (NPCs) derived from human pluripotent stem cells (hPSCs) represent an attractive tool for the in vitro generation of various neural cell types. However, the developmentally early NPCs emerging during hPSC differentiation typically show a strong propensity for neuronal differentiation, with more limited potential for generating astrocytes and, in particular, for generating oligodendrocytes. This phenomenon corresponds well to the consecutive and protracted generation of neurons and GLIA during normal human development. To obtain a more gliogenic NPC type, we combined growth factor-mediated expansion with pre-exposure to the differentiation-inducing agent retinoic acid and subsequent immunoisolation of CD133-positive cells. This protocol yields an adherent and self-renewing population of hindbrain/spinal cord radial glia (RG) like neural precursor cells (RGL-NPCs) expressing typical neural stem cell markers such as nestin, ASCL1, SOX2, and PAX6 as well as RG markers BLBP, GLAST, vimentin, and GFAP. While RGL-NPCs maintain the ability for tripotential differentiation into neurons, astrocytes, and oligodendrocytes, they exhibit greatly enhanced propensity for oligodendrocyte generation. Under defined differentiation conditions promoting the expression of the major oligodendrocyte fate-determinants OLIG1/2, NKX6.2, NKX2.2, and SOX10, RGL-NPCs efficiently convert into NG2-positive oligodendroglial progenitor cells (OPCs) and are subsequently capable of in vivo myelination. Representing a stable intermediate between PSCs and OPCs, RGL-NPCs expedite the generation of PSC-derived oligodendrocytes with O4-, 4860-, and myelin basic protein (MBP)-positive cells that already appear within 7 weeks following growth factor withdrawal-induced differentiation. Thus, RGL-NPCs may serve as robust tool for time-efficient generation of human oligodendrocytes from embryonic and induced pluripotent stem cells. PMID- 26123133 TI - A qualitative analysis of the barriers and facilitators of HIV counselling and testing perceived by adolescents in South Africa. AB - BACKGROUND: Youth in South Africa have been identified as a high-risk group for contracting HIV. In response, the South African Integrated School Health Policy (ISHP) has been developed with the aim of guiding the provision of comprehensive healthcare services within South African schools. Accordingly, the scale-up of HIV counselling and testing (HCT) in high schools is a priority. This study examines the factors affecting the utilisation of HCT services amongst learners in high schools in the KwaZulu-Natal province of South Africa. METHODS: Focus group discussions were conducted in 12 rural schools in the Vulindlela sub district of uMgungundlovu in KwaZulu-Natal. A total of 158 randomly selected learners took part, aged 16 years and older from grades 10, 11 and 12. Qualitative analysis was conducted using the framework approach, providing a systematic structure allowing for a priori and emergent codes, with social cognitive theory as a theoretical framework. RESULTS: The stigma and discrimination attached to testing, along with the inherent fear of a positive result were the biggest barriers to HCT uptake. Fear and the subsequent negative beliefs around HCT were borne out of insufficient knowledge. These fears were exacerbated by the perceived or real attitudes of peers, partners and family towards HIV. The prospect of a positive result and the possible resultant societal backlash hinders high and regular uptake of HCT. Stigma and discrimination remain the foremost barriers to HIV testing despite the presence of localised and convenient testing. Interventions aimed at addressing these challenges could increase the demand for HIV testing amongst adolescents. CONCLUSIONS: Increasing education about the importance of HCT and creating awareness about available HCT services will not be enough to increase uptake in schools in South Africa. Efforts to decrease stigma around HIV and HCT by integrating testing into general and sexual reproductive health services offered to youth, and normalising the epidemic within the community could go some way to allaying the fears shrouding testing, if such services are designed with the specific needs of youth in mind. This paper adds to the body of literature informing the design of policy in South Africa aimed at integrating HCT into school health services. PMID- 26123134 TI - Progression of myocardial fibrosis in hypertrophic cardiomyopathy. PMID- 26123135 TI - The pathophysiology of hypertensive acute heart failure. AB - While acute heart failure (AHF) is often regarded as a single disorder, an evolving understanding recognises the existence of multiple phenotypes with varied pathophysiological alterations. Herein we discuss hypertensive AHF and provide insight into a mechanism where acute fluid redistribution is caused by a disturbance in the ventricular-vascular coupling relationship. In this relationship, acute alterations in vascular elasticity, vasoconstriction and reflected pulse waves lead to increases in cardiac work and contribute to decompensated LV function with associated subendocardial ischaemia and end-organ damage. Chronic predisposing factors (neurohormonal activity, nitric oxide insensitivity, arterial stiffening) and physiological stressors (sympathetic surge, volume overload, physical exertion) that are causally linked to acute symptom onset are discussed. Lastly, we review treatment options including both nitrovasodilators and promising novel therapeutics, and discuss future directions in the management of this phenotypic variant. PMID- 26123136 TI - TAVI in 2015: who, where and how? PMID- 26123138 TI - Genotype by environment interaction for livability of dairy calves from first parity cows. AB - Death of calves around parturition is a matter of concern for dairy farmers. Relatively high stillbirth rates and unfavourable trends have been reported for Holstein heifers in the Netherlands and several other countries. In our study, we investigated herd differences, genetic parameters and genotype by environment interaction for heifer calf livability. A large dataset with data from calvings between 1993 and 2012 of Dutch dairy farms was used. There were considerable differences between herds in livability of calves from heifers, with averages ranging from 74% to 95%. Both herds with relatively high and low averages showed the same negative trend between 1993 and 2012, with largest declines in herds with the lowest averages. We found that heritability and genetic variation of first parity livability were substantially larger in herd environments where the likelihood of stillbirth was high v. environments where stillbirth was at a low level. The genetic correlations between herd environment levels were all very close to unity, indicating that ranking of sires was similar for all environments. However, for herds with a relatively high stillbirth incidence selecting sires with favourable breeding values is expected to be twice as profitable as in herds with a relatively low stillbirth incidence. PMID- 26123137 TI - Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: A randomized controlled trial. AB - BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after surgery is frequent, and is an important factor adversely influencing the long-term survival of patients. This prospective study evaluated whether adjuvant chemotherapy with oral tegafur/uracil (UFT) reduces the recurrence rate of HCC. In addition, expression of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) were investigated in resected tumors and nontumorous tissues, and the relationship between their expression and the effectiveness of UFT was examined. METHODS: A total of 117 patients who underwent curative hepatic resection for HCC were randomly allocated to UFT 400 mg/d (n = 24, UFT group) or surgery alone (n = 56, control group). The primary endpoint was the recurrence-free survival rate, and the secondary endpoint was the overall survival rate. Expression of the DPD and TS genes were quantified with TaqMan reverse transcription-polymerase chain reaction assay using beta-actin as an internal standard. The cut-off value was set at the mean value of TS and DPD expression. RESULTS: Among the 61 patients in the UFT group, 37 patients (60.6%) discontinued UFT within 1 month. Recurrence free survival (p = 0.16) and overall survival (p = 0.29) were similar in the two groups. In the UFT group, recurrence-free survival did not differ significantly between high-TS (TS > 3.6) and high-DPD (DPD > 8.9; n = 10), and low-TS (TS <= 3.6) and low-DPD (DPD <= 8.9; n = 9) groups. However, there was a significant difference between the two groups in overall survival (p = 0.04). CONCLUSION: Peroral UFT administration fails to prolong the recurrence-free rates and overall survival rates, in comparison with surgery alone. However, oral administration of UFT may improve the survival of HCC patients when the levels of TS and DPD mRNA are low in the tumor tissue. PMID- 26123139 TI - Estrogen regulation of microcephaly genes and evolution of brain sexual dimorphism in primates. AB - BACKGROUND: Sexual dimorphism in brain size is common among primates, including humans, apes and some Old World monkeys. In these species, the brain size of males is generally larger than that of females. Curiously, this dimorphism has persisted over the course of primate evolution and human origin, but there is no explanation for the underlying genetic controls that have maintained this disparity in brain size. RESULTS: In the present study, we tested the effect of the female hormone (estradiol) on seven genes known to be related to brain size in both humans and nonhuman primates, and we identified half estrogen responsive elements (half EREs) in the promoter regions of four genes (MCPH1, ASPM, CDK5RAP2 and WDR62). Likewise, at sequence level, it appears that these half EREs are generally conserved across primates. Later testing via a reporter gene assay and cell-based endogenous expression measurement revealed that estradiol could significantly suppress the expression of the four affected genes involved in brain size. More intriguingly, when the half EREs were deleted from the promoters, the suppression effect disappeared, suggesting that the half EREs mediate the regulation of estradiol on the brain size genes. We next replicated these experiments using promoter sequences from chimpanzees and rhesus macaques, and observed a similar suppressive effect of estradiol on gene expression, suggesting that this mechanism is conserved among primate species that exhibit brain size dimorphism. CONCLUSIONS: Brain size dimorphism among certain primates, including humans, is likely regulated by estrogen through its sex-dependent suppression of brain size genes during development. PMID- 26123140 TI - Occupational wellbeing in anaesthesiologists: its relationship with educational methodology. PMID- 26123141 TI - Use of sugammadex on burn patients: descriptive study. AB - OBJECTIVES: A burn patient is a challenge for any anesthesiologist, undergoing several surgeries during admission, and requiring general anesthesia and muscle relaxation most of the times. The victim may have respiratory system impairment and a response to muscle relaxants that differs from the healthy patient, thus proper monitoring and reversal is crucial. We analyzed sugammadex effectiveness and safety in this population. MATERIALS AND METHODS: It was a prospectively descriptive study, including 4 patients, and all of them were considered major burn patients, who underwent escharotomy with general anesthesia and neuromuscular relaxation. The main variable was the time for recovery of a TOF higher than 0.9 after the administration of sugammadex before extubation. RESULTS: Mean time of recovery from a TOF ratio higher than 0.9 following the administration of Sugammadex was of 4.95min 95% CI (3.25-6.64, p=.53). CONCLUSIONS: The reversion of neuromuscular relaxation with sugammadex appears to be effective and safe in the burn patient. More analytical, comparative studies of larger populations would be necessary to confirm these data. PMID- 26123142 TI - Comparison of droperidol and ondansetron prophylactic effect on subarachnoid morphine-induced pruritus. AB - BACKGROUND AND OBJECTIVES: The prophylactic effect of ondansetron on subarachnoid morphine-induced pruritus is controversial, while evidence suggests that droperidol prevents pruritus. The aim of this study is to compare the effects of droperidol and ondansetron on subarachnoid morphine-induced pruritus. METHODS: 180 ASA I or II patients scheduled to undergo cesarean sections under subarachnoid anesthesia combined with morphine 0.2mg were randomized to receive, after the child's birth, metoclopramide 10mg (Group I - control), droperidol 2.5mg (Group II) or ondansetron 8mg (Group III). Postoperatively, the patients were assessed for pruritus (absent, mild, moderate or severe) or other side effects by blinded investigators. Patients were also blinded to their group allocation. The tendency to present more severe forms of pruritus was compared between groups. NNT was also determined. RESULTS: Patients assigned to receive droperidol [Proportional odds ratio: 0.45 (95% confidence interval 0.23-0.88)] reported less pruritus than those who received metoclopramide. Ondansetron effect was similar to metoclopramide [Proportional odds ratio: 0.95 (95% confidence interval 0.49-1.83)]. The NNT for droperidol and ondansetron was 4.0 and 14.7, respectively. CONCLUSIONS: Ondansetron does not inhibit subarachnoid morphine induced pruritus. PMID- 26123143 TI - Carotid endarterectomy: review of 10 years of practice of general and locoregional anesthesia in a tertiary care hospital in Portugal. AB - BACKGROUND: Retrospective and prospective randomized studies have compared general and locoregional anesthesia for carotid endarterectomy, but without definitive results. OBJECTIVES: Evaluate the incidence of complications (medical, surgical, neurological, and hospital mortality) in a tertiary center in Portugal and review the literature. METHODS: Retrospective analysis of patients undergoing endarterectomy between 2000 and 2011, using a software for hospital consultation. RESULTS: A total of 750 patients were identified, and locoregional anesthesia had to be converted to general anesthesia in 13 patients. Thus, a total of 737 patients were included in this analysis: 74% underwent locoregional anesthesia and 26% underwent general anesthesia. There was no statistically significant difference between the two groups regarding per operative variables. The use of shunt was more common in patients undergoing general anesthesia, a statistically significant difference. The difference between groups of strokes and mortality was not statistically significant. The average length of stay was shorter in patients undergoing locoregional anesthesia with a statistically significant difference. CONCLUSIONS: We found that our data are overlaid with the literature data. After reviewing the literature, we found that the number of studies comparing locoregional and general anesthesia and its impact on delirium, cognitive impairment, and decreased quality of life after surgery is still very small and can provide important data to compare the two techniques. Thus, some questions remain open, which indicates the need for randomized studies with larger number of patients and in new centers. PMID- 26123144 TI - Analgesic efficacy of the ultrasound-guided blockade of the transversus abdominis plane - a systematic review. AB - BACKGROUND: The transverse abdominal plan blockade is a block of abdominal wall that has diffused rapidly in the clinical practice as part of a multimodal analgesia for abdominal surgery. The performance of the ultrasound-guided technique has allowed the lowering of potential complications, as well as new approaches that were carried out according to the descriptions, and the prospective studies would make it possible to utilize the transverse abdominal plan blockade in different surgical interventions; however, the results obtained in randomized clinical trials are inconsistent. OBJECTIVES: To prepare a systematic review aiming to determine the efficacy of the ultrasound-guided transverse abdominal plan blockade for different surgical interventions, as well as the indications according to the approaches and their influences. METHODS: Two research approaches, one manual, and the other in Pubmed returned 28 randomized clinical trials where intervention with ultrasound-guided transverse abdominal plan blockades was performed to compare the analgesic efficacy in contrast to another technique in adults, published between 2007 and October 2013, in English or Spanish, with Jadad score>1, according to the inclusion criteria for this review. The authors analyzed independently all the randomized clinical trials. CONCLUSIONS: The transverse abdominal plan blockades have been shown to be an effective technique in colorectal surgery, cesarean section, cholecystectomy, hysterectomy, appendectomy, donor nephrectomy, retropubic prostatectomy, and bariatric surgery. However, the data found in randomized clinical trial are not conclusive, and as a result, it is necessary to develop new and well designed randomized clinical trial, with enough statistical power to compare different approaches, drugs, doses, and volumes for the same intervention, aiming to answer the current questions and their effects in the habitual clinical practice. PMID- 26123145 TI - Colloids versus crystalloids in objective-guided fluid therapy, systematic review and meta-analysis. Too early or too late to draw conclusions. AB - INTRODUCTION: Several clinical trials on Goal directed fluid therapy (GDFT) were carried out, many of those using colloids in order to optimize the preload. After the decision of European Medicines Agency, there is such controversy regarding its use, benefits, and possible contribution to renal failure. The objective of this systematic review and meta-analysis is to compare the use of last-generation colloids, derived from corn, with crystalloids in GDFT to determine associated complications and mortality. METHODS: A bibliographic research was carried out in MEDLINE PubMed, EMBASE and Cochrane Library, corroborating randomized clinical trials where crystalloids are compared to colloids in GDFT for major non-cardiac surgery in adults. RESULTS: One hundred thirty references were found and among those 38 were selected and 29 analyzed; of these, six were included for systematic review and meta-analysis, including 390 patients. It was observed that the use of colloids is not associated with the increase of complications, but rather with a tendency to a higher mortality (RR [95% CI] 3.87 [1.121-13.38]; I(2)=0.0%; p=0.635). CONCLUSIONS: Because of the limitations of this meta analysis due to the small number of randomized clinical trials and patients included, the results should be taken cautiously, and the performance of new randomized clinical trials is proposed, with enough statistical power, comparing balanced and unbalanced colloids to balanced and unbalanced crystalloids, following the protocols of GDFT, considering current guidelines and suggestions made by groups of experts. PMID- 26123146 TI - Perioperative anaphylaxis. AB - BACKGROUND AND OBJECTIVE: Anaphylaxis remains one of the potential causes of perioperative death, being generally unanticipated and quickly progress to a life threatening situation. A narrative review of perioperative anaphylaxis is performed. CONTENT: The diagnostic tests are primarily to avoid further major events. The mainstays of treatment are adrenaline and intravenous fluids. CONCLUSION: The anesthesiologist should be familiar with the proper diagnosis, management and monitoring of perioperative anaphylaxis. PMID- 26123147 TI - Anesthetic management for surgery of esophagus atresia in a newborn with Goldenhar's syndrome. AB - BACKGROUND AND OBJECTIVES: Goldenhar's syndrome is a polymalformative condition consisting of a craniofacial dysostosis that determines difficult airway in up to 40% of cases. We described a case of a newborn with Goldenhar's syndrome with esophageal atresia and tracheoesophageal fistula who underwent repair surgery. CASE REPORT: We report the case of a 24-h-old newborn with Goldenhar's syndrome. He had esophageal atresia with distal tracheoesophageal fistula. It was decided that an emergency surgery would be performed for repairing it. It was carried out under sedation, intubation with fibrobronchoscope distal to the fistula, to limit the air flow into the esophagus, and possible abdominal distension. Following complete repair of the esophageal atresia and fistula ligation, the patient was transferred to the intensive care unit and intubated under sedation and analgesia. CONCLUSIONS: The finding of a patient with Goldenhar's syndrome and esophageal atresia assumes an exceptional situation and a challenge for anesthesiologists, since the anesthetic management depends on the patient comorbidity, the type of tracheoesophageal fistula, the usual hospital practice and the skills of the anesthesiologist in charge, with the main peculiarity being maintenance of adequate pulmonary ventilation in the presence of a communication between the airway and the esophagus. Intubation with fibrobronchoscope distal to the fistula deals with the management of a probably difficult airway and limits the passage of air to the esophagus through the fistula. PMID- 26123148 TI - Ultrasound-guided paravertebral block for pyloromyotomy in 3 neonates with congenital hypertrophic pyloric stenosis. AB - BACKGROUND AND OBJECTIVES: Hypertrophic pyloric stenosis is a relatively common affection of gastrointestinal tract in childhood that results in symptoms, such as projectile vomiting and metabolic disorders that imply a high risk of aspiration during anesthetic induction. In this way, the carrying out of a technique with general anesthesia and intravenous rapid sequence induction, preoxygenation and cricoid pressure are recommended. After the correction of systemic metabolic alkalosis and pH normalization, cerebrospinal fluid can keep a state of metabolic alkalosis. This circumstance, in addition to the residual effect of neuromuscular blocking agents, inhalant anesthetics and opioids could increase the risk of postoperative apnea after a general anesthesia. CASE REPORT: We present the successful management in 3 neonates in those a pyloromyotomy was carried out because they had presented congenital hypertrophic pyloric stenosis. This procedure was done under general anesthesia with orotracheal intubation and rapid sequence induction. Then, ultrasound-guided paravertebral block was performed as analgesic method without the need for administrating opioids within intraoperative period and keeping an appropriate analgesic level. CONCLUSIONS: Local anesthesia has demonstrated to be safe and effective in pediatric practice. We consider the ultrasound-guided paravertebral block with one dose as a possible alternative for other local techniques described, avoiding the use of opioids and neuromuscular blocking agents during general anesthesia, and reducing the risk of central apnea within postoperative period. PMID- 26123149 TI - Bilateral subdural hematoma secondary to accidental dural puncture. AB - We report the case of a 25-year-old woman, who received epidural analgesia for labor pain and subsequently presented post-dural puncture headache. Conservative treatment was applied and epidural blood patch was performed. In the absence of clinical improvement and due to changes in the postural component of the headache, a brain imaging test was performed showing a bilateral subdural hematoma. The post-dural puncture headache is relatively common, but the lack of response to established medical treatment as well as the change in its characteristics and the presence of neurological deficit, should raise the suspicion of a subdural hematoma, which although is rare, can be lethal if not diagnosed and treated at the right time. PMID- 26123150 TI - Effect of head rotation on intraocular pressure in prone position: randomized study. PMID- 26123151 TI - A question about ropivacaine for unilateral spinal anesthesia: hypobaric solution. PMID- 26123152 TI - Familial Power and Women's Contradictory Responses to Attitudinal Questions About Intimate Partner Violence in Rural Bangladesh. AB - Research is lacking on how power processes can influence women's reporting of their attitudes about intimate partner violence (IPV) against women. Structural elements of textual data were investigated as potential evidence of latent power. Overall, the majority of the women switched their response at least once throughout the interview, and the context of these contradictory responses provide evidence that women's reporting of attitudes about IPV against women may be understood as arising in part from latent power processes. New methodological tools are needed to better understand women's personal attitudes about IPV against women. PMID- 26123155 TI - Durability of small-for-size living donor allografts. AB - Our aim was to study the long-term outcomes of living donor liver transplantation using small-for-size (SFS) grafts. From July 2002 to July 2009, 233 patients received a right liver graft with a middle hepatic vein from a living donor in our center. Recipients were stratified according to the graft weight to recipient standard liver volume (GW/SLV) ratio into 4 groups: >50% (n = 89), >40% to 50% (n = 85), >35% to 40% (n = 38), and <= 35% (n = 21). They were compared in terms of graft survivals, biliary stricture rates, renal function in terms of estimated glomerular filtration rate (eGFR), platelet counts, and graft function in terms of serum bilirubin and international normalized ratio (INR). The 5-year graft survivals for patients with GW/SLV of >50%, >40% to 50%, >35% to 40% and <= 35% were 88.8%, 88.2%, 81.5%, and 81.0%, respectively. Transplantation for hepatocellular carcinoma affected graft survivals (P = 0.02), but graft size did not (P = 0.66). There were no differences in frequency of biliary stricture (21.3% versus 17.1% versus 21.1% versus 28.6%; P = 0.75). At each year after transplant, their platelet counts (P = 0.12-0.65), eGFR (P = 0.49-0.91), bilirubin (P = 0.14-0.51), and INR (P = 0.20-0.98) remained comparable. SFS grafts with GW/SLV <= 35% and >35% to 40% had comparable long-term outcomes with larger liver grafts. Graft size did not affect long-term graft survivals. PMID- 26123156 TI - [Acute pancreatitis associated with hypercalcaemia]. AB - BACKGROUND: Hypercalcaemia due to primary hyperparathyroidism is a rare cause of acute pancreatitis, with a reported prevalence of 1.5 to 8%. There is no clear pathophysiological basis, but elevated parathyroid hormone and high serum calcium levels could be responsible for calcium deposit in the pancreatic ducts and activation of pancreatic enzymes, which may be the main risk factor for developing acute pancreatitis. The aim of this report is to describe four cases. CLINICAL CASE: Four cases are reported of severe pancreatitis associated with hypercalcaemia secondary to primary hyperparathyroidism; three of them with complications (two pseudocysts and one pancreatic necrosis). Cervical ultrasound, computed tomography, and scintigraphy using 99mTc-Sestambi, studies showed the parathyroid adenoma. Surgical resection was the definitive treatment in all four cases. None of the patients had recurrent acute pancreatitis events during follow up. CONCLUSIONS: Acute pancreatitis secondary to hypercalcaemia of primary hyperparathyroidism is rare; however, when it occurs it is associated with severe pancreatitis. It is suspected in patients with elevated serum calcium and high parathyroid hormone levels. Imaging techniques such as cervical ultrasound, computed tomography, and scintigraphy using 99mTc-Sestambi, should be performed, to confirm clinical suspicion. Surgical resection is the definitive treatment with excellent results. PMID- 26123153 TI - Roles for the endocannabinoid system in ethanol-motivated behavior. AB - Alcohol use disorder represents a significant human health problem that leads to substantial loss of human life and financial cost to society. Currently available treatment options do not adequately address this human health problem, and thus, additional therapies are desperately needed. The endocannabinoid system has been shown, using animal models, to modulate ethanol-motivated behavior, and it has also been demonstrated that chronic ethanol exposure can have potentially long lasting effects on the endocannabinoid system. For example, chronic exposure to ethanol, in either cell culture or preclinical rodent models, causes an increase in endocannabinoid levels that results in down-regulation of the cannabinoid receptor 1 (CB1) and uncoupling of this receptor from downstream G protein signaling pathways. Using positron emission tomography (PET), similar down regulation of CB1 has been noted in multiple regions of the brain in human alcoholic patients. In rodents, treatment with the CB1 inverse agonist SR141716A (Rimonabant), or genetic deletion of CB1 leads to a reduction in voluntary ethanol drinking, ethanol-stimulated dopamine release in the nucleus accumbens, operant self-administration of ethanol, sensitization to the locomotor effects of ethanol, and reinstatement/relapse of ethanol-motivated behavior. Although the clinical utility of Rimonabant or other antagonists/inverse agonists for CB1 is limited due to negative neuropsychiatric side effects, negative allosteric modulators of CB1 and inhibitors of endocannabinoid catabolism represent therapeutic targets worthy of additional examination. PMID- 26123157 TI - [Infected jejunal mesenteric pseudocyst: A case report]. AB - BACKGROUND: Mesenteric cysts are very rare abdominal growths, generally asymptomatic, and which are usually detected incidentally while performing a physical examination or an imaging test. Complications such as infections, haemorrhage, torsion, rupture, or bowel obstruction, are seldom found in this pathology, but they can be a cause of acute abdomen. The purpose of this report is to describe the characteristics and the clinical outcome of a male patient with an infected mesenteric pseudocyst of the jejunum. CLINICAL CASE: A 49 year old male was admitted to the emergency department with 6-day onset of abdominal pain, bowel obstruction signs, palpable tumour located in the upper hemi-abdomen, systemic inflammatory response syndrome, 36,100/mm(3) white cells, 4.21 ng/ml procalcitonin, abdominal computed tomography scan with evidence of a mesenteric cystic tumour. An exploratory laparotomy was performed, finding the presence of a mesenteric pseudocyst of the jejunum with infection signs, extirpated and sent for histopathological examination. The clinical progress of the patient was satisfactory with the discharge of the patient 7 days after the surgical intervention. CONCLUSION: These cysts can debut as an acute abdomen due to haemorrhage, infection, obstruction and/or bowel perforation, complications can be life threatening if not detected and surgically treated at an early stage by performing a resection of the pseudocysts, with or without bowel resection, depending on the location and the size of the cyst. PMID- 26123159 TI - A new drimane sesquiterpenoid and a new triterpene lactone from fungus of Fomes officinalis. AB - A new sesquiterpenoid fomeffic acid (1) and a new triterpene lactone fomefficinin (2) were isolated from the fungus Fomes officinalis, together with another six known compounds fomitopsin C (3), dehydrosulfurenic acid (4), dehydroeburiconic acid (5), dehydroeburicoic acid (6), 3-keto-dehydrosulfurenic acid (7), and laricinolic acid (8). The structures and stereochemistry of 1 and 2 were determined by NMR and X-ray diffraction analyses. The sesquiterpenoid and five triterpenes were tested for cytotoxicity against HL-60, Bel-7402, and KB cancer lines in vitro, and they appeared to be modestly active. PMID- 26123158 TI - Barriers and facilitators to patient retention in HIV care. AB - BACKGROUND: Retention in HIV care improves survival and reduces the risk of HIV transmission to others. Multiple quantitative studies have described demographic and clinical characteristics associated with retention in HIV care. However, qualitative studies are needed to better understand barriers and facilitators. METHODS: Semi-structured interviews were conducted with 51 HIV-infected individuals, 25 who were retained in care and 26 not retained in care, from 3 urban clinics. Interview data were analyzed for themes using a modified grounded theory approach. Identified themes were compared between the two groups of interest: patients retained in care and those not retained in care. RESULTS: Overall, participants identified 12 barriers and 5 facilitators to retention in HIV care. On average, retained individuals provided 3 barriers, while persons not retained in care provided 5 barriers. Both groups commonly discussed depression/mental illness, feeling sick, and competing life activities as barriers. In addition, individuals not retained in care commonly reported expensive and unreliable transportation, stigma, and insufficient insurance as barriers. On average, participants in both groups referenced 2 facilitators, including the presence of social support, patient-friendly clinic services (transportation, co-location of services, scheduling/reminders), and positive relationships with providers and clinic staff. CONCLUSIONS: In our study, patients not retained in care faced more barriers, particularly social and structural barriers, than those retained in care. Developing care models where social and financial barriers are addressed, mental health and substance abuse treatment is integrated, and patient-friendly services are offered is important to keeping HIV-infected individuals engaged in care. PMID- 26123160 TI - Bayesian meta-analysis of Cronbach's coefficient alpha to evaluate informative hypotheses. AB - This paper proposes a new method to evaluate informative hypotheses for meta analysis of Cronbach's coefficient alpha using a Bayesian approach. The coefficient alpha is one of the most widely used reliability indices. In meta analyses of reliability, researchers typically form specific informative hypotheses beforehand, such as 'alpha of this test is greater than 0.8' or 'alpha of one form of a test is greater than the others.' The proposed method enables direct evaluation of these informative hypotheses. To this end, a Bayes factor is calculated to evaluate the informative hypothesis against its complement. It allows researchers to summarize the evidence provided by previous studies in favor of their informative hypothesis. The proposed approach can be seen as a natural extension of the Bayesian meta-analysis of coefficient alpha recently proposed in this journal (Brannick and Zhang, 2013). The proposed method is illustrated through two meta-analyses of real data that evaluate different kinds of informative hypotheses on superpopulation: one is that alpha of a particular test is above the criterion value, and the other is that alphas among different test versions have ordered relationships. Informative hypotheses are supported from the data in both cases, suggesting that the proposed approach is promising for application. PMID- 26123161 TI - Spontaneous disappearance of Holmes' tremor in a patient with a midbrain cavernous hemangioma. PMID- 26123162 TI - The Functions of Antioxidants and Heat Shock Proteins Are Altered in the Immune Organs of Selenium-Deficient Broiler Chickens. AB - Despite increasing evidence indicating the essential involvement of selenium (Se) in the immune system, the effect of Se deficiency on the regulation of oxidative stress and heat shock proteins (Hsps) in broiler chickens is still unclear. In the present study, we established an exudative diathesis (ED) broiler chicken model caused by Se deficiency. We then analyzed histological observations and detected the expression levels of Hsps and antioxidant indexes in immune tissues. The antioxidant function declined remarkably, and most of the Hsp expression levels increased significantly in the spleen, thymus, and bursa of Fabricius of the broiler chicks with ED (except the messenger RNA (mRNA) levels of Hsp27, Hsp40, and Hsp70, which decreased in thymus tissues from the treatment groups); therefore, constitutive oxidation resistance and higher Hsps in broiler chicks with ED caused defects in immune organ morphology and function, as evidenced by abnormal histological structures: red pulp broadening and lymphocytes in the cortex and medulla of the thymic lobule decreased distinctly and distributed loosely. These results underscore the importance of Se in establishing an immune organ microenvironment conducive to normal function. PMID- 26123163 TI - T-2 Toxin Alters the Levels of Collagen II and Its Regulatory Enzymes MMPs/TIMP-1 in a Low-Selenium Rat Model of Kashin-Beck Disease. AB - The objectives of this study are to assess T-2 toxin's involvement in low selenium (Se)-induced Kashin-Beck disease (KBD) in rats and unveil the mechanisms underlying this disease. Two hundred thirty rats were randomly divided into two groups after weaning and fed normal or low-Se diets (n = 115), respectively, for a month. After low-Se model confirmation, rats in each group were subdivided into five: two subgroups (n = 20) were fed their current diets (normal or low-Se diets, respectively) for 30 and 90 days, respectively; two other subgroups (n = 25) received their current diets + low T-2 toxin (100 ng/g BW/day) for 30 and 90 days, respectively; and 25 rats were fed their current diets + high T-2 toxin (200 ng/g BW/day) for 30 days. Articular cartilage samples were extracted for hematoxylin and eosin (H&E) staining and immunohistochemistry. Western blot and reverse transcription-polymerase chain reaction (RT-PCR) were used to assess protein and mRNA levels, respectively, of collagen II, matrix metalloproteinase (MMP-1), MMP -3, MMP-13, and tissue inhibitor of metalloproteinase-1 (TIMP-1). Low Se and T-2 toxin synergistically affected animal fitness. Interestingly, low Se + T-2 toxin groups showed KBD characteristics. MMP-1, -3, and -13 mRNA and protein levels generally increased in low-Se groups, while collagen II and TIMP-1 levels showed a downward trend, compared with normal diet fed animals for the same treatment (P < 0.05). T-2 toxin's effect was dose but not time dependent. Low Se and T-2 toxin synergistically alter the expression levels of collagen II as well as its regulatory enzymes MMP-1, MMP-3, MMP-13, and TIMP-1, inducing cartilage damage. Therefore, T-2 toxin may cause KBD in low-Se conditions. PMID- 26123164 TI - Evaluated the Twenty-Six Elements in the Pectoral Muscle of As-Treated Chicken by Inductively Coupled Plasma Mass Spectrometry. AB - This study assessed the impacts of dietary arsenic trioxide on the contents of 26 elements in the pectoral muscle of chicken. A total of 100 Hy-line laying cocks were randomly divided into two groups (n = 50), including an As-treated group (basic diet supplemented with arsenic trioxide at 30 mg/kg) and a control group (basal diet). The feeding experiment lasted for 90 days and the experimental animals were given free access to feed and drinking water. The elements lithium (Li), boron (B), natrum (Na), magnesium (Mg), aluminium (AI), silicium (Si), kalium (K), calcium (Ca), vanadium (V), chromium (Cr), manganese (Mn), ferrum (Fe), cobalt (Co.), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), molybdenum (Mo), cadmium (Cd), stannum (Sn), stibium (Sb), barium (Ba), hydrargyrum (Hg), thallium (Tl) and plumbum (Pb) in the pectoral muscles were determined using inductively coupled plasma mass spectrometry (ICP-MS). The resulted data indicated that Li, Na, AI, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sn, Ba, Tl and Pb were significantly increased (P < 0.05) in chicken exposed to As2O3 compared to control chicken, while Mg, Si, K, As and Cd decreased significantly (P < 0.05). These results suggest that ICP-MS determination of elements in chicken tissues enables a rapid analysis with good precision and accuracy. Supplementation of high levels of As affected levels of 20 elements (Li, Na, AI, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sn, Ba, Tl, Pb, Mg, Si, K, As and Cd) in the pectoral muscles of chicken. Thus, it is needful to monitor the concentration of toxic metal (As) in chicken for human health. PMID- 26123165 TI - Effects of Supplemental Chromium Source and Concentration on Growth, Carcass Characteristics, and Serum Lipid Parameters of Broilers Reared Under Normal Conditions. AB - An experiment was conducted to investigate the effects of dietary chromium (Cr) source and concentration on growth performance, carcass traits, and some serum lipid parameters of broilers under normal rearing conditions for 42 days. A total of 252 1-day-old Cobb 500 commercial female broilers were randomly allotted by body weight (BW) to one of six replicate cages (six broilers per cage) for each of seven treatments in a completely randomized design involved in a 2 * 3 factorial arrangement of treatments with three Cr sources (Cr propionate (CrPro), Cr picolinate (CrPic), Cr chloride (CrCl3)) and two concentrations of added Cr (0.4 and 2.0 mg of Cr/kg) plus a Cr-unsupplemented control diet. The results showed that dietary Cr supplementation tended to increase the breast muscle percentage compared with the Cr-unsupplemented control group (P = 0.0784), while Cr from CrPic tended to have higher breast muscle percentage compared with Cr from CrCl3 (P = 0.0881). Chromium from CrPic also tended to increase the breast intramuscular fat (IMF) compared with Cr from CrCl3 (P = 0.0648). In addition, supplementation of 0.4 mg/kg Cr tended to decrease low-density lipoprotein cholesterol (LDL-C) (P = 0.0614). Compared with the control group, broilers fed Cr-supplemented diets had higher triglyceride (TG) (P = 0.0129) regardless of Cr source and Cr concentration. Chromium from CrPro and CrPic had lower total cholesterol (TC) compared with Cr from CrCl3 (P = 0.0220). These results indicate that dietary supplementation of Cr has effects on carcass characteristics and serum lipid parameters of broilers under normal rearing conditions, while supplementation of organic Cr can improve carcass characteristics and reduce the cholesterol content in serum. PMID- 26123166 TI - The Antagonistic Effect of Selenium on Lead Toxicity Is Related to the Ion Profile in Chicken Liver. AB - The interactions between the essential element selenium (Se) and the toxic element lead (Pb) have been reported extensively; however, limited data are available regarding the effects of Se on Pb and the ion profile in chicken liver. Whether the change in the ion profile was involved in the protective process of Se and the toxic effect of Pb is unknown. In the present study, we detected 26 ion profiles (including those of Na, Mg, K, Ca, B, Si, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Se, Mo, Sb, Ba, Tl, Li, Al, As, Cd, Sn, Hg, and Pb) in chicken liver following treatment with Se or Pb and with the compound treatment of Se and Pb. The results showed that Se supplementation decreased the content of B and Cr and increased that of Zn and Ba (P < 0.05); however, Pb exposure decreased Cr, Mn, Cu, Se, Mo, and Hg and increased V, Fe, Cd, and Sn (P < 0.05). The results showed that Se and Pb primarily influenced essential microelements and toxic microelements in the chicken liver. In this process, Se alleviated the increased Cd and Pb induced by Pb exposure but aggravated the decreased Cu and Mn. The results also indicated that there existed both synergistic and antagonistic interactions between different ions, further verifying the principal component analysis. Thus, the results showed that prolonged exposure to Se and Pb influences the ion profiles in chicken liver. The protective role of Se and toxic effect of Pb may be related to these changing ion profiles in chicken liver. PMID- 26123167 TI - Mesenchymal signaling in dorsoventral differentiation of palatal epithelium. AB - After palatal fusion, the dorsal and ventral epithelia of the palatal shelf differentiate into the nasal and oral mucosa, respectively. The tissue-specific differentiation of palatal epithelia along the dorsal-ventral axis is regulated by the signaling molecules expressed in the underlying mesenchyme. Thus, as in many other epithelial organs, differentiation relies on epithelial-mesenchymal interactions. To screen for region-specific mesenchymal signaling molecules that determine the fate of the palatal epithelia, we employed a laser microdissection (LMD) method. LMD allowed us to collect region-specific mesenchymal tissues at E13, prior to palatal fusion and the development of distinct dorsal and ventral epithelial morphology. Genome-wide screening was performed on the tissues collected using LMD to identify candidate mesenchymal signaling molecules. The microarray results were validated using real-time quantitative (qPCR) and in situ hybridization methods. The developmental role and interactions of the candidate genes were evaluated in in vitro-cultivated E13 palates using an anti-sense oligodeoxynucleotide (AS-ODN)-based loss-of-function approach. Apparent changes in the expression patterns of Runt-related transcription factor 2 (Runx2) and LIM homeobox 8 (Lhx8) were observed after knocking down each gene. Knock-down of Runx2 and Lhx8 also altered the immunolocalization pattern of cytokeratin18 (CK18), an established marker for nasal epithelium. These results were confirmed using Runx2 heterozygote mice. The mesenchymal signaling molecules Runx2 and Lhx8, which possess region-specific expression patterns along the dorsoventral axis, functionally interact to regulate the cellular and molecular characteristics of dorsal and ventral epithelia, suggesting that mesenchymal signaling molecules determine the dorsoventral fate of epithelial structures in the developing palate. PMID- 26123168 TI - Enhancement of trypsin-like enzymes by A23187 ionophore is crucial for sperm penetration through the egg vestment of the giant freshwater prawn. AB - We report the presence of trypsin-like enzymes preferring Boc-QAR-MCA substrate in sperm collected from different portions of male reproductive tracts of the giant freshwater prawn, Macrobrachium rosenbergii and compare enzyme activities before and after an A23187 calcium ionophore treatment. Fluorogenic enzyme assays revealed that testicular sperm lysates showed high trypsin-like enzyme activity but the activity was relatively low in vas deferens sperm lysates as well as in the live sperm. Upon sperm treatment with A23187, trypsin-like activity was greatly enhanced in distal vas deferens sperm. Substrate- and inhibitor-based localization studies indicated that the sperm trypsin-like enzymes were not of a soluble type but were rather of a membrane-borne type, localized at the anterior spike and upper part of the main body. Notable structural changes were also evident in A23187-induced sperm including extensive ruffling of the sperm membrane structure at the base of the main body thereby supporting the acrosome reaction response in this species. We further proved by substrate inhibition assays that the enhanced trypsin-like enzyme activity participates in sperm penetration through the vitelline envelope, a novel sperm-egg penetration mechanism that is unique in this species. PMID- 26123169 TI - Surgery for localized pulmonary mycotic infections in patients with hematopoietic disorder. AB - BACKGROUND: Surgical resection is considered to be the most effective treatment for localized pulmonary mycotic infections. However it is also a particularly challenging procedure because it is associated with considerable mortality and morbidity. Furthermore, hematopoietic disorders usually cause immunosuppression, anemia, and coagulopathy, which are definite risk factors for surgery. The purpose of this study is to evaluate the surgical outcomes of pulmonary mycotic infections in hematopoietic disorder patients. METHODS: Between 2011 and 2013, 23 patients underwent surgical treatment for pulmonary mycotic infections at a single institution. The patients were divided into two groups; Group A (hematopoietic disorder patients, n = 9) and Group B (n = 14). We retrospectively reviewed medical and radiologic data. RESULTS: The complex type was more frequent in group A (66.6 %) than in group B (35.7 %). Postoperatively, there was no mortality. However, morbidity was 22.2 % (2 incomplete expansion) in group A, and 35.6 % (1 prolonged air leak, 3 bleeding, 1 Bronchopleural fistula) in group B. The difference in morbidity between the groups did not show any statistical significance (p = 0.657) as well as duration of chest tube drainage, and postoperative hospital stay. The hematopoietic disorder patients did not impose a risk factor for morbidity and mortality. CONCLUSIONS: Although hematopoietic disorder patients have many surgical risk factors, the surgical treatment of pulmonary mycotic infections produces very acceptable outcomes in selected cases. PMID- 26123170 TI - Lowered paraoxonase 1 (PON1) activity is associated with increased cytokine levels in drug naive first episode psychosis. AB - BACKGROUND: Activated immune-inflammatory pathways play an important role in the pathophysiology of schizophrenia. Paraoxonase 1 (PON1) activity is inversely associated with inflammatory responses in numerous clinical conditions. The aims of this study were to delineate serum arylesterase PON1 activity in drug-naive first episode psychosis (FEP) patients and a healthy control group, and to assess whether there are inverse relationships between PON1 activity and cytokine levels. METHODS: A total of 51 drug-naive FEP patients and 61 healthy controls were enrolled in this study. Levels of interleukin (IL)-4, IL-10, IL-6, tumor necrosis factor (TNF)-alpha and activity of PON1 were quantified. RESULTS: Compared to healthy controls, FEP patients showed lower serum PON1 activity and higher levels of IL-4, IL-10 and TNF-alpha. A significant inverse relationship between PON1 activity and IL-4, IL-6 and IL-10 levels was detected, but not for TNF-alpha. Subjects with very low PON1 activity (25th quartile) presented significantly higher levels of IL-6, IL-10 and IL-4 than those with higher PON1 activity (75th quartile). CONCLUSION: The present study provides evidence that FEP is characterized by an inverse relationship between lowered activity of the anti-inflammatory/antioxidant enzyme PON1 and increased cytokine levels, including IL-6, IL-4 and IL-10. It is hypothesized that lowered PON1 activity may play a role in the immune-inflammatory response that accompanies FEP and that increased cytokine levels may further modulate PON1 activity. PMID- 26123172 TI - Acquired Port-wine Stain with Local Heat. PMID- 26123171 TI - Effects of oxytocin and genetic variants on brain and behaviour: Implications for treatment in schizophrenia. AB - Impairments in social cognition and poor social functioning are core features of schizophrenia-spectrum disorders. In recent years, there has been a move towards developing new treatment strategies that specifically target social cognitive and social behavioural deficits. Oxytocin (OXT) is one such strategy that has gained increasing attention. There is a strong rationale for studying OXT in psychosis, from both an evolutionary perspective and neurodevelopmental-cognitive model of schizophrenia. Thus, the aim of this review was to critique and examine the observational and clinical oxytocin trial literature in schizophrenia-spectrum disorders. A handful of clinical trials suggest that OXT treatment may be beneficial for remediating social cognitive impairments, psychiatric symptoms, and improving social outcomes. However, inconsistencies exist in this literature, which may be explained by individual differences in the underlying neural response to OXT treatment and/or variation in the oxytocin and oxytocin receptor genes. Therefore, we additionally reviewed the evidence for structural and functional neural intermediate phenotypes in humans that link genetic variants to social behaviour/thinking, and discuss the implications of such interactions in the context of dysfunctional brain networks in schizophrenia. Factors that pose challenges for future OXT clinical research include the impact of age, sex, and ancestry, task-specific effects, bioavailability and pharmacokinetics, as well as neurotransmitter and drug interactions. While initial findings from OXT single dose/clinical trial studies are promising, more interdisciplinary research in both healthy and psychiatric populations is needed before determining whether OXT is a viable treatment option/adjunct for addressing poor illness outcomes in psychotic disorders. PMID- 26123173 TI - Hemophagocytic lymphohistiocytosis with a leukemoid reaction in an infant with scrub typhus. AB - A two-month-old male infant presented with a clinical picture suggestive of fever without focus. Treatment was initiated with broad spectrum intravenous antibiotics. The infant subsequently developed septic shock, hepatosplenomegaly and tachypnoea with oxygen dependency. There was laboratory evidence of anemia, thrombocytopenia and a leukemoid reaction. Infection induced hemophagocytic lymphohistiocytosis with a leukemoid reaction was suspected because of fever, splenomegaly and bicytopenia in conjunction with elevated serum triglycerides and ferritin. Empiric therapy with doxycycline caused a rapid resolution of the fever, and the diagnosis of scrub typhus was confirmed by a positive scrub IgM ELISA. HLH with a leukemoid reaction secondary to scrub typhus has not previously been reported in early infancy. PMID- 26123174 TI - Discovery of novel purine-based heterocyclic P2X7 receptor antagonists. AB - The pyridine core skeleton of the previously reported dichloropyridine-based potent hP2X7 receptor antagonist 5 (IC50 = 13 nM in hP2X7-expressing HEK293 cells) was modified with various heterocyclic scaffolds. Among the derivatives with quinoline, quinazoline, acridine, and purine scaffolds, the chloropurine based analog 9o exhibited the most potent antagonistic activity, with an IC50 value of 176 +/- 37 nM in an ethidium bromide uptake assay. In addition, 9o significantly inhibited IL-1beta release in THP-1 cells stimulated with LPS/IFN gamma/BzATP (IC50 = 120 +/- 15 nM). Although 9o was less active than the previous antagonist 5, 9o exhibited greatly improved metabolic stability in the in vitro evaluation (71.4% in human, 72.3% in mouse). PMID- 26123175 TI - hCAS/CSE1L regulates RAD51 distribution and focus formation for homologous recombinational repair. AB - Homologous recombinational repair (HR) is one of the major repair systems for DNA double-strand breaks. RAD51 is a key molecule in HR, and the RAD51 concentration in the cell nucleus increases after DNA damage induction. However, the mechanism that regulates the intracellular distribution of RAD51 is still unclear. Here, we show that hCAS/CSE1L associates with RAD51 in human cells. We found that hCAS/CSE1L negatively regulates the nuclear protein level of RAD51 under normal conditions. hCAS/CSE1L is also required to repress the DNA damage-induced focus formation of RAD51. Moreover, we show that hCAS/CSE1L plays roles in the regulation of the HR activity and in chromosome stability. These findings suggest that hCAS/CSE1L is responsible for controlling the HR activity by directly interacting with RAD51. PMID- 26123177 TI - Exact optimum coin bias in Efron's randomization procedure. AB - Efron's biased coin design is a restricted randomization procedure that has very favorable balancing properties, yet it is fully randomized, in that subjects are always randomized to one of two treatments with a probability less than 1. The parameter of interest is the bias p of the coin, which can range from 0.5 to 1. In this note, we propose a compound optimization strategy that selects p based on a subjected weighting of the relative importance of the two fundamental criteria of interest for restricted randomization mechanisms, namely balance between the treatment assignments and allocation randomness. We use exact and asymptotic distributional properties of Efron's coin to find the optimal p under compound criteria involving imbalance variability, expected imbalance, selection bias, and accidental bias, for both small/moderate trials and large samples. PMID- 26123176 TI - Use of methanol as cryoprotectant and its effect on sox genes and proteins in chilled zebrafish embryos. AB - Methanol is a widely used cryoprotectant (CPA) in cryopreservation of fish embryos, however little is known about its effect at the molecular level. This study investigated the effect of methanol on sox gene and protein expression in zebrafish embryos (50% epiboly) when they were chilled for 3 h and subsequently warmed and cultured to the hatching stages. Initial experiments were carried out to evaluate the chilling tolerance of 50% epiboly embryos which showed no significant differences in hatching rates for up to 6 h chilling in methanol (0.2 , 0.5- and 1 M). Subsequent experiments in embryos that had been chilled for 3 h in 1 M methanol and warmed and cultured up to the hatching stages found that sox2 and sox3 gene expression were increased significantly in hatched embryos that had been chilled compared to non-chilled controls. Sox19a gene expression also remained above control levels in the chilled embryos at all developmental stages tested. Whilst stable sox2 protein expression was observed between non-chilled controls and embryos chilled for 3 h with or without MeOH, a surge in sox19a protein expression was observed in embryos chilled for 3 h in the presence of 1 M MeOH compared to non-chilled controls and then returned to control levels by the hatching stage. The protective effect of MeOH was increased with increasing concentrations. Effect of methanol at molecular level during chilling was reported here first time which could add new parameter in selection of cryoprotectant while designing cryopreservation protocol. PMID- 26123178 TI - Isolation and Characterization of a Novel Virulent Phage of Lactobacillus casei ATCC 393. AB - A new virulent phage (Lcb) of Lactobacillus casei ATCC 393 was isolated from Chinese sauerkraut. It was specific to L. casei ATCC 393. Electron micrograph revealed that it had an icosahedral head (60.2 +/- 0.8 nm in diameter) and a long tail (251 +/- 2.6 nm). It belonged to the Siphoviridae family. The genome of phage Lcb was estimated to be approximately 40 kb and did not contain cohesive ends. One-step growth kinetics of its lytic development revealed latent and burst periods of 75 and 45 min, respectively, with a burst size of 16 PFU per infected cell. The phage was able to survive in a pH range between 4 and 11. However, a treatment of 70 degrees C for 30 min and 75% ethanol or isopropanol for 20 min was observed to inactivate phage Lcb thoroughly. The presence of both Ca(2+) and Mg(2+) showed a little influence on phage adsorption, but they were indispensable to gain complete lysis and improve plaque formation. The adsorption kinetics were similar on viable or nonviable cells, and high adsorption rates maintained between 10 and 37 degrees C. The highest adsorption rate was at 30 degrees C. This study increased the knowledge on phages of L. casei. The characterization of phage Lcb is helpful to establish a basis for adopting effective strategies to control phage attack in industry. PMID- 26123179 TI - Comment on 'Where are we going in the management of interstitial lung disease in patients with systemic sclerosis?'. PMID- 26123180 TI - Jump Forward to Get Back to Basics. PMID- 26123181 TI - Screening Tests for Osteoporosis: Too Few for Some, Too Many for Others. PMID- 26123182 TI - Re: Underuse and Overuse of Osteoporosis Screening in a Regional Health System: A Retrospective Cohort Study. PMID- 26123183 TI - Resonant-scanning dual-color STED microscopy with ultrafast photon counting: A concise guide. AB - STED (stimulated emission depletion) is a popular super-resolution fluorescence microscopy technique. In this paper, we present a concise guide to building a resonant-scanning STED microscope with ultrafast photon-counting acquisition. The STED microscope has two channels, using a pulsed laser and a continuous-wave (CW) laser as the depletion laser source, respectively. The CW STED channel preforms time-gated detection to enhance optical resolution in this channel. We use a resonant mirror to attain high scanning speed and ultrafast photon counting acquisition to scan a large field of view, which help reduce photobleaching. We discuss some practical issues in building a STED microscope, including creating a hollow depletion beam profile, manipulating polarization, and monitoring optical aberration. We also demonstrate a STED image enhancement method using stationary wavelet expansion and image analysis methods to register objects and to quantify colocalization in STED microscopy. PMID- 26123184 TI - A straightforward approach for gated STED-FCS to investigate lipid membrane dynamics. AB - Recent years have seen the development of multiple technologies to investigate, with great spatial and temporal resolution, the dynamics of lipids in cellular and model membranes. One of these approaches is the combination of far-field super-resolution stimulated-emission-depletion (STED) microscopy with fluorescence correlation spectroscopy (FCS). STED-FCS combines the diffraction unlimited spatial resolution of STED microscopy with the statistical accuracy of FCS to determine sub-millisecond-fast molecular dynamics with single-molecule sensitivity. A unique advantage of STED-FCS is that the observation spot for the FCS data recordings can be tuned to sub-diffraction scales, i.e. <200 nm in diameter, in a gradual manner to investigate fast diffusion of membrane incorporated labelled entities. Unfortunately, so far the STED-FCS technology has mostly been applied on a few custom-built setups optimised for far-red fluorescent emitters. Here, we summarise the basics of the STED-FCS technology and highlight how it can give novel details into molecular diffusion modes. Most importantly, we present a straightforward way for performing STED-FCS measurements on an unmodified turnkey commercial system using a time-gated detection scheme. Further, we have evaluated the STED-FCS performance of different commonly used green emitting fluorescent dyes applying freely available, custom-written analysis software. PMID- 26123185 TI - Single-molecule microscopy of molecules tagged with GFP or RFP derivatives in mammalian cells using nanobody binders. AB - With the recent development of single-molecule localization-based superresolution microscopy, the imaging of cellular structures at a resolution below the diffraction-limit of light has become a widespread technique. While single fluorescent molecules can be resolved in the nanometer range, the delivery of these molecules to the authentic structure in the cell via traditional antibody mediated techniques can add substantial error due to the size of the antibodies. Accurate and quantitative labeling of cellular molecules has thus become one of the bottlenecks in the race for highest resolution of target structures. Here we illustrate in detail how to use small, high affinity nanobody binders against GFP and RFP family proteins for highly generic labeling of fusion constructs with bright organic dyes. We provide detailed protocols and examples for their application in superresolution imaging and single particle tracking and demonstrate advantages over conventional labeling approaches. PMID- 26123186 TI - Differences in 4-hydroxyestradiol levels in leukocytes are related to CYP1A1(*)2C, CYP1B1(*)3 and COMT Val158Met allelic variants. AB - Exposure to estrogen and its metabolites, including catechol estrogens (CEs) and catechol estrogen quinones (CE-Qs) is closely related to breast cancer. Polymorphisms of the genes involved in the catechol estrogens metabolism pathway (CEMP) have been shown to affect the production of CEs and CE-Qs. In this study, we measured the induction of CYP1A1, CYP1B1, COMT, and GSTP1 by 17beta-estradiol (17beta-E2) in leukocytes with CYP1A1(*)2C, CYP1B1(*)3, COMT Val158Met and GSTP1 Ile105Val polymorphisms by semi quantitative RT-PCR and compared the values to those of leukocytes with wild type alleles; we also compared the differences in formation of 4- hydroxyestradiol (4-OHE2) and DNA-adducts. The data show that in the leukocytes with mutant alleles treatment with 17beta-E2 up-regulates CYP1A1 and CYP1B1 and down-regulates COMT mRNA levels, resulting in major increments in 4-OHE2 levels compared to leukocytes with wild-type alleles. Therefore, we propose induction levels of gene expression and intracellular 4-OHE2 concentrations associated with allelic variants in response to exposure of 17beta E2 as a noninvasive biomarker that can help determine the risk of developing non hereditary breast cancer in women. PMID- 26123187 TI - Vitamin and mineral status in patients with hyperphenylalaninemia. AB - Natural sources of protein and some vitamins and minerals are limited in phenylketonuria (PKU) treated patients, who should receive optimal supplementation although this is not yet fully established. We conducted a cross sectional observational multicenter study including 156 patients with hyperphenylalaninemia. Patients were stratified by age, phenotype, disease detection and type of treatment. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, and biochemical parameters (total protein, prealbumin, electrolytes, selenium, zinc, B12, folic acid, ferritin, 25 OH vitamin D) were collected in all patients. 81.4% of patients had biochemical markers out of recommended range but no clinical symptoms. Total protein, calcium, phosphorus, B12, ferritin, and zinc levels were normal in most patients. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing almost all (96.3%) an adequate adherence to diet. Selenium was diminished in 25% of patients (95% with PKU phenotype) and also 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and B12 levels were found diminished in patients with low adherence to diet. Patients under BH4 therapy only showed significant lower levels of B12. This study shows a high percentage of prealbumin and selenium deficiencies as well as an increased level of folic acid in PKU treated patients, which should lead us to assess an adjustment for standards supplements formulated milks. PMID- 26123188 TI - Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency. AB - Sepiapterin reductase deficiency (SRD) causes depletion of biogenic amines in the brain, early onset motor disorder, and intellectual disability. The diagnostic marker for this rare disease is increased sepiapterin and biopterin in CSF. Through a new analytic methodology we demonstrated accumulation of sepiapterin in urine of four SRD patients several times greater than that found in healthy controls and carriers, regardless of age or treatment. Our findings suggest a new interpretation of current theories of peripheral pterin metabolism and provide a new noninvasive diagnostic tool for children with early onset cryptogenetic developmental delay and/or movement disorder. PMID- 26123190 TI - Histopathological effects of intranasal phototherapy and nasal corticosteroids in allergic rhinitis in a rabbit model. AB - Allergic rhinitis is one of the most common health problems and has a major effect on quality of life. Although new-generation antihistamines and nasal steroids are the main treatment options, complete resolution cannot be obtained in some patients. Besides common side effects such as nasal irritation and epistaxis, the use of these drugs is controversial in some patients, such as pregnant or breastfeeding women. These findings highlight the need for new treatment options. Although phototherapy has been successfully used in the treatment of atopic dermatitis, which is an IgE-mediated disease and shares several common pathogenic features with allergic rhinitis, there are limited studies about its role in the treatment of allergic rhinitis. In this study, we aimed to evaluate and compare the histopathological effects of intranasal phototherapy (Rhinolight) and nasal corticosteroid treatment on the nasal mucosa in allergic rhinitis in a rabbit model and we found that both treatment options significantly reduced inflammation in the nasal mucosa without increasing apoptosis of mucosal cells. PMID- 26123189 TI - Stromal Caveolin-1 Is Associated With Response and Survival in a Phase II Trial of nab-Paclitaxel With Carboplatin for Advanced NSCLC Patients. AB - In this phase II trial, carboplatin with nanoparticle albumin-bound (nab) paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC) was evaluated. Most patients had squamous cell histology. Tumor-associated stromal caveolin-1 (Cav-1) expression was correlated with improved response rate and survival in NSCLC patients who received nab-paclitaxel in this phase II trial. These results suggest Cav-1 might serve as a potential biomarker in this patient population. BACKGROUND: The combination of bevacizumab with platinum based chemotherapy results in greater response rate (RR) and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Bevacizumab is contraindicated in patients with squamous histology or hemoptysis. Nanoparticle albumin-bound (nab)-paclitaxel is a novel formulation of paclitaxel with greater dose tolerance and improved efficacy. We hypothesized that nab-paclitaxel and carboplatin would be superior to alternative doublets in advanced NSCLC patients ineligible for bevacizumab. PATIENTS AND METHODS: We conducted a single-arm phase II trial (NCT00729612) with carboplatin and nab-paclitaxel on day 1 of a 21-day cycle to evaluate RR (primary end point), safety, toxicity, and OS. Eligibility included: squamous histology, hemoptysis, or ongoing anticoagulation. Correlative studies included immunohistochemistry for secreted protein acid rich in cysteine (SPARC) and caveolin-1 (Cav-1). RESULTS: Sixty-three patients were enrolled. Most patients had squamous cell carcinoma (n = 48); other reasons for eligibility included hemoptysis (n = 11) and anticoagulation (n = 2). Toxicity Grade >= 3/4 included neuropathy, cytopenias, and fatigue. RR was 38% (24 partial response/0 complete response); 20 patients had stable disease (32%). Median progression-free survival was 5 months and median OS was 9.7 months. Immunohistochemistry for SPARC and Cav-1 was performed in 38 and 37 patients respectively. Although no association was found for SPARC expression in tumor or stroma with RR or OS, we found that higher Cav-1 levels in tumor-associated stroma was associated with improved RR and OS. CONCLUSION: Carboplatin and nab-paclitaxel every 21 days demonstrated promising efficacy with tolerable toxicity in NSCLC patients ineligible for bevacizumab therapy. Further analysis and validation of Cav-1 and SPARC expression in tumor and stromal compartments as prognostic and/or predictive biomarkers of NSCLC or nab-paclitaxel treatment is warranted. PMID- 26123191 TI - Characterization of the structural changes and photochemical activity of photosystem I under Al(3+) effect. AB - The photochemical activity of photosystem I (PSI) as affected by Al(3+) was investigated in thylakoid membranes and PSI submembrane fractions isolated from spinach. Biophysical and biochemical techniques such as oxygen uptake, light induced absorbance changes at 820nm, chlorophyll fluorescence emission, SDS polyacrylamide gel electrophoresis, and FTIR spectroscopy have been used to analyze the sites and action modes of this cation on the PSI complex. Our results showed that Al(3+) above 3mM induces changes in the redox state of P700 reflected by an increase of P700 photooxidation phase and a delay of the slower rate of P700 re-reduction which reveals that Al(3+) exerted an inhibitory action at the donor side of PSI especially at plastocyanin (PC). Furthermore, results of P700 photooxidation monitored in the presence of DCMU with or without MV suggested that the same range of Al(3+) concentrations impairs the photochemical reaction centers (RC) of PSI, as shown by the decline in the amount of active population of P700, and disrupts the charge separation between P700 and the primary electron acceptor A0 leading to the inhibition of electron transfer at the acceptor side of PSI. These inhibitory actions were also accompanied by an impairment of the energy transfer from light harvesting complex (LHCI) to RC of PSI, following the disconnection of LHCI antenna as illustrated by an enhancement of chlorophyll fluorescence emission spectra at low temperature (77K). The above results coincided with FTIR measurements that indicated a conformational change of the protein secondary structures in PSI complex where 25% of alpha-helix was converted into beta-sheet, beta-antiparallel and turn structures. These structural changes in PSI complex proteins are closely related with the alteration photochemical activity of PSI including the inhibition of the electron transport through both acceptor and donor sides of PSI. PMID- 26123192 TI - Echinococcus granulosus infection dynamics in livestock of Greece. AB - An epidemiological and molecular survey on the occurrence of Echinococcus hydatid cysts in livestock was conducted in Greece. In total 898 sheep, 483 goats, 38 buffaloes, 273 wild boars and 15 deer were examined and 30.2% (6.45% cyst fertility), 7.86% (3.2% cyst fertility), 42% (7.9% cyst fertility), 1.1% (0% cyst fertility), 0% of them were found infected, respectively. Infection rate in different geographical regions varied between 26.1 and 53.8% (cyst fertility 2.04 and 34.6%) in sheep, 7.33 and 13.3% (cyst fertility 0 and 3.2%) in goats. Genotyping, based on cox1 and nad1 analyses, demonstrated the predominance of E. granulosus s.s. (G1 genotype). The presence of one single genotype-complex within a relatively large spectrum of intermediate host species in Greece indicates the presence of a dominant transmission dog-sheep cycle involving additional host species which may act as disease reservoir for human infections. PMID- 26123193 TI - Of bipolar cell synapses, light-activated K+ channels, and substrate binding to DAT. PMID- 26123194 TI - Regulation of the transient receptor potential channel TRPM3 by phosphoinositides. AB - The transient receptor potential (TRP) channel TRPM3 is a calcium-permeable cation channel activated by heat and by the neurosteroid pregnenolone sulfate (PregS). TRPM3 is highly expressed in sensory neurons, where it plays a key role in heat sensing and inflammatory hyperalgesia, and in pancreatic beta cells, where its activation enhances glucose-induced insulin release. However, despite its functional importance, little is known about the cellular mechanisms that regulate TRPM3 activity. Here, we provide evidence for a dynamic regulation of TRPM3 by membrane phosphatidylinositol phosphates (PIPs). Phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) and ATP applied to the intracellular side of excised membrane patches promote recovery of TRPM3 from desensitization. The stimulatory effect of cytosolic ATP on TRPM3 reflects activation of phosphatidylinositol kinases (PI-Ks), leading to resynthesis of PIPs in the plasma membrane. Various PIPs directly enhance TRPM3 activity in cell-free inside-out patches, with a potency order PI(3,4,5)P3 > PI(3,5)P2 > PI(4,5)P2 ~ PI(3,4)P2 >> PI(4)P. Conversely, TRPM3 activity is rapidly and reversibly inhibited by activation of phosphatases that remove the 5-phosphate from PIPs. Finally, we show that recombinant TRPM3, as well as the endogenous TRPM3 in insuloma cells, is rapidly and reversibly inhibited by activation of phospholipase C-coupled muscarinic acetylcholine receptors. Our results reveal basic cellular mechanisms whereby membrane receptors can regulate TRPM3 activity. PMID- 26123195 TI - Transient receptor potential melastatin 3 is a phosphoinositide-dependent ion channel. AB - Phosphoinositides are emerging as general regulators of the functionally diverse transient receptor potential (TRP) ion channel family. Phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) has been reported to positively regulate many TRP channels, but in several cases phosphoinositide regulation is controversial. TRP melastatin 3 (TRPM3) is a heat-activated ion channel that is also stimulated by chemical agonists, such as pregnenolone sulfate. Here, we used a wide array of approaches to determine the effects of phosphoinositides on TRPM3. We found that channel activity in excised inside-out patches decreased over time (rundown), an attribute of PI(4,5)P2-dependent ion channels. Channel activity could be restored by application of either synthetic dioctanoyl (diC8) or natural arachidonyl stearyl (AASt) PI(4,5)P2. The PI(4,5)P2 precursor phosphatidylinositol 4 phosphate (PI(4)P) was less effective at restoring channel activity. TRPM3 currents were also restored by MgATP, an effect which was inhibited by two different phosphatidylinositol 4-kinase inhibitors, or by pretreatment with a phosphatidylinositol-specific phospholipase C (PI-PLC) enzyme, indicating that MgATP acted by generating phosphoinositides. In intact cells, reduction of PI(4,5)P2 levels by chemically inducible phosphoinositide phosphatases or a voltage-sensitive 5'-phosphatase inhibited channel activity. Activation of PLC via muscarinic receptors also inhibited TRPM3 channel activity. Overall, our data indicate that TRPM3 is a phosphoinositide-dependent ion channel and that decreasing PI(4,5)P2 abundance limits its activity. As all other members of the TRPM family have also been shown to require PI(4,5)P2 for activity, our data establish PI(4,5)P2 as a general positive cofactor of this ion channel subfamily. PMID- 26123197 TI - A marginal band of microtubules transports and organizes mitochondria in retinal bipolar synaptic terminals. AB - A set of bipolar cells in the retina of goldfish contains giant synaptic terminals that can be over 10 um in diameter. Hundreds of thousands of synaptic vesicles fill these terminals and engage in continuous rounds of exocytosis. How the cytoskeleton and other organelles in these neurons are organized to control synaptic activity is unknown. Here, we used 3-D fluorescence and 3-D electron microscopy to visualize the complex subcellular architecture of these terminals. We discovered a thick band of microtubules that emerged from the axon to loop around the terminal periphery throughout the presynaptic space. This previously unknown microtubule structure associated with a substantial population of mitochondria in the synaptic terminal. Drugs that inhibit microtubule-based kinesin motors led to accumulation of mitochondria in the axon. We conclude that this prominent microtubule band is crucial to the transport and localization of mitochondria into the presynaptic space to provide the sustained energy necessary for continuous transmitter release in these giant synaptic terminals. PMID- 26123196 TI - Membrane potential and Ca2+ concentration dependence on pressure and vasoactive agents in arterial smooth muscle: A model. AB - Arterial smooth muscle (SM) cells respond autonomously to changes in intravascular pressure, adjusting tension to maintain vessel diameter. The values of membrane potential (Vm) and sarcoplasmic Ca(2+) concentration (Ca(in)) within minutes of a change in pressure are the results of two opposing pathways, both of which use Ca(2+) as a signal. This works because the two Ca(2+)-signaling pathways are confined to distinct microdomains in which the Ca(2+) concentrations needed to activate key channels are transiently higher than Ca(in). A mathematical model of an isolated arterial SM cell is presented that incorporates the two types of microdomains. The first type consists of junctions between cisternae of the peripheral sarcoplasmic reticulum (SR), containing ryanodine receptors (RyRs), and the sarcolemma, containing voltage- and Ca(2+)-activated K(+) (BK) channels. These junctional microdomains promote hyperpolarization, reduced Ca(in), and relaxation. The second type is postulated to form around stretch-activated nonspecific cation channels and neighboring Ca(2+)-activated Cl(-) channels, and promotes the opposite (depolarization, increased Ca(in), and contraction). The model includes three additional compartments: the sarcoplasm, the central SR lumen, and the peripheral SR lumen. It incorporates 37 protein components. In addition to pressure, the model accommodates inputs of alpha- and beta-adrenergic agonists, ATP, 11,12-epoxyeicosatrienoic acid, and nitric oxide (NO). The parameters of the equations were adjusted to obtain a close fit to reported Vm and Ca(in) as functions of pressure, which have been determined in cerebral arteries. The simulations were insensitive to +/- 10% changes in most of the parameters. The model also simulated the effects of inhibiting RyR, BK, or voltage-activated Ca(2+) channels on Vm and Ca(in). Deletion of BK beta1 subunits is known to increase arterial-SM tension. In the model, deletion of beta1 raised Ca(in) at all pressures, and these increases were reversed by NO. PMID- 26123198 TI - The effect of prolonged of warm ischaemic injury on renal function in an experimental ex vivo normothermic perfusion system. AB - BACKGROUND: Donation after circulatory death (DCD) kidney transplants inevitably sustain a degree of warm ischaemic injury, which is manifested clinically as delayed graft function. The aim of this study was to define the effects of prolonged periods of warm ischaemic injury on renal function in a normothermic haemoperfused kidney model. METHODS: Porcine kidneys were subjected to 15, 60, 90 (n = 6 per group) and 120 min (n = 4) of in situ warm ischaemia (WI) and then retrieved, flushed with cold preservation fluid and stored in ice for 2 h. Kidneys then underwent 3 h of normothermic reperfusion with a whole blood-based perfusate using an ex vivo circuit developed from clinical grade cardiopulmonary bypass technology. RESULTS: Creatinine clearance, urine output and fractional excretion of sodium deteriorated sequentially with increasing warm time. Renal function was severely compromised after 90 or 120 min of WI but haemodynamic, metabolic and histological parameters demonstrated the viability of kidneys subjected to prolonged warm ischaemia. CONCLUSIONS: Isolated kidney perfusion using a warm, oxygenated, red cell-based perfusate allows an accurate ex vivo assessment of the potential for recovery from warm ischaemic injury. Prolonged renal warm ischaemic injury caused a severe decrement in renal function but was not associated with tissue necrosis. PMID- 26123199 TI - High rates of anaerobic methane oxidation in freshwater wetlands reduce potential atmospheric methane emissions. AB - The role of anaerobic oxidation of methane (AOM) in wetlands, the largest natural source of atmospheric methane, is poorly constrained. Here we report rates of microbially mediated AOM (average rate=20 nmol cm(-3) per day) in three freshwater wetlands that span multiple biogeographical provinces. The observed AOM rates rival those in marine environments. Most AOM activity may have been coupled to sulphate reduction, but other electron acceptors remain feasible. Lipid biomarkers typically associated with anaerobic methane-oxidizing archaea were more enriched in (13)C than those characteristic of marine systems, potentially due to distinct microbial metabolic pathways or dilution with heterotrophic isotope signals. On the basis of this extensive data set, AOM in freshwater wetlands may consume 200 Tg methane per year, reducing their potential methane emissions by over 50%. These findings challenge precepts surrounding wetland carbon cycling and demonstrate the environmental relevance of an anaerobic methane sink in ecosystems traditionally considered strong methane sources. PMID- 26123200 TI - Hypnic headache in childhood: A literature review. AB - Hypnic headache (HH) is a rare benign disorder described initially by Raskin in 1988. It is characterized by recurrent nocturnal episodes of headache that periodically awaken the sleeping patient and usually occur in the elderly. This review is aimed at describing the clinical features of the HH cases in childhood that have been published in literature so far. Based on a literature search in the major medical databases (LiLacs, SciELO, Bireme, Scopus, EBSCO and PubMed), we have analyzed the case reports on HH in childhood that have been published between 1988 (the first description) and 2014. In this review, we have described five children (3 girls and 2 boys) diagnosed with HH. The average age was 9.0 +/- 1.6 years (95% CI 7.6-10.4), ranging from 7 to 11 years. The diagnosis was made 15.8 +/- 25.0 months (range 1 to 60 months) after the headache started. Three patients (60.0%) were awakened a few hours after falling asleep. The headache lasted up to 30 min in four (80.0%) patients. The headache was bilaterally localized (4/5; 80.0%), had a throbbing/pulsating character (3/5; 60.0%) and a severe intensity (4/5; 80.0%). The frequency was less than 15 days per month (4/5; 80.0%). The absence of autonomic symptoms was reported by all patients. There was successful treatment with melatonin in 2/5 (40.0%) of the patients. HH is very rare in childhood; its clinical features are inconsistent and still need further evaluation. PMID- 26123201 TI - Cognitive and neuroanatomical correlates of neuropsychiatric symptoms in Parkinson's disease: A systematic review. AB - INTRODUCTION: Neuropsychiatric symptoms are one of the most common non-motor symptoms in Parkinson's disease (PD). These symptoms have a negative impact on daily living activities and cognitive abilities. This review will be centred on published articles which focused on clarifying the cognitive and neuroanatomical features associated with the appearance of specific neuropsychiatric symptoms in this disease. METHODS: All articles indexed in the Web of Science and PubMed databases were reviewed for potential inclusion in October 2014. In the first stage of the review, we identified 41 articles that investigated neuropsychiatric symptoms and cognitive impairments in PD. In the second stage, there were 26 published articles on the neural bases of neuropsychiatric symptoms in PD. RESULTS: The main findings revealed that executive dysfunctions were common in patients with depression, apathy, visual hallucinations (VH), impulse control disorders (ICDs) and anxiety, whereas, memory deficits were associated mainly with depression and VH. Imaging studies have shown that frontal lobe atrophy was frequently observed in patients with depression, apathy, VH and ICDs. CONCLUSION: This review gives a snapshot of those cognitive and neural correlates of neuropsychiatric symptoms in PD. Methodological shortcoming in the available studies were identified, however, of which the most critical appeared neglecting the presence of multiple neuropsychiatric symptoms in some of the patients included in studies of specific individual symptoms. Additionally, in most studies only patients in the moderate to severe stages were included which limits possible inferences to the early stage of the disease. PMID- 26123202 TI - Crystallinity of tellurium capping and epitaxy of ferromagnetic topological insulator films on SrTiO3. AB - Thin films of topological insulators are often capped with an insulating layer since topological insulators are known to be fragile to degradation. However, capping can hinder the observation of novel transport properties of the surface states. To understand the influence of capping on the surface states, it is crucial to understand the crystal structure and the atomic arrangement at the interfaces. Here, we use x-ray diffraction to establish the crystal structure of magnetic topological insulator Cr-doped (Bi,Sb)2Te3 (CBST) films grown on SrTiO3 (1 1 1) substrates with and without a Te capping layer. We find that both the film and capping layer are single crystal and that the crystal quality of the film is independent of the presence of the capping layer, but that x-rays cause sublimation of the CBST film, which is prevented by the capping layer. Our findings show that the different transport properties of capped films cannot be attributed to a lower crystal quality but to a more subtle effect such as a different electronic structure at the interface with the capping layer. Our results on the crystal structure and atomic arrangements of the topological heterostructure will enable modelling the electronic structure and design of topological heterostructures. PMID- 26123203 TI - Functional POR A503V is associated with the risk of bladder cancer in a Chinese population. AB - Human cytochrome P450 oxidoreductase (POR) plays important roles in the metabolism of exogenous carcinogens and endogenous sterol hormones. However, few studies have explored the association between POR variants and the risk of bladder cancer. In this study, we first sequenced all 16 POR exons among 50 randomly selected controls, and found three variants, rs1135612, rs1057868 (A503V) and rs2228104, which were then assessed the relation to risk of bladder cancer in a case-control study of 1,050 bladder cancer cases and 1,404 cancer free controls in a Chinese population. People with A503V TT genotype have a decreased risk of bladder cancer in a recessive model (TT vs. CC/CT, OR = 0.73, 95% CI = 0.57-0.93), which was more pronounced among elderly male, non-smoking, subjects. Especially, A503V TT genotype showed a protective effect in the invasive tumor stage. Functional analysis revealed that A503V activity decreased in cytochrome c reduction (50.5 units/mg vs. 135.4 units/mg), mitomycin C clearance (38.3% vs. 96.8%), and mitomycin C-induced colony formation (78.0 vs 34.3 colonies per dish). The results suggested that POR A503V might decrease the risk of bladder cancer by reducing its metabolic activity, and should be a potential biomarker for predicting the susceptibility to human bladder cancer. PMID- 26123204 TI - Investigation of cancer mortality inequalities between rural and urban areas in South Korea. AB - OBJECTIVE: Little is known about rural-urban cancer disparities, particularly in South Korea, and this study is to identify cancer-specific mortality inequalities between the rural and urban areas of the country. DESIGN, SETTING, AND PARTICIPANTS: For 11 specific cancer sites, age-standardised mortality rates were analysed for the rural and urban administrative districts of South Korea during 2006-2011. MAIN OUTCOME MEASURES: The Poisson log linear regression models were employed to estimate cancer-specific mortality rates, and Bonferroni comparison method was used to identify rural-urban disparities. RESULTS: There were significant rural-urban disparities observed for all cancer sites except prostate, pancreas and leukaemia. The mortality rates of lung, liver and stomach cancers, the three most common cancers in the country, were observed to be significantly higher in rural areas than in metropolitan areas. In contrast, the reverse relationship was observed for the reproductive system (breast and uterus) and colon cancers. Central nervous system cancer mortality was observed to be significantly higher in rural areas than in non-metro urban areas. CONCLUSIONS: For the first time ever, significant rural-urban disparity patterns in cancer mortality rates in South Korea have been identified in this paper. Future investigations on cancer risk factors for the country should address these disparity patterns. PMID- 26123205 TI - Lexical organization of language-ambiguous and language-specific words in bilinguals. AB - Previous research has shown the importance of sublexical orthographic cues in determining the language of a given word when the two languages of a bilingual reader share the same script. In this study, we explored the extent to which cross-language sublexical characteristics of words-measured in terms of bigram frequencies-constrain selective language activation during reading. In Experiment 1, we investigated the impact of language-nonspecific and language-specific orthography in letter detection using the Reicher-Wheeler paradigm in a seemingly monolingual experimental context. In Experiment 2, we used the masked translation priming paradigm in order to better characterize the role of sublexical language cues during lexical access in bilinguals. Results show that bilinguals are highly sensitive to statistical orthographic regularities of their languages and that the absence of such cues promotes language-nonspecific lexical access, whereas their presence partially reduces parallel language activation. We conclude that language coactivation in bilinguals is highly modulated by sublexical processing and that orthographic regularities of the two languages of a bilingual are a determining factor in lexical access. PMID- 26123206 TI - Does religious coping and spirituality have a moderating role on depression and anxiety in patients with spinal cord injury? A study from Iran. AB - OBJECTIVES: We evaluate the level of anxiety and depression among patients with spinal cord injury (SCI) in relation with their religious coping and spiritual health. SETTING: Brain and Spinal Cord Injury Repair Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. METHODS: A sample of patients with SCI participated in this cross-sectional study. They completed a sociodemographic questionnaire, the Hospital Anxiety and Depression Scale, the Brief Religious Coping Questionnaire and the Spiritual Well being Scale. Then, the association between anxiety, depression and independent variables was examined. RESULTS: In all, 213 patients with SCI were studied. Of these, 64 (30%) have had anxiety and 32 (15%) have had depression. Multiple logistic regression analyses revealed that gender (odds ratio (OR) for female=3.34, 95% confidence interval (CI)=1.31-8.51, P=0.011), employment (OR for unemployed=5.71, 95% CI=1.17-27.78, P=0.031), negative religious coping (OR=1.15, 95% CI=1.04-1.28, P=0.006) and existential spiritual well-being (OR=0.93, 95% CI=0.89-0.97, P=0.003) were significant contributing factors to anxiety (Table 3), whereas negative religious coping (OR=1.21, 95% CI=1.06-1.37, P=0.004) and existential spiritual well-being (OR=0.90, 95% CI=0.84-0.96, P=0.001) were significant contributing factors to depression. CONCLUSION: The findings indicated that depression and anxiety are two psychologically important side effects after SCI. The findings also indicated that religion and spiritual well being have a moderating role on occurrence of depression and anxiety. PMID- 26123207 TI - Change in body surface temperature as an ancillary measurement to motor evoked potentials. AB - STUDY DESIGN: Experimental study. OBJECTIVES: To study the role of surface temperature as an adjunct to motor evoked potentials (MEPs) in rabbit spinal cord injury (SCI) model. SETTING: Department of Orthopedics, Korea University Guro Hospital, Seoul, Korea. METHODS: Rabbits (n =18) were divided into Complete (n = 9) and Incomplete (n = 9) SCI groups. Complete SCI was defined as being non responsive to a wake-up test with loss of MEPs after transection of spinal cord. Incomplete SCI was defined as being responsive to a wake-up test with significant attenuation (? 80%) of MEPs after impaction on spinal cord. Surface temperature of upper and lower extremities, core temperature and MEPs signals were checked before, during and after SCI for 20 min. A wake-up test was conducted and spinal cord was histologicaly evaluated. RESULTS: Experimental conditions between the two groups were statistically similar (P > 0.005 for all values). After SCI, upper extremity temperatures did not change in either group (P > 0.005); however, the surface temperature of the lower extremities in the Complete SCI Group elevated to 1.7 +/- 0.5 degrees C in comparison to 0.5 +/- 0.1 degrees C in the Incomplete SCI Group (P < 0.001). The scores of wake-up test in the Incomplete SCI Group were significantly different from that of the Complete SCI Group (P < 0.001), while white and gray matter damage was variable on histology. CONCLUSIONS: Monitoring of changes of body surface temperature of the lower extremities can be potentially used to identify the completeness of SCI in a rabbit model. PMID- 26123208 TI - Tumefactive demyelination of the spinal cord: a case report. AB - STUDY DESIGN: Case report. OBJECTIVES: We report on a 52-year-old male patient with tumefactive demyelination of the spinal cord. SETTING: University Hospital and Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia. BACKGROUND: In contrast to relatively frequent tumefactive fulminant lesions in the brain, cases affecting the spinal cord in isolation have been reported less frequently. METHODS: Description of the case report. RESULTS: Clinical, neuroradiological and necropsy findings are described in a 52-year-old man with tumefactive fulminant demyelination of the spinal cord. Progression of the demyelination process produced paraplegia, mild paresis of the right upper limb, neurogenic bladder and sensitive loss over 2 weeks. MRI scans revealed several ovoid lesions in cervical segments and tumefactive T2-hyperintense signals with oedema and post-contrast enhancement located in thoracic segments Th3 to Th6. Cerebrospinal fluid (CSF) examination displayed lymphomonocytic pleocytosis with normal proteinorhachia, positive CSF oligoclonal IgG bands (OCB) and elevated IgG index (1.55). Serum anti-AQP4-Ab was not tested. Stored frozen CSF samples were later repeatedly examined with negative findings of anti-AQP4-Ab. Treatment with high-dose methylprednisolon and plasma exchange had limited effect. Immunosuppressive medication was interrupted because of an acute urinary infection. The patient died suddenly because of pulmonary embolism as a secondary complication. Histopathology of the spinal cord confirmed active demyelination. We considered that tumefactive demyelination could be a variant of neuromyelitis optica. CONCLUSION: Our case could be anti-AQP4-Ab-negative longitudinally extensive transverse myelitis, a variant of neuromyelitis optica. PMID- 26123209 TI - Risk factors of urethral diverticula in male patients with spinal cord injury. AB - STUDY DESIGN: A case-control study in a series of 55 males with urethral diverticula (UD) and their correspondent control, matched by age and time of radiological assessments. OBJECTIVES: To evaluate the risk factors to develop UD in males with spinal cord injury (SCI) and the place in the urethra where they are, most commonly, allocated. SETTING: Toledo, Spain. METHODS: Clinical histories and urodynamic studies, of all patients, were reviewed. The study was completed with a telephone survey according to an established protocol. RESULTS: The univariate analysis study showed the following risk factors: the age of onset of the spinal injury, the sphincterotomy procedure, personal history of lower urinary tract infections (LUTIs) and the chronic need of either indwelling catheter (IC) or the external condom drainage (ECD). Regarding the location of the UD, we have found the stress urinary incontinence as the only risk factor to develop UD in the prostatic urethra.On the other hand, we can conclude that the sphincterotomy, the ECD, the personal history of LUTIs and the detrusor external sphincter dyssynergia seem to be risk factors to develop diverticula in the bulbo membranous urethra. Finally, we could point out the IC as the only risk factor for penile UD. Multivariate analysis showed that all of these risk factors were independent among them except the age of the onset of the injury and the ECD for UD in the bulbo-membranous urethra. CONCLUSION: According to our study, there is evidence of some specific risk factors for the development of UD in male patients with SCI, and therefore we should adopt the appropriate preventive measures to prevent them. PMID- 26123210 TI - Match activity and physiological load in wheelchair tennis players: a pilot study. AB - STUDY DESIGN: There is a lack of information about the physiological and psychological parameters in competition that shows a comprehensive profile of the demands of the game situation. OBJECTIVE: The aim of the present study was to examine the activity patterns and physiological-perceptual responses (heart rate (HR), blood lactate concentrations (LA) and the rate of perceived exertion (RPE), respectively, during singles wheelchair tennis (WT) matches. METHODS: A total of four WT players played three matches each. HR, LA and RPE were measured during each match. An activity pattern analysis was performed during all matches. Furthermore, LA and RPE were compared between service and return games. RESULTS: The results show a mean (s.d.) total match time of 69.04 (2.3) minutes, an effective playing time of 17.65% (0.03%), a work:rest (W:R) time ratio of 1:4.6 (0.48) and a rally length of 7.04 (4.44) seconds. Most of the points end in three or fewer shots. The mean (s.d.) physiological load during the matches were as follows: HR 124.25 (24.7) beats per minute, %HRmax 66.31% (4.5%), LA 1.41 (0.43) mmol l(-)(1) and RPE 12.45 (1.91). No significant differences were found in LA and RPE between service and return games (P>0.05). CONCLUSIONS: In this descriptive study, match activity and physiological load in WT are described. Match activities are similar to conventional tennis, although the physiological load is lower. Service and return situations show similar physiological and perceptual responses. These results might be used to develop specific interval training protocols for a male WT player. PMID- 26123211 TI - Proximal tibia fracture in a patient with incomplete spinal cord injury associated with robotic treadmill training. AB - STUDY DESIGN: One case report of proximal tibia fracture in a patient with incomplete spinal cord injury (SCI) associated with robotic treadmill training. OBJECTIVE: To raise the awareness that bone densitometry may be recommended before starting the robotic treadmill therapy, as well as the active vigilance of symptoms after therapy. SETTING: Institute of Physical and Rehabilitation Medicine, Lucy Montoro Institute for Rehabilitation, Hospital das Clinicas, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil. CASE REPORT: The patient, female gender, with a fracture of vertebra T12 and arthrodesis from T9 to L1 (American Spinal Injury Association Classification (ASIA-C)). Training on Lokomat consisted of five 30-min weekly sessions, under the supervision of a qualified professional. At the beginning of the 19th session, the patient complained of pain in the anterior region of the left knee. Lokomat and any other body support therapy were discontinued. Magnetic resonance imaging (MRI) evidenced a transverse, oblique, metaphyseal proximal anterior and medial tibial fracture. CONCLUSION: Fractures are among the chronic complications of a SCI, affecting 34% and many times arising from minimal traumas. Lokomat resembles physiological walking, and more studies show its benefits. Many studies encourage the use of robotic devices for the rehabilitation of lower limbs, but there are still several unanswered questions. However, there are not enough studies to show whether there is a higher risk of fracture incidence in patients with osteopenia or osteoporosis who trained on the Lokomat. PMID- 26123212 TI - Discrepancies between clinical assessments of sensory function and electrical perceptual thresholds after incomplete chronic cervical spinal cord injury. AB - STUDY DESIGN: Prospective experimental. OBJECTIVES: To compare sensory function as revealed by light touch and pin prick tests of the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the electrical perceptual threshold (EPT) exams in individuals with chronic incomplete cervical spinal cord injury (SCI). SETTING: Pittsburgh, United States. METHODS: EPT was tested using cutaneous electrical stimulation (0.5 ms pulse width, 3 Hz) in 32 healthy controls and in 17 participants with SCI over key points on dermatomes C2 to T4 on each side of the body. Light touch and pin prick ISNCSCI scores were tested at the same key dermatomes in SCI participants. RESULTS: In controls, EPT values were higher in older males (1.26+/-0.2 mA, mean+/-s.d.) compared with younger males (1.0+/-0.2 mA) and older females (0.9+/-0.2 mA), regardless of the dermatome and side tested. Fifteen out of the seventeen SCI participants showed that the level of sensory impairment detected by the EPT was below the level detected by the ISNCSCI (mean=4.5+/-2.4, range 1-9). The frequency distribution of EPTs was similar to older male controls in dermatomes above but not below the ISNCSCI sensory level. The difference between EPT and ISNCSCI sensory level was negatively correlated with the time post injury. CONCLUSIONS: The results show that, in the chronic stage of cervical SCI, the EPT reveals spared sensory function at lower (~5) spinal segments compared with the ISNCSCI sensory exam. It is hence found that the EPT is a sensitive tool to assess recovery of sensory function after chronic SCI. PMID- 26123213 TI - Positive Selection Analysis of Overlapping Reading Frames Is Invalid. PMID- 26123214 TI - Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. AB - BACKGROUND: Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT. OBJECTIVES: To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations. SELECTION CRITERIA: We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT. DATA COLLECTION AND ANALYSIS: Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). MAIN RESULTS: We included 11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life. AUTHORS' CONCLUSIONS: NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT. PMID- 26123215 TI - Enhanced neutrophil phagocytic capacity in rheumatoid arthritis related to the autoantibodies rheumatoid factor and anti-cyclic citrullinated peptides. AB - BACKGROUND: There is no consensus on the mechanisms by which anti-cyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) influence the pathogenesis of rheumatoid arthritis (RA). The current study verified if the presence of RF or anti-CCP is associated with phagocytic capacity and reactive oxygen species (ROS) production by phagocytes in RA patients to better clarify the role played by these antibodies in pathogenesis of the disease. METHODS: A cohort of 30 RA patients followed from early stages of the disease were characterized by positivity for RF or anti-CCP, disease activity score (DAS-28), health assessment questionnaire (HAQ), use of synthetic or biologic therapy, lifestyle, comorbidities and radiographic erosions. Phagocytic capacity against Saccharomyces cerevisiae and superoxide anion production were assessed in RA patients and compared with 20 healthy controls. Phagocytic capacity and superoxide anion production were also compared between RF- and anti-CCP-positive and -negative RA patients. RESULTS: Anti-CCP- and RF-positive RA patients had higher neutrophil phagocytic capacity than anti-CCP- (p = 0.005) and RF (p = 0.005)-negative individuals through pattern-recognition receptors. As assessed via pattern recognition or opsonin receptors, neutrophils and monocytes from RA patients presented overall higher phagocytic capacity than neutrophils and monocytes from healthy controls (p < 0.05). Furthermore, RA patients also showed a higher capacity for producing cytotoxic oxygen radicals (p = 0.0026). Phagocytosis and superoxide anion production did not correlate with any of the clinical variables analyzed in this study. CONCLUSIONS: This study showed increased phagocytosis by neutrophils in RA patients who were positive for anti CCP and RF autoantibodies. Furthermore, there was an overall hyperactivation of the phagocytes in RA patients. Our data suggest that anti-CCP and RF may indirectly enhance the inflammation cascade involving neutrophils and may indirectly sustain tissue damage in RA. Targeting the production of these autoantibodies may be a promising strategy in the management of RA. PMID- 26123217 TI - Self-assembly concepts for multicompartment nanostructures. AB - Compartmentalization is ubiquitous to many biological and artificial systems, be it for the separate storage of incompatible matter or to isolate transport processes. Advancements in the synthesis of sequential block copolymers offer a variety of tools to replicate natural design principles with tailor-made soft matter for the precise spatial separation of functionalities on multiple length scales. Here, we review recent trends in the self-assembly of amphiphilic block copolymers to multicompartment nanostructures (MCNs) under (semi-)dilute conditions, with special emphasis on ABC triblock terpolymers. The intrinsic immiscibility of connected blocks induces short-range repulsion into discrete nano-domains stabilized by a third, soluble block or molecular additive. Polymer blocks can be synthesized from an arsenal of functional monomers directing self assembly through packing frustration or response to various fields. The mobility in solution further allows the manipulation of self-assembly processes into specific directions by clever choice of environmental conditions. This review focuses on practical concepts that direct self-assembly into predictable nanostructures, while narrowing particle dispersity with respect to size, shape and internal morphology. The growing understanding of underlying self-assembly mechanisms expands the number of experimental concepts providing the means to target and manipulate progressively complex superstructures. PMID- 26123216 TI - Associations between ambient air pollutant mixtures and pediatric asthma emergency department visits in three cities: a classification and regression tree approach. AB - BACKGROUND: Characterizing multipollutant health effects is challenging. We use classification and regression trees to identify multipollutant joint effects associated with pediatric asthma exacerbations and compare these results with those from a multipollutant regression model with continuous joint effects. METHODS: We investigate the joint effects of ozone, NO2 and PM2.5 on emergency department visits for pediatric asthma in Atlanta (1999-2009), Dallas (2006-2009) and St. Louis (2001-2007). Daily concentrations of each pollutant were categorized into four levels, resulting in 64 different combinations or "Day Types" that can occur. Days when all pollutants were in the lowest level were withheld as the reference group. Separate regression trees were grown for each city, with partitioning based on Day-Type in a model with control for confounding. Day-Types that appeared together in the same terminal node in all three trees were considered to be mixtures of potential interest and were included as indicator variables in a three-city Poisson generalized linear model with confounding control and rate ratios calculated relative to the reference group. For comparison, we estimated analogous joint effects from a multipollutant Poisson model that included terms for each pollutant, with concentrations modeled continuously. RESULTS AND DISCUSSION: No single mixture emerged as the most harmful. Instead, the rate ratios for the mixtures suggest that all three pollutants drive the health association, and that the rate plateaus in the mixtures with the highest concentrations. In contrast, the results from the comparison model are dominated by an association with ozone and suggest that the rate increases with concentration. CONCLUSION: The use of classification and regression trees to identify joint effects may lead to different conclusions than multipollutant models with continuous joint effects and may serve as a complementary approach for understanding health effects of multipollutant mixtures. PMID- 26123218 TI - Trachoma in remote Indigenous Australia: a review and public health perspective. AB - OBJECTIVES: Trachoma remains a major health concern in many remote Indigenous Australian communities, despite behaviour-modifying and biomedical strategies. This review aims to examine the social epidemiology of trachoma in remote Indigenous communities and identify practical, sustainable strategies to alter the social determinants of the disease. METHODS: A systematic search and critical review explored the proximal, intermediate and distal determinants of trachoma. The impact of swimming pools in remote Indigenous communities on trachoma and other infectious diseases was further examined. RESULTS: Having a clean face was found to be protective for trachoma, but face-washing education programs have produced no significant benefits. Sanitation infrastructure in a community was the key determinant of facial cleanliness. Installation of swimming pools in remote Indigenous communities has been demonstrated to reduce the prevalence of several common childhood infections. However, minimal research has explored the impact of pools on trachoma rates. CONCLUSIONS: The locally supported construction of pools in remote Indigenous communities may contribute to a decline in trachoma. A prospective, controlled trial is needed to test this hypothesis in endemic communities. IMPLICATIONS: If validated by a well-designed study, pool construction may provide a much sought-after practical government strategy to combat trachoma in remote Indigenous communities. PMID- 26123219 TI - Rapid assessment of quantitative T1, T2 and T2* in lower extremity muscles in response to maximal treadmill exercise. AB - MRI provides a non-invasive diagnostic platform to quantify the physical and physiological attributes of skeletal muscle at rest and in response to exercise. MR relaxation parameters (T1, T2 and T2*) are characteristic of tissue composition and metabolic properties. With the recent advent of quantitative techniques that allow rapid acquisition of T1, T2 and T2* maps, we posited that an integrated treadmill exercise-quantitative relaxometry paradigm can rapidly characterize exercise-induced changes in skeletal muscle relaxation parameters. Accordingly, we investigated the rest/recovery kinetics of T1, T2 and T2* in response to treadmill exercise in the anterior tibialis, soleus and gastrocnemius muscles of healthy volunteers, and the relationship of these parameters to age and gender. Thirty healthy volunteers (50.3 +/- 16.6 years) performed the Bruce treadmill exercise protocol to maximal exhaustion. Relaxometric maps were sequentially acquired at baseline and for approximately 44 minutes post-exercise. Our results show that T1, T2 and T2* are significantly and differentially increased immediately post-exercise among the leg muscle groups, and these values recover to near baseline within 30-44 minutes. Our results demonstrate the potential to characterize the kinetics of relaxation parameters with quantitative mapping and upright exercise, providing normative values and some clarity on the impact of age and gender. PMID- 26123220 TI - Osmunda pulchella sp. nov. from the Jurassic of Sweden--reconciling molecular and fossil evidence in the phylogeny of modern royal ferns (Osmundaceae). AB - BACKGROUND: The classification of royal ferns (Osmundaceae) has long remained controversial. Recent molecular phylogenies indicate that Osmunda is paraphyletic and needs to be separated into Osmundastrum and Osmunda s.str. Here, however, we describe an exquisitely preserved Jurassic Osmunda rhizome (O. pulchella sp. nov.) that combines diagnostic features of both Osmundastrum and Osmunda, calling molecular evidence for paraphyly into question. We assembled a new morphological matrix based on rhizome anatomy, and used network analyses to establish phylogenetic relationships between fossil and extant members of modern Osmundaceae. We re-analysed the original molecular data to evaluate root placement support. Finally, we integrated morphological and molecular data-sets using the evolutionary placement algorithm. RESULTS: Osmunda pulchella and five additional Jurassic rhizome species show anatomical character suites intermediate between Osmundastrum and Osmunda. Molecular evidence for paraphyly is ambiguous: a previously unrecognized signal from spacer sequences favours an alternative root placement that would resolve Osmunda s.l. as monophyletic. Our evolutionary placement analysis identifies fossil species as probable ancestral members of modern genera and subgenera, which accords with recent evidence from Bayesian dating. CONCLUSIONS: Osmunda pulchella is likely a precursor of the Osmundastrum lineage. The recently proposed root placement in Osmundaceae-based solely on molecular data-stems from possibly misinformative outgroup signals in rbcL and atpA genes. We conclude that the seemingly conflicting evidence from morphological, anatomical, molecular, and palaeontological data can instead be elegantly reconciled under the assumption that Osmunda is indeed monophyletic. PMID- 26123222 TI - Agreement on the prescription of antimicrobial drugs. AB - BACKGROUND: There is universal awareness of the difficulties faced by doctors when prescribing antimicrobials. METHODS: Over a six-month period patients hospitalized in the ICU and under treatment with antibiotics and/or antifungals were eligible to participate in the study. The data were assessed by two infectious diseases specialists. Once completed, all case forms were sent independently to both evaluators (TZSC and ARM) by e-mail. Based on the data received, the evaluator completed a form automatically generated on the e-mail and returned it to the original mailbox for further analysis. We assessed the level of agreement between infectious disease specialists and the physicians directly responsible for the decision to begin antimicrobial therapy, as well as to assess the appropriateness of the regimen prescribed. RESULTS: Among the antimicrobial regimens prescribed to the 177 patients, 36% were considered inappropriate by specialist #1 and 38% were considered inappropriate by specialist #2. We found 78% agreement by at least one of the infectious disease specialists with the prescribed antimicrobial regimen, and in 49% of cases both specialists agreed with the prescribed regimen. Both disagreed with the prescribed regimen in 22% of the cases and they disagreed between themselves in 29% of the cases. CONCLUSION: This study highlights the difficulties in prescribing effective empirical antimicrobial therapy--they are of such magnitude that even two specialists in infectious diseases, well acquainted with our hospital's resistance patterns and our patients' profiles have considerable disagreement. PMID- 26123223 TI - Identification of the novel allele, HLA-C*15:02:01:03, by full-length genomic sequencing. AB - The HLA-C*15:02:01:03 allele differs from the HLA-C*15:02:01:01 allele by a single-nucleotide substitution in the 5' untranslated region (-42 C>A). PMID- 26123224 TI - Staphylococcus aureus dynamically adapts global regulators and virulence factor expression in the course from acute to chronic infection. AB - Staphylococcus aureus is an important pathogen of severe invasive tissue infection, e.g. osteomyelitis that can develop to chronicity and become extremely difficult to treat. Recent research revealed that S. aureus can dynamically switch to small colony variants (SCVs) that are adapted bacterial phenotypes for long-term persistence. The underlying mechanisms of the bacterial switching and adaptation process are largely dependent on an intact Sigma B regulon. As SigB is known as a transcription factor that modulates the stress response of several Gram-positive bacteria, it is most likely required by the bacteria to cope with the intracellular stress conditions. Here, we demonstrate in a long-term infection model of human osteoblasts that S. aureus continuously upregulated the expression of SigB during intracellular persistence. The increased SigB expression was accompanied by upregulation of adhesins and downregulation of toxins, which are characteristics for SCV phenotypes. These data further stress the role of SigB during chronic infections that could be a novel target for preventive or therapeutic measures to avoid chronic infections. PMID- 26123225 TI - Haemoglobin Variant Screening in Jamaica: Meeting Student's Request. PMID- 26123226 TI - Reply: To PMID 25545787. PMID- 26123227 TI - Economic burden of Clostridium difficile associated diarrhoea: a cost-of-illness study from a German tertiary care hospital. AB - PURPOSE: Clostridium difficile associated diarrhoea (CDAD) is the most common cause of health-care-associated infectious diarrhoea. In the context of the German health-care system, direct and indirect costs of an initial episode of CDAD and of CDAD recurrence are currently unknown. METHODS: We defined CDAD as presence of diarrhoea (>=3 unformed stools/day) in association with detection of Clostridium difficile toxin in an unformed faecal sample. Patients treated with metronidazole (PO or IV) and/or vancomycin (PO) were included. Comprehensive data of patients were retrospectively documented into a database using the technology of the Cologne Cohort of Neutropenic Patients (CoCoNut). Patients with CDAD were matched to control patients in a 1:1 ratio. Analysis was split in three groups: incidence group (CDAD patients without recurrence), recurrence group (CDAD patients with >=1 recurrence) and control group (matched non-CDAD patients). RESULTS: Between 02/2010 and 12/2011, 150 patients with CDAD (114 patients in the incidence and 36 (24 %) in the recurrence group) and 150 controls were analysed. Mean length of stay was: 32 (95 %CI: 30-37), 94 (95 %CI: 76-112) and 24 days (95 %CI: 22-27; P = <0.001), resulting in mean overall direct treatment costs per patient of ?18,460 (95 %CI: ?14,660-?22,270), ?73,900 (95 %CI: ?50,340-?97,460) and ?14,530 (95 %CI: ?11,730-?17,330; P = <0.001). In the incidence and recurrence group, the mean cumulative number of antibiotic CDAD treatment days was 11 (95 %CI: 10-12) and 36 (95 %CI: 27-45; P = <0.001). CONCLUSIONS: Especially CDAD recurrence was associated with excessive costs, which were mostly attributable to a significantly longer overall length of stay. Innovative treatment strategies are warranted to reduce treatment costs and prevent recurrence of CDAD. PMID- 26123228 TI - Development of visceral leishmaniasis in an HIV(+) patient upon immune reconstitution following the initiation of antiretroviral therapy. AB - CASE PRESENTATION: Here, we report on a case of VL in an HIV-infected patient from the Republic of Georgia who had moved to Germany 14 years before and who had travelled several times to southern Europe in between. After presenting with typical Pneumocystis jiroveci pneumonia, which was treated appropriately, the patient was started on antiretroviral therapy. Shortly thereafter, however, he developed fever of unknown origin. All laboratory assays for the diagnosis of various infectious agents including serological assays and polymerase chain reaction testing of bone marrow aspirate to diagnose VL did not yield positive results at first. Only upon repetition of these tests, diagnosis of VL could be made and the patient treated accordingly. CASE DISCUSSION: Visceral leishmaniasis (VL) is a common opportunistic infection in HIV-positive patients from endemic countries but occurs rarely following antiretroviral treatment. This case demonstrates that patients who develop VL upon immune reconstitution may not be diagnosed initially by standard laboratory assays for the diagnosis of VL and underlines the necessity to repeat serologic and molecular biologic testing for VL in cases of fever of unknown origin in patients from or with travel history to endemic countries. PMID- 26123229 TI - Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies. AB - MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. PMID- 26123230 TI - Corneal Opacity in Domestic Ducks Experimentally Infected With H5N1 Highly Pathogenic Avian Influenza Virus. AB - Domestic ducks can be a key factor in the regional spread of H5N1 highly pathogenic avian influenza (HPAI) virus in Asia. The authors performed experimental infections to examine the relationship between corneal opacity and H5N1 HPAI virus infection in domestic ducks (Anas platyrhyncha var domestica). A total of 99 domestic ducks, including 3 control birds, were used in the study. In experiment 1, when domestic ducks were inoculated intranasally with 2 H5N1 HPAI viruses, corneal opacity appeared more frequently than neurologic signs and mortality. Corneal ulceration and exophthalmos were rare findings. Histopathologic examinations of the eyes of domestic ducks in experiment 2 revealed that corneal opacity was due to the loss of corneal endothelial cells and subsequent keratitis with edema. Influenza viral antigen was detected in corneal endothelial cells and some other ocular cells by immunohistochemistry. Results suggest that corneal opacity is a characteristic and frequent finding in domestic ducks infected with the H5N1 HPAI virus. Confirming this ocular change may improve the detection rate of infected domestic ducks in the field. PMID- 26123231 TI - Reduction in delta activity predicted improved negative affect in Major Depressive Disorder. AB - While prior research has demonstrated a paradoxical antidepressant effect of slow wave disruption (SWD), the specific dimensions of depression affected is still unclear. The current study aimed to extend this research by utilizing a dimensional approach in examining the antidepressant effects of SWD. Of particular interest is the affective dimension, as negative affect in depression is arguably the most salient characteristic of depression. This sample included 16 individuals with depression (10 female) recruited from the community. Participants slept in the lab for three nights (adaptation, baseline night, and SWD) with polysomnography, and completed measures of negative affect and depression severity the following morning. Results show that reduction in delta power was linearly associated with improved negative affect. Comparison of individual change scores revealed that half of the individuals showed improved negative affect, which is comparable to the reported 40-60% antidepressant response rate to sleep deprivation. Results suggest that vulnerability in the sleep homeostatic system may be a contributing individual differences factor in response to slow-wave disruption in depression. PMID- 26123232 TI - Excited-State Proton Transfer of Weak Photoacids Adsorbed on Biomaterials: Proton Transfer on Starch. AB - Steady-state and time-resolved fluorescence techniques were employed to study the excited-state proton transfer (ESPT) from a photoacid adsorbed on starch to a nearby water molecule. Starch is composed of ~30% amylose and ~70% amylopectin. We found that the ESPT rate of adsorbed 8-hydroxy-1,3,6-pyrenetrisulfonate (HPTS) on starch arises from two time constants of 300 ps and ~3 ns. We explain these results by assigning the two different ESPT rates to HPTS adsorbed on amylose and on amylopectin. When adsorbed on amylose, the ESPT rate is ~3 * 10(9 )s(-1), whereas on amylopectin, it is only ~3 * 10(8) s(-1). PMID- 26123233 TI - Meta-analysis of survival curve data using distributed health data networks: application to hip arthroplasty studies of the International Consortium of Orthopaedic Registries. AB - The motivating example for this paper comes from a distributed health data network, the International Consortium of Orthopaedic Registries (ICOR), which aims to examine risk factors for orthopedic device failure for registries around the world. Unfortunately, regulatory, privacy, and propriety concerns made sharing of raw data impossible, even if de-identified. Therefore, this article describes an approach to extraction and analysis of aggregate time-to-event data from ICOR. Data extraction is based on obtaining a survival probability and variance estimate for each unique combination of the explanatory variables at each distinct event time for each registry. The extraction procedure allows for a great deal of flexibility; models can be specified after the data have been collected, for example, modeling of interaction effects and selection of subgroups of patients based on their values on the explanatory variables. Our analysis models are adapted from models presented elsewhere--but allowing for censoring in the calculation of the correlation between serial survival probabilities and using the square root of the covariance matrix to transform the data to avoid computational problems in model estimation. Simulations and a real data example are provided with strengths and limitations of the approach discussed. PMID- 26123234 TI - Chlorhexidine hexametaphosphate nanoparticles as a novel antimicrobial coating for dental implants. AB - Dental implants are an increasingly popular solution to missing teeth. Implants are prone to colonisation by pathogenic oral bacteria which can lead to inflammation, destruction of bone and ultimately implant failure. The aim of this study was to investigate the use of chlorhexidine (CHX) hexametaphosphate (HMP) nanoparticles (NPs) with a total CHX concentration equivalent to 5 mM as a coating for dental implants. The CHX HMP NPs had mean diameter 49 nm and composition was confirmed showing presence of both chlorine and phosphorus. The NPs formed micrometer-sized aggregated surface deposits on commercially pure grade II titanium substrates following immersion-coating for 30 s. When CHX HMP NP-coated titanium specimens were immersed in deionised water, sustained release of soluble CHX was observed, both in the absence and presence of a salivary pellicle, for the duration of the study (99 days) without reaching a plateau. Control specimens exposed to a solution of aqueous 25 uM CHX (equivalent to the residual aqueous CHX present with the NPs) did not exhibit CHX release. CHX HMP NP-coated surfaces exhibited antimicrobial efficacy against oral primary colonising bacterium Streptococcus gordonii within 8 h. The antimicrobial efficacy was greater in the presence of an acquired pellicle which is postulated to be due to retention of soluble CHX by the pellicle. PMID- 26123235 TI - Methamphetamine use and treatment in Iran: A systematic review from the most populated Persian Gulf country. AB - AIM: Methamphetamine use is a new health concern in Iran, the most populated Persian Gulf country. However, there is no well-documented literature. The current study objectives were to systematically review all published English and Persian studies of the prevalence of methamphetamine use, the general physical and psychiatric-related harms and the availability of methamphetamine treatment and harm reduction services for adult users in Iran. MATERIALS AND METHODS: A comprehensive search of the international peer-reviewed and gray literature was undertaken. Multiple electronic and scientific English and Persian databases were systematically searched from January 2002 to September 2014. Additionally, English and Persian gray literature on methamphetamine use was sought using online gray literature databases, library databases and general online searches over the same period of time. RESULTS: Nineteen thousand and two hundred and eight studies, reports and conference papers were identified but only 42 studies were relevant to the study objectives. They were mainly published in 2010-2014. The search results confirmed the seizures of methamphetamine (six studies), the prevalence of methamphetamine use among the general population (three studies), drug users (four studies), women (nine studies) and opiate users in opiate treatment programs (five studies). In addition, methamphetamine use had resulted in blood-borne viral infections (one study), psychosis and intoxication (ten studies). Different reasons had facilitated methamphetamine use. However, the Matrix Model, community therapy and harm reduction services (four studies) had been provided for methamphetamine users in some cities. CONCLUSION: The current situation of methamphetamine use necessitates more research on the epidemiology and health-related implications. These studies should help in identifying priorities for designing and implementing prevention and educational programs. More active models of engagement with Persian methamphetamine users and the provision of services that meet their specific treatment needs are required. PMID- 26123236 TI - Weight gain and reduced energy expenditure in low-income Brazilian women living in slums: a 4-year follow-up study. AB - The present study aimed to investigate the possible changes in anthropometric and biochemical parameters in low-income women living in the outskirts of Maceio (northeast Brazil), and to explore the possible role of dietary intake and physical activity in these changes. A prospective longitudinal study was conducted in a cohort of mothers of malnourished children who attended the Center for Nutritional Recovery and Education, an outreach programme of the Federal University of Alagoas. Socio-economic, anthropometric, biochemical and dietary intake data were assessed at baseline and after a follow-up period of 4 years. Energy expenditure (using doubly labelled water) and physical activity (using triaxial accelerometers) were assessed only in a subgroup of women after 4 years. A total of eighty-five women were assessed. Participants showed an altered biochemical profile, increased systolic blood pressure, decreased thyroid hormone levels, and body-weight gain. However, dietary intakes of the participants did not include large quantities of highly processed and high-glycaemic index foods. The energy intake of the participants did not differ from their total energy expenditure (7990.3 (7173.7-8806.8) v. 8798.1 (8169.0-9432.4) kJ, respectively; P= 0.084). Multivariate analyses showed a significant effect of time spent watching television (beta = 0.639 (0.003 to 1.275); P= 0.048) and dietary diversity score (beta = -1.039 ( -2.010 to -0.067); P = 0.036) on weight gain. The present study indicates that poor women, who are mothers of malnourished children and have a reasonably balanced dietary intake, exhibit weight gain and are at risk of developing chronic diseases. PMID- 26123238 TI - Haloarchaeobius amylolyticus sp. nov., isolated from a marine solar saltern. AB - Halophilic archaeal strain XD48(T) was isolated from a Chinese marine solar saltern. Cells were pleomorphic, stained Gram-negative and formed red-pigmented colonies on solid media. Strain XD48(T) was found to be able to grow at 25-50 degrees C (optimum 37 degrees C), at 0.9-4.8 M NaCl (optimum 3.1 M NaCl), at 0 1.0 M MgCl2 (optimum 0.3 MgCl2) and at pH 5.0-9.5 (optimum pH 6.5). The cells lysed in distilled water, and the minimal NaCl concentration to prevent cell lysis was found to be 5% (w/v). The major polar lipids of the strain were phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylglycerol phosphate methyl ester (PGP-Me), phosphatidylglycerol sulfate (PGS), sulfated galactosyl mannosyl glucosyl diether (S-TGD-1), sulfated mannosyl glucosyl diether (S-DGD-1) and six unknown glycolipids. The 16S rRNA gene and rpoB' gene of strain XD48(T) were phylogenetically related to the corresponding genes of Haloarchaeobius members (92.4-93.9 and 89.6-90.5% similarities, respectively). The DNA G + C content of strain XD48(T) was determined to be 65.3 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain XD48(T) (=CGMCC 1.12230(T) = JCM 18642(T)) represents a new species of Haloarchaeobius, for which the name Haloarchaeobius amylolyticus sp. nov. is proposed. PMID- 26123237 TI - Wastewater analysis of Census day samples to investigate per capita input of organophosphorus flame retardants and plasticizers into wastewater. AB - The use of organophosphate esters (PFRs) as flame retardants and plasticizers has increased due to the ban of some brominated flame retardants. There is however some concern regarding the toxicity, particularly carcinogenicity and neurotoxicity, of some of the PFRs. In this study we applied wastewater analysis to assess use of PFRs by the Australian population. Influent samples were collected from eleven wastewater treatment plants (STPs) in Australia on Census day and analysed for PFRs using gas chromatography coupled with mass spectrometry (GC-MS). Per capita mass loads of PFRs were calculated using the accurate Census head counts. The results indicate that tris(2-butoxyethyl) phosphate (TBOEP) has the highest per capita input into wastewater followed by tris(2-chloroisopropyl) phosphate (TCIPP), tris(isobutyl) phosphate (TIBP), tris(2-chloroethyl) phosphate (TCEP) and tris(1,3-dichloroisopropyl) phosphate (TDCIPP). Similar PFR profiles were observed across the Australian STPs and a comparison with European and U.S. STPs indicated similar PFR concentrations. We estimate that approximately 2.1 mg person(-1) day(-1) of PFRs are input into Australian wastewater which equates to 16 tonnes per annum. PMID- 26123239 TI - An ecological role of fungal endophytes to ameliorate plants under biotic stress. AB - It is our consensus that plants survive and flourish in stressed ecosystems because of endosymbiotic organisms that have co-evolved and were essential for their adaptation to changing environments. Some of these microbial components are noncultivable and vertically transmitted from generation to generation. They represent a vast reservoir of heritable DNA that can enhance plant performance in changing environments and add genetic flexibility to adaptation of long-lived plants. If such endophytes can be identified that not only persist in progeny of novel hosts, but can confer benefits in mechanized, agricultural systems, they would be increasingly important in agricultural production and lead to a rapid and economical method of providing novel germplasms of native and crop plants. In the present review, authors advocate the deployment of fungal diversity and its role to overcome the biotic stress in plants. Endophytic fungal association with plants helps it to protect from various pathogen and pests and adapt to survive in harsh biotic and abiotic stress condition. PMID- 26123240 TI - Correction: Combination of inverse electron-demand Diels-Alder reaction with highly efficient oxime ligation expands the toolbox of site-selective peptide conjugations. AB - Correction for 'Combination of inverse electron-demand Diels-Alder reaction with highly efficient oxime ligation expands the toolbox of site-selective peptide conjugations' by S. Horner, et al., Chem. Commun., 2015, DOI: 10.1039/c5cc03434e. PMID- 26123241 TI - Melanoma with BRAF Mutation in Circulating Cell-free DNA despite no Mutation in the Primary Lesion: A Case Report. PMID- 26123242 TI - Increased levels of vascular endothelial growth factor in patients with major depressive disorder: A meta-analysis. AB - The regulation of neurotrophic factors plays an important role in the pathophysiology of major depressive disorder (MDD). Vascular endothelial growth factor (VEGF) has been shown to promote neurogenesis, neuroprotection, and influence synaptic transmission. Many studies have examined the VEGF levels in patients with depression, however the results have been inconsistent. In the current meta-analysis, we compared blood VEGF levels between MDD patients and control subjects (16 articles including 872 patients and 882 control subjects). The effect sizes of individual studies were synthesized using a random effect model. We found that the blood VEGF levels in the patients with MDD were significantly higher than those in the healthy controls (p<0.001), and the difference was negatively correlated with mean age (p=0.01). Other variables including proportion of female subjects, body mass index, severity of depression, duration of illness, and age at onset were not significantly correlated with the difference. Our results highlight that elevated blood VEGF levels may be a disease marker in patients with MDD. Further studies are needed to examine the relationship between VEGF levels in central and peripheral environments, and clarify the role of VEGF in the pathophysiology of MDD. PMID- 26123243 TI - Ketamine amplifies induced gamma frequency oscillations in the human cerebral cortex. AB - At subanaesthetic doses, ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant efficacy in patients with treatment-resistant depression. The mechanism of action of ketamine is complex and not fully understood, with altered glutamatergic function and alterations of high-frequency oscillatory power (Wood et al., 2012) noted in animal studies. Here we used magnetoencephalography (MEG) in a single blind, crossover study to assess the neuronal effects of 0.5mg/kg intravenous ketamine on task-related high-frequency oscillatory activity in visual and motor cortices. Consistent with animal findings, ketamine increased beta amplitudes, decreased peak gamma frequency in visual cortex and significantly amplified gamma-band amplitudes in motor and visual cortices. The amplification of gamma-band activity has previously been linked in animal studies to cortical pyramidal cell disinhibition. This study provides direct translatable evidence of this hypothesis in humans, which may underlie the anti-depressant actions of ketamine. PMID- 26123244 TI - Does transition from the da Vinci Si to Xi robotic platform impact single-docking technique for robot-assisted laparoscopic nephroureterectomy? AB - OBJECTIVES: To describe our robot-assisted nephroureterectomy (RNU) technique for benign indications and RNU with en bloc excision of bladder cuff (BCE) and lymphadenectomy (LND) for malignant indications using the da Vinci Si and da Vinci Xi robotic platform, with its pros and cons. The port placement described for Si can be used for standard and S robotic systems. This is the first report in the literature on the use of the da Vinci Xi robotic platform for RNU. PATIENTS AND METHODS: After a substantial experience of RNU using different da Vinci robots from the standard to the Si platform in a single-docking fashion for benign and malignant conditions, we started using the newly released da Vinci Xi robot since 2014. The most important differences are in port placement and effective use of the features of da Vinci Xi robot while performing simultaneous upper and lower tract surgery. Patient positioning, port placement, step-by-step technique of single docking RNU-LND-BCE using the da Vinci Si and da Vinci Xi robot are shown in an accompanying video with the goal that centres using either robotic system benefit from the hints and tips. The first segment of video describes RNU-LND-BCE using the da Vinci Si followed by the da Vinci Xi to highlight differences. There was no need for patient repositioning or robot re docking with the new da Vinci Xi robotic platform. RESULTS: We have experience of using different robotic systems for single docking RNU in 70 cases for benign (15) and malignant (55) conditions. The da Vinci Xi robotic platform helps operating room personnel in its easy movement, allows easier patient side-docking with the help of its boom feature, in addition to easy and swift movements of the robotic arms. The patient clearance feature can be used to avoid collision with the robotic arms or the patient's body. In patients with challenging body habitus and in situations where bladder cuff management is difficult, modifications can be made through reassigning the camera to a different port with utilisation of the retargeting feature of the da Vinci Xi when working on the bladder cuff or in the pelvis. The vision of the camera used for da Vinci Xi was initially felt to be inferior to that of the da Vinci Si; however, with a subsequent software upgrade this was much improved. The base of the da Vinci Xi is bigger, which does not slide and occasionally requires a change in table placement/operating room setup, and requires side-docking especially when dealing with very tall and obese patients for pelvic surgery. CONCLUSIONS: RNU alone or with LND-BCE is a challenging surgical procedure that addresses the upper and lower urinary tract simultaneously. Single docking and single robotic port placement for RNU-LND-BCE has evolved with the development of different generations of the robotic system. These procedures can be performed safely and effectively using the da Vinci S, Si or Xi robotic platform. The new da Vinci Xi robotic platform is more user friendly, has easy installation, and is intuitive for surgeons using its features. PMID- 26123245 TI - Physiologically relevant factors influence tau phosphorylation by leucine-rich repeat kinase 2. AB - Hyperphosphorylation and aggregation of tau are observed in multiple neurodegenerative diseases termed tauopathies. Tau has also been implicated in the pathogenesis of Parkinson's disease (PD) and parkinsonisms. Some PD patients with mutations in the leucine-rich repeat kinase 2 (LRRK2) gene exhibit tau pathology. Mutations in LRRK2 are a major risk factor for PD, but LRRK2 protein function remains unclear. The most common mutation, G2019S, is located in the kinase domain of LRRK2 and enhances kinase activity in vitro. This suggests that the kinase activity of LRRK2 may underlie its cellular toxicity. Recently, in vitro studies have suggested a direct interaction between tubulin-bound tau and LRRK2 that results in tau phosphorylation at one identified site. Here we present data suggesting that microtubules (MTs) enhance LRRK2-mediated tau phosphorylation at three different epitopes. We also explore the effect of divalent cations as catalytic cofactors for G2019S LRRK2-mediated tau phosphorylation and show that manganese does not support kinase activity but inhibits the efficient ability of magnesium to catalyze LRRK2-mediated phosphorylation of tau. These results suggest that cofactors such as MTs and cations in the cellular milieu have an important impact on LRRK2-tau interactions and resultant tau phosphorylation. PMID- 26123246 TI - Assessing coexisting plant extinction debt and colonization credit in a grassland forest change gradient. AB - Changes in species richness along the ecological succession gradient may be strongly determined by coexisting extinction debts of species from the original habitats and colonization credits of those from the replacing habitats. The magnitude of these processes and their causes remain largely unknown. We explored the extinction debt and colonization credit for grassland and forest specialist plants, respectively, and the local and landscape factors associated to the richness of these species groups in a 50-year process of forest encroachment into semi-natural Mediterranean grasslands. A set of sampling plots of persistent grasslands and forests and their transitional habitat (wooded grasslands) was selected within fixed-area sites distributed across the landscape. Our results confirm the extinction debt and suggest colonization credit (according to observed trends and model predictions) in wooded grasslands when compared to persistent forests, despite wooded grasslands and persistent forests having similar tree cover. Grassland connectivity and solar radiation had opposing effects on the richness of both grassland and forest specialists, and it is possible that the availability of seed sources from old forests may have accelerate the payment of colonization credit in the wooded grasslands. These results suggest that extinction debt and colonization credit have driven species turnover during the 50 years of forest encroachment, but at different rates, and that local and landscape factors have opposing effects on these two phenomena. They also highlight the importance of documenting biodiversity time lags following habitat change when they are still in progress in order to timely and adequately manage habitats of high conservation value such as the grasslands studied here. PMID- 26123247 TI - Myoclonus secondary to use of anti-flu drug. PMID- 26123248 TI - Antiviral glycosidic bisindole alkaloids from the roots of Isatis indigotica. AB - Seven new glycosidic bisindole alkaloids, isatindigobisindolosides A-G (1-7), were isolated from an aqueous extract of the Isatis indigotica roots. Their structures including absolute configurations were determined by spectroscopic and chemical methods, together with calculations of electronic circular dichroism (ECD) spectra based on the quantum-mechanical time-dependent density functional theory. In the NMR spectra of 1-3, it is found that integration of H-2 and intensity of C-2 are affected not only by a substitution group at C-2 but also by solvents. Influences of the glucopyranosyloxy on the calculated ECD spectra of the glycosidic bisindole alkaloids are discussed. Compounds 2, 5, and 6 showed antiviral activity against both the influenza virus A/Hanfang/359/95 (H3N2) and Coxsackie virus B3 with IC50 values of 8.4-100.0 MUM. PMID- 26123249 TI - A quantitative evaluation of the extent of fluralaner uptake by ticks (Ixodes ricinus, Ixodes scapularis) in fluralaner (Bravecto) treated vs. untreated dogs using the parameters tick weight and coxal index. AB - BACKGROUND: Fluralaner is a new antiparasitic drug that was recently introduced as Bravecto chewable tablets for the treatment of tick and flea infestations in dogs. Most marketed tick products exert their effect via topical application and contact exposure to the parasite. In contrast, Bravecto delivers its acaricidal activity through systemic exposure. Tick exposure to fluralaner occurs after attachment to orally treated dogs, which induces a tick-killing effect within 12 h. The fast onset of killing lasts over the entire treatment interval (12 weeks) and suggests that only marginal uptake by ticks is required to induce efficacy. Three laboratory studies were conducted to quantify the extent of uptake by comparison of ticks' weight and coxal index obtained from Bravecto-treated and negative-control dogs. METHODS: Three studies were conducted using experimental tick infestation with either Ixodes ricinus or Ixodes scapularis after oral administration of fluralaner to dogs. All studies included a treated (Bravecto chewable tablets, MSD Animal Health) and a negative control group. Each study had a similar design for assessing vitality and weighing of ticks collected from dogs of both groups. Additionally, in one study the coxal index (I. ricinus) was calculated as a ratio of tick's ventral coxal gap and dorsal width of scutum. Tick weight data and coxal indices from Bravecto-treated and negative-control groups were compared via statistical analysis. RESULTS: Ticks collected from Bravecto-treated dogs weighed significantly less (p <= 0.0108) than ticks collected from negative-control dogs, and their coxal index was also significantly lower (p < 0.0001). The difference in tick weights was demonstrated irrespective of the tick species investigated (I. ricinus, I. scapularis). At some assessments the mean tick weights of Bravecto-treated dogs were significantly lower than those of unfed pre-infestation (baseline) ticks. The demonstrated tick-killing efficacy was in the range of 94.6 - 100%. CONCLUSIONS: Tick weights and coxal indices confirm that a minimal uptake results in a sufficient exposure of ticks to fluralaner (Bravecto) and consequently in a potent acaricidal effect. PMID- 26123250 TI - Childhood Obesity and Cognitive Achievement. AB - Obese children tend to perform worse academically than normal-weight children. If poor cognitive achievement is truly a consequence of childhood obesity, this relationship has significant policy implications. Therefore, an important question is to what extent can this correlation be explained by other factors that jointly determine obesity and cognitive achievement in childhood? To answer this question, we exploit a rich longitudinal dataset of Australian children, which is linked to national assessments in math and literacy. Using a range of estimators, we find that obesity and body mass index are negatively related to cognitive achievement for boys but not girls. This effect cannot be explained by sociodemographic factors, past cognitive achievement or unobserved time-invariant characteristics and is robust to different measures of adiposity. Given the enormous importance of early human capital development for future well-being and prosperity, this negative effect for boys is concerning and warrants further investigation. PMID- 26123251 TI - We-ness and the Cultivation of Wisdom in Couple Therapy. AB - Wisdom has played a key role in the attempt to understand the positive nature of human behavior since the time of Aristotle. In the past decade, psychology and related fields have experienced an expanding interest in the empirical and theoretical pursuit of wisdom. The relational dimension of wisdom has received less attention, although it may be viewed as embedded in the practice of all couple therapists. This article integrates previous work on resilience and positive functioning in committed partnerships and proposes relational wisdom to be a master virtue of relationship development, one that can be cultivated across the lifespan of the partnership. The aspects of relational wisdom such as self reflection, attunement to self and other, balancing conflicting partner aims, the interpretation of rules and principles in light of the uniqueness of each situation and the capacity to learn from experience point to couples therapy as an ideal context for such skill building. Wisdom is built through dialog and the resulting individual and couple stories can serve as touchstones to what is most precious and vital in the relationship as well as guides for action through challenges and conflict. A clinical case is described to illustrate selected aspects of relational wisdom and implications for therapeutic practice. PMID- 26123252 TI - Toward therapeutic targets for SCA3: Insight into the role of Machado-Joseph disease protein ataxin-3 in misfolded proteins clearance. AB - Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3, SCA3), an autosomal dominant neurological disorder, is caused by an abnormal expanded polyglutamine (polyQ) repeat in the ataxin-3 protein. The length of the expanded polyQ stretch correlates positively with the severity of the disease and inversely with the age at onset. To date, we cannot fully explain the mechanism underlying neurobiological abnormalities of this disease. Yet, accumulating reports have demonstrated the functions of ataxin-3 protein in the chaperone system, ubiquitin-proteasome system, and aggregation-autophagy, all of which suggest a role of ataxin-3 in the clearance of misfolded proteins. Notably, the SCA3 pathogenic form of ataxin-3 (ataxin-3(exp)) impairs the misfolded protein clearance via mechanisms that are either dependent or independent of its deubiquitinase (DUB) activity, resulting in the accumulation of misfolded proteins and the progressive loss of neurons in SCA3. Some drugs, which have been used as activators/inducers in the chaperone system, ubiquitin-proteasome system, and aggregation-autophagy, have been demonstrated to be efficacious in the relief of neurodegeneration diseases like Huntington's disease (HD), Parkinson's (PD), Alzheimer's (AD) as well as SCA3 in animal models and clinical trials, putting misfolded protein clearance on the list of potential therapeutic targets. Here, we undertake a comprehensive review of the progress in understanding the physiological functions of ataxin-3 in misfolded protein clearance and how the polyQ expansion impairs misfolded protein clearance. We then detail the preclinical studies targeting the elimination of misfolded proteins for SCA3 treatment. We close with future considerations for translating these pre-clinical results into therapies for SCA3 patients. PMID- 26123254 TI - Physician Treatment Orders in Dutch Nursing Homes. AB - OBJECTIVES: Physician treatment orders (PTOs) prevent burdensome unnecessary medical treatment of frail nursing home patients. The aim was to determine the prevalence of PTOs and time duration between nursing home admittance and PTO completion. DESIGN: Population-based, retrospective cohort study. SETTING: Nursing homes across the Netherlands. DATA COLLECTION: Digital medical records of patients who subsequently were submitted to 14 Dutch nursing homes across The Netherlands were studied between 2010 and 2013. The prevalence's of do resuscitate, do-not-resuscitate, life-sustaining, and palliative care PTOs and the time intervals between nursing home admittance and documentation of PTOs were measured. Information regarding demographic patient characteristics, type of nursing home ward, and mention of a discussion of PTOs with the patient or caregivers was obtained. RESULTS: Eighty-two percent of the nursing home patients received a PTO regarding resuscitation, life-sustaining, or palliative care treatment. Twenty-four percent of the patients received a do-resuscitation PTO, 55% received a do-not-resuscitate PTO, 44% a life-sustaining PTO, and 16% a palliative care PTO. The median duration between nursing home admittance and documentation of the first PTO was 1 day. Most nursing home patients had PTOs within 1 week after admittance. CONCLUSION: A minority (18%) of Dutch nursing home patients has no documented PTOs during their nursing home stay, which could have negative effects on end-of-life care of nursing home residents. PMID- 26123253 TI - SPECT/CT Imaging of High-Risk Atherosclerotic Plaques using Integrin-Binding RGD Dimer Peptides. AB - Vulnerable atherosclerotic plaques with unique biological signatures are responsible for most major cardiovascular events including acute myocardial infarction and stroke. However, current clinical diagnostic approaches for atherosclerosis focus on anatomical measurements such as the degree of luminal stenosis and wall thickness. An abundance of neovessels with elevated expression of integrin alphavbeta3 is closely associated with an increased risk of plaque rupture. Herein we evaluated the potential of an alphavbeta3 integrin-targeting radiotracer, (99m)Tc-IDA-D-[c(RGDfK)]2, for SPECT/CT imaging of high-risk plaque in murine atherosclerosis models. In vivo uptake of (99m)Tc-IDA-D-[c(RGDfK)]2 was significantly higher in atherosclerotic aortas than in relatively normal aortas. Comparison with the negative-control peptide, (99m)Tc-IDA-D-[c(RADfK)]2, proved specific binding of (99m)Tc-IDA-D-[c(RGDfK)]2 for plaque lesions in in vivo SPECT/CT and ex vivo autoradiographic imaging. Histopathological characterization revealed that a prominent SPECT signal of (99m)Tc-IDA-D-[c(RGDfK)]2 corresponded to the presence of high-risk plaques with a large necrotic core, a thin fibrous cap, and vibrant neoangiogenic events. Notably, the RGD dimer based (99m)Tc-IDA-D [c(RGDfK)]2 showed better imaging performance in comparison with the common monomeric RGD peptide probe (123)I-c(RGDyV) and fluorescence tissue assay corroborated this. Our preclinical data demonstrated that (99m)Tc-IDA-D [c(RGDfK)]2 SPECT/CT is a sensitive tool to noninvasively gauge atherosclerosis beyond vascular anatomy by assessing culprit plaque neovascularization. PMID- 26123255 TI - Frailty in China. PMID- 26123256 TI - Does Low Dose Angiotensin Converting Enzyme Inhibitor Prevent Pneumonia in Older People With Neurologic Dysphagia--A Randomized Placebo-Controlled Trial. AB - OBJECTIVE: To examine if angiotensin converting enzyme inhibitor reduces the risk of pneumonia in older patients on tube-feeding because of dysphagia from cerebrovascular diseases. DESIGN: Randomized placebo-controlled trial. SETTING: Acute and subacute geriatrics units, speech therapists' clinic, and nursing home. PARTICIPANTS: Older patients on tube-feeding for >2 weeks because of dysphagia secondary to cerebrovascular diseases. INTERVENTION: Participants were randomized to lisinopril 2.5 mg or placebo once daily for 26 weeks. MEASUREMENTS: Participants were followed up at weeks 12 and 26. The primary outcome was the incidence rate of pneumonia as determined by pneumonic changes on x-ray and clinical criteria. The secondary outcomes were mortality rate and swallowing ability as defined by the Royal Brisbane Hospital Outcome Measure for Swallowing at week 12. RESULTS: A total of 93 older patients were randomized. In interim analysis, 71 completed the trial, whereas 15 had dropped out. Among those who had completed the trial, odds ratio (OR) for death was significantly higher in the intervention group (unadjusted OR 2.94, P = .030; fully adjusted OR 7.79, P = .018). There was no difference in the incidence of pneumonia or fatal pneumonia in the 2 groups. The intervention group had a marginally better swallowing function at week 12 (Royal Brisbane Hospital Outcome Measure for Swallowing score: 4.2 +/- 1.5 in intervention group, 3.5 +/- 1.5 in placebo group, P = .053). As a result of the interim finding on mortality, the trial was prematurely terminated with 7 participants still in the trial. CONCLUSIONS: Low dose lisinopril given to older tube-fed patients with neurologic dysphagia resulted in increased mortality, although swallowing function showed marginal improvement. ACE inhibitors did not prevent pneumonia in older patients with neurologic dysphagia and might increase mortality. PMID- 26123257 TI - Treatment of Nonagenarians With Atrial Fibrillation: Insights From the Berlin Atrial Fibrillation (BAF) Registry. AB - OBJECTIVES: The objective of this study was to determine course and treatment of atrial fibrillation (AF) in nonagenarians. Incidence of AF increases with age. Due to the demographic change in the industrialized world, an increase of AF in the group of elderly and very elderly is expected in the next decades. However, only few data exist on the clinical relevance of AF in patients aged 89 years or older. DESIGN: Observational, mono-centric registry. SETTING: University hospital. PARTICIPANTS: Of the 11,888 patients included in the Berlin Atrial Fibrillation (BAF) Registry, 279 patients aged 89 years or older were identified. All patients presented to our hospital with AF between January 2001 and December 2014. MEASUREMENTS: AF type, symptoms, comorbidities, CHA2DS2-VASc and HAS-BLED, treatment strategy, and anticoagulant treatment were assessed at baseline. A composite of stroke/transient ischemic attack (TIA), thromboembolic events, major bleeding, and death was the primary endpoint. Stroke/TIA, thromboembolic events and major bleeding, presence of AF, new onset of heart failure and change of NYHA class, and bradyarrhythmia necessitating pacemaker implantation were secondary endpoints. RESULTS: Patients (age 92 +/- 2.7 years, range 89-108) presented in EHRA class I in 38.4% of the cases, class II in 49.5%, class III in 10%, and class IV in 2%. Rhythm control was attempted in 37 (13.3%) of the patients. Baseline CHA2DS2-VASc and HAS-BLED were 5.0 +/- 1.3 and 3.1 +/- 0.9, respectively. Oral anticoagulation (OAC) was initiated in 74 (26.5 %) of the patients. Of all patients, 33 (11.8%) patients died in hospital. Of the remaining patients, 104 were followed over 13.8 +/- 17.5 months with 3.5 +/- 2.3 visits during follow-up. Rhythm control was attempted in 10 patients (9.6%). OAC was initiated in 37 patients (35.6 %). Fifty-nine (56.7%) patients reached the primary composite endpoint. Stroke/TIA (34.6%) and heart failure (49%) were common. Subgroup analysis revealed no significant differences in any of the endpoints between patients undergoing rhythm versus rate control and between patients under OAC compared with patients without OAC. INR at follow-up and TTR were 1.76 +/- 1.0 and 29.5% +/- 37.8% in patients receiving VKA. CONCLUSION: In this real-world cohort of very elderly patients with AF, a rhythm control strategy and OAC treatment were chosen only in a minority of the cases. If OAC was initiated, most received VKAs with a poor TTR during follow-up. A high incidence of stroke/TIA was observed in patients with and without OAC. Further data are needed to define optimal treatment of AF in this particular patient group. PMID- 26123258 TI - Anorexia in human and experimental animal models: physiological aspects related to neuropeptides. AB - Anorexia, a loss of appetite for food, can be caused by various physiological and pathophysiological conditions. In this review, firstly, clinical aspects of anorexia nervosa are summarized in brief. Secondly, hypothalamic neuropeptides responsible for feeding regulation in each hypothalamic nucleus are discussed. Finally, three different types of anorexigenic animal models; dehydration-induced anorexia, cisplatin-induced anorexia and cancer anorexia-cachexia, are introduced. In conclusion, hypothalamic neuropeptides may give us novel insight to understand and find effective therapeutics strategy essential for various kinds of anorexia. PMID- 26123259 TI - The state of the art in non-pharmacological interventions for developmental stuttering. Part 1: a systematic review of effectiveness. AB - BACKGROUND: The growing range of available treatment options for people who stutter presents a challenge for clinicians, service managers and commissioners, who need to have access to the best available treatment evidence to guide them in providing the most appropriate interventions. While a number of reviews of interventions for specific populations or a specific type of intervention have been carried out, a broad-based systematic review across all forms of intervention for adults and children was needed to provide evidence to underpin future guidelines, inform the implementation of effective treatments and identify future research priorities. AIMS: To identify and synthesize the published research evidence on the clinical effectiveness of the broad range of non pharmacological interventions for the management of developmental stuttering. METHODS & PROCEDURES: A systematic review of the literature reporting interventions for developmental stuttering was carried out between August 2013 and April 2014. Searches were not limited by language or location, but were restricted by date to studies published from 1990 onwards. Methods for the identification of relevant studies included electronic database searching, reference list checking, citation searching and hand searching of key journals. Appraisal of study quality was performed using a tool based on established criteria for considering risk of bias. Due to heterogeneity in intervention content and outcomes, a narrative synthesis was completed. MAIN CONTRIBUTION: The review included all available types of intervention and found that most may be of benefit to at least some people who stutter. There was evidence, however, of considerable individual variation in response to these interventions. The review indicated that effects could be maintained following all types of interventions (although this was weakest with regard to feedback and technology interventions). CONCLUSIONS: This review highlights a need for greater consensus with regard to the key outcomes used to evaluate stuttering interventions, and also a need for enhanced understanding of the process whereby interventions effect change. Further analysis of the variation in effectiveness for different individuals or groups is needed in order to identify who may benefit most from which intervention. PMID- 26123261 TI - Ion and seed dependent fibril assembly of a spidroin core domain. AB - Recombinant eADF4(C16) represents an engineered spider silk variant based on the sequence of the core domain of the natural dragline silk protein ADF4 of Araneus diadematus. Previously eADF4(C16) has been shown to self-assemble into cross-beta fibrils in a two-step process of nucleus formation and fibril growth. Here, it is shown that structurally converted low molecular weight oligomers can act as nuclei. Further, it could be determined that specifically potassium and phosphate ions strongly influence both nucleus formation as well as fibril growth. Nucleation of fibril assembly could be surpassed by seeding soluble protein with pre-assembled fibrils but also, unexpectedly, with eADF4(C16) sub-micrometer particles. The latter finding reveals that spider silk fibril assembly seems to be rather dependent on the protein sequence than on the structural features, since cross-seeding with other proteins was not possible. PMID- 26123260 TI - Association between IL7R polymorphisms and severe liver disease in HIV/HCV coinfected patients: a cross-sectional study. AB - BACKGROUND: Interleukin-7 (IL-7) is a critical factor for T cell development and for maintaining and restoring homeostasis of mature T cells. Polymorphisms at alpha-chain of the IL-7 receptor (IL7R or CD127) gene are related to evolution of HIV-infection, but there are no data concerning the evolution of hepatitis C virus (HCV) infection. The aim of this study was to analyze the association between IL7R polymorphisms and severe liver disease in HCV/HIV coinfected patients. METHODS: We performed a cross-sectional study in 220 naive patients who underwent a liver biopsy. IL7R polymorphisms (rs6897932, rs987106 and rs3194051) were genotyped using the GoldenGate((r)) assay. The outcome variables were: (a) liver biopsy: advanced fibrosis (F >= 3), severe activity grade (A3); (b) non invasive indexes: advanced fibrosis (APRI >=1.5 and FIB-4 >=3.25). Logistic regression analysis was used to investigate the association between IL7R polymorphisms and outcome variables. This test gives the differences between groups and the odds ratio (OR) for liver disease. RESULTS: Patients with rs6897932 CC genotype had higher likelihood of having A3 than patients with rs6897932 CT/TT (adjusted odds ratio (aOR) = 4.16; p = 0.026). Patients with rs987106 TT genotype had higher odds of having F >= 3 (aOR = 3.09; p = 0.009) than rs987106 AA/AT carriers. Finally, patients with rs3194051 AA genotype had higher odds of having severe liver fibrosis (F >= 3; APRI >=1.5, and FIB4 >=3.25) than patients with rs3194051 AG/GG genotype [aOR = 2.73 (p = 0.010); aOR = 2.52 (p = 0.029); and aOR = 4.01 (p = 0.027); respectively]. The CTA haplotype (comprised of rs6897932, rs987106, and rs3194051) carriers had higher odds of having F >= 3 (aOR = 1.85; p = 0.012), APRI >=1.5 (aOR = 1.94; p = 0.023), and FIB4 >=3.25 (aOR = 2.47; p = 0.024). Conversely, the CAG haplotype carriers had lower odds of having F >= 3 (aOR = 0.48; p = 0.011), APRI >=1.5 (aOR = 0.48; p = 0.029), and FIB4 >=3.25 (aOR = 0.29; p = 0.010). CONCLUSIONS: The presence of IL7R polymorphisms seems to be related to severe liver disease in HIV/HCV coinfected patients, because patients with unfavorable IL7R genotypes (rs6897932 CC, rs987106 TT, and rs3194051AA) had a worse prognosis of CHC. PMID- 26123262 TI - Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. AB - The four secreted R-spondin (Rspo1-4) proteins of vertebrates function as stem cell growth factors and potentiate canonical Wnt signalling. Rspo proteins act by cross-linking members of two cell surface receptor families, complexing the stem cell markers LGR4-6 with the Frizzled-specific E3 ubiquitin ligases ZNRF3/RNF43. The consequent internalisation of the ternary LGR-Rspo-E3 complex removes the E3 ligase activity, which otherwise targets the Wnt receptor Frizzled for degradation, and thus enhances Wnt signalling. Multiple combinations of LGR4-6, Rspo1-4 and ZNRF3/RNF43 are possible, implying the existence of generic interaction determinants, but also of specific differences in complex architecture and activity. We present here a high resolution crystal structure of an ectodomain variant of human LGR5 (hLGR5ecto) complexed with a signalling competent fragment of mouse Rspo2 (mRspo2Fu1-Fu2). The structure shows that the particularly potent Rspo2 ligand engages LGR5 in a fashion almost identical to that reported for hRSPO1. Comparison of our hLGR5ecto structure with previously published structures highlights a surprising plasticity of the LGR ectodomains, characterised by a nearly 9 degrees or larger rotation of the N-terminal half of the horseshoe-like fold relative to the C-terminal half. We also report a low resolution hLGR5-mRspo2Fu1-Fu2-mZNRF3ecto ternary complex structure. This crystal structure confirms our previously suggested hypothesis, showing that Rspo proteins cross-link LGRs and ZNRF3 into a 2:2:2 complex, whereas a 1:1:1 complex is formed with RNF43. PMID- 26123263 TI - The 3D model of the lipase/acyltransferase from Candida parapsilosis, a tool for the elucidation of structural determinants in CAL-A lipase superfamily. AB - Because lipids are hydrophobic, the development of efficient bioconversions in aqueous media free of organic solvents is particularly challenging for green oleochemistry. Within this aim, enzymes exhibiting various abilities to catalyze acyltransfer reaction in water/lipid systems have been identified. Among these, CpLIP2 from Candida parapsilosis has been characterized as a lipase/acyltransferase, able to catalyze acyltransfer reactions preferentially to hydrolysis in the presence of particularly low acyl acceptor concentration and high thermodynamic activity of water (aw>0.9). Lipase/acyltransferases are thus of great interest, being able to produce new esters at concentrations above the thermodynamic equilibrium of hydrolysis/esterification with limited to no release of free fatty acids. Here, we present a 3D model of CpLIP2 based on homologies with crystallographic structures of Pseudozyma antarctica lipase A. Indeed, the two enzymes have 31% of identity in their primary sequence, yielding a same general structure, but different catalytic properties. The quality of the calculated CpLIP2 model was confirmed by several methods. Limited proteolysis confirmed the location of some loops at the surface of the protein 3D model. Directed mutagenesis also supported the structural model constructed on CAL-A template: the functional properties of various mutants were consistent with their structure-based putative involvement in the oxyanion hole, substrate specificity, acyltransfer or hydrolysis catalysis and structural stability. The CpLIP2 3D model, in comparison with CAL-A 3D structure, brings insights for the elucidation and improvement of the structural determinants involved in the exceptional acyltransferase properties of this promising biocatalyst and of homologous enzymes of the same family. PMID- 26123264 TI - An induced folding process characterizes the partial-loss of function mutant LptAI36D in its interactions with ligands. AB - Lipopolysaccharide (LPS) is an essential glycolipid of the outer membrane (OM) of Gram-negative bacteria with a tripartite structure: lipid A, oligosaccharide core and O antigen. Seven essential LPS-transport proteins (LptABCDEFG) move LPS to the cell surface. Lpt proteins are linked by structural homology, featuring a beta-jellyroll domain that mediates protein-protein interactions and LPS binding. Analysis of LptA-LPS interaction by fluorescence spectroscopy is used here to evaluate the contribution of each LPS moiety in protein-ligand interactions, comparing the wild-type (wt) protein to the I36D mutant. In addition to a crucial role of lipid A, an unexpected contribution emerges for the core region in recognition and binding of Lpt proteins. PMID- 26123265 TI - Heart rate variability predicts mortality in peritoneal dialysis patients. AB - BACKGROUND: The predictive value of heart rate variability (HRV) in peritoneal dialysis (PD) has never been tested. METHODS: In this study, the associations between HRV measures and the mortality in 81 PD patients were analyzed. HRV was measured by using 5-min recordings of a stationary system by a standardized method. Both time domain and frequency domain parameters were analyzed. RESULTS: During a follow-up period of 43.78 +/- 14.77 months, 25 patients died, four patients were transferred to hemodialysis. Of the 81 patients, the time domain parameters, such as the standard deviation of differences between adjacent normal sinus to normal sinus (NN) intervals (SDSD) and the square root of the mean of the squared differences between adjacent normal NN intervals (RMSSD), were higher; the frequency domain parameters, such as the ratio of low-frequency power to high-frequency power (LF/HF) and the normalized LF, were lower, and the normalized HF was higher in the non-survived group as compared with the survived group. A Cox proportional hazards model analysis revealed that, of the HRV measures, decrease of the normalized LF, LF/HF and increase of rMSSD, SDSD, normalized HF had significant predictive value for mortality. After adjustment for other univariate predictors including age, urine volume, renal Kt/V, high sensitivity C-reactive protein (hs-CRP), the predictive value of decreased LF/HF remained significant. Kaplan-Meier survival analysis showed mortality rate was much higher in patients with a low LF/HF (median value of 1.56). CONCLUSION: The decreases of LF/HF which reflects impaired sympathetic nerve regulation is an independent predictor of mortality in PD patients. PMID- 26123266 TI - Urinary tuberculosis: a cohort of 79 adult cases. AB - We aimed to investigate the demographic, clinical, diagnostic, treatment and outcome features of patients with urinary tuberculosis (UTB). Patients with UTB admitted to seven separate centers across Turkey between 1995 and 2013 were retrospectively evaluated. The diagnosis of UTB was made by the presence of any clinical finding plus positivity of one of the following: (1) acid-fast bacilli (AFB) in urine, (2) isolation of Mycobacterium tuberculosis, (3) polymerase chain reaction (PCR) for M. tuberculosis, (4) histopathological evidence for TB. Seventy-nine patients (49.36% male, mean age 50.1 +/- 17.4 years) were included. Mean time between onset of symptoms and clinical diagnosis was 9.7 +/- 8.9 months. The most common signs and symptoms were hematuria (79.7%), sterile pyuria (67.1%), dysuria (51.9%), weakness (51.9%), fever (43%) and costovertebral tenderness (38%). Cystoscopy was performed in 59 (74.6%), bladder biopsy in 18 (22.8%), kidney biopsy in 1 (1.26%) and nephrectomy in 12 (15.2%) patients. Histopathological verification of UTB was achieved in 12 (63.1%) patients who undergone biopsy and in 100% of those undergone nephrectomy. Mycobacterium tuberculosis was isolated in the urine of 50 (63.3%) cases. Four-drug standard anti-TB treatment was the preferred regimen for 87.3% of the patients. Mean treatment duration was 10.5 +/- 2.7 months. Deterioration of renal function occurred in 15 (18.9%) patients two of whom progressed to end-stage renal disease and received hemodialysis. Only one patient died after 74-day medical treatment period. Cases with UTB may present with non-specific clinical features. All diagnostic studies including radiology, cyctoscopy and histopathology are of great importance to exclude UTB and prevent renal failure. PMID- 26123267 TI - Assessment of left ventricular function by tissue Doppler echocardiography in pediatric chronic kidney disease. AB - BACKGROUND: Cardiovascular (CV) disease remains the most common cause of mortality in chronic kidney disease (CKD). METHODS: In this cross-sectional study, 43 pediatric patients with CKD were divided into two groups according to their estimated glomerular filtration rate (eGFR): groups 1 and 2 (eGR; 29-75 and 15-29 mL/min/1.73 m(2), respectively). M - mode, conventional pulsed wave Doppler (cPWD) echocardiography and tissue Doppler imaging (TDI) were performed in all patients and 16 healthy controls. Maximal early (E wave) and late (A wave) diastolic flow velocities were assessed by cPWD. Using TDI, the early (E') and late (A') diastolic filling velocities were recorded. Early and late diastoles were evaluated using E' values and E/E' ratios, respectively. RESULTS: Left ventricular hypertrophy (LVH) was determined in 19/43 (44.2%) patients. The E/E' ratio was significantly higher in group 2 than in group 1 and controls. E/E' was found to be positively correlated with left ventricular mass (LVM) index, and negatively with hemoglobin (Hb) levels. Low Hb levels were only independent predictor of E/E' (p = 0.001, beta: -0.470, 95% CI: -0.764; -0.196). E' ratio was significantly lower in both patient groups compared to the controls. CONCLUSIONS: LVH and diastolic dysfunction are already present in early stages of CKD. Treatment of risk factors, such as anemia, is important to improve the clinical outcome. PMID- 26123268 TI - Inhibition of inflammation may enhance nitric oxide availability in patients undergoing bariatric surgery for weight loss. AB - BACKGROUND: Weight loss surgery is the most effective treatment for morbid obesity. The mechanisms underlying the beneficial cardiovascular effects are poorly understood, although inhibition of inflammatory markers has been demonstrated. We hypothesized that anti-inflammatory and antioxidative stress reactions are responsible for the beneficial effects of bariatric surgery that have been shown in clinical trials. METHODS: The inflammatory system was studied by measuring mRNA levels of E-selectin, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and in a cell line (HUVEC-CS) of human umbilical vein endothelial cells that were incubated for 4 h with pools of serum, collected before and 3 months after surgery, from 20 women who underwent bariatric surgery for weight loss. The oxidative stress pathway was examined by mRNA expression of NADPH oxidase (P22(phox) ), paraoxonase (PON2), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx) and catalase following incubation of the cells for 4 h with serum pools. The nitric oxide (NO) pathway was studied by measuring mRNA levels of inducible NOS and endothelial NOS and by determining nitrite and nitrate levels. To study the functional behaviour of endothelial cells under stress, primary human umbilical vein endothelial cells (PECs) were incubated with the serum pools for 48 h, with lipopolysaccharide (LPS) for the last 4 h. RESULTS: The inflammatory system: incubation of HUVEC-CS cells with serum from women who underwent bariatric surgery led to a significant decrease in mRNA expression of E-selectin and IL-6 postsurgery. Stimulation of PECs with LPS in the presence of serum from women who underwent bariatric surgery caused a more significant difference in E-selectin and TNF-alpha mRNA expression before and after surgery. The antioxidant system: incubation of HUVEC-CS cells with serum from women who underwent bariatric surgery did not lead to any difference in mRNA expression of P22(phox) , PON2, SOD2, GPx or catalase. Stimulation of PECs with LPS showed that obese women had higher levels of P22(phox) , PON2 and the antioxidant enzymes SOD2, GPx and catalase before and after surgery, compared to the control group. The NO pathway: HUVEC-CS cells incubated with serum from women who underwent bariatric surgery secreted higher nitrite/nitrate levels compared to presurgery serum (P = 0.04). CONCLUSIONS: Inhibition of inflammation and enhanced availability of NO 3 months after bariatric surgery could partly explain the beneficial effects of surgery for weight loss. PMID- 26123269 TI - Preparation of Graphene Oxide-Based Hydrogels as Efficient Dye Adsorbents for Wastewater Treatment. AB - Graphene oxide (GO) sheets exhibit superior adsorption capacity for removing organic dye pollutants from an aqueous environment. In this paper, the facile preparation of GO/polyethylenimine (PEI) hydrogels as efficient dye adsorbents has been reported. The GO/PEI hydrogels were achieved through both hydrogen bonding and electrostatic interactions between amine-rich PEI and GO sheets. For both methylene blue (MB) and rhodamine B (RhB), the as-prepared hydrogels exhibit removal rates within about 4 h in accordance with the pseudo-second-order model. The dye adsorption capacity of the hydrogel is mainly attributed to the GO sheets, whereas the PEI was incorporated to facilitate the gelation process of GO sheets. More importantly, the dye-adsorbed hydrogels can be conveniently separated from an aqueous environment, suggesting potential large-scale applications of the GO-based hydrogels for organic dye removal and wastewater treatment. PMID- 26123270 TI - Design High-Efficiency III-V Nanowire/Si Two-Junction Solar Cell. AB - In this paper, we report the electrical simulation results of a proposed GaInP nanowire (NW)/Si two-junction solar cell. The NW physical dimensions are determined for optimized solar energy absorption and current matching between each subcell. Two key factors (minority carrier lifetime, surface recombination velocity) affecting power conversion efficiency (PCE) of the solar cell are highlighted, and a practical guideline to design high-efficiency two-junction solar cell is thus provided. Considering the practical surface and bulk defects in GaInP semiconductor, a promising PCE of 27.5 % can be obtained. The results depict the usefulness of integrating NWs to construct high-efficiency multi junction III-V solar cells. PMID- 26123271 TI - Electronic Coupling in Nanoscale InAs/GaAs Quantum Dot Pairs Separated by a Thin Ga(Al)As Spacer. AB - The electronic coupling in vertically aligned InAs/GaAs quantum dot (QD) pairs is investigated by photoluminescence (PL) measurements. A thin Al0.5Ga0.5As barrier greatly changes the energy transfer process and the optical performance of the QD pairs. As a result, the QD PL intensity ratio shows different dependence on the intensity and wavelength of the excitation laser. Time-resolved PL measurements give a carrier tunneling time of 380 ps from the seed layer QDs to the top layer QDs while it elongates to 780 ps after inserting the thin Al0.5Ga0.5As barrier. These results provide useful information for fabrication and investigation of artificial QD molecules for implementing quantum computation applications. PMID- 26123272 TI - Effects of Laser Annealing Parameters on Optical and Electrical Properties of ITO/Metallic Glass Alloy Bi-layer Films. AB - AgAlMg (AAM) films with three different atomic percentage compositions are prepared, namely, Ag12Al62Mg26 (denoted as A1AM), Ag22Al46Mg32 (denoted as A2AM), and Ag36Al25Mg39 (denoted as A3AM). In addition, the AAM films are deposited with four different thicknesses, i.e., 3, 6, 9, and 12 nm. The indium-tin oxide thickness is assigned a constant value of 30 nm in every case. The results show that the optical transmittance of the AAM/IAAM films improves (i.e., increases) with a reducing AAM film thickness, while the electrical resistivity improves (i.e., reduces) with an increasing film thickness. It is shown that the IA2AM film with an AMM thickness of 9 nm yields the optimal compromise between the optical transmittance and the electrical resistivity. The as-deposited IAAM films are found to have optical transmittance and electric resistivity values of 65 % and 90 Omega/?, respectively. The IA2AM films are annealed using a near-infrared laser at different pulse energies with a wavelength of 1064 nm and repetition rates ranging from 100 ~ 400 kHz. For both films, the optical and electrical properties are enhanced as the pulse energy increases to a certain critical value due to a transition from an amorphous microstructure to a crystalline structure. Given a repetition rate of 400 kHz and a pulse energy of 1.03 MUJ, the optical transmittance and sheet resistance of the IAAM film are found to be 80 % and 15 Omega/?, respectively. The corresponding value of the Haacke figure of merit changed from 0.15 * 10(-3) to 7.16 * 10(-3) Omega(-1) due to the optimal laser annealing conditions. PMID- 26123273 TI - A New Phase Change Material Based on Potassium Nitrate with Silica and Alumina Nanoparticles for Thermal Energy Storage. AB - In this study different nanofluids with phase change behavior were developed by mixing a molten salt base fluid (KNO3 selected as phase change material) with nanoparticles using the direct synthesis method. The thermal properties of the nanofluids obtained were investigated. Following the improvement in the specific heat achieved, these nanofluids can be used in concentrating solar plants with a reduction of storage material. The nanoparticles used (1.0 wt.%) were silica (SiO2), alumina (Al2O3), and a mix of silica-alumina (SiO2-Al2O3) with an average diameter of 7, 13, and 2-200 nm respectively. Each nanofluid was prepared in water solution, sonicated, and evaporated. Measurements of the thermophysical properties were performed by DSC analysis, and the dispersion of the nanoparticles was analyzed by SEM microscopy. The results obtained show that the addition of 1.0 wt.% of nanoparticles to the base salt increases the specific heat of about 5-10 % in solid phase and of 6 % in liquid phase. In particular, this research shows that the addition of silica nanoparticles has significant potential for enhancing the thermal storage characteristics of KNO3. The phase change temperature of potassium nitrate was lowered up to 3 degrees C, and the latent heat was increased to 12 % with the addition of silica nanoparticles. These results deviated from the predictions of theoretical simple mixing model used. The stored heat as a function of temperature was evaluated for the base salt, and the nanofluids and the maximum values obtained were 229, 234, 242, and 266 J/g respectively. The maximum total gain (16 %) due to the introduction of the nanoparticles (calculated as the ratio between the total stored heat of the nanofluids and the base salt in the range of temperatures 260-390 degrees C) was also recorded with the introduction of silica. SEM and EDX analysis showed the presence of aggregates in all nanofluids: with silica nanoparticles they were homogenously present while with alumina and silica-alumina also zones with pure salt could be detected. PMID- 26123274 TI - Simulation Analysis on Photoelectric Conversion Characteristics of Silicon Nanowire Array Photoelectrodes. AB - Semiconductor nanowire photoelectrochemical cells have attracted extensive attention in the light-conversion field owing to the low-cost preparation, excellent optical absorption, and short distance of carrier collection. Although there are numbers of experimental investigations to improve the device performance, the understanding of the detailed process of photoelectric conversion needs to be further improved. In this work, a thorough optoelectronic simulation is employed to figure out how the nanowire diameter, doping concentration, and illumination wavelength affect the photoelectric conversion characteristics of the silicon nanowire array photoelectrodes. We find that two balances should be carefully weighted between optical absorption and photogenerated-carrier collection, along with between short-circuit photocurrent density and open-circuit voltage. For the small-diameter nanowire array photoelectrodes, the overall absorption is higher than that of the larger diameter ones with the most contribution from the nanowires. However, the substrate shows increasing absorption with increasing illumination wavelength. Higher doping density leads to a larger open-circuit voltage; while lower doping density can guarantee a relatively higher short-circuit photocurrent. To obtain high-light-conversion-efficiency photoelectrodes, the doping density should be carefully chosen with considerations of illumination wavelength and surface recombination. Suppressing the surface recombination velocity can effectively enhance the short-circuit photocurrent (open-circuit voltage) for the lightly (heavily) doped nanowire array photoelectrodes. Our systematical results provide a theoretical guidance for the photoelectrochemical devices based on semiconductor nanostructures. PMID- 26123275 TI - Orbitrap mass spectrometry characterization of hybrid chondroitin/dermatan sulfate hexasaccharide domains expressed in brain. AB - In the central nervous system, chondroitin/dermatan sulfate (CS/DS) glycosaminoglycans (GAGs) modulate neurotrophic effects and glial cell maturation during brain development. Previous reports revealed that GAG composition could be responsible for CS/DS activities in brain. In this work, for the structural characterization of DS- and CS-rich domains in hybrid GAG chains extracted from neural tissue, we have developed an advanced approach based on high-resolution mass spectrometry (MS) using nanoelectrospray ionization Orbitrap in the negative ion mode. Our high-resolution MS and multistage MS approach was developed and applied to hexasaccharides obtained from 4- and 14-week-old mouse brains by GAG digestion with chondroitin B and in parallel with AC I lyase. The expression of DS- and CS-rich domains in the two tissues was assessed comparatively. The analyses indicated an age-related structural variability of the CS/DS motifs. The older brain was found to contain more structures and a higher sulfation of DS rich regions, whereas the younger brain was found to be characterized by a higher sulfation of CS-rich regions. By multistage MS using collision-induced dissociation, we also demonstrated the incidence in mouse brain of an atypical [4,5-Delta-GlcAGalNAc(IdoAGalNAc)2], presenting a bisulfated CS disaccharide formed by 3-O-sulfate-4,5-Delta-GlcA and 6-O-sulfate-GalNAc moieties. PMID- 26123277 TI - An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach. AB - Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastric juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in the stomach, meaning that a higher percentage of the Cr6 dose may escape stomach reduction in that species. Similarly, both models predict that humans exhibit the highest extent of reduction at low doses. PMID- 26123276 TI - Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment. AB - Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment. PMID- 26123278 TI - (1)H nuclear magnetic resonance (NMR) as a tool to measure dehydration in mice. AB - Dehydration is a prevalent pathology, where loss of bodily water can result in variable symptoms. Symptoms can range from simple thirst to dire scenarios involving loss of consciousness. Clinical methods exist that assess dehydration from qualitative weight changes to more quantitative osmolality measurements. These methods are imprecise, invasive, and/or easily confounded, despite being practiced clinically. We investigate a non-invasive, non-imaging (1)H NMR method of assessing dehydration that attempts to address issues with existing clinical methods. Dehydration was achieved by exposing mice (n = 16) to a thermally elevated environment (37 degrees C) for up to 7.5 h (0.11-13% weight loss). Whole body NMR measurements were made using a Bruker LF50 BCA-Analyzer before and after dehydration. Physical lean tissue, adipose, and free water compartment approximations had NMR values extracted from relaxation data through a multi exponential fitting method. Changes in before/after NMR values were compared with clinically practiced metrics of weight loss (percent dehydration) as well as blood and urine osmolality. A linear correlation between tissue relaxometry and both animal percent dehydration and urine osmolality was observed in lean tissue, but not adipose or free fluids. Calculated R(2) values for percent dehydration were 0.8619 (lean, P < 0.0001), 0.5609 (adipose, P = 0.0008), and 0.0644 (free fluids, P = 0.3445). R(2) values for urine osmolality were 0.7760 (lean, P < 0.0001), 0.5005 (adipose, P = 0.0022), and 0.0568 (free fluids, P = 0.3739). These results suggest that non-imaging (1)H NMR methods are capable of non invasively assessing dehydration in live animals. PMID- 26123279 TI - Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. AB - BACKGROUND: Transthyretin (TTR) V122I (rs76992529) is one of 111 variants caused by point mutations in the coding sequence of the human TTR gene that are associated with systemic amyloidosis. It results from a G to A transition at a CG dinucleotide in codon 142(122 of the mature protein) of the gene and has been described almost exclusively in people of African descent. Several series have reported allele frequencies from 0.015 to 0.020 in African-Americans. OBJECTIVE: To define more accurately the frequency of the TTR V122I variant allele in the African-American population. METHODS: DNA isolated from blood spots from 1688 New York State African-American newborns was genotyped for the TTR V122I allele. We also compiled new data from the Jackson Heart Study and previously unpublished data from the Dallas Heart Study, plus data from a San Diego "wellness study", providing 15 650 additional allelotypes to those already reported. RESULTS: Among the New York newborns, the TTR V122I allele was present in 65/3376 alleles (allele prevalence 0.0193). The combined available data from all the non-selected African-American cohorts showed the TTR variant allele to be present in 451/26 062 alleles (allele prevalence of 0.0173), slightly but not significantly lower than our previously published estimates. CONCLUSIONS: The allele prevalence for TTR V122I in African-Americans is 0.0173. Of African-Americans under age 65, 3.43% carry at least one copy of the variant amyloidogenic allele. PMID- 26123280 TI - Effects of liver transplantation and tafamidis in hereditary transthyretin amyloidosis caused by transthyretin Leu55Pro mutation: a case report. PMID- 26123281 TI - A Novel Audiovisual Brain-Computer Interface and Its Application in Awareness Detection. AB - Currently, detecting awareness in patients with disorders of consciousness (DOC) is a challenging task, which is commonly addressed through behavioral observation scales such as the JFK Coma Recovery Scale-Revised. Brain-computer interfaces (BCIs) provide an alternative approach to detect awareness in patients with DOC. However, these patients have a much lower capability of using BCIs compared to healthy individuals. This study proposed a novel BCI using temporally, spatially, and semantically congruent audiovisual stimuli involving numbers (i.e., visual and spoken numbers). Subjects were instructed to selectively attend to the target stimuli cued by instruction. Ten healthy subjects first participated in the experiment to evaluate the system. The results indicated that the audiovisual BCI system outperformed auditory-only and visual-only systems. Through event-related potential analysis, we observed audiovisual integration effects for target stimuli, which enhanced the discriminability between brain responses for target and nontarget stimuli and thus improved the performance of the audiovisual BCI. This system was then applied to detect the awareness of seven DOC patients, five of whom exhibited command following as well as number recognition. Thus, this audiovisual BCI system may be used as a supportive bedside tool for awareness detection in patients with DOC. PMID- 26123282 TI - Perinatal influences on the uptake of newborn Vitamin K prophylaxis--a retrospective cohort study. AB - OBJECTIVES: To describe rates of newborn vitamin K prophylaxis uptake according to method of administration (intramuscular [IM], oral, refused) and identify predictors for the choice of oral administration and for refusal of vitamin K prophylaxis. METHODS: A retrospective cohort study examined the relationship between method of vitamin K administration and various exposure factors (infant, maternal, socio-demographic and healthcare professional). Written and electronic data for births from a single tertiary birthing unit in New Zealand (NZ) were examined over a four-year period from January 2009 to December 2012. RESULTS: Records for 7,089 mothers/babies were examined. Of these, 92.9% of infants received IM and 5.4% oral vitamin K. Refusal of vitamin K was associated with (OR [95%CI]): Asian ethnicity (5.87 [3.61 to 9.53] p<0.001); vaginal delivery (2.85 [1.83 to 4.43] p<0.001); and gestational age, per additional week, (1.24 [1.10 to 1.39) p<0.001). Oral vitamin K was associated with (OR [95%CI]): Asian ethnicity (2.61 [1.80 to 3.79] p<0.001); obstetric nurse as the Lead Maternity Carer (LMC) (2.65 [1.73 to 4.06] p<0.001); vaginal delivery (2.34 [1.84 to 2.96] p<0.001); gestational age, per week, (1.14 [1.07 to 1.21] p<0.001); and LMC experience, per decade (0.61 [0.51 to 0.74] p<0.001). CONCLUSIONS: This study reveals several important and novel associations with mode of administration of newborn vitamin K prophylaxis. IM vitamin K uptake was also lower than international data, largely due to increased oral uptake. IMPLICATIONS: Uptake of vitamin K is associated with ethnicity and also factors in the infant that might imply a perceived protection against vitamin K deficiency bleeding. Further investigation is required for a fuller understanding of the motivations for choosing differing routes of vitamin K administration in newborns, with particular emphasis on factors influencing parental choice. PMID- 26123283 TI - Concurrent ordering and phase transformation in SmCo7 nanograins. AB - Sm-Co alloys with the stabilized SmCo7 phase are most prominent candidates for advanced high temperature permanent magnets, where the stabilization of the SmCo7 phase can be effectuated by nanostructuring. The complex concurrent processes of ordering and phase transformation in a SmCo7 nanograin are characterized on the atomic scale. For the first time early stages of the phase transformation are made visible by highlighting specific superstructures in single nanograins using Fourier reconstruction of high-resolution transmission electron microscopy images. The superstructures are only detectable and can only be distinguished in specific crystallographic orientations. The evolution of the atom arrangement in the crystal structures is demonstrated for the concurrent ordering process and phase transformation. During decomposition of the metastable SmCo7 phase, the hexagonal Sm2Co17 superstructure (2:17H) forms at first as a precursor of the rhombohedral Sm2Co17 superstructure (2:17R) - this can only be detected by analysis of individual grains and has not been described so far. By extensive crystallographic analysis of individual nanograins, a distinct correlation between the fraction of the superstructure phases and the grain size is found, showing directly and unambiguously the grain size dependence of the phase transformation in the nanocrystalline alloy, a phenomenon that so far has only been shown indirectly using volume averaging methods. PMID- 26123284 TI - Surgical adjunctive procedures for accelerating orthodontic treatment. AB - BACKGROUND: A range of surgical and non-surgical techniques have received increasing attention in recent years in an effort to reduce the duration of a course of orthodontic treatment. Various surgical techniques have been used; however, uncertainty exists in relation to the effectiveness of these procedures and the possible adverse effects related to them. OBJECTIVES: To assess the effects of surgically assisted orthodontics on the duration and outcome of orthodontic treatment. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 10 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8), MEDLINE via OVID (1946 to 10 September 2014), EMBASE via OVID (1980 to 10 September 2014), LILACS via BIREME (1980 to 10 September 2014), metaRegister of Controlled Trials (to 10 September 2014), ClinicalTrials.gov (to 10 September 2014), and the World Health Organization (WHO) International Clinical Trials Registry Platform (to 10 September 2014). We checked the reference lists of all trials identified for further studies. There were no restrictions regarding language or date of publication in the electronic searches. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating the effect of surgical adjunctive procedures for accelerating tooth movement compared with conventional treatment (no surgical adjunctive procedure). DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed the risk of bias in the trials and extracted data. We used the fixed-effect model and expressed results as mean differences (MD) with 95% confidence intervals (CI). We investigated heterogeneity with reference to both clinical and methodological factors. MAIN RESULTS: We included four RCTs involving a total of 57 participants ranging in age from 11 to 33 years. The interventions evaluated were corticotomies to facilitate orthodontic space closure or alignment of an ectopic maxillary canine, with the effect of repeated surgical procedures assessed in one of these studies. The studies did not report directly on the primary outcome as prespecified in our protocol: duration of orthodontic treatment, number of visits during active treatment (scheduled and unscheduled) and duration of visits. The main outcome assessed within the trials was the rate of tooth movement, with periodontal effects assessed in one trial and pain assessed in one trial. A maximum of just three trials with small sample sizes were available for each comparison and outcome. We assessed all of the studies as being at unclear risk of bias.Tooth movement was found to be slightly quicker with surgically assisted orthodontics in comparison with conventional treatment over periods of one month (MD 0.61 mm; 95% CI 0.49 to 0.72; P value < 0.001) and three months (MD 2.03 mm, 95% CI 1.52 to 2.54; P value < 0.001). Our results and conclusions should be interpreted with caution given the small number of included studies. Information on adverse events was sought; however, no data were reported in the included studies. AUTHORS' CONCLUSIONS: This review found that there is limited research concerning the effectiveness of surgical interventions to accelerate orthodontic treatment, with no studies directly assessing our prespecified primary outcome. The available evidence is of low quality, which indicates that further research is likely to change the estimate of the effect. Based on measured outcomes in the short-term, these procedures do appear to show promise as a means of accelerating tooth movement. It is therefore possible that these procedures may prove useful; however, further prospective research comprising assessment of the entirety of treatment with longer follow-up is required to confirm any possible benefit. PMID- 26123285 TI - Facile route to freestanding CH3NH3PbI3 crystals using inverse solubility. AB - CH3NH3PbI3 was found to exhibit inverse solubility at high temperatures in gamma butyrolactone. Making use of this unusual, so far unreported phenomenon, we present a facile method for the growth of freestanding crystals of CH3NH3PbI3 from solution without addition of any capping agents or seed particles. Large, strongly faceted crystals could be grown within minutes. This finding may aid in understanding the crystallization process of CH3NH3PbI3 from solution that may lead to improved morphological control of film deposition for a range of device architectures. Our process offers a facile and rapid route to freestanding crystals for use in a broad range of characterization techniques. PMID- 26123286 TI - Multicentre randomized controlled trial comparing ferric(III)carboxymaltose infusion with oral iron supplementation in the treatment of preoperative anaemia in colorectal cancer patients. AB - BACKGROUND: At least a third of patients with a colorectal carcinoma who are candidate for surgery, are anaemic preoperatively. Preoperative anaemia is associated with increased morbidity and mortality. In general practice, little attention is paid to these anaemic patients. Some will have oral iron prescribed others not. The waiting period prior to elective colorectal surgery could be used to optimize a patients' physiological status. The aim of this study is to determine the efficacy of preoperative intravenous iron supplementation in comparison with the standard preoperative oral supplementation in anaemic patients with colorectal cancer. METHODS/DESIGN: In this multicentre randomized controlled trial, patients with an M0-staged colorectal carcinoma who are scheduled for curative resection and with a proven iron deficiency anaemia are eligible for inclusion. Main exclusion criteria are palliative surgery, metastatic disease, neoadjuvant chemoradiotherapy (5 * 5 Gy = no exclusion) and the use of Recombinant Human Erythropoietin within three months before inclusion or a blood transfusion within a month before inclusion. Primary endpoint is the percentage of patients that achieve normalisation of the haemoglobin level between the start of the treatment and the day of admission for surgery. This study is a superiority trial, hypothesizing a greater proportion of patients achieving the primary endpoint in favour of iron infusion compared to oral supplementation. A total of 198 patients will be randomized to either ferric(III)carboxymaltose infusion in the intervention arm or ferrofumarate in the control arm. This study will be performed in ten centres nationwide and one centre in Ireland. DISCUSSION: This is the first randomized controlled trial to determine the efficacy of preoperative iron supplementation in exclusively anaemic patients with a colorectal carcinoma. Our trial hypotheses a more profound haemoglobin increase with intravenous iron which may contribute to a superior optimisation of the patient's condition and possibly a decrease in postoperative morbidity. TRIAL REGISTRATION: ClincalTrials.gov: NCT02243735 . PMID- 26123287 TI - Anticancer effect of tectochrysin in colon cancer cell via suppression of NF kappaB activity and enhancement of death receptor expression. AB - BACKGROUND: Flavonoids are a diverse family of natural phenolic compounds commonly found in fruits and vegetables. Epidemiologic studies showed that flavonoids also reduce the risk of colon cancer. Tectochrysin is one of the major flavonoids of Alpinia oxyphylla Miquel. However, the anti-cancer effects and the molecular mechanisms of tectochrysin in colon cancer cells have not yet been reported. We investigated whether tectochrysin could inhibit colon cancer cell growth at 1, 5, 10 MUg/ml. In in vivo study, we injected a tectochrysin treatment dose of 5 mg/kg to each mouse. RESULTS: Tectochrysin suppressed the growth of SW480 and HCT116 human colon cancer cells. The expression of DR3, DR4 and Fas were significantly increased, and pro-apoptotic proteins were also increased. Tectochrysin treatment also inhibited activity of NF-kappaB. A docking model indicated that tectochrysin binds directly to the p50 unit. In in vivo, tumor weights and volumes in mice were reduced when treated with tectochrysin. Tectochrysin leads to apoptotic cell death in colon cancer cells through activation of death receptors expression via the inhibition of NF-kappaB. CONCLUSIONS: Tectochrysin can be a useful agent for the treatment of colon cancer cell growth as well as an adjuvant agent for chemo-resistant cancer cells growth. PMID- 26123288 TI - Evolution of anthozoan polyp retraction mechanisms: convergent functional morphology and evolutionary allometry of the marginal musculature in order Zoanthidea (Cnidaria: Anthozoa: Hexacorallia). AB - BACKGROUND: Retraction is among the most important basic behaviors of anthozoan Cnidaria polyps and is achieved through the coordinated contraction of at least six different muscle groups. Across the Anthozoa, these muscles range from unrecognizable atrophies to massive hypertrophies, producing a wide diversity of retraction abilities and functional morphologies. The marginal musculature is often the single largest component of the retraction mechanism and is composed of a diversity of muscular, attachment, and structural features. Although the arrangements of these features have defined the higher taxonomy of Zoanthidea for more than 100 years, a decade of inferring phylogenies from nucleotide sequences has demonstrated fundamental misconceptions of their evolution. RESULTS: Here we expand the diversity of known marginal muscle forms from two to at least ten basic states and reconstruct the evolution of its functional morphology across the most comprehensive molecular phylogeny available. We demonstrate that the evolution of these forms follows a series of transitions that are much more complex than previously hypothesized and converge on similar forms multiple times. Evolution of the marginal musculature and its attachment and support structures are partially scaled according to variation in polyp and muscle size, but also vary through evolutionary allometry. CONCLUSIONS: Although the retraction mechanisms are diverse and their evolutionary histories complex, their morphologies are largely reflective of the evolutionary relationships among Zoanthidea higher taxa and may offer a key feature for integrative systematics. The convergence on similar forms across multiple linages of Zoanthidea mirrors the evolution of the marginal musculature in another anthozoan order (Actiniaria). The marginal musculature varies through evolutionary allometry of functional morphologies in response to requirements for additional force and resistance, and the specific ecological and symbiotic functions of individual taxa. PMID- 26123289 TI - Heterologous expression and comparative characterization of vacuolar invertases from Cu-tolerant and non-tolerant populations of Elsholtzia haichowensis. AB - KEY MESSAGE: Vacuolar invertases (VINs) from Cu-tolerant and non-tolerant populations of Elsholtzia haichowensis have similar enzyme properties, and the enzyme protein divergences contribute little to the varied VIN activities between the contrasting populations. In our previous studies of Elsholtzia haichowensis, vacuolar invertase (VIN) activity in roots of a Cu-tolerant population was found to be significantly higher than that of a non-tolerant population under Cu stress. Divergences of amino acid residues in a sucrose-binding box and other regions of the VINs were detected. To test whether the amino acid divergences influence the enzyme properties of VINs, and thus are relevant to the differences in enzyme activities between the contrasting populations of E. haichowensis, two VIN genes from the Cu-tolerant population (EhCvINV) and non-tolerant population (EhNvINV) were heterologously expressed in Pichia pastoris, and the enzyme properties of the recombinants were characterized and compared. Both of the recombinant enzymes showed temperature optima of 70 degrees C and pH optima of 4.5-5.5. Copper as well as other heavy metals caused almost the same inhibition to EhNvINV and EhCvINV. No statistically significant differences were observed between EhNvINV and EhCvINV in K m and k cat values for sucrose. The results provided evidence that the observed residue divergences had little influence on the enzyme properties of VIN in E. haichowensis, and the varied VIN activities between the contrasting populations under Cu stress were not relevant to the amino acid divergences in the proteins. Also, some other possible reasons accounting for this difference in invertase activities were discussed, such as up regulation of expression of the EhCvINV gene under Cu stress, as Cu tolerance mechanisms in Cu-mine plants. PMID- 26123290 TI - The promoter of the AlSAP gene from the halophyte grass Aeluropus littoralis directs a stress-inducible expression pattern in transgenic rice plants. AB - KEY MESSAGE: When fused to " Pr AlSAP " promoter, transcripts of gusA exhibited similar accumulation patterns in transgenic rice as AlSAP transcripts in A. littoralis. Pr AlSAP can be used for engineering abiotic stress tolerance. We previously showed that ectopic expression of a stress-associated protein gene from Aeluropus littoralis (AlSAP) enhances tolerance to multiple abiotic stresses in tobacco, wheat and rice. The ortholog of AlSAP in rice is OsSAP9. Here, we demonstrate that AlSAP transcripts accumulate in Aeleuropus in response to multiple abiotic stresses and at a higher level in roots, while those of OsSAP9 are preferentially induced by cold and heat treatments and accumulate preferentially in leaves of rice. In silico analysis of the AlSAP promoter "Pr AlSAP " predicted several cis-acting elements responsible for gene regulation by dehydration, salt, heat, ABA, SA, wounding and tissue-specific expression. The Pr AlSAP promoter was fused to the gusA gene and used to produce transgenic rice plants. Transcripts of gusA exhibited similar accumulation patterns in transgenic rice as AlSAP transcripts in A. littoralis. Indeed, accumulation of gusA transcripts was higher in roots than in leaves and induced by salt, drought, cold and heat treatments. GUS activity was confirmed in roots, coleoptiles, leaves and glumes, but absent in the root cell elongation zone and in dry seeds. A wound treatment strongly induced GUS accumulation in leaves and imbibed seeds. Altogether, these results indicate that the regulatory regions of two ortholog genes "AlSAP" and "OsSAP9" have diverged in the specificity of the signals promoting their induction, but that the trans-acting elements allowing the correct spatiotemporal regulation and stress induction of Pr AlSAP exist in rice. Therefore, the AlSAP promoter appears to be an interesting candidate for engineering abiotic stress tolerance in cereals. PMID- 26123291 TI - FISH and GISH: molecular cytogenetic tools and their applications in ornamental plants. AB - KEY MESSAGE: The innovations in chromosome engineering have improved the efficiency of interrogation breeding, and the identification and transfer of resistance genes from alien to native species. Recent advances in molecular biology and cytogenetics have brought revolutionary, conceptual developments in mitosis and meiosis research, chromosome structure and manipulation, gene expression and regulation, and gene silencing. Cytogenetic studies offer integrative tools for imaging, genetics, epigenetics, and cytological information that can be employed to enhance chromosome and molecular genomic research in plant taxa. In situ hybridization techniques, such as fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH), can identify chromosome morphologies and sequences, amount and distribution of various types of chromatin in chromosomes, and genome organization during the metaphase stage of meiosis. Over the past few decades, various new molecular cytogenetic applications have been developed. The FISH and GISH techniques present an authentic model for analyzing the individual chromosome, chromosomal segments, or the genomes of natural and artificial hybrid plants. These have become the most reliable techniques for studying allopolyploids, because most cultivated plants have been developed through hybridization or polyploidization. Moreover, introgression of the genes and chromatin from the wild types into cultivated species can also be analyzed. Since hybrid derivatives may have variable alien chromosome numbers or chromosome arms, the use of these approaches opens new avenues for accurately identifying genome differences. PMID- 26123292 TI - Q&A: How do plants sense and respond to UV-B radiation? AB - Plants are able to sense UV-B through the UV-B photoreceptor UVR8. UV-B photon absorption by a UVR8 homodimer leads to UVR8 monomerization and interaction with the downstream signaling factor COP1. This then initiates changes in gene expression, which lead to several metabolic and morphological alterations. A major response is the activation of mechanisms associated with UV-B acclimation and UV-B tolerance, including biosynthesis of sunscreen metabolites, antioxidants and DNA repair enzymes. To balance the response, UVR8 is inactivated by regulated re-dimerization. Apart from their importance for plants, UVR8 and its interacting protein COP1 have already proved useful for the optogenetic toolkit used to engineer synthetic light-dependent responses. PMID- 26123293 TI - Bioactive Structure of Membrane Lipids and Natural Products Elucidated by a Chemistry-Based Approach. AB - Determining the bioactive structure of membrane lipids is a new concept, which aims to examine the functions of lipids with respect to their three-dimensional structures. As lipids are dynamic by nature, their "structure" does not refer solely to a static picture but also to the local and global motions of the lipid molecules. We consider that interactions with lipids, which are completely defined by their structures, are controlled by the chemical, functional, and conformational matching between lipids and between lipid and protein. In this review, we describe recent advances in understanding the bioactive structures of membrane lipids bound to proteins and related molecules, including some of our recent results. By examining recent works on lipid-raft-related molecules, lipid protein interactions, and membrane-active natural products, we discuss current perspectives on membrane structural biology. PMID- 26123294 TI - Quest for stress-free surgery revisited. PMID- 26123295 TI - Trends in survival of multiple myeloma patients in Germany and the United States in the first decade of the 21st century. AB - Multiple myeloma is a chronic, incurable but highly treatable neoplasm. Recent population-based studies have shown improvements in survival for patients diagnosed in the early 21st century. Here, we examine trends in survival for patients diagnosed with multiple myeloma in Germany and the United States (US) between 2002 and 2010. Data were extracted from 11 population-based cancer registries in Germany and from the Surveillance, Epidemiology and End Results database in the US. Myeloma patients aged 15-74 years with diagnosis and follow up between 1997 and 2010 from Germany and the US were included. Period analysis was employed to assess trends in 5-year relative survival in Germany and the US between 2002-04 and 2008-10. Age-adjusted 5-year relative survival increased from 47.3% to 53.8% in Germany and from 39.8% to 53.2% in the US between 2002-04 and 2008-10. There was a strong age gradient with lower survival among older patients, which persisted over time and was more pronounced in Germany than the US. Five-year relative survival estimates for patients diagnosed with multiple myeloma below 75 years of age steadily increased throughout the first decade of the 21st century and reached levels above 50% in both Germany and the US, probably reflecting the increased use of newer agents in myeloma treatment. PMID- 26123297 TI - Neural correlates of observing joint actions with shared intentions. AB - Studies on the neural bases of action perception have largely focused on the perception of individual actions. Little is known about perception of joint actions where two or more individuals coordinate their actions based on a shared intention. In this fMRI study we asked whether observing situations where two individuals act on a shared intention elicits a different neural response than observing situations where individuals act on their independent parallel intentions. We compared the neural response to perceptually identical yet intentionally ambiguous actions observed in varying contexts. A dialog between two individuals conveyed either a shared intention or two independent parallel intentions. The dialogs were followed by an identical video clip where the two individuals performed certain actions. In one task condition participants tracked the intentions of the actors, in the other, they monitored moving colored dots placed on the same videos. We found that in the intention task versus the color task, observing joint actions based on shared intentions activated the temporal poles, precuneus, and the ventral striatum compared to observing interactions based on parallel intentions. Precuneus and the temporal poles are thought to support mental state reasoning, the latter with a more specific role in retrieving memories associated with social scripts. Activation in the ventral striatum, an area involved in reward processing, likely indicates a hedonistic response to observed shared intentional relations similarly to those experienced when personally sharing mental states with others. PMID- 26123296 TI - Section's osseous slice biopsy during major amputation of lower extremity: preliminary results of prospective cohort study. AB - BACKGROUND: The purpose of this cohort study was to assess the incidence of positive cultures in section's osseous slice biopsy (SOB) taken at the level of major limb amputation. In case of positive cultures we sought whether the microorganisms present in SOB could take origin from the primary infection site necessitating the amputation. The impact of diabetes on culture results was also investigated. METHODS: This prospective cohort study, which aimed to confirm the results of the pilot study, analysed patients who underwent major limb amputation between 2012 and 2013 in three Lithuanian hospitals. SOBs at the amputation site (surgical bone biopsies) and percutaneous bone biopsies of the distal site were performed simultaneously during limb amputation. Tissue cultures were analysed by microbiologists, and species along with antibiograms were reported. Histopathological assessment and bacterial typing were also evaluated. A positive culture was defined as the identification of at least 1 bacteria not belonging to the skin flora, at least 2 bacteria belonging to the skin flora with the same antibiotic susceptibility profiles or the same bacteria belonging to the skin flora in two different sites. Fisher's exact test and Student's test were used to compare the populations and the microbiological results. The statistical significance level was set at P < 0.05. RESULTS: Sixty-nine patients (35 males/34 females), mean age 68.7 (S = 13.6) years, including 21 (30.4%) with diabetes underwent the major limb amputation. Forty-five amputations (65.2%) were done above the knee. In total, 207 SOBs and 207 percutaneous distal site biopsies were studied. SOB cultures were positive in 11 (15.9%) cases. In 5 (45.5%) cases the same microorganisms were identified in both SOB and distal biopsy cultures. No association between culture results and presence of diabetes was identified. CONCLUSIONS: Our results suggest that, independently of the diabetes status, foot infection may silently spread along the bone and can achieve the site of major limb amputation. Additional investigations aiming to confirm this hypothesis and to evaluate a prognostic value are in progress. PMID- 26123298 TI - Predictive value of the neutrophil-to-lymphocyte ratio in patients with deep neck space infection secondary to acute bacterial tonsillitis. AB - OBJECTIVE: The aim of this study was to determine whether the neutrophil-to lymphocyte ratio (NLR) can be used as a predictor for deep neck space infections (DNSIs) that occur as a complication of acute bacterial tonsillitis in the pediatric population. MATERIALS AND METHODS: We evaluated the NLR values of 180 pediatric patients diagnosed with acute bacterial tonsillitis with or without DNSI who presented to the Otolaryngology Department of Marmara University Hospital between 2010 and 2013. In cases in which DNSI was suspected, the patients underwent complete otolaryngological examination and radiological imaging including CT and MRI. NLR was calculated in all the subjects and was compared between the patients with acute bacterial tonsillitis without DNSI and those with DNSI. RESULTS: With regard to the tonsillitis-related complications, 17 patients had peritonsillar abscess (9.4%); five, parapharyngeal abscess (2.8%); and two, retropharyngeal abscess (1.1%). The mean NLR was significantly higher in the patients of acute bacterial tonsillitis with DNSI (P<0.05). The optimum cut-off value of NLR was determined to be 5.4. CONCLUSION: This study is the first to investigate the relationship between NLR and DNSI as a complication of acute bacterial tonsillitis. The results demonstrated that the NLR value could be a potential laboratory parameter for diagnosing DNSIs. PMID- 26123299 TI - Introduction: G Protein-coupled Receptors and RGS Proteins. AB - Here, we provide an overview of the role of regulator of G protein-signaling (RGS) proteins in signaling by G protein-coupled receptors (GPCRs), the latter of which represent the largest class of cell surface receptors in humans responsible for transducing diverse extracellular signals into the intracellular environment. Given that GPCRs regulate virtually every known physiological process, it is unsurprising that their dysregulation plays a causative role in many human diseases and they are targets of 40-50% of currently marketed pharmaceuticals. Activated GPCRs function as GTPase exchange factors for Galpha subunits of heterotrimeric G proteins, promoting the formation of Galpha-GTP and dissociated Gbetagamma subunits that regulate diverse effectors including enzymes, ion channels, and protein kinases. Termination of signaling is mediated by the intrinsic GTPase activity of Galpha subunits leading to reformation of the inactive Galphabetagamma heterotrimer. RGS proteins determine the magnitude and duration of cellular responses initiated by many GPCRs by functioning as GTPase accelerating proteins (GAPs) for specific Galpha subunits. Twenty canonical mammalian RGS proteins, divided into four subfamilies, act as functional GAPs while almost 20 additional proteins contain nonfunctional RGS homology domains that often mediate interaction with GPCRs or Galpha subunits. RGS protein biochemistry has been well elucidated in vitro, but the physiological functions of each RGS family member remain largely unexplored. This book summarizes recent advances employing modified model organisms that reveal RGS protein functions in vivo, providing evidence that RGS protein modulation of G protein signaling and GPCRs can be as important as initiation of signaling by GPCRs. PMID- 26123300 TI - RGS-Insensitive G Proteins as In Vivo Probes of RGS Function. AB - Guanine nucleotide-binding proteins of the inhibitory (Gi/o) class play critical physiological roles and the receptors that activate them are important therapeutic targets (e.g., mu opioid, serotonin 5HT1a, etc.). Gi/o proteins are negatively regulated by regulator of G protein signaling (RGS) proteins. The redundant actions of the 20 different RGS family members have made it difficult to establish their overall physiological role. A unique G protein mutation (G184S in Galphai/o) prevents RGS binding to the Galpha subunit and blocks all RGS action at that particular Galpha subunit. The robust phenotypes of mice expressing these RGS-insensitive (RGSi) mutant G proteins illustrate the profound action of RGS proteins in cardiovascular, metabolic, and central nervous system functions. Specifically, the enhanced Galphai2 signaling through the RGSi Galphai2(G184S) mutant knock-in mice shows protection against cardiac ischemia/reperfusion injury and potentiation of serotonin-mediated antidepressant actions. In contrast, the RGSi Galphao mutant knock-in produces enhanced mu opioid receptor-mediated analgesia but also a seizure phenotype. These genetic models provide novel insights into potential therapeutic strategies related to RGS protein inhibitors and/or G protein subtype-biased agonists at particular GPCRs. PMID- 26123301 TI - RGS Protein Regulation of Phototransduction. AB - First identified in yeast and worm and later in other species, the physiological importance of Regulators of G-protein Signaling (RGS) in mammals was first demonstrated at the turn of the century in mouse retinal photoreceptors, in which RGS9 is needed for timely recovery of rod phototransduction. The role of RGS in vision has also been established a synapse away in retinal depolarizing bipolar cells (DBCs), where RGS7 and RGS11 work redundantly and in a complex with Gbeta5 S as GAPs for Goalpha in the metabotropic glutamate receptor 6 pathway situated at DBC dendritic tips. Much less is known on how RGS protein subserves vision in the rest of the visual system. The research into the roles of RGS proteins in vision holds great potential for many exciting new discoveries. PMID- 26123304 TI - Keeping the Balance Right: Regulator of G Protein Signaling 5 in Vascular Physiology and Pathology. AB - The cardiovascular system including the heart and intricate network of arteries, veins, and capillaries is essential for normal organ homeostasis and tightly controlled by G protein-coupled receptor (GPCR) signaling cascades. Imbalances of these signaling systems can manifest in cardiovascular disease. There has been a recent surge in studies on modulators of GPCR activity, so-called regulator of G protein signaling (RGS) molecules, due to their potential as pharmacological targets. Among RGS proteins, RGS5 is prominently expressed in arterial vascular smooth muscle cells (vSMC) suggesting an important role in vascular function. Although apparently dispensable for embryonic development, RGS5 has now emerged as a crucial regulator of adaptive cardiovascular processes, including remodeling of the vascular wall under stress. RGS5 has been shown to regulate signaling pathways which shape vSMC differentiation, migration, contraction, as well as tissue inflammation and fibrosis. Indeed, studies in RGS5 mutant mice have confirmed a crucial and nonredundant role as regulator of cardiac function, blood pressure homeostasis, and adult neovascularization such as angiogenesis and arteriogenesis. In response to environmental cues, RGS5 is dynamically controlled at both mRNA and protein levels. This enables direct, precise, and rapid modulation of Galphaq- and Galphai-coupled GPCR signaling which also integrates receptor tyrosine kinases (RTK) and Galphas/Galpha12/13-mediated GPCR signal transduction. Although RGS5's endogenous role in a spatiotemporal context is still largely unknown, its prominence in vascular tissue makes it an important molecule to study and a prime candidate for therapeutic intervention. PMID- 26123303 TI - Regulator of G Protein Signaling 2: A Versatile Regulator of Vascular Function. AB - Regulators of G protein signaling (RGS) proteins of the B/R4 family are widely expressed in the cardiovascular system where their role in fine-tuning G protein signaling is critical to maintaining homeostasis. Among members of this family, RGS2 and RGS5 have been shown to play key roles in cardiac and smooth muscle function by tightly regulating signaling pathways that are activated through Gq/11 and Gi/o classes of heterotrimeric G proteins. This chapter reviews accumulating evidence supporting a key role for RGS2 in vascular function and the implication of changes in RGS2 function and/or expression in the pathogenesis of blood pressure disorders, particularly hypertension. With such understanding, RGS2 and the signaling pathways it controls may emerge as novel targets for developing next-generation antihypertensive drugs/agents. PMID- 26123305 TI - Two for the Price of One: G Protein-Dependent and -Independent Functions of RGS6 In Vivo. AB - Regulator of G protein signaling 6 (RGS6) is unique among the members of the RGS protein family as it remains the only protein with the demonstrated capacity to control G protein-dependent and -independent signaling cascades in vivo. RGS6 inhibits signaling mediated by gamma-aminobutyric acid B receptors, serotonin 1A receptors, MU opioid receptors, and muscarinic acetylcholine 2 receptors. RGS6 deletion triggers distinct behavioral phenotypes resulting from potentiated signaling by these G protein-coupled receptors namely ataxia, a reduction in anxiety and depression, enhanced analgesia, and increased parasympathetic tone, respectively. In addition, RGS6 possesses potent proapoptotic and growth suppressive actions. In heart, RGS6-dependent reactive oxygen species (ROS) production promotes doxorubicin (Dox)-induced cardiomyopathy, while in cancer cells RGS6/ROS signaling is necessary for activation of the ataxia telangiectasia mutated/p53/apoptosis pathway required for the chemotherapeutic efficacy of Dox. Further, by facilitating Tip60 (trans-acting regulator protein of HIV type 1 interacting protein 60 kDa)-dependent DNA methyltransferase 1 degradation, RGS6 suppresses cellular transformation in response to oncogenic Ras. The culmination of these G protein-independent actions results in potent tumor suppressor actions of RGS6 in the murine mammary epithelium. This work summarizes evidence from human genetic studies and model animals implicating RGS6 in normal physiology, disease, and the pharmacological actions of multiple drugs. Though efforts by multiple laboratories have contributed to the ever-growing RGS6 oeuvre, the pleiotropic nature of this gene will likely lead to additional work detailing the importance of RGS6 in neuropsychiatric disorders, cardiovascular disease, and cancer. PMID- 26123306 TI - Physiology of RGS10 in Neurons and Immune Cells. AB - Regulator of G protein signaling-10 (RGS10), a GTPase-activating protein (GAP) for Galphai3, Galphaq, and Galphaz, belongs to the D/R12 subfamily based on the homology within the RGS domain and is one of the smallest RGS proteins, outside the RGS box. Although RGS10 lacks the flanking domains or motifs, RGS10 can be targeted to membrane by palmitoylation which markedly increases its net GAP activity. The cAMP-dependent protein kinase A phosphorylates RGS10 on serine 168 (Ser(168)) which promotes translocation of RGS10 from the cytosol to nucleus. In addition to its GAP function, RGS10 modulates adenylyl cyclase (AC) activity as well as the G protein-gated inwardly rectifying potassium channels. Although the roles of various RGS proteins have been well addressed in previous reviews, the function and mechanism of RGS10 in particular has not been reviewed in-depth. Moreover, recent arrays of studies implicate a role for RGS10 in immune and neuronal cells. RGS10 has been localized to various cell compartments including the cytoplasm and nucleus. In this chapter, we will review its role in neurons and immune cells. PMID- 26123307 TI - Regulator of G Protein Signaling 14: A Molecular Brake on Synaptic Plasticity Linked to Learning and Memory. AB - The regulators of G protein signaling (RGS) proteins are a diverse family of proteins that function as central components of G protein and other signaling pathways. In the brain, regulator of G protein signaling 14 (RGS14) is enriched in neurons in the hippocampus where the mRNA and protein are highly expressed. This brain region plays a major role in processing learning and forming new memories. RGS14 is an unusual RGS protein that acts as a multifunctional scaffolding protein to integrate signaling events and pathways essential for synaptic plasticity, including conventional and unconventional G protein signaling, mitogen-activated protein kinase, and, possibly, calcium signaling pathways. Within the hippocampus of primates and rodents, RGS14 is predominantly found in the enigmatic CA2 subfield. Principal neurons within the CA2 subfield differ from neighboring hippocampal regions in that they lack a capacity for long term potentiation (LTP) of synaptic transmission, which is widely viewed as the cellular substrate of learning and memory formation. RGS14 was recently identified as a natural suppressor of LTP in hippocampal CA2 neurons as well as forms of learning and memory that depend on the hippocampus. Although CA2 has only recently been studied, compelling recent evidence implicates area CA2 as a critical component of hippocampus circuitry with functional roles in mediating certain types of learning and memory. This review will highlight the known functions of RGS14 in cell signaling and hippocampus physiology, and discuss potential roles for RGS14 in human cognition and disease. PMID- 26123302 TI - Role of Regulators of G Protein Signaling Proteins in Bone Physiology and Pathophysiology. AB - Regulators of G protein signaling (RGS) proteins enhance the intrinsic GTPase activity of alpha subunits of the heterotrimeric G protein complex of G protein coupled receptors (GPCRs) and thereby inactivate signal transduction initiated by GPCRs. The RGS family consists of nearly 37 members with a conserved RGS homology domain which is critical for their GTPase accelerating activity. RGS proteins are expressed in most tissues, including heart, lung, brain, kidney, and bone and play essential roles in many physiological and pathological processes. In skeletal development and bone homeostasis as well as in many bone disorders, RGS proteins control the functions of various GPCRs, including the parathyroid hormone receptor type 1 and calcium-sensing receptor and also regulate various critical signaling pathways, such as Wnt and calcium oscillations. This chapter will discuss the current findings on the roles of RGS proteins in regulating signaling of key GPCRs in skeletal development and bone homeostasis. We also will examine the current updates of RGS proteins' regulation of calcium oscillations in bone physiology and highlight the roles of RGS proteins in selected bone pathological disorders. Despite the recent advances in bone and mineral research, RGS proteins remain understudied in the skeletal system. Further understanding of the roles of RGS proteins in bone should not only provide great insights into the molecular basis of various bone diseases but also generate great therapeutic drug targets for many bone diseases. PMID- 26123308 TI - Preface. RGS Protein Physiology and Pathophysiology. PMID- 26123309 TI - Ariadne's Thread: A Robust Software Solution Leading to Automated Absolute and Relative Quantification of SRM Data. AB - Selected reaction monitoring (SRM) MS is a highly selective and sensitive technique to quantify protein abundances in complex biological samples. To enhance the pace of SRM large studies, a validated, robust method to fully automate absolute quantification and to substitute for interactive evaluation would be valuable. To address this demand, we present Ariadne, a Matlab software. To quantify monitored targets, Ariadne exploits metadata imported from the transition lists, and targets can be filtered according to mProphet output. Signal processing and statistical learning approaches are combined to compute peptide quantifications. To robustly estimate absolute abundances, the external calibration curve method is applied, ensuring linearity over the measured dynamic range. Ariadne was benchmarked against mProphet and Skyline by comparing its quantification performance on three different dilution series, featuring either noisy/smooth traces without background or smooth traces with complex background. Results, evaluated as efficiency, linearity, accuracy, and precision of quantification, showed that Ariadne's performance is independent of data smoothness and complex background presence and that Ariadne outperforms mProphet on the noisier data set and improved 2-fold Skyline's accuracy and precision for the lowest abundant dilution with complex background. Remarkably, Ariadne could statistically distinguish from each other all different abundances, discriminating dilutions as low as 0.1 and 0.2 fmol. These results suggest that Ariadne offers reliable and automated analysis of large-scale SRM differential expression studies. PMID- 26123310 TI - Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2 associated post-polycythemia myelofibrosis. AB - BACKGROUND: A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 (JAK2) mutation involving duplication of exon 12. The patient presented with 1-2 day long self-limited periodic episodes of high fever that became more frequent as the hematologic disease progressed. METHODS: After ruling out other causes for recurrent fever, analysis of the pyrin encoding Mediterranean fever gene (MEFV) was carried out by Sanger sequencing in peripheral blood DNA samples obtained 4 years apart, in buccal cells, laser dissected kidney tubular cells, and FACS sorted CD3-positive or depleted mononucleated blood cells. Hematopoeitc cells results were validated by targeted deep sequencing. A Sanger sequence based screen for pathogenic variants of the autoinflammatory genes NLRP3, TNFRSF1A and MVK was also performed. RESULTS: A rare, c.1955G>A, p.Arg652His MEFV gene variant was identified at negligible levels in an early peripheral blood DNA sample, but affected 46 % of the MEFV alleles and was restricted to JAK2-positive, polymorphonuclear and CD3-depleted mononunuclear DNA samples obtained 4 years later, when the patient experienced fever bouts. The patient was also heterozygous for the germ line, non-pathogenic NLRP3 gene variant, p.Q705K. Upon the administration of colchicine, the gold standard treatment for familial Mediterranean fever (FMF), the fever attacks subsided. CONCLUSIONS: This is the first report of non-transmitted, acquired FMF, associated with a JAK2 driven clonal expansion of a somatic MEFV exon 10 mutation. The non-pathogenic germ line NLRP3 p.Q705K mutation possibly played a modifier role on the disease phenotype. PMID- 26123311 TI - Leiomyosarcoma: investigation of prognostic factors for risk-stratification model. AB - BACKGROUND: We performed this study to define distinctive clinical features of leiomyosarcoma by assessing prognostic factors. METHODS: Between 1988 and 2011, 129 leiomyosarcoma patients who underwent surgical resection with curative intent were retrospectively reviewed. RESULTS: Of the 129 leiomyosarcoma patients, the distribution of anatomic locations was: extremity (n = 25), pelvis (n = 40), thoracic cavity (n = 11), intra-abdomen (n = 19), retroperitoneum (n = 23), and head/neck (n = 11). We classified the anatomic locations into two categories as abdominal (intra-abdomen and retroperitoneum, n = 42) and extra-abdominal (extremity, pelvis, thoracic cavity, and head/neck, n = 87). Prognosis was worse for the abdominal group than for the extra-abdominal group (median DFS 2.9 9.0 years, P = 0.04). Similarly, overall survival (OS) was also significantly worse for abdominal group (P = 0.027). Independent prognostic factors for survival were primary site (P = 0.041, hazard ratio (HR) 1.7; 95 % CI 1.2-2.8), tumor size (P = 0.038, HR 1.9; 95 % CI 1.13-3.38), margin status (P = 0.019, HR 2.1; 95 % CI 1.13 3.88), and histology grade (P = 0.01, HR 3.59; 95 % CI 1.64-7.87). We identified four different risk groups with different survival outcome: group 1 (n = 8), no adverse factors; groups 2 (n = 37) and 3 (n = 61) with one and two adverse factors, and group 4 (n = 23) with 3 or 4 adverse factors. CONCLUSION: Primary site, tumor size, resection margin, and histology subtype were independently associated with survival outcome. A prognostic model for leiomyosarcoma patients revealed four distinct groups of patients with good prognostic discrimination. PMID- 26123312 TI - Use of warm Ringer's lactate solution in the management of locally advanced giant cell tumor of bone. AB - BACKGROUND: This study was conducted to discover the effectiveness and safety of using warm Ringer's lactate solution (RLS) as a local treatment in the management of locally advanced giant cell tumor of bone with marked soft tissue invasion, including nearby neurovascular bundles. PATIENTS AND METHODS: This was a longitudinal cohort study with an average follow-up period of 4.6 +/- 0.3 years, ranging from 4.2 to 5.9 years. There were 21 patients (9 male and 12 female), with the ages of subjects ranging from 12 to 64 years. Eight patients (38 %) were tumor recurrence cases. Pathological fracture was found in 15 patients (71 %). After extended curettage, warm RLS (50 degrees C) was locally applied for 20 min. Bone stabilization and reconstruction were then performed. RESULTS: All patients survived the operation. No additional neurovascular injury resulting from the use of warm RLS was found. Patients who had neurological deficit before the operation experienced significant improvement in motor and sensory function during the follow-up period. Complication was found in one patient (5 %). Two patients (9.5 %), had tumor recurrence and 19 patients (90.5 %) were tumor-free with good to acceptable function. CONCLUSION: Use of warm Ringer's lactate solution as an adjunctive local treatment during intra-lesional curettage of giant cell tumor with locally soft tissue extension was found to be safe with relatively low recurrence rate. However, additional studies to identify the optimum thermoablation dose at each part of the body should be undertaken before this technique can be used as a standard treatment. PMID- 26123313 TI - Irinotecan and nedaplatin as salvage therapy for patients with advanced germ cell tumors following intensive treatment with cisplatin-based combination chemotherapies. AB - BACKGROUND: To analyze the clinical outcomes of the irinotecan plus nedaplatin (IN) regimen in patients with advanced germ cell tumors (GCTs) refractory to cisplatin-based combination chemotherapies. METHODS: This study included a total of 20 consecutive advanced GCT patients who were categorized into intermediate- or poor-risk GCT groups according to the International Germ Cell Consensus Classification, and were judged to show refractory or relapsed disease after bleomycin, etoposide and cisplatin and cisplatin, ifosfamide and paclitaxel therapies. All 20 patients subsequently received IN therapy (irinotecan 100 mg/m(2) on days 1 and 15; nedaplatin 100 mg/m(2) on day 1) every 4 weeks. RESULTS: Following a median of 3 cycles of IN, 9 patients (45 %) achieved normalization of serum tumor markers. In addition, surgical resection of the residual tumors following IN was performed in 5 patients, of whom 4 were pathologically diagnosed with no viable cancer cells. At a median follow-up of 9 months, 11 patients (55 %) were alive, including 7 (35 %) with no evidence of disease, whereas the remaining 9 (45 %) died of disease progression. The median duration of overall survival after the introduction of IN to these 20 patients was 13.4 months. Severe hematological toxicities were observed in all patients, but were manageable. Although fatal treatment-related interstitial pneumonia occurred in 1 patient, other non-hematological toxicities were generally tolerable. CONCLUSIONS: Considering the markedly unfavorable characteristics of the included patients with advanced GCT who were intensively treated with cisplatin-based combination chemotherapies, IN could be regarded as having promising therapeutic activity with an acceptable toxicity profile. PMID- 26123314 TI - Prognostic model for survival based on readily available pretreatment factors in patients with advanced pancreatic cancer receiving palliative chemotherapy. AB - BACKGROUND: We aimed to construct a prognostic model to predict survival in patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy using readily available pretreatment factors. METHODS: The model was constructed using data from 306 consecutive patients with APC who received palliative chemotherapy between January 2006 and March 2013. The predictive accuracy of the model was assessed using a concordance index (c-index) and calibration curves. RESULTS: Among the 12 potential prognostic factors investigated, multivariate analysis identified the following six independent negative prognostic factors performance status (PS), the presence of distant metastatic disease, the status of initially unresectable disease, carcinoembryonic antigen (CEA) level, carbohydrate antigen 19-9 (CA19-9) level, and neutrophil-lymphocyte ratio (NLR). A prognostic index (PI) based on the coefficients of these factors was constructed as follows-PI = 2 (if PS 2-3) + 1 (if distant metastatic disease) + 1 (if initially unresectable disease) + 1 (if CEA level >=5.0 ng/ml) + 1 (if CA 19 9 level >=1,000 U/ml) + 2 (if NLR >=5). The patients were classified into three prognostic groups-favorable (PI 0-1, n = 73), intermediate (PI 2-3, n = 145), and poor (PI 4-8, n = 88). The median overall survival times for each prognostic group were 16.5, 12.3, and 6.2 months, respectively (P < 0.001). Bootstrapping verified the good fitness of this model for predicting 1-year survival, and the c index was 0.658. CONCLUSIONS: This simple prognostic model could help clinicians to estimate survival in patients with APC who receive palliative chemotherapy. PMID- 26123316 TI - Fast multi-dimensional NMR acquisition and processing using the sparse FFT. AB - Increasing the dimensionality of NMR experiments strongly enhances the spectral resolution and provides invaluable direct information about atomic interactions. However, the price tag is high: long measurement times and heavy requirements on the computation power and data storage. We introduce sparse fast Fourier transform as a new method of NMR signal collection and processing, which is capable of reconstructing high quality spectra of large size and dimensionality with short measurement times, faster computations than the fast Fourier transform, and minimal storage for processing and handling of sparse spectra. The new algorithm is described and demonstrated for a 4D BEST-HNCOCA spectrum. PMID- 26123315 TI - Neural commitment of human pluripotent stem cells under defined conditions recapitulates neural development and generates patient-specific neural cells. AB - Standardization of culture methods for human pluripotent stem cell (PSC) neural differentiation can greatly contribute to the development of novel clinical advancements through the comprehension of neurodevelopmental diseases. Here, we report an approach that reproduces neural commitment from human induced pluripotent stem cells using dual-SMAD inhibition under defined conditions in a vitronectin-based monolayer system. By employing this method it was possible to obtain neurons derived from both control and Rett syndrome patients' pluripotent cells. During differentiation mutated cells displayed alterations in the number of neuronal projections, and production of Tuj1 and MAP2-positive neurons. Although investigation of a broader number of patients would be required, these observations are in accordance with previous studies showing impaired differentiation of these cells. Consequently, our experimental methodology was proved useful not only for the generation of neural cells, but also made possible to compare neural differentiation behavior of different cell lines under defined culture conditions. This study thus expects to contribute with an optimized approach to study the neural commitment of human PSCs, and to produce patient specific neural cells that can be used to gain a better understanding of disease mechanisms. PMID- 26123317 TI - NMR structure calculation for all small molecule ligands and non-standard residues from the PDB Chemical Component Dictionary. AB - An algorithm, CYLIB, is presented for converting molecular topology descriptions from the PDB Chemical Component Dictionary into CYANA residue library entries. The CYANA structure calculation algorithm uses torsion angle molecular dynamics for the efficient computation of three-dimensional structures from NMR-derived restraints. For this, the molecules have to be represented in torsion angle space with rotations around covalent single bonds as the only degrees of freedom. The molecule must be given a tree structure of torsion angles connecting rigid units composed of one or several atoms with fixed relative positions. Setting up CYANA residue library entries therefore involves, besides straightforward format conversion, the non-trivial step of defining a suitable tree structure of torsion angles, and to re-order the atoms in a way that is compatible with this tree structure. This can be done manually for small numbers of ligands but the process is time-consuming and error-prone. An automated method is necessary in order to handle the large number of different potential ligand molecules to be studied in drug design projects. Here, we present an algorithm for this purpose, and show that CYANA structure calculations can be performed with almost all small molecule ligands and non-standard amino acid residues in the PDB Chemical Component Dictionary. PMID- 26123318 TI - Clinical and prognostic significance of OPN and VEGF expression in patients with non-small-cell lung cancer. AB - BACKGROUND: Osteopontin (OPN) and vascular endothelial growth factor (VEGF) play important roles in cancer progression and angiogenesis. In the current study we aimed to investigate the clinical significance of OPN and VEGF expression in patients with non-small-cell lung cancer (NSCLC) and to investigate their prognostic value for NSCLC. METHODS: Immunohistochemical staining was used to detect the expression of OPN and VEGF in 146 NSCLC patients undergoing surgical resection in our hospital between 2006 and 2008. The associations between OPN and VEGF expression and clinicopathological data were analyzed using chi-square test analysis. Survival analysis was performed using the Kaplan-Meier method. The prognostic values of OPN and VEGF were evaluated by univariate and multivariate Cox proportional hazard model analysis. RESULTS: OPN and VEGF expression was positive in 94 and 86 out of 146 NSCLC specimens, respectively. OPN expression was significantly associated with gender (P=0.002), TNM stage (P<0.001) and tumor differentiation (P=0.008). VEGF expression was significantly associated with TNM stage (P=0.015), tumor differentiation (P=0.032) and lymph-node status (P<0.001). There was a significant correlation between OPN and VEGF expression (P=0.035). Survival analysis indicated that OPN(+)/VEGF(+) patients had the worst prognosis. Furthermore, univariate and multivariate analysis suggested that tumor stage, lymph-node metastases, OPN expression and VEGF expression were independent prognostic factors for NSCLC. CONCLUSION: The data suggest that OPN and VEGF expressions could serve as prognostic factors for NSCLC. PMID- 26123319 TI - Vaccination of multiple myeloma: Current strategies and future prospects. AB - Tumor immunotherapy holds great promise in controlling multiple myeloma (MM) and may provide an alternative treatment modality to conventional chemotherapy for MM patients. For this reason, a major area of investigation is the development of cancer vaccines to generate myeloma-specific immunity. Several antigens that are able to induce specific T-cell responses are involved in different critical mechanisms for cell differentiation, inhibition of apoptosis, demethylation and proliferation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of dendritic cell/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs may synergize with immunotherapies. The task ahead is to evaluate these approaches in appropriate clinical settings, and to couple them with strategies to overcome mechanisms of immunoparesis as a means to induce more robust clinically significant immune responses. PMID- 26123320 TI - Rapid changes in key ruminal microbial populations during the induction of and recovery from diet-induced milk fat depression in dairy cows. AB - The ruminant provides a powerful model for understanding the temporal dynamics of gastrointestinal microbial communities. Diet-induced milk fat depression (MFD) in the dairy cow is caused by rumen-derived bioactive fatty acids, and is commonly attributed to the changes in the microbial population. The aim of the present study was to determine the changes occurring in nine ruminal bacterial taxa with well-characterised functions, and abundance of total fungi, ciliate protozoa and bacteria during the induction of and recovery from MFD. Interactions between treatment and time were observed for ten of the twelve populations. The total number of both fungi and ciliate protozoa decreased rapidly (days 4 and 8, respectively) by more than 90% during the induction period and increased during the recovery period. The abundance of Streptococcus bovis (amylolytic) peaked at 350% of control levels on day 4 of induction and rapidly decreased during the recovery period. The abundance of Prevotella bryantii (amylolytic) decreased by 66% from day 8 to 20 of the induction period and increased to the control levels on day 12 of the recovery period. The abundance of Megasphaera elsdenii and Selenomonas ruminantium (lactate-utilising bacteria) increased progressively until day 12 of induction (>170%) and decreased during the recovery period. The abundance of Fibrobacter succinogenes (fibrolytic) decreased by 97% on day 4 of induction and increased progressively to an equal extent during the recovery period, although smaller changes were observed for other fibrolytic bacteria. The abundance of the Butyrivibrio fibrisolvens/Pseudobutyrivibrio group decreased progressively during the induction period and increased during the recovery period, whereas the abundance of Butyrivibrio hungatei was not affected by treatment. Responsive taxa were modified rapidly, with the majority of changes occurring within 8 d and their time course was similar to the time course of the induction of MFD, demonstrating a strong correlation between changes in ruminal microbial populations and MFD. PMID- 26123322 TI - Zileuton for Pruritus in Sjogren-Larsson Syndrome: A Randomized Double-blind Placebo-controlled Crossover Trial. PMID- 26123323 TI - Reactive simulation of the chemistry behind the condensed-phase ignition of RDX from hot spots. AB - Chemical events that lead to thermal initiation and spontaneous ignition of the high-pressure phase of RDX are presented using reactive molecular dynamics simulations. In order to initiate the chemistry behind thermal ignition, approximately 5% of RDX crystal is subjected to a constant temperature thermal pulse for various time durations to create a hot spot. After application of the thermal pulse, the ensuing chemical evolution of the system is monitored using reactive molecular dynamics under adiabatic conditions. Thermal pulses lasting longer than certain time durations lead to the spontaneous ignition of RDX after an incubation period. For cases where the ignition is observed, the incubation period is dominated by intermolecular and intramolecular hydrogen transfer reactions. Contrary to the widely accepted unimolecular models of initiation chemistry, N-N bond dissociations that produce NO2 species are suppressed in the condensed phase. The gradual temperature and pressure increase in the incubation period is accompanied by the accumulation of short-lived, heavier polyradicals. The polyradicals contain intact triazine rings from the RDX molecules. At certain temperatures and pressures, the polyradicals undergo ring-opening reactions, which fuel a series of rapid exothermic chemical reactions leading to a thermal runaway regime with stable gas-products such as N2, H2O and CO2. The evolution of the RDX crystal throughout the thermal initiation, incubation and thermal runaway phases observed in the reactive simulations contains a rich diversity of condensed-phase chemistry of nitramines under high-temperature/pressure conditions. PMID- 26123321 TI - Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice. AB - RATIONALE: Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown. OBJECTIVE: This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2). METHODS: Male C57BL/6J mice were trained to lever press on a fixed ratio-4 schedule of 9% ethanol + 2% sucrose (ethanol) or 2% sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0-1.7 MUg/side) in PFC, NAC, or AMY prior to self-administration. RESULTS: pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 MUg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions. CONCLUSIONS: Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug. PMID- 26123325 TI - Safer trocar insertion for closed laparoscopic access: ex vivo assessment of an improved Veress needle. AB - INTRODUCTION: Laparoscopic surgery is widely practiced surgical technique in the modern surgical toolbox. The Veress needle insertion technique, while faster and easier, is associated with higher rates of iatrogenic complications (injury to internal organs, major blood vessels, etc.), morbidity and even mortality with a reported overall risk of 0.32% during surgical interventions. In order to increase the safety and ease of closed insertion technique, we designed and tested an improved prototype of the Veress needle. METHODS: The new Veress needle includes a distal expandable portion that allows elevation of the abdominal wall and safe insertion of the first trocar over it. The needle was assessed by measurement of ease of insertion, ease of trocar advancement, associated tissue damage, device integrity and weight-bearing capacity on an ex vivo Gallus domesticus animal model: The prototype was tested over 20 times using different traction forces. The experiment was qualitatively repeated on an ex vivo porcine model. RESULTS: In the G. domesticus model, the improved needle supported forces of up to 5.75 kg F. No damage or mechanical malfunction was seen at any stage of the experiment. Needle penetration, ease of trocar insertion, system anchoring and weight-bearing capacity were rated (1-5) by four raters--mean 4.9 +/- 0.31. Inter-rater agreement was high (free marginal kappa 0.75). The porcine experiment revealed similar ease of use with neither complication nor damage to the abdominal wall. CONCLUSIONS: We believe that the new Veress system is easy to use, requires no additional training, non-inferior in its capabilities compared to the traditional Veress needle, with the advantage of improving the safety of the first trocar insertion phase of the operation. PMID- 26123324 TI - MIR137HG risk variant rs1625579 genotype is related to corpus callosum volume in schizophrenia. AB - Genome-wide association studies implicate the MIR137HG risk variant rs1625579 (MIR137HGrv) within the host gene for microRNA-137 as a potential regulator of schizophrenia susceptibility. We examined the influence of MIR137HGrv genotype on 17 subcortical and callosal volumes in a large sample of individuals with schizophrenia and healthy controls (n=841). Although the volumes were overall reduced relative to healthy controls, for individuals with schizophrenia the homozygous MIR137HGrv risk genotype was associated with attenuated reduction of mid-posterior corpus callosum volume (p=0.001), along with trend-level effects in the adjacent central and posterior corpus callosum. These findings are unique in the literature and remain robust after analysis in ethnically homogenous and single-scanner subsets of the larger sample. Thus, our study suggests that the mechanisms whereby MIR137HGrv works to increase schizophrenia risk are not those that generate the corpus callosum volume reductions commonly found in the disorder. PMID- 26123326 TI - Binding pancreaticogastrostomy in laparoscopic central pancreatectomy: a novel technique in laparoscopic pancreatic surgery. AB - BACKGROUND: Even though more and more cases of laparoscopic central pancreatectomy (LCP) are reported (Machado et al. in Surg Laparosc Endosc Percutan Tech 23(6):486-490, 2013; Hong et al. in World J Surg Oncol 10:223, 2012; Gonzalez et al. in JOP 14(3):273-276, 2013, Zhang et al. in J Laparoendosc Adv Surg Tech A 23(11):912-918, 2013; Sucandy et al. in N Am J Med Sci 2(9):438 441, 2010; Sa Cunha et al. in Surgery 142(3):405-409, 2007), the management for pancreatic stumps remains the most technically challenging part which is the same as in pancreatoduodenectomy (PD), making it the bottleneck for laparoscopic pancreatic surgery. In open surgery, various pancreatic reconstruction techniques designed for either pancreaticojejunostomy (PJ) or pancreaticogastrostomy (PG) have been attempted to reduce the postoperative pancreatic fistula (POPF), including the binding anastomosis, invented by our team, i.e., binding PG (BPG) and binding PJ, which have been proved to be effective to reduce the POPF (Hong et al. 2012; Peng et al. in Ann Surg 245(5):692-698, 2007; Peng et al. in Updates Surg 63(2):69-74, 2011). However, despite of this, few reports are seen addressing such technique for laparoscopic surgery even though laparoscopic pancreatic surgery is more performed. After a previous successful laparoscopic BPG in a case of laparoscopic CP (LCP; Hong et al. 2012) and more than 50 cases of open PD and CP (Peng et al. 2011), we further performed laparoscopic BPG in 10 consecutive cases of LCP with satisfactory outcomes. OBJECTIVE: To explore the feasibility and efficacy of LCP with BPG. METHODS: Between October 2011 and July 2014, LCP with laparoscopic BPG was performed in ten consecutive patients with lesions of benign or low malignancy at the pancreatic neck. Operative and pathological data, complications, hospital stay and details on the surgical techniques were introduced. RESULTS: The operations were successfully performed in all the ten cases, with no conversions. The tumor size ranged from 2.0-3.0 to 2.5-3.0 cm, average (2.50 +/- 0.35) to (2.66 +/- 0.35) cm, and the diameter of pancreatic duct was (1.6-2.1) mm, average (1.71 +/- 0.17) mm. Operation time was 170-250 (198.50 +/- 25.82) min, and blood loss was 20-300 (125 +/- 107.31) mL. Three cases had grade A pancreatic fistula (PF), and one case had delayed gastric emptying, which were all managed with conservative treatment. Upper GI bleeding occurred in one case which was cured with second operation, time for the recovery of bowl movement was 3-5 (4.2 +/- 0.8) days, the time for semifluid dieting was 6 10 (8.2 +/- 1.5) days, and the hospital stay was 8-20 (12.8 +/- 4.63) days. The postoperative fast blood sugar was (6.3 +/- 1.6) mmol/L with the normal diet, which was not significantly different from the preoperative data (5.3 +/- 0.5) mmol/L (P > 0.05). The postoperative pathology was as follows: five cases of cystic serous adenoma, one case of intraductal papillary mucinous neoplasm, two cases of neuroendocrine tumor, and two cases of solid pseudopapillary tumor of pancreas. All the patients were followed up for 7-40 months, no recurrence happened, and no new incidence of diabetes or insufficiency of pancreatic exocrine function occurred. CONCLUSIONS: LCP with BPG is feasible and safe; the advantages lie in its minimal invasiveness, the efficacy for avoiding PF, and the preservation of the pancreatic endocrine and exocrine function insufficiency, making it an ideal procedure for the benign or low-malignant lesions at the pancreatic neck. PMID- 26123327 TI - Comparison of laparoscopic radiofrequency ablation versus open resection in the treatment of symptomatic-enlarging hepatic hemangiomas: a prospective study. AB - BACKGROUND: Radiofrequency ablation (RFA) has been demonstrated to be a promising therapy for symptomatic large hepatic hemangioma. However, there is a lack of studies to demonstrate the benefits and disadvantages of RFA as compared with surgical resection for managing hepatic hemangioma. The aim of this study was to evaluate the outcomes of RFA compared with conventional open resection (ORES) for the treatment of symptomatic-enlarging hepatic hemangiomas. METHODS: A total of 66 patients with symptomatic-enlarging hepatic hemangiomas (4 cm <= diameter < 10 cm) who required surgical treatment were divided into two groups: 32 patients underwent laparoscopic radiofrequency ablation (LRFA) and the other 34 patients underwent ORES. We compared the two groups in terms of radiologic response, clinical response, operative time, estimated blood loss, postoperative pain score and analgesic requirement, length of hospital stay, postoperative complications and hospital cost. RESULTS: The radiologic and clinical responses were comparable between groups. LRFA had significantly shorter operative time (138 vs. 201 min, P < 0.001) and less blood loss (P < 0.001) than ORES. Patients after LRFA experienced significantly less pain and required less analgesia use. Moreover, patients underwent LRFA had significantly shorter length of hospital stay (P < 0.001) and lower hospital cost (P = 0.017). No severe morbidities or mortality was observed, and the overall morbidity rate was similar between groups. CONCLUSIONS: As a new minimal invasive treatment option, laparoscopic radiofrequency ablation is as safe and effective a procedure as open resection for patients with symptomatic-enlarging hepatic hemangiomas smaller than 10 cm. PMID- 26123328 TI - Robotic versus laparoscopic resections of posterosuperior segments of the liver: a propensity score-matched comparison. AB - BACKGROUND: Open parenchymal-preserving resection is the current standard of care for lesions in the posterosuperior liver segments. Laparoscopy and robot-assisted surgery are emergent surgical approaches for liver resections, even in posteriorly located lesions. The objective of this study was to compare robot assisted to laparoscopic parenchymal-preserving liver resections for lesions located in segments 7, 8, 4a, and 1. METHODS: Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent laparoscopic and robot-assisted liver resection in two centers for lesions in the posterosuperior segments between June 2008 and February 2014 were reviewed. A 1:2 matched propensity score analysis was performed by individually matching patients in the robotic cohort to patients in the laparoscopic cohort based on demographics, comorbidities, performance status, tumor stage, location, and type of resection. RESULTS: Thirty-six patients who underwent robot-assisted liver resection were matched with 72 patients undergoing laparoscopic liver resection. Matched patients displayed no significant differences in postoperative outcomes as measured by blood loss, hospital stay, R0 negative margin rate, and mortality. The overall morbidity according to the comprehensive complication index was also similar (34.6 +/- 33 vs. 18.4 +/- 11.3, respectively, for robotic and laparoscopic approach, p = 0.11). Patients undergoing robotic liver surgery had significantly longer inflow occlusion time (77 vs. 25 min, p = 0.001) as compared with their laparoscopic counterparts. CONCLUSIONS: Although number and severity of complications in the robotic group appears to be higher, robotic and laparoscopic parenchymal-preserving liver resections in the posterosuperior segments display similar safety and feasibility. PMID- 26123329 TI - Raising the quality of hernia care: Is there a need? AB - INTRODUCTION: With a focus on raising the quality of hernia care through creation of educational programs, SAGES formed the Hernia Task Force (HTF). This study used needs assessment survey to target opportunities for improving surgical training and thus patient outcomes and experience. METHODS: This qualitative study included structured interviews and online surveys of key stakeholders: HTF members, surgeons, nurses, patients, hospital administrators, healthcare payers and medical suppliers. Questions included perceptions of recurrence and complication rates, their etiologies, perceived deficits in current hernia care and the most effective and training modalities. RESULTS: A total of 841 participants included 665 surgeons, 66 patient care team members, 12 hospital administrators and 14 medical supply providers. Assessment of technical approach revealed that nearly 26 % of surgeons apply the same, limited range of techniques to all patients without evaluation of patient-specific factors. The majority (71 %) of surgeon respondents related hernia recurrence rates nearing 25 % or more. HTF members implicated surgeon factors (deficits in knowledge/technique, etc.) as primary determinants of recurrences, whereas nurses, medical supply providers and hospital administrators implicated patient health factors. Surgeons preferred attending conferences (82 %), reading periodicals/publications (71 %), watching videos (59 %) and communicating with peers (57 %) for learning and skill improvement. Topics of the greatest interest were advanced techniques for hernia repairs (71 %), preoperative and intraoperative decision making (56 %) and patient outcomes (64 %). Eighty-six percent of nurses felt that there was room for improvement in hernia patient safety and teamwork in the OR. Only 24 % believed that the patients had adequate preoperative education. CONCLUSIONS: Major reported deficits in hernia care include: lack of standardization in training and care, "one size fits all" technical approach and inadequate patient follow-up/outcome measures. There is a need for a comprehensive, flexible and tailored educational program to equip surgeons and their teams to raise the quality of hernia care and bring greater value to their patients. PMID- 26123330 TI - Novel flower-type covered metal stent to prevent cholecystitis: experimental study in a pig model. AB - BACKGROUND: Covered self-expandable metal stent (CSEMS) has the risk of obstruction of the cystic duct, and the main and branch pancreatic ducts due to strong radial force and covering material, which results in cholecystitis and pancreatitis. A flower-type covered self-expandable metal stent (F-CSEMS) having a five-petal-shaped design with side grooves was constructed to prevent the obstruction of the cystic duct orifice. This study investigated the value of the F-CSEMS in protection for cholecystitis in a pig model. METHODS: Fourteen pigs randomly underwent endoscopic placement of either F-CSEMS or conventional CSEMS (C-CSEMS). The stent was placed across the cystic duct orifice to impede bile drainage from the gallbladder. Drainage was checked at 24, 48, 120 and 168 h after implantation. Blood was collected at baseline, on days 2 and 7 following implantation. The animals were killed for histologic evaluation on day 7. RESULTS: All stents were successfully inserted into bile duct without any procedure-related complications. At 48 h, the rate of contrast drainage from the gallbladder was higher in the F-CSEMS group than the C-CSEMS group without significant difference (71.4 vs. 28.6% p = 0.28). C-CSEMS was associated with higher levels of C-reactive protein (35.2 vs. 20.5 ug/dl, p = 0.03) and histologic inflammatory scores of gallbladder (score 4 vs. 2; p = 0.03). CONCLUSION: The F-CSEMS appears safe and helpful to prevent cholecystitis without disturbance of bile flow in a pig model. PMID- 26123331 TI - Phase II clinical experience and long-term follow-up using the next-generation single-incision platform FMX314. AB - BACKGROUND: Single-incision minimally invasive surgery has previously been associated with incisions 2.0-3.0 cm in length. We present a novel single incision surgical platform compatible for insertion through a standard 15-mm trocar we previously described in six patients with short-term follow-up data. The objective of this phase II study was to evaluate the safety and feasibility of the platform in a larger collective and to evaluate 1-year follow-up data of the phase I trial. METHODS: The technology features a multiple-use introducer, accommodating the articulating instruments, and is inserted through a 15-mm laparoscopic trocar. Cholecystectomy is performed through an umbilical incision. A prospective feasibility study was performed at a single center. Inclusion criteria were age of 18-75 years and biliary colic, exclusion criteria were acute cholecystitis, dilation of the biliary tree, severe coagulopathy, BMI > 40 kg/m(2), or choledocholithiasis. Endpoints included complications, length of stay, pain medication, cosmetic results, and the presence of hernia. RESULTS: Twenty-seven patients (23 females; phase I: 6 patients, phase II: 21 patients) with an average age of 41.7 years and BMI 26.6 kg/m(2) were recruited for the study. Umbilical incision length did not exceed 15 mm. There were no intraoperative complications. Average OR time decreased from 91 min for the first six cases to 56 min for the last six cases. Average length of stay was 7.8 h. Pain control was achieved with diclofenac for no more than 7 days. All patients had no adverse events at 5-month follow-up, and all phase I patients had no adverse events nor evidence of umbilical hernia at 1 year. CONCLUSION: This study demonstrates that single-incision cholecystectomy with the platform is feasible, safe, and reproducible in a larger patient population. Long-term follow-up showed no hernias or other adverse events. Further studies will be needed to evaluate longer-term hernia rates. PMID- 26123332 TI - Gastroesophageal reflux symptoms do not correlate with objective pH testing after peroral endoscopic myotomy. AB - INTRODUCTION: Peroral endoscopic myotomy (POEM) is an emerging treatment for esophageal achalasia. Postoperative reflux has been found in a significant number of patients, but it is unknown whether subjective reports of reflux correlate with objective pH testing. The purpose of this study was to compare the objective rate of reflux with standardized reflux symptom scales after POEM. Our hypothesis was that subjective symptoms would not correlate with objective measurement of reflux. METHODS AND PROCEDURES: Data on all patients undergoing POEM were collected prospectively between August 2012 and June 2014 and included demographics, objective testing (48-h pH probe, manometry, endoscopy), as well as gastroesophageal reflux disease health-related quality of life (GERD-HRQL), GERD symptom scale (GERSS), and antacid use. RESULTS: Forty-three patients underwent POEM during the study period. The mean age was 53.5 +/- 17.4 years with a BMI of 29.6 +/- 8.4 kg/m(2), and 27 (63%) were male. Forty-two patients (98%) completed at least 6 months of follow-up, and 26 (60%) underwent repeat pH measurement. Dysphagia scores improved from 4 (0-5) at baseline to 0 (0-3) (p < 0.001). On follow-up pH testing, 11 (42%) were normal and 15 (58%) had elevated DeMeester scores. Postoperative GERSS or GERD-HRQL scores did not correlate with DeMeester scores on Spearman's rank-order tests (r = 0.02, p = 0.93 and r = 0.04, p = 0.50, respectively). Postoperative PPI use was not significantly associated with normal or abnormal pH testing: 5 of 7 (71%) patients who were taking PPIs postoperatively had abnormal DeMeester scores compared to 9 of 18 (50%) of patients who were not taking PPIs (p = 0.332). CONCLUSIONS: Peroral endoscopic myotomy provides excellent dysphagia relief for patients with achalasia, but is associated with a high rate of reflux on pH testing postoperatively. Subjective symptoms are not a reliable indicator of postoperative reflux. Routine pH testing should be considered in all patients following POEM. PMID- 26123333 TI - Effectiveness of peroral direct cholangioscopy using an ultraslim endoscope for the treatment of hepatolithiasis in patients with hepaticojejunostomy (with video). AB - BACKGROUND: Hepatolithiasis is a postoperative complication of hepaticojejunostomy (HJ) performed for various pancreatobiliary diseases. Hepatolithiasis can cause repeated cholangitis. Complete stone removal and bile stasis elimination are therefore necessary. Here, we evaluated the effectiveness of peroral direct cholangioscopy (PDCS) using an ultraslim endoscope for treating hepatolithiasis in HJ patients. METHODS: We studied 14 patients with hepatolithiasis who underwent bowel reconstruction with HJ between April 2012 and May 2014. Diagnostic and therapeutic endoscopic retrograde cholangiography using a short double-balloon enteroscope (DBE) was initially performed. Following stone removal, the DBE was exchanged for an ultraslim endoscope through the balloon overtube for PDCS. RESULTS: The success rate of PDCS procedure was 85.7% (12/14). In 5 of 12 (41.7%) patients with successful PDCS, the residual stones were detected and removed completely using a 5-Fr basket catheter and suction after normal saline irrigation. In the remaining 7 (58.3%) patients, no residual stone was detected. The median procedure time was 14 min (range 8-36) with no serious postoperative complications. The median follow-up time after PDCS was 21 months (range 5-26), and only 1 patient (8.3%) had IHBD stone recurrence with an anastomotic stricture. CONCLUSIONS: PDCS using an ultraslim endoscope appears to be useful for detecting and removing residual stones following hepatolithiasis treatment using a DBE. The combined use of a DBE and PDCS may reduce the risk of hepatolithiasis recurrence in HJ patients. PMID- 26123334 TI - CT/MRI pelvimetry as a useful tool when selecting patients with rectal cancer for transanal total mesorectal excision. AB - BACKGROUND: The quality of a total mesorectal excision (TME) is one of the most important prognostic factors for local recurrence of rectal carcinoma. The aim of this study was to clarify the manner in which lesser pelvis dimensions affect the quality of TME via the transabdominal approach, while simultaneously defining the criteria for selecting patients most likely to have Grade 3 TME outcomes for a transanal approach using the TaTME technique. METHODS: An analysis from the registry was conducted using 93 of total 198 patients with rectal cancer of the mid- and lower third of the rectum who underwent: (1) a low anterior resection, (2) an ultra-low resection with coloanal anastomosis, or (3) an intersphincteric rectal resection, all with total mesorectal excision. The procedures were carried out at the Department of Surgery at the University Hospital Hradec Kralove between 2011 and 2014. Rectal specimens were histopathologically examined according to a standardized protocol. Pelvimetry data were obtained using anteroposterior, transverse, and sagittal CT or MRI scans. RESULTS: A correlation was found between the quality of the TME and pelvimetry parameter A5, i.e., the angle between the longitudinal axis of the symphysis, and the lines between the symphysis and the promontory (R(2) = -0.327, p < 0.001). The ordinal regression method was used to identify parameters of the model describing levels of probability for TME quality. These relationships were described by equations that provide probability of the achievement of each grade of TME. CONCLUSION: The correlation described by obtained equations between pelvimetry parameters and the quality of TME represents a new tool for use in preoperative decision-making with regard to resection via the transanal approach (TaTME). PMID- 26123335 TI - A simple sensor calibration technique for estimating the 3D pose of endoscopic instruments. AB - INTRODUCTION: The aim of this study was to describe a simple and easy-to-use calibration method that is able to estimate the pose (tip position and orientation) of a rigid endoscopic instrument with respect to an electromagnetic tracking device attached to the handle. METHODS: A two-step calibration protocol was developed. First, the orientation of the instrument shaft is derived by performing a 360 degrees rotation of the instrument around its shaft using a firmly positioned surgical trocar. Second, the 3D position of the instrument tip is obtained by allowing the tip to come in contact with a planar surface. RESULTS: The results indicate submillimeter accuracy in the estimation of the tooltip position, and subdegree accuracy in the estimation of the shaft orientation, both with respect to a known reference frame. The assets of the proposed method are also highlighted by illustrating an indicative application in the field of augmented reality simulation. CONCLUSIONS: The proposed method is simple, inexpensive, does not require employment of special calibration frames, and has potential applications not only in training systems but also in the operating room. PMID- 26123336 TI - Prior treatment does not influence the performance or early outcome of per-oral endoscopic myotomy for achalasia. AB - INTRODUCTION: Per-oral endoscopic myotomy (POEM) is an emerging treatment for achalasia. Pneumatic dilation, botulinum toxin injection, and previous myotomy increase the difficulty of subsequent Heller myotomy, but their impact on POEM remains unknown. The purpose of this study was to compare patients who had undergone prior treatment for their achalasia to those undergoing POEM as an initial therapy. METHODS AND PROCEDURES: All patients undergoing POEM were entered into a prospective database from August 2012 to October 2014. Data collected included demographics, dysphagia and symptom survey scores, operative time, clips required for mucosotomy closure, perioperative complications and length of hospital stay. RESULTS: Forty-five patients underwent POEM during the study period. Fifteen (30%) had undergone previous treatment (seven Botox injection, five pneumatic dilation and three Heller myotomy). Primary POEM patients were younger than those who had had prior treatment (mean age 46 +/- 17 vs. 64 +/- 12 years, p < 0.001), but gender, body mass index and ASA class were not significantly different. There were no conversions to Heller myotomy or perioperative complications in either group. Operative time for primary POEM was 103 +/- 27 versus 102 +/- 29 min following prior treatment (p = 0.84). Mucosotomy closure required a median 7 (4-16) and 8 (5-16) clips, respectively (p = 0.08). Length of stay was 1 day in each group. Median dysphagia scores decreased from 4 (0-5) to 1 (0-4) following primary POEM and 4 (0-5) to 0 (0-4) in the prior treatment group (p = 0.45) during a median follow-up of 10 months (5-17 months). All patients in each group expressed satisfaction with their procedure and would undergo the procedure again given the benefit of hindsight. CONCLUSION: Per-oral endoscopic myotomy is a safe and effective treatment for achalasia which improves dysphagia and disease-specific quality of life. Previous endoscopic or laparoscopic treatment of achalasia does not affect the performance or early outcome of POEM. PMID- 26123337 TI - Laparoscopic gastrectomy for gastric cancer in the elderly patients. AB - BACKGROUND: This study aimed to investigate the short-term surgical outcomes of laparoscopic gastrectomy for gastric cancer in elderly patients in order to determine the safety, feasibility, and risk factors for postoperative complications associated with this procedure. METHODS: We retrospectively investigated 208 patients who underwent laparoscopic gastrectomy for gastric cancer between January 2007 and September 2014. After excluding 15 patients with unusual medical histories or surgical treatments, 193 were selected for this cohort study. We divided the patients into two cohorts: elderly patients (>=75 years old) and non-elderly patients (<74 years old). We compared these cohorts with respect to clinicopathological characteristics and intraoperative and postoperative parameters. RESULTS: The overall complication rates were 11.4% (8 of 70 patients) in the elderly cohort and 8.1% (10 of 123 patients) in the non elderly cohort (P = 0.449). In a univariate analysis, Charlson comorbidity index (CCI) of >=3, American Society of Anesthesiologists (ASA) score of 3, operative time of >=330 min, and intraoperative blood loss of >=50 ml were found to correlate significantly with postoperative complications. In a multivariate analysis, CCI of >=3 (P = 0.034), ASA score of 3 (P = 0.019), and intraoperative blood loss of >=50 ml (P = 0.016) were found to be independent risk factors of postoperative complications. In contrast, age was not found to significantly affect the risk of postoperative complications. CONCLUSIONS: Laparoscopic gastrectomy for gastric cancer can be successfully performed in elderly patients with an acceptable complication rate. This study suggested that high CCI, ASA score, and intraoperative blood loss volume were identified as independent predictors of postoperative complications after laparoscopic gastrectomy for gastric cancer. PMID- 26123338 TI - Room air versus carbon dioxide pneumoperitoneum: effects on oxidative state, apoptosis and histology of splanchnic organs. AB - BACKGROUND: Although CO2 is the insufflation gas of choice in laparoscopic procedures, room air is usually used in natural orifice transluminal endoscopic surgery. The aim of the present study was to compare the safety of room air versus CO2 pneumoperitoneum in terms of their effect on the oxidative state, apoptosis and tissue injury of splanchnic organs. METHODS: Eighteen Wistar rats were assigned to three groups (n = 6 per group) and were subjected to 8 mm Hg room air (group Pne-Air) or CO2 pneumoperitoneum (group Pne-CO2) or sham operation for 60 min. Forty-five minutes postdeflation, tissue samples were excised from the liver, stomach, ileum and kidneys for reduced glutathione-to glutathione disulfide (GSH/GSSG) ratio, caspase-8 and caspase-3 and hypoxia inducible factor-1alpha (HIF-1alpha) immunohistochemical assessment and histopathologic examination. RESULTS: GSH/GSSG ratio substantially declined in both pneumoperitoneum groups. No change was noted in HIF-1alpha expression. Mild upregulation of caspase-8 and caspase-3 was noted in both pneumoperitoneum groups being less pronounced in group Pne-Air. Histopathologic score was increased in all organs studied, but the stomach, in both pneumoperitoneum groups. CONCLUSION: Pneumoperitoneum established by either room air or CO2 induced substantial oxidative stress, mild apoptosis and mild tissue injury in splanchnic organs. While air pneumoperitoneum conferred a less pronounced apoptotic effect, the oxidative state and histopathologic profile of splanchnic organs did not differ between insufflation gases. PMID- 26123339 TI - Early experience and lessons learned in a new minimally invasive esophagectomy program. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) is gaining increasing popularity in the treatment of esophageal cancer. In fact, while surgical and oncologic outcomes are not inferior to those achieved through a traditional open approach, patients undergoing MIE benefit from shorter length of stay, lesser pain and prompter recovery. This technique is, however, highly challenging, and the development of a MIE program, even in the setting of a tertiary center, requires time and progressive honing of surgical skills. METHODS: We use a minimally invasive Ivor Lewis approach. The abdominal phase of the procedure includes complete celiac lymphadenectomy and tubularization of the stomach, which will constitute the neo-esophagus. The video-assisted thoracoscopic surgery portion of the operation takes place in left lateral decubitus and allows for optimal thoracic lymphadenectomy and anastomosis. RESULTS: From October 2011 to January 2015, we treated 52 patients with the above-described procedure. The evolution of our anastomotic technique included a first group of circular stapled anastomosis with OrvilTM and 3.5-mm EEATM (n = 16 patients), subsequently abandoned in favor of a linear anastomosis (n = 12), before going back to the OrvilTM coupled with 4.8-mm EEATM (n = 22) in more recent times. There were also an additional two anastomoses that did not fall under any of these categories. We experienced two postoperative deaths. The overall leak rate was 14%, but fell down to 4% in the last group. Median LOS was 9 days. Lymph node retrieval was adequate throughout the whole series. CONCLUSIONS: Developing a MIE program requires a significant learning curve before the results plateau. Only once a technique of choice is refined and mastered, the advantages granted by MIE become apparent. PMID- 26123340 TI - Rapid growth in surgeons' use of secure messaging in a patient portal. AB - BACKGROUND: Use of secure messaging through patient portals has risen substantially in recent years due to provider incentives and consumer demand. Secure messaging may increase patient satisfaction and improve outcomes, but also adds to physician workload. Most prior studies of secure messaging focused on primary care and medical specialties. We examined surgeons' use of secure messaging and the contribution of messaging to outpatient interactions in a broadly deployed patient portal. METHODS: We determined the number of clinic visits and secure messages for surgical providers in the first 3 years (2008 2010) after patient portal deployment at an academic medical center. We calculated the proportion of outpatient interaction conducted through messaging for each specialty. Logistic regression models compared the likelihood of message based versus clinic outpatient interaction across surgical specialties. RESULTS: Over the study period, surgical providers delivered care in 648,200 clinic visits and received 83,912 messages, with more than 200% growth in monthly message volume. Surgical specialties receiving the most messages were orthopedics/podiatry (25.1%), otolaryngology (20.1%), urology (10.8%), and general surgery (9.6%); vascular surgery (0.8%) and pediatric general surgery (0.2%) received the fewest. The proportion of outpatient interactions conducted through secure messaging increased significantly from 5.4% in 2008 to 15.3% in 2010 (p < 0.001) with all specialties experiencing growth. Heart/lung transplantation (74.9%), liver/kidney/pancreas transplantation (69.5%), and general surgery (48.7%) had the highest proportion of message-based outpatient interaction by the end of the study. CONCLUSIONS: This study demonstrates rapid adoption of online secure messaging across surgical specialties with significant growth in its use for outpatient interaction. Some specialties, particularly those with long-term follow-up, interacted with patients more through secure messaging than in person. As surgeons devote more time to secure messaging, additional research will be needed to understand the care delivered through online interactions and to develop models for reimbursement. PMID- 26123341 TI - Locoregional steroid injection prevents stricture formation after endoscopic submucosal dissection for esophageal cancer: a propensity score matching analysis. AB - BACKGROUND: Although endoscopic submucosal dissection (ESD) has become accepted for the treatment of superficial esophageal cancer, the incidence of stricture formation caused by ESD for widespread lesions is high and leads to a low quality of life. A few studies reported that locoregional steroid injections are useful for the prevention of such stricture formation compared with historical controls. We evaluated the efficacy of prophylactic locoregional steroid injections for stricture formation caused by ESD using quasi-randomized analysis. METHODS: This matched case-control study included 461 superficial esophageal cancers from 305 patients who underwent ESD between 2006 and 2013. We used two methods of locoregional steroid injection to prevent stricture formation after ESD. A propensity score matching analysis was performed to reduce the effects of a selection bias for steroid injections and other potential confounding factors. In addition, generalized estimating equations were used to analyze repeated measures data. We compared the incidence of stricture formation with or without steroid injections. RESULTS: Forty-two lesions were treated with locoregional steroid injection (dexamethasone/triamcinolone, 23/19) after ESD and esophageal stricture formation occurred in 36 lesions. Fifty-six lesions treated with or without steroid injections were matched after propensity score matching. Locoregional steroid injection reduced the incidence of stricture formation to 10.7% (3/28) of patients compared with 35.7% (10/28) in the control group (odds ratio 4.63, 95% confidence interval 1.11-19.25, p = 0.035). CONCLUSIONS: Locoregional steroid injections could be efficient for the prevention of stricture formation after ESD for superficial esophageal cancer. PMID- 26123343 TI - Do not rush for surgery; stent placement may be an effective step for definitive treatment of initially unextractable common bile duct stones with ERCP. AB - BACKGROUND AND AIMS: Endoscopically unextractable common bile duct stones may be challenging for the endoscopist. In this study, we investigated the rate of stone removal after the endoscopic insertion of a biliary stent in patients with common bile duct stones unextractable via ERCP. METHODS: Records of patients with common bile duct stone/s who underwent ERCP at single center were retrospectively analyzed. Only patients with common bile duct stone/s who had a stent placed due to unyielding stone removal were eligible for inclusion into this study. Endoscopic biliary stents were placed in cases of unextractable stone. After a follow-up period, a second ERCP procedure was performed. Major outcomes were the rate of stent insertion because of unextractable bile duct stones, the rate of spontaneous stone passage and the rate of stone extraction after the endoscopic insertion of a biliary stent. RESULTS: A total of 66 (28%) patients had a stent placed due to unyielding attempts for stone removal, and 43 patients were included in the study. The second ERCP procedure revealed that 10 patients (23%) had spontaneous stone passage and 5 (12%) had spontaneous passage of both the stone and the stent. In the second procedure, biliary balloon was used successfully to extract the retained stone in 22 (51%) patients. Thus, a total of 37 patients (86%) with retained stones had a successful stone extraction during the second ERCP procedure. CONCLUSION: Biliary stenting may be an effective step for definitive treatment of initially unextractable common bile duct stones with ERCP. PMID- 26123344 TI - Laparoscopic versus open surgery for T4 colon cancer: evaluation of margin status. AB - BACKGROUND: Laparoscopic resection has been considered a relative contraindication for T4 colonic and rectal lesions due to concern over inadequate margins. The objective of this study was to compare planned laparoscopic and open resections of T4 lesions with respect to the positive margin rate. METHODS: Data were obtained from the American College of Surgeons National Surgical Quality Improvement Program participant use file to perform a retrospective cohort analysis. The study population consisted of patients that underwent a colorectal resection for a primary T4 lesion during 2011 and 2012. A multiple logistic regression analysis was conducted to determine the adjusted odds ratio (OR) of positive margins based on surgical approach. An inverse probability of treatment weighting (IPTW) analysis was used to account for confounding by indication. A sensitivity analysis including only "as-treated" cases was also performed. RESULTS: The sub-selected population consisted of 455 and 406 patients in the laparoscopic and open group, respectively. In the original cohort, demographic variables were similar. The open group had a higher incidence of comorbidities, metastatic disease, and emergency cases. Laparoscopic surgery was found to be no different than open surgery with respect to positive margin status (OR 1.10, p = 0.54). After IPTW adjustment, surgical approach remained a nonsignificant predictor of positive margins (OR 1.18, p = 0.31). The "as-treated" analysis also showed that surgical approach had no significant effect on the positive margin rate (OR 1.24, p = 0.24). CONCLUSIONS: Using this large national surgical database, select patients with T4 lesions who underwent planned laparoscopic colorectal resections did not have a significantly higher positive margin rate compared with patients with open operations. Further research is needed to identify the role of laparoscopy in managing T4b lesions before any consensus can be reached regarding its application in locally advanced colon cancer. PMID- 26123342 TI - Thoracic sympathectomy: a review of current indications. AB - BACKGROUND: Thoracic sympathetic ablation was introduced over a century ago. While some of the early indications have become obsolete, new ones have emerged. Sympathetic ablation is being still performed for some odd indications thus prompting the present study, which reviews the evidence base for current practice. METHODS: The literature was reviewed using the PubMed/Medline Database, and pertinent articles regarding the indications for thoracic sympathectomy were retrieved and evaluated. Old, historical articles were also reviewed as required. RESULTS AND CONCLUSIONS: Currently, thoracic sympathetic ablation is indicated mainly for primary hyperhidrosis, especially affecting the palm, and to a lesser degree, axilla and face, and for facial blushing. Despite modern pharmaceutical, endovascular and surgical treatments, sympathetic ablation has still a place in the treatment of very selected cases of angina, arrhythmias and cardiomyopathy. Thoracic sympathetic ablation is indicated in several painful conditions: the early stages of complex regional pain syndrome, erythromelalgia, and some pancreatic and other painful abdominal pathologies. Although ischaemia was historically the major indication for sympathetic ablation, its use has declined to a few selected cases of thromboangiitis obliterans (Buerger's disease), microemboli, primary Raynaud's phenomenon and Raynaud's phenomenon secondary to collagen diseases, paraneoplastic syndrome, frostbite and vibration syndrome. Thoracic sympathetic ablation for hypertension is obsolete, and direct endovascular renal sympathectomy still requires adequate clinical trials. There are rare publications of sympathetic ablation for primary phobias, but there is no scientific basis to support sympathetic surgery for any psychiatric indication. PMID- 26123345 TI - International expert consensus on endpoints for full-thickness laparoendoscopic colonic excision. AB - BACKGROUND: Full-thickness laparoendoscopic excision has been reported for complex endoscopically unresectable colonic polyps. However, the endpoints used in these studies vary significantly and therefore making definitive conclusions regarding the novel procedure would be improved if a common data set were adopted. This study sought to define most appropriate endpoints that should be measured and reported for research on full-thickness laparoendoscopic excision of colonic polyps. METHODS: A Web-based Delphi Questionnaire was developed using a systematic literature review of reported endpoints. Outcomes were grouped into general, complication, technical and histopathology endpoints. International specialists in laparoscopic surgery, endoscopy and transanal endoscopic microsurgery were invited to participate. The questionnaire required prioritization of outcomes on a 5-point Likert scale. Respondents were then sent a second questionnaire containing feedback on scores from round 1 and asked to re prioritize outcomes based on the feedback received to identify a final core outcome set. RESULTS: A total of 33 (75% response rate) participants from 11 countries completed the round 1 Delphi of 28 proposed endpoints, and all completed the second round. Eight endpoints were rated the most important to stakeholders within the four domains--reoperation (general); anastomotic leak, mortality (complications); secure closure of the excision site, macroscopic completeness of excision (technical); presence of cancer, clearance of resected margins and en bloc specimen production (histopathology). CONCLUSIONS: This study has developed a provisional consensus on a minimum number of feasible and clinically meaningful outcome measures to use in studies of full-thickness laparoendoscopic excision of colonic polyps. Widespread adoption will allow better reporting of the technique and more efficient development in clinical practice. PMID- 26123346 TI - The short-term and oncologic outcomes of laparoscopic versus open surgery for T4 colon cancer. AB - PURPOSE: To compare R0 resection rates and short-term and oncologic outcomes between laparoscopy and open surgery for T4 colon cancer. METHODS: Patients with non-metastatic T4 colon cancer (n = 117) underwent treatment either through laparoscopy (n = 51) or open surgery (n = 66). Conversion to open surgery occurred in seven cases (13.7%). RESULTS: History of abdominal surgery (2.0 vs. 12.1%) and emergency operation (2.1 vs. 24.2%) were less frequent in the laparoscopy group. Conversion to open surgery occurred in seven cases (13.7%). Resection of adjacent organs was less frequently performed in the laparoscopy group (27.5 vs. 53.0%, p = .005). The mean operative time (189 vs. 210 min) and rate of 30-day postoperative complications (12 vs. 24%) were similar between the two groups. Shorter time to soft diet (7 vs. 9 days, p = .018) and hospital stay (14 vs. 18 days, p = .044) were observed in the laparoscopy group. T4b tumor was also less frequent in the laparoscopy group (3.9 vs. 18.2%, p = .018), while R0 resection rates were similar between the laparoscopy (96.1%) and open surgery group (95.5%). The mean number of lymph nodes was 22 in the laparoscopy group and 27 in the open surgery group (p = .021). No differences in 3-year overall survival rate (82.5 vs. 75.7%), recurrence-free survival rate (61.9 vs. 63.5%), and local recurrence-free survival rate (89.8 vs. 88.5%) were observed between the groups. Operation time, blood loss, 30-day complication rate, time to diet, duration of hospital stay, R0 resection rate, 3-year overall and local recurrence free survival rates showed no difference between the converted and open surgery groups. CONCLUSIONS: Our results indicate that laparoscopy is a surgically safe and oncologically acceptable approach and thus could be considered for well selected patients with T4 colon cancer in order to allow faster short-term recovery. PMID- 26123347 TI - New alpha-pyrone and phthalide from the Xylariaceae fungus. AB - A new alpha-pyrone xylaripyrone A (1) and a new phthalide xylariphthalide A (2) were isolated from the Xylariaceae fungus (no. 63-19-7-3), along with four related known phthalides (3-6): 4-[(acetyloxy)methyl]-7-methoxy-6-methyl-1(3H) isobenzofuranone (3), convolvulol (4), 7-methoxy-4,6-dimethyl-3H-isobenzofuran-1 one (5), and convolvulanic acid B (6). Their structures were determined on the basis of IR, MS, and NMR spectroscopic analyses. PMID- 26123348 TI - Rapid identification of polystyrene foam wastes containing hexabromocyclododecane or its alternative polymeric brominated flame retardant by X-ray fluorescence spectroscopy. AB - The brominated flame retardant hexabromocyclododecane (HBCDD) was added to Annex A of the list of persistent organic pollutants (POPs) of the Stockholm Convention. Thus, production and use of HBCDD will be banned, and the recycling of HBCDD-containing foam waste will be restricted. In reaction a special polymeric brominated flame retardant (PolyFR) was developed to replace HBCDD in expanded and extruded polystyrene foams for building and construction applications. A decision has to be made at some future time whether expanded and extruded polystyrene foam waste is to be subjected to incineration (with HBCDD) or to recycling (without HBCDD). Therefore, an appropriate and rapid field method is required to distinguish between foams containing HBCDD and foams free from HBCDD. Here we present a screening method for identifying HBCDD containing expanded and extruded polystyrene foams. The test principle is based on the fact that PolyFR (a brominated polymeric macromolecule) is not extractable whereas HBCDD (a low molecular weight substance) is extractable. Following rapid extraction of HBCDD the brominated flame retardant is identified and quantified via bromine analysis using a handheld X-ray fluorescence instrument. The method was applied successfully to 27 expanded and extruded polystyrene foam samples (foams and extruded polystyrene foam raw materials), which were provided without any information about the applied flame retardant. The presence of HBCDD was confirmed for all HBCDD-positive samples in the test. A robustness test revealed a high degree of correctness and a high repeatability for the test system: samples containing HBCDD and HBCDD-free samples were identified correctly with relative standard deviations of quantitative results below 14%. Moreover, X-ray fluorescence spectroscopy test results agree well with HBCDD determinations performed in a laboratory with a gas chromatograph coupled to a flame ionisation detector. PMID- 26123349 TI - Evaluation and selection of decision-making methods to assess landfill mining projects. AB - For the first time in Austria, fundamental technological and economic studies on recovering secondary raw materials from large landfills have been carried out, based on the 'LAMIS - Landfill Mining Austria' pilot project. A main focus of the research - and the subject of this article - was to develop an assessment or decision-making procedure that allows landfill owners to thoroughly examine the feasibility of a landfill mining project in advance. Currently there are no standard procedures that would sufficiently cover all the multiple-criteria requirements. The basic structure of the multiple attribute decision making process was used to narrow down on selection, conceptual design and assessment of suitable procedures. Along with a breakdown into preliminary and main assessment, the entire foundation required was created, such as definitions of requirements to an assessment method, selection and accurate description of the various assessment criteria and classification of the target system for the present 'landfill mining' vs. 'retaining the landfill in after-care' decision-making problem. Based on these studies, cost-utility analysis and the analytical hierarchy process were selected from the range of multiple attribute decision making procedures and examined in detail. Overall, both methods have their pros and cons with regard to their use for assessing landfill mining projects. Merging these methods or connecting them with single-criteria decision-making methods (like the net present value method) may turn out to be reasonable and constitute an appropriate assessment method. PMID- 26123350 TI - [Response to the letter by Montani D. et al. regarding their comments on the article "Anti-synthetase syndrome with pulmonary hypertension: 4 original observations" by Lecomte R. et al]. PMID- 26123351 TI - Geriatric assessment findings independently associated with clinical depression in 1092 older patients with cancer: the ELCAPA Cohort Study. AB - OBJECTIVE: We aim to assess the prevalence and associated factors of clinical depression in older patients with cancer. METHODS: We studied a prospective cohort of cancer patients aged >= 70 years and referred to geriatric oncology clinics between 2007 and 2012. A multidimensional geriatric assessment was performed before choosing the cancer-treatment strategy. Clinical depression was diagnosed by senior geriatricians by a semi-structured interview. It encompassed criteria of the Diagnostic and Statistical Manual of Mental Disorders (fourth edition) and of the International Classification of Diseases (10th edition). Multivariate logistic regression was performed. RESULTS: Of 1121 consecutive patients, 1092 had available data (mean age, 80.4 years; women, 48.8%; metastases, 51.3%; cancer location: colorectal 21.1%, breast 16.8%, kidney, bladder or urinary tract 14.0%, and prostate 11.4%). The overall prevalence of clinical depression was 28.4% (95% confidence interval, 25.7-31.2). Factors independently associated with clinical depression by multivariate analysis adjusting for all following factors plus gender, and metastasis were impaired mobility (adjusted odds ratio [aOR], 2.35; 1.59-3.46), impaired functional status defined as Eastern Cooperative Oncology Group Performance Status >= 2 (aOR, 2.39; 1.66-3.43) or as activities of daily living < 6 (aOR, 2.43; 1.73-3.41), inpatient status (aOR, 1.68; 1.20-2.37), inadequate social support (aOR, 1.66; 1.16-2.37), cognitive impairment (aOR, 1.76; 1.24-2.49), polypharmacy defined as five or more non-antidepressant drugs (aOR, 1.65; 1.14-2.38), multimorbidity (aOR additional CIRS-G point , 1.08; 1.04-1.12), and cancer-related pain (aOR, 1.76; 1.26-2.46). CONCLUSION: In older patients with as-yet untreated cancer at various sites and stages, clinical depression was highly prevalent. Clinical depression was independently associated with several geriatric assessment findings (impaired mobility and function, inadequate social support, cognitive impairment, polypharmacy, and multimorbidity) independently from gender, tumor site, and metastatic status. PMID- 26123352 TI - Imaging of Cell-Cell Communication in a Vertical Orientation Reveals High Resolution Structure of Immunological Synapse and Novel PD-1 Dynamics. AB - The immunological synapse (IS) is one of the most pivotal communication strategies in immune cells. Understanding the molecular basis of the IS provides critical information regarding how immune cells mount an effective immune response. Fluorescence microscopy provides a fundamental tool to study the IS. However, current imaging techniques for studying the IS cannot sufficiently achieve high resolution in real cell-cell conjugates. In this study, we present a new device that allows for high-resolution imaging of the IS with conventional confocal microscopy in a high-throughput manner. Combining micropits and single cell trap arrays, we have developed a new microfluidic platform that allows visualization of the IS in vertically "stacked" cells. Using this vertical cell pairing (VCP) system, we investigated the dynamics of the inhibitory synapse mediated by an inhibitory receptor, programed death protein-1, and the cytotoxic synapse at the single-cell level. In addition to the technique innovation, we have demonstrated novel biological findings by this VCP device, including novel distribution of F-actin and cytolytic granules at the IS, programed death protein 1 microclusters at the NK IS, and kinetics of cytotoxicity. We propose that this high-throughput, cost-effective, easy-to-use VCP system, along with conventional imaging techniques, can be used to address a number of significant biological questions in a variety of disciplines. PMID- 26123353 TI - Adaptive Immune-like gamma/delta T Lymphocytes Share Many Common Features with Their alpha/beta T Cell Counterparts. AB - To better apprehend gamma/delta T cell biological functions in the periphery, it appears crucial to identify markers highlighting the existence of distinct phenotypic and functional gamma/delta T cell subsets. Interestingly, the expression of CD44 and Ly-6C subdivides murine peripheral gamma/delta T cells into several subsets, with Ly-6C(-) CD44(hi) gamma/delta T cells corresponding to the IL-17-producing CD27(-) gamma/delta T cell subset exhibiting innate-like features. By comparing the other subsets to naive and memory CD8(+) alpha/beta T cells, in this study, we show that Ly-6C(- or +) CD44(lo) and Ly-6C(+)CD44(hi) gamma/delta T cells greatly resemble, and behave like, their CD8(+) alpha/beta T cell counterparts. First, like memory CD8(+) alpha/beta T cells, Ly-6C(+)CD44(hi) gamma/delta T cells are sparse in the thymus but largely increased in proportion in tissues. Second, similarly to naive CD8 alpha/beta T cells, CD44(lo) gamma/delta T cells are poorly cycling in vivo in the steady state, and their proportion declines with age in secondary lymphoid organs. Third, CD44(lo) gamma/delta T cells undergo spontaneous proliferation and convert to a memory like Ly-6C(+)CD44(hi) phenotype in response to lymphopenia. Finally, CD44(lo) gamma/delta T cells have an intrinsic high plasticity as, upon appropriate stimulation, they are capable of differentiating nonetheless into Th17-like and Th1-like cells but also into fully functional Foxp3(+) induced regulatory T cell like gamma/delta T cells. Thus, peripheral CD27(+) gamma/delta T cells, commonly considered as a functionally related T cell compartment, actually share many common features with adaptive alpha/beta T cells, as both lineages include naive like and memory-like lymphocytes with distinct phenotypic, functional, and homeostatic characteristics. PMID- 26123354 TI - Human Anti-CD40 Antibody and Poly IC:LC Adjuvant Combination Induces Potent T Cell Responses in the Lung of Nonhuman Primates. AB - Nonlive vaccine platforms that induce potent cellular immune responses in mucosal tissue would have broad application for vaccines against infectious diseases and tumors. Induction of cellular immunity could be optimized by targeted activation of multiple innate and costimulatory signaling pathways, such as CD40 or TLRs. In this study, we evaluated immune activation and elicitation of T cell responses in nonhuman primates after immunization with peptide Ags adjuvanted with an agonistic anti-CD40Ab, with or without the TLR3 ligand poly IC:LC. We found that i.v. administration of the anti-CD40Ab induced rapid and transient innate activation characterized by IL-12 production and upregulated costimulatory and lymph node homing molecules on dendritic cells. Using fluorescently labeled Abs for in vivo tracking, we found that the anti-CD40Ab bound to all leukocytes, except T cells, and disseminated to multiple organs. CD4(+) and CD8(+) T cell responses were significantly enhanced when the anti-CD40Ab was coadministered with poly IC:LC compared with either adjuvant given alone and were almost exclusively compartmentalized to the lung. Notably, Ag-specific T cells in the bronchoalveolar lavage were sustained at ~5-10%. These data indicate that systemic administration of anti-CD40Ab may be particularly advantageous for vaccines and/or therapies that require T cell immunity in the lung. PMID- 26123355 TI - Opposing Roles of Dectin-1 Expressed on Human Plasmacytoid Dendritic Cells and Myeloid Dendritic Cells in Th2 Polarization. AB - Dendritic cells (DCs) can induce and control host immune responses. DC subset dependent functional specialties and their ability to display functional plasticity, which is mainly driven by signals via pattern recognition receptors, identify DCs as immune orchestrators. A pattern recognition receptor, Dectin-1, is expressed on myeloid DCs and known to play important roles in Th17 induction and activation during fungal and certain bacterial infections. In this study, we first demonstrate that human plasmacytoid DCs express Dectin-1 in both mRNA and protein levels. More interestingly, Dectin-1-activated plasmacytoid DCs promote Th2-type T cell responses, whereas Dectin-1-activated myeloid DCs decrease Th2 type T cell responses. Such contrasting outcomes of Th2-type T cell responses by the two DC subsets are mainly due to their distinct abilities to control surface OX40L expression in response to beta-glucan. This study provides new insights for the regulation of host immune responses by Dectin-1 expressed on DCs. PMID- 26123356 TI - Human Umbilical Cord Mesenchymal Stromal Cell Transplantation in Myocardial Ischemia (HUC-HEART Trial). A Study Protocol of a Phase 1/2, Controlled and Randomized Trial in Combination with Coronary Artery Bypass Grafting. AB - Mesenchymal stem cells (MSCs), which may be obtained from the bone marrow, have been studied for more than a decade in the setting of coronary artery disease (CAD). Adipose tissue-derived MSCs have recently come into focus and are being tested in a series of clinical trials. MSC-like cells have also been derived from a variety of sources, including umbilical cord stroma, or HUC-MSCs. The HUC-HEART trail (ClinicalTrials.gov Identifier: NCT02323477) is a phase 1/2, controlled, multicenter, randomized clinical study of the intramyocardial delivery of allogeneic HUC-MSCs in patients with chronic ischemic cardiomyopathy. A total of 79 patients (ages 30-80) with left ventricle ejection fractions ranging between 25 and 45% will be randomized in a 2:1:1 pattern in order to receive an intramyocardial injection of either HUC-MSCs or autologous bone marrow-derived mononuclear cells (BM-MNCs) in combination with coronary arterial bypass grafting (CABG) surgery. The control group of patients will receive no cells and undergo CABG alone. Human HUC-MSCs will be isolated, propagated and banked in accordance with a cGMP protocol, whereas the autologous BM-MNCs will be isolated via aspiration from the iliac crest and subsequently process in a closed-circuit cell purification system shortly before cell transplantation. The cell injections will be implemented in 10 peri-infarct areas. Baseline and post-transplantation outcome measures will be primarily utilized to test both the safety and the efficacy of the administered cells for up to 12 months. PMID- 26123359 TI - Clinical Presentation of Native Mitral Valve Infective Endocarditis Determines Long-Term Outcome after Surgery. AB - BACKGROUND AND AIM: Surgery is performed in up to half of all cases of active infective endocarditis (IE) but the associated mortality remains high. The aim was to examine the effect of the preoperative clinical presentation on long-term survival of patients undergoing surgery for isolated native mitral valve infective endocarditis. METHODS: A retrospective study was conducted on 100 patients who had undergone mitral valve surgery from 1998 to 2014 for ongoing isolated, native valve IE. Patients were stratified depending on preoperative symptoms: clinical stroke due to septic cerebral embolism, congestive heart failure, and uncontrolled bacteremia. Group A had none of the clinical symptoms, Group B had one of the above clinical symptoms, and Group C had >=2 symptoms. Follow-up was 100% complete for survival (median 3.8 years, IQR 0.8-7.7). Event rates were estimated with the Kaplan-Meier method and Cox-regression was performed. RESULTS: Overall 30-day mortality was 5% (n = 5); 0% in Group A; 8% in Group B (n = 4); and 8% in Group C (n = 1), p = 0.24. Five-year survival was 87.0 +/- 6.1% in Group A, 62.6 +/- 7.1% in Group B, and 33.8 +/- 15.2% in Group C. Grouping by clinical presentation was found to be an independent predictor of mortality (Group B, HR 2.37, 95% CI 1.02-5.50; Group C, HR 4.07, 95% CI 1.56 10.6). CONCLUSIONS: Long-term survival after surgery for native mitral valve IE was independently influenced by the presence of preoperative embolic stroke, congestive heart failure or uncontrolled bacteremia alone, or in combination. PMID- 26123357 TI - Stem Cells for Temporomandibular Joint Repair and Regeneration. AB - Temporomandibular Disorders (TMD) represent a heterogeneous group of musculoskeletal and neuromuscular conditions involving the temporomandibular joint (TMJ), masticatory muscles and/or associated structures. They are a major cause of non-dental orofacial pain. As a group, they are often multi-factorial in nature and have no common etiology or biological explanations. TMD can be broadly divided into masticatory muscle and TMJ disorders. TMJ disorders are characterized by intra-articular positional and/or structural abnormalities. The most common type of TMJ disorders involves displacement of the TMJ articular disc that precedes progressive degenerative changes of the joint leading to osteoarthritis (OA). In the past decade, progress made in the development of stem cell-based therapies and tissue engineering have provided alternative methods to attenuate the disease symptoms and even replace the diseased tissue in the treatment of TMJ disorders. Resident mesenchymal stem cells (MSCs) have been isolated from the synovia of TMJ, suggesting an important role in the repair and regeneration of TMJ. The seminal discovery of pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have provided promising cell sources for drug discovery, transplantation as well as for tissue engineering of TMJ condylar cartilage and disc. This review discusses the most recent advances in development of stem cell-based treatments for TMJ disorders through innovative approaches of cell-based therapeutics, tissue engineering and drug discovery. PMID- 26123358 TI - Practical Issues with the Use of Stem Cells for Cancer Gene Therapy. AB - Stem cell-based drug delivery for cancer therapy has steadily gained momentum in the past decade as several studies have reported stem cells' inherent tropism towards tumors. Since this science is still in its early stages and there are many factors that could significantly impact tumor tropism of stem cells, some contradictory results have been observed. This review starts by examining a number of proof-of-concept studies that demonstrate the potential application of stem cells in cancer therapy. Studies that illustrate stem cells' tumor tropism and discuss the technical difficulties that could impact the therapeutic outcome are also highlighted. The discussion also emphasizes stem cell imaging/tracking, as it plays a crucial role in performing reliable dose-response studies and evaluating the therapeutic outcome of treatment protocols. In each section, the pros and cons associated with each method are highlighted, limitations are underlined, and potential solutions are discussed. The overall intention is to familiarize the reader with important practical issues related to stem cell cancer tropism and in vivo tracking, underline the shortcomings, and emphasize critical factors that need to be considered for effective translation of this science into the clinic. PMID- 26123362 TI - Heparin in malignant glioma: review of preclinical studies and clinical results. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor that is invariably lethal. Novel treatments are desperately needed. In various cancers, heparin and its low molecular weight derivatives (LMWHs), commonly used for the prevention and treatment of thrombosis, have shown therapeutic potential. Here we systematically review preclinical and clinical studies of heparin and LMWHs as anti-tumor agents in GBM. Even though the number of studies is limited, there is suggestive evidence that heparin may have various effects on GBM. These effects include the inhibition of tumor growth and angiogenesis in vitro and in vivo, and the blocking of uptake of extracellular vesicles. However, heparin can also block the uptake of (potential) anti-tumor agents. Clinical studies suggest a non significant trend of prolonged survival of LMWH treated GBM patients, with some evidence of increased major bleedings. Heparin mimetics lacking anticoagulant effect are therefore a potential alternative to heparin/LMWH and are discussed as well. PMID- 26123363 TI - The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression. AB - Cell-mediated suppression of anti-tumor immunity is multifactorial in patients with cancer, and recent studies have focused on several distinct cellular agents that are associated with this phenomenon. This review will focus on the potential role of regulatory T cells (Tregs) and microglia in the suppression of cellular immunity observed in patients with glioblastoma. We discuss the ontogeny, basic biology, evidence for activity, and potential clinical options for targeting Tregs and microglia as part of immunotherapy in affected patients. PMID- 26123364 TI - Long noncoding RNA expression profiles in gut tissues constitute molecular signatures that reflect the types of microbes. AB - The gut microbiota is commonly referred to as a hidden organ due to its pivotal effects on host physiology, metabolism, nutrition and immunity. The gut microbes may be shaped by environmental and host genetic factors, and previous studies have focused on the roles of protein-coding genes. Here we show a link between long non-coding RNA (lncRNA) expression and gut microbes. By repurposing exon microarrays and comparing the lncRNA expression profiles between germ-free, conventional and different gnotobiotic mice, we revealed subgroups of lncRNAs that were specifically enriched in each condition. A nearest shrunken centroid methodology was applied to obtain lncRNA-based signatures to identify mice in different conditions. The lncRNA-based prediction model successfully identified different gnotobiotic mice from conventional and germ-free mice, and also discriminated mice harboring transplanted microbes from fecal samples of mice or zebra fishes. To achieve optimal prediction accuracy, fewer lncRNAs were required in the prediction model than protein-coding genes. Taken together, our study demonstrated the effecacy of lncRNA expression profiles in discriminating the types of microbes in the gut. These results also provide a resource of gut microbe-associated lncRNAs for the development of lncRNA biomarkers and the identification of functional lncRNAs in host-microbes interactions. PMID- 26123365 TI - New therapeutic approaches in myelodysplastic syndromes: Hypomethylating agents and lenalidomide. AB - Recent advances in the treatment of myelodysplastic syndromes have come from the use of the hypomethylating agents decitabine and azacitidine as well as the immunomodulatory drug lenalidomide. Their clinical benefit has been demonstrated by randomized phase III clinical trials, mostly in high-risk and del(5q) myelodysplastic syndromes, respectively. Neither drug, however, appears to eradicate myelodysplastic stem cells, and thus they currently do not represent curative options. Here, we review data from both clinical and translational research on those drugs to identify their molecular and cellular mechanisms of action and to delineate paths for improved treatment allocation and further therapeutic advances in myelodysplastic syndromes. PMID- 26123366 TI - Novel biological insights in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of blood cancer that accounts for about 15% of pediatric and 25% of adult acute lymphoblastic leukemia (ALL) cases. It is considered as a paradigm for the multistep nature of cancer initiation and progression. Genetic and epigenetic reprogramming events, which transform T-cell precursors into malignant T-ALL lymphoblasts, have been extensively characterized over the past decade. Despite our comprehensive understanding of the genomic landscape of human T-ALL, leukemia patients are still treated by high-dose multiagent chemotherapy, potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable acute and long-term side effects, about 15% of pediatric and 40% of adult T-ALL patients still relapse, owing to acquired therapy resistance, and present with very dismal survival perspectives. Unfortunately, the molecular mechanisms by which residual T-ALL tumor cells survive chemotherapy and act as a reservoir for leukemic progression and hematologic relapse remain poorly understood. Nevertheless, it is expected that enhanced molecular understanding of T-ALL disease biology will ultimately facilitate a targeted therapy driven approach that can reduce chemotherapy associated toxicities and improve survival of refractory T-ALL patients through personalized salvage therapy. In this review, we summarize recent biological insights into the molecular pathogenesis of T-ALL and speculate how the genetic landscape of T-ALL could trigger the development of novel therapeutic strategies for the treatment of human T-ALL. PMID- 26123367 TI - SYRA3 COST Action--Microbeam radiation therapy: Roots and prospects. AB - Microbeam radiation therapy (MRT) is an irradiation modality for therapeutic purposes which uses arrays of collimated quasi parallel microbeams, each up to 100 MUm wide, to deliver high radiation doses. Several studies have reported the extraordinary tolerance of normal tissues to MRT irradiation; conversely, MRT has been shown to be highly efficient on tumor growth control. The original and most widely developed application of MRT, yet in the preclinical phase, consists in using spatially fractionated X-ray beams issued from a synchrotron radiation source in the treatment of brain tumors. More recently, MRT has been tested in successful pioneering assays to reduce or interrupt seizures in preclinical models of epilepsy. The MRT concept has also been extended to proton therapy. The development of MRT towards its clinical implementation is presently driven by an EU-supported consortium of laboratories from 16 countries within the COST Action TD1205 (SYRA3). The results of the first SYRA3 workshop on "Radiation Therapy with Synchrotron Radiation: Achievements and Challenges" held in Krakow (Poland) during March 25-26 2014 are summarized in this issue with an overview presented in this paper. The papers reflect the multidisciplinary international activities of SYRA3. The topics covered in this focus issue include medical physics aspects, pre-clinical studies, clinical applications, and an industrial perspective; finally an outlook towards future prospects of compact sources and proton microbeams. PMID- 26123368 TI - Location of radiosensitive organs inside pediatric anthropomorphic phantoms: Data required for dosimetry. AB - PURPOSE: The aim of this study was to determine the location of radiosensitive organs in the interior of four pediatric anthropomorphic phantoms for dosimetric purposes. METHODS: Four pediatric anthropomorphic phantoms representing the average individual as newborn, 1-year-old, 5-year-old and 10-year-old child underwent head, thorax and abdomen CT scans. CT and MRI scans of all children aged 0-16 years performed during a 5-year-period in our hospital were reviewed, and 503 were found to be eligible for normal anatomy. Anterior-posterior and lateral dimensions of twelve of the above children closely matched that of the phantoms' head, thoracic and abdominal region in each four phantoms. The mid sagittal and mid-coronal planes were drawn on selected matching axial images of patients and phantoms. Multiple points outlining large radiosensitive organs in patient images were identified at each slice level and their orthogonal distances from the mid-sagittal and mid-coronal planes were measured. In small organs, the coordinates of organs' centers were similarly determined. The outlines and centers of all radiosensitive organs were reproduced using the coordinates of each organ on corresponding phantoms' transverse images. RESULTS: The locations of the following radiosensitive organs in the interior of the four phantoms was determined: brain, eye lenses, salivary glands, thyroid, lungs, heart, thymus, esophagus, breasts, adrenals, liver, spleen, kidneys, stomach, gallbladder, small bowel, pancreas, colon, ovaries, bladder, prostate, uterus and rectum. CONCLUSIONS: The production of charts of radiosensitive organs inside pediatric anthropomorphic phantoms was feasible and may provide users reliable data for positioning of dosimeters during direct organ dose measurements. PMID- 26123369 TI - Assessment and treatment of short-term and working memory impairments in stroke aphasia: a practical tutorial. AB - BACKGROUND: Aphasia following stroke refers to impairments that affect the comprehension and expression of spoken and/or written language, and co-occurring cognitive deficits are common. In this paper we focus on short-term and working memory impairments that impact on the ability to retain and manipulate auditory verbal information. Evidence from diverse paradigms (large group studies, case studies) report close links between short-term/working memory and language functioning in aphasia. This evidence leads to the hypothesis that treating such memory impairments would improve language functioning. This link has only recently been acknowledged in aphasia treatment but has not been embraced widely by clinicians. AIMS: To examine the association between language, and short-term and working memory impairments in aphasia. To describe practical ways of assessing short-term and working memory functioning that could be used in clinical practice. To discuss and critically appraise treatments of short-term and working memory reported in the literature. METHODS & PROCEDURES: Taking a translational research approach, this paper provides clinicians with current evidence from the literature and practical information on how to assess and treat short-term and working memory impairments in people with aphasia. Published treatments of short-term and/or working memory in post-stroke aphasia are discussed through a narrative review. MAIN CONTRIBUTIONS: This paper provides the following. A theoretical rationale for adopting short-term and working memory treatments in aphasia. It highlights issues in differentially diagnosing between short-term, working memory disorders and other concomitant impairments, e.g. apraxia of speech. It describes short-term and working memory assessments with practical considerations for use with people with aphasia. It also offers a description of published treatments in terms of participants, treatments and outcomes. Finally, it critically appraises the current evidence base relating to the treatment of short-term and working memory treatments. CONCLUSIONS: The links between short-term/working memory functioning and language in aphasia are generally acknowledged. These strongly indicate the need to incorporate assessment of short-term/working memory functioning for people with aphasia. While the supportive evidence for treatment is growing and appears to highlight the benefits of including short-term/working memory in aphasia treatment, the quality of the evidence in its current state is poor. However, because of the clinical needs of people with aphasia and the prevalence of short-term/working memory impairments, incorporating related treatments through practice-based evidence is advocated. PMID- 26123370 TI - Evaluation of BHV-1 antibody titer in a cattle herd against different BHV-1 strains. AB - Although modified-live multivalent vaccines, such as PregGuard GOLD and Bovi Shield Gold, have been used routinely in both beef and dairy cattle in the US, abortion and respiratory diseases still occasionally occur following vaccination. To determine whether the antibody induced by the multivalent vaccine can recognize BHV-1 isolates from aborted animals, BHV-1 antibody titer was evaluated with two isolates from abortion cases and two vaccine BHV-1 viruses. Cattle serum was collected from a dairy herd that was vaccinated annually with Bovi-Shield Gold 5 vaccine. Among the 28 cattle tested, no statistical significant difference in serum neutralization titer was observed when test virus was either vaccine virus or clinical isolates. It suggests that the BHV-1 antibody from the vaccinated cattle can recognize both the vaccine virus and clinical isolates. However, it is noticed that cows at 5 years old or older had a significantly lower BHV-1 antibody titer on average than the average of SN titer in 3 year-old cows. Similarly, cows at 5 years or older had a significantly lower BVDV antibody titer than cows at about 2 years of age. In addition, cattle vaccinated within 0 2 months had a significantly higher BHV-1 titer than those that received vaccination 6 months or greater prior to titer measurement. In contrast, cattle that received a vaccination 6 months prior had a significantly higher anti-BVDV antibody titer than those vaccinated within 1-2 months. The BVDV antibody titers remained relatively unchanged between 6 months and 1 year post-vaccination. Our study suggests little antigenic variation exists between BHV-1 disease isolates and BHV-1 of the multivalent vaccines. In addition, BHV-1 antibody titer is relatively lower at 6 months post vaccination in those tested animals. However, the BVDV antibody titer remained relatively high after 6 months from time of vaccination. PMID- 26123371 TI - Activation of persistent Streptococcus equi subspecies zooepidemicus in mares with subclinical endometritis. AB - Endometritis in horses caused by Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) may be underdiagnosed due to traditional diagnostic methods lacking sensitivity and specificity. We serendipitously identified a bacterial growth medium (bActivate) that appeared capable of inducing growth of dormant S. zooepidemicus, which subsequently allowed detection by standard diagnostics. To assess the effect of bActivate we compared its ability to activate dormant S. zooepidemicus in a group of potentially infected subfertile mares with phosphate buffered saline (PBS). All mares had to test negative for S. zooepidemicus on a low-volume uterine lavage, be negative on endometrial cytology and without clinical signs of endometritis to be included in the investigation. The mares were instilled with bActivate or PBS in the uterus. Growth of S. zooepidemicus was induced by bActivate in 64% (16/25) and PBS in 8% (1/12) of the mares, respectively (p<0.002). In vitro studies supported that some strains of S. zooepidemicus were able to form persister cells tolerating 32-times of the minimal inhibitory concentration of penicillin compared to normal growing cells. Persister cells had not acquired penicillin resistance, but seemed to tolerate the antimicrobial due to dormancy. This is, to our knowledge, the first description of controlled growth induction of dormant bacteria from a subclinical infection. Moreover we demonstrated how endometritis can origin from a reservoir of dormant bacteria residing within the endometrium, and not only as an ascending infection. Further studies should aim at determining the prevalence of dormant S. zooepidemicus, impact of activation on diagnostic and treatment efficacy, uterine health and mare fertility. PMID- 26123372 TI - Developing a Competency-based Curriculum in Basic and Clinical Pharmacology--A Delphi Study among Physicians. AB - A new curriculum is planned for the medical school at Lund University, Sweden. Pharmacology, in a broad sense, has been identified as a subject that needs to be strengthened based on needs in the healthcare system. The aim was to identify the competencies in basic and clinical pharmacology that a newly qualified physician needs. Using a modified three-round Delphi technique, 31 physicians were invited to list necessary competencies (round 1). After content analysis, these panel members classified the list by importance on two occasions (rounds 2 and 3) using a 4-point scale (4 = necessary, 3 = desirable, 2 = useful, 1 = not necessary). Competencies with the highest ranks based on necessity were retained. Thirty physicians accepted the invitation and 25 (83%) of them completed all three rounds. Round 1 resulted in 258 suggestions, which were subsequently reduced to 95 competencies. Of these 95 competencies, 40 were considered necessary by at least 75% of the panel members. The degree of consensus increased between round 2 and round 3. Using a modified Delphi technique, we identified 40 competencies that could be transferred to learning outcomes for a new curriculum in basic and clinical pharmacology at medical school. PMID- 26123374 TI - Prefrontal cortex dopamine release measured in vivo with positron emission tomography: Implications for the stimulant paradigm. AB - Experimental tasks and stimulant paradigms in combination with D2/3 emission tomography have been essential in understanding the dopamine (DA) system. However, whereas task-induced DA release is dependent on a mechanism that is largely similar throughout the brain, the DA-increasing stimulant mechanism of action changes drastically from striatum to cortex. We posit the problems that may be encountered when translating the stimulant emission tomography paradigm from striatum to PFC. After comparing the available human data on task- and stimulant-induced changes in extracellular PFC DA assessed with PET, we hypothesize that the stimulant paradigm in the PFC, even with high affinity tracers, may not completely capture the true effect of stimulants on extracellular PFC DA levels. Task-induced and stimulant-induced effects on extracellular PFC DA measured with emission tomography should therefore be regarded as different phenomena. We conclude with future directions and alternative probes to measure PFC DA transmission with emission tomography. PMID- 26123373 TI - Re-examining overlap between tactile and visual motion responses within hMT+ and STS. AB - Here, we examine overlap between tactile and visual motion BOLD responses within the human MT+ complex. Although several studies have reported tactile responses overlapping with hMT+, many used group average analyses, leaving it unclear whether these responses were restricted to subregions of hMT+. Moreover, previous studies either employed a tactile task or passive stimulation, leaving it unclear whether or not tactile responses in hMT+ are simply the consequence of visual imagery. Here, we carried out a replication of one of the classic papers finding tactile responses in hMT+. We mapped MT and MST in individual subjects using visual field localizers. We then examined responses to tactile motion on the arm, either presented passively or in the presence of a visual task performed at fixation designed to minimize visualization of the concurrent tactile stimulation. To our surprise, without a visual task, we found only weak tactile motion responses in MT (6% of voxels showing tactile responses) and MST (2% of voxels). With an unrelated visual task designed to withdraw attention from the tactile modality, responses in MST were reduced to almost nothing (<1% regions). Consistent with previous results, we did observe tactile responses in STS regions superior and anterior to hMT+. Despite the lack of individual overlap, group averaged responses produced strong spurious overlap between tactile and visual motion responses within hMT+ that resembled those observed in previous studies. The weak nature of tactile responses in hMT+ (and their abolition by withdrawal of attention) suggests that hMT+ may not serve as a supramodal motion processing module. PMID- 26123375 TI - Neuroanatomical correlates of the sense of control: Gray and white matter volumes associated with an internal locus of control. AB - A belief that effort is rewarded can develop incentive, achievement motivation, and self-efficacy. Individuals with such a belief attribute causes of events to themselves, not to external, uncontrollable factors, and are thus said to have an internal locus of control. An internal locus of control is a positive personality trait and has been thoroughly studied in applied psychology, but has not been widely examined in neuroscience. In the present study, correlations between locus of control assessment scores and brain volumes were examined in 777 healthy young adults using magnetic resonance imaging. A whole-brain multiple regression analysis with corrections for the effects of age, gender, and intelligence was conducted. Voxel-based morphometry analyses revealed that gray matter volumes in the anterior cingulate cortex, striatum, and anterior insula positively correlated with higher scores, which indicate an internal LOC. In addition, white matter volumes in the striatum showed significant correlations with an internal locus of control. These results suggest that cognitive, socioemotional, self regulatory, and reward systems might be associated with internal control orientation. The finding of greater volumes in several brain regions in individuals with a stronger internal locus of control indicates that there is a neuroanatomical basis for the belief that one's efforts are rewarded. PMID- 26123378 TI - Neural underpinnings of nocebo hyperalgesia in visceral pain: A fMRI study in healthy volunteers. AB - Despite the clinical relevance of nocebo effects, few studies have addressed their underlying neural mechanisms in clinically-relevant pain models. We aimed to address the contribution of nocebo effects and their underlying neural circuitry to central pain amplification in visceral pain, as it may develop over repeated painful experiences due to negative pain-related expectations. Healthy volunteers received verbal suggestions of pain sensitization (nocebo group, N=28) or neutral instructions (control group, N=16). fMRI was used to investigate changes in neural responses during cued pain anticipation and painful rectal distensions delivered in successive fMRI sessions. Pain intensity was rated trial by-trial, and expected pain intensity, state anxiety and tension were assessed prior to each session. Behavioral analyses demonstrated significantly greater increases in both expected and perceived pain in the nocebo group. The fMRI analysis performed on nocebo-responders only (N=14) revealed that these behavioral changes were associated with increased activation within the secondary somatosensory cortex and amygdala during pain anticipation and within the thalamus, insula and amygdala during painful stimulation when compared to controls. A subsequent psycho-physiological interaction analysis of the pain phase showed increased functional connectivity between the anterior insula, which was set-up as seed region based on group results, and midcingulate cortex as a function of negative expectations. These findings support that negative pain related expectations can play a crucial role in pain amplification of visceral pain, which is mediated, at least in part, by a neural up-regulation of pain associated areas and their connectivity. These findings may have implications for the pathophysiology and treatment of chronic abdominal pain. PMID- 26123377 TI - Development of the human fetal hippocampal formation during early second trimester. AB - Development of the fetal hippocampal formation has been difficult to fully describe because of rapid changes in its shape during the fetal period. The aims of this study were to: (1) segment the fetal hippocampal formation using 7.0 T MR images from 41 specimens with gestational ages ranging from 14 to 22 weeks and (2) reveal the developmental course of the fetal hippocampal formation using volume and shape analyses. Differences in hemispheric volume were observed, with the right hippocampi being larger than the left. Absolute volume changes showed a linear increase, while relative volume changes demonstrated an inverted-U shape trend during this period. Together these exhibited a variable developmental rate among different regions of the fetal brain. Different sub-regional growth of the fetal hippocampal formation was specifically observed using shape analysis. The fetal hippocampal formation possessed a prominent medial-lateral bidirectional shape growth pattern during its rotation process. Our results provide additional insight into 3D hippocampal morphology in the assessment of fetal brain development and can be used as a reference for future hippocampal studies. PMID- 26123379 TI - Brain networks underlying bistable perception. AB - Bistable stimuli, such as the Necker Cube, demonstrate that experience can change in the absence of changes in the environment. Such phenomena can be used to assess stimulus-independent aspects of conscious experience. The current study used resting state functional magnetic resonance imaging (rs-fMRI) to index stimulus-independent changes in neural activity to understand the neural architecture that determines dominance durations during bistable perception (using binocular rivalry and Necker cube stimuli). Anterior regions of the Superior Parietal Lobule (SPL) exhibited robust connectivity with regions of primary sensorimotor cortex. The strength of this region's connectivity with the striatum predicted shorter dominance durations during binocular rivalry, whereas its connectivity to pre-motor cortex predicted longer dominance durations for the Necker Cube. Posterior regions of the SPL, on the other hand, were coupled to associative cortex in the temporal and frontal lobes. The posterior SPL's connectivity to the temporal lobe predicted longer dominance during binocular rivalry. In conjunction with prior work, these data suggest that the anterior SPL contributes to perceptual rivalry through the inhibition of incongruent bottom up information, whereas the posterior SPL influences rivalry by supporting the current interpretation of a bistable stimulus. Our data suggests that the functional connectivity of the SPL with regions of sensory, motor, and associative cortex allows it to regulate the interpretation of the environment that forms the focus of conscious attention at a specific moment in time. PMID- 26123376 TI - Psychosocial versus physiological stress - Meta-analyses on deactivations and activations of the neural correlates of stress reactions. AB - Stress is present in everyday life in various forms and situations. Two stressors frequently investigated are physiological and psychosocial stress. Besides similar subjective and hormonal responses, it has been suggested that they also share common neural substrates. The current study used activation-likelihood estimation meta-analysis to test this assumption by integrating results of previous neuroimaging studies on stress processing. Reported results are cluster level FWE corrected. The inferior frontal gyrus (IFG) and the anterior insula (AI) were the only regions that demonstrated overlapping activation for both stressors. Analysis of physiological stress showed consistent activation of cognitive and affective components of pain processing such as the insula, striatum, or the middle cingulate cortex. Contrarily, analysis across psychosocial stress revealed consistent activation of the right superior temporal gyrus and deactivation of the striatum. Notably, parts of the striatum appeared to be functionally specified: the dorsal striatum was activated in physiological stress, whereas the ventral striatum was deactivated in psychosocial stress. Additional functional connectivity and decoding analyses further characterized this functional heterogeneity and revealed higher associations of the dorsal striatum with motor regions and of the ventral striatum with reward processing. Based on our meta-analytic approach, activation of the IFG and the AI seems to indicate a global neural stress reaction. While physiological stress activates a motoric fight-or-flight reaction, during psychosocial stress attention is shifted towards emotion regulation and goal-directed behavior, and reward processing is reduced. Our results show the significance of differentiating physiological and psychosocial stress in neural engagement. Furthermore, the assessment of deactivations in addition to activations in stress research is highly recommended. PMID- 26123380 TI - Cortical kinematic processing of executed and observed goal-directed hand actions. AB - Motor information conveyed by viewing the kinematics of an agent's action helps to predict how the action will unfold. Still, how observed movement kinematics is processed in the brain remains to be clarified. Here, we used magnetoencephalography (MEG) to determine at which frequency and where in the brain, the neural activity is coupled with the kinematics of executed and observed motor actions. Whole-scalp MEG signals were recorded from 11 right handed healthy adults while they were executing (Self) or observing (Other) similar goal-directed hand actions performed by an actor placed in front of them. Actions consisted of pinching with the right hand green foam-made pieces mixed in a heap with pieces of other colors placed on a table, and put them in a plastic pot on the right side of the heap. Subjects' and actor's forefinger movements were monitored with an accelerometer. The coherence between movement acceleration and MEG signals was computed at the sensor level. Then, cortical sources coherent with movement acceleration were identified with Dynamic Imaging of Coherent Sources. Statistically significant sensor-level coherence peaked at the movement frequency (F0) and its first harmonic (F1) in both movement conditions. Apart from visual cortices, statistically significant local maxima of coherence were observed in the right posterior superior temporal gyrus (F0), bilateral superior parietal lobule (F0 or F1) and primary sensorimotor cortex (F0 or F1) in both movement conditions. These results suggest that observing others' actions engages the viewer's brain in a similar kinematic-related manner as during own action execution. These findings bring new insights into how human brain activity covaries with essential features of observed movements of others. PMID- 26123381 TI - Degree centrality and fractional amplitude of low-frequency oscillations associated with Stroop interference. AB - Stroop paradigms are commonly used as an index of attention deficits and a tool for investigating functions of the frontal lobes and other associated structures. Here we investigated the correlation between resting-state functional magnetic imaging (fMRI) measures [degree centrality (DC)/fractional amplitude of low frequency fluctuations (fALFFs)] and Stroop interference. We examined this relationship in the brains of 958 healthy young adults. DC reflects the number of instantaneous functional connections between a region and the rest of the brain within the entire connectivity matrix of the brain (connectome), and thus how much of the node influences the entire brain areas, while fALFF is an indicator of the intensity of regional brain spontaneous activity. Reduced Stroop interference was associated with larger DC in the left lateral prefrontal cortex, left IFJ, and left inferior parietal lobule as well as larger fALFF in the areas of the dorsal attention network and the precuneus. These findings suggest that Stroop performance is reflected in resting state functional properties of these areas and the network. In addition, default brain activity of the dorsal attention network and precuneus as well as higher cognitive processes represented there, and default stronger global influence of the areas critical in executive functioning underlie better Stroop performance. PMID- 26123382 TI - Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it. AB - Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors (PNETs) can be functional, hormone secreting tumors, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNETs, usually present later either incidentally or due to tumor bulk symptoms. Currently Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is the most promising drug for patients with unresectable, metastatic disease, in progressive well-differentiated PNETs and many studies are ongoing to demonstrate its effects on the other neuroendocrine histotipes. Food and Drug Administration (FDA) and European Medicines Agency (EMA) registered Everolimus in advanced/metastatic breast cancer, in advanced/metastatic renal cell carcinoma and in well/moderately differentiated pancreatic neuroendocrine tumors. Nevertheless only a subset of patients respond to the therapy due to the development of drug resistance. Thus the powerful Everolimus antitumor activity have prompted extensive efforts to overcome drug resistance and to maximize clinical benefit. In this review we aim to summarize current knowledge on mechanisms of Everolimus and other mTOR inhibitors molecules resistance with the intent to overcome it. PMID- 26123383 TI - Metastases of pancreatic adenocarcinoma: A systematic review of literature and a new functional concept. AB - INTRODUCTION: Pancreatic cancer, especially Pancreatic Adenocarcinoma, is still associated with a high mortality and morbidity for affected patients notwithstanding considerable progresses in diagnosis and both surgical pharmacological therapy. Despite metastases from colorectal, gastric and neuroendocrine primary tumor and their treatment are widely reported, the literature has been rarely investigated the impact of localization and numbers of pancreatic metastases. This study performed a systematic analysis of the most recent scientific literature on the natural history of Pancreatic Adenocarcinoma focusing attention on the role that the "M" parameter has on a possible prognostic stratification of these patients. MATERIAL AND METHODS: PubMed and Science Direct databases were searched for relevant articles on these issue. RESULTS: Initial database searches yielded 7231 studies from PubMed and 29101 from Science Direct. We evaluated 1031 eligible full text articles. CONCLUSIONS: An updated insight into the world of Pancreatic Tumors might help physicians in better evaluating mechanisms of metastases, patients selection and survival and in programming appropriate interventions to modify the worst outcomes of advanced disease. PMID- 26123384 TI - The effect of 0.9% saline versus plasmalyte on coagulation in patients undergoing lumbar spinal surgery; a randomized controlled trial. AB - INTRODUCTION: In multi-level lumbar spinal fusion surgery yielding a large amount of blood loss, choice of fluid for volume resuscitation is an important issue since it can influence acid-base status, coagulation, and patients' outcome. This study compared the effect of plasmalyte to 0.9% saline on coagulation assessed by rotation thromboelastometry (ROTEM) and acid-base balance in the aforementioned patients. METHODS: Fifty patients were randomly allocated to receive either 0.9% saline or plasmalyte during operation and until postoperative 12 h. ROTEM was performed at 10 min after anesthetic induction and end of surgery. Arterial blood gas analyses were serially performed from 10 min after anesthetic induction until postoperative 12 h. Fluid balance, blood loss, and transfusion requirement were assessed. RESULTS: ROTEM variables showed sporadic deterioration in both groups after surgery without intergroup differences. Intraoperatively, arterial pH, base excess, and bicarbonate concentrations were lower and serum chloride concentrations were higher in the 0.9% saline group compared with the plasmalyte group. The differences in base excess and bicarbonate concentrations persisted until postoperative 12 h. Fluid balance, blood loss, and transfusion requirement were similar between the groups while urine output was greater in the plasmalyte group compared with the 0.9% saline group (3.2 +/- 1.6 ml/kg/h vs. 1.8 +/- 1.1 ml/kg/h, p = 0.001). CONCLUSION: In contrast to plasmalyte, fluid therapy with 0.9% saline resulted in transient hyperchloremic acidosis in patients undergoing multi-level lumbar spinal fusion, while coagulation assessed by ROTEM analysis and the amount of blood loss were similar between the groups. PMID- 26123385 TI - Electrochemotherapy as a new approach on pancreatic cancer and on liver metastases. AB - Electrochemotherapy is a local non-thermal treatment for cancer ablation. Currently, many studies and case report have investigated the differences in effectiveness of electrochemotherapy with respect to tumor type, chemotherapeutic drug, and route of drug administration. ESOPE trial validated standard operating procedures [SOP] for ECT using the Cliniporator device and demonstrated that ECT is a simple, highly efficacious, and cost-effective treatment of cutaneous and subcutaneous nodules from different primary tumors for cutaneous or superficial lesions. This review has the purpose to summarize current knowledge about clinical effectiveness of electrochemotherapy and future prospects regarding its use on pancreatic cancer and liver metastasis not only. PMID- 26123386 TI - Pancreatic cancer and diabetes: A two-way relationship in the perspective of diabetologist. AB - Diabetes is a risk factor for pancreatic cancer as roughly half of all patients with pancreatic cancer are found to have diabetes at time of diagnosis. Moreover, an around 2-fold risk of pancreatic malignancy in diabetic patients has even be recently resulted from two meta-analysis. Actually, there is a bidirectional association between the two entities that implies a complex and reverse causality. In fact, while the risk for pancreatic cancer is modestly but significantly increased in patients with long-standing diabetes, recent-onset diabetes appears to be very frequently associated with pancreatic malignancy. Therefore, diabetes could serve as an excellent clue for early detection of pancreatic cancer. Moreover, recent epidemiological findings support the hypothesis that chronic exposure to hyperglycemia, higher insulin concentrations, and insulin resistance may be responsible for the enhanced risk of developing pancreatic cancer. Epidemiological data suggest that the type of anti-diabetic therapy may affect the risk of developing pancreatic cancer. In particular, metformin has been shown to reduce the risk of pancreatic cancer, as well as several other malignancies. On the other hand, some hypoglycemic agents could determine an increase of pancreatic cancer risk. These last findings were not confirmed. Finally, pancreatic cancer necessitates of a multidisciplinary management, primarily including surgeons and oncologists. In this context, the diabetologist plays an important role, given that his actions may influence the prevention and early diagnosis of pancreatic cancer, the perioperative complications associated to glycemic derangement, as well as the proper treatment of postpancreactomy diabetes. PMID- 26123387 TI - Laparoscopic pancreatectomy: Did the indications change? A review from literature. AB - Pancreatic Cancer (PC) is the fourth cause of death for tumors in Western countries. Symptoms are not specific, and can vary according to the tumor size and place. Diagnostic workup includes CA 19-9, CT and MRI. Surgery is the only treatment for PC, associated to radio-chemo therapy. Laparoscopic approaches are actually used for PC treatment in few specialized centers, and could be an alternative to laparotomic surgery. The aim of our study is to evaluate the efficacy of laparoscopy for PC treatment compared to laparotomy. We reviewed 19 articles in literature to assess the feasibility and efficacy of Laparoscopic Distal Pancreatectomy (LDP) and Laparoscopic Pancreaticoduodenectomy (LPD). The results have shown that LDP is nowadays a safe technique, and the outcomes are comparable to laparotomic surgery. Regarding to LPD instead, results are controversial and the data are still not sufficient to consider this technique as a valid alternative to laparotomic surgery. PMID- 26123388 TI - Enhanced stress response by a bilateral feet compared to a unilateral hand Cold Pressor Test. AB - The Cold Pressor Test (CPT) is a frequently employed laboratory stress protocol. However, with many experimental designs the application in its classic form (immersion of the dominant hand into ice-water) is problematic as unilateral stimulation may need to be avoided and/or hands are required for further measurements. Here, we describe a simple modification of the classic CPT in which both feet are immersed into ice-water and compare the evoked neuroendocrine stress response to the classic CPT in a within-subjects design. Twenty-four healthy participants were exposed to each of both CPT versions on two subsequent days in randomized order. Heart rate, blood pressure, salivary alpha-amylase and cortisol were measured at baseline and during or after CPT exposition, respectively, along with subjective ratings of pain and stress. The bilateral feet CPT induced marked increases in all measured stress parameters. Moreover, with the exception of blood pressure, autonomic and endocrine responses were enhanced compared to the classic CPT. The bilateral feet CPT thus is a valid and simple modification and may be useful when the application of the classic CPT is unfeasible or a stronger neuroendocrine stress response is of interest. PMID- 26123389 TI - A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden. AB - In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events. PMID- 26123391 TI - Multiple allosteric effectors control the affinity of DasR for its target sites. AB - The global transcriptional regulator DasR connects N-acetylglucosamine (GlcNAc) utilization to the onset of morphological and chemical differentiation in the model actinomycete Streptomyces coelicolor. Previous work revealed that glucosamine-6-phosphate (GlcN-6P) acts as an allosteric effector which disables binding by DasR to its operator sites (called dre, for DasR responsive element) and allows derepression of DasR-controlled/GlcNAc-dependent genes. To unveil the mechanism by which DasR controls S. coelicolor development, we performed a series of electromobility shift assays with histidine-tagged DasR protein, which suggested that N-acetylglucosamine-6-phosphate (GlcNAc-6P) could also inhibit the formation of DasR-dre complexes and perhaps even more efficiently than GlcN-6P. The possibility that GlcNAc-6P is indeed an efficient allosteric effector of DasR was further confirmed by the high and constitutive activity of the DasR-repressed nagKA promoter in the nagA mutant, which lacks GlcNAc-6P deaminase activity and therefore accumulates GlcNAc-6P. In addition, we also observed that high concentrations of organic or inorganic phosphate enhanced binding of DasR to its recognition site, suggesting that the metabolic status of the cell could determine the selectivity of DasR in vivo, and hence its effect on the expression of its regulon. PMID- 26123390 TI - Sparse temporally dynamic resting-state functional connectivity networks for early MCI identification. AB - In conventional resting-state functional MRI (R-fMRI) analysis, functional connectivity is assumed to be temporally stationary, overlooking neural activities or interactions that may happen within the scan duration. Dynamic changes of neural interactions can be reflected by variations of topology and correlation strength in temporally correlated functional connectivity networks. These connectivity networks may potentially capture subtle yet short neural connectivity disruptions induced by disease pathologies. Accordingly, we are motivated to utilize disrupted temporal network properties for improving control patient classification performance. Specifically, a sliding window approach is firstly employed to generate a sequence of overlapping R-fMRI sub-series. Based on these sub-series, sliding window correlations, which characterize the neural interactions between brain regions, are then computed to construct a series of temporal networks. Individual estimation of these temporal networks using conventional network construction approaches fails to take into consideration intrinsic temporal smoothness among successive overlapping R-fMRI sub-series. To preserve temporal smoothness of R-fMRI sub-series, we suggest to jointly estimate the temporal networks by maximizing a penalized log likelihood using a fused sparse learning algorithm. This sparse learning algorithm encourages temporally correlated networks to have similar network topology and correlation strengths. We design a disease identification framework based on the estimated temporal networks, and group level network property differences and classification results demonstrate the importance of including temporally dynamic R-fMRI scan information to improve diagnosis accuracy of mild cognitive impairment patients. PMID- 26123392 TI - Inhibition of SH2-domain-containing inositol 5-phosphatase (SHIP2) ameliorates palmitate induced-apoptosis through regulating Akt/FOXO1 pathway and ROS production in HepG2 cells. AB - The serine-threonine kinase Akt regulates proliferation and survival by phosphorylating a network of protein substrates; however, the role of a negative regulator of the Akt pathway, the SH2-domain-containing inositol 5-phosphatase (SHIP2) in apoptosis of the hepatocytes, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to apoptosis using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to palmitate (0.5 mM). Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) significantly reduced palmitate-induced apoptosis in HepG2 cells, as these cells had increased cell viability, decreased apoptotic cell death and reduced the activity of caspase-3, cytochrome c and poly (ADP-ribose) polymerase. Overexpression of the wild-type SHIP2 gene led to a massive apoptosis in HepG2 cells. The protection from palmitate-induced apoptosis by SHIP2 inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). In addition, SHIP2 inhibition was accompanied by an increased Akt and FOXO-1 phosphorylation, whereas overexpression of the wild-type SHIP2 gene had the opposite effects. Taken together, these findings suggest that SHIP2 expression level is an important determinant of hepatic lipoapotosis and its inhibition can potentially be a target in treatment of hepatic lipoapoptosis in diabetic patients. PMID- 26123393 TI - CSP41b, a protein identified via FOX hunting using Eutrema salsugineum cDNAs, improves heat and salinity stress tolerance in transgenic Arabidopsis thaliana. AB - Eutrema salsugineum (also known as Thellungiella salsuginea and formerly Thellungiella halophila), a species closely related to Arabidopsis thaliana, shows tolerance not only to salt stress, but also to chilling, freezing, and high temperatures. To identify genes responsible for stress tolerance, we conducted Full-length cDNA Over-eXpressing gene (FOX) hunting among a collection of E. salsugineum cDNAs that were stress-induced according to gene ontology analysis or over-expressed in E. salsugineum compared with A. thaliana. We identified E. salsugineum CSP41b (chloroplast stem-loop-binding protein of 41 kDa; also known as CRB, chloroplast RNA binding; named here as EsCSP41b) as a gene that can confer heat and salinity stress tolerance on A. thaliana. A. thaliana CSP41b is reported to play an important role in the proper functioning of the chloroplast: the atcsp41b mutant is smaller and paler than wild-type plants and shows altered chloroplast morphology and photosynthetic performance. We observed that AtCSP41b overexpressing transgenic A. thaliana lines also exhibited marked heat tolerance and significant salinity stress tolerance. The EsCSP41b-overexpressing transgenic A. thaliana lines showed significantly higher photosynthesis activity than wild type plants not only under normal growth conditions but also under heat stress. In wild-type plants, the expression levels of both EsCSP41b and AtCSP41b were significantly reduced under heat or salinity stress. We conclude that maintenance of CSP41b expression under abiotic stresses may alleviate photoinhibition and improve survival under such stresses. PMID- 26123394 TI - Cues from chewing insects - the intersection of DAMPs, HAMPs, MAMPs and effectors. AB - Chewing herbivores cause massive damage when crushing plant tissues with their mandibles, thus releasing a vast array of cues that may be perceived by the plant to mobilize defenses. Besides releasing damage cues in wounded tissues, herbivores deposit abundant cues from their saliva, regurgitant and feces that trigger herbivore specific responses in plants. Herbivores can manipulate the perception mechanisms and defense signals to suppress plant defenses by secreting effectors and/or by exploiting their associated oral microbes. Recent studies indicate that both the composition of herbivore cues and the plant's ability to recognize them are highly dependent upon the specific plant-herbivore system. There is a growing amount of work on identifying herbivore elicitors and effectors, but the most significant bottleneck in the discipline is the identification and characterization of plant receptors that perceive these herbivore-specific cues. PMID- 26123396 TI - Tracing the evolutionary path to nitrogen-fixing crops. AB - Nitrogen-fixing symbioses between plants and bacteria are restricted to a few plant lineages. The plant partner benefits from these associations by gaining access to the pool of atmospheric nitrogen. By contrast, other plant species, including all cereals, rely only on the scarce nitrogen present in the soil and what they can glean from associative bacteria. Global cereal yields from conventional agriculture are dependent on the application of massive levels of chemical fertilisers. Engineering nitrogen-fixing symbioses into cereal crops could in part mitigate the economic and ecological impacts caused by the overuse of fertilisers and provide better global parity in crop yields. Comparative phylogenetics and phylogenomics are powerful tools to identify genetic and genomic innovations behind key plant traits. In this review we highlight recent discoveries made using such approaches and we discuss how these approaches could be used to help direct the engineering of nitrogen-fixing symbioses into cereals. PMID- 26123395 TI - Small RNAs--the secret agents in the plant-pathogen interactions. AB - Eukaryotic regulatory small RNAs (sRNAs) that induce RNA interference (RNAi) are involved in a plethora of biological processes, including host immunity and pathogen virulence. In plants, diverse classes of sRNAs contribute to the regulation of host innate immunity. These immune-regulatory sRNAs operate through distinct RNAi pathways that trigger transcriptional or post-transcriptional gene silencing. Similarly, many pathogen-derived sRNAs also regulate pathogen virulence. Remarkably, the influence of regulatory sRNAs is not limited to the individual organism in which they are generated. It can sometimes extend to interacting species from even different kingdoms. There they trigger gene silencing in the interacting organism, a phenomenon called cross-kingdom RNAi. This is exhibited in advanced pathogens and parasites that produce sRNAs to suppress host immunity. Conversely, in host-induced gene silencing (HIGS), diverse plants are engineered to trigger RNAi against pathogens and pests to confer host resistance. Cross-kingdom RNAi opens up a vastly unexplored area of research on mobile sRNAs in the battlefield between hosts and pathogens. PMID- 26123397 TI - Molecular hydrogen: A novel therapy for the treatment of pulmonary hypertension. PMID- 26123399 TI - Structural, mechanical, and electronic properties of Rh2B and RhB2: first principles calculations. AB - The crystal structures of Rh2B and RhB2 at ambient pressure were explored by using the evolutionary methodology. A monoclinic P21/m structure of Rh2B was predicted and donated as Rh2B-I, which is energetically much superior to the previously experimentally proposed Pnma structure. At the pressure of about 39 GPa, the P21/m phase of Rh2B transforms to the C2/m phases. For RhB2, a new monoclinic P21/m phase was predicted, named as RhB2-II, it has the same structure type with Rh2B. Rh2B-I and RhB2-II are both mechanically and dynamically stable. They are potential low compressible materials. The analysis of electronic density of states and chemical bonding indicates that the formation of strong and directional covalent B-B and Rh-B bonds in these compounds contribute greatly to their stabilities and high incompressibility. PMID- 26123400 TI - Direct dynamic measurement of intracellular and extracellular lactate in small volume cell suspensions with (13)C hyperpolarised NMR. AB - Hyperpolarised (HP) (13)C NMR allows enzymatic activity to be probed in real time in live biological systems. The use of in vitro models gives excellent control of the cellular environment, crucial in the understanding of enzyme kinetics. The increased conversion of pyruvate to lactate in cancer cells has been well studied with HP (13)C NMR. Unfortunately, the equally important metabolic step of lactate transport out of the cell remains undetected, because intracellular and extracellular lactate are measured as a single resonance. Furthermore, typical experiments must be performed using tens of millions of cells, a large amount which can lead to a costly and sometimes highly challenging growing procedure. We present a relatively simple set-up that requires as little as two million cells with the spectral resolution to separate the intracellular and extracellular lactate resonances. The set-up is tested with suspensions of prostate cancer carcinoma cells (PC3) in combination with HP [1-(13)C]pyruvate. We obtained reproducible pyruvate to lactate label fluxes of 1.2 and 1.7 nmol/s per million cells at 2.5 and 5.0 mM pyruvate concentrations. The existence of a 3-Hz chemical shift difference between intracellular and extracellular lactate enabled us to determine the lactate transport rates in PC3. We deduced a lactate export rate of 0.3 s(-1) and observed a decrease in lactate transport on addition of the lactate transport inhibitor alpha-cyano-4-hydroxycinnamic acid. PMID- 26123398 TI - Early emergence of Yersinia pestis as a severe respiratory pathogen. AB - Yersinia pestis causes the fatal respiratory disease pneumonic plague. Y. pestis recently evolved from the gastrointestinal pathogen Y. pseudotuberculosis; however, it is not known at what point Y. pestis gained the ability to induce a fulminant pneumonia. Here we show that the acquisition of a single gene encoding the protease Pla was sufficient for the most ancestral, deeply rooted strains of Y. pestis to cause pneumonic plague, indicating that Y. pestis was primed to infect the lungs at a very early stage in its evolution. As Y. pestis further evolved, modern strains acquired a single amino-acid modification within Pla that optimizes protease activity. While this modification is unnecessary to cause pneumonic plague, the substitution is instead needed to efficiently induce the invasive infection associated with bubonic plague. These findings indicate that Y. pestis was capable of causing pneumonic plague before it evolved to optimally cause invasive infections in mammals. PMID- 26123401 TI - Lack of association between leptin, leptin receptor, adiponectin gene polymorphisms and epicardial adipose tissue, abdominal visceral fat volume and atherosclerotic burden in psoriasis patients. AB - CONTEXT: Identifying psoriasis patients who present a higher risk of developing cardiovascular co-morbidities is of upmost importance. Two key adipokines, leptin and adiponectin, may play a role connecting psoriasis and its major co morbidities. OBJECTIVE: To evaluate the potential contribution of LEPrs2167270(19 G/A), LEPRrs1137100(326 A/G) and ADIPOQrs1501299(276 G/T) gene polymorphisms in psoriasis susceptibility and their influence in epicardial adipose tissue and abdominal visceral fat volume and subclinical atherosclerosis in severe psoriasis patients. MATERIALS AND METHODS: One hundred severe psoriasis patients underwent clinical and laboratory evaluation, DNA genotyping and multi-detector computed tomography scan for epicardial adipose tissue, abdominal visceral fat and coronary artery calcification assessment. DNA control group was obtained from a previously anonymized biobank of 206 adult subjects without psoriasis. RESULTS: No association was observed between the studied gene polymorphisms and psoriasis susceptibility, CAC or increased EAT or AVF volume. DISCUSSION AND CONCLUSION: The studied polymorphisms do not seem, at least in this cohort of patients, to be a genetic risk factor for the development of atherosclerosis or increased adiposity in psoriasis. PMID- 26123403 TI - The recording of Aboriginal and Torres Strait Islander status in general practice clinical records: a cross-sectional study. AB - OBJECTIVES: To document the frequency of recording of Aboriginal and Torres Strait Islander status in general practice (GP) clinical records and to establish associations of this recording. METHODS: Cross-sectional analysis of recording of patients' Aboriginal and Torres Strait Islander status in GP clinical records from GP training practices in four Australian states. RESULTS: Of the 9,704 clinical records examined, the patients' Aboriginal and Torres Strait Islander status had been documented in 5,165 (53.2%). Higher rates of recording were associated with older patient age, practices outside a major city, patients who were not new to the practice and the patient being Aboriginal and Torres Strait Islander. In encounters with Aboriginal and Torres Strait Islander patients, the patient's status had been documented in 82% of records. Those attending larger practices were less likely to have had their status recorded. CONCLUSIONS: This is the first report of Aboriginal and Torres Strait Islander status recording in GP clinical records. Almost 20% of Aboriginal and Torres Strait Islander patients did not have their status recorded in the clinical record, with indications that recording may be unsystematic. IMPLICATIONS: Our findings reinforce the need for a systematic approach to identification of Aboriginal and Torres Strait Islander status in general practice and will inform policy and practice in this important area. PMID- 26123404 TI - Conceptual, self-assembling graphene nanocontainers. AB - We show that graphene nano-sheets, when appropriately functionalised, can form self-assembling nanocontainers which may be opened or closed using a chemical trigger such as pH or polarity of solvent. Conceptual design rules are presented for different container structures, whose ability to form and encapsulate guest molecules is verified by molecular dynamics simulations. The structural simplicity of the graphene nanocontainers offers considerable scope for scaling the capacity, modulating the nature of the internal environment, and defining the trigger for encapsulation or release of the guest molecule(s). This design study will serve to provide additional impetus to developing synthetic approaches for selective functionalisation of graphene. PMID- 26123402 TI - Sequential Therapy for Helicobacter pylori Infection in Treatment-naive Children. AB - The goal of first-line Helicobacter pylori therapy is to reach an eradication rate of 90% to avoid further investigations, antibiotic use, and spreading of resistant strains. AIM: To evaluate the eradication rate of high-dose sequential therapy in treatment-naive children and to assess factors associated with failure. METHODS: Prospective data assessed in a registry from nine European centers between October 2009 and December 2011. Children with biopsy-proven Helicobacter pylori infection were prescribed 5 days of esomeprazole and amoxicillin, followed by 5 days of esomeprazole, clarithromycin, and metronidazole according to bodyweight. Eradication was assessed after 8-12 weeks. Primary endpoint was the eradication rate in children who received at least one dose and had follow-up data. Multivariate analysis evaluated potential factors for treatment success including sex, age, center, migrant status, antibiotic resistance, and adherence to therapy. RESULTS: Follow-up was available in 209 of 232 patients (age range 3.1-17.9 years, 118 females). Primary resistance occurred for clarithromycin in 30 of 209 (14.4%), for metronidazole in 32 (15.3%), for both antibiotics in 7 (3.3%), and culture failed in 6 (2.9%). Eradication was achieved in 168 of 209 children (80.4%, 95% CI 75.02-85.78), in 85.8% with no resistance, 72.6% with single resistance, and 28.6% with double resistance. Independent factors affecting eradication rate included resistance to clarithromycin (adjusted ORs 0.27 (0.09-0.84), p = .024), to metronidazole (0.25 (0.009-0.72), p = .010) or to both (0.04 (0.01-0.35), p = .004), and intake of <= 90% of prescribed drugs (0.03 (0.01-0.18), p < .001). CONCLUSION: A high-dose 10 day sequential therapy cannot be recommended in treatment-naive children. PMID- 26123405 TI - The Paternal Provisioning Hypothesis: effects of workload and testosterone production on men's musculature. AB - OBJECTIVES: Testosterone supports male reproduction through a broad range of behavioral and physiological effects, including the maintenance of sexually dimorphic muscle used in male-male competition. Although it is often assumed that a persistent relationship exists between men's testosterone production and musculature, most studies either fail to find evidence for such a relationship, or document very weak associations. In nonhuman primates, by contrast, correlations between testosterone and muscle mass are higher. Here, we propose the "Paternal Provisioning Hypothesis," which predicts that men's skeletal muscle is less dependent on the effects of androgens than that of other primates, and more sensitive to the physical demands of men's work. This permits human fathers to downregulate testosterone, which has negative impacts on pair-bonding and parenting effort, but without sacrificing the strength and musculature necessary to provision mates and offspring. METHODS: We tested predictions of the Paternal Provisioning Hypothesis by assessing parental status, salivary testosterone levels, anthropometry, and strength among 122 men (ages 18-78) at the Mogielica Human Ecology Study Site in rural Poland. We chose this population because men practice subsistence agriculture, regularly engaging in physically demanding labor. Grip and chest strength were assessed using a dynamometer, and upper-body musculature was estimated from arm muscle circumference. RESULTS: In this population, testosterone showed no association with measures of strength or musculature, and was lower in older men and pair-bonded fathers. Marital and parental status and workload, by contrast, were positive predictors of muscle mass and strength measures. DISCUSSION: These findings offer support for the Paternal Provisioning Hypothesis. PMID- 26123407 TI - Intraprocedural blood volume measurement using C-arm CT as a predictor for treatment response of malignant liver tumours undergoing repetitive transarterial chemoembolization (TACE). AB - PURPOSE: To evaluate feasibility of measuring parenchymal blood volume (PBV) of malignant hepatic tumours using C-arm CT, test the changes in PBV following repeated transarterial chemoembolization (TACE) and correlate these changes with the change in tumour size in MRI. METHODS: 111 patients with liver malignancy were included. Patients underwent MRI and TACE in a 4- to 6-week interval. During intervention C-arm CT was performed. Images were post-processed to generate PBV maps. Blood volume data in C-arm CT and change in size in MRI were evaluated. The correlation between PBV and size was tested using Spearman rank test. RESULTS: Pre-interventional PBV maps showed a mean blood volume of 84.5 ml/1000 ml +/- 62.0, follow-up PBV maps after multiple TACE demonstrated 61.1 ml/1000 ml +/- 57.5. The change in PBV was statistically significant (p = 0.02). Patients with initial tumour blood volume >100 ml/1000 ml dropped 7.1% in size and 47.2% in blood volume; 50-100 ml/1000 ml dropped 4.6% in size and 25.7% in blood volume; and <50 ml/1000 ml decreased 2.8% in size and increased 82.2% in blood volume. CONCLUSION: PBV measurement of malignant liver tumours using C-arm CT is feasible. Following TACE PBV decreased significantly. Patients with low initial PBV show low local response rates and further increase in blood volume, whereas high initial tumour PBV showed better response to TACE. KEY POINTS: Parenchymal blood volume assessment of malignant hepatic lesions using C-arm CT is feasible. The parenchymal blood volume is reduced significantly following transarterial chemoembolization. Parenchymal blood volume can monitor the response of tumours after transarterial chemoembolization. Although not significant, high initial parenchymal blood volume yields better response to TACE. PMID- 26123406 TI - Phenotypic and evolutionary implications of modulating the ERK-MAPK cascade using the dentition as a model. AB - The question of phenotypic convergence across a signalling pathway has important implications for both developmental and evolutionary biology. The ERK-MAPK cascade is known to play a central role in dental development, but the relative roles of its components remain unknown. Here we investigate the diversity of dental phenotypes in Spry2(-/-), Spry4(-/-), and Rsk2(-/Y) mice, including the incidence of extra teeth, which were lost in the mouse lineage 45 million years ago (Ma). In addition, Sprouty-specific anomalies mimic a phenotype that is absent in extant mice but present in mouse ancestors prior to 9 Ma. Although the mutant lines studied display convergent phenotypes, each gene has a specific role in tooth number determination and crown patterning. The similarities found between teeth in fossils and mutants highlight the pivotal role of the ERK-MAPK cascade during the evolution of the dentition in rodents. PMID- 26123408 TI - Dedicated sub 0.1 mSv 3DCT using MBIR in children with suspected craniosynostosis: quality assessment. AB - OBJECTIVE: To retrospectively compare image quality of a lowered dose CT protocol to a standard CT protocol in children with suspicion of craniosynostosis. METHODS: Forty-eight patients (age 0- 35 months), who presented with a cranial deformity underwent cranial 3D CT to assess sutural patency: between 2009 - 2010, 24 patients were imaged with a standard protocol (CTDIvol 32.18 mGy), from 2011 2012, 24 underwent a low dose protocol (0.94 mGy) combined with iterative reconstruction. Image quality was evaluated by both expert reading and objective analysis. Differences were assessed by independent t-test and Mann-Whitney U test, interreader agreement by Cohen's Kappa test. RESULTS: Effective dose of the low dose protocol was 0.08 mSv, corresponding to a reduction of 97 %. Image quality was similar in both groups in terms of overall diagnostic acceptability, objective noise measurements, subjective cranial bone edge sharpness and presence of artefacts. For objective sharpness of cranial bone-brain interface and subjective perception of noise, the images of the low dose protocol were superior. For all evaluated structures, interreader agreement was moderate to almost perfect. CONCLUSION: In the diagnosis of craniosynostosis in children with cranial deformities, a dedicated sub 0.1 mSv cranial 3DCT protocol can be used without loss in image quality. KEY POINTS: 3DCT is used for the diagnosis of craniosynostosis. Imaging protocols should be optimized to minimize radiation exposure to children. Combining 80 kVp with iterative reconstruction can help to reduce dose. A sub 0.1 mSv cranial 3DCT protocol can be used without loss of diagnostic quality. PMID- 26123409 TI - Correlation of force control with regional spinal DTI in patients with cervical spondylosis without signs of spinal cord injury on conventional MRI. AB - OBJECTIVES: The aim of this study was to investigate spinal cord structure in patients with cervical spondylosis where conventional MRI fails to reveal spinal cord damage. METHODS: We performed a cross-sectional study of patients with cervical spondylosis without conventional MRI findings of spinal cord damage and healthy controls. Subjects were studied using spinal diffusion tensor imaging (DTI), precision grip and foot force-tracking tasks, and a clinical examination including assessment of neurological signs. A regional analysis of lateral and medial spinal white matter across multiple cervical levels (C1-C5) was performed. RESULTS: DTI revealed reduced fractional anisotropy (FA) and increased radial diffusivity (RD) in the lateral spinal cord at the level of greatest compression (lowest Pavlov ratio) in patients (p < 0.05). Patients with spondylosis had greater error and longer release duration in both grip and foot force-tracking. Similar spinal cord deficits were present in patients without neurological signs. Increased error in grip and foot tracking (low accuracy) correlated with increased RD in the lateral spinal cord at the level of greatest compression (p <= 0.01). CONCLUSIONS: Spinal DTI can detect subtle spinal cord damage of functional relevance in cervical spondylosis, even in patients without signs on conventional T2-imaging and without neurological signs. KEY POINTS: DTI reveals spinal cord changes in cervical spondylosis with few symptoms. DTI changes were present despite normal spinal cord on conventional MRI. DTI parameters correlated with force control accuracy in hand and foot. Spinal DTI is a promising technique for patients with cervical spondylosis. PMID- 26123411 TI - Reply to "Association of mean arterial pressure during cardiopulmonary bypass with acute kidney injury". PMID- 26123410 TI - MRI in multiple sclerosis: an intra-individual, randomized and multicentric comparison of gadobutrol with gadoterate meglumine at 3 T. AB - OBJECTIVES: To compare contrast effects of gadobutrol with gadoterate meglumine for brain MRI in multiple sclerosis (MS) in a multicentre, randomized, prospective, intraindividual study at 3 T. METHODS: Institutional review board approval was obtained. Patients with known or suspected active MS lesions were included. Two identical MRIs were performed using randomized contrast agent order. Four post-contrast T1 sequences were acquired (start time points 0, 3, 6 and 9 min). If no enhancing lesion was present in first MRI, second MRI was cancelled. Quantitative (number and signal intensity of enhancing lesions) and qualitative parameters (time points of first and all lesions enhancing; subjective preference regarding contrast enhancement and lesion delineation; global preference) were evaluated blinded. RESULTS: Seventy-four patients (male, 26; mean age, 35 years) were enrolled in three centres. In 45 patients enhancing lesions were found. Number of enhancing lesions increased over time for both contrast agents without significant difference (median 2 for both). Lesions signal intensity was significantly higher for gadobutrol (p < 0.05 at time points 3, 6 and 9 min). Subjective preference rating showed non-significant tendency in favour of gadobutrol. CONCLUSION: Both gadobutrol and gadoterate meglumine can be used for imaging of acute inflammatory MS lesions. However, gadobutrol generates higher lesion SI. KEY POINTS: Contrast-enhanced MRI plays a key role in the management of multiple sclerosis. Different gadolinium-based contrast agents are available. Number of visibly enhancing lesions increases over time after contrast injection. Gadobutrol and gadoterate meglumine do not differ in number of visible lesions. Gadobutrol generates higher signal intensity than gadoterate meglumine. PMID- 26123412 TI - Partial axillary lymph node dissection inferior to the intercostobrachial nerves complements sentinel node biopsy in patients with clinically node-negative breast cancer. AB - BACKGROUND: The practice of breast cancer diagnosis and treatment in China varies to that in western developed countries. With the unavailability of radioactive tracer technique for sentinel lymph nodes biopsy (SLNB), using blue dye alone has been the only option in China. Also, the diagnosis of breast malignant tumor in most Chinese centres heavily relies on intraoperative instant frozen histology which is normally followed by sentinel lymph nodes mapping, SLNB and the potential breast and axillary operations in one consecutive session. This practice appears to cause a high false negative rate (FNR) for SLNB. The present study aimed to investigate the impact of the current practice in China on the accuracy of SLNB, and whether partial axillary lymph node dissection (PALND), dissection of lymph nodes inferior to the intercostobrachial nerve (ICBN), was a good complementary procedure following SLNB using blue dye. METHODS: 289 patients with clinically node-negative breast cancer were identified and recruited. Tumorectomy, intraoperative instant frozen histological diagnosis, SLNB using methylene blue dye, and PALND or complete axillary node dissection (ALND) were performed in one consecutive operative session. The choice of SLNB only, SLNB followed by PALND or by ALND was based on the pre-determined protocol and preoperative choice by the patient. Clinical parameters were analyzed and survival analysis was performed. RESULTS: 37% patients with clinically negative nodes were found nodes positive. 59 patients with positive SLN underwent ALND, including 47 patients with up to two positive nodes which were all located inferior to the ICBN. 9 patients had failed SLNB and underwent PALND. Among them, 3 (33.3%) patients were found to have one metastatic node. 149 patients showed negative SLNB but chose PALND. Among them, 30 (20.1%), 14 (9.4) and 1 (0.7%) patients were found to have one, two and three metastatic node(s), respectively. PALND detected 48 (30.4%) patients who had either failed SLNB or negative SLNB to have additional positive nodes. All the patients with up to two positive nodes had their nodes located inferior to the ICBN. The FNR of SLNB was 43%. The accuracy rate was 58%. The follow-up ranged 12-33 months. The incidence of lymphedema for SLNB, PALND, and ALND was 0%, 0%, and 25.4%, respectively (P < 0.005). The disease-free survivals for SLNB, PALND, and ALND groups were 95.8%, 96.8%, and 94.9%, respectively (p > 0.05). CONCLUSIONS: Under the circumstances of current practice in China, PALND is a good complementary procedure following SLNB in clinically node-negative breast cancer. PMID- 26123413 TI - Risk patterns in drug safety study using relative times by accelerated failure time models when proportional hazards assumption is questionable: an illustrative case study of cancer risk of patients on glucose-lowering therapies. AB - Observational drug safety studies may be susceptible to confounding or protopathic bias. This bias may cause a spurious relationship between drug exposure and adverse side effect when none exists and may lead to unwarranted safety alerts. The spurious relationship may manifest itself through substantially different risk levels between exposure groups at the start of follow-up when exposure is deemed too short to have any plausible biological effect of the drug. The restrictive proportional hazards assumption with its arbitrary choice of baseline hazard function renders the commonly used Cox proportional hazards model of limited use for revealing such potential bias. We demonstrate a fully parametric approach using accelerated failure time models with an illustrative safety study of glucose-lowering therapies and show that its results are comparable against other methods that allow time-varying exposure effects. Our approach includes a wide variety of models that are based on the flexible generalized gamma distribution and allows direct comparisons of estimated hazard functions following different exposure-specific distributions of survival times. This approach lends itself to two alternative metrics, namely relative times and difference in times to event, allowing physicians more ways to communicate patient's prognosis without invoking the concept of risks, which some may find hard to grasp. In our illustrative case study, substantial differences in cancer risks at drug initiation followed by a gradual reduction towards null were found. This evidence is compatible with the presence of protopathic bias, in which undiagnosed symptoms of cancer lead to switches in diabetes medication. PMID- 26123414 TI - A refined model of the genomic basis for phenotypic variation in vertebrate hemostasis. AB - BACKGROUND: Hemostasis is a defense mechanism that enhances an organism's survival by minimizing blood loss upon vascular injury. In vertebrates, hemostasis has been evolving with the cardio-vascular and hemodynamic systems over the last 450 million years. Birds and mammals have very similar vascular and hemodynamic systems, thus the mechanism that blocks ruptures in the vasculature is expected to be the same. However, the speed of the process varies across vertebrates, and is particularly slow for birds. Understanding the differences in the hemostasis pathway between birds and mammals, and placing them in perspective to other vertebrates may provide clues to the genetic contribution to variation in blood clotting phenotype in vertebrates. We compiled genomic data corresponding to key elements involved in hemostasis across vertebrates to investigate its genetic basis and understand how it affects fitness. RESULTS: We found that: i) fewer genes are involved in hemostasis in birds compared to mammals; and ii) the largest differences concern platelet membrane receptors and components from the kallikrein-kinin system. We propose that lack of the cytoplasmic domain of the GPIb receptor subunit alpha could be a strong contributor to the prolonged bleeding phenotype in birds. Combined analysis of laboratory assessments of avian hemostasis with the first avian phylogeny based on genomic-scale data revealed that differences in hemostasis within birds are not explained by phylogenetic relationships, but more so by genetic variation underlying components of the hemostatic process, suggestive of natural selection. CONCLUSIONS: This work adds to our understanding of the evolution of hemostasis in vertebrates. The overlap with the inflammation, complement and renin angiotensin (blood pressure regulation) pathways is a potential driver of rapid molecular evolution in the hemostasis network. Comparisons between avian species and mammals allowed us to hypothesize that the observed mammalian innovations might have contributed to the diversification of mammals that give birth to live young. PMID- 26123417 TI - Fluidic system for long-term in vitro culturing and monitoring of organotypic brain slices. AB - Brain slice preparations cultured in vitro have long been used as a simplified model for studying brain development, electrophysiology, neurodegeneration and neuroprotection. In this paper an open fluidic system developed for improved long term culturing of organotypic brain slices is presented. The positive effect of continuous flow of growth medium, and thus stability of the glucose concentration and waste removal, is simulated and compared to the effect of stagnant medium that is most often used in tissue culturing. Furthermore, placement of the tissue slices in the developed device was studied by numerical simulations in order to optimize the nutrient distribution. The device was tested by culturing transverse hippocampal slices from 7 days old NMRI mice for a duration of 14 days. The slices were inspected visually and the slices cultured in the fluidic system appeared to have preserved their structure better than the control slices cultured using the standard interface method. PMID- 26123415 TI - Dobutamine Therapy is Associated with Worse Clinical Outcomes Compared with Nesiritide Therapy for Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Inotropes and natriuretic peptides are essential components of current therapeutic options for acute decompensated heart failure (ADHF). This systematic review examines the therapeutic effectiveness of dobutamine and brain natriuretic peptide, nesiritide, in reducing mortality and readmission rates for ADHF treatment. METHODS: Published studies related to dobutamine and nesiritide therapy in ADHF were identified via an exhaustive search of scientific literature databases. The identified studies, published between 2002 and 2012, were carefully screened based on our predefined inclusion criteria. Selected studies were pooled, and odds ratios (ORs) and 95% confidence intervals (95% CI) for each outcome were calculated. Subgroup analysis was conducted to assess the influence of ethnicity on the study outcome. RESULTS: Seven cohort studies were selected for this meta-analysis. These seven studies included 959 ADHF patients who underwent nesiritide treatment and 1748 ADHF patients who received dobutamine therapy. Our meta-analysis revealed a significantly lower survival rate in dobutamine-treated patients compared with nesiritide-treated patients (OR 0.48, 95% CI 0.36-0.63, P < 0.001). Additionally, a markedly higher readmission rate was associated with dobutamine treatment compared with nesiritide treatment (OR 0.52, 95% CI 0.36-0.73, P < 0.001). A stratified analysis based on ethnicity revealed a significantly lower survival in dobutamine-treated ADHF patients in Caucasian and mixed populations compared with nesiritide treatment (Caucasian: OR 0.60, 95% CI 0.38-0.94, P = 0.024; Mixed: OR 0.38, 95% CI 0.26-0.56, P < 0.001). However, a similar association was not detected in Asian populations (P = 0.738). Further, dobutamine-treated ADHF patients displayed higher readmission rates than did nesiritide-treated patients in both Caucasian and mixed-race populations (all P < 0.05). CONCLUSIONS: Our study suggests that dobutamine therapy is associated with poorer outcomes, with higher in-hospital mortality rates and increased readmission rates compared with nesiritide therapy in ADHF patients. Thus, current treatment strategies need to be redesigned for better outcomes. PMID- 26123416 TI - Functional studies cast light on receptor states. AB - Contemporary analysis of the functional responses of G-protein-coupled receptors (GPCRs) usually addresses drug-receptor interactions from the perspective of the average behavior of the receptor population. This behavior is characterized in terms of observed affinity and efficacy. Efficacy is a measure of how well a drug activates the receptor population and observed affinity a measure of how potently a drug occupies the receptor population. The latter is quantified in terms of the dissociation constant of the ligand-receptor complex. At a deeper level of analysis, drug-receptor interactions are described in terms of ligand affinity constants for active and inactive receptor states. Unlike observed affinity and efficacy, estimates of receptor state affinity constants are unperturbed by G proteins, guanine nucleotides, or other signaling proteins that interact with the receptor. Recent advances in the analysis of the functional responses of GPCRs have enabled the estimation of receptor state affinity constants. These constants provide a more fundamental measure of drug-receptor interactions and are useful in analyzing structure-activity relationships and in quantifying allosterism, biased signaling, and receptor-subtype selectivity. PMID- 26123418 TI - Hypomorphic interleukin-7 receptor alpha-chain mutations and T-cell deficiency: a delay in diagnosis. PMID- 26123419 TI - Sublingual immunotherapy: focus on tablets. PMID- 26123420 TI - Underuse of guideline-recommended long-term asthma management in children hospitalized to the intensive care unit: a multicenter observational study. AB - BACKGROUND: Despite the significant burden of childhood asthma, little is known about prevention-oriented management before and after hospitalizations for asthma exacerbation. OBJECTIVE: To investigate the proportion and characteristics of children admitted to the intensive care unit (ICU) for asthma exacerbation and the frequency of guideline-recommended outpatient management before and after the hospitalization. METHODS: A 14-center medical record review study of children aged 2 to 17 years hospitalized for asthma exacerbation during 2012-2013. Primary outcome was admission to the ICU; secondary outcomes were 2 preventive factors: inhaled corticosteroid (ICS) use and evaluation by asthma specialists in the pre- and posthospitalization periods. RESULTS: Among 385 children hospitalized for asthma, 130 (34%) were admitted to the ICU. Risk factors for ICU admission were female sex, having public insurance, a marker of chronic asthma severity (ICS use), and no prior evaluation by an asthma specialist. Among children with ICU admission, guideline-recommended outpatient management was suboptimal (eg, 65% were taking ICSs at the time of index hospitalization, and 19% had evidence of a prior evaluation by specialist). At hospital discharge, among children with ICU admission who had not previously used controller medications, 85% were prescribed ICSs. Furthermore, 62% of all children with ICU admission were referred to an asthma specialist during the 3-month posthospitalization period. CONCLUSION: In this multicenter study of US children hospitalized with asthma exacerbation, one third of children were admitted to the ICU. In this high-risk group, we observed suboptimal pre- and posthospitalization asthma care. These findings underscore the importance of continued efforts to improve prevention-oriented asthma care at all clinical encounters. PMID- 26123421 TI - Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma. AB - BACKGROUND: Impulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. OBJECTIVE: To ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. METHODS: Patients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (<=1,000 MUg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. RESULTS: The magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4-57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7-27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. CONCLUSION: The potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01074853). PMID- 26123422 TI - Pediatric emergency department visits and hospitalizations due to food-induced anaphylaxis in Illinois. AB - BACKGROUND: Rates of food-induced anaphylaxis among children remain uncertain. In addition, little is known about the demographics of children who have experienced food-induced anaphylaxis resulting in emergency department (ED) visits and/or subsequent hospitalizations. OBJECTIVES: To evaluate trends in ED visits and hospital admissions due to food-induced anaphylaxis among Illinois children and to identify socioeconomic variation in trend distribution. METHODS: Illinois hospital discharge data compiled by the Illinois Hospital Association were used to identify ED visits or hospitalizations for food-induced anaphylaxis in Illinois hospitals from 2008-2012. Data for children aged 0 to 19 years who were Illinois residents and received a diagnosis of food-induced anaphylaxis based on International Classification of Diseases, Ninth Revision, Clinical Modification codes (995.60 through 995.69) were included for analysis. RESULTS: There was a significant increase in the rate of ED visits and hospital admissions due to food induced anaphylaxis among children in Illinois during the 5-year period, with an annual percent increase of 29.1% from 6.3 ED visits and hospital admissions per 100,000 children in 2008 to 17.2 in 2012 (P < .001). Increases in visit frequency were observed for all study variables, including age, sex, race/ethnicity, insurance type, metropolitan status, hospital type, and allergenic food. Visits were most frequent each year for Asian children and children with private insurance. However, the annual percent increase in visits was most pronounced among Hispanic children (44.3%, P < .001) and children with public insurance (30.2%, P < .001). CONCLUSION: ED visits and hospital admissions for food-induced anaphylaxis have increased during a 5-year period among children in Illinois, regardless of race/ethnicity and socioeconomic status. PMID- 26123423 TI - Reduced airway microbiota diversity is associated with elevated allergic respiratory inflammation. AB - BACKGROUND: An increased prevalence of allergic disorders in developed countries has been associated with decreased exposure to environmental micro-organisms and an alteration of microbiota colonization. An appropriate model is needed to investigate the mechanisms by which hygiene environment-driven changes in microbiota could regulate allergic disorders. OBJECTIVE: To discover the correlation between the higher incidence and severity of allergies with the relative hygiene environment in a developed country. METHODS: Allergic respiratory inflammation was induced in specific pathogen-free and control rats by sensitization and challenge with ovalbumin. The diversity of lower airway bacteria community was analyzed by polymerase chain reaction denaturing gradient gel electrophoresis and sequencing before ovalbumin sensitization. Allergic respiratory inflammation resulting in cellular infiltrate was measured after the last challenge. RESULTS: The diversity of microbiota in the airway of specific pathogen-free rats decreased compared with the control rats; the more frequent microbiota in the control rats were Proteobacteria and Bacteroidetes. In addition, increased nasal rubbing and sneezing combined with exaggerated IgE production and leukocyte number was observed in ovalbumin-treated specific pathogen-free rats. CONCLUSION: These data indicate that the excessive "hygienic" environment resulted in a decreased bacterial diversity in the airway during infancy, leading to an increased susceptibility to allergic disease. PMID- 26123424 TI - Resonant frequency as a predictor of phase 3 slope of nitrogen single-breath washout in asthma. PMID- 26123425 TI - Basophil activation test in the diagnosis of patent blue V anaphylaxis. PMID- 26123426 TI - A new subset of common variable immune deficiency characterized by reduced C1 esterase inhibitor levels. PMID- 26123427 TI - Effect of poverty, urbanization, and race/ethnicity on perceived food allergy in the United States. PMID- 26123428 TI - Allergen of the Month--Assassin Bug. PMID- 26123429 TI - Significance of tonsillectomy combined with steroid pulse therapy for IgA nephropathy with mild proteinuria. AB - BACKGROUND: Medical intervention for patients with IgA nephropathy and mild proteinuria (<1.0 g/day) is controversial, and the effectiveness of tonsillectomy plus steroid pulse therapy (TSP) for such patients remains obscure. METHODS: Among 323 patients in our multicenter cohort study, 79 who had mild proteinuria (0.4-1.0 g/day) at diagnosis were eligible to participate in this study. We compared the clinicopathological findings at diagnosis, a decline in renal function defined as a 50 or 100% increase in serum creatinine (sCr) and clinical remission (CR) defined as the disappearance of hematuria and proteinuria (<0.3 g/day) among groups given TSP (n = 46), steroid therapy (ST) (n = 9), and non-ST (n = 24). Factors contributing to CR were also evaluated using multivariate analysis. RESULTS: Background factors at diagnosis including age, ratio (%) of patients with hypertension, sCr, proteinuria, and histological severity did not significantly differ among the groups. Only two patients each in the TSP (4.3%) and non-ST (8.3%) groups achieved a 50% increase in sCr during a mean follow-up period of 4.7 years. At the final observation, 71.7, 44.4, and 41.7% of patients in the TSP, ST, and non-ST groups, respectively, achieved CR (p = 0.032). Cox proportional hazards models revealed that TSP led to CR more effectively than non TSP by a factor of about threefold (hazard ratio, 2.74; p = 0.008). CONCLUSION: TSP therapy has potential for inducing CR in patients with IgAN and mild proteinuria (<1.0 g/day). PMID- 26123430 TI - "We get what we deserve": the belief in a just world and its health consequences for Blacks. AB - This study explored whether individual differences in the endorsement of the belief that the world is a just place (i.e., the just world belief) would predict individual differences in resilience/vulnerability to the negative health consequences of discrimination. One-hundred and thirty Blacks participated in a vital check and completed a computer-based questionnaire that included measures of the just world belief, perceived discrimination, physical and mental health, and the presence/absence of chronic illnesses. Endorsement of the just world belief was not associated with self-reported physical/mental health; however, it moderated the effects of perceived discrimination on the number of chronic illnesses and systolic blood pressure. These findings suggest that Blacks who believe that the world is a just place where they get what they deserve may be at a particularly higher risk for the negative health consequences of discrimination. Theoretical and clinical implications of the findings are discussed. PMID- 26123432 TI - Rapid processes for purification of capsular polysaccharides from Neisseria meningitidis serogroups A and C. AB - The glycoconjugate vaccines against Neisseria meningitidis are highly effective, however most of these vaccines are expensive and still out of reach in the developing world as well as the technical know-how and the set-up required for the consistent production of pure polysaccharide is limited. Our laboratory has developed rapid, efficient and scalable processes for the downstream purification of N. meningitidis serogroup A (MenA) and serogroup C (MenC) capsular polysaccharides (PS). The MenC-PS was purified with a novel 2-step procedure including de-O-acetylation and hydrophobic interaction chromatography whereas, MenA-PS was purified using a rapid method as compared to the prior art. The purified PSs were analyzed by various analytical tests including nuclear magnetic resonance, molecular weight, composition and purity analyses to meet desired specifications. Our results provide a proof of principle for the purification of MenA-PS and MenC-PS with reduced timelines. PMID- 26123433 TI - Engineering foot-and-mouth disease virus serotype O IND R2/1975 for one-step purification by immobilized metal affinity chromatography. AB - Immobilized metal affinity chromatography (IMAC) allows for the efficient protein purification via metal affinity tag such as hexa-histidine (His6) sequence. To develop a new chromatography strategy for the purification and concentration of foot-and-mouth disease virus (FMDV) particles, we inserted the His6-tag at the earlier reported site in the VP1 G-H loop of the FMD virus serotype O vaccine strain IND R2/1975. Display of the His6-tag on the capsid surface, endowed the virus with an increased affinity for immobilized nickel ions. We demonstrated that the His6-tagged FMDV could be produced to high titre and purified from the infected BHK-21 cell lysates by IMAC efficiently. Further, a 1150-fold reduction in protein contaminant level and an 8400-fold reduction in DNA contaminant level were achieved in the IMAC purification of His6-tagged FMDV. Through various functional assays it has been found that the tagged virus retains its functionality and infectivity similar to the non-tagged virus. The affinity purification of the His6-tagged FMDV may offer a feasible, alternative approach to the current methods of FMDV antigen purification, concentration and process scalability. PMID- 26123431 TI - Priorities and trends in the study of proteins in eye research, 1924-2014. AB - PURPOSE: To identify the proteins that are relevant to eye research and develop assays for the study of a set of these proteins. EXPERIMENTAL DESIGN: We conducted a bibliometric analysis by merging gene lists for human and mouse from the National Center for Biotechnology Information FTP site and combining them with PubMed references that were retrieved with the search terms "eye" [MeSH Terms] OR "eye" [All Fields] OR "eyes" [All Fields]. RESULTS: For human and mouse eye studies, respectively, the total number of publications was 13,525 and 23,895 and the total number of proteins was 4050 and 4717. For proteins in human and mouse eye studies, respectively, 88.7 and 81.7% had five or fewer citations. The top 50 most intensively studied proteins for human and mouse eye studies were generally in the areas of photoreceptors and phototransduction, inflammation, and angiogenesis, neurodevelopment, lens transparency, and cell-cycle and cellular processes. We proposed selected reaction monitoring assays that were developed in silico for the top fifty most intensively studied proteins in human and mouse eye research. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that scientists engaged in eye research tend to focus on the same proteins. Newer resources and tools in proteomics can expand the investigations to lesser-known proteins of the eye. PMID- 26123434 TI - Atraumatic splenic rupture from Babesia: A disease of the otherwise healthy patient. AB - Babesiosis, an infection caused by the protozoan Babesia microti and transmitted by the Ixodes scapularis tick, is commonly described in the literature with an approximate incidence of 1000 cases per year (Herwaldt et al., 2012). Infections in North America occur most frequently during the spring and summer months in the Northeastern and Midwestern United States. Babesia can cause a wide spectrum of clinical manifestations ranging from a self-limited febrile illness or mild anemia to severe illness causing acute respiratory distress syndrome (ARDS), disseminated intravascular coagulopathy (DIC) and multisystem organ failure. Severe illness most commonly occurs in elderly, immunocompromised, or asplenic patients (Vannier and Krause, 2012). Splenic rupture has been generally described as a complication of severe illness secondary to babesiosis. We describe a case of spontaneous splenic rupture in an otherwise healthy woman that required emergent splenectomy. Recent case reports suggest that splenic rupture occurs in people without known risk factors for severe babesiosis. Physicians should be aware of this acute presentation in otherwise healthy individuals. PMID- 26123435 TI - Origin authentication of distillers' dried grains and solubles (DDGS)- application and comparison of different analytical strategies. AB - In the context of products from certain regions or countries being banned because of an identified or non-identified hazard, proof of geographical origin is essential with regard to feed and food safety issues. Usually, the product labeling of an affected feed lot shows origin, and the paper documentation shows traceability. Incorrect product labeling is common in embargo situations, however, and alternative analytical strategies for controlling feed authenticity are therefore needed. In this study, distillers' dried grains and solubles (DDGS) were chosen as the product on which to base a comparison of analytical strategies aimed at identifying the most appropriate one. Various analytical techniques were investigated for their ability to authenticate DDGS, including spectroscopic and spectrometric techniques combined with multivariate data analysis, as well as proven techniques for authenticating food, such as DNA analysis and stable isotope ratio analysis. An external validation procedure (called the system challenge) was used to analyze sample sets blind and to compare analytical techniques. All the techniques were adapted so as to be applicable to the DDGS matrix. They produced positive results in determining the botanical origin of DDGS (corn vs. wheat), and several of them were able to determine the geographical origin of the DDGS in the sample set. The maintenance and extension of the databanks generated in this study through the analysis of new authentic samples from a single location are essential in order to monitor developments and processing that could affect authentication. PMID- 26123436 TI - Bromine isotope ratio measurements in seawater by multi-collector inductively coupled plasma-mass spectrometry with a conventional sample introduction system. AB - A simple and accurate methodology for Br isotope ratio measurements in seawater by multi-collector inductively coupled plasma-mass spectrometry (MC-ICP-MS) with pneumatic nebulization for sample introduction was developed. The Br(+) signals could be measured interference-free at high mass resolution. Memory effects for Br were counteracted using 5 mmol L(-1) of NH4OH in sample, standard, and wash solutions. The major cation load of seawater was removed via cation exchange chromatography using Dowex 50WX8 resin. Subsequent Br preconcentration was accomplished via evaporation of the sample solution at 90 degrees C, which did not induce Br losses or isotope fractionation. Mass discrimination was corrected for by external correction using a Cl-matched standard measured in a sample standard bracketing approach, although Sr, Ge, and Se were also tested as potential internal standards for internal correction for mass discrimination. The delta(81)Br (versus standard mean ocean bromide (SMOB)) values thus obtained for the NaBr isotopic reference material NIST SRM 977 and for IRMM BCR-403 seawater certified reference material are in agreement with literature values. For NIST SRM 977, the (81)Br/(79)Br ratio (0.97291) was determined with a precision <=0.080/00 relative standard deviation (RSD). PMID- 26123437 TI - Structure characterization of unexpected covalent O-sulfonation and ion-pairing on an extremely hydrophilic peptide with CE-MS and FT-ICR-MS. AB - In this study, we characterized unexpected side-products in a commercially synthesized peptide with the sequence RPRTRLHTHRNR. This so-called peptide D3 was selected by mirror phage display against low molecular weight amyloid-beta peptide (Abeta) associated with Alzheimer's disease. Capillary electrophoresis (CE) was the method of choice for structure analysis because the extreme hydrophilicity of the peptide did not allow reversed-phase liquid chromatography (RPLC) and hydrophilic interaction stationary phases (HILIC). CE-MS analysis, applying a strongly acidic background electrolyte and different statically adsorbed capillary coatings, provided fast and efficient analysis and revealed that D3 unexpectedly showed strong ion-pairing with sulfuric acid. Moreover, covalent O-sulfonation at one or two threonine residues was identified as a result of a side reaction during peptide synthesis, and deamidation was found at either the asparagine residue or at the C-terminus. In total, more than 10 different species with different m/z values were observed. Tandem-MS analysis with collision induced dissociation (CID) using a CE-quadrupole-time-of-flight (QTOF) setup predominantly resulted in sulfate losses and did not yield any further characteristic fragment ions at high collision energies. Therefore, direct infusion Fourier transform ion cyclotron resonance (FT-ICR) MS was employed to identify the covalent modification and discriminate O-sulfonation from possible O-phosphorylation by using an accurate mass analysis. Electron transfer dissociation (ETD) was used for the identification of the threonine O sulfation sites. In this work, it is shown that the combination of CE-MS and FT ICR-MS with ETD fragmentation was essential for the full characterization of this extremely basic peptide with labile modifications. PMID- 26123438 TI - Tip-enhanced Raman spectroscopic imaging shows segregation within binary self assembled thiol monolayers at ambient conditions. AB - Phase segregation of coadsorbed thiol molecules on a gold surface was investigated with nanoscale chemical imaging using tip-enhanced Raman spectroscopy (TERS). Samples were prepared using mixed solutions containing thiophenol (PhS) and an oligomeric phenylene-ethynylene (OPE) thiol, with 10:1, 2:1, and 1:1 molar ratios. Phase segregation into domains with sizes from ~30 to 240 nm is observed with these molar ratios. A comparison of TERS images with different pixel sizes indicates that a pixel size bigger than 15 nm is not reliable in defining nanodomains, because of undersampling. In this study, the formation of nanodomains was clearly evident based on the molecular fingerprints provided by TERS, while ambient scanning tunneling microscopy (STM) was not capable of discerning individual domains via their apparent height difference. TERS therefore allows to image nanodomains in binary self-assembled monolayers, which are invisible to methods solely relying on topographic or electron density characteristics of self-assembled monolayers. Moreover, TERS mapping provides statistical data to describe the distribution of molecules on the sample surface in a well-defined manner. Peak ratio histograms of selected TERS signals from samples prepared with different mixing ratios give a better understanding of the adsorption preference of the thiols studied, and the relationship of their mixing ratio in solution and adsorbed on the surface. PMID- 26123439 TI - Comprehensive evaluation of methods to isolate, quantify, and characterize circulating cell-free DNA from small volumes of plasma. AB - Circulating cell-free DNA (ccfDNA) has great potential for non-invasive diagnostics, and prediction and monitoring of treatment response, but its amount is usually limited. Therefore, the choice of methods to extract and characterize ccfDNA is crucial. In the current study, we performed the most comprehensive comparison of methods for ccfDNA extraction (11 methods), quantification (3 methods), and estimation of the integrity index (2 methods) from small quantities of different kinds of plasma. The QIAamp(r) Circulating Nucleic Acid Kit and the Norgen Plasma/Serum Circulating DNA Purification Mini Kit showed the best accuracy and reproducibility, but the Norgen kit allowed to extract a higher amount of ccfDNA. This workflow provides a reliable protocol for the multiple applications of ccfDNA in biomedicine. PMID- 26123440 TI - Magnetic resonance spectroscopy and imaging on fresh human brain tumor biopsies at microscopic resolution. AB - The metabolic composition and concentration knowledge provided by magnetic resonance spectroscopy (MRS) liquid and high-resolution magic angle spinning spectroscopy (HR-MAS) has a relevant impact in clinical practice during magnetic resonance imaging (MRI) monitoring of human tumors. In addition, the combination of morphological and chemical information by MRI and MRS has been particularly useful for diagnosis and prognosis of tumor evolution. MRI spatial resolution reachable in human beings is limited for safety reasons and the demanding necessary conditions are only applicable on experimental model animals. Nevertheless, MRS and MRI can be performed on human biopsies at high spatial resolution, enough to allow a direct correlation between the chemical information and the histological features observed in such biopsies. Although HR-MAS is nowadays a well-established technique for spectroscopic analysis of tumor biopsies, with this approach just a mean metabolic profile of the whole sample can be obtained and thus the high histological heterogeneity of some important tumors is mostly neglected. The value of metabolic HR-MAS data strongly depends on a wide statistical analysis and usually the microanatomical rationale for the correlation between histology and spectroscopy is lost. We present here a different approach for the combined use of MRI and MRS on fresh human brain tumor biopsies with native contrast. This approach has been designed to achieve high spatial (18 * 18 * 50 MUm) and spectral (0.031 MUL) resolution in order to obtain as much spatially detailed morphological and metabolical information as possible without any previous treatment that can alter the sample. The preservation of native tissue conditions can provide information that can be translated to in vivo studies and additionally opens the possibility of performing other techniques to obtain complementary information from the same sample. PMID- 26123441 TI - Identification of microplastics by FTIR and Raman microscopy: a novel silicon filter substrate opens the important spectral range below 1300 cm(-1) for FTIR transmission measurements. AB - The presence of microplastics in aquatic ecosystems is a topical problem and leads to the need of appropriate and reliable analytical methods to distinctly identify and to quantify these particles in environmental samples. As an example transmission, Fourier transform infrared (FTIR) imaging can be used to analyze samples directly on filters without any visual presorting, when the environmental sample was afore extracted, purified, and filtered. However, this analytical approach is strongly restricted by the limited IR transparency of conventional filter materials. Within this study, we describe a novel silicon (Si) filter substrate produced by photolithographic microstructuring, which guarantees sufficient transparency for the broad mid-infrared region of 4000-600 cm(-1). This filter type features holes with a diameter of 10 MUm and exhibits adequate mechanical stability. Furthermore, it will be shown that our Si filter substrate allows a distinct identification of the most common microplastics, polyethylene (PE), and polypropylene (PP), in the characteristic fingerprint region (1400-600 cm(-1)). Moreover, using the Si filter substrate, a differentiation of microparticles of polyesters having quite similar chemical structure, like polyethylene terephthalate (PET) and polybutylene terephthalate (PBT), is now possible, which facilitates a visualization of their distribution within a microplastic sample by FTIR imaging. Finally, this Si filter can also be used as substrate for Raman microscopy-a second complementary spectroscopic technique-to identify microplastic samples. PMID- 26123442 TI - Raman spectroscopic differentiation of planktonic bacteria and biofilms. AB - Both biofilm formations as well as planktonic cells of water bacteria such as diverse species of the Legionella genus as well as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli were examined in detail by Raman microspectroscopy. Production of various molecules involved in biofilm formation of tested species in nutrient-deficient media such as tap water was observed and was particularly evident in the biofilms formed by six Legionella species. Biofilms of selected species of the Legionella genus differ significantly from the planktonic cells of the same organisms in their lipid amount. Also, all Legionella species have formed biofilms that differ significantly from the biofilms of the other tested genera in the amount of lipids they produced. We believe that the significant increase in the synthesis of this molecular species may be associated with the ability of Legionella species to form biofilms. In addition, a combination of Raman microspectroscopy with chemometric approaches can distinguish between both planktonic form and biofilms of diverse bacteria and could be used to identify samples which were unknown to the identification model. Our results provide valuable data for the development of fast and reliable analytic methods based on Raman microspectroscopy, which can be applied to the analysis of tap water-adapted microorganisms without any cultivation step. PMID- 26123443 TI - Optimization strategies of in-tube extraction (ITEX) methods. AB - Microextraction techniques, especially dynamic techniques like in-tube extraction (ITEX), can require an extensive method optimization procedure. This work summarizes the experiences from several methods and gives recommendations for the setting of proper extraction conditions to minimize experimental effort. Therefore, the governing parameters of the extraction and injection stages are discussed. This includes the relative extraction efficiencies of 11 kinds of sorbent tubes, either commercially available or custom made, regarding 53 analytes from different classes of compounds. They cover aromatics, heterocyclic aromatics, halogenated hydrocarbons, fuel oxygenates, alcohols, esters, and aldehydes. The number of extraction strokes and the corresponding extraction flow, also in dependence of the expected analyte concentrations, are discussed as well as the interactions between sample and extraction phase temperature. The injection parameters cover two different injection methods. The first is intended for the analysis of highly volatile analytes and the second either for the analysis of lower volatile analytes or when the analytes can be re-focused by a cold trap. The desorption volume, the desorption temperature, and the desorption flow are compared, together with the suitability of both methods for analytes of varying volatilities. The results are summarized in a flow chart, which can be used to select favorable starting conditions for further method optimization. PMID- 26123444 TI - Expanded preconception carrier screening in clinical practice: cutting the Gordian Knot. PMID- 26123445 TI - The CD200 tolerance-signaling molecule and its receptor, CD200R1, are expressed in human placental villus trophoblast and in peri-implant decidua by 5 weeks' gestation. AB - CD200 expression in murine trophoblast and decidua prevents semi-allogeneic and LPS-induced abortions by binding to CD200 receptor-bearing cells to suppress NK activity, induces IDO in macrophages, and promotes the generation of regulatory T cell subsets. CD200 and its receptor CD200R1 reported in 7-9 weeks' gestation human villus trophoblasts are reduced in spontaneous abortion syncytiotrophoblasts. By specific antibody staining, we find that both CD200 and CD200R1 are expressed even earlier, by 5 weeks' gestation, by villus trophoblasts and by decidual cells. Expression of CD200 was validated using two independent antibodies. CD200-CD200R1 signaling may be required for human pregnancy success. PMID- 26123446 TI - Australia's nutrition transition 1961-2009: a focus on fats. AB - Since the 1960s, Australian diets have changed considerably, influenced by a burgeoning multicultural cuisine, increase in urbanisation and food technology advances. This has been described as a 'nutrition transition', resulting in the adoption of a Western diet pattern, with a shift away from unrefined foods towards a diet higher in both plant-derived high PUFA and total fats and refined carbohydrates. Utilising the 1961-2009 annual food supply data from the UN FAO, the present study investigated changes in the intake of macronutrient and specific fatty acid in the Australian population, including that of the PUFA linoleic acid (LA), due to its hypothesised role in inflammation and risk for obesity. Cumulative change over time for the contribution of specific nutrients to total available energy (TAE) was calculated, as was linearity of change. Over the time period analysed, the cumulative change in TAE from carbohydrate was 9.35 and +16.67 % from lipid. The cumulative change in TAE from LA was +120.48 %. Moreover, the cumulative change in the contribution of LA to total PUFA availability was +7.1 %. Utilising the average g/d per capita of LA from selected dietary sources, the change in the contribution of specific foodstuffs was assessed, with total plant oils having a cumulative change of +627.19 % to LA availability, equating to a cumulative change of +195.61 % in contribution to total LA availability. The results of the present study indicate that LA availability in Australia has increased over the previous five decades as a result of the availability of increased plant oils, as has total fat, possibly contributing to the increasing rates of obesity and obesity-associated co morbidities. PMID- 26123448 TI - An auxilliary grid method for the calculation of electrostatic terms in density functional theory on a real-space grid. AB - In this work we show the implementation of a linear scaling algorithm for the calculation of the Poisson integral. We use domain decomposition and non-uniform auxiliary grids (NGs) to calculate the electrostatic interaction. We demonstrate the approach within the PARSEC density functional theory code and perform calculations of long 1D carbon chains and other long molecules. Finally, we discuss possible applications to additional problems and geometries. PMID- 26123447 TI - Airway Remodeling in Chronic Obstructive Pulmonary Disease and Asthma: the Role of Matrix Metalloproteinase-9. AB - Chronic obstructive pulmonary disease (COPD) and asthma are both associated with airflow restriction and progressive remodeling, which affect the respiratory tract. Among various biological factors involved in the pathomechanisms of both diseases, proteolytic enzymes--matrix metalloproteinases (MMPs)--play an important role, especially MMP-9. In this review, the authors discuss the current topics of research concerning the possible role of MMP-9 in both mentioned diseases. They include the analysis of protein levels, nucleotide polymorphisms of MMP-9 gene and their possible correlation with asthma and COPD. Finally, the authors refer to the studies on MMP-9 inhibition as a new perspective for increasing the effectiveness of treatment in asthma and COPD. PMID- 26123449 TI - A voxel-based morphometry study of gray matter correlates of facial emotion recognition in bipolar disorder. AB - Facial emotion recognition (FER) is one of the many cognitive deficits reported in bipolar disorder (BD) patients. The aim of this study was to investigate neuroanatomical correlates of FER impairments in BD type I (BD-I). Participants comprised 21 euthymic BD-I patients without Axis I DSM IV-TR comorbidities and 21 healthy controls who were assessed using magnetic resonance imaging and the Penn Emotion Recognition Test (ER40). Preprocessing of images used DARTEL (diffeomorphic anatomical registration through exponentiated Lie algebra) for optimized voxel-based morphometry in SPM8. Compared with healthy subjects, BD-I patients performed poorly in on the ER40 and had reduced gray matter volume (GMV) in the left orbitofrontal cortex, superior portion of the temporal pole and insula. In the BD-I group, the statistical maps indicated a direct correlation between FER on the ER40 and right middle cingulate gyrus GMV. Our findings are consistent with the previous studies regarding the overlap of multiple brain networks of social cognition and BD neurobiology, particularly components of the anterior-limbic neural network. PMID- 26123451 TI - Reset osmostat: a rare cause of hyponatraemia. AB - Neonatal hyponatraemia is common, and related to significant morbidity and mortality. We report a case of a preterm newborn (gestational age of 36 weeks) with hyponatraemia, and with a prenatal diagnosis of cleft lip and palate, with a normal fetal karyotype. On the seventh day of life, a biochemical evaluation for jaundice and mild signs of dehydration showed hyponatraemia of 124 mmol/L. Investigation showed normal adrenal and thyroid functions, plasma hyposmolality (258 mOsm/kg); high urinary sodium (73 mmol/L) and high urinary osmolality (165 mOsm/kg). Despite oral sodium supplementation and fludrocortisone treatment, sodium levels remained between 124 and 130 mmol/L. Cranial ultrasound, brain MRI and renal ultrasound were normal. The diagnosis of hyponatraemia was unpredicted and the investigation was suggestive of reset osmostat, a subtype of the syndrome of inappropriate secretion of antidiuretic hormone, characterised by a subnormal threshold for antidiuretic hormone secretion. PMID- 26123450 TI - Alterations in hippocampal connectivity across the psychosis dimension. AB - Recent evidence demonstrates that hippocampal hyperactivity helps mediate psychosis. Using resting state functional magnetic resonance imaging (rsfMRI), we examined hippocampal connectivity alterations in individuals with psychosis (PS) versus healthy controls (HC). Because of its putative greater involvement in psychiatric disorders, we hypothesized that the anterior hippocampus network would show greater dysconnectivity in psychosis. We tested rsfMRI connectivity in 88 PS (including 21 with schizophrenia; 40 with schizoaffective disorder; 27 with psychotic bipolar I disorder) and 65 HC. Seed-based voxel-wise connectivity analyses were carried out using whole, anterior, and posterior hippocampal seeds. No significant differences in functional hippocampal connectivity were found across the three conventional diagnoses. PS were then contrasted with HC, showing strong reductions in anterior hippocampal connectivity to anterior neocortical regions, including medial frontal and anterior cingulate cortices, as well as superior temporal gyrus, precuneus, thalamus and cerebellum. Posterior hippocampal seeds also demonstrated decreased connectivity in PS, with fewer dysconnected regions and a posterior/cerebellar distribution. Whole hippocampal outcomes were consistent with anterior/posterior hippocampal connectivity changes. Connectivity alterations did not correlate with cognition, clinical symptoms, or medication effect variables. Our results suggest a psychosis network of decreased hippocampal connectivity with limbic and frontal contributions, independent of diagnostic categories. PMID- 26123452 TI - Subdural empyema and unilateral pansinusitis due to a tooth infection. AB - Paranasal sinus infections are very common. Dental infections, tumours and anatomical malformations can cause unilateral sinusitis. Most cases can be treated without complications. However, rare life-threatening intracranial complications can occur. Generally, an intracranial complication progresses rapidly and can cause meningismus, focal neurological disorders, loss of consciousness and seizures. In such cases, an emergency craniotomy and concurrent sinus surgery are required. This article presents a 16-year-old patient with pansinusitis and subdural empyema that developed after a dental abscess. PMID- 26123453 TI - Is this still just sarcoidosis, or should we a-DRESS a different diagnosis? AB - An Afro-Caribbean woman presented with worsening breathlessness, weight loss, lethargy and fevers, developing a bilateral florid erythematous rash on her legs. She was recently diagnosed with rheumatoid arthritis and bilateral hilar lymphadenopathy was found on thoracic CT imaging. She was tachycardic and investigations revealed pancytopenia, eosinophilia, raised serum ACE, acute kidney injury and deranged liver function tests. Biopsy of the lymphadenopathy revealed mixed lymphoid cells and liver biopsy revealed extramedullary haematopoiesis, with hypercellular marrow found on bone marrow biopsy. Cardiac MRI was normal, excluding cardiac sarcoid. The patient developed status epilepticus and phenytoin was started. She subsequently developed skin desquamation, in keeping with toxic epidermal necrosis. Skin biopsies revealed atypical granulomas and multinucleated giant cells, which subsequently resolved on steroid treatment. This case highlights an overlap syndrome, with an unclear diagnosis between sarcoidosis, drug reaction or rash with eosinophilia and systemic symptoms and/or hypereosinophilic syndrome and Still's disease. Hence varied serological and clinical features can complicate the distinction between diagnoses. PMID- 26123454 TI - Spontaneous gallbladder perforation in a patient of situs inversus totalis, misdiagnosed as perforation peritonitis due to gas under the right dome of the diaphragm. AB - Acute biliary tract disease is a common condition in adults. Apart from bile duct perforation, spontaneous perforation of the gallbladder itself is very rare in all age groups; to date, all recorded cases are secondary to coexistent disease. We present the case report of a 60-year-old adult having an idiopathic gallbladder perforation. In our case, an unusual presentation was situs inversus totalis and fundal gas shadow was considered as free air under the right dome of the diaphragm by mistake. The patient underwent laparotomy and emergency cholecystectomy was performed in the perforated gallbladder. To date, no case has been described in the literature. PMID- 26123455 TI - Down syndrome, insulin-dependent diabetes mellitus and hyperthyroidism: a rare association. AB - The association between Down syndrome (DS) and autoimmune endocrinopathies is well established. These disorders become increasingly frequent as children grow older and the onset of one often predisposes to the development of others. However, there are few cases in the literature reporting the simultaneous onset of type 1 diabetes mellitus and hyperthyroidism in children with DS. We describe a case of an 8-year-old girl with DS who presented at the emergency department with hyperglycaemia and ketosis as a primary manifestation of type 1 diabetes mellitus. During the initial investigation, hyperthyroidism was detected, with thyroid-stimulating hormone<0.01 uUI/mL, positive antithyroid antibodies and an increase in thyroid gland on ultrasound. The authors present this case to underline the usefulness of monitoring thyroid function at the diagnosis of diabetes, even without apparent clinical manifestations, and to alert for the possibility of autoimmune endocrine dysfunction in children with DS. PMID- 26123456 TI - Left gastric artery aneurysm in Marfan syndrome: a unique case. AB - A 78-year-old man presented with abdominal pain, high International Normalised Ratio and rapidly falling haemoglobin. He had a background of Marfan syndrome and was on warfarin following mechanical aortic valve replacement. Abdominal CT imaging showed haemoperitoneum with a leaking aneurysm of the left gastric artery measuring 10 mm in diameter. The decision whether to reverse his anticoagulation provided a difficult clinical scenario given the risk of thrombosis associated with the mechanical aortic valve. The patient went on to have a successful percutaneous embolisation of the aneurysm using a metallic coil and Onyx. Left gastric artery aneurysms are rare and have a reported mortality of up to 70%. This is the first case of gastric artery aneurysm described in a patient with Marfan syndrome. PMID- 26123457 TI - Cauda equina syndrome caused by a spontaneous spinal haematoma. PMID- 26123458 TI - Diffuse cholangiocarcinoma presenting with hepatic failure and extensive portal and mesenteric vein thrombosis. AB - A 64-year-old previously healthy man presented with a 4-week history of vague right upper quadrant abdominal pain. Imaging studies revealed extensive portal, splenic, superior and inferior mesenteric vein thrombosis with mosaic perfusion and wedge-shaped areas of liver perfusion abnormalities. An extensive thrombophilia workup including tests for factor V Leiden, prothrombin G20210A, lupus anticoagulant, paroxysmal nocturnal haemoglobinuria, protein C and S, homocysteine and antinuclear antibody titres were all negative. Other laboratory testing revealed an elevated alkaline phosphatase (340 IU/L). Surgical exploration and catheter-directed thrombolysis were not felt to be feasible given the extensive clot burden. He was started on anticoagulation therapy. Over the next 10 days, he required intensive care unit admission due to progressive hepatic encephalopathy and fulminant liver failure. He continued to decline and eventually died of multiorgan failure. Autopsy revealed extensive, diffuse intrahepatic cholangiocarcinoma that had almost entirely replaced his normal liver parenchyma. PMID- 26123459 TI - Endogenous endophthalmitis secondary to erysipelas. AB - A 64-year-old woman with chronic right arm lymphoedema presented with progressive and painful vision loss in the right eye following diagnosis of erysipelas in the ipsilateral arm. Visual acuity was light perception. Biomicroscopy revealed marked conjunctival injection, decreased corneal transparency and an inflammatory mass in the anterior chamber, which precluded fundoscopy. The ocular ultrasonography features were consistent with acute endophthalmitis, and the patient was admitted to the hospital. A systemic evaluation, including complete physical examination, echocardiography and blood tests, ruled out other sources of infection besides the cutaneous site. Blood cultures were positive for group A Streptococcus. A diagnosis of unilateral acute endophthalmitis due to group A Streptococcus bacteraemia secondary to erysipelas was made and successfully treated with optimal medical care, including prompt intravitreal and systemic antibiotic administration. Despite resolution of the infectious process, visual acuity did not improve. PMID- 26123460 TI - Initial experience of coiling cerebral aneurysms using the new Comaneci device. AB - We present our initial patient experience with an innovative temporary bridging device, the Comaneci (Rapid Medical, Israel), to assist in the coiling of cerebral aneurysms. The Comaneci device confers the same benefits as balloon remodeling but without the risks of parent artery occlusion. This alleviates time pressure on the clinician, and could reduce the risk of parent artery thrombosis. Three patients were treated with the Comaneci device. Two patients had acute ruptured posterior communicating aneurysms and one patient was treated electively for a carotico-ophthalmic aneurysm. Excellent occlusion of all three aneurysms was obtained. One patient developed a distal middle cerebral artery clot, that was treated with intravenous aspirin, with minor neurological consequences. These early results show that the Comaneci device can be used to achieve good cerebral aneurysm occlusion. Vessel patency is maintained throughout the procedure with potential advantages over conventional balloon assisted coiling. PMID- 26123461 TI - Reactivation of chronic hepatitis B during treatment with tenofovir disoproxil fumarate: drug interactions or low adherence? AB - We describe a case of a 61-year-old man with chronic hepatitis B, hepatitis B e antibody (HBeAb) positive, treated with tenofovir disoproxil fumarate (TDF), who developed virological and biochemical viremic reactivation with an increase in transaminase plasma levels. The patient's history revealed that he had discontinued TDF about 5 days before admission and, from December 2013, had been taking venlafaxine, paroxetine and zolpidem for some episodes of depression. Clinical evaluation and laboratory findings excluded the presence of systemic diseases that might have been able to explain the drug inefficacy, while pharmacological evaluation suggested a possible drug-drug interaction. In order to assess the possible occurrence of resistance, mutational analysis of hepatitis B virus (HBV) was performed and excluded the presence of resistance for TDF. TDF was prescribed, and venlafaxine, paroxetine and zolpidem were discontinued. The follow-up at 3, 6 and 12 months documented a good response to TDF with a time related decrease of HBV-DNA and alanine aminotransferase. PMID- 26123462 TI - Bilateral big-bubble deep anterior lamellar keratoplasty for vascularised corneal opacity in a patient with xeroderma pigmentosum. AB - A 16-year-old male patient diagnosed with xeroderma pigmentosum developed bilateral vascularised corneal opacities after treatment for ocular surface squamous neoplasia. The patient underwent an uneventful big-bubble deep anterior lamellar keratoplasty in both eyes. The grafts remained clear and the corrected distance visual acuity was 20/30 in both the eyes at the final follow-up visit. PMID- 26123463 TI - Malignant mixed Mullerian tumour of uterus secondary to tamoxifen therapy for hormone responsive breast cancer. AB - Tamoxifen is used in the treatment of hormone responsive breast cancer because of its antiestrogenic effect. However, it also has an estrogenic effect on the uterus, thereby increasing the risk of endometrial hyperplasia, endometrial polyp and endometrial neoplasms such as endometrial adenocarcinoma and malignant mixed Mullerian tumour (MMMT). This case describes the possible pathogenesis and risk of developing MMMT due to long-term tamoxifen intake in hormone responsive breast cancer. PMID- 26123464 TI - Refractory hypocalcaemia complicating metastatic prostatic carcinoma. AB - A 72-year-old man with a background of ischaemic heart disease was referred to the accident and emergency department with a 1-week history of worsening dyspnoea and lethargy. A chest X-ray revealed a right-sided lobar pneumonia and a prolonged corrected QT interval was noted on his ECG at presentation. Laboratory investigations confirmed severe hypocalcaemia, significant vitamin D deficiency and relative hypoparathyroidism. A markedly elevated prostate-specific antigen was also identified. Bone scintigraphy demonstrated widespread osteoblastic bone metastases. Severe hypocalcaemia persisted despite treatment and he succumbed after 60 days of hospitalisation. PMID- 26123465 TI - Intrapleural cisplatin for management of malignant pleural effusion in a patient with plasma cell leucaemia. AB - Plasma cell leucaemia (PCL) is a rare aggressive form of multiple myeloma. It occasionally involves the pleura, causing malignant pleural effusion (MPE). MPE presents a management dilemma for physicians, given the different treatment options available with varying efficacy and side effects. We report a case of a 64-year-old man with MPE due to PCL, successfully managed with intrapleural cisplatin and a tunnelled pleural catheter. We believe this to be the first report of management of PCL-associated MPE with intrapleural cisplatin. PMID- 26123466 TI - A slow progressor HIV-infected boy developing quadriplegia with evidence of Epstein-Barr virus associated smooth muscle tumour of the cervical spinal cord. AB - The authors report a case of slowly progressive HIV in an 11-year-old boy whose initial presenting AIDS-defining symptom was progressive quadriplegia with complete cord compression and pathological confirmation of Epstein-Barr virus associated smooth muscle tumour. Despite tumour removal, quadriplegia persisted as did ventilator dependence. PMID- 26123467 TI - Leptomeningeal metastases in pineoblastoma. PMID- 26123468 TI - An unusual case of invasive aspergillosis in an immunocompetent individual. AB - Invasive aspergillosis is a highly lethal opportunistic infection that poses a significant threat to immunocompromised patients. With studies suggesting that the incidence of this disease is increasing, and mortality rates remain high, early diagnosis and treatment are very important to improve patient survival. We present the case of a 33-year-old immunocompetent woman who presented with a history of cough and severe breathlessness, and was diagnosed to have invasive aspergillosis. This case emphasises the importance of maintaining a high index of suspicion and also of remembering that invasive aspergillosis is no longer only a disease of immunocompromised individuals. In addition, this case tells us that aspergillosis is one of the new emerging infections in intensive care units. PMID- 26123469 TI - 'Pitted' to 'Pleasing' in 20 min. AB - In recent times, as a result of extensive drinking water fluoridation, the number of patients affected by fluorosis has increased considerably. The purpose of this clinical report is to describe the use of enamel microabrasion for a patient with severe fluorosis using 37% phosphoric acid and pumice mixture. The results were pleasing, and hence 37% phosphoric acid can be recommended as a safe and easily available alternative in microabrasion procedures. PMID- 26123470 TI - Unilateral nevoid acanthosis nigricans. PMID- 26123471 TI - Sudden cardiac arrest in a healthy young athlete. PMID- 26123472 TI - Benign mixed tumour of the breast and breast skin, two cases with diagnostic difficulties. AB - We present two cases of pleomorphic adenoma, one that developed in the breast parenchyma and the other in the breast skin, with their histopathological differential diagnosis. PMID- 26123473 TI - Nowcasting daily minimum air and grass temperature. AB - Site-specific and accurate prediction of daily minimum air and grass temperatures, made available online several hours before their occurrence, would be of significant benefit to several economic sectors and for planning human activities. Site-specific and reasonably accurate nowcasts of daily minimum temperature several hours before its occurrence, using measured sub-hourly temperatures hours earlier in the morning as model inputs, was investigated. Various temperature models were tested for their ability to accurately nowcast daily minimum temperatures 2 or 4 h before sunrise. Temperature datasets used for the model nowcasts included sub-hourly grass and grass-surface (infrared) temperatures from one location in South Africa and air temperature from four subtropical sites varying in altitude (USA and South Africa) and from one site in central sub-Saharan Africa. Nowcast models used employed either exponential or square root functions to describe the rate of nighttime temperature decrease but inverted so as to determine the minimum temperature. The models were also applied in near real-time using an open web-based system to display the nowcasts. Extrapolation algorithms for the site-specific nowcasts were also implemented in a datalogger in an innovative and mathematically consistent manner. Comparison of model 1 (exponential) nowcasts vs measured daily minima air temperatures yielded root mean square errors (RMSEs) <1 degrees C for the 2-h ahead nowcasts. Model 2 (also exponential), for which a constant model coefficient (b = 2.2) was used, was usually slightly less accurate but still with RMSEs <1 degrees C. Use of model 3 (square root) yielded increased RMSEs for the 2-h ahead comparisons between nowcasted and measured daily minima air temperature, increasing to 1.4 degrees C for some sites. For all sites for all models, the comparisons for the 4 h ahead air temperature nowcasts generally yielded increased RMSEs, <2.1 degrees C. Comparisons for all model nowcasts of the daily grass and grass-surface minima yielded increased RMSEs compared to those for air temperature at 2 m. The sufficiently small RMSEs using the 2-h ahead nowcasts of the air temperature minimum, for the exponential model, demonstrate that the methodology used may be applied operationally but with increased errors for grass minimum temperature and the 4-h nowcasts. PMID- 26123474 TI - A tsunami of unmet needs: pancreatic and ampullary cancer patients' supportive care needs and use of community and allied health services. AB - OBJECTIVE: People diagnosed with pancreatic cancer have the worst survival prognosis of any cancer. No previous research has documented the supportive care needs of this population. Our objective was to describe people's needs and use of support services and to examine whether these differed according to whether or not patients had undergone surgical resection. METHODS: Queensland pancreatic or ampullary cancer patients (n = 136, 54% of those eligible) completed a survey, which assessed 34 needs across five domains (Supportive Care Needs Survey-Short Form) and use of health services. Differences by resection were compared with Chi squared tests. RESULTS: Overall, 96% of participants reported having some needs. More than half reported moderate-to-high unmet physical (54%) or psychological (52%) needs, whereas health system/information (32%), patient care (21%) and sexuality needs (16%) were described less frequently. The three most frequently reported moderate-to-high needs included 'not being able to do things they used to do' (41%), 'concerns about the worries of those close' (37%) and 'uncertainty about the future' (30%). Patients with non-resectable disease reported greater individual information needs, but their needs were otherwise similar to patients with resectable disease. Self-reported use of support was low; only 35% accessed information, 28%, 18% and 15% consulted a dietician, complementary medicine practitioner or mental health practitioner, respectively. Palliative care access was greater (59% vs 27%) among those with non-resectable disease. CONCLUSION: Very high levels of needs were reported by people with pancreatic or ampullary cancer. Future work needs to elucidate why uptake of appropriate supportive care is low and which services are required. PMID- 26123475 TI - A systematic review of the cost and cost effectiveness of using standard oral nutritional supplements in the hospital setting. AB - BACKGROUND & AIMS: There is limited information about the economic impact of nutritional support despite its known clinical benefits. This systematic review examined the cost and cost effectiveness of using standard (non-disease specific) oral nutritional supplements (ONS) administered in the hospital setting only. METHODS: A systematic literature search of multiple databases, data synthesis and analysis were undertaken according to recommended procedures. RESULTS: Nine publications comprising four full text papers, two abstracts and three reports, one of which contained 11 cost analyses of controlled cohort studies, were identified. Most of these were based on retrospective analyses of randomised controlled trials designed to assess clinically relevant outcomes. The sample sizes of patients with surgical, orthopaedic and medical problems and combinations of these varied from 40 to 1.16 million. Of 14 cost analyses comparing ONS with no ONS (or routine care), 12 favoured the ONS group, and among those with quantitative data (12 studies) the mean cost saving was 12.2%. In a meta-analysis of five abdominal surgical studies in the UK, the mean net cost saving was L746 per patient (se L338; P = 0.027). Cost savings were typically associated with significantly improved outcomes, demonstrated through the following meta-analyses: reduced mortality (Risk ratio 0.650, P < 0.05; N = 5 studies), reduced complications (by 35% of the total; P < 0.001, N = 7 studies) and reduced length of hospital stay (by ~2 days, P < 0.05; N = 5 surgical studies) corresponding to ~13.0% reduction in hospital stay. Two studies also found ONS to be cost effective, one by avoiding development of pressure ulcers and releasing hospital beds, and the other by gaining quality adjusted life years. CONCLUSION: This review suggests that standard ONS in the hospital setting produce a cost saving and are cost effective. The evidence base could be further strengthened by prospective studies in which the primary outcome measures are economic. PMID- 26123476 TI - "Nothing About Me Without Me": An Interpretative Review of Patient Accessible Electronic Health Records. AB - BACKGROUND: Patient accessible electronic health records (PAEHRs) enable patients to access and manage personal clinical information that is made available to them by their health care providers (HCPs). It is thought that the shared management nature of medical record access improves patient outcomes and improves patient satisfaction. However, recent reviews have found that this is not the case. Furthermore, little research has focused on PAEHRs from the HCP viewpoint. HCPs include physicians, nurses, and service providers. OBJECTIVE: We provide a systematic review of reviews of the impact of giving patients record access from both a patient and HCP point of view. The review covers a broad range of outcome measures, including patient safety, patient satisfaction, privacy and security, self-efficacy, and health outcome. METHODS: A systematic search was conducted using Web of Science to identify review articles on the impact of PAEHRs. Our search was limited to English-language reviews published between January 2002 and November 2014. A total of 73 citations were retrieved from a series of Boolean search terms including "review*" with "patient access to records". These reviews went through a novel scoring system analysis whereby we calculated how many positive outcomes were reported per every outcome measure investigated. This provided a way to quantify the impact of PAEHRs. RESULTS: Ten reviews covering chronic patients (eg, diabetes and hypertension) and primary care patients, as well as HCPs were found but eight were included for the analysis of outcome measures. We found mixed outcomes across both patient and HCP groups, with approximately half of the reviews showing positive changes with record access. Patients believe that record access increases their perception of control; however, outcome measures thought to create psychological concerns (such as patient anxiety as a result of seeing their medical record) are still unanswered. Nurses are more likely than physicians to gain time efficiencies by using a PAEHR system with the main concern from physicians being the security of the PAEHRs. CONCLUSIONS: This review implements a novel scoring system, which shows there is a lack of rigorous empirical testing that separates the effect of record access from other existing disease management programs. Current research is too targeted within certain clinical groups' needs, and although there are positive signs for the adoption of PAEHRs, there is currently insufficient evidence about the effect of PAEHRs on health outcomes for patients or HCPs. PMID- 26123477 TI - CD33, not early precursor T-cell phenotype, is associated with adverse outcome in adult T-cell acute lymphoblastic leukaemia. PMID- 26123478 TI - Therapeutic plasma exchange as a therapeutic modality for the treatment of IVIG complications. AB - Intravenous immunoglobulin (IVIG) is used for the treatment of a number of inflammatory conditions. Hemolysis due to passive transfer of blood group antibodies is a well recognized complication of IVIG therapy. Therapy is largely supportive and consists of blood product support and hemodialysis. We report the use of therapeutic plasma exchange (TPE) as adjunct therapy for three patients with complications attributed to IVIG. Two patients had hemolysis attributed to IVIG; one patient was blood group A and the other blood group O. The third patient was an orthotopic heart transplant recipient with a type A donor heart, and anti-A antibodies detected after infusion of IVIG for suspected antibody mediated rejection. Two patients had anti-A titers available that decreased after initiation of plasma exchange. The blood group O patient with hemolysis had a gradual stabilization of hemoglobin and resolution of the positive DAT. TPE may be useful therapy for patients with severe hemolysis caused by IVIG or at risk for tissue damage by blood group antibodies. PMID- 26123479 TI - 2015 American Heart Association/American Stroke Association Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. AB - PURPOSE: The aim of this guideline is to provide a focused update of the current recommendations for the endovascular treatment of acute ischemic stroke. When there is overlap, the recommendations made here supersede those of previous guidelines. METHODS: This focused update analyzes results from 8 randomized, clinical trials of endovascular treatment and other relevant data published since 2013. It is not intended to be a complete literature review from the date of the previous guideline publication but rather to include pivotal new evidence that justifies changes in current recommendations. Members of the writing committee were appointed by the American Heart Association/American Stroke Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association/American Stroke Association Manuscript Oversight Committee. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Recommendations follow the American Heart Association/American Stroke Association methods of classifying the level of certainty of the treatment effect and the class of evidence. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statement Oversight Committee and Stroke Council Leadership Committee. RESULTS: Evidence-based guidelines are presented for the selection of patients with acute ischemic stroke for endovascular treatment, for the endovascular procedure, and for systems of care to facilitate endovascular treatment. CONCLUSIONS: Certain endovascular procedures have been demonstrated to provide clinical benefit in selected patients with acute ischemic stroke. Systems of care should be organized to facilitate the delivery of this care. PMID- 26123480 TI - Genes involved in muscle contractility and nutrient signaling pathways within celiac disease risk loci show differential mRNA expression. AB - BACKGROUND: Risk gene variants for celiac disease, identified in genome-wide linkage and association studies, might influence molecular pathways important for disease development. The aim was to examine expression levels of potential risk genes close to these variants in the small intestine and peripheral blood and also to test if the non-coding variants affect nearby gene expression levels in children with celiac disease. METHODS: Intestinal biopsy and peripheral blood RNA was isolated from 167 children with celiac disease, 61 with potential celiac disease and 174 disease controls. Transcript levels for 88 target genes, selected from celiac disease risk loci, were analyzed in biopsies of a smaller sample subset by qPCR. Differentially expressed genes (3 from the pilot and 8 previously identified) were further validated in the larger sample collection (n = 402) of both tissues and correlated to nearby celiac disease risk variants. RESULTS: All genes were significantly down- or up-regulated in the intestinal mucosa of celiac disease children, NTS being most down-regulated (Fold change 3.6, p < 0.001). In contrast, PPP1R12B isoform C was up-regulated in the celiac disease mucosa (Fold change 1.9, p < 0.001). Allele specific expression of GLS (rs6741418, p = 0.009), INSR (rs7254060, p = 0.003) and NCALD (rs652008, p = 0.005) was also detected in the biopsies. Two genes (APPL2 and NCALD) were differentially expressed in peripheral blood but no allele specific expression was observed in this tissue. CONCLUSION: The differential expression of NTS and PPP1R12B indicate a potential role for smooth muscle contractility and cell proliferation in celiac disease, whereas other genes like GLS, NCALD and INSR suggests involvement of nutrient signaling and energy homeostasis in celiac disease pathogenesis. A disturbance in any of these pathways might contribute to development of childhood celiac disease. PMID- 26123481 TI - Effect of nurses' work environment on patient satisfaction: A cross-sectional study of four hospitals in Japan. AB - AIM: The Magnet Recognition Program is a system in the USA that recognizes a hospital as a magnet hospital for having a high retention rate of nurses and providing high quality patient care. The purpose of this study was to examine the effect of nurses' work environment with characteristics that are similar to those of magnet hospitals on patient satisfaction in Japan. METHODS: The authors distributed anonymous self-administered questionnaires in August 2011 to all nurses via the directors of the nursing departments of four private hospitals. The response rates were 91% (n = 425) for nurses and 51% (n = 379) for patients. In the questionnaire for nurses, the items addressed basic attributes and a scale of work environment characteristics of a magnet hospital (the Japanese version of the Practice Environment Scale of the Nursing Work Index [PES-NWI]). The questionnaire for patients addressed basic attributes, information about their hospitalization, and items to assess patient satisfaction. To examine the effects of the PES-NWI subscales on patient satisfaction, the authors conducted multivariate logistic regression analysis for groups, which were dichotomized by 75 percentile of the scores of patient satisfaction. RESULTS: The result of model 1 in the multivariate logistic regression analysis demonstrated that collegial nurse-physician relations showed significant relationships with low patient satisfaction (odds ratio = 0.144, P < 0.05), while the significance was diminished in model 2, in which dummy variables of hospitals were entered into the equation. CONCLUSION: These findings suggested that a favorable work environment for nurses, which is similar to that of magnet hospitals, may influence patient satisfaction in hospitals in Japan. PMID- 26123482 TI - Increased Expression of Mitochondrial Inner-Membrane Protein Mpv17 After Intracerebral Hemorrhage in Adult Rats. AB - The Mpv17 gene encodes a mitochondrial inner-membrane protein that has been implicated in several cell activities. Almost all studies have previously indicated that loss of function or gene-inactivated in Mpv17 can induce the development of disease. Here, we explored the roles of Mpv17 protein in the pathophysiology of intracerebral hemorrhage (ICH). An ICH rat model was established and assessed by behavioral tests. Using western blot and immunohistochemistry, significant up-regulation of Mpv17 was found in neurons in brain areas surrounding the hematoma following ICH. The increase of Mpv17 expression was found to be accompanied by the enhanced expression of p53, Bax, cytochrome c (Cyt c) and active caspase-3, and decreased expression of Bcl-2 in the pathological process of rat ICH. Furthermore, immunofluorescent staining revealed that Mpv17 co-localized with p53, Bax and active caspase-3 in neurons, suggesting its biological function in the process of neuronal apoptosis. Our in vitro study, using Mpv17 RNA interference in primary cortical neurons, indicated that Mpv17 might exert its anti-apoptotic function in neuronal apoptosis. Thus, Mpv17 may play a role in protecting the brain from secondary damage following ICH. PMID- 26123483 TI - A novel embryonic plasticity gene signature that predicts metastatic competence and clinical outcome. AB - Currently, very few prognosticators accurately predict metastasis in cancer patients. In order to complete the metastatic cascade and successfully colonize distant sites, carcinoma cells undergo dynamic epithelial-mesenchymal-transition (EMT) and its reversal, mesenchymal-epithelial-transition (MET). While EMT centric signatures correlate with response to therapy, they are unable to predict metastatic outcome. One reason is due to the wide range of transient phenotypes required for a tumor cell to disseminate and recreate a similar histology at distant sites. Since such dynamic cellular processes are also seen during embryo development (epithelial-like epiblast cells undergo transient EMT to generate the mesoderm, which eventually redifferentiates into epithelial tissues by MET), we sought to utilize this unique and highly conserved property of cellular plasticity to predict metastasis. Here we present the identification of a novel prognostic gene expression signature derived from mouse embryonic day 6.5 that is representative of extensive cellular plasticity, and predicts metastatic competence in human breast tumor cells. This signature may thus complement conventional clinical parameters to offer accurate prediction for outcome among multiple classes of breast cancer patients. PMID- 26123484 TI - [Applicability of the da Vinci robotic system in the skull base surgical approach. Preclinical investigation]. AB - INTRODUCTION: The role of robotic surgery is well established in various specialties such as urology and general surgery, but not in others such as neurosurgery and otolaryngology. In the case of surgery of the skull base, it has just emerged from an experimental phase. OBJECTIVE: To investigate possible applications of the da Vinci surgical robot in transoral skull base surgery, comparing it with the authors' experience using conventional endoscopic transnasal surgery in the same region. METHODS: A transoral transpalatal approach to the nasopharynx and medial skull base was performed on 4 cryopreserved cadaver heads. We used the da Vinci robot, a 30 degrees standard endoscope 12mm thick, dual camera and dual illumination, Maryland forceps on the left terminal and curved scissors on the right, both 8mm thick. Bone drilling was performed manually. For the anatomical study of this region, we used 0.5cm axial slices from a plastinated cadaver head. RESULTS: Various skull base structures at different depths were reached with relative ease with the robot terminals CONCLUSIONS: Transoral robotic surgery with the da Vinci system provides potential advantages over conventional endoscopic transnasal surgery in the surgical approach to this region. PMID- 26123485 TI - Selective expression of Parkinson's disease-related Leucine-rich repeat kinase 2 G2019S missense mutation in midbrain dopaminergic neurons impairs dopamine release and dopaminergic gene expression. AB - Preferential dysfunction/degeneration of midbrain substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons contributes to the main movement symptoms manifested in Parkinson's disease (PD). Although the Leucine-rich repeat kinase 2 (LRRK2) G2019S missense mutation (LRRK2 G2019S) is the most common causative genetic factor linked to PD, the effects of LRRK2 G2019S on the function and survival of SNpc DA neurons are poorly understood. Using a binary gene expression system, we generated transgenic mice expressing either wild-type human LRRK2 (WT mice) or the LRRK2 G2019S mutation (G2019S mice) selectively in the midbrain DA neurons. Here we show that overexpression of LRRK2 G2019S did not induce overt motor abnormalities or substantial SNpc DA neuron loss. However, the LRRK2 G2019S mutation impaired dopamine homeostasis and release in aged mice. This reduction in dopamine content/release coincided with the degeneration of DA axon terminals and decreased expression of DA neuron-enriched genes tyrosine hydroxylase (TH), vesicular monoamine transporter 2, dopamine transporter and aldehyde dehydrogenase 1. These factors are responsible for dopamine synthesis, transport and degradation, and their expression is regulated by transcription factor paired like homeodomain 3 (PITX3). Levels of Pitx3 mRNA and protein were similarly decreased in the SNpc DA neurons of aged G2019S mice. Together, these findings suggest that PITX3-dependent transcription regulation could be one of the many potential mechanisms by which LRRK2 G2019S acts in SNpc DA neurons, resulting in downregulation of its downstream target genes critical for dopamine homeostasis and release. PMID- 26123486 TI - POLG2 disease variants: analyses reveal a dominant negative heterodimer, altered mitochondrial localization and impaired respiratory capacity. AB - Human mitochondrial DNA (mtDNA) is replicated and repaired by the mtDNA polymerase gamma, polgamma. Polgamma is composed of three subunits encoded by two nuclear genes: (1) POLG codes for the 140-kilodalton (kDa) catalytic subunit, p140 and (2) POLG2 encodes the ~110-kDa homodimeric accessory subunit, p55. Specific mutations are associated with POLG- or POLG2-related disorders. During DNA replication the p55 accessory subunit binds to p140 and increases processivity by preventing polgamma's dissociation from the template. To date, studies have demonstrated that homodimeric p55 disease variants are deficient in the ability to stimulate p140; however, all patients currently identified with POLG2-related disorders are heterozygotes. In these patients, we expect p55 to occur as 25% wild-type (WT) homodimers, 25% variant homodimers and 50% heterodimers. We report the development of a tandem affinity strategy to isolate p55 heterodimers. The WT/G451E p55 heterodimer impairs polgamma function in vitro, demonstrating that the POLG2 c.1352G>A/p.G451E mutation encodes a dominant negative protein. To analyze the subcellular consequence of disease mutations in HEK293 cells, we designed plasmids encoding p55 disease variants tagged with green fluorescent protein (GFP). P205R and L475DfsX2 p55 variants exhibit irregular diffuse mitochondrial fluorescence and unlike WT p55, they fail to form distinct puncta associated with mtDNA nucleoids. Furthermore, homogenous preparations of P205R and L475DfsX2 p55 form aberrant reducible multimers. We predict that abnormal protein folding or aggregation or both contribute to the pathophysiology of these disorders. Examination of mitochondrial bioenergetics in stable cell lines overexpressing GFP-tagged p55 variants revealed impaired mitochondrial reserve capacity. PMID- 26123487 TI - FANCB is essential in the male germline and regulates H3K9 methylation on the sex chromosomes during meiosis. AB - Fanconi anemia (FA) is a recessive X-linked and autosomal genetic disease associated with bone marrow failure and increased cancer, as well as severe germline defects such as hypogonadism and germ cell depletion. Although deficiencies in FA factors are commonly associated with germ cell defects, it remains unknown whether the FA pathway is involved in unique epigenetic events in germ cells. In this study, we generated Fancb mutant mice, the first mouse model of X-linked FA, and identified a novel function of the FA pathway in epigenetic regulation during mammalian gametogenesis. Fancb mutant mice were infertile and exhibited primordial germ cell (PGC) defects during embryogenesis. Further, Fancb mutation resulted in the reduction of undifferentiated spermatogonia in spermatogenesis, suggesting that FANCB regulates the maintenance of undifferentiated spermatogonia. Additionally, based on functional studies, we dissected the pathway in which FANCB functions during meiosis. The localization of FANCB on sex chromosomes is dependent on MDC1, a binding partner of H2AX phosphorylated at serine 139 (gammaH2AX), which initiates chromosome-wide silencing. Also, FANCB is required for FANCD2 localization during meiosis, suggesting that the role of FANCB in the activation of the FA pathway is common to both meiosis and somatic DNA damage responses. H3K9me2, a silent epigenetic mark, was decreased on sex chromosomes, whereas H3K9me3 was increased on sex chromosomes in Fancb mutant spermatocytes. Taken together, these results indicate that FANCB functions at critical stages of germ cell development and reveal a novel function of the FA pathway in the regulation of H3K9 methylation in the germline. PMID- 26123488 TI - Increased neuronal PreP activity reduces Abeta accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model. AB - Accumulation of amyloid-beta (Abeta) in synaptic mitochondria is associated with mitochondrial and synaptic injury. The underlying mechanisms and strategies to eliminate Abeta and rescue mitochondrial and synaptic defects remain elusive. Presequence protease (PreP), a mitochondrial peptidasome, is a novel mitochondrial Abeta degrading enzyme. Here, we demonstrate for the first time that increased expression of active human PreP in cortical neurons attenuates Alzheimer disease's (AD)-like mitochondrial amyloid pathology and synaptic mitochondrial dysfunction, and suppresses mitochondrial oxidative stress. Notably, PreP-overexpressed AD mice show significant reduction in the production of proinflammatory mediators. Accordingly, increased neuronal PreP expression improves learning and memory and synaptic function in vivo AD mice, and alleviates Abeta-mediated reduction of long-term potentiation (LTP). Our results provide in vivo evidence that PreP may play an important role in maintaining mitochondrial integrity and function by clearance and degradation of mitochondrial Abeta along with the improvement in synaptic and behavioral function in AD mouse model. Thus, enhancing PreP activity/expression may be a new therapeutic avenue for treatment of AD. PMID- 26123489 TI - Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington's disease. AB - Cumulative evidence indicates that the onset and severity of Huntington's disease (HD) symptoms correlate with connectivity deficits involving specific neuronal populations within cortical and basal ganglia circuits. Brain imaging studies and pathological reports further associated these deficits with alterations in cerebral white matter structure and axonal pathology. However, whether axonopathy represents an early pathogenic event or an epiphenomenon in HD remains unknown, nor is clear the identity of specific neuronal populations affected. To directly evaluate early axonal abnormalities in the context of HD in vivo, we bred transgenic YFP(J16) with R6/2 mice, a widely used HD model. Diffusion tensor imaging and fluorescence microscopy studies revealed a marked degeneration of callosal axons long before the onset of motor symptoms. Accordingly, a significant fraction of YFP-positive cortical neurons in YFP(J16) mice cortex were identified as callosal projection neurons. Callosal axon pathology progressively worsened with age and was influenced by polyglutamine tract length in mutant huntingtin (mhtt). Degenerating axons were dissociated from microscopically visible mhtt aggregates and did not result from loss of cortical neurons. Interestingly, other axonal populations were mildly or not affected, suggesting differential vulnerability to mhtt toxicity. Validating these results, increased vulnerability of callosal axons was documented in the brains of HD patients. Observations here provide a structural basis for the alterations in cerebral white matter structure widely reported in HD patients. Collectively, our data demonstrate a dying-back pattern of degeneration for cortical projection neurons affected in HD, suggesting that axons represent an early and potentially critical target for mhtt toxicity. PMID- 26123490 TI - Subcellular localization and RNAs determine FUS architecture in different cellular compartments. AB - Mutations in Fused in sarcoma (FUS) gene cause a subset of familial amyotrophic lateral sclerosis (ALS), a fatal motor neuron degenerative disease. Wild-type FUS is largely localized in the nucleus, but mutant FUS accumulates in the cytoplasm and forms inclusions. It is unclear whether FUS depletion from the nucleus or FUS inclusions in the cytoplasm triggers motor neuron degeneration. In this study, we revealed that the nuclear and cytoplasmic FUS proteins form distinct local distribution patterns. The nuclear FUS forms oligomers and appears granular under confocal microscope. In contrast, the cytoplasmic FUS forms inclusions with no oligomers detected. These patterns are determined by the subcellular localization of FUS, regardless of wild-type or mutant protein. Moreover, mutant FUS remained or re-directed in the nucleus can oligomerize and behave similarly to the wild type FUS protein. We further found that nuclear RNAs are critical to its oligomerization. Interestingly, the formation of cytoplasmic FUS inclusions is also dependent on RNA binding. Since the ALS mutations disrupt the nuclear localization sequence, mutant FUS is likely retained in the cytoplasm after translation and interacts with cytoplasmic RNAs. We therefore propose that local RNA molecules interacting with the FUS protein in different subcellular compartments play a fundamental role in determining FUS protein architecture and function. PMID- 26123492 TI - Diabetogenic milieus induce specific changes in mitochondrial transcriptome and differentiation of human pancreatic islets. AB - In pancreatic beta-cells, mitochondria play a central role in coupling glucose metabolism to insulin secretion. Chronic exposure of beta-cells to metabolic stresses impairs their function and potentially induces apoptosis. Little is known on mitochondrial adaptation to metabolic stresses, i.e. high glucose, fatty acids or oxidative stress; being all highlighted in the pathogenesis of type 2 diabetes. Here, human islets were exposed for 3 days to 25 mm glucose, 0.4 mm palmitate, 0.4 mm oleate and transiently to H2O2. Culture at physiological 5.6 mm glucose served as no-stress control. Expression of mitochondrion-associated genes was quantified, including the transcriptome of mitochondrial inner membrane carriers. Targets of interest were further evaluated at the protein level. Three days after acute oxidative stress, no significant alteration in beta-cell function or apoptosis was detected in human islets. Palmitate specifically increased expression of the pyruvate carriers MPC1 and MPC2, whereas the glutamate carrier GC1 and the aspartate/glutamate carrier AGC1 were down regulated by palmitate and oleate, respectively. High glucose decreased mRNA levels of key transcription factors (HNF4A, IPF1, PPARA and TFAM) and energy sensor SIRT1. High glucose also reduced expression of 11 mtDNA-encoded respiratory chain subunits. Interestingly, transcript levels of the carriers for aspartate/glutamate AGC2, malate DIC and malate/oxaloacetate/aspartate UCP2 were increased by high glucose, a profile suggesting important mitochondrial anaplerotic/cataplerotic activities and NADPH-generating shuttles. Chronic exposure to high glucose impaired glucose-stimulated insulin secretion, decreased insulin content, promoted caspase-3 cleavage and cell death, revealing glucotoxicity. Overall, expression profile of mitochondrion-associated genes was selectively modified by glucose, delineating a glucotoxic-specific signature. PMID- 26123491 TI - Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type dependent changes in trophicity: novel insights in nemaline myopathy. AB - Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin's functional roles in adult muscle, we studied a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscles, but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survive to adulthood with low nebulin levels (<5% of control), contain nemaline rods and undergo fiber-type switching toward oxidative types. Nebulin deficiency causes a large deficit in specific force, and mechanistic studies provide evidence that a reduced fraction of force-generating cross-bridges and shortened thin filaments contribute to the force deficit. Muscles rich in glycolytic fibers upregulate proteolysis pathways (MuRF-1, Fbxo30/MUSA1, Gadd45a) and undergo hypotrophy with smaller cross-sectional areas (CSAs), worsening their force deficit. Muscles rich in oxidative fibers do not have smaller weights and can even have hypertrophy, offsetting their specific force deficit. These studies reveal nebulin as critically important for force development and trophicity in adult muscle. The Neb cKO phenocopies important aspects of NEM (muscle weakness, oxidative fiber-type predominance, variable trophicity effects, nemaline rods) and will be highly useful to test therapeutic approaches to ameliorate muscle weakness. PMID- 26123493 TI - Mutations of protocadherin 19 in female epilepsy (PCDH19-FE) lead to allopregnanolone deficiency. AB - Protocadherin 19 (PCDH19) female limited epilepsy (PCDH19-FE; also known as epilepsy and mental retardation limited to females, EFMR; MIM300088) is an infantile onset epilepsy syndrome with or without intellectual disability (ID) and autism. We investigated transcriptomes of PCDH19-FE female and control primary skin fibroblasts, which are endowed to metabolize neurosteroid hormones. We identified a set of 94 significantly dysregulated genes in PCDH19-FE females. Intriguingly, 43 of the 94 genes (45.7%) showed gender-biased expression; enrichment of such genes was highly significant (P = 2.51E-47, two-tailed Fisher exact test). We further investigated the AKR1C1-3 genes, which encode crucial steroid hormone-metabolizing enzymes whose key products include allopregnanolone and estradiol. Both mRNA and protein levels of AKR1C3 were significantly decreased in PCDH19-FE patients. In agreement with this, the blood levels of allopregnanolone were also (P < 0.01) reduced. In conclusion, we show that the deficiency of neurosteroid allopregnanolone, one of the most potent GABA receptor modulators, may contribute to PCDH19-FE. Overall our findings provide evidence for a role of neurosteroids in epilepsy, ID and autism and create realistic opportunities for targeted therapeutic interventions. PMID- 26123494 TI - Identification of a novel MKS locus defined by TMEM107 mutation. AB - Meckel-Gruber syndrome (MKS) is a perinatally lethal disorder characterized by the triad of occipital encephalocele, polydactyly and polycystic kidneys. Typical of other disorders related to defective primary cilium (ciliopathies), MKS is genetically heterogeneous with mutations in a dozen genes to date known to cause the disease. In an ongoing effort to characterize MKS clinically and genetically, we implemented a gene panel and next-generation sequencing approach to identify the causal mutation in 25 MKS families. Of the three families that did not harbor an identifiable causal mutation by this approach, two mapped to a novel disease locus in which whole-exome sequencing revealed the likely causal mutation as a homozygous splicing variant in TMEM107, which we confirm leads to aberrant splicing and nonsense-mediated decay. TMEM107 had been independently identified in two mouse models as a cilia-related protein and mutant mice display typical ciliopathy phenotypes. Our analysis of patient fibroblasts shows marked ciliogenesis defect with an accompanying perturbation of sonic hedgehog signaling, highly concordant with the cellular phenotype in Tmem107 mutants. This study shows that known MKS loci account for the overwhelming majority of MKS cases but additional loci exist including MKS13 caused by TMEM107 mutation. PMID- 26123495 TI - Brain Metastasis in Colorectal Cancer Patients: Survival and Analysis of Prognostic Factors. AB - BACKGROUND: The purpose of the study was to characterize the rare cohort of patients (pts) with metastatic colorectal cancer (mCRC) and brain metastasis (BM) and to identify prognostic subgroups. PATIENTS AND METHODS: In collaboration with the Munich Cancer Registry, pts with mCRC and BM who were diagnosed between 1998 and 2011 were identified. Survival from the time of first diagnosis of colorectal cancer (CRC) (OS-1), from the time of diagnosis of metastatic disease (OS-2) and of BM (OS-3) was calculated regarding (1) the temporal occurrence of extra- and intracranial metastasis (meta- vs. synchronous) and (2) tumor and patient characteristics. For survival analysis the Kaplan-Meier estimator and Cox regression models were used. RESULTS: A total of 228 pts (134 male [59%], 94 female [41%]) were identified. The median age was 63 years (142 pts [62%] were 65 years of age or younger). Most pts presented with primary tumors staged T3/4, N+, Grade 2. The primary tumor was located predominantly in the left colon (155 pts; 68%), especially in the rectum (95 pts; 42%). Median OS-1 was 35.6 months (95% confidence interval [CI], 30.1-41.1 months), OS-2 was 16.5 months (95% CI, 13.9 19.1 months), and OS-3 was 2.0 months (95% CI, 1.5-2.5 months). Median time from first CRC diagnosis to BM was 29.2 months. Subsequent BM after extracranial metastasis were observed in 184 pts (80.7%), whereas 31 pts (13.6%) presented with solitary BM. Univariate analysis did not reveal a prognostic variable for overall survival after diagnosis of BM. CONCLUSION: This study presents the largest number of pts with mCRC and BM analyzed to date. The results show that most mCRC pts develop BM as a late step in the course of disease. Median time from first CRC diagnosis to BM is 29.2 months. Only a few pts were diagnosed with BM early in the disease or with solitary BM. When BM is present survival is poor. PMID- 26123496 TI - Effect of Adjuvant FOLFOX Chemotherapy Duration on Outcomes of Patients With Stage III Colon Cancer. AB - BACKGROUND: Studies have demonstrated that patients with stage III colon cancer who receive adjuvant FOLFOX (5-fluorouracil and oxaliplatin) chemotherapy experience an improved disease-free (DFS) and overall survival (OS). However, the magnitude of benefit among patients who discontinue FOLFOX early is not well known. We sought to examine the rate of FOLFOX treatment completion, determine the factors associated with adherence, and explore the relationship between duration of FOLFOX treatment and survival. PATIENTS AND METHODS: We analyzed patients diagnosed with stage III colon cancer from 2006 to 2010 and initiated at least 1 cycle of adjuvant FOLFOX at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the clinical factors associated with treatment completion, which was defined as receipt of >= 10 cycles of FOLFOX. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between early FOLFOX discontinuation and DFS and OS. RESULTS: We identified 616 patients: median age of 62 years (range, 26-80), 321 (52%) men, 536 (87%) with T3/4 tumors, and 245 (40%) with N2 disease. Among them, 183 (30%) received < 10 and 433 (70%) received >= 10 cycles. Adjusting for covariates, female sex and the absence of obstruction or perforation were each associated with receiving >= 10 cycles of FOLFOX (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.12-2.32; P = .01 and OR, 1.82; 95% CI, 1.08-3.05; P = .02, respectively). In multivariate analyses, early discontinuation of FOLFOX did not affect DFS or OS (hazard ratio [HR], 1.16; 95% CI, 0.82-1.63; P = .40 and HR, 1.07; 95% CI, 0.70-1.61; P = .76, respectively). CONCLUSION: Early discontinuation of FOLFOX was not associated with differences in survival outcomes, lending support to clinical trials that are under way to evaluate the efficacy of shorter durations of therapy. PMID- 26123497 TI - The participants' perspective: how biographic-narrative intervention influences identity negotiation and quality of life in aphasia. AB - BACKGROUND: People with aphasia experience a pronounced decrease in quality of life (QoL). Beyond that identity negotiation is hindered, which is crucial for QoL. Biographic-narrative approaches use life story telling to support identity (re)development after disruptive events like stroke. Because of the language deficits inherent in aphasia such 'talk-based' approaches have to be modified for an optimal use. AIMS: To evaluate an adapted interdisciplinary biographic narrative intervention using quantitative measures of health-related quality of life (HRQL) and mood. Additionally, semi-structured interviews were conducted to gain a deeper understanding of identity development processes in people with aphasia. METHODS & PROCEDURES: Twenty-seven participants with various types of chronic aphasia were enrolled. The biographic narrative intervention consisted of five face-to-face in-depth interviews and seven group sessions conducted over 10 weeks in a mixed-method design with pre- and post-tests and a follow-up assessment 3 months post-intervention. For quantitative evaluation the Aachen Life Quality Inventory (ALQI), the Satisfaction with Life Scale (SWLS) and the Visual Analog Mood Scales (VAMS) were used. Semi-structured interviews were conducted post-treatment, including questions concerning the participants' experiences with the intervention and identity change. Results were analysed using interpretative principles from Grounded Theory. OUTCOMES & RESULTS: For all 27 participants, we found significant and stable growth in HRQL. Self-reported states of mood also improved. As expected, overall cognitively based life satisfaction did not change. The interviews revealed two main categories: 'evaluation of the face-to-face interviews' and 'evaluation of the group sessions'. Further analysis found four overlapping main themes which were identified as identity issues: agency, control, disease concept and doing things. CONCLUSIONS & IMPLICATIONS: Our quantitative and qualitative results demonstrated the benefits associated with the biographic-narrative intervention. The participants' sense of self changed through the approach. The findings provide foundations for future work using biographic narrative interventions to influence QoL and identity renegotiation in people with aphasia. PMID- 26123498 TI - Complementary effect of oral administration of Lactobacillus paracasei K71 on canine atopic dermatitis. AB - BACKGROUND: Atopic dermatitis is a common skin disease encountered in dogs. Glucocorticoids are commonly recommended for symptomatic therapy and well tolerated adjunctive therapies may help to reduce the necessary dose and associated risks of chronic glucocorticoid use. HYPOTHESIS/OBJECTIVES: The purpose of this study was to evaluate the complementary efficacy of oral administration of Lactobacillus paracasei K71 in canine atopic dermatitis (cAD). ANIMALS: Forty one dogs with mild to moderate cAD were recruited by19 animal hospitals. METHODS: Dogs were assigned to receive either the investigational agent (K71 group; n = 20) or cetirizine hydrochloride (control group; n = 21). Previously prescribed medications were allowed to be continued during the 12 week trial. Dogs were assessed by the investigators using the cAD Extent and Severity Index (CADESI) and a medication scoring system. Pet owners assessed their dogs using a visual analog scale (VAS) and pruritus scores. RESULTS: The CADESI scores, VAS and pruritus scores in both groups at 12 weeks were improved compared with their baselines. The CADESI and pruritus scores in the K71 group were slightly lower than those in the control group and the reduction of medication scores in the K71 group was significantly lower compared with the control group (P < 0.05; Student's t-test). CONCLUSIONS AND CLINICAL IMPORTANCE: Oral administration of K71 can be useful in dogs with cAD as a complementary therapy, by providing a steroid-sparing effect. PMID- 26123499 TI - STAT4 controls GM-CSF production by both Th1 and Th17 cells during EAE. AB - BACKGROUND: In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, mice genetically deficient in the transcription factor signal transducer and activator of transcription 4 (STAT4) are resistant to disease. In contrast, deletion or inhibition of the Th1-associated cytokines IL-12 or IFNgamma which act upstream and downstream of STAT4, respectively, does not ameliorate disease. These discordant findings imply that STAT4 may act in a non canonical role during EAE. Recently, STAT4 has been shown to regulate GM-CSF production by CD4 T cells and this cytokine is necessary for the induction of EAE. However, it is not known if STAT4 controls GM-CSF production by both Th1 and Th17 effector CD4 T cells. METHODS: This study utilized the MOG(35-55) peptide immunization model of EAE. Intracellular cytokine staining and novel mixed bone marrow chimeric mice were used to study the CD4 T cell-intrinsic role of STAT4 during disease. STAT4 chromatin-immunoprecipitation (ChIP-PCR) experiments were performed to show STAT4 directly interacts with the Csf2 gene loci. RESULTS: Herein, we demonstrate that STAT4 controls CD4 T cell-intrinsic GM-CSF production by both Th1 and Th17 CD4 T cells during EAE as well as in vitro. Importantly, we show that STAT4 interacts with the Csf2 locus in MOG(35-55)-activated effector CD4 T cells demonstrating direct modulation of GM-CSF. CONCLUSIONS: Overall, these studies illustrate a previously unrecognized role of STAT4 to regulate GM CSF production by not only Th1 cells, but also Th17 effector CD4 T cell subsets during EAE pathogenesis. Critically, these data highlight for the first time that STAT4 is able to modulate the effector profile of Th17 CD4 T cell subsets, which redefines our current understanding of STAT4 as a Th1-centric factor. PMID- 26123500 TI - Determination of dopamine concentrations in brain extracellular fluid using microdialysis with short sampling intervals, analyzed by ultra high performance liquid chromatography tandem mass spectrometry. AB - INTRODUCTION: An increase in striatal dopamine is considered essential for the rewarding and reinforcing effects of drugs of abuse. We have developed and validated an ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the analysis of dopamine in rat brain extracellular fluid (ECF) sampled with microdialysis. The method was applied to monitor changes in dopamine concentrations over time after an intravenous bolus injection of heroin. METHODS: Dopamine and dopamine-d3 were analyzed using a 2.1*100mm Aquity T3 column, 1.7MUm particle size, with a formic acid and methanol gradient. The run time of the method was 2.5min including equilibration time. RESULTS: The method had an LOQ of 0.15ng/mL, which equals 0.55pg on column. The calibration curves were linear in the tested area of 0.15 to 16ng/mL. Inter-assay coefficients of variation varied between 5-17%, with an accuracy expressed as bias of -10 to 5%. The intra-assay coefficients of variation varied between 9 15%, with an accuracy of -3-7%. DISCUSSION: Heroin metabolism is very rapid. Sampling intervals of only 2min were thus required to obtain an adequate number of samples of dopamine analysis accompanying the concentration-time profile of opioids in the brain. Applying a flow of 2MUL/min, 4MUL of dialysate were sampled at 2min intervals, in 7MUL internal standard. The injection volume onto the UPLC column was 10MUL. Analyses of microdialysate samples from a rat given heroin i.v. showed that it was possible to measure baseline levels and rapid changes in dopamine concentrations with very short sampling periods. PMID- 26123501 TI - Seizure Freedom Rates and Prognostic Indicators After Resection of Gangliogliomas: A Review. AB - Gangliogliomas are rare tumors that comprise up to 40% of lesional epilepsy. Seizure control represents an important quality-of-life determinant in patients with these tumors. Here we present results of a literature review addressing rates of seizure freedom in in patients with gangliogliomas. Across studies, seizure freedom occurred in 63%-100% of patients. Many studies included follow-up times of greater than 5 years, suggesting that the responses are durable. We discuss potential prognostic factors associated with seizure freedom, including the duration of epilepsy, patient age, frequency and semiology of seizures, tumor location, extent of surgical resection, and operative strategy, including surgical approach and use of invasive monitoring. Although significant differences in study populations and treatments preclude meta-analysis, we discuss prognostic factors identified in individual studies. Increased extent of resection, lesser duration of epilepsy, and younger age at surgery have been associated with increased seizure freedom rates in at least 2 studies each. Although all studies were retrospective in nature and are consequently limited by the weaknesses inherent to such investigations, the literature suggests that surgery is able to relieve most ganglioglioma patients--regardless of patient demographics, tumor characteristics, and operative variables--of seizures. PMID- 26123502 TI - One Fusion, Two Pathologies: It Works. PMID- 26123503 TI - Surgical Skills: How Can They Be Assessed? PMID- 26123504 TI - The Pathogenetic Mechanism of Delayed Ischemic Deficit in Aneurysmal Subarachnoid Hemorrhage: A Still-Unsolved Issue. PMID- 26123505 TI - Traumatic Subarachnoid Hemorrhage Originating from Mid-Cervical Arterial Injury. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) occasionally originates from extracranial arteries, and SAH caused by cervical trauma is even rarer. CASE REPORT: A 17-year-old male patient was admitted to our emergency department aftera bike accident; he was drowsy and showed left hemiparesis. Initial computed tomography (CT) of the brain showed SAH into the cervicomedullary cistern. A 4 hour follow-up brain CT revealed heavy bleeding into the basal cistern. Because CT angiography did not show any vascular injury, we performed imaging studies of the cervical spine. Magnetic resonance imaging revealed a blood clot located ventral to the C4-C5 level of the spinal cord without any flow void. The patient's condition deteriorated over time, and he was accordingly referred for surgery. Intraoperatively, a thick subarachnoid hematoma ventral to the spinal cord was observed. The hematoma was removed and hemostasis by bipolar cauterization was performed for bleeding from a small branch of the anterior spinal artery. Postoperatively, the weakness of the lower extremity improved considerably. CONCLUSION: In young adult patients with SAH of unexplained origin, we suggest that the cervical region be considered as the bleeding focus; in such cases, surgical evacuation of bleeding can save some patients. PMID- 26123506 TI - The Need for Cost-Effective Neurosurgical Innovation--A Global Surgery Initiative. AB - The authors discuss the unmet needs for neurosurgical care around the world and some of the innovative work being done to address this need. The growing demonstration of surgical innovation and cost-effective technology represents an opportunity within neurosurgery to achieve the goal of making surgical care more accessible to the global population. PMID- 26123507 TI - The comprehensive mechanisms underlying nonhierarchical follicular development in geese (Anser cygnoides). AB - The laying performance of poultry primarily depends on the growth and development of the ovarian follicles. Yet, little is known about the underlying mechanisms responsible for nonhierarchical follicular development in avian species. The aim of the present study is identify genes that are differentially expressed during nonhierarchical follicular development in geese by performing a transcriptome screen. A sequencing depth of 13.9 and 14.9 million mapped tags was obtained in pools of small white follicles (SWF) and small yellow follicles (SYF), respectively, and a total of 160 differentially expressed genes were identified. The fold-changes of eight differentially expressed genes, identified using qRT PCR, were consistent with the Digital Gene Expression Profiling (DGE) data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses showed that lipid metabolism, steroid secretion, extracellular ligand reactions, enzyme activities, the cell cycle, ECM-receptor interactions and the extracellular matrix are involved in follicular development. The majority of the newly identified genes could be considered to be new candidate genes with potential roles in regulating follicular development. These results provide useful information for future in-depth studies associated with nonhierarchical follicular development in goose reproduction. PMID- 26123508 TI - Binding studies of terbutaline sulfate to calf thymus DNA using multispectroscopic and molecular docking techniques. AB - The interaction of terbutaline sulfate (TS) with calf thymus DNA (ctDNA) were investigated by fluorescence quenching, UV-vis absorption, viscosity measurements, ionic strength effect, DNA melting experiments and molecular docking. The binding constants (Ka) of TS to ctDNA were determined as 4.92*10(4), 1.26*10(4) and 1.16*10(4) L mol(-1) at 17, 27 and 37 degrees C, respectively. Stern-Volmer plots suggested that the quenching of fluorescence of TS by ctDNA was a static quenching. The absorption spectra of TS with ctDNA revealed a slight blue shift and hyperchromic effect. The relative viscosity ctDNA was hardly changed by TS, and melting temperature varied slightly. For the system of TS ctDNA, the intensity of fluorescence decreased with the increase of ionic strength. Also, the Ka for TS-double stranded DNA (dsDNA) was clearly weaker than that for TS-single stranded DNA (ssDNA). All these results revealed that the binding mode of TS with ctDNA should be groove binding. The enthalpy change and entropy change suggested that van der Waals force or hydrogen bonds was a main binding force between TS and ctDNA. Furthermore, the quantum yield of TS was measured by comparing with the standard solution. Based on the Forster energy transference theory (FRET), the binding distance between the acceptor and donor was calculated. Molecular docking showed that TS was a minor groove binder of ctDNA and preferentially bound to A-T rich regions. PMID- 26123509 TI - Pyrene functionalized molecular beacon with pH-sensitive i-motif in a loop. AB - In this work, we present a spectral characterization of pH-sensitive system, which combines the i-motif properties with the spatially sensitive fluorescence signal of pyrene molecules attached to hairpin ends. The excimer production (fluorescence max. ~480 nm) by pyrene labels at the ends of the molecular beacon is driven by pH-dependent i-motif formation in the loop. To illustrate the performance and reversible work of our systems, we performed the experiments with repeatedly pH cycling between pH values of 7.5+/-0.3 and 6.5+/-0.3. The sensor gives analytical response in excimer-monomer switching mode in narrow pH range (1.5 pH units) and exhibits high pH resolution (0.1 pH unit). PMID- 26123510 TI - Carbon dots preparation as a fluorescent sensing platform for highly efficient detection of Fe(III) ions in biological systems. AB - Water-soluble carbon dots (CDs) were prepared, using a facile hydrothermal oxidation route of cyclic oligosaccharide alpha-CD, as carbon sources, and alkali as additives. The successful synthesis of CDs was confirmed by scanning electron microscopy (SEM), dynamic light scattering (DLS), FTIR, UV-visible absorption, and emission fluorescence. The characterizations showed that the prepared CDs are spherical and well-dispersed in water with average diameters of approximately 2 nm. These water-soluble CDs have excellent photo stability towards photo bleaching during 30 days. The obtained CDs showed a strong emission at the wavelength of 450 nm, with an optimum excitation of 360 nm. The fluorescence quenching of CDs in the presence of Fe(III) ions was used as fluorescent probes for quantifying Fe(III) ions in aqueous solution. Under optimum condition, the fluorescence intensity versus Fe(III) concentration gave a linear response, according to Stern-Volmer equation. The linearity range of the calibration curve and the limit of detection were 1.60*10(-5) to 16.6*10(-5) mol L(-1), and 6.05*10(-6) mol L(-1), respectively, which was in the range for serum analysis of Fe(III). It was concluded that the prepared CDs had a great potential as fluorescent probes for applications in analysis of Fe(III) ions in the blood serum samples, which is hardly interfered by other ions. PMID- 26123511 TI - Conventional univariate versus multivariate spectrophotometric assisted techniques for simultaneous determination of perindopril arginin and amlodipine besylate in presence of their degradation products. AB - The resolving power of spectrophotometric assisted mathematical techniques were demonstrated for the simultaneous determination of perindopril arginin (PER) and amlodipine besylate (AML) in presence of their degradation products. The conventional univariate methods include the absorptivity factor method (AFM) and absorption correction method (ACM), which were able to determine the two drugs, simultaneously, but not in the presence of their degradation products. In both methods, amlodipine was determined directly at 360 nm in the concentration range of 8-28 MUg mL(-1), on the other hand perindopril was determined by AFM at 222.2 nm and by ACM at 208 nm in the concentration range of 10-70 MUg mL(-1). Moreover, the applied multivariate calibration methods were able for the determination of perindopril and amlodipine in presence of their degradation products using concentration residuals augmented classical least squares (CRACLS) and partial least squares (PLS). The proposed multivariate methods were applied to 19 synthetic samples in the concentration ranges of 60-100 MUg mL(-1) perindopril and 20-40 MUg mL(-1) amlodipine. Commercially available tablet formulations were successfully analysed using the developed methods without interference from other dosage form additives except PLS model, which failed to determine both drugs in their pharmaceutical dosage form. PMID- 26123512 TI - Comparative studies between 4-allyl-, 4-phenyl- and 4-ethyl-1-(2-hydroxybenzoyl) thiosemicarbazides and the synthesis, characterization and DFT calculations of binary and ternary complexes derived from 4-ethyl (L(1)) and 2,2'-dipyridyl. AB - The metal complexes of 4-ethyl-1-(2-hydroxybenzoyl) thiosemicarbazide (L(1)) with MCl2 (M=Co(2+), Cu(2+) and Zn(2+)) and Zn(Ac)2 in EtOH were synthesized and characterized using spectral (IR, (1)H-NMR, mass, UV-Visible), magnetic moment and thermal measurements. Binary and ternary complexes with the general formulae, [Cu(L(1)-H)2].EtOH, [Co(L(1)-H)2], [Zn3(L(1)-H)(L(1))(Ac)5], [Cu2(L(2))2(L(1) 2H)2(H2O)2].4H2O, [Co(L(2))(L(1)-2H)].3H2O and [Zn2(L(2))(OH)(L(1) 3H)(H2O)].1/2EtOH where L(2) is 2,2'-dipyridyl, have been suggested and characterized. The bond lengths, bond angles, chemical reactivates, energy components, binding energies and dipole moments for the isolated complexes were evaluated by DFT method from DMOL(3). Also, the MEP for L(1) is illustrated. The existence of the OH group in the Zn(2+) ternary complexes is confirmed by IR, mass and (1)H-NMR spectra. Biological activity for the L(1) and some its complexes was tested against DNA. Comparative studies between the ligation behavior and reactivity of our previous work derived from 4-phenyl- and 4-allyl-1 (2-hydroxybenzoyl) thiosemicarbazides have been investigated. PMID- 26123513 TI - Solvatochromic Stokes shift and determination of excited state dipole moments of free base and zinc octaethylporphyrin. AB - Solvent effects on the photophysical properties of free base octaethylporphyrin and zinc octaethylporphyrin are investigated at the ambient temperature (300 K). Steady state electronic absorption and emission spectra of the porphyrins are recorded in different organic solvents of varying polarity. By using solvatochromic Stokes shift method, the dipole moments associated with the first excited singlet states of the presently used porphyrin molecules are determined for the first time, to the best of our knowledge, from Lippert-Mataga, Bakhshiev and Reichardt equations. The dipole moments associated with the singlet ground state of the porphyrin molecules are calculated theoretically by using density functional theory (DFT) method by adopting B3LYP/6-31G(d,p) level using Gaussian 03 package. Moreover, some other photophysical properties (fluorescence quantum yield, fluorescence lifetime, decay rates, etc.) of the porphyrins are measured in different solvents of varying polarity. PMID- 26123514 TI - A new Salen-type azo-azomethine ligand and its Ni(II), Cu(II) and Zn(II) complexes: Synthesis, spectral characterization, crystal structure and photoluminescence studies. AB - A novel Salen-type azo-azomethine ligand H2agen, 2,2'-{ethane-1,2 diylbis[nitrilomethylylidene]}bis{4-[ethylphenyldiazenyl]phenol}, formed by the 1:2M condensation of ethane-1,2-diamine with 5-[(4-ethylphenyl)diazenyl]-2 hydroxybenzaldehyde and its nickel(II), copper(II), and zinc(II) complexes were synthesized and characterized by the spectroscopic and analytical methods. The UV vis spectra of the ligand were investigated in three organic solvents (DMSO, DMF and CHCl3). The ligand shows two absorption bands assigned to pi-pi(*) and n pi(*) transitions in the solvents used. Cu(II), and Ni(II) are tetra-coordinate binding to two phenolic oxygens and two imine nitrogens in approximate square planar geometry. Zn(II) also coordinates using the same sites like other metals but gave tetragonal configuration. Molecular structure of the Cu(II) complex [Cu(agen)] was determined by single crystal X-ray diffraction study. The X-ray data revealed that crystallographic imposed symmetry was absent for the complex molecule. In the structure, the Cu(II) ion is coordinated to two phenolate oxygen atoms and two imine nitrogen atoms of the azo-azomethine ligand with approximate square planar geometry. The ligand H2agen and its metal complexes exhibit strong blue emissions with irradiation. Fluorescence quantum yields and excited-state lifetimes for the ligand and its complexes were obtained. The H2agen ligand had a 35% quantum yield and a 3.27 ns excited-state lifetime. Complexation with metal ions caused reductions in intensities and quantum yields. PMID- 26123515 TI - Structural, spectral, thermodynamical, NLO, HOMO, LUMO and NBO analysis of fluconazole. AB - Fluconazole is an efficient antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. The molecular structure, fundamental vibrational wavenumber and intensity of the vibrational bands are interpreted, aided by density functional theory method. The results of the calculations were applied to simulated spectra of the title compound, which show excellent agreement with observed spectra. The vibrational analysis of the title compound has been carried out using FT-IR and FT-Raman spectra. Stability of the molecule arising from hyperconjugative interactions and charge delocalization has been analyzed using natural bond orbital analysis. The present investigation is extended to calculate the HOMO-LUMO energy gap, polarizability, Mulliken charges and thermodynamical properties of fluconazole at different temperature. The calculated HOMO-LUMO energy gap shows that the charge transfer occurs within the molecule. The frontier orbital and molecular electrostatic potential surface studies have been employed to understand the active sites of fluconazole. Nonlinear optical properties related to polarizability and hyperpolarizability are also discussed. The absorption characteristics and solvent analysis of fluconazole have been made using UV-Vis spectroscopic method. PMID- 26123516 TI - New photophysical insights on effect of gold nanoparticles on the interaction between phthalocyanine and PC(70)BM in solution. AB - Photoinduced processes in phthalocyanine/functionalized gold nanoparticles (Pc/AuNps) have been investigated by spectroscopic measurements. It is observed while AuNps reduce the magnitude of binding constant for the non-covalent complexation between [6,6]-phenyl C71 butyric acid methyl ester (PC70BM) and H2 Pc by 15.8 times in comparison to PC70BM/ZnPc system in toluene, fluorescence of ZnPc is strongly quenched in presence of AuNp. Fluorescence lifetime determined by time-correlated single photon counting is also strongly reduced for ZnPc in presence of AuNp compared to H2-Pc. Symbolic enhancement in quantum yield of charge-separation associated with well-defined electrostatic interaction has been confirmed for PC70BM/ZnPc supramolecule in presence of AuNp. Transient absorption measurements establish that energy transfer mechanism is operative for both PC70BM/H2-Pc and PC70BM/ZnPc supramolecules in absence and presence of AuNp in toluene. PMID- 26123517 TI - Trends in Prostate-specific Antigen Screening, Prostate Biopsies, Urology Visits, and Prostate Cancer Treatments From 2000 to 2012. AB - OBJECTIVE: To determine whether the rates of prostate-specific antigen (PSA) screening, related biopsies and subsequent prostate cancer utilization decreased between 2000 and 2012 in a large, managed care organization. METHODS: Male members of Kaiser Permanente Southern California who were aged >=40 years and had no history of prostate cancer (N = 15,326) were passively followed through electronic health plan files from January 1, 2000, through December 31, 2012 (N = 1,539,469). The rates of PSA testing, elevated PSA tests, prostate biopsies, prostate cancer treatment (surgery and radiation), and urology visits were calculated per year among eligible men and stratified by age group. RESULTS: A 59% decrease in PSA screening occurred among men aged >=75 years beginning in 2008, followed by 49% in ages 65-74, 20% in ages 50-64, and 33% in ages 40-49 years in 2009. However, the number of elevated PSA tests remained largely unchanged in all groups except in men aged >=75 years (45% decrease). Prostate biopsy rates and urology visits remained consistent among elderly men. CONCLUSION: Among men in this managed care setting, although there was a sharp decline in PSA testing among men aged >=75 years after 2008, prostate biopsy rates remained constant, and subsequent prostate cancer treatment remained highest among men in this age group. These results suggest that the guidelines recommending against PSA and the subsequent provider-targeted interventions implemented in this system resulted in decreased screening across age groups and potentially led to more discriminant screening among those aged >=75 years. PMID- 26123518 TI - Contrast-enhanced Ultrasonography for Surveillance of Radiofrequency-ablated Renal Tumors: A Prospective, Radiologist-blinded Pilot Study. AB - OBJECTIVE: To prospectively evaluate the performance of contrast-enhanced ultrasonography (CEUS) for surveillance after radiofrequency ablation (RFA) of small renal masses by comparing CEUS to the contrast-enhanced computed tomography (CECT), the current gold standard. PATIENTS AND METHODS: Patients underwent surveillance after RFA of small renal masses (<=4 cm) consisting of CECT scans at 3 and 6 months and every 6 months thereafter. Participants additionally underwent >=1 CEUS within 90 days before CECT. Percutaneous biopsy was performed for lesions suspicious for recurrence on CECT. Independent, blinded radiologists interpreted CEUS and CECT scans. Intermodality agreement was evaluated with the kappa coefficient. RESULTS: In total, 37 pairs of CEUS and CECT scans were performed. Median tumor size was 2.5 cm (range, 1.4-4.0 cm). Median follow-up from RFA to CEUS was 25 months. Renal tumor recurrences were diagnosed by CECT in 3 patients and confirmed histopathologically by percutaneous biopsy; 34 CECT scans were negative for recurrence. The diagnostic rate of CEUS was 94.6%; 2 CEUS scans were nondiagnostic because of patient body habitus. Among diagnostic CEUS scans, tumor enhancement was present in 3 and absent in 32. We observed perfect concordance between CEUS and CECT (=1.0; P <.0001). CONCLUSION: This is the first prospective study incorporating radiologist blinding to evaluate CEUS for RFA surveillance. Our findings suggest CEUS may ultimately be incorporated into RFA surveillance protocols. The operator dependency of CEUS is a possible barrier to its widespread adoption. These findings justify larger studies with longer follow up. PMID- 26123519 TI - Robot-Assisted Ureteral Reconstruction Using Buccal Mucosa. AB - OBJECTIVE: To describe the technique of robotic buccal mucosa graft ureteroplasty as a minimally invasive alternative method of ureteral reconstruction for proximal or multifocal ureteral strictures not amenable to primary anastomosis. METHODS: Between October 2013 and May 2014, we performed robotic-assisted ureteral reconstruction using buccal mucosa grafts in four patients (mean age 41.5, range 23-67). The indication for surgery was a proximal or multifocal stricture not amenable to ureteroureterostomy or ureteropyelostomy. Buccal mucosa grafts were harvested to be the length of the strictured segment and 1 cm in width and placed in the ureter as an anterior or posterior onlay. Follow up was performed with diuretic renogram at least 3 months postoperatively and renal ultrasound as well as clinical assessment of symptoms. RESULTS: All 4 patients underwent successful robotic-assisted reconstruction of the ureter using buccal mucosa graft. There were no intraoperative complications. At a median follow up of 15.5 months (range 10.7-18.6), there has been 100% success. CONCLUSION: Robotic buccal mucosa graft ureteroplasty is a feasible option for reconstruction of proximal or multifocal ureteral strictures that are not amenable to primary anastomosis and it avoids the morbidity of alternative procedures. PMID- 26123520 TI - Urological Surveillance and Medical Complications after Spinal Cord Injury in the United States. AB - OBJECTIVE: To evaluate the national patterns of urologic follow up after spinal cord injury (SCI) and the occurrence and predictors of urological complications. MATERIALS AND METHODS: This retrospective cohort study used a 5% sample of Medicare data 2007-2010. The minimum adequate urologic surveillance was defined as a urologist visit, serum creatinine evaluation, and upper urinary tract imaging study within the 2-year period. Patients were classified to their most severe complication in a multivariate linear regression model. RESULTS: Among the 7162 patients with SCI, the majority were functionally paraplegic (82.4%) and Caucasian (80.9%). Among them, 4.9% received no screening studies over the 2-year period; 70.5% received some, but not all screening; and 24.6% received all three screening tests. Patients traveled a mean of 21.3 +/- 27.5 miles to receive care. A total of 35.7% of patients saw a urologist during the 2-year period; 48.6% had some form of upper tract evaluation, with the majority being computed tomography scans; and 90.7% had serum creatinine evaluation. Of all patients, 35.8% had a minor complication during their 2-year follow up, 17.1% had a moderate complication, and 8.0% had a severe complication. In our prediction model, patient factors that correlated with increased complications included male gender, African American race, paraplegia, and receiving some or all of the neurogenic bladder recommended screening. Patients' distance of travel to their treating physician (urologist or physiatrist) did not affect the rate of complications. CONCLUSION: Urological complications are common in patients with SCI who receive Medicare. Most of these patients with SCI are not receiving even the minimum recommended surveillance for these urological complications. PMID- 26123521 TI - Translocator protein (18 kDa) as a pharmacological target in adipocytes to regulate glucose homeostasis. AB - As a major regulator in obesity and its associated metabolic complications, the proper functioning of adipocytes is crucial for health maintenance, thus serving as an important target for the development of anti-obese and anti-diabetic therapies. There is increasing evidence that mitochondrial malfunction is a pivotal event in disturbing adipocyte cell homeostasis. Among major mitochondrial structure components, the high-affinity drug- and cholesterol-binding outer mitochondrial membrane translocator protein (18 kDa; TSPO) has shown importance across a broad spectrum of mitochondrial functions. Recent studies demonstrated the presence of TSPO in white adipocyte mitochondria of mice, and administration of TSPO drug ligands to obese mice reduced weight gain and lowered glucose level. Therefore, it is of great interest to assess whether TSPO in adipocytes could serve as a drug target to regulate adipocyte activities with potential influence on weight control and glucose metabolism. Two structurally distinct TSPO drug ligands, PK 11195 and FGIN-1-27, improved the intracellular dynamics of 3T3-L1 adipocytes, such as the production and release of adipokines, glucose uptake, and adipogenesis. TSPO knockdown in either differentiated adipocytes or preadipocytes impaired these functions. Findings from 3T3-L1 cells were related to human primary cells, where TSPO expression was tightly associated with the metabolic state of primary adipocytes and the differentiation of primary preadipocytes. These results suggest that TSPO expression is essential to safeguard healthy adipocyte functions, and that TSPO activation in adipocytes improves their metabolic status in regulating glucose homeostasis. Adipocyte TSPO may serve as a pharmacologic target for the treatment of obesity and diabetes. PMID- 26123522 TI - Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders. AB - Prostaglandin (PG)E2 encompasses crucial roles in pain, fever, inflammation and diseases with inflammatory component, such as cancer, but is also essential for gastric, renal, cardiovascular and immune homeostasis. Cyclooxygenases (COX) convert arachidonic acid to the intermediate PGH2 which is isomerized to PGE2 by at least three different PGE2 synthases. Inhibitors of COX - non-steroidal anti inflammatory drugs (NSAIDs) - are currently the only available therapeutics that target PGE2 biosynthesis. Due to adverse effects of COX inhibitors on the cardiovascular system (COX-2-selective), stomach and kidney (COX-1/2 unselective), novel pharmacological strategies are in demand. The inducible microsomal PGE2 synthase (mPGES)-1 is considered mainly responsible for the excessive PGE2 synthesis during inflammation and was suggested as promising drug target for suppressing PGE2 biosynthesis. However, 15 years after intensive research on the biology and pharmacology of mPGES-1, the therapeutic value of mPGES-1 as drug target is still vague and mPGES-1 inhibitors did not enter the market so far. This commentary will first shed light on the structure, mechanism and regulation of mPGES-1 and will then discuss its biological function and the consequence of its inhibition for the dynamic network of eicosanoids. Moreover, we (i) present current strategies for interfering with mPGES-1-mediated PGE2 synthesis, (ii) summarize bioanalytical approaches for mPGES-1 drug discovery and (iii) describe preclinical test systems for the characterization of mPGES-1 inhibitors. The pharmacological potential of selective mPGES-1 inhibitor classes as well as dual mPGES-1/5-lipoxygenase inhibitors is reviewed and pitfalls in their development, including species discrepancies and loss of in vivo activity, are discussed. PMID- 26123523 TI - LECT2 induces atherosclerotic inflammatory reaction via CD209 receptor-mediated JNK phosphorylation in human endothelial cells. AB - OBJECTIVE: Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered novel hepatokine, leading to skeletal muscle insulin resistance by activating c Jun N-terminal kinase (JNK). However, its role in atherosclerotic inflammatory reactions has not been examined. Therefore, we investigated the function of LECT2 on the expression of vascular adhesion molecules and inflammatory cytokines in human endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) and THP-1 cells were treated with various doses of LECT2 and the functions and signaling pathways were analyzed through Western blot and quantitative real-time PCR (qPCR). RESULTS: The level of phosphorylated c-Jun N-terminal kinases (JNK) was significantly increased by LECT2 treatment in HUVECs and THP-1 cells, an effect that was not seen in cells treated with CD209 siRNA, a known LECT2 receptor. LECT2 treatment efficiently increased the expression of intercellular adhesion molecule-1 (ICAM-1) and pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha), monocyte chemo-attractant protein-1 (MCP-1), and interleukin 1beta (IL-1beta) in HUVECs and THP-1 cells. However, all these reactions were significantly reduced in response to treatment with JNK inhibitor. Furthermore, LECT2 treatment significantly exacerbated the adhesion of monocytic cells to human endothelial cells, which was also efficiently attenuated by JNK inhibitor. CONCLUSIONS: LECT2 significantly induced adhesion molecules and pro-inflammatory cytokines in HUVECs via CD209-mediated JNK phosphorylation, suggesting that liver derived novel hepatokine, LECT2, might directly mediate in the atherosclerotic inflammatory reactions in human endothelial cells. PMID- 26123525 TI - Hypertension: high prevalence and a positive association with obesity among Aboriginal and Torres Strait Islander youth in far north Queensland. AB - OBJECTIVE: Hypertension and other chronic disease risks are common among Aboriginal and Torres Strait Islander adults but there is little evidence regarding the epidemiology of these risk factors during adolescence. This study examines the prevalence of pre-hypertension, hypertension and other cardiovascular risk factors in Aboriginal and Torres Strait Islander people aged 15-24 years living in remote Indigenous communities in north Queensland. In so doing, it aims to better inform the approach to cardiovascular disease in this population. METHODS: This is a descriptive study that retrospectively examines health service data from a program of community screening, the Young Persons Check (YPC). Participants were 1,883 Aboriginal and Torres Strait Islander people aged 15-24 years who attended for a YPC in 11 remote communities in north Queensland between March 2009 and April 2011. RESULTS: Overall, the prevalence of pre-hypertension was 34.0%; stage I hypertension was 17.7% and stage II hypertension was 3.3%. The prevalence of elevated waist circumference was 47.6%, overweight or obesity 45.9%, elevated triglycerides 18.3%, decreased HDL 54.8% and proteinuria 24.3%. The prevalence of hypertension (stage I or II) among Torres Strait Islander males was 34.1%, Aboriginal males 26.9%, Torres Strait Islander females 12.6% and Aboriginal females 13.0%. Hypertension was associated with sex (males) (OR= 4.37, p<0.000), overweight (OR=2.46, p<0.000), obesity (OR=4.59, p<0.000) and elevated triglycerides (OR=2.38, p<0.000). CONCLUSION: Pre hypertension, hypertension and other cardiovascular risk in this population is highly prevalent. Hypertension was particularly prevalent among male participants. The results reiterate the importance of early life experience in cardiovascular disease prevention. PMID- 26123524 TI - PPL2ab neurons restore sexual responses in aged Drosophila males through dopamine. AB - Male sexual desire typically declines with ageing. However, our understanding of the neurobiological basis for this phenomenon is limited by our knowledge of the brain circuitry and neuronal pathways controlling male sexual desire. A number of studies across species suggest that dopamine (DA) affects sexual desire. Here we use genetic tools and behavioural assays to identify a novel subset of DA neurons that regulate age-associated male courtship activity in Drosophila. We find that increasing DA levels in a subset of cells in the PPL2ab neuronal cluster is necessary and sufficient for increased sustained courtship in both young and aged male flies. Our results indicate that preventing the age-related decline in DA levels in PPL2ab neurons alleviates diminished courtship behaviours in male Drosophila. These results may provide the foundation for deciphering the circuitry involved in sexual motivation in the male Drosophila brain. PMID- 26123526 TI - Preoperative Methods to Reduce Liver Volume in Bariatric Surgery: a Systematic Review. AB - BACKGROUND: Patients qualified for gastric bypass surgery have an enlarged and fatty liver. An essential step in gastric bypass surgery is elevation of the left liver lobe to expose the gastroesophageal junction. An enlarged and fatty liver complicates the surgical procedure and increases the risk for laceration of the liver. The aim of our study was to evaluate methods to reduce liver volume in patients prior to gastric bypass surgery. METHODS: A systematic literature search of multiple databases, including PubMed, EMBASE.com, and the Cochrane Library and a hand search of reference lists, was performed. We used the search terms morbid obesity and liver, including their synonyms and controlled terms. Inclusion criteria were as follows: patients with morbid obesity who qualified for bariatric surgery, the use of a preoperative treatment to reduce liver volume, and the use of imaging techniques before and after treatment. RESULTS: In total, 281 patients in 11 different studies were included. Preoperative diets reduced liver size by an average of 14%, alternative methods including nutritional supplements, reduced liver size between 20 and 43%, and an intragastric balloon by 32%. CONCLUSIONS: This review showed that nutritional supplements and intragastric balloon are more effective than low calorie diets in reducing liver volume prior to gastric bypass surgery. However, low calorie diet is the preferable method to reduce liver volume, considering the level of evidence and practical applicability. There is a need for well-designed randomized studies with sufficient power in order to confirm the effectiveness of preoperative methods to reduce liver volume. PMID- 26123527 TI - The spontaneous arterial blood pressure rise after aneurysmal subarachnoid hemorrhage - a biphasic phenomenon. AB - OBJECTIVES: A spontaneous blood pressure (BP) rise is frequently observed after aneurysmal subarachnoid hemorrhage (aSAH). The current study was designed to characterize the time course of this BP rise and its relation to clinical and radiological parameters. METHODS: The diastolic (DBP), mean (MAP), and systolic (SBP) BP values were determined in 61 aSAH patients from day 0 to 9. The patient's initial status was evaluated by the world federation of neurological surgeons scale and the Hijdra scale. The clinical outcome was quantified by the modified Rankin Scale, the Glasgow Outcome Scale Extended, and the National Institute of Health Stroke Scale. The degree of proximal and global vasospasm was calculated by comparison of the baseline angiography on day 0 and the control angiography on day 8. Furthermore, the influence of propofol and norepinephrine application was analyzed. RESULTS: DBP, MAP, and SBP demonstrated an early rise in all patients from day 2 till 5 (p<0.001) and remained hypertensive until day 9. No significant correlation could be detected between this early BP rise and most clinical and radiological variables. From day 8 onwards, a divergence of the SBP courses was detected between patients with severe vs. non-severe global vasospasm. There was a secondary, norepinephrine independent SBP rise in patients with severe global vasospasm that significantly correlated with the initial Hijdra-scale and an unfavorable clinical outcome. CONCLUSIONS: The results demonstrate a biphasic BP course with a uniform early BP rise in all patients and an additional delayed SBP rise in patients with severe global vasospasm. PMID- 26123528 TI - The cost-effectiveness of surgery for trigeminal neuralgia in surgically naive patients: a retrospective study. AB - OBJECTIVE: For 75% of patients with trigeminal neuralgia (TN), the pain can be controlled with medication. For those who fail medication therapy, surgical options include microvascular decompression (MVD), percutaneous radiofrequency rhizotomy (RFR), and stereotactic radiosurgery (SRS). Few studies have explored the relative cost-effectiveness of these interventions, particularly in surgically naive patients. METHODS: A retrospective chart review performed between January 2003 and January 2013 identified a total of 89 patients who underwent surgical treatment for TN (MVD=27, RFR=23, SRS=39). Outcome measures included facial pain (excellent=no pain, no medications; good=no pain, medications required; fair=>50% decrease in pain; and poor=<50% decrease in pain/secondary surgery), numbness, cost, and the need for a subsequent procedure. RESULTS: The average age of patients for each procedure was MVD=53.9+/-16, RFR=76.2+/-16, and SRS=74.5+/-12 (p<0.001 MVD vs. other modalities). Total charges for the procedures (US dollars) were MVD=50,100+/-9600, RFR=4700+/-2200, and SRS=39,300+/-6000 (p<0.001). Actual collections varied by insurance. Percentages of postoperative facial numbness were MVD=11%, RFR=52%, and SRS=28% (p<0.01). At two years, the rates of recurrence requiring a second procedure were MVD=22%, RFR=74%, and SRS=31% (p<0.01). Average times to secondary procedure in months were MVD=26+/-29, RFR=59+/-76, and SRS=35+/-25. Mean quality adjusted pain free years were MVD=1.58, RFR=2.28, and SRS=0.99. Cost-effectiveness calculations in US dollars showed MVD=31,800, RFR=2100, and SRS=39,600 (p<0.001). CONCLUSION: There are significant cost differences among the three most common surgical procedures for TN. MVD was the most expensive procedure, was more likely to be performed on younger patients, had the lowest rate of facial numbness, and had the lowest rate of recurrence requiring a secondary procedure. SRS was slightly less costly, more likely to be performed on an older population, and had a rate of recurrence similar to MVD. RFR was the least expensive procedure, provided immediate relief, but was associated with the highest rates of facial numbness and recurrence. Based on cost-effectiveness, considering both cost and outcome, RFR was the most cost-effective, followed by MVD, and finally SRS. PMID- 26123529 TI - Editorial--Avoiding Unethical Helicobacter pylori Clinical Trials: Susceptibility Based Studies and Probiotics as Adjuvants. AB - As a general rule, any clinical study where the result is already known or when the investigator(s) compares an assigned treatment against another assigned treatment known to be ineffective in the study population (e.g., in a population with known clarithromycin resistance) is unethical. As susceptibility-based therapy will always be superior to empiric therapy in any population with a prevalence of antimicrobial resistance >0%, any trial that randomizes susceptibility-based therapy with empiric therapy would be unethical. The journal Helicobacter welcomes susceptibility or culture-guided studies, studies of new therapies, and studies of adjuvants and probiotics. However, the journal will not accept for review any study we judge to be lacking clinical equipoise or which assign subjects to a treatment known to be ineffective, such as a susceptibility based clinical trial with an empiric therapy comparator. To assist authors, we provide examples and suggestions regarding trial design for comparative studies, for susceptibility-based studies, and for studies testing adjuvants or probiotics. PMID- 26123531 TI - Reversible control of pore size and surface chemistry of mesoporous silica through dynamic covalent chemistry: philicity mediated catalysis. AB - Here, we report the synthesis of adaptive hybrid mesoporous silica having the ability to reconfigure its pore properties such as pore size and philicity in response to the external environment. Decyl chains were reversibly appended to the pore walls of silica through imine motifs as dynamic covalent modules to switch the pore size and philicity in response to pH. This switching of pore properties was used to gate the access of reactants to the gold nanoparticles immobilized inside the nanopores, thus enabling us to turn-on/turn-off the catalytic reaction. The use of such dynamic covalent modules to govern pore properties would enable the realization of intelligent hybrids capable of controlling many such chemical processes in response to stimuli. PMID- 26123530 TI - Consequences of Nosema apis infection for male honey bees and their fertility. AB - The queens of eusocial bees, ants and wasps mate only during a very short period early in life and males therefore produce ejaculates consisting of large numbers of high quality sperm. Such extreme selection for high fecundity resulted in males investing minimally into their somatic survival, including their immune system. However, if susceptible males are unable to protect their reproductive tissue from infections, they compromise queen fitness if they transfer pathogens during mating. We used the honey bee Apis mellifera and investigated the course of infection of the sexually transmitted pathogen Nosema apis. We predicted that honey bee males are susceptible but protect their reproductive tissues from infections. We investigated the effects of N. apis infections on the midgut, the accessory glands and the accessory testes and quantified the consequences of infection on male survival and fecundity. We found that N. apis is able to infect males, and as infections progressed, it significantly impacted fertility and survival in older males. Even though we confirm males to be able to minimize N. apis infections of their reproductive tissues, the parasite is present in ejaculates of older males. Consequently N. apis evolved alternative routes to successfully infect ejaculates and get sexually transmitted. PMID- 26123532 TI - Rapid endosomal escape of prickly nanodiamonds: implications for gene delivery. AB - The prickly nanodiamonds easily entered cells via endocytosis followed by unique intracellular translocation characteristics-quick endosomal escape followed by stable residence in cytoplasm. Endosomal membrane rupturing is identified as the major route of nanodiamonds' escaping the vesicle confinement and to the cytoplasm. Little cytotoxicity is observed to associate with the nanodiamonds' cytosolic release. Such features enable its application for gene delivery, which requires both effective cellular uptake and cytosolic release of the gene. Taking green fluorescent protein gene as an example, we demonstrate the successful cytosolic delivery and expression of such a gene using the prickly nanodiamonds as carrier. PMID- 26123533 TI - Within-strain variation in behavior differs consistently between common inbred strains of mice. AB - Genetic and environmental factors interact throughout life and give rise to individual differences, i.e., individuality. The diversifying effect of environmental factors is counteracted by genetic mechanisms to yield persistence of specific features (robustness). Here, we compared robustness between cohorts of isogenic mice of eight different commonly used strains by analyzing to what extent environmental variation contributed to individuality in each of the eight genotypes, using a previously published dataset. Behavior was assessed in the home-cage, providing control over environmental factors, to reveal within-strain variability in numerous spontaneous behaviors. Indeed, despite standardization and in line with previous studies, substantial variability among mice of the same inbred strain was observed. Strikingly, across a multidimensional set of 115 behavioral parameters, several strains consistently ranked high in within-strain variability (DBA/2J, 129S1/Sv A/J and NOD/LtJ), whereas other strains ranked low (C57BL/6J and BALB/c). Strain rankings of within-strain variability in behavior were confirmed in an independent, previously published behavioral dataset using conventional behavioral tests administered to different mice from the same breeding colonies. Together, these show that genetically inbred mouse strains consistently differ in phenotypic robustness against environmental variation, suggesting that genetic factors contribute to variation in robustness. PMID- 26123534 TI - The Mouse Genomes Project: a repository of inbred laboratory mouse strain genomes. AB - The Mouse Genomes Project was initiated in 2009 with the goal of using next generation sequencing technologies to catalogue molecular variation in the common laboratory mouse strains, and a selected set of wild-derived inbred strains. The initial sequencing and survey of sequence variation in 17 inbred strains was completed in 2011 and included comprehensive catalogue of single nucleotide polymorphisms, short insertion/deletions, larger structural variants including their fine scale architecture and landscape of transposable element variation, and genomic sites subject to post-transcriptional alteration of RNA. From this beginning, the resource has expanded significantly to include 36 fully sequenced inbred laboratory mouse strains, a refined and updated data processing pipeline, and new variation querying and data visualisation tools which are available on the project's website ( http://www.sanger.ac.uk/resources/mouse/genomes/ ). The focus of the project is now the completion of de novo assembled chromosome sequences and strain-specific gene structures for the core strains. We discuss how the assembled chromosomes will power comparative analysis, data access tools and future directions of mouse genetics. PMID- 26123535 TI - Medication of inclusion body myositis: a systematic review. AB - To investigate the existing evidence on the effectiveness of approaches to treating inclusion body myositis and to assess the methodological quality of this evidence. The Cochrane Controlled Trials Register (CENTRAL), Medline, Embase, Cinahl, Physiotherapy Evidence (Pedro), McMaster and Web of Science databases were searched. The references of identified articles and reviews were also checked for relevancy. The methodological quality was assessed according to the Cochrane Collaboration's domain-based evaluation framework. Of the 331 identified records, 10 were considered relevant for a qualitative analysis. The risk of bias was considered being low for six studies and high for four. Eight studies were randomized controlled trials, and two were controlled clinical trials. In the samples, male gender predominated, and the mean age of the participants varied from 51 to 72 years. The duration of intervention varied from 3 to 17 months. One small trial on the effect of oxandrolone reported a significant positive result. The other trials observed no improvement or insignificant improvement among the participants treated with intravenous immunoglobulin, methotrexate, etanercept or interferon. Thus far, there is no evidence indicating that any specific treatment is the effective in treating inclusion body myositis. PMID- 26123537 TI - Dynamic compression combined with SOX-9 overexpression in rabbit adipose-derived mesenchymal stem cells cultured in a three-dimensional gradual porous PLGA composite scaffold upregulates HIF-1alpha expression. AB - There is considerable interest in how the fate of adipose-derived stem cells is determined. Physical stimuli play a crucial role in skeletogenesis and in cartilage repair and regeneration. In the present study, we investigated the comparative and interactive effects of dynamic compression and SRY-related high mobility group box gene-9 (SOX-9) on chondrogenesis of rabbit adipose-derived stem cells in three-dimensional gradual porous PLGA (polylactic-co-glycolic acid) composite scaffolds. Articular cartilage is stratified into zones delineated by characteristic changes in cellular, matrix, and nutritive components. As a consequence, biochemical and biomechanical properties vary greatly between the different zones, giving the tissue its unique structure and, thus, the ability to cope with extreme loading. The effects on development of the cartilage were examined using a combination of computational modeling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations. In addition, early chondrogenic differentiation was assessed via real-time PCR of mRNA expression levels for bone- and cartilage-specific gene markers. Our findings define the important role of dynamic compression combined with SOX-9 overexpression during in vitro generation of tissue-engineering cartilage and suggest that a 3D gradual porous PLGA composite scaffold may benefit articular cartilage tissue engineering in cartilage regeneration for better force distribution. PMID- 26123539 TI - Nerve ultrasound in Miller Fisher variant of Guillain-Barre syndrome. AB - INTRODUCTION: Focal enlargement of the peripheral and spinal nerves, visualized using high-resolution ultrasound (HRUS), has been reported in early Guillain Barre syndrome, but not in the Miller Fisher variant. We report the use of HRUS in 2 patients who presented with acute ataxic neuropathy, areflexia, and ophthalmoparesis. METHODS: Ultrasound and/or nerve conduction studies (NCS) of peripheral nerves, the vagus, and spinal nerves C5/6 were performed at onset and 2 weeks after immunoglobulin therapy. RESULTS: Both patients fulfilled criteria for diagnosis of Miller Fisher syndrome (MFS). Laboratory findings revealed elevated ganglioside Q1b antibodies in both and an albuminolocytologic dissociation in 1 patient. In addition, 1 patient had NCS evidence for demyelinating neuropathy. However, ultrasound showed focal enlargement in the vagus, the spinal nerves, and/or in the peripheral nerves in both patients. After therapy, nerve enlargement decreased in parallel with clinical improvement. CONCLUSION: Spinal and/or peripheral nerve enlargement supports the diagnosis of MFS in early phases of the disease. PMID- 26123538 TI - Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib. AB - First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents, primarily due to secondary EGFR mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of afatinib, an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the EGFR, human epidermal growth factor receptor (HER)-2, HER3, and HER4 receptors. In two phase III trials in patients with EGFR mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) and health related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, afatinib significantly improved overall survival in patients harboring EGFR Del19 mutations. Afatinib has also demonstrated clinical activity in NSCLC patients who had progressed on erlotinib/gefitinib, particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with paclitaxel versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung. The activity of afatinib in both first line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events. PMID- 26123540 TI - Environmental contaminants of emerging concern in seafood--European database on contaminant levels. AB - Marine pollution gives rise to concern not only about the environment itself but also about the impact on food safety and consequently on public health. European authorities and consumers have therefore become increasingly worried about the transfer of contaminants from the marine environment to seafood. So-called "contaminants of emerging concern" are chemical substances for which no maximum levels have been laid down in EU legislation, or substances for which maximum levels have been provided but which require revision. Adequate information on their presence in seafood is often lacking and thus potential risks cannot be excluded. Assessment of food safety issues related to these contaminants has thus become urgent and imperative. A database (www.ecsafeseafooddbase.eu), containing available information on the levels of contaminants of emerging concern in seafood and providing the most recent data to scientists and regulatory authorities, was developed. The present paper reviews a selection of contaminants of emerging concern in seafood including toxic elements, endocrine disruptors, brominated flame retardants, pharmaceuticals and personal care products, polycyclic aromatic hydrocarbons and derivatives, microplastics and marine toxins. Current status on the knowledge of human exposure, toxicity and legislation are briefly presented and the outcome from scientific publications reporting on the levels of these compounds in seafood is presented and discussed. PMID- 26123541 TI - Prevalence of urinary incontinence in older Turkish women, risk factors, and effect on activities of daily living. AB - PURPOSE: The study was conducted to determine the prevalence of urinary incontinence (UI) among older women, risk factors, and the effect on activities of daily living (ADLs). METHOD: The study was conducted in family health centers located in a city in eastern Turkey. The study population consisted of 1094 women age 65 and older chosen with a simple random sampling method. The inclusion criteria were 65 years and older, female, and not diagnosed with mental or emotional diseases or conditions that obstruct communication. Data were collected in face-to-face interviews with the Questionnaire and Daily Life Activities Data Form created by the researchers based on the Roper, Logan, and Tierney model. RESULTS: The prevalence of UI in women age 65 and older was 51.6%, and the most common type was urge incontinence. The number of births, number of abortions, age at last birth, and home births affected the development of UI (p<0.001). In addition, body mass index, constipation, urinary tract infection, cough, hormone replacement therapy, genital prolapse, cystocele, urogenital surgery, nocturia, and daily urine output were determined to be risk factors (p<0.001). Among the ADLs, 13.7% with UI reported that they had fallen when getting up from the toilet, 34.3% had experienced a sense of shame, 45.8% avoided coughing, and 46.5% restricted fluid intake. CONCLUSION: Prevalence of UI in women age 65 and older was high, and the most common was urge incontinence. UI has many risk factors and affects many ADLs. PMID- 26123542 TI - Heterologous expression of flax PHOSPHOLIPID:DIACYLGLYCEROL CHOLINEPHOSPHOTRANSFERASE (PDCT) increases polyunsaturated fatty acid content in yeast and Arabidopsis seeds. AB - BACKGROUND: Flax (Linum usitatissimum L.) is an agriculturally important crop with seed oil enriched in alpha-linolenic acid (18:3 (cisDelta9, 12, 15); ALA). This polyunsaturated fatty acid (PUFA) is the major determinant for the quality of flax seed oil in food, nutraceuticals and industrial applications. The recently identified enzyme: phosphatidylcholine diacylglycerol cholinephosphotransferase (PDCT), catalyzes the interconversion between phosphatidylcholine (PC) and diacylglycerol (DAG), and has been shown to play an important role in PUFA accumulation in Arabidopsis thaliana seeds. METHODS: Two flax PDCT genes were identified using homology-based approach. RESULTS: In this study, we describe the isolation and characterization of two PDCT genes from flax (LuPDCT1 and LuPDCT2) with very high nucleotide sequence identity (97%) whose deduced amino acid sequences exhibited approximately 55% identity with that of A. thaliana PDCT (AtROD1). The genes encoded functionally active enzymes that were strongly expressed in developing embryos. Complementation studies with the A. thaliana rod1 mutant demonstrated that the flax PDCTs were capable of restoring PUFA levels in planta. Furthermore, PUFA levels increased in Saccharomyces cerevisiae when the flax PDCTs were co-expressed with FATTY ACID DESATURASES (FADs), FAD2 and FAD3, while seed-specific expression of LuPDCT1 and LuPDCT2 in A. thaliana resulted in 16.4% and 19.7% increases in C18-PUFAs, respectively, with a concomitant decrease in the proportion of oleic acid (18:1 (cisDelta9); OA). CONCLUSIONS: The two novel PDCT homologs from flax are capable of increasing C18-PUFA levels substantially in metabolically engineered yeast and transgenic A. thaliana seeds. These flax PDCT proteins appear to play an important dual role in the determination of PUFA content by efficiently channelling monounsaturated FAs into PC for desaturation and moving the resulting PUFAs out of PC for subsequent use in TAG synthesis. These results indicate that flax PDCTs would be useful for bioengineering of oil crops to increase PUFA levels for applications in human food and nutritional supplements, animal feed and industrial bioproducts. PMID- 26123543 TI - Role of epithelial-mesenchymal transition markers in triple-negative breast cancer. AB - Triple-negative breast cancers (TNBCs) are a heterogeneous group of breast tumours that are often associated with adverse pathological characteristics, poorer clinical outcomes and lack of targeted therapeutic options. Epithelial mesenchymal transition, which plays a crucial role in tumour development and progression, is characterised by a transition from epithelial to mesenchymal phenotype and loss of proteins involved in maintaining cell junctions. We aimed to correlate protein expression of E-cadherin, Snail2 and transforming growth factor beta (TGF-beta) with clinicopathological parameters and survivals of a series of patients with TNBC. The study cohort comprised 767 TNBCs diagnosed at the Department of Pathology, Singapore General Hospital from 1994 to 2012. Immunohistochemistry was performed on sections cut from tissue microarrays using the polymeric method. Staining intensity and percentage of positive tumour cells were evaluated and correlated with clinicopathological findings and clinical outcomes. Loss of E-cadherin expression, Snail2 positivity, cytoplasmic and nuclear expression of TGF-beta were observed in 265 (35.2 %), 241 (32.0 %), 272 (36.2 %) and 262 (34.8 %) tumours, respectively. Histological grade significantly correlated with Snail2 positivity (P < 0.001) and loss of membranous E-cadherin expression (P = 0.003). Nuclear expression of TGF-beta was inversely correlated with histological grade (P = 0.010). Median follow-up was 73 months, with a maximum of 236 months. Despite a graphical curve for earlier recurrence in patients with tumours harbouring a combinational phenotype of loss of membranous E-cadherin and positive Snail2 expression, there was no statistical significance. Similarly for women with tumours expressing cytoplasmic TGF-beta, graphical representation showed poorer metastasis-free survival but without statistical significance. Loss of membranous E-cadherin and positive Snail2 expression are significantly associated with high-grade TNBCs. More work is needed to improve understanding of the role of TGF-beta in TNBC. PMID- 26123545 TI - Extensive range overlap between heliconiine sister species: evidence for sympatric speciation in butterflies? AB - BACKGROUND: Sympatric speciation is today generally viewed as plausible, and some well-supported examples exist, but its relative contribution to biodiversity remains to be established. We here quantify geographic overlap of sister species of heliconiine butterflies, and use age-range correlations and spatial simulations of the geography of speciation to infer the frequency of sympatric speciation. We also test whether shifts in mimetic wing colour pattern, host plant use and climate niche play a role in speciation, and whether such shifts are associated with sympatry. RESULTS: Approximately a third of all heliconiine sister species pairs exhibit near complete range overlap, and analyses of the observed patterns of range overlap suggest that sympatric speciation contributes 32%-95% of speciation events. Mullerian mimicry colour patterns and host plant choice are highly labile traits that seem to be associated with speciation, but we find no association between shifts in these traits and range overlap. In contrast, climatic niches of sister species are more conserved. CONCLUSIONS: Unlike birds and mammals, sister species of heliconiines are often sympatric and our inferences using the most recent comparative methods suggest that sympatric speciation is common. However, if sister species spread rapidly into sympatry (e.g. due to their similar climatic niches), then assumptions underlying our methods would be violated. Furthermore, although we find some evidence for the role of ecology in speciation, ecological shifts did not show the associations with range overlap expected under sympatric speciation. We delimit species of heliconiines in three different ways, based on "strict and " "relaxed" biological species concepts (BSC), as well as on a surrogate for the widely-used "diagnostic" version of the phylogenetic species concept (PSC). We show that one reason why more sympatric speciation is inferred in heliconiines than in birds may be due to a different culture of species delimitation in the two groups. To establish whether heliconiines are exceptional will require biogeographic comparative studies for a wider range of animal taxa including many more invertebrates. PMID- 26123546 TI - Exploration of the treatment challenges in men with intellectual difficulties and testicular cancer as seen in Down syndrome: single centre experience. AB - Down syndrome is the most common chromosomal disorder in humans as well as the most common cause of inherited intellectual disability. A spectrum of physical and functional disability is associated with the syndrome as well as a predisposition to developing particular malignancies, including testicular cancers. These tumours ordinarily have a high cure rate even in widely disseminated disease. However, individuals with Down syndrome may have learning difficulties, behavioural problems, and multiple systemic complications that have the potential to make standard treatment more risky and necessitates individualized approach in order to avoid unacceptable harm. There is also suggestion that tumours may have a different natural history. Further, people with learning disabilities have often experienced poorer healthcare than the general population. In order to address these inequalities, legislation, professional bodies, and charities provide guidance; however, ultimately, consideration of the person in the context of their own psychosocial issues, comorbidities, and possible treatment strategies is vital in delivering optimal care. We aim to present a review of our own experience of delivering individualized care to this group of patients in order to close the existing health inequality gap. PMID- 26123547 TI - Steenbeek Brace: Patterns of Wear. AB - Steenbeek foot abduction brace (SFAB) is an essential orthotic for maintaining correction in congenital talipes equinovarus treated with Ponseti method. As the brace is used up to 3 to 4 years of age, we examined the brace wear pattern according to a child's development and age. We studied 100 SFABs that were rendered unusable or returned by parents due to advanced brace wear. SFABs returned due to other reasons such as foot outgrowing shoe size were excluded. Each part of the brace (outer sole, insole, upper leather, abduction bar, shoe laces) was carefully inspected to observe any pattern of damage. We grouped the pattern of brace wear as per the probable causative factors into 3 broad categories: due to general use in all age groups, sitters and crawlers, and walking children. Shredded tongue, elongated/torn shoelace hole, peeled paint of metal abduction bar, shredded outer sole, and frayed shoelace were due to general use. Due to sitting and crawling with the brace on, shoe wore on its anteromedial, anterolateral, and posterolateral parts at the junction of the upper leather and outer sole. The commonest area of shoe wear in walkers was the abduction bar, which either broke from the welded junction between bar and metal or was bent at midpoint. The SFAB wear pattern was related to the age of the child and his/her activities. The reusability of the brace can probably be extended with simple improvisations and instructing parents about the correct use of the brace. LEVELS OF EVIDENCE: Prognostic, Level IV: Case series. PMID- 26123544 TI - Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. AB - RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-kappaB and beta-catenin) in regulating hallmarks of cancer has also been discussed. PMID- 26123548 TI - Musculoskeletal Health Literacy in Patients With Foot and Ankle Injuries: A Cross Sectional Survey of Comprehension. AB - PURPOSE: Approximately 33% of Americans have inadequate health literacy, which is associated with decreased medical knowledge, increased hospitalization and use of emergency care, and worse control of diseases. In this study, the Literacy in Musculoskeletal Problems (LiMP) questionnaire was used to evaluate the prevalence of limited musculoskeletal literacy in patients presenting to the emergency department (ED) with foot and ankle-related complaints, as these individuals may be at increased risk for inferior outcomes. METHODS: In this cross-sectional study, individuals >=18 years of age presenting with foot and ankle-related complaints to the ED were invited to participate. Participants completed a demographic survey and the LiMP questionnaire, with scores >=6 indicative of adequate musculoskeletal literacy. The prevalence of adequate health literacy and the influence of demographic parameters was assessed. P values <.05 were considered significant. RESULTS: The mean LiMP score was 5 +/- 2.06. Limited musculoskeletal health literacy was seen in 32% of participants (18/56). Although gender (male), a current or prior employment in a health care field, and having previously seen a physician for a musculoskeletal complaint correlated with higher literacy rates, these values did not reach statistical significance (P > .05). However, Caucasians and those with higher levels of education (equal to or more than college) were significantly more likely to possess adequate literacy (P = .008, P = .04, respectively). CONCLUSIONS: Approximately one third of patients presenting to the ED with foot and ankle-related complaints have limited musculoskeletal literacy and may lack the necessary skills required for making informed decisions regarding their care. This is concerning and has tremendous socioeconomic implications, as more than 23 000 people per day require medical care for ankle sprains in the United States, with average treatment costs for this injury in the ED setting estimated at $1498. Identification of those most at risk is thus crucial and will facilitate the development of interventions geared toward those most vulnerable. LEVELS OF EVIDENCE: Prognostic, Level IV study. PMID- 26123549 TI - Midtarsal Reconstructive Arthrodesis Using a Multi-Axial Correction Fixator in Charcot Midfoot Arthropathy. AB - Reconstructive surgeries for Charcot foot are challenging due to complicated conditions and comorbidities including poor bone quality, sensory abnormalities, poor vascularity, and immunity impairment. Although various fixation devices, including screws, plates, and external fixators, have been used in the surgical reconstruction of the Charcot midfoot, all of these devices are associated with some disadvantages. This study aims to evaluate the outcome of the Multi-Axial Correction (MAC) monolateral external fixation system for the reconstructive surgery of midfoot Charcot neuroarthropathy. A total of 11 feet with midfoot Charcot arthropathy were treated surgically using the MAC fixation system solely or accompanied with minimal internal fixation. The mean postoperative follow-up was 29 (range = 12-44) months. The mean postoperative timing of the MAC system removal was 8.7 (range = 5-14) weeks. No pin tract infections were observed. All patients went on to successful union and correction of a rocker bottom deformity. No cases resulted in limb amputation. All patients were able to ambulate with custom diabetic shoes and insoles in 9 patients (10 feet) and commercially available shoes in 1 patient (1 foot). This study suggests that the MAC system can be an acceptable, easy option for the surgical treatment of midfoot Charcot arthropathy. LEVEL OF EVIDENCE: Therapeutic, Level IV: Case series. PMID- 26123550 TI - Evaluating the Quality, Accuracy, and Readability of Online Resources Pertaining to Hallux Valgus. AB - BACKGROUND: The Internet is one of the most widely utilized resources for health related information. Evaluation of the medical literature suggests that the quality and accuracy of these resources are poor and written at inappropriately high reading levels. The purpose of our study was to evaluate the quality, accuracy, and readability of online resources pertaining to hallux valgus. METHODS: Two search terms ("hallux valgus" and "bunion") were entered into Google, Yahoo, and Bing. With the use of scoring criteria specific to hallux valgus, the quality and accuracy of online information related to hallux valgus was evaluated by 3 reviewers. The Flesch-Kincaid score was used to determine readability. Statistical analysis was performed with t tests and significance was determined by P values <.05. RESULTS: Sixty-two unique websites were evaluated. Quality was significantly higher with use of the search term "bunion" as compared to "hallux valgus" (P = .045). Quality and accuracy were significantly higher in resources authored by physicians as compared to nonphysicians (quality, P = .04; accuracy, P < .001) and websites without commercial bias (quality, P = .038; accuracy, P = .011). However, the reading level was significantly more advanced for websites authored by physicians (P = .035). Websites written above an eighth grade reading level were significantly more accurate than those written at or below an eighth-grade reading level (P = .032). CONCLUSION: The overall quality of online information related to hallux valgus is poor and written at inappropriate reading levels. Furthermore, the search term used, authorship, and presence of commercial bias influence the value of these materials. It is important for orthopaedic surgeons to become familiar with patient education materials, so that appropriate recommendations can be made regarding valuable resources. LEVELS OF EVIDENCE: Level IV. PMID- 26123551 TI - Patient-Reported Outcomes Following Living Kidney Donation: A Single Center Experience. AB - This article describes the development and implementation of an initiative at one transplant center to annually assess psychosocial outcomes of living kidney donors. The current analysis focuses on a cohort of adults (n = 208) who donated a kidney at BIDMC between September 2005 and August 2012, in which two post donation annual assessments could be examined. One and two year post-donation surveys were returned by 59 % (n = 123) and 47 % (n = 98) of LKDs, respectively. Those who did not complete any survey were more likely to be younger (p = 0.001), minority race/ethnicity (p < 0.001), and uninsured at the time of donation (p = 0.01) compared to those who returned at least one of the two annual surveys. The majority of donors reported no adverse physical or psychosocial consequences of donation, high satisfaction with the donation experience, and no donation decision regret. However, a sizable minority of donors felt more pain intensity than expected and recovery time was much slower than expected, and experienced a clinically significant decline in vitality. We describe how these outcomes are used to inform clinical practice at our transplant center as well as highlight challenges in donor surveillance over time. PMID- 26123552 TI - Long-term outcomes and safety of laparoscopic liver resection surgery for hepatocellular carcinoma and metastatic colorectal cancer. PMID- 26123553 TI - Olfactory Discrimination Learning in an Outbred and an Inbred Strain of Mice. AB - The present study compared olfactory discrimination learning in CD-1 mice, a widely used outbred strain of mice with that of C57BL/6J mice, one of the most widely used inbred mouse strains. Using an automated olfactometer and a standard operant conditioning procedure, I found that CD-1 mice needed 60 trials to reach learning criterion in an initial 2-odor discrimination task. They improved in learning speed in subsequent discrimination tasks in which either the rewarded or the unrewarded stimulus was replaced for a new stimulus. C57BL/6J mice, in contrast, needed 120 trials to reach learning criterion in an initial 2-odor discrimination task and also needed significantly more trials than the CD-1 mice in 3 of the 4 subsequent discrimination tasks. Further, the results showed that discrimination learning performance of both mouse strains was largely unaffected by the odor stimuli used. The results of the present study demonstrate differences between an outbred and an inbred strain of mice with regard to odor discrimination learning, a classical measure of cognitive performance in comparative psychology. Thus, they emphasize the need to be careful with generalizing statements as to cognitive or sensory abilities of Mus musculus when inbred strains of mice are used. PMID- 26123555 TI - Leg Swelling and Mildly Deranged Liver Tests: An Unusual Presentation of a Usual Diagnosis. Multiple Simple Liver Cysts. PMID- 26123554 TI - Cartilage in facet joints of patients with ankylosing spondylitis (AS) shows signs of cartilage degeneration rather than chondrocyte hypertrophy: implications for joint remodeling in AS. AB - INTRODUCTION: In ankylosing spondylitis (AS), joint remodeling leading to joint ankylosis involves cartilage fusion. Here, we analyzed whether chondrocyte hypertrophy is involved in cartilage fusion and subsequent joint remodeling in AS. METHODS: We assessed the expression of chondrocyte hypertrophy markers runt related transcription factor 2 (Runx2), type X collagen (COL10), matrix metalloproteinase 13 (MMP13), osteocalcin and beta-catenin and the expression of positive bone morphogenic proteins (BMPs) and negative regulators (dickkopf-1 (DKK-1)), sclerostin, (wingless inhibitory factor 1 (wif-1)) of chondrocyte hypertrophy in the cartilage of facet joints from patients with AS or osteoarthritis (OA) and from autopsy controls (CO) by immunohistochemistry. Sex determining region Y (SRY)-box 9 (Sox9) and type II collagen (COL2) expression was assessed as indicators of chondrocyte integrity and function. RESULTS: The percentage of hypertrophic chondrocytes expressing Runx2, COL10, MMP13, osteocalcin or beta-catenin was significantly increased in OA but not in AS joints compared to CO joints. Frequencies of sclerostin-positive and DKK-1 positive chondrocytes were similar in AS and CO. In contrast, wif-1- but also BMP 2- and BMP-7-expressing and Sox9-expressing chondrocytes were drastically reduced in AS joints compared to CO as well as OA joints whereas the percentage of COL2 expressing chondrocytes was significantly higher in AS joints compared to CO joints. CONCLUSIONS: We found no evidence for chondrocyte hypertrophy within hyaline cartilage of AS joints even in the presence of reduced expression of the wnt inhibitor wif-1 suggesting that chondrocyte hypertrophy is not a predominant pathway involved in joint fusion and remodeling in AS. In contrast, the reduced expression of Sox9, BMP-2 and BMP-7 concomitantly with induced COL2 expression rather point to disturbed cartilage homeostasis promoting cartilage degeneration in AS. PMID- 26123557 TI - A Rare Cause of Abdominal Pain by Pancreatic Mass in a Young Female Patient. Carcinosarcoma of the Pancreas. PMID- 26123558 TI - An Unusual Cause of Anterior Abdominal Wall Abscess. Left Anterior Abdominal Wall Abscess Secondary to Fish Bone Migration from the Gastrointestinal Tract. PMID- 26123559 TI - Abdominal Distension in a Patient With Hepatocellular Carcinoma. Benign Pneumatosis Intestinalis and Pneumoperitoneum Associated With Sorafenib Therapy. PMID- 26123560 TI - Esophageal Ulcer in a Lung Cancer Patient. Crizotinib-induced Esophageal Injury. PMID- 26123561 TI - Reduction in Human Papillomavirus Vaccine Type Prevalence Among Young Women Screened for Cervical Cancer in an Integrated US Healthcare Delivery System in 2007 and 2012-2013. AB - BACKGROUND: In the United States, human papillomavirus (HPV) vaccine is recommended for 11- or 12-year-olds, and for young adults not previously vaccinated. Early vaccine impact can be measured by reductions in vaccine-type (VT) HPV prevalence. METHODS: Consecutive residual cervical specimens were retained from women aged 20-29 years at Kaiser Permanente Northwest in 2007, 2012, and 2013. HPV genotypes were determined using L1 consensus polymerase chain reaction with type-specific hybridization to detect 37 types, including VT HPV (HPV type 6, 11, 16, and 18). We compared HPV prevalence in 2007 and 2012-2013, and we evaluated predictors of VT HPV and any-HPV prevalence in 2012-2013. RESULTS: In 2012-2013, 31.9% of 4181 women had initiated HPV vaccination. VT HPV prevalence decreased from 10.6% in 2007 to 6.2% in 2012-2013 (P < .001). In 2012 2013, VT HPV prevalence was significantly lower among those who initiated vaccination <19 years (adjusted prevalence ratio, 0.1; 95% confidence interval, .1-.3) than among those who were not vaccinated, and higher among those who had chlamydia, human immunodeficiency virus, or pregnancy testing in the past year than among those who did not (adjusted prevalence ratio, 1.4; 95% confidence interval, 1.1-1.8). CONCLUSIONS: Reduction in VT HPV was found in young women in an integrated healthcare delivery system within 6 years of vaccine introduction, indicating early HPV vaccine impact. PMID- 26123562 TI - A Bivalent Vaccine Based on a PB2-Knockout Influenza Virus Protects Mice From Secondary Pneumococcal Pneumonia. AB - BACKGROUND: Secondary bacterial infections after influenza can be a serious problem, especially in young children and the elderly, yet the efficacy of current vaccines is limited. Earlier work demonstrated that a replication incompetent PB2-knockout (PB2-KO) influenza virus possessing a foreign gene in the coding region of its PB2 segment can serve as a platform for a bivalent vaccine. METHODS: In the current study, we generated the PB2-KO virus expressing pneumococcal surface protein A (PspA), PB2-KO-PspA virus, the replication of which is restricted to PB2-expressing cells. We then examined the protective efficacy of intranasal immunization with this virus as a bivalent vaccine in a mouse model. RESULTS: High levels of influenza virus-specific and PspA-specific antibodies were induced in the serum and airways of immunized mice. The intranasally immunized mice were protected from lethal doses of influenza virus or Streptococcus pneumoniae. These mice were also completely protected from secondary pneumococcal pneumonia after influenza virus infection. CONCLUSIONS: These findings indicate that our recombinant influenza virus serves as a novel and powerful bivalent vaccine against primary and secondary pneumococcal pneumonia as well as influenza. PMID- 26123563 TI - Pharmacological Measures of Treatment Adherence and Risk of HIV Infection in the VOICE Study. AB - BACKGROUND: None of the 3 regimens tested in the VOICE study showed protection against human immunodeficiency virus (HIV) infection in intent-to-treat analyses. Plasma tenofovir concentrations demonstrated poor adherence to the study product among study subjects. Statistical analyses to explore the causal treatment effect on the prevention of HIV infection among adherent individuals are needed. METHODS: We developed an analytical strategy to evaluate whether conventional covariate adjustment removes confounding and thereby reveals a prevention effect among adherent individuals. We applied this strategy to the VOICE study, using 2 dichotomized proxy measures of product use: detection of tenofovir in plasma at least once during follow-up and detection of tenofovir in plasma at the 3-month follow-up visit. RESULTS: After adjustment for a set of baseline predictors of the risk of HIV transmission, the confounding associated with comparison of adherent individuals in the tenofovir gel arm to placebo recipients was nearly eliminated. The relative risk for a prevention effect among those ever having tenofovir detected was 0.53 (P = .038); the relative risk among those having tenofovir detected at 3 months was 0.40 (P = .045). CONCLUSIONS: A novel regression approach was proposed for causal as-treated analyses in the VOICE study. While intent-to-treat analyses yield null results, this exploratory approach presented evidence suggesting a prevention effect among gel users. CLINICAL TRIALS REGISTRATION: NCT00705679. PMID- 26123564 TI - Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk of First-Line Treatment Failure and Symptomatic Relapse. AB - Treatment failure and symptomatic relapse are major concerns in American tegumentary leishmaniasis (TL). Such complications are seen frequently in Leishmania guyanensis infections, in which patients respond variously to first line antileishmanials and are more prone to develop chronic cutaneous leishmaniasis. The factors underlying this pathology, however, are unknown. Recently, we reported that a double-stranded RNA virus, Leishmania RNA virus 1 (LRV1), nested within L. guyanensis parasites is able to exacerbate experimental murine leishmaniasis by inducing a hyperinflammatory response. This report investigates the prevalence of LRV1 in human L. guyanensis infection and its effect on treatment efficacy, as well as its correlation to symptomatic relapses after the completion of first-line treatment. In our cohort of 75 patients with a diagnosis of primary localized American TL, the prevalence of LRV1-positive L. guyanensis infection was elevated to 58%. All patients infected with LRV1 negative L. guyanensis were cured after 1 dose (22 of 31 [71%]) or 2 doses (31 of 31 [100%]) of pentamidine. In contrast, 12 of 44 LRV1-positive patients (27%) presented with persistent infection and symptomatic relapse that required extended therapy and the use of second-line drugs. Finally, LRV1 presence was associated with a significant increase in levels of intra-lesional inflammatory markers. In conclusion, LRV1 status in L. guyanensis infection is significantly predictive (P = .0009) of first-line treatment failure and symptomatic relapse and has the potential to guide therapeutic choices in American TL. PMID- 26123565 TI - Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for Human Leishmaniasis Caused by Leishmania braziliensis in Peru and Bolivia. AB - Cutaneous and mucosal leishmaniasis, caused in South America by Leishmania braziliensis, is difficult to cure by chemotherapy (primarily pentavalent antimonials [Sb(V)]). Treatment failure does not correlate well with resistance in vitro, and the factors responsible for treatment failure in patients are not well understood. Many isolates of L. braziliensis (>25%) contain a double stranded RNA virus named Leishmaniavirus 1 (LRV1), which has also been reported in Leishmania guyanensis, for which an association with increased pathology, metastasis, and parasite replication was found in murine models. Here we probed the relationship of LRV1 to drug treatment success and disease in 97 L. braziliensis-infected patients from Peru and Bolivia. In vitro cultures were established, parasites were typed as L. braziliensis, and the presence of LRV1 was determined by reverse transcription-polymerase chain reaction, followed by sequence analysis. LRV1 was associated significantly with an increased risk of treatment failure (odds ratio, 3.99; P = .04). There was no significant association with intrinsic Sb(V) resistance among parasites, suggesting that treatment failure arises from LRV1-mediated effects on host metabolism and/or parasite survival. The association of LRV1 with clinical drug treatment failure could serve to guide more-effective treatment of tegumentary disease caused by L. braziliensis. PMID- 26123567 TI - (11)B MAS NMR study of Ga1-xFexBO3 mixed crystals. AB - Mixed iron-gallium borate crystals Ga1-xFexBO3 have been studied by Magic Angle Spinning (MAS) NMR of (11)B isotope. Experimental MAS NMR spectra have been computer simulated using a laboratory-developed code. The quadrupole parameters and isotropic chemical shift for (11)B are consistent with threefold-coordination of boron atoms. A detailed fitting to the experimental NMR spectra reveals the existence of a certain local disorder in Ga1-xFexBO3 crystals. PMID- 26123566 TI - Use of Pharmacokinetic Data in Novel Analyses to Determine the Effect of Topical Microbicides as Preexposure Prophylaxis Against HIV Infection. PMID- 26123568 TI - A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder. AB - BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterised by abnormal ciliary motion and impaired mucociliary clearance, leading to recurrent respiratory infections, sinusitis, otitis media and male infertility. Some patients also have laterality defects. We recently reported the identification of three disease-causing PCD genes in the Irish Traveller population; RSPH4A, DYX1C1 and CCNO. We have since assessed an additional Irish Traveller family with a complex phenotype involving PCD who did not have any of the previously identified PCD mutations. CASE PRESENTATION: In this study we report on a family with three children with PCD and various laterality defects. In addition, one child (V:1) has mild-to-moderate developmental delay and one child has speech delay (V:2). Developmental delay is not usually associated with PCD and is likely to be caused by an additional genetic abnormality. Transmission electron microscopy showed variable inner and outer dynein arm defects. Exome sequencing identified a homozygous missense variant in CCDC103 (c.461A > C; p.His154Pro) as the most likely cause of the PCD and laterality defects in this family. However, as mutation in CCDC103 would not account for the developmental delay, array comparative genomic hybridisation was undertaken and identified a maternally inherited gain of ~1.6 Mb (chr17:34,611,352-36,248,918). Gains at this locus are associated with 17q12 duplication syndrome which includes speech and language delay. CONCLUSION: We report on a variable and complex phenotype caused by the co-inheritance of a single gene mutation in CCDC103 and a microduplication at 17q12, both on chromosome 17. The co-existence of a single gene and chromosome disorder is unusual but accounts for the spectrum of clinical features in this family. In addition, our study brings the total number of PCD genes in the Irish Traveller population to four and we suspect additional PCD genes are yet to be identified. Although, on a global scale, PCD is associated with extensive genetic heterogeneity, finding such a high number of causative PCD genes within the relatively small Irish Traveller population was unexpected. PMID- 26123569 TI - Generating induced pluripotent stem cell derived endothelial cells and induced endothelial cells for cardiovascular disease modelling and therapeutic angiogenesis. AB - Standard therapy for atherosclerotic coronary and peripheral arterial disease is insufficient in a significant number of patients because extensive disease often precludes effective revascularization. Stem cell therapy holds promise as a supplementary treatment for these patients, as pre-clinical and clinical research has shown transplanted cells can promote angiogenesis via direct and paracrine mechanisms. Induced pluripotent stem cells (iPSCs) are a novel cell type obtained by reprogramming somatic cells using exogenous transcription factor cocktails, which have been introduced to somatic cells via viral or plasmid constructs, modified mRNA or small molecules. IPSCs are now being used in disease modelling and drug testing and are undergoing their first clinical trial, but despite recent advances, the inefficiency of the reprogramming process remains a major limitation, as does the lack of consensus regarding the optimum transcription factor combination and delivery method and the uncertainty surrounding the genetic and epigenetic stability of iPSCs. IPSCs have been successfully differentiated into vascular endothelial cells (iPSC-ECs) and, more recently, induced endothelial cells (iECs) have also been generated by direct differentiation, which bypasses the pluripotent intermediate. IPSC-ECs and iECs demonstrate endothelial functionality in vitro and have been shown to promote neovessel growth and enhance blood flow recovery in animal models of myocardial infarction and peripheral arterial disease. Challenges remain in optimising the efficiency, safety and fidelity of the reprogramming and endothelial differentiation processes and establishing protocols for large-scale production of clinical-grade, patient-derived cells. PMID- 26123570 TI - Folic acid supplement use and menstrual cycle characteristics: a cross-sectional study of Danish pregnancy planners. AB - PURPOSE: To examine the association between folic acid (FA) supplementation obtained through either single FA tablets or multivitamins (MVs) and menstrual cycle characteristics among 5386 women aged 18-40 years, enrolled in an Internet based study of Danish women attempting pregnancy during 2007-2011. METHODS: In a cross-sectional study, we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of FA supplementation with menstrual cycle regularity; short (<27 days), long (30-33 days), and very long (>=34 days) cycle lengths; and duration and intensity of menstrual bleeding. RESULTS: Compared with nonuse, FA supplementation was associated with reduced odds of short cycle length (OR = 0.80, 95% CI: 0.68-0.94) and a trend toward increased odds of very long cycle length (OR = 1.21, 95% CI: 0.87-1.68) compared with cycle length of 27-29 days. The inverse association with short cycle length was stronger among 18- to 30-year-old women (OR = 0.68, 95% CI: 0.53-0.87), nulliparous women (OR = 0.66, 95% CI: 0.52-0.84), and women who used both FA and MVs (OR = 0.75, 95% CI: 0.60-0.95). We found no clear association between FA supplementation and cycle regularity and duration and intensity of menstrual bleeding. CONCLUSIONS: FA supplementation was inversely associated with short menstrual cycle length. This association was strongest among women aged 18-30 years, nulliparous women, and women who used both FA and MVs. PMID- 26123571 TI - A strange form of dysphonia... . Laryngeal paraganglioma. PMID- 26123573 TI - Kidney transplantation without interruption of warfarin. PMID- 26123572 TI - A Herpesvirus Specific Motif of Epstein-Barr Virus DNA Polymerase Is Required for the Efficient Lytic Genome Synthesis. AB - Epstein-Barr virus (EBV) is associated with several malignancies, including Burkitt lymphoma and nasopharyngeal carcinoma. To overcome such disorders, understanding the molecular mechanisms of the EBV replication is important. The EBV DNA polymerase (Pol) is one of the essential factors for viral lytic DNA replication. Although it is well known that its C-terminal half, possessing DNA polymerase and 3'-5' exonuclease activity, is highly conserved among Family B Pols, the NH2-terminal half has yet to be characterized in detail. In this study, we show that a stretch of hydrophobic amino acids within the pre-NH2-terminal domain of EBV Pol plays important role. In addition, we could identify the most essential residue for replication in the motif. These findings will shed light on molecular mechanisms of viral DNA synthesis and will help to develop new herpesviruses treatments. PMID- 26123574 TI - Randomized psychosocial interventions for breast cancer: impact on life purpose. AB - OBJECTIVE: The present study sought to identify mediators underlying the effects of an education and a peer support intervention for women with breast cancer and to determine if the efficacy of a peer support intervention is moderated by cancer severity. METHODS: Participants included 180 patients with early stage (I or II) and 65 patients with late stage (IV) breast cancer. The study was originally planned as a 2 (early stage, late stage) * 3 (education intervention, peer support intervention, control condition) design; however, the education condition for the late stage cancer group was dropped, because of slow recruitment. Participants completed measures of well-being prior to being randomized (Time 1), then again 2 weeks after the group meetings ended (Time 2), and 6 months later (Time 3). RESULTS: Among the participants who had attended at least one group meeting, the education intervention predicted more life purpose and marginally predicted more perceived physical health at Time 2. The peer support intervention predicted more life purpose and less depressive symptoms at Time 2. Cancer severity did not moderate these effects. The effect of the peer support intervention on depressive symptoms was mediated by life purpose. None of the intervention effects were evident at Time 3. CONCLUSIONS: Peer support interventions have positive short-term effects on well-being, among women with late and early stage breast cancer, and these effects are partially mediated by changes in life purpose. Education interventions have positive short-term effects on well-being among women with early stage breast cancer. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26123576 TI - Molecular identification and seasonal infections of species of Fasciola in ruminants from two provinces in China. AB - We determined the prevalence and seasonality of infections by Fasciola of goats and bovine species (cattle and water buffalo) in Hubei and Anhui provinces of China. Faecal samples were collected at 2- to 3-month intervals from 200 goats in Hubei province and from 152 bovine species in Anhui province. All faecal samples were examined for the presence of parasites. We determined the nucleotide sequences of the first and second internal transcribed spacers (ITS-1 and ITS-2) of the nuclear ribosomal DNA (rDNA) of 39 Fasciola worms from Anhui province. The prevalence of Fasciola infection in goats ranged between 3.5 and 37.0%, with mean eggs per gram (EPG) ranging between 29.0 and 166.0. Prevalence and EPG exhibited downward trends over time with significant differences. The prevalence of Fasciola infection in cattle ranged between 13.3 and 46.2% (mean EPG, 36.4 100.0), and that of water buffalo ranged between 10.3 and 35.4% (mean EPG, 25.0 89.6), with a higher prevalence of infection and EPG from June to October compared with December to March. Analysis of ITS-1 and ITS-2 sequences revealed that F. hepatica and F. gigantica were present in all bovine species of Anhui province and that F. gigantica mainly infected water buffalo. This is the first demonstration of Fasciola infection in Hubei province and detection of F. hepatica and F. gigantica in Anhui province. The present study of Hubei province shows that mass treatment of livestock with closantel sodium injections in April and August/September controlled Fasciola infection effectively. PMID- 26123575 TI - Disease progression despite protective HLA expression in an HIV-infected transmission pair. AB - BACKGROUND: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA B*57:01. RESULTS: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles. CONCLUSIONS: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes. PMID- 26123577 TI - [Hospital biomedical research through the satisfaction of a Health Research Institute professionals]. AB - OBJECTIVE: A Health Research Institute is a powerful strategic commitment to promote biomedical research in hospitals. To assess user satisfaction is an essential quality requirement. The aim of this study is to evaluate the professional satisfaction in a Health Research Institute, a hospital biomedical research centre par excellence. METHODS: Observational study was conducted using a satisfaction questionnaire on Health Research Institute researchers. The explored dimensions were derived from the services offered by the Institute to researchers, and are structured around 4 axes of a five-year Strategic Plan. A descriptive and analytical study was performed depending on adjustment variables. Internal consistency was also calculated. RESULTS: The questionnaire was completed by 108 researchers (15% response). The most valued strategic aspect was the structuring Areas and Research Groups and political communication and dissemination. The overall rating was 7.25 out of 10. Suggestions for improvement refer to the need for help in recruitment, and research infrastructures. High internal consistency was found in the questionnaire (Cronbach alpha of 0.9). CONCLUSIONS: So far research policies in health and biomedical environment have not been sufficiently evaluated by professionals in our field. Systematic evaluations of satisfaction and expectations of key stakeholders is an essential tool for analysis, participation in continuous improvement and advancing excellence in health research. PMID- 26123578 TI - Identification of Behavior Change Techniques and Engagement Strategies to Design a Smartphone App to Reduce Alcohol Consumption Using a Formal Consensus Method. AB - BACKGROUND: Digital interventions to reduce excessive alcohol consumption have the potential to have a broader reach and be more cost-effective than traditional brief interventions. However, there is not yet strong evidence for their ability to engage users or their effectiveness. OBJECTIVE: This study aimed to identify the behavior change techniques (BCTs) and engagement strategies most worthy of further study by inclusion in a smartphone app to reduce alcohol consumption, using formal expert consensus methods. METHODS: The first phase of the study consisted of a Delphi exercise with three rounds. It was conducted with 7 international experts in the field of alcohol and/or behavior change. In the first round, experts identified BCTs most likely to be effective at reducing alcohol consumption and strategies most likely to engage users with an app; these were rated in the second round; and those rated as effective by at least four out of seven participants were ranked in the third round. The rankings were analyzed using Kendall's W coefficient of concordance, which indicates consensus between participants. The second phase consisted of a new, independent group of experts (n=43) ranking the BCTs that were identified in the first phase. The correlation between the rankings of the two groups was assessed using Spearman's rank correlation coefficient. RESULTS: Twelve BCTs were identified as likely to be effective. There was moderate agreement among the experts over their ranking (W=.465, chi(2) 11=35.8, P<.001) and the BCTs receiving the highest mean rankings were self-monitoring, goal-setting, action planning, and feedback in relation to goals. There was a significant correlation between the ranking of the BCTs by the group of experts who identified them and a second independent group of experts (Spearman's rho=.690, P=.01). Seventeen responses were generated for strategies likely to engage users. There was moderate agreement among experts on the ranking of these engagement strategies (W=.563, chi(2) 15=59.2, P<.001) and those with the highest mean rankings were ease of use, design - aesthetic, feedback, function, design - ability to change design to suit own preferences, tailored information, and unique smartphone features. CONCLUSIONS: The BCTs with greatest potential to include in a smartphone app to reduce alcohol consumption were judged by experts to be self-monitoring, goal-setting, action planning, and feedback in relation to goals. The strategies most likely to engage users were ease of use, design, tailoring of design and information, and unique smartphone features. PMID- 26123580 TI - Seeded growth of ferrite nanoparticles from Mn oxides: observation of anomalies in magnetic transitions. AB - A series of magnetically active ferrite nanoparticles (NPs) are prepared by using Mn oxide NPs as seeds. A Verwey transition is identified in Fe3O4 NPs with an average diameter of 14.5 nm at 96 K, where a sharp drop of magnetic susceptibility occurs. In MnFe2O4 NPs, a spin glass-like state is observed with the decrease in magnetization below the blocking temperature due to the disordered spins during the freezing process. From these MnFe2O4 NPs, MnFe2O4@Mn(x)Fe(1-x)O core-shell NPs are prepared by seeded growth. The structure of the core is cubic spinel (Fd3-m), and the shell is composed of iron-manganese oxide (Mn(x)Fe(1-x)O) with a rock salt structure (Fm3-m). Moire fringes appear perpendicular to the <110> directions on the cubic shape NPs through the plane matched epitaxial growth. These fringes are due to the difference in the lattice spacings between MnFe2O4 and Mn(x)Fe(1-x)O. Exchange bias is observed in these MnFe2O4@Mn(x)Fe(1-x)O core-shell NPs with an enhanced coercivity, as well as the shift of hysteresis along the field direction. PMID- 26123579 TI - Association of hydrogen sulfide with alterations of monocyte chemokine receptors, CCR2 and CX3CR1 in patients with coronary artery disease. AB - OBJECTIVES: Recent data in human and mice suggest that monocyte chemokine receptors CX3CR1 and CCR2 are involved in the pathogenesis of atherosclerosis. Our previous study showed that hydrogen sulfide, a novel gaseous mediator hampered the progression of atherosclerosis in fat-fed apoE(-/-) mice with downregulating CX3CR1 and CX3CL1 expressions. However, there is a paucity of information regarding the clinical association between endogenous H2S metabolism and alterations of monocyte chemokine receptors in patients with cardiovascular disease. Therefore, in this study, we investigated circulating monocyte heterogeneity with differential expressions of CCR2 and CX3CR1 and its relevance to plasma H2S level in patients with coronary artery disease (CAD). METHODS: Sixty-three CAD patients with acute coronary syndrome (ACS, n = 46) or stable angina pectoris (SAP, n = 17) undergoing either percutaneous coronary intervention or coronary angiography and eleven non-CAD patients were enrolled in the study. Plasma levels of H2S as well as chemokines (CCL2 and CX3CL1) and expressions of CCR2 and CX3CR1 on peripheral monocytes were measured. RESULTS: It was found that plasma H2S level was significantly reduced, whereas plasma CCL2 and CX3CL1 levels were substantially elevated in patients with ACS, as compared with patients with SAP or non-CAD patients. Furthermore, patients with ACS had significantly higher proportion of CD14(+)CCR2(+)CX3CR1(+) and CD14(+)CCR2( )CX3CR1(+) monocytes but lower percentage of CD14(+)CCR2(+)CX3CR1(-) monocytes than SAP or non-CAD patients did. Lastly, plasma H2S level showed a significantly negative correlation with the proportion of CD14(+)CCR2(+)CX3CR1(+) monocytes, but not other monocyte subsets. CONCLUSIONS: These data indicate that decreased endogenous H2S production may predispose stable CAD patients to rupture of vulnerable plaque and thus to ACS, probably in relation to circulating monocyte phenotypic transformation with differential expressions of CCR2 and CX3CR1. PMID- 26123581 TI - Urine flow cytometry can rule out urinary tract infection, but cannot identify bacterial morphologies correctly. AB - The diagnosis of urinary tract infection (UTI) by urine culture is a time consuming and costly procedure. Usage of a screening method, to identify negative samples, would therefore affect time-to-diagnosis and laboratory cost positively. Urine flow cytometers are able to identify particles in urine. Together with the introduction of a cut-off value, which determines if a urine sample is subsequently cultured or not, the number of cultures can be reduced, while maintaining a low level of false negatives and a high negative predictive value. Recently, Sysmex developed additional software for their urine flow cytometers. Besides measuring the number of bacteria present in urine, information is given on bacterial morphology, which may guide the physician in the choice of antibiotic. In this study, we evaluated this software update. The UF1000i classifies bacteria into two categories: 'rods' and 'cocci/mixed'. Compared to the actual morphology of the bacterial pathogen found, the 'rods' category scores reasonably well with 91% chance of classifying rod-shaped bacteria correctly. The 'cocci/mixed' category underperforms, with only 29% of spherical-shaped bacteria (cocci) classified as such. In its current version, the bacterial morphology software does not classify bacteria, according to their morphology, well enough to be of clinical use in this study population. PMID- 26123582 TI - Drebrin and cognitive impairment. AB - The kinetics of cytoskeletal networks, with actin as a key factor, play a key role in regulating the morphology and function of dendritic spines. Drebrin is a neuron growth and brain development-related actin-binding protein and is present in 70% of the dendritic spines of excitatory synapses. It regulates the development and formation of dendritic spines and well-developed dendritic spines pave the way for presynaptic elements. Well-developed and mature synapses are prerequisite for maintaining nervous system physiology. Abnormal morphology of dendritic spines and loss of synapses are seen in many neurologic diseases associated with cognitive decline. However, the mechanisms governing these pathologic changes and their correlation with drebrin remain unclear. Exploring the relationship between drebrin and cognitive function may provide insight into the early prevention of cognitive impairment and in the diagnosis and treatment of Alzheimer's disease. PMID- 26123583 TI - Activation of FoxO1/ PGC-1alpha prevents mitochondrial dysfunction and ameliorates mesangial cell injury in diabetic rats. AB - The generation of hyperglycemia-induced mitochondrial reactive oxygen species (ROS) is a key event in diabetic nephropathy development. The forkhead-box class O1 (FoxO1) and peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) proteins are implicated in oxidative stress. We investigated the in vivo association of FoxO1 and PGC-1alpha in renal cortices from streptozotocin-induced diabetic rats and in rat kidney mesangial cells (MCs) treated with high glucose, in vitro. High-glucose induced FoxO1 inhibition was associated with decreased PGC-1alpha expression in MCs. These changes were accompanied by mitochondrial dysfunction and increased ROS generation. However, constitutive FoxO1 activation increased PGC-1alpha expression and partially reversed these changes, which were significantly decreased by the treatment of PGC-1alpha-small interfering RNA. We identified PGC-1alpha as a direct FoxO1 transcriptional target by chromatin immunoprecipitation. In addition, lentiviral mediated FoxO1 overexpression in diabetic-rat kidneys significantly increased PGC 1alpha, NRF-1, and Mfn2 expression, and decreased malondialdehyde production and proteinuria. These data suggest that FoxO1/PGC-1alpha activation protected rats against high-glucose-induced MC injury by attenuating mitochondrial dysfunction and cellular ROS production. PMID- 26123584 TI - Hepatic nutrient and hormonal regulation of the PANcreatic-DERived factor (PANDER) promoter. AB - PANcreatic-DERived factor (PANDER, FAM3B) has been shown to regulate glycemic levels via interactions with both pancreatic islets and the liver. Although PANDER is predominantly expressed from the endocrine pancreas, recent work has provided sufficient evidence that the liver may also be an additional tissue source of PANDER production. At physiological levels, PANDER is capable of disrupting insulin signaling and promoting increased hepatic glucose production. As shown in some animal models, strong expression of PANDER, induced by viral delivery within the liver, induces hepatic steatosis. However, no studies to date have explicitly characterized the transcriptional regulation of PANDER from the liver. Therefore, our investigation elucidated the nutrient and hormonal regulation of the hepatic PANDER promoter. Initial RNA-ligated rapid amplification of cDNA ends identified a novel transcription start site (TSS) approximately 26 bp upstream of the PANDER translational start codon not previously revealed in pancreatic beta-cell lines. Western evaluation of various murine tissues demonstrated robust expression in the liver and brain. Promoter analysis identified strong tissue-specific activity of the PANDER promoter in both human and murine liver-derived cell lines. The minimal element responsible for maximal promoter activity within hepatic cell lines was located between -293 and -3 of the identified TSS. PANDER promoter activity was inhibited by both insulin and palmitate, whereas glucose strongly increased expression. The minimal element was responsible for maximal glucose-responsive and basal activity. Co transfection reporter assays, chromatin-immunoprecipitation (ChIP) and site directed mutagenesis revealed that the carbohydrate-responsive element binding protein (ChREBP) increased PANDER promoter activity and interacted with the PANDER promoter. E-box 3 was shown to be critical for basal and glucose responsive expression. In summary, in-vitro and in-vivo glucose is a potent stimulator of the PANDER promoter within the liver and this response may be facilitated by ChREBP. PMID- 26123585 TI - The role of pancreatic polypeptide in the regulation of energy homeostasis. AB - Imbalances in normal regulation of food intake can cause obesity and related disorders. Inadequate therapies for such disorders necessitate better understanding of mechanisms that regulate energy homeostasis. Pancreatic polypeptide (PP), a robust anorexigenic hormone, effectively modulates food intake and energy homeostasis, thus potentially aiding anti-obesity therapeutics. Intra-gastric and intra-intestinal infusion of nutrients stimulate PP secretion from the gastrointestinal tract, leading to vagal stimulation that mediates complex actions via the neuropeptide Y4 receptor in arcuate nucleus of the hypothalamus, subsequently activating key hypothalamic nuclei and dorsal vagal complex of the brainstem to influence energy homeostasis and body composition. Novel studies indicate affinity of PP for the relatively underexplored neuropeptide y6 receptor, mediating actions via the suprachiasmatic nucleus and pathways involving vasoactive intestinal polypeptide and insulin like growth factor 1. This review highlights detailed mechanisms by which PP mediates its actions on energy balance through various areas in the brain. PMID- 26123586 TI - The role of sleep in the regulation of body weight. AB - Sleep participates in the regulation of body weight. The amount of sleep and synchronization of the biological clock are both necessary to achieve the energy balance and the secretion of hormones that contribute to weight regulation. In this review, we first reconsider what normal physiological sleep is and what the normative values of sleep are in the general population. Second, we explain how the biological clock regulates the hormones that may be involved in weight control. Third, we provide some recent data on how sleep may be disturbed by sleep disorders or reduced by sleep debt with consequences on weight. Finally, we explore the relationships between sleep debt and obesity. PMID- 26123587 TI - Cortisol-secreting adrenocortical tumours in dogs and their relevance for human medicine. AB - Spontaneous cortisol-secreting adrenocortical tumours in pet dogs are an attractive animal model for their human counterparts. Adrenal morphology and function are similar in dogs and humans, and adrenocortical tumours have comparable clinical and pathological characteristics. Their relatively high incidence in pet dogs represents a potential source of adrenocortical tumour tissue to facilitate research. The molecular characteristics of canine cortisol secreting adrenocortical tumours suggest that they will be useful for the study of angiogenesis, the cAMP/protein kinase A pathway, and the role of Steroidogenic Factor-1 in adrenal tumourigenesis. Pet dogs with spontaneous cortisol-secreting adrenocortical tumours may also be useful in clinical testing of new drugs and in investigating the molecular background of adrenocortical tumours. PMID- 26123588 TI - From Nf1 to Sdhb knockout: Successes and failures in the quest for animal models of pheochromocytoma. AB - Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors characterized by a high frequency of hereditary forms. Based on transcriptome classification, PPGL can be classified in two different clusters. Cluster 1 tumors are caused by mutations in SDHx, VHL and FH genes and are characterized by a pseudohypoxic signature. Cluster 2 PPGL carry mutations in RET, NF1, MAX or TMEM127 genes and display an activation of the MAPK and mTOR signaling pathways. Many genetically engineered and allografted mouse models have been generated these past 30 years to investigate the mechanisms of PPGL tumorigenesis and test new therapeutic strategies. Among them, only Cluster 2-related models have been successful while no Cluster 1-related knockout mouse was so far reported to develop a PPGL. In this review, we present an overview of existing, successful or not, PPGL models, and a description of our own experience on the quest of Sdhb knockout mouse models of PPGL. PMID- 26123590 TI - Oxidative activity of 17beta-hydroxysteroid dehydrogenase on testosterone in male abdominal adipose tissues and cellular localization of 17beta-HSD type 2. AB - Testosterone can be converted into androstenedione (4-dione) by 17beta hydroxysteroid dehydrogenase (HSD) activity likely performed by 17beta-HSD type 2. Our objective was to evaluate the rate of testosterone conversion to 4-dione as well as expression and localization of 17beta-HSD type 2 in omental (OM) vs. subcutaneous (SC) adipose tissues of men. Formation of 4-dione from testosterone was significantly higher in homogenates (p <= 0.001) and explants (p <= 0.01) of OM than SC tissue. Microscopy analyses and biochemical assays in cell fractions localized the enzyme in the vasculature/endothelial cells of adipose tissues. Conversion of testosterone to 4-dione was weakly detected in most OM and/or SC preadipocyte cultures. Positive correlations were found between 17beta-HSD type 2 activity in whole tissue and BMI or SC adipocyte diameter. We conclude that conversion of testosterone to 4-dione detected in abdominal adipose tissue is caused by 17beta-HSD type 2 which is localized in the vasculature of the adipose compartment. PMID- 26123589 TI - Mouse models of thyroid cancer: A 2015 update. AB - Thyroid cancer is the most common endocrine neoplasm, and its rate is rising at an alarming pace. Thus, there is a compelling need to develop in vivo models which will not only enable the confirmation of the oncogenic potential of driver genes, but also point the way towards the development of new therapeutics. Over the past 20 years, techniques for the generation of mouse models of human diseases have progressed substantially, accompanied by parallel advances in the genetics and genomics of human tumors. This convergence has enabled the development of mouse lines carrying mutations in the genes that cause thyroid cancers of all subtypes, including differentiated papillary and follicular thyroid cancers, poorly differentiated/anaplastic cancers, and medullary thyroid cancers. In this review, we will discuss the state of the art of mouse modeling of thyroid cancer, with the eventual goal of providing insight into tumor biology and treatment. PMID- 26123591 TI - Effects of chronic growth hormone overexpression on appetite-regulating brain gene expression in coho salmon. AB - Organisms must carefully regulate energy intake and expenditure to balance growth and trade-offs with other physiological processes. This regulation is influenced by key pathways controlling appetite, feeding behaviour and energy homeostasis. Growth hormone (GH) transgenesis provides a model where food intake can be elevated, and is associated with dramatic modifications of growth, metabolism, and feeding behaviour, particularly in fish. RNA-Seq and qPCR analyses were used to compare the expression of multiple genes important in appetite regulation within brain regions and the pituitary gland (PIT) of GH transgenic (fed fully to satiation or restricted to a wild-type ration throughout their lifetime) and wild type coho salmon (Oncorhynchus kisutch). RNA-Seq results showed that differences in both genotype and ration levels resulted in differentially expressed genes associated with appetite regulation in transgenic fish, including elevated Agrp1 in hypothalamus (HYP) and reduced Mch in PIT. Altered mRNA levels for Agrp1, Npy, Gh, Ghr, Igf1, Mch and Pomc were also assessed using qPCR analysis. Levels of mRNA for Agrp1, Gh, and Ghr were higher in transgenic than wild-type fish in HYP and in the preoptic area (POA), with Agrp1 more than 7-fold higher in POA and 12 fold higher in HYP of transgenic salmon compared to wild-type fish. These data are consistent with the known roles of orexigenic factors on foraging behaviour acting via GH and through MC4R receptor-mediated signalling. Igf1 mRNA was elevated in fully-fed transgenic fish in HYP and POA, but not in ration restricted fish, yet both of these types of transgenic animals have very pronounced feeding behaviour relative to wild-type fish, suggesting IGF1 is not playing a direct role in appetite stimulation acting via paracrine or autocrine mechanisms. The present findings provide new insights on mechanisms ruling altered appetite regulation in response to chronically elevated GH, and on potential pathways by which elevated feeding response is controlled, independently of food availability and growth. PMID- 26123593 TI - Reference intervals for serum concentrations of three bone turnover markers for men and women. PMID- 26123592 TI - Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction. AB - CONTEXT: Young amenorrheic athletes (AA) have lower bone mineral density (BMD) and an increased prevalence of fracture compared with eumenorrheic athletes (EA) and non-athletes. Trabecular morphology is a determinant of skeletal strength and may contribute to fracture risk. OBJECTIVES: To determine the variation in trabecular morphology among AA, EA, and non-athletes and to determine the association of trabecular morphology with fracture among AA. DESIGN AND SETTING: A cross-sectional study performed at an academic clinical research center. PARTICIPANTS: 161 girls and young women aged 14-26 years (97 AA, 32 EA, and 32 non-athletes). MAIN OUTCOME MEASURE: We measured volumetric BMD (vBMD) and skeletal microarchitecture using high-resolution peripheral quantitative computed tomography. We evaluated trabecular morphology (plate-like vs. rod-like), orientation, and connectivity by individual trabecula segmentation. RESULTS: At the non-weight-bearing distal radius, the groups did not differ for trabecular vBMD. However, plate-like trabecular bone volume fraction (pBV/TV) was lower in AA vs. EA (p=0.03), as were plate number (p=0.03) and connectivity (p=0.03). At the weight-bearing distal tibia, trabecular vBMD was higher in athletes vs. non athletes (p=0.05 for AA and p=0.009 for EA vs. non-athletes, respectively). pBV/TV was higher in athletes vs. non-athletes (p=0.04 AA and p=0.005 EA vs. non athletes), as were axially-aligned trabeculae, plate number, and connectivity. Among AA, those with a history of recurrent stress fracture had lower pBV/TV, axially-aligned trabeculae, plate number, plate thickness, and connectivity at the distal radius. CONCLUSIONS: Trabecular morphology and alignment differ among AA, EA, and non-athletes. These differences may be associated with increased fracture risk. PMID- 26123594 TI - Interactions between osteopontin and vascular endothelial growth factor: Implications for skeletal disorders. AB - Osteopontin (OPN) and vascular endothelial growth factor (VEGF) are characterized by a convergence in function for maintaining the homeostasis of the skeletal and renal systems (the bone-renal-vascular axis regulates bone metabolism). The two cytokines contribute to bone remodeling, dental healing, kidney function, and the adjustment to microgravity. Often, they are co-expressed or one molecule induces the other, however, in some settings OPN-associated pathways and VEGF-associated pathways are distinct. In bone remodeling, OPN and VEGF are regulated under the influence of growth factors and hormones, hypoxia and inflammation, the micro environment, and various physical forces. Their abundance can be affected by drug treatment. OPN and VEGF are variably associated with kidney disease. Their balanced levels are critical for restoring endothelial cell function and ameliorating the adverse effects of microgravity. Here, we review the relevant 83 papers of 257 articles published, and listed in PubMed under the key words OPN and VEGF. PMID- 26123595 TI - Bilateral pneumothorax: A rare complication of central venous catheter placement for plasmapheresis years after thymectomy. PMID- 26123596 TI - Impact factors 2014. PMID- 26123597 TI - HCN Channel C-Terminal Region Speeds Activation Rates Independently of Autoinhibition. AB - Hyperpolarization- and cyclic nucleotide-activated (HCN) channels contribute to rhythmic oscillations in excitable cells. They possess an intrinsic autoinhibition with a hyperpolarized V 1/2, which can be relieved by cAMP binding to the cyclic nucleotide binding (CNB) fold in the C-terminal region or by deletion of the CNB fold. We questioned whether V 1/2 shifts caused by altering the autoinhibitory CNB fold would be accompanied by parallel changes in activation rates. We used two-electrode voltage clamp on Xenopus oocytes to compare wildtype (WT) HCN2, a constitutively autoinhibited point mutant incapable of cAMP binding (HCN2 R591E), and derivatives with various C-terminal truncations. Activation V 1/2 and deactivation t 1/2 measurements confirmed that a truncated channel lacking the helix alphaC of the CNB fold (DeltaalphaC) had autoinhibition comparable to HCN2 R591E; however, DeltaalphaC activated approximately two-fold slower than HCN2 R591E over a 60-mV range of hyperpolarizations. A channel with a more drastic truncation deleting the entire CNB fold (DeltaCNB) had similar V 1/2 values to HCN2 WT with endogenous cAMP bound, confirming autoinhibition relief, yet it surprisingly activated slower than the autoinhibited HCN2 R591E. Whereas CNB fold truncation slowed down voltage-dependent reaction steps, the voltage-independent closed-open equilibrium subject to autoinhibition in HCN2 was not rate-limiting. Chemically inhibiting formation of the endogenous lipid PIP2 hyperpolarized the V 1/2 of HCN2 WT but did not slow down activation to match DeltaCNB rates. Our findings suggest a "quickening conformation" mechanism, requiring a full-length CNB that ensures fast rates for voltage-dependent steps during activation regardless of potentiation by cAMP or PIP2. PMID- 26123598 TI - The state of the art in non-pharmacological interventions for developmental stuttering. Part 2: qualitative evidence synthesis of views and experiences. AB - BACKGROUND: A range of interventions have been developed to treat stuttering in recent years. The effectiveness of these interventions has largely been assessed in studies focusing on the impact of specific types of therapy on patient outcomes. Relatively little is known about the factors that influence how the delivery and impact of different types of intervention may be experienced from the perspective of both people who deliver as well as those who receive interventions. AIMS: To synthesize the available evidence in relation to factors that might enhance or mitigate against successful outcomes following interventions for stuttering by identifying and synthesizing relevant qualitative research that explored the experiences of people delivering and receiving interventions that aim to improve fluency. METHODS & PROCEDURES: We carried out a systematic review including research that had used in-depth interviews and focus groups and conducted a substantive qualitative analysis of the data collected. Included study populations were either adults or children affected by a diagnosed stutter and/or providers of therapy for stuttering. An iterative approach was used to search for published qualitative evidence in relevant databases from 1990 to 2014. Retrieved citations were sifted for relevance and the data from articles that met the inclusion criteria were extracted. Each included paper was assessed for quality and a thematic analysis and synthesis of findings was carried out. MAIN CONTRIBUTION: Synthesized qualitative evidence highlights the changing experiences for people who stutter both historically and, for individuals, over the life course. Barriers and facilitators to the implementation of interventions for stuttering are encountered at the individual, intervention, interpersonal and social levels. Interventions may be particularly pertinent at certain transition points in the life course. Attention to emotional as well as practical aspects of stuttering is valued by people receiving therapy. The client-therapist relationship and support from others are also key factors in achieving successful outcomes. CONCLUSIONS & IMPLICATIONS: A synthesis of qualitative findings from published papers has added to the effectiveness data reported in an accompanying paper in understanding how stuttering impacts on people across the life course. Evidence suggests that a client-centred and individually tailored approach enhances the likelihood of successful intervention outcomes through attention to emotional, situational and practical needs. PMID- 26123599 TI - Trastuzumab in metastatic breast cancer after complete remission: How long is enough? PMID- 26123600 TI - Pericyte antigens in angiomyolipoma and PEComa family tumors. AB - Perivascular epithelioid cell tumors (PEComas) are an uncommon family of soft tissue tumors with dual myoid-melanocytic differentiation. Although PEComa family tumors commonly demonstrate a perivascular growth pattern, pericyte antigen expression has not yet been examined among this unique tumor group. Previously, we demonstrated that a subset of perivascular soft tissue tumors exhibit a striking pericytic immunophenotype, with diffuse expression of alphaSMA, CD146, and PDGFRbeta. Here, we describe the presence of pericyte antigens across a diverse group of PEComa family tumors (n = 19 specimens). Results showed that pericyte antigens differed extensively by histological appearance. Typical angiomyolipoma (AML) specimens showed variable expression of pericyte antigens among both perivascular and myoid-appearing cells. In contrast, AML specimens with a predominant spindled morphology showed diffuse expression of pericyte markers, including alphaSMA, CD146, and PDGFRbeta. AML samples with predominant epithelioid morphology showed a marked reduction in or the absence of immunoreactivity for pericyte markers. Lymphangiomyoma samples showed more variable and partial pericyte marker expression. In summary, pericyte antigen expression is variable among PEComa family tumors and largely varies by tumor morphology. Pericytic marker expression in PEComa may represent a true pericytic cell of origin, or alternatively aberrant pericyte marker adoption. Markers of pericytic differentiation may be of future diagnostic utility for the evaluation of mesenchymal tumors, or identify actionable signaling pathways for future therapeutic intervention. PMID- 26123601 TI - The course of fatigue and its correlates in colorectal cancer survivors: a prospective cohort study of the PROFILES registry. AB - PURPOSE: Colorectal cancer (CRC) survivors who remain fatigued during long-term follow-up are at risk for worse health outcomes and need relevant interventions most. The aim of this study is to prospectively assess cancer-related fatigue (CRF) and four categories of CRF correlates (clinical characteristics, demographic characteristics, behavior/well-being, functional status). METHODS: CRC survivors diagnosed between 2000 and 2009, as registered in the population based Eindhoven Cancer Registry, completed the Fatigue Assessment Scale at three annual time points. Linear mixed models were used to assess the course of CRF and identify its correlates. RESULTS: CRF levels were relatively stable over time. Being female, young (<=65 years of age), and single; having a low educational level; treatment with chemotherapy; and having one or more comorbid conditions were associated with higher CRF scores. Years since diagnosis, radiotherapy, and disease stage were not related to CRF over time. Significant between- and within subject effects were found for all well-being factors (social, emotional, and cognitive functioning, and global quality of life), symptoms (anxiety, depression, pain, and insomnia), and functional status (physical and role functioning, physical activity levels) in relation to CRF. The differences in CRF levels could, for a large part, be attributed to differences in behavior/well being (59 %), functional status (37 %), and, to a lesser extent, to sociodemographic (4 %) and clinical characteristics (8 %). CONCLUSION: This study showed that sociodemographic and clinical factors were associated with CRF levels over time among CRC survivors; however, behavior/well-being and functional status explained a larger part of the variance in levels of CRF. PMID- 26123603 TI - Detection of adulteration in acetonitrile using near infrared spectroscopy coupled with pattern recognition techniques. AB - In this paper, near infrared spectroscopy (NIR) in cooperation with the pattern recognition techniques were used to determine the type of neat acetonitrile and the adulteration in acetonitrile. NIR spectra were collected between 400 nm and 2498 nm. The experimental data were first subjected to analysis of principal component analysis (PCA) to reveal significant differences and potential patterns between samples. Then support vector machine (SVM) were applied to develop classification models and the best parameter combination was selected by grid search. Under the best parameter combination, the classification accuracy rates of three types of neat acetonitrile reached 87.5%, and 100% for the adulteration with different concentration levels. The results showed that NIR spectroscopy combined with SVM could be utilized for determining the potential adulterants including water, ethanol, isopropyl alcohol, acrylonitrile, methanol, and by products associated with the production of acetonitrile. PMID- 26123602 TI - Quality of life across chemotherapy lines in patients with advanced colorectal cancer: a prospective single-center observational study. AB - BACKGROUND: Palliative chemotherapy in patients with nonresectable advanced colorectal carcinoma is performed to prolong survival, alleviate tumor-associated symptoms, and maintain or improve health-related quality of life (HRQOL). In this prospective single-center observational study, we assessed HRQOL across the various lines of palliative chemotherapy. METHODS: HRQOL data were acquired using the EORTC Quality of Life Questionnaire-C30 (QLQ-C30) questionnaire. The first assessment was performed at the beginning of each chemotherapy line, the second after three cycles, and the third at the end of chemotherapy. Further assessments were conducted during checkups every 3 months in our outpatient unit. RESULTS: In total, 100 consecutive patients with colorectal carcinoma (mean age 66.4 years; 60 % men) treated with palliative chemotherapy were recruited. Generally, QOL deteriorated constantly across time. Physical functioning, fatigue, pain, dyspnea, and appetite worsened steadily from first-line chemotherapy to the later treatment phase. Global QOL, emotional functioning, and role functioning improved slightly after the end of first-line chemotherapy, deteriorated during second line chemotherapy to the level of first-line chemotherapy, and further deteriorated in the later treatment phases. In additional analyses, we found the largest differences between patients with and without a treatment response for pain (19.0 vs. 37.2 points) and appetite loss (17.4 vs. 32.7 points). CONCLUSION: The individual QOL domains deteriorated constantly across time. Our data indicate that patients undergoing first- and second-line palliative chemotherapy experience stabilization of global QOL and psychosocial symptoms. We also found that unselected patients who achieved a treatment response had a lower symptom burden and better QOL than did patients with progressive disease. PMID- 26123604 TI - Interaction of gamma-Fe2O3 nanoparticles with fibrinogen. AB - In this article, an attempt is made to analysis the binding mechanism of gamma Fe2O3 nanoparticles with fibrinogen by using a combination of circular dichroism, UV-vis, fluorescence spectroscopic and computational methods. The multi spectroscopic data revealed that the complex easily formed between gamma-Fe2O3 nanoparticles and fibrinogen by mainly hydrogen bonding forces. The binding constants of fibrinogen with gamma-Fe2O3 nanoparticles were 2.24*10(7), 1.15*10(7) and 0.72*10(7)Lmol(-1) at 298, 304, and 310K, respectively. Furthermore, the results from circular dichroism, UV-vis, synchronous fluorescence, and three-dimensional fluorescence studies showed that the strong binding interaction of gamma-Fe2O3 nanoparticles with fibrinogen induced an obvious perturbation in the protein secondary and tertiary structure. Moreover, the results of molecular modeling indicated the existence of the preferable binding site on fibrinogen for gamma-Fe2O3 NPs model. PMID- 26123605 TI - Determination of tritium concentrations in humans before the development of a nuclear power plant in Turkey. AB - The most widely used method to determine the level of tritium in humans is testing urine. Tritium concentrations in urine samples of 100 persons aged 18-66 years selected randomly from a pilot region in Turkey were analysed. The average activity concentration of urine samples was 4.66 +/- 1.94 Bq L(-1) and the maximum activity concentration was 27.91 Bq L(-1). The minimum detectable activity was 2.38 Bq L(-1). The annual effective dose from tritium was also evaluated on the basis of the measurement results and reference values recommended by the International Commission on Radiological Protection. The effective doses for males and females were 4.56 and 3.54 nSv, respectively. These results were lower than the permissible annual effective dose for members of the public. PMID- 26123606 TI - Creation of Simple Biochemical Systems to Study Early Cellular Life. AB - A constructive model of the minimal cell that can produce lipids internally was proposed by reconstructing a set of enzymes involved in phospholipid biosynthesis. This will be an promising approach to study not only for potential reconstruction of LUCA-like organisms but also for construction of artificial cells. PMID- 26123607 TI - Sweat osmolarity shows intra-animal regional variation in the horse. AB - BACKGROUND: Sweating is important in regulating body temperature but can be a source of loss of both fluids and electrolytes. Although the process has been studied in horses, the variation in sweat osmolarity across the body has not. OBJECTIVES: This work describes an investigation to determine if there is regional variation in the osmolarity of sweat across different anatomical regions of the horse. ANIMALS: Ten horses were used in the study and were animals either stabled for riding lessons or had livery on-site. METHODS: Sweat samples were collected from five regions on each horse following exercise and the osmolarity measurements were made using an Osmomat 030 (Gonotec, Berlin, Germany). Values were analysed by paired t-tests and analysis of variance. RESULTS: Samples from the back and ears had statistically (P < 0.05) lower osmolarity values than those seen for the neck and forelimb, with thigh values intermediate between the other two sets of values. CONCLUSIONS AND CLINICAL IMPORTANCE: Previous studies have used osmolarity values based on the sweat collected from the horse's back. The current work demonstrates that these values are probably an underestimation of electrolyte loss, which may have implications for the composition and administration of rehydration compounds. PMID- 26123608 TI - Focused transesophageal echocardiography for emergency physicians-description and results from simulation training of a structured four-view examination. AB - BACKGROUND: Transesophageal echocardiography (TEE) offers several advantages over transthoracic echocardiography (TTE). Despite these advantages, use of TEE by emergency physicians (EPs) remains rare, as no focused TEE protocol for emergency department (ED) use has been defined nor have methods of training been described. OBJECTIVE: This study aims to develop a focused TEE examination tailored for the ED and to evaluate TEE skill acquisition and retention by TEE-naive EPs following a focused 4-h curriculum. METHODS: Academic EPs were invited to participate in a 4-h didactic and simulation-based workshop. The seminar emphasized TEE principles and views obtained from four vantage points. Following the training, participants engaged in an assessment of their abilities to carry out a focused TEE on a high fidelity simulator. A 6-week follow-up session assessed skill retention. RESULTS: Fourteen EPs participated in this study. Immediately following the seminar, 14 (100 %; k = 1.0) and 10 (71.4 %, k = 0.65) successfully obtained an acceptable mid-esophageal four-chamber and mid-esophageal long-axis view. Eleven (78.6 %, k = 1.0) participants were able to successfully obtain an acceptable transgastric short-axis view, and 11 (78.6 %, k = 1.0) EPs successfully obtained a bicaval view. Twelve participants engaged in a 6-week retention assessment, which revealed acceptable images and inter-rater agreement as follows: mid-esophageal four-chamber, 12 (100 %; k = 0.92); mid-esophageal long axis, 12 (100 %, k = 0.67); transgastric short-axis, 11 (91.7 %, k = 1.0); and bicaval view, 11 (91.7 %, k = 1.0). CONCLUSION: This study has illustrated that EPs can successfully perform this focused TEE protocol after a 4-h workshop with retention of these skills at 6 weeks. PMID- 26123609 TI - Perceived barriers in the use of ultrasound in developing countries. AB - BACKGROUND: Access to ultrasound has increased significantly in resource-limited settings, including the developing world; however, there remains a lack of sonography education and ultrasound-trained physician support in developing countries. To further investigate this potential knowledge gap, our primary objective was to assess perceived barriers to ultrasound use in resource-limited settings by surveying care providers who practice in low- and middle-income settings. METHODS: A 25-question online survey was made available to health care providers who work with an ultrasound machine in low- and middle-income countries (LMICs), including doctors, nurses, technicians, and clinical officers. This was a convenience sample obtained from list-serves of ultrasound and radiologic societies. The survey was analyzed, and descriptive results were obtained. RESULTS: One hundred and thirty-eight respondents representing 44 LMICs including countries from the continents of Africa, South America, and Asia completed the survey, with a response rate of 9.6 %. Ninety-one percent of the respondents were doctors, and 9 % were nurses or other providers. Applications for ultrasound were diverse, including obstetrics (75 %), DVT evaluation (51 %), abscess evaluation (54 %), cardiac evaluation (64 %), inferior vena cava (IVC) assessment (49 %), Focused Assessment Sonography for Trauma (FAST) exam (64 %), biliary tree assessment (54 %), and other applications. The respondents identified the following barriers to use of ultrasound: lack of training (60 %), lack of equipment (45 %), ultrasound machine malfunction (37 %), and lack of ultrasound maintenance capability (47 %). Seventy-four percent of the respondents wished to have further training in ultrasound, and 82 % were open to receiving distance learning or telesonography training. Subjects used communication tools including Skype, Dropbox, emailed photos, and picture archiving and communication system (PACS) as ways to communicate and receive feedback on ultrasound images. CONCLUSIONS: Health care providers in the developing world identify lack of training as a primary barrier to regular use of ultrasound in their practice. While equipment requirements including maintenance and cost of machines are also important factors, future research is warranted on best practices for training methods, including telesonography and distance learning to enhance ultrasound use in low-resource settings. PMID- 26123610 TI - Respiratory variation in carotid peak systolic velocity predicts volume responsiveness in mechanically ventilated patients with septic shock: a prospective cohort study. AB - BACKGROUND: The evaluation of fluid responsiveness in patients with hemodynamic instability remains to be challenging. This investigation aimed to determine whether respiratory variation in carotid Doppler peak velocity (DeltaCDPV) predicts fluid responsiveness in patients with septic shock and lung protective mechanical ventilation with a tidal volume of 6 ml/kg. METHODS: We performed a prospective cohort study at an intensive care unit, studying the effect of 59 fluid challenges on 19 mechanically ventilated patients with septic shock. Pre fluid challenge DeltaCDPV and other static or dynamic measurements were obtained. Fluid challenge responders were defined as patients whose stroke volume index increased more than 15 % on transpulmonary thermodilution. The area under the receiver operating characteristic curve (AUROC) was compared for each predictive parameter. RESULTS: Fluid responsiveness rate was 51 %. The DeltaCDPV had an AUROC of 0.88 (95 % confidence interval (CI) 0.77-0.95); followed by stroke volume variation (0.72, 95 % CI 0.63-0.88), passive leg raising (0.69, 95 % CI 0.56-0.80), and pulse pressure variation (0.63, 95 % CI 0.49-0.75). The DeltaCDPV was a statistically significant superior predictor when compared with the other parameters. Sensitivity, specificity, and positive and negative predictive values were also the highest for DeltaCDPV, with an optimal cutoff at 14 %. There was good correlation between DeltaCDPV and SVI increment after the fluid challenge (r = 0.84; p < 0.001). CONCLUSIONS: DeltaCDPV can be more accurate than other methods for assessing fluid responsiveness in patients with septic shock receiving lung protective mechanical ventilation. DeltaCDPV also has a high correlation with SVI increase after fluid challenge. PMID- 26123612 TI - The trials and hopes for drug development in sickle cell disease. AB - Although sickle cell disease (SCD) is highly prevalent worldwide, it is a rare disease in the United States and Europe. Over the past decade, there has been an increased understanding of the pathophysiology of SCD. While multiple drugs have been tested, only one drug, hydroxycarbamide, is approved by the relevant regulatory agencies specifically for this disease. Due to the combination of an improved understanding of disease pathophysiology, governmental support and the success of several recently approved drugs for other orphan diseases, there is an increased interest in the development of targeted drugs for SCD. Novel drugs that are currently being evaluated include haemoglobin F inducers, anti-sickling agents, anti-oxidants, anti-adhesive agents, anti-inflammatory agents, anticoagulants and anti-platelet agents. In addition to the evaluation of acute pain crisis as a study endpoint, clinical trials employing other SCD-related complications, exercise capacity, as well as patient reported outcomes are warranted and necessary in order to advance the development of these novel therapeutic agents. Finally, despite the availability of multiple biomarkers, many of these are of limited clinical value in SCD and require further assessment in prospective studies to validate their prognostic importance before they are acceptable as surrogate endpoints. PMID- 26123611 TI - Clostridium amazonense sp. nov. an obliqately anaerobic bacterium isolated from a remote Amazonian community in Peru. AB - A strictly anaerobic Gram-stain positive, spore-forming, rod-shaped bacterium designated NE08V(T), was isolated from a fecal sample of an individual residing in a remote Amazonian community in Peru. Phylogenetic analysis based on the 16S rRNA gene sequence showed the organism belonged to the genus Clostridium and is most closely related to Clostridium vulturis (97.4% sequence similarity) and was further characterized using biochemical and chemotaxonomic methods. The major cellular fatty acids were anteiso C13:0 and C16:0 with a genomic DNA G + C content of 31.6 mol%. Fermentation products during growth with PYG were acetate and butyrate. Based on phylogenetic, phenotypic and chemotaxonomic information, strain NE08V was identified as representing a novel species of the genus Clostridium, for which the name Clostridium amazonense sp. nov. is proposed. The type strain is NE08V(T) (DSM 23598(T) = CCUG 59712(T)). PMID- 26123613 TI - Incidence and survival of childhood central nervous system tumors: A report of the regional registry of childhood cancers in Auvergne-Limousin. AB - INTRODUCTION: Central nervous system tumors (CNST) are the most lethal of solid tumors in childhood cancer. PATIENTS AND METHODS: We report incidence and survival data for all CNST (International Classification of Diseases for Oncology third edition, category III or Xa) recorded in children under 15 years of age by the Auvergne-Limousin cancer registry for the period 1986-2009. RESULTS: Annual incidence of all CNST was 3.27 per 100,000 and the male to female ratio was 0.95. Over 45.0% of CNST were glial. Astrocytomas (36.2%) showed the highest incidence for each age group except between 1 and 4 years where embryonal tumors were more common. For all CNST, no significant variation in incidence over time was observed for the evaluated period of 23 years (annual percent change: -0.4%, 95% CI, [-2.8-2.1]). Globally, 5 years overall survival was 67% [59-73] and had increased by more than 16% between 1986-1999 and 2000-2009, mainly due to better survival for astrocytomas, other gliomas, ependymomas and choroid plexus tumors (P=0.01). CONCLUSION: We report that the incidence of CNST in Auvergne-Limousin is similar to that in the literature and did not increase between 1986 and 2009. In addition, 5 years overall survival increased after 1999, especially for surgically treatable tumors. PMID- 26123614 TI - The cephaloceles: A clinical, epidemiological and therapeutic study of 50 cases. AB - INTRODUCTION: Cephaloceles are congenital malformations characterized by externalization of the meninges and/or brain tissue through a congenital skull bone defect. In developed countries, this malformation is rare but in our developing countries, this pathology remains one of our concerns. OBJECTIVE: To describe the epidemiological, clinical and therapeutic aspects of the cephaloceles. MATERIALS AND METHOD: A retrospective study was conducted from 2007 to 2013 on all cases of cephalocele supported in the department of neurosurgery of the Yalgado Ouedraogo University Teaching Hospital of Ouagadougou. The malformations were supplemented by CT scan. All patients were operated. The surgical procedure in cephaloceles of the convexity consisted of a direct approach. Sincipital cephaloceles were operated by transcranial approach or combined approach associating transcranial and transnasal approaches. RESULTS: Fifty patients were gathered during the 7-year period. There were 18 boys and 32 girls. The ages ranged from 1 day to 11 years. The cephaloceles were located on the vault of the skull in 78%; the lesion was sincipital in 22%. The malformation was covered with normal skin in 92%; it was pediculated in 78%. CT scan allowed the classification of cases as meningo-encephaloceles in 31 cases (62%) and meningoceles in 18 cases (36%) and one pure encephalocele. The immediate postoperative course was uneventful in 42 cases (84%); 8 postoperative deaths were recorded. At medium and long term, 4 patients (8%) developed complications of psychomotor deficiency in 3 cases and hydrocephalus in 1 case. The main reasons for the poor prognosis were superinfection, hydrocephalus and/or other brain malformations. CONCLUSION: Cephaloceles remain relatively frequent in our practice. After surgery, mental failure and hydrocephalus can occur impairing the prognosis. The most suitable solution is a policy of prevention with folic acid treatment before and during pregnancy and following up adequate pregnancies. PMID- 26123615 TI - In vivo nanoparticle-mediated radiopharmaceutical-excited fluorescence molecular imaging. AB - Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts gamma and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications. PMID- 26123616 TI - Experiences of diagnosis, care and treatment among Aboriginal people living with hepatitis C. AB - OBJECTIVE: Aboriginal Australians are disproportionately affected by hepatitis C (HCV). There are a range of barriers to HCV care, often beginning with poor diagnosis experiences. Little research exists on the experiences of Aboriginal Australians living with HCV. This study aimed to describe their patterns of HCV care and treatment with specific emphasis on the impact of their being informed of their diagnosis in a culturally sensitive manner. METHODS: A total of 203 Aboriginal people living with HCV were recruited to complete a survey assessing experiences of HCV testing and care, HCV knowledge, lifestyle changes after diagnosis, perceived stigma and discrimination. RESULTS: Of the sample, 58% were male and 96% identified as Aboriginal, with a mean age of 28 years. Correlation analysis revealed that satisfaction with the cultural appropriateness of the diagnosis was associated with: being offered pre- and post-test counselling; satisfaction with HCV care; decreased feelings of HCV-related stigma; lower scores on the medical mistrust scale; and greater intentions to access HCV treatment. CONCLUSIONS: These findings confirm the importance of providing a HCV diagnosis in a culturally appropriate way for Aboriginal people. IMPLICATIONS: Satisfaction with HCV diagnosis appears essential in establishing patterns of greater engagement with HCV care and treatment for this group. PMID- 26123617 TI - Clinical implications of the CKD epidemiology collaboration (CKD-EPI) equation compared with the modification of diet in renal disease (MDRD) study equation for the estimation of renal dysfunction in patients with cardiovascular disease. AB - The CKD-EPI equation is more accurate than the MDRD equation in the general population. We performed this study to establish whether chronic kidney disease (CKD) is commonly recognized by clinicians and whether the CKD-EPI equation improves prognosis estimation in patients with chronic cardiovascular disease (CVD). We analyzed data on 12394 CVD patients consecutively examined at the Cardiovascular Center of Trieste (Italy) between November 2009 and October 2013. The outcomes were all-cause death and a composite outcome of death/hospitalization for CV events (D+cvH). CKD-EPI formula reclassified 1786 (14.4 %) patients between KDIGO categories compared to the MDRD: 2.3 % (n = 280) placed in a lower risk and 12.1 % (n = 1506) into a higher risk group. CKD, defined as eGFR-CKD-EPI formula <60 ml/min, was present in 3083 patients (24.9 %) but not recognized by clinicians in 1946 (63.1 % of patients with CKD). The lack of recognition of CKD was inversely proportional to the KDIGO class for both equations. There were 986 deaths and 2726 D+cvH during 24 months follow-up. The incidence of death and D+cvH was about twice as high in patients with unrecognized CKD than in those with normal renal function (31 % vs. 17.1 %, aHR: 1.35, 95 % CI: 1.15 to 1.60), even in those patients with eGFR-MDRD >60 but eGFR CKD-EPI formula <60 (31.1 % vs 17.1 %, p < 0.001). CKD-EPI equation provides more accurate risk stratification than MDRD equation in patients with CVD. CKD was unrecognized in nearly two-thirds of these patients but clinical outcomes were similar in those for patients with recognized CKD. PMID- 26123618 TI - Impact of metabolic syndrome on the survival of Chinese patients with resectable esophageal squamous cell carcinoma. AB - Metabolic syndrome (MetS) is associated with the risk of esophageal squamous cell carcinoma (ESCC). However, the impact of MetS on survival has not been evaluated. A retrospective review was performed on 596 consecutive Chinese patients with esophageal squamous cell carcinoma who received surgery between January 2005 and October 2007. The clinical data and pretreatment information related to MetS were reviewed. The impact of MetS on overall survival (OS) was estimated by Kaplan Meier and Cox proportional hazards analyses. MetS was a significant and independent predictor for better survival in patients with resectable ESCC. The 3 year OS and 5-year OS for patients with and without MetS were 75.0% versus 57.8% and 65.1% versus 44.6%, respectively (P = 0.005 in the univariate analysis, P = 0.010 in multivariate analysis). However, there was no apparent influence of any single component of MetS on OS. The other independent prognostic factors identified in the univariate analysis included the following: gender, smoking status, alcohol use, the extent of radical surgical resection, T and N stage, and tumor differentiation. The results of the multivariate analysis included the extent of radical surgery resection, T and N stage, and tumor differentiation. MetS was also associated with greater tumor cell differentiation (P = 0.036). There was no association found between MetS status and postoperative complications. MetS is an independent prognostic factor for OS in patients with ESCC and is associated with better tumor cell differentiation. PMID- 26123619 TI - Corrigendum: Carnival or football, is there a real risk for acquiring dengue fever in Brazil during holidays seasons? PMID- 26123620 TI - Experimental study of Lucilia sericata (Diptera Calliphoridae) larval development on rat cadavers: Effects of climate and chemical contamination. AB - Household products such as bleach, gasoline or hydrochloric acid have been used to mask the presence of a cadaver or to prevent the colonization of insects. These types of chemicals affect insect development and alter the forensic entomology analysis. This study was designed to test the effects of six household products (bleach, mosquito repellent, perfume, caustic soda, insecticide and unleaded gasoline) on blowfly (Lucilia sericata, Diptera: Calliphoridae) larval development. Furthermore, the effects of climate (rain or dry conditions) on larval development were analyzed. For each replication, 100 first instars were placed on a rat cadaver on which one household product was spilled. We observed a decrease in the survival rates of the larvae but no significant effect on their development times or the adult size. The same trends were observed under rainy conditions. However, the rain altered the effects of some tested household products, especially gasoline. These results demonstrate for the first time the successful development of necrophagous larvae on chemically contaminated cadavers, and provide evidence for the range of possible effects to expect. PMID- 26123621 TI - High binding yet accelerated guest rotation within a cucurbit[7]uril complex. Toward paramagnetic gyroscopes and rolling nanomachines. AB - The (15-oxo-3,7,11-triazadispiro[5.1.5.3]hexadec-7-yl)oxidanyl, a bis spiropiperidinium nitroxide derived from TEMPONE, can be included in cucurbit[7]uril to form a strong (K(a)~ 2 * 10(5) M(-1)) CB[7]@bPTO complex. EPR and MS spectra, DFT calculations, and unparalleled increased resistance (a factor of ~10(3)) toward ascorbic acid reduction show evidence of deep inclusion of bPTO inside CB[7]. The unusual shape of the CB[7]@bPTO EPR spectrum can be explained by an anisotropic Brownian rotational diffusion, the global tumbling of the complex being slower than rotation of bPTO around its "long molecular axis" inside CB[7]. The CB[7] (stator) with the encapsulated bPTO (rotator) behaves as a supramolecular paramagnetic rotor with increased rotational speed of the rotator that has great potential for advanced nanoscale machines requiring wheels such as cucurbiturils with virtually no friction between the wheel and the axle for optimum wheel rotation (i.e. nanopulleys and nanocars). PMID- 26123622 TI - Participation in Physical Activity, Fitness, and Risk for Obesity in Children with Developmental Coordination Disorder: A Cross-cultural Study. AB - Decreased physical activity has been linked to poor fitness and obesity, resulting in increased risk for health concerns. The objective is to study the relationships between children's motor coordination and their physical activity, sedentary behaviour, fitness and weight status in a cross-cultural study in the United States and Israel. Participants included 118 children 6-11 years of age: 53 children with developmental coordination disorder (DCD) and 65 typical children. The US sample included 31 DCD children and 44 typical children. The Israeli sample included 22 DCD children and 21 typical children. Participants were assessed on Movement Assessment Battery for Children 2, strength test of the Bruininks-Oseretsky Test of Motor Proficiency 2 and Six-minute Walk Test and wore an accelerometer. Parents completed physical activity questionnaires and demographic information. Body mass index was calculated based on height and weight. Testing took place in two sessions. Findings are that in both Israel and the United States, children with DCD demonstrated significantly reduced physical activity, increased sedentary behaviour, poorer fitness and increased overweight compared with typical children. No significant differences were found for country. With relevance to clinical practice, fitness and obesity are major concerns for children with DCD in both countries. Inclusion of occupational therapy in health promotion for this population is critical. Additional studies with testers blind to group, larger samples and other countries are recommended. PMID- 26123624 TI - Pembrolizumab: a novel antiprogrammed death 1 (PD-1) monoclonal antibody for treatment of metastatic melanoma. AB - WHAT IS KNOWN AND OBJECTIVE: To review the pharmacology, efficacy, safety, formulary and economic considerations of pembrolizumab, a novel, first-in-class, anti-PD-1 monoclonal antibody for treatment of advanced melanoma. METHODS: A literature search was conducted using PubMed (July 2013-December 2014) with search terms: pembrolizumab, MK-3475 and lambrolizumab. Additional sources were identified through a subsequent review of all relevant papers, clinicaltrials.gov, product labelling and media releases. All English-language studies conducted in humans with clinical data were included. Review papers were excluded from analysis. RESULTS AND DISCUSSION: Patients with advanced melanoma have limited options available. Immune therapies have shown promise in treating advanced melanoma, but can have significant toxicities. Identification of the role of PD-1 in tumour immune evasion and the subsequent development of pembrolizumab, a novel agent that inhibits PD-1, has led to the availability of an additional treatment option for patients who have progressive disease despite treatment with currently approved agents. Phase I cohort studies have demonstrated promising overall response rates and an estimated progression-free survival of approximately 5.5 months. Minimal toxicity has been observed in patients receiving pembrolizumab, although significant severe immune-mediated reactions have been reported. WHAT IS NEW AND CONCLUSION: Pembrolizumab is a novel anti-PD-1 monoclonal antibody that is an effective option for advanced melanoma previously treated with agents such as ipilimumab and BRAF inhibitors. Additional studies will provide the necessary data for determining its true place in therapy for advanced melanoma and exploring its efficacy in additional malignant indications. PMID- 26123623 TI - Matrix Metalloproteinase-3 -1171 5A/6A Polymorphism (rs35068180) is Associated with Risk of Periodontitis. AB - Matrix metalloproteinase-3 (MMP3) plays a key role in tissue degradation in periodontitis. The relationship between the MMP3 -1171 5A/6A polymorphism (rs35068180) and periodontitis has been widely studied. However, existing studies have yielded contradictory results. We therefore conducted a meta-analysis to comprehensively investigate these inconclusive findings. Several electronic databases were searched for eligible articles. Seven case-control studies from 6 articles were searched without any language restrictions. Pooled estimates indicated that MMP3 -1171 5A/6A polymorphism is associated with a decreased risk of periodontitis (allelic genetic model: OR = 0.70, 95% CI: 0.62-0.80, P(heterogeneity) = 0.315; heterozygous model: OR = 0.50, 95% CI: 0.39-0.65, P(heterogeneity) = 0.221; homozygous model: OR = 0.42, 95% CI: 0.25-0.69, P(heterogeneity) = 0.265; dominant model: OR = 0.49, 95% CI: 0.38-0.62, P(heterogeneity) = 0.238, respectively). Similar results were also found in chronic periodontitis (CP), Asian, Asian&CP, and non-smokers subgroups. Moreover, MMP3 rs35068180 polymorphism might be associated with a lower risk of aggressive periodontitis (AgP) in Asians (allelic genetic model: OR = 0.66, 95% CI: 0.48 0.91, P(heterogeneity) = 0.945), and CP in Caucasians and Brazilians. In conclusion, this meta-analysis demonstrates that MMP3 -1171 5A/6A polymorphism may be associated with decreased risk of both CP and AgP in Asians. Large independent studies to replicate these results are necessary to validate these associations in other populations. PMID- 26123625 TI - Pregnancy outcomes in breech presentation analyzed according to intended mode of delivery. AB - INTRODUCTION: Optimal mode of delivery in breech presentation has been widely examined and debated. The aim of this study was to compare perinatal and maternal outcomes with either a policy of planned vaginal delivery or planned cesarean section in breech presentation. MATERIAL AND METHODS: This was a registry-based retrospective cohort study from Turku University Hospital, Finland with 1418 singleton breech deliveries at term over a period of 11 years (January 2002 to December 2012). Data were collected from the mothers' medical records. RESULTS: Apgar scores at 5 min as well as umbilical artery pH values were significantly lower in the planned vaginal breech delivery group compared with the planned cesarean section group, suggesting a short-lasting delayed recovery after birth. There were more puerperal infections in planned cesarean section group compared with the planned vaginal delivery group. CONCLUSIONS: The results confirm that planned vaginal breech delivery results in short-lasting delayed recovery after birth compared with planned cesarean section. PMID- 26123627 TI - The fabrication of double layer tubular vascular tissue engineering scaffold via coaxial electrospinning and its 3D cell coculture. AB - A continuous electrospinning technique was applied to fabricate double layer tubular tissue engineering vascular graft (TEVG) scaffold. The luminal layer was made from poly(E-caprolac-tone)(PCL) ultrafine fibers via common single axial electrospinning followed by the outer layer of core-shell structured nanofibers via coaxial electrospinning. For preparing the outer layernano-fibers, the PCL was electrospun into the shell and both bovine serum albumin (BSA) and tetrapeptide val-gal-pro-gly (VAPG) were encapsulated into the core. The core shell structure in the outer layer fibers was observed by transmission electron microscope (TEM). The in vitro release tests exhibited the sustainable release behavior of BSA and VAPG so that they provided a better cell growth environment in the interior of tubular scaffold wall. The in vitro culture of smooth muscle cells (SMCs) demonstrated their potential to penetrate into the scaffold wall for the 3D cell culture. Subsequently, 3D cell coculture was conducted. First, SMCs were seeded on the luminal surface of the scaffold and cultured for 5 days, and then endothelial cells (ECs) were also seeded on the luminal surface and cocultured with SMCs for another 2 days. After stained with antibodies, 3D cell distribution on the scaffold was revealed by confocal laser scanning microscopy (CLSM) where ECs were mainly located on the luminal surface whereas SMCs penetrated into the surface and distributed inside the scaffold wall. This double layer tubular scaffold with 3D cell distribution showed the promise to develop it into a novel TEVG for clinical trials in the near future. PMID- 26123626 TI - Humans as cucinivores: comparisons with other species. AB - We discuss the relations of processed foods, especially cooked foods, in the human diet to digestive tract form and function. The modern consumption of over 70% of foods and beverages in highly refined form favours the diet-related classification of humans as cucinivores, rather than omnivores. Archaeological evidence indicates that humans have consumed cooked food for at least 300-400,000 years, and divergence in genes associated with human subpopulations that utilise different foods has been shown to occur over periods of 10-30,000 years. One such divergence is the greater presence of adult lactase persistence in communities that have consumed dairy products, over periods of about 8,000 years, compared to communities not consuming dairy products. We postulate that 300-400,000 years, or 10,000-14,000 generations, is sufficient time for food processing to have influenced the form and function of the human digestive tract. It is difficult to determine how long humans have prepared foods in other ways, such as pounding, grinding, drying or fermenting, but this appears to be for at least 20,000 years, which has been sufficient time to influence gene expression for digestive enzymes. Cooking and food processing expands the range of food that can be eaten, extends food availability into lean times and enhances digestibility. Cooking also detoxifies food to some extent, destroys infective agents, decreases eating time and slightly increases the efficiency of assimilation of energy substrates. On the other hand, cooking can destroy some nutrients and produce toxic products. The human digestive system is suited to a processed food diet because of its smaller volume, notably smaller colonic volume, relative to the intestines of other species, and because of differences from other primates in dentition and facial muscles that result in lower bite strength. There is no known group of humans which does not consume cooked foods, and the modern diet is dominated by processed foods. We conclude that humans are well adapted as consumers of processed, including cooked, foods. PMID- 26123628 TI - Safety Profile and Costs of Related Adverse Events of Trastuzumab Emtansine for the Treatment of HER2-Positive Locally Advanced or Metastatic Breast Cancer Compared to Capecitabine Plus Lapatinib from the Perspective of the Canadian Health-Care System. AB - BACKGROUND AND OBJECTIVES: Trastuzumab emtansine (T-DM1, KADCYLA((r))) is an antibody-drug conjugate comprised of the cytotoxic agent DM1 and trastuzumab (HERCEPTIN((r))). The safety profile of T-DM1 in human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer previously treated with trastuzumab and a taxane was investigated in the phase III EMILIA trial. The trial demonstrated clinically and statistically meaningful differences in the safety profile between T-DM1 and capecitabine plus lapatinib (CAP + LAP). The objective of this study was to estimate the costs of managing treatment-related grade >= 3 adverse events (AEs) that occurred in >= 2% of patients and grade 2 AEs that occurred in >= 5% of patients taking T-DM1 compared with patients taking CAP + LAP based on the EMILIA trial, from the perspective of Canadian public payers. METHODS: An Excel-based model was utilized to estimate the relevant costs. Clinical data were obtained from the EMILIA trial. Cost information was obtained from the literature, clinical experts, and standard cost sources. The analysis was conducted from the Canadian public-payer perspective and reported in 2014 Canadian dollars (CAD). RESULTS: The management of included treatment-related AEs resulted in higher estimated per-patient costs of CAD6901 for CAP + LAP versus CAD3380 for T-DM1, resulting in savings of CAD3521. CONCLUSIONS: From a Canadian perspective, this analysis demonstrated that utilizing T-DM1 for the management of HER2-positive metastatic breast cancer results in substantial savings to the public health-care system when considering the costs of treatment-related AEs, due to fewer amount of toxicities compared with CAP + LAP. Results of various sensitivity analyses investigating changes in number and costs of AEs confirmed the findings; however, the magnitude of cost savings varied. Further analyses are necessary to determine whether these cost savings would occur in other countries and health-care systems. PMID- 26123629 TI - Comparing Gabapentin with Clonazepam for Residual Sleeping Problems following Antidepressant Therapy in Patients with Major Depressive Disorder: A Randomized Clinical Trial. AB - BACKGROUND AND OBJECTIVE: Residual sleeping disturbances after improvement of depression in major depressed patients are associated with more functional problems, increased relapses and more risk of becoming resistant to treatment. The aim of this study was to compare the efficacy of gabapentin with clonazepam for treating residual sleeping disturbances. METHODS: This comparative trial was designed as a randomized, controlled, double-blind study. Sixty-three patients with a DSM-IV diagnosis of major depressive disorder (MDD) who had been treated with one of the selective serotonin reuptake inhibitors (SSRIs; fluoxetine, citalopram or sertraline) were included in the study. The patients' depression had improved [Hamilton Depression Rating Scale (HDRS) <10] but they were complaining of sleeping problems [Pittsburgh Sleep Quality Index (PSQI) >5; Insomnia Severity Index (ISI) >8]. Patients were randomized to receive a flexible dose of gabapentin (100-600 mg/day) or clonazepam (0.5-2 mg/day) beside their current antidepressant medication for a period of 4 weeks. Outcome measures were PSQI, ISI and Clinical Global Impression (CGI). RESULTS: Our results demonstrated that similar to the clonazepam group, sleeping problems improved significantly in the gabapentin group at the end of the trial (PSQI: P = 0.001, Z = 3.549; ISI: P = 0.001, Z = 3.347). The two groups did not show a significant difference in treating residual sleep disturbances (PSQI: P = 0.234, Z = 1.432; ISI: P = 0.456, Z = 1.347). CONCLUSION: This study revealed that gabapentin is comparable to clonazepam for treating sleeping problems associated with major depression. PMID- 26123630 TI - SDA 7: A modular and parallel implementation of the simulation of diffusional association software. AB - The simulation of diffusional association (SDA) Brownian dynamics software package has been widely used in the study of biomacromolecular association. Initially developed to calculate bimolecular protein-protein association rate constants, it has since been extended to study electron transfer rates, to predict the structures of biomacromolecular complexes, to investigate the adsorption of proteins to inorganic surfaces, and to simulate the dynamics of large systems containing many biomacromolecular solutes, allowing the study of concentration-dependent effects. These extensions have led to a number of divergent versions of the software. In this article, we report the development of the latest version of the software (SDA 7). This release was developed to consolidate the existing codes into a single framework, while improving the parallelization of the code to better exploit modern multicore shared memory computer architectures. It is built using a modular object-oriented programming scheme, to allow for easy maintenance and extension of the software, and includes new features, such as adding flexible solute representations. We discuss a number of application examples, which describe some of the methods available in the release, and provide benchmarking data to demonstrate the parallel performance. PMID- 26123632 TI - 10th European Cytogenetics Conference 2015 : 4-7 July 2015, Strasbourg - France. PMID- 26123631 TI - Factors affecting dairy farmers' attitudes towards antimicrobial medicine usage in cattle in England and Wales. AB - There has been growing concern about bacterial resistance to antimicrobials in the farmed livestock sector. Attention has turned to sub-optimal use of antimicrobials as a driver of resistance. Recent reviews have identified a lack of data on the pattern of antimicrobial use as an impediment to the design of measures to tackle this growing problem. This paper reports on a study that explored use of antibiotics by dairy farmers and factors influencing their decision-making around this usage. We found that respondents had either recently reduced their use of antibiotics, or planned to do so. Advice from their veterinarian was instrumental in this. Over 70% thought reducing antibiotic usage would be a good thing to do. The most influential source of information used was their own veterinarian. Some 50% were unaware of the available guidelines on use in cattle production. However, 97% thought it important to keep treatment records. The Theory of Planned Behaviour was used to identify dairy farmers' drivers and barriers to reduce use of antibiotics. Intention to reduce usage was weakly correlated with current and past practice of antibiotic use, whilst the strongest driver was respondents' belief that their social and advisory network would approve of them doing this. The higher the proportion of income from milk production and the greater the chance of remaining in milk production, the significantly higher the likelihood of farmers exhibiting positive intention to reduce antibiotic usage. Such farmers may be more commercially minded than others and thus more cost-conscious or, perhaps, more aware of possible future restrictions. Strong correlation was found between farmers' perception of their social referents' beliefs and farmers' intent to reduce antibiotic use. Policy makers should target these social referents, especially veterinarians, with information on the benefits from, and the means to, achieving reductions in antibiotic usage. Information on sub-optimal use of antibiotics as a driver of resistance in dairy herds and in humans along with advice on best farm practice to minimize risk of disease and ensure animal welfare, complemented with data on potential cost savings from reduced antibiotic use would help improve poor practice. PMID- 26123633 TI - Natural phenolics greatly increase flax (Linum usitatissimum) oil stability. AB - BACKGROUND: Flaxseed oil is characterized by high content of essential polyunsaturated fatty acids (PUFA) promoted as a human dietary supplement protecting against atherosclerosis. The disadvantage of the high PUFA content in flax oil is high susceptibility to oxidation, which can result in carcinogenic compound formation. Linola flax cultivar is characterized by high linoleic acid content in comparison to traditional flax cultivars rich in linolenic acid. The changes in fatty acid proportions increase oxidative stability of Linola oil and broaden its use as an edible oil for cooking. However one of investigated transgenic lines has high ALA content making it suitable as omega-3 source. Protection of PUFA oxidation is a critical factor in oil quality. The aim of this study was to investigate the impact of phenylpropanoid contents on the oil properties important during the whole technological process from seed storage to grinding and oil pressing, which may influence health benefits as well as shelf life, and to establish guidelines for the selection of new cultivars. METHODS: The composition of oils was determined by chromatographic (GS-FID and LC-PDA-MS) methods. Antioxidant properties of secondary metabolites were analyzed by DPPH method. The stability of oils was investigated: a) during regular storage by measuring acid value peroxide value p-anisidine value malondialdehyde, conjugated dienes and trienes; b) by using accelerated rancidity tests by TBARS reaction; c) by thermoanalytical - differential scanning calorimetry (DSC). RESULTS: In one approach, in order to increase oil stability, exogenous substances added are mainly lipid soluble antioxidants from the isoprenoid pathway, such as tocopherol and carotene. The other approach is based on transgenic plant generation that accumulates water soluble compounds. Increased accumulation of phenolic compounds in flax seeds was achieved by three different strategies that modify genes coding for enzymes from the phenylpropanoid pathway. The three types of transgenic flax had different phenylpropanoid profiles detected in oil, highly increasing its stability. CONCLUSIONS: We found that hydrophilic phenylpropanoids more than lipophilic isoprenoid compounds determine oil stability however they can work synergistically. Among phenolics the caffeic acid was most effective in increasing oil stability. PMID- 26123635 TI - Impact of high pressure processing on color, bioactive compounds, polyphenol oxidase activity, and microbiological attributes of pumpkin puree. AB - Physicochemical parameters, bioactive compounds' content (carotenoids and total phenols), total antioxidant activity, and enzymatic activity of polyphenol oxidase (PPO) were evaluated after high pressure processing (HPP) on a pumpkin puree (cv. 'Butternut'). Three pressure levels (400, 500, and 600 MPa) were combined with three holding times (200, 400, and 600 s). The applied treatments reduced the levels of total aerobic mesophilic (TAM), total psychrophilic and psychrotrophic bacteria (TPP), and molds and yeasts (M&Y). All applied treatments did not affect enzymatic activity of PPO. Pressure level increased CIE L* values, which could enhance the lightness perception of high pressure (HP)-treated purees. No differences were found between the untreated and HP-treated purees regarding total phenols and carotenoids content (lutein, alpha-carotene, and beta carotene) and total antioxidant activity. HPP did not affect most quality parameters and maintained the levels of bioactive compounds. However, it did not achieve the complete inhibition of PPO, which could reduce the shelf-life of the pumpkin puree. PMID- 26123636 TI - Time trends in the prevalence and incidence of Parkinson's disease in Taiwan: A nationwide, population-based study. AB - BACKGROUND/PURPOSE: Identifying trends in the prevalence and incidence of Parkinson's disease (PD) may yield information that supports public health goals. Our aim was to evaluate time-trend changes in the prevalence and incidence of PD in Taiwan between 2004 and 2011. METHODS: This retrospective, nationwide, longitudinal study used the Taiwan National Health Insurance Research Database to identify patients with PD from 2004 to 2011 based on having ICD-9-CM diagnostic codes, which were assigned by neurologists, and being prescribed PD medication. Annual incidence and prevalence were calculated, and time-trend analyses were estimated assuming a Poisson distribution. RESULTS: Over the study period, 19,302 patients in 2004 and 41,606 patients in 2011 fulfilling the study criteria for PD were included in the analysis. The average age-standardized prevalence of PD per 100,000 of population was 84.8 in 2004 and 147.7 in 2011, with a 7.9% yearly increase. Increasing prevalence trends of PD were statistically significant (p < 0.001) in all age groups, with the steepest rate among those aged >= 80 years. In contrast, the average age-standardized incidence of PD decreased steadily from 35.3 per 100,000 in 2005 to 28.8 per 100,000 in 2011. The incidence rate was higher in men than in women, and increased with age. CONCLUSION: We identified an increasing trend in the annual prevalence rates of PD from 2004 to 2011; however, the substantial decline in the incidence of PD suggests that some major environmental risk factors for PD were removed from this population during this time period. PMID- 26123637 TI - Bite-force difference among obese adolescents in central Taiwan. AB - BACKGROUND/PURPOSE: Maximal bite force of the jaw can cause thorough food chewing and result in good digestion. Bite force is related to the health of the masticatory muscles. Muscle force is frequently affected by obesity in adolescence, however, little is known about how obesity influences the maximum bite force and the difference between genders. METHODS: Five hundred and seventy seven adolescent students (292 girls and 285 boys), aged 13-16 years, from central Taiwan were recruited for a cross-sectional study in 2009. The maximum bite force, hand strength, triceps skin-fold fat thickness, serum level of testosterone, and body mass index (BMI) were measured. Dental health was evaluated based on malocclusion and dental caries. RESULTS: Bite force in girls was highest in the obese group (32.49 +/- 19.13 kg, mean +/- standard deviation), whereas in boys it was higher in the overweight group (41.89 +/- 19.3 kg) than in the obese group (33.21 +/- 17.12 kg). The prevalence of obesity was twofold higher in boys (14.39%) than in girls (7.88%). The mean serum level of testosterone increased with BMI in girls (p = 0.0172), whereas it decreased with BMI in boys (p = 0.0014). The relationships of serum testosterone level and bite force with BMI were similar in the two gender groups. CONCLUSION: The maximum bite force decreased in obese boys but increased in obese girls, which may be due to the sensitivity to testosterone being modulated by the fat level. PMID- 26123634 TI - Aspirin and multiple sclerosis. AB - Aspirin is widely used to lessen the risks of cardiovascular events. Some studies suggest that patients with multiple sclerosis have an increased risk for some cardiovascular events, for example, venous thromboembolism and perhaps ischemic strokes, raising the possibility that aspirin could lessen these increased risks in this population or subgroups (patients with limited mobility and/or antiphospholipid antibodies). However, aspirin causes a small increased risk of hemorrhagic stroke, which is a concern as it could potentially worsen a compromised blood-brain barrier. Aspirin has the potential to ameliorate the disease process in multiple sclerosis (for example, by limiting some components of inflammation), but aspirin also has the potential to inhibit mitochondrial complex I activity, which is already reduced in multiple sclerosis. In an experimental setting of a cerebral ischemic lesion, aspirin promoted the proliferation and/or differentiation of oligodendrocyte precursors, raising the possibility that aspirin could facilitate remyelination efforts in multiple sclerosis. Other actions by aspirin may lead to small improvements of some symptoms (for example, lessening fatigue). Here we consider potential benefits and risks of aspirin usage by patients with multiple sclerosis. PMID- 26123638 TI - Pharmacokinetics of vancomycin in adults receiving extracorporeal membrane oxygenation. AB - BACKGROUND/PURPOSE: Extracorporeal membrane oxygenation (ECMO) alters the pharmacokinetics (PK) of vancomycin in neonates; but data on adults is limited. METHODS: This is a prospective, matched cohort, single center, pharmacokinetic study. For each adult patient who received vancomycin therapy in the ECMO group (with either centrifugal pump or roller pump), a control patient was matched by age (>= 60 years or < 60 years), gender, and creatinine clearance (CLCr) in intensive care units. After vancomycin was administered for at least four doses, serial blood samples were drawn at 0.5 hours, 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 11 hours, 23 hours, 35 hours, and 47 hours post vancomycin infusion according to the dosing intervals. The serum concentration-time profile was fitted to a noncompartment model and a nonlinear mixed effect model to determine the PK parameters. RESULTS: Twenty-two critically ill adults without renal replacement therapy were enrolled. There were no significant differences between the ECMO group and the matched group in demographics, renal function, and PK parameters. However, vancomycin clearance in the roller pump group was significantly lower than that in the matched control (0.83 +/- 0.43 mL/min/kg vs. 0.97 +/- 0.43 mL/min/kg, p = 0.002). CONCLUSION: Vancomycin clearance in patients receiving ECMO with a roller pump was significantly lower than that in the matched cohort. Vancomycin PK parameters in patients on ECMO with a centrifugal pump were comparable to those in the matched control group. PMID- 26123639 TI - Gender Differences in Institutional Long-Term Care Transitions. AB - INTRODUCTION: This study investigates the relationship between gender, the likelihood of discharge from institutional long-term care (LTC) facilities, and post-discharge living arrangements, highlighting sociodemographic, health, socioeconomic, and family characteristics. METHODS: We use the Health and Retirement Study to examine individuals age 65 and older admitted to LTC facilities between 2000 and 2010 (n = 3,351). We examine discharge patterns using survival analyses that account for the competing risk of death and estimate the probabilities of post-discharge living arrangements using multinomial logistic regression models. RESULTS: Women are more likely than men to be discharged from LTC facilities during the first year of stay. Women are more likely to live alone or with kin after discharge, whereas men are more likely to live with a spouse or transfer to another institution. Gender differences in the availability and use of family support may partly account for the gender disparity of LTC discharge and post-discharge living arrangements. CONCLUSION: Our findings suggest that women and men follow distinct pathways after LTC discharge. As local and federal efforts begin to place more emphasis on the transition from LTC facilities to prior communities (e.g., transitional care initiatives under the Patient Protection and Affordable Care Act), policymakers should take these gender differences into account in the design of community transition programs. PMID- 26123640 TI - Reproductive Life Planning in Primary Care: A Qualitative Study of Women Veterans' Perceptions. AB - BACKGROUND: Women veterans using Veterans Administration (VA) health care have high rates of medical and mental health comorbidities, placing them at increased risk of poor outcomes from unplanned pregnancy. Reproductive life planning is a strategy recommended by the U.S. Centers of Disease Control and Prevention that could promote healthy pregnancies and reduce unplanned pregnancy in the VA. However, no data exist on women veterans' perceptions of reproductive life planning discussions. METHODS: We trained six VA primary care physicians at two VA Women's Health Clinics to conduct reproductive life planning discussions with veterans aged 18 to 44 during primary care visits. After the visit, we performed semistructured telephone interviews with consenting veterans to explore perceptions of 1) reproductive life planning content and 2) provider-patient communication in reproductive life planning discussions. Interviews were audiorecorded, transcribed, and analyzed using content analysis. RESULTS: We interviewed 27 veterans with a mean age of 31 years (range, 22-42). Women veterans perceived generally reproductive life planning discussions as important opportunities to discuss reproductive goals with providers and to obtain new and relevant information about contraception, planning healthy pregnancies, and available VA reproductive health services. Perceptions of reproductive life planning content were influenced by women's pregnancy intentions. Perceptions related to provider-patient communication included preferences for provider initiated discussions and nonjudgmental counseling that incorporates patients' values and preferences. CONCLUSIONS: Women veterans perceived reproductive life planning as valuable and important to their health. Reproductive life planning has the potential to enhance patient-centered delivery of reproductive health services in VA primary care. PMID- 26123641 TI - Posttraumatic Stress Disorder Symptom Severity and Socioeconomic Factors Associated with Veterans Health Administration Use among Women Veterans. AB - BACKGROUND: The Veterans Health Administration (VA) has historically focused on treating men. Although women veterans' VA use is increasing, they remain more likely than male veterans to receive their care in non-VA settings. To date, there is limited research on factors associated with VA use among women. We examined the relationship between demographic, civilian, military, and health related variables with past-year VA use among women veterans. METHODS: Women veterans were recruited over the internet to participate in an anonymous national survey (n = 617) in 2013. An empirically derived decision tree was computed using signal detection software for iterative receiver operator characteristics (ROC) to identify variables with the best sensitivity/specificity balance associated with past-year VA use. RESULTS: ROC analysis indicated that 85% of participants with high posttraumatic stress disorder (PTSD) and depressive symptoms and who were younger than 54 years of age used VA in the past year. Of those who were 54 years of age or older and had very high PTSD symptoms, 94% used the VA in the last year. By contrast, only 40% of participants with relatively lower PTSD symptoms had VA past-year use, although among these individuals, VA past-year use increased to 65% for those with a relatively lower income. CONCLUSIONS: Findings suggest that greater PTSD symptoms, depressive symptoms, and low income correlate with VA use, with very high PTSD symptoms in older groups, high PTSD symptoms coupled with high depressive symptoms in younger groups, and low income in those with lower PTSD symptoms each associated with greater past-year VA use. Ensuring PTSD assessment and treatment, and addressing socioeconomic factors, may be key strategies for health care delivered directly or through contract with VA facilities. PMID- 26123642 TI - The interaction of 4-thiazolidinone derivatives containing indolin-2-one moiety with P-glycoprotein studied using K562 cell lines. AB - P-glycoprotein (P-gp) is an active drug efflux pump, which exists widely in various MDR tumor cells, conferring drug resistance to tumor cells during chemotherapy. Some 4-thiazolidinone derivatives containing indolin-2-one moiety are novel anti-tumor compounds. The aim of this study was to evaluate the transport activity of P-gp towards 4-thiazolidinone derivatives containing indolin-2-one moiety (as mixtures of 2Z, 5Z and 2E, 5Z isomers) and the transport inhibition activities of the derivatives to P-gp, the results of which could provide crucial information for the further separation of and development on the derivatives with excellent anti-tumor activities. The results indicate that the further separation and development should be focused on compounds 7, 10, 12 and 13 (tumor cell cytotoxic P-gp modulators) and compounds 8, 9, 17 and 18 (non substrates of P-gp), which exhibit anti-tumor activities and could overcome P-gp mediated MDR. Furthermore, the results of molecular docking indicate that Ser222, a residue in TM4 domain of P-gp, exhibits an intriguing feature in that it interacts with all of the derivatives related with P-gp transport in a significant way, including both typical substrates and modulators of P-gp. Meanwhile, the compounds showing no interaction with Ser222 are mainly from the category of non-substrates of P-gp. Therefore, the interaction between Ser222 and the tested derivative would provide useful information for the further development on 4-thiazolidinone derivatives containing indolin-2-one moiety. PMID- 26123643 TI - Synthesis and biological evaluation of novel myrtucommulones and structural analogues that target mPGES-1 and 5-lipoxygenase. AB - The natural acylphloroglucinol myrtucommulone A (1) inhibits microsomal prostaglandin E2 synthase (mPGES)-1 and 5-lipoxygenase (5-LO), and induces apoptosis of cancer cells. Starting from 1 as lead, 28 analogues were synthesized following a straightforward modular strategy with high yielding convergent steps. Major structural variations concerned (I) replacement of the syncarpic acid moieties by dimedone or indandione, (II) cyclization of the syncarpic acid with the acylphloroglucinol core, and (III) substitution of the methine bridges and the acyl residue with isopropyl, isobutyl, n-pentyl or phenyl groups, each. The potency for mPGES-1 inhibition was improved by 12.5-fold for 43 (2-(1-(3-hexanoyl 2,4,6-trihydroxy-5-(1-(3-hydroxy-1-oxo-1H-inden-2-yl)-2-methylpropyl)phenyl)-2 methylpropyl)-3-hydroxy-1H-inden-1-one) with IC50 = 0.08 MUM, and 5-LO inhibition was improved 33-fold by 47 (2-((3-hexanoyl-2,4,6-trihydroxy-5-((3-hydroxy-1-oxo 1H-inden-2-yl) (phenyl)methyl)phenyl) (phenyl)methyl)-3-hydroxy-1H-inden-1-one) with IC50 = 0.46 MUM. SAR studies revealed divergent structural determinants for induction of cell death and mPGES-1/5-LO inhibition, revealing 43 and 47 as non cytotoxic mPGES-1 and 5-LO inhibitors that warrant further preclinical assessment as anti-inflammatory drugs. PMID- 26123644 TI - Cardiologist Point of View on the Exercise Echocardiography and Multidetector Computed Tomography for the Evaluation of Acute Chest Pain. Response. PMID- 26123645 TI - Identification of potential therapeutic targets by molecular profiling of 628 cases of uterine serous carcinoma. AB - BACKGROUND: Therapeutic options are limited for uterine serous carcinoma (USC). TP53, PIK3CA, FBXW7, and ERBB mutations, as well as HER2 and EGFR overexpression have been reported. We aim to evaluate patterns of molecular, genomic and protein changes in 628USC tumors. METHODS: 628 consecutive cases of USC submitted to Caris Life Sciences from Mar, 2011 to July, 2014 were reviewed. These were analyzed using the Illumina TruSeq Amplcon Cancer panel to search for sequenced variants in 47 genes commonly implicated in carcinomatosis. In situ hybridization and immunohistochemistry were also used to assess copy number and protein expression, respectively, of selected genes. RESULTS: 31 out of 47 genes of interest harbored mutations, including TP53 (76%), PIK3CA (29%), FBXW7 (12%) and KRAS (9.3%). BRCA1 and BRCA2 were mutated in 9.1% and 6.3%, respectively. ERCC1 and MGMT were absent in 81% and 46% of tumors analyzed, respectively, suggesting potential benefit from platinum and alkylating agents. While not traditionally considered hormone-dependent, our cohort showed high ERalpha (60%), PR (32%), and AR (27%) expression. HER2 overexpression was 10% via IHC, amplification was 17% via CISH/FISH and mutation was 2% via NGS. While low in PTEN mutation frequency (7%), 45% of USC showed PTEN loss on IHC, and 29% harbored PIK3A mutation, suggesting deregulation of P13K/AKT pathway in a subset of patients. 11% expressed PDL1 and 67% expressed PD1. CONCLUSIONS: Our findings suggest hormonal receptors, as well as genes implicated in DNA repair, cell proliferation and cell cycle pathways are of interest in USC. PMID- 26123646 TI - Antioxidant and phytochemical analysis of Ranunculus arvensis L. extracts. AB - BACKGROUND: Ranunculus arvensis L. (R. arvensis) has long been used to treat a variety of medical conditions such as arthritis, asthma, hay fever, rheumatism, psoriasis, gut diseases and rheumatic pain. Here, we screened R. arvensis for antioxidant activity, phytochemical and high performance liquid chromatography (HPLC) analyses. METHODS: The chloroform, chloroform:methanol, methanol, methanol:acetone, acetone, methanol:water and water extracts of R. arvensis were examined for DPPH (1, 1-diphenyl-2-picrylhydrazyl) free radical scavenging assay, hydrogen peroxide scavenging assay, phosphomolybdenum assay, reducing power assay, flavonoid content, phenolic content and high performance liquid chromatography analysis. RESULTS: Significant antioxidant activity was displayed by methanol extract (IC 50 34.71 +/- 0.02) in DPPH free radical scavenging assay. Total flavonoids and phenolics ranged 0.96-6.0 mg/g of extract calculated as rutin equivalent and 0.48-1.43 mg/g of extract calculated as gallic acid equivalent respectively. Significant value of rutin and caffeic acid was observed via high performance liquid chromatography. CONCLUSIONS: These results showed that extracts of R. arvensis exhibited significant antioxidant activities. Moreover, R. arvensis is a rich source of rutin, flavonoids and phenolics. PMID- 26123647 TI - Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate. AB - Nonsyndromic orofacial cleft (NSOFC) is a complex disease of still unclear genetic etiology. To investigate the contribution of rare epithelial cadherin (CDH1) gene variants to NSOFC, we target sequenced 221 probands. Candidate variants were evaluated via in vitro, in silico, or segregation analyses. Three probably pathogenic variants (c.760G>A [p.Asp254Asn], c.1023T>G [p.Tyr341*], and c.2351G>A [p.Arg784His]) segregated according to autosomal dominant inheritance in four nonsyndromic cleft lip with or without cleft palate (NSCL/P) families (Lod score: 5.8 at theta = 0; 47% penetrance). A fourth possibly pathogenic variant (c.387+5G>A) was also found, but further functional analyses are needed (overall prevalence of CDH1 candidate variants: 2%; 15.4% among familial cases). CDH1 mutational burden was higher among probands from familial cases when compared to that of controls (P = 0.002). We concluded that CDH1 contributes to NSCL/P with mainly rare, moderately penetrant variants, and CDH1 haploinsufficiency is the likely etiological mechanism. PMID- 26123648 TI - Extrapolating Dynamic Leidenfrost Principles to Metallic Nanodroplets on Asymmetrically Textured Surfaces. AB - In an effort to enhance our knowledge on how to control the movement of metallic nanodroplets, here we have used classical molecular dynamics simulations to investigate whether Cu nanostructures deposited on nanopillared substrates can be made to jump at desired angles. We find that such control is possible, especially for Cu nanostructures that are symmetric; for asymmetric nanostructures, however, control is more uncertain. The work presented here borrows ideas from two seemingly different fields, metallic droplets and water droplets in the dynamic Leidenfrost regime. Despite the differences in the respective systems, we find common ground in their behavior on nanostructured surfaces. Due to this, we suggest that the ongoing research in Leidenfrost droplets is a fertile area for scientists working on metallic nanodroplets. PMID- 26123649 TI - Levels of Ancylostoma infections and phylogenetic analysis of cox 1 gene of A. ceylanicum in stray cat faecal samples from Guangzhou, China. AB - Ancylostoma ceylanicum is a common zoonotic nematode. Cats act as natural reservoirs of the hookworm and are involved in transmitting infection to humans, thus posing a potential risk to public health. The prevalence of feline A. ceylanicum in Guangzhou (South China) was surveyed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). In total, 112 faecal samples were examined; 34.8% (39/112) and 43.8% (49/112) samples were positive with hookworms by microscopy and PCR method, respectively. Among them, 40.8% of samples harboured A. ceylanicum. Twelve positive A. ceylanicum samples were selected randomly and used for cox 1 sequence analysis. Sequencing results revealed that they had 97-99% similarity with A. ceylanicum cox 1 gene sequences deposited in GenBank. A phylogenetic tree showed that A. ceylanicum isolates were divided into two groups: one comprising four isolates from Guangzhou (South China), and the other comprising those from Malaysia, Cambodia and Guangzhou. In the latter group, all A. ceylanicum isolates from Guangzhou were clustered into a minor group again. The results indicate that the high prevalence of A. ceylanicum in stray cats in South China poses a potential risk of hookworm transmission from pet cats to humans, and that A. ceylanicum may be a species complex worldwide. PMID- 26123650 TI - [Urinary tract infections: Economical impact of water intake]. AB - BACKGROUNDS: This study aims to estimate the impact of preventing urinary tract infections (UTI), using a strategy of increased water intake, from the payer's perspective in the French health care system. METHODS: A Markov model enables a comparison of health care costs and outcomes for a virtual cohort of subjects with different levels of daily water intake. The analysis of the budgetary impact was based on a period of 5years. The analysis was based on a 25-year follow-up period to assess the effects of adequate water supply on long-term complications. RESULTS: The authors estimate annual primary incidence of UTI and annual risk of recurrence at 5.3% and 30%, respectively. Risk reduction associated with greater water intake reached 45% and 33% for the general and recurrent populations, respectively. The average total health care cost of a single UTI episode is ?1074; for a population of 65 millions, UTI management represents a cost of ?3.700 millions for payers. With adequate water intake, the model indicates a potential cost savings of ?2.288 millions annually, by preventing 27 million UTI episodes. At the individual level, the potential cost savings is approximately ?2915. CONCLUSIONS: Preventing urinary tract infections using a strategy of adequate water intake could lead to significant cost savings for a public health care system. Further studies are needed to assess the effectiveness of such an approach. PMID- 26123652 TI - The Future of the Journal of Insect Science. PMID- 26123651 TI - ANCA positive crescentic glomerulonephritis outcome in a Central East European cohort: a retrospective study. AB - BACKGROUND: The recently suggested distinct pathogenic pathways for myeloperoxidase (MPO) and proteinase 3 (PR3) anti-neutrophilic cytoplasmic antibodies (ANCA) associated vasculitis could result in different modes of presentation and outcome. Moreover, kidney outcome was related to a new histopathologic classification of pauci-immune glomerulonephritis. As reports were not always concordant, possible because differences in severity of organ lesions and ethnicity, we evaluated the outcome of a cohort of Central-East European patients with crescentic glomerulonephritis in relation with ANCA specificity and histopathological classification. METHODS: Seventy-five patients were consecutively diagnosed by kidney biopsy (76 % MPO-ANCA specificity, 52 % crescentic) and followed for a median period of 3.2 years. Study end-points were response to therapy, end stage renal disease (ESRD) and death. RESULTS: PR3-ANCA patients were younger, in higher proportion male and had higher Birmingham Vasculitis Activity Scores (BVAS). The kidney disease was severe at presentation (median creatinine 5 mg/dL; 27 % required temporary dialysis) and worst in PR3 ANCA positive patients (50 % patients needed temporary dialysis vs. 19 %). The lung was the second most affected organ (31 % severe lung hemorrhage). Lung and kidney damage were related; the odds of hemorrhagic alveolitis in patients needing dialysis at presentation were 4 (95 % CI 1-13; p = 0.006) times higher than in those who did not. The rate of response to therapy (without signs of active vasculitis and stable or declining serum creatinine) was 60 % and was associated with dialysis independency, older age and higher platelet number at presentation. The probabilities to survival 1 and 5 years for kidney and patient were 93 and 64 %, and respectively 88 and 67 %. Kidney survival was predicted by response to therapy and dialysis independency at presentation. Patients with BVAS < 15 and responding to induction therapy had better chances of survival. Neither response to therapy nor outcome was influenced by ANCA specificity or by the histopathological class. CONCLUSIONS: When kidney damage is severe in ANCA vasculitis, the need of dialysis at presentation and the response to induction therapy overcome the prognostic utility of both ANCA specificity and histopathological class. PMID- 26123653 TI - Sector analysis provides additional spatial information on the permanent prostate brachytherapy learning curve. AB - PURPOSE: To evaluate the permanent prostate brachytherapy (PPB) learning curve using postimplant multisector dosimetric analysis and to assess the correlation between sector -specific dosimetry and patient-reported outcome measures (PROMs). METHODS AND METHODS: First 200 patients treated with (125)I PPB monotherapy (145 Gy) at a single institution were assessed. Postimplant dosimetry (PID) using CT was evaluated for whole prostate (global) and 12 sectors, assessing minimum dose to 90% of prostate (D90) and dose to 0.1 cm(3) of rectum (D0.1cc). Global and sector PID results were evaluated to investigate changes in D90 with case number. Urinary and bowel PROMs were assessed using the International Prostate Symptom Score and the Expanded Prostate Cancer Index Composite questionnaire. The correlation between global and individual sector PID and urinary/bowel PROMs was also evaluated. RESULTS: Linear regression confirmed a significant improvement in global D90 with case number (r(2) = 0.20; p = 0.001) at a rate of 0.11 Gy/case. Postimplant D90 of base sectors increased at a rate of 0.11-0.15 Gy/case (p = 0.0001) and matched global improvement. The regression lines of midgland and apex sectors were significantly different from global D90 (p = 0.01). Posterior midgland sectors showed a significant reduction in D90 with case number at a rate of 0.13-0.19 Gy/case (p = 0.01). Dose to posterior midgland sectors correlated with rectal D0.1cc dose but not bowel PROMs. Dose to posterior midgland sectors correlated with urinary International Prostate Symptom Score change, which was not apparent when global D90 alone was considered. CONCLUSIONS: Sector analysis provided increased spatial information regarding the PPB learning curve. Furthermore, sector analysis correlated with urinary PROMs and rectal dose. PMID- 26123655 TI - A microspectroscopic insight into the resistivity switching of individual Ag-TCNQ nanocrystals. AB - We investigate the resistivity switching in individual Ag-TCNQ wires with on/off ratios of up to 10(3). Raman and soft X-ray absorption microspectroscopy studies disclose reverse charge transfer. Quantifying of the fraction of neutral TCNQ within the switched material yields values up to 22.3%. These findings expedite the understanding of the switching process in Ag-TCNQ nanowires. PMID- 26123654 TI - Relations of participation in organized activities to smoking and drinking among Japanese youth: contextual effects of structural social capital in high school. AB - OBJECTIVES: This cross-sectional study examined the effect of school-level structural social capital on smoking and drinking among Japanese youth. METHODS: Self-administered anonymous questionnaires were distributed to 3248 students at 29 high schools across Okinawa, Japan in 2008. Structural social capital was measured by students' participation in organized activities: student council, extracurricular activities, volunteer activities, community sports clubs, and youth associations. Contextual-level social capital was measured by aggregated school-level individual responses. RESULTS: At the individual level, extracurricular activity participation was negatively associated with smoking and drinking, whereas participation in youth associations was positively associated with smoking and drinking. School-level extracurricular activity participation was negatively associated with smoking among boys, whereas school-level participation in youth associations was positively associated with smoking among boys and girls and drinking among boys. CONCLUSIONS: This study suggests that structural social capital measured by participation in organized activities, especially extracurricular activities, might be an important way for youths to attain good health. This study also supports the idea that particular type of activities, such as youth associations, can lead to the so-called "dark side of social capital". PMID- 26123656 TI - Pleomorphic adenoma of an accessory submandibular salivary gland: a rare entity. AB - An accessory submandibular salivary gland is a rare anatomical variant, and a tumour within one is even rarer. We describe a 54-year-old man who presented with a slowly-enlarging mass in the right submandibular region which on magnetic resonance imaging (MRI) seemed to be close to, but not arising from, the right submandibular salivary gland. This was found to be a benign pleomorphic adenoma arising from an accessory submandibular salivary gland. To our knowledge it is only the second report of a pleomorphic adenoma that developed within an accessory submandibular salivary gland. PMID- 26123657 TI - LTP3 contributes to disease susceptibility in Arabidopsis by enhancing abscisic acid (ABA) biosynthesis. AB - Several plant lipid transfer proteins (LTPs) act positively in plant disease resistance. Here, we show that LTP3 (At5g59320), a pathogen and abscisic acid (ABA)-induced gene, negatively regulates plant immunity in Arabidopsis. The overexpression of LTP3 (LTP3-OX) led to an enhanced susceptibility to virulent bacteria and compromised resistance to avirulent bacteria. On infection of LTP3 OX plants with Pseudomonas syringae pv. tomato, genes involved in ABA biosynthesis, NCED3 and AAO3, were highly induced, whereas salicylic acid (SA) related genes, ICS1 and PR1, were down-regulated. Accordingly, in LTP3-OX plants, we observed increased ABA levels and decreased SA levels relative to the wild type. We also showed that the LTP3 overexpression-mediated enhanced susceptibility was partially dependent on AAO3. Interestingly, loss of function of LTP3 (ltp3-1) did not affect ABA pathways, but resulted in PR1 gene induction and elevated SA levels, suggesting that LTP3 can negatively regulate SA in an ABA independent manner. However, a double mutant consisting of ltp3-1 and silent LTP4 (ltp3/ltp4) showed reduced susceptibility to Pseudomonas and down-regulation of ABA biosynthesis genes, suggesting that LTP3 acts in a redundant manner with its closest homologue LTP4 by modulating the ABA pathway. Taken together, our data show that LTP3 is a novel negative regulator of plant immunity which acts through the manipulation of the ABA-SA balance. PMID- 26123658 TI - Does Helicobacter pylori infection modify lung development, height or simply reflect shared environmental exposures? PMID- 26123659 TI - A 4-year prospective evaluation of protocols to improve clinical outcomes for patients with lymphangioleiomyomatosis in a national clinical centre. AB - Lymphangioleiomyomatosis (LAM) is a rare multisystem disease. Progressive airflow limitation, pneumothorax and angiomyolipoma-related bleeding are major morbidities. As treatments are available for these complications, we prospectively audited loss of FEV1 (DeltaFEV1), pneumothorax and angiomyolipoma bleeding against clinical standards over 4 years at the UK Clinical Centre. DeltaFEV1 for these patients is lower than previously reported and rates of pneumothorax and angiomyolipoma haemorrhage are low. This suggests that real-time analysis of clinical data with targeted interventions can reduce morbidity in LAM. These measures could be applied as quality standards to compare the emerging LAM clinical networks worldwide. PMID- 26123661 TI - A case-based discussion from the Medical Intensive Care Unit of Sahloul University Hospital of Tunisia: an unusual cause of alveolar hypoventilation in a patient with COPD. PMID- 26123660 TI - Nox2 up-regulation is associated with an enhanced risk of atrial fibrillation in patients with pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) may be complicated by atrial fibrillation (AF) but the underlying mechanism is still unclear. Nox2-derived oxidative stress has been suggested to favour AF. METHODS: We consecutively enrolled 432 patients hospitalised for CAP. Nox2 activity, as assessed by serum levels of soluble Nox2 (sNox2-dp), was evaluated in each CAP patient. A 12-lead electrocardiography was repeated every 24 h. All patients were followed up until discharge. RESULTS: Forty-one patients with CAP (9.5%) experienced a new episode of AF within 24-72 h after hospital admission. Patients who experienced AF showed higher blood levels of sNox2-dp compared to those who did not (35.2+/-15.1 vs 27.0+/-12.5 pg/mL; p<0.001). Pneumonia Severity Index score (p=0.014), history of paroxysmal AF (p<0.001) and sNox2-dp (p=0.019) were independently associated with AF. At discharge, serum sNox2-dp levels were significantly decreased in the entire cohort (27.8+/-13.0 vs 21.9+/-6.8 pg/mL; p<0.001). Twenty-three out of 41 CAP patients with AF returned to sinus rhythm (56%); patients who remained in AF showed significantly higher baseline and discharge levels of sNox2-dp compared to those without AF (p<0.001) or with the 23 AF patients who returned to sinus rhythm (p<0.05). In vitro study showed that platelets or leucocytes incubated with endotoxin, at concentrations similar to those found in the circulation of CAP patients, elicited Nox2 up-regulation, suggesting endotoxin as a trigger of oxidative stress. CONCLUSIONS: AF may be detected in the early phase of CAP and is associated with Nox2 activation, suggesting a role for oxidative stress in promoting this cardiac arrhythmia. TRIAL REGISTRATION NUMBER: NCT01773863. PMID- 26123662 TI - Influence of survivin-targeted therapy on chemosensitivity in the treatment of acute myeloid leukemia. AB - Overexpression of survivin is observed in various hematological malignancies, including acute myeloid leukemia (AML). Studies show that elevated expression of survivin correlates with a worse clinic outcome in AML patients. It remains unclear whether inhibition of survivin may alter the efficacy of chemotherapy against AML. Here, we evaluate the effects of specific knockdown of survivin on AML cells' sensitivity to chemotherapy, and investigate the therapeutic potential of the transcription inhibitor of survivin YM155 either alone or in combination with chemotherapeutic agents. We found Kasumi-1 and HL-60 cells had relatively higher expression levels of survivin among all AML cell lines tested. Specific knockdown of survivin in Kasumi-1 and HL-60 cells resulted in: inhibition of cell proliferation; cell cycle G2/M arrest; induction of DNA damage response and apoptosis. Downregulation of survivin enhanced etoposide- or doxorubicin-induced anti-proliferative/anti-survival activity in AML cells. The small molecule inhibitor YM155 reduced survivin in a dose- and time-dependent manner and trigged apoptosis in Kasumi-1 and HL-60 cells. The combinatorial effects of YM155 and chemotherapeutics were either synergetic or antagonistic, depending upon the drugs used for combination and the type of AML cells being treated. Collectively, our data demonstrate that survivin plays an important role in the maintenance and proliferation of AML cells. While specific knockdown of survivin enhances chemosensitivity, the combinations of YM155 and chemotherapeutic agents exhibit synergetic or antagonistic effects on AML cells. Our findings provide a rationale for further assessment of survivin-targeted therapy in the treatment of patients with AML. PMID- 26123664 TI - Role of chemokine pathways in hepatobiliary cancer. AB - Persistent hepatic inflammation resulting from hepatitis B or C virus infections (HBV or HCV, respectively), obesity-associated non-alcoholic steatohepatitis (NASH) or alcohol abuse is a hallmark feature of chronic liver diseases and appears to be an essential prerequisite of hepatocarcinogenesis. The inflammatory processes in the liver are regulated by various chemokines, which orchestrate the interaction between parenchymal liver cells, Kupffer cells (resident macrophages), hepatic stellate cells (HSC), endothelial cells, and infiltrating immune cells. In consequence, these cellular interactions result in the re modeling of the hepatic microenvironment toward a pro-inflammatory, pro-fibrotic, pro-angiogenic and thus pre-neoplastic milieu. Once developed, liver neoplasms provoke pro- and anti-tumor immune responses that are also critically regulated through differential activation of chemokine pathways. With respect to hepatobiliary cancers, including hepatocellular carcinoma (HCC), gallbladder cancer and cholangiocellular carcinoma (cholangiocarcinoma), together belonging to the highest causes of cancer-related deaths worldwide, this review article will give an overview of chemokine pathways involved in both the establishment of a pro-tumorigenic microenvironment as well as the development and progression of hepatobiliary cancer. Pharmaceutical targeting of chemokine pathways is a promising approach to treat or even prevent hepatobiliary cancer. PMID- 26123663 TI - MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma. AB - LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3'UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefore establishing an MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promoter, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underline the importance of MYCN regulated miRNAs in establishing the MYCN-driven oncogenic process. PMID- 26123665 TI - Simultaneous determination of eight chemicals in Fufang Xueshuantong capsules by LC-MS-MS with periodic polarity switching. AB - A rapid, sensitive, selective and periodic polarity-switching liquid chromatography-tandem mass spectrometry(LC-MS-MS) method was developed for the simultaneous determination of eight components in an important traditional Chinese medicinal capsule, Fufang Xueshuantong. LC analysis was carried out on a Kinetex 2.6 um XB-C18 column by gradient elution. The detection was performed by multiple reaction monitoring (MRM) with a periodic polarity-switching electrospray ionization (ESI) source across five periods of switching between positive and negative mode. Periodic polarity-switching was used to acquire maximal responses and to simultaneously detect eight constituents in one analysis run lasting 8 min. All of the analytes showed good linearity (r > 0.9947) in the tested ranges. The average recoveries were in the range of 95.4-103.9% with relative standard deviations <=6.3%, and the intra- and inter-day variations were <=3.7%. The developed method was successfully employed to analyze three batches of Fufang Xueshuantong capsule samples. The results showed that the levels of notoginsenoside R1, ginsenoside Rb1 and salvianolic acid B were clearly different in different batches of Fufang Xueshuantong capsules. Furthermore, the new established periodic polarity-switching LC-MS-MS method was proven to be highly sensitive and effective in evaluating the quality of Fufang Xueshuantong capsules. PMID- 26123666 TI - Evaluation of angiotensin-converting enzyme inhibitor's absorption with retention data of micellar thin-layer chromatography and suitable molecular descriptor. AB - Twelve angiotensin-converting enzyme (ACE) inhibitors were studied to evaluate correlation between their absorption (ABS) data available in the literature (22 96%) and hydrophobicity parameters (km and Pm/w) obtained in micellar thin-layer chromatography (MTLC) using Brij 35. The theoretical considerations showed that the geometric molecular descriptor-volume value (Vol) should be considered as an independent variable simultaneously with calculated hydrophobicity parameters in multiple linear regression analysis to obtain reliable correlation between ACE inhibitor's absorption and lipophilicity (calculated KOWWINlog P) and that captopril should be excluded from further correlations. The results of MTLC confirmed that between the two hydrophobicity parameters km and Pm/w, for absorption prediction of 11 ACE inhibitors, the micelle-water partition coefficient Pm/w provided higher correlation (R(2) = 0.756), while for the km parameter R(2) = 0.612 was obtained. The micelle-water partition coefficient Pm/w could be considered as analogous to hydrophobicity parameter C0 from reversed phase thin-layer chromatography. Dissimilar retention behavior of lisinopril indicated its lowest non-polar interaction with micelle, because of its di-acid form. The proposed model which included ACE inhibitors on the opposite site of lipophilicity-lisinopril and fosinopril (KOWWINlog P = -0.96 and KOWWINlog P = 6.61, respectively), both with similar absorption values (25 and 36%, respectively), could indicate that absorption of investigated compounds occurs via two different mechanisms: active and passive transport. PMID- 26123667 TI - Unilateral versus bilateral percutaneous kyphoplasty for osteoporotic vertebral compression fractures: A systematic review and meta-analysis of RCTs. AB - The purpose of this research was to compare the efficacy and safety of unilateral versus bilateral PKP for osteoporotic vertebral compression fractures (OVCFs). Six databases (Cochrane, PubMed, MEDLINE, EMBASE, SinoMed, and CNKI) were searched without language restrictions. Twelve randomized controlled trials involving a total of 1,030 patients were identified. The results indicate that unilateral PKP had a better degree of pain relief (visual analog scale) than bilateral PKP (p = 0.04; 95%CI = -0.36 to -0.00) with short-term follow-up (within 4 weeks) after operation. The radiological outcome assessment with short term follow-up after operation indicates bilateral PKP had a better degree of anterior vertebral height restoration (p = 0.03; 95%CI = -2.58 to -0.14). Operation time and cement dosage were less for unilateral PKP (p < 0.05). There were no differences in complications such as cement leakage and adjacent vertebral fractures between two approaches (p = 0.06 and p = 0.97, respectively). Life quality assessment (SF-36) indicates unilateral PKP had a better result of bodily pain relief (p < 0.05; 95%CI = 3.93 to 7.48) and general health benefit (p < 0.05; 95%CI = 0.02 to 2.93) with short-term follow-up after operation. We suggest that a unilateral PKP is advantageous. PMID- 26123668 TI - New insight in impaired binding capacity for albumin in uraemic patients. PMID- 26123669 TI - Prosodic skills in children with Down syndrome and in typically developing children. AB - BACKGROUND: Many studies have analysed language development in children with Down syndrome to understand better the nature of their linguistic delays and the reason why these delays, particularly those in the morphosyntactic area, seem greater than their cognitive impairment. However, the prosodic characteristics of language development in children with Down syndrome have been scarcely investigated. AIMS: To analyse the prosodic skills of children with Down syndrome in the production of multi-word utterances. Data on the prosodic skills of these children were compared with data on typically developing children matched on developmental age and vocabulary size. Between-group differences and the relationships between prosodic and syntactic skills were investigated. METHODS & PROCEDURES: The participants were nine children with Down syndrome (who ranged in chronological age from 45 to 63 months and had a mean developmental age of 30 months) and 12 30-month-old typically developing children. The children in both groups had a vocabulary size of approximately 450 words. The children's spontaneous productions were recorded during observations of mother-child play sessions. OUTCOMES & RESULTS: Data analyses showed that despite their morphosyntactic difficulties, children with Down syndrome were able to master some aspects of prosody in multi-word utterances. They were able to produce single intonation multi-word utterances on the same level as typically developing children. In addition, the intonation contour of their utterances was not negatively influenced by syntactic complexity, contrary to what occurred in typically developing children, although it has to be considered that the utterances produced by children with Down syndrome were less complex than those produced by children in the control group. However, children with Down syndrome appeared to be less able than typically developing children to use intonation to express the pragmatic interrogative function. CONCLUSIONS & IMPLICATIONS: The findings are discussed considering the effects of social experience on the utterance prosodic realization. PMID- 26123671 TI - Single patient in GCK-MODY family successfully re-diagnosed into GCK-PNDM through targeted next-generation sequencing technology. PMID- 26123670 TI - Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine). AB - Dimebon (latrepirdine) is an anti-histaminergic agent which belongs to a fast growing group of "old" medicines suggested to be of therapeutic utility for pathological conditions different from their original design ("repositioning"). Here, we overview the most recent studies on Dimebon directed to pathological processes in the brain-involving in vivo models of proteinopathies. In the latter, neurodegenerative effects are attributed to a group of aggregate-prone proteins such as gamma-synuclein, hyperphosphorylated tau, and fused in sarcoma (FUS), which are engaged in numerous neurological diseases. We also focus on in vitro models comprised of cultured SH-SY5Y neuroblastoma cells expressing mutant forms of transactive response DNA binding protein 43 kDa (TDP-43) and showing a reduced number of TDP-43 inclusion-containing cells upon Dimebon treatment along with activation of autophagy markers. Finally, we discuss Dimebon's action in improving cellular energy balance, stabilizing mitochondrial function by increasing the threshold for nonselective mitochondrial pore opening, as well as increasing the calcium retention capacity of mitochondria and reducing lipid peroxidation. Our results, together with data from other laboratories, warrant re evaluation of the therapeutic potential of Dimebon and its newly designed analogs as promising disease-modifying agents to treat neurodegenerative disorders. Further, emerging data favor a possible anti-aging effect and application of Dimebon for the treatment of depression, anxiety, and ischemia. The most pronounced effect of Dimebon is observed when treatment starts early in disease onset. This is a major factor which needs to be taken into account when planning future clinical trials. PMID- 26123672 TI - Continuous subcutaneous insulin pump treatment associated with absence of recurrent kidney allograft diabetic nephropathy. PMID- 26123673 TI - Genetic diversity and relationship of Indian cattle inferred from microsatellite and mitochondrial DNA markers. AB - BACKGROUND: Indian agriculture is an economic symbiosis of crop and livestock production with cattle as the foundation. Sadly, the population of indigenous cattle (Bos indicus) is declining (8.94% in last decade) and needs immediate scientific management. Genetic characterization is the first step in the development of proper management strategies for preserving genetic diversity and preventing undesirable loss of alleles. Thus, in this study we investigated genetic diversity and relationship among eleven Indian cattle breeds using 21 microsatellite markers and mitochondrial D loop sequence. RESULTS: The analysis of autosomal DNA was performed on 508 cattle which exhibited sufficient genetic diversity across all the breeds. Estimates of mean allele number and observed heterozygosity across all loci and population were 8.784 +/- 0.25 and 0.653 +/- 0.014, respectively. Differences among breeds accounted for 13.3% of total genetic variability. Despite high genetic diversity, significant inbreeding was also observed within eight populations. Genetic distances and cluster analysis showed a close relationship between breeds according to proximity in geographic distribution. The genetic distance, STRUCTURE and Principal Coordinate Analysis concluded that the Southern Indian Ongole cattle are the most distinct among the investigated cattle populations. Sequencing of hypervariable mitochondrial DNA region on a subset of 170 cattle revealed sixty haplotypes with haplotypic diversity of 0.90240, nucleotide diversity of 0.02688 and average number of nucleotide differences as 6.07407. Two major star clusters for haplotypes indicated population expansion for Indian cattle. CONCLUSIONS: Nuclear and mitochondrial genomes show a similar pattern of genetic variability and genetic differentiation. Various analyses concluded that the Southern breed 'Ongole' was distinct from breeds of Northern/ Central India. Overall these results provide basic information about genetic diversity and structure of Indian cattle which should have implications for management and conservation of indicine cattle diversity. PMID- 26123674 TI - Imaging of Bacterial and Fungal Cells Using Fluorescent Carbon Dots Prepared from Carica papaya Juice. AB - In this paper, we have described a simple hydrothermal method for preparation of fluorescent carbon dots (C-dots) using Carica papaya juice as a precursor. The synthesized C-dots show emission peak at 461 nm with a quantum yield of 7.0 %. The biocompatible nature of C-dots was confirmed by a cytotoxicity assay on E. coli. The C-dots were used as fluorescent probes for imaging of bacterial (Bacillus subtilis) and fungal (Aspergillus aculeatus) cells and emitted green and red colors under different excitation wavelengths, which indicates that the C dots can be used as a promising material for cell imaging. PMID- 26123675 TI - Biogenic Synthesis of Fluorescent Carbon Dots at Ambient Temperature Using Azadirachta indica (Neem) gum. AB - Synthesis of fluorescent Carbon Dots (CDs) from various carbonaceous materials apparently has acquired lots of interest amongst researchers as the corollary of the properties of CDs; which are subsequently getting unveiled. In this study we report the use of Azadirachta indica (Neem) Gum as a novel natural pre-cursor for synthesis of CDs at room temperature. Water soluble CDs of around 5-8 nm were obtained after treatment of the gum with ethanol and NaOH. These CDs exhibited green fluorescence in UV-light (lambda = 365 nm). These CDs were found to be stable, having many bio-linkers attached on their surface, making it suitable for drug attachment and hence can serve as potential candidates for applications like drug delivery vehicles as well as for biosensors. PMID- 26123676 TI - Interpulse multifrequency electrical impedance measurements during electroporation of adherent differentiated myotubes. AB - In this study, electrical impedance spectroscopy measurements are performed during electroporation of monolayers of differentiated myotubes. The time resolution of the system (1 spectrum/ms) enable 860 full spectra (21 frequencies from 5 kHz to 1.3 MHz) to be acquired during the time gap between consecutive pulses (interpulse) of a classical electroporation treatment (8 pulses, 100 MUs, 1 Hz). Additionally, the characteristics of the custom microelectrode assembly used allow the experiments to be performed directly in situ in standard 24 multi well plates. The impedance response dynamics are studied for three different electric field intensities (400, 800 and 1200 V/cm). The multifrequency information, analysed with the Cole model, reveals a short-term impedance recovery after each pulse in accordance with the fast resealing of the cell membrane, and a long-term impedance decay over the complete treatment in accordance with an accumulated effect pulse after pulse. The analysis shows differences between the lowest electric field condition and the other two, suggesting that different mechanisms that may be related with the reversibility of the process are activated. As a result of the multifrequency information, the system is able to measure simultaneously the conductivity variations due to ion diffusion during electroporation. Finally, in order to reinforce the physical interpretation of the results, a complementary electrical equivalent model is used. PMID- 26123677 TI - Formation and characterisation of a modifiable soft macro-porous hyaluronic acid cryogel platform. AB - A facile method for the synthesis of cell supportive, highly macro-porous hyaluronic acid (HA) hydrogels via cryogelation is presented. Unmodified HA was chemically cross-linked via EDC/NHS zero-length cross-linking at sub-zero temperatures to yield cryogels with high porosity and high pore interconnectivity. The physical properties of the HA cryogels including porosity, average pore size, elasticity and swelling properties were characterised as a function of cryogelation conditions and composition of the precursor solution. The HA cryogels swell extensively in water, with the average porosities observed being ~90% under all conditions explored. The morphology of the cryogels can be controlled, allowing scaffolds with an average pore size ranging from 18 +/- 2 to 87 +/- 5 MUm to be formed. By varying the cross-linking degree and HA concentration, a wide range of bulk elastic properties can be achieved, ranging from ~1 kPa to above 10 kPa. Preliminary cell culture experiments, with NIH 3T3 and HEK 293 cell lines, performed on biochemically modified and unmodified gels show the cryogels support cell proliferation and cell interactions, illustrating the biomedical potential of the platform. PMID- 26123678 TI - Home-based smoking prevention program Smoke-free Kids on smoking-related cognitions: Secondary outcomes from a cluster randomized controlled trial. AB - OBJECTIVES: The home-based smoking prevention programme 'Smoke-free Kids' did not have an effect on primary outcome smoking initiation. A possible explanation may be that the programme has a delayed effect. The aim of this study was to evaluate the effects on the development of important precursors of smoking: smoking related cognitions. METHODS: We used a cluster randomised controlled trial in 9- to 11-year-old children and their mothers. The intervention condition received five activity modules, including a communication sheet for mothers, by mail at four-week intervals. The control condition received a fact-based programme. Secondary outcomes were attitudes, self-efficacy and social norms. Latent growth curves analyses were used to calculate the development of cognitions over time. Subsequently, path modelling was used to estimate the programme effects on the initial level and growth of each cognition. RESULTS: Analyses were performed on 1398 never-smoking children at baseline. Results showed that for children in the intervention condition, perceived maternal norms increased less strongly as compared to the control condition (beta = -.10, p = .03). No effects were found for the other cognitions. CONCLUSION: Based on the limited effects, we do not assume that the programme will have a delayed effect on smoking behaviour later during adolescence. PMID- 26123679 TI - Alopecia areata universalis in a dog. AB - BACKGROUND: Alopecia areata is a T-cell mediated autoimmune disease that occurs in humans and various other mammalian species. When the disease progresses to total alopecia it is defined as alopecia areata universalis (AAU), although this outcome has only been described in humans. HYPOTHESIS/OBJECTIVES: To describe a case of canine alopecia areata universalis and its clinical outcome after 22 months of follow-up. ANIMAL: A 9-year-old intact male cross-breed hunting dog was presented with generalized and complete noninflammatory alopecia of 12-14 months duration. METHODS: Clinical examination; histopathological and immunohistochemical examination of skin biopsies. RESULTS: There was loss of all body hair including eyelashes and vibrissae. The histopathological and immunohistochemical findings supported a diagnosis of long-standing alopecia areata. Treatment with oral ciclosporin was associated with hair regrowth but muzzle hair, most eyelashes and whiskers were still lacking after 17 months of therapy. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the author's knowledge this is the first documented case of canine AAU. The clinical and histopathological features were consistent with a diagnosis of AAU as defined in humans. Treatment with oral ciclosporin resulted in near complete resolution of the alopecia, but after 5 months without treatment the alopecia did not relapse and spontaneous resolution cannot be ruled out. PMID- 26123680 TI - Influence of the Size of Cohorts in Adaptive Design for Nonlinear Mixed Effects Models: An Evaluation by Simulation for a Pharmacokinetic and Pharmacodynamic Model for a Biomarker in Oncology. AB - PURPOSE: In this study we aimed to evaluate adaptive designs (ADs) by clinical trial simulation for a pharmacokinetic-pharmacodynamic model in oncology and to compare them with one-stage designs, i.e., when no adaptation is performed, using wrong prior parameters. METHODS: We evaluated two one-stage designs, xi0 and xi*, optimised for prior and true population parameters, Psi0 and Psi*, and several ADs (two-, three- and five-stage). All designs had 50 patients. For ADs, the first cohort design was xi0. The next cohort design was optimised using prior information updated from the previous cohort. Optimal design was based on the determinant of the Fisher information matrix using PFIM. Design evaluation was performed by clinical trial simulations using data simulated from Psi*. RESULTS: Estimation results of two-stage ADs and xi * were close and much better than those obtained with xi 0. The balanced two-stage AD performed better than two stage ADs with different cohort sizes. Three- and five-stage ADs were better than two-stage with small first cohort, but not better than the balanced two-stage design. CONCLUSIONS: Two-stage ADs are useful when prior parameters are unreliable. In case of small first cohort, more adaptations are needed but these designs are complex to implement. PMID- 26123681 TI - Using Environment-Sensitive Fluorescent Probes to Characterize Liquid-Liquid Phase Separation in Supersaturated Solutions of Poorly Water Soluble Compounds. AB - PURPOSE: Highly supersaturated aqueous solutions of poorly soluble compounds can undergo liquid-liquid phase separation (LLPS) when the concentration exceeds the "amorphous solubility". This phenomenon has been widely observed during high throughput screening of new molecular entities as well as during the dissolution of amorphous solid dispersions. In this study, we have evaluated the use of environment-sensitive fluorescence probes to investigate the formation and properties of the non-crystalline drug-rich aggregates formed in aqueous solutions as a result of LLPS. METHODS: Six different environment-sensitive fluorophores were employed to study LLPS in highly supersaturated solutions of several model compounds, all dihydropyridine derivatives. RESULTS: Each fluoroprobe exhibited a large hypsochromic shift with decreasing environment polarity. Upon drug aggregate formation, the probes partitioned into the drug rich phase and exhibited changes in emission wavelength and intensity consistent with sensing a lower polarity environment. The LLPS onset concentrations determined using the fluorescence measurements were in good agreement with light scattering measurements as well as theoretically estimated amorphous solubility values. CONCLUSIONS: Environment-sensitive fluorescence probes are useful to help understand the phase behavior of highly supersaturated aqueous solutions, which in turn is important in the context of developing enabling formulations for poorly soluble compounds. PMID- 26123682 TI - Randomized Controlled Intervention of the Effects of Alcohol on Blood Pressure in Premenopausal Women. AB - Alcohol has been consistently demonstrated to elevate blood pressure (BP) in intervention studies in men. There are uncertainties, however, as to the nature of the relationship in women. We, therefore, determined in healthy premenopausal women the dose-dependent effects of alcohol on ambulatory BP. Twenty-four participants aged 25 to 49 years, with a mean alcohol intake of 202+/-94 g alcohol/wk and mean 24-hour systolic and diastolic BP of 110.2+/-8.9/68.9+/-5.7 mm Hg, were randomized to a 3-period cross-over study. Each evening they consumed higher volume red wine (lower level drinkers, 146 g alcohol/wk; higher level drinkers, 218 g alcohol/wk), lower volume red wine (lower level drinkers, 42 g alcohol/wk; higher level drinkers, 73 g alcohol/wk), or dealcoholized red wine, each for a period of 4 weeks. Higher volume red wine significantly increased 24 hours systolic and diastolic BP relative to dealcoholized red wine (by 2.0+/ 0.6/1.2+/-0.4 mm Hg; P=0.001 and P=0.028, respectively). There were similar changes for higher volume red wine relative to lower volume red wine (by 1.6+/ 0.6/1.4+/-0.4 mm Hg; P=0.014 and P=0.005, respectively). These effects were predominantly on awake rather than asleep BP. There was no significant difference in BP between lower volume red wine and dealcoholized red wine. We conclude that in healthy premenopausal women regular consumption of alcohol as 200 to 300 mL red wine/d (146-218 g alcohol/wk) elevates 24 hours systolic and diastolic BP. The magnitude of the increase in BP is similar to that previously reported in intervention studies in men. PMID- 26123684 TI - Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension. AB - Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09*10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73*10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. PMID- 26123683 TI - Endotoxin and beta-1,3-d-Glucan in Concentrated Ambient Particles Induce Rapid Increase in Blood Pressure in Controlled Human Exposures. AB - Short-term exposure to particulate matter (PM) is associated with increased blood pressure (BP) in epidemiological studies. Understanding the impact of specific PM components on BP is essential in developing effective risk-reduction strategies. We investigated the association between endotoxin and beta-1,3-d-Glucan-two major biological PM components-and BP. We also examined whether vascular endothelial growth factor, a vasodilatory inflammatory marker, modified these associations. We conducted a single-blind, randomized, crossover trial of controlled human exposure to concentrated ambient particles with 50 healthy adults. Particle associated-endotoxin and beta-1,3-d-Glucan were sampled using polycarbonate membrane-filters. Supine resting systolic BP and diastolic BP were measured pre-, 0.5-hour post-, and 20-hour postexposure. Urine vascular endothelial growth factor concentration was determined using enzyme-linked immunosorbant assay and creatinine-corrected. Exposures to endotoxin and beta-1,3-d-Glucan for 130 minutes were associated with increases in BPs: at 0.5-hour postexposure, every doubling in endotoxin concentration was associated with 1.73 mm Hg higher systolic BP (95% confidence interval, 0.28, 3.18; P=0.02) and 2.07 mm Hg higher diastolic BP (95% confidence interval, 0.74, 3.39; P=0.003); every doubling in beta-1,3-d-Glucan concentration was associated with 0.80 mm Hg higher systolic BP (95% confidence interval, -0.07, 1.67; P=0.07) and 0.88 mm Hg higher diastolic BP (95% confidence interval, 0.09, 1.66; P=0.03). Vascular endothelial growth factor rose after concentrated ambient particle endotoxin exposure and attenuated the association between endotoxin and 0.5-hour postexposure diastolic BP (Pinteraction=0.02). In healthy adults, short-term endotoxin and beta-1,3-d Glucan exposures were associated with increased BP. Our findings suggest that the biological PM components contribute to PM-related cardiovascular outcomes, and postexposure vascular endothelial growth factor elevation might be an adaptive response that attenuates these effects. PMID- 26123685 TI - Ambient Air Pollution and Increases in Blood Pressure: Role for Biological Constituents of Particulate Matter. PMID- 26123686 TI - The Toxicologist as Educator: Addressing Pain Management in the Midst of an Opioid Epidemic. PMID- 26123687 TI - [Assessment of a "Yoga and relaxation" workshop as part of a therapeutic education program "Live with your lymphedema"]. PMID- 26123689 TI - Recent advances in the pathobiology and management of Kasabach-Merritt phenomenon. AB - Kasabach-Merritt Phenomenon (KMP) refers to the clinical constellation of thrombocytopenia, consumptive coagulopathy and purpura associated with Kaposiform haemangioedothelioma or tufted angioma, but not the more common infantile haemangioma. It shows a variable and unpredictable response to traditional pharmacological agents, such as steroids, vincristine or interferon alpha 2a or 2b. More recently, the interaction between platelets and endothelial cells and the proangiogenic phenotype that results has been recognized to underly the pathogenesis of this disorder. Recent efforts have attempted to target the platelet by using antiplatelet agents and by the withholding of platelet transfusions even in those patients who have significant thrombocytopenia and laboratory evidence of coagulopathy. Excellent response rates and prompt results have been achieved by combining antiplatelet therapy with vincristine, without the need for steroid use. This synergistic approach moves away from the conventional wisdom of treating the underlying lesion to control the coagulopathy. Sirolimus, which is directed against the PI3/AKT/mTOR downstream signalling pathway involved in lymphangiogenesis, has also shown promising results, although further study is needed. PMID- 26123690 TI - Supramolecular amplification of amyloid self-assembly by iodination. AB - Amyloid supramolecular assemblies have found widespread exploitation as ordered nanomaterials in a range of applications from materials science to biotechnology. New strategies are, however, required for understanding and promoting mature fibril formation from simple monomer motifs through easy and scalable processes. Noncovalent interactions are key to forming and holding the amyloid structure together. On the other hand, the halogen bond has never been used purposefully to achieve control over amyloid self-assembly. Here we show that single atom replacement of hydrogen with iodine, a halogen-bond donor, in the human calcitonin-derived amyloidogenic fragment DFNKF results in a super-gelator peptide, which forms a strong and shape-persistent hydrogel at 30-fold lower concentration than the wild-type pentapeptide. This is remarkable for such a modest perturbation in structure. Iodination of aromatic amino acids may thus develop as a general strategy for the design of new hydrogels from unprotected peptides and without using organic solvents. PMID- 26123691 TI - The value of partnerships: lessons from a multi-site evaluation of a national social and emotional wellbeing program for Indigenous youth. AB - OBJECTIVE: To evaluate the first three years of a national program to improve the social and emotional wellbeing of Indigenous youth in remote and regional Australia. METHODS: Combination of open inquiry and audit review involving investigation of process and outcomes, with a broad national overview supplemented by five in-depth case studies in diverse settings. RESULTS: Community development principles were applied at all 14 sites. There were many examples of collaborative, community-driven health promotion initiatives, with most progress observed where there were strong local partnerships. Within the range of activities, education sessions on alcohol and other drugs, mental health and violence were facilitated by program staff. There was a tension between community development and specific program delivery, with the balance reflecting the needs and capacity of individual sites, program staff expertise and contractual requirements. CONCLUSIONS AND IMPLICATIONS: The main lessons concern program design and resourcing and ways of working. Program staff at each site learned to be not too ambitious, but to work consistently with the community, establishing partnerships and engaging and training community members. Community and stakeholder capacity enhancement should be regarded as core, and evaluation built in. Activities directed at youth must be engaging and effective, and integrated with other programs and services. PMID- 26123688 TI - Temporally coordinated signals progressively pattern the anteroposterior and dorsoventral body axes. AB - The vertebrate body plan is established through the precise spatiotemporal coordination of morphogen signaling pathways that pattern the anteroposterior (AP) and dorsoventral (DV) axes. Patterning along the AP axis is directed by posteriorizing signals Wnt, fibroblast growth factor (FGF), Nodal, and retinoic acid (RA), while patterning along the DV axis is directed by bone morphogenetic proteins (BMP) ventralizing signals. This review addresses the current understanding of how Wnt, FGF, RA and BMP pattern distinct AP and DV cell fates during early development and how their signaling mechanisms are coordinated to concomitantly pattern AP and DV tissues. PMID- 26123692 TI - Inhibition of Cycloartenol Synthase (CAS) Function in Tobacco BY-2 Cell Suspensions: A Proteomic Analysis. AB - The effect of an inhibitor of cycloartenol synthase (CAS, EC 5.4.99.8) on the proteome of tobacco BY-2 cells has been examined. CAS catalyzes the first committed step in phytosterol synthesis in plants. BY-2 cells were treated with RO 48-8071, a potent inhibitor of oxidosqualene cyclization. Proteins were separated by two-dimensional electrophoresis and spots, that clearly looked differentially accumulated after visual inspection, were cut, in-gel trypsin digested, and peptides were analyzed by nano-HPLC-MS/MS. Distinct peptides were compared to sequences in the data banks and attributed to corresponding proteins and genes. Inhibition of CAS induced proteins that appear to mitigate the negative effects of the chemical exposure. However, as all enzymes that are directly involved in phytosterol biosynthesis are low-abundant proteins, significant changes in their levels could not be observed. Differences could be seen with enzymes involved in primary metabolism (glycolysis, pentose phosphate pathway etc.), in proteins of the chaperonin family, and those, like actin, that participate in formation and strengthening of the cytoskeleton and have some impact on cell growth and division. PMID- 26123693 TI - Separation and Identification of Odd Chain Triacylglycerols of the Protozoan Khawkinea quartana and the Mold Mortierella alpina Using LC-MS. AB - Liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (LC-MS/APCI) with reversed- and chiral phases was used for separation of triacylglycerols (TAG) from protozoan and mold. This study describes the separation and identification of odd numbered chains of regioisomers and enantiomers of triacylglycerols from different natural sources, i.e., the protozoan Khawkinea quartana and the mold Mortierella alpina. Using the above mentioned separation methods and the synthesis of appropriate standards of TAG, we identified regioisomers and enantiomers of both even and odd numbered TAG. The biosynthesis of odd numbered TAG was found to be strictly stereospecific and to depend on the production microorganism, one enantiomer predominating in the protozoan and the other in the mold. It was proved that even numbered TAG are synthesized in a higher optical purity, which can be explained by a higher affinity of acyltransferases to the respective substrate, i.e., to even chain PUFA. PMID- 26123694 TI - Phosphatidylethanolamine, but not Phosphatidylglycerol-Cardiolipin, Isolated from Two Species of Helicobacter Binds Cholesterol over Cholesteryl Ester. AB - This study demonstrated that the cells of Helicobacter felis and Helicobacter cinaedi spontaneously absorb cholesterol added to the medium. A recent study by our group has revealed that phosphatidylethanolamine (PtdEtn) of Helicobacter pylori contains myristic acid as the most predominant saturated fatty acid and that the PtdEtn of this bacterium binds cholesterol more selectively than cholesteryl ester. We, therefore, isolated the PtdEtn from the two Helicobacter species to analyze the hydrophobic interaction between cholesterol and its glycerophospholipid. PtdEtn of the Helicobacter bacteria interacted more selectively with cholesterol than with cholesteryl ester, and the degree of the selective binding of cholesterol was higher in the PtdEtn than in the phosphatidylglycerol-cardiolipin of the same bacteria. These results suggest the possibility that the cells of H. felis and H. cinaedi may contain abundant PtdEtn with myristic acid. On this basis, we analyzed the PtdEtn molecular species of the Helicobacter bacteria and demonstrated that the PtdEtn containing myristic acid accounts for more than 35% in the total PtdEtn. These results suggest that the myristoyl PtdEtn takes part in the absorption of cholesterol in H. felis and H. cinaedi. PMID- 26123695 TI - Learning curve for endoscopic submucosal dissection of esophageal neoplasms. AB - There is a significant learning curve for endoscopic submucosal dissection of esophageal neoplasms that has not been fully characterized. This retrospective study included 33 consecutive superficial esophageal neoplasms for analysis of the learning curve for esophageal endoscopic submucosal dissection based on a single, novice endoscopist's experience. The study was divided into three periods (T1, T2, and T3) of 10 endoscopic submucosal dissection procedures in chronological order, with 13 procedures in the last period. Patient factors (age, sex, coexistent esophageal varices, or submucosal fibrosis) and tumor factors (location at upper esophagus, involving >3/4 esophageal circumference) for endoscopic submucosal dissection were not statistically different between the periods. The mean procedure time was 74.6 min/cm(2) , 23.4 min/cm(2) , and 10.5 min/cm(2) for T1, T2, and T3, respectively. The procedure time decreased over time (P = 0.02) and post hoc test revealed significant difference was only between T3 and T1 (P = 0.019). The en bloc resection rate was 50%, 100%, and 92.3% for T1, T2, and T3, respectively (P for trend = 0.015). R0 resection rate was 40%, 100%, and 84.6% for T1, T2, and T3, respectively (P for trend = 0.023). Two patients had complications: each one patient in T1 and T3 period experienced major bleeding during the procedure (P for trend = 0.875). None of the patients had esophageal perforation. The results of the study concluded that at least 30 cases of endoscopic submucosal dissection of esophageal neoplasms are needed for a novice endoscopist to gain early proficiency in this technique. PMID- 26123696 TI - Enantioselective cooperative catalysis. AB - In recent years, enantioselective cooperative catalytic reactions, wherein two catalysts work simultaneously to form products which cannot be obtained by the use of a single catalyst alone, have attracted considerable attention. This review focuses on this emerging field, with particular emphasis on mechanistic aspects, which will help readers to understand the role of each catalyst. PMID- 26123698 TI - Contribution of Congenital Anomalies to Neonatal Mortality Rates in Malta. AB - BACKGROUND: Neonatal mortality is a public health concern, and congenital anomalies contribute significantly to this mortality. This paper describes trends in neonatal mortality in Malta separately for congenital anomaly and non congenital anomaly causes. METHODS: Data for neonatal deaths of 22-week gestation onwards registered between 1994-2013 were obtained from the National Mortality Register. Chi-square tests were used to analyse 5-year time trends and differences in proportions of causes of neonatal deaths. Neonatal mortality was compared with other European countries. RESULTS: Between 1994 and 2013, 441 neonatal deaths and 84 821 livebirths were registered, giving a neonatal mortality of 5.2 per 1000 livebirths. Congenital anomalies accounted for 36.7% (n = 162) of the neonatal deaths, while the remaining 63.3% (n = 279) were attributed to non-congenital causes. During the 20-year period, neonatal mortality due to non-congenital causes decreased from 4.6 per 1000 livebirths in 1994-98 to 2.5 per 1000 in 2009-13, while that due to congenital anomalies remained stable (2.0 per 1000 livebirths in 1994-98 and 2.2 per 1000 in 2009-13). This has resulted in comparatively higher proportions of neonatal deaths attributed to congenital anomalies in recent years (45.9% in 2009-13 vs. 29.9% in 1994-98). Comparing neonatal mortality reported from European countries, Malta has a high rate most marked for deaths due to congenital anomalies. CONCLUSIONS: During 1994-2013, neonatal mortality has decreased due to a decline of non congenital causes of death, possibly related to improved health care. The proportionate neonatal mortality attributed to congenital anomalies has increased and is the highest reported from Europe. This may be explained by the fact that termination of pregnancy is illegal in Malta. PMID- 26123697 TI - The Neuropeptide Allatostatin A Regulates Metabolism and Feeding Decisions in Drosophila. AB - Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and energy mobilization are regulated by the glucagon-related adipokinetic hormone (AKH) and the Drosophila insulin-like peptides (DILPs). Here, we provide evidence that the Drosophila neuropeptide Allatostatin A (AstA) regulates AKH and DILP signaling. The AstA receptor gene, Dar-2, is expressed in both the insulin and AKH producing cells. Silencing of Dar-2 in these cells results in changes in gene expression and physiology associated with reduced DILP and AKH signaling and animals lacking AstA accumulate high lipid levels. This suggests that AstA is regulating the balance between DILP and AKH, believed to be important for the maintenance of nutrient homeostasis in response to changing ratios of dietary sugar and protein. Furthermore, AstA and Dar-2 are regulated differentially by dietary carbohydrates and protein and AstA-neuronal activity modulates feeding choices between these types of nutrients. Our results suggest that AstA is involved in assigning value to these nutrients to coordinate metabolic and feeding decisions, responses that are important to balance food intake according to metabolic needs. PMID- 26123699 TI - The efficacy and safety of endoscopic submucosal dissection compared with endoscopic mucosal resection for colorectal tumors: a meta-analysis. PMID- 26123700 TI - Letter to the editor: gallstone ileus, volvulus, and intestinal perforation in a patient with cholecystotomy and choledochoduodenostomy: a case report. PMID- 26123701 TI - The effects of genetics on pouch neoplasia following restorative proctocolectomy for ulcerative colitis. PMID- 26123703 TI - Cell proliferation, measured as flow cytometric S-phase fraction, is a strong prognostic indicator in FIGO stage I endometrioid endometrial carcinoma: a population-based study. AB - INTRODUCTION: In early-stage endometrial carcinoma, there is controversy regarding the prognostic value of the flow cytometric variables DNA ploidy (diploid vs. aneuploid) and S-phase fraction. In Sweden, the former is included in national guidelines despite poor scientific support and the latter is not used clinically. This study investigates the prognostic properties of these variables, together with classical histopathological variables, in multivariate analysis in a stringently stratified material. MATERIAL AND METHODS: Consecutive, population based patient material restricted to International Federation of Gynecology and Obstetrics (FIGO) 2009 stage I endometrioid endometrial carcinoma (n = 1140) was retrospectively collected from routinely reported data from medical records. Data on age, FIGO stage, degree of differentiation, S-phase fraction, DNA ploidy status, and adjuvant treatment were included in the study. Cumulative incidence curves with other causes of death as a competing risk were used for univariable analysis for the primary endpoint endometrial cancer death. Cox proportional hazards regression analysis was used for multivariate modeling of all endpoints, and for univariable analysis for the secondary endpoints overall survival and time to progression. RESULTS: An S-phase fraction value of >5.5% was associated with worse outcome (for endometrial cancer death: hazard ratio 2.25; 95% CI 1.38 3.67; p = 0.001, adjusted) and DNA ploidy status was not, for all endpoints tested. CONCLUSIONS: In FIGO stage I endometrioid endometrial carcinoma, DNA ploidy status had no prognostic value, whereas the S-phase fraction may be used to identify those with a higher risk of adverse clinical outcome. PMID- 26123702 TI - NF-kappaB decoy oligodeoxynucleotide inhibits wear particle-induced inflammation in a murine calvarial model. AB - Wear particles induce periprosthetic inflammation and osteolysis through activation of nuclear factor kappa B (NF-kappaB), which up-regulates the downstream target gene expression for proinflammatory cytokines in macrophages. It was hypothesized that direct suppression of NF-kappaB activity in the early phases of this disorder could be a therapeutic strategy for preventing the inflammatory response to wear particles, potentially mitigating osteolysis. NF kappaB activity can be suppressed via competitive binding with double stranded NF kappaB decoy oligodeoxynucleotides (ODNs) that blocks this transcription factor from binding to the promoter regions of targeted genes. In this murine calvarial study, clinically relevant polyethylene particles (PEs) with/without ODN were subcutaneously injected over the calvarial bone. In the presence of PE particles, macrophages migrated to the inflammatory site and induced tumor necrosis factor alpha (TNF-alpha) and receptor activator of nuclear factor kappa B ligand (RANKL) expression, resulting in an increase in the number of osteoclasts. Local injections of ODN mitigated the expression of TNF-alpha, RANKL, and induced the expression of two anti-inflammatory, antiresorptive cytokines: interleukin-1 receptor antagonist and osteoprotegerin. Local intervention with NF-kappaB decoy ODN in early cases of particle-induced inflammation in which the prosthesis is still salvageable may potentially preserve periprosthetic bone stock. PMID- 26123704 TI - Effects of Cytochrome P450 Inhibition and Induction on the Phenotyping Metrics of the Basel Cocktail: A Randomized Crossover Study. AB - BACKGROUND AND OBJECTIVE: Activity of human cytochrome P450 enzymes (CYPs) shows high inter-and intra-individual variability, which is determined by genetic and non-genetic factors. Using a combination of CYP-specific probe drugs, phenotyping cocktails allow simultaneous assessment of the activity of different CYP isoforms. The objective of this study was to characterize the phenotyping metrics of the Basel cocktail in healthy male subjects with induced and inhibited CYP activity. METHODS: In a randomized crossover study, the probe drugs for simultaneous phenotyping of CYP1A2 (caffeine), CYP2B6 (efavirenz), CYP2C9 (losartan), 2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam) were administered to 16 subjects without pretreatment (baseline), after pretreatment with a combination of CYP inhibitors (ciprofloxacin, ketoconazole, and paroxetine), and after CYP induction with rifampicin. All subjects were genotyped. Pharmacokinetic profiles of the probe drugs and their main metabolites and metabolic ratios 2, 4, 6, and 8 h after probe drug application were determined in plasma and compared with the corresponding area under the plasma concentration-time curve (AUC) ratios. RESULTS: The Basel phenotyping cocktail was well tolerated by all subjects independent of pretreatment. Good correlations of metabolic ratios with AUC ratios of the corresponding probe drugs and their metabolites for all three conditions (baseline, CYP inhibition, and CYP induction) were found at 2 h after probe drug administration for CYP3A4, at 4 h for CYP1A2 and CYP2C19, and at 6 h for CYP2B6 and CYP2D6. While CYP inhibition significantly changed AUC ratios and metabolic ratios at these time points for all six CYP isoforms, CYP induction did not significantly change AUC ratios for CYP2C9. For CYP3A4, total 1'-hydroxymidazolam concentrations after pretreatment of samples with beta-glucuronidase were needed to obtain adequate reflection of CYP induction by the metabolic ratio. CONCLUSIONS: Inhibition of CYP activity can be detected with the Basel phenotyping cocktail for all six tested CYP isoforms at the proposed time points. The AUC ratio of losartan:losartan carboxylic acid in plasma does not seem suitable to detect induction of CYP2C9. The observed metabolic ratios for inhibited and induced CYP activity need to be confirmed for extensive metabolizers, and typical ratios for subjects with genetically altered CYP activity will need to be established in subsequent studies. ClinicalTrials.gov-ID: NCT01386593. PMID- 26123706 TI - How to Improve the Safe and Effective Use of Doxorubicin in Children with Cancer. PMID- 26123707 TI - H/D isotope effect on charge-inverted hydrogen-bonded systems: Systematic classification of three different types in H3XH...YH3 (X = C, Si, or Ge, and Y = B, Al, or Ga) with multicomponent calculation. AB - Three different H/D isotope effect in nine H3 XH(D)...YH3 (X = C, Si, or Ge, and Y = B, Al, or Ga) hydrogen-bonded (HB) systems are classified using MP2 level of multicomponent molecular orbital method, which can take account of the nuclear quantum nature of proton and deuteron. First, in the case of H3 CH(D)...YH3 (Y = B, Al, or Ge) HB systems, the deuterium (D) substitution induces the usual H/D geometrical isotope effect such as the contraction of covalent R(C-H(D)) bonds and the elongation of intermolecular R(H(D)...Y) and R(C...Y) distances. Second, in the case of H3 XH(D)...YH3 (X = Si or Ge, and Y = Al or Ge) HB systems, where H atom is negatively charged called as charge-inverted hydrogen-bonded (CIHB) systems, the D substitution leads to the contraction of intermolecular R(H(D)...Y) and R(X...distances. Finally, in the case of H3 XH(D)...BH3 (X = Si or Ge) HB systems, these intermolecular R(H(D)...Y) and R(X...Y) distances also contract with the D substitution, in which the origin of the contraction is not the same as that in CIHB systems. The H/D isotope effect on interaction energies and spatial distribution of nuclear wavefunctions are also analyzed. PMID- 26123705 TI - Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis. AB - Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-alpha drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-alpha mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity. PMID- 26123708 TI - Harnessing magnetic-mechano actuation in regenerative medicine and tissue engineering. AB - Mechanical stimulus is of upmost importance in tissues developmental and regeneration processes as well as in maintaining body homeostasis. Classical physiological reactions encompass an increase of blood vessel diameter upon exposure to high blood pressure, or the expansion of cortical bone after continuous high-impact exercise. At a cellular level, it is well established that extracellular stiffness, topography, and remote magnetic actuation are instructive mechanical signals for stem cell differentiation. Based on this, biomaterials and their properties can be designed to act as true stem cell regulators, eventually leading to important advances in conventional tissue engineering techniques. This review identifies the latest advances and tremendous potential of magnetic actuation within the scope of regenerative medicine and tissue engineering. PMID- 26123709 TI - Callous-Unemotional Traits as Markers for Conduct Problem Severity in Early Childhood: A Meta-analysis. AB - Extensive research has shown that callous-unemotional (CU) traits in middle childhood and adolescence are markers for a particularly severe and chronic pattern of antisocial behavior (Frick et al. in Psychol Bull 140:1-57, 2014). Comparatively little, however, is known about the relationship between CU traits and antisocial behavior in early childhood. A meta-analysis of k = 10 studies comprising n = 5731 participants was conducted to examine the relationship between CU traits and conduct problem severity prior to 5 years of age. Overall, a significant positive relationship was found between CU traits and conduct problem severity, in the order of large effect size (r = .39, p < .001). Moderator analyses revealed that this relationship differed based on use of same versus different informant across measures, but was consistent across sex and sample type (at-risk/clinic referred or community). This supports the view that CU traits represent a potentially informative focus for clinical assessment in early childhood. PMID- 26123711 TI - A building-block approach to 3D printing a multichannel, organ-regenerative scaffold. AB - Multichannel scaffolds, formed by rapid prototyping technologies, retain a high potential for regenerative medicine and the manufacture of complex organs. This study aims to optimize several parameters for producing poly(lactic-co-glycolic acid) (PLGA) scaffolds by a low-temperature, deposition manufacturing, three dimensional printing (3DP, or rapid prototyping) system. Concentration of the synthetic polymer solution, nozzle speed and extrusion rate were analysed and discussed. Polymer solution with a concentration of 12% w/v was determined as optimal for formation; large deviation of this figure failed to maintain the desired structure. The extrusion rate was also modified for better construct quality. Finally, several solid organ scaffolds, such as the liver, with proper wall thickness and intact contour were printed. This study gives basic instruction to design and fabricate scaffolds with de novo material systems, particularly by showing the approximation of variables for manufacturing multichannel PLGA scaffolds. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26123712 TI - Timing of emergence of the first primary tooth in preterm and full-term infants. AB - Variations in the timing of emergence of primary teeth are under strong genetic control, but there is also a significant contribution from external factors. The aim of this study was to evaluate the influence of preterm birth, birth weight and length, and feeding practices during the first 6 months of life on the timing of emergence of the first primary tooth. Data on pregnancy duration, birth weight and length, feeding practice, time of emergence and first emerged primary tooth were collected by electronic questionnaires. The study included 409 parents and 592 children of both genders. The sample was divided into two groups according to pregnancy duration (<37 weeks and >=37 weeks), three groups according to feeding practice (exclusively breastfed, exclusively bottle fed, and a combination of breast feeding and bottle feeding), three groups by birth length (<50, 50-53, >53cm), and four groups by birth weight (<1500, 1500-2500, 2501-3500, >3500g). Data were analyzed considering chronological and postmenstrual age-which is the gestational age plus the infant's chronological age at the month of emergence of the first primary tooth. The mean time of first primary tooth emergence was 7.55+/-2.67 months when chronological age was considered. The first emerged tooth in most cases was a lower incisor (82.33%). There was a statistically significant difference in the timing of the first tooth emergence between preterm and full term groups when chronological age was considered (p<0.005). However, no difference was found when age was adjusted. The age of emergence of the first tooth differed significantly when feeding, weight, and length groups (p<0. 05) were taken into account. In conclusion, the study indicates that shortened gestational age and very low birth weight are predictors for later ages of emergence of the first primary tooth. PMID- 26123713 TI - Prevalence, and early childhood caries risk indicators in preschool children in suburban Nigeria. AB - BACKGROUND: Early Childhood Caries (ECC) is defined as the presence of caries lesion in an primary tooth in children below the age of 71 months. It is a significant public health problem with consequences for the growth and development of affected children. The objective of this study was to determine the prevalence and ECC risk indicators in a suburban population in Nigeria. METHODS: The data of 497 children aged 6 months to 71 months who were recruited through a household survey conducted in Ile-Ife, Nigeria was analysed for prevalence of ECC and risk indicators. Information on children's ages, sex, socioeconomic status, tooth brushing habits, sugary snacks consumption, use of fluoridated toothpaste, birth rank, infant-feeding practices, breastfeeding practices, maternal age at childbirth, and maternal knowledge of oral health was obtained. Children's oral hygiene and caries status was also determined. Risk factors associated with ECC were determined using logistic regression analysis. RESULTS: Thirty-three (6.6%) children had ECC. Four (0.8%) had severe ECC. The four risk indicators for ECC were the child's gender, mothers' knowledge of oral health, consumption of sugary snacks in between meals more than three times a day, and the child's oral hygiene status. Females (PR: -0.06; 95% CI: -0.01- 0.01; p = 0.02), and children with mothers who had good knowledge of oral health (PR: -0.06; 95% CI: -0.11--0.008; p = 0.02) were less likely to have ECC. Children who consumed sugary snacks in between meals three times a day or more (PR: 0.05; CI: 0.003 - 0.01; P = 0.04) and children with fair oral hygiene (PR: 0.05; 95% CI: 0.005-0.10; p = 0.03) were more likely to have ECC. CONCLUSIONS: The prevalence of ECC in the study population was low. Promoting good oral hygiene practices and enhancing mothers' knowledge of oral health may help reduce further, the risk for ECC in the study population. PMID- 26123715 TI - MADIT-CRT and his many sons. PMID- 26123714 TI - Integrated approaches to miRNAs target definition: time-series analysis in an osteosarcoma differentiative model. AB - BACKGROUND: microRNAs (miRs) are small non-coding RNAs involved in the fine regulation of several cellular processes by inhibiting their target genes at post transcriptional level. Osteosarcoma (OS) is a tumor thought to be related to a molecular blockade of the normal process of osteoblast differentiation. The current paper explores temporal transcriptional modifications comparing an osteosarcoma cell line, Saos-2, and clones stably transfected with CD99, a molecule which was found to drive OS cells to terminally differentiate. METHODS: Parental cell line and CD99 transfectants were cultured up to 14 days in differentiating medium. In this setting, OS cells were profiled by gene and miRNA expression arrays. Integration of gene and miRNA profiling was performed by both sequence complementarity and expression correlation. Further enrichment and network analyses were carried out to focus on the modulated pathways and on the interactions between transcriptome and miRNome. To track the temporal transcriptional modification, a PCA analysis with differentiated human MSC was performed. RESULTS: We identified a strong (about 80 %) gene down-modulation where reversion towards the osteoblast-like phenotype matches significant enrichment in TGFbeta signaling players like AKT1 and SMADs. In parallel, we observed the modulation of several cancer-related microRNAs like miR-34a, miR-26b or miR-378. To decipher their impact on the modified transcriptional program in CD99 cells, we correlated gene and microRNA time-series data miR-34a, in particular, was found to regulate a distinct subnetwork of genes with respect to the rest of the other differentially expressed miRs and it appeared to be the main mediator of several TGFbeta signaling genes at initial and middle phases of differentiation. Integration studies further highlighted the involvement of TGFbeta pathway in the differentiation of OS cells towards osteoblasts and its regulation by microRNAs. CONCLUSIONS: These data underline that the expression of miR-34a and down-modulation of TGFbeta signaling emerge as pivotal events to drive CD99-mediated reversal of malignancy and activation of differentiation in OS cells. Our results describe crucial and specific interacting actors providing and supporting their relevance as potential targets for therapeutic differentiative strategies. PMID- 26123716 TI - Cardiovascular adaptation in athletes. PMID- 26123718 TI - Fractionation in position-specific isotope composition during vaporization of environmental pollutants measured with isotope ratio monitoring by 13C nuclear magnetic resonance spectrometry. AB - Isotopic fractionation of pollutants in terrestrial or aqueous environments is a well-recognized means by which to track different processes during remediation. As a complement to the common practice of measuring the change in isotope ratio for the whole molecule using isotope ratio monitoring by mass spectrometry (irm MS), position-specific isotope analysis (PSIA) can provide further information that can be exploited to investigate source and remediation of soil and water pollutants. Position-specific fractionation originates from either degradative or partitioning processes. We show that isotope ratio monitoring by (13)C NMR (irm (13)C NMR) spectrometry can be effectively applied to methyl tert-butylether, toluene, ethanol and trichloroethene to obtain this position-specific data for partitioning. It is found that each compound exhibits characteristic position specific isotope fractionation patterns, and that these are modulated by the type of evaporative process occurring. Such data should help refine models of how remediation is taking place, hence back-tracking to identify pollutant sources. PMID- 26123719 TI - Influences of ambient air PM2.5 concentration and meteorological condition on the indoor PM2.5 concentrations in a residential apartment in Beijing using a new approach. AB - PM2.5 concentrations in a typical residential apartment in Beijing and immediately outside of the building were measured simultaneously during heating and non-heating periods. The objective was to quantitatively explore the relationship between indoor and outdoor PM2.5 concentrations. A statistical method for predicting indoor PM2.5 concentrations was proposed. Ambient PM2.5 concentrations were strongly affected by meteorological conditions, especially wind directions. A bimodal distribution was identified during the heating season due to the frequent and rapid transition between severe pollution events and clean days. Indoor PM2.5 concentrations were significantly correlated with outdoor PM2.5 concentrations but with 1-2 h delay, and the differences can be explained by ambient meteorological features, such as temperature, humidity, and wind direction. These results indicate the potential to incorporate indoor exposure features to the regional air quality model framework and to more accurately estimate the epidemiological relationship between human mortality and air pollution exposure. PMID- 26123717 TI - A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004-2014. AB - This report describes results from a systematic literature review examining gender differences in U.S. prevalence rates of current use of tobacco and nicotine delivery products and how they intersect with other vulnerabilities to tobacco use. We searched PubMed on gender differences in tobacco use across the years 2004-2014. For inclusion, reports had to be in English, in a peer-reviewed journal or federal government report, report prevalence rates for current use of a tobacco product in males and females, and use a U.S. nationally representative sample. Prevalence rates were generally higher in males than in females across all products. This pattern remained stable despite changes over time in overall prevalence rates. Gender differences generally were robust when intersecting with other vulnerabilities, although decreases in the magnitude of gender differences were noted among younger and older users, and among educational levels and race/ethnic groups associated with the highest or lowest prevalence rates. Overall, these results document a pervasive association of gender with vulnerability to tobacco use that acts additively with other vulnerabilities. These vulnerabilities should be considered whenever formulating tobacco control and regulatory policies. PMID- 26123720 TI - Colocalization of low-methylesterified pectins and Pb deposits in the apoplast of aspen roots exposed to lead. AB - Low-methylesterified homogalacturonans have been suggested to play a role in the binding and immobilization of Pb in CW. Using root apices of hybrid aspen, a plant with a high phytoremediation potential, as a model, we demonstrated that the in situ distribution pattern of low-methylesterified homogalacturonan, pectin epitope (JIM5-P), reflects the pattern of Pb occurrence. The region which indicated high JIM5-P level corresponded with "Pb accumulation zone". Moreover, JIM5-P was especially abundant in cell junctions, CWs lining the intercellular spaces and the corners of intercellular spaces indicating the highest accumulation of Pb. Furthermore, JIM5-P and Pb commonly co-localized. The observations indicate that low-methylesterified homogalacturonan is the CW polymer that determines the capacity of CW for Pb sequestration. Our results suggest a promising directions for CW modification for enhancing the efficiency of plant roots in Pb accumulation, an important aspect in the phytoremediation of soils contaminated with trace metals. PMID- 26123721 TI - Modeling TiO2 nanoparticle phototoxicity: The importance of chemical concentration, ultraviolet radiation intensity, and time. AB - As a semiconductor with wide band gap energy, TiO2 nanoparticles (nano-TiO2) are highly photoactive, and recent efforts have demonstrated phototoxicity of nano TiO2 to aquatic organisms. However, a dosimetry model for the phototoxicity of nanomaterials that incorporates both direct UV and photo-activated chemical toxicity has not yet been developed. In this study, a set of Hyalella azteca acute toxicity bioassays at multiple light intensities and nano-TiO2 concentrations, and with multiple diel light cycles, was conducted to assess how existing phototoxicity models should be adapted to nano-TiO2. These efforts demonstrated (a) adherence to the Bunsen-Roscoe law for the reciprocity of light intensity and time, (b) no evidence of damage repair during dark periods, (c) a lack of proportionality of effects to environmental nano-TiO2 concentrations, and (d) a need to consider the joint effects of nano-TiO2 phototoxicity and direct UV toxicity. PMID- 26123722 TI - Slash-and-char: An ancient agricultural technique holds new promise for management of soils contaminated by Cd, Pb and Zn. AB - Heavy metal contamination of agricultural soils is of worldwide concern. Unfortunately, there are currently no efficient and sustainable approaches for addressing this concern. In this study, we conducted a field experiment in which an agricultural soil highly contaminated by cadmium (Cd), lead (Pb) and zinc (Zn) was treated on-site by an ancient agricultural technique, 'slash-and-char', that was able to convert the biomass feedstock (rice straw) into biochar in only one day. We found evidence that in comparison to the untreated soil, the treated soil was associated with decreased bioavailability of the heavy metals and increased vegetable yields. Most importantly, the treatment was also coupled with dramatic reductions in concentrations of the heavy metals in vegetables, which made it possible to produce safe crops in this highly contaminated soil. Collectively, our results support the idea that slash-and-char offers new promise for management of soils contaminated by Cd, Pb and Zn. PMID- 26123723 TI - A statistical model for determining impact of wildland fires on Particulate Matter (PM2.5) in Central California aided by satellite imagery of smoke. AB - As the climate in California warms and wildfires become larger and more severe, satellite-based observational tools are frequently used for studying impact of those fires on air quality. However little objective work has been done to quantify the skill these satellite observations of smoke plumes have in predicting impacts to PM2.5 concentrations at ground level monitors, especially those monitors used to determine attainment values for air quality under the Clean Air Act. Using PM2.5 monitoring data from a suite of monitors throughout the Central California area, we found a significant, but weak relationship between satellite-observed smoke plumes and PM2.5 concentrations measured at the surface. However, when combined with an autoregressive statistical model that uses weather and seasonal factors to identify thresholds for flagging unusual events at these sites, we found that the presence of smoke plumes could reliably identify periods of wildfire influence with 95% accuracy. PMID- 26123724 TI - Altered immune response in mallard ducklings exposed to lead through maternal transfer in the wild. AB - Lead (Pb) poisoning has caused significant mortality in waterfowl populations worldwide. In spite of having been banned since 2003, prevalence of Pb shot ingestion in mallards (Anas platyrhynchos) from the Ebro delta was still 15.5% in 2011-12. We collected mallard eggs from this area to study the effects of maternally transferred Pb on eggshell properties and on immune response and oxidative balance of ducklings. Eggshell Pb levels were positively correlated with Pb levels in the blood of ducklings. Ducklings with blood Pb levels above 180 ng mL(-1) showed reduced body mass and died during the first week post hatching. Blood Pb levels positively correlated with humoral immune response, endogenous antioxidants and oxidative stress biomarkers, and negatively correlated with cellular immune response. Pb shot ingestion in birds can result in maternal transfer to the offspring that can affect their developing immune system and reduce their survival in early life stages. PMID- 26123725 TI - Temperature as a modifier of the effects of fine particulate matter on acute mortality in Hong Kong. AB - Interactions between particulate matter with aerodynamic diameter less than or equal to 2.5 MUm (PM2.5) and temperature on mortality have not been well studied, and results are difficult to synthesize. We aimed to assess modification of temperature on the association between PM2.5 and cause-specific mortality by stratifying temperature into low, medium, and high stratum in Hong Kong, using data from 1999 to 2011. The mortality effects of PM2.5 were stronger in low temperature stratum than those in high. The excess risk (%) per 10 MUg/m(3) increase in PM2.5 at lag 0-1 in low temperature stratum were 0.94% (95% confidence interval: 0.65, 1.24) for all natural, 0.88% (0.38, 1.37) for cardiovascular, and 1.15% (0.51, 1.79) for respiratory mortality. We found statistically significant interaction of PM2.5 and temperature between low and high temperature stratum for all natural mortality. Our results suggested that temperature might modify mortality effects of PM2.5 in Hong Kong. PMID- 26123726 TI - Targeted Feedback in the Milestones Era: Utilization of the Ask-Tell-Ask Feedback Model to Promote Reflection and Self-Assessment. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education's Milestones Project focuses trainee education on the formation of valued behaviors and skills believed to be necessary for trainees to become independent practitioners. The development and refinement of behaviors and skills outlined within the milestones will require learners to monitor, reflect, and assess their own performance over time. External feedback provides an opportunity for learners to recalibrate their self-assessments, thereby enabling them to develop better self-monitoring and self-assessment skills. Yet, feedback to trainees is frequently generic, such as "great job," "nice work," or "you need to read more." PURPOSE: In this article, we describe a feedback model that faculty can use to provide specific feedback, while increasing accountability for learners. We offer practical examples of its use in a variety of settings in the milestone era. INNOVATION: The Ask-Tell-Ask (ATA) patient communication skills strategy, which was adapted for use as a trainee feedback model 10 years ago at our institution, is a learner-centered approach for reinforcing and modifying behaviors. The model is efficient, promotes learner accountability, and helps trainees develop reflection and self assessment skills. A feedback agreement further enhances ATA by establishing a shared understanding of goals for the educational encounter. CONCLUSION: The ATA feedback model, combined with a feedback agreement, encourages learners to self identify strengths and areas for improvement, before receiving feedback. Personal monitoring, reflection, self-assessment, and increased accountability make ATA an ideal learner-centered feedback model for the milestones era, which focuses on performance improvement over time. We believe the introduction of the ATA feedback model in surgical training programs is a step in the right direction towards meaningful programmatic culture change. PMID- 26123728 TI - Molecular and phylogenetic analysis of the filarial nematode Micipsella numidica from the hare Lepus europaeus in Italy. AB - The genus Micipsella comprises three species of filariae to date identified in lagomorphs only, whereas the other genera belonging to the subfamily Splendidofilariinae are described as parasites of birds, reptiles and mammals. In the present study seven specimens of Micipsella numidica (Seurat, 1917), collected from the hare Lepus europaeus in Italy, were characterized genetically by molecular amplification of the mitochondrial genes (12S rDNA; cox1) and the 5S rDNA gene spacer region. Phylogenetic trees inferred using available sequences from filariae and those identified in this study evidenced a close relationship between M. numidica and Splendidofilariinae of other mammals and reptiles (Rumenfilaria andersoni and Madathamugadia hiepei). The present findings, apart from adding new data about the hosts in Italy, support the taxonomic position of M. numidica and highlight the substantial biological and molecular differences existing between Splendidofilariinae and other Onchocercidae. The study also contributes to our knowledge of the molecular/genetic diagnosis of filarial parasites of veterinary and medical concern in any vertebrate or invertebrate host. PMID- 26123727 TI - WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease. AB - Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration. PMID- 26123729 TI - Cytoplasmic nucleophosmin has elevated T199 phosphorylation upon which G2/M phase progression is dependent. AB - The cytoplasmic mutant of nucleophosmin (NPMc) is found approximately in one third of acute myeloid leukemia (AML) cases and is highly associated with normal karyotype. Whereas previous studies have focused on wtNPM in centrosome duplication, we further elucidate the role of NPM in the cell cycle by utilizing the increased cytoplasmic load of NPMc. Overexpression of NPMc causes increased phosphorylation of NPM on T199 and, to a lesser degree, S4. T199 phosphorylation is dependent on cdk2 but activators of cdk2 were not elevated. Upon inhibition of cdk2, NPMc-overexpressing cells demonstrate a greater G2/M phase arrest than wtNPM or GFP counterparts. However, the number of cells with 2 centrosomes did not increase concordantly. This suggests that the arrest was caused by a delay in centrosome duplication, most likely due to the inhibition of centrosome duplication caused by unphosphorylated NPMc. Overall, these results suggest that the phosphorylation of T199 is important in the mitotic progression of NPMc expressing cells. This further supports the hypothesis that NPMc is associated with normal karyotypes in AML because the higher cytoplasmic load of NPM can better suppress centrosome overduplication which would otherwise result in unequal segregation of chromosomes during mitosis, leading to aneuploidy and other genomic instabilities. PMID- 26123730 TI - Construction and applications of exon-trapping gene-targeting vectors with a novel strategy for negative selection. AB - BACKGROUND: Targeted gene modification by homologous recombination provides a powerful tool for studying gene function in cells and animals. In higher eukaryotes, non-homologous integration of targeting vectors occurs several orders of magnitude more frequently than does targeted integration, making the gene targeting technology highly inefficient. For this reason, negative-selection strategies have been employed to reduce the number of drug-resistant clones associated with non-homologous vector integration, particularly when artificial nucleases to introduce a DNA break at the target site are unavailable or undesirable. As such, an exon-trap strategy using a promoterless drug-resistance marker gene provides an effective way to counterselect non-homologous integrants. However, constructing exon-trapping targeting vectors has been a time-consuming and complicated process. RESULTS: By virtue of highly efficient att-mediated recombination, we successfully developed a simple and rapid method to construct plasmid-based vectors that allow for exon-trapping gene targeting. These exon trap vectors were useful in obtaining correctly targeted clones in mouse embryonic stem cells and human HT1080 cells. Most importantly, with the use of a conditionally cytotoxic gene, we further developed a novel strategy for negative selection, thereby enhancing the efficiency of counterselection for non homologous integration of exon-trap vectors. CONCLUSIONS: Our methods will greatly facilitate exon-trapping gene-targeting technologies in mammalian cells, particularly when combined with the novel negative selection strategy. PMID- 26123731 TI - Comparison of lateral photographic and radiographic sagittal analysis in relation to Angle's classification. AB - OBJECTIVE: The goal of this study was to compare sagittal jaw relationships derived from standardized profile photographs (soft tissue) to those derived from lateral cephalograms (hard tissue) with respect to Angle's classification of malocclusion. METHODS: A total of 110 randomly selected subjects (mean age: 13.75 +/- 1.46 years) undergoing treatment (Postgraduate Program in Orthodontics at Tel Aviv University) were assigned to three groups based on Angle's classification (Class I: n = 30; Class II: n = 50; Class III: n = 30). Standardized profile-view photographs and lateral radiographs (cephalograms) were compared using 11 soft tissue and 8 skeletal measurements, respectively. RESULTS: Tragus, infra-orbital, nasion, A point, B point, and pogonion were found to be the most reliable soft tissue reference points. A similar pattern of diversity was found between the three groups of Angle's classification (Class I/II/III) for the photographic soft,-tissue and the radiographic skeletal measurements (e.g., soft tissue A'N'B' =11.43 degrees /13.30 degrees /8.85 degrees and hard tissue ANB = 3.13 degrees /4.64 degrees /-1.31 degrees ). Soft tissue A'N'B' measurement provides complementary information to hard tissue ANB measurement. CONCLUSION: Analyzing profile photographs for evaluating sagittal jaw relationships is a practical tool in determining soft tissue harmony. Soft tissue measurements provide a sagittal differential diagnosis in relation to Angle's classification of malocclusion. PMID- 26123732 TI - Association of temporomandibular disorder pain with awake and sleep bruxism in adults. AB - OBJECTIVES: Parafunctional habits such as clenching or grinding (bruxism) during daytime and at night are considered to have a great impact on the etiopathogenesis of temporomandibular disorders (TMD). However, the size of the effect and how daytime activities interact with nocturnal activities is not yet clear. The aim of this study was to assess the association of TMD pain with both awake and sleep bruxism in adults. MATERIALS AND METHODS: In this case-control study, data of a consecutive sample of 733 TMD patients (cases; mean age +/- SD: 41.4 +/- 16.3 years; 82% women) with at least one pain-related TMD diagnosis according to the German version of the Research Diagnostic Criteria for TMD (RDC/TMD) and of a community-based probability sample of 890 subjects (controls; mean age +/- SD: 40.4 +/- 11.8 years; 57% female) without TMD were evaluated. Clenching or grinding while awake and/or asleep was assessed with self-reports. Association of TMD pain with awake and sleep bruxism was analyzed using multiple logistic regression analyses and controlled for potential confounders. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: While 11.2% of the controls reported clenching or grinding while awake, this proportion was significantly higher in TMD patients (33.9%; p < 0.001). Nocturnal clenching or grinding was reported by 23.5% of the controls and 49.4% of the TMD patients (p < 0.001). Risk for TMD pain did not differ substantially for the separate reports of awake (OR 1.7; CI 1.0-2.7) or sleep bruxism (OR 1.8; CI 1.4-2.4). However, risk for TMD pain substantially increased in cases of simultaneous presence of awake and sleep bruxism (OR 7.7; CI 5.4-11.1). CONCLUSION: When occurring separately, awake and sleep bruxism are significant risk factors for TMD pain. In case of simultaneous presence, the risk for TMD pain is even higher. PMID- 26123733 TI - Dimensional accuracy of jaw scans performed on alginate impressions or stone models: A practice-oriented study. AB - OBJECTIVES: Digital jaw models offer more extensive possibilities for analysis than casts and make it easier to share and archive relevant information. The aim of this study was to compare the dimensional accuracy of scans performed on alginate impressions and on stone models to reference scans performed on underlying resin models. METHODS: Precision spheres 5 mm in diameter were occlusally fitted to the sites of the first premolars and first molars on a pair of jaw models fabricated from resin. A structured-light scanner was used for digitization. Once the two reference models had been scanned, alginate impressions were taken and scanned after no later than 1 h. A third series of scans was performed on type III stone models derived from the impressions. All scans were analyzed by performing five repeated measurements to determine the distances between the various sphere centers. RESULTS: Compared to the reference scans, the stone-model scans were larger by a mean of 73.6 um (maxilla) or 65.2 um (mandible). The impression scans were only larger by 7.7 um (maxilla) or smaller by 0.7 um (mandible). Median standard deviations over the five repeated measurements of 1.0 um for the reference scans, 2.35 um for the impression scans, and 2.0 um for the stone-model scans indicate that the values measured in this study were adequately reproducible. CONCLUSION: Alginate impressions can be suitably digitized by structured-light scanning and offer considerably better dimensional accuracy than stone models. Apparently, however, both impression scans and stone-model scans can offer adequate precision for orthodontic purposes. The main issue of impression scans (which is incomplete representation of model surfaces) is being systematically explored in a follow-up study. PMID- 26123734 TI - Three-dimensional analysis of maxillary development in patients with unilateral cleft lip and palate during the first six years of life. AB - OBJECTIVES: The purpose of this work was to analyse early upper-jaw development in patients with unilateral cleft lip and palate (UCLP) treated using two different concepts and to compare shape and size developments between these two groups and a group of noncleft patients. MATERIALS AND METHODS: A total of 204 maxillary casts available for this study from 50 UCLP patients were analyzed for upper-jaw development based on three-dimensional measurements performed with a Reflex Microscope from birth up to 71 months of age. Thirty-five of these 50 patients were part of an early treatment group (two-stage cleft closure with single-stage palatoplasty at an age of 10-14 months) and 15 were part of a late treatment group (two-stage cleft closure with palatoplasty at an age of 4-7 years). The control group included 39 casts of 17 noncleft patients. RESULTS: Analysis of shape and size between the patients in the three groups yielded statistically significant differences between the cleft and the noncleft patients. In both treatment groups, we made observations typically associated with cleft formation like lateralization, asymmetry of the greater and lesser cleft segments, and pronounced vertical deviations of the segments. Viewed in all dimensions, however, the patients in the early treatment group approached the control group more closely, although a statistically significant difference was still observed. CONCLUSION: Our results suggest that the timing of hard-palate closure is not a decisive factor for upper-jaw development. Intrinsic factors (initial cleft width, presence of tooth buds) and the surgeon's skills appear to have a much more defining role. PMID- 26123736 TI - Health sciences journals: an overview of outputs by Chinese authors. AB - OBJECTIVES: To analyse the contributions of authors from three major regions of China - the Mainland (ML), Hong Kong (HK) and Taiwan (TW) - in the field of health care sciences and services. METHODS: Articles published by Chinese authors between 1998 and 2012 in the category of health care sciences and services were retrieved from the Science Citation Index Expanded (SCIE) database. The numbers of total articles, impact factors, citations, articles included in the top 10 highest impact journals and the 10 journals that published the most papers were recorded. RESULTS: ML, HK and TW published 615, 415 and 1162, respectively, with accumulated impact factors of 1281.65, 904.29 and 2361.44; average impact factor of 2.08, 2.18 and 2.03; and total citation times of 2313, 2652, and 4818. Regarding the top 10 high-impact journals, ML, HK and TW accounted for 28.25%, 27.68% and 44.07%, respectively. Total impact factors of the most popular 10 journals for ML, HK and TW were 20.86, 22.08 and 18.92, respectively. DISCUSSION AND CONCLUSIONS: Both the quality and quantity of papers published in health care sciences and services journals from ML, HK and TW have greatly improved. ML and HK have different strong points, while the gap with TW diminished. PMID- 26123737 TI - Interventional Radiology Symposium for Medical Students: Raising Awareness, Understanding, and Interest. PMID- 26123735 TI - Association of overjet and overbite with esthetic impairments of oral health related quality of life. AB - OBJECTIVE: Esthetics is an important part of quality of life and a frequent reason for orthodontic treatment demand. It was the aim of this study to investigate whether esthetic impairments, related to overjet and overbite, can be assessed with an established oral health-related quality of life instrument. MATERIALS AND METHODS: Data from 1968 participants (age: 16-90 years; 69.8% female) from three German surveys were analyzed. Esthetic impairments of oral health-related quality of life were measured with four questions of the Oral Health Impact profile (OHIP), which comprise esthetic aspects of oral health related quality of life. Higher values represent greater esthetic impairment (sum score: 0-16). Overbite and overjet values were categorized (<= - 1 mm, 0-1 mm, 2 3 mm, 4-5 mm, >= 6 mm). The specific impact of each category on esthetic impairment, in relation to the reference category (2-3 mm), was calculated in linear regression analyses. The type of relationship and the specific impact of overbite and overjet were evaluated in regression analyses with fractional polynomials. RESULTS: Overbite ranged from - 5 to 15 mm (mean: 3.2 mm) and overjet from - 7 to 19 mm (mean: 3.1 mm). Both an increase and a decrease in overjet, in relation to the reference category, resulted in more esthetic-related oral health-related quality of life impairments. However, in this model, only the effect for increased overjet was statistically significant (4-5 mm: + 0.4 OHIP points; >= 6 mm: + 0.9 OHIP points). In the regression analysis with fractional polynomials, both an increase and a decrease in overjet resulted in more esthetic impairments, characterized by a U-shaped relationship. No association could be verified for overbite. CONCLUSION: A substantial increase or decrease of overjet from the reference values is associated with esthetic impairments of oral health related quality of life, whereas the extent of overbite seems to have no impact on esthetics. PMID- 26123738 TI - A multicenter cardiovascular MR network for tele-training and beyond: setup and initial experiences. AB - PURPOSE: Training in cardiovascular MR (CMR) is an important topic in times of growing acceptance of the method for accurate diagnosis and management of cardiovascular disease. However, off-site training is becoming less acceptable with increasing cost and time pressures. We introduce a novel CMR network, capable of providing, remotely, part of CMR training and continuous expert support. By providing a technical and operational blueprint, we want to share our experience in building teaching networks. METHODS: Conceptual, technical, and content-related characteristics of our teaching methods are introduced. A total of 97 participants in traditional fellowship CMR teaching and novel module-based network teaching were surveyed to assess their CMR performance. RESULTS: The number of hospitals in our CMR network increased from five in 2009 to 14 in 2014. A total of 79% of network hospitals conducted >100 CMR scans annually. Among these network hospitals are four small institutions (<400 beds), and five medium sized hospitals (400-1,000 beds). Network teaching reduced off-site training to only five weeks. The time to the first independently conducted CMR scans was one week, with network teaching, but >1 month for 32% of participants in traditional CMR teaching. The CMR network enables experts from distant locations to supervise and control CMR scans in a distant hospital, in real time. CONCLUSIONS: CMR networks provide an efficient teaching platform with a minimum of off-site time for trainees. Real-time remote supervision and scan control capabilities support the decentralization of CMR expertise and enables even small and rurally located institutions to offer high-quality CMR scans. PMID- 26123739 TI - A simple model for exploring the role of quantum coherence and the environment in excitonic energy transfer. AB - We investigate the role of quantum coherence in modulating the energy transfer rate between two independent energy donors and a single acceptor participating in an excitonic energy transfer process. The energy transfer rate depends explicitly on the nature of the initial coherent superposition state of the two donors and we connect it to the observed absorption profile of the acceptor and the stimulated emission profile of the energy donors. We consider simple models with mesoscopic environments interacting with the donors and the acceptor and compare the expression we obtained for the energy transfer rate with the results of numerical integration. PMID- 26123740 TI - The Tenth Step of the BFHI: What midwives need to know about optimal support for mothers, post-discharge. AB - This commentary discusses the 10th Step of the Baby-Friendly Hospital Initiative (BFHI), the only step that goes beyond the hospital to provide for the mother to receive breast-feeding support after she returns to the community. The reasons why such support is needed, and how this support has been provided in different settings, will be discussed. Post-discharge support for breast-feeding mothers takes many forms and is optimised when mothers can access both professional and peer support. The mother-baby dyad is best served by the right advice from the right person at the right time. Midwives who assist the new mother with information about easily accessible support in the community enable the care she has received during her short hospital stay and during any midwifery home visiting to continue when she is in an environment that may not be supportive of breast feeding. PMID- 26123741 TI - A realist evaluation of an antenatal programme to change drinking behaviour of pregnant women. AB - OBJECTIVE: to use realist evaluation to describe and explain how and in what circumstances screening and alcohol brief interventions work in routine antenatal care. DESIGN: a realist evaluation incorporating systematic reviews and qualitative data. SETTING: NHS Lothian, which is one of the 14 Scottish health boards. PARTICIPANTS: participants were recruited from two maternity units. In phase one, interviews were conducted with four participants responsible for policy implementation. These data were supported by two systematic reviews. In phase two, 17 pregnant women and 15 midwives participated in interviews, with a further six midwifery team leaders involved in a focus group. FINDINGS: training and resources provided to midwives as part of the programme acted as facilitating mechanisms that improved their skills and confidence to screen and deliver alcohol brief interventions. The programme elicited positive change in attitudes to drinking in pregnancy and possibly stimulated drinking behaviour change amongst pregnant women. However, the small numbers of pregnant women being identified for alcohol brief interventions meant delivery was infrequent and resulted in the programme not working as anticipated. The findings also revealed contextual issues around midwife-pregnant woman relationship and the challenges of negotiating the timing of screening and alcohol brief interventions delivery. CONCLUSIONS: Drinking in pregnancy is an emotive issue, therefore delivering alcohol brief interventions at the first antenatal appointment when they are more likely to achieve the most benefits poses challenges. When training midwives to screen and deliver alcohol brief interventions, special attention is needed to improve person-centred communication skills to overcome barriers associated with discussing sensitive prenatal alcohol use and enhance early identification and delivery of alcohol brief interventions at the first antenatal appointment. PMID- 26123743 TI - Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes. AB - The mechanism of perturbed immune function in patients with T2DM is poorly understood. Recent studies imply a role for ER stress in linking immune-system alterations and metabolism. Here, we investigated whether ER stress markers and its downstream effector signals are altered in patients with type 2 diabetes along with proinflammatory augmentation. In our study, gene and protein expression of ER stress markers (GRP-78, PERK, IRE1alpha, ATF6, XBP-1 and CHOP) was elevated significantly (P < 0.05) in PBMCs from T2DM patients compared with control subjects. The mRNA expression of both the proinflammatory cytokines (TNF alpha and IL-6) and oxidative stress markers (p22(phox), TXNIP, and TRPC-6; P < 0.05) was also increased in PBMCs from patients with T2DM. SOCS3 mRNA expression was reduced significantly (P < 0.05) in diabetes patients. mRNA expression of most of the ER stress markers from PBMCs correlated significantly and positively with poor glycemic control, dyslipidemia, IR, and inflammatory and oxidative stress markers. Chronic ER stress in PBMCs from patients with T2DM was evident from the increased caspase-3 activity (P < 0.01), which is an executioner of apoptosis. Along with an impairment of miR-146a levels, the downstream targets of miR-146a, viz., IRAK1 and TRAF6 mRNA levels, were also elevated significantly (P < 0.01) in patients with T2DM. There was an inverse relationship among miR-146a levels and ER stress markers, inflammatory markers, and glycemic control. We demonstrate evidence of increased ER stress markers with impaired miR-146a levels and increased proinflammatory signals in patients with type 2 diabetes. PMID- 26123742 TI - PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study, pre-operative recognition of high risk endometrial carcinoma: a multicentre prospective cohort study. AB - BACKGROUND: Endometrial carcinoma is the most common gynaecologic malignancy in industrialised countries and the incidence is still rising. Primary treatment is based on preoperative risk classification and consists in most cases of hysterectomy with bilateral salpingo-oophorectomy. In patients with serous and clear cell histology a complete surgical staging is mandatory. However, in routine clinical practice final histology regularly does not correspond with the preoperative histological diagnosis. This results in both over and under treatment. METHODS/DESIGN: The aim of this multicentre, prospective cohort study is to select a panel of prognostic biomarkers to improve preoperative diagnosis of endometrial carcinoma in order to identify those patients that need extended surgery and/or additional treatment. Additionally, we will determine whether incorporation of cervical cytology and comorbidity could improve this preoperative risk classification. All patients treated for endometrial carcinoma in the participating hospitals from September 2011 till December 2013 are included. Patient characteristics, as well as comorbidity are registered. Patients without preoperative histology, history of hysterectomy and/or endometrial carcinoma or no surgical treatment including hysterectomy are excluded. The preoperative histology and final pathology will be reviewed and compared by expert pathologists. Additional immunohistochemical analysis of IMP3, p53, ER, PR, MLH1, PTEN, beta-catenin, p16, Ki-67, stathmin, ARID1A and L1CAM will be performed. Preoperative histology will be compared with the final pathology results. Follow-up will be at least 24 months to determine risk factors for recurrence and outcome. DISCUSSION: This study is designed to improve surgical treatment of endometrial carcinoma patients. A total of 432 endometrial carcinoma patients were enrolled between 2011 and 2013. Follow-up will be completed in 2015. Preoperative histology will be evaluated systematically and background endometrium will be classified. This is the first study incorporating immunohistochemistry, cervical cytology and comorbidity to define the optimal panel of prognostic biomarkers that contribute in clinical decision making in the management of endometrial carcinoma. TRIAL REGISTRATION: Netherlands Trial Register number NTR3503. PMID- 26123745 TI - Sub-functionalization to ovule development following duplication of a floral organ identity gene. AB - Gene duplications result in paralogs that may be maintained due to the gain of novel functions (neo-functionalization) or the partitioning of ancestral function (sub-functionalization). Plant genomes are especially prone to duplication; paralogs are particularly widespread in the floral MADS box transcription factors that control organ identity through the ABC model of flower development. C class genes establish stamen and carpel identity and control floral meristem determinacy, and are largely conserved across the angiosperm phylogeny. Originally, an additional D class had been identified as controlling ovule identity; yet subsequent studies indicated that both C and D lineage genes more commonly control ovule development redundantly. The ranunculid Thalictrum thalictroides has two orthologs of the Arabidopsis thaliana C class gene AGAMOUS (AG), ThtAG1 and ThtAG2 (Thalictrum thalictroides AGAMOUS1/2). We previously showed that ThtAG1 exhibits typical C class function; here we examine the role of its paralog, ThtAG2. Our phylogenetic analysis shows that ThtAG2 falls within the C lineage, together with ThtAG1, and is consistent with previous findings of a Ranunculales-specific duplication in this clade. However, ThtAG2 is not expressed in stamens, but rather solely in carpels and ovules. This female-specific expression pattern is consistent with D lineage genes, and with other C lineage genes known to be involved in ovule identity. Given the divergent expression of ThtAG2, we tested the hypothesis that it has acquired ovule identity function. Molecular evolution analyses showed evidence of positive selection on ThtAG2-a pattern that supports divergence of function by sub-functionalization. Down regulation of ThtAG2 by virus-induced gene silencing resulted in homeotic conversions of ovules into carpel-like structures. Taken together, our results suggest that, although ThtAG2 falls within the C lineage, it has diverged to acquire "D function" as an ovule identity gene, and does not appear to require a direct interaction with the ThtAG1 protein. We therefore present a functional example of ovule identity being specified by either a single gene or a gene pair within the C lineage, with no D lineage contribution. In conclusion, following a Ranunculales-wide duplication in the AG lineage, functional divergence has led to the evolution of ovule identity-specificity in a T. thalictroides C lineage gene. PMID- 26123744 TI - The KCNE2 K+ channel regulatory subunit: Ubiquitous influence, complex pathobiology. AB - The KCNE single-span transmembrane subunits are encoded by five-member gene families in the human and mouse genomes. Primarily recognized for co-assembling with and functionally regulating the voltage-gated potassium channels, the broad influence of KCNE subunits in mammalian physiology belies their small size. KCNE2 has been widely studied since we first discovered one of its roles in the heart and its association with inherited and acquired human Long QT syndrome. Since then, physiological analyses together with human and mouse genetics studies have uncovered a startling array of functions for KCNE2, in the heart, stomach, thyroid and choroid plexus. The other side of this coin is the variety of interconnected disease manifestations caused by KCNE2 disruption, involving both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia. Kcne2 deletion in mice has been particularly instrumental in illustrating the potential ramifications within a monogenic arrhythmia syndrome, with removal of one piece revealing the unexpected complexity of the puzzle. Here, we review current knowledge of the function and pathobiology of KCNE2. PMID- 26123746 TI - RNA interference-mediated knockdown of Smad1 inhibits receptor activator of nuclear factor kappaB ligand expression induced by BMP-2 in primary osteoblasts. AB - OBJECTIVE: BMP-2 induces osteoblast differentiation and activates osteoclast formation. Here, we investigated the role of Smad1, a molecule that signals downstream of BMP-2, in mediating the effects of BMP-2 on osteoclast differentiation induced by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in osteoblasts. DESIGN: The effects of 1,25(OH)2D3 and BMP-2 in osteoclasts were examined using polymerase chain reaction and Western blotting to measure changes in target gene and protein expression. Immunostaining was carried out to investigate the localization of the vitamin D receptor (VDR) in the nucleus in response to BMP-2. RESULTS: Stimulation with both 1,25(OH)2D3 and BMP-2 resulted in significantly greater osteoclast formation and receptor activator of nuclear factor kappaB ligand (RANKL) mRNA expression compared to stimulation with 1,25(OH)2D3 alone. In addition, expression of the VDR protein was increased, enhancing the activity of 1,25(OH)2D3. Interestingly, knockdown of Smad1 resulted in reduced osteoclast formation, RANKL mRNA expression, and VDR protein expression compared with control cells. Costimulation with 1,25(OH)2D3 and BMP-2 enhanced VDR localization in the nucleus. CONCLUSIONS: We found that BMP-2 induced Smad1 activation, thereby influencing the localization of VDR in the nucleus in the presence of 1,25(OH)2D3 and resulting in increased RANKL mRNA expression. These effects ultimately resulted in enhanced osteoclast differentiation. PMID- 26123747 TI - Tormentic acid inhibits LPS-induced inflammatory response in human gingival fibroblasts via inhibition of TLR4-mediated NF-kappaB and MAPK signalling pathway. AB - OBJECTIVE: Periodontal disease is one of the most prevalent oral diseases, which is associated with inflammation of the tooth-supporting tissues. Tormentic acid (TA), a triterpene isolated from Rosa rugosa, has been reported to exert anti inflammatory effects. The aim of this study was to investigate the anti inflammatory effects of TA on lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (HGFs). METHODS: The levels of inflammatory cytokines such as interleukin (IL)-6 and chemokines such as IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). The expression of Toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-kappaB), IkappaBalpha, p38, extracellular signal regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) was determined by Western blotting. RESULTS: The results showed that Porphyromonas gingivalis LPS significantly upregulated the expression of IL-6 and IL-8. TA inhibited the LPS induced production of IL-6 and IL-8 in a dose-dependent manner. Furthermore, TA inhibited LPS-induced TLR4 expression; NF-kappaB activation; IkappaBalpha degradation; and phosphorylation of ERK, JNK, and P38. CONCLUSION: TA inhibits the LPS-induced inflammatory response in HGFs by suppressing the TLR4-mediated NF kappaB and mitogen-activated protein kinase (MAPK) signalling pathway. PMID- 26123748 TI - Response to tumor necrosis factor-alpha mediated inflammation involving activation of prostaglandin E2 and Wnt signaling in nucleus pulposus cells. AB - The cyclooxygenase 2 (COX-2) product, prostaglandin E2 (PGE2 ), acts through a family of G protein-coupled receptors designated E-prostanoid (EP) receptors that mediate intracellular signaling by multiple pathways. However, it is not known whether crosstalk between tumor necrosis factor-alpha(TNF-alpha)-PGE2 -mediated signaling and Wnt signaling plays a role in the regulation of intervertebral disc (IVD) cells. In this study, we investigated the relationship between TNF-alpha PGE2 signaling and Wnt signaling in IVD cells. TNF-alpha increased the expression of COX-2 in IVD cells. The EP receptors EP1, EP3, and EP4 were expressed in IVD cells, and TNF-alpha significantly increased PGE2 production. Stimulation with TNF-alpha also upregulated EP3 and EP4 mRNA and protein expression in IVD cells. The inductive effect of the EP3 and EP4 receptors on Topflash promoter activity was confirmed through gain- and loss-of-function studies using selective EP agonists and antagonists. PGE2 treatment activated Wnt-beta-catenin signaling through activation of EP3. We conclude that TNF-alpha-induced COX-2 and PGE2 stimulate Wnt signaling and activate Wnt target genes. Suppression of the EP3 receptor via TNF-alpha-PGE2 signaling seems to suppress IVD degeneration by controlling the activation of Wnt signaling. These findings may help identify the underlying mechanism and role of Wnt signaling in IVD degeneration. PMID- 26123749 TI - What are the relative merits of interventions used to reduce the occurrences of disruptive vocalisation in persons with dementia? - a systematic review. AB - INTRODUCTION: Dementia is a major health issue, and many people who have the progressive disease express disruptive vocalisation. These behaviours place large burdens on carers, family and on the individual themselves. BACKGROUND: This systematic review explored the use of interventions that could be used within practice to reduce the occurrences of disruptive vocalisation in people with dementia. METHODS: Three online databases (CINAHL, MEDLINE and EMBASE) were searched for papers published after 1997 against two concept criteria of dementia and disruptive vocalisation. Any person diagnosed with dementia or suspected of having dementia symptoms were included identifying any interventions. Studies were appraised and data extracted using the Joanna Briggs Institute frameworks. RESULTS: This systematic review identified eight relevant papers for inclusion, and these assessed the implementation of eight separate interventions that could be used within practice. Three interventions were found to be supported by statistically significant research: a staff training programme, a behavioural management technique using cue cards and hand massage. CONCLUSION: The overall conclusion is that the evidence base is insufficient to make recommendations for practice. However, the studies gave some indication of how research and practice might develop in this area. In particular, five elements were identified that appear to promote the best patient outcomes. These include making sure interventions are person-centred, individualised, adaptable, with the use of multiple approaches, carried out by staff trained in the identification of disruptive vocalisation and ways to avoid triggering these behaviours. IMPLICATIONS FOR PRACTICE: Triggers which lead to older people with dementia expressing disruptive vocalisation should be identified. Multiple individualised interventions should be used to reduce the occurrences of the disruptive vocalisation. PMID- 26123750 TI - Mutation analysis of SLC3A1 and SLC7A9 genes in patients with cystinuria. AB - Cystinuria is an autosomal inherited disorder of renal reabsorption of cystine, arginine, lysine, and ornithine. Increased urinary excretion of cystine results in the formation of kidney stones. Considering the few studies on the genetic basis of the cystinuria in the Middle East and the population-specific distribution of mutations in the SLC3A1 and SLC7A9 genes, in the present study, mutation analysis of these two genes was performed in a cohort of Iranian patients with cystinuria. Thirty unrelated cystinuria patients were analyzed for four of the most common mutations using ARMS-PCR (M467T, T216M) and RFLP-PCR (G105R, R333W) methods. For negative sample, two exons of both genes, which harbor many mutations, were subject to DNA sequencing. Eight variants were identified including missense, polymorphism, intron variant, and a novel variant. The most frequent mutations were not detected in our patients and only G105R was found. Since the molecular genetic testing results may influence the therapy and prognosis of cystinuria, this paper contributes to understanding of the molecular basis of cystinuria in the Iranian patients. PMID- 26123751 TI - Antilithic effects of extracts from different polarity fractions of Desmodium styracifolium on experimentally induced urolithiasis in rats. AB - Desmodium styracifolium (D. styracifolium) has been widely used in traditional Chinese medicine for the treatment of urolithiasis. This work was undertaken to investigate extracts from different polarity fractions of D. styracifolium for possible antilithic effects as well as antioxidant potential to explore the underlying phytochemically active constituents of this plant. The extracts of D. styracifolium were divided into four different polarity fractions by petroleum ether (Fr. PE), chloroform (Fr. CH), ethyl acetate (Fr. EA), and n-butyl alcohol (Fr. NB). The antilithic and antioxidant effects were evaluated and compared in vivo on an animal model of calcium oxalate (CaOx) urolithiasis, which was established by administration of 1 % ethylene glycol along with 2 % ammonium chloride in drinking water for 28 days. A total of 60 male Sprague-Dawley rats were randomly divided into six groups: normal control group, lithogenic group, and four different polarity fractions of D. styracifolium-treated groups. At the end of the study, urine, blood, and kidney tissue samples were all collected for evaluation. Among the four polarity fractions of D. styracifolium extracts, the Fr. PE and Fr. NB treatment significantly reduced the CaOx crystal deposition in kidneys, prevented the renal toxic changes like pH, Cr, and BUN. In addition, Fr. PE and Fr. NB treatment significantly decreased urinary excretion of oxalate along with a increase of citrate excretion. The increased amounts of malondialdehyde and decreased activities of superoxide dismutase, catalase, and glutathione peroxidase were detected in lithogenic group, D. styracifolium extracts treatment prevented the oxidative stress changes especially for the Fr. PE and Fr. NB extracts. In conclusion, our data suggest that the extracts from D. styracifolium possess the antiurolithic activity, possibly mediated through the inhibition of CaOx crystal aggregation as well as the alleviation of oxidative injury in the kidney, and the Fr. PE and Fr. NB extracts are the active fractions of D. styracifolium extract. PMID- 26123752 TI - Tubeless percutaneous nephrolithotomy with non-absorbable hemostatic sealant (Quikclot(r)) versus nephrostomy tube placement: a propensity score-matched analysis. AB - The purpose of this study was to determine the efficacy and safety of tubeless percutaneous nephrolithotomy (PNL) using a non-absorbable hemostatic sealant (Quikclot((r))) as an adjunct compared to nephrostomy tube placement in patients exhibiting significant parenchymal bleeding following PNL. We identified 113 PNL cases performed between May 2011 and October 2014. For patients with insignificant parenchymal bleeding following stone removal, defined as a clear visualization of the surgical field at full irrigation of the nephroscope, tubeless PNL was performed. For patients with significant parenchymal bleeding, we introduced the tubeless Quikclot((r)) technique as of September 2013 and have performed it ever since. Formerly, nephrostomy placement PNL was performed. In this study, 40 Quikclot((r)) applied PNL cases were matched with an equal number of nephrostomy placement cases by propensity scoring based on body mass index, stone size, and Guy's stone score. The mean postoperative drop in hematocrit was comparative between the Quikclot((r)) group and the nephrostomy group on both postoperative days 1 (p = 0.459) and 2 (p = 0.325). Quikclot((r)) application was associated with lower VAS scores throughout the postoperative period, lower cumulative analgesic requirement (p = 0.025), and with shorter hospitalization (p = 0.002). Complication rates were comparable with no need for blood transfusions in any patients. Tubeless Quikclot((r)) PNL was safe and provided effective hemostasis of significant parenchymal bleeding. By avoiding nephrostomy placement, we were able to reduce postoperative pain, analgesic requirements, and hospitalization. Application of Quikclot((r)) may be considered prior to nephrostomy placement in patients with significant parenchymal bleeding. PMID- 26123753 TI - Safety and efficacy of long-term tolvaptan therapy for decompensated liver cirrhosis. AB - AIM: Recently, the short-term efficacy of the vasopressin V2 receptor antagonist tolvaptan for the treatment of ascites in cirrhosis was reported. However, the long-term effects remain unknown. Here, we report the clinical features of decompensated cirrhosis treated using long-term tolvaptan therapy, and evaluate its safety and efficacy. METHODS: Fifty-five cirrhotic patients hospitalized due to ascites, despite receiving appropriate diuretic treatment, were treated with tolvaptan. We excluded 35 patients due to liver transplant (20.0%), death (28.6%), poor general status (14.3%), improved ascites (5.7%) or other reasons (31.4%). In 20 cases treated with tolvaptan for 6 months, total body water (TBW) and extracellular fluids (ECW) were measured using bioelectric impedance analysis (BIA) with an InBody720. RESULTS: The median age of the 20 patients was 64 years (range, 48-90), and 60% were male. The etiology of cirrhosis included hepatitis C (45%), alcohol-induced (20%) and other (35%). The percentage of patients with Child-Pugh class A, B and C was 0%, 40% and 60%, respectively. Biochemical findings revealed that serum creatinine levels and estimated glomerular filtration rate were not affected during 6 months of treatment with tolvaptan, and there was no renal disturbance. The median serum sodium levels were increased from 138 to 139 mEq/L, but serious adverse events related to renal and liver function were not observed. Data also revealed that long-term treatment reduced the BIA-estimated ECW/TBW ratio. CONCLUSION: Long-term tolvaptan treatment was a safe and effective treatment for decompensated cirrhosis. PMID- 26123754 TI - WT1 expression is increased in primary fibroblasts derived from Dupuytren's disease tissues. AB - Dupuytren's disease (DD) is a fibroproliferative and contractile fibrosis of the palmar fascia that, like all other heritable fibroses, is currently incurable. While DD is invariably benign, it exhibits some molecular similarities to malignant tumours, including increased levels of beta-catenin, onco-fetal fibronectin, periostin and insulin-like growth factor (IGF)-II. To gain additional insights into the pathogenesis of DD, we have assessed the expression of WT1, encoding Wilm's tumour 1, an established tumour biomarker that is syntenic with IGF2, the gene encoding IGF-II in humans. We found that WT1 expression is robustly and consistently up regulated in primary fibroblasts derived from the fibrotic palmar fascia of patients with DD (DD cells), whereas syngeneic fibroblasts derived from the macroscopically unaffected palmar fascia in these patients and allogeneic fibroblasts derived from normal palmar fascia exhibited very low or undetectable WT1 transcript levels. WT1 immunoreactivity was evident in a subset of cells in the fibrotic palmar fascia of patients with DD, but not in macroscopically unaffected palmar fascia. These findings identify WT1 expression as a novel biomarker of fibrotic palmar fascia and are consistent with the hypothesis that the pathogeneses of DD and malignant tumours have molecular similarities. PMID- 26123755 TI - Correlation between histological invasiveness and the computed tomography value in pure ground-glass nodules. AB - PURPOSE: The purpose of this study was to evaluate the correlation between histological invasiveness and the computed tomography (CT) value and size in pure ground-glass nodules (GGNs) to determine optimal "follow-up or resection" strategies. METHODS: Between 2001 and 2014, 78 resected, pure GGNs were retrospectively evaluated. The maximum diameter and CT value of pure GGNs were measured using a computer graphics support system. RESULTS: All GGNs with a maximum diameter <=10 mm and CT value <=-600 Hounsfield units (HU) were considered to be noninvasive lesions, while 21 of 26 (81 %) with a maximum diameter >10 mm and CT value >-600 HU were considered to be invasive lesions. With respect to the correlation between each histological type and pure GGN with a maximum diameter <=10 mm and CT value <=-600 HU, the specificity was 90 % and the sensitivity and negative predictive value were both 100 % in atypical adenomatous hyperplasia (AAH), while the specificity was 58 % and the sensitivity and positive predictive value were 0 % in minimally invasive and invasive adenocarcinoma. CONCLUSION: Pure GGNs with a maximum diameter of <=10 mm and CT value of <=-600 HU are nearly always pre-invasive lesions; therefore, surgery should be carefully selected in such patients. PMID- 26123756 TI - Alcohol Use and Sexual Risk Behaviors in a Migrant Worker Community. AB - There are not many studies exploring the association between alcohol use and risky sexual behaviors among migrant workers. This study analyzed how changes in alcohol use was associated with changes in risky sexual behavior and psychosocial variables. Data for this study was drawn from an HIV risk reduction project. Repeated measures ANOVA and Linear mixed model statistical method was conducted to find changes and association between alcohol use, sexual risk and psychosocial variables over time. The sample (n = 203) was composed of African Americans (33.0 %) and Hispanics (77.0 %) men. Both groups, over time, showed reduction in sexual risk in accordance with reduction in alcohol use. Changes in alcohol use and psychosocial variables showed significant association with sexual risk changes over time. Psychological strategies like building social support should be considered for HIV risk reduction intervention directed towards high alcohol consuming migrant workers. PMID- 26123758 TI - In vitro evaluation of random and aligned polycaprolactone/gelatin fibers via electrospinning for bone tissue engineering. AB - Scaffold, as an essential element of tissue engineering, should provide proper chemical and structural cues to direct tissue regeneration. In this study, aligned and random polycaprolactone (PCL)/gelatin fibrous scaffolds with different mass ratio were electrospun. Chemical, structural, and mechanical properties of PCL/gelatin fibrous scaffolds were characterized by FTIR and tensile measurements. The average diameters of different groups were between 334.96 +/- 41.43 nm and 363.78 +/- 50.49 nm. Blending PCL with gelatin increased the mechanical properties of the scaffolds. The cell culture results demonstrated that the mass ratio of PCL and gelatin showed no obvious effects on cell behavior, whereas the cell growth behavior was affected by the fibers orientation. Higher elongation ratio, enhanced cell proliferation and elevated alkaline phosphatase activity were observed for cells cultured on aligned fibers. The findings in our research provide insightful information for the design and fabrication of scaffolds for bone tissue engineering. PMID- 26123757 TI - Bypass of a 5',8-cyclopurine-2'-deoxynucleoside by DNA polymerase beta during DNA replication and base excision repair leads to nucleotide misinsertions and DNA strand breaks. AB - 5',8-Cyclopurine-2'-deoxynucleosides including 5',8-cyclo-dA (cdA) and 5',8-cyclo dG (cdG) are induced by hydroxyl radicals resulting from oxidative stress such as ionizing radiation. 5',8-cyclopurine-2'-deoxynucleoside lesions are repaired by nucleotide excision repair with low efficiency, thereby leading to their accumulation in the human genome and lesion bypass by DNA polymerases during DNA replication and base excision repair (BER). In this study, for the first time, we discovered that DNA polymerase beta (pol beta) efficiently bypassed a 5'R-cdA, but inefficiently bypassed a 5'S-cdA during DNA replication and BER. We found that cell extracts from pol beta wild-type mouse embryonic fibroblasts exhibited significant DNA synthesis activity in bypassing a cdA lesion located in replication and BER intermediates. However, pol beta knock-out cell extracts exhibited little DNA synthesis to bypass the lesion. This indicates that pol beta plays an important role in bypassing a cdA lesion during DNA replication and BER. Furthermore, we demonstrated that pol beta inserted both a correct and incorrect nucleotide to bypass a cdA at a low concentration. Nucleotide misinsertion was significantly stimulated by a high concentration of pol beta, indicating a mutagenic effect induced by pol beta lesion bypass synthesis of a 5',8 cyclopurine-2'-deoxynucleoside. Moreover, we found that bypass of a 5'S-cdA by pol beta generated an intermediate that failed to be extended by pol beta, resulting in accumulation of single-strand DNA breaks. Our study provides the first evidence that pol beta plays an important role in bypassing a 5',8-cyclo-dA during DNA replication and repair, as well as new insight into mutagenic effects and genome instability resulting from pol beta bypassing of a cdA lesion. PMID- 26123759 TI - Measuring wheelchair confidence among power wheelchair users: an adaptation of the WheelCon-M using focus groups and a think aloud process. AB - PURPOSE: The aim of this study was to adapt the WheelCon-M, an outcome measure used to assess confidence with manual wheelchair use, into a version that is applicable for power wheelchair users (WheelCon-P). METHODS: Adaptation of the WheelCon-M into the WheelCon-P occurred in two phases: (1) item modification was conducted using focus groups and (2) item refinement was done using a think aloud process. RESULTS: The healthcare professionals (n = 12) were mostly female, mostly occupational therapists and practiced an average of 14 years. The power wheelchair users (n = 8) were 50% men with an average of 8 years of power wheelchair experience and a range of diagnoses. In phase 1, of the 63 WheelCon-M items, 6 remained the same, 18 were removed, 38 modified and 15 new items added to develop the WheelCon-P. In phase 2, 15 WheelCon-P items were refined. CONCLUSIONS: This study resulted in the modification of the WheelCon-M into the WheelCon-P, a 59-item, self-report outcome measure designed to assess confidence with power wheelchair use. The next step in the evolution of this promising new measure is the assessment of its measurement properties. Implications for Rehabilitation The WheelCon-P is a new outcome measure designed to assess confidence with power wheelchair use. This study suggests that the items in this measure will be interpreted as intended. PMID- 26123760 TI - P53 codon 72 polymorphism, human papillomavirus infection, and their interaction to oral carcinoma susceptibility. AB - BACKGROUND: Tumor suppressor gene p53 plays an important role in the maintenance of the genomic integrity, and mutation in the gene may alter an individual's susceptibility to various carcinomas. P53 Arg72Pro or codon 72 polymorphism has been indicated to increase the risk of developing certain cancers such as bladder cancer and cervical cancer. Human papillomavirus (HPV) infection has been shown as a risk factor for certain cancers such as cervical cancer and oral cancer as well, and the HPV oncoprotein E6 may induce the degradation of p53 function. However, the association between p53 Arg72Pro polymorphism and the risk of oral cancer with HPV infection remains inconclusive. Therefore, this meta-analysis involving 5,614 participants was performed to investigate the relations among the p53 Arg72Pro polymorphism, HPV infection, and the risk of developing oral cancer. RESULTS: A search of the literature by PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases was conducted to identify studies based on the inclusion and exclusion criteria. Odds ratios with 95% confidence intervals were combined using a random-effect model or a fixed-effect model. The current study was conducted with 13 studies consisting of 2,413 cases and 3,201 controls. Neither overall analysis nor stratified analyses detected any obvious evidence of association between p53 Arg72Pro polymorphism and oral cancer susceptibility in all genetic models. However, a significant association between p53 Arg72Pro polymorphism and the risk of oral cancer with HPV infection was detected in the Arg/Arg vs. Arg/Pro + Pro/Pro model. CONCLUSION: In the current meta-analysis which used the quantitative data synthesis for the first time, our study demonstrated that p53 Arg72Pro polymorphism together with HPV infection might jointly alter an individual's susceptibility to the risk of oral cancer. Our results suggested that p53 Arg72Pro polymorphism may partly contribute to the pathogenesis of oral cancer development. PMID- 26123761 TI - The quality of life in acromegalic patients with biochemical remission by surgery alone is superior to that in those with pharmaceutical therapy without radiotherapy, using the newly developed Japanese version of the AcroQoL. AB - PURPOSE: To develop a Japanese version of the acromegaly quality of life (QoL) questionnaire (AcroQoL) and investigate the factors associated with impaired QoL in patients with acromegaly. METHODS: We developed a Japanese version of the AcroQoL by a forward-backward method and evaluated QoL in 38 patients with acromegaly who had been followed up at an outpatient clinic at Kobe University Hospital. Its reliability was examined with Cronbach's alpha and item-total correlations. Second examination was performed for concurrent validity by assessment of correlations with the Short Form-36 (SF-36) and longitudinal analysis of the AcroQoL in 25 patients. RESULTS: Cronbach's alpha and item-total correlations showed a range of 0.76-0.93 and 0.20-0.84, respectively, and significant correlations were found between the AcroQoL and the SF-36. Younger age and a history of radiotherapy were associated with worse total score by the multivariate linear regression analysis (p = 0.020 and p = 0.042, respectively). Intriguingly, in the biochemically-controlled group after the exclusion of patients who received radiotherapy, patients who underwent surgery alone exhibited a higher psychological (75.0 vs. 65.7 %, p = 0.036) and appearance (64.3 vs. 53.6 %, p = 0.036) score than those who are treating with pharmaceutical therapy. CONCLUSIONS: The reliability of the Japanese version of the AcroQoL was satisfactory. Younger age and a history of radiotherapy were associated with lower QoL in patients with acromegaly. In biochemically controlled acromegaly, patients who underwent surgery alone exhibited better QoL than those under pharmaceutical therapy. PMID- 26123762 TI - Cultural Connections: the Key to Retention of Black, Latina, and Arab Women in the Kin Keeper(SM) Cancer Prevention Intervention Studies. AB - Diverse racial and ethnic populations must be included in research studies in order to address health disparities. Retaining hard-to-reach populations including poor, underserved, and racial/ethnic groups in longitudinal studies can be quite difficult. Using innovative retention strategies that address culture and community are imperative. The objective of this report is to identify and describe strategies for successful retention rates among a unique group of hard to-reach racial/ethnic participants. We analyzed the follow-up rates in two different cohorts using the Kin Keeper(SM) study design. The aim of Study A was to examine the capability of the Kin Keeper(SM) education to increase health literacy in breast and cervical cancer. The primary aim of Study B was to measure changes in breast and cervical cancer screening after receiving the Kin Keeper(SM) education. Retention rates were analyzed and compared over 12 months for both cohorts. We found good retention rates for both cohorts with each having a unique set of differences. The overall follow-up rate was 82 % for Study A and 88 % for Study B with demographic differences between the studies reported herein. Despite changing cultural, community, and geopolitical factors, we were able to maintain consistent participation for each study. We attribute high retention rates to trusted cultural connections and the flexibility to adjust retention strategies. PMID- 26123763 TI - PEP Talk: Prostate Education Program, "Cutting Through the Uncertainty of Prostate Cancer for Black Men Using Decision Support Instruments in Barbershops". AB - The objective of this study was to investigate the effectiveness of using decision support instruments (DSI) to assist African-American (AA) men in making a prostate cancer (CaP) screening decision. This nonrandomized pretest-posttest comparison study assessed two DSI that were either culturally tailored or culturally nonspecific. CaP knowledge, intention to screen, and preferences were assessed before and after exposure to DSI using a convenience sample of 120 AA men aged 40 years and above. Participants interested in screening were referred to healthcare providers through a community-based patient navigator to obtain prostate-specific antigen (PSA) testing. We followed up 3 months after to determine if participants screened for CaP. CaP knowledge increased following exposure to both DSI in equivalent proportions. While similar proportions of men ultimately intended on having a PSA test following both DSI, bivariate analysis revealed that the culturally tailored DSI demonstrated a statistically significant increase in intention to screen. Participants' degree of certainty in their decision-making process with regard to CaP screening increased following the culturally tailored DSI (p < .001). The majority of participants planned on discussing CaP screening with a healthcare provider upon completion of the study. Barbershop-based health education can change the knowledge, preferences, intentions, and behaviors of this at-risk population. At 3 months follow-up, half (n = 58) of the participants underwent PSA testing, which led to the diagnosis of CaP in one participant. Community-led interventions for CaP, such as cluster randomized designs in barbershops, are needed to better assess the efficacy of DSI in community settings. PMID- 26123764 TI - A Nationwide Medical Student Assessment of Oncology Education. AB - Cancer is the second leading cause of death in the USA, but there is minimal data on how oncology is taught to medical students. The purpose of this study is to characterize oncology education at US medical schools. An electronic survey was sent between December 2014 and February 2015 to a convenience sample of medical students who either attended the American Society for Radiation Oncology annual meeting or serve as delegates to the American Association of Medical Colleges. Information on various aspects of oncology instruction at participants' medical schools was collected. Seventy-six responses from students in 28 states were received. Among the six most common causes of death in the USA, cancer reportedly received the fourth most curricular time. During the first, second, and third years of medical school, participants most commonly reported 6-10, 16-20, and 6 10 h of oncology teaching, respectively. Participants were less confident in their understanding of cancer treatment than workup/diagnosis or basic science/natural history of cancer (p < 0.01). During the preclinical years, pathologists, scientists/Ph.D.'s, and medical oncologists reportedly performed the majority of teaching, whereas during the clinical clerkships, medical and surgical oncologists reportedly performed the majority of teaching. Radiation oncologists were significantly less involved during both periods (p < 0.01). Most schools did not require any oncology-oriented clerkship. During each mandatory rotation, <20 % of patients had a primary diagnosis of cancer. Oncology education is often underemphasized and fragmented with wide variability in content and structure between medical schools, suggesting a need for reform. PMID- 26123765 TI - Information concerning multidrug-resistant bacterial colonization or infection in the medical transfer letter. AB - OBJECTIVES: The aim of this study was to evaluate the proportion of transfer letters that contained information relative to infection or colonization by multidrug-resistant (MDR) bacteria and factors associated with the presence of that information. PATIENTS AND METHODS: Patients for whom at least one of these selected MDR bacteria (methicillin-resistant Staphylococcus aureus, extended spectrum beta-lactamase-producing Enterobacteriaceae, or MDR Pseudomonas aeruginosa) was isolated during their hospitalization and who were transferred to another health care facility between 2009 and 2012 were included. Information of the MDR bacterium and the mention of isolation precautions were evaluated in the electronic medical record. RESULTS: Information (mention of MDR bacterium or isolation precaution) was present in 57% [52; 65] of records. Full information (genus and species, concept of MDR bacterium and mention of isolation precaution) was found in 20% [16; 25]. The presence of a dedicated item in the standard medical discharge letter was associated with more frequent information. Less information was retrieved with P. aeruginosa cases than with the other 2 MDR bacteria. CONCLUSION: The presence of the information has improved, but it is still insufficiently reported. Measures to improve information are needed. Indeed, information on MDR bacterial colonization or infection is the first step for isolation precautions. An item could be added to all standard medical discharge letters. An item could also be added to the indicators used to assess quality and safety in healthcare facilities. PMID- 26123766 TI - Octupolar order in two dimensions. AB - Octupolar order is described in two space dimensions in terms of the maxima (and conjugated minima) of the probability density associated with a third-rank, fully symmetric and traceless tensor. Such a representation is shown to be equivalent to diagonalizing the relevant third-rank tensor, an equivalence which however is only valid in the two-dimensional case. PMID- 26123767 TI - Equilibrium gels of trivalent DNA-nanostars: Effect of the ionic strength on the dynamics. AB - Self-assembling DNA-nanostars are ideal candidates to explore equilibrium gelation in systems composed of limited-valence particles. We present here a light scattering study of the dynamics in a trivalent DNA-nanostars equilibrium gel and of its dependence on ionic strength and concentration. Reversible bonds between different nanostars, whose formation is sensitively dependent on temperature, concentration and ionic strength, are provided by complementary DNA sticky ends. We find that the decay of the density correlations is described by a two-step relaxation process characterised by: i) a slow time scale that varies over nearly four orders of magnitude in a temperature window of less than 30 degrees; ii) an increase of the amplitude (the so-called non-ergodicity factor) of the slow relaxation. The slow process follows an Arrhenius law with temperature. We observe that the activation enthalpy does not depend on the ionic strength and that the dependence of the relaxation time on the ionic strength can be rationalized in terms of the free-energy cost of forming a sticky-end duplex. Finally, we observe that dynamics is insensitive to nanostar concentration, in full agreement with the predicted behaviour in equilibrium gels. PMID- 26123768 TI - Wetting morphologies on randomly oriented fibers. AB - We characterize the different morphologies adopted by a drop of liquid placed on two randomly oriented fibers, which is a first step toward understanding the wetting of fibrous networks. The present work reviews previous modeling for parallel and touching crossed fibers and extends it to an arbitrary orientation of the fibers characterized by the tilting angle and the minimum spacing distance. Depending on the volume of liquid, the spacing distance between fibers and the angle between the fibers, we highlight that the liquid can adopt three different equilibrium morphologies: 1) a column morphology in which the liquid spreads between the fibers, 2) a mixed morphology where a drop grows at one end of the column or 3) a single drop located at the node. We capture the different morphologies observed using an analytical model that predicts the equilibrium configuration of the liquid based on the geometry of the fibers and the volume of liquid. PMID- 26123770 TI - Erratum to: Straight contact lines on a soft, incompressible solid. PMID- 26123769 TI - Macroscopic behavior of ferrocholesteric liquid crystals and ferrocholesteric gels and elastomers. AB - We study the influence of macroscopic chirality on the macroscopic properties of superparamagnetic liquid crystals and gels. Specifically we derive macroscopic dynamic equations for ferrocholesteric low molecular weight (LMW) liquid crystals and for ferrocholesteric gels and elastomers in the local description using the director field as macroscopic variable. The magnetization is treated as a macroscopic dynamic degree of freedom and its coupling to all other macroscopic variables is examined in detail. We incorporate into our dynamic analysis terms that are linear in a magnetic field giving rise to a number of cross-coupling terms not possible otherwise. A number of properties that are unique to the class of systems studied arise. As an example for a static property we find a term in the generalized energy which is linear in the electric field and quadratic in the magnetic field. We find that applying a magnetic field to a ferrocholesteric can lead to reversible electric currents, heat currents and concentration currents, which change their sign with a sign change of macroscopic chirality. As an example of a rather intriguing dissipative dynamic contribution we point out that for ferrocholesterics and for ferrocholesteric gels and elastomers in a magnetic field extensional flow leads to electric and heat currents. PMID- 26123771 TI - Foam-improved oil recovery: Modelling the effect of an increase in injection pressure. AB - A model, called pressure-driven growth, is analysed for propagation of a foam front through an oil reservoir during improved oil recovery using foam. Numerical simulations of the model predict, not only the distance over which the foam front propagates, but also the instantaneous front shape. A particular case is studied here in which the pressure used to drive the foam along is suddenly increased at a certain point in time. This transiently produces a concave front shape (seen from the domain ahead of the front): such concavities are known to be delicate to handle numerically. As time proceeds however, the front evolves back towards a convex shape, and this can be predicted by a long-time asymptotic analysis of the model. The increase in driving pressure is shown to be beneficial to the improved oil recovery process, because it gives a more uniform sweep of the oil reservoir by the foam. PMID- 26123772 TI - Shear-enhanced adsorption of a homopolymeric globule mediated by surface catch bonds. AB - The adsorption of a single collapsed homopolymer onto a planar smooth surface in shear flow is investigated by means of Brownian hydrodynamics simulation. While cohesive intra-polymer forces are modeled by Lennard-Jones potentials, surface monomer interactions are described by stochastic bonds whose two-state kinetics is characterized by three parameters: bond formation rate, bond dissociation rate and an effective catch bond parameter that describes how the force acting on a surface-monomer bond influences the dissociation rate. We construct adsorption state diagrams as a function of shear rate and all three surface-monomer bond parameters. We find shear-induced adsorption in a small range of parameters for low dissociation and association rates and only when the surface-monomer bond is near the transition between slip and catch bond behavior. By mapping on a simple surface-monomer interaction model with conservative pair potentials we try to estimate the conservative potential parameters necessary to observe shear-induced surface adsorption phenomena. PMID- 26123773 TI - Monte Carlo simulation of kinetically slowed down phase separation. AB - Supercooled colloidal or molecular systems at low densities are known to form liquid, crystalline or glassy drops, which may remain isolated for a long time before they aggregate. This paper analyses the properties of this large time window, and how it can be tackled by computer simulation. We use single-particle and virtual move Monte Carlo simulations of short-range attractive spheres which are undercooled to the temperature region, where the spinodal intersects the attractive glass line. We study two different systems and we report the following kinetic behavior. A low-density system is shown to exhibit universal linear growth regimes under single-particle Monte Carlo correlating the growth rate to the local structure. These regimes are suppressed under collective motion, where droplets aggregate into a single large disordered domain. It is shown that the aggregation can be avoided and linear regimes recovered, if long-range repulsion is added to the short-range attraction. The results provide an insight into the behavior of the virtual move algorithm generating cluster moves according to the local forcefields. We show that different choices of maximum Monte Carlo displacement affect the dynamical trajectories but lead to the same kinetically slowed down or arrested states. PMID- 26123774 TI - Convection and fluidization in oscillatory granular flows: The role of acoustic streaming. AB - Convection and fluidization phenomena in vibrated granular beds have attracted a strong interest from the physics community since the last decade of the past century. As early reported by Faraday, the convective flow of large inertia particles in vibrated beds exhibits enigmatic features such as frictional weakening and the unexpected influence of the interstitial gas. At sufficiently intense vibration intensities surface patterns appear bearing a stunning resemblance with the surface ripples (Faraday waves) observed for low-viscosity liquids, which suggests that the granular bed transits into a liquid-like fluidization regime despite the large inertia of the particles. In his 1831 seminal paper, Faraday described also the development of circulation air currents in the vicinity of vibrating plates. This phenomenon (acoustic streaming) is well known in acoustics and hydrodynamics and occurs whenever energy is dissipated by viscous losses at any oscillating boundary. The main argument of the present paper is that acoustic streaming might develop on the surface of the large inertia particles in the vibrated granular bed. As a consequence, the drag force on the particles subjected to an oscillatory viscous flow is notably enhanced. Thus, acoustic streaming could play an important role in enhancing convection and fluidization of vibrated granular beds, which has been overlooked in previous studies. The same mechanism might be relevant to geological events such as fluidization of landslides and soil liquefaction by earthquakes and sound waves. PMID- 26123775 TI - A porous metal-organic framework with ultrahigh acetylene uptake capacity under ambient conditions. AB - Acetylene, an important petrochemical raw material, is very difficult to store safely under compression because of its highly explosive nature. Here we present a porous metal-organic framework named FJI-H8, with both suitable pore space and rich open metal sites, for efficient storage of acetylene under ambient conditions. Compared with existing reports, FJI-H8 shows a record-high gravimetric acetylene uptake of 224 cm(3) (STP) g(-1) and the second-highest volumetric uptake of 196 cm(3) (STP) cm(-3) at 295 K and 1 atm. Increasing the storage temperature to 308 K has only a small effect on its acetylene storage capacity (~200 cm(3) (STP) g(-1)). Furthermore, FJI-H8 exhibits an excellent repeatability with only 3.8% loss of its acetylene storage capacity after five cycles of adsorption-desorption tests. Grand canonical Monte Carlo simulation reveals that not only open metal sites but also the suitable pore space and geometry play key roles in its remarkable acetylene uptake. PMID- 26123776 TI - Educating future nursing scientists: Recommendations for integrating omics content in PhD programs. AB - Preparing the next generation of nursing scientists to conduct high-impact, competitive, sustainable, innovative, and interdisciplinary programs of research requires that the curricula for PhD programs keep pace with emerging areas of knowledge and health care/biomedical science. A field of inquiry that holds great potential to influence our understanding of the underlying biology and mechanisms of health and disease is omics. For the purpose of this article, omics refers to genomics, transcriptomics, proteomics, epigenomics, exposomics, microbiomics, and metabolomics. Traditionally, most PhD programs in schools of nursing do not incorporate this content into their core curricula. As part of the Council for the Advancement of Nursing Science's Idea Festival for Nursing Science Education, a work group charged with addressing omics preparation for the next generation of nursing scientists was convened. The purpose of this article is to describe key findings and recommendations from the work group that unanimously and enthusiastically support the incorporation of omics content into the curricula of PhD programs in nursing. The work group also calls to action faculty in schools of nursing to develop strategies to enable students needing immersion in omics science and methods to execute their research goals. PMID- 26123777 TI - Comparative methane emission by ratites: Differences in food intake and digesta retention level out methane production. AB - Ratites differ in the anatomy of their digestive organs and their digesta excretion patterns. Ostriches (Struthio camelus) have large fermentation chambers and long digesta retention, emus (Dromaius novaehollandiae) have a short gut and short retention times, and rheas (Rhea americana) are intermediate. A recent study showed that ostriches produce as much methane (CH4) as expected for a similar-sized, non-ruminant mammalian herbivore. We hypothesized that emus and rheas produce less CH4 than ostriches. We individually measured, by chamber respirometry, the amount of O2 consumed as well as CO2 and CH4 emitted from six adult rheas (body mass 23.4+/-8.3 kg) and two adult emus (33.5 and 32.0 kg) during 23-hour periods on a pelleted lucerne diet. In contrast to previous studies, which classified emus as non-producers, we measured CH4 emissions at 7.39 and 6.25 L/day for emus and 2.87+/-0.82 L/day for rheas, which is close to values expected for similar-sized non-ruminant mammals for both species. O2 consumption was of a similar magnitude as reported previously. Across ratites, CH4 yield (L/kg dry matter intake) was positively correlated with mean retention time of food particles in the gut, similar to findings within ruminant species. In ratites, this relationship leads to similar body mass-specific CH4 production for a high intake/short retention and a low intake/long retention strategy. Therefore, when investigating CH4 production in herbivorous birds, it is advisable to consider various CH4 measures, not only yield or absolute daily amount alone. PMID- 26123778 TI - Effects of feed restriction on salinity tolerance in white sturgeon (Acipenser transmontanus). AB - A multistressor study was conducted to investigate interactive effects of nutritional status and salinity on osmoregulation of juvenile white sturgeon. Our hypothesis was that lower nutritional status would decrease the salinity tolerance of juvenile white sturgeon. A four-week feed restriction (12.5%, 25%, 50%, 100% of optimum feeding rate: OFR defined as the rate (% body weight per day) at which growth is maximal) trial was performed, and relevant indices of nutritional status were measured. Following the trial, sturgeon were acutely exposed to various salinities (0, 8, 16, 24 ppt) for 120 h, and relevant osmoregulatory measurements were made at 12, 72, and 120 h post-salinity exposures. The feed-restriction trial resulted in a graded nutritional response with the most feed-restricted group (12.5% OFR) showing the lowest nutritional status. The salinity exposure trial showed clear evidence that lower nutritional status decreased the salinity tolerance of juvenile white sturgeon. Increasing salinities resulted in significant alterations in osmoregulatory indices of all feeding groups; however, a significantly slower acclimatory response to 24 ppt was detected in the most feed-restricted group compared to the non-feed restricted group (100% OFR). Furthermore, evaluation of the effect of nutritional status on the relationship between osmoregulatory measurements and body size showed that there was a significant negative relationship between osmoregulatory performance and body size within the most feed-restricted group. This suggests that there is a certain body size range (200-300 g based on our finding) where juvenile white sturgeon can maximize osmoregulatory capacity at a salinity of 24 ppt. PMID- 26123779 TI - Renal plasticity in response to feeding in the Burmese python, Python molurus bivittatus. AB - Burmese pythons are sit-and-wait predators that are well adapted to go long periods without food, yet subsequently consume and digest single meals that can exceed their body weight. These large feeding events result in a dramatic alkaline tide that is compensated by a hypoventilatory response that normalizes plasma pH; however, little is known regarding how plasma HCO3(-) is lowered in the days post-feeding. The current study demonstrated that Burmese pythons contain the cellular machinery for renal acid-base compensation and actively remodel the kidney to limit HCO3(-) reabsorption in the post-feeding period. After being fed a 25% body weight meal plasma total CO2 was elevated by 1.5-fold after 1 day, but returned to control concentrations by 4 days post-feeding (d pf). Gene expression analysis was used to verify the presence of carbonic anhydrase (CA) II, IV and XIII, Na(+) H(+) exchanger 3 (NHE3), the Na(+) HCO3(-) co-transporter (NBC) and V-type ATPase. CA IV expression was significantly down regulated at 3 dpf versus fasted controls. This was supported by activity analysis that showed a significant decrease in the amount of GPI-linked CA activity in isolated kidney membranes at 3 dpf versus fasted controls. In addition, V-type ATPase activity was significantly up-regulated at 3 dpf; no change in gene expression was observed. Both CA II and NHE3 expression was up regulated at 3 dpf, which may be related to post-prandial ion balance. These results suggest that Burmese pythons actively remodel their kidney after feeding, which would in part benefit renal HCO3(-) clearance. PMID- 26123780 TI - Cold acclimation increases levels of some heat shock protein and sirtuin isoforms in threespine stickleback. AB - Molecular chaperones [heat shock proteins (HSPs)] increase in response to rapid changes in temperatures, but long-term acclimation to cold temperature may also warrant elevations in HSPs. In fishes, cold acclimation increases mitochondrial density and oxidative stress in some tissues, which may increase demand for HSPs. We hypothesized that levels of HSPs, as well as sirtuins (SIRTs), NAD-dependent deacetylases that mediate changes in metabolism and responses to oxidative stress (including increases in HSPs), would increase during cold acclimation of threespine stickleback (Gasterosteus aculeatus). Transcript levels of hsp70, hsc70, hsp60 and hsp90-alpha, sirts1-4, as well as protein levels of HSP60, HSP90 and HSC70 were quantified in liver and pectoral adductor muscle of stickleback during cold acclimation from 20 degrees C to 8 degrees C. In liver, cold acclimation stimulated a transient increase in mRNA levels of hsp60 and hsc70. Transcript levels of sirt1 and sirt2 also increased in response to cold acclimation and remained elevated. In pectoral muscle, mRNA levels of hsp60, hsp90-alpha, hsc70 and sirt1 all transiently increased in response to cold acclimation, while levels of sirts2-4 remained constant or declined. Similar to transcript levels, protein levels of HSC70 increased in both liver and pectoral muscle. Levels of HSP90 also increased in liver after 4 weeks at 8 degrees C. HSP60 remained unchanged in both tissues, as did HSP90 in pectoral muscle. Our results indicate that while both HSPs and SIRTs increase in response to cold acclimation in stickleback, the response is tissue and isoform specific, likely reflecting differences in metabolism and oxidative stress. PMID- 26123781 TI - Australian trampoline injury patterns and trends. AB - OBJECTIVES: To examine national trampoline injury patterns and trends in the context of improved product safety standards and trampoline design modifications. METHOD: Review of National Hospital Morbidity data. RESULTS: There were an average 1,737 trampoline injuries reported nationally each year from 2002 to 2011. Both injury frequency and rate grew. Statistically significant rate increases were observed among all age groups, although both are highest among children aged 5-9 years. From 2008/09 there is a possible decreasing trend among the 5-9 age group. Falls predominate and 81% of falls result in fracture. Non fall injuries increased annually as a proportion of all hospitalised injury although they did not comprise more than 2.4% in any one year. CONCLUSIONS: History provides no evidence of an observable effect of voluntary Australian Standards for trampoline safety on population rates for trampoline injury. The major design modification--netted enclosures--could contribute to the risk of injury by leading parents to falsely believe that a netted enclosure eradicates the risk of injury. PMID- 26123782 TI - In vitro characterisation of the fermentation profile and prebiotic capacity of gold-fleshed kiwifruit. AB - A new Actinidia chinensis gold-fleshed kiwifruit cultivar 'Zesy002' was tested to investigate whether it could positively modulate the composition of the human colonic microbiota. Digested Zesy002 kiwifruit was added to in vitro pH controlled anaerobic batch fermenters that were inoculated with representative human faecal microbiota. Alterations to the gut microbial ecology were determined by 16S rRNA gene sequencing and metabolic end products were measured using gas chromatography and liquid chromatography - mass spectrometry. Results indicated a substantial shift in the composition of bacteria within the gut models caused by kiwifruit supplementation. Zesy002 supplemented microbiota had a significantly higher abundance of Bacteroides spp., Parabacteroides spp. and Bifidobacterium spp. after 48 h of fermentation compared with the start of the fermentation. Organic acids from kiwifruit were able to endure simulated gastrointestinal digestion and were detectable in the first 10 h of fermentation. The fermentable carbohydrates were converted to beneficial organic acids with a particular predilection for propionate production, corresponding with the rise in Bacteroides spp. and Parabacteroides spp. These results support the claim that Zesy002 kiwifruit non-digestible fractions can effect favourable changes to the human colonic microbial community and primary metabolites, and demonstrate a hitherto unknown effect of Zesy002 on colonic microbiota under in vitro conditions. PMID- 26123783 TI - Probiotics: can they be used to improve oral health? AB - The role of probiotic bacteria in improving human health has been an attractive subject for researchers since the beginning of the 20(th) century. They have been used to control gastro-intestinal infections, to promote immunity and to prevent various diseases (allergies, urogenital infections, etc.). However, the use of beneficial bacteria in the field of dentistry has only recently gained interest. Investigation of the effects of probiotic bacteria on oral health has become an important research subject. These studies are still in the early stages, however results show that probiotic bacteria are effective against tooth caries, periodontal disease, oral mucosal lesions and oral malodour. This review provides information on the effects of probiotics--well-known for their effects on general health, and therefore more widely used in healthcare--on oral and dental health, in order to promote their use/prescription by physicians and patients. PMID- 26123784 TI - Histo-FISH protocol to detect bacterial compositions and biofilms formation in vivo. AB - The study of biofilm function in vivo in various niches of the gastrointestinal tract (GIT) is rather limited. It is more frequently used in in vitro approaches, as an alternative to the studies focused on formation mechanisms and function of biofilms, which do not represent the actual in vivo complexity of microbial structures. Additionally, in vitro tests can sometimes lead to unreliable results. The goal of this study was to develop a simple approach to detect bacterial populations, particularly Lactobacillus and Bifidobacterium in biofilms, in vivo by the fluorescent in situ hybridisation (FISH) method. We standardised a new Histo-FISH method based on specific fluorochrome labelling probes which are able to detect Lactobacillus spp. and Bifidobacterium spp. within biofilms on the mucosal surface of the GIT embedded in paraffin in histological slices. This method is also suitable for visualisation of bacterial populations in the GIT internal content. Depending on the labelling probes, the Histo-FISH method has the potential to detect other probiotic strains or pathogenic bacteria. This original approach permits us to analyse bacterial colonisation processes as well as biofilm formation in stomach and caecum of BALB/c and germ-free mice. PMID- 26123785 TI - Probiotic lactobacilli: a potential prophylactic treatment for reducing pesticide absorption in humans and wildlife. AB - Numerous pesticides are used in agriculture, gardening, and wildlife-control. Despite their intended toxicity to pests, these compounds can also cause harm to wildlife and humans due to their ability to potentially bioaccumulate, leach into soils, and persist in the environment. Humans and animals are commonly exposed to these compounds through agricultural practices and consumption of contaminated foods and water. Pesticides can cause a range of adverse effects in humans ranging from minor irritation, to endocrine or nervous system disruption, cancer, or even death. A convenient and cost-effective method to reduce unavoidable pesticide absorption in humans and wildlife could be the use of probiotic lactobacilli. Lactobacillus is a genus of Gram-positive gut commensal bacteria used in the production of functional foods, such as yoghurt, cheese, sauerkraut and pickles, as well as silage for animal feed. Preliminary in vitro experiments suggested that lactobacilli are able to degrade some pesticides. Probiotic Lactobacillus rhamnosus GR-1-supplemented yoghurt reduced the bioaccumulation of mercury and arsenic in pregnant women and children. A similar study is warranted to test if this approach can reduce pesticide absorption in vivo, given that the lactobacilli can also attenuate reactive oxygen production, enhance gastrointestinal barrier function, reduce inflammation, and modulate host xenobiotic metabolism. PMID- 26123786 TI - Multiple organ embolization with vegetation on an elephant trunk graft. AB - We encountered a rare case of infection in a vascular graft created using the elephant trunk technique. A 65-year-old woman who underwent total arch replacement with the elephant trunk technique was re-admitted with fever. She developed embolization of multiple organs from vegetation attached to the elephant trunk graft which was elucidated by transesophageal echocardiography. Surgery for ruptured jejunal artery aneurysm was performed, and the graft infection healed after long-term antibiotic therapy with the prosthesis left in situ. Graft infection may generate vegetations on an elephant trunk graft. Transesophageal echocardiography is a helpful tool for accurate diagnosis. PMID- 26123787 TI - Prognostic and clinical impact of sarcopenia in esophageal squamous cell carcinoma. AB - Recently, depletion of skeletal muscle mass (sarcopenia) has been linked to poor prognosis in several types of cancers, but has not been investigated in esophageal squamous cell carcinoma (ESCC). This retrospective study investigates the relationship between sarcopenia and clinical outcome in ESCC patients treated by surgical resection or definitive chemoradiation therapy (dCRT). The study was retrospectively conducted in a single academic hospital in Kumamoto, Japan, and involved 325 ESCC patients (256 surgical cases and 69 dCRT cases) treated between April 2005 and April 2011. Skeletal muscle mass was quantified by radiologic measures using standard computed tomography scans. The skeletal muscle tissue in the 325 ESCC patients was distributed as follows: mean: 47.10; median: 46.88; standard deviation (SD): 7.39; range: 31.48-71.11; interquartile range, 46.29 47.90. Skeletal muscle tissue was greater in male patients than in female patients (P < 0.0001), but was independent of other clinical and tumor features. Sarcopenia was not significantly associated with overall survival (log rank P = 0.54). Lymph node involvement significantly altered the relationship between sarcopenia and survival rate (P for interaction = 0.026). Sarcopenia significantly reduced the overall survival of patients without lymph node involvement (log rank P = 0.035), but was uncorrelated with overall survival in patients with lymph involvement (log rank, P = 0.31). The anastomosis leakage rate was significantly higher in the sarcopenia group than in the non-sarcopenia group (P = 0.032), but other surgical complications did not significantly differ between the two groups. Sarcopenia in ESCC patients without lymph node involvement is associated with poor prognosis, indicating sarcopenia as a potential biomarker for identifying patients likely to experience an inferior outcome. Moreover, sarcopenia was associated with anastomosis leakage but no other short-term surgical outcome. PMID- 26123788 TI - Self-organized iron-oxide cementation geometry as an indicator of paleo-flows. AB - Widespread iron oxide precipitation from groundwater in fine-grained red beds displays various patterns, including nodulation, banding and scallops and fingers. Hematite nodules have been reported also from the Meridiani Planum site on Mars and interpreted as evidence for the ancient presence of water on the red planet. Here we show that such patterns can autonomously emerge from a previously unrecognized Ostwald ripening mechanism and they capture rich information regarding ancient chemical and hydrologic environments. A linear instability analysis of the reaction-transport equations suggests that a pattern transition from nodules to bands may result from a symmetry breaking of mineral dissolution and precipitation triggered by groundwater advection. Round nodules tend to develop under nearly stagnant hydrologic conditions, while repetitive bands form in the presence of persistent water flows. Since water circulation is a prerequisite for a sustainable subsurface life, a Martian site with iron oxide precipitation bands, if one were found, may offer a better chance for detecting extraterrestrial biosignatures on Mars than would sites with nodules. PMID- 26123790 TI - Luminescent zinc metal-organic framework (ZIF-90) for sensing metal ions, anions and small molecules. AB - We synthesize a zinc zeolite-type metal-organic framework, the zeolitic imidazolate framework (ZIF-90), which exhibits an intense blue luminescence excited under visible light. Luminescent studies indicate that ZIF-90 could be an efficient multifunctional fluorescence material for high sensitivity metal ions, anions and organic small molecules, especially for Cd(2+), Cu(2+), CrO4(2-) and acetone. The luminescence intensity of ZIF-90 increases with the concentration of Cd(2+) and decreases proportionally with the concentration of Cu(2+), while the same quenched experimental phenomena appear in the sensing of CrO4(2-). With the increase of the amount of acetone, the luminescence intensity decreases gradually in the emulsions of ZIF-90. The mechanism of the sensing properties is studied in detail as well. This study shows that ZIF-90 could be a useful luminescent sensor for metal ions, anions and organic small molecules. PMID- 26123789 TI - Modulation of the lipidomic profile due to a lipid challenge and fitness level: a postprandial study. AB - BACKGROUND: The lipid composition of plasma is known to vary due to both phenotypic factors such as age, gender and BMI as well as with various diseases including cancer and neurological disorders. However, there is little investigation into the variation in the lipidome due to exercise and/ or metabolic challenges. The objectives of this present study were (i) To identify the glycerophospholipid, sphingolipids and ceramide changes in response to an oral lipid tolerance test (OLTT) in healthy adults and (ii) To identify the effect of aerobic fitness level on lipidomic profiles. METHODS: 214 healthy adults aged 18-60 years were recruited as part of a metabolic challenge study. A sub-group of 40 volunteers were selected for lipidomic analysis based on their aerobic fitness level. Ceramides, glycerophospholipids and sphingomyelins were quantified in baseline fasting plasma samples as well as at 60, 120, 180, 240 and 300 min following a lipid challenge using high-throughput flow injection ESI MS/MS. RESULTS: Mixed model repeated measures analysis identified lipids which were significantly changing over the time course of the lipid challenge. Included in these lipids were lysophosphoethanolamines (LPE), phosphoethanolamines (PE), phosphoglycerides (PG) and ceramides (Cer). Five lipids (LPE a C18:2, LPE a C18:1, PE aa C36:2, PE aa C36:3 and N-C16:1-Cer) had a fold change > 1.5 at 120 min following the challenge and these lipids remained elevated. Furthermore, three of these lipids (LPE a C18:2, PE aa C36:2 and PE aa C36:3) were predictive of fasting and peak plasma TAG concentrations following the OLTT. Further analysis revealed that fitness level has a significant impact on the response to the OLTT: in particular significant differences between fitness groups were observed for phosphatidylcholines (PC), sphingomyelins (SM) and ceramides. CONCLUSION: This study identified specific lipids which were modulated by an acute lipid challenge. Furthermore, it identified a series of lipids which were modulated by fitness level. Future lipidomic studies should take into account environmental factors such as diet and fitness level during biomarker discovery work. TRIAL REGISTRATION: Data, clinicaltrials.gov, NCT01172951. PMID- 26123791 TI - Tobacco drought stress responses reveal new targets for Solanaceae crop improvement. AB - BACKGROUND: The Solanaceae are an economically important family of plants that include tobacco (Nicotiana tabacum L.), tomato, and potato. Drought is a major cause of crop losses. RESULTS: We have identified major changes in physiology, metabolites, mRNA levels, and promoter activities during the tobacco response to drought. We have classified these as potential components of core responses that may be common to many plant species or responses that may be family/species specific features of the drought stress response in tobacco or the Solanaceae. In tobacco the largest increase in any metabolite was a striking 70-fold increase in 4-hydroxy-2-oxoglutaric acid (KHG) in roots that appears to be tobacco/Solanaceae specific. KHG is poorly characterized in plants but is broken down to pyruvate and glyoxylate after the E. coli SOS response to facilitate the resumption of respiration. A similar process in tobacco would represent a mechanism to restart respiration upon water availability after drought. At the mRNA level, transcription factor gene induction by drought also showed both core and species/family specific responses. Many Group IX Subgroup 3 AP2/ERF transcription factors in tobacco appear to play roles in nicotine biosynthesis as a response to herbivory, whereas their counterparts in legume species appear to play roles in drought responses. We observed apparent Solanaceae-specific drought induction of several Group IId WRKY genes. One of these, NtWRKY69, showed ABA-independent drought stress-inducible promoter activity that moved into the leaf through the vascular tissue and then eventually into the surrounding leaf cells. CONCLUSIONS: We propose components of a core metabolic response to drought stress in plants and also show that some major responses to drought stress at the metabolome and transcriptome levels are family specific. We therefore propose that the observed family-specific changes in metabolism are regulated, at least in part, by family specific changes in transcription factor activity. We also present a list of potential targets for the improvement of Solanaceae drought responses. PMID- 26123792 TI - Antitumor and antimetastasis effects of macerating solutions from an injectable chitosan-based hydrogel on hepatocarcinoma. AB - In our previous studies, injectable chitosan-based hydrogel (CH) was prepared and its application in surgery removal of tumor was studied. In this study, the antitumor and antimetastasis effects of the macerating solutions from CH were investigated. Our in vitro results showed that macerating solutions from CH significantly increased the proliferation of human normal liver L02 cells. In contrast, macerating solutions from CH showed significant inhibitory effects on the growth of human hepatoma Bel-7402 cells. In a mouse H22 tumor model, intraperitoneal injection of macerating solutions from CH decreased tumor growth and prevented tumor diffusion. Tumor weight was decreased dramatically in mice treated with macerating solutions from CH. The thymus index and spleen index were significantly increased by treatment with macerating solutions from CH. Administration of macerating solutions from CH also remarkably increased serum levels of TNF-alpha, IL-2, IFN-gamma, and decreased serum VEGF content as compared with the control group treated with saline. The antimetastasis studies showed that the number of pulmonary nodules, pulmonary metastases index, and lymph nodes index were significantly decreased in experimental groups treated with macerating solutions from CH. This study provided more supporting data for the potential clinical application of CH after surgical removal of tumor. PMID- 26123794 TI - Deregulated JAK/STAT signalling in lymphomagenesis, and its implications for the development of new targeted therapies. AB - Gene expression profiling has implicated several intracellular signalling cascades, including the JAK/STAT pathway, in the pathogenesis of particular subtypes of lymphoma. In marked contrast to the situation in patients with either acute lymphoblastic leukaemia or a myeloproliferative neoplasm, JAK2 coding sequence mutations are rare in lymphoma patients with an activated JAK/STAT "signature". This is instead the consequence of mutational events that result in the increased expression of non-mutated JAK2; positively or negatively affect the activity of other components of the JAK/STAT pathway; or establish an autocrine signalling loop that drives JAK-mediated cytokine-independent proliferation. Here, we detail these genetic lesions, their functional consequences, and impact on patient outcome. In light of the approval of a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, and preliminary studies evaluating the efficacy of other JAK inhibitors, the therapeutic potential of compounds that target JAK/STAT signalling in the treatment of patients with lymphoma is also discussed. PMID- 26123795 TI - Use of FTA cards for the storage of breast carcinoma nucleic acid on fine-needle aspiration samples. AB - BACKGROUND: The preservation and storage of nucleic acids is important for DNA molecular techniques. The material obtained by fine-needle aspiration (FNA) is often scanty and can not be wasted. FTA cards are filter papers that immobilize and stabilize nucleic acids and can be stored at room temperature. The current study evaluated whether nucleic acids of breast carcinoma cells, obtained by FNA in a clinical setting, may be collected, stored, and preserved on FTA cards. METHODS: Thirty breast carcinoma, 5 non-Hodgkin lymphoma (NHL), and 5 benign reactive lymph node (RLN) cell samples obtained by FNA were stored at -80 degrees C and on FTA cards. DNA extraction and polymerase chain reaction were performed on cells at -80 degrees C and on 2 punched disks of FTA cards. Fifty nanograms of extracted DNA from both sample types were used to amplify the Janus Kinase 2 (JAK2) gene. RESULTS: The mean value of DNA extracted from breast carcinoma cells was 28.19 ng/uL for that stored at -80 degrees C and 3.28 ng/uL for that stored on FTA cards. Agarose gel analysis demonstrated expected bands of DNA in 29 cases (97%) with both methods. The mean value of DNA extracted from NHL and RLN samples was 37.54 ng/uL and 4.28 ng/uL, respectively, and agarose gel analysis demonstrated bands of high molecular weight DNA in both methods. Significant differences in DNA yield were found between storage at -80 degrees C and FTA cards (P<.0001), but no differences were detected between 260/280 nm ratios in breast carcinoma and NHL/RLN samples. CONCLUSIONS: FTA cards can be conveniently used for the storage of breast carcinoma cells obtained by FNA, thus providing a reliable alternative to traditional methods. PMID- 26123796 TI - Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism. AB - CONTEXT: Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized. OBJECTIVE: To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients. DESIGN AND SETTING: Retrospective study in nine referral centres. PARTICIPANTS: Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included. MAIN OUTCOME MEASURES: Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results. RESULTS: Subtype diagnosis using common trunk and central vein was discordant in 10 (4.6%) of the 217 patients (kappa = 0.87, P < 0.05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data. CONCLUSION: In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required. PMID- 26123797 TI - Polycystic ovary syndrome: cardiovascular risk factors according to specific phenotypes. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance. The objective of this cross-sectional study was to investigate the impact of insulin resistance and body mass index (BMI) on inflammatory and hemostatic variables associated with long-term risk of cardiovascular disease in women with PCOS. MATERIAL AND METHODS: 149 premenopausal women with PCOS were recruited consecutively from April 2010 to February 2012 at three Danish University Hospitals. The study was conducted at the Department of Gynecology and Obstetrics, Herlev University Hospital, Denmark. PCOS was diagnosed in accordance with the Rotterdam criteria and the women were classified into four phenotypes according to BMI and insulin resistance measured by the homeostasis model assessment of insulin resistance index. Body composition was determined by dual-energy X-ray absorptiometry. Main outcome measures were the biomarkers C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI 1), and von Willebrand factor antigen. RESULTS: Normal weight insulin-resistant PCOS women were characterized by abdominal obesity and elevated levels of plasma PAI-1. Overweight/obese insulin-resistant PCOS women had increased levels of both PAI-1 and CRP. Of the three Rotterdam criteria, only hyperandrogenemia was significantly associated with the hemostatic risk marker of long-term cardiovascular disease risk. CONCLUSIONS: Surrogate risk markers for cardiovascular disease are elevated in women with PCOS, especially insulin resistant and overweight/obese women. PMID- 26123798 TI - Superdiffusion dominates intracellular particle motion in the supercrowded cytoplasm of pathogenic Acanthamoeba castellanii. AB - Acanthamoebae are free-living protists and human pathogens, whose cellular functions and pathogenicity strongly depend on the transport of intracellular vesicles and granules through the cytosol. Using high-speed live cell imaging in combination with single-particle tracking analysis, we show here that the motion of endogenous intracellular particles in the size range from a few hundred nanometers to several micrometers in Acanthamoeba castellanii is strongly superdiffusive and influenced by cell locomotion, cytoskeletal elements, and myosin II. We demonstrate that cell locomotion significantly contributes to intracellular particle motion, but is clearly not the only origin of superdiffusivity. By analyzing the contribution of microtubules, actin, and myosin II motors we show that myosin II is a major driving force of intracellular motion in A. castellanii. The cytoplasm of A. castellanii is supercrowded with intracellular vesicles and granules, such that significant intracellular motion can only be achieved by actively driven motion, while purely thermally driven diffusion is negligible. PMID- 26123799 TI - Cyclic mechanical stimulation rescues achilles tendon from degeneration in a bioreactor system. AB - Physiotherapy is one of the effective treatments for tendinopathy, whereby symptoms are relieved by changing the biomechanical environment of the pathological tendon. However, the underlying mechanism remains unclear. In this study, we first established a model of progressive tendinopathy-like degeneration in the rabbit Achilles. Following ex vivo loading deprivation culture in a bioreactor system for 6 and 12 days, tendons exhibited progressive degenerative changes, abnormal collagen type III production, increased cell apoptosis, and weakened mechanical properties. When intervention was applied at day 7 for another 6 days by using cyclic tensile mechanical stimulation (6% strain, 0.25 Hz, 8 h/day) in a bioreactor, the pathological changes and mechanical properties were almost restored to levels seen in healthy tendon. Our results indicated that a proper biomechanical environment was able to rescue early-stage pathological changes by increased collagen type I production, decreased collagen degradation and cell apoptosis. The ex vivo model developed in this study allows systematic study on the effect of mechanical stimulation on tendon biology. PMID- 26123800 TI - An Iron-Regulated Autolysin Remodels the Cell Wall To Facilitate Heme Acquisition in Staphylococcus lugdunensis. AB - Bacteria alter their cell surface in response to changing environments, including those encountered upon invasion of a host during infection. One alteration that occurs in several Gram-positive pathogens is the presentation of cell wall anchored components of the iron-regulated surface determinant (Isd) system, which extracts heme from host hemoglobin to fulfill the bacterial requirement for iron. Staphylococcus lugdunensis, an opportunistic pathogen that causes infective endocarditis, encodes an Isd system. Unique among the known Isd systems, S. lugdunensis contains a gene encoding a putative autolysin located adjacent to the Isd operon. To elucidate the function of this putative autolysin, here named IsdP, we investigated its contribution to Isd protein localization and hemoglobin dependent iron acquisition. S. lugdunensis IsdP was found to be iron regulated and cotranscribed with the Isd operon. IsdP is a specialized peptidoglycan hydrolase that cleaves the stem peptide and pentaglycine crossbridge of the cell wall and alters processing and anchoring of a major Isd system component, IsdC. Perturbation of IsdC localization due to isdP inactivation results in a hemoglobin utilization growth defect. These studies establish IsdP as an autolysin that functions in heme acquisition and describe a role for IsdP in cell wall reorganization to accommodate nutrient uptake systems during infection. PMID- 26123801 TI - Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF. AB - Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-kappaB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and activating bactericidal mechanisms. Administration of TNF-neutralizing biologics disrupted the control of mycobacterial infection in huTNF KI mice, leading to an increased bacterial burden and hyperinflammation. Thus, our findings demonstrate that human TNF can functionally replace murine TNF in vivo, providing mycobacterial resistance that could be compromised by TNF neutralization. This new animal model will be helpful for the testing of specific biologics neutralizing human TNF. PMID- 26123802 TI - Role of CD4+ Foxp3+ Regulatory T Cells in Protection Induced by a Live Attenuated, Replicating Type I Vaccine Strain of Toxoplasma gondii. AB - Vaccination with the live attenuated Toxoplasma gondii Mic1.3KO strain induced long-lasting immunity against challenge with Toxoplasma gondii type I and type II strains. The involvement of regulatory T cells (Tregs) in the protection mechanism was investigated. Intraperitoneal injection of Mic1.3KO induced a weak and transient influx of CD4(+) Foxp3(+) T regulatory cells followed by recruitment/expansion of CD4(+) Foxp3(-) CD25(+) effector cells and control of the parasite at the site of infection. The local and systemic cytokine responses associated with this recruitment of Tregs were of the TH1/Treg-like type. In contrast, injection of RH, the wild-type strain from which the vaccinal strain is derived, induced a low CD4(+) Foxp3(+) cell influx and uncontrolled multiplication of the parasites at this local site, followed by death of the mice. The associated local and systemic cytokine responses were of the TH1/TH17 like type. In addition, in vivo Treg induction in RH-infected mice with interleukin-2 (IL-2)/anti-IL-2 complexes induced control of the parasite and a TH1/Treg cytokine response similar to the response after Mic1.3KO vaccination. These results suggest that Tregs may contribute to the protective response after vaccination with Mic1.3KO. PMID- 26123804 TI - Bacterial Internalization, Localization, and Effectors Shape the Epithelial Immune Response during Shigella flexneri Infection. AB - Intracellular pathogens are differentially sensed by the compartmentalized host immune system. Nevertheless, gene expression studies of infected cells commonly average the immune responses, neglecting the precise pathogen localization. To overcome this limitation, we dissected the transcriptional immune response to Shigella flexneri across different infection stages in bulk and single cells. This identified six distinct transcriptional profiles characterizing the dynamic, multilayered host response in both bystander and infected cells. These profiles were regulated by external and internal danger signals, as well as whether bacteria were membrane bound or cytosolic. We found that bacterial internalization triggers a complex, effector-independent response in bystander cells, possibly to compensate for the undermined host gene expression in infected cells caused by bacterial effectors, particularly OspF. Single-cell analysis revealed an important bacterial strategy to subvert host responses in infected cells, demonstrating that OspF disrupts concomitant gene expression of proinflammatory, apoptosis, and stress pathways within cells. This study points to novel mechanisms through which bacterial internalization, localization, and injected effectors orchestrate immune response transcriptional signatures. PMID- 26123805 TI - CRISPRs provide broad and robust protection to oral microbial flora of gingival health against bacteriophage challenge. PMID- 26123803 TI - Evolution of the Immune Response to Chronic Airway Colonization with Aspergillus fumigatus Hyphae. AB - Airway colonization by the mold Aspergillus fumigatus is common in patients with underlying lung disease and is associated with chronic airway inflammation. Studies probing the inflammatory response to colonization with A. fumigatus hyphae have been hampered by the lack of a model of chronic colonization in immunocompetent mice. By infecting mice intratracheally with conidia embedded in agar beads (Af beads), we have established an in vivo model to study the natural history of airway colonization with live A. fumigatus hyphae. Histopathological examination and galactomannan assay of lung homogenates demonstrated that hyphae exited beads and persisted in the lungs of mice up to 28 days postinfection without invasive disease. Fungal lesions within the airways were surrounded by a robust neutrophilic inflammatory reaction and peribronchial infiltration of lymphocytes. Whole-lung cytokine analysis from Af bead-infected mice revealed an increase in proinflammatory cytokines and chemokines early in infection. Evidence of a Th2 type response was observed only early in the course of colonization, including increased levels of interleukin-4 (IL-4), elevated IgE levels in serum, and a mild increase in airway responsiveness. Pulmonary T cell subset analysis during infection mirrored these results with an initial transient increase in IL 4-producing CD4(+) T cells, followed by a rise in IL-17 and Foxp3(+) cells by day 14. These results provide the first report of the evolution of the immune response to A. fumigatus hyphal colonization. PMID- 26123806 TI - Hanging by a thread: exploring the features of nonresponse in an online young adult cancer survivorship support community. AB - PURPOSE: Finding helpful information can be challenging for young adult (YA) cancer survivors; thus, it is critical to examine features of online posts that successfully solicit responses and assess how these differ from posts that do not solicit responses. METHODS: Using posts from an online YA cancer support community, we analyzed initial posts that did and did not receive replies utilizing Linguistic Inquiry Word Count (LIWC). RESULTS: Independent t tests revealed significant differences between the sets of posts regarding content, emotions, cognitive processes, pronoun use, and linguistic complexity. More specifically, posts with replies contained fewer words per sentence, had more first-person pronouns, had more expressions of negative emotions, and contained more present tense and past tense verbs. CONCLUSIONS: The findings of this study can help improve peer-exchanged support in online communities so that YA cancer survivors can more effectively receive digital support. This research also provides communication researchers, health educators, and care providers a lens for understanding the YA cancer survivorship experience. IMPLICATIONS FOR CANCER SURVIVORS: This research helps survivors be strategic in how they use online forums to seek advice and support. More complete understanding of what kinds of prompts produce responses allows those in need to craft messages in ways that are most likely to elicit support from fellow cancer survivors. These implications for message design extend beyond blogging and can be applicable for text message and email exchanges between cancer patients and their care providers. PMID- 26123807 TI - Vibrational spectroscopy at electrolyte/electrode interfaces with graphene gratings. AB - Microscopic understanding of physical and electrochemical processes at electrolyte/electrode interfaces is critical for applications ranging from batteries, fuel cells to electrocatalysis. However, probing such buried interfacial processes is experimentally challenging. Infrared spectroscopy is sensitive to molecule vibrational signatures, yet to approach the interface three stringent requirements have to be met: interface specificity, sub-monolayer molecular detection sensitivity, and electrochemically stable and infrared transparent electrodes. Here we show that transparent graphene gratings electrode provide an attractive platform for vibrational spectroscopy at the electrolyte/electrode interfaces: infrared diffraction from graphene gratings offers enhanced detection sensitivity and interface specificity. We demonstrate the vibrational spectroscopy of methylene group of adsorbed sub-monolayer cetrimonium bromide molecules and reveal a reversible field-induced electrochemical deposition of cetrimonium bromide on the electrode controlled by the bias voltage. Such vibrational spectroscopy with graphene gratings is promising for real time and in situ monitoring of different chemical species at the electrolyte/electrode interfaces. PMID- 26123808 TI - Libcint: An efficient general integral library for Gaussian basis functions. AB - An efficient integral library Libcint was designed to automatically implement general integrals for Gaussian-type scalar and spinor basis functions. The library is able to evaluate arbitrary integral expressions on top of p, r and sigma operators with one-electron overlap and nuclear attraction, two-electron Coulomb and Gaunt operators for segmented contracted and/or generated contracted basis in Cartesian, spherical or spinor form. Using a symbolic algebra tool, new integrals are derived and translated to C code programmatically. The generated integrals can be used in various types of molecular properties. To demonstrate the capability of the integral library, we computed the analytical gradients and NMR shielding constants at both nonrelativistic and 4-component relativistic Hartree-Fock level in this work. Due to the use of kinetically balanced basis and gauge including atomic orbitals, the relativistic analytical gradients and shielding constants requires the integral library to handle the fifth-order electron repulsion integral derivatives. The generality of the integral library is achieved without losing efficiency. On the modern multi-CPU platform, Libcint can easily reach the overall throughput being many times of the I/O bandwidth. On a 20-core node, we are able to achieve an average output 8.3 GB/s for C60 molecule with cc-pVTZ basis. PMID- 26123809 TI - CT-Guided Percutaneous Cryoablation in Renal Cell Carcinoma: Factors Affecting Local Tumor Control. AB - PURPOSE: To retrospectively evaluate factors affecting local tumor control in cryoablation of renal cell carcinomas (RCCs). MATERIALS AND METHODS: This study examined 61 patients (43 men, 18 women) with a mean age of 69.1 years +/- 10.8 (range 38-87 y) who underwent computed tomography (CT)-guided percutaneous cryoablation for a single RCC and were followed for 6 months or longer. Maximum tumor diameter was 0.8-4.8 cm (mean +/- standard deviation, 2.4 +/- 0.9 cm). Factors affecting local tumor control were evaluated. Deep tumor location was defined as the center side of the body perpendicular to the kidney midline. RESULTS: Median follow-up was 12.7 months. Residual unablated tumors and local tumor progression were observed after initial cryoablation in 4 patients each (13%, 8 of 61). All uncontrolled tumors were located in the deep side of the kidney (100%, 8 of 8), and were covered by an ice-ball margin of 5 mm or less. Deep tumor location (P = .005) and ice-ball margin (P = .002) were detected as significant factors affecting local tumor control on univariate analysis, and ice ball margin remained significant in a stepwise logistic regression model (P = .006; odds ratio, 0.57; 95% confidence interval, 0.38-0.83). Complete tumor control rates were 42.9% (3 of 7), 92.6% (50 of 54), and 100% (20 of 20) with ice ball margins of less than 3 mm, 3 mm or larger, and 6 mm or larger, respectively. CONCLUSIONS: Deep tumor location and ice-ball margins less than 6 mm were associated with incomplete local control following CT-guided percutaneous cryoablation for RCC. PMID- 26123810 TI - The Influence of Fluid Overload on the Length of Mechanical Ventilation in Pediatric Congenital Heart Surgery. AB - Fluid overload and prolonged mechanical ventilation lead to worse outcomes in critically ill children. However, the association between these variables in children following congenital heart surgery is unknown. The objectives of this study were to describe the association between fluid overload and duration of mechanical ventilation, oxygen requirement and radiologic findings of pulmonary and chest wall edema. This study is a retrospective chart review of patients who underwent congenital heart surgery between June 2010 and December 2013. Univariate and multivariate associations between maximum cumulative fluid balance and length of mechanical ventilation and OI were tested using the Spearman correlation test and multiple linear regression models, respectively. There were 85 eligible patients. Maximum cumulative fluid balance was associated with duration of mechanical ventilation (adjusted analysis beta coefficient = 0.53, CI 0.38-0.66, P < 0.001), length of stay in the pediatric intensive care unit (Spearman's correlation = 0.45, P < 0.001), and presence of chest wall edema and pleural effusions on chest radiograph (Mann-Whitney test, P = 0.003). Amount of red blood cells transfused and use of nitric oxide were independently associated with increased duration of mechanical ventilation (P = 0.012 and 0.014, respectively). Fluid overload is associated with prolonged duration of mechanical ventilation and PICU length of stay after congenital heart surgery. Fluid overload was also associated with physiological markers of respiratory restriction. A randomized controlled trial of a restrictive versus liberal fluid replacement strategy is necessary in this patient population, but in the meantime, accumulating observational evidence suggests that cautious use of fluid in the postoperative care may be warranted. PMID- 26123811 TI - Competency Testing for Pediatric Cardiology Fellows Learning Transthoracic Echocardiography: Implementation, Fellow Experience, and Lessons Learned. AB - There is currently great interest in measuring trainee competency at all levels of medical education. In 2007, we implemented a system for assessing cardiology fellows' progress in attaining imaging skills. This paradigm could be adapted for use by other cardiology programs. METHODS: Evaluation consisted of a two-part exercise performed after years 1 and 2 of pediatric cardiology training. Part 1: a directly observed evaluation of technical skills as fellows imaged a normal subject (year 1) and a patient with complex heart disease (year 2). Part 2: fellows interpreted and wrote reports for two echocardiograms illustrating congenital heart disease. These were graded for accuracy and facility with communicating pertinent data. After 5 years of testing, fellows were surveyed about their experience. In 5 years, 40 fellows were tested at least once. Testing identified four fellows who underperformed on the technical portion and four on the interpretive portion. Surveys were completed by 33 fellows (83 %). Most (67 %) felt that intermittent observation by faculty was inadequate for assessing skills and that procedural volume was a poor surrogate for competency (58 %). Posttest feedback was constructive and valuable for 90, and 70 % felt the process helped them set goals for skill improvement. Overall, fellows felt this testing was fair and should continue. Fellow performance and responses identified programmatic issues that were creating barriers to learning. We describe a practical test to assess competency for cardiology fellows learning echocardiography. This paradigm is feasible, has excellent acceptance among trainees, and identifies trainees who need support. Materials developed could be easily adapted to help track upcoming ACGME-mandated metrics. PMID- 26123812 TI - Serum Level of Heart-Type Fatty Acid Binding Protein (H-FABP) Before and After Treatment of Congestive Heart Failure in Children. AB - Remodeling of the heart following injury affects the morbidity and mortality in children presented with heart failure (HF). Heart-type fatty acid binding protein (H-FABP) is a novel biomarker that could be of help to predict the prognosis and risk stratification in those children. We aimed to evaluate the diagnostic and prognostic value of H-FABP in children with heart failure before and after treatment. The study was conducted as a prospective cohort study. It included 30 children with HF as a patient group and 20 healthy children matched for age and sex as a control group. Echocardiographic assessment of the heart was done using conventional Doppler echocardiography. Serum levels of (H-FABP) were measured using enzyme-linked immunosorbent assay before and after treatment of HF. All patients were observed during follow-up period of 3 months. There was a significant difference in the serum level of H-FABP in our patients before treatment (5.278 +/- 3.253 ng/ml) compared with after treatment (2.089 +/- 0.160 ng/ml) with significant difference compared with the control group. There was a significant increase in the serum level of H-FABP with increase in the severity of heart failure according to Ross classification. Significant increase in the H FABP was associated with adverse outcome. Serum levels of H-FABP strongly correlated with clinical and echocardiographic assessment of LV performance of children with HF, and its levels significantly increased in children with adverse outcome suggesting its value as a useful diagnostic and prognostic predictor (with high sensitivity and specificity). PMID- 26123813 TI - Timing of Dynamic NT-proBNP and hs-cTnT Response to Exercise Challenge in Asymptomatic Children with Moderate Aortic Valve Regurgitation or Moderate Aortic Valve Stenosis. AB - Patients with congenital aortic valve stenosis (AVS) can remain asymptomatic but may develop progressive and often underestimated exercise intolerance. The risk of increased left ventricular (LV) wall stress, irreversible myocardial fibrosis and sudden death in untreated patients warrants earlier intervention. The timing for curative therapy for severe AVS is clear, but optimal timing for moderate stenosis (modAS) is unknown. AVS often coexists with aortic regurgitation, which adds a volume overload to an already pressure-overloaded LV, adding an additional challenge to the estimation of disease severity. We investigated the possible value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) upon treadmill exercise challenge in children with asymptomatic modAS versus moderate regurgitation (modAR). The aim was to determine optimal timing of peak biochemical response. Blood samples were obtained at rest, and then at 20, 40 and 60 min after peak exercise comparing modAS and modAR to healthy controls. Exercise performance was equivalent in all groups, with no difference for biomarker levels at rest. The increase in NT proBNP was significant in modAR at 40 min (99.2 +/- 48.6 ng/L; p = 0.04) and 60 min into recovery (100.0 +/- 53.7 ng/L; p = 0.01), but not in modAS. The increase in hs-cTnT was significant only at 60 min into recovery for modAS and modAR. NT proBNP and hs-cTnT following exercise challenge are possible discriminant biomarkers of modAR from modAS and controls at 60 min into recovery despite comparable exercise performance. This offers a promising avenue for future stratification of aortic valve disease and optimal timing of intervention. PMID- 26123814 TI - Possible peroxidase active site environment in amyloidogenic proteins: Native monomer or misfolded-oligomer; which one is susceptible to the enzymatic activity, with contribution of heme? AB - Amyloid states of many proteins complex with heme and exhibit significant non specific peroxidase activity, compared to free heme. Neurotransmitter deficiency, generation of neurotoxins, altered activity/metabolism of key enzymes and cellular DNA damage are possible evidences highlighting the importance of the uncontrollable peroxidase activity in Alzheimer's disease (AD)-involved brain cells. Despite extensive experimental work was carried out on this field, discrepancy on chronological precedence of amyloid aggregation and oxidative reactions as well as the mechanism involved in the peroxidase-induced oxidative stress is still not completely understood. In this study, we highlight further that heme cofactor readily complexes with structural intermediates of amyloid aggregates of ovalbumin, lactoglobulin and crystallin and report the ability of "heme-amyloid aggregate/oligomer") to produce peroxidase-like active site. Histidine side chains are also proposed as both distal and proximal residues required for proper function of these peroxidase systems. Taking uncontrollable peroxidase activity of "Abeta-heme" complex into account, it appears that this process, as a new opened dimension in AD pathologic research, provides structural/mechanistic basis for more efficient therapeutic strategies against neurodegenerative diseases. PMID- 26123815 TI - A green approach to prepare silver nanoparticles loaded gum acacia/poly(acrylate) hydrogels. AB - In this work, gum acacia (GA)/poly(sodium acrylate) semi-interpenetrating polymer networks (Semi-IPN) have been fabricated via free radical initiated aqueous polymerization of monomer sodium acrylate (SA) in the presence of dissolved Gum acacia (GA), using N,N'-methylenebisacrylamide (MB) as cross-linker and potassium persulphate (KPS) as initiator. The semi-IPNs, synthesized, were characterized by various techniques such as X-ray diffraction (XRD), thermo gravimetric analysis (TGA) and Fourier transform infrared (FTIR) spectroscopy. The dynamic water uptake behavior of semi-IPNs was investigated and the data were interpreted by various kinetic models. The equilibrium swelling data were used to evaluate various network parameters. The semi-IPNs were used as template for the in situ preparation of silver nanoparticles using extract of Syzygium aromaticum (clove). The formation of silver nanoparticles was confirmed by surface plasmon resonance (SPR), XRD and transmission electron microscopy (TEM). Finally, the antibacterial activity of GA/poly(SA)/silver nanocomposites was tested against E. coli. PMID- 26123816 TI - Antibacterial silver nanoparticles in polyvinyl alcohol/sodium alginate blend produced by gamma irradiation. AB - Polyvinyl alcohol/sodium alginate/nano silver (PVA/SA/Ag) composite films were made by solution casting method. Gamma irradiation was used to synthesize silver nanoparticles in situ via reduction of silver nitrate without using harmful chemical agents for biomedical applications. UV-vis and XRD results demonstrated that spherical silver nanoparticles were produced even at low irradiation dose of 5 kGy. By increasing irradiation dose, more nanoparticles were synthesized while no PVA hydrogel was formed up to 15 kGy. Also the size of nanoparticles was reduced with increasing gamma dose evidenced by higher release rate of silver nanoparticles in lukewarm water and SEM images. Comparing SEM images with DLS results indicated good performance of PVA/SA as an efficient stabilizer in preventing agglomeration of the silver nanoparticles. Good miscibility of polyvinyl alcohol and sodium alginate observed on the SEM images was supported with FTIR spectroscopy. Upon addition of sodium alginate to polyvinyl alcohol and increasing silver nanoparticles, the melting peak shifted to lower temperature and crystallinity percent was decreased. Addition of sodium alginate led to remarkable increase in rigidity of PVA. The composites exhibited strong antibacterial activity against Staphylococcus aureus and Escherichia coli even at very low level of silver nanoparticles. PMID- 26123817 TI - Influence of collagen addition on the thermal and morphological properties of chitosan/xanthan hydrogels. AB - This study investigates the collagen influence on thermal and morphological characteristics of chitosan/xanthan hydrogels for potential tissue engineering applications. Anionic collagen was prepared by selective hydrolysis of type I collagen found in bovine tendons. Chitosan was obtained from the partial deacetylation of squid pen beta-chitin and xanthan was acquired from Fluka. The hydrogels were obtained in different ratios and were characterized by thermal and morphological analysis. FT-IR suggested only electrostatic interactions between NH3(+) groups of chitosan and COO(-) groups of xanthan and collagen. Thermogravimetric curves showed that hydrogels contain a great amount of water (above 98%) and the presence of collagen does not change this characteristic. Freezing-bound water transition in DSC curves was shifted to higher values due to the increase of water/polymer interaction, mainly when different ratios of chitosan and xanthan were used. SEM images showed sheet-form structures with the presence of collagen promoting an increase in pore size. PMID- 26123818 TI - Purification and biochemical characterization of a novel fibrinolytic enzyme, PSLTro01, from a medicinal animal Porcellio scaber Latreille. AB - A novel protease, named PSLTro01, with fibrinolytic and anticoagulant activity was isolated from Porcellio scaber Latreille and was purified by a combination of hollow fibre membrane molecular weight cut-off (MWCO), ammonium sulfate fractionation, gel filtration and ion-exchange chromatography. PSLTro01 is a single-chain protein with a molecular mass of 38,497 Da as estimated by non reduced SDS-PAGE and MALDI-TOF MS spectrometry, and its N-terminal 15 amino acid sequence was determined as DINGGGATLPQPLYQ. PSLTro01 is stable in the range of 20 40 degrees C and pH 6.0-10.0, with a maximum fibrinolytic activity at 40 degrees C and pH 7.0. The PSLTro01-induced fibrinolytic activity was not influenced by K(+) or Na(+) but was slightly increased by Mg(2+) and completely inhibited by aprotinin and pepstatin A. Fibrin plate assays revealed that PSLTro01 could not directly degrade fibrin but was a plasminogen activator. PSLTro01 exhibited high specificity for the substrate S-2251 for plasmin, followed by S-2238 for thrombin and S-2444 for urokinase. Moreover, the fibrinogenolysis pattern of PSLTro01 was Aalpha-chains>Bbeta-chains>gamma-chain. Tail-thrombus of the enzyme treated group was significantly shorter than the physiological saline treated group and the thrombus decrement was correlated with the enzyme dose. PSLTro01 prolongs both thrombin time (TT) and activated partial thromboplastin time (APTT). These results indicate that PSLTro01 may have potential applications in the prevention and treatment of thrombosis. PMID- 26123819 TI - Effect of ultrasonic treatment on immunological activities of polysaccharides from adlay. AB - Alkali-extractable polysaccharides from the seed of adlay and their two polysaccharide sub-fractions (AAP-1 and AAP-2) were isolated and purified by anion-exchange and gel filtration chromatography. Ultrasonic treatment was put in place to obtain AAP-1' and AAP-2'. Average molecular weights (Mws) of AAP-1, AAP 1', AAP-2, and AAP-2' were 94.2 kDa, 63.1 kDa, 82.3 kDa, and 60.4 kDa, respectively. Monosaccharides composition analysis indicated that AAP-1 and AAP 1' were composed of Rha, Ara, Glc, and Gal in a molar ratio of 1.1:0.4:0.7:0.5 and 1.4:1.6:0.4:0.7. AAP-2 and AAP-2' were composed of Xyl, Rha, Gal and Glc in a molar percent of 0.4:1.4:1.6:0.5 and 0.3:1.6:1.1:0.7. In vitro study showed that AAP-1, AAP-1', AAP-2, and AAP-2' were all able to encourage the production of secretory molecules (NO, TNF-alpha and IL-6) of RAW264.7 murine macrophages in concentrations determines manner. AAP-2' seemed to be the most potent and induced significantly higher the NO production. These findings suggest that the ultrasonic polysaccharides isolated in our study have immune potentiation effects on macrophages and should serve as a beneficial health food. PMID- 26123821 TI - Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Despite advances in its diagnosis and treatment, the prognosis of patients with advanced HCC remains unfavorable. Recent advances in stem cell biology and associated technologies have enabled the identification of minor components of tumorigenic cells, termed cancer stem cells (CSC) or tumor-initiating cells, in cancers such as HCC. Furthermore, because CSC play a central role in tumor development, metastasis and recurrence, they are considered to be a therapeutic target in cancer treatment. Hepatic CSC have been successfully identified using functional and cell surface markers. The analysis of purified hepatic CSC has revealed the molecular machinery and signaling pathways involved in their maintenance. In addition, epigenetic transcriptional regulation has been shown to be important in the development and maintenance of CSC. Although inhibitors of CSC show promise as CSC-targeting drugs, novel therapeutic approaches for the eradication of CSC are yet to be established. In this review, we describe recent progress in hepatic CSC research and provide a perspective on the available therapeutic approaches based on stem cell biology. PMID- 26123820 TI - Lights and shadows in the management of old and new oral anticoagulants in the real world of atrial fibrillation by Italian internists. A survey from the Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment Collaborative Italian Study. PMID- 26123822 TI - Nanocarriers for photodynamic therapy-rational formulation design and medium scale manufacture. AB - The development and manufacture of novel nanocarriers for drug delivery has proved challenging with regards to scale-up and pharmaceutical quality. Polymeric nanocarriers composed of poly(lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) were prepared and the photosensitizer meso-tetrakis(3-hydroxyphenyl) chlorin (mTHPC) was effectively encapsulated. Furthermore, the interplay of various process and formulation parameters and their impact on the most important product specifications were investigated by using a factorial design and a central composite design in a microfluidic manufacturing process. These nanoparticles for intravenous administration with a size of 97 +/- 0.13 nm, narrow size distribution, and an encapsulation efficiency of more than 80% were produced at high throughput. In vitro stability and in vitro drug release testing were applied for quality control purposes. Finally, the toxicity of the photosensitizer was tested in vitro. The cytotoxicity was successfully reduced while the efficacy of the formulation was maintained. First observations using in vivo imaging suggest effective distribution of the nanocarrier system after injection into rodents. Thus, further in vivo testing of the beneficial effects of nanoencapsulation into the matrix system and its formulation will be considered for the delivery of mTHPC to tumor tissues during photodynamic therapy. PMID- 26123823 TI - Signaling through alternative Integrated Stress Response pathways compensates for GCN2 loss in a mouse model of soft tissue sarcoma. AB - The tumor microenvironment is characterized by deficiencies in oxygen and nutrients, such as glucose and amino acids. Activation of the GCN2 arm of the Integrated Stress Response (ISR) in response to amino acid deprivation is one mechanism by which tumor cells cope with nutrient stress. GCN2 phosphorylates the alpha subunit of the eukaryotic translation initiation factor eIF2, leading to global downregulation of translation to conserve amino acids and initiation of a transcriptional program through ATF4 to promote recovery from nutrient deprivation. Loss of GCN2 results in decreased tumor cell survival in vitro under amino acid deprivation and attenuated tumor growth in xenograft tumor models. However, it is not known what effects GCN2 loss has on the growth of autochthonous tumors that arise in their native microenvironment. Here, we demonstrate in a genetically engineered mouse model of soft tissue sarcoma that loss of GCN2 has no effect on tumor growth or animal survival. The sarcomas displayed compensatory activation of PERK or phospho-eIF2alpha independent upregulation of ATF4 in order to maintain ISR signaling, indicating that this pathway is critical for tumorigenesis. These results have important implications for the development and testing of small molecule inhibitors of ISR kinases as cancer therapeutics. PMID- 26123824 TI - Dexketoprofen/tramadol: randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain. AB - BACKGROUND: Combination analgesics are effective in acute pain, and a theoretical framework predicts efficacy for combinations. The combination of dexketoprofen and tramadol is untested, but predicted to be highly effective. METHODS: This was a randomised, double-blind, double-dummy, parallel-group, placebo-controlled, single-dose trial in patients with moderate or severe pain following third molar extraction. There were ten treatment arms, including dexketoprofen trometamol (12.5 mg and 25 mg) and tramadol hydrochloride (37.5 mg and 75 mg), given as four different fixed combinations and single components, with ibuprofen 400 mg as active control as well as a placebo control. The study objective was to evaluate the superior analgesic efficacy and safety of each combination and each single agent versus placebo. The primary outcome was the proportion of patients with at least 50 % max TOTPAR over six hours. RESULTS: 606 patients were randomised and provided at least one post-dose assessment. All combinations were significantly better than placebo. The highest percentage of responders (72%) was achieved in the dexketoprofen trometamol 25 mg plus tramadol hydrochloride 75 mg group (NNT 1.6, 95% confidence interval 1.3 to 2.1). Addition of tramadol to dexketoprofen resulted in greater peak pain relief and greater pain relief over the longer term, particularly at times longer than six hours (median duration of 8.1 h). Adverse events were unremarkable. CONCLUSIONS: Dexketoprofen trometamol 25 mg combined with tramadol hydrochloride 75 mg provided good analgesia with rapid onset and long duration in a model of moderate to severe pain. The results of the dose finding study are consistent with pre-trial calculations based on empirical formulae. TRIAL REGISTRATION: EudraCT (2010-022798-32); Clinicaltrials.gov (NCT01307020). PMID- 26123825 TI - Non-invasive vagus nerve stimulation for acute treatment of high-frequency and chronic migraine: an open-label study. AB - BACKGROUND: The treatment of migraine headache is challenging given the lack of a standardized approach to care, unsatisfactory response rates, and medication overuse. Neuromodulation therapy has gained interest as an alternative to pharmacologic therapy for primary headache disorders. This study investigated the effects of non-invasive vagus nerve stimulation (nVNS) in patients with high frequency episodic migraine (HFEM) and chronic migraine (CM). FINDINGS: In this open-label, single-arm, multicenter study, patients with HFEM or CM self-treated up to 3 consecutive mild or moderate migraine attacks that occurred during a 2 week period by delivering two 120-s doses of nVNS at 3-min intervals to the right cervical branch of the vagus nerve. Of the 50 migraineurs enrolled (CM/HFEM: 36/14), 48 treated 131 attacks. The proportion of patients reporting pain relief, defined as a >=50% reduction in visual analog scale (VAS) score, was 56.3% at 1 h and 64.6% at 2 h. Of these patients, 35.4% and 39.6% achieved pain-free status (VAS = 0) at 1 and 2 h, respectively. When all attacks (N = 131) were considered, the pain-relief rate was 38.2% at 1 h and 51.1% at 2 h, whereas the pain-free rate was 17.6% at 1 h and 22.9% at 2 h. Treatment with nVNS was safe and well tolerated. CONCLUSION: Non-invasive vagus nerve stimulation may be effective as acute treatment for HFEM or CM and may help to reduce medication overuse and medication-associated adverse events. PMID- 26123826 TI - Backbone resonance assignments of ferric human cytochrome c and the pro-apoptotic G41S mutant in the ferric and ferrous states. AB - Human cytochrome c is a multi-functional protein with key roles in both the mitochondrial electron transfer chain and in apoptosis. In the latter, a complex formed between the mitochondrial phospholipid cardiolipin and cytochrome c is crucial for instigating the release of pro-apoptotic factors, including cytochrome c, from the mitochondrion into the cytosol. The G41S mutant of human cytochrome c is the only known disease-related variant of cytochrome c and causes increased apoptotic activity in patients with autosomal dominant thrombocytopenia. NMR spectroscopy can be used to investigate the interaction of human cytochrome c with cardiolipin and the structural and dynamic factors, which may contribute to enhanced apoptotic activity for the G41S mutant. We present here essentially full backbone amide resonance assignments for ferric human cytochrome c (98 %) as well as assignments of both the ferric (92 %) and ferrous (95 %) forms of the G41S mutant. Backbone amide chemical shift differences between the wild type and G41S mutant in the ferric state reveals significant changes around the mutation site, with many other amides also affected. This suggests the possibility of increased dynamics and/or a change in the paramagnetic susceptibility tensor of the G41S mutant relative to the wild type protein. PMID- 26123827 TI - Modeling the stretching of wormlike chains in the presence of excluded volume. AB - We propose an interpolation formula (the EV-WLC relation) for the force-extension behavior of wormlike chains in the presence of hard-core excluded volume interactions, analogous to the classic interpolation formula from Marko and Siggia for ideal wormlike chains. Using pruned-enriched Rosenbluth method (PERM) simulations of asymptotically long, discrete wormlike chains in an external force, we show that the error in the EV-WLC interpolation formula to describe discrete wormlike chains is systematically smaller than the error in the Marko Siggia interpolation formula, except for the saturation region in which both formulas have the same limiting behavior. We anticipate that the EV-WLC interpolation formula will prove useful in the coarse-graining of wormlike chain models for dynamic simulations. Related results for the excess free energy due to excluded volume provide strong support for the physical basis of the Pincus regime. PMID- 26123828 TI - Long-term changes in renal function and perfusion in heart failure patients with reduced ejection fraction. AB - INTRODUCTION: Little is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF). METHODS AND RESULTS: We prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with (125)I iothalamate/(131)I-hippuran clearances with a mean follow-up of 34.6 +/- 4.4 months. Fifteen percent were female, with age 58 +/- 12 years and left ventricular ejection fraction (LVEF) 29 +/- 10%. Baseline GFR was 81 +/- 23 mL/min/1.73 m(2) and declined 0.6 +/- 4.7 mL/min/1.73 m(2) per year. Baseline ERPF was 292 +/- 83 mL/min/1.73 m(2) and declined 4.3 +/- 19 mL/min/1.73 m(2) per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (p < 0.05). Following stepwise backward analysis, only age (p < 0.001) remained significant. In addition, we found an association between change in GFR and changes in ERPF, N terminal pro-brain natriuretic peptide and renovascular resistance. In the multivariable analysis, only the change in ERPF remained significantly associated with a change in GFR (p < 0.001). CONCLUSION: In this cohort of stable chronic HFREF patients, the average decline in GFR over time was small. The decline of GFR was associated with a higher age and a lower baseline GFR, and was strongly related to changes in renal perfusion. PMID- 26123829 TI - Quantitative assessment of atrial conduit function: a new index of diastolic dysfunction. AB - BACKGROUND: Heart failure (HF) epidemic has increased need for accurate diastolic dysfunction (DD) quantitation. Cardiac MRI can elucidate left atrial (LA) phasic function, and accurately quantify its conduit contribution to left ventricular (LV) filling, but has limited availability. We hypothesized that the percentage of LV stroke volume due to atrial conduit volume (LACV), as assessed using 3D echocardiography, can differentiate among progressive degrees of DD in HF patients. METHODS AND RESULTS: Sixty-three subjects (66 +/- 12 years) with DD and ejection fraction (EF) ranging 14-62% underwent full-volume 3D-echocardiography. Simultaneous LA and LV volume curves as function of time (t) were calculated, with LACV as LACV(t) = [LV(t) - LV minimum] - [LA maximum LA(t)], expressed as % of stroke volume. Patients were assigned to four (0-3, from none to severe) DD grades, according to classical Doppler parameters. In this population DD is linked to LACV, with progressively higher percentages of conduit contribution to stroke volume associated with higher degrees of DD (p = 0.0007). Patients were then dichotomized into no-mild (n = 26) or severe (n = 37) DD groups. Apart from atrial volume, larger (p < 0.02) in severe DD group, no differences between groups were found for LV diastolic and stroke volume, EF, mass and flow propagation velocity. However, a significant difference was found for LACV expressed as % of LV stroke volume (29 +/- 15 vs. 43 +/- 23%, p = 0.016). CONCLUSIONS: Our study confirms that LACV contribution to stroke volume increases along with worsening DD, as assessed in the context of (near) constant-volume four-chamber heart physiology. Thus, LACV can serve as new parameter for DD grading severity in HF patients. PMID- 26123830 TI - Safety of symptom-limited exercise testing in a big cohort of a modern ICD population. AB - BACKGROUND: Exercise may predispose to ventricular arrhythmias especially in patients with congestive heart failure. As therapy with implanted cardioverter defibrillators (ICDs) has become standard medical care, there is an emerging number of exercise tests that need to be performed in patients with ICDs. In contrast, little is known about the safety of symptom-limited exercise testing in these patients. METHODS AND RESULTS: 400 ICD patients performed symptom-limited exercise treadmill testing. 200 patients performed a ramp protocol with an initial workload of 0 W increased by 15 W every minute. Another 200 ICD patients did a slightly modified ramp protocol with again an initial workload of 0 W but with an increased capacity of 15 W every 2 min. The study population consists mainly of patients with ischemic (63%) and non-ischemic (34%) heart disease. Atrial fibrillation was present in 16% of the subjects. The mean ejection fraction was 28 +/- 8, and 78% of the patients had an ejection fraction below 30%. In this cohort of patients, no sustained ventricular arrhythmias and no deaths occurred during or after exercise testing. No inappropriate shock delivery was observed. The modified ramp protocol resulted in a prolonged exercise time with equal exercise capacity but does not result in an enhanced susceptibility for ventricular arrhythmias. CONCLUSIONS: Symptom-limited exercise treadmill testing in heart failure patients with ICDs is a safe procedure. The use of a ramp protocol is sufficient in terms of safety and is easy to perform in general practice. The exercise duration in heart failure patients with ICDs does not predict serious adverse events. PMID- 26123831 TI - From T cell "exhaustion" to anti-cancer immunity. AB - The immune system has the potential to protect from malignant diseases for extended periods of time. Unfortunately, spontaneous immune responses are often inefficient. Significant effort is required to develop reliable, broadly applicable immunotherapies for cancer patients. A major innovation was transplantation with hematopoietic stem cells from genetically distinct donors for patients with hematologic malignancies. In this setting, donor T cells induce long-term remission by keeping cancer cells in check through powerful allogeneic graft-versus-leukemia effects. More recently, a long awaited breakthrough for patients with solid tissue cancers was achieved, by means of therapeutic blockade of T cell inhibitory receptors. In untreated cancer patients, T cells are dysfunctional and remain in a state of T cell "exhaustion". Nonetheless, they often retain a high potential for successful defense against cancer, indicating that many T cells are not entirely and irreversibly exhausted but can be mobilized to become highly functional. Novel antibody therapies that block inhibitory receptors can lead to strong activation of anti-tumor T cells, mediating clinically significant anti-cancer immunity for many years. Here we review these new treatments and the current knowledge on tumor antigen-specific T cells. PMID- 26123832 TI - Does intensive multimodal treatment for maternal ADHD improve the efficacy of parent training for children with ADHD? A randomized controlled multicenter trial. AB - BACKGROUND: This is the first randomized controlled multicenter trial to evaluate the effect of two treatments of maternal attention-deficit hyperactivity disorder (ADHD) on response to parent-child training targeting children's external psychopathology. METHODS: Mother-child dyads (n = 144; ADHD according to DSM-IV; children: 73.5% males, mean age 9.4 years) from five specialized university outpatient units in Germany were centrally randomized to multimodal maternal ADHD treatment [group psychotherapy plus open methylphenidate medication; treatment group (TG): n = 77] or to clinical management [supportive counseling without psychotherapy or psychopharmacotherapy; control group (CG): n = 67]. After 12 weeks, the maternal ADHD treatment was supplemented by individual parent-child training for all dyads. The primary outcome was a change in the children's externalizing symptom scores (investigator blinded to the treatment assignment) from baseline to the end of the parent-child training 6 months later. Maintenance therapy continued for another 6 months. An intention-to-treat analysis was performed within a linear regression model, controlling for baseline and center after multiple imputations of missing values. RESULTS: Exactly, 206 dyads were assessed for eligibility, 144 were randomized, and 143 were analyzed (TG: n = 77; CG: n = 66). After 6 months, no significant between-group differences were found in change scores for children's externalizing symptoms (adjusted mean TG-mean CG=1.1, 95% confidence interval -0.5-2.7; p = .1854), although maternal psychopathology improved more in the TG. Children's externalizing symptom scores improved from a mean of 14.8 at baseline to 11.4 (TG) and 10.3 (CG) after 6 months and to 10.8 (TG) and 10.1 (CG) after 1 year. No severe harms related to study treatments were found, but adverse events were more frequent in TG mothers than in CG mothers. CONCLUSIONS: The response in children's externalizing psychopathology did not differ between maternal treatment groups. However, multimodal treatment was associated with more improvement in maternal ADHD. Child and maternal treatment gains were stable (CCT-ISRCTN73911400). PMID- 26123833 TI - An Improved RSA Based User Authentication and Session Key Agreement Protocol Usable in TMIS. AB - Recently, Giri et al.'s proposed a RSA cryptosystem based remote user authentication scheme for telecare medical information system and claimed that the protocol is secure against all the relevant security attacks. However, we have scrutinized the Giri et al.'s protocol and pointed out that the protocol is not secure against off-line password guessing attack, privileged insider attack and also suffers from anonymity problem. Moreover, the extension of password guessing attack leads to more security weaknesses. Therefore, this protocol needs improvement in terms of security before implementing in real-life application. To fix the mentioned security pitfalls, this paper proposes an improved scheme over Giri et al.'s scheme, which preserves user anonymity property. We have then simulated the proposed protocol using widely-accepted AVISPA tool which ensures that the protocol is SAFE under OFMC and CL-AtSe models, that means the same protocol is secure against active and passive attacks including replay and man-in the-middle attacks. The informal cryptanalysis has been also presented, which confirmed that the proposed protocol provides well security protection on the relevant security attacks. The performance analysis section compares the proposed protocol with other existing protocols in terms of security and it has been observed that the protocol provides more security and achieves additional functionalities such as user anonymity and session key verification. PMID- 26123834 TI - Therapeutic combination of radiolabeled CLR1404 with external beam radiation in head and neck cancer model systems. AB - BACKGROUND AND PURPOSE: CLR1404 is a phospholipid ether that exhibits selective uptake and retention in malignant tissues. Radiolabeled CLR1404 enables tumor specific positron-emission tomography (PET) imaging ((124)I) and targeted delivery of ionizing radiation ((131)I). Here we describe the first preclinical studies of this diapeutic molecule in head and neck cancer (HNC) models. MATERIAL AND METHODS: Tumor-selective distribution of (124)I-CLR1404 and therapeutic efficacy of (131)I-CLR1404 were tested in HNC cell lines and patient-derived xenograft tumor models. Monte Carlo dose calculations and (124)I-CLR1404 PET/CT imaging were used to examine (131)I-CLR1404 dosimetry in preclinical HNC tumor models. RESULTS: HNC tumor xenograft studies including patient-derived xenografts demonstrate tumor-selective uptake and retention of (124)I-CLR1404 resulting in a model of highly conformal dose distribution for (131)I-CLR1404. We observe dose dependent response to (131)I-CLR1404 with respect to HNC tumor xenograft growth inhibition and this effect is maintained together with external beam radiation. CONCLUSIONS: We confirm the utility of CLR1404 for tumor imaging and treatment of HNC. This promising agent warrants further investigation in a developing phase I trial combining (131)I-CLR1404 with reduced-dose external beam radiation in patients with loco-regionally recurrent HNC. PMID- 26123836 TI - The Case for Universal Testing of Colorectal Tumors for Microsatellite Instability: A Coming Mismatch Between Clinical and Laboratory Testing. PMID- 26123835 TI - Enrichment of single neurons and defined brain regions from human brain tissue samples for subsequent proteome analysis. AB - Brain function in normal aging and neurological diseases has long been a subject of interest. With current technology, it is possible to go beyond descriptive analyses to characterize brain cell populations at the molecular level. However, the brain comprises over 100 billion highly specialized cells, and it is a challenge to discriminate different cell groups for analyses. Isolating intact neurons is not feasible with traditional methods, such as tissue homogenization techniques. The advent of laser microdissection techniques promises to overcome previous limitations in the isolation of specific cells. Here, we provide a detailed protocol for isolating and analyzing neurons from postmortem human brain tissue samples. We describe a workflow for successfully freezing, sectioning and staining tissue for laser microdissection. This protocol was validated by mass spectrometric analysis. Isolated neurons can also be employed for western blotting or PCR. This protocol will enable further examinations of brain cell specific molecular pathways and aid in elucidating distinct brain functions. PMID- 26123837 TI - Predictors of Early Hospitalization After Deceased Donor Liver Transplantation. AB - Hospitalizations after solid organ transplantation may affect patient outcomes. Identification of the factors attributed to them may decrease hospitalization rates, reduce overall cost, and improve post-transplant outcomes. We examined the risk factors for early hospitalization within 30 and 90 days after liver transplantation (LT). METHODS: Data on all deceased donor LT recipients (age >=18 years) transplanted between 2/28/2002-2/27/2007 and discharged alive from the index hospitalization within 30 days of LT were collected (N = 267). Patients were followed up until December 31, 2013. Logistic regression was used to identify the predictors of 30-day hospitalization, and linear regression was used to identify the factors associated with number of days hospitalized during 30- and 90-day hospitalization after LT. Renal risk index (RRI), a recently developed and validated risk score that accurately predicts the post-LT ESRD based upon recipient factors at LT, was computed using RRI calculator ( http://rri.med.umich.edu ). RESULTS: One-third and more than half of the patients had at least one 30- and 90-day hospitalization, respectively. RRI decile (OR 1.12, P = 0.02) and serum sodium at LT (OR 0.90, P < 0.001) were independently associated with 30-day hospitalization after adjusting for MELD score. Serum creatinine at LT (beta = 4.34, P = 0.001) and pre-LT admission days (beta = 0.15, P = 0.027) affected the number of days hospitalized for 90-day hospitalization. RRI was also an independent predictor of post-LT mortality. CONCLUSION: Early hospitalizations within 30 and 90 days after deceased donor LT are common. While all post-LT hospitalization cannot be prevented, efforts should be directed toward risk-based post-discharge care, and coordination of effective transitional care through ambulatory clinics. Implementation of such processes may attenuate early post-LT hospitalization and resource utilization and improve quality. PMID- 26123840 TI - Phosphonic anchoring groups in organic dyes for solid-state solar cells. AB - We report the synthesis and the optoelectronic characterization of three new 4H pyran-4-ylidene and thiazole derivatives (pyt) as metal-free organic dyes for solid-state dye-sensitized solar cells (DSSCs). We investigate the performance and the long-term stability of devices employing pyt dyes functionalized with carboxylic and phosphonic acids as TiO2 anchoring groups. In contrast to reports on liquid electrolyte DSSCs, we show that solid-state DSSCs prepared with phosphoric pyt derivatives can achieve similar power conversion efficiency to their carboxyl analogues. We make use of the Mott-Schottky analysis and equivalent circuit models to demonstrate that a phosphonic group induces a significant increase in built-in voltage at the TiO2-hole transporter interface, which results in a higher open circuit voltage. PMID- 26123838 TI - Upregulated HOXC8 Expression Is Associated with Poor Prognosis and Oxaliplatin Resistance in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide. It is indispensable to understanding molecular mechanisms of HCC progression and to developing clinically useful biomarkers for this disease. AIM: In this article, we examined whether HOXC8 was associated with the poor prognosis of hepatocellular carcinoma and explored the possible underlying mechanism. METHODS: The HOXC8 and Ki67 expression levels in 86 patients with hepatocellular carcinoma were examined using immunohistochemistry. HOXC8 levels in HCC cells were downregulated by siRNA transfection. The cycle progression and cell proliferation status of HCC cells and the oxaliplatin effectiveness were evaluated by flow cytometry and CCK-8 assay. HOXC8, CyclinD1, PCNA, Nkd2, and cleaved caspase-3 levels were detected by western blot. RESULTS: HOXC8 was upregulated in HCC tissues, compared with adjacent non-tumor ones. HOXC8 expression levels in 86 patients with hepatocellular carcinoma were positively correlated with histological grade. Univariate and multivariate survival analysis revealed that HOXC8 was a significant predictor for overall survival of HCC patients. HOXC8 siRNA knockdown delayed the G1-S phase transition, inhibited cell proliferation, and attenuated resistance to oxaliplatin. CONCLUSIONS: HOXC8 promoted HCC proliferation and predicted poor prognosis. Furthermore, upregulated HOXC8 expression was associated with oxaliplatin resistance in hepatocellular carcinoma. PMID- 26123839 TI - Multicenter Study Assessing Physician Recommendations Regarding the Continuation of Aspirin and/or NSAIDs Prior to Gastrointestinal Endoscopy. AB - BACKGROUND: In 2009 the American Society for Gastrointestinal Endoscopy (ASGE) guidelines advised that both aspirin and NSAIDs be continued prior to low-risk gastrointestinal endoscopic procedures. We sought to determine physician knowledge regarding these guidelines. METHODS: A survey questionnaire was developed based on the ASGE guidelines. Physicians were queried about whether they would continue/stop aspirin in a patient with cardiac disease and in a patient taking NSAIDs for arthritis whether they would continue/stop NSAIDs prior to endoscopy. The survey was administered at three academic medical centers. Demographic information: level of training, board certification, teaching trainees, percentage of time in clinical practice, year of medical school graduation, and location of medical school were all reviewed. The primary outcome was number of questions answered correctly and predictors of correct responses. RESULTS: The survey was administered to 941 participants with 12 declining to participate, while 80% (740/929) of the subjects completed the survey; 20% (150/740) respondents answered both questions correctly and 42% (310/740) answered one question correctly. There was no significant difference between institutions (p = 0.6) or between attendings and trainees (p = 0.75). Multivariate predictors of correct answers were self-reported familiarity with the guideline (-0.029; 95% CI -0.003 to -0.056, p < 0.031), level of training (0.050; 95% CI 0.012-0.088, p = 0.010), and specialty (0.108; 95% CI 0.058-0.159, p < 0.0001). Finally, there was an inverse, linear relationship between postgraduate year and percent questions correct. CONCLUSION: Physician knowledge of guidelines regarding the use of aspirin and NSAIDs prior to endoscopy is suboptimal. Interventions are necessary to improve knowledge of the current pre procedure guidelines. PMID- 26123841 TI - Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and is one of the leading causes of cancer-related death. The risk factors for HCC include cirrhosis, chronic viral hepatitis, heavy alcohol intake and metabolic diseases such as obesity, type 2 diabetes and metabolic syndrome. Insulin resistance is a common denominator of all of these conditions and is tethered to hyperinsulinaemia. Here, we give an overview of the recent advances linking hyperinsulinaemia to HCC development and progression. In particular, we summarise the underlying causes of hyperinsulinaemia in the setting of chronic liver diseases. We present epidemiological evidence linking metabolic diseases to HCC risk and HCC-related mortality, as well as the pathogenic cellular and molecular mechanisms explaining this relation. A better understanding of the mechanisms by which insulin participates in HCC biology might ultimately provide novel opportunities for prevention and treatment. PMID- 26123842 TI - Evaluation of Crohn's disease activity by MR enterography: Derivation and histopathological comparison of an MR-based activity index. AB - AIMS: To compose a qualitative magnetic resonance imaging (MRI) activity index showing Crohn disease (CD) activity, and to compare magnetic resonance enterography (MRE) findings with histopathology results. MATERIALS AND METHODS: Twenty-six patients (11 male and 15 female; mean age 36.7) who had MRE and colonoscopic biopsy between October 2011 and August 2012 were included in the study. On MRE the following parameters were evaluated: bowel wall thickness, bowel wall T2 signal, bowel wall contrast enhancement pattern and degree, length and number of involved bowel segments, perimural T2 signal, mesenteric inflammation, mesenteric lymph nodes and complications of CD. Each parameter was scored to calculate MRI activity index. Biopsy specimens were retrospectively evaluated, histopathologic and endoscopic acute inflammmation scores (AIS, eAIS) were calculated. Each parameter and total MRI activity index were compared with the pathology scores (AIS, eAIS) by Mann-Whitney U test and Spearman correlation. RESULTS: Statistically significant positive correlation was found between AIS and eAIS, mural thickness and eAIS. Moderate correlation was found between MRI activity index and eAIS, mural enhancement degree and eAIS; and poor correlation was found between mesenteric inflammation score and eAIS, MRI activity index and AIS, however they were not statistically significant. CONCLUSIONS: In CD, bowel wall thickness measured by MRE is best correlated with the histopathologic results which are accepted as the reference standard. In cases with high MRI activity index, eAIS is also generally high. MRI activity index which is measured simply and noninvasively can be used in the follow up of CD. PMID- 26123843 TI - Unfused or twig-like middle cerebral artery. AB - INTRODUCTION: The knowledge of anatomic variations of the cerebral arterial circulation may be important to decide on the safest surgical or endovascular treatment method. Variations in the middle cerebral artery (MCA) territory seems to be less frequent than the other intracranial arteries. During the embryonic stage the primitive MCA is hypothesized to be made up of arterial twigs and these twigs will generate the definitive MCA at the end of the development stage. As in our cases, an early interruption in this period will prevent the evolution of MCA normally and a plexiform arterial network will create the M1 segment of MCA which is the so-called extremely rare unfused or twig-like (Uf/Tw) MCA variation. Our aim is to define and evaluate the angiographical features of Uf/Tw MCA. METHODS: The diagnosis of Uf/Tw MCA was evaluated in a total of 4855 diagnostic cerebral catheter angiograms, retrospectively. The coexisting intracranial pathologies were also interpreted with former radiological examinations. A review of the literature is provided. RESULTS: A total of six cases of Uf/Tw MCA was identified on angiograms accompanying ipsilateral internal carotid artery (ICA) occlusion and contralateral ICA supraclinoid segment aneurysm in one case, and cingulate gyrus AVM in the other. In two different cases, CT or MRI examinations revealed coexisting subarachnoid hemorrhage and misdiagnosis of forniceal AVM in one case, and temporal arachnoid cyst and parenchymal hematoma in the other. CONCLUSION: Lack of data and knowledge about the Uf/Tw MCA variation may cause misdiagnosis and unnecessary treatment attempts. PMID- 26123844 TI - The frog skin host-defense peptide CPF-SE1 improves glucose tolerance, insulin sensitivity and islet function and decreases plasma lipids in high-fat fed mice. AB - The frog skin host-defense peptide CPF-SE1 has previously been shown to stimulate the in vitro release of insulin from clonal BRIN-BD11 beta-cells. In this study, the in vivo effects of the peptide were investigated in male NIH Swiss mice maintained on a high-fat diet to induce obesity and insulin resistance. Insulin secretory responses of islets isolated from treated and untreated mice and changes in islet morphology were also examined. Total body fat, plasma glucagon, triglyceride and cholesterol concentrations were measured at the end of the treatment period. Acute intraperitoneal administration of CPF-SE1 (75 nmol body weight) to high-fat fed mice together with glucose (18 mmol/kg body weight) improved glucose tolerance and insulin responses compared to high-fat fed controls. Long term administration of CPF-SE1 (twice-daily administration of 75 nmol/kg body weight for 28 days) did not affect body weight or energy intake but decreased circulating glucose and increased insulin concentrations. Insulin sensitivity and insulin-secretory responses of islets to secretagogues were also significantly improved at 28 days in peptide-treated mice. In addition, significant decreases in plasma glucagon concentrations, pancreatic insulin and glucagon content, islet and beta cell area, body fat and plasma triglyceride levels were observed in CPF-SE1 treated with mice. In conclusion, CPF-SE1 improves beta cell function, insulin sensitivity and glycaemic control whilst reducing total body fat and circulating triglyceride levels. The peptide shows potential for development into an agent for treatment of patients with metabolic syndrome and type 2 diabetes. PMID- 26123845 TI - Signal pathways involved in the biological effects of sulfur dioxide. AB - Gasotransmitters, such as nitric oxide, carbon monoxide and hydrogen sulfide, play important roles in life and have attracted great interest in scientists. In recent years, sulfur dioxide (SO2) has also been found to play important roles in mammals. The redox pathway is involved in the biological effects of SO2, such as the protective effect on myocardial ischemia reperfusion, myocardial injury, pulmonary hypertension and atherosclerosis. Ion channels, such as L-type calcium and adenosine triphosphate-sensitive potassium channels, as well as 3'-5'-cyclic guanosine monophosphate and 3'-5'-cyclic adenosine monophosphate pathways are also involved in the vasorelaxant effect of SO2. The mitogen-activated protein kinase pathway plays roles in vascular remodeling during pulmonary hypertension and vascular smooth muscle cell proliferation. Understanding these signaling mechanisms would help to clarify the pathophysiological effect and therapeutic potential of SO2. PMID- 26123846 TI - Opening the window: Ischemic postconditioning reduces the hyperemic response of delayed tissue plasminogen activator and extends its therapeutic time window in an embolic stroke model. AB - It has been reported that ischemic postconditioning (PC) changes the reperfusion pattern in permanent or transient models of stroke and confers neuroprotection. However, the effects of PC and subsequent use of tissue plasminogen activator (tPA) for the treatment of embolic stroke have not yet been investigated. Rats were subjected to stroke by injection of a preformed clot into the middle cerebral artery and randomly assigned to vehicle (saline 0.1 ml/100 g), tPA (3 mg/kg), PC only or PC+tPA (3 mg/kg). tPA was injected at 6 h after embolic stroke and PC was conducted at 6.5 h after ischemia by using five cycles of a 10 s occlusion and 30 s of reopening of the bilateral common carotid arteries. Cerebral blood flow (CBF) was monitored for 60 min from the time of tPA injection. Infarct size, blood brain barrier disruption, edema, neurological deficits, reactive oxygen species and apoptosis were measured 2 days later. PC decreased infarct volume, but PC+tPA was more neuroprotective than PC alone. While tPA alone dramatically increased CBF, conducting PC caused a gradual increase in CBF. A combination of PC+tPA reduced BBB leakage, brain edema, apoptosis and reactive oxygen species levels. Furthermore, a combination of PC+tPA improved neurological functions at 48 h after the induced stroke. In conclusion, PC hampered malignant hyperemia after reperfusion with tPA and extended its therapeutic window up to 6 h. Compared to PC alone, combination of thrombolysis and PC showed a better neuroprotection. PMID- 26123847 TI - FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies. AB - Free Fatty Acid 4 receptor (FFA4 receptor or GPR120), a rhodopsin-like G protein coupled receptor (GPCR) subfamily member, is a receptor that senses specific fatty acids such as omega-3 fatty acid in fish oil or the endogenous signaling lipid, PHASA. FFA4 receptor is enriched in lung, colon and adipose tissue but is also detected in many other tissues and cells. The activation of FFA4 receptor has multiple effects, including but not limited to inhibition of inflammation, improving insulin sensitivity and adipogenesis, and regulating hormone secretion from the gastro-intestinal system and pancreatic islets. The important role of FFA4 receptor in maintaining metabolic homeostasis strongly indicates the great potential of selective FFA4 receptor agonizts to treat diabetes and inflammation. In this review, we summarize recent research progress in the physiological and biochemical studies of FFA4 receptor and highlight its underlying signaling mechanisms and ligand identification to assist future research to exploit FFA4 receptor as a drug target. PMID- 26123848 TI - Loss of JAM-C leads to impaired esophageal innervations and megaesophagus in mice. AB - Megaesophagus is a disease where peristalsis fails to occur properly and esophagus is enlarged. The etiology and mechanism of megaesophagus are not well understood. In this study, we reported that junctional adhesion molecule C (JAM C) knockout mice on a C57/B6 background developed progressive megaesophagus from embryonic day (E) 15.5 onward with complete penetrance. JAM-C knockout mice exhibited a significant reduction in the number of nerve fibers/ganglia in the wall of the esophagus. However, histological analysis revealed that the esophageal wall thickness and structure of JAM-C knockout mice at embryonic stages and young adult were comparable to that of control littermates. Thus, megaesophagus observed in JAM-C knockout mice could be attributed, at least in part, to impaired esophageal innervations. Our data suggest JAM-C as a potential candidate gene for human megaesophagus, and JAM-C knockout mice might serve as a model for the study of human megaesophagus. PMID- 26123849 TI - Cell-specific transcriptomic analyses of three-dimensional shoot development in the moss Physcomitrella patens. AB - Haploid moss gametophytes harbor distinct stem cell types, including tip cells that divide in single planes to generate filamentous protonemata, and bud cells that divide in three planes to yield axial gametophore shoots. This transition from filamentous to triplanar growth occurs progressively during the moss life cycle, and is thought to mirror evolution of the first terrestrial plants from Charophycean green algal ancestors. The innovation of morphologically complex plant body plans facilitated colonization of the vertical landscape, and enabled development of complex vegetative and reproductive plant morphologies. Despite its profound evolutionary significance, the molecular programs involved in this transition from filamentous to triplanar meristematic plant growth are poorly understood. In this study, we used single-cell type transcriptomics to identify more than 4000 differentially expressed genes that distinguish uniplanar protonematal tip cells from multiplanar gametophore bud cells in the moss Physcomitrella patens. While the transcriptomes of both tip and bud cells show molecular signatures of proliferative cells, the bud cell transcriptome exhibits a wider variety of genes with significantly increased transcript abundances. Our data suggest that combined expression of genes involved in shoot patterning and asymmetric cell division accompanies the transition from uniplanar to triplanar meristematic growth in moss. PMID- 26123850 TI - Biosynthesized silver nanoparticles performing as biogenic SERS-nanotags for investigation of C26 colon carcinoma cells. AB - In this work, two classes of silver nanoparticles (AgNPs) were biosynthesized with the goal to assess their reliability in vitro as surface-enhanced Raman scattering (SERS) nanotags. Mycosynthesized silver nanoparticles (MAgNPs) and phytosynthesized silver nanoparticles (PAgNPs) were produced through environmentally friendly procedures by reduction of silver nitrate with Fusarium oxysporum cell filtrate and Azadirachta indica extract, respectively. Two cell lines, namely C26 murine colon carcinoma cells as example of cancer cells and human immortalized keratinocyte cells (HaCaT) as representative of healthy cell line, were selected for in vitro investigation. The in vitro toxicity studies show that M(P)AgNPs present lower cytotoxic effect on both cell lines as compared with standard citrate coated AgNPs. The internalization of M(P)AgNPs by colon carcinoma cells and structural alterations induced in the morphology of treated cells were analyzed by dark-field (DF) and differential interference contrast (DIC) microscopy, respectively. The most informative data about the cellular uptake and tracking potential of M(P)AgNPs were provided by scanning Confocal Raman Microscopy (CRM) and multivariate K-means cluster analysis of collected Raman spectra. The analysis reveals the subcellular components and the localization of AgNPs inside the cell via the intrinsic SERS signature of biogenic coating material. The use of unique biological material to perform synthesis, stability, biocompatibility and SERS tagging is relevant both from the point of view of encoding nanoparticles with Raman reporters and further applications in cell investigation via Raman/SERS imaging. PMID- 26123851 TI - Response of osteoblasts and preosteoblasts to calcium deficient and Si substituted hydroxyapatites treated at different temperatures. AB - Hydroxyapatite (HA) is a calcium phosphate bioceramic widely used for bone grafting and augmentation purposes. The biological response of HA can be improved through chemical and microstructural modifications, as well as by manufacturing it as macroporous implants. In the present study, calcium deficient hydroxyapatite (CDHA) and Si substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to obtain different microstructural properties, the scaffolds have been treated at 700 degrees C and 1250 degrees C. The scaffolds have been characterized and tested as supports for both osteoblast growth and pre-osteoblast differentiation, as fundamental requisite for their potential use in bone tissue engineering. Morphology, viability, adhesion, proliferation, cell cycle, apoptosis, intracellular content of reactive oxygen species and interleukin-6 production were evaluated after contact of osteoblasts-like cells with CDHA and SiHA materials. An adequate interaction of osteoblasts-like cells and preosteoblasts-like cells with all these scaffolds was observed. However, the higher bone cell proliferation and differentiation on CDHA and SiHA scaffolds treated at 1250 degrees C and the lower adsorption of albumin and fibrinogen on these materials in comparison to those treated at 700 degrees C, suggest a better tissue response to CDHA and SiHA materials treated at high temperature. PMID- 26123852 TI - Galactosylated chitosan-grafted multiwall carbon nanotubes for pH-dependent sustained release and hepatic tumor-targeted delivery of doxorubicin in vivo. AB - Carbon nanotubes (CNTs) are well known for their distinctive drug-loading ability that is mainly due to their large surface area, which permits covalent attachment of various target ligands or drug molecules by pi-pi stacking, allowing them to act as potential tumor-targeting carriers. Herein, we describe the development of galactosylated chitosan-graftedoxidized CNTs (O-CNTs-LCH) for pH-dependent sustained release and hepatic tumor-targeted delivery of doxorubicin (DOX). The in vitro release behavior in aqueous release media of different pH values (5.5, 6.5 and 7.4) verified the pH-dependent sustained release of DOX from O-CNTs-LCH DOX. Moreover, these nanocarriers exhibited significant in vitro tumor-targeting properties, with a higher cellular uptake efficiency than that of free DOX in HepG2 cells. In addition, the good biocompatibility and low toxicity of O-CNTs LCH-DOX was demonstrated by evaluating HepG2 cytotoxicity, vascular irritation and the maximum tolerated dose. Moreover, after intravenous administration in mice bearing the H22 tumor, O-CNTs-LCH-DOX showed higher antitumor activity and stronger fluorescent intensity in tumor tissue compared to free DOX. These results indicated the selective hepatic tumor targeting and the therapeutic effect of those nanocarriers. PMID- 26123853 TI - New glycosylated conjugate copolymer N-acetyl-beta-D-glucosaminyl-pluronic: Synthesis, self-assembly and biological assays. AB - This work describes the synthesis of a new glycosylated conjugate copolymer, GlcNAc-PEO75-PPO30-PEO75-GlcNAc (GlcNAc-PluronicF68-GlcNAc), using click chemistry from Pluronic((r)) F68 and propargyl-2-N-acetamido-2-deoxy-beta-D glucopyranoside. Micelles were prepared by the self-assembly of GlcNAc PluronicF68-GlcNAc in phosphate-buffered solution. The critical micelle concentration was determined by fluorescence spectroscopy, and the value was found to be equal to 5.8mgmL(-1). The Gibbs free energy (DeltaG) of micellization is negative, indicating that the organization of amphiphiles is governed by the hydrophobic effects in an entropy-driven process. The scattering characterization of GlcNAc-PluronicF68-GlcNAc micelles showed a hydrodynamic radius of 8.7nm and negative zeta potential (-21.0+/-0.9mV). The TEM image evidences the spherical shape of the objects self-assemble into highly regular micelles having a mean diameter of 10nm. The SAXS profile confirmed the spherical shape of the assemblies comprising a swollen PPO core (Rcore=2.25nm) stabilized by PEO chains following Gaussian statistics. The results of the comet assay showed that the GlcNAc-PluronicF68-GlcNAc micelles were not genotoxic, and the cell viability test was higher than 97% for all concentrations, demonstrating that GlcNAc PluronicF68-GlcNAc is not toxic. PMID- 26123854 TI - Liposomal voriconazole (VOR) formulation for improved ocular delivery. AB - Treating infectious eye diseases topically requires a drug delivery system capable of overcoming the eye's defense mechanisms, which efficiently reduce the drug residence time right after its administration, therefore reducing absorption. In order to try to surpass such administration issues and improve life quality for patients with fungal keratitis, liposomal voriconazol (VOR) formulations were prepared. Formulations were composed of soy phosphatidylcholine (PC) containing or not 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and cholesterol. Liposomes were characterized by their drug entrapment efficiency (EE), drug recovery (DR), average diameter (size) and polydispersivity index (PdI). In vitro mucosal interaction and irritancy levels, ex vivo permeation, as well as the short-term stability were also assessed. Liposomal VOR formulation produced with 7.2:40mM VOR:PC showed to be the most promising formulation: mean size of 116.6+/-5.9nm, narrow PdI (0.17+/-0.06), negative zeta potential (~-7mV) and over 80% of EE and yield, remaining stable for at least 30 days in solution and 90 days after lyophilization. This formulation was classified as 'non irritant' after HET-CAM's test and was able to deliver about 47.85+/ 5.72MUg/cm(2) of VOR into porcine cornea after 30min of permeation test. Such drug levels are higher than the minimal inhibitory concentrations (MIC) of several fungi species isolated from clinical cases of corneal keratitis. Overall results suggest VOR can be effectively incorporated in liposomes for potential topical treatment of fungal keratitis. PMID- 26123855 TI - [Critical reading of analytical observational studies]. AB - Analytical observational studies provide very important information about real life clinical practice and the natural history of diseases and can suggest causality. Furthermore, they are very common in scientific journals. The aim of this article is to review the main concepts necessary for the critical reading of articles about radiological studies with observational designs. It reviews the characteristics that case-control and cohort studies must have to ensure high quality. It explains a method of critical reading that involves checking the attributes that should be evaluated in each type of article using a structured list of specific questions. It underlines the main characteristics that confer credibility and confidence on the article evaluated. Readers are provided with tools for the critical analysis of the observational studies published in scientific journals. PMID- 26123856 TI - Does type of disability and participation in rehabilitation affect satisfaction of stroke survivors? Results from the 2013 Behavioral Risk Surveillance System (BRFSS). AB - BACKGROUND: Studies show that stroke survivors typically have lower life satisfaction than persons who have not been diagnosed with stroke. OBJECTIVE: To determine if significant differences in life satisfaction exist between stroke survivors with and without functional limitations and whether specific functional limitations, as well as participation in outpatient rehabilitation affect the odds of reported life satisfaction for stroke survivors. METHOD: Chi square analysis was used to examine data from the 2013 BRFSS to determine the relationship of functional limitations as well as participation in rehabilitation services to life satisfaction for stroke survivors. Logistic regression analysis was used to determine what variables increased the odds of reported poor life satisfaction. RESULTS: Stroke survivors experiencing difficulty with cognition, depression and IADLs showed significantly lower life satisfaction than those who did not experience these functional limitations. Survivors exhibiting activity limitations had almost twice the odds of reporting poor life satisfaction and those experiencing limitations in cognition and IADLs had 2.88 times and 1.81 times the odds as others without these limitations of reporting poor life satisfaction, respectively. Participation in outpatient rehabilitation reduced the odds of reporting of poor life satisfaction by approximately one half. CONCLUSIONS: Rehabilitation focused on addressing these functional limitations would increase life satisfaction for persons diagnosed with stroke. Future research on specific types of cognitive and daily living limitations would assist policy makers and referral sources in making appropriate referrals to rehabilitation. PMID- 26123857 TI - Quality of life in Mexican patients with primary neurological or musculoskeletal disabilities. AB - BACKGROUND: As the population with a disability increases both in number and life expectancy, so does its demand for health services. Very little original research has been done in Mexican populations regarding the effect of disability on quality of life. OBJECTIVES: 1) Assessing the subjective quality of life of patients with neuromusculoskeletal and movement-related function disabilities and, 2) Analyzing the possible effect of the medical condition (diseases of the nervous system vs. diseases of the musculoskeletal system and connective tissue) and its interaction with sex and age. METHODS: In a cross-sectional design 330 participants were recruited from a public institution in Mexico providing specialized outpatient rehabilitation. After signing informed consent they responded a brief sociodemographic questionnaire and the WHOQOL-BREF scale. RESULTS: In general quality of life levels were satisfactory. Female and elderly patients with diseases of the nervous system were particularly affected in the physical and psychological dimensions. Women with diseases of the nervous system also showed a negatively affected social quality of life. Elderly with diseases of the musculoskeletal system and connective tissue scored the lowest in general health perception. CONCLUSIONS: Even though most patients were quite satisfied with their quality of life, not all aspects or cases have such positive perceptions; both the physical and psychological dimensions were particularly negative in female and elderly patients with nervous system diseases. Clinicians would do well to thoughtfully assess patients in these groups and adjust treatment to achieve the greatest possible rehabilitation. PMID- 26123858 TI - Social-ecological influences on interpersonal support in people with physical disability. AB - BACKGROUND: People with physical disability report lower amounts of emotional and informational social support compared with other populations but it is unclear how influences at the broader societal level impact support in this population. OBJECTIVE: To address this question, Berkman and Glass's social-ecological model was used to examine the influence of upstream factors on interpersonal support in people with physical disability. It was predicted that these factors would influence support even after controlling for the traditional measures linked to social support. METHODS: 331 adult participants with physical disability (43% female; mean age = 42.7; 88% White) completed an online cross-sectional survey measuring types and sources of social support, social integration, disability impact in social domains, environmental barriers, and relevant psychosocial variables such as depression. RESULTS: A hierarchical linear regression analysis showed that level of disability, perceived tangible support, social integration, depressive symptoms, environmental barriers, occupational independence, and having family or friends as primary support sources were significantly associated with perceived support at the final step (R(2) = .60, F(22, 255) = 17.68, p < .001). The social-ecological measures, environmental barriers and social integration, had the largest associations with interpersonal support. CONCLUSIONS: Results demonstrate the importance of measuring distinct support constructs and how the broader social environment may matter more in interpersonal support perceptions for people with disability than typical measures studied in the literature. Improving environmental factors will help improve social support. PMID- 26123859 TI - The modifying role of caregiver burden on predictors of quality of life of caregivers of hospitalized chronic stroke patients. AB - BACKGROUND: Caregiver burden is an important predictor of quality of life (QoL) among caregivers of stroke patients. While caregiver burden and QoL might be closely related, caregiver burden seems also to be a potential modifier of the associations between patients' and caregivers' characteristics and caregivers' QoL. OBJECTIVE: The purpose of this study was to investigate the effect of caregiver burden in caregivers of hospitalized chronic stroke patients and the predictors of caregivers' QoL by level of caregiver burden. METHODS: A total of 238 patients and their caregivers were interviewed using questionnaires consisting of the Zarit Burden Interview and the Korean-version of the World Health Organization Quality of Life-BREF. Multiple hierarchical regression analyses were performed to determine the predictors of caregivers' QoL among caregivers stratified by median caregiver burden score (high/low). RESULTS: Caregiver burden had a modifying effect on caregivers' QoL. In caregivers with high burden, the patient characteristics of being unemployed and the caregiver characteristics of poor health status, lower income, and being a spouse were negative predictors of caregivers' QoL. In caregivers with low burden, the patient characteristics of being hospitalized for a longer duration and the caregiver characteristics of poor health status were negative predictors of caregivers' QoL (all ps < 0.05). CONCLUSIONS: This study found that in South Korea, more attention should be paid to spouses who are caring for hospitalized chronic stroke patients, particularly with regard to their health status and financial problems. Further studies are needed to examine the impact of factors not examined in the Korean cultural context. PMID- 26123860 TI - Corticosteroids for the treatment of human infection with influenza virus: a systematic review and meta-analysis. AB - Administration of corticosteroids to patients affected by influenza virus, especially pandemic avian influenza virus, although relatively common, remains controversial. A systematic review and meta-analysis was performed to assess the impact of corticosteroid treatment on outcomes of patients with influenza virus infection. The PubMed, EMBASE, Web of Science and Cochrane Library databases were searched up to February, 2015. Studies comparing corticosteroid treatment with no corticosteroid treatment in patients with influenza virus infection were included. The primary outcomes assessed were the association of mortality and nosocomial infection with corticosteroid treatment. Two authors independently extracted the data. ORs and weighted mean differences (WMDs) were used to describe dichotomous data and continuous data, respectively. Nineteen studies with 4916 patients were included in this meta-analysis. The results showed that corticosteroid treatment was significantly associated with mortality (OR 1.98, 95% CI 1.62-2.43, p < 0.00001) and nosocomial infection (OR 3.16, 95% CI 2.09 4.78, p < 0.00001). The durations of mechanical ventilation (WMD 3.82, 95% CI 1.49-6.15, p 0.001) and intensive-care unit stay (WMD 4.78, 95% CI 2.27-7.29, p 0.0002) were both markedly longer in the corticosteroid treatment group than in the control group. These findings suggest that routine steroid use may not be ideal for influenza virus infection. However, these results are derived from observational studies, with some important biases. They should be examined in future sufficiently powered randomized trials. PMID- 26123861 TI - Predicting Early Death Among Elderly Dialysis Patients: Development and Validation of a Risk Score to Assist Shared Decision Making for Dialysis Initiation. AB - BACKGROUND: A shared decision-making tool could help elderly patients with advanced chronic kidney disease decide about initiating dialysis therapy. Because mortality may be high in the first few months after initiating dialysis therapy, incorporating early mortality predictors in such a tool would be important for an informed decision. Our objective is to derive and validate a predictive risk score for early mortality after initiating dialysis therapy. STUDY DESIGN: Retrospective observational cohort, with development and validation cohorts. SETTING & PARTICIPANTS: US Renal Data System and claims data from the Centers for Medicare & Medicaid Services for 69,441 (aged >=67 years) patients with end-stage renal disease with a previous 2-year Medicare history who initiated dialysis therapy from January 1, 2009, to December 31, 2010. CANDIDATE PREDICTORS: Demographics, predialysis care, laboratory data, functional limitations, and medical history. OUTCOMES: All-cause mortality in the first 3 and 6 months. ANALYTICAL APPROACH: Predicted mortality by logistic regression. RESULTS: The simple risk score (total score, 0-9) included age (0-3 points), low albumin level, assistance with daily living, nursing home residence, cancer, heart failure, and hospitalization (1 point each), and showed area under the receiver operating characteristic curve (AUROC)=0.69 in the validation sample. A comprehensive risk score with additional predictors was also developed (with AUROC=0.72, high concordance between predicted vs observed risk). Mortality probabilities were estimated from these models, with the median score of 3 indicating 12% risk in 3 months and 20% in 6 months, and the highest scores (>=8) indicating 39% risk in 3 months and 55% in 6 months. LIMITATIONS: Patients who did not choose dialysis therapy and did not have a 2-year Medicare history were excluded. CONCLUSIONS: Routinely available information can be used by patients with chronic kidney disease, families, and their nephrologists to estimate the risk of early mortality after dialysis therapy initiation, which may facilitate informed decision making regarding treatment options. PMID- 26123862 TI - Proton pump inhibitors and hypomagnesemia in the general population: a population based cohort study. AB - BACKGROUND: Proton pump inhibitor (PPI) use has been associated with hypomagnesemia in case reports and hospital-based cohort studies. Our objective was to determine whether PPI use is associated with hypomagnesemia in the general population and whether this is also found in histamine 2 receptor antagonist (H2RA) users. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 9,818 individuals from the general population (Rotterdam Study). PREDICTOR: PPI use and H2RA use compared to no use. OUTCOMES & MEASUREMENTS: Serum magnesium and hypomagnesemia (serum magnesium <= 1.44 mEq/L). Analyses were adjusted for age, sex, body mass index, kidney function, comorbid conditions, and alcohol and diuretic use. RESULTS: Serum magnesium level was 0.022 mEq/L lower in PPI users (n=724; 95% CI, -0.032 to -0.014 mEq/L) versus those with no use. PPI use was associated with increased risk of hypomagnesemia (n=36; OR, 2.00; 95% CI, 1.36 2.93) compared to no use. Effect modification was found between the use of PPIs and loop diuretics; in participants using loop diuretics (n=270), PPI use was associated with a further increased risk of hypomagnesemia (n=5; OR, 7.22; 95% CI, 1.69-30.83) compared to no use. The increased risk with PPIs was only seen after prolonged use (range, 182-2,618 days; OR, 2.99; 95% CI, 1.73-5.15). Including dietary magnesium intake into the model did not alter results (available for 2,504 participants, including 231 PPI users). H2RA users (n=250) also had a lower serum magnesium level (-0.016 [95% CI, -0.032 to -0.002] mEq/L) and increased risk of hypomagnesemia (n=12; OR, 2.00; 95% CI, 1.08-3.72) compared to those with no use, but no interaction with loop diuretics. LIMITATIONS: Cross sectional analysis with single serum magnesium measurement. CONCLUSIONS: PPI use is associated with hypomagnesemia in the general population. Prolonged PPI use and concomitant loop diuretic use are associated with a stronger risk increase. Similar but weaker associations were found in H2RA users, except for interaction with loop diuretics. PMID- 26123863 TI - Temperature responsive hydrogels enable transient three-dimensional tumor cultures via rapid cell recovery. AB - Recovery of live cells from three-dimensional (3D) culture would improve analysis of cell behaviors in tissue engineered microenvironments. In this work, we developed a temperature responsive hydrogel to enable transient 3D culture of human glioblastoma (GBM) cells. N-isopropylacrylamide was copolymerized with hydrophilic grafts and functionalized with the cell adhesion peptide RGD to yield the novel copolymer poly(N-isopropylacrylamide-co-Jeffamine((r)) M-1000 acrylamide-co-hydroxyethylmethacrylate-RGD), or PNJ-RGD. This copolymer reversibly gels in aqueous solutions when heated under normal cell culture conditions (37 degrees C). Moreover, these gels redissolve within 70 s when cooled to room temperature without the addition of any agents to degrade the synthetic scaffold, thereby enabling rapid recollection of viable cells after 3D culture. We tested the efficiency of cell recovery following extended 3D culture and were able to recover more than 50% of viable GBM cells after up to 7 days in culture. These data demonstrate the utility of physically crosslinked PNJ-RGD hydrogels as a platform for culture and recollection of cells in 3D. PMID- 26123864 TI - Conservation laws, radiative decay rates, and excited state localization in organometallic complexes with strong spin-orbit coupling. AB - There is longstanding fundamental interest in 6-fold coordinated d(6) (t(2g)(6)) transition metal complexes such as [Ru(bpy)3](2+) and Ir(ppy)3, particularly their phosphorescence. This interest has increased with the growing realisation that many of these complexes have potential uses in applications including photovoltaics, imaging, sensing, and light-emitting diodes. In order to design new complexes with properties tailored for specific applications a detailed understanding of the low-energy excited states, particularly the lowest energy triplet state, T1, is required. Here we describe a model of pseudo-octahedral complexes based on a pseudo-angular momentum representation and show that the predictions of this model are in excellent agreement with experiment - even when the deviations from octahedral symmetry are large. This model gives a natural explanation of zero-field splitting of T1 and of the relative radiative rates of the three sublevels in terms of the conservation of time-reversal parity and total angular momentum modulo two. We show that the broad parameter regime consistent with the experimental data implies significant localization of the excited state. PMID- 26123865 TI - Constructing the meaning of quality of life for residents in care homes in the Lebanon: perspectives of residents, staff and family. AB - AIM: Located in two care homes in Lebanon, the study explores the perspectives of quality of life for a sample of older residents, care staff and family caregivers. BACKGROUND: Quality of life for older people living in care homes is traditionally reported in the literature as a Westernised construct and so far little is known about its meanings from an Arabic cultural perspective and context. There is also a knowledge gap about the conditions of older people living in care homes in Lebanon. METHOD: The study was a qualitative exploration of perspectives of quality of life of older residents, care staff and family caregivers. Two care homes for older people situated in Beirut took part in the study. Between 2010 and 2011 semi-structured interviews were undertaken with a sample of 20 residents, eight family caregivers and 11 care staff. Data were analysed using the constant comparative method. FINDINGS: Four categories emerged from this analytical process: (i) maintaining family connectedness; (ii) engaging in worthwhile activities; (iii) maintaining and developing significant relationships; and (iv) holding and practicing spiritual beliefs. The emergence of these categories confirmed the complex, interrelated and multidimensional nature of quality of life for residents and other stakeholders. CONCLUSION: The findings supplement an emerging body of knowledge about the composition of quality of life for older residents in Lebanon. Improving the quality of life of older residents will require action in respect of all of the domains identified in study. IMPLICATIONS FOR PRACTICE: Moving nursing practice from task-based care to relationship-centred approaches was seen as pivotal in helping to develop quality of life for residents living in the participating care homes. The findings have implications for education, nursing practice and research in Lebanon and help start an evidence base for care. PMID- 26123866 TI - Dose- and time-dependent effects of Garcinia kola seed extract on sexual behaviour and reproductive parameters in male Wistar rats. AB - The aim of the present study was to investigate the effects of a crude extract of Garcinia kola on male sexual function after subchronic and chronic treatment periods at different sublethal doses. Adult male Wistar rats were treated orally with 100, 200 and 400 mg kg(-1) of a 70% ethanolic extract of G. kola daily for 56 days. Sexual behaviour studies were performed on days 28 and 50. At termination on day 56, organ weights, sperm count, reproductive hormone levels and testicular histology were assessed. Subchronic and chronic treatment of normal male rats with G. kola extract resulted in overall increase in components of libido, erection and ejaculation in treated rats - with lower doses being more efficient than the higher dose. There was a slight reduction in some components of sexual behaviour with prolonged time of treatment. G. kola treatment at all doses resulted in increased testicular weights, increased sperm count with no change in motility and increased serum testosterone levels with no change in gonadotropin levels. Gross testicular histology was not affected by treatment. We conclude that G. kola seed extract possesses potent aphrodisiac activity in male albino rats with resultant increase in sperm count and testosterone levels. PMID- 26123867 TI - Measurement and modeling of coronary blood flow. AB - Ischemic heart disease that comprises both coronary artery disease and microvascular disease is the single greatest cause of death globally. In this context, enhancing our understanding of the interaction of coronary structure and function is not only fundamental for advancing basic physiology but also crucial for identifying new targets for treating these diseases. A central challenge for understanding coronary blood flow is that coronary structure and function exhibit different behaviors across a range of spatial and temporal scales. While experimental studies have sought to understand this feature by isolating specific mechanisms, in tandem, computational modeling is increasingly also providing a unique framework to integrate mechanistic behaviors across different scales. In addition, clinical methods for assessing coronary disease severity are continuously being informed and updated by findings in basic physiology. Coupling these technologies, computational modeling of the coronary circulation is emerging as a bridge between the experimental and clinical domains, providing a framework to integrate imaging and measurements from multiple sources with mathematical descriptions of governing physical laws. State-of-the-art computational modeling is being used to combine mechanistic models with data to provide new insight into coronary physiology, optimization of medical technologies, and new applications to guide clinical practice. PMID- 26123868 TI - High performance wash-free magnetic bioassays through microfluidically enhanced particle specificity. AB - Magnetic biosensors have emerged as a sensitive and versatile platform for high performance medical diagnostics. These magnetic biosensors require well-tailored magnetic particles as detection probes, which need to give rise to a large and specific biological signal while showing very low nonspecific binding. This is especially important in wash-free bioassay protocols, which do not require removal of particles before measurement, often a necessity in point of care diagnostics. Here we show that magnetic interactions between magnetic particles and magnetized sensors dramatically impact particle transport and magnetic adhesion to the sensor surfaces. We investigate the dynamics of magnetic particles' biomolecular binding and magnetic adhesion to the sensor surface using microfluidic experiments. We elucidate how flow forces can inhibit magnetic adhesion, greatly diminishing or even eliminating nonspecific signals in wash free magnetic bioassays, and enhancing signal to noise ratios by several orders of magnitude. Our method is useful for selecting and optimizing magnetic particles for a wide range of magnetic sensor platforms. PMID- 26123870 TI - Long Curriculum in Resident Education. PMID- 26123871 TI - Proximal femoral excision with interposition myoplasty for cerebral palsy patients with painful chronic hip dislocation. AB - PURPOSE: Proximal femoral excision is a salvage procedure for painful chronic hip dislocation in cerebral palsy (CP) patients. The primary objective of this article is to describe our experience of an amplified interposition myoplasty, with appropriate peri-operative pain and tone management strategies, in a cohort of non-ambulatory CP patients with painful chronic hip dislocation. Our secondary objective is to present the clinical outcomes of these patients. METHODS: We describe our experience in 20 CP patients (25 procedures) at mean 54-month (range 27-169) follow-up with a surgical technique that includes an augmented interposition myoplasty and tone management. The indications for surgery were pain (21 hips), poor sitting tolerance (11) and difficulty with perineal care (8). RESULTS: The mean age was 22 years (range 10-40) with 11 patients Gross Motor Function Classification Scale (GMFCS) IV and 9 patients GMFCS V. Mean length of stay was 13 days (3-35). One procedure required revision at 12 months. Mean pain score improved from 7.8 (5-10) pre-operatively to 2.8 (1-5) post operatively (p < 0.001). Sitting tolerance improved in all patients and in 75 % (15) perineal care was easier. CONCLUSIONS: Our interposition myoplasty technique with individualised pain/tone management has good outcomes in this cohort of patients with multiple co-morbidities. PMID- 26123869 TI - Relationship between synovial fluid ARGS-aggrecan fragments, cytokines, MMPs, and TIMPs following acute ACL injury: A cross-sectional study. AB - Severe knee trauma, such as an ACL disruption, produces aggrecan degradation as evidenced by elevated synovial fluid (SF) N-terminal (393) Alanine-Arginine Glycine-Serine (ARGS) neoepitope (or ARGS-aggrecan) and is associated with inflammatory activity soon after injury. However, it is not known if this process persists for a substantial time interval following the initial trauma. The purpose of this study was to evaluate relationships between SF ARGS concentrations and an array of cytokines, matrix metalloproteases (MMPs), and tissue inhibitor of metalloproteases (TIMPs) during the initial 6 months following ACL rupture. SF samples from 67 ACL-injured subjects (29 women) were analyzed within 6 months of injury (18-155 days), immediately prior to surgical ACL reconstruction. Relationships between ARGS and individual analyte concentrations, as well as MMP/TIMP ratios were evaluated. Statistically significant relationships were found between ARGS and basic fibroblast growth factor (FGF2) (p=0.03) and TIMP-3 (p=0.01). Our findings suggest that FGF2, considered to be primarily catabolic in articular cartilage, is not downregulated as ARGS concentration declines over time since injury. In addition, these results support the hypothesis that an upregulation of TIMP-3, the primary aggrecanase inhibitor, is elicited in response to increased aggrecan degradation, which may inhibit further cleavage. PMID- 26123872 TI - Variable Holocene deformation above a shallow subduction zone extremely close to the trench. AB - Histories of vertical crustal motions at convergent margins offer fundamental insights into the relationship between interplate slip and permanent deformation. Moreover, past abrupt motions are proxies for potential tsunamigenic earthquakes and benefit hazard assessment. Well-dated records are required to understand the relationship between past earthquakes and Holocene vertical deformation. Here we measure elevations and (230)Th ages of in situ corals raised above the sea level in the western Solomon Islands to build an uplift event history overlying the seismogenic zone, extremely close to the trench (4-40 km). We find marked spatiotemporal heterogeneity in uplift from mid-Holocene to present: some areas accrue more permanent uplift than others. Thus, uplift imposed during the 1 April 2007 Mw 8.1 event may be retained in some locations but removed in others before the next megathrust rupture. This variability suggests significant changes in strain accumulation and the interplate thrust process from one event to the next. PMID- 26123873 TI - The futility study--Progress over the last decade. AB - We review the futility clinical trial design (also known as the non-superiority design) with respect to its emergence and methodologic developments over the last decade, especially in regard to its application to clinical trials for neurological disorders. We discuss the design's strengths as a programmatic screening device to weed out unpromising new treatments, its limitations and pitfalls, and a recent critique of the logic of the method. PMID- 26123874 TI - Benzodiazepine Use and Risk of Developing Alzheimer's Disease or Vascular Dementia: A Case-Control Analysis. AB - INTRODUCTION: Previous observational studies have associated benzodiazepine use with an increased risk of dementia. However, limitations in the study methods leave questions unanswered regarding the interpretation of the findings. METHODS: A case-control analysis was conducted using data from the UK-based Clinical Practice Research Datalink (CPRD). A total of 26,459 patients aged >=65 years with newly diagnosed Alzheimer's disease (AD) or vascular dementia (VaD) between 1998 and 2013 were identified and matched 1:1 to dementia-free controls on age, sex, calendar time, general practice, and number of years of recorded history. Adjusted odds ratios (aORs) were calculated with 95% confidence intervals (CIs) of developing AD or VaD in relation to previous benzodiazepine use, stratified by duration and benzodiazepine type. RESULTS: The aOR (95% CI) of developing AD for those who started benzodiazepines <1 year before diagnosis was 2.20 (1.91-2.53), and fell to the null for those who started between 2 and <3 years before [aOR 0.99 (0.84-1.17)]. The aOR (95% CI) of developing VaD for those who started benzodiazepines <1 year before diagnosis was 3.30 (2.78-3.92), and fell close to the null for those who started between 3 and <4 years before [aOR 1.16 (0.96 1.40)]. After accounting for benzodiazepine use initiated during this prodromal phase, long-term use of benzodiazepines was not associated with an increased risk of developing AD [aOR 0.69 (0.57-0.85)] or VaD [aOR 1.11 (0.85-1.45)]. CONCLUSION: After taking a prodromal phase into consideration, benzodiazepine use was not associated with an increased risk of developing AD or VaD. PMID- 26123875 TI - Cerebral Small-Vessel Disease in Neuro-Behcet Disease. AB - BACKGROUND: Involvement of central nervous system is very common in Behcet disease, known as neuro-Behcet disease (NBD). However, there have been few reports which evaluated stroke-like cerebral small-vessel disease associated with Behcet disease. OBJECTIVE: We evaluated cerebral small-vessel lesions by using magnetic resonance imaging in 2 patients with NBD. CLINICAL CASES: In a 41-year old woman case, who developed dysarthria and left hemiparesis, diffusion-weighted images (DWI) showed small high-intensity areas in the bilateral internal capsule. The right lesion had a low apparent diffusion coefficient (ADC) value, whereas the left one had a high value. In a 59-year-old woman case, who developed dysarthria and left hemihypesthesia, DWI showed high-intensity areas in the right side of the pons and in the right peduncle of the midbrain. The lesion in the pons had a low ADC value, whereas the lesion in the midbrain had a high value. ADC map may be useful to identify symptomatic lesions in the brain, because only the lesions with low ADC values were symptomatic. CONCLUSIONS: NBD should be considered in those who had not had any risk factors for ischemic stroke but experienced cerebral small-vessel disease. PMID- 26123876 TI - Repeated Transient Wallenberg's Syndrome: Probable Association with Ipsilateral Vertebral Artery Hypoplasia and Aortic Valve Disease. AB - BACKGROUND: Here we report a rare case of repeated transient Wallenberg's syndrome and discuss its mechanism. METHODS: Case report and literature review. RESULTS: A 57-year-old man was admitted for 1.5-month repeated transient Wallenberg's syndrome, including right-sided Horner's syndrome, lower limb weakness, and paresthesia on the right side of the body and face. His symptom appeared mostly during physical activity. Symptoms occurred nearly everyday and lasted from 5 minutes to 30 minutes. His cranial magnetic resonance imaging (MRI) including diffusion-weighted MRI imaging was normal, and his cervical contrast enhanced magnetic resonance angiography reflected right vertebral artery hypoplasia. Twenty-four-hour electrocardiogram and electroencephalography showed no abnormalities. Echocardiography showed aortic valve calcification with moderate aortic stenosis, moderate aortic insufficiency, and dilated aorta. Dual antiplatelets or warfarin (international normalized ratio reached 2.07) were not effective to reduce the attacks. CONCLUSIONS: Hemodynamic instability due to valve disease combined with right vertebral artery hypoplasia could lead to transient Wallenberg's syndrome. Antithrombotics are often ineffective for this kind of patients and the best therapy for them could be to cure their valve disease. Repeated transient Wallenberg's syndrome is rare and that caused by ipsilateral vertebral artery hypoplasia and severe valve disease has not been reported up till now to our knowledge, so it will widen the knowledge on etiologies of transient ischemic attacks and provide information and reference to cardiologists and neurologists in diagnosis and treatment for patients with similar clinical manifestations. PMID- 26123877 TI - Pantomiming tool use with an imaginary tool in hand as compared to demonstration with tool in hand specifically modulates the left middle and superior temporal gyri. AB - Neuropsychological lesion studies evidence the necessity to differentiate between various forms of tool-related actions such as real tool use, tool use demonstration with tool in hand and without physical target object, and pantomime without tool in hand. However, thus far, neuroimaging studies have primarily focused only on investigating tool use pantomimes. The present fMRI study investigates pantomime without tool in hand as compared to tool use demonstration with tool in hand in order to explore patterns of cerebral signal modulation associated with acting with imaginary tools in hand. Fifteen participants performed with either hand (i) tool use pantomime with an imaginary tool in hand in response to visual tool presentation and (ii) tool use demonstration with tool in hand in response to visual-tactile tool presentation. In both conditions, no physical target object was present. The conjunction analysis of the right and left hands executions of tool use pantomime relative to tool use demonstration yielded significant activity in the left middle and superior temporal lobe. In contrast, demonstration relative to pantomime revealed large bihemispherically distributed homologous areas of activity. Thus far, fMRI studies have demonstrated the relevance of the left middle and superior temporal gyri in viewing, naming, and matching tools and related actions and contexts. Since in our study all these factors were equally (ir)relevant both in the tool use pantomime and the tool use demonstration conditions, the present findings enhance the knowledge about the function of these brain regions in tool-related cognitive processes. The two contrasted conditions only differ regarding the fact that the pantomime condition requires the individual to act with an imaginary tool in hand. Therefore, we suggest that the left middle and superior temporal gyri are specifically involved in integrating the projected mental image of a tool in the execution of a tool-specific movement concept. PMID- 26123878 TI - Experiences of Detention under the Mental Health Act for Adults with Anorexia Nervosa. AB - People with Anorexia Nervosa are often resistant to treatment and can be detained under the Mental Health Act. Detention can be distressing for some client groups; however, there is little research to explore how people with Anorexia Nervosa experience detention and how these experiences impact on recovery. This study utilized a qualitative methodology to develop a model for understanding how people perceive, experience and process detention under the Mental Health Act. Data from 12 participants was analysed using constructivist grounded theory. Four overarching categories conceptualize their experience over time: 'the battle', 'the bubble', 'stepping out of the bubble' and 'the anorexic self'. Within each overarching category are further subordinate categories that represent the nuances of the data. The resultant model is discussed in relation to the literature, whilst recommendations have been made to embed person-centred, recovery practice into inpatient services. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: People detained under the mental health act with anorexia nervosa often respond by engaging in a battle with clinicians. This follows by the person withdrawing into a 'bubble' where the individual starts to feel some relief that they are no longer in control of their eating, but this competes with the lack of self and the emerging anorexic self. Clinicians need to be aware that individuals detained may have mixed feelings about their hospital admission. PMID- 26123879 TI - Anaerobic blood culture isolates in a Norwegian university hospital: identification by MALDI-TOF MS vs 16S rRNA sequencing and antimicrobial susceptibility profiles. AB - We investigated 197 anaerobic isolates recovered from blood cultures in the period 2009-2013. The isolates included were Bacteroides spp., Clostridium spp., Prevotella spp., Fusobacterium spp. and Gram-positive anaerobic cocci (GPAC). Identification results by MALDI-TOF MS were compared to those obtained by 16S rRNA sequencing, and the MICs of benzylpenicillin, clindamycin, piperacillin tazobactam, meropenem and metronidazole were determined by Etests. The MALDI-TOF MS correctly identified 94.9% of the anaerobes to the genus level, and 86.8% to the species level, with errors mainly among the non-fragilis Bacteroides spp. and GPAC. About 73.3% of the isolates were non-susceptible to penicillin, mainly due to high resistance rates in the Bacteroides spp. (99.2%) and Prevotella spp. (69.2%). About 18.5% of the isolates were clindamycin resistant. Piperacillin tazobactam had an excellent activity against all anaerobes except the non fragilis Bacteroides spp., of which 43.8% were non-susceptible. The clinical significance of such a high resistance rate is unclear. Meropenem and metronidazole were the most active antibiotics, with 96.9% and 97.9% of the isolates being susceptible. PMID- 26123880 TI - Divergence and convergence of commercial and scientific priorities in drug development: The case of Zelmid, the first SSRI antidepressant. AB - Based on a realist conceptualization of interests, this paper explores how commercial and scientific priorities appear to have converged and diverged during the development of the antidepressant Zelmid. The drug represents the first of the selective serotonin reuptake inhibitors (SSRIs) to reach the market. Zelmid was synthesized in 1971 and launched by the Swedish firm Astra in 1982, but subsequently withdrawn the next year because of adverse neurological effects. This paper draws on in-depth interviews with scientists representing both industry and academia who had high-level involvement in various phases of the project (experimental, pre-clinical and clinical), as well as on textual sources such as scientific articles and memoirs. Zelmid was a product of mechanism-based or "rational" drug discovery from the early 1960s and the associated intermingling of science and commerce. It is argued that both scientists and the pharmaceutical company shared an interest in embracing mechanism-based drug discovery because it simultaneously promised medico-scientific advances and profits. However, the intermingling of science and commerce also strained the relationship between scientific and commercial priorities further along the trajectory of the drug; for example, concerning issues such as dosage strategy and drug use in primary care, where corporate management allegedly took decisions contrary to the recommendations of both academic and company scientists. On such occasions the asymmetry in power became apparent in scientists' narratives: commercial considerations trumped those of science since, ultimately, decisions rest with management, not with scientists. In addition, temporality appears to be associated with the divergence of commercial and scientific priorities. While rare during experimental and pre-clinical phases, divergence was concentrated downstream to the clinical testing and post-marketing phases. It is hypothesized that a similar pattern of convergence and divergence of commercial and scientific priorities may exist in the trajectory of other drugs. PMID- 26123881 TI - The effects of utility evaluations, biomedical knowledge and modernization on intention to exclusively use biomedical health facilities among rural households in Mozambique. AB - In resource-limited settings, the choice between utilizing biomedical health services and/or traditional healers is critical to the success of the public health mission. In the literature, this choice has been predicted to be influenced by three major factors: knowledge about biomedical etiologies; cultural modernization; and rational choice. The current study investigated all three of these predicted determinants, applying data from a general household survey conducted in 2010 in Zambezia Province of Mozambique involving 1045 randomly sampled rural households. Overall, more respondents (N = 802) intended to continue to supplement their biomedical healthcare with traditional healer services in comparison with those intending to utilize biomedical care exclusively (N = 243). The findings strongly supported the predicted association between rational utility (measured as satisfaction with the quality of service and results from past care) with the future intention to continue to supplement or utilize biomedical care exclusively. Odds of moving away from supplementation increase by a factor of 2.5 if the respondent reported seeing their condition improve under government/private biomedical care. Odds of staying with supplementation increase by a factor 3.1 if the respondent was satisfied with traditional care and a factor of 16 if the condition had improved under traditional care. Modernization variables (education, income, religion, and Portuguese language skills) were relevant and provided a significant component of the best scientific model. Amount of biomedical knowledge was not a significant predictor of choice. There was a small effect on choice from knowing the limitations of biomedical care. The findings have implications for public healthcare promotion activities in areas where biomedical care is introduced as an alternative to traditional healing. PMID- 26123882 TI - Migrants' and professionals' views on culturally sensitive pre-hospital emergency care. AB - This study was designed to explore the views of migrants and professionals on culturally sensitive pre-hospital emergency care in order to adapt such care to migrants' needs. Interviews were conducted with 41 migrants who had received direct (as a patient) or indirect (as a significant other) pre-hospital emergency care. Furthermore, 20 professionals in the field of pre-hospital emergency care were interviewed. The content analysis showed five distinguishable categories based on the statements by the migrants and six categories based on the statements by the professionals. While migrants gave priority to basic proficiencies of first responders such as 'social/emotional competencies' and 'communication skills', the professionals considered '(basic) cultural knowledge', 'awareness' and 'attitude' the most important. Furthermore, migrants provided practical indications, e.g. regarding areas of cultural knowledge, whereas professionals seemed to view the issue of culturally pre-hospital emergency care from a more theoretical perspective. The issues of the culturally sensitive pre-hospital emergency care itself, as well as the varying points of view of the two groups interviewed, resulted in eight recommendations for culturally sensitive pre-hospital emergency care. PMID- 26123883 TI - Impact of the policy of expanding benefit coverage for cancer patients on catastrophic health expenditure across different income groups in South Korea. AB - To increase financial protection for catastrophic illness, South Korean government expanded the National Health Insurance (NHI) benefit coverage for cancer patients in September 2005. This paper investigated whether the policy has reduced inequality in catastrophic payments, defined as annual out-of-pocket (OOP) health payments exceeding 10% annual income, across different income groups. This study used the NHI claims data from 2002 to 2004 and 2006 to 2010. Triple difference estimator was employed to compare cancer patients as a treatment group with those with liver and cardio-cerebrovascular diseases as control groups and the low-income with the high-income groups. While catastrophic payments decreased in cancer patients compared with those of two diseases, they appeared to decrease more in the high-income than the low-income group. Considering that increased health care utilization and poor economic capacity may lead to a smaller reduction in catastrophic payments for the low-income than the high-income patients, the government needs to consider additional policy measures to increase financial protection for the poor. PMID- 26123884 TI - Drug use and social control: The negotiation of moral ambivalence. AB - Illicit drugs occupy an ambivalent position in late modern society; one that revolves around the twin themes of pleasure and disapproval. Drawing on Freudian psychoanalysis and Eliasian sociology this article considers how people, particularly those who use drugs, negotiate such ambivalence. Patterns of drug use and associated attitudes are examined on the basis of the Crime Survey for England and Wales and a specialist survey of largely recreational drug users in the United Kingdom. Although illicit drugs have become increasingly familiar, their use is still widely thought to be harmful and morally dubious, creating a series of challenges for those who engage in such behaviour. Ambivalence among drug users is evident in an awareness of potential costs as well as benefits; a tendency to avoid more harmful substances; a general emphasis on moderation; and a desire to use less. Building on previous work, which highlights the role of neutralisations in sustaining drug using behaviour, particular attention is paid to users' judgements about how their levels of consumption compare with other users. The analysis identifies a tendency among users to downplay their relative levels of use, which, it is argued, serves to shield them from some of the imperatives that may lead to decisions to cut down. As such, normalisation is said to be an intra-personal as well inter-personal process. The article concludes by discussing the potential of web-based personalised feedback as a harm reduction approach. PMID- 26123886 TI - Absent cavum septum pellucidum: a review with emphasis on associated commissural abnormalities. AB - The cavum septum pellucidum (CSP) is an important fetal midline forebrain landmark, and its absence often signifies additional underlying malformations. Frequently detected by prenatal sonography, absence of the CSP requires further imaging with pre- or postnatal MRI to characterize the accompanying abnormalities. This article reviews the developmental anatomy of the CSP and the pivotal role of commissurization in normal development. An understanding of the patterns of commissural abnormalities associated with absence of the CSP can lead to improved characterization of the underlying spectrum of pathology. PMID- 26123888 TI - Recombinant expression and functional analysis of an isoform of anti lipopolysaccharide factors (FcALF5) from Chinese shrimp Fenneropenaeus chinensis. AB - Antimicrobial peptides (AMPs) have a great potential to be used as a substitute for antibiotics since AMPs don't lead to bacteria's drug resistance. Anti lipopolysaccharide factors (ALFs) are one type of AMPs and exist in crustaceans. In the present study, we produced a recombinant protein (rFcALF5) of an ALF isoform (FcALF5) from Chinese shrimp Fenneropenaeus chinensis through a prokaryotic expression system. The rFcALF5 exhibited varied antibacterial activities against different bacteria. Besides its antibacterial activities, it could also inhibit the infection of white spot syndrome virus (WSSV) to shrimp after pre-incubation with this virus. In order to learn the antiviral mechanism on how rFcALF5 influences WSSV infection, the interaction between the total proteins of WSSV and rFcALF5 was analyzed and the data showed that rFcALF5 had direct interaction with the envelope protein VP24 of WSSV. The LPS binding domain (LBD) of FcALF5 also showed direct interaction with VP24 of WSSV. Therefore we inferred that the antiviral activity of FcALF5 might be achieved through the binding of its LBD to VP24 of WSSV. These findings provided more information to develop new strategies for the control of shrimp disease in aquaculture. PMID- 26123889 TI - Differential immune gene expression profiles in susceptible and resistant full sibling families of Atlantic salmon (Salmo salar) challenged with infectious pancreatic necrosis virus (IPNV). AB - This study aims to identify at the expression level the immune-related genes associated with IPN-susceptible and resistant phenotypes in Atlantic salmon full sibling families. We have analyzed thirty full-sibling families infected by immersion with IPNV and then classified as resistant or susceptible using a multivariate survival analysis based on a gamma-Cox frailty model and the Kaplan Meier mortality curves. In four families within each group head kidneys were pooled for real-time PCR and one-color salmon-specific oligonucleotide microarray (21K) analysis at day 1 and 5 post-infection. Transcripts involved in innate response (IL-6, IFN-alpha), antigen presentation (HSP-70, HSP-90, MHC-I), TH1 response (IL-12, IFN-gamma, CRFB6), immunosuppression (IL-10, TGF-beta1) and leukocyte activation and migration (CCL-19, CD18) showed a differential expression pattern between both phenotypes, except in IL-6. In susceptible families, except for IFN-gamma, the expressions dropped to basal values at day 5 post-infection. In resistant families, unlike susceptible families, levels remained high or increased (except for IL-6) at day 5. Transcriptomic analysis showed that both families have a clear differential expression pattern, resulting in a marked down-regulation in immune related genes involved in innate response, complement system, antigen recognition and activation of immune response in IPN resistant. Down-regulation of genes, mainly related to tissue differentiation and protein degradation metabolism, was also observed in resistant families. We have identified an immune-related gene patterns associated with susceptibility and resistance to IPNV infection of Atlantic salmon. This suggests that a limited immune response is associated with resistant fish phenotype to IPNV challenge while a highly inflammatory but short response is associated with susceptibility. PMID- 26123890 TI - An inducible transgene reports activation of macrophages in live zebrafish larvae. AB - Macrophages are the most functionally heterogenous cells of the hematopoietic system. Given many diseases are underpinned by inappropriate macrophage activation, macrophages have emerged as a therapeutic target to treat disease. A thorough understanding of what controls macrophage activation will likely reveal new pathways that can be manipulated for therapeutic benefit. Live imaging fluorescent macrophages within transgenic zebrafish larvae has provided a valuable window to investigate macrophage behavior in vivo. Here we describe the first transgenic zebrafish line that reports macrophage activation, as evidenced by induced expression of an immunoresponsive gene 1(irg1):EGFP transgene. When combined with existing reporter lines that constitutively mark macrophages, we reveal this unique transgenic line can be used to live image macrophage activation in response to the bacterial endotoxin lipopolysaccharide and xenografted human cancer cells. We anticipate the Tg(irg1:EGFP) line will provide a valuable tool to explore macrophage activation and plasticity in the context of different disease models. PMID- 26123891 TI - Chondrogenic Differentiation Processes in Human Bone Marrow Aspirates upon rAAV Mediated Gene Transfer and Overexpression of the Insulin-Like Growth Factor I. AB - Direct therapeutic gene transfer in marrow concentrates is an attractive strategy to conveniently enhance the chondrogenic differentiation processes as a means to improve the healing response of damaged articular cartilage upon reimplantation in sites of injury. In the present study, we evaluated the ability of the clinically adapted recombinant adeno-associated virus (rAAV) vectors to mediate overexpression of the insulin-like growth factor I (IGF-I) in human bone marrow aspirates that may modulate the proliferative, anabolic activities, and chondrogenic differentiation potential in such samples in vitro. The results demonstrate that successful, significant rAAV-mediated IGF-I gene transfer and expression were achieved in transduced aspirates (up to 105.9+/-35.1 pg rhIGF I/mg total proteins) over time (21 days) at very high levels (~80% of cells expressing the candidate IGF-I transgene), leading to increased levels of proliferation, matrix synthesis, and chondrogenic differentiation over time compared with the control (lacZ) condition. Treatment with the candidate IGF-I vector also stimulated the hypertrophic and osteogenic differentiation processes in the aspirates, suggesting that the regulation of IGF-I expression through rAAV will be a prerequisite for future translation of the approach in vivo. However, these findings show the possible benefits of this vector class to directly modify marrow concentrates as a convenient tool for strategies that aim at improving the repair of articular cartilage lesions. PMID- 26123892 TI - The effect of medical cannabis laws on juvenile cannabis use. AB - BACKGROUND: A number of states in the United States legally allow the use of cannabis as a medical therapy to treat an illness or to alleviate symptoms. Concern persists as to whether these types of laws are increasing juvenile recreational cannabis use. It is also plausible that medical cannabis laws engender an escalation of illicit non-cannabis drug use among juveniles because cannabis is frequently considered to be a gateway drug. METHODS: This study uses longitudinal data drawn from the National Survey on Drug Use and Health for the 50 U.S. states and a cross-sectional pooled-time series research design to investigate the effect of medical cannabis laws on juvenile cannabis use and on juvenile non-cannabis illicit drug use. Our study period encompasses five measurement periods calibrated in two-year intervals (2002-2003 to 2010-2011). This research design is advantageous in that it affords us the ability not only to assess the effect of the implementation of medical cannabis laws on juvenile drug use, but also to consider other state-specific factors that may explain variation in drug use that cannot be accounted for using a single time series. RESULTS: Findings show that medical cannabis laws amplify recreational juvenile cannabis use. Other salient predictors of juvenile cannabis use at the state level of analysis include perceived availability of cannabis, percent of juveniles skipping school, severity of perceived punishment for cannabis possession, alcohol consumption, percent of respondents with a father residing in household, and percent of families in the state receiving public assistance. There is little empirical evidence to support the view that medical cannabis laws affect juveniles' use of illicit non-cannabis drugs. CONCLUSION: Based on our findings, it seems reasonable to speculate that medical cannabis laws amplify juveniles' use of cannabis by allaying the social stigma associated with recreational cannabis use and by placating the fear that cannabis use could potentially result in a negative health outcome. PMID- 26123893 TI - Expansion of HCV treatment access to people who have injected drugs through effective translation of research into public health policy: Scotland's experience. AB - Seven years have elapsed since the Scottish Government launched its Hepatitis C Action Plan - a Plan to improve services to prevent transmission of infection, particularly among people who inject drugs (PWID), identify those infected and ensure those infected receive optimal treatment. The Plan was underpinned by industrial scale funding (around L100 million, in addition to the general NHS funding, will have been invested by 2015), and a web of accountable national and local multi-disciplinary multi-agency networks responsible for the planning, development and delivery of services. Initiatives ranged from the introduction of testing in specialist drug services through finger-prick blood sampling by non clinical staff, to the setting of government targets to ensure rapid scale-up of antiviral therapy. The Plan was informed by comprehensive national monitoring systems, indicating the extent of the problem not just in terms of numbers infected, diagnosed and treated but also the more penetrative data on the number advancing to end-stage liver disease and death, and also through compelling modelling work demonstrating the potential beneficial impact of scaling-up therapy and the mounting cost of not acting. Achievements include around 50% increase in the proportion of the infected population diagnosed (38% to 55%); a sustained near two-and-a-half fold increase in the annual number of people initiated onto therapy (470 to 1050) with more pronounced increases among PWID (300 to 840) and prisoners (20 to 140); and reversing of an upward trend in the overall number of people living with chronic infection. The Action Plan has demonstrated that a Government-backed, coordinated and invested approach can transform services and rapidly improve the lives of thousands. Cited as "an impressive example of a national strategy" by the Global Commission on Drug Policy, the Scottish Plan has also provided fundamental insights of international relevance into the management of HCV among PWID. PMID- 26123894 TI - Opioid substitution treatment in Tihar prisons, India: Process of implementation. PMID- 26123895 TI - Science 1, Religion 5: A reply to. PMID- 26123896 TI - Service use before and after the provision of scatter-site Housing First for chronically homeless individuals with severe alcohol use disorders. PMID- 26123897 TI - Reality and feasibility for pharmacy-delivered services for people who inject drugs in Xichang, China: Comparisons between pharmacy staff and people who inject drugs. AB - BACKGROUND: In 2010, the reported overall HIV prevalence in Liangshan China (1.14%) was 19.7 times of the overall estimated prevalence in China (0.058%), and injection drug use contributed to 60.0% of overall HIV infections in Xichang, the Capital city of Liangshan. With one national methadone clinic and three outpatient service sites, and three NEP sites, the HIV prevalence among people who inject drugs (PWID) in Xichang was estimated as 18.0% (2.8 times of national HIV prevalence among PWID) in 2012. METHODS: Face-to-face questionnaire interviews were used in a cross-sectional study to assess experience, attitudes, possibility and acceptability of implementing 8 pharmacy-delivered services among PWID (n=403). The concordance of attitudes, possibility and acceptability between PWID and pharmacy staff (n=50) was examined. RESULTS: Rather than medical facility (23.1%), and NEP (8.9%), pharmacies were the main source of syringes for PWID in the last 12 months (82.1%), PWID (63.5%) reported syringes could be bought in single piece and at the price of $0.16 USD (59.3%). In the last 30 days, only 1 PWID brought used syringes back to a pharmacy. Pharmacy staff's attitudes were generally negative but nearly neutral (average score -0.18), discrimination/business concerns against pharmacy-delivered services existed, and 4 of 5 compared attitude questions between PWID and pharmacy staff were statistically different (p<0.01). 5 of 8 pharmacy-delivered services were available for PWID at low level (<=16.9%). Pharmacy staff's supportive perception for pharmacy-delivered services focused on pharmacies' initiate roles targeting on general population more than on PWID. PWID were more supportive and optimistic than pharmacy staff toward potential usage of pharmacy-delivered services (p<0.05). CONCLUSION: Pharmacy-delivered services for PWID in Xichang were partly in reality, and could be feasible. It is urgently needed to address the legal requirements and remuneration for pharmacies. Pharmacy staff should receive additional training on services related knowledge and skills, cultural sensitivity toward PWID. Successful pharmacy-delivered services would benefit from identifying mutual interest and benefit between pharmacies and PWID. PMID- 26123898 TI - Methods and predictors of tampering with a tamper-resistant controlled-release oxycodone formulation. AB - BACKGROUND: In April 2014, a tamper-resistant controlled-release oxycodone formulation was introduced into the Australian market. This study aimed to identify the level and methods of tampering with reformulated oxycodone, demographic and clinical characteristics of those who reported tampering with reformulated oxycodone, and perceived attractiveness of original and reformulated oxycodone for misuse (via tampering). METHODS: A prospective cohort of 522 people who regularly tampered with pharmaceutical opioids and had tampered with the original oxycodone product in their lifetime completed two interviews before (January-March 2014: Wave 1) and after (May-August 2014: Wave 2) introduction of reformulated oxycodone. RESULTS: Four-fifths (81%) had tampered with the original oxycodone formulation in the month prior to Wave 1; use and attempted tampering with reformulated oxycodone amongst the sample was comparatively low at Wave 2 (29% and 19%, respectively). Reformulated oxycodone was primarily swallowed (15%), with low levels of recent successful injection (6%), chewing (2%), drinking/dissolving (1%), and smoking (<1%). Participants who tampered with original and reformulated oxycodone were socio-demographically and clinically similar to those who had only tampered with the original formulation, except the former were more likely to report prescribed oxycodone use and stealing pharmaceutical opioid, and less likely to report moderate/severe anxiety. There was significant diversity in the methods for tampering, with attempts predominantly prompted by self-experimentation (rather than informed by word-of mouth or the internet). Participants rated reformulated oxycodone as more difficult to prepare and inject and less pleasant to use compared to the original formulation. CONCLUSION: Current findings suggest that the introduction of the tamper-resistant product has been successful at reducing, although not necessarily eliminating, tampering with the controlled-release oxycodone formulation, with lower attractiveness for misuse. Appropriate, effective treatment options must be available with increasing availability of abuse deterrent products, given the reduction of oxycodone tampering and use amongst a group with high rates of pharmaceutical opioid dependence. PMID- 26123899 TI - Successful treatment of Batrachochytrium salamandrivorans infections in salamanders requires synergy between voriconazole, polymyxin E and temperature. AB - Chytridiomycosis caused by the chytrid fungus Batrachochytrium salamandrivorans (Bsal) poses a serious threat to urodelan diversity worldwide. Antimycotic treatment of this disease using protocols developed for the related fungus Batrachochytrium dendrobatidis (Bd), results in therapeutic failure. Here, we reveal that this therapeutic failure is partly due to different minimum inhibitory concentrations (MICs) of antimycotics against Bsal and Bd. In vitro growth inhibition of Bsal occurs after exposure to voriconazole, polymyxin E, itraconazole and terbinafine but not to florfenicol. Synergistic effects between polymyxin E and voriconazole or itraconazole significantly decreased the combined MICs necessary to inhibit Bsal growth. Topical treatment of infected fire salamanders (Salamandra salamandra), with voriconazole or itraconazole alone (12.5 MUg/ml and 0.6 MUg/ml respectively) or in combination with polymyxin E (2000 IU/ml) at an ambient temperature of 15 degrees C during 10 days decreased fungal loads but did not clear Bsal infections. However, topical treatment of Bsal infected animals with a combination of polymyxin E (2000 IU/ml) and voriconazole (12.5 MUg/ml) at an ambient temperature of 20 degrees C resulted in clearance of Bsal infections. This treatment protocol was validated in 12 fire salamanders infected with Bsal during a field outbreak and resulted in clearance of infection in all animals. PMID- 26123901 TI - Pathological and prognostic significance of matrix metalloproteinase-2 expression in ovarian cancer: a meta-analysis. AB - Matrix metalloproteinase-2 (MMP-2) has been linked with tumor invasion and metastasis. However, the role of MMP-2 expression in ovarian cancer remains controversial. By searching the PubMed, Embase, Wanfang, and China National Knowledge Infrastructure databases, we conducted a meta-analysis to evaluate the pathological and prognostic significance of MMP-2 in ovarian cancer. Studies were pooled, and the odds ratio (OR) and its corresponding 95 % confidence interval (CI) were calculated. Version 11.0 STATA software was used for statistical analysis. Twenty-seven relevant articles were included for this meta-analysis study. The expression of MMP-2 in cancer tissue was significantly higher than that in benign or normal ovarian tissue [cancer vs. benign, OR 10.09 (95 % CI 6.95-14.64); P < 0.001; cancer vs. normal, OR 30.48 (95 % CI 17.19-54.05); P < 0.001; benign vs. normal, OR 1.88 (95 % CI 1.08-3.29); P = 0.025]. The expression of MMP-2 in stage III-IV or lymph node metastasis was significantly higher than that in stage I-II or that without metastasis, respectively [OR 5.83 (95 % CI 4.32-7.85); P < 0.001; OR 7.20 (95 % CI 4.75-10.91); P < 0.001]. MMP-2 was associated with histological types and grade of ovarian cancer [serous vs. mucinous, OR 1.67 (95 % CI 1.17-2.39); P = 0.004; grade 3 vs. 1, 2, OR 3.23 (95 % CI 2.29-4.55); P < 0.001]. However, the age of patients was not associated with MMP-2 expression [OR 1.25 (95 % CI 0.61-2.58); P = 0.546]. In conclusion, MMP-2 is related to the malignant degree, FIGO stage, histological types and grade, and lymph node metastasis of ovarian cancer. It may play a significant role in clinical guidelines for the treatment and prognostic evaluation. PMID- 26123900 TI - Toll-like receptor 3 expression and function in childhood idiopathic nephrotic syndrome. AB - The efficacy of steroids and immunosuppressive treatments in idiopathic nephrotic syndrome (INS) hints at the implication of immune cells in the pathophysiology of the disease. Toll-like receptor (TLR) dysfunctions are involved in many kidney diseases of immune origin, but remain little described in INS. We investigated the expression and function of TLRs in peripheral blood mononuclear cells (PBMC) of INS children, including 28 in relapse, 23 in remission and 40 controls. No child had any sign of infection, but a higher Epstein-Barr virus viral load was measured in the PBMC of relapsing patients. TLR-3 expression was increased in B cells only during INS remission. There was a negative correlation between proteinuria and TLR-3 expression in total and the main subsets of PBMC from INS patients. The expression of TLR-8 was also increased in both CD4(+) T cells and B cells in INS remission. There was a negative correlation between proteinuria and TLR-8 expression in total PBMC, CD4(+) T cells and B cells of INS patients. Nevertheless, TLR-3 and TLR-8 expression was normalized in all PBMC subsets in an additional group of 15 INS patients in remission with B cell repletion after rituximab therapy. Paradoxically, interferon (IFN) regulatory factor 3 transactivation was increased in PBMC of all INS patients. In-vitro secretion of IFN-alpha and interleukin 6 were increased spontaneously in PBMC of INS remission patients, whereas PBMC from all INS patients displayed an impaired IFN-alpha secretion after TLR-3 stimulation. Thus, TLR-3 pathway dysfunctions may be closely involved in INS pathogenesis. PMID- 26123902 TI - Estradiol levels modulate brain activity and negative responses to psychosocial stress across the menstrual cycle. AB - Although ovarian hormones are thought to have a potential role in the well-known sex difference in mood and anxiety disorders, the mechanisms through which ovarian hormone changes contribute to stress regulation are not well understood. One mechanism by which ovarian hormones might impact mood regulation is by mediating the effect of psychosocial stress, which often precedes depressive episodes and may have mood consequences that are particularly relevant in women. In the current study, brain activity and mood response to psychosocial stress was examined in healthy, normally cycling women at either the high or low estradiol phase of the menstrual cycle. Twenty eight women were exposed to the Montreal Imaging Stress Task (MIST), with brain activity determined through functional magnetic resonance imaging, and behavioral response assessed with subjective mood and stress measures. Brain activity responses to psychosocial stress differed between women in the low versus high estrogen phase of the menstrual cycle: women with high estradiol levels showed significantly less deactivation in limbic regions during psychosocial stress compared to women with low estradiol levels. Additionally, women with higher estradiol levels also had less subjective distress in response to the MIST than women with lower estradiol levels. The results of this study suggest that, in normally cycling premenopausal women, high estradiol levels attenuate the brain activation changes and negative mood response to psychosocial stress. Normal ovarian hormone fluctuations may alter the impact of psychosocially stressful events by presenting periods of increased vulnerability to psychosocial stress during low estradiol phases of the menstrual cycle. This menstrual cycle-related fluctuation in stress vulnerability may be relevant to the greater risk for affective disorder or post-traumatic stress disorder in women. PMID- 26123903 TI - Reviewing Japanese Concepts of Amae and Ie to Deeper Understand the Relevance of Secure-Base Behavior in the Context of Japanese Caregiver-Child Interactions. AB - Attachment theorists believe that children rely on their caregivers for protection and exploration. Due to this emphasis on independent exploration, however, the extent to which this notion of secure-base behavior is valid in societies emphasizing belongingness, such as Japan, has been questioned. By conducting an in-depth exploration of two Japanese collectivistic concepts, amae and ie, the present paper reexamines the relevance of secure-base behavior in Japan. Current discussions of amae have relied on psychoanalytic concepts that were developed in Western culture, and thus may not accurately represent Japanese parent-child relations. By examining another traditional concept of the family system, ie, this paper proposes that attachment theory is relevant in Japanese culture because children's individual competence is important to their families. PMID- 26123904 TI - Patient-Centred Coordinated Care in Times of Emerging Diseases and Epidemics. Contribution of the IMIA Working Group on Patient Safety. AB - OBJECTIVES: In this paper the researchers describe how existing health information technologies (HIT) can be repurposed and new technologies can be innovated to provide patient-centered care to individuals affected by new and emerging diseases. METHODS: The researchers conducted a focused review of the published literature describing how HIT can be used to support safe, patient centred, coordinated care to patients who are affected by Ebola (an emerging disease). RESULTS: New and emerging diseases present opportunities for repurposing existing technologies and for stimulating the development of new HIT innovation. Innovative technologies may be developed such as new software used for tracking patients during new or emerging disease outbreaks or by repurposing and extending existing technologies so they can be used to support patients, families and health professionals who may have been exposed to a disease. The paper describes the development of new technologies and the repurposing and extension of existing ones (such as electronic health records) using the most recent outbreak of Ebola as an example. PMID- 26123905 TI - Does Informatics Enable or Inhibit the Delivery of Patient-centred, Coordinated, and Quality-assured Care: a Delphi Study. A Contribution of the IMIA Primary Health Care Informatics Working Group. AB - BACKGROUND: Primary care delivers patient-centred and coordinated care, which should be quality-assured. Much of family practice now routinely uses computerised medical record (CMR) systems, these systems being linked at varying levels to laboratories and other care providers. CMR systems have the potential to support care. OBJECTIVE: To achieve a consensus among an international panel of health care professionals and informatics experts about the role of informatics in the delivery of patient-centred, coordinated, and quality-assured care. METHOD: The consensus building exercise involved 20 individuals, five general practitioners and 15 informatics academics, members of the International Medical Informatics Association Primary Care Informatics Working Group. A thematic analysis of the literature was carried out according to the defined themes. RESULTS: The first round of the analysis developed 27 statements on how the CMR, or any other information system, including paper-based medical records, supports care delivery. Round 2 aimed at achieving a consensus about the statements of round one. Round 3 stated that there was an agreement on informatics principles and structures that should be put in place. However, there was a disagreement about the processes involved in the implementation, and about the clinical interaction with the systems after the implementation. CONCLUSIONS: The panel had a strong agreement about the core concepts and structures that should be put in place to support high quality care. However, this agreement evaporated over statements related to implementation. These findings reflect literature and personal experiences: whilst there is consensus about how informatics structures and processes support good quality care, implementation is difficult. PMID- 26123906 TI - Usability Flaws in Medication Alerting Systems: Impact on Usage and Work System. AB - OBJECTIVES: Previous research has shown that medication alerting systems face usability issues. There has been no previous attempt to systematically explore the consequences of usability flaws in such systems on users (i.e. usage problems) and work systems (i.e. negative outcomes). This paper aims at exploring and synthesizing the consequences of usability flaws in terms of usage problems and negative outcomes on the work system. METHODS: A secondary analysis of 26 papers included in a prior systematic review of the usability flaws in medication alerting was performed. Usage problems and negative outcomes were extracted and sorted. Links between usability flaws, usage problems, and negative outcomes were also analyzed. RESULTS: Poor usability generates a large variety of consequences. It impacts the user from a cognitive, behavioral, emotional, and attitudinal perspective. Ultimately, usability flaws have negative consequences on the workflow, the effectiveness of the technology, the medication management process, and, more importantly, patient safety. Only few complete pathways leading from usability flaws to negative outcomes were identified. CONCLUSION: Usability flaws in medication alerting systems impede users, and ultimately their work system, and negatively impact patient safety. Therefore, the usability dimension may act as a hidden explanatory variable that could explain, at least partly, the (absence of) intended outcomes of new technology. PMID- 26123907 TI - Why Patient Centered Care Coordination Is Important in Developing Countries? Contribution of the IMIA Health Informatics for Development Working Group. AB - Patient Centered Care Coordination (PCCC) focuses on the patient health care needs. PCCC involves the organization, the patients and their families, that must coordinate resources in order to accomplish the goals of PCCC. In developing countries, where disparities are frequent, PCCC could improve clinical outcomes, costs and patients satisfaction. OBJECTIVE: the IMIA working group Health Informatics for Development analyzes the benefits, identifies the barriers and proposes strategies to reach PCCC. METHODS: Discussions about PCCC emerged from a brief guide that posed questions about what is PCCC, why consider PCCC important, barriers to grow in this direction and ask about resources considered relevant in the topic. RESULTS: PCCC encompasses a broad definition, includes physical, mental, socio-environmental and self care. Even benefits are proved, in developing countries the lack of a comprehensive and integrated healthcare network is one of the main barriers to reach this objective. Working hard to reach strong health policies, focus on patients, and optimizing the use of resources could improve the performance in the devolvement of PCCC programs. International collaboration could bring benefits. We believe information IT, and education in this field will play an important role in PCCC. CONCLUSION: PCCC in developing countries has the potential to improve quality of care. Education, IT, policies and cultural issues must be addressed in an international collaborative context in order to reach this goal. PMID- 26123908 TI - From Dyadic Ties to Information Infrastructures: Care-Coordination between Patients, Providers, Students and Researchers. Contribution of the Health Informatics Education Working Group. AB - OBJECTIVE: To share how an effectual merging of local and online networks in low resource regions can supplement and strengthen the local practice of patient centered care through the use of an online digital infrastructure powered by all stakeholders in healthcare. User Driven Health Care offers the dynamic integration of patient values and evidence based solutions for improved medical communication in medical care. INTRODUCTION: This paper conceptualizes patient care-coordination through the lens of engaged stakeholders using digital infrastructures tools to integrate information technology. We distinguish this lens from the prevalent conceptualization of dyadic ties between clinician patient, patient-nurse, clinician-nurse, and offer the holistic integration of all stakeholder inputs, in the clinic and augmented by online communication in a multi-national setting. METHODS: We analyze an instance of the user-driven health care (UDHC), a network of providers, patients, students and researchers working together to help manage patient care. The network currently focuses on patients from LMICs, but the provider network is global in reach. We describe UDHC and its opportunities and challenges in care-coordination to reduce costs, bring equity, and improve care quality and share evidence. CONCLUSION: UDHC has resulted in coordinated global based local care, affecting multiple facets of medical practice. Shared information resources between providers with disparate knowledge, results in better understanding by patients, unique and challenging cases for students, innovative community based research and discovery learning for all. PMID- 26123909 TI - Patient Portals as a Means of Information and Communication Technology Support to Patient- Centric Care Coordination - the Missing Evidence and the Challenges of Evaluation. A joint contribution of IMIA WG EVAL and EFMI WG EVAL. AB - OBJECTIVES: To review the potential contribution of Information and Communication Technology (ICT) to enable patient-centric and coordinated care, and in particular to explore the role of patient portals as a developing ICT tool, to assess the available evidence, and to describe the evaluation challenges. METHODS: Reviews of IMIA, EFMI, and other initiatives, together with literature reviews. RESULTS: We present the progression from care coordination to care integration, and from patient-centric to person-centric approaches. We describe the different roles of ICT as an enabler of the effective presentation of information as and when needed. We focus on the patient's role as a co-producer of health as well as the focus and purpose of care. We discuss the need for changing organisational processes as well as the current mixed evidence regarding patient portals as a logical tool, and the reasons for this dichotomy, together with the evaluation principles supported by theoretical frameworks so as to yield robust evidence. CONCLUSIONS: There is expressed commitment to coordinated care and to putting the patient in the centre. However to achieve this, new interactive patient portals will be needed to enable peer communication by all stakeholders including patients and professionals. Few portals capable of this exist to date. The evaluation of these portals as enablers of system change, rather than as simple windows into electronic records, is at an early stage and novel evaluation approaches are needed. PMID- 26123910 TI - Medical Informatics Education & Research in Greece. AB - OBJECTIVES: This paper aims to present an overview of the medical informatics landscape in Greece, to describe the Greek ehealth background and to highlight the main education and research axes in medical informatics, along with activities, achievements and pitfalls. METHODS: With respect to research and education, formal and informal sources were investigated and information was collected and presented in a qualitative manner, including also quantitative indicators when possible. RESULTS: Greece has adopted and applied medical informatics education in various ways, including undergraduate courses in health sciences schools as well as multidisciplinary postgraduate courses. There is a continuous research effort, and large participation in EU-wide initiatives, in all the spectrum of medical informatics research, with notable scientific contributions, although technology maturation is not without barriers. Wide-scale deployment of eHealth is anticipated in the healthcare system in the near future. While ePrescription deployment has been an important step, ICT for integrated care and telehealth have a lot of room for further deployment. CONCLUSIONS: Greece is a valuable contributor in the European medical informatics arena, and has the potential to offer more as long as the barriers of research and innovation fragmentation are addressed and alleviated. PMID- 26123911 TI - An Opening Chapter of the First Generation of Artificial Intelligence in Medicine: The First Rutgers AIM Workshop, June 1975. AB - The first generation of Artificial Intelligence (AI) in Medicine methods were developed in the early 1970's drawing on insights about problem solving in AI. They developed new ways of representing structured expert knowledge about clinical and biomedical problems using causal, taxonomic, associational, rule, and frame-based models. By 1975, several prototype systems had been developed and clinically tested, and the Rutgers Research Resource on Computers in Biomedicine hosted the first in a series of workshops on AI in Medicine that helped researchers and clinicians share their ideas, demonstrate their models, and comment on the prospects for the field. These developments and the workshops themselves benefited considerably from Stanford's SUMEX-AIM pioneering experiment in biomedical computer networking. This paper focuses on discussions about issues at the intersection of medicine and artificial intelligence that took place during the presentations and panels at the First Rutgers AIM Workshop in New Brunswick, New Jersey from June 14 to 17, 1975. PMID- 26123912 TI - Health Information Technology Challenges to Support Patient-Centered Care Coordination. AB - OBJECTIVES: To provide an editorial introduction to the 2015 IMIA Yearbook of Medical Informatics. METHODS: We provide a brief overview of the 2015 special topic "Patient-Centered Care Coordination", discuss the addition of two new sections to the Yearbook, Natural Language Processing and Public Health & Epidemiology Informatics, and present our editorial plans for the upcoming celebration of the 25th anniversary of the Yearbook. RESULTS: Care delivery currently occurs through the processing of complex clinical pathways designed for increasingly multi-morbid patients by various practitioners in different settings. To avoid the consequences of the fragmentation of services, care should be organized to coordinate all providers, giving them the opportunity to share the same holistic view of the patient's condition, and to be informed of the planned clinical pathway that establishes the roles and interventions of each one. The adoption and use of electronic health records (EHRs) is a solution to address health information sharing and care coordination challenges. However, while EHRs are necessary, they are not sufficient to achieve care coordination, creating information availability does not mean the information will be accessed. This edition of the Yearbook acknowledges the fact that health information technology (HIT), and EHRs in particular, are not yet fully addressing the challenges in care coordination. Emerging trends, tools, and applications of HIT to support care coordination are presented through the keynote paper, survey papers, and working group contributions. CONCLUSIONS: In 2015, the IMIA Yearbook has been extended to emphasize two fields of biomedical informatics through new sections. Next year, the 25th anniversary of the Yearbook will be celebrated in grand style! A special issue with a touch of reflection, a bit of rediscovery, and some "science-fiction" will be published in addition to the usual edition. PMID- 26123913 TI - Health Information Technology and Care Coordination: The Next Big Opportunity for Informatics? AB - The costs of care in the U.S. are very high, in part because canre is relatively uncoordinated. To begin to address this and other issues, health care reform was passed, including the notion of accountable care. Under acountable care arrangements, providers are at risk for the costs of the care they provide to groups of patients. Evaluation of costs has made it clear that a large proportion of these costs are in the post-acute setting, and also that many specific problems such as adverse events and unnecessary readmissions occur following transitions. However, the electronic health records of today do not provide a great deal of assistance with the coordination of care, and even the best organizations have relatively primitive systems with respect to care coordination, even though communication is absolutely central to better coordination of care and health information technology (HIT) is a powerful lever for improving communication. This paper identifies specific gaps in care coordination today, presents a framework for better coordinating care using HIT, then describes how specific technologies can be leveraged. Also discussed are the need to build and test specific interventions to improve HIT-related care coordination tools, and the key policy steps needed to accomplish this. PMID- 26123914 TI - Embracing Strategies for eHealth. PMID- 26123915 TI - Relationship between fruit and vegetable intake and interference control in breast cancer survivors. AB - PURPOSE: Nutrition plays an important role in brain structure and function, and the effects of diet may even be greater in those at greater risk of cognitive decline, such as individuals with cancer-related cognitive impairment. However, the relation of dietary components to cognitive function in cancer survivors is unknown. The objective of this study was to determine whether breast cancer survivors (BCS) evidenced impairments in interference control, a component of cognitive control, compared to age-matched women with no prior history of cancer, and to examine the moderating role of diet on cognitive function. METHODS: In this cross-sectional study, a modified flanker task was used to assess interference control in BCS (n = 31) and age-matched women with no prior history of cancer (n = 30). Diet was assessed with 3-day food records. Differences between BCS and age-matched controls were assessed using linear mixed models, and multilevel regression analyses were conducted to assess the moderating role of diet on cognitive performance. RESULTS: Cognitive performance was not different between groups. Fruit intake and vegetable intake were significantly associated with better performance on the incompatible condition of the flanker task (i.e., shorter reaction time and increased accuracy), independent of disease status. The association between dietary components and cognition was stronger for the incompatible incongruent condition, suggesting that fruit and vegetables may be important for the up-regulation of cognitive control when faced with higher cognitive demands. CONCLUSIONS: There was no difference in performance on an interference control task between BCS and age-matched controls. The data suggest that greater fruit intake and vegetable intake were positively associated with interference control in both BCS and age-matched controls. PMID- 26123916 TI - Genetic mapping of a QTL controlling source-sink size and heading date in rice. AB - Source size, sink size and heading date (HD) are three important classes of traits that determine the productivity of rice. In this study, a set of recombinant inbred lines (RILs) derived from the cross between an elite indica line Big Grain1 (BG1) and a japonica line Xiaolijing (XLJ) were used to map quantitative trait loci (QTLs) for source-sink size and heading date. Totally, thirty-one QTLs for source size, twenty-two for sink size, four for heading date and seven QTL clusters which included QTLs for multiple traits were identified in three environmental trials. Thirty QTLs could be consistently detected in at least two trials and generally located in the clusters. Using a set of BC4F2 lines, the QTL cluster in C5-1-C5-2 on chromosome 5 was validated to be a major QTL pleiotropically affecting heading date, source size (flag leaf area) and panicle type (neck length of panicle, primary branching number and the ratio of secondary branching number to primary branching number), and was narrowed down to a 309.52Kb region. QTL clusters described above have a large effect on source sink size and/or heading date, therefore they should be good resources to improve the adaptability and high yield potential of cultivars genetically. PMID- 26123917 TI - A genome survey sequencing of the Java mouse deer (Tragulus javanicus) adds new aspects to the evolution of lineage specific retrotransposons in Ruminantia (Cetartiodactyla). AB - Ruminantia, the ruminating, hoofed mammals (cow, deer, giraffe and allies) are an unranked artiodactylan clade. Around 50-60 million years ago the BovB retrotransposon entered the ancestral ruminantian genome through horizontal gene transfer. A survey genome screen using 454-pyrosequencing of the Java mouse deer (Tragulus javanicus) and the lesser kudu (Tragelaphus imberbis) was done to investigate and to compare the landscape of transposable elements within Ruminantia. The family Tragulidae (mouse deer) is the only representative of Tragulina and phylogenetically important, because it represents the earliest divergence in Ruminantia. The data analyses show that, relative to other ruminantian species, the lesser kudu genome has seen an expansion of BovB Long INterspersed Elements (LINEs) and BovB related Short INterspersed Elements (SINEs) like BOVA2. In comparison the genome of Java mouse deer has fewer BovB elements than other ruminants, especially Bovinae, and has in addition a novel CHR-3 SINE most likely propagated by LINE-1. By contrast the other ruminants have low amounts of CHR SINEs but high numbers of actively propagating BovB-derived and BovB-propagated SINEs. The survey sequencing data suggest that the transposable element landscape in mouse deer (Tragulina) is unique among Ruminantia, suggesting a lineage specific evolutionary trajectory that does not involve BovB mediated retrotransposition. This shows that the genomic landscape of mobile genetic elements can rapidly change in any lineage. PMID- 26123918 TI - PPR protein PDM1/SEL1 is involved in RNA editing and splicing of plastid genes in Arabidopsis thaliana. AB - After transcription, most chloroplast precursor RNAs undergo further post transcriptional processing including cleavage, editing, and splicing. Previous investigation has shown that the cleavage of the rpoA transcript and most editing sites, including accD-1, are defective in the knockout mutant of PDM1/SEL1, a PLS type PPR protein, and that PDM1 is associated with the rpoA transcript. In this work, we found that the splicing of group II introns in trnK and ndhA is also affected in pdm1. Co-immunoprecipitation mass spectrometry experiments were performed to identify proteins that are associated with PDM1. We obtained 126 non redundant proteins, of which MORF9 was reported to be involved in RNA editing in chloroplast. Yeast two-hybrid assays showed that PDM1 interacts directly with MORF9, MORF2, and MORF8. RNA immunoprecipitation showed that PDM1 associates with the transcripts of trnK and ndhA, as well as accD-1, suggesting that PDM1 is involved in RNA editing and splicing. Therefore, PDM1 is an important protein for post-transcriptional regulation in chloroplast. PMID- 26123919 TI - Using early biomarker data to predict long-term bone mineral density: application of semi-mechanistic bone cycle model on denosumab data. AB - Osteoporosis is a chronic skeletal disease characterized by low bone strength resulting in increased fracture risk. New treatments for osteoporosis are still an unmet medical need because current available treatments have various limitations. Bone mineral density (BMD) is an important endpoint for evaluating new osteoporosis treatments; however, the BMD response is often slower and less profound than that of bone turnover markers (BTMs). If the relationship between BTMs and BMD can be quantified, the BMD response can be predicted by the changes in BTM after a single dose; therefore, a decision based on BMD changes can be informed early. We have applied a bone cycle model to a phase 2 denosumab dose ranging study in osteopenic women to quantitatively link serum denosumab pharmacokinetics, BTMs, and lumbar spine (LS) BMD. The data from two phase 3 denosumab studies in patients with low bone mass, FREEDOM and DEFEND, were used for external validation. Both internal and external visual predictive checks demonstrated that the model was capable of predicting LS BMD at the denosumab regimen of 60 mg every 6 months. It has been demonstrated that the model, in combination with the changes in BTMs observed from a single-dose study in men, is capable of predicting long-term BMD outcomes (e.g., LS BMD response in men after 1 year of treatment) in different populations. We propose that this model can be used to inform drug development decisions for osteoporosis treatment early via evaluating LS BMD response when BTM data become available in early trials. PMID- 26123921 TI - On the optimal degree of fluctuations in practice for motor learning. AB - In human movement science, it is widely accepted that random practice generally enhances complex motor-skill learning compared to repetitive practice. In two experiments, a particular variability-related concept is put to empirical test, namely the concept of differencial learning (DL), which assumes (i) that learners should not be distracted from task-space exploration by corrections, and (ii) that learning is facilitated by large inter-trial fluctuations. In both experiments, the advantage of DL over repetitive learning was not statistically significant. Moreover, learning was more pronounced when participants either received corrections in addition to DL (Exp. 1) or practiced in an order in which differences between consecutive trials were relatively small (Exp. 2). These findings suggest that the positive DL effects reported in literature cannot be attributed to the reduction of feedback or to the increase of inter-trial fluctuations. These results are discussed in the light of the structural-learning approach and the two-state model of motor learning in which structure-related learning effects are distinguished from the capability to adapt to current changes. PMID- 26123922 TI - Identification and characterization of a novel Geobacillus thermoglucosidasius bacteriophage, GVE3. AB - The study of extremophilic phages may reveal new phage families as well as different mechanisms of infection, propagation and lysis to those found in phages from temperate environments. We describe a novel siphovirus, GVE3, which infects the thermophile Geobacillus thermoglucosidasius. The genome size is 141,298 bp (G+C 29.6%), making it the largest Geobacillus spp-infecting phage known. GVE3 appears to be most closely related to the recently described Bacillus anthracis phage vB_BanS_Tsamsa, rather than Geobacillus-infecting phages described thus far. Tetranucleotide usage deviation analysis supports this relationship, showing that the GVE3 genome sequence correlates best with B. anthracis and Bacillus cereus genome sequences, rather than Geobacillus spp genome sequences. PMID- 26123920 TI - A semi-mechanistic model of bone mineral density and bone turnover based on a circular model of bone remodeling. AB - Development of novel therapies for bone diseases can benefit from mathematical models that predict drug effect on bone remodeling biomarkers. Therefore, a bone cycle model (BCM) was developed that takes into consideration the concept of the basic multicellular unit and the dynamic equilibrium of bone remodeling. The model is a closed form cyclical model with four compartments representing resorption, formation, primary mineralization, and secondary mineralization. Equations describing the time course of bone turnover biomarkers were developed using the flow rate of bone cycle units (BCU) between the compartments or the amount of BCU in each compartment. A disease progression model representing bone loss in osteoporosis, a vitamin D and calcium supplementation (placebo) model, and a drug model for antiresorptive treatments were added to the model. Initial model parameter values were derived from published bone turnover data. The BCM accurately described biomarker-time profiles in postmenopausal women receiving either placebo or bisphosphonate treatment. The slow continual increase in bone mineral density (BMD) observed after 1 year of treatment was accurately described when changes in bone turnover were combined with increases in mineralization. For this purpose, the secondary mineralization compartment was replaced by three catenary chain compartments representing increasing mineral content. The refined BCM satisfactorily predicted biomarker profiles after long-term (10-year) bisphosphonate treatment. Furthermore, the model successfully described individual bone turnover markers and BMD results following treatment with denosumab in postmenopausal women. Analyses with this model could be used to optimize dosing regimens and to predict effects of novel osteoporotic treatments. PMID- 26123923 TI - Analysis of synonymous codon usage in the VP2 protein gene of infectious bursal disease virus. AB - Infectious bursal disease virus (IBDV) is an important poultry pathogen. The VP2 protein of IBDV is the major host-protective immunogen. Although the functions of the VP2 protein have been well studied, the factors shaping synonymous codon usage bias and nucleotide composition in the VP2 gene have not yet been reported. In the present study, we have analyzed the relative synonymous codon usage and effective number of codons (ENC) using 69 IBDV VP2 genes. The major trend in codon usage variation was studied using correspondence analysis. The plot of ENC values and GC3s as well as the correlation between base composition and codon usage bias suggests that mutational pressure rather than natural selection is the main factor that determines the codon usage bias in the VP2 gene. In addition, other factors, such as the aromaticity, hydrophobicity and aliphatic index also influence the codon usage variation of the VP2 gene. This study represents a comprehensive analysis of IBDV VP2 gene codon usage patterns and provides a basic understanding of the codon usage bias. PMID- 26123924 TI - Differential nucleobase protection against 5-fluorouracil toxicity for squamous and columnar cells: implication for tissue function and oncogenesis. AB - PURPOSE: The goal of these studies was to test if local excess of a normal nucleobase substrate prevents the toxicity of protracted 5FU exposure used in human cancer treatment. METHODS: Messenger RNA expression studies were performed of 5FU activating enzymes in human colon cancer cells lines (CaCo-2, HT-29), primary human gingival cells (HEGP), and normal esophageal and gastric clinical tissue samples. Excess nucleobase was then used in vitro to protect cells from 5FU toxicity. RESULTS: Pyrimidine salvage pathways predominate in squamous cells of the gingiva (HEGP) and esophageal tissue. Excess salvage nucleobase uracil but not adenine prevented 5FU toxicity in HEGP cells. Pyrimidine de novo synthesis predominates in columnar Caco-2, HT-29 and gastric tissue. Excess nucleobase adenine but not uracil prevented 5FU toxicity to Caco-2 and HT-29 cells. CONCLUSION: The directed application of the normal nucleobase uracil to the squamous cells of the oral mucosa and palms and soles together with the delivery of the normal nucleobase adenine to the columnar cells of the GI tract may enable the safe delivery of higher 5FU dose intensity. These results also suggest a feature of tissue function where squamous cells grow largely by recycling overlying tissue cell components. Columnar cells use absorbed surface nutrients for de novo growth. A disruption of this tissue function can result in growth derived from an underlying nutrient source. That change would also cause the loss of the region of cell turnover at the tissue surface. Subsequent cell proliferation with limiting nutrient availability could promote oncogenesis in such initiated tissue. PMID- 26123925 TI - P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib. AB - INTRODUCTION: Palbociclib is a cyclin dependent kinase (CDK) 4/6 inhibitor with nanomolar potency and was recently approved for treatment of breast cancer. The drug may also be useful in glioblastoma (GBM) and diffuse intrinsic pontine gliomas (DIPG), which often have an activated CDK4/6-retinoblastoma signaling pathway. However, GBM and DIPG spread widely into the surrounding brain, which calls for a CDK4/6 inhibitor with sufficient blood-brain barrier penetration. METHODS: We first performed in vitro transwell assays and demonstrate that palbociclib is a substrate of both P-gp and BCRP. Next, we conducted pharmacokinetic studies using wildtype, Abcg2(-/-), Abcb1a/b(-/-) and Abcg2; Abcb1a/b(-/-) mice. RESULTS: The plasma levels were about 3000 and 500 nM and similar in all genotypes at 1 and 4 h after i.v. administration of 10 mg/kg. At 4 h the brain-to-plasma ratios were 0.3 in WT and Abcg2(-/-) mice versus 5.5 and 15 in Abcb1a/b(-/-) and Abcg2; Abcb1a/b(-/-) mice, respectively. The oral bioavailability of palbociclib was high (63 %) in WT mice and increased only modestly and non-significantly in Abcg2; Abcb1a/b(-/-) mice. The plasma level after oral dosing of 150 mg/kg was already much higher than observed in patients (200-400 nM) and exceeded 2500 nM for up to 24 h. This latter dose is commonly used in preclinical studies, which calls into question their predictive value as they were conducted at dose levels causing a clinically non-relevant systemic drug exposure. CONCLUSION: Thus, the brain penetration of palbociclib is restricted by P-gp and BCRP, which may restrict the efficacy against GBM and DIPG. Moreover, preclinical studies with this agent should be conducted at a more clinically relevant dose level. PMID- 26123927 TI - The importance of current contributions to shielding constants in density functional theory. AB - The sources of error in the calculation of nuclear-magnetic-resonance shielding constants determined by density-functional theory are examined. Highly accurate Kohn-Sham wave functions are obtained from coupled-cluster electron density functions and used to define accurate-but current independent-density-functional shielding constants. These new reference values, in tandem with high-accuracy coupled-cluster shielding constants, provide a benchmark for the assessment of errors in common density-functional approximations. In particular the role of errors arising in the diamagnetic and paramagnetic terms is investigated, with particular emphasis on the role of current-dependence in the latter. For carbon and nitrogen the current correction is found to be, in some cases, larger than 10 ppm. This indicates that the absence of this correction in general purpose exchange-correlation functionals is one of the main sources of error in shielding calculations using density functional theory. It is shown that the current correction improves the shielding performance of many popular approximate DFT functionals. PMID- 26123926 TI - Phase II study of tivantinib (ARQ 197) in patients with metastatic triple negative breast cancer. AB - BACKGROUND: MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. METHODS: Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. RESULTS: 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade >=3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). CONCLUSION: This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy. PMID- 26123928 TI - Impact of device selection and clip duration on lung ultrasound assessment in patients with heart failure. AB - OBJECTIVES: Pulmonary edema is a common sign of heart failure and can be quantified by counting vertical artifacts (B-lines) on lung ultrasound (LUS). The primary aim of this study was to compare a pocket size ultrasound device to high end ultrasound systems on the measured number of B-lines. We also compared the impact of different-length ultrasound clips on the measured number of B-lines. METHODS AND RESULTS: We studied 21 hospitalized patients with heart failure (81% men; median age, 73; 71% Caucasian) who underwent concurrent 8- and 4-zone LUS using both a pocket ultrasound device and a high-end ultrasound system. For the 4 zone scanning method, the median B line number was 2 (interquartile range, 1-4) for the pocket device and 3 (1-5) for the high-end system (P = .67). For the 8 zone method, the median B-line number was 4 (2-7) for the pocket device and 5 (3 7) for the high-end system (P = .18). A higher number of B-lines was identified on the 4- vs 2-second LUS clips (P < .001 for 4 zones, P = .001 for 8 zones), and on the 6- vs 4-second LUS clips (P=0.057 for 4 zones, P=0.018 for 8 zones). CONCLUSIONS: Our findings suggest significant differences based on LUS clip duration rather than the type of ultrasound device used, with respect to the number of B-lines detectable in patients with heart failure. These factors should be considered in the design and reporting of LUS studies and in longitudinal assessments of heart failure patients. PMID- 26123929 TI - Successful use of targeted temperature management in pregnancy after out-of hospital cardiac arrest. AB - Targeted temperature management (TTM) may be considered on an individual basis after cardiac arrest in a comatose pregnant patient. The only 3 cases published so far describing the use of TTM in this setting have conflicting results in terms of fetal outcome. PMID- 26123930 TI - Protective effect of ischemic preconditioning on the jejunal graft mucosa injury during cold preservation. AB - Protection of intestinal graft mucosa during cold preservation is still an unmet need in clinical practice, thus affecting the success of transplantation. The present study investigates the ability of two ischemic preconditioning (IPC) procedures to limit cold preservation injury. Three groups of Sprague-Dawley rats were recruited (n=11 each) as follows: the short IPC (SIPC) performed through 4 cycles of mesenteric ischemia of 4 min each followed by 10 min of reperfusion, the long IPC (LIPC) obtained by 2 ischemic cycles of 12 min each followed by 10 min of reperfusion, and the control group (C) without IPC. Grafts were then stored in cold histidine-tryptophan-ketoglutarate solution and samples were taken at 0, 3, 6 and 9 h lasting preservation. Both IPC groups showed an advanced degree of preservation with delayed development of graft mucosa damage, mainly in the crypt region. At the beginning of preservation, the graft mucosa in both IPC groups showed lower degree of mucosal injury index (MII) by 50% in comparison with C group. Specifically, a significant improvement of MII was observed after 3h of preservation in the LIPC group (p<0.05) in comparison with untreated C grafts. Significant atrophy of the intestinal mucosa in C group was found after 3h of preservation (p<0.01), in SIPC group the progress of atrophy was delayed to 6 h (p<0.001), and in LIPC group only moderate decrease in that was found. A parallel increase of laminin expression with the MII rate after 6 and 9h of preservation in comparison with the level at time 0 was observed in all grafts (p<0.001 and p<0.01, respectively). In both IPC groups the apoptotic cell (AC) rate was significantly reduced at the beginning of cold preservation (p<0.05 both). Moreover, in both the SIPC and C groups, the progressive increase in MII rate connected with AC rate decrease was due to a predominance of necrosis. By contrast in the LIPC group, after an increase of nearly 50% in the AC rate at the 3rd hour, its level remained fairly constant during the further 6 h of preservation, thus probably preventing necrosis and improving graft viability. PMID- 26123931 TI - Reply to Young et al. PMID- 26123932 TI - Relevance of EORTC Criteria for the Diagnosis of Invasive Aspergillosis in HIV Infected Patients, and Survival Trends Over a 20-Year Period in France. AB - BACKGROUND: Before the advent of combination antiretroviral therapy (cART), roughly 50% of cases of invasive aspergillosis (IA) associated with human immunodeficiency virus (HIV) infection involved individuals without classical predisposing host factors, and the median survival time was <4 months after diagnosis. We examined if the situation evolved over time using the revised European Organisation for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC) definition and analyzed survival trends after diagnosis over 20 years. METHODS: A data review committee evaluated 342 medical records that mentioned IA in the French Hospital Database on HIV. Validated cases were classified as fulfilling the EORTC criteria or otherwise as "HIV-related IA." Three periods were analyzed: pre-cART (before 1996), cART era prevoriconazole (1996-2001), and 2002-2011. RESULTS: Among 242 validated cases of IA, 124 (51%) fulfilled the EORTC criteria (EORTC-IA) and 118 (49%) were classified as "HIV-related," with similarly low CD4 cell counts in both groups. The proportion of EORTC-IA cases remained stable across the 3 periods (50%, 48%, and 54%, respectively). The 3-month survival rate improved after the advent of cART (38% vs 69%), with no difference between EORTC-IA and HIV-related IA (hazard ratio [HR], 1.2 95% confidence interval [CI] {0.7-1.8}). Voriconazole exposure decreased mortality in 2002-2011 (HR, 0.1 95% CI [0.01 0.8]). CONCLUSIONS: In the cART era, EORTC criteria, developed for use in hematology/oncology, still applied to only half the cases diagnosed among HIV infected patients. A rapid diagnosis of IA is paramount to improve survival. For patients who do not fulfill the EORTC definition, we suggest that the addition of "HIV infected with a CD4 count <100 cells/uL" to the EORTC host criteria be validated. PMID- 26123933 TI - Disease Burden of Invasive Meningococcal Disease in the Netherlands Between June 1999 and June 2011: A Subjective Role for Serogroup and Clonal Complex. AB - BACKGROUND: Several countries consider the implementation of a meningococcal serogroup B vaccine for young children and/or serogroup C or ACWY conjugate vaccine for adolescents. Representative information on clinical course of invasive meningococcal disease (IMD) is useful to evaluate cost-effectiveness of vaccination. Information on the relation between infecting meningococcal clonal complex (CC), disease course and outcome of IMD is scarce. METHODS: A retrospective study using Dutch surveillance data on IMD from June 1999 to June 2011. Clinical information was retrieved from hospital records. The effect of age, comorbidity, clinical manifestation, serogroup, and CC on disease course and outcome was assessed in multivariable analyses. Meningococcal CCs were assessed by multilocus sequence typing. RESULTS: Clinical information was retrieved for 879 IMD cases: 48% of patients presented with meningitis, 17% with septic shock, and 22% with septic shock plus meningitis. Development of septic shock was not related to CC or serogroup. Median (interquartile range) duration of hospital admission was 10 (8-13) days. Intensive care unit admittance (38%) was higher for patients aged >=10 years and patients with septic shock (P-values <=.001). Case fatality rate (8%) and development of sequelae (29%) was dependent on age and clinical manifestation (P-values <=.001) and not affected by comorbidity, CC, or serogroup. CONCLUSIONS: IMD still coincides with a considerable disease burden and mortality. Disease course and outcome depend mainly on age and clinical manifestation and less on meningococcal CC or serogroup. PMID- 26123934 TI - Incomplete Modeling of the Effect of Antiretroviral Therapy on the Risk of Cardiovascular Events. PMID- 26123935 TI - Neonatal Invasive Haemophilus influenzae Disease and Genotypic Characterization of the Associated Strains in Italy. PMID- 26123936 TI - Chicago Ebola Response Network (CERN): A Citywide Cross-hospital Collaborative for Infectious Disease Preparedness. AB - The 2014-2015 Ebola virus disease (EVD) epidemic and international public health emergency has been referred to as a "black swan" event, or an event that is unlikely, hard to predict, and highly impactful once it occurs. The Chicago Ebola Response Network (CERN) was formed in response to EVD and is capable of receiving and managing new cases of EVD, while also laying the foundation for a public health network that can anticipate, manage, and prevent the next black swan public health event. By sharing expertise, risk, and resources among 4 major academic centers, Chicago created a sustainable network to respond to the latest in a series of public health emergencies. In this respect, CERN is a roadmap for how a region can prepare to respond to public health emergencies, thereby preventing negative impacts through planning and implementation. PMID- 26123937 TI - Single-Tablet Emtricitabine-Rilpivirine-Tenofovir as HIV Postexposure Prophylaxis in Men Who Have Sex With Men. AB - BACKGROUND: Completion rates for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) are low. We investigated the adherence and safety of coformulated emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF) as a 3-drug, single-tablet regimen for PEP in men who have sex with men (MSM). METHODS: In an open-label, single-arm study at 2 public sexual health clinics and 2 hospital emergency departments in urban Australia, 100 HIV uninfected MSM requiring 3-drug PEP received single-tablet FTC-RPV-TDF once daily for 28 days. The primary endpoint was premature PEP cessation or primary HIV infection through week 12. Additional endpoints were adherence (by self-report of doses missed or not ingested with a meal, by pill count, and by plasma concentrations of tenofovir and FTC at week 4); and safety (clinical and laboratory adverse events [AEs]). RESULTS: PEP completion was 92% (95% confidence interval, 85%-96%); premature cessation resulted from loss to follow-up (6%), AEs (1%), or study burden (1%). No participant was found to acquire HIV through week 12. Adherence was 98.6% (standard deviation [SD], 2.4) by pill count and 98.5% (SD, 2.7) by self-report; 86% reported taking all doses with food, and 88% of the subset tested had plasma tenofovir levels suggesting full adherence (>40 ng/mL). Eighty-eight participants experienced at least 1 clinical AE; 4 had grade 3 AEs or higher, possibly attributable to study drug. Fifty-six participants experienced at least 1 laboratory AE; 4 had AEs of grade 3 or higher, possibly attributable to study drug. CONCLUSIONS: A single-tablet regimen of FTC-RPV-TDF was well tolerated as once-daily PEP, with high levels of adherence and completion. CLINICAL TRIALS REGISTRATION: NCT01715636. PMID- 26123938 TI - [Reply to "Comment on article "Anesthesiology treatment of an 'open book' pelvic fracture due to an explosion""]. PMID- 26123939 TI - The cost of promiscuity: sexual transmission of Nosema microsporidian parasites in polyandrous honey bees. AB - Multiple mating (and insemination) by females with different males, polyandry, is widespread across animals, due to material and/or genetic benefits for females. It reaches particularly high levels in some social insects, in which queens can produce significantly fitter colonies by being polyandrous. It is therefore a paradox that two thirds of eusocial hymenopteran insects appear to be exclusively monandrous, in spite of the fitness benefits that polyandry could provide. One possible cost of polyandry could be sexually transmitted parasites, but evidence for these in social insects is extremely limited. Here we show that two different species of Nosema microsporidian parasites can transmit sexually in the honey bee Apis mellifera. Honey bee males that are infected by the parasite have Nosema spores in their semen, and queens artificially inseminated with either Nosema spores or the semen of Nosema-infected males became infected by the parasite. The emergent and more virulent N. ceranae achieved much higher rates of infection following insemination than did N. apis. The results provide the first quantitative evidence of a sexually transmitted disease (STD) in social insects, indicating that STDs may represent a potential cost of polyandry in social insects. PMID- 26123940 TI - A probabilistic approach for estimating the spatial extent of pesticide agricultural use sites and potential co-occurrence with listed species for use in ecological risk assessments. AB - A crop footprint refers to the estimated spatial extent of growing areas for a specific crop, and is commonly used to represent the potential "use site" footprint for a pesticide labeled for use on that crop. A methodology for developing probabilistic crop footprints to estimate the likelihood of pesticide use and the potential co-occurrence of pesticide use and listed species locations was tested at the national scale and compared to alternative methods. The probabilistic aspect of the approach accounts for annual crop rotations and the uncertainty in remotely sensed crop and land cover data sets. The crop footprints used historically are derived exclusively from the National Land Cover Database (NLCD) Cultivated Crops and/or Pasture/Hay classes. This approach broadly aggregates agriculture into 2 classes, which grossly overestimates the spatial extent of individual crops that are labeled for pesticide use. The approach also does not use all the available crop data, represents a single point in time, and does not account for the uncertainty in land cover data set classifications. The probabilistic crop footprint approach described herein incorporates best available information at the time of analysis from the National Agricultural Statistics Service (NASS) Cropland Data Layer (CDL) for 5 y (2008-2012 at the time of analysis), the 2006 NLCD, the 2007 NASS Census of Agriculture, and 5 y of NASS Quick Stats (2008-2012). The approach accounts for misclassification of crop classes in the CDL by incorporating accuracy assessment information by state, year, and crop. The NLCD provides additional information to improve the CDL crop probability through an adjustment based on the NLCD accuracy assessment data using the principles of Bayes' Theorem. Finally, crop probabilities are scaled at the state level by comparing against NASS surveys (Census of Agriculture and Quick Stats) of reported planted acres by crop. In an example application of the new method, the probabilistic crop footprint for soybean resulted in national and statewide soybean acreages that are within the error bounds of the average reported NASS yearly soybean acreage over the same time period, whereas the method using only NLCD resulted in an acreage that is over 4 times the survey acreage. When the probabilistic crop footprint for soybean was used in a co occurrence analysis with listed species locations, the number of potentially proximal species identified was half the number based on the standard NLCD crop footprint method (276 species with the probabilistic crop footprint vs 511 for the conventional method). The probabilistic crop footprint methodology allows for a more comprehensive and representative understanding of the potential pesticide use footprint co-occurrence with endangered species locations for use in effects determinations. PMID- 26123942 TI - Pleistocene glaciations, demographic expansion and subsequent isolation promoted morphological heterogeneity: A phylogeographic study of the alpine Rosa sericea complex (Rosaceae). AB - While most temperate plants probably underwent glacial constriction to refugia and interglacial expansion, another type of interglacial refugia might have existed to maintain alpine plants during warm periods. To test this hypothesis, we applied phylogeographic methods to 763 individuals (62 populations) which belong to 7 taxonomically difficult species of the Rosa sericea complex distributed in alpine regions of the temperate and subtropical zones in eastern Asia. We used three chloroplast (cp) DNA fragments (trnL-trnF, ndhF-rpl32 and ndhJ-trnF) approximately 3,100 bp and nuclear microsatellite (nSSR) on eight sites to determine whether cold tolerant plants experienced expansion during the Pleistocene. The neutral test and mismatch distribution analysis (MDA) indicated that whole populations and major lineages of the Qinghai-Tibet Plateau (QTP) underwent expansion during the middle to late Pleistocene. Environmental niche modeling (ENM) indicates more suitable habitats during the Last Glacial Maximum (LGM) than at present. We concluded that the demographic history of R. sericea, which diverged in the middle Pleistocene, was mostly affected by climatic oscillations instead of by geographical barriers. The low genetic divergence, as well as the weak phylogenetic structure in the R. sericea complex both support treating this complex as a single taxon. PMID- 26123943 TI - Comparison of volumetric bone mineral density in the operated and contralateral knee after anterior cruciate ligament and reconstruction: A 1-year follow-up study using peripheral quantitative computed tomography. AB - The purpose of this study was to quantify changes in volumetric bone mineral density (vBMD) in the tibial plateau of the operated and contralateral leg measured using peripheral quantitative computed tomography (pQCT) before and 3, 6, and 12 months after anterior cruciate ligament (ACL) reconstruction. The ACL was reconstructed with a hamstring tendon autograft using press-fit fixation. pQCT measurements of the proximal tibia were obtained in 61 patients after ACL reconstruction, and total, cortical, and trabecular vBMD were calculated. vBMD in the operated leg decreased from baseline to 3 months (-12% [total], -11% [cortical], and -12.6% [trabecular]; p<0.001) and remained below baseline for 12 months after surgery (6 months: -9.5%, -9.4%, and -9.6%, p<0.001; 12 months: -8%, -5%, and -11%, p<0.001). vBMD in the contralateral leg was slightly reduced only 6 months after surgery. Including age and sex as covariates into the analysis did not affect the results. ACL reconstruction contributed to loss in bone mineral density within the first year after surgery. The role of factors such as time of weight-bearing, joint mechanics, post-traumatic inflammatory reactions, or genetic predisposition in modulating the development of posttraumatic knee osteoarthritis after ACL injury should be further elucidated. PMID- 26123944 TI - Melanotic neuroectodermal tumour of infancy: surgical and chemotherapeutic management. AB - Melanotic neuroectodermal tumour of infancy (MNTI) is a rare pigmented neoplasm of neural crest origin. It usually presents in the first year of life in the maxilla as a fast growing lesion. We describe the case of a 3-month-old boy who presented with an enlarging swelling of left maxillary alveolus. He was treated with combined surgical and chemotherapy modalities. MNTI is complicated by high recurrence rate, local invasion and malignancy has been reported. This report describes the diagnosis, treatment and follow-up of recurrent MNTI. PMID- 26123945 TI - Prescribing and practice development decision-making in Irish general practices. AB - BACKGROUND: In Ireland, primary care is considered the appropriate setting to meet the majority of health and personal social service needs, with GPs central to its provision. Irish general practices are characterised by considerable autonomy in terms of commercial practice and the range of medical services they provide; however, little is known about what influences their decision-making with respect to the adoption of new health-care technologies. AIM: The aim of this paper is to provide a holistic overview on prescribing and practice development decision-making in Irish general practices. METHODS: A summary of recent publications examining the factors influencing the adoption of new drugs, medical equipment and information and communications technology (ICT) by Irish GPs is undertaken. RESULTS: These studies identify experiential learning, connectedness with others, and GP and practice characteristics as significant influences in the adoption of new drugs, medical equipment and ICT in Irish general practices. CONCLUSIONS: This summary identifies possible levers for encouraging the adoption of health-care technologies by Irish GPs. PMID- 26123946 TI - A comparison between direct TMR measurements and TMRs calculated from PDDs using BJR Supplement 25 data for flattened and unflattened photon beams. AB - This study assessed the validity of the conversion from percentage depth dose (PDD) to tissue maximum ratio (TMR) using BJR Supplement 25 data for flattened and flattening filter free (FFF) beams. PDD and TMR scans for a variety of field sizes were measured in water using a Sun Nuclear Corporation 3D SCANNERTM on a Varian TrueBeam linear accelerator in 6 MV, 10 MV and 6 MV FFF beams. The BJR Supplement 25 data was used to convert the measured PDDs to TMRs and these were compared with the directly measured TMR data. The TMR plots calculated from PDD were within 1% for the 10 MV and 6 MV flattened beams, for field sizes 3 cm * 3 cm to 40 cm * 40 cm inclusive, at depths measured beyond the depth of maximum dose. The disagreement between the measured and calculated TMR plots for the 6 MV FFF beam increased with depth and field size to a maximum of 1.7% for a 40 cm * 40 cm field. The results found in this study indicate that the BJR Supplement 25 data should not be used for field sizes larger than 20 cm * 20 cm at depths greater than 15 cm for the 6 MV FFF beam. It is advised that PDD to TMR conversion for FFF beams should be done with phantom scatter ratios appropriate to FFF beams, or the TMR should be directly measured if required. PMID- 26123947 TI - Therapeutic Strategies to Treat Dry Eye in an Aging Population. AB - Dry eye (DE) is a prevalent ocular disease that primarily affects the elderly. Affecting up to 30% of adults aged 50 years and older, DE affects both visual function and quality of life. Symptoms of DE, including ocular pain (aching, burning), visual disturbances, and tearing, can be addressed with therapeutic agents that target dysfunction of the meibomian glands, lacrimal glands, goblet cells, ocular surface, and/or neural network. This review provides an overview of the efficacy, use, and limitations of current therapeutic interventions being used to treat DE. PMID- 26123948 TI - Bone Disease in HIV: Recommendations for Screening and Management in the Older Patient. AB - Availability of potent antiretroviral therapy (ART) has resulted in markedly improved survival for people with human immunodeficiency virus (HIV) infection, as well as an aging HIV population. Increasing morbidity from age-related conditions has resulted in the need to understand the complex roles HIV and its treatment play in the pathogenesis of these conditions. Bone disease and fragility fractures are conditions that occur more frequently in HIV. It is therefore recommended that risk assessment for fragility fracture using the Fracture Risk Assessment Tool (FRAX((r))) algorithm, and low bone mass by dual energy X-ray absorptiometry (DXA) scan, be performed in all patients with HIV infection over the age of 50 years and in those with a history of fragility fracture, and should be repeated every 2-3 years. Because many HIV experts believe that HIV infection and its treatment is a secondary cause of osteoporosis, it should be included as such in the FRAX((r)) assessment tool. Management of osteoporosis in HIV infection should follow the same guidelines as that in the general population. Attention to lifestyle factors, including vitamin D replacement, should be emphasized. Whether cessation of tenofovir- or protease inhibitor-based ART regimens should be considered prior to bisphosphonate treatment is currently unknown and should only occur in patients with active alternative ART regimens. The use of bisphosphonates has been shown to be safe and effective in HIV patients, and while there is limited data on second-line osteoporosis regimens, there is no reason to suggest they would not be effective in people with HIV. PMID- 26123949 TI - Diagnosis and Management of Late-Onset Spondyloarthritis: Implications of Treat to-Target Recommendations. AB - Spondyloarthritis (SpA) is usually observed in young patients while onset in the elderly is less common. Late-onset forms of SpA may become more common due to longer life expectancy. The clinical spectrum of late-onset SpA is as broad as in young people, with a predominance of peripheral SpA over pure axial disease. The Assessment of SpondyloArthritis international Society (ASAS) has developed new criteria for axial or peripheral SpA that allow patients aged under 45 years at the time of disease onset to be identified. These criteria are not theoretically adapted for the classification of patients with late-onset disease but they are useful for the diagnosis. Similarly, magnetic resonance imaging (MRI) is now widely used for the early recognition of sacroiliitis or spinal inflammation in SpA, and sacroiliitis as evidenced by MRI is included in the ASAS criteria for axial SpA. Nevertheless, the utility of sacroiliac joint and/or spine inflammation as detected by MRI has mostly been described in young patients with ankylosing spondylitis, SpA, or inflammatory back pain, but not in the elderly. The management of SpA is now more focused on remission or, alternatively, low disease activity, according to the treat-to-target recommendations. Such an optimized approach to therapy is thought to improve patient outcomes and ultimately long-term quality of life. The same principles of treatment should apply in the elderly, but require certain adjustments, especially with biological agents. Tumor necrosis factor-alpha blocking agents are very effective in SpA, but seem slightly less effective in the elderly and are associated with an increased risk of infection in this population. A careful and rigorous evaluation is thus required before initiating these agents in elderly subjects. PMID- 26123950 TI - Validation of clinical scores for right ventricular failure prediction after implantation of continuous-flow left ventricular assist devices. AB - BACKGROUND: Several clinical prediction schemes for right ventricular failure (RVF) risk after left ventricular assist device (LVAD) implantation have been developed in both the pulsatile- and continuous-flow LVAD eras. The performance of these models has not been evaluated systematically in a continuous-flow LVAD cohort. METHODS: We evaluated 6 clinical RVF prediction models (Michigan, Penn, Utah, Kormos et al, CRITT, Pittsburgh Decision Tree) in 116 patients (age 51 +/- 13 years; 41.4% white and 56.0% black; 66.4% men; 56.0% bridge to transplant, 37.1% destination therapy, 17.4% bridge to decision) who received a continuous flow LVAD (HeartMate II: 79 patients, HeartWare: 37 patients) between 2008 and 2013. RESULTS: Overall, 37 patients (31.9%) developed RVF, defined: as pulmonary vasodilator use for >=48 hours or inotrope use for >=14 days post-operatively; re institution of inotropes; multi-organ failure due to RVF; or need for mechanical RV support. Median (Quartile 1 to Quartile 3) time to initial discontinuation of inotropes was 6 (range 4 to 8) days. Among scores, the Michigan score reached significance for RVF prediction but discrimination was modest (C = 0.62 [95% CI 0.52 to 0.72], p = 0.021; positive predictive value [PPV] 60.0%; negative predictive value [NPV] 75.8%), followed by CRITT (C = 0.60 [95% CI 0.50 to 0.71], p = 0.059; PPV 40.5%; NPV 72.2%). Other models did not significantly discriminate RVF. The newer, INTERMACS 3.0 definition for RVF, which includes inotropic support beyond 7 days, was reached by 57 patients (49.1%). The Kormos model performed best with this definition (C = 0.62 [95% CI 0.54 to 0.71], p = 0.005; PPV 64.3%; NPV 59.5%), followed by Penn (C = 0.61), Michigan (C = 0.60) and CRITT (C = 0.60), but overall score performance was modest. CONCLUSION: Current schemes for post-LVAD RVF risk prediction perform only modestly when applied to external populations. PMID- 26123951 TI - Effect of persistent versus transient donor-specific HLA antibodies on graft outcomes in pediatric cardiac transplantation. AB - BACKGROUND: De novo donor-specific HLA antibodies (DSA) are a risk for poor graft outcomes, but there is little evidence of their long-term effect in pediatric cardiac transplantation or of the effect of transient versus persistent DSA found using newer antibody testing methods. METHODS: Archived serum samples were obtained from patients <18 years of age who underwent primary cardiac transplantation during the period from 1996 to 2009. Luminex antibody testing was performed at 3 months, 6 months and 1 year post-transplant, and then annually. Outcomes including cardiac allograft vasculopathy (CAV), rejection and graft loss were correlated with the presence or absence of DSA or non-donor-specific HLA (non-DSA) antibodies. RESULTS: Six hundred ninety-one samples from 108 patients, with mean age at transplant of 7.4 (0.1 to 15.9) years and mean follow-up 8.2 (1.9 to 15.7) years, were studied. Forty-three (40%) patients had DSA (which were persistent in 58%), 41 (38%) had non-DSA (persistent in 46%) and 24 (22%) had no antibodies. In those with DSA, 30% had Class I antibodies, 47% Class II and 23% both Class I and II, whereas, in the subgroup with persistent DSA, 88% had Class II antibodies. There were 14 cases of graft loss, 9 of these in patients with persistent DSA. All had Class II antibodies. There was an increased incidence of CAV, rejection and graft loss in those with persistent DSA. Outcomes were similar between the group with non-DSA antibodies and the group with no antibodies. CONCLUSIONS: De novo HLA antibodies are detectable post-transplant in the majority of patients, but non-DSA and transient DSA do not appear to be associated with poor outcomes. Patients with persistent DSA, especially those with Class II DQ antibodies, have worse survival. PMID- 26123952 TI - The ethics of risk and innovation. PMID- 26123953 TI - Shared Sanitation Versus Individual Household Latrines in Urban Slums: A Cross Sectional Study in Orissa, India. AB - A large and growing proportion of the global population rely on shared sanitation facilities despite evidence of a potential increased risk of adverse health outcomes compared with individual household latrines (IHLs). We sought to explore differences between households relying on shared sanitation versus IHLs in terms of demographics, sanitation facilities, and fecal exposure. We surveyed 570 households from 30 slums in Orissa, India, to obtain data on demographics, water, sanitation, and hygiene. Latrine spot-checks were conducted to collect data on indicators of use, privacy, and cleanliness. We collected samples of drinking water and hand rinses to assess fecal contamination. Households relying on shared sanitation were poorer and less educated than those accessing IHLs. Individuals in sharing households were more likely to practice open defecation. Shared facilities were less likely to be functional, less clean, and more likely to have feces and flies. No differences in fecal contamination of drinking water or hand rinse samples were found. Important differences exist among households accessing shared facilities versus IHLs that may partly explain the apparent adverse health outcomes associated with shared sanitation. As these factors may capture differences in risk and promote sanitary improvements, they should be considered in future policy. PMID- 26123954 TI - Safety, Tolerability, and Compliance with Long-Term Antimalarial Chemoprophylaxis in American Soldiers in Afghanistan. AB - Long-term antimalarial chemoprophylaxis is currently used by deployed U.S. military personnel. Previous small, short-term efficacy studies have shown variable rates of side effects among patients taking various forms of chemoprophylaxis, though reliable safety and tolerability data on long-term use are limited. We conducted a survey of troops returning to Fort Drum, NY following a 12-month deployment to Operation Enduring Freedom, Afghanistan from 2006 to 2007. Of the 2,351 respondents, 95% reported taking at least one form of prophylaxis during their deployment, and 90% were deployed for > 10 months. Compliance with daily doxycycline was poor (60%) compared with 80% with weekly mefloquine (MQ). Adverse events (AEs) were reported by approximately 30% with both MQ and doxycycline, with 10% discontinuing doxycycline compared with 4% of MQ users. Only 6% and 31% of soldiers reported use of bed nets and skin repellents, respectively. Compliance with long-term malaria prophylaxis was poor, and there were substantial tolerability issues based on these anonymous survey results, though fewer with MQ than doxycycline. Given few long-term antimalarial chemoprophylaxis options, there is an unmet medical need for new antimalarials safe for long-term use. PMID- 26123955 TI - Baylisascaris procyonis and Herpes Simplex Virus 2 Coinfection Presenting as Ocular Larva Migrans with Granuloma Formation in a Child. AB - Ocular Baylisascaris procyonis infection results from ingestion of infective eggs of B. procyonis, the raccoon ascarid. Herpes simplex virus type 2 (HSV-2) infection of the retina is the result of either primary infection or reactivated disease. Herein, we report a case of a 12-year-old female resident of the Bronx in New York City, who presented with pan-uveitis and vision loss. Initial evaluation for etiologic causes was nondiagnostic. Serology for anti Baylisascaris procyonis antibodies in serum and vitreous fluid were both positive. Polymerase chain reaction (PCR) of vitreous fluid was positive for HSV 2. Treatment with vitrectomy, albendazole, and acyclovir resulted in mild improvement of visual acuity. The atypical presentation of B. procyonis in this case, as ocular larva migrans with a peripheral granuloma and retinal detachment, underscores the importance of maintaining a high degree of suspicion for this pathogen even in non-diffuse unilateral subacute neuroretinitis (DUSN) patients in urban areas. This case further illustrates that it is possible to have coexisting infections in cases of posterior uveitis. PMID- 26123956 TI - Evaluation of Polysaccharide-Based Latex Agglutination Assays for the Rapid Detection of Antibodies to Burkholderia pseudomallei. AB - Melioidosis is a severe disease caused by the Gram-negative bacterium Burkholderia pseudomallei. Diagnosis of melioidosis currently relies on the isolation of B. pseudomallei from clinical samples, which can take several days. An indirect hemagglutination assay (IHA) is widely used for serodiagnosis, but it has a short shelf life, is poorly standardized, and requires a viable bacteria culture performed in a biosafety level 3 (BSL-3) laboratory. To improve the diagnostic methods, we have developed two rapid latex agglutination tests based on purified B. pseudomallei O-polysaccharide (OPS) and capsular polysaccharide (CPS) antigens. The immunodiagnostic potential of these tests was evaluated using serum from culture-confirmed melioidosis patients (N = 143) and healthy donors from either endemic (N = 199) or non-endemic areas (N = 90). The sensitivity of the OPS-based latex agglutination assay (OPS-latex; 84.4%) was significantly higher than both the CPS-latex (69.5%) (P < 0.001) and IHA (69.5%) (P = 0.001). When evaluated with Thai donor serum, the OPS-latex had comparable specificity (56.9%) to the CPS-latex (63.8%) (P = 0.053), but was significantly lower than the IHA (67.6%) (P = 0.002). In contrast, all tests with U.S. donor serum were highly specific (>= 97.8%). These results suggest that polysaccharide-based latex agglutination assays may be useful for serodiagnosis of melioidosis in non endemic areas. PMID- 26123957 TI - Epidemiology of Ciguatera in Florida. AB - Ciguatera is the most commonly reported marine food-borne illness worldwide. Because there is a biological plausibility that ciguatera may be impacted by long term climate variability and Florida is on the northern border of the geographic distribution of ciguatera, it is important to update our understanding of its epidemiology in Florida. We performed an analysis of 291 reports in Florida from 2000 to 2011 and an e-mail survey of 5,352 recreational fishers to estimate incidence and underreporting and identify high risk demographic groups, fish types, and catch locations. Incidence was 5.6 per 100,000 adjusted for underreporting. Hispanics had the highest incidence rate (relative risk [RR] = 3.4) and were more likely to eat barracuda than non-Hispanics. The most common catch locations for ciguatera-causing fish were the Bahamas and Florida Keys. Cases caused by fish from northern Florida were infrequent. These results indicate that ciguatera incidence is higher than estimated from public health reports alone. There is little evidence that incidence or geographic range has increased because of increased seawater temperatures since earlier studies. PMID- 26123958 TI - Traveler's Diarrhea in Foreign Travelers in Southeast Asia: A Cross-Sectional Survey Study in Bangkok, Thailand. AB - The effect of origin and destination country on traveler's diarrhea incidence rates in Southeast Asia is poorly understood, and research generally only addresses diarrhea in travelers from the developed world. This study evaluated the attack rate and effects of traveler's diarrhea by origin and destination and analyzed key risk factors. A self-administered questionnaire was provided to foreign travelers departing Southeast Asia from Suvarnabhumi Airport, Bangkok, Thailand. It evaluated traveler demographics, relevant knowledge and practices, experiences of diarrhea, and the details and consequences of each diarrheal episode. A total of 7,963 questionnaires were completed between April 2010 and July 2011. Respondents were 56% male (mean age 35) with a mean and median duration of stay of 28 days and 10 days, respectively. Most respondents were from Europe (36.8%) or East Asia (33.4%). The attack rate of traveler's diarrhea was 16.1%, with an incidence rate of 32.05 per 100 person months. Travelers' origin and destination countries significantly related to diarrhea risk. Oceanians had the highest risk (32.9%) and East Asians the lowest (2.6%). Vietnam and Indonesia were the highest risk destinations (19.3%). Other significant factors were youth, trip duration, number of countries visited, and frequently drinking beverages with ice. PMID- 26123959 TI - Mother-to-Child Transmission of Chagas Disease in El Salvador. AB - To estimate the incidence (any mother to child) and rate (from seropositive mother to child) of mother-to-child transmission of Trypanosoma cruzi, a serological census was conducted, targeting pregnant women and infants born to seropositive mothers, in four municipalities of El Salvador. Of 943 pregnant women, 36 (3.8%) were seropositive for T. cruzi. Of 36, 32 proceeded to serological tests of their infants when they became 6-8 months of age. Six infants seropositive at the age of 6-8 months further proceeded to second-stage serological test at the age of 9-16 months. As the result, one infant was congenitally infected. Thus, serological tests at the age of 6-8 months produced five false positives. To ensure earlier effective medication only for true positives, identification of seropositive infants at the age of 9-16 months is crucial. Incidence and rate of mother-to-child transmission were 0.14 (per 100 person-years) and 4.0%, respectively. Estimated number of children infected through mother-to-child transmission in El Salvador (170 per year) was much higher than that of human immunodeficiency virus (HIV; seven per year). It is recommended that serological testing for T. cruzi be integrated into those for HIV and syphilis as part of antenatal care package. PMID- 26123960 TI - Detection of Entamoeba histolytica by Recombinase Polymerase Amplification. AB - Amebiasis is an important cause of diarrheal disease worldwide and has been associated with childhood malnutrition. Traditional microscopy approaches are neither sensitive nor specific for Entamoeba histolytica. Antigen assays are more specific, but many cases are missed unless tested by molecular methods. Although polymerase chain reaction (PCR) is effective, the need for sophisticated, expensive equipment, infrastructure, and trained personnel limits its usefulness, especially in the resource-limited, endemic areas. Here, we report development of a recombinase polymerase amplification (RPA) method to detect E. histolytica specifically. Using visual detection by lateral flow (LF), the test was highly sensitive and specific and could be performed without additional equipment. The availability of this inexpensive, sensitive, and field-applicable diagnostic test could facilitate rapid diagnosis and treatment of amebiasis in endemic regions. PMID- 26123961 TI - Implementation of a Training Course Increased the Diagnosis of Histoplasmosis in Colombia. AB - Histoplasmosis causes a significant mortality, especially persons living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) from developing countries where access to both appropriate diagnostic methods and antiretroviral therapy are limited. A total of 81 physicians assigned to 17 Colombian departments (states) received training in the clinical, epidemiological, and diagnostic aspects of histoplasmosis. Once this training was received and during the period of October 2009-November 2012, these physicians sent biological samples for immunodiagnostic, mycological, and molecular tests from their patients with suspicion of histoplasmosis. A total of 1,536 samples from 768 patients were evaluated. Of the 768 patients studied, 463 (60%) were HIV positive, 214 (28%) HIV negative, and in 91 (12%) this diagnosis was unknown, and 538 (70%) were males. The 1,536 specimens studied comprised 722 sera, 439 blood samples, and 241 urines, which were tested by immunodiffusion (ID), culture, and antigenuria, respectively; in addition, 134 specimens were tested by performing a molecular assay. Histoplasmosis was diagnosed in 133 patients (17%). After the training, we observed more diagnoses from 27 to 44 cases per year. In this study, a significantly increased number of histoplasmosis cases reported by year were observed after implementing an educational training program. PMID- 26123962 TI - First Report of a Foodborne Providencia alcalifaciens Outbreak in Kenya. AB - Providencia alcalifaciens is an emerging bacterial pathogen known to cause acute gastroenteritis in children and travelers. In July 2013, P. alcalifaciens was isolated from four children appearing for diarrhea at Kiambu District Hospital (KDH) in Kenya. This study describes the outbreak investigation, which aimed to identify the source and mechanisms of infection. We identified seven primary and four secondary cases. Among primary cases were four mothers who had children and experienced mild diarrhea after eating mashed potatoes. The mothers reported feeding children after visiting the toilet and washing their hands without soap. P. alcalifaciens was detected from all secondary cases, and the isolates were found to be clonal by random amplified polymorphic DNA (RAPD) fingerprinting. Our study suggests that the outbreak was caused by P. alcalifaciens, although no fluid accumulation was observed in rabbit ileal loops. The vehicle of the outbreak was believed to be the mashed potato dish, but the source of P. alcalifaciens could not be confirmed. We found that lack of hygiene, inadequate food storage, and improper hand washing before food preparation was the likely cause of the current outbreak. This is the first report of a foodborne infection caused by P. alcalifaciens in Kenya. PMID- 26123963 TI - Cryptosporidium and Giardia in Humans, Domestic Animals, and Village Water Sources in Rural India. AB - Cryptosporidium parvum and Giardia lamblia are zoonotic enteric protozoa of significant health concern where sanitation, hygiene, and water supplies are inadequate. We examined 85 stool samples from diarrhea patients, 111 pooled fecal samples by species across seven domestic animal types, and water from tube wells (N = 207) and ponds (N = 94) across 60 villages in coastal Odisha, India, for Cryptosporidium oocysts and Giardia cysts to measure occurrence, concentration/shedding, and environmental loading rates. Oocysts/cysts were detected in 12% of diarrhea patients. Detection ranged from 0% to 35% for Cryptosporidium and 0% to 67% for Giardia across animal hosts. Animal loading estimates indicate the greatest contributors of environmental oocysts/cysts in the study region are cattle. Ponds were contaminated with both protozoa (oocysts: 37%, cysts: 74%), as were tube wells (oocysts: 10%, cysts: 14%). Future research should address the public health concern highlighted from these findings and investigate the role of domestic animals in diarrheal disease transmission in this and similar settings. PMID- 26123965 TI - Executive Summary of Key Concepts. PMID- 26123964 TI - Fluvastatin delays propagation of viral infection in isolated rat FDB myofibers but does not affect exocytic membrane trafficking. AB - We have utilized the enveloped viral model to study the effect of fluvastatin on membrane trafficking in isolated rat myofibers. Our immunofluorescence studies constantly showed that infections in myofibers, which were treated with fluvastatin prior and during the infection with either vesicular stomatitis virus (VSV) or influenza A virus, propagated more slowly than in control myofibers without drug treatment. Experiments with a virus expressing Dad1 tagged with green fluorescent protein (GFP-Dad1) showed that fluvastatin did not affect its distribution within the ER/SR network and immunofluorescence staining for GM130 did not show any marked effect on the structure of the Golgi components. Furthermore, fluvastatin did not inhibit trafficking of the chimeric transport marker VSV temperature sensitive G protein (tsG-GFP) from the ER to the Golgi. We next subjected VSV infected myofibers for pulse-chase labeling experiments and found that fluvastatin did not slow down the ER-to-Golgi trafficking or Golgi to plasma membrane trafficking of the viral glycoprotein. These studies show that fluvastatin inhibited the propagation of viral infection in skeletal myofibers but no adverse effect on the exocytic trafficking could be demonstrated. These results suggest that other effects of statins rather than inhibition of ER-to Golgi trafficking might be behind the myotoxic effects of the statins. PMID- 26123966 TI - Sharing the Outcomes of Evidence-Based and Research Projects. PMID- 26123967 TI - Demonstrating the Effect of the Built Environment on Staff Health-Related Quality of Life in Ambulatory Care Environments. AB - OBJECTIVE: To determine the impact of the built environment on staff health related quality of life (HRQoL) in a federally qualified health center (FQHC). BACKGROUND: Staff within FQHCs face many challenges that can significantly impact their HRQoL. Design features directed toward reducing stress have been shown to improve staff health outcomes in acute care environments. However, minimal literature exists linking design features to health outcomes within FQHCs. METHOD: A cross-sectional, observational study was conducted involving three FQHCs that contain varying levels of enhancements to their interior features. A total of 75 staff across the sites participated in the indoor environmental quality (IEQ) survey, measuring satisfaction and perceived productivity. Measurements for staff HRQoL were captured using the quality of well-being (QWB) scale, which was administered to 10 staff at each site. Standard regression diagnostics were used to examine fit and find influential observations. RESULTS: QWB scores were normally distributed, and a dose-response relationship was found between QWB scores and level of enhancements. As the categories of satisfaction and perceived productivity increased, the average QWB score increased. Regression models showed overall statistical significance and predicted between a quarter to a half of the change in QWB scores. CONCLUSIONS: This pilot study suggests that the more enhancements included in the interior features of a FQHC, the greater the returns to staff HRQoL. Findings also suggest that staff with a lower QWB appreciate enhancements more. Design strategies associated with improved staff well-being should be evaluated in terms of the amount of HRQoL they contribute. PMID- 26123968 TI - Evidence-Based and Value-Based Decision Making About Healthcare Design: An Economic Evaluation of the Safety and Quality Outcomes. AB - OBJECTIVE: This study describes a vision and framework that can facilitate the implementation of evidence-based design (EBD), scientific knowledge base into the process of the design, construction, and operation of healthcare facilities and clarify the related safety and quality outcomes for the stakeholders. The proposed framework pairs EBD with value-driven decision making and aims to improve communication among stakeholders by providing a common analytical language. BACKGROUND: Recent EBD research indicates that the design and operation of healthcare facilities contribute to an organization's operational success by improving safety, quality, and efficiency. However, because little information is available about the financial returns of evidence-based investments, such investments are readily eliminated during the capital-investment decision-making process. METHOD: To model the proposed framework, we used engineering economy tools to evaluate the return on investments in six successful cases, identified by a literature review, in which facility design and operation interventions resulted in reductions in hospital-acquired infections, patient falls, staff injuries, and patient anxiety. RESULTS: In the evidence-based cases, calculated net present values, internal rates of return, and payback periods indicated that the long-term benefits of interventions substantially outweighed the intervention costs. This article explained a framework to develop a research-based and value based communication language on specific interventions along the planning, design and construction, operation, and evaluation stages. CONCLUSIONS: Evidence-based and value-based design frameworks can be applied to communicate the life-cycle costs and savings of EBD interventions to stakeholders, thereby contributing to more informed decision makings and the optimization of healthcare infrastructures. PMID- 26123969 TI - Effects of Newly Designed Hospital Buildings on Staff Perceptions: A Pre-Post Study to Validate Design Decisions. AB - OBJECTIVE: This study investigates effects of the newly built nonpatient-related buildings of a large university medical center on staff perceptions and whether the design objectives were achieved. BACKGROUND: The medical center is gradually renewing its hospital building area of 200,000 m.(2) This redevelopment is carefully planned and because lessons learned can guide design decisions of the next phase, the medical center is keen to evaluate the performance of the new buildings. METHOD: A pre- and post-study with a control group was conducted. Prior to the move to the new buildings an occupancy evaluation was carried out in the old setting (n = 729) (pre-study). Post occupation of the new buildings another occupancy evaluation (post-study) was carried out in the new setting (intervention group) and again in some old settings (control group) (n = 664). The occupancy evaluation consisted of an online survey that measured the perceived performance of different aspects of the building. Longitudinal multilevel analysis was used to compare the performance of the old buildings with the new buildings. RESULTS: Significant improvements were found in indoor climate, perceived safety, working environment, well-being, facilities, sustainability, and overall satisfaction. Commitment to the employer, working atmosphere, orientation, work performance, and knowledge sharing did not improve. The results were interpreted by relating them to specific design choices. CONCLUSION: We showed that it is possible to measure the performance improvements of a complex intervention being a new building design and validate design decisions. A focused design process aiming for a safe, pleasant and sustainable building resulted in actual improvements in some of the related performance measures. PMID- 26123970 TI - Hospital Patient Room Design: The Issues Facing 23 Occupational Groups Who Work in Medical/Surgical Patient Rooms. AB - OBJECTIVE: The aim of this study was to learn from a wide range of hospital staff members about how the design of the patient room in which they work adversely affects their ergonomics or hinders their job performance. BACKGROUND: In addition to providing a healing space for patients, hospital patient rooms need to serve as functional workplaces for the people who provide clinical care, to clean, or to maintain room functions. Therefore, from a design perspective, it is important to understand the needs of all the users of hospital patient rooms with regard to room design. METHOD: One hundred forty-seven people, representing 23 different occupational stakeholder groups, participated in either focus groups or interviews in which they were asked to identify room design issues that affect the performance of their work tasks. RESULTS: Key issues shared across multiple stakeholder groups included an inability to have eye contact with the patient when entering the room, inadequate space around the bed for the equipment used by stakeholders, the physical demands experienced as stakeholders move furnishings to accomplish their activities or access equipment, and a lack of available horizontal surfaces. Unique issues were also identified for a number of stakeholder groups. CONCLUSIONS: There are a number of issues that should be addressed in the next generation of hospital patient rooms, or when refurbishing existing facilities, so that all occupational stakeholder groups can work effectively, efficiently, and without undue physical stress. PMID- 26123971 TI - Loving Nature From the Inside Out: A Biophilia Matrix Identification Strategy for Designers. AB - OBJECTIVE: The development of the Biophilic Design Matrix (BDM) was to aid designers or other specialists in identifying and quantifying biophilic features through a visual inventory of interior spaces. BACKGROUND: With mounting evidence to support the healing attributes of biophilic environments, we propose a method to identify biophilic content within interior spaces. Such a strategy offers much promise to the advancement of restorative environments. METHODS: The BDM was based on Stephen Kellert's biophilic design attribute list and modified to be appropriate for interior environments, specifically children's healthcare spaces. A photo-ethnographic documentation method of 24 child life play spaces within a South Atlantic state was used to determine whether the BDM could reliably reveal biophilic features (listed as attributes by Kellert in 2008). RESULTS: This matrix appears useful in documenting biophilia within the pediatric healthcare context, attesting to the usability and functionality of the BDM for this special population. Specifically, the BDM revealed that biophilic attributes were constantly present in some spaces while others were completely absent. When a biophilic attribute was present, the BDM indicated that they varied considerably in type and occurrence. Thus, use of the BDM in the hospital areas designed for patient recreation and play successfully provided a visual inventory of biophilic features as well as the frequency of application. CONCLUSIONS: Further use of the BDM as a tool for strategizing biophilic feature inclusion can thus increase the connections available with nature in the interior, beneficial for optimizing health and wellness. PMID- 26123972 TI - Disseminating Project Outcomes in a Scholarly Poster. PMID- 26123973 TI - Applied Research in Practice: Partnering With Clients and Academia. PMID- 26123974 TI - Curing a large endogenous plasmid by single substitution of a partitioning gene. AB - To investigate whether plasmid-free cells of pathogenic Escherichia coli can be isolated by disrupting a single gene in an endogenous plasmid without further treatment, the effect of the disruption of partitioning genes on the inheritance of the endogenous plasmid pUTI89 of the uropathogenic E. coli strain UTI89 was studied. We found that mutation of parB, which encodes a type Ib partitioning protein, could cause loss of the endogenous plasmid at a ratio of about 1%. Clones derived from parB mutants, identified by antibiotic sensitivity, were all plasmid free. Plasmid instability caused by the parB mutation was found to correlate with a negative effect on host cell growth. Thus, in this pathogenic E. coli, an endogenous plasmid as large as 114 kbp could be cured effectively by targeting a single type Ib partitioning gene followed by passaging, which may facilitate further investigations on the function of endogenous plasmids in their natural hosts. PMID- 26123976 TI - The financial attractiveness assessment of large waste management projects registered as clean development mechanism. AB - This study illustrates the financial analyses for demonstration and assessment of additionality presented in the project design (PDD) and enclosed documents of the 431 large Clean Development Mechanisms (CDM) classified as the 'waste handling and disposal sector' (13) over the past ten years (2004-2014). The expected certified emissions reductions (CER) of these projects total 63.54 million metric tons of CO2eq, where eight countries account for 311 projects and 43.36 million metric tons. All of the projects declare themselves 'not financially attractive' without CER with an estimated sum of negative results of approximately a half billion US$. The results indicate that WM benchmarks and indicators are converging and reducing in variance, and the sensitivity analysis reveals that revenues have a greater effect on the financial results. This work concludes that an extensive financial database with simple standards for disclosure would greatly diminish statement problems and make information more comparable, reducing the risk and capital costs of WM projects. PMID- 26123975 TI - The immunotranscriptome of the Caribbean reef-building coral Pseudodiploria strigosa. AB - The viability of coral reefs worldwide has been seriously compromised in the last few decades due in part to the emergence of coral diseases of infectious nature. Despite important efforts to understand the etiology and the contribution of environmental factors associated to coral diseases, the mechanisms of immune response in corals are just beginning to be studied systematically. In this study, we analyzed the set of conserved immune response genes of the Caribbean reef-building coral Pseudodiploria strigosa by Illumina-based transcriptome sequencing and annotation of healthy colonies challenged with whole live Gram positive and Gram-negative bacteria. Searching the annotated transcriptome with immune-related terms yielded a total of 2782 transcripts predicted to encode conserved immune-related proteins that were classified into three modules: (a) the immune recognition module, containing a wide diversity of putative pattern recognition receptors including leucine-rich repeat-containing proteins, immunoglobulin superfamily receptors, representatives of various lectin families, and scavenger receptors; (b) the intracellular signaling module, containing components from the Toll-like receptor, transforming growth factor, MAPK, and apoptosis signaling pathways; and (3) the effector module, including the C3 and factor B complement components, a variety of proteases and protease inhibitors, and the melanization-inducing phenoloxidase. P. strigosa displays a highly variable and diverse immune recognition repertoire that has likely contributed to its resilience to coral diseases. PMID- 26123977 TI - Sulfate and organic matter concentration in relation to hydrogen sulfide generation at inert solid waste landfill site - Limit value for gypsum. AB - In order to suggest a limit value for gypsum (CaSO4) for the suppression of hydrogen sulfide (H2S) generation at an inert solid waste landfill site, the relationship between raw material (SO4 and organic matter) for H2S generation and generated H2S concentration, and the balance of raw material (SO4) and product (H2S) considering generation and outflow were investigated. SO4 concentration should be less than approximately 100mg-SO4/L in order to suppress H2S generation to below 2000ppm. Total organic carbon (TOC) concentration should be less than approximately 200mg-C/L assuming a high SO4 concentration. The limit value for SO4 in the ground is 60mg-SO4/kg with 0.011wt% as gypsum dihydrate, i.e., approximately 1/10 of the limit value in inert waste as defined by the EU Council Decision (560mg-SO4/kg-waste). The limit value for SO4 in inert waste as defined by the EU Council Decision is high and TOC is strictly excluded. The cumulative amount of SO4 outflow through the liquid phase is much larger than that through the gas phase. SO4 concentration in pore water decreases with time, reaching half the initial concentration around day 100. SO4 reduction by rainfall can be expected in the long term. PMID- 26123978 TI - Regression modeling and prediction of road sweeping brush load characteristics from finite element analysis and experimental results. AB - Rotary cup brushes mounted on each side of a road sweeper undertake heavy debris removal tasks but the characteristics have not been well known until recently. A Finite Element (FE) model that can analyze brush deformation and predict brush characteristics have been developed to investigate the sweeping efficiency and to assist the controller design. However, the FE model requires large amount of CPU time to simulate each brush design and operating scenario, which may affect its applications in a real-time system. This study develops a mathematical regression model to summarize the FE modeled results. The complex brush load characteristic curves were statistically analyzed to quantify the effects of cross-section, length, mounting angle, displacement and rotational speed etc. The data were then fitted by a multiple variable regression model using the maximum likelihood method. The fitted results showed good agreement with the FE analysis results and experimental results, suggesting that the mathematical regression model may be directly used in a real-time system to predict characteristics of different brushes under varying operating conditions. The methodology may also be used in the design and optimization of rotary brush tools. PMID- 26123979 TI - Environmental impact of rejected materials generated in organic fraction of municipal solid waste anaerobic digestion plants: Comparison of wet and dry process layout. AB - Anaerobic digestion of source separated organic fraction of municipal solid waste is an increasing waste valorization alternative instead of incineration or landfilling of untreated biodegradable wastes. Nevertheless, a significant portion of biodegradable wastes entering the plant is lost in pre-treatments and post-treatments of anaerobic digestion facilities together with other improper materials such as plastics, paper, textile materials and metals. The rejected materials lost in these stages have two main implications: (i) less organic material enters to digesters and, as a consequence, there is a loss of biogas production and (ii) the rejected materials end up in landfills or incinerators contributing to environmental impacts such as global warming or eutrophication. The main goals of this study are (i) to estimate potential losses of biogas in the rejected solid materials generated during the pre- and post-treatments of two full-scale anaerobic digestion facilities and (ii) to evaluate the environmental burdens associated to the final disposal (landfill or incineration) of these rejected materials by means of Life Cycle Assessment. This study shows that there is a lost of potential biogas production, ranging from 8% to 15%, due to the loss of organic matter during pre-treatment stages in anaerobic digestion facilities. From an environmental point of view, the Life Cycle Assessment shows that the incineration scenario is the most favorable alternative for eight out of nine impact categories compared with the landfill scenario. The studied impact categories are Climate Change, Fossil depletion, Freshwater eutrophication, Marine eutrophication, Ozone depletion, Particulate matter formation, Photochemical oxidant formation, Terrestrial acidification and Water depletion. PMID- 26123980 TI - Improvement in Detection of Wrong-Patient Errors When Radiologists Include Patient Photographs in Their Interpretation of Portable Chest Radiographs. AB - This study was conducted to determine whether facial photographs obtained simultaneously with radiographs improve radiologists' detection rate of wrong patient errors, when they are explicitly asked to include the photographs in their evaluation. Radiograph-photograph combinations were obtained from 28 patients at the time of portable chest radiography imaging. From these, pairs of radiographs were generated. Each unique pair consisted of one new and one old (comparison) radiograph. Twelve pairs of mismatched radiographs (i.e., pairs containing radiographs of different patients) were also generated. In phase 1 of the study, 5 blinded radiologist observers were asked to interpret 20 pairs of radiographs without the photographs. In phase 2, each radiologist interpreted another 20 pairs of radiographs with the photographs. Radiologist observers were not instructed about the purpose of the photographs but were asked to include the photographs in their review. The detection rate of mismatched errors was recorded along with the interpretation time for each session for each observer. The two tailed Fisher exact test was used to evaluate differences in mismatch detection rates between the two phases. A p value of <0.05 was considered significant. The error detection rates without (0/20 = 0%) and with (17/18 = 94.4%) photographs were different (p = 0.0001). The average interpretation times for the set of 20 radiographs were 26.45 (SD 8.69) and 20.55 (SD 3.40) min, for phase 1 and phase 2, respectively (two-tailed Student t test, p = 0.1911). When radiologists include simultaneously obtained photographs in their review of portable chest radiographs, there is a significant improvement in the detection of labeling errors. No statistically significant difference in interpretation time was observed. This may lead to improved patient safety without affecting radiologists' throughput. PMID- 26123981 TI - Illness Schema Activation and the Effects of Illness Seasonality on Accessibility of Implicit Illness-Related Information. PMID- 26123982 TI - Nrf2 and beyond: deciphering the mode of action of fumarates in the inflamed central nervous system. PMID- 26123983 TI - Ostomy-related problems and their impact on quality of life of colorectal cancer ostomates: a systematic review. AB - AIM: Many long-term ostomates are 'out-of-sight' of healthcare, and it is unknown how ostomates deal with ostomy-related problems and how these problems affect their quality of life (QOL). The aim is to examine patient-related studies describing ostomy-related problems and their impact on the perceived QOL of long term colostomates. METHODS: The electronic databases PubMed (MEDLINE), CINAHL, Cochrane Library and PsycINFO were systematically searched. All studies were included in which ostomy-specific QOL was measured using validated multidimensional instruments. RESULTS: Of the 6447 citations identified, 14 prevailingly descriptive cross-sectional studies were included. Three different validated multidimensional instruments for measuring QOL in ostomates were used (EORTC C30/CR38, MCOHQOLQO, Stoma QOL Questionnaire). All studies demonstrated that living with a colostomy influences the overall QOL negatively. The ostomy related problems described included sexual problems, depressive feelings, gas, constipation, dissatisfaction with appearance, change in clothing, travel difficulties, feeling tired and worry about noises. CONCLUSION: In conclusion, all 14 studies gave an indication of the impact of ostomy-related problems on the perceived QOL and demonstrated that a colostomy influences the QOL negatively. There is a wide range of ostomy-specific QOL scores, and there seem to be higher QOL scores in the studies where the MCOHQOLQO instrument was used. The MCOHQOLQO and the Stoma QOL Questionnaire gave the most detailed information about which ostomy-related problems were experienced. This review adds knowledge about the impact of stoma-related problems on QOL of long-term ostomates, but more research has to be conducted, to detect ostomy-related problems and especially possible care needs. PMID- 26123984 TI - Sulfonylurea monotherapy and emergency room utilization among elderly patients with type 2 diabetes. AB - AIM: In elderly Americans with type 2 diabetes, use of insulin and oral antidiabetic drugs (OADs) accounts for almost one-fourth of drug adverse event related hospitalizations. It is not clear, however, if sulfonylureas (SUs), frequently prescribed OADs known to cause hypoglycemia, increase the risk of emergency room (ER) visits compared to other OADs. The aim of this study was to compare the emergency room utilization between US elderly patients with diabetes on SU monotherapy vs. other non-SU monotherapies. METHODS: This retrospective cohort study was conducted using MarketScan((r)) database (2009-10) and aimed to evaluate the association between use of SU and ER visits. The analysis included 28,533 patients (aged >=65 years) receiving SU monotherapy at baseline and 1:1 propensity score (PS)-matched group receiving monotherapy with other OADs. ER utilization was determined during a 1-year follow-up period. RESULTS: The SU and non-SU groups were overall well balanced after PS matching. The mean (SD) number of ER visits during the follow-up was 0.56 among users of SU users compared to 0.49 (P<0.0001) among non-users. In multivariable analysis, the adjusted odds ratios for >=2 ER visits were 1.21 (95% CI=1.13-1.30) comparing SU users to non users and 1.31 (95% CI=1.21-1.41) for SU vs. metformin users. CONCLUSION: Elderly patients with type 2 diabetes on SU monotherapy were more likely to use ER than those on other monotherapies. Further studies are needed to confirm our findings and evaluate other factors associated with ER visits. PMID- 26123985 TI - Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease. AB - It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from L arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH2) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives. PMID- 26123986 TI - The L-arginine/NO pathway, homoarginine, and nitrite-dependent renal carbonic anhydrase activity in young people with type 1 diabetes mellitus. AB - High circulating levels of asymmetric dimethylarginine (ADMA) and low circulating levels of homoarginine (hArg) are known cardiovascular risk factors in adults. While in adults with type 1 diabetes mellitus (T1DM) circulating ADMA is significantly elevated, in children and adolescents the reported ADMA data are contradictory. In 102 children with T1DM and 95 healthy controls (HC) serving as controls, we investigated the L-arginine (Arg)/nitric oxide (NO) pathway. Children with T1DM were divided into two groups, i.e., in children with newly diagnosed diabetes mellitus [T1DM-ND; n = 10; age, 8.8 (4.4-11.2) years; HbA1c, 13 (8.9-13.9) %] and in those with long-term treatment [T1DM-T; n = 92; age, 12.5 (10.5-15.4) years; HbA1c, 8.0 (7.2-8.6) %]. The age of the HC was 11.3 (8-13.3) years. Amino acids and NO metabolites of the Arg/NO pathway, creatinine and the oxidative stress biomarker malondialdehyde (MDA) were measured by GC-MS or GC MS/MS. Plasma hArg, ADMA and the hArg/ADMA molar ratio did not differ between the T1DM and HC groups. There was a significant difference between T1DM-T and HC with regard to plasma nitrite [0.53 (0.48-0.61) vs 2.05 (0.86-2.36) uM, P < 0.0001] as well as to urinary nitrite [0.09 (0.06-0.17) vs 0.22 (0.13-0.37) MUmol/mmol creatinine, P < 0.0001]. Plasma, but not urinary nitrite, differed between T1DM ND and HC [0.55 (0.50-0.66) vs 2.05 (0.86-2.36) uM, P < 0.0001]. Plasma MDA did not differ between the groups. The urinary nitrate-to-nitrite molar ratio (UNOXR), a measure of nitrite-dependent renal carbonic anhydrase (CA) activity, was higher in T1DM-T [1173 (738-1481), P < 0.0001] and T1DM-ND [1341 (1117-1615), P = 0.0007] compared to HC [540 (324-962)], but did not differ between T1DM-T and T1DM-ND (P = 0.272). The lower nitrite excretion in the children with T1DM may indicate enhanced renal CA-dependent nitrite reabsorption compared with healthy children. Yet, lower plasma nitrite concentration in the T1DM patients may have also contributed to the higher UNOXR. Patients' age correlated positively with plasma hArg and hArg/ADMA and urinary DMA/ADMA. Plasma ADMA and urinary ADMA, DMA, nitrite and nitrate correlated negatively with age of the T1DM-T children. Significant correlations were found between plasma hArg and plasma Arg (r = 0.468, P < 0.0001), and urinary DMA (r = -0.426, P = 0.0001), ADMA (r = -0.266, P = 0.021) and nitrate (r = -0.234, P = 0.043). Plasma hArg correlated positively with age at diagnosis (r = +0.337, P = 0.002). ADMA, but not hArg, correlated with HbA1c in T1DM-T (r = -0.418, P < 0.0001) and T1DM-ND (r = +0.879, P = 0.0016). The greatest differences between T1DM-T and T1DM-ND were observed for urinary ADMA, DMA/ADMA ratio, nitrite and nitrate. The Arg/NO pathway is altered in T1DM in childhood and adolescence, yet the role and the importance of hArg and ADMA in T1DM remain to be elucidated. In young T1DM patients, oxidative stress (lipid peroxidation) is not elevated. PMID- 26123987 TI - Homoarginine (hArg) and asymmetric dimethylarginine (ADMA) in short stature children without and with growth hormone deficiency: hArg and ADMA are involved differently in growth in the childhood. AB - Adult subjects with growth hormone (GH) deficiency (GHD) are known to have reduced life expectancy due to increased cardiovascular and cerebrovascular events. In adults, these events are associated with elevated circulating concentrations of asymmetric dimethylarginine (ADMA) which is an endogenous inhibitor of L-arginine (Arg)-derived nitric oxide (NO). Low circulating concentrations of homoarginine (hArg) emerged as a cardiovascular risk factor. In adults, hArg seems to antagonize ADMA. In the present work, we tested the hypothesis that children with short stature without or with GHD have altered Arg/NO pathway as compared to children with normal growth. We studied 66 short stature children (38 boys, 28 girls) aged 3.5-17.3 years, who underwent the routine L-Arginine Test to diagnose presence of GHD. GHD was confirmed in 47 children (GHD group; 30 boys, 17 girls) and was absent in the remaining 19 children (non-GHD group; 8 boys, 11 girls). In addition, we investigated 24 healthy age- and gender-matched children (10 boys, 14 girls) with normal growth. In EDTA plasma samples of all children, we determined by mass spectrometry-based methods the concentrations of Arg, hArg and ADMA, and calculated the Arg/ADMA and hArg/ADMA molar ratios. With respect to these biochemical parameters, we did not find statistically significant differences between the GHD and non-GHD groups. Comparing short with normal stature children, we found small differences regarding plasma hArg concentrations [mean +/- SD; median (25th-75th percentile)]: 2.06 +/- 0.52 uM; 2.12 (1.74-2.36) uM vs. 1.7 +/- 0.5 uM; 1.6 (1.4 1.8) uM, P < 0.001. Compared to normal stature children, short stature children had considerably higher plasma concentrations of ADMA [0.77 +/- 0.15 uM; 0.77 (0.66-0.85) uM vs. 0.57 +/- 0.09 uM; 0.58 (0.50-0.63) uM, P < 0.001], but not of Arg [83.3 +/- 19.2 uM; 82.2 (71.9-90.3) uM vs. 86.5 +/- 17.8 uM; 84.8 (77.2-94.8) uM, P = 0.336], or the hArg/ADMA ratio [2.74 +/- 0.76; 2.7 (2.2-3.1) vs. 3.1 +/- 1.2; 2.85 (2.42-3.66), P = 0.161. hArg in the GHD group (r = 0.41, P = 0.004) and the hArg/ADMA ratio in both groups (r = 0.44, P = 0.002 in GHD; r = 0.55, P = 0.01 in non-GHD)], but not ADMA were positively correlated with insulin-like growth factor-1 (IGF-1). hArg and hArg/ADMA differed between girls and boys in the GHD and non-GHD groups but in the normal growth group. The hArg/ADMA ratio increased with age in all groups. Our study suggests that hArg and ADMA are involved in growth in the childhood, presumably in an antagonistic manner, with ADMA slowing and hArg accelerating growth. PMID- 26123988 TI - beta-Lactoglobulin detected in human milk forms noncovalent complexes with maltooligosaccharides as revealed by chip-nanoelectrospray high-resolution tandem mass spectrometry. AB - Cow's milk protein allergy in exclusively breastfed infants, the main cause of food intolerance during the first 6 months of life, is triggered by the mother's diet. beta-Lactoglobulin (BLG) present in cow's milk is one of the most potent allergens for newborns. Since no prophylactic treatment is available, finding ligands capable of binding BLG and reducing its allergenicity is currently the focus of research. In this work, an innovative methodology encompassing microfluidics based on fully automated chip-nanoelectrospray ionization (nanoESI), coupled with high-resolution mass spectrometry (MS) on a quadrupole time-of-flight (QTOF MS) instrument was developed. This platform was employed for the assessment of the noncovalent interactions between maltohexaose (Glc6) and beta-lactoglobulin extracted from human milk upon deliberate intake of cow's milk. The experiments were carried out in (+) ESI mode, using ammonium acetate (pH 6.0) as the buffer and also in pure water. In both cases, the MS analysis revealed the formation of BLG-Glc6 complex, which was characterized by top-down fragmentation in tandem MS (MS/MS) using collision-induced dissociation (CID). Our findings have a significant biomedical impact, indicating that Glc6 binds BLG under conditions mimicking the in vivo environment and therefore might represent a ligand, able to reduce its allergenicity. PMID- 26123989 TI - Effects of chronic oral L-arginine administration on the L-arginine/NO pathway in patients with peripheral arterial occlusive disease or coronary artery disease: L Arginine prevents renal loss of nitrite, the major NO reservoir. AB - Despite saturation of nitric oxide (NO) synthase (NOS) by its substrate L arginine (Arg), oral and intravenous supplementation of Arg may enhance NO synthesis, a phenomenon known as "The L-arginine paradox". Yet, Arg is not only a source of NO, but is also a source for guanidine-methylated (N (G)) arginine derivatives which are all inhibitors of NOS activity. Therefore, Arg supplementation may not always result in enhanced NO synthesis. Concomitant synthesis of N (G)-monomethyl arginine (MMA), N (G),N (G)-dimethylarginine (asymmetric dimethylarginine, ADMA) and N (G),N (G')-dimethylarginine (symmetric dimethylarginine, SDMA) from supplemented Arg may outweigh and even outbalance the positive effects of Arg on NO. Another possible, yet little investigated effect of Arg supplementation may be alteration of renal function, notably the influence on the excretion of nitrite in the urine. Nitrite is the autoxidation product of NO and the major reservoir of NO in the circulation. Nitrite and Arg are reabsorbed in the proximal tubule of the nephron and this reabsorption is coupled, at least in part, to the renal carbonic anhydrase (CA) activity. In the present placebo-controlled studies, we investigated the effect of chronic oral Arg supplementation of 10 g/day for 3 or 6 months in patients suffering from peripheral arterial occlusive disease (PAOD) or coronary artery disease (CAD) on the urinary excretion of nitrite relative to nitrate. We determined the urinary nitrate-to-nitrite molar ratio (UNOxR), which is a measure of nitrite-dependent renal CA activity before and after oral intake of Arg or placebo by the patients. The UNOxR was also determined in 6 children who underwent the Arg test, i.e., intravenous infusion of Arg (0.5 g Arg/kg bodyweight) for 30 min. Arg was well tolerated by the patients of the three studies. Oral Arg supplementation increased Arg (plasma and urine) and ADMA (urine) concentrations. No appreciable changes were seen in NO (in PAOD and CAD) and prostacyclin and thromboxane synthesis (in PAOD). In the PAOD study, UNOxR did not change in the Arginine group (480 +/- 51 vs 486 +/- 50), but fell in the Placebo group (422 +/- 67 vs 332 +/- 42, P = 0.025). In the CAD study, UNOxR did not change significantly in the Arginine group (518 +/- 77 at start vs 422 +/- 40 after 3 months vs 399 +/- 66 after 6 months), but fell in the Placebo group (524 +/- 69 vs 302 +/- 36 vs 285 +/- 31; P = 0.025 for 0 vs 3 months). Infusion of Arg tended to decrease the UNOxR in the children (317 +/- 41 vs 208 +/- 16, P = 0.06). We propose that oral long-term Arg supplementation prevents loss of NO bioactivity by saving nitrite. The optimum Arg dose needs to be elaborated and is likely to be less than 10 g per day in adults. Orally and intravenously administered arginine was well tolerated by the elderly patients and young children, respectively. PMID- 26123990 TI - Hyperargininemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. AB - Hyperargininemia is caused by deficiency of arginase 1, which catalyzes the hydrolysis of L-arginine to urea as the final enzyme in the urea cycle. In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life and hepatic pathology, such as neonatal cholestasis, acute liver failure, or liver fibrosis. Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. This article provides an update on the first patients ever described, gives an overview of the distinct clinical characteristics, biochemical as well as genetical background and discusses treatment options. PMID- 26123991 TI - Neonatal taurine and alanine modulate anxiety-like behavior and decelerate cortical spreading depression in rats previously suckled under different litter sizes. AB - The amino acids taurine and alanine play a role in several physiological processes, including behavior and the electrical activity of the brain. In this study, we investigated the effect of treatment with taurine or alanine on anxiety like behavior and the excitability-dependent phenomenon known as cortical spreading depression (CSD), using rats suckled in litters with 9 and 15 pups (groups L9 and L15). From postnatal days 7 to 27, the animals received per gavage 300 mg/kg/day of taurine or alanine or both. At 28 days, we tested the animals in the elevated plus maze, and at 33-35 days, we recorded CSD and analyzed its velocity of propagation, amplitude, and duration. Compared with water-treated controls, the L9 groups treated with taurine or alanine displayed anxiolytic behavior (higher number of entries in the open arms; p < 0.05), and reduced CSD velocity (p < 0.001). The effect of both amino acids on CSD was also found in the L15 groups and in five additional L9 groups (naive, water, taurine, alanine, or both) treated at adulthood (90-110 days). The L15 condition resulted in smaller durations and higher CSD velocities compared with the L9 condition. Besides reinforcing previous evidence of behavioral modulation by taurine and alanine, our data are the first confirmation that treatment with these amino acids decelerates CSD regardless of lactation conditions (normal versus unfavorable lactation) or age at amino acid administration (young versus adult). The results suggest a modulating role for both amino acids on anxiety behavior and neuronal electrical activity. PMID- 26123992 TI - Can abundance of methanogen be a good indicator for CH4 flux in soil ecosystems? AB - Methane, which is produced by methanogenic archaea, is the second most abundant carbon compound in the atmosphere. Due to its strong radiative forcing, many studies have been conducted to determine its sources, budget, and dynamics. However, a mechanistic model of methane flux has not been developed thus far. In this study, we attempt to examine the relevance of the abundance of methanogen as a biological indicator of methane flux in three different types of soil ecosystems: permafrost, rice paddy, and mountainous wetland. We measured the annual average methane flux and abundance of methanogen in the soil ecosystems in situ. The correlation between methane flux and the abundance of methanogen exists only under a specific biogeochemical conditions such as SOM of higher than 60%, pH of 5.6-6.4, and water-saturated. Except for these conditions, significant correlations were absent. Therefore, microbial abundance information can be applied to a methane flux model selectively depending on the biogeochemical properties of the soil ecosystem. PMID- 26123993 TI - Disaggregation-induced fluorescence enhancement of NIAD-4 for the optical imaging of amyloid-beta fibrils. AB - The main hallmark of Alzheimer's disease is the deposition of amyloid-beta (Abeta) aggregates in the brain. An early diagnosis of the disease requires a fast and accurate detection of such aggregates in vivo. NIAD-4 is one of the most promising in vivo markers developed due to its high emission at lambda > 600 nm and its ability to rapidly cross the blood-brain barrier (BBB) and target Abeta deposits. Furthermore, it shows a dramatic fluorescence enhancement upon binding to amyloid fibrils, which is essential for attaining good imaging contrast. Aiming at establishing novel design concepts for the preparation of optimized optical probes, the current work rationalizes the excellent performance of NIAD-4 by using a pool of computational (TD-DFT and CASPT2 calculations, ab initio molecular dynamics and protein energy landscape exploration) and spectroscopic techniques. Unlike other markers operating as molecular rotors or polarity sensitive dyes, we uncover herein that the high fluorescence imaging contrast observed upon NIAD-4 binding to amyloid fibrils results from reversible aggregation. NIAD-4 forms non-emissive assemblies in aqueous solution already at very low concentrations, which convert into the highly fluorescent monomeric species by diffusion into the hydrophobic voids of Abeta deposits. This result paves the way to exploit aggregation-induced processes as a new strategy towards advanced fluorescence markers for amyloid detection. PMID- 26123994 TI - Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification in stage IB lung adenocarcinoma. AB - BACKGROUND: Patients with pathological stage IB lung adenocarcinoma have a variable prognosis, even if received the same treatment. This study investigated the prognostic value of the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification in resected stage IB lung adenocarcinoma. METHODS: We identified 276 patients with pathological stage IB adenocarcinoma who had undergone surgical resection at the Nanjing Chest Hospital between 2005 and 2010. The histological subtypes of all patients were classified according to the 2011 IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. Kaplan-Meier and Cox regression analyses were used to analyze the correlation between the IASLC/ATS/ERS classification and patients' prognosis. RESULTS: Two hundred and seventy-six patients with pathological stage IB adenocarcinoma had an 86.2% 5-year overall survival (OS) and 80.4% 5-year disease-free survival (DFS). Patients with micropapillary and solid predominant tumors had a significantly worse OS and DFS as compared to those with other subtypes predominant tumors (p = 0.003 and 0.001). Multivariate analysis revealed that the new classification was an independent prognostic factor for both OS and DFS of pathological stage IB adenocarcinoma (p = 0.009 and 0.003). CONCLUSION: Our study revealed that the new IASLC/ATS/ERS classification was an independent prognostic factor of pathological stage IB adenocarcinoma. This new classification is valuable of screening out high risk patients to receive postoperative adjuvant therapy. PMID- 26123995 TI - Espresso coffee residues as a nitrogen amendment for small-scale vegetable production. AB - BACKGROUND: Espresso coffee grounds constitute a residue which is produced daily in considerable amounts, and is often pointed out as being potentially interesting for plant nutrition. Two experiments (incubations and field experiments) were carried out to evaluate the potential nitrogen (N) and phosphorus (P) supply for carrot (Daucus carota L.), spinach (Spinacea oleracea L.) and lettuce (Lactuca sativa L.) nutrition. RESULTS: Immobilisation of nitrogen and phosphorus was detected in all the incubations and, in the field experiments, germination and yield growth were decreased by the presence of espresso coffee grounds, in general for all the species studied. CONCLUSION: The study showed an inhibition of N and P mineralisation and a reduction of plant germination and growth. Further research is required to determine whether this is related to the immobilising capacity of the residue or possibly due to the presence of caffeine. PMID- 26123996 TI - Catalysing transdisciplinary synthesis in ecosystem science and management. PMID- 26123997 TI - Description and phylogenetic affinities of two new species of Nomadolepis (Eucestoda, Hymenolepididae) from Eastern Palearctic. AB - Two new species of hymenolepidid cestodes belonging to the genus Nomadolepis are described from small mammals in western Siberia and the Far East, Russian Federation. Nomadolepis fareasta n. sp. is described from the striped dwarf hamster Cricetulus barabensis in Amurskaya Oblast' and Nomadolepis shiloi n. sp. is described from the Eurasian harvest mouse Micromys minutus from Novosibirskaya Oblast' and Amurskaya Oblast'. Nomadolepis fareasta n. sp. differs from Nomadolepis merionis, Nomadolepis ellobii and N. shiloi n. sp. in having a substantially longer strobila, longer cirrus-sac and wider ovary. Furthermore, N. fareasta n. sp. can be readily distinguished from its congeners by the arrangement of the testes and the number and size of rostellar hooks. Nomadolepis shiloi n. sp. differs from N. merionis, N. ellobii and N. fareasta n. sp. by the number and length of the rostellar hooks, the presence of irregular transverse anastomoses as well as the length of the cirrus-sac and position of the cirrus sac in relation to the poral ventral osmoregulatory canal. Morphological differentiation of the two new species from morphologically similar Palearctic species of the related genus Rodentolepis (sensu lato) from rodents is also provided. Phylogenetic affinities of Nomadolepis were studied for the first time using partial sequences of the nuclear ribosomal 28S DNA gene. Phylogenetic analysis strongly supported the status of Nomadolepis as a separate genus closest to Pararodentolepis. PMID- 26123999 TI - Evaluating the role of coastal habitats and sea-level rise in hurricane risk mitigation: An ecological economic assessment method and application to a business decision. AB - Businesses may be missing opportunities to account for ecosystem services in their decisions, because they do not have methods to quantify and value ecosystem services. We developed a method to quantify and value coastal protection and other ecosystem services in the context of a cost-benefit analysis of hurricane risk mitigation options for a business. We first analyze linked biophysical and economic models to examine the potential protection provided by marshes. We then applied this method to The Dow Chemical Company's Freeport, Texas facility to evaluate natural (marshes), built (levee), and hybrid (marshes and a levee designed for marshes) defenses against a 100-y hurricane. Model analysis shows that future sea-level rise decreases marsh area, increases flood heights, and increases the required levee height (12%) and cost (8%). In this context, marshes do not provide sufficient protection to the facility, located 12 km inland, to warrant a change in levee design for a 100-y hurricane. Marshes do provide some protection near shore and under smaller storm conditions, which may help maintain the coastline and levee performance in the face of sea-level rise. In sum, the net present value to the business of built defenses ($217 million [2010 US$]) is greater than natural defenses ($15 million [2010 US$]) and similar to the hybrid defense scenario ($229 million [2010 US$]). Examination of a sample of public benefits from the marshes shows they provide at least $117 million (2010 US$) in coastal protection, recreational value, and C sequestration to the public, while supporting 12 fisheries and more than 300 wildlife species. This study provides information on where natural defenses may be effective and a replicable approach that businesses can use to incorporate private, as well as public, ecosystem service values into hurricane risk management at other sites. PMID- 26124000 TI - Changing SERKs and priorities during plant life. AB - SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASES (SERKs) are coreceptors for diverse extracellular signals. SERKs are involved in a wide array of developmental and immune related processes first discovered in Arabidopsis. Recent work demonstrates the evolutionary conservation of SERKs in all multicellular plants, and highlights their functional conservation in monocots and dicots. PMID- 26123998 TI - Bach1 Represses Wnt/beta-Catenin Signaling and Angiogenesis. AB - RATIONALE: Wnt/beta-catenin signaling has an important role in the angiogenic activity of endothelial cells (ECs). Bach1 is a transcription factor and is expressed in ECs, but whether Bach1 regulates angiogenesis is unknown. OBJECTIVE: This study evaluated the role of Bach1 in angiogenesis and Wnt/beta-catenin signaling. METHODS AND RESULTS: Hind-limb ischemia was surgically induced in Bach1(-/-) mice and their wild-type littermates and in C57BL/6J mice treated with adenoviruses coding for Bach1 or GFP. Lack of Bach1 expression was associated with significant increases in perfusion and vascular density and in the expression of proangiogenic cytokines in the ischemic hindlimb of mice, with enhancement of the angiogenic activity of ECs (eg, tube formation, migration, and proliferation). Bach1 overexpression impaired angiogenesis in mice with hind-limb ischemia and inhibited Wnt3a-stimulated angiogenic response and the expression of Wnt/beta-catenin target genes, such as interleukin-8 and vascular endothelial growth factor, in human umbilical vein ECs. Interleukin-8 and vascular endothelial growth factor were responsible for the antiangiogenic response of Bach1. Immunoprecipitation and GST pull-down assessments indicated that Bach1 binds directly to TCF4 and reduces the interaction of beta-catenin with TCF4. Bach1 overexpression reduces the interaction between p300/CBP and beta-catenin, as well as beta-catenin acetylation, and chromatin immunoprecipitation experiments confirmed that Bach1 occupies the TCF4-binding site of the interleukin-8 promoter and recruits histone deacetylase 1 to the interleukin-8 promoter in human umbilical vein ECs. CONCLUSIONS: Bach1 suppresses angiogenesis after ischemic injury and impairs Wnt/beta-catenin signaling by disrupting the interaction between beta-catenin and TCF4 and by recruiting histone deacetylase 1 to the promoter of TCF4-targeted genes. PMID- 26124001 TI - Maternal effects on tree phenotypes: considering the microbiome. AB - The biotic and abiotic environmental experience of plants can influence the offspring without any changes in DNA sequence. These effects can modulate the development of the progeny and their interaction with microorganisms. This interaction includes fungal endophytic communities which have significant effects on trees and their associated ecosystems. In this opinion article, we highlight potential maternal mechanisms through which endophytes could influence the progeny. We argue that a better understanding of these interactions might help to predict the response of trees to stress conditions and enhance the efficiency of tree breeding programs. PMID- 26124002 TI - Characterization of neopeptides in equine articular cartilage degradation. AB - Osteoarthritis is characterized by a loss of extracellular matrix that leads to cartilage degradation and joint space narrowing. Specific proteases, including the aggrecanases ADAMTS-4 and matrix metalloproteinase 3, are important in initiating and promoting cartilage degradation in osteoarthritis. This study investigated protease-specific and disease-specific cleavage patterns of particular extracellular matrix proteins by comparing new peptide fragments, neopeptides, in specific exogenous protease-driven digestion of a crude cartilage proteoglycan extract and an in-vitro model of early osteoarthritis. Additionally, equine cartilage explants were treated with interleukin-1 and the media collected. Proteolytic cleavage products following trypsin digestion were then identified using tandem mass spectrometry. Complete sequences of proteolytically cleaved neopeptides were determined for the major cartilage proteoglycans aggrecan, biglycan, decorin, fibromodulin plus cartilage oligomeric matrix protein. The generation of neopeptides varied with enzyme specificity; however, some peptides were common to all samples. Previous known and novel cleavage sites were identifies. The identification of novel peptide fragments provides a platform for the development of antibodies that could assist in the identification of biomarkers for osteoarthritis (OA), as well as the identification of basic biochemical processes underlying OA. PMID- 26124003 TI - Activated Pak4 expression correlates with poor prognosis in human gastric cancer patients. AB - Despite considerable advances in gastrectomy and chemotherapy, the prognosis of gastric cancer (GC) has not noticeably improved due to lymph node or distant metastases. P21-activated serine/threonine kinase 4 (Pak4) plays an important role in cell morphology and cytoskeletal reorganization-both prerequisite steps for cell migration. However, it is still unclear if activated Pak4 (p-Pak4) is related to prognosis in GC patients. In our study, the level of p-Pak4 in 95 GC tissue specimens was examined by immunohistochemistry (IHC). We observed significant correlation between the level of p-Pak4 and grosstype (advanced stage GC vs. early stage GC, P = 0.04). Moreover, GC patients with higher p-Pak4 levels had a poorer prognosis than those with lower p-Pak4 levels (17 vs. 38 months, P = 0.001). Multivariate analysis showed that high phosphorylation level of Pak4, advanced stage GC, and lymph node metastasis were independent prognostic factors for GC patients (p-Pak4, P = 0.026; advanced stage GC, P = 0.030; lymph node metastasis, P = 0.016). In addition, in vitro assays indicated that knockdown of Pak4 accompanied with decreased p-Pak4, inhibited cell migration via downregulation of the traditional downstream signaling pathways of Pak4, LIMK1, and cofilin. In conclusion, this report reveals that high level of p-Pak4 correlates with poor prognosis in GC, thereby suggesting that p-Pak4 might be a potential prognostic marker for GC. PMID- 26124004 TI - The clinicopathological significances and biological functions of parafibromin expression in head and neck squamous cell carcinomas. AB - Downregulated parafibromin expression is involved in the pathogenesis and progression of parathyroid, breast, gastric, colorectal, and lung cancers. To investigate the roles of parafibromin expression in tumorigenesis, progression, and prognostic evaluation of head and neck squamous cell carcinomas (HNSCCs), we transfected parafibromin-expressing plasmid into HNSCC cell and examined the phenotypes and their relevant molecules. Parafibromin expression was detected on tissue microarray containing squamous epithelium, dysplasia, and carcinoma of head and neck by immunohistochemistry. Parafibromin overexpression was found to suppress growth, migration, and invasion, and induce apoptosis, S arrest, and mesenchymal to epithelial transition (EMT), compared with the mock and control (P < 0.05). Both overexpression of Cyclin E1, Bax, and E-cadherin and hypoexpression of c-myc, Bcl-xL, and slug were detected in B88 transfectants, in comparison to mock and control by real-time PCR. Parafibromin expression was weaker in primary cancers than those in normal squamous tissue and dysplasia (P < 0.05), but stronger than the metastatic cancers in lymph node (P < 0.05). Parafibromin expression was negatively correlated with lymph node metastasis, tumor-node metastasis (TNM) staging, but positively with human papillomavirus (HPV) positivity (P < 0.05). The HNSCCs in tongue showed more parafibromin expression than those in larynx (P < 0.05). There was stronger parafibromin expression in moderately-than poorly-differentiated carcinomas (P < 0.05). The significantly positive correlation was observed between parafibromin expression and relapse free survival rate by Kaplan-Meier curves (P < 0.05). Cox's proportional hazard model indicated that distant metastasis and parafibromin expression were independent prognostic factors for overall and relapse-free survival of HNSCC, respectively (P < 0.05). These findings suggest that downregulated expression of parafibromin protein plays an important role in the pathogenesis, differentiation, and metastasis of HNSCCs possibly by inducing apoptosis, suppressing proliferation, cell cycle progression, migration, invasion, and EMT. Parafibromin expression is an independent factor for relapse-free survival of HNSCCs. PMID- 26124005 TI - Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L OHP cells by preventing activation of NF-kappaB signaling and suppressing cAMP responsive element transcriptional activity. AB - Resveratrol, a natural polyphenolic compound found in foods and beverages, has attracted increasing attention in recent years because of its potent chemopreventive and anti-tumor effects. In this study, the effects of resveratrol on the expression of P-glycoprotein/multi-drug resistance protein 1 (P-gp/MDR1), and the underlying molecular mechanisms, were investigated in oxaliplatin (L-OHP) resistant colorectal cancer cells (HCT116/L-OHP). Resveratrol downregulated MDR1 protein and mRNA expression levels and reduced MDR1 promoter activity. It also enhanced the intracellular accumulation of rhodamine 123, suggesting that resveratrol can reverse multi-drug resistance by downregulating MDR1 expression and reducing drug efflux. Resveratrol treatment also reduced nuclear factor kappaB (NF-kappaB) activity, reduced phosphorylation levels of IkappaBalpha, and reduced nuclear translocation of the NF-kappaB subunit p65. Moreover, downregulation of MDR1 expression and promoter activity was mediated by resveratrol-induced AMP-activated protein kinase (AMPK) phosphorylation. The inhibitory effects of resveratrol on MDR1 expression and cAMP-responsive element binding protein (CREB) phosphorylation were reversed by AMPKalpha siRNA transfection. We found that the transcriptional activity of cAMP-responsive element (CRE) was inhibited by resveratrol. These results demonstrated that the inhibitory effects of resveratrol on MDR1 expression in HCT116/L-OHP cells were closely associated with the inhibition of NF-kappaB signaling and CREB activation in an AMPK-dependent manner. PMID- 26124006 TI - Association between polymorphisms of BAG-1 and XPD and chemotherapy sensitivity in advanced non-small-cell lung cancer patients treated with vinorelbine combined cisplatin regimen. AB - BCL-2 Associated athanogene 1 (BAG-1) and Xeroderma pigmentosum group D (XPD) are involved in the nucleotide excision repair pathway and DNA repair. We aimed to investigate whether polymorphisms in BAG-1 and XPD have effects on chemotherapy sensitivity and survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with vinorelbine combined cisplatin (NP) regimen. A total of 142 patients with diagnosed advanced NSCLC were recruited in the current study. NP regimen was applied for all eligible patients. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used for BAG-1 (codon 324) and XPD (codons 312 and 751) genotyping. The treatment response was evaluated according to the RECIST guidelines. Progression-free survival (PFS) and overall survival (OS) were record as median and end point, respectively. As for BAG-1 codon 324, the chemotherapy sensitivity in NSCLC patients with CT genotype was 0.383 times of those with CC genotype (P < 0.05). With respect to XPD codon 751, the chemotherapy sensitivity in NSCLC patients with Lys/Gln genotype was 0.400 times of those with Lys/Lys genotype (P < 0.05). In addition, NSCLC patients carrying combined C/C genotype at codon 324 in BAG-1, Asp/Asp of XPD codon 312, and Lys/Lys of XPD codon 751 produced a higher efficacy of NP chemotherapy compared to those carrying mutation genotypes (all P < 0.05). Further, there were significant differences in PFS between patients with combined C/C genotype of BAG-1 codon 324, Lys/Lys genotype of XPD codon 751, and Asp/Asp genotype of XPD codon 312 and patients carrying BAG-1 codon 324 C/T genotype, XPD codon751 Lys/Gln genotype, and XPD codon312 Asp/Asn genotype (P < 0.05). Multivariate Cox regression analysis indicated that the combined wild-type of codon 324 XPD, codon 751 XPD, and codon 312 BAG-1 is the protective factor for OS and PFS, and clinical stages is the risk factor for OS and PFS. In conclusion, our research demonstrated the combined effects of BAG-1 and XPD polymorphisms on chemotherapy sensitivity and survival in patients with advanced NSCLC, which might be the important predictive markers for platinum-based chemotherapy efficacy. PMID- 26124007 TI - BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation. AB - Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT 116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N cadherin was increased in the spheres' cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers. PMID- 26124008 TI - Assessment of the anticancer mechanism of ferulic acid via cell cycle and apoptotic pathways in human prostate cancer cell lines. AB - Studies on genetic changes underlying prostate cancer and the possible signaling pathways are getting increased day by day, and new treatment methods are being searched for. The aim of the present study is to investigate the effects of ferulic acid (FA), a phenolic compound, on cell cycle, apoptosis, invasion, and colony formation in the PC-3 and LNCaP prostate cancer cells. The effect of FA on cell viability was determined via a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H tetrazolium-5-carboxanilide (XTT) method. Total RNA was isolated with Tri Reagent. Expression of 84 genes for both cell cycle and apoptosis separately was evaluated by reverse transcriptase PCR (RT-PCR). Protein expressions were evaluated by Western blot analysis. Furthermore, apoptotic effects of FA were observed with terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assay. Effects of FA on cell invasion and colony formation were determined using Matrigel chamber and colony assay, respectively. The half maximal inhibitory concentration (IC50) dose of FA was found to be 300 MUM in PC-3 cells and 500 MUM in LNCaP cells. According to RT-PCR results, it was observed that FA inhibited cell proliferation by increasing the gene expressions of ATR, ATM, CDKN1A, CDKN1B, E2F4, RB1, and TP53 and decreasing the gene expressions of CCND1, CCND2, CCND3, CDK2, CDK4, and CDK6 in PC-3 cells. On the other hand, it was seen that FA suppressed cell proliferation by increasing in the gene expressions of CASP1, CASP2, CASP8, CYCS, FAS, FASLG, and TRADD and decreasing in the gene expressions of BCL2 and XIAP in LNCaP cells. In this study, protein expression of CDK4 and BCL2 genes significantly decreased in these cells. It could induce apoptosis in PC-3 and LNCaP cells. Also, it was observed that FA suppressed the invasion in PC-3 and LNCaP cells. Moreover, it suppressed the colony formation. In conclusion, it has been observed that FA may lead to cell cycle arrest in PC-3 cells while it may cause apoptosis in LNCaP cells. PMID- 26124009 TI - Elevated miR-483-3p expression is an early event and indicates poor prognosis in pancreatic ductal adenocarcinoma. AB - MiR-483-3p has been reported to be widely involved in diverse human malignancies. However, the exact role of miR-483-3p remains elusive in pancreatic ductal adenocarcinoma (PDAC). The objective of this study is to determine the expression pattern and clinical implications of miR-483-3p in PDAC. MiR-483-3p levels were evaluated by locked nucleic acid-in situ hybridization (LNA-ISH) in a tissue microarray including 63 PDAC tumors and 10 normal pancreatic tissues, followed by evaluation in an independent set of 117 pairs of matched PDAC tumors and adjacent tumor-free pancreatic tissues. Expression of miR-483-3p was further evaluated in pancreatic intra-epithelial neoplasias (PanINs) and chronic pancreatitis (CP). The impact of miR-483-3p on cell proliferation, growth, and anchorage-independent colony formation was also assessed in vitro and in vivo. Microarray analysis revealed that miR-483-3p was positively stained in 61 (96.8 %) PDAC samples, but not detectable in normal pancreatic duct tissue. In the 117 PDAC samples, 100 % were miR-483-3p positive, with 55.6 % (65/117) strongly positive, compared to only 13.7 % (16/117) weakly positive in adjacent normal pancreatic duct tissues. MiR-483-3p expression was associated with tumor grading (p < 0.05) and was an independent predictor of poor overall survival in multivariate analysis (HR = 2.584; 95 % CI = 1.268-5.264). Moreover, from PanIN1 to PanIN3, the rate of strong miR-483-3p-positive staining was 0 % (0/39), 14.8 % (4/27), and 87.5 % (14/16), respectively. Six (54.5 %) CP samples were only weakly stained for miR 483-3p. Inhibition of miR-483-3p suppressed cell proliferation, growth, and colony formation in vitro and decreased tumor cell growth in nude mouse xenografts in vivo. These results suggest that aberrant miR-483-3p expression is an early event in PDAC tumorigenesis and is associated with tumor differentiation and prognosis. It also may be a potential target for PDAC molecular therapeutics. PMID- 26124011 TI - Multifractal nature of particulate matters (PMs) in Hong Kong urban air. AB - In this study, we investigate the persistent variation and the multifractal nature of particulate matter (PM) concentrations from vehicle emissions at a typical traffic intersection of street canyon in Hong Kong. Six size groups of PMs are measured and collected during rush hour sessions on different dates respectively. A recently developed model, namely multifractal detrended fluctuation analysis (MF-DFA), is employed to decompose and analyze the collected database. Through estimating the scaling exponent, it is found that the PM levels from vehicular emissions display long-term correlation characters. By employing MF-DFA method to calculate the generalized Hurst exponent and discuss the multifractal spectrums of all size groups, it is noticed that the fine particulate matters in grain diameter of 0.3-0.499 MUm present strong multifractal nature, intensive oscillations of concentration variations, and long term persistence. For fine particulate matters in the grain diameter ranges from 0.5 MUm to 4.99 MUm, their similar and weak multifractal natures reflect the self similarity behaviors among these groups and the gradual decreases of the lasting effects. For large size particulate matters, i.e., grain diameter above 5 MUm, certain mono-fractal nature and sharp decay of long-term persistence are obtained, even for intermittent effects. It can therefore be concluded that the fine particulate matter diffuses anomaly and persists for a long time. PMID- 26124010 TI - Single nucleotide polymorphisms (SNPs) of hOGG1 and XRCC1 DNA repair genes and the risk of ovarian cancer in Polish women. AB - The aim of this study was to determine single nucleotide polymorphisms in hOGG1 (Ser326Cys (rs13181)) and XRCC1 (Arg194Trp (rs1799782)) genes, respectively, and to identify the correlation between them and the overall risk, grading and staging of ovarian cancer in Polish women. Our study comprised 720 patients diagnosed with ovarian cancer and 720 healthy controls. The genotype analysis of hOGG1 and XRCC1 polymorphisms was performed using polymerase chain reaction (PCR) based restriction fragment length polymorphism (PCR-RFLP). Odds ratios (OR) and 95 % confidence intervals (CI) for each genotype and allele were calculated. Results revealed an association between hOGG1 Ser326Cys polymorphism and the incidence of ovarian cancer. Variant Cys allele of hOGG1 increased the overall cancer risk (OR 2.89; 95 % CI 2.47-3.38; p < .0001). Moreover, ovarian cancer grading remained in a relationship with both analysed polymorphisms; G1 tumours presented increased frequencies of hOGG1 Cys/Cys homozygotes (OR 18.33; 95 % CI 9.38-35.81; p < .0001) and XRCC1 Trp/Trp homozygotes (OR 20.50; 95 % CI 10.17 41.32; p < .0001). Furthermore, G1 ovarian cancers displayed an overrepresentation of Cys and Trp allele. In conclusion, hOGG1 Ser326Cys and XRCC1 Arg194Trp polymorphisms may be regarded as risk factors of ovarian cancer. PMID- 26124012 TI - Perennial crop growth in oil-contaminated soil in a boreal climate. AB - Soil contamination by petroleum hydrocarbons is a global problem. Phytoremediation by plants and their associated microorganisms is a cost effective strategy to degrade soil contaminants. In boreal regions the cool climate limits the efficiency of phytoremediation. The planting of oil-tolerant perennial crops, especially legumes, in oil-contaminated soil holds promise for great economic benefits for bioenergy and bio-fertilizer production while accelerating the oil degradation process. We established a multi-year field experiment to study the ecological and agronomic feasibility of phytoremediation by a legume (fodder galega) and a grass (smooth brome) in a boreal climate. In 40 months, soil oil content decreased by 73%-92%, depending on the crop type. The oil degradation followed first-order kinetics with the reduction rates decreasing as follows: bare fallow > galega-brome grass mixture > brome grass > galega. Surprisingly, the presence of oil enhanced crop dry matter and nitrogen yield, particularly in the fourth year. The unfertilized galega-brome grass mixture out yielded the N-fertilized pure grass swards over years by an average of 33%. Thus, a perennial legume-grass mixture is both ecologically and agronomically sustainable as a cropping system to alleviate soil contamination in the boreal zone, with considerable potential for bioenergy and bio-fertilizer production. PMID- 26124013 TI - Occurrence and removal of frequently prescribed pharmaceuticals and corresponding metabolites in wastewater of a sewage treatment plant. AB - The present study determines removal rates (RR) of 56 pharmaceuticals and metabolites, respectively, in an urban sewage treatment plant using mass flow analysis by comparing influent and effluent loads over a consecutive ten-day monitoring period. Besides well investigated compounds like carbamazepine and metoprolol, less researched targets, such as topiramate, pregabalin, telmisartan, and human metabolites of pharmaceuticals were included. Another aim was to determine the ratio of pharmaceuticals and corresponding metabolites in raw wastewater. Valsartan and gabapentin were detected at the highest average concentrations in influent (c(val) = 29.7 (+/- 8.1) MUg/L, c(gab) = 13.2 (+/- 3.3) MUg/L) and effluent (c(val) = 22.1 (+/- 5.1) MUg/L, c(gab) = 12.1 (+/- 2.6) MUg/L) samples. The comparison of mass loads in influent and effluent showed a significant removal (p<0.1) for 20 compounds but only enalapril, eprosartan, losartan, pregabalin, and quetiapine were removed from the aqueous phase by more than 50%. Another 20 compounds were determined without significant difference and for five compounds (clindamycin, lamotrigine, oxcarbazepine, O-desmethyl venlafaxine, triamterene), a significant higher mass load in the effluent than in the influent was observed. It has to be noticed that metabolites like 10,11 dihydro-10-hydroxy carbamazepine (MHD) are found in higher mass loads than the corresponding parent compound in the sewage samples. Furthermore, metabolites and parent compound behave differently in the sewage treatment process. While MHD (RR = 15.1%) was detected with lower mass load in the effluent than in the influent, oxcarbazepine (RR = -73.2%) showed the contrary pattern. When comparing expected and measured ratios of parent compound and metabolite in raw sewage, citalopram/N desmethyl citalopram for example, showed good results. However, a major problem exists due to insufficient data regarding metabolism and excretion of many pharmaceuticals. This complicates the prediction of relevant metabolites and further efforts are needed to overcome this problem. PMID- 26124014 TI - Author! Author! PMID- 26124015 TI - Breaking an old tradition. PMID- 26124016 TI - Celebration '15! PMID- 26124017 TI - Bias is the key challenge in orthodontic research. PMID- 26124018 TI - Author's response. PMID- 26124019 TI - Postexpansion changes related to condylar position. PMID- 26124020 TI - Authors' response. PMID- 26124022 TI - Know when to fold 'em. PMID- 26124023 TI - Alton W. Moore, 1916-2007. PMID- 26124024 TI - The measure of Alton W. Moore-teacher. PMID- 26124025 TI - Evolution of Class III treatment in orthodontics. AB - Angle, Tweed, and Moyers classified Class III malocclusions into 3 types: pseudo, dentoalveolar, and skeletal. Clinicians have been trying to identify the best timing to intercept a Class III malocclusion that develops as early as the deciduous dentition. With microimplants as skeletal anchorage, orthopedic growth modification became more effective, and it also increased the scope of camouflage orthodontic treatment for patients who were not eligible for orthognathic surgery. However, orthodontic treatment combined with orthognathic surgery remains the only option for patients with a severe skeletal Class III malocclusion or a craniofacial anomaly. Distraction osteogenesis can now be performed intraorally at an earlier age. The surgery-first approach can minimize the length of time that the malocclusion needs to worsen before orthognathic surgery. Finally, the use of computed tomography scans for 3-dimensional diagnosis and treatment planning together with advances in imaging technology can improve the accuracy of surgical movements and the esthetic outcomes for these patients. PMID- 26124026 TI - Growth modification of the face: A current perspective with emphasis on Class III treatment. AB - A summary of the current status of modification of jaw growth indicates the following. 1. Transverse expansion of the maxilla is easy before adolescence, requires heavy forces to create microfractures during adolescence, and can be accomplished only with partial or complete surgical osteotomy after adolescence. Transverse expansion of the mandible or constriction of either jaw requires surgery. 2. Acceleration of mandibular growth in preadolescent or adolescent patients can be achieved, but slower than normal growth afterward reduces or eliminates a long-term increase in size of the mandible. Restraint of maxillary growth occurs with all types of appliances to correct skeletal Class II problems. For short-face Class II patients, increasing the face height during preadolescent or adolescent orthodontic treatment is possible, but it may make the Class II problem worse unless favorable anteroposterior growth occurs. For those with a long face, controlling excessive vertical growth during adolescence is rarely successful. 3. Attempts to restrain mandibular growth in Class III patients with external forces largely result in downward and backward rotation of the mandible. Moving the maxilla forward with external force is possible before adolescence; moving it forward and simultaneously restricting forward mandibular growth without rotating the jaw is possible during adolescence with intermaxillary traction to bone anchors. The amount of skeletal change with this therapy often extends to the midface, and the short-term effects on both jaws are greater than with previous approaches, but individual variations in the amount of maxillary vs mandibular response occur, and it still is not possible to accurately predict the outcome for a patient. For all types of growth modification, 3-dimensional imaging to distinguish skeletal changes and better biomarkers or genetic identification of patient types to indicate likely treatment responses are needed. PMID- 26124027 TI - Early orthodontic treatment for Class II malocclusion reduces the chance of incisal trauma: Results of a Cochrane systematic review. AB - In this article, we summarize the most clinically relevant findings of our recently updated Cochrane systematic review into the treatment of Class II Division 1 malocclusion. METHODS: A systematic review of the databases was performed to identify all randomized controlled trials evaluating early treatment with functional appliances to correct Class II Division 1 malocclusion. RESULTS: Three early treatment studies with data from 353 participants were included in this review. The results showed no significant difference for any outcomes, except new incidence of incisor trauma, which was significantly less for the early treatment group. The risk ratio analysis for new incisor trauma showed that providing early treatment reduced the risk of trauma by 33% and 41% in the functional and headgear groups, respectively. However, when the numbers needed to treat were calculated, early treatment with functional appliances prevents 1 incidence of incisal trauma for every 10 patients (95% CI, 5-174), and headgear treatment prevents 1 incidence of incisal trauma for every 6 patients (95% CI, 3 23). CONCLUSIONS: Orthodontic treatment for young children, followed by a later phase of treatment when the child is in early adolescence, appears to reduce the incidence of new incisal trauma significantly compared with treatment that is provided in 1 phase when the child is in early adolescence. However, these data should be interpreted with caution because of the high degree of uncertainty. There are no other advantages in providing 2-phase treatment compared with 1 phase in early adolescence. PMID- 26124028 TI - Accuracy of digital American Board of Orthodontics Discrepancy Index measurements. AB - INTRODUCTION: A digital analysis that is shown to be accurate will ease the demonstration of initial case complexity. To date, no literature exists on the accuracy of the digital American Board of Orthodontics Discrepancy Index (DI) calculations when applied to pretreatment digital models. METHODS: Plaster models were obtained from 45 previous patients with varying degrees of malocclusion. Total DI scores and the target disorders were computed manually with a periodontal probe on the original plaster casts (gold standard) and digitally using Ortho Insight 3D (Motion View Software, Hixson, Tenn) and OrthoCAD (Cadent, Carlstadt, NJ). Intrarater and interrater reliabilities were assessed for 15 subjects using the Spearman rho correlation test. Accuracies of the DI scores and target disorders were assessed for all 45 subjects using Wilcoxon signed ranks tests. RESULTS: Intrarater and interrater reliabilities were high for total DI scores and most target disorders (r > 0.8). No significant difference was found between total DI score when measured with OrthoCAD compared with manual calculations. The total DI scores calculated by Ortho Insight 3D were found to be significantly greater than those by manual calculation by 2.71 points. CONCLUSIONS: The findings indicate that a DI calculated by Ortho Insight 3D may lead the clinician to overestimate case complexity. OrthoCAD's DI module was demonstrated to be a clinically acceptable alternative to manual calculation of the total scores. PMID- 26124029 TI - Retrospective investigation of the effects and efficiency of self-ligating and conventional brackets. AB - INTRODUCTION: The purpose of this retrospective cohort study was to assess the effects and efficiency of self-ligating brackets compared with conventional brackets. A secondary purpose was to identify the pretreatment factors associated with the choice of self-ligating or conventional brackets. METHODS: The subjects were treated by 2 private practitioners who used both self-ligating and conventional brackets in their practices. The self-ligating subjects were consecutively identified (treatment completed between January 2011 and April 2012), and then an age- and sex-matched control group was chosen from the same office. The outcome measures were changes in arch dimensions, changes in mandibular incisor inclinations, final peer assessment rating (PAR) scores, percentages of PAR reduction, overall treatment times, total number of visits, and number of emergency visits. All cast and cephalometric measurements were performed on digital records in a blinded manner. Two calibrated assessors measured the PAR scores. RESULTS: The final sample comprised 74 patients from clinician 1 and 34 patients from clinician 2. The practitioners had significant differences for several treatment parameters; therefore, the data from the 2 clinicians were analyzed separately. For clinician 1, no significant differences were observed between the self-ligating and conventional groups, other than increased arch length in the self-ligating group. The self-ligation patients treated by clinician 2 demonstrated significant increases in transverse dimensions, lower percentages of reduction in PAR scores, shorter treatment times, fewer visits, and more wire-sliding emergencies than the conventional bracket group. CONCLUSIONS: Although some significant findings were observed, the small sample and the lack of consistent findings between the 2 clinicians made it difficult to draw strong conclusions. PMID- 26124030 TI - Effect of clinical use of nickel-titanium springs. AB - INTRODUCTION: Our objectives were to determine whether there are changes on the load deflection rate (L/DP) and the average force (FP) of the superelastic pseudoplateau, and whether permanent deformation is changed in nickel-titanium closed-coil springs (CCSs) after 6 months of clinical use. METHODS: Twenty-two nickel-titanium CCSs (Sentalloy 100 g; Dentsply GAC, York, Pa) were subjected to tensile mechanical testing at 37 degrees C on activations varying from 3.2 to 16.0 mm before and after 6 months of clinical use. A regression line was fitted over the most horizontal area of the unloading part of the stress-strain graph of every CCS, and its slope was used as L/DP. The FP was determined by the midpoint of the longest segment of the curve that could be fit within the regression line with a R(2) of at least 0.999, and permanent deformation was determined graphically by obtaining the strain value when the measured stress reached zero. The data were analyzed by 3 analyses of variance at 2 levels, with 5% of significance. RESULTS: Time and activation significantly influenced the variables tested (P < 0.001). Time increased the L/DP and permanent deformation but decreased the FP. Activation decreased L/DP, FP, and permanent deformation. Significant interactions between time and activation were detected for FP (P = 0.013) and deformation (P < 0.001). CONCLUSIONS: After 6 months of active clinical use, the analyzed springs had a significant but small increase in their L/DP; FP dropped up to 88%, and the CCSs deformed up to 1.26 mm. PMID- 26124031 TI - Effects of magnitude of intrusive force on pulpal blood flow in maxillary molars. AB - INTRODUCTION: In this study, we aimed to evaluate and compare blood-flow changes in the pulp tissues of maxillary molars over a 6-month period after orthodontic intrusion using different magnitudes of force. METHODS: Twenty patients were randomly divided into 2 groups (n = 10) according to the amount of intrusive force applied. An intrusive force of either 125 g (light) or 250 g (heavy) was applied to the overerupted maxillary first molars using mini-implants; no force was applied to the contralateral molars. Laser Doppler flowmetry was used to measure pulpal blood flow (PBF) at baseline and during intrusion at 24 hours, 3 days, 7 days, 3 weeks, 4 weeks, 3 months, and 6 months. The data were analyzed with the Mann-Whitney U and Wilcoxon signed rank tests, with P <0.05 considered statistically significant. RESULTS: PBF decreased significantly at 3 days and continued to remain suppressed until 3 weeks, after which a gradual trend of recovery was observed until 3 months, when the levels returned to near those measured before intrusion. When the data were analyzed with regard to the amount of applied force, significant differences were observed between the 2 groups only at 3 and 7 days. CONCLUSIONS: These findings demonstrate that despite slight regressive changes in pulpal tissue over the short term, PBF values tend to return to their initial levels within 3 months, indicating that changes observed in PBF are reversible, even during radical intrusions of molars with 125 and 250 g of forces. PMID- 26124032 TI - Gingival crevicular fluid alkaline phosphate activity during the retention phase of maxillary expansion in prepubertal subjects: A split-mouth longitudinal study. AB - INTRODUCTION: The aim of this study was to monitor the alveolar bone formation at the tension sites of teeth supporting the appliances for rapid maxillary expansion (RME) during the retention phase according to the local gingival crevicular fluid (GCF) alkaline phosphatase (ALP) activity. METHODS: This split mouth prospective study included 23 prepubertal subjects (15 girls, 8 boys; mean age, 9.0 +/- 1.4 years) who had a constricted maxillary arch and were undergoing RME. Periodontal parameters, including probing depth, were recorded at 3 and 6 months after RME. Furthermore, the GCF ALP activity was measured at the tension sites of the supporting test teeth (TT) and at the antagonist control teeth (CT) sites. RESULTS: Periodontal parameters were generally similar between the TT and CT sites during the study, with the exception that probing depth underwent a slight increase at the TT sites. At baseline, the GCF ALP activity was similar between the TT and CT sites; however, at both 3 and 6 months, significantly greater enzymatic activity was seen at the TT sites. The overall probing depth changes were not significantly correlated with the corresponding GCF ALP activity changes for either the TT or the CT sites. CONCLUSIONS: Alveolar bone formation at the tension sites would last up to 6 months of retention after RME. These results warrant more comprehensive studies to assess whether the GCF ALP activity has potential as a diagnostic tool for bone formation during the retention phase of RME. PMID- 26124033 TI - Periodontal, dentoalveolar, and skeletal effects of tooth-borne and tooth-bone borne expansion appliances. AB - INTRODUCTION: The purposes of this study were to evaluate and compare the periodontal, dentoalveolar, and skeletal effects of tooth-borne and tooth-bone borne expansion devices using cone-beam computed tomography. METHODS: Twenty-five patients requiring maxillary expansion were randomly allocated into 2 groups. A tooth-borne hyrax appliance was used in the first group, consisting of 13 patients (8 girls, 5 boys; mean age, 14.3 +/- 2.3 years), and a tooth-bone-borne hybrid hyrax appliance was used in the second group of 12 patients (6 girls, 6 boys; mean age, 13.8 +/- 2.2 years). Cone-beam computed tomography records were taken before and 3 months after expansion, and periodontal, dentoalveolar, and skeletal measurements were made on the cone-beam computed tomography images with a software program. The 2 independent-samples t test and the Mann-Whitney U test were used to evaluate treatment changes for both groups. Paired-samples t test and Wilcoxon test were used to compare the measurements at 2 time points for variables. RESULTS: Significant skeletal changes and increases in interdental distances were observed in both groups. However, the distances between the first and second premolars increased more with the hyrax appliance (7.5 +/- 4.2 and 7.9 +/- 3.3 mm, respectively) than with the hybrid hyrax (3.2 +/- 2.6 and 4.5 +/- 3.8 mm, respectively) (P <0.05). Similar reductions in buccal bone plate thickness and increases in palatal bone plate thickness of the anchored teeth occurred in both groups, whereas changes in buccal and palatal bone thicknesses of the left first premolars significantly differed between groups (P <0.001). No significant intergroup difference was found in terms of absolute dental tipping. CONCLUSIONS: Both tooth-borne and tooth-bone-borne rapid expansion are effective methods for treating a narrow maxilla. However, the hyrax appliance resulted in greater expansion in the premolar region. On the other hand, the hybrid hyrax appliance did not cause changes in the bony support of the first premolars. PMID- 26124034 TI - Effects of a newly designed orthodontic miniplate platform for elevating the miniplate over the gingiva: A 3-dimensional finite element analysis. AB - INTRODUCTION: Miniplates are the treatment of choice for complex orthodontic and orthopedic problems. However, they require surgical placement and removal, and complications such as infection and mobility can occur. The aim of this finite element analysis was to investigate the effects of a newly designed miniplate platform to elevate the miniplate above the gingiva. METHODS: A bone block was modeled in 3 dimensions, and 2 N of force was applied on miniplates in 2 scenarios. In scenario 1, the miniplate was fixed with 2 miniscrews on both ends; in scenario 2, miniplate platforms were first seated on the cortical bone surface with their spikes fully penetrating, and then the miniplate was fixed on top with 2 miniscrews. RESULTS: The highest von Mises stress on the cortical bone decreased from 0.5 to 0.3 MPa when miniplate platforms were used. In scenario 2, the principal maximum stresses on the cortical bone around the miniscrews decreased from 0.42 and 0.48 MPa to 0.20 and 0.22 MPa, and the principal minimum stresses decreased from -0.45 and -0.48 MPa to -0.01 MPa. CONCLUSIONS: Miniplate platforms used to elevate the miniplate lowered the stresses generated on cortical bone around the miniscrews by distributing the stresses on the cortical bone surface. Patients can clean the miniplate more readily because it is elevated above the soft tissues. Placing the miniplate platforms requires only removing the gingiva with a punch, and their removal does not require flap surgery. PMID- 26124035 TI - Prevalence and patterns of tooth agenesis in Angle Class II Division 2 malocclusion in Japan. AB - INTRODUCTION: The purpose of this study was to evaluate the prevalence and patterns of tooth agenesis in subjects with Angle Class II Division 2 malocclusion compared with general orthodontic patients in Japan. METHODS: Panoramic radiographs, dental casts, and cephalograms of 76 patients with Class II Division 2 malocclusions (52 female, 24 male) and 270 orthodontic patients as the control group (168 female, 102 male) who were 14 years of age or older were selected. The prevalences of tooth agenesis in this cohort and in each tooth type were calculated and compared between the groups with the chi-square test. Odds ratios and corresponding 95% confidence intervals were also calculated. RESULTS: The prevalence of tooth agenesis excluding the third molars was significantly higher in the Class II Division 2 group (22.4%) than in the control group (11.9%) (P <0.05); the odds ratio was 2.14 (95% CI, 1.12-4.12). A higher prevalence of tooth agenesis excluding the third molars was observed in the Class II Division 2 group for the mandibular second premolar (P <0.05) and the maxillary lateral incisor (P <0.01). The prevalence of third molar agenesis was also significantly higher in the Class II Division 2 group (42.1%) compared with the control group (26.7%) (P <0.05); the odds ratio was 2.00 (95% CI, 1.18-3.40). CONCLUSIONS: Compared with the general orthodontic patient population, permanent tooth agenesis was observed approximately 2 times more frequently, and a distinctive agenesis pattern was found in the Class II Division 2 group in Japan. PMID- 26124036 TI - Osteogenesis imperfecta and rapid maxillary expansion: Report of 3 patients. AB - INTRODUCTION: The aim of this study was to analyze the effects of orthopedic therapy with rapid maxillary expansion (RME) in growing patients affected by osteogenesis imperfecta and treated with bisphosphonates. METHODS: Three boys with osteogenesis imperfecta (mean age, 10.6 years) were treated with RME. They all had treatment with quarterly intravenous infusions of bisphosphonates. They were in either the early or the late mixed dentition and had indications for RME. The expansion screw was activated twice daily until correction of the transverse relationships was achieved. The retention period with the expander in place was 6 months. In 2 Class III patients, RME was associated with the use of a facemask. In all patients, occlusal radiographs were taken at the end of active RME therapy to assess the opening of the midpalatal suture and 1 year after the end of active expansion therapy to evaluate the reossification and reorganization of the midpalatal suture. RESULTS: In all patients, the opening of the midpalatal suture and the healing with reorganization of the midpalatal suture were documented with the occlusal radiographs. No complications were found after a 1-year follow-up. CONCLUSIONS: In growing patients affected by osteogenesis imperfecta and treated with bisphosphonates, it is possible to perform RME with a standard protocol with no complications after a 1-year follow-up. PMID- 26124037 TI - Corticotomy-assisted rapid maxillary expansion: A novel approach with a 3-year follow-up. AB - This case report introduces a new approach of corticotomy-assisted rapid maxillary expansion for treating a severe maxillary transverse discrepancy in a skeletally mature patient. This approach uses piezo-bone perforation in conjunction with a fixed appliance and an expander. This report describes the treatment of a 14-year-old girl with a severe maxillary transverse discrepancy. She had a straight profile, severe maxillary crowding, a maxillomandibular transverse differential index of 9 mm, and a Class I skeletal relationship. The treatment protocol consisted of surgical intervention with piezo-bone perforation and active orthodontic therapy. Immediately after the piezo-bone perforation on the lateral buccal side of the maxilla, active orthodontic therapy was started with activation of an expander. The expander was reactivated weekly. Treatment duration was 5 months 2 weeks. Proper overbite and overjet, facial balance, and occlusion were achieved. The treatment outcome was stable at the 3-year follow up. This treatment approach considerably reduced the treatment time and gained bony volume. Additionally, it transformed the periodontal biotype in contrast to conventional therapy. This approach is a good alternative for treating a severe maxillary transverse discrepancy in a skeletally mature patient, especially for a patient who does not want surgical rapid palatal expansion. PMID- 26124038 TI - Treatment of unilateral posterior crossbite with facial asymmetry in a female patient with transverse discrepancy. AB - A unilateral posterior crossbite with facial asymmetry is difficult to correct with orthodontic treatment alone. This case report describes the orthodontic treatment and additional plasty without orthognathic surgery for a 19-year-old woman with a transverse discrepancy. The posterior crossbite was resolved by expansion of the narrow maxillary arch and space closure in the mandibular arch. This accelerated the correction of the functional shift of the mandible. After resolution of the unilateral posterior crossbite, the problems of the anteroposterior molar relationship were treated using orthodontic mini-implants. Mandibular angle reduction plasty was performed for the asymmetric mandibular border to improve the facial appearance. After treatment, the patient had a more symmetrical facial appearance, normal overjet and overbite, and midline coincidence. The treatment results remained stable 1 year after treatment. This case report demonstrates that a minimally invasive treatment can successfully correct a unilateral posterior crossbite with a transverse discrepancy. PMID- 26124039 TI - Anchorage reinforcement with a fixed functional appliance during protraction of the mandibular second molars into the first molar extraction sites. AB - Protraction of posterior teeth into edentulous spaces is a challenge. This report describes the treatment of a 19-year-old woman with missing mandibular first molars owing to caries. A fixed functional appliance was used for anchorage reinforcement during mandibular second molar protraction. Eight millimeters of bilateral protraction was done with bodily mesial movement of the molars and no lingual tipping of the incisors. PMID- 26124040 TI - Novel universal system for 3-dimensional orthodontic force-moment measurements and its clinical use. AB - INTRODUCTION: Orthodontic treatment is an important part of dental health care in Europe: the percentages of the population undergoing therapy vary from 10% to 55%. Therefore, quantifying effective orthodontic loads is a challenging topic with regard to the predictability of tooth movements and the reduction of traumatic side effects. METHODS: A customized measuring platform was developed and used for detecting orthodontic forces in a range between 0.1 and 2 N. The system consists of 6 load cells, each equipped with 6 strain gauges. The tests were conducted on a 3-dimensional printed malocclused mouth model and on a plaster cast. Four types of superelastic ligation and 2 types of invisible aligners were tested to analyze, respectively, a malocclusion with a high maxillary canine, and the effects on the axial rotation of a maxillary central incisor with and without a divot in the invisible aligners. RESULTS: Optimal treatment forces are exerted by low-friction wires, especially if they are partially engaged. Moreover, by reducing the treatment force, there is less necessity of anchoring to surrounding teeth, thus decreasing the side effects. The efficacy of using invisible aligners with a divot was validated. CONCLUSIONS: This platform allowed measurement, at the radicular level, of the resultant forces of orthodontic treatments performed with different orthodontic appliances. In addition to customizing and calibrating the therapy for each patient, this platform could be used to develop new specific instruments able to exert lower treatment forces, thus preventing irreversible damages. PMID- 26124041 TI - Litigation and Legislation. Destroying records. PMID- 26124042 TI - Calculating the P value and carrying out a statistical test. PMID- 26124043 TI - Reply to the Editor--Myocardial tissue characterization by cardiovascular magnetic resonance. PMID- 26124044 TI - Extended arrays for nonlinear susceptibility magnitude imaging. AB - This study implements nonlinear susceptibility magnitude imaging (SMI) with multifrequency intermodulation and phase encoding. An imaging grid was constructed of cylindrical wells of 3.5-mm diameter and 4.2-mm height on a hexagonal two-dimensional 61-voxel pattern with 5-mm spacing. Patterns of sample wells were filled with 40-MUl volumes of Fe3O4 starch-coated magnetic nanoparticles (mNPs) with a hydrodynamic diameter of 100 nm and a concentration of 25 mg/ml. The imaging hardware was configured with three excitation coils and three detection coils in anticipation that a larger imaging system will have arrays of excitation and detection coils. Hexagonal and bar patterns of mNP were successfully imaged (R2>0.9) at several orientations. This SMI demonstration extends our prior work to feature a larger coil array, enlarged field-of-view, effective phase encoding scheme, reduced mNP sample size, and more complex imaging patterns to test the feasibility of extending the method beyond the pilot scale. The results presented in this study show that nonlinear SMI holds promise for further development into a practical imaging system for medical applications. PMID- 26124045 TI - Is omitting the 3rd hour measurement in the 100 g oral glucose tolerance test feasible? AB - BACKGROUND: To evaluate the diagnostic value of the 3rd hour plasma glucose level in the 100 g oral glucose tolerance test (OGTT). METHODS: Records of all pregnant patients with abnormal 50 g glucose challenge test (GCT) between January 2005 and December 2013 were reviewed (n=1963). The 100 g OGTT results were analyzed separately for both Carpenter & Couston (CC) and National Diabetes Data Group (NDDG) criteria. RESULTS: The number of patients diagnosed with gestational diabetes mellitus (GDM) was 297 (15.1%) according to CC criteria and 166 (8.4%) according to NDDG criteria. The 1st hour plasma glucose level showed the highest correlation with GDM diagnosis (rho=0.595 for CC and rho=0.567 for NDDG). However, the 3rd hour plasma glucose level showed the weakest correlation with GDM diagnosis (rho=0.216 for CC and rho=0.213 for NDDG). The 3rd hour value of 100 g OGTT was one of the two elevated measurements in 10.8% of patients when CC criteria are used and in 13.8% of patients when NDDG criteria are used. CONCLUSION: Omitting 3rd hour plasma glucose measurement in 100 g OGTT results in unacceptable rates of underdiagnosed patients. PMID- 26124046 TI - Is intrauterine surgery justified? Report from the working group on ultrasound in obstetrics of the World Association of Perinatal Medicine (WAPM). AB - Fetal surgery involves a large number of heterogeneous interventions that vary from simple and settled procedures to very sophisticated or still-in-development approaches. The overarching goal of fetal interventions is clear: to improve the health of children by intervening before birth to correct or treat prenatally diagnosed abnormalities. This article provides an overview of fetal interventions, ethical approaches in fetal surgery, and benefits obtained from antenatal surgeries. PMID- 26124047 TI - Maternal characteristics of pregnancies with intrauterine fetal demise. AB - OBJECTIVE: To identify maternal characteristics independently associated with pregnancies resulting in intrauterine fetal demise (IUFD). STUDY DESIGN: This was a population-based cohort study of all births taking place at the McGill University Health Centre in Montreal, Canada, between 2001 and 2007, using the McGill University Obstetrics and Neonatal Database. Maternal characteristics were compared between pregnancies that resulted in IUFD and control pregnancies resulting in live newborns. A logistic regression analysis was constructed to identify parameters independently associated with IUFD. RESULTS: We identified 20,744 births during the study period, 87 of which were complicated by IUFD. Mothers with IUFD were more likely to be younger, with less formal education, higher rates of smoking during pregnancy, and more fetal anomalies (42.5% vs. 7.5%, P<0.001). After exclusion of pregnancies with congenital and/or chromosomal abnormalities, less formal education (7 vs. 13.6 school years, P<0.001) and smoking during pregnancy (24% vs. 7.7%, P<0.001) remained significantly more common in pregnancies resulting in IUFD. In the multivariable regression analysis both smoking and number of maternal school years were independently associated with IUFD pregnancies (OR 2.22 for smoking, P=0.007 and OR 0.865 for number of school years, P<0.001). CONCLUSION: Lower levels of education and smoking during pregnancy are independent predictors of IUFD. PMID- 26124048 TI - The health of Swiss adolescents and its implications for training of health professionals in Switzerland. AB - Swiss adolescents generally enjoy satisfying life conditions. Nonetheless, violence, suicide and mental health are the main concerns together with injuries, chronic conditions and eating disorders. Adolescents still face barriers to access the care they need. Adequate training can improve practitioners' skills when dealing with adolescents. The last two decades have seen the development of innovative adolescent health units and networks in various regions of Switzerland as well as research and public health programmes. Training programmes in adolescent health (continuous medical education, post-graduate or pre-graduate) for physicians and nurses are developing but still patchy in Switzerland. Adolescent health is not a sub-specialty as such. Efforts have to be made in order to link with professional associations and institutions to implement adolescent health curricula more efficiently. PMID- 26124049 TI - Activation of insulin signaling and energy sensing network by AICAR, an AMPK activator in insulin resistant rat tissues. AB - BACKGROUND: The energy status of the cell is regulated by the energy sensing network constituted by AMP-activated protein kinase (AMPK), the NAD+-dependent type III deacetylase silence information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha). This study investigates the potential effect of 5-aminoimidazole-4-carboximide-1-b-D ribofuranoside (AICAR), an AMPK activator on insulin signaling and energy sensing network in insulin resistant rats. METHODS: Adult male albino Wistar rats with body weight of 150-180 g were fed high-fructose diet (HFD) for 60 days to induce insulin resistance. Rats fed HFD were divided into two and were treated or untreated with AICAR (0.7 mg/kg bw, i.p.) for the last 2 weeks. RESULTS: Insulin resistant rats displayed increased glucose and insulin levels and reduced tyrosine phosphorylation of insulin resistance receptor and insulin receptor substrate 1. The downstream signaling and glucose transport were also affected. Phosphorylation of AMPK, SIRT1 protein abundance and mRNA expression of PGC 1alpha were reduced. Treatment with AICAR reduced hyperglycemia and hyperinsulinemia and improved the activation of the key molecules of insulin signaling. Improved action of energy sensing network was noted after AICAR treatment. AICAR showed higher binding affinity with Akt (-8.2 kcal/mol) than with AMPK or insulin receptor (-8.0 kcal/mol) in the in silico study. CONCLUSIONS: The findings suggest that AICAR, the AMPK activator, influences insulin signaling proteins and molecules involved in energy modulation during insulin resistance. PMID- 26124050 TI - Methanolic extract of Moringa oleifera leaves improves glucose tolerance, glycogen synthesis and lipid metabolism in alloxan-induced diabetic rats. AB - BACKGROUND: Glucose-lowering effects of Moringa oleifera extracts have been reported. However, the mechanism for its hypoglycemic effects is not yet understood. This study investigated the effect of oral administration of methanolic extracts of M. oleifera (MOLE) on glucose tolerance, glycogen synthesis, and lipid metabolism in rats with alloxan-induced diabetes. METHODS: MOLE was screened for key phytochemicals and its total flavonoids and phenolic contents were quantified. Diabetes was induced by intraperitoneal injection of 120 mg/kg BW alloxan. Normal and diabetic control rats received saline, while rats in other groups received 300 or 600 mg/kg body weight of MOLE or metformin (100 mg/kg body weight of metformin) for 6 weeks. Food intake and body weight were monitored throughout the experiment. Intraperitoneal glucose tolerance was assessed and serum glucose, insulin, and lipids were measured at the end of the experiment. Liver and muscle glycogen synthase activities, glycogen content, and glucose uptake were determined. RESULTS: Administration of MOLE did not affect food intake but inhibited weight loss, significantly (p<0.01) improved glucose tolerance, and increased serum insulin levels by 1.3-1.7-fold (p<0.01). MOLE treatment significantly (p<0.001) reduced serum concentrations of triglyceride, total cholesterol, and low-density lipoprotein (LDL)-cholesterol and enhanced serum level of high-density lipoprotein (HDL) by 2.4- to 3.2-fold (p<0.001). Glycogen synthase activities and glycogen contents were higher in MOLE-treated rats compared with rats receiving metformin or saline and the extract improved glucose uptake by 49%-59% (p<0.01). CONCLUSIONS: These results showed that hypoglycemic effects of MOLE might be mediated through the stimulation of insulin release leading to enhanced glucose uptake and glycogen synthesis. PMID- 26124051 TI - Elevated Pressure Enhanced Trail-Induced Apoptosis in Hepatocellular Carcinoma Cells Via Erk1/2-Inactivation. AB - The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs. PMID- 26124052 TI - HsOrc4-Dependent Dna Remodeling of the ori-beta Dhfr Replicator. AB - Replication of DNA in multicellular organisms initiates from origin of replication (ori) sequences, which significantly differ in length and complexity. One of the best characterized is hamster dihydrofolate reductase (DHFR), which contains the ori-beta sequence with several functionally relevant domains, such as an AT-rich region, dinucleotide repeat element (DNR), sequence-induced bend DNA (BEND) and a RIP60 protein-binding site (RIP60). Prior to initiation, ori sequences are recognized by origin recognition complex (ORC), which is a hetero hexamer complex that serves as the landing pad for proteins of the pre replication complex. The function of each ORC subunit is still unclear. In this study, we analyze the function of subunit 4 of the human ORC complex (HsOrc4) in interaction with a plasmid bearing the ori-beta DHFR sequence. We show that the topologically closed DHFR ori-beta replicator contains a bubble-like structure within its AT-rich region and that it is reversibly modified in the interaction with HsOrc4. The non-canonical structure of the AT-rich region in the topologically closed ori sequence is recognized and changed by HsOrc4 using the energy of supercoiled DNA. These findings could help to further elucidate DNA replication and its possible association with human genetic diseases. PMID- 26124053 TI - Time from symptom onset influences high-sensitivity troponin T diagnostic accuracy for the diagnosis of acute myocardial infarction. AB - BACKGROUND: The time required for patients with acute chest pain to reach a hospital emergency department varies, possibly lowering the diagnostic performance of a general cut-off value for high-sensitivity cardiac troponin T (hs-cTnT) in diagnosing acute myocardial infarction (AMI). The aim of this study was to determine the cut-off values as calculated by receiver operating characteristic (ROC) of hs-cTnT at different times from onset of symptoms to admission, and to evaluate their diagnostic performance. METHODS: Our study included 3096 patients with symptoms suggestive of AMI. These patients were classified according to time from onset of symptoms to admission. The diagnostic accuracy was quantified by the area under the ROC curve (AUC). RESULTS: Of the patients, 1082 (49.3%) were diagnosed as having AMI (317 were non-ST segment elevation myocardial infarction [NSTEMI]). The AUC for hs-cTnT to diagnose AMI was 0.881 at <3 h after symptom onset, 0.940 at 3-6 h after symptom onset, 0.966 at 6-12 h after symptom onset, and 0.974 at >12 h after symptom onset. The threshold as determined by ROC of hs-cTnT was 13.5 ng/L to diagnose AMI at <=3 h after symptom onset with a sensitivity of 81.8% and a specificity of 80.1%, 17.8 ng/L at 3-6 h after symptom onset with a sensitivity of 94.6% and a specificity of 84.3%, 30.0 ng/L at 6-12 h after symptom onset with a sensitivity of 95.9% and a specificity of 85.5%, and 58.0 ng/L at >12 h after symptom onset with a sensitivity of 92.7% and a specificity of 93.3%. The same observations were performed for the diagnosis of NSTEMI. CONCLUSIONS: The ROC-determined cut-off value of hs-cTnT for AMI or NSTEMI diagnosis gradually increased with time from onset of symptoms to presentation. Using a higher cut-off value by ROC for hs cTnT will improve its accuracy in diagnosing AMI or NSTEMI patients in late presenters. The higher value will enable physicians to more quickly rule in patients compared to the 99th percentile cut-off, and can rule out patients safely. PMID- 26124054 TI - Performance characteristics of the VIDAS(r) 25-OH Vitamin D Total assay - comparison with four immunoassays and two liquid chromatography-tandem mass spectrometry methods in a multicentric study. AB - BACKGROUND: The study was conducted to evaluate the analytical and clinical performance of the VIDAS(r) 25-OH Vitamin D Total assay. The clinical performance of the assay was compared with four other immunoassays against the results of two different liquid chromatography/mass spectrometry methods (LC-MS/MS) standardized to NIST reference materials. METHODS: VIDAS(r) 25-OH Vitamin D Total assay precision, linearity, detection limits and sample matrix comparison were assessed following CLSI guidelines. For method comparison, a total of 150 serum samples ranging from 7 to 92 ng/mL were analyzed by all the methods. Correlation was studied using Passing-Bablok regression and Bland-Altman analysis. The concordance correlation coefficient (CCC) was calculated to evaluate agreement between immunoassays and the reference LC-MS/MS method. In addition, samples containing endogenous 25(OH)D2 were used to assess each immunoassay's ability to detect this analyte. Pregnancy and hemodialysis samples were used to the study the effect of vitamin D binding protein (DBP) concentration over VIDAS(r) assay performance. RESULTS: The VIDAS(r) 25-OH Vitamin D Total assay showed excellent correlation to the LC-MS/MS results (y=1.01x+0.22 ng/mL, r=0.93), as obtained from two different sites and distinct LC-MS/MS methods. The limit of quantification was determined at 8.1 ng/mL. Cross-reactivity for 25(OH)D2 was over 80%. At concentrations of 10.5, 26 and 65.1 ng/mL, within-run CVs were 7.9%, 3.6% and 1.7%, while total CVs (between runs, calibrations, lots and instruments) were 16.0%, 4.5% and 2.8%. The VIDAS(r) performance was not influenced by altered DBP levels, though under-recovery of 25(OH)D as compared to LC-MS/MS was observed for hemodialysis samples. CONCLUSIONS: The VIDAS(r) 25-OH Vitamin D Total assay is therefore considered suitable for assessment of vitamin D status in clinical routine. PMID- 26124055 TI - Correlates of serum hepcidin levels and its association with cardiovascular disease in an elderly general population. AB - BACKGROUND: The expression of the key iron regulatory hormone hepcidin is regulated by iron availability, inflammation, hormones, hypoxia, and anaemia. Increased serum concentrations of hepcidin have recently been linked to atherosclerosis. We studied demographic, haematologic, biochemical, and dietary correlates of serum hepcidin levels and its associations with incident cardiovascular disease and with carotid atherosclerosis. METHODS: Serum hepcidin concentrations were measured by tandem mass spectrometry in samples taken in 2000 from 675 infection-free participants of the prospective population-based Bruneck study (age, mean+/-standard deviation, 66.0+/-10.2; 48.1% male). Blood parameters were measured by standard methods. Dietary intakes of iron and alcohol were surveyed with a food frequency questionnaire. Carotid atherosclerosis (365 cases) was assessed by ultrasound and subjects were observed for incident stroke, myocardial infarction, or sudden cardiac death (91 events) until 2010. RESULTS: Median (interquartile range) hepcidin levels were 2.27 nM (0.86, 4.15). Most hepcidin correlates were in line with hepcidin as an indicator of iron stores. Independently of ferritin, hepcidin was related directly to physical activity (p=0.024) and fibrinogen (p<0.0001), and inversely to alcohol intake (p=0.006), haemoglobin (p=0.027), and gamma-glutamyltransferase (p<0.0001). Hepcidin and hepcidin-to-ferritin ratio were not associated with prevalent carotid atherosclerosis (p=0.43 and p=0.79) or with incident cardiovascular disease (p=0.62 and p=0.33). CONCLUSIONS: In this random sample of the general community, fibrinogen and gamma-glutamyltransferase were the most significant hepcidin correlates independent of iron stores, and hepcidin was related to neither atherosclerosis nor cardiovascular disease. PMID- 26124056 TI - Prognostic significance of serum albumin level changes in acute ischemic stroke: the role of biological and analytical variation. AB - BACKGROUND: Animal studies have shown a neuroprotective effect of human serum albumin (sAlb) in ischemic stroke (IS). Previous studies have shown an association of high sAlb with better outcome. Our aim is to investigate the kinetics of sAlb in acute IS and its possible correlation with outcome taking into account the analytical and biological variation of sAlb measurement. METHODS: In a prospective observational study, we enrolled 105 patients with acute IS. sAlb was measured upon admission, at 24 h, 48 h, 72 h and Day 7 thereafter. Stroke severity was assessed upon admission and at 72 h, and functional outcome on Day 7. Patients were divided into two groups according to functional outcome on discharge. Calculation of reference change value was used to assess the clinical significance of sAlb changes and multiple logistic regression to assess the independent association between variables and outcome. RESULTS: Fifty-one patients (48.6%) had poor outcome. Their sAlb levels exhibit a significant daily decrease until 72 h (35.9 g/L) compared to baseline (41.1 g/L) and remained low until Day 7 (36.0 g/L). These changes were clinically significant only from 72 h on. Among non-poor outcome patients a significant daily decrease until 72 h (40.9 g/L) was followed by recovery on Day 7 (41.2 g/L), but these changes were not clinically significant. sAlb was not independently associated with the functional outcome at any time-point. CONCLUSIONS: This study shows that sAlb levels might change during the first days after an acute IS, but these changes although statistically significant are not clinically significant if we take into account the analytical and biological variation of sAlb. PMID- 26124057 TI - Clinical utility of one versus two faecal immunochemical test samples in the detection of advanced colorectal neoplasia in symptomatic patients. AB - BACKGROUND: The utility of faecal immunochemical tests (FIT) in assessment of symptomatic patients with lower gastrointestinal symptoms has not been well explored. The aims of this study were to evaluate the diagnostic yield for advanced colorectal neoplasia (ACRN) in symptomatic patients using the first of two FIT samples (FIT/1) and the higher concentration of two FIT samples (FIT/max). METHODS: Samples from two consecutive bowel motions from 208 symptomatic patients who required colonoscopy were analysed using the HM-JACKarc analyser (Kyowa Medex Co., Ltd., Tokyo, Japan). Patients were categorised into two groups: patients with any ACRN and individuals with other diagnoses or normal colonoscopy. RESULTS: Colonoscopy detected ACRN in 29 patients. In these patients, FIT/1 and FIT/max were significantly higher than in patients with low risk adenoma (p=0.006 and p=0.024), other findings (p=0.002 and p=0.002) and normal colonoscopy (p<0.001 and p<0.001). The areas under the curves (AUC) of FIT/1 and FIT/max were 0.71 and 0.69, respectively. Undetectable FIT/1 rules out 96.6% of ACRN and the specificity was 10.6%. Increasing the FIT/1 cut-off to 10 MUg Hb/g faeces, sensitivity and specificity were 34.5% and 87.2%, respectively. Similar results were obtained using FIT/max with 20 MUg Hb/g faeces cut-off, providing a sensitivity and specificity of 34.5% and 85.6%, respectively. CONCLUSIONS: Undetectable FIT is a good strategy to rule-out ACRN in symptomatic patients. The diagnostic yield of collecting two samples for FIT can be achieved with one sample, but a lower faecal haemoglobin concentrations (f-Hb) cut-off is required. PMID- 26124058 TI - Homocitrulline: a new marker for differentiating acute from chronic renal failure. AB - BACKGROUND: Carbamylation is a non-enzymatic post-translational modification of proteins characterized by the addition of isocyanic acid to amino groups. As isocyanic acid mainly originates from the spontaneous dissociation of urea, carbamylation rate is increased during renal failure. The aim of the study was to evaluate serum homocitrulline (HCit), which results from the carbamylation of epsilon-amino groups of lysine (Lys) residues, in acute renal failure (ARF) and to determine if it could be useful for differentiating acute from chronic renal failure (CRF). METHODS: In total, 213 patients with renal failure referred to the nephrology department of the university hospital of Reims were included. Patients were classified into three groups: patients with ARF (ARF group, n=39), patients with CRF complicated with ARF (A/CRF group, n=29) and patients with CRF (CRF group, n=145). Serum HCit concentrations were measured by LC-MS/MS. Concentration kinetics of HCit and urea were studied in patients suffering from ARF. The HCit thresholds distinguishing ARF and CRF were investigated. RESULTS: HCit concentrations increased in ARF patients reaching a peak delayed compared to urea concentration peak. HCit concentrations were positively correlated with urea concentrations (r=0.51) and with the time elapsed since the estimated onset of ARF (r=0.57). Serum HCit concentrations were higher (p<0.05) in CRF group compared to ARF group. The receiver operating characteristic curve analysis showed that HCit concentrations <289 MUmol/mol Lys were predictive of ARF (Sensitivity: 83%, Specificity: 72%, AUC: 0.856). CONCLUSIONS: Our results demonstrate that HCit is a promising biomarker for distinguishing between ARF and CRF patients. PMID- 26124059 TI - Lipiduria--with special relevance to Fabry disease. AB - Examination of the urine under the microscope using polarised light is invaluable for detecting and identifying lipid particles. Attention to the shape of these Maltese cross bearing bodies can distinguish conventional fat particles from Fabry bodies with great sensitivity and specificity across a wide phenotypic spectrum. This could be a cheap and rapid tool for screening subjects suspected of having Fabry disease for renal involvement. It remains to be seen whether there is value in integrating polarised light into automated urine microscopy machines, but potentially this could greatly help the pathologist or nephrologist in identifying unusual urinary particles, and broaden the capacity for larger scale screening. PMID- 26124060 TI - The beneficial role of anti-inflammatory dietary ingredients in attenuating markers of chronic low-grade inflammation in aging. AB - Aging in humans is associated with chronic low-grade inflammation (systemic), and this condition is sometimes referred to as "inflammaging". In general, canines also age similarly to humans, and such aging is associated with a decline in mobility, joint problems, weakened muscles and bones, reduced lean body mass, cancer, increased dermatological problems, decline in cognitive ability, reduced energy, decreased immune function, decreased renal function, and urinary incontinence. Each of these conditions is also associated with an increase in pro inflammatory cytokines. An inflammatory state characterized by an increase in pro inflammatory markers including but not restricted to tumor necrosis factor-alpha, interleukin-6, IL-1beta, and C-reactive protein (CRP) is believed to contribute to or worsen a general decline in biological mechanisms responsible for physical function with aging. Nutritional management of inflammation in aging dogs is important in maintaining health. In particular, natural botanicals have bioactive components that appear to have robust anti-inflammatory effects and, when included in the diet, may contribute to a reduction in inflammation. While there are scientific data to support the anti-inflammatory effects and the efficacy of such bioactive molecules from botanicals, the clinical data are limited and more studies are needed to validate the efficacy of these ingredients. This review will summarize the role of dietary ingredients in reducing inflammatory molecules as well as review the evidence available to support the role of diet and nutrition in reducing chronic low-grade systemic inflammation in animal and human studies with a special reference to canines, where possible. PMID- 26124061 TI - Antibacterial activity of combination of synthetic and biopolymer non-woven structures. AB - BACKGROUND: Fibrous structures and synthetic polymer blends offer potential usages in making biomedical devices, textiles used in medical practices, food packaging, tissue engineering, environmental applications and biomedical arena. These products are also excellent candidates for building scaffolds to grow stem cells for implantation, to make tissue engineering grafts, to make stents to open up blood vessels caused by atherosclerosis or narrowed by blood clots, for drug delivery systems for micro- to nano-medicines, for transdermal patches, and for healing of wounds and burn care. The current study was designed to evaluate the antimicrobial activity of woven and non-woven forms of nano- and macro-scale blended polymers having biocompatible and biodegradable characteristics. METHODS: The antimicrobial activity of non-woven fibrous structures created with the combination of synthetic and biopolymer was assessed using Gram-negative, Gram positive bacteria, such as Staphylococcus aureus, Proteus vulgaris, Escherichia coli and Enterobacter aerogenes using pour plate method. Structural evaluation of the fabricated samples was performed by Fourier transform infrared spectroscopy. RESULTS: Broad spectrum antibacterial activities were found from the tested materials consisting of polyvinyl alcohol (PVA) with chitosan and nylon-6 combined with chitosan and formic acid. CONCLUSIONS: The combination of PVA with chitosan was more bactericidal or bacteriostatic than that of nylon-6 combined with chitosan and formic acid. PVA combination with chitosan appears to be a broad-spectrum antimicrobial agent. PMID- 26124063 TI - A study on the characteristics of the deflagration of hydrogen-air mixture under the effect of a mesh aluminum alloy. AB - Mesh aluminum alloys (MAAs) have been widely used in military and civilian applications to suppress the explosion of flammable gases (fluids) inside containers. However, MAAs have not been tested in or applied to the hydrogen suppression-explosions. Hence, a typical MAA product, i.e., one that has been in wide use, is selected as the experimental material in the present study. The characteristics of the deflagration of hydrogen-air mixture inside an MAA-filled tube are investigated, and the effects of the filling density of the MAA and the concentration of hydrogen in air on the deflagration are examined. The suppressing effect of the MAA on the deflagration of hydrogen-air mixture is compared with its effect on the deflagration of a typical hydrocarbon fuel in air. The results show that not only is the existing MAA product unable to effectively suppress the deflagration of hydrogen-air mixture, but it also increases the maximum explosion pressure, which is opposite to the satisfactory suppressing effect of the MAA product on the deflagration of hydrocarbon fuels such as methane. The results of this study provide a scientific basis for the effective prevention of explosion accidents with hydrogen and for the development of explosion-suppression products. PMID- 26124064 TI - Recycling of MSWI fly ash by means of cementitious double step cold bonding pelletization: Technological assessment for the production of lightweight artificial aggregates. AB - In this work, an extensive study on the recycling of municipal solid waste incinerator fly ash by means of cold bonding pelletization is presented. The ash comes from an incineration plant equipped with rotary and stoker furnaces, in which municipal, hospital and industrial wastes are treated. Fly ash from waste incineration is classified as hazardous and cannot be utilized or even landfilled without prior treatment. The pelletization process uses cement, lime and coal fly ash as components of the binding systems. This process has been applied to several mixes in which the ash content has been varied from 50% (wt.%) up to a maximum of 70%. An innovative additional pelletization step with only cementitious binder has been performed in order to achieve satisfactory immobilization levels. The obtained lightweight porous aggregates are mostly suitable for recovery in the field of building materials with enhanced sustainability properties. Density, water absorption and crushing strength ranged from 1000 to 1600 kg/m(3), 7 to 16% and 1.3 to 6.2 MPa, respectively, and the second pelletization step increased stabilization efficiency. The feasibility of the process has been analyzed by testing also concrete specimens containing the artificial aggregates, resulting in lightweight concrete of average performance. PMID- 26124062 TI - Pretreatment of Mesenchymal Stem Cells Manipulates Their Vasculoprotective Potential While Not Altering Their Homing Within the Injured Gut. AB - Mesenchymal stem cells (MSCs) have shown therapeutic promise in many experimental and clinical models of inflammation. However, a commonly reported feature of MSC transplantation is poor homing to injured tissues. Previously, we have shown that pretreatment with cytokines/chemical factors enhances hematopoietic SC adhesion within intestinal microvasculature following ischemia-reperfusion (IR) injury. Using intravital microscopy, the ability of similar pretreatment strategies to enhance the recruitment of murine MSCs to murine intestinal microvasculature following IR injury was investigated. Primary MSCs were isolated from bone marrow and selected on the basis of platelet-derived growth factor receptor-alpha and SC antigen-1 positivity (PDGFRalpha(+) /Sca-1(+) ). MSC recruitment was similar in IR injured gut mucosa when compared with sham operated controls, with limited cell adhesion observed. MSCs appeared contorted in microvessels, suggesting physical entrapment. Although not recruited specifically by injury, MSC administration significantly reduced neutrophil recruitment and improved tissue perfusion in the severely injured jejunum. Vasculoprotective effects were not demonstrated in the lesser injured ileum. Pretreatment of MSCs with tumor necrosis factor (TNF)-alpha, CXCL12, interferon (IFN)-gamma, or hydrogen peroxide did not enhance their intestinal recruitment. In fact, TNFalpha and IFNgamma removed the previous therapeutic ability of transplanted MSCs to reduce neutrophil infiltration and improve perfusion in the jejunum. We provide direct evidence that MSCs can rapidly limit leukocyte recruitment and improve tissue perfusion following intestinal IR injury. However, this study also highlights complexities associated with strategies to improve MSC therapeutic efficacy. Future studies using cytokine/chemical pretreatments to enhance MSC recruitment/function require careful consideration and validation to ensure therapeutic function is not impeded. PMID- 26124065 TI - Reactive red 120 retention through ultrafiltration enhanced by synthetic and natural polyelectrolytes. AB - Two cationic chelating polymers, namely synthetic polyethylenimine (PEI), and biopolymer chitosan were employed in the present study to bring about the retention of anionic reactive red 120 (RR 120) from its aqueous solutions by way of polymer enhanced ultrafiltration (PEUF). The effects of process parameters, namely, cross-flow rate, transmembrane pressure, time, polyelectrolyte loading, and ionic strength on dye retention and permeation flux were examined. PEI enhanced ultrafiltration achieved dye retentions as high as 99.9%, and significant permeation fluxes around 148 L/m(2)h. However, in case of chitosan, relatively low retention (88%), and flux (120 L/m(2)h) levels were observed. A careful comparison of the changes induced in the UV-vis spectra of RR 120 by PEI and chitosan indicated a predominant electrostatic interaction between PEI and RR 120, as opposed to the relatively weak and sterically as well as chemically hindered interaction between chitosan and the dye ion. The respective binding constants of PEI-RR 120, and PEI-chitosan complexes, in addition to the relatively more pronounced permeation flux decline witnessed in the presence of chitosan, clearly advocated the use of PEI, rather than chitosan, as the most appropriate complexing agent in the present context. PMID- 26124066 TI - Emissions of polychlorinated diphenyl ethers from a municipal solid waste incinerator during the start-up operation. AB - This study examines the emissions of polychlorinated diphenyl ethers (PCDEs) during the start-up processes of a municipal solid waste incinerator (MSWI). Both normal and modified emission control start-ups were tested. Fifteen samples were taken from the flue gas with increasing furnace temperature. Peak PCDE concentrations of 1.48-10.3 ng/Nm(3) were observed at 8-11 h after the start of combustion, when the furnace temperature was in the range of 267-440 degrees C, that also needed for PCDD/F formation by de novo synthesis. The PCDE emissions could thus, be reduced by current control techniques. Furthermore, the modified control strategies inhibited PCDE formation at the beginning of combustion, and led to an 86% reduction in the maximum PCDE concentration. The overall start-up emissions were calculated as 1.01-3.08 mg, while the annual PCDE emissions with one start-up operation were found to be 7.48-9.64 mg. However, total PCDE emissions will increase by 12-69% if the number of start-up runs increases to between two and eight times per year. Consequently, the prevention of the unnecessary start-ups and advanced activation of the related emission control system are both efficient ways to reduce PCDE emissions. PMID- 26124067 TI - Antibiotic resistance genes in manure-amended soil and vegetables at harvest. AB - Lettuce and endive, which can be eaten raw, were planted on the manure-amended soil in order to explore the influence of plants on the abundance of antibiotic resistance genes (ARGs) in bulk soil and rhizosphere soil, and the occurrence of ARGs on harvested vegetables. Twelve ARGs and one integrase gene (intI1) were detected in all soil samples. Five ARGs (sulI, tetG, tetC, tetA, and tetM) showed lower abundance in the soil with plants than those without. ARGs and intI1 gene were also detected on harvested vegetables grown in manure-amended soil, including endophytes and phyllosphere microorganisms. The results demonstrated that planting had an effect on the distribution of ARGs in manure-amended soil, and ARGs were detected on harvested vegetables after growing in manure-amended soil, which had potential threat to human health. PMID- 26124068 TI - Expression and rapid purification of recombinant biologically active ovine growth hormone with DsbA targeting to Escherichia coli inner membrane. AB - This study shows expression of recombinant ovine growth hormone (roGH) and targeting to the inner membrane using signal sequence, DsbA, in Escherichia coli (E. coli) cell. Factors such as temperature, IPTG induction, and expression conditions were studied and show diverse optical density with different media compositions. The optimum expression level of roGH in terrific broth medium was at 25 degrees C on induction with 20 MUM IPTG in early logarithmic phase. SDS PAGE analysis of expression and subcellular fractions of recombinant constructs revealed the translocation of roGH to the inner membrane of E. coli with DsbA signal sequence at the N terminus of roGH. The protein was easily solubilized by 40 % acetonitrile with ~90 % purity and was identified by Western blot, and analysis on MALDI-TOF/TOF confirmed a size of 21,059 Da. Relatively high soluble protein yield of 65.3 mg/L of roGH was obtained. The biological function of roGH was confirmed by HeLa cell line proliferation. This is the first study describing achievement of biologically active soluble roGH targeted to the inner membrane of E. coli and rapid purification with high yield. PMID- 26124069 TI - Flavonoid glucosylation by non-Leloir glycosyltransferases: formation of multiple derivatives of 3,5,7,3',4'-pentahydroxyflavane stereoisomers. AB - Flavonoids are known to possess a multitude of biological activities. Therefore, diversification of the core structures is of considerable interest. One of nature's important tailoring reactions in the generation of bioactive compounds is glycosylation, which is able to influence numerous molecular properties. Here, we examined two non-Leloir glycosyltransferases that use sucrose as an inexpensive carbohydrate donor, glycosyltransferase R from Streptococcus oralis (GtfR) and amylosucrase from Neisseria polysaccharea (Ams), for the glucosylation of flavonoids. Flavones generally were poor substrates. Several inhibited Ams. In contrast, flavanes were well accepted by both enzymes. All glucose attachments occurred via alpha1 linkages. Comparison of the three available stereoisomers of 3,5,7,3',4'-pentahydroxyflavane revealed significant differences in glycoside formation between them as well as between the two enzymes. The latter were shown to possess largely complementary product ranges. Altogether, three of the four hydroxy substituents of the terminal flavonoid rings were glycosylated. Typically, Ams glucosylated the B ring at position 3', whereas GtfR glucosylated this ring at position 4' and/or the A ring at position 7. In several instances, short carbohydrate chains were attached to the aglycones. These contained alpha 1 4 linkages when formed by Ams, but alpha 1-3 bonds when generated by GtfR. The results show that both enzymes are useful catalysts for the glucodiversification of flavanes. In total, more than 16 products were formed, of which seven have previously not been described. PMID- 26124070 TI - Whey-derived valuable products obtained by microbial fermentation. AB - Whey, the main by-product of the cheese industry, is considered as an important pollutant due to its high chemical and biological oxygen demand. Whey, often considered as waste, has high nutritional value and can be used to obtain value added products, although some of them need expensive enzymatic synthesis. An economical alternative to transform whey into valuable products is through bacterial or yeast fermentations and by accumulation during algae growth. Fermentative processes can be applied either to produce individual compounds or to formulate new foods and beverages. In the first case, a considerable amount of research has been directed to obtain biofuels able to replace those derived from petrol. In addition, the possibility of replacing petrol-derived plastics by biodegradable polymers synthesized during bacterial fermentation of whey has been sought. Further, the ability of different organisms to produce metabolites commonly used in the food and pharmaceutical industries (i.e., lactic acid, lactobionic acid, polysaccharides, etc.) using whey as growth substrate has been studied. On the other hand, new low-cost functional whey-based foods and beverages leveraging the high nutritional quality of whey have been formulated, highlighting the health-promoting effects of fermented whey-derived products. This review aims to gather the multiple uses of whey as sustainable raw material for the production of individual compounds, foods, and beverages by microbial fermentation. This is the first work to give an overview on the microbial transformation of whey as raw material into a large repertoire of industrially relevant foods and products. PMID- 26124071 TI - Effects of brief intervention on subgroups of injured patients who drink at risk levels. AB - Alcohol-related injuries are a major source of admission for trauma care. Screening and brief intervention (SBI) for injured patients can result in decreased drinking and risk behaviors. It is not clear SBI is equally beneficial for all injured patients. A secondary data analysis of 553 patients admitted to two Level-1 trauma centers was conducted. Latent class analysis was used to identify patient subgroups based on injury-related risks and consequences of alcohol use. Intervention effects on drinking were examined among subgroups. Five subgroups were identified. Drinking improved in patients reporting multiple risks and injuries/accidents and drinking and driving. Patients that reported drinking and driving and taking foolish risks or fighting while drinking and taking foolish risks did not show improvements. Trauma centers may benefit from targeting interventions based on injury-related risks and consequences of alcohol use. Further research is needed to test bedside approaches for tailored interventions. PMID- 26124072 TI - Association between New Jersey's Graduated Driver Licensing decal provision and crash rates of young drivers with learners' permits. AB - New Jersey (NJ) implemented the first-in-the-US Graduated Driver Licensing (GDL) decal provision in May 2010 for young drivers with learner's permits or intermediate licenses. Previous analyses found an association between the provision and crash reduction among intermediate drivers. The aim of this study is to examine the association between NJ's provision and GDL citation and crash rates among drivers aged <21 years with learner's permits. We estimated monthly per-driver rates from January 2006 through June 2012. Negative binomial modeling compared pre and post decal crash rates adjusted for gender, age, calendar month, and gas price. The monthly GDL citation rate was two per 10,000 drivers in the predecal and postdecal periods. Crashes were rare and rates declined similarly pre and post decal (adjusted rate ratio of postdecal vs predecal slope: 1.04 (0.97 to 1.12)). NJ's GDL decal provision was not associated with a change in citation or crash rates among young NJ drivers with learner's permits. PMID- 26124073 TI - Gun ownership and social gun culture. AB - We assessed gun ownership rates in 2013 across the USA and the association between exposure to a social gun culture and gun ownership. We used data from a nationally representative sample of 4000 US adults, from 50 states and District of Columbia, aged >18 years to assess gun ownership and social gun culture performed in October 2013. State-level firearm policy information was obtained from the Brady Law Center and Injury Prevention and Control Center. One-third of Americans reported owning a gun, ranging from 5.2% in Delaware to 61.7% in Alaska. Gun ownership was 2.25-times greater among those reporting social gun culture (PR=2.25, 95% CI 2.02 to 2.52) than those who did not. In conclusion, we found strong association between social gun culture and gun ownership. Gun cultures may need to be considered for public health strategies that aim to change gun ownership in the USA. PMID- 26124074 TI - Submucosal tunneling and endoscopic resection of a large, esophageal leiomyoma. PMID- 26124075 TI - Detection of buried Barrett's glands after radiofrequency ablation with volumetric laser endomicroscopy. AB - BACKGROUND AND AIMS: The prevalence and clinical relevance of buried Barrett's glands (BB) after radiofrequency ablation (RFA) in Barrett's esophagus (BE) are debated. Recent optical coherence tomography studies demonstrated a high prevalence of BBs. Direct histological correlation, however, has been lacking. Volumetric laser endomicroscopy (VLE) is a second-generation optical coherence tomography system capable of scanning a large surface of the esophageal wall layers with low-power microscopy resolution. The aim was to evaluate whether post RFA subsquamous glandular structures (SGSs), detected with VLE, actually correspond to BBs by pursuing direct histological correlation with VLE images. METHODS: In vivo VLE was performed to detect SGSs in patients with endoscopic regression of BE post-RFA. A second in vivo VLE scan was performed to confirm correct delineation of the SGSs. After endoscopic resection, the specimens were imaged ex vivo with VLE. Extensive histological sectioning of SGS areas was performed, and all histology slides were evaluated by an expert BE pathologist. RESULTS: Seventeen patients underwent successful in vivo VLE (histological diagnosis before endoscopic treatment: early adenocarcinoma in 8 patients and high-grade dysplasia in 9). In 4 of 17 patients, no SGSs were identified during VLE, and a random resection was performed. In the remaining 13 patients (76%), VLE detected SGS areas, which were all confirmed on a second in vivo VLE scan and subsequently resected. Most SGSs identified by VLE corresponded to normal histological structures (eg, dilated glands and blood vessels). However, 1 area containing BBs was found on histology. No specific VLE features to distinguish between BBs and normal SGSs were identified. CONCLUSIONS: VLE is able to detect subsquamous esophageal structures. One area showed BBs beneath endoscopically normal-appearing neosquamous epithelium; however, most post-RFA SGSs identified by VLE correspond to normal histological structures. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR4056.). PMID- 26124076 TI - Isolation and characterization of Paenibacillus polymyxa LY214, a camptothecin producing endophytic bacterium from Camptotheca acuminata. AB - Camptothecin (CPT) is mainly produced and extracted from Camptotheca acuminata and Nothapodytes foetida for pharmaceutical use, i.e., the starting material for chemical conversion to the clinical CPT-type drugs. As the third largest plant anticancer drug, the heavy demand on CPT from global market leads to many research efforts to identify new sources for CPT production. Herein we report the isolation and characterization of a CPT-producing endophytic bacterium Paenibacillus polymyxa LY214 from Camptotheca acuminata. A 10.7 MUg l(-1) of CPT was presented in the fermentation broth of P. polymyxa LY214. Its CPT production decreased sharply when the strain of the 2nd generation of P. polymyxa LY214 was cultured and fermented. However, the CPT production remained relatively constant from 2.8 MUg l(-1) of the 2nd generation to 0.8 MUg l(-1) of the 8th generation of P. polymyxa LY214 under optimized fermentation conditions. A 15- to 30-fold increase of CPT yield was observed when the optimized fermentation conditions, together with the addition of putative biosynthetic precursors of CPT and adsorbent resin XAD16, were applied to ferment the strains of the 7th and 8th generation of P. polymyxa LY214. Bioinformatics analysis of the relative species of P. polymyxa LY214 indicates its potential to produce CPT, which will be helpful to decipher the mysteries of CPT biosynthesis. PMID- 26124077 TI - Evaluation of pedicle screw placement by pedicle channel grade in adolescent idiopathic scoliosis: should we challenge narrow pedicles? AB - BACKGROUND: Surgeons often have concerns about whether to place screws in narrow pedicles for correction of scoliosis. The aim of this study was to use pedicle channel grades based on preoperative CT to evaluate pedicle screw placement in posterior surgery for adolescent idiopathic scoliosis. METHODS: The subjects comprised 55 patients who underwent posterior correction and fusion, and a total of 810 pedicles were examined in which screw placement had been planned and probing had been performed. Pedicle channel grades were determined by measuring inner pedicle diameter on preoperative CT scans. The grades were defined as grade 1 with an inner diameter of >= 4 mm, grade 2 with an inner diameter of >= 2 mm and < 4 mm, grade 3 with an inner diameter of >= 1 mm and < 2 mm, and grade 4 for a "cortical channel" with an inner diameter of < 1 mm. RESULTS: The failure rate of screw placement was 0.5 % for pedicle channel grade 1, 2.9 % for grade 2, 12.0 % for grade 3, and 31.5 % for grade 4, showing significant differences (p < 0.001). For the laterality of curvature, the failure rate was 5.9 % for the convex side, 8.0 % for the neutral vertebra, and 9.0 % for the concave side, showing no significant difference. There was also no significant difference in failure rate between degrees of curvature of < 60 degrees (8.2 %) and >= 60 degrees (5.6 %). Logistic analysis showed that the pedicle channel grade was a significant risk factor for failure (odds ratio 4.0, p < 0.001). CONCLUSIONS: The failure rate of screw placement was 31.5 % for a cortical channel with a pedicle inner diameter of < 1 mm. Screw placement should be attempted in pedicles with an inner diameter of 1 mm or larger. PMID- 26124078 TI - Preservation of different fig cultivars (Ficus carica L.) under modified atmosphere packaging during cold storage. AB - BACKGROUND: The effect of modified atmosphere packaging (MAP) on the stability of 'Cuello Dama Blanco' (CDB), 'Cuello Dama Negro' (CDN) and 'San Antonio' (SA) figs during post-harvest cold storage was evaluated by using three different films with a diverse number of microperforations (diameter, o = 100 um): M10 (16 holes), M30 (five holes) and M50 (three holes). A macroperforated film was used as control (five holes, o = 9 mm). Gas composition, weight loss, percentage disorder, microbial counts and physico-chemical parameters were monitored during cold storage for 21 days. Furthermore, sensory quality was also evaluated. RESULTS: MAP has allowed the extension of cold storage and distribution time for the three different cultivars of figs, minimising weight loss and delaying pathological disorders related to endosepsis, smut, and souring. Of the three cultivars, the M50 batch (one hole per 50 mm) showed the best efficiency in terms of physico-chemical quality and delay of post-harvest decay, although the M30 batch was also found to be suitable for delaying the post-harvest decay, especially for the CDB cultivar. CONCLUSION: MAP is a useful tool to extend the storability with optimal quality properties for CDN and SA during 21 days of cold storage and 14-17 days of cold storage for CDB. PMID- 26124079 TI - FBXL12-Mediated Degradation of ALDH3 is Essential for Trophoblast Differentiation During Placental Development. AB - How stem cells maintain their stemness or initiate exit from the stem cell state for differentiation remains largely unknown. Aldehyde dehydrogenase (ALDH) activity is a hallmark of stem cells-including embryonic, adult tissue, and cancer stem cells-and is essential for their maintenance. The mechanisms by which ALDH activity is regulated in stem cells have remained poorly understood, however. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Most mice deficient in FBXL12 died during the embryonic or perinatal period probably as a result of abnormal development of the placenta, characterized by impaired formation of the junctional zone. ALDH3 accumulated in the FBXL12-deficient placenta, and forced expression of ALDH3 in wild-type TSCs phenocopied the differentiation defect of FBXL12-deficient TSCs. Conversely, inhibition of ALDH3 activity by gossypol rescued the phenotype of FBXL12 deficiency. Our results suggest that FBXL12 plays a key role in the downregulation of ALDH3 activity in TSCs and thereby initiates trophoblast differentiation during placental development. PMID- 26124080 TI - Epigenetic silencing of NKD2, a major component of Wnt signaling, promotes breast cancer growth. AB - Naked cuticle homolog 2 (NKD2) has been reported to antagonize Wnt signaling in zebrafish, mouse and mammals. The aim of this study is to investigate the epigenetic changes and mechanisms of NKD2 in human breast cancer development. Six breast cancer cell lines (MCF-7, ZR75-1, MDA-MB-468, MDA-MB-231, T47D and BT474) and 68 cases of primary human breast cancer were studied using methylation specific PCR, immunohistochemistry, western blot, flow cytometry techniques and a xenograft mouse model. The expression of NKD1 and NKD2 was regulated by promoter region methylation in breast cancer cells. No NKD1 methylation was found in primary human breast cancer. NKD2 was methylated in 51.4% (35/68) of human primary breast cancer samples. NKD2 methylation was significantly associated with reduction of NKD2 expression, and tumor stage (p < 0.05). NKD2 suppressed breast cancer cell proliferation both in vitro and in vivo. NKD2 induced G1/S arrest and inhibited Wnt signaling in breast cancer cells. In conclusion, NKD2 is frequently methylated in human breast cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses breast cancer proliferation by inhibiting Wnt signaling. PMID- 26124081 TI - MicroRNA-153/Nrf-2/GPx1 pathway regulates radiosensitivity and stemness of glioma stem cells via reactive oxygen species. AB - Glioma stem cells (GSCs) exhibit stem cell properties and high resistance to radiotherapy. The main aim of our study was to determine the roles of ROS in radioresistance and stemness of GSCs. We found that microRNA (miR)-153 was down regulated and its target gene nuclear factor-erythroid 2-related factor-2 (Nrf-2) was up-regulated in GSCs compared with that of non-GSCs glioma cells. The enhanced Nrf-2 expression increased glutathione peroxidase 1 (GPx1) transcription and decreased ROS level leading to radioresistance of GSCs. MiR-153 overexpression resulted in increased ROS production and radiosensitization of GSCs. Moreover, miR-153 overexpression led to decreased neurosphere formation capacity and stem cell marker expression, and induced differentiation through ROS mediated activation of p38 MAPK in GSCs. Nrf-2 overexpression rescued the decreased stemness and radioresistance resulting from miR-153 overexpression in GSCs. In addition, miR-153 overexpression reduced tumorigenic capacity of GSCs and increased survival in mice bearing human GSCs. These findings demonstrated that miR-153 overexpression decreased radioresistance and stemness of GSCs through targeting Nrf-2/GPx1/ROS pathway. PMID- 26124082 TI - Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer. AB - Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions. PMID- 26124083 TI - In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters. AB - Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1 ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID- 26124085 TI - Eating disorders in persons with type 1 diabetes: A focus group investigation of early eating disorder risk. AB - Through focus groups, we examined the development and maintenance of an eating disorder in 16 females with type 1 diabetes and an eating disorder. The quotes and qualitative data summaries provide rich insights into understanding why those with type 1 diabetes are at increased risk for eating disorders. Content analyses revealed five themes pertinent to the dual diagnosis (feeling different, difficulty with control/coping, body image, feelings, and quality of life) of which four themes were relevant to eating disorder development. Findings support early identification of those at risk and inform interventions to mitigate development of an eating disorder. PMID- 26124084 TI - Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma. AB - Previously, we conducted a randomized phase III trial of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy in surgically managed locally advanced oral squamous cell carcinoma (OSCC) and found no improvement in overall survival. This study reports long-term follow-up results from our initial trial. All patients had clinical stage III or IVA locally advanced OSCC. In the experimental group, patients received two cycles of TPF induction chemotherapy (75mg/m2 docetaxel d1, 75mg/m2 cisplatin d1, and 750mg/m2/day 5-fluorouracil d1 5) followed by radical surgery and post-operative radiotherapy; in the control group, patients received upfront radical surgery and post-operative radiotherapy. The primary endpoint was overall survival. Among 256 enrolled patients with a median follow-up of 70 months, estimated 5-year overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 61.1%, 52.7%, 55.2%, and 60.4%, respectively. There were no significant differences in survival rates between experimental and control groups. However, patients with favorable pathologic responses had improved outcomes compared to those with unfavorable pathologic responses and to those in the control group. Although TPF induction chemotherapy did not improve long-term survival compared to surgery upfront in patients with stage III and IVA OSCC, a favorable pathologic response after induction chemotherapy may be used as a major endpoint and prognosticator in future studies. Furthermore, the negative results observed in this trial may be represent type II error from an underpowered study. Future larger scale phase III trials are warranted to investigate whether a significant benefit exists for TPF induction chemotherapy in surgically managed OSCC. PMID- 26124086 TI - Coping and quality of life of patients following microsurgical treatment for breast cancer-related lymphedema. AB - Breast cancer-related lymphedema is associated with numerous adverse outcomes. This study investigated the extent clinical factors, lymphedema symptoms, lymphedema-related appearance, and coping strategies predicted quality of life. Female patients who underwent microsurgical treatment for lymphedema (n = 54) participated. Lymphedema symptoms were associated with physical and functional well-being, but not emotional and social well-being. Clinical factors and lymphedema-related appearance were not significantly associated with quality of life. Compared to adaptive coping strategies, maladaptive coping strategies (e.g. denial, venting, self-blame) were more strongly associated with quality of life. This suggests psychosocial interventions aimed at modifying maladaptive coping behaviors can potentially improve quality of life for this patient population. PMID- 26124087 TI - Clarifying the associations between anxiety, depression and fatigue following stroke. AB - Both psychological distress and fatigue are common post stroke. Although there is recognition that the phenomena are related, the nature of the relationship is unclear.Cross-sectional study of 98 independently functioning participants within 2 years of stroke. Significant relationships were observed between fatigue and general anxiety, health-related anxiety and stroke-specific anxiety (r range from .31 to .37). In the final regression model, depression, pain and stroke-specific anxiety were significant, accounting for 32 per cent of the variance in fatigue scores (p < .001). The findings provide insight into the importance of anxiety related factors post stroke, their relevance to our understanding of post-stroke fatigue and their implications for post-stroke intervention. PMID- 26124088 TI - How useful is optogenetic activation in determining neuronal function within dynamic circuits? PMID- 26124089 TI - PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. AB - Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target. PMID- 26124090 TI - Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations. AB - While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN Brazil Initiative, the most comprehensive up to-date genomic analysis of any Latin-American population. A population-based genome-wide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6-8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes. PMID- 26124091 TI - Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson's disease. AB - Parkinson's disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1-2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino 7-chloroquinoline, suggesting a critical structure-activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine stimulate the transcriptional function of Nurr1 through physical interaction with its ligand binding domain (LBD). Remarkably, these compounds were able to enhance the contrasting dual functions of Nurr1 by further increasing transcriptional activation of mDA-specific genes and further enhancing transrepression of neurotoxic proinflammatory gene expression in microglia. Importantly, these compounds significantly improved behavioral deficits in 6-hydroxydopamine lesioned rat model of PD without any detectable signs of dyskinesia-like behavior. These findings offer proof of principle that small molecules targeting the Nurr1 LBD can be used as a mechanism-based and neuroprotective strategy for PD. PMID- 26124092 TI - FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP. AB - Pre-mRNA splicing is coupled to transcription by RNA polymerase II (RNAP II). We previously showed that U1 small nuclear ribonucleoprotein (snRNP) associates with RNAP II, and both RNAP II and U1 snRNP are also the most abundant factors associated with the protein fused-in-sarcoma (FUS), which is mutated to cause the neurodegenerative disease amyotrophic lateral sclerosis. Here, we show that an antisense morpholino that base-pairs to the 5' end of U1 snRNA blocks splicing in the coupled system and completely disrupts the association between U1 snRNP and both FUS and RNAP II, but has no effect on the association between FUS and RNAP II. Conversely, we found that U1 snRNP does not interact with RNAP II in FUS knockdown extracts. Moreover, using these extracts, we found that FUS must be present during the transcription reaction in order for splicing to occur. Together, our data lead to a model that FUS functions in coupling transcription to splicing via mediating an interaction between RNAP II and U1 snRNP. PMID- 26124093 TI - Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection. AB - Traditional approaches to antimicrobial drug development are poorly suited to combatting the emergence of novel pathogens. Additionally, the lack of small animal models for these infections hinders the in vivo testing of potential therapeutics. Here we demonstrate the use of the VelocImmune technology (a mouse that expresses human antibody-variable heavy chains and kappa light chains) alongside the VelociGene technology (which allows for rapid engineering of the mouse genome) to quickly develop and evaluate antibodies against an emerging viral disease. Specifically, we show the rapid generation of fully human neutralizing antibodies against the recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) and development of a humanized mouse model for MERS-CoV infection, which was used to demonstrate the therapeutic efficacy of the isolated antibodies. The VelocImmune and VelociGene technologies are powerful platforms that can be used to rapidly respond to emerging epidemics. PMID- 26124094 TI - Archaeal actin from a hyperthermophile forms a single-stranded filament. AB - The prokaryotic origins of the actin cytoskeleton have been firmly established, but it has become clear that the bacterial actins form a wide variety of different filaments, different both from each other and from eukaryotic F-actin. We have used electron cryomicroscopy (cryo-EM) to examine the filaments formed by the protein crenactin (a crenarchaeal actin) from Pyrobaculum calidifontis, an organism that grows optimally at 90 degrees C. Although this protein only has ~ 20% sequence identity with eukaryotic actin, phylogenetic analyses have placed it much closer to eukaryotic actin than any of the bacterial homologs. It has been assumed that the crenactin filament is double-stranded, like F-actin, in part because it would be hard to imagine how a single-stranded filament would be stable at such high temperatures. We show that not only is the crenactin filament single-stranded, but that it is remarkably similar to each of the two strands in F-actin. A large insertion in the crenactin sequence would prevent the formation of an F-actin-like double-stranded filament. Further, analysis of two existing crystal structures reveals six different subunit-subunit interfaces that are filament-like, but each is different from the others in terms of significant rotations. This variability in the subunit-subunit interface, seen at atomic resolution in crystals, can explain the large variability in the crenactin filaments observed by cryo-EM and helps to explain the variability in twist that has been observed for eukaryotic actin filaments. PMID- 26124095 TI - Mapping the binding interface of ERK and transcriptional repressor Capicua using photocrosslinking. AB - Extracellular signal-regulated kinase (ERK) coordinates cellular responses to a range of stimuli by phosphorylating its numerous substrates. One of these substrates, Capicua (Cic), is a transcriptional repressor that was first identified in Drosophila and has been implicated in a number of human diseases. Here we use a chemical biology approach to map the binding interface of ERK and Cic. The noncanonical amino acid p-azidophenylalanine (AzF) was introduced into the ERK-binding region of Drosophila Cic, and photocrosslinking and tandem mass spectrometry were used to pinpoint its binding site on ERK. We also identified the ERK-binding region of human Cic and showed that it binds to the same site on ERK despite lacking conservation with the Drosophila Cic binding region. Finally, we mapped the amino acids involved in human Cic binding to ERK using AzF-labeled ERK. These results reveal the molecular details of the ERK-Cic interaction and demonstrate that the photocrosslinking approach is complementary to existing methods for mapping kinase-substrate binding interfaces. PMID- 26124097 TI - The maize disease resistance gene Htn1 against northern corn leaf blight encodes a wall-associated receptor-like kinase. AB - Northern corn leaf blight (NCLB) caused by the hemibiotrophic fungus Exserohilum turcicum is an important foliar disease of maize that is mainly controlled by growing resistant maize cultivars. The Htn1 locus confers quantitative and partial NCLB resistance by delaying the onset of lesion formation. Htn1 represents an important source of genetic resistance that was originally introduced from a Mexican landrace into modern maize breeding lines in the 1970s. Using a high-resolution map-based cloning approach, we delimited Htn1 to a 131.7 kb physical interval on chromosome 8 that contained three candidate genes encoding two wall-associated receptor-like kinases (ZmWAK-RLK1 and ZmWAK-RLK2) and one wall-associated receptor-like protein (ZmWAK-RLP1). TILLING (targeting induced local lesions in genomes) mutants in ZmWAK-RLK1 were more susceptible to NCLB than wild-type plants, both in greenhouse experiments and in the field. ZmWAK-RLK1 contains a nonarginine-aspartate (non-RD) kinase domain, typically found in plant innate immune receptors. Sequence comparison showed that the extracellular domain of ZmWAK-RLK1 is highly diverse between different maize genotypes. Furthermore, an alternative splice variant resulting in a truncated protein was present at higher frequency in the susceptible parents of the mapping populations compared with in the resistant parents. Hence, the quantitative Htn1 disease resistance in maize is encoded by an unusual innate immune receptor with an extracellular wall-associated kinase domain. These results further highlight the importance of this protein family in resistance to adapted pathogens. PMID- 26124096 TI - O-glycans direct selectin ligands to lipid rafts on leukocytes. AB - Palmitoylated cysteines typically target transmembrane proteins to domains enriched in cholesterol and sphingolipids (lipid rafts). P-selectin glycoprotein ligand-1 (PSGL-1), CD43, and CD44 are O-glycosylated proteins on leukocytes that associate with lipid rafts. During inflammation, they transduce signals by engaging selectins as leukocytes roll in venules, and they move to the raft enriched uropods of polarized cells upon chemokine stimulation. It is not known how these glycoproteins associate with lipid rafts or whether this association is required for signaling or for translocation to uropods. Here, we found that loss of core 1-derived O-glycans in murine C1galt1(-/-) neutrophils blocked raft targeting of PSGL-1, CD43, and CD44, but not of other glycosylated proteins, as measured by resistance to solubilization in nonionic detergent and by copatching with a raft-resident sphingolipid on intact cells. Neuraminidase removal of sialic acids from wild-type neutrophils also blocked raft targeting. C1galt1(-/-) neutrophils or neuraminidase-treated neutrophils failed to activate tyrosine kinases when plated on immobilized anti-PSGL-1 or anti-CD44 F(ab')2. Furthermore, C1galt1(-/-) neutrophils incubated with anti-PSGL-1 F(ab')2 did not generate microparticles. In marked contrast, PSGL-1, CD43, and CD44 moved normally to the uropods of chemokine-stimulated C1galt1(-/-) neutrophils. These data define a role for core 1-derived O-glycans and terminal sialic acids in targeting glycoprotein ligands for selectins to lipid rafts of leukocytes. Preassociation of these glycoproteins with rafts is required for signaling but not for movement to uropods. PMID- 26124098 TI - Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells. AB - A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonfouling background, creating isolated culture environments on a solid substrate. Significant results can be obtained by testing <6% of the cells required for a typical 96-well plate. Reliability was demonstrated by an average coefficient of variation of 14% between all of the microarrays and 13% between identical conditions within a single microarray. Using the drug-eluting array, colorectal CSCs isolated from two patients exhibited unique responses to drug combinations when cultured on the drug-eluting microarray, highlighting the potential as a prognostic tool to identify personalized chemotherapeutic regimens targeting CSCs. PMID- 26124099 TI - MicroRNA-148a reduces tumorigenesis and increases TRAIL-induced apoptosis in NSCLC. AB - Nonsmall cell lung cancer (NSCLC) is one of the leading causes of death worldwide. TNF-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in malignant cells without inducing significant toxicity in normal cells. However, several carcinomas, including lung cancer, remain resistant to TRAIL. MicroRNAs (miRNAs) are small noncoding RNAs of ~ 24 nt that block mRNA translation and/or negatively regulate its stability. They are often aberrantly expressed in cancer and have been implicated in increasing susceptibility or resistance to TRAIL-induced apoptosis by inhibiting key functional proteins. Here we show that miR-148a is down-regulated in cells with acquired TRAIL-resistance compared with TRAIL-sensitive cells. Enforced expression of miR-148a sensitized cells to TRAIL and reduced lung tumorigenesis in vitro and in vivo through the down-modulation of matrix metalloproteinase 15 (MMP15) and Rho-associated kinase 1 (ROCK1). These findings suggest that miR-148a acts as a tumor suppressor and might have therapeutic application in the treatment of NSCLC. PMID- 26124100 TI - Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress. AB - Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a beta-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that beta-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma. PMID- 26124101 TI - Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase gamma. AB - Nucleoside analog reverse transcriptase inhibitors (NRTIs) are the essential components of highly active antiretroviral (HAART) therapy targeting HIV reverse transcriptase (RT). NRTI triphosphates (NRTI-TP), the biologically active forms, act as chain terminators of viral DNA synthesis. Unfortunately, NRTIs also inhibit human mitochondrial DNA polymerase (Pol gamma), causing unwanted mitochondrial toxicity. Understanding the structural and mechanistic differences between Pol gamma and RT in response to NRTIs will provide invaluable insight to aid in designing more effective drugs with lower toxicity. The NRTIs emtricitabine [(-)-2,3'-dideoxy-5-fluoro-3'-thiacytidine, (-)-FTC] and lamivudine, [(-)-2,3'-dideoxy-3'-thiacytidine, (-)-3TC] are both potent RT inhibitors, but Pol gamma discriminates against (-)-FTC-TP by two orders of magnitude better than (-)-3TC-TP. Furthermore, although (-)-FTC-TP is only slightly more potent against HIV RT than its enantiomer (+)-FTC-TP, it is discriminated by human Pol gamma four orders of magnitude more efficiently than (+)-FTC-TP. As a result, (-)-FTC is a much less toxic NRTI. Here, we present the structural and kinetic basis for this striking difference by identifying the discriminator residues of drug selectivity in both viral and human enzymes responsible for substrate selection and inhibitor specificity. For the first time, to our knowledge, this work illuminates the mechanism of (-)-FTC-TP differential selectivity and provides a structural scaffold for development of novel NRTIs with lower toxicity. PMID- 26124103 TI - Lose biodiversity, gain disease. PMID- 26124102 TI - Redesigning photosynthesis to sustainably meet global food and bioenergy demand. AB - The world's crop productivity is stagnating whereas population growth, rising affluence, and mandates for biofuels put increasing demands on agriculture. Meanwhile, demand for increasing cropland competes with equally crucial global sustainability and environmental protection needs. Addressing this looming agricultural crisis will be one of our greatest scientific challenges in the coming decades, and success will require substantial improvements at many levels. We assert that increasing the efficiency and productivity of photosynthesis in crop plants will be essential if this grand challenge is to be met. Here, we explore an array of prospective redesigns of plant systems at various scales, all aimed at increasing crop yields through improved photosynthetic efficiency and performance. Prospects range from straightforward alterations, already supported by preliminary evidence of feasibility, to substantial redesigns that are currently only conceptual, but that may be enabled by new developments in synthetic biology. Although some proposed redesigns are certain to face obstacles that will require alternate routes, the efforts should lead to new discoveries and technical advances with important impacts on the global problem of crop productivity and bioenergy production. PMID- 26124104 TI - Circadian clock gene LATE ELONGATED HYPOCOTYL directly regulates the timing of floral scent emission in Petunia. AB - Flowers present a complex display of signals to attract pollinators, including the emission of floral volatiles. Volatile emission is highly regulated, and many species restrict emissions to specific times of the day. This rhythmic emission of scent is regulated by the circadian clock; however, the mechanisms have remained unknown. In Petunia hybrida, volatile emissions are dominated by products of the floral volatile benzenoid/phenylpropanoid (FVBP) metabolic pathway. Here we demonstrate that the circadian clock gene P. hybrida LATE ELONGATED HYPOCOTYL (LHY; PhLHY) regulates the daily expression patterns of the FVBP pathway genes and floral volatile production. PhLHY expression peaks in the morning, antiphasic to the expression of P. hybrida GIGANTEA (PhGI), the master scent regulator ODORANT1 (ODO1), and many other evening-expressed FVBP genes. Overexpression phenotypes of PhLHY in Arabidopsis caused an arrhythmic clock phenotype, which resembles those of LHY overexpressors. In Petunia, constitutive expression of PhLHY depressed the expression levels of PhGI, ODO1, evening expressed FVBP pathway genes, and FVBP emission in flowers. Additionally, in the Petunia lines in which PhLHY expression was reduced, the timing of peak expression of PhGI, ODO1, and the FVBP pathway genes advanced to the morning. Moreover, PhLHY protein binds to cis-regulatory elements called evening elements that exist in promoters of ODO1 and other FVBP genes. Thus, our results imply that PhLHY directly sets the timing of floral volatile emission by restricting the expression of ODO1 and other FVBP genes to the evening in Petunia. PMID- 26124105 TI - Statistical universals reveal the structures and functions of human music. AB - Music has been called "the universal language of mankind." Although contemporary theories of music evolution often invoke various musical universals, the existence of such universals has been disputed for decades and has never been empirically demonstrated. Here we combine a music-classification scheme with statistical analyses, including phylogenetic comparative methods, to examine a well-sampled global set of 304 music recordings. Our analyses reveal no absolute universals but strong support for many statistical universals that are consistent across all nine geographic regions sampled. These universals include 18 musical features that are common individually as well as a network of 10 features that are commonly associated with one another. They span not only features related to pitch and rhythm that are often cited as putative universals but also rarely cited domains including performance style and social context. These cross cultural structural regularities of human music may relate to roles in facilitating group coordination and cohesion, as exemplified by the universal tendency to sing, play percussion instruments, and dance to simple, repetitive music in groups. Our findings highlight the need for scientists studying music evolution to expand the range of musical cultures and musical features under consideration. The statistical universals we identified represent important candidates for future investigation. PMID- 26124106 TI - Longitudinal study of fingerprint recognition. AB - Human identification by fingerprints is based on the fundamental premise that ridge patterns from distinct fingers are different (uniqueness) and a fingerprint pattern does not change over time (persistence). Although the uniqueness of fingerprints has been investigated by developing statistical models to estimate the probability of error in comparing two random samples of fingerprints, the persistence of fingerprints has remained a general belief based on only a few case studies. In this study, fingerprint match (similarity) scores are analyzed by multilevel statistical models with covariates such as time interval between two fingerprints in comparison, subject's age, and fingerprint image quality. Longitudinal fingerprint records of 15,597 subjects are sampled from an operational fingerprint database such that each individual has at least five 10 print records over a minimum time span of 5 y. In regard to the persistence of fingerprints, the longitudinal analysis on a single (right index) finger demonstrates that (i) genuine match scores tend to significantly decrease when time interval between two fingerprints in comparison increases, whereas the change in impostor match scores is negligible; and (ii) fingerprint recognition accuracy at operational settings, nevertheless, tends to be stable as the time interval increases up to 12 y, the maximum time span in the dataset. However, the uncertainty of temporal stability of fingerprint recognition accuracy becomes substantially large if either of the two fingerprints being compared is of poor quality. The conclusions drawn from 10-finger fusion analysis coincide with the conclusions from single-finger analysis. PMID- 26124107 TI - Neural activity and CaMKII protect mitochondria from fragmentation in aging Caenorhabditis elegans neurons. AB - Decline in mitochondrial morphology and function is a hallmark of neuronal aging. Here we report that progressive mitochondrial fragmentation is a common manifestation of aging Caenorhabditis elegans neurons and body wall muscles. We show that sensory-evoked activity was essential for maintaining neuronal mitochondrial morphology, and this activity-dependent mechanism required the Degenerin/ENaC sodium channel MEC-4, the L-type voltage-gated calcium channel EGL 19, and the Ca/calmodulin-dependent kinase II (CaMKII) UNC-43. Importantly, UNC 43 phosphorylated and inhibited the dynamin-related protein (DRP)-1, which was responsible for excessive mitochondrial fragmentation in neurons that lacked sensory-evoked activity. Moreover, enhanced activity in the aged neurons ameliorated mitochondrial fragmentation. These findings provide a detailed description of mitochondrial behavior in aging neurons and identify activity dependent DRP-1 phosphorylation by CaMKII as a key mechanism in neuronal mitochondrial maintenance. PMID- 26124108 TI - F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress. AB - The tumor suppressor p53 plays a critical role in maintaining genomic stability. In response to genotoxic stress, p53 levels increase and induce cell-cycle arrest, senescence, or apoptosis, thereby preventing replication of damaged DNA. In unstressed cells, p53 is maintained at a low level. The major negative regulator of p53 is MDM2, an E3 ubiquitin ligase that directly interacts with p53 and promotes its polyubiquitination, leading to the subsequent destruction of p53 by the 26S proteasome. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 stability. Because of the important role of MDM2 in modulating p53 function, it is critical to understand how MDM2 levels are regulated. Here we show that the F-box protein FBXO31, a candidate tumor suppressor encoded in 16q24.3 for which there is loss of heterozygosity in various solid tumors, is responsible for promoting MDM2 degradation. Following genotoxic stress, FBXO31 is phosphorylated by the DNA damage serine/threonine kinase ATM, resulting in increased levels of FBXO31. FBXO31 then interacts with and directs the degradation of MDM2, which is dependent on phosphorylation of MDM2 by ATM. FBXO31 mediated loss of MDM2 leads to elevated levels of p53, resulting in growth arrest. In cells depleted of FBXO31, MDM2 is not degraded and p53 levels do not increase following genotoxic stress. Thus, FBXO31 is essential for the classic robust increase in p53 levels following DNA damage. PMID- 26124109 TI - The MYB36 transcription factor orchestrates Casparian strip formation. AB - The endodermis in roots acts as a selectivity filter for nutrient and water transport essential for growth and development. This selectivity is enabled by the formation of lignin-based Casparian strips. Casparian strip formation is initiated by the localization of the Casparian strip domain proteins (CASPs) in the plasma membrane, at the site where the Casparian strip will form. Localized CASPs recruit Peroxidase 64 (PER64), a Respiratory Burst Oxidase Homolog F, and Enhanced Suberin 1 (ESB1), a dirigent-like protein, to assemble the lignin polymerization machinery. However, the factors that control both expression of the genes encoding this biosynthetic machinery and its localization to the Casparian strip formation site remain unknown. Here, we identify the transcription factor, MYB36, essential for Casparian strip formation. MYB36 directly and positively regulates the expression of the Casparian strip genes CASP1, PER64, and ESB1. Casparian strips are absent in plants lacking a functional MYB36 and are replaced by ectopic lignin-like material in the corners of endodermal cells. The barrier function of Casparian strips in these plants is also disrupted. Significantly, ectopic expression of MYB36 in the cortex is sufficient to reprogram these cells to start expressing CASP1-GFP, correctly localize the CASP1-GFP protein to form a Casparian strip domain, and deposit a Casparian strip-like structure in the cell wall at this location. These results demonstrate that MYB36 is controlling expression of the machinery required to locally polymerize lignin in a fine band in the cell wall for the formation of the Casparian strip. PMID- 26124110 TI - DDT-based indoor residual spraying suboptimal for visceral leishmaniasis elimination in India. AB - Indoor residual spraying (IRS) is used to control visceral leishmaniasis (VL) in India, but it is poorly quality assured. Quality assurance was performed in eight VL endemic districts in Bihar State, India, in 2014. Residual dichlorodiphenyltrichloroethane (DDT) was sampled from walls using Bostik tape discs, and DDT concentrations [grams of active ingredient per square meter (g ai/m(2))] were determined using HPLC. Pre-IRS surveys were performed in three districts, and post-IRS surveys were performed in eight districts. A 20% threshold above and below the target spray of 1.0 g ai/m(2) was defined as "in range." The entomological assessments were made in four districts in IRS and non IRS villages. Vector densities were measured: pre-IRS and 1 and 3 mo post-IRS. Insecticide susceptibility to 4% DDT and 0.05% deltamethrin WHO-impregnated papers was determined with wild-caught sand flies. The majority (329 of 360, 91.3%) of pre-IRS samples had residual DDT concentrations of <0.1 g ai/m(2). The mean residual concentration of DDT post-IRS was 0.37 g ai/m(2); 84.9% of walls were undersprayed, 7.4% were sprayed in range, and 7.6% were oversprayed. The abundance of sand flies in IRS and non-IRS villages was significantly different at 1 mo post-IRS only. Sand flies were highly resistant to DDT but susceptible to deltamethrin. The Stockholm Convention, ratified by India in 2006, calls for the complete phasing out of DDT as soon as practical, with limited use in the interim where no viable IRS alternatives exist. Given the poor quality of the DDT-based IRS, ready availability of pyrethroids, and susceptibility profile of Indian sand flies, the continued use of DDT in this IRS program is questionable. PMID- 26124111 TI - Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer's disease amyloid plaques. AB - Through a comprehensive analysis of organellar markers in mouse models of Alzheimer's disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of beta-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer's disease, beta-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular beta-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer's disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology. PMID- 26124112 TI - Tracking ongoing cognition in individuals using brief, whole-brain functional connectivity patterns. AB - Functional connectivity (FC) patterns in functional MRI exhibit dynamic behavior on the scale of seconds, with rich spatiotemporal structure and limited sets of whole-brain, quasi-stable FC configurations (FC states) recurring across time and subjects. Based on previous evidence linking various aspects of cognition to group-level, minute-to-minute FC changes in localized connections, we hypothesized that whole-brain FC states may reflect the global, orchestrated dynamics of cognitive processing on the scale of seconds. To test this hypothesis, subjects were continuously scanned as they engaged in and transitioned between mental states dictated by tasks. FC states computed within windows as short as 22.5 s permitted robust tracking of cognition in single subjects with near perfect accuracy. Accuracy dropped markedly for subjects with the lowest task performance. Spatially restricting FC information decreased accuracy at short time scales, emphasizing the distributed nature of whole-brain FC dynamics, beyond univariate magnitude changes, as valuable markers of cognition. PMID- 26124113 TI - Notch1-STAT3-ETBR signaling axis controls reactive astrocyte proliferation after brain injury. AB - Defining the signaling network that controls reactive astrogliosis may provide novel treatment targets for patients with diverse CNS injuries and pathologies. We report that the radial glial cell antigen RC2 identifies the majority of proliferating glial fibrillary acidic protein-positive (GFAP(+)) reactive astrocytes after stroke. These cells highly expressed endothelin receptor type B (ETB(R)) and Jagged1, a Notch1 receptor ligand. To study signaling in adult reactive astrocytes, we developed a model based on reactive astrocyte-derived neural stem cells isolated from GFAP-CreER-Notch1 conditional knockout (cKO) mice. By loss- and gain-of-function studies and promoter activity assays, we found that Jagged1/Notch1 signaling increased ETB(R) expression indirectly by raising the level of phosphorylated signal transducer and activator of transcription 3 (STAT3), a previously unidentified EDNRB transcriptional activator. Similar to inducible transgenic GFAP-CreER-Notch1-cKO mice, GFAP-CreER ETB(R)-cKO mice exhibited a defect in reactive astrocyte proliferation after cerebral ischemia. Our results indicate that the Notch1-STAT3-ETB(R) axis connects a signaling network that promotes reactive astrocyte proliferation after brain injury. PMID- 26124114 TI - New Age of Fishes initiated by the Cretaceous-Paleogene mass extinction. AB - Ray-finned fishes (Actinopterygii) comprise nearly half of all modern vertebrate diversity, and are an ecologically and numerically dominant megafauna in most aquatic environments. Crown teleost fishes diversified relatively recently, during the Late Cretaceous and early Paleogene, although the exact timing and cause of their radiation and rise to ecological dominance is poorly constrained. Here we use microfossil teeth and shark dermal scales (ichthyoliths) preserved in deep-sea sediments to study the changes in the pelagic fish community in the latest Cretaceous and early Paleogene. We find that the Cretaceous-Paleogene (K/Pg) extinction event marked a profound change in the structure of ichthyolith communities around the globe: Whereas shark denticles outnumber ray-finned fish teeth in Cretaceous deep-sea sediments around the world, there is a dramatic increase in the proportion of ray-finned fish teeth to shark denticles in the Paleocene. There is also an increase in size and numerical abundance of ray finned fish teeth at the boundary. These changes are sustained through at least the first 24 million years of the Cenozoic. This new fish community structure began at the K/Pg mass extinction, suggesting the extinction event played an important role in initiating the modern "age of fishes." PMID- 26124115 TI - A circadian oscillator in the fungus Botrytis cinerea regulates virulence when infecting Arabidopsis thaliana. AB - The circadian clock of the plant model Arabidopsis thaliana modulates defense mechanisms impacting plant-pathogen interactions. Nevertheless, the effect of clock regulation on pathogenic traits has not been explored in detail. Moreover, molecular description of clocks in pathogenic fungi--or fungi in general other than the model ascomycete Neurospora crassa--has been neglected, leaving this type of question largely unaddressed. We sought to characterize, therefore, the circadian system of the plant pathogen Botrytis cinerea to assess if such oscillatory machinery can modulate its virulence potential. Herein, we show the existence of a functional clock in B. cinerea, which shares similar components and circuitry with the Neurospora circadian system, although we found that its core negative clock element FREQUENCY (BcFRQ1) serves additional roles, suggesting extracircadian functions for this protein. We observe that the lesions produced by this necrotrophic fungus on Arabidopsis leaves are smaller when the interaction between these two organisms occurs at dawn. Remarkably, this effect does not depend solely on the plant clock, but instead largely relies on the pathogen circadian system. Genetic disruption of the B. cinerea oscillator by mutation, overexpression of BcFRQ1, or by suppression of its rhythmicity by constant light, abrogates circadian regulation of fungal virulence. By conducting experiments with out-of-phase light:dark cycles, we confirm that indeed, it is the fungal clock that plays the main role in defining the outcome of the Arabidopsis-Botrytis interaction, providing to our knowledge the first evidence of a microbial clock modulating pathogenic traits at specific times of the day. PMID- 26124117 TI - Human impacts on fisheries across the land-sea interface. PMID- 26124116 TI - Synchronizing theta oscillations with direct-current stimulation strengthens adaptive control in the human brain. AB - Executive control and flexible adjustment of behavior following errors are essential to adaptive functioning. Loss of adaptive control may be a biomarker of a wide range of neuropsychiatric disorders, particularly in the schizophrenia spectrum. Here, we provide support for the view that oscillatory activity in the frontal cortex underlies adaptive adjustments in cognitive processing following errors. Compared with healthy subjects, patients with schizophrenia exhibited low frequency oscillations with abnormal temporal structure and an absence of synchrony over medial-frontal and lateral-prefrontal cortex following errors. To demonstrate that these abnormal oscillations were the origin of the impaired adaptive control in patients with schizophrenia, we applied noninvasive dc electrical stimulation over the medial-frontal cortex. This noninvasive stimulation descrambled the phase of the low-frequency neural oscillations that synchronize activity across cortical regions. Following stimulation, the behavioral index of adaptive control was improved such that patients were indistinguishable from healthy control subjects. These results provide unique causal evidence for theories of executive control and cortical dysconnectivity in schizophrenia. PMID- 26124118 TI - Integrated reactive nitrogen budgets and future trends in China. AB - Reactive nitrogen (Nr) plays a central role in food production, and at the same time it can be an important pollutant with substantial effects on air and water quality, biological diversity, and human health. China now creates far more Nr than any other country. We developed a budget for Nr in China in 1980 and 2010, in which we evaluated the natural and anthropogenic creation of Nr, losses of Nr, and transfers among 14 subsystems within China. Our analyses demonstrated that a tripling of anthropogenic Nr creation was associated with an even more rapid increase in Nr fluxes to the atmosphere and hydrosphere, contributing to intense and increasing threats to human health, the sustainability of croplands, and the environment of China and its environs. Under a business as usual scenario, anthropogenic Nr creation in 2050 would more than double compared with 2010 levels, whereas a scenario that combined reasonable changes in diet, N use efficiency, and N recycling could reduce N losses and anthropogenic Nr creation in 2050 to 52% and 64% of 2010 levels, respectively. Achieving reductions in Nr creation (while simultaneously increasing food production and offsetting imports of animal feed) will require much more in addition to good science, but it is useful to know that there are pathways by which both food security and health/environmental protection could be enhanced simultaneously. PMID- 26124119 TI - Structural insights into the assembly of the histone deacetylase-associated Sin3L/Rpd3L corepressor complex. AB - Acetylation is correlated with chromatin decondensation and transcriptional activation, but its regulation by histone deacetylase (HDAC)-bearing corepressor complexes is poorly understood. Here, we describe the mechanism of assembly of the mammalian Sin3L/Rpd3L complex facilitated by Sds3, a conserved subunit deemed critical for proper assembly. Sds3 engages a globular, helical region of the HDAC interaction domain (HID) of the scaffolding protein Sin3A through a bipartite motif comprising a helix and an adjacent extended segment. Sds3 dimerizes through not only one of the predicted coiled-coil motifs but also, the segment preceding it, forming an ~ 150-A-long antiparallel dimer. Contrary to previous findings in yeast, Sin3A rather than Sds3 functions in recruiting HDAC1 into the complex by engaging the latter through a highly conserved segment adjacent to the helical HID subdomain. In the resulting model for the ternary complex, the two copies of the HDACs are situated distally and dynamically because of a natively unstructured linker connecting the dimerization domain and the Sin3A interaction domain of Sds3; these features contrast with the static organization described previously for the NuRD (nucleosome remodeling and deacetylase) complex. The Sds3 linker features several conserved basic residues that could potentially maintain the complex on chromatin by nonspecific interactions with DNA after initial recruitment by sequence-specific DNA-binding repressors. PMID- 26124120 TI - CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency. AB - Activation of the CB2 receptor is apparently an endogenous protective mechanism. Thus, it restrains inflammation and protects the skeleton against age-related bone loss. However, the endogenous cannabinoids, as well as Delta(9) tetrahydrocannabinol, the main plant psychoactive constituent, activate both cannabinoid receptors, CB1 and CB2. HU-308 was among the first synthetic, selective CB2 agonists. HU-308 is antiosteoporotic and antiinflammatory. Here we show that the HU-308 enantiomer, designated HU-433, is 3-4 orders of magnitude more potent in osteoblast proliferation and osteoclast differentiation culture systems, as well as in mouse models, for the rescue of ovariectomy-induced bone loss and ear inflammation. HU-433 retains the HU-308 specificity for CB2, as shown by its failure to bind to the CB1 cannabinoid receptor, and has no activity in CB2-deficient cells and animals. Surprisingly, the CB2 binding affinity of HU 433 in terms of [(3)H]CP55,940 displacement and its effect on [(35)S]GTPgammaS accumulation is substantially lower compared with HU-308. A molecular-modeling analysis suggests that HU-433 and -308 have two different binding conformations within CB2, with one of them possibly responsible for the affinity difference, involving [(35)S]GTPgammaS and cAMP synthesis. Hence, different ligands may have different orientations relative to the same binding site. This situation questions the usefulness of universal radioligands for comparative binding studies. Moreover, orientation-targeted ligands have promising potential for the pharmacological activation of distinct processes. PMID- 26124122 TI - A superarmored lobopodian from the Cambrian of China and early disparity in the evolution of Onychophora. AB - We describe Collinsium ciliosum from the early Cambrian Xiaoshiba Lagerstatte in South China, an armored lobopodian with a remarkable degree of limb differentiation including a pair of antenna-like appendages, six pairs of elongate setiferous limbs for suspension feeding, and nine pairs of clawed annulated legs with an anchoring function. Collinsium belongs to a highly derived clade of lobopodians within stem group Onychophora, distinguished by a substantial dorsal armature of supernumerary and biomineralized spines (Family Luolishaniidae). As demonstrated here, luolishaniids display the highest degree of limb specialization among Paleozoic lobopodians, constitute more than one third of the overall morphological disparity of stem group Onychophora, and are substantially more disparate than crown group representatives. Despite having higher disparity and appendage complexity than other lobopodians and extant velvet worms, the specialized mode of life embodied by luolishaniids became extinct during the Early Paleozoic. Collinsium and other superarmored lobopodians exploited a unique paleoecological niche during the Cambrian explosion. PMID- 26124121 TI - Triangulation of the neurocomputational architecture underpinning reading aloud. AB - The goal of cognitive neuroscience is to integrate cognitive models with knowledge about underlying neural machinery. This significant challenge was explored in relation to word reading, where sophisticated computational-cognitive models exist but have made limited contact with neural data. Using distortion corrected functional MRI and dynamic causal modeling, we investigated the interactions between brain regions dedicated to orthographic, semantic, and phonological processing while participants read words aloud. We found that the lateral anterior temporal lobe exhibited increased activation when participants read words with irregular spellings. This area is implicated in semantic processing but has not previously been considered part of the reading network. We also found meaningful individual differences in the activation of this region: Activity was predicted by an independent measure of the degree to which participants use semantic knowledge to read. These characteristics are predicted by the connectionist Triangle Model of reading and indicate a key role for semantic knowledge in reading aloud. Premotor regions associated with phonological processing displayed the reverse characteristics. Changes in the functional connectivity of the reading network during irregular word reading also were consistent with semantic recruitment. These data support the view that reading aloud is underpinned by the joint operation of two neural pathways. They reveal that (i) the ATL is an important element of the ventral semantic pathway and (ii) the division of labor between the two routes varies according to both the properties of the words being read and individual differences in the degree to which participants rely on each route. PMID- 26124123 TI - Fault rheology beyond frictional melting. AB - During earthquakes, comminution and frictional heating both contribute to the dissipation of stored energy. With sufficient dissipative heating, melting processes can ensue, yielding the production of frictional melts or "pseudotachylytes." It is commonly assumed that the Newtonian viscosities of such melts control subsequent fault slip resistance. Rock melts, however, are viscoelastic bodies, and, at high strain rates, they exhibit evidence of a glass transition. Here, we present the results of high-velocity friction experiments on a well-characterized melt that demonstrate how slip in melt-bearing faults can be governed by brittle fragmentation phenomena encountered at the glass transition. Slip analysis using models that incorporate viscoelastic responses indicates that even in the presence of melt, slip persists in the solid state until sufficient heat is generated to reduce the viscosity and allow remobilization in the liquid state. Where a rock is present next to the melt, we note that wear of the crystalline wall rock by liquid fragmentation and agglutination also contributes to the brittle component of these experimentally generated pseudotachylytes. We conclude that in the case of pseudotachylyte generation during an earthquake, slip even beyond the onset of frictional melting is not controlled merely by viscosity but rather by an interplay of viscoelastic forces around the glass transition, which involves a response in the brittle/solid regime of these rock melts. We warn of the inadequacy of simple Newtonian viscous analyses and call for the application of more realistic rheological interpretation of pseudotachylyte-bearing fault systems in the evaluation and prediction of their slip dynamics. PMID- 26124124 TI - Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. AB - Ran is a small GTP-binding protein of the Ras superfamily regulating fundamental cellular processes: nucleo-cytoplasmic transport, nuclear envelope formation and mitotic spindle assembly. An intracellular Ran*GTP/Ran*GDP gradient created by the distinct subcellular localization of its regulators RCC1 and RanGAP mediates many of its cellular effects. Recent proteomic screens identified five Ran lysine acetylation sites in human and eleven sites in mouse/rat tissues. Some of these sites are located in functionally highly important regions such as switch I and switch II. Here, we show that lysine acetylation interferes with essential aspects of Ran function: nucleotide exchange and hydrolysis, subcellular Ran localization, GTP hydrolysis, and the interaction with import and export receptors. Deacetylation activity of certain sirtuins was detected for two Ran acetylation sites in vitro. Moreover, Ran was acetylated by CBP/p300 and Tip60 in vitro and on transferase overexpression in vivo. Overall, this study addresses many important challenges of the acetylome field, which will be discussed. PMID- 26124125 TI - Intrinsic unfoldase/foldase activity of the chaperonin GroEL directly demonstrated using multinuclear relaxation-based NMR. AB - The prototypical chaperonin GroEL assists protein folding through an ATP dependent encapsulation mechanism. The details of how GroEL folds proteins remain elusive, particularly because encapsulation is not an absolute requirement for successful re/folding. Here we make use of a metastable model protein substrate, comprising a triple mutant of Fyn SH3, to directly demonstrate, by simultaneous analysis of three complementary NMR-based relaxation experiments (lifetime line broadening, dark state exchange saturation transfer, and Carr-Purcell-Meinboom Gill relaxation dispersion), that apo GroEL accelerates the overall interconversion rate between the native state and a well-defined folding intermediate by about 20-fold, under conditions where the "invisible" GroEL-bound states have occupancies below 1%. This is largely achieved through a 500-fold acceleration in the folded-to-intermediate transition of the protein substrate. Catalysis is modulated by a kinetic deuterium isotope effect that reduces the overall interconversion rate between the GroEL-bound species by about 3-fold, indicative of a significant hydrophobic contribution. The location of the GroEL binding site on the folding intermediate, mapped from (15)N, (1)HN, and (13)Cmethyl relaxation dispersion experiments, is composed of a prominent, surface-exposed hydrophobic patch. PMID- 26124126 TI - High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice. AB - Mitochondria are highly adaptable organelles that can facilitate communication between tissues to meet the energetic demands of the organism. However, the mechanisms by which mitochondria can nonautonomously relay stress signals remain poorly understood. Here we report that mitochondrial mutations in the young, preprogeroid polymerase gamma mutator (POLG) mouse produce a metabolic state of starvation. As a result, these mice exhibit signs of metabolic imbalance including thermogenic defects in brown adipose tissue (BAT). An unexpected benefit of this adaptive response is the complete resistance to diet-induced obesity when POLG mice are placed on a high-fat diet (HFD). Paradoxically, HFD further increases oxygen consumption in part by inducing thermogenesis and mitochondrial biogenesis in BAT along with enhanced expression of fibroblast growth factor 21 (FGF21). Collectively, these findings identify a mechanistic link between FGF21, a long-known marker of mitochondrial disease, and systemic metabolic adaptation in response to mitochondrial stress. PMID- 26124127 TI - Highly compacted biodegradable DNA nanoparticles capable of overcoming the mucus barrier for inhaled lung gene therapy. AB - Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(beta-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration. PMID- 26124128 TI - The role of clade competition in the diversification of North American canids. AB - The history of biodiversity is characterized by a continual replacement of branches in the tree of life. The rise and demise of these branches (clades) are ultimately determined by changes in speciation and extinction rates, often interpreted as a response to varying abiotic and biotic factors. However, understanding the relative importance of these factors remains a major challenge in evolutionary biology. Here we analyze the rich North American fossil record of the dog family Canidae and of other carnivores to tease apart the roles of competition, body size evolution, and climate change on the sequential replacement of three canid subfamilies (two of which have gone extinct). We develop a novel Bayesian analytic framework to show that competition from multiple carnivore clades successively drove the demise and replacement of the two extinct canid subfamilies by increasing their extinction rates and suppressing their speciation. Competitive effects have likely come from ecologically similar species from both canid and felid clades. These results imply that competition among entire clades, generally considered a rare process, can play a more substantial role than climate change and body size evolution in determining the sequential rise and decline of clades. PMID- 26124129 TI - Nature experience reduces rumination and subgenual prefrontal cortex activation. AB - Urbanization has many benefits, but it also is associated with increased levels of mental illness, including depression. It has been suggested that decreased nature experience may help to explain the link between urbanization and mental illness. This suggestion is supported by a growing body of correlational and experimental evidence, which raises a further question: what mechanism(s) link decreased nature experience to the development of mental illness? One such mechanism might be the impact of nature exposure on rumination, a maladaptive pattern of self-referential thought that is associated with heightened risk for depression and other mental illnesses. We show in healthy participants that a brief nature experience, a 90-min walk in a natural setting, decreases both self reported rumination and neural activity in the subgenual prefrontal cortex (sgPFC), whereas a 90-min walk in an urban setting has no such effects on self reported rumination or neural activity. In other studies, the sgPFC has been associated with a self-focused behavioral withdrawal linked to rumination in both depressed and healthy individuals. This study reveals a pathway by which nature experience may improve mental well-being and suggests that accessible natural areas within urban contexts may be a critical resource for mental health in our rapidly urbanizing world. PMID- 26124130 TI - Maternal intestinal HIF-2alpha is necessary for sensing iron demands of lactation in mice. AB - The mechanisms that are essential for the maintenance of nutrient status in breast milk are unclear. Our data demonstrate that the intestine via hypoxia inducible factor (HIF)-2alpha is an essential regulatory mechanism for maintaining the quality of breast milk. During lactation, intestinal HIF-2alpha is highly increased, leading to an adaptive induction of apical and basolateral iron transport genes. Disruption of intestinal HIF-2alpha (but not HIF-1alpha) or the downstream target gene divalent metal transporter (DMT)-1 in lactating mothers did not alter systemic iron homeostasis in the mothers, but led to anemia, decreased growth, and truncal alopecia in pups which was restored following weaning. Moreover, pups born from mothers with a disruption of intestinal HIF-2alpha led to long-term cognitive defects. Cross-fostering experiments and micronutrient profiling of breast milk demonstrated that the defects observed were due to decreased maternal iron delivery via milk. Increasing intestinal iron absorption by activation of HIF-2alpha or parenteral administration of iron-dextran in HIF-2alpha knockout mothers ameliorated anemia and restored neonatal development and adult cognitive functions. The present work details the importance of breast milk iron in neonatal development and uncovers an unexpected molecular mechanism for the regulation of nutritional status of breast milk through intestinal HIF-2alpha. PMID- 26124131 TI - Magnetic levitation of single cells. AB - Several cellular events cause permanent or transient changes in inherent magnetic and density properties of cells. Characterizing these changes in cell populations is crucial to understand cellular heterogeneity in cancer, immune response, infectious diseases, drug resistance, and evolution. Although magnetic levitation has previously been used for macroscale objects, its use in life sciences has been hindered by the inability to levitate microscale objects and by the toxicity of metal salts previously applied for levitation. Here, we use magnetic levitation principles for biological characterization and monitoring of cells and cellular events. We demonstrate that each cell type (i.e., cancer, blood, bacteria, and yeast) has a characteristic levitation profile, which we distinguish at an unprecedented resolution of 1 * 10(-4) g ? mL(-1). We have identified unique differences in levitation and density blueprints between breast, esophageal, colorectal, and nonsmall cell lung cancer cell lines, as well as heterogeneity within these seemingly homogenous cell populations. Furthermore, we demonstrate that changes in cellular density and levitation profiles can be monitored in real time at single-cell resolution, allowing quantification of heterogeneous temporal responses of each cell to environmental stressors. These data establish density as a powerful biomarker for investigating living systems and their responses. Thereby, our method enables rapid, density-based imaging and profiling of single cells with intriguing applications, such as label-free identification and monitoring of heterogeneous biological changes under various physiological conditions, including antibiotic or cancer treatment in personalized medicine. PMID- 26124132 TI - Constitutive phosphorylation of cardiac myosin regulatory light chain prevents development of hypertrophic cardiomyopathy in mice. AB - Myosin light chain kinase (MLCK)-dependent phosphorylation of the regulatory light chain (RLC) of cardiac myosin is known to play a beneficial role in heart disease, but the idea of a phosphorylation-mediated reversal of a hypertrophic cardiomyopathy (HCM) phenotype is novel. Our previous studies on transgenic (Tg) HCM-RLC mice revealed that the D166V (Aspartate166 -> Valine) mutation-induced changes in heart morphology and function coincided with largely reduced RLC phosphorylation in situ. We hypothesized that the introduction of a constitutively phosphorylated Serine15 (S15D) into the hearts of D166V mice would prevent the development of a deleterious HCM phenotype. In support of this notion, MLCK-induced phosphorylation of D166V-mutated hearts was found to rescue some of their abnormal contractile properties. Tg-S15D-D166V mice were generated with the human cardiac RLC-S15D-D166V construct substituted for mouse cardiac RLC and were subjected to functional, structural, and morphological assessments. The results were compared with Tg-WT and Tg-D166V mice expressing the human ventricular RLC-WT or its D166V mutant, respectively. Echocardiography and invasive hemodynamic studies demonstrated significant improvements of intact heart function in S15D-D166V mice compared with D166V, with the systolic and diastolic indices reaching those monitored in WT mice. A largely reduced maximal tension and abnormally high myofilament Ca(2+) sensitivity observed in D166V mutated hearts were reversed in S15D-D166V mice. Low-angle X-ray diffraction study revealed that altered myofilament structures present in HCM-D166V mice were mitigated in S15D-D166V rescue mice. Our collective results suggest that expression of pseudophosphorylated RLC in the hearts of HCM mice is sufficient to prevent the development of the pathological HCM phenotype. PMID- 26124133 TI - West African monsoon dynamics inferred from abrupt fluctuations of Lake Mega Chad. AB - From the deglacial period to the mid-Holocene, North Africa was characterized by much wetter conditions than today. The broad timing of this period, termed the African Humid Period, is well known. However, the rapidity of the onset and termination of the African Humid Period are contested, with strong evidence for both abrupt and gradual change. We use optically stimulated luminescence dating of dunes, shorelines, and fluviolacustrine deposits to reconstruct the fluctuations of Lake Mega-Chad, which was the largest pluvial lake in Africa. Humid conditions first occur at ~ 15 ka, and by 11.5 ka, Lake Mega-Chad had reached a highstand, which persisted until 5.0 ka. Lake levels fell rapidly at ~ 5 ka, indicating abrupt aridification across the entire Lake Mega-Chad Basin. This record provides strong terrestrial evidence that the African Humid Period ended abruptly, supporting the hypothesis that the African monsoon responds to insolation forcing in a markedly nonlinear manner. In addition, Lake Mega-Chad exerts strong control on global biogeochemical cycles because the northern (Bodele) basin is currently the world's greatest single dust source and possibly an important source of limiting nutrients for both the Amazon Basin and equatorial Atlantic. However, we demonstrate that the final desiccation of the Bodele Basin occurred around 1 ka. Consequently, the present-day mode and scale of dust production from the Bodele Basin cannot have occurred before 1 ka, suggesting that its role in fertilizing marine and terrestrial ecosystems is either overstated or geologically recent. PMID- 26124134 TI - Dynamical malaria models reveal how immunity buffers effect of climate variability. AB - Assessing the influence of climate on the incidence of Plasmodium falciparum malaria worldwide and how it might impact local malaria dynamics is complex and extrapolation to other settings or future times is controversial. This is especially true in the light of the particularities of the short- and long-term immune responses to infection. In sites of epidemic malaria transmission, it is widely accepted that climate plays an important role in driving malaria outbreaks. However, little is known about the role of climate in endemic settings where clinical immunity develops early in life. To disentangle these differences among high- and low-transmission settings we applied a dynamical model to two unique adjacent cohorts of mesoendemic seasonal and holoendemic perennial malaria transmission in Senegal followed for two decades, recording daily P. falciparum cases. As both cohorts are subject to similar meteorological conditions, we were able to analyze the relevance of different immunological mechanisms compared with climatic forcing in malaria transmission. Transmission was first modeled by using similarly unique datasets of entomological inoculation rate. A stochastic nonlinear human-mosquito model that includes rainfall and temperature covariates, drug treatment periods, and population variability is capable of simulating the complete dynamics of reported malaria cases for both villages. We found that under moderate transmission intensity climate is crucial; however, under high endemicity the development of clinical immunity buffers any effect of climate. Our models open the possibility of forecasting malaria from climate in endemic regions but only after accounting for the interaction between climate and immunity. PMID- 26124135 TI - CD300f associates with IL-4 receptor alpha and amplifies IL-4-induced immune cell responses. AB - IL-4 receptor (R) alpha, the common receptor chain for IL-4 and IL-13, is a critical component in IL-4- and IL-13-mediated signaling and subsequent effector functions such as those observed in type 2 inflammatory responses. Nonetheless, the existence of intrinsic pathways capable of amplifying IL-4Ralpha-induced responses remains unknown. In this study, we identified the myeloid-associated Ig receptor CD300f as an IL-4-induced molecule in macrophages. Subsequent analyses demonstrated that CD300f was colocalized and physically associated with IL 4Ralpha. Using Cd300f(-/-) cells and receptor cross-linking experiments, we established that CD300f amplified IL-4Ralpha-induced responses by augmenting IL 4/IL-13-induced signaling, mediator release, and priming. Consistently, IL-4- and aeroallergen-treated Cd300f(-/-) mice displayed decreased IgE production, chemokine expression, and inflammatory cell recruitment. Impaired responses in Cd300f(-/-) mice were not due to the inability to generate a proper Th2 response, because IL-4/IL-13 levels were markedly increased in allergen-challenged Cd300f( /-) mice, a finding that is consistent with decreased cytokine consumption. Finally, CD300f expression was increased in monocytes and eosinophils obtained from allergic rhinitis patients. Collectively, our data highlight a previously unidentified role for CD300f in IL-4Ralpha-induced immune cell responses. These data provide new insights into the molecular mechanisms governing IL-4Ralpha induced responses, and may provide new therapeutic tools to target IL-4 in allergy and asthma. PMID- 26124136 TI - Phosphatidylinositol-4-phosphate-dependent membrane traffic is critical for fungal filamentous growth. AB - The phospholipid phosphatidylinositol-4-phosphate [PI(4)P], generated at the Golgi and plasma membrane, has been implicated in many processes, including membrane traffic, yet its role in cell morphology changes, such as the budding to filamentous growth transition, is unknown. We show that Golgi PI(4)P is required for such a transition in the human pathogenic fungus Candida albicans. Quantitative analyses of membrane traffic revealed that PI(4)P is required for late Golgi and secretory vesicle dynamics and targeting and, as a result, is important for the distribution of a multidrug transporter and hence sensitivity to antifungal drugs. We also observed that plasma membrane PI(4)P, which we show is functionally distinct from Golgi PI(4)P, forms a steep gradient concomitant with filamentous growth, despite uniform plasma membrane PI-4-kinase distribution. Mathematical modeling indicates that local PI(4)P generation and hydrolysis by phosphatases are crucial for this gradient. We conclude that PI(4)P regulated membrane dynamics are critical for morphology changes. PMID- 26124137 TI - Virtual groundwater transfers from overexploited aquifers in the United States. AB - The High Plains, Mississippi Embayment, and Central Valley aquifer systems within the United States are currently being overexploited for irrigation water supplies. The unsustainable use of groundwater resources in all three aquifer systems intensified from 2000 to 2008, making it imperative that we understand the consumptive processes and forces of demand that are driving their depletion. To this end, we quantify and track agricultural virtual groundwater transfers from these overexploited aquifer systems to their final destination. Specifically, we determine which US metropolitan areas, US states, and international export destinations are currently the largest consumers of these critical aquifers. We draw upon US government data on agricultural production, irrigation, and domestic food flows, as well as modeled estimates of agricultural virtual water contents to quantify domestic transfers. Additionally, we use US port-level trade data to trace international exports from these aquifers. In 2007, virtual groundwater transfers from the High Plains, Mississippi Embayment, and Central Valley aquifer systems totaled 17.93 km(3), 9.18 km(3), and 6.81 km(3), respectively, which is comparable to the capacity of Lake Mead (35.7 km(3)), the largest surface reservoir in the United States. The vast majority (91%) of virtual groundwater transfers remains within the United States. Importantly, the cereals produced by these overexploited aquifers are critical to US food security (contributing 18.5% to domestic cereal supply). Notably, Japan relies upon cereals produced by these overexploited aquifers for 9.2% of its domestic cereal supply. These results highlight the need to understand the teleconnections between distant food demands and local agricultural water use. PMID- 26124138 TI - Role of RAG1 autoubiquitination in V(D)J recombination. AB - The variable domains of Ig and T-cell receptor genes in vertebrates are assembled from gene fragments by the V(D)J recombination process. The RAG1-RAG2 recombinase (RAG1/2) initiates this recombination by cutting DNA at the borders of recombination signal sequences (RSS) and their neighboring gene segments. The RAG1 protein is also known to contain a ubiquitin E3 ligase activity, located in an N-terminal region that is not strictly required for the basic recombination reaction but helps to regulate recombination. The isolated E3 ligase domain was earlier shown to ubiquitinate one site in a neighboring RAG1 sequence. Here we show that autoubiquitination of full-length RAG1 at this specific residue (K233) results in a large increase of DNA cleavage by RAG1/2. A mutational block of the ubiquitination site abolishes this effect and inhibits recombination of a test substrate in mouse cells. Thus, ubiquitination of RAG1, which can be promoted by RAG1's own ubiquitin ligase activity, plays a significant role in governing the level of V(D)J recombination activity. PMID- 26124139 TI - Snapshot of insect-fungus arms race. PMID- 26124140 TI - Hydrodynamic collective effects of active protein machines in solution and lipid bilayers. AB - The cytoplasm and biomembranes in biological cells contain large numbers of proteins that cyclically change their shapes. They are molecular machines that can function as molecular motors or carry out various other tasks in the cell. Many enzymes also undergo conformational changes within their turnover cycles. We analyze the advection effects that nonthermal fluctuating hydrodynamic flows induced by active proteins have on other passive molecules in solution or membranes. We show that the diffusion constants of passive particles are enhanced substantially. Furthermore, when gradients of active proteins are present, a chemotaxis-like drift of passive particles takes place. In lipid bilayers, the effects are strongly nonlocal, so that active inclusions in the entire membrane contribute to local diffusion enhancement and the drift. All active proteins in a biological cell or in a membrane contribute to such effects and all passive particles, and the proteins themselves, will be subject to them. PMID- 26124141 TI - Nanoscale beta-nuclear magnetic resonance depth imaging of topological insulators. AB - Considerable evidence suggests that variations in the properties of topological insulators (TIs) at the nanoscale and at interfaces can strongly affect the physics of topological materials. Therefore, a detailed understanding of surface states and interface coupling is crucial to the search for and applications of new topological phases of matter. Currently, no methods can provide depth profiling near surfaces or at interfaces of topologically inequivalent materials. Such a method could advance the study of interactions. Herein, we present a noninvasive depth-profiling technique based on beta-detected NMR (beta-NMR) spectroscopy of radioactive (8)Li(+) ions that can provide "one-dimensional imaging" in films of fixed thickness and generates nanoscale views of the electronic wavefunctions and magnetic order at topological surfaces and interfaces. By mapping the (8)Li nuclear resonance near the surface and 10-nm deep into the bulk of pure and Cr-doped bismuth antimony telluride films, we provide signatures related to the TI properties and their topological nontrivial characteristics that affect the electron-nuclear hyperfine field, the metallic shift, and magnetic order. These nanoscale variations in beta-NMR parameters reflect the unconventional properties of the topological materials under study, and understanding the role of heterogeneities is expected to lead to the discovery of novel phenomena involving quantum materials. PMID- 26124142 TI - Drosophila circadian rhythms in seminatural environments: Summer afternoon component is not an artifact and requires TrpA1 channels. AB - Under standard laboratory conditions of rectangular light/dark cycles and constant warm temperature, Drosophila melanogaster show bursts of morning (M) and evening (E) locomotor activity and a "siesta" in the middle of the day. These M and E components have been critical for developing the neuronal dual oscillator model in which clock gene expression in key cells generates the circadian phenotype. However, under natural European summer conditions of cycling temperature and light intensity, an additional prominent afternoon (A) component that replaces the siesta is observed. This component has been described as an "artifact" of the TriKinetics locomotor monitoring system that is used by many circadian laboratories world wide. Using video recordings, we show that the A component is not an artifact, neither in the glass tubes used in TriKinetics monitors nor in open-field arenas. By studying various mutants in the visual and peripheral and internal thermo-sensitive pathways, we reveal that the M component is predominantly dependent on visual input, whereas the A component requires the internal thermo-sensitive channel transient receptor potential A1 (TrpA1). Knockdown of TrpA1 in different neuronal groups reveals that the reported expression of TrpA1 in clock neurons is unlikely to be involved in generating the summer locomotor profile, suggesting that other TrpA1 neurons are responsible for the A component. Studies of circadian rhythms under seminatural conditions therefore provide additional insights into the molecular basis of circadian entrainment that would otherwise be lost under the usual standard laboratory protocols. PMID- 26124143 TI - Structural asymmetry in a conserved signaling system that regulates division, replication, and virulence of an intracellular pathogen. AB - We have functionally and structurally defined an essential protein phosphorelay that regulates expression of genes required for growth, division, and intracellular survival of the global zoonotic pathogen Brucella abortus. Our study delineates phosphoryl transfer through this molecular pathway, which initiates from the sensor kinase CckA and proceeds through the ChpT phosphotransferase to two regulatory substrates: CtrA and CpdR. Genetic perturbation of this system results in defects in cell growth and division site selection, and a specific viability deficit inside human phagocytic cells. Thus, proper control of B. abortus division site polarity is necessary for survival in the intracellular niche. We further define the structural foundations of signaling from the central phosphotransferase, ChpT, to its response regulator substrate, CtrA, and provide evidence that there are at least two modes of interaction between ChpT and CtrA, only one of which is competent to catalyze phosphoryltransfer. The structure and dynamics of the active site on each side of the ChpT homodimer are distinct, supporting a model in which quaternary structure of the 2:2 ChpT-CtrA complex enforces an asymmetric mechanism of phosphoryl transfer between ChpT and CtrA. Our study provides mechanistic understanding, from the cellular to the atomic scale, of a conserved transcriptional regulatory system that controls the cellular and infection biology of B. abortus. More generally, our results provide insight into the structural basis of two-component signal transduction, which is broadly conserved in bacteria, plants, and fungi. PMID- 26124144 TI - Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers. AB - Sex hormones and their receptors play critical roles in the development and progression of the breast and prostate cancers. Here we report that a novel type of transfer RNA (tRNA)-derived small RNA, termed Sex HOrmone-dependent TRNA derived RNAs (SHOT-RNAs), are specifically and abundantly expressed in estrogen receptor (ER)-positive breast cancer and androgen receptor (AR)-positive prostate cancer cell lines. SHOT-RNAs are not abundantly present in ER(-) breast cancer, AR(-) prostate cancer, or other examined cancer cell lines from other tissues. ER dependent accumulation of SHOT-RNAs is not limited to a cell culture system, but it also occurs in luminal-type breast cancer patient tissues. SHOT-RNAs are produced from aminoacylated mature tRNAs by angiogenin-mediated anticodon cleavage, which is promoted by sex hormones and their receptors. Resultant 5'- and 3'-SHOT-RNAs, corresponding to 5'- and 3'-tRNA halves, bear a cyclic phosphate (cP) and an amino acid at the 3'-end, respectively. By devising a "cP RNA-seq" method that is able to exclusively amplify and sequence cP-containing RNAs, we identified the complete repertoire of 5'-SHOT-RNAs. Furthermore, 5'-SHOT RNA, but not 3'-SHOT-RNA, has significant functional involvement in cell proliferation. These results have unveiled a novel tRNA-engaged pathway in tumorigenesis of hormone-dependent cancers and implicate SHOT-RNAs as potential candidates for biomarkers and therapeutic targets. PMID- 26124145 TI - Enzyme mechanism-based, oxidative DNA-protein cross-links formed with DNA polymerase beta in vivo. AB - Free radical attack on the C1' position of DNA deoxyribose generates the oxidized abasic (AP) site 2-deoxyribonolactone (dL). Upon encountering dL, AP lyase enzymes such as DNA polymerase beta (Polbeta) form dead-end, covalent intermediates in vitro during attempted DNA repair. However, the conditions that lead to the in vivo formation of such DNA-protein cross-links (DPC), and their impact on cellular functions, have remained unknown. We adapted an immuno-slot blot approach to detect oxidative Polbeta-DPC in vivo. Treatment of mammalian cells with genotoxic oxidants that generate dL in DNA led to the formation of Polbeta-DPC in vivo. In a dose-dependent fashion, Polbeta-DPC were detected in MDA-MB-231 human cells treated with the antitumor drug tirapazamine (TPZ; much more Polbeta-DPC under 1% O2 than under 21% O2) and even more robustly with the "chemical nuclease" 1,10-copper-ortho-phenanthroline, Cu(OP)2. Mouse embryonic fibroblasts challenged with TPZ or Cu(OP)2 also incurred Polbeta-DPC. Nonoxidative agents did not generate Polbeta-DPC. The cross-linking in vivo was clearly a result of the base excision DNA repair pathway: oxidative Polbeta-DPC depended on the Ape1 AP endonuclease, which generates the Polbeta lyase substrate, and they required the essential lysine-72 in the Polbeta lyase active site. Oxidative Polbeta-DPC had an unexpectedly short half-life (~ 30 min) in both human and mouse cells, and their removal was dependent on the proteasome. Proteasome inhibition under Cu(OP)2 treatment was significantly more cytotoxic to cells expressing wild-type Polbeta than to cells with the lyase-defective form. That observation underscores the genotoxic potential of oxidative Polbeta-DPC and the biological pressure to repair them. PMID- 26124147 TI - Drosophila reproduction: Molecules meet morphology. PMID- 26124146 TI - Arabidopsis MZT1 homologs GIP1 and GIP2 are essential for centromere architecture. AB - Centromeres play a pivotal role in maintaining genome integrity by facilitating the recruitment of kinetochore and sister-chromatid cohesion proteins, both required for correct chromosome segregation. Centromeres are epigenetically specified by the presence of the histone H3 variant (CENH3). In this study, we investigate the role of the highly conserved gamma-tubulin complex protein 3 interacting proteins (GIPs) in Arabidopsis centromere regulation. We show that GIPs form a complex with CENH3 in cycling cells. GIP depletion in the gip1gip2 knockdown mutant leads to a decreased CENH3 level at centromeres, despite a higher level of Mis18BP1/KNL2 present at both centromeric and ectopic sites. We thus postulate that GIPs are required to ensure CENH3 deposition and/or maintenance at centromeres. In addition, the recruitment at the centromere of other proteins such as the CENP-C kinetochore component and the cohesin subunit SMC3 is impaired in gip1gip2. These defects in centromere architecture result in aneuploidy due to severely altered centromeric cohesion. Altogether, we ascribe a central function to GIPs for the proper recruitment and/or stabilization of centromeric proteins essential in the specification of the centromere identity, as well as for centromeric cohesion in somatic cells. PMID- 26124148 TI - Active and widespread halogen chemistry in the tropical and subtropical free troposphere. AB - Halogens in the troposphere are increasingly recognized as playing an important role for atmospheric chemistry, and possibly climate. Bromine and iodine react catalytically to destroy ozone (O3), oxidize mercury, and modify oxidative capacity that is relevant for the lifetime of greenhouse gases. Most of the tropospheric O3 and methane (CH4) loss occurs at tropical latitudes. Here we report simultaneous measurements of vertical profiles of bromine oxide (BrO) and iodine oxide (IO) in the tropical and subtropical free troposphere (10 degrees N to 40 degrees S), and show that these halogens are responsible for 34% of the column-integrated loss of tropospheric O3. The observed BrO concentrations increase strongly with altitude (~ 3.4 pptv at 13.5 km), and are 2-4 times higher than predicted in the tropical free troposphere. BrO resembles model predictions more closely in stratospheric air. The largest model low bias is observed in the lower tropical transition layer (TTL) over the tropical eastern Pacific Ocean, and may reflect a missing inorganic bromine source supplying an additional 2.5 6.4 pptv total inorganic bromine (Bry), or model overestimated Bry wet scavenging. Our results highlight the importance of heterogeneous chemistry on ice clouds, and imply an additional Bry source from the debromination of sea salt residue in the lower TTL. The observed levels of bromine oxidize mercury up to 3.5 times faster than models predict, possibly increasing mercury deposition to the ocean. The halogen-catalyzed loss of tropospheric O3 needs to be considered when estimating past and future ozone radiative effects. PMID- 26124149 TI - Structural basis for the activation of the C. elegans noncanonical cytoplasmic poly(A)-polymerase GLD-2 by GLD-3. AB - The Caenorhabditis elegans germ-line development defective (GLD)-2-GLD-3 complex up-regulates the expression of genes required for meiotic progression. GLD-2-GLD 3 acts by extending the short poly(A) tail of germ-line-specific mRNAs, switching them from a dormant state into a translationally active state. GLD-2 is a cytoplasmic noncanonical poly(A) polymerase that lacks the RNA-binding domain typical of the canonical nuclear poly(A)-polymerase Pap1. The activity of C. elegans GLD-2 in vivo and in vitro depends on its association with the multi-K homology (KH) domain-containing protein, GLD-3, a homolog of Bicaudal-C. We have identified a minimal polyadenylation complex that includes the conserved nucleotidyl-transferase core of GLD-2 and the N-terminal domain of GLD-3, and determined its structure at 2.3-A resolution. The structure shows that the N terminal domain of GLD-3 does not fold into the predicted KH domain but wraps around the catalytic domain of GLD-2. The picture that emerges from the structural and biochemical data are that GLD-3 activates GLD-2 both indirectly by stabilizing the enzyme and directly by contributing positively charged residues near the RNA-binding cleft. The RNA-binding cleft of GLD-2 has distinct structural features compared with the poly(A)-polymerases Pap1 and Trf4. Consistently, GLD-2 has distinct biochemical properties: It displays unusual specificity in vitro for single-stranded RNAs with at least one adenosine at the 3' end. GLD-2 thus appears to have evolved specialized nucleotidyl-transferase properties that match the 3' end features of dormant cytoplasmic mRNAs. PMID- 26124150 TI - Reply to Liu et al.: HNF4A and PTBP1 expression in the brain of neurodegenerative disease patients. PMID- 26124151 TI - Expression quantitative trait loci regulate HNF4A and PTBP1 expression in human brains. PMID- 26124152 TI - Reply to Grace: Role of cholinergic neurons in rapid eye movement (REM) sleep control. PMID- 26124153 TI - Mutation at embB codon 306, a potential marker for the identification of multidrug resistance associated with ethambutol in Mycobacterium tuberculosis. AB - Ethambutol inhibits arabinogalactan and lipoarabinomannan biosynthesis in mycobacteria. The occurrence of mutations in embB codon 306 in ethambutol susceptible isolates and their absence in resistant isolates has raised questions regarding the utility of this codon as a potential marker for resistance against ethambutol. The characterization of mutations on embB 306 will contribute to a better understanding of the mechanisms of resistance to this drug; therefore, the purpose of this study was to investigate the association between embB 306 mutations and first-line drug resistance profiles in tuberculosis isolates. We sequenced the region surrounding the embB 306 codon in 175 tuberculosis clinical isolates, divided according to drug sensitivity, in three groups: 110 were resistant to at least one first-line drug, of which 61 were resistant to ethambutol (EMB(r)), 49 were sensitive to ethambutol (EMB(s)) but were resistant to another drug, and 65 were pansensitive isolates (P(s)). The associations between embB 306 mutations and phenotypic resistance to all first-line drugs were determined, and their validity and safety as a diagnostic marker were assessed. One of the P(s) isolates (1/65), one of the EMB(s) isolates (1/49), and 20 of the EMB(r) isolates (20/61) presented with an embB 306 mutation. Four different single-nucleotide polymorphisms (SNPs) at embB 306 were associated with simultaneous resistance to ethambutol, isoniazid, and rifampin (odds ratio [OR], 17.7; confidence interval [CI], 5.6 to 56.1) and showed a positive predictive value of 82%, with a specificity of 97% for diagnosing multidrug resistance associated with ethambutol, indicating its potential as a molecular marker for several drugs. PMID- 26124154 TI - Prevalence of Plasmodium falciparum resistance markers to sulfadoxine pyrimethamine among pregnant women receiving intermittent preventive treatment for malaria in Uganda. AB - The aim of this study was to assess the prevalence of mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes among pregnant women using sulfadoxine-pyrimethamine (SP) as an intermittent preventive treatment (IPTp). A molecular epidemiological study of P. falciparum parasite resistance markers to SP was conducted from August 2010 to February 2012 in Mukono district in central Uganda. DNA was extracted from 413 P. falciparum-positive samples. Real-time PCR, followed by melting curve analysis, was used to characterize point mutations in the Pfdhfr and Pfdhps genes that are associated with SP resistance. The prevalence of the single-nucleotide mutations in Pfdhfr at codons 51I, 59R, and 108N and in Pfdhps at codons 437G and 540E was high (>98%), reaching 100% fixation after one dose of SP, while the prevalence of 581G was 3.3% at baseline, reaching 12.5% after one dose of SP. At baseline, the prevalence of Pfdhfr and Pfdhps quintuple mutations was 89%, whereas the sextuple mutations (including 581G) were not prevalent (3.9%), reaching 16.7% after one dose of SP. However, the numbers of infections at follow-up visits were small, and hence there was insufficient statistical power to test whether there was a true rise in the prevalence of this allele. The overall high frequency of Pfdhfr and Pfdhps quintuple mutations throughout pregnancy excluded further analyses of possible associations between certain haplotypes and the risk of lower birth weight and anemia. However, women infected with P. falciparum had 1.3-g/dl-lower hemoglobin levels (P = 0.001) and delivered babies with a 400-g-lower birth weight (P = 0.001) compared to nonparasitemic women. Despite this, 44 women who were P. falciparum positive at baseline became negative after one or two doses of SP (i.e., 50.5%), implying that SP-IPTp still has some efficacy. P. falciparum resistance markers to SP are high in this population, whereas P. falciparum infection was associated with poor birth outcomes. PMID- 26124155 TI - The ribosomal S10 protein is a general target for decreased tigecycline susceptibility. AB - Tigecycline is a translational inhibitor with efficacy against a wide range of pathogens. Using experimental evolution, we adapted Acinetobacter baumannii, Enterococcus faecium, Escherichia coli, and Staphylococcus aureus to growth in elevated tigecycline concentrations. At the end of adaptation, 35 out of 47 replicate populations had clones with a mutation in rpsJ, the gene that encodes the ribosomal S10 protein. To validate the role of mutations in rpsJ in conferring tigecycline resistance, we showed that mutation of rpsJ alone in Enterococcus faecalis was sufficient to increase the tigecycline MIC to the clinical breakpoint of 0.5 MUg/ml. Importantly, we also report the first identification of rpsJ mutations associated with decreased tigecycline susceptibility in A. baumannii, E. coli, and S. aureus. The identified S10 mutations across both Gram-positive and -negative species cluster in the vertex of an extended loop that is located near the tigecycline-binding pocket within the 16S rRNA. These data indicate that S10 is a general target of tigecycline adaptation and a relevant marker for detecting reduced susceptibility in both Gram-positive and -negative pathogens. PMID- 26124156 TI - Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr). AB - There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-d xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs. PMID- 26124157 TI - Pharmacokinetics and pharmacodynamics of continuous-infusion meropenem in pediatric hematopoietic stem cell transplant patients. AB - This study explored the pharmacokinetics and the pharmacodynamics of continuous infusion meropenem in a population of pediatric hematopoietic stem cell transplant (HSCT) patients who underwent therapeutic drug monitoring. The relationship between meropenem clearance (CLM) and estimated creatinine clearance (CLCR) was assessed by nonlinear regression. A Monte Carlo simulation was performed to investigate the predictive performance of five dosing regimens (15 to 90 mg/kg of body weight/day) for the empirical treatment of severe Gram negative-related infections in relation to four different categories of renal function. The optimal target was defined as a probability of target attainment (PTA) of >=90% at steady-state concentration-to-MIC ratios (C SS/MIC) of >=1 and >=4 for MICs of up to 8 mg/liter. A total of 21 patients with 44 meropenem C SS were included. A good relationship between CLM and estimated CLCR was observed (r (2) = 0.733). Simulations showed that at an MIC of 2 mg/liter, the administration of continuous-infusion meropenem at doses of 15, 30, 45, and 60 mg/kg/day may achieve a PTA of >=90% at a C SS/MIC ratio of >=4 in the CLCR categories of 40 to <80, 80 to <120, 120 to <200, and 200 to <300 ml/min/1.73 m(2), respectively. At an MIC of 8 mg/liter, doses of up to 90 mg/kg/day by continuous infusion may achieve optimal PTA only in the CLCR categories of 40 to <80 and 80 to <120 ml/min/1.73 m(2). Continuous-infusion meropenem at dosages up to 90 mg/kg/day might be effective for optimal treatment of severe Gram-negative-related infections in pediatric HSCT patients, even when caused by carbapenem-resistant pathogens with an MIC of up to 8 mg/liter. PMID- 26124158 TI - Adequacy of high-dose cefepime regimen in febrile neutropenic patients with hematological malignancies. AB - While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT>MIC). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT>MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT>MIC in the 3rd and 6th dosing intervals. A 100% fT>MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is <=4 mg/liter but may fail to cover less susceptible organisms. PMID- 26124159 TI - ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. AB - ELQ-300 is a preclinical candidate that targets the liver and blood stages of Plasmodium falciparum, as well as the forms that are crucial to transmission of disease: gametocytes, zygotes, and ookinetes. A significant obstacle to the clinical development of ELQ-300 is related to its physicochemical properties. Its relatively poor aqueous solubility and high crystallinity limit absorption to the degree that only low blood concentrations can be achieved following oral dosing. While these low blood concentrations are sufficient for therapy, the levels are too low to establish an acceptable safety margin required by regulatory agencies for clinical development. One way to address the challenging physicochemical properties of ELQ-300 is through the development of prodrugs. Here, we profile ELQ-337, a bioreversible O-linked carbonate ester prodrug of the parent molecule. At the molar equivalent dose of 3 mg/kg of body weight, the delivery of ELQ-300 from ELQ-337 is enhanced by 3- to 4-fold, reaching a maximum concentration of drug in serum (C max) of 5.9 MUM by 6 h after oral administration, and unlike ELQ 300 at any dose, ELQ-337 provides single-dose cures of patent malaria infections in mice at low-single-digit milligram per kilogram doses. Our findings show that the prodrug strategy represents a viable approach to overcome the physicochemical limitations of ELQ-300 to deliver the active drug to the bloodstream at concentrations sufficient for safety and toxicology studies, as well as achieving single-dose cures. PMID- 26124160 TI - Preliminary method for direct quantification of colistin methanesulfonate by attenuated total reflectance Fourier transform infrared spectroscopy. AB - Colistin use has increased in response to the advent of infections caused by multidrug-resistant organisms. It is administered parenterally as an inactive prodrug, colistin methanesulfonate (CMS). Various formulations of CMS and labeling conventions can lead to confusion about colistin dosing, and questions remain about the pharmacokinetics of CMS. Since CMS does not have strong UV absorbance, current methods employ a laborious process of chemical conversion to colistin followed by precolumn derivatization to detect formed colistin by high performance liquid chromatography. Here, we report a method for direct quantification of colistin methanesulfonate by attenuated total reflectance Fourier transform infrared spectroscopy (ATR FTIR). PMID- 26124161 TI - Nephrotoxicity comparison of two commercially available generic vancomycin products. AB - To date, no comparative clinical studies have investigated the effects of different vancomycin products on nephrotoxicity. The objective of this single center, retrospective, matched-cohort study was to investigate the impact of two different vancomycin products on the development of nephrotoxicity. The study population included adults receiving a single vancomycin product, from either Pfizer or Hospira, for their entire course of therapy. Patients were matched based on underlying nephrotoxicity risk factors. Secondary outcomes included the need for renal replacement therapy, length of hospital stay, and in-hospital mortality. One-hundred forty-six matched pairs (n = 292) were included, and they had no significant differences in demographics, comorbid conditions, severity of illness, or vancomycin-associated nephrotoxicity risk factors. The frequency of nephrotoxicity was 8.9% in the Pfizer group and 11.0% in the Hospira group as defined by the 2009 consensus vancomycin guidelines (P = 0.56), 17.1% in the Pfizer group and 13.0% in the Hospira group as defined by the Acute Kidney Injury Network (AKIN) (P = 0.33), and 10.3% in the Pfizer group and 11.6% in the Hospira group as defined by RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria (P = 0.71). There were no differences between groups in regard to nephrotoxicity by any definition or in secondary outcomes. In multivariate analysis of overall nephrotoxicity risk factors, the type of vancomycin product was not independently associated with increased odds of developing nephrotoxicity according to the RIFLE criteria. Based on our results, there are no discernible differences between Pfizer and Hospira vancomycin products in the frequency of nephrotoxicity. Confirmation of these results with other types of vancomycin and different patient populations is warranted. PMID- 26124162 TI - Telavancin demonstrates activity against methicillin-resistant Staphylococcus aureus isolates with reduced susceptibility to vancomycin, daptomycin, and linezolid in broth microdilution MIC and one-compartment pharmacokinetic/pharmacodynamic models. AB - Methicillin-resistant Staphylococcus aureus (MRSA) isolates have arisen with reduced susceptibility to several anti-MRSA agents. Telavancin (TLV), a novel anti-MRSA agent, retains low MICs against these organisms. Our objective was to determine the MICs for TLV, daptomycin (DAP), vancomycin (VAN), and linezolid (LZD) against daptomycin-nonsusceptible (DNS) S. aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and linezolid-resistant (LZD(r)) S. aureus. We also evaluated these agents against each phenotype in pharmacokinetic/pharmacodynamic (PK/PD) models. Seventy DNS, 100 VISA, 180 hVISA, and 25 LZD(r) MRSA isolates were randomly selected from our library and tested to determine their MICs against TLV, DAP, VAN, and LZD via broth microdilution and a Trek panel. Four isolates were randomly selected for 168-h in vitro models to evaluate treatment with TLV at 10 mg/kg of body weight/day, DAP at 10 mg/kg/day, VAN at 1 g every 12 h (q12h), and LZD at 600 mg q12h. The MIC50/90 for TLV, DAP, VAN, and LZD against 70 DNS S. aureus isolates were 0.06/0.125 MUg/ml, 2/4 MUg/ml, 1/2 MUg/ml, and 2/2 MUg/ml, respectively. Against 100 VISA isolates, the MIC50/90 were 0.06/0.125 MUg/ml, 1/1 MUg/ml, 4/8 MUg/ml, and 1/2 MUg/ml, respectively. Against 170 hVISA isolates, the MIC50/90 were 0.06/0.125 MUg/ml, 0.5/1 MUg/ml, 1/2 MUg/ml, and 1/2 MUg/ml, respectively. Against 25 LZD(r) isolates, the MIC50/90 were 0.03/0.06 MUg/ml, 1/1 MUg/ml, 2/2 MUg/ml, and 8/8 MUg/ml, respectively. The TLV MIC was >0.125 MUg/ml for 10/365 (2.7%) isolates. In PK/PD models, TLV was universally bactericidal at 168 h and statistically superior to all antibiotics against DNS S. aureus strain R2334. These data further establish the potency of TLV against resistant MRSA. The model data demonstrate in vitro bactericidal activity of TLV against hVISA, VISA, DNS S. aureus, and LZD(r) S. aureus strains. Further clinical research is warranted. PMID- 26124163 TI - Discrimination between native and Tn6010-associated oqxAB in Klebsiella spp., Raoultella spp., and other Enterobacteriaceae by using a two-step strategy. AB - We developed a two-step PCR-based strategy to detect genes encoding OqxAB, allowing a specific assignment of Tn6010-associated oqxAB in Enterobacteriaceae. Chromosomal location in this setup was confirmed by hybridization with I-CeuI restricted genomes. This approach led us to find that Klebsiella sp. and Raoultella sp. reference strains chromosomally carried oqxAB. PMID- 26124164 TI - Development of a novel real-time PCR assay with high-resolution melt analysis to detect and differentiate OXA-48-Like beta-lactamases in carbapenem-resistant Enterobacteriaceae. AB - The rapid global spread of carbapenem-resistant Enterobacteriaceae (CRE) poses an urgent threat to public health. More than 250 class D beta-lactamases (OXAs) have been described in recent years, with variations in hydrolytic activity for beta lactams. The plasmid-borne OXA-48 beta-lactamase and its variants are identified only sporadically in the United States but are common in Europe. Recognition of these OXA-48-like carbapenemases is vital in order to control their dissemination. We developed a real-time PCR assay based on high-resolution melt analysis, using bla OXA-48-like-specific primers coupled with an unlabeled 3' phosphorylated oligonucleotide probe (LunaProbe) homologous to OXA-48-like carbapenemase genes. The assay was validated using genomic DNA from 48 clinical isolates carrying a variety of carbapenemase genes, including bla KPC, bla SME, bla IMP, bla NDM-1, bla VIM, bla OXA-48, bla OXA-162, bla OXA-181, bla OXA-204, bla OXA-244, bla OXA-245, and bla OXA-232. Our assay identified the presence of bla OXA-48-like beta-lactamase genes and clearly distinguished between bla OXA-48 and its variants in control strains, including between bla OXA-181 and bla OXA 232, which differ by only a single base pair in the assay target region. This approach has potential for use in epidemiological investigations and continuous surveillance to help control the spread of CRE strains producing OXA-48-like enzymes. PMID- 26124165 TI - Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and resistant Candida albicans in a murine model of vaginal candidiasis. AB - Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of <=0.015 and MIC90 of 0.12 MUg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 MUg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 MUg/ml) but fully sensitive in vitro to VT 1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 MUg/ml) and moderately resistant to fluconazole (MIC of 8 MUg/ml) was used, VT 1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 MUg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC. PMID- 26124166 TI - Nucleoside inhibitors of tick-borne encephalitis virus. AB - Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza 2'-C-methyladenosine (7-deaza-2'-CMA), 2'-C-methyladenosine (2'-CMA), and 2'-C methylcytidine (2'-CMC) inhibited TBEV replication. These compounds showed dose dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC50]of 5.1 +/- 0.4 MUM for 7-deaza-2'-CMA, 7.1 +/- 1.2 MUM for 2'-CMA, and 14.2 +/- 1.9 MUM for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of ~50 MUM). The anti-TBEV effect of 2'-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2'-CMA showed no detectable cellular toxicity (CC50 > 50 MUM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2'-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2'-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection. PMID- 26124167 TI - In vitro study of the variable effects of proton pump inhibitors on voriconazole. AB - Voriconazole is a broad-spectrum antifungal agent used for the treatment of severe fungal infections. Maintaining therapeutic concentrations of 1 to 5.5 MUg/ml is currently recommended to maximize the exposure-response relationship of voriconazole. However, this is challenging, given the highly variable pharmacokinetics of the drug, which includes metabolism by cytochrome P450 (CYP450) isotypes CYP2C19, CYP3A4, and CYP2C9, through which common metabolic pathways for many medications take place and which are also expressed in different isoforms with various metabolic efficacies. Proton pump inhibitors (PPIs) are also metabolized through these enzymes, making them competitive inhibitors of voriconazole metabolism, and coadministration with voriconazole has been reported to increase total voriconazole exposure. We examined the effects of five PPIs (rabeprazole, pantoprazole, lansoprazole, omeprazole, and esomeprazole) on voriconazole concentrations using four sets of human liver microsomes (HLMs) of different CYP450 phenotypes. Overall, the use of voriconazole in combination with any PPI led to a significantly higher voriconazole yield compared to that achieved with voriconazole alone in both pooled HLMs (77% versus 59%; P < 0.001) and individual HLMs (86% versus 76%; P < 0.001). The mean percent change in the voriconazole yield from that at the baseline after PPI exposure in pooled microsomes ranged from 22% with pantoprazole to 51% with esomeprazole. Future studies are warranted to confirm whether and how the deliberate coadministration of voriconazole and PPIs can be used to boost voriconazole levels in patients with difficult-to-treat fungal infections. PMID- 26124168 TI - Imidazolium salts as small-molecule urinary bladder exfoliants in a murine model. AB - We present a novel family of small-molecule urinary bladder exfoliants that are expected to be of great value in preclinical studies of urologic conditions and have improved potential for translation compared with prior agents. There is broad urologic interest in the therapeutic potential of such exfoliating agents. The primary agent used in preclinical models, the cationic peptide protamine sulfate (PS), has limited translational potential due to concerns including systemic adverse reactions and bladder tissue injury. Intravesical application of a safe, systemically nontoxic exfoliant would have potential utility in the eradication of Escherichia coli and other uropathogens that reside in the bladder epithelium following cystitis, as well as in chronic bladder pain and bladder cancer. Here, we introduce a family of imidazolium salts with potent and focused exfoliating activity on the bladder epithelium. Synthesis and purification were straightforward and scalable, and the compounds exhibited prolonged stability in lyophilized form. Most members of the compound family were cytotoxic to cultured uroepithelial cells, with >10-fold differences in potency across the series. Upon topical (intravesical) administration of selected compounds to the murine bladder, complete epithelial exfoliation was achieved with physiologically relevant imidazolium concentrations and brief contact times. The exfoliative activity of these compounds was markedly improved in comparison to PS, as assessed by microscopy, immunofluorescence, and immunoblotting for uroplakins. Bladder uroepithelium regenerated within days to yield a histologically normal appearance, and no toxicity was observed. Finally, the chemical scaffold offers an opportunity for inclusion of antimicrobials or conjugation with chemotherapeutic or other moieties. PMID- 26124169 TI - Pharmacodynamics of fosfomycin: insights into clinical use for antimicrobial resistance. AB - The aim of this study was to improve the understanding of the pharmacokinetic pharmacodynamic relationships of fosfomycin against extended-spectrum beta lactamase (ESBL)-producing Escherichia coli strains that have different fosfomycin MICs. Our methods included the use of a hollow fiber infection model with three clinical ESBL-producing E. coli strains. Human fosfomycin pharmacokinetic profiles were simulated over 4 days. Preliminary studies conducted to determine the dose ranges, including the dose ranges that suppressed the development of drug-resistant mutants, were conducted with regimens from 12 g/day to 36 g/day. The combination of fosfomycin at 4 g every 8 h (q8h) and meropenem at 1 g/q8h was selected for further assessment. The total bacterial population and the resistant subpopulations were determined. No efficacy was observed against the Ec42444 strain (fosfomycin MIC, 64 mg/liter) at doses of 12, 24, or 36 g/day. All dosages induced at least initial bacterial killing against Ec46 (fosfomycin MIC, 1 mg/liter). High-level drug-resistant mutants appeared in this strain in response to 12, 15, and 18 g/day. In the study arms that included 24 g/day, once or in a divided dose, a complete extinction of the bacterial inoculum was observed. The combination of meropenem with fosfomycin was synergistic for bacterial killing and also suppressed all fosfomycin-resistant clones of Ec2974 (fosfomycin MIC, 1 mg/liter). We conclude that fosfomycin susceptibility breakpoints (<=64 mg/liter according to CLSI [for E. coli urinary tract infections only]) should be revised for the treatment of serious systemic infections. Fosfomycin can be used to treat infections caused by organisms that demonstrate lower MICs and lower bacterial densities, although relatively high daily dosages (i.e., 24 g/day) are required to prevent the emergence of bacterial resistance. The ratio of the area under the concentration-time curve for the free, unbound fraction of fosfomycin versus the MIC (fAUC/MIC) appears to be the dynamically linked index of suppression of bacterial resistance. Fosfomycin with meropenem can act synergistically against E. coli strains in preventing the emergence of fosfomycin resistance. PMID- 26124170 TI - High prevalence of the animal-associated bla CTX-M-1 IncI1/ST3 plasmid in human Escherichia coli isolates. PMID- 26124171 TI - In vivo biocompatibility and in vitro efficacy of antimicrobial gendine-coated central catheters. AB - Antimicrobial peripherally inserted central catheters (PICCs) might reduce the incidence of central line-associated bloodstream infections (CLABSI). We tested the biocompatibility of a novel gendine-coated (combination of chlorhexidine [CHX] and gentian violet [GV]) PICC in a rabbit intravascular model and tested antimicrobial efficacy in comparison with commercially available minocycline/rifampin (M/R)- and CHX-treated PICCs in an in vitro biofilm colonization model. Gendine-coated and uncoated control PICCs were inserted in the jugular veins of rabbits for 4 days. Histopathological analysis was performed at the end of the 4-day period, and circulating levels of CHX and GV in the blood were measured at different time points using liquid chromatography-mass spectrometry. The antimicrobial efficacy of the PICCs was tested following simulated intravascular indwells of 24 h and 1 week against clinical isolates of methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Enterobacter cloacae, Candida albicans, and Candida glabrata. Rabbits implanted with gendine coated PICCs exhibited reduced levels of thrombosis and inflammation compared to those of the rabbits with uncoated controls. No GV was detected in blood samples over the entire study period, and trace concentrations of CHX were detected. The gendine-coated PICCs completely prevented the adherence of all pathogens from 24 h to 1 week (P <= 0.001), while M/R-treated, CHX-treated, and control PICCs did not. Gendine-coated PICCs were highly effective in preventing biofilm formation of multidrug-resistant pathogenic bacteria and fungi. Gendine-coated PICCs were biocompatible in an intravascular setting. Further, the pharmacokinetic testing established that acute systemic exposures of CHX and GV from the gendine-coated catheters were well within safe levels. PMID- 26124172 TI - Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements. AB - Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 . (residual diuresis/100) and V = 33.00 . (weight/73)(2.07), where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the f uT >MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the f uT >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population. PMID- 26124173 TI - Noninvasive Streptococcus pneumoniae serotypes recovered from hospitalized adult patients in the United States in 2009 to 2012. AB - This study was conducted to determine the serotype distribution and trends over time of Streptococcus pneumoniae strains associated with noninvasive infections among adult patients >=18 years of age in the United States (2009 to 2012). A total of 2,927 S. pneumoniae isolates recovered from patients presenting with respiratory infections and obtained mainly (87.0%) from lower respiratory tract specimens (sputum) were included. The levels of the 7-valent pneumococcal conjugate vaccine (PCV7) serotypes remained stable over the 4-year study period (4.6% to 5.5%; P = 0.953). Overall, 13-valent pneumococcal conjugate vaccine (PCV13) serotypes were identified in 32.7% of samples, declining from 33.7% to 35.5% in 2009 to 2011 to 28.2% in 2012 (P = 0.007), with a significant decrease in the levels of serotypes 7F (P = 0.013) and 6A (P = 0.010). The levels of 19A remained constant (15.8% to 17.1%) during 2009 to 2011, dropping to 12.2% in 2012 (P = 0.089). The prevalence of serotypes associated with the 23-valent pneumococcal polysaccharide vaccine (PPSV23), but not PCV13, remained generally stable; however, the prevalence of serotypes 15B and 15C (15B/15C) increased from 2.7% to 6.3% (P = 0.010). The proportion of nonvaccine serotypes increased gradually during the study period (P = 0.044), particularly for serotype 35B (from 3.6% in 2009 to 8.2% in 2012; P = 0.001). Nonsusceptibility rates for penicillin (susceptible breakpoint, <=2 MUg/ml) and clindamycin against PCV7 serotypes decreased over the period. These results suggest the emergence of indirect effects following introduction of PCV13 for infants and young children; continued surveillance is needed to assess the burden of PCV13 serotypes in the adult population after the implementation of age-based recommendations in the United States. PMID- 26124174 TI - In vitro activities of 21 antimicrobial agents alone and in combination with aminoglycosides or fluoroquinolones against extended-spectrum-beta-lactamase producing Escherichia coli isolates causing bacteremia. AB - We evaluated the in vitro activity of various antimicrobials alone and in combination against 291 extended-spectrum-beta-lactamase-producing Escherichia coli (ESBL-EC) isolates causing bacteremia in South Korean hospitals. Ceftazidime, cefepime, and piperacillin-tazobactam in combination with amikacin showed greater activity than found in combination with ciprofloxacin. In settings with a high prevalence of ESBL-producing pathogens, combination aminoglycoside antimicrobial therapy, especially with amikacin, may be considered for empirical therapy against suspected Gram-negative sepsis as a carbapenem-saving strategy. PMID- 26124175 TI - Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone. AB - Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCtau) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCtau for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCtau was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID- 26124176 TI - Alkaloids as inhibitors of malate synthase from Paracoccidioides spp.: receptor ligand interaction-based virtual screening and molecular docking studies, antifungal activity, and the adhesion process. AB - Paracoccidioides is the agent of paracoccidioidomycosis. Malate synthase plays a crucial role in the pathogenicity and virulence of various fungi, such as those that are human pathogens. Thus, an inhibitor of this enzyme may be used as a powerful antifungal without side effects in patients once these enzymes are absent in humans. Here, we searched for compounds with inhibitory capacity against the malate synthase of Paracoccidioides species (PbMLS). The three dimensional (3D) structure of PbMLS was determined using the I-TASSER server. Compounds were selected from the ZINC database. Based on the mechanism underlying the interaction of the compounds with PbMLS, it was possible to identify beta carboline moiety as a standard key structure. The compounds with beta-carboline moiety that are available in our laboratories were investigated. A total of nine alkaloid compounds were selected. The primary mechanisms of interaction of the alkaloid compounds in the binding pocket of PbMLS were identified and compared with the mechanism of interaction of acetyl coenzyme A (acetyl-CoA). We discovered that the amphipathic nature of the compounds, concomitant with the presence of beta-carboline moiety, was crucial for their stability in the binding pocket of PbMLS. In addition, the importance of a critical balance of the polar and nonpolar contacts of the compounds in this region was observed. Four beta carboline alkaloid compounds showed the ability to inhibit recombinant PbMLS (PbMLSr) activity, Paracoccidioides species growth, and adhesion of the fungus and PbMLSr to the extracellular matrix components. The cytotoxicity of the alkaloids was also evaluated. PMID- 26124177 TI - Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion. AB - Drosophila homologue of Diaphanous 1 (DIAPH1) regulates actin polymerization and microtubule (MT) stabilization upon stimulation with lysophosphatidic acid (LPA). Recently, we showed strongly reduced lung metastasis of DIAPH1-depleted colon cancer cells but we found accumulations of DIAPH1-depleted cells in bone marrow. Here, we analyzed possible organ- or tissue-specific metastasis of DIAPH1 depleted HCT-116 cells. Our data confirmed that depletion of DIAPH1 strongly inhibited lung metastasis and revealed that, in contrast to control cells, DIAPH1 depleted cells did not form metastases in further organs. Detailed mechanistic analysis on cells that were not stimulated with LPA to activate the cytoskeleton modulating activity of DIAPH1, revealed that even under basal conditions DIAPH1 was essential for cellular adhesion to collagen. In non-stimulated cells DIAPH1 did not control actin dynamics but, interestingly, was essential for stabilization of microtubules (MTs). Additionally, DIAPH1 controlled directed vesicle trafficking and with this, local clustering of the adhesion protein integrin-beta1 at the plasma membrane. Therefore, we conclude that under non stimulating conditions DIAPH1 controls cellular adhesion by stabilizing MTs required for local clustering of integrin-beta1 at the plasma membrane. Thus, blockade of DIAPH1-tubulin interaction may be a promising approach to inhibit one of the earliest steps in the metastatic cascade of colon cancer. PMID- 26124178 TI - Retargeted human avidin-CAR T cells for adoptive immunotherapy of EGFRvIII expressing gliomas and their evaluation via optical imaging. AB - There has been significant progress in the design of chimeric antigen receptors (CAR) for adoptive immunotherapy targeting tumor-associated antigens. However, the challenge of monitoring the therapy in real time has been continually ignored. To address this issue, we developed optical molecular imaging approaches to evaluate a recently reported novel CAR strategy for adoptive immunotherapy against glioma xenografts expressing EGFRvIII. We initially biotinylated a novel anti-EGFRvIII monoclonal antibody (biotin-4G1) to pre-target EGFRvIII+ gliomas and then redirect activated avidin-CAR expressing T cells against the pre targeted biotin-4G1. By optical imaging study and bio-distribution analysis, we confirmed the specificity of pre-target and target and determined the optimal time for T cells adoptive transfer in vivo. The results showed this therapeutic strategy offered efficient therapy effect to EGFRvIII+ glioma-bearing mice and implied that optical imaging is a highly useful tool in aiding in the instruction of clinical CAR-T cells adoptive transfer in future. PMID- 26124179 TI - Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers. AB - The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers. PMID- 26124180 TI - High EGFR and low p-Akt expression is associated with better outcome after nimotuzumab-containing treatment in esophageal cancer patients: preliminary clinical result and testable hypothesis. AB - The epidermal growth factor receptor (EGFR) is widely overexpressed in esophageal squamous cell carcinoma (ESCC) and it results is associated with a poor prognosis. Identifying the subgroup of ESCC patients who are sensitive to EGFR targeted therapy is a key point to facilitate its medical use.We retrospectively analyzed 32 ESCC patients treated with the combination of nimotuzumab (h-R3) and radiotherapy (RT) or chemoradiotherapy (CRT). Expression of EGFR and phosphorylated proteins associated with EGFR signaling pathway, i.e. p-Akt and p Erk, were assessed with immunohistochemistry (IHC) for all patients. Correlations between these proteins' expression levels and overall survival (OS) were assessed.High expression of EGFR, p-Akt and p-Erk was detected in 53.1% (17/32), 54.8% (17/31) and 59.4% (19/32) of tumors respectively. No significant differences in OS were found between high EGFR, p-Akt and p-Erk expression groups and their respective counterparts. Of note, significantly better overall survival was observed in patients with coexistence of high EGFR expression and low p-Akt expression (p = 0.030).Our data allowed us to put forward a hypothesis that high EGFR and low p-Akt expression may predict a clinical benefit of EGFR antagonists such as nimotuzumab combined with RT or CRT. This can be discussed in the terms of oncogene addiction and synthetic lethality concepts. This hypothesis can be further tested in larger groups of patients. PMID- 26124181 TI - miR-93/miR-106b/miR-375-CIC-CRABP1: a novel regulatory axis in prostate cancer progression. AB - Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 (SCA1) neurodegenerative disease and some types of cancer; however, the role of CIC in prostate cancer remains unknown. Here we show that CIC suppresses prostate cancer progression. CIC expression was markedly decreased in human prostatic carcinoma. CIC overexpression suppressed prostate cancer cell proliferation, invasion, and migration, whereas CIC RNAi exerted opposite effects. We found that knock-down of CIC derepresses expression of ETV5 and CRABP1 in LNCaP and PC-3 cells, respectively, thereby promoting cell proliferation and invasion. We also discovered that miR-93, miR-106b, and miR-375, which are known to be frequently overexpressed in prostate cancer patients, cooperatively down-regulate CIC levels to promote cancer progression. Altogether, we suggest miR-93/miR-106b/miR-375-CIC CRABP1 as a novel key regulatory axis in prostate cancer progression. PMID- 26124182 TI - Doxorubicin induces apoptosis by targeting Madcam1 and AKT and inhibiting protein translation initiation in hepatocellular carcinoma cells. AB - Doxorubicin (Doxo) is one of the most widely used chemotherapeutic drugs for patients with hepatocellular carcinoma (HCC). Doxo is a DNA intercalating drug that inhibits topoisomerase II. Thereby Doxo has the ability to block DNA replication and induce apoptosis. However, the other targets and mechanisms through which Doxo induces apoptosis to treat HCC still remain unknown. Here, we identified Mucosal vascular addressin cell adhesion molecule 1 (Madcam1) as a potential Doxo target because Madcam1 overexpression suppressed, while Madcam1 depletion stimulated Doxo-induced apoptosis. Furthermore, we first revealed that Doxo can induce apoptosis by blocking protein translation initiation. In contrast, Madcam1 activated protein translation through an opposite mechanism. We also found de-phosphorylation of AKT may be an important pro-apoptotic event that is triggered by Doxo-induced Madcam1 down-regulation. Finally, we revealed that Madcam1 promoted increased AKT phosphorylation, which is essential for maintaining the sensitivity of HCC cells to Doxo treatment. Taken together, we uncovered a potential mechanism for Doxo-induced apoptosis in HCC treatment through targeting Madcam1 and AKT and blocking protein translation initiation. PMID- 26124183 TI - Impact of genetic polymorphisms on paediatric atopic dermatitis. AB - In order to investigate whether polymorphisms of genes encoding some factors of innate and adaptive immunity play a role in the development of, or protection against atopic dermatitis (AD) and condition its severity, we genotyped 33 candidate genes and 47 single nucleotide polymorphisms (SNPs) using Custom TaqMan Array Microfluidic Cards and an ABI 7900HT analyser (Applied Biosystems, Foster City, CA, USA). The study involved 104 children with AD (29 with mild-to-moderate and 75 with severe disease; 42 girls; mean age +/- SD, 5.8 +/- 3.3 years) and 119 healthy controls (49 girls; mean age, 4.8 +/- 3.0 years). IL10-rs1800872T, TG and MBL2-rs500737AG were all significantly more frequent among the children with AD (P = 0.015, P = 0.004 and P = 0.030), whereas IL10-rs1800896C and TC were more frequent in those without AD (P = 0.028 and P = 0.032). The VEGFA-rs2146326A and CTLA4-rs3087243AG SNPs were significantly more frequent in the children with mild/moderate AD than in those with severe AD (P = 0.048 andP = 0.036). IL10 rs1800872T and TG were significantly more frequent in the children with AD and other allergic diseases than in the controls (P = 0.014 and P = 0.007), whereas IL10-rs1800896TC and C were more frequent in the controls than in the children with AD and other allergic diseases (P = 0.0055 and P = 0.0034). These findings show that some of the polymorphisms involved in the immune response are also involved in some aspects of the development and course of AD and, although not conclusive, support the immunological hypothesis of the origin of the inflammatory lesions. PMID- 26124184 TI - Trauma and Posttraumatic Stress Disorder: Emerging Risk Factors for Cardiovascular Disease in Women? PMID- 26124187 TI - Misdiagnosed or Incidentally Detected Hepatocellular Carcinoma in Explanted Livers: Lessons Learned. AB - BACKGROUND: Misdiagnosed or incidentally detected hepatocellular carcinoma (HCC) in liver explant is an undesirable surprise that might pose a medical challenge in the post-transplant setting. MATERIAL AND METHODS: From May 2001 to the end of December 2013, 463 and 137 liver transplants for adult and pediatric patients, respectively, were performed at our center. Ten cases were found to have misdiagnosed or incidental malignant lesions on pathological examination of the explant. RESULTS: We considered 105 patients for LT because of presence of HCC; 102 patients were accurately diagnosed by pretransplant imaging and the other 3 patients were misdiagnosed as HCC and then found to have mixed HCC cholangiocarcinoma (CC) (2.9% misdiagnosis rate). Seven more patients were found to have i-HCC in explanted livers. Therefore, 109 patients were transplanted for presence of HCC (6.5% of them diagnosed incidentally). The overall rate of incidental HCC (i-HCC) among all liver explants was 1.2%. In the adult group no subjects had HCC recurrence, while only 1 subject had HCC recurrence in the pediatric group. All mixed HCC-CC lesions were found in adult patients. Two patients died from recurrence of cholangiocarcinoma after liver transplant. The other patient is still surviving with no recurrence at 13-month follow-up. CONCLUSIONS: Misdiagnosed or incidental malignancy is a rare but reported finding following liver transplantation. Their preoperative suspicion is quite challenging. A thorough explant pathology study is needed to diagnose this condition. It is evident that the outcome of this undesirable finding was judged mainly by tumor biology. PMID- 26124186 TI - Trauma Exposure and Posttraumatic Stress Disorder Symptoms Predict Onset of Cardiovascular Events in Women. AB - BACKGROUND: Psychological stress is a proposed risk factor for cardiovascular disease (CVD), and posttraumatic stress disorder (PTSD), the sentinel stress related mental disorder, occurs twice as frequently in women as men. However, whether PTSD contributes to CVD risk in women is not established. METHODS AND RESULTS: We examined trauma exposure and PTSD symptoms in relation to incident CVD over a 20-year period in 49 978 women in the Nurses' Health Study II. Proportional hazards models estimated hazard ratios and 95% confidence intervals for CVD events confirmed by additional information or medical record review (n=548, including myocardial infarction [n=277] and stroke [n=271]). Trauma exposure and PTSD symptoms were assessed by using the Brief Trauma Questionnaire and a PTSD screen. In comparison with no trauma exposure, endorsing >=4 PTSD symptoms was associated with increased CVD risk after adjusting for age, family history, and childhood factors (hazard ratio,1.60; 95% confidence interval, 1.20 2.13). Being trauma-exposed and endorsing no PTSD symptoms was associated with elevated CVD risk (hazard ratio, 1.45; 95% confidence interval, 1.15-1.83), although being trauma-exposed and endorsing 1 to 3 PTSD symptoms was not. After adjusting for adult health behaviors and medical risk factors, this pattern of findings was maintained. Health behaviors and medical risk factors accounted for 14% of the trauma/no symptoms-CVD association and 47% of the trauma/4+ symptoms CVD association. CONCLUSION: Trauma exposure and elevated PTSD symptoms may increase the risk of CVD in this population of women. These findings suggest that screening for CVD risk and reducing health risk behaviors in trauma-exposed women may be promising avenues for prevention and intervention. PMID- 26124188 TI - Pancreatic cancer: current understanding of molecular and genetic aetiologies. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers where prognosis has not improved over the past few decades. However, there have been several advances in our understanding of the disease leading to earlier detection and targeted therapeutic treatment. It is now understood that specific somatic and germline mutations lead to the development of the disease, and the risk factors associated with this are clearer. Further, several precursor lesions have been identified which, with early detection and surveillance, allows treatment before the development of carcinoma. PDAC can now be diagnosed with a high sensitivity and specificity following advances in radiology, and treatment can be commenced at an earlier stage of the disease. With continued research we are hopeful that the next decade will see an improved survival rate for all patients with pancreatic cancer. PMID- 26124185 TI - Estimated Global, Regional, and National Disease Burdens Related to Sugar Sweetened Beverage Consumption in 2010. AB - BACKGROUND: Sugar-sweetened beverages (SSBs) are consumed globally and contribute to adiposity. However, the worldwide impact of SSBs on burdens of adiposity related cardiovascular diseases (CVDs), cancers, and diabetes mellitus has not been assessed by nation, age, and sex. METHODS AND RESULTS: We modeled global, regional, and national burdens of disease associated with SSB consumption by age/sex in 2010. Data on SSB consumption levels were pooled from national dietary surveys worldwide. The effects of SSB intake on body mass index and diabetes mellitus, and of elevated body mass index on CVD, diabetes mellitus, and cancers were derived from large prospective cohort pooling studies. Disease-specific mortality/morbidity data were obtained from Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We computed cause-specific population-attributable fractions for SSB consumption, which were multiplied by cause-specific mortality/morbidity to compute estimates of SSB-attributable death/disability. Analyses were done by country/age/sex; uncertainties of all input data were propagated into final estimates. Worldwide, the model estimated 184 000 (95% uncertainty interval, 161 000-208 000) deaths/y attributable to SSB consumption: 133 000 (126 000-139 000) from diabetes mellitus, 45 000 (26 000-61 000) from CVD, and 6450 (4300-8600) from cancers. Five percent of SSB-related deaths occurred in low-income, 70.9% in middle-income, and 24.1% in high-income countries. Proportional mortality attributable to SSBs ranged from <1% in Japanese >65 years if age to 30% in Mexicans <45 years of age. Among the 20 most populous countries, Mexico had largest absolute (405 deaths/million adults) and proportional (12.1%) deaths from SSBs. A total of 8.5 (2.8, 19.2) million disability-adjusted life years were related to SSB intake (4.5% of diabetes mellitus-related disability-adjusted life years). CONCLUSIONS: SSBs are a single, modifiable component of diet that can impact preventable death/disability in adults in high-, middle-, and low-income countries, indicating an urgent need for strong global prevention programs. PMID- 26124189 TI - MiR-181a-5p inhibits cell proliferation and migration by targeting Kras in non small cell lung cancer A549 cells. AB - MicroRNAs play important roles in carcinogenesis and tumor progress. Lung cancer is the leading cause of cancer mortality worldwide. In this study, the function of miR-181a-5p was investigated in non-small-cell lung cancer (NSCLC). Results showed that miR-181a-5p was significantly decreased in NSCLC tissues and cell lines. The proliferation and migration of A549 cells transfected with miR-181a-5p mimic was significantly inhibited. Luciferase activity assay results demonstrated that two binding sites of Kras could be directly targeted by miR-181a-5p. Furthermore, Kras was down-regulated by miR-181a-5p at both transcriptional and translational levels. SiRNA-mediated Kras down-regulation could mimic the effects of miR-181a-5p mimic in A549 cells. Our findings suggest that miR-181a-5p plays a potential role in tumor suppression by partially targeting Kras and has the potential therapeutic application in NSCLC patients. PMID- 26124190 TI - Elevated Serum Levels of NSE and S-100beta Correlate with Increased Risk of Acute Cerebral Infarction in Asian Populations. AB - BACKGROUND: We investigated the clinical value of serum levels of neuron-specific enolase (NSE) and human soluble protein-100beta (S-100beta) in acute cerebral infarction (ACI) patients. MATERIAL AND METHODS: A literature search of electronic databases identified relevant case-control studies that examined the correlations between NSE and S-100beta serum levels, and ACI. The retrieved studies were screened based on our strict inclusion and exclusion criteria, and high-quality studies were subsequently selected for meta-analysis. STATA software (Version 12.0, Stata Corporation, College Station, TX, USA) was utilized for statistical analysis. RESULTS: A total of 13 case-control studies, containing 911 ACI patients and 686 healthy controls, were enrolled in this meta-analysis. The results of the meta-analysis showed that serum levels of NSE and S-100beta in ACI patients were significantly higher than the control group. Subgroup analysis based on ethnicity revealed that the serum levels of NSE and S-100beta in ACI patients were significantly higher than the control group in Asian population. In Caucasian population, the serum levels of NSE in case group was significantly higher than the control group, but no significant differences in serum levels of S-100beta were observed between ACI patients and the control group. CONCLUSIONS: Based on our results, we conclude that serum levels of NSE and S-100beta strongly correlate with ACI in Asian population, and may be important clinical markers for diagnosis and treatment of ACI. PMID- 26124191 TI - Unexpected Toxicology Findings in Rats Dosed With an Antihuman IL-13 Monoclonal Antibody. AB - Interleukin 13 (IL-13) is a type 2 helper T cytokine involved in allergic inflammation and immune responses to parasites. CNTO5825 is an antihuman IL-13 monoclonal antibody that inhibits the pharmacological activity of human, cynomolgus monkey, and rat IL-13. Repeated dose toxicology studies of 1- to 6 month duration were conducted in both rats and monkeys at doses of 20 to 100 mg/kg/wk. A decrease in the T cell-dependent antibody response to Keyhole Limpet Hemocyanin immunization was observed in monkeys but not in rats. In the 6-month rat study, there was a 2.2-fold increase in eosinophils in males at 3 and 6 months that was reversible. At necropsy (main and 4-month recovery), rats from control and CNTO5825-dosed groups were found to have pin worms, which may have contributed to the elevations in eosinophil. Testicular toxicity (dilatation of seminiferous tubules, atrophy, and degeneration of the germinal epithelium) was observed in 2 rats at 20 mg/kg and in 5 rats at 100 mg/kg (main and recovery). Brain lesions (unilateral focal accumulation of cells in the white matter of the cerebral cortex) were observed in 2 rats at 100 mg/kg, and vascular neoplasms (1 fatal multicentric hemangiosarcoma and 1 benign hemangioma) were observed at 100 mg/kg/wk. Overall, these studies show that CNTO5825 was without toxicity when administered to rats for up to 6 weeks and to monkeys for up to 6 months. However, when administered to rats for 6 months, a number of seemingly unrelated events occurred that could not be clearly linked to CNTO5825 administration, inhibition of IL-13, or to the immunological status of the animals. PMID- 26124193 TI - The ubiquitous weekend effect: moving past proving it exists to clarifying what causes it. PMID- 26124192 TI - A new cellular target for Yersinia pestis. PMID- 26124194 TI - Aberrations and adaptive optics in super-resolution microscopy. AB - As one of the most powerful tools in the biological investigation of cellular structures and dynamic processes, fluorescence microscopy has undergone extraordinary developments in the past decades. The advent of super-resolution techniques has enabled fluorescence microscopy - or rather nanoscopy - to achieve nanoscale resolution in living specimens and unravelled the interior of cells with unprecedented detail. The methods employed in this expanding field of microscopy, however, are especially prone to the detrimental effects of optical aberrations. In this review, we discuss how super-resolution microscopy techniques based upon single-molecule switching, stimulated emission depletion and structured illumination each suffer from aberrations in different ways that are dependent upon intrinsic technical aspects. We discuss the use of adaptive optics as an effective means to overcome this problem. PMID- 26124195 TI - Challenges From and Beyond Symptomatology: Stereotype Threat in Young Adults With ADHD. AB - OBJECTIVE: Stereotype threat-faced when one confronts a personally relevant stereotype in a domain-relevant context-can significantly jeopardize individual performance in test-taking situations. Research has overlooked the potential for mental health labels to serve as bases for stereotype threat in such situations. This study examines whether ADHD, a disorder frequently serving as a basis for standardized testing accommodation, may trigger stereotype threat in testing situations. METHOD: Drawing from a sample of 114 participants (53 reporting a history of ADHD and 61 not reporting a history of ADHD), this study considers whether stereotype threat invoked on the basis of ADHD hinders performance on Graduate Record Examination (GRE) questions beyond the impact of symptomatology. RESULTS: Participants reporting ADHD achieved significantly lower scores on verbal and quantitative GRE questions than participants without ADHD. Participants between the ages of 18 and 24 reporting ADHD who were explicitly exposed to stereotype threat achieved significantly lower scores on quantitative GRE questions than their ADHD-reporting peers who were not explicitly exposed to stereotype threat. CONCLUSION: Domain-relevant mental health labels may trigger stereotype threat in test-taking situations. PMID- 26124196 TI - Comparison of the effects of pretreatment with repeated electroacupuncture at GV20 and ST36 on fatigue in rats. AB - OBJECTIVE: To investigate and compare the effects of electroacupuncture (EA) pretreatment at GV20 and ST36 on fatigue in rats. METHODS: Rats were randomly allocated into 4 groups: control, fatigue, fatigue+GV20 and fatigue+ST36. The last two groups received EA pretreatment at GV20 or ST36 for 5 days before being maintained in cages filled with water to a height of 1.5 cm to establish an animal model of fatigue. We used the weight-loaded forced swimming test and open field test and measured 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratios and serum levels of blood urea nitrogen (BUN), lactic dehydrogenase (LDH) and testosterone as behavioural and biochemical markers of fatigue in the rats. RESULTS: Compared with controls, rats in the (untreated) fatigue group exhibited reduced weight-loaded swimming times and total movement/distance in the open-field test, plus higher BUN/LDH and lower testosterone levels. Both EA pretreatment at GV20 and ST36 increased swimming times, and reduced serum BUN/LDH. EA pretreatment at GV20 (but not ST36) increased serum testosterone. The 5-HIAA/5-HT ratios in four brain regions were decreased in the fatigue+GV20 group compared with the fatigue group (p<0.05). By contrast, 5-HIAA/5-HT ratios in striatum and hypothalamus (but not hippocampus or midbrain) were decreased in the fatigue+ST36 group compared with the fatigue group (p<0.05). Furthermore, only pretreatment at GV20 affected the results of the open-field test. CONCLUSIONS: These results suggest that EA pretreatment had a positive effect on the prevention of fatigue. Pretreatment at GV20 had a greater anti-fatigue effect than pretreatment at ST36. PMID- 26124197 TI - Trial of intensive acupuncture for smoking cessation: a pilot study. AB - BACKGROUND: Despite the significant decline in smoking rates in the USA over the last 50 years, 42 million Americans continue to smoke. Although the combination of behavioural counselling with FDA-approved medications offers the best evidence based treatment approach, 12-month relapse rates remain at >60%. Both healthcare providers and patients are searching for alternative treatment options. Most acupuncture trials have yielded poor results for smoking cessation; however, most trials have not used an intense treatment protocol and maintained treatment for at least 12 weeks. METHODS: We designed a pilot study to address these methodological problems. Twenty-eight smokers were recruited to attend two 1 h acupuncture sessions weekly for 12 weeks. Primary endpoints included completion rate, acceptability of the protocol and side effects. Secondary endpoints included carbon monoxide (CO)-confirmed, 7-day point prevalence quit rates at 12 weeks and 26 weeks. RESULTS: Sixteen of the 28 patients enrolled (57%) completed 12 weeks of treatment. Of the 17 patients who completed the end-of-study questionnaire, 94% (16/17) rated the programme as helpful, and 82% noted they would recommend it to friends for smoking cessation. Three of the 28 who initially enrolled in the study were confirmed abstinent at 12 weeks (10.7%); one of the 28 (3.6%) was abstinent at 26 weeks. CONCLUSIONS: A larger study with a slightly less rigorous and more acceptable treatment protocol is feasible and should be considered. PMID- 26124198 TI - Natural history and clinical features of sporadic amyotrophic lateral sclerosis in China. AB - OBJECTIVES: To describe the natural history and clinical features of sporadic amyotrophic lateral sclerosis (ALS) in Chinese patients, and to report data on the prognostic factors for survival. METHODS: All patients referred to our ALS centre between 2003 and 2012 were followed up every 3 months. Survival and tracheotomy were predefined as primary outcome measures. Group differences were analysed using parametric and non-parametric tests as appropriate. Survival was analysed using the Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 1624 patients with ALS, 75.1% had limb-onset, 14.0% had bulbar-onset, 7.8% had flail-arm syndrome (FAS), 2.6% had progressive muscular atrophy and 0.5% had primary lateral sclerosis. The male:female ratio was 1.7:1, and the mean age at onset was 49.8 years. The median diagnostic delay was 14 months, and the median survival time after symptom onset was 71 months. Male gender, older age at symptom onset, lower body mass index, shorter diagnostic delay, bulbar-onset ALS phenotype, higher Airlie House category at presentation, rural place of residence, use of traditional Chinese medicine and a history of contact with pesticides were associated with poorer survival, whereas female gender or an FAS phenotype may have a better prognosis. CONCLUSIONS: The clinical characteristics and outcomes of Chinese patients with sporadic ALS were different compared with patients from other countries. Compared with other studies, the age at onset of Chinese patients was earlier, the percentage of bulbar-onset ALS was lower and the prognosis was better. This study substantially advances the understanding of the clinical features and epidemiology of this rare disease. PMID- 26124199 TI - Highly sampled tetranucleotide and tetraloop motifs enable evaluation of common RNA force fields. AB - Recent modifications and improvements to standard nucleic acid force fields have attempted to fix problems and issues that have been observed as longer timescale simulations have become routine. Although previous work has shown the ability to fold the UUCG stem-loop structure, until now no group has attempted to quantify the performance of current force fields using highly converged structural populations of the tetraloop conformational ensemble. In this study, we report the use of multiple independent sets of multidimensional replica exchange molecular dynamics (M-REMD) simulations with different initial conditions to generate well-converged conformational ensembles for the tetranucleotides r(GACC) and r(CCCC), as well as the larger UUCG tetraloop motif. By generating what is to our knowledge the most complete RNA structure ensembles reported to date for these systems, we remove the coupling between force field errors and errors due to incomplete sampling, providing a comprehensive comparison between current top performing MD force fields for RNA. Of the RNA force fields tested in this study, none demonstrate the ability to correctly identify the most thermodynamically stable structure for all three systems. We discuss the deficiencies present in each potential function and suggest areas where improvements can be made. The results imply that although "short" (nsec-MUsec timescale) simulations may stay close to their respective experimental structures and may well reproduce experimental observables, inevitably the current force fields will populate alternative incorrect structures that are more stable than those observed via experiment. PMID- 26124200 TI - The NMR structure of the II-III-VI three-way junction from the Neurospora VS ribozyme reveals a critical tertiary interaction and provides new insights into the global ribozyme structure. AB - As part of an effort to structurally characterize the complete Neurospora VS ribozyme, NMR solution structures of several subdomains have been previously determined, including the internal loops of domains I and VI, the I/V kissing loop interaction and the III-IV-V junction. Here, we expand this work by determining the NMR structure of a 62-nucleotide RNA (J236) that encompasses the VS ribozyme II-III-VI three-way junction and its adjoining stems. In addition, we localize Mg(2+)-binding sites within this structure using Mn(2+)-induced paramagnetic relaxation enhancement. The NMR structure of the J236 RNA displays a family C topology with a compact core stabilized by continuous stacking of stems II and III, a cis WC/WC G*A base pair, two base triples and two Mg(2+) ions. Moreover, it reveals a remote tertiary interaction between the adenine bulges of stems II and VI. Additional NMR studies demonstrate that both this bulge-bulge interaction and Mg(2+) ions are critical for the stable folding of the II-III-VI junction. The NMR structure of the J236 RNA is consistent with biochemical studies on the complete VS ribozyme, but not with biophysical studies performed with a minimal II-III-VI junction that does not contain the II-VI bulge-bulge interaction. Together with previous NMR studies, our findings provide important new insights into the three-dimensional architecture of this unique ribozyme. PMID- 26124201 TI - Targeting Acidity in Pancreatic Adenocarcinoma: Multispectral Optoacoustic Tomography Detects pH-Low Insertion Peptide Probes In Vivo. AB - BACKGROUND: pH-low insertion peptides (pHLIP) can serve as a targeting moiety that enables pH-sensitive probes to detect solid tumors. Using these probes in conjunction with multispectral optoacoustic tomography (MSOT) is a promising approach to improve imaging for pancreatic cancer. METHODS: A pH-sensitive pHLIP (V7) was conjugated to 750 NIR fluorescent dye and evaluated as a targeted probe for pancreatic adenocarcinoma. The pH-insensitive K7 pHLIP served as an untargeted control. Probe binding was assessed in vitro at pH 7.4, 6.8, and 6.6 using human pancreatic cell lines S2VP10 and S2013. Using MSOT, semiquantitative probe accumulation was then assessed in vivo with a murine orthotopic pancreatic adenocarcinoma model. RESULTS: In vitro, the V7-750 probe demonstrated significantly higher fluorescence at pH 6.6 compared with pH 7.4 (S2VP10, P = 0.0119; S2013, P = 0.0160), whereas no difference was observed with the K7-750 control (S2VP10, P = 0.8783; S2013, P = 0.921). In the in vivo S2VP10 model, V7 750 probe resulted in 782.5 MSOT a.u. signal compared with 5.3 MSOT a.u. in K7 750 control in tumor (P = 0.0001). Similarly, V7-750 probe signal was 578.3 MSOT a.u. in the S2013 model compared with K7-750 signal at 5.1 MSOT a.u. (P = 0.0005). There was minimal off-target accumulation of the V7-750 probe within the liver or kidney, and probe distribution was confirmed with ex vivo imaging. CONCLUSIONS: Compared with pH-insensitive controls, V7-750 pH-sensitive probe specifically targets pancreatic adenocarcinoma and has minimal off-target accumulation. The noninvasive detection of pH-targeted probes by means of MSOT represents a promising modality to improve the detection and monitoring of pancreatic cancer. PMID- 26124203 TI - Analysis of Inflammatory and Anemia-Related Biomarkers in a Randomized, Double Blind, Placebo-Controlled Study of Siltuximab (Anti-IL6 Monoclonal Antibody) in Patients With Multicentric Castleman Disease. AB - PURPOSE: Siltuximab (IL6 antibody) is approved for the treatment of multicentric Castleman disease (MCD). Effects of IL6 inhibition on the inflammatory milieu accompanying MCD have not been characterized. EXPERIMENTAL DESIGN: Trends in inflammatory- and anemia-associated markers, measured over the course of a placebo-controlled study of siltuximab (11 mg/kg q3w) in patients with MCD (n = 79), were characterized. RESULTS: Baseline IL6 and C-reactive protein (CRP) levels were significantly correlated (r = 0.708; P < 0.0001). CRP levels decreased (median, 92%) by cycle 1 day 8 (C1D8), remaining suppressed during siltuximab treatment while remaining stable in the placebo group. There were no associations between baseline CRP or IL6 and MCD symptom burden, histologic subtype, ethnicity, maximum CRP decrease, and response parameters. A hemoglobin response (change >= 15 g/L at week 13) was observed with siltuximab (61%; P = 0.0002). Median hepcidin decrease from baseline at C1D8 with siltuximab was 47% versus median 11% increase with placebo. Maximum post-baseline changes in hepcidin levels among siltuximab recipients were correlated with maximum changes for hemoglobin (r = -0.395; P = 0.00607), total iron-binding capacity (TIBC; r = 0.354; P = 0.01694), and ferritin (r = 0.599; P = 0.0001). Greater median changes from baseline in ferritin, hemoglobin, and TIBC were observed in anemic siltuximab-treated patients. CONCLUSIONS: IL6 neutralization with siltuximab resulted in sustained CRP suppression and improvement of anemia, in part, by hepcidin pathway inhibition. PMID- 26124202 TI - Wee-1 Kinase Inhibition Sensitizes High-Risk HPV+ HNSCC to Apoptosis Accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic Proteins. AB - PURPOSE: Although the majority of patients with HPV(+) oropharyngeal cancers have a favorable prognosis, there are some patients with tumors that are resistant to aggressive chemoradiotherapy with unusual patterns of locoregional and systemic recurrences. Therefore, more effective therapies are needed. In this study, we investigated the chemosensitizing efficacy of the selective Wee-1 kinase inhibitor, AZD-1775, in HPV(+) head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Clonogenic survival assays and an orthotopic mouse model of HPV(+) oral cancer were used to examine the in vitro and in vivo sensitivity of HPV(+) HNSCC cell lines to AZD-1775 in combination with cisplatin, respectively. Cell-cycle analysis, DNA damage (gammaH2AX), homologous recombination (HR), and apoptosis were examined to dissect molecular mechanisms. RESULTS: We found that AZD-1775 displays single-agent activity and enhances the response of HPV(+) HNSCC cells to cisplatin both in vitro and in vivo. The sensitivity of the HPV(+) HNSCC cells to AZD-1775 alone or in combination with cisplatin was associated with G2 checkpoint abrogation, persistent DNA damage, and apoptosis induction. This finding of AZD-1775 increasing the sensitivity of HPV(+) HNSCC cells to cisplatin through apoptosis was not seen previously in the HPV(-) HNSCC cancer cells and is accompanied by a decreased expression of the antiapoptotic proteins, MCl-1and XIAP, which appear to be cleaved following AZD-1775 treatment. CONCLUSIONS: AZD 1775 selectively sensitizes HPV(+) HNSCC cells and orthotopic oral xenografts to cisplatin through apoptosis and support the clinical investigation of AZD-1775 in combination with cisplatin particularly in patients with advanced and recurrent metastatic HPV(+) HNSCC tumors. PMID- 26124204 TI - SMO Gene Amplification and Activation of the Hedgehog Pathway as Novel Mechanisms of Resistance to Anti-Epidermal Growth Factor Receptor Drugs in Human Lung Cancer. AB - PURPOSE: Resistance to tyrosine kinase inhibitors (TKI) of EGF receptor (EGFR) is often related to activation of other signaling pathways and evolution through a mesenchymal phenotype. EXPERIMENTAL DESIGN: Because the Hedgehog (Hh) pathway has emerged as an important mediator of epithelial-to-mesenchymal transition (EMT), we studied the activation of Hh signaling in models of EGFR-TKIs intrinsic or acquired resistance from both EGFR-mutated and wild-type (WT) non-small cell lung cancer (NSCLC) cell lines. RESULTS: Activation of the Hh pathway was found in both models of EGFR-mutated and EGFR-WT NSCLC cell line resistant to EGFR-TKIs. In EGFR-mutated HCC827-GR cells, we found SMO (the Hh receptor) gene amplification, MET activation, and the functional interaction of these two signaling pathways. In HCC827-GR cells, inhibition of SMO or downregulation of GLI1 (the most important Hh-induced transcription factor) expression in combination with MET inhibition exerted significant antitumor activity.In EGFR-WT NSCLC cell lines resistant to EGFR inhibitors, the combined inhibition of SMO and EGFR exerted a strong antiproliferative activity with a complete inhibition of PI3K/Akt and MAPK phosphorylation. In addition, the inhibition of SMO by the use of LDE225 sensitizes EGFR-WT NSCLC cells to standard chemotherapy. CONCLUSIONS: This result supports the role of the Hh pathway in mediating resistance to anti EGFR-TKIs through the induction of EMT and suggests new opportunities to design new treatment strategies in lung cancer. PMID- 26124205 TI - Sex Differences in Long-Term Outcomes With Cardiac Resynchronization Therapy in Mild Heart Failure Patients With Left Bundle Branch Block. AB - BACKGROUND: Previous studies have shown conflicting results regarding the benefit of cardiac resynchronization therapy (CRT) by sex and QRS duration. METHODS AND RESULTS: In the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT), we evaluated long-term clinical outcome of heart failure (HF) or death, death, and HF alone by sex and QRS duration (dichotomized at 150 ms) in left bundle-branch block patients with CRT with defibrillator backup (CRT-D) versus implantable cardioverter-defibrillator (ICD) only. There were 394 women (31%) and 887 men with left bundle-branch block. During the median follow-up of 5.6 years, women derived greater clinical benefit from CRT-D compared with implantable cardioverter-defibrillator only, with a significant 71% reduction in HF or death (hazard ratio [HR] 0.29, P<0.001) and a 77% reduction in HF alone (HR 0.23, P<0.001) compared with men, who had a 41% reduction in HF or death (HR 0.59, P<0.001) and a 50% reduction in HF alone (HR 0.50, P<0.001) (all sex-by-treatment interaction P<0.05). Men and women had similar reduction in long-term mortality with CRT-D versus implantable cardioverter-defibrillator only (men: HR 0.70, P=0.03; women: HR 0.59, P=0.04). The incremental benefit of CRT-D in women for HF or death and HF alone was consistent with QRS <150 or >150 ms. CONCLUSIONS: During long-term follow-up of mild HF patients with left ventricular dysfunction and wide QRS, both women and men with left bundle-branch block derived sustained benefit from CRT-D versus implantable cardioverter-defibrillator only, with significant reduction in HF or death, HF alone, and all-cause mortality regardless of QRS duration. There is an incremental benefit with CRT-D in women for the end points of HF or death and HF alone. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110. PMID- 26124207 TI - Obituary: Niclas Jonzen (1973-2015). PMID- 26124206 TI - Rho-GTPase and Atherosclerosis: Pleiotropic Effects of Statins. PMID- 26124208 TI - Feasibility and Acceptability of an Alcohol Addiction Therapy Integrated in a Transplant Center for Patients Awaiting Liver Transplantation. AB - AIMS: To evaluate the feasibility and acceptability of an addiction program within the setting of liver transplantation, with classification of behavior change techniques used to reduce excessive drinking. METHOD: Patients with alcohol-related liver disease (N = 100) participated in a manualized addiction group therapy over 12 sessions, pre-transplantation. Relapses were identified by measurement of urinary ethyl glucuronide (EtG). RESULTS: Two groups were identified according to the frequency of participation: completers (n = 42) vs. drop-outs (n = 58). A total of 16.5% of the samples of completers in comparison to 30.5% of the samples of drop-outs tested positive for EtG (P < 0.001). CONCLUSIONS: The results suggest that implementation of an addiction therapy program during the waiting time might help to limit the frequency of drinking. These patients appeared often to under-report their alcohol consumption; including a biomarker such as urinary EtG in such settings is recommended. PMID- 26124213 TI - Isolation of novel IncA/C and IncN fluoroquinolone resistance plasmids from an antibiotic-polluted lake. AB - OBJECTIVES: Antibiotic-polluted environments may function as reservoirs for novel resistance plasmids not yet encountered in pathogens. The aims of this study were to assess the potential of resistance transfer between bacteria from such environments and Escherichia coli, and to characterize the conjugative elements involved. METHODS: Sediment samples from Kazipally lake and Asanikunta tank, two Indian lakes with a history of severe pollution with fluoroquinolones, were investigated. Proportions of resistant bacteria were determined by selective cultivation, while horizontal gene transfer was studied using a GFP-tagged E. coli as recipient. Retrieved transconjugants were tested for susceptibility by Etest((r)) and captured conjugative resistance elements were characterized by WGS. RESULTS: The polluted lakes harboured considerably higher proportions of ciprofloxacin-resistant and sulfamethoxazole-resistant bacteria than did other Indian and Swedish lakes included for comparison (52% versus 2% and 60% versus 7%, respectively). Resistance plasmids were captured from Kazipally lake, but not from any of the other lakes; in the case of Asanikunta tank because of high sediment toxicity. Eight unique IncA/C and IncN resistance plasmids were identified among 11 sequenced transconjugants. Five plasmids were fully assembled, and four of these carried the quinolone resistance gene qnrVC1, which has previously only been found on chromosomes. Acquired resistance genes, in the majority of cases associated with class 1 integrons, could be linked to decreased susceptibility to several different classes of antibiotics. CONCLUSIONS: Our study shows that environments heavily polluted with antibiotics contain novel multiresistance plasmids transferrable to E. coli. PMID- 26124214 TI - Filling the map for antimicrobial resistance in sub-Saharan Africa: ampicillin resistant Enterococcus from non-clinical sources in Angola. PMID- 26124215 TI - 3D-printed Bioresorbable Scaffold for Periodontal Repair. PMID- 26124216 TI - Three-Dimensional Bioprinting for Regenerative Dentistry and Craniofacial Tissue Engineering. AB - Craniofacial tissues are organized with complex 3-dimensional (3D) architectures. Mimicking such 3D complexity and the multicellular interactions naturally occurring in craniofacial structures represents one of the greatest challenges in regenerative dentistry. Three-dimensional bioprinting of tissues and biological structures has been proposed as a promising alternative to address some of these key challenges. It enables precise manufacture of various biomaterials with complex 3D architectures, while being compatible with multiple cell sources and being customizable to patient-specific needs. This review describes different 3D bioprinting methods and summarizes how different classes of biomaterials (polymer hydrogels, ceramics, composites, and cell aggregates) may be used for 3D biomanufacturing of scaffolds, as well as craniofacial tissue analogs. While the fabrication of scaffolds upon which cells attach, migrate, and proliferate is already in use, printing of all the components that form a tissue (living cells and matrix materials together) to produce tissue constructs is still in its early stages. In summary, this review seeks to highlight some of the key advantages of 3D bioprinting technology for the regeneration of craniofacial structures. Additionally, it stimulates progress on the development of strategies that will promote the translation of craniofacial tissue engineering from the laboratory bench to the chair side. PMID- 26124217 TI - M1-like Macrophage Polarization Promotes Orthodontic Tooth Movement. AB - Macrophages play a crucial role in inflammatory-mediated bone loss. Orthodontic tooth movement (OTM) is associated with inflammatory bone remodeling. However, whether and how macrophages contribute to mechanical force-induced OTM remains unknown. In this study, we hypothesized that polarization of M1-like macrophages may contribute to the OTM. Orthodontic nickel-titanium springs were applied to the upper first molars of rats or mice to induce OTM. The distance of OTM gradually increased after mechanical force was applied to the rats for 5 and 10 d. M1-like macrophage polarization and expression of M1 cytokine tumor necrosis factor (TNF)-alpha also increased after force application. More importantly, monocyte/macrophage depletion in mice by injection of clodronate liposomes decreased the distance of OTM and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts and CD68(+) macrophages, accompanied by reduced expressions of M1 markers TNF-alpha and inducible nitric oxide synthase (iNOS), whereas systemic transfusion of M1 macrophages in mice increased them. Further experiments showed that injection of recombinant TNF-alpha increased the distance of OTM and the number of TRAP-positive osteoclasts and CD68(+) macrophages, as well as upregulated the expression of TNF-alpha and iNOS. Blockage of TNF-alpha by etanercept injection reduced the distance of OTM and the number of TRAP-positive osteoclasts and CD68(+) macrophages, as well as decreased the levels of TNF-alpha and iNOS. These data suggest that M1-like macrophage polarization promotes alveolar bone resorption and consequent OTM after mechanical force application. PMID- 26124218 TI - Elevated Level of Circulating Platelet-derived Microparticles in Oral Cancer. AB - Numerous studies have demonstrated that circulating microparticles (MPs) play important roles in a variety of diseases (e.g., atherosclerosis, hypertension, and diabetes), but the association between circulating MPs and oral squamous cell carcinoma (OSCC) remains largely unknown. In the present study, the circulating platelet-derived MPs (PMPs) in 63 patients with OSCC, 22 patients with infected keratocystic odontogenic tumor, and 31 healthy volunteers were characterized and quantified by flow cytometric analysis. The coagulation function of patients with OSCC was correspondingly evaluated. Meanwhile, the inflammation-related cytokines were detected in plasma by enzyme-linked immunosorbent assay and in tumor tissues by immunohistochemistry. Our results showed that the plasma level of circulating PMPs was significantly higher in OSCC patients compared with healthy volunteers and patients with infected keratocystic odontogenic tumor, and they showed positive correlation with the increased level of fibrinogen. Moreover, the coagulation time was significantly shorter after the MPs were added to the MP free plasma. Most important, the levels of interleukin 6 and tumor necrosis factor alpha in plasma and tumor tissues were significantly increased in OSCC patients, which were closely correlated with the elevated level of circulating PMPs. In summary, this study suggests that the elevated level of circulating PMPs, showing close correlation with the secretion of inflammation-related factors, may contribute to the increased procoagulant activity in patients with OSCC. PMID- 26124219 TI - Novel MMP20 and KLK4 Mutations in Amelogenesis Imperfecta. AB - In order to achieve highly mineralized tooth enamel, enamel proteinases serve the important function of removing the remaining organic matrix in the mineralization and maturation of the enamel matrix. Mutations in the kallikrein 4 (KLK4), enamelysin (MMP20), and WDR72 genes have been identified as causing hypomaturation enamel defects in an autosomal-recessive hereditary pattern. In this report, 2 consanguineous families with a hypomaturation-type enamel defect were recruited, and mutational analysis was performed to determine the molecular genetic etiology of the disease. Whole exome sequencing and autozygosity mapping identified novel homozygous mutations in the KLK4 (c.620_621delCT, p.Ser207Trpfs*38) and MMP20 (c.1054G>A, p.Glu352Lys) genes. Further analysis on the effect of the mutations on the translation, secretion, and function of KLK4 and MMP20 revealed that mutant KLK4 was degraded intracellularly and became inactive while mutant MMP20 was expressed at a normal level but secreted only minimally with proteolytic function. PMID- 26124220 TI - Effect of Alendronate on Bone Formation during Tooth Extraction Wound Healing. AB - Alendronate (ALN) is an antiresorptive agent widely used for the treatment of osteoporosis. Its suppressive effect on osteoclasts has been extensively studied. However, the effect of ALN on bone formation is not as clear as its effect on resorption. The objective was to determine the effect of short-term ALN on bone formation and tooth extraction wound healing. Molar tooth extractions were performed in mice. ALN, parathyroid hormone (PTH), or saline (vehicle control) was administered. PTH was used as the bone anabolic control. Mice were euthanized at 3, 5, 7, 10, and 21 d after extractions. Hard tissue healing was determined histomorphometrically. Neutrophils and lymphatic and blood vessels were quantified to evaluate soft tissue healing. Gene expression in the wounds was assessed at the RNA level. Furthermore, the vossicle bone transplant system was used to verify findings from extraction wound analysis. Alkaline phosphatase (ALP) was visualized in the vossicles to assess osteoblast activity. ALN exhibited no negative effect on bone formation. In intact tibiae, ALN increased bone mass significantly more than PTH did. Consistently, significantly elevated osteoblast numbers were noted. In the extraction sockets, bone fill in the ALN treated mice was equivalent to the control. Genes associated with bone morphogenetic protein signaling, such as bmp2, nog, and dlx5, were activated in the extraction wounds of the ALN-treated animals. Bone formation in vossicles was significantly enhanced in the ALN versus PTH group. In agreement with this, ALN upregulated ALP activity considerably in vossicles. Neutrophil aggregation and suppressed lymphangiogenesis were evident in the soft tissue at 21 d after extraction, although gross healing of extraction wounds was uneventful. Bone formation was not impeded by short-term ALN treatment. Rather, short-term ALN treatment enhanced bone formation. ALN did not alter bone fill in extraction sockets. PMID- 26124221 TI - The ADAMTS1 Gene Is Associated with Familial Mandibular Prognathism. AB - Mandibular prognathism is a facial skeletal malocclusion. Until now, the genetic mechanism has been unclear. The goal of this study was to identify candidate genes or genomic regions directly associated with mandibular prognathism development, by employing whole genome sequencing. A large Chinese family was recruited, composed of 9 affected and 12 unaffected individuals, and the inheritance pattern of this family tends to be autosomal dominant. A single nucleotide missense mutation in the ADAMTS1 gene (c. 742I>T) was found to segregate in the family, given that the affected individuals must be heterozygous for the mutation. For mutation validation, we screened this candidate mutation and 15 tag single-nucleotide polymorphisms in the coding sequence of ADAMTS1 among 230 unrelated cases and 196 unrelated controls using Sequenom Massarray and found that 3 in 230 cases carried this mutation and none of the controls did. Final results suggested that 2 single-nucleotide polymorphisms (rs2738, rs229038) of ADAMTS1 were significantly associated with mandibular prognathism. PMID- 26124222 TI - The Influence of Smoking on the Peri-Implant Microbiome. AB - Smokers are at high risk for 2 bacterially driven oral diseases: peri-implant mucositis and peri-implantitis. Therefore, the purpose of this investigation was to use a deep-sequencing approach to identify the effect of smoking on the peri implant microbiome in states of health and disease. Peri-implant biofilm samples were collected from 80 partially edentulous subjects with peri-implant health, peri-implant mucositis, and peri-implantitis. Bacterial DNA was isolated and 16S ribsomal RNA gene libraries sequenced using 454-pyrosequencing targeting the V1 to V3 and V7 to V9 regions. In total, 790,692 classifiable sequences were compared against the HOMD database for bacterial identification. Community-level comparisons were carried out using UniFrac and nonparametric tests. Microbial signatures of health in smokers exhibited lower diversity compared to nonsmokers, with significant enrichment for disease-associated species. Shifts from health to mucositis were accompanied by loss of several health-associated species, leading to a further decrease in diversity. Peri-implantitis did not differ significantly from mucositis in species richness or evenness. In nonsmokers, by contrast, the shift from health to mucositis resembled primary ecological succession, with acquisition of several species without replacement of pioneer organisms, thereby creating a significant increase in diversity. Again, few differences were detected between peri-implantitis and mucositis. Thus, our data suggest that smoking shapes the peri-implant microbiomes even in states of clinical health, by supporting a pathogen-rich community. In both smokers and nonsmokers, peri implant mucositis appears to be a pivotal event in disease progression, creating high-at-risk-for-harm communities. However, ecological succession follows distinctly divergent pathways in smokers and nonsmokers, indicating a need for personalized therapeutics for control and prevention of disease in these 2 cohorts. PMID- 26124223 TI - Washington 'Steps' Up: A 10-Step Quality Improvement Initiative to Optimize Breastfeeding Support in Community Health Centers. AB - BACKGROUND: Breastfeeding initiation in Washington State (Northwest United States) is high, yet rates plummet by 3 months postpartum. In the United States, national quality improvement (QI) efforts to improve breastfeeding outcomes have largely focused on hospital maternity care practices through implementation of the Ten Steps to Successful Breastfeeding. This framework has not extended similarly to primary care clinics, a key site for supporting continued breastfeeding following hospital discharge. This article details a pilot effort with community clinics to implement 10 evidence-based steps to support breastfeeding in the clinic setting and to evaluate the process and outcomes. OBJECTIVE: A public-private-academic partnership developed and piloted a 10-step clinic breastfeeding support strategy and focused resources, training, and technical assistance on primary care clinics to help facilitate best-practice policy and environmental changes to improve clinic breastfeeding support. METHODS: Eight health centers, serving predominantly Latino and Native American communities, worked to systematically implement 10 evidence-based steps developed for the community primary care setting. An evidence table, self-assessment with scoring criteria, tool kit, and provider reference documents were developed to guide clinics. RESULTS: At baseline, clinics had 2 steps, on average, already in practice (range, 1-4 steps); by final assessment, an average of 7 steps was implemented (range, 5-9 steps). Within 6 months from pre-intervention to post, clinics fully operationalized between 2 and 7 steps. CONCLUSION: Catalyzing clinic QI efforts through an evidence-based 10-step model is an effective way to optimize primary care breastfeeding support and to strengthen the continuum of care for breastfeeding mothers and babies following hospital discharge. PMID- 26124224 TI - Workplace Violence in the Health Sector in Turkey: A National Study. AB - Violence in the workplace is an increasing occupational health concern worldwide. Health care workers are at high risk of assault. To develop, monitor, and manage prevention policies, baseline data should be available. This cross-sectional study was designed to determine the current extent of workplace violence nationwide in Turkey. The study population of 12.944 health care workers was a stratified sample of all health care workers (612,639) in the country. A probabilistic sampling was made on the basis of the "multistage stratified random cluster sampling method." This study was conducted by a structured questionnaire in a face-to-face interview. The questionnaire items were adapted and translated into Turkish based on questionnaires of International Labor Organization, International Council of Nurses, World Health Organization, and Public Services International. The percentage of health care workers who experienced workplace violence in Turkey in the previous 12 months was 44.7%. The types of violence included physical 6.8%, verbal 43.2%, mobbing (bullying) 2.4%, and sexual harassment 1%. Multivariate analysis showed that level of health care system, type of institution, gender, occupation, age, working hours, and shift work were independent risk factors for experiencing workplace violence ( p < .05). Our study indicates that the workplace violence among health care workers is a significant problem. The results of the study can serve as the basis for future analytical studies and for development of appropriate prevention efforts. PMID- 26124225 TI - Social media embraces suicide prevention. PMID- 26124226 TI - Parliamentary report calls for action on Wi-Fi. PMID- 26124227 TI - Lymphedema-distichiasis syndrome. PMID- 26124228 TI - Tamper-resistant drugs cannot solve the opioid crisis. PMID- 26124229 TI - Health research among hard-to-reach people: six degrees of sampling. PMID- 26124230 TI - Heyde syndrome: gastrointestinal bleeding and aortic stenosis. PMID- 26124231 TI - What is government's role in medical apps? PMID- 26124233 TI - HIV in Saskatchewan merits urgent response. PMID- 26124234 TI - Aboriginal youth suicide rises in Northern Ontario. PMID- 26124235 TI - Contributions of individual acculturation and neighborhood ethnic density to variations in Hispanic children's respiratory health in a US-Mexican border metropolis. AB - BACKGROUND: We used an expanded conceptualization of ethnic density at the neighborhood level, tailored to Hispanic majority communities in the USA, and a robust measure of children's acculturation at the individual level, to predict Hispanic children's respiratory health. METHODS: We conducted a cross-sectional survey of 1904 children in 2012 in El Paso, TX, USA. One thousand one hundred and seven Hispanic children nested within 72 census tracts were analyzed. Multilevel logistic regression models with cross-level interactions were used to predict bronchitis, asthma and wheezing during sleep. RESULTS: A neighborhood-level ethnic density factor was a non-significant risk factor while individual-level acculturation was a significant risk factor for the three outcomes. Pest troubles and not having been breastfed as an infant intensified the positive association between ethnic density and bronchitis. Increases in ethnic density intensified the odds of wheezing in sleep if the child was not low birth weight or was not economically deprived. CONCLUSIONS: Results suggest that increasing individual level acculturation is detrimental for US Hispanic children's respiratory health in this Hispanic majority setting, while high ethnic density neighborhoods are mildly risky and pose more significant threats when other individual-level factors are present. PMID- 26124236 TI - Serum neuron specific enolase - a novel indicator for neuropsychiatric systemic lupus erythematosus? AB - OBJECTIVE: Neuropsychiatric (NP) lupus, a common manifestation of systemic lupus erythematosus (SLE), is still insufficiently understood, in part, because of the lack of specific biomarkers. Neuron specific enolase (NSE), an important neuronal glycolytic enzyme, shows increased serum levels following acute brain injury, and decreased serum levels in several chronic disorders of the nervous system, including multi infarct dementia, multiple sclerosis and depression. The aim of the study was to evaluate serum NSE levels in SLE patients with and without nervous system involvement, and in healthy controls, and to assess the correlation of NSE serum levels of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) with clinical parameters. METHODS: The study comprised 47 SLE patients and 28 controls. SLE activity was assessed using the Systemic Lupus Activity Measure (SLAM). A neurologist and a psychiatrist examined all patients. NP involvement was diagnosed according to strict NPSLE criteria proposed by Ainiala and coworkers, as modification to American College of Rheumatology (ACR) nomenclature and case definitions. NSE serum levels were determined by use of an immunoassay. RESULTS: Mean NSE serum concentrations in patients with NPSLE were significantly lower than in non-NPSLE patients (6.3 +/- 2.6 ug/L vs. 9.7 +/- 3.3 ug/L, p < 0.01) and in controls (8.8 +/- 3.3 ug/L, p < 0.05). There were significant negative correlations between NSE serum levels and SLE activity (r = 0.42, p < 0.05) and the number of NPSLE manifestations diagnosed (-0.37; p = 0.001). CONCLUSION: Decreased serum concentrations of NSE may reflect chronic neuronal damage with declined metabolism of the nervous tissue in patients with NPSLE. PMID- 26124237 TI - Cognitive dysfunction and functional magnetic resonance imaging in systemic lupus erythematosus. AB - Cognitive dysfunction is a common aspect of systemic lupus erythematosus (SLE) and is increasingly reported as a problem by patients. In many cases the exact cause is unclear. Limited correlations between specific autoantibodies or structural brain abnormalities and cognitive dysfunction in SLE have been reported. It may be that the most appropriate biomarkers have yet to be found. Functional magnetic resonance imaging (fMRI) is a technique used in many other conditions and provides sensitive measures of brain functionality during cognitive tasks. It is now beginning to be employed in SLE studies. These studies have shown that patients with SLE often perform similarly to healthy controls in terms of behavioural measures on cognitive tasks. However, SLE patients appear to employ compensatory brain mechanisms, such as increased response in fronto parietal regions, to maintain adequate cognitive performance. As there have been only a few studies using fMRI in SLE to investigate cognitive dysfunction, many questions remain unanswered. Further research could, however, help to identify biomarkers for cognitive dysfunction in SLE. PMID- 26124238 TI - Cyclic Di-GMP Regulates Type IV Pilus-Dependent Motility in Myxococcus xanthus. AB - The nucleotide-based second messenger bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) is involved in regulating a plethora of processes in bacteria that are typically associated with lifestyle changes. Myxococcus xanthus undergoes major lifestyle changes in response to nutrient availability, with the formation of spreading colonies in the presence of nutrients and spore-filled fruiting bodies in the absence of nutrients. Here, we investigated the function of c-di-GMP in M. xanthus and show that this bacterium synthesizes c-di-GMP during growth. Manipulation of the c-di-GMP level by expression of either an active, heterologous diguanylate cyclase or an active, heterologous phosphodiesterase correlated with defects in type IV pilus (T4P)-dependent motility, whereas gliding motility was unaffected. An increased level of c-di-GMP correlated with reduced transcription of the pilA gene (which encodes the major pilin of T4P), reduced the assembly of T4P, and altered cell agglutination, whereas a decreased c-di-GMP level correlated with altered cell agglutination. The systematic inactivation of the 24 genes in M. xanthus encoding proteins containing GGDEF, EAL, or HD-GYP domains, which are associated with c-di-GMP synthesis, degradation, or binding, identified three genes encoding proteins important for T4P-dependent motility, whereas all mutants had normal gliding motility. Purified DmxA had diguanylate cyclase activity, whereas the hybrid histidine protein kinases TmoK and SgmT, each of which contains a GGDEF domain, did not have diguanylate cyclase activity. These results demonstrate that c-di-GMP is important for T4P-dependent motility in M. xanthus. IMPORTANCE: We provide the first direct evidence that M. xanthus synthesizes c-di-GMP and demonstrate that c di-GMP is important for T4P-dependent motility, whereas we did not obtain evidence that c-di-GMP regulates gliding motility. The data presented uncovered a novel mechanism for regulation of T4P-dependent motility, in which increased levels of c-di-GMP inhibit transcription of the pilA gene (which encodes the major pilin of T4P), ultimately resulting in the reduced assembly of T4P. Moreover, we identified an enzymatically active diguanylate cyclase that is important for T4P-dependent motility. PMID- 26124239 TI - Xanthomonas campestris pv. vesicatoria Secretes Proteases and Xylanases via the Xps Type II Secretion System and Outer Membrane Vesicles. AB - Many plant-pathogenic bacteria utilize type II secretion (T2S) systems to secrete degradative enzymes into the extracellular milieu. T2S substrates presumably mediate the degradation of plant cell wall components during the host-pathogen interaction and thus promote bacterial virulence. Previously, the Xps-T2S system from Xanthomonas campestris pv. vesicatoria was shown to contribute to extracellular protease activity and the secretion of a virulence-associated xylanase. The identities and functions of additional T2S substrates from X. campestris pv. vesicatoria, however, are still unknown. In the present study, the analysis of 25 candidate proteins from X. campestris pv. vesicatoria led to the identification of two type II secreted predicted xylanases, a putative protease and a lipase which was previously identified as a virulence factor of X. campestris pv. vesicatoria. Studies with mutant strains revealed that the identified xylanases and the protease contribute to virulence and in planta growth of X. campestris pv. vesicatoria. When analyzed in the related pathogen X. campestris pv. campestris, several T2S substrates from X. campestris pv. vesicatoria were secreted independently of the T2S systems, presumably because of differences in the T2S substrate specificities of the two pathogens. Furthermore, in X. campestris pv. vesicatoria T2S mutants, secretion of T2S substrates was not completely absent, suggesting the contribution of additional transport systems to protein secretion. In line with this hypothesis, T2S substrates were detected in outer membrane vesicles, which were frequently observed for X. campestris pv. vesicatoria. We, therefore, propose that extracellular virulence-associated enzymes from X. campestris pv. vesicatoria are targeted to the Xps-T2S system and to outer membrane vesicles. IMPORTANCE: The virulence of plant-pathogenic bacteria often depends on TS2 systems, which secrete degradative enzymes into the extracellular milieu. T2S substrates are being studied in several plant pathogenic bacteria, including Xanthomonas campestris pv. vesicatoria, which causes bacterial spot disease in tomato and pepper. Here, we show that the T2S system from X. campestris pv. vesicatoria secretes virulence-associated xylanases, a predicted protease, and a lipase. Secretion assays with the related pathogen X. campestris pv. campestris revealed important differences in the T2S substrate specificities of the two pathogens. Furthermore, electron microscopy showed that T2S substrates from X. campestris pv. vesicatoria are targeted to outer membrane vesicles (OMVs). Our results, therefore, suggest that OMVs provide an alternative transport route for type II secreted extracellular enzymes. PMID- 26124240 TI - Structural Characterization of the Fla2 Flagellum of Rhodobacter sphaeroides. AB - Rhodobacter sphaeroides is a free-living alphaproteobacterium that contains two clusters of functional flagellar genes in its genome: one acquired by horizontal gene transfer (fla1) and one that is endogenous (fla2). We have shown that the Fla2 system is normally quiescent and under certain conditions produces polar flagella, while the Fla1 system is always active and produces a single flagellum at a nonpolar position. In this work we purified and characterized the structure and analyzed the composition of the Fla2 flagellum. The number of polar filaments per cell is 4.6 on average. By comparison with the Fla1 flagellum, the prominent features of the ultra structure of the Fla2 HBB are the absence of an H ring, thick and long hooks, and a smoother zone at the hook-filament junction. The Fla2 helical filaments have a pitch of 2.64 MUm and a diameter of 1.4 MUm, which are smaller than those of the Fla1 filaments. Fla2 filaments undergo polymorphic transitions in vitro and showed two polymorphs: curly (right-handed) and coiled. However, in vivo in free-swimming cells, we observed only a bundle of filaments, which should probably be left-handed. Together, our results indicate that Fla2 cell produces multiple right-handed polar flagella, which are not conventional but exceptional. IMPORTANCE: R. sphaeroides possesses two functional sets of flagellar genes. The fla1 genes are normally expressed in the laboratory and were acquired by horizontal transfer. The fla2 genes are endogenous and are expressed in a Fla1(-) mutant grown phototrophically and in the absence of organic acids. The Fla1 system produces a single lateral or subpolar flagellum, and the Fla2 system produces multiple polar flagella. The two kinds of flagella are never expressed simultaneously, and both are used for swimming in liquid media. The two sets of genes are certainly ready for responding to specific environmental conditions. The characterization of the Fla2 system will help us to understand its role in the physiology of this microorganism. PMID- 26124241 TI - Deletion of nfnAB in Thermoanaerobacterium saccharolyticum and Its Effect on Metabolism. AB - NfnAB catalyzes the reversible transfer of electrons from reduced ferredoxin and NADH to 2 NADP(+). The NfnAB complex has been hypothesized to be the main enzyme for ferredoxin oxidization in strains of Thermoanaerobacterium saccharolyticum engineered for increased ethanol production. NfnAB complex activity was detectable in crude cell extracts of T. saccharolyticum. Activity was also detected using activity staining of native PAGE gels. The nfnAB gene was deleted in different strains of T. saccharolyticum to determine its effect on end product formation. In wild-type T. saccharolyticum, deletion of nfnAB resulted in a 46% increase in H2 formation but otherwise little change in other fermentation products. In two engineered strains with 80% theoretical ethanol yield, loss of nfnAB caused two different responses: in one strain, ethanol yield decreased to about 30% of the theoretical value, while another strain had no change in ethanol yield. Biochemical analysis of cell extracts showed that the DeltanfnAB strain with decreased ethanol yield had NADPH-linked alcohol dehydrogenase (ADH) activity, while the DeltanfnAB strain with unchanged ethanol yield had NADH linked ADH activity. Deletion of nfnAB caused loss of NADPH-linked ferredoxin oxidoreductase activity in all cell extracts. Significant NADH-linked ferredoxin oxidoreductase activity was seen in all cell extracts, including those that had lost nfnAB. This suggests that there is an unidentified NADH:ferredoxin oxidoreductase (distinct from nfnAB) playing a role in ethanol formation. The NfnAB complex plays a key role in generating NADPH in a strain that had become reliant on NADPH-ADH activity. IMPORTANCE: Thermophilic anaerobes that can convert biomass-derived sugars into ethanol have been investigated as candidates for biofuel formation. Many anaerobes have been genetically engineered to increase biofuel formation; however, key aspects of metabolism remain unknown and poorly understood. One example is the mechanism for ferredoxin oxidation and transfer of electrons to NAD(P)(+). The electron-bifurcating enzyme complex NfnAB is known to catalyze the reversible transfer of electrons from reduced ferredoxin and NADH to 2 NADP(+) and is thought to play key roles linking NAD(P)(H) metabolism with ferredoxin metabolism. We report the first deletion of nfnAB and demonstrate a role for NfnAB in metabolism and ethanol formation in Thermoanaerobacterium saccharolyticum and show that this may be an important feature among other thermophilic ethanologenic anaerobes. PMID- 26124244 TI - Twistors and amplitudes. AB - A brief review is given of why twistor geometry has taken a central place in the theory of scattering amplitudes for fundamental particles. The emphasis is on the twistor diagram formalism as originally proposed by Penrose, the development of which has now led to the definition by Arkani-Hamed et al. of the 'amplituhedron'. PMID- 26124245 TI - Lorentzian quantum reality: postulates and toy models. AB - We describe postulates for a novel realist version of relativistic quantum theory or quantum field theory in Minkowski space and other background space-times, and illustrate their application with toy models. PMID- 26124242 TI - From (p)ppGpp to (pp)pGpp: Characterization of Regulatory Effects of pGpp Synthesized by the Small Alarmone Synthetase of Enterococcus faecalis. AB - The bacterial stringent response (SR) is a conserved stress tolerance mechanism that orchestrates physiological alterations to enhance cell survival. This response is mediated by the intracellular accumulation of the alarmones pppGpp and ppGpp, collectively called (p)ppGpp. In Enterococcus faecalis, (p)ppGpp metabolism is carried out by the bifunctional synthetase/hydrolase E. faecalis Rel (RelEf) and the small alarmone synthetase (SAS) RelQEf. Although Rel is the main enzyme responsible for SR activation in Firmicutes, there is emerging evidence that SASs can make important contributions to bacterial homeostasis. Here, we showed that RelQEf synthesizes ppGpp more efficiently than pppGpp without the need for ribosomes, tRNA, or mRNA. In addition to (p)ppGpp synthesis from GDP and GTP, RelQEf also efficiently utilized GMP to form GMP 3'-diphosphate (pGpp). Based on this observation, we sought to determine if pGpp exerts regulatory effects on cellular processes affected by (p)ppGpp. We found that pGpp, like (p)ppGpp, strongly inhibits the activity of E. faecalis enzymes involved in GTP biosynthesis and, to a lesser extent, transcription of rrnB by Escherichia coli RNA polymerase. Activation of E. coli RelA synthetase activity was observed in the presence of both pGpp and ppGpp, while RelQEf was activated only by ppGpp. Furthermore, enzymatic activity of RelQEf is insensitive to relacin, a (p)ppGpp analog developed as an inhibitor of "long" RelA/SpoT homolog (RSH) enzymes. We conclude that pGpp can likely function as a bacterial alarmone with target-specific regulatory effects that are similar to what has been observed for (p)ppGpp. IMPORTANCE: Accumulation of the nucleotide second messengers (p)ppGpp in bacteria is an important signal regulating genetic and physiological networks contributing to stress tolerance, antibiotic persistence, and virulence. Understanding the function and regulation of the enzymes involved in (p)ppGpp turnover is therefore critical for designing strategies to eliminate the protective effects of this molecule. While characterizing the (p)ppGpp synthetase RelQ of Enterococcus faecalis (RelQEf), we found that, in addition to (p)ppGpp, RelQEf is an efficient producer of pGpp (GMP 3'-diphosphate). In vitro analysis revealed that pGpp exerts complex, target-specific effects on processes known to be modulated by (p)ppGpp. These findings provide a new regulatory feature of RelQEf and suggest that pGpp may represent a new member of the (pp)pGpp family of alarmones. PMID- 26124243 TI - IscR Regulates Synthesis of Colonization Factor Antigen I Fimbriae in Response to Iron Starvation in Enterotoxigenic Escherichia coli. AB - Iron availability functions as an environmental cue for enteropathogenic bacteria, signaling arrival within the human host. As enterotoxigenic Escherichia coli (ETEC) is a major cause of human diarrhea, the effect of iron on ETEC virulence factors was evaluated here. ETEC pathogenicity is directly linked to production of fimbrial colonization factors and secretion of heat-labile enterotoxin (LT) and/or heat-stable enterotoxin (ST). Efficient colonization of the small intestine further requires at least the flagellin binding adhesin EtpA. Under iron starvation, production of the CFA/I fimbriae was increased in the ETEC H10407 prototype strain. In contrast, LT secretion was inhibited. Furthermore, under iron starvation, gene expression of the cfa (CFA/I) and etp (EtpBAC) operons was induced, whereas transcription of toxin genes was either unchanged or repressed. Transcriptional reporter fusion experiments focusing on the cfa operon further showed that iron starvation stimulated cfaA promoter activity in ETEC, indicating that the impact of iron on CFA/I production was mediated by transcriptional regulation. Evaluation of cfaA promoter activity in heterologous E. coli single mutant knockout strains identified IscR as the regulator responsible for inducing cfa fimbrial gene expression in response to iron starvation, and this was confirmed in an ETEC DeltaiscR strain. The global iron response regulator, Fur, was not implicated. IscR binding sites were identified in silico within the cfaA promoter and fixation confirmed by DNase I footprinting, indicating that IscR directly binds the promoter region to induce CFA/I. IMPORTANCE: Pathogenic enterobacteria modulate expression of virulence genes in response to iron availability. Although the Fur transcription factor represents the global regulator of iron homeostasis in Escherichia coli, we show that several ETEC virulence factors are modulated by iron, with expression of the major fimbriae under the control of the iron-sulfur cluster regulator, IscR. Furthermore, we demonstrate that the apo form of IscR, lacking an Fe-S cluster, is able to directly fix the corresponding promoter region. These results provide further evidence implicating IscR in bacterial virulence and suggest that IscR may represent a more general regulator mediating the iron response in enteropathogens. PMID- 26124246 TI - Models on the boundary between classical and quantum mechanics. AB - Arguments that quantum mechanics cannot be explained in terms of any classical theory using only classical logic seem to be based on sound mathematical considerations: there cannot be physical laws that require 'conspiracy'. It may therefore be surprising that there are several explicit quantum systems where these considerations apparently do not apply. In this report, several such counterexamples are shown. These are quantum models that do have a classical origin. The most curious of these models is superstring theory. So now the question is asked: how can such a model feature 'conspiracy', and how bad is that? Is there conspiracy in the vacuum fluctuations? Arguments concerning Bell's theorem are further sharpened. PMID- 26124247 TI - Spectral presheaves as quantum state spaces. AB - For each quantum system described by an operator algebra [Formula: see text] of physical quantities, we provide a (generalized) state space, notwithstanding the Kochen-Specker theorem. This quantum state space is the spectral presheaf [Formula: see text]. We formulate the time evolution of quantum systems in terms of Hamiltonian flows on this generalized space and explain how the structure of the spectral presheaf [Formula: see text] geometrically mirrors the double role played by self-adjoint operators in quantum theory, as quantum random variables and as generators of time evolution. PMID- 26124248 TI - Geometry of mass. AB - We study the effect of mass on geometric descriptions of gauge field theories. In an approach in which the massless theory resembles general relativity, the introduction of the mass entails non-zero torsion and the generalization to Einstein-Cartan-Sciama-Kibble theories. The relationships to pure torsion formulations (teleparallel gravity) and to higher gauge theories are also discussed. PMID- 26124249 TI - New geometric concepts in the foundations of physics. PMID- 26124250 TI - Locally covariant quantum field theory and the problem of formulating the same physics in all space-times. AB - The framework of locally covariant quantum field theory is discussed, motivated in part using 'ignorance principles'. It is shown how theories can be represented by suitable functors, so that physical equivalence of theories may be expressed via natural isomorphisms between the corresponding functors. The inhomogeneous scalar field is used to illustrate the ideas. It is argued that there are two reasonable definitions of the local physical content associated with a locally covariant theory; when these coincide, the theory is said to be dynamically local. The status of the dynamical locality condition is reviewed, as are its applications in relation to (i) the foundational question of what it means for a theory to represent the same physics in different space-times and (ii) a no-go result on the existence of natural states. PMID- 26124251 TI - Towards quantized number theory: spectral operators and an asymmetric criterion for the Riemann hypothesis. AB - This research expository article not only contains a survey of earlier work but also contains a main new result, which we first describe. Given c>=0, the spectral operator [Formula: see text] can be thought of intuitively as the operator which sends the geometry onto the spectrum of a fractal string of dimension not exceeding c. Rigorously, it turns out to coincide with a suitable quantization of the Riemann zeta function zeta=zeta(s): a=zeta(?), where ?=?(c) is the infinitesimal shift of the real line acting on the weighted Hilbert space [Formula: see text]. In this paper, we establish a new asymmetric criterion for the Riemann hypothesis (RH), expressed in terms of the invertibility of the spectral operator for all values of the dimension parameter [Formula: see text] (i.e. for all c in the left half of the critical interval (0,1)). This corresponds (conditionally) to a mathematical (and perhaps also, physical) 'phase transition' occurring in the midfractal case when [Formula: see text]. Both the universality and the non-universality of zeta=zeta(s) in the right (resp., left) critical strip [Formula: see text] (resp., [Formula: see text]) play a key role in this context. These new results are presented here. We also briefly discuss earlier joint work on the complex dimensions of fractal strings, and we survey earlier related work of the author with Maier and with Herichi, respectively, in which were established symmetric criteria for the RH, expressed, respectively, in terms of a family of natural inverse spectral problems for fractal strings of Minkowski dimension D?(0,1), with [Formula: see text], and of the quasi invertibility of the family of spectral operators [Formula: see text] (with [Formula: see text]). PMID- 26124252 TI - The geometric semantics of algebraic quantum mechanics. AB - In this paper, we will present an ongoing project that aims to use model theory as a suitable mathematical setting for studying the formalism of quantum mechanics. We argue that this approach provides a geometric semantics for such a formalism by means of establishing a (non-commutative) duality between certain algebraic and geometric objects. PMID- 26124253 TI - Quantum mechanics, gravity and modified quantization relations. AB - In this paper, we investigate a possible energy scale dependence of the quantization rules and, in particular, from a phenomenological point of view, an energy scale dependence of an effective [Formula: see text] (reduced Planck's constant). We set a bound on the deviation of the value of [Formula: see text] at the muon scale from its usual value using measurements of the anomalous magnetic moment of the muon. Assuming that inflation has taken place, we can conclude that nature is described by a quantum theory at least up to an energy scale of about 10(16) GeV. PMID- 26124254 TI - Quantum theory with bold operator tensors. AB - In this paper, we present a formulation of quantum theory in terms of bold operator tensors. A circuit is built up of operations where an operation corresponds to a use of an apparatus. We associate collections of operator tensors (which together comprise a bold operator) with these apparatus uses. We give rules for combining bold operator tensors such that, for a circuit, they give a probability distribution over the possible outcomes. If we impose certain physicality constraints on the bold operator tensors, then we get exactly the quantum formalism. We provide both symbolic and diagrammatic ways to represent these calculations. This approach is manifestly covariant in that it does not require us to foliate the circuit into time steps and then evolve a state. Thus, the approach forms a natural starting point for an operational approach to quantum field theory. PMID- 26124255 TI - Palatial twistor theory and the twistor googly problem. AB - A key obstruction to the twistor programme has been its so-called 'googly problem', unresolved for nearly 40 years, which asks for a twistor description of right-handed interacting massless fields (positive helicity), using the same twistor conventions that give rise to left-handed fields (negative helicity) in the standard 'nonlinear graviton' and Ward constructions. An explicit proposal for resolving this obstruction--palatial twistor theory--is put forward (illustrated in the case of gravitation). This incorporates the concept of a non commutative holomorphic quantized twistor 'Heisenberg algebra', extending the sheaves of holomorphic functions of conventional twistor theory to include the operators of twistor differentiation. PMID- 26124256 TI - Bell's conspiracy, Schrodinger's black cat and global invariant sets. AB - A locally causal hidden-variable theory of quantum physics need not be constrained by the Bell inequalities if this theory also partially violates the measurement independence condition. However, such violation can appear unphysical, implying implausible conspiratorial correlations between the hidden variables of particles being measured and earlier determinants of instrumental settings. A novel physically plausible explanation for such correlations is proposed, based on the hypothesis that states of physical reality lie precisely on a non-computational measure-zero dynamically invariant set in the state space of the universe: the Cosmological Invariant Set Postulate. To illustrate the relevance of the concept of a global invariant set, a simple analogy is considered where a massive object is propelled into a black hole depending on the decay of a radioactive atom. It is claimed that a locally causal hidden-variable theory constrained by the Cosmological Invariant Set Postulate can violate the Clauser-Horne-Shimony-Holt inequality without being conspiratorial, superdeterministic, fine-tuned or retrocausal, and the theory readily accommodates the classical compatibilist notion of (experimenter) free will. PMID- 26124257 TI - Flash to bang: psychological trauma, veterans and military families: can services cope? PMID- 26124258 TI - Commentary: The use of creatine supplements in the military. PMID- 26124259 TI - The use of creatine supplements in the military. AB - INTRODUCTION: Creatine is considered an effective nutritional ergogenic aid to enhance exercise performance. In spite of the publication of several reviews in the last decade on the topic of exercise performance/sports and creatine there is a need for an update related to the military given the lack of information in this area. The aim of this study was to critically assess original research addressing the use of creatine supplements in the military. METHODS: A search of the electronic databases PubMed and SPORTDiscus, for the following key words: military personnel, trainees, recruit, soldier, physical fitness, physical conditioning, creatine supplementation, creatine ingestion, nutritional supplements to identify surveys and randomised clinical trials from journal articles and technical reports investigating the effect of creatine supplementation on military populations. RESULTS: Thirty-three out of 90 articles examined the use of creatine as a dietary supplement in military personnel. Twenty-one studies were finally selected on the basis of stated inclusion criteria for military surveys and randomised clinical trials. Most of the surveys (15/17) in the military indicate a high popularity of creatine (average 27%) among supplement users. In contrast, in most of the exercise protocols used (6/9) during randomised clinical trials creatine has produced a non-significant performance-enhancing effect. CONCLUSIONS: Creatine is one of the most widely used supplemental compounds in the military. It is not considered a doping infraction or related to any adverse health effects but its long-term usage needs further investigation. Experimental research suggests that creatine supplementation does not enhance physical performance in the military. However, limitations in creatine dosage, military fitness testing and sample group selection might have underestimated the ergogenic properties of creatine. Recent studies also indicate positive effects on various aspects of total force fitness such as cognitive-psychomotor performance, bone health, musculoskeletal damage and neuromuscular function. PMID- 26124260 TI - Design and fabrication of a multipurpose thyroid phantom for medical dosimetry and calibration. AB - A multipurpose anthropomorphic neck phantom was designed and fabricated for use in medical applications. The designed neck phantom is composed of seven elliptic cylindrical slices with a semi-major axis of 14 cm and a semi-minor axis of 12.5 cm, each having the thickness of 2 cm. The thyroid gland, bony part of the neck, and the windpipe were also built inside the neck phantom. For the purpose of medical dosimetry, some holes were drilled inside the phantom to accommodate the thermoluminescence dosemeters with different shapes and dimensions. For testing the quality of images in nuclear medicine, the thyroid gland was built separately to accommodate the radioactive iodine. Finally, the nuclear medicine images were obtained by inserting (131)I in both male and female thyroid parts. PMID- 26124261 TI - HPV-Positive Oropharyngeal Carcinoma: A Systematic Review of Treatment and Prognosis. AB - OBJECTIVE: Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma is increasing in incidence and appears to exhibit improved response to treatment and better survival than that of HPV- head and neck squamous cell carcinoma. The purpose of this systematic review was to examine the current literature regarding treatment and prognosis of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) and identify whether type of treatment (primarily surgery vs primarily radiation) significantly affects survival rates. DATA SOURCES: PubMed and Cochrane Library databases. REVIEW METHODS: A computerized search of the PubMed and Cochrane Library databases was performed to identify English-language articles published between January 1, 2000, and October 21, 2014. Studies were included only if they were prospective or retrospective observational series of OPSCC patients that reported HPV status, treatment regimen, and survival outcomes. Outcomes were determined for HPV+ and HPV- OPSCC patients, with subanalyses according to the type of treatment received. RESULTS: Fifty-six articles were eligible for this review. In the HPV+ analysis, the unadjusted hazard rate ratio (HR) for surgery vs radiation treatment was 1.33 (P = .114). Nine confounders were considered, and HRs were adjusted for each covariate. While HRs were almost all >1 for all covariates, none of the HRs was statistically significant at P < .05. The HR for HPV- OPSCC was higher for radiation than surgery. CONCLUSIONS: HPV+ OPSCC has an improved prognosis and lower rates of adverse events when compared with HPV- OPSCC. HPV- OPSCC had significantly worse outcomes when treated with primary radiation as compared with primary surgery. There was no statistically significant difference in HRs for HPV+ OPSCC with primary radiation vs primary surgery treatment. PMID- 26124262 TI - Change in Quality of Life with Velopharyngeal Insufficiency Surgery. AB - OBJECTIVES: (1) To define the minimal clinically important difference (MCID) of the Velopharyngeal Insufficiency (VPI) Effects on Life Outcomes (VELO) instrument, and (2) to test for the change in quality of life (QOL) after VPI surgery. STUDY DESIGN: Prospective observational cohort. SETTING: VPI clinic at a tertiary pediatric medical center. SUBJECTS AND METHODS: Children with VPI and their parents completed the VELO instrument (higher score is better QOL) at enrollment and then underwent VPI surgery (Furlow palatoplasty or sphincter pharyngoplasty, n = 32), other treatments (obturator or oronasal fistula repair, n = 7), or no treatment (n = 18). They completed the VELO instrument again and an instrument of global rating of change in QOL at 1 year. The MCID was anchored to the global change instrument scores corresponding to "a little" or "somewhat" better. Within-group (paired t test) and between-group (Student t test) changes in VELO scores were tested for the VPI surgery and no treatment groups. The association between treatment group and change in VELO scores was tested with multivariate linear regression, adjusting for confounders. RESULTS: Follow-up was obtained for 37 of 57 (65%) patients. The mean (+/-standard deviation) change in VELO scores corresponding to the MCID anchor was 15 +/- 13. The VELO score improved significantly more in the VPI surgery group (change, 22 +/- 15; P < .001) than in the no treatment group (change, 9 +/- 12; P = .04), after adjusting for confounders (P = .007 between groups). CONCLUSION: VPI surgery using the Furlow palatoplasty or sphincter pharyngoplasty improves VPI-specific QOL, and the improvement is clinically important. PMID- 26124263 TI - Multicenter Evaluation of the Effectiveness of Systemic Propranolol in the Treatment of Airway Hemangiomas. AB - OBJECTIVE: To evaluate the effectiveness of systemic propranolol in airway infantile hemangioma (AIH) treatment. DESIGN: Case series with chart review. PARTICIPANTS: Patients with AIH treated with propranolol between 2009 and 2012 with at least a 1-year follow-up. OUTCOMES: Presenting age, treating institution, syndrome presence, presenting AIH stage, endoscopy status, propranolol initiation location/dose/duration, time to stridor resolution, adjunctive medical and surgical therapy, and treatment-associated complications. RESULTS: Twenty-seven patients met inclusion criteria. Average age of diagnosis was 2.3 months (range, 1-5 months). The AIHs were stage 1 in 7 of 27 (26%), stage 2 in 12 of 27 (44%), and stage 3 in 8 of 27 (30%). Propranolol initiation was inpatient in 25 of 27 (93%) and outpatient in 2 of 27 (7%). Propranolol dose was maintained at 2 mg/kg/d in all patients for a minimum of 7 months (range, 7-34 months; median, 15 months). Stridor was eliminated within 24 hours or less of propranolol initiation in 23 of 27 (85%). At diagnosis, staging and propranolol initiation in 11 of 27 (41%) were managed with propranolol alone; the remaining 16 of 27 (59%) also had a steroid injection. The use of adjuvant therapy at the time of propranolol initiation and the size of the AIH were not statistically correlated. Twelve patients had additional treatments after the initiation of propranolol due to recurrence of respiratory symptoms, 1 of 27 (4%) of whom was considered a nonresponder. No complications related to propranolol use were noted. CONCLUSIONS: This multisite study of AIH treatment with propranolol demonstrates similar effectiveness to surgical treatment modalities. Propranolol therapy for AIH had no complications, had potentially lower resource utilization, and should be considered a first-line AIH treatment. PMID- 26124264 TI - Does Race/Ethnicity or Socioeconomic Status Influence Patient Satisfaction in Pediatric Surgical Care? AB - OBJECTIVE: To evaluate patient satisfaction in outpatient pediatric surgical care and assess differences in scores by race/ethnicity and socioeconomic status (SES). STUDY DESIGN: Observational, cross-sectional analysis. SETTING: Outpatient pediatric surgical specialty clinics at a tertiary academic center. SUBJECT AND METHODS: Families of patients received a patient satisfaction survey following their initial care visit in 2012. Mean scores were calculated and compared by child race/ethnicity and insurance type, where insurance with medical assistance (MA) served as a proxy for low SES. Kruskal-Wallis tests were used to compare scores between groups. Surveys were dichotomized to low and high scorers, and multivariate logistic regression was used to calculate the likelihood of high satisfaction. RESULTS: Of 527 surveys completed, 132 (25%) were for children with MA and 143 (27%) were for racial/ethnic minority children. The overall satisfaction score for all specialties was 84.8, which did not significantly differ by SES (P = .98) or minority status (P = .52). The survey item with the highest score in both SES groups was "degree to which provider talked with you using words you could understand" (overall mean 91.94, P = .23). Multivariate analysis showed that patient age, sex, race/ethnicity, insurance type, neighborhood SES, neighborhood diversity, or surgical department did not significantly influence satisfaction. CONCLUSION: This is the first study to evaluate the relationship between SES and race/ethnicity with patient satisfaction in outpatient pediatric surgical specialty care. In this analysis, no disparities were identified in the patient experience by individual- or community-level factors. Although the survey methodologies may be limited, these findings suggest that provision of care in pediatric surgical specialties can be simultaneously equitable, culturally competent, and family centered. PMID- 26124265 TI - Is Intraoperative Parathyroid Hormone Monitoring Warranted in Cases of 4D CT/Ultrasound Localized Single Adenomas? AB - OBJECTIVE: To analyze the utility of intraoperative parathyroid hormone (IOPTH) monitoring for patients with primary hyperparathyroidism who had evidence of single-gland disease on preoperative imaging with modified 4-dimensional computed tomography that was done in conjunction with ultrasonography (Mod 4D-CT/US). STUDY DESIGN: Case series with chart review. SETTING: Tertiary care university medical center. SUBJECTS AND METHODS: Patients were drawn from consecutive directed parathyroidectomies performed between December 2001 and June 2013 by the senior authors. All patients had primary hyperparathyroidism and underwent a Mod 4D-CT/US study that showed findings on both studies that were consistent with a single adenoma. The modified Miami criteria were used for IOPTH monitoring (parathyroid hormone decrease by >50% and into the normal range). RESULTS: Of 356 patients who underwent parathyroid surgery, 206 had a single gland localized on the Mod 4D-CT and the US studies. IOPTH monitoring was used in 172 cases, of which 169 had adequate clinical follow-up to assess the surgical outcome. Twenty one patients (12.4%) had IOPTH values that did not meet modified Miami criteria after removal of one gland, of which 7 were found to have multigland disease (4.1%). Three patients (1.8%) had persistent primary hyperparathyroidism despite an IOPTH that met modified Miami criteria. CONCLUSIONS: Although IOPTH monitoring correctly identifies a small percentage of patients with multigland disease, some patients will be subjected to unnecessary neck explorations that can result in difficult intraoperative decisions, such as whether to remove normal or equivocal sized glands when they are encountered. PMID- 26124266 TI - Using Polysomnography and Airway Evaluation to Predict Successful Decannulation in Children. AB - OBJECTIVE: Decannulation readiness is approached in several ways and is tailored to the individual patient. While microlaryngoscopy and bronchoscopy evaluate airway patency at all levels, polysomnography assesses sleep-related upper airway physiology. There are limited data in the literature on the utility of these tools. Thus, the main objectives of this study were (1) to identify sleep and respiratory parameters associated with successful decannulation and (2) to determine the agreement between microlaryngoscopy and bronchoscopy and polysomnography. STUDY DESIGN: Case series with chart review. SETTING: Quaternary care pediatric hospital. SUBJECTS AND METHODS: A retrospective review of medical records, microlaryngoscopy and bronchoscopy, and polysomnographs was performed on subjects preparing for decannulation from 2005 to 2010. Fifty-nine subjects who underwent overnight polysomnography with a tracheostomy capping trial and microlaryngoscopy and bronchoscopy were included. Prediction of successful decannulation from polysomnography parameters was determined using logistic regression analysis. RESULTS: Fifty-nine subjects with a total of 78 polysomnographs were subdivided into 2 groups: 42 polysomnographs were classified as successfully decannulated, and 36 polysomnographs belonged to the group that did not decannulate. Logistic regression analysis determined that the Apnea Hypopnea Index (P = .0423) and maximal end-tidal CO2 (P = .046) were significant predictors for successful decannulation. CONCLUSION: Airway evaluation by microlaryngoscopy and bronchoscopy is an essential tool in the assessment of decannulation readiness. Polysomnography is an important additional tool for children with complex airway problems. Our results indicate that certain polysomnographic parameters such as Apnea Hypopnea Index and maximal end-tidal CO2 are valuable in predicting successful tracheostomy decannulation. PMID- 26124267 TI - Expression of Apoptotic vs Antiapoptotic Proteins in Middle Ear Cholesteatoma. AB - OBJECTIVES: To explore the role of antiapoptotic and apoptotic processes in the development of cholesteatoma by investigating the expression of an antiapoptotic (c-FLIP) and apoptotic (p53) protein relative to the expression of a proliferation marker (Ki-67). STUDY DESIGN: Basic science study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: An immunohistochemical investigation was performed on 35 cholesteatoma specimens (21 acquired, 14 congenital) and 10 normal retroauricular skins to evaluate the expression of c FLIP, p53, and Ki-67. The expression rate of each marker was measured to assess the difference between retroauricular skin and cholesteatoma, as well as between congenital and acquired cholesteatoma. RESULTS: c-FLIP expression was significantly higher in the cholesteatoma specimens than in retroauricular skin (P < .05), while the expression of p53 did not significantly differ between the two. Ki-67 expression in cholesteatoma was significantly higher than in retroauricular skin (P < .001). The c-FLIP expression rate was positively correlated with that of Ki-67 (r = 0.47, P = .001), and there was no significant correlation between the expression level of p53 and that of Ki-67 (r = 0.152, P = .319). In addition, no differences in c-FLIP, p53, and Ki-67 expression rates were evident between congenital and acquired cholesteatoma. CONCLUSIONS: The upregulation of c-FLIP together with unchanged p53 suggests an altered equilibrium between apoptosis and antiapoptosis, favoring antiapoptosis, and may play a role in the pathogenesis of cholesteatoma. PMID- 26124268 TI - Laryngeal Verrucous Carcinoma: A Population-Based Analysis. AB - OBJECTIVE: Verrucous carcinoma of the larynx (VCL) is a rare entity with reportedly favorable prognosis. Current analyses are limited primarily to case reports and case series, thus making a population-based analysis useful in characterizing frequency, incidence, and survival trends to guide clinical diagnosis and decision making. STUDY DESIGN: Analysis of the National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) database. METHODS: Cases of VCL diagnosed between 1973 and 2011 were searched in the SEER database. Analysis was carried out with respect to patient demographics, tumor characteristics, incidence, treatment modality, and survival. RESULTS: In sum, 516 patients with VCL were identified. Males composed 88.4% of cases. Whites accounted for 88.4% of cases, with 8.1% of cases occurring in black patients. Most cases (79.7%) arose in the glottis, a statistically significant predilection when compared with other laryngeal malignancies (P < .0001). Incidence of VCL decreased from 2000 to 2011, with an annual percent change of -5.4%. Overall 1-, 5-, and 10-year disease-specific survival for VCL was 97.5%, 88.0%, and 77.4%, while 1-, 5-, and 10-year relative survival was 98.1%, 85.5%, and 74.2%, respectively. Surgery seemed to confer better prognosis when compared with other treatment modalities. CONCLUSIONS: This large population-based analysis of VCL demonstrates that this entity has a good prognosis, arises in the glottis, and is decreasing in incidence. Five-year survival seems highest when surgery is utilized. However, this finding may be subject to selection bias in high-stage lesions. PMID- 26124269 TI - Evidence-Based Medicine in Otolaryngology, Part 5: Patient Decision Aids. AB - Modern medical decision making is a complex task requiring collaboration between patients and physicians. Related clinical evidence may delineate a clearly favorable path, but in other instances, uncertainty remains. Even in these circumstances, however, there are techniques that optimize decision making by blending existing evidence with individual patient values in the context of physician counseling. This installment of "Evidence-Based Medicine in Otolaryngology" focuses on the crucial issue of how practitioners may approach clinical situations where the data do not delineate a single irrefutable path. We describe decision aids-tools that can educate patients about data related to complex clinical decisions. We review their definition, quality standards, patient interface, benefits, and limitations. We also discuss the related concept of option grids and the role of decision aids in evidence-based practice. PMID- 26124270 TI - Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice. AB - Mucin-type core 1-derived O-glycans, one of the major types of O-glycans, are highly expressed in mammary gland epithelium. Abnormal O-glycans such as Tn antigen are found in over 90% of breast cancers; however, the in vivo role of these aberrant O-glycans in the etiology of breast cancer is unclear. We generated mice with mammary epithelial specific deletion of core 1-derived O glycans. By crossing with two spontaneous mouse breast cancer models, we determined that loss of core 1-derived O-glycans delays the onset and progression of breast cancer development. Deficiency of core 1 O-glycosylation impaired the localization of Muc1, a major O-glycoprotein, on the apical surfaces of mammary epithelium. Signaling mediated by Muc1, which is critical for breast cancer development, was also defective in the absence of core 1 O-glycans. This study reveals an unexpected role of core 1-derived O-glycans in breast cancer development in mice. PMID- 26124271 TI - PHD3 Stabilizes the Tight Junction Protein Occludin and Protects Intestinal Epithelial Barrier Function. AB - Prolyl hydroxylase domain proteins (PHDs) control cellular adaptation to hypoxia. PHDs are found involved in inflammatory bowel disease (IBD); however, the exact role of PHD3, a member of the PHD family, in IBD remains unknown. We show here that PHD3 plays a critical role in maintaining intestinal epithelial barrier function. We found that genetic ablation of Phd3 in intestinal epithelial cells led to spontaneous colitis in mice. Deletion of PHD3 decreases the level of tight junction protein occludin, leading to a failure of intestinal epithelial barrier function. Further studies indicate that PHD3 stabilizes occludin by preventing the interaction between the E3 ligase Itch and occludin, in a hydroxylase independent manner. Examination of biopsy of human ulcerative colitis patients indicates that PHD3 is decreased with disease severity, indicating that PHD3 down regulation is associated with progression of this disease. We show that PHD3 protects intestinal epithelial barrier function and reveal a hydroxylase independent function of PHD3 in stabilizing occludin. These findings may help open avenues for developing a therapeutic strategy for IBD. PMID- 26124272 TI - Quantitative Characterization of E-selectin Interaction with Native CD44 and P selectin Glycoprotein Ligand-1 (PSGL-1) Using a Real Time Immunoprecipitation based Binding Assay. AB - Selectins (E-, P-, and L-selectins) interact with glycoprotein ligands to mediate the essential tethering/rolling step in cell transport and delivery that captures migrating cells from the circulating flow. In this work, we developed a real time immunoprecipitation assay on a surface plasmon resonance chip that captures native glycoforms of two well known E-selectin ligands (CD44/hematopoietic cell E /L-selectin ligand and P-selectin glycoprotein ligand-1) from hematopoietic cell extracts. Here we present a comprehensive characterization of their binding to E selectin. We show that both ligands bind recombinant monomeric E-selectin transiently with fast on- and fast off-rates, whereas they bind dimeric E selectin with remarkably slow on- and off-rates. This binding requires the sialyl Lewis x sugar moiety to be placed on both O- and N-glycans, and its association, but not dissociation, is sensitive to the salt concentration. Our results suggest a mechanism through which monomeric selectins mediate initial fast on and fast off kinetics to help capture cells out of the circulating shear flow; subsequently, tight binding by dimeric/oligomeric selectins is enabled to significantly slow rolling. PMID- 26124273 TI - Assembly and turnover of short actin filaments by the formin INF2 and profilin. AB - INF2 (inverted formin 2) is a formin protein with unique biochemical effects on actin. In addition to the common formin ability to accelerate actin nucleation and elongation, INF2 can also sever filaments and accelerate their depolymerization. Although we understand key attributes of INF2-mediated severing, we do not understand the mechanism by which INF2 accelerates depolymerization subsequent to severing. Here, we show that INF2 can create short filaments (<60 nm) that continuously turn over actin subunits through a combination of barbed end elongation, severing, and WH2 motif-mediated depolymerization. This pseudo-steady state condition occurs whether starting from actin filaments or monomers. The rate-limiting step of the cycle is nucleotide exchange of ADP for ATP on actin monomers after release from the INF2/actin complex. Profilin addition has two effects: 1) to accelerate filament turnover 6 fold by accelerating nucleotide exchange and 2) to shift the equilibrium toward polymerization, resulting in longer filaments. In sum, our findings show that the combination of multiple interactions of INF2 with actin can work in concert to increase the ATP turnover rate of actin. Depending on the ratio of INF2:actin, this increased flux can result in rapid filament depolymerization or maintenance of short filaments. We also show that high concentrations of cytochalasin D accelerate ATP turnover by actin but through a different mechanism from that of INF2. PMID- 26124274 TI - cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice. AB - Photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. We have shown endoplasmic reticulum (ER) stress-associated apoptotic cone death and increased phosphorylation of the ER Ca(2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in CNG channel-deficient mice. We also presented a remarkable elevation of cGMP and an increased activity of the cGMP-dependent protein kinase (protein kinase G, PKG) in CNG channel deficiency. This work investigated whether cGMP/PKG signaling regulates ER stress and IP3R1 phosphorylation in CNG channel-deficient cones. Treatment with PKG inhibitor and deletion of guanylate cyclase-1 (GC1), the enzyme producing cGMP in cones, were used to suppress cGMP/PKG signaling in cone-dominant Cnga3(-/-)/Nrl(-/-) mice. We found that treatment with PKG inhibitor or deletion of GC1 effectively reduced apoptotic cone death, increased expression levels of cone proteins, and decreased activation of Muller glial cells. Furthermore, we observed significantly increased phosphorylation of IP3R1 and reduced ER stress. Our findings demonstrate a role of cGMP/PKG signaling in ER stress and ER Ca(2+) channel regulation and provide insights into the mechanism of cone degeneration in CNG channel deficiency. PMID- 26124275 TI - Evidence That Bacteriophage lambda Kil Peptide Inhibits Bacterial Cell Division by Disrupting FtsZ Protofilaments and Sequestering Protein Subunits. AB - The effects of Kil peptide from bacteriophage lambda on the assembly of Escherichia coli FtsZ into one subunit thick protofilaments were studied using combined biophysical and biochemical methods. Kil peptide has recently been identified as the factor from bacteriophage lambda responsible for the inhibition of bacterial cell division during lytic cycle, targeting FtsZ polymerization. Here, we show that this antagonist blocks FtsZ assembly into GTP-dependent protofilaments, producing a wide distribution of smaller oligomers compared with the average size of the intact protofilaments. The shortening of FtsZ protofilaments by Kil is detectable at concentrations of the peptide in the low micromolar range, the mid-point of the inhibition being close to its apparent affinity for GDP-bound FtsZ. This antagonist not only interferes with FtsZ assembly but also reverses the polymerization reaction. The negative regulation by Kil significantly reduces the GTPase activity of FtsZ protofilaments, and FtsZ polymers assembled in guanosine-5'-[(alpha,beta)-methyleno]triphosphate are considerably less sensitive to Kil. Our results suggest that, at high concentrations, Kil may use an inhibition mechanism involving the sequestration of FtsZ subunits, similar to that described for other inhibitors like the SOS response protein SulA or the moonlighting enzyme OpgH. This mechanism is different from those employed by the division site selection antagonists MinC and SlmA. This work provides new insight into the inhibition of FtsZ assembly by phages, considered potential tools against bacterial infection. PMID- 26124276 TI - An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death. AB - Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as "apoptosis-necrosis continuum." To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like cell death. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death. PMID- 26124277 TI - Physiological Consequences of Compartmentalized Acyl-CoA Metabolism. AB - Meeting the complex physiological demands of mammalian life requires strict control of the metabolism of long-chain fatty acyl-CoAs because of the multiplicity of their cellular functions. Acyl-CoAs are substrates for energy production; stored within lipid droplets as triacylglycerol, cholesterol esters, and retinol esters; esterified to form membrane phospholipids; or used to activate transcriptional and signaling pathways. Indirect evidence suggests that acyl-CoAs do not wander freely within cells, but instead, are channeled into specific pathways. In this review, we will discuss the evidence for acyl-CoA compartmentalization, highlight the key modes of acyl-CoA regulation, and diagram potential mechanisms for controlling acyl-CoA partitioning. PMID- 26124278 TI - Independent Effects of gamma-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis. AB - Breakdown of the major sleep-promoting neurotransmitter, gamma-aminobutyric acid (GABA), in the GABA shunt generates catabolites that may enter the tricarboxylic acid cycle, but it is unknown whether catabolic by-products of the GABA shunt actually support metabolic homeostasis. In Drosophila, the loss of the specific enzyme that degrades GABA, GABA transaminase (GABAT), increases sleep, and we show here that it also affects metabolism such that flies lacking GABAT fail to survive on carbohydrate media. Expression of GABAT in neurons or glia rescues this phenotype, indicating a general metabolic function for this enzyme in the brain. As GABA degradation produces two catabolic products, glutamate and succinic semialdehyde, we sought to determine which was responsible for the metabolic phenotype. Through genetic and pharmacological experiments, we determined that glutamate, rather than succinic semialdehyde, accounts for the metabolic phenotype of gabat mutants. This is supported by biochemical measurements of catabolites in wild-type and mutant animals. Using in vitro labeling assays, we found that inhibition of GABAT affects energetic pathways. Interestingly, we also observed that gaba mutants display a general disruption in bioenergetics as measured by altered levels of tricarboxylic acid cycle intermediates, NAD(+)/NADH, and ATP levels. Finally, we report that the effects of GABAT on sleep do not depend upon glutamate, indicating that GABAT regulates metabolic and sleep homeostasis through independent mechanisms. These data indicate a role of the GABA shunt in the development of metabolic risk and suggest that neurological disorders caused by altered glutamate or GABA may be associated with metabolic disruption. PMID- 26124279 TI - 129-Derived Mouse Strains Express an Unstable but Catalytically Active DNA Polymerase Iota Variant. AB - Mice derived from the 129 strain have a nonsense codon mutation in exon 2 of the polymerase iota (Poliota) gene and are therefore considered Poliota deficient. When we amplified Poliota mRNA from 129/SvJ or 129/Ola testes, only a small fraction of the full-length cDNA contained the nonsense mutation; the major fraction corresponded to a variant Poliota isoform lacking exon 2. Poliota mRNA lacking exon 2 contains an open reading frame, and the corresponding protein was detected using a polyclonal antibody raised against the C terminus of the murine Poliota protein. The identity of the corresponding protein was further confirmed by mass spectrometry. Although the variant protein was expressed at only 5 to 10% of the level of wild-type Poliota, it retained de novo DNA synthesis activity, the capacity to form replication foci following UV irradiation, and the ability to rescue UV light sensitivity in Poliota(-/-) embryonic fibroblasts derived from a new, fully deficient Poliota knockout (KO) mouse line. Furthermore, in vivo treatment of 129-derived male mice with Velcade, a drug that inhibits proteasome function, stabilized and restored a substantial amount of the variant Poliota in these animals, indicating that its turnover is controlled by the proteasome. An analysis of two xeroderma pigmentosum-variant (XPV) cases corresponding to missense mutants of Poleta, a related translesion synthesis (TLS) polymerase in the same family, similarly showed a destabilization of the catalytically active mutant protein by the proteasome. Collectively, these data challenge the prevailing hypothesis that 129-derived strains of mice are completely deficient in Poliota activity. The data also document, both for 129-derived mouse strains and for some XPV patients, new cases of genetic defects corresponding to the destabilization of an otherwise functional protein, the phenotype of which is reversible by proteasome inhibition. PMID- 26124280 TI - Analysis of the Role of the C-Terminal Tail in the Regulation of the Epidermal Growth Factor Receptor. AB - The ~230-residue C-terminal tail of the epidermal growth factor receptor (EGFR) is phosphorylated upon activation. We examined whether this phosphorylation is affected by deletions within the tail and whether the two tails in the asymmetric active EGFR dimer are phosphorylated differently. We monitored autophosphorylation in cells using flow cytometry and found that the first ~80 residues of the tail are inhibitory, as demonstrated previously. The entire ~80 residue span is important for autoinhibition and needs to be released from both kinases that form the dimer. These results are interpreted in terms of crystal structures of the inactive kinase domain, including two new ones presented here. Deletions in the remaining portion of the tail do not affect autophosphorylation, except for a six-residue segment spanning Tyr 1086 that is critical for activation loop phosphorylation. Phosphorylation of the two tails in the dimer is asymmetric, with the activator tail being phosphorylated somewhat more strongly. Unexpectedly, we found that reconstitution of the transmembrane and cytoplasmic domains of EGFR in vesicles leads to a peculiar phenomenon in which kinase domains appear to be trapped between stacks of lipid bilayers. This artifactual trapping of kinases between membranes enhances an intrinsic functional asymmetry in the two tails in a dimer. PMID- 26124281 TI - SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing. AB - Myelodysplastic syndromes (MDS) are a group of neoplasms characterized by ineffective myeloid hematopoiesis and various risks for leukemia. SRSF2, a member of the serine/arginine-rich (SR) family of splicing factors, is one of the mutation targets associated with poor survival in patients suffering from myelodysplastic syndromes. Here we report the biological function of SRSF2 in hematopoiesis by using conditional knockout mouse models. Ablation of SRSF2 in the hematopoietic lineage caused embryonic lethality, and Srsf2-deficient fetal liver cells showed significantly enhanced apoptosis and decreased levels of hematopoietic stem/progenitor cells. Induced ablation of SRSF2 in adult Mx1-Cre Srsf2(flox/flox) mice upon poly(I):poly(C) injection demonstrated a significant decrease in lineage(-) Sca(+) c-Kit(+) cells in bone marrow. To reveal the functional impact of myelodysplastic syndromes-associated mutations in SRSF2, we analyzed splicing responses on the MSD-L cell line and found that the missense mutation of proline 95 to histidine (P95H) and a P95-to-R102 in-frame 8-amino acid deletion caused significant changes in alternative splicing. The affected genes were enriched in cancer development and apoptosis. These findings suggest that intact SRSF2 is essential for the functional integrity of the hematopoietic system and that its mutations likely contribute to development of myelodysplastic syndromes. PMID- 26124282 TI - Phosphatidic Acid Increases Epidermal Growth Factor Receptor Expression by Stabilizing mRNA Decay and by Inhibiting Lysosomal and Proteasomal Degradation of the Internalized Receptor. AB - Overexpression of epidermal growth factor receptor (EGFR) is one of the frequent mechanisms implicated in cancer progression, and so is the overexpression of the enzyme phospholipase D (PLD) and its reaction product, phosphatidic acid (PA). However, an understanding of how these signaling molecules interact at the level of gene expression is lacking. Catalytically active PLD enhanced expression of EGFR in human breast cancer cells. Overexpression of the PLD2 isoform increased EGFR mRNA and protein expression. It also negated an EGFR downregulation mediated by small interfering RNA targeting EGFR (siEGFR). Several mechanisms contributed to the alteration in EGFR expression. First was the stabilization of EGFR transcripts as PLD2 delayed mRNA decay, which prolonged their half-lives. Second, RNase enzymatic activity was inhibited by PA. Third, protein stabilization also occurred, as indicated by PLD resistance to cycloheximide-induced EGFR protein degradation. Fourth, PA inhibited lysosomal and proteasomal degradation of internalized EGFR. PLD2 and EGFR colocalized at the cell membrane, and JAK3 phosphorylation at Tyr980/Tyr981 followed receptor endocytosis. Further, the presence of PLD2 increased stabilization of intracellular EGFR in large recycling vesicles at ~15 min of EGF stimulation. Thus, PLD2-mediated production of PA contributed to the control of EGFR exposure to ligand through a multipronged transcriptional and posttranscriptional program during the out-of-control accumulation of EGFR signaling in cancer cells. PMID- 26124283 TI - MicroRNA 665 Regulates Dentinogenesis through MicroRNA-Mediated Silencing and Epigenetic Mechanisms. AB - Studies of proteins involved in microRNA (miRNA) processing, maturation, and silencing have indicated the importance of miRNAs in skeletogenesis, but the specific miRNAs involved in this process are incompletely defined. Here, we identified miRNA 665 (miR-665) as a potential repressor of odontoblast maturation. Studies with cultured cell lines and primary embryonic cells showed that miR-665 represses the expression of early and late odontoblast marker genes and stage-specific proteases involved in dentin maturation. Notably, miR-665 directly targeted Dlx3 mRNA and decreased Dlx3 expression. Furthermore, RNA induced silencing complex (RISC) immunoprecipitation and biotin-labeled miR-665 pulldown studies identified Kat6a as another potential target of miR-665. KAT6A interacted physically and functionally with RUNX2, activating tissue-specific promoter activity and prompting odontoblast differentiation. Overexpression of miR-665 reduced the recruitment of KAT6A to Dspp and Dmp1 promoters and prevented KAT6A-induced chromatin remodeling, repressing gene transcription. Taken together, our results provide novel molecular evidence that miR-665 functions in an miRNA-epigenetic regulatory network to control dentinogenesis. PMID- 26124284 TI - Concentration and Localization of Coexpressed ELAV/Hu Proteins Control Specificity of mRNA Processing. AB - Neuronally coexpressed ELAV/Hu proteins comprise a family of highly related RNA binding proteins which bind to very similar cognate sequences. How this redundancy is linked to in vivo function and how gene-specific regulation is achieved have not been clear. Analysis of mutants in Drosophila ELAV/Hu family proteins ELAV, FNE, and RBP9 and of genetic interactions among them indicates that they have mostly independent roles in neuronal development and function but have converging roles in the regulation of synaptic plasticity. Conversely, ELAV, FNE, RBP9, and human HuR bind ELAV target RNA in vitro with similar affinities. Likewise, all can regulate alternative splicing of ELAV target genes in nonneuronal wing disc cells and substitute for ELAV in eye development upon artificially increased expression; they can also substantially restore ELAV's biological functions when expressed under the control of the elav gene. Furthermore, ELAV-related Sex-lethal can regulate ELAV targets, and ELAV/Hu proteins can interfere with sexual differentiation. An ancient relationship to Sex-lethal is revealed by gonadal expression of RBP9, providing a maternal fail safe for dosage compensation. Our results indicate that highly related ELAV/Hu RNA binding proteins select targets for mRNA processing through alteration of their expression levels and subcellular localization but only minimally by altered RNA binding specificity. PMID- 26124286 TI - Commentary on 'Treatment-resistant major depressive disorder and assisted dying'. PMID- 26124285 TI - Quantitative Proteomics Reveals the Roles of Peroxisome-associated Proteins in Antiviral Innate Immune Responses. AB - Compared with whole-cell proteomic analysis, subcellular proteomic analysis is advantageous not only for the increased coverage of low abundance proteins but also for generating organelle-specific data containing information regarding dynamic protein movement. In the present study, peroxisome-enriched fractions from Sendai virus (SeV)-infected or uninfected HepG2 cells were obtained and subjected to quantitative proteomics analysis. We identified 311 proteins that were significantly changed by SeV infection. Among these altered proteins, 25 are immune response-related proteins. Further bioinformatic analysis indicated that SeV infection inhibits cell cycle-related proteins and membrane attack complex related proteins, all of which are beneficial for the survival and replication of SeV within host cells. Using Luciferase reporter assays on several innate immune related reporters, we performed functional analysis on 11 candidate proteins. We identified LGALS3BP and CALU as potential negative regulators of the virus induced activation of the type I interferons. PMID- 26124287 TI - Hypoactive sexual desire disorder: inventing a disease to sell low libido. AB - Condition branding is a marketing technique in which companies develop conditions concurrently with developing drugs; examples include gastro-oesophageal reflux disease, premenstrual dysphoric disorder, social anxiety disorder, erectile dysfunction and hypoactive sexual desire disorder. Although it is illegal for pharmaceutical companies to market drugs prior to regulatory approval, there are no restrictions on marketing diseases, and industry seeks to establish a disease state in the minds of clinicians years before an expected drug launch. Continuing medical education (CME) courses are an important part of promotion prior to drug approval and have become a key marketing tool for increasing clinician receptivity to new products. We systematically identified 14 free, internet based, industry-funded, accredited CME modules on hypoactive sexual desire disorder in women which came out before a new drug, flibanserin, was being considered for regulatory approval in the USA. Common themes in these modules included the following: (1) Hypoactive sexual desire disorder is common, underdiagnosed and can have a profound effect on quality of life. (2) Women may not be aware that they are sick or distressed. (3) Simple questionnaires can assist clinicians in diagnosing the disorder. (4) It is problematic that there are medicines available to treat sexual problems for men but not women. In fact, there is no scientifically established norm for sexual activity, feelings or desire, and there is no evidence that hypoactive sexual desire disorder is a medical condition. Hypoactive sexual desire disorder is a typical example of a condition that was sponsored by industry to prepare the market for a specific treatment. PMID- 26124288 TI - VAMP8-dependent fusion of recycling endosomes with the plasma membrane facilitates T lymphocyte cytotoxicity. AB - Cytotoxic T lymphocytes (CTLs) eliminate infected and neoplastic cells through directed release of cytotoxic granule contents. Although multiple SNARE proteins have been implicated in cytotoxic granule exocytosis, the role of vesicular SNARE proteins, i.e., vesicle-associated membrane proteins (VAMPs), remains enigmatic. VAMP8 was posited to represent the cytotoxic granule vesicular SNARE protein mediating exocytosis in mice. In primary human CTLs, however, VAMP8 colocalized with Rab11a-positive recycling endosomes. Upon stimulation, these endosomes rapidly trafficked to and fused with the plasma membrane, preceding fusion of cytotoxic granules. Knockdown of VAMP8 blocked both recycling endosome and cytotoxic granule fusion at immune synapses, without affecting activating signaling. Mechanistically, VAMP8-dependent recycling endosomes deposited syntaxin-11 at immune synapses, facilitating assembly of plasma membrane SNARE complexes for cytotoxic granule fusion. Hence, cytotoxic granule exocytosis is a sequential, multivesicle fusion process requiring VAMP8-mediated recycling endosome fusion before cytotoxic granule fusion. Our findings imply that secretory granule exocytosis pathways in other cell types may also be more complex than previously appreciated. PMID- 26124289 TI - CENP-C is a blueprint for constitutive centromere-associated network assembly within human kinetochores. AB - Kinetochores are multisubunit complexes that assemble on centromeres to bind spindle microtubules and promote faithful chromosome segregation during cell division. A 16-subunit complex named the constitutive centromere-associated network (CCAN) creates the centromere-kinetochore interface. CENP-C, a CCAN subunit, is crucial for kinetochore assembly because it links centromeres with the microtubule-binding interface of kinetochores. The role of CENP-C in CCAN organization, on the other hand, had been incompletely understood. In this paper, we combined biochemical reconstitution and cellular investigations to unveil how CENP-C promotes kinetochore targeting of other CCAN subunits. The so-called PEST domain in the N-terminal half of CENP-C interacted directly with the four-subunit CCAN subcomplex CENP-HIKM. We identified crucial determinants of this interaction whose mutation prevented kinetochore localization of CENP-HIKM and of CENP-TW, another CCAN subcomplex. When considered together with previous observations, our data point to CENP-C as a blueprint for kinetochore assembly. PMID- 26124290 TI - The ciliary transition zone functions in cell adhesion but is dispensable for axoneme assembly in C. elegans. AB - Cilia are cellular projections that perform sensory and motile functions. A key ciliary subdomain is the transition zone, which lies between basal body and axoneme. Previous work in Caenorhabditis elegans identified two ciliopathy associated protein complexes or modules that direct assembly of transition zone Y links. Here, we identify C. elegans CEP290 as a component of a third module required to form an inner scaffolding structure called the central cylinder. Co inhibition of all three modules completely disrupted transition zone structure. Surprisingly, axoneme assembly was only mildly perturbed. However, dendrite extension by retrograde migration was strongly impaired, revealing an unexpected role for the transition zone in cell adhesion. PMID- 26124291 TI - A stable microtubule array drives fission yeast polarity reestablishment upon quiescence exit. AB - Cells perpetually face the decision to proliferate or to stay quiescent. Here we show that upon quiescence establishment, Schizosaccharomyces pombe cells drastically rearrange both their actin and microtubule (MT) cytoskeletons and lose their polarity. Indeed, while polarity markers are lost from cell extremities, actin patches and cables are reorganized into actin bodies, which are stable actin filament-containing structures. Astonishingly, MTs are also stabilized and rearranged into a novel antiparallel bundle associated with the spindle pole body, named Q-MT bundle. We have identified proteins involved in this process and propose a molecular model for Q-MT bundle formation. Finally and importantly, we reveal that Q-MT bundle elongation is involved in polarity reestablishment upon quiescence exit and thereby the efficient return to the proliferative state. Our work demonstrates that quiescent S. pombe cells assemble specific cytoskeleton structures that improve the swiftness of the transition back to proliferation. PMID- 26124293 TI - A Few Thoughts about ACO Antitrust Issues from a Local Enforcement Perspective. AB - Accountable care organizations (ACOs), joint ventures of commercial insurers and various groups of medical providers such as physicians, specialists, and hospitals whose development in California has been quickened by the Affordable Care Act, carry with them both promise and pitfalls. On the positive side of the ledger, ACOs may improve the quality of medical care even as they lower the costs of that care. On the negative side of the ledger, ACOs may lead to a gain in market power for their participations, allowing those participants to increase the prices they charge to commercial insurers. It is thus a key question for antitrust enforcers to figure out how to separate the sheep from the goats. This article, representing our personal views as state antitrust enforcers in the California attorney general's office, offers our reflection on a number of ACO articles and studies in this special issue through the prism of this key question and sets out a number of additional issues that we believe warrant study in conjunction with ACOs. PMID- 26124294 TI - Review of Medicare, Medicaid, and Commercial Quality of Care Measures: Considerations for Assessing Accountable Care Organizations. AB - Accountable care organizations (ACOs) have proliferated under the Affordable Care Act (ACA). If ACOs are to improve health care quality and lower costs, quality measures will be increasingly important in determining if provider consolidations associated with the development of ACOs are achieving their intended purpose. This article assesses quality measurement across public and private sectors. We reviewed available quality measures for a subset of programs in six organizations and assessed the number and domain of measures (structure, process, outcomes, and patient experience). Two-thirds of all quality measures were categorized as process measures. Outcome measures made up nearly 20 percent of measures. Patient experience and structure measures made up approximately 8 percent and 7 percent, respectively. We propose further improvements to quality measurement initiatives. For example, programs that reward providers should consider reward size and distribution within the organization. Quality improvement initiatives should consider what encourages provider buy-in and participation and the effects on populations with disproportionate health care needs. As the focus of quality initiatives may change from year to year, measures should be periodically revisited to ensure continued improvement and sustainability. Finally, we suggest quality measures that regulators could use prior to ACO formation or in the year or two following formation. PMID- 26124296 TI - Antitrust and Provider Collaborations: Where We've Been and What Should Be Done Now. AB - Antitrust enforcement has a crucial role to play in consolidated health care markets as providers undertake mergers, acquisitions, and other types of collaborations to integrate care and achieve greater size and scale. But antitrust enforcers and policy makers need to refine their approach in two fundamental ways. First, in addition to focusing on whether particular transactions or conduct will increase prices above competitive levels, a more pressing concern should be on assuring that health care markets are conducive to fundamental changes in how care is reimbursed and delivered - that is, the impact on payment and health care delivery innovation. Second, it is important to recognize the practical limits that apply to antitrust enforcement, both in terms of existing law and precedent and the constrained resources available to government enforcers. Government resources can be leveraged substantially through greater collaboration among federal and state antitrust enforcers, government payers, health care regulators, and economists and other policy makers. This can result in not only better-targeted antitrust enforcement actions but also payment and regulatory initiatives that can produce better-functioning and more competitive health care markets. PMID- 26124292 TI - Mio depletion links mTOR regulation to Aurora A and Plk1 activation at mitotic centrosomes. AB - Coordination of cell growth and proliferation in response to nutrient supply is mediated by mammalian target of rapamycin (mTOR) signaling. In this study, we report that Mio, a highly conserved member of the SEACAT/GATOR2 complex necessary for the activation of mTORC1 kinase, plays a critical role in mitotic spindle formation and subsequent chromosome segregation by regulating the proper concentration of active key mitotic kinases Plk1 and Aurora A at centrosomes and spindle poles. Mio-depleted cells showed reduced activation of Plk1 and Aurora A kinase at spindle poles and an impaired localization of MCAK and HURP, two key regulators of mitotic spindle formation and known substrates of Aurora A kinase, resulting in spindle assembly and cytokinesis defects. Our results indicate that a major function of Mio in mitosis is to regulate the activation/deactivation of Plk1 and Aurora A, possibly by linking them to mTOR signaling in a pathway to promote faithful mitotic progression. PMID- 26124295 TI - Accountable Care Organizations: The National Landscape. AB - There are now more than seven hundred accountable care organizations (ACOs) in the United States. This article describes some of their most salient characteristics including the number and types of contracts involved, organizational structures, the scope of services offered, care management capabilities, and the development of a three-category taxonomy that can be used to target technical assistance efforts and to examine performance. The current evidence on the performance of ACOs is reviewed. Since California has the largest number of ACOs (N=67) and a history of providing care under risk-bearing contracts, some additional assessments of quality and patient experience are made between California ACOs and non-ACO provider organizations. Six key issues likely to affect future ACO growth and development are discussed, and some potential "diagnostic" indicators for assessing the likelihood of potential antitrust violations are presented. PMID- 26124297 TI - The Economics of Provider Payment Reform: Are Accountable Care Organizations the Answer? AB - A remarkable consensus has developed that the fee-for-service (FFS) approach for paying medical providers must be replaced. This payment approach is said to increase the volume of services without improving care coordination. In response to these calls, Medicare and private payers are experimenting with payment systems that combine the basic element of FFS - a fee for each service - with arrangements that allow providers to share the savings if they hold total spending per patient below a targeted amount. Medicare's accountable care organizations (ACOs) embody the shared savings approach to payment reform. Private payers have introduced total cost of care contracting (TCOC) in several locations. This article questions the consensus that FFS must go. If the fees are too high, then someone needs to "bite the bullet" and reduce fees in key areas. Hoping to control overspending by investment in ACOs is wishful thinking. I describe the theory and practice of shared savings payment systems and summarize recent TCOC contracting initiatives in the private sector. Medicare's shared savings approach is likely to be less effective than private contracts. Cutting providers' fees would be more efficient. Finally, the new payment models in the Affordable Care Act will not ease the problem of high prices for private payers. PMID- 26124298 TI - Commentary - Patients' Rights Matter in Regulating Accountable Care Organizations. PMID- 26124299 TI - Commentary - Accountable Care Organizations and Narrow Network Insurance Plans. PMID- 26124300 TI - The Affordable Care Act versus Medicare for All. AB - Many problems facing the Affordable Care Act would disappear if the nation were instead implementing Medicare for All - the extension of Medicare to every age group. Every American would be automatically covered for life. Premiums would be replaced with a set of Medicare taxes. There would be no patient cost sharing. Individuals would have free choice of doctors. Medicare's single-payer bargaining power would slow price increases and reduce medical cost as a percentage of gross domestic product (GDP). Taxes as a percentage of GDP would rise from below average to average for economically advanced nations. Medicare for All would be phased in by age. PMID- 26124301 TI - Accountable Care Organizations in California: Market Forces at Work? AB - Accountable care organizations (ACOs), one of the most recent and promising health care delivery innovations, encourage care coordination among providers. While ACOs hold promise for decreasing costs by reducing unnecessary procedures, improving resource use as a result of economies of scale and scope, ACOs also raise concerns about provider market power. This study examines the market-level competition factors that are associated with ACO participation and the number of ACOs. Using data from California, we find that higher levels of preexisting managed care leads to higher ACO entry and enrollment growth, while hospital concentration leads to fewer ACOs and lower enrollment. We find interesting results for physician market power - markets with concentrated physician markets have a smaller share of individuals in commercial ACOs but a larger number of commercial ACO organizations. This finding implies smaller ACOs in these markets. PMID- 26124302 TI - Addressing Pricing Power in Integrated Delivery: The Limits of Antitrust. AB - Prices are the major driver of why the United States spends so much more on health care than other countries do. The pricing power that hospitals have garnered recently has resulted from consolidated delivery systems and concentrated markets, leading to enhanced negotiating leverage. But consolidation may be the wrong frame for viewing the problem of high and highly variable prices; many "must-have" hospitals achieve their pricing power from sources other than consolidation, for example, reputation. Further, the frame of consolidation leads to unrealistic expectations for what antitrust's role in addressing pricing power should be, especially because in the wake of two periods of merger "manias" and "frenzies" many markets already lack effective competition. It is particularly challenging for antitrust to address extant monopolies lawfully attained. New payment and delivery models being pioneered in Medicare, especially those built around accountable care organizations (ACOs), offer an opportunity to reduce pricing power, but only if they are implemented with a clear eye on the impact on prices in commercial insurance markets. This article proposes approaches that public and private payers should consider to complement the role of antitrust to assure that ACOs will actually help control costs in commercial markets as well as in Medicare and Medicaid. PMID- 26124303 TI - Growth of Accountable Care Organizations in California: Number, Characteristics, and State Regulation. AB - Accountable care organizations (ACOs) result in physician organizations' and hospitals' receiving risk-based payments tied to costs, health care quality, and patient outcomes. This article (1) describes California ACOs within Medicare, the commercial market, and Medi-Cal and the safety net; (2) discusses how ACOs are regulated by the California Department of Managed Health Care and the California Department of Insurance; and (3) analyzes the increase of ACOs in California using data from Cattaneo and Stroud. While ACOs in California are well established within Medicare and the commercial market, they are still emerging within Medi-Cal and the safety net. Notwithstanding, the state has not enacted a law or issued a regulation specific to ACOs; they are regulated under existing statutes and regulations. From August 2012 to February 2014, the number of lives covered by ACOs increased from 514,100 to 915,285, representing 2.4 percent of California's population, including 10.6 percent of California's Medicare fee-for service beneficiaries and 2.3 percent of California's commercially insured lives. By emphasizing health care quality and patient outcomes, ACOs have the potential to build and improve on California's delegated model. If recent trends continue, ACOs will have a greater influence on health care delivery and financial risk sharing in California. PMID- 26124304 TI - Accountable Care Organizations: Integrated Care Meets Market Power. AB - Will accountable care organizations (ACOs) deliver high-quality care at lower costs? Or will their potential market power lead to higher prices and lower quality? ACOs appear in various forms and structures with financial and clinical integration at their core; however, the tools to assess their quality and the incentive structures that will determine their success are still evolving. Both market forces and regulatory structures will determine how these outcomes emerge. This introduction reviews the evidence presented in this special issue to tackle this thorny trade-off. In general the evidence is promising, but the full potential of ACOs to improve the health care delivery system is still uncertain. This introductory review concludes that the current consensus is to let ACOs grow, anticipating that they will make a contribution to improve our poor-quality and high-cost delivery system. PMID- 26124305 TI - Accountable Care Organizations and Population Health Organizations. AB - Accountable care organizations (ACOs) and hospitals are investing in improving "population health," by which they nearly always mean the health of the "population" of patients "attributed" by Medicare, Medicaid, or private health insurers to their organizations. But population health can and should also mean "the health of the entire population in a geographic area." We present arguments for and against ACOs and hospitals investing in affecting the socioeconomic determinants of health to improve the health of the population in their geographic area, and we provide examples of ACOs and hospitals that are doing so in a limited way. These examples suggest that ACOs and hospitals can work with other organizations in their community to improve population health. We briefly present recent proposals for such coalitions and for how they could be financed to be sustainable. PMID- 26124306 TI - Commentary - Payment Policy Disruption and Policy Drift. PMID- 26124307 TI - Integration of Substance Abuse Treatment Organizations into Accountable Care Organizations: Results from a National Survey. AB - To meet their aims of managing population health to improve the quality and cost of health care in the United States, accountable care organizations (ACOs) will need to focus on coordinating care for individuals with substance abuse disorders. The prevalence of these disorders is high, and these individuals often suffer from comorbid chronic medical and social conditions. This article examines the extent to which the nation's fourteen thousand specialty substance abuse treatment (SAT) organizations, which have a daily census of more than 1 million patients, are contracting with ACOs across the country; we also examine factors associated with SAT organization involvement with ACOs. We draw on data from a recent (2014) nationally representative survey of executive directors and clinical supervisors from 635 SAT organizations. Results show that only 15 percent of these organizations had signed contracts with ACOs. Results from multivariate analyses show that directors' perceptions of market competition, organizational ownership, and geographic location are significantly related to SAT involvement with ACOs. We discuss implications for integrating the SAT specialty system with the mainstream health care system. PMID- 26124308 TI - Commentary - Competition Policy after Health Care Reform: Mending Holes in Antitrust Law's Protective Net. PMID- 26124309 TI - Accountable Care Organizations and Antitrust Enforcement: Promoting Competition and Innovation. AB - The antitrust laws stand to protect consumers of health care services from conduct that would raise prices, lower quality, and decrease innovation by lessening competition. Importantly, though, vigorous antitrust enforcement does not impede accountable care organizations (ACOs) and similar collaborations that advance these same goals of better and more efficient care; in fact, by fostering competitive markets, the antitrust laws encourage such initiatives. This article summarizes the legal framework that the federal antitrust agencies - the Federal Trade Commission and the Antitrust Division of the US Department of Justice - use to analyze ACOs and other collaborations among health care providers. It outlines the guidance provided by the federal antitrust agencies concerning when ACOs and other provider collaborations likely would harm competition and consumers. In addition, it reviews common antitrust issues that can arise with ACOs and provides examples of enforcement actions that have prevented health care providers from taking or continuing anticompetitive actions. PMID- 26124310 TI - Medicare for All - If It Were Politically Possible - Would Necessarily Replicate the Defects of Our Current System. AB - Medicare for All, ideally implemented, could offer powerful advantages over our current health care financial system. Unfortunately, the political obstacles to such a system are formidable and are likely to remain so for decades. More to the point, a politically viable single-payer system would not replace our currently dysfunctional health care politics. It would be a product of that same legislative process and political economy and thus be disfigured by the same interest group politics, path dependence, and fragmentation that Laurence Seidman rightly laments. PMID- 26124311 TI - Increasing placebo response in antipsychotic trials: a clinical perspective. AB - An increase in placebo response is often cited as rationale for the continuously diminishing drug-placebo differences in randomized controlled trials (RCTs) evaluating antipsychotic and antidepressant drugs. As a consequence, the probability for negative study results in placebo-controlled RCTs grows. This alarming trend conveys the impression that the newer marked psychopharmacological medications are less efficacious compared to the older ones although particularly trial methodological reasons contribute to the mitigation of the drug-placebo contrasts over the last decades. With regard to antipsychotic RCTs, the present article aims to elucidate the magnitude of the raising placebo response, factors contributing to this increase, and potential reasons for this phenomenon. Therefore, we summarize and critically discuss the findings of two recent meta analyses on this topic. Both research projects revealed that the mean improvement of schizophrenic symptoms in the placebo groups of antipsychotic trials increased considerably over time. Factors that were significantly associated with larger placebo response in antipsychotic trials comprise with respect to participants characteristics younger age and shorter duration of illness. The results in terms of symptom severity at baseline were conflictive. In terms of trial methodology factors, shorter study duration, a larger number of study sites and participants, fewer academic/university sites, and a lower percentage of patients randomized to placebo were identified as potential predictors for high placebo response. The implications of these findings for the interpretation of antipsychotic trial results and meta-analyses are presented. PMID- 26124313 TI - Portal inflammation during NAFLD is frequent and associated with the early phases of putative hepatic progenitor cell activation. AB - AIMS: We investigated whether portal tract inflammation observed in non-alcoholic fatty liver disease (NAFLD) is associated with hepatic progenitor cell compartment activation, as thoroughly evaluated with different markers of the staminal lineage. METHODS: Fifty-two patients with NAFLD were studied. NAFLD activity score, fibrosis and portal inflammation were histologically evaluated. Putative hepatic progenitor cells, intermediate hepatobiliary cells and bile ductules/interlobular bile ducts were evaluated by immunohistochemistry for cytokeratin (CK)-7, CK-19 and epithelial cell adhesion molecule (EpCAM), and a hepatic progenitor cell compartment score was derived. Hepatic stellate cell and myofibroblast activity was determined by immunohistochemistry for alpha-smooth muscle actin. RESULTS: Portal inflammation was absent in a minority of patients, mild in 40% of cases and more than mild in about half of patients, showing a strong correlation with fibrosis (r=0.76, p<0.001). Portal inflammation correlated with CK-7-counted putative hepatic progenitor cells (r=0.48, p<0.001), intermediate hepatobiliary cells (r=0.6, p<0.001) and bile ductules/interlobular bile ducts (r=0.6, p<0.001), and with the activity of myofibroblasts (r=0.5, p<0.001). Correlations were confirmed when elements were counted by immunostaining for CK-19 and EpCAM. Lobular inflammation, ballooning, myofibroblast activity and hepatic progenitor cell compartment activation were associated with portal inflammation by univariate analysis. In the multivariate model, the only variable independently associated with portal inflammation was hepatic progenitor cell compartment activation (OR 3.7, 95% CI 1.1 to 12.6). CONCLUSIONS: Portal inflammation is frequent during NAFLD and strongly associated with activation of putative hepatic progenitor cells since the first steps of their differentiation, portal myofibroblast activity and fibrosis. PMID- 26124312 TI - Membrane protrusion powers clathrin-independent endocytosis of interleukin-2 receptor. AB - Endocytosis controls many functions including nutrient uptake, cell division, migration and signal transduction. A clathrin- and caveolin-independent endocytosis pathway is used by important physiological cargos, including interleukin-2 receptors (IL-2R). However, this process lacks morphological and dynamic data. Our electron microscopy (EM) and tomography studies reveal that IL 2R-pits and vesicles are initiated at the base of protrusions. We identify the WAVE complex as a specific endocytic actor. The WAVE complex interacts with IL 2R, via a WAVE-interacting receptor sequence (WIRS) present in the receptor polypeptide, and allows for receptor clustering close to membrane protrusions. In addition, using total internal reflection fluorescent microscopy (TIRF) and automated analysis we demonstrate that two timely distinct bursts of actin polymerization are required during IL-2R uptake, promoted first by the WAVE complex and then by N-WASP. Finally, our data reveal that dynamin acts as a transition controller for the recruitment of Arp2/3 activators required for IL-2R endocytosis. Altogether, our work identifies the spatio-temporal specific role of factors initiating clathrin-independent endocytosis by a unique mechanism that does not depend on the deformation of a flat membrane, but rather on that of membrane protrusions. PMID- 26124314 TI - Procalcitonin. AB - Procalcitonin (PCT) is the 116 amino acid precursor of the hormone calcitonin, produced by the C cells of the thyroid. Its synthesis is upregulated in bacterial infection and downregulated by viral infection. Consequently, with the increasing development of antibiotic resistance, interest has focused on the ability of this marker to not only diagnose infection but to tailor antibiotic treatment and help reduce the development of antibiotic resistance. The value of PCT depends on the specific clinical situation and pretest probability of disease. This article discusses the role of PCT in these different situations, namely primary care, the emergency department and the intensive care unit. The true cost effectiveness of this test remains difficult to prove as evidence for the potential impact of using PCT on slowing the development of bacterial resistance remains largely circumstantial. PMID- 26124315 TI - CD10-positive mantle cell lymphoma: biologically distinct entity or an aberrant immunophenotype? Insight, through gene expression profile in a unique case series. AB - BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics. AIMS AND METHODS: A series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10 negative MCL cases (controls), which were randomly selected from our institutional registry. RESULTS: GEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data. CONCLUSIONS: This study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications. PMID- 26124316 TI - The RNA surveillance complex Pelo-Hbs1 is required for transposon silencing in the Drosophila germline. AB - Silencing of transposable elements (TEs) in the metazoan germline is critical for genome integrity and is primarily dependent on Piwi proteins and associated RNAs, which exert their function through both transcriptional and posttranscriptional mechanisms. Here, we report that the evolutionarily conserved Pelo (Dom34)-Hbs1 mRNA surveillance complex is required for transposon silencing in the Drosophila germline. In pelo mutant gonads, mRNAs and proteins of some selective TEs are up regulated. Pelo is not required for piRNA biogenesis, and our studies suggest that Pelo may function at the translational level to silence TEs: This function requires interaction with Hbs1, and overexpression of RpS30a partially reverts TE silencing defects in pelo mutants. Interestingly, TE silencing and spermatogenesis defects in pelo mutants can also effectively be rescued by expressing the mammalian ortholog of Pelo. We propose that the Pelo-Hbs1 surveillance complex provides another level of defense against the expression of TEs in the germline of Drosophila and possibly all metazoa. PMID- 26124317 TI - Mitochondrial DNA Deficiency in Ovarian Cancer Cells and Cancer Stem Cell-like Properties. AB - BACKGROUND: A low quantity of mitochondrial DNA (mtDNA) is a risk factor in a variety of tumor types. However, it is unclear how mtDNA reduction influences tumor behavior. MATERIAL AND METHODS: mtDNA-deficient ovarian cancer cells were established by ethidium bromide (EtBr) treatment with additive combination of pyruvate and uridine. RESULTS: The mtDNA-deficient cells had a low growth and colony-forming efficiency compared to the control cells. RNA sequencing revealed down-regulation of mitochondrion-related genes and up-regulation of genes related to cell proliferation and anti-apoptosis. The expression of genes involved in cancer metastasis, proliferation, angiogenesis, drug resistance and cancer cell stemness were also up-regulated. Intriguingly, cancer stem cell markers CD90 and CD117 were both up-regulated by EtBr dose-dependently in both cell lines. CONCLUSION: MtDNA deficiency may induce ovarian cancer stem cell-like properties through different ways in vitro, therefore contributing to different tumor behaviors. PMID- 26124318 TI - Real-time Non-invasive Spectral Imaging of Orthotopic Red Fluorescent Protein expressing Lung Tumor Growth in Nude Mice. AB - BACKGROUND/AIM: Orthotopic implantation of cancer allows metastasis to occur. The most patient-like metastatic orthotopic models are developed with surgical orthotopic implantation using intact tissue in order to preserve the natural tissue structure of the tumor which contains both cancer cells and stroma. MATERIALS AND METHODS: In the present study, we performed a simple thoracotomy by making an intercostal incision between the fourth and fifth ribs on the left side of the chest of nude mice. Lung tumor fragments expressing red fluorescent protein were then implanted on the left lung. RESULTS: It was possible to monitor tumor formation in the lung non-invasively by spectral imaging using the Maestro system with a liquid tunable filter. The model described here has high tumorigenicity in the lung (100%) and a low mortality rate (5%). CONCLUSION: This imageable nude mouse model using surgical orthotopic implantation of lung cancer will be useful for all types of longitudinal studies. PMID- 26124319 TI - Systematic Review of Candidate Single-nucleotide Polymorphisms as Biomarkers for Responsiveness to Neoadjuvant Chemoradiation for Rectal Cancer. AB - BACKGROUND/AIM: Treatment of rectal cancer has improved significantly with the addition of neoadjuvant chemoradiation. Certain patients have experienced a complete pathological response to chemoradiation, as observed in surgically resected tissue samples, thus calling into question the necessity of radical surgery in this population of patients. Pharmacogenetic studies now implicate the role that genetic biomarkers, such as single nucleotide polymorphisms, play in an individual's response to chemoradiation. The aim of this review was to provide a comprehensive evaluation of a group of candidate single nucleotide polymorphisms associated with chemoradiotherapy response and an assessment of techniques that can be used to easily identify the presence of these single nucleotide polymorphisms in patient samples. MATERIALS AND METHODS: Relevant primary research articles were identified in the Medline Database from January 1, 2006 to May 31, 2012. We included nine relevant articles addressing the correlation between six candidate single nucleotide polymorphisms and one candidate variable number tandem repeat in six genes, namely thymidylate synthase, epidermal growth factor, epidermal growth factor receptor, superoxide dismutase 2, interleukin-13, and cyclin D1, with tumor down-staging and patient survival after neoadjuvant chemotherapy or chemoradiotherapy. RESULTS: Specific alleles of each of the candidate single nucleotide polymorphisms were significantly associated with either a major response in tumor down-staging or a minor to non-existent response following neoadjuvant chemotherapy, individually or in combination with other single nucleotide polymorphisms. However, studies present conflicting results regarding the effect of certain candidate single nucleotide polymorphisms on tumor down-staging. CONCLUSION: Through further research into candidate single nucleotide polymorphisms and potential identification of other polymorphisms, clinicians may be able to create individualized treatment plans in accordance with the genotype of individual patients with rectal cancer, in order to reduce morbidity and mortality. PMID- 26124320 TI - Expression of Stem Cell-associated Marker HES77 in Rectal Neuroendocrine Tumors. AB - BACKGROUND: Expression of novel stem cell-associated marker human embryonic stem cell 77 (HES77) was studied in rectal neuroendocrine tumors (NETs), which comprise 10 to 15% of gastroenteropancreatic NETs, some with metastatic potential. MATERIALS AND METHODS: WHO 2010 classification was applied, and immunohistochemical positivity for HES77 was assessed in 72 primary tumors and 6 metastases. Correlations were calculated between HES77 expression, metastasis and patient survival. RESULTS: Expression of HES77 strongly positively correlated with metastatic potential and poorer prognosis. The proliferative index determined in the metastasis did not correlate with patient survival. CONCLUSION: Novel stem cell-associated marker HES77 has a strong prognostic value in patients with rectal NETs and may be useful in selecting those who are at-risk for developing metastatic disease, and who may benefit from intensive adjuvant therapy. Proliferative index in the metastasis did not predict for outcome. Characterization of the HES77 epitope would certainly enhance the interest in the antibody. PMID- 26124321 TI - Molecular Mechanism(s) Involved in 25-Hydroxyvitamin D's Antiproliferative Effects in CYP27B1-transfected LNCaP Cells. AB - BACKGROUND/AIM: 1alpha,25(OH)2D has been shown to induce cell-cycle regulation, apoptosis and differentiation in prostate cancer cells. Previous studies have demonstrated that prostate and some prostate cancer cells have the ability to convert 25(OH)D3 to 1alpha,25(OH)2D3. The aim of the present study was to elucidate the role of 1alpha,25(OH)2D3 production by 25-hydroxyvitamin D-1alpha hydroxylase (CYP27B1) on prostate cancer cell growth. MATERIALS AND METHODS: LNCaP cells were stably transfected with CYP27B. RESULTS: Stably-transfected 1alpha-OHase LNCaP cells converted 25(OH)D3 to 1alpha,25(OH)2D3 unlike untransfected LNCaP cells. There was a dose-dependent decrease in (3)H-thymidine incorporation in 1alpha,25(OH)2D3-treated LNCaP cells, not seen with 25(OH)D3 treatment, and in stably transfected 1alpha-OHase LNCaP cells treated with 25(OH)D3. 1alpha,25(OH)2D3-treated LNCaP cells and 25(OH)D3-treated stably transfected 1alpha-OHase LNCaP cells demonstrated an increased G1 phase accumulation and apoptosis, while 25(OH)D3 treatment had no effect in LNCaP cells. CONCLUSION: The present study supports the hypothesis that local production of 1alpha,25(OH)2D is important in inhibiting prostate cancer development and growth. PMID- 26124322 TI - Analysis of the Antitumor Activity of Clotrimazole on A375 Human Melanoma Cells. AB - AIM: The current study was designed to characterize the anticancer effects of clotrimazole on human cutaneous melanoma cells. MATERIALS AND METHODS: The v-raf murine sarcoma viral oncogene homolog B1 V600E mutant melanoma cell line A375 was used as an in vitro model. Characterization tools included analyses of cell viability, gene expression, cell-cycle progression, annexin V reactivity and internucleosomal DNA fragmentation. RESULTS: Clotrimazole induced cytotoxicity in A375 human melanoma cells without significant changes of human keratinocyte cell viability. Clotrimazole, at a concentration that approximates the inhibitory concentration 50% (IC50) value (i.e. 10 MUM), reduced the expression of hexokinase type-II, induced cell-cycle arrest at G1-S phase transition, altered annexin V reactivity and induced DNA fragmentation without evidence of necrosis. CONCLUSION: The current study provides evidence of a remarkable pro-apoptotic effect by clotrimazole against human melanoma cells, with a different mechanism of action and timeline of the apoptosis-related events when compared to cisplatin. PMID- 26124323 TI - CD114 Expression Mediates Melanoma Tumor Cell Growth and Treatment Resistance. AB - BACKGROUND/AIM: Melanoma tumor cell sub-populations expressing a variety of specific molecular markers have been identified. We hypothesized that expression of CD114, the cell surface receptor for granulocyte-colony stimulating factor (G CSF), would be associated with melanoma tumor cell growth and response to treatment. MATERIALS AND METHODS: We determined the expression of CD114 expression in tumor cell lines by flow cytometry. We separated melanoma tumor cells into CD114-positive and - negative populations by fluorescence-activated cell sorting (FACS) and measured cell growth and responses to temozolomide and etoposide and the anticancer agent nifurtimox. RESULTS: All tested cell lines demonstrated a sub-population of cells with CD114 surface expression. CD114 positive sub-populations grew faster than CD114-negative ones and demonstrated resistance to temozolomide, etoposide, and nifurtimox. CONCLUSION: CD114 expression defines a sub-population of melanoma tumor cells with altered growth and resistance to treatment. Further studies on the role of CD114 in melanoma pathogenesis are warranted. PMID- 26124324 TI - PDGFR-alpha and CD117 Expression Pattern in Esophageal Carcinomas. AB - BACKGROUND: Despite advanced diagnostics and multimodal treatments, the overall 5 year survival rate for patients with esophageal cancer remains low. In the past, several specific antibodies, including tyrosine kinase inhibitors, targeting different steps of carcinogenesis were investigated. We examined two receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR-alpha) and mast/stem cell growth factor receptor (CD117) in esophageal carcinomas. MATERIALS AND METHODS: Tissue samples of 52 Norwegian patients who underwent esophagectomy were examined using immunohistochemistry. RESULTS: PDGFR-alpha and CD117 expression was observed in cancer cells in all samples of both carcinoma types. A higher PDGFR-alpha immunoreactivity was detected in the squamous cell carcinoma group (p=0.032). Surprisingly, a higher number of PDGFR-alpha-positive cells in the analyzed samples for the entire population was associated with longer survival (p=0.05). CONCLUSION: The findings of our study need to be further validated as we examined a low number of patients. Both PDGFR-alpha and CD117 probably play an important role in the progression of esophageal carcinoma, and they may possibly be targets for biological anticancer therapy in the future. PMID- 26124325 TI - MMP9, Cyclin D1 and beta-Catenin Are Useful Markers of p16-positive Squamous Cell Carcinoma in Therapeutic EGFR Inhibition In Vitro. AB - BACKGROUND/AIM: In the United States 53,640 new cases of head and neck cancer were estimated in 2013. Over 95% of these cases were evaluated as squamous cell carcinoma (SCC). At present, smoking, drinking alcohol, chewing betel and infection with high-risk types of human papilloma virus (HPV) are classified as risk factors of oropharyngeal squamous cancer cell carcinoma (OPSCC). It could be suggested that patients with HPV-positive OPSCC have a better response to chemoradiotherapy than patients without. In many studies, there was observed an inverse correlation between epithelial growth factor receptor (EGFR) expression and HPV status in p16-positive SCC. Therefore, it is of great clinical interest to specify the phenotype of cancer cells in order to further individualize treatment modalities. The aim of the study was to investigate the expression pattern of specific markers in p16-positive SCC cells after stimulation with lapatinib and gefitinib. MATERIALS AND METHODS: We incubated p16-positive CERV196 cells with lapatinib and gefitinib (2 MUg/ml) and after 5, 24 and 96 h determined E-cadherin, vimentin, matrix metalloproteinase-9 (MMP9), cyclin D1 and beta catenin by immunocytochemistry, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction (PCR). RESULTS: We found an increase of E cadherin and a decrease of vimentin in unstimulated cells. We detected an alteration of expression of vimentin and E-cadherin level after treatment with lapatinib and gefitinib. We demonstrated a statistically significant lapatinib- and gefitinib-induced repression of cyclin D1, MMP9 and beta-catenin in CERV196 cells dependent on incubation time. CONCLUSION: Cyclin D1 and MMP9 expression profiles may represent an early measure of sensitivity and level of response to lapatinib and gefitinib. The presented cell culture model is, therefore, well suited for further study of epigenetic regulation of molecular targeted-therapy by EGFR inhibition and prevention of mesenchymal transition in p16-positive SCC cells. PMID- 26124326 TI - SPINK1 Promoter Variants Are Associated with Prostate Cancer Predisposing Alterations in Benign Prostatic Hyperplasia Patients. AB - BACKGROUND/AIM: Several studies reported that patients with benign prostatic hyperplasia (BPH) experienced a 10% increased incidence of prostate cancer (PCa) after the first 5 years of diagnosis. We investigated the association between single nucleotide polymorphisms (SNPs) in the promoter of Serine Protease Inhibitor Kazal Type 1 (SPINK1) and the increased risk of BPH and PCa. MATERIALS AND METHODS: We genotyped three SNPs in a cases-control study, including BPH and PCa cases. Multiple logistic regression models were applied to analyze clinical and genotypic data. RESULTS: We found an inverse association between SNP rs10035432 and BPH under the log-additive (p=0.007) model. No association was found between these SNPs and PCa risk. However, we observed a possible association between rs1432982 and lower-grade PCa (p=0.05) under the recessive model. CONCLUSION: SPINK1 promoter variants are likely to be associated with the risk of BPH. PMID- 26124327 TI - Establishment and Characterization of Two Novel Human Pancreatic Carcinoma Cell Lines. AB - BACKGROUND: Pancreatic carcinoma (PC) is among the most lethal types of carcinomas worldwide. We aimed to establish well-defined PC cell lines in order to determine their resistance to chemotherapy. MATERIALS AND METHODS: Cells cultured from the tumors of two patients were analyzed for xenograft formation, V Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and TP53 mutations, chemosensitivity, and mRNAs encoding rate-limiting enzymes that metabolize anticancer drugs. RESULTS: The TYPK-1 and TYPK-2 cell lines were established from the lymph node of a locally advanced PC and from the ascites of a multi metastatic and multi-chemoresistant PC, respectively. Each cell line generated tumors in nude mice. KRAS and TP53 mutations were detected in TYPK-1 but not TYPK 2 cells. TYPK-1 cells were resistant to gemcitabine, and TYPK-2 cells were resistant to oxaliplatin. The gemcitabine sensitivity of each cell line correlated with the expression of mRNAs encoding DCK and SLCAC29A1. CONCLUSION: TYPK-1 and TYPK-2 cells may contribute to investigations of resistance to anticancer drugs. PMID- 26124328 TI - Co-treatment with BEZ235 Enhances Sensitivity of BRCA1-negative Breast Cancer Cells to Olaparib. AB - The poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib has been reported as having preferential anti-proliferative effects on breast cancer 1 (BRCA1) deficient breast and ovarian cancer cells and was recently approved by the US Food and Drug Administration (FDA) for advanced, BRCA1-mutated ovarian cancer. Herein, we show that BEZ235, a protein kinase inhibitor, enhanced the tumor cell killing effect of olaparib in BRCA1-mutated breast cancer cells in vitro. BEZ235 reduced olaparib-induced phosphorylation of p53 binding protein 1 (53BP1) and 53BP1 foci formation, as well as phosphorylation of AKT (S473). Long-term colony formation assay revealed more strong synergistic effects of this combination in SUM149PT and MDA-MB-468 breast cancer cell lines. BEZ235 treatment combined with olaparib may be a candidate for effective therapeutic treatment of BRCA1-mutated breast cancer. PMID- 26124329 TI - High-fat Diet Enhances and Plasminogen Activator Inhibitor-1 Deficiency Attenuates Bone Loss in Mice with Lewis Lung Carcinoma. AB - This study determined the effects of a high-fat diet and plasminogen activator inhibitor-1 deficiency (Pai1(-/-)) on the bone structure in male C57BL/6 mice bearing Lewis lung carcinoma (LLC) in lungs. Significant reduction in bone volume fraction (BV/TV), trabecular number (Tb.N) and bone mineral density (BMD) in femurs and vertebrae were found in LLC-bearing mice compared to non-tumor-bearing mice. In LLC-bearing mice, the high-fat diet compared to the AIN93G control diet significantly reduced BV/TV, Tb.N and BMD in femurs and BV/TV in vertebrae. The high-fat diet significantly reduced BMD in vertebrae in wild-type mice but not in Pai1(-/-) mice. Compared to wild-type mice, PAI1 deficiency significantly increased BV/TV and Tb.N in femurs. The plasma concentration of osteocalcin was significantly lower and that of tartrate-resistant acid phosphatase 5b (TRAP5b) was significantly higher in LLC-bearing mice. The high-fat diet significantly reduced plasma osteocalcin and increased TRAP5b. Deficiency in PAI1 prevented the high-fat diet-induced increases in plasma TRAP5b. These findings demonstrate that a high-fat diet enhances, whereas PAI1 deficiency, attenuates metastasis associated bone loss, indicating that a high-fat diet and PAI1 contribute to metastasis-associated bone deterioration. PMID- 26124330 TI - Design, Synthesis and Biological Evaluation of Novel HIF1alpha Inhibitors. AB - Elevated levels of hypoxia inducible factor-1 (HIF1) are linked to tumor metastasis, angiogenesis, poor patient prognosis and response to chemotherapy. HIF1alpha is a master regulator of the hypoxic response, including in cancer cells, through transcriptional activation of several target genes. Previously, we identified compound CJ-3k with high anti-HIF1alpha activity based on the structure of a well-known HIF1alpha inhibitor, YC-1. In this study, the CJ-3k scaffold was systematically modified to explore the structure-activity relationships. Fifty-three new CJ-3k analogs were synthesized and screened for their anti-HIF-1alpha activity in a luciferase-transfected human breast cancer cell line (MDA-MB-231). Some of these new analogs have a significantly greater activity than that of CJ-3k and hold potential for development as new therapeutic agents for the treatment of cancer. PMID- 26124331 TI - High-mobility Group Box 1 and Mitogen-activated Protein Kinase activated Protein Kinase-2 Are Up-regulated in Gemcitabine-resistant Pancreatic Cancer Cells. AB - BACKGROUND: Results of our previous studies demonstrated that the expression of heat-shock protein 27 (HSP27) was increased and HSP27 was phosphorylated in the GEM-resistant pancreatic cancer cell line, KLM1-R. The expression of HSP27 is regulated mainly by heat-shock factor 1, but other transcription factors or kinases have been reported to activate HSP27. High-mobility group box 1 (HMGB1) is a nuclear transcription factor. It has been reported that HMGB1 regulates HSP27 gene expression. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) phosphorylates HSP27. In the present study, we investigated the expression of HMGB1 and MAPKAPK2 in KLM1-R cells. MATERIALS AND METHODS: The expression levels of HMGB1 and MAPKAPK2 were compared between KLM1 and KLM1-R cells by western blotting. RESULTS: The protein expression of both HMGB1 and MAPKAPK2 were increased in KLM1-R cells compared to KLM1 cells. CONCLUSION: The increase of both HMGB1 and MAPKAPK2 in KLM1-R cells compared to KLM1 suggest the possibility of the activation of the pathway of HSP27 by HMGB1 and MAPKAPK2 in gemcitabine-resistant KLM1-R cells. PMID- 26124332 TI - Curcumin Triggers DNA Damage and Inhibits Expression of DNA Repair Proteins in Human Lung Cancer Cells. AB - The study goal was to evaluate the effects of curcumin on DNA damage and expression of DNA-repair proteins in human lung cancer. Thus, NCI-H460 cells were used to study the effects of curcumin on DNA damage and repair in vitro. We investigated curcumin induces DNA damage by comet the assay and 4',6-diamidino-2 phenylindole (DAPI) staining. The DNA damage/repair-related protein levels were examined and monitored by western blotting and confocal microscopy. Curcumin significantly increased the length of comet tails and DNA condensation in NCI H460 cells. Curcumin reduced expression of DNA-repair proteins such as 14-3-3 protein sigma (14-3-3sigma), O6-methylguanine-DNA methyltransferase (MGMT), breast cancer susceptibility gene 1 (BRCA1), and mediator of DNA damage checkpoint 1 (MDC1). Curcumin also increased phosphorylation of p53 and Histone H2A.X (S140) in the nuclei of NCI-H460 cells. Taken together, our findings indicated that curcumin triggered DNA damage and inhibited expression of DNA repair-associated proteins in NCI-H460 cells. PMID- 26124333 TI - Protective Effect of Leuprorelin on Radiation-induced Intestinal Toxicity. AB - BACKGROUND/AIM: Patients with prostate cancer treated with neoadjuvant androgen ablation experience less radiation-induced intestinal toxicity, mostly due to a reduction of the volume of normal tissue exposed to high radiation doses. We aimed to evaluate if the anti-androgenic drug leuprorelin itself exerts a protective effect on irradiated bowel. MATERIALS AND METHODS: Female, intact and castrated male C57BL/6J mice underwent 12-Gy total body irradiation, with or without a three-month leuprorelin (0.054 mg/kg/month i.p.) pre-treatment. After 24-72 h, mice were sacrificed and intestinal segments collected for histological, immunohistochemical and molecular analyses. RESULTS: Leuprorelin markedly reduced radiation-induced jejunal and colonic histological alterations in mice, increased the number of regenerating crypts vs. irradiation, and reduced radiation-induced nitrotyrosine immunoreactivity. Leuprorelin significantly reduced radiation induced matrix metallo-proteinase-2 (Mmp2) and -13, collagen 1 and -3, transforming growth factor-beta (Tgfb), p53, interleukin 6 (Il6), and B-cell lymphoma 2 (Bcl2)-associated X protein (Bax) gene expressions, and nuclear factor kappa B (NFkappaB) and TGFbeta protein expression, and hampered radiation-induced BCL2 protein down-regulation. CONCLUSION: Leuprorelin protects mice from radiation-induced intestinal injury, likely through a reduction of tissue oxidative stress. These findings give a biological interpretation to clinical observations of improved intestinal tolerance in patients undergoing androgen ablation before RT. PMID- 26124334 TI - Effectiveness of Tyrosine Kinase Inhibitors in Japanese Patients with Non-small Cell Lung Cancer Harboring Minor Epidermal Growth Factor Receptor Mutations: Results from a Multicenter Retrospective Study (HANSHIN Oncology Group 0212). AB - AIM: Non-small cell lung cancer (NSCLC) with minor mutations in the epidermal growth factor receptor (EGFR) gene, except for the common 15 base-pair deletions in exon 19 and the L858R mutation in exon 21, is rare, and only few data exist on this patient population. The aim of the present study was to describe the clinical characteristics and to clarify the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in patients with NSCLC harboring minor mutations of the EGFR gene. PATIENTS AND METHODS: This was a multicenter, retrospective study that analyzed specimens from patients with NSCLC who had minor EGFR gene mutations and were treated with EGFR-TKIs between June 2002 and March 2012. RESULTS: Out of 56 patients with minor mutations of the EGFR gene, 44 were treated with either gefitinib or erlotinib. Mutation sites were G719X in exon 18 (n=35), L861Q in exon 21 (n=11), and G874S in exon 21 (n=1). Three patients had both the G719S and the L861Q mutation. The response rate to TKI treatment was 29.5%, and the disease control rate was 63.6%. The median progression-free survival (PFS) was 6.7 months [95% confidence interval (CI)=2.06-8.66 months]. The median PFS was 7.2 months (95% CI=4.23-12.3 months) in 32 patients who received first- or second-line treatment with EGFR-TKIs, whereas the median PFS was 1.57 months (95% CI=0.73-3.8 months) in 12 patients treated with EGFR-TKIs as a third-line or later treatment. In multivariate Cox analysis, erlotinib therapy was associated with a longer PFS than gefitinib (p=0.025). CONCLUSION: Patients with NSCLC harboring minor mutations of the EGFR gene exhibited a modest response to EGFR-TKI treatment. Treatment with first-generation EGFR-TKIs, in particular erlotinib, may be considered a first- or second-line option for patients with NSCLC with minor EGFR mutations. PMID- 26124335 TI - Contribution of Genotype of DNA Double-strand Break Repair Gene XRCC3, Gender, and Smoking Behavior to Lung Cancer Risk in Taiwan. AB - AIM: The present study evaluated the contribution of genotype of X-ray repair cross-complementing group 3 (XRCC3), age, gender, and smoking to lung cancer risk in Taiwan. MATERIALS AND METHODS: A total of 358 patients with lung cancer and 716 controls were investigated for their XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotype, epidemiological and clinical data for association and gene-Iifestyle interactions. RESULTS: The results showed that CT and TT genotypes of XRCC3 rs861539 were associated with increased lung cancer risk (odds ratio=1.81, 95% confidence interval=1.18-2.78; odds ratio=3.43, 95% confidence interval=1.12-10.60, respectively). This polymorphism also influenced lung cancer susceptibility in males and smokers (p=0.0017 and 0.0045, respectively). CONCLUSION: The T allele of XRCC3 rs861539 contributes to increased risk of lung cancer in Taiwanese, particularly those who are male and smokers. PMID- 26124336 TI - Sulforaphene Synergistically Sensitizes Cisplatin via Enhanced Mitochondrial Dysfunction and PI3K/PTEN Modulation in Ovarian Cancer Cells. AB - AIM: To explore if a natural isothiocyanate, sulforaphene (SFE), sensitizes ovarian cancer cells to the chemotherapy drug cisplatin (CDDP). MATERIALS AND METHODS: We studied reactive oxygen species (ROS), mitochondrial membrane depolarization and cell-cycle distribution in two ovarian cancer cell lines SKOV3 and SNU 8 treated with SFE and cisplatin. We further analyzed the expression of caspases 3, 8, and 9, Phosphoinositide 3-kinase (PI3K) and Phosphatase and tensin homolog (PTEN) by western blotting. RESULTS: SFE sensitized cells to cisplatin by enhancing ROS and mitochondrial membrane depolarization that released cytochrome c and activated caspase 9 and caspase 3 in the mitochondrial pathway. It also inhibited extrinsic pathway protein caspase 8, growth-related protein PI3K and further activated PTEN in combination with cisplatin. CONCLUSION: SFE synergistically inhibited proliferation and induced apoptosis of SKOV3 and SNU8 cells in combination with cisplatin by activating multiple apoptotic pathways. Therefore, we suggest sulforaphene as a chemo-enhancing adjuvant to improve the efficacy of cisplatin in ovarian cancer treatment. PMID- 26124337 TI - Ataxia-Telangiectasia and RAD3-Related and Ataxia-Telangiectasia-Mutated Proteins in Epithelial Ovarian Carcinoma: Their Expression and Clinical Significance. AB - BACKGROUND/AIM: The expression patterns of the key DNA damage response-related proteins, ataxia-telangiectasia and tfiih/ner complex atp-dependent 5'-3' dna helicase subunit rad3 (RAD3)-related (ATR) and ataxia-telangiectasia-mutated (ATM) proteins in ovarian cancer are not well-known. This study aimed to evaluate the expressions of ATR and ATM proteins, and to investigate their clinical significance in epithelial ovarian carcinoma (EOC). MATERIALS AND METHODS: The expressions of nuclear/cytoplasmic Ser428-phosphorylated ATR (p-ATR) and Ser1981 phosphorylated ATM (p-ATM) were evaluated by immunohistochemistry in 100 patients with EOC. The clinical significances of p-ATR and p-ATM protein expression were evaluated in terms of tumor progression and survival. RESULTS: Low expression of cytoplasmic p-ATR was significantly associated with advanced stage, serous histology, large residual mass, and high preoperative serum CA125 level. Univariate survival analysis revealed that low expression of cytoplasmic p-ATR protein was significantly associated with poor disease-free survival and poor overall survival. CONCLUSION: Our study demonstrates that cytoplasmic ATR protein might serve as a prognostic biomarker for patients with EOC. PMID- 26124338 TI - Stimulation by Monocyte Chemoattractant Protein-1 Modulates the Ex-vivo Colony Formation by Head and Neck Squamous Cell Carcinoma Cells. AB - BACKGROUND: The outcome of patients with head and neck squamous cell carcinoma (HNSCC) is still poor. To improve therapy of HNSCC, biomarkers indicating progression of the disease or modifiers with potential as therapeutic targets and therapy need to be investigated. Since monocyte chemoattractant protein (MCP1) is potentially involved in tumorigenesis of HNSCC, we aimed to clarify its role in HNSCC and investigated the influence of stimulation by MCP1 and its depletion using antibodies against MCP1 (anti-MCP1) on colony formation by HNSCC cells. MATERIALS AND METHODS: Biopsies of HNSCC were treated according to the protocol of the FLAVINO assay with cisplatin, docetaxel, temsirolimus or cilengitide alone, or combined with MCP1 or anti-MCP1. After a 72-h incubation, ethanol-fixed and fluoresceine-isothiocyanate (FITC)-labeled epithelial colonies were counted. RESULTS: Colony formation was significantly suppressed by MCP1 and 3.3 MUM cisplatin, while docetaxel, cilengitide and temsirolimus at concentrations of 0.275, 10 and 0.50 MUM caused insignificant effects. Addition of MCP1 to cisplatin, docetaxel and cilengitide increased efficacy of cytostatics in inhibition of colony formation, whereas those with temsirolimus were increased by anti-MCP1 that when applied alone failed to modulate colony formation. Overall regarding facilitated chemosensitivity, there was a statistical trend in favor of MCP1 stimulation over depletion. CONCLUSION: Our ex vivo results show context dependent effects of MCP1 in HNSCC cells. An increase of MCP1 level or its addition to cisplatin, docetaxel and cilengitide reduce colony formation but the efficacy of temsirolimus is augmented by MCP1 depletion. These context dependently opposite outcomes call for further translational investigations in HNSCC. PMID- 26124339 TI - Altered Expression of Yes-associated Protein and beta-Catenin in Non-neoplastic and Neoplastic Gastric Surface Epithelia. AB - AIM: To investigate whether differential expression of Yes-associated protein (YAP) and beta-catenin is important in gastric carcinogenesis. MATERIALS AND METHODS: A total of 284 paraffin-embedded samples collected from 232 patients with gastric adenocarcinoma were used to evaluate YAP and beta-catenin expression by immunohistochemistry, and the experimental findings were compared against those for gastric adenocarcinoma cell lines. RESULTS: Nuclear YAP expression gradually increased from non-neoplastic epithelia to tubular or papillary adenocarcinomas (TPADs) and decreased in signet-ring cell carcinoma (SRCC). Cytoplasmic beta-catenin expression increased from non-neoplastic epithelia to high-grade dysplasia and was decreased in TPAD and SRCC. YAP-overexpressing cell lines exhibited marked tumor cell invasion, whereas YAP-depleted cells showed reduced invasion. CONCLUSION: Nuclear YAP and cytoplasmic beta-catenin play important roles in carcinogenesis, and the differential patterns YAP and beta catenin expression between TPAD and SRCC imply the existence of different carcinogenic pathways in these conditions. PMID- 26124340 TI - Distribution and Effects of CDKN2 p16 540 C>G and 580 C>T, and MDM2 SNP309 T>G Polymorphisms in Patients with Primary Brain Tumors. AB - BACKGROUND/AIM: Primary brain tumors are unique tumors due to their different pathobiological behavior, while they rarely metastasize outside the central nervous system. Regarding the oncogenesis of primary brain tumors, it was shown that changes in functions of p16 and mouse double minute 2 homolog (MDM2) are related to tumor pathogenesis by enhancing cell proliferation and malign development. The present study aims to evaluate the possible associations between cyclin-dependent kinase 2 (CDKN2) p16 540 C>G and 580 C>T, MDM2 single nucleotide polymorphism 309 (SNP309) T>G polymorphisms and primary brain tumor. MATERIALS AND METHODS: Using polymerase chain reaction-restriction fragment length polymorphism technique, we determined SNPs in 67 patients with primary brain tumors and 71 healthy volunteers without malignancy. RESULTS: The frequency of CC genotype for CDKN2 p16 540 C>G was significantly two-fold higher (p<0.001) and possessing a C allele conferred a ~7-fold increased risk (p=0.005) of primary brain tumor. We also found that the CC genotype produced a higher ~4-fold risk of glioma (p=0.001) and the G allele had a possibly protective role against meningioma (~4.8-fold reduced risk, p=0.001). We found no significant associations for CDKN2 p16 580 C>T and MDM2 SNP309 T>G variants between cases and controls. CGT haplotype was significantly less frequent in patients with primary brain tumors and glioma cases (p=0.009 and p=0.028, respectively) than controls. CGG haplotype was significantly less frequent in patients with meningioma versus the control group (p=0.023). CONCLUSION: These findings show that CDKN2 p16 540 C>G, CDKN2 p16 580 C>T and MDM2 SNP309 T>G variants and their haplotypes may be risk factors for the development of primary brain tumors, especially of glioma. PMID- 26124341 TI - Phthalocyanine-mediated Photodynamic Treatment of Tumoural and Non-tumoural cell lines. AB - This study deals with the use of cationic far-red absorbing photosensitizers (lambda(max) ~740 nm) from the group of the phthalocyanines, in photodynamic therapy. The photosensitizers differed in their central atom, bearing either hydrogen, zinc or magnesium. These photosensitizers were tested in vitro on the tumour cell line HeLa (cervical cancer) and non-tumour cell line NIH3T3 (mouse fibroblast). The following tests were performed: measurement of reactive oxygen species production, viability testing, Comet assay and cell type detection (apoptotic, necrotic and living cells). The best results were achieved with zinc derivative at relatively low half-maximum inhibitory concentration (0.04 MUM) and a total radiation dose of 15 J cm(-2). PMID- 26124342 TI - Expression of the Epithelial Cell Adhesion Molecule and Cytokeratin 8 in Head and Neck Squamous Cell Cancer: A Comparative Study. AB - The epithelial cell adhesion molecule (EpCAM) is a well-known and widely accepted tumor-associated antigen in head and neck squamous cell carcinoma (HNSCC). In contrast, little is known about cytokeratin 8 (CK8), an intermediary filament protein, recently associated with HNSCC. Studies demonstrated an aberrant expression on the cell surface of different carcinomas of both antigens. We performed an immunohistochemical study on the expression pattern of CK8 in comparison to EpCAM on cryosections, followed by microscopic quantitative and semi-qualitative analyses. Both antigens showed heterogenous expression both in individual carcinomas and between different carcinoma types. Furthermore, the expression of CK8 is clearly dependent on the degree of histological tumor cell differentiation. With increasing de-differentiation, the amount of CK8 expression increased, which was not seen for EpCAM. The expression of EpCAM was high on all carcinomas independent of their anatomical localization. Regarding CK8, there seems to be a correlation between the expression grade and the anatomical site. The application of CK8 may provide additional supplementary information on HNSCC. PMID- 26124343 TI - Expression of EMT Markers SLUG and TWIST in Breast Cancer. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) has been observed in progression of in situ breast cancer to the invasive form and might be initiated by snail family zinc finger 2 (SLUG) and twist family bHLH transcription factor 1 (TWIST) protein overexpression. During this phenomenon, cells lose their epithelial phenotype and acquire mesenchymal features. The aim of the study was to examine the association of EMT markers SLUG and TWIST with clinicopathological data and the possibility of using these proteins as prognostic markers of breast cancer. MATERIALS AND METHODS: Immunohistochemical analysis (IHC) of SLUG and TWIST expression was performed on archival paraffin samples of 19 cases with fibrocystic breast changes (control group), 148 cases of invasive ductal breast cancer (IDC) and 26 of invasive lobular breast cancer (ILC). Laser capture microdissection for isolation of cells from 17 frozen samples of IDC was employed and subsequently SLUG and TWIST mRNA expression in cancer and stromal cells was detected separately by real-time polymerase chain reaction. RESULTS: SLUG and TWIST expression in IDC was significant higher in stromal cells regardless of the method of quantification used (p<0.001 for SLUG mRNA, and p<0.0001 for SLUG IHC, TWIST IHC and TWIST mRNA expression). Positive correlation of SLUG and TWIST protein and mRNA expression was observed in stromal cells of IDC (r=0.347; p<0.0001 and r=0.704; p<0.01, respectively). Expression of TWIST protein in IDC was higher in cancer cells of cases with shorter event-free survival period, as well as in stromal cells of cases with shorter overall survival period (p<0.05 for both). CONCLUSION: Stromal cells could play a role in the regulation of EMT in breast cancer. PMID- 26124344 TI - microRNA Expression in Prospectively Collected Blood as a Potential Biomarker of Breast Cancer Risk in the BCFR. AB - BACKGROUND/AIM: Current breast cancer risk assessment models have moderate discriminatory ability. We evaluated whether microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMC) could be a useful biomarker of risk in high-risk women. MATERIALS AND METHODS: Next-generation sequencing evaluated miR expression in PBMCs of 20 women who were unaffected at the time of recruitment and later diagnosed with breast cancer and 20 unaffected women. RESULTS: Out of the 5 miRNAs identified as potential risk markers, miR-144-3p, miR-451a, miR-144-5p and miR-183-5p were up-regulated, while miR-708-5p was down regulated. We then evaluated these miRs in 28 additional case/control pairs using quantitative reverse transcription polymerase chain reaction (PCR). None of the results in the validation sample were statistically significant possibly due to the much longer interval between blood collection and diagnosis in the validation set. CONCLUSIONS: Differentially expressed miRNAs from PBMCs may be potential non invasive biomarkers for breast cancer prediction. Larger prospective studies are required to confirm whether our findings with specific miRNA loci were related to timing before diagnosis. PMID- 26124345 TI - Patients with Non-small Cell Lung Cancer Analyzed for EGFR: Adherence to Guidelines, Prevalence and Outcome. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) analysis is the first molecular test introduced in the routine care of patients with non-small cell lung cancer (NSCLC). In the present study, we describe the prevalence of EGFR mutations and the adherence to testing and treatment guidelines in a population based Swedish NSCLC cohort. MATERIALS AND METHODS: Patients with NSCLC analyzed for EGFR mutations were identified and their characteristics and survival data were retrieved. We compared the study cohort to a matched lung cancer population. RESULTS: The EGFR mutation frequency was 10%. Mutations were enriched in women and in adenocarcinoma cases. Out of patients with advanced-stage NSCLC with non squamous histology, only 49% were referred for EGFR analysis. Out of the patients with EGFR mutation and advanced disease, only 38% received EGFR-tyrosine kinase inhibitor (TKI) in first-line therapy. CONCLUSION: The EGFR-mutated NSCLC population studied is similar to other Western populations. Surprisingly, a large proportion of patients were not referred for EGFR analysis. Out of the patients with EGFR mutation, fewer than 40% received EGFR-TKI as first-line treatment. Our results highlight the need for follow-up of treatment and diagnostic algorithms in routine healthcare. PMID- 26124346 TI - Evaluation of Bone Metastasis Using Serial Measurements of Serum N-Telopeptides of Type I Collagen in Patients with Lung Cancer: A Prospective Study. AB - BACKGROUND/AIM: The bone resorption biomarker cross-linked N-Telopeptides of type I collagen (NTx) has been shown to aid in the diagnosis of metastatic bone disease from lung cancer (MBDLC). Patients with MBDLC are often treated with zoledronic acid (ZA). ZA reduces the levels of NTx and also lowers the risk of skeletal adverse events in patients with MBDLC. PATIENTS AND METHODS: Patients with MBDLC at initial diagnosis were included in the study. NTx was measured in serum (sNTx) once a month using the OSTEOMARKTM sNTx assay. MBDLC was assessed by monthly physical examinations and bone scintigraphy every 3 months for 12 months. RESULTS: Twenty patients were enrolled between June and December 2010. The sNTx concentration at baseline was 19.8 +/- 5.8 nmol bone collagen equivalents (nmol BCE)/l. In the 16 patients receiving ZA, the level of sNTx significantly decreased after the first month of treatment (baseline vs. 1 month of treatment: 21.3 +/- 5.5 vs. 13.6 +/- 2.7 nmol BCE/l; p<0.01). During the follow-up period, 13 of the patients treated with ZA experienced worsening of bone metastasis. There were statistically significant differences in the levels of sNTx at baseline (20.3 +/- 4.8 nmol BCE/l), at the lowest levels after administration of ZA (11.8 +/- 2.9 nmol BCE/l vs. baseline; p<0.001), and at the time of measurable disease progression (14.1 +/- 4.6 nM BCE/l vs. baseline; p<0.05). CONCLUSION: Serial measurements of sNTx in patients with MBDLC treated with ZA may effectively predict disease progression. PMID- 26124347 TI - Several Site-specific Cancers are Increased in the Volcanic Area in Sicily. AB - BACKGROUND: Worldwide, thyroid cancer incidence is increased in many volcanic areas. Whether the incidence of other types of cancers are also increased is not known. MATERIALS AND METHODS: We analyzed cancer registries covering 82% of the population of Sicily to compare the incidence of 34 site-specific types of cancer in area around the volcano Mt. Etna (where thyroid cancer is very high) with adjacent non-volcanic areas. Differences in crude incidence rate ratios (IRR) between the two areas were calculated. RESULTS: Considering 72,197 incident cases, thyroid cancer (IRR=1.68 in females and 1.40 in males) and lymphatic leukemia (IRR: females=1.48, males=1.39) were significantly increased in the volcanic area in both men and women. Hodgkin's lymphoma, stomach and breast cancer in women and prostate cancer in men were also significantly increased in the volcanic area. CONCLUSION: Several, but not all types of cancers are significantly increased in the volcanic area of Sicily, indicating that an active volcanic environment may be a risk factor for cancer other than thyroid cancer. PMID- 26124348 TI - Safety and Pharmacokinetics of Second-line Ramucirumab plus FOLFIRI in Japanese Patients with Metastatic Colorectal Carcinoma. AB - BACKGROUND: This phase Ib study evaluated the pharmacokinetic profile and safety of ramucirumab, a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor 2, in combination with irinotecan, levofolinate and 5-fluorouracil (FOLFIRI) in Japanese patients with metastatic colorectal carcinoma (mCRC). PATIENTS AND METHODS: Eligible patients had Eastern Cooperative Oncology Group performance status 0-1, and disease progression during or within 6 months following first-line therapy with bevacizumab, oxaliplatin and a fluoropyrimidine. Six enrolled patients received 8 mg/kg ramucirumab plus FOLFIRI every 2 weeks. RESULTS: One out of six patients experienced a dose-limiting toxicity (grade 2 proteinuria and grade 4 neutropenia, resulting in a dose delay >2 weeks). All patients experienced at least one grade 3 or higher adverse event: neutropenia (five patients, 83%), proteinuria (two patients; 33%) and anemia, thrombocytopenia and hypertension (one patient each, 17%). There were no serious adverse events or deaths. CONCLUSION: Ramucirumab plus FOLFIRI was well-tolerated in Japanese patients with mCRC, warranting further investigation of this combination therapy. PMID- 26124349 TI - Trichloroethylene Is Associated with Kidney Cancer Mortality: A Population-based Analysis. AB - AIM: To examine the association between the distribution of trichloroethylene (TCE) exposure and mortality from kidney cancer (Kca) across United States counties. MATERIALS AND METHODS: Multiple linear regression was used to assess the association of TCE discharges from industrial sites and age-adjusted incidence and mortality rates for Kca during 2005 through 2010, controlling for confounders. A total of 163 counties were included in analysis. RESULTS: We observed an excess risk of Kca mortality associated with higher amounts of environmental TCE releases. A significant dose-response relationship was observed between TCE releases and Kca mortality in females. Smoking, education, income, hypertension, and obesity were significant predictors of incidence and mortality, consistent with previous research on the epidemiology of Kca. CONCLUSION: TCE exposure may increase the risk of mortality from Kca, an association not highlighted before. There is a need for policy measures to limit TCE discharge to the environment if these results are validated. PMID- 26124350 TI - Incidence Changes of Human Papillomavirus in Oropharyngeal Squamous Cell Carcinoma and Effects on Survival in the Netherlands Cancer Institute, 1980-2009. AB - AIM: Human papillomavirus (HPV) is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC), with an increasing incidence. The present study aimed to determine the changing incidence of HPV in patients with OPSCC in the period 1980 2009 and its influence on survival. PATIENTS AND METHODS: We randomly sampled 158 patients from a cohort of 828 patients with OPSCC stratified by decade (1980 1989, 1990-1999, 2000-2009). Formalin-fixed paraffin-embedded material was tested for HPV DNA by SPF-10 polymerase chain reaction (PCR) and immunohistochemically stained for p16 and p53. RESULTS: DNA from 146 patients was suitable for HPV detection. HPV DNA was detected in 13/47 (28%), 18/47 (38%), and 20/52 (38%) patients in the cohorts of 1980-1989, 1990-1999, and 2000-2009, respectively (p value for trend=0.269). Lack of further increase during the most recent decade is inconsistent with the rising incidence and higher prevalence reported in other Western countries. Patients with HPV-positive OPSCC had a better survival in spite of higher tumor stage. PMID- 26124351 TI - Prognostic Significance of VEGFC and VEGFR1 mRNA Expression According to HER2 Status in Breast Cancer: A Study of Primary Tumors from Patients with High-risk Early Breast Cancer Participating in a Randomized Hellenic Cooperative Oncology Group Trial. AB - BACKGROUND: Vascular endothelial growth factor C (VEGFC) and vascular endothelial growth factor receptor 1 (VEGFR1) mRNA overexpression has recently been shown to have strong predictive and prognostic value in patients with high-risk early breast cancer undergoing adjuvant chemotherapy. The present study evaluated associations of VEGFC and VEGFR1 with human epidermal growth factor receptor 2 (HER2) and their prognostic value dependent on HER2 status. PATIENTS AND METHODS: RNA was isolated from 298 formalin-fixed paraffin-embedded tumor tissue samples from the HeCOG 10/97 (HE10/97) trial, evaluating adjuvant dose-dense sequential chemotherapy with epirubicin followed by cyclophosphamide, methotrexate and 5 fluorouracil therapy with or without paclitaxel (E-T-CMF vs. E-CMF). A fully automated method based on magnetic beads was applied for RNA extraction, followed by one-step quantitative reverse transcription-polymerase chain reaction. RESULTS: At 13.3 years of median follow-up, 116 patients (38.9%) had experienced relapse and 115 (38.6%) had died. There were strong associations between VEGFC/VEGFR1 mRNA expression and HER2 and estrogen receptor/progesterone receptor status. In multivariate analysis, both VEGFC and VEGFR1 were found to be associated with risk for death or relapse, but such associations depended on HER2 status and treatment group. High VEGFC was a negative prognostic factor for disease-free survival [hazard ratio (HR)=1.79, 95% confidence interval (CI)=1.05 3.05, Wald's p=0.032], with a trend for overall survival (HR=1.80, 95% CI=0.94 3.47, p=0.078) in patients treated with E-CMF adjusted for clinicopathological characteristics, while high VEGFR1 was associated with increased risk for death, yet non significantly in patients with HER2-negative disease (HR=1.51, 95% CI=0.82-2.77, p=0.18), regardless of treatment. CONCLUSION: VEGFC and VEGFR1 mRNA overexpression is of prognostic value, dependent on HER2 status, in patients with high-risk early breast cancer undergoing adjuvant treatment. Among HER2-negative cases, these angiogenic markers could identify more aggressive tumors with worse prognosis. Further studies are warranted to validate VEGFC and VEGFR1 as potential biomarkers in adjuvant therapy and their use in identifying sub-groups that could benefit from anti-VEGF strategies. PMID- 26124352 TI - Acute Liver Failure Due to Regorafenib May Be Caused by Impaired Liver Blood Flow: A Case Report. AB - BACKGROUND/AIM: Regorafenib has been approved for treatment of patients with unresectable or recurrent gastrointestinal stromal tumors resistant to imatinib or sunitinib. However, regorafenib has severe side-effects, including acute liver failure. We describe the case of a patient with multiple liver metastases of a small intestinal stromal tumor who experienced acute liver failure while being treated with regorafenib. CASE REPORT: A 50-year-old patient with an unresectable small intestinal stromal tumor resistant to prior treatment with imatinib and sunitinib was started on regorafenib, but experienced acute liver failure 10 days later. Plasma exchange and steroid pulse treatment improved her liver function. During liver failure, abdominal ultrasonography showed to-and-fro flow in the portal vein. Lactate dehydrogenase concentration was markedly elevated to 1633 U/l. These findings indicate that liver failure in this patient was due to impaired liver blood flow. CONCLUSION: Regorafenib may impair liver blood flow, inducing acute liver failure. PMID- 26124353 TI - Death Receptor Expression on Blasts in AML Is Associated with Unfavorable Prognosis. AB - BACKGROUND: Tumor necrosis factor (TNF) receptor family members play a key role in the regulation of biological functions such as differentiation, proliferation and apoptosis of various cell types. MATERIALS AND METHODS: We studied co expression profiles of death receptors from the TNF family [TNF-related apoptosis inducing ligand receptor (TRAILR) 1 to 3, TNF receptor 1 (TNFR1) and FAS receptor (FAS)] on peripheral blood blasts from 46 patients with acute myeloid leukemia (AML) at first diagnosis by flow cytometry and correlated the obtained specific fluorescence indices (SFI) with morphological, cytogenetic and clinical parameters. RESULTS: We found that the expression of TRAILR2 and R3 was significantly increased in unfavorable risk groups, according to the National Comprehensive Cancer Network. Additionally, cut-off analyses for TRAILR2 and TNFR1 showed significantly shorter overall survival, earlier disease onset, higher proportions of cases with unfavorable prognosis and higher probability of relapse when SFIs were above the established cut-off. CONCLUSION: We demonstrate that high co-expression of death receptors on blasts is an independent predictor of poor prognosis in AML. PMID- 26124354 TI - Obesity and Lymphovascular Invasion in Women with Uterine Endometrioid Carcinoma. AB - AIM: Obesity is classically linked to type I endometrial cancer (EC). Lymphovascular invasion (LVI) is a well-known adverse prognostic factor in EC. In other disease sites, it has been reported that obesity and LVI are strongly associated. The objective of the present study was to investigate the association between obesity and LVI in women with EC. PATIENTS AND METHODS: For this Institutional Review Board (IRB)-approved study, we reviewed our prospectively maintained uterine cancer database of 1,950 patients with EC International Federation of Gynecology and Obstetrics (FIGO) stages I-IV who underwent hysterectomy from 1/1988 through 12/2011. Bivariate and multivariate analyses were conducted to investigate the relationships between obesity, as measured by body mass index (BMI) at the time of hysterectomy and tumor features including LVI. RESULTS: A total of 1,341 patients with uterine endometrioid carcinoma were identified. All patients underwent hysterectomy, and salpingoophrectomy with or without lymph node dissection. The median BMI for study patients was 34.3 (range=15.7-71.3) kg/m(2). 46.8% of the patients were morbidly obese. 625 patients (46.7%) were <60 years at diagnosis with a median BMI of 36.31 (range=19.7-69.8) kg/m(2) while the median BMI for women 61 years or older was 32.2 (15.7-71.3) kg/m(2) (p=0.002). In univariate analyses, high BMI was not significantly associated with LVI. In multivariate analyses, higher BMI was independently associated with younger age at diagnosis (odd ratio (OR)=0.97, 95% confidence interval (CI)=0.96-9.97) and the presence of lower tumor FIGO grade (OR=0.98, 95% CI=0.97-0.99). CONCLUSION: Increased BMI was significantly associated with lower tumor grade and younger patient age at diagnosis. Increased body mass index was not associated with LVI. The higher prevalence of obesity in young women with EC is alarming. PMID- 26124355 TI - Investigation of Regorafenib-induced Hypothyroidism in Patients with Metastatic Colorectal Cancer. AB - Hypothyroidism is one of the side-effects caused by regorafenib. In the Japanese subset of the CORRECT study, hypothyroidism developed in 1.5% of the patients, but was not grade 3 or higher in any patient. Regorafenib is an oral multi-kinase inhibitor that has the same mechanism of action as sunitinb. However, the reported incidence of sunitinb-related hypothyroidism varies widely, ranging from 16.0% in clinical trials to 35.4% in post-marketing surveillance studies. In general, symptoms of hypothyroidism include fatigue and dysphonia. Hyperthyroidism must, therefore, be appropriately managed in order to maintain patient quality of life and avoid a critical level of hypothyroidism. During the first cycle of treatment with regorafenib, the incidence of abnormal thyroid stimulating hormone (TSH) elevation was 31.4%. Our results suggest that thyroid function tests should be performed from day 1 of treatment with regorafenib. It would be prudent to consider routine monitoring of thyroid function in all patients who receive regorafenib and to recommend endocrinological consultation as necessary. PMID- 26124356 TI - Prognostic Role of Nodal Status and Clinically Asymptomatic Valvular Insufficiency in Patients with HER2-positive Breast Cancer Treated with Chemotherapy, Radiotherapy and Trastuzumab in an Adjuvant Setting. AB - AIM: The aim of the present study was to assess metastasis-free survival of 134 patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy, radiotherapy and trastuzumab in an adjuvant setting, according to sub-clinical cardiac side-effects (parameters not tested previously) evaluated before, during and after trastuzumab therapy, as well as selected clinicopathological parameters. RESULTS: In our series, left ventricular ejection fraction decreased significantly from 68.1% before trastuzumab treatment to 66.7% after therapy (p<0.001). Further analysis revealed that this decrease was significant only in patients who received radiotherapy and developed valve insufficiency during or after (but not before) trastuzumab therapy (p<0.001). Cox multivariate analysis revealed that both pN2a tumor stage and valve regurgitation during/after trastuzumab therapy (vs. lack of valve insufficiency or insufficiency before trastuzumab therapy) were significant independent factors for a negative prognosis. CONCLUSION: Valve insufficiency diagnosed during or after trastuzumab application might be cancer-unrelated indicator of decreased sensitivity to trasuzumab. PMID- 26124357 TI - Case Mix Difference Can Affect Evaluation of Outcome of Treatment for Colorectal Cancer. AB - AIM: To explore the potential effects of patient selection, for example by organization, on survival as outcome parameter in colorectal cancer treatment. PATIENTS AND METHODS: The main cohort was identified in a Hospital-based registry and outcome data of all 2,717 patients operated on for colorectal cancer between 2000-2011 were evaluated. A simulation of different center settings was performed using several potential selection criteria, including emergency cases, referral surgery and palliative resection, and used for comparison of outcome data. RESULTS: Overall survival and cancer-specific survival can be significantly affected in both short-term (30-/90-day) mortality and long-term survival by factors of organizational level. CONCLUSION: Survival data as an outcome parameter can be affected by the composition of the patient cohort and thus reflect possible selection bias for example due to organization, referral patterns and practice customs. This potential bias should be acknowledged when making inter-hospital comparisons of outcome. PMID- 26124358 TI - Splenectomy Followed by Hepatectomy for Hepatocellular Carcinoma with Hypersplenism and Portal Hypertension Caused by Macroglobulinemia. AB - AIM: To describe a patient with hepatocellular carcinoma (HCC), accompanied by hypersplenism and portal hypertension caused by macroglobulinemia, who underwent splenectomy followed by hepatectomy. CASE REPORT: A 74-year-old man was admitted to our Hospital. He had previously developed primary macroglobulinemia, which had been completely cured by chemotherapy. At admission, he had a low platelet count (52 * 10(3)/MUl), and his liver function was impaired. Imaging showed a 5-cm sized tumor, an esophageal varix, and splenomegaly, but not liver cirrhosis. The patient underwent splenectomy for hypersplenism and portal hypertension; the weight of his spleen was 2,400 g. After splenectomy, his platelet count increased to 259 * 10(3)/MUl and his liver function was improved. He safely underwent hepatectomy for HCC. The patient was discharged 14 days later without morbidity. CONCLUSION: These findings suggest that hepatectomy following splenectomy for hypersplenism and portal hypertension caused by macroglobulinemia, may effectively cure HCC in patients with liver dysfunction and thrombocytopenia. PMID- 26124359 TI - Treatment Planning Comparison for Carbon Ion Radiotherapy, Proton Therapy and Intensity-modulated Radiotherapy for Spinal Sarcoma. AB - BACKGROUND/AIM: Carbon ion radiotherapy (CIRT), proton therapy (PT) and intensity modulated radiotherapy (IMRT) are new radiation modalities suitable for treatment of spinal sarcomas. The objective of the study was to compare the treatment planning of these modalities. PATIENTS AND METHODS: We conducted a treatment planning comparison of the three modalities using a phantom imitating a spinal sarcoma and then six actual cases with spinal tumors. A uniform biological effective dose (BED) of 90 Gy10 was prescribed in previously reported fractionation schedules for each modality. The surface/center spinal cord dose constraints were set to BED of 96/77 Gy(E)3, respectively. RESULTS: CIRT achieved better homogeneity of dose distribution and coverage of target than PT independently of tumor extent around the spinal cord. In IMRT plans, the spinal cord dose was higher than that under CIRT and PT and coverage of the target deteriorated depending on the tumor extension. CONCLUSION: CIRT was most appropriate for the treatment of advanced spinal sarcomas. PMID- 26124360 TI - The Role of Adjuvant Chemotherapy for Patients with Stage IB Gastric Cancer. AB - AIM: The present study aimed to examine the survival benefit of adjuvant chemotherapy for the patients with stage IB gastric cancer according to the second English edition of the Japanese Classification of Gastric Carcinoma (2nd JCGC). PATIENTS AND METHODS: In total, 201 consecutive patients who underwent curative surgery for stage IB gastric cancer according to the 2nd JCGC were retrospectively analyzed. RESULTS: Seventy-four (36.8%) received adjuvant chemotherapy, and 72 (35.8%) had stage II diseases as defined by the 3rd JCGC. The 5-year overall survival (OS) was 86.9%. Multivariate analysis showed that adjuvant chemotherapy was an independent prognostic factor. In the sub-group analysis by stage according to the 3rd JCGC, those with stage II disease had better OS in the adjuvant-chemotherapy group than in the group treated with surgery alone (5-year OS 94.5% vs. 73.9%, p=0.002). CONCLUSION: Among patients with stage IB gastric cancer by 2nd JCGC, and especially patients with stage II defined by the 3rd JCGC, should be considered for adjuvant-chemotherapy. PMID- 26124361 TI - Results of Primary Cytoreductive Surgery in Advanced-stage Epithelial Ovarian Cancer: A Single-center Experience. AB - AIM: To determine the impact of maximal cytoreductive surgery on overall survival in advanced epithelial ovarian cancer. PATIENTS AND METHODS: We retrospectively reviewed medical data of patients submitted to primary cytoreductive surgery for advanced epithelial cancer in the Fundeni Clinical Hospital between 1 January 2002 and 1 April 2014. RESULTS: A total of 338 patients were eligible for the study. Complete cytoreduction was achieved in 242 patients and was associated with a significantly improved survival (p<0.001), when compared to patients in whom incomplete debulking surgery was performed. Other prognostic factors associated with an improved survival were stage by the International Federation of Gynecology and Obstetrics and the preoperative biological status of the patient. CONCLUSION: A more extensive surgical approach is perfectly justified and associated with improved survival in patients with advanced-stage epithelial ovarian cancer. However, patient selection should be performed carefully because the general preoperative status can significantly impact survival. PMID- 26124362 TI - Predicting Survival After Irradiation of Metastases from Pancreatic Cancer. AB - BACKGROUND/AIM: Patients with metastases from pancreas cancer benefit from individualized care, including radiotherapy for symptom control. To administer the optimal radiation therapy, it is important to understand a patient's prognosis. PATIENTS AND METHODS: Seven variables were analyzed regarding their relationship with survival: age, gender, Karnofsky performance score (KPS), number of metastatic sites, interval from diagnosis of pancreatic cancer to irradiation of metastases, type of irradiated metastasis, and radiation dose. RESULTS: On univariate analysis, survival was positively associated with age <= 67 years (p=0.045), KPS >70 (p<0.001), and involvement of only one metastatic site (p=0.013). A longer interval between diagnosis and irradiation of metastases showed a trend for better survival (p=0.077). On multivariate analysis, age [risk ratio (RR)=4.29; p=0.004], KPS (RR=1.95; p=0.020), number of metastatic sites (RR=2.20; p=0.009) and interval to irradiation (RR=4.41; p=0.005) achieved significance. CONCLUSION: The present study identified four independent predictors of survival in patients with pancreatic cancer irradiated for metastasis and thus contributes to treatment optimization. PMID- 26124363 TI - Neoadjuvant Chemoradiotherapy with Volumetric-modulated Arc Therapy for Medium distal Oesophageal and Gastro-oesophageal Junction Carcinoma. AB - AIM: to appraise the role of volumetric-modulated arc therapy (VMAT) in the neoadjuvant chemoradiotherapy management of advanced medium and distal oesophageal cancer in terms of toxicity and response to treatment. PATIENTS AND METHODS: Thirty patients were treated according to the neoadjuvant chemoradiation followed by surgery versus surgery-alone trial scheme with VMAT radiation therapy. Patients presented mainly T3-T4 stage (80%) and N1-2 (96.6%) disease. The chemotherapy scheme consisted of 3-5 cycles, while a radiotherapy course of 41.4 Gy in 23 fractions was administered to all patients. RESULTS: The median age of patients was 65 years, and there was a predominance of males (80%), smokers or ex-smokers (90%) and modest alcohol habit (80% negative). Primary tumor localisation was in the medium and distal third of the oesophagus in 57% of the cases, the rest being in the gastro-oesophageal junction. Modest toxicity profiles were observed, with limited incidence of grade 2-3 events. Partial or complete response was observed in more than 90% of the cases (radiological/metabolic) and was confirmed after surgical intervention (67% partial or complete and 27% stable response). Tumor down-staging was recorded in 67% of patients and nodal down-staging in 50%. CONCLUSION: VMAT was applied in the context of neoadjuvant chemoradiotherapy for the treatment of medium and distal oesophageal carcinoma with satisfactory results in terms of tolerance and toxicity. PMID- 26124364 TI - Epidermal Growth Factor Receptor Expression May Correlate with Survival Through Clinical and Radiological Features of Aggressiveness in Glioblastoma Treated with Radiochemotherapy. AB - AIM: To analyze the correlation between epidermal growth factor receptor (EGFR) expression and clinicoradiological features in patients with glioblastoma. PATIENTS AND METHODS: Select clinical (age, Karnofsky performance status, neurological performance status) and neuroradiological (multiple tumor incidence, peritumoral edema, response to treatment) prognostic variables were correlated with EGFR expression levels estimated on pathological samples in 144 patients who had undergone postoperative radiochemotherapy treatment. RESULTS: Clinical and radiological prognostic parameters, including synchronous multiple tumor, extent of edema, and radiological response after therapy, showed a statistically significant correlation with the EGFR expression score. Patients with a high EGFR expression seemed to present worse cliniconeurological status and radiological features of tumor aggressiveness (higher incidence of multiple tumor, major extent of peritumoral edema and poorer radiological response to treatment). CONCLUSION: A potential correlation between high EGFR expression and aggressive clinical and radiological features of GB seems to exist, leading to worse prognosis in these patients. PMID- 26124365 TI - Pancreatic Resection as Part of Cytoreductive Surgery in Advanced-stage and Recurrent Epithelial Ovarian Cancer--A Single-center Experience. AB - AIM: To demonstrate the efficacy of pancreatic resection as part of cytoreductive surgery for advanced-stage and recurrent epithelial ovarian cancer. PATIENTS AND METHODS: Data of patients submitted to cytoreductive surgery for advanced-stage and relapsed epithelial ovarian cancer at the Dan Setlacec Center of Gastrointestinal Disease and Liver Transplantation, Fundeni Clinical Institute, Romania, treated between January 2002 and May 2014 were retrospectively reviewed. RESULTS: A total of six cases were eligible for the study: one case was submitted to pancreatic resection in the context of primary cytoreduction, four cases were submitted to pancreatic resection during secondary cytoreduction, while the sixth case was submitted to distal pancreatectomy as part of tertiary cytoreduction. The early postoperative course was uneventful in four cases, while the other two developed pancreatic fistulas. In one case, the leak was managed in a conservative manner, while in the second case re-operation was required. Thirty day mortality was zero. At the time of writing, the patient submitted to pancreatic resection during primary cytoreduction was still alive with disease at 54 months and proposed for secondary cytoreduction. The median overall survival for cases submitted to pancreatic resection in the context of secondary cytoreduction was 36.38 months, while the patient submitted to distal pancreatectomy at the moment of tertiary cytoreduction was dead of disease 10 months after surgery. CONCLUSION: Pancreatic resections can be safely performed in the context of cytoreductive surgery for advanced-stage and relapsed epithelial ovarian cancer, with acceptable rates of morbidity, therefore benefit in terms of survival might be achieved. PMID- 26124366 TI - Second Primary Malignancy in Anal Carcinoma--A US Population-based Study. AB - BACKGROUND/AIM: To our knowledge, there are no data on second primary malignancies in anal cancer. This study was conducted to evaluate the risk of second primary malignancies in patients with anal carcinoma. PATIENTS AND METHODS: We selected adult patients diagnosed with anal cancer from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) 13 database. We calculated the risk of second primary malignancies in these patients using multiple primary standardized incidence ratio (MP-SIR) session of SEER statistical software. RESULTS: Among 7,661 patients, 675 (9.07%) developed 747 second primary malignancies, with an observed/expected ratio of 1.41 (95% confidence interval=1.32-1.52, p<0.001), and an absolute excess risk of ~55 per 10,000 population. Significant excess risks were observed for tumors of the oral cavity and pharynx, rectum and anal canal, larynx, lung and bronchus, ovary, vagina, and vulva, and Kaposi's sarcoma and hematological malignancies. The risk of specific second primary malignancies was related to the age of patients, exposure to radiotherapy and latency period. CONCLUSION: The risk of second primary malignancies in adult patients with anal cancer is significantly increased compared to the general population. PMID- 26124367 TI - Characteristics and Treatment Strategies for Small Bowel Adenocarcinoma in Advanced-stage Cases. AB - BACKGROUND: Small bowel adenocarcinoma is an uncommon disease with poor prognosis. Therefore, characteristics and treatment strategies for small bowel adenocarcinoma should be elucidated sufficiently, not only for surgery, but also for chemotherapy. PATIENTS AND METHODS: Medical records were abstracted to identify patients with small bowel adenocarcinoma who were treated at the Iizuka Hospital, Fukuoka, Japan, between 2004 and 2014. The results of surgical treatment for stage II/III cases and the efficacy of chemotherapy for unresectable stage IV cases were investigated. RESULTS: The median tumor size was 25.6 +/- 19.2 mm, and tumor size was not associated with primary symptoms. Nine of the patients were diagnosed with stage II/III disease and underwent surgical resection. The other three patients were diagnosed with stage IV disease, and two out of those three cases received definitive chemotherapy. In two out of the nine resected cases, recurrence was observed; however, surgical resection of the recurrent tumor was associated with a good prognosis. In stage IV cases that received chemotherapy, survival durations of over 11 months were achieved. In contrast, overall survival in the stage IV case without chemotherapy was 3.3 months. CONCLUSION: Curative resection and definitive chemotherapy for unresectable cases are effective treatment strategies for small bowel adenocarcinoma. PMID- 26124368 TI - Maspin, a Marker of Serrated Colorectal Polyps. AB - The serine proteinase inhibitor maspin is a tumor-suppressor protein that stimulates apoptosis and inhibits motility, invasion and cancer metastasis. Mutant maspin galvanises partial loss of tumor-suppressor function, reducing susceptibility to apoptosis and facilitating malignant progression. Mutant maspin has been reported in many tumor types. We recently analyzed maspin expression in 128 colorectal lesions: 39 hyperplastic polyps (HPs), 29 sessile serrated adenoma/polyps (SSA/Ps), three traditional serrated adenomas (TSAs), 20 conventional colorectal adenomas (CCRAs), 5 carcinomas evolving from CCRA, 12 active inflammatory bowel disease (IBD), 2 ulcerative colitis (UC) in remission, 4 solitary ulcers (rectum) and 12 normal colorectal mucosa. The topographic distribution of maspin in the cytoplasm was classified into i) extensive, ii) focal, or iii) negative. The intensity of maspin expression in the cytoplasm was classified into i) unquestionable or ii) negative. Cases with faint (questionable) maspin expression were also recorded as negative. Extensive maspin expression was recorded in 95% (39/41) of the HPs, in 100% (29/29) of the SSA/Ps (including one carcinoma arising in a SSA/P), in 66% (2/3) of the TSAs, but only in 10% (2/20) of the CCRAs. None of the specimens with carcinoma arising in CCRA, with UC in remission or with solitary ulcer exhibited extensive maspin expression. Importantly, maspin was not expressed in the normal mucosa (including that adjacent to HP, SSA/P, TSA and CCRA). It is submitted that extensive maspin expression might be a manifestation of mutant maspin in lesions central to the serrated pathway of colorectal carcinogenesis. PMID- 26124369 TI - Contemporary Incidence and Mortality Rates of Neuroendocrine Prostate Cancer. AB - AIM: The purpose of the study was to provide an update ever the incidence and mortality for neuroendocrine prostate cancer (NEPC) in the United States. PATIENTS AND METHODS: Using a large national database, we examined changes in age adjusted incidence (AAIR), mortality rates (MR) and 5-year cancer-specific survival (CSS) for 378 patients diagnosed with NEPC between 1992 and 2011. Analysis was performed for all NEPC and for its two major sub-groups [small cell carcinoma (SCC) and neuroendocrine carcinoma (NEC)]. RESULTS: AAIR of NEPC continues to rise in recent years (2004-2011:+6.8%/year, p>0.05). AAIR of SCC has been increasing significantly by 6.94%/year since 2001 (from 0.470 to 0.582/1,000,000 person years, p<0.05). Overall incidence-based mortality rates for NEPC did not change significantly since 1992 and similar trends were observed for SCC and NEC. CONCLUSION: The AAIR of SCC is increasing with no change in the MR of NEPC over the past 20 years. PMID- 26124370 TI - Prophylactic Radiotherapy to Intervention Sites in Malignant Pleural Mesothelioma -Single-institution Experience and Literature Review. AB - AIM: To evaluate the efficacy of prophylactic radiotherapy at intervention sites in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: From 05/2010 to 12/2014, 53 patients with histologically confirmed MPM were treated in order to prevent interventional site metastases. Irradiation was carried out with 3 * 7=21 Gy with 6-18 MeV electrons. RESULTS: The mean follow-up period was 14.4 months (range=0-37 months). At the time of the analysis, 20 patients were alive. Three patients had developed a local recurrence within the irradiated site, representing a local recurrence rate of 5.7%. Toxicity was low, with transient grade I erythema found in 20.7% of patients. No grade II or higher toxicity was observed. CONCLUSION: Our simple and time-saving RT approach to interventional sites in patients with MPM was both effective and well-tolerated. This approach is easily integrated into general treatment concepts. Until publication of results from prospective randomized trials, prophylactic RT to intervention sites should remain standard. PMID- 26124371 TI - Exclusive Radiotherapy for Early-stage Glottic Cancer: A Single-institution Retrospective Analysis with a Focus on Voice Quality. AB - AIM: To report on clinical outcomes of patients with early-stage glottic cancer treated with exclusive radiotherapy with specific analysis of voice quality. PATIENTS AND METHODS: A consecutive cohort of 55 patients with early glottic cancer was retrospectively analyzed. Patients were treated with exclusive radiation up to a conventionally fractionated total dose of 66-70 Gy with a 3 dimensional conformal technique. Oncological outcomes and toxicity profiles were investigated. A sub-sample of this cohort was also analyzed in terms of voice quality employing subjective and objective tools such as the Voice Handicap Index 10 (VHI-10) and the Multidimensional Voice Program (MDVPTM) software and was compared to a group of similar patients treated with CO2 laser cordectomy. RESULTS: after a median observation time of 74.5 months, 5- and 10-year local control was 89% [95% confidence interval (CI)=70.7-93.1%] and 86% (95% CI=68.7 89.6%), respectively. Larynx-preservation rate was 91.8% (95% CI=82.4%-94.9%) at 10 years. Five- and 10-year actuarial overall survival was 72% (95% CI=50.4 79.2%) and 56% (95% CI=48.7-64.3%). Maximum detected acute toxicity included G3 dermatitis (5.4%) and G4 dyspnea (1.8%). Late toxicity profile was mild. VHI-10 scores showed a mild voice disability in both groups, with no statistically significant difference (p=0.12), even when investigating different domains. Patients treated with radiation had a lower deterioration rate in all parameters excluding low voice, interruptions of sound and diplophony. CONCLUSION: Exclusive radiation proved an effective treatment for patients with early glottic cancer in terms of both oncological outcome and voice quality. PMID- 26124372 TI - Adjuvant Chemotherapy in Locally Advanced Cervical Cancer After Treatment with Concomitant Chemoradiotherapy--Room for Improvement? AB - BACKGROUND: The standard treatment for locally advanced cervical cancer (LACC) is concomitant chemoradiotherapy. In the majority of patients with LACC after properly executed concomitant chemoradiotherapy local control of the disease is achieved, and consequently distant relapse becomes the main cause of death for these patients. In an attempt to improve the outcome of patients with LACC, we designed a regimen of concomitant chemobrachyradiotherapy with cisplatin and ifosfamide followed by consolidation chemotherapy. PATIENTS AND METHODS: Between 1999 and 2012, 118 patients diagnosed with LACC, The International Federation of Gynecology and Obstetrics (FIGO) stages IB2-IVA, regardless of histology, were treated with concomitant chemobrachyradiotherapy and consolidation chemotherapy at our Institution. Chemotherapy consisted of two cycles of cisplatin and ifosfamide applied concomitantly with two intracavitary low-dose rate brachytherapy applications, and of four cycles of the same drug combination as an adjuvant/consolidation part of the treatment. The primary outcome in this analysis was distant disease-specific survival. RESULTS: A total of 18 patients had documented relapse of cervical cancer, with only three local recurrences observed; 15 patients developed only distant recurrence, and one patient developed both local and distant recurrence. The distant disease-specific survival after a median follow-up of 96 months was 86.4%. CONCLUSION: Consolidation or adjuvant chemotherapy that follows concomitant chemoradiotherapy has a potential role in further improving control of the disease, especially distant control of the disease. PMID- 26124373 TI - Outcomes After Laparoscopic Hepatectomy in the Semi-prone Position for Hepatocellular Carcinoma Located in Segment 6, 7, or 8. AB - BACKGROUND: This retrospective study investigated outcomes after laparoscopic hepatectomy in the semi-prone position compared to open hepatectomy in the conventional supine position, for HCC (hepatocellular carcinoma) located in segment 6, 7, or 8. PATIENTS AND METHODS: Patients were divided into two groups according to the surgical approach. The clinicopathological and surgical outcomes were analyzed. RESULTS: There were no significant differences in patient-related or tumor-related factors between the two groups. The laparoscopic-hepatectomy group had significantly less blood loss, fewer postoperative complications, and a shorter hospital stay than the open-hepatectomy group. There were no in-hospital deaths. The postoperative change in the serum C-reactive protein was a significantly larger decrease in the group treated with laparoscopic hepatectomy than that in the open-hepatectomy group. CONCLUSION: Laparoscopic hepatectomy in the semi-prone position for HCC is safe and minimally invasive, and can reduce intraoperative bleeding, postoperative complications, and hospital stay compared to open hepatectomy. PMID- 26124374 TI - Stereotactic Body Radiation Therapy for Liver Lesions. A Single-institution Experience. AB - AIM: To evaluate survival and toxicity in a cohort of patients treated with stereotactic body radiation therapy (SBRT) for unresectable intrahepatic malignancies. PATIENTS AND METHODS: From 2007 to 2014, 23 patients with 34 lesions (three primary and 31 metastatic liver tumors) were treated with SBRT. RESULTS: The median follow-up was 9 months (range=1-76) for all patients. Local control was reached in 27 out of 34 (79%) treated lesions, with 1 and 2 years rates of 93% and 73%, respectively. The progression-free survival at 1-year and 2 year was 50% and 25%, respectively. Median overall survival was 16 months (95% confidence interval=8-24 months), with 1-year and 2-year rates of 58% and 41%, respectively. Toxicity was very low consisting mainly of grade 1 and 2 events. CONCLUSION: SBRT provides good local control for both primary and metastatic liver lesions, with minimal toxicity. PMID- 26124375 TI - Image-guided Intensity-modulated Radiotherapy for Prostate Cancer Employing Hypofractionation and Simultaneous Integrated Boost: Results of a Consecutive Case Series with Focus on Erectile Function. AB - AIM: To report on clinical outcomes of prostate cancer patients treated with hypofractionated radiotherapy employing a simultaneous integrated boost strategy. PATIENTS AND METHODS: A consecutive series of 104 patients affected with prostate cancer was treated with intensity-modulated radiotherapy using a hypofractionated schedule and a simultaneous integrated boost consisting of 70 Gy (2.5 Gy daily) to the prostate gland, 63 Gy to the seminal vesicles (2.25 Gy daily) and 53.2 Gy to the pelvic nodes (1.9 Gy daily) when needed, delivered in 28 fractions. All patients underwent image-guided radiotherapy procedure consisting of daily cone beam computed tomography. RESULTS: After a median observation time of 26 (range=15-48) months, the 3-year biochemical failure-free survival was 96.5% [95% confidence interval (CI)=89%-98%], 3-year cancer-specific survival was 98.5% (95% CI=91%-99%) and 3-year overall survival was 96.5% (95% CI=89%-98%). The gastrointestinal and genitourinary toxicity profiles were mild with fewer than 2% of grade 3 events. Erectile function was partially affected by radiation in men potent at baseline. CONCLUSION: Hypofractionation delivered with intensity modulated radiotherapy and a simultaneous integrated boost approach proved to be a safe and effective treatment option for patients with prostate cancer. Patients with a preserved baseline erectile function experience a decrease in functionality correlated with the mean dose received by penile bulb. PMID- 26124376 TI - Reliability of Endocervical Curettage in the Diagnosis of High-grade Cervical Neoplasia and Cervical Cancer in Selected Patients. AB - AIM: To analyze the reliability of endocervical curettage (ECC) in the diagnosis of high-grade cervical intraepithelial neoplasia and cervical cancer, and to identify risk factors associated with diagnostic underestimation. MATERIALS AND METHODS: A retrospective study was carried-out involving 445 patients who underwent ECC for: endocervical lesion incompletely visible on colposcopy or inaccessible to biopsy; atypical glandular cells on smear, or discrepancy between colposcopic impression and cytological abnormalities. RESULTS: Comparison between ECC and final diagnosis showed a perfect match in 362 patients (81.3%). For 189 patients with pre-cancerous or cancerous endocervical lesions, the sensitivity, specificity, and positive and negative predictive values were 87.3%, 96.9%, 95.4% and 91.9%, respectively. No clinical, cytological or colposcopic characteristics were associated with significantly increased risk of diagnostic underestimation with ECC. CONCLUSION: ECC is a very reliable tool for reducing the number of unnecessary treatments, without increasing the risk of allowing some lesions to evolve into cancer. PMID- 26124377 TI - Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting. AB - BACKGROUND: We evaluated chemotherapy with itraconazole (a common anti-fungal agent that is a potent inhibitor of the Hedgehog pathway, P-glycoprotein, and angiogenesis) for treating progressive pancreatic cancer. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of patients with histologically diagnosed pancreatic cancer who had received first- or second-line chemotherapy and subsequent chemotherapy with itraconazole. RESULTS: A total of 38 patients received docetaxel (35 mg/m(2)), gemcitabine (1,000 mg/m(2)), and carboplatin (area under the curve, 4 mg/min/ml) on day 1 and oral itraconazole solution (400 mg) on days -2 to 2, repeated every 2 weeks. One complete response and 13 partial responses were observed, for a response rate of 37%. Eight (21%) patients experienced febrile neutropenia. The median overall survival was 11.4 months (95% confidence interval=8.5-21.2 months). CONCLUSION: Combination chemotherapy with itraconazole is promising for prolonging overall survival, with acceptable toxicities in the second-line setting of pancreatic cancer. PMID- 26124379 TI - Curative Resection After Gemcitabine, Cisplatin and S-1 Chemotherapy for Initially Unresectable Biliary Duct Cancer: A Case Report. AB - A 68-year-old woman was diagnosed with unresectable upper bile duct cancer with suspected invasion of the right hepatic artery and para-aortic lymph node metastasis (T4N3M0, stage IVb). She underwent plastic stent placement for obstructive jaundice and enrolled in our phase I study for unresectable biliary tract cancer consisting of cisplatin (25 mg/m(2) i.v. for 120 min) followed by gemcitabine (1,000 mg/m(2) i.v. for 30 min) on days 1 and 8, and oral S-1 on alternate days. After 8 courses of neoadjuvant chemotherapy without adverse effects, computed tomography showed near-complete disappearance of the tumor of the upper bile duct and of swollen lymph nodes. She then underwent sub-total stomach-preserving pancreatico duodenectomy and lymph node dissection. The pathological stage was pT1N0M0, stage I. The patient made a satisfactory recovery, was discharged 29 days after operation, and remains free of disease at 3 months after the operation under adjuvant chemotherapy using S-1. PMID- 26124378 TI - Utility of Human Papillomavirus Genotyping for Triage of Patients with Atypical Squamous Cells of Undetermined Significance by Cervical Cytology. AB - BACKGROUND/AIM: No human papillomavirus (HPV) type-specific guidelines exist for managing cases of patients with atypical squamous cells of undetermined significance (ASC-US) by cervical cytology. Herein, we investigated ASC-US triage strategies using HPV genotyping to identify methods that are potentially superior to triage, using Hybrid Capture 2. MATERIALS AND METHODS: In this retrospective cohort study, 144 Korean women with ASC-US cytology underwent HPV genotyping and punch biopsy under colposcopy/endocervical curettage. We created a model for ASC US triage using HPV genotyping in these patients. The sensitivity of the final triage criterion was internally validated using bootstrapping. RESULTS: Positivity for HPV16, 18, 31, 33, 52 and 58 genotype corresponded to a referral rate of 63% and detection of 92% of cases of cervical intraepithelial neoplasia grade 2 or higher. The referral and detection rates for such cases increased in proportion to the number of high-risk HPV types. The sensitivity of genotyping for HPV16, 18, 31, 33, 52 and 58 was 92%. CONCLUSION: The study demonstrates that HPV genotyping of specific HR-HPV types may be an effective strategy in ASC-US triage and may replace conventional HPV tests. PMID- 26124380 TI - Cetuximab Might Be Detrimental to Metastatic Colorectal Cancer Patients with KRAS Codon 12 Mutations. AB - BACKGROUND: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies benefit patients with wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). However, their effect in KRAS-mutant mCRC remains unclear. PATIENTS AND METHODS: This was a retrospective study enrolling 163 patients with unresectable KRAS mutant mCRC diagnosed at the National Taiwan University Hospital between 2007 and 2011. RESULTS: The median overall survival (mOS) was 29.5 months in patients who had never used cetuximab and 19.0 months in those who had (p=0.040). The mOS was 32.0 months in patients with mutant KRAS codon 12 who had never used cetuximab and 17.5 months in those who had (p=0.017). In patients with mutant KRAS codon 13, the mOS was not significantly different. Univariate and multivariate Cox proportional hazards analysis revealed that absence of cetuximab treatment was an independent prognostic factor for longer mOS in patients with unresectable KRAS mutant mCRC. CONCLUSION: Cetuximab usage might be detrimental to patients with mCRC with mutant KRAS codon 12. PMID- 26124381 TI - Estimation of the Six-month Survival Probability After Radiosurgery for Brain Metastases from Kidney Cancer. AB - AIM: To generate an overall survival score for patients with kidney cancer who underwent radiosurgery for brain metastases. PATIENTS AND METHODS: Thirty-six patients who received radiosurgery alone for 1-3 brain metastases from kidney cancer were included. On multivariate analysis of a preceding study of such patients, Karnofsky performance score (KPS) and extracranial spread were significantly associated with overall survival and formed the basis for this score. For each patient, the prognostic score was derived from adding the points of KPS and extracranial spread resulting in a score of 9, 12, 15 or 18 points. RESULTS: Six-month overall survival rates were 13% for patients with 9 points, 80% for those with 12 points, 79% for those with 15 points and 100% for those with 18 points, respectively. Three groups of patients were defined with scores of 9, 12-15 and 18 points. Six-month overall survival rates were 13%, 79% and 100%, respectively (p=0.004). CONCLUSION: This new score facilitates personalized treatment decisions for patients with kidney cancer with very few brain metastases. PMID- 26124382 TI - Value of the Nottingham Histological Grading Parameters and Nottingham Prognostic Index in Canine Mammary Carcinoma. AB - BACKGROUND/AIM: In the past decade, the human Nottingham histological grade (NHG) has been applied to canine mammary carcinomas (CMC). The Nottingham Prognostic Index (NPI) enables identification of more aggressive human breast cancer. The prognostic value of grading parameters and NPI has never been detailed in CMC. The aim of the present study was to assess the prognostic value of NHG, its parameters and NPI. MATERIALS AND METHODS: Univariable and multivariable analyses were used to assess the prognostic value of NHG, its parameters and NPI in a cohort of 59 dogs with CMC. RESULTS: Short disease-free interval and overall survival were associated with higher NHG, particularly of grade III. Only high nuclear pleomorphism score was significantly associated with poor survival. NPI exhibited a strong predictive value for disease progression. CONCLUSION: NHG, nuclear pleomorphism and NPI have prognostic value in CMC. Nuclear pleomorphism is an independent prognostic factor. Evaluation of nuclear pleomorphism should be included in routine pathology reports. PMID- 26124383 TI - Factors Predictive of Re-excision After Oncoplastic Breast-conserving Surgery. AB - BACKGROUND: Oncoplastic surgery (OPS) consists of breast-conserving surgery (BCS) that allows for oncologically safe breast conservation and breast remodeling, thus reducing postoperative deformities. The purpose of the present study was to identify factors determining the risk of re-excision and complications after OPS. PATIENTS AND METHODS: A retrospective analysis was conducted on patients who underwent OPS between 2009 and 2013, regardless of whether neoadjuvant chemotherapy was administered. Clinical and pathological factors were evaluated. Recursive partitioning analysis (RPA) was used to build regression trees for the prediction of re-excision. RESULTS: Amongst the 129 patients treated by OPS procedures, 30.3% required re-excision. Predictive factors for re-excision were: being overweight (p=0.02), the presence of microcalcifications on mammography (p=0.003), and tumor multifocality (p=0.03). The RPA identified five terminal nodes based on microcalcifications on mammography, being overweight and the presence of ductal carcinoma in situ. Another model included minimal invasive margins (p<0.001), being overweight (p=0.02) and the presence of microcalcifications (p=0.01) on mammography yielded a model with an area under the receiver operating characteristic curve of 0.875. CONCLUSION: Microcalcifications, tumor multifocality and being overweight were the factors identified as predictors of re-excision after OPS. These factors can serve as decisional tools before surgery. PMID- 26124384 TI - Effect of Celecoxib on Survival of Mobile Tongue Cancer. AB - AIM: The goal of the present study was to evaluate the effects of celecoxib on treatment outcomes of squamous cell carcinoma of the mobile tongue. PATIENTS AND METHODS: Among 158 patients who were diagnosed with mobile tongue cancer, 19 received celecoxib during the preoperative, postoperative, or post-recurrence phase. Differences in disease-specific survival (DSS) and recurrence-free survival (RFS) between patients who received celecoxib (study group) and those who did not (control group) were analyzed. RESULTS: For the entire cohort, DSS and RFS were not significantly different according to duration of celecoxib treatment (p=0.293 and 0.703, respectively). Among patients who received chemotherapy, DSS was significantly higher in the study group than in the control group (p=0.048), but RFS was not different between the two groups (p=0.117). CONCLUSION: When combined with chemotherapy, celecoxib may have a beneficial effect on the survival of patients with mobile tongue cancer. PMID- 26124385 TI - Effect of Race and Insurance on the Outcome of Stage I Non-small Cell Lung Cancer. AB - BACKGROUND: Lung cancer is the leading cause of death in the United States, with reported inferior survival among African-Americans. PATIENTS AND METHODS: Kaplan Meier and Cox regression methods were used to compare survival outcomes of 569 patients diagnosed with stage I non-small cell lung cancer from 2001-2010. RESULTS: African-Americans and Whites differed significantly by age, sex, and insurance type. The median follow-up was 2.3 years. The 2-, 5- and 8-year overall survival was 72%, 47%, and 38%, respectively. Age, stage, insurance type, and surgery were significant predictors of overall survival which remained significant after adjusting for other variables, including race, gender, histology, smoking history, treatment era, chemotherapy or radiotherapy which were not. CONCLUSION: Insurance status but not race is an important predictor of survival in patients with stage I non-small cell lung cancer. PMID- 26124386 TI - Association of Basal and Calcium-stimulated Calcitonin Levels with Pathological Findings After Total Thyroidectomy. AB - BACKGROUND/AIM: Medullary thyroid carcinoma (MTC) originates from thyroid C-cells and is a calcitonin-secreting tumor. Calcitonin is also elevated in C-cell hyperplasia (CCH). The objective of the study was to determine the optimal basal (bCT) and peak stimulated calcitonin (psCT) cut-off value for differentiating MTC from CCH, and to examine the histological findings of thyroidectomy in patients with maximum psCT >100 pg/ml. PATIENTS AND METHODS: Fifty-five patients had a maximum calcium-psCT >100 pg/ml and underwent total thyroidectomy. RESULTS: A total of 20 patients were diagnosed with MTC and the remaining 35 with CCH. A bCT level >17.4 pg/ml and psCT level >452 pg/ml demonstrated the best sensitivity and positive predictive value for differenting MTC from CCH. CONCLUSION: The overlap of calcitonin levels between MTC and CCH reduces the accuracy of the calcium stimulation test. Remarkably, an appreciable number of patients with psCT levels >100 pg/ml harbor differentiated thyroid carcinoma of follicular origin. PMID- 26124387 TI - Efficacy and Safety of Combined Carboplatin, Paclitaxel, and Bevacizumab for Patients with Advanced Non-squamous Non-small Cell Lung Cancer with Pre-existing Interstitial Lung Disease: A Retrospective Multi-institutional Study. AB - AIM: To investigate the efficacy and safety of carboplatin, paclitaxel, and bevacizumab (CPB) combination chemotherapy in patients with non-squamous non small cell lung cancer (NSCLC) with pre-existing interstitial lung disease (ILD). PATIENTS AND METHODS: Twenty-five patients with non-squamous NSCLC with ILD who underwent CPB therapy between March 2007 and July 2013 were analyzed for treatment profiles. RESULTS: The median age was 67 (range=53-79) years and 96% were men. The triplet chemotherapy was repeated for a median of four cycles. The objective response rate was 72% (18/25), the median progression-free survival time was 7.2 months, and the median overall survival time was 8.5 months. The most frequent adverse event of grade 3 or more was neutropenia (72%, 18/25). Chemotherapy-induced acute exacerbation of ILD occurred in 12% of patients. CONCLUSION: CPB therapy may be an effective and feasible regimen even for patients with ILD, although clinicians should be concerned regarding neutropenia and acute exacerbation of ILD. PMID- 26124388 TI - 111In-Pentetreotide SPECT/CT in Pulmonary Carcinoid. AB - AIM: We evaluated somatostatin receptor scintigraphy (SRS) with (111)In pentetreotide incremental value in pulmonary carcinoid (PC) diagnosis compared to contrast enhanced Computed Tomography (ceCT). PATIENTS AND METHODS: We enrolled 81 patients with ascertained PC, 39 at initial staging and 42 in follow-up; the primary tumor had already been excised in 68 cases. Single Photon emission Computed Tomography (SPECT) images were reconstructed with the iterative method and fused with non-enhanced Computed tomography (CT) images. RESULTS: Primary PC or metastatic lesions were ascertained in 55/81 patients and SPECT/CT was positive in 50/55 cases, while ceCT was positive in 44/55. Comparing SPECT/CT with ceCT results, we found a sensitivity of 96 vs. 87.5%, and specificity of 92% vs. 97% for the detection of primary lesion or recurrent disease. A total of 198 lesions were ascertained at SPECT/CT, while 161 at ceCT, with values of sensitivity and specificity of 85.5% and 84.6% for SRS and 75.2% and 90.5% respectively. CONCLUSION: (111)In-Pentetreotide SPECT/CT proved to be more sensitive and accurate than ceCT, thus enhancing its role in evaluating patients with PC. PMID- 26124389 TI - Plasma Tumor M2-Pyruvate Kinase Levels in Different Cancer Types. AB - BACKGROUND/AIM: Tumor M2-pyruvate kinase (M2-PK) is up-regulated in proliferating tissues. It has been shown that tumor M2-PK is detectable and quantifiable in the stool and plasma of patients with colorectal cancer (CRC). Tumor M2-PK has been extensively studied in gastrointestinal tumors but its role in other cancer types has not yet been deeply evaluated. The aim of the study was to determine and compare plasma tumor M2-PK levels in different cancer types. MATERIALS AND METHODS: All patients undergoing diagnostics for cancer at our Hospital during 2011 were included in the study (n=139). Plasma tumor M2-PK concentration was analyzed by an enzyme-linked immunosorbent assay. RESULTS: The different cancer types found in the study were: 60 colorectal, 43 breast, 8 lung, 5 prostatic, 4 ovarian and the remaining 19 cases were other uncommon tumor types. Most tumors had high concentrations of tumor M2-PK; prostatic, pharyngeal and testicular tumors had levels lower than or near the cut-off. Plasma tumor M2-PK levels were significantly higher in patients with distant metastases and stage IV by TNM. CONCLUSION: Plasma tumor M2-PK is not a specific marker for CRC and is elevated in many other types of cancers, including breast, lung, ovarian, and thyroid. Small amounts are found in prostatic, pharyngeal and testicular tumors. PMID- 26124390 TI - Female Gender Is an Age-dependent Negative Prognostic Factor for Patients with Upper Tract Urothelial Carcinoma. AB - AIM: To analyze female gender as a possible age-dependent prognostic factor for overall (OS) and cancer-specific survival (CSS) in patients with upper urinary tract urothelial carcinoma (UUTUC) after radical nephroureterectomy (RNU). PATIENTS AND METHODS: A total of 167 men and 101 women with UUTUC treated with RNU with bladder cuff resection at our clinic were retrospectively analyzed. Female patients were divided into pre- and post-menopausal groups and compared against male patients of the same age. We used a cut-off age of 59 years or more as a surrogate for the post-menopausal hormonal status of women. Kaplan-Meier analyses and multivariate Cox proportional hazards regression analyses were performed to analyze gender as a possible prognostic factor of OS and CSS. RESULTS: Women aged 59 years or more had a significantly worse CSS with an average of 231 months after RNU compared to 303 months for their male counterparts (p=0.011). Univariate Cox regression analysis showed a 2.44-fold higher risk of death (p=0.013), while multivariate analyses, adjusted for tumor stage and tumor grade, showed a 2.92-fold higher risk (p=0.011) of cancer specific death for women aged 59 years or more. CONCLUSION: Female gender is an age-dependent prognostic factor for CSS for patients with UUTUC treated with RNU. PMID- 26124391 TI - Errata. PMID- 26124392 TI - Retraction. PMID- 26124429 TI - Right upper lobe lung cancer: Resection through left anterior mediastinotomy. AB - There is sparse information concerning approaches to metachronous lung cancer in patients who had a previous pneumonectomy for lung carcinoma. We describe the case of a 55-year-old woman who underwent a left pneumonectomy for lung carcinoma. Four years later, a radiological examination revealed a hypermetabolic nodule in the right upper lobe, which was located in the left hemithorax because of right lung hyperinflation and a mediastinal shift to the left. Wedge resection was carried out through a left anterior mediastinotomy. We believe that an anterior mediastinotomy represents a valuable option for the management of recurrent lung cancer after previous surgery. PMID- 26124430 TI - Uniportal thoracoscopic management of middle lobe torsion after upper lobectomy. AB - Lobar torsion is a rare but potentially life-threatening complication following pulmonary resection. Surgical management usually entails an exploratory thoracotomy and resection of the involved lobe if nonviable. We present the case of a 67-year-old woman diagnosed with right middle lobe torsion 5 days after thoracotomy and right upper lobectomy for squamous carcinoma of the lung. A thoracoscopic right middle lobectomy was successfully performed utilizing a single 4-cm port placed along the midaxillary line in the 5th intercostal space. PMID- 26124431 TI - Tuberculous constrictive pericarditis and atrial septal defect: Surgical challenge. AB - Tuberculous constrictive pericarditis with atrial septal defect is very rare. A 23-year-old man required pericardiectomy and atrial septal defect closure under cardiopulmonary bypass by cannulating the aorta and right atrium because femoral cannulation was not possible and the venae cavae could not be visualized. He was discharged in a satisfactory condition on the 15th postoperative day, but returned one month later with swelling all over his body and dyspnea on exertion. Echocardiography showed atrial septal defect patch dehiscence and a bidirectional shunt with a collection or mass compressing the right ventricle. Subxiphoid exploration was carried out, and the swelling subsided. PMID- 26124432 TI - Efficacy of minimally invasive surgery in diagnosis of interstitial lung disease. AB - OBJECTIVE: This study aimed to evaluate the efficacy and safety of video-assisted thoracic surgery in reaching a specific diagnosis in patients with interstitial lung disease. METHODS: Thirty-eight patients with interstitial lung disease (19 males, 19 females; mean age 47.73 years) who had undergone video-assisted thoracic surgery at Ghaem Hospital, Mashhad, Iran, between 2010 and 2013 were evaluated retrospectively in this study. Preoperative evaluations including cardiac and pulmonary assessments were performed. Data were recorded in forms prepared for this study and included age, sex, symptoms, imaging findings, operation duration, chest drain withdrawal time, postoperative hospital stay, hospital mortality, and specific diagnosis of the disease. RESULTS: The most common symptom was dyspnea (38 patients, 100%). The most common computed tomography finding was a reticular pattern (30 patients, 78.94%). Surgery complications included persistent air leak in 3 (7.9%) cases and wound infection in 2 (5.26%). There was no hospital death and no need for reoperation. The average of operative time was 50 min. The mean time for chest drain withdrawal and postoperative hospitalization was 4 and 5 days, respectively. The most common diagnoses were usual interstitial pneumonia in 9 (23.68%) patients and sarcoidosis in 6 (15.78%). A specific diagnosis was not reached in 2/38 (5.26%) patients after video-assisted thoracic surgery. CONCLUSION: Video-assisted thoracic surgery is a highly effective and safe method for establishing a specific diagnosis in patients with interstitial lung disease. PMID- 26124433 TI - Movement of mitral fibrous components in an isolated porcine working heart model. AB - BACKGROUND: There is little research regarding the movement of mitral fibrous components. We analyzed changes in mitral fibrous components in normal and deteriorated isolated working swine hearts. METHODS: In 5 swine hearts, 6 sonomicrometry transducers were placed around the mitral annulus and 2 in the papillary muscle tip. During the working cycle, we evaluated the annular dimension and calculated the contraction range and contraction ratio during the cardiac cycle in normal and deteriorated modes. RESULTS: The transverse (24.5 +/- 2.3 vs. 27.4 +/- 2.4 mm) and posterior longitudinal diameter (18.3 +/- 7.0 vs. 22.5 +/- 5.5 mm) increased significantly in deteriorated mode. The contraction range in transverse (1.8 +/- 0.6 vs. 0.8 +/- 0.7 mm) and posterior longitudinal (1.6 +/- 0.6 vs. 0.8 +/- 0.3 mm) diameters decreased significantly in deteriorated mode. The contraction range of the strut chordae was less than 1.0 mm in both modes, with no significant differences. The contraction ratio of the anterior strut chordae was significantly reduced in deteriorated mode (3.2 +/- 1.1% vs. 2.2 +/- 1.1%). The contraction ratio of the annulus was significantly lower in deteriorated mode with respect to transverse (6.9 +/- 2.1% vs. 2.9 +/- 2.9%) and longitudinal (13.3 +/- 4.5% vs. 8.6 +/- 5.1%) diameters. CONCLUSIONS: In the deteriorated hearts, the mitral annulus was dilated and contractility decreased. The length of the strut chordae differed 1 mm between the deteriorated and normal modes; however, the contraction ratio of the anterior chordae during the cardiac cycle was reduced, indicating increased stretching. PMID- 26124434 TI - Coronary artery dimensions: Iranian population versus Indo-Asians and Caucasians. AB - BACKGROUND: The dimensions of the coronary arteries have been shown to vary among ethnic groups. There are no data available regarding the normal size of coronary arteries in Iranians. This study aimed to investigate normal coronary artery dimensions in a Northwestern Iranian population and to compare it with pooled data of Indo-Asians and Caucasians in previous studies. METHODS: The study included 200 adults with suspected coronary disease who were referred for elective coronary angiography between June 2012 and March 2013 and were found to have normal epicardial flow in the coronary arteries. Quantitative coronary angiography was carried out on the longest atheroma-free part of the proximal segment of each coronary artery in all patients. Two Indo-Asian and Caucasian groups were selected and pooled for comparison with the available reports on individuals without coronary artery disease. RESULTS: The mean diameters of the left main coronary artery, proximal left anterior descending artery, proximal left circumflex, and proximal right coronary artery were 4.58 +/- 0.80, 3.69 +/- 0.64, 3.37 +/- 0.73, and 3.47 +/- 0.68 mm, respectively. The dimensions of the proximal part of the left main coronary artery and right coronary artery were significantly greater in the Northwestern Iranian population compared to the pooled Caucasian group. This difference was maintained even after correction for body surface area. CONCLUSION: Our data indicate larger coronary diameters in the Iranian population compared to Caucasians or South-Asians. Hence the high prevalence of coronary artery disease in Iran cannot be explained by coronary dimensions. PMID- 26124435 TI - "False" aortic dissection. PMID- 26124437 TI - Correction. PMID- 26124438 TI - Correction. PMID- 26124436 TI - Very-long-chain fatty acid sphingomyelin in nuclear lipid microdomains of hepatocytes and hepatoma cells: can the exchange from C24:0 to C16:0 affect signal proteins and vitamin D receptor? AB - Lipid microdomains localized in the inner nuclear membrane are considered platforms for active chromatin anchoring. Stimuli such as surgery, vitamin D, or glucocorticoid drugs influence their gene expression, DNA duplication, and RNA synthesis. In this study, we used ultrafast liquid chromatography-tandem mass spectrometry to identify sphingomyelin (SM) species coupled with immunoblot analysis to comprehensively map differences in nuclear lipid microdomains (NLMs) purified from hepatocytes and hepatoma cells. We showed that NLMs lost saturated very-long-chain fatty acid (FA; C24:0) SM in cancer cells and became enriched in long-chain FA (C16:0) SM. We also found that signaling proteins, such as STAT3, Raf1, and PKCzeta, were increased and vitamin D receptor was reduced in cancer cells. Because recent researches showed a shift in sphingolipid composition from C24:0 to C16:0 in relation to cell life, we performed a comparative analysis of properties among C16:0 SM, C24:0 SM, and cholesterol. Our results led us to hypothesize that the enrichment of C16:0 SM could determine enhanced dynamic properties of NLMs in cancer cells with an increased shuttling of protein signaling molecules. PMID- 26124441 TI - Primary health care quality and hospitalizations for ambulatory care sensitive conditions in the public health system in Porto Alegre, Brazil. AB - PURPOSE: To investigate the relation of hospitalization for ambulatory care sensitive conditions (ACSC) with the quality of public primary care health services in Porto Alegre, Brazil. METHODS: Cohort study constructed by probabilistic record linkage performed from August 2006 to December 2011 in a population >=18 years of age that attended public primary care health services. The Primary Care Assessment Tool (PCATool-Brazil) was used for evaluation of primary care services. RESULTS: Of 1200 subjects followed, 84 were hospitalized for primary care sensitive conditions. The main causes of ACSC hospital admissions were cardiovascular (40.5%) and respiratory (16.2%) diseases. The PCATool average score was 5.3, a level considerably below that considered to represent quality care. After adjustment through Cox proportional hazard modelling for covariates, >60 years of age [hazard ratio (HR): 1.13; P = 0.001), lesser education (HR: 0.66; P = 0.02), ethnicity other than white (HR: 1.77; P = 0.01) and physical inactivity (HR: 1.65; P = 0.04) predicted hospitalization, but higher quality of primary health care did not. CONCLUSION: Better quality of health care services, in a setting of overwhelmingly low quality services not adapted to the care of chronic conditions, did not influence the rate of avoidable hospitalizations, while social and demographic characteristics, especially non-white ethnicity and lesser schooling, indicate that social inequities play a predominant role in health outcomes. PMID- 26124442 TI - Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer. AB - Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = -0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation. IMPLICATIONS: The relationship of this activation score to sensitivity to anti-PI3K agents remains to be tested but may provide more precision guidance when selecting patients for these therapies. PMID- 26124443 TI - Structure, Dynamics, and Functionality of Tankyrase Inhibitor-Induced Degradasomes. AB - Tankyrase (TNKS) enzymes, due to their poly(ADP-ribose) polymerase activity, have emerged as potential targets in experimental cancer therapy. However, the functional consequences of TNKS inhibition remain incompletely resolved because of the binding promiscuity of TNKS. One of the hallmarks of small-molecule TNKS inhibitors (TNKSi) is the stabilization of AXIN, which plays a pivotal role in the WNT/beta-catenin signaling pathway. The present study focused on the known ability of TNKSi to induce cytoplasmic puncta (degradasomes) consisting of components of the signal-limiting WNT/beta-catenin destruction complex. Using the colorectal cancer cell line SW480 stably transfected with GFP-TNKS1, it was demonstrated that a TNKS-specific inhibitor (G007-LK) induces highly dynamic and mobile degradasomes that contain phosphorylated beta-catenin, ubiquitin, and beta TrCP. Likewise, G007-LK was found to induce similar degradasomes in other colorectal cancer cell lines expressing wild-type or truncated versions of the degradasome component APC. Super-resolution and electron microscopy revealed that the induced degradasomes in SW480 cells are membrane-free structures that consist of a filamentous assembly of high electron densities and discrete subdomains of various destruction complex components. Fluorescence recovery after photobleaching experiments further demonstrated that beta-catenin-mCherry was rapidly turned over in the G007-LK-induced degradasomes, whereas GFP-TNKS1 remained stable. In conclusion, TNKS inhibition attenuates WNT/beta-catenin signaling by promoting dynamic assemblies of functional active destruction complexes into a TNKS-containing scaffold even in the presence of an APC truncation. IMPLICATIONS: This study demonstrates that beta-catenin is rapidly turned over in highly dynamic assemblies of WNT destruction complexes (degradasomes) upon tankyrase inhibition and provides a direct mechanistic link between degradasome formation and reduced WNT signaling in colorectal cancer cells. PMID- 26124444 TI - Gene Expression Changes Associated With the Developmental Plasticity of Sea Urchin Larvae in Response to Food Availability. AB - Planktotrophic sea urchin larvae are developmentally plastic: in response to food scarcity, development of the juvenile rudiment is suspended and larvae instead develop elongated arms, thus increasing feeding capacity and extending larval life. Here, data are presented on the effect of different feeding regimes on gene expression in larvae of the green sea urchin Strongylocentrotus droebachiensis. These data indicate that during periods of starvation, larvae down-regulate genes involved in growth and metabolic activity while up-regulating genes involved in lipid transport, environmental sensing, and defense. Additionally, we show that starvation increases FoxO activity and that in well-fed larvae rapamycin treatment impedes rudiment growth, indicating that the latter requires TOR activity. These results suggest that the developmental plasticity of echinoplutei is regulated by genes known to control aging and longevity in other animals. PMID- 26124445 TI - Temperature Effects on Reproductive Allocation in the Sandhopper Talorchestia capensis. AB - In invertebrates, environmental temperature may induce mothers to invest differently in the early development of their offspring. In ectotherms, temperature affects offspring phenotype so that colder mothers produce larger eggs. However, developmental mode and maternal size also contribute to the determination of optimal offspring size. When the maternal experience closely matches the offspring's probable future conditions (e.g., direct developers), it is expected that mothers will produce eggs of similar size within the same brood. While temperature directly affects the size of the eggs (temperature size rule), with potential indirect links to egg number (trade-off between egg size/number), maternal size can be a limiting factor in determining the optimal number of eggs, especially if eggs are brooded. We evaluated the role of temperature in shaping early ontogeny in the sandhopper Talorchestia capensis (Crustacea: Amphipoda), investigating within-brood and among-female variation in the size of the eggs. To test for causal relationships among temperature, maternal size, egg size and number, we used an information theoretic approach combined with path analysis. Sandhoppers invested in smaller eggs at higher temperatures, with no significant within-brood variation in the size of the eggs. Regardless of temperature, we found significantly different investment in egg size among females. Path analyses showed a simultaneous contribution of temperature and maternal size to the optimal size and number of eggs within a single clutch. Strong inter-individual variability in maternal investment could generate phenotypic variation within a population and promote population fitness. PMID- 26124446 TI - Quantifying the Effects of Predator and Prey Body Size on Sea Star Feeding Behaviors. AB - Body size plays a crucial role in determining the strength of species interactions, population dynamics, and community structure. We measured how changes in body size affect the trophic relationship between the sea star Pisaster ochraceus and its prey, the mussel Mytilus trossulus. We tested the effects of a wide range of predator and prey sizes on sea stars' prey-size preference, feeding rate, and prey tissue consumption. We found that preferred prey size increased with sea star size. Pisaster consumption rate (mussels consumed per day) and tissue intake rate (grams of tissue consumed per day) also increased with sea star size. Pisaster consumption rate, but not tissue intake rate, decreased with increasing mussel size. Juvenile sea stars preferred the most profitable prey sizes-that is, those that maximized tissue consumed per unit handling time. When adult sea stars were offered larger, more profitable mussels, tissue intake rates (grams per day) tended to increase, although this relationship was not statistically significant. Our results indicate that the Pisaster-Mytilus interaction depends on the sizes of both predator and prey, that predation rates are sensitive to even small changes in body size, and that shifts in size distributions may affect predator energetics and prey numbers differently depending on the factors that limit tissue consumption rates. PMID- 26124447 TI - Evidence of a Native Northwest Atlantic COI Haplotype Clade in the Cryptogenic Colonial Ascidian Botryllus schlosseri. AB - The colonial ascidian Botryllus schlosseri should be considered cryptogenic (i.e., not definitively classified as either native or introduced) in the Northwest Atlantic. Although all the evidence is quite circumstantial, over the last 15 years most research groups have accepted the scenario of human-mediated dispersal and classified B. schlosseri as introduced; others have continued to consider it native or cryptogenic. We address the invasion status of this species by adding 174 sequences to the growing worldwide database for the mitochondrial gene cytochrome c oxidase subunit I (COI) and analyzing 1077 sequences to compare genetic diversity of one clade of haplotypes in the Northwest Atlantic with two hypothesized source regions (the Northeast Atlantic and Mediterranean). Our results lead us to reject the prevailing view of the directionality of transport across the Atlantic. We argue that the genetic diversity patterns at COI are far more consistent with the existence of at least one haplotype clade in the Northwest Atlantic (and possibly a second) that substantially pre-dates human colonization from Europe, with this native North American clade subsequently introduced to three sites in Northeast Atlantic and Mediterranean waters. However, we agree with past researchers that some sites in the Northwest Atlantic have more recently been invaded by alien haplotypes, so that some populations are currently composed of a mixture of native and invader haplotypes. PMID- 26124448 TI - Dual Cellular Supporters: Multi-Layer Glial Wrapping and the Penetrative Matrix Specialized in Deep-Sea Hydrothermal Vent Endemic Scale-Worms. AB - Hydrothermal vent organisms undergo extreme environments that may require unique innovations. The present study reports a distinct case of cellular supportive systems in the nervous systems of a scale-worm, Branchinotogluma japonica, endemic to deep-sea hydrothermal vents. We found two organizations in the tissues of these animals. First, multi-layers of glia ensheath the ventral cell bodies of the brain and ventral nerve cord, in a manner similar to that of myelin or lamellar ensheathments. Second, matrices of numerous penetrative fibers, or tonofilaments, composed of bundles of ca. 20-nm fibers, are directly connected with the basal parts of epidermal cuticles and run into the diffuse intercellular spaces of the brain neuropils and peripheral nerves. Both types of tissue might be mechanical supportive structures for the neuronal cell bodies. In addition, as a glial function, the multi-layer membranes and the epithelial support cells may be required for physicochemical homeostatic regulation to filter toxic heavy metals and for inhibiting breakdown of glial membrane integrity under strong oxidative stress imposed by hypoxia in the hydrothermal vent environment. Similar functions are known in the well-studied cases of the blood-brain barrier in mammalian brains, including in human stroke. PMID- 26124449 TI - Transcriptome-wide Changes in Coral Gene Expression at Noon and Midnight Under Field Conditions. AB - Reef-building corals experience high daily variation in their environment, food availability, and physiological activities such as calcification and photosynthesis by endosymbionts. On Ofu Island, American Samoa, we investigated day-night differences in gene expression under field conditions of changing pH, temperature, light, and oxygen. Using RNASeq techniques, we compared two replicate transcriptomes from a single coral colony of Acropora hyacinthus over six noons and five midnights. We identified 344 contigs with significant expression differences across 16,800 contigs in the transcriptome, most with small fold-changes. However, there were 21 contigs with fold-changes ranging from 10 to 141. The largest changes were in a set of transcription factors strongly associated with day-night gene regulation in other animals, including cryptochromes, thyrotroph embryonic factor, and D site-binding protein. We also found large daytime increases in a set of genes involved in glucose transport and glycogen storage. We found small expression differences in genes associated with aerobic ATP production and hypoxia response, along with slightly higher expression of most calcification genes at noon. Although >40-fold-changes in expression occur in important transcription factors, downstream gene regulation seems very stable in corals from day to night compared to other animals studied. PMID- 26124450 TI - Respiratory Properties of Hemocyanin From Wild and Aquacultured Penaeid Shrimp and the Effects of Chronic Exposure to Hypoxia. AB - Properties of hemocyanins vary greatly among crustaceans due to environmental conditions, lifestyle, and genetic variation. These properties can also be modified to maintain aerobic respiration in response to ambient hypoxia, as experienced by both aquacultured and wild populations of penaeid shrimp. Under normoxic conditions, hemocyanin concentrations were significantly higher (P < 0.001) in aquacultured Pacific whiteleg shrimp, Litopenaeus vannamei (10.3 g/100 ml +/- 0.23 SEM, n = 49), compared to those in individuals of wild-caught L. vannamei (7.0 g/100 ml +/- 0.52 SEM, n = 10), wild Farfantepenaeus aztecus (7.10 g/100 ml +/- 0.48 SEM, n = 28), and wild Litopenaeus setiferus (8.0 g/100 ml +/- 0.22 SEM, n = 37). Oxygen affinity of hemocyanin at 25 degrees C in both populations of L. vannamei was higher (Kruskal-Wallis ANOVA on ranks, P < 0.001) (aquacultured P50 = 1.47 kPa +/- 0.03 SEM; wild P50 = 1.72 kPa +/- 0.01 SEM at pH 7.4) than that of both Atlantic species (F. aztecus P50 = 3.94 kPa +/- 0.06 SEM, L. setiferus P50 = 3.98 kPa +/- 0.04 SEM at pH 7.4). The effect of l-lactate on oxygen affinity was similar among all wild groups, but significantly smaller in the aquacultured L. vannamei. Total hemocyanin concentration and oxygen binding properties were measured after exposure to 12 days and 25-31 days of hypoxia (30% air saturation). Aquacultured L. vannamei showed no change in hemocyanin concentration for up to 31 days, but both wild F. aztecus and wild L. setiferus displayed a significant increase over the same time period. No discernible change in oxygen affinity of hemocyanin was detected in any of the three species. Hypoxia tolerance appears to differ among these species of penaeid shrimp, due to either an inherent difference among the species, domestication by aquaculture, or a combination of both. PMID- 26124451 TI - Effects of Holothuroid Ichtyotoxic Saponins on the Gills of Free-Living Fishes and Symbiotic Pearlfishes. AB - Several carapid fishes, known as pearlfishes, are endosymbiotic in holothuroids and asteroids. These echinoderms contain a strong concentration of saponins that are efficient membranolytic repellents to predators. We compared the effects of exposure to saponins from the sea cucumber body wall and from the Cuvierian tubules on the behavior and gill ultrastructure of pearlfishes and free-living fishes. Saponins were extracted from the body wall of two holothuroids, the Mediterranean Holothuria forskali and the tropical Bohadschia atra, and from the water surrounding the Cuvierian tubules of B. atra. Five species of carapids that live in symbiosis with holothuroids and seven species of free-living fishes were exposed to these extracts. The free-living fishes exhibited a stress response and died about 45 times faster than pearlfishes when exposed to the same quantity of saponins. Cuvierian tubules and saponins extracted from the body wall were lethal to the free-living fishes, whereas the carapids were much less sensitive. The carapids did not exhibit a stress response. The high toxicity shown by Cuvierian tubules was not explained by the nature of the saponins that were identified by mass spectrometry, but it is likely due to the higher concentration of saponins in the tubules. Histology and scanning and transmission electron microscopy of the gills of the free-living fishes and pearlfishes showed that saponins act at the level of the secondary lamellae where they induce the detachment of the epithelia, create edema at the level of the epithelia, and induce pores in the epithelial cells that lead to their destruction and the invasion of inner cells (pillar cells and red blood cells). This sequence of events happens 5 min after saponin exposure in free-living fishes and after 1 h in carapids. PMID- 26124454 TI - Editor's Choice-Clinical impact of delirium and antipsychotic therapy: 10-Year experience from a referral coronary care unit. AB - BACKGROUND: Little is known about safety of antipsychotic therapy for delirium in the coronary care unit (CCU). Our aim was to examine the effect of delirium and antipsychotic therapy among CCU patients. METHODS AND RESULTS: Pre-study Confusion Assessment Method-Intensive Care Unit (CAM-ICU) criteria were implemented in screening consecutive patients admitted to a referral CCU from 2004-2013. Death status was prospectively ascertained. Of 11,079 study patients, the incidence of delirium was 8.3% ( n=925). Delirium was associated with an increased risk of in-hospital mortality (adjusted odds ratio (OR) 1.49; 95% confidence interval (CI), 1.08-2.08; p=0.02) and one-year mortality among patients who survived from CCU admission (adjusted hazard ratio (HR) 1.46; 95% CI, 1.12-1.87; p=0.005). A total of 792 doses of haloperidol (5 mg/day; interquartile range (IQR) 3-10) or quetiapine (25 mg/day; IQR 13-50) were given to 244 patients with delirium. The clinical characteristics of patients with delirium who did and did not receive antipsychotic therapy were not different (baseline corrected QT (QTc) interval 457+/-58 ms vs 459+/-60 ms, respectively; p=0.65). In comparison to baseline, mean QTc intervals after the first and third doses of the antipsychotics were not significantly prolonged in haloperidol (448+/-56, 458+/-57 and 450+/-50 ms, respectively) or quetiapine groups (470+/ 66, 467+/-68 and 462+/-46 ms, respectively) ( p>0.05 for all). Additionally, in hospital mortality (adjusted OR 0.67; 95% CI, 0.42-1.04; p=0.07), ventricular arrhythmia (adjusted OR 0.87; 95% CI, 0.17-3.62; p=0.85) and one-year mortality among the hospital survivors (adjusted HR 0.86; 95% CI 0.62-1.17; p=0.34) were not different in patients with delirium irrespective of whether or not they received antipsychotics. CONCLUSION: In patients admitted to the CCU, delirium was associated with an increase in both in-hospital and one-year mortality. Low doses of haloperidol and quetiapine appeared to be safe, without an increase in risk of sudden cardiac death, in-hospital mortality, or one-year mortality in carefully monitored patients. PMID- 26124453 TI - Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma. AB - Real-time quantitative RT-PCR (qRT-PCR) is a powerful technique used for the relative quantification of target genes, using reference (housekeeping) genes for normalization to ensure the generation of accurate and robust data. A systematic examination of the suitability of endogenous reference genes for gene expression studies in endometrial cancer tissues is absent. The aims of this study were therefore to identify and evaluate from the thirty-two possible reference genes from a TaqMan((r)) array panel their suitability as an internal control gene. The mathematical software packages geNorm qBasePLUS identified Pumilio homolog 1 (Drosophila) (PUM1), ubiquitin C (UBC), phosphoglycerate kinase (PGK1), mitochondrial ribosomal protein L19 (MRPL19) and peptidylpropyl isomerase A (cyclophilin A) (PPIA) as the best reference gene combination, whilst NormFinder identified MRPL19 as the best single reference gene, with importin 8 (IPO8) and PPIA being the best combination of two reference genes. BestKeeper ranked MRPL19 as the most stably expressed gene. In addition, the study was validated by examining the relative expression of a test gene, which encodes the cannabinoid receptor 1 (CB1). A significant difference in CB1 mRNA expression between malignant and normal endometrium using MRPL19, PPIA, and IP08 in combination was observed. The use of MRPL19, IPO8 and PPIA was identified as the best reference gene combination for the normalization of gene expression levels in endometrial carcinoma. This study demonstrates that the arbitrary selection of endogenous control reference genes for normalization in qRT-PCR studies of endometrial carcinoma, without validation, risks the production of inaccurate data and should therefore be discouraged. PMID- 26124455 TI - Is routine post-procedural anticoagulation warranted after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction? Insights from the HORIZONS-AMI trial. AB - AIM: Post-procedural anticoagulation (AC) for routine prophylaxis may be administered after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI), but the risks and benefits of this practice are uncertain. We therefore sought to assess the utility of routine post procedural AC after primary PCI. METHODS AND RESULTS: Patients undergoing primary PCI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial were grouped according to whether they received post-PCI AC for routine prophylaxis. Outcomes were assessed using propensity-adjusted multivariable analysis. Among 2932 patients in whom primary PCI for STEMI was performed, 869 (29.6%) received post-PCI AC for routine prophylaxis (median duration four days) and 2063 (70.4%) received no post-PCI AC. Time from PCI to ambulation was similar in both groups (median 0.9 vs 1.0 days, p=0.40), although hospitalization was prolonged in patients receiving AC for routine prophylaxis (median 6.0 vs 4.0 days, p<0.0001). After propensity adjustment, patients who received and did not receive AC for routine prophylaxis after PCI experienced similar rates of 30-day adverse ischemic and major bleeding events. Deep venous thrombosis or pulmonary emboli developed rarely (0.3%) within 30 days, and were not significantly reduced by use of post-PCI AC for routine prophylaxis. CONCLUSIONS: In this large-scale prospective study, use of post procedural AC for routine prophylaxis was relatively common, and was not associated with improved clinical outcomes, although the duration of hospitalization was prolonged. These data suggest that post-PCI AC for routine prophylaxis may not provide benefit after successful primary PCI in patients in whom early ambulation is likely. PMID- 26124456 TI - Antithrombotic therapy before, during and after emergency angioplasty for ST elevation myocardial infarction. AB - The first three hours after symptom onset hold the maximum potential for myocardial reperfusion and salvage in ST-elevation myocardial infarction (STEMI) patients. During this period timely primary percutaneous coronary intervention (PPCI) or, when PPCI is not promptly feasible, pre-hospital administration of fibrinolyis or a glycoprotein IIb/IIIa-inhibitor (GPI) have been shown to restore coronary patency and reperfusion and even result in myocardial infarction (MI) abortion. On the other hand, oral antiplatelet therapy may not yet guarantee sufficient platelet inhibition. Patients presenting after this golden time have less, if any, benefit from an aggressive antithrombotic treatment prior to PPCI. Antithrombotic treatment during primary angioplasty should be tailored on the basis of the coronary thrombotic burden, vascular approach and the patient's risk of bleeding complications. A GPI-based approach may be favourable in patients presenting early with large MI and high thrombus burden, whereas a bivalirudin based approach without GPI may be preferred in patients with higher bleeding risk. There are no data to support the use of GPI in bailout conditions. The powerful oral P2Y12 inhibitors, prasugrel and ticagrelor, have been clearly shown to prevent stent thrombosis and recurrent ischaemic events after emergency percutaneous coronary intervention in STEMI patients. Open issues remaining are the treatment of patients with high bleeding risk, such as the elderly and those requiring anticoagulation, as well as the duration of dual antiplatelet therapy after STEMI. PMID- 26124457 TI - Association of anemia and renal dysfunction with in-hospital mortality among patients hospitalized for acute heart failure syndromes with preserved or reduced ejection fraction. AB - BACKGROUND: The aim of this study was to evaluate the association of anemia and renal dysfunction with in-hospital outcomes in acute heart failure syndromes patients with preserved or reduced ejection fraction. METHODS AND RESULTS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4693 patients were evaluated to investigate the association among anemia, renal dysfunction, a preserved or reduced ejection fraction and in hospital mortality. They were divided into four groups based on hemoglobin and estimated glomerular filtration rate at admission. The in-hospital mortality rate was 5.9% and 6.9% of the preserved and reduced ejection fraction groups, respectively. After adjustment for multiple comorbidities, there was no association of either anemia or renal dysfunction alone with in-hospital mortality in preserved ejection fraction patients, but the combination of anemia and renal dysfunction was associated with a somewhat higher risk of in-hospital mortality than that without either condition (odds ratio (OR), 2.75; 95% confidence interval (CI), 0.72-10.41; p=0.137). In reduced ejection fraction patients, adjusted analysis showed that a significantly higher risk of in hospital mortality was associated with anemia alone (OR, 2.56; 95% CI, 1.10 5.94; p=0.029) and with anemia plus renal dysfunction (OR, 2.34; 95% CI, 1.09 5.03; p=0.029) relative to the risk without either condition. CONCLUSIONS: Our findings demonstrate that anemia combined with renal dysfunction is not a risk factor for in-hospital mortality in patients with a preserved ejection fraction, whereas anemia is an independent predictor of in-hospital mortality risk in reduced ejection fraction patients regardless of renal dysfunction. PMID- 26124458 TI - European Society of Cardiology-Acute Cardiovascular Care Association Position paper on acute heart failure: A call for interdisciplinary care. AB - Acute heart failure (AHF) continues to have unacceptably high rates of mortality and morbidity. This position paper highlights the need for more intense interdisciplinary cooperation as one key element to overcome the challenges associated with fragmentation in the care of AHF patients. Additional aspects discussed include the importance of early diagnosis and treatment, options for initial treatment, referral bias as a potential cause for treatment preferences among experts, considerable uncertainty regarding patient disposition, the diagnosis of accompanying acute myocardial infarction, the need for antibiotic therapy, as well as assessment of intravascular volume status. PMID- 26124459 TI - Can FLAIR hyperintense vessel (FHV) signs be influenced by varying MR parameters and flow velocities? A flow phantom analysis. AB - BACKGROUND: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) have been used to assess leptomeningeal collateral flow in acute ischemic stroke. However, prior FHVs studies showed inconsistent results, which may be ascribable to different magnetic resonance (MR) parameters used. PURPOSE: To evaluate whether FHVs could be influenced by varying MR parameters and flow velocities, using a flow phantom. MATERIAL AND METHODS: A total of 512 sets of FLAIRs were performed with varying parameters and flow velocities, using a flow phantom. Flow phantom was manufactured with 3.5% agarose solution, an 8-mm inner diameter silicone tube and non-pulsatile pump. Varying MR parameters were repetition time (TR)/inversion time (TI), echo time (TE), flip angle (FA) of refocusing pulse, and periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER). The signal intensity of flow were measured and regarded as the degree of FHVs. Simple and multiple linear regression analyses were applied to evaluate the association between the degree of FHVs and varying MR parameters as well as flow velocities. RESULTS: On univariate analysis, PROPELLER technique (R(2 )= 0.448) demonstrated strongest correlation with the degree of FHV, followed by flow velocities (R(2 )= 0.204), FA (R(2 )= 0.126), and TE (R(2 )= 0.031), whereas TR/TI showed no significant correlations. On multivariate analysis, TE, FA, PROPELLER technique, and flow velocities were independent factors influencing the degree of FHVs (<0.001). CONCLUSION: Flow velocities, FA of refocusing pulse, TE, and PROPELLER technique significantly affected the degree of FHVs. Optimized MR parameters should be used consistently in future studies, which may provide more reliable results. PMID- 26124460 TI - Corneal inlay implantation complicated by infectious keratitis. AB - BACKGROUND/AIMS: To report five cases of infectious keratitis following corneal inlay implantation for the surgical correction of presbyopia. METHODS: This was a retrospective, observational case series. Five eyes of five patients were identified consecutively in two emergency departments during a 1-year period, from November 2013 to November 2014. Patients' demographics, clinical features, treatment and outcomes are described. RESULTS: There were four female patients and one male, aged 52-64 years. Three patients had the KAMRA inlay (AcuFocus) and two had the Flexivue Microlens inlay (Presbia Cooperatief U.A.) inserted for the treatment of presbyopia and they presented from 6 days to 4 months postoperatively. Presenting uncorrected vision ranged from 6/38 to counting fingers. One patient's corneal scrapings were positive for a putatively causative organism, Corynebacterium pseudodiphtheriticum, and all patients responded to broad-spectrum fortified topical antibiotics. All patients lost vision with final uncorrected visual acuity ranging from 6/12 to 6/60 and best-corrected vision ranging from 6/7.5 to 6/12. Two patients' corneal inlays were explanted and three remained in situ at last follow-up. CONCLUSIONS: Infectious keratitis can occur at an early or late stage following corneal inlay implantation. Final visual acuity can be limited by stromal scarring; in the cases where the infiltrate was small and off the visual axis at the time of presentation, the final visual acuity was better than those patients who presented with larger lesions affecting the visual axis. Though infection may necessitate removal of the inlay, early positive response to treatment may enable the inlay to be left in situ. PMID- 26124461 TI - Clinical features, microbiological profile and treatment outcome of patients with Corynebacterium endophthalmitis: review of a decade from a tertiary eye care centre in southern India. AB - AIMS: To report the clinical and microbiological profile along with treatment outcome of patients with endophthalmitis caused by Corynebacterium sp. METHODS: This is a retrospective, consecutive, non-comparative case series of patients with culture-proven Corynebacterium endophthalmitis seen between August 2004 and July 2014. RESULTS: Of 5439 patients clinically diagnosed as infective endophthalmitis, vitreous samples were culture positive for bacteria in 1488 (27%). Sixteen patients (1%) were identified as Corynebacterium endophthalmitis. The clinical settings included trauma (n=10), post-cataract surgery (n=5) and post-penetrating keratoplasty (n=1). In 7/16 (44%) patients, the organisms were visualised in direct microscopy. Tested by disc-diffusion method, all isolates were vancomycin sensitive. However, 9 of 10 isolates were resistant to ceftazidime and 5 of 14 isolates were resistant to amikacin. Initial treatment strategies included pars plana vitrectomy with intravitreal antibiotics (vancomycin and amikacin/ceftazidime) injection (n=9) and pars plana lensectomy along with pars plana vitrectomy and intravitreal antibiotics (vancomycin and amikacin/ceftazidime) injection (n=7). Final visual acuity was 20/200 or better in 11 (69%) of 16 patients. CONCLUSIONS: The prevalence of corynebacterial endophthalmitis is low. The organisms are susceptible to vancomycin, and early appropriate treatment results in favourable outcome. PMID- 26124462 TI - Long-term outcomes of intravitreal ranibizumab for neovascular age-related macular degeneration in a well defined region of the UK. AB - AIMS: To study long-term, whole population 'real-world' clinical outcomes of ranibizumab therapy in treatment-naive eyes for neovascular age-related macular degeneration. METHODS: Data collected prospectively from a single centre serving a defined population using an electronic medical record included: demographics, Early Treatment Diabetic Retinopathy Study visual acuity (ETDRS VA) at all visits, injection dates, central 1 mm retinal thickness, and operative and postoperative complications. RESULTS: 1483 eyes from 1278 patients were included in this study. The median age at the time of the patient's first injection was 82.5 years, 64.9% of patients were female, and another ocular pathology was present in 7.3% eyes. The baseline VA was 23-39, 40-54, 55-70 and >70 ETDRS letters for 17.3%, 23.1%, 42.7% and 16.9% of eyes, respectively. The median VA in all baseline VA groups improved after the loading phase but declined back to the baseline level by 2-5 years. The rate of endophthalmitis following intravitreal injection was 1 in 2124 injections. CONCLUSIONS: These long-term real-world data demonstrate that in general VA increases during the loading phase but returns to near baseline levels after 2-5 years of treatment for each baseline VA category. Patients should be identified and treated as early as possible, since presenting VA predicts the VA maintained after 5 years of treatment. National Institute of Health and Care Excellence guidance advising treatment only for eyes with vision below 70 letters does not promote best long-term VA outcomes for patients. PMID- 26124463 TI - Highlights from the Current Issue: July 2015. PMID- 26124464 TI - An Administrative Data Approach to Examining Perioperative Antibiotic Use in Head and Neck Oncologic Surgery. AB - The choice of perioperative antibiotics for head and neck oncologic surgery is the subject of significant controversy. Given the ever-increasing number of antibiotic options available, as well as the growing problem of antibiotic resistance, there is a need for renewed research on this important topic. In their recent publication, Langerman and colleagues explore the relationship between antibiotic choice, surgical site infections, and antibiotic-induced complications in patients undergoing total laryngectomy. They demonstrate wide variability in antibiotic regimens among patients undergoing total laryngectomy, as well as an association between increased risk of surgical site infections and clindamycin use. This study addresses a controversial subject affecting the daily care of patients with head and neck cancer, and the findings have the potential to significantly affect management. It also highlights the strengths and inherent limitations of an administrative data approach to head and neck cancer clinical research. PMID- 26124465 TI - Re: "Laryngeal Reconstruction with a Sternohyoid Muscle Flap after Supracricoid Laryngectomy: Postoperative Respiratory and Swallowing Evaluation". PMID- 26124466 TI - Head and Neck Complications after PCV7 Vaccine: Additional Considerations. PMID- 26124467 TI - Response to Letter to the Editor Regarding: Head and Neck Complications after PCV7 Vaccination. PMID- 26124469 TI - Perspectives of Health Care Providers on US South Asians' Attitudes Toward Pain Management at End of Life. AB - A lack of research on pain management among seriously ill South Asians reveals a critical gap in the knowledge base regarding culturally responsive end-of-life care. This qualitative descriptive study investigated the perspectives of health care providers that have cared for seriously ill older South Asians, on the attitudes of US South Asians toward the management of pain experienced at end of life and the factors that influenced these attitudes. Thematic analysis of interviews and focus group discussions with 57 health care providers indicated that providers perceive South Asian patients and families to be generally reluctant to use medications to treat pain experienced at end of life. Detailed description of patient-related and culturally based reasons for this reluctance is provided along with implications for hospice and palliative care. PMID- 26124470 TI - My Jump for vertical jump assessment. PMID- 26124471 TI - Ten essential BJSM podcasts that will improve your practice. PMID- 26124472 TI - Successful Implementation of an Automated Sedation Vacation Process in Intensive Care Units. AB - This quality improvement initiative sought to develop a sedation vacation (SV) protocol to increase SV performance and ensure sustainability. A standardized, nurse-driven SV protocol within the electronic medical record was implemented in adult intensive care units (ICUs) at Boston Medical Center. For 6 months, data were collected on the number of assessments performed, SV completion, SV eligibility, and reason for exclusion. Secondary outcomes included ICU length of stay (LOS) and ventilator LOS. Of 1730 patient-days during this 6-month period, SV assessments were performed 70% (n = 1211) of the time. SVs were conducted on 60.0% (n = 726) during days in which an assessment occurred. There was no significant change in ICU LOS or ventilator LOS during the study period. This SV protocol attained a 70% adherence rate, which was sustained over the 6-month period. There were no significant changes in secondary outcomes. PMID- 26124473 TI - To BRCA or Not to PALB. PMID- 26124474 TI - BRAF Mutation and Thyroid Cancer Recurrence. PMID- 26124475 TI - Safety of Infusing Ipilimumab Over 30 Minutes. AB - PURPOSE: The approved dose of ipilimumab is 3 mg/kg infused over 90 minutes; however, in clinical trials, 10 mg/kg has also been infused over 90 minutes. At this higher dose, patients receive 3 mg/kg within the first 27 minutes of treatment. We sought to determine whether the standard dose of 3 mg/kg could be safely infused over 30 minutes. METHODS: We reviewed retrospectively the incidence of infusion-related reactions (IRRs) to ipilimumab at our institution in patients receiving doses of either 3 or 10 mg/kg infused over 90 minutes. Our findings led to a change in institutional guidelines for ipilimumab infusion time from 90 minutes to 30 minutes. We reviewed the first 14 months of our prospective experience using a 30-minute infusion of ipilimumab. RESULTS: Between April 1, 2008, and June 30, 2013, 595 patients received 2,507 doses of ipilimumab infused at either 3 mg/kg (n = 457) or 10 mg/kg (n = 138) over 90 minutes. Although the 10 mg/kg group had a higher incidence of IRRs (4.3%) than the 3 mg/kg group (2.2%), this difference was not statistically significant (P = .22). In 120 patients treated prospectively with ipilimumab 3 mg/kg infused over 30 minutes, seven patients (5.8%) had an IRR (P = .06 compared with 90-minute infusions). All IRRs occurred at dose 2; six were grade 2, and one was grade 3. All seven patients received subsequent doses of ipilimumab safely, the majority with premedication. CONCLUSION: Ipilimumab at 3 mg/kg can be infused safely over 30 minutes with an acceptably low incidence of IRRs. After an IRR, patients can safely receive additional doses of ipilimumab with premedication. PMID- 26124476 TI - Evaluating Prognostic Markers Using Relative Utility Curves and Test Tradeoffs. PMID- 26124477 TI - Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer. AB - PURPOSE: CS-1008 (tigatuzumab) is a humanized, monoclonal immunoglobulin G1 (IgG1) agonistic antibody to human death receptor 5. The purpose of this study was to investigate the impact of CS-1008 dose on the biodistribution, quantitative tumor uptake, and antitumor response in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC who had received at least one course of chemotherapy were assigned to one of five dosage cohorts and infused with a weekly dose of CS-1008. Day 1 and day 36 doses were trace-labeled with indium-111 ((111)In), followed by whole-body planar and regional single-photon emission computed tomography (SPECT) imaging at several time points over the course of 10 days. RESULTS: Nineteen patients were enrolled. (111)In-CS-1008 uptake in tumor was observed in only 12 patients (63%). (111)In CS-1008 uptake and pharmacokinetics were not affected by dose or repeated drug administration. (111)In-CS-1008 biodistribution showed gradual blood-pool clearance and no abnormal uptake in normal tissue. No anti-CS-1008 antibody development was detected. One patient achieved partial response (3.7 months duration), eight patients had stable disease, and 10 patients had progressive disease. Clinical benefit rate (stable disease + partial response) in patients with (111)In-CS-1008 uptake in tumor was 58% versus 28% in patients with no uptake. An analysis of individual lesions showed that lesions with antibody uptake were one third as likely to progress as those without antibody uptake (P = .07). Death-receptor-5 expression in archived tumor samples did not correlate with (111)In-CS-1008 uptake (P = .5) or tumor response (P = .6). CONCLUSION: Death-receptor-5 imaging with (111)In-CS-1008 reveals interpatient and intrapatient heterogeneity of uptake in tumor, is not dose dependent, and is predictive of clinical benefit in the treatment of patients who have mCRC. PMID- 26124479 TI - Germline BRCA1/2 Mutations: Are They Good Enough to Determine Who Will Respond to Poly(ADP-Ribose) Polymerase Inhibitor Therapy in Advanced Cancer? PMID- 26124478 TI - Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial. AB - PURPOSE: The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup. PATIENTS AND METHODS: A total of 349 pretreatment specimens (bevacizumab arm, n = 171; placebo arm, n = 178) from AVAglio patients (total, N = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype. RESULTS: A multivariable analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the proneural subtype biomarker and treatment arm (P = .023). The group of patients with mesenchymal and proneural tumors derived a PFS benefit from bevacizumab compared with placebo; however, this translated to an OS benefit in the proneural subset only. CONCLUSION: Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type proneural glioblastoma may derive an OS benefit from first-line bevacizumab treatment. The predictive value of the proneural subtype observed in AVAglio should be validated in an independent data set. PMID- 26124480 TI - Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma. AB - PURPOSE: To develop and validate a histopathologic scoring system for measuring response to neoadjuvant chemotherapy in interval debulking surgery specimens of stage IIIC to IV tubo-ovarian high-grade serous carcinoma. PATIENTS AND METHODS: A six-tier histopathologic scoring system was proposed and applied to a test cohort (TC) of 62 patients treated with neoadjuvant chemotherapy and interval debulking surgery. Adnexal and omental sections were independently scored by three pathologists. On the basis of TC results, a three-tier chemotherapy response score (CRS) system was developed and applied to an independent validation cohort of 71 patients. RESULTS: The initial system showed moderate interobserver reproducibility and prognostic stratification of TC patients when applied to the omentum but not to the adnexa. Condensed to a three-tier score, the system was highly reproducible (kappa, 0.75). When adjusted for age, stage, and debulking status, the score predicted progression-free survival (PFS; score 2 v 3; median PFS, 11.3 v 32.1 months; adjusted hazard ratio, 6.13; 95% CI, 2.13 to 17.68; P < .001). The three-tier CRS system applied to omental samples from the validation cohort showed high reproducibility (kappa, 0.67) and predicted PFS (CRS 1 and 2 v 3: median, 12 v 18 months; adjusted hazard ratio, 3.60; 95% CI, 1.69 to 7.66; P < .001). CRS 3 also predicted sensitivity to first-line platinum therapy (94.3% negative predictive value for progression < 6 months). A Web site was established to train pathologists to use the CRS system. CONCLUSION: The CRS system is reproducible and shows prognostic significance for high-grade serous carcinoma. Implementation in international pathology reporting has been proposed by the International Collaboration on Cancer Reporting, and the system could potentially have an impact on patient care and research. PMID- 26124481 TI - Reply to C. Bal et al and M. Xing. PMID- 26124483 TI - Reply to M.G. McNamara et al and M.S. Copur et al. PMID- 26124482 TI - Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. AB - PURPOSE: Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death. PATIENTS AND METHODS: In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility. RESULTS: Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index-adjusted hazard ratio, 19.8). CONCLUSION: In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials. PMID- 26124484 TI - Reply to C. Bal et al. PMID- 26124485 TI - Mapisal Versus Urea Cream as Prophylaxis for Capecitabine-Associated Hand-Foot Syndrome: A Randomized Phase III Trial of the AIO Quality of Life Working Group. AB - PURPOSE: Hand-foot syndrome (HFS) is a frequently occurring adverse event associated with anticancer drugs. This study compares a newly introduced ointment containing several antioxidants and exhibiting high radical protection factor, which has been available on the German market since 2011, with urea cream for prevention of HFS in patients treated with capecitabine. PATIENTS AND METHODS: Patients with GI tumors or breast cancer treated with capecitabine were included in this randomized phase III study. The primary end point was prevention of HFS of any grade within 6 weeks of treatment as indicated by a standardized patient diary. The study had 80% power to show a 20% reduction of the incidence of HFS with the new ointment. Secondary end points included time to development of HFS greater than grade 1, evaluation of capecitabine dose intensity, and quality of life analyses. RESULTS: A total of 152 patients were evaluable. In total, 47 of 152 patients experienced HFS (30.9%), 39.5% with the new ointment and 22.4% in the urea arm (stratified odds ratio, 2.37; P = .02). Time to HFS greater than grade 1 was comparable, but time to any-grade HFS was significantly longer in the urea group (P = .03). Capecitabine dose intensity, time under study, and percentage of days with correct administration of study medication were identical, as were adverse events except for HFS. Skin-related quality of life was significantly worse in the group treated with the new ointment at the end of study treatment. CONCLUSION: This trial demonstrated that 10% urea cream was superior to the new ointment at preventing HFS over the first 6 weeks of treatment with capecitabine. PMID- 26124486 TI - Pemetrexed Plus Cisplatin Versus Gemcitabine Plus Cisplatin According to Thymidylate Synthase Expression in Nonsquamous Non-Small-Cell Lung Cancer: A Biomarker-Stratified Randomized Phase II Trial. AB - PURPOSE: We investigated whether thymidylate synthase (TS) expression is a predictive marker for the clinical outcome of pemetrexed/cisplatin in patients with nonsquamous non-small-cell lung cancer. PATIENTS AND METHODS: Eligible patients were tested for TS expression by immunohistochemistry and stratified into either a TS-negative or a TS-positive group. After stratification, patients in each group were randomly assigned (1:1 ratio) to receive either pemetrexed/cisplatin or gemcitabine/cisplatin for a maximum of six cycles until disease progression. The primary end point was evaluation of the interaction between TS groups and treatment allocation for objective response rate. RESULTS: Of 321 enrolled patients with nonsquamous non-small-cell lung cancer, 315 received at least one dose of study chemotherapy and were analyzed. By investigator assessment, response rates were 47% for the pemetrexed/cisplatin arm and 21% for the gemcitabine/cisplatin arm in the TS-negative group and 40% and 39%, respectively, for the TS-positive group (interaction P = .0084). By independent reviewers, response rates of pemetrexed/cisplatin and gemcitabine/cisplatin were 39% and 21%, respectively, in the TS-negative group and 40% and 48% in the TS-positive group (interaction P = .0077). The median progression-free survival times for the pemetrexed/cisplatin and the gemcitabine/cisplatin arms were 6.4 and 5.5 months, respectively, in the TS negative group and 5.9 and 5.3 months in the TS-positive group (interaction P = .07). CONCLUSION: With regard to response rate and progression-free survival, pemetrexed/cisplatin was superior to gemcitabine/cisplatin in the TS-negative group but not in the TS-positive group, indicative of TS expression as a potential predictive marker. Additional prospective studies involving larger cohorts are warranted to confirm the predictive role of TS expression. PMID- 26124487 TI - Clinical Utility of Patient-Derived Xenografts to Determine Biomarkers of Prognosis and Map Resistance Pathways in EGFR-Mutant Lung Adenocarcinoma. AB - PURPOSE: Although epidermal growth factor receptor (EGFR) -mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR targeted therapies. METHODS: Surgically resected early-stage non-small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 MUL. Gene expression analysis was performed using a microarray platform. RESULTS: Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs. CONCLUSION: PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies. PMID- 26124488 TI - Citrus Consumption and Risk of Cutaneous Malignant Melanoma. AB - PURPOSE: Citrus products are widely consumed foods that are rich in psoralens and furocoumarins, a group of naturally occurring chemicals with potential photocarcinogenic properties. We prospectively evaluated the risk of cutaneous malignant melanoma associated with citrus consumption. METHODS: A total of 63,810 women in the Nurses' Health Study (1984 to 2010) and 41,622 men in the Health Professionals Follow-Up Study (1986 to 2010) were included. Dietary information was repeatedly assessed every 2 to 4 years during follow-up. Incident melanoma cases were identified through self-report and confirmed by pathologic records. RESULTS: Over 24 to 26 years of follow-up, we documented 1,840 incident melanomas. After adjustment for other risk factors, the pooled multivariable hazard ratios for melanoma were 1.00 for overall citrus consumption < twice per week (reference), 1.10 (95% CI, 0.94 to 1.30) for two to four times per week, 1.26 (95% CI, 1.08 to 1.47) for five to six times per week, 1.27 (95% CI, 1.09 to 1.49) for once to 1.5 times per day, and 1.36 (95% CI, 1.14 to 1.63) for >= 1.6 times per day (Ptrend < .001). Among individual citrus products, grapefruit showed the most apparent association with risk of melanoma, which was independent of other lifestyle and dietary factors. The pooled multivariable hazard ratio for melanoma comparing the extreme consumption categories of grapefruit (>= three times per week v never) was 1.41 (95% CI, 1.10 to 1.82; Ptrend < .001). CONCLUSION: Citrus consumption was associated with an increased risk of malignant melanoma in two cohorts of women and men. Nevertheless, further investigation is needed to confirm our findings and explore related health implications. PMID- 26124489 TI - Breaking Bad News in Oncology: A Metasynthesis. AB - PURPOSE: The delivery of bad news by oncologists to their patients is a key moment in the physician-patient relationship. We performed a systematic review of qualitative studies (a metasynthesis) that focused on the experiences and points of view of oncologists about breaking bad news to patients. METHODS: We searched international publications to identify relevant qualitative research exploring oncologists' perspectives about this topic. Thematic analysis, which compensates for the potential lack of generalizability of the primary studies by their conjoint interpretation, was used to identify key themes and synthesize them. NVivo qualitative analysis software was used. RESULTS: We identified 40 articles (> 600 oncologists) from 12 countries and assessed their quality as good according to the Critical Appraisal Skills Programme (CASP). Two main themes emerged: the patient-oncologist encounter during the breaking of bad news, comprising essential aspects of the communication, including the process of dealing with emotions; and external factors shaping the patient-oncologist encounter, composed of factors that influence the announcement beyond the physician-patient relationship: the family, systemic and institutional factors, and cultural factors. CONCLUSION: Breaking bad news is a balancing act that requires oncologists to adapt continually to different factors: their individual relationships with the patient, the patient's family, the institutional and systemic environment, and the cultural milieu. Extending the development of the ability to personalize and adapt therapeutic treatment to this realm of communications would be a major step forward from the stereotyped way that oncologists are currently trained in communication skills. PMID- 26124490 TI - Is There Any True Association Between BRAF V600E Mutation and Recurrence, Particularly in Low-Risk, Papillary Thyroid Cancer? PMID- 26124491 TI - Dietary Advice for Melanoma: Not Ready for Prime Time. PMID- 26124492 TI - Predictive Value of Combination of Neutrophil-Lymphocyte Ratio and Platelet Lymphocyte Ratio for Prognosis. PMID- 26124493 TI - Vascular Complications Following Transradial and Transulnar Coronary Angiography in 1600 Consecutive Patients. AB - BACKGROUND: Major, noncoronary complications are rarely encountered following transradial coronary procedures. METHODS AND RESULTS: Among 1600 prospectively studied patients with complete follow-up, 7 patients experienced major complications following coronary forearm procedures corresponding to an incidence of 0.44%. We found inadvertent symptomatic intramyocardial contrast medium injection, 2 cases with compartment syndrome of which 1 was managed surgically, exertional hand ischemia due to radial artery occlusion, a large ulnar artery pseudoaneurysm, an ulnar arteriovenous fistula, and 1 critical hand ischemia due to late occlusion of the distal brachial artery. CONCLUSIONS: Although infrequent, surveillance for major complications should be encouraged after forearm coronary procedures. PMID- 26124494 TI - Assessment of Platelet-Lymphocyte Ratio Based on EDTA-Dependent Pseudothrombocytopenia. PMID- 26124495 TI - Live cell evaluation of granzyme delivery and death receptor signaling in tumor cells targeted by human natural killer cells. AB - Growing interest in natural killer (NK) cell-based therapy for treating human cancer has made it imperative to develop new tools to measure early events in cell death. We recently demonstrated that protease-cleavable luciferase biosensors detect granzyme B and pro-apoptotic caspase activation within minutes of target cell recognition by murine cytotoxic lymphocytes. Here we report successful adaptation of the biosensor technology to assess perforin-dependent and -independent induction of death pathways in tumor cells recognized by human NK cell lines and primary cells. Cell-cell signaling via both Fc receptors and NK activating receptors led to measurable luciferase signal within 15 minutes. In addition to the previously described aspartase-cleavable biosensors, we report development of granzyme A and granzyme K biosensors, for which no other functional reporters are available. The strength of signaling for granzyme biosensors was dependent on perforin expression in IL-2-activated NK effectors. Perforin-independent induction of apoptotic caspases was mediated by death receptor ligation and was detectable after 45 minutes of conjugation. Evidence of both FasL and TRAIL-mediated signaling was seen after engagement of Jurkat cells by perforin-deficient human cytotoxic lymphocytes. Although K562 cells have been reported to be insensitive to TRAIL, robust activation of pro-apoptotic caspases by NK cell-derived TRAIL was detectable in K562 cells. These studies highlight the sensitivity of protease-cleaved luciferase biosensors to measure previously undetectable events in live cells in real time. Further development of caspase and granzyme biosensors will allow interrogation of additional features of granzyme activity in live cells including localization, timing, and specificity. PMID- 26124496 TI - Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. AB - Although most patients with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal response, or quickly lose their response. To identify genes that may predict response to ruxolitinib, we performed targeted next-generation sequencing (NGS) of a panel of 28 genes recurrently mutated in hematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study. We also tested for CALR deletions by standard polymerase chain reaction methods. Ninety-eight percent of patients had a mutation in >=1 gene. Seventy-nine (82.1%) patients had the JAK2(V617F) mutation, 9 (9.5%) had CALR mutations (7 type 1, 2 type 2), 3 (3.1%) had MPL mutations, and 4 (4.2%) were negative for all 3. ASXL1/JAK2 and TET2/JAK2 were the most frequently comutated genes. Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 were found in <5% of patients. Spleen response (>=50% reduction in palpable spleen size) was inversely correlated with the number of mutations; patients with <=2 mutations had ninefold higher odds of a spleen response than those with >=3 mutations (odds ratio = 9.37; 95% confidence interval, 1.86-47.2). Patients with >=3 mutations also had a shorter time to treatment discontinuation and shorter overall survival than those with fewer mutations. In multivariable analysis, only number of mutations and spleen response remained associated with time to treatment discontinuation. Patients with >=3 mutations had the worst outcomes, suggesting that multigene profiling may be useful for therapeutic planning for MF. PMID- 26124499 TI - Man with locked-in syndrome challenges GMC ruling on doctors' involvement in ending his life. PMID- 26124497 TI - Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232. AB - Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B ALL study AALL0232, we investigated MRD in subjects randomized in a 2 * 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD >=0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% +/- 1% vs 74% +/- 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% +/- 5% 5 year disease-free survival vs 39% +/- 7% for those with MRD >=0.01%. Although HD MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% +/- 2% vs 58% +/- 4% for MRD-negative vs positive C-MTX subjects; 88% +/- 2% vs 68% +/- 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725. PMID- 26124500 TI - Yemen's health system buckles under Saudi led bombardment and blockade. PMID- 26124498 TI - Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants. AB - Sickle cell disease (SCD) and thalassemias (Thal) are common congenital disorders, which can be diagnosed early in gestation and result in significant morbidity and mortality. Hematopoietic stem cell transplantation, the only curative therapy for SCD and Thal, is limited by the absence of matched donors and treatment-related toxicities. In utero hematopoietic stem cell transplantation (IUHCT) is a novel nonmyeloablative transplant approach that takes advantage of the immunologic immaturity and normal developmental properties of the fetus to achieve mixed allogeneic chimerism and donor-specific tolerance (DST). We hypothesized that a combined strategy of IUHCT to induce DST, followed by postnatal nonmyeloablative same donor "booster" bone marrow (BM) transplants in murine models of SCD and Thal would result in high levels of allogeneic engraftment and donor hemoglobin (Hb) expression with subsequent phenotypic correction of SCD and Thal. Our results show that: (1) IUHCT is associated with DST and low levels of allogeneic engraftment in the murine SCD and Thal models; (2) low-level chimerism following IUHCT can be enhanced to high-level chimerism and near complete Hb replacement with normal donor Hb with this postnatal "boosting" strategy; and (3) high-level chimerism following IUHCT and postnatal "boosting" results in phenotypic correction in the murine Thal and SCD models. This study supports the potential of IUHCT, combined with a postnatal nonmyelablative "boosting" strategy, to cure Thal and SCD without the toxic conditioning currently required for postnatal transplant regimens while expanding the eligible transplant patient population due to the lack of a restricted donor pool. PMID- 26124501 TI - Incentives could help delivery of essential health services by frontline workers, study finds. PMID- 26124502 TI - Margaret McCartney: The ethics of behavioural incentives. PMID- 26124503 TI - Hamburg's refugee policy is criticised after pregnant woman sent on long train trip miscarries. PMID- 26124504 TI - MPs table bill to restrict role of commercial companies in NHS. PMID- 26124505 TI - High rates of false positives are likely in diabetes screening programmes in India. PMID- 26124506 TI - Providing welfare advice in GP surgeries can benefit patients, says report. PMID- 26124507 TI - Bangladesh's ignored female sex workers. PMID- 26124508 TI - A randomised controlled trial to prevent smoking relapse among recently quit smokers enrolled in employer and health plan sponsored quitlines. AB - OBJECTIVE: To test adding an interactive voice response (IVR)-supported protocol to standard quitline treatment to prevent relapse among recently quit smokers. DESIGN: Parallel randomised controlled trial with three arms: standard quitline, standard plus technology enhanced quitline with 10 risk assessments (TEQ-10), standard plus 20 TEQ assessments (TEQ-20). SETTING: Quit For Life (QFL) programme. PARTICIPANTS: 1785 QFL enrolees through 19 employers or health plans who were 24+ h quit. INTERVENTIONS: QFL is a 5-call telephone-based cessation programme including medications and web-based support. TEQ interventions included 10 or 20 IVR-delivered relapse risk assessments over 8 weeks with automated transfer to counselling for those at risk. MAIN OUTCOME MEASURES: Self-reported 7 day and 30-day abstinence assessed at 6-month and 12-month post-enrolment (response rates: 61% and 59%, respectively). Missing data were imputed. RESULTS: 1785 were randomised (standard n=592, TEQ-10 n=602, TEQ-20 n=591). Multiple imputation-derived, intent-to-treat 30-day quit rates (95% CI) at 6 months were 59.4% (53.7% to 63.8%) for standard, 62.3% (57.7% to 66.9%) for TEQ-10, 59.4% (53.7% to 65.1%) for TEQ-20 and 30-day quit rates at 12 months were 61.2% (55.6% to 66.8%) for standard, 60.6% (56.0% to 65.2%) for TEQ-10, 54.9% (49.0% to 60.9%) for TEQ-20. There were no significant differences in quit rates. 73.3% of TEQ participants were identified as at-risk by IVR assessments; on average, participants completed 0.41 IVR-transferred counselling calls. Positive risk assessments identified participants less likely (OR=0.56, 95% CI 0.42 to 0.76) to be abstinent at 6 months. CONCLUSIONS: Standard treatment was highly effective, with 61% remaining abstinent at 12 months using multiple imputation intent-to treat (intent-to-treat missing=smoking quit rate: 38%). TEQ assessments identified quitters at risk for relapse. However, adding IVR-transferred counselling did not yield higher quit rates. Research is needed to determine if alternative designs can improve outcomes. TRIAL REGISTRATION NUMBER: NCT00888992. PMID- 26124509 TI - Using decision trees to understand structure in missing data. AB - OBJECTIVES: Demonstrate the application of decision trees--classification and regression trees (CARTs), and their cousins, boosted regression trees (BRTs)--to understand structure in missing data. SETTING: Data taken from employees at 3 different industrial sites in Australia. PARTICIPANTS: 7915 observations were included. MATERIALS AND METHODS: The approach was evaluated using an occupational health data set comprising results of questionnaires, medical tests and environmental monitoring. Statistical methods included standard statistical tests and the 'rpart' and 'gbm' packages for CART and BRT analyses, respectively, from the statistical software 'R'. A simulation study was conducted to explore the capability of decision tree models in describing data with missingness artificially introduced. RESULTS: CART and BRT models were effective in highlighting a missingness structure in the data, related to the type of data (medical or environmental), the site in which it was collected, the number of visits, and the presence of extreme values. The simulation study revealed that CART models were able to identify variables and values responsible for inducing missingness. There was greater variation in variable importance for unstructured as compared to structured missingness. DISCUSSION: Both CART and BRT models were effective in describing structural missingness in data. CART models may be preferred over BRT models for exploratory analysis of missing data, and selecting variables important for predicting missingness. BRT models can show how values of other variables influence missingness, which may prove useful for researchers. CONCLUSIONS: Researchers are encouraged to use CART and BRT models to explore and understand missing data. PMID- 26124510 TI - What matters most for end-of-life care? Perspectives from community-based palliative care providers and administrators. AB - OBJECTIVES: There has been little research conducted to understand the essential meaning of quality, community-based, end-of-life (EOL) care, despite the expansion of these services. The purpose of this study was to define what matters most for EOL care from the perspective of a diverse range of palliative care providers in the community who have daily encounters with death and dying. METHODS: We used interviews to explore the perceptions of providers and administrators from 14 specialised palliative care teams in Ontario, Canada. Participants were prompted with the question 'What matters most for EOL care?' Responses were analysed using a phenomenological approach to derive themes depicting the universal essence of EOL care. RESULTS: Data from 107 respondents were obtained and analysed, from which 40 formulated concepts emerged; these were further grouped into 9 themes. Of the respondents, 39% were nurses, 19% physicians, 27% were supervisors or executives and 15% other. The most predominate concept was that Patient's Wishes are Fulfilled, cited by almost half the respondents. The most prominent themes were Addressing the Non-physical Needs, Healthcare Teams' Nature of Palliative Care Delivery, Patient Wishes are Honoured, Addressing the Physical Needs, Preparing for and Accepting Death, Communication and Relationship Development, and Involving and Supporting the Family. CONCLUSIONS: 9 critical domains of EOL care evolved from the interviews, indicating that quality EOL care extends beyond managing physical pain, but includes a holistic perspective of care, a healthcare team dedicated to the EOL journey and a patient-centred pathway. Tailoring the provision of care to consider these important elements plays a critical role in supporting a positive EOL experience for patients and families. PMID- 26124511 TI - Association of endothelial lipase gene-384A/C with coronary artery disease in Han Chinese people. AB - OBJECTIVES: The endothelial lipase gene (LIPG) is one of the important genes in the metabolism of high-density lipoprotein cholesterol (HDL-C) and may be involved in the pathogenesis of coronary artery disease (CAD). MATERIALS AND METHODS: To investigate the relationship between the common single nucleotide polymorphisms (SNPs) 584C/T (rs2000813) and -384A/C (rs3813082) in the LIPG gene and CAD, allele and genotype frequencies of the two SNPs were analysed in 287 Chinese patients with CAD and 367 controls by the high-resolution melting curve (HRM) method. RESULTS: For 584C/T, no significant difference in polymorphic distribution was observed between patients and controls. However, the frequencies of allele C (20.2% vs 15%, p=0.013, OR=1.437, 95% CI 1.078 to 1.915) at -384A/C were significantly increased in patients compared with controls. Haplotype analysis also showed that haplotype CT (12.37% vs 8.72%, p=0.035, OR=1.478, 95% CI 1.034 to 2.112) was significantly higher in patients compared with controls. CONCLUSIONS: These results suggested that the SNP -384A/C in the LIPG gene may be associated with risk for CAD and the LIPG gene may play a role in CAD in the Han Chinese. PMID- 26124512 TI - Is social deprivation an independent predictor of outcomes following cardiac surgery? An analysis of 240,221 patients from a national registry. AB - OBJECTIVES: Social deprivation impacts on healthcare outcomes but is not included in the majority of cardiac surgery risk prediction models. The objective was to investigate geographical variations in social deprivation of patients undergoing cardiac surgery and identify whether social deprivation is an independent predictor of outcomes. METHODS: National Adult Cardiac Surgery Audit data for coronary artery bypass graft (CABG), or valve surgery performed in England between April 2003 and March 2013, were analysed. Base hospitals in England were divided into geographical regions. Social deprivation was measured by quintile groups of the index of multiple deprivation (IMD) score with the first quintile group (Q1) being the least, and the last quintile group (Q5) the most deprived group. In-hospital mortality and midterm survival were analysed using mixed effects logistic, and stratified Cox proportional hazards regression models respectively. RESULTS: 240,221 operations were analysed. There was substantial regional variation in social deprivation with the proportion of patients in IMD Q5 ranging from 34.5% in the North East to 6.5% in the East of England. Following adjustment for preoperative risk factors, patients undergoing all cardiac surgery in IMD Q5 were found to have an increased risk of in-hospital mortality relative to IMD Q1 (OR=1.13; 95%CI 1.03 to 1.24), as were patients undergoing isolated CABG (OR=1.19; 95%CI 1.03 to 1.37). For midterm survival, patients in IMD Q5 had an increased hazard in all groups (HRs ranged between 1.10 (valve+CABG) and 1.26 (isolated CABG)). For isolated CABG, the median postoperative length of stay was 6 and 7 days, respectively, for IMD Q1-Q4 and Q5. CONCLUSIONS: Significant regional variation exists in the social deprivation of patients undergoing cardiac surgery in England. Social deprivation is associated with an increased risk of in-hospital mortality and reduced midterm survival. These findings have implications for health service provision, risk prediction models and analyses of surgical outcomes. PMID- 26124513 TI - Palliative care in patients with liver cirrhosis: it is the time to deal with the burden. PMID- 26124514 TI - Initiative for capacity building in academic psychiatry in India: The E-Journal Club of the Indian Psychiatric Society. PMID- 26124515 TI - The right to mental health and parity. PMID- 26124516 TI - Decriminalization of attempted suicide law: Journey of Fifteen Decades. PMID- 26124517 TI - Current challenges in practice of psychiatry in India. PMID- 26124518 TI - Violence against women: Where are the solutions? PMID- 26124520 TI - An epidemiological study of sexual disorders in south Indian rural population. AB - BACKGROUND: Sexuality is an important aspect of the personality of an individual and influences psychological, physical and social well-being of both men and women. It is a paradox, that in the country where 'kamasutra' (by Vatsyayana) took birth, there is a lack of research publications and sexuality related literature; hence the current study was conducted, to estimate the prevalence and association of sexual disorders with various socio-demographic variables, in the selected rural population. MATERIALS AND METHODS: Subjects who were sexually active and fulfilled the study criteria were administered Arizona Sexual Experience Scale as screening tool for the presence of sexual problems. Those who were found to be having sexual problems were interviewed further using appropriate questionnaires. RESULTS: 21.15% of the male subjects were diagnosed to have one (or more) sexual disorder. Prevalence of erectile dysfunction was found to be 15.77%, male hypoactive sexual desire disorder (HSDD) 2.56%; premature ejaculation was found to be prevalent in 8.76% of the male subjects. Around 14% of the female subjects were diagnosed to have female sexual disorders. Prevalence of female arousal dysfunction was found to be 6.65%, female HSDD 8.87%, female anorgasmia 5.67%, female dyspareunia 2.34% and female sexual aversion disorder was found to be prevalent in 0.37% of the female subjects. CONCLUSION: This study concluded that one in five males and one in seven females were suffering from one (or more) sexual disorder. Improving the training of undergraduate medical and nursing students in sexuality related issues, increasing trained individuals in sexual medicine by starting new courses, providing sex education to the general population using media and merging sexual health care with primary care, are likely to play a significant role in addressing the increasing sexual health morbidity. PMID- 26124521 TI - Antenatal prevalence of fear associated with childbirth and depressed mood in primigravid women. AB - AIM: To investigate the antenatal prevalence of fear of childbirth and its association with depressed mood in low-risk primigravidae in a referral teaching hospital. SETTINGS AND DESIGN: The study was conducted in a tertiary referral center catering to three districts in the state of Kerala. This was a cross sectional study with internal comparison of associated factors. MATERIALS AND METHODS: Malayalam translation (translation back translation) of Edinburgh Postnatal Depression Scale (EPDS) was self-administered by the participants. It was followed by a structured interview based on the International Classification of Diseases 10 (ICD 10) after which the EPDS scale was scored. STATISTICAL ANALYSIS: Chi-square test was used to compare the presence of fear in women with a EPDS of >= 12 and the association of fear and depression. RESULTS: Fear associated with childbirth was expressed by 17.7% women. The prevalence of depressed mood based on the EPDS (score > 12) was 9.8% but based on the ICD 10 criteria, the prevalence of depression was 8.7%. A significant number of women with depressed mood and clinical depression had fear of childbirth of some sort. CONCLUSIONS: A significant number of primigravid women with depressed mood and clinical depression had fear of childbirth of some sort. PMID- 26124519 TI - Cannabis and psychopathology: The meandering journey of the last decade. AB - Since its inception cannabis has been observed to be associated with various psycho-pathology. In this paper, the authors have reviewed the advancement made in this area over the last decade. The association between cannabis and schizophrenia has been researched more intensively. The controversy regarding the reliability, clinical utility, and the existence of a cannabis withdrawal syndrome has also been settled. Recent studies also buttressed the possibility of acute and chronic effect of cannabis on various cognitive functions. There has been a plethora of research regarding the treatment for cannabis use disorders. But the new and most interesting area of research is concentrated on the endocannabinoid system and its contribution in various psychiatric disorders. PMID- 26124522 TI - Day care as an innovative approach in psychiatry: Analysis of Lucknow experience. AB - CONTEXT: This article aims at demonstrating the effectiveness of day care centers in Indian setting. This is to provide impetus for an innovative approach in psychiatric practice in India. AIMS: The aim was to narrate the experiences of a day care center being practiced in India. SETTINGS AND DESIGN: The study provides the experiences gained in a day care center at Lucknow. The center was started in a hired building with a minimum of staff. The cost of the program is around 30,000/months. SUBJECTS AND METHODS: The day care center has been run for nearly 5 years. During this period, 95 clients visited the center and 69 enrolled in the day care. Nearly 35 continued and 34 dropped out due to various reasons. STATISTICAL ANALYSIS: Descriptive study. RESULTS: There were 49 patients suffering from schizophrenia, 11 from affective disorders, and 9 patients were clubbed in the miscellaneous group. The miscellaneous group consisted of pervasive developmental disorders, slow learners, obsessive compulsive disorders (OCD) and borderline subnormality with psychosis. Most patients had a long duration of illness. The patients of schizophrenia continued in the program more often than other group. Nearly 50% of patients have obtained jobs. The exposure to day care improved the patient's social and occupational behavior. The core symptoms did not change substantially. The families were greatly empowered, and they developed a positive attitude toward illness. CONCLUSIONS: Of the 59 patients who joined the day care program 35 could continue regularly. Among these patients, nearly 50% could take up jobs. Social and occupational behaviors improved remarkably. The families were empowered, and they developed a positive attitude toward mental illness. Such programs can be improvised with minimal costs and can be value addition in psychiatric practice. We need to develop indigenous know-how for such programs. This is a preliminary communication. PMID- 26124523 TI - Stigma of mental illness: An interventional study to reduce its impact in the community. AB - BACKGROUND: Research literature has documented the nature of stigma associated with mental illness (MI) and its consequences in all spheres of life of ill persons and their families. It is also suggested that there is a need to develop intervention strategies to reduce stigma. However, very little is reported about these initiatives in the Indian context. AIM: To understand the nature of stigma associated with MI in a rural and semi-urban community in India and to develop an intervention package and study its impact. MATERIALS AND METHODS: The study adopted a pre- and post-experimental/action research design with a random sample of community members including persons with chronic MI and their caregivers from rural and semi-urban areas. A semi structured interview schedule was used to assess the nature of stigma. An intervention package, developed on the basis of initial findings, was administered, and two post assessments were carried out. RESULTS: Stigmatized attitude related to various aspects of MI were endorsed by the respondents. Caregivers had less stigmatizing attitude than the members of the community. Postintervention assessments (PIAs) revealed significant changes in attitudes towards some aspects of MI and this improved attitude was sustained during the second PIA, that is, after 3 months of intervention. CONCLUSION: People in the rural and semi-urban community have stigmatizing attitude toward MI. Intervention package focusing on the relevant aspect of MI can be used for reducing stigma of MI. PMID- 26124524 TI - Human rights violations among economically disadvantaged women with mental illness: An Indian perspective. AB - BACKGROUND: Globally women confront manifold violations of human rights and women with poverty and mental illness are doubly disadvantaged. AIM: The aim was to examine the influence of poverty in meeting human rights needs among recovered women with mental illness at family and community level. MATERIALS AND METHODS: This was a descriptive study carried out among randomly selected (n = 100) recovered women with mental illness at a tertiary care center. Data were collected through face-to-face interview using structured needs assessment questionnaire. RESULTS: Our findings revealed that below poverty line (BPL) participants were not satisfied in meeting their physical needs such as "access to safe drinking water" (chi(2) = 8.994, P < 0.02), "served in the same utensils" (chi(2) = 13.648, P < 0.00), had adequate food (chi(2) = 11.025, P < 0.02), and allowed to use toilet facilities (chi(2) = 13.565, P < 0.00). The human rights needs in emotional dimension, that is, afraid of family members (chi(2) = 8.233, P < 0.04) and hurt by bad words (chi(2) = 9.014, P < 0.02) were rated higher in above poverty line (APL) participants. Similarly, 88.9% of women from APL group expressed that they were discriminated and exploited by the community members (chi(2) = 17.490, P < 0.00). More than three-fourths of BPL participants (76.1%) believed that there were wondering homeless mentally ill in their community (chi(2) = 11.848, P < 0.01). CONCLUSION: There is an urgent need to implement social welfare programs to provide employment opportunities, disability allowance, housing and other social security for women with mental illness. Further, mental health professionals play an essential role in educating the family and public regarding human rights of people with mental illness. PMID- 26124525 TI - Indian Psychiatric Society multicentric study on assessment of health-care needs of patients with severe mental illnesses as perceived by their family caregivers and health-care providers. AB - AIM: To study the health-care needs of the patients with severe mental disorders as perceived by their family caregivers and the treating psychiatrists. MATERIALS AND METHODS: Caregivers of patients with severe mental disorders and their treating psychiatrists were assessed using Camberwell Assessment of Need-Research Version (CAN-R) scale and indigenously designed Supplementary Assessment of Needs Scale (SNAS). RESULTS: The study included 1494 patients recruited from 15 centers. The mean needs as per the CAN-R, perceived by the caregivers were 7.8 and treating psychiatrists were 8.1. About one-third of needs were unmet. On SNAS, both caregivers and treating psychiatrists reported a mean of 7.9 needs, of which more than half were unmet as per the caregivers. As per the treating psychiatrists, 45.5% of the needs as assessed on SNAS were unmet. There was a high level of correlation between needs perceived by the patients, caregivers and the treating psychiatrists. On CAN-R, main domains of needs as reported by the caregivers were those of money, relief of psychological distress, information about the illness and treatment, welfare benefits, transport, company and food. As per the treating psychiatrists, the most common total needs identified were those of relief of psychological distress, welfare benefits, information about the illness and treatment, money, transport, company self-care and physical health. The most common domains of needs as assessed on SNAS as per the caregivers were those of free treatment, medical reimbursement, psychoeducation, financial help, social support, insurance, more time from the clinicians and travel concession. The treating psychiatrists identified dealing with caregiver's stress as the most common need. CONCLUSIONS: According to the family caregivers and treating psychiatrists, about one-third of the needs of the patients as assessed using CAN-R and about half of the needs as assessed using SNAS are unmet. PMID- 26124526 TI - Attitude of doctors towards mentally ill in Hyderabad, India: Results of a prospective survey. AB - BACKGROUND: Wide prevalence of mental illness has been documented in South India; however, the magnitude of stigma is unclear. AIMS: The aim was to investigate the magnitude of stigma prevalent among medical professionals in Hyderabad, India. MATERIALS AND METHODS: A prospective survey of seven common psychiatric disorders for eight specified perceptions was conducted. Responses of 226 out of 250 (90%) doctors were analyzed. RESULTS: Significant overall negative perception (P < 0.001), with drug addiction (52.8%) and alcoholism (48.2%) eliciting most negative perceptions (Chi-square: P <0.05) was observed. Significant negative perceptions were also seen among married doctors and those with < 10 years experience. Even though, there was no overall difference based on gender (P = 0.242), more females had significant negative perception toward eating disorders, depression, dementia, alcoholism and schizophrenic patients (P <= 0.05). CONCLUSIONS: This study revealed negative attitude of doctors toward mentally ill and highlighted the gender difference in perceptions. PMID- 26124528 TI - Cushing's syndrome presenting as treatment-resistant bipolar affective disorder: A step in understanding endocrine etiology of mood disorders. AB - Cushing's syndrome (CS) is the multisystem disorder which is due to cortisol excess. It is very difficult to diagnose in early stages, especially when psychiatric manifestations are the predominant complaints. It could result in significant morbidity and mortality. We report a case of resistant bipolar affective disorder secondary to CS. Early diagnosis and treatment will lead to better functional outcome and prevention of neurocognitive side-effects of excessive cortisol. PMID- 26124527 TI - P wave dispersion in obsessive-compulsive disorder. AB - BACKGROUND: P wave dispersion (Pd) is defined as the difference between the maximum and the minimum P wave duration. It has recently been associated with increased anxiety levels, thereby predisposing affected individuals to fatal heart disease. Despite of evidence of this autonomous nervous system (ANS) relationship, there are no electrocardiography (ECG) studies in the patients with obsessive-compulsive disorder (OCD). Thus, in this study, we aimed to evaluate the Pd in OCD patients. MATERIALS AND METHODS: The study consisted of a total of 25 patients with OCD and same number of physically and mentally healthy age- and gender-matched controls. For psychological testing, Yale-Brown Obsession and Compulsion (Y-BOCS) was administered. RESULTS: Pmax was found to be significantly higher in the patients compared to controls. Pmin did not differ between groups. Left atrium sizes were not different between groups. As for the main parameter investigated in the present study, it was found that Pd was significantly increased in the OCD patients than the controls. Y-BOCS scores for the patient group was positively correlated with Pd (r = 0.73, P < 0.01). CONCLUSIONS: In conclusion, our results suggest that Pd may be associated with OCD though our sample is too small to allow us to obtain a clear conclusion. Future studies with larger sample evaluating the effects of treatment are required. PMID- 26124529 TI - Suicide due to sulfuric acid ingestion in a case of major depressive disorder. AB - A case of Sulphuric acid ingestion with an intention to commit suicide in a patient of Major Depressive Disorder which resulted in death is reported. Aspects of this mode of suicide and legal issues concerning suicide in mentally ill patient have been discussed. PMID- 26124530 TI - Periodic limb movements and insomnia, a common but under-recognized association. AB - Periodic limb movements unlike restless leg syndrome is under diagnosed and unrecognized in medical arena. While robust Western trials have elucidated the association between periodic limb movements and sleep disturbances, it is not well received and recognized in India even in well sophisticated tertiary care hospital. We report a chronic insomnia patient who had sleep disturbances for past 30 years due to periodic limb movements alone. This was diagnosed through polysomnography. This case emphasizes monitoring leg movements during sleep study. This report may open new horizons in improving monitoring in sleep study in clinical setting. PMID- 26124531 TI - X-linked adrenoleukodystrophy presenting as attention deficit hyperactivity disorder. AB - X-linked adrenoleukodystrophy (X-ALD) is one the leukodystrophies causing a progressive decline in neurological function mainly affecting the children. The most common symptoms are changes in behavior, including social withdrawal or aggression, poor memory or poor scholastic performance. Here, we present a 7-year old boy who presented with symptoms of inattention and hyperactivity and later turned out to be a case of X-ALD. PMID- 26124532 TI - India's rich musical heritage has a lot to offer to modern psychiatry. AB - Music with its instantaneous pleasing effect can be an answer to misery. It is a form of art that is easily accessible anytime and anywhere. This article gives an overview of music therapy practiced in ancient India, its influence on emotion and mind, and speculates its possible clinical applications in the modern era based on the available scientific literature. PMID- 26124533 TI - Madness and Rulers: Events in Coorg and London in 1810, as observed by the Hon. Arthur Cole, the resident at Mysore. AB - What happens if a King becomes mentally ill? Excerpts from the personal papers of Arthur Henry Cole, Resident to the Kingdom of Mysore in 1809, open up fascinating insights into the madness of rulers, in neighboring Coorg and faraway London, and ways in which different societies responded to this. Musings on legal capacity and restrictions imposed on account of insanity, as well as migration and ennui in imperial colonies inevitably follow. PMID- 26124534 TI - A case of hypomania with low-dose lamotrigine. PMID- 26124535 TI - Epigenetics as a link between psychosocial factors and mental disorders. PMID- 26124536 TI - Catalytic acceptorless dehydrogenations: Ru-Macho catalyzed construction of amides and imines. AB - A commercially available ruthenium (II) PNP type pincer catalyst (Ru-Macho) promotes formation of amides and imines from alcohols and amines via an acceptorless dehydrogenation pathway. The formation of secondary amides, tertiary amides, and secondary ketimines occurs in yields ranging from 35%-95%. PMID- 26124537 TI - Dimerization and comments on the reactivity of homophthalic anhydride. AB - Homophthalic anhydride (HPA) dimerizes under the influence of base to provide, sequentially, the (3-4')-C-acyl dimer, a pair of chiral diastereomeric bis(lactones), 3-(2-carboxybenzyl)isocoumarin-4-carboxylic acid, and finally, 3 (2-carboxybenzyl)isocoumarin. The structures of the bis(lactones) were misassigned in 1970 based on the (presumed) cis thermal decarboxylative elimination reaction of the lower melting one. The preferred pathway should be trans-anti, however, and crystallographic analysis of one of the bis(lactones) reverses the earlier assignment. The formal cycloaddition reaction of HPA with imines occurs in preference to HPA dimerization; the mechanistic implications of this reactivity difference are discussed. PMID- 26124538 TI - Phonological Neighborhood Competition Affects Spoken Word Production Irrespective of Sentential Context. AB - Two experiments examined the influence of phonologically similar neighbors on articulation of words' initial stop consonants in order to investigate the conditions under which lexically-conditioned phonetic variation arises. In Experiment 1, participants produced words in isolation. Results showed that the voice-onset time (VOT) of a target's initial voiceless stop was predicted by its overall neighborhood density, but not by its having a voicing minimal pair. In Experiment 2, participants read aloud the same targets after semantically predictive sentence contexts and after neutral sentence contexts. Results showed that, although VOTs were shorter in words produced after predictive contexts, the neighborhood density effect on VOT production persisted irrespective of context. These findings suggest that global competition from a word's neighborhood affects spoken word production independently of contextual modulation and support models in which activation cascades automatically and obligatorily among all of a selected target word's phonological neighbors during acoustic-phonetic encoding. PMID- 26124539 TI - Children's Elicitation of Changes in Parenting during the Early Childhood Years. AB - Using a subsample of the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n = 1,550), this study identified parents who engaged in more developmentally problematic parenting-in the form of low investment, above average television watching, and use of spanking-when their children were very young (M = 24.41 months, SD = 1.23) but changed their parenting in more positive directions over time. Latent profile analysis and other techniques revealed that parents who demonstrated less optimal parenting behaviors when their children were 2 years old were more likely to be African American, from lower socioeconomic backgrounds, and experiencing greater depressive symptoms. Approximately half of such parents, however, made positive changes in their parenting practices, with 5% in the profile characterized by high investment and low use of spanking by the time that their children were in elementary school. These positive changes in parenting behavior were more likely to occur among parents whose children were already demonstrating early reading skills and less problem behavior. These potential "child effects", suggesting that children elicited improvements in parenting, were more pronounced among higher income families but did not vary according to parents' educational attainment. Findings from this study have important implications for intervention programs, suggesting that children's academic and behavioral skills can be leveraged as one means of facilitating positive parenting. PMID- 26124540 TI - A Proposed Neurological Interpretation of Language Evolution. AB - Since the very beginning of the aphasia history it has been well established that there are two major aphasic syndromes (Wernicke's-type and Broca's-type aphasia); each one of them is related to the disturbance at a specific linguistic level (lexical/semantic and grammatical) and associated with a particular brain damage localization (temporal and frontal-subcortical). It is proposed that three stages in language evolution could be distinguished: (a) primitive communication systems similar to those observed in other animals, including nonhuman primates; (b) initial communication systems using sound combinations (lexicon) but without relationships among the elements (grammar); and (c) advanced communication systems including word-combinations (grammar). It is proposed that grammar probably originated from the internal representation of actions, resulting in the creation of verbs; this is an ability that depends on the so-called Broca's area and related brain networks. It is suggested that grammar is the basic ability for the development of so-called metacognitive executive functions. It is concluded that while the lexical/semantic language system (vocabulary) probably appeared during human evolution long before the contemporary man (Homo sapiens sapiens), the grammatical language historically represents a recent acquisition and is correlated with the development of complex cognition (metacognitive executive functions). PMID- 26124541 TI - Confrontation Naming and Reading Abilities at Primary School: A Longitudinal Study. AB - BACKGROUND: Confrontation naming tasks are useful in the assessment of children with learning and language disorders. OBJECTIVES: The aims of this study were (1) providing longitudinal data on confrontation naming; (2) investigating the role of socioeconomic status (SES), intelligence, age, and gender in confrontation naming; (3) identifying relationship between confrontation naming and reading abilities (fluency, accuracy, and comprehension). METHOD: A five-year longitudinal investigation of confrontation naming (i.e., the Boston Naming Test (BNT)) in a nonclinical sample of Italian primary school children was conducted (n = 126), testing them at the end of each school year, to assess nonverbal intelligence, confrontation naming, and reading abilities. RESULTS: Performance on the BNT emerged as a function of IQ and SES. Significant correlations between confrontation naming and reading abilities, especially comprehension, were found; BNT scores correlated better with reading fluency than with reading accuracy. CONCLUSIONS: The longitudinal data obtained in this study are discussed with regard to reading abilities, intelligence, age, gender, and socioeconomic status. PMID- 26124542 TI - empowering the neurogenetic testing services in developing countries: use the basic skills with speed and scale. PMID- 26124543 TI - good doctors for indian villages. PMID- 26124544 TI - Motor conduction parameters in recently diagnosed and untreated hypothyroidism. AB - BACKGROUND: The severity of neuromuscular symptoms and signs in hypothyroidism is known to be related to the duration and degree of hormone deficiency. PURPOSE: The present study was aimed to assess whether recently diagnosed and untreated hypothyroidism affects peripheral nervous system. METHODS: The study included a total of 120 female subjects with age ranging from 20 to 45 years. The motor nerve conduction parameters viz. Distal latency (DL), amplitude of compound muscle action potential (CMAP) and motor nerve conduction velocity (MNCV) were recorded bilaterally in median, ulnar and posterior tibial nerves using standard protocols and settings. RESULTS: The observations revealed significantly prolonged distal motor latencies, reduced CMAP amplitudes and slowed MNCV in the peripheral nerves in hypothyroid. CONCLUSION: The results indicated that the alteration in motor conduction parameters in recently diagnosed and untreated hypothyroidism might be due to various functional and structural changes in peripheral nerves associated with deficiency of thyroid hormones. PMID- 26124545 TI - Neuroprotective potential of escitalopram against behavioral, mitochondrial and oxidative dysfunction induced by 3-nitropropionic acid. AB - BACKGROUND: Huntington's disease (HD) is a neurodegenerative syndrome that leads to marked decline in cognitive functioning along with uncharacteristic body movements called chorea. There exists no therapeutic agent to address the disease.3-Nitropropionic acid (3-NP) which is a suicide inhibitor of succinate dehydrogenase and a well-known experimental model to study Huntington's disease, causes substantial impairment in gait and memory through oxidative and neuronal damage. PURPOSE: In the present study protective effect of escitalopram against 3 NP induced neurotoxicity was explored. METHODS: Adult female Wistar ratswere subjected to per oral administration of 2 different doses of escitalopram (10 and 20 mg/kg) for 12 days followed by intraperitoneal injection of 3-NP (20 mg/kg) on the last four days. RESULTS: Intraperitoneal injection of 3-NP lead to significant induction of HD like symptoms in rats such as impaired memory, reduced locomotor activity, hind limb impairment, decreased body weight, oxidative damage and mitochondrial dysfunction. Treatment with 2 different dose of escitalopram helped reverse the mitochondrial enzyme dysfunction along with reversal of behavioural and biochemical anomaly induced by 3-NP. Further, histopathological examination confirmed the neuroprotective potential of escitalopram against 3-NP induced pathological lesions. CONCLUSION: The results obtained thus substantiate the claim that escitalopram might play an antioxidant and neuroprotective role against 3-NP induced alterations in rats and can prove to be a promising candidate for the management of HD. PMID- 26124546 TI - Bax modulates neuronal survival while p53 is unaltered after Cytochrome C induced oxidative stress in the adult olfactory bulb in vivo. AB - BACKGROUND: The granule and periglomerular cells of the olfactory bulb migrate from the sub-ventricular zone (SVZ) as progenitor cell forming the neuronal stream of the rostral olfactory bulb. These cells are characterized by their ability to divide while expressing adult proteins; a phenomenon attributed to the prolonged cell cycle and the regulatory activities of proteins which modulates apoptosis and proliferation in the developing nervous system. Of interest are the proteins concerned with tumor suppression (p53) and cell cycle exit (Bax) and how they regulate survivability of these neurons in the adult system after an induced oxidative stress. PURPOSE: This study sets to investigate the interplay between p53 and Bax in the adult olfactory bulb (periglomerular and granule cell layer), and how these proteins determine proliferation and neuronal survival after Cytochrome C induced-oxidative stress. Also, we demonstrate the effect of the induced-stress threshold on such regulation in vivo. METHODS: Adult Wistar rats were segregated into three groups. 10 and 20 mg/Kg BW of potassium cyanide (KCN) was administered to the treatment groups for 15 days while the control received normal saline for the same duration. The olfactory bulb was dissected and processed for general histology and immunohistochemistry of p53/Bax in the periglomerular and granule cell layers. Total (Histology) and immunopositive (p53 and Bax) cell count was done using Image J. Subsequently, we determined the analysis of variance with significance set at *P<0.05. RESULTS: We observed an increase in cell count for the 10 mg/KgBW treatment; this was characterized by a significant decrease in Bax expression and no change in p53 expression when this treatment group was compared to the control. However, no change was observed in the total cell count for 20 mg/Kg BW treatment for the same duration of exposure. Interestingly, there was also no significant change in Bax and p53 for this treatment when compared with the control. CONCLUSION: Although p53 plays an important role in development of the olfactory bulb neurons, our findings suggests it has little contribution in neuronal cell viability and proliferation in the adult olfactory bulb. No significant change in p53 was observed irrespective of treatment dose and cell count while Bax expression was reduced at 10 mg/Kg BW treatment and was associated with an increased cell count. We conclude that regulation of survival of neurons in the adult olfactory bulb, following induced-oxidative stress was more dependent of the expression of Bax and the threshold of the induced stress rather than p53 expression. PMID- 26124547 TI - Possible alteration of catecholaminergic transporters in specific brain areas of iron deficit rats. AB - BACKGROUND: In humans, early ID (iron deficiency) may cause impairment of dopamine (DA) metabolism including DA clearance, transporter density, and dopamine receptor (D1 and D2) densities. PURPOSE: The present study aims to examine the effects of early ID on the catecholaminergic system within certain brain areas related to attention. METHODS: Sprague-Dawley rats were divided into 2 groups; control (CN) fed a diet containing 80 ppm Fe and the iron deficient (ID) fed a diet containing 4 ppm Fe. At the end of study rats were sacrificed and brains were dissected. Catecholaminergic neurotransmitters were estimated in specific brain areas using radioactive ligand techniques. RESULTS: Our results revealed a significant effect of age on DAT levels in the nucleus accumbens (NA), olfactory tubercle (OT), and substantia nigra (SN) but not in the striatum. Specifically, 21-day-old rats had greater DAT levels compared to 45-day-old rats when in the NA, OT, and SN as well as in the OT compared to 75-day-old rats. Additionally, there is a significant age difference on NET levels in the dentate gyrus but not in the frontal cortex or the locus coeruleus. Specifically, NET levels were increased among 45-day-old rats compared to 75-day-old rats. CONCLUSIONS: There is a significant age effect on DAT and NET levels in some examined brain areas. These findings are very important as they elucidate the impact of iron deficiency on catecholaminergic systems in the brain. This may explain most of the neurobehavioral sequales of infantile iron deficiency. PMID- 26124548 TI - Hippocampal and striatal histomorphology following chronic nicotine administration in female and male rats. AB - BACKGROUND: Nicotine is a subject of continuous research because of its likely ameliorative effects on neurologic and neurodegenerative disorders. PURPOSE: This study examined the effects of its chronic subcutaneous administration on hippocampal and striatal microstructure in both female and male rats. METHODS: Forty adult female and male Wistar rats were divided into 4 groups. Three experimental groups were administered nicotine via subcutaneous injections at doses of 0.25, 2 and 4 mg/kg body weight for 28 days. Control groups received normal saline. Following administration, routine processing of brain tissues was carried out. Sections obtained were stained using routine H&E methods for general histological appearance, Cresyl violet methods for nissl substances, and Bielschwolsky silver impregnation method for neuritic plaques and neurofibrillary tangles. RESULTS: The study showed significant increase in percentage of neurons showing degenerating features in the hippocampus and striatum of both female and male rats following the higher doses of nicotine treatment. Only female rats showed positive agyrophilic (black-coloured) aggregations in the hippocampal and striatal regions after nicotine treatment. CONCLUSION: The present study indicates that higher dose of chronic nicotine administration may induce hippocampal and striatal neurodegenerative changes. However, further studies using more specific method for studying neurodegeneration within brain regions is recommended. PMID- 26124549 TI - Revisiting the dilution factor as vital parameter for sensitivity of ELISA assay in CSF and Plasma. AB - BACKGROUND: Enzyme Linked Immunosorbent Assay (ELISA) is very sensitive assay which provides quantitative data about expression of antigens. However, its utility is based on certain parameters which vary in the experimental situations. PURPOSE: We aimed to analyse the dilution factor as an important parameter for determining the sensitivity of ELISA in human samples. METHODS: Total of n = 57 ALS patients and n = 48 normal controls were selected for the study. All the patients were recruited from, Department for Neurology and Anaesthesia, PGIMER. Blood and CSF sample was collected and ELISA run was performed in both plasma and blood sample. ELISA of OPTN and TDP-43 was employed to check the respective protein concentration in CSF and Plasma. RESULTS: There was no significant difference which was reported for Plasma as well as CSF values of TDP-43 and OPTN. Dilution test prior to actual experiment made a significant impact in deciding the actual concentration of sample and led to overshootingbeyond range of reference protein. CONCLUSION: Negative results from our study highlights the significance of determining the dilution factor as an important parameter for conduct of ELISA. PMID- 26124550 TI - Plasma cells within granulomatous inflammation display signs pointing to autoreactivity and destruction in granulomatosis with polyangiitis. Artiritis Research and Therapy 2014, 16: R55. PMID- 26124551 TI - An urgent need for experimental animal model of autism in drug development. AB - Construct, face and predictive validities are necessary for any disease model. Although rodent models are used to investigate the neurobiology of autism, however, till date there is no such ideal animal model which can fulfill all the above said validities. Available drug therapy to treat autism is very limited and less effective. In this review, we summarize the work done with rodent models of autism and highlight different validities. We found that, very few studies have studied all the validities in a single study and none of the study fulfilled all the validities. We also reviewed the drugs used in the treatment of autism. Here we propose the limitations of available animal models. We also propose the urgent need of additional models to fulfill all the validities and to understand autism in a better way. PMID- 26124552 TI - Extra pontine osmotic demyelination syndrome. AB - The osmotic demyelination syndrome (ODS) has been identified as a complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium which cause a rapid changes in osmolality of the interstitial (extracellular) compartment of the brain leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Slow correction of the serum sodium concentration and additional administration of corticosteroids seems to be a major prevention step in ODS patients. In the current report we aimed to share a rare case which we observed in our hospital. A 65 year old female admitted as altered sensorium with history of vomiting, diarrhea was managed with intravenous fluids for 2 days at a peripheral health centre. Patient was referred to our centre with encephalopathy, evaluated and found to have hyponatremia and hypokalemia rest of biochemical parameters and septic profile were normal. Patient's electrolyte disturbances were managed as per guidelines but encephalopathy persisted. Supportive treatment was continued and patient was discharged after 2 wks of stay in hospital after gaining full sensorium and neurological functions. PMID- 26124553 TI - Immunodetection of oligoclonal bands in serum and CSF of Multiple Sclerosis patients. PMID- 26124554 TI - Omics Metadata Management Software (OMMS). AB - Next-generation sequencing projects have underappreciated information management tasks requiring detailed attention to specimen curation, nucleic acid sample preparation and sequence production methods required for downstream data processing, comparison, interpretation, sharing and reuse. The few existing metadata management tools for genome-based studies provide weak curatorial frameworks for experimentalists to store and manage idiosyncratic, project specific information, typically offering no automation supporting unified naming and numbering conventions for sequencing production environments that routinely deal with hundreds, if not thousands of samples at a time. Moreover, existing tools are not readily interfaced with bioinformatics executables, (e.g., BLAST, Bowtie2, custom pipelines). Our application, the Omics Metadata Management Software (OMMS), answers both needs, empowering experimentalists to generate intuitive, consistent metadata, and perform analyses and information management tasks via an intuitive web-based interface. Several use cases with short-read sequence datasets are provided to validate installation and integrated function, and suggest possible methodological road maps for prospective users. Provided examples highlight possible OMMS workflows for metadata curation, multistep analyses, and results management and downloading. The OMMS can be implemented as a stand alone-package for individual laboratories, or can be configured for webbased deployment supporting geographically-dispersed projects. The OMMS was developed using an open-source software base, is flexible, extensible and easily installed and executed. The OMMS can be obtained at http://omms.sandia.gov. AVAILABILITY: The OMMS can be obtained at http://omms.sandia.gov. PMID- 26124555 TI - BlastXtract2: Improving early exploration of (meta) genomes. AB - To manage and intelligently mine the avalanche of genomic sequences intuitive and user-friendly graphical interfaces are required. Here we present BlastXtract2 which exclusively facilitates early exploration of un-annotated genomic and metagenomic sequences. Various formats of translated searches, including the commonly used BlastX, of multiple sequences against multiple protein databases can be uploaded to a relational database server, which can be accessed via a locally installed web-server. There, an intuitive GUI allows straightforward data mining and enables quick detection of potential frameshifts and poorly sequenced or assembled regions, thereby contributing in making BlastXtract2 a unique and valuable tool for early exploration of (meta)genomic sequences. AVAILABILITY: Source code, documentation and an online demo version are available at https://github.com/ ClaessonLab/BlastXtract2. PMID- 26124556 TI - Major bioactive metabolites from marine fungi: A Review. AB - Biologists and chemists of the world have been attracted towards marine natural products for the last five decades. Approximately 16,000 marine natural products have been isolated from marine organisms which have been reported in approximately 6,800 publications, proving marine microorganisms to be a invaluable source for the production of novel antibiotic, anti tumor, and anti inflammatory agents. The marine fungi particularly those associated with marine alga, sponge, invertebrates, and sediments appear to be a rich source for secondary metabolites, possessing Antibiotic, antiviral, antifungal and antiyeast activities. Besides, a few growth stimulant properties which may be useful in studies on wound healing, carcinogenic properties, and in the study of cancers are reported. Recent investigations on marine filamentous fungi looking for biologically active secondary metabolites indicate the tremendous potential of them as a source of new medicines. The present study reviews about some important bioactive metabolites reported from marine fungal strains which are anti bacterial, anti tumour and anti inflammatory in action. It highlights the chemistry and biological activity of the major bioactive alkaloids, polyketides, terpenoids, isoprenoid and non-isoprenoid compounds, quinones, isolated from marine fungi. PMID- 26124557 TI - Evolution of bacterial and fungal growth media. AB - Microbial media has undergone several changes since its inception but some key challenges remain. In recent years, there has been exploration of several alternative nutrient sources, both to cater to the specificity in requirement of growth of "fussy microorganisms" and also to reduce costs for large-scale fermentation that is required for biotechnology. Our mini-review explores these developments and also points at lacunas in the present areas of exploration, such as a lack of concerted effort in pH and osmolarity regulation. We hope that our commentary provides direction for future research in microbial media. PMID- 26124558 TI - Chemosensory apparatus of Drosophila larvae. AB - Many insects, including Drosophila melanogaster, have a rich repertoire of olfactory behavior. Combination of robust behavioral assays, physiological and molecular tools render D. melanogaster as highly suitable system for olfactory studies. The small number of neurons in the olfactory system of fruit flies, especially the number of sensory neurons in the larval stage, makes the exploration of sensory coding at all stages of its nervous system a potentially tractable goal, which is not possible in the foreseeable future in any mammalian preparation. Advances in physiological recordings, olfactory signaling and detailed analysis of behavior, can place larvae in a position to ask previously unanswerable questions. PMID- 26124559 TI - In silico inhibition of GABARAP activity using antiepileptic medicinal derived compounds. AB - Epilepsy is a neurological disorder affecting more than 50 million people worldwide. It can be controlled by antiepileptic drugs (AEDs) but more than 30% patients are still resistant to AEDs. To overcome this problem, researchers are trying to develop novel approaches to treat epilepsy including the use of herbal medicines. The gamma-amino butyric acid type-A receptor associated protein (GABARAP) is ubiquitin-like modifier implicated in the intracellular trafficking of GABAAR. An in silico mutation was created at 116 amino acid position G116A, and an in silico study was carried out to identify the potential binding inhibitors (with antiepileptic properties) against the active sites of GABARAP. Five different plant derived compounds namely (a) Aconitine (b) Berberine (c) Montanine (d) Raubasine (e) Safranal were selected, and their quantitative structure-activity relationships (QSAR) have been conducted to search the inhibitory activity of the selected compounds. The results have shown maximum number of hydrogen bond (H-bond) interactions of Raubasine with highest interaction energy among all of the five compounds. So, Raubasine could be the best fit ligand of GABARAP but in vitro, and in vivo studies are necessary for further confirmation. PMID- 26124560 TI - Molecular docking of selected phytocompounds with H1N1 Proteins. AB - The H1N1 influenza virus is a serious threat to human population. Oseltamivir and Zanamivir are known antiviral drugs for swine flu with observed side effects. These drugs are viral neuraminidase and hemagglutinin inhibitor prevents early virus multiplication by blocking sialic acid cleavage on host cells. Therefore, it is of interest to identify naturally occurring novel compounds to control viral growth. Thus, H1N1 proteins (neuraminidase and hemagglutinin) were screened with phytocompounds isolated from Tulsi plant (Ocimum sanctum L.) using molecular docking tools. This identified Apigenin as an alternative to Oseltamivir and Zanamivir with improved predicted binding properties. Hence, it is of interest to consider this compound for further in vitro and in vivo evaluation. PMID- 26124561 TI - Antifungal drug resistance pattern of Candida. spp isolated from vaginitis in Ilam-Iran during 2013-2014. AB - Vaginal Candidiasis is the most common and important opportunistic fungal infection in women. By increasing use of antifungal drugs in recent years, it has caused drug resistance. This study aims to evaluate antifungal drugs susceptibility of Candida. spp isolated of women with vaginitis from Ilam-Iran during 2013-2014. samples were collected and cultured from 385 women with vaginitis, then Candida.spp was diagnosed by standard method. Antifungal drug susceptibility test for nystatin 100 unit/disk, fluconazole 10ug/disk, itraconazole 10ug/disk, ketoconazole 10ug/disk, amphotericinB 20ug/disk, clotrimazole 10ug/disk, posaconazole 5ug/disk, and voriconazole 1ug/disk were carried out by M44-A method(CLSI). From all culture positive samples, 150 isolates were Candida albicans and 89 isolates were non-albicans. The resistance to fluconazole, itraconazole, ketoconazole, clotrimazole, voriconazole, posaconazole, nystatin and amphotericin B was 76%, 62%, 72%, 55%, 6%, 7%, 1% and 0%. The highest resistance was seen for fluconazole , itraconazole, and the highest susceptible was seen for nystatin and amphotericin B. These results indicate nystatin and amphotericin B can be used as the first line for empirical therapy of vaginal candidiasis in the district. PMID- 26124562 TI - Identification of collaborative activities with oxidative phosphorylation in bipolar disorder. AB - Bipolar disorder (BD) is a psychiatric disease considered to polygenic with multiple factors in genetics, each of which is not dominant but collaborative during pathogenic progression. We describe a method that estimates the collaborative contribution to the disease between a certain well-studied pathway and the other candidate pathway using Gene Set Enrichment Analysis (GSEA). We describe a modified GSEA (improved derivation) to identify genes that are significantly and differentially expressed between disease and non-disease states and that are consistently co-expressed with a target pathway which is deeply related to disease etiology. The modified GSEA uses available gene expression data to identify molecular mechanism (ubiquitin-proteasome and inflammatory response) associated with the disease. We believe that this approach could reveal hidden relations between a certain well-studied pathway and the other candidate pathway known in literature. ABBREVIATIONS: ATP5I - ATP synthase H+ transporting mitochondrial F0 complex subunit E, ATP5J - ATP synthase H+ transporting mitochondrial F0 complex subunit F6, BAD - Bcl-2-associated death promoter, BAX - Bcl-2-associated x protein, Bcl-2 - B-cell lymphoma 2, BDNF - brain derived neurotrophic factor, COX5B - Cytochrome c oxidase subunit Vb, COX7A2 - cytochrome c oxidase subunit VIIa polypeptide 2, DLK - dual leucine zipper-bearing kinase, GABA - Gamma aminobutyric acid, IL-8 - Interleukin 8, NDUFA1 - NADH dehydrogenase 1 alpha subcomplex 1, NDUFB2 - NADH dehydrogenase1 beta subcomplex 2, NDUFS4 - NADH dehydrogenase Fe-S protein 4, NGF - nerve growth factor, PPP2R5C - protein phosphatase 2 regulatory subunit B gamma, PSMA3 - proteasome subunit alpha type 3, PSMA7 - proteasome subunit alpha type 7, PSMB1 - proteasome subunit beta type 1, PSMB6 - proteasome subunit beta type 6, PSMB7 - proteasome subunit beta type 7, PSMC2 - proteasome 26S subunit ATPase 2, PSMC5 - proteasome 26S subunit ATPase 5, SLC6A4 - solute carrier family 6 member 4, TNFa - tumor necrosis factor a, UBE2A - ubiquitinconjugating enzyme E2A, UCRC - ubiquinol-cytochrome c reductase complex, UFC1 - ubiquitin-fold modifier conjugating enzyme 1, UQCRQ - ubiquinol cytochrome c reductase complex III subunit VII, USP14 - ubiquitin specific protease 14. PMID- 26124563 TI - Piroxicam confer neuroprotection in Cerebral Ischemia by inhibiting Cyclooxygenases, Acid- Sensing Ion Channel-1a and Aquaporin-4: an in silico comparison with Aspirin and Nimesulide. AB - Cerebral ischemia (CI), caused by the deprivation of oxygen and glucose to the brain, is the leading cause of permanent disability. Neuronal demise in CI has been linked to several pathways which include cyclooxygenases (COX) - mediated production of prostaglandins (PGs) and subsequently reactive oxygen species (ROS), aquaporin-4 (AQ-4) - mediated brain edema and acidsensing ion channel-1a (ASIC-1a) - mediated acidotoxicity, matrix remodeling, in addition to others. Several non-steroidal antiinflammatory drugs (NSAIDs) are presently in use to prevent these pathways. However, owing to the large number of processes involved, there is high drug load. So, identifying drugs with multimodal role has always been a frequently sought venture. The present in silico study has been performed to find out the relative efficacy of three different NSAIDs (Piroxicam, Aspirin and Nimesulide) in preventing neurodegeneration in CI, with respect to their inhibitory potential on COXs, AQ-4 and ASIC-1a. We find that piroxicam is the most potent inhibitor of these receptors as compared to the NSAIDs under investigation. Since piroxicam has already been reported to inhibit N-methyl-D aspartate (NMDA) receptor and matrix metalloproteinases (MMPs), which are also linked to CI-induced neurodegeneration, we hereby propose piroxicam to be a gold standard drug in preventing neurodegeneration in CI. PMID- 26124564 TI - Erratum: Correction in Co-Author name To: Reliability of Quality Assessments in Research Synthesis: Securing the Highest Quality Bioinformation for HIT. AB - [This corrects the article on p. 691 in vol. 8, PMID: 23055612.]. PMID- 26124565 TI - Modeling Based Structural Insights into Biodegradation of the Herbicide Diuron by Laccase-1 from Ceriporiopsis subvermispora. AB - The herbicide diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is used in many agricultural crops and non-crop areas worldwide, leading to the pollution of the aquatic environment by soil leaching. White rot fungi and its lignin modifying enzymes, peroxidases and laccases, are responsible for its degradation. Therefore, it is of interest to explore the potential use of Ceriporiopsis subvermispora laccase (CersuLac1) in the biotransformation of this herbicide by using its enzyme laccase. However, the structure of laccase from Ceriporiopsis subvermispora is still unknown. Hence, a model of laccase was constructed using homology modeling. The model was further used to dock p-methylbenzoate in the presence of four copper ions to analyze molecular basis of its binding and interaction. The ligand-protein interaction is stereo-chemically favorable in nature. The presence of the single protonated Lys457 was necessary for catalysis, being coordinated by a cupper ion. The best pose of diuron on CersuLac1 has a theoretical Ki of 2.91 mM. This is comparable to the KM values for laccases from other organisms with similar compounds. Thus, we document the insights for the potential use of laccase from Ceriporiopsis subvermispora in the biotransfrormation of diuron. PMID- 26124566 TI - An in silico analytical study of lung cancer and smokers datasets from gene expression omnibus (GEO) for prediction of differentially expressed genes. AB - Smoking is the leading cause of lung cancer development and several genes have been identified as potential biomarker for lungs cancer. Contributing to the present scientific knowledge of biomarkers for lung cancer two different data sets, i.e. GDS3257 and GDS3054 were downloaded from NCBI's GEO database and normalized by RMA and GRMA packages (Bioconductor). Diffrentially expressed genes were extracted by using and were R (3.1.2); DAVID online tool was used for gene annotation and GENE MANIA tool was used for construction of gene regulatory network. Nine smoking independent gene were found whereas average expressions of those genes were almost similar in both the datasets. Five genes among them were found to be associated with cancer subtypes. Thirty smoking specific genes were identified; among those genes eight were associated with cancer sub types. GPR110, IL1RN and HSP90AA1 were found directly associated with lung cancer. SEMA6A differentially expresses in only non-smoking lung cancer samples. FLG is differentially expressed smoking specific gene and is related to onset of various cancer subtypes. Functional annotation and network analysis revealed that FLG participates in various epidermal tissue developmental processes and is co expressed with other genes. Lung tissues are epidermal tissues and thus it suggests that alteration in FLG may cause lung cancer. We conclude that smoking alters expression of several genes and associated biological pathways during development of lung cancers. PMID- 26124567 TI - Computer aided screening of natural compounds targeting the E6 protein of HPV using molecular docking. AB - The cancer profile in the Indian state of Uttarakhand reveals that the breast cancer is the most prevalent type of cancers in females followed by cervical and ovarian type. Literature survey shows that the E6 protein of Human Papilloma Virus-16 (HPV-16) is responsible for causing several forms of cancer in human. Therefore, it is of interest to screen HPV-16 E6 target protein with known natural compounds using computer aided molecular modeling and docking tools. The complete structure of E6 is unknown. Hence, the E6 structure model was constructed using different online servers followed by molecular docking of Colchine, Curcumin, Daphnoretin, Ellipticine and Epigallocatechin-3-gallate; five known natural compounds with best E6 protein model predicted by Phyre2 server. The screening exercise shows that Daphnoretin (with binding free energy of -8.3 kcal/mol), a natural compound derived from Wikstroemia indica has the top binding properties. Thus, it is of interest to consider the compound for further validation. PMID- 26124568 TI - Molecular docking based screening of predicted potential inhibitors for VP40 from Ebola virus. AB - Ebola virus is a member of Filoviridae and cause severe human disease with 90 percent mortality. The life cycle of Ebola contains an assembly stage which is mediated by VP40 proteins. VP40 subunits oligomerize and form ring-structures which are either octamers or hexamers. Prevention of VP40 matrix protein assembly prevents virus particle formation as well as virus budding. In the present study we simulated the biological condition for a single VP40 subunit. Then a library containing 120.000 drugs like chemicals was used as the virtual screening database. Top 10 successive hits were then analyzed regarding absorption, distribution, metabolism, and excretion properties. Moreover probable accessorial human protein targets and toxicity properties of successive hits were analyzed by in silico tools. We found 4 chemicals that could bind VP40 subunits in a manner that by making an interfering steric condense prevents matrix protein oligomerization. The pharmacokinetic and toxicity studies also validated the potential of 4 finlay successive hits to be considered as a new anti-Ebola drugs. PMID- 26124569 TI - Molecular docking and simulation of Curcumin with Geranylgeranyl Transferase1 (GGTase1) and Farnesyl Transferase (FTase). AB - Protein prenylation is a posttranslational modification that is indispensable for translocation of membrane GTPases like Ras, Rho, Ras etc. Proteins of Ras family undergo farnesylation by FTase while Rho family goes through geranylgeranylation by GGTase1. There is only an infinitesimal difference in signal recognition between FTase and GGTase1. FTase inhibitors mostly end up selecting the cells with mutated Ras proteins that have acquired affinity towards GGTase1 in cancer microcosms. Therefore, it is of interest to identify GGTase1 and FTase dual inhibitors using the docking tool AutoDock Vina. Docking data show that curcumin (from turmeric) has higher binding affinity to GGTase1 than that of established peptidomimetic GGTase1 inhibitors (GGTI) such as GGTI-297, GGTI-298, CHEMBL525185. Curcumin also interacts with FTase with binding energy comparable to co-crystalized compound 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4 [1-amino-1-(1-methyl-1h-imidizol-5-yl)-ethyl]-benzonitrile (BNE). The docked complex was further simulated for 10 ns using molecular dynamics simulation for stability. Thus, the molecular basis for curcumin binding to GGTase1 and FTase is reported. PMID- 26124570 TI - Current status of preimplantation genetic diagnosis in Japan. AB - This is a retrospective study aimingto clarify the current status of preimplantation genetic diagnosis (PGD) in Japan. Our data were collected from 12 facilities between September 2004 and September 2012, and entered into a database. A majority of PGD in Japan was performed for balanced structural chromosomal abnormalities in couples with recurrent miscarriage. PGD for monogenic diseases was performed only in two facilities. The average maternal age was 38 years for monogenic diseases and 40 years for chromosomal abnormalities. Overall there have been671 cycles to oocyte retrieval reported. Of these cycles, 85% (572 cycles)were for chromosomal abnormalities, and 15% (99 cycles) for monogenic diseases. Diagnosis rates in the current study were 70.8% for monogenic diseases and 94.0% for chromosomal abnormalities. Rates of embryo transfer of PGD were 62.7% for monogenic diseases and 25.5% for chromosomal abnormalities. Clinical pregnancy rates per embryo transfer were 12.0% for monogenic diseases and 35.6% for chromosomal abnormalities. Our study is the first PGD report from all facilities which had the approval of the ethics committee of the Japanese Society of Obstetrics and Gynecology. We have built a basis for gathering continuous PGD data in Japan. PMID- 26124571 TI - Effect of combined herbal feed additives on methane, total gas production and rumen fermentation. AB - The present study was to evaluate effect of herbal feed additives on methane and total gas production during the rumen fermentation for environment and animal health concern. Different parts of the five medicinal plants were selected such as leaf and small stems of Ocimum sanctum (Tulsi), roots of Curcuma longa (Haldi), fruits of Emblica officinalis (Amla), leaves of Azadirachta indica (Neem) and leaves and small stem of Clerodendrum phlomidis (Arni) for our study. Addition of different herbal additive combinations did not influence IVDMD and total gas production however methane production (mg/g of substrate DM) was significantly (P<0.05) reduced in Amla: Neem and Neem: Arni combinations. Total nitrogen significantly (P<0.01) increased in the combinations of Tulsi: Haldi and Amla: Neem. TCA-ppt-N is significantly (P<0.01) increased in Tulsi: Haldi, Haldi: Amla, Amla: Neem and Neem: Arni however NH3-N (mg/dl) significantly decreased in all treatments. We conclude that the screening of plant combinations, Amla: Neem and Neem: Arni have potential to decrease methane production and our herbal feed supplements have no side-effects on the ruminant in small amount. PMID- 26124572 TI - Compression of Large genomic datasets using COMRAD on Parallel Computing Platform. AB - The big data storage is a challenge in a post genome era. Hence, there is a need for high performance computing solutions for managing large genomic data. Therefore, it is of interest to describe a parallel-computing approach using message-passing library for distributing the different compression stages in clusters. The genomic compression helps to reduce the on disk"foot print" of large data volumes of sequences. This supports the computational infrastructure for a more efficient archiving. The approach was shown to find utility in 21 Eukaryotic genomes using stratified sampling in this report. The method achieves an average of 6-fold disk space reduction with three times better compression time than COMRAD. AVAILABILITY: The source codes are written in C using message passing libraries and are available at https:// sourceforge.net/ projects/ comradmpi/files / COMRADMPI/. PMID- 26124573 TI - Effect of Soft Drinks and Fresh Fruit Juice on Surface Roughness of Commonly used Restorative Materials. AB - In this in vitro study, the effects of a Cola drink, and fresh fruit juice (citrus) on the surface roughness on flowable composite and resin-modified glass ionomer cement (RMGIC) each was evaluated and compared. Using a brass mold 70 pellets each of flowable composite (FiltekTM Flow) and RMGIC tricure restorative material were prepared according to the manufacturer's instructions. Two groups (groups I and II) were formed containing 30 pellets of each material. Remaining 10 pellets of each restorative material did form the control group [water (group III)]. Experimental group pellets were again divided into three subgroups (mild, moderate and severe) containing 10 pellets each and were kept in plastic containers with 30 ml Cola drink (group I) and fresh fruit juice (group II) respectively. Immersion regime was followed according to M aupome G et al. Baseline and final surface roughness (Ra) value for each pellet was evaluated using a profilometer. Statistical analysis was done with Wilcoxon's signed rank test and analysis of variance (ANOVA) followed by Mann-Whitney test. Results showed that the erosive effect of both Cola drink and fresh fruit juice caused significant surface roughness on both flowable composite and RMGIC restorative materials in the mild, moderate and severe immersion regimes. How to cite this article: Maganur P, Satish V, Prabhakar AR, Namineni S. Effect of Soft Drinks and Fresh Fruit Juice on Surface Roughness of Commonly used Restorative Materials. Int J Clin Pediatr Dent 2015;8(1):1-5. PMID- 26124574 TI - Recent vs Conventional Methods of Caries Removal: A Comparative in vivo Study in Pediatric Patients. AB - AIMS: To compare the three different methods of caries removal, conventional method using Airotor and chemomechanical method using Carisolv and Papacarie. SETTINGS AND DESIGN: The patients with multiple carious teeth were selected either in the deciduous dentition or mixed dentition. Ninety primary molars were selected from 30 children (10 males and 20 females) between the age group 6 and 9 years. MATERIALS AND METHODS: After caries excavation, cavities were evaluated for caries removal or clinical efficacy by the tactile and visual criteria, microbiological efficacy, time taken for the procedure. Patient acceptability toward the treatment was also checked with the help of a visual analog scale (VAS). The observations thus obtained were subjected to statistical analysis using analysis of variance (ANOVA), Mann-Whitney U-test and Kruskal-Wallis test. RESULTS: The clinical efficacy of caries removal was highest with Airotor while the microbiological efficacy of caries removal was almost comparable with Airotor, Carisolv and Papacarie caries removal methods. The time taken to remove caries by Airotor method was observed to be least while the patient acceptance was found to be highest with Papacarie method. How to cite this article: Chowdhry S, Saha S, Samadi F, Jaiswal JN, Garg A, Chowdhry P. Recent vs Conventional Methods of Caries Removal: A Comparative in vivo Study in Pediatric Patients. Int J Clin Pediatr Dent 2015;8(1):6-11. PMID- 26124575 TI - Effect of Catalase and Sodium Fluoride on Human Enamel bleached with 35% Carbamide Peroxide. AB - AIM: To evaluate the effects of postbleaching antioxidant application fluoridation treatment on the surface morphology and microhardness of human enamel. MATERIALS AND METHODS: Ten freshly extracted human maxillary central incisors were cut at cementoenamel junction. Crown portion was sectioned into six slabs which were divided into five groups: group A - untreated controls; group B 35% carbamide peroxide (CP); group C - 35% CP and catalase; group D - treatment with 35% CP and 5% sodium fluoride; group E - 35% CP, catalase and 5% sodium fluoride. Thirty-five percent carbamide peroxide application included two applications of 30 minutes each at a 5-day interval. After treatment, the slabs were thoroughly washed with water for 10 seconds and stored in artificial saliva at 37 degrees C until the next treatment. Two percent sodium fluoride included application for 5 minutes. Three catalase included application for 3 minutes. RESULTS: After 5 days, groups B and C showed significantly decreased enamel microhardness compared to control. Group D specimens showed relatively less reduction in enamel micro-hardness than group C specimens. There is a marked increase in enamel microhardness in group E specimens. CONCLUSIONS: Fluoride take up was comparatively enhanced after catalase application resulting in less demineralization and increased microhardness. How to cite this article: Thakur R, Shigli AL, Sharma DS, Thakur G. Effect of Catalase and Sodium Fluoride on Human Enamel bleached with 35% Carbamide Peroxide. Int J Clin Pediatr Dent 2015;8(1):12 17. PMID- 26124576 TI - Laser Pulpotomy-An Effective Alternative to Conventional Techniques: A 12 Months Clinicoradiographic Study. AB - BACKGROUND: Vital pulpotomy is a single-stage procedure of surgical amputation of the coronal portion of exposed vital pulp, usually as a means of preserving the vitality and function of the remaining radicular portion. AIMS AND OBJECTIVES: The aim of this study was to compare the clinical and radiographic success rates for ferric sulfate (FS), electrosurgery (ES) and laser pulpotomy in human primary molars. MATERIALS AND METHODS: In a randomized clinical trial, 30 primary molars indicated for pulpotomy in children aged 4 to 10 years were treated using either a FS (10 teeth), ES technique (10 teeth) and laser (10 teeth). Following the pulpotomy, the teeth were evaluated for clinical and radiographic success at 3, 6, 9 and 12 months on the basis of the presence of pain, sinus, mobility, internal and external resorption, periapical radiolucency, calcification in the canal and bone loss. STATISTICAL ANALYSIS: The data were assessed with Chi-square test. RESULTS: After 12 months of follow-up, both clinical and radiographic success rates were 100% in the laser group but only 80% in both ES and FS groups. There was statistically significant difference between the success rates of three groups (p < 0.05). CONCLUSION: Laser pulpotomy showed better clinical as well as radiographical results than ES and FS pulpotomy. Laser pulpotomy was also found superior in terms of operating time, patient cooperation, ease of use and pain. Although results of the study showed the failure rates for electrosurgical pulpotomy to be equal to those for FS pulpotomy, electrosurgical pulpotomy being a nonpharmacological technique considered more favorable. Further studies using larger sample size and longer evaluation periods are suggested. How to cite this article: Gupta G, Rana V, Srivastava N, Chandna P. Laser Pulpotomy-An Effective Alternative to Conventional Techniques: A 12 Months Clinicoradiographic Study. Int J Clin Pediatr Dent 2015;8(1):18-21. PMID- 26124577 TI - Evaluation of the Load-bearing Capacity of Fractured Incisal Edge of Maxillary Permanent Central Incisors restored with a Glass Fiber-reinforced Nanocomposite: An in vitro Study. AB - OBJECTIVES: The aim of this study was to evaluate and compare the load-bearing capacity of fractured incisal edge of maxillary permanent central incisors restored with a nanocomposite and a glass fiber-reinforced nanocomposite. MATERIALS AND METHODS: Thirty-six extracted sound maxillary central incisors randomly divided in three groups were used for the present study. Group I (control) contained untreated teeth. Samples in experimental groups II and III were prepared by cutting the incisal (one-third) part of the crown horizontally and subjected to enamel preparations and restored with a nanocomposite and a glass fiber-reinforced nanocomposite respectively. All restored teeth were stored in distilled water at room temperature for 24 hours. Fracture resistance was evaluated as peak load at failure (Newton) for samples tested in a cantilever bending test using Hounsfield universal testing machine. Failure modes were microscopically examined. RESULTS: Highest mean peak failure load (Newton) among experimental groups was observed in glass fiber-reinforced nano composite group (863.50 +/- 76.12 N) followed by nanocomposite group (633.67 +/- 40.14 N). One way analysis of variance (ANOVA) revealed that the restoration technique significantly affected the load-bearing capacity (p < 0.001). Scheffe's post-hoc comparison test (subset for alpha = 0.05) revealed that there was significant difference in the mean peak failure load values of nanocomposite and glass fiber reinforced nanocomposite groups when considered together (p < 0.001). Experimental groups showed similar types of failure modes with majority occurring ascohesive and mixed type. Fifty-eight percent of the teeth in glass fiber reinforced nanocomposite group fractured below the cementoenamel junction. CONCLUSION: By using fiber-reinforced composite substructure under conventional composites in the repair of fractured incisors, the load-bearing capacity of the restored incisal edge could be substantially increased. How to cite this article: Kumar PSP, Srilatha KT, Nandlal B, Dhull KS. Evaluation of the Load-bearing Capacity of Fractured Incisal Edge of Maxillary Permanent Central Incisors restored with a Glass Fiber-reinforced Nanocomposite: An in vitro Study. Int J Clin Pediatr Dent 2015;8(1):22-29. PMID- 26124578 TI - A Comparative Evaluation of the Efficacy of Etching by the Total Etch and Self etch Dentin Bonding Systems in the Primary Teeth: An in vitro Study. AB - OBJECTIVE: Early childhood caries is now affecting the children in dangerous proportions. There is a wide spread loss of the tooth material irrespective of the type of the carious lesion. Restoration of such lesions with a strong permanent bond between the dental tissues and the restorative dental materials would be a highly desirable requisite. Ultramorphological characterizations show that the interfacial morphology and the chemical characterization of the bonding systems appear to be strongly associated with each other and, therefore, observing and understanding the interfacial phenomenon and its quality would be of great importance in the selection of a dental adhesive for its use in pediatric restorative dentistry. STUDY DESIGN: Human primary molars, which were indicated for extraction, for an array of reasons like caries, normal exfoliation, pathological root resorption, over-retained and serial extraction, were collected for the study purpose. Total number of teeth was then equally distributed into two subgroups, each namely A1 (Prime and Bond NT) and A2 (Xeno III). RESULTS: The type of etching pattern that was observed in group A1 (Prime and Bond NT) of Silverstone's type II compared to the Silverstone's type III observed in group A2 (Xeno III). CONCLUSION: RESULTS of this study indicate that the use of an etchant separately followed by the application of the bonding system-Prime and Bond NT-would provide a better quality of adhesion thus improving the quality and longevity of the restoration done within the limits of enamel in primary dentition. How to cite this article: Mithiborwala SH, Chaugule V, Katge F, Poojari M, Pujari P, Pammi T. A Comparative Evaluation of the Efficacy of Etching by the Total Etch and Self-etch Dentin Bonding Systems in the Primary Teeth: An in vitro Study. Int J Clin Pediatr Dent 2015;8(1):30-36. PMID- 26124579 TI - A Comparative Study of Biodegradation of Nickel and Chromium from Space Maintainers: An in vitro Study. AB - OBJECTIVE: The aim of the study was to compare and evaluate the in vitro biodegradation of nickel and chromium from space maintainers, made of three different companies, i.e (Dantaurum, Rocky mountain and Dtech) in artificial saliva. MATERIALS AND METHODS: The study comprised of 30 space maintainers out of which 10 were fabricated using Dantaurum, 10 using Rocky mountain and 10 using Dtech band materials. Stainless steel wire (Dantaurum, Rocky mountain and Konark) was used for making loops and Leone solder and flux was used for soldering. Each group was further divided into four subgroups containing 1, 2, 3 and 4 space maintainers respectively. The space maintainers in each subgroup were placed in separate glass beakers containing 100 ml of artificial saliva at 37 degrees C for 4 weeks. Salivary samples from each beaker was analyzed for nickel and chromium ions separately on days 1, 7, 14, 21 and 28 days using inductively coupled plasma optical emission spectrophotometer. RESULTS: Total release of nickel and chromium from all band and loop space maintainers ranged from 0.020 to 1.524 ppm and 0.002 to 0.289 ppm respectively. The release of nickel and chromium between the groups and within the groups was not significant (p < 0.5). CONCLUSION: There was no substantial release of nickel and chromium from space maintainers made of Dantaurum, Rocky mountain and Dtech which could cause any toxicity. How to cite this article: Anand A, Sharma A, Kumar P, Sandhu M, Sachdeva S, Sachdev V. A Comparative Study of Biodegradation of Nickel and Chromium from Space Maintainers: An in vitro Study. Int J Clin Pediatr Dent 2015; 8(1):37-41. PMID- 26124580 TI - A Polarized Light Microscopic Study to Comparatively evaluate Four Remineralizing Agents on Enamel viz CPP-ACPF, ReminPro, SHY-NM and Colgate Strong Teeth. AB - AIM: To compare and evaluate the remineralizing potential of four commercially available products namely SHY-NM, GC Tooth Mousse Plus, ReminPro and Colgate strong teeth on demineralized human teeth. MATERIALS AND METHODS: The study included 50 extracted premolars having 3 * 3 mm window prepared on the middle third of the tooth, which was then subjected to demineralization for 48 hours at 37 degrees C. Teeth were randomly selected and grouped into five study groups of 10 teeth in each. Each group was treated with respective remineralizing agent and sectioned using hard-tissue microtome. Each section obtained was visualized under polarized light microscope and analyzed using Image J software. RESULTS: The statistically evaluated results revealed that SHY-NM has the most remineralizing potential followed by ReminPro, GC Tooth Mousse Plus and fluoridated toothpaste. CONCLUSION: Based on the study, the SHY-NM was superior to the GC Tooth Mousse Plus, ReminPro and Colgate strong teeth on demineralized human teeth. How to cite this article: Rajan R, Krishnan R, Bhaskaran B, Kumar SV. A Polarized Light Microscopic Study to Comparatively evaluate Four Remineralizing Agents on Enamel viz CPP-ACPF, ReminPro, SHY-NM and Colgate Strong Teeth. Int J Clin Pediatr Dent 2015;8(1):42-47. PMID- 26124582 TI - Oral Rehabilitation for Amniotic Band Syndrome: An Unusual Presentation. AB - Amniotic band syndrome (ABS) is a congenital disorder caused by entrapment of fetal parts in fibrous amniotic bands while in utero. The syndrome is underdiagnosed and its presentation is variable. The syndrome has been well described in the pediatric, orthopedic and obstetric literature; however, despite the discernable craniomaxillofacial involvement, ABS has not been reported in the dental literature very often. The present report describes a case of a patient with ABS and concomitant dental findings. How to cite this article: Hotwani K, Sharma K. Oral Rehabilitation for Amniotic Band Syndrome: An Unusual Presentation. Int J Clin Pediatr Dent 2015;8(1):55-57. PMID- 26124581 TI - Methods of Intracanal Reinforcement in Primary Anterior Teeth-Assessing the Outcomes through a Systematic Literature Review. AB - AIM: To assess how the various methods of intracanal reinforcement (short root canal posts) performed in their clinical and radiographic outcomes for restoring grossly broken down primary anterior teeth after pulpectomy for 1 year or longer follow-up period. MATERIALS AND METHODS: Literature search of electronic databases (Sept 2013) and various journals (1980-Sept 2013) using medical subject headings and free text terms was conducted. For inclusion in quality assessment, prespecified inclusion criteria were applied. Quality assessment was performed by using 'The Cochrane collaboration's tool for assessing risk of bias'. RESULTS: Seven relevant papers were selected for full text evaluation. After applying the inclusion criteria, only two trials could be considered for quality assessment. Both of these were classified as having high risk of bias. CONCLUSION: The evidence to support any method of intracanal reinforcement for restoring grossly broken down anterior teeth is presently lacking. Further trials with well-defined methodology are needed. How to cite this article: Mittal N, Bhatia HP, Haider K. Methods of Intracanal Reinforcement in Primary Anterior Teeth- Assessing the Outcomes through a Systematic Literature Review. Int J Clin Pediatr Dent 2015;8(1):48-54. PMID- 26124583 TI - Single Visit Apexification Procedure of a Traumatically Injured Tooth with a Novel Bioinductive Material (Biodentine). AB - Aim of this article is to present a case wherein single visit apexification of a traumatically injured tooth was done with a bioactive material-Biodentine. An injury sustained between the ages of 6 and 14 can adversely affect pulpal health and interrupt root development. In these instances, apexification is generally the preferred treatment. A 10 years old male patient presented with coronal fracture of the left upper central incisor. Clinical and radiographic assessment showed negative pulpal sensibility and arrested apical root development. Artificial apical barrier induction with Biodentine followed by endodontic treatment and prosthetic rehabilitation was decided as the line of treatment. To conclude, this bioactive and biocompatible calcium-based cement can regenerate damaged dental tissues and represents a promising alternative to the conventional multivisit apexification technique. CLINICAL SIGNIFICANCE: Biodentine which is a biologically active cement can be an efficient alternative to the conventional apexification materials which were hitherto recommended. How to cite this article: Bajwa NK, Jingarwar MM, Pathak A. Single Visit Apexification Procedure of a Traumatically Injured Tooth with a Novel Bioinductive Material (Biodentine). Int J Clin Pediatr Dent 2015;8(1):58-61. PMID- 26124584 TI - Fiber-reinforced Composite Resin Bridge: A Treatment Option in Children. AB - A number of treatment options, ranging from Maryland bridges to implants, are available for the replacement of congenitally or traumatically missing permanent anterior teeth. But, there are several limitations of these therapeutic options when they have to be used before the completion of the growth, particularly in children. Reinforcement of composite resins with polyethylene fibers significantly improves their mechanical properties. Fiber-reinforced composite (FRC) bridge can offer a good alternative to conventional treatment options in replacing a missing permanent anterior tooth until a more definitive prosthesis can be provided at the end of the growth period. The purpose of this article is to present a clinical case of a single tooth replacement utilizing noninvasive and metal free fixed FRC bridge in a 13 years old child as an interim treatment option. How to cite this article: Gupta A, Yelluri RK, Munshi AK. Fiber reinforced Composite Resin Bridge: A Treatment Option in Children. Int J Clin Pediatr Dent 2015;8(1):62-65. PMID- 26124585 TI - Anterior Sectional Twin Bracket Appliance - Innovative Use for Correction of Single Tooth Crossbite: A Case Report with Biomechanics. AB - Anterior sectional twin bracket appliance (ASTBA) is a sectional mechanism that involves two brackets on upper central incisors. This appliance is previously been used for correction of rotated incisors and midline spacing. But, detail biomechanics for single tooth crossbite correction is not previously explained. Here, in this article, we are presenting a detailed biomechanics of ASTBA for anterior single tooth crossbite correction along with case report. How to cite this article: Verma RK, Raghav P, Reddy MC, Kanwal R. Anterior Sectional Twin Bracket Appliance- Innovative Use for Correction of Single Tooth Crossbite: A Case Report with Biomechanics. Int J Clin Pediatr Dent 2015;8(1): 66-69. PMID- 26124586 TI - Replantation of Displaced Underlying Successor and Marsupialization of Radicular Cyst associated with a Primary Molar. AB - Radicular cysts are by far the most common cystic lesions of the jaw. However, those arising from primary teeth are comparatively rare, comprising only 0.5 to 3.3%. The aim of this paper is to present clinical, radiographic and histopathological characteristics of radicular cyst associated with a primary mandibular molar causing unusual displacement of the permanent successor. Extraction of primary tooth along with extirpation of cyst was done under local anesthesia. The displaced premolar was also extracted and then replanted in the socket after proper alignment. Healing was uneventful and the space of missing primary molar was maintained by band and loop space maintainer. The relationship between intracanal medicaments and rapid growth of cyst, as mentioned in literature was observed in our case too. Thus, pulpotomy treated primary teeth should receive periodic postoperative radiographic examination and absence of clinical symptoms does not mean that a pulpotomy treated tooth is healthy. How to cite this article: Lamba G, Ravi GR. Replantation of Displaced Underlying Successor and Marsupialization of Radicular Cyst associated with a Primary Molar. Int J Clin Pediatr Dent 2015;8(1):70-74. PMID- 26124587 TI - Congenital Insensitivity to Pain and Anhydrosis: Diagnostic and Therapeutic Dilemmas revisited. AB - First described in 1932 by Dearborn as 'congenital pure analgesia', congenital insensitivity to pain and anhydrosis (CIPA) or hereditary sensory and autonomic neuropathy (HSAN) type IV is an extremely rare autosomal recessive disorder. A 7 year-old female child who is an established case of congenital insensitivity to pain and anhydrosis visited the department of pediatric medicine with osteoarthritic neuropathy. A multidisciplinary team approach was utilized to treat the child under general anesthesia. This article also discusses the diagnostic and therapeutic dilemmas involved in treating this type of children. How to cite this article: Ravichandra KS, Kandregula CR, Koya S, Lakhotia D. Congenital Insensitivity to Pain and Anhydrosis: Diagnostic and Therapeutic Dilemmas revisited. Int J Clin Pediatr Dent 2015;8(1):75-81. PMID- 26124589 TI - Guest Editorial. AB - Despite the advancements in dentistry, dental caries still remains the most common disease of the oral cavity. A major reason for this scenario is because the dental professionals are still clinging to the outdated surgical model of dental caries. This traditional approach of caries management forces the tooth to enter into the 'restoration cycle' which usually involves several lifetime replacement procedures, resulting in increased restoration size, even more invasive procedures and finally a prosthesis. We need to acknowledge that, by simply drilling and filling the carious lesions, this disease cannot be controlled. Like other infectious diseases of the human body, if the etiological factors are not identified and managed appropriately, the disease will continue. PMID- 26124588 TI - Three-Alarm System: Revisited to treat Thumb-sucking Habit. AB - Thumb and digit-sucking habits or non-nutritive sucking are considered to be the most prevalent among oral habits. Most children stop thumb sucking on their own. If the habit continues beyond 3 to 4 years of age, it not only affects the dental occlusion, but the shape of the thumb/digit may be altered as well. This article presents the management of thumb sucking by modified RURS, elbow guard incorporated with revised 'three-alarm' system. How to cite this article: Shetty RM, Shetty M, Shetty NS, Deoghare A. Three-Alarm System: Revisited to treat Thumb sucking Habit. Int J Clin Pediatr Dent 2015;8(1):82-86. PMID- 26124590 TI - Prevalence of Impacted Pre-Molar Teeth in College of Dentistry, King Khalid University, Abha, Kingdom of Saudi Arabia. AB - BACKGROUND: An impacted tooth is one which fails to reach the occlusal plane even after two-third's of its root completion. Though the etiology is multi-factorial, most common reason is crowding of teeth with lack of space for eruption. Mandibular third molars are the most commonly impacted teeth. Very few studies have been done to assess the prevalence of impacted premolar teeth. MATERIALS AND METHODS: This study had been undertaken at College of Dentistry, King Khalid University, Abha, Kingdom of Saudi Arabia to report the prevalence of impacted premolar teeth and its relation to age group and gender. This retrospective study involved 3800 panoramic radiographs of subjects aged 18-45 years who had presented to the College of Dentistry, King Khalid University, Abha, Kingdom of Saudi Arabia, for oral care during the period from February 2009 to February 2011. All panoramic radiographs were taken with standardized equipment and specifications. RESULTS: The study sample comprised of 3800 panoramic radiographs. A total of 45 impacted premolar teeth were identified (1.2%) (P = 0.89). The male to female ratio with impacted premolars was 35:10 (3.5:1). Age Group 1 (i.e., 20-25 years) had the highest prevalence of premolar tooth impaction (75.5%) and this decreased with increasing age. Of the 45 impacted premolars, mandibular premolars were most commonly encountered (75.6%), followed by impacted teeth in the mandibular arch (24.4%). The ratio of mandibular to maxillary third molar impaction was 3:1. CONCLUSION: (1) The prevalence of impacted premolar teeth is more in mandibular arch than in the maxillary arch, (2) females had higher prevalence of impacted teeth than men, (3) age group 25-30 years had high rate of prevalence of impacted premolars. PMID- 26124591 TI - Two Years Retrospective Evaluation of Overdenture Retained by Symphyseal Single Implant Using Two Types of Attachments. AB - BACKGROUND: This study was aimed to evaluate complete mandibular overdentures retained by a symphyseal single implant using ball and magnet attachments in both clinical and radiographic evaluation. MATERIALS AND METHODS: Ten dental press fit titanium implants were installed in the lower jaws of completely edentulous patients according to two-stage surgical protocol. For each patient, one implant was installed in the symphyseal midline region, and left submerged and unloaded for 4 months. The patients were then divided into two equal groups. The first group received mandibular overdentures retained by ball and socket attachment. The second group received mandibular overdentures retained by magnet attachment. Both groups were supplied with conventional maxillary complete dentures. All patients were evaluated immediately after denture insertion, 6 months, and 12 months and after 24 months of overdenture insertion. RESULTS: The study showed insignificant difference regarding the clinical condition and the marginal bone height changes in both groups during the follow-up period. CONCLUSION: Single implant retained overdenture with ball and socket or magnetic attachments was easy in construction, required less home care to maintain gingival health and give satisfactory clinical results. PMID- 26124592 TI - Prevalence and Attitude of Cigarette Smoking Among Indian Expatriates Living in Jeddah, Kingdom of Saudi Arabia. AB - BACKGROUND: The objective was to determine the prevalence and attitudes of smoking among expatriate Indian workers living in Jeddah, Saudi Arabia. METHODS: A cross-sectional analytical study was done. All the data were collected using a questionnaire-based interview. RESULTS: A total of 421 people were interviewed. Almost half (42%) of the participants were between 31 and 40 years old and 7% were over 51 years. The majority of participants (63%) reported to be non smokers. The maximum number of smokers was between 41 and 50 years old (42%) and most of them were regular smokers. Almost a third of the subjects (30%) had a higher secondary level of education, and 7% were illiterate. There was a significant association between the prevalence of smoking and the level of education (P < 0.001). Among smokers, half of them smoked more than 21 cigarettes/day. More than half, 238 (57%) of participants agreed that the tobacco was harmful to their health, and 50% agreed that tobacco sales should be banned. Among all, 92% were concerned about their health and 98% accepted that the tobacco causes diseases. The majority of smokers cited stress, loneliness financial responsibilities and a lack of socializing as reasons for their smoking habit. CONCLUSION: Although the prevalence was relatively high, the majority was aware of the harmful effects of smoking and was keen to have the sale of tobacco banned. Due to their possible loneliness and stress, many felt that smoking helped ease their stress and tension. PMID- 26124593 TI - Determination of the Apical Sealing Abilities of Mineral Trioxide Aggregate, Portland Cement, and Bioaggregate After Irrigation with Different Solutions. AB - OBJECTIVES: The purpose of this study was to investigate the sealing ability of root-end filling materials such as mineral trioxide aggregate (MTA), Portland cement, and bioaggregate (BA) after irrigation with different solutions. MATERIALS AND METHODS: We examined 130 human maxillar central teeth. After cutting the teeth at the cementoenamel junction, the root canals were expanded using nickel-titanium rotary instruments. Root canals were filled with AH-plus and gutta-percha. Then, the roots were cut apically, and 3 mm deep retrograde cavities were prepared. The roots were divided 12 experimental groups, consisting 10 teeth each; the positive and negative control groups contained five teeth each. The retrograde cavities were rinsed using ethylenediaminetetraacetic acid (EDTA), chlorhexidine (CHX), BioPure(TM) mixture of a tetracycline isomer, an acid, and a detergent (MTAD), or distilled water. Next, groups 1, 2, 3, and 4 were sealed with MTA; groups 5, 6, 7, and 8 were sealed with Portland cement; and groups 9, 10, 11, and 12 were sealed with BA. Then, apical microleakage was evaluated by using a computerized fluid filtration method. The results of the leakage test were statistically evaluated by the post-hoc Tukey's test. RESULTS: MTA, Portland cement, and BA root-end filling materials showed the least leakage in the CHX and distilled water groups. The highest leakage was observed in the EDTA and MTAD groups. CONCLUSIONS: The sealing ability of BA was as good as that of MTA. EDTA and MTAD increased the apical leakage and CHX and distilled water decreased the leakage of the root-end filling materials examined in this study. PMID- 26124594 TI - Comparative Evaluation of Sustained Release Collagen Device Containing 5% Metronidazole (Metrogene) along With and Without Scaling and Root Planing at Regular Intervals with Treatment of Chronic Periodontitis: A Case Control Study. AB - BACKGROUND: A short-term study was undertaken with an objective to demonstrate the therapeutic benefit resulting from the use of Metronidazole sponges combined with and without mechanical debridement to mechanical treatment alone in the treatment of periodontal pockets in chronic periodontitis. MATERIALS AND METHODS: The study compared the plaque index, gingival index, sulcus bleeding index and probing pocket depth in twenty control sites that received superficial scaling and root planing without the local drug delivery with experimental site A (20 sites that received local drug delivery (5% metronidazole) without superficial scaling and root planing) and experimental site B (20 sites received superficial scaling, root planing and local drug delivery (5% metronidazole) at "0" day, 15(th) day and 30(th) day. RESULTS: There was a significant reduction in plaque index, gingival index, sulcus bleeding index and probing pocket depth in both experimental sites A and B at different intervals from the baseline. CONCLUSION: From the above conclusions, it can be suggested that a single subgingival application of 5% metronidazole in a collagen carrier can be effective, when associated with debridement in the treatment of adult periodontitis. PMID- 26124595 TI - Expression of CD105 in tumor angiogenesis a comparative study (ameloblastoma, keratocystic odontogenic tumor and dentigerous cyst). AB - BACKGROUND: Demonstrate the expression of CD105 (angiogenetic marker) in ameloblastoma (AM), keratocystic odontogenic tumor (KCOT) and dentigerous cyst (DC). MATERIAL AND METHODS: Assessment of microvessel density (MVD) in 70 cases, including 20 KCOT, 20 DC and 20 solid AMs. Assessment of MVD should be done as the mean number of microvessels per high-power-field. RESULTS: AM and KCOT demonstrated a higher mean value of 7.98 (+/-2.70) and 6.25 (+/-2.88) respectively while DC demonstrated a lower mean of 3.75 (+/-1.42). There was no statistically significant difference between AM and KCOT (P > 0.05). The difference between AM and DC; and between KCOT and DC were statistically significant (P < 0.05). CONCLUSION: The present study suggested that angiogenesis may be one of the mechanisms possibly contributing to the different biological behaviors of KCOT, DCs and solid AMs. PMID- 26124596 TI - Argon Ion Laser Polymerized Acrylic Resin: A Comparative Analysis of Mechanical Properties of Laser Cured, Light Cured and Heat Cured Denture Base Resins. AB - BACKGROUND: Dentistry in general and prosthodontics in particular is evolving at greater pace, but the denture base resins poly methyl methacrylate. There has been vast development in modifying chemically and the polymerization techniques for better manipulation and enhancement of mechanical properties. One such invention was introduction of visible light cure (VLC) denture base resin. Argon ion lasers have been used extensively in dentistry, studies has shown that it can polymerize restorative composite resins. Since composite resin and VLC resin share the same photo initiator, Argon laser is tested as activator for polymerizing VLC resin. In the Phase 1 study, the VLC resin was evaluated for exposure time for optimum polymerization using argon ion laser and in Phase 2; flexural strength, impact strength, surface hardness and surface characteristics of laser cured resin was compared with light cure and conventional heat cure resin. MATERIALS AND METHODS: Phase 1; In compliance with American Dental Association (ADA) specification no. 12, 80 samples were prepared with 10 each for different curing time using argon laser and evaluated for flexural strength on three point bend test. Results were compared to established performance requirement specified. Phase 2, 10 specimen for each of the mechanical properties (30 specimen) were polymerized using laser, visible light and heat and compared. Surface and fractured surface of laser, light and heat cured resins were examined under scanning electron microscope (SEM). RESULTS: In Phase 1, the specimen cured for 7, 8, 9 and 10 min fulfilled ADA requirement. 8 min was taken as suitable curing time for laser curing. Phase 2 the values of mechanical properties were computed and subjected to statistical analysis using one-way ANOVA and Tukey post hoc test. The means of three independent groups showed significant differences between any two groups (P < 0.001). CONCLUSION: Triad VLC resin can be polymerized by argon ion laser with 1 W/mm(2) power and exposure time of 8 min to satisfy ADA specification. Impact strength, surface hardness of laser cure was better than light cure and heat cure resin. Flexural strength of light cure was better than laser cure and heat cure resin. The SEM study showed similar density on surface, the fractured surface of heat cure resin was dense and compact. PMID- 26124597 TI - Assessment of Image Distortion from Head Rotation in Lateral Cephalometry. AB - BACKGROUND: The patient's head can be slightly rotated sagitally vertically or transversely within the head holding device. Because of such improper positions due to the head rotation, an error can occur in cephalometric measurements. The purpose of this study was to identify the potential projection errors of lateral cephalometric radiograph due to head rotation toward X-ray film in the vertical Z axis. MATERIALS AND METHODS: Totally, 10 human dry skulls with permanent dentition were collected from the Department of Anatomy, J.J.M.C. Medical College, Davanagere. Each dry skull was rotated from 0 degrees to -20 degrees at 5 degrees intervals. A vertical axis, the Z-axis, was used as a rotational axis to have 100 lateral cephalometric radiographs exposed. Four linear (S-N, Go Me, N-Me, S-Go) and six angular measurements (SNA, SNB, N-S-Ar, S-Ar-Go, Ar-Go Me, AB-Mandibular plane angle) were calculated manually. RESULTS: The findings were that: (1) Angular measurements have fewer projection errors than linear measurements; (2) the greater the number of landmarks on the midsagittal plane that are included in angular measurements, the fewer the projection errors occurring; (3) the horizontal linear measurements have more projection errors than vertical linear measurements according to head rotation. CONCLUSION: In summary the angular measurements of lateral cephalometric radiographs are more useful than linear measurements in minimizing the projection errors associated with head rotation on a vertical axis. PMID- 26124598 TI - Assessment of Antero-Posterior Skeletal and Soft Tissue Relationships of Adult Indian Subjects in Natural Head Position and Centric Relation. AB - BACKGROUND: The aim of this study was to verify the intra-individual reproducibility of natural head position (NHP) in centric relation (CR) position, to prove the inter-individual differences in the Frankfort horizontal plane and sella-nasion line compared with the true horizontal line, and to establish linear norms from A-point, B-point, Pog as well as soft tissue A-point, soft tissue B point, and soft tissue Pog to nasion true vertical line (NTVL) in adult Indian subjects. METHODS: Lateral cephalograms (T1) of Angle's Class I subjects were taken in NHP and with bite in CR. A second lateral cephalogram (T2) of these subjects with ANB angle in the range 1-4 degrees were taken after 1 week using the same wax bite and both the radiographs were analyzed based on six angular parameters using cephalometric software (Do-it, Dental studio NX version 4.1) to assess the reproducibility of NHP. Linear values of six landmarks were taken in relation to NTVL, and the mean values were calculated. A total of 116 subjects were included in this study. RESULTS: When the cephalometric values of T1 and T2 were analyzed, it was found that, the parameters showed a P < 0.001, indicating the reproducibility of NHP in CR. Mean values for point A, point B, Pog and their soft tissue counterparts were also obtained. CONCLUSION: The study proved that NHP is a reproducible and accurate when recorded with the mandible in CR. Linear norms for skeletal Class I subjects in relation to NTVL were established. PMID- 26124599 TI - A Comparison of Accuracy of Matrix Impression System with Putty Reline Technique and Multiple Mix Technique: An In Vitro Study. AB - BACKGROUND: The difficulty in obtaining an acceptable impression increases exponentially as the number of abutments increases. Accuracy of the impression material and the use of a suitable impression technique are of utmost importance in the fabrication of a fixed partial denture. This study compared the accuracy of the matrix impression system with conventional putty reline and multiple mix technique for individual dies by comparing the inter-abutment distance in the casts obtained from the impressions. MATERIALS AND METHODS: Three groups, 10 impressions each with three impression techniques (matrix impression system, putty reline technique and multiple mix technique) were made of a master die. Typodont teeth were embedded in a maxillary frasaco model base. The left first premolar was removed to create a three-unit fixed partial denture situation and the left canine and second premolar were prepared conservatively, and hatch marks were made on the abutment teeth. The final casts obtained from the impressions were examined under a profile projector and the inter-abutment distance was calculated for all the casts and compared. RESULTS: The results from this study showed that in the mesiodistal dimensions the percentage deviation from master model in Group I was 0.1 and 0.2, in Group II was 0.9 and 0.3, and Group III was 1.6 and 1.5, respectively. In the labio-palatal dimensions the percentage deviation from master model in Group I was 0.01 and 0.4, Group II was 1.9 and 1.3, and Group III was 2.2 and 2.0, respectively. In the cervico-incisal dimensions the percentage deviation from the master model in Group I was 1.1 and 0.2, Group II was 3.9 and 1.7, and Group III was 1.9 and 3.0, respectively. In the inter-abutment dimension of dies, percentage deviation from master model in Group I was 0.1, Group II was 0.6, and Group III was 1.0. CONCLUSION: The matrix impression system showed more accuracy of reproduction for individual dies when compared with putty reline technique and multiple mix technique in all the three directions, as well as the inter-abutment distance. PMID- 26124600 TI - Effect of Rubber Dam on Arterial Oxygen Saturation in Children. AB - BACKGROUND: The placement of rubber dam has the potential to alter the airflow through nasal and oral cavities. Pediatric dentist should be aware whether the use of a rubber dam affects the oxygen saturation (SpO2) in children. To assess the effect of rubber dam on arterial blood SpO2 in children of 6-12 years age. MATERIALS AND METHODS: Totally, 60 ASA Class I patients of 6-12 years age, randomly allocated in two groups: Group A: Rubber dam isolation of maxilla and Group B: Isolation of the mandible. A pulse oximeter was used to detect SpO2. To establish a baseline, each patient's SpO2 was recorded every 30 s for 2 min. A rubber dam was then placed which extended over the nose. Class I cavity and glass ionomer cements restoration were performed. The rubber dam was cut to expose the nasal cavities SpO2 were recorded every 30 s for 5 min throughout the procedure. A two-way ANOVA test was applied. RESULTS: In both groups there was no significant difference in SpO2 after rubber dam placement with nose covered or uncovered (P > 0.05). CONCLUSION: There was no significant change in SpO2 after rubber dam isolation with nose covered or uncovered in children of 6-12 years age. PMID- 26124601 TI - Dental Caries Status and Oral Hygiene Practices of Lock Factory Workers in Aligarh City. AB - BACKGROUND: The aim was to evaluate the oral hygiene practices and dental caries status of lock factory workers in Aligarh city. MATERIALS AND METHODS: WHO Oral Health Assessment form (2013) was used to collect data from each subject. A total of 850 subjects constituted the final sample size. Information was obtained regarding the oral hygiene practices and clinical examinations were conducted. Descriptive analysis was done and the data were analyzed using Chi-square test. RESULTS: The prevalence of dental caries was 46.5%. Almost half of the workers i.e., 456 (53.6%) used brush to clean their teeth. Majority of the subjects i.e., 784 (92.2%) cleaned their teeth once a day. It was found that 466 (54.8%) used toothpaste for maintaining oral hygiene. Almost half of the subjects consumed tobacco in form of gutkha, cigarette, and in multiple forms. CONCLUSION: The results of the study showed that dental caries and poor oral hygiene are major public health problems among the factory workers. Primary oral health-care programs like dental screening and oral health education at regular intervals should be made mandatory, which will help to prevent accumulation of health-care demands of the factory employees. PMID- 26124602 TI - Association of Dental Anomalies with Different Types of Malocclusions in Pretreatment Orthodontic Patients. AB - BACKGROUND: The study is planned to correlate the existence of dental anomalies with different types of malocclusion as the occurrence of anomalies is common in malocclusion. MATERIALS AND METHODS: The present study was conducted among 430 patients with different types of malocclusion as 161 patients having Class I, 203 with Class II, and 66 with Class III malocclusion. The age of the patients ranged from 12 to 15 years. Diagnosis was done on the basis of history, clinical, cephalometric, radiographs, and dental cast examination. The level of significance was set at P = 0.05. RESULTS: Most common anomaly was rotation of teeth (18.80%), followed by hypodontia (10.90%), and least occurring was gemination, fusion, talon's cusp, and dilacerations. 31.4% showed one dental anomaly, whereas 11.9% exhibited two or more dental anomalies. The highest mean value of all the dental anomalies was seen with severe cases of malocclusion and also significant differences were observed according to gender. CONCLUSIONS: The present study investigated various dental anomalies in relation to malocclusion. It was found that 31.4% showed one dental anomaly, whereas 11.9% exhibited two or more dental anomalies. Hence, careful prior investigation of dental anomalies is necessary for better orthodontic treatment planning to reduce the complications. PMID- 26124603 TI - Evaluation of the Oral Health Knowledge, Attitude and Behavior of the Preclinical and Clinical Dental Students. AB - BACKGROUND: Dentists play very important role in the oral health education of the community. Thus it is important to know the status of knowledge, attitude, and behavior toward the maintenance of oral health at the student level. The aim of the present study was to evaluate the oral health knowledge, attitude, and behavior among preclinical and clinical dental students. MATERIALS AND METHODS: A cross-sectional study was conducted on 147 dental students from 1(st) to 4(th) year of Malabar Dental College, Kerala, in the year of March-June 2010 and was carried out with the help of 30 questionnaires. Age, gender and academic year data were recorded. Statistical analysis was performed with the help of SPSS version 20 using the Student's t-test and one-way ANOVA tests. RESULTS: The difference in scores of oral health knowledge, attitude and behavior between preclinical and clinical dental students was found statistically highly significant (Student's t-test, P < 0.001). The variation of scores of knowledge, attitude, and behavior also showed highly significant increase with the year of study (one-way ANOVA, P < 0.001). While the difference in scores between males and females showed that females have better oral health knowledge than males, but the difference was not statistically significant (Student's t-test, P > 0.01). The present study thus showed improvement of knowledge, attitude and behavior with the academic years and there was no bias of gender with reference to oral health. CONCLUSIONS: Although oral health knowledge, attitude and behavior showed improved results from 1(st) to 4(th) year dental students, it should be improved in order to serve better for the community in the future. PMID- 26124604 TI - Effect of Reinforcement Using Stainless Steel Mesh, Glass Fibers, and Polyethylene on the Impact Strength of Heat Cure Denture Base Resin - An In Vitro Study. AB - BACKGROUND: The impact strength of denture base resin is of great concern and many approaches have been made to strengthen acrylic resin dentures. The objective of this study was to compare the impact strength of the denture base resin with and without reinforcement and to evaluate the impact strength of denture base resin when reinforced with stainless steel mesh, glass fiber, and polyethylene fibers in the woven form. MATERIALS AND METHODS: The specimens (maxillary denture bases) were fabricated using a standard polyvinylsiloxane mold with conventional heat cured polymethyl methacrylate resin. The specimens were divided into four groups (n = 10). Group I specimens or control group were not reinforced. Group II specimens were reinforced with stainless steel mesh and Group III and Group IV specimens were reinforced with three percent by weight of glass fibers and polyethylene fibers in weave form respectively. All the specimens were immersed in water for 1-week before testing. The impact strength was measured with falling weight impact testing machine. One-way analysis of variance and Tukey's post-hoc test were used for statistical analysis. RESULTS: Highest impact strength values were exhibited by the specimens reinforced with polyethylene fibers followed by glass fibers, stainless steel mesh, and control group. CONCLUSIONS: Reinforcement of maxillary complete dentures showed a significant increase in impact strength when compared to unreinforced dentures. Polyethylene fibers exhibit better impact strength followed by glass fibers and stainless steel mesh. By using pre-impregnated glass and polyethylene fibers in woven form (prepregs) the impact strength of the denture bases can be increased effectively. PMID- 26124605 TI - The Effect of Disinfectants and a Surface Wetting Agent on the Wettability of Elastomeric Impression Materials: An In Vitro Study. AB - BACKGROUND: This study was carried out to evaluate the effect of two commercially available chemical disinfectants namely sodium hypochlorite and glutaraldehyde and a surface wetting agent on the wettability of three high precision elastomeric impression materials, addition silicone, condensation silicone and polyether. MATERIALS AND METHODS: Three different types of elastomeric impression materials commonly used in prosthodontic practice were selected. The glutaraldehyde and sodium hypochloride solutions were employed to disinfect the impressions made with the above-mentioned elastomeric impression materials. True Blue surface wetting agent was selected. GBX contact angle analyzer was used to measure advancing and receding contact angle. RESULTS: The results of this study have demonstrated that the polyether impression material was the most hydrophilic of all the materials, followed by hydrophilic addition silicone. Condensation silicone was least hydrophilic. All materials showed improvement in the wettability when a topical surfactant was used. CONCLUSION: The short term disinfection of the three elastomeric impression materials does not affect the wettability of these impression materials. PMID- 26124606 TI - Quantification of Dental Health Care Waste Generated among Private Dental Practices in Bengaluru City. AB - BACKGROUND: Bengaluru, in India has more than 1148 practicing dentists for a population of 8.42 million. The amount and type of dental health care waste (DHCW) generated by the dental practitioners has to be assessed prior to chalking out and implementation of an effective DCHW management plan. Currently, there is no evidence available regarding the quantity, type, and method of disposal adopted by these practitioners. Hence, this study was conducted with the objective of estimating the quantity of DHCW by the private dental practitioners in Bengaluru city. MATERIALS AND METHODS: The sample size was estimated to be 110. The sampling frame was constituted from the registered dental practitioners in Bengaluru with the Department of Health and Family Welfare, Govt. of Karnataka. Sampling strategy employed included a probability proportional sampling strategy for the four zones in Bengaluru followed by a simple random sampling of clinics from each zone. Standardized weight method was followed to estimate the quantity of different category of waste. Three data collectors who were trained and calibrated collected the information regarding the type and quantity of waste generated, the nature of practice and years of establishment. RESULTS: Total quantity of waste generated was 0.161 kg/clinic/day with 0.130 kg and 0.026 kg of infectious and recyclables, respectively. The projected data for the actual number of private practices in Bengaluru city showed alarming figures of 41,535 kg and 8307 kg of infectious and recyclable waste being generated every year. Data also showed poor management practices of lead foil and plaster of paris and alarming figures projected annual quantity. CONCLUSION: The data demonstrated large quantities of hazardous waste generation and poor segregation practices of the practitioners. This warrants the immediate need for collective, voluntary measures to be initiated for appropriate and effective management of DHCW. PMID- 26124607 TI - Evaluation of an Indigenously Prepared Herbal Extract (EndoPam) as an Antimicrobial Endodontic Irrigant: An Ex Vivo Study. AB - BACKGROUNDG: Root canal irrigation plays a pivotal role in endodontics. Constant increase in antibiotic resistance and side effects caused by synthetic irrigants has shifted the research toward developing herbal alternatives. The current study aims to assess the ex vivo effectiveness of an indigenously prepared herbal extract "EndoPam" and compare it with the conventional endodontic irrigants for disinfection of root canals infected with Enterococcus faecalis. MATERIALS AND METHODS: As a preliminary study of the antimicrobial efficacy of the test irrigants, an Agar diffusion study was conducted, and zone of inhibition measured. Forty extracted mandibular premolars with straight root canals were selected and standardized to 12 +/- 1 mm in length. Root canals were prepared using rotary ProTaper system until F3 instrument and were infected with the culture of E. faecalis for three weeks. Specimens were divided into four groups (n = 10). Group 1: EndoPam (. INGREDIENTS: Syzigium aromaticum, Eucalyptus globulus, Cinnamomum zeylanicum and Mentha piperita), Group 2: 2% chlorhexidine, Group 3: 5.25% Sodium hypochlorite, Group 4: Normal Saline. Irrigation was performed for each group. Samples were inoculated and incubated for 24 h at 37 degrees C for qualitative analysis qualitative analysis. RESULTS: In the preliminary Agar diffusion study, EndoPam exhibited a zone of inhibition comparable to that of sodium hypochrorite. The diameter of the inhibition zone was in the following order: 2% chlorhexidine gluconate > EndoPam > 5.25% NaOCl > Normal Saline. The qualitative assay done by culturing the bacteria after a period of 3 weeks showed no bacterial growth in any of the tested irrigants, except in normal saline. CONCLUSION: It was found that the experimental product was as effective as conventional irrigants in reducing the microbial count. PMID- 26124608 TI - Minimal Apical Enlargement for Penetration of Irrigants to the Apical Third of Root Canal System: A Scanning Electron Microscope Study. AB - BACKGROUND: The aim of this study was to determine minimal apical enlargement for irrigant penetration into apical third of root canal system using scanning electron microscope (SEM). MATERIALS AND METHODS: Distobuccal canals of 40 freshly extracted human maxillary first molar teeth were instrumented using crown down technique. The teeth were divided into four test groups according to size of their master apical file (MAF) (#20, #25, #30, #35 0.06% taper), and two control groups. After final irrigation, removal of debris and smear layer from the apical third of root canals was determined under a SEM. Data was analyzed using Kruskal Wallis and Mann-Whitney tests. RESULTS: Smear layer removal in apical third for MAF size #30 was comparable with that of the control group (size #40). CONCLUSION: Minimal apical enlargement for penetration of irrigants to the apical third of root canal system is #30 size. PMID- 26124609 TI - Evaluation of Antimicrobial and Antifungal Efficacy of Inter Appointment Intracanal Medicaments against Enterococcus and Candida albicans: An In Vitro Study. AB - BACKGROUND: Microorganisms and their by-products in pulpal and periapical diseases are to be considered as the primary etiological agents of the pulpal necrosis and apical periodontitis. Enterococcus faecalis, which is the most common organism isolated from failed root canals, is a Gram-positive facultative anaerobe. Yeasts can be detected in 7-18% of infected root canals. MATERIALS AND METHODS: Designed to evaluate the antimicrobial and antifungal efficacy of chlorhexidine gutta-percha (CHX-GP), and calcium hydroxide GP points against E. faecalis and Candida albicans. The test materials used are divided into 3 groups; Group A - Control, Regular GP, Group B - CHX-GP, Group C - Calcium hydroxide GP. Detail Method is explained in the article. RESULTS: There was a significant difference in the inhibition of E. faecalis, in different materials at each time interval period (P < 0.05). Similarly, the inhibition of C. albicans in the different materials at each time period was found to be statistically significant (P < 0.05). Calcium hydroxide GP did not exhibit any antimicrobial effect on any of tested microorganisms for all the time periods. CONCLUSION: CHX-GP had the maximum effect on the test microorganisms, with the maximum efficacy on E. faecalis followed by C. albicans. Regular GP also had a significant efficacy on test microorganisms, with the maximum efficacy on E. faecalis followed by C. albicans. Calcium hydroxide GP did not have any effect on any test microorganisms during the entire test periods. PMID- 26124610 TI - Evaluation of the Various Drying Methods on Surface Hardness of Type IV Dental Stone. AB - BACKGROUND: Studies regarding the effect of various methods to increase the surface hardness of Type IV dental stone are not conclusive. Therefore, this study was carried out to evaluate the effect of air drying, micro oven drying and die hardener on surface hardness of Type IV dental stone. MATERIALS AND METHODS: A standard metal die was fabricated; polyvinyl siloxane impression material was used to make the molds of metal die. A total of 120 specimens were obtained from two different die stones and were grouped as Group A (kalrock) and Group B (pearl stone), and were subjected to air drying for 24 h, micro oven drying and application of die hardener. These models were then subjected to surface hardness testing using the knoop hardness instrument. The obtained data were subjected to statistical analysis. RESULTS: The hardness of Group A specimens was 64 +/- 0.54 Knoop hardness number (KHN) after application of die hardener, 60.47 +/- 0.41 KHN after 24 h air drying, 58.2 +/- 0.88 after microwave oven drying and 24.6 +/- 0.4 after 1 h air drying. The hardness of Group B specimens was 45.59 +/- 0.63 KHN after application of die hardener, 40.2 +/- 0.63 KHN after 24 h air drying, 38.28 +/- 0.55 KHN after microwave oven drying and 19.91 +/- 0.64 KHN after 1 h air drying. CONCLUSION: Group A showed better results than Group B at all times. Application of the die hardener showed highest hardness values followed in the order by 24 h air drying, microwave oven drying and 1 h air drying in both groups. The study showed that air drying the dies for 24 h followed by application of a single layer of the die hardener produced the best surface hardness and is recommended to be followed in practice. PMID- 26124611 TI - Cone Beam Computed Tomography Assisted Endodontic Management of a Rare Case of Mandibular First Premolar with Three Roots. AB - Understanding the morphological anatomy of the root and root canal systems of the teeth increases the success rate of endodontic therapy. Advanced diagnostic imaging techniques like cone beam computed tomography (CBCT) are an essential aid in understanding the anatomy of teeth especially in mandibular premolars. Most commonly mandibular first and second premolars have a single root and a single canal. However, multiple root and canals have also been reported. The present case report discusses endodontic management of a three rooted mandibular first premolar using CBCT. PMID- 26124612 TI - Palatogingival Groove: Recognizing and Managing the Hidden Tract in a Maxillary Incisor: A Case Report. AB - Palatogingival grooves are developmental malformations quite notorious for precipitating endodontic - periodontal lesions. Owing to their inconspicuous occurrence, funnel-shaped morphology and variable extent on tooth root, they promote adherence of plaque and bacteria to levels significant for the development of pathology. Several treatment approaches have been recognized in literature for the management of this anomaly. Here in this report, a 25-year-old patient reported with the complaint of pain and swelling in maxillary right lateral incisor. Clinical examination confirmed an endodontic - periodontal lesion in relation to palatogingival groove. Endodontic treatment was instituted, followed by odontoplasty of the groove and restoration with newer calcium silicate cement, Biodentine. Combined endodontic - periodontal approach was successful in resolving the pathology with complete healing seen both clinically and radiographically. Timely diagnosis, prevention and management are highly recommended to prevent tooth loss due to complications arising secondary to their presence. PMID- 26124613 TI - Surgical Management of Ossifying Fibroma in Maxilla: Report of Two Cases. AB - Ossifying fibroma is a rare benign osteogenic neoplasm arising from undifferentiated cells of the periodontal ligament. Ossifying fibroma have a well defined border that differentiates it from fibrous dysplasia clinically, these tumors manifest as a round or ovoid, expansile, painless, slow-growing mass may displace the roots of adjacent teeth and also cause root resorption. They occur at second to fourth decade of life. Radiologically the lesion appears as a dense radiopaque mass surrounded by a thin, well-defined regular radiolucent rim. Patient underwent thorough history taking and complete face, ear, nose, and throat examination. Computed tomography maxilla, orthopantomogram, paranasal sinus reveals entire maxillary sinus involved in one case. Nasal septum deviated to the opposite side, airway reduced on the side of swelling seen in one case. Root resorption seen in two cases and missing teeth in seen in case 1. In our study in case 1, the tumor involved maxillary sinus, medial wall of the nose. The tumors were excised by Weber-Fergusson and in case 2 the tumor was excised by maxillary vestibular approach. Overall recurrence rates after resection is reported to range from 30 to 56%. PMID- 26124614 TI - Lasers: The Magic Wand in Esthetic Dentistry!! AB - In this era of fast developing technologies and innovative ideas, the need for faster treatment has become a necessity. Treatment with lasers that is much less time-consuming and painless is accepted and appreciated by the patient. Use of Lasers is not new; they have been in use for decades since their development by Maiman in 1960. Lasers have travelled a long way from ruby lasers to erbium lasers and are being fondly used in every aspect of dental treatment. This article aims at elaborate the use and applications of lasers in the field of esthetic dentistry. PMID- 26124615 TI - Dual Role of Autophagy in Oral Cancer. PMID- 26124616 TI - Ethiopia Successfully Attaining the Millennium Development Goals. PMID- 26124617 TI - Eclapmsia: The Major Cause of Maternal Mortality in Eastern India. AB - BACKGROUND: Eclampsia is a very serious complication of pregnancy which is responsible for high maternal and perinatal mortality. Worldwide, it accounts for 50,000 maternal deaths annually. In spite of several global and regional interventions and initiatives from governments and other concerned agencies, maternal mortality is still very high in India, with eclampsia as a major cause. This study was conducted to determine the mode of deaths and incidence of maternal mortality associated with eclampsia and to assess how socio-demographic and clinical characteristics of the women influence the deaths. MATERIALS AND METHODS: This is a retrospective study of 111 eclampsia related maternal deaths over a period of 5 years from January 2008 to December 2012. Data pertaining to their age, parity, booking status, gestational age at delivery, and time interval from admission to death were also obtained from the records for analysis. RESULTS: Eclampsia accounted for 43.35% of total maternal deaths, with case fatality of 4.960%. The commonest mode of death in eclampsia is pulmonary oedema. Death due to eclampsia commonly occurs in younger age group of 19-24 years and in primi gravid. Eclampsia related deaths were mostly seen in illiterate and unbooked cases. Maternal deaths were also very common in lower socio economic status. CONCLUSION: Eclampsia still remains the major cause of maternal mortality in this region resulting from unsupervised pregnancies and deliveries. There is a need to educate and encourage the general public for antenatal care and hospital delivery by which we can defeat this powerful enemy. PMID- 26124618 TI - Microbiological Assessment of Indoor Air of Teaching Hospital Wards: A case of Jimma University Specialized Hospital. AB - BACKGROUND: Hospital environment represents a congenial situation where microorganisms and susceptible patients are indoors together. Thus, the objective of this study is to provide fundamental data related to the microbial quality of indoor air of Jimma University Specialized Hospital wards, to estimate the health hazard and to create standards for indoor air quality control. METHODS: The microbial quality of indoor air of seven wards of Jimma University Specialized Hospital was determined. Passive air sampling technique, using open Petri-dishes containing different culture media, was employed to collect sample twice daily. RESULTS: The concentrations of bacteria and fungi aerosols in the indoor environment of the wards ranged between 2123 - 9733 CFU/m(3). The statistical analysis showed that the concentrations of bacteria that were measured in all studied wards were significantly different from each other (p-value=0.017), whereas the concentrations of fungi that were measured in all sampled wards were not significantly different from each other (p-value=0.850). Moreover, the concentrations of bacteria that were measured at different sampling time (morning and afternoon) were significantly different (p-value =0.001). CONCLUSION: All wards that were included in the study were heavily contaminated with bacteria and fungi. Thus, immediate interventions are needed to control those environmental factors which favor the growth and multiplication of microbes, and it is vital to control visitors and students in and out the wards. Moreover, it is advisable that strict measures be put in place to check the increasing microbial load in the hospital environment. PMID- 26124619 TI - Premature Graying of Hair: An Independent Risk Marker for Coronary Artery Disease in Smokers - A Retrospective Case Control Study. AB - BACKGROUND: Premature graying of hair as a risk marker among young smokers has a potential of identifying coronary artery disease (CAD) at a very early stage. There is absence of literature that assesses premature graying of hair as an independent marker of CAD in smokers. MATERIAL AND METHODS: The present single centre case control study enrolled a total of 62 consecutive chronic smokers (<= 45 years) (Group I) and 60 consecutive young CAD patients (<=45 years) who were chronic smokers (Group II). Another group comprising of 114 patients (<=45 years) having no smoking history and no cardiac ailments either (Group III) was enrolled as control population. All subjects were males. A detailed history and clinical examination regarding conventional coronary risk factors and carotid intima media thickness was done in both groups. RESULTS: The carotid intima media thickness, dyslipidemia and blood pressure were significantly higher in group I and II as compared to group III. When the groups were compared for graying of hair, it was found that the group II (i.e., smokers and CAD) had maximum prevalence of graying which was significantly higher than the control as well as smoker groups. The presence of premature graying of hair was associated with 3.24 times the risk of CAD on multiple logistic regression analysis. CONCLUSION: The presence of premature graying of hair was associated with an increased risk of CAD in young smokers. Premature graying of hair can be used as preliminary evidence by clinicians for classifying patients at risk for premature CAD especially in smokers. PMID- 26124620 TI - Correlation of Climate Variability and Malaria: A Retrospective Comparative Study, Southwest Ethiopia. AB - BACKGROUND: Climatic variables can determine malaria transmission dynamics. To see the correlation between malaria occurrence and climatic variables, records of malaria episodes over eight years period were analyzed incorporating climatic variables around Gilgel-Gibe Hydroelectric Dam and control sites. METHODS: Records of 99,206 confirmed malaria episodes registered between 2003 and 2011 were analyzed along with local meteorological data of the same duration. Data were analyzed with SPSS statistical software version 20 for Windows. Spearman correlation coefficient was estimated as a measure of the correlation. RESULTS: The major peaks of malaria prevalence were observed following the peaks of rainfall in the Gilgel-Gibe Hydroelectric Dam site. In the control site, the peaks of malaria in some years coincided with the peaks of rainfall, and the pattern of rainfall was relatively less fluctuating. Mean rainfall was negatively correlated with number of malaria cases at lags of 0 and 1 month, but positively correlated at lags of 2 to 4 months. Mean relative humidity showed significant positive correlations at lags of 3 to 4 months. Monthly mean maximum and minimum temperatures weakly correlated at lags of 0 to 4 months. CONCLUSIONS: Correlations of malaria and climate variables were different for the two sites; in Gilgel-Gibe, rainfall and relative humidity showed positive correlations. However, in the control site, the correlation of weather variables and malaria episodes were insignificant. Exploration of additional factors such as vegetation index and physico-chemical nature of mosquito breeding site may improve understanding of determinants of malaria dynamics in the area. PMID- 26124621 TI - In Vivo Analgesic and Antipyretic Activities of N-Butanol and Water Fractions of Ocimum Suave Aqueous Leaves Extract in Mice. AB - BACKGROUND: Ocimum suave willd is one of the plants traditionally used for the treatment of inflammation and related disorders in different parts of Ethiopia. The aim of the current study was to evaluate the analgesic and antipyretic activities of the solvent fractions (n-butanol and water) of O. suave aqueous leaves extract. MATERIALS AND METHODS: Acetic acid writhing and tail flick tests were used to evaluate the analgesic activity, and yeast-induced fever in mice was used to evaluate the antipyretic activity of the solvent fractions. RESULTS: Both solvent fractions exhibited inhibitory effect against acetic acid induced writhing at all tested dose levels in a dose dependent manner. The water fraction inhibited writhing by 47.69% at a dose of 200 mg/kg which was comparable to that by ASA, the standard drug. In the tail flick test, 200 mg/kg dose of both solvent fractions showed significant activity (P<0.05) after 0.5h, 1h and 3hrs of their administration. Both n- butanol and water fractions produced significant reduction in yeast induced fever at all doses employed. CONCLUSION: From these findings, it can be concluded that the n-butanol and water fractions of O. suave aqueous leaves extract have potential analgesic and antipyretic activity in mice. PMID- 26124622 TI - Health Information-Seeking Behavior Among Hypothyroid Patients at Saveetha Medical College and Hospital. AB - BACKGROUND: Hypothyroidism causes considerable morbidity. Low knowledge coupled with inadequate health literacy may lead to poor prevention and management. This study aimed to assess health information-seeking behavior and hypothyroid knowledge among South Indian hypothyroid patients. METHODS: This cross-sectional study was conducted in October 2013 in Saveetha Medical College, Chennai, India. Hundred clinically diagnosed hypothyroid patients >=18 years were interviewed in a hospital using a 57-item questionnaire to gather information on their socio demographics, self-reported disease history, hypothyroid-related knowledge, health information sources, health literacy and health information-seeking behavior. Hypothyroidism was assessed by free T3 and T4 levels. RESULTS: Mean age of participants was 38 years (SD=12) with median age of 39.5 years, majority of the participants being females (77%) and living in urban setting (52%). Mean free T3 level was 0.0137ng/dl (SD= 0.003) and mean free T4 was 0.7ng/dl (SD= 0.06). Ninety three percent of the participants received initial hypothyroidism education from their physicians at the time of diagnosis. Half of the participants had incorrect hypothyroidism-related knowledge; similar between both genders. Participants with inadequate health literacy had poor knowledge about the hypothyroidism. Hypothyroidism-related health information was sought almost exclusively from health professionals, predominantly regarding treatment, linked to their faith in qualified medical assistance. Economic status primarily determined healthcare-seeking behavior. Marital status, education level, annual household income and health literacy were significantly associated with knowledge. CONCLUSION: Participants having higher educational qualification, higher annual household income and adequate health literacy had considerable knowledge about hypothyroidism. Developing multi-factorial and tailored health education for patients with marginal or inadequate health literacy is needed. Exploring healthcare institutions as a medium for delivery of such education should be explored. PMID- 26124623 TI - Anemia and Associated Factors Among Pregnant Women Attending Antenatal Care Clinic in Wolayita Sodo Town, Southern Ethiopia. AB - BACKGROUND: Anemia during pregnancy is a common problem which affects both the mother's and her child's health. The main aim of the study was to determine the prevalence and associated risk factors of anemia among pregnant women. METHODS: We conducted a facility based cross-sectional study on 363 pregnant women attending antenatal care clinic in Wolayita Soddo Otona Hospital from January to March 2014. Sociodemographic data were collected through questionnaire based interview. Four milliliter of venous blood and five grams of fecal samples were collected from each pregnant woman. Hematological parameters were determined using CELL DYN 1800((r)) (Abott, USA) Hematology analyzer. Stool samples were checked for intestinal parasites using both direct wet mount and formol-ether concentration techniques. Data were analyzed using SPSS version 20 software. RESULTS: Overall, the prevalence of anemia was 39.94% (95% CI: 34.7 - 45.2%), of which the majority (60%) had moderate anemia. The mean hemoglobin concentration was 11.55+/-2.97 g/dl. Age 15-24 years (AOR: 9.89, 95%CI:2.68-21.41), family size >5 (AOR:7.74, 95%CI:4.15-16.47), multigravida (AOR:2.66, 95%CI:1.1.31-4.53), having low income (AOR:5.81, 95%CI:2.93-14.11), current clinical illness (AOR: 6.38, 95%CI:3.13-13.00), intestinal parasitic infection (AOR:2.41, 95%CI:1.08 5.81), no history of contraceptive usage (AOR:5.02 95%CI:2.21-11.47), being in third trimesters (AOR:11.37, 95%CI:4.56-24.82), history of excess menstrual bleeding (AOR:9.82, 95%CI:3.27-21.35) and low body mass index (AOR:9.44, 95%CI:7.79-22.18) were identified as independent predictors of anemia among pregnant women. CONCLUSION: Anemia prevalence was found out to be moderate public health importance. Identified risk factors should be considered for prevention and control of anemia among pregnant women. PMID- 26124625 TI - Meaning of Self-Care: Lived Experiences of Iranian Diabetic Patients. AB - BACKGROUND: Diabetes continuously disrupts a patient's well-being and quality of life. Successful self-care could potentially decrease overall costs and rates of mortality and morbidity. Patients' experiences could be used to elucidate what they believe about illness and its management. The overall aim of this study was to illuminate the meaning of self-care among diabetic patients in Southeast of Iran. METHODS: Sixteen diabetic patients with a mean age of 34 and 10 years' experience in self-care for their disease were interviewed. The interviews were recorded, transcribed verbatim, and analyzed with a Ricoeur's phenomenological hermeneutic method. RESULTS: The meaning of self- care was comprehensively understood as being empowered. This can be divided into four themes: seeking information, being independent, being optimistic or pessimistic and trust in God. CONCLUSION: The results in this study suggest that cultural and religious components could affect diabetic patients' self-care. Nurses might use patients' religious beliefs to relieve their stress, help them to retain a sense of control, maintain hope and sense of meaning and purpose in their life. PMID- 26124624 TI - Adherence to Two Methods of Education and Metabolic Control in Type 2 Diabetics. AB - BACKGROUND: Education in diabetes optimizes metabolic control, prevents acute and chronic complications, and improves quality of life. Our main objective was to evaluate if a better metabolic control is achieved in diabetic patients undergoing a program of intensive interactive care than in those with traditional care and written information. METHODS: Patients with type 2 diabetes mellitus (T2DM), aged 20-60 years, education level at least of primary school, serum creatinine <= 2.5 mg/dl, self-sufficient and HbA1c >= 7.1% were allocated in two groups of education, 1) minimal education (MEG) and 2) full education (FEG). The MEG patients followed predefined diet; FEG patients chose the diet by selecting foods from each group in a list of matches, teaching them to count nutrients, kilocalories (kcal) and percentage of nutrients. RESULTS: A follow-up of 31 patients in each group was obtained. The proportion of patients who had initial adherence was 13.33% in the MEG group and 9.67% in the FEG group while, at the end of the study, these percentages were of 73.3% and 58.38% respectively. The final HbA1c decreased in both groups, with or without good adherence. The FEG group had a higher decline in the values of cholesterol (p = 0.036) and LDL (p = 0.002) than the MEG group. CONCLUSION: Education programs in T2DM contribute to a decrease in HbA1c within six months, but an intensive program is more effective in reducing cholesterol and LDL. PMID- 26124626 TI - Intussusception as a Cause of Bowel Obstruction in Adults from a Resource Limited Area, Cameroon. AB - BACKGROUND: Intussusception refers to the telescoping of a proximal segment of bowel into a distal segment. It is a rare cause of intestinal obstruction in adulthood. CASE DETAILS: We report two cases of adult intussusception in a post operative period following Caesarean Section (with no lead point) and Appendicectomy (due to colonic adenocarcinoma) respectively. CONCLUSION: Though rare in adulthood, intussusception should be considered as a differential diagnosis to bowel obstruction in adults even in the post-operative period. PMID- 26124627 TI - Banger-Related Ocular Injuries During New Year Festivities in Osogbo, SW Nigeria. AB - BACKGROUND: Different types of ocular injuries could be sustained following banger explosives. This case report could be the first of such reports in West Africa. CASE DETAILS: We report cases of ocular injuries caused by bangers. This was a hospital-based study of 3 consecutive cases that presented during the New Year festival. Injuries were classified according to Birmingham eye trauma terminology system (BETTS). Two of the patients ended up with irreversible loss of vision. Another two of the three were bystanders. CONCLUSION: As banger related ocular injuries result in significant morbidity, public education regarding the proper use of bangers would help in preventing the incidence of ocular injuries and blindness. Advocacy for a strict legislation to regulate its use is strongly recommended. PMID- 26124628 TI - Pleomorphic Adenoma of the Parotid Gland: Report of a Case With Review of Literature. AB - BACKGROUND: Pleomorphic adenomas are benign salivary gland tumors, which predominantly affect the superficial lobe of the parotid gland. The "pleomorphic" nature of the tumor can be explained on the basis of its epithelial and connective tissue origin. The tumor has a female predilection between 30-50 years of age. Slowly progressing asymptomatic swelling is the usual presentation of the tumor. Surgical excision of the tumor mass forms the mainstay of treatment, with utmost care taken to preserve the facial nerve. CASE DETAILS: This case report aims to throw light on an interesting case of pleomorphic adenoma of the parotid gland in a 50 years old female patient. The patient presented with a slowly progressing asymptomatic swelling on the left side of the face. There is also a special emphasis to a detailed review of literature. CONCLUSION: Salivary gland neoplasms can occur at any site where salivary tissue is present. Pleomorphic adenoma is the commonest salivary gland tumor characterized by diverse histomorphological features. Early diagnosis and treatment plan entails thorough history taking, clinical examination, coupled with radiographic and histopathological findings. PMID- 26124629 TI - Spontaneous Rupture: An Uncommon Complication of Ventral Hernia. AB - BACKGROUND: Literature is scarce about spontaneous rupture of hernia because spontaneous rupture of here is uncommon (1). Reported cases are complications of incisional hernias, recurrent inguinal hernia, and umbilical hernias. It is potentially life threatening (1) because the ensuing entrapment and tension on bowel mesentery may lead to vasovagal shock or strangulation. In addition to systemic problems and increased intra-abdominal pressure that lead to the herniation, the spontaneous rupture and evisceration is usually preceded by other factors such as inflammation that weaken the hernia covering (1, 2).We a report a case of spontaneous rupture of an incisional ventral hernia referred to the University of Ilorin teaching hospital. PMID- 26124630 TI - MSL: A Measure to Evaluate Three-dimensional Patterns in Gene Expression Data. AB - Microarray technology is highly used in biological research environments due to its ability to monitor the RNA concentration levels. The analysis of the data generated represents a computational challenge due to the characteristics of these data. Clustering techniques are widely applied to create groups of genes that exhibit a similar behavior. Biclustering relaxes the constraints for grouping, allowing genes to be evaluated only under a subset of the conditions. Triclustering appears for the analysis of longitudinal experiments in which the genes are evaluated under certain conditions at several time points. These triclusters provide hidden information in the form of behavior patterns from temporal experiments with microarrays relating subsets of genes, experimental conditions, and time points. We present an evaluation measure for triclusters called Multi Slope Measure, based on the similarity among the angles of the slopes formed by each profile formed by the genes, conditions, and times of the tricluster. PMID- 26124631 TI - Microbiologic spectrum and susceptibility of isolates in delayed post-cataract surgery endophthalmitis. AB - The objective of this study was to evaluate the microbiological spectrum and antimicrobial susceptibility of isolates in delayed post-cataract surgery endophthalmitis. A retrospective review of 33 consecutive patients with culture proven delayed post-cataract surgery endophthalmitis was done from January 2006 to March 2013. There were 22 bacterial and eleven fungal cases. Common isolates were Streptococci (seven cases), coagulase-negative staphylococci (five), Gram negative bacilli (seven), Nocardia (two), Aspergillus (five), Candida (five). Gram-positive cocci were most susceptible to vancomycin and gatifloxacin (91.7%). Gram-negative isolates were most susceptible to ofloxacin (85.7%). Fungi being slow growing organisms are an important cause of delayed post-cataract surgery endophthalmitis. PMID- 26124632 TI - Vitamin D deficiency and posterior subcapsular cataract. AB - PURPOSE: To evaluate risk factors associated with posterior subcapsular cataract (PSC) development and the relationship between vitamin D deficiency and etiology of PSC. METHODS: Of 195 consecutive patients from a private ophthalmology practice, diagnosed with PSC, serum vitamin D3 (25-OH D) levels were obtained for 175, and associations among risk factors, comorbidities, and PSC were assessed. RESULTS: In all 175 PSC patients, mean 25-OH D levels were low (24 ng/mL +/-11 SD) compared with age/sex-matched standards. Significant differences in 25-OH D levels were noted between PSC subjects taking/not taking calcium supplements, systemic steroids, osteoporosis medications, etc. Alone, smoking status and calcium channel blockers and/or topical steroids use made no significant difference in PSC subjects 25-OH D levels, but two or more of these factors were associated with lowered levels of 25-OH D (P<0.001). Low vitamin D was correlated with female sex, autoimmune disease, and non-skin cancer diagnosis, but not with age, or other comorbidities or medication use. In five early-stage PSC patients taking 5,000 IU of 25-OH D daily for vitamin D deficiency, there was resolution of their cataracts during the 2-year follow-up period. CONCLUSION: Vitamin D levels for most PSC patients fell below the 30 ng/mL calcium homeostasis threshold. Some comorbidities and non-ophthalmic interventions are associated with the development of PSC at less depressed levels of 25-OH D. In this series, vitamin D deficiency was associated with PSC cataract, suggesting that raising the level of vitamin D intake may reduce PSC incidence. PMID- 26124633 TI - Long-term (60-month) results for the implantable miniature telescope: efficacy and safety outcomes stratified by age in patients with end-stage age-related macular degeneration. AB - BACKGROUND: The purpose of this study was to evaluate the long-term results of an implantable miniature telescope (IMT) in patients with bilateral, end-stage, age related macular degeneration (AMD). METHODS: A prospective, open-label, multicenter clinical trial with fellow eye controls enrolled 217 patients (mean age 76 years) with AMD and moderate-to-profound bilateral central visual acuity loss (20/80-20/800) resulting from untreatable geographic atrophy, disciform scars, or both. A subgroup analysis was performed with stratification for age (patient age 65 to <75 years [group 1; n=70] and patient age >=75 years [group 2; n=127]), with a comparative evaluation of change in best-corrected distance visual acuity (BCDVA), quality of life, ocular complications from surgery, adverse events, and endothelial cell density (ECD). Follow-up in an extension study was 60 months. RESULTS: Data were available for 22, 38, and 31 patients in group 1 and 42, 46, and 32 patients in group 2 at 36, 48, and 60 months, respectively. Mean BCDVA improvement from baseline to 60 months was 2.41+/-2.69 lines in all patients (n=76), with 2.64+/-2.55 lines in group 1 and 2.09+/-2.88 lines in group 2. Quality of life scores were significantly higher in group 1. The most common significant surgery-related ocular complications in group 1 were iritis >30 days after surgery (7/70; 10%) and persistent corneal edema (3/70; 4.3%); and in group 2 were a decrease in BCDVA in the implanted eye or IMT removal (10/127 each; 7.9%), corneal edema >30 days after surgery (9/127; 7.1%), and persistent corneal edema (6/127; 4.7%). Significant adverse events included four corneal transplants, comprising two (2.9%) in group 1 and two (1.6%) in group 2. At 60 months, one patient in group 1 (3.2%) and three patients in group 2 (9.4%) had lost >=2 lines of vision. The IMT was removed in one (1.4%) and ten (7.9%) patients in group 1 and group 2, respectively. Mean ECD loss was 20% at 3 months. Chronic loss was 3% per year. ECD loss was less in group 1 than in group 2 (35% versus 40%, respectively) at 60 months. CONCLUSION: Long-term results show substantial retention of improvement in BDCVA. Chronic ECD loss was consistent with that reported for conventional intraocular lenses. The IMT performed as well in group 1 (the younger group) as it did in group 2 through month 60. Younger patients retained more vision than their older counterparts and had fewer adverse events. Although not a specified outcome for this study, patients younger than 65 years also fared better than those in group 2 and retained more vision with fewer adverse events through month 60. PMID- 26124634 TI - Phase II study of reintroduction of oxaliplatin for advanced colorectal cancer in patients previously treated with oxaliplatin and irinotecan: RE-OPEN study. AB - BACKGROUND: The effectiveness of reintroducing oxaliplatin in patients with metastatic colorectal cancer refractory to standard chemotherapy has not been verified. We performed a single-arm, open-label, Phase II study to evaluate the safety and efficacy of reintroducing oxaliplatin. METHODS: Eligible patients had received prior chemotherapy including oxaliplatin and irinotecan that achieved a response or stable disease followed by confirmed disease progression >=6 months previously during prior oxaliplatin-based therapy. The primary endpoint was the disease control rate (DCR) after 12 weeks of treatment starting. The DCR was defined as the sum of patients with complete response, partial response, and stable disease. RESULTS: Thirty-three patients were enrolled. The median age was 62 (range: 35-77) years and the male/female ratio was 19/14. Eastern Cooperative Oncology Group performance status was 0 in 84.8%. Fourteen primary tumors were in the colon and 19 were in the rectum. All patients received modified FOLFOX6 as the protocol treatment. After 12 weeks of treatment starting, the DCR was 39.4% (95% confidence interval 21.8-57.0) and the response rate (complete response and partial response) was 6.1%. The median number of chemotherapy cycles was five and the median total dose of oxaliplatin was 425 mg/m(2). Median progression-free survival time was 98 days and median overall survival was 300 days. The incidence of grade >=1 and grade >=3 allergic reactions was 28.1% and 3.1%, respectively. The incidence of grade >=1 and grade >=3 peripheral sensory neuropathy was 53.1% and 0%, respectively. There were no other severe adverse events and no treatment related deaths. CONCLUSION: Reintroducing oxaliplatin can be both safe and effective. This may be a salvage option for patients with metastatic colorectal cancer who achieved a response or stable disease with prior oxaliplatin-based therapy followed by disease progression >=6 months previously during prior oxaliplatin-based therapy. PMID- 26124635 TI - Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery. AB - Insulin is a life-saving medication for people with type 1 diabetes, but traditional insulin replacement therapy is based on multiple daily subcutaneous injections or continuous subcutaneous pump-regulated infusion. Nonphysiologic delivery of subcutaneous insulin implies a rapid and sustained increase in systemic insulin levels due to the loss of concentration gradient between portal and systemic circulations. In fact, the liver degrades about half of the endogenous insulin secreted by the pancreas into the venous portal system. The reverse insulin distribution has short- and long-term effects on glucose metabolism. Thus, researchers have explored less-invasive administration routes based on innovative pharmaceutical formulations, which preserve hormone stability and ensure the therapeutic effectiveness. This review examines some of the recent proposals from clinical and material chemistry point of view, giving particular attention to patients' (and diabetologists') ideal requirements that organic chemistry could meet. PMID- 26124636 TI - Anticancer activity of Nigella sativa (black seed) and its relationship with the thermal processing and quinone composition of the seed. AB - The traditional preparation process of Nigella sativa (NS) oil starts with roasting of the seeds, an allegedly unnecessary step that was never skipped. The aims of this study were to investigate the role and boundaries of thermal processing of NS seeds in the preparation of therapeutic extracts and to elucidate the underlying mechanism. NS extracts obtained by various seed thermal processing methods were investigated in vitro for their antiproliferative activity in mouse colon carcinoma (MC38) cells and for their thymoquinone content. The effect of the different methods of thermal processing on the ability of the obtained NS oil to inhibit the nuclear factor kappa B (NF-kappaB) pathway was then investigated in Hodgkin's lymphoma (L428) cells. The different thermal processing protocols yielded three distinct patterns: heating the NS seeds to 50 degrees C, 100 degrees C, or 150 degrees C produced oil with a strong ability to inhibit tumor cell growth; no heating or heating to 25 degrees C had a mild antiproliferative effect; and heating to 200 degrees C or 250 degrees C had no effect. Similar patterns were obtained for the thymoquinone content of the corresponding oils, which showed an excellent correlation with the antiproliferative data. It is proposed that there is an oxidative transition mechanism between quinones after controlled thermal processing of the seeds. While NS oil from heated seeds delayed the expression of NF-kappaB transcription, non-heated seeds resulted in only 50% inhibition. The data indicate that controlled thermal processing of NS seeds (at 50 degrees C-150 degrees C) produces significantly higher anticancer activity associated with a higher thymoquinone oil content, and inhibits the NF-kappaB signaling pathway. PMID- 26124637 TI - Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits. AB - The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas forming agent. All the formulations were evaluated for compendial and non compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of (153)Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern. PMID- 26124638 TI - Histone demethylase LSD1-mediated repression of GATA-2 is critical for erythroid differentiation. AB - BACKGROUND: The transcription factor GATA-2 is predominantly expressed in hematopoietic stem and progenitor cells and counteracts the erythroid-specific transcription factor GATA-1, to modulate the proliferation and differentiation of hematopoietic cells. During hematopoietic cell differentiation, GATA-2 exhibits dynamic expression patterns, which are regulated by multiple transcription factors. METHODS: Stable LSD1-knockdown cell lines were established by growing murine erythroleukemia (MEL) or mouse embryonic stem cells together with virus particles, in the presence of Polybrene((r)) at 4 MUg/mL, for 24-48 hours followed by puromycin selection (1 MUg/mL) for 2 weeks. Real-time polymerase chain reaction (PCR)-based quantitative chromatin immunoprecipitation (ChIP) analysis was used to test whether the TAL1 transcription factor is bound to 1S promoter in the GATA-2 locus or whether LSD1 colocalizes with TAL1 at the 1S promoter. The sequential ChIP assay was utilized to confirm the role of LSD1 in the regulation of H3K4me2 at the GATA-2 locus during erythroid differentiation. Western blot analysis was employed to detect the protein expression. The alamarBlue((r)) assay was used to examine the proliferation of the cells, and the absorbance was monitored at optical density (OD) 570 nm and OD 600 nm. RESULTS: In this study, we showed that LSD1 regulates the expression of GATA-2 during erythroid differentiation. Knockdown of LSD1 results in increased GATA-2 expression and inhibits the differentiation of MEL and embryonic stem cells. Furthermore, we demonstrated that LSD1 binds to the 1S promoter of the GATA-2 locus and suppresses GATA-2 expression, via histone demethylation. CONCLUSION: Our data revealed that LSD1 mediates erythroid differentiation, via epigenetic modification of the GATA-2 locus. PMID- 26124640 TI - The impact of lipocalin-type-prostaglandin-D-synthase as a predictor of kidney disease in patients with type 2 diabetes. AB - Hypertension and diabetes are clinical conditions which contribute to the development of chronic kidney disease as well as risk factors for cardiovascular events. In recent years, lipocalin-type-prostaglandin-D-synthase (beta trace protein; BTP) has increasingly been studied as an alternative to creatinine for the evaluation of renal function as well as for being a possible biomarker for cardiovascular disease. It is expected that the levels of BTP in patients with cardiovascular disease are elevated, as is the case with patients with renal dysfunction. The objective of this study is to realize a systematic review of the pertinent literature in respect to BTP as a biomarker of renal dysfunction in diabetic patients. Using the database MEDLINE, a search up to year 2014 was conducted using the follow descriptors: "lipocalin type prostaglandin d synthase" AND "diabetes"; "lipocalin type prostaglandin d synthase" and "diabetic nephropathy"; "beta trace protein" AND "diabetes"; "beta trace protein" AND "diabetic nephropathy". The criteria used for inclusion were the presence of the referring to terms in title or abstract and study conducted in humans. About 17 articles were selected, of which six articles were duplicates, and of which six articles did not investigate any possible relationship between the protein (BTP) and either diabetes or nephropathy. The final result yielded five articles to be analyzed. This review found BTP is not influenced by race, by body mass index nor by patient's sex. BTP can be considered as a reliable early biomarker of renal dysfunction in diabetics. BTP is associated with metabolic syndrome and is also associated with greater cardiovascular risk. Prospective data establishing a correlation between BTP and mortality would have been of great interest, but such articles were not found in this review. PMID- 26124639 TI - Therapeutic effects of C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28 oic acid (CDDO-Me; bardoxolone methyl) on radiation-induced lung inflammation and fibrosis in mice. AB - The C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO-Me), one of the synthetic triterpenoids, has been found to have potent anti inflammatory and anticancer properties in vitro and in vivo. However, its usefulness in mitigating radiation-induced lung injury (RILI), including radiation-induced lung inflammation and fibrosis, has not been tested. The aim of this study was to explore the therapeutic effect of CDDO-Me on RILI in mice and the underlying mechanisms. Herein, we found that administration of CDDO-Me improved the histopathological score, reduced the number of inflammatory cells and concentrations of total protein in bronchoalveolar lavage fluid, suppressed secretion and expression of proinflammatory cytokines, including transforming growth factor-beta and interleukin-6, elevated expression of the anti inflammatory cytokine interleukin-10, and downregulated the mRNA level of profibrotic genes, including for fibronectin, alpha-smooth muscle actin, and collagen I. CDDO-Me attenuated radiation-induced lung inflammation. CDDO-Me also decreased the Masson's trichrome stain score, hydroxyproline content, and mRNA level of profibrotic genes, and blocked radiation-induced collagen accumulation and fibrosis. Collectively, these findings suggest that CDDO-Me ameliorates radiation-induced lung inflammation and fibrosis, and this synthetic triterpenoid is a promising novel therapeutic agent for RILI. Further mechanistic, efficacy, and safety studies are warranted to elucidate the role of CDDO-Me in the management of RILI. PMID- 26124641 TI - Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy. AB - BACKGROUND: Ovarian cancer is the leading cause of death in women with gynecological malignancy worldwide. Despite multiple new approaches to treatment, relapse remains almost inevitable in patients with advanced disease. The poor outcome of advanced ovarian cancer treated with conventional therapy stimulated the search for new strategies to improve therapeutic efficacy. Although epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) inhibitors have known activity in advanced ovarian cancer, the effect of combined therapy against EGFR and PARP in this population has not been reported. In the current study, we investigated the mechanisms of erlotinib used alone or in combination with olaparib (AZD2281), a potent inhibitor of PARP, in an EGFR-overexpressing ovarian tumor xenograft model. METHODS: A2780 (EGFR-overexpressing, BRCA1/2 wild type) cells were subcutaneously injected into nude mice, which were then randomly assigned to treatment with vehicle, erlotinib, AZD2281, or erlotinib + AZD2281, for up to 3 weeks. All mice were then sacrificed and tumor tissues were subjected to Western blot analysis and monodansylcadervarine staining (for analysis of autophagy). RESULTS: Erlotinib could slightly inhibit growth of A2780 tumor xenografts, and AZD2281 alone had similar effects on tumor growth. However, the combination treatment had a markedly enhanced antitumor effect. Western blot analysis revealed that treatment with erlotinib could significantly reduce the phosphorylation level of ERK1/2 and AKT in A2780 tumor tissue. Of interest, monodansylcadervarine staining showed that the autophagic effects were substantially enhanced when the agents were combined, which may be due to downregulation of apoptosis. CONCLUSION: These results suggest that combination of a selective EGFR inhibitor and a PARP inhibitor is effective in ovarian cancer A2780 xenografts, and depends on enhanced autophagy. PMID- 26124642 TI - Characterization of renal biomarkers for use in clinical trials: effect of preanalytical processing and qualification using samples from subjects with diabetes. AB - BACKGROUND: Identifying the potential for drug-induced kidney injury is essential for the successful research and development of new drugs. Newer and more sensitive preclinical drug-induced kidney injury biomarkers are now qualified for use in rat toxicology studies, but biomarkers for clinical studies are still undergoing qualification. The current studies investigated biomarkers in healthy volunteer (HV) urine samples with and without the addition of stabilizer as well as in urine from patients with normoalbuminuric diabetes mellitus (P-DM). METHODS: Urine samples from 20 male HV with stabilizer, 69 male HV without stabilizer, and 95 male DM without stabilizer (39 type 1 and 56 type 2) were analyzed for the following bio-markers using multiplex assays: alpha-1 microglobulin (A1M), beta-2-microglobulin, calbindin, clusterin, connective tissue growth factor (CTGF), creatinine, cystatin-C, glutathione S-transferase alpha (GSTalpha), kidney injury marker-1 (KIM-1), microalbumin, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein (THP), tissue inhibitor of metalloproteinase 1, trefoil factor 3 (TFF3), and vascular endothelial growth factor. RESULTS: CTGF and GSTalpha assays on nonstabilized urine were deemed nonoptimal (>50% of values below assay lower limits of quantification). "Expected values" were determined for HV with stabilizer, HV without stabilizer, and P-DM without stabilizer. There was a statistically significant difference between HV with stabilizer compared to HV without stabilizer for A1M, CTGF, GSTalpha, and THP. DM urine samples differed from HV (without stabilizer) for A1M CTGF, GSTalpha, KIM-1, microalbumin, osteopontin, and TFF3. A1M also correctly identified HV and DM with an accuracy of 89.0%. SUMMARY: These studies: 1) determined that nonstabilized urine can be used for assays under qualification; and 2) documented that A1M, CTGF, GSTalpha, KIM-1, microalbumin, osteopontin, and TFF3 were significantly increased in urine from P-DM. In addition, the 89.0% accuracy of A1M in distinguishing P-DM from HV may allow this biomarker to be used to monitor efficacy of potential renal protective agents. PMID- 26124643 TI - Patient-reported treatment satisfaction and choice of dosing frequency with biologic treatment for moderate to severe plaque psoriasis. AB - BACKGROUND: Moderate to severe plaque psoriasis has a serious effect on health related quality of life. Patients treated with biologic medications place importance on satisfaction and treatment frequency options. We assessed patient reported treatment satisfaction and dosing frequency choice with biologics. METHODS: We used a health care claims database to identify patients with moderate to severe plaque psoriasis. Participants completed the Treatment Satisfaction Questionnaire for Medication. Results were compared between patients experienced with biologics (adalimumab, etanercept, or ustekinumab) or not (cyclosporine or methotrexate). Participants were asked for their choices of dosing options of once every 1-2 weeks, 3-4 weeks, 1-2 months, or 2-3 months. Participants were also asked for their choices of dosing options of every 1, 2, 3, and so on up to every 12+ weeks. RESULTS: A total of 426 patients completed the survey (263 biologic-experienced and 163 biologic-naive patients). Patient satisfaction with psoriasis treatment was significantly higher in the biologic-experienced cohort. The most frequently chosen option (38.8% of all participating patients) was every 2-3 months; 37.3% chose once every 1-2 weeks. Significant differences were found in the percentage of biologic-naive patients choosing 2-3-month (49.7%) over 1-2 week (20.9%) dosing (P<0.001). Among biologic-experienced patients, the difference between the percentage of patients choosing the 2-3-month (35.7%) and 1-2-week (41.8%) options was not significant (P=0.264). The two most often week specific intervals chosen by biologic-naive patients were 12+ weeks (42.3%) and 4 weeks (15.6%). The biologic-experienced patients most often chose 12+ weeks (31.2%) and 1 week (25.9%). CONCLUSION: Patients using biologics reported satisfaction with their treatment, which may positively affect outcomes. Longer dosing intervals were chosen most frequently among all patients combined. Reports of patient satisfaction with prior treatments and choices regarding dosing frequency, among all other considerations, should be evaluated in determining an appropriate biologic medication for psoriasis. PMID- 26124644 TI - Design, construction, and implementation of an online platform for patients with type 1 diabetes: EncoDiab. AB - PURPOSE: The purpose of this study was to develop, build, and implement a virtual platform equipped with practical tools, relevant contents, and communication rooms, with the aim of facilitating patients' self-management of type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: The design of the platform was based on the suggestions of T1DM patients who were being managed at two reference hospitals. Patients' needs and preferences were identified in group discussion sessions. Before having access to the platform, patients underwent a baseline assessment, which included physical examination and the administration of validated questionnaires for evaluation of clinical background, quality of life, treatment satisfaction, and well-being. RESULTS: A total of 33 patients were included in the study; 54.5% of them were men, their median age was 34 (18-50) years, the median duration of diabetes was 15 (1-38) years, and the median A1C was 7.4% (6%-12.6%). Based on their suggestions and requests, the online platform EncoDiab was built and organized into four domains: a personal domain, two domains shared by the patients and the staff of each of the two participating hospitals, and one domain that was accessible to all participants. The platform included practical tools (a body mass index calculator, a carbohydrate counting tool, and an insulin-dose calculator), a library with relevant information (documents on prevention and treatment of acute complications, nutrition, exercise, etc), and a chat room. CONCLUSION: Although the study is still ongoing, our current results demonstrate the feasibility of building and implementing an online platform for helping T1DM patients in the self-management of their disease in the public health setting. PMID- 26124645 TI - Prevalence and risk factor analysis of lower extremity abnormal alignment characteristics among rice farmers. AB - BACKGROUND: Rice farming activities involve prolonged manual work and human machine interaction. Prolonged farming risk-exposure may result in lower limb malalignment. This malalignment may increase the risk of lower extremity injury and physical disabilities. However, the prevalence and factors associated with lower extremity malalignment have not yet been reported. This study aimed to investigate the prevalence and risk factors of lower extremity malalignment among rice farmers. METHODS: A cross-sectional survey was conducted with 249 rice farmers. Lower extremity alignment assessment included: pelvic tilt angle, limb length equality, femoral torsion, quadriceps (Q) angle, tibiofemoral angle, genu recurvatum, rearfoot angle, and medial longitudinal arch angle. Descriptive statistics were used to analyze participant characteristics and prevalence of lower extremity malalignment. Logistic regression analysis was used to identify risk factors. RESULTS: The highest prevalence of lower extremity malalignment was foot pronation (36.14%), followed by the abnormal Q angle (34.94%), tibiofemoral angle (31.73%), pelvic tilt angle (30.52%), femoral antetorsion (28.11%), limb length inequality (22.49%), tibial torsion (21.29%), and genu recurvatum (11.24%). In females, the risk factors were abnormal Q angle, tibiofemoral angle, and genu recurvatum. Being overweight was a risk factor for abnormal pelvic tilt angle, Q angle, and tibiofemoral angle. Age was a risk factor for limb length inequality. Years of farming were a major risk factor for abnormal Q angle, tibiofemoral angle, and foot malalignment. CONCLUSION: Prevalence of lower extremity malalignment was reported in this study. Female sex, being overweight, and years of farming were major risk factors for lower extremity malalignment. Lower extremity screening should assist in the identification of foot and knee malalignment in rice farmers. This may then lead to early prevention of musculoskeletal disorders arising from such malalignment. PMID- 26124646 TI - Effect of pharmaceutical care on medication adherence of patients newly prescribed insulin therapy: a randomized controlled study. AB - BACKGROUND: Poor adherence to insulin medications leads to a high rate of hospital admissions and poor health-related quality of life in the patients with diabetes mellitus. However, few strategies are effective and acceptable in improving medication adherence. The objectives of this study are to evaluate the effectiveness of pharmaceutical care by clinical pharmacists on medication adherence of patients newly prescribed insulin therapy. PATIENTS AND METHODS: A single-center, prospective randomized controlled study (pharmaceutical care group and control group) was performed from January 1, 2014 to December 30, 2014. Medication adherence was measured at the baseline and up to 12 months with Morisky-Green test and computerized dispensed medication history. The absolute change in A1c vs baseline, the change of hospitalization between two groups, and the number of patients to achieve Chinese Diabetes Society (CDS) goals at the baseline were the main outcome measures. RESULTS: A total of 322 patients were included in the study. After the 12-month interventions, significant improvements in the medication adherence were verified for the pharmaceutical care group according to the Morisky-Green test (50.8% of adherent patients at baseline vs 80.7% of adherent patients after 12-month interventions; P<0.01) and the computerized dispensed medication history (55.2% at baseline vs 83.3% after interventions; P<0.01), while no significant changes were verified in the control group. After follow-up, the pharmaceutical care group showed a greater percent change in A1c (2.2+/-0.4 vs 0.8+/-0.2, P<0.05). CONCLUSION: This study provides new evidence from a randomized controlled trial on the beneficial effect of pharmaceutical care to enhance adherence in patients newly prescribed insulin therapy. Intervention by the pharmacist might potentially improve clinical outcomes on reducing hemoglobin A1c and enhancing the number of patients fulfilling the Chinese Diabetes Society goal on hemoglobin A1c. PMID- 26124647 TI - Exploring motivations to seek and undergo prosthodontic care: a cross-sectional study in a Brazilian adult sample. AB - This study explored the influence of individual and social factors regarding intentions and behaviors related to prosthodontic treatment, using the theory of planned behavior (TPB). A cross-sectional study was designed with a sample of 225 individuals with some degree of tooth loss. A questionnaire was used containing factors that would have potential influence on the intentions and behaviors of individuals, as well as clinical and sociodemographic data. Descriptive statistics, internal consistency analysis, chi-square test for trend, and logistic regression were used for data analysis. The TPB components - attitude toward the behavior (ATB), subjective norm (SN), and perceived behavioral control (PBC) - showed good internal consistency (alpha = 0.60-0.78). Intention and behavior were associated with TPB components and the overall scale. Similarly, positive intentions and behaviors were associated with age, upper tooth loss, anterior tooth loss, and higher social status. Multiple logistic regression showed that intention was associated with PBC (OR =1.57; P<0.016), while behavior was associated with tooth loss in both arches (OR =9.3; P<0.001), anterior tooth loss (OR =5.13; P<0.001), higher social status (OR =3.06; P<0.03), and PBC (OR =1.38; P=0.03). The presence of anterior tooth loss was the most relevant factor for prosthodontic treatment demand and utilization, while socioeconomic status and an individual's perceived ease or difficulty in undergoing treatment played a significant, but secondary, role in behavior toward prosthodontic care. PMID- 26124648 TI - Older patients' perceived burdens of their health problems: a cross-sectional analysis in 74 German general practices. AB - BACKGROUND: Older patients often experience the burden of multiple health problems. Physicians need to consider them to arrive at a holistic treatment plan. Yet, it has not been systematically investigated as to which personal burdens ensue from certain health conditions. OBJECTIVE: The objective of this study is to examine older patients' perceived burden of their health problems. PATIENTS AND METHODS: The study presents a cross-sectional analysis in 74 German general practices; 836 patients, 72 years and older (mean 79+/-4.4), rated the burden of each health problem disclosed by a comprehensive geriatric assessment. Patients rated each burden using three components: importance, emotional impact, and impact on daily activities. Cluster analyses were performed to define patterns in the rating of these components of burden. In a multilevel logistic regression analysis, independent factors that predict high and low burden were explored. RESULTS: Patients had a median of eleven health problems and rated the burden of altogether 8,900 health problems. Four clusters provided a good clustering structure. Two clusters describe a high burden, and a further two, a low burden. Patients attributed a high burden to social and psychological health problems (especially being a caregiver: odds ratio [OR] 10.4, 95% confidence interval [CI] 4.4-24.4), to specific symptoms (eg, claudication: OR 2.3, 95% CI 1.3-4.0; pain: OR 2.3, 95% CI 1.6-3.1), and physical disabilities. Patients rated a comparatively low burden for most of their medical findings, for cognitive impairment, and lifestyle issues (eg, hypertension: OR 0.2, 95% CI 0.2-0.3). CONCLUSION: The patients experienced a relatively greater burden for physical disabilities, mood, or social issues than for diseases themselves. Physicians should interpret these burdens in the individual context and consider them in their treatment planning. PMID- 26124649 TI - Rates and predictors of uncontrolled bronchial asthma in elderly patients from western Romania. AB - PURPOSE: Bronchial asthma (BA) is a chronic inflammatory disorder of the airways, featuring variable and often reversible airflow limitations. An accurate assessment of BA control is difficult in practice, especially in the elderly, requiring the assessment of several clinical and paraclinical parameters that are influenced not only by asthma, but also by comorbidities. The purpose of this study was to evaluate the predictors of uncontrolled BA in a group of elderly patients from western Romania. PATIENTS AND METHODS: We retrospectively evaluated 126 elderly patients (aged $ 65 years), who were consecutively evaluated in the Pulmonology Department of Victor Babes Hospital, Timisoara, Romania, between March 2009 and July 2012. We collected demographic data, performed pulmonary function testing and an asthma control test (ACT), and evaluated the level of BA control based on the 2012 Global Initiative for Asthma guidelines. Statistical processing of the data was done using the Epi Info and STATA programs. RESULTS: In our study group, 36 (29%) patients were men and 90 (71%) were women; their mean age was 74.42+/-8.32 years (range: 65-85 years). A total of 14.28% of patients were smokers. About 30.15% of patients had an ACT score <19, 54.76% had an ACT score 20-24, and 15.09% had an ACT of 25. Moreover, 59.52% had normal spirometry results. Infectious exacerbations were found in 58.73% of patients. A history of allergies was demonstrated in 48.41% of patients, 34.12% had occupational exposure, and 82.53% of patients were treated with inhaled corticosteroids. Our results showed that 30.15% of patients had uncontrolled BA. We found six predictive factors for uncontrolled BA: infectious exacerbation, occupational exposure, mixed (obstructive and restrictive) ventilatory dysfunction, persistent airway obstruction on spirometry, duration of disease in months, and current smoking status. Infectious exacerbations, persistent airway obstructions, and occupational exposure were the most powerful predictors. CONCLUSION: Elderly patients represent an important group that is at risk for developing uncontrolled BA. Predictors may identify those elderly patients with uncontrolled BA and facilitate early medical interventions. PMID- 26124650 TI - Development, validation, and administration of a treatment-satisfaction questionnaire for caregivers of dependent type 2 diabetic patients. AB - BACKGROUND: Satisfaction with treatment is considered a relevant factor for assessing results in clinical practice. However, when assessing satisfaction in dependent patients, the opinion of their caregivers becomes crucial, since implicit in satisfaction is the degree of caregiver involvement, of adherence to treatment, and lastly of better care of these patients. PURPOSE: The purpose of this study was to develop, validate, and administer two versions of a specific questionnaire to assess satisfaction with blood glucose-lowering treatment in caregivers of dependent type 2 diabetic patients. PATIENTS AND METHODS: This was an observational, descriptive, epidemiological study conducted in the Los Montalvos Internal Medicine Department at the University Hospital of Salamanca (Spain). Two versions of the questionnaire to assess caregivers' satisfaction with current treatment and after introducing changes in therapy were created and validated according to model procedures. Once validated, the questionnaires were implemented in 219 cases. RESULTS: Cronbach's alpha-coefficient, correlation between all the items, intraclass correlation coefficient, and correlation between the obtained scores and satisfaction with blood glucose levels all satisfied the standard for validation. Significant levels of correlation were observed between the degree of satisfaction and the number of daily administrations of the blood glucose-lowering medication (Spearman's r=-0.21, P<0.05). Caregivers of patients receiving more frequent administration of their antidiabetic medication prior to the change were more satisfied with the change (r=0.24, P<0.001). Similarly, significant correlation was found between the number of daily administrations for blood glucose-lowering medication after the change and the degree of satisfaction (r=-0.43, P<0.001). CONCLUSION: A useful novel instrument to assess caregivers' satisfaction was validated. When applied to our cohort of cases, the obtained data suggest that simplicity in antidiabetic therapy should be considered in the management of dependent type 2 diabetic patients when caregivers' satisfaction is an additional objective. PMID- 26124651 TI - Causes and predictors of hospital readmissions in patients older than 65 years hospitalized for heart failure with preserved left ventricular ejection fraction in western Romania. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is more frequent in the elderly and is associated with important economic implications because of repetitive and prolonged hospitalizations, due to both cardiovascular and noncardiovascular causes. PURPOSE: To identify the causes, as well as the clinical and biological markers, that could be used as predictors of hospital readmissions in HFpEF patients aged >=65 years. PATIENTS AND METHODS: Consecutive eligible patients hospitalized for a first heart failure (HF) episode were prospectively included and divided into one of two age groups (elderly: >=65 years; and nonelderly: <65 years). The clinical features, therapeutic approaches, and clinical outcomes during the 1-year follow-up period were analyzed. RESULTS: A total of 178 patients were included, with a mean age of 64.6+/-8.6 years; 80 (45%) were women. A total of 98 patients (55%) were aged >=65 years, and 80 (45%) were aged <65 years. In the group aged >=65 years, 58 patients (59%) were women, while in the group aged <65 years, 22 patients (28%) were women (P=0.0001). During the 1-year follow-up, no patients died or were lost to follow-up. Moreover, 116 (65%) of the HFpEF patients experienced hospital readmissions. The elderly patients had a significantly higher readmission rate (73% vs 55%, respectively; P<0.02); readmissions due to aggravated HF were significantly more frequent in this age group (41% vs 18%, respectively; P<0.002). Multivariate logistic regression analysis indicated that the independent predictors of readmission due to HF aggravation included plasma levels of brain natriuretic peptide >450 pg/mL (P<0.01) and N-terminal-pro-brain natriuretic peptide >477 pg/mL (P<0.02) in the elderly group, while in the nonelderly group, the independent predictors of this outcome were a New York Heart Association functional class of IV at initial hospitalization (P<0.04), as well as plasma levels of brain natriuretic peptide >390 pg/mL (P=0.03) and tumor necrosis factor (TNF)-alpha >7.1 pg/mL (P<0.001). Readmissions due to noncardiovascular causes were independently predicted by plasma levels of TNF-alpha >10 pg/mL in the elderly (P=0.003) and of interleukin (IL)-6 >1.9 pg/mL in the nonelderly (P<0.04). CONCLUSION: We conclude that in HFpEF patients aged >=65 years, the main cause of rehospitalization during the 1-year follow-up was HF aggravation. The risk of this outcome was independently predicted by increased levels of cardiac peptides, while the risk of noncardiovascular readmissions was predicted by increased levels of inflammatory biomarkers. Increased TNF-alpha levels predicted both cardiovascular and noncardiovascular readmissions, while increased levels of high-sensitivity C-reactive protein did not predict any of these outcomes in our study. PMID- 26124652 TI - Dosing of U-100 insulin and associated outcomes among Medicare enrollees with type 1 or type 2 diabetes. AB - OBJECTIVE: To examine costs, resource utilization, adherence, and hypoglycemic events among various doses of U-100 insulin regimens among elderly patients (age >=65 years) diagnosed with diabetes. METHODS: Truven Health Analytics Medicare databases from January 1, 2008 through December 31, 2011 were utilized. General linear models with a gamma distribution and log link were used to examine costs, while logistic and negative binomial regressions were used to examine resource utilization and hypoglycemic events. Analyses controlled for patient characteristics, pre-period comorbidities, general health, and use of antidiabetic medications as well as index dose of insulin. RESULTS: All-cause inpatient, emergency room, and outpatients costs, as well as diabetes-related inpatient costs, were highest among individuals who were treated with an index dose of 10-100 units/day followed by >300 units/day, while drug costs and total costs generally increased as index dosage increased. Resource utilization generally followed the same pattern as costs, with number of office visits increasing as the dose increased and the highest hospital length of stay, number of hospitalizations, number of emergency room visits, and number of diabetes related hospitalizations were generally highest among those in the lowest and highest index dose cohorts. Compared to patients who initiated with an index dose of 10-100 units/day, all other patients were significantly less likely to achieve an adherence threshold of 80% based upon index dose range, and while those with an index dose of >100-150 units/day were significantly more likely to experience a hypoglycemic event. CONCLUSION: These results suggest that, for elderly individuals with diabetes, there is a higher patient burden among those who receive the lowest and highest insulin doses. PMID- 26124653 TI - Effects of indacaterol versus tiotropium on respiratory mechanics assessed by the forced oscillation technique in patients with chronic obstructive pulmonary disease. AB - The forced oscillation technique (FOT) can measure respiratory mechanics and has attracted attention in chronic obstructive pulmonary disease (COPD). We aimed to evaluate the effects of only indacaterol and tiotropium monotherapies on airflow limitation and respiratory impedance. Pulmonary function tests, COPD assessment test (CAT), and multifrequency FOT with MostGraph-01 were performed at the beginning and after 8 weeks of treatment with indacaterol or tiotropium. The resistance index, resistance at 5 Hz (R5), resistance at 20 Hz (R20), reactance index, reactance at 5 Hz (X5), resonant frequency (Fres), and low-frequency reactance area (ALX) were determined at whole-breath, inspiratory, and expiratory phases. Eighty-two patients (mean age: 73 years; mean forced expiratory volume in 1 second (FEV1): 61.6%+/-19.0% predicted) were randomized to indacaterol or tiotropium treatment. Both bronchodilators improved airflow limitation, with mean trough improvements in FEV1 of 165 mL and 80 mL in the indacaterol and tiotropium groups, respectively. The CAT score decreased in the indacaterol group (P<0.001; 11.2+/-6.6 to 7.5+/-5.6). Compared with tiotropium, indacaterol significantly improved FEV1, percent predicted FEV1, and CAT score (P=0.042, P=0.008, and P=0.027, respectively). For respiratory impedance, indacaterol and tiotropium changed R5, X5, Fres, and ALX at whole-breath, inspiratory, and expiratory phases. In the indacaterol group, the changes in R5, R5-R20, X5, Fres, and ALX were significantly correlated with the changes in FEV1. The use of the FOT may enable the evaluation of the effects of bronchodilators in addition to FEV1 indicated therapeutic effects in COPD. PMID- 26124654 TI - Severe hypoalbuminemia is a strong independent risk factor for acute respiratory failure in COPD: a nationwide cohort study. AB - BACKGROUND: Acute respiratory failure (ARF) is a life-threatening event, which is frequently associated with the severe exacerbations of chronic obstructive pulmonary disease (COPD). Hypoalbuminemia is associated with increased mortality in patients with COPD. However, to date, little is known regarding whether or not hypoalbuminemia is a risk factor for developing ARF in COPD. METHODS: We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. A total of 42,732 newly diagnosed COPD patients (age >=40 years) from 1997 to 2011 were enrolled. Among them, 1,861 (4.36%) patients who had received albumin supplementation were defined as hypoalbuminemia, and 40,871 (95.6%) patients who had not received albumin supplementation were defined as no hypoalbuminemia. RESULTS: Of 42,732 newly diagnosed COPD patients, 5,248 patients (12.3%) developed ARF during the 6 years follow-up period. Patients with hypoalbuminemia were older, predominantly male, had more comorbidities, and required more steroid treatment and blood transfusions than patients without hypoalbuminemia. In a multivariable Cox regression analysis model, being elderly was the strongest independent risk factor for ARF (adjusted hazard ratio [HR]: 4.63, P<0.001), followed by hypoalbuminemia (adjusted HR: 2.87, P<0.001). However, as the annual average dose of albumin supplementation was higher than 13.8 g per year, the risk for ARF was the highest (adjusted HR: 11.13, 95% CI: 10.35-11.98, P<0.001). CONCLUSION: Hypoalbuminemia is a strong risk factor for ARF in patients with COPD. Therefore, further prospective studies are required to verify whether or not albumin supplementation or nutritional support may help to reduce the risk of ARF in patients with COPD. PMID- 26124655 TI - Bronchial hyperresponsiveness, airway inflammation, and reversibility in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Bronchial hyperresponsiveness (BHR), sputum eosinophilia, and bronchial reversibility are often thought to be a hallmark of asthma, yet it has been shown to occur in COPD as well. OBJECTIVES: To evaluate the relationship between BHR, lung function, and airway inflammation in COPD patients. METHODS: Thirty-one, steroid-free patients with stable, mild and moderate COPD were studied. The following tests were carried out: baseline lung function, reversibility, provocative dose of methacholine causing a 20% fall in forced expiratory volume in 1 second, a COPD symptom score, and sputum induction. RESULTS: Twenty-nine patients completed the procedures. About 41.4% had BHR, 31.0% had increased sputum eosinophils, and 37.9% had bronchial reversibility. Some of the patients had only one of these characteristics while others had two or the three of them. Patients with BHR had higher sputum eosinophils than patients without BHR (P=0.046) and those with sputum eosinophils >=3% had more exacerbations in the previous year and a higher COPD symptom score than patients with sputum eosinophils <3% (P=0.019 and P=0.031, respectively). In patients with BHR, the cumulative dose of methacholine was negatively related to the symptom score and the number of exacerbations in the previous year. When patients with bronchial reversibility were considered, bronchodilation was positively related to sputum eosinophils. CONCLUSION: Our study showed that BHR, sputum eosinophilia, and bronchial reversibility were not clustered in one single phenotype of COPD but could be present alone or together. Of interest, BHR and airway eosinophilia were associated with clinical data in terms of exacerbations and symptoms. Further investigation is needed to clarify this topic. PMID- 26124656 TI - Test-retest reliability of lower limb isokinetic endurance in COPD: A comparison of angular velocities. AB - BACKGROUND: The purpose of this study was to determine and compare the test retest reliability of quadriceps isokinetic endurance testing at two knee angular velocities in patients with chronic obstructive pulmonary disease (COPD). METHODS: After one familiarization session, 14 patients with moderate to severe COPD (mean age 65+/-4 years; forced expiratory volume in 1 second (FEV1) 55%+/ 18% predicted) performed two quadriceps isokinetic endurance tests on two separate occasions within a 5-7-day interval. Quadriceps isokinetic endurance tests consisted of 30 maximal knee extensions at angular velocities of 90 degrees and 180 degrees per second, performed in random order. Test-retest reliability was assessed for peak torque, muscle endurance, work slope, work fatigue index, and changes in FEV1 for dyspnea and leg fatigue from rest to the end of the test. The intraclass correlation coefficient, minimal detectable change, and limits of agreement were calculated. RESULTS: High test-retest reliability was identified for peak torque and muscle total work at both velocities. Work fatigue index was considered reliable at 90 degrees per second but not at 180 degrees per second. A lower reliability was identified for dyspnea and leg fatigue scores at both angular velocities. CONCLUSION: Despite a limited sample size, our findings support the use of a 30-maximal repetition isokinetic muscle testing procedure at angular velocities of 90 degrees and 180 degrees per second in patients with moderate to severe COPD. Endurance measurement (total isokinetic work) at 90 degrees per second was highly reliable, with a minimal detectable change at the 95% confidence level of 10%. Peak torque and fatigue index could also be assessed reliably at 90 degrees per second. Evaluation of dyspnea and leg fatigue using the modified Borg scale of perceived exertion was poorly reliable and its clinical usefulness is questionable. These results should be useful in the design and interpretation of future interventions aimed at improving muscle endurance in COPD. PMID- 26124657 TI - Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD. AB - Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting beta2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a beta2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat((r)) Soft MistTM inhaler at doses of 2.5/5 MUg and 5/5 MUg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting beta2-agonist with long-acting muscarinic antagonist combinations and delivery devices. PMID- 26124658 TI - Multiple cues on the physiochemical, mesenchymal, and intracellular trafficking interactions with nanocarriers to maximize tumor target efficiency. AB - Over the past 60 years, numerous medical strategies have been employed to overcome neoplasms. In fact, with the exception of lung, bronchial, and pancreatic cancers, the 5-year survival rate of most cancers currently exceeds 70%. However, the quality of life of patients during chemotherapy remains unsatisfactory despite the increase in survival rate. The side effects of current chemotherapies stem from poor target efficiency at tumor sites due to the uncontrolled biodistribution of anticancer agents (ie, conventional or current approved nanodrugs). This review discusses the effective physiochemical factors for determining biodistribution of nanocarriers and, ultimately, increasing tumor targeting probability by avoiding the reticuloendothelial system. Second, stem cell-conjugated nanotherapeutics was addressed to maximize the tumor searching ability and to inhibit tumor growth. Lastly, physicochemical material properties of anticancer nanodrugs were discussed for targeting cellular organelles with modulation of drug-release time. A better understanding of suggested topics will increase the tumor-targeting ability of anticancer drugs and, ultimately, promote the quality of life of cancer patients during chemotherapy. PMID- 26124659 TI - Application of nanoparticles for oral delivery of acid-labile lansoprazole in the treatment of gastric ulcer: in vitro and in vivo evaluations. AB - The aim of this study was to develop nanoparticles for oral delivery of an acid labile drug, lansoprazole (LPZ), for gastric ulcer therapy. LPZ-loaded positively charged Eudragit((r)) RS100 nanoparticles (ERSNPs-LPZ) and negatively charged poly(lactic-co-glycolic acid) nanoparticles (PLGANPs-LPZ) were prepared. The effect of charge on nanoparticle deposition in ulcerated and non-ulcerated regions of the stomach was investigated. The cellular uptake of nanoparticles in the intestine was evaluated in a Caco-2 cell model. The pharmacokinetic performance and ulcer healing response of LPZ-loaded nanoparticles following oral administration were evaluated in Wistar rats with induced ulcers. The prepared drug-loaded ERSNPs-LPZ and PLGANPs-LPZ possessed opposite surface charge (+38.5+/ 0.3 mV versus -27.3+/-0.3 mV, respectively) and the particle size was around 200 nm with a narrow size distribution. The negatively charged PLGANPs adhered more readily to the ulcerated region (7.22%+/-1.21% per cm(2)), whereas the positively charged ERSNPs preferentially distributed in the non-ulcerated region (8.29%+/ 0.35% per cm(2)). Both ERSNPs and PLGANPs were prominent uptake in Caco-2 cells, too. The nanoparticles sustained and prolonged LPZ concentrations up to 24 hours, and the half-life and mean residence time of LPZ were prolonged by 3.5-fold and 4.5-fold, respectively, as compared with LPZ solution. Oral administration of LPZ loaded nanoparticles healed 92.6%-95.7% of gastric ulcers in Wistar rats within 7 days. PMID- 26124660 TI - Sustained release of VH and rhBMP-2 from nanoporous magnesium-zinc-silicon xerogels for osteomyelitis treatment and bone repair. AB - Nanoporous magnesium-zinc-silicon (n-MZS) xerogels with a pore size ~4 nm, a surface area of 718 cm(2)/g, and a pore volume of 1.24 cm(3)/g were synthesized by a sol-gel method. The n-MZS xerogels had high capacity to load vancomycin hydrochloride (VH) and human bone morphogenetic protein-2 (rhBMP-2), after soaking in phosphate buffered saline (PBS) for 24 hours (1.5 and 0.8 mg/g, respectively). Moreover, the n-MZS xerogels exhibited the sustained release of VH and rhBMP-2 as compared with magnesium-zinc-silicon (MZS) xerogels without nanopores (showing a burst release). The VH/rhBMP-2/n-MZS system not only exhibited a good antibacterial property but also promoted the MG63 cell proliferation and differentiation demonstrating good bactericidal activity and cytocompatibility. The results suggested that n-MZS with larger surface area and high pore volume might be a promising carrier for loading and sustained release of VH and rhBMP-2. Hence, the VH/rhBMP-2/n-MZS system might be one of the promising biomaterials for osteomyelitis treatment and bone repair. PMID- 26124661 TI - Oral administration of iron-saturated bovine lactoferrin-loaded ceramic nanocapsules for breast cancer therapy and influence on iron and calcium metabolism. AB - We determined the anticancer efficacy and internalization mechanism of our polymeric-ceramic nanoparticle system (calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate nanocapsules/nanocarriers [ACSC NCs]) loaded with iron-saturated bovine lactoferrin (Fe-bLf) in a breast cancer xenograft model. ACSC-Fe-bLf NCs with an overall size of 322+/-27.2 nm were synthesized. In vitro internalization and anticancer efficacy were evaluated in the MDA-MB-231 cells using multicellular tumor spheroids, CyQUANT and MTT assays. These NCs were orally delivered in a breast cancer xenograft mice model, and their internalization, cytotoxicity, biodistribution, and anticancer efficacy were evaluated. Chitosan-coated calcium phosphate Fe-bLf NCs effectively (59%, P<=0.005) internalized in a 1-hour period using clathrin-mediated endocytosis (P<=0.05) and energy-mediated pathways (P<=0.05) for internalization; 3.3 mg/mL of ACSC-Fe-bLf NCs completely disintegrated (~130-fold reduction, P<=0.0005) the tumor spheroids in 72 hours and 96 hours. The IC50 values determined for ACSC-Fe bLf NCs were 1.69 mg/mL at 10 hours and 1.62 mg/mL after 20 hours. We found that Fe-bLf-NCs effectively (P<=0.05) decreased the tumor size (4.8-fold) compared to the void NCs diet and prevented tumor recurrence when compared to intraperitoneal injection of Taxol and Doxorubicin. Receptor gene expression and micro-RNA analysis confirmed upregulation of low-density lipoprotein receptor and transferrin receptor (liver, intestine, and brain). Several micro-RNAs responsible for iron metabolism upregulated with NCs were identified. Taken together, orally delivered Fe-bLf NCs offer enhanced antitumor activity in breast cancer by internalizing via low-density lipoprotein receptor and transferrin receptor and regulating the micro-RNA expression. These NCs also restored the body iron and calcium levels and increased the hematologic counts. PMID- 26124662 TI - Targeted tumor imaging of anti-CD20-polymeric nanoparticles developed for the diagnosis of B-cell malignancies. AB - The expectations of nanoparticle (NP)-based targeted drug delivery systems in cancer, when compared with convectional therapeutic methods, are greater efficacy and reduced drug side effects due to specific cellular-level interactions. However, there are conflicting literature reports on enhanced tumor accumulation of targeted NPs, which is essential for translating their applications as improved drug-delivery systems and contrast agents in cancer imaging. In this study, we characterized biodegradable NPs conjugated with an anti-CD20 antibody for in vivo imaging and drug delivery onto tumor cells. NPs' binding specificity mediated by anti-CD20 antibody was evaluated on MEC1 cells and chronic lymphocytic leukemia patients' cells. The whole-body distribution of untargeted NPs and anti-CD20 NPs were compared by time-domain optical imaging in a localized human/mouse model of B-cell malignancy. These studies provided evidence that NPs' functionalization by an anti-CD20 antibody improves tumor pharmacokinetic profiles in vivo after systemic administration and increases in vivo imaging of tumor mass compared to non-targeted NPs. Together, drug delivery and imaging probe represents a promising theranostics tool for targeting B-cell malignancies. PMID- 26124663 TI - Circulating thymus and activation-regulated chemokine/CC chemokine ligand 17 is a strong candidate diagnostic marker for interstitial lung disease in patients with malignant tumors: a result from a pilot study. AB - INTRODUCTION: Serum Krebs von den Lungen-6 (KL-6) level is an established diagnostic marker of interstitial lung disease (ILD). However, it is also elevated in patients with non-small cell lung cancer (NSCLC). The significance of circulating thymus and activation-regulated chemokine (TARC)/CC chemokine ligand 17 (CCL17) in malignant diseases remains unknown. METHODS: We measured circulating TARC/CCL17 and KL-6 using enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay, respectively, in 26 patients with malignant disease and six patients with benign lung disease (BLD). The cutoff levels were 500 U/mL for KL-6 and 450 pg/mL for TARC/CCL17. The significance of the markers was evaluated in relationship to the presence of ILD (n=10). The statistical significance was set at P<0.05. RESULTS: The KL-6 positive ratio was significantly higher in the patients with NSCLC (n=17) than in those with BLD. There was a significant difference in the KL-6 positive ratio between the patients with NSCLC without ILD and those with BLD without ILD. However, there were no significant differences in the TARC/CCL17 positive ratio between the patients with NSCLC and BLD or between those with NSCLC without ILD and those with BLD without ILD. The TARC/CCL17 positive ratio was significantly higher in the patients with malignancy and ILD than in those without ILD. There was also a significant difference in the TARC/CCL17 positive ratio between the patients with NSCLC without ILD and those with ILD. CONCLUSION: TARC/CCL17 may be useful for the diagnosis of ILD in patients with malignancies. Confirmation of the results is warranted through a large-scale study. PMID- 26124664 TI - Boussignac CPAP system for brain death confirmation with apneic test in case of acute lung injury/adult respiratory distress syndrome - series of cases. AB - INTRODUCTION: There are some patients with severe respiratory disturbances like adult respiratory distress syndrome (ARDS) and suspicion of brain death, for whom typical performance of the apneic test is difficult to complete because of quick desaturation and rapid deterioration without effective ventilation. To avoid failure of brain death confirmation and possible loss of organ donation another approach to apneic test is needed. We present two cases of patients with clinical symptoms of brain death, with lung pathology (acute lung injury, ARDS, lung embolism and lung infection), in whom apneic tests for recognizing brain death were difficult to perform. During typical performance of apneic test involving the use of oxygen catheter for apneic oxygenation we observed severe desaturation with growing hypotension and hemodynamic destabilization. But with the use of Boussignac CPAP system all necessary tests were successfully completed, confirming the patient's brain death, which gave us the opportunity to perform procedures for organ donation. The main reason of apneic test difficulties was severe gas exchange disturbances secondary to ARDS. Thus lack of positive end expiratory pressure during classical performance of apneic test leads to quick desaturation and rapid hemodynamic deterioration, limiting the observation period below dedicated at least 10-minute interval. CONCLUSION: The Boussignac CPAP system may be an effective tool for performing transparent apneic test in case of serious respiratory disturbances, especially in the form of acute lung injury or ARDS. PMID- 26124665 TI - Should We Put Our Feet in the Water? Use of a Survey to Assess Recreational Exposures to Contaminants in the Anacostia River. AB - The Anacostia River, a tributary of the Potomac River that flows into the Chesapeake Bay, is highly contaminated with raw sewage, heavy metals, oil and grease, trash, pathogens, excessive sediments, and organic chemicals. Despite this contamination, recreation on the river is very popular, including kayaking, canoeing, rowing, and sport fishing. There is currently no information available on the potential health risks faced by recreational users from exposure to the river's pollutants. A total of 197 recreational users of the Anacostia River were surveyed regarding general demographic information and their recreational behavior over the previous year, including frequency and duration of recreation and specific questions related to their water exposure. 84.1% of respondents who engaged in canoeing, kayaking, rowing, rafting, or paddling were exposed to water on their bodies during recreation. Some 27.2% of those exposed to water reported getting water in their mouth while recreating, and 60.7% of that group reported swallowing some of this water. This is the first study to examine the exposure to contaminants faced by the recreational population of the Anacostia River. PMID- 26124666 TI - Antischistosomal Activity of Two Active Constituents Isolated from the Leaves of Egyptian Medicinal Plants. AB - In this paper, we investigate the role of two active constituents isolated from the leaves of Egyptian medicinal plants. D-mannitol a naturally occurring sugar isolated from the leaves Ixora undulata Roxb., and the pectin a linear chain homogalacturonan (HG) polysaccharide isolated from the leaves of Linum grandiflorum Desf. (scarlet flax). Both are evaluated for their therapeutic effect against schistosomiasis with biochemical and histochemical evaluations and compared with praziquantel, a reference drug. Biochemical studies of hepatic glucose, the glycogen content, and total serum protein were carried out, and histochemical evaluations through serum protein fractions separated by polyacrylamide gel electrophoresis with different molecular weights (260-10 kDa) were made in all groups, in addition to liver and body weight. D-mannitol and pectin show a remarkable effect in enhancing liver and kidney functions through enhancing most protein fractions in the serum of mice infected with Schistosoma mansoni. Also, the glucose and glycogen content in injured liver tissues improved, in addition liver and body weight in the infected groups. Thus they may be of therapeutic potential in the treatment hepatoxicity and nephrotoxicity. PMID- 26124667 TI - A comparison of the prognostic value of preoperative inflammation-based scores and TNM stage in patients with gastric cancer. AB - BACKGROUND: People's Republic of China is one of the countries with the highest incidence of gastric cancer, accounting for 45% of all new gastric cancer cases in the world. Therefore, strong prognostic markers are critical for the diagnosis and survival of Chinese patients suffering from gastric cancer. Recent studies have begun to unravel the mechanisms linking the host inflammatory response to tumor growth, invasion and metastasis in gastric cancers. Based on this relationship between inflammation and cancer progression, several inflammation based scores have been demonstrated to have prognostic value in many types of malignant solid tumors. OBJECTIVE: To compare the prognostic value of inflammation-based prognostic scores and tumor node metastasis (TNM) stage in patients undergoing gastric cancer resection. METHODS: The inflammation-based prognostic scores were calculated for 207 patients with gastric cancer who underwent surgery. Glasgow prognostic score (GPS), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), prognostic nutritional index (PNI), and prognostic index (PI) were analyzed. Linear trend chi-square test, likelihood ratio chi-square test, and receiver operating characteristic were performed to compare the prognostic value of the selected scores and TNM stage. RESULTS: In univariate analysis, preoperative serum C-reactive protein (P<0.001), serum albumin (P<0.001), GPS (P<0.001), PLR (P=0.002), NLR (P<0.001), PI (P<0.001), PNI (P<0.001), and TNM stage (P<0.001) were significantly associated with both overall survival and disease-free survival of patients with gastric cancer. In multivariate analysis, GPS (P=0.024), NLR (P=0.012), PI (P=0.001), TNM stage (P<0.001), and degree of differentiation (P=0.002) were independent predictors of gastric cancer survival. GPS and TNM stage had a comparable prognostic value and higher linear trend chi-square value, likelihood ratio chi-square value, and larger area under the receiver operating characteristic curve as compared to other inflammation-based prognostic scores. CONCLUSION: The present study indicates that preoperative GPS and TNM stage are robust predictors of gastric cancer survival as compared to NLR, PLR, PI, and PNI in patients undergoing tumor resection. PMID- 26124668 TI - IL-27 rs153109 polymorphism increases the risk of colorectal cancer in Chinese Han population. AB - IL-27, a new member of the IL-12 family, has been found to have antitumor effects in colorectal cancer (CRC); therefore, polymorphisms of this protein may modulate CRC carcinogenesis. So, we studied the association of single nucleotide polymorphisms of the IL-27 gene with the risk of CRC occurrence using a case control using 600 CRC patients and matched healthy controls. The IL-27 rs153109 polymorphism was analyzed with polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Data indicate that GG, GA, and combined A-variant genotypes (GG + GA) conferred significantly greater risk of CRC (P=0.034, 0.002, and 0.001, respectively), and that G alleles were associated with higher susceptibility to CRC (P=0.001). However, no correlation was found between the IL-27 rs153109 polymorphism and particular clinical features. In conclusion, our data demonstrated a clear association of IL-27 rs153109 polymorphism and the risk of CRC development. PMID- 26124669 TI - Axillary and internal mammary sentinel lymph node biopsy in male breast cancer patients: case series and review. AB - Male breast cancer (MBC) is considered as a rare disease that accounts for less than 1% of all breast cancers, and its treatment has been based on the evidence available from female breast cancer. Axillary sentinel lymph node biopsy (SLNB) is now regarded as the standard of care for both female and male patients without clinical and imaging evidence of axillary lymph node metastases, while internal mammary SLNB has rarely been performed. Internal mammary chain metastasis is an independent prognostic predictor. Internal mammary SLNB should be performed to complete nodal staging and guide adjuvant therapy in MBC patients with preoperative lymphoscintigraphic internal mammary chain drainage. We report both axillary and internal mammary SLNB in two cases with MBC. Internal mammary sentinel lymph node did contain metastasis in one case. PMID- 26124670 TI - Detection of epidermal growth factor receptor mutation in lung cancer by droplet digital polymerase chain reaction. AB - BACKGROUND: Two types of epidermal growth factor receptor (EGFR) mutations in exon 19 and exon 21 (ex19del and L858R) are prevalent in lung cancer patients and sensitive to targeted EGFR inhibition. A resistance mutation in exon 20 (T790M) has been found to accompany drug treatment when patients relapse. These three mutations are valuable companion diagnostic biomarkers for guiding personalized treatment. Quantitative polymerase chain reaction (qPCR)-based methods have been widely used in the clinic by physicians to guide treatment decisions. The aim of this study was to evaluate the technical and clinical sensitivity and specificity of the droplet digital polymerase chain reaction (ddPCR) method in detecting the three EGFR mutations in patients with lung cancer. METHODS: Genomic DNA from H1975 and PC-9 cells, as well as 92 normal human blood specimens, was used to determine the technical sensitivity and specificity of the ddPCR assays. Genomic DNA of formalin-fixed, paraffin-embedded specimens from 78 Chinese patients with lung adenocarcinoma were assayed using both qPCR and ddPCR. RESULTS: The three ddPCR assays had a limit of detection of 0.02% and a wide dynamic range from 1 to 20,000 copies measurement. The L858R and ex19del assays had a 0% background level in the technical and clinical settings. The T790M assay appeared to have a 0.03% technical background. The ddPCR assays were robust for correct determination of EGFR mutation status in patients, and the dynamic range appeared to be better than qPCR methods. The ddPCR assay for T790M could detect patient samples that the qPCR method failed to detect. About 49% of this patient cohort had EGFR mutations (L858R, 15.4%; ex19del, 29.5%; T790M, 6.4%). Two patients with the ex19del mutation also had a naive T790M mutation. CONCLUSION: These data suggest that the ddPCR method could be useful in the personalized treatment of patients with lung cancer. PMID- 26124671 TI - Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis. AB - Tumor metastasis is the most common cause of death and poor prognosis for cancer patients. Therapeutics that prevent tumor metastasis are the key to prolonging the lifespan of cancer patients. Cancer stem cells are believed to be critical in the metastatic process. Recently, drug screening for cancer stem cells reports that antipsychotic drugs displayed potential anticancer activity. Thioridazine, one of the antipsychotic drugs for dopamine receptors (DRs), is shown to induce the differentiation of cancer stem cells in leukemic disease and breast cancer, but it is not known if this drug would affect liver cancer. In this study, expression of DR5 was higher in tumors than in nontumor adjacent tissues, while DR1 was lower in human hepatocellular carcinoma (HCC) than those in the adjacent tissues. Other DRs were very low or undetectable. Treatment of HCC cells with thioridazine displays a dose-dependent response in HCC cell lines SNU449, LM3, and Huh7. Thioridazine treatment reduced cell viability and sphere formation of HCC cell lines through induction of G0/G1 cell cycle arrest and suppression of stemness genes CD133, OCT4, and EpCam. It also inhibited cell migration via suppression of epithelial-mesenchymal transition (EMT)-related genes such as twist2 and E-cadherin. Thioridazine-pretreated LM3 cells decreased the capacity of tumorigenesis in nude mice. Taken together, our data suggest that thioridazine may have the potential role in treatment of HCC. PMID- 26124672 TI - Enhanced NK cell adoptive antitumor effects against breast cancer in vitro via blockade of the transforming growth factor-beta signaling pathway. AB - Natural killer (NK) cells have great potential for improving cancer immunotherapy. Adoptive NK cell transfer, an adoptive immunotherapy, represents a promising nontoxic anticancer therapy. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effects in the tumor microenvironment, and the therapeutic activity of adoptive NK cell transfer is not as efficient as anticipated. Transforming growth factor beta (TGF-beta) is a potent immunosuppressant. Genetic and epigenetic events that occur during mammary tumorigenesis circumvent the tumor-suppressing activity of TGF-beta, thereby permitting late-stage breast cancer cells to acquire an invasive and metastatic phenotype in response to TGF-beta. To block the TGF-beta signaling pathway, NK cells were genetically modified with a dominant-negative TGF-beta type II receptor by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK cells were insensitive to TGF beta and resisted the suppressive effect of TGF-beta on MCF-7 breast cancer cells in vitro. Our results demonstrate that blocking the TGF-beta signaling pathway to modulate the tumor microenvironment can improve the antitumor activity of adoptive NK cells in vitro, thereby providing a new rationale for the treatment of breast cancer. PMID- 26124673 TI - Early-switch/early-discharge opportunities for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections: proof of concept in the United Arab Emirates. AB - OBJECTIVES: To describe real-world treatment patterns and health care resource use and to estimate opportunities for early-switch (ES) from intravenous (IV) to oral (PO) antibiotics and early-discharge (ED) for patients hospitalized in the United Arab Emirates (UAE) with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections. METHODS: This retrospective observational medical chart review study enrolled physicians from four UAE sites to collect data for 24 patients with documented MRSA complicated skin and soft tissue infections, hospitalized between July 2010 and June 2011, and discharged alive by July 2011. Data include clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and PO antibiotic use, and ES and ED eligibility using literature-based and expert-validated criteria. RESULTS: Five included patients (20.8%) were switched from IV to PO antibiotics while being inpatients. Actual length of MRSA-active treatment was 10.8+/-7.0 days, with 9.8+/-6.6 days of IV therapy. Patients were hospitalized for a mean 13.9+/-9.3 days. The most frequent initial MRSA-active therapies used were vancomycin (37.5%), linezolid (16.7%), and clindamycin (16.7%). Eight patients were discharged with MRSA-active antibiotics, with linezolid prescribed most frequently (n=3; 37.5%). Fifteen patients (62.5%) met ES criteria and potentially could have discontinued IV therapy 8.3+/-6.0 days sooner, and eight (33.3%) met ED criteria and potentially could have been discharged 10.9+/-5.8 days earlier. CONCLUSION: While approximately one-fifth of patients were switched from IV to PO antibiotics in the UAE, there were clear opportunities for further optimization of health care resource use. Over half of UAE patients hospitalized for MRSA complicated skin and soft tissue infections could be eligible for ES, with one third eligible for ED opportunities, resulting in substantial potential for reductions in IV days and bed days. PMID- 26124675 TI - A survey of French general practitioners on the epidemiology of wounds in family practice. AB - BACKGROUND: To measure the frequency and nature of wounds in patients treated in general practice and to describe the patients' tetanus vaccination status and the sources providing information about this status. METHODS: A descriptive, prospective, week-long, national electronic survey was conducted among general practitioners within the Sentinelles network. RESULTS: The participation rate was 12.6% (95% confidence interval [CI], 10.6%-14.6%; 130 general practitioners): 197 patients with wounds were reported, and 175 of them were described. Wound frequency was 1.4 (95% CI, 1.2-1.6) per 100 consultations. These wounds had an acute character in 76 (95% CI, 69.7-82.3) of cases, were mostly of traumatic origin (54.8% of cases; 95% CI, 47.5%-62.1%), were more than 24 hours old (67.1%; 95% CI, 59.1%-75.1%), and were clean, without bone and/or muscle decay (94%; 95% CI, 90.5%-97.5%). Vaccination status was known for 71 (95% CI, 64-78) patients. According to the 2013 immunization schedule, 21% (95% CI, 13.9%-28.1%) of the patients had not updated their vaccinations, mostly among the patients older than 75 years. CONCLUSION: This survey describes in detail the wounds treated in general practice in France and the associated patients' immunization status. It also shows how difficult it is for general practitioners to assess the risk of contracting tetanus and the disease's development. It highlights as well the fact that the ideal solution to assess tetanus risk is an up-to-date immunization schedule. PMID- 26124676 TI - 2-methoxyestradiol Prevents LNCaP Tumor Development in Nude Mice: Potential Role of G2/M Regulatory Proteins. AB - Nontoxic naturally occurring metabolite of estrogen namely 2-methoxyestradial (2ME2) found in serum and urine has been shown to be antitumorigenic in various tumor models including the prostate. A recent study conducted in breast cancer cells showed growth stimulatory effect of 2ME2 when used at low concentrations (10-750 nM). Studies from our laboratory has demonstrated prostate tumor preventive ability of 50 mg/kg 2-ME2. In this study we show that concentrations of 2-ME2 as low as 1 uM is sufficient to inhibit proliferation and induce apoptosis in androgen responsive LNCaP cells. In addition oral administration of doses lower than 50 mg/kg prevented prostate tumor development in LNCaP xenograft model. The observed tumor growth inhibition was associated with induction of apoptosis, increased expression of Wee1 kinase and p34cdc2. In addition administration of 25 mg/kg 2-ME2 prevented tumor development significantly that is associated with reduction in serum PSA levels. PMID- 26124674 TI - Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome. AB - Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent 1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential. PMID- 26124677 TI - RTKN2 Induces NF-KappaB Dependent Resistance to Intrinsic Apoptosis in HEK Cells and Regulates BCL-2 Genes in Human CD4(+) Lymphocytes. AB - The gene for Rhotekin 2 (RTKN2) was originally identified in a promyelocytic cell line resistant to oxysterol-induced apoptosis. It is differentially expressed in freshly isolated CD4(+) T-cells compared with other hematopoietic cells and is down-regulated following activation of the T-cell receptor. However, very little is known about the function of RTKN2 other than its homology to Rho-GTPase effector, rhotekin, and the possibility that they may have similar roles. Here we show that stable expression of RTKN2 in HEK cells enhanced survival in response to intrinsic apoptotic agents; 25-hydroxy cholesterol and camptothecin, but not the extrinsic agent, TNFalpha. Inhibitors of NF-KappaB, but not MAPK, reversed the resistance and mitochondrial pro-apoptotic genes, Bax and Bim, were down regulated. In these cells, there was no evidence of RTKN2 binding to the GTPases, RhoA or Rac2. Consistent with the role of RTKN2 in HEK over-expressing cells, suppression of RTKN2 in primary human CD4(+) T-cells reduced viability and increased sensitivity to 25-OHC. The expression of the pro-apoptotic genes, Bax and Bim were increased while BCL-2 was decreased. In both cell models RTKN2 played a role in the process of intrinsic apoptosis and this was dependent on either NF-KappaB signaling or expression of downstream BCL-2 genes. As RTKN2 is a highly expressed in CD4(+) T-cells it may play a role as a key signaling switch for regulation of genes involved in T-cell survival. PMID- 26124679 TI - Increased Mitochondrial Activity in Anthrax-Induced Cell Death. AB - Pathogenesis of anthrax lethal toxin (LT) is attributed to its ability to cause death of infected cells. New work has demonstrated that increase of mitochondrial F1F0 ATPase activity and subsequent depletion of cellular ATP level are critical early events during LT-induced cell death. PMID- 26124678 TI - ATP Depletion Via Mitochondrial F1F0 Complex by Lethal Factor is an Early Event in B. Anthracis-Induced Sudden Cell Death. AB - Bacillus anthracis' primary virulence factor is a tripartite anthrax toxin consisting of edema factor (EF), lethal factor (LF) and protective antigen (PA). In complex with PA, EF and LF are internalized via receptor-mediated endocytosis. EF is a calmodulin-dependent adenylate cyclase that induces tissue edema. LF is a zinc-metalloprotease that cleaves members of mitogen-activated protein kinase kinases. Lethal toxin (LT: PA plus LF)-induced death of macrophages is primarily attributed to expression of the sensitive Nalp1b allele, inflammasome formation and activation of caspase-1, but early events that initiate these processes are unknown. Here we provide evidence that an early essential event in pyroptosis of alveolar macrophages is LF-mediated depletion of cellular ATP. The underlying mechanism involves interaction of LF with F1F0-complex gamma and beta subunits leading to increased ATPase activity in mitochondria. In support, mitochondrial DNA-depleted MH-S cells have decreased F1F0 ATPase activity due to the lack of F06 and F08 polypeptides and show increased resistance to LT. We conclude that ATP depletion is an important early event in LT-induced sudden cell death and its prevention increases survival of toxin-sensitive cells. PMID- 26124680 TI - A Novel High-Throughput Technique for Identifying Monoclonal Antibodies Capable of Death Receptor Induced Apoptosis. AB - The study of death receptor family induced apoptosis has gained momentum in recent years with the knowledge that therapeutic antibodies targeting DR4 and DR5 (death receptor's 4 and 5) have proved efficacious in multiple clinical trials. The therapeutic rationale is based on targeting and amplifying a tumour tissues normal cell death programme (apoptosis). While advances in the targeting of DR4 and DR5 have been successful the search for an agonistic antibody to another family member, the Fas receptor, has proven more elusive. This is partly due to the differing in vitro and in vivo characteristics of individual antibodies. In order to induce Fas targeted cell death an antibody must be capable of binding to and trimerising the receptor. It has been shown that antibodies capable of performing this function in vivo, with the assistance of tumour associated cells, do not always induce apoptosis in vitro. As a result the use of current methodologies to detect functional antibodies in vitro may have dismissed potential therapeutic candidates ('false negative'). Here we report a novel high throughput screening technique which artificially cross-links antibodies bound to the Fas receptor. By combining this process with Annexin-V and Prodidium Iodide (PI) staining we can select for antibodies which have the potential to induce apoptosis in vivo. PMID- 26124681 TI - The impact of 5-hydroxytryptamine-receptor antagonists on chemotherapy treatment adherence, treatment delay, and nausea and vomiting. AB - PURPOSE: To determine the incidence of chemotherapy-induced nausea/vomiting (CINV) and chemotherapy treatment delay and adherence among patients receiving palonosetron versus other 5-hydroxytryptamine receptor antagonist (5-HT3 RA) antiemetics. MATERIALS AND METHODS: This retrospective claims analysis included adults with primary malignancies who initiated treatment consisting of single-day intravenous highly emetogenic chemotherapy (HEC) or moderately EC (MEC) regimens. Treatment delay was defined as a gap in treatment at least twice the National Comprehensive Cancer Network-specified cycle length, specific to each chemotherapy regimen. Treatment adherence was determined by the percentage of patients who received the regimen-specific recommended number of chemotherapy cycles within the recommended time frame. RESULTS: We identified 1,832 palonosetron and 2,387 other 5-HT3 RA ("other") patients who initiated HEC therapy, and 1,350 palonosetron users and 1,379 patients on other antiemetics who initiated MEC therapy. Fewer patients receiving palonosetron experienced CINV versus other (HEC, 27.5% versus 32.2%, P=0.0011; MEC, 36.1% versus 41.7%, P=0.0026), and fewer treatment delays occurred among patients receiving palonosetron versus other (HEC, 3.2% versus 6.0%, P<0.0001; MEC, 17.0% versus 26.8%, P<0.0001). Compared with the other cohort, patients receiving palonosetron were significantly more adherent to the index chemotherapy regimen with respect to the recommended time frame (HEC, 74.7% versus 69.7%, P=0.0004; MEC, 43.1% versus 37.3%, P=0.0019) and dosage (HEC, 27.3% versus 25.8%, P=0.0004; MEC, 15.0% versus 12.6%, P=0.0019). CONCLUSION: Palonosetron more effectively reduced occurrence of CINV in patients receiving HEC or MEC compared with other agents in this real-world setting. Additionally, patients receiving palonosetron had better adherence and fewer treatment delays than patients receiving other 5-HT3 RAs. PMID- 26124682 TI - Critical appraisal of paroxetine for the treatment of vasomotor symptoms. AB - BACKGROUND: Vasomotor symptoms (VMS), characterized by hot flashes and night sweats, are the most commonly reported symptoms associated with estrogen deficiency during menopause and occur in up to 70% of women. The goal of treatment is to reduce the frequency and severity of symptoms. Although hormone therapy (HT) is generally recommended as first-line treatment, it is not appropriate for all patients. Antidepressants, specifically selective serotonin reuptake inhibitors, have been evaluated and utilized internationally for alternative treatment for VMS. In 2013, paroxetine mesylate (Brisdelle((r))) received a US Food and Drug Administration-labeled indication for moderate-to severe hot flashes, making it the first nonhormonal treatment for VMS associated with menopause. The objective of this review is to critically evaluate available clinical data regarding the efficacy and safety of paroxetine for the treatment of VMS in menopausal women. METHODS: MEDLINE, PubMed, and Google Scholar were searched using the keywords paroxetine, vasomotor symptoms, hot flashes, and menopause. Searches were limited to humans, English language, and clinical trial design with a primary outcome of hot flash/vasomotor changes. RESULTS: Paroxetine (hydrochloride and mesylate) has been associated with a 33%-67% reduction in hot flash frequency with 6-12 weeks of treatment compared to 13.7%-37.8% reductions with placebo in patients both with and without a history of breast cancer. It was also associated with significant reductions in hot flash severity. Benefits of treatment persisted through 24 weeks in the study of the longest duration. Most adverse effects reported were of mild-to-moderate severity, with improved tolerability associated with lower doses (7.5-12.5 mg/day). CONCLUSION: Paroxetine is a safe and effective therapy for the treatment of VMS during menopause. Paroxetine (7.5-12.5 mg/day) should be considered a first-line therapy option for VMS in patients when HT is either inappropriate or intolerable. PMID- 26124683 TI - Suture locking of isolated internal locking knotless suture anchors is not affected by bone quality. AB - PURPOSE: The purpose of this study was to evaluate the mechanical performance of different suture locking mechanisms including: i) interference fit between the anchor and the bone (eg, 4.5 mm PushLock, 5.5 mm SwiveLock), ii) internal locking mechanism within the anchor itself (eg, 5.5 mm SpeedScrew), or iii) a combination of interference fit and internal locking (eg, 4.5 mm MultiFIX P, 5.5 mm MultiFIX S). METHODS: Anchors were tested in foam blocks representing normal (20/8 foam) or osteopenic (8/8 foam) bone, using standard suture loops pulled in-line with the anchor to isolate suture locking. Mechanical testing included cyclic testing for 500 cycles from 10 N to 60 N at 60 mm/min, followed by failure testing at 60 mm/min. Displacement after 500 cycles at 60 N, number of cycles at 3 mm displacement, load at 3 mm displacement, and maximum load were evaluated. RESULTS: Comparing 8/8 foam to 20/8 foam, load at 3 mm displacement and maximum load were significantly decreased (P<0.05) with decreased bone quality for anchors that, even in part, relied on an interference fit suture locking mechanism (ie, 4.5 mm PushLock, 5.5 mm SwiveLock, 4.5 mm MultiFIX P, 5.5 mm MultiFIX S). Bone quality did not affect the mechanical performance of 5.5 mm SpeedScrew anchors which have an isolated internal locking mechanism. CONCLUSION: The mechanical performance of anchors that relied, even in part, on interference fit were affected by bone quality. Isolated internal locking knotless suture anchors functioned independently of bone quality. Anchors with a combined type (interference fit and internal locking) suture locking mechanism demonstrated similar mechanical performance to isolated internal locking anchors in osteopenic foam comparing similar sized anchors. CLINICAL RELEVANCE: In osteopenic bone, knotless suture anchors that have an internal locking mechanism (isolated or combined type) may be advantageous for secure tendon fixation to bone. PMID- 26124684 TI - Perspectives on differing health outcomes by city: accounting for Glasgow's excess mortality. AB - Several health outcomes (including mortality) and health-related behaviors are known to be worse in Scotland than in comparable areas of Europe and the United Kingdom. Within Scotland, Greater Glasgow (in West Central Scotland) experiences disproportionately poorer outcomes independent of measurable variation in socioeconomic status and other important determinants. Many reasons for this have been proposed, particularly related to deprivation, inequalities, and variation in health behaviors. The use of models (such as the application of Bradford Hill's viewpoints on causality to the different hypotheses) has provided useful insights on potentially causal mechanisms, with health behaviors and inequalities likely to represent the strongest individual candidates. This review describes the evolution of our understanding of Glasgow's excess mortality, summarizes some of the key work in this area, and provides some suggestions for future areas of exploration. In the context of demographic change, the experience in Glasgow is an important example of the complexity that frequently lies behind observed variations in health outcomes within and between populations. A comprehensive explanation of Glasgow's excess mortality may continue to remain elusive, but is likely to lie in a complex and difficult-to-measure interplay of health determinants acting at different levels in society throughout the life course. Lessons learned from the detailed examination of different potentially causative determinants in Scotland may provide useful methodological insights that may be applied in other settings. Ongoing efforts to unravel the causal mechanisms are needed to inform public health efforts to reduce health inequalities and improve outcomes in Scotland. PMID- 26124685 TI - Sleep deprivation does not affect neuronal susceptibility to mild traumatic brain injury in the rat. AB - Mild and moderate traumatic brain injuries (TBIs) (and concussion) occur frequently as a result of falls, automobile accidents, and sporting activities, and are a major cause of acute and chronic disability. Fatigue and excessive sleepiness are associated with increased risk of accidents, but it is unknown whether prior sleep debt also affects the pathophysiological outcome of concussive injury. Using the "dark neuron" (DN) as a marker of reversible neuronal damage, we tested the hypothesis that acute (48 hours) total sleep deprivation (TSD) and chronic sleep restriction (CSR; 10 days, 6-hour sleep/day) affect DN formation following mild TBI in the rat. TSD and CSR were administered using a walking wheel apparatus. Mild TBI was administered under anesthesia using a weight-drop impact model, and the acute neuronal response was observed without recovery. DNs were detected using standard bright-field microscopy with toluidine blue stain following appropriate tissue fixation. DN density was low under home cage and sleep deprivation control conditions (respective median DN densities, 0.14% and 0.22% of neurons), and this was unaffected by TSD alone (0.1%). Mild TBI caused significantly higher DN densities (0.76%), and this was unchanged by preexisting acute or chronic sleep debt (TSD, 0.23%; CSR, 0.7%). Thus, although sleep debt may be predicted to increase the incidence of concussive injury, the present data suggest that sleep debt does not exacerbate the resulting neuronal damage. PMID- 26124686 TI - Eye Injuries Among Primary School Children in Enugu, Nigeria: Rural vs Urban. AB - A cross-sectional survey of the prevalence of eye injuries among primary school children in two noncontiguous local government areas of Enugu State of Nigeria was undertaken. One of the local government areas was urban, while the other one was rural. Children who were <15 years in two randomly selected primary schools in the urban area and three randomly selected schools in the rural area were interviewed and examined with Snellen chart, pen torch, head loupe, and direct ophthalmoscope. The findings were recorded using a semi-structured questionnaire and the World Health Organization Programme for Prevention of Blindness (WHO/PBL) eye examination form. Training on visual acuity measurement was done for each of the class teachers. A total of 1,236 children <15 years of age were studied and analyzed. Slightly more females, 652 (52.8%), than males, 584 (47.2%), constituted the sample population giving a female/male ratio of 1.1:1. A total of 98 (7.93%) children had evidence of injury to the eye or its adnexa. Eyelid scar was the commonest (5.34%) followed by eyebrow scar (2.10%). Canthal scar was the next (0.32%). Two girls had monocular blindness from eye trauma (0.16%). One had leucoma, while the other had a dislocated lens. All the monocular blind children of this study were from the urban area. The home was the commonest environment for an eye injury (69.39%) followed by the school (20.41%). The farm was next in frequency (7.14%), especially among boys in the rural area. The church and the road/street constituted the remainder. Regarding persons causing the injury, the child's playmate was the commonest (55.10%) followed by self (27.55%). Parents and guardians were the next (9.18%). These were injuries associated with corporal punishment. Corporal punishment-related eye injury, according to this study, appears to be common in the rural area and affects boys predominantly. Other human intermediary agents that cause an eye injury include passersby (2.04%), RTA (2.04%), siblings (2.04%), and others (1.02%). The primary agents that caused an eye injury were sticks/wood, 29 (29.60%); stone, 21 (21.43%); pieces of metal, 19 (19.39%); fall, 10 (10.20%); fight/fist blow, 9 (9.918%); plastic, 2 (2.04%); fingernails, 2 (2.04%); farm tools/fruits, 2 (2.04%); and RTA, glass, and headbutt, each 1.02%. Farm implements/fruits as well as fingernails appear to be fairly common primary agents that cause an eye injury in the rural Enugu, Nigeria. In terms of prevalence, there was no significant difference between the urban and rural areas. The findings from this study showed a high prevalence of eye injury among primary school children. In terms of treatment, 58.16% of the children with an eye injury had no form of treatment for it. The children from this study with monocular blindness did not receive adequate medical treatment. Treatment of an eye injury, according to this study, was sought from chemists (19.39%), at hospital/health centers (16.33%), at home (3.06%), and from traditional healers (3.06%). The persons who treated an eye injury, as observed from this study, were doctors (14.29%), nurses (4.08%), chemists (17.35%), and traditional healers and fathers (3.06% each). The frequency of noninjury-related diagnosis made in this study was refractive error, 4.85%; allergic conjunctivitis, 1.94%; oculocutaneous albinism, 0.24%; prepapillary vascular loops, 0.40%; and then ptosis, exotropia, stye, corneal opacity, and retinitis pigmentosa, 0.08% each. The annual incidence of an eye injury according to this study was 3.48%. The majority of the causes of an eye injury, as per this study, were preventable. Appropriate promotion of preventive eye care among children may go a long way in reducing the burden of blindness from eye injuries. PMID- 26124687 TI - Issues in assessing products for the treatment of hemophilia - the intersection between efficacy, economics, and ethics. AB - Following the obviation of the pathogen safety threats posed by previous generations of clotting factor concentrates for the treatment of hemophilia, the principal issue facing the patient community is timely access to adequate supplies of continuously improving therapies. The application of evidence-based medicine has enhanced the basis of hemophilia therapy, while resulting in some challenges to patient care. Increasingly, the criteria used for the approval and payment of treatment products by regulatory and reimbursement agencies, respectively, are becoming inflexible and unrealistic. This is occurring particularly in the requirements for demonstrating product efficacy. Concurrently, emerging evidence of the interpatient variability in the clinical response to therapy has led to the proposed personalization of therapeutic regimens. Possible impediments to optimal care include competitive tensions among suppliers who seek to gain label claims for reimbursement purposes, which result in clinical trial designs of, arguably, unethical design, carried out in poor countries. We synthesize these converging developments to suggest some changes to the current hemophilia treatment paradigm, which should make it more patient centric and enable speedier access to new therapies. PMID- 26124688 TI - Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions. AB - Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence. PMID- 26124689 TI - Factors that influence the preventive care offered to adolescents accessing Public Oral Health Services, NSW, Australia. AB - BACKGROUND: Many adolescents are at risk of dental caries and periodontal disease, which may be controlled through health education and clinical preventive interventions provided by oral health and dental therapists (therapists). Senior clinicians (SCs) can influence the focus of dental care in the New South Wales (NSW) Public Oral Health Services as their role is to provide clinical support and advice to therapists, advocate for their communities, and inform Local Health District (LHD) managers of areas for clinical quality improvement. The objective of this study was to record facilitating factors and strategies that are used by SCs to encourage therapists to provide preventive care and advice to adolescent patients. METHODS: In-depth, semistructured interviews were undertaken with 16 SCs from all of the 15 NSW LHDs (nine rural and six metropolitan). A framework matrix was used to systematically code data and enable key themes to be identified for analysis. RESULTS: All SCs from the 15 NSW Health LHDs participated in the study. Factors influencing SCs' ability to integrate preventive care into clinical practice were: 1) clinical leadership and administrative support, 2) professional support network, 3) clinical and educational resources, 4) the clinician's patient management aptitude, and 5) clinical governance processes. Clinical quality improvement and continuing professional development strategies equipped clinicians to manage and enhance adolescents' confidence toward self-care. CONCLUSION: This study shows that SCs have a clear understanding of strategies to enhance the therapist's offer of scientific-based preventive care to adolescents. The problem they face is that currently, success is measured in terms of relief of pain activities, restorations placed, and extraction of teeth, which is an outdated concept. However, to improve clinical models of care will require the overarching administrative authority, NSW Health, to accept that the scientific evidence relating to dental care has changed and that management monitoring information should be incorporated into NSW Health reforms. PMID- 26124690 TI - Promoting family meals: a review of existing interventions and opportunities for future research. AB - Evidence suggests that regular family meals protect against unhealthy eating and obesity during childhood and adolescence. However, there is limited information on ways to promote family meals as part of health promotion and obesity prevention efforts. The primary aim of this review was to synthesize the literature on strategies to promote family meals among families with school-aged children and adolescents. First, we reviewed interventions that assess family meals as an outcome and summarized strategies that have been used in these interventions. Second, we reviewed correlates and barriers to family meals to identify focal populations and target constructs for consideration in new interventions. During May 26-27, 2014, PubMed and PsycInfo databases were searched to identify literature on family meals published between January 1, 2000 and May 27, 2014. Two reviewers coded 2,115 titles/abstracts, yielding a sample of 139 articles for full-text review. Six interventions and 43 other studies presenting data on correlates of or barriers to family meals were included in the review. Four interventions resulted in greater family meal frequency. Although there were a small number of interventions, intervention settings were diverse and included the home, community, medical settings, the workplace, and the Internet. Common strategies were goal setting and interactive group activities, and intervention targets included cooking and food preparation, cost, shopping, and adolescent influence. Although methodological nuances may contribute to mixed findings, key correlates of family meals were employment, socioeconomic and demographic factors, family structure, and psychosocial constructs. Barriers to consider in future interventions include time and scheduling challenges, cost, and food preferences. Increasing youth involvement in mealtime, tailoring interventions to family characteristics, and providing support for families experiencing time-related barriers are suggested strategies for future research. PMID- 26124691 TI - Left Ventricle-Arterial System Interaction in Heart Failure. AB - Ejection fraction (EF) has been viewed as an important index in assessing the contractile state of the left ventricle (LV). However, it is frequently inadequate for the diagnosis and management of heart failure (HF), as a significant subset of HF patients have been found to have reduced EF (HFrEF) whereas others have preserved EF (HFpEF). It should be noted that the function of the LV is dependent on both preload and afterload, as well as its intrinsic contractile state. Furthermore, stroke volume (SV) is dependent on the properties of the arterial system (AS). Thus, the LV-arterial system interaction plays an important role in those patients with HF. This aspect is investigated through the analysis of the specific parameters involved in the coupling of the LV and AS. This includes contractility and the systolic/diastolic indices of the LV. Furthermore, AS afterload parameters such as vascular stiffness and arterial compliance, and their derived coupling coefficient, are also investigated. We conclude that those parameters, which relate to LV structural changes, are most appropriate in quantifying the LV-AS interaction. PMID- 26124692 TI - Pulmonary Hypertension an Independent Risk Factor for Death in Intensive Care Unit: Correlation of Hemodynamic Factors with Mortality. AB - OBJECTIVE: Critically ill patients with pulmonary hypertension (PH) pose additional challenges due to the existence of right ventricular (RV) dysfunction. The purpose of this study was to assess the impact of hemodynamic factors on the outcome. METHODS: We reviewed the records of patients with a diagnosis of PH admitted to the intensive care unit. In addition to evaluating traditional hemodynamic parameters, we defined severe PH as right atrial pressure >20 mmHg, mean pulmonary artery pressure >55 mmHg, or cardiac index (CI) <2 L/min/m(2). We also defined the RV functional index (RFI) as pulmonary artery systolic pressure (PASP) adjusted for CI as PASP/CI; increasing values reflect RV dysfunction. RESULTS: Fifty-three patients (mean age 60 years, 72% women, 79% Blacks), were included in the study. Severe PH was present in 68% of patients who had higher Sequential Organ Failure Assessment (SOFA) score (6.8 +/- 3.3 vs 3.8 +/- 1.6; P = 0.001) and overall in-hospital mortality (36% vs 6%; P = 0.02) compared to nonsevere patients, although Acute Physiology and Chronic Health Evaluation (APACHE) II scores (19.9 +/- 7.5 vs 18.5 +/- 6.04; P = 0.52) were similar and sepsis was more frequent among nonsevere PH patients (31 vs 64%; P = 0.02). Severe PH (P = 0.04), lower mean arterial pressure (P = 0.04), and CI (P = 0.01); need for invasive ventilation (P = 0.02) and vasopressors (P = 0.03); and higher SOFA (P = 0.001), APACHE II (P = 0.03), pulmonary vascular resistance index (PVRI) (P = 0.01), and RFI (P = 0.004) were associated with increased mortality. In a multivariate model, SOFA [OR = 1.45, 95% confidence interval (C.I.) = 1.09 1.93; P = 0.01], PVRI (OR = 1.12, 95% C.I. = 1.02-1.24; P = 0.02), and increasing RFI (OR = 1.06, 95% C.I. = 1.01-1.11; P = 0.01) were independently associated with mortality. CONCLUSION: PH is an independent risk factor for mortality in critically ill patients. Composite factors rather than individual hemodynamic parameters are better predictors of outcome. Monitoring of RV function using composite hemodynamic factors resulting in specific interventions is likely to improve survival and needs to be studied further. PMID- 26124694 TI - Comment on "Safety and Tolerance Evaluation of Milk Fat Globule Membrane-Enriched Infant Formulas: A Randomized Controlled Multicenter Non-Inferiority Trial in Healthy Term Infants". PMID- 26124693 TI - The Relationship between Stapes Prosthesis Length and Rate of Stapedectomy Success. AB - OBJECTIVES: To identify whether measurement of the prosthesis length is mandatory in patients requiring otosclerosis surgeries and to assess their postoperative audiometric outcomes. In addition, evaluation of prosthesis length used in revision compared to primary stapedectomy was carried out. STUDY DESIGN: Case series with chart review. METHODS: Chart review of 393 patients undergoing primary (321) versus revision stapedectomy (72) was performed in a tertiary referral center. The indication for surgery was the presence or persistence/recurrence of an air-bone gap (ABG) greater than 20 dB. Air and bone conduction thresholds (ACT and BCT, respectively), ABG as well as pure tone averages (PTAs) were determined for all patients, and the results were compared preoperatively and postoperatively. RESULTS: Prosthesis length used ranged from 3.0 to 6.0 mm without differences between primary and revision groups. Of the revision surgeries, 62.5% were stapedectomies versus stapedotomies (P < 0.001). Patients showed significant decrease in speech discrimination score, with increased air and bone conduction thresholds as well as mean ABG and PTA before the revision surgeries as a first procedure failure. Prosthesis length changes occurred in 73.5% of the cases, with an average absolute change of 0.55 mm. Prosthesis length did not affect postoperative audiometric results between primary and revision groups, in all surgeries combined. When grouping stapes surgery into accurately versus inaccurately measured incus-footplate distance, significant differences were observed in prosthesis length employed (P < 0.01). Hearing outcomes were also better in the group in which an accurately measured prosthesis was chosen, as opposed to "standard-length" prosthesis. CONCLUSIONS: This study corroborates postoperative success rates of revision surgeries, which show smaller improvements in hearing compared to a primary intervention. Accurate intra-operative measurement of prosthesis length was correlated with better audiometric results postoperatively. PMID- 26124695 TI - Presentation of a Clitoral Mass in a Prepubescent Female: A Case Report and Discussion of the Evaluation. AB - Clitoral masses are rare. We present a case report of a prepubescent female with a periclitoral mass. PMID- 26124696 TI - Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence. AB - BACKGROUND: Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. AIM: To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. METHODS: We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. RESULTS: MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder. CONCLUSION: Clinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research. PMID- 26124698 TI - Stromal-epithelial responses to fractionated radiotherapy in a breast cancer microenvironment. AB - BACKGROUND: The stromal-epithelial-cell interactions that are responsible for directing normal breast-tissue development and maintenance play a central role in the progression of breast cancer. In the present study, we continued our development of three-dimensional (3-D) cell co-cultures used to study cancerous mammary cell responses to fractionated radiotherapy. In particular, we focused on the role of the reactive stroma in determining the therapeutic ratio for post surgical treatment. METHODS: Cancerous human mammary epithelial cells (MRC-7) were cultured in a 3-D collagen matrix with human fibroblasts (MRC-5) stimulated by various concentrations of transforming growth factor beta 1 (TGF-beta1). These culture samples were designed to model the post-lumpectomy mammary stroma in the presence of residual cancer cells. We tracked over time the changes in medium stiffness, fibroblast-cell activation (MRC-5 converted to cancer activated fibroblasts (CAFs)), and proliferation of both cell types under a variety of fractionated radiotherapy protocols. Samples were exposed to 6 MV X-rays from a linear accelerator in daily fraction sizes of 90, 180 and 360 cGy over five days in a manner consistent with irradiation exposure during radiotherapy. RESULTS: We found in fractionation studies with MRC-5 fibroblasts and CAFs that higher doses per fraction may be more effective early on in deactivating cancer-harboring cellular environments. Higher-dose fraction schemes inhibit contractility in CAFs and prevent differentiation of fibroblasts, thereby metabolically uncoupling tumor cells from their surrounding stroma. However, higher dose fraction appears to increase ECM stiffening. CONCLUSIONS: The findings suggest that dose escalation to the region with residual disease can deactivate the reactive stroma, thus minimizing the cancer promoting features of the cellular environment. Large-fraction irradiation may be used to sterilize residual tumor cells and inhibit activation of intracellular transduction pathways that are promoted during the post-surgical wound-healing period. The higher dose fractions may slow wound healing and increase ECM stiffening that could stimulate proliferation of surviving cancer cells. PMID- 26124697 TI - The potential role of COX-2 in cancer stem cell-mediated canine mammary tumor initiation: an immunohistochemical study. AB - Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs. PMID- 26124699 TI - Implementation of non-vitamin K antagonist oral anticoagulants in daily practice: the need for comprehensive education for professionals and patients. AB - Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for the prevention and treatment of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. NOACs do not require routine coagulation monitoring, creating a challenge to established systems for patient follow-up based on regular blood tests. Healthcare professionals (HCPs) are required to cope with a mixture of patients receiving either a vitamin K antagonist or a NOAC for the same indications, and both professionals and patients require education about the newer drugs. A European working group convened to consider the challenges facing HCPs and healthcare systems in different countries and the educational gaps that hinder optimal patient management. Group members emphasised the need for regular follow-up and noted national, regional and local variations in set-up and resources for follow-up. Practical incorporation of NOACs into healthcare systems must adapt to these differences, and practical follow-up that works in some systems may not be able to be implemented in others. The initial prescriber of a NOAC should preferably be a true anticoagulation specialist, who can provide initial patient education and coordinate the follow-up. The long-term follow-up care of patients can be managed through specialist coagulation nurses, in a dedicated anticoagulation clinic or by general practitioners trained in NOAC use. The initial prescriber should be involved in educating those who perform the follow-up. Specialist nurses require access to tools, potentially including specific software, to guide systematic patient assessment and workflow. Problem cases should be referred for specialist advice, whereas in cases for which minimal specialist attention is required, the general practitioner could take responsibility for patient follow-up. Hospital departments and anticoagulation clinics should proactively engage with all downstream HCPs (including pharmacists) to ensure their participation in patient management and reinforcement of patient education at every opportunity. Ideally, (transmural) protocols for emergency situations should be developed. Last but not least, patients should be well-informed about their condition, the treatment, possible risk scenarios, including the consequences of non-adherence to prescribed therapy, and the organisation of follow-up care. PMID- 26124700 TI - Cost-utility analysis of certolizumab pegol versus alternative tumour necrosis factor inhibitors available for the treatment of moderate-to-severe active rheumatoid arthritis in Spain. AB - BACKGROUND: Certolizumab pegol, a PEGylated tumour necrosis factor (TNF) inhibitor, improves the clinical signs and symptoms of rheumatoid arthritis (RA) when used in combination with methotrexate or as monotherapy. This study evaluatedthe cost-utility of certolizumab pegol versusTNF-inhibitors plus methotrexate in the treatment of moderate-to-severe RA in Spain. METHODS: A Markov cohort health state transition model was developed to evaluate the cost utility (costs and quality-adjusted life years [QALYs]) of certolizumab pegol versus other TNF-inhibitors licensed in Spain in 2009. Efficacy was measured using the American College of Rheumatology (ACR) responses at 6 months, based on adjusted indirect comparisons from published clinical trials. Utilities were derived from EQ-5D data from certolizumab pegol RA clinical trials. Clinical history and resource use data came from published literature. Unit costs were taken from Spanish databases or published data (cost year 2009). Base case analyses were conducted from the payer perspective, with a lifetime horizon, 3.5 % annual discounting rates for costs and outcomes, and 3 % inflation rate for 2009 onwards. One-way sensitivity analyses were conducted. RESULTS: The average lifetime costs for certolizumab pegol, etanercept, adalimumab (every 2 weeks and weekly) and infliximab (3 mg/kg and 5 mg/kg) in combination with methotrexate were ?140,971, ?141,197, ?139,148, ?164,741, ?136,961 and ?152,561, respectively. The QALYs gained were 6.578, 6.462, 6.430 (for both adalimumab doses), 6.430, and 6.318 (for both infliximab doses), respectively. At a ?30,000/QALY willingness-to pay threshold, certolizumab pegol plus methotrexate dominated adalimumab weekly, etanercept, and infliximab 5 mg/kg, and was cost-effective versus adalimumab every 2 weeks and infliximab 3 mg/kg (all with methotrexate), with estimated ICERs of ?12,346/QALY and ?15,414/QALY, respectively. Certolizumab pegol monotherapy was more cost-effective versus adalimumab, and less expensive with similar health gains versus etanercept (6.416 QALYs vs 6.492). Univariate analysis showed ICERs to be sensitive to changes in time horizon, ACR response time point, baseline Heath Assessment Questionnaire (HAQ) score, and rate of HAQ disability index deterioration after discontinuing treatment. CONCLUSIONS: This analysis shows that certolizumab pegol is cost-effective compared with other TNF inhibitors recommended in Spain for the treatment of RA. PMID- 26124701 TI - Testosterone is associated with cooperation during intergroup competition by enhancing parochial altruism. AB - The steroid hormone testosterone is widely associated with negative behavioral effects, such as aggression or dominance. However, recent studies applying economic exchange tasks revealed conflicting results. While some point to a prosocial effect of testosterone by increasing altruistic behavior, others report that testosterone promotes antisocial tendencies. Taking into account additional factors such as parochial altruism (i.e., ingroup favoritism and outgroup hostility) might help to explain this contradiction. First evidence for a link between testosterone and parochial altruism comes from recently reported data of male soccer fans playing the ultimatum game. In this study high levels of endogenous testosterone predicted increased altruistic punishment during outgroup interactions and at the same time heightened ingroup generosity. Here, we report findings of another experimental task, the prisoner's dilemma, applied in the same context to examine the role of testosterone on parochial tendencies in terms of cooperation. In this task, 50 male soccer fans were asked to decide whether or not they wanted to cooperate with partners marked as either fans of the subject's own favorite team (ingroup) or fans of other teams (outgroups). Our results show that high testosterone levels were associated with increased ingroup cooperation during intergroup competition. In addition, subjects displaying a high degree of parochialism during intergroup competition had significantly higher levels of testosterone than subjects who did not differentiate much between the different groups. In sum, the present data demonstrate that the behavioral effects of testosterone are not limited to aggressive and selfish tendencies but may imply prosocial aspects depending on the context. By this means, our results support the previously reported findings on testosterone-dependent intergroup bias and indicate that this social hormone might be an important factor driving parochial altruism. PMID- 26124702 TI - Brain-to-text: decoding spoken phrases from phone representations in the brain. AB - It has long been speculated whether communication between humans and machines based on natural speech related cortical activity is possible. Over the past decade, studies have suggested that it is feasible to recognize isolated aspects of speech from neural signals, such as auditory features, phones or one of a few isolated words. However, until now it remained an unsolved challenge to decode continuously spoken speech from the neural substrate associated with speech and language processing. Here, we show for the first time that continuously spoken speech can be decoded into the expressed words from intracranial electrocorticographic (ECoG) recordings.Specifically, we implemented a system, which we call Brain-To-Text that models single phones, employs techniques from automatic speech recognition (ASR), and thereby transforms brain activity while speaking into the corresponding textual representation. Our results demonstrate that our system can achieve word error rates as low as 25% and phone error rates below 50%. Additionally, our approach contributes to the current understanding of the neural basis of continuous speech production by identifying those cortical regions that hold substantial information about individual phones. In conclusion, the Brain-To-Text system described in this paper represents an important step toward human-machine communication based on imagined speech. PMID- 26124703 TI - The role of the ubiquitin-editing enzyme A20 in diseases of the central nervous system and other pathological processes. AB - In recent years, the ubiquitin-editing enzyme A20 has been shown to control a large set of molecular pathways involved in the regulation of protective as well as self-directed immune responses. Here, we assess the current and putative roles of A20 in inflammatory, vascular and degenerative diseases of the central nervous system and explore future directions of research. PMID- 26124704 TI - Wnt-related SynGAP1 is a neuroprotective factor of glutamatergic synapses against Abeta oligomers. AB - Wnt-5a is a synaptogenic factor that modulates glutamatergic synapses and generates neuroprotection against Abeta oligomers. It is known that Wnt-5a plays a key role in the adult nervous system and synaptic plasticity. Emerging evidence indicates that miRNAs are actively involved in the regulation of synaptic plasticity. Recently, we showed that Wnt-5a is able to control the expression of several miRNAs including miR-101b, which has been extensively studied in carcinogenesis. However, its role in brain is just beginning to be explored. That is why we aim to study the relationship between Wnt-5a and miRNAs in glutamatergic synapses. We performed in silico analysis which predicted that miR 101b may inhibit the expression of synaptic GTPase-Activating Protein (SynGAP1), a Ras GTPase-activating protein critical for the development of cognition and proper synaptic function. Through overexpression of miR-101b, we showed that miR 101b is able to regulate the expression of SynGAP1 in an hippocampal cell line. Moreover and consistent with a decrease of miR-101b, Wnt-5a enhances SynGAP expression in cultured hippocampal neurons. Additionally, Wnt-5a increases the activity of SynGAP in a time-dependent manner, with a similar kinetic to CaMKII phosphorylation. This also, correlates with a modulation in the SynGAP clusters density. On the other hand, Abeta oligomers permanently decrease the number of SynGAP clusters. Interestingly, when neurons are co-incubated with Wnt-5a and Abeta oligomers, we do not observe the detrimental effect of Abeta oligomers, indicating that, Wnt-5a protects neurons from the synaptic failure triggered by Abeta oligomers. Overall, our findings suggest that SynGAP1 is part of the signaling pathways induced by Wnt-5a. Therefore, possibility exists that SynGAP is involved in the synaptic protection against Abeta oligomers. PMID- 26124705 TI - Impact of electromagnetic fields on stem cells: common mechanisms at the crossroad between adult neurogenesis and osteogenesis. AB - In the recent years adult neural and mesenchymal stem cells have been intensively investigated as effective resources for repair therapies. In vivo and in vitro studies have provided insights on the molecular mechanisms underlying the neurogenic and osteogenic processes in adulthood. This knowledge appears fundamental for the development of targeted strategies to manipulate stem cells. Here we review recent literature dealing with the effects of electromagnetic fields on stem cell biology that lends support to their use as a promising tool to positively influence the different steps of neurogenic and osteogenic processes. We will focus on recent studies revealing that extremely-low frequency electromagnetic fields enhance adult hippocampal neurogenesis by inducing epigenetic modifications on the regulatory sequences of genes responsible for neural stem cell proliferation and neuronal differentiation. In light of the emerging critical role played by chromatin modifications in maintaining the stemness as well as in regulating stem cell differentiation, we will also attempt to exploit epigenetic changes that can represent common targets for electromagnetic field effects on neurogenic and osteogenic processes. PMID- 26124706 TI - Functional expression of bradykinin B1 and B2 receptors in neonatal rat trigeminal ganglion neurons. AB - Bradykinin (BK) and its receptors (B1 and B2 receptors) play important roles in inflammatory nociception. However, the patterns of expression and physiological/pathological functions of B1 and B2 receptors in trigeminal ganglion (TG) neurons remain to be fully elucidated. We investigated the functional expression of BK receptors in rat TG neurons. We observed intense immunoreactivity of B2 receptors in TG neurons, while B1 receptors showed weak immunoreactivity. Expression of the B2 receptor colocalized with immunoreactivities against the pan-neuronal marker, neurofilament H, substance P, isolectin B4, and tropomyosin receptor kinase A antibodies. Both in the presence and absence of extracellular Ca(2+) ([Ca(2+)]o), BK application increased the concentration of intracellular free Ca(2+) ([Ca(2+)]i). The amplitudes of BK induced [Ca(2+)]i increase in the absence of [Ca(2+)]o were significantly smaller than those in the presence of Ca(2+). In the absence of [Ca(2+)]o, BK-induced [Ca(2+)]i increases were sensitive to B2 receptor antagonists, but not to a B1 receptor antagonist. However, B1 receptor agonist, Lys-[Des-Arg(9)]BK, transiently increased [Ca(2+)]i in primary cultured TG neurons, and these increases were sensitive to a B1 receptor antagonist in the presence of [Ca(2+)]o. These results indicated that B2 receptors were constitutively expressed and their activation induced the mobilization of [Ca(2+)]i from intracellular stores with partial Ca(2+) influx by BK. Although constitutive B1 receptor expression could not be clearly observed immunohistochemically in the TG cryosection, cultured TG neurons functionally expressed B1 receptors, suggesting that both B1 and B2 receptors involve pathological and physiological nociceptive functions. PMID- 26124707 TI - Neuronal response impedance mechanism implementing cooperative networks with low firing rates and MUs precision. AB - Realizations of low firing rates in neural networks usually require globally balanced distributions among excitatory and inhibitory links, while feasibility of temporal coding is limited by neuronal millisecond precision. We show that cooperation, governing global network features, emerges through nodal properties, as opposed to link distributions. Using in vitro and in vivo experiments we demonstrate microsecond precision of neuronal response timings under low stimulation frequencies, whereas moderate frequencies result in a chaotic neuronal phase characterized by degraded precision. Above a critical stimulation frequency, which varies among neurons, response failures were found to emerge stochastically such that the neuron functions as a low pass filter, saturating the average inter-spike-interval. This intrinsic neuronal response impedance mechanism leads to cooperation on a network level, such that firing rates are suppressed toward the lowest neuronal critical frequency simultaneously with neuronal microsecond precision. Our findings open up opportunities of controlling global features of network dynamics through few nodes with extreme properties. PMID- 26124709 TI - Neuroanatomical association of hypothalamic HSD2-containing neurons with ERalpha, catecholamines, or oxytocin: implications for feeding? AB - This study used immunohistochemical methods to investigate the possibility that hypothalamic neurons that contain 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2) are involved in the control of feeding by rats via neuroanatomical associations with the alpha subtype of estrogen receptor (ERalpha), catecholamines, and/or oxytocin (OT). An aggregate of HSD2-containing neurons is located laterally in the hypothalamus, and the numbers of these neurons were greatly increased by estradiol treatment in ovariectomized (OVX) rats compared to numbers in male rats and in OVX rats that were not given estradiol. However, HSD2 containing neurons were anatomically segregated from ERalpha-containing neurons in the Ventromedial Hypothalamus and the Arcuate Nucleus. There was an absence of OT-immunolabeled fibers in the area of HSD2-labeled neurons. Taken together, these findings provide no support for direct associations between hypothalamic HSD2 and ERalpha or OT neurons in the control of feeding. In contrast, there was catecholamine-fiber labeling in the area of HSD2-labeled neurons, and these fibers occasionally were in close apposition to HSD2-labeled neurons. Therefore, we cannot rule out interactions between HSD2 and catecholamines in the control of feeding; however, given the relative sparseness of the appositions, any such interaction would appear to be modest. Thus, these studies do not conclusively identify a neuroanatomical substrate by which HSD2-containing neurons in the hypothalamus may alter feeding, and leave the functional role of hypothalamic HSD2-containing neurons subject to further investigation. PMID- 26124710 TI - Characterizing the therapeutic response to deep brain stimulation for treatment resistant depression: a single center long-term perspective. AB - The number of depressed patients treated with deep brain stimulation (DBS) is relatively small. However, experience with this intervention now spans more than 10 years at some centers, with study subjects typically monitored closely. Here we describe one center's evolving impressions regarding optimal patient selection for DBS of the subcallosal cingulate (SCC) as well as observations of short- and long-term patterns in antidepressant response and mood reactivity. A consistent time course of therapeutic response with distinct behavioral phases is observed. Early phases are characterized by changes in mood reactivity and a transient and predictable worsening in self ratings prior to stabilization of response. It is hypothesized that this characteristic recovery curve reflects the timeline of neuroplasticity in response to DBS. Further investigation of these emerging predictable psychiatric, biological, and psychosocial patterns will both improve treatment optimization and enhance understanding and recognition of meaningful DBS antidepressant effects. PMID- 26124708 TI - Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry. AB - The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact ("liking") and motivational incentive salience ("wanting") of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including "liking" and "wanting" for food rewards. PMID- 26124711 TI - A time estimation task as a possible measure of emotions: difference depending on the nature of the stimulus used. AB - OBJECTIVE: Time perception is fundamental for human experience. A topic which has attracted the attention of researchers for long time is how the stimulus sensory modality (e.g., images vs. sounds) affects time judgments. However, so far, no study has directly compared the effect of two sensory modalities using emotional stimuli on time judgments. METHODS: In the present two studies, healthy participants were asked to estimate the duration of a pure sound preceded by the presentation of odors vs. emotional videos as priming stimuli (implicit emotion eliciting task). During the task, skin conductance (SC) was measured as an index of arousal. RESULTS: Olfactory stimuli resulted in an increase in SC and in a constant time overestimation. Video stimuli resulted in an increase in SC (emotional arousal), which decreased linearly overtime. Critically, video stimuli resulted in an initial time underestimation, which shifted progressively towards a time overestimation. These results suggest that video stimuli recruited both arousal-related and attention-related mechanisms, and that the role played by these mechanisms changed overtime. CONCLUSIONS: These pilot studies highlight the importance of comparing the effect of different kinds on temporal estimation tasks, and suggests that odors are well suited to investigate arousal-related temporal distortions, while videos are ideal to investigate both arousal-related and attention-related mechanisms. PMID- 26124712 TI - Childhood Poverty Predicts Adult Amygdala and Frontal Activity and Connectivity in Response to Emotional Faces. AB - Childhood poverty negatively impacts physical and mental health in adulthood. Altered brain development in response to social and environmental factors associated with poverty likely contributes to this effect, engendering maladaptive patterns of social attribution and/or elevated physiological stress. In this fMRI study, we examined the association between childhood poverty and neural processing of social signals (i.e., emotional faces) in adulthood. Fifty two subjects from a longitudinal prospective study recruited as children, participated in a brain imaging study at 23-25 years of age using the Emotional Faces Assessment Task. Childhood poverty, independent of concurrent adult income, was associated with higher amygdala and medial prefrontal cortical (mPFC) responses to threat vs. happy faces. Also, childhood poverty was associated with decreased functional connectivity between left amygdala and mPFC. This study is unique, because it prospectively links childhood poverty to emotional processing during adulthood, suggesting a candidate neural mechanism for negative social emotional bias. Adults who grew up poor appear to be more sensitive to social threat cues and less sensitive to positive social cues. PMID- 26124713 TI - Benefits of listening to a recording of euphoric joint music making in polydrug abusers. AB - BACKGROUND AND AIMS: Listening to music can have powerful physiological and therapeutic effects. Some essential features of the mental mechanism underlying beneficial effects of music are probably strong physiological and emotional associations with music created during the act of music making. Here we tested this hypothesis in a clinical population of polydrug abusers in rehabilitation listening to a previously performed act of physiologically and emotionally intense music making. METHODS: Psychological effects of listening to self-made music that was created in a previous musical feedback intervention were assessed. In this procedure, participants produced music with exercise machines (Jymmin) which modulate musical sounds. RESULTS: The data showed a positive effect of listening to the recording of joint music making on self-efficacy, mood, and a readiness to engage socially. Furthermore, the data showed the powerful influence of context on how the recording evoked psychological benefits. The effects of listening to the self-made music were only observable when participants listened to their own performance first; listening to a control music piece first caused effects to deteriorate. We observed a positive correlation between participants' mood and their desire to engage in social activities with their former training partners after listening to the self-made music. This shows that the observed effects of listening to the recording of the single musical feedback intervention are influenced by participants recapitulating intense pleasant social interactions during the Jymmin intervention. CONCLUSIONS: Listening to music that was the outcome of a previous musical feedback (Jymmin) intervention has beneficial psychological and probably social effects in patients that had suffered from polydrug addiction, increasing self-efficacy, mood, and a readiness to engage socially. These intervention effects, however, depend on the context in which the music recordings are presented. PMID- 26124714 TI - Dopamine-dependent oscillations in frontal cortex index "start-gun" signal in interval timing. PMID- 26124715 TI - Using brain potentials to understand prism adaptation: the error-related negativity and the P300. AB - Prism adaptation (PA) is both a perceptual-motor learning task as well as a promising rehabilitation tool for visuo-spatial neglect (VSN)-a spatial attention disorder often experienced after stroke resulting in slowed and/or inaccurate motor responses to contralesional targets. During PA, individuals are exposed to prism-induced shifts of the visual-field while performing a visuo-guided reaching task. After adaptation, with goggles removed, visuomotor responding is shifted to the opposite direction of that initially induced by the prisms. This visuomotor aftereffect has been used to study visuomotor learning and adaptation and has been applied clinically to reduce VSN severity by improving motor responding to stimuli in contralesional (usually left-sided) space. In order to optimize PA's use for VSN patients, it is important to elucidate the neural and cognitive processes that alter visuomotor function during PA. In the present study, healthy young adults underwent PA while event-related potentials (ERPs) were recorded at the termination of each reach (screen-touch), then binned according to accuracy (hit vs. miss) and phase of exposure block (early, middle, late). Results show that two ERP components were evoked by screen-touch: an error-related negativity (ERN), and a P300. The ERN was consistently evoked on miss trials during adaptation, while the P300 amplitude was largest during the early phase of adaptation for both hit and miss trials. This study provides evidence of two neural signals sensitive to visual feedback during PA that may sub-serve changes in visuomotor responding. Prior ERP research suggests that the ERN reflects an error processing system in medial-frontal cortex, while the P300 is suggested to reflect a system for context updating and learning. Future research is needed to elucidate the role of these ERP components in improving visuomotor responses among individuals with VSN. PMID- 26124716 TI - Functional networks and structural connectivity of visuospatial and visuoperceptual working memory. AB - Neural correlates of working memory (WM) in healthy subjects have been extensively investigated using functional MRI (fMRI). However it still remains unclear how cortical areas forming part of functional WM networks are also connected by white matter fiber bundles, and whether DTI measures, used as indices of microstructural properties and directionality of these connections, can predict individual differences in task performance. fMRI data were obtained from 23 healthy young subjects while performing one visuospatial (square location) and one visuoperceptual (face identification) 2-back task. Diffusion tensor imaging (DTI) data were also acquired. We used independent component analysis (ICA) of fMRI data to identify the main functional networks involved in WM tasks. Voxel-wise DTI analyses were performed to find correlations between structural white matter and task performance measures, and probabilistic tracking of DTI data was used to identify the white matter bundles connecting the nodes of the functional networks. We found that functional recruitment of the fusiform and the inferior frontal cortex was specific for the visuoperceptual working memory task, while there was a high overlap in brain activity maps in parietal and middle frontal areas for both tasks. Axial diffusivity and fractional anisotropy, of the tracts connecting the fusiform with the inferior frontal areas correlated with processing speed in the visuoperceptual working memory task. Although our findings need to be considered as exploratory, we conclude that both tasks share a highly-overlapping pattern of activity in areas of frontal and parietal lobes with the only differences in activation between tasks located in the fusiform and inferior frontal regions for the visuoperceptual task. Moreover, we have found that the DTI measures are predictive of the processing speed. PMID- 26124718 TI - Inter-hemispheric integration of tactile-motor responses across body parts. AB - In simple detection tasks, reaction times (RTs) are faster when stimuli are presented to the visual field or side of the body ipsilateral to the body part used to respond. This advantage, the crossed-uncrossed difference (CUD), is thought to reflect inter-hemispheric interactions needed for sensorimotor information to be integrated between the two cerebral hemispheres. However, it is unknown whether the tactile CUD is invariant when different body parts are stimulated. The most likely structure mediating such processing is thought to be the corpus callosum (CC). Neurophysiological studies have shown that there are denser callosal connections between regions that represent proximal parts of the body near the body midline and more sparse connections for regions representing distal extremities. Therefore, if the information transfer between the two hemispheres is affected by the density of callosal connections, stimuli presented on more distal regions of the body should produce a greater CUD compared to stimuli presented on more proximal regions. This is because interhemispheric transfer of information from regions with sparse callosal connections will be less efficient, and hence slower. Here, we investigated whether the CUD is modulated as a function of the different body parts stimulated by presenting tactile stimuli unpredictably on body parts at different distances from the body midline (i.e., Middle Finger, Forearm, or Forehead of each side of the body). Participants detected the stimulus and responded as fast as possible using either their left or right foot. Results showed that the magnitude of the CUD was larger on the finger (~2.6 ms) and forearm (~1.8 ms) than on the forehead (?0.9 ms). This result suggests that the interhemispheric transfer of tactile stimuli varies as a function of the strength of callosal connections of the body parts. PMID- 26124717 TI - Is There a Relation between EEG-Slow Waves and Memory Dysfunction in Epilepsy? A Critical Appraisal. AB - Is there a relationship between peri-ictal slow waves, loss of consciousness, memory, and slow-wave sleep, in patients with different forms of epilepsy? We hypothesize that mechanisms, which result in peri-ictal slow-wave activity as detected by the electroencephalogram, could negatively affect memory processes. Slow waves (<=4 Hz) can be found in seizures with impairment of consciousness and also occur in focal seizures without impairment of consciousness but with inhibited access to memory functions. Peri-ictal slow waves are regarded as dysfunctional and are probably caused by mechanisms, which are essential to disturb the consolidation of memory entries in these patients. This is in strong contrast to physiological slow-wave activity during deep sleep, which is thought to group memory-consolidating fast oscillatory activity. In patients with epilepsy, slow waves may not only correlate with the peri-ictal clouding of consciousness, but could be the epiphenomenon of mechanisms, which interfere with normal brain function in a wider range. These mechanisms may have transient impacts on memory, such as temporary inhibition of memory systems, altered patterns of hippocampal-neocortical interactions during slow-wave sleep, or disturbed cross-frequency coupling of slow and fast oscillations. In addition, repeated tonic-clonic seizures over the years in uncontrolled chronic epilepsy may cause a progressive cognitive decline. This hypothesis can only be assessed in long-term prospective studies. These studies could disentangle the reversible short-term impacts of seizures, and the impacts of chronic uncontrolled seizures. Chronic uncontrolled seizures lead to irreversible memory impairment. By contrast, short-term impacts do not necessarily lead to a progressive cognitive decline but result in significantly impaired peri-ictal memory performance. PMID- 26124719 TI - Restructuring consciousness -the psychedelic state in light of integrated information theory. AB - The psychological state elicited by the classic psychedelics drugs, such as LSD and psilocybin, is one of the most fascinating and yet least understood states of consciousness. However, with the advent of modern functional neuroimaging techniques, the effect of these drugs on neural activity is now being revealed, although many of the varied phenomenological features of the psychedelic state remain challenging to explain. Integrated information theory (IIT) is one of the foremost contemporary theories of consciousness, providing a mathematical formalization of both the quantity and quality of conscious experience. This theory can be applied to all known states of consciousness, including the psychedelic state. Using the results of functional neuroimaging data on the psychedelic state, the effects of psychedelic drugs on both the level and structure of consciousness can be explained in terms of the conceptual framework of IIT. This new IIT-based model of the psychedelic state provides an explanation for many of its phenomenological features, including unconstrained cognition, alterations in the structure and meaning of concepts and a sense of expanded awareness. This model also suggests that whilst cognitive flexibility, creativity, and imagination are enhanced during the psychedelic state, this occurs at the expense of cause-effect information, as well as degrading the brain's ability to organize, categorize, and differentiate the constituents of conscious experience. Furthermore, the model generates specific predictions that can be tested using a combination of functional imaging techniques, as has been applied to the study of levels of consciousness during anesthesia and following brain injury. PMID- 26124720 TI - A practical approach to communicating benefit-risk decisions of medicines to stakeholders. AB - PURPOSE: The importance of a framework for a systematic structured assessment of the benefits and risks has been established, but in addition, it is necessary that the benefit-risk decisions and the processes to derive those decisions are documented and communicated to various stakeholders for accountability. Hence there is now a need to find appropriate tools to enhance communication between regulators and other stakeholders, in a manner that would uphold transparency, consistency and standards. METHODS: A retrospective, non-comparative study was conducted to determine the applicability and practicality of a summary template in documenting benefit-risk assessment and communicating benefit-risk balance and conclusions for reviewers to other stakeholders. The benefit-risk (BR) Summary Template and its User Manual was evaluated by 12 reviewers within a regulatory agency in Singapore, the Health Sciences Authority (HSA). RESULTS: The BR Summary Template was found to be adequate in documenting benefits, risks, relevant summaries and conclusions, while the User Manual was useful in guiding the reviewer in completing the template. The BR Summary Template was also considered a useful tool for communicating benefit-risk decisions to a variety of stakeholders. CONCLUSIONS: The use of a template may be of value for the communicating benefit-risk assessment of medicines to stakeholders. PMID- 26124721 TI - Modeling of interactions between xenobiotics and cytochrome P450 (CYP) enzymes. AB - The adverse effects to humans and environment of only few chemicals are well known. Absorption, distribution, metabolism, and excretion (ADME) are the steps of pharmaco/toxicokinetics that determine the internal dose of chemicals to which the organism is exposed. Of all the xenobiotic-metabolizing enzymes, the cytochrome P450 (CYP) enzymes are the most important due to their abundance and versatility. Reactions catalyzed by CYPs usually turn xenobiotics to harmless and excretable metabolites, but sometimes an innocuous xenobiotic is transformed into a toxic metabolite. Data on ADME and toxicity properties of compounds are increasingly generated using in vitro and modeling (in silico) tools. Both physics-based and empirical modeling approaches are used. Numerous ligand-based and target-based as well as combined modeling methods have been employed to evaluate determinants of CYP ligand binding as well as predicting sites of metabolism and inhibition characteristics of test molecules. In silico prediction of CYP-ligand interactions have made crucial contributions in understanding (1) determinants of CYP ligand binding recognition and affinity; (2) prediction of likely metabolites from substrates; (3) prediction of inhibitors and their inhibition potency. Truly predictive models of toxic outcomes cannot be created without incorporating metabolic characteristics; in silico methods help producing such information and filling gaps in experimentally derived data. Currently modeling methods are not mature enough to replace standard in vitro and in vivo approaches, but they are already used as an important component in risk assessment of drugs and other chemicals. PMID- 26124722 TI - Regulators of Slc4 bicarbonate transporter activity. AB - The Slc4 family of transporters is comprised of anion exchangers (AE1-4), Na(+) coupled bicarbonate transporters (NCBTs) including electrogenic Na/bicarbonate cotransporters (NBCe1 and NBCe2), electroneutral Na/bicarbonate cotransporters (NBCn1 and NBCn2), and the electroneutral Na-driven Cl-bicarbonate exchanger (NDCBE), as well as a borate transporter (BTR1). These transporters regulate intracellular pH (pHi) and contribute to steady-state pHi, but are also involved in other physiological processes including CO2 carriage by red blood cells and solute secretion/reabsorption across epithelia. Acid-base transporters function as either acid extruders or acid loaders, with the Slc4 proteins moving HCO(-) 3 either into or out of cells. According to results from both molecular and functional studies, multiple Slc4 proteins and/or associated splice variants with similar expected effects on pHi are often found in the same tissue or cell. Such apparent redundancy is likely to be physiologically important. In addition to regulating pHi, a HCO(-) 3 transporter contributes to a cell's ability to fine tune the intracellular regulation of the cotransported/exchanged ion(s) (e.g., Na(+) or Cl(-)). In addition, functionally similar transporters or splice variants with different regulatory profiles will optimize pH physiology and solute transport under various conditions or within subcellular domains. Such optimization will depend on activated signaling pathways and transporter expression profiles. In this review, we will summarize and discuss both well known and more recently identified regulators of the Slc4 proteins. Some of these regulators include traditional second messengers, lipids, binding proteins, autoregulatory domains, and less conventional regulators. The material presented will provide insight into the diversity and physiological significance of multiple members within the Slc4 gene family. PMID- 26124725 TI - Distinctive effects of fear and sadness induction on anger and aggressive behavior. AB - A recent study has reported that the successful implementation of cognitive regulation of emotion depends on higher-level cognitive functions, such as top down control, which may be impaired in stressful situations. This calls for "cognition free" self-regulatory strategies that do not require top-down control. In contrast to the cognitive regulation of emotion that emphasizes the role of cognition, traditional Chinese philosophy and medicine views the relationship among different types of emotions as promoting or counteracting each other without the involvement of cognition, which provides an insightful perspective for developing "cognition free" regulatory strategies. In this study, we examined two hypotheses regarding the modulation of anger and aggressive behavior: sadness counteracts anger and aggressive behavior, whereas fear promotes anger and aggressive behavior. Participants were first provoked by reading extremely negative feedback on their viewpoints (Study 1) and by watching anger-inducing movie clips (Study 2). Then, these angry participants were assigned to three equivalent groups and viewed sad, fear-inducing, or neutral materials to evoke the corresponding emotions. The results showed that participants displayed a lower level of aggressive behavior when sadness was later induced and a higher level of anger when fear was later induced. These results provide evidence that supports the hypothesis of mutual promotion and counteraction relationships among these types of emotions and imply a "cognition free" approach to regulating anger and aggressive behavior. PMID- 26124724 TI - Cognitive aging and hearing acuity: modeling spoken language comprehension. AB - The comprehension of spoken language has been characterized by a number of "local" theories that have focused on specific aspects of the task: models of word recognition, models of selective attention, accounts of thematic role assignment at the sentence level, and so forth. The ease of language understanding (ELU) model (Ronnberg et al., 2013) stands as one of the few attempts to offer a fully encompassing framework for language understanding. In this paper we discuss interactions between perceptual, linguistic, and cognitive factors in spoken language understanding. Central to our presentation is an examination of aspects of the ELU model that apply especially to spoken language comprehension in adult aging, where speed of processing, working memory capacity, and hearing acuity are often compromised. We discuss, in relation to the ELU model, conceptions of working memory and its capacity limitations, the use of linguistic context to aid in speech recognition and the importance of inhibitory control, and language comprehension at the sentence level. Throughout this paper we offer a constructive look at the ELU model; where it is strong and where there are gaps to be filled. PMID- 26124726 TI - Metacognitive training for delusions (MCTd): effectiveness on data-gathering and belief flexibility in a Chinese sample. AB - Metacognitive training (MCT) was developed to promote awareness of reasoning biases among patients with schizophrenia. While MCT has been translated into 31 languages, most MCT studies were conducted in Europe, including newer evidence recommending an individualized approach of delivery. As reasoning biases covered in MCT are separable processes and are associated with different symptoms, testing the effect of selected MCT modules would help to develop a targeted and cost-effective intervention for specific symptoms and associated mechanisms. This study tested the efficacy of a four-session metacognitive training for delusions, MCTd (in Traditional Chinese with cultural adaptations, provided individually), as an adjunct to antipsychotics in reducing severity and conviction of delusions, jumping to conclusions (JTC) bias and belief inflexibility. Forty-four patients with delusions were randomized into the MCTd or the wait-list control condition. Patients on wait-list received the same MCTd after 4 weeks of treatment as usual (TAU). Assessment interviews took place before and after the treatment, and at 4 week follow-up. There was an additional baseline assessment for the controls. JTC and belief flexibility were measured by the beads tasks and the Maudsley Assessment of Delusions Scale. Attendance rate of the MCTd was satisfactory (84.5%). Compared to TAU, there was a greater reduction in psychotic symptoms, delusional severity and conviction following MCTd. There was a large treatment effect size in improvement in belief flexibility. Improvement in reaction to hypothetical contradiction predicted treatment effect in positive symptoms and delusions. JTC bias was reduced following MCTd, although the treatment effect was not significantly larger than TAU. Our results support the use of process-based interventions that target psychological mechanisms underlying specific psychotic symptoms as adjuncts to more conventional approaches. PMID- 26124727 TI - Timing in turn-taking and its implications for processing models of language. AB - The core niche for language use is in verbal interaction, involving the rapid exchange of turns at talking. This paper reviews the extensive literature about this system, adding new statistical analyses of behavioral data where they have been missing, demonstrating that turn-taking has the systematic properties originally noted by Sacks et al. (1974; hereafter SSJ). This system poses some significant puzzles for current theories of language processing: the gaps between turns are short (of the order of 200 ms), but the latencies involved in language production are much longer (over 600 ms). This seems to imply that participants in conversation must predict (or 'project' as SSJ have it) the end of the current speaker's turn in order to prepare their response in advance. This in turn implies some overlap between production and comprehension despite their use of common processing resources. Collecting together what is known behaviorally and experimentally about the system, the space for systematic explanations of language processing for conversation can be significantly narrowed, and we sketch some first model of the mental processes involved for the participant preparing to speak next. PMID- 26124728 TI - The use of content and timing to predict turn transitions. AB - For addressees to respond in a timely fashion, they cannot simply process the speaker's utterance as it occurs and wait till it finishes. Instead, they predict both when the speaker will conclude and what linguistic forms will be used. While doing this, they must also prepare their own response. To explain this, we draw on the account proposed by Pickering and Garrod (2013a), in which addressees covertly imitate the speaker's utterance and use this to determine the intention that underlies their upcoming utterance. They use this intention to predict when and how the utterance will end, and also to drive their own production mechanisms for preparing their response. Following Arnal and Giraud (2012), we distinguish between mechanisms that predict timing and content. In particular, we propose that the timing mechanism relies on entrainment of low-frequency oscillations between speech envelope and brain. This constrains the context that feeds into the determination of the speaker's intention and hence the timing and form of the upcoming utterance. This approach typically leads to well-timed contributions, but also provides a mechanism for resolving conflicts, for example when there is unintended speaker overlap. PMID- 26124729 TI - Face processing in Williams syndrome is already atypical in infancy. AB - Face processing is a crucial socio-cognitive ability. Is it acquired progressively or does it constitute an innately-specified, face-processing module? The latter would be supported if some individuals with seriously impaired intelligence nonetheless showed intact face-processing abilities. Some theorists claim that Williams syndrome (WS) provides such evidence since, despite IQs in the 50s, adolescents/adults with WS score in the normal range on standardized face-processing tests. Others argue that atypical neural and cognitive processes underlie WS face-processing proficiencies. But what about infants with WS? Do they start with typical face-processing abilities, with atypicality developing later, or are atypicalities already evident in infancy? We used an infant familiarization/novelty design and compared infants with WS to typically developing controls as well as to a group of infants with Down syndrome matched on both mental and chronological age. Participants were familiarized with a schematic face, after which they saw a novel face in which either the features (eye shape) were changed or just the configuration of the original features. Configural changes were processed successfully by controls, but not by infants with WS who were only sensitive to featural changes and who showed syndrome specific profiles different from infants with the other neurodevelopmental disorder. Our findings indicate that theorists can no longer use the case of WS to support claims that evolution has endowed the human brain with an independent face-processing module. PMID- 26124730 TI - Editorial: Theories of visual attention-linking cognition, neuropsychology, and neurophysiology. PMID- 26124723 TI - Homeostasis or channelopathy? Acquired cell type-specific ion channel changes in temporal lobe epilepsy and their antiepileptic potential. AB - Neurons continuously adapt the expression and functionality of their ion channels. For example, exposed to chronic excitotoxicity, neurons homeostatically downscale their intrinsic excitability. In contrast, the "acquired channelopathy" hypothesis suggests that proepileptic channel characteristics develop during epilepsy. We review cell type-specific channel alterations under different epileptic conditions and discuss the potential of channels that undergo homeostatic adaptations, as targets for antiepileptic drugs (AEDs). Most of the relevant studies have been performed on temporal lobe epilepsy (TLE), a widespread AED-refractory, focal epilepsy. The TLE patients, who undergo epilepsy surgery, frequently display hippocampal sclerosis (HS), which is associated with degeneration of cornu ammonis subfield 1 pyramidal cells (CA1 PCs). Although the resected human tissue offers insights, controlled data largely stem from animal models simulating different aspects of TLE and other epilepsies. Most of the cell type-specific information is available for CA1 PCs and dentate gyrus granule cells (DG GCs). Between these two cell types, a dichotomy can be observed: while DG GCs acquire properties decreasing the intrinsic excitability (in TLE models and patients with HS), CA1 PCs develop channel characteristics increasing intrinsic excitability (in TLE models without HS only). However, thorough examination of data on these and other cell types reveals the coexistence of protective and permissive intrinsic plasticity within neurons. These mechanisms appear differentially regulated, depending on the cell type and seizure condition. Interestingly, the same channel molecules that are upregulated in DG GCs during HS-related TLE, appear as promising targets for future AEDs and gene therapies. Hence, GCs provide an example of homeostatic ion channel adaptation which can serve as a primer when designing novel anti-epileptic strategies. PMID- 26124731 TI - Clinical investigations of receptive and expressive musical functions after stroke. AB - There is a long tradition of investigating various disorders of musical abilities after stroke. These impairments, associated with acquired amusia, can be highly selective, affecting only music perception (i.e., receptive abilities/functions) or expression (music production abilities), and some patients report that these may dramatically influence their emotional state. The aim of this study was to systematically test both the melodic and rhythmic domains of music perception and expression in left- and right-sided stroke patients compared to healthy subjects. Music perception was assessed using rhythmic and melodic discrimination tasks, while tests of expressive function involved the vocal or instrumental reproduction of rhythms and melodies. Our approach revealed deficits in receptive and expressive functions in stroke patients, mediated by musical expertise. Those patients who had experienced a short period of musical training in childhood and adolescence performed better in the receptive and expressive subtests compared to those without any previous musical training. While discrimination of specific musical patterns was unimpaired after a left-sided stroke, patients with a right sided stroke had worse results for fine melodic and rhythmic analysis. In terms of expressive testing, the most consistent results were obtained from a test that required patients to reproduce sung melodies. This implies that the means of investigating production abilities can impact the identification of deficits. PMID- 26124732 TI - The student-institution fit at university: interactive effects of academic competition and social class on achievement goals. AB - As compared to continuing-generation students, first-generation students are struggling more at university. In the present article, we question the unconditional nature of such a phenomenon and argue that it depends on structural competition. Indeed, most academic departments use harsh selection procedure all throughout the curriculum, fostering between-student competition. In these departments, first-generation students tend to suffer from a lack of student institution fit, that is, inconsistencies with the competitive institution's culture, practices, and identity. However, one might contend that in less competitive academic departments continuing-generation students might be the ones experiencing a lack of fit. Using a cross-sectional design, we investigated the consequences of such a context- and category-dependent lack of fit on the endorsement of scholastically adaptive goals. We surveyed N = 378 first- and continuing-generation students from either a more competitive or a less competitive department in their first or final year of bachelor's study. In the more competitive department, first-to-third year decrease of mastery goals (i.e., the desire to learn) was found to be steeper for first- than for continuing generation students. In the less competitive department, the reversed pattern was found. Moreover, first-to-third year decrease of performance goals (i.e., the desire to outperform others) was found to be steeper within the less competitive department but did not depend on social class. This single-site preliminary research highlights the need to take the academic context into account when studying the social class graduation gap. PMID- 26124733 TI - Do motivations for using Facebook moderate the association between Facebook use and psychological well-being? AB - Previous investigations of the relationship between Facebook use and psychological well-being have most commonly considered variables relating to the quantity (e.g., time spent online) and underlying motivations (e.g., making new friends) of Facebook consumption. However, previous research has reached contradictory conclusions in that quantity of Facebook use has been linked to both higher and lower levels of psychological well-being. The current study investigated whether these contradictory findings of quantity of Facebook use could be explained by considering users' motivations for accessing Facebook. We predicted that quantity of use would be positively associated with psychological well-being when users primarily accessed Facebook to maintain existing relationships but negatively associated with psychological well-being when primarily accessed to create new relationships. In a sample of college undergraduates (N = 119), we found that the relationship of quantity of Facebook use on psychological well-being was moderated by the motivation of the user. Quantity of Facebook use was associated with higher levels of psychological well being among users that accessed Facebook for friendship purposes but was negatively associated with psychological well-being among users that accessed Facebook for connection purposes (e.g., making new friends). We also replicated our results across dimensions of psychological well-being (e.g., anxiety and life satisfaction). The current findings provide initial evidence that quantity and motivations of Facebook use interact with potentially serious implications for psychological well-being and also provide a possible explanation for why quantity of Facebook use can be linked with both positive and negative psychological well being. PMID- 26124735 TI - Word-by-word entrainment of speech rhythm during joint story building. AB - Movements and behavior synchronize during social interaction at many levels, often unintentionally. During smooth conversation, for example, participants adapt to each others' speech rates. Here we aimed to find out to which extent speakers adapt their turn-taking rhythms during a story-building game. Nine sex matched dyads of adults (12 males, 6 females) created two 5-min stories by contributing to them alternatingly one word at a time. The participants were located in different rooms, with audio connection during one story and audiovisual during the other. They were free to select the topic of the story. Although the participants received no instructions regarding the timing of the story building, their word rhythms were highly entrained (overlineR = 0.70, p < 0.001) even though the rhythms as such were unstable (overlineR = 0.14 for pooled data). Such high entrainment in the absence of steady word rhythm occurred in every individual story, independently of whether the subjects were connected via audio-only or audiovisual link. The observed entrainment was of similar strength as typical entrainment in finger-tapping tasks where participants are specifically instructed to synchronize their behavior. Thus, speech seems to spontaneously induce strong entrainment between the conversation partners, likely reflecting automatic alignment of their semantic and syntactic processes. PMID- 26124734 TI - When interoception helps to overcome negative feelings caused by social exclusion. AB - Social exclusion affects mental and physical health. The ability to regulate emotional responses to social exclusion is therefore essential for our well being. As individual differences in detecting bodily signals (interoceptive sensitivity, IS) have been associated with the ability of emotion regulation, we aimed at exploring whether IS fosters coping with social exclusion and flexibility in emotion regulation. The first study investigated subjective feelings and behavioral affiliation tendencies in response to ostracism using a cyberball paradigm. Sixty-nine participants were assessed who differed with respect to IS. The second study examined habitual emotion regulation processes focusing on suppression and reappraisal as well as IS in 116 participants. Main results were that the effect of ostracism on distress and behavioral affiliation tendencies were qualified by IS-being ostracized had less impact on participants with stronger IS. Furthermore, Study 2 revealed that IS was associated with habitually stronger emotion regulation strategies. We conclude that having access to bodily signals helps (IS) reducing aversive states provoked by social exclusion, probably due to the fact that IS is associated with emotion regulation strategies. PMID- 26124736 TI - Emotional contagion and proto-organizing in human interaction dynamics. AB - This paper combines the complexity notions of phase transitions and tipping points with recent advances in cognitive neuroscience to propose a general theory of human proto-organizing. It takes as a premise that a necessary prerequisite for organizing, or "proto-organizing," occurs through emotional contagion in subpopulations of human interaction dynamics in complex ecosystems. Emotional contagion is posited to engender emotional understanding and identification with others, a social process that acts as a mechanism that enables (or precludes) cooperative responses to opportunities and risks. Propositions are offered and further research is suggested. PMID- 26124737 TI - Friendly touch increases gratitude by inducing communal feelings. AB - Communion among people is easily identifiable. Close friends or relatives frequently touch each other and this physical contact helps identifying the type of relationship they have. We tested whether a friendly touch and benefits elicit the emotion of gratitude given the close link between gratitude and communal relations. In Study 1, we induced a communal mindset and manipulated friendly touch (vs. non-touch) and benefit to female participants by a female confederate. We measured pre- and post-benefit gratitude, communal feelings, and liking toward the toucher, as well as general affect. In Study 2, we manipulated mindset, friendly touch and benefit, and measured the same variables in female pairs (confederate and participants). In both studies the results showed a main effect of touch on pre-benefit gratitude: participants who were touched by the confederate indicated more gratitude than those not touched. Moreover, benefit increased gratitude toward a confederate in the absence of touch, but not in the presence of touch. Additionally, perceiving the relationship as communal, and not merely liking the confederate, or a positive mood mediated the link between touch and gratitude. The results further support a causal model where touch increases communal feelings, which in turn increase gratitude at the end of the interaction, after having received a benefit from the interaction partner. These results support a broader definition of gratitude as an emotion embodied in communal relationship cues. PMID- 26124738 TI - The speaker behind the voice: therapeutic practice from the perspective of pragmatic theory. AB - Many attempts at understanding auditory verbal hallucinations have tried to explain why there is an auditory experience in the absence of an appropriate stimulus. We suggest that many instance of voice-hearing should be approached differently. More specifically, they could be viewed primarily as hallucinated acts of communication, rather than hallucinated sounds. We suggest that this change of perspective is reflected in, and helps to explain, the successes of two recent therapeutic techniques. These two techniques are: Relating Therapy for Voices and Avatar Therapy. PMID- 26124739 TI - How our body influences our perception of the world. AB - Incorporating the fact that the senses are embodied is necessary for an organism to interpret sensory information. Before a unified perception of the world can be formed, sensory signals must be processed with reference to body representation. The various attributes of the body such as shape, proportion, posture, and movement can be both derived from the various sensory systems and can affect perception of the world (including the body itself). In this review we examine the relationships between sensory and motor information, body representations, and perceptions of the world and the body. We provide several examples of how the body affects perception (including but not limited to body perception). First we show that body orientation effects visual distance perception and object orientation. Also, visual-auditory crossmodal-correspondences depend on the orientation of the body: audio "high" frequencies correspond to a visual "up" defined by both gravity and body coordinates. Next, we show that perceived locations of touch is affected by the orientation of the head and eyes on the body, suggesting a visual component to coding body locations. Additionally, the reference-frame used for coding touch locations seems to depend on whether gaze is static or moved relative to the body during the tactile task. The perceived attributes of the body such as body size, affect tactile perception even at the level of detection thresholds and two-point discrimination. Next, long-range tactile masking provides clues to the posture of the body in a canonical body schema. Finally, ownership of seen body parts depends on the orientation and perspective of the body part in view. Together, all of these findings demonstrate how sensory and motor information, body representations, and perceptions (of the body and the world) are interdependent. PMID- 26124740 TI - Neurodynamics of executive control processes in bilinguals: evidence from ERP and source reconstruction analyses. AB - The present study was designed to examine the impact of bilingualism on the neuronal activity in different executive control processes namely conflict monitoring, control implementation (i.e., interference suppression and conflict resolution) and overcoming of inhibition. Twenty-two highly proficient but non balanced successive French-German bilingual adults and 22 monolingual adults performed a combined Stroop/Negative priming task while event-related potential (ERP) were recorded online. The data revealed that the ERP effects were reduced in bilinguals in comparison to monolinguals but only in the Stroop task and limited to the N400 and the sustained fronto-central negative-going potential time windows. This result suggests that bilingualism may impact the process of control implementation rather than the process of conflict monitoring (N200). Critically, our study revealed a differential time course of the involvement of the anterior cingulate cortex (ACC) and the prefrontal cortex (PFC) in conflict processing. While the ACC showed major activation in the early time windows (N200 and N400) but not in the latest time window (late sustained negative-going potential), the PFC became unilaterally active in the left hemisphere in the N400 and the late sustained negative-going potential time windows. Taken together, the present electroencephalography data lend support to a cascading neurophysiological model of executive control processes, in which ACC and PFC may play a determining role. PMID- 26124741 TI - Pupillometric evidence for the locus coeruleus-noradrenaline system facilitating attentional processing of action-triggered visual stimuli. AB - It has been argued that attentional processing of visual stimuli is facilitated by a voluntary action that triggers the stimulus onset. However, the relationship between action-induced facilitation of attention and the neural substrates has not been well established. The present study investigated whether the locus coeruleus-noradrenaline (LC-NA) system is involved in this facilitation effect. A rapid serial visual presentation paradigm was used to assess the dynamics of transient attention in humans. Participants were instructed to change a digit stream to a letter stream by pressing a button and specifying successive targets of four letters. Pupil dilation was measured as an index of LC-NA function. Accuracy of target identification was better when the temporal delay between participants' key press and target onset was 800 ms than when targets appeared just after the key press or when targets appeared without key press. Accuracy of target identification was positively correlated with both the peak amplitude of pupil dilation and the pupil size at the time of the key press. These results indicate that target identification in the visual task is closely linked to pupil dilation. We conclude that the LC-NA system plays an important role in the facilitation of transient attention driven by voluntary action. PMID- 26124742 TI - Emotional reactions to deviance in groups: the relation between number of angry reactions, felt rejection, and conformity. AB - How many members of a group need to express their anger in order to influence a deviant group member's behavior? In two studies, we examine whether an increase in number of angry group members affects the extent to which a deviant individual feels rejected, and we investigate downstream effects on conformity. We show that each additional angry reaction linearly increases the extent to which a deviant individual feels rejected, and that this relation is independent of the total number of majority members (Study 1). This felt rejection is then shown to lead to anti-conformity unless two conditions are met: (1) the deviant is motivated to seek reacceptance in the group, and (2) conformity is instrumental in gaining reacceptance because it is observable by the majority (Study 2). These findings show that angry reactions are likely to trigger anti-conformity in a deviant, but they are also consistent with a motivational account of conformity, in which conformity is strategic behavior aimed at gaining reacceptance from the group. PMID- 26124743 TI - The Temporal Pattern of Changes in Serum Biomarker Levels Reveals Complex and Dynamically Changing Pathologies after Exposure to a Single Low-Intensity Blast in Mice. AB - Time-dependent changes in blood-based protein biomarkers can help identify the pathological processes in blast-induced traumatic brain injury (bTBI), assess injury severity, and monitor disease progression. We obtained blood from control and injured mice (exposed to a single, low-intensity blast) at 2-h, 1-day, 1 week, and 1-month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1alpha, ceruloplasmin), vascular function (AQP1, AQP4, VEGF, vWF, Flk-1), inflammation (OPN, CINC1, fibrinogen, MIP-1a, OX 44, p38, MMP-8, MCP-1 CCR5, CRP, galectin-1), cell adhesion and the extracellular matrix (integrin alpha6, TIMP1, TIMP4, Ncad, connexin-43), and axonal (NF-H, Tau), neuronal (NSE, CK-BB) and glial damage (GFAP, S100beta, MBP) at various post-injury time points. Our findings indicate that the exposure to a single, low intensity blast results in metabolic and vascular changes, altered cell adhesion, and axonal and neuronal injury in the mouse model of bTBI. Interestingly, serum levels of several inflammatory and astroglial markers were either unchanged or elevated only during the acute and subacute phases of injury. Conversely, serum levels of the majority of biomarkers related to metabolic and vascular functions, cell adhesion, as well as neuronal and axonal damage remained elevated at the termination of the experiment (1 month), indicating long-term systemic and cerebral alterations due to blast. Our findings show that the exposure to a single, low-intensity blast induces complex pathological processes with distinct temporal profiles. Hence, monitoring serum biomarker levels at various post injury time points may provide enhanced diagnostics in blast-related neurological and multi-system deficits. PMID- 26124744 TI - Stroke Outreach in an Inner City Market: A Platform for Identifying African American Males for Stroke Prevention Interventions. AB - BACKGROUND: There are significant racial disparities in stroke incidence and mortality. Health fairs and outreach programs can be used to increase stroke literacy, but they often fail to reach those at highest risk, including African American males. METHODS: We conducted a stroke outreach and screening program at an inner city market in order to attract a high-risk group for a stroke education intervention. A modified Framingham risk tool was used to estimate stroke risk and a 10-item quiz was developed to assess stroke literacy among 80 participants. We report results of the demographic and stroke risk analyses and stroke knowledge assessment. RESULTS: The program attracted a majority male (70%) and African American (95%) group of participants. Self-reported hypertension (57.5%), tobacco use (40%), and diabetes (23.8%) were prevalent. Knowledge of stroke warning signs, risk factors, and appropriate action to take for stroke symptoms was not poor when compared to the literature. CONCLUSION: Stroke outreach and screening in an inner city public market may be an effective way to target a high risk population for stroke prevention interventions. Stroke risk among participants was high despite adequate stroke knowledge. PMID- 26124746 TI - Interactions of Human Autoantibodies with Hippocampal GABAergic Synaptic Transmission - Analyzing Antibody-Induced Effects ex vivo. AB - Autoantibodies (aAB) to the presynaptic located enzyme glutamate decarboxylase 65 (GAD65) are a characteristic attribute for a variety of autoimmune diseases of the central nervous system including subtypes of limbic encephalitis, stiff person-syndrome, cerebellar ataxia, and Batten's disease. Clinical signs of hyperexcitability and improvement of disease symptoms upon immunotherapy in some of these disorders suggest a possible pathogenic role of associated aAB. Recent experimental studies report inconsistent results regarding a direct pathogenic influence of anti-GAD65 aAB affecting inhibitory synaptic transmission in central GABAergic pathways. We here provide a method for direct evaluation of aAB-induced pathomechanisms in the intact hippocampal network. Purified patient IgG fractions containing aAB to GAD65 together with fixable lipophilic styryl dyes (FMdyes) are stereotactically injected into the hilus and the dentate gyrus in anesthetized mice. Twenty-four hours after intrahippocampal injection, acute hippocampal slices are prepared and transferred to a patch-clamp recording setup equipped with a fluorescence light source. Intraneural incorporated FMdyes show correct injection site for patch-clamp recording. Whole-cell patch-clamp recordings are performed from granule cells in the dentate gyrus and extracellular stimulation is applied in the border area of the dentate gyrus-hilus region to stimulate GABAergic afferents arising from parvalbumin positive basket cells. GABA-A receptor mediated inhibitory postsynaptic currents (IPSC) and miniature IPSC are recorded after blocking glutamatergic transmission. This approach allows investigation of potential aAB-induced effects on GABA-A receptor signaling ex vivo in an intact neuronal network. This offers several advantages compared to experimental procedures used in previous studies by in vitro AB preincubation of primary neurons or slice preparations. Furthermore, this method requires only small amounts of patient material that are often limited in rare diseases. PMID- 26124747 TI - Thyroid Function/Antibodies in Sudanese Patients with Preeclampsia. AB - Preeclampsia is an important cause of maternal and prenatal morbidity and mortality in the developing countries. Changes in thyroid function/antibodies profiles in preeclamptic women are controversial and were never investigated before in Sudan. A case-control study was conducted at Medani Hospital, Sudan, to investigate thyroid function/antibodies in preeclampsia. The sociodemographic, medical history was gathered using questionnaires. Thyroid hormones [thyroid stimulating hormone (TSH), free tri-iodothyronine (T3), and free thyroxine (T4)] and anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies were measured using ELISA. The three groups [controls, mild, and severe preeclampsia (SP) (55 women in each arm)] were matched in age and parity. While median (interquartile range) of TSH was significantly lower, both free T3 and free T4 levels were significantly higher in women with preeclampsia than in the healthy controls. There was no significant difference in the TSH levels in women with MP and SP. In comparison with women with MP, women with SP had significantly higher levels of free T3 and significantly lower levels of free T4. While anti-TPO antibodies were significantly higher, anti-TG antibodies were significantly lower in women with preeclampsia. Likewise, anti-TPO antibodies were significantly higher and anti-TG antibodies were significantly lower in women with SP than in women with MP. In linear regression, preeclampsia was significantly associated with TSH (-0.675 IU/ml, P = 0.009), free T3 (0.977 pg/ml, P < 0.001), and free T4 (0.186 ng/dl, P < 0.001) levels. In contrast to anti-TG antibodies and TSH, Sudanese patients with preeclampsia had higher levels of T3 and T4 hormones and anti-TPO antibodies irrespective of parity, gestational age, and hemoglobin levels. PMID- 26124745 TI - Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal. AB - Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Recent technological advances have illuminated the role of GABAergic neurons in control of cortical arousal and sleep. Sleep-promoting GABAergic neurons in the preoptic hypothalamus are well-known. Less well-appreciated are GABAergic projection neurons in the brainstem, midbrain, hypothalamus, and basal forebrain, which paradoxically promote arousal and fast electroencephalographic (EEG) rhythms. Thus, GABA is not purely a sleep-promoting neurotransmitter. GABAergic projection neurons in the brainstem nucleus incertus and ventral tegmental nucleus of Gudden promote theta (4-8 Hz) rhythms. Ventral tegmental area GABAergic neurons, neighboring midbrain dopamine neurons, project to the frontal cortex and nucleus accumbens. They discharge faster during cortical arousal and regulate reward. Thalamic reticular nucleus GABAergic neurons initiate sleep spindles in non-REM sleep. In addition, however, during wakefulness, they tonically regulate the activity of thalamocortical neurons. Other GABAergic inputs to the thalamus arising in the globus pallidus pars interna, substantia nigra pars reticulata, zona incerta, and basal forebrain regulate motor activity, arousal, attention, and sensory transmission. Several subpopulations of cortically projecting GABAergic neurons in the basal forebrain project to the thalamus and neocortex and preferentially promote cortical gamma band (30-80 Hz) activity and wakefulness. Unlike sleep-active GABAergic neurons, these ascending GABAergic neurons are fast-firing neurons which disinhibit and synchronize the activity of their forebrain targets, promoting the fast EEG rhythms typical of conscious states. They are prominent targets of GABAergic hypnotic agents. Understanding the properties of ascending GABAergic neurons may lead to novel treatments for diseases involving disorders of cortical activation and wakefulness. PMID- 26124748 TI - The New Age of Sudomotor Function Testing: A Sensitive and Specific Biomarker for Diagnosis, Estimation of Severity, Monitoring Progression, and Regression in Response to Intervention. AB - Sudorimetry technology has evolved dramatically, as a rapid, non-invasive, robust, and accurate biomarker for small fibers that can easily be integrated into clinical practice. Though skin biopsy with quantitation of intraepidermal nerve fiber density is still currently recognized as the gold standard, sudorimetry may yield diagnostic information not only on autonomic dysfunction but also enhance the assessment of the small somatosensory nerves, disease detection, progression, and response to therapy. Sudorimetry can be assessed using SudoscanTM, which measures electrochemical skin conductance (ESC) of hands and feet. It is based on different electrochemical principles (reverse iontophoresis and chronoamperometry) to measure sudomotor function than prior technologies, affording it a much more practical and precise performance profile for routine clinical use with potential as a research tool. Small nerve fiber dysfunction has been found to occur early in metabolic syndrome and diabetes and may also be the only neurological manifestation in small fiber neuropathies, beneath the detection limits of traditional nerve function tests. Test results are robust, accomplished within minutes, require little technical training and no calculations, since established norms have been provided for the effects of age, gender, and ethnicity. Sudomotor testing has been greatly under-utilized in the past, restricted to specialized centers capable of handling the technically demanding and expensive technology. Yet, evaluation of autonomic and somatic nerve function has been shown to be one of the best estimates of cardiovascular risk. Evaluation of sweating has the appeal of quantifiable non-invasive determination of the integrity of the peripheral autonomic nervous system, and can now be accomplished rapidly at point of care clinics with the determination of ESC, allowing intervention for morbid complications prior to permanent structural nerve damage. We review here sudomotor function testing technology, the research evidence accumulated supporting the clinical utility of measuring ESC, the medical applications of sudorimetry now available to physicians with this device, and clinical vignettes illustrating its use in the clinical decision making process. PMID- 26124749 TI - Molecular and Cellular Mechanisms of Aldosterone Producing Adenoma Development. AB - Primary aldosteronism (PA) is the most common form of secondary hypertension with an estimated prevalence of ~10% in referred patients. PA occurs as a result of a dysregulation of the normal mechanisms controlling adrenal aldosterone production. It is characterized by hypertension with low plasma renin and elevated aldosterone and often associated with hypokalemia. The two major causes of PA are unilateral aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia, accounting together for ~95% of cases. In addition to the well characterized effect of excess mineralocorticoids on blood pressure, high levels of aldosterone also have cardiovascular, renal, and metabolic consequences. Hence, long-term consequences of PA include increased risk of coronary artery disease, myocardial infarction, heart failure, and atrial fibrillation. Despite recent progress in the management of patients with PA, critical issues related to diagnosis, subtype differentiation, and treatment of non-surgically correctable forms still persist. A better understanding of the pathogenic mechanisms of the disease should lead to the identification of more reliable diagnostic and prognostic biomarkers for a more sensitive and specific screening and new therapeutic options. In this review, we will summarize our current knowledge on the molecular and cellular mechanisms of APA development. On one hand, we will discuss how various animal models have improved our understanding of the pathophysiology of excess aldosterone production. On the other hand, we will summarize the major advances made during the last few years in the genetics of APA due to transcriptomic studies and whole exome sequencing. The identification of recurrent and somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) allowed highlighting the central role of calcium signaling in autonomous aldosterone production by the adrenal. PMID- 26124750 TI - Progress in the Diagnosis and Classification of Pituitary Adenomas. AB - Pituitary adenomas are common neoplasms. Their classification is based upon size, invasion of adjacent structures, sporadic or familial cases, biochemical activity, clinical manifestations, morphological characteristics, response to treatment and recurrence. Although they are considered benign tumors, some of them are difficult to treat due to their tendency to recur despite standardized treatment. Functional tumors present other challenges for normalizing their biochemical activity. Novel approaches for early diagnosis, as well as different perspectives on classification, may help to identify subgroups of patients with similar characteristics, creating opportunities to match each patient with the best personalized treatment option. In this paper, we present the progress in the diagnosis and classification of different subgroups of patients with pituitary tumors that may be managed with specific considerations according to their tumor subtype. PMID- 26124751 TI - Crosstalk between the HpArsRS two-component system and HpNikR is necessary for maximal activation of urease transcription. AB - Helicobacter pylori NikR (HpNikR) is a nickel dependent transcription factor that directly regulates a number of genes in this important gastric pathogen. One key gene that is regulated by HpNikR is ureA, which encodes for the urease enzyme. In vitro DNA binding studies of HpNikR with the ureA promoter (PureA ) previously identified a recognition site that is required for high affinity protein/DNA binding. As a means to determine the in vivo significance of this recognition site and to identify the key DNA sequence determinants required for ureA transcription, herein, we have translated these in vitro results to analysis directly within H. pylori. Using a series of GFP reporter constructs in which the PureA DNA target was altered, in combination with mutant H. pylori strains deficient in key regulatory proteins, we confirmed the importance of the previously identified HpNikR recognition sequence for HpNikR-dependent ureA transcription. Moreover, we identified a second factor, the HpArsRS two-component system that was required for maximum transcription of ureA. While HpArsRS is known to regulate ureA in response to acid shock, it was previously thought to function independently of HpNikR and to have no role at neutral pH. However, our qPCR analysis of ureA expression in wildtype, DeltanikR and DeltaarsS single mutants as well as a DeltaarsS/nikR double mutant strain background showed reduced basal level expression of ureA when arsS was absent. Additionally, we determined that both HpNikR and HpArsRS were necessary for maximal expression of ureA under nickel, low pH and combined nickel and low pH stresses. In vitro studies of HpArsR-P with the PureA DNA target using florescence anisotropy confirmed a direct protein/DNA binding interaction. Together, these data support a model in which HpArsRS and HpNikR cooperatively interact to regulate ureA transcription under various environmental conditions. This is the first time that direct "cross-talk" between HpArsRS and HpNikR at neutral pH has been demonstrated. PMID- 26124752 TI - RNA-Seq analysis of isolate- and growth phase-specific differences in the global transcriptomes of enteropathogenic Escherichia coli prototype isolates. AB - Enteropathogenic Escherichia coli (EPEC) are a leading cause of diarrheal illness among infants in developing countries. E. coli isolates classified as typical EPEC are identified by the presence of the locus of enterocyte effacement (LEE) and the bundle-forming pilus (BFP), and absence of the Shiga-toxin genes, while the atypical EPEC also encode LEE but do not encode BFP or Shiga-toxin. Comparative genomic analyses have demonstrated that EPEC isolates belong to diverse evolutionary lineages and possess lineage- and isolate-specific genomic content. To investigate whether this genomic diversity results in significant differences in global gene expression, we used an RNA sequencing (RNA-Seq) approach to characterize the global transcriptomes of the prototype typical EPEC isolates E2348/69, B171, C581-05, and the prototype atypical EPEC isolate E110019. The global transcriptomes were characterized during laboratory growth in two different media and three different growth phases, as well as during adherence of the EPEC isolates to human cells using in vitro tissue culture assays. Comparison of the global transcriptomes during these conditions was used to identify isolate- and growth phase-specific differences in EPEC gene expression. These analyses resulted in the identification of genes that encode proteins involved in survival and metabolism that were coordinately expressed with virulence factors. These findings demonstrate there are isolate- and growth phase-specific differences in the global transcriptomes of EPEC prototype isolates, and highlight the utility of comparative transcriptomics for identifying additional factors that are directly or indirectly involved in EPEC pathogenesis. PMID- 26124754 TI - Microbial electron transport and energy conservation - the foundation for optimizing bioelectrochemical systems. AB - Microbial electrochemical techniques describe a variety of emerging technologies that use electrode-bacteria interactions for biotechnology applications including the production of electricity, waste and wastewater treatment, bioremediation and the production of valuable products. Central in each application is the ability of the microbial catalyst to interact with external electron acceptors and/or donors and its metabolic properties that enable the combination of electron transport and carbon metabolism. And here also lies the key challenge. A wide range of microbes has been discovered to be able to exchange electrons with solid surfaces or mediators but only a few have been studied in depth. Especially electron transfer mechanisms from cathodes towards the microbial organism are poorly understood but are essential for many applications such as microbial electrosynthesis. We analyze the different electron transport chains that nature offers for organisms such as metal respiring bacteria and acetogens, but also standard biotechnological organisms currently used in bio-production. Special focus lies on the essential connection of redox and energy metabolism, which is often ignored when studying bioelectrochemical systems. The possibility of extracellular electron exchange at different points in each organism is discussed regarding required redox potentials and effect on cellular redox and energy levels. Key compounds such as electron carriers (e.g., cytochromes, ferredoxin, quinones, flavins) are identified and analyzed regarding their possible role in electrode-microbe interactions. This work summarizes our current knowledge on electron transport processes and uses a theoretical approach to predict the impact of different modes of transfer on the energy metabolism. As such it adds an important piece of fundamental understanding of microbial electron transport possibilities to the research community and will help to optimize and advance bioelectrochemical techniques. PMID- 26124753 TI - The membrane: transertion as an organizing principle in membrane heterogeneity. AB - The bacterial membrane exhibits a significantly heterogeneous distribution of lipids and proteins. This heterogeneity results mainly from lipid-lipid, protein protein, and lipid-protein associations which are orchestrated by the coupled transcription, translation and insertion of nascent proteins into and through membrane (transertion). Transertion is central not only to the individual assembly and disassembly of large physically linked groups of macromolecules (alias hyperstructures) but also to the interactions between these hyperstructures. We review here these interactions in the context of the processes in Bacillus subtilis and Escherichia coli of nutrient sensing, membrane synthesis, cytoskeletal dynamics, DNA replication, chromosome segregation, and cell division. PMID- 26124755 TI - Cell age dependent concentration of Escherichia coli divisome proteins analyzed with ImageJ and ObjectJ. AB - The rod-shaped Gram-negative bacterium Escherichia coli multiplies by elongation followed by binary fission. Longitudinal growth of the cell envelope and synthesis of the new poles are organized by two protein complexes called elongasome and divisome, respectively. We have analyzed the spatio-temporal localization patterns of many of these morphogenetic proteins by immunolabeling the wild type strain MC4100 grown to steady state in minimal glucose medium at 28 degrees C. This allowed the direct comparison of morphogenetic protein localization patterns as a function of cell age as imaged by phase contrast and fluorescence wide field microscopy. Under steady state conditions the age distribution of the cells is constant and is directly correlated to cell length. To quantify cell size and protein localization parameters in 1000s of labeled cells, we developed 'Coli-Inspector,' which is a project running under ImageJ with the plugin 'ObjectJ.' ObjectJ organizes image-analysis tasks using an integrated approach with the flexibility to produce different output formats from existing markers such as intensity data and geometrical parameters. ObjectJ supports the combination of automatic and interactive methods giving the user complete control over the method of image analysis and data collection, with visual inspection tools for quick elimination of artifacts. Coli-inspector was used to sort the cells according to division cycle cell age and to analyze the spatio-temporal localization pattern of each protein. A unique dataset has been created on the concentration and position of the proteins during the cell cycle. We show for the first time that a subset of morphogenetic proteins have a constant cellular concentration during the cell division cycle whereas another set exhibits a cell division cycle dependent concentration variation. Using the number of proteins present at midcell, the stoichiometry of the divisome is discussed. PMID- 26124757 TI - CXCL12/SDF-1 and CXCR4. PMID- 26124756 TI - The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases. AB - Dendritic cells (DCs) are key antigen-presenting cells that have an important role in autoimmune pathogenesis. DCs control both steady-state T cell tolerance and activation of pathogenic responses. The balance between these two outcomes depends on several factors, including genetic susceptibility, environmental signals that stimulate varied innate responses, and which DC subset is presenting antigen. Although the specific DC phenotype can diverge depending on the tissue location and context, there are four main subsets identified in both mouse and human: conventional cDC1 and cDC2, plasmacytoid DCs, and monocyte-derived DCs. In this review, we will discuss the role of these subsets in autoimmune pathogenesis and regulation, as well as the genetic and environmental signals that influence their function. Specific topics to be addressed include impact of susceptibility loci on DC subsets, alterations in DC subset development, the role of infection- and host-derived innate inflammatory signals, and the role of the intestinal microbiota on DC phenotype. The effects of these various signals on disease progression and the relative effects of DC subset composition and maturation level of DCs will be examined. These areas will be explored using examples from several autoimmune diseases but will focus mainly on type 1 diabetes. PMID- 26124759 TI - Editorial: NLR-Protein Functions in Immunity. PMID- 26124758 TI - Role of Innate T Cells in Anti-Bacterial Immunity. AB - Innate T cells are a heterogeneous group of alphabeta and gammadelta T cells that respond rapidly (<2 h) upon activation. These innate T cells also share a non MHC class I or II restriction requirement for antigen recognition. Three major populations within the innate T cell group are recognized, namely, invariant NKT cells, mucosal associated invariant T cells, and gamma delta T cells. These cells recognize foreign/self-lipid presented by non-classical MHC molecules, such as CD1d, MR1, and CD1a. They are activated during the early stages of bacterial infection and act as a bridge between the innate and adaptive immune systems. In this review, we focus on the functional properties of these three innate T cell populations and how they are purposed for antimicrobial defense. Furthermore, we address the mechanisms through which their effector functions are targeted for bacterial control and compare this in human and murine systems. Lastly, we speculate on future roles of these cell types in therapeutic settings such as vaccination. PMID- 26124760 TI - Role of Macrophage Migration Inhibitory Factor in Obesity, Insulin Resistance, Type 2 Diabetes, and Associated Hepatic Co-Morbidities: A Comprehensive Review of Human and Rodent Studies. AB - Obesity is associated with a chronic low-grade inflammatory state that drives the -development of obesity-related co-morbidities such as insulin resistance/type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease. This metabolic inflammation is thought to originate in the adipose tissue, which becomes inflamed and insulin resistant when it is no longer able to expand in response to excess caloric and nutrient intake. The production of inflammatory mediators by dysfunctional adipose tissue is thought to drive the development of more complex forms of disease such as type 2 diabetes and NAFLD. An important factor that may contribute to metabolic inflammation is the cytokine macrophage migration inhibitory factor (MIF). Increasing evidence suggests that MIF is released by adipose tissue in obesity and that it is also involved in metabolic and inflammatory processes that underlie the development of obesity-related pathologies. This review provides a comprehensive summary of our current knowledge on the role of MIF in obesity, its production by adipose tissue, and its involvement in the development of insulin resistance, type 2 diabetes, and NAFLD. We discuss the main findings from recent clinical studies in obese subjects and weight-loss intervention studies as well as results from clinical studies in patients with insulin resistance and type 2 diabetes. Furthermore, we summarize findings from experimental disease models studying the contribution of MIF in obesity and insulin resistance, type 2 diabetes, and hepatic lipid accumulation and fibrosis. Although many of the findings support a pro inflammatory role of MIF in disease development, recent reports also provide indications that MIF may exert protective effects under certain conditions. PMID- 26124762 TI - Anatomy of a nonhost disease resistance response of pea to Fusarium solani: PR gene elicitation via DNase, chitosan and chromatin alterations. AB - Of the multiplicity of plant pathogens in nature, only a few are virulent on a given plant species. Conversely, plants develop a rapid "nonhost" resistance response to the majority of the pathogens. The anatomy of the nonhost resistance of pea endocarp tissue against a pathogen of bean, Fusarium solani f.sp. phaseoli (Fsph) and the susceptibility of pea to F. solani f sp. pisi (Fspi) has been described cytologically, biochemically and molecular-biologically. Cytological changes have been followed by electron microscope and stain differentiation under white and UV light. The induction of changes in transcription, protein synthesis, expression of pathogenesis-related (PR) genes, and increases in metabolic pathways culminating in low molecular weight, antifungal compounds are described biochemically. Molecular changes initiated by fungal signals to host organelles, primarily to chromatin within host nuclei, are identified according to source of the signal and the mechanisms utilized in activating defense genes. The functions of some PR genes are defined. A hypothesis based on this data is developed to explain both why fungal growth is suppressed in nonhost resistance and why growth can continue in a susceptible reaction. PMID- 26124763 TI - The K-segments of wheat dehydrin WZY2 are essential for its protective functions under temperature stress. AB - Dehydrins (DHNs), group 2 of late embryogenesis abundant (LEA) proteins, are up regulated in most plants during cold, drought, heat, or salinity stress. All DHNs contain at least one K-segment, which is believed to play a significant role in DHN function by forming an amphipathic helix. In previous studies, wzy2, an YSK2 type DHN gene, was isolated from the Zhengyin 1 cultivar of Triticum aestivum under cold and drought stress treatment conditions. Four WZY2 truncated derivatives were constructed to knock out the K-, Y- or S-segment, which potentially affect the function of the protein. In vivo assays of Escherichia coli viability enhancement, in vitro lactate dehydrogenase (LDH) activity protection and ex vivo protein aggregation prevention assays revealed that WZY2 acted as a protectant and improved stress tolerance during temperature variation. The results also showed that unlike the truncated derivative without K-segments, the derivative containing two K-segments had remarkable effects that were similar to those of full-length WZY2, indicating that the K-segment is the major functional component of WZY2. Moreover, compared with the other segments, the first K-segment might be the most critical contributor to WZY2 functionality. In general, this work highlights the behavior of DHNs in relieving cold stress ex vivo and the contribution of the K-segment to DHN function. PMID- 26124761 TI - Human and Mouse Mononuclear Phagocyte Networks: A Tale of Two Species? AB - Dendritic cells (DCs), monocytes, and macrophages are a heterogeneous population of mononuclear phagocytes that are involved in antigen processing and presentation to initiate and regulate immune responses to pathogens, vaccines, tumor, and tolerance to self. In addition to their afferent sentinel function, DCs and macrophages are also critical as effectors and coordinators of inflammation and homeostasis in peripheral tissues. Harnessing DCs and macrophages for therapeutic purposes has major implications for infectious disease, vaccination, transplantation, tolerance induction, inflammation, and cancer immunotherapy. There has been a paradigm shift in our understanding of the developmental origin and function of the cellular constituents of the mononuclear phagocyte system. Significant progress has been made in tandem in both human and mouse mononuclear phagocyte biology. This progress has been accelerated by comparative biology analysis between mouse and human, which has proved to be an exceptionally fruitful strategy to harmonize findings across species. Such analyses have provided unexpected insights and facilitated productive reciprocal and iterative processes to inform our understanding of human and mouse mononuclear phagocytes. In this review, we discuss the strategies, power, and utility of comparative biology approaches to integrate recent advances in human and mouse mononuclear phagocyte biology and its potential to drive forward clinical translation of this knowledge. We also present a functional framework on the parallel organization of human and mouse mononuclear phagocyte networks. PMID- 26124764 TI - Early embryo achievement through isolated microspore culture in Citrus clementina Hort. ex Tan., cvs. 'Monreal Rosso' and 'Nules'. AB - Microspore embryogenesis is a method of achieving complete homozygosity from plants. It is particularly useful for woody species, like Citrus, characterized by long juvenility, a high degree of heterozygosity and often self incompatibility. Anther culture is currently the method of choice for microspore embryogenesis in many crops. However, isolated microspore culture is a better way to investigate the processes at the cellular, physiological, biochemical, and molecular levels as it avoids the influence of somatic anther tissue. To exploit the potential of this technique, it is important to separate the key factors affecting the process and, among them, culture medium composition and particularly the plant growth regulators and their concentration, as they can greatly enhance regeneration efficiency. To our knowledge, the ability of meta Topolin, a naturally occurring aromatic cytokinin, to induce gametic embryogenesis in isolated microspores of Citrus has never been investigated. In this study, the effect of two concentrations of meta-Topolin instead of benzyladenine or zeatin in the culture medium was investigated in isolated microspore culture of two genotypes of Citrus. After 11 months of isolated microspore culture, for both genotypes and for all the four tested media, the microspore reprogramming and their sporophytic development was observed by the presence of multinucleated calli and microspore-derived embryos at different stages. Microsatellite analysis of parental and embryo samples was performed to determine the embryo alleles constitution of early embryos produced in all tested media, confirming their origin from microspores. To our knowledge, this is the first successful report of Citrus microspore embryogenesis with isolated microspore culture in Citrus, and in particular in Citrus clementina Hort. ex Tan, cvs. 'Monreal Rosso' and 'Nules.' PMID- 26124765 TI - A comprehensive survey of the grapevine VQ gene family and its transcriptional correlation with WRKY proteins. AB - WRKY proteins are a class of transcription factors (TFs) involved in the regulation of various physiological processes, including the plant response to biotic and abiotic stresses. Recent studies in Arabidopsis have revealed that some WRKY TFs interact with a class of proteins designed as VQ proteins because of their typical conserved motif (FxxxVQxLTG). So far, no information is available about the genomic organization and the function of VQ motif-containing protein in grapevine (Vitis vinifera L). In the current study, we analyzed the 12X V1 prediction of the nearly homozygous PN40024 genotype identifying up to 18 predicted VQ genes (VvVQ). VvVQs phylogenetic and bioinformatic analyses indicated that the intron-exon structures and motif distribution are highly divergent between different members of the grapevine VQ family. Moreover, the analysis of the V. vinifera cv. Corvina expression atlas revealed a tissue- and stage-specific expression of several members of the family which also showed a significant correlation with WRKY TFs. Grapevine VQ genes also exhibited altered expression in response to drought, powdery mildew infection, salicylic acid (SA) and ethylene (ETH) treatments. The present study represents the first characterization of VQ genes in a grapevine genotype and it is a pivotal foundation for further studies aimed at functionally characterizing this mostly unknown grapevine multigenic family. PMID- 26124766 TI - Using 7 cm immobilized pH gradient strips to determine levels of clinically relevant proteins in wheat grain extracts. AB - The aim of the work was to test a relatively simple proteomics approach based on phenol extraction and two-dimensional gel electrophoresis (2-DE) with 7 cm immobilized pH gradient strips for the determination of clinically relevant proteins in wheat grain. Using this approach, 157 2-DE spots were quantified in biological triplicate, out of which 55 were identified by matrix-assisted laser desorption/ionization - time of flight tandem mass spectrometry. Clinically relevant proteins associated with celiac disease, wheat dependent exercise induced anaphylaxis, baker's asthma, and food allergy, were detected in 24 2-DE spots. However, alcohol-soluble gliadins were not detected with this approach. The comparison with a recent quantitative study suggested that gel-based and gel free proteomics approaches are complementary for the detection and quantification of clinically relevant proteins in wheat grain. PMID- 26124768 TI - An improved fruit transcriptome and the identification of the candidate genes involved in fruit abscission induced by carbohydrate stress in litchi. AB - Massive young fruit abscission usually causes low and unstable yield in litchi (Litchi chinensis Sonn.), an important fruit crop cultivated in tropical and subtropical areas. However, the molecular mechanism of fruit drop has not been fully characterized. This study aimed at identification of molecular components involved in fruitlet abscission in litchi, for which reference genome is not available at present. An improved de novo transcriptome assembly was firstly achieved by using an optimized assembly software, Trinity. Using improved transcriptome assembly as reference, digital transcript abundance (DTA) profiling was performed to screen and identify candidate genes involved in fruit abscission induced by girdling plus defoliation (GPD), a treatment significantly decreased the soluble sugar contents causing carbohydrate stress to fruit. Our results showed that the increasing fruit abscission rate after GPD treatment was associated with higher ethylene production and lower glucose levels in fruit. A total of 2,771 differentially expressed genes were identified as GPD-responsive genes, 857 of which were defined by GO and KEGG enrichment analyses as the candidate genes involved in fruit abscission process. These genes were involved in diverse metabolic processes and pathways, including carbohydrate metabolism, plant hormone synthesis, and signaling, transcription factor activity and cell wall modification that were rapidly induced in the early stages (within 2 days after treatment). qRT-PCR was used to explore the expression pattern of 15 selected candidate genes in the abscission zone, pericarp, and seed, which confirmed the accuracy of our DTA data. More detailed information for different functional categories was also analyzed. This study profiled the gene expression related to fruit abscission induced by carbohydrate stress at whole transcriptome level and thus provided a better understanding of the regulatory mechanism of young fruit abscission in litchi. PMID- 26124767 TI - Circadian rhythms and post-transcriptional regulation in higher plants. AB - The circadian clock of plants allows them to cope with daily changes in their environment. This is accomplished by the rhythmic regulation of gene expression, in a process that involves many regulatory steps. One of the key steps involved at the RNA level is post-transcriptional regulation, which ensures a correct control on the different amounts and types of mRNA that will ultimately define the current physiological state of the plant cell. Recent advances in the study of the processes of regulation of pre-mRNA processing, RNA turn-over and surveillance, regulation of translation, function of lncRNAs, biogenesis and function of small RNAs, and the development of bioinformatics tools have helped to vastly expand our understanding of how this regulatory step performs its role. In this work we review the current progress in circadian regulation at the post transcriptional level research in plants. It is the continuous interaction of all the information flow control post-transcriptional processes that allow a plant to precisely time and predict daily environmental changes. PMID- 26124769 TI - Development and regulation of pedicel abscission in tomato. AB - To shed unfertilized flowers or ripe fruits, many plant species develop a pedicel abscission zone (AZ), a specialized tissue that develops between the organ and the main body of the plant. Regulation of pedicel abscission is an important agricultural concern because pre-harvest abscission can reduce yields of fruit or grain crops, such as apples, rice, wheat, etc. Tomato has been studied as a model system for abscission, as tomato plants develop a distinct AZ at the midpoint of the pedicel and several tomato mutants, such as jointless, have pedicels that lack an AZ. This mini-review focuses on recent advances in research on the mechanisms regulating tomato pedicel abscission. Molecular genetic studies revealed that three MADS-box transcription factors interactively play a central role in pedicel AZ development. Transcriptome analyses identified activities involved in abscission and also found novel transcription factors that may regulate AZ activities. Another study identified transcription factors mediating abscission pathways from induction signals to activation of cell wall hydrolysis. These recent findings in tomato will enable significant advances in understanding the regulation of abscission in other key agronomic species. PMID- 26124771 TI - Transient transformation meets gene function discovery: the strawberry fruit case. AB - Beside the well known nutritional and health benefits, strawberry (FragariaXananassa) crop draws increasing attention as plant model system for the Rosaceae family, due to the short generation time, the rapid in vitro regeneration, and to the availability of the genome sequence of F.Xananassa and F. vesca species. In the last years, the use of high-throughput sequence technologies provided large amounts of molecular information on the genes possibly related to several biological processes of this crop. Nevertheless, the function of most genes or gene products is still poorly understood and needs investigation. Transient transformation technology provides a powerful tool to study gene function in vivo, avoiding difficult drawbacks that typically affect the stable transformation protocols, such as transformation efficiency, transformants selection, and regeneration. In this review we provide an overview of the use of transient expression in the investigation of the function of genes important for strawberry fruit development, defense and nutritional properties. The technical aspects related to an efficient use of this technique are described, and the possible impact and application in strawberry crop improvement are discussed. PMID- 26124772 TI - Caenorhabditis elegans expressing the Saccharomyces cerevisiae NADH alternative dehydrogenase Ndi1p, as a tool to identify new genes involved in complex I related diseases. AB - Isolated complex I deficiencies are one of the most commonly observed biochemical features in patients suffering from mitochondrial disorders. In the majority of these clinical cases the molecular bases of the diseases remain unknown suggesting the involvement of unidentified factors that are critical for complex I function. The Saccharomyces cerevisiae NDI1 gene, encoding the mitochondrial internal NADH dehydrogenase was previously shown to complement a complex I deficient strain in Caenorhabditis elegans with notable improvements in reproduction and whole organism respiration. These features indicate that Ndi1p can functionally integrate the respiratory chain, allowing complex I deficiency complementation. Taking into account the Ndi1p ability to bypass complex I, we evaluate the possibility to extend the range of defects/mutations causing complex I deficiencies that can be alleviated by NDI1 expression. We report here that NDI1 expressing animals unexpectedly exhibit a slightly shortened lifespan, a reduction in the progeny, and a depletion of the mitochondrial genome. However, Ndi1p is expressed and targeted to the mitochondria as a functional protein that confers rotenone resistance to those animals without affecting their respiration rate and ATP content. We show that the severe embryonic lethality level caused by the RNAi knockdowns of complex I structural subunit encoding genes (e.g., NDUFV1, NDUFS1, NDUFS6, NDUFS8, or GRIM-19 human orthologs) in wild type animals is significantly reduced in the Ndi1p expressing worm. All together these results open up the perspective to identify new genes involved in complex I function, assembly, or regulation by screening an RNAi library of genes leading to embryonic lethality that should be rescued by NDI1 expression. PMID- 26124770 TI - Prunus transcription factors: breeding perspectives. AB - Many plant processes depend on differential gene expression, which is generally controlled by complex proteins called transcription factors (TFs). In peach, 1533 TFs have been identified, accounting for about 5.5% of the 27,852 protein-coding genes. These TFs are the reference for the rest of the Prunus species. TF studies in Prunus have been performed on the gene expression analysis of different agronomic traits, including control of the flowering process, fruit quality, and biotic and abiotic stress resistance. These studies, using quantitative RT-PCR, have mainly been performed in peach, and to a lesser extent in other species, including almond, apricot, black cherry, Fuji cherry, Japanese apricot, plum, and sour and sweet cherry. Other tools have also been used in TF studies, including cDNA-AFLP, LC-ESI-MS, RNA, and DNA blotting or mapping. More recently, new tools assayed include microarray and high-throughput DNA sequencing (DNA-Seq) and RNA sequencing (RNA-Seq). New functional genomics opportunities include genome resequencing and the well-known synteny among Prunus genomes and transcriptomes. These new functional studies should be applied in breeding programs in the development of molecular markers. With the genome sequences available, some strategies that have been used in model systems (such as SNP genotyping assays and genotyping-by-sequencing) may be applicable in the functional analysis of Prunus TFs as well. In addition, the knowledge of the gene functions and position in the peach reference genome of the TFs represents an additional advantage. These facts could greatly facilitate the isolation of genes via QTL (quantitative trait loci) map-based cloning in the different Prunus species, following the association of these TFs with the identified QTLs using the peach reference genome. PMID- 26124773 TI - Admixture mapping of tuberculosis and pigmentation-related traits in an African European hybrid cattle population. AB - Admixture mapping affords a powerful approach to genetic mapping of complex traits and may be particularly suited to investigation in cattle where many breeds and populations are hybrids of the two divergent ancestral genomes, derived from Bos taurus and Bos indicus. Here we design a minimal genome wide SNP panel for tracking ancestry in recent hybrids of Holstein-Friesian and local Arsi zebu in a field sample from a region of high bovine tuberculosis (BTB) endemicity in the central Ethiopian highlands. We first demonstrate the utility of this approach by mapping the red coat color phenotype, uncovering a highly significant peak over the MC1R gene and a second peak with no previously known candidate gene. Secondly, we exploit the described differential susceptibility to BTB between the ancestral strains to identify a region in which Bos taurus ancestry associates, at suggestive significance, with skin test positivity. Interestingly, this association peak contains the toll-like receptor gene cluster on chromosome 6. With this work we have shown the potential of admixture mapping in hybrid domestic animals with divergent ancestral genomes, a recurring condition in domesticated species. PMID- 26124774 TI - Analysis of the type II-A CRISPR-Cas system of Streptococcus agalactiae reveals distinctive features according to genetic lineages. AB - CRISPR-Cas systems (clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins) are found in 90% of archaea and about 40% of bacteria. In this original system, CRISPR arrays comprise short, almost unique sequences called spacers that are interspersed with conserved palindromic repeats. These systems play a role in adaptive immunity and participate to fight non-self DNA such as integrative and conjugative elements, plasmids, and phages. In Streptococcus agalactiae, a bacterium implicated in colonization and infections in humans since the 1960s, two CRISPR-Cas systems have been described. A type II-A system, characterized by proteins Cas9, Cas1, Cas2, and Csn2, is ubiquitous, and a type I-C system, with the Cas8c signature protein, is present in about 20% of the isolates. Unlike type I-C, which appears to be non functional, type II-A appears fully functional. Here we studied type II-A CRISPR cas loci from 126 human isolates of S. agalactiae belonging to different clonal complexes that represent the diversity of the species and that have been implicated in colonization or infection. The CRISPR-cas locus was analyzed both at spacer and repeat levels. Major distinctive features were identified according to the phylogenetic lineages previously defined by multilocus sequence typing, especially for the sequence type (ST) 17, which is considered hypervirulent. Among other idiosyncrasies, ST-17 shows a significantly lower number of spacers in comparison with other lineages. This characteristic could reflect the peculiar virulence or colonization specificities of this lineage. PMID- 26124775 TI - Prevalence of hepatitis B and C and relationship to liver damage in HIV infected patients attending Joint Clinical Research Centre Clinic (JCRC), Kampala, Uganda. AB - BACKGROUND: Hepatitis B and C viruses cause death due to liver disease worldwide among Human Immunodeficiency Virus (HIV) positive individuals. Hepatitis B (HBV) and HIV have similar routes of transmission primarily; sexual, intravenous injections and prenatal while hepatitis C (HCV) is transmitted mainly through blood transfusion. Human immunodeficiency virus increases the pathological effect of hepatitis viruses and potentiates re-activation of latent hepatitis infections as a result of reduced immunity. The increase in use of antiretroviral (ARVs) drugs has led to longer period for patient survival and apparent increase in liver disease among HIV positive individuals. OBJECTIVE: This study aimed at determining the prevalence of HBV, HCV, their co-infection with HIV and their effect on liver cell function. METHOD: This was a cross sectional study conducted at the Joint Clinical Research Centre (JCRC) among HIV positive individuals attending the clinic. Patients were enrolled after obtaining a signed informed consent or assent for children below 17 years. Serum samples were collected for detection of Hepatitis B surface antigen (HBsAg), HCV specific antibodies and alanine aminotransferase (ALT) liver enzyme. RESULTS: Of the 89 patients enrolled, 20 (22.5%) had at least one hepatitis virus, 15 tested positive for HBsAg (16.9%) and 5 for HCV (5.6%), one had both viruses. Hepatitis B was more prevalent among women (13 out of 57, 22.8%) than men, (2 out of 32, 6.2%), while HCV was higher among men (4 out of 32, 12.5%) than women (1 out of 57, 1.8%). Seven of 89 patients (7.9%) had elevated ALT, indicative of liver cell injury. Of these with liver cell injury, one individual tested positive for HBsAg and another one individual tested positive for HCV specific antibodies. CONCLUSION: The prevalence of HBV is high in HIV positive individuals with more women commonly infected. The Prevalence of HCV is lower than that of HBV with more men commonly infected. Co-infection of Hepatitis B and C viruses was uncommon. This study reveals a high prevalence of liver cell injury among HIV positive individuals although the injury due to HBV or HCV infection was lower than that which has been documented. From this study, the high prevalence of HBV and HCV among HIV positive individuals point to a need for screening of HIV positive individuals for the hepatitis viruses. PMID- 26124776 TI - Hepatitis B and HIV co-infection is still treated using lamivudine-only antiretroviral therapy combination in Uganda. AB - BACKGROUND: Hepatitis B virus (HBV) and HIV are endemic in Uganda. Co-infection is common and leads to rapid progression of liver disease. Burden of co-infection is unknown yet most patients are on lamivudine-only ART where resistance is frequent. Most patients are initiated on antiretroviral therapy (ART) without knowing their HBV status. OBJECTIVES: To determine burden of co-infection and HBV viral suppression among patients on ART in Northern Uganda. METHODS: We recruited HIV infected adult patients on ART in a cross-sectional study. Age, sex, ART regimen and duration were recorded. Hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBcAb) and liver panel were performed. For those HBsAg+, hepatitis B e antigen (HBeAg) and HBV DNA were performed. CD4 cell count was recorded. RESULTS: Three hundred patients were recruited. Twenty (6.7%) were co-infected, while 41% were anti-HBcAb+. Overall 188 (62.7%) were on lamivudine- only HBV active drug. Median ART duration 2 years (IQR 1-5), mean CD4+ cell count 317 cells/microlitre (SD 255-557). Of 20 HIV/HBV co-infected, 11/20 (55%) were on lamivudine-only ART, median duration 1.5 years. Nineteen (95%) had undetectable HBV DNA. Seventeen (85%) were HBeAg negative. Mean CD4+ cell count 327 cells/microlitre (SD 197-482). CONCLUSION: A large proportion of patients were on lamivudine- only HBV-active ART. Resistance may occur long term thus testing for HBV and correct ART is recommended. PMID- 26124777 TI - A non-specific biomarker of disease activity in HIV/AIDS patients from resource limited environments. AB - BACKGROUND: A general non-specific marker of disease activity that could alert the clinician and prompt further investigation would be of value in patients with HIV/AIDS, especially in resource limited environments. OBJECTIVE: To investigate the potential of neopterin as non-specific biomarker in patients with advanced HIV/AIDS. METHODS: Cross-sectional study in 105 HIV positive patients (75 on highly active antiretroviral treatment (HAART). Neopterin was assessed by enzyme linked immune-absorbent assay and cytokines by flow cytometry. RESULTS: Neopterin levels were significantly higher (p<0.001) for the total patient than for the control group. Significant correlations between neopterin and plasma indicators of inflammation showed neopterin to be a good indicator of active inflammatory status and of the effect of HAART on the immune system. Neopterin was superior to C-reactive protein and to individual cytokines as indicator of immune deficiency. Increased neopterin levels were associated with a decline in albumin, haemoglobin and the albumin/globulin ratio, and with increases in red cell distribution width. CONCLUSIONS: Plasma neopterin is a good non-specific biomarker of disease activity in HIV/AIDS patients. It is a good indicator of inflammatory activity, perpetuation of inflammation-associated co-morbidities, degree of immune deficiency and has predictive value for underlying disease, and for monitoring the HAART response. PMID- 26124778 TI - Factors affecting disclosure of serostatus to children attending Jinja Hospital Paediatric HIV clinic, Uganda. AB - BACKGROUND: Disclosure of HIV status is important for optimal adherence to antiretroviral therapy in children. Identifying factors that affect disclosure of sero-status to children will help improve the process of disclosure. The purpose of the study was to determine the rate of HIV disclosure by the parents/caretakers to their children and other factors affecting disclosure. METHODS: A cross sectional study among 174 caretakers of children age 5-8 years, twenty children and all (ten) health workers at Jinja Hospital paediatric HIV clinic. Data was collected with standardized questionnaires on socio-demographic factors, disclosure status, health facility factors, fears and perceived benefits of disclosure. RESULTS: We found disclosure rates in 56% of the children. Among those not disclosed to, non-disclosure was 19% and deception 25%. Factors associated with disclosure of sero-status to a child were age of child (X2 37.4 df 1 p< 0.001), child being on antiretroviral therapy (OR 2.0 CI 1.1-3.6 p=0.024) and child attending psychosocial support group (OR 7.4 CI 3.6-15.3 p < 0.001). There were no appropriate guidelines on disclosure and only half of health providers had training on disclosure of HIV serostatus to children. CONCLUSION: The overall prevalence of disclosure was low. Psychosocial support groups promoted disclosure. PMID- 26124779 TI - A retrospective evaluation of critically ill patients infected with H1N1 influenza A virus in Bursa, Turkey, during the 2009-2010 pandemic. AB - BACKGROUND: H1N1 influenza A virus infections were first reported in April 2009 and spread rapidly, resulting in mortality worldwide. The aim of this study was to evaluate patients with H1N1 infection treated in the intensive care unit (ICU) in Bursa, Turkey. METHODS: Demographic characteristics, clinical features, and outcome relating to H1N1 infection were retrospectively analysed in patients treated in the ICU. RESULTS: Twenty-three cases of H1N1 infection were treated in the ICU. The mean age of patients was 37 years range: (17-82). Fifteen patients were female (65.2%). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 19 range: (5-39). The most common symptoms were dyspnea (73.9%), fever (69.6%), and cough (60.9%). Mechanical ventilation was required for all patients. Oseltamivir and antibiotics were administered to all patients. Six (26.1%) patients died. APACHE II scores were higher in the deceased 28.5 range: [16-39] vs. 14 range: [5-28] in survivors; p = 0.013). CONCLUSION: When compared to the literature, the demographic, epidemiological, and clinical characteristics were similar in the cases we encountered. The mortality rate was high despite the use of appropriate treatment. We believe that the high mortality is related to higher APACHE II scores. The H1N1 virus should be considered in community acquired pneumonia, especially in younger patients presenting with severe pneumonia. PMID- 26124780 TI - Evaluation of the diagnostic performance and operational characteristics of four rapid immunochromatographic syphilis tests in Burkina Faso. AB - BACKGROUND AND OBJECTIVE: Little information is available on the rapid diagnostic testing for syphilis in Burkina Faso. The objectives of the study were (i) to assess the sensitivity and specificity of four on site rapid tests in comparison with Treponema pallidum haemagglutination assay (TPHA) as a gold standard and (ii) to evaluate the operational characteristics of those tests among health workers in a maternity unit. METHODS: Four rapid syphilis tests commercially available in Burkina Faso were evaluated using archived serum samples and Treponema pallidum hemagglutination assay (TPHA) as the gold standard. Blood samples were collected between November 2011 and June 2012 from blood donors at the Regional Blood Transfusion Center of Ouagadougou. The sensitivity and specificity of the tests were calculated. Evaluation of operational characteristics such as clarity of pamphlet, complexity of technique, duration, was conducted in a first-level healthcare center with health workers in maternity unit. RESULTS: Alere DetermineTM Syphilis was the most sensitive of the four rapid syphilis tests evaluated. It was followed by SD Bioline Syphilis 3.0, Cypress Diagnostics Syphilis Quick test and Accu-Tell (r) Rapid Anti-TP, which was the least sensitive. The four tests demonstrated a good diagnostic specificity for syphilis (95-98%), and healthcare workers found them easy to use. CONCLUSIONS: The study allowed confirming the good performance of three of four rapid syphilis tests in Burkina Faso. More research will be conducted to assess the feasibility of introducing selected rapid tests for syphilis in antenatal care services. PMID- 26124781 TI - Risk factors for multidrug resistant tuberculosis patients in Amhara National Regional State. AB - BACKGROUND: Multidrug resistant tuberculosis(MDR-TB) is becoming a major threat to tuberculosis control programs in Ethiopia. OBJECTIVES: To determine risk factors of MDR-TB patients in Amhara National Regional State, Ethiopia. METHODS: Case-control study was conducted from May 2013 to January 2014. Resistance to rifampicin and isoniazid were done molecularly using line probe assay. TB patients infected with MDR-M.tuberculosis and non MDR-M.tuberculosis strain were considered as cases and controls, respectively. Data was collected using structured questionnaire with face to face interview. Patients' clinical record review was also done.Multivariate analysis was computed to determine the risk factors of MDR-TB. RESULTS: A total of 153 MDR-TB and equal number of non MDR-TB patients' participated in the study. Patients who had TB treatment failure (AOR=13.5,CI=2.69-70), cavitations on chest x-ray (AOR=1.9,CI=1.1-3.38) and contact with MDR-TB patients (AOR=1.4,CI=0.19-0.39) were more likely to be MDR-TB patients. Low monthly income (AOR=1.1,CI=0.34-0.47),alcohol consumption (AOR=1.5,CI=0.2-0.98) and young age (AOR=2.9,CI=1.07-7.68) were the other risk factors of MDR-TB. CONCLUSIONS: TB treatment failure, cavitation on chest X-ray, contact with MDR-TB patients and low socioeconomic status were important risk factors for development of MDR-TB. Therefore, strict adherence to directly observed therapy, appropriate management of TB patients and advice on the value of nutrients are helpful to control the spreading of MDR-TB. PMID- 26124782 TI - Emotional distress in Angolan patients with several types of tuberculosis. AB - BACKGROUND: There is growing evidence that emotional distress expressed in terms of anxiety and depression is very high among tuberculosis (TB) patients. OBJECTIVES: This study aims to determine levels of anxiety, depression and emotional distress in patients with several types of TB and to determine the association between social-demographic and economical factors, clinical variables and anxiety, depression and emotional distress. METHODS: A cross-sectional study was performed in a sample of 81 TB patients. A social-demographic and economical questionnaire was used, followed by the hospital anxiety and depression scale. RESULTS: 38.3% and 49.4% of our sample presented significant levels of anxiety and depression. 44.4% of patients had significant levels of emotional distress.Married subjects, a diagnosis of extra-pulmonary TB and multidrug resistant TB were related to higher risk for anxiety. Gender, extra-pulmonary and multidrug resistant TB were associated to depression. Female gender and cases of extra-pulmonary TB presented a 1.5 times risk for emotional distress. CONCLUSIONS: Our study found high rates of anxiety, depression and emotional distress among TB patients. Marital status, gender, type and treatment of TB were related to higher levels of emotional disorder. Mental health services should be an integral part of programs against tuberculosis. PMID- 26124783 TI - Illness perceptions and quality of life among tuberculosis patients in Gezira, Sudan. AB - AIMS: This study aimed to answer the following research question: What is the level of illness perceptions and quality of life among TB patients in Gezira state?. METHODS: A descriptive study design was used. Newly diagnosed smear positive TB patients registered in Gezira state in 2010 (n=425) formed the study population. The illness perceptions were measured by using Brief Illness Perceptions Questionnaire (BIPQ). Health Related Quality of Life (HRQoL) was assessed by means of the 12-item short form Health Survey questionnaire (FS-12). RESULTS: TB patients saw TB as having minor consequences, TB not being very well controlled by treatment, and TB as lasting long as a disease; they also associated several symptoms with TB. Furthermore, the patients had relatively poor physical and mental quality of life. Identity, consequences, personal control and emotional representations were associated with poor physical quality of life while concern about illness was associated with poor mental quality of life. CONCLUSION: The illness perceptions of the TB patients might influence their adherence to treatment. The poor quality of life of the TB patients in the different areas of quality of life such as daily activities and work, calls for programmes to strengthen TB information, education and counselling. PMID- 26124784 TI - Prevalence of Giardia intestinalis and Hymenolepis nana in Afghan refugee population of Mianwali district, Pakistan. AB - BACKGROUND: Present study aimed to investigate prevalence of Giardia intestinalis and Hymenolepis nana in Afghan refugees visiting Central Health Unit (CHU), Kot Chandana (Mianwali, Northern Punjab) during two years period (February 2007 to December 2009). METHODS: A total of 687 stool samples were collected from different age groups of both genders. Samples were processed under sterile conditions after gross examination. Microscopic examination was done on same day along with eggs (H. nana), cyst and trophozoites (G. intestinalis) detection after staining. RESULTS: The prevalence of G. intestinalis was significantly higher (x2=59.54, p<0.001) than that of H. nana. Females were found more likely to be infected as compared to males (OR: 1.40, 95% CI=1.03-1.92). Prevalence of both parasites decreased with age and highest prevalence was observed in young individuals belonging to 1-15 years of age group (41.8% and 48.7% respectively for H. nana and G. intestinalis, p<0.001). Abdominal distress (OR: 1.13, 95%CI=0.83-1.53), vomiting (OR: 1.13, 95%CI=1.13-1.81) and rectal prolapse (OR: 4.26, 95%CI=1.38-13.16) were the gastro-intestinal clinical symptoms observed in G. intestinalis. Whereas, bloody diarrhea (OR: 1.56, 95%CI=1.00-2.43) and rectal prolapse (OR: 5.79, 95%CI=1.87-17.91) were associated with H. nana infections. CONCLUSIONS: Intestinal parasitic infections are common among Afghan refugees and serious preventive measures should be implemented to promote the safety and healthy lifestyle of these people. PMID- 26124785 TI - Knowledge and practices on malaria prevention in two rural communities in Wakiso District, Uganda. AB - BACKGROUND: Malaria is the leading cause of morbidity and mortality in Uganda particularly among children under 5 years of age. OBJECTIVES: The study assessed the knowledge and practices on malaria prevention in 2 rural communities in Wakiso District, Uganda with emphasis on the various prevention methods. METHODS: The study was a cross-sectional survey carried out among 376 households using both quantitative and qualitative methods. Log-binomial regression, chi square and Spearman's rank order correlation were used to test for associations. RESULTS: The majority of participants (64.6%) had low knowledge on malaria prevention methods, with untreated mosquito nets (81.7%), mosquito coils (36.9%) and insecticide treated nets (29.6%) being the most known methods. Knowledge on malaria prevention methods was associated with age (chi2 = 32.1; p < 0.01), employment status (chi2 = 18.1; p < 0.01), education (chi2 = 20.3; p = 0.01), income (chi2 = 14.5; p = 0.01) and having heard a malaria message in the previous 12 months (chi2 = 92.3; p < 0.01). Households that had at least one mosquito net were 45.5% and net ownership increased with household income. Only 0.5% of the houses had undergone indoor residual spraying in the previous 12 months, while 2.1% had complete mosquito proofing in windows and ventilators to prevent mosquito entry. CONCLUSION: There is potential to improve practices on malaria prevention by targeting other methods beyond mosquito nets such as installing proofing in windows and ventilators. The integrated approach to malaria prevention which advocates the use of several malaria prevention methods in a holistic manner should be explored for this purpose. PMID- 26124786 TI - Factors influencing the usage of different types of malaria prevention methods during pregnancy in Kenya. AB - BACKGROUND: In sub-Saharan Africa, malaria is a leading cause of morbidity and mortality, which, during pregnancy, is associated with adverse health outcomes for both mother and foetus. Utilization of Insecticide Treated Nets (ITNs) and Intermittent Preventive Therapy (IPTp) is advocated to prevent malaria during pregnancy. OBJECTIVE: To examine factors which influence the use of different types of malaria prevention methods among pregnant women in Kenya. METHODS: This study used 2008-09 Kenya Demographic and Health survey. Pregnant women aged 15-49 years were included (622 women). Distribution of the study population was assessed in frequency tables. Bivariate and multivariate logistic regression analysis was employed. RESULTS: Fifty-two percent of women used ITNs and 38.5% reported uptake of IPTp. In multivariate analysis age, malaria risk areas, religion, education and income influenced ITN usage, whereas only age, malaria risk areas and marital status were found to influence IPTP uptake. CONCLUSIONS: ITN use and IPTp uptake were well below the 80% Kenya Malaria Strategy 2006 target. In an effort to increase uptake it is vital for future research to understand reasons for low usage and uptake of malaria prevention programmes so as to enable policy-makers to make informed decisions. PMID- 26124787 TI - Response of patent medicine vendors in rural areas of Lagos state Nigeria to antimalarial policy change. AB - BACKGROUND: Patent medicine vendors (PMVs) play an important role in the treatment of malaria, especially in the rural areas. Nigeria recently changed her antimalarial treatment policy from chloroquine to artemisinin-based combination therapy (ACT). OBJECTIVES: To determine the response of PMVs to the new policy. METHODS: A baseline study was conducted in two local government areas (LGAs) of Lagos state Nigeria as the first phase in an intervention study aimed at improving the malarial treatment practices of PMVs in rural Lagos. A mixed method design involving a questionnaire survey of 180 PMVs and four key informant interviews were used. An antimalarial drug (AMD) audit was also performed. RESULTS: More than 80% of respondents were aware of the policy change in malaria treatment, but only 23.9% sold an ACT for the last case of malaria treated in an under five child. The main determining factor of the particular AMD sold was PMV's personal choice (70.6%). About half (58.9%) of the shops stocked ACTs, the newly recommended antimalarials. CONCLUSIONS: The high awareness of the policy change did not translate to a commensurate increase in the sale of the new drugs. Factors beyond the PMVs need to be addressed for a successful adoption of the new policy. PMID- 26124788 TI - Adolescent low back pain among secondary school students in Ibadan, Nigeria. AB - BACKGROUND: Adolescent low back pain (ALBP) can be considered a signal or precursor of a serious organic disease or telltale sign of future incidence of low back pain in adulthood. Published articles on ALBP in Nigeria are not readily available. OBJECTIVES: The study's objectives were to investigate the prevalence of Adolescent Low Back Pain (ALBP) among secondary school students in Ibadan, Nigeria and the prevalence's association with some socio-demographic variables. METHODS: Participants were adolescent students from 15 secondary schools in Ibadan. Data was collected using a respondent-administered, validated questionnaire on low back pain in adolescents. Participants (Female: 298; Male: 273) aged 14.23 +/-2.27 years (range 10-19) were recruited through multi-stage random sampling. Five hundred and seventy-one (83.97%) of the 680 copies of the questionnaire administered were returned. Data was analysed using mean, standard deviation, frequency, percentages, and Chi-square test with alpha level at 0.05. RESULT: Lifetime, twelve-month, one-month and point prevalence rates of ALBP were 58.0%, 43.8%, 25.6% and 14.7% respectively. Age at first experience of ALBP was 11.86 +/- 2.36 years. Gender was not significantly associated with any rate (p >=0.317). Age (p <= 0.043) and engagement in commercial activities (p <= 0.025) were significantly associated with all period prevalence rates while injury to the back was significantly associated with all period prevalence rates except point prevalence (p = 0.087). CONCLUSION: Adolescent low back pain is common among secondary school students in Ibadan and its prevalence is significantly associated with age and engagement in commercial activities, but not with gender. PMID- 26124789 TI - A report from the first regional pain medicine symposia in East, Central and Southern African region. (ECSA-R)-"The Rhino Model in Pain Education in Africa". PMID- 26124790 TI - Musculoskeletal disorders among first-year Ghanaian students in a nursing college. AB - OBJECTIVE: To estimate the prevalence and extent of MSDs among a sample of freshmen in a nursing college in Ghana. METHODS: A semi-structured self-reported questionnaire including the Nordic Musculoskeletal Questionnaire (NMQ) was used to collect information on age, gender and musculoskeletal complaints among a random sample of 200 students at a nursing and midwifery college in the Eastern region of Ghana. RESULTS: Out of the 200 questionnaires administered, 160 were retrieved of which 3 were found to be incomplete and void, yielding a total of 157 evaluable questionnaires, a response rate of 78.5%. One hundred and ten (70.1%) students reported having MSDs in the previous 12 months, of which a total 88 (56.1%) suffered disabling effects, while 70(44.6%) students reported having MSDs in the past 7 days. The prevalence of MSDs in the different body regions was generally low with clustered distribution in the neck, upper back, wrists/hands and lower back. CONCLUSION: Nursing students are at reasonably high risk of MSDs. Strategies to prevent this important public health problem amongst future generation of nursing students must be given utmost priority. This study provides the baseline data for more elaborative studies in the Ghanaian population. PMID- 26124791 TI - Satisfaction and adherence of patients with amputations to physiotherapy service at public hospitals in KwaZulu-Natal, South Africa. AB - BACKGROUND: Individuals who have undergone a lower limb amputation require comprehensive rehabilitation from the multidisciplinary team to ensure optimal treatment outcomes and social integration. Physiotherapists play a pivotal role within the multidisciplinary team and offer patients physical and psychosocial rehabilitative care. Determining patients' satisfaction levels and exploring factors affecting adherence to physiotherapy interventions can inform practice and improve service delivery of rehabilitation within resource poor settings such as South Africa. OBJECTIVES: To determine the level of satisfaction with physiotherapy services rendered to acute and sub-acute in-patients with lower limb amputations and to explore factors affecting adherence to physiotherapy intervention. METHODS: A prospective survey of 35 patients with lower limb amputations from four public hospitals in South Africa was undertaken. A modified version of the Hampstead rehabilitation centre patient satisfaction questionnaire was utilised. RESULTS: Majority of participants were satisfied with the physiotherapy services whilst a few reported dissatisfaction. Three themes emerged whilst exploring the patients' experience relating to adherence to physiotherapy programmes. Themes included service delivery, patient-therapist interaction and participation barriers and facilitators. CONCLUSION: Recommendations aimed to improve quality of care and healthcare outcomes thereby enhancing the participants' adherence to the physiotherapy programme. PMID- 26124792 TI - Overcrowding of accident & emergency units: is it a growing concern in Nigeria? AB - BACKGROUND: The inability of the Nigeria's Accident and Emergency Departments (AED) to meet current demands is growing among the public and health care professionals. The data supporting perceptions of insufficient capacity are limited. Therefore, this study was intended to determine the prevalence, causes, and effects of overcrowding AEDs in Nigeria. MATERIALS AND METHODS: This was a cross sectional, descriptive study carried out among AED staff of 3 referral teaching hospitals in Nigeria, using a pre-tested and validated structured questionnaire. RESULTS: The analysis of the 267 AED staff revealed 20-56 years (36.40+5.1 mean) age range. One hundred and twenty eight (47.9%) were males, 139 (52.1%) females. Two hundred and fifty nine (97%) agreed that an AED should have a bed capacity of 21-30. Agreement to AED overcrowding in Nigeria was quite considerable. The frequency of AED overcrowding per week was 4-7 times. The average bed occupancy level was 3.25. Agreed common causes of prolonged AED admissions were to be a high volume of critically ill patients, Delayed transfer of patients to the wards, delay in theatre operation, delay in radiological investigations and exceptionally high proportion of patients requiring admission in AED. Also, long pre-review waiting time and haematological delays were more causes. The average waiting time for victims to be seen was 29.7 minutes. CONCLUSION: There are many causes of AED overcrowding in this environment. However, improving AED bed management, better organized and diligent discharge planning, and reducing access block should be a priority to reduce AED overcrowding. PMID- 26124793 TI - A randomized controlled trial comparing haemodynamic stability in elderly patients undergoing spinal anaesthesia at L5, S1 versus spinal anaesthesia at L3, 4 at a tertiary African hospital. AB - BACKGROUND: Spinal anaesthesia is a routinely used anaesthetic technique in elderly patients (> 60 years) undergoing operations involving the lower limbs, lower abdomen, pelvis and the perineum. Spinal anaesthesia has several advantages over general anaesthesia including stable haemodynamic variables, less blood loss, less post-operative pain, faster recovery time and less post-operative confusion. Despite these advantages, the sympathetic blockade induced by spinal anaesthesia can result in hypotension, bradycardia, dysrhythmias and cardiac arrests. Conventionally, spinal anaesthesia is performed at the level of L3,4 interspace; with a reported incidence of hypotension in the elderly ranging between 65% and 69%. A possible strategy for reducing spinal induced hypotension would be to minimize the peak block height to as low as possible for the planned procedure. OBJECTIVE: To determine the difference in haemodynamic stability between elderly patients undergoing spinal anaesthesia at L5, S1 interspace compared to those at L3, 4. METHODS: Thirty two elderly patients scheduled for lower limb or pelvic surgery under spinal anaesthesia were randomized into 2 groups (control group and intervention group) using a computer generated table of numbers. Control group; received 2.5 mls 0.5% hyperbaric bupivacaine injected intrathecally at the L3, 4 interspace and Intervention group; 2.5mls 0.5% hyperbaric bupivacaine injected intrathecally at the L5, S1 interspace. RESULTS: The two groups had similar baseline characteristics in age, sex, body mass index and use of anti-hypertensive medications. There was 68.8% proportion of hypotension in the control group and 75% in the intervention group. The difference was not found to be statistically significant (p= 0.694). During the study period, there were 106 episodes of hypotension, out of which, 65 were in the control group and 41 in the intervention group (p=0.004).. Linear regression analysis of the decrease in mean arterial pressures (MAP) showed a higher decrease in MAP in the control group (p 0.018). There were more crystalloids used in the control group (1006mls +/- 374) than in the intervention group (606mls +/ 211) with a p< 0.0001. There was no difference in the amounts of vasopressors used between the two groups (p=0.288). There was no difference in the change in heart rates, conversion to general anaesthesia, use of supplementary intravenous fentanyl and the peak maximum block level achieved. The time to peak maximum sensory block level was 9.06min and 13.07min in the control group and intervention groups, respectively (p<0.0001). CONCLUSION: Among this population, there was no difference in the proportion of those with hypotension between the elderly patients who received their spinal anaesthesia at L3,4 and those who received spinal anaesthesia at L5,S1. The intervention group had better outcomes with significantly less episodes of hypotension. It took a longer time to achieve a maximum peak sensory block in the intervention group. Performing spinal anaesthesia at the level of L5,S1 was found to provide an adequate sensory block for a wide range of pelvic, perineal and lower limb surgeries. PMID- 26124794 TI - Epidemiology of road traffic crashes among long distance drivers in Ibadan, Nigeria. AB - BACKGROUND: Road Traffic Crashes (RTCs) are major causes of morbidity and mortality in Nigeria. Few studies in Ibadan have focused on the distribution and determinants of RTC among long distance drivers. OBJECTIVE: To describe the distribution of crashes by place, times of occurrence, characteristics of persons involved and identify associated factors. METHODS: A cross-sectional study was carried out among consenting long distance drivers within selected parks in Ibadan. RESULTS: Respondents (592) were males, with median age of 42.0 years (range 22.0-73.0 years). Secondary education was the highest level of education attained by 38.0%. About 34.0% reported current use of alcohol. The life-time prevalence of crashes was 35.3% (95% CI= 31.5-39.2%) and 15.9% (95% CI=13.1 19.0%) reported having had at least one episode of crash in the last one year preceding the study. The crash occurred mainly on narrow roads [32/94 (34.0%,)] and bad portions of tarred roads [35/94 (37.2%,)] with peak of occurrence on Saturdays 18/94 (19.1%,). Significantly higher proportions of drivers aged <=39years (23.4%) versus >39years (11.7%), those with no education (29.9%) versus the educated (13.8%) and those who reported alcohol use (21.9%) versus non users (12.8%) were involved in crashes in the year preceding the study. Significant predictor of the last episode of crashes in the last one year were age (OR=2.2, 95% CI=1.4-3.5), education (OR=2.7, 95% CI=1.5-4.6) and alcohol use (OR=1.8, 95% CI=1.2-3.0). CONCLUSION: Road traffic crashes occurred commonly on bad roads, in the afternoon and during weekends, among young and uneducated long-distance drivers studied. Reconstruction of bad roads and implementation of road safety education programmes aimed at discouraging the use of alcohol and targeting the identified groups at risk are recommended. PMID- 26124795 TI - Epicardial fat thickness in patients with rheumatoid arthritis. AB - BACKGROUND: Epidemiologic data indicates that rheumatoid arthritis is an independent risk factor for cardiovascular disease. Epicardial adipose tissue is a novel cardio-metabolic risk factor. Our aim was to evaluate epicardial fat thickness (EFT) using echocardiography in patients with rheumatoid arthritis compared to healthy control subjects. Secondly, we investigated relationship between epicardial fat thickness and clinical and echocardiographic parameters in patients with rheumatoid arthritis. METHOD: The study population included 76 consecutive patients with rheumatoid arthritis (64 female; mean age, 53 +/-11 years, median disease duration, 7.8 years) and 50 healthy subjects as controls (39 female; mean age, 52 +/- 6 years). All patients underwent echocardiography to assess left ventricular diastolic dysfunction, left ventricular hypertrophy and EFT. All values were compared between groups. RESULTS: EFT was higher in rheumatoid arthritis patients than in healthy controls (0.66+/-0.20 vs. 0.54+/ 0.18; p= 0.003). Thickness of Intra Ventricular Septum (IVS) (1.1+/-0.06 and 9.8+/-0.08; p=0.001) and posterior wall (PW) (0.98+/-0.05 and 0.93+/-0.08; p=0.015) was higher in patients with rheumatoid arthritis compared to healthy controls. Early diastolic myocardiac peak velocity or late diastolic mitral peak velocity (E/A) ratio was lower in rheumatoid arthritis patients compared to healthy patients (1.1 +/-0.8 and 1.24+/-0.1 p=0.001) as well as, E/e' was higher in Rheumatoid arthritis (RA) patients than healthy patients. (E/e':8.7+/-1.6 and 8.0+/-1.4 p=0.020). In patients with rheumatoid arthritis, EFT was positively correlated with hypertension and duration of disease and E/e' (r: 0.10, p: 0.010, r: 0.306, p: 0.004 and r: 0.465 p: 0.007 respectively) and EFT was negatively correlated with E/A (r: -.262 p:0.022). CONCLUSION: To our knowledge, this is the first report about epicardial adipose tissue in rheumatoid arthritis patients. Epicardial fat thickness as an indicator of cardiovascular involvement was higher in rheumatoid arthritis patients. PMID- 26124796 TI - Plants used to manage type II diabetes mellitus in selected districts of central Uganda. AB - BACKGROUND: Chronic diseases such as diabetes mellitus are increasing in incidence in sub-Saharan Africa. African traditional medicine is part and parcel of the health care system in Uganda. Majority of the indigenous population will have visited a traditional health care practioner or self-administered herbal medicines before seeking conventional health care. However, documentation of the various medicinal plants is still lacking, necessitating a well-organized information search for such knowledge through research. Such information can lay a firm and clear foundation for scientific investigation of the purported therapeutic benefits of the said plants. The objective of this study was to collect names of medicinal plants used to manage diabetes mellitus type II in selected districts of central Uganda. METHODS: In this ethnobotanical survey, names, of plants used to manage diabetes mellitus type II as well as the methods of preparation, routes of administration and the plant parts used in the districts of Mukono, Kampala, Wakiso and Masaka in the central region of Uganda were documented using a researcher administered questionnaire. Participants were recruited using a snow ball approach in which one individual directed us to another. Informant consensus was determined for each of the plants mentioned. RESULTS: A total of 18 names of medicinal plants were recorded of which Aloe vera var, Solanum indicum and Vernonia amygydalina were the most commonly mentioned plants and thus had the highest informant consensus. Leaves were the main parts that were used to prepare the herbal medicine while water as the solvent used in all the preparations. In all the cases, only the oral route was used for administration of the medicines. CONCLUSION: Documentation of medicinal plants used to manage diabetes can further improve on the formalization process of the Ugandan traditional medicine system as well as lay a basis for further scientific investigation with emphasis on the plants whose informant consensus is high. PMID- 26124797 TI - Psychological wellbeing and biochemical modulation in response to weight loss in obese type 2 diabetes patients. AB - BACKGROUND: Obesity in type 2 diabetes patients is a serious health issue by itself; it is also associated with other health problems including psychiatric illnesses. The psychological effects of dieting and weight loss have been a matter of controversy in the field of obesity management. OBJECTIVE: The aim of this study was to compare the impact of weight loss because of aerobic exercise training and dietary measures on psychological wellbeing and biochemical modulation in obese type 2 diabetes patients. MATERIAL AND METHODS: One hundred obese type 2 diabetes patients of both sexes participated in this study, and were included into two equal groups. The first group (A) received aerobic exercise training, three sessions per week for three months combined with dietary measures. The second group (B) received no training intervention for three months. RESULTS: There was a significant decrease in body mass index (BMI), leptin, total cholesterol (TC), low density lipoprotein cholesterol (LDL-c), triglycerides(TG), homeostasis model assessment-insulin resistance- index (HOMA IR) , beck depression inventory (BDI ) & profile of mood states(POMS) and increase in high density lipoprotein cholesterol (HDL-c) & Rosenberg self-esteem scale (RSES) of group (A) after treatments, but the changes of group (B) were not significant. Moreover, there were significant differences between mean levels of the investigated parameters of group (B) and group (A) at the end of the study. CONCLUSION: Physical training and dietary measures can be used as methods of choice for psychological wellbeing and biochemical modulation in obese type 2 diabetes patients. PMID- 26124798 TI - Medication adherence in type 2 diabetes patients: study of patients in Alimosho General Hospital, Igando, Lagos, Nigeria. AB - BACKGROUND: Poor adherence is an obstacle in therapeutic control of diabetes. Despite the advances in the treatment of diabetes mellitus over the years, diabetes places an immense burden on the individuals living with the condition, their families and the overall health care system. OBJECTIVE: Evaluation of the impact of medication adherence on the clinical outcomes of type 2 diabetes patients at Alimosho general hospital, Igando Lagos state. METHOD: The medication adherence study was both descriptive (retrospective) and prospective. The retrospective study assessed the prevalence of medication non-adherence leading to poor glycemic control. This involved the review of case notes of one-hundred and fifty two randomly selected patients. Prospective study was done by counselling and educating the patients on medication adherence and assessing their medication adherence and the impact of medication adherence on glycemic control. RESULTS: The proportions of females/males with type 2 DM was found to be 69% and 31% respectively. 51.32% of these patients viewed their medications to be unaffordable. 56.6% of the patient population were 61 years and above in age. There was a significant relationship between patient age, gender and adherence to medication. There was however no significant P >= 0.05 association between educational level and adherence. Health education and counselling resulted in adherence rate and clinical parameters improvements. CONCLUSION: Non-adherence is a major factor that could lead to morbidity and mortality in diabetic patients. The overall improvement in adherence rate of 86.8% was observed with a decline in non- adherence rate after interventions. PMID- 26124799 TI - Relation of maternal vitamin D status with gestational diabetes mellitus and perinatal outcome. AB - OBJECTIVE: To investigate the relationship between maternal vitamin D status and glucose intolerance, and its impact on pregnant women and their newborns. METHODS: A cohort of pregnant women were divided into three groups: women with gestational diabetes mellitus, ones with normal results both after the 50 gr and 100 gr OGTT (CG-1) and ones having a positive result after the 50 gr OGTT screening but negative results for gestational diabetes mellitus (GDM) after the 100 gr OGTT (CG-2). RESULTS: The newborn length in CG-1 was greater than in GDM and CG-2 (p= 0.002 and p= 0.02). Fasting blood glucose and insulin resistance (IR) were negatively correlated with length of the newborns (r=-0.3, p=0.03 and r=-0.3, p=0.01). The newborns of women with GDM had lower APGAR-1 and 5 scores than those of CG-1 and CG-2 (APGAR-1 p= 0.001 and p= 0.004, APGAR-5 p=0.005 and p=0.007, respectively). APGAR scores were correlated negatively with IR (APGAR-1 r=-0.32, p=0.01, APGAR-5 r=-0.3, p=0.03) and positively with 25OHD levels (APGAR 1 r=0.3, p=0.01, APGAR-5 r=0.3, p=0.02). CONCLUSION: Vitamin D deficiency, gestational diabetes and insulin resistance are interrelated. Severe vitamin D deficiency during pregnancy is associated with poor pregnancy and neonatal outcome. PMID- 26124801 TI - Determinants of fertility in Ethiopia. AB - BACKGROUND: The most important elements to determine the rate of population growth is fertility. Fertility is the main element to affect the welfare of mother. The survival of a child can be affected by high fertility and shorter birth intervals. METHODS: For this study, the linear mixed model was used to determine factors affecting fertility status of women in Ethiopia. The 2011 Ethiopian demographic and health survey data was used for this study. RESULTS: From the result, materials used for roof, wall and floor were found to have a significant relation to fertility level of women in the last five years. Moreover, family size and births in the last five years were found to have a significant relationship. CONCLUSION: Significant variation in fertility level was observed among rural and urban residents of Ethiopia. To reduce the gap of fertility between rural and urban population, it is important to modernize different factors. These factors could be access to education, media, and providing employment opportunities in the modern economic sector. Besides this, it is important to develop and maintain the access of family planning services. PMID- 26124800 TI - Maternal nutrition: how is Eastern and Southern Africa faring and what needs to be done? AB - BACKGROUND: The progress in key maternal health indicators in the Eastern and Southern Africa Region (ESAR) over the past two decades has been slow. OBJECTIVE: This paper analyzed available information on nutrition programs and nutrition specific interventions targeting maternal nutrition in the ESAR and proposes steps to improve maternal nutrition in this region. METHODS: Search was conducted in relevant databases. Meta-analysis was done where there was sufficient data, while data from the nutrition programs was abstracted for objectives, settings, beneficiaries, stakeholders, impact of interventions and barriers encountered during implementation. RESULTS: Findings from our review suggest that multiple nutrition programs are in place in the ESAR; including programs that directly address nutrition indicators and those that integrate corresponding sectors like agriculture, health, education, and water and sanitation. However, their scale and depth differ considerably. These programs have been implemented by a diverse range of players including respective government ministries, international agencies, non government organisations and the private sector in the region. Most of these programs are clustered in a few countries like Kenya, Uganda and Ethiopia while others e.g. Comoros, Somalia and Swaziland have only had a limited number of initiatives. CONCLUSION: These programs have been associated with some improvements in overall maternal health and nutritional indicators; however these are insufficient to significantly contribute to the progress in the region. Efforts should be prioritized in countries with the greatest burden of maternal undernutrition and associated risk factors with a focus on existing promising interventions to improve maternal nutrition. PMID- 26124802 TI - Partograph utilization and associated factors among obstetric care providers in North Shoa Zone, Central Ethiopia: a cross sectional study. AB - BACKGROUND: Globally, prolonged and obstructed labor contributed to 8% of maternal deaths which can be reduced by proper utilization of partograph during labor. METHODS: An Institution based cross-sectional study was conducted in June, 2013 on 403 obstetric care providers. A pre-tested and structured questionnaire was used to collect data. Data was entered to EpiInfo version 3.5.1 statistical package and exported to SPSS version 20.0 for further analysis. Logistic regression analyses were used to see the association of different variables. RESULTS: Out of 403 obstetric care providers, 40.2% utilized partograph during labor.Those who were midwives by profession were about 8 times more likely to have a consistent utilization of the partograph than general practitioners (AOR=8. 13, 95% CI: 2.67, 24.78). Similarly, getting on job training (AOR=2. 86, 95% CI: 1.69, 4.86), being knowledgeable on partograph (AOR=3. 79, 95% CI: 2.05, 7.03) and having favorable attitude towards partograph (AOR=2. 35, 95% CI: 1.14, 4.87) were positively associated with partograph utilization. CONCLUSION: Partograph utilization in labor monitoring was found to be low. Being a midwife by profession, on job training, knowledge and attitude of obstetric care providers were factors affecting partograph utilization. Providing on job training for providers would improve partograph utilization. PMID- 26124804 TI - Knowledge and willingness of prenatal women in Enugu Southeastern Nigeria to use in labour non-pharmacological pain reliefs. AB - BACKGROUND: Nigerian parturients desire, but experience unsatisfactory pain relief as labour analgesia is underutilised and unpopular among skilled-birth attendants. OBJECTIVES: To assess pregnant women's knowledge and willingness to use non-pharmacological labour pain reliefs. METHODS: Using a descriptive cross sectional design, a pre-tested, structured questionnaire was interviewer administered to a convenient sample of 245 prenatal women at a specialist maternity hospital in Enugu. RESULTS: Majority (68.6%) of the women knew, but 31.4% were unaware that non-pharmacological labour pain reliefs exist in the study facility. Only 34.7% were able to identify at least four such methods, 21.2% could elicit two (each) advantages and disadvantages, and 0% to 28.3% had perceived self-efficacy of how to use each method. The leading four methods identified were breathing exercises (51.8%), massage (36.7), position changes (32.2%), and relaxation techniques (26.5%). Majority (59.6%) of the women expressed willingness to use non-pharmacological pain strategies in future labour, which is associated with increased knowledge of the methods, and parity (p<0.001). CONCLUSION: Pregnant women had limited knowledge of, but majority expressed willingness to use in labour non-pharmacological pain reliefs. Nurses/midwives should give adequate childbirth information and preparation on labour pain reliefs to antenatal women to inform their choices and effective use during labour. PMID- 26124803 TI - Gender preferences among antenatal women: a cross-sectional study from coastal South India. AB - BACKGROUND: A balanced sex ratio is essential for a stable society. OBJECTIVE: The main objective of the present research was to study the perceptions of women attending the antenatal care (ANC) facility regarding their gender preferences and family composition. METHOD: In this cross-sectional study 132 antenatal women were interviewed in their preferred language using a predesigned semi-structured questionnaire. The collected information was analyzed using SPSS version 11.5. RESULTS: The mean age of the study participants was 27.2 +/- 4.1 years. The majority of the antenatal women (60.6%, n=80) did not have any gender preferences. Among those who had a gender preference (39.4%, n=52), male and female preference was reported by 55.7% (n=29) and 44.3% (n=23) of the participants respectively. The overall son preference index was observed to be 1.3. No consistent relationship could be established between the socio demographic factors and the preference for gender. The mean preferred family size in our study was 1.85+/-0.531 and more than half of the participants had a balanced gender preference. The majority of the participants were aware that the adverse sex ratio can lead to fall in the number of brides and that it would bring about a social imbalance. CONCLUSION: As a developed society we need to ensure that both the genders get equal respect and are free from any sort of preferences and prejudices. To achieve this, more and more people need to be made aware of the consequences of gender imbalance and adverse sex ratio in a society. PMID- 26124805 TI - Pattern & presentation of colorectal cancer in central Sudan, a retrospective descriptive study, 2010-2012. AB - AIMS & OBJECTIVE: To determine the age and gender distribution and clinical presentation of patients together with histological types of colorectal cancer cases presented to Ibn Sina specialized hospital. PATIENTS AND METHODS: This retrospective study was conducted in Ibn Sina Hospital (Sudan). Seventy three (73) patients of colorectal cancer who presented in the period from January 2010 to December 2012 were included. Data were collected from their hospital records and analyzed using SPSS computer program 17. RESULTS: More than 17 % of the study populations was below the age of 40 years, and 43.84% was below 50 years. The male to female ratio was 1:1.02. Rectal bleeding is the commonest presenting symptom and well differentiated adenocarcinoma is the dominating tumor grade. 8.3 % of patients presented with liver metastasis. CONCLUSION: Colorectal cancer in this study was found more in young age groups with a peak frequency at the fifth and sixth decades. PMID- 26124806 TI - Comparison of absolute neutrophil to CD4 lymphocyte values as a marker of immunosuppression in cancer patients on cytotoxic chemotherapy. AB - BACKGROUND: The absolute neutrophil count (ANC) is currently used to assess immune status of patients on cytotoxic therapy. The CD4 lymphocytes have also been shown to be of importance in protection against opportunistic infections. In people of African descent a low baseline ANC has been recorded and the currently accepted neutropaenic threshold may not be appropriate. OBJECTIVE: This study was aimed at comparing the change in ANC to CD4 lymphocyte count in adult cancer patients following chemotherapy. PATIENTS AND METHODS: Eighty chemotherapy-naive patients with various malignancies had their ANC and CD4 lymphocyte counts done at days 0 and 12 of the first cycle of various chemotherapeutic regimens. The paired sample t-test was done to assess the significance between these values. Socio-demographic data was obtained using questionnaires. RESULTS: ANC and CD4 pre-chemotherapy differed significantly from their post-chemotherapy values (p=0.001) for both parameters). The CD4 count showed significant reduction in patients with Non-Hodgkin's lymphoma (p=0.043), colorectal carcinoma (p=0.037) and other malignancies (p=0.030), while the ANC did not. Patients who had received COPP for Hodgkin's lymphoma also had significant CD4 depletion (p=0.037). CONCLUSION: The CD4 lymphocyte count may be a more suitable parameter than ANC, for monitoring immuno-depletion in cancer patients on cytotoxic chemotherapy. Further studies are required to validate these findings, especially in the Negroid population. PMID- 26124807 TI - Drug-drug interation prediction between ketoconazole and anti-liver cancer drug Gomisin G. AB - BACKGROUND: Gomisin G, isolated from herb Schisandra chinensis, exhibits anti tumor activities. Therefore, Gomisin G is a drug candidate for anti-liver cancer therapy. AIMS: To predict the metabolic behavior and metabolism-based drug-drug interaction of gomisin G. METHODS: Molecular docking method was used. The crystal structure of CYP3A4 with the ligand ketoconazole was chosen from protein data bank (http://www.rcsb.org/pdb). Chemdraw software was used to draw the two dimensional structure of gomisin G with standard bond lengths and angles. RESULTS: Gomisin G can be well docked into the activity site of CYP3A4, and distance between gomisin G the heme active site was 2.75 A. To evaluate whether the inhibitors of CYP3A4 can affect the metabolism of gomisin G, co-docking of gomisin G and ketoconazole was further performed. The distance between ketoconazole and activity center (2.10 A) is closer than the distance between gomisin G and activity center of CYP3A4, indicating the easy influence of CYP3A4's strong inhibitor towards the metabolism of gomisin G. CONCLUSION: Gomisin G is a good substrate of CYP3A4, and CYP3A4 inhibitors easily affect the metabolism of Gomisin G. PMID- 26124808 TI - The therapy of gefitinib towards breast cancer partially through reversing breast cancer biomarker arginine. AB - BACKGROUND: Breast cancer remains the leading reason of cancer death among women worldwide, and gefitinib is the efficient drug for breast cancer. AIMS: To use targeted metabolomics method to elucidate the therapeutic mechanism of gefitinib through profiling the amino acids. METHODS: Healthy women (n=56) and women with breast cancer (n=60) were enrolled in Affiliated Yuhuangding hospital, medical college of Qingdao University from 2012-2014. API 3200 triple quadrupole mass spectrometer was used to analyze the serum samples. RESULTS: The concentration of amino acids was compared between healthy women and women with breast cancers. Compared with the healthy women, the concentration of arginine in breast cancer women significantly decreased (p<0.0001). To show the representative capability of arginine towards the pathogenesis of breast cancers, the receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to be 0.96 +/- 0.02, indicating the high predictive capability of arginine for breast cancer . The reversing ability of gefitinib towards the level of arginine was further determined, and 1 month treatment of gefitinib (500 mg/day) significantly reversed the arginine level of breast cancer patients (p<0.0001). CONCLUSION: The therapy of gefitinib towards breast cancer through reversing breast cancer biomarker arginine was demonstrated. PMID- 26124809 TI - The protective effects of aqueous extract of Carica papaya seeds in paracetamol induced nephrotoxicity in male wistar rats. AB - BACKGROUND: Oxidative stress plays a crucial role in the development of drug induced nephrotoxicity. The study aimed to determine the nephroprotective and ameliorative effects of Carica papaya seed extract in paracetamol-induced nephrotoxicity in rats. OBJECTIVES: To carry out phytochemical screening of Carica papaya, measure serum urea, creatinine and uric acid and describe the histopathological status of the kidneys in the treated and untreated groups. METHODS: Phytochemical screening of the extract was done. Thirty two adult male Wistar rats were divided into four groups (n= 8 in each group). Group A (control) animals received normal saline for seven days, group B (paracetamol group) received normal saline, and paracetamol single dose on the 8th day. Group C received Carica papaya extract (CPE) 500 mg/kg, and paracetamol on the 8th day, while group D, rats were pretreated with CPE 750 mg/kg/day,and paracetamol administration on the 8th day. Samples of kidney tissue were removed for histopathological examination. RESULTS: Screening of Carica papaya showed presence of nephroprotective pytochemicals. Paracetamol administration resulted in significant elevation of renal function markers. CPE ameliorated the effect of paracetamol by reducing the markers as well as reversing the paracetamol-induced changes in kidney architecture. CONCLUSION: Carica papaya contains nephroprotective phytochemicals and may be useful in preventing kidney damage induced by paracetamol. PMID- 26124810 TI - Comparative study on the effects of aqueous extracts of viscum album (mistletoe) from three host plants on hematological parameters in albino rats. AB - BACKGROUND: The extract of the leaves of Viscum album (mistletoe) has been used for centuries in traditional medicine in many parts of the world. However, like many medicinal plants, the belief that things of natural origin are safe may not be entirely true. The blood is a good indicator of health and pathological mirror of the entire body. OBJECTIVE: Therefore, in this study, the acute effects of extracts of mistletoe, harvested from three hosts, on haematology indices of wistar albino rats was investigated. METHODS: Graded doses (400, 800, 1600 and 3200mg/kg body weight) of aqueous extracts of mistletoe from three different host plants, coffee (Coffee arabica), kola (Kola nitida), cocoa (Theobromae cacao), were administered orally to wistar albino rats for 14 days. Full haematological parameters were evaluated on whole blood collected from rats twenty four hours after the administration of the last dose. RESULTS: Mistletoe from kola caused a concentration dependent and statistically significant (p<0.05) reduction in platelets count in rats. Administration of mistletoe extract from cocoa and coffee led to reduction in hemoglobin concentration. Reductions in packed cell volume (PCV) and red blood cell (RBC) and increase in white blood cells (WBC) were also observed in rats administered all the extracts. CONCLUSION: Increase in the WBC count observed in rats administered mistletoe suggests that mistletoe extract contains agents that could stimulate the production of leucocytes and could serve as immune booster. However, there is need to be cautious in administration at high doses to prevent the risk of anaemia. PMID- 26124811 TI - Anti-inflammatory and antioxidant properties of Eriobotrya japonica leaves extracts. AB - BACKGROUND: In the present work we determined phenolic and flavonoids content of Eriobotrya japonica leaves extracts and fractions and their antioxidant and anti inflammatory properties. OBJECTIVES: To evaluate the inhibition of inflammatory PLA2 and antioxidant effects of extracts and fractions from Eriobotrya japonica leaves. METHODS: Antioxidant activity was evaluated with DPPH radical scavenging assay and anti-inflammatory effect of fractions was measured by their inhibition potency on the human pro-inflammatory phospholipase A2 (group IIA). RESULTS: The EtOH/EtOAc 2:1 extract exhibited a potent inhibition of the hG-IIA with an IC50 values of 8 ug/ml. It also shows an antioxidant activity measured on DPPH with an IC50 of 42 ug/ml. Fractionation shows that CH2Cl2/MeOH 0:1 fraction was the rich one on flavonoids compounds (4.3 mg/g dry weight) and demonstrates a high antioxidant activity with an IC50 of 12 ug/ml. The anti-inflammatory evaluation demonstrates that the same fraction was the best one to inhibit the pro inflammatory phospholipase A2 group IIA with an IC50 of 4 ug/ml. CONCLUSION: Study conducted on Eriobotrya japonica shows that CH2Cl2/MeOH 0:1 fraction inhibits efficiently the hG-IIA phospholipase. which is considered as pro inflammatory enzyme. PMID- 26124812 TI - Assessment of subjective sleep quality in iron deficiency anaemia. AB - OBJECTIVES: We aimed to assess the effect of anemia on subjective sleep quality in patients with iron deficiency anemia (IDA). METHODS: One hundred and four patients diagnosed with IDA and 80 healthy individuals, who are gender and age matched, were included in the study. All participants were requested to fill 3 forms: a socio-demographic form (age, gender, marital status, income level and educational status), hospital anxiety and depression (HAD) scale and pittsburgh sleep quality index (PSQI). RESULTS: According to the HAD scale, the average anxiety score was found 9.24+/-4.37 in patients and 7.58+/- 4.07 in controls. And, the average depression score was 7.53+/-4.10 in patients and 6.41+/-2.74 in controls. The total sleep quality score was 6.71+/-3.02 in patients and 4.11+/ 1.64 in controls. There was a statistically significant difference in terms of anxiety, depression and sleep quality scores. Linear regression analysis showed no association between anxiety and depression with poor sleeping. CONCLUSION: IDA affects sleep quality irrespective of psychological symptoms such as depression and anxiety. PMID- 26124813 TI - The anthropological approach challenges the conventional approach to bioethical dilemmas: a Kenyan Maasai perspective. AB - BACKGROUND: The cultural background, religion and societal norms have a huge influence on the decision making process for physicians, patients and their families, when faced with medical ethical dilemmas. While the medical professionals, through their training, can rely on the principles of autonomy, justice, beneficence and non-maleficence to guide them, the patients can only draw from their personal and cultural experiences. OBJECTIVE: To explore some of the challenges that face physicians when presented with ethical dilemmas. METHODS: A review of the literature on the principles of medical ethics and the cultural practices of the Maasai tribe, as well as, interview, interaction and observation of the patients and family during patient. management. RESULTS: In the Maasai community in Kenya, where family is the center of all attention and decision-making, the listed ethical principles and rules have a very different understanding of the self-determination, and autonomy becomes collective rather than individualistic. Medical practitioners when faced with ethical medical dilemmas are neither comfortable in adopting the conventional bioethical guidelines, nor in offering a health care purely based on cultural and historical practice. CONCLUSION: In our set up, developing culturally relevant principles of bioethics appears to be the most effective solution in addressing medical ethical dilemmas. PMID- 26124814 TI - Towards bio monitoring of toxic (lead) and essential elements in whole blood from 1- to 72-month old children: a cross-sectional study. AB - OBJECTIVES: Minerals such as zinc, copper, selenium, calcium, and magnesium are essential for normal human development and functioning of the body. They have been found to play important roles in immuno-physiologic functions. The study is to evaluate the distribution and correlation of nonessential (lead) and essential elements in whole blood from 1- to 72-month old children. METHODS: The cross sectional study was performed in 1551 children. Six element concentrations, including copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), iron (Fe) and lead (Pb) in the blood were determined by atomic absorption spectrometry. Distributions and correlations of trace elements in different age groups were analyzed and compared. A Pearson correlation controlled for age and gender was used to assess the relationship of non essential (lead) and essential elements. RESULTS: Levels of copper and magnesium were 18.09 +/- 4.42 umol/L and 1.42 +/- 0.12 mmol/L, respectively. 6.04% of all children showed copper levels below the normal threshold, the levels of Magnesium were stable in different age groups. Though the overall mean blood zinc and iron concentrations (61.19 +/- 11.30 umol/L and 8.24 +/- 0.59 mmol/L, respectively) gradually increased with age and the overall deficiency levels (24.1% and 36.0%, respectively) decreased with age, zinc and iron deficiencies were still very stable. Controlling for gender and age, significant positive correlations were found when comparing copper to zinc, calcium, magnesium, and iron ((r = 0.333, 0.241, 0.417, 0.314 ,p < 0.01); zinc to magnesium and iron (r = 0.440, 0.497p < 0.01); and magnesium to Calcium and iron (r = 0.349, 0.645, p < 0.01). The overall mean blood lead levels (41.16 +/- 16.10) were relatively unstable among different age groups. The prevalence of lead intoxication in all children was 1.3% .Calcium levels decreased gradually with age, with an overall concentration of 1.78 +/- 0.13 mmol/L. CONCLUSION: Significant negative correlations were also noted between Pb and Zn, Fe (r = 0.179, -0.124.p < 0.01) .The importance of calcium deficiency and supplementation is well realized, but the severity of iron and zinc deficiency is not well recorded. The degree of lead intoxication in all the children studied was low; The established reference intervals for Cu, Zn, Ca and Mg provide an important guidance for the reasonable supplementation of essential elements during different age groups. PMID- 26124815 TI - Comparison of a fluorometric assay kit with high-performance liquid chromatography for the assessment of serum retinol concentration. AB - BACKGROUND: Although high-performance liquid chromatography (HPLC) is the commonly used method for the analysis of retinol in biological samples, simple and rapid test kits are available. OBJECTIVES: This study compared a rapid test kit (ICHECK Fluoro(r)) to HPLC for the assessment of serum retinol concentrations. METHODS: For the analysis by HPLC, sample preparation included standard deproteinization and extraction phases. The analysis by ICHECK was performed by injecting serum into IEX reagent vials (n=89) and mixing manually for separation. After precipitation of the proteins, the vial was introduced into the chamber of the ICHECK Fluoro and analysed at 0 min (ICHECK0min) and 15 min later (ICHECK15min). Bland and Altman approach was applied to test the agreement between HPLC and ICHECK. RESULTS: Mean HPLC, ICHECK0min and ICHECK15min values were 421.2+/-106.0 ug/L, 423.1+/-118.3 ug/L and 413.2+/-107.6 ug/L, respectively. Retinol concentrations significantly decreased in the IEX solution over time (p<0.001). No significant proportional bias was observed between HPLC and ICHECK0min (r-0.038, p=0.73) and ICHECK15min (r=-0.024, p=0.82). Fixed biases (HPLC minus ICHECK) for ICHECK0min and ICHECK15min were respectively -1.9+/-23.1 ug/l (p=0.45) and 8.0+/-22.7 ug/l (p=0.002). CONCLUSION: ICHECK Fluoro may offer a reliable mean for assessing serum retinol for measurements performed with no significant time delay. PMID- 26124816 TI - Educational audit on drug dose calculation learning in a Tanzanian school of nursing. AB - BACKGROUND: Patient safety is a key concern for nurses; ability to calculate drug doses correctly is an essential skill to prevent and reduce medication errors. Literature suggests that nurses' drug calculation skills should be monitored. OBJECTIVE: The aim of the study was to conduct an educational audit on drug dose calculation learning in a Tanzanian school of nursing. Specific objectives were to assess learning from targeted teaching, to identify problem areas in performance and to identify ways in which these problem areas might be addressed. METHODS: A total of 268 registered nurses and nursing students in two year groups of a nursing degree programme were the subjects for the audit; they were given a pretest, then four hours of teaching, a post-test after two weeks and a second post-test after eight weeks. RESULTS: There was a statistically significant improvement in correct answers in the first post-test, but none between the first and second post-tests. Particular problems with drug calculations were identified by the nurses / students, and the teacher; these identified problems were not congruent. CONCLUSION: Further studies in different settings using different methods of teaching, planned continuing education for all qualified nurses, and appropriate pass marks for students in critical skills are recommended. PMID- 26124817 TI - Antibiogram of E. coli serotypes isolated from children aged under five with acute diarrhea in Bahir Dar town. AB - BACKGROUND: Diarrheal disease and its complications remain a major cause of morbidity and mortality in children. The prevalence and antibiogram of E. coli as causative agents of diarrhea vary from region to region, and even within countries in the same geographical area. OBJECTIVES: To determine the serotype and antimicrobial susceptibility of E. coli in children under-five years of age. METHODS: A cross-sectional study was conducted among 422 children with diarrhea from December 2011 to February 2012. Identification of E. coli and antimicrobial susceptibility testing were done following standard procedures. RESULTS: The overall isolation rate of E. coli was 48.3%. Poly 2 sero-groups, poly 3 sero groups, poly 4 sero-groups and E. coli O157:H7 accounted for 80 (39.2%), 40 (19.6%), 25 (12.3%), and 59 (28.9%) of the isolates, respectively. Poly 2 sero groups, constituting isolates belonging to enteropathogenic E. coli were the most commonly isolated serotypes. E. coli exhibited high levels of antimicrobial resistance to ampicillin (86.8%), tetracycline (76%) and cotrimoxazole (76%). Low levels of resistance to ciprofloxacin (6.9%) and norfloxacin (9.3%) were documented. CONCLUSION: High prevalence of diarrheagenic E. coli compounded by alarming antimicrobial resistances is a serious public health problem. Regular determination of antibiogram and public education are recommended. PMID- 26124818 TI - Life within chronic care: is this a service or sentence? AB - BACKGROUND: Understanding the meaning of one's lived experiences improves one's understanding of what it means to be human, in association with the social, cultural and historical context in which being a human occurs. The authors in this study describe the lived experiences of residents within a chronic care facility including the practitioner and family perspectives. METHODS: A qualitative approach was employed with a single-site, descriptive, instrumental case study design. Purposive sampling was utilised to select the chronic facility. Multiple sources of evidence included narratives, semi-structured interviews with staff, residents and family members, and activity profiles of the residents augmented by an ergonomic evaluation of the facility. Content analysis using within-case analysis was implemented. RESULTS: The greatest impact on the quality of the resident's lived experiences emanates from the physical, organisational and social environments in which they reside. Limited resources, poor staff attitudes and routines that are enforced both on the staff of the facility and the residents appear to reduce optimal functioning within the facility. Furthermore the residents' intrinsic motivation, presence of enforced idleness, learned helplessness and institutionalisation is often intensified and becomes characteristic of the residents lived experiences. DISCUSSION: The lived experiences of the residents are described according to quality of life indicators that were identified during the study and supported by literature. These include the influence of the physical, social and organizational environments on the residents' functional status, which comprises physical well being and emotional well-being and engagement in meaningful occupations including social interaction and relationships with other individuals. CONCLUSIONS: Findings of this study may be valuable in understanding and facilitating a positive change in service delivery within chronic care centres. PMID- 26124819 TI - Medical ethics in sub-Sahara Africa: closing the gaps. AB - BACKGROUND: Health care providers are expected to have the skills and knowledge relevant to their field and should also be familiar with the ethical and legal expectations that arise out of the standard practices. OBJECTIVES: To elucidate the practice of the health care providers in relation to healthcare ethics in Nigeria. METHODS: A self-administered structured questionnaire was devised and distributed to staff of two tertiary health care facilities in Northern Nigeria. The questionnaire comprised of detailed questions regarding day-to-day aspects of Medical ethical issues. RESULTS: A total of 307(76.2%) out of 403 health care providers responded to the questionnaire. The median age of the respondents was 34 years. More than half 168(54.7%) of the respondents disagreed as to whether "Ethical conduct is important only to avoid legal action. Many respondents 135 (44.0%) agreed to adhering to "patient's wishes", on the other hand over two third of the respondents 211 (68.7%) agreed that "doctor should do what is best" irrespective of the patient's opinion. There were significant differences (p<0.05) between the perception of physicians and non-physicians on many ethical issues. CONCLUSION: This study has shown gap in knowledge and practice of healthcare ethics among health care providers. There is a need for periodic education on clinical ethics in our hospitals. PMID- 26124820 TI - Alpha thalassemia among sickle cell anaemia patients in Kampala, Uganda. AB - BACKGROUND: Sickle cell anaemia is prevalent in sub Saharan Africa. While alpha+ thalassaemia is known to modulate sickle cell anaemia, its magnitude and significance in Uganda have hitherto not been described. OBJECTIVES: To determine the prevalence of alpha+thalassaemia among sickle cell anaemia patients in Mulago Hospital and to describe the clinical and laboratory findings in these patients. METHODS: A cross sectional study was carried out on patients with sickle cell anaemia in Kampala. Dried blood spots were used to analyze for the deletional alpha+ thalassaemia using multiplex polymerase chain reaction. RESULTS: Of the 142 patients with sickle cell anaemia, 110 (77.5%) had the alphaalpha+thalassaemia deletion. The gene frequency of (-alpha) was 0.425. Ninety one percent (100/110) of those with alpha+thalassaemia were heterozygous (alphaalpha/alpha-). Amongst the patients older than 60 months, 15 (83.3%) of those without alphaalpha+thalassaemia had significant hepatomegaly of greater than 4 cm compared to 36 (45.6%) of those with alpha+thalassaemia (p=0.003). CONCLUSION: The gene frequency of (-alpha) of 0.425 noted in this study is higher than that reported from many places in Africa. Concurrent alpha thalassemia might be a protective trait against significant hepatomegaly in sickle cell anaemia patients more than 60 months of age at Mulago hospital. PMID- 26124821 TI - Children with bronchial asthma assessed for psychosocial problems in a teaching hospital in Nigeria. AB - BACKGROUND: Paediatric bronchial asthma causes respiratory related mortality and morbidity globally and elevates the risk of psychological and social problems (psychosocial problems); which may result in poorer asthma control. The rate of and associated factors for psychosocial problems among our asthmatic children was assessed in this study. METHODS: Seventy five (75) children aged 7 to 14 years with bronchial asthma who were attending clinics at the University of Ilorin Teaching Hospital, Ilorin, Nigeria, were assessed with Child behaviour questionnaire and a semi-structured questionnaire. RESULTS: Probable psychological morbidity was present in 25% of the children. The most frequently reported social impairments associated with the disease were: interference with play (60%), domestic work (49%), fear of dying anytime (29%) and feeling of being a burden on the family (25%). Psychological morbidity was significantly associated with lower maternal education (p=0.020) and occupation (p=0.038), polygamy (p=0.012), fathers having more than 5 children (p=0.027) and mothers having inadequate spousal support (p=0.012). Inadequate spousal support and lower maternal occupational level were the significant predictors of morbidity following logistic regression. CONCLUSION: Routine psychosocial assessment and care for children with asthma needs to be introduced into our clinics to help protect them and their families from avoidable suffering. PMID- 26124822 TI - Miliary tuberculosis after in vitro fertilization and embryo transplantation. AB - BACKGROUND: With the development of assisted reproductive technology, more patients with infertility prefer to get pregnant by in vitro fertilization and embryo transplantation (IVF-ET). But the indications of IVF-ET must be strictly controlled by the clinicians. CASE REPORT: We described a case of a 29-year-old pregnant Chinese woman with military tuberculosis. She was admitted to the hospital with complaints of fever and shortness of breath. She received IVF-ET 83 days ago, because of infertility with bilateraltubal occlusion, and was in pregnancy status. We presented the clinical, laboratory and two chest CT scan features of the patient. The second chest CT scan showed randomly distributed, innumerable tiny, military nodules throughout the lungs. The fluorescence quantitative PCR of the bronchoalveolar lavage fluid (BALF) was positive for Mycobacterium tuberculosis. The M. tuberculosis was cultured from BALF on Day 29. So we made the diagnosis of military tuberculosis. CONCLUSION: It is important to rule out tuberculosis for the infertility patients especially with bilateraltubal occlusion before IVF-ET in order to avoid tuberculosis disseminate during pregnancy. PMID- 26124823 TI - Acute cortical blindness caused by pre-eclampsia in the antepartum; posterior reversible encephalopathy syndrome (PRES). PMID- 26124824 TI - Crossroad between camel bites and crocodile bites. PMID- 26124825 TI - Infectious diseases and chronic care in Africa. PMID- 26124826 TI - The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes. AB - In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 MUg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation by beta-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications. PMID- 26124828 TI - Epicardial Adipose Tissue Is Nonlinearly Related to Anthropometric Measures and Subcutaneous Adipose Tissue. AB - Introduction. Adipose tissue is the largest endocrine organ, composed of subcutaneous (SAT) and visceral adipose tissue (VAT), the latter being highly associated with coronary artery disease (CAD). Expansion of epicardial adipose tissue (EAT) is linked to CAD. One way of assessing the CAD risk is with low-cost anthropometric measures, although they are inaccurate and cannot discriminate between VAT and SAT. The aim of this study is to evaluate (1) the relationship between EAT thickness, SAT thickness and anthropometric measures in a cohort of patients assessed at the cardiology unit and (2) determine predictive power of anthropometric measures and EAT and SAT thickness in establishment of CAD. Methods. Anthropometric measures were obtained from 53 CAD and 42 non-CAD patients. Vascular and structural statuses were obtained with coronarography and echocardiography, as well as measurements of the EAT and SAT thickness. Results. Anthropometric measures showed moderate positive correlation with EAT and SAT thickness. Anthropometric measures and SAT follow nonlinear S curve relationship with EAT. Strong nonlinear power curve relationship was observed between EAT and SAT thinner than 10 mm. Anthropometric measures and EAT and SAT were poor predictors of CAD. Conclusion. Anthropometric measures and SAT have nonlinear relationship with EAT. EAT thickness and anthropometric measures have similar CAD predictive value. PMID- 26124827 TI - Coronary Microvascular Function and Beyond: The Crosstalk between Hormones, Cytokines, and Neurotransmitters. AB - Beyond its hemodynamic function, the heart also acts as a neuroendocrine and immunoregulatory organ. A dynamic communication between the heart and other organs takes place constantly to maintain cardiovascular homeostasis. The current understanding highlights the importance of the endocrine, immune, and nervous factors to fine-tune the crosstalk of the cardiovascular system with the entire body. Once disrupted, this complex interorgan communication may promote the onset and the progression of cardiovascular diseases. Thus, expanding our knowledge on how these factors influence the cardiovascular system can lead to novel therapeutic strategies to improve patient care. In the present paper, we review novel concepts on the role of endocrine, immune, and nervous factors in the modulation of microvascular coronary function. PMID- 26124829 TI - Adrenergic System Activation Mediates Changes in Cardiovascular and Psychomotoric Reactions in Young Individuals after Red Bull ((c)) Energy Drink Consumption. AB - Objectives. To assess the effect of Red Bull((c)) on (1) blood glucose and catecholamine levels, (2) cardiovascular and respiratory function changes before, during, and after exercise, (3) reaction time, (4) cognitive functions, and (5) response to mental stress test and emotions in young healthy individuals (N=38). Methods. Heart rate (HR) and arterial blood pressure (ABP), blood glucose, adrenaline, and noradrenalin plasma levels were measured before and after Red Bull((c)) intake. Participants were subjected to 4 different study protocols by randomized order, before and 30 minutes after consumption of 500 mL of Red Bull((c)). Results. Mean ABP and HR were significantly increased at rest after Red Bull((c)) intake. Blood glucose level and plasma catecholamine levels significantly increased after Red Bull((c)) consumption. Heart rate, respiration rate, and respiratory flow rate were significantly increased during exercise after Red Bull((c)) consumption compared to control condition. Intake of Red Bull((c)) significantly improved reaction time, performance in immediate memory test, verbal fluency, and subject's attention as well as performance in mental stress test. Conclusion. This study demonstrated that Red Bull((c)) has beneficial effect on some cognitive functions and effect on cardiovascular and respiratory system at rest and during exercise by increasing activity of the sympathetic nervous system. PMID- 26124832 TI - Myocardial Infarction and Stroke Risk in Young Healthy Men Treated with Injectable Testosterone. AB - This study was conducted to examine the association between testosterone therapy and new myocardial infarction (MI) and stroke events in a series of patients treated at Low T Centers across the United States, consisting of mainly young (mean age = 46), otherwise, healthy men. Electronic medical records were queried between the years 2009 and 2014 to identify patients diagnosed with hypogonadism, MI, and stroke, as indicated by ICD-9 codes. The incidence of MI and stroke events was compared to community-based registries. 39,936 patients recruited from 40 Low T Centers across the United States were treated and 19,968 met eligibility criteria for receiving testosterone treatment. The incidence rate ratio (IRR) for MI in testosterone- (T-) treated versus nontreated patients was 0.14 (C.I. = 0.08 to 0.18, P < 0.0001) whereas the IRR for stroke for T-treated versus nontreated patients was 0.11 (C.I. = 0.02 to 0.13, P < 0.0001). There was no evidence of worsening preexisting MI or stroke in patients treated with testosterone. The experience in Low T Centers shows that, in an injectable testosterone patient registry, testosterone is generally safe for younger men who do not have significant risk factors. Of patients that developed MI with testosterone, there was no association with testosterone or hematocrit levels. PMID- 26124830 TI - Polycystic Ovary Syndrome: Important Underrecognised Cardiometabolic Risk Factor in Reproductive-Age Women. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age. Although PCOS is diagnosed exclusively based on reproductive criteria, it is also a metabolic disorder. Insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, obesity, and dyslipidemia are more common in women with PCOS than in age-comparable women without PCOS. Many of the metabolic abnormalities that manifest in PCOS are worsened by the concurrent incidence of obesity. However, some of these metabolic perturbations occur even in lean women with PCOS and therefore are rightfully recognized as intrinsic to PCOS. The intrinsic factors that produce these metabolic disturbances are reviewed in this paper. The consequences of obesity and the other metabolic aberrations are also discussed. The metabolic perturbations in PCOS patients lead to chronic low-grade inflammation and to cardiovascular impairments that heighten the risk of having cardiovascular disease. Even though many studies have shown an elevation in surrogate biomarkers of cardiovascular disease in PCOS women, it is still not clear to what extent and magnitude the elevation precipitates more frequent and earlier events. PMID- 26124833 TI - Various Techniques to Increase Keratinized Tissue for Implant Supported Overdentures: Retrospective Case Series. AB - Purpose. The purpose of this retrospective case series is to describe and compare different surgical techniques that can be utilized to augment the keratinized soft tissue around implant-supported overdentures. Materials and Methods. The data set was extracted as deidentified information from the routine treatment of patients at the Ashman Department of Periodontology and Implant Dentistry at New York University College of Dentistry. Eight edentulous patients were selected to be included in this study. Patients were treated for lack of keratinized tissue prior to implant placement, during the second stage surgery, and after delivery of the final prosthesis. Results. All 8 patients in this study were wearing a complete maxillary and/or mandibular denture for at least a year before the time of the surgery. One of the following surgical techniques was utilized to increase the amount of keratinized tissue: apically positioned flap (APF), pedicle graft (PG), connective tissue graft (CTG), or free gingival graft (FGG). Conclusions. The amount of keratinized tissue should be taken into consideration when planning for implant-supported overdentures. The apical repositioning flap is an effective approach to increase the width of keratinized tissue prior to the implant placement. PMID- 26124831 TI - Optimizing Bone Health in Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA. PMID- 26124834 TI - Quality of Root Canals Performed by the Inaugural Class of Dental Students at Libyan International Medical University. AB - Objective. The purpose of this study was to radiographically evaluate technical quality of root canal fillings performed by dental undergraduates at Libyan International Medical University in Libya. Methods. Root canal cases were treated at university dental clinic from the fall of 2012 to the fall of 2013 by the fourth and fifth year dental students. Students used step-back preparation and cold lateral compaction in the treatment. Radiographs were reviewed over a two year period from initial procedure to final restoration. Radiographs were evaluated for adequacy or inadequacy by length, density, and taper. Length inadequacy was classified as short or overextended. Overall quality was considered "adequate" based on all three variables. Chi-square tested differences between teeth groupings and adequacy classification. Significant p value results were adjusted by Bonferroni correction. Results. Adequate length of root canal fillings were observed in roughly half of all samples (48.6%). Density was adequate in 75.8% of the samples. Taper was observed as adequate in 68.8%. Higher quality was evident in anterior teeth (plus premolars) versus molars (65.6% versus 43.3%, resp.; p < 0.04). Conclusion. Overall quality of endodontic treatment performed by undergraduate dental students was adequate in 53.9% of the cases. Significant opportunity exists to improve the quality of root canals provided by dental students. PMID- 26124835 TI - Clinical Advantages and Limitations of Monolithic Zirconia Restorations Full Arch Implant Supported Reconstruction: Case Series. AB - Purpose. The purpose of this retrospective case series is to evaluate the clinical advantages and limitations of monolithic zirconia restorations for full arch implant supported restorations and report the rate of complications up to 2 years after insertion. Materials and Methods. Fourteen patients received implant placement for monolithic zirconia full arch reconstructions. Four implants were placed in seven arches, eleven arches received six implants, two arches received seven implants, two arches received eight implants, and one arch received nine implants. Results. No implant failures or complications were reported for an implant survival rate of 100% with follow-up ranging from 3 to 24 months. Conclusions. Monolithic zirconia CAD-/CAM-milled framework restorations are a treatment option for full arch restorations over implants, showing a 96% success rate in the present study. Some of the benefits are accuracy, reduced veneering porcelain, and minimal occlusal adjustments. The outcome of the present study showed high success in function, aesthetics, phonetics, and high patient satisfaction. PMID- 26124836 TI - Zirconia Implants in Esthetic Areas: 4-Year Follow-Up Evaluation Study. AB - Objectives. The aim is to evaluate the survival and success rates, as well as the marginal bone loss (MBL) and periodontal indexes of zirconia implants positioned in the esthetic jaw areas. Materials and Method. 13 patients were selected and 20 one-piece zirconia implants were used for the rehabilitation of single tooth or partially edentulous ridge in the esthetic jaw areas. Six months after surgery and then once a year, a clinical-radiographic evaluation was performed in order to estimate peri-implant tissue health and marginal bone loss. Results. The survival and success rates were 100%. The average marginal bone loss from baseline to 48 months after surgery was +2.1 mm. Four years after surgery, the median and the mode for visible Plaque Index and Bleeding On Probing resulted 1 whereas Probing Pocket Depth amounted to 3 mm (SD = +/-0.49 mm). Conclusion. One piece zirconia dental implants are characterized by high biocompatibility, low plaque adhesion, and absence of microgap that can be related to the clinical success of these implants even in the esthetic areas. PMID- 26124837 TI - Soft Tissue Surgical Procedures for Optimizing Anterior Implant Esthetics. AB - Implant dentistry has been established as a predictable treatment with excellent clinical success to replace missing or nonrestorable teeth. A successful esthetic implant reconstruction is predicated on two fundamental components: the reproduction of the natural tooth characteristics on the implant crown and the establishment of soft tissue housing that will simulate a healthy periodontium. In order for an implant to optimally rehabilitate esthetics, the peri-implant soft tissues must be preserved and/or augmented by means of periodontal surgical procedures. Clinicians who practice implant dentistry should strive to achieve an esthetically successful outcome beyond just osseointegration. Knowledge of a variety of available techniques and proper treatment planning enables the clinician to meet the ever-increasing esthetic demands as requested by patients. The purpose of this paper is to enhance the implant surgeon's rationale and techniques beyond that of simply placing a functional restoration in an edentulous site to a level whereby an implant-supported restoration is placed in reconstructed soft tissue, so the site is indiscernible from a natural tooth. PMID- 26124838 TI - Stem Cell-Biomaterial Interactions for Tissue Engineering. PMID- 26124839 TI - All-Trans Retinoic Acid Improves the Effects of Bone Marrow-Derived Mesenchymal Stem Cells on the Treatment of Ankylosing Spondylitis: An In Vitro Study. AB - Previous studies have demonstrated the immunosuppressive effects of both all trans retinoic acid (ATRA) and mesenchymal stem cells (MSCs). The present study aimed to assess the immunoregulatory effects of ATRA on MSCs in the treatment of ankylosing spondylitis (AS). Bone marrow-derived MSCs from healthy donors were pretreated with ATRA and cocultured with CD3/28-activated peripheral blood mononuclear cells (PBMCs) derived from AS patients. Frequencies of Th17 and regulatory T (Treg) cells were analyzed using flow cytometry. The secretion and the mRNA level of key cytokines were measured with cytometric bead array and quantitative real-time PCR, respectively. ATRA pretreatment increased interleukin 6 (IL-6) secretion of MSCs. Th17 and Treg subset populations were increased and reduced by ATRA-pretreated MSCs, respectively. ATRA-pretreated MSCs significantly decreased not only the vital pathogenic cytokine in AS, tumor necrosis factor alpha (TNF-alpha), but also AS-boosting factors interleukin-17 (IL-17A) and interferon-gamma (IFN-gamma). These results indicated that IL-6 may be a potential protective factor in AS and highlighted the promising role of ATRA in improving the efficacy of MSC-based treatment of AS. PMID- 26124840 TI - Electrospun Gelatin/beta-TCP Composite Nanofibers Enhance Osteogenic Differentiation of BMSCs and In Vivo Bone Formation by Activating Ca (2+) Sensing Receptor Signaling. AB - Calcium phosphate- (CaP-) based composite scaffolds have been used extensively for the bone regeneration in bone tissue engineering. Previously, we developed a biomimetic composite nanofibrous membrane of gelatin/beta-tricalcium phosphate (TCP) and confirmed their biological activity in vitro and bone regeneration in vivo. However, how these composite nanofibers promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is unknown. Here, gelatin/beta-TCP composite nanofibers were fabricated by incorporating 20 wt% beta-TCP nanoparticles into electrospun gelatin nanofibers. Electron microscopy showed that the composite beta-TCP nanofibers had a nonwoven structure with a porous network and a rough surface. Spectral analyses confirmed the presence and chemical stability of the beta-TCP and gelatin components. Compared with pure gelatin nanofibers, gelatin/beta-TCP composite nanofibers caused increased cell attachment, proliferation, alkaline phosphatase activity, and osteogenic gene expression in rat BMSCs. Interestingly, the expression level of the calcium sensing receptor (CaSR) was significantly higher on the composite nanofibrous scaffolds than on pure gelatin. For rat calvarial critical sized defects, more extensive osteogenesis and neovascularization occurred in the composite scaffolds group compared with the gelatin group. Thus, gelatin/beta-TCP composite scaffolds promote osteogenic differentiation of BMSCs in vitro and bone regeneration in vivo by activating Ca(2+)-sensing receptor signaling. PMID- 26124841 TI - Modulation of Dental Pulp Stem Cell Odontogenesis in a Tunable PEG-Fibrinogen Hydrogel System. AB - Injectable hydrogels have the great potential for clinical translation of dental pulp regeneration. A recently developed PEG-fibrinogen (PF) hydrogel, which comprises a bioactive fibrinogen backbone conjugated to polyethylene glycol (PEG) side chains, can be cross-linked after injection by photopolymerization. The objective of this study was to investigate the use of this hydrogel, which allows tuning of its mechanical properties, as a scaffold for dental pulp tissue engineering. The cross-linking degree of PF hydrogels could be controlled by varying the amounts of PEG-diacrylate (PEG-DA) cross-linker. PF hydrogels are generally cytocompatible with the encapsulated dental pulp stem cells (DPSCs), yielding >85% cell viability in all hydrogels. It was found that the cell morphology of encapsulated DPSCs, odontogenic gene expression, and mineralization were strongly modulated by the hydrogel cross-linking degree and matrix stiffness. Notably, DPSCs cultured within the highest cross-linked hydrogel remained mostly rounded in aggregates and demonstrated the greatest enhancement in odontogenic gene expression. Consistently, the highest degree of mineralization was observed in the highest cross-linked hydrogel. Collectively, our results indicate that PF hydrogels can be used as a scaffold for DPSCs and offers the possibility of influencing DPSCs in ways that may be beneficial for applications in regenerative endodontics. PMID- 26124842 TI - Modulating Mesenchymal Stem Cell Behavior Using Human Hair Keratin-Coated Surfaces. AB - Human mesenchymal stem cells (hMSCs) have shown great potential for therapeutic purposes. However, the low frequencies of hMSCs in the body and difficulties in expanding their numbers in vitro have limited their clinical use. In order to develop an alternative strategy for the expansion of hMSCs in vitro, we coated tissue culture polystyrene with keratins extracted from human hair and studied the behavior of cells from 2 donors on these surfaces. The coating resulted in a homogeneous distribution of nanosized keratin globules possessing significant hydrophilicity. Results from cell attachment assays demonstrated that keratin coated surfaces were able to moderate donor-to-donor variability when compared with noncoated tissue culture polystyrene. STRO-1 expression was either sustained or enhanced on hMSCs cultured on keratin-coated surfaces. This translated into significant increases in the colony-forming efficiencies of both hMSC populations, when the cells were serially passaged. Human hair keratins are abundant and might constitute a feasible replacement for other biomaterials that are of animal origin. In addition, our results suggest that hair keratins may be effective in moderating the microenvironment sufficiently to enrich hMSCs with high colony-forming efficiency ex vivo, for clinical applications. PMID- 26124843 TI - Graphene: A Versatile Carbon-Based Material for Bone Tissue Engineering. AB - The development of materials and strategies that can influence stem cell attachment, proliferation, and differentiation towards osteoblasts is of high interest to promote faster healing and reconstructions of large bone defects. Graphene and its derivatives (graphene oxide and reduced graphene oxide) have received increasing attention for biomedical applications as they present remarkable properties such as high surface area, high mechanical strength, and ease of functionalization. These biocompatible carbon-based materials can induce and sustain stem cell growth and differentiation into various lineages. Furthermore, graphene has the ability to promote and enhance osteogenic differentiation making it an interesting material for bone regeneration research. This paper will review the important advances in the ability of graphene and its related forms to induce stem cells differentiation into osteogenic lineages. PMID- 26124845 TI - Approaches to the diagnosis and management of chronic urticaria in children. AB - Most guidelines for chronic urticaria (CU) in infants and children are based on limited pediatric evidence. Current evidence used to guide treatment in children is extrapolated from data focusing on older age groups. CU in children is a different and complex condition than that in adults. Furthermore, there is little published information regarding urticaria in Korean children. The aim of the present article is to review recent research on chronic childhood urticaria and improve the current understanding of its pathogenesis and management. The classification and definition of urticaria in adults also applies to children. CU is defined as a daily occurrence of spontaneous wheals, angioedema, or both for >6 weeks. The precise pathophysiology of CU is unknown and the rates of successful identification of a cause in children with CU vary from 20%-50%. There is no established laboratory test to evaluate the presence of urticaria. The natural course of childhood CU is undetermined, with limited reports discussing long-term outcomes. Second-generation H1 antihistamines are the cornerstone of management, while limited therapeutic drugs are available for adults. PMID- 26124846 TI - Association between serum alanine aminotransferase level and obesity indices in Korean adolescents. AB - PURPOSE: To analyze the correlation between serum alanine aminotransferase (ALT) and obesity indices including body mass index (BMI), body fat percentage (BFP), total fat mass (FM), truncal fat mass (TFM), waist circumference (WC), and waist to-height ratio (WHtR) in Korean adolescents. METHODS: This was a cross-sectional study based on data derived from the 2010-2011 Korean National Health and Nutrition Examination Surveys (KNHANES). Subjects were Korean adolescents aged 10 18 years (871 total; 475 boys and 396 girls) who participated in KNHANES. RESULTS: In both sexes, BMI, FM, TFM, WC, and WHtR were higher when ALT levels were in the 4th quartile. In boys, there was a significant positive correlation between ALT level and BMI, BFP, FM, TFM, WC, and WHtR (r=0.55, P<0.0001 for BMI; r=0.52, P<0.0001 for BFP; r=0.58, P<0.0001 for FM; r=0.61, P<0.0001 for TFM; and r=0.56, P<0.0001 for WC; r=0.62, P<0.0001 for WHtR), and the correlation coefficient was higher than that in girls. CONCLUSION: Our results suggest a significant positive association between serum ALT level and obesity indices in male adolescents. PMID- 26124847 TI - Epidemiological comparison of three Mycoplasma pneumoniae pneumonia epidemics in a single hospital over 10 years. AB - PURPOSE: Mycoplasma pneumoniae (MP) pneumonia epidemics have occurred in 3- to 4 year cycles in Korea. We evaluated the epidemiologic characteristics of MP pneumonia in Daejeon, Korea, from 2003 to 2012. METHODS: We retrospectively analyzed 779 medical records of children (0-15 years of old) with MP pneumonia admitted to our institution and compared the data from 3 recent epidemics. RESULTS: In 779 patients, the mean age and male-to-female ratio were 5.0+/-2.2 years and 1:1, and most cases were observed in autumn. There were three epidemics during the study period, in 2003, 2006-2007, and 2011. In our comparison of the three epidemics, we found no differences in mean age, the male-to-female ratio, hospital stay, or the rate of seroconverters during hospitalization. All three epidemics began in early summer and peaked in September 2003 and 2011 and in October 2006 and then gradually decreased until the next year's spring season, although the 2006 epidemic extended further into 2007. The peak age groups in the children in 2003 and 2006 were 3-6 year-olds (57.5% and 56%, respectively), but in the 2011 epidemic, the peak group was 1-4 year-olds (46.5%). The proportion of the <2 years of age group was 20%, 15.7% and 28.8%, and >10 years of age group was 5.2%, 13.8%, and 14.8% of total patients, respectively. CONCLUSION: MP pneumonia outbreaks occurred every 3-4 years. The pattern of 3 recent epidemics was similar in demographic characteristics and seasonality with some variations in each outbreak. PMID- 26124844 TI - Hydrogels and Cell Based Therapies in Spinal Cord Injury Regeneration. AB - Spinal cord injury (SCI) is a central nervous system- (CNS-) related disorder for which there is yet no successful treatment. Within the past several years, cell based therapies have been explored for SCI repair, including the use of pluripotent human stem cells, and a number of adult-derived stem and mature cells such as mesenchymal stem cells, olfactory ensheathing cells, and Schwann cells. Although promising, cell transplantation is often overturned by the poor cell survival in the treatment of spinal cord injuries. Alternatively, the therapeutic role of different cells has been used in tissue engineering approaches by engrafting cells with biomaterials. The latter have the advantages of physically mimicking the CNS tissue, while promoting a more permissive environment for cell survival, growth, and differentiation. The roles of both cell- and biomaterial based therapies as single therapeutic approaches for SCI repair will be discussed in this review. Moreover, as the multifactorial inhibitory environment of a SCI suggests that combinatorial approaches would be more effective, the importance of using biomaterials as cell carriers will be herein highlighted, as well as the recent advances and achievements of these promising tools for neural tissue regeneration. PMID- 26124848 TI - Association of CD4(+)CD25(+)FoxP3(+) regulatory T cells with natural course of childhood chronic immune thrombocytopenic purpura. AB - PURPOSE: The purpose of this study was to determine the frequency of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg) in the peripheral blood of patients with childhood chronic immune thrombocytopenic purpura (ITP) exhibiting thrombocytopenia and spontaneous remission. The findings of this study indicate the possibility of predicting spontaneous recovery and pathogenesis of childhood chronic ITP. METHODS: Eleven children with chronic ITP (seven thrombocytopenic and four spontaneous remission cases; mean age, 8.8 years; range, 1.7-14.9 years) were enrolled in this study. Five healthy children and eight healthy adults were included as controls. The frequency of Treg was evaluated by flow cytometry in the peripheral blood. RESULTS: In this study, four patients (36%) achieved spontaneous remission within 2.8 years (mean year; range, 1.0-4.4 years). The frequency of Treg was significantly lower in patients with persisting thrombocytopenia (0.13%+/-0.09%, P<0.05), than that in the patients with spontaneous remission (0.30%+/-0.02%), healthy adults controls (0.55%+/-0.44%), and healthy children controls (0.46%+/-0.26%). A significantly positive correlation was found between the frequency of Treg and the platelet count in children. CONCLUSION: These data suggest that a lower frequency of Treg contributes to the breakdown of self-tolerance, and may form the basis for future development of specific immunomodulatory therapies. Furthermore, Treg frequency has prognostic implication toward the natural course and long-term outcomes of childhood chronic ITP. PMID- 26124849 TI - Validity of bag urine culture for predicting urinary tract infections in febrile infants: a paired comparison of urine collection methods. AB - PURPOSE: Catheter urine (CATH-U) and suprapubic aspiration (SPA) are reliable urine collection methods for confirming urinary tract infections (UTI) in infants. However, noninvasive and easily accessible collecting bag urine (CBU) is widely used, despite its high contamination rate. This study investigated the validity of CBU cultures for diagnosing UTIs, using CATH-U culture results as the gold standard. METHODS: We retrospectively analyzed 210 infants, 2- to 24-month old, who presented to a tertiary care hospital's pediatrics department between September 2008 and August 2013. We reviewed the results of CBU and CATH-U cultures from the same infants. RESULTS: CBU results, relative to CATH-U culture results (>=10(4) colony-forming units [CFU]/mL) were widely variable, ranging from no growth to >=10(5) CFU/mL. A CBU cutoff value of >=10(5) CFU/mL resulted in false-positive and false-negative rates of 18% and 24%, respectively. The probability of a UTI increased when the CBU bacterial count was >=10(5)/mL for all infants, both uncircumcised male infants and female infants (likelihood ratios [LRs], 4.16, 4.11, and 4.11, respectively). UTIs could not be excluded for female infants with a CBU bacterial density of 10(4)-10(5) (LR, 1.40). The LRs for predicting UTIs based on a positive dipstick test and a positive urinalysis were 4.19 and 3.11, respectively. CONCLUSION: The validity of obtaining urine sample from a sterile bag remains questionable. Inconclusive culture results from CBU should be confirmed with a more reliable method. PMID- 26124850 TI - Case of seropositive allergic bronchopulmonary aspergillosis in a 10-year-old girl without previously documented asthma. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease due to bronchial colonization of Aspergillus fumigatus that occurs in susceptible patients with asthma or cystic fibrosis. A 10-year-old girl was referred to the Department of Pediatric Pulmonology for persistent consolidations on chest radiography. Pulmonary consolidations were observed in the right upper and left lower lobes and were not resolved with a 4-week prescription of broad-spectrum antibiotics. The patient had a history of atopic dermatitis and allergic rhinitis but no history of asthma. She had no fever but produced thick and greenish sputum. Her breathing sounds were clear. On laboratory testing, her total blood eosinophil count was 1,412/mm(3) and total serum IgE level was 2,200 kU/L. Aspergillus was isolated in the sputum culture. The A. fumigatus-specific IgE level was 15.4 kU/L, and the Aspergillus antibody test was also positive. A chest computed tomography scan demonstrated bronchial wall thickening and consolidation without bronchiectasis. An antifungal agent was added but resulted in no improvement of pulmonary consolidations after 3 weeks. Pulmonary function test was normal. Methacholine provocation test was performed, revealing bronchial hyperreactivity (PC20=5.31 mg/mL). Although the patient had no history of asthma or bronchiectasis, ABPA-seropositivity was suspected. Oral prednisolone (1 mg/kg/day) combined with antifungal therapy was started. Pulmonary consolidations began decreasing after 1 week of treatment and completely resolved after 1 month. This is the first observed and treated case of seropositive ABPA in Korean children without previously documented asthma. PMID- 26124851 TI - Chronic inflammatory demyelinating polyneuropathy in children: a report of four patients with variable relapsing courses. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing symmetric sensorimotor disorder presumed to occur because of immunologic antibody-mediated reactions. To understand the clinical courses of CIDP, we report variable CIDP courses in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. Four patients who were diagnosed with acute-onset and relapsing CIDP courses at Severance Children's Hospital, Seoul, Korea, were enrolled in this retrospective study. We diagnosed each patient on the basis of the CIDP diagnostic criteria developed in 2010 by the European Federation of Neurological Societies/Peripheral Nerve Society Guidelines. We present the cases of four pediatric patients diagnosed with CIDP to understand the variable clinical course of the disease in children. Our four patients were all between 8 and 12 years of age. Patients 1 and 2 were diagnosed with acute cerebellar ataxia or Guillain Barre syndrome as initial symptoms. While patients 1 and 4 were given only intravenous dexamethasone (0.3 mg/kg/day) for 5 days at the first episode, Patients 2 and 3 were given a combination of intravenous immunoglobulin (2 g/kg) and dexamethasone (0.3 mg/kg/day). All patients were maintained with oral prednisolone at 30 mg/day, but their clinical courses were variable in both relapse intervals and severity. We experienced variable clinical courses of CIDP in children with respect to initial presentation, responsiveness to medical treatment, and recurrence interval. PMID- 26124852 TI - Mindfulness Trait Predicts Neurophysiological Reactivity Associated with Negativity Bias: An ERP Study. AB - This study explored the relationship of mindfulness trait with the early and late stages of affective processing, by examining the two corresponding ERP components, P2 and LPP, collected from twenty-two male Chinese participants with a wide range of meditation experiences. Multiple regression analyses was performed on the mindfulness scores, as measured by CAMS-R, with the subjective affective ratings and ERP data collected during an emotion processing task. The results showed that increased mindfulness scores predicted increased valence ratings of negative stimuli (less negative), as well as increased P2 amplitudes at the frontocentral location for positive compared to negative stimuli. Based on these findings, a plausible mechanism of mindfulness in reducing negativity bias was discussed. Moreover, our results replicated previous findings on the age related increase of P2 amplitudes at the frontal sites for positive compared to neutral stimuli. Since the locations at which P2 amplitudes were found as associated with age and mindfulness differed, as did the emotional contents of the stimuli being compared, indicating that the effect of age did not confound our findings on mindfulness and the two factors might operate on early affective processing from distinct sources and mechanisms. PMID- 26124853 TI - Naringin Attenuates Autophagic Stress and Neuroinflammation in Kainic Acid Treated Hippocampus In Vivo. AB - Kainic acid (KA) is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in animal models from neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. In the present study, we examined its beneficial effects involved in antiautophagic stress and antineuroinflammation in the KA-treated hippocampus. Our results showed that naringin treatment delayed the onset of KA-induced seizures and decreased the occurrence of chronic spontaneous recurrent seizures (SRS) in KA-treated mice. Moreover, naringin treatment protected hippocampal CA1 neurons in the KA-treated hippocampus, ameliorated KA-induced autophagic stress, confirmed by the expression of microtubule-associated protein light chain 3 (LC3), and attenuated an increase in tumor necrosis factor-alpha (TNFalpha) in activated microglia. These results suggest that naringin may have beneficial effects of preventing epileptic events and neuronal death through antiautophagic stress and antineuroinflammation in the hippocampus in vivo. PMID- 26124854 TI - Application of Cornelian Cherry Iridoid-Polyphenolic Fraction and Loganic Acid to Reduce Intraocular Pressure. AB - One of the most common diseases of old age in modern societies is glaucoma. It is strongly connected with increased intraocular pressure (IOP) and could permanently damage vision in the affected eye. As there are only a limited number of chemical compounds that can decrease IOP as well as blood flow in eye vessels, the up-to-date investigation of new molecules is important. The chemical composition of the dried Cornelian cherry (Cornus mas L.) polar, iridoid polyphenol-rich fraction was investigated. Loganic acid (50%) and pelargonidin-3 galactoside (7%) were found as the main components. Among the other constituents, iridoid compound cornuside and the anthocyans cyanidin 3-O-galactoside, cyanidin 3-O-robinobioside, and pelargonidin 3-O-robinobioside were quantified in the fraction. In an animal model (New Zealand rabbits), the influence of loganic acid and the polyphenolic fraction isolated from Cornelian cherry fruit was investigated. We found a strong IOP-hypotensive effect for a 0.7% solution of loganic acid, which could be compared with the widely ophthalmologically used timolol. About a 25% decrease in IOP was observed within the first 3 hours of use. PMID- 26124855 TI - The Influence of DNA Configuration on the Direct Strand Break Yield. AB - PURPOSE: To study the influence of DNA configuration on the direct damage yield. No indirect effect has been accounted for. METHODS: The GEANT4-DNA code was used to simulate the interactions of protons and alpha particles with geometrical models of the A-, B-, and Z-DNA configurations. The direct total, single, and double strand break yields and site-hit probabilities were determined. Certain features of the energy deposition process were also studied. RESULTS: A slight increase of the site-hit probability as a function of the incident particle linear energy transfer was found for each DNA configuration. Each DNA form presents a well-defined site-hit probability, independently of the particle linear energy transfer. Approximately 70% of the inelastic collisions and ~60% of the absorbed dose are due to secondary electrons. These fractions are slightly higher for protons than for alpha particles at the same incident energy. CONCLUSIONS: The total direct strand break yield for a given DNA form depends weakly on DNA conformation topology. This yield is practically determined by the target volume of the DNA configuration. However, the double strand break yield increases with the packing ratio of the DNA double helix; thus, it depends on the DNA conformation. PMID- 26124856 TI - Preliminary Investigation of Microdosimetric Track Structure Physics Models in Geant4-DNA and RITRACKS. AB - The major differences between the physics models in Geant4-DNA and RITRACKS Monte Carlo packages are investigated. Proton and electron ionisation interactions and electron excitation interactions in water are investigated in the current work. While these packages use similar semiempirical physics models for inelastic cross sections, the implementation of these models is demonstrated to be significantly different. This is demonstrated in a simple Monte Carlo simulation designed to identify differences in interaction cross-sections. PMID- 26124857 TI - Has the airway microbiome been overlooked in respiratory disease? AB - The respiratory disease field is changing because of recent advances in our understanding of the airway microbiome. Central to this is dysbiosis, an imbalance of microbial communities that can lead to and flag inflammation in the airways. The increasing momentum of research in this area holds promise for novel treatment strategies. PMID- 26124858 TI - Hetero-Diels-Alder reactions of hetaryl and aryl thioketones with acetylenic dienophiles. AB - Selected hetaryl and aryl thioketones react with acetylenecarboxylates under thermal conditions in the presence of LiClO4 or, alternatively, under high pressure conditions (5 kbar) at room temperature yielding thiopyran derivatives. The hetero-Diels-Alder reaction occurs in a chemo- and regioselective manner. The initially formed [4 + 2] cycloadducts rearrange via a 1,3-hydrogen shift sequence to give the final products. The latter were smoothly oxidized by treatment with mCPBA to the corresponding sulfones. PMID- 26124859 TI - Synthesis of 1,2-cis-2-C-branched aryl-C-glucosides via desulfurization of carbohydrate based hemithioacetals. AB - 1-C and 2-C-branched carbohydrates are present as substructures in a number of biologically important compounds. Although the synthesis of such carbohydrate derivatives is extensively studied, the synthesis of 1,2-cis-2-C-branched C-, S-, and N-glycosides is less explored. In this article a synthetic strategy for the synthesis of 1,2-cis-2-C-branched-aryl-C-glucosides is reported via a hydrogenolytic desulfurization of suitably orientated carbohydrate based hemithioacetals. 1,2-cis-2-Hydroxymethyl and 2-carbaldehyde of aryl-C-glucosides have been synthesized using the current strategy in very good yields. The 2 carbaldehyde-aryl-C-glucosides have been identified as suitable substrates for the stereospecific preparation of 2,3-unsaturated-aryl-C-glycosides (Ferrier products). PMID- 26124860 TI - Potential of acylated peptides to target the influenza A virus. AB - For antiviral drug design, especially in the field of influenza virus research, potent multivalent inhibitors raise high expectations for combating epidemics and pandemics. Among a large variety of covalent and non-covalent scaffold systems for a multivalent display of inhibitors, we created a simple supramolecular platform to enhance the antiviral effect of our recently developed antiviral Peptide B (PeB(GF)), preventing binding of influenza virus to the host cell. By conjugating the peptide with stearic acid to create a higher-order structure with a multivalent display, we could significantly enhance the inhibitory effect against the serotypes of both human pathogenic influenza virus A/Aichi/2/1968 H3N2, and avian pathogenic A/FPV/Rostock/34 H7N1 in the hemagglutination inhibition assay. Further, the inhibitory potential of stearylated PeB(GF) (C18 PeB(GF)) was investigated by infection inhibition assays, in which we achieved low micromolar inhibition constants against both viral strains. In addition, we compared C18-PeB(GF) to other published amphiphilic peptide inhibitors, such as the stearylated sugar receptor mimicking peptide (Matsubara et al. 2010), and the "Entry Blocker" (EB) (Jones et al. 2006), with respect to their antiviral activity against infection by Influenza A Virus (IAV) H3N2. However, while this strategy seems at a first glance promising, the native situation is quite different from our experimental model settings. First, we found a strong potential of those peptides to form large amyloid-like supramolecular assemblies. Second, in vivo, the large excess of cell surface membranes provides an unspecific target for the stearylated peptides. We show that acylated peptides insert into the lipid phase of such membranes. Eventually, our study reveals serious limitations of this type of self-assembling IAV inhibitors. PMID- 26124861 TI - Novel stereocontrolled syntheses of tashiromine and epitashiromine. AB - A novel stereocontrolled approach has been developed for the syntheses of tashiromine and epitashiromine alkaloids from cyclooctene beta-amino acids. The synthetic concept is based on the azetidinone opening of a bicyclic beta-lactam, followed by oxidative ring opening through ring C-C double bond and reductive ring-closure reactions of the cis- or trans-cyclooctene beta-amino acids. PMID- 26124862 TI - Weakly nucleophilic potassium aryltrifluoroborates in palladium-catalyzed Suzuki Miyaura reactions: relative reactivity of K[4-RC6F4BF3] and the role of silver assistance in acceleration of transmetallation. AB - Small differences in the reactivity of weakly nucleophilic potassium aryltrifluoroborates are revealed in the silver-assisted Pd-catalyzed cross coupling of K[4-RC6F4BF3] (R = H, Bu, MeO, EtO, PrO, iPrO, BuO, t-BuO, CH2=CHCH2O, PhCH2O, PhCH2CH2O, PhO, F, pyrazol-1-yl, pyrrol-1-yl, and indol-1-yl) with ArX (4-BrC6H4CH3, 4-IC6H4F and 3-IC6H4F). An assumed role of silver(I) compounds Ag m Y (Y = O, NO3, SO4, BF4, F) consists in polarization of the Pd-X bond in neutral complex ArPdL n X with the generation of the related transition state or formation of [ArPdL n ][XAg m Y] with a highly electrophilic cation and subsequent transmetallation with the weakly nucleophilic borate. Efficiency of Ag m Y as a polarizing agent decreases in order Ag2O > AgNO3 ~ Ag2SO4 > Ag[BF4] > AgF. No clear correlation between the reactivity of K[4-RC6F4BF3] and substituent electron parameters, sigmaI and sigmaR degrees , of the aryl group 4-RC6F4 was found. PMID- 26124863 TI - Automated solid-phase synthesis of oligosaccharides containing sialic acids. AB - A sialic acid glycosyl phosphate building block was designed and synthesized. This building block was used to prepare alpha-sialylated oligosaccharides by automated solid-phase synthesis selectively. PMID- 26124864 TI - Hydrogenation of unactivated enamines to tertiary amines: rhodium complexes of fluorinated phosphines give marked improvements in catalytic activity. AB - In the hydrogenation of sluggish unactivated enamine substrates, Rh complexes of electron-deficient phosphines are demonstrated to be far more reactive catalysts than those derived from triphenylphosphine. These operate at low catalyst loadings (down to 0.01 mol %) and are able to reduce tetrasubstituted enamines. The use of the sustainable and environmentally benign solvent (R)-limonene for the reaction is also reported with the amine isolated by acid extraction. PMID- 26124865 TI - TTFs nonsymmetrically fused with alkylthiophenic moieties. AB - Two new dithiolene ligand precursors, containing fused TTF and alkyl thiophenic moieties 3,3'-{[2-(5-(tert-butyl)thieno[2,3-d][1,3]dithiol-2-ylidene)-1,3 dithiole-4,5-diyl]bis[sulfanediyl]}dipropanenitrile (alpha-tbtdt, 1), and 3,3' {[2-(5-methylthieno[2,3-d][1,3]dithiol-2-ylidene)-1,3-dithiole-4,5 diyl]bis[sulfanediyl]}dipropanenitrile (alpha-mtdt, 2), were synthesized and characterized. The electrochemical properties of these electronic donors were studied by cyclic voltammetry (CV) in dichloromethane. Both compounds show two quasi-reversible oxidation processes, versus Ag/AgCl, typical of TTF donors at E (1) 1/2 = 279 V and E (2) 1/2 = 680 V for 1 and E (1) 1/2 = 304 V and E (2) 1/2 = 716 V in the case of 2. The single-crystal X-ray structure of 1 and of a charge transfer salt of 2, (alpha-mtdt)[Au(mnt)2] (3), are reported. PMID- 26124866 TI - Synthesis of multivalent carbohydrate mimetics with aminopolyol end groups and their evaluation as L-selectin inhibitors. AB - In this article a series of divalent and trivalent carbohydrate mimetics on the basis of an enantiopure aminopyran and of serinol is described. These aminopolyols are connected by amide bonds to carboxylic acid derived spacer units either by Schotten-Baumann acylation or by coupling employing HATU as reagent. The O-sulfation employing the SO3.DMF complex was optimized. It was crucial to follow this process by 700 MHz (1)H NMR spectroscopy to ensure full conversion and to use a refined neutralization and purification protocol. Many of the compounds could not be tested as L-selectin inhibitor by SPR due to their insolubility in water, nevertheless, a divalent and a trivalent amide showed surprisingly good activities with IC50 values in the low micromolar range. PMID- 26124867 TI - Trifluoromethyl-substituted tetrathiafulvalenes. AB - A series of tetrathiafulvalenes functionalized with one or two trifluoromethyl electron-withdrawing groups (EWG) is obtained by phosphite coupling involving CF3 substituted 1,3-dithiole-2-one derivatives. The relative effects of the EWG such as CF3, CO2Me and CN on the TTF core were investigated from a combination of structural, electrochemical, spectrochemical and theoretical investigations. Electrochemical data confirm the good correlations between the first oxidation potential of the TTF derivatives and the sigmameta Hammet parameter, thus in the order CO2Me < CF3 < CN, indicating that, in any case, the mesomeric effect of the substituents is limited. Besides, crystal structure determinations show that the deformation of the unsymmetrically substituted dithiole rings, when bearing one, or two different EWG, and attributed to the mesomeric effect of ester or nitrile groups, is not notably modified or counter-balanced by the introduction of a neighboring trifluoromethyl group. DFT calculations confirm these observations and also show that the low energy HOMO-LUMO absorption band found in nitrile or ester-substituted TTFs is not found in TTF-CF3, where, as in TTF itself, the low energy absorption band is essentially attributable to a HOMO->LUMO + 1 transition. Despite relatively high oxidation potentials, these donor molecules with CF3 EWG can be involved in charge transfer complexes or cation radical salts, as reported here for the CF3-subsituted EDT-TTF donor molecule. A neutral charge transfer complex with TCNQ, (EDT-TTF-CF3)2(TCNQ) was isolated and characterized through alternated stacks of EDT-TTF-CF3 dimers and TCNQ in the solid state. A radical cation salt of EDT-TTF-CF3 is also obtained upon electrocrystallisation in the presence of the FeCl4 (-) anion. In this salt, formulated as (EDT-TTF-CF3)(FeCl4), the (EDT-TTF-CF3)(+*) radical cations are associated two-by-two into centrosymmetric dyads with a strong pairing of the radical species in a singlet state. PMID- 26124869 TI - Synthesis of carbohydrate-scaffolded thymine glycoconjugates to organize multivalency. AB - Multivalency effects are essential in carbohydrate recognition processes as occurring on the cell surface. Thus many synthetic multivalent glycoconjugates have been developed as important tools for glycobiological research. We are expanding this collection of molecules by the introduction of carbohydrate scaffolded divalent glycothymine derivatives that can be intramolecularily dimerized by [2 + 2] photocycloaddition. Thus, thymine functions as a control element that allows to restrict the conformational flexibility of the scaffolded sugar ligands and thus to "organize" multivalency. With this work we add a parameter to multivalency studies additional to valency. PMID- 26124868 TI - Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores. AB - The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are reported. The tri- and tetravalent systems designed as molecular probes and synthesized by way of Cu(I) catalysed azide-alkyne cycloadditions are fluorescent analogues of potent pharmacological chaperones/correctors recently reported in the field of Gaucher disease and cystic fibrosis, two rare genetic diseases caused by protein misfolding. PMID- 26124870 TI - CO2 Chemistry. PMID- 26124871 TI - Synthesis of tripodal catecholates and their immobilization on zinc oxide nanoparticles. AB - A common approach to generate tailored materials and nanoparticles (NPs) is the formation of molecular monolayers by chemisorption of bifunctional anchor molecules. This approach depends critically on the choice of a suitable anchor group. Recently, bifunctional catecholates, inspired by mussel-adhesive proteins (MAPs) and bacterial siderophores, have received considerable interest as anchor groups for biomedically relevant metal surfaces and nanoparticles. We report here the synthesis of new tripodal catecholates as multivalent anchor molecules for immobilization on metal surfaces and nanoparticles. The tripodal catecholates have been conjugated to various effector molecules such as PEG, a sulfobetaine and an adamantyl group. The potential of these conjugates has been demonstrated with the immobilization of tripodal catecholates on ZnO NPs. The results confirmed a high loading of tripodal PEG-catecholates on the particles and the formation of stable PEG layers in aqueous solution. PMID- 26124872 TI - First principle investigation of the linker length effects on the thermodynamics of divalent pseudorotaxanes. AB - The Gibbs energies of association (Gibbs free (binding) energies) for divalent crown-8/ammonium pseudorotaxanes are determined by investigating the influence of different linkers onto the binding. Calculations are performed with density functional theory including dispersion corrections. The translational, rotational and vibrational contributions are taken into account and solvation effects including counter ions are investigated by applying the COSMO-RS method, which is based on a continuum solvation model. The calculated energies agree well with the experimentally determined ones. The shortest investigated linker shows an enhanced binding strength due to electronic effects, namely the dispersion interaction between the linkers from the guest and the host. For the longer linkers this ideal packing is not possible due to steric hindrance. PMID- 26124873 TI - Self-assembly of heteroleptic dinuclear metallosupramolecular kites from multivalent ligands via social self-sorting. AB - A Troger's base-derived racemic bis(1,10-phenanthroline) ligand (rac)-1 and a bis(2,2'-bipyridine) ligand with a central 1,3-diethynylbenzene unit 2 were synthesized. Each of these ligands acts as a multivalent entity for the binding of two copper(I) ions. Upon coordination to the metal ions these two ligands undergo selective self-assembly into heteroleptic dinuclear metallosupramolecular kites in a high-fidelity social self-sorting manner as evidenced by NMR spectroscopy and mass spectrometry. PMID- 26124874 TI - Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW. AB - The coupling of peptides to polyglycerol carriers represents an important route towards the multivalent display of protein ligands. In particular, the inhibition of low affinity intracellular protein-protein interactions can be addressed by this design. We have applied this strategy to develop binding partners for FBP21, a protein which is important for the splicing of pre-mRNA in the nucleus of eukaryotic cells. Firstly, by using phage display the optimized sequence WPPPPRVPR was derived which binds with K Ds of 80 MUM and 150 uM to the individual WW domains and with a K D of 150 MUM to the tandem-WW1-WW2 construct. Secondly, this sequence was coupled to a hyperbranched polyglycerol (hPG) that allowed for the multivalent display on the surface of the dendritic polymer. This novel multifunctional hPG-peptide conjugate displayed a K D of 17.6 uM which demonstrates that the new carrier provides a venue for the future inhibition of proline-rich sequence recognition by FBP21 during assembly of the spliceosome. PMID- 26124875 TI - Probing multivalency in ligand-receptor-mediated adhesion of soft, biomimetic interfaces. AB - Many biological functions at cell level are mediated by the glycocalyx, a dense carbohydrate-presenting layer. In this layer specific interactions between carbohydrate ligands and protein receptors are formed to control cell-cell recognition, cell adhesion and related processes. The aim of this work is to shed light on the principles of complex formation between surface anchored carbohydrates and receptor surfaces by measuring the specific adhesion between surface bound mannose on a concanavalin A (ConA) layer via poly(ethylene glycol) (PEG)-based soft colloidal probes (SCPs). Special emphasis is on the dependence of multivalent presentation and density of carbohydrate units on specific adhesion. Consequently, we first present a synthetic strategy that allows for controlled density variation of functional groups on the PEG scaffold using unsaturated carboxylic acids (crotonic acid, acrylic acid, methacrylic acid) as grafting units for mannose conjugation. We showed by a range of analytic techniques (ATR-FTIR, Raman microscopy, zeta potential and titration) that this synthetic strategy allows for straightforward variation in grafting density and grafting length enabling the controlled presentation of mannose units on the PEG network. Finally we determined the specific adhesion of PEG-network-conjugated mannose units on ConA surfaces as a function of density and grafting type. Remarkably, the results indicated the absence of a molecular-level enhancement of mannose/ConA interaction due to chelate- or subsite-binding. The results seem to support the fact that weak carbohydrate interactions at mechanically flexible interfaces hardly undergo multivalent binding but are simply mediated by the high number of ligand-receptor interactions. PMID- 26124876 TI - Glycodendrimers: tools to explore multivalent galectin-1 interactions. AB - Four generations of lactose-functionalized polyamidoamine (PAMAM) were employed to further the understanding of multivalent galectin-1 mediated interactions. Dynamic light scattering and fluorescence microscopy were used to study the multivalent interaction of galectin-1 with the glycodendrimers in solution, and glycodendrimers were observed to organize galectin-1 into nanoparticles. In the presence of a large excess of galectin-1, glycodendrimers nucleated galectin-1 into nanoparticles that were remarkably homologous in size (400-500 nm). To understand augmentation of oncologic cellular aggregation by galectin-1, glycodendrimers were used in cell-based assays with human prostate carcinoma cells (DU145). The results revealed that glycodendrimers provided competitive binding sites for galectin-1, which diverted galectin-1 from its typical function in cellular aggregation of DU145 cells. PMID- 26124877 TI - Discrete multiporphyrin pseudorotaxane assemblies from di- and tetravalent porphyrin building blocks. AB - Two pairs of divalent and tetravalent porphyrin building blocks carrying the complementary supramolecular crown ether/secondary ammonium ion binding motif have been synthesized and their derived pseudorotaxanes have been studied by a combination of NMR spectroscopy in solution and ESI mass spectrometry in the gas phase. By simple mixing of the components the formation of discrete dimeric and trimeric (metallo)porphyrin complexes predominates, in accordance to binding stoichiometry, while the amount of alternative structures can be neglected. Our results illustrate the power of multivalency to program the multicomponent self assembly of specific entities into discrete functional nanostructures. PMID- 26124878 TI - Multivalent dendritic polyglycerolamine with arginine and histidine end groups for efficient siRNA transfection. AB - The success of siRNA-based therapeutics highly depends on a safe and efficient delivery of siRNA into the cytosol. In this study, we post-modified the primary amines on dendritic polyglycerolamine (dPG-NH2) with different ratios of two relevant amino acids, namely, arginine (Arg) and histidine (His). To investigate the effects from introducing Arg and His to dPG, the resulting polyplexes of amino acid functionalized dPG-NH2s (AAdPGs)/siRNA were evaluated regarding cytotoxicity, transfection efficiency, and cellular uptake. Among AAdPGs, an optimal vector with (1:3) Arg to His ratio, showed efficient siRNA transfection with minimal cytotoxicity (cell viability >= 90%) in NIH 3T3 cells line. We also demonstrated that the cytotoxicity of dPG-NH2 decreased as a result of amino acid functionalization. While the incorporation of both cationic (Arg) and pH responsive residues (His) are important for safe and efficient siRNA transfection, this study indicates that AAdPGs containing higher degrees of His display lower cytotoxicity and more efficient endosomal escape. PMID- 26124879 TI - Regulation of integrin and growth factor signaling in biomaterials for osteodifferentiation. AB - Stem cells respond to the microenvironment (niche) they are located in. Under natural conditions, the extracellular matrix (ECM) is the essential component the in stem cell niche, in which both integrin ligands and growth factors are important regulators to directly or indirectly modulate the cell behavior. In this review, we summarize the current knowledge about the potential of integrin ligands and growth factors to induce osteogenic differentiation of stem cells, and discuss the signaling pathways that are initiated by both individual and cooperative parameters. The joint effect of integrin ligands and growth factors is highlighted as the multivalent interactions for bone therapy. PMID- 26124880 TI - Orthogonal dual-modification of proteins for the engineering of multivalent protein scaffolds. AB - To add new tools to the repertoire of protein-based multivalent scaffold design, we have developed a novel dual-labeling strategy for proteins that combines residue-specific incorporation of unnatural amino acids with chemical oxidative aldehyde formation at the N-terminus of a protein. Our approach relies on the selective introduction of two different functional moieties in a protein by mutually orthogonal copper-catalyzed azide-alkyne cycloaddition (CuAAC) and oxime ligation. This method was applied to the conjugation of biotin and beta-linked galactose residues to yield an enzymatically active thermophilic lipase, which revealed specific binding to Erythrina cristagalli lectin by SPR binding studies. PMID- 26124881 TI - Impact of multivalent charge presentation on peptide-nanoparticle aggregation. AB - Strategies to achieve controlled nanoparticle aggregation have gained much interest, due to the versatility of such systems and their applications in materials science and medicine. In this article we demonstrate that coiled-coil peptide-induced aggregation based on electrostatic interactions is highly sensitive to the length of the peptide as well as the number of presented charges. The quaternary structure of the peptide was found to play an important role in aggregation kinetics. Furthermore, we show that the presence of peptide fibers leads to well-defined nanoparticle assembly on the surface of these macrostructures. PMID- 26124882 TI - Influence of length and flexibility of spacers on the binding affinity of divalent ligands. AB - We present a quantitative model for the binding of divalent ligand-receptor systems. We study the influence of length and flexibility of the spacers on the overall binding affinity and derive general rules for the optimal ligand design. To this end, we first compare different polymeric models and determine the probability to simultaneously bind to two neighboring receptor binding pockets. In a second step the binding affinity of divalent ligands in terms of the IC50 value is derived. We find that a divalent ligand has the potential to bind more efficiently than its monovalent counterpart only, if the monovalent dissociation constant is lower than a critical value. This critical monovalent dissociation constant depends on the ligand-spacer length and flexibility as well as on the size of the receptor. Regarding the optimal ligand-spacer length and flexibility, we find that the average spacer length should be equal or slightly smaller than the distance between the receptor binding pockets and that the end-to-end spacer length fluctuations should be in the same range as the size of a receptor binding pocket. PMID- 26124883 TI - Mechanical stability of bivalent transition metal complexes analyzed by single molecule force spectroscopy. AB - Multivalent biomolecular interactions allow for a balanced interplay of mechanical stability and malleability, and nature makes widely use of it. For instance, systems of similar thermal stability may have very different rupture forces. Thus it is of paramount interest to study and understand the mechanical properties of multivalent systems through well-characterized model systems. We analyzed the rupture behavior of three different bivalent pyridine coordination complexes with Cu(2+) in aqueous environment by single-molecule force spectroscopy. Those complexes share the same supramolecular interaction leading to similar thermal off-rates in the range of 0.09 and 0.36 s(-1), compared to 1.7 s(-1) for the monovalent complex. On the other hand, the backbones exhibit different flexibility, and we determined a broad range of rupture lengths between 0.3 and 1.1 nm, with higher most-probable rupture forces for the stiffer backbones. Interestingly, the medium-flexible connection has the highest rupture forces, whereas the ligands with highest and lowest rigidity seem to be prone to consecutive bond rupture. The presented approach allows separating bond and backbone effects in multivalent model systems. PMID- 26124884 TI - Peptide-polymer ligands for a tandem WW-domain, an adaptive multivalent protein protein interaction: lessons on the thermodynamic fitness of flexible ligands. AB - Three polymers, poly(N-(2-hydroxypropyl)methacrylamide) (pHPMA), hyperbranched polyglycerol (hPG), and dextran were investigated as carriers for multivalent ligands targeting the adaptive tandem WW-domain of formin-binding protein (FBP21). Polymer carriers were conjugated with 3-9 copies of the proline-rich decapeptide GPPPRGPPPR-NH2 (P1). Binding of the obtained peptide-polymer conjugates to the tandem WW-domain was investigated employing isothermal titration calorimetry (ITC) to determine the binding affinity, the enthalpic and entropic contributions to free binding energy, and the stoichiometry of binding for all peptide-polymer conjugates. Binding affinities of all multivalent ligands were in the uM range, strongly amplified compared to the monovalent ligand P1 with a K D > 1 mM. In addition, concise differences were observed, pHPMA and hPG carriers showed moderate affinity and bound 2.3-2.8 peptides per protein binding site resulting in the formation of aggregates. Dextran-based conjugates displayed affinities down to 1.2 uM, forming complexes with low stoichiometry, and no precipitation. Experimental results were compared with parameters obtained from molecular dynamics simulations in order to understand the observed differences between the three carrier materials. In summary, the more rigid and condensed peptide-polymer conjugates based on the dextran scaffold seem to be superior to induce multivalent binding and to increase affinity, while the more flexible and dendritic polymers, pHPMA and hPG are suitable to induce crosslinking upon binding. PMID- 26124885 TI - Multivalency as a chemical organization and action principle. PMID- 26124886 TI - Copper ion salts of arylthiotetrathiafulvalenes: synthesis, structure diversity and magnetic properties. AB - The combination of CuBr2 and arylthio-substituted tetrathiafulvalene derivatives (1-7) results in a series of charge-transfer (CT) complexes. Crystallographic studies indicate that the anions in the complexes, which are derived from CuBr2, show diverse configurations including linear [Cu(I)Br2](-), tetrahedral [Cu(II)Br4](2-), planar [Cu(II)2Br6](2-), and coexistence of planar [Cu(II)Br4](2 ) and tetrahedral [Cu(II)Br3](-) ions. On the other hand, the TTFs show either radical cation or dication states that depend on their redox potentials. The central TTF framework on most of TTFs is nearly planar despite the charge on them, whereas the two dithiole rings on molecule 4 in complex 4.CuBr4 are significantly twisted with a dihedral angle of 38.3 degrees . The magnetic properties of the complexes were elucidated. The temperature-dependent magnetic susceptibility of complex 5.Cu2Br6 shows the singlet-triplet transition with coupling constant J = -248 K, and that of 3.(CuBr4)0.5.CuBr3.THF shows the abrupt change at 270 K caused by the modulation of intermolecular interactions. The thermo variation of magnetic susceptibility for the other complexes follows the Curie-Weiss law, indicating the weak antiferromagnetic interaction at low temperature. PMID- 26124887 TI - Tuning of tetrathiafulvalene properties: versatile synthesis of N-arylated monopyrrolotetrathiafulvalenes via Ullmann-type coupling reactions. AB - An Ullmann-type coupling reaction was employed for the preparation of several N arylated monopyrrolotetrathiafulvalenes with variable substitution patterns. Spectroscopic and electrochemical properties of the coupling products strongly depend on the electronic nature of the aromatic substituents due to their direct conjugation with the tetrathiafulvalene chromophore. The crystal packing of the arylated monopyrrolotetrathiafulvalenes is primarily defined by networks of C H...X weak hydrogen bonds and short S...S contacts involving the tetrathiafulvalene moieties. PMID- 26124888 TI - N-Alkyl derivatives of diosgenyl 2-amino-2-deoxy-beta-D-glucopyranoside; synthesis and antimicrobial activity. AB - Diosgenyl 2-amino-2-deoxy-beta-D-glucopyranoside is a synthetic saponin exhibiting attractive pharmacological properties. Different pathways tested by us to obtain this glycoside are summarized here. Moreover, the synthesis of N-alkyl and N,N-dialkyl derivatives of the glucopyranoside is presented. Evaluation of antibacterial and antifungal activities of these derivatives indicates that they have no inhibitory activity against Gram-negative bacteria, whereas many of the tested N-alkyl saponins were found to inhibit the growth of Gram-positive bacteria and human pathogenic fungi. PMID- 26124889 TI - Thiazole formation through a modified Gewald reaction. AB - The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. 1,4 Dithiane-2,5-diol was used as the aldehyde precursor to give either 2-substituted thiazoles or 2-substituted aminothiophenes depending on the substitution of the alpha-carbon to the cyano group. PMID- 26124891 TI - Is organic chemistry science - and does this question make any sense at all? PMID- 26124890 TI - An intramolecular C-N cross-coupling of beta-enaminones: a simple and efficient way to precursors of some alkaloids of Galipea officinalis. AB - 2-Aroylmethylidene-1,2,3,4-tetrahydroquinolines with the appropriate substituents can be suitable precursors for the synthesis of alkaloids from Galipea officinalis (cuspareine, galipeine, galipinine, angustureine). However, only two, rather low-yielding procedures for their synthesis are described in the literature. We have developed a simple and efficient protocol for an intramolecular, palladium or copper-catalysed amination of both chloro- and bromo substituted 3-amino-1,5-diphenylpent-2-en-1-ones leading to the above-mentioned tetrahydroquinoline moiety. The methodology is superior to the methods published to date. PMID- 26124892 TI - Gold-catalyzed formation of pyrrolo- and indolo-oxazin-1-one derivatives: The key structure of some marine natural products. AB - Various N-propargylpyrrole and indolecarboxylic acids were efficiently converted into 3,4-dihydropyrrolo- and indolo-oxazin-1-one derivatives by a gold(III) catalyzed cyclization reaction. Some of the products underwent TFA-catalyzed double bond isomerization and some did not. Cyclization reactions in the presence of alcohol catalyzed by Au(I) resulted in the formation of hemiacetals after cascade reactions. PMID- 26124893 TI - DBU-promoted carboxylative cyclization of o-hydroxy- and o-acetamidoacetophenone. AB - The carboxylative cyclization of o-hydroxy- and o-acetamidoacetophenone with carbon dioxide promoted by the organic base 1,8-diazabicycloundec-7-ene (DBU) is reported. This reaction provides convenient access to the biologically important compounds 4-hydroxy-2H-chromen-2-one and 4-hydroxy-2(1H)-quinolinone in moderate to good yields using carbon dioxide as the carboxylation reagent. An acyl migration from nitrogen to carbon is observed in the reaction of o acetamidoacetophenone. PMID- 26124894 TI - Terminal lipophilization of a unique DNA dodecamer by various nucleolipid headgroups: Their incorporation into artificial lipid bilayers and hydrodynamic properties. AB - A series of six cyanine-5-labeled oligonucleotides (LONs 10-15), each terminally lipophilized with different nucleolipid head groups, were synthesized using the recently prepared phosphoramidites 4b-9b. The insertion of the LONs within an artificial lipid bilayer, composed of 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), was studied by single molecule fluorescence spectroscopy and microscopy with the help of an optically transparent microfluidic sample carrier with perfusion capabilities. The incorporation of the lipo-oligonucleotides into the bilayer was studied with respect to efficiency (maximal bilayer brightness) as well as stability against perfusion (final stable bilayer brightness). Attempts to correlate these parameters with the log P values of the corresponding nucleolipid head groups failed, a result which clearly demonstrates that not only the lipophilicity but mainly the chemical structure and topology of the head group is of decisive importance for the optimal interaction of a lipo oligonucleotide with an artificial lipid bilayer. Moreover, fluorescence half live and diffusion time values were measured to determine the diffusion coefficients of the lipo-oligonucleotides. PMID- 26124896 TI - Electrosynthesis and electrochemistry. PMID- 26124897 TI - Synthesis and characterization of the cyanobenzene-ethylenedithio-TTF donor. AB - A dissymmetric TTF-type electron donor, cyanobenzene-ethylenedithio tetrathiafulvalene (CNB-EDT-TTF), was obtained in high yield, by a cross-coupling reaction with triethyl phosphite between 2-thioxobenzo[d][1,3]dithiole-5 carbonitrile and 5,6-dihydro-[1,3]dithiolo[4,5-b][1,4]dithiin-2-one. This new donor was characterized namely by single crystal X-ray diffraction, cyclic voltammetry, NMR, UV-visible and IR spectroscopy. PMID- 26124895 TI - Interactions between tetrathiafulvalene units in dimeric structures - the influence of cyclic cores. AB - A selection of cyclic and acyclic acetylenic scaffolds bearing two tetrathiafulvalene (TTF) units was prepared by different metal-catalyzed coupling reactions. The bridge separating the two TTF units was systematically changed from linearly conjugated ethyne, butadiyne and tetraethynylethene (trans substituted) units to a cross-conjugated tetraethynylethene unit, placed in either acyclic or cyclic arrangements. The cyclic structures correspond to so called radiaannulenes having both endo- and exocyclic double bonds. Interactions between two redox-active TTF units in these molecules were investigated by cyclic voltammetry, UV-vis-NIR and EPR absorption spectroscopical methods of the electrochemically generated oxidized species. The electron-accepting properties of the acetylenic cores were also investigated electrochemically. PMID- 26124898 TI - Carboxylated dithiafulvenes and tetrathiafulvalene vinylogues: synthesis, electronic properties, and complexation with zinc ions. AB - A class of carboxyl and carboxylate ester-substituted dithiafulvene (DTF) derivatives and tetrathiafulvalene vinylogues (TTFVs) has been synthesized and their electronic and electrochemical redox properties were characterized by UV vis spectroscopic and cyclic voltammetric analyses. The carboxyl-TTFV was applied as a redox-active ligand to complex with Zn(II) ions, forming a stable Zn-TTFV coordination polymer. The structural, electrochemical, and thermal properties of the coordination polymer were investigated by infrared spectroscopy, cyclic voltammetry, powder X-ray diffraction, and differential scanning calorimetric analyses. Furthermore, the microscopic porosity and surface area of the Zn-TTFV coordination polymer were measured by nitrogen gas adsorption analysis, showing a BET surface of 148.2 m(2) g(-1) and an average pore diameter of 10.2 nm. PMID- 26124899 TI - Tuning the size of a redox-active tetrathiafulvalene-based self-assembled ring. AB - The synthesis of a new Pd coordination-driven self-assembled ring M6L3 constructed from a concave tetrapyridyl pi-extended tetrathiafulvalene ligand (exTTF) is described. The same ligand is also able to self-assemble in a M4L2 mode as previously described. Herein, we demonstrate that the bulkiness of the ancillary groups in the Pd complex allows for modulating the size and the shape of the resulting discrete self-assembly, which therefore incorporate two (M4L2) or three (M6L3) electroactive exTTF sidewalls. PMID- 26124900 TI - Antenatal Diagnosis of Jeune Syndrome (Asphyxiating Thoracic Dysplasia) with Micromelia and Facial Dysmorphism on Second-Trimester Ultrasound. AB - BACKGROUND: Jeune syndrome is a rare congenital malformation with a reported incidence of 1 in 100,000-130,000 live births. Thoracic hypoplasia is the most striking abnormality of this disorder. Here we report a case of Jeune syndrome with marked thoracic hypoplasia, micromelia and facial dysmorphism, which was diagnosed on a second-trimester antenatal real-time three-dimensional ultrasound. CASE REPORT: A 24-year-old primigravida came for routine anomaly scan at 19 weeks of gestation. Transabdominal grey scale and real time 3D ultrasound (US) was done with GE Logiq P5 with curvilinear array transducers (4C and 4D3C-L). US findings were consistent with the diagnosis of Jeune syndrome (Asphyxiating thoracic dysplasia). CONCLUSIONS: Jeune syndrome is an extremely rare congenital disorder with a spectrum of abnormalities of which thoracic hypoplasia is the most striking. It can be diagnosed on early antenatal US by its characteristic skeletal and morphological features which can guide further management of pregnancy in form of termination or preparation for surgical correction of the deformity. PMID- 26124901 TI - MRI of Residual Red Bone Marrow in the Distal Femur of Healthy Subjects. AB - BACKROUND: The purpose of our study is to examine the correlation of the residual red bone marrow areas of distal femoral metaphysis with the age, gender, weight and hemoglobin (hgb) values; evaluate the results, and comprehend the importance of these residual areas in the light of the results. MATERIAL/METHODS: 140 nonsmoking patients between the ages of 26 and 72 (92 women, 48 men) who had knee MR examinations were included in the study. The residual red bone marrow areas in the distal femoral metaphysis in MR images were examined by a radiologist. The areas were separated into grades according to their sizes. The hemoglobin values of the cases were measured. The size of the residual red bone marrow area and the age, gender, weight and hemoglobin values of the cases were compared by using the Tukey and Chi-Square Tests. RESULTS: Although no significant differences were observed between the mean ages, weights and hemoglobin values of the grades, a significant difference was detected between the gender distribution The male group had less residual red bone marrow in the distal femoral metaphysis than the female group (p=0.003). CONCLUSIONS: We observed that the hypointensities due to residual red bone marrow observed in the T1WS of the distal femoral metaphysis are not related with the age, weight and hemoglobin values. No grade 2 and grade 3 patient was detected in male group. We observed that these hypointense areas showed difference according to the gender variable; however, were not affected by the hemoglobin values over certain levels. PMID- 26124902 TI - Thyrolipomas - Prevalence in Computed Tomography and Suggestions for Pragmatic Management. AB - BACKGROUND: Thyrolipomas seem to be a rare occurrence and until now their prevalence has only been reported in two studies. Because of the known significant geographic variations of thyroid disease, generalizability of these findings is uncertain as well as the management of found thyrolipomas. MATERIAL/METHODS: Retrospective study of 107 computed tomography scans of the chest of a European inpatient population. A literature review was performed and considerations for pragmatic management were proposed. RESULTS: Thyrolipomas were found in 2.8% of patients. All thyrolipomas were smaller than 15 mm. In all patients these were incidental findings unrelated to patients symptoms. No secondary signs of malignancy could be detected. CONCLUSIONS: Thyrolipomas are a common finding on cross sectional imaging. Like in this study they seem to be incidental findings lacking clinical relevance. Because of the rare possibility of an thyroid cancer with inclusion of mature fat, sonographic follow-up of incidentally discovered thyrolipomas larger than 15 mm should be suggested. PMID- 26124903 TI - Impact of Physical Activity on the Self-Perceived Quality of Life in Non-Frail Older Adults. AB - As the population of older adults increases, healthy aging has become a global public health issue. Physical activity can help older adults reclaim or maintain a healthy aging process. The purpose of this paper is to investigate the relationship between physical activity, physical performance, quality of life and cognition in non-frail adults aged 65 and older. English articles in peer reviewed journals about healthy, non-frail adults aged 65 and older were included in the present review. Additionally, articles were obtained from reviewing the reference lists of the aforementioned articles. Research proves an overwhelmingly positive correlation between physical activity and the reduction of preventable chronic illnesses, lower healthcare costs, improved cognition, improved muscle function, decreased fear of falling, and thereby, inevitably, an increased self perceived quality of life. There is research evidence on healthy aging and the effect of physical activity, which could be of importance in a public health perspective. PMID- 26124904 TI - Laparoscopic Versus Open Colorectal Resection Within Fast Track Programs: An Update Meta-Analysis Based on Randomized Controlled Trials. AB - The objective of the study was to assess the safety and efficacy of laparoscopic colorectal surgery by comparing open operation within fast track (FT) programs. The Cochrane Library, PubMed, Embase and Chinese Biological Medicine Database were searched to identify all available randomized controlled trials (RCTs) comparing laparoscopic with open colorectal resection within FT programs. A total of seven RCTs were finally included, enrolling 714 patients with colorectal cancer: 373 patients underwent laparoscopic surgery and FT programs (laparoscopic/FT group) and 341 patients received open operation and FT programs (open/FT group). Postoperative hospital stay (weighted mean difference (WMD): 0.66; 95% CI: 0.27 - 1.04; P < 0.05), total hospital stay (WMD: 1.46; 95% CI: 0.40 - 2.51; P < 0.05) and overall complications (RR: 1.31; 95% CI: 1.12 - 1.54; P < 0.05) were significantly lower in laparoscopic/FT group than in open/FT group. However, no statistically significant differences on mortality (risk ratio (RR): 2.26; 95% CI: 0.62 - 8.22; P = 0.21), overall surgical complications (RR: 1.19; 95% CI: 0.94 - 1.51; P = 0.15) and readmission rates (RR: 1.33; 95% CI: 0.79 - 2.22; P = 0.28) were found between both groups. The laparoscopic colorectal surgery combined with FT programs shows high-level evidence on shortening postoperative and total hospital stay, reducing overall complications without compromising patients' safety. PMID- 26124905 TI - Knee and Ankle Joint Angles Influence the Plantarflexion Torque of the Gastrocnemius. AB - BACKGROUND: The gastrocnemius (GA) is the lone bi-articular muscle of the leg, crossing both the knee and ankle. As with any bi-articular muscle, both joints affect its length/tension curve. The role of the GA as a plantarflexor is firmly established; however, no current research has investigated how changes in knee and ankle joint positions on its ability to generate a plantarflexion (PF) torque. This paper reports on the PF force generated by the GA at specific knee and ankle joint combinations. METHODS: The right GA of 26 participants was electrically stimulated via surface electrodes following a standardized protocol at 24 knee and ankle joint combinations. Three stimulations were applied at each of the 24 positions. Data were recorded on three dependent measures: the passive moment, which was the PF moment created by the tissue without stimulation, the maximum moment, which was the highest PF moment during the stimulation and included the passive moment, and the stimulated moment, which reflected the PF moment during stimulation minus the passive moment. RESULTS: A straight knee and dorsiflexed ankle create the position in which the GA generates the greatest PF moment, but it is also the position of greatest length. This finding is in contrast to conclusions from previous research with bi-articular muscles, which has consistently shown that the greatest length is not a muscle's optimal length. The full ranges of motion for the knee and ankle apparently do not elongate the GA beyond its optimal length for producing a PF moment. Clinicians commonly evaluate GA status with the patient seated and the foot subject to gravity. CONCLUSIONS: The present results indicate that manual testing of the GA in isolation should be performed, whenever possible, with the knee extended and the ankle dorsiflexed to potentially elicit the maximum PF torque from the GA. PMID- 26124906 TI - Factors Predicting Therapeutic Efficacy of Combination Treatment With Sitagliptin and Insulin in Type 2 Diabetic Patients: The ASSIST-K Study. AB - BACKGROUND: It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A1c (HbA1c) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. METHODS: A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA1c. RESULTS: Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA1c, older age, and lower body mass index influenced the change of HbA1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. CONCLUSIONS: These results emphasize the importance of a higher HbA1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications. PMID- 26124907 TI - Effect of Atorvastatin and Pioglitazone on Plasma Levels of Adhesion Molecules in Non-Diabetic Patients With Hypertension or Stable Angina or Both. AB - BACKGROUND: It was to study the effect of atorvastatin, pioglitazone and their combination on plasma levels of adhesion molecules in patients with hypertension or stable angina or both. METHODS: It was an open-label, randomized parallel group study. Forty-five atorvastatin-naive patients with hypertension or stable angina or both, were randomized to receive either atorvastatin (19 patients; 10 mg OD for 12 weeks) or pioglitazone (26 patients; 30 mg OD for 12 weeks). Another group of 30 patients who were already on atorvastatin were put on add-on pioglitazone therapy (pioglitazone (15 mg OD) + atorvastatin (10 mg OD) for 12 weeks). Plasma high-sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were measured at baseline and after 12 weeks of therapy. RESULTS: Atorvastatin monotherapy significantly reduced plasma sICAM-1, but pioglitazone monotherapy did not produce any significant effect. Addition of pioglitazone in patients already receiving atorvastatin also significantly reduced plasma sICAM-1 level. However, there was no significant change in plasma hsCRP and sVCAM-1 levels in any of the groups after 12 weeks of therapy. CONCLUSION: There is therapeutic advantage of combining pioglitazone and atorvastatin on plasma sICAM-1 levels. PMID- 26124908 TI - Predictive Factors for Non-Sentinel Lymph Node Metastasis in the Case of Positive Sentinel Lymph Node Metastasis in Two or Fewer Nodes in Breast Cancer. AB - BACKGROUND: In breast cancer, recent clinical trials have shown that sentinel lymph node biopsy (SLNB) alone without axillary lymph node dissection results in excellent prognosis if there is sentinel lymph node (SLN) metastasis in two or fewer nodes. The aim of the present study was to investigate the association between non-SLN metastasis and clinicopathological factors in case of SLN metastasis in two or fewer nodes in breast cancer. METHODS: Patients who underwent SLNB for invasive breast cancer and were found to have positive SLN in two or fewer nodes were evaluated. The associations between non-SLN metastasis and clinicopahological factors were examined. Statistical analyses were performed using the Mann-Whitney and Chi-square tests, with statistical significance set at P < 0.05. RESULTS: A total of 358 patients were enrolled during the study period and all of these patients were female and 54 patients had SLN metastasis (15%). Positive SLN in two or fewer nodes was identified in 44 patients (81.5%). Among these patients, 17 (38.6%) were found to have non-SLN metastasis. Non-SLN metastasis was associated with invasive tumor size (P = 0.015) and lymphatic involvement (P = 0.035). Multivariate analysis showed that tumor size (P = 0.011) and lymphatic involvement (P = 0.019) remained significant independent predictors of non-SLN metastasis, and that an invasive tumor size cut-off point of 28 mm was useful for dividing patients with positive SLN in two or fewer nodes into non-SLN positive and non-SLN-negative groups. CONCLUSIONS: Non-SLN metastasis was found in more than 30% of patients with SLN metastasis present in two or fewer nodes. Large tumor size and the presence of lymphatic involvement were significantly associated with non-SLN metastasis. PMID- 26124909 TI - Prevalence of Acute Coronary Syndrome in Patients Suspected for Pulmonary Embolism or Acute Aortic Syndrome: Rationale for the Triple Rule-Out Concept. AB - BACKGROUND: The aims of the study were to evaluate the prevalence of acute coronary syndrome (ACS) among patients presenting with atypical chest pain who are evaluated for acute aortic syndrome (AAS) or pulmonary embolism (PE) with computed tomoangiography (CTA) and discuss the rationale for the use of triple rule-out (TRO) protocol for triaging these patients. METHODS: This study is a retrospective analysis of patients presenting with atypical chest pain and evaluated with thoracic (CTA), for suspicion of AAS/PE. Two physicians reviewed patient files for demographic characteristics, initial CT and final clinical diagnosis. Patients were classified according to CTA finding into AAS, PE and other diagnoses and according to final clinical diagnosis into AAS, PE, ACS and other diagnoses. RESULTS: Four hundred and sixty-seven patients were evaluated: 396 (84.8%) patients for clinical suspicion of PE and 71 (15.2%) patients for suspicion of AAS. The prevalence of ACS and AAS was low among the PE patients: 5.5% and 0.5% respectively (P = 0.0001), while the prevalence of ACS and PE was 18.3% and 5.6% among AAS patients (P = 0.14 and P = 0.34 respectively). CONCLUSION: The prevalence of ACS and AAS among patients suspected clinically of having PE is limited while the prevalence of ACS and PE among patients suspected clinically of having AAS is significant. Accordingly patients suspected for PE could be evaluated with dedicated PE CTA while those suspected for AAS should still be triaged using TRO protocol. PMID- 26124910 TI - Voice and Functional Outcomes of Transoral Laser Microsurgery for Early Glottic Cancer: Ventricular Fold Resection as a Surrogate. AB - BACKGROUND: The aim of the study was to evaluate the oncological and functional outcomes with transoral laser microsurgery (TOLM) of patients with early glottic cancer. METHODS: We have prospectively evaluated patients treated with TOLM for Tis, T1 or T2 glottic squamous cell carcinoma. Evaluation of oncological outcomes, and voice and functional outcomes was assessed using voice-handicap index 10 (VHI-10) and performance status scale for head & neck cancer patients (PSS-H&N). Predictors of poor voice quality were evaluated using Student's t test. RESULTS: Thirty patients were included, with 17.7 months mean follow-up. There were no cases of locoregional recurrence. Twelve patients (40%) were considered as having a problematic voice outcome. Four subjects out of 30 (13.3%) had significant problems with understandability of speech. Significant differences (P < 0.05) in VHI-10 score were found with tumor stage and partial resection of the ventricular fold. CONCLUSIONS: We report excellent oncological and functional outcomes in early glottic cancer treated with TOLM, with advanced tumors and partial resection of the ventricular fold as a surrogate predicting worse voice outcomes. PMID- 26124912 TI - Reasons Why Some Japanese Pregnant Women Choose Trial of Labor After Cesarean. AB - BACKGROUND: We examined whether or not the Japanese pregnant women with a history of a cesarean section have the knowledge about the benefits and harms of trial of labor after cesarean (TOLAC) and elective repeat cesarean delivery (ERCD). METHODS: We reviewed the obstetric records of 121 Japanese women with a prior cesarean section who visited our hospital for reservation of their second delivery between January and December 2013. RESULTS: Forty-five (37%) of them wanted to perform TOLAC at the first interview. Of these, 14 women (31%) with a history of an urgent cesarean chose TOLAC because of the insufficient anesthetic effect during cesarean, while 11 women (24%) with a history of an elective cesarean did not have the knowledge of the risks of TOLAC and urgent cesarean. Nineteen of those (76%) selected ERCD following the counseling. CONCLUSIONS: Some Japanese pregnant women with TOLAC hope seemed to have insufficient knowledge about the benefits and harms of TOLAC and ERCD. Therefore, the improvement of the process of counseling and decision making may be needed for pregnant women with a history of a cesarean section in Japan. PMID- 26124911 TI - Leptospira Exposure and Waste Pickers: A Case-Control Seroprevalence Study in Durango, Mexico. AB - BACKGROUND: Infection with Leptospira may occur by contact with Leptospira infected animals. Waste pickers are in contact with rodents and dogs while picking in the garbage. Whether waste pickers are at risk for Leptospira infection is largely unknown. This study was aimed to determine the association of Leptospira IgG seroprevalence with the occupation of waste picking, and to determine the epidemiological characteristics of the waste pickers with Leptospira exposure. METHODS: Through a case-control study, we determined the seroprevalence of anti-Leptospira IgG antibodies in 90 waste pickers and 90 age- and gender-matched control subjects in Durango City, Mexico using an enzyme immunoassay. Data were analyzed by bivariate and multivariate analyses. RESULTS: The prevalence of anti-Leptospira IgG antibodies was similar in waste pickers (4/90: 4.4%) to that in control subjects (5/90: 5.6%) (P = 1.00). Bivariate analysis showed that Leptospira exposure in waste pickers was associated with increasing age (P = 0.009), no education (P = 0.008), and consumption of rat meat (P = 0.04). However, these associations were no longer found by multivariate analysis. Leptospira exposure in waste pickers was not associated with health status, duration in the activity, wearing hand gloves and facemasks, history of injuries with sharp material of the garbage, or contact with animals or soil. CONCLUSIONS: This is the first study about Leptospira exposure in waste pickers. Results suggest that waste pickers are not at increasing risk for Leptospira exposure in Durango City, Mexico. Further research with a larger sample size to elucidate the association of Leptospira exposure with waste picking activity is needed. PMID- 26124913 TI - A New Early Finding of Moyamoya-Like Phenomena. AB - Moyamoya disease (MMD) primarily causes constriction of internal carotid artery, but it is known to extend to the middle and anterior cerebral arteries. Some of the symptoms caused by MMD include transient ischemic attack (TIA) and seizures. The etiology of MMD from Graves' disease (GD) is mostly caused by thyrotoxicosis, but our finding of leukocytosis indicates a new finding that may help physicians prepare for the pending outcome of MMD from GD with leukocytosis. A 26-year-old Hispanic woman with a significant past medical history of GD and hypertension presented to the emergency department complaining of cough and shortness of breath for the past 5 days. During the patient's stay in the hospital, the patient suddenly developed numbness of the right arm with subsequent right arm weakness 10 minutes later. The head CT showed no acute intercranial hemorrhage, but MRA showed right intracranial internal carotid artery stenosis, with marked focal stenosis along the proximal supraclinoid segment, moderate stenosis along its distal supraclinoid segment with marked stenosis along the origin of the right A1 segment. It was therefore believed to be moyamoya-like phenomena. We discuss an atypical presentation that led to moyamoya-like phenomena which we believe has not been described before. We believe that presentation of idiopathic leukocytosis may have triggered the cerebral stenosis. PMID- 26124914 TI - Tracheobronchial Tuberculosis Without Lung Involvement. AB - Endotracheal tuberculosis (ETTB) is an infrequent form of tuberculosis whose major feature is the infection of the tracheobronchial tree by Mycobacterium tuberculosis. This case presents a 73-year-old man admitted to our hospital with fatigue, weakness, dry cough and weight loss. His chest X-ray was normal but the high resolution computed tomography (HRCT) showed normal parenchyma images with mediastinal and hilar lymphadenopathy. There was inflammation of the tracheal wall and infiltrates in pavement epithelium; however, the tracheal biopsy for acid-fast bacilli was negative. He was finally diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of the lymph nodes. Four drugs were prescribed and symptoms improved. EBUS-TBNA contributed to prompt diagnosis. The patient was treated and evolved without complications, such as tracheal stenosis. PMID- 26124915 TI - Persistent Coughing as the First Symptom of Primary Mucinous Appendiceal Adenocarcinoma. AB - Primary appendiceal adenocarcinomas are extremely rare entities. Preoperative diagnosis is very difficult and is mainly based on computed tomography (CT) scan findings. Furthermore, in many cases, difficulties in establishing an accurate intraoperative diagnosis have resulted in a two-stage surgical intervention. We herein report a case of a primary appendiceal mucinous adenocarcinoma in a 67 year-old Caucasian man who presented with atypical symptoms of persistent coughing and weight loss. The chest CT showed lesions with features favorable of malignancy. Further investigation with abdominal CT and colonoscopy revealed a large tumor of the cecum expanding to the ascending colon. Typical right hemicolectomy was performed and the histopathological examination confirmed mucinous adenocarcinoma of the appendix. As some cases are accidentally discovered, the presented case describes an extremely rare first presentation of this tumor and emphasizes that the preoperative diagnosis of appendiceal cancer is challenging due to the lack of specific symptoms and signs. PMID- 26124916 TI - Immunoglobulin D Multiple Myeloma With Rapidly Progressing Renal Failure. AB - Immunoglobulin D (IgD) multiple myeloma (MM) is a very rare form of myeloma affecting less than 2% of all myeloma patients. It has a multiorgan involvement with renal failure being the key feature. We present here a case of IgD MM in a 62-year-old white male, smoker with past medical history of hypertension, who presented to emergency department with complaints of lower abdominal pain, constipation and decreased urination. Physical exam was unremarkable. Laboratory investigation showed S.Cr 5.99 mg/dL, hemoglobin 8.7 g/dL and corrected S.Ca 10.6 mg/dL. Urine dipstick showed 100 protein and TP/Cr ratio was 23. Serology was positive for serum free lambda chain level of 8,947.6 mg/L as well with free kappa/lambda ratio < 0.01. The results of serum and urine electrophoresis and immunofixation were also supportive of diagnosis of IgD MM. IgD level was remarkably elevated (27,300 mg/L) too. CT scan of abdomen/pelvis was negative for obstructive uropathy. Skeletal survey showed a solitary lytic lesion in the iliac crest. His kidney function deteriorated next day requiring hemodialysis. The bone marrow biopsy was positive for plasma cell hypercellularity (70-80%) and flow cytometry showed 8% monoclonal IgD lambda plasma cells. The patient was started on bortezomib and dexamethasone and he underwent bone marrow transplant 6 months later. He is doing well hematologically now but he remains dialysis-dependent. IgD MM is a very rare disease affecting younger population with poor prognosis; patients often end up on hemodialysis despite better control of the hematological component. PMID- 26124917 TI - Favorable Outcome and Survival Using a Hypothermia Protocol After Successful Cardiopulmonary Resuscitation. PMID- 26124918 TI - Wee1 and Chk1 - crosstalk between key players in replicative stress. PMID- 26124920 TI - Chronic inflammation: is it the driver or is it paving the road for malignant transformation? AB - Chronic inflammation in well-defined mouse models such as Gialpha2 knock out mouse has been shown to trigger formation and expansion of hypoxic niches and also leads to up regulation of NFKB, offering cells which have adapted their genetic machinery to hypoxia a unique survival advantage. These adapted cells have been shown to acquire stem cell-like capabilities as shown by up regulation of stem cell markers. Such long lived cells become permanent residents in sub mucosa and acquire a malignant phenotype from long-term exposure to noxious environmental agents due to a barrier defect secondary to down regulation of barrier proteins such as Zo1 and Occludin. Indeed mitotic spindle disorientation in such mice has been proposed as another contributory factor to malignant transformation. Sterilization of bowel lumen of these mice through different techniques has prevented malignant transformation in the presence of chronic inflammation. These facts stand strongly against chronic inflammation as a true driver of carcinogenesis but clearly support its role in facilitating the emergence of the neoplastic clone. PMID- 26124921 TI - CArG-driven GADD45alpha activated by resveratrol inhibits lung cancer cells. AB - We report anticarcinogenic effects of suicide gene therapy that relies on the use of resveratrol-responsive CArG elements from the Egr-1 promoter to induce GADD45alpha. In A549 lung cancer cells, endogenous GADD45alpha was not induced upon resveratrol treatment. Therefore, induction of exogenous GADD45alpha resulted in growth inhibition. Resveratrol transiently induced Egr-1 through ERK/JNK-ElK-1. Hence, we cloned natural or synthetic Egr-1 promoter upstream of GADD45alpha cDNA to create a suicide gene therapy vector. Since natural promoter may have antagonized effects, we tested synthetic promoter that contains either five, six or nine repeats of CArG elements essential in the Egr-1 promoter to drive the expression of GADD45alpha upon resveratrol treatment. Further analysis confirmed that both synthetic promoter and natural Egr-1 promoter were able to "turn on" the expression of GADD45alpha when combined with resveratrol, and subsequently led to suppression of cell proliferation and apoptosis. PMID- 26124922 TI - RASSF10 suppresses hepatocellular carcinoma growth by activating P53 signaling and methylation of RASSF10 is a docetaxel resistant marker. AB - Hepatocellular carcinoma (HCC) is one of the most common malignances and the second leading cause of cancer related death worldwide. RASSF10 is located on chromosome 11p15.2, a region that shows frequent loss of heterozygosity (LOH) in several cancer types. Our previous study found that RASSF10 suppresses colorectal cancer growth by activating P53 signaling. To explore the epigenetic changes and the mechanism of RASSF10 in human HCC, 69 cases of primary HCC, twenty cases of normal liver tissue samples and 17 HCC cell lines were involved in this study. We found that RASSF10 was methylated in 82.6% (57/69) of human primary HCC and methylation of RASSF10 was significantly associated with tumor size (P < 0.05) and TNM stage (P < 0.05). The expression of RASSF10 was regulated by promoter region methylation. Restoration of RASSF10 expression suppressed cell proliferation, induced apoptosis and G2/M phase arrest, as well as sensitized cells to docetaxel and activated P53 signaling in HepG2 and QGY7703 cells. In conclusion, we demonstrated that RASSF10 is frequently methylated in human HCC and its methylation is a potential docetaxel resistant marker. Our data also indicate that RASSF10 suppresses human HCC growth by activating P53 signaling. PMID- 26124919 TI - Histone acetyltransferases and histone deacetylases in B- and T-cell development, physiology and malignancy. AB - The development of B and T cells from hematopoietic precursors and the regulation of the functions of these immune cells are complex processes that involve highly regulated signaling pathways and transcriptional control. The signaling pathways and gene expression patterns that give rise to these developmental processes are coordinated, in part, by two opposing classes of broad-based enzymatic regulators: histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs and HDACs can modulate gene transcription by altering histone acetylation to modify chromatin structure, and by regulating the activity of non-histone substrates, including an array of immune-cell transcription factors. In addition to their role in normal B and T cells, dysregulation of HAT and HDAC activity is associated with a variety of B- and T-cell malignancies. In this review, we describe the roles of HATs and HDACs in normal B- and T-cell physiology, describe mutations and dysregulation of HATs and HDACs that are implicated lymphoma and leukemia, and discuss HAT and HDAC inhibitors that have been explored as treatment options for leukemias and lymphomas. PMID- 26124923 TI - Screening of suppressors of bax-induced cell death identifies glycerophosphate oxidase-1 as a mediator of debcl-induced apoptosis in Drosophila. AB - Members of the Bcl-2 family are key elements of the apoptotic machinery. In mammals, this multigenic family contains about twenty members, which either promote or inhibit apoptosis. We have previously shown that the mammalian pro apoptotic Bcl-2 family member Bax is very efficient in inducing apoptosis in Drosophila, allowing the study of bax-induced cell death in a genetic animal model. We report here the results of the screening of a P[UAS]-element insertion library performed to identify gene products that modify the phenotypes induced by the expression of bax in Drosophila melanogaster. We isolated 17 putative modifiers involved in various function or process: the ubiquitin/proteasome pathway; cell growth, proliferation and death; pathfinding and cell adhesion; secretion and extracellular signaling; metabolism and oxidative stress. Most of these suppressors also inhibit debcl-induced phenotypes, suggesting that the activities of both proteins can be modulated in part by common signaling or metabolic pathways. Among these suppressors, Glycerophosphate oxidase-1 is found to participate in debcl-induced apoptosis by increasing mitochondrial reactive oxygen species accumulation. PMID- 26124924 TI - PSCA s2294008 C>T and rs2976392 G>A polymorphisms contribute to cancer susceptibility: evidence from published studies. AB - PSCA gene plays an important role in cell adhesion, proliferation and survival. Increasing studies have focused on the association of PSCA gene rs2294008 C>T and rs2976392 G>A with cancer risk. However, the conclusions were inconsistent. Therefore, we performed a meta-analysis to elucidate whether there is a true association, or artifact. We systematically searched eligible studies from MEDLINE, EMBASE and CBM database. Odds ratios and 95% confidence intervals were used to evaluate the strength of the association. The final analysis included 32 studies consisting of 30028 cases and 38765 controls for the rs2294008 C>T polymorphism, and 14 studies with 8190 cases and 7176 controls for the rs2976392 G>A polymorphism. Consequently, the PSCA rs2294008 C>T polymorphism was significantly associated with increased overall cancer risk. Further stratifications indicated the increased risk was more pronounced for gastric (diffused type and non-gastric cardia adenocarcinoma) and bladder cancer. A similar association was observed for the rs2976392 G>A polymorphism. This meta analysis demonstrated that both of the PSCA rs2294008 C>T and rs2976392 G>A polymorphisms are associated with increased cancer risk, especially for gastric cancer and bladder cancer. Further large-scale studies with different ethnicities and subtypes of gastric cancer are required to confirm the results from this meta analysis. PMID- 26124925 TI - 3,3'-Diindolylmethane (DIM) and its ring-substituted halogenated analogs (ring DIMs) induce differential mechanisms of survival and death in androgen-dependent and -independent prostate cancer cells. AB - We recently reported that novel ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells. In this paper, we have focused on the mechanism(s) associated with ring-DIM-mediated cell death, and on identifying the specific intracellular target(s) of these compounds. The 4,4'- and 7,7'-dichloroDIMs and 4,4'- and 7,7'-dibromoDIMs induced the death of LNCaP, C42B and DU145 prostate cancer cells, but not that of immortalized normal human prostate epithelial (RWPE 1) cells. Ring-DIMs caused the early loss of mitochondrial membrane potential (MMP) and decreased mitochondrial ATP generation in prostate cancer cells. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore, inhibited ring-DIM-mediated cell death, and salubrinal, an inhibitor of ER stress, inhibited cell death mediated only by 4,4'-dihaloDIMs. We found that although salubrinal did not inhibit the onset of ER stress, it prevented 4,4' dibromoDIM mediated loss of MMP. Salubrinal potentiated cell death in response to 7,7'-dihaloDIMs and DIM, and this effect concurred with increased loss of MMP. Using in silico 3-D docking affinity analysis, we identified Ca2+/calmodulin dependent kinase II (CaMKII) as a potential direct target for the most toxic ring DIM, 4,4'-dibromoDIM. An inhibitor of CaMKII, KN93, but not its inactive analog KN92, abrogated cell death mediated by 4,4'-dibromoDIM. The ring-DIMs induced ER stress and autophagy, but these processes were not necessary for ring-DIM mediated cell death. Inhibition of autophagy with bafilomycin A1, 3-methyladenine or by LC3B gene silencing sensitized LNCaP and C42B, but not ATG5-deficient DU145 cells to ring-DIM- and DIM-mediated cell death. We propose that autophagy induced by the ring-DIMs and DIM has a cytoprotective function in prostate cancer cells. PMID- 26124926 TI - Circulating microRNAs - a new horizon in molecular diagnosis of breast cancer. AB - BACKGROUND: The potential use of microRNAs (miRNAs) as ideal tumor markers has been the focus of recent research. OBJECTIVE: Our hypothesis was that circulating miRNAs are differentially expressed in pretherapeutic sera of breast cancer patients compared to controls. MATERIALS AND METHODS: Using real-time quantitative polymerase chain reaction (qPCR) analysis, levels of 5 candidate miRNAs (miR10b, miR34a, miR155, miR195 and miR16) were quantified in sera of breast cancer patients and control individuals. RESULTS: Levels of preoperative sera showed significant upregulation of 3.36 fold rise in miR10b (p<0.001), a 2.07 fold rise in miR155 (p =0.005) and remarkable over expression of 11.9 fold rise in miR195 (p<0.001) of cases than controls. There was significant down regulation of miR34a (0.032, p<0.001). The comparison with the clinicopathological data of the breast cancer patients revealed significant high serum level of miR155 (p =0.004) and miR195 (p =0.002) in patients with lymph node metastasis and higher levels of miR10b (p =0.001) and miR155 (p <0.001) with distant metastasis (M1) than without metastasis (M0), in addition to significant decrease in miR34a (p <0.001) level in M1 than M0 cases. CONCLUSIONS: These findings suggest that systemic circulating miRNAs have potential use as novel biomarkers for breast cancer. PMID- 26124927 TI - Systematic enrichment analysis of microRNA expression profiling studies in endometriosis. AB - OBJECTIVES: The purpose of this study was to conduct a meta-analysis on human microRNAs (miRNAs) expression data of endometriosis tissue profiles versus those of normal controls and to identify novel putative diagnostic markers. MATERIALS AND METHODS: PubMed, Embase, Web of Science, Ovid Medline were used to search for endometriosis miRNA expression profiling studies of endometriosis. The miRNAs expression data were extracted, and study quality of each article was assessed. The frequently reported miRNAs with consistent regulation were screened out by a meta-profiling algorithm. The putative targets of consistently expressed miRNAs were predicted by using four target prediction tools (TargetScan, PicTar, miRanda, miRDB), and gene ontology pathway enrichment analysis (KEGG and Panther pathways) of the miRNA targets were carried out with GeneCodis web tool. RESULTS: A total of 194 related literatures were retrieved in four databases. One hundred and thirty four differentially expressed miRNAs were found in the 12 microRNA expression profiling studies that compared endometriosis tissues with normal tissues, with 28 miRNAs reported in at least two studies, and 9882 candidate genes retrieved for 13 consistently expressed miRNAs. Kyoto encyclopedia of genes and genomes (KEGG) and Panther pathways enrichment analysis showed that endometriosis related differently expressed miRNA targets were mainly enriched in cancer, endocytosis, Wnt signalling pathway, and angiogenesis. It showed that these differently expressed miRNAs and gene are potential biomarkers of endometriosis. CONCLUSION: miRNAs appear to be potent regulators of gene expression in endometriosis and its associated reproductive disorders, raising the prospect of using miRNAs as biomarkers and therapeutic agent in endometriosis. PMID- 26124929 TI - Effect of blockade of neuropeptide Y receptor on aortic intima-media thickness and adipose tissue characteristics in normal and obese mice. AB - OBJECTIVES: Atherosclerosis is an important risk factor for coronary heart disease. Neuropeptide Y (NPY) and its receptors, located in peripheral tissue such as white adipose tissue, have been linked to obesity and fat storage. The role of NPY in atherosclerosis has not yet been fully studied, so this study was conducted to further investigate the effect of BIIE 0246, an NPY receptor antagonist, on aortic intima-media thickness and size and number of adipocyte cells in normal and obese mice. MATERIALS AND METHODS: Tests were performed on 24 male C57BL/6 mice. The animals were divided into four groups as follows: control (normal), obese (high-fat diet), normal+NPY receptor antagonist (1 MUM, 100 ul/Kg BIIE0246 intraperitoneally) and obese+NPY receptor antagonist (n=6 each). After 14 days, the animals were sacrificed and epididymal adipose tissue and thoracic aorta were removed. Evaluations were made for adipocyte cell number and size and for aortic intima-media thickness. RESULTS: The group on a high-fat diet showed a significantly decreased number of adipocyte cells and increased cell size (P<0.05). BIIE0246 application changed the cell number of adipocyte in normal mice (P=0.05); however, it did not change adipocyte cell size and aortic intima media thickness in obese and normal mice (P>0.05). CONCLUSION: NPY receptor antagonist had no effect on adipocyte cell size and aortic intima-media thickness; however, it decreased cell number in the normal group indicating likely involvement in the progression of obesity. PMID- 26124928 TI - Adiponectin: an adipokine with protective features against metabolic syndrome. AB - Metabolic syndrome (MetS) as a collection of obesity-associated disorders is associated with inflammation, oxidative stress, pro-thrombotic state, elevated risk of developing cardiovascular disease and type 2 diabetes. Adiponectin is one of the most abundant peptide hormones derived from adipose tissue. This protein plays a major role in glucose and lipid metabolism and prevents development of vascular changes. Anti-oxidative and anti-inflammatory effects are the other features of adiponectin. Hypoadiponectinemia is associated with hypertension and pro-thrombotic state. In this review, we discuss the crucial role of adiponectin in prevention of metabolic syndrome considering its effects on the components of this syndrome. Pharmacological interventions and lifestyle modification may increase plasma adiponectin level or tissue sensitivity which seems to be a promising target for prevention and therapeutic approaches of MetS and related diseases. PMID- 26124930 TI - Effect of Crocus sativus extracts and its active constituent safranal on the harmaline-induced tremor in mice. AB - OBJECTIVES: Due to unsatisfactory response or intolerable side effects of current drugs, treatment of essential tremor remains inadequate. Thus, we aimed to investigate the protective and therapeutic effects of aqueous and ethanolic extracts of Crocus sativus (saffron), and its active consistent, safranal, on the harmaline-induced tremor in mice. MATERIALS AND METHODS: To induce tremor, harmaline (30 mg/kg) was injected intraperitoneally. Test groups were also given the aqueous and ethanolic extracts of saffron (40, 80, and 160 mg/kg) as well as safranal (0.1, 0.3, and 0.5 ml/kg), intraperitoneally, 10 min before harmaline administration (prophylactic study) or 10 min after the onset of tremors (curative study). The latency of onset, duration, and intensity of tremor were recorded. RESULTS: The extracts (80 and160 mg/kg) dose dependently attenuated duration of harmaline-induced tremors as did reference drug, propranolol (2 and 5 mg/kg). Only the highest dose of extracts (160 mg/kg) attenuated intensity of harmaline-induced tremors throughout the study. Safranal at the doses of (0.1 and 0.3 ml/kg) but not 0.5 ml/kg attenuated duration and intensity of tremor. Onset of tremor increased with the extracts (80 and 160 mg/kg) in prophylactic study, as the effect observed with propranolol at the dose of 5 mg/kg. Safranal did not affect the latency of tremor. CONCLUSION: Both aqueous and ethanolic extracts of saffron and with a less effect, low doses of safranal, have relatively protective and suppressive effects on the harmaline-induced tremor and different constituents of extracts seem to participate in the protective effects against harmaline induced tremor. PMID- 26124931 TI - The Lcn2-engineered HEK-293 cells show senescence under stressful condition. AB - OBJECTIVES: Lipocalin2 (Lcn2) gene is highly expressed in response to various types of cellular stresses. The precise role of Lcn2 has not been fully understood yet. However, it plays a key role in controlling vital cellular processes such as proliferation, apoptosis and metabolism. Recently it was shown that Lcn2 decreases senescence and increases proliferation of mesenchymal stem cells (MSC) with finite life span under either normal or oxidative stress conditions. However, Lcn2 effects on immortal cell line with infinite proliferation are not defined completely. Materials and. MATERIALS AND METHODS: HEK-293 cells were transfected with recombinant pcDNA3.1 containing Lcn2 fragment (pcDNA3.1-Lcn2). Expression of lipocalin2 in transfected cells was evaluated by RT-PCR, real time RT-PCR, and ELISA. Different cell groups were treated with H2O2 and WST-1 assay was performed to determine their proliferation rate. Senescence was studied by beta-galactosidase and gimsa staining methods as well as evaluation of the expression of senescence-related genes by real time RT-PCR. RESULTS: Lcn2 increased cell proliferation under normal culture condition, while the proliferation slightly decreased under oxidative stress. This decrease was further found to be attributed to senescence. CONCLUSION: Our findings indicated that under harmful conditions, Lcn2 gene is responsible for the regulation of cell survival through senescence. PMID- 26124932 TI - Investigation of FOXP3 genetic variations at positions -2383 C/T and IVS9+459 T/C in southern Iranian patients with lung carcinoma. AB - OBJECTIVES: FOXP3 gene is an X-linked gene that encodes FOXP3 protein, an essential transcription factor in CD4+CD25+FOXP3+ regulatory T (Treg) cells. We aimed, in the present study, to investigate the association of two FOXP3 polymorphisms, -2383 C/T (rs3761549) and IVS9+459 T/C (rs2280883), with lung cancer. MATERIALS AND METHODS: In a case-control study we analyzed genotypes and alleles frequencies at -2383 C/T and IVS9+459 T/C positions in 156 patients with lung cancer and 156 age and sex matched healthy controls in Southern Iranian population, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The data were verified by direct automated DNA sequencing. RESULTS: The frequency of -2383 T allele was significantly higher in the patients than in the control group (11.8% versus 5.9%, P-value=0.04, OR=2.13, 95%CI=1.04-4.54). T allele frequency at IVS9+459 T/C position was higher, compared to the controls, in the patients who presented the disease over 55 years old (69.9% versus 59.1%, P-value=0.04, OR=1.61, 95%CI=1.01-2.55) and also in SCLC patients (77.8% versus 59.1%, P-value=0.03, OR=2.42, 95%CI=1.05-5.59). No significant differences were found in the genotypes and haplotypes distributions between the cases and controls. A high degree of linkage disequilibrium was observed between two polymorphisms. CONCLUSION: As the first study dealing with 2383 C/T and IVS9+459 T/C in lung cancer, our data conclusively suggest the association of -2383 T allele with susceptibility to lung cancer in Iranian population. The association of IVS9+459 T allele with susceptibility to lung cancer in old patients suggests the age-dependent effects of FOXP3 gene on cancer occurrence. PMID- 26124933 TI - PI3K/Akt inhibition and down-regulation of BCRP re-sensitize MCF7 breast cancer cell line to mitoxantrone chemotherapy. AB - OBJECTIVES: Multidrug resistance (MDR) of cancer cells is a major obstacle to successful chemotherapy. Overexpression of breast cancer resistance protein (BCRP) is one of the major causes of MDR. In addition, it has been shown that PI3K/Akt signaling pathway involves in drug resistance. Therefore, we evaluated the effects of novel approaches including siRNA directed against BCRP and targeted therapy against PI3K/Akt signaling pathway using LY294002 (LY) to re sensitize breast cancer MCF7 cell line to mitoxantrone (MTX) chemotherapy. MATERIALS AND METHODS: Anticancer effects of MTX, siRNA, and LY alone and in combination were evaluated in MCF7 cells using MTT cytotoxicity assay and flow cytometry analysis of cell cycle distribution and apoptosis induction. RESULTS: MTT and apoptosis assays showed that both MTX and LY inhibited cell proliferation and induced apoptosis in MCF7 cells. Results indicated that inhibition of BCRP by siRNA or PI3K/Akt signaling pathway by LY significantly increased sensitivity of MCF7 cells to antiproliferation and apoptosis induction of MTX. Furthermore, MTX showed G2/M arrest, whereas LY induced G0/G1 arrest in cell cycle distribution of MCF7 cells. Combination of siRNA or LY with MTX chemotherapy significantly increased accumulation of MCF7 cells in the G2/M phase of cell cycle. CONCLUSION: Combination of MTX chemotherapy with BCRP siRNA and PI3K/Akt inhibition can overcome MDR in breast cancer cells. This study furthermore suggests that novel therapeutic approaches are needed to enhance anticancer effects of available drugs in breast cancer. PMID- 26124934 TI - Ferulic acid protects PC12 neurons against hypoxia by inhibiting the p-MAPKs and COX-2 pathways. AB - OBJECTIVES: Hypoxia induces cellular oxidative stress that is associated with neurodegenerative diseases. Here, the protective effects of ferulic acid (FA) on hypoxia-induced neurotoxicity in PC12 cells were evaluated. MATERIALS AND METHODS: We investigated the effect of FA on PC12 cells subjected to hypoxia stress, in vitro. RESULTS: FA increased cell viability, prevented membrane damage (LDH release), scavenged free radicals, increased superoxide dismutase (SOD) activity, and attenuated the elevation of intracellular free Ca(2+), lipid peroxidation, apoptosis (evaluated by TUNEL staining) and PGE2 production in hypoxia-stressed PC12 cells. MAPKs were activated during hypoxia. FA reduced p p38 MAPK, caspase-3, and COX-2 activation which correlated well with diminished LDH release in PC12 cells under hypoxia. Furthermore, FA reduced lipid peroxidation in PC12 cells subjected to hypoxia. CONCLUSION: Taken together, these results indicate that FA antioxidant effects could partly be involved in inhibition of p38 MAPK pathway and apoptosis through scavenging ROS in hypoxia stressed PC12 cells. PMID- 26124935 TI - Inhibitory effect of corcin on aggregation of 1N/4R human tau protein in vitro. AB - OBJECTIVES: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. One of the hallmarks of AD is an abnormal accumulation of fibril forms of tau protein which is known as a microtubule associated protein. In this regard, inhibition of tau aggregation has been documented to be a potent therapeutic approach in AD and tauopathies. Unfortunately, the available synthetic drugs have modest beneficial efficacy with several side effects. Therefore, pipeline drugs from natural sources with anti aggregation properties can be useful in the prevention and treatment of AD. Among medicinal plants, saffron (Crocus sativus, L.), as a traditional herbal medicine has different pharmacological properties and can be used as treatment for several nervous system impairment including depression and dementia. Crocin as a major constituent of saffron is the glycosylated form of crocetin. MATERIALS AND METHODS: In this study, we investigated the inhibitory effect of crocin on aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods and cell culture. RESULTS: Results revealed that tau protein under the fibrillation condition and in the presence of crocin had enough stability with low tendency for aggregation. Crocin inhibited tau aggregation with IC50 of 100 ug/ml. Furthermore, transmission electron microscopy images confirmed that crocin could suppress the formation of tau protein filaments. CONCLUSION: Inhibitory effect of crocin could be related to its interference with nucleation phase that led to increases in monomer species of tau protein. Based on our results, crocin is recommended as a proper candidate to be used in AD treatment. PMID- 26124936 TI - Gabapentin prevents oxaliplatin-induced central sensitization in the dorsal horn neurons in rats. AB - OBJECTIVES: The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin-induced neuropathic pain in rats. MATERIALS AND METHODS: Oxaliplatin (5 mg/kg) or saline was administered to adult male Sprague-Dawley rats. Gabapentin (60 mg/kg, IP) or vehicle was injected daily. Mechanical allodynia was assessed using a series of von Frey filaments. The expression of glutamate receptor subunits (NR2B and GluR1) and brain-derived neurotrophic factor (BDNF) was measured in the dorsal horn. The glutamatergic strength was recorded in the spinal cord slices. RESULTS: Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats, which was attenuated by gabapentin. Significant increase in the expression of BDNF was found in the dorsal horn in rats receiving oxaliplatin, which was prevented by gabapentin. Further studies also observed a significant increase in the expression of GluR1 and NR2B, as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin. The upregulation of glutamatergic transmission was significantly reversed by gabapentin. CONCLUSION: These results illustrated an increased expression of BDNF and enhanced glutamatergic transmission in rats with oxaliplatin-induced neuropathic pain, which was markedly attenuated by gabapentin. PMID- 26124937 TI - Cloning, molecular analysis and epitopics prediction of a new chaperone GroEL Brucella melitensis antigen. AB - OBJECTIVES: Brucellosis is a well-known domestic animal infectious disease, which is caused by Brucella bacterium. GroEL antigen increases Brucella survival and is one of the major antigens that stimulates the immune system. Hence, the objective of the present study was cloning and bioinformatics analysis of GroEL gene. MATERIALS AND METHODS: The full-length open reading frame of this gene was amplified by specific primers and cloned into pTZ57R/T vector. Also, the sequence of this gene in the Brucella melitensis strain Rev 1 was submitted to the NCBI gene bank for the first time. Several prediction software applications were also used to predict B and T-cell epitopes, secondary and tertiary structures, antigenicity ability and enzymatic degradation sites. The used software applications validated experimental results. RESULTS: The results of phylogenetic analysis showed that the GroEL sequence had near homology with other species instead of other Brucella spp. The bioinformatics tools used in the current study were validated by the results of four different experimental epitope predictions. Bioinformatics analysis identified eight B and seven T-cell epitopes. CONCLUSION: According to the antigenic ability and proteasomal cleavage sites, four (150-160, 270-285,351-361 and 385-395) common epitopes were predicted for GroEL gene. Bioinformatics analysis showed that these regions had proper epitope characterization and so may be useful for stimulation of cell-mediated and humoral immunity system. PMID- 26124938 TI - Preparation and characterization of different liposomal formulations containing P5 HER2/neu-derived peptide and evaluation of their immunological responses and antitumor effects. AB - OBJECTIVES: Tumor-associated antigen (TAA) subunit-based vaccines constitute promising tools for anticancer immunotherapy. However, a major limitation in the development of such vaccines is the poor immunogenicity of peptides when used alone. The aim of this study was to develop an efficient vaccine delivery system and adjuvant to enhance anti-tumor activity of a synthetic HER2/neu derived peptide (P5). MATERIALS AND METHODS: P5 peptide was encapsulated with different liposomal formulations composed of DMPC:DMPG:Chol:DOPE and loaded with monophosphoryl lipid A (MPL). All formulations were characterized for their physicochemical properties. To evaluate vaccine efficacy, BALB/c mice were first immunized with free peptide or liposomal formulations, then, inoculated with a subcutaneous injection of TUBO tumor cells. Enzyme-linked immunospot, cytotoxicity and intracellular cytokine assays, as well as tumor size and animal survival analysis, were performed to evaluate the immune responses. RESULTS: The results demonstrated that P5 encapsulated into liposomal formulations was not able to induce CD8 and CD4 T cells to produce IFN-gamma. That is why, a potent CTL response and antitumor immunity was not induced. CONCLUSION: The Lip-DOPE-P5 MPL formulation in spite of using pH-sensitive lipid to direct intracellular trafficking of peptide to MHC I presentation pathway and MPL to enhance peptide adjuvanticity was interesting. The failure in inducing anti-tumor immunity may be attributed to low uptake of anionic conventional liposomes by dendritic cells (DCs) that have negative surface charge. PMID- 26124939 TI - The reduction of aorta histopathological images through inhibition of reactive oxygen species formation in hypercholesterolemia rattus norvegicus treated with polysaccharide peptide of Ganoderma lucidum. AB - OBJECTIVES: Atherosclerosis is chronic inflammatory process triggered by oxidative stress. Oxidative stress can increase hydrogen peroxide (H2O2) level, which induce atherosclerosis through the processes such as formation of perivascular adipose tissue (PVAT), foam cells, and atherosclerotic plaque. Antioxidant is needed to control negative effects of oxidative stress. One source of antioxidant, which has potential to be developed, is PsP from Ganoderma lucidum. This study aims to prove the effect of PsP in decreasing H2O2, PVAT, foam cells and atherosclerotic plaque. MATERIALS AND METHODS: This study was experimental randomized post-test with control group design using 25 Rattus norvegicus Wistar strain rats. Rats were divided into 5 groups (negative control, positive control, and 3 high-fat diet group with PsP dose: 50, 150, 300 mg/kgBW). Measured parameters were H2O2, PVAT, foam cell, and atherosclerotic plaques. Analysis of variance (ANOVA) was used for statistical analysis, followed by post hoc test. RESULTS: Mean H2O2 levels, PVAT thickness, foam cell numbers, and atherosclerotic plaque were low in negative control group. ANOVA showed that PsP significantly (P<0.05) reduced H2O2 levels, PVAT thickness, foam cells numbers and atherosclerotic plaque width. CONCLUSION: PsP dose of 300 mg/kgBW has the most significant effect in decreasing H2O2 levels, PVAT thickness, number of foam cells, and atherosclerotic plaque width. Based on the results of this research, PsP can be recommended as antioxidant to control pathogenesis of atherosclerosis. PMID- 26124940 TI - The effect of intrathecal delivery of bone marrow stromal cells on hippocampal neurons in rat model of Alzheimer's disease. AB - OBJECTIVES: Intracerebral injection of bone marrow stromal cells (BMSCs) is being investigated as a therapeutic tool to prevent Alzheimer's disease (AD). Our aim was to investigate the effects of BMSCs by intrathecal injection in AD rat model. MATERIALS AND METHODS: BMSCs were obtained from the bone marrow of Wistar rat and transplanted into AD rat model via intrathecal injection. The rat model had received an injection of beta amyloid into the hippocampus for histological and immunohistochemical studies. RESULTS: Histological examination of the brains in transplanted rats compared to controls demonstrated the migration of BrdU-labeled BMSCs from the site of delivery, confirmed the differentiation of BMSCs transplanted cells into the cholinergic neurons, and increased number of healthy and decreased number of dark neurons. CONCLUSION: Our results showed that BMSCs intratechal administration could be a promising method for treatment of Alzheimer's disease in rat model. PMID- 26124941 TI - The RETN gene rs1862513 polymorphism as a novel predisposing marker for familial Acne vulgaris in a Pakistani population. AB - Resistin (RETN), recently found to be relevant to inflammation and inflammatory disorders. We, therefore, aimed to investigate the potential role of RETN gene polymorphism in pathogenesis of acne vulgaris with familial history. We investigated the RETN-420C/G polymorphism in 180 patients with acne vulgaris and 180 healthy individuals in a case-control association analysis. In this study, we also investigated the heritability of the RETN susceptible allele from 140 trio families with acne affected offspring. The genotyping was performed by polymerase chain reaction and direct DNA sequencing. The RETN-420C/G polymorphism was significantly associated with acne in patients compared with healthy controls (P=0.014). The minor allele G at -420 was more prevalent in cases vs. controls (P=0.002). The RETN-420C/G polymorphism was significantly associated with severity of acne vulgaris in patients (P=0.0097). The results of a transmission disequilibrium test revealed a significant association between the RETN-420C/G polymorphism and acne vulgaris (P<0.001). For the first time in the literature, to our knowledge, we demonstrate a significant association of the RETN-420C/G functional polymorphism with familial acne vulgaris. PMID- 26124942 TI - Inequality in Utilization of In-patients Health Services in Iran. AB - BACKGROUND: Health services for those in need. Inpatient care shows a more serious side of individual care and patients and their family members perceive a high level of stress and urge. We conducted this study to determine inequalities of in-patient health care utilization in Iranian people and to assess factors that influence utilization. METHODS: In each province, the sample was comprised of 380 urban and 380 rural households that were recruited by a systematic random sampling method. A total of 23,560 households, which included around 102,000 individuals were recruited. We used the questionnaire for data collection. Met admission need (MAN) was the main variable and was considered household assets for determining the economic status. We did all analyses using the STATA version 9.1. RESULTS: The rates of MAN for urban and rural areas were 83% and 81.3% respectively. The rate of MAN was significantly higher in patients with higher educational level. Patients with primary health insurance coverage had significantly higher rate of MAN. CONCLUSIONS: Meeting admission needs was estimated around 84% and it seems that modifying insurance coverage is the most feasible intervention for increasing utilization of health services. PMID- 26124943 TI - Knowledge and Practice of People toward their Rights in Urban Family Physician Program: A Population-Based Study in Shiraz, Southern Iran. AB - BACKGROUND: Urban family physician program has been launched as a pilot in Fars and Mazandaran provinces of Iran since 2012. Attitudes of policy makers and people toward urban family physician program have become challenging. This study shows what people know and practice toward this program. METHODS: This cross sectional population-based study was conducted by a multistage randomized sampling in Shiraz, Southern Iran. Knowledge and practice of adults toward urban family physician program were queried through filing the questionnaires. Single and multiple variable analyzes of data were performed. RESULTS: Participation rate was 1257 of 1382 (90.9%), and the mean age of the respondents was 38.1 +/- 13.2 years. Of 1257, 634 (50.4%) were men and 882 (70.2%) were married. Peoples' total knowledge toward urban family physician program was 5 +/- 2.7 of 19, showed that 1121 (89.2%) had a low level of knowledge. This was correlated positively and in order to being under coverage of this program (P < 0.001), being under coverage of one of the main insurance systems (P = 0.04) and being married (P = 0.002). The mean score of people's practice toward the program was 2.3 +/- 0.9 of total score 7, showed that 942 (74%) had poor performance, and it was correlated positively and in order to being under coverage of this program (P < 0.001) and having higher than 1000$ monthly income (P = 0.004). Correlation of people's knowledge and practice toward the program was 24%. CONCLUSIONS: Current evidences show a low level of knowledge, poor practice and weak correlation of knowledge practice of people toward urban family physician program. PMID- 26124944 TI - Comment on: Pomegranate Flower Extract Does Not Prevent Cisplatin-induced Nephrotoxicity in Female Rats. PMID- 26124945 TI - Self-reported Practices and Attitudes of Community Health Workers (Accredited Social Health Activist) in Tobacco Control - Findings from two states in India. AB - BACKGROUND: The 1978 declaration (Alma-Ata declaration) made at the International Conference on Primary Health Care, meeting in Alma-Ata highlighted the critical role played by Community Health Workers (CHWs) to link communities to the health system. The flagship program of Government of India proposed introduction of CHWs namely Accredited Social Health Activist (ASHA). As a link between community and health system ASHA is in a unique position to generate awareness on tobacco related issues. However, there is limited evidence on practices of ASHAs in tobacco control in India. The present study explores whether CHWs such as ASHAs can be utilized as a resource for informing and educating community on tobacco and its harmful effects. The study captured perceptions and practices of ASHAs regarding tobacco control. METHODS: The study was a cross-sectional study conducted among 512 ASHAs in six intervention districts each in Gujarat and Andhra Pradesh. The study settings (i.e., health facilities and villages) were selected through systematic random sampling. The study participants were selected through simple random sampling. Responses were captured through self-administered questionnaire. Logistic regression model was applied to measure associations between variables such as knowledge level of ASHAs and information provided on different tobacco-related diseases by them in both the states, with statistical significance based on the Chi-square test. RESULTS: Our findings indicate that ASHAs linked tobacco usage to diseases such as respiratory problems, lung cancer, tuberculosis, and oral disease. Only one-third of ASHAs reported informing all patients about the harmful health effects of tobacco, whereas more than half of them reported providing information only to patients suffering from specific illness. ASHAs who reported having received training in tobacco control were about Two times more likely to give information on effects of tobacco on respiratory diseases (odds ratio [OR]-1.5; confidence interval [CI]: 1.1-2.4) and adverse reproductive outcomes (OR-2.1; CI: 1.1-20.2). CONCLUSIONS: Study findings reflect suboptimal engagement of ASHAs in providing information pertaining to specific tobacco-related diseases. There is an urgent need to sensitize and train ASHAs in appropriate tobacco control practices. PMID- 26124946 TI - Role of Heart and its Diseases in the Etiology of Depression According to Avicenna's Point of View and its Comparison with Views of Classic Medicine. AB - BACKGROUND: Depression is one of the most important medical problems in today's world; despite its high prevalence, its causes unfortunately remain not fully known. Among important issues regarding this is its relation with heart diseases. Based on studies this comorbidity increase morbidity and mortality and leads to worst prognosis. However the cause of such high rate of comorbidity is unclear and instead of efforts to understand this correlation has prompted the medical world to consult other medicinal disciplines, not only to find the answer but also to increase the effectiveness of treatment and decrease its cost. METHODS: We first reviewed the most important ancient causes for depression mentioned by Avicenna and considered those as the key words for our next step. Then, we made a literature search (PubMed and Scopus) with those key words to find out new scientific findings in modern medicine about the Avicenna's suggestions. RESULTS: Avicenna does not regard depression as only a mental ailment, but as a disorder resulted by the involvement of brain, heart and blood. He believed that the main causes of depressive events are rooted in heart diseases; in most cases brain is only affected secondary to the heart. Thus he declared that for the treatment of depressive disorders, the underlying cardiovascular diseases should be considered. CONCLUSIONS: It is worthwhile to consider the Avicenna's recommended causes of depression and to design future scientific studies based on his suggestions. PMID- 26124947 TI - Influence of Anthropometric Measurements in Lung Function in Patients With Asthma. AB - BACKGROUND: Obesity is commonly regarded as a risk factor for asthma development, poor asthma control, and poor response to asthma therapy. METHODS: In a cross sectional study, 85 asthmatics (37 male and 48 female) participated. Pulmonary function tests (PFTs) and anthropometric parameters were measured for each patient. RESULTS: Mean age and median duration were 43.9 +/- 10.61 and 6 (3-14) years, respectively. Among anthropometric parameters, only waist-to-hip ratio (WHR) indicated significant correlation with PFTs in both sex (P < 0.05). There were negative associations between waist circumference, hip circumference and WHR with PFTs only in overweight and obese women (P < 0.05). CONCLUSIONS: Some anthropometric parameters affected lung function, and it seems that gender differentially contributes to this effect. PMID- 26124948 TI - Pustular Bacterid: Look at the Throat for Prevention over Treatment. PMID- 26124949 TI - Reduction of Methylphenidate Induced Anxiety, Depression and Cognition Impairment by Various doses of Venlafaxine in Rat. AB - BACKGROUND: Methylphenidate (MPH) is a neural stimulant agent, which its neurochemical and behavioral effect remain unclear. Venlafaxine is a serotonin norepinephrine reuptake inhibitor antidepressant, which was used for management of depression and anxiety. In this study, protective effects of venlafaxine on MPH induced anxiety, depression and cognition impairment were investigated. METHODS: Forty-eight adult male rats were divided randomly to 5 groups. Group 1, received normal saline (0.2 ml/rat) for 21 days and served as control group. Group 2, received MPH (10 mg/kg) for 21 days. Groups, 3, 4, 5 and 6 concurrently were treated by MPH (10 mg/kg) and venlafaxine at doses of 25, 50, 75 and 100 mg/kg respectively for 21 days. On day 22, elevated plus maze (EPM), open field test (OFT), forced swim test (FST) and tail suspension test (TST) were used to investigate the level of anxiety and depression in animals. In addition, between days 17 and 21, Morris water maze (MWM) was used to evaluate the effect of MPH on spatial learning and memory. RESULTS: MPH caused depression and anxiety in a dose dependent manner in FST, OFT, EPM and TST, which were significantly different compared with control group. Furthermore, MPH can significantly attenuate the motor activity in OFT. Venlafaxine in all doses can attenuate MPH induced anxiety, depression and motor activity alterations. MPH also can disturb learning and memory in MWM, but venlafaxine did not alter this effect of MPH. CONCLUSIONS: We conclude that venlafaxine can be protective in the brain against MPH induced anxiety and depression. PMID- 26124950 TI - The psychometric properties of the Quantitative-Checklist for Autism in Toddlers (Q-CHAT) as a measure of autistic traits in a community sample of Singaporean infants and toddlers. AB - BACKGROUND: There is growing research evidence that subclinical autistic traits are elevated in relatives of individuals with autism spectrum disorder (ASD), continuously distributed in the general population and likely to share common etiology with ASD. A number of measures have been developed to assess autistic traits quantitatively in unselected samples. So far, the Quantitative-Checklist for Autism in Toddlers (Q-CHAT) is one of very few measures developed for use with toddlers as young as 18 months, but little is known about its measurement properties and factor structure. METHODS: The present study examined internal consistency, factor structure, test-retest stability, and convergent validity of the Q-CHAT in a sample of toddlers in Singapore whose caregivers completed the Q CHAT at 18 (n = 368) and 24 months (n = 396). RESULTS: Three factors were derived accounting for 38.1 % of the variance: social/communication traits, non social/behavioral traits, and a speech/language factor. Internal consistency was suboptimal for the total and speech/language scores, but acceptable for the social/communication and non-social/behavioral factor scores. Scores were generally stable between 18 and 24 months. Convergent validity was found with the Pervasive Developmental Disorders subscale of the Child Behavior Checklist (CBCL) completed by caregivers when their children were 24 months. Q-CHAT total scores in this sample were higher than those reported in other unselected samples from the UK. CONCLUSIONS: The Q-CHAT was found to have a three-factor structure, acceptable internal consistency for its two main factor scores (social/communication and non-social/behavioral), normally distributed scores in an unselected sample, and similar structure and measurement properties as those reported in other published studies. Findings are discussed in relation to existing literature and future directions for the validation of the Q-CHAT. PMID- 26124951 TI - Evaluation of fractionated and repeated sonodynamic therapy by using dual frequency for murine model of breast adenocarcinoma. AB - BACKGROUND: Sonodynamic therapy (SDT) is a new approach for cancer treatment. Repair by reoxygenation induces cell damage in all treatment which uses photo- and sonosensitizers. In this study, the in vivo antitumor effect of dual frequency sonication is investigated at low-level intensity and hematoporphyrin (Hp). It is used for the treatment of spontaneous breast adenocarcinoma of Balb/c mice with a variety of dose repetition and fractionation regimes. METHODS: Eighty tumor-bearing mice were divided into eight groups, the control group (A); the sham group (B); the injection of Hp alone group (C); 30-min dual-frequency sonication with Hp injection in one repetition at the first day group (D); two repetitions at the first and sixth days group (E); three repetitions at the first, sixth, and twelfth days group (F); four repetitions at the first, sixth, twelfth, and eighteenth days (30 min/repetition) group (G); and the fractional treatment group treated by dual-frequency sonication and Hp injection at the first, third, sixth, and ninth days (7.5 min/fraction) (H). For each group, the tumor growth delay was calculated during 30 days after treatment. These tumors were studied histopathologically. RESULTS: The results show that the treatment with ultrasound dose repetition in two, three, and four times (E, F, and G groups) were effective in delaying tumor growth compared with one-time sonication (D group) (p < 0.05). Also, the ultrasound dose fractionation is more effective in decreasing the tumor growth rate compared with the ultrasound dose repetition in four repeats and in one repeat from the 12th to the 30th day (p < 0.05). Histopathological studies indicated that the mitotic activity of tumor cells was reduced following treatment with four fraction and four repetition protocols. CONCLUSION: The ultrasound dose fractionation and repetition technique with dual frequency sonication can have a useful therapeutic effect in sonodynamic therapy with the possibility of use in future clinical applications. PMID- 26124952 TI - Spontaneous diabetic myonecrosis: report of four cases from a tertiary care institute. AB - Spontaneous diabetic muscle infarction (DMI) is a rare and under diagnosed complication of diabetes mellitus. Clinically it presents with acute to subacute onset swelling, pain and tenderness of muscle(s) without systemic manifestations. MRI is helpful in diagnosis, exclusion of other causes and for localization of affected muscle for biopsy in atypical cases. Muscles of the thighs are commonly affected in diabetic myonecrosis (DMN). Here we present the summary of four cases seen in the last 3 years in a tertiary care centre with simultaneous or sequential involvement of multiple groups of muscles or involvement of uncommon sites. All these patients had advanced duration of diabetes with microvascular complications and poor glycemic control. Conservative management including rest and analgesics is the treatment of choice. Short-term prognosis is good but there may be recurrence. LEARNING POINTS: A high index of suspicion is required for the diagnosis of DMN which can avoid inadvertent use of antibiotics.Acute-subacute onset severe focal muscle pain in the absence of systemic symptoms in a female patient with long-standing diabetes with microvascular complications suggests DMI.MRI is the most sensitive test for diagnosis.Muscle biopsy should be reserved for atypical cases.Conservative management including rest and analgesics has good outcome.Improvement usually occurs within 6-8 weeks, but there may be recurrence. PMID- 26124953 TI - Management of adrenocortical insufficiency with continuous subcutaneous hydrocortisone infusion: long-term experience in three patients. AB - To assess continuous subcutaneous hydrocortisone infusion (CSHI) in patients with adrenocortical insufficiency (AI) and difficulties with oral replacement. Three patients with AI and frequent hospital admissions attributed to adrenal crises were treated with CSHI, which was delivered via a continuous subcutaneous infusion. All three patients preferred CSHI and remained on it long term, which permitted prolonged follow-up analysis. All three patients reported symptomatic improvement, and in two cases, reduced hospital admission rates and inpatient stay lengths were observed. The cost of hospital admissions and overall treatment was reduced in all cases. CSHI offers a practical and acceptable alternative to oral replacement in a subset of patients with AI. The cost of initiating and maintaining the pump is offset in the long term by reduced frequency and duration of emergency admissions. CSHI can therefore be considered in a select group of patients who are resistant to treatment with conventional oral glucocorticoids. LEARNING POINTS: Continuous subcutaneous infusion of cortisol is a viable alternative in patients unable to take oral steroids.Patient acceptability was high, with three out of three patients preferring to remain on pump treatment.Hospital admissions were reduced in response to pump therapy, which compensated for the increased treatment cost.The daily dosage of hydrocortisone can be reduced by using pump therapy. PMID- 26124954 TI - Pituitary hyperplasia: case series and literature review of an under-recognised and heterogeneous condition. AB - Pituitary hyperplasia (PH) occurs in heterogeneous settings and remains under recognised. Increased awareness of this condition and its natural history should circumvent unnecessary trans-sphenoidal surgery. We performed an observational case series of patients referred to a single endocrinologist over a 3-year period. Four young women were identified with PH manifesting as diffuse, symmetrical pituitary enlargement near or touching the optic apparatus on MRI. The first woman presented with primary hypothyroidism and likely had thyrotroph hyperplasia given prompt resolution with thyroxine. The second and third women were diagnosed with pathological gonadotroph hyperplasia due to primary gonadal insufficiency, with histopathological confirmation including gonadal-deficiency cells in the third case where surgery could have been avoided. The fourth woman likely had idiopathic PH, though she had concomitant polycystic ovary syndrome which is a debated cause of PH. Patients suspected of PH should undergo comprehensive hormonal, radiological and sometimes ophthalmological evaluation. This is best conducted by a specialised multidisciplinary team with preference for treatment of underlying conditions and close monitoring over surgical intervention. LEARNING POINTS: Normal pituitary dimensions are influenced by age and gender with the greatest pituitary heights seen in young adults and perimenopausal women.Pituitary enlargement may be seen in the settings of pregnancy, end-organ insufficiency with loss of negative feedback, and excess trophic hormone from the hypothalamus or neuroendocrine tumours.PH may be caused or exacerbated by medications including oestrogen, GNRH analogues and antipsychotics.Management involves identification of cases of idiopathic PH suitable for simple surveillance and reversal of pathological or iatrogenic causes where they exist.Surgery should be avoided in PH as it rarely progresses. PMID- 26124955 TI - Spontaneous cervical haemorrhage of a parathyroid adenoma. AB - Haemorrhage of a parathyroid adenoma is a rare clinical presentation. This report describes a previously fit and well 54-year-old woman who presented with acute neck swelling and pain with an overlying ecchymosis. Admission laboratory tests revealed a raised parathyroid hormone and hypercalcaemia. A computed tomography (CT) scan showed widespread anterior cervical haemorrhage and a lesion at the inferior pole of the left thyroid gland. A working diagnosis of spontaneous haemorrhage from a parathyroid adenoma was made. As she was haemodynamically stable, she was treated conservatively with a period of observation in hospital to monitor for signs of neck organ compression. Follow-up imaging with CT, ultrasound and sestamibi confirmed the likely source of haemorrhage as a parathyroid nodule with significant vascularity. The diagnosis was confirmed on histopathological analysis after elective surgical exploration of the neck 6 months after her presentation. This revealed a benign parathyroid adenoma with evidence of acute and chronic bleeding. The patient made a full recovery with immediate normalisation of her biochemistry post-operatively. Despite developing a hoarse voice in the immediate post-operative period, this resolved completely within 1 month. This case report provides further evidence to support a minimal delay for elective surgery after conservative management to reduce the risks associated with recurrent bleeding. LEARNING POINTS: Haemorrhage of a parathyroid adenoma should be a differential for all cases of acute cervical swelling or ecchymosis with no precipitating factor.The clerking should identify any risk factors for endocrine disease.Blood tests to screen for abnormal parathyroid biochemistry should be performed on admission.Detailed imaging of the neck is essential to identify the source of haemorrhage and risk of compression to vital neck organs.Conservative management is a suitable option for patients who remain haemodynamically stable but all should undergo a period of observation in hospital.Conservatively managed patients should be considered for definitive surgical exploration within a month of presentation to avoid the risks of recurrent bleeding. PMID- 26124956 TI - Erratum: Quadricuspid pulmonic valve found on well exam. AB - [This corrects the article DOI: 10.1186/s40779-015-0037-2.]. PMID- 26124957 TI - Eye Motility Alterations in Retinitis Pigmentosa. AB - Purpose. We evaluated a sample of individuals with retinitis pigmentosa (RP) with the aim of assessing the presence or absence of ocular motility (OM) disorders. Materials and Methods. We included 23 out of the 25 individuals from the sample (9 females and 14 males) with an average visual acuity of 6/10. Results. The cover test about the vertical deviation in near distance showed an r/l in 3.45% and an l/r in 6.9%. The assessment of OM showed that 39.1% of the sample had a severe hyperfunction of the IO of the right eye and a severe hyperfunction (34.5%) of the SO of the left eye; 21.8% had a moderate hypofunction of right SO with a moderate percentage of hypofunction of 17.5% for the SO of the left eye; 30.5%, however, showed a serious hypofunction of the SR of both eyes; 21.7% of the sample showed a hyperfunction in both eyes of the IR. Conclusion. This alteration, however, is not attributable to either a high refractive defect (medium-low myopia: -1 diopter +/-3 SD) or to a severely impaired binocular vision (visual acuity, motor fusion, and stereopsis are normal or within a range of values commonly accepted). Therefore, the disorders of OM lead to a genetic origin. PMID- 26124958 TI - Self-Testing of Vision in Age-Related Macula Degeneration: A Longitudinal Pilot Study Using a Smartphone-Based Rarebit Test. AB - Purpose. There is a need for efficient self-tests of vision in patients with neovascular age-related macula degeneration. A new tablet/smartphone application aiming to meet this need is described and its performance is assessed in a longitudinal pilot study. Materials and Methods. The new MultiBit Test (MBT) employs segmented digits defined by rarebits, that is, receptive field-size bright dots briefly presented against a dark background. The number of rarebits per digit segment was varied in a cyclic fashion, in preset steps. There were no fixation demands. Twenty-eight patients with neovascular AMD of varying severity were monitored for an average of 30 weeks. Test scores were evaluated on an individual basis, by contrasting observed trends with the clinical status recorded at independently scheduled clinical examinations. Results. Serial plots of MBT results revealed gradual improvement after successful antineovascular treatment. Recurrences were signalled by gradual deteriorations of results. Test results remained stable during clinically stable time intervals. MBT results agreed well with clinical assessments whereas an acuity test performed at chance level. The MBT was well accepted by all subjects. Conclusions. The MBT appears to have a good potential for effective self-testing of vision in AMD and merits large-scale studies. Exploration of MBT performance with other forms of macula conditions may be worthwhile. PMID- 26124959 TI - Histological Characterization of the Dicer1 Mutant Zebrafish Retina. AB - DICER1, a multidomain RNase III endoribonuclease, plays a critical role in microRNA (miRNA) and RNA-interference (RNAi) functional pathways. Loss of Dicer1 affects different developmental processes. Dicer1 is essential for retinal development and maintenance. DICER1 was recently shown to have another function of silencing the toxicity of Alu RNAs in retinal pigment epithelium (RPE) cells, which are involved in the pathogenesis of age related macular degeneration. In this study, we characterized a Dicer1 mutant fish line, which carries a nonsense mutation (W1457Ter) induced by N-ethyl-N-nitrosourea mutagenesis. Zebrafish DICER1 protein is highly conserved in the evolution. Zebrafish Dicer1 is expressed at the earliest stages of zebrafish development and persists into late developmental stages; it is widely expressed in adult tissues. Homozygous Dicer1 mutant fish (DICER1(W1457Ter/W1457Ter)) have an arrest in early growth with significantly smaller eyes and are dead at 14-18 dpf. Heterozygous Dicer1 mutant fish have similar retinal structure to that of control fish; the retinal pigment epithelium (RPE) cells are normal with no sign of degeneration at the age of 20 months. PMID- 26124961 TI - Retinitis Pigmentosa Treatment with Western Medicine and Traditional Chinese Medicine Therapies. AB - Current management of retinitis pigmentosa (RP) includes an attempt at slowing down the degenerative process through therapies that use either Western or traditional Chinese medicine (TCM). Novel therapies in Western medicine (WM) include use of tailor-made gene therapy, transplantation of stem cells, or neuroprotection treatment. TCM treatment includes two major approaches. These are orally applied herbal decoctions and acupuncture. In fact, all TCM treatments are based on the differentiation of a symptom-complex, which is the characteristic essence of TCM. Thus, diagnosed RP may be treated via the liver, the kidney, and the spleen. The principle behind these treatments is to invigorate the blood and brighten the eyes by toning up the liver and the kidney. Also treatments to cope with deficiencies in the two concepts that are unique and fundamental to TCM are considered: Qi or "vital energy" and Yin and Yang or the harmony of all the opposite elements and forces that make up existence. In particular, the Qi deficiency that results from blood stasis is addressed in these treatments. This paper also puts forward the existing problems and the prospect of the future development on integrating TCM with WM. PMID- 26124960 TI - The Role of RPGR and Its Interacting Proteins in Ciliopathies. AB - Ciliopathies encompass a group of genetic disorders characterized by defects in the formation, maintenance, or function of cilia. Retinitis pigmentosa (RP) is frequently one of the clinical features presented in diverse ciliopathies. RP is a heterogeneous group of inherited retinal disorders, characterized by the death of photoreceptors and affecting more than one million individuals worldwide. The retinitis pigmentosa GTPase regulator (RPGR) gene is mutated in up to 20% of all RP patients. RPGR protein has different interacting partners to function in ciliary protein trafficking. In this review, we specifically focus on RPGR and its two interacting proteins: RPGRIP1 and RPGRIP1L. We summarize the function of the three proteins and highlight recent studies that provide insight into the cellular function of those proteins. PMID- 26124962 TI - iTRAQ-Based Proteomic Analysis of Visual Cycle-Associated Proteins in RPE of rd12 Mice before and after RPE65 Gene Delivery. AB - Purpose. To investigate the iTRAQ-based proteomic changes of visual cycle associated proteins in RPE of rd12 mice before and after RPE65 gene delivery. Mehtods. The right eyes of rd12 mice underwent RPE65 gene delivery by subretinal injection at P14, leaving the left eyes as control. C57BL/6J mice were served as a wide-type control group. ERGs were recorded at P42, and RPE-choroid-sclera complex was collected to evaluate the proteomic changes in visual cycle associated proteins by iTRAQ-based analysis. Western blot was used to confirm the changes in the differentially expressed proteins of interest. Results. ERG parameters improved dramatically at P42 after RPE65 delivery. The proteomics analysis identified a total 536 proteins with a global false discovery rate of 0.21%, out of which 7 were visual cycle-associated proteins. RALBP-1, RBP-1, and IRBP were reduced in the untreated rd12 eyes and the former two were improved after gene therapy, confirmed by Western blot analysis. Conclusions. RPE65 gene delivery restored retinal function at P42 and modified the expression of other functional proteins implicated in the visual cycle. The level of RALBP-1 was still below the normal level after gene therapy in rd12 mice, which may explain the delayed dark adaption in LCA patients undergoing similar therapy. PMID- 26124963 TI - Exome Sequencing Identified a Recessive RDH12 Mutation in a Family with Severe Early-Onset Retinitis Pigmentosa. AB - Retinitis pigmentosa (RP) is the most important hereditary retinal disease caused by progressive degeneration of the photoreceptor cells. This study is to identify gene mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in a Chinese family using next-generation sequencing technology. A Chinese family with 7 members including two individuals affected with severe early-onset RP was studied. All patients underwent a complete ophthalmic examination. Exome sequencing was performed on a single RP patient (the proband of this family) and direct Sanger sequencing on other family members and normal controls was followed to confirm the causal mutations. A homozygous mutation c.437T6 years). Renal function improved and maintained by long-term sustained eculizumab treatment, presumably by clearance of iron from the kidney as well as inhibition of the production of anaphylatoxin C5a, even in advanced stages of CKD, is one of the benefits of eculizumab treatment in PNH. PMID- 26124969 TI - Actinomyces meyeri Empyema: A Case Report and Review of the Literature. AB - Actinomyces meyeri is an uncommon cause of human actinomycosis. Here, we report a rare case of empyema caused by A. meyeri. A 49-year-old male presented with a history of 10 days of dyspnea and chest pain. A large amount of loculated pleural effusion was present on the right side and multiple lung nodules were documented on radiological studies. A chest tube was inserted and purulent pleural fluid was drained. A. meyeri was isolated in anaerobic cultures of the pleural fluid. The infection was alleviated in response to treatment with intravenous penicillin G (20 million IU daily) and oral amoxicillin (500 mg every 8 hours) for 4 months, demonstrating that short-term antibiotic treatment was effective. PMID- 26124970 TI - Myocarditis and Rhabdomyolysis in a Healthy Young Man Caused by Salmonella Gastroenteritis. AB - Salmonella gastroenteritis is a common, self-limiting, foodborne disease and a rare cause of life-threatening complications especially in immunocompetent individuals. Moreover, bacterial infections of the GI tract have been rarely reported as a cause of serious complications like acute myocarditis and rhabdomyolysis. While viral infections are commonly associated with myocarditis, bacterial infections are infrequently seen with these conditions. Similarly, bacterial infections may lead to only 5% of adult rhabdomyolysis events whereas viral-induced myositis appears to be the commonest. A 28-year-old young male with no past medical problems presented with acute salmonella gastroenteritis that was complicated by myocardial injury (most likely myocarditis), rhabdomyolysis, acute renal failure, and shock. He made an uneventful complete recovery of all complications by early recognition of these rare complications and prompt institution of appropriate therapy. PMID- 26124971 TI - Extensive Thrombosis of the Inferior Vena Cava and Left Renal Vein in a Neonate. AB - Antenatal renal vein thrombosis is a rarely described diagnostic finding, with variable consequences on kidney function. We present the case of an affected fetus, born at 35-week gestation, with intrauterine oligohydramnios and two small kidneys. A renal ultrasound carried out after birth confirmed the presence of prenatal abnormalities. Renal vein thrombosis was not diagnosed at the time. The baby died 20 days later of kidney failure, metabolic acidosis, and polypnea with severe hypotrophy. Autopsy revealed atrophied kidneys and adrenal glands. The vena cava had thrombosis occupying most of its length. The right renal vein was normal, while the left renal vein was threadlike and not permeable. Histologically, there was necrosis of the left adrenal gland with asymmetrical bilateral renal impairment and signs of ischemic and hemorrhagic lesions. A review of thrombophilia was carried out and a heterozygous mutation in Factor V was found in both the mother and the child. PMID- 26124972 TI - Bilateral Dome-Shaped Macula with Serous Macular Detachment in a Child. AB - Dome-shaped macula is a structural disorder and optical coherence tomography (OCT) helps us to confirm macular convexity. We describe the first case of bilateral dome-shaped macula in an 8-year-old boy with subretinal fluid. The patient was diagnosed using spectral-domain OCT and received indocyanine green angiography-guided half-fluence photodynamic therapy as treatment. PMID- 26124973 TI - Internal Carotid Artery Aneurysm Mimicking Peritonsillar Abscess. AB - The extracranial internal carotid artery aneurysm (EICAA) is an uncommon arterial lesion. Patients typically present with neurologic symptoms resulting from impaired cerebral perfusion and compression symptoms of cranial nerves. Often EICAA presents as a pulsatile neck mass, which is otherwise asymptomatic. We present a case of an 84-year-old female, who was initially referred to the Emergency Department for Otolaryngology with suspected peritonsillar abscess. The patient had a history of recent upper airway infection and cardiovascular comorbidities, including hypertension and ischaemic stroke complicated by extensive neurologic deficits. Physical examination revealed a compact, nonpulsatile mass in the lateral parapharyngeal space and local erythema of the mucosa. Duplex Doppler Ultrasonography and Computed Tomography revealed an atherosclerotic aneurysm of the right internal carotid artery, measuring 63 * 55 * 88 mm, stretching from the skull base to the angle of the mandible. PMID- 26124974 TI - A Case of Disseminated Cryptococcal Infection and Concurrent Lung Tuberculosis in a Patient under Steroid Therapy for Interstitial Pneumonia. AB - Both disseminated cryptococcal infection and tuberculosis occur in hosts with impaired cell-mediated immunity, but there have been few reports about the concurrent infections in patients without human immunodeficiency virus infection. A 64-year-old man, who had been taking corticosteroids for interstitial pneumonia, was diagnosed with disseminated cryptococcal infection. While the patient was receiving anticryptococcal therapy, pulmonary tuberculosis also emerged. The patient developed acute exacerbation of interstitial pneumonia and passed away. Based on the patient's clinical course, serial computed tomography images, and autopsy results, we believe that the preceding several months of corticosteroid treatment might have contributed to these coinfections in the lungs already vulnerable due to underlying fibrosis. PMID- 26124975 TI - Endovascular Treatment of a Dissected Celiac Trunk Aneurysm Complicated with Consequent Pseudoaneurysm: Primary Treatment and Treatment Relapse after 5 Years. AB - We report on an asymptomatic 56-year-old male with incidental diagnosis of celiac trunk aneurysm, diagnosed during an ultrasound scan performed to control polycystic kidney disease. The CT scan revealed a 3.8 cm saccular aneurysm of the celiac artery dissected in the superior wall with a consequent 4.3 cm pseudoaneurysm; we adopted an endovascular approach to exclude the lesion by catheterizing the celiac trunk and positioning a vascular plug in the common hepatic artery and a covered stent in the splenic artery; finally we fulfilled the aneurysm sac with Onyx. 30-day control CT scan revealed procedural success. Five years later he came back to our department for an aneurysm relapse in the common hepatic artery. We performed a second endovascular approach with a superselective catheterization of the pancreaticoduodenal arcade in order to exclude the lesion with Onyx and microcoils. Nowadays the patient is in good clinical conditions. Endovascular approach is a valuable method to treat visceral aneurysms; however, long-term imaging follow-up is essential to monitor the risk of relapse. PMID- 26124976 TI - Oral Calcidiol Is More Effective Than Cholecalciferol Supplementation to Reach Adequate 25(OH)D Levels in Patients with Autoimmune Diseases Chronically Treated with Low Doses of Glucocorticoids: A "Real-Life" Study. AB - Glucocorticoids (GCs) are the cornerstone of the therapy in many autoimmune and inflammatory diseases. However, it is well known that their use is a double edged sword, as their beneficial effects are associated almost universally with unwanted effects, as, for example glucocorticoid-induced osteoporosis (GIO). Over the last years, several clinical practice guidelines emphasize the need of preventing bone mass loss and reduce the incidence of fractures associated with GC use. Calcium and vitamin D supplementation, as adjunctive therapy, are included in all the practice guidelines. However, no standard vitamin D dose has been established. Several studies with postmenopausal women show that maintaining the levels above 30-33 ng/mL help improve the response to bisphosphonates. It is unknown if the response is the same in GIO, but in the clinical practice the levels are maintained at around the same values. In this study we demonstrate that patients with autoimmune diseases, undergoing glucocorticoid therapy, often present suboptimal 25(OH)D levels. Patients with higher body mass index and those receiving higher doses of glucocorticoids are at increased risk of having lower levels of 25(OH)D. In these patients, calcidiol supplementations are more effective than cholecalciferol to reach adequate 25(OH)D levels. PMID- 26124978 TI - Vascular contributions to cognitive impairment. AB - Unlike many neurodegenerative causes of cognitive impairment and dementia, vascular damage is preventable. Despite the heterogeneity of vascular cognitive impairment (VCI) and the complexity of its clinical presentations, the potential for limiting progression and changing the trajectory of damage makes it all the more important for physicians to be educated about the syndrome and to remain vigilant when taking care of patients. In this review, we outline an approach to patients with possible VCI, summarize current treatment and prevention guidelines, and provide an overview with case examples. PMID- 26124977 TI - Understanding spatial organizations of chromosomes via statistical analysis of Hi C data. AB - Understanding how chromosomes fold provides insights into the transcription regulation, hence, the functional state of the cell. Using the next generation sequencing technology, the recently developed Hi-C approach enables a global view of spatial chromatin organization in the nucleus, which substantially expands our knowledge about genome organization and function. However, due to multiple layers of biases, noises and uncertainties buried in the protocol of Hi-C experiments, analyzing and interpreting Hi-C data poses great challenges, and requires novel statistical methods to be developed. This article provides an overview of recent Hi-C studies and their impacts on biomedical research, describes major challenges in statistical analysis of Hi-C data, and discusses some perspectives for future research. PMID- 26124979 TI - HIV-associated neurocognitive disorders: Five new things. AB - HIV-associated neurocognitive disorders (HAND) remain an important cause of cognitive dysfunction. Current nomenclature for HAND includes HIV-associated dementia and milder forms known as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND). ANI and MND remain highly prevalent despite combined antiretroviral therapy (cART). These mild forms of HAND must be diagnosed through neuropsychological testing. If a patient has HAND, it remains unclear whether using a cART regimen with theoretically superior CNS penetration improves the prognosis. Nevertheless, a CNS penetration effectiveness score for antiretrovirals is available. Other factors to consider when diagnosing and treating HIV infection and HAND include the HIV clade or subtype. Data suggest that HAND occurs more often in association with certain clades, and higher vigilance for cognitive dysfunction may be recommended. Finally, comorbidities, such as diseases associated with advanced age, other infections, and drug abuse, need to be considered as cofactors for cognitive dysfunction and treated accordingly. PMID- 26124980 TI - Dystonia: Five new things. AB - There has been considerable progress in our understanding of dystonia over the last century. Growing recognition of dystonia has enhanced awareness of its diverse motor phenomenology and brought attention to the importance that nonmotor features may play in this disorder, once considered to be purely motor. Using the latest technologies in human genetics, new genetic links are being discovered at an ever-quickening pace and expanding our knowledge of the disorder's complex pathogenesis. Furthermore, as we gain clearer insight into the pathophysiology of dystonia and an appreciation of the involvement of dysfunction outside the basal ganglia, dystonia has been increasingly viewed as a network disorder. Here we briefly discuss some of the recent noteworthy advances. PMID- 26124981 TI - Providing neurologic care in criminal systems and state mental hospitals. AB - As health care laws and payment structures change in the near future, neurologists may pursue other practice settings in which to provide care as a way to diversify their practice. Here we describe the challenges and opportunities involved with working in correctional and state mental hospital systems compared to a typical private practice: logistical challenges, patient and provider safety, patient characteristics, and cultural differences. Neurologists may take these factors into consideration when choosing whether to add this health care setting to their current practice. PMID- 26124982 TI - Do efforts to decrease door-to-needle time risk increasing stroke mimic treatment rates? AB - An unintended consequence of rapid thrombolysis may be more frequent treatment of stroke mimics, nonvascular conditions that simulate stroke. We explored the relationship between door-to-needle (DTN) times and thrombolysis of stroke mimics at a single academic center by analyzing consecutive quartiles of patients who were treated with IV tissue plasminogen activator for suspected stroke from January 1, 2010 to February 28, 2014. An increase in the proportion of stroke mimic patients (6.7% in each of the 1st and 2nd, 12.9% in the 3rd, and 30% in the last consecutive case quartile; p = 0.03) and a decrease in median DTN time from 89 to 56 minutes (p < 0.01) was found. As more centers reduce DTN times, the rates of stroke mimic treatment should be carefully monitored. PMID- 26124983 TI - To treat or not to treat, that really is not the question. PMID- 26124984 TI - Cerebral bleed after shunt for normal pressure hydrocephalus with cerebral amyloid angiopathy: Coincidence or consequence? PMID- 26124985 TI - On the history of plasma treatment and comparison of microbiostatic efficacy of a historical high-frequency plasma device with two modern devices. AB - BACKGROUND: Cold atmospheric pressure plasma (CAP) with its many bioactive properties has defined a new medical field: the plasma medicine. However, in the related form of high-frequency therapy, CAP was even used briefly a century ago. The aim of this study was to review historic CAP treatments and to obtain data regarding the antimicrobial efficacy of a historical high-frequency plasma device. METHODS: First, historic literature regarding the history of CAP treatment was evaluated, because in the modern literature no data were available. Second, the susceptibility of 5 different bacterial wound isolates, cultured on agar, to a historic plasma source (violet wand [VW]) and two modern devices (atmospheric pressure plasma jet [APPJ] and Dielectric Barrier Discharge [DBD]) was analyzed . The obtained inhibition areas (IA) were compared. RESULTS: First, the most convenient popular historical electromedical treatments produced a so called effluvia by using glass electrodes, related to today's CAP. Second, all three tested plasma sources showed complete eradication of all tested microbial strains in the treated area. The "historical" cold VW plasma showed antimicrobial effects similar to those of modern APPJ and DBD regarding the diameter of the IA. CONCLUSION: Some retrograde evidence may be deducted from this, especially for treatment of infectious diseases with historical plasma devices. The underlying technology may serve as model for construction of modern sucessive devices. PMID- 26124986 TI - Analysis of antibiotic consumption in burn patients. AB - Infection control is very important in burn care units, because burn wound infection is one of the main causes of morbidity and mortality among burn patients. Thus, the appropriate prescription of antibiotics can be helpful, but unreasonable prescription can have detrimental consequences, including greater expenses to patients and community alike. The aim of this study was to determine the effect of antibiotic therapy on the emergence of antibiotic-resistant bacteria. 525 strains of Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus were isolated from 335 hospitalized burn patients. Antibiotic susceptibility tests were performed after identification the strains. The records of patients were audited to find the antibiotic used. The results indicated that P. aeruginosa is the most prevalent Gram-negative bacteria. Further, it showed a relation between abuse of antibiotics and emergence of antibiotic resistance. Control of resistance to antibiotics by appropriate prescription practices not only facilitates prevention of infection caused by multi-drug resistant (MDR) microorganisms, but it can also decrease the cost of treatment. PMID- 26124987 TI - The Role of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Understanding How Data Can Inform Clinical Practice in Korea. AB - Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce glycosylated hemoglobin (HbA1c, 0.5% to 1.0%), and are associated with moderate weight loss and a relatively low risk of hypoglycemia. There are differences between Asian and non-Asian populations. We reviewed available data on GLP-1RAs, focusing on Korean patients, to better understand their risk/benefit profile and help inform local clinical practice. Control of postprandial hyperglycemia is important in Asians in whom the prevalence of post-challenge hyperglycemia is higher (vs. non Asians). The weight lowering effects of GLP-1RAs are becoming more salient as the prevalence of overweight and obesity among Korean patients increases. The higher rate of gastrointestinal adverse events amongst Asian patients in clinical trials may be caused by higher drug exposure due to the lower body mass index of the participants (vs. non-Asian studies). Data on the durability of weight loss, clinically important health outcomes, safety and optimal dosing in Korean patients are lacking. Use of GLP-1RAs is appropriate in several patient groups, including patients whose HbA1c is uncontrolled, especially if this is due to postprandial glucose excursions and patients who are overweight or obese due to dietary problems (e.g., appetite control). The potential for gastrointestinal adverse events should be explained to patients at treatment initiation to facilitate the promotion of better compliance. PMID- 26124990 TI - Dipeptidyl Peptidase-4 Inhibitor Alarms: Is Heart Failure Caused by a Class Effect? PMID- 26124989 TI - Gut Microbiota and Metabolic Disorders. AB - Gut microbiota plays critical physiological roles in the energy extraction and in the control of local or systemic immunity. Gut microbiota and its disturbance also appear to be involved in the pathogenesis of diverse diseases including metabolic disorders, gastrointestinal diseases, cancer, etc. In the metabolic point of view, gut microbiota can modulate lipid accumulation, lipopolysaccharide content and the production of short-chain fatty acids that affect food intake, inflammatory tone, or insulin signaling. Several strategies have been developed to change gut microbiota such as prebiotics, probiotics, certain antidiabetic drugs or fecal microbiota transplantation, which have diverse effects on body metabolism and on the development of metabolic disorders. PMID- 26124988 TI - Pyruvate Dehydrogenase Kinases: Therapeutic Targets for Diabetes and Cancers. AB - Impaired glucose homeostasis is one of the risk factors for causing metabolic diseases including obesity, type 2 diabetes, and cancers. In glucose metabolism, pyruvate dehydrogenase complex (PDC) mediates a major regulatory step, an irreversible reaction of oxidative decarboxylation of pyruvate to acetyl-CoA. Tight control of PDC is critical because it plays a key role in glucose disposal. PDC activity is tightly regulated using phosphorylation by pyruvate dehydrogenase kinases (PDK1 to 4) and pyruvate dehydrogenase phosphatases (PDP1 and 2). PDKs and PDPs exhibit unique tissue expression patterns, kinetic properties, and sensitivities to regulatory molecules. During the last decades, the up-regulation of PDKs has been observed in the tissues of patients and mammals with metabolic diseases, which suggests that the inhibition of these kinases may have beneficial effects for treating metabolic diseases. This review summarizes the recent advances in the role of specific PDK isoenzymes on the induction of metabolic diseases and describes the effects of PDK inhibition on the prevention of metabolic diseases using pharmacological inhibitors. Based on these reports, PDK isoenzymes are strong therapeutic targets for preventing and treating metabolic diseases. PMID- 26124991 TI - A Smartphone Application Significantly Improved Diabetes Self-Care Activities with High User Satisfaction. AB - BACKGROUND: We developed for the first time a smartphone application designed for diabetes self-management in Korea and registered a patent for the relevant algorithm. We also investigated the user satisfaction with the application and the change in diabetes related self-care activities after using the application. METHODS: We conducted a questionnaire survey on volunteers with diabetes who were using the application. Ninety subjects responded to the questionnaire between June 2012 and March 2013. A modified version of the Summary of Diabetes Self-Care Activities (SDSCA) was used in this study. RESULTS: The survey results exhibited a mean subject age of 44.0 years old, and males accounted for 78.9% of the subjects. Fifty percent of the subjects had diabetes for less than 3 years. The majority of respondents experienced positive changes in their clinical course after using the application (83.1%) and were satisfied with the structure and completeness of the application (86.7%). Additionally, the respondents' answers indicated that the application was easy to use (96.7%) and recommendable to others (97.7%) and that they would continue using the application to manage their diabetes (96.7%). After using the Diabetes Notepad application, diabetes related self-care activities assessed by SDSCA displayed statistically significant improvements (P<0.05), except for the number of days of drinking. CONCLUSION: This smartphone-based application can be a useful tool leading to positive changes in diabetes related self-care activities and increase user satisfaction. PMID- 26124992 TI - Prevalence of Depression and Glucose Abnormality in an Urbanizing Rural Population of Bangladesh. AB - BACKGROUND: Depression and glucose abnormality are increasing in Bangladesh including its rural area. This study was designed to determine the prevalence of depression in an urbanizing rural population of Bangladesh with or without glucose abnormality (including diabetes mellitus [DM], and pre-diabetes which combines impaired fasting glucose and impaired glucose tolerance pre-DM). METHODS: A total of 2,293 subjects aged >=20 years were investigated. Sociodemographic and anthropometric details, blood pressure, fasting (fasting plasma glucose) and 2 hours after 75 g plasma glucose (2-hour plasma glucose), were studied. Montgomery-Asberg Depression Rating Scale was used to assess depression. RESULTS: The overall prevalence of DM was 7.9% and pre-DM was 8.6%. Prevalence of depression was 15.31% (n=351; 95% confidence interval [CI], 1.59 to 1.36) with mean depressive score 17.62+/-3.49. Female were more likely to have depression (17.16%). The 22.35% of male and 29.46% of female with pre-DM and 26.58% male and 36.27% female with DM had depressive symptoms. There was no significant variation in the mean age of different groups (healthy, depressed and with glucose abnormality). Depression was significantly associated with age, marital status, occupation, high physical activity, and low body mass index. The odds ratio (OR) for depression was significantly increased in patients with glucose abnormality compared with those without pre-DM (OR, 2.49; 95% CI, 1.76 to 3.51; P<0.000) and DM (OR, 3.27; 95% CI, 2.33 to 4.60; P<0.000). CONCLUSION: Prevalence of depression found alarming in our study area though lesser than previous studies and it is significantly related to glucose abnormality. The study reveals that mental health should get more focused specially along with metabolic diseases. PMID- 26124993 TI - Serum Ceruloplasmin Level as a Predictor for the Progression of Diabetic Nephropathy in Korean Men with Type 2 Diabetes Mellitus. AB - BACKGROUND: Oxidative stress is known to be associated with progression of diabetic kidney disease. Ceruloplasmin acts as a pro-oxidant under conditions of severe oxidative stress. Thus, we conducted a longitudinal observational study to evaluate whether the serum ceruloplasmin level is a predictive biomarker for progression of diabetic nephropathy. METHODS: A total of 643 Korean men with type 2 diabetes mellitus were enrolled. Serum ceruloplasmin was measured using a nephelometric method. Progression of diabetic nephropathy was defined as transition in albuminuria class (i.e., normoalbuminuria to microalbuminuria, microalbuminuria to macroalbuminuria, or normoalbuminuria to macroalbuminuria) and/or a greater than 2-fold increase of serum creatinine at follow-up compared with the baseline value. RESULTS: During the follow-up period (median, 2.7 years; range, 0.3 to 4.4 years), 49 of 643 patients (7.6%) showed the progression of diabetic nephropathy and three patients (0.5%) developed end-stage renal disease. Baseline ceruloplasmin levels were higher in the progressors than in the nonprogressors (262.6+/-40.9 mg/L vs. 233.3+/-37.8 mg/L, P<0.001). Kaplan-Meier analysis showed a significantly higher incidence of nephropathy progression according to ceruloplasmin tertile (log-rank test, P<0.001). The hazard ratio (HR) for progression of diabetic nephropathy was significantly higher in the highest ceruloplasmin tertile category compared with the lowest ceruloplasmin tertile category, even after adjusting for confounding variables (HR, 3.32; 95% confidence interval, 1.28 to 8.61; P=0.003). CONCLUSION: Baseline serum ceruloplasmin is an independent predictive factor for the progression of diabetic nephropathy in patients with type 2 diabetes mellitus. PMID- 26124994 TI - The Relationship between Anemia and the Initiation of Dialysis in Patients with Type 2 Diabetic Nephropathy. AB - BACKGROUND: Anemia is associated with various poor clinical outcomes in chronic kidney disease patients. The aim of this study was to investigate the relationship between anemia and the initiation degree and time of dialysis in type 2 diabetic nephropathy patients. METHODS: This observational retrospective study included 130 type 2 diabetic nephropathy patients in Korea. The existence of anemia, the degree and time of dialysis initiation were reviewed. Clinical characteristics and variables were also compared. RESULTS: The levels of hemoglobin and serum creatinine were significantly correlated with the dialysis initiation (P<0.05) during the 10-year follow-up period. Patients with anemia showed rapid decline of renal function, causing significantly more dialysis initiation (54.1% vs. 5.4%, P<0.05) compare to the patients without anemia. Average time to initiate dialysis in patients with anemia was 45.1 months (range, 8.0 to 115.8 months), which was significantly faster than that (68.3 months [range, 23.3 to 108.8 months]) in patients without anemia (P<0.01). The risk to dialysis initiation was significantly increased in patients with anemia compared to the patients without anemia (adjusted hazard ratio, 8.1; 95% confidence interval, 2.4 to 27.0; P<0.05). CONCLUSION: Anemia is associated with rapid decline of renal dysfunction and faster initiation of dialysis in diabetic nephropathy patients. Therefore, clinicians should pay an earlier attention to anemia during the management of diabetes. PMID- 26124995 TI - Increased Risk of Hospitalization for Heart Failure with Newly Prescribed Dipeptidyl Peptidase-4 Inhibitors and Pioglitazone Using the Korean Health Insurance Claims Database. AB - BACKGROUND: We assessed the association of dipeptidyl peptidase 4 inhibitors (DPP4i) with hospitalization for heart failure (HF) using the Korean Health Insurance claims database. METHODS: We collected data on newly prescribed sitagliptin, vildagliptin, and pioglitazone between January 1, 2009 and December 31, 2012 (mean follow-up of 336.8 days) to 935,519 patients with diabetes (518,614 males and 416,905 females) aged 40 to 79 years (mean age of 59.4 years). RESULTS: During the study, 998 patients were hospitalized for primary HF (115.7 per 100,000 patient-years). The incidence rate of hospitalization for HF was 117.7 per 100,000 per patient-years among patients on pioglitazone, 105.7 for sitagliptin, and 135.8 for vildagliptin. The hospitalization rate for HF was greatest in the first 30 days after starting the medication, which corresponded to a significantly higher incidence at days 0 to 30 compared with days 31 to 360 for all three drugs. The hazard ratios were 1.85 (pioglitazone), 2.00 (sitagliptin), and 1.79 (vildagliptin). The incidence of hospitalization for HF did not differ between the drugs for any time period. CONCLUSION: This study showed an increase in hospitalization for HF in the initial 30 days of the DPP4i and pioglitazone compared with the subsequent follow-up period. However, the differences between the drugs were not significant. PMID- 26124996 TI - Optimal Waist Circumference Cutoff Value Based on Insulin Resistance and Visceral Obesity in Koreans with Type 2 Diabetes. AB - BACKGROUND: Visceral obesity is the most powerful contributor to the development of metabolic syndrome (MetS) and cardiovascular diseases. In light of visceral obesity, however, there is a paucity of data on the appropriate cutoff point of waist circumference (WC) in subjects with type 2 diabetes. The aim of this study was to investigate the optimal cutoff value for WC that signals insulin resistance (IR) and visceral obesity in Koreans with type 2 diabetes. METHODS: We evaluated 4,252 patients with type 2 diabetes (male 2,220, female 2,032, mean age 57.24 years) who visited our clinic between January 2003 and June 2009. WC was measured at the midpoint between the lower rib and the iliac crest, and insulin sensitivity was assessed by the rate constant of plasma glucose disappearance (Kitt %/min) using an insulin tolerance test. Visceral fat thickness was measured using ultrasonography. Statistical analysis was performed using receiver operating characteristic curve. RESULTS: The optimal cutoff points for WC for identifying the presence of IR and visceral obesity, as well as two or more metabolic components, were 87 cm for men and 81 cm for women. Moreover, these cutoff points had the highest predictive powers for the presence of visceral obesity. The MetS defined by new criteria correlated with the increased carotid intima-media thickness in female subjects. CONCLUSION: Our results suggest that the optimal cutoff values for WC in Koreans with type 2 diabetes should be reestablished based on IR and visceral obesity. PMID- 26124997 TI - Effect of Low Frequency Neuromuscular Electrical Stimulation on Glucose Profile of Persons with Type 2 Diabetes: A Pilot Study. AB - The purpose of this study was to examine the effect of low-frequency neuromuscular electrical stimulation (NMES) on glucose profile in persons with type 2 diabetes mellitus (T2DM). Eight persons with T2DM (41 to 65 years) completed a glucose tolerance test with and without NMES delivered to the knee extensors for a 1-hour period at 8 Hz. Three blood samples were collected: at rest, and then 60 and 120 minutes after consumption of a glucose load on the NMES and control days. In NMES groups glucose concentrations were significantly lower (P<0.01) than in the control conditions. Moreover, a significant positive correlation (r=0.9, P<0.01) was obtained between the intensity of stimulation and changes in blood glucose. Our results suggest that low-frequency stimulation seem suitable to induce enhance glucose uptake in persons with T2DM. Moreover, the intensity of stimulation reflecting the motor contraction should be considered during NMES procedure. PMID- 26124998 TI - Letter: Normal Glucose Tolerance with a High 1-Hour Postload Plasma Glucose Level Exhibits Decreased beta-Cell Function Similar to Impaired Glucose Tolerance (Diabetes Metab J 2015;39:147-53). PMID- 26124999 TI - Response: Normal Glucose Tolerance with a High 1-Hour Postload Plasma Glucose Level Exhibits Decreased beta-Cell Function Similar to Impaired Glucose Tolerance (Diabetes Metab J 2015;39:147-53). PMID- 26125000 TI - Corrigendum: Increasing Prevalence of Type 2 Diabetes in a Rural Bangladeshi Population: A Population Based Study for 10 Years. AB - [This corrects the article on p. 46 in vol. 37, PMID: 23439676.]. PMID- 26125001 TI - Evaluation of linear measurements of implant sites based on head orientation during acquisition: An ex vivo study using cone-beam computed tomography. AB - PURPOSE: This study evaluated the effect of various head orientations during cone beam computed tomography (CBCT) image acquisition on linear measurements of potential implant sites. MATERIALS AND METHODS: Six dry human skulls with a total of 28 implant sites were evaluated for seven different head orientations. The scans were acquired using a Hitachi CB-MercuRay CBCT machine. The scanned volumes were reconstructed. Horizontal and vertical measurements were made and were compared to measurements made after simulating the head position to corrected head angulations. Data was analyzed using a two-way ANOVA test. RESULTS: Statistical analysis revealed a significant interaction between the mean errors in vertical measurements with a marked difference observed at the extension head position (P<0.05). Statistical analysis failed to yield any significant interaction between the mean errors in horizontal measurements at various head positions. CONCLUSION: Head orientation could significantly affect the vertical measurements in CBCT scans. The main head position influencing the measurements is extension. PMID- 26125002 TI - The effects of noise reduction, sharpening, enhancement, and image magnification on diagnostic accuracy of a photostimulable phosphor system in the detection of non-cavitated approximal dental caries. AB - PURPOSE: Contrast, sharpness, enhancement, and density can be changed in digital systems. The important question is to what extent the changes in these variables affect the accuracy of caries detection. MATERIALS AND METHODS: Forty eight extracted human posterior teeth with healthy or proximal caries surfaces were imaged using a photostimulable phosphor (PSP) sensor. All original images were processed using a six-step method: (1) applying "Sharpening 2" and "Noise Reduction" processing options to the original images; (2) applying the "Magnification 1:3" option to the image obtained in the first step; (3) enhancing the original images by using the "Diagonal/" option; (4) reviewing the changes brought about by the third step of image processing and then, applying "Magnification 1:3"; (5) applying "Sharpening UM" to the original images; and (6) analyzing the changes brought about by the fifth step of image processing, and finally, applying "Magnification 1:3." Three observers evaluated the images. The tooth sections were evaluated histologically as the gold standard. The diagnostic accuracy of the observers was compared using a chi-squared test. RESULTS: The accuracy levels irrespective of the image processing method ranged from weak (18.8%) to intermediate (54.2%), but the highest accuracy was achieved at the sixth image processing step. The overall diagnostic accuracy level showed a statistically significant difference (p=0.0001). CONCLUSION: This study shows that the application of "Sharpening UM" along with the "Magnification 1:3" processing option improved the diagnostic accuracy and the observer agreement more effectively than the other processing procedures. PMID- 26125003 TI - Can pterygoid plate asymmetry be linked to temporomandibular joint disorders? AB - PURPOSE: This study was performed to evaluate the relationship between pterygoid plate asymmetry and temporomandibular joint disorders. MATERIALS AND METHODS: Cone-beam computed tomography (CBCT) images of 60 patients with temporomandibular disorders (TMD) involving pain were analyzed and compared with images of 60 age- and gender-matched controls. Three observers performed linear measurements of the lateral pterygoid plates. RESULTS: Statistically significant differences were found between measurements of the lateral pterygoid plates on the site that had pain and the contralateral site (p<0.05). The average length of the lateral pterygoid plates (LPPs) in patients with TMD was 17.01+/-3.64 mm on the right side and 16.21+/-3.51 mm on the left side, and in patients without TMD, it was 11.86+/-1.97 mm on the right side and 11.98+/-1.85 mm on the left side. Statistically significant differences in the LPP length, measured on CBCT, were found between patients with and without TMD (p<0.05). The inter-examiner reliability obtained in this study was very high for all the examiners (0.99, 95% confidence interval: 0.98-0.99). CONCLUSION: Within the limits of the present study, CBCT lateral pterygoid plate measurements at the side with TMD were found to be significantly different from those on the side without TMD. More research is needed to explore potential etiological correlations and implications for treatment. PMID- 26125004 TI - Characterization of mandibular molar root and canal morphology using cone beam computed tomography and its variability in Belgian and Chilean population samples. AB - PURPOSE: This study used cone-beam computed tomography (CBCT) to characterize mandibular molar root and canal morphology and its variability in Belgian and Chilean population samples. MATERIALS AND METHODS: We analyzed the CBCT images of 515 mandibular molars (257 from Belgium and 258 from Chile). Molars meeting the inclusion criteria were analyzed to determine (1) the number of roots; (2) the root canal configuration; (3) the presence of a curved canal in the cross sectional image of the distal root in the mandibular first molar and (4) the presence of a C-shaped canal in the second mandibular molar. A descriptive analysis was performed. The association between national origin and the presence of a curved or C-shaped canal was evaluated using the chi-squared test. RESULTS: The most common configurations in the mesial root of both molars were type V and type III. In the distal root, type I canal configuration was the most common. Curvature in the cross-sectional image was found in 25% of the distal canals of the mandibular first molars in the Belgian population, compared to 11% in the Chilean population. The prevalence of C-shaped canals was 10% or less in both populations. CONCLUSION: In cases of unclear or complex root and canal morphology in the mandibular molars, CBCT imaging might assist endodontic specialists in making an accurate diagnosis and in treatment planning. PMID- 26125005 TI - Severe bony ankylosis of the temporomandibular joint on one side and contralateral adhesion: A case report. AB - Bony fusion between the mandibular condyle and skull base involves temporomandibular joint (TMJ) bony ankylosis. This condition might originate from trauma, infection, or systemic disease. TMJ adhesion can develop after synovial damage. Both TMJ ankylosis and adhesion lead to functional impairment and pain. Here, we present a case of a 50-year-old female who had bony ankylosis of the right TMJ and adhesion of the left TMJ. She had otitis media in the right ear. A large mass in the right TMJ was observed on computed tomograph. Magnetic resonance image showed a large fused bone mass with normal bone marrow in the right TMJ and flattening of the condyle with a thin disk in the left TMJ. Gap arthroplasty with temporal fascia was performed on the right TMJ, and discectomy, high condylectomy, and coronoidectomy were performed on the left TMJ. During a 2 year follow-up after surgery, the patient had no recurrence. PMID- 26125006 TI - Central odontogenic fibroma (simple type) in a four-year-old boy: atypical cone beam computed tomographic appearance with periosteal reaction. AB - Central odontogenic fibroma (COF) is a rare benign tumor that accounts for 0.1% of all odontogenic tumors. A case of COF (simple type) of the mandible in a four year-old boy is described in this report. The patient showed asymptomatic swelling in the right inferior border of the lower jaw for one week. A panoramic radiograph showed a poorly-defined destructive unilocular radiolucent area. Cone beam computed tomography showed expansion and perforation of the adjacent cortical bone plates. A periosteal reaction with the Codman triangle pattern was clearly visible in the buccal cortex. Since the tumor had destroyed a considerable amount of bone, surgical resection was performed. No recurrence was noted. PMID- 26125007 TI - A new bite block for panoramic radiographs of anterior edentulous patients: A technical report. AB - PURPOSE: Panoramic radiographs taken using conventional chin-support devices have often presented problems with positioning accuracy and reproducibility. The aim of this report was to propose a new bite block for panoramic radiographs of anterior edentulous patients that better addresses these two issues. MATERIALS AND METHODS: A new panoramic radiography bite block similar to the bite block for dentulous patients was developed to enable proper positioning stability for edentulous patients. The new bite block was designed and implemented in light of previous studies. The height of the new bite block was 18 mm and to compensate for the horizontal edentulous space, its horizontal width was 7 mm. The panoramic radiographs using the new bite block were compared with those using the conventional chin-support device. RESULTS: Panoramic radiographs taken with the new bite block showed better stability and bilateral symmetry than those taken with the conventional chin-support device. Patients also showed less movement and more stable positioning during panoramic radiography with the new bite block. CONCLUSION: Conventional errors in panoramic radiographs of edentulous patients could be caused by unreliability of the chin-support device. The newly proposed bite block for panoramic radiographs of edentulous patients showed better reliability. Further study is required to evaluate the image quality and reproducibility of images with the new bite block. PMID- 26125008 TI - The current approach to the diagnosis of vascular anomalies of the head and neck: A pictorial essay. AB - Throughout the years, various classifications have evolved for the diagnosis of vascular anomalies. However, it remains difficult to classify a number of such lesions. Because all hemangiomas were previously considered to involute, if a lesion with imaging and clinical characteristics of hemangioma does not involute, then there is no subclass in which to classify such a lesion, as reported in one of our cases. The recent classification proposed by the International Society for the Study of Vascular Anomalies (ISSVA, 2014) has solved this problem by including non-involuting and partially involuting hemangioma in the classification. We present here five cases of vascular anomalies and discuss their diagnosis in accordance with the ISSVA (2014) classification. A non involuting lesion should not always be diagnosed as a vascular malformation. A non-involuting lesion can be either a hemangioma or a vascular malformation depending upon its clinicopathologic and imaging characteristics. PMID- 26125009 TI - Level of knowledge of dental practitioners in Isfahan, Iran about cone-beam computed tomography and digital radiography. PMID- 26125010 TI - Re: Byung-Do Lee, Wan Lee, Kyung-Hwan Kwon, Moon-Ki Choi, Eun-Joo Choi and Jung Hoon Yoon. Glandular odontogenic cyst mimicking ameloblastoma in a 78-year-old female: A case report. Imaging Science in Dentistry 2014; 44(3): 249-52. PMID- 26125011 TI - Response to letter to the editors "Re: Byung-Do Lee, Wan Lee, Kyung-Hwan Kwon, Moon-Ki Choi, Eun-Joo Choi and Jung-Hoon Yoon. Glandular odontogenic cyst mimicking ameloblastoma in a 78-year-old female: a case report. Imaging Science in Dentistry 2014; 44(3): 249-52.". PMID- 26125012 TI - Concurrent Diabetes Mellitus may Negatively Influence Clinical Progression and Response to Androgen Deprivation Therapy in Patients with Advanced Prostate Cancer. AB - OBJECTIVE: To determine if a concurrent diagnosis of diabetes mellitus is associated with worse outcomes in advanced prostate cancer (PC). The effect diabetes may have on the progression of advanced PC is poorly understood. METHODS: Data on 148 advanced PC patients (35 with concurrent diabetes) were collected from an institutional database to obtain diabetic status, data on treatment types and durations, and prostate-specific antigen (PSA) values before, during, and after treatment. Time to castration resistance following the onset of androgen deprivation therapy (ADT) and overall survival (OS) in patients with and without diabetes were compared using univariate Cox regression analyses as the primary endpoints. Differences in PSA response to treatments were compared using chi-squared tests as a secondary endpoint. RESULTS: With a median follow-up of 29 months, time to castration resistance did not differ significantly between patients with and without diabetes who underwent ADT. However, in a subset of patients who received ADT without radiographic evidence of metastases (N = 47), those with diabetes progressed to castration-resistant disease more quickly than those without DM (hazard ratio for progression with diabetes = 4.58; 95% CI: 1.92 10.94; p = 0.0006). Also, a lower percentage of patients undergoing ADT with diabetes had PSA declines of at least 50% (p = 0.17) and reached a nadir PSA <0.2 ng/mL (p = 0.06). OS did not differ based on diabetic status. No differences were seen in response to first-line therapy for castration-resistant prostate cancer. CONCLUSION: Diabetes mellitus may have a detrimental effect on progression of advanced PC, particularly in those patients without radiographic evidence of metastases. Further study is necessary to fully elucidate the effect of diabetes on PC outcomes. PMID- 26125013 TI - Episensitization: Defying Time's Arrow. AB - The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of "episensitization," or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses, and RRx-001. PMID- 26125014 TI - Nutritional Status in Children with Un-Operated Congenital Heart Disease: An Egyptian Center Experience. AB - BACKGROUND: Malnutrition is a common cause of morbidity and mortality in children with congenital heart disease (CHD). This study aimed to identify prevalence and predictors of malnutrition in Egyptian children with symptomatic CHD. METHODS: This case-control study included 100 children with symptomatic CHD (76 acyanotic and 24 cyanotic) and 100 healthy children matched for age and sex as a control group. Clinical Evaluation and Laboratory Assessment of Nutritional Status were documented. Anthropometric measurements were recorded and Z scores for weight for age (WAZ), weight for height (WHZ), and height for age (HAZ) have been calculated. Malnutrition was defined as weight, height, and weight/height Z score <=-2. RESULTS: The overall prevalence of malnutrition was 84.0% in patients with CHD and 20% in controls. Severe malnutrition was diagnosed in 71.4% of cases. All anthropometric measurements and levels of biochemical markers of nutritional state were significantly lower in the patients group compared to controls. In patients with acyanotic CHD, stunting was proportionately higher (57.89%) than in cyanotic CHD, while wasting was predominant (45.83%) in the latter. Malnutrition correlated significantly with low hemoglobin level, low arterial oxygen saturation, heart failure, pulmonary hypertension, and poor dietary history. CONCLUSION: Malnutrition is a very common problem in children with symptomatic CHD and predicted by the presence of low hemoglobin level, low arterial oxygen saturation, heart failure, poor dietary history, and pulmonary hypertension. PMID- 26125015 TI - Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology. AB - Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future. PMID- 26125016 TI - Dental Services Funding and Affordability in Serbia - Decade-Long Perspective. PMID- 26125017 TI - Universal Free School Breakfast: A Qualitative Model for Breakfast Behaviors. AB - In recent years, the provision of school breakfast has increased significantly in the UK. However, research examining the effectiveness of school breakfast is still within relative stages of infancy, and findings to date have been rather mixed. Moreover, previous evaluations of school breakfast schemes have been predominantly quantitative in their methodologies. Currently, there are few qualitative studies examining the subjective perceptions and experiences of stakeholders, and thereby an absence of knowledge regarding the sociocultural impacts of school breakfast. The purpose of this study was to investigate the beliefs, views and attitudes, and breakfast consumption behaviors, among key stakeholders, served by a council-wide universal free school breakfast initiative, within the North West of England, UK. A sample of children, parents, and school staff were recruited from three primary schools, participating in the universal free school breakfast scheme, to partake in semi-structured interviews and small focus groups. A Grounded Theory analysis of the data collected identified a theoretical model of breakfast behaviors, underpinned by the subjective perceptions and experiences of these key stakeholders. The model comprises of three domains relating to breakfast behaviors, and the internal and external factors that are perceived to influence breakfast behaviors, among children, parents, and school staff. Findings were validated using triangulation methods, member checks, and inter-rater reliability measures. In presenting this theoretically grounded model for breakfast behaviors, this paper provides a unique qualitative insight into the breakfast consumption behaviors and barriers to breakfast consumption, within a socioeconomically deprived community, participating in a universal free school breakfast intervention program. PMID- 26125018 TI - The Spillover of US Immigration Policy on Citizens and Permanent Residents of Mexican Descent: How Internalizing "Illegality" Impacts Public Health in the Borderlands. AB - BACKGROUND: The militarization of the US-Mexico border region exacerbates the process of "Othering" Latino immigrants - as "illegal aliens." The internalization of "illegality" can manifest as a sense of "undeservingness" of legal protection in the population and be detrimental on a biopsychological level. OBJECTIVE: We explore the impacts of "illegality" among a population of US citizen and permanent resident farmworkers of Mexican descent. We do so through the lens of immigration enforcement-related stress and the ability to file formal complaints of discrimination and mistreatment perpetrated by local immigration enforcement agents, including local police authorized to enforce immigration law. METHODS: Drawing from cross-sectional data gathered through the National Institute of Occupation Safety and Health, "Challenges to Farmworker Health at the US-Mexico Border" study, a community-based participatory research project conducted at the Arizona-Sonora border, we compared Arizona resident farmworkers (N = 349) to Mexico-based farmworkers (N = 140) or Transnational farmworkers who cross the US-Mexico border daily or weekly to work in US agriculture. RESULTS: Both samples of farmworkers experience significant levels of stress in anticipation of encounters with immigration officials. Fear was cited as the greatest factor preventing individuals from reporting immigration abuses. The groups varied slightly in the relative weight attributed to different types of fear. CONCLUSION: The militarization of the border has consequences for individuals who are not the target of immigration enforcement. These spillover effects cause harm to farmworkers in multiple ways. Multi-institutional and community-centered systems for reporting immigration-related victimization is required. Applied participatory research with affected communities can mitigate the public health effects of state-sponsored immigration discrimination and violence among US citizen and permanent residents. PMID- 26125019 TI - An Investigation of Bilateral Symmetry During Manual Wheelchair Propulsion. AB - Studies of manual wheelchair propulsion often assume bilateral symmetry to simplify data collection, processing, and analysis. However, the validity of this assumption is unclear. Most investigations of wheelchair propulsion symmetry have been limited by a relatively small sample size and a focus on a single propulsion condition (e.g., level propulsion at self-selected speed). The purpose of this study was to evaluate bilateral symmetry during manual wheelchair propulsion in a large group of subjects across different propulsion conditions. Three-dimensional kinematics and handrim kinetics along with spatiotemporal variables were collected and processed from 80 subjects with paraplegia while propelling their wheelchairs on a stationary ergometer during three different conditions: level propulsion at their self-selected speed (free), level propulsion at their fastest comfortable speed (fast), and propulsion on an 8% grade at their level, self selected speed (graded). All kinematic variables had significant side-to-side differences, primarily in the graded condition. Push angle was the only spatiotemporal variable with a significant side-to-side difference, and only during the graded condition. No kinetic variables had significant side-to-side differences. The magnitudes of the kinematic differences were low, with only one difference exceeding 5 degrees . With differences of such small magnitude, the bilateral symmetry assumption appears to be reasonable during manual wheelchair propulsion in subjects without significant upper-extremity pain or impairment. However, larger asymmetries may exist in individuals with secondary injuries and pain in their upper extremity and different etiologies of their neurological impairment. PMID- 26125020 TI - MetabNet: An R Package for Metabolic Association Analysis of High-Resolution Metabolomics Data. AB - Liquid-chromatography high-resolution mass spectrometry provides capability to measure >40,000 ions derived from metabolites in biologic samples. This presents challenges to confirm identities of known chemicals and delineate potential metabolic pathway associations of unidentified chemicals. We provide an R package for metabolic network analysis, MetabNet, to perform targeted metabolome-wide association study of specific metabolites to facilitate detection of their related metabolic pathways and network structures. PMID- 26125021 TI - Metal-Based Nanoparticles and the Immune System: Activation, Inflammation, and Potential Applications. AB - Nanomaterials, including metal-based nanoparticles, are used for various biological and medical applications. However, metals affect immune functions in many animal species including humans. Different physical and chemical properties induce different cellular responses, such as cellular uptake and intracellular biodistribution, leading to the different immune responses. The goals of this review are to summarize and discuss the innate and adaptive immune responses triggered by metal-based nanoparticles in a variety of immune system models. PMID- 26125022 TI - Three-Day Continuous Exposure Monitoring of CNT Manufacturing Workplaces. AB - Continuous monitoring for possible exposure to carbon nanotubes was conducted over a period of 2 to 3 days at workplaces that manufacture multiwall carbon nanotubes (MWCNTs) and single wall carbon nanotubes (SWCNTs). To estimate the potential emission of carbon nanotubes (CNTs) and potential exposure of workers, personal sampling, area monitoring, and real-time monitoring using an scanning mobility particle sizer (SMPS) and dust monitor were conducted at workplaces where the workers manufactured CNTs. The personal and area sampling of the total suspended particulate (TSP) at the MWCNT manufacturing facilities ranged from 0.031 to 0.254 and from N.D (not detected) to 0.253 mg/m(3), respectively. This 2 to 3-day monitoring study found that nanoparticles were released when opening the chemical vapor deposit (CVD) reactor door after the synthesis of MWCNTs, when transferring the MWCNTs to containers and during blending and grinding. However, distinguishing the background concentration from the work process particle emission was complicated due to sustained and even increased particle concentrations after the work processes were terminated. The MWCNTs sampled for transmission electron microscopy (TEM) observation exhibited a tangled shape with no individual dispersed CNT structures. PMID- 26125023 TI - Micro- and Nanosized Particles in Nasal Mucosa: A Pilot Study. AB - OBJECTIVE: The aim of this prospective study is to evaluate presence and quantity of micro- and nanosized particles (NPs) and interindividual differences in their distribution and composition in nasal mucosa. METHODS: Six samples of nasal mucosa obtained by mucotomy from patients with chronic hypertrophic rhinosinusitis were examined. Samples divided into 4 parts according to the distance from the nostrils were analyzed by scanning electron microscopy and Raman microspectroscopy to detect solid particles and characterize their morphology and composition. A novel method of quantification of the particles was designed and used to evaluate interindividual differences in distribution of the particles. The findings were compared with patients' employment history. RESULTS: In all the samples, NPs of different elemental composition were found (iron, barium, copper, titanium, etc.), predominantly in the parts most distant from nostrils, in various depths from the surface of the mucosa and interindividual differences in their quantity and composition were found, possibly in relation to professional exposition. CONCLUSIONS: This study has proven the possibility of quantification of distribution of micro- and nanosized particles in tissue samples and that the NPs may deposit in deeper layers of mucosa and their elemental composition may be related to professional exposition to the sources of NPs. PMID- 26125024 TI - Workplace Exposure to Titanium Dioxide Nanopowder Released from a Bag Filter System. AB - Many researchers who use laboratory-scale synthesis systems to manufacture nanomaterials could be easily exposed to airborne nanomaterials during the research and development stage. This study used various real-time aerosol detectors to investigate the presence of nanoaerosols in a laboratory used to manufacture titanium dioxide (TiO2). The TiO2 nanopowders were produced via flame synthesis and collected by a bag filter system for subsequent harvesting. Highly concentrated nanopowders were released from the outlet of the bag filter system into the laboratory. The fractional particle collection efficiency of the bag filter system was only 20% at particle diameter of 100 nm, which is much lower than the performance of a high-efficiency particulate air (HEPA) filter. Furthermore, the laboratory hood system was inadequate to fully exhaust the air discharged from the bag filter system. Unbalanced air flow rates between bag filter and laboratory hood systems could result in high exposure to nanopowder in laboratory settings. Finally, we simulated behavior of nanopowders released in the laboratory using computational fluid dynamics (CFD). PMID- 26125025 TI - Aquatic Toxicity Comparison of Silver Nanoparticles and Silver Nanowires. AB - To better understand the potential ecotoxicological impact of silver nanoparticles (AgNPs) and silver nanowires (AgNWs) released into freshwater environments, the toxicities of these nanomaterials were assessed and compared using Organization for Economic Cooperation and Development (OECD) test guidelines, including a "Daphnia sp., acute immobilization test," "Fish, acute toxicity test," and "freshwater alga and cyanobacteria, growth inhibition test." Based on the estimated median lethal/effective concentrations of AgNPs and AgNWs, the susceptibility to the nanomaterials was different among test organisms (daphnia > algae > fish), suggesting that the AgNPs are classified as "category acute 1" for Daphnia magna, "category acute 2" for Oryzias latipes, and "category acute 1" for Raphidocelis subcapitata, while the AgNWs are classified as "category acute 1" for Daphnia magna, "category acute 2" for Oryzias latipes, and "category acute 2" for Raphidocelis subcapitata, according to the GHS (Globally Harmonized System of Classification and Labelling of Chemicals). In conclusion, the present results suggest that more attention should be paid to prevent the accidental or intentional release of silver nanomaterials into freshwater aquatic environments. PMID- 26125026 TI - Trends in IT Innovation to Build a Next Generation Bioinformatics Solution to Manage and Analyse Biological Big Data Produced by NGS Technologies. AB - Sequencing the human genome began in 1994, and 10 years of work were necessary in order to provide a nearly complete sequence. Nowadays, NGS technologies allow sequencing of a whole human genome in a few days. This deluge of data challenges scientists in many ways, as they are faced with data management issues and analysis and visualization drawbacks due to the limitations of current bioinformatics tools. In this paper, we describe how the NGS Big Data revolution changes the way of managing and analysing data. We present how biologists are confronted with abundance of methods, tools, and data formats. To overcome these problems, focus on Big Data Information Technology innovations from web and business intelligence. We underline the interest of NoSQL databases, which are much more efficient than relational databases. Since Big Data leads to the loss of interactivity with data during analysis due to high processing time, we describe solutions from the Business Intelligence that allow one to regain interactivity whatever the volume of data is. We illustrate this point with a focus on the Amadea platform. Finally, we discuss visualization challenges posed by Big Data and present the latest innovations with JavaScript graphic libraries. PMID- 26125027 TI - Vibration Training Triggers Brown Adipocyte Relative Protein Expression in Rat White Adipose Tissue. AB - Recently, vibration training is considered as a novel strategy of weight loss; however, its mechanisms are still unclear. In this study, normal or high-fat diet induced rats were trained by whole body vibration for 8 weeks. We observed that the body weight and fat metabolism index, blood glucose, triglyceride, cholesterol, and free fatty acid in obesity rats decreased significantly compared with nonvibration group (n = 6). Although intrascapular BAT weight did not change significantly, vibration enhanced ATP reduction and increased protein level of the key molecule of brown adipose tissue (BAT), PGC-1alpha, and UCP1 in BAT. Interestingly, the adipocytes in retroperitoneal white adipose tissue (WAT) became smaller due to vibration exercise and had higher protein level of the key molecule of brown adipose tissue (BAT), PGC-1alpha, and UCP1 and inflammatory relative proteins, IL-6 and TNFalpha. Simultaneously, ATP content and PPARgamma protein level in WAT became less in rats compared with nonvibration group. The results indicated that vibration training changed lipid metabolism in rats and promoted brown fat-like change in white adipose tissues through triggering BAT associated gene expression, inflammatory reflect, and reducing energy reserve. PMID- 26125028 TI - Quantification of Internalized Silica Nanoparticles via STED Microscopy. AB - The development of safe engineered nanoparticles (NPs) requires a detailed understanding of their interaction mechanisms on a cellular level. Therefore, quantification of NP internalization is crucial to predict the potential impact of intracellular NP doses, providing essential information for risk assessment as well as for drug delivery applications. In this study, the internalization of 25 nm and 85 nm silica nanoparticles (SNPs) in alveolar type II cells (A549) was quantified by application of super-resolution STED (stimulated emission depletion) microscopy. Cells were exposed to equal particle number concentrations (9.2 * 10(10) particles mL(-1)) of each particle size and the sedimentation of particles during exposure was taken into account. Microscopy images revealed that particles of both sizes entered the cells after 5 h incubation in serum supplemented and serum-free medium. According to the in vitro sedimentation, diffusion, and dosimetry (ISDD) model 20-27% of the particles sedimented. In comparison, 10(2)-10(3) NPs per cell were detected intracellularly serum containing medium. Furthermore, in the presence of serum, no cytotoxicity was induced by the SNPs. In serum-free medium, large agglomerates of both particle sizes covered the cells whereas only high concentrations (>= 3.8 * 10(12) particles mL(-1)) of the smaller particles induced cytotoxicity. PMID- 26125029 TI - Overweight and Obesity Based on Four Reference Systems in 18,382 Paediatric Patients with Type 1 Diabetes from Germany and Austria. AB - AIM: To evaluate the prevalence of overweight and obesity in paediatric type 1 diabetes (T1D) subjects, based on four commonly used reference populations. METHODS: Using WHO, IOTF, AGA (German pediatric obesity), and KiGGS (German Health Interview and Examination Survey for Children and Adolescents) reference populations, prevalence of overweight (>=90th percentile) and obesity (>=97th percentile) and time trend between 2000 (n = 9,461) and 2013 (n = 18,382) were determined in 2-18-year-old T1D patients documented in the German/Austrian DPV database. RESULTS: In 2000, the overweight prevalence was the highest according to IOTF (22.3%), followed by WHO (20.8%), AGA (15.5%), and KiGGS (9.4%). The respective rates in 2013 were IOTF (24.8%), WHO (22.9%), AGA (18.2%), and KiGGS (11.7%). Obesity prevalence in 2000 was the highest according to WHO (7.9%), followed by AGA (4.5%), IOTF (3.1%), and KiGGS (1.8%). In 2013, the respective rates were WHO (9.6%), AGA (6.2%), IOTF (4.5%), and KiGGS (2.6%). Overall, the prevalence of overweight and obesity increased from 2000 to 2006 (p < 0.001) but showed stabilization thereafter in girls and overweight in boys. CONCLUSION: Overweight and obesity prevalence in T1D subjects differs significantly if it is assessed by four separate reference populations. More detailed assessment of each child is required to determine obesity-related risks. PMID- 26125031 TI - Antiseptic Body Washes for Reducing the Transmission of Methicillin-Resistant Staphylococcus aureus: A Cluster Crossover Study. AB - Background. Limiting the spread of methicillin-resistant Staphylococcus aureus (MRSA) within healthcare facilities where the organism is highly endemic is a challenge. The use of topical antiseptic agents may help interrupt the transmission of MRSA and reduce the risk of clinical infection. Octenidine dihydrochloride is a topical antiseptic that exhibits in vitro efficacy against a wide variety of bacteria, including S aureus. Methods. We conducted a prospective cluster crossover study to compare the use of daily octenidine body washes with soap and water in patients identified by active surveillance cultures to be MRSA-colonized, to prevent the acquisition of MRSA in patients with negative screening swabs. Five adult medical and surgical wards and 2 intensive care units were selected. The study involved an initial 6-month phase using octenidine or soap washes followed by a crossover in each ward to the alternative product. The primary and secondary outcomes were the rates of new MRSA acquisitions and MRSA clinical infections, respectively. Results. A total of 10 936 patients admitted for >=48 hours was included in the analysis. There was a small reduction in MRSA acquisition in the intervention group compared with controls (3.0% vs 3.3%), but this reduction was not significant (odds ratio, 0.89; 95% confidence interval, .72-1.11; P = .31). There were also no significant differences in clinical MRSA infection or incidence of MRSA bacteremia. Conclusions. This study suggests that the targeted use of routine antiseptic washes may not in itself be adequate to reduce the transmission of MRSA in an endemic hospital setting. PMID- 26125030 TI - Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. AB - This article provides a comprehensive review of currently available treatment options for infections due to carbapenem-resistant Enterobacteriaceae (CRE). Antimicrobial resistance in Gram-negative bacteria is an emerging and serious global public health threat. Carbapenems have been used as the "last-line" treatment for infections caused by resistant Enterobacteriaceae, including those producing extended spectrum beta-lactamases. However, Enterobacteriaceae that produce carbapenemases, which are enzymes that deactivate carbapenems and most other beta-lactam antibiotics, have emerged and are increasingly being reported worldwide. Despite this increasing burden, the most optimal treatment for CRE infections is largely unknown. For the few remaining available treatment options, there are limited efficacy data to support their role in therapy. Nevertheless, current treatment options include the use of older agents, such as polymyxins, fosfomycin, and aminoglycosides, which have been rarely used due to efficacy and/or toxicity concerns. Optimization of dosing regimens and combination therapy are additional treatment strategies being explored. Carbapenem-resistant Enterobacteriaceae infections are associated with poor outcomes and high mortality. Continued research is critically needed to determine the most appropriate treatment. PMID- 26125032 TI - Fatal Human Meningoencephalitis due to Halicephalobus Nematodes, Germany. AB - Infections with Halicephalobus nematodes, causative agents of severe meningoencephalitis in horses, have rarely been reported in humans. In this study, the clinical, serological, cytokine, and histopathological findings of a rapidly progressive and eventually fatal meningoencephalitis in a previously healthy human are described. The helminth was finally diagnosed by specific polymerase chain reactions from post mortem tissue. PMID- 26125033 TI - Success of Standard Dose Vitamin D Supplementation in Treated Human Immunodeficiency Virus Infection. AB - Background. Vitamin D insufficiency is prevalent in human immunodeficiency virus positive (HIV+) persons. Human immunodeficiency virus and antiretroviral therapy (ART) may create unique risk factors, and the optimal vitamin D repletion and maintenance regimen in HIV+ persons remains unclear. Methods. Human immunodeficiency virus-positive adults on suppressive ART underwent routine serum 25-hydroxyvitamin D (25OHD) screening. Persons with vitamin D insufficiency (25OHD <30 ng/mL) received open-label, oral vitamin D3 50 000 international units (IU) twice weekly for 5 weeks, then 2000 IU daily to complete 12 weeks. We predicted 70% (95% confidence interval, 60%-80%) repletion to 25OHD >=30 ng/mL compared with 85% among historical HIV-negative controls. Eighty participants provided 91% power to detect this difference. Ability to maintain 25OHD >=30 ng/mL after 24 weeks was also assessed. Results. Baseline characteristics were similar between the 82 vitamin D insufficient and 40 sufficient persons enrolled: 95% male, 60% white, 88% nonsmokers, median age 49 years, body mass index 26 kg/m(2), and CD4(+) T lymphocyte count 520 cells/mm(3). After 12 weeks, 81% (66 of 82) of insufficient persons achieved 25OHD >=30 ng/mL (P = .32 vs historical controls), with only older age (odds ratio [OR] = 1.06; P = .06), higher baseline 25OHD (OR = 1.14; P < .01), white race (OR = 3.39; P = .04), and current smoking (OR = 0.25; P = .06) associated with successful repletion. After 24 weeks, 73% (48 of 66) maintained 25OHD >=30 ng/mL, with tenofovir (OR = 5.00; P = .01) and abacavir use (OR = 0.23; P = .02) associated with success and failure, respectively, to maintain 25OHD levels. Conclusions. The 25OHD repletion rates were comparable between HIV+ adults on suppressive ART and historical HIV negative controls, indicating that successful oral repletion can be achieved in this population. PMID- 26125034 TI - Combination Therapy for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: Whom, When, and Where? PMID- 26125035 TI - Detection of Mycobacterium tuberculosis (MTB) in Fecal Specimens From Adults Diagnosed With Pulmonary Tuberculosis Using the Xpert MTB/Rifampicin Test. AB - Background. The Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) is a fully automated diagnostic test that allows for the detection of MTB including its RIF resistance. Although the test is used for the diagnosis of tuberculosis (TB) in sputum samples worldwide, studies using fecal specimens are scarce. We therefore evaluated the efficacy of the Xpert MTB/RIF test for detection of MTB in fecal specimens obtained from adult pulmonary TB patients, confirmed by culture and/or molecular diagnostic methods. Methods. We conducted a retrospective case-control study to provide proof-of-concept regarding the efficacy of the Xpert MTB/RIF test using fecal samples for diagnosing pulmonary TB via detection of MTB in adult patients (>=20 years) at the Fukujuji Hospital in Tokyo, Japan. Results. Fecal specimens were obtained from 56 active pulmonary TB patients (including 48 sputum smear-positive and 8 sputum smear-negative patients), 10 non-TB patients (including 4 Myocobacterium avium complex infections), and 27 healthy individuals who were exposed to active pulmonary TB patients. The sensitivity of the fecal Xpert MTB/RIF was 100% (81.7%-100%) for detection of MTB in specimens from sputum smear-positive (1+ to 3+) patients, 81.0% (58.1%-94.6%) in specimens from sputum smear scanty positive patients, and 50.0% (15.7%-84.3%) in specimens from sputum smear-negative patients. Meanwhile, each of the fecal specimens from the non-TB group was negative for MTB (specificity 100%; 95% confidence interval, 86.2-100). Conclusions. The fecal Xpert MTB/RIF test could detect MTB in a large proportion of smear-positive pulmonary TB patients, without frequent false-positive results at a TB referral hospital in Japan. PMID- 26125036 TI - A second trigeminal CGRP receptor: function and expression of the AMY1 receptor. AB - OBJECTIVE: The trigeminovascular system plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal system. METHODS: Receptor expression was determined using Taqman G protein-coupled receptor arrays and immunohistochemistry in trigeminal ganglia (TG) and the spinal trigeminal complex of the brainstem in rat and human. Receptor pharmacology was quantified using sensitive signaling assays in primary rat TG neurons. RESULTS: mRNA and histological expression analysis in rat and human samples revealed the presence of two CGRP-responsive receptors (AMY1: calcitonin receptor/receptor activity-modifying protein 1 [RAMP1]) and the CGRP receptor (calcitonin receptor-like receptor/RAMP1). In support of this finding, quantification of agonist and antagonist potencies revealed a dual population of functional CGRP-responsive receptors in primary rat TG neurons. INTERPRETATION: The unexpected presence of a functional non-canonical CGRP receptor (AMY1) at neural sites important for craniofacial pain has important implications for targeting the CGRP axis in migraine. PMID- 26125037 TI - Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis. AB - OBJECTIVE: In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8(+) T cells. These clones have been assumed - but never demonstrated - to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8(+) T cells in the disease. METHODS: For the first time, TCR Vbeta repertoire from paired blood (purified CD8(+) and CD4(+) T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8(+) T cells were characterized by fluorescent staining. RESULTS: TCR Vbeta repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8(+) T cells. In parallel, we showed that blood oligoclonal CD8(+) T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. INTERPRETATION: This study highlights the predominant implication of CD8(+) T cells in MS pathophysiology and demonstrates that potentially aggressive CD8(+) T cells can be easily identified and characterized from blood and CSF samples. PMID- 26125038 TI - De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. AB - OBJECTIVE: To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children. METHODS: Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function. RESULTS: All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay. INTERPRETATION: De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients. PMID- 26125039 TI - Alzheimer's loci: epigenetic associations and interaction with genetic factors. AB - OBJECTIVE: We explore the role of DNA methylation in Alzheimer's disease (AD). To elucidate where DNA methylation falls along the causal pathway linking risk factors to disease, we examine causal models to assess its role in the pathology of AD. METHODS: DNA methylation profiles were generated in 740 brain samples using the Illumina HumanMet450K beadset. We focused our analysis on CpG sites from 11 AD susceptibility gene regions. The primary outcome was a quantitative measure of neuritic amyloid plaque (NP), a key early element of AD pathology. We tested four causal models: (1) independent associations, (2) CpG mediating the association of a variant, (3) reverse causality, and (4) genetic variant by CpG interaction. RESULTS: Six genes regions (17 CpGs) showed evidence of CpG associations with NP, independent of genetic variation - BIN1 (5), CLU (5), MS4A6A (3), ABCA7 (2), CD2AP (1), and APOE (1). Together they explained 16.8% of the variability in NP. An interaction effect was seen in the CR1 region for two CpGs, cg10021878 (P = 0.01) and cg05922028 (P = 0.001), in relation to NP. In both cases, subjects with the risk allele rs6656401(AT) (/) (AA) display more methylation being associated with more NP burden, whereas subjects with the rs6656401(TT) protective genotype have an inverse association with more methylation being associated with less NP. INTERPRETATION: These observations suggest that, within known AD susceptibility loci, methylation is related to pathologic processes of AD and may play a largely independent role by influencing gene expression in AD susceptibility loci. PMID- 26125041 TI - Differential involvement of Ras-GRF1 and Ras-GRF2 in L-DOPA-induced dyskinesia. AB - OBJECTIVE: Recent findings have shown that pharmacogenetic manipulations of the Ras-ERK pathway provide a therapeutic means to tackle l-3,4 dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID). First, we investigated whether a prolonged l-DOPA treatment differentially affected ERK signaling in medium spiny neurons of the direct pathway (dMSNs) and in cholinergic aspiny interneurons (ChIs) and assessed the role of Ras-GRF1 in both subpopulations. Second, using viral-assisted technology, we probed Ras-GRF1 and Ras-GRF2 as potential targets in this pathway. We investigated how selective blockade of striatal Ras-GRF1 or Ras-GRF2 expression impacted on LID (induction, maintenance, and reversion) and its neurochemical correlates. METHODS: We used both Ras-GRF1 knockout mice and lentiviral vectors (LVs) delivering short-hairpin RNA sequences (shRNAs) to obtain striatum-specific gene knockdown of Ras-GRF1 and Ras-GRF2. The consequences of these genetic manipulations were evaluated in the 6 hydroxydopamine mouse model of Parkinson's disease. Escalating doses of l-DOPA were administered and then behavioral analysis with immunohistochemical assays and in vivo microdialysis were performed. RESULTS: Ras-GRF1 was found essential in controlling ERK signaling in dMSNs, but its ablation did not prevent ERK activation in ChIs. Moreover, striatal injection of LV-shRNA/Ras-GRF1 attenuated dyskinesia development and ERK-dependent signaling, whereas LV-shRNA/Ras-GRF2 was without effect, ruling out the involvement of Ras-GRF2 in LID expression. Accordingly, Ras-GRF1 but not Ras-GRF2 striatal gene-knockdown reduced l-DOPA induced GABA and glutamate release in the substantia nigra pars reticulata, a neurochemical correlate of dyskinesia. Finally, inactivation of Ras-GRF1 provided a prolonged anti-dyskinetic effect for up to 7 weeks and significantly attenuated symptoms in animals with established LID. INTERPRETATION: Our results suggest that Ras-GRF1 is a promising target for LID therapy based on Ras-ERK signaling inhibition in the striatum. PMID- 26125040 TI - Altered PLP1 splicing causes hypomyelination of early myelinating structures. AB - OBJECTIVE: The objective of this study was to investigate the genetic etiology of the X-linked disorder "Hypomyelination of Early Myelinating Structures" (HEMS). METHODS: We included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs. RESULTS: All patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction structure in the secondary PLP1 RNA fragment involved in regulating PLP1/DM20 alternative splicing. Splicing studies in fibroblasts and transfected cells confirmed a decreased PLP1/DM20 ratio. INTERPRETATION: Brain structures that normally myelinate early are poorly myelinated in HEMS, while they are the best myelinated structures in Pelizaeus Merzbacher disease, also caused by PLP1 alterations. Our data extend the phenotypic spectrum of PLP1-related disorders indicating that normal PLP1/DM20 alternative splicing is essential for early myelination and support the need to include intron 3 in diagnostic sequencing. PMID- 26125042 TI - Tablet-based screening improves continence management in multiple sclerosis. AB - OBJECTIVE: To investigate whether electronic continence questionnaires aid early identification and optimizes management of sphincter dysfunction in a multiple sclerosis clinic. METHODS: A custom designed, tablet-based cross-platform software tool was designed to capture validated multiple sclerosis (MS) patient reported outcomes. An unselected cohort of MS patients from a tertiary referral clinic completed electronic tablet-based versions of the Bladder Control Scale (BLCS) and the Bowel Control Scale in the waiting room. Data were captured wirelessly "on-the-fly" and stored in a deidentified, secure database; and individual questionnaire results were immediately available to the treating neurologist in the electronic medical record. Scores of >=2 on either questionnaire generated an automated electronic referral to the clinic MS continence nurse (MS CN). RESULTS: One hundred and fifty-seven MS patients completed a total of 184 electronic continence test sets and on two occasions only the BLCS was completed. An automatic electronic referral for formal continence review was generated 128 times in 108 patients. Fifty-seven formal continence assessments were undertaken by the MS CN following automated referral. All reviews resulted in at least one clinical intervention being made. INTERPRETATION: Tablet-based data capture and automated continence referral using this software tool is an efficient, sensitive, and feasible method of screening MS patients for bladder and bowel dysfunction. Concordance with the results of formal continence assessment in this pilot study validates the use of this technology as a screening tool. PMID- 26125043 TI - Cardiorespiratory fitness is associated with white matter integrity in aging. AB - OBJECTIVE: Aging is associated with reduced neural integrity, yet there are remarkable individual differences in brain health among older adults (OA). One factor that may attenuate age-related neural decline is cardiorespiratory fitness (CRF). The primary aim of this study was to link CRF to neural white matter microstructure using diffusion tensor imaging in OA. METHODS: Young adults (YA; n = 32) and OA (n = 27) completed a graded maximal exercise test to evaluate CRF and diffusion tensor magnetic resonance imaging to examine neural white matter integrity. RESULTS: As expected, pervasive age-related declines in white matter integrity were observed when OA were compared to YA. Further, peak VO2 was positively associated with fractional anisotropy (FA), an indicator of white matter integrity, in multiple brain regions in OA, but not YA. In multiple posterior regions such as the splenium, sagittal stratum, posterior corona radiata, and superior parietal white matter, FA values were similar in YA and OA classified as higher fit, with both groups having greater FA than lower fit OA. However, age-related differences in FA values remained in other regions, including the body and genu of the corpus callosum, precuneus, and superior frontal gyrus. INTERPRETATION: CRF is positively associated with neural white matter microstructure in aging. The relationship between peak VO2 and FA appears to be tract-specific, as equivalent FA values were observed in higher fit OA and YA in some white matter tracts, but not others. Further, the association between peak VO2 and FA appears to be age-dependent. PMID- 26125044 TI - Torin 1 partially corrects vigabatrin-induced mitochondrial increase in mouse. AB - Recent findings in mice with targeted deletion of the GABA-metabolic enzyme succinic semialdehyde dehydrogenase revealed a new role for supraphysiological GABA (4-aminobutyric acid) in the activation of the mechanistic target of rapamycin (mTOR) that results in disruption of endogenous mitophagy. Employing biochemical and electron microscopic methodology, we examined the hypothesis that similar outcomes would be observed during intervention with vigabatrin, whose antiepileptic capacity hinges on central nervous system GABA elevation. Vigabatrin intervention was associated with significantly enhanced mitochondrial numbers and areas in normal mice that could be selectively normalized with the rapalog and mechanistic target of rapamycin inhibitor, Torin 1. Moreover, short term administration of vigabatrin induced apoptosis and enhanced phosphorylation of mechanistic target of rapamycin Ser 2448 in liver. Our results provide new insight into adverse outcomes associated with vigabatrin intervention, and the first evidence that its administration is associated with increased mitochondrial number in central and peripheral tissues that may associate with mechanistic target of rapamycin function and enhanced cell death. PMID- 26125045 TI - Intraoperative neurophysiology in deep brain surgery for psychogenic dystonia. AB - Psychogenic dystonia is a challenging entity to diagnose and treat because little is known about its pathophysiology. We describe two cases of psychogenic dystonia who underwent deep brain stimulation when thought to have organic dystonia. The intraoperative microelectrode recordings in globus pallidus internus were retrospectively compared with those of five patients with known DYT1 dystonia using spontaneous discharge parameters of rate and bursting, as well as movement related discharges. Our data suggest that simple intraoperative neurophysiology measures in single subjects do not differentiate psychogenic dystonia from DYT1 dystonia. PMID- 26125049 TI - A Framework and Improvements of the Korea Cloud Services Certification System. AB - Cloud computing service is an evolving paradigm that affects a large part of the ICT industry and provides new opportunities for ICT service providers such as the deployment of new business models and the realization of economies of scale by increasing efficiency of resource utilization. However, despite benefits of cloud services, there are some obstacles to adopt such as lack of assessing and comparing the service quality of cloud services regarding availability, security, and reliability. In order to adopt the successful cloud service and activate it, it is necessary to establish the cloud service certification system to ensure service quality and performance of cloud services. This paper proposes a framework and improvements of the Korea certification system of cloud service. In order to develop it, the critical issues related to service quality, performance, and certification of cloud service are identified and the systematic framework for the certification system of cloud services and service provider domains are developed. Improvements of the developed Korea certification system of cloud services are also proposed. PMID- 26125047 TI - The immediate eff ect of the Same-Sex Marriage Prohibition Act on stigma, discrimination, and engagement on HIV prevention and treatment services in men who have sex with men in Nigeria: analysis of prospective data from the TRUST cohort. AB - BACKGROUND: In January, 2014, the Same-Sex Marriage Prohibition Act was signed into law in Nigeria, further criminalising same-sex sexual relationships. We aimed to assess the immediate effect of this prohibition act on stigma, discrimination, and engagement in HIV prevention and treatment services in men who have sex with men (MSM) in Nigeria. METHODS: The TRUST cohort study uses respondent-driven sampling to assess the feasibility and effectiveness of engagement of MSM in HIV prevention and treatment services at a clinical site located with a community-based organisation trusted by the MSM community. TRUST is a prospective implementation research cohort of MSM (>=16 years) in Abuja, Nigeria. We compared HIV clinical outcomes and stigma, including fear and avoidance of health care, across baseline and quarterly visits before and after implementation of the the Same-Sex Marriage Prohibition Act. Outcomes assessed were measures of stigma and discrimination, loss to follow-up, antiretroviral therapy status, and viral load. We compared outcomes before and after the legislation with chi2 statistics, and estimated incident stigma-related events and loss to follow-up with Poisson regression. FINDINGS: Between March 19, 2013, and Aug 7, 2014, 707 MSM participated in baseline study procedures, contributing to 756 before legislation (prelaw) and 420 after legislation (postlaw) visits. Reported history of fear of seeking health care was significantly higher in postlaw visits than in prelaw visits (n=161 [38%] vs n=187 [25%]; p<0?0001), as was avoidance of health care (n=118 [28%] vs n=151 [20%]; p=0?001). In incidence analyses, of 192 MSM with follow-up data and no history of an event at baseline, reported fear of seeking health care was higher in the postlaw than the prelaw period (n=144; incidence rate ratio 2?57, 95% CI 1?29-5?10; p=0?007); loss to follow-up and incident healthcare avoidance were similar across periods. Of the 161 (89%) of 181 HIV-infected MSM with HIV viral loads available, those who had disclosed sexual behaviour with a health-care provider were more often virally suppressed at baseline than those with no previous disclosure (18 [29%] of 62 vs 13 [13%] of 99 men; p=0?013). INTERPRETATION: These analyses represent individual level, quantitative, real-time prospective data for the health-related effects resulting from the enactment of legislation further criminalising same-sex practices. The negative effects of HIV treatment and care in MSM reinforce the unintended consequences of such legislation on global goals of HIV eradication. Strategies to reach MSM less likely to engage in HIV testing and care in highly stigmatised environments are needed to reduce time to HIV diagnosis and treatment. FUNDING: National Institutes of Health. PMID- 26125048 TI - Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis. AB - The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI. PMID- 26125050 TI - (Fuzzy) Ideals of BN-Algebras. AB - The notions of an ideal and a fuzzy ideal in BN-algebras are introduced. The properties and characterizations of them are investigated. The concepts of normal ideals and normal congruences of a BN-algebra are also studied, the properties of them are displayed, and a one-to-one correspondence between them is presented. Conditions for a fuzzy set to be a fuzzy ideal are given. The relationships between ideals and fuzzy ideals of a BN-algebra are established. The homomorphic properties of fuzzy ideals of a BN-algebra are provided. Finally, characterizations of Noetherian BN-algebras and Artinian BN-algebras via fuzzy ideals are obtained. PMID- 26125052 TI - Erratum: Back to Back column in our March 2015 issue. PMID- 26125051 TI - Time for a change of guard. PMID- 26125053 TI - A drug by any other name... generic and brand-name drugs are clinically equivalent. PMID- 26125054 TI - The impact on health outcome measures of switching to generic medicines consequent to reference pricing: the case of olanzapine in New Zealand. AB - INTRODUCTION: New Zealand's Pharmaceutical Management Agency (PHARMAC) manages the list of medicines available for prescribing with government subsidy, within a fixed annual medicines budget. PHARMAC achieves this through a mix of pricing strategies including reference pricing. In 2011, PHARMAC applied generic reference pricing to olanzapine tablets. AIM: This study sought to evaluate change in outcome measures of patients switching from originator to generic olanzapine consequent to the introduction of the policy. METHODS: A retrospective study using national health data collections was conducted. Outcome measures included medicines indicators (change in dosage, concomitant therapy and treatment cessation), health care service indicators (use of emergency departments, hospitals and specialist services), surveillance reports of adverse events, and mortality. RESULTS: Subsequent to the removal of funding for originator brand olanzapine tablets, 99.7% of patients meeting the inclusion criteria switched to using generic olanzapine. Limited case reports of suspected therapeutic loss were received in the study time period. No increase in use of additional oral or injectable antipsychotic medication was observed after switching, nor any increase in other unique, non-antipsychotic prescription items. However, a high incidence of multiple switching between available brands was found. No net impact of switching brands on health service utilisation or mortality was found. DISCUSSION: The study shows that a switch can be made safely from originator olanzapine to a generic brand, and suggests that switching to generics should generally be viewed more positively. Generic reference pricing achieves considerable savings and, as a pricing policy, could be applied more widely. PMID- 26125055 TI - Prevalence of intimate partner violence disclosed during routine screening in a large general practice. AB - INTRODUCTION: Domestic violence in its myriad shapes and forms is a crime affecting every level of society. Gaining a true understanding of intimate partner violence (IPV) victimology allows for the meaningful provision of intervention services. AIM: To explore the prevalence of IPV disclosure during routine screening in a large general practice in provincial New Zealand. METHODS: Data were collected from 13 October 2008 to 30 June 2014 from 6827 individuals screened for IPV on 10 062 occasions and were analysed relative to age, ethnicity, gender, screening outcome, screener and health centre enrolled status. RESULTS: Analysis indicated an overall ever-positive disclosure rate of IPV of 11.1%, lower than New Zealand studies that place ever-positive prevalence as high as 78%. Maori women disclosed an ever-positive rate of 21.6%, Pacific women 13.2%, compared to 8.9% for NZ European/Other women. Casual patients positively disclosed in 13.7% of instances as opposed to enrolled patients in 10.5%. Disclosure of past abuse was made 1.3 times more often than that of a current abusive situation. Those aged between 16 and 65 years disclosed an ever-positive rate >=10%. While nurses screened 5.5 times more patients than doctors, the doctors facilitated a higher percentage of positive disclosures than the nurses. DISCUSSION: Disclosure rates from a general practice setting do not mirror those of population studies or administrative datasets due to differences in samples and data collection methods. Routine annual screening is effective, with both doctors and nurses providing support for approximately equal numbers of patients in immediate danger. PMID- 26125057 TI - Self-reported health-related quality of life of mental health service users with serious mental illness in New Zealand. AB - INTRODUCTION: Although people with serious mental illness (SMI) have a high prevalence of physical illness, health-related quality of life (HQoL) has not been sufficiently explored. AIM: To explore the self-reported HQoL of mental health service users in New Zealand. METHODS: Responses on the Medical Outcomes Study 36 Item Short Form (SF-36) measure of HQoL from 404 adult mental health service users in a metropolitan district health board area in New Zealand were analysed and compared to a representative sample of the general population. RESULTS: Mental health service users scored significantly lower on all eight domains of the SF-36 than the general population, the largest difference being in the role limitation-emotional domain. DISCUSSION: Being female, younger than 25, obese or overweight, or of New Zealand European/Other ethnicity were associated with poorer functioning on multiple HQoL domains. Future studies should seek to understand the factors contributing to perceptions of HQoL of mental health service users in New Zealand. PMID- 26125056 TI - Investigation of fatigue by Australian general practice registrars: a cross sectional study. AB - INTRODUCTION: Fatigue is the most common undifferentiated problem presenting in general practice. Previous studies have shown that this presentation leads to multiple investigations. There is no published literature describing the management of patients with fatigue by general practice (GP) registrars. AIM: To document the investigation-ordering behaviour of GP registrars in managing patients with a new diagnosis of unexplained fatigue. METHODS: This was a cross sectional analysis of data from Registrar Clinical Encounters in Training (ReCEnT), an ongoing cohort study of GP registrars' consultations. We established the prevalence of new diagnoses of unexplained fatigue and associations with that diagnosis, the rate of test ordering and the number and types of investigations ordered. RESULTS: 644 registrars contributed data from 68 986 encounters. In 0.78% of patient encounters, a new diagnosis of unexplained fatigue was made. Pathology was ordered in 78.4% of these problems (versus 18.1% in non-fatigue problems), at a rate of 488 tests per 100 new fatigue problems. DISCUSSION: Our study suggests that unexplained fatigue elicits a non-rational approach to test ordering by registrars. These findings contribute to the understanding of GP registrar management of fatigue, and undifferentiated presentations more broadly, and suggest educational approaches to improve practice, including dealing with uncertainty. PMID- 26125058 TI - How and why patients use acupuncture: an interpretive phenomenological study. AB - INTRODUCTION: The usual drivers of health care provision, namely efficacy and cost, might be expected to drive down the use of Complementary and Alternative Medicines (CAMs), given the relative paucity of evidence of efficacy for many CAMs. Usage of CAMs remains extensive and little attention has been given to explaining this paradox. This paper explores how patients integrate acupuncture, as a CAMs exemplar, within their personal schemes of health care. METHODS: An interpretive phenomenological approach underpinned the inquiry, which gathered data from in-depth interviews with 12 participants who had recently consulted acupuncturists. Thematic analysis was conducted using a constant comparison methodology. FINDINGS: Participants mostly accessed acupuncture for musculoskeletal and pain-related conditions. Usage was often initially motivated by dissatisfaction with conventional health care, perceptions that the source of the problem had not been addressed, and sometimes was due to negative experiences with medical professionals. Previous positive outcomes with acupuncture motivated more extensive use, as did personal health ideologies. Acupuncture was viewed to be appropriate for treating chronic and quality of life health issues, while treatment-associated cost was identified as a barrier to access. CONCLUSIONS: CAMs usage has been explained variously by 'push' and 'pull' factors; however, this study has shown that reasons for patient use of acupuncture may be complex and change over time. This qualitative study suggests that acupuncture fulfils specific health needs unmet in conventional health care, but also that patients view CAMs treatment as part of a broader and more pluralistic scheme of health care. PMID- 26125059 TI - Patient expectations for chronic pain management. AB - INTRODUCTION: In New Zealand, one in six people report chronic pain, but the literature indicates only a 30% pain reduction is typically achieved in about half of treated patients. Most patients expecting a cure of their pain, or even substantial pain reduction, are therefore likely to be disappointed. It is important to align patient expectations with this reality. METHODS: This study analysed the responses of 250 patients referred to a Pain Management Centre to the free-text question: 'What are your main goals or reasons for attending the Pain Management Centre?' Free-text comments were analysed using ethnographic content analysis, an inductive approach in which the themes and subthemes are not predetermined, but emerge from the data during analysis, and thus reflect the issues of importance to patients themselves. FINDINGS: Three themes emerged from the analysis: patients' desire to understand their pain, regain 'normality', and concerns about medication. Responses were divided into those with an expectation of cure, and those who seemed to be more accepting of their pain and who desired management. CONCLUSION: Patients hope to return to what they perceive as normal and to have clear, relevant information about their diagnosis, prognosis and medications. Those desiring cure, or significant pain reduction, present more of a challenge to their general practitioners and the Pain Management Centre. When referring a patient for chronic pain management, there is a need to align patient expectations at the point of referral with what can realistically be achieved. PMID- 26125060 TI - Midlife safer sex challenges for heterosexual New Zealand women re-partnering or in casual relationships. AB - INTRODUCTION: The rate of sexually transmitted infections (STIs) amongst midlife and older heterosexual women in New Zealand is rising. Popular culture celebrates a heightened sexuality for this population group. However, depictions of sexually savvy 'cougars' are at odds with reality for many women. International literature highlights that these women are often ill-equipped to negotiate safer sex and condom use, instead focusing on pleasing men and attributing their silence to spontaneity. The study aimed to explore barriers to safer heterosexual sex as perceived by midlife and older New Zealand women who are re-partnering or in casual relationships. METHODS: This qualitative study utilised Interpretive Phenomenology Analysis, supported by the theory of gender and power, to examine the gender-normative assumptions and behaviours in women's accounts of unprotected sex. Eight single women aged 40-69 participated in individual, in depth interviews. This exploration included eliciting women's accounts of potential information resources, such as clinical consultations. FINDINGS: Analysis indicated that these women held misconceptions about STI transmission but had not sought educational material, nor discussed their sexual health with health professionals. Results highlighted women's ambivalence about prioritising safer sex, preferring to comply with partners' wishes, particularly when under the influence of alcohol. Women described valuing their own pleasure and their distaste for condom use, but data emphasised that women predominantly aligned their choices with men's preferences. CONCLUSION: This study highlights that the women were both ill-informed and vulnerable with regards to sexual health. General practitioners are well placed to provide education and sexual health advice. PMID- 26125061 TI - Dunedin's free clinic: an exploration of its model of care using case study methodology. AB - INTRODUCTION: Models of care are important therapeutic modalities for achieving the goals of health care teams, but they are seldom explicitly stated or investigated. AIM: To describe the model of care at Dunedin's free clinic, and assess whether this model catered to the particular needs of enrolled patients. METHODS: A mixed methods study was conducted using case study methodology to construct the clinic's model of care from multiple data sources, and to create a profile of patients' needs. A nested case study of patients with diabetes examined patients' social vulnerability characteristics. The pattern matching analytic technique was used to assess the degree of alignment between the model of care and patients' needs. RESULTS: Patients were not only high users of both primary and secondary health care, but also of justice and social welfare sector services. The care of patients with diabetes was complicated by coexisting social vulnerability and medical comorbidities. Surveyed patients placed high value on interpersonal dimensions of care, the Christian ethos of the clinic, and the wider range of services available. DISCUSSION: This study suggests a degree of 'fit' between the clinic's model of care and the needs of enrolled patients. A model of care that caters to the needs of patients with complex needs is important for securing their engagement in health services. PMID- 26125062 TI - Health promotion funding, workforce recruitment and turnover in New Zealand. AB - INTRODUCTION: Almost a decade on from the New Zealand Primary Health Care Strategy and amidst concerns about funding of health promotion, we undertook a nationwide survey of health promotion providers. AIM: To identify trends in recruitment and turnover in New Zealand's health promotion workforce. METHODS: Surveys were sent to 160 organisations identified as having a health focus and employing one or more health promoter. Respondents, primarily health promotion managers, were asked to report budget, retention and hiring data for 1 July 2009 through 1 July 2010. RESULTS: Responses were received from 53% of organisations. Among respondents, government funding for health promotion declined by 6.3% in the year ended July 2010 and health promoter positions decreased by 7.5% (equalling 36.6 full-time equivalent positions). Among staff who left their roles, 79% also left the field of health promotion. Forty-two organisations (52%) reported employing health promoters on time-limited contracts of three years or less; this employment arrangement was particularly common in public health units (80%) and primary health organisations (57%). Among new hires, 46% (n=55) were identified as Maori. DISCUSSION: Low retention of health promoters may reflect the common use of limited-term employment contracts, which allow employers to alter staffing levels as funding changes. More than half the surveyed primary health organisations reported using fixed-term employment contracts. This may compromise health promotion understanding, culture and institutional memory in these organisations. New Zealand's commitment to addressing ethnic inequalities in health outcomes was evident in the high proportion of Maori who made up new hires. PMID- 26125063 TI - New Zealand doctors should be allowed to prescribe cannabis for pain: Yes. PMID- 26125064 TI - New Zealand doctors should be allowed to prescribe cannabis for pain: No. PMID- 26125065 TI - Ageing is not for the faint-hearted: are we making it worse? Polypharmacy-related harm in the elderly. PMID- 26125066 TI - Poverty, medicines and health care: It's the little things.... AB - Small patient charges and policies and events that may seem minor to health care professionals can have a big impact on the wellbeing of people living in poverty. Despite good intentions, policies can have unintended consequences for those who are struggling to access health care. PMID- 26125067 TI - Health literacy and patient portals. AB - Health literacy has been described as the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. Improving health literacy may serve to promote concordance with therapy, engage patients in their own health care, and improve health outcomes. Patient portal technology aims at enabling patients and families to have easy access to key information in their own medical records and to communicate with their health care providers electronically. However, there is a gap in our understanding of how portals will improve patient outcome. The authors believe patient portal technology presents an opportunity to improve patient concordance with prescribed therapy, if adequate support is provided to equip patients (and family/carers) with the knowledge needed to utilise the health information available via the portals. Research is needed to understand what a health consumer will use patient portals for and how to support a user to realise the technology's potential. PMID- 26125068 TI - Nickel-catalyzed asymmetric transfer hydrogenation of conjugated olefins. AB - Asymmetric transfer hydrogenation of electron-deficient olefins is realized with nickel catalysts supported by strongly sigma-donating bisphosphines. Deuterium labeling experiments point to a reaction sequence of formate decarboxylation, asymmetric hydride insertion and non-stereoselective protonation of resulting nickel enolates. PMID- 26125069 TI - An in situ self-developed graphite as high capacity anode of lithium-ion batteries. AB - Graphite with a large inter-planar distance (0.357 nm) was obtained from pig bone. It delivered an improving specific capacity which increased continuously to 538 mA h g(-1) at 1 A g(-1) after 1000 cycles. With microscopic characterization, it has been found that the pig-bone-based graphite was exfoliated to graphene during the charge-discharge process. PMID- 26125070 TI - Plasmonic Ge-doped ZnO nanocrystals. AB - We present the first colloidal synthesis of Ge-doped ZnO nanocrystals, which are produced by a scalable method that uses only air and moisture stable precursors. The incorporation of tetravalent Ge ions within ZnO nanocrystals generates a surface plasmon resonance in the near-mid infrared, and induces a change in morphology, from isotropic spheroidal nanocrystals to rod-like, elongated structures with a distinctive c-axis orientation. PMID- 26125072 TI - 2014 Pitkin Award and 2014 Kaminetzky Prize Paper. PMID- 26125073 TI - Reply to RP Glahn. PMID- 26125074 TI - Reply to Brown et al. PMID- 26125075 TI - Reply to Conlon et al. PMID- 26125077 TI - New Strategies to Address Critical Challenges. PMID- 26125078 TI - Journal of Nuclear Medicine Technology. EDITOR'S PAGE. PMID- 26125079 TI - A New Measure of Research Participant Burden: Brief Report. AB - Effective conceptualizations of research burden should address indirect burdens related to research duration, intensity, and invasiveness. Introducing the concept of perceived research burden, we developed, tested, and validated a new instrument, the Perceived Research Burden Assessment (PeRBA). Initial psychometric evaluation of PeRBA reveals good internal consistency, evidence of face validity, and acceptable convergent and discriminant validity. PMID- 26125080 TI - [Between dog and wolf]. PMID- 26125081 TI - [Self neglect at the center of nursing care. "How can one live like this" ]. PMID- 26125082 TI - Development of Safe and Effective Botanical Dietary Supplements. AB - Regulated differently than drugs or foods, the market for botanical dietary supplements continues to grow worldwide. The recently implemented U.S. FDA regulation that all botanical dietary supplements must be produced using good manufacturing practice is an important step toward enhancing the safety of these products, but additional safeguards could be implemented, and unlike drugs, there are currently no efficacy requirements. To ensure a safe and effective product, botanical dietary supplements should be developed in a manner analogous to pharmaceuticals that involves identification of mechanisms of action and active constituents, chemical standardization based on the active compounds, biological standardization based on pharmacological activity, preclinical evaluation of toxicity and potential for drug-botanical interactions, metabolism of active compounds, and finally, clinical studies of safety and efficacy. Completing these steps will enable the translation of botanicals from the field to safe human use as dietary supplements. PMID- 26125083 TI - Hydroxyl-Directed Cross-Coupling: A Scalable Synthesis of Debromohamigeran E and Other Targets of Interest. AB - A hydroxyl functional group positioned beta to a pinacol boronate can serve to direct palladium-catalyzed cross-coupling reactions. This feature can be used to control the reaction site in multiply borylated substrates and can activate boronates for reaction that would otherwise be unreactive. PMID- 26125084 TI - Antipsychotic-Induced Movement Disorder: Screening via Telemental Health. AB - BACKGROUND: The purpose of this brief report is to make clinical and research recommendations to advance current knowledge and practices related to the assessment of antipsychotic drug-induced movement disorders (DIMDs) via live interactive videoconferencing. MATERIALS AND METHODS: The authors provide an overview of the frequent neurological side effects of antipsychotic drugs and review relevant telemedicine research. DIMD prevention is critical, but these disorders remain underdetected and under-reported. Although there are not yet formal recommendations for specific screening tools or screening frequency, baseline and annual assessments are generally agreed-upon minimums. As DIMD awareness increases and more specific guidelines are developed to steer assessments, telemental health may aid practitioners in efficiently and regularly monitoring onset and severity. Research shows that videoconferencing can be used for effective psychiatric treatments and assessment, with at least one study validating the use of videoconference assessment for a subset of movement disorders. RESULTS AND CONCLUSIONS: Clinical recommendations include developing practice-level protocols and procedures that include regular DIMD assessment (either in-person or via telemedicine) for the full spectrum of possible movement disorders for all patients taking antipsychotic medications. Research and evaluation recommendations include replicating and expanding upon the existing study using videoconferencing to assess movement disorder symptoms, using asynchronous telemental health assessments of DIMDs, and pilot-testing facial and movement recognition software to allow for clinical comparison of patients' movement patterns over time. PMID- 26125085 TI - IMPACT OF OBESITY ON ENDOTOXIN-INDUCED DISSEMINATED INTRAVASCULAR COAGULATION. AB - An early activation of coagulation and fibrinolysis occurs during sepsis, leading to the syndrome of disseminated intravascular coagulation (DIC). Obesity has been demonstrated to be a hypercoagulable and hypofibrinolytic state, but its impact on DIC has never been studied. In this study, we aimed to determine if obesity impairs DIC in an acute endotoxic shock model using minipigs. This was a prospective, comparative, and experimental ancillary study approved by the Animal Ethics Committee. Pigs were chosen as a clinically relevant species, resembling humans in coagulation reactions. Four groups of five "Yucatan" minipigs were studied: lean and obese control groups, a lean lipopolysaccharide (LPS) group receiving Escherichia coli endotoxin (LPS), and an obese LPS group receiving the same endotoxin dose. We measured standard coagulation parameters (prothrombin time [PT], platelet count, and fibrinogen levels), thrombin-antithrombin complexes, tissue-type plasminogen activator, and plasminogen activator inhibitor 1. All measurements were performed at baseline and 30, 60, 90, 150, and 300 min. Results were given as median with interquartile ranges. At baseline, platelet count (477 [428 - 532] G/L vs. 381 [307 - 442] G/L; P = 0.005) and fibrinogen levels (4.6 [3.8 - 5.2] g/L vs. 2 [1.8 - 2.9] g/L; P < 0.001) were significantly higher, whereas PT (80% [76% - 92%] vs. 96% [89% - 100%]; P = 0.01) was significantly lower in obese pigs compared with lean pigs. In the LPS groups, administration of endotoxin resulted in a typical hypokinetic shock with DIC. The decrease in coagulation parameters (PT, platelet count, and fibrinogen levels) and the increase in thrombin-antithrombin complexes (581 [382 - 1,057] MUg/mL vs. 247 [125 - 369] MUg/mL at 150 min; P = 0.03) were significantly more important in the obese LPS group compared with those in the lean LPS group. Concerning the fibrinolytic reaction, we found a slightly more elevated increase of plasminogen activator inhibitor-1 in the obese LPS group at 300 min (481 [365 - 617] ng/mL vs. 355 [209 - 660] ng/mL; P = 0.66). In our model of endotoxic shock, obese pigs developed a more severe DIC with a more severe procoagulant response. PMID- 26125086 TI - ANGIOGENESIS INHIBITOR ENDOSTATIN PROTECTS MICE WITH SEPSIS FROM MULTIPLE ORGAN DYSFUNCTION SYNDROME. AB - Endostatin is an endogenous inhibitor of vascular endothelium. It can inhibit endothelial cell migration, proliferation, and vascular angiogenesis and is mainly used for anticancer therapy. We have previously found that endostatin is an important node protein in the pathogenesis of sepsis. However, its impacts on sepsis have not yet been reported. We established a septic mouse model using cecal ligation and puncture (CLP) and gave the mice either endostatin or placebo (saline). The effects of endostatin on serum enzyme, Evans blue leakage, lung wet to-dry weight ratio, and cytokine (tumor necrosis factor alpha, interleukin 1beta [IL-1beta], and IL-6) production were assessed. Survival rates were observed for up to 3 days. In addition, we examined the effects of endostatin on serum vascular endothelial growth factor A (VEGF-A), VEGF-C, and pathological changes and scores of lung tissues as well as the phosphorylation of JNK, p38, and ERKl/2 proteins in lung tissues of mice with sepsis. We found that endostatin can increase the survival of septic mice in a time- and dose-dependent manner probably by reducing multiorgan dysfunctions shown by serum indicators, morphologic changes, Evans blue leakage, wet-to-dry weight ratio, and inflammation of lung tissues. In addition, endostatin could reduce serum tumor necrosis factor alpha, IL-1beta, IL-6, and VEGF-C levels in septic mice as well as inhibit phosphorylation of p38 and ERK1/2 in lung tissues of septic mice. This is the first study demonstrating the protective effect of endostatin on sepsis and its possible underlying mechanisms from the aspects of inhibiting inflammatory responses, blocking VEGF receptor, attenuating VEGF-C expression, and reducing vascular permeability. Overall, the study revealed the potential protect role for endostatin in the treatment of sepsis. PMID- 26125087 TI - NOREPINEPHRINE: NOT TOO MUCH, TOO LONG. AB - The study was designed to assess whether high dosages of norepinephrine are associated with increased death rate and to determine the dosage of norepinephrine associated with an intensive care unit (ICU) death rate greater than 90%. We conducted a retrospective, noninterventional, observational study in a single ICU (15 beds) of an academic hospital. From January 2009 to May 2013, data of all patients with a diagnosis of septic shock were extracted from our database. Data were collected at the time of the admission in ICU, at the onset of septic shock, and when the maximal posology of norepinephrine was reached. Mortality was assessed in ICU, in hospital, and at day 90. Among the 324 patients with septic shock, the death rate was 48%. The death rate reached 90% for the quantile of patients receiving more than 1 MUg/kg per minute of norepinephrine. In our cohort, four independent factors associated with mortality were identified: age (odds ratio, 1.02 [95% confidence interval, 1.00-1.04]; P = 0.02), thrombocytopenia (odds ratio, 3.8 [95% confidence interval, 1.8-8.5]; P < 0.001), urine output less than 500 mL (odds ratio, 8.7 [95% confidence interval, 3.6-25]; P < 0.001), and dosage of norepinephrine greater than 1 MUg/kg per minute (odds ratio, 9.7 [95% confidence interval, 4.5-23]; P < 0.001). However, because of the study's design, unmeasured confounding factors should be taken into account in our findings. PMID- 26125090 TI - Copper-/Cobalt-Catalyzed Highly Selective Radical Dioxygenation of Alkenes. AB - A highly selective radical dioxygenation of alkenes using hydroxamic acid and O2 was developed, and copper/cobalt was used as the catalyst without assistance of any additional ligands or bases. Mechanistic investigation disclosed that copper salt and O2 work in concert to activate hydroxamic acid, with Cu(I) and Cu(II) concurrently existing in this reaction. PMID- 26125091 TI - Healthcare professionals' stigmatization of men with anabolic androgenic steroid use and eating disorders. AB - Building upon previous research on the stigmatization of individuals with eating disorders (EDs), the present study sought to evaluate healthcare providers' attitudes toward male anabolic androgenic steroid (AAS) users. Healthcare providers (N=148) were first randomly assigned to read one of four vignettes describing a male AAS user, ED patient, cocaine user, or healthy control. Each provider then rated, on a scale of -3 to +3, how strongly either word in one of 22 word-pairs described his or her feelings toward the person described in the vignette. Results indicated that providers perceived the ED and AAS use patients less favorably than the cocaine user or healthy adult, suggesting that the two groups may be stigmatized by health providers. Given the psychiatric and medical risks associated with AAS use and EDs, reducing bias may help reduce the personal suffering and public health burden related to these behaviors. PMID- 26125088 TI - ENDOPLASMIC RETICULUM STRESS IN SEPSIS. AB - Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units. Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration, is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle, is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under stress and inflammatory conditions, ER loses homeostasis in its function, which is termed ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once stress is beyond the compensatory capacity of UPR or protracted, apoptosis would be initiated by triggering cell injuries, even cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidence that ER stress participates in the pathogenesis of sepsis. In this review, we summarize current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma-hemorrhage and ischemia/reperfusion injury. We also discuss the potential implications of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis. PMID- 26125092 TI - Quantitative Evaluation of Peptide-Material Interactions by a Force Mapping Method: Guidelines for Surface Modification. AB - Peptide coatings on material surfaces have demonstrated wide application across materials science and biotechnology, facilitating the development of nanobio interfaces through surface modification. A guiding motivation in the field is to engineer peptides with a high and selective binding affinity to target materials. Herein, we introduce a quantitative force mapping method in order to evaluate the binding affinity of peptides to various hydrophilic oxide materials by atomic force microscopy (AFM). Statistical analysis of adhesion forces and probabilities obtained on substrates with a materials contrast enabled us to simultaneously compare the peptide binding affinity to different materials. On the basis of the experimental results and corresponding theoretical analysis, we discuss the role of various interfacial forces in modulating the strength of peptide attachment to hydrophilic oxide solid supports as well as to gold. The results emphasize the precision and robustness of our approach to evaluating the adhesion strength of peptides to solid supports, thereby offering guidelines to improve the design and fabrication of peptide-coated materials. PMID- 26125093 TI - Evaluating the Effects of an Interdisciplinary Practice Model with Pharmacist Collaboration on HIV Patient Co-Morbidities. AB - Treatment of HIV now occurs largely within the primary care setting, and the principal focus of most visits has become the management of chronic disease states. The clinical pharmacist's potential role in improving chronic disease outcomes for HIV patients is unknown. A retrospective cohort study was performed for HIV-positive patients also diagnosed with diabetes, hypertension, or hyperlipidemia. Characteristics and outcomes in 96 patients treated by an interdisciplinary team that included a clinical pharmacist (i.e., the intervention group) were compared to those in 50 patients treated by an individual healthcare provider (i.e., the control group). Primary outcomes were changes from baseline over 18 months of HbA1c, low density lipoprotein (LDL), and blood pressure, respectively. Secondary outcomes included number of drug-drug interactions, HIV viral load, CD4 count, percent change in smoking status, and percent of patients treated to cardiovascular guideline recommendations. The interdisciplinary team had a significant improvement in lipid management over the control group (LDL: -8.8 vs. +8.4 mg/dL; p=0.014), and the smoking cessation rate over the study period was doubled in the interdisciplinary group (20.4% vs. 11.8%). Among those with an indication for aspirin, a significantly higher percentage of patients were prescribed the medication in the interdisciplinary group compared to the control group (85.5% vs. 64.9%; p=0.014). An informal cost analysis estimated savings of more than $3000 per patient treated by the interdisciplinary team. Based on these results, pharmacist involvement in an HIV primary care clinic appears to lead to more appropriate management of chronic co morbidities in a cost-effective manner. PMID- 26125094 TI - Interplay between spin-orbit coupling and crystal-field effect in topological insulators. AB - Band inversion, one of the key signatures of time-reversal invariant topological insulators (TIs), arises mostly due to the spin-orbit (SO) coupling. Here, based on ab initio density-functional calculations, we report a theoretical investigation of the SO-driven band inversion in isostructural bismuth and antimony chalcogenide TIs from the viewpoint of its interplay with the crystal field effect. We calculate the SO-induced energy shift of states in the top valence and bottom conduction manifolds and reproduce this behavior using a simple one-atom model adjusted to incorporate the crystal-field effect. The crystal-field splitting is shown to compete with the SO coupling, that is, stronger crystal-field splitting leads to weaker SO band shift. We further show how both these effects can be controlled by changing the chemical composition, whereas the crystal-field splitting can be tuned by means of uniaxial strain. These results provide a practical guidance to the rational design of novel TIs as well as to controlling the properties of existing materials. PMID- 26125095 TI - Selecting Patients for Endocervical Curettage. PMID- 26125096 TI - Impact of Possibly Oncogenic High-Risk Human Papillomavirus (HPV) Types in Triage for ASC-US Cervical Cytology Results. AB - OBJECTIVE: Current guidelines recommend including 13 or 14 high-risk human papillomavirus (HPV) types for triage of atypical squamous cells of undetermined significance (ASC-US) cervical cytology; however, at least 13 additional types are considered possibly oncogenic. We evaluated the effect of including possibly oncogenic HPV types in the test panel. METHODS: Outcomes for all women 30 years or older with ASC-US and positive HPV testing who underwent colposcopic biopsy at University of Washington Medical Center-affiliated clinics between 2010 and 2011 were reviewed. We compared biopsy results between cases that were HPV positive for 1 or more of 13 possibly oncogenic types only (26/53/55/62/64/67/69/71/73/82/83/84/IS39) versus 1 or more of the 14 established high-risk types (16/18/31/33/35/39/45/51/52/56/58/59/66/68). We used the Fisher exact test to compare cervical intraepithelial neoplasia grade 2 or higher (CIN2+) diagnoses between HPV risk groups. RESULTS: Three hundred twenty-six ASC US HPV-positive cervical cytology results were identified, with 170 that were linked to subsequent cervical biopsy results. Among 51 cases positive for possibly oncogenic types only, 31 (61%) had no neoplasia, 20 (39%) had CIN1, and none had CIN2+. Among 119 controls positive for at least one established high risk type, 64 (53%) had no neoplasia, 42 (35%) had CIN1, and 13 (11%) had CIN2+ (p = .01 for the comparison of CIN2+ diagnoses between groups). CONCLUSIONS: The inclusion of possibly oncogenic types in the HPV test panel led to an additional 51 colposcopy biopsies (33% increase), with no additional cases of CIN 2+. Our results suggest that including possibly oncogenic HPV types increases the number of colposcopy biopsies with minimal improvements in detection of CIN2 +. PMID- 26125098 TI - Sub-0.5 nm equivalent oxide thickness scaling for Si-doped Zr1-xHfxO2 thin film without using noble metal electrode. AB - The dielectric properties of the Si-doped Zr1-xHfxO2 thin films were investigated over a broad compositional range with the goal of improving their properties for use as DRAM capacitor materials. The Si-doped Zr1-xHfxO2 thin films were deposited on TiN bottom electrodes by atomic layer deposition using a TEMA Zr/TEMA-Hf mixture precursor for deposition of Zr1-xHfxO2 film and Tris-EMASiH as a Si precursor. The Si stabilizer increased the tetragonality and the dielectric constant; however, at high fractions of Si, the crystal structure degraded to amorphous and the dielectric constant decreased. Doping with Si exhibited a larger influence on the dielectric constant at higher Hf content. A Si-doped Hf rich Zr1-xHfxO2 thin film, with tetragonal structure, exhibited a dielectric constant of about 50. This is the highest value among all reported results for Zr and Hf oxide systems, and equivalent oxide thickness (EOT) value of under 0.5 nm could be obtained with a leakage current of under 10(-7) A.cm(-2), which is the lowest EOT value ever reported for a DRAM storage capacitor system without using a noble-metal-based electrode. PMID- 26125097 TI - The Effect of Cryotherapy on Human Papillomavirus Clearance Among HIV-Positive Women in Lusaka, Zambia. AB - OBJECTIVE: We sought to investigate the progression of human papillomaviruses (HPV) infection in HIV-positive women after cryotherapy. METHODS: We examined changes in detection of high-risk HPV (hrHPV) cervical infections among HIV infected women over a 12-week period after cryotherapy using stored specimens from a cohort study conducted between June 2009 and March 2011 in Lusaka, Zambia. Samples from visits at baseline and weeks 4, 8, and 12 were tested using the Roche Linear Array assay. RESULTS: A total of 89 women were included in the analysis. The median age was 32 years (interquartile range [IQR], 28-36 years). The median CD4+ cell count was 350 cells/MUL (IQR, 214-470 cells/MUL), and 66% of women were receiving antiretroviral therapy. At baseline, the prevalence of hrHPV was 91% (95% confidence interval [CI], 83%-95%). HPV45 was the most common HPV type, present in (30%) women, followed by HPV16 (27%), HPV18 (27%), HPV51 (20%), and HPV58 (22%). Among women with valid results both at baseline and 12 weeks, 25% (17/67) cleared their initial hrHPV infection within 12 weeks of treatment, although 65% (11/17) had new hrHPV types detected. CONCLUSIONS: Cryotherapy led to clearance of 25% of hrHPV infections within 12 weeks of treatment. However, hrHPV infection remained persistent in most women, and new hrHPV types were detected often, explaining the high rate of persistence and recurrence of cervical disease in this population. Continued efforts to scale up HPV vaccination and cervical screening should remain a priority in high HIV burden settings such as Zambia. PMID- 26125099 TI - Pleural effusion levels of DJ-1 are increased in elderly lung cancer patients with malignant pleural effusions. AB - OBJECTIVES: DJ-1 is a multifunctional protein implicated in redox dependent cell fate decisions. The aim of our study was to determine the pleural fluid (PF) levels of DJ-1 in malignant pleural effusions (MPEs) secondary to lung cancer. Additionally, we opted to assess potential correlations of DJ-1 PF levels with the PF levels of superoxide dismutase-1 (SOD1) and 8-isoprostane that are known antioxidant enzymes and have been previously reported in MPEs. METHODS: Forty lung cancer patients with cytological proof of MPE were enrolled in this study. The PF levels of DJ-1, SOD1, and 8-isoprostane were measured by means of enzyme linked immunosorbent assay. RESULTS: The median PF levels of DJ-1 were 826 ng/mL (interquartile range, IQR: 482-1010 ng/mL). DJ-1 PF levels significantly correlated with PF Cu/Zn-SOD1 and PF 8-isoprostane levels (Spearman's rho, r; r = -0.476, P = 0.002 and r = -0.264, P = 0.033, respectively), PF lactate dehydrogenase (r = -0.497, P = 0.001) and total PF cell counts (r = -0.325, P = 0.041). Finally, in patients aged over 65 the PF DJ-1 levels were significantly higher than patients aged less than 65 (875 ng/mL vs. 607 ng/mL, respectively, P = 0.037). DISCUSSION: To our knowledge, this is the first report to determine DJ 1's levels in MPEs due to lung cancer. The negative correlations between DJ-1, SOD1, and 8-isorpostane warrant further investigation regarding the altered redox regulation associated with MPEs. PMID- 26125100 TI - DNA is an efficient booster of dendritic cell-based vaccine. AB - DC-based therapeutic vaccines as a promising strategy against chronic infections and cancer have been validated in several clinical trials. However, DC-based vaccines are complex and require many in vitro manipulations, which makes this a personalized and expensive therapeutic approach. In contrast, DNA-based vaccines have many practical advantages including simplicity, low cost of manufacturing and potent immunogenicity already proven in non-human primates and humans. In this study, we explored whether DC-based vaccines can be simplified by the addition of plasmid DNA as prime or boost to achieve robust CD8-mediated immune responses. We compared the cellular immunity induced in BALB/c and C57BL/6 mice by DC vaccines, loaded either with peptides or optimized SIV Env DNA, and plasmid DNA-based vaccines delivered by electroporation (EP). We found that mature DC loaded with peptides (P-mDC) induced the highest CD8(+) T cell responses in both strains of mice, but those responses were significantly higher in the C57BL/6 model. A heterologous prime-boost strategy (P-DC prime-DNA boost) induced CD8(+) T cell responses similar to those obtained by the P-DC vaccine. Importantly, this strategy elicited robust polyfunctional T cells as well as highest antigen specific central memory CD8+ T cells in C57BL/6 mice, suggesting long-term memory responses. These results indicate that a DC-based vaccine in combination with DNA in a heterologous DC prime-DNA boost strategy has potential as a repeatedly administered vaccine. PMID- 26125101 TI - Randomized comparison of health-related quality of life in women with ectopic pregnancy or pregnancy of unknown location treated with systemic methotrexate or expectant management. AB - OBJECTIVE: To study the impact on health-related quality of life (HRQoL) of treatment with systemic methotrexate (MTX) or expectant management in women with ectopic pregnancy or pregnancy of unknown location (PUL) with low and plateauing serum hCG concentrations. STUDY DESIGN: HRQoL was assessed alongside a randomized clinical trial (RCT) with the use of standard self-administered psychometric measure questionnaires. PATIENTS AND SETTING: All women who participated in the multicenter RCT comparing treatment with systemic MTX to expectant management in women with ectopic pregnancy or persisting PUL were eligible for the HRQoL measurements. MAIN OUTCOME MEASURE: HRQoL measures of three standardized questionnaires (SF-36, RSCL, HADS). RESULTS: Data were available for 64 of 73 women (78%) randomized in the RCT. We found no difference in HRQoL between the two treatment groups. The need for additional treatment, i.e. additional MTX injections or surgical intervention, had no impact on HRQoL. CONCLUSION: Women treated with MTX or expectant management for an ectopic pregnancy or persisting PUL have comparable quality of life. PMID- 26125102 TI - The role of neutrophils in the pathogenesis of systemic lupus erythematosus. AB - PURPOSE OF REVIEW: Recent discoveries implicate neutrophils as important regulators of innate and adaptive immunity and in the development of organ damage in systemic autoimmune diseases, including systemic lupus erythematosus (SLE). RECENT FINDINGS: Various putative SLE biomarkers are neutrophil-related, including neutrophil granular proteins and histones undergoing post-translational modifications during neutrophil extracellular trap (NET) formation. In the bone marrow, lupus neutrophils can drive B and T cell abnormalities, at least in part, by their enhanced production of type-I interferons, tumor necrosis factor-alpha (TNFalpha) and the B-cell stimulating factors B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Lupus neutrophils and, in particular, lupus low-density granulocytes (a distinct pathogenic subset) display epigenetic modifications and genomic alterations that may be relevant to their deleterious roles in SLE. Proteins and enzymes externalized by lupus NETs can affect vascular health by inducing endothelial apoptosis and oxidizing lipoproteins. Hampering NET formation through peptidylarginine deiminase inhibitors abrogates lupus phenotype and atherosclerosis in murine studies. SUMMARY: Recent discoveries support the notion that neutrophils, low-density granulocytes and aberrant NET formation and clearance play important roles in lupus pathogenesis. Future studies should focus on how to selectively target these immunostimulatory pathways in this disease. PMID- 26125104 TI - Update on the pathogenesis and treatment of the antiphospholipid syndrome. AB - PURPOSE OF REVIEW: Many advancements in our understanding of the pathogenic mechanisms of the antiphospholipid syndrome (APS) have been accomplished over the recent months. Such progresses are paralleled by the development of innovative pharmacological tools that could provide novel therapeutic windows in APS management. The most recent and innovative findings about the biologic effects of antiphospholipid antibodies (aPLs) and the treatment APS will be hereby critically appraised. RECENT FINDINGS: Antibodies against the domain I of beta2 glycoprotein I (beta2GPI) are increasingly recognized as the main pathogenic subset; pioneer therapeutic options exploiting the pathogenicity of anti-domain I antibodies have been developed. AnnexinA2 and toll-like receptor (TLR)4 have been identified as the main receptors for beta2GPI/anti-beta2GPI antibodies on target cells; additional co-receptors might include TLR1, TLR2 and TLR6. Upon binding, aPLs engage intracellular mediators as nuclear factor kappa B and mammalian target of rapamycin, which provide potential therapeutic targets. Current innovative treatment options include novel oral anticoagulants and the complement inhibitor eculizumab. The addition to standard treatment of pleiotropic agents such as hydroxychloroquine, statins and vitamin D could allow better disease control. SUMMARY: The lively and intense research in the APS field opens new frontiers in aPL pathogenic mechanisms, as well as diagnosis and treatment of the syndrome. VIDEO ABSTRACT: http://links.lww.com/COR/A26. PMID- 26125103 TI - Preclinical lupus. AB - PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is often preceded by immune dysregulation and clinical manifestations below the threshold for SLE classification. This review discusses current and evolving concepts about the preclassification period of SLE, including clinical and mechanistic observations, and potential avenues for early identification and intervention. RECENT FINDINGS: Although incomplete lupus erythematosus (ILE) involves fewer clinical manifestations than SLE, ILE patients can suffer organ damage and early mortality. Common clinical features in ILE include antinuclear antibody seropositivity, polyarthritis, immunologic manifestations, and hematological disorders. Despite having lower disease activity and damage scores than SLE patients, ILE patients may develop pulmonary arterial hypertension, or renal, neurological, or peripheral vascular damage. The recently proposed Systemic Lupus International Collaborating Clinics SLE classification criteria could shift the period considered 'preclinical SLE'. Murine studies suggest that the balance of T helper/T-regulatory cells, peroxisome proliferator-activated receptor gamma activity, and plasmacytoid dendritic cell pathways may be valuable targets for early intervention. SUMMARY: Advances in our understanding of early SLE, including stages before clinical features are fully developed, will improve our ability to identify individuals at high risk of classification for potential prevention trials, provide necessary information to improve diagnostic testing, and perhaps identify novel targets for directed therapeutics in clinical SLE. PMID- 26125105 TI - Malignancies in systemic lupus erythematosus: a 2015 update. AB - PURPOSE OF REVIEW: Patients with systemic lupus erythematosus (SLE) have altered incidences of certain malignancies as compared with the general population. This review summarizes the recent literature on risk of malignancy in SLE and proposed mechanisms for these altered susceptibilities. RECENT FINDINGS: Recent studies have confirmed previous data showing an increased risk of non-Hodgkin's lymphoma, lung, liver, vulvar/vaginal, and thyroid malignancies, whereas demonstrating a decreased risk of breast and prostate cancer. Lymphomagenesis in SLE has been linked to increased activity of multiple inflammatory cytokines as well as possible viral diseases. The decreased rates of hormone-sensitive cancers, such as breast and prostate, are speculated to be related to the presence of lupus autoantibodies and downregulation of certain proteins in SLE. This knowledge has been utilized to investigate new therapeutic modalities for these malignancies. SUMMARY: Recent data confirm previously reported altered malignancy rates in SLE. Most striking in recent years are publications further elucidating mechanisms underlying cancer development in SLE, and subsequent investigations of potential therapeutics modulating these pathways. PMID- 26125106 TI - A Concise and Atom-Economical Suzuki-Miyaura Coupling Reaction Using Unactivated Trialkyl- and Triarylboranes with Aryl Halides. AB - A concise and atom-economical Suzuki-Miyaura coupling of trialkyl- and triarylboranes with aryl halides is described. This new protocol represents the first general, practical method that efficiently utilizes peralkyl and peraryl groups of the unactivated trialkyl- and triarylboranes for the Suzuki-Miyaura coupling reaction. PMID- 26125108 TI - Computed tomography measurement of hepatic steatosis: Prevalence of hepatic steatosis in a Canadian population. PMID- 26125107 TI - Partially covered self-expandable metal stents versus polyethylene stents for malignant biliary obstruction: a cost-effectiveness analysis. AB - BACKGROUND/ OBJECTIVE: Partially covered self-expandable metal stents (SEMS) and polyethylene stents (PES) are both commonly used in the palliation of malignant biliary obstruction. Although SEMS are significantly more expensive, they are more efficacious than PES. Accordingly, a cost-effectiveness analysis was performed. METHODS: A cost-effectiveness analysis compared the approach of initial placement of PES versus SEMS for the study population. Patients with malignant biliary obstruction underwent an endoscopic retrograde cholangiopancreatography to insert the initial stent. If the insertion failed, a percutaneous transhepatic cholangiogram was performed. If stent occlusion occurred, a PES was inserted at repeat endoscopic retrograde cholangiopancreatography, either in an outpatient setting or after admission to hospital if cholangitis was present. A third-party payer perspective was adopted. Effectiveness was expressed as the likelihood of no occlusion over the one-year adopted time horizon. Probabilities were based on a contemporary randomized clinical trial, and costs were issued from national references. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: A PES-first strategy was both more expensive and less efficacious than an SEMS-first approach. The mean per-patient costs were US$6,701 for initial SEMS and US$20,671 for initial PES, which were associated with effectiveness probabilities of 65.6% and 13.9%, respectively. Sensitivity analyses confirmed the robustness of these results. CONCLUSION: At the time of initial endoscopic drainage for patients with malignant biliary obstruction undergoing palliative stenting, an initial SEMS insertion approach was both more effective and less costly than a PES-first strategy. PMID- 26125110 TI - Bilayer Molecular Metals Based on Dissymmetrical Electron Donors. AB - The electrocrystallization from solutions of cyanobenzene-ethylenedithio tetrathiafulvalene (CNB-EDT-TTF) in the presence of different anions X = ClO4(-), PF6(-), and I3(-), affords a new type of 2D molecular metals with composition (CNB-EDT-TTF)4X based on an unprecedented bilayer structure of the donors induced by effective head to head interdonor interactions through the nitrile groups, which is responsible for 2D metallic systems with unusual properties such as the higher band filling, larger effective mass of carriers, and almost degenerated double Fermi surfaces. PMID- 26125109 TI - Clinicians' guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease. AB - BACKGROUND: Objective monitoring of the severity of inflammation in patients with inflammatory bowel disease (IBD) is an essential part of disease management. However, repeat endoscopy to define extent and severity of inflammation is not practical. Fecal calprotectin (FC) is a biomarker that can be used as a surrogate test to distinguish inflammatory from noninflammatory gastrointestinal disease. METHODS: A targeted search of the literature regarding FC, focusing primarily on the past three years, was conducted to develop practical clinical guidance on the current utility of FC in the routine management of IBD patients. RESULTS: It is recommended that samples for FC testing be obtained from the first bowel excretion of the day. FC testing should be used as standard of care to accurately confirm inflammation and 'real-time' disease activity when a clinician suspects an IBD flare. Although FC is a reliable marker of inflammation, its role in routine monitoring in improving long-term outcomes has not yet been fully assessed. Based on available evidence, the authors suggest the following cut-off values and management strategies: when FC levels are <50 ug/g to 100 ug/g, quiescent disease is likely and therapy should be continued; when FC levels are >100 ug/g to 250 ug/g, inflammation is possible and further testing (eg, colonoscopy) is required to confirm inflammation; and when FC levels are >250 ug/g, active inflammation is likely and strategies to control inflammation should be initiated (eg, optimizing current therapies or switching to an alternative therapy). DISCUSSION: FC is a useful biomarker to accurately assess the degree of inflammation and should be incorporated into the management of patients with IBD. PMID- 26125111 TI - Assessment of fat and lean mass by quantitative magnetic resonance: a future technology of body composition research? AB - PURPOSE OF REVIEW: For the assessment of energy balance or monitoring of therapeutic interventions, there is a need for noninvasive and highly precise methods of body composition analysis that are able to accurately measure small changes in fat and fat-free mass (FFM). RECENT FINDINGS: The use of quantitative magnetic resonance (QMR) for measurement of body composition has long been established in animal studies. There are, however, only a few human studies that examine the validity of this method. These studies have consistently shown a high precision of QMR and only a small underestimation of fat mass by QMR when compared with a 4-compartment model as a reference. An underestimation of fat mass by QMR is also supported by the comparison between measured energy balance (as a difference between energy intake and energy expenditure) and energy balance predicted from changes in fat mass and FFM. Fewer calories were lost and gained as fat mass compared with the value expected from measured energy balance. SUMMARY: Current evidence in healthy humans has shown that QMR is a valid and precise method for noninvasive measurement of body composition. Contrary to standard reference methods, such as densitometry and dual X-ray absorptiometry, QMR results are independent of FFM hydration. However, despite a high accuracy and a low minimal detectable change, underestimation of fat mass by QMR is possible and limits the use of this method for quantification of energy balance. PMID- 26125112 TI - A changing landscape: web-based methods for dietary assessment in adolescents. AB - PURPOSE OF REVIEW: Adolescents' dietary intake is an important determinant of health and well-being and is influenced by a complex interaction of environmental, social, psychological, and physiological factors. The complexity of the adolescent diet makes its assessment prone to error, which has prompted researchers and clinicians to turn to technology to reduce this error. Previous reviews have been conducted regarding the use of technology in dietary assessment for adults; however, there are no known reviews for adolescents. Therefore, the purpose of this review is to describe the practical considerations for web-based dietary assessment methods and to evaluate recent evidence on their validity and implications. RECENT FINDINGS: There are numerous web-based dietary assessment methods that are available, valid, and reliable for use in the adolescent population. Web-based methods include both native and web-based applications (or 'apps'), and have been developed for use as food records, 24-h dietary recalls, and food frequency questionnaires. SUMMARY: Web-based methods provide an efficient, cost-effective and practical solution to assess dietary intake; they are less burdensome to respondents and reduce errors and bias. Furthermore, adolescents are technologically savvy and often prefer the use of technology. Web based methods should be considered when assessing adolescents' dietary intake. PMID- 26125113 TI - Surgical Site Infections Rates in More Than 13,000 Surgical Procedures in Three Cities in Peru: Findings of the International Nosocomial Infection Control Consortium. AB - BACKGROUND: Surgical site infections (SSIs) are a threat to patient safety. However, there are not available data on SSI rates stratified by surgical procedure (SP) in Peru. METHODS: From January 2005 to December 2010, a cohort prospective surveillance study on SSIs was conducted by the International Nosocomial Infection Control Consortium (INICC) in four hospitals in three cities of Peru. Data were recorded from hospitalized patients using the U.S. Centers for Disease Control and Prevention-National Healthcare Safety Network (CDC-NHSN) methods and definitions for SSI. Surgical procedures (SPs) were classified into 4 types, according to ICD-9 criteria. RESULTS: We recorded 352 SSIs, associated to 13,904 SPs (2.5%; CI, 2.3-2.8) SSI rates per type of SP were the following for this study's Peruvian hospitals, compared with rates of the INICC and CDC-NHSN reports, respectively: 2.9% for appendix surgery (vs. 2.9% vs. 1.4%); 2.8% for gallbladder surgery (vs. 2.5% vs. 0.6%); 2.2% for cesarean section (vs. 0.7% vs. 1.8%); 2.8% for vaginal hysterectomy (vs. 2.0% vs. 0.9%). CONCLUSIONS: Our SSIs rates were higher in all of the four analyzed types of SPs compared with CDC NHSN, whereas compared with INICC, most rates were similar. This study represents an important advance in the knowledge of SSI epidemiology in Peru that will allow us to introduce targeted interventions. PMID- 26125114 TI - Cyclin B3 controls anaphase onset independent of spindle assembly checkpoint in meiotic oocytes. AB - Cyclin B3 is a relatively new member of the cyclin family whose functions are little known. We found that depletion of cyclin B3 inhibited metaphase-anaphase transition as indicated by a well-sustained MI spindle and cyclin B1 expression in meiotic oocytes after extended culture. This effect was independent of spindle assembly checkpoint activity, since both Bub3 and BubR1 signals were not observed at kinetochores in MI-arrested cells. The metaphase I arrest was not rescued by either Mad2 knockdown or cdc20 overexpression, but it was rescued by securin RNAi. We conclude that cyclin B3 controls the metaphase-anaphase transition by activating APC/C(cdc20) in meiotic oocytes, a process that does not rely on SAC activity. PMID- 26125116 TI - Interaction of menthol with mixed-lipid bilayer of stratum corneum: A coarse grained simulation study. AB - Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. Although there are many studies focused on the penetration-enhancing activity of menthol, the details of molecular mechanism are rarely involved in the discussion. In this study, we present a series of coarse-grained molecular dynamics simulations to investigate the interaction of menthol with a mixed-lipid bilayer model consisting of ceramides, cholesterol and free fatty acids in a 2:2:1 molar ratio. Taking both the concentration of menthol and temperature into consideration, it was found that a rise in temperature and concentration within a specific range (1-20%) could improve the penetration enhancing property of menthol and the floppiness of the bilayer. However, at high concentrations (30% and more), menthol completely mixed with the lipids and the membrane can no longer maintain a bilayer structure. Our results elucidates some of the molecular basis for menthol's penetration enhancing effects and may provide some assistance for the development and applications of menthol as a penetration enhancer. Furthermore, we establish a method to investigate the penetration enhancement mechanism of traditional Chinese medicine using the mixed lipid bilayer model of stratum corneum by molecular dynamics simulations. PMID- 26125117 TI - American Academy of Periodontology Task Force Report on the Update to the 1999 Classification of Periodontal Diseases and Conditions. PMID- 26125118 TI - In Search of an Efficient Photoswitch for Functional RNA: Design Principles from a Microscopic Analysis of Azobenzene-linker-RNA Dynamics with Different Linkers. AB - The design of optimal photoswitches to regulate nucleic acid functionality is a considerable challenge. Azobenzene switches that are covalently bound to the nucleic acid backbone are a paradigm example that has been studied using different types of linker species connecting the chromophore to the backbone. To support experimental efforts to construct optimal azobenzene-linker-RNA combinations, we introduce here a systematic approach for theoretical analysis, which provides criteria for the local embedding of the chromophore via a chosen linker. Using a local reference frame adapted to the chromophore, quantitative measures are provided for (i) the propensity of stacking in competition with a drift toward the minor or major groove, (ii) the tendency to disrupt the native hydrogen bond network, (iii) the structural flexibility of the chromophore-linker combination, and (iv) the correlations with the presence of a base in the opposite strand. Large differences in structural stability between the trans and cis forms of the azobenzene chromophore, according to these criteria, indicate good functionality and lead to significant differences in melting temperatures. In particular, a recently synthesized deoxyribose linker proves optimal within the set of azobenzene-linker-RNA combinations considered. PMID- 26125120 TI - Impact of outpatient non-myeloablative haematopoietic stem cell transplantation in quality of life vs. conventional therapy. AB - The role of outpatient hematopoietic stem cell transplantation (HSCT) as a therapeutic tool has been strengthened significantly because of the increasing number of patients undergoing this treatment. Due the very nature of this procedure, one of the aspects that should not be overlooked is the quality of life (QOL) of patients undergoing HSCT. Thus, one must consider not only health status after treatment, but also, the psychosocial implications for the patient. This is an observational, longitudinal, and prospective study to assess QOL in patients undergoing outpatient HSCT vs. similar patients receiving medical treatment (MxTx). By applying the COOP/WONKA charts on five occasions (pre HSCT/initial, post-HSCT/first month, and at 3, 6, and 9 months), thirty-eight patients were analysed, 19 with HSCT and 19 with MxTx with no differences in age, gender or diagnosis. The initial survey found significant differences only in pain perception, which was higher in the HSCT group (p = .08); at the first month, there was a greater tendency for feelings of depression or anxiety in the HSCT group (p = .016), with more limitations in social (p = .003) and daily (p = .044) activities. From 3 months post-HSCT, the results were very similar. The differences persisted only in the area of social activities. Four patients developed graft-versus-host disease with no significant difference in the scores obtained compared to other transplant patients at 3, 6, and 9 months (p = .26) of follow-up. PMID- 26125119 TI - Baseline brain perfusion and brain structure in patients with major depression: a multimodal magnetic resonance imaging study. AB - BACKGROUND: Abnormal regional cerebral blood flow (rCBF) and grey matter volume have been frequently reported in patients with major depressive disorder (MDD). However, it is unclear to what extent structural and functional change co-occurs in patients with MDD and whether markers of neural activity, such as rCBF, can be predicted by structural change. METHODS: Using MRI, we investigated resting-state rCBF and brain structure in patients with MDD and healthy controls between July 2008 and January 2013. We acquired perfusion images obtained with continuous arterial spin labelling, used voxel-based morphometry to assess grey matter volume and integrated biological parametric mapping analyses to investigate the impact of brain atrophy on rCBF. RESULTS: We included 43 patients and 29 controls in our study. Frontotemporal grey matter volume was reduced in patients compared with controls. In patients, rCBF was reduced in the anterior cingulate and bilateral parahippocampal areas and increased in frontoparietal and striatal regions. These abnormalities were confirmed by analyses with brain volume as a covariate. In patients with MDD there were significant negative correlations between the extent of depressive symptoms and bilateral parahippocampal rCBF. We found a positive correlation between depressive symptoms and rCBF for right middle frontal cortical blood flow. LIMITATIONS: Medication use in patients has to be considered as a limitation of our study. CONCLUSION: Our data suggest that while changes of cerebral blood flow and brain volume co-occur in patients with MDD, structural change is not sufficient to explain altered neural activity in patients at rest. Abnormal brain structure and function in patients with MDD appear to reflect distinct levels of neuropathology. PMID- 26125121 TI - Predawn respiration rates during flowering are highly predictive of yield response in Gossypium hirsutum when yield variability is water-induced. AB - Respiratory carbon evolution by leaves under abiotic stress is implicated as a major limitation to crop productivity; however, respiration rates of fully expanded leaves are positively associated with plant growth rates. Given the substantial sensitivity of plant growth to drought, it was hypothesized that predawn respiration rates (RPD) would be (1) more sensitive to drought than photosynthetic processes and (2) highly predictive of water-induced yield variability in Gossypium hirsutum. Two studies (at Tifton and Camilla Georgia) addressed these hypotheses. At Tifton, drought was imposed beginning at the onset of flowering (first flower) and continuing for three weeks (peak bloom) followed by a recovery period, and predawn water potential (PsiPD), RPD, net photosynthesis (AN) and maximum quantum yield of photosystem II (Fv/Fm) were measured throughout the study period. At Camilla, plants were exposed to five different irrigation regimes throughout the growing season, and average PsiPD and RPD were determined between first flower and peak bloom for all treatments. For both sites, fiber yield was assessed at crop maturity. The relationships between PsiPD, RPD and yield were assessed via non-linear regression. It was concluded for field-grown G. hirsutum that (1) RPD is exceptionally sensitive to progressive drought (more so than AN or Fv/Fm) and (2) average RPD from first flower to peak bloom is highly predictive of water-induced yield variability. PMID- 26125122 TI - Proline synthesis in barley under iron deficiency and salinity. AB - This work investigates proline synthesis in six barley varieties subjected to iron deficiency, salinity or both stresses. The highest growth under Fe sufficiency corresponded to Belgrano and Shakira. A moderate augment of leaf phosphoenolpyruvate carboxylase (PEPC) activity was observed in all six varieties in response to Fe deficiency, consistently in leaves and sporadically in roots. All six varieties accumulated proline under Fe deficiency, to a higher extent in leaves than in roots. The decrease of Fe supply from 100 MUM NaFe(III)-EDTA to 0.5 MUM NaFe(III)-EDTA reduced growth and photosynthetic pigments similarly in the six barley varieties. On the contrary, differences between varieties could be observed with respect to increased or, conversely, decreased proline content as a function of the amount of NaFe(III)-EDTA supplied. These two opposite types were represented by Belgrano (higher proline under Fe deficiency) and Shakira (higher proline under Fe sufficiency). Time-course experiments suggested that leaf PEPC activity was not directly responsible for supplying C for proline synthesis under Fe deficiency. High proline levels in the leaves of Fe-deficient Belgrano plants in salinity were associated to a better performance of this variety under these combined stresses. PMID- 26125123 TI - Regulation of invertase activity in different root zones of wheat (Triticum aestivum L.) seedlings in the course of osmotic adjustment under water deficit conditions. AB - Osmotic adjustment of roots is an essential adaptive mechanism to sustain water uptake and root growth under water deficit. In this paper, the role of invertases (beta-fructofuranosidase, EC 3.2.1.26) in osmotic adjustment was investigated in the root tips (cell division and elongation zone) and the root maturation zone of wheat (Triticum aestivum L. cv. Josef) in the course of osmotic stress imposed by 20% polyethylene glycol (PEG) 6000. The two root zones investigated differed distinctly in the response of invertases to water deprivation. In the root tips, the activity of the vacuolar and cell wall-bound invertases increased markedly under water stress resulting in the accumulation of hexoses (glucose and fructose) that contributed significantly to osmotic adjustment. A transient rise in hydrogen peroxide (H2O2) preceded the enhancement of invertases upon exposure to osmotic stress. Treatment with the NADPH oxidase inhibitor diphenylene iodonium (DPI) abolished the stress induced H2O2 production and suppressed the stimulation of the vacuolar invertase activity, whereas the activity of the cell wall-bound invertase was not influenced by DPI. As a consequence of the inhibitory effect of DPI on the vacuolar invertase, hexose levels and osmotic adjustment were also markedly decreased in the root tips under water deficit in the presence of DPI. These data suggest that H2O2 probably generated by a NADPH oxidase is required as a signalling molecule for the up-regulation of the vacuolar invertase activity in the root tips under osmotic stress, thereby enhancing the capacity for osmotic adjustment. In the root maturation zone, an early H2O2 signal could not be detected in response to PEG application. Only an increase in the glucose level that was not paralleled by fructose and a slight stimulation of the activity of the vacuolar invertase occurred in the maturation zone after water deprivation. The stress induced accumulation of glucose in the maturation zone was not affected by DPI and thus seems to be not regulated by NADPH oxidase-derived H2O2. Altogether, osmotic adjustment was considerably smaller in the maturation zone than in the root tips. PMID- 26125124 TI - Therapeutic management of evans syndrome in a pregnancy with maternal systemic lupus erythematosus. AB - A 31-year-old 2 G 1 P was referred to our unit of prenatal medicine at 35+3 weeks of gestation with a spontaneously conceived singleton pregnancy of a female fetus without detectable anomalies. Maternal hematological evaluation revealed an Evans syndrome-related thrombocytopenia based on a lupus erythematosus. The former delivery was aggravated by a severe hemorrhage several years before. Anti autoimmunologic therapy was started and maternal platelets count increased to physiological values. Uneventful ceasarean section was performed at 37 weeks of gestation with favourable outcome for mother and child. This case is the first report of a successful therapy in maternal Evans syndrome in pregnancy combined with a lupus erythematosus. PMID- 26125125 TI - Electrocatalytic Dihydrogen Production by an Earth-Abundant Manganese Bipyridine Catalyst. AB - Earth-abundant manganese bipyridine complexes have been extensively studied as homogeneous electrocatalysts for proton-coupled CO2 reduction. To date, these manganese complexes have not been examined as catalysts for the reduction of other small molecules. We report electrocatalytic H2 production by [Mn(mesbpy)(CO)3(MeCN)](OTf)]. In acetonitrile, this manganese electrocatalyst displays a turnover frequency (TOF) of 5500 s(-1) at an overpotential of 0.90 V (at Ecat/2) for the reduction of protons to H2 using trifluoroacetic acid (TFA) as the acid source. These findings show the flexibility of these manganese bipyridine complexes to serve as catalysts for a variety of small molecule reductions. PMID- 26125126 TI - An overview of experimental and early investigational therapies for the treatment of polycystic kidney disease. AB - INTRODUCTION: At present, treatment of autosomal dominant polycystic kidney disease (ADPKD) is essentially supportive as there is still no specific therapy. However, recent advances with ADPKD pathophysiology have stimulated research for new therapeutic strategies. AREAS COVERED: The aim of this systematic review is to analyze the experimental and early investigational therapies currently under evaluation in this field. Data from completed clinical trials were retrieved from the currently available scientific literature and from the ClinicalTrials.gov website. EXPERT OPINION: Among the drugs currently being explored, mammalian target of rapamycin inhibitors reduce kidney volume enlargement but their role remains uncertain. The most promising drug is the V2 receptor antagonist tolvaptan, which reduces the increased rate of total kidney volume and slows down glomerular filtration rate decline. The main candidates for the treatment of cysts growth, both in the kidney and in the liver whenever present, are the somatostatin analogues, such as lanreotide and octreotide and more recently pasireotide. As for other therapies, some favorable results have been achieved but data are still not sufficient to establish if these approaches may be beneficial in slowing ADPKD progression in the future. PMID- 26125127 TI - Recognition of Corynebacterium pseudodiphtheriticum by Toll-like receptors and up regulation of antimicrobial peptides in human corneal epithelial cells. AB - Bacterial keratitis is a major cause of corneal ulcers in developing and industrialized nations. In this study, we examined the host innate immune responses to Corynebacterium pseudodiphtheriticum, often overlooked as commensal, in human corneal epithelial cells. The expressions of innate immune mediators were determined by quantitative PCR from corneal ulcers of patients and immortalized human corneal epithelial cells (HCEC). We have found an elevated expression of Toll like receptors (TLRs) along with IL-6 and IL-1beta from both ulcers and epithelial cells infected with C. pseudodiphtheriticum. Activation of NF-kappaB and MAPK signaling pathways were also observed in HCEC in response to C. pseudodiphtheriticum. In addition, we found a significant increase in the expression of antimicrobial peptides S100A8, S100A9 and human beta-defensin 1 from both corneal ulcers and HCEC. PMID- 26125128 TI - Potential therapeutic targets in ARID1A-mutated cancers. AB - ARID1A is a subunit of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that regulates gene expression by controlling gene accessibility. ARID1A shows one of the highest mutation rates across different human cancer types. For example, ARID1A is mutated in ~ 50% of ovarian clear cell carcinoma (OCCC). There is considerable interest in developing cancer therapeutics that correlate with ARID1A mutational status. A recent study demonstrated a synthetic lethality by targeting EZH2 histone methyltransferase activity in ARID1A-mutated OCCC using a clinically applicable small-molecule inhibitor. The observed synthetic lethality correlated with inhibition of PI3K/AKT signaling. In addition, there is evidence indicating that ARID1A-mutated cancer may also be subjected to therapeutic intervention by targeting residual SWI/SNF activity, the PI3K/AKT pathway, the DNA damage response, the tumor immunological microenvironment and stabilizing wild-type p53. In summary, we propose EZH2 inhibitor-based combinatorial strategies for targeting ARID1A mutated cancers. PMID- 26125129 TI - Shift work and serum 25-OH vitamin D status among factory workers in Northern Italy: Cross-sectional study. AB - Low levels of vitamin D are related to muscle weakness, poor balance, and higher risk of falls, and can therefore have a major impact on performance and safety at work. Little knowledge exists on the association between work environment and vitamin D status. This study evaluates vitamin D status in shift workers. In this cross-sectional study, led during early springtime, 96 male shift workers at an engineering factory in Northern Italy, and 100 male daily workers operating nearby, participated. 25-OH vitamin D concentration, anthropometric indexes, fasting glycemia and triglycerides were detected. 51 shift workers underwent anamnesis collection on lifestyle and habits and determination of heel bone mineral density. Vitamin D levels were lower in shift workers than daily ones (13.4 +/- 5.3 ng/mL versus 21.9 +/- 10.7 ng/mL, p < 0.001). Linear regression analysis adjusted for age, body mass index and smoking habits confirms a statistically significant association between shift work and vitamin D levels (p < 0.0001). An association trend between cigarette smoking and low vitamin D values was found. No significant association was detected between the heel bone mineral density values and vitamin D levels or smoking habits. In conclusion, this cross-sectional study highlights the high prevalence of vitamin D deficit among shift workers compared with daily ones. PMID- 26125130 TI - The hepatic circadian clock regulates the choline kinase alpha gene through the BMAL1-REV-ERBalpha axis. AB - The circadian timing system adapts most of the mammalian physiology and behaviour to the 24 h light/dark cycle. This temporal coordination relies on endogenous circadian clocks present in virtually all tissues and organs and implicated in the regulation of key cellular processes including metabolism, transport and secretion. Environmental or genetic disruption of the circadian coordination causes metabolic imbalance leading for instance to fatty liver, dyslipidaemia and obesity, thereby contributing to the development of a metabolic syndrome state. In the liver, a key metabolic organ, the rhythmic regulation of lipid biosynthesis is known, yet the molecular mechanisms through which the circadian clock controls lipogenesis, in particular, that of phospholipids, is poorly characterised. In this study, we show that the wild-type mice display a rhythmic accumulation of hepatic phosphatidylcholine with a peak at ZT 22-0 while clock deficient Bmal1(-/-) mice show elevated phosphatidylcholine levels in the liver associated with an atherogenic lipoprotein profile. Profiling of the mRNA expression of enzymes from the Kennedy and phosphatidylethanolamine N methyltransferase pathways which control the production of hepatic phosphatidylcholine revealed a robust circadian pattern for Chkalpha while other mRNA showed low amplitude (Chkbeta and Pemt) or no rhythm (Cctalpha and Chpt1). Chkalpha mRNA expression was increased and no longer rhythmic in the liver from clock-deficient Bmal1(-/-) mice. This change resulted in the upregulation of the CHKalpha protein in these animals. We further show that the robust circadian expression of Chkalpha is restricted to the liver and adrenal glands. Analysis of the Chkalpha gene promoter revealed the presence of a conserved response element for the core clock transcription factors REV-ERB and ROR. Consistent with the antiphasic phase relationship between Chkalpha and Rev-erbalpha expression, in cotransfection experiments using HepG2 cells we show that RORalpha4-dependent transactivation of this element is repressed by REV-ERBalpha. Correspondingly, Rev-erbalpha(-/-)mice displayed higher Chkalpha mRNA levels in liver at ZT 12. Collectively, these data establish that hepatic phosphatidylcholine is regulated by the circadian clock through a Bmal1-Rev-erbalpha-Chkalpha axis and suggest that an intact circadian timing system is important for the temporal coordination of phospholipid metabolism. PMID- 26125131 TI - Association between circadian preference and academic achievement: A systematic review and meta-analysis. AB - The association between circadian preference and academic achievement has been assessed through a systematic review and meta-analysis. The literature searches retrieved 1647 studies; 31 studies, with a total sample size of 27 309 participants, fulfilled the inclusion criteria and were included in the meta analysis. With reference to all these 31 studies, before running the meta analysis, the sign of the correlation between the investigated variables was set in a way that a positive correlation showed that eveningness was related to worse academic performance. The meta-analysis yielded a small overall effect size of 0.143 (CI [0,129; 0,156]) under a fixed effects model (Z = 20.584, p < 0.001, I(2)( )= 72.656; Q = 109.715) and of 0.145 (CI [0.117; 0.172]) under a random effects model (Z = 10.077, p < 0.001). A random effects model with a grouping variable (participants) revealed 15 studies based on school pupils and 16 on university students. The random model showed a higher effect size in school pupils (0.166, CI from 0.127 to 0.206) compared to university students (0.121, CI from 0.080 to 0.163). Self-report measures of grades revealed a stronger effect size (0.171; CI: 0.137 to 0.206; N = 20) compared to objective measures (0.093; CI: 0.047 to 0.140; N = 19). Overall, the present results suggest that evening orientation is associated with a worse academic performance, both in school pupils and university students; for the first time, it has been shown that such relationship changes over time, being weaker in university students. PMID- 26125132 TI - Prenatal examination of the area and morphology of the atrioventricular valves using four-dimensional ultrasound in normal and abnormal hearts. AB - OBJECTIVE: Our aim is to evaluate the feasibility to examine the morphology and area of the atrioventricular (AV) valves in normal fetuses and fetuses with cardiac defects using spatiotemporal image correlation (STIC). METHODS: Atrioventricular valves were analyzed longitudinally in STIC volumes of 74 normal fetuses between the 15th and 36th week of pregnancy. The valve area was measured in a rendered view in diastole, the number of valve leaflets in systole. Longitudinal data analysis was performed using linear mixed models. Fifty fetuses with cardiac defects were examined. RESULTS: Examination of 355 STIC volumes of normal fetuses showed in 82.5% sufficient quality. The tricuspid valve leaflets were seen in 200 (68.3%) volumes and the mitral valve leaflets in 219 (74.7%) volumes. The tricuspid valve showed in 61.1% a round, 29.0% rectangle, and 8.9% elliptical shape and the mitral valve in 60.1% round, 28.0% rectangle, and 10.9% elliptical. Regression analysis revealed a positive relationship of the valve area with gestational age (p < 0.0001). Most heart defects with stenosis showed an area below the 5th percentile. CONCLUSION: Prenatal examination of the morphology and area of the AV valves using four-dimensional ultrasound is feasible. A rectangular valve opening is normal, which was visualized in about one third of the normal fetuses. PMID- 26125133 TI - Correction to On the Analytical Superiority of 1D NMR for Fingerprinting the Higher Order Structure of Protein Therapeutics Compared to Multidimensional NMR Methods. PMID- 26125134 TI - Predicting Treatment Time and Long-Term Outcome of the Lidcombe Program: A Replication and Reanalysis. AB - PURPOSE: The present study presents treatment duration and outcome data on 14 children who stutter (CWS) recently treated by the Lidcombe Program (LP). These data were then combined with data from a previous LP treatment study (Miller & Guitar, 2009) to examine predictor variables for treatment duration and outcome. The present study also provides evidence of the effectiveness of LP from researchers who are independent of the developers of the program. METHOD: Fourteen preschool CWS were assessed on stuttering severity variables and participant characteristics prior to treatment, given LP treatment, and reassessed 2 years after the children achieved stable fluency. These children's data were added to the data of 15 previously treated CWS to examine predictors of treatment duration and long-term outcome. Preliminary analysis lead to the identification of two predictors that were tested in a generalized linear model. RESULTS: For the new group of 14 CWS, median treatment duration was 15 clinic visits and resulted in near-zero stuttering long term for most of the children and substantial reductions in stuttering for all of the children. For the combined group of 29 children, pretreatment stuttering frequency and severity were the best predictors of treatment duration in both clinic visits and weeks. CONCLUSIONS: Children with more frequent and more severe stuttering may take longer in LP treatment. Long-term outcome may best be predicted by pretreatment stuttering and sex. PMID- 26125135 TI - A tale of two viruses: HIV, Ebola and health systems. PMID- 26125136 TI - Identification and characterization of a subpocket on the N-trimer of HIV-1 Gp41: implication for viral entry and drug target. AB - OBJECTIVE: Crystallographic studies of HIV-1 gp41 demonstrate a stable six-helix bundle (6-HB) folded by trimeric N and C-terminal heptad repeats (NHR and CHR), and a deep hydrophobic pocket (pocket-1) on the NHR helices (N-trimer); however, previous crystal structures of 6-HB core were determined by peptide fragments missing the downstream sequence of pocket-1; thus, the structural features of this site could not be observed. DESIGN: We recently determined several 6-HB structures containing the pocket-1 and its downstream site. Here, we focused to investigate the structural features of N-trimer previously uncharacterized. METHODS: Biophysical, biochemical and functional approaches were combined to characterize the downstream residues of pocket-1. RESULTS: A subpocket (designated pocket-2) was visualized on the C-terminal portion of N-trimer, which is formed by a cluster of seven residues, including Leu587, Lys588 and Glu584 on one NHR helix and Tyr586, Val583, Ala582 and Arg579 of another NHR helix. Mutagenesis studies demonstrated that the pocket-2 residues play essential roles for HIV-1 Env-mediated cell entry and critically determine the antiviral activity of NHR-derived peptide fusion inhibitor T21. Further, the pocket-2 mutations dramatically impaired the thermostability and conformation of 6-HB structure and reduced the binding affinity of CHR-derived inhibitor HP23 that specifically targets the deep pocket-1. CONCLUSION: These data have provided important information for the structure-function relationship of HIV-1 gp41 and for the development of antiviral entry inhibitors. PMID- 26125137 TI - Low cross-neutralization of hepatitis C correlates with liver disease in immunocompromized patients. AB - BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection causes severe liver disease in HIV-infected patients and liver transplant recipients. The impact of serum and immunoglobulin on viral entry was analysed in these patients. METHOD: Sera from 60 anti-HCV positive patients, including 30 who were also anti HIV positive, were tested with HCVpp from different genotypes (1a, 1b, 3 and 4) and with HCVcc (H77/JFH1). Seventeen HIV-seropositive and 13 HIV-seronegative patients with decompensated liver disease were studied before and after liver transplant. RESULTS: Serum neutralization was markedly lower after liver transplant and in HIV patients than in mono-infected immune-competent individuals. This effect was due to low antibody-mediated neutralization. In HIV patients, low neutralization was correlated with low lymphocyte T CD4 cell counts and the severity of liver disease. To characterize neutralization, we tested HCVpp lacking hypervariable region (HVR1) and SR-BI receptor cholesterol transfer inhibition by BLT-4. These experiments showed that neutralization was strongly dependent on the HVR1 and the SR-BI receptor. HVR1 sequences showed that selective pressures were low in immune-compromised patients and highly correlated to HCV neutralization after liver transplant. Neutralization experiments were reproduced with HCV strain JFH1. CONCLUSION: Serum neutralization in HIV coinfected patients and HCV-infected liver transplant recipients is poor enhancing HCV entry through HVR1/SR-BI interplay. This may contribute to the severity of hepatitis C in these settings. PMID- 26125138 TI - White matter microstructure among youth with perinatally acquired HIV is associated with disease severity. AB - OBJECTIVES: We investigated whether HIV disease severity was associated with alterations in structural brain connectivity, and whether those alterations in turn were associated with cognitive deficits in youth with perinatally acquired HIV (PHIV). DESIGN: PHIV youth (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) (mean age: 16 +/- 2 years) were included to evaluate how current and past disease severity measures (recent/nadir CD4%; peak viral load) relate to white matter microstructure within PHIV youth. PHIV youth were compared with 314 controls from the Pediatric Imaging, Neurocognition and Genetics (PING) study. METHODS: Diffusion tensor imaging and tractography were utilized to assess white matter microstructure. Mediation analyses were conducted to examine whether microstructure alterations contributed to relationships between higher disease severity and specific cognitive domains in PHIV youth. RESULTS: Whole brain fractional anisotropy was reduced, but radial and mean diffusivity were increased in PHIV compared with control youth. Within PHIV youth, more severe past HIV disease was associated with reduced fractional anisotropy of the right inferior fronto-occipital (IFO) and left uncinate tracts; elevated mean diffusivity of the F minor; and increased streamlines comprising the left inferior longitudinal fasciculus (ILF). Associations of higher peak viral load with lower working memory performance were partly mediated by reductions in right IFO fractional anisotropy levels. CONCLUSION: Our findings suggest that PHIV youth have a higher risk of alterations in white matter microstructure than typically developing youth, and certain alterations are related to past disease severity. Further, white matter alterations potentially mediate associations between HIV disease and working memory. PMID- 26125139 TI - The burden of dialysis-requiring acute kidney injury among hospitalized adults with HIV infection: a nationwide inpatient sample analysis. AB - OBJECTIVE: The objective of this study was to describe the incidence of acute kidney injury (AKI) requiring renal replacement therapy ('dialysis-requiring AKI') and the impact on in-hospital mortality among hospitalized adults with HIV infection. DESIGN: A longitudinal analysis of a nationally representative administrative database. METHODS: We reviewed the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample Database, a large, nationally representative sample of inpatient hospital admissions, to identify all adult hospitalizations with an associated diagnosis of HIV infection from 2002 to 2010. We analysed temporal trends in the incidence of dialysis-requiring AKI and the associated odds of in-hospital mortality. We also explored potential reasons behind temporal changes. RESULTS: Among 183 0041 hospitalizations with an associated diagnosis of HIV infection, the proportion complicated by dialysis requiring AKI increased from 0.7% in 2002 to 1.35% in 2010. This temporal rise was completely explained by changes in demographics and an increase in concurrent comorbidities and procedure utilization. The adjusted odds of in-hospital mortality associated with dialysis-requiring AKI also increased over the study period, from 1.45 [95% confidence interval (95% CI) 0.97-2.12] in 2002 to 2.64 (95% CI 2.04-3.42) in 2010. CONCLUSION: These data suggest that the incidence of dialysis-requiring AKI among hospitalized adults with HIV infection continues to increase, and that severe AKI remains a significant predictor of in-hospital mortality in this population. The increased incidence of dialysis-requiring AKI was largely explained by ageing of the HIV population and increasing prevalence of chronic non-AIDS comorbidities, suggesting that these trends will continue. PMID- 26125140 TI - CD4+ gain percentile curves for monitoring response to antiretroviral therapy in HIV-infected adults. AB - OBJECTIVES: We constructed CD4 cell count gain percentile distributions standardized by baseline CD4 cell count and assessed the association between poor CD4 cell count gain and subsequent death and virological failure on antiretroviral therapy (ART). DESIGN: Secondary analysis of 10 years of clinical data from a cohort of adults initiated on ART at the Themba Lethu clinic in Johannesburg, South Africa. METHODS: The generalized additive model for location, scale and shape was used to construct percentile curves for CD4 cell count gain standardized by baseline CD4 cell count in the first 28 months of ART. Cox proportional models were used to assess the association between lower percentiles (<50th) of CD4 cell count gain, and subsequent death and virological failure. RESULTS: Among 9640 nonpregnant adults 7406, with available CD4 cell count results for CD4 gain calculation at 4 months of ART, 843 (8.7%) died subsequently and 1101 (11.4%) experienced virologic failure, respectively. For CD4 gains below the third percentile, the adjusted hazard ratios at different time points ranged between 2.72 and 5.73 for death, and between 1.48 and 6.93 for virologic failure. The CD4 percentile curves revealed a gradient of increasing risk of subsequent death and virological failure, with lower CD4 gain percentiles and increasing time on ART, and were more informative than the WHO criteria for immunological failure or current CD4 cell count. CONCLUSION: Percentile curves of CD4 cell count gain provide a simple tool for healthcare workers in low-resource settings to monitor response to ART with improved information regarding risk of death and virological failure compared to current WHO criteria for immunological failure. PMID- 26125141 TI - Changes in the contribution of genital tract infections to HIV acquisition among Kenyan high-risk women from 1993 to 2012. AB - OBJECTIVE: The objective of this study was to understand temporal trends in the contribution of different genital tract infections to HIV incidence over 20 years of follow-up in a cohort of high-risk women. DESIGN: A prospective cohort study. METHODS: We performed monthly evaluations for HIV, vaginal yeast, bacterial vaginosis, Trichomonas vaginalis, Neisseria gonorrhoeae, nonspecific cervicitis, herpes simplex virus type two (HSV-2), genital ulcer disease (GUD) and genital warts. We used Cox regression to evaluate the association between sexually transmitted infections (STIs) and HIV acquisition over four time periods (1993 1997, 1998-2002, 2003-2007, 2008-2012). Models were adjusted for age, workplace, sexual risk behaviour, hormonal contraceptive use and other STIs. The resulting hazard ratios were used to calculate population attributable risk percentage (PAR%). RESULTS: Between 1993 and 2012, 1964 women contributed 6135 person-years of follow-up. The overall PAR% for each infection was prevalent HSV-2 (48.3%), incident HSV-2 (4.5%), bacterial vaginosis (15.1%), intermediate microbiota (7.5%), vaginal yeast (6.4%), T. vaginalis (1.1%), N. gonorrhoeae (0.9%), nonspecific cervicitis (0.7%), GUD (0.8%) and genital warts (-0.2%). Across the four time periods, the PAR% for prevalent HSV-2 (40.4%, 61.8%, 58.4%, 48.3%) and bacterial vaginosis (17.1%, 19.5%, 14.7%, 17.1%) remained relatively high and had no significant trend for change over time. The PAR% for trichomoniasis, gonorrhoea, GUD and genital warts remained less than 3% across the four periods. CONCLUSION: Bacterial vaginosis and HSV-2 have consistently been the largest contributors to HIV acquisition risk in the Mombasa Cohort over the past 20 years. Interventions that prevent these conditions would benefit women's health and could reduce their risk of becoming infected with HIV. PMID- 26125142 TI - Protease inhibitors exposure is not related to lung cancer risk in HIV smoker patients: a nested case-control study. AB - OBJECTIVE: We aimed at assessing in persons living with HIV with a smoking history an association between lung cancer risk and protease inhibitors exposure, especially ritonavir. DESIGN: A nested case-control study was conducted within the ANRS CO4 FHDH, CO3 Aquitaine and Tenon's Hospital Cohorts. METHODS: Cases and controls were eligible if they were ex-smokers or current smokers at the index date, and had a CD4 cell count reported in the year preceding the index date. Cases were incident cases of lung cancer diagnosed between 1 January 2000 and 31 December 2011. All cancer cases were validated and histological types identified when available. Three controls were randomly selected by incidence density sampling using calendar time as the time axis, with individual matching on cohort, age (+/- 5 years), route of HIV acquisition, sex and hospital. Analyses were performed using conditional logistic regression adjusted for nadir CD4 cell count and smoking status. Ritonavir and protease inhibitors exposures were represented in separate models using categorical variables (never exposed, ever exposed). Several sensitivity analyses were performed. RESULTS: This study performed in 1447 persons living with HIV with a smoking history (383 lung cancer cases and 1064 control patients) did not evidence any association between lung cancer risk and protease inhibitors exposure including ritonavir. CONCLUSION: These results suggest that the risk of lung cancer is not influenced by pharmacologically induced P450 cytochrome protease inhibitors inhibition among smokers or ex-smokers. PMID- 26125143 TI - HAART and lungs: do HIV protease inhibitors impact cancer risk? PMID- 26125144 TI - Anti-tumor necrosis factor monoclonal antibody for steroid-dependent TB-IRIS in AIDS. PMID- 26125145 TI - Acute myocardial infarction following thalidomide treatment for AIDS-related ulcers. PMID- 26125146 TI - Cobicistat-vinblastine interaction and severe peripheral neuropathy. PMID- 26125147 TI - Serum Zinc, Copper, Iron, and Magnesium Levels in Iranian Drug Users: A Case Control Study. AB - INTRODUCTION: The changes in concentration of trace elements have effects on many organ systems, including the immune system. There have been conflicting reports on serum trace element levels in heroin users. This study was carried out to compare serum trace element concentrations in opium, heroin, and methamphetamine users. METHODS: The study was done on 90 chronically illegal drug users (n = 30 per group) and 30 controls of the similar sex and age range (from 20 to 40 years). The control group was healthy subjects with no lifetime history of substance abuse or dependence. All of the substance users were selected from among those who had a history of substance use, for a minimum of 1 year. Serum zinc (Zn), copper (Cu), iron (Fe), and magnesium (Mg) were measured spectrophotometrically using chemistry analyzer. RESULTS: Serum Fe concentration was decreased in heroin (P = 0.026) and methamphetamine (P = 0.0001) users compared with healthy subjects, whereas serum Cu was higher in opium, heroin, and methamphetamine users (P < 0.01). Copper was negatively and significantly correlated with Fe in all groups (P < 0.05). There was no statistically significant difference between drug users and healthy subjects in serum concentrations of Zn and Mg. CONCLUSIONS: This study showed decreased in serum concentration of iron and increase in serum copper in drug users when compared with controls. PMID- 26125148 TI - Comparison of Peripheral Nerve Axonal Area Differences in Central and Peripheral Zones of Injured and Repaired Nerves. AB - BACKGROUND: Histological analysis remains a cornerstone approach for the investigation of peripheral nerve regeneration. This study investigates a newly recognized histological difference between peripheral and central zones within the regenerating nerve trunks. PURPOSE: The purpose of the study was to determine if the nerve axonal area (NXA) in regenerating peripheral nerves differs within central and peripheral areas, when viewed in cross-section. METHODS: A total of 14 rats were divided into two groups, and subjected to different injuries to the right sciatic nerve. Group 1: Transection injury with immediate repair. Group 2: Crush injury without any treatment. The left sciatic nerve was left uninjured and served as a control in each rat. Following 4 weeks of recovery, nerve trunk cross sections were prepared. Computerized techniques were then employed to divide nerve sections into central and peripheral zones and calculate corresponding NXA values for subsequent statistical analysis. RESULTS: NXA of injured nerves was greater within peripheral as compared with the central zones, independent of injury type (p < 0.05). No statistically significant difference existed within the control groups or between the injury methods with regards to NXA regeneration extent. CONCLUSION: NXA in regenerating peripheral nerves was greater in the peripheral zones than within the central zones. PMID- 26125149 TI - Effects of Traditional Chinese Medicine Huangqi Injection (Radix astragali) on Random Skin Flap Survival in Rats. AB - BACKGROUND: Huangqi (Radix astragali) is a traditional Chinese drug, designed to "buqi," which means invigorating vital energy, widely used in clinical settings. We investigated the effect of Huangqi injection on the survival of random skin flaps. METHODS: McFarlane flaps were established in 60 rats divided into two groups. Postoperative celiac injections were given to both groups for 7 days. Huangqi was injected into the test group, and saline was injected into controls. On day 7, tissues were stained with hematoxylin and eosin, immunohistochemically evaluated, and the expression levels of xanthine oxidase determined. RESULT: The mean area of flap survival in the test group was significantly higher compared with the controls. Expression of vascular endothelial growth factor and superoxide dismutase, and microvessel development, were markedly increased in the test group, and the malondialdehyde level was reduced. CONCLUSION: Huangqi injection promotes random skin flap survival. PMID- 26125150 TI - Regenerated Nerve Defects with a Nerve Conduit Containing Dental Pulp Stem Cells in Pigs: An Immunohistochemical and Electrophysiological Evaluation. AB - BACKGROUND: Dental pulp stem cells (DPSCs) present an exciting new tool in the field of peripheral nerve regeneration due to their close embryonic origin. In this study, we examined their potential in pigs, using biodegradable collagen conduits filled with DPSCs. To our knowledge, this is the first time DPCSs are tested for peripheral nerve regeneration in such large animal model. MATERIALS AND METHODS: The second lateral incisor was extracted from every animal's lower jaw and stem cells were isolated and cultured. The collagen nerve conduits containing the DPSCs were subsequently transplanted into the transected fifth and sixth intercostal nerves, while the seventh intercostal nerve was used as a control and no stem cells were added on the respective collagen conduit. RESULTS: A histological examination was performed on the 3rd and 6th postoperative months and showed the gradual development of neural tissue and immunohistochemical expression of neuron-specific enolase. An electrophysiological study was performed on the 6th postoperative month and showed similar potentials between the stem cell infusion region (5 +/- 0.04 units) and their proximal stumps (5 +/- 0.05 units) and slightly smaller potentials in the respective distal stumps (4 +/ 0.045 units). CONCLUSION: The nerves where DPSCs were injected exhibited morphological and functional recovery, in contrast to the control nerves where no recovery was detected; thus, there is a first evidence of the therapeutic potential of DPSCs in peripheral nerve regeneration. PMID- 26125151 TI - Pd(II)-Catalyzed Cycloisomerization/Dipolar Cycloaddition Cascade of N Arylnitrone Alkynes with Olefins. AB - A cycloisomerization/dipolar cycloaddition tandem reaction of nitrone alkynes and electron-deficient olefins was described by employing a simple palladium catalyst. N-Arylnitrone alkynes, which were not well tolerated in previously reported methodologies, were successfully incorporated in the tandem reaction with generally good yields and moderate diastereoselectivities. PMID- 26125152 TI - Meta-analysis of osteoporosis: fracture risks, medication and treatment. AB - Osteoporosis is a brittle bone disease that can cause fractures mostly in older men and women. Meta-analysis is the statistical method which is applied in the frame work for the assessment of results obtained from various research studies conducted in several years. A meta-analysis of osteoporotic fracture risk with medication non-adherence has been described to assess the bone fracture risk among patients non-adherent versus adherent to therapy for osteoporosis by many researchers. Osteoporosis therapy reduces the risk of fracture in clinical trials, and real-world adherence to therapy which is suboptimal and can reduce the effectiveness of intervention. The methods of Medline, Embase, and CINAHL were literature searched for these observational studies from year 1998 to 2009, and up to 2015. The results of meta-analysis of osteoporosis research on fractures of postmenopausal women and men are presented. The use of bisphosphonate therapy for osteoporosis has been described with other drugs. The authors, design, studies (women %), years (data), follow-up (wks), fractures (types), and compliance or persistence results from years 2004 to 2009 from are shown in a brief table. The meta-analysis studies have been reviewed from other researchers on osteoporosis and fractures, medications and treatments. PMID- 26125153 TI - The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function. AB - The concept of cognitive reserve (CR) has been proposed to account for observed discrepancies between pathology and its clinical manifestation due to underlying differences in brain structure and function. In 433 healthy older adults participating in the Tasmanian Healthy Brain Project, we investigated whether common polymorphic variations in apolipoprotein E (APOE) or brain-derived neurotrophic factor (BDNF) influenced the association between CR contributors and cognitive function in older adults. We show that BDNF Val66Met moderates the association between CR and executive function. CR accounted for 8.5% of the variance in executive function in BDNF Val homozygotes, but CR was a nonsignificant predictor in BDNF Met carriers. APOE polymorphisms were not linked to the influence of CR on cognitive function. This result implicates BDNF in having an important role in capacity for building or accessing CR. PMID- 26125154 TI - Increased anterior insula activity in anxious individuals is linked to diminished perceived control. AB - Individuals with high-trait anxiety frequently report decreased perceived control. However, it is unclear how these processes are instantiated at a neural level. Prior research suggests that individuals prone to anxiety may have exaggerated activity in the anterior insula and altered activity in the cingulate cortex during anticipation of aversive events. Thus, we hypothesized that anxiety proneness influences anterior insula activation during anticipation of unpredictable threat through decreased perceived control. Forty physically healthy adults underwent neuroimaging while they explored computer-simulated contexts associated either with or without the threat of an unpredictable shock. Skin conductance, anxiety ratings and blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging were used to assess responses to threat versus no threat. Perceived control was measured using the Anxiety Control Questionnaire-Revised. Mediation analysis examined how anxiety proneness influenced BOLD activity. Anticipation of unpredictable threat resulted in increased skin conductance responses, anxiety ratings and enhanced activation in bilateral insula, anterior midcingulate cortex (aMCC) and bed nucleus of the stria terminalis. Individuals with greater anxiety proneness and less perceived control showed greater activity in dorsal anterior insula (dAI). Perceived control mediated the relationship between anxiety proneness and dAI activity. Increased dAI activity was associated with increased activity in aMCC, which correlated with increased exploratory behavior. Results provide evidence that exaggerated insula activation during the threat of unpredictable shock is directly related to low perceived control in anxiety-prone individuals. Perceived control thus may constitute an important treatment target to modulate insula activity during anxious anticipation in anxiety-disordered individuals. PMID- 26125155 TI - Major depressive disorder and current psychological distress moderate the effect of polygenic risk for obesity on body mass index. AB - Major depressive disorder (MDD) and obesity are frequently co-morbid and this correlation is partly due to genetic factors. Although specific genetic risk variants are associated with body mass index (BMI) and with larger effect sizes in depressed individuals, the genetic overlap and interaction with depression has not been addressed using whole-genome data. Polygenic profile scores for MDD and BMI were created in 13,921 members of Generation Scotland: the Scottish Family Health Study and tested for their association with BMI, MDD, neuroticism and scores on the General Health Questionnaire (GHQ) (current psychological distress). The association between BMI polygenic profile scores and BMI was tested fitting GHQ, neuroticism or MDD status as an interaction term to test for a moderating effect of mood disorder. BMI polygenic profile scores were not associated with lifetime MDD status or neuroticism although a significant positive association with GHQ scores was found (P = 0.0001, beta = 0.034, r(2) = 0.001). Polygenic risk for MDD was not associated with BMI. A significant interaction between BMI polygenic profile scores and MDD (P = 0.0003, beta = 0.064), GHQ (P = 0.0005, beta = 0.027) and neuroticism (P = 0.003, beta = 0.023) was found when BMI was the dependent variable. The effect of BMI-increasing alleles was greater in those with MDD, high neuroticism or current psychological distress. MDD, neuroticism and current psychological distress amplify the effect of BMI polygenic profile scores on BMI. Depressed individuals with a greater polygenic load for obesity are at greater risk of becoming obese than control individuals. PMID- 26125156 TI - Psychometric precision in phenotype definition is a useful step in molecular genetic investigation of psychiatric disorders. AB - Affective disorders are highly heritable, but few genetic risk variants have been consistently replicated in molecular genetic association studies. The common method of defining psychiatric phenotypes in molecular genetic research is either a summation of symptom scores or binary threshold score representing the risk of diagnosis. Psychometric latent variable methods can improve the precision of psychiatric phenotypes, especially when the data structure is not straightforward. Using data from the British 1946 birth cohort, we compared summary scores with psychometric modeling based on the General Health Questionnaire (GHQ-28) scale for affective symptoms in an association analysis of 27 candidate genes (249 single-nucleotide polymorphisms (SNPs)). The psychometric method utilized a bi-factor model that partitioned the phenotype variances into five orthogonal latent variable factors, in accordance with the multidimensional data structure of the GHQ-28 involving somatic, social, anxiety and depression domains. Results showed that, compared with the summation approach, the affective symptoms defined by the bi-factor psychometric model had a higher number of associated SNPs of larger effect sizes. These results suggest that psychometrically defined mental health phenotypes can reflect the dimensions of complex phenotypes better than summation scores, and therefore offer a useful approach in genetic association investigations. PMID- 26125158 TI - Cinnarizine for Sea Sickness During a Remote Pacific Ocean Rescue Mission. AB - Motion sickness can be a limiting factor for sea and air missions. We report the experience of a Pararescue (PJ) team on a Pacific Ocean rescue mission in which motion sickness was prevalent. Cinnarizine, an antagonist of H1-histamine receptors, was used to treat affected PJs. We also report findings of a survey of PJs regarding motion sickness. A family of four on a disabled sailboat 900 miles off the coast of Mexico sent out a distress call because their 1-year-old daughter became severely ill with fever and diarrhea. Four PJs were deployed on a C-130, performed a free-fall parachute insertion into the ocean, and boarded the sailboat. All four PJs experienced onset of motion sickness at some point during the early part of the mission and symptoms persisted through the first 24 hours. Three PJs experienced ongoing nausea, vomiting, dizziness, and sensory imbalances. The captain of the sailboat offered the three sick PJs approximately 18mg of cinnarizine two or three times a day with relief of symptoms and improvement on operational effectiveness. A new, anonymous, voluntary survey of Air National Guard PJs and combat rescue officers revealed that 78.4% of Operators have experienced motion sickness at sea. We discuss the current theories on motion sickness, the effect of motion sickness on operational effectiveness, and research on treatment of motion sickness, including the medication cinnarizine. PMID- 26125157 TI - Causality Analysis: Identifying the Leading Element in a Coupled Dynamical System. AB - Physical systems with time-varying internal couplings are abundant in nature. While the full governing equations of these systems are typically unknown due to insufficient understanding of their internal mechanisms, there is often interest in determining the leading element. Here, the leading element is defined as the sub-system with the largest coupling coefficient averaged over a selected time span. Previously, the Convergent Cross Mapping (CCM) method has been employed to determine causality and dominant component in weakly coupled systems with constant coupling coefficients. In this study, CCM is applied to a pair of coupled Lorenz systems with time-varying coupling coefficients, exhibiting switching between dominant sub-systems in different periods. Four sets of numerical experiments are carried out. The first three cases consist of different coupling coefficient schemes: I) Periodic-constant, II) Normal, and III) Mixed Normal/Non-normal. In case IV, numerical experiment of cases II and III are repeated with imposed temporal uncertainties as well as additive normal noise. Our results show that, through detecting directional interactions, CCM identifies the leading sub-system in all cases except when the average coupling coefficients are approximately equal, i.e., when the dominant sub-system is not well defined. PMID- 26125159 TI - Oral Steroids for Dermatitis. AB - Contact/allergic dermatitis is frequently treated inappropriately with lower-than recommended doses or inadequate duration of treatment with oral and intramuscular glucocorticoids. This article highlights a case of dermatitis in a Ranger Assessment and Selection Program student who was improperly treated over 2 weeks with oral steroids after being bit by Cimex lectularius, commonly known as bed bugs. The article also highlights the pitfalls of improper oral steroid dosing and provides reasoning for longer-duration oral steroid treatment. PMID- 26125160 TI - Treatment of Psoriasis in the Deployed Setting. AB - Psoriasis is a chronic immune-mediated disorder that can be triggered by environmental changes, illness, smoking, or medications. This case describes a 25 year-old, active-duty Marine Corps Sergeant with a severe perideployment psoriatic flare, and illustrates treatment limitations, restricted access to specialized care, and the importance of mitigating triggers in the deployed setting. PMID- 26125161 TI - Replacement of Promethazine With Ondansetron for Treatment of Opioid- and Trauma Related Nausea and Vomiting in Tactical Combat Casualty Care. AB - The current Tactical Combat Casualty Care (TCCC) Guidelines recommend parenteral promethazine as the single agent for the treatment of opioid-induced nausea and/or vomiting and give a secondary indication of "synergistic analgesic effect." Promethazine, however, has a well-documented history of undesired side effects relating to impairment and dysregulation of the central and autonomic nervous systems, such as sedation, extrapyramidal symptoms, dystonia, impairment of psychomotor function, neuroleptic malignant syndrome, and hypotension. These may be particularly worrisome in the combat casualty. Additionally, since 16 September 2009, there has been a US Food and Drug Administration (FDA) black box warning for the injectable form of promethazine, due to "the risk of serious tissue injury when this drug is administered incorrectly." Conversely, ondansetron, which is now available in generic form, has a well-established favorable safety profile and demonstrated efficacy in undifferentiated nausea and vomiting in the emergency department and prehospital settings. It has none of the central and autonomic nervous system side effects noted with promethazine and carries no FDA black box warning. Ondansetron is available in parenteral form and an orally disintegrating tablet, providing multiple safe and effective routes of administration. Despite the fact that it is an off-label use, ondansetron is being increasingly given for acute, undifferentiated nausea and vomiting and is presently being used in the field on combat casualties by some US and Allied Forces. Considering the risks involved with promethazine use, and the efficacy and safety of ondansetron and ondansetron?s availability in a generic form, we recommend removing promethazine from the TCCC Guidelines and replacing it with ondansetron. PMID- 26125162 TI - Saving Lives on the Battlefield (Part II) ? One Year Later A Joint Theater Trauma System and Joint Trauma System Review of Prehospital Trauma Care in Combined Joint Operations Area?Afghanistan (CJOA-A) Final Report, 30 May 2014. AB - The United States has achieved unprecedented survival rates, as high as 98%, for casualties arriving alive at the combat hospital. Our military medical personnel are rightly proud of this achievement. Commanders and Servicemembers are confident that if wounded and moved to a Role II or III medical facility, their care will be the best in the world. Combat casualty care, however, begins at the point of injury and continues through evacuation to those facilities. With up to 25% of deaths on the battlefield being potentially preventable, the prehospital environment is the next frontier for making significant further improvements in battlefield trauma care. Strict adherence to the evidence-based Tactical Combat Casualty Care (TCCC) Guidelines has been proven to reduce morbidity and mortality on the battlefield. However, full implementation across the entire force and commitment from both line and medical leadership continue to face ongoing challenges. This report on prehospital trauma in the Combined Joint Operations Area?Afghanistan (CJOA-A) is a follow-on to the one previously conducted in November 2012 and published in January 2013. Both assessments were conducted by the US Central Command (USCENTCOM) Joint Theater Trauma System (JTTS). Observations for this report were collected from December 2013 to January 2014 and were obtained directly from deployed prehospital providers, medical leaders, and combatant leaders. Significant progress has been made between these two reports with the establishment of a Prehospital Care Division within the JTTS, development of a prehospital trauma registry and weekly prehospital trauma conferences, and CJOA-A theater guidance and enforcement of prehospital documentation. Specific prehospital trauma-care achievements include expansion of transfusion capabilities forward to the point of injury, junctional tourniquets, and universal approval of tranexamic acid. PMID- 26125163 TI - Role of the Windlass in Improvised Tourniquet Use on a Manikin Hemorrhage Model. AB - BACKGROUND: In emergencies when commercially designed tourniquets are unavailable, hemorrhage may need to be controlled with improvised tourniquets. In the aftermath of the Boston Marathon bombing, no improvised strap-and-windlass tourniquets were used to treat casualties; tourniquets without windlasses were used. The purpose of the present study is to determine the effectiveness of improvised tourniquets with and without a windlass to better understand the role of the windlass in tightening the tourniquet strap. METHODS: An experiment was designed to test the effectiveness of improvised strap-and-windlass tourniquets fashioned out of a tee shirt on a manikin thigh. Two users conducted 40 tests each with and without the use of a windlass. RESULTS: Without a windlass, improvised tourniquets failed to stop bleeding in 99% of tests (79 of 80 tests). With a windlass, improvised tourniquets failed to stop bleeding in 32% of tests (p < .0001). In tests with no windlass, attempts to stop the pulse completely failed (100%, 80 of 80 tests). With a windlass, however, attempts to stop the pulse failed 31% of the time (25 of 80 tests); the difference in proportions was significant (p < .0001). CONCLUSIONS: Improvised strap-and-windlass tourniquets were more effective than those with no windlass, as a windlass allowed the user to gain mechanical advantage. However, improvised strap-and-windlass tourniquets failed to control hemorrhage in 32% of tests. PMID- 26125164 TI - Prehospital Use of Hemostatic Bandages and Tourniquets: Translation From Military Experience to Implementation in Civilian Trauma Care. AB - BACKGROUND: While the military use of tourniquets and hemostatic gauze is well established, few data exist regarding civilian emergency medical services (EMS) systems experience. METHODS: A retrospective review was performed of consecutive patients with prehospital tourniquet and hemostatic gauze application in a single ground and rotor-wing rural medical transport service. Standard EMS registry data were reviewed for each case. RESULTS: During the study period, which included 203,301 Gold Cross Ambulance and 8,987 Mayo One Transport records, 125 patients were treated with tourniquets and/or hemostatic gauze in the prehospital setting. Specifically, 77 tourniquets were used for 73 patients and 62 hemostatic dressings were applied to 52 patients. Seven patients required both interventions. Mechanisms of injury (MOIs) for tourniquet use were blunt trauma (50%), penetrating wounds (43%), and uncontrolled hemodialysis fistula bleeding (7%). Tourniquet placement was equitably distributed between upper and lower extremities, as well as proximal and distal locations. Mean tourniquet time was 27 minutes, with 98.7% success. Hemostatic bandage MOIs were blunt trauma (50%), penetrating wounds (35%), and other MOIs (15%). Hemostatic bandage application was head and neck (50%), extremities (36%), and torso (14%), with a 95% success rate. Training for both interventions was computer-based and hands-on, with maintained proficiency of %gt;95% after 2 years. CONCLUSION: Civilian prehospital use of tourniquets and hemostatic gauze is feasible and effective at achieving hemostasis. Online and practical training programs result in proficiency of skills, which can be maintained despite infrequent use. PMID- 26125165 TI - Potential of Visual Sensory Screening, Diagnostic Evaluation, and Training for Treatment of Postconcussive Symptoms and Performance Enhancement for Special Forces Qualified Personnel. AB - Mild traumatic brain injury (mTBI) or concussive injuries remain a challenge for both athletes and clinicians, given high incidence rates and heterogeneous clinical trajectories. Moreover, exposure to blast in combat is compounded by chronic, frequent exposure to a variety of subclinical impacts and overpressure, in some cases annually over many years. Subsequent injuries are often more severe than the original and lead to higher incidence of chronic symptoms in combat units, particularly Special Operations Forces (SOF), which is compounded by a propensity to underreport or avoid Army medical systems altogether. The unique nature and psychological makeup of SOF Soldiers suggest that new guidelines for progressive return-to-activity and return-to-duty decision-making within the traditional medical setting may not be generalizable to this population. Further, the traditional criteria for return to duty and return to play in sport may be insensitive to persistent deficits, resulting in premature return. There is presidential and Department of Defense mandates for continued research in the areas of diagnostics, treatment, and assessments for return to duty. With recent shift toward understanding clinical trajectories, particularly visual and vestibular trajectories, promising new technology from the field of sports vision may prove useful toward that endeavor. Since the advent of performance programs within SOF units, these Soldiers build trust with performance personnel, which include rehabilitative personnel, through consistent and regular shared experience. Implementation of comprehensive vision and visual performance screening in conjunction with the study of sports vision technology within the performance setting, in conjunction with unit medical personnel, may yield important findings for diagnosis and treatment of mTBI; to include the chronically symptomatic postconcussive Soldiers. Last, with a wealth of literature supporting visual skills training for athlete populations, to include competitive shooters, the implementation of visual skills training will likely be a useful adjunct to performance training of SOF personnel. PMID- 26125166 TI - Injuries, Medical Conditions, and Changes in Blood Levels in German Special Operations Forces Selection. AB - BACKGROUND: Medical conditions often develop during military training. The aim of this study was to compile medical conditions and injuries sustained during a 5 day military exercise, compare them with incidences at similar civilian events, and subsequently identify differences between those who finished the exercise (Finishers) and those who did not (Nonfinishers) to identify preventable causes for not finishing and to reduce unnecessary health risks. METHODS: Fifty-one soldiers had their blood parameters (creatine kinase [CK], aspartate transaminase [AST], alanine transaminase [ALT], gamma-glutamyl transferase [GGT], C-reactive protein [CRP], leukocytes, sodium), weight loss, and body temperature determined after the exercise. Additionally, the injuries and conditions that led the Nonfinishers to drop out were recorded. RESULTS: The main reasons why Nonfinishers did not complete the exercise were physical exhaustion and minor injuries. After exercise, the Finishers showed only slightly increased incidence of hyponatremia, higher levels of CK, and significantly higher levels of AST, ALT, and CRP, and body weight loss. The Nonfinishers? results were significant for an elevated leukocyte count and lower mean temperatures. CONCLUSION: The specifics of military training did not influence the kind or the number of exertion-related medical conditions compared to similar civilian events. Both Finishers and Nonfinishers are at risk of developing exertion-related medical conditions such as rhabdomyolysis and hyponatremia. However, plain water did not increase the risk of exertional hyponatremia. Leukocytosis found in the Nonfinisher group could have been due to acute excessive exertion and, therefore, may be an indicator of general systemic fatigue. This could be used to differ between physical and psychological reasons for not finishing. PMID- 26125167 TI - Rationale for Use of Intravenous Acetaminophen in Special Operations Medicine. AB - Use of intravenous acetaminophen has increased recently as an opioid-sparing strategy for patients undergoing major surgery. Its characteristics and efficacy suggest that it would a useful adjunct in combat trauma medicine. This article reviews those characteristics, which include rapid onset, high peak plasma concentration, and favorable side-effect profile. Also discussed is the hepatotoxicity risk of acetaminophen in a combat trauma patient. It concludes that intravenous acetaminophen should be considered as an addition to the US Special Operations Command Tactical Trauma Protocols and supplied to medics for use in field care. PMID- 26125168 TI - Emergency Department Patients Support the Use of Combat Medics in Their Clinical Care. AB - BACKGROUND: As US military combat operations draw down in Afghanistan, the military health system will shift focus to garrison- and hospital-based care. Maintaining combat medical skills while performing routine healthcare in military hospitals and clinics is a critical challenge for Combat medics. Current regulations allow for a wide latitude of Combat medic functions. The Surgeon General considers combat casualty care a top priority. Combat medics are expected to provide sophisticated care under the extreme circumstances of a hostile battlefield. Yet, in the relatively safe and highly supervised setting of contiguous US-based military hospitals, medics are rarely allowed to perform the procedures or administer medications they are expected to use in combat. This study sought to determine patients? opinions on the use of combat medics in their healthcare. METHODS: Patients in hospital emergency department (EDs) were offered anonymous surveys. Examples of Combat medic skills were provided. Participants expressed agreement using the Likert scale (LS), with scores ranging from "strongly agree" (LS score, 1) to "strongly disagree" (LS score, 5). The study took place in the ED at Bayne-Jones Army Community Hospital, Fort Polk, Louisiana. Surveys were offered to adult patients when they checked into the ED or to adults with other patients. RESULTS: A total of 280 surveys were completed and available for analysis. Subjects agreed that Combat medic skills are important for deployment (LS score, 1.4). Subjects agreed that Combat medics should be allowed to perform procedures (LS score, 1.6) and administer medications (LS score, 1.6). Subjects would allow Combat medics to perform procedures (LS score, 1.7) and administer medications (LS score, 1.7) to them or their families. Subjects agreed that Combat medic activities should be a core mission for military treatment facilities (MTFs) (LS score, 1.6). CONCLUSION: Patients support the use of Combat medics during clinical care. Patients agree that Combat medic use should be a core mission for MTFs. Further research is needed to optimize Combat medic integration into patient healthcare. PMID- 26125169 TI - Clinical Guidelines for Stellate Ganglion Block to Treat Anxiety Associated With Posttraumatic Stress Disorder. AB - Multiple case series published in the peer-reviewed medical literature have demonstrated the safety and efficacy of right-sided stellate ganglion block (SGB) for the treatment of anxiety symptoms associated with posttraumatic stress disorder (PTSD). As this is a new indication for a well-established procedure, there is relatively little information available to assist clinicians in determining the utility of SGB for their patients. Presented are clinical guidelines to assist the provider with patient selection, patient education, and follow-up. Also described is a technique to perform SGB under ultrasound guidance. Although additional rigorous clinical research is needed to further investigate SGB for the treatment of anxiety symptoms associated with PTSD, these guidelines can also assist clinical investigators in their participant selection, design, and conduct of future research as it pertains to this important topic. PMID- 26125170 TI - Interobserver Variability in Injury Severity Scoring After Combat Trauma: Different Perspectives, Different Values? AB - BACKGROUND: Anatomic measures of injury burden provide key information for studies of prehospital and in-hospital trauma care. The military version of the Abbreviated Injury Scale [AIS(M)] is used to score injuries in deployed military hospitals. Estimates of total trauma burden are derived from this. These scores are used for categorization of patients, assessment of care quality, and research studies. Scoring is normally performed retrospectively from chart review. We compared data recorded in the UK Joint Theatre Trauma Registry (JTTR) and scores calculated independently at the time of surgery by the operating surgeons to assess the concordance between surgeons and trauma nurse coordinators in assigning injury severity scores. METHODS: Trauma casualties treated at a deployed Role 3 hospital were assigned AIS(M) scores by surgeons between 24 September 2012 and 16 October 2012. JTTR records from the same period were retrieved. The AIS(M), Injury Severity Score (ISS), and New Injury Severity Score (NISS) were compared between datasets. RESULTS: Among 32 matched casualties, 214 injuries were recorded in the JTTR, whereas surgeons noted 212. Percentage agreement for number of injuries was 19%. Surgeons scored 75 injuries as "serious" or greater compared with 68 in the JTTR. Percentage agreement for the maximum AIS(M), ISS, and NISS assigned to cases was 66%, 34%, and 28%, respectively, although the distributions of scores were not statistically different (median ISS: surgeons: 20 [interquartile range (IQR), 9-28] versus JTTR: 17.5 [IQR, 9-31.5], p = .7; median NISS: surgeons: 27 [IQR, 12-42] versus JTTR: 25.5 [IQR, 11.5-41], p = .7). CONCLUSION: There are discrepancies in the recording of AIS(M) between surgeons directly involved in the care of trauma casualties and trauma nurse coordinators working by retrospective chart review. Increased accuracy might be achieved by actively collaborating in this process. PMID- 26125171 TI - "It's What Color?". AB - The series objective is to review various clinical conditions/presentations, including the latest evidence on management, and to dispel common myths. In the process, core knowledge and management principles are enhanced. A clinical case will be presented. Cases will be drawn from real life but phrased in a context that is applicable to the Special Operations Forces (SOF) or tactical emergency medical support (TEMS) environment. Details will be presented in such a way that the reader can follow along and identify how they would manage the case clinically depending on their experience and environment situation. Commentary will be provided by currently serving military medical technicians. The medics and author will draw on their SOF experience to communicate relevant clinical concepts pertinent to different operational environments including SOF and TEMS. Commentary and input from active special operations medical technicians will be part of the feature. PMID- 26125172 TI - Monitoring Training for Human Performance Optimization. AB - Physical fitness can significantly impact the mission success of Special Operations Forces (SOF). Much like athletes, Operators have multiple training components including technical, tactical, physical and mental conditioning, which must simultaneously be developed for mission success. Balancing multiple physical stressors to ensure positive results from training can be achieved through periodization?the intentional planning for success. Monitoring the training load can assist SOF in managing training stress and designing periodization that minimizes fatigue. The present article provides an overview of modern technology developed to quantify the stress of training. The training load maintained by SOF consists of external loads created through physical work and internal units of load determined by the rate of perceived effort during training that must be integrated in a manner that minimizes the accumulation of fatigue. Methods for determining training load are discussed in this article and examples are provided for determining training load, developing conditioning sessions and utilizing training load to maintain physical fitness, and improve return from injury. PMID- 26125173 TI - Q Fever. AB - Q fever is a zoonotic disease found throughout the world. It is caused by the intracellular gram-negative bacterium Coxiella burnetii. Infection by C. burnetii occurs primarily by inhalation of the aerosolized bacteria from birthing animals or contaminated dust. The bacterium is very resistant to drying and heat, and is considered highly endemic in the Middle East, where it is likely underdiagnosed. Special Operations Forces medical providers should be aware of this disease, which must be in the differential diagnosis of a patient who has a history of fever, elevated liver enzymes, pneumonia in its acute form, and endocarditis, especially in those with existing valvular heart disease in its chronic form. PMID- 26125174 TI - The Importance of Physical Fitness for Injury Prevention: Part 2. AB - This report examines associations between injuries and flexibility, stretching, warm-up, and body composition. Military studies show that either too much or too little flexibility increases injury risk. Static stretching prior to exercise does not appear to reduce the overall injury incidence, although further research is needed on some types of injuries. Static stretching also appears to reduce strength and power (explosive strength). Warm-up (low intensity activity prior to exercise or sports) appears to reduce injury risk. Body mass index (BMI; weight in kg/ height in m2) is a surrogate measure of body fat because it is highly related to laboratory measures of body fat. However, Soldiers can also have a high BMI because of higher muscle mass. If high BMI reflects a larger percentage of body fat relative to height, injury risk might be increased because the additional fat would increase the intensity of physical activity, leading to more rapid fatigue and repetitive stress on the musculoskeletal system. Low BMI could reflect a paucity of fat or muscle/ bone, or both. Low BMI may make Soldiers more susceptible to injury if they lack the muscle mass or strength in the supportive structures (ligaments, bones) required to perform certain physical tasks, and if they overexert or overuse the available muscle mass or supportive structures. Studies in basic combat training show that both high and low BMI increases injury risk. However, studies among active duty Soldiers only show that injury risk increases as BMI increases, possibly because very few active duty Soldiers have very low BMI (i.e., less than 18 kg/m2). PMID- 26125175 TI - A Descriptive Analysis of US Prehospital Care Response to Law Enforcement Tactical Incidents. AB - BACKGROUND: Law enforcement tactical incidents involve high-risk operations that exceed the capabilities of regular, uniformed police. Despite the existence of tactical teams for 50 years, little is known about the frequency or nature of emergency medical services (EMS) response to tactical events in the United States. The purpose of this study was to perform a descriptive analysis of tactical events reported to a national EMS database. METHODS: Descriptive analysis of the 2012 National Emergency Medical Services Information System (NEMSIS) Public Release research data set, containing EMS emergency response data from 41 states. RESULTS: A total of 17,479,328 EMS events were reported, of which 3,953 events were coded as "Activation-Tactical or SWAT Specialty Service/Response Team." The most common level of prehospital care present on scene was basic life support (55.2%). The majority (72.3%) of tactical incident activations involved a single patient; mass casualty incidents occurred in 0.5% of events. The most common EMS response locations were homes (48.4%), streets or highways (37.0%), and public buildings (6.3%). The mean age of treated patients was 44.1 years +/- 22.0 years; 3.5% of tactical incident activation patients were aged 8 years or less. Injuries were coded as firearm assault in 14.8% and as chemical exposure in 8.9% of events. Cardiac arrest occurred in 5.1% of patients, with the majority (92.2%) occurring prior to EMS arrival. The primary symptoms reported by EMS personnel were pain (37.4%), change in responsiveness (13.1%), and bleeding (8.1%). Advanced airway procedures occurred in 30 patients. No patients were documented as receiving tourniquets or needle thoracostomy. CONCLUSION: Approximately 11 EMS responses in support of law enforcement tactical operations occur daily in the United States. The majority occur in homes and involve a single patient. Advanced airway procedures are required in a minority of patients. Cardiac arrest is rare and occurs prior to EMS response in the majority of cases. Better understanding of the nature and location of EMS responses to tactical incidents is required to develop consistent EMS policies in support of law enforcement tactical operations. PMID- 26125176 TI - A Case Study of MEDCANGRO Relative to RAND Conceptual Framework. AB - The 2010 Department of Defense (DoD) Instruction 6000.16, Military Health Support for Stability Operations, established medical stability operations as a core military mission. National military leaders appreciated that to better manage risks for US military personnel operating in far forward locations, reduce cost and footprint requirements for operations, and aid partner nations with providing service to relevant populations in underserviced/undergoverned the US military would need to be employed strategically in efforts to build partner nation medical capacity. Medical Stability Operations has evolved into Global Health Engagement in the lexicon of planners but the goal is still the same. This article used a technical report authored by the RAND Corporation as the basis of a case study of a Special Operations Command Africa (SOCAF) Mission to the country of Niger to build a casualty evacuation capability. The case study evaluates the utility of a hypothetical framework developed by the RAND researchers relative to the actual events and outcomes of an actual mission. The principal finding is that the RAND technical report is of value to planners, Operators, and trainers as a systematic approach to successful building partner capacity in health (BPC-H) missions. The article also offers several examples of metrics that aid leadership in making better decisions as to when corrective actions might be required. PMID- 26125177 TI - Psoriasis. AB - An active duty Sailor has a long history of skin lesions on his scalp, chest, back, and legs. He was evaluated and treated previously but could not recall the specific details. He is diagnosed with plaque psoriasis, an immune-mediated chronic disease. This article reviews the etiology, morphology, diagnosis, and treatment of psoriasis. PMID- 26125178 TI - Preventive Medicine and Its Role in the Special Operation Forces Medical Team. AB - Throughout history, Soldiers in wartime have been especially vulnerable to infectious diseases, which have devastated and decimated entire armies, causing suspension and, in some cases, complete cancellation of military operations. Dr. William Foege,1 a renowned Harvard epidemiologist, and his colleagues claim that throughout history, infectious diseases have killed more Soldiers than have weapons. Reality shows that it does not matter if your Soldiers had the best training available with the best equipment and top of the world intelligence: if your personnel get sick, they become more of a liability than an asset for a combat operation. This article presents some of the key findings that continue to affect our Special Operations Forces (SOF) and how the use of specifically designed new products can help in controlling short- and long-term consequences of infectious diseases. PMID- 26125179 TI - POW and Detainee Operations: Lessons Unlearned. AB - Throughout the history of modern warfare, tales of atrocities have repeatedly surfaced that depict active and passive aggression toward prisoners of war (POWs). Yet, with each conflict, new tales are born and an undeniable reality of warfare inflicts fresh scars for aggressors to bear. It is understandable, based on human nature and the goals of war, that a government (or its representatives) will feel malice toward enemy prisoners captured during a conflict. It is unquestionably a challenge to overcome that human nature, despite the statutes that outline lawful treatment of POWs. While most aspects of warfare have been revolutionized throughout history, the means by which a military deals with its POWs remains somewhat mired in the reticence of leaders to acknowledge that it will factor into every conflict--that it will, in fact, become a source of controversy as long as it is handled as an afterthought. As shown in accounts dating back to the Revolutionary War, the law can only influence human nature to a point, especially when resources are limited, ignorance is a reality, and no one is watching. PMID- 26125180 TI - Fuzileiros Portugueses (Portuguese Marines). PMID- 26125182 TI - Correction: Altered Ca2+ Kinetics Associated with alpha-Actinin-3 Deficiency May Explain Positive Selection for ACTN3 Null Allele in Human Evolution. PMID- 26125181 TI - The Differential Expression of Immune Genes between Water Buffalo and Yellow Cattle Determines Species-Specific Susceptibility to Schistosoma japonicum Infection. AB - Water buffalo are less susceptible to Schistosoma japonicum infection than yellow cattle. The factors that affect such differences in susceptibility remain unknown. A Bos taurus genome-wide gene chip was used to analyze gene expression profiles in the peripheral blood of water buffalo and yellow cattle pre- and post infection with S. japonicum. This study showed that most of the identified differentially expressed genes (DEGs) between water buffalo and yellow cattle pre and post-infection were involved in immune-related processes, and the expression level of immune genes was lower in water buffalo. The unique DEGs (390) in yellow cattle were mainly associated with inflammation pathways, while the unique DEGs (2,114) in water buffalo were mainly associated with immune-related factors. The 83 common DEGs may be the essential response genes during S. japonicum infection, the highest two gene ontology (GO) functions were associated with the regulation of fibrinolysis. The pathway enrichment analysis showed that the DEGs constituted similar immune-related pathways pre- and post-infection between the two hosts. This first analysis of the transcriptional profiles of natural hosts has enabled us to gain new insights into the mechanisms that govern their susceptibility or resistance to S. japonicum infections. PMID- 26125183 TI - Occurrence of Isopenicillin-N-Synthase Homologs in Bioluminescent Ctenophores and Implications for Coelenterazine Biosynthesis. AB - The biosynthesis of the luciferin coelenterazine has remained a mystery for decades. While not all organisms that use coelenterazine appear to make it themselves, it is thought that ctenophores are a likely producer. Here we analyze the transcriptome data of 24 species of ctenophores, two of which have published genomes. The natural precursors of coelenterazine have been shown to be the amino acids L-tyrosine and L-phenylalanine, with the most likely biosynthetic pathway involving cyclization and further modification of the tripeptide Phe-Tyr-Tyr ("FYY"). Therefore, we searched the ctenophore transcriptome data for genes with the short peptide "FYY" as part of their coding sequence. We recovered a group of candidate genes for coelenterazine biosynthesis in the luminous species which encode a set of highly conserved non-heme iron oxidases similar to isopenicillin N-synthase. These genes were absent in the transcriptomes and genome of the two non-luminous species. Pairwise identities and substitution rates reveal an unusually high degree of identity even between the most unrelated species. Additionally, two related groups of non-heme iron oxidases were found across all ctenophores, including those which are non-luminous, arguing against the involvement of these two gene groups in luminescence. Important residues for iron binding are conserved across all proteins in the three groups, suggesting this function is still present. Given the known functions of other members of this protein superfamily are involved in heterocycle formation, we consider these genes to be top candidates for laboratory characterization or gene knockouts in the investigation of coelenterazine biosynthesis. PMID- 26125184 TI - Menstrual Hygiene Practices, WASH Access and the Risk of Urogenital Infection in Women from Odisha, India. AB - Menstrual hygiene management (MHM) practices vary worldwide and depend on the individual's socioeconomic status, personal preferences, local traditions and beliefs, and access to water and sanitation resources. MHM practices can be particularly unhygienic and inconvenient for girls and women in poorer settings. Little is known about whether unhygienic MHM practices increase a woman's exposure to urogenital infections, such as bacterial vaginosis (BV) and urinary tract infection (UTI). This study aimed to determine the association of MHM practices with urogenital infections, controlling for environmental drivers. A hospital-based case-control study was conducted on 486 women at Odisha, India. Cases and controls were recruited using a syndromic approach. Vaginal swabs were collected from all the participants and tested for BV status using Amsel's criteria. Urine samples were cultured to assess UTI status. Socioeconomic status, clinical symptoms and reproductive history, and MHM and water and sanitation practices were obtained by standardised questionnaire. A total of 486 women were recruited to the study, 228 symptomatic cases and 258 asymptomatic controls. Women who used reusable absorbent pads were more likely to have symptoms of urogenital infection (AdjOR=2.3, 95%CI1.5-3.4) or to be diagnosed with at least one urogenital infection (BV or UTI) (AdjOR=2.8, 95%CI1.7-4.5), than women using disposable pads. Increased wealth and space for personal hygiene in the household were protective for BV (AdjOR=0.5, 95%CI0.3-0.9 and AdjOR=0.6, 95%CI0.3-0.9 respectively). Lower education of the participants was the only factor associated with UTI after adjusting for all the confounders (AdjOR=3.1, 95%CI1.2-7.9). Interventions that ensure women have access to private facilities with water for MHM and that educate women about safer, low-cost MHM materials could reduce urogenital disease among women. Further studies of the effects of specific practices for managing hygienically reusable pads and studies to explore other pathogenic reproductive tract infections are needed. PMID- 26125185 TI - A Comparative Study of Early Afterdepolarization-Mediated Fibrillation in Two Mathematical Models for Human Ventricular Cells. AB - Early afterdepolarizations (EADs), which are abnormal oscillations of the membrane potential at the plateau phase of an action potential, are implicated in the development of cardiac arrhythmias like Torsade de Pointes. We carry out extensive numerical simulations of the TP06 and ORd mathematical models for human ventricular cells with EADs. We investigate the different regimes in both these models, namely, the parameter regimes where they exhibit (1) a normal action potential (AP) with no EADs, (2) an AP with EADs, and (3) an AP with EADs that does not go back to the resting potential. We also study the dependence of EADs on the rate of at which we pace a cell, with the specific goal of elucidating EADs that are induced by slow or fast rate pacing. In our simulations in two- and three-dimensional domains, in the presence of EADs, we find the following wave types: (A) waves driven by the fast sodium current and the L-type calcium current (Na-Ca-mediated waves); (B) waves driven only by the L-type calcium current (Ca mediated waves); (C) phase waves, which are pseudo-travelling waves. Furthermore, we compare the wave patterns of the various wave-types (Na-Ca-mediated, Ca mediated, and phase waves) in both these models. We find that the two models produce qualitatively similar results in terms of exhibiting Na-Ca-mediated wave patterns that are more chaotic than those for the Ca-mediated and phase waves. However, there are quantitative differences in the wave patterns of each wave type. The Na-Ca-mediated waves in the ORd model show short-lived spirals but the TP06 model does not. The TP06 model supports more Ca-mediated spirals than those in the ORd model, and the TP06 model exhibits more phase-wave patterns than does the ORd model. PMID- 26125187 TI - Identification of Essential Proteins Based on a New Combination of Local Interaction Density and Protein Complexes. AB - BACKGROUND: Computational approaches aided by computer science have been used to predict essential proteins and are faster than expensive, time-consuming, laborious experimental approaches. However, the performance of such approaches is still poor, making practical applications of computational approaches difficult in some fields. Hence, the development of more suitable and efficient computing methods is necessary for identification of essential proteins. METHOD: In this paper, we propose a new method for predicting essential proteins in a protein interaction network, local interaction density combined with protein complexes (LIDC), based on statistical analyses of essential proteins and protein complexes. First, we introduce a new local topological centrality, local interaction density (LID), of the yeast PPI network; second, we discuss a new integration strategy for multiple bioinformatics. The LIDC method was then developed through a combination of LID and protein complex information based on our new integration strategy. The purpose of LIDC is discovery of important features of essential proteins with their neighbors in real protein complexes, thereby improving the efficiency of identification. RESULTS: Experimental results based on three different PPI(protein-protein interaction) networks of Saccharomyces cerevisiae and Escherichia coli showed that LIDC outperformed classical topological centrality measures and some recent combinational methods. Moreover, when predicting MIPS datasets, the better improvement of performance obtained by LIDC is over all nine reference methods (i.e., DC, BC, NC, LID, PeC, CoEWC, WDC, ION, and UC). CONCLUSIONS: LIDC is more effective for the prediction of essential proteins than other recently developed methods. PMID- 26125186 TI - Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults. AB - Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious. PMID- 26125188 TI - Genome-Wide Analysis of the NAC Gene Family in Physic Nut (Jatropha curcas L.). AB - The NAC proteins (NAM, ATAF1/2 and CUC2) are plant-specific transcriptional regulators that have a conserved NAM domain in the N-terminus. They are involved in various biological processes, including both biotic and abiotic stress responses. In the present study, a total of 100 NAC genes (JcNAC) were identified in physic nut (Jatropha curcas L.). Based on phylogenetic analysis and gene structures, 83 JcNAC genes were classified as members of, or proposed to be diverged from, 39 previously predicted orthologous groups (OGs) of NAC sequences. Physic nut has a single intron-containing NAC gene subfamily that has been lost in many plants. The JcNAC genes are non-randomly distributed across the 11 linkage groups of the physic nut genome, and appear to be preferentially retained duplicates that arose from both ancient and recent duplication events. Digital gene expression analysis indicates that some of the JcNAC genes have tissue specific expression profiles (e.g. in leaves, roots, stem cortex or seeds), and 29 genes differentially respond to abiotic stresses (drought, salinity, phosphorus deficiency and nitrogen deficiency). Our results will be helpful for further functional analysis of the NAC genes in physic nut. PMID- 26125191 TI - Behavior of Ants Escaping from a Single-Exit Room. AB - To study the rules of ant behavior and group-formation phenomena, we examined the behaviors of Camponotus japonicus, a species of large ant, in a range of situations. For these experiments, ants were placed inside a rectangular chamber with a single exit that also contained a filter paper soaked in citronella oil, a powerful repellent. The ants formed several groups as they moved toward the exit to escape. We measured the time intervals between individual escapes in six versions of the experiment, each containing an exit of a different width, to quantify the movement of the groups. As the ants exited the chamber, the time intervals between individual escapes changed and the frequency distribution of the time intervals exhibited exponential decay. We also investigated the relationship between the number of ants in a group and the group flow rate. PMID- 26125189 TI - Plasmodium vivax Diversity and Population Structure across Four Continents. AB - Plasmodium vivax is the geographically most widespread human malaria parasite. To analyze patterns of microsatellite diversity and population structure across countries of different transmission intensity, genotyping data from 11 microsatellite markers was either generated or compiled from 841 isolates from four continents collected in 1999-2008. Diversity was highest in South-East Asia (mean allelic richness 10.0-12.8), intermediate in the South Pacific (8.1-9.9) Madagascar and Sudan (7.9-8.4), and lowest in South America and Central Asia (5.5 7.2). A reduced panel of only 3 markers was sufficient to identify approx. 90% of all haplotypes in South Pacific, African and SE-Asian populations, but only 60 80% in Latin American populations, suggesting that typing of 2-6 markers, depending on the level of endemicity, is sufficient for epidemiological studies. Clustering analysis showed distinct clusters in Peru and Brazil, but little sub structuring was observed within Africa, SE-Asia or the South Pacific. Isolates from Uzbekistan were exceptional, as a near-clonal parasite population was observed that was clearly separated from all other populations (FST>0.2). Outside Central Asia FST values were highest (0.11-0.16) between South American and all other populations, and lowest (0.04-0.07) between populations from South-East Asia and the South Pacific. These comparisons between P. vivax populations from four continents indicated that not only transmission intensity, but also geographical isolation affect diversity and population structure. However, the high effective population size results in slow changes of these parameters. This persistency must be taken into account when assessing the impact of control programs on the genetic structure of parasite populations. PMID- 26125192 TI - Elastic and magnetoelastic relaxation behaviour of multiferroic (ferromagnetic + ferroelectric + ferroelastic) Pb(Fe0.5Nb0.5)O3 perovskite. AB - Resonant Ultrasound Spectroscopy has been used to characterize elastic and anelastic anomalies in a polycrystalline sample of multiferroic Pb(Fe(0.5)Nb(0.5))O(3) (PFN). Elastic softening begins at ~550 K, which is close to the Burns temperature marking the development of dynamical polar nanoregions. A small increase in acoustic loss at ~425 K coincides with the value of T(*) reported for polar nanoregions starting to acquire a static or quasi-static component. Softening of the shear modulus by ~30-35% through ~395-320 K, together with a peak in acoustic loss, is due to classical strain/order parameter coupling through the cubic -> tetragonal -> monoclinic transition sequence of ferroelectric/ferroelastic transitions. A plateau of high acoustic loss below ~320 K is due to the mobility under stress of a ferroelastic microstructure but, instead of the typical effects of freezing of twin wall motion at some low temperature, there is a steady decrease in loss and increase in elastic stiffness below ~85 K. This is attributed to freezing of a succession of strain-coupled defects with a range of relaxation times and is consistent with a report in the literature that PFN develops a tweed microstructure over a wide temperature interval. No overt anomaly was observed near the expected Neel point, ~145 K, consistent with weak/absent spin/lattice coupling but heat capacity measurements showed that the antiferromagnetic transition is actually smeared out or suppressed. Instead, the sample is weakly ferromagnetic up to ~560 K, though it has not been possible to exclude definitively the possibility that this could be due to some magnetic impurity. Overall, evidence from the RUS data is of a permeating influence of static and dynamic strain relaxation effects which are attributed to local strain heterogeneity on a mesoscopic length scale. These, in turn, must have a role in determining the magnetic properties and multiferroic character of PFN. PMID- 26125190 TI - Sex-Specific Mediating Role of Insulin Resistance and Inflammation in the Effect of Adiposity on Blood Pressure of Prepubertal Children. AB - OBJECTIVE: To evaluate the association between obesity indices and blood pressure (BP) at 4 years of age, in each sex, and to quantify to which extent this association is mediated by inflammation and insulin resistance (IR). MATERIALS AND METHODS: We studied 1250 4-year-old children selected from the population based birth cohort Generation XXI. Associations between body mass index (BMI) z score and waist-to-height ratio (WHtR), office BP, inflammation (high sensitivity C-reactive protein) and IR (HOMA-IR index) were assessed. Path Analysis, a modified multivariate regression approach, was applied to test causal models and quantify direct and indirect effects of predictors of systolic (SBP) and diastolic BP (DBP). RESULTS: SBP and DBP increased significantly with BMI and WHtR in both sexes. There was a strong direct association (explaining 74.1-93.2% of the total association) of both measures of adiposity with SBP, in both sexes. This association was additionally indirectly mediated by IR, particularly regarding WHtR (20.5% in girls and 9.4% in boys). Mediation by inflammation did not reach statistical significance in either sex. Regarding DBP, the direct effect of adiposity was strong (>95% for BMI and WHtR in boys) and the mediation by IR was much smaller in boys than in girls. DISCUSSION: The direct association between adiposity and BP in healthy 4-year-old children is strong and IR plays an important mediating role. The strength of effects of IR and inflammation suggests sex differences in the complex interplay between BP, adiposity and inflammation. PMID- 26125193 TI - Multiple interventions improve analgesic treatment of supracondylar humerus fractures in a pediatric emergency department. AB - BACKGROUND: Provision of appropriate and timely treatment for pain in the pediatric population has been challenging. Children with painful conditions commonly present to emergency departments (EDs), a setting in which it may be particularly difficult to consistently provide timely analgesic interventions. OBJECTIVES: To measure the effectiveness of a set of interventions in improving the rate and timeliness of analgesic medication administration, as well as appropriate backslab immobilization (application of a moldable plaster or fiberglass splint), in a pediatric ED. METHODS: Data regarding pain management were collected on a consecutive sample of cases of supracondylar fracture over a 13-month period. This followed the implementation of a formal triage pain assessment and treatment medical directive, supplemented with relevant education of nursing and house staff, and posters in the ED. These data were compared with data previously collected from a similar cohort of cases, which presented before the interventions. RESULTS: Postintervention, the proportion of patients treated with an analgesic within 60 min of triage increased from 15% to 54% (P<0.001), and the median time to administration of an analgesic decreased from 72.5 min to 11 min (P<0.001). Rates for backslab application before radiography were similar before and after the intervention (29% and 33%, respectively; P=0.646). CONCLUSIONS: A multifaceted approach to improving early analgesic interventions was associated with considerably improved rates of early analgesic treatments for supracondylar fracture; however, no improvement in early immobilization was observed. PMID- 26125194 TI - Effects of continuous fascia iliaca compartment blocks for postoperative analgesia in patients with hip fracture AB - BACKGROUND: Effective analgesia is essential for the postoperative care of orthopedic patients. OBJECTIVES: To evaluate the efficacy of continuous fascia iliaca compartment block (FIB) as postoperative analgesia after hip fracture surgery, and to compare FIB with patient-controlled intravenous analgesia (PCIA) using fentanyl for 48 h postoperatively. METHODS: Patients with hip fractures who were scheduled for open reduction and internal fixation surgery using the antirotation proximal femoral nail technique were randomly assigned to the FIB or PCIA groups. Postoperative pain was assessed using a numeral rating scale at 2 h, 4 h, 6 h, 12 h, 24 h and 48 h after analgesia was started. Delirium, postoperative nausea and vomiting (PONV), and pruritus were also monitored. RESULTS: Patients in the FIB group reported less pain than those in the PCIA group (P=0.039, d=-0.3). The change in pain scores over time was similar between the two groups. There were six patients with PONV and five patients with pruritus in the PCIA group, while no PONV or pruritus was noticed in the FIB group (P=0.013). Ten (19.6%) patients in the FIB group and three (5.7%) patients in the PCIA group developed postoperative delirium (P=0.032, d=0.77). CONCLUSION: Continuous FIB is a safe and effective technique for postoperative analgesia after hip fracture surgery, making it an option for pain management in elderly patients with hip fractures. PMID- 26125196 TI - Folate and Vitamin B12 Status in Latin America and the Caribbean: An Update. AB - Background: The current magnitude of folate and vitamin B12 deficiency in Latin America and the Caribbean is uncertain. OBJECTIVE: To summarize data on plasma or serum vitamin B12 and folate concentrations in Latin America and the Caribbean reported since 1990, a period that covers the era before and after the introduction of folic acid fortification. METHODS: A systematic review was conducted in 2012 and updated in 2014. Studies and surveys using biochemical biomarkers and conducted in apparently healthy individuals were identified. RESULTS: Folate deficiency in Latin America and the Caribbean appears not to be a public health problem (prevalence < 5%) after the introduction of folic acid fortification. However, there is some indication that high rates of low or marginal vitamin B12 status remain in most locations and across population groups. CONCLUSIONS: Adding vitamin B12 as a fortificant with folic acid may be the best strategy in areas where vitamin B12 deficiency is an established concern. PMID- 26125195 TI - Modifiable lifestyle factors are associated with lower pain levels in adults with knee osteoarthritis. AB - BACKGROUND: With no cure or effective treatments for osteoarthritis (OA), the need to identify modifiable factors to decrease pain and increase physical function is well recognized. OBJECTIVE: To examine factors that characterize OA patients at different levels of pain, and to investigate the relationships among these factors and pain. METHODS: Details of OA characteristics and lifestyle factors were collected from interviews with healthy adults with knee OA (n=197). The Western Ontario and McMaster Universities Osteoarthritis Index was used to assess pain. Factors were summarized across three pain score categories, and chi(2) and Kruskal-Wallis tests were used to examine differences. Multiple linear regression analysis using a stepwise selection procedure was used to examine associations between lifestyle factors and pain. RESULTS: Multiple linear regression analysis indicated that pain was significantly higher with the use of OA medications and higher body mass index category, and significantly lower with the use of supplements and meeting physical activity guidelines (>= 150 min/week). Stiffness and physical function scores, bilateral knee OA, body mass index category and OA medication use were significantly higher with increasing pain, whereas self-reported health, servings of fruit, supplement use and meeting physical activity guidelines significantly lower. No significant differences across pain categories were found for sex, age, number of diseases, duration of OA, ever smoked, alcoholic drinks/week, over-the-counter pain medication use, OA supplement use, physical therapy use, servings of vegetables or minutes walked/week. CONCLUSIONS: Healthy weight maintenance, exercise for at least 150 min/week and appropriate use of medications and supplements represent important modifiable factors related to lower knee OA pain. PMID- 26125197 TI - Prevalence of Anemia in Latin America and the Caribbean. AB - BACKGROUND: In Latin America and the Caribbean, anemia has been a public health problem that affects mainly women of childbearing age and children under 6 years of age. However, the current prevalence of anemia in this region is unknown. OBJECTIVE: To examine the latest available prevalence data on anemia in Latin America and the Caribbean. METHODS: A systematic review was conducted in 2011 and updated in 2014. Studies determining the prevalence of anemia conducted in apparently healthy populations with national or regional representativeness were included in the review. RESULTS: The lowest prevalence rates of anemia among children under 6 years of age were found in Chile (4.0%), Costa Rica (4.0%), Argentina (7.6%), and Mexico (19.9%). In Nicaragua, Brazil, Ecuador, El Panama, and Honduras, anemia was a moderate public health problem, with prevalence ranging Salvador, Cuba, Colombia, the Dominican Republic, Peru, from 20.1% to 37.3%. Anemia was a severe public health problem in Guatemala, Haiti, and Bolivia. The prevalence of anemia among women of childbearing age was lowest in Chile (5.1%). In Colombia, El Salvador, Costa Rica, Nicaragua, Ecuador, Mexico, Peru, Honduras, and Argentina, anemia was a mild public health problem, with prevalence ranging from 7.6% to 18.7%. In Guatemala, Brazil, the Dominican Republic, and Bolivia, anemia was a moderate public health problem, with prevalence ranging from 21.4% to 38.3%. Panama and Haiti had the highest reported prevalence rates (40.0% and 45.5%, respectively), and anemia was considered a severe public health problem in those countries. CONCLUSIONS: Anemia remains a public health problem in children under 6 years of age and women of childbearing age in most Latin America and Caribbean countries for which data are available. PMID- 26125198 TI - Zinc Deficiency in Latin America and the Caribbean. AB - BACKGROUND: Zinc deficiency affects multiple vital functions in the life cycle, especially growth. Limited information is available on the magnitude of zinc deficiency in Latin America and the Caribbean. OBJECTIVE: To examine the latest available information on both the prevalence of zinc deficiency and the risk of zinc deficiency in Latin America and the Caribbean. METHODS: The prevalence of zinc deficiency was identified through a systematic review looking for the latest available data on serum zinc concentrations from surveys or studies with national representativeness conducted in Latin America and the Caribbean. The risk of zinc deficiency in Latin America and the Caribbean was estimated based on dietary zinc inadequacy (according to the 2011 National Food Balance Sheets) and stunting in children under 5 years of age. RESULTS: Only four countries had available national biochemical data. Mexican, Colombian, Ecuadorian, and Guatemalan children under 6 years of age and women 12 to 49 years of age had a high prevalence of zinc deficiency (19.1% to 56.3%). The countries with the highest risk of zinc deficiency (estimated prevalence of inadequate zinc intake > 25% plus prevalence of stunting > 20%) were Belize, Bolivia, El Salvador, Guatemala, Haiti, Honduras, Nicaragua, and Saint Vincent and the Grenadines. Zinc dietary inadequacy was directly correlated with stunting (r = 0.64, p < .001). CONCLUSIONS: Prevalence data from the four available Latin America and Caribbean national surveys indicate a high prevalence of zinc deficiency in children under 6 years of age and women 12 to 49 years of age. High rates of both estimated zinc dietary inadequacy and stunting were also reported in most Latin America and Caribbean countries. PMID- 26125199 TI - Introduction: Prevalence of Micronutrient Deficiencies in Latin America and the Caribbean. AB - This Food and Nutrition Bulletin supplement summarizes updated prevalence data on micronutrient deficiencies in Latin America and the Caribbean (LAC). In order to provide an updated view of micronutrient status in LAC, systematic reviews were performed utilizing national health surveys and research-oriented studies focused on the prevalence of deficiencies of vitamin A, folate, anemia (as a proxy of iron deficiency), and zinc. Results show that the prevalence of vitamin A deficiency has been reduced in many countries, folate deficiency is now almost non-existent, low or marginal vitamin B12 status is still prevalent in most locations, anemia remains a public health problem among children under 6 years of age and women of childbearing age in most surveyed countries, and there is a high prevalence of zinc deficiency in children under 6 years of age and girls and women 12 to 49 years of age. Thus, regardless of improvements in the overall rates of economic growth in LAC, deficiencies of these micronutrients still remain a public health problem. PMID- 26125200 TI - Interpretation of Serum Retinol Data From Latin America and the Caribbean. AB - BACKGROUND: In recent decades, the general socioeconomic situation in Latin America and the Caribbean countries has improved, and many vitamin A programs have been implemented in an attempt to reduce vitamin A deficiency in the region. OBJECTIVE: To examine vitamin A status in Latin America and the Caribbean based on serum retinol concentrations and to contrast available data published before and after 1998. METHODS: A systematic review was performed. National surveys or representative studies that reported vitamin A status were selected. RESULTS: Ten national surveys and six representative studies were identified. Data for children under 6 years of age indicate that Guatemala and Nicaragua have practically eradicated vitamin A deficiency (less than 2% prevalence of serum retinol < 20 MUg/dL). In Costa Rica, Cuba, El Salvador, and Panama, the prevalence of vitamin A deficiency ranged from 2.8% to 9.4%. In Peru, Honduras, Argentina, Ecuador, and Brazil, vitamin A deficiency is a moderate public health problem (prevalence from 14.0% to 17.4%), while in Colombia, Mexico, and Haiti it is a severe public health problem (prevalence from 24.3% to 32.0%). Disadvantaged groups (indigenous people and those of Afro-Colombian descent) have the highest rates of deficiency. The prevalence of vitamin A deficiency is under 20% in school-children and adult women. When data published before and after 1998 for children under 6 years of age were compared, most Central American countries had a reduction in the prevalence of vitamin A deficiency (p < .05), whereas in South American countries, the prevalence of vitamin A deficiency increased over time (p < .05). CONCLUSIONS: The prevalence of vitamin A deficiency in children under 6 years of age has decreased in many Central American countries, but vitamin A deficiency still remains a public health problem in numerous Latin America and Caribbean countries, especially among disadvantaged and vulnerable groups. Because of issues with the accuracy of the serum retinol biomarker reflecting body stores, these results must be interpreted with caution. PMID- 26125201 TI - Structural Requirements for CNS Active Opioid Glycopeptides. AB - Glycopeptides related to beta-endorphin penetrate the blood-brain barrier (BBB) of mice to produce antinociception. Two series of glycopeptides were assessed for opioid receptor binding affinity. Attempts to alter the mu-selectivity of [D Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO)-related glycopeptides by altering the charged residues of the amphipathic helical address were unsuccessful. A series of pan-agonists was evaluated for antinociceptive activity (55 degrees C tail flick) in mice. A flexible linker was required to maintain antinociceptive activity. Circular dichroism (CD) in H2O, trifluoroethanol (TFE), and SDS micelles confirmed the importance of the amphipathic helices (11s -> 11sG -> 11) for antinociception. The glycosylated analogues showed only nascent helices and random coil conformations in H2O. Chemical shift indices (CSI) and nuclear Overhauser effects (NOE) with 600 MHz NMR and CD confirmed helical structures in micelles, which were rationalized by molecular dynamics calculations. Antinociceptive studies with mice confirm that these glycosylated endorphin analogues are potential drug candidates that penetrate the BBB to produce potent central effects. PMID- 26125203 TI - Highly Reproducible Perovskite Solar Cells with Average Efficiency of 18.3% and Best Efficiency of 19.7% Fabricated via Lewis Base Adduct of Lead(II) Iodide. AB - High efficiency perovskite solar cells were fabricated reproducibly via Lewis base adduct of lead(II) iodide. PbI2 was dissolved in N,N-dimethyformamide with equimolar N,N-dimethyl sulfoxide (DMSO) and CH3NH3I. Stretching vibration of S?O appeared at 1045 cm(-1) for bare DMSO, which was shifted to 1020 and 1015 cm(-1) upon reacting DMSO with PbI2 and PbI2 + CH3NH3I, respectively, indicative of forming the adduct of PbI2.DMSO and CH3NH3I.PbI2.DMSO due to interaction between Lewis base DMSO and/or iodide (I(-)) and Lewis acid PbI2. Spin-coating of a DMF solution containing PbI2, CH3NH3I, and DMSO (1:1:1 mol %) formed a transparent adduct film, which was converted to a dark brown film upon heating at low temperature of 65 degrees C for 1 min due to removal of the volatile DMSO from the adduct. The adduct-induced CH3NH3PbI3 exhibited high charge extraction characteristics with hole mobility as high as 3.9 * 10(-3) cm(2)/(V s) and slow recombination rate. Average power conversion efficiency (PCE) of 18.3% was achieved from 41 cells and the best PCE of 19.7% was attained via adduct approach. PMID- 26125202 TI - Breast Metastasis of Extraskeletal Myxoid Chondrosarcoma: A Case Report. AB - BACKGROUND: Extraskeletal myxoid chondrosarcoma is a unique and distinct clinicopathological entity in terms of its origin, morphology, and biologic behavior. Despite being a slow-growing tumor, it has a high rate of local recurrences and history of metastases to uncommon sites like the mandible, liver, retroperitoneum, right ventricle, pancreas, and central nervous system. Here, we report a very unique case of extraskeletal myxoid chondrosarcoma that metastasized to the breast, which itself is a very rare site for metastases. CASE REPORT: A 58-year-old woman presented with a large, firm, and tender soft-tissue mass (6.0*7.0 cm) underneath the sole of the left foot. A computerized tomography (CT) scan showed a heterogeneous lobulated mass in the plantar aspect of the forefoot, measuring 8.6*8.0*7.1 cm. Punch biopsies revealed histology consistent with extraskeletal myxoid chondrosarcoma. Metastatic work-up was negative. The mass was fully resected with left below-knee amputation. The histology of the resected mass was consistent with extraskeletal myxoid chondrosarcoma. A follow up CT showed a new right breast nodule along with metastases to lung and bones. The results of the core needle biopsies of the right breast masses seen on mammogram were morphologically identical to extraskeletal myxoid chondrosarcoma. CONCLUSIONS: Although rare, metastases to the breast should be considered in the differential diagnosis of a breast mass. A close long-term follow-up is needed due to the unpredictable behavior of extraskeletal myxoid chondrosarcoma and the high frequency of local recurrences, metastases, and death due to disease. PMID- 26125204 TI - Robust magnetic domains in fluorinated ReS22monolayer. AB - Transition metal dichalcogenides are layered materials that are typically bound together by van der Waals forces. An exception in the family is ReS2; the geometrical distortion of its lattice structure due to Peierls distortion dimerizes Re atoms to form zigzag chains, thus decoupling the layers electronically and vibrationally. This in turn reduces the layer dependence of its physical and chemical properties. In order to tailor the properties of ReS2 monolayer, an alternative way by fluorination above and between Re chains in the lattice is investigated. The results of density functional theory calculations show the site-dependent electronic properties of fluorinated ReS2: (i) F atoms above the Re chains induce metallic mid-gap states which are ferromagnetically coupled within the Re chains, and antiferromagnetically-coupled between chains; (ii) F atoms between the Re chains induce semiconducting mid-gap states which are non-magnetic. Unlike other states observed, the mid-gap states associated with top sites above the Re chains are generally insusceptible to the external electric field. The electron localization and negative Laplacian plots show that not only bonds between F and S atoms are ionic in character, the Re chains are also coupled ionically. The emergence of these robust metallic mid-gap states in the localized domains suggest that electrons could conduct along the Re chains by hopping. The electron conduction in such functionalized ReS2 is anisotropic in nature, and hence could be applied in spintronic devices, such as spin-transfer torque and spin-wave logic devices. PMID- 26125205 TI - Embracing change: is it possible? PMID- 26125207 TI - Coding for "incident-to" services. PMID- 26125206 TI - Black salve and bloodroot extract in dermatologic conditions. AB - Due to extensive advertising of black salve's effectiveness in "curing" skin cancers and healing other skin conditions, many patients are turning to self treating with black salve. Although black salve has not been proven to have anticancer properties, application of black salve has been shown to cause damage to healthy tissue and the need for further treatment. We describe a 35-year-old woman whose one-time application of black salve to a healing biopsy site resulted in skin erosion and formation of a dermatitic plaque with subsequent scarring. Dermatologists and other health professionals need to be aware of this increasingly popular product to be able to better inform and treat their patients. PMID- 26125208 TI - Prevalence and impact of health-related internet and smartphone use among dermatology patients. AB - Health information is increasingly accessible via the Internet and smartphone applications (apps), and patients may perceive these resources as tools for self education and/or self-diagnosis. The objective of this study was to assess the characteristics of dermatology patients who use the Internet and/or smartphone apps to access health information and to evaluate the impact that these resources have on patients' health care-seeking behavior and interactions with physicians. Online resources offer both opportunities and challenges for dermatologists. Because patients often consult online resources for information about dermatologic conditions and may rely on these resources instead of seeking the care of a dermatologist, it is important for dermatologists to be involved in the development of high-quality online content that educates the public while also emphasizing the need to seek in-person medical care. PMID- 26125209 TI - Rare angioinvasive fungal infection in association with leukemia cutis. AB - Leukemia cutis (LC) is characterized by the infiltration of malignant neoplastic leukocytes or their precursors into the skin and is most often seen in conjunction with systemic leukemia. Patients with LC frequently are in a relative or absolute immunocompromised state. We report the case of a 52-year-old man with primary refractory acute myelogenous leukemia (AML) following allogeneic stem cell transplant (SCT) who presented with a progressive reddish purple nodule with surrounding erythema and central necrosis in the setting of leukocytosis and possible fungal pneumonia. Histopathologic examination revealed an ulcerated dense diffuse dermal infiltrate of large atypical lymphocytes consistent with LC and septate hyphae with acute-angle branching in the dermal blood vessels. Cultures from a biopsied lesion grew Paecilomyces species, a rare but emerging opportunistic infection, despite the patient being on antifungal prophylaxis. This novel report of a rare angioinvasive infection occurring within a lesion of LC supports the need to maintain a high index of suspicion for invasive infection in patients with hematologic malignancy, even those on antifungal prophylaxis. PMID- 26125210 TI - Hidradenitis suppurativa and concomitant pyoderma gangrenosum treated With infliximab. AB - Pyoderma gangrenosum (PG) and hidradenitis suppurativa (HS) are rare chronic inflammatory dermatoses of unknown etiologies that often are refractory to conventional treatments. The therapeutic benefits of tumor necrosis factor a (TNF alpha) inhibitors have been reported in patients with refractory PG or HS. The copresentation of these 2 diseases has previously been described in several cases in the literature and may present a therapeutic challenge. We present the case of a 51-year-old man who developed widespread inflammatory ulcers affecting approximately 50% of the body surface area and subsequent chronic debilitation from severe pain. He was ultimately diagnosed with concurrent PG and HS. Both diseases remitted in response to treatment with infliximab, which resulted in complete restoration of skin integrity and resolution of his chronic severe pain. PMID- 26125211 TI - Pruritic urticarial papules and plaques of pregnancy occurring postpartum. AB - Pruritic urticarial papules and plaques of pregnancy (PUPPP)(also known as polymorphic eruption of pregnancy in Europe) is an intensely pruritic eruption that affects women during the third trimester of pregnancy. Treatment usually is aimed at symptom relief until delivery, as the eruption usually resolves rapidly in the postpartum period. We report the case of a 30-year-old woman who presented 2 weeks postpartum with an intensely pruritic generalized eruption. The eruption started on the abdominal striae within 24 hours of delivery and gradually spread to the buttocks, legs, and arms. Punch biopsy confirmed a diagnosis of PUPPP. Pruritic urticarial papules and plaques of pregnancy presenting in the postpartum period is extremely rare. We present this case for clinical interest and to remind clinicians to keep PUPPP as a consideration in the differential diagnosis when evaluating pruritic eruptions in women who are in the postpartum period. PMID- 26125212 TI - Imiquimod-induced subacute cutaneous lupus erythematosus-like changes. AB - Imiquimod is a topical immunomodulator used to treat genital warts and cutaneous malignancies that exerts its effects via induction of proinflammatory cytokines through activation of toll-like receptor (TLR) 7. Although subacute cutaneous lupus erythematosus (SCLE) has been reported in association with multiple systemic medications, SCLE in patients treated with topical agents has not been widely reported. We report the case of a 50-year-old woman with local induction of lesions that clinically and histologically resembled SCLE following treatment with topical imiquimod. PMID- 26125213 TI - Extramammary Paget disease. PMID- 26125214 TI - What is your diagnosis? onychomadesis following hand-foot-and-mouth disease. PMID- 26125215 TI - Cystic nodule on the palm. PMID- 26125216 TI - Benign cephalic histiocytosis. PMID- 26125217 TI - Leukemia cutis presenting as scrotal ulcerations in a patient with acute myelogenous leukemia. PMID- 26125218 TI - Firm plaques and nodules over the body. PMID- 26125219 TI - Primary localized cutaneous nodular amyloidosis of the thighs. AB - Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare form of cutaneous amyloidosis. We report the case of a 65-year-old woman with multiple asymptomatic discrete nodules and atrophic plaques on the thighs of 4 years' duration that had increased in number and size. Results of extensive clinical, histologic, and laboratory evaluation showed no evidence of systemic amyloidosis or myeloma. A diagnosis of PLCNA was made. The patient refused treatment due to the asymptomatic nature of the lesions, and follow-up examination 2.5 years later showed minimal progression of the disease. PMID- 26125220 TI - Minimize that "pinch and burn": tips and tricks to reduce injection pain with local anesthetics. AB - Local anesthetics are commonly utilized in the practice of dermatology. Minimizing local anesthetic injection pain can be beneficial to both physicians and patients. Easily implemented techniques that reduce injection pain of intralesional local anesthetics are reviewed. PMID- 26125221 TI - Non-HIV-related Kaposi sarcoma in 2 Hispanic patients arising in the setting of chronic venous insufficiency. AB - Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that can be confused with the clinical and histological findings of chronic venous insufficiency. Definitive diagnosis of KS can only be achieved by performing a polymerase chain reaction for HHV-8 or by immunostaining for the HHV-8 antigen. We describe 2 unusual clinical presentations of KS in the setting of chronic venous insufficiency with clinical and histologic features consistent with stasis dermatitis but positive HHV-8 immunostaining. Both patients had no known risk factors for KS. We propose the possibility that these cases may represent a new clinical variant of KS that may become more prevalent over time. Further studies are needed to identify the risk factors involved. Meanwhile, skin biopsy with HHV-8 testing may be warranted for violaceous patches and plaques arising on the legs in the setting of chronic venous insufficiency, especially in patients who are unresponsive to treatment. PMID- 26125222 TI - Indurated erythematous papules and plaques on the forearm. PMID- 26125223 TI - Remission of psoriasis 13 years after autologous stem cell transplant. PMID- 26125224 TI - Idiopathic follicular mucinosis or mycosis fungoides? classification and diagnostic challenges. AB - In recent years, the distinction between idiopathic follicular mucinosis (FM) and lymphoma-associated follicular mucinosis (LAFM) has been made through assessment of T-cell receptor gene rearrangement, flow cytometry, and immunohistochemistry. These methods, among others, have mostly identified monoclonality as a defining characteristic of LAFM; however, this finding cannot be considered conclusive, as monoclonality also has been described in benign inflammatory dermatoses such as lichen planus and idiopathic FM. Pure histologic diagnosis also is unreliable in many cases, as the histologic patterns of idiopathic FM and LAFM overlap. In this article, we discuss the importance of close clinical follow-up in patients with patch-stage mycosis fungoides (MF) or FM who have had a nondiagnostic histopathologic evaluation. We also highlight the value of ancillary testing, including T-cell receptor gene rearrangement, flow cytometry, and immunohistochemistry, as a component in the diagnostic process rather than the sole diagnostic moiety. Diagnosis and classification of idiopathic FM and LAFM continue to pose challenges for dermatologists, oncologists, and pathologists, and no single diagnostic tool is sufficient in providing diagnostic certainty; rather, a collective evaluation of pathologic, molecular, and clinical criteria is required. Currently, classification of idiopathic FM and LAFM incorporates clinical information and histologic assessment, but little consideration is given to the implications of the diagnosis from the patient's perspective. Revisiting histologic classification of these entities while incorporating the patient's perspective may prove beneficial to dermatologists as well as patients. PMID- 26125225 TI - Field effects on spontaneous magnetization reversal of bulk BiFe0.5Mn0.5O3, an effective strategy for the study of magnetic disordered systems. AB - We report a comprehensive study of the spontaneous magnetization reversal (MRV) performed on the disordered polycrystalline perovskite BiFe(0.5)Mn(0.5)O(3), an intriguing compound synthesized in high pressure-high temperature conditions. In disordered systems, the origin of MRV is not completely clarified, yet. In BiFe(0.5)Mn(0.5)O(3), compositional disorder involves the ions on the B-site of the perovskite determining the presence of mesoscopic clusters, characterized by high concentrations of iron or manganese and thus by different resultant magnetization. This leads to the observation of two singular fields H(1) and H(2) dependent on the degree of inhomogeneity, unpredictably changing from sample to sample due to synthesis effects. These fields separate different magnetic responses of the system; for applied fields H < H(1), the Fe and Mn clusters weakly interact in a competitive way, giving rise to MRV, while for an intermediate field regime the energy of this weak interaction becomes comparable to the energy of the system under field application. As a consequence, the zero field cooled magnetization thermal evolution depends on the sample degree of inhomogeneity. In this field regime, applied field Mossbauer spectroscopy indicates that the iron rich clusters are highly polarized by the field, while the largest part of the material, consisting of AFM clusters characterized by axial anisotropy and uncompensated moments, shows soft or hard magnetism depending on T. Above the higher singular field, the M(T) curves show the trend expected for a classical antiferromagnetic material and the competitive character is suppressed. The MRV phenomenon results to be highly sensitive on both the thermal and magnetic measurement conditions; for this reason the present work proposes a characterization strategy that in principle has a large applicability in the study of disordered perovskites showing similar phenomenology. PMID- 26125226 TI - Toxic and nutrient elements in yerba mate (Ilex paraguariensis). AB - Toxic and nutrient elements were investigated in yerba mate (Ilex paraguariensis) from South America. Fifty-four brands of commercialised yerba mate from Argentina, Brazil, Paraguay and Uruguay were analysed for Al, Ba, Ca, Cu, Fe, K, Mg, Mn, P, Sr, and Zn, using inductively coupled plasma optical emission spectrometry (ICP-OES), and Li, Be, Ti, V, Cr, Ni, Co, As, Se, Rb, Mo, Ag, Cd, Sb, La, Ce, Pb, Bi and U using inductively coupled plasma mass spectrometry (ICP MS). Antimony, Se, Ag and Bi were not detected in any sample whereas the limits of detection (LODs) of these elements were 0.19, 0.40, 0.003 and 0.001 MUg g(-1), respectively. Analysis of variance (ANOVA) revealed that the concentrations of Cd, Ti, Ni, As, Mo, U, Li and Be in yerba mate were not statistically different with regard to the country of origin, while those of the other investigated elements differed. PMID- 26125227 TI - Direct regulation of E-cadherin by targeted histone methylation of TALE-SET fusion protein in cancer cells. AB - TALE-nuclease chimeras (TALENs) can bind to and cleave specific genomic loci and, are used to engineer gene knockouts and additions. Recently, instead of using the FokI domain, epigenetically active domains, such as TET1 and LSD1, have been combined with TAL effector domains to regulate targeted gene expression via DNA and histone demethylation. However, studies of histone methylation in the TALE system have not been performed. Therefore, in this study, we established a novel targeted regulation system with a TAL effector domain and a histone methylation domain. To construct a TALE-methylation fusion protein, we combined a TAL effector domain containing an E-Box region to act as a Snail binding site and the SET domain of EHMT 2 to allow for histone methylation. The constructed TALE-SET module (TSET) repressed the expression of E-cadherin via by increasing H3K9 dimethylation. Moreover, the cells that overexpressed TSET showed increased cell migration and invasion. This is the first phenotype-based study of targeted histone methylation by the TALE module, and this new system can be applied in new cancer therapies to reduce side effects. PMID- 26125228 TI - Epi-reevesioside F inhibits Na+/K+-ATPase, causing cytosolic acidification, Bak activation and apoptosis in glioblastoma. AB - Epi-reevesioside F, a new cardiac glycoside isolated from the root of Reevesia formosana, displayed potent activity against glioblastoma cells. Epi-reevesioside F was more potent than ouabain with IC50 values of 27.3+/-1.7 vs. 48.7+/-1.8 nM (P < 0.001) and 45.0+/-3.4 vs. 81.3+/-4.3 nM (P < 0.001) in glioblastoma T98 and U87 cells, respectively. However, both Epi-reevesioside F and ouabain were ineffective in A172 cells, a glioblastoma cell line with low Na+/K+-ATPase alpha3 subunit expression. Epi-reevesioside F induced cell cycle arrest at S and G2 phases and apoptosis. It also induced an increase of intracellular concentration of Na+ but not Ca2+, cleavage and exposure of N-terminus of Bak, loss of mitochondrial membrane potential, inhibition of Akt activity and induction of caspase cascades. Potassium supplements significantly inhibited Epi-reevesioside F-induced effects. Notably, Epi-reevesioside F caused cytosolic acidification that was highly correlated with the anti-proliferative activity. In summary, the data suggest that Epi-reevesioside F inhibits Na+/K+-ATPase, leading to overload of intracellular Na+ and cytosolic acidification, Bak activation and loss of mitochondrial membrane potential. The PI3-kinase/Akt pathway is inhibited and caspase-dependent apoptosis is ultimately triggered in Epi-reevesioside F-treated glioblastoma cells. PMID- 26125229 TI - Upregulation of FAM83D affects the proliferation and invasion of hepatocellular carcinoma. AB - The identification of potential oncogenes plays an important role in finding novel therapeutic targets for many cancers, including hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. In our previous research, using microarray technology, we found that FAM83D was overexpressed in HCCs. However, whether the overexpression of FAM83D contributes to hepatocarcinogenesis remains unclear. In this study, we found that FAM83D was significantly upregulated in 76.6% (167 of 218) of the HCC specimens at the mRNA level and in 69.44% (50 of 72) of the HCC specimens at the protein level compared with adjacent non-cancerous liver specimens, as indicated by RT-PCR and immunohistochemical staining, respectively. The FAM83DmRNA expression level was positively correlated with the level of alpha-fetoprotein (AFP) (>=100 ng/ml), the clinical TNM stage, the presence of a portal vein tumor thrombus (PVTT), disease-free survival (DFS) and the overall survival (OS) time of the HCC patients (P < 0.05). Knocking down FAM83D significantly promoted the growth of Huh7 and HepG2 cells, as demonstrated in an RNA interference assay. Moreover, the DNA methylation status of the FAM83D promoter was significantly reduced in the HCC specimens with overexpression of FAM83D gene. Our data suggest that the upregulation of FAM83D, a potential oncotarget gene, may be triggered by epigenetic events and can contribute to hepatocarcinogenesis. PMID- 26125230 TI - The MDM2-inhibitor Nutlin-3 synergizes with cisplatin to induce p53 dependent tumor cell apoptosis in non-small cell lung cancer. AB - The p53/MDM2 interaction has been a well-studied target for new drug design leading to the development of the small molecule inhibitor Nutlin-3. Our objectives were to combine Nutlin-3 with cisplatin (CDDP), a well-known activator of the p53 pathway, in a series of non-small cell lung cancer cell lines in order to increase the cytotoxic response to CDDP. We report that sequential treatment (CDDP followed by Nutlin-3), but not simultaneous treatment, resulted in strong synergism. Combination treatment induced p53's transcriptional activity, resulting in increased mRNA and protein levels of MDM2, p21, PUMA and BAX. In addition we report the induction of a strong p53 dependent apoptotic response and induction of G2/M cell cycle arrest. The strongest synergistic effect was observed at low doses of both CDDP and Nutlin-3, which could result in fewer (off target) side effects while maintaining a strong cytotoxic effect. Our results indicate a promising preclinical potential, emphasizing the importance of the applied treatment scheme and the presence of wild type p53 for the combination of CDDP and Nutlin-3. PMID- 26125231 TI - The Accuracy of Hospital Discharge Diagnosis Codes for Major Birth Defects: Evaluation of a Statewide Registry With Passive Case Ascertainment. AB - CONTEXT: Birth defects prevention, research, education, and support activities can be improved through surveillance systems that collect high-quality data. OBJECTIVE: To estimate the overall and defect-specific accuracy of Florida Birth Defects Registry (FBDR) data, describe reasons for false-positive diagnoses, and evaluate the impact of statewide case confirmation on frequencies and prevalence estimates. DESIGN: Retrospective cohort evaluation study. PARTICIPANTS: A total of 8479 infants born to Florida resident mothers between January 1, 2007, and December 31, 2011, and diagnosed with 1 of 13 major birth defects in the first year of life. MAIN OUTCOME MEASURES: Positive predictive value: calculated overall (proportion of FBDR-identified cases confirmed by medical record review, regardless of which of the 13 defects were confirmed) and defect-specific (proportion of FBDR-identified cases confirmed by medical record review with the same defect) indices. RESULTS: The FBDR's overall positive predictive value was 93.3% (95% confidence interval, 92.7-93.8); however, there was variation in accuracy across defects, with positive predictive values ranging from 96.0% for gastroschisis to 54.4% for reduction deformities of the lower limb. Analyses suggested that International Classification of Diseases, Ninth Edition, Clinical Modification, codes, upon which FBDR diagnoses are based, capture the general occurrence of a defect well but often fail to identify the specific defect with high accuracy. Most infants with false-positive diagnoses had some type of birth defect that was incorrectly documented or coded. If prevalence rates reported by the FBDR for these 13 defects were adjusted to incorporate statewide case confirmation, there would be an overall 6.2% rate reduction from 82.6 to 77.5 per 10 000 live births. CONCLUSIONS: A statewide birth defects surveillance system, relying on linkage of administrative databases, is capable of achieving high accuracy (>93%) for identifying infants with any one of the 13 major defects included in this study. However, the level of accuracy and the ability to minimize false-positive diagnoses vary depending on the defect. PMID- 26125232 TI - Development of Guidelines for Health Impact Assessment in Southern Italy. AB - Health impact assessment (HIA) is a multidisciplinary method aimed at assessing the health effects of policies, plans, and projects using quantitative, qualitative, and participatory techniques. In many European countries, such as in Italy, there is a lack of implementation of HIA procedures and it would be necessary to develop instruments and protocols in order to improve the specific skills of professionals involved in the assessment process. This article aims to describe the development and implementation of HIA guidelines, promoted by the Italian National Agency for Regional Health Services (AGENAS), in 4 Southern Italian regions. Public health search engine and institutional Web sites were consulted to collect international data existing in this field. Monthly workshops were then organized with regional representatives to discuss the scientific literature and to identify the guidelines' contents: source of data, stakeholders, screening- and scoping-phase checklist tools, priority areas, monitoring, and reporting plans. Four regions (Calabria, Campania, Puglia, and Sicilia) took part in the project. This article describes the methodology of development and implementation of HIA guidelines in the Italian context. The tools created to collect data and assess health consequences (such as screening and scoping grids) are reported. This project represents the first structured initiative proposed and supported by the Ministry of Health aiming to introduce HIA in Italy. HIA should be considered a priority in the public health agenda, as a fundamental instrument in helping decision makers to make choices about alternatives to prevent disease/injury and to actively promote health. PMID- 26125233 TI - Static Foot Posture and Mobility Associated With Postural Sway in Elderly Women Using a Three-dimensional Foot Scanner. AB - BACKGROUND: Maintaining balance is a complex phenomenon that is influenced by a range of sensorimotor factors. Foot posture and mobility may also influence balance and postural sway. Recently, three-dimensional foot scanners have been used to assess foot posture. This tool allows many individuals to be scanned quickly and easily and helps reduce patients' radiation exposure. The objective of this study was to determine whether static foot posture and mobility are independently associated with postural sway in a large community sample of older women using objective measures of balance status and the recently launched technology of three-dimensional foot scanning. METHODS: This cross-sectional study included 140 community-dwelling elderly women (mean +/- SD age, 73.9 +/- 5.1 years) recruited in Kasama City, Japan. The postural sway variables were total path length and area and were measured by force plate. We measured static foot posture, sitting and standing navicular height, and mobility using a three dimensional foot scanner. Foot mobility was determined as the amount of vertical navicular excursion between the positions of the subtalar joint, from neutral in sitting position to relaxed bilateral standing. RESULTS: After adjusting for potential cofounders, analysis of covariance revealed that sitting navicular height was associated with total path length (P = .038) and area (P = .031). Foot mobility was associated with total path length (P = .018). CONCLUSIONS: These findings suggest that sitting navicular height and foot mobility are associated with postural sway in elderly women and might be an important factor in defining balance control in older adults. PMID- 26125234 TI - Use of caffeinated energy drinks among secondary school students in Ontario: Prevalence and correlates of using energy drinks and mixing with alcohol. AB - OBJECTIVES: Caffeinated energy drinks have become increasingly popular among young people, raising concern about possible adverse effects, including increased alcohol consumption and related risk behaviours. The current study examined consumption of caffeinated energy drinks and use of energy drinks with alcohol, as well as associations with socio-demographic and behavioural characteristics, among a sample of secondary school students in Ontario. METHODS: Survey data from 23,610 grade 9-12 students at 43 purposefully sampled Ontario secondary schools participating in the baseline wave (2012/13) of the COMPASS study were analyzed using generalized linear mixed-effects models. Outcomes were any energy drink use, frequency of use, and use of alcohol mixed with energy drinks; covariates were age, sex, race, spending money, bodymass index (BMI), weight-related efforts and alcohol use. Two-way interactions between sex and other covariates were tested. RESULTS: Nearly one in five students (18.2%) reported consuming energy drinks in a usual week. Use of energy drinks was associated (p < 0.01) with all socio-demographic variables examined and was more common among students who were male, off-reserve Aboriginal, had some spending money, had a BMI outside of "healthy" range, were trying to lose weight, and/or reported a higher intensity of alcohol use. Interactions with sex were observed for age, spending money and weight-related efforts. Use of energy drinks mixed with alcohol in the previous 12 months was reported by 17.3% of the sample, and was associated with race, spending money, and more frequent binge drinking. CONCLUSION: Regular use of energy drinks was common among this sample of students and strongly linked to alcohol consumption. PMID- 26125235 TI - Exploring the prevalence and correlates of meeting health behaviour guidelines among university students. AB - OBJECTIVE: To examine the prevalence of students meeting physical activity, diet and smoking health recommendations and to examine the correlates of meeting these guidelines. METHODS: Randomly selected students at the University of Toronto (N = 2,812; female = 71.60%, mean age = 22.11 +/- 5.24 years, mean body mass index = 22.80 kg/m2) completed the National College Health Assessment-II survey in spring of 2013. RESULTS: Only 0.1% of the sample reported meeting physical activity, diet and non-smoking guidelines. Males were more likely than females to meet physical activity and both physical activity and fruit and vegetable guidelines (X2 [1, 2812] = 7.33, p < 0.05). Women were more likely than men to be nonsmokers (X2 [1, 2812] = 7.80, p < 0.05). Being overweight was associated with meeting physical activity guidelines. Being a healthy weight was associated with meeting both physical activity and fruit and vegetable guidelines (X2 [1, 2812] = 6.29, p < 0.05). Underweight participants were more likely to be nonsmokers (X2 [2, 2812] = 6.36, p < 0.05). In the logistic regression, being Caucasian and male and trying to change weight were correlated with meeting moderate-to-vigorous physical activity and strength training guidelines. Being older, Caucasian and trying to change weight were correlates of consuming greater than five fruits and vegetables per day. Beings Caucasian, female, and trying to change weight were correlates of being a non-smoker. CONCLUSION: University health promotion programs should be targeted to specific age, ethnicity and weight status groups, as there are distinct differences among those not meeting physical activity, diet and non-smoking guidelines. PMID- 26125236 TI - Patterns and trends in gambling participation in the Quebec population between 2009 and 2012. AB - OBJECTIVES: To describe gambling practices and trends in Quebec between 2009 and 2012 given that, in Canada, public funding allocation to address the risks associated with gambling practices should be based on valid prevalence data and knowledge of patterns and trends in vulnerable populations. METHODS: The study data were taken from the 2009 and 2012 cross-sectional waves of the Enquete sur les habitudes de jeu des Quebecois (ENHJEU-Quebec). The analytical sample consisted of 11,888 respondents in 2009 and 12,008 respondents in 2012. RESULTS: The prevalence of lifetime non-gamblers in the adult population of Quebec increased from 13.6% in 2009 to 16.4% in 2012, and past-year gambling participation decreased from 70.5% to 66.2%. Changes in gambling patterns were not contingent on demographic characteristics; gambling prevalence decreased in all subcategories. The proportion of problem and low-risk gamblers remained unchanged, whereas the prevalence of non-problem gamblers decreased significantly from 66.1% in 2009 to 61.5% in 2012. CONCLUSION: Gambling participation in Quebec is decreasing, though the proportion of problem gamblers remains stable. Given these findings, allocation of public resources for health care services should be maintained. Secondary and primary prevention efforts need to be initiated or maintained to prevent gambling harm. PMID- 26125237 TI - Waterpipe use among high school students in Ontario: Demographic and substance use correlates. AB - OBJECTIVE: To examine waterpipe use and its association with demographic factors, tobacco cigarette smoking, ever use of electronic cigarettes (e-cigarettes) and alcohol use among high school students. METHODS: Data were derived from the 2013 Ontario Student Drug Use and Health Survey, a school-based survey of 7th to 12th grade students. This province-wide survey was based on a stratified two-stage cluster design. Analyses were based on a subsample of 2,873 high school students and included adjustments for the complex sample design. RESULTS: Overall, 12.5% of high school students (grades 9-12) had used a waterpipe in the previous year. Awareness of waterpipes was high - 68.4% of students reported that they were aware of waterpipes but had not used one in the past year; 19.1% had never heard of waterpipes or hookah. The percentage of high school students reporting waterpipe use in the past year was similar to reports of tobacco cigarette use (12.5% and 11% respectively). Waterpipe use was highly associated with past-year tobacco cigarette and regular alcohol use as well as ever use of e-cigarettes. In multivariate analyses, males and females had similar odds of waterpipe use, and non-White students and those in higher grades had greater odds of use after controlling for other substance use. CONCLUSION: These findings suggest that waterpipe use among high school students should be of some concern and suggest the need for policy measures to address potential risks associated with use. PMID- 26125239 TI - Growing social inequality in the prevalence of type 2 diabetes in Canada, 2004 2012. AB - OBJECTIVES: The prevalence of diabetes in Canada has nearly doubled since 2000. Trends in social inequalities in diabetes across Canada and its different regions have not been assessed. We estimated relative and absolute social inequalities in type 2 diabetes prevalence in Canada between 2004 and 2012. METHODS: We used the relative (RII) and slope (SII) indices of inequality to measure relative and absolute education-based inequalities respectively in type 2 diabetes prevalence in a sample of 413,453 men and women surveyed as part of the Canadian Community Health Survey between 2004 and 2012. RESULTS: Across regions and time periods, inequalities were more pronounced for women than for men, both on the absolute and relative scales. The difference in the prevalence of type 2 diabetes between individuals with the highest level of educational attainment compared to the lowest, as reflected by the SII, expanded from approximately 2.5% to 4.5% for women and 1.4% to 2.3% for men between 2004 and 2012. CONCLUSIONS: Monitoring and tracking social inequalities in the burden of diabetes over time can help to assess whether Canadian diabetes strategies are effective at reaching marginalized populations and mitigating inequalities. Our results signal the need for interventions to address growing social inequalities in Canada with regard to type 2 diabetes, particularly among women. PMID- 26125238 TI - Visits to physicians for oral health-related complaints in Ontario, Canada. AB - OBJECTIVE: Canada's national system of health insurance facilitates equitable access to health care; however, since dental care is generally privately financed and delivered, access to oral health care remains uneven and inequitable. To avoid the upfront costs, many argue that socially marginalized groups should seek oral health care from medical providers. This study therefore explored the rates and numbers of visits to physicians for oral health-related diagnoses in Ontario, Canada's most populated province. METHODS: A retrospective secondary data analysis of health system utilization in Ontario was conducted for visits to physicians for oral health-related diagnoses. Data for all Ontario Health Insurance Plan (OHIP) approved billing claims were accessed over 11 fiscal years (2001-2011). Age- and sex-adjusted rates were calculated. RESULTS: Approximately 208,375 visits per year, with an average of 1,298/100,000 persons, were made to physicians for oral health-related diagnoses. Women, irrespective of the year, made more visits, and there was an increasing trend in visits made by elderly people. CONCLUSION: The number of people visiting physicians for oral health reasons is arguably high. The public health system is being billed for services for oral health issues that the provider is not appropriately trained to treat. Provision of timely and accessible oral health care for socially marginalized populations needs to be prioritized in health care policy. PMID- 26125240 TI - Rural food insecurity: When cooking skills, homegrown food, and perseverance aren't enough to feed a family. AB - OBJECTIVE: More than 1 in 10 Canadians experience food insecurity, and a growing number of families rely on food banks each month. This ethnographic study aimed to give voice to rural families about their experiences with food insecurity while situating the findings within the broader social, political and economic context. METHODS: Semi-structured interviews were conducted with women who had children living at home, and interviewer observations within the food bank were recorded as field notes. Content analysis was combined with the constant comparison method of data analysis to identify common themes regarding the experience of living with food insecurity and the influence of public policy. RESULTS: Seven female participants described the emotional toll that food insecurity had on their well-being and relationships, with stress and depression common to many women. Strategies used to stretch resources included cooking from scratch, growing produce, stocking up on sale items, hunting and fishing, and paying half-bills. Many participants described going without food so that their children could eat first, and three participants went without prescription medications. Rurality and social programs were identified as both supports and barriers to overcoming food insecurity. CONCLUSION: Participants in this study were highly skilled in attempting to feed their families with limited resources, although this proved inadequate to overcome their food insecurity. This highlights the need for policy initiatives to address the root causes of food insecurity and health inequities, including access to rural employment and high quality child care, drug benefits and guaranteed annual income programs. PMID- 26125241 TI - Cross-sectional analysis of a community-based cooperative grocery store intervention in Saskatoon, Canada. AB - OBJECTIVES: The aim of this research is to examine the awareness and use of the Good Food Junction (GFJ), a not-for-profit full service cooperative grocery store in a former food desert in Saskatoon, Canada. METHODS: Through door-to-door sampling, 365 residents in their neighbourhoods surrounding the GFJ grocery store were recruited. Quantitative surveys examined awareness, use and primary use of GFJ, mode of transportation to and from GFJ and primary grocery stores, other food program use and demographic data. Differences between those who had or had not shopped at GFJ were characterized using descriptive statistics and Pearson's chi-square test. Univariate and multivariate logistic regression models were developed to predict shopping at GFJ and the use of GFJ as a primary grocery store. RESULTS: Of those surveyed, 69% had shopped at GFJ. A significant proportion of shoppers were Aboriginal, had an annual household income per person of less than $20,000, and participated in other food-based programs and initiatives. Aboriginal people (OR = 2.0, p = 0.03) and users of neighbourhood based fruit and vegetable markets (OR = 2.7, p = 0.04) were significantly more likely, but new immigrants to Canada (OR = 0.3, p = 0.05) were significantly less likely to have ever shopped at GFJ. Aboriginal respondents (OR = 2.6, p = 0.04) were significantly more likely to use GFJ as their primary grocery store. CONCLUSION: Our results confirm both that GFJ is able to serve households where food insecurity is likely and, based on the prevalence of users, the importance and need for a full-service supermarket in Saskatoon's inner city. PMID- 26125242 TI - [Community health workers: a health model without walls]. AB - The aim of this commentary is to respond to a published Canadian Journal of Public Health article on Brazil's family health strategy, in order to clarify some aspects - in particular, the work of community health workers - that make the strategy a unique experience. In the same vein, the authors explore the similarities, differences and peculiarities between Brazil and Quebec with regard to the organizational model for primary health care. PMID- 26125243 TI - Community health workers in Canada and other high-income countries: A scoping review and research gaps. AB - OBJECTIVES: Community health workers (CHWs) have been deployed to provide health related services to their fellow community members and to guide them through often complex health systems. They help address concerns about how marginalized populations in many countries experience health inequities that are due, in part, to lack of appropriate primary health care services, possibly resulting in inappropriate use of higher-cost health services or facilities. This paper reviews studies on CHW interventions in a number of high-income countries, including Canada, to identify research gaps on CHW roles. METHODS: A scoping review using 68 sources of interventions involving CHWs was undertaken. The five step Arksey and O'Malley model guided this review with the aim of summarizing research findings and identifying research gaps in the existing literature on CHWs in Canada (23 sources). A standardized extraction tool was employed to synthesize the literature. SYNTHESIS: We found that CHWs provide a wide range of health-related services but in a manner that, in Canada, is unrecognized and unregulated. In highincome countries, CHW interventions have contributed to health-related issues in communities and demonstrated potential to both reduce health inequity in marginalized populations and reduce the cost of medical services. CONCLUSION: CHWs are an under-recognized, and therefore underutilized, public health workforce, which has a promising capacity to reduce health inequities in marginalized populations in Canada. There is growing support to suggest that CHW roles need to be better integrated within the broader health and social services systems to enable their full potential to be realized. PMID- 26125244 TI - Response to Johnson and Beaudet's commentary: Moving beyond sex and gender reporting in health research. PMID- 26125245 TI - Quebec's public health cuts. PMID- 26125246 TI - Advocacy: It's not a dirty word, it's a duty. PMID- 26125247 TI - Community pharmacists' knowledge, beliefs and attitudes towards immunization in Quebec. AB - OBJECTIVES: To describe the knowledge, beliefs and attitudes of Quebec's pharmacists towards immunization and determine their perceived barriers to pharmacist-led immunization. METHODS: The current study was a descriptive survey of pharmacists working in a community setting in Quebec. Pharmacists were randomly chosen from a list of Quebec's community pharmacies and were contacted by phone from January 17 to 25, 2013. Participating pharmacists were given a web link to the online questionnaire. An e-mail reminder was sent 5-7 days after the first contact. RESULTS: A total of 201 community pharmacists were contacted during the study period, and 115 answered the survey, generating a 57% response rate. The vast majority of respondents answered that vaccines have more benefits than adverse effects. Approximately 52% answered that pharmacists should be able to prescribe and administer vaccines, pending a legislative change. These pharmacists were more interested in administering travel (92%), flu (88%) and pandemic (85%) vaccines than regularly scheduled vaccines for adults (65%) or children (18%). Leading barriers to pharmacist-led immunization were lack of time (90%) and training (92%), and the most common factors that would help its implementation were increased immunization training (95%) and adequate remuneration (92%). CONCLUSION: These findings should push for a renewed discussion about the role of pharmacists as immunization agents in Canadian provinces where pharmacists do not have the right to administer vaccines. PMID- 26125248 TI - Variations over four decades in body mass index trajectories prior to diagnosis of diabetes mellitus: The Manitoba Follow-up Study, 1948-2007. AB - OBJECTIVE: The aim of the study was to explore the variations in body mass index (BMI) trajectories during the 20 years before diagnosis of type 2 diabetes mellitus (T2DM) over four decades between 1968 and 2007. METHODS: Longitudinal measurements of BMI from 437 men, all with a diagnosis of T2DM, were used in the analysis. A mixed method approach was used to fit individual patterns of BMI measurements during the 20 years before diagnosis of T2DM. RESULTS: The mean BMI at diagnosis was 26.7 kg/m2 (95% confidence interval, 26.4-27.1). Compared with men whose condition was diagnosed between 1968 and 1977, for men with a diagnosis between 1978 and 2007 the mean BMI about 10 years before diagnosis significantly increased by 0.92 to 1.54 BMI units. Decades also varied in how long there was a persistent increase in BMI during the 20 years before diagnosis. The rate of change in mean BMI among men whose T2DM was diagnosed in the most recent two decades increased by 8.8% to 22.6% during the 10-year interval before diagnosis, but there was no significant difference among men given a diagnosis between 1978 and 1987. The quadratic trend of BMI prior to diagnosis was also significantly affected by age at diagnosis. CONCLUSION: The BMI trajectories during the 20 years leading up to T2DM varied by decade of diagnosis. The increase in BMI persisted for much longer among relatively younger men with a diagnosis in more recent decades. Strategies to prevent T2DM, informed by the pattern of BMI trajectories, should be customized to consider a potential age-period effect. PMID- 26125250 TI - Left atrial dynamic function and interatrial block in hemodialysis patients: the importance of P-wave morphology analysis. PMID- 26125249 TI - Tuberculosis vaccine development: Shifting focus amid increasing development challenges. AB - A new tuberculosis vaccine is needed to replace or enhance BCG, which induces variable protection against Mycobacterium tuberculosis pulmonary infections in adults. Development of new TB vaccine candidates is severely hampered by the lack of a correlate of immunity, unproven animal models, and limited funding opportunities. One candidate, MVA85A, recently failed to meet its efficacy endpoint goals despite promising early-phase trial data. As a result, some in the field believe we should now shift our focus away from product development and toward a research-oriented approach. Here, we outline our suggestions for this research-oriented strategy including diversification of the candidate pipeline, expanding measurements of immunity, improving pre-clinical animal models, and investing in combination pre-clinical/experimental medicine studies. As with any evolution, this change in strategy comes at a cost but may also represent an opportunity for advancing the field. PMID- 26125251 TI - Levobupivacaine for local intraperitoneal anesthetics as a supplement to general anesthesia for laparoscopic surgery: a randomized double blind study. PMID- 26125252 TI - Evaluation of cytotoxicity of some common ophthalmic drugs. AB - OBJECTIVE: The study was aimed at evaluating the in vitro cytotoxicity of some commonly used drugs in ophthalmology. Hydrocortisone sodium succinate, Dexamethasone sodium phosphate, 5-Fluorouracil, Tobramycin and Pilocarpine nitrate are frequently used in various indications involving eye care, and the aim was to test the safety of these in cell culture. MATERIALS AND METHODS: The in vitro cytotoxicity was carried out on the NIH 3T3 cell line by the Sulforhodamine B (SRB) assay. RESULTS: With the exception of 5-Fluorouracil, none of the other drugs demonstrated appreciable cytotoxicity up to high concentrations of 200 ug/ml at 48 hours of drug exposure. CONCLUSIONS: Hydrocortisone sodium succinate, Dexamethasone sodium phosphate, Tobramycin and Pilocarpine nitrate were confirmed to be non-cytotoxic while 5-Fluorouracil was highly cytotoxic especially at 48 hours at very low concentrations. PMID- 26125253 TI - The histological analysis of the anterior cruciate ligament of canine after radiofrequency shrinkage. AB - OBJECTIVE: Radiofrequency (RF) shrinkage has been widely conducted in clinical practice and the anterior cruciate ligament (ACL) laxity is regarded as one of the indications. However, basic researches regarding the postoperative histological changes were still insufficient. The study aimed to investigate postoperative histological changes of different areas of ACL for further identifying the optimal area for RF shrinkage. MATERIALS AND METHODS: A total of 29 healthy canine (16.5 +/- 2.2 kg, 4.1 +/- 0.7 years) were recruited, 24 of which were randomly divided into group A and group B. The epiphyseal arrest was confirmed by X-ray examination in all animals. On one canine, an ACL's vascular perfusion model was established by the ink-perfusion method to observe the blood supply of the ACL. The mid-portion of ACL was conducted by RF in group A while the amph-portions of ACL were conducted in group B. Two legs of each canine were sub-divided into fixation group (group A1 and B1) and non-fixation group (group A2 and B2). 8 ACLs were separated from the rest 4 canine. 2 ACLs were sent for the histological examination after RF shrinkage and the rest 6 ACLs were served as blank controls. Masson staining and hematoxylin-eosin (H-E) staining were applied to observe the features of inner fibrous changes of ACL, cell count and vascular density. RESULTS: According to the Masson staining, collagenous tissues were observed in area after RF shrinkage, which was more evident among group B1 than the others. The cellar density in both group A and B was found lower at 12 weeks postoperatively than that at 6 weeks postoperatively (p < 0.05). In addition, the cellar density in B1 group was found higher than that in A1 group at both 6 and 12 weeks postoperatively (p < 0.05). The density of subsynovial vessel in B1 group was found higher than that in A1 group at 6 weeks postoperatively (p < 0.05) and the density of subsynovial vessel in both A1 and B1 groups was found lower at 12 postoperatively weeks than that at 6 weeks postoperatively (p < 0.05). In both A2 and B2 groups, all ACLs were found ruptured at 12 weeks postoperatively. CONCLUSIONS: The postoperative revascularization pattern of RF-treated ACL was permeating from the synovium to the RF-treated areas, and the best area for the RF shrinkage treatment was the amph-portions of the ACL. Moreover, the application of postoperative external fixation to restrict the movement of injured limb was necessary. PMID- 26125254 TI - Multiple repeat cesarean delivery is associated with increased maternal morbidity irrespective of placenta accreata. AB - OBJECTIVE: The present study aimed to investigate the perinatal morbidity associated with multiple repeat cesarean deliveries (CD) and, thus, to achieve a body of evidence for the current practice of discouraging pregnancy after undergoing three CDs. PATIENTS AND METHODS: This study prospectively reviewed a total of 500 women who consecutively underwent CD between January 1, 2009 and April 1, 2009. The patients were allocated into four groups based on the number of CDs they had undergone (Group 1: first CD, Group 2: second CD, Group 3: third CD, Group 4: fourth CD). Data related with their demographic and clinical characteristics were recorded as well as their perioperative characteristics and clinical characteristics of the neonates born to them. Cochran-Armitage test for trends and Spearman rank correlation analysis test was used to evaluate the trend of perioperative complications and neonatal outcome with the increasing number of CDs. RESULTS: The mean age, gravidity and parity were significantly higher in groups 2-4 than those of the women who had their first CD (Group 1). The average operation time and mean delivery time as well as severe adhesions, bowel injury increased significantly with the number of CD. Neonatal characteristics were similar among groups except for a trend towards a decrease in the rate of meconium stained and a trend towards increase in the rate of neonatal sepsis with the increasing number of CD. CONCLUSIONS: We have found positive correlation between the maternal morbidity and the number of CDs. The occurrence of adhesions emerges as the most significant indicator of maternal morbidity, eventually leading to the neighboring organ injury and prolonged operation time. PMID- 26125255 TI - Environment and Endometriosis: a toxic relationship. AB - Endometriosis is a common, benign, estrogen-dependent gynecological disease that represents one of the main causes of hospitalization in industrialized countries. It is well established that a large amount of natural and man-made chemicals are present in the environment and both humans and animals are exposed to them. Dioxin and dioxin-like compounds have long biological half-life, can accumulate within the organism and could negatively affect several physiological processes. The purpose of this review is to provide an overview of the possible relationship between these chemicals and the pathogenesis of endometriosis. PMID- 26125256 TI - Spiral brush cervical biopsy experience in a community clinic. AB - OBJECTIVE: This article seeks to demonstrate the experience of implementing the spiral brush in several community clinic locales. Before the introduction of the spiral brush cervical biopsy in 2002 there were few alternatives to colposcopy directed punch biopsy when evaluating and managing abnormal dysplastic Papanicolaou (pap) smear or a visually abnormal cervix. Subsequent investigations validated the spiral brush usage but there are limited reports for its implementation in primary care colposcopy. PATIENTS AND METHODS: Over a two year period (2004-2006) patients with internal referrals for colposcopy received the spiral brush cervical biopsy. Those that resulted in the diagnoses of high grade squamous intraepithelial lesion (HSIL) diagnoses (CIN2-3) were compared to the final pathology diagnosis from the loop excision specimen. RESULTS: 15 cases of HSIL were identified with subsequent loop excision. Comparison of the pathology diagnosis from the loop excision and the spiral brush biopsy resulted in 13.3% (n=2) of cases differing. In both cases, low grade squamous intraepithelial lesion (LSIL) diagnoses (CIN1) were found whereas the remainder had the same diagnosis of HSIL. CONCLUSIONS: These results showed acceptable rates of concordance with traditional pathology specimens which supports the use of this Food and Drug Administration (FDA) approved device within a primary care setting. PMID- 26125257 TI - Efficacy of type a botulinum toxin injections and infrared polarized light on treating chronic migraine. AB - OBJECTIVE: To investigate the clinical value of the combination of ultrasound-and hyponome-guided type A botulinum toxin injection and infrared polarized light on treating chronic migraine. PATIENTS AND METHODS: Ninety-one patients with chronic migraine were randomly divided into four groups: in the control group (group A, 22 cases in total), nimodipine was used in the treatment of chronic migraine for two months; in the infrared polarized light therapy group (group B, 22 cases in total), infrared polarized light was adopted in the treatment of chronic migraine for 50-60d; in the botulinum toxin treatment group (group C, 24 cases in total), ultrasound-and-hyponome-guided type A botulinum toxin was injected into frontal, temporal, and occipital muscles in treating chronic migraine; in the joint treatment group (group D, 23 cases in total), ultrasound-and-hyponome-guided type A botulinum toxin injection in group C and infrared polarized light in group B were both used here in the treatment of chronic migraine. Infrared polarized light therapy lasted 50-60d and the time of study lasted six months. The survey would include the conditions of patients with chronic migraine three months before treatment and at one, three and six months after treatment. Patients were asked to fill the MIDAS (migraine disability assessment questionnaire) and were graded on the evaluation scale of life quality, so that the researchers would be able to compare attack frequency, duration of attack, attack severity, the use of painkillers and their recovery from chronic migraine, and then observe their adverse reactions. RESULTS: Eleven cases dropped out during the treatment, three cases in A group, two cases in group B, four cases in group C and two cases in group D. One, three and six months after treatment, the MIDAS scores in group A, B, C and D were significantly lower than before the treatment. Hence, the differences were statistically significant (p < 0.01). The scores in quality of life rating scale were significantly higher than pre-treatment scores, so the difference was statistically significant (p < 0.01). The MIDAS scores and quality of life rating scale scores in group D were compared with those in group A, B, and C respectively, and the differences were statistically significant (p < 0.05). Two patients were recorded with dizziness, and the dizziness disappeared after two weeks with no treatments at all. Forehead lines and crow's feet of 21 patients shallowed or disappeared in varying degrees after the injection. CONCLUSIONS: The combination of ultrasound-and-hyponome-guided type A botulinum toxin injection and infrared polarized light on treating chronic migraine demonstrated a significant clinical effect. PMID- 26125258 TI - Serum myeloperoxidase levels in predicting the severity of stroke and mortality in acute ischemic stroke patients. AB - OBJECTIVE: The aim of this study was to examine the level of myeloperoxidase (MPO) measured before specific treatment in patients presenting to the Emergency Department with acute ischemic stroke and its correlation to mortality and the severity of the stroke. PATIENTS AND METHODS: The study was carried out on 55 patients with a confirmed diagnosis of ischemic stroke, and on 44 healthy control group. Before specific intervention, serum samples were taken to measure levels of MPO. The medical records, demographic, clinical, laboratory and neuro-imaging data were noted. The National Institutes of Health Stroke Scale was used to determine the severity of the stroke. RESULTS: A total of 55 patients, of whom 32 (58.2%) were male, who had presented within 24 hours of the onset of symptoms of acute ischemic stroke were included in the study. Fifteen of these patients (27.2%), of whom five were women, died. There was a statistically significant difference in the serum MPO levels of patients who survived and those who died. When the patients were grouped as high or normal in terms of plasma MPO levels, a significant correlation was found between MPO level, cortical + subcortical stroke location and strokes with a lesion diameter of more than 4 cm. In the high MPO group, Troponin T and CRP levels were significantly higher than those of the normal MPO group. CONCLUSIONS: The level of myeloperoxidase in the serum of acute ischemic stroke patients rises and there is a correlation between myeloperoxidase level and prognosis. PMID- 26125259 TI - Efficacy analysis of ultrasound-guided local injection of botulinum toxin type A treatment with orthopedic joint brace in patients with cervical dystonia. AB - OBJECTIVE: To study the efficacy of ultrasound-guided local injection of botulinum toxin type A (BTX-A) treatment with orthopedic joint brace in patients with cervical dystonia (CD). PATIENTS AND METHODS: A total of 105 patients with cervical dystonia were selected and randomly divided into medication treatment group (A group), botulinum toxin treatment group under the guidance of ultrasound treatment (B group) and botulinum toxin under the guidance of ultrasound treatment combined with orthopedic joint brace treatment group (C group). Tsui scale and Spitzer quality of life index was applied to evaluate the spasm and quality of life. The scores of Tsui scale and Spitzer quality of life index were compared after ultrasound-guided local treatment for one month, three months and six months. RESULTS: The difference in Tsui and Spitzer scores before and after the treatment of oral medications were not statistically significant (p > 0.05). Whereas, the differences in Tsui and Spitzer scores before and after the treatment between local injection of BTX-A treatment group and orthopedic joint brace combined with BTX-A injection group were statistically significant (p < 0.05). Also, the difference in Tsui and Spitzer scores of orthopedic joint brace combined with BTX-A injection group at 3 months, and 6 months were statistically significant compared to local injection of BTX-A treatment group (p < 0.05). CONCLUSIONS: Ultrasound-guided local injection of BTX-A combined with orthopedic brace could significantly reduce muscle tension and improve quality of life. PMID- 26125260 TI - Effect of 5-fluorouracil mobilized bone marrow regenerative cells transplantation on brain injury following focal cerebral ischemia in rats. AB - OBJECTIVE: The aim of this study was to evaluate the effect of 5-fluorouracil mobilized bone marrow regenerative cells (BMRCs) transplantation on brain injury following focal cerebral ischemia and to explore the mechanisms. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MACO) for 120 minutes, followed by intravenous administration of DAPI labeled 1*10(7) 5-fluorouracil mobilized BMRCs at 24 h post MACO. Infarct volumes, neurological deficit score, angiogenesis and cytokine expression were evaluated at specific time point after cell transplantation. RESULTS: Comparable number of BMRCs and bone marrow cells (BMCs) were found in the infarcted area at Day 3 and Day 14 post MACO. Significant decreased infarcted size and neurological deficit score were found in the animals receiving BMRCs. The microvessel density was significantly increased after BMRCs transplantation. Moreover, the expression of vessel endothelial growth factor (VEGF) was increased significantly after BMRCs transplantation. CONCLUSIONS: Intravenous 5-fluorouracil mobilized BMRCs were neuroprotective following MACO and might be considered as therapeutic choice in the treatment of transient focal cerebral ischemia. PMID- 26125261 TI - Rhythmic auditory stimulation with visual stimuli on motor and balance function of patients with Parkinson's disease. AB - OBJECTIVE: Discuss the effect of rhythmic auditory stimulation with visual stimuli on motor and balance function in patients with Parkinson's disease (PD). PATIENTS AND METHODS: One hundred and sixteen patients with PD participated in this study. The control group used a routine drug treatment for eight weeks. The comprehensive treatment group used conventional drug treatment with sound rhythm metronome released as the rhythmical auditory stimulation, in accordance with the ground fixed ribbon rhythmic visual stimulation walking training for eight weeks. After four and eight weeks, the two groups of subjects took the walking parameters test, and used the disease Parkinson score scale to assess the damaged degree of motor function of PD patients. The Berg Balance Scale was used to evaluate the balance function of the PD patients. A six minute walk test was used to evaluate the walking motor function of the patients. RESULTS: The comparison between the groups suggests that after treatment of rhythmic auditory stimulation with visual stimulation group, the step size increased, frequency decreased, pace increased, and PD score scale part II decreased. As well, the PD score scale part III reduced, the six minute walking distance increased, and the Berg Balance Scale score increased significantly. There were significant differences compared with the control group after the treatment (p < 0.01). Comparison of time points suggests that after rhythmic auditory stimulation with visual stimulation group trained for eight weeks, the step size increased, frequency decreased, pace increased, and PD score scale part II were reduced. As well the PD score scale part III reduced, six minute walking distance increased, Berg Balance Scale increased. There were significant differences compared with the parameters of training for four weeks (p < 0.01). CONCLUSIONS: Rhythmic auditory stimulation with visual stimulation can improve motor and balance function of patients with PD. PMID- 26125262 TI - Role of peripheral eosinophilia in adverse cutaneous drug reactions. AB - OBJECTIVE: The objective of this retrospective study was to verify whether peripheral eosinophilia (PE) may be a marker of severity for adverse cutaneous drug reactions (ACDR). PATIENTS AND METHODS: We investigated for PE in sixty three patients diagnosed as adverse cutaneous drug reactions. All the patients underwent blood tests at baseline visit. Only patients that showed a very likely connection between ACDR and the suspected causative drug were induced in the study. RESULTS: We found that 11 out of 63 patients (17%) presented PE for values >= 0.6 x 10(9) cells/l or for a percentage of total leukocytes >= 6%. These 11 patients compared to patients without eosinophilia had a longer recovery time, they showed diffuse severe cutaneous reactions and they all needed a systemic therapy compared to the 41% of patients without eosinophilia. CONCLUSIONS: These outcomes prompt us to believe that peripheral eosinophilia may be an index of severity for adverse cutaneous drug reactions. Therefore, we suggest physicians to always detect the presence of peripheral eosinophilia in order to not underestimate the reaction and to promptly start an appropriate therapy. PMID- 26125263 TI - Regulatory T cells in the pathogenesis of type 2 diabetes mellitus retinopathy by miR-155. AB - OBJECTIVE: To explore the regulatory T cells (Treg) in the peripheral blood of diabetic retinopathy patients by microRNA-155 (miR-155), and investigate the mechanisms of regulatory T cells and miR-155 in the pathogenesis of diabetic retinopathy. PATIENTS AND METHODS: The study explores the percentage of CD4+ CD25+ Foxp3+ T cells (Treg cells) and the expression of miR-155 in the peripheral blood of 20 cases with background diabetic retinopathy (BDR group) and 20 cases with proliferative diabetic retinopathy (PDR group). Flow cytometry and RT-PCR determined 18 cases with non-diabetic retinopathy (NDR group) and 20 cases of healthy control (NC group). ELISA determined the expression of TGF-beta. RESULTS: The percentages of Treg cells in the peripheral blood of patients in BDR group, PDR group, and NDR group had significantly decreased compared to that in the NC group (p < 0.05). The percentages of the Treg cells in the BDR and PDR groups were lower than those in NDR group (p < 0.05 in both cases). The percentage of Treg cells in the PDR group was lower than that in the BDR group (p < 0.05). The expression levels of miR-155 in the peripheral blood of the patients in the BDR group, PDR group, and NDR group had significantly increased compared to that in NC group (p < 0.05). The expression levels of miR-155 in the BDR group and PDR group were higher than that in the NDR group (p < 0.05 in both cases). The expression level of miR-155 in the PDR group was higher than that in the BDR group (p < 0.05). The expression levels of TGF-beta in the BDR group and PDR group were significantly decreased compared to those in the NDR group and NC group (p < 0.05 in both cases). The expression of miR-155 was negatively related to the Treg cells and the expression level of TGF-beta2 (r1 = -0.835, p1 = 0.000, r2 = -0.771, p2 = 0.000). CONCLUSIONS: In type 2 diabetes mellitus (T2DM) retinopathy, miR-155 may play an important role in the pathogenesis of T2DM retinopathy by regulating the Treg cells with TGF-beta. PMID- 26125264 TI - Survival and associated mortality risk factors among post-treatment pulmonary tubercolosis patients in the northwest of China. AB - OBJECTIVE: The tuberculosis (TB) program was carried out in the Changji zone in northwest of China. Directly Observed Treatment, Short-Course (DOTS) is a modern control strategy against tuberculosis recommended by World Health Organization. The purpose of this work is to describe the survival of post-treatment TB (PTB) patients and to identify the risk factors associated with mortality and treatment outcomes, so that effective measures and interventions could be used to decrease the mortality rate. PATIENTS AND METHODS: Registry of 4501 TB patients at Center for Disease Control and Prevention (CDC) treated from 2007 to 2014 were collected. Mortality was used as an outcome measure and calculated per 100 person years of observation (PYO) from the date of completion of the treatment to the date of interview if the patients were alive or to the date of death. Kaplan Meier and Cox regression methods were used to determine the survival and hazard ratios. An indirect method of standardization was used to calculate the standard mortality ratio (SMR). RESULTS: The average PYO was 5.0 and the total was 21851. Mortality per 100 PYO was 1.9/100 PYO [223/11871] for smear-positive, 3.4/100 PYO [305/9048] for smear-negative and 2.4/100 PYO [22/932] for EPTB cases. Univariate and Cox regression analysis showed that age (p < 0.01), education (p < 0.01), occupation (p < 0.01) and economic status (p < 0.01) were associated with increased mortality. DISCUSSION: Since the mortality rate was higher in Post treatment TB patients than the general population these patients need special health care. An integrated survival and associated mortality risk factors and information system is necessary for TB surveillance, personal health status and treatment management. Further studies are required to identify the causes of death in these patients. PMID- 26125265 TI - Angiotensin-converting enzyme gene insertion deletion (ACE I/D) polymorphism in Saudi children with congenital heart disease. AB - OBJECTIVE: Congenital heart diseases (CHDs) are the leading cause of infant deaths worldwide. Angiotensin-converting enzyme (ACE) gene I/D polymorphism is associated with many cardiovascular diseases. The precise relationship between this polymorphism and CHDs is not clear. The aim of this work is to determine the normal distribution of I/D polymorphism in Saudi citizens and to test for any association between this polymorphism and CHDs in Saudi children. PATIENTS AND METHODS: Ninety-six CHD cases and 145 controls were included in this study. DNA was isolated from their peripheral blood, and then ACE I/D gene polymorphism was assayed by polymerase chain reaction (PCR). RESULTS: There was no significant difference among the frequencies of the DD, DI and II genotypes in patients and controls [39 (41%), 64 (44%), 48 (51%) and 62 (43%), 7 (7%), 19 (13%)] respectively (p-value = 0.3 and OR (95% CI) = 0.3). There was no significant difference between D allele (DD+DI) and II genotype distribution among patients and controls [p-value = 0.2 & OR (95% CI) = 1.9 (0.8-4.7)]. Moreover, there was no difference between I allele (II+DI) and DD frequency [p-value = 0.8 & OR = 0.9, CI = 0.5-1.5]. CONCLUSIONS: ACE I/D gene polymorphism is not associated with CHDs in Saudi children. Further large-scale studies are necessary to establish our findings. PMID- 26125266 TI - Prevalence of Helicobacter pylori infection in pediatric celiac disease. AB - OBJECTIVE: A lower risk of celiac disease (CD) in patients with Helicobacter pylori (Hp) infection has been reported when Hp infection prevalence in CD patients was compared against CD-negative symptomatic persons with indications for diagnostic gastroduodenoscopy. Therefore, we aimed to determine Hp infection frequency in a group of pediatric CD patients at diagnosis and to compare obtained results to data coming from age-matched healthy population. PATIENTS AND METHODS: The study population consisted of 74 CD subjects aged 3 to 12 years in whom the presence of Hp was diagnosed routinely in the course of differential diagnosis with the use of stable isotope breath test which is the gold standard. The control group consisted of 296 healthy age-matched subjects. RESULTS: Hp infection was diagnosed in 4 CD patients and 20 healthy subjects. Its prevalence in CD patients and HS did not differ neither in the entire age group undergoing comparison (5.4% vs. 6.8%, p = 0.5713) nor in the selected age subgroups (3-6 years: 2.5% vs. 3.7%, p = 0.8551; 7-12 years: 8.8% vs. 11.0%, p = 0.8742). CONCLUSIONS: The prevalence of Hp infection in CD patients does not seem to be different than that in general population. However, further studies are needed to assess the potential role of Hp in the pathogenesis of CD. PMID- 26125267 TI - The mechanisms and strategies to protect from hepatic ischemia-reperfusion injury. AB - Hepatic ischemia-reperfusion injury is a major cause of post-operative hepatic dysfunction and liver failure after transplantation. This review summarizes the mechanisms of ischemia-reperfusion injury and analyzes the protective strategies based on the recent developments in the field. Development of hepatic ischemia reperfusion injury is associated with metabolic acidosis, calcium overloading, and changes of mitochondrial membrane permeability. Hypoxia-induced activation of Kupffer cells results in generation of reactive oxygen species (ROS). These processes lead to activation of inflammation and immune responses that involve multiple cells and signaling molecules and result in increased level of apoptosis and necrosis. Generation of ROS is one of the major risk factors in the hepatic ischemia-reperfusion injury. A number of methods aimed to reduce the oxidative stress have been investigated, and some of them have been applied clinically. The methods mainly rely on the activation of pro-survival genes and associated mechanisms capable of reducing the level of ROS and inflammation at pre-treatment and post-conditioning stages. Potential benefits of these clinical approaches have been discussed here. PMID- 26125268 TI - Bone Morphogenetic Protein-2 regulates in vitro osteogenic differentiation of mouse adipose derived stem cells. AB - OBJECTIVE: The aim of this study is to investigate the feasibility and efficiency of Bone Morphogenetic Protein-2 (BMP-2) in regulating in vitro osteogenic differentiation of mouse adipose derived stem cells (ADSCs). MATERIALS AND METHODS: Mouse ADSCs were isolated from adipose tissues of C57/BL6 mice (age of 4 6 w) and cultured. Surface antigens of passage 3 (P3) ADSCs, including CD31, CD34, CD90, CD105 and CD133, were analyzed using flow cytometry. Overexpression of BMP-2 was achieved through gene transfection of ADSCs. In vitro osteogenic differentiation of transfected and non-transfected ADSCs cultured in specific induction media was evaluated by Alizarin Red staining. In addition, expression of osteoblast-specific gene, Runx2, was analyzed by quantitative RT-PCR (qRT PCR). RESULTS: Abundant ADSCs could be isolated from adipose tissue. P3 ADSCs expressed stem cell-specific molecular markers, CD90 and CD105 but did not express CD31, CD34 or CD133. BMP-2 could efficiently transfect mouse ADSCs. Alizarin Red staining revealed that more calcified nodules were formed in BMP-2 transfected ADSCs. qRT-PCR further confirmed higher level of Runx2 expression in BMP-2 transfected ADSCs (p < 0.05). CONCLUSIONS: BMP-2 can promote in vitro osteogenic differentiation of mouse adipose stem cells. PMID- 26125269 TI - Bioinformatics analysis of gene expression profiles in hepatocellular carcinoma. AB - OBJECTIVE: The aim of this study is to identify the gene expression profile specific to Hepatocellular Carcinoma (HCC) by comparing the different expression profiles in cirrhosis, dysplastic nodule (DN) and HCC tissues. MATERIALS AND METHODS: The microarray data were downloaded from Gene Expression Omnibus (GEO) repository, involving 39 samples of normal liver tissues, 33 samples of cirrhosis, 17 samples of DNs and 286 samples of HCCs of different stages. Differential Expressed Genes (DEGs) of cirrhosis, DN and HCC liver tissues were analyzed by BRB-ArrayTool software; besides, the Gene Ontology (GO) analysis, Kyoto encyclopedia of Genes and Genomes (KEGG) and Biocarta pathway enrichment analysis were also performed. A protein-protein interaction (PPI) network was then constructed by STRING software using the genes in significantly different pathways. The resulting network was analyzed by Cytoscape software with CentiScaPe plugin to calculate the topological characteristics of the network and its individual node. Key genes were screened according to betweenness and degree of nodes. RESULTS: few overlaps occurred in the GO categories of DEGs and in the gene sets from pathway analysis between HCCs, cirrhosis and DNs. DEGs in abnormal tissues were shown to be enriched in 29 KEGG pathways and 18 Biocarta pathways; and 43 key genes were identified to be involved in the maintenance of PPI network. In addition, the gene expression profiles were significantly different among cirrhosis, DN and HCC tissues. CONCLUSIONS: The bioinformatic analysis of GEO datasets of HCC identified the functional gene sets associated with the genesis and development of HCC, and the key genes that were playing important roles in the maintenance of the molecular network for biological function specific to HCC. It provides the insights for more precise understandings of pathogenic mechanism, which will further expand the study on biomarker and targeted therapy of HCC. PMID- 26125270 TI - YM155 inhibits tumor growth and enhances chemosensitivity to cisplatin in osteosarcoma. AB - OBJECTIVE: Chemoresistance is the principal reason for poor survival and disease recurrence in osteosarcoma patients. Survivin, a family member of the inhibitor of apoptosis proteins, plays an important role in inhibition of apoptosis. Survivin is expressed in a vast majority of human cancers, which is often correlated with poor prognosis in a wide variety of cancer patients. Furthermore, survivin expression is often related with chemoresistance in cancer cells, including osteosarcoma (OS). Here, we evaluated the therapeutic potential of YM155, a selective survivin suppressant alone and in combination with cisplatin using human OS models. MATERIALS AND METHODS: U-2 OS, SW1353, MG-63 cells were treated with YM155, and/or cisplatin, and cell viability, apoptosis, survivin protein expression levels were then evaluated. Furthermore, the efficacy of YM155 combined with cisplatin was further examined in established xenograft models. RESULTS: YM155 was sufficient to induce spontaneous apoptosis of OS cells. Combination with YM155 significantly augmented the cytotoxicity of cisplatin in OS cells. Combination treatment of YM155 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single treatment rates and promoted tumor regression in established OS xenograft models. CONCLUSIONS: Our findings provide evidence that YM155 could act as a survivin inhibitor on OS cells. Chemotherapeutic approaches using YM155 might enhance the benefit of the cisplatin in the treatment of OS cells. YM155 could be further developed as a potential therapeutic agent for the treatment of OS. PMID- 26125271 TI - Glial cell line-derived neurotrophic factor promotes proliferation of neuroglioma cells by up-regulation of cyclins PCNA and Ki-67. AB - OBJECTIVE: We wished to test whether glial cell line-derived neurotrophic factor (GDNF) stimulates proliferation of gliomas by up-regulating expression of nuclear cyclins PCNA and Ki37. MATERIALS AND METHODS: As a model, we tested rat C6 glioma cell line exposed to basal conditions, vehicle control, or exogenous GDNF at different concentrations (0-90 ug/L) or different times (0-72 hours). Cell proliferation was quantified by MTT test, cell cycle by flow cytometry and propidium iodide staining, expression of PCNA and Ki67 by intracellular antibody staining and flow cytometry. RESULTS: We first observed that cell proliferation was most stimulated by GDNF at concentration of 70 ug/L and incubation time of 48 hours. Using this concentration and incubation time, we next documented that GDNF increased the percentage of cells in the S phase (47.98% vs. 32.57% in basal cells; p < 0.05), while not affecting the percentage of cells in G0/G1 or G2/M phases. Finally, we demonstrated that expression of both PCNA and Ki67 was significantly increased in cells exposed to GDNF. CONCLUSIONS: We demonstrate that GDNF stimulates proliferation of glioma cells by up-regulating expression of cyclins PCNA and Ki-67. PMID- 26125272 TI - Acid sphingomyelinase, a novel negative biomarker of ovarian cancer. AB - OBJECTIVE: Ovarian cancer is the sixth most common cancer and the main cause of death in women. However, the molecular mechanism for the cause of the ovarian cancer has not been fully elucidated. Acid sphingomyelinase (ASM), a lipid hydrolase, has been suggested for treating cancer and may affect the development of ovarian cancer. We want to find the function of ASM in the development of ovarian cancer. PATIENTS AND METHODS: Human ovarian cancer cells HO 8910 (HOCC) and human primary ovarian cells (HPOC) were transfected with ASM gene and ASM RNAi. Real-time qPCR and western blot analysis was carried out to examine the level of ASM. The growth rate of transfected and non-transfected cells was measured. Ovarian biopsies were collected from 80 ovarian cancer patients and 20 healthy subjects. RESULTS: The growth rate of HOCC and HPOC was decreased by 22% and 19% in the ASM-transfected group compared with non-transfected group. Inversely, the growth rate of HOCC and HPOC was increased by 16% and 35% in the ASM-RNAi-transfected group compared with non-transfected group. In the transfected and non-transfected cells, the change level of SAM was approved by Real-time qPCR and western blot analysis. The levels of SAM were reducing with the development of ovarian cancer. CONCLUSIONS: SAM is higher expressed in normal cell than that in ovarian cancer, and can be a negative biomarker for the diagnosis of ovarian cancer. SAM can be developed a new drug for the ovarian cancer therapy. PMID- 26125273 TI - Underlying mechanism of 2-methoxyestradiol-induced apoptosis and growth arrest in SKOV3 human ovarian cancer cells. AB - OBJECTIVE: In this study, we sought to investigate the effects of 2 methoxyestradiol (2-ME) on cisplatin-induced apoptosis and growth inhibition in SKOV3 ovarian cancer cells. MATERIALS AND METHODS: Cells were treated with 2-ME, carboplatin, or both, the control group, and cell viability and growth inhibition assays were performed using the MTT method. Apoptosis was detected by flow cytometry analysis. Reverse transcription polymerase chain reaction and western blotting were used to monitor the mRNA and protein expression of the pro apoptotic genes bax and caspase-3 and the anti-apoptotic gene bcl-2. The phosphorylation of Bcl-2 protein was monitored by western blotting. RESULTS: Cell viability was inhibited by all three treatments in a time-dependent manner. Importantly, the combination treatment resulted in significantly reduced cell growth compared with the other groups. The mRNA and protein expression of Bax and caspase-3 were increased in the combination treatment group, and the expression of Bcl-2 was decreased in the combination treatment group as compared with the other two groups. The ratio of bax to Bcl-2 mRNA in the combination treatment group was higher than that in the carboplatin-treated group. Finally, phosphorylation of Bcl-2 protein was increased stronger in the combination treatment group compared with the carboplatin-treated group. CONCLUSIONS: 2-ME promoted the growth inhibitory and apoptosis-inducing effects of platinum-based agents in SKOV3 ovarian cancer cells. The mechanism mediating this effect may be related to the phosphorylation of Bcl-2 protein, which reduces the formation of dimers and, thereby, increases apoptosis. Moreover, 2-ME promoted the mRNA and protein expression of Bax, thereby, increasing the Bax/Bcl-2 expression ratio and activating the mitochondrial apoptosis pathway. PMID- 26125274 TI - Hsa-miR-206 represses the proliferation and invasion of breast cancer cells by targeting Cx43. AB - OBJECTIVE: Hsa-miR-206, a microRNA, was found to be able to switch subtypes by targeting ER-alpha in breast cancer. However, there are few studies addressing the role of miR-206 in triple-negative breast cancer (TNBC). The purpose of this study was to evaluate the metastatic-regulatory ability of miR-206 in TNBC. MATERIALS AND METHODS: We treated two TNBC lines (MDA-MB-231 and MDA-MB-436) with miR-206 mimics, inhibitors and paired controls and examined the in vitro and in vivo functions of miR-206 via the degradation of Connexin43 (Cx43). A luciferase reporter assay was used to identify the binding site of GJA1 (gap junctional intercellular communication) (Cx43) and miR-206. Furthermore, quantitative RT-PCR was used to evaluate miR-206 expression in 77 breast cancer samples to determine the association with lymph node status and Cx43 expression. RESULTS: Up regulation of miR-206 in TNBC contributed to a decreasing metastatic potential, as demonstrated by a reduction of cell viability and proliferation, decreased cell migration and invasion, lower expression levels of matrix metalloproteinase (MMP)-2, MMP-9 and a higher expression level of breast cancer metastatic suppressor (BRMS)-1. In vitro dual luciferase assays showed GJA1 (Cx43) is a target of miR-206. Quantitative RT-PCR was conducted to evaluate miR-206 expression in 77 breast cancer samples to determine the associations between miR 206 levels and both lymph node status and Cx43 expression. Restoring Cx43 expression positively regulated cell adhesion and GJA1, which may facilitate metastasis. MiR-206 significantly attenuated the proliferation and metastatic potential of cancer cells but did not inhibit tumor onset in a mouse xenograft model because of the dual function of Cx43. CONCLUSIONS: Our results suggest hsa miR-206 may repress the tumor proliferation and invasion in breast cancer by targeting Cx43. PMID- 26125275 TI - RLIP76 expression as a prognostic marker of breast cancer. AB - OBJECTIVE: RLIP (Ral-interacting protein)-76/RalBP11 (Ral-binding protein-1), a multifunctional protein and stress-inducible non-ABC transporter, have been proven to serve as a critical role in cancer development and progression; however, little is known about the pathological role of RLIP76 in breast cancer patients. The study aimed to determine the correlation between RLIP76 expression in breast cancer patient and clinical outcomes. PATIENTS AND METHODS: Using RT PCR and Western blot, messenger RNA (mRNA) and protein expression of RLIP76 were determined in breast cancer and adjacent normal mammary tissues. The relationship of RLIP76 expression with clinical characteristics of 245 breast cancer patients was analyzed by immunohistochemistry. RESULTS: In the present study, our results indicated that RLIP76 mRNA and protein were highly expressed in the breast cancer tissues while compared with adjacent normal mammary tissues and the correlation with RLIP76 protein expression was significantly associated with age (the non-ABC transporter, stage and the expression were significantly associated-T2 vs. T3-T4, p < 0.01), lymph node metastasis (N0-N1 vs. N2-N3, p < 0.01), and PR (positive vs. negative, p < 0.01) in breast cancer patients; furthermore, we also found that RLIP76 protein overexpression was an unfavorable prognostic factor in the patients suffered from breast cancer. CONCLUSIONS: RLIP76 overexpression serves as an unfavorable prognostic biomarker in breast cancer patients. PMID- 26125276 TI - The cancer-associated fibroblasts and drug resistance. AB - The present treatment of solid tumors is plagued by drug resistance. Despite continued development of meticulously designed therapeutic scheme, cancer cells remain poorly being completely eliminated. Because therapeutic resistance is a problem with the drug used in cancer therapy, most of the studies about the drugs resistance have focused on the role of epithelial cancer cells themselves. However, it is becoming increasingly apparent that tumor microenvironment could provide a shelter for tumor cells which keep their survival after initial drug exposure. Cancer-associated fibroblasts (CAFs) are the crucial component of the tumor microenvironment; substantial evidence suggests that the CAFs mediate resistance of solid tumor cells to the anticancer drugs. In this review, we describe how the CAFs may be involved in the resistance of tumor cells to the therapeutic agents and present some of the emerging therapeutic targets for modulation this resistant phenotype. PMID- 26125277 TI - Pregabalin versus sertraline in generalized anxiety disorder. An open label study. AB - OBJECTIVE: Generalized Anxiety Disorder (GAD) is a chronic mental illness with a prevalence of 5-7% in the general population. t GAD is characterized by extreme persistent worry, mostly about minor problems, involving pathological fear with high occurrences of vegetative disturbance. GAD leads to functional impairment and a significantly reduced patient's quality of life. According to the guidelines of the World Federation of Societies of Biological Psychiatry (WFSBP), the first-line treatments for GAD are Serotonin selective reuptake inhibitors (SSRIs), Selective serotonin- and norepinephrine reuptake inhibitors (SNRIs) and pregabalin, an atypical anxiolytic. In this study, both efficacy and tolerability of pregabalin were evaluated and compared with efficacy and tolerability of sertraline, an SSRI antidepressant. PATIENTS AND METHODS: 107 patients both male and female, aged 20-60 were included in the study. All patients were hospitalized outward at the Psychiatric Clinic. Patients fulfilled criteria for GAD, according to ICD-X and DSM-IV. Each patient was randomly assigned to 4 weeks of treatment with pregabalin (n=47) or sertraline (n=60). Patients treated with sertraline were previously treated with SSRIs and SNRIs without remission, according to the latest National Clinical Guideline issued by the National Institute of Health and Clinical Excellence for treating GAD (NICE). The primary analysis was the change in the Hamilton Rating Scale for Anxiety (HAMA), a total score from baseline to endpoint. The second indicator of efficacy was the change in the HAMA psychic (emotional) and somatic (physical) scores, weekly, till endpoint. Global clinical assessment was conducted by using the Clinical Global Impression change rating (CGI). RESULTS: Both pregabalin and sertraline showed good results in treating symptoms of Generalized Anxious Disorder. The onset of action was shorter in treatment with pregabalin compared to the treatment with sertraline. In the patients treated with sertraline, the anxiolytic effect was detectable after at least 14 days while pregabalin showed initial good results during the first week of treatment. Adverse effects were reported in 28% patients treated with pregabalin and 27% of patients treated with sertraline, without significant differences. There were no drop-out patients in neither group. Beside pharmacotherapy, each patient received 8 weeks of cognitive/behavior therapy. In concomitant therapy benzodiazepine was used (klonazepam, in low doses). In all patients adverse events were short-lasting withmild intensity and there were no withdrawal events during this study. CONCLUSIONS: Efficacy and tolerability of pregabalin were high. Compared to sertraline, pregabalin showed more rapid onset of action and equal efficacy. Adverse reactions are short-lasting and the dose depends. Our investigation showed that pregabalin, an atypic anxiolytic is efficient and well tolerable in treatment of GAD. PMID- 26125279 TI - The effect of alpha lipoic acid on rat kidneys in methotrexate induced oxidative injury. AB - OBJECTIVE: The purpose of this study is to determine the antioxidant and anti inflammatory effects of alpha lipoic acid (ALA) on methotrexate (MTX) induced kidney injury in rats. MATERIALS AND METHODS: Thirty-two rats were equally divided into four groups; control, ALA, MTX and MTX with ALA groups. A single dose of MTX (20 mg/kg) was administered to make kidney injury to groups 3 and 4, intraperitoneally. The ALA was administered intraperitonealy in groups 2 and 4 and the other groups received saline injection for five days. On the sixth day the blood samples and kidney tissues were obtained for the measurement of TNF alpha, IL-1beta, malondialdehyde, glutathione, myeloperoxidase and sodium potassium-adenosine triphosphatase levels and histological examination. RESULTS: Administration of MTX caused a decrease in tissue GSH, and Na+, K+-ATPase activity significantly. A significant increase in tissue MDA and MPO activities were also seen. The pro-inflammatory cytokines (TNF-alpha, IL-beta) were increased in the MTX group significantly. ALA treatment reversed all biochemical indices as well as histopathological alterations induced by MTX administration. CONCLUSIONS: MTX made oxidative damage on kidneys of rat and it was partially prevented by anti-inflammatory and antioxidant effects of ALA treatment. PMID- 26125278 TI - Effect of garlic component s-allyl cysteine sulfoxide on glycated human serum albumin induced activation of endothelial cells: an in vitro study. AB - OBJECTIVE: Alternative medicine or herbal therapies have been in use for blood glucose control in patients with diabetes for considerable time. Effect of garlic, more specifically its biologically active component s-allyl cysteine, on amelioration of hyperglycemia has also been reported. However, the cellular or molecular target of this compound is little known. This study was designed to determine the action of s-allyl cysteine sulfoxide (SACSO) at the cellular and molecular level in the widely reported HUVEC model when activated with advanced glycation end products (AGEs). MATERIALS AND METHODS: AGE-HSA was derived from non-enzymatic glycation of human serum albumin in the presence of 20 mM glucose. AGE-HSA induced expression of receptors of AGEs, namely RAGE and galectin-3 has been assayed. Activity of endothelial nitric oxide synthase (NOS) denoting normal endothelial function and expression of AGE-RAGE triggered inflammatory marker sICAM-1 is also evaluated in the presence or absence of SACSO. RESULTS: In presence of SACSO, AGE-HSA induced expression of RAGE was down-regulated, galectin-3 was significantly up-regulated, NOS activity was enhanced and sICAM-1 expression was reduced. CONCLUSIONS: The data suggest that SACSO exerts an attenuating effect on 20 mM glucose derived AGE-HSA induced inflammation, by selectively inhibiting RAGE while stimulating galectin-3 expression. The former triggers inflammatory pathways while the latter sequesters AGE molecules and prevents AGE-RAGE engagement. This may form the basis for its therapeutic action. PMID- 26125280 TI - Predictive value of cyclooxygenase-2 over expression for identifying prostate cancer from benign prostatic hyperplasia in prostate biopsy specimens. AB - BACKGROUND: We studied cyclooxygenase-2 (COX-2) immunohistochemical staining intensity both in prostatic biopsy and surgical samples of patients with prostate cancer to determine if it might provide prognostic information for the decision of re-biopsy indication. METHODS: Twenty-eight patients undergone radical prostatectomy whose final pathologic examination revealed prostatic adenocarcinoma were included in the study. Twelve patients with BPH in their pathological examination of both prostatic biopsy and open prostatectomy were considered as a control group. Intensity of COX-2 receptor was examined with immunohistochemical staining according to standard techniques. RESULTS: Positive COX-2 receptor staining was obtained 89.3% of biopsy samples and 93% of surgical samples in all cancer patients. The rate of agreement in COX-2 receptor staining of biopsy samples and radical prostatectomy samples was 76% in same patients (P=0.54). Similarly, the COX-2 receptor levels in biopsy specimens of patients with BPH open surgery compared with samples of the agreement still rate was 41% (P=0.41). Prostate cancer exchanging COX-2 receptor levels in patients with biopsy specimens in patients with BPH were found significantly more (P=0.008). CONCLUSIONS: In this study the feasibility of presence of COX-2 receptor staining in biopsy samples was shown. We have also demonstrated that COX-2 staining intensity was higher in prostatic biopsy samples of patients with prostatic cancer than patients with BPH. This leads a conclusion that, higher COX-2 expression levels in biopsy specimens may be used to decide re-biopsy in borderline preoperative PSA levels as well as in the cases with suspicious pathological findings for cancer. PMID- 26125281 TI - The relationship between FGF-23 and ghrelin levels in CKD patients: preliminary data. AB - BACKGROUND: Fibroblast growth factor (FGF)-23 is a recently discovered phosphaturic hormone that increases in chronic kidney disease (CKD). It has been accepted as a determinant of mortality and a therapeutic target in these patients. Ghrelin is a hormone that has roles in energy and nutrient metabolism. Ghrelin level was found to be increased in CKD patients. This is a controlled study in which the relationship between FGF-23 and ghrelin levels in CKD patients has been studied. METHODS: Three groups were involved: 88 individuals. Dialysis group (DG, 33 patients) including patients on hemodialysis (21 patients) or peritoneal dialysis program (12 patients); predialysis group (PG, 29 patients) consisting of patients with stage-3 CKD; and the control group (CG, 29 individuals) of healthy adults. Serum FGF-23 and ghrelin levels were measured as well as routine biochemical parameters. RESULTS: FGF-23 levels were similar within the groups (CG: 268+/-45 pg/mL, PG: 284+/-94 pg/mL, DG: 259+/-87 pg/mL, P=0.11). Ghrelin level was higher in the PG group compared with the DG and CG, while DG had higher ghrelin level than the CG (CG: 2.79+/-0.38 ng/mL, PG: 4.53+/ 1.18 ng/mL, DG: 3.98+/-0.89 ng/mL). When all groups were studied together; a strong correlation was found between FGF-23 and ghrelin levels. When the analysis was repeated with PG and DG accepted as CKD group; this strong correlation persisted; while it was not true for the CG. CONCLUSIONS: There might be a strong correlation between FGF-23 and ghrelin levels irrespective of the stage of CKD and the dialysis modality. There is need for further studies to clarify the pathophysiological link between these parameters. PMID- 26125282 TI - X-ray Photochemistry of Prussian Blue Cellulosic Materials: Evidence for a Substrate-Mediated Redox Process. AB - Beside its promising applications in the design of multifunctional materials, batteries and biosensors, the pigment Prussian blue is still studied in heritage science because of its capricious fading behavior due to a complex light-induced redox mechanism. We studied model heritage materials composed of Prussian blue embedded into a cellulosic fiber substrate by means of X-ray absorption near-edge spectroscopy. Significant X-ray radiation damage was observed and characterized. X-ray radiation induced first a reduction of Prussian blue, in a similar way to what visible light does, followed by a complete degradation of the pigment and the formation of iron(III) oxyhydroxide. We took advantage of this X-ray photochemistry to investigate in depth the redox behavior of Prussian blue. We could particularly demonstrate that the rate, extent, and quality of Prussian blue photoreduction can be tuned by modifying the pH and alkali cation content of the cellulosic substrate. The present study represents a step further in the understanding of Prussian blue heritage materials from an electrochemical viewpoint and provides evidence of substrate-mediated photochemistry applicable to a wider class of Prussian blue composite materials. PMID- 26125283 TI - The Effects of Solvent Polarity on Hypoglycemic and Hypolipidemic Activities of Securigera Securidaca (L.) Seeds. AB - The search for indigenous natural antidiabetic and antilipidemec agents is still ongoing. Medicinal plants are widely used for this purpose. These herbs are very rich sources of bioactive compounds as flavonoids, polyphenols, tannins, alkaloids which have been reported as effective role to reduce blood glucose and lipid levels. Securigera securidaca seed is reputed in folk medicine for their value as antidiabetic and antilipidemec drugs. In this research, the effect of solvent polarity in bioactive extraction contents of this plant was evaluated by GC-MS analysis. Then antidiabetic and antilipidemic activies of different extracts were investigated in streptozotocine-induced diabetic rats and compared to glibenclamide as known chemical drug for diabetes.The results indicated that, carbon tetrachloride extract of Securigera securidaca seeds showed the best and significant hypoglycemic and hypolipidemic activities compared to other extracts because of its more sterols and fatty acids content with beta cells protecting effect from high glucose-induced apoptosis and also increasing in insulin level and sensitivity. PMID- 26125284 TI - The Beneficial Effects of the DPP-4 Inhibitor Alogliptin on Hemoglobin A1c and Serum Lipids in Japanese Patients with Type 2 Diabetes. AB - It has been reported that dipeptidyl peptidase-4 (DPP-4) inhibitors improve hemoglobin A1c (HbA1c) levels in diabetic patients and may also improve the serum lipids. However, few studies have examined relationship between the effects of the DPP-4 inhibitor and the pretreatment HbA1c levels in diabetic patients. Furthermore, it has been reported that prolonged treatment with DPP-4 inhibitors may make glycemic control difficult in some patients. In the present study, we investigated (1) the effect of the DPP-4 inhibitor alogliptin on HbA1c, blood glucose (BG), and serum lipid in Japanese patients with type 2 diabetes, (2) the relationship between the HbA1c levels at baseline and the effects of alogliptin, and (3) the effects of switching of the DPP-4 inhibitor to alogliptin after 12 months' administration of sitagliptin on glycemic control and serum lipids. After 6-months' treatment with alogliptin, we found reductions of HbA1c, BG, and serum total cholesterol, and LDL cholesterol levels. Pretreatment level of HbA1c was well correlated with the degree of reduction of both HbA1c and BG levels after the treatment. Also, alogliptin kept levels of HbA1c and BG reduced by sitagliptin for 12 months, and relapsing of these levels and serum lipids were not observed. This study revealed that alogliptin improved HbA1c, BG, and serum lipid profiles in type 2 diabetic patients, and the effect of alogliptin on HbA1c and BG levels was correlated with HbA1c level at pretreatment. Furthermore, long term treatment with alogliptin did not cause relapsing of glycemic control and serum lipids. PMID- 26125285 TI - Evaluation of Levothyroxine Bioavailability after Oral Administration of a Fixed Combination of Soy Isoflavones in Post-menopausal Female Volunteers. AB - BACKGROUND: Post-menopausal women under treatment with levothyroxine for their medical conditions may take concomitantly dietary supplements containing soy isoflavones in combination to treat their post-menopausal symptoms. The aim of this study was to investigate the effect of a fixed combination of soy isoflavones on the oral bioavailability of levothyroxine in post-menopausal female volunteers. METHODS: 12 healthy post-menopausal female, who were on stable oral levothyroxine as replacement/supplementation therapy for hypothyroidism, received a single recommended oral dose of a food supplement containing 60 mg of soy isoflavones (>19% genistin and daidzin) concomitantly with (test) and 6 h later (reference) the administration of levothyroxine in a randomized, open label, crossover fashion. Plasma concentrations of levothyroxine and soy isoflavones (daidzin, daidzein, genistin, genistein, S-equol) were determined by LC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analysis. No effect of soy isoflavones was assumed if the 90% confidence intervals (CIs) for the estimated ratio test/reference was included in the acceptance limits 0.80-1.25 for PK parameters Cmax and AUCt. RESULTS: The test/reference ratios Cmax and AUCt of levothyroxine were very close to unity (1.02 and 0.99, respectively) and the corresponding 90% CIs (0.99-1.04 and 0.88 1.12, respectively) fell entirely within the acceptance bioequivalence limits. CONCLUSION: The combination of soy isoflavones used in the present investigation does not affect the rate and extent of levothyroxine absorption when administered concomitantly in post-menopausal women. PMID- 26125286 TI - Rembrandt's Ocular Pathologies. AB - PURPOSE: This article aims to medically and artistically analyze various ophthalmological ailments documented in self-portraits of Rembrandt to determine if those ailments were medical conditions or stylistic and age-related changes. METHODS: A systematic literature review using Pub Med and Google Scholar found 232 results from a search of "Rembrandt" and more than 5,000 results for "Rembrandt Aging." After extensive review of the literature, the authors found 17 relevant sources. These sources were then supplemented with historical books on Rembrandt and the aging processes of artists. Analytical observations with proportional measurements of anthropometrical landmarks (from self-portraits of Rembrandt at various ages) were studied, measured, analyzed, and compared using a standardized technique via MB ruler graphic software to assess age- or medically related changes. RESULTS: The ophthalmological problems cited in the literature related to Rembrandt's periorbital structures were found by the authors to be false. Signs of inappropriate aging and ailments, such as hyperthyroidism were deemed inaccurate by the authors based on absence of classical disease progression. Ophthalmological problems cited in the literature on Rembrandt's visual acuity were found to be stylistic changes or considered normal aging. Finally, the authors found that ophthalmological problems relating to Rembrandt's eye and orbital adnexa are unfitting because these problems were not seen in subsequent paintings. CONCLUSIONS: The authors believe that all the physical changes seen in Rembrandt's portraits represent natural age-related or stylistic changes, and do not represent signs or symptoms of diseases in the master. PMID- 26125287 TI - External Compression Versus Intravascular Injection: A Mechanistic Animal Model of Filler-Induced Tissue Ischemia. AB - PURPOSE: Soft tissue ischemia is a devastating and unpredictable complication following dermal filler injection. Multiple mechanisms to explain this complication have been proposed, including vascular compression, vessel damage, and intraarterial filler emboli. To elucidate the mechanism of injury, the authors introduce a mouse model, imaged with optical microangiography and laser speckle contrast imaging technologies, to demonstrate in vivo microvascular response to soft tissue and intravascular filler injection. METHODS: To determine the effect of external vascular compression on distal perfusion, the authors attempted to occlude vessels with subcutaneous hyaluronic acid gel (HAG) bolus injections into the pinna of hairless mice. The authors also performed suture ligation of a major vascular bundle. Following these interventions, laser speckle and optical microangiography were performed serially over 1 week follow up. To determine the effect of intravascular HAG injection, the authors devised and validated a novel method of cannulating the mouse external carotid artery for intraarterial access to the pinna vasculature. Using this model, the authors performed intraarterial HAG injections and completed optical microangiography and laser speckle contrast imaging. RESULTS: Despite large HAG bolus injections directly adjacent to vascular bundles, the authors were unable to induce compressive occlusion of the mouse pinna vessels. Vascular occlusion was successfully performed with suture ligation, but optical microangiography and laser speckle contrast imaging confirmed undisturbed distal capillary bed perfusion. With intravascular HAG injection, large segments of pinna showed distinct perfusion reduction along a vascular distribution when compared with preinjection images, most noticeably at the capillary level. CONCLUSIONS: The novel mouse pinna model combining intravascular access and in vivo microvascular perfusion imaging has furthered the understanding of the mechanism of filler induced tissue ischemia. Distal capillary perfusion was maintained despite external vascular compression. Intraarterial HAG filler injection, however, resulted in large areas of capillary nonperfusion and is the most likely etiology for filler-induced tissue necrosis that is observed clinically. PMID- 26125288 TI - Total Synthesis of (-)-Nemorosone and (+)-Secohyperforin. AB - A general strategy for the synthesis of polycyclic polyprenylated acylphloroglucinols is described in which a scalable, Lewis acid catalyzed epoxide-opening cascade cyclization is used to furnish common intermediate 4. The utility of this approach is exemplified by the total syntheses of both ent nemorosone and (+)-secohyperforin, which were each accomplished in four steps from this intermediate. PMID- 26125289 TI - Deubiquitinase MYSM1 Is Essential for Normal Fetal Liver Hematopoiesis and for the Maintenance of Hematopoietic Stem Cells in Adult Bone Marrow. AB - MYSM1 is a chromatin-interacting deubiquitinase recently shown to be essential for hematopoietic stem cell (HSC) function and normal progression of hematopoiesis in both mice and humans. However, it remains unknown whether the loss of function in Mysm1-deficient HSCs is due to the essential role of MYSM1 in establishing the HSC pool during development or due to a continuous requirement for MYSM1 in adult HSCs. In this study we, for the first time, address these questions first, by performing a detailed analysis of hematopoiesis in the fetal livers of Mysm1-knockout mice, and second, by assessing the effects of an inducible Mysm1 ablation on adult HSC functions. Our data indicate that MYSM1 is essential for normal HSC function and progression of hematopoiesis in the fetal liver. Furthermore, the inducible knockout model demonstrates a continuous requirement for MYSM1 to maintain HSC functions and antagonize p53 activation in adult bone marrow. These studies advance our understanding of the role of MYSM1 in HSC biology, and provide new insights into the human hematopoietic failure syndrome resulting from MYSM1 deficiency. PMID- 26125291 TI - [Overview of Alternative Methods of Cochleostomy with Focus on Laser Ablative Techniques]. AB - BACKGROUND: Bone removal during mastoidectomy and cochleostomy or round window enlargement prior to electrode insertion is typically performed with a drill. The present work is a review of alternate methods of mastoidectomy and cochleostomy/round window enlargement that may reduce the risk of acoustic inner ear trauma associated with use of surgical drills during cochlear implant surgery. MATERIALS AND METHODS: MEDLINE database search was conducted using PubMed and Google Scholar search engines. Inclusion criteria for this study was the use of a laser to ablate the bone respectively the opening of Cochlear in terms of Cochleostomy. RESULTS: For the experimental studies, a total number of 4 papers were found, which deal with the application of the widely used CO2 laser. A comparison of the works could only partially under the above criteria, since no single study protocol was used and not always the sound pressure levels were determined occurring or evidence of damage to the inner ear missing. But for all that, a comparison of the work has been attempted because it is the authors' opinion about a promising approach to the atraumatic opening of the inner ear. CONCLUSION: There are promising approaches, using a laser to realize the erosion of bone and perform the opening of the inner ear. Nevertheless, there is a significant need for further investigations and in particular, the acoustic injury is not well enough understood here. PMID- 26125292 TI - [From the Expert's Office: Noise Induced Hearing Loss by Dog-barking?]. PMID- 26125293 TI - [Actinic Keratosis]. AB - Actinic keratosis is a cutaneous lesion characterized by proliferation of atypical epidermal keratinocytes due to prolonged exposure to exogenous factors such as ultraviolet radiation. AKs are in-situ-squamous cell carcinomas (PEC) of the skin. AK typically presents as erythematous, scaly patch or papule (classic AK), occasionally as thick, adherent scale on an erythematous base. Mostly fair skinned adults are affected. AKs typically occur in areas of frequent sun exposure (balding scalp, face, "H-region", lateral neck, decollete, dorsum of the hand and lower extremities). Actinic Cheilitis is the term used for AKs appearing on the lips. The diagnosis of AK is based on clinical examination including inspection and palpation. The typical palpable rough surface of AK often precedes a visible lesion. Dermoscopy may provide additional information. If diagnosis is uncertain and invasion suspected, biopsy and histopathologic evaluation should be performed. The potential for progression to invasive PECs mandates therapeutic intervention. Treatment options include topical and systemic therapies. Topical therapies are classified into physical, medical and combined physical-chemical approaches and a sequential combination of treatment modalities is possible. Topical-physical cryotherapy is the treatment of choice for isolated, non hypertrophic AK. Topical-medical treatment, e. g. 5-fluoruracil (5FU) cream or Imiquomod or Ingenolmebutat application is used for multiple, non-hypertrophic AKs. For hypertrophic AKs, a dehorning pretreatment with salicinated vaseline is recommended. Isolated hypertrophic AKs often need cryotherapy with prolonged freezing time or several consecutive applications. Sequentially combined approaches are recommended for multiple, hypertrophic AKs. Photodynamic therapy (PDT) as example for a combined physical-chemical approach is an established treatment for multiple, non-hypertrophic and hypertrophic AKs. Prevention includes avoidance of sun and application of sunscreen with high sun protection factor. Regular clinical checkups aid in early recognition of AKs. PMID- 26125294 TI - [Preventing and managing complications]. PMID- 26125295 TI - Regulation of the plasma amino acid profile by leucine via the system L amino acid transporter. AB - Plasma concentrations of amino acids reflect the intracellular amino acid pool in mammals. However, the regulatory mechanism requires clarification. In this study, we examined the effect of leucine administration on plasma amino acid profiles in mice with and without the treatment of 2-aminobicyclo-(2,2,1)-heptane-2 carboxylic acid (BCH) or rapamycin as an inhibitor of system L or mammalian target of rapamycin complex 1, respectively. The elevation of plasma leucine concentration after leucine administration was associated with a significant decrease in the plasma concentrations of isoleucine, valine, methionine, phenylalanine, and tyrosine; BCH treatment almost completely blocked the leucine induced decrease in plasma amino acid concentrations. Rapamycin treatment had much less effects on the actions of leucine than BCH treatment. These results suggest that leucine regulates the plasma concentrations of branched-chain amino acids, methionine, phenylalanine, and tyrosine, and that system L amino acid transporters are involved in the leucine action. PMID- 26125296 TI - Functional and Anatomical Brain Abnormalities and Effects of Antidepressant in Major Depressive Disorder: Combined Application of Voxel-Based Morphometry and Amplitude of Frequency Fluctuation in Resting State. AB - OBJECTIVE: Convergent studies suggest that functional and morphological abnormalities of the brain circuits may contribute to the pathophysiology of major depressive disorders (MDD). However, few study has been conducted to examine how or whether functional abnormalities are related to anatomical alterations in the brain. We used voxel-based morphometry and amplitude of frequency fluctuation (ALFF) methods to investigate their association. METHODS: Twenty MDD participants, 16 treated MDD participants and 18 healthy controls acquired baseline high-resolution structural magnetic resonance imaging and functional magnetic resonance imaging scans. Using SPM8 and REST1.8 software to analyze the imaging data. RESULTS: The MDDs had decreased gray matter volume and ALFF values in different brain regions. Compared to pretreatment, posttreatment MDDs had increased gray matter volume and ALFF values in some brain regions. CONCLUSIONS: There is no overlap of brain regions with the functional and anatomical alterations, and they may alter independently in MDDs. PMID- 26125297 TI - Low Dose Computed Tomography for 3D Planning of Total Hip Arthroplasty: Evaluation of Radiation Exposure and Image Quality. AB - OBJECTIVE: The aim of the study was to compare radiation exposure and image quality between dedicated computed tomography (CT) protocols for preoperative total hip arthroplasty (THA) planning. METHODS: Three protocols with automated tube current modulation using 64-slice (n = 177) and 128-slice CT scanners without (n = 129) and with automated tube voltage preselection (n = 84) were compared. RESULTS: All 390 CTs were of sufficient quality for THA planning. Mean DLP was 235.0 mGy*cm (effective dose 2.8 mSv). Lowest radiation exposure (2.5 mSv) was seen with automated voltage preselection and the algorithm's selection was 100 kV (90.5% of patients) and 120 kV. Lowest image noise was seen in the highest dose group (3.1 mSv, 128-slice CT fixed tube voltage). A significant difference in cortical bone radiodensity was seen between 100 kV and 120 kV (P < 0.0001). CONCLUSIONS: Preoperative pelvic CT for THA planning is possible with very low radiation dose and reliable quality. Automated voltage preselection further decreases the effective dose by 18.2%. PMID- 26125298 TI - Low-Dose Pelvic Computed Tomography Using Adaptive Iterative Dose Reduction 3 Dimensional Algorithm: A Phantom Study. AB - OBJECTIVE: To evaluate the image quality and radiation dose reduction in pelvic computed tomography (CT) achieved with an adaptive iterative dose reduction 3 dimensional (AIDR 3D) algorithm using a phantom model. METHODS: Two phantoms were scanned using a 320-detector row CT scanner with 8 tube current levels, and the images were reconstructed with a standard filtered back projection (FBP) algorithm and with an AIDR 3D algorithm. RESULTS: Compared with FBP, AIDR 3D reduced image noise and improved contrast-to-noise ratios. The diagnostic performance for detection of low-contrast targets of AIDR 3D images obtained with 100 mA at 120 kVp was almost as good as that of the FBP images obtained with 200 mA. CONCLUSIONS: The AIDR 3D algorithm substantially reduced image noise and improved the image quality of pelvic CT images compared with those obtained with the FBP algorithm and can thus be considered a promising technique for low-dose pelvic CT examinations. PMID- 26125299 TI - Myocardial Fibrosis in Hypertrophic Cardiomyopathy: Volumetric Assessment of Late Enhancement Provided by Cardiac Computed Tomography. AB - INTRODUCTION: With subgroups of patients with hypertrophic cardiomyopathy (HCM) confers a 4% to 5% risk for adverse prognosis. Besides left-ventricular muscle mass (LV-MM) myocardial fibrosis (MF) assessable by late gadolinium enhancement in cardiovascular magnetic resonance (LGE-CMR) has been related to that. Myocardial fibrosis can also be demonstrated by late enhancement (LE) in late enhanced multislice computed tomography (leMDCT). This analysis investigates leMDCT whether to enable quantification of LE load in terms of LE mass by percent LV-MM in HCM. METHODS: In a prospective validation study, we included 30 consecutive patients with HCM who underwent leMDCT (64 slice) and LGE-CMR (1.5 T). The leMDCT scan was performed 7 minutes after injection of iodine contrast (Iopromid). Endocardial and epicardial planimetry served for the assessment of LV MM. Visually detectable LE was quantified using the manual quantification method resulting in LE by percent LV-MM (%LE). The LGE-CMR data served for validation. RESULTS: Mean (SD) age was 64.1 (13.9) years. Myocardial fibrosis prevalence was 63.3% (19/30 patients indentified by both leMDCT and LGE-CMR). In leMDCT, tissue density in LE areas compared with normal myocardium was higher (138.2 [23.9] HU vs 98.4 [16.5] HU, P < 0.001) but lower than in the LV cavity (138.2 [23.9] HU vs 169.2 [35.9] HU, P < 0.001). Late enhancement mass in leMDCT seemed to be 7.9 (8.5) g LE versus 8.6 [11] g LGE in CMR (P = 0.497, r = 0.95) resulting in a leMDCT/LGE-CMR relation of 1.2. Referring LE mass to LV-MM gave an LE proportion measured by leMDCT of 4 (3.9) %LE versus 3.9 (4.1) %LGE in LGE-CMR (r = 0.88, P = 0.75). Intraobserver/interobserver reliability of LE mass assessment showed an intraclass correlation coefficient of 0.99 and 0.97. CONCLUSIONS: In patients with HCM, leMDCT provides volumetric assessment of LE mass-absolutely and by percent LV-MM. PMID- 26125300 TI - Decoration of Micro-/Nanoscale Noble Metal Particles on 3D Porous Nickel Using Electrodeposition Technique as Electrocatalyst for Hydrogen Evolution Reaction in Alkaline Electrolyte. AB - Micro-/nanoscale noble metal (Ag, Au, and Pt) particle-decorated 3D porous nickel electrodes for hydrogen evolution reaction (HER) in alkaline electrolyte are fabricated via galvanostatic electrodeposition technique. The developed electrodes are characterized by field emission scanning electron microscopy and electrochemical measurements including Tafel polarization curves, cyclic voltammetry, and electrochemical impedance spectroscopy. It is clearly shown that the enlarged real surface area caused by 3D highly porous dendritic structure has greatly reinforced the electrocatalytic activity toward HER. Comparative analysis of electrodeposited Ag, Au, and Pt particle-decorated porous nickel electrodes for HER indicates that both intrinsic property and size of the noble metal particles can lead to distinct catalytic activities. Both nanoscale Au and Pt particles have further reinforcement effect toward HER, whereas microscale Ag particles exhibit the reverse effect. As an effective 3D hydrogen evolution cathode, the nanoscale Pt-particle-decorated 3D porous nickel electrode demonstrates the highest catalytic activity with an extremely low overpotential of -0.045 V for hydrogen production, a considerable exchange current density of 9.47 mA cm(-2) at 25 degrees C, and high durability in long-term electrolysis, all of which are attributed to the intrinsic catalytic property and the extremely small size of Pt particles. PMID- 26125301 TI - Oxaliplatin for the treatment of ovarian cancer. AB - INTRODUCTION: Oxaliplatin is an important drug in treatment of several solid tumors. Ovarian cancer (OC) is sensitive to chemotherapy and the overall response rate with primary therapy is about 75%. Unfortunately, 60 - 70% of patients experience recurrence requiring additional treatments and finally die of progressive disease within 5 years of the initial diagnosis. Currently, a platinum-based combination therapy is recommended in platinum-sensitive disease while a non-platinum single-agent therapy is preferred in platinum-resistant disease that is characterized by a low response rate. AREAS COVERED: In this article, the authors review the Phase II and Phase III studies of oxaliplatin as an OC therapy. Furthermore, the authors discuss the pharmacokinetic and pharmacodynamic features of oxaliplatin. EXPERT OPINION: Platinum emerged as the mainstay of OC treatment in frontline therapy, and platinum compounds remain a critical component of chemotherapy also in relapsed disease. Unfortunately, increasing exposure to carboplatin/cisplatin raises the risk of resistance or hypersensitivity to platinum. Several studies have demonstrated the safety and effectiveness of oxaliplatin, both alone and in combination regimens, in relapsed OC, demonstrating a good tolerability profile. Moreover, the therapeutic spectrum of oxaliplatin might be extended to OC patients who experienced hypersensitivity to carboplatin because of its favorable toxicity profile and at least equal efficacy. PMID- 26125302 TI - RECQL: a new breast cancer susceptibility gene. AB - Identifying and characterizing novel genetic risk factors for BRCA1/2 negative breast cancers is highly relevant for early diagnosis and development of a management plan. Mutations in a number of DNA repair genes have been associated with genomic instability and development of breast and various other cancers. Whole exome sequencing efforts by 2 groups have led to the discovery in distinct populations of multiple breast cancer susceptibility mutations in RECQL, a gene that encodes a DNA helicase involved in homologous recombination repair and response to replication stress. RECQL pathogenic mutations were identified that truncated or disrupted the RECQL protein or introduced missense mutations in its helicase domain. RECQL mutations may serve as a useful biomarker for breast cancer. Targeting RECQL associated tumors with novel DNA repair inhibitors may provide a new strategy for anti-cancer therapy. PMID- 26125303 TI - The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas. AB - OBJECTIVES: Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). MATERIALS AND METHODS: Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan-Meyer, and Cox regression were used for statistical analyses. RESULTS: Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). CONCLUSIONS: This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis. PMID- 26125304 TI - Do Prostate Cancer Patients With Markedly Elevated PSA Benefit From Radiation Therapy?: A Population-based Study. AB - OBJECTIVES: Patients with clinically localized prostate cancer but markedly elevated prostate-specific antigen (PSA) are often treated with systemic agents alone. We hypothesized that they would benefit from radiation therapy. METHODS: We utilized the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with nonmetastatic prostate cancer from 2004 to 2008. Patients treated surgically or with brachytherapy were excluded. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. Propensity score was used to adjust for the nonrandomized assignment of local therapies. RESULTS: A total of 75,539 nonmetastatic prostate cancer patients were identified who received either radiotherapy or no local treatment. Median age was 70 years. Median follow-up of alive subjects was 60 months, with an interquartile range of 47 to 77 months. Estimated 4-year overall survival of entire population was 88%. Significant prognostic variables for overall survival on multivariate analysis included age, grade, PSA level, T stage, and use of radiation therapy. Use of radiation therapy was the most powerful predictor of both cause-specific and overall survival (HR=0.41 and 0.46, respectively, P<0.001). The benefit conferred by local treatment was seen even in subjects with PSA>=75 ng/mL. Four-year cancer specific survival was 93.8% in those receiving radiation treatments versus 76.5% in those who did not receive any local treatment. CONCLUSIONS: Survival was significantly improved by radiotherapy for localized prostate cancer. Extremely high PSA levels (>=25 ng/mL) should not be considered a contraindication to local treatment. PMID- 26125305 TI - Psychosocial consequences of living with breathlessness due to advanced disease. AB - PURPOSE OF REVIEW: Breathlessness is one of the most important symptoms of patients with advanced life-limiting disease, such as chronic obstructive pulmonary disease, chronic heart failure, cancer, or pulmonary fibrosis. Breathlessness has major implications for patients as well as their family caregivers. The present review provides an overview of recent knowledge concerning the psychological and social consequences of breathlessness, including behavioural responses to breathlessness, and the impact of breathlessness on the family caregiver. RECENT FINDINGS: Breathlessness results in avoidance of exertion and deterioration of functional status. Functional impairment leads to care dependency and social limitations, resulting in a change in social role. Anxiety is an emotional response to breathlessness, but also increases the perception of breathlessness. Family caregivers of patients have to cope with changes in daily life, witnessing breathlessness and adapt to new and challenging role as family caregiver. SUMMARY: The consequences of living with breathlessness are multidimensional and arise in all aspects of daily life of patients, their family caregivers and their social environment. Multidimensional treatment programmes should become widely available to support patients with advanced disease and their family caregivers in coping with the functional, psychological and social consequences of living with breathlessness. PMID- 26125306 TI - Perioperative chemotherapy for muscle invasive bladder cancer. AB - PURPOSE OF REVIEW: Radical cystectomy with or without systemic chemotherapy is considered a standard of care for patients with muscle invasive bladder cancer (MIBC). The purpose of this review is to provide an update on current and recent literature published within the last 12 months reviewing the evidence for use of perioperative chemotherapy for patients with MIBC. RECENT FINDINGS: In the neoadjuvant chemotherapy (NAC) setting, the evidence demonstrates clinical efficacy and lower rate of toxicity with the use of high-dose methotrexate, vinblastine, doxorubicin, and cyclophosphamide (MVAC) compared with standard MVAC. Higher quality evidence for the use of gemcitabine with cisplatin is not yet available. Meta-analysis of cisplatin-based regimens in the adjuvant setting demonstrates significant benefit in overall survival and disease-free survival specifically in patients with lymph-node-positive disease. SUMMARY: The available evidence suggests that along with radical cystectomy, cisplatin-based perioperative chemotherapy should be the standard of care in patients with MIBC with a higher quality and quantity of literature in support of the NAC approach. Adoption of perioperative chemotherapy for MIBC is on the rise in North America, which is reassuring. Novel therapeutic approaches for cisplatin-ineligible patients are currently being investigated. PMID- 26125307 TI - Nonopioid medication for the relief of refractory breathlessness. AB - PURPOSE OF REVIEW: To provide an overview of recent evidence relating to nonopioid medication for the treatment of refractory breathlessness. RECENT FINDINGS: A search of publications since 2013 found systematic reviews on phenothiazines and nebulized medications, together with one study examining the use of benzodiazepines and another nebulized furosemide. However, all provided limited data and concluded that further clinical trials are required. SUMMARY: Based on this review, there is insufficient evidence to support the routine use of nonopioid medication in the treatment of refractory breathlessness. PMID- 26125308 TI - Specialized programs to support young women with breast cancer. AB - PURPOSE OF REVIEW: Because of the recognized impact of breast cancer and its treatment on a young woman's life, initiatives are being established worldwide. The main aim of this review was to describe existing specialized programs that support young women with breast cancer (YWBC), advances to date, current challenges and future actions. RECENT FINDINGS: Current programs for YWBC are now educating professionals, patients, and communities on their specific needs. Also, support groups have helped break isolation and connect YWBC together. Research on biology, treatment, adverse effects, risk factors, genetics, and social aspects on YWBC is now being actively conducted. In low- and middle-income countries, the particular issues of young women are, however, still not systematically addressed, because of scarce funding, lack of awareness of YWBC needs, and deficient provider training. SUMMARY: Practice guidelines and algorithms should be disseminated and available for their widespread use to allow standard clinical and supportive care for YWBC even in oncologic centers where no specific programs exist. Also, cancer centers should formally commit to financing, at least partially, dedicated services, and existing programs for YWBC, guaranteeing their continuity. Finally, interinstitutional and international collaborations should be encouraged to facilitate adequately powered research, to avoid repetitive efforts, and to promote knowledge sharing and translation. PMID- 26125309 TI - Chronic refractory breathlessness is a distinct clinical syndrome. PMID- 26125310 TI - Breast cancer in young women: challenges, progress, and barriers. PMID- 26125311 TI - Counseling About Weight Gain Guidelines and Subsequent Gestational Weight Gain. AB - BACKGROUND: The purpose of this study was to investigate what percentage of postpartum women were informed about how much weight to gain during pregnancy, the accuracy of the weight gain recommendations based on the 2009 Institute of Medicine (IOM) gestational weight gain (GWG) recommendations and whether being informed was associated with greater likelihood of meeting the recommendations. METHODS: This was a cross-sectional study of postpartum women interviewed in maternity recovery rooms at two large urban hospitals. Body mass index was obtained from medical records, and adherence to gestational weight gain guidelines was determined based on the 2009 IOM recommendations. RESULTS: One hundred thirty four women with a mean pregravid body mass index of 28.0 kg/m(2) were studied. Sixty-seven percent of participants reported receiving weight gain recommendations. A greater percentage of healthy weight women (78.6%) reported being informed of a GWG recommendation than overweight (53.8%) or obese women (64.9%), (chi-squared=6.6, p=0.04). Of the women given information about gestational weight gain, 40 (54.8%) received GWG recommendations consistent with the IOM and 33 (45.2%) received discrepant information. The accuracy of the GWG recommendation varied based on weight status. Women of healthy weight were much more likely to be given information in accordance with the IOM recommendations (86.8%) than women who were overweight (12.5%) or obese (26.3%) (chi squared=33.5, p<0.001). Meeting the IOM recommendations did not differ depending on whether women were told how much weight to gain during pregnancy. CONCLUSIONS: Women who are overweight or obese are less likely to be informed about weight gain recommendations than healthy weight women, and nearly half of women receive information inconsistent with the IOM recommendations. There may be a need for further practitioner education on GWG recommendations and increased patient counseling to help promote healthy weight gain during pregnancy. PMID- 26125312 TI - Lewis Acid/Rhodium-Catalyzed Formal [3 + 3]-Cycloaddition of Enoldiazoacetates with Donor-Acceptor Cyclopropanes. AB - A formal [3 + 3]-cycloaddition of enoldiazoacetates with donor-acceptor cyclopropanes was realized by the combination of a Lewis acid-catalyzed diastereoselective [3 + 2]-cycloaddition and a subsequent rhodium-catalyzed chemoselective ring expansion. This tandem transformation provides an efficient approach to highly functionalized cyclohexenes. PMID- 26125314 TI - Cyclometalated Iridium(III) Imidazole Phenanthroline Complexes as Luminescent and Electrochemiluminescent G-Quadruplex DNA Binders. AB - Six cyclometalated iridium(III) phenanthroimidazole complexes with different modifications to the imidazole phenanthroline ligand exhibit enhanced luminescence when bound to guanine (G-) quadruplex DNA sequences. The complexes bind with low micromolar affinity to human telomeric and c-myc sequences in a 1:1 complex:quadruplex stoichiometry. Due to the luminescence enhancement upon binding to G-quadruplex DNA, the complexes can be used as selective quadruplex indicators. In addition, the electrogenerated chemiluminescence of all complexes increases in the presence of specific G-quadruplex sequences, demonstrating potential for the development of an ECL-based G-quadruplex assay. PMID- 26125315 TI - Diabetes associated with pancreatic diseases. AB - PURPOSE OF REVIEW: A relevant number of patients with pancreatic disorders suffer from secondary diabetes. Recent data have shed light on the link between pancreatic damage and subsequent impairments in glucose homeostasis. Furthermore, epidemiological studies provided insights into the relationship between diabetes and the risk of pancreatic carcinoma or pancreatitis. Pancreaticogenic diabetes requires a tailored therapeutic approach taking into account the individual properties of the available glucose-lowering drugs. RECENT FINDINGS: We review the available literature concerning diabetes in patients with acute or chronic pancreatitis or pancreatic carcinoma. The relationship between the pancreatic damage and alterations in insulin and glucose homeostasis is summarized as well as the effect of diabetes mellitus on the risk of pancreatic cancer and pancreatitis. Caveats in the treatment of pancreaticogenic diabetes with currently available drugs are being discussed. SUMMARY: Patients with pancreatic diseases should be screened for diabetes by means of an oral glucose tolerance test. There is a close inverse relationship between pancreatic beta-cell loss and postchallenge hyperglycemia. The risk of hypoglycemia may be increased in patients with pancreaticogenic diabetes. Newly diagnosed diabetes may be a harbinger of pancreatic cancer. There is increasing evidence suggesting an increased risk for (pancreatic) cancer and pancreatitis in patients with diabetes mellitus. Further studies on the ideal glucose-lowering treatment of patients with pancreaticogenic diabetes will be required. PMID- 26125313 TI - The Use of SGLT-2 Inhibitors in Type 2 Diabetes and Heart Failure. AB - The concurrent management of type 2 diabetes mellitus (T2DM) and chronic congestive heart failure presents several therapeutic challenges. Of concern is that insulin and insulin-sensitizing medications detrimentally "flood" the heart with energy-providing substrates, including fats and glucose. In this population, treatment of T2DM should focus on the reduction of increased substrate supply. Sodium glucose cotransporter-2 (SGLT-2) inhibitors, a new class of antidiabetic medication, operate via this principle by blocking the reabsorption of glucose in the kidney and subsequently releasing glucose through the urine. In this review, we begin with an examination of the mechanisms of glucotoxicity and lipotoxicity in the heart. Then we analyze the potential role of SGLT-2 inhibitor therapy in patients with concurrent T2DM and chronic heart failure. Based on the available evidence, SGLT-2 inhibitors are safe and can be recommended to treat T2DM in patients with chronic heart failure and intact renal function. Further studies are in progress to assess long-term survival benefits. PMID- 26125316 TI - Intraductal papillary mucinous neoplasms. AB - PURPOSE OF REVIEW: Our understanding of intraductal papillary mucinous neoplasm (IPMN) of the pancreas has remarkably grown within the last decade; nonetheless there is still an ongoing controversy if the majority of these potentially malignant neoplasms need to be resected or if observation in a subset is well tolerated. RECENT FINDINGS: Novel cyst fluid biomarkers, like Gnas mutations or mab DAS-1, could play a pivotal role in the distinction of IPMN vs. other cystic lesions, in the sub-classification of IPMN and in the detection of IPMN with high grade dysplasia or invasive cancer. Other recent studies focused on natural history of minimal- and extensive-mixed IPMN and the safety of the 2012 AIP guidelines. Small series also described that observation can be an option in selected frail patients with MD-IPMN. Further, data from a large European multicenter study analysis indicated that patients with IPMN do not have an increased frequency of extrapancreatic malignancies. SUMMARY: Increasing knowledge about the nature of IPMN and their subtypes has resulted in an individualized approach in diagnosis and treatment. Owing to the availability of accurate diagnostic instruments, timing and indication for pancreatic resection have become more selective, sparing patients with harmless IPMN from major surgery. PMID- 26125317 TI - Pancreatic stellate cell: physiologic role, role in fibrosis and cancer. AB - PURPOSE OF REVIEW: Ever since the first descriptions of methods to isolate pancreatic stellate cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these cells and their functions in health and disease. This review updates recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer. RECENT FINDINGS: Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer. SUMMARY: Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer. PMID- 26125318 TI - First Record of Paratenic Hosts of the Swimbladder Nematode Anguillicola crassus in North America. AB - Anguillicola crassus is a non-native parasite of the American eel, Anguilla rostrata. Since being introduced into North America, the nematode has spread rapidly across the range of A. rostrata, but paratenic hosts, which may facilitate parasite dispersion, have yet to be identified in the region. We investigated infection of larval A. crassus in 261 fish specimens belonging to 23 species and 12 orders collected from estuarine habitats in South Carolina (salinities 0-9 ppt) and Nova Scotia (10-18 ppt). A total of 35 fish belonging to 5 species and 3 orders were infected with the third-stage larvae (L3) of A. crassus, providing the first record of paratenic hosts for the parasite in North America. In South Carolina, high prevalence and abundance of the worm were found in spot (Leiostomus xanthurus), silver perch (Bairdiella chrysoura), and highfin goby (Gobionellus oceanicus), and a high prevalence but lower abundance was found in mummichog (Fundulus heteroclitus). In Nova Scotia, 2 nematodes were found in a single specimen of tomcod (Microgadus tomcod). All of the infected species are associated with a benthic lifestyle, and some of them are known to move between estuaries along the coastline. Lower infection rates in Nova Scotia may be associated with lower water temperatures and/or higher salinity of the sampling site. Most of the L3 were found encapsulated in mesenteric tissue around the intestine and stomach. No L4 or pre-adult worms were found. Mean body length of the L3 was smaller than L3 stages found in American eels from Cape Breton. This suggests that development of A. crassus is arrested at the L3 in the 5 fish species reported here, supporting their status as paratenic hosts. PMID- 26125319 TI - Carfilzomib for the treatment of patients with relapsed and/or refractory multiple myeloma. AB - Carfilzomib is a proteasome inhibitor that irreversibly binds to its target, resulting in sustained proteasomal inhibition with minimal off-target effects. As a single agent, carfilzomib has demonstrated durable antimyeloma activity with manageable toxicities, which has resulted in its approval in Argentina, Israel, Mexico and the USA for the treatment of patients with relapsed and refractory multiple myeloma. Data from ongoing Phase III studies that are evaluating carfilzomib in earlier lines of therapy may facilitate an expanded indication for this agent, as well as for regulatory approval in the EU. This article summarizes the chemistry, pharmacokinetics, pharmacodynamics and available clinical data for carfilzomib in the treatment of patients with multiple myeloma. PMID- 26125320 TI - Mini-Review: Impaired Axonal Transport and Glaucoma. AB - Glaucoma is increasingly recognized as a neurodegenerative disorder, characterized by the accelerated loss of retinal ganglion cells (RGCs) and their axons. Impaired axonal transport has been implicated as a pathogenic mechanism in a number of neurodegenerative diseases, including glaucoma. The long RGC axon, with its high metabolic demand and crucial role in conveying neurotrophic signals, relies heavily on intact axonal transport. In this mini review, we consider the evidence for transport disruption along RGCs in association with glaucoma and other intraocular pressure models. We give a brief overview of the axonal transport process and the methods by which it is assessed. Spatial and temporal patterns of axonal transport disruption are considered as well as the reversibility of these changes. Biomechanical, metabolic and cytoskeletal insults may underlie the development of axonal transport deficits, and there are multiple perspectives on the impact that transport disruption has on the RGC. Eliciting the role of impaired axonal transport in glaucoma pathogenesis may uncover novel therapeutic targets for protecting the optic nerve and preventing vision loss in glaucoma. PMID- 26125321 TI - Reversible Semiconducting-to-Metallic Phase Transition in Chemical Vapor Deposition Grown Monolayer WSe2 and Applications for Devices. AB - Two-dimensional (2D) semiconducting monolayer transition metal dichalcogenides (TMDCs) have stimulated lots of interest because they are direct bandgap materials that have reasonably good mobility values. However, contact between most metals and semiconducting TMDCs like 2H phase WSe2 are highly resistive, thus degrading the performance of field effect transistors (FETs) fabricated with WSe2 as active channel materials. Recently, a phase engineering concept of 2D MoS2 materials was developed, with improved device performance. Here, we applied this method to chemical vapor deposition (CVD) grown monolayer 2H-WSe2 and demonstrated semiconducting-to-metallic phase transition in atomically thin WSe2. We have also shown that metallic phase WSe2 can be converted back to semiconducting phase, demonstrating the reversibility of this phase transition. In addition, we fabricated FETs based on these CVD-grown WSe2 flakes with phase engineered metallic 1T-WSe2 as contact regions and intact semiconducting 2H-WSe2 as active channel materials. The device performance is substantially improved with metallic phase source/drain electrodes, showing on/off current ratios of 10(7) and mobilities up to 66 cm(2)/V.s for monolayer WSe2. These results further suggest that phase engineering can be a generic strategy to improve device performance for many kinds of 2D TMDC materials. PMID- 26125322 TI - High Concentrations of the Antibiotic Spiramycin in Wastewater Lead to High Abundance of Ammonia-Oxidizing Archaea in Nitrifying Populations. AB - To evaluate the potential effects of antibiotics on ammonia-oxidizing microbes, multiple tools including quantitative PCR (qPCR), 454-pyrosequencing, and a high throughput functional gene array (GeoChip) were used to reveal the distribution of ammonia-oxidizing archaea (AOA) and archaeal amoA (Arch-amoA) genes in three wastewater treatment systems receiving spiramycin or oxytetracycline production wastewaters. The qPCR results revealed that the copy number ratios of Arch-amoA to ammonia-oxidizing bacteria (AOB) amoA genes were the highest in the spiramycin full-scale (5.30) and pilot-scale systems (1.49 * 10(-1)), followed by the oxytetracycline system (4.90 * 10(-4)), with no Arch-amoA genes detected in the control systems treating sewage or inosine production wastewater. The pyrosequencing result showed that the relative abundance of AOA affiliated with Thaumarchaeota accounted for 78.5-99.6% of total archaea in the two spiramycin systems, which was in accordance with the qPCR results. Mantel test based on GeoChip data showed that Arch-amoA gene signal intensity correlated with the presence of spiramycin (P < 0.05). Antibiotics explained 25.8% of variations in amoA functional gene structures by variance partitioning analysis. This study revealed the selection of AOA in the presence of high concentrations of spiramycin in activated sludge systems. PMID- 26125323 TI - Regional Variability and Uncertainty of Electric Vehicle Life Cycle CO2 Emissions across the United States. AB - We characterize regionally specific life cycle CO2 emissions per mile traveled for plug-in hybrid electric vehicles (PHEVs) and battery electric vehicles (BEVs) across the United States under alternative assumptions for regional electricity emission factors, regional boundaries, and charging schemes. We find that estimates based on marginal vs average grid emission factors differ by as much as 50% (using National Electricity Reliability Commission (NERC) regional boundaries). Use of state boundaries versus NERC region boundaries results in estimates that differ by as much as 120% for the same location (using average emission factors). We argue that consumption-based marginal emission factors are conceptually appropriate for evaluating the emissions implications of policies that increase electric vehicle sales or use in a region. We also examine generation-based marginal emission factors to assess robustness. Using these two estimates of NERC region marginal emission factors, we find the following: (1) delayed charging (i.e., starting at midnight) leads to higher emissions in most cases due largely to increased coal in the marginal generation mix at night; (2) the Chevrolet Volt has higher expected life cycle emissions than the Toyota Prius hybrid electric vehicle (the most efficient U.S. gasoline vehicle) across the U.S. in nearly all scenarios; (3) the Nissan Leaf BEV has lower life cycle emissions than the Prius in the western U.S. and in Texas, but the Prius has lower emissions in the northern Midwest regardless of assumed charging scheme and marginal emissions estimation method; (4) in other regions the lowest emitting vehicle depends on charge timing and emission factor estimation assumptions. PMID- 26125324 TI - Post-Assembly Covalent Di- and Tetracapping of a Dinuclear [Fe2L3](4+) Triple Helicate and Two [Fe4L6](8+) Tetrahedra Using Sequential Reductive Aminations. AB - The use of a highly efficient reductive amination procedure for the postsynthetic end-capping of metal-templated helicate and tetrahedral supramolecular structures bearing terminal aldehyde groups is reported. Metal template formation of a [Fe2L3](4+) dinuclear helicate and two [Fe4L6](8+) tetrahedra (where L is a linear ligand incorporating two bipyridine domains separated by one or two 1,4 (2,5-dimethoxyaryl) linkers and terminated by salicylaldehyde functions is described. Postassembly reaction of each of these "open" di- and tetranuclear species with excess ammonium acetate (as a source of ammonia) and sodium cyanoborohydride results in a remarkable reaction sequence whereby the three aldehyde groups terminating each end of the helicate, or each of the four vertices of the respective tetrahedra, react with ammonia then undergo successive reductive amination to yield corresponding fully tertiary-amine capped cryptate and tetrahedral covalent cages. PMID- 26125325 TI - Water in Hydration Shell of an Iodide Ion: Structure and Dynamics of Solute-Water Hydrogen Bonds and Vibrational Spectral Diffusion from First-Principles Simulations. AB - The dynamics of hydrogen bonds and vibrational spectral diffusion of water in the hydration shell of an iodide ion and in bulk have been investigated for aqueous iodide solutions of two different concentrations by using ab initio molecular dynamics simulations. The effects of dispersion interactions on the dynamics have also been investigated by using a dispersion corrected density functional. For the dilute solution containing a single iodide ion, three time scales are found for the spectral diffusion of solvation shell water: A short time scale of ~150 fs, a slower time scale of ~2-3 ps and a yet longer time scale of ~14-16 ps. The long time scale of ~14-16 ps is not noticed when calculations are done for all OD modes for both the dilute and concentrated solutions. It is found that a clear separation between the solvation shell and bulk water does not exist in terms of OD stretching frequencies for the concentrated solution. The dynamics of vibrational spectral diffusion is explained in terms of hydrogen bond dynamics, other dynamical modes such as orientational relaxation and molecular diffusion, and also structural aspects of water molecules in the solvation shells. The current results are compared with those of available experimental and other theoretical studies. PMID- 26125326 TI - Role of Solvent and Effect of Substituent on Azobenzene Isomerization by Using Room-Temperature Ionic Liquids as Reaction Media. AB - The effects of a para substituent, as the electron-donating -OCH3 and -OtBu groups and the electron-withdrawing -Br and -F atoms, on azobenzene isomerization have been investigated in a series of imidazolium ionic liquids (BMIM PF6, BMIM BF4, BMIM Tf2N, EMIM Tf2N, BM2IM Tf2N, and HMIM Tf2N). The thermal cis-trans conversion tends to be improved in the presence of the substituent, as pointed out by the first-order rate constants measured at 25 degrees C. Both the rotation and the inversion mechanisms occur in BMIM Tf2N, EMIM Tf2N, and HMIM Tf2N, as highlighted by typical V-shape Hammett plots, but only rotation takes place in BMIM PF6, BMIM BF4, and BM2IM Tf2N. The possible interactions between the cation and the anion of the solvent and both the isomers of the azobenzene derivatives have been studied by small-wide-angle X-ray scattering (SWAXS). The calculated cis population in the photostationary state and the hardness parameter eta of the trans isomer show that azobenzene and F-azobenzene are the less reactive molecules for the trans-cis conversion in all the investigated ionic liquids. PMID- 26125327 TI - Structure-Affinity Relationships (SARs) and Structure-Kinetics Relationships (SKRs) of Kv11.1 Blockers. AB - Kv11.1 (hERG) blockers with comparable potencies but different binding kinetics might display divergent pro-arrhythmic risks. In the present study, we explored structure-kinetics relationships in four series of Kv11.1 blockers next to their structure-affinity relationships. We learned that despite dramatic differences in affinities and association rates, there were hardly any variations in the dissociation rate constants of these molecules with residence times (RTs) of a few minutes only. Hence, we synthesized 16 novel molecules, in particular in the pyridinium class of compounds, to further address this peculiar phenomenon. We found molecules with very short RTs (e.g., 0.34 min for 37) and much longer RTs (e.g., 105 min for 38). This enabled us to construct a k on-k off-KD kinetic map for all compounds and subsequently divide the map into four provisional quadrants, providing a possible framework for a further and more precise categorization of Kv11.1 blockers. Additionally, two representative compounds (21 and 38) were tested in patch clamp assays, and their RTs were linked to their functional IC50 values. Our findings strongly suggest the importance of the simultaneous study of ligand affinities and kinetic parameters, which may help to explain and predict Kv11.1-mediated cardiotoxicity. PMID- 26125328 TI - Carpenter's Rule Folding in Rigid-Flexible Block Copolymers with Conjugation Interrupting, Flexible Tethers Between Oligophenylenevinylenes. AB - Rigid-flexible segmented block copolymers were synthesized and characterized as 4.5-oligophenylenevinylene chromophores tethered by flexible, conjugation interrupting 1,2-ethanedioxy or 1,4-butanedioxy units. The flexible tethers allow the possibility of collapsed order chromophore assemblies within individual polymers by chain folding at specific sites much like an old fashioned, folding carpenter's rule. Our results indicate that using a short, flexible tether in a rigid-flexible segmented copolymer can result in collapsed rodlike structures as signaled by strongly quenched photoluminescence, even after thermal annealing. Such ability to "program" folding and tertiary structure in conjugated copolymers is important for solid-state organic light emitting materials and understanding of organic chromophore self-assembly. PMID- 26125329 TI - Acetate anion-triggered peroxygenation of non-native substrates by wild-type cytochrome P450s. AB - Cytochrome P450SPalpha (P450SPalpha) and cytochrome P450BSbeta (P450BSbeta) belonging to the CYP152 family of enzymes (CYP152s) can utilize H2O2 efficiently as an oxidant for the generation of compound I. Although P450SPalpha and P450BSbeta have very high substrate specificity and catalyse hydroxylation of long-chain fatty acids exclusively, we found that they can oxidize non-native substrates such as styrene simply by including medium chain length n-alkyl carboxylic acids as "decoy molecules." Although we had assumed that acetic acid did not serve as a decoy molecule, P450SPalpha and P450BSbeta efficiently catalysed oxidation of non-native substrates when the reaction was carried out at a high concentration of acetate anion. The turnover rate for epoxidation of styrene catalysed by P450BSbeta in the presence of 1 M acetate anion reached 590 +/- 30 min(-1). PMID- 26125330 TI - Comparison of a Wipe Method With and Without a Rinse to Recover Wall Losses in Closed Face 37-mm Cassettes used for Sampling Lead Dust Particulates. AB - Closed-face 37-mm polystyrene cassettes are often used for exposure monitoring of metal particulates. Several methods have been proposed to account for the wall loss in air sampling cassettes, including rinsing, wiping, within-cassette dissolution, and an internal capsule fused to the filter that could be digested with the filter. Until internal capsules replace filters, other methods for assessing wall losses may be considered. To determine if rinsing and wiping or wiping alone is adequate to determine wall losses on cassettes, we collected 54 full-shift area air samples at a battery recycling facility. We collected six replicate samples at three locations within the facility for three consecutive days. The wall losses of three replicate cassettes from each day-location were analyzed following a rinse and two consecutive wipes. The wall losses of the other three replicates from each day-location were analyzed following two consecutive wipes only. Mixed-cellulose ester membrane filter, rinse, and wipes were analyzed separately following NIOSH Method 7303. We found an average of 29% (range: 8-54%) recovered lead from the cassette walls for all samples. We also found that rinsing prior to wiping the interior cassette walls did not substantially improve recovery of wall losses compared to wiping alone. A rinse plus one wipe recovered on average 23% (range: 13-33%) of the lead, while one wipe alone recovered on average 21% (range: 16-22%). Similarly, we determined that a second wipe did not provide substantial additional recovery of lead (average: 4%, range: 0.4-19%) compared to the first wipe disregarding the rinse (average: 18%, range: 4-39%). We concluded that when an internal capsule is not used, wall losses of lead dust in air sampling cassettes can be adequately recovered by wiping the internal wall surfaces of the cassette with a single wipe. PMID- 26125331 TI - The Relationship between the Hydrophilicity and Surface Chemical Composition Microphase Separation Structure of Multicomponent Silicone Hydrogels. AB - Three series of multicomponent silicone hydrogels were prepared by the copolymerization of two hydrophobic silicon monomers bis(trimethylsilyloxy) methylsilylpropyl glycerol methacrylate (SiMA) and tris(trimethylsiloxy) 3 methacryloxypropylsilane (TRIS) with three hydrophilic monomers. The surface hydrophilicity of the silicone hydrogels was characterized by contact angle measurements, and an interesting phenomenon was found that the silicone hydrogels made from less hydrophobic monomer SiMA possess more hydrophobic surfaces than those made from TRIS. The surface properties such as morphology and elemental composition of the silicone hydrogels were explored by scanning electron microscopy (SEM) imaging and energy dispersive spectrometry (EDS) analysis, and their relationships with the surface hydrophilicity were investigated in details. The results show neither the surface morphology nor the elemental composition has obvious impact on the surface hydrophilicity. Atomic force microscopy (AFM) imaging revealed that SiMA hydrogel had a more significant phase separation structure, which also made its surface uneven: a lot of tiny holes were observed on the surface. This surface phase separation structure made SiMA hydrogel more difficult to be wetted by water or PBS buffer, i.e., more hydrophobic than TRIS hydrogel. On the basis of these results, we propose that the phase separation structure as well as the nature of silicon monomers might be the fundamental reasons of surface hydrophilicity. These results could help to design a silicone hydrogel with better surface properties and wider application. PMID- 26125332 TI - Ultrasensitive Electrochemical Detection of Nucleic Acids Based on the Dual Signaling Electrochemical Ratiometric Method and Exonuclease III-Assisted Target Recycling Amplification Strategy. AB - Because of the intrinsic importance of nucleic acids as biotargets, the simple and sensitive detection of nucleic acids is very essential for biological studies and medical diagnostics. In this work, a novel, simple, and selective electrochemical DNA biosensor for the sensitive detection of target DNA (T-DNA) has been developed based on the dual-signaling electrochemical ratiometric method and exonuclease III (Exo III)-assisted target recycling amplification strategy. The assay strategy includes both "signal-on" and "signal-off" elements. The stem loop (hairpin) DNA capture probe (HP), which was labeled by thiolated methylene blue (MB) at the 3'-protruding termini and ferrocene (Fc) in the middle of the loop, first self-assembled on the gold electrode surface via a Au-S bond. In the presence of T-DNA, the T-DNA hybridized with HP, which triggered the Exo III cleavage process and accompanied the release of T-DNA. As a result, the MB tags were away from and the Fc tags close to the gold electrode surface, leading to the decrease of the oxidation peak current of MB (I(MB)) and the increase of that of Fc (I(Fc)). The value of DeltaI(Fc)/|DeltaI(MB)| (DeltaI(Fc) and DeltaI(MB) are the change values of the oxidation peak currents of Fc and MB, respectively) is linear with the concentration of T-DNA from 0.01 pM to 0.8 pM. The detection limit (4.16 fM) of the developed method is much lower than that of the most reported electrochemical DNA biosensors. This strategy provides a simple and sensitive approach for the detection of T-DNA and has promising applications in bioanalysis, disease diagnostics, and clinical biomedicine. PMID- 26125333 TI - Growing Zigzag (16,0) Carbon Nanotubes with Structure-Defined Catalysts. AB - The growth of zigzag single-walled carbon nanotubes (SWNTs) is most challenging among all types of SWNTs, with the highest reported selectivity of ~7%. Here we realized the dominant growth of (16,0) tubes at the abundance near ~80% by using intermetallic W6Co7 catalysts containing plenty of (1 1 6) planes together with optimizing the growth conditions. These (1 1 6) planes may act as the structure templates for (16,0) SWNTs due to the geometrical match between the open end of the (16,0) tube and the atomic arrangements of the (1 1 6) planes in W6Co7. Using catalysts with designed structure as solid state template at suitable kinetic conditions offers a strategy for selective growth of zigzag SWNTs. PMID- 26125335 TI - Parts-per-trillion-level detection of nitrogen dioxide by cantilever-enhanced photo-acoustic spectroscopy. AB - We present a simple and highly sensitive cantilever-enhanced photo-acoustic sensor for detection of nitrogen dioxide. A noise equivalent detection limit of 50 parts-per-trillion in 1 s is demonstrated. The limit was reached with an average optical power of 4.7 W using a continuous-wave laser at 532 nm. The achieved normalized noise equivalent absorption coefficient was 2.6*10(-10) W cm(-1) Hz(-1/2). PMID- 26125334 TI - Proteomic analysis of extracellular medium of cryopreserved carp (Cyprinus carpio L.) semen. AB - During freezing and thawing, spermatozoa are exposed to physical and chemical stressors that result in adverse changes in sperm structures and physiological functions. The present study provides, for the first time, a comprehensive description of protein changes in the extracellular medium of cryopreserved semen. Using 2D-DIGE and a combination of protein fractionation by one dimensional gel electrophoresis and high performance liquid chromatography electrospray ionization tandem mass spectrometry, 183 proteins released from sperm to an extracellular medium were identified. The majority of released proteins were involved in metabolism and energy production. Moreover, proteins associated with a response to stress, apoptosis, small GTPase mediated signal transduction, transcription, translation, protein folding and turnover, reproduction and DNA repair were identified. The dominant group of released proteins was related to cytoplasm. Moreover, specific proteins associated with the membrane, mitochondria and nucleus were identified. The identification of a high number of proteins released from sperm provides new insight into the mechanism of cryodamage to the particular sperm structure and to specific metabolic pathways, which were affected by cryopreservation. The availability of a catalog of carp sperm proteins altered by cryopreservation provides a crucial tool for the development of novel potential biomarkers of cryoinjuries and for the improvement of a long-term sperm preservation procedure. PMID- 26125336 TI - General closed-form bit-error rate expressions for coded M-distributed atmospheric optical communications. AB - In this Letter, general closed-form expressions for the average bit error rate in atmospheric optical links employing rate-adaptive channel coding are derived. To characterize the irradiance fluctuations caused by atmospheric turbulence, the Malaga or M distribution is employed. The proposed expressions allow us to evaluate the performance of atmospheric optical links employing channel coding schemes such as OOK-GSc, OOK-GScc, HHH(1,13), or vw-MPPM with different coding rates and under all regimes of turbulence strength. A hyper-exponential fitting technique applied to the conditional bit error rate is used in all cases. The proposed closed-form expressions are validated by Monte-Carlo simulations. PMID- 26125337 TI - Synthetic gauge fields for light beams in optical resonators. AB - A method to realize artificial magnetic fields for light waves trapped in passive optical cavities with anamorphic optical elements is theoretically proposed. In particular, when a homogeneous magnetic field is realized, a highly degenerate Landau-level structure for the frequency spectrum of the transverse resonator modes is obtained, corresponding to a cyclotron motion of the optical-cavity field. This can be probed by transient excitation of the passive optical resonator. PMID- 26125338 TI - Plasmonic Zitterbewegung in binary graphene sheet arrays. AB - We theoretically investigate the plasmonic Zitterbewegung (ZB) effect in binary graphene sheet arrays (GSAs). The surface plasmon polariton (SPP) modes of two minibands are realized by alternately varying the chemical potentials of individual graphene sheets in the arrays. Numerical simulations show that SPPs in the array experience characteristic trembling motion. The oscillating periods of the plasmonic ZB are strongly dependent on the propagation constant mismatch and varied in the range of micrometer, while the amplitude reaches tens of nanometers, making the ZB effect easier to be observed in practice. PMID- 26125339 TI - Extreme amplitude spikes in a laser model described by the complex Ginzburg Landau equation. AB - We have found new dissipative soliton in the laser model described by the complex cubic-quintic Ginzburg-Landau equation. The soliton periodically generates spikes with extreme amplitude and short duration. At certain range of the equation parameters, these extreme spikes appear in pairs of slightly unequal amplitude. The bifurcation diagram of spike amplitude versus dispersion parameter reveals the regions of both regular and chaotic evolution of the maximal amplitudes. PMID- 26125340 TI - Optical nonlinearity in the nematic phase of bent-core mesogens. AB - Nonlinear optical response of the cybotactic nematic phase of a bent-core mesogen has been investigated for the first time through self-phase modulation induced by a Gaussian beam. The material exhibits a high nonlinear response achieving a nonlinear index n(2)~5*10(-5) cm(2)/W and an unconventional behavior characterized by two different regimes. While the high-intensity regime can be easily explained in terms of a thermal indexing effect, the low-intensity regime is metastable and characterized by an unusual dependence on the irradiation energy. It is suggested that a change of the director configuration, possibly due to a light-induced modification of surface anchoring, is responsible for the observed behavior. PMID- 26125341 TI - Talbot cavity redesigned for increased supermode discrimination with reduced loss. AB - Talbot effect is a well known optical phenomenon that can be used to perform passive coherent laser combination. Using an appropriately configured Talbot cavity, an array of laser elements can be forced to oscillate in a single supermode with a spatially coherent output. One disadvantage of the Talbot cavity is the high loss incurred when the array is configured to provide good supermode discrimination. In this Letter, we present a new arrangement of the laser elements in the cavity with all of the elements pointing toward the common center of the array in the plane of the coupled feedback. This configuration provides significantly increased supermode discrimination along with significantly reduced loss. PMID- 26125342 TI - Enhanced spin Hall effect of transmitted light through a thin epsilon-near-zero slab. AB - Spin Hall effect (SHE) of transmitted light is small even near the Brewster angle in general case, e.g., at the air-glass interface. However, we find that the SHE can be enhanced when a linearly polarized Gaussian beam transmits through a thin epsilon-near-zero slab due to the difference between the Fresnel transmission coefficients t(p) and t(s). For a vertically polarized incident beam, the spin dependent transverse displacement of transmitted beam is enhanced near the Brewster angle, while it takes large value over a large angle scale for a horizontally polarized incident beam. PMID- 26125343 TI - 109 MHz optical tomography using temporal magnification. AB - Ultrafast optical tomographic imaging with a 109 MHz A-scan rate is achieved by using temporal magnification. Based on two four-wave mixing (FWM) time lenses with carefully designed group delay dispersion, we construct a temporal imaging system with a magnification factor of 48.3*. The two time-lens scheme not only relaxes the requirement for the pump source but also facilitates the application for tomographic imaging. As a proof-of-concept demonstration, our system achieves an axial resolution of 140 MUm in air (~105 MUm in biosample) over a 28 mm depth range with sensitivity up to 55 dB. We then evaluate the imaging performance using a fish-eye lens at a 109 MHz A-scan rate. Utilizing better dispersion engineered nonlinear media, resolution of less than 5 MUm in the biosample with higher sensitivity may be achieved. We believe this scheme will provide a promising solution for video-rate 3D tomographic imaging. PMID- 26125344 TI - Single-mode selection for hard x-ray cavity resonance. AB - Single-mode selection is realized for hard x-ray cavity resonance using a three mirror crystal device. The developed device consists of two coupled Si Fabry Perot resonators (FPRs) and uses (12 4 0) backward diffraction to reflect back and forth the incident 14.4388 keV x-ray beam. The coupling between the two cavities gives an effective single-mode spectrum with a bandwidth of 0.81 meV. This method can be used to enhance the longitudinal coherent length without affecting transverse coherence, and is potentially useful in generating nearly total coherent beams in synchrotron or free-electron laser facilities. PMID- 26125345 TI - Power scaling of narrowband high-power all-fiber superfluorescent fiber source to 1.87 kW. AB - We demonstrate a high-power narrowband all-fiber superfluorescent fiber source employing three-stages master oscillator power-amplifier chain. Narrowband seed light is selected from a broadband-amplified spontaneous-emission source by a spectrum filter combing with fiber circulator and fiber Bragg grating. In the main amplifier, the maximal output power is 1.87 kW with an optical-to-optical conversion efficiency of 77.4% and a full width at half-maximum (FWHM) linewidth of 1.7 nm. The corresponding power fluctuation is +/-1.4% in 100 s operation, and no parasitic oscillation or self pulsation is observed. A beam quality of M(2)=1.71 is measured at 1.4 kW output power. This manuscript investigates the spectral evolution in high-power amplification. The central wavelength shifted from 1079.5 nm to 1080.7 nm, and the FWHM linewidth narrowed from 2 nm to 1.7 nm at full power, respectively. These effects could be inferred as hybrid effects of many factors, such as wavelength shifting of pump LD, nonoptimized length of gain fiber, and enhancement of temperature level of gain fiber. The narrowband maintained characteristic in spectral domain under high-power amplification is significant for applications such as spectral beam combination, and further power scaling is available as the output power is only limited by the pump power. PMID- 26125346 TI - Ultra-wide free spectral range, enhanced sensitivity, and removed mode splitting SOI optical ring resonator with dispersive metal nanodisks. AB - A refractive index sensor with a free spectral range that is unlimited by neighboring mode spacing (10 fold increase with respect to 20 nm of an unmodified ring), based on an optical silicon-on-insulator microring resonator patterned with periodically arranged set of gold nanodisks, is presented and numerically verified. It is shown that the particular periodic arrangement of nanodisks selects a single resonance from a wide set of ring resonator modes and removes mode splitting. Extraction of the waveguided electromagnetic energy into evanescent plasmonic modes enhances light-analyte interaction and increases device sensitivity to variation of refractive index up to 176 nm/RIU (about 2 fold increase compared to the unmodified ring), which is useful for sensor applications. Proof of the concept is presented by finite-difference time-domain simulations of a design readily practicable by means of modern nanotechnology. PMID- 26125347 TI - Beam self-cleanup by use of self-written waveguide generated by photopolymerization. AB - A novel method for multimode fiber (MMF) laser-beam cleanup is introduced based on the optically induced growth and interaction of self-written waveguides (SWWs) in a photopolymer material. Theoretically, it is predicted that when the light is introduced into a free-radical photopolymerizable system from a MMF, the incident multichannel and structured beam shape can be caused to merge to form a single channel Gaussian-like beam under specific exposure and material conditions. Experimental validation was carried out using a dry acrylamide/polyvinyl alcohol (AA/PVA) photopolymer sample. This work opens the door to studies involving self developing laser beam cleanup and also to possible applications in photonic telecommunication systems and integrated optical devices. PMID- 26125348 TI - Timing jitter characterization of mode-locked lasers with <1 zs/?Hz resolution using a simple optical heterodyne technique. AB - Timing jitter characterization of free-running mode-locked lasers with an unprecedented resolution is demonstrated using an optical heterodyne technique. A highly sensitive timing jitter phase-discrimination signal with low-parasitic amplitude sensitivity is achieved. Analytical and numerical methods are used to analyze the properties of the discrimination signal. For an experimental demonstration, we measure the timing jitter between two loosely synchronized mode locked Er:Yb:glass lasers with 500-MHz fundamental repetition rates. The timing jitter-detection noise floor for a single mode-locked laser reaches 2.8*10(-13) fs(2)/Hz (~530 ys/?Hz), and the integrated timing jitter is 16.3 as from 10 kHz to the Nyquist frequency (250 MHz). These results show that this approach can be a simpler alternative to the well-established balanced optical cross-correlation technique. PMID- 26125349 TI - Fast two-dimensional super-resolution image reconstruction algorithm for ultra high emitter density. AB - Single-molecule localization microscopy achieves sub-diffraction-limit resolution by localizing a sparse subset of stochastically activated emitters in each frame. Its temporal resolution is limited by the maximal emitter density that can be handled by the image reconstruction algorithms. Multiple algorithms have been developed to accurately locate the emitters even when they have significant overlaps. Currently, compressive-sensing-based algorithm (CSSTORM) achieves the highest emitter density. However, CSSTORM is extremely computationally expensive, which limits its practical application. Here, we develop a new algorithm (MempSTORM) based on two-dimensional spectrum analysis. With the same localization accuracy and recall rate, MempSTORM is 100 times faster than CSSTORM with l(1)-homotopy. In addition, MempSTORM can be implemented on a GPU for parallelism, which can further increase its computational speed and make it possible for online super-resolution reconstruction of high-density emitters. PMID- 26125350 TI - Multilayer photo-aligned thin-film structure for polarizing photonics. AB - In this Letter, an advanced multilayer photo-aligned liquid crystal polymer (LCP) thin-film structure with multiple optical functions is introduced. Within each LCP layer, a spatially distribution of local optical axes can be controlled by a patterned photo-alignment layer. As an embodiment of the proposed structure, a two-layer structure with pixelated controlled light-propagation directions and polarizations has been studied, which has shown the potential to be used as a photomask for generating multi-domain photo-alignment structures with a single exposure step. The combination of the multilayer structure with patterned photo alignment technology provides a new perspective of designing optical structures for polarizing photonics applications. PMID- 26125351 TI - Frequency conversion of mode-locked and Q-switched CO laser radiation with efficiency up to 37%. AB - Frequency conversion of CO laser radiation was experimentally studied in ZnGeP(2) and GaSe nonlinear crystals. To enhance conversion efficiency, we applied a CO laser system "master oscillator power amplifier" with concurrent mode locking and Q switching. The laser system emitted ~1-MUs train of ns pulses. Internal efficiency of frequency doubling reached 37% in ZnGeP(2) crystal and 5% in GaSe crystal. Two-stage frequency conversion (including second-harmonic and difference frequency generation) in ZnGeP(2) crystal under optical pumping by a selective two-spectral line CO laser was studied. PMID- 26125353 TI - 1000-1400-nm partially mode-locked pulse from a simple all-fiber cavity. AB - We demonstrate a partially mode-locked pulse laser delivering ultra-wideband optical spectrum, i.e., 1000-1400 nm at 30 dB, from a simple all-fiber short cavity with all-normal dispersion. Examined by both real-time temporal and spectral analyzers, the partially mode-locked pulse exhibits double-scale noise like characteristics-the fast L-shaped mode-locked pulse modulated by slow free running Q-switched envelopes. Moreover, the statistical analysis as a function of its optical bandwidth shows that the spectral tuning does not compromise the temporal stability, but affects the pulsing periodicity. It is believed that the wide spectrum of knowledge obtained here would enrich the field of noise-like pulse, such as being beneficial to the rogue wave generation. PMID- 26125352 TI - Depth resolved imaging by digital holography with an illumination of constantly changing curvature. AB - In this Letter, a single wavelength digital holographic method is proposed to achieve depth resolved imaging by recording a series of holograms in the reflection geometry with an illumination of constantly changing curvature. A proper algorithm is employed to selectively generate the images of the object at different depths, including the phase and the modulus information. Theoretical analysis is supported by a visible light experiment to illustrate the feasibility of the proposed method. PMID- 26125354 TI - Spatial-domain interferometer for measuring plasma mirror expansion. AB - We present a practical spatial-domain interferometer for characterizing the electronic density gradient of laser-induced plasma mirrors with sub-30 femtosecond temporal resolution. Time-resolved spatial imaging of an intensity shaped pulse reflecting off an expanding plasma mirror induced by a time-delayed pre-pulse allows us to measure characteristic plasma gradients of 10-100 nm with an expansion velocity of 10.8 nm/ps. Spatial-domain interferometry (SDI) can be generalized to the ultrafast imaging of nm to MUm size laser-induced phenomena at surfaces. PMID- 26125355 TI - Low-loss waveguides in a single-crystal lithium niobate thin film. AB - We report low-loss channel waveguides in a single-crystal LiNbO(3) thin film achieved using the annealed proton exchange process. The simulation indicated that the mode size of the alpha phase channel waveguide could be as small as 1.2 MUm(2). Waveguides with several different widths were fabricated, and the 4 MUm wide channel waveguide exhibited a mode size of 4.6 MUm(2). Its propagation loss was accurately evaluated to be as low as 0.6 dB/cm at 1.55 MUm. The single crystal lattice structure in the LiNbO(3) thin film was preserved by a moderate annealed proton exchange process (5 min of proton exchange at 200 degrees C, followed by 3 h annealing at 350 degrees C), as revealed by measuring the extraordinary refractive index change and x ray rocking curve. A longer proton exchange time followed by stronger annealing would destroy the crystal structure and induce a high loss in the channel waveguides. PMID- 26125356 TI - Fast calculation method of computer-generated cylindrical hologram using wave front recording surface. AB - Fast calculation method for a computer-generated cylindrical hologram (CGCH) is proposed. The method consists of two steps: the first step is a calculation of a virtual wave-front recording surface (WRS), which is located between the 3D object and CGCH. In the second step, in order to obtain a CGCH, we execute the diffraction calculation based on the fast Fourier transform (FFT) from the WRS to the CGCH, which are in the same concentric arrangement. The computational complexity is dramatically reduced in comparison with direct integration method. The simulation results confirm that our proposed method is able to improve the computational speed of CGCH. PMID- 26125357 TI - Optical torque on small bi-isotropic particles. AB - We establish the equations for the time-averaged optical torque on dipolar bi isotropic particles. Due to the interference of the scattered fields, it has a term additional to the one that is commonly employed in theory and experiments. Its consequences for conservation of energy, angular momentum, and effects like negative torques are discussed. PMID- 26125358 TI - Unrepeatered Nyquist PDM-16QAM transmission over 364 km using Raman amplification and multi-channel digital back-propagation. AB - Transmission of a net 467-Gb/s PDM-16QAM Nyquist-spaced superchannel is reported with an intra-superchannel net spectral efficiency (SE) of 6.6 (b/s)/Hz, over 364 km SMF-28 ULL ultra-low loss optical fiber, enabled by bi-directional second order Raman amplification and digital nonlinearity compensation. Multi-channel digital back-propagation (MC-DBP) was applied to compensate for nonlinear interference; an improvement of 2 dB in Q(2) factor was achieved when 70-GHz DBP bandwidth was applied, allowing an increase in span length of 37 km. PMID- 26125359 TI - Low-power continuous-wave four-wave mixing wavelength conversion in AlGaAs nanowaveguide microresonators. AB - We experimentally demonstrate enhanced wavelength conversion in a Q~7500 deeply etched AlGaAs-nanowaveguide microresonator via degenerate continuous-wave four wave mixing with a pump power of 24 mW. The maximum conversion efficiency is -43 dB and accounts for 12 dB enhancement compared to that of a straight nanowaveguide. The experimental results and theoretical predictions agree very well and show optimized conversion efficiency of -15 dB. This work represents a step toward realizing a fully integrated optical devices for generating new optical frequencies. PMID- 26125360 TI - Highly birefringent polymer side-hole fiber for hydrostatic pressure sensing. AB - We report on the fabrication of a birefringent side-hole polymer optical fiber with an elliptical core made of polymethyl metacrylate-polystyrene (PMMA/PS) copolymer and pure PMMA cladding. The fiber core is located in a narrow PMMA bridge separating the holes. Two fibers with different bridge thickness were fabricated and characterized. We demonstrate, experimentally and numerically, that, by narrowing the bridge between the holes, one can increase simultaneously the fiber birefringence and the polarimetric sensitivity to hydrostatic pressure. In the fiber with the bridge as narrow as 5 MUm, we achieved a record-high polarimetric sensitivity to hydrostatic pressure ranging between 175 and 140 rad/MPa/m in the spectral range of 600-830 nm. The phase modal birefringence in this fiber is also high and exceeds 3*10(-5) at 600 nm, which results in small polarization cross talk. PMID- 26125361 TI - Direct design of aspherical lenses for extended non-Lambertian sources in two dimensional geometry. AB - Illumination design for extended sources is very important for practical applications. The existing direct methods that are all developed for extended Lambertian sources are not applicable to extended non-Lambertian sources whose luminance is a function of position and direction. What we present in this Letter is to our knowledge the first direct method for extended non-Lambertian sources. In this method, the edge rays and the interior rays are both used, and the output intensity at a given direction is calculated to be the integral of the luminance function of all the outgoing rays at this direction. No cumbersome iterative illuminance compensation is needed. Two examples are presented to demonstrate the elegance of this method in prescribed intensity design for extended non Lambertian sources in two-dimensional geometry. PMID- 26125362 TI - p-type doping of MgZnO films and their applications in optoelectronic devices. AB - A lithium and nitrogen codoping method has been employed to prepare p-type MgZnO films, and p-MgZnO/i-ZnO/n-ZnO structured light-emitting devices (LEDs) and photodetectors have been fabricated. The LEDs can work continuously for about 97 h under the injection of a 20 mA continuous current, which is the best value ever reported for ZnO-based LEDs. The performance of the photodetectors degrades little after several running cycles. The above results reveal the applicability of the p-MgZnO films in optoelectronic devices. PMID- 26125363 TI - Ultrawideband compressed sensing of arbitrary multi-tone sparse radio frequencies using spectrally encoded ultrafast laser pulses. AB - We demonstrate a photonic system for pseudorandom sampling of multi-tone sparse radio-frequency (RF) signals in an 11.95-GHz bandwidth using <1% of the measurements required for Nyquist sampling. Pseudorandom binary sequence (PRBS) patterns are modulated onto highly chirped laser pulses, encoding the patterns onto the optical spectra. The pulses are partially compressed to increase the effective sampling rate by 2.07*, modulated with the RF signal, and fully compressed yielding optical integration of the PRBS-RF inner product prior to photodetection. This yields a 266* reduction in the required electronic sampling rate. We introduce a joint-sparsity-based matching-pursuit reconstruction via bagging to achieve accurate recovery of tones at arbitrary frequencies relative to the reconstruction basis. PMID- 26125364 TI - Design and development of a high-power LED-pumped Ce:Nd:YAG laser. AB - By studying quasi-continuous wave (QCW) operation of a Ce:Nd:YAG solid-state laser directly pumped by LED arrays, we demonstrate the feasibility of direct-LED pumping as an alternative to direct-diode or flashlamp pumping. LEDs emitting either at 460 or 810 nm were used to pump an uncooled Ce:Nd:YAG laser rod (at 30 Hz repetition rate for tens of seconds). Pumping at 460 nm was made possible by the Ce(3+) co-dopant that enables transfer of excitations near to Nd(3+) ions in the YAG lattice. Comparison of these two pumping schemes has allowed for a thorough analysis of the performance and efficiency of this laser system. QCW output energies as high as 18 mJ/pulse are reported, which to the best of our knowledge is the highest output pulse energy achieved by an LED-pumped solid state laser to date. PMID- 26125365 TI - Broadband-tunable CW laser operation of Pr(3+):LiYF(4) around 900 nm. AB - We present here the first broadband-tunable CW laser operation of a Pr(3+)-doped LiYF(4) crystal in the 900-nm spectral range after pumping with an optically pumped semiconductor laser at 479 nm. It is confirmed that the entire emission band can be assigned to the same set of thermalized emitting levels (I(6)1,P3(0,1)). It is also demonstrated that laser performance could be improved up to laser slope efficiencies of about 33% with threshold absorbed pump powers not exceeding 100 mW. PMID- 26125366 TI - III-V-on-silicon anti-colliding pulse-type mode-locked laser. AB - An anti-colliding pulse-type III-V-on-silicon passively mode-locked laser is presented for the first time based on a III-V-on-silicon distributed Bragg reflector as outcoupling mirror implemented partially underneath the III-V saturable absorber. Passive mode-locking at 4.83 GHz repetition rate generating 3 ps pulses is demonstrated. The generated fundamental RF tone shows a 1.7 kHz 3 dB linewidth. Over 9 mW waveguide coupled output power is demonstrated. PMID- 26125367 TI - Highly efficient source for frequency-entangled photon pairs generated in a 3(rd) order periodically poled MgO-doped stoichiometric LiTaO(3) crystal. AB - We present a highly efficient source for discrete frequency-entangled photon pairs based on spontaneous parametric down-conversion using 3rd-order type-0 quasi-phase matching in a periodically poled MgO-doped stoichiometric LiTaO(3) crystal pumped by a 355.66-nm laser. Correlated two-photon states were generated with automatic conservation of energy and momentum in two given spatial modes. These states have a wide spectral range, even under small variations in crystal temperature, which consequently results in higher discreteness. Frequency entanglement was confirmed by measuring two-photon quantum interference fringes without any spectral filtering. PMID- 26125368 TI - Linewidth narrowing of a tunable mode-locked pumped continuous-wave Ce:LiCAF laser. AB - We report birefringent tuning using single and multiple magnesium fluoride (MgF(2)) Brewster tuning plates in a mode-locked pumped continuous-wave Ce:LiCAF laser. Depending on the thickness of the MgF(2) plates used, continuous tuning over a range of up to 13 nm from 284.5 to 297.5 nm with a full width at half maximum linewidth of 14 pm (50 GHz) was achieved. By combining MgF(2) plates with etalons, the linewidth of the laser was narrowed down to 0.75 pm (2.7 GHz). This generated narrowband output is suitable for many applications in spectroscopy, cold-atom manipulation, and sensing. PMID- 26125369 TI - Optimal design of radial Bragg cavities and lasers. AB - We present a new and optimal design approach for obtaining maximal confinement of the field in radial Bragg cavities and lasers for TM polarization. The presented approach outperforms substantially the previously employed periodic and semi periodic design schemes of such lasers. We show that in order to obtain maximal confinement, it is essential to consider the complete reflection properties (amplitude and phase) of the propagating radial waves at the interfaces between Bragg layers. When these properties are taken into account, we find that it is necessary to introduce a wider ("half-wavelength") layer at a specific radius in the "quarter-wavelength" radial Bragg stack. It is shown that this radius corresponds to the cylindrical equivalent of Brewster's angle. The confinement and field profile are calculated numerically by means of transfer matrix method. PMID- 26125370 TI - Convolution of degrees of coherence. AB - The conditions under which convolution of two degrees of coherence represents a novel legitimate degree of coherence are established for wide-sense statistically stationary Schell-model beam-like optical fields. Several examples are given to illustrate how convolution can be used for generation of a far field being a modulated version of another one. Practically, the convolutions of the degrees of coherence can be achieved by programming the liquid crystal spatial light modulators. PMID- 26125371 TI - Polarization changes in light beams trespassing anisotropic turbulence. AB - The polarization properties of deterministic or random light with isotropic source correlations propagating in anisotropic turbulence along horizontal paths are considered for the first time and predicted to change on the basis of the second-order coherence theory of beam-like fields and the extended Huygens Fresnel integral. Our examples illustrate that the beams whose degree of polarization is unaffected by free-space propagation or isotropic turbulence can either decrease or increase on traversing the anisotropic turbulence, depending on the polarization state of the source. PMID- 26125372 TI - Coherent pseudo-mode decomposition of a new partially coherent source class. AB - We introduce a new class of Schell-model temporal sources that admit a closed form analytical decomposition in terms of coherent pseudo-modes. We explore the source mode and the corresponding eigenvalue structure and demonstrate that the lowest-order mode profile reflects the distribution of the source intensity as a function of time. We also examine the global degree of coherence of the class and show that it is virtually independent of the pulse intensity profile particulars at the source. PMID- 26125373 TI - Duration-tunable picosecond source at 560 nm with watt-level average power. AB - A pulse source at 560 nm that is tunable in duration between 50 ps and 2.7 ns with >1 W of average power and near diffraction-limited beam quality is demonstrated. The source is based on efficient (up to 50%) second-harmonic generation in a periodically poled lithium tantalate crystal of a linearly polarized fiber-integrated Raman amplifier operating at 1120 nm. A duration tunable ytterbium master-oscillator power-fiber amplifier is used to pulse-pump the Raman amplifier, which is seeded by a continuous-wave distributed-feedback laser diode at 1120 nm. The performance of the system using two different master oscillator schemes is compared. A pulse energy of up to 765 nJ is achieved with a conversion efficiency of 25% from the ytterbium fiber pump, demonstrating a compact and turn-key architecture for obtaining high peak-power radiation at 560 nm. PMID- 26125374 TI - Direct detection of super-thermal photon-number statistics in second-harmonic generation. AB - Changes in the statistical properties of light undergoing second-harmonic generation are investigated in the photon-number-resolving domain. We theoretically demonstrate that when a portion of multimode thermal light produced by parametric down-conversion is up-converted, both the second-harmonics and the residual beam at the fundamental wavelength are endowed with super-thermal photon number distributions. The experimental results, which were obtained by exploiting the photo-number-resolving capability of hybrid photodetectors, are in excellent agreement with the theoretical expectations. PMID- 26125375 TI - 2-MUm Ho emitter-based coherent DIAL for CO(2) profiling in the atmosphere. AB - We report on the use of a thulium-fiber-pumped holmium-based emitter in a coherent differential absorption lidar (CDIAL) experiment for high time and space resolution of CO(2) absorption field in the atmosphere. The 2-MUm high-power dual wavelength single-mode Q-switched Ho:YLF oscillator delivers 10-mJ pulses with a duration of 40 ns at 2 kHz. Both short pulse duration and high repetition rate were chosen to increase the DIAL precision and time and space resolution in coherent detection. The CDIAL provides 150-m range and 15-min time-resolved CO(2) absorption coefficient with a calculated instrumental error of 0.5% at 500 m and less than 2% at 1 km. Dry-air CO(2) mixing ratio estimates from the DIAL system are compared with simultaneous in situ gas analyzer measurements during a 20-h long experiment. PMID- 26125376 TI - Integrated heterodyne interferometer with on-chip modulators and detectors. AB - We demonstrate, to our knowledge, the first on-chip heterodyne interferometer fabricated on a 300-mm CMOS compatible process that exhibits root-mean-square (RMS) position noise on the order of 2 nm. Measuring 1 mm by 6 mm, the interferometer is also, to our knowledge, the smallest heterodyne interferometer demonstrated to date and will surely impact numerous interferometric and metrology applications, including displacement measurement, laser Doppler velocimetry and vibrometry, Fourier transform spectroscopy, imaging, and light detection and ranging (LIDAR). Here we present preliminary results that demonstrate the displacement mode. PMID- 26125377 TI - Statistics of a turbulent Raman fiber laser. AB - We report the experimental study of statistical properties of partially coherent waves emitted by a Raman fiber laser operating in the normal dispersion regime. Using an asynchronous optical sampling technique, we accurately measure the probability density function of the optical power of the Stokes wave that exhibits strong and fast fluctuations. As predicted from numerical simulations presented by Randoux et al. [Opt. Lett.36, 790 (2011)], the statistical distributions of the intracavity Stokes power are found to be very different before and after reflection on the cavity Bragg mirrors. In particular, the Stokes wave incident on fiber Bragg grating mirrors exhibits statistics with tails that are much lower than those defined by the normal law. PMID- 26125378 TI - Vacancy-induced transmission in three-dimensional photonic crystal slabs. AB - The transmission spectra of finite-thickness slabs of three-dimensional (3D) diamond-lattice photonic crystals of air spheres in a dielectric background in which various concentrations of randomly located vacancies are present are studied. We find that resonant modes associated with isolated defects couple to form an extended defect band, leading to a significant increase in transmission for frequencies inside the 3D photonic bandgap. Outside the 3D gap, vacancies induce scattering from evanescent to propagating modes, leading to an increase in transmission near the pseudo-gap edges within the gap. The local defect density of states for several concentrations of vacancies is computed; thus, it is shown that the total number of defect states and the range of supported frequencies increase due to increasing vacancy density. PMID- 26125379 TI - Cladding waveguide gratings in standard single-mode fiber for 3D shape sensing. AB - Femtosecond laser pulses were used for the direct point-by-point inscription of waveguides into the cladding of standard single-mode fibers. Homogeneous S-shaped waveguides have been processed as a bundle of overlapping lines without damaging the surrounding material. Within these structures, FBGs have been successfully inscribed and characterized. A sensor device to measure the bending direction of a fiber was created by two perpendicular inscribed cladding waveguides with FBG. Finally, a complete 3D shape sensor consisting of several bending sensor planes, capable of detecting bending radii even below 2.5 cm is demonstrated. PMID- 26125380 TI - Photonic crystal fiber interferometric vector bending sensor. AB - A compact and highly sensitive interferometric bending sensor (inclinometer) capable of distinguishing the bending or inclination orientation is demonstrated. The device operates in reflection mode and consists of a short segment of photonic crystal fiber (PCF) inserted in conventional single-mode optical fiber (SMF). A microscopic collapsed zone in the PCF-SMF junction allows the excitation and recombination of core modes, hence, to build a mode interferometer. Bending on the device induces asymmetric refractive index changes in the PCF core as well as losses. As a result, the effective indices and intensities of the interfering modes are altered, which makes the interference pattern shift and shrink. The asymmetric index changes in the PCF make our device capable of distinguishing the bending orientation. The sensitivity of our sensor is up to 1225 pm/degree and it can be used to monitor small bending angles (+/-2 degrees ). We believe that the attributes of our sensor make it appealing in a number of applications. PMID- 26125381 TI - Regenerative Fourier transformation for dual-quadrature regeneration of multilevel rectangular QAM. AB - We propose a new nonlinear optical loop mirror based configuration capable of regenerating regular rectangular quadrature amplitude modulated (QAM) signals. The scheme achieves suppression of noise distortion on both signal quadratures through the realization of two orthogonal regenerative Fourier transformations. Numerical simulations show the performance of the scheme for high constellation complexities (including 256-QAM formats). PMID- 26125382 TI - Investigations on spatio-spectrally resolved Stokes polarization parameters of oxide-confined vertical-cavity surface-emitting lasers. AB - Recently, we have shown [Opt. Lett.37, 4799 (2012)] that the amount of unpolarized light, quantified by the degree of polarization (DOP), is strongly enhanced by increasing the oxide aperture of vertical-cavity surface-emitting lasers (VCSELs). Here, we reveal the physical mechanism of the DOP reduction when investigating spatio-spectrally resolved Stokes polarization parameters of transverse multi-mode VCSELs. These results uncover a complementary polarization behavior of each particular transverse mode contributing to the total emission, resulting in the observed unpolarized state of light. PMID- 26125383 TI - Mode multiplexer based on integrated horizontal and vertical polymer waveguide couplers. AB - We demonstrate a mode demultiplexer with two cascaded few-mode polymer waveguide directional couplers fabricated on the same substrate along the horizontal and vertical directions, respectively. The three waveguides that form the two couplers have the same core size. The horizontal and vertical couplers are designed to provide complete power transfer for the LP(11a) and LP(11b) modes, with the LP(01) mode staying in the central core that incorporates a biconical taper to suppress any remaining LP(11) modes. A typical fabricated demultiplexer, which is 18.5 mm long, shows a coupling ratio higher than ~96% in the wavelength range of 1530-1570 nm for both couplers. The device shows negligible crosstalk to the LP(01)-mode channel, while the crosstalks to the LP(11)-mode channels are lower than -15.6 and -13.4 dB for the TE and TM polarizations, respectively. The device can be considered polarization insensitive. The propagation losses for the three modes are about 2.0 dB/cm. This device could find applications in mode division-multiplexing systems. PMID- 26125384 TI - Accurate quantification of fluorescent targets within turbid media based on a decoupled fluorescence Monte Carlo model. AB - We propose a method based on a decoupled fluorescence Monte Carlo model for constructing fluorescence Jacobians to enable accurate quantification of fluorescence targets within turbid media. The effectiveness of the proposed method is validated using two cylindrical phantoms enclosing fluorescent targets within homogeneous and heterogeneous background media. The results demonstrate that our method can recover relative concentrations of the fluorescent targets with higher accuracy than the perturbation fluorescence Monte Carlo method. This suggests that our method is suitable for quantitative fluorescence diffuse optical tomography, especially for in vivo imaging of fluorophore targets for diagnosis of different diseases and abnormalities. PMID- 26125385 TI - Tunneling-induced giant Goos-Hanchen shift in quantum wells. AB - Tunneling-induced quantum interference experienced by an incident probe in the asymmetric double AlGaAs/GaAs quantum well (QW) structure can be modulated by means of an external control light beam and the tunable coupling strengths of resonant tunneling. These phenomena can be exploited to devise a novel intracavity medium to control Goos-Hanchen (GH) shifts of a mid-infrared probe beam incident on a cavity. For a suitably designed QW structure, our results show that maximum negative shift of 2.62 mm and positive shift of 0.56 mm are achievable for GH shifts in the reflected and transmitted light. PMID- 26125386 TI - Accurate determination of absolute carrier-envelope phase dependence using photo ionization. AB - The carrier-envelope phase (CEP) dependence of few-cycle above-threshold ionization (ATI) of Xe is calibrated for use as a reference measurement for determining and controlling the absolute CEP in other interactions. This is achieved by referencing the CEP-dependent ATI measurements of Xe to measurements of atomic H, which are in turn referenced to ab initio calculations for atomic H. This allows for the accurate determination of the absolute CEP dependence of Xe ATI, which enables relatively easy determination of the offset between the relative CEP measured and/or controlled by typical devices and the absolute CEP in the interaction. PMID- 26125387 TI - Broadband supercontinuum laser absorption spectrometer for multiparameter gas phase combustion diagnostics. AB - We report on the development and application of a broadband absorption spectrometer utilizing a pulsed supercontinuum laser light source and dispersion compensating fiber with a single-pass absorption path to obtain absolute methane mole fractions in a laminar nonpremixed CH(4)/air flame supported on a Wolfhard Parker burner. The basic principle of supercontinuum broadband absorption spectroscopy (SCLAS) provides advantageous means of combustion diagnostics since the broad spectral coverage allows for use in high-pressure high-temperature environments. Furthermore, a previously validated tunable diode laser absorption spectroscopy fitting algorithm was applied to the recorded spectra and found to be applicable to SCLAS measurements as well, by comparison of fitted methane gas concentrations to reference measurements on the Wolfhard-Parker burner. The spectrometer reached spectral resolutions of up to 0.152 cm(-1), while providing a spectral coverage of over 110 cm(-1), with an absorption path length of only 41 mm. First measurements of absolute CH(4) mole fractions showed the suitability of SCL-based spectroscopy for combustion diagnostics with short absorption path lengths in the nIR spectral region. Here, we achieved in-flame methane mole fraction resolutions of 3%(Vol.) (1210 ppm.m) and optical resolutions of up to 1.1*10(-2). Based on this first validation, this method can now be extended to other species and combustion parameters such as temperature and pressure. PMID- 26125388 TI - Turbulence-induced persistence in laser beam wandering. AB - We have experimentally confirmed the presence of long-memory correlations in the wandering of a thin Gaussian laser beam over a screen after propagating through a turbulent medium. A laboratory-controlled experiment was conducted in which coordinate fluctuations of the laser beam were recorded at a sufficiently high sampling rate for a wide range of turbulent conditions. Horizontal and vertical displacements of the laser beam centroid were subsequently analyzed by implementing detrended fluctuation analysis. This is a very well-known and widely used methodology to unveil memory effects from time series. Results obtained from this experimental analysis allow us to confirm that both coordinates behave as highly persistent signals for strong turbulent intensities. This finding is relevant for a better comprehension and modeling of the turbulence effects in free-space optical communication systems and other applications related to propagation of optical signals in the atmosphere. PMID- 26125389 TI - Statistical generalized phase-shifting digital holography with a continuous fringe-scanning scheme. AB - We propose a novel statistical generalized phase-shifting digital holography using a continuous fringe-scanning scheme. In this method, the continuous fringe scanning scheme is implemented using a PC-based measurement system without any synchronous circuit between the digital camera and the phase shifter. Thus, nonuniformly phase-shifted interference fringes are captured sequentially because of the fluctuation of the image-capturing interval. To cope with the nonuniform phase shifts, we employ a statistical generalized phase-shifting approach. Since the algorithm is designed to use an arbitrary phase shift, the nonuniform phase shifts do not obstruct object wave retrieval. Simulations and experiments demonstrate that the proposed method can be used to implement a practical and accurate digital holography system. PMID- 26125390 TI - Silicon-based on-chip electrically tunable sidewall Bragg grating Fabry-Perot filter. AB - We report the design, fabrication, and testing of a silicon-based on-chip electrically tunable sidewall Bragg grating Fabry-Perot filter. Spectral measurement shows that the filter has a narrow notch in reflection of approximately 46 pm, a Q-factor of 33,500, and an extinction ratio of 16.4 dB. DC measurement shows that the average central wavelength shift rates with forward and reverse bias are -1.15 nm/V and 4.2 pm/V, respectively. Due to strong light confinement in the Fabry-Perot cavity, the electro-optic frequency response shows that the filter has a 3-dB modulation bandwidth of ~5.6 GHz. The performance of using the filter to perform modulation of a 3.5 Gb/s2(7)-1 nonreturn-to-zero pseudorandom binary sequence is evaluated. PMID- 26125391 TI - Optical-phase demodulation using zero-index metamaterials. AB - We theoretically demonstrate that zero-index materials junction with three ports can realize functions of optical interferometer in optical phase demodulator to finish a critical step of phase demodulation. When the junction is made up of epsilon-near-zero (ENZ) materials, performances of the proposed structure get worse due to impedance mismatch, which result in distortion and decrease of final demodulation outputs. To improve performances, three approaches including narrowing the ENZ junction, embedding proper defect, and using anisotropy ENZ junction are proposed. Our work provides an effective way for optical phase demodulation based on zero-index metamaterials. PMID- 26125392 TI - Passive absorption in a classical photonic crystal-based organic solar cell. AB - We study the light trapping efficiency of a bidimensional photonic crystal (PC) integrated in a classical organic multilayer solar cell. The role of the PC is to enhance light absorption in the active layer by leveraging resonant mode excitation. However the light trapping efficiency is drastically inhibited by the overall absorption of the entire multilayer, which includes absorption by the passive layers that do not contribute to the photocurrent. This study focuses on the impact of passive absorption in ITO and PEDOT, which is often neglected in the study of light trapping organic solar cell systems, despite the significant role it plays in highly absorbing devices. Indeed, we show here that the absorption enhancement in the active layer can vary between 23% and 46% depending on the optical properties of the passive layers, which are dependent on fabrication conditions. We also detail how the PC behaves with coupled parameters such as the optical indices of the passive layers, as well as the period and the air filling fraction of the PC. PMID- 26125393 TI - Rapid scanning catheterscope for expanded forward-view volumetric imaging with optical coherence tomography. AB - We demonstrate a novel catheterscope, based on scanning fiber endoscopy, for volumetric imaging with optical coherence tomography (OCT), which possesses a high resonance frequency (>2 kHz) and a small outer diameter (OD) (1.07 mm). Our design is the fastest volumetric-scanning, forward-viewing catheterscope for OCT, and the scanning package has the smallest OD of any such OCT package published to date. Using a proof-of-operation catheterscope with commercial lenses, we demonstrate high-quality in vivo and ex vivo volumetric imaging and extend the 1.1 mm diameter field of view more than 200-fold by mosaicking. Due to its small OD, short rigid tip length, and fast scan rate, this scope is the leading candidate design to enable early detection and staging of bladder cancer during flexible white light cystoscopy. PMID- 26125394 TI - Measurement of absolute optical thickness of mask glass by wavelength-tuning Fourier analysis. AB - Optical thickness is a fundamental characteristic of an optical component. A measurement method combining discrete Fourier-transform (DFT) analysis and a phase-shifting technique gives an appropriate value for the absolute optical thickness of a transparent plate. However, there is a systematic error caused by the nonlinearity of the phase-shifting technique. In this research the absolute optical-thickness distribution of mask blank glass was measured using DFT and wavelength-tuning Fizeau interferometry without using sensitive phase-shifting techniques. The error occurring during the DFT analysis was compensated for by using the unwrapping correlation. The experimental results indicated that the absolute optical thickness of mask glass was measured with an accuracy of 5 nm. PMID- 26125395 TI - Homodyne detection of coherence and phase shift of a quantum dot in a cavity. AB - A homodyne measurement technique is demonstrated that enables direct observation of the coherence and phase of light that passed through a coupled quantum dot (QD)-microcavity system, which in turn enables clear identification of coherent and incoherent QD transitions. As an example, we study the effect of power induced decoherence, where the QD transition saturates and incoherent emission from the excited state dominates at higher power. Further, we show that the same technique allows measurement of the quantum phase shift induced by a single QD in the cavity, which is strongly enhanced by cavity quantum electrodynamics effects. PMID- 26125396 TI - Strong coupling between localized and propagating plasmon polaritons. AB - We investigate plasmon-plasmon (PP) coupling in the strongly interacting regimes by using a tunable plasmonic platform consisting of triangular Ag nanoprisms placed nanometers away from Ag thin films. The nanoprisms are colloidally synthesized using a seed-mediated growth method and having size-tunable localized surface plasmon polariton (SPP) resonances immobilized on Si(3)N(4) films. The PP coupling between the localized SPPs of metal nanoprisms and the propagating SPPs of the metal film is controlled by the nanoprism concentration and the plasmon damping in the metal film. Results reveal that Rabi splitting energy determining the strength of the coupling can reach up to several hundreds meV, thus demonstrating the ultrastrong coupling occurring between localized and propagating SPPs. The metal nanoparticle-metal thin film hybrid system over the square-centimeter areas presented here provides a unique configuration to study PP coupling all the way from the weak to ultrastrong coupling regimes in a broad range of wavelengths. PMID- 26125397 TI - All optical mode controllable Er-doped random fiber laser with distributed Bragg gratings. AB - An all-optical method to control the lasing modes of Er-doped random fiber lasers (RFLs) is proposed and demonstrated. In the RFL, an Er-doped fiber (EDF) recoded with randomly separated fiber Bragg gratings (FBG) is used as the gain medium and randomly distributed reflectors, as well as the controllable element. By combining random feedback of the FBG array and Fresnel feedback of a cleaved fiber end, multi-mode coherent random lasing is obtained with a threshold of 14 mW and power efficiency of 14.4%. Moreover, a laterally-injected control light is used to induce local gain perturbation, providing additional gain for certain random resonance modes. As a result, active mode selection of the RFL is realized by changing locations of the laser cavity that is exposed to the control light. PMID- 26125398 TI - Realization of broadband cross-polarization conversion in transmission mode in the terahertz region using a single-layer metasurface. AB - We present the design specifications and in-depth analysis of a terahertz (THz) broadband cross-polarization converter composed of a single-layer metasurface. This device can convert linearly polarized light into its cross-polarization in transmission mode. Different from other polarization conversion devices, this effect results from the suppression and enhancement for different electric components. The broadband characteristic is also achieved by specific partial symmetries designed in the structure. The proposed polarization converter can aid in the development of novel plasmonic polarization devices, and can help to overcome certain limitations of the customary designs that have been proposed thus far. PMID- 26125399 TI - Frequency analysis of a self-bending point spread function for 3D localization based optical microscopy. AB - We developed several approaches to characterize the recently reported self bending point spread function for 3D localization-based light microscopy. Experimentally, we generated Gaussian, astigmatic, and self-bending point spread functions. We compared the optical transfer functions, ambiguity functions, and Fisher information of these point spread functions. Our comprehensive frequency domain analysis describes quantitative tools for the development of engineered point spread functions for 3D imaging systems. PMID- 26125400 TI - Generation of Airy vortex and Airy vector beams based on the modulation of dynamic and geometric phases. AB - We propose a novel method for the generation of Airy vortex and Airy vector beams based on the modulation of dynamic and geometric phases. In our scheme, the Airy beam is generated by the dynamic phase with a spatial light modulator, and the vortex phase or the vector polarization is modulated by the geometric phase with a dielectric metasurface. The modulation of the geometric phase provides an extra degree of freedom to manipulate the phase and the polarization of Airy beams. This scheme can be extended to generate any other types of optical beams with desirable phase and polarization. PMID- 26125401 TI - Trapping waves with terahertz metamaterial absorber based on isotropic Mie resonators. AB - Quasi-monodisperse dielectric particles organized in a periodic hexagonal network on an aluminum surface are exploited numerically and experimentally as a single layered near-perfect absorber in the terahertz regime. Of particular interest are titanium dioxide (TiO(2)) microspheres because of their large dielectric permittivity and isotropic shape leading to Mie resonances with insensitive polarization. Absorption higher than 80% at normal incidence covering two distinct ranges of frequencies is demonstrated experimentally. Furthermore, the performance of the metamaterial absorber is kept over a wide range of incident angles. PMID- 26125402 TI - Multi-view second-harmonic generation imaging of mouse tail tendon via reflective micro-prisms. AB - Here we experimentally show that second-harmonic generation (SHG) imaging is not sensitive to collagen fibers oriented parallel to the direction of laser propagation and, as a consequence, can potentially miss important structural information. As an alternative approach, we demonstrate the use of reflective micro-prisms to enable multi-view SHG imaging of mouse tail tendon by redirecting the focused excitation and collection of subsequent emission. Our approach data corroborates the theoretical treatment on vanishing and nonvanishing orientations, where fibers along the laser direction are largely transparent by SHG. In strong contrast, the two-photon excited fluorescence of dye-labeled collagen fibers is isotropic and is not subject to this constraint. We utilized Pearson correlation to quantify differences in fluorescent and backward detected SHG images of the tendon fiber structure, where the SHG and TPEF were highly statistically correlated (0.6-0.8) for perpendicular excitation but were uncorrelated for excitation parallel to the fiber axis. The results suggest that improved imaging of 3D collagen structure is possible with multi-view SHG microscopy. PMID- 26125403 TI - Fourier transform holography with high harmonic spectra for attosecond imaging applications. AB - We demonstrate a method of using a Fourier holographic technique to utilize attosecond soft x-ray pulses to image nanometer-scale objects. A discrete frequency comb of laser-generated high-order harmonics, yielding a train of attosecond pulses, has been used to record spatially and spectrally resolved images. The individual wavelengths were also combined to form a single image, albeit with lower spatial resolution, demonstrating the applicability of the method to using isolated attosecond pulses with continuous bandwidths. PMID- 26125404 TI - Electroluminescence of GeSn/Ge MQW LEDs on Si substrate. AB - Multi-quantum well light-emitting diodes, consisting of ten alternating GeSn/Ge layers, were grown by molecular beam epitaxy on Si. The Ge barriers were 10 nm thick, and the GeSn wells were grown with 7% Sn and thicknesses between 6 and 12 nm. The electroluminescence spectra measured at 300 and 80 K yield a broad and intensive luminescence band. Deconvolution revealed three major lines produced by the GeSn wells that can be interpreted in terms of quantum confinement. We interpret that the three lines represent two direct lines, formed by transitions with the light and heavy hole band, respectively, and an indirect line. Biaxial compressive strain causes a splitting of light and heavy holes in the GeSn wells. This interpretation is supported by an effective mass band structure calculation. PMID- 26125405 TI - Energy enhancement of mixed Nd:LuYSGG crystal in passively Q-switched lasers. AB - The continuous-wave (cw) and passively Q-switched laser performances of mixed Nd:Lu(2)YSc(1.5)Ga(3.5)O(12) (Nd:LuYSGG) crystal at 1.06 MUm were reported for the first time. The cw output power reached 4.39 W at the absorbed pump power of 10.34 W with slope efficiency of 48.0%. With a Cr(4+):YAG crystal as both the saturable absorber and output coupler, a passively Q-switched laser was realized with the maximum average output power of 1.43 W and slope efficiency of 21.0%. The shortest pulse width, largest pulse energy, and highest peak power were 4.1 ns, 157.1 MUJ, and 38.3 kW, respectively. Compared with Nd:Lu(3)Sc(1.5)Ga(3.5)O(12) (Nd:LuSGG) crystal, the pulse energy and peak power are enhanced over more than two times for Nd:LuYSGG. The results show that Nd:LuYSGG crystal is a promising laser material with large energy storage capacities and suitable for the application of pulsed lasers with shorter pulses and larger energies. PMID- 26125406 TI - Miniature spectrometer based on diffraction in a dispersive hole array. AB - We present an ultra-compact spectrometer that uses a 10*10 hole array as the dispersive component. Our analysis shows that the two-dimensional intensity distribution can be modeled by a system of simultaneous linear equations when the size of each hole in the dispersive component has been pre-designed appropriately. One can readily recover the spectral contents of the input radiation by solving the linear equation system with regularized procedure. Experimental results show that the reconstruction range is at least within the entire visible band, which can be further extended if a near-infrared CCD is used. One therefore envisions strong potential for many wavelength analysis applications. PMID- 26125407 TI - Nocardia Colonization: A Risk Factor for Lung Deterioration in Cystic Fibrosis Patients? AB - BACKGROUND: Cystic fibrosis (CF) patients are predisposed to infection and colonization with different microbes. Some cause deterioration of lung functions, while others are colonizers without clear pathogenic effects. Our aim was to understand the effects of Nocardia species in sputum cultures on the course of lung disease in CF patients. MATERIAL AND METHODS: A retrospective study analyzing the impact of positive Nocardia spp. in sputum of 19 CF patients over a period of 10 years, comparing them with similar status patients without Nocardia growth. Pulmonary function tests (PFTs) are used as indicators of lung disease severity and decline rate in functions per year is calculated. RESULTS: No significant difference in PFTs of CF patients with positive Nocardia in sputum was found in different sub-groups according to number of episodes of growth, background variables, or treatment plans. The yearly decline in PFTs was similar to that recognized in CF patients. The control group patients showed similar background data. However, a small difference was found in the rate of decline of their PFTs, which implies a possibly slower rate of progression of lung disease. CONCLUSIONS: The prognosis of lung disease in CF patients colonized with Nocardia does not seem to differ based on the persistence of growth on cultures, different treatment plans or risk factors. Apparently, Nocardia does not cause a deterioration of lung functions with time. However, it may show a trend to faster decline in PFTs compared to similar status CF patients without isolation of this microorganism in their sputum. PMID- 26125408 TI - Is long range transport of pollen in the NW Mediterranean basin influenced by Northern Hemisphere teleconnection patterns? AB - Climatic oscillations triggered by the atmospheric modes of the Northern Hemisphere teleconnection patterns have an important influence on the atmospheric circulation at synoptic scale in Western Mediterranean Basin. Simultaneously, this climate variability could affect a variety of ecological processes. This work provides a first assessment of the effect of North Atlantic Oscillation (NAO), Arctic Oscillation (AO) and Western Mediterranean Oscillation (WeMO) on the atmospheric long-range pollen transport episodes in the North-Eastern Iberian Peninsula for the period 1994-2011. Alnus, Ambrosia, Betula, Corylus and Fagus have been selected as allergenic pollen taxa with potential long-range transport associated to the Northern Hemisphere teleconnection patterns in the Western Mediterranean Basin. The results showed an increase of long range pollen transport episodes of: (1) Alnus, Corylus and Fagus from Western and Central Europe during the negative phase of annual NAO and AO; (2) Ambrosia, Betula and Fagus from Europe during the negative phase of winter WeMO; (3) Corylus and Fagus from Mediterranean area during the positive phase of the annual AO; and (4) Ambrosia from France and Northern Europe during the positive phase of winter WeMO. Conversely, the positive phase of annual NAO and AO are linked with the regional transport of Alnus, Betula and Corylus from Western Iberian Peninsula. The positive phase of annual WeMO was also positively correlated with regional transport of Corylus from this area. PMID- 26125409 TI - Density of river otters (Lontra canadensis) in relation to energy development in the Green River Basin, Wyoming. AB - Exploration and extraction of oil and natural gas have increased in recent years and are expected to expand in the future. Reduction in water quality from energy extraction may negatively affect water supply for agriculture and urban use within catchments as well as down river. We used non-invasive genetic techniques and capture-recapture modeling to estimate the abundance and density of North American river otters (Lontra canadensis), a sentinel species of aquatic ecosystems, in Southwestern Wyoming. While densities in two of three river reaches were similar to those reported in other freshwater systems in the western US (1.45-2.39 km per otter), otters appeared to avoid areas near energy development. We found no strong difference in habitat variables, such as overstory cover, at the site or reach level. Also, fish abundance was similar among the three river reaches. Otter activity in our study area could have been affected by elevated levels of disturbance surrounding the industrial gas fields, and by potential surface water contamination as indicated by patterns in water conductivity. Continued monitoring of surface water quality in Southwestern Wyoming with the aid of continuously recording devices and sentinel species is warranted. PMID- 26125410 TI - Layer-preferential substitutions and magnetic properties of pyrrhotite-type Fe7 yMyX8 chalcogenides (X = S, Se; M = Ti, Co). AB - A comparative study of four series of pyrrhotite-type chalcogenide compounds Fe(7 y)M(y)X(8) (X = S, Se) with substitution of Ti or Co for iron has been performed by means of x-ray and neutron powder diffraction, and by magnetization measurements. In Fe(7-y)M(y)X(8) compounds having a ferrimagnetic order at y = 0, the substitution of either Ti or Co for iron is observed to result in a monotonous decrease of the magnetic ordering temperature, while the resultant magnetization shows a non-monotonous behavior with a minimum around y = 1.0-1.5 in all the Fe(7-y)M(y)X(8) families except Fe(7-y)Co(y)Se(8). Suppression of a magnetically ordered state with substitutions in Fe(7-y)M(y)X(8) is ascribed to nearly zero values of Ti and Co magnetic moments, while the non-monotonous changes of the resultant magnetization are explained by the compensation of the sublattice magnetizations due to the non-random substitutions in alternating metallic layers. The difference in the cation partitioning observed in Fe(7 y)Ti(y)X(8) and Fe(7-y)Co(y)X(8) is attributed to the difference in the spatial extension of Ti and Co 3d orbitals. High coercive field values (20-24 kOe) observed at low temperatures in the Ti-containing compounds Fe(7-y)Ti(y)X(8) with y ? 3 are suggested to result from the enhancement of Fe orbital moment due to the Ti for Fe substitution. PMID- 26125411 TI - Hepcidin-ferroportin axis controls toll-like receptor 4 dependent macrophage inflammatory responses in human atherosclerotic plaques. AB - OBJECTIVES: Toll-like Receptor 4 (TLR4) is implicated in modulating inflammatory cytokines though its role in atherosclerosis remains uncertain. We have recently described a non-foam cell macrophage phenotype driven by ingestion of hemoglobin:haptoglobin complexes (HH), via the scavenger receptor CD163, characterized by reduced inflammatory cytokine production. In this study, we examined the role of iron metabolism in modulating TLR4 signaling in these cells. METHODS AND RESULTS: Areas in human atherosclerotic plaque with non-foam cell, CD163 positive macrophages demonstrated reduced expression of tumor necrosis factor alpha (TNF-alpha) and interferon-beta (INF-beta) compared to foam cells. Human macrophages differentiated in hemoglobin:haptoglobin (HH) complexes expressed the CD163 positive non-foam cell phenotype and demonstrated significantly less TNF-alpha and INF-beta compared to control macrophages when exposed to oxidized LDL (oxLDL) or lipopolysaccharide (LPS). LPS stimulated expression of TNF-alpha and INF-beta could be restored in HH macrophages by pretreatment with hepcidin, an endogenous suppressor of ferroportin1 (FPN), or by genetic suppression of FPN in macrophages derived from myeloid specific FPN knockout mice. LPS stimulated control macrophages demonstrated increase in TLR4 trafficking to lipid rafts; this response was suppressed in HH macrophages but was restored upon pretreatment with hepcidin. Using a pharmacologic hepcidin suppressor, we observed a decrease in cytokine expression and TLR4-lipid raft trafficking in LPS-stimulated in a murine macrophage model. CONCLUSION: TLR4 dependent macrophage signaling is controlled via hepcidin-ferroportin1 axis by influencing TLR4-lipid raft interactions. Pharmacologic manipulation of iron metabolism may represent a promising approach to limiting TLR4-mediated inflammatory responses. PMID- 26125412 TI - Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events. AB - AIMS: The small leucine-rich proteoglycans fibromodulin and lumican are functionally related extracellular matrix proteins involved in the regulation of collagen fiber formation. Fibromodulin-deficient apolipoprotein E-null mice have decreased vascular retention of lipids and reduced development of atherosclerosis suggesting that fibromodulin may influence the disease process. The aim of the present study was to investigate if fibromodulin and lumican are expressed in human carotid plaques and to determine if their expression is associated with the occurrence of preoperative symptoms and with risk for postoperative cardiovascular events. METHODS AND RESULTS: 153 plaques (51% symptomatic) obtained by carotid endarterectomy were included in this study. Plaque content was analyzed by immunohistochemistry and plaque cytokine content by multiplex technology. Fibromodulin and lumican were widely expressed in plaques and fibromodulin expression was significantly higher in symptomatic plaques. Expression of fibromodulin was significantly higher in plaques obtained from patients with diabetes and a high fibromodulin expression was associated with a higher incidence of post-operative cerebrovascular events, whereas no such associations were seen for lumican. Fibromodulin expression also correlated with plaque lipids and several pro-inflammatory cytokines. In addition, fibromodulin expression correlated with low levels of smooth muscle cells and the anti inflammatory cytokine IL-10. CONCLUSIONS: These observations support previous experimental findings in mice for a role of fibromodulin in atherosclerosis and provide clinical evidence of the involvement of fibromodulin in the inflammatory processes that characterize atherosclerotic plaque vulnerability. They also suggest that this is of particular importance in diabetes. PMID- 26125413 TI - Apolipoprotein A-I mimetic peptide reverses impaired arterial healing after injury by reducing oxidative stress. AB - OBJECTIVE: Endothelial cell (EC) migration is essential for healing of arterial injuries caused by angioplasty, but a high cholesterol diet inhibits endothelial repair. In vivo studies suggest that apolipoprotein A-I (apoA-I), the major protein constituent of HDL, is essential for normal healing of arterial injuries. ApoA-I mimetics, including 4F, have been designed to mimic the amphipathic portion of the apoA-I molecule. This study was undertaken to determine if 4F improves endothelial migration and healing. METHODS: A razor scrape assay was used to analyze the effect of 4F on EC migration in vitro. Endothelial healing in vivo was assessed following electrical injury of carotid arteries in mice. Markers of oxidative stress were also examined. RESULTS: Lipid oxidation products inhibited EC migration in vitro, but preincubation with L-4F preserved EC migration. Endothelial healing of carotid arterial injuries in mice on a high cholesterol diet was delayed compared with mice on a chow diet with 27.8% vs. 48.2% healing, respectively, at 5 days. Administration of D-4F improved endothelial healing in mice on a high cholesterol diet to 43.4%. D-4F administration had no effect on lipid levels but decreased markers of oxidation. In vivo, there was a significant inverse correlation between endothelial healing and plasma markers of oxidative stress. CONCLUSION: These studies suggested that an apoA-I mimetic can improve endothelial healing of arterial injuries by decreasing oxidative stress. PMID- 26125414 TI - Aflatoxin M1 in processed milk and infant formulae and corresponding exposure of adult population in Serbia in 2013-2014. AB - Aflatoxin M1 (AFM1) occurrence was analysed in 80 samples of milk and 21 samples of infant formulae on the Serbian market, using high-performance liquid chromatography with fluorescence detection. All milk samples collected in 2013 showed AFM1 contamination in the range 0.02-0.32 MUg kg(-1), with a mean level of 0.13 MUg kg(-1). The EU maximum level for AFM1 in milk (0.05 MUg kg(-1)) was exceeded in 75% of the samples. In 2014, AFM1 was found in 83%, 70%, 80% and 58% of the samples collected in April, July, September and December, respectively, exceeding the limit in 5% of the samples taken in July. The additional number of liver cancer cases per year associated with exposure to AFM1 was estimated to be 0.004 in the adult population. Regarding infant formulae, AFM1 was found in only one sample. PMID- 26125415 TI - A randomized trial of mobile health support for heart failure patients and their informal caregivers: impacts on caregiver-reported outcomes. AB - BACKGROUND: Mobile health services may improve chronic illness care, but interventions rarely support informal caregivers' efforts. OBJECTIVES: To determine whether automated feedback to caregivers of chronic heart failure patients impacts caregiving burden and assistance with self-management. RESEARCH DESIGN: Randomized comparative effectiveness trial. SUBJECTS: A total of 369 heart failure patients were recruited from a Veterans Health Administration health care system. All patients participated with a "CarePartner" or informal caregiver outside their household. INTERVENTION: Patients randomized to "standard mHealth" received weekly automated self-care support calls for 12 months with notifications about problems sent to clinicians. "mobile health+CarePartner" (mHealth+CP) patients received identical services, plus email summaries and suggestions for self-care assistance automatically sent to their CarePartners. MEASURES: At baseline, 6, and 12 months, CarePartners completed assessments of caregiving strain, depressive symptoms, and participation in self-care support. RESULTS: mHealth+CP CarePartners reported less caregiving strain than controls at both 6 and 12 months (both P<=0.03). That effect as well as improvements in depressive symptoms were seen primarily among CarePartners reporting greater burden at baseline (P<=0.03 for interactions between arm and baseline strain/depression at both endpoints). Although most mHealth+CP CarePartners increased the amount of time spent in self-care support, those with the highest time commitment at baseline reported decreases at both follow-ups (all P<0.05). mHealth+CP CarePartners reported more frequently attending patients' medical visits at 6 months (P=0.049) and greater involvement in medication adherence at both endpoints (both P<=0.032). CONCLUSIONS: When CarePartners experienced significant caregiving strain and depression, systematic feedback about their patient-partner decreased those symptoms. Feedback also increased most CarePartners' engagement in self-care. PMID- 26125416 TI - Hospital comparisons based on mortality: revisiting the choice of postadmission timeframe and evaluating the contribution of cause-of-death data, France, 2009. AB - BACKGROUND: In-hospital mortality is widely used to judge the quality of hospital care, but is biased by discharge patterns. Fixed-timeframe indicators have thus been recommended. However, the 30-day postadmission indicator may underestimate hospital-wide mortality, as patients dying in hospital >30 days after admission are considered as survivors. OBJECTIVES: To identify the most relevant timeframes and to assess the contribution of cause-of-death data. METHODS: The 2009 French hospital discharge database was linked to vital status records and to the causes of death register for 11.5 million hospital stays by beneficiaries of French general health insurance. Correlations and agreements between the 30-day hospital standardized mortality ratio (HSMR) and the in-hospital, 60-, 90-, 180-, and 365 day postadmission HSMRs were estimated. RESULTS: A total of 7.8%, 1.5%, and 0.5% of patients who died during their hospital stay were considered as survivors by the 30-, 60-, and 90-day HSMRs, respectively. The 30-day HSMR correlated strongly with the 60-day HSMR (Pearson coefficient=0.92), and their agreement on outlier status was excellent (kappa coefficient=0.80). The association remained substantial at 90 days, but weakened at 180 days and even more so at 365 days. Regardless of the timeframe, exclusion of deaths likely due to independent causes barely modified the indicators. CONCLUSIONS: This nationwide study shows that 60- and 90-day HSMRs encompass in-hospital deaths better than the 30-day HSMR, while capturing the same interhospital variations. They should thus be preferred. The contribution of cause-of-death data to hospital-wide indicators seems negligible. PMID- 26125417 TI - First trimester initiation of prenatal care in the US-Mexico border region. AB - OBJECTIVES: To systematically examine prevalence of first trimester prenatal care (FTPNC) in the 44 US counties and 80 Mexican municipios of the binational border region; and to describe disparities between border and nonborder areas within states, border states, and countries. METHODS: We combined 2009 records of singleton live births from the 10 US-Mexico border states (N=1,370,206) into a single file. We included FTPNC; county/municipio, state, and country of maternal residence; and demographic variables common to all records. We computed prevalence of FTPNC for border and nonborder residents by state and country. Using multivariable regression, we computed adjusted prevalence ratios (aPR) for FTPNC in border relative to nonborder residents, states relative to one another, and the US relative to Mexico. RESULTS: In 2009, 68.8% of US-Mexico border mothers and 72.9% of nonborder mothers received FTPNC. After adjustment, nonborder residents had higher prevalence of FTPNC than border residents in Sonora, New Mexico, Arizona, Coahuila, and Chihuahua (aPR=1.09-124). In US states, prevalence was 13%-36% higher in New Mexico, Arizona, and California than Texas. In Mexico, when compared with Coahuila, adjusted prevalence was 12%-20% higher in neighboring states. Between countries, FTPNC prevalence in border counties/municipios was higher in Mexico among women with low parity/low education and in the United States among women with high parity/high education. CONCLUSIONS: In the US and Mexico, women in border counties/municipios receive less timely prenatal care than their nonborder counterparts, but the magnitude of the disparity varies by state. Lack of a consistent, binational approach to birth data collection requires cautious interpretation of findings. PMID- 26125418 TI - Does mandating nursing home participation in quality reporting make a difference? Evidence from Massachusetts. AB - BACKGROUND: Quality report cards have been shown to be effective in influencing patients' referrals and promoting quality improvement in some instances and not others. In this study, we investigate one of the mechanisms that may detract from their effectiveness: voluntary versus mandatory participation of nursing homes in public quality reporting. OBJECTIVES: To answer 2 questions: (1) Were the nursing homes choosing not to participate low-quality performers relative to those who chose to participate? (2) Once participation became mandatory, did those that did not voluntarily participate initially, improve more than those that participated voluntarily? RESEARCH DESIGN: Massachusetts published the Massachusetts Satisfaction Survey report card for nursing homes for the years 2005, 2007, and 2009. Nursing homes' participation was voluntary in 2005 and mandatory in 2007 and 2009. We performed a retrospective statistical analysis of the relationship between nursing homes' decision to participate in quality reporting and 12 quality outcomes: deficiency citations, staffing, and 8 survey domains. SUBJECTS: A total of 424 Massachusetts nursing homes. RESULTS: Sixty-seven percent of nursing homes participated in reporting voluntarily. Volunteer nursing homes had better quality for all measures (significant at the 0.05 level or trending toward significance at the 0.10 level for all but 2). Once reporting became mandatory, nonvolunteers improved more than volunteers in all but 2 staffing measures (trending toward significance at the 0.10 level in 5). CONCLUSIONS: Report cards are more effective if nursing homes' participation is mandated. Nonmandatory reporting systems, as those implemented by some states and professional associations, lead to missed opportunities for quality improvements. PMID- 26125419 TI - Racial differences in false-positive mammogram rates: results from the ACRIN Digital Mammographic Imaging Screening Trial (DMIST). AB - BACKGROUND: Mammography screening reduces breast cancer mortality, but false positive tests are common. Few studies have assessed racial differences in false positive rates. OBJECTIVES: We compared false-positive mammography rates for black and white women, and the effect of patient and facility characteristics on false positives. RESEARCH DESIGN AND SUBJECTS: A prospective cohort study. From a sample of the American College of Radiology Imaging Network (ACRIN) Digital Mammographic Imaging Screening Trial (DMIST), we identified black/African American (N=3176) or white (N=26,446) women with no prior breast surgery or breast cancer. MEASURES: Race, demographics, and breast cancer risk factors were self-reported. Results of initial digital and film mammograms were assessed. False positives were defined as a positive mammogram (Breast Imaging Reporting and Data System category 0, 4, 5) with no cancer diagnosis within 15 months. RESULTS: The false-positive rate for digital mammograms was 9.2% for black women compared with 7.8% for white women (P=0.009). After adjusting for age, black women had 17% increased odds of false-positive digital mammogram compared with whites (OR=1.17; 95% CI, 1.01-1.35; P=0.033). This association was attenuated after adjusting for patient factors, prior films, and study site (OR=1.04; 95% CI, 0.91-1.20; P=0.561). There was no difference in the occurrence of false positives by race for film mammography. CONCLUSIONS: Black women had higher frequency of false-positive digital mammograms explained by lack of prior films and study site.The variation in the disparity between the established technique (film) and the new technology (digital) raises the possibility that racial differences in screening quality may be greatest for new technologies. PMID- 26125420 TI - Sentinel Node Biopsy After Neoadjuvant Chemotherapy: Prechemotherapy Nodal Status Is Crucial for Test Performance. PMID- 26125421 TI - In Reply. PMID- 26125422 TI - In Reply. PMID- 26125423 TI - Ongoing Marrow Adequacy Issue. PMID- 26125424 TI - Smart Phones and Microscopic Image Capturing: Searching, Finding, Capturing, Talking About, as Well as Sharing Microscopic Images of Pathologic Conditions Form Another Type of Learning Module. PMID- 26125425 TI - Difficult Diagnostic Problems in Pancreatobiliary Neoplasia. AB - CONTEXT: Many common diagnostic dilemmas are encountered in pancreatobiliary pathology, frequently resulting in uncertainty on behalf of the pathologist and referral for a second opinion. OBJECTIVES: To review 4 common diagnostic dilemmas encountered in the practice of pancreatobiliary pathology: (1) pancreatic ductal adenocarcinoma versus chronic pancreatitis; (2) pancreatic ductal carcinoma versus adenocarcinomas arising in the ampulla and intrapancreatic common bile duct; (3) the distinction of uncommon intraductal neoplasms--intraductal oncocytic papillary neoplasm, intraductal tubulopapillary neoplasm, and intraductal acinar cell carcinoma; and (4) intrahepatic cholangiocarcinoma versus metastatic carcinoma. DATA SOURCES: A review of pertinent literature, along with the authors' personal experience, based on institutional and consultation materials. CONCLUSIONS: Important diagnostic features for a few challenging problems in pancreatobiliary pathology are reviewed. Careful study of the microscopic features along with awareness of differential diagnoses and diagnostic pitfalls generally allows distinction of these entities. We also highlight established and novel ancillary studies that help to arrive at an accurate diagnosis. PMID- 26125426 TI - Pathophysiology and Diseases of the Proximal Pathways of the Biliary System. AB - CONTEXT: Diseases of the proximal pathways of the biliary system can be divided into those that affect the interlobular bile ducts and those that affect the bile canaliculi. The former include primary biliary cirrhosis, small-duct variant of primary sclerosing cholangitis, graft-versus-host disease, and drug-induced liver injury, whereas the latter include progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis, intrahepatic cholestasis of pregnancy, and drug-induced liver injury. OBJECTIVE: To summarize the current state of knowledge of diseases of the proximal pathways of the biliary system, with special emphasis on clinical presentation, pathological features, and differential diagnosis. DATA SOURCES: Clinicopathological information was extracted from pertinent published literature. CONCLUSIONS: Care of the patient with cholestasis hinges on identifying the etiology. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging, distinct serological studies, and liver biopsy. Primary biliary cirrhosis is characterized by distinctive serological and histological findings. The small duct variant of primary sclerosing cholangitis is very rare and difficult to diagnose; imaging of the bile ducts is not helpful. Graft-versus-host disease is characterized by damage and loss of intrahepatic bile ducts. Drugs can cause injury variably at the level of bile canaliculus or the interlobular bile duct. Loss of bile ducts may be seen with primary biliary cirrhosis, primary sclerosing cholangitis, graft-versus-host disease, and drug-induced liver injury. Progressive familial intrahepatic cholestasis and progressive familial intrahepatic cholestasis represent 2 extreme ends of the spectrum of abnormalities in transporters responsible for bile formation. Intrahepatic cholestasis of pregnancy has a variable incidence in different parts of the world and may be due to abnormalities in transporter molecules. PMID- 26125427 TI - Hepatic Granulomas: A Review With Emphasis on Infectious Causes. AB - CONTEXT: Many diseases that cause granulomas or granulomatous inflammation involve the liver. Some of these disease processes are intrinsic hepatic diseases, whereas others are disseminated systemic diseases that involve the liver as well as other organs. OBJECTIVE: To review the evaluation of granulomas in the liver with an emphasis on infectious causes, as well as the use of special stains, serologic studies, and molecular diagnostic techniques. Pertinent noninfectious causes of hepatic granulomas that are in the differential diagnosis are also discussed. DATA SOURCES: Literature review and cases acquired during years of practice. CONCLUSIONS: A wide variety of infectious and noninfectious entities cause hepatic granulomas. PMID- 26125428 TI - Drug-Induced Liver Injury. AB - CONTEXT: Drug-induced liver injury (DILI) represents a diverse set of responses following exposure to any manufactured or naturally occurring chemical compound. Drug-induced liver injury is of major concern owing to the ever increasing number of compounds introduced into the market for treatment of various diseases as well as the increasing popularity of herbals, which lend themselves to self-medication but are not rigorously regulated. OBJECTIVE: To provide an overview of the prevalence, classification, and diagnosis of DILI with emphasis on pathogenesis and the role of a liver biopsy. To focus on the most common, emerging, and herbal agents that cause DILI with emphasis on the histologic pattern of injury observed. DATA SOURCES: A review of the literature was drawn from the PubMed (US National Library of Medicine) repository, textbooks, and online databases. All figures were taken from cases seen at our tertiary referral center, which is 1 of 12 participating sites in the National Institutes of Health-funded Drug-Induced Liver Injury Network. CONCLUSIONS: Drug-induced liver injury due to prescription, over-the-counter, and herbal products is a major cause of liver disease in the United States and around the world. Diagnosis of DILI is challenging because there is no single clinical, laboratory, or histologic feature specific to DILI. Accurate diagnosis requires establishing a causal relationship with the suspected agent and excluding competing causes of liver injury. The liver biopsy is an essential component in the management of DILI by offering clues to the underlying pathogenesis, providing prognostic information, and guiding therapy. PMID- 26125429 TI - Design of a Genomics Curriculum: Competencies for Practicing Pathologists. AB - CONTEXT: The field of genomics is rapidly impacting medical care across specialties. To help guide test utilization and interpretation, pathologists must be knowledgeable about genomic techniques and their clinical utility. The technology allowing timely generation of genomic data is relatively new to patient care and the clinical laboratory, and therefore, many currently practicing pathologists have been trained without any molecular or genomics exposure. Furthermore, the exposure that current and recent trainees receive in this field remains inconsistent. OBJECTIVE: To assess pathologists' learning needs in genomics and to develop a curriculum to address these educational needs. DESIGN: A working group formed by the College of American Pathologists developed an initial list of genomics competencies (knowledge and skills statements) that a practicing pathologist needs to be successful. Experts in genomics were then surveyed to rate the importance of each competency. These data were used to create a final list of prioritized competencies. A subset of the working group defined subtopics and tasks for each competency. Appropriate delivery methods for the educational material were also proposed. RESULTS: A final list of 32 genomics competency statements was developed. A prioritized curriculum was created with designated subtopics and tasks associated with each competency. CONCLUSIONS: We present a genomics curriculum designed as a first step toward providing practicing pathologists with the competencies needed to practice successfully. PMID- 26125430 TI - Clinical Laboratory Quality Practices When Hemolysis Occurs. AB - CONTEXT: Hemolyzed specimens delay clinical laboratory results, proliferate unnecessary testing, complicate physician decisions, injure patients indirectly, and increase health care costs. OBJECTIVE: To determine quality improvement practices when hemolysis occurs. DESIGN: We used the College of American Pathologists (CAP) Survey Program to distribute a Q-Probes-type questionnaire about hemolysis practices to CAP Chemistry Survey participants. RESULTS: Of 3495 participants sent the questionnaire, 846 (24%) responded. Although 85%, 69%, and 55% of participants had written hemolysis policies for potassium, lactate dehydrogenase, and glucose, respectively, only a few (46%, 40%, and 40%) had standardized hemolysis reports between their primary and secondary chemistry analyzers for these 3 analytes. Most participants (70%) had not attempted to validate the manufacturers' hemolysis data for these 3 analytes; however, essentially all who tried, succeeded. Forty-nine percent of participants had taken corrective action to reduce hemolysis during the past year and used, on average, 2.4 different actions, with collection and distribution of hemolysis data to administrative leadership (57%), troubleshooting outliers (55%), retraining phlebotomist (53%), and establishment of quality improvement teams among the laboratory and at problem locations (37%) being the most common actions. When asked to assess their progress in reducing hemolysis, 70% noted slow to no progress, and 2% gave up on improvement. Upon measuring potassium, lactate dehydrogenase, and glucose, approximately 60% of participants used the same specimen flag for hemolysis as for lipemia and icterus. CONCLUSIONS: Hemolysis decreases the quality and increases the cost of health care. Practices for measuring, reporting, and decreasing hemolysis rates need improvement. PMID- 26125431 TI - Routine Clinical Mutation Profiling of Non-Small Cell Lung Cancer Using Next Generation Sequencing. AB - CONTEXT: The availability of massive, parallel-sequencing technologies makes possible efficient, simultaneous detection of driver and druggable mutations in cancer. OBJECTIVE: To develop an amplicon-based, next-generation sequencing, mutation-detection assay for lung cancer using the 454 GS Junior (Roche Applied Science, Indianapolis, Indiana) platform. DESIGN: Fusion primers incorporating target sequence, 454 adaptors, and multiplex identifiers were designed to generate 35 amplicons (median length 246 base pairs) covering 8.9 kilobases of mutational hotspots in AKT1, BRAF, EGFR, ERBB2, HRAS, KRAS, NRAS, PIK3CA, and MAP2K1 genes and all exons of the PTEN gene. RESULTS: The assay was validated on 23 formalin-fixed, paraffin-embedded lung cancer specimens. A minimum number of reads was consistently achieved with overall median read depth of 529* per amplicon. In total, 25 point mutations and 4 insertions/deletions (indels) with a frequency of 5.5% to 93.1% mutant alleles were detected. All EGFR, ERBB2, KRAS, PIK3CA, KRAS, and PTEN mutations, as detected by next-generation sequencing, were confirmed by pyrosequencing, with the exception of 3 point mutations in a tumor sample with low mutant-allele burden (below the pyrosequencing limit of detection). CONCLUSIONS: The GS Junior-based, targeted, resequencing assay for a focused set of non-small cell lung cancer driver genes allows for quick and sensitive detection of point mutations and indels for the most relevant therapeutic genes in this type of cancer. PMID- 26125432 TI - Evaluation of HER2/neu Status by Immunohistochemistry Using Computer-Based Image Analysis and Correlation With Gene Amplification by Fluorescence In Situ Hybridization Assay: A 10-Year Experience and Impact of Test Standardization on Concordance Rate. AB - CONTEXT: The American Society of Clinical Oncology/College of American Pathologists proposed several recommendations for human epidermal growth factor receptor 2 (HER2) test standardization. One suggestion was that image analysis (IA) could be useful for scoring of HER2/neu immunohistochemistry. The utilization of IA in a real-world practice in a large cohort of cases has not been previously reported. OBJECTIVES: To compare HER2/neu quantification by IA with gene amplification by fluorescence in situ hybridization (FISH); to determine sensitivity, specificity, and concordance rates with the FISH assay; and to determine association between HER2 status with estrogen receptor (ER), progesterone receptor (PR), and Ki-67 expression. DESIGN: We evaluated HER2 results performed by immunohistochemistry and FISH in conjunction with ER, PR, and Ki-67 in 3093 invasive breast cancer cases from 2002 to 2011. RESULTS: The overall concordance between immunohistochemistry and FISH was 87.3% (1768 of 2026). When analyzed by year, there was an improvement in the positive concordance rate from 49.4% (44 of 89) to 95.0% (57 of 60) (P < .001). The negative concordance rate was at least 95% with a median false-negative rate of 1.5%. In the FISH+ group, amplification ratio showed significant correlation with IA scores (P < .001). Positive versus negative HER2 status was associated with lower ER and PR levels (P < .001) and higher Ki-67 expression (P < .001). CONCLUSION: Scoring of HER2/neu by IA was associated with high false-positive rates before 2008. Improvement in concordance rate after 2008 may be due to proper tissue handling, improved HER2/neu scoring by IA, and assay standardization. PMID- 26125433 TI - Artificial Intelligence for Pathologists Is Not Near--It Is Here: Description of a Prototype That Can Transform How We Practice Pathology Tomorrow. AB - CONTEXT: Pathologists' daily tasks consist of both the professional interpretation of slides and the secretarial tasks of translating these interpretations into final pathology reports, the latter of which is a time consuming endeavor for most pathologists. OBJECTIVE: To describe an artificial intelligence that performs secretarial tasks, designated as Secretary-Mimicking Artificial Intelligence (SMILE). DESIGN: The underling implementation of SMILE is a collection of computer programs that work in concert to "listen to" the voice commands and to "watch for" the changes of windows caused by slide bar code scanning; SMILE responds to these inputs by acting upon PowerPath Client windows (Sunquest Information Systems, Tucson, Arizona) and its Microsoft Word (Microsoft, Redmond, Washington) Add-In window, eventuating in the reports being typed and finalized. Secretary-Mimicking Artificial Intelligence also communicates relevant information to the pathologist via the computer speakers and message box on the screen. RESULTS: Secretary-Mimicking Artificial Intelligence performs many secretarial tasks intelligently and semiautonomously, with rapidity and consistency, thus enabling pathologists to focus on slide interpretation, which results in a marked increase in productivity, decrease in errors, and reduction of stress in daily practice. Secretary-Mimicking Artificial Intelligence undergoes encounter-based learning continually, resulting in a continuous improvement in its knowledge-based intelligence. CONCLUSIONS: Artificial intelligence for pathologists is both feasible and powerful. The future widespread use of artificial intelligence in our profession is certainly going to transform how we practice pathology. PMID- 26125434 TI - Calcifying Fibrous Tumor of the Gastrointestinal Tract. AB - Calcifying fibrous tumor is a benign mass lesion classically described as a soft tissue tumor. However, a thorough review of the literature reveals that it can occur virtually anywhere, including the tubular gastrointestinal (GI) tract. Its clinical manifestations are variable in the GI tract, and its imaging findings are nonspecific. However, it has unique histologic and immunophenotypical features that must be recognized by GI pathologists to differentiate it from an assortment of other rare mesenchymal lesions of the abdomen and GI tract. Calcifying fibrous tumor is composed of a paucicellular collagen matrix, interspersed calcified bodies, and a sparse inflammatory infiltrate. Although calcifying fibrous tumor is benign, pathologists must be aware that it may occur in the GI tract to differentiate it from other potentially more aggressive, rare mesenchymal lesions. PMID- 26125435 TI - Clinicopathologic Correlates of Primary Aldosteronism. AB - Primary aldosteronism is the most common cause of secondary hypertension, incurring significant cardiovascular morbidity and mortality. Our understanding of this disease has evolved substantially during the past decade. Recently, the molecular basis of primary aldosteronism has begun to be unraveled, with the discovery of mutations in potassium channel (KCNJ5), ATPases (ATP1A1, ATP2B3), and calcium channel (CACNA1D), and aberrant Wnt/beta-catenin signaling. The most recent data suggest that 95% of cases are sporadic, whereas 5% of cases are hereditary. Pathologic correlates of primary aldosteronism include adrenal cortical hyperplasia, adenoma, and carcinoma. Although the most common clinical presentation is bilateral adrenal cortical hyperplasia, this entity is usually treated medically. Therefore, in the setting of primary aldosteronism, surgical pathologists are most commonly exposed to adrenocortical adenomas and the odd occasional carcinoma. This review provides an update on the current knowledge of primary aldosteronism and discusses the clinicopathologic correlations of this important disease. PMID- 26125436 TI - Gene-based vaccines and immunotherapeutic strategies against neurodegenerative diseases: Potential utility and limitations. AB - There has been a recent expansion of vaccination and immunotherapeutic strategies from controlling infectious diseases to the targeting of non-infectious conditions including neurodegenerative disorders. In addition to conventional vaccine and immunotherapeutic modalities, gene-based methods that express antigens for presentation to the immune system by either live viral vectors or non-viral naked DNA plasmids have been developed and evaluated. This mini review/commentary summarizes the advantages and disadvantages, as well as the research findings to date, of both of these gene-based vaccination approaches in terms of how they can be targeted against appropriate antigens within the Alzheimer and Parkinson disease pathogenesis processes as well as potentially against targets in other neurodegenerative diseases. Most recently, the novel utilization of these viral vector and naked DNA gene-based technologies includes the delivery of immunoglobulin genes from established biologically active monoclonal antibodies. This modified passive immunotherapeutic strategy has recently been applied to deliver passive antibody immunotherapy against the pathologically relevant amyloid beta protein in Alzheimer disease. The advantages and disadvantages of this technological application of gene-based immune interventions, as well as research findings to date are also summarized. In sum, it is suggested that further evaluation of gene based vaccines and immunotherapies against neurodegenerative diseases are warranted to determine their potential clinical utility. PMID- 26125438 TI - Extracellularly secreted APE1/Ref-1 triggers apoptosis in triple-negative breast cancer cells via RAGE binding, which is mediated through acetylation. AB - The present study evaluated the mechanism of apoptosis caused by post translational modification, hyperacetylation in triple-negative breast cancer (TNBC) cells. We previously showed that trichostatin A (TSA) induced secretion of acetylated apurinic apyrimidinic endonuclease 1/redox factor-1 (Ac-APE1/Ref-1). This is the first report showing that Ac-APE1/Ref-1 initiates apoptosis in TNBC cells by binding to the receptor for advanced glycation end products (RAGE). The functional significance of secreted Ac-APE1/Ref-1 was studied by induction of intracellular hyperacetylation through co-treatment with acetylsalicylic acid and TSA in MDA-MB-231 cells. In response to hyperacetylation, secretion of Ac APE1/Ref-1 in vesicles was observed, resulting in significantly decreased cell viability and induction of apoptosis with increased expression of RAGE. The hyperacetylation-induced apoptosis was similar in two other TNBC cell lines: BT 459 and MDA-MB-468. Therefore, hyperacetylation may be a therapeutic target for treatment of TNBCs. This study introduces a novel paradigm whereby post translational modification induces apoptotic cell death in breast cancer cells resistant to standard chemotherapeutic agents through secretion of auto- or paracrine molecules such as Ac-APE1/Ref-1. PMID- 26125439 TI - miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR 193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention. PMID- 26125441 TI - Critical role of Wnt/beta-catenin signaling in driving epithelial ovarian cancer platinum resistance. AB - Resistance to platinum-based chemotherapy is the major barrier to treating epithelial ovarian cancer. To improve patient outcomes, it is critical to identify the underlying mechanisms that promote platinum resistance. Emerging evidence supports the concept that platinum-based therapies are able to eliminate the bulk of differentiated cancer cells, but are unable to eliminate cancer initiating cells (CIC). To date, the relevant pathways that regulate ovarian CICs remain elusive. Several correlative studies have shown that Wnt/beta-catenin pathway activation is associated with poor outcomes in patients with high-grade serous ovarian cancer (HGSOC). However, the functional relevance of these findings remain to be delineated. We have uncovered that Wnt/beta-catenin pathway activation is a critical driver of HGSOC chemotherapy resistance, and targeted inhibition of this pathway, which eliminates CICs, represents a novel and effective treatment for chemoresistant HGSOC. Here we show that Wnt/beta-catenin signaling is activated in ovarian CICs, and targeted inhibition of beta-catenin potently sensitized cells to cisplatin and decreased CIC tumor sphere formation. Furthermore, the Wnt/beta-catenin specific inhibitor iCG-001 potently sensitized cells to cisplatin and decreased stem-cell frequency in platinum resistant cells. Taken together, our data is the first report providing evidence that the Wnt/beta catenin signaling pathway maintains stem-like properties and drug resistance of primary HGSOC PDX derived platinum resistant models, and therapeutic targeting of this pathway with iCG-001/PRI-724, which has been shown to be well tolerated in Phase I trials, may be an effective treatment option. PMID- 26125442 TI - The genomic evolution of human prostate cancer. AB - Prostate cancers are highly prevalent in the developed world, with inheritable risk contributing appreciably to tumour development. Genomic heterogeneity within individual prostate glands and between patients derives predominantly from structural variants and copy-number aberrations. Subtypes of prostate cancers are being delineated through the increasing use of next-generation sequencing, but these subtypes are yet to be used to guide the prognosis or therapeutic strategy. Herein, we review our current knowledge of the mutational landscape of human prostate cancer, describing what is known of the common mutations underpinning its development. We evaluate recurrent prostate-specific mutations prior to discussing the mutational events that are shared both in prostate cancer and across multiple cancer types. From these data, we construct a putative overview of the genomic evolution of human prostate cancer. PMID- 26125443 TI - Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer. AB - BACKGROUND: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. METHODS: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. RESULTS: Patients with low expression of VEGF-D (0, 1p) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CBpCBM), 0.21; 95% CI, 0.08-0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13-0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2p PFS HR, 0.67; 95% CI, 0.45-1.00; OS HR, 0.82; 95% CI, 0.52-1.30; VEGF-D 3p PFS HR, 0.77; 95% CI, 0.50-1.17; OS HR, 1.28; 95% CI, 0.79-2.09) (P interaction o0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. CONCLUSIONS: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation. PMID- 26125440 TI - Targeting cancer by binding iron: Dissecting cellular signaling pathways. AB - Newer and more potent therapies are urgently needed to effectively treat advanced cancers that have developed resistance and metastasized. One such strategy is to target cancer cell iron metabolism, which is altered compared to normal cells and may facilitate their rapid proliferation. This is supported by studies reporting the anti-neoplastic activities of the clinically available iron chelators, desferrioxamine and deferasirox. More recently, ligands of the di-2-pyridylketone thiosemicarbazone (DpT) class have demonstrated potent and selective anti proliferative activity across multiple cancer-types in vivo, fueling studies aimed at dissecting their molecular mechanisms of action. In the past five years alone, significant advances have been made in understanding how chelators not only modulate cellular iron metabolism, but also multiple signaling pathways implicated in tumor progression and metastasis. Herein, we discuss recent research on the targeting of iron in cancer cells, with a focus on the novel and potent DpT ligands. Several key studies have revealed that iron chelation can target the AKT, ERK, JNK, p38, STAT3, TGF-beta, Wnt and autophagic pathways to subsequently inhibit cellular proliferation, the epithelial-mesenchymal transition (EMT) and metastasis. These developments emphasize that these novel therapies could be utilized clinically to effectively target cancer. PMID- 26125444 TI - Family history of cancer and the risk of squamous cell carcinoma of oesophagus: a case-control study in Kashmir, India. AB - BACKGROUND: Only a few studies have examined the association between family history of cancer (FHC) and the risk of oesophageal squamous cell carcinoma (ESCC) in high incidence areas of ESCC. We conducted a case-control study to evaluate the relationship between FHC and ESCC risk in Kashmir, India, with analysis of detailed epidemiological data and information on multiple gene polymorphisms. METHODS: We collected detailed information on FHC and a number of socio-demographic and lifestyle factors, and also obtained blood samples for genetic analysis from 703 histopathologically confirmed ESCC cases and 1664 individually matched controls. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Participants who had FHC showed a strong association with ESCC risk, and the risk was stronger when first-degree relatives (FDRs) had FHC (OR=6.8; 95% CI=4.6-9.9). Having a sibling with a cancer showed the strongest association (OR=10.8; 95% CI=6.0-19.3), but having a child with a cancer was not associated with ESCC risk. A history of any cancer in the spouse was also associated with ESCC risk (OR=4.1; 95% CI=1.6-10.2). Those with two or more relatives with FHC were at a higher risk of ESCC. After restricting FHC to familial ESCC only, the above associations were strengthened, except when spouses were affected with ESCC (OR=2.5; 95% CI=0.7 8.9). When we examined the associations between several single-nucleotide polymorphisms and ESCC in those with and without FHC, the associations of variant genotypes in cytochrome P450 (CYP) 2C19 and CYP2D6 and the wild genotype of CYP2E1 with ESCC were much stronger in those with FHC. The FHC had an additive interaction with several risk factors of ESCC in this population. CONCLUSION: Our results showed that FHC was strongly associated with ESCC risk in Kashmir. It seems both genetic factors and shared environment are involved in this association. PMID- 26125445 TI - Bone marrow-derived stromal cells are associated with gastric cancer progression. AB - BACKGROUND: The aim of this study was to clarify the role of bone marrow-derived stromal cells (BM-SCs) expressing CD271 in the development of gastric cancer. METHODS: The effect of human BM-SCs on the proliferation and motility of six gastric cancer cell lines, OCUM-2M, OCUM-2MD3, OCUM-12, KATO-III, NUGC-3, and MKN 74, was examined. CD271 expression levels in BM-SCs were analysed by flow cytometry. We also generated a gastric tumour model by orthotopic inoculation of OCUM-2MLN cells in mice that had received transplantation of bone marrow from the CAG-EGFP mice. The correlation between the clinicopathological features of 279 primary gastric carcinomas and CD271 expression in tumour stroma was examined by immunohistochemistry. RESULTS: Numerous BM-SCs infiltrated the gastric tumour microenvironment; CD271 expression was found in ~25% of BM-SCs. Conditioned medium from BM-SCs significantly increased the proliferation of gastric cancer cell lines. Furthermore, conditioned medium from gastric cancer cells significantly increased the number of BM-SCs, whereas migration of OCUM-12 and NUGC-3 cells was significantly increased by conditioned medium from BM-SCs. CD271 expression in stromal cells was significantly associated with macroscopic type-4 cancers, diffuse-type tumours, and tumour invasion depth. The overall survival of patients (n=279) with CD271-positive stromal cells was significantly worse compared with that of patients with CD271-negative stromal cells. This is the first report of the significance of BM-SCs in gastric cancer progression. CONCLUSIONS: Bone marrow-derived stromal cells might have an important role in gastric cancer progression, and CD271-positive BM-SCs might be a useful prognostic factor for gastric cancer patients. PMID- 26125446 TI - Early diagnosis of bladder cancer through the detection of urinary tyrosine phosphorylated proteins. AB - BACKGROUND: A noninvasive, highly sensitive and specific urine test is needed for bladder cancer (BC) diagnosis and surveillance in addition to the invasive cystoscopy. We previously described the diagnostic effectiveness of urinary tyrosine-phosphorylated proteins (UPY) and a new assay (UPY-A) for their measurement in a pilot study. The aim of this work was to evaluate the performances of the UPY-A using an independent cohort of 262 subjects. METHODS: Urinary tyrosine-phosphorylated proteins were measured by UPY-A test. The area under ROC curve, cutoff, sensitivity, specificity and predictive values of UPY-A were determined. The association of UPY levels with tumour staging, grading, recurrence and progression risk was analysed by Kruskal-Wallis and Wilcoxon's test. To test the probability to be a case if positive at the UPY-A, a logistic test adjusted for possible confounding factor was used. RESULTS: Results showed a significant difference of UPY levels between patients with BC vs healthy controls. For the best cutoff value, 261.26 Standard Units (SU), the sensitivity of the assay was 80.43% and the specificity was 78.82%. A statistically significant difference was found in the levels of UPY at different BC stages and grades between Ta and T1 and with different risk of recurrence and progression. A statistically significant increased risk for BC at UPY-A ?261.26 SU was observed. CONCLUSIONS: The present study supplies important information on the diagnostic characteristics of UPY-A revealing remarkable performances for early stages and allowing its potential use for different applications encompassing the screening of high-risk subjects, primary diagnosis and posttreatment surveillance. PMID- 26125447 TI - Cell-free DNA levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease. AB - BACKGROUND: The analysis of plasma cell-free DNA (cfDNA) is expected to provide useful biomarkers for early diagnosis of non-small-cell lung cancer (NSCLC). However, it remains unclear whether the intense release of cfDNA into the bloodstream of NSCLC patients results from malignancy or chronic inflammatory response. Consequently, the current diagnostic utility of plasma cfDNA quantification has not been thoroughly validated in subjects with chronic respiratory inflammation. Here we assess the effect of chronic respiratory inflammation on plasma cfDNA levels and evaluate the potential clinical value of this phenomenon as an early lung cancer diagnostic tool. METHODS: We measured plasma cfDNA concentrations in 50 resectable NSCLC patients, 101 patients with chronic respiratory inflammation (chronic obstructive pulmonary disease, sarcoidosis, or asthma) and 40 healthy volunteers using real-time PCR. RESULTS: We found significantly higher plasma cfDNA levels in NSCLC patients than in subjects with chronic respiratory inflammation and healthy individuals (P<0.0001). There were no significant differences in plasma cfDNA levels between patients with chronic respiratory inflammation and healthy volunteers. The cutoff point of >2.8 ng ml(-1) provided 90% sensitivity and 80.5% specificity in discriminating NSCLC from healthy individuals (area under the curve (AUC)=0.90). The receiver-operating characteristics curve distinguishing NSCLC patients from subjects with chronic respiratory inflammation indicated 56% sensitivity and 91% specificity at the >5.25-ng ml(-1) cutoff (AUC=0.76). CONCLUSIONS: We demonstrated that elevated plasma cfDNA levels in NSCLC resulted primarily from tumour development rather than inflammatory response, raising the potential clinical implications for lung cancer screening and early diagnosis. Further research is necessary to better characterise and identify factors and processes regulating cfDNA levels in the blood under normal and pathological conditions. PMID- 26125448 TI - Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. AB - BACKGROUND: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). METHODS: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. RESULTS: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. CONCLUSION: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity. PMID- 26125449 TI - Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. AB - BACKGROUND: Patients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy. METHODS: Using an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethasone dose that yielded the greatest statistical difference in overall survival (OS). The results were validated in a separate cohort treated in a single institution with TTFields and their T lymphocytes were correlated with OS. RESULTS: Patients who used dexamethasone doses >4.1 mg per day had a significant reduction in OS when compared with those who used ?4.1 mg per day, 4.8 vs 11.0 months respectively (chi(2)=34.6, P<0.0001) in the TTField-treated cohort and 6.0 vs 8.9 months respectively (chi(2)=10.0, P<0.0015) in the chemotherapy-treated cohort. In a single institution validation cohort treated with TTFields, the median OS of patients who used dexamethasone >4.1 mg per day was 3.2 months compared with those who used ?4.1 mg per day was 8.7 months (chi(2)=11.1, P=0.0009). There was a significant correlation between OS and T lymphocyte counts. CONCLUSIONS: Dexamethasone exerted profound effects on both TTFields and chemotherapy efficacy resulting in lower patient OS. Therefore, global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma. PMID- 26125450 TI - Cancer symptom awareness and barriers to symptomatic presentation in England--are we clear on cancer? AB - BACKGROUND: Low cancer awareness may contribute to delayed diagnosis and poor cancer survival. We aimed to quantify socio-demographic differences in cancer symptom awareness and barriers to symptomatic presentation in the English population. METHODS: Using a uniquely large data set (n=49 270), we examined the association of cancer symptom awareness and barriers to presentation with age, gender, marital status and socio-economic position (SEP), using logistic regression models to control for confounders. RESULTS: The youngest and oldest, the single and participants with the lowest SEP recognised the fewest cancer symptoms, and reported most barriers to presentation. Recognition of nine common cancer symptoms was significantly lower, and embarrassment, fear and difficulties in arranging transport to the doctor's surgery were significantly more common in participants living in the most deprived areas than in the most affluent areas. Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor. CONCLUSIONS: Large and robust socio-demographic differences in recognition of some cancer symptoms, and perception of some barriers to presentation, highlight the need for targeted campaigns to encourage early presentation and improve cancer outcomes. PMID- 26125451 TI - miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells. AB - BACKGROUND: The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC. METHODS: MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines). RESULTS: In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and beta-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1. CONCLUSIONS: MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells. PMID- 26125452 TI - Systemic neutrophil-to-lymphocyte ratio in colorectal cancer: the relationship to patient survival, tumour biology and local lymphocytic response to tumour. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of mortality and morbidity. The impact of inflammatory biomarkers (C-reactive protein etc.) on CRC is increasingly studied including systemic neutrophil-to-lymphocyte ratio (NLR) as they seem to predict outcome. METHODS: All patients who underwent curative resection for CRC from 2000 to 2004 at Leeds Teaching Hospitals NHS Trust had pre operative NLR calculated. Demographic, histopathological and survival data were collected. Tissue microarrays were created and stained to determine the mismatch repair (MMR) protein status of each tumour. Local lymphocytic response to the tumour was assessed and graded. RESULTS: About 358 patients were eligible. Of these 88 had an NLR ?5, which predicted lower overall survival and greater disease recurrence. A high NLR is associated with higher pT- and pN-stage and a greater incidence of extramural venous invasion. MMR protein status was not associated with NLR. A pronounced lymphocytic reaction at the invasive margin (IM) indicated a better prognosis and was associated with a lower NLR. CONCLUSION: Neutrophil-to-lymphocyte ratio predicts disease-free and overall survival and is associated with a more aggressive tumour phenotype. The lymphocytic response to tumour at the IM is associated with NLR however dMMR is not. Neutrophil-to-lymphocyte ratio is a cheap, easy-to-access test that predicts outcome in CRC. PMID- 26125453 TI - gamma-Turn Mimicry with Benzodiazepinones and Pyrrolobenzodiazepinones Synthesized from a Common Amino Ketone Intermediate. AB - To investigate diazepinone analogues as gamma-turn mimics, seven 1,4 benzodiazepin-2-ones 6 and fourteen pyrrolo[1,2-d][1,4]benzodiazepin-6-ones 4 and 5 were synthesized from 1-(2-aminophenyl)pent-4-en-1-one (7). Acylation of aniline 7 with N-Boc-amino acids, olefin oxidation, Boc removal, and intramolecular Paal-Knorr condensation gave 4 and 5. Alternatively, Boc removal prior to oxidation gave benzodiazepinones 6, which were converted to 4 by ozonolysis and cyclization. Comparison of dihedral angle values for the amino acid component from X-ray analyses of 4g, 5f, and 6f and related diazepinones has catalogued the manner by which ring substituents affect the component's ability to mimic the central residues of gamma-turns. PMID- 26125455 TI - Evaluation of Quality, Content, and Use of the Web Site Prepared for Family Members Giving Care to Stroke Patients. AB - This study was designed to evaluate the quality, content, usability, and efficacy of a Web site prepared for the purpose of improving the caregiving capability of family members who provide care for stroke survivors at home. The DISCERN score for the Web site was found to be 4.35 over 5. The first section that assesses reliability of the Web site was 4.38 over 5; mean score of the second section that measures the quality of the provided information on treatment/care options was 4.30, and mean score of the third section that gives a general evaluation of the material was 4.1. The Web site content achieved an average score of 3.47 over 4 after evaluation by experts. The Web site system usability score was found to be 79.4 over 100. The Web site was utilized mostly for exercises in bed (76.3%; n = 29), use of medications, and patient safety (68.4%; n = 26). It was determined that those who were younger and employed and had no previous experience of nursing any patient utilized relatively more from the section of patient nutrition and oral care and married family caregivers from the body hygiene section. The Web site quality and content were judged to be good and reliable to use. The Web site was efficiently used by caregivers. PMID- 26125454 TI - The Effects of Local Warming on Surgical Site Infection. AB - BACKGROUND: Surgical site infections (SSI) account for a major proportion of hospital-acquired infections. They are associated with longer hospital stay, readmissions, increased costs, mortality, and morbidity. Reducing SSI is a goal of the Surgical Care Improvement Project and identifying interventions that reduce SSI effectively is of interest. In a single-blinded randomized controlled trial (RCT) we evaluated the effect of localized warming applied to surgical incisions on SSI development and selected cellular (immune, endothelial) and tissue responses (oxygenation, collagen). METHODS: After Institutional Review Board approval and consent, patients having open bariatric, colon, or gynecologic oncologic related operations were enrolled and randomly assigned to local incision warming (6 post-operative treatments) or non-warming. A prototype surgical bandage was used for all patients. The study protocol included intra operative warming to maintain core temperature >=36 degrees C and administration of 0.80 FIO2. Patients were followed for 6 wks for the primary outcome of SSI determined by U.S. Centers for Disease Control (CDC) criteria and ASEPSIS scores (additional treatment; presence of serous discharge, erythema, purulent exudate, and separation of the deep tissues; isolation of bacteria; and duration of inpatient stay). Tissue oxygen (PscO2) and samples for cellular analyses were obtained using subcutaneous polytetrafluoroethylene (ePTFE) tubes and oxygen micro-electrodes implanted adjacent to the incision. Cellular and tissue ePTFE samples were evaluated using flow cytometry, immunohistochemistry, and SircolTM collagen assay (Biocolor Ltd., Carrickfergus, United Kingdom). RESULTS: One hundred forty-six patients participated (n=73 per group). Study groups were similar on demographic parameters and for intra-operative management factors. The CDC defined rate of SSI was 18%; occurrence of SSI between groups did not differ (p=0.27). At 2 wks, warmed patients had better ASEPSIS scores (p=0.04) but this difference was not observed at 6 wks. There were no significant differences in immune, endothelial cell, or collagen responses between groups. On post-operative days one to two, warmed patients had greater PscO2 change scores with an average PscO2 increase of 9-10 mm Hg above baseline (p<0.04). CONCLUSIONS: Post-operative local warming compared with non-warming followed in this study, which included intra-operative warming to maintain normothermia and FIO2 level of 0.80, did not reduce SSI and had no effect on immune, endothelial cell presence, or collagen synthesis. PscO2 increased significantly with warming, however, the increase was modest and less than expected or what has been observed in studies testing other interventions. PMID- 26125456 TI - Honeycomb-like Porous Carbon-Cobalt Oxide Nanocomposite for High-Performance Enzymeless Glucose Sensor and Supercapacitor Applications. AB - Herein, we report the preparation of Pongam seed shells-derived activated carbon and cobalt oxide (~2-10 nm) nanocomposite (PSAC/Co3O4) by using a general and facile synthesis strategy. The as-synthesized PSAC/Co3O4 samples were characterized by a variety of physicochemical techniques. The PSAC/Co3O4-modified electrode is employed in two different applications such as high performance nonenzymatic glucose sensor and supercapacitor. Remarkably, the fabricated glucose sensor is exhibited an ultrahigh sensitivity of 34.2 mA mM(-1) cm(-2) with a very low detection limit (21 nM) and long-term durability. The PSAC/Co3O4 modified stainless steel electrode possesses an appreciable specific capacitance and remarkable long-term cycling stability. The obtained results suggest the as synthesized PSAC/Co3O4 is more suitable for the nonenzymatic glucose sensor and supercapacitor applications outperforming the related carbon based modified electrodes, rendering practical industrial applications. PMID- 26125457 TI - Yvh1 protein phosphatase is required for pre-autophagosomal structure formation after TORC1 inactivation. AB - The pre-autophagosomal structure (PAS) is a putative site for autophagosome formation in budding yeast. Upon nutrient depletion or rapamycin treatment, target of rapamycin complex 1 (TORC1) becomes inactive, inducing PAS formation and autophagy. Here, we show that Yvh1 phosphatase is critical for PAS formation, but not autophagy induction, after TORC1 inactivation. PMID- 26125458 TI - Endoscopic Management of Early Esophageal Cancer. AB - The absolute incidence of esophageal adenocarcinoma has increased 7-fold over the past 5 decades, and esophageal adenocarcinoma is the most rapidly increasing epithelial malignancy in the United States. The incidence of early esophageal cancer has also increased proportionately. In the past decade, radiofrequency ablation has become the standard first-line therapy for high-grade dysplasia when found in the precursor lesion to esophageal adenocarcinoma, Barrett's esophagus. Success in the endoscopic management of high-grade dysplasia has furthered efforts to treat early esophageal cancers endoscopically. Although surgery remains the mainstay of treatment for more advanced tumors, national guidelines now recommend endoscopic mucosal resection followed by radiofrequency ablation for intramucosal carcinomas and T1a cancers. T1b cancers represent a more challenging group-very good results have been reported in highly selected subsets of patients with T1b tumors; however, many recommendations favor individualization or a surgical approach for this stage. This review examines the current data and recommendations regarding the endoscopic management of early esophageal adenocarcinomas. PMID- 26125459 TI - What is the Risk of Colorectal Cancer After an Episode of Acute Diverticulitis in Conservatively Treated Patients? AB - GOALS: The goal is to find the risk of colorectal cancer after an episode of acute diverticulitis in conservatively treated patients. Secondly, to determine the benefit of colonoscopy in these patients. BACKGROUND: In the Netherlands, it is a common practice to routinely perform a colonoscopy after an episode of conservatively treated diverticulitis to exclude a malignancy. Yet according to the Dutch guidelines, these patients should not undergo a colonoscopy on a routine basis. The aim of this study is to determine the benefit of a colonoscopy in patients who have been treated for diverticulitis conservatively. STUDY: This retrospective study includes patients who were diagnosed with acute diverticulitis (Hinchey 0 and I) and were treated conservatively, with or without antibiotics. Only patients who underwent colonoscopy were included for analysis. In addition, the outcome (yes or no colorectal cancer) of colonoscopy was analyzed according to patients' presentation of alarm symptoms for colorectal cancer. RESULTS: Between January 2008 and June 2013, 977 patients were treated conservatively for an episode of acute diverticulitis. Of those, 645 underwent colonoscopy during follow-up. Alarm symptoms for colorectal cancer were present in 205 patients. Nine of them were diagnosed with colorectal cancer (4.4%) versus 1 patient (0.2%, P=0.0002) in the group without alarm symptoms (N=440). CONCLUSIONS: This study confirms that routine colonoscopy is not indicated after acute diverticulitis which has been treated conservatively in a large series. Only in case of alarm symptoms a colonoscopy is mandatory, but even then the actual finding of a colorectal cancer is rare. PMID- 26125460 TI - Long-term Follow-up Study of Fecal Microbiota Transplantation for Severe and/or Complicated Clostridium difficile Infection: A Multicenter Experience. AB - GOAL: Our aim was to investigate fecal microbiota transplantation (FMT) efficacy in patients with severe and/or complicated Clostridium difficile infection (CDI). BACKGROUND: FMT is successful for recurrent CDI, although its benefit in severe or complicated CDI has not specifically been evaluated. STUDY METHODS: A multicenter long-term follow-up study was performed in patients who received FMT for severe and/or complicated CDI (diagnosed using standard criteria). Pre-FMT and post-FMT questionnaires were completed. Study outcomes included cure rates and time to resolution of symptoms. RESULTS: A total of 17 patients (82% inpatients, 18% outpatients) were included (76.4% women; mean age, 66.4 y; mean follow-up, 11.4 mo). Patients had severe and complicated (76.4%) or either severe or complicated (23.6%) CDI. Sixteen patients (94.1%) had diarrhea, which resolved in 12 (75%; mean time to resolution, 5.7 d) and improved in 4 (25%) after FMT. Eleven patients (64.7%) had abdominal pain, which resolved in 8 (72.7%; mean time to resolution, 9.6 d) and improved in 3 (27.3%) after FMT. Two of 17 patients experienced early CDI recurrence (<=90 d) after FMT (primary cure rate, 88.2%); and in 1 patient, a second FMT resulted in cure (secondary cure rate, 94.1%). Late CDI recurrence (>=90 d) was seen in 1 of 17 patients (5.9%) in association with antibiotics and was successfully treated with a repeat FMT. No adverse effects directly related to FMT occurred. CONCLUSIONS: FMT was successful and safe in this cohort of patients with severe or complicated CDI. Primary and secondary cure rates were 88.2% and 94.1%, respectively. PMID- 26125461 TI - Fellowship Colonoscopy Training and Preparedness for Independent Gastroenterology Practice. AB - GOALS: To objectively assess when gastroenterology (GI) fellows achieve technical competency to perform colonoscopy independently. BACKGROUND: New guidelines to assess the procedural competency of GI fellows in training have been developed. Although comprehensive, they do not account for the quality metrics to which independently practicing gastroenterologists are held. STUDY: We performed a prospective study examining consecutive colonoscopies performed by GI fellows from November 2013 through March 2014 at an academic medical center. Using a brief postprocedure questionnaire and the online medical record, we measured rates of independent fellow cecal intubation rate (CIR), insertion time to the cecum (cecal IT), and independent polypectomy rate. Our secondary outcomes were adenoma detection rate and polyp detection rate. RESULTS: A total of 898 colonoscopies performed by 10 GI fellows were analyzed. In the multivariate analysis, CIR [odds ratio (OR)=1.29, P=0.012], cecal IT (beta-coefficient=0.19, P=0.006), and rates of unassisted independent snare polypectomy (OR=1.36, P<0.001) all improved significantly with increased number of procedures performed (OR and beta-coefficient per 100 colonoscopies performed). After performing 500 colonoscopies, fellows achieved a mean CIR>90%, cecal IT between 7 and 10 minutes, and independent polypectomy rate of 90% with further improvement in cecal IT to <7 minutes, and independent snare polypectomy of >95% after 700 cases. CONCLUSIONS: Current procedural recommendations for fellowship training may underestimate the technical skill necessary for independent GI practice upon completion of fellowship. Technical proficiency in snare polypectomy may lag behind proficiency in cecal intubation. PMID- 26125462 TI - Development and Internal Validation of a Model for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis. AB - BACKGROUND: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis; however, early detection efforts are limited by suboptimal effectiveness. AIM: To derive and validate a model to accurately distinguish cirrhotic patients with and without HCC and compare the accuracy of the model to that of alpha-fetoprotein (AFP) alone. METHODS: We conducted a case control study of cirrhotic patients with and without HCC seen at a large urban hospital system between January 2005 and June 2012. We derived multivariate logistic regression models for the presence of HCC and early-stage HCC. Discriminatory power was evaluated using receiver operating characteristic curve analysis in derivation and validation cohorts using a 10-fold cross-validation approach. RESULTS: We identified 1356 patients with cirrhosis, with (n=455, 147 early stage) and without (n=901) HCC. We found that AFP>20 ng/mL and FIB-4, a noninvasive marker of fibrosis, were significantly associated with the presence of HCC (OR=10.5; 95% CI, 7.9-13.9 and OR=1.05; 95% CI, 1.03-1.07, respectively) and early-stage HCC (OR=4.4; 95% CI, 2.9-6.5 and OR=1.06; 95% CI, 1.03-1.09, respectively). Models incorporating AFP and FIB-4 had good discriminatory power, with c-statistics of approximately 0.80, in both derivation and validation cohorts. The model for early-stage HCC had higher discriminatory power than AFP alone (c-statistic 0.73; 95% CI, 0.69-0.78) in derivation and validation cohorts (P=0.02 and 0.15, respectively). CONCLUSIONS: Models including AFP and FIB-4 can accurately discriminate cirrhotic patients with early-stage HCC from those without HCC. PMID- 26125463 TI - Chemokine Ligand 20: A Signal for Leukocyte Recruitment During Human Ovulation? AB - Ovulation is one of the cornerstones of female fertility. Disruption of the ovulatory process results in infertility, which affects approximately 10% of couples. Using a unique model in which the dominant follicle is collected across the periovulatory period in women, we have identified a leukocyte chemoattractant, chemokine ligand 20 (CCL20), in the human ovary. CCL20 mRNA is massively induced after an in vivo human chorionic gonadotropin (hCG) stimulus in granulosa (>10 000-fold) and theca (>4000-fold) cells collected during the early ovulatory (12-18 h) and late ovulatory (18-34 h) periods after hCG administration. Because the LH surge sets in motion an inflammatory reaction characterized by an influx of leukocytes and CCL20 is known to recruit leukocytes in other systems, the composition of ovarian leukocytes (CD45+) containing the CCL20 receptor CCR6 was determined immediately prior to ovulation. CD45+/CCR6+ cells were primarily natural killer cells (41%) along with B cells (12%), T cells (11%), neutrophils (10%), and monocytes (9%). Importantly, exogenous CCL20 stimulated ovarian leukocyte migration 59% within 90 minutes. Due to the difficulties in obtaining human follicles, an in vitro model was developed using granulosa-lutein cells to explore CCL20 regulation. CCL20 expression increased 40 fold within 6 hours after hCG, was regulated partially by the epithelial growth factor pathway, and was positively correlated with progesterone production. These results demonstrate that hCG dramatically increases CCL20 expression in the human ovary, that ovarian leukocytes contain the CCL20 receptor, and that CCL20 stimulates leukocyte migration. Our findings raise the prospect that CCL20 may aid in the final ovulatory events and contribute to fertility in women. PMID- 26125465 TI - Pancreatic PYY Is Critical in the Control of Insulin Secretion and Glucose Homeostasis in Female Mice. AB - Insulin secretion is tightly controlled through coordinated actions of a number of systemic and local factors. Peptide YY (PYY) is expressed in alpha-cells of the islet, but its role in control of islet function such as insulin release is not clear. In this study, we generated a transgenic mouse model (Pyy(tg/+)/Rip Cre) overexpressing the Pyy gene under the control of the rat insulin 2 gene promoter and assessed the impact of islet-released PYY on beta-cell function, insulin release, and glucose homeostasis in mice. Our results show that up regulation of PYY in islet beta-cells leads to an increase in serum insulin levels as well as improved glucose tolerance. Interestingly, PYY-overproducing mice show increased lean mass and reduced fat mass with no significant changes in food intake or body weight. Energy expenditure is also increased accompanied by increased respiratory exchange ratio. Mechanistically, the enhanced insulin levels and improved glucose tolerance are primarily due to increased beta-cell mass and secretion. This is associated with alterations in the expression of genes important for beta-cell proliferation and function as well as the maintenance of the beta-cell phenotype. Taken together, these data demonstrate that pancreatic islet-derived PYY plays an important role in controlling glucose homeostasis through the modulation of beta-cell mass and function. PMID- 26125466 TI - TNF-alpha Suppressed FSH-Induced LH Receptor Expression Through Transcriptional Regulation in Rat Granulosa Cells. AB - Several inflammatory cytokines regulate ovarian function. TNF-alpha is produced in granulosa cells under physiological conditions and has a reciprocal action on follicle development. In contrast, in pelvic inflammatory diseases, TNF-alpha is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-alpha on the expression of LH receptor (LHR) in immature rat granulosa cells. TNF-alpha suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. By using a luciferase assay, the construct containing base pairs -1389 to -1 of the rat Lhcgr promoter revealed that TNF-alpha decreased FSH-induced promoter activity. In response to TNF-alpha, nuclear factor (NF)-kappaB p65 was translocated to the nucleus, and the suppressive effect of TNF-alpha on LHR mRNA expression was abrogated by an NF-kappaB inhibitor. In a chromatin immunoprecipitation assay, TNF-alpha induced the association of NF-kappaB p65 with the rat Lhcgr transcriptional promoter region. NF-kappaB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-alpha-induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-kappaB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-alpha action on the regulation of LHR. PMID- 26125464 TI - miR-122 Regulates LH Receptor Expression by Activating Sterol Response Element Binding Protein in Rat Ovaries. AB - LH/human chorionic gonadotropin receptor (LHR) undergoes down-regulation during preovulatory LH surge or in response to exposure to a supraphysiological concentration of its ligands through a posttranscriptional mechanism involving an RNA binding protein designated as LHR mRNA binding protein (LRBP). miR-122, a short noncoding RNA, has been shown to mediate the up-regulation of LRBP. In the present study, we show that inhibition of miR-122 using a locked nucleic acid (LNA)-conjugated antagomir suppressed human chorionic gonadotropin (hCG)-induced up-regulation of LRBP as well as its association with LHR mRNA, as analyzed by RNA EMSA. Most importantly, inhibition of miR-122 resulted in the abolishment of hCG-mediated LHR mRNA down-regulation. We also show that the transcription factor, sterol regulatory element binding protein (SREBP) (SREBP-1a and SREBP-2 isoforms), is an intermediate in miR-122-mediated LHR mRNA regulation. HCG stimulated increase in the activation of both SREBP-1a and SREBP-2 was inhibited by pretreatment with the miR-122 antagomir. The inhibition of cAMP/protein kinase A (PKA) and ERK pathways, upstream activators of miR-122, abolished SREBP activation after hCG treatment. SREBP-mediated regulation of LRBP expression is mediated by recruitment of LRBP promoter element to SREBP-1a, because chromatin immunoprecipitation assay revealed that association of LRBP promoter to SREBP was increased by hCG treatment. Pretreatment with miR-122 antagomir suppressed this response. Inhibition of SREBP activation by pretreating the rats with a chemical compound, fatostatin abrogated hCG-induced up-regulation of LRBP mRNA and protein. Fatostatin also inhibited LHR-LRBP mRNA-protein complex formation and LHR down-regulation. These results conclusively show that miR-122 plays a regulatory role in LH/hCG-induced LHR mRNA down-regulation by increasing LRBP expression through the activation of SREBP pathway. PMID- 26125468 TI - Solid/fluid interface: general discussion. PMID- 26125467 TI - Overexpression of monocarboxylate anion transporter 1 and 4 in T24-induced cancer associated fibroblasts regulates the progression of bladder cancer cells in a 3D microfluidic device. AB - Stromal fibroblasts are essential for tumor proliferation and invasion. Here we presented a 3-dimensional (3D) microfluidic co-culture device to reconstruct an in vivo-like tumor microenvironment for investigation of the interactions of cancer-associated fibroblasts (CAFs) and bladder cancer cells. With this device, we verified that the cytokines secreted by bladder cancer cells T24 effectively transform the fibroblasts into CAFs. Compared to fibroblasts, the CAFs, which undergo the aerobic glycolysis, showed higher ability to produce lactate and provide energy for bladder cancer cell proliferation and invasion. We also demonstrated that this kind of tumor-promoting effect was associated with the upregulation of monocarboxylate anion transporter 1 (MCT1) and MCT4 expression in CAFs. We concluded that MCT1 and MCT4 are involved in bladder cancer cell proliferation and invasiveness. Moreover, this 3D microfluidic co-culture device allows for the assay to characterize various cellular events in a single device sequentially, facilitating a better understanding of the interactions among heterotypic cells in a sophisticated microenvironment. PMID- 26125469 TI - On Time. PMID- 26125470 TI - Task Specific Tremors. AB - VIDEO: A patient reported bilateral hand tremors when writing but not with other tasks. These "task specific" tremors are considered subcategories of essential tremor. Primary writing tremor, in which the tremor occurs only with writing, is probably the most common. The important teaching point is that the "standard" tremor assessment, watching the patient holding a sustained posture and touching his finger to the examiner's and then back to the nose is not adequate. Patients should be tested doing the activity that causes them the most difficulty. PMID- 26125471 TI - Overview of Brown's Unique 8-year Program in Liberal Medical Education (PLME). PMID- 26125473 TI - Reflections from Students in PLME Senior Seminar, Doctoring Courses. PMID- 26125474 TI - The 'L' in PLME: A Broad Approach to Medical Education. PMID- 26125475 TI - A Student Collaboration to Address Mental Health Wellness in Medical School. PMID- 26125476 TI - Heat Illness - A Practical Primer. AB - Heat stroke is one of the top three causes of death for athletes. Vigilance is required to prevent these illnesses and when faced with an individual who is suffering an exertional heat stroke, the goal is to aggressively cool the patient to 102 degrees F within 30 minutes to optimize survival. The elderly are also at risk for heat illness and physicians caring for these patients should discuss prevention and treatment plans. PMID- 26125477 TI - Attending Physician Attitudes Toward Choice of Oral Anticoagulant for the Treatment of Venous Thromboembolism. AB - Until recently, warfarin has been the primary treatment of venous thromboembolism (VTE). Limited data are available regarding physician attitudes toward anticoagulant choice in the setting of novel oral anticoagulant (NOAC) availability. This study sought to evaluate attending physician attitudes toward NOACs. A survey was sent to attending physicians from internal medicine (primary care and hospitalist medicine), family medicine, cardiology, and hematology oncology asking about their preference and reasoning for choice of oral anticoagulant for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Warfarin was the most common choice of initial treatment of both DVT (85.6%) and PE (89%). Among the specialties surveyed, cardiologists were more likely to use rivaroxaban as initial treatment of VTE as compared to other specialties including internal medicine or hematology (p=0.011 for DVT and 0.004 for PE). Cost-effectiveness and lack of a reversal agent were cited as the major disadvantages for NOAC use. PMID- 26125478 TI - Adult Spinal Deformity: Contemporary Treatment and Patient Outcomes. AB - The incidence of symptomatic adult spinal deformity (ASD) is increasing due to aging of the population, iatrogenic factors, and an increasingly active elderly population. Spinal deformity in the adult population can produce major functional disability. Patients with less severe forms of ASD can generally be managed without operative intervention. For those individuals with disabling pain, functional impairment, or progressive spinal malalignment, surgical treatment is available and effective. However, the surgery is complex and associated with a significant risk of perioperative complications. Efficacy and safety is optimal when operative intervention is performed by a surgical team (and hospital system) experienced in the management of complex spinal pathology. Quality of life for the ASD patient can be greatly improved with proper patient selection, technical execution, and perioperative care. PMID- 26125479 TI - An Electrical Burn. PMID- 26125480 TI - Implications of the Affordable Care Act on Access to Effective HIV Services in Rhode Island. PMID- 26125482 TI - Multiple Drug Transport Pathways through Human P-Glycoprotein. AB - P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 A through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented. PMID- 26125483 TI - Social, Reproductive, and Attitudinal Factors Associated with U.S. Women's Disagreement with the Passage of the Affordable Care Act. AB - BACKGROUND: Notably absent from research and public and policy dialogue on the Affordable Care Act (ACA) and reproductive health care are women's perspectives and a broader understanding of factors that shape ACA attitudes. We investigated social, reproductive, and attitudinal factors associated with women's disagreement with the passage of the ACA. METHODS: Data were drawn from the Women's Health Care Experiences and Preferences Study, our population-based internet survey of 1,078 randomly sampled United States women ages 18-55 years conducted in September 2013. Items measured ACA attitudes, including disagreement with the ACA's passage. We examined relationships between ACA disagreement, sociodemographic and reproductive characteristics, health service experiences, and reproductive health care and policy attitudes with logistic regression. RESULTS: Among women who had heard of the ACA (n=888), 35% disagreed with it and 38% did not know how they felt. Black women (adjusted odds ratio [aOR] 0.12, 95% confidence interval [CI] 0.03-0.55) and women with incomes of >$75k (aOR 0.38, CI 0.17-0.88), Medicare/Medicaid insurance (aOR 0.24, CI 0.10-0.61), and infrequent religious service attendance (aOR 0.57, CI 0.35-0.93) were less likely to disagree with the ACA's passage, compared with their counterparts. Republican party affiliation was the strongest predictor of ACA disagreement (aOR 17.10, CI 9.12-32.09). Negative beliefs about the ACA's ability to improve access to preferred care and regarding employers' and the government's roles in reproductive health care were positively associated with ACA disagreement. CONCLUSIONS: Many women who could benefit from the ACA disagree with or do not know how they feel about its passage, which may influence participation in ACA benefits and services. PMID- 26125484 TI - Onset Time and Durability of Huntingtin Suppression in Rhesus Putamen After Direct Infusion of Antihuntingtin siRNA. AB - One possible treatment for Huntington's disease involves direct infusion of a small, interfering RNA (siRNA) designed to reduce huntingtin expression into brain tissue from a chronically implanted programmable pump. Here, we studied the suppression of huntingtin mRNA achievable with short infusion times, and investigated how long suppression may persist after infusion ceases. Rhesus monkeys received 3 days of infusion of Magnevist into the putamen to confirm catheter patency and fluid distribution. After a 1-week washout period, monkeys received radiolabeled siRNA targeting huntingtin. After 1 or 3 days of siRNA delivery, monkeys were either terminated, or their pumps were shut off and they were terminated 10 or 24 days later. Results indicate that the onset of huntingtin mRNA suppression in the rhesus putamen occurs rapidly, achieving a plateau throughout the putamen within 4 days. Conversely, loss of huntingtin suppression progresses slowly, persisting an estimated 27-39 days in the putamen and surrounding white matter. These findings indicate the rapid onset and durability of siRNA-mediated target gene suppression observed in other organs also occurs in the brain, and support the use of episodic delivery of siRNA into the brain for treatment of Huntington's disease and possibly other neurodegenerative diseases. PMID- 26125485 TI - Effect of hemodynamics on the recurrence of posterior communicating artery aneurysm: a computational fluid dynamics simulation study. AB - AIM: To compare the hemodynamic characteristics of posterior communicating artery aneurysm before and after embolization and investigate its relationship with aneurysm recurrence using a computational fluid dynamics simulation study. METHODS: Thirteen patients undergone embolization of posterior communicating artery aneurysm between January 2008 and February 2010 were enrolled and divided into recurrent and recovered group according to their follow-up angiographic data. Aneurysm models were established using three-dimensional cerebral angiography data collected before and after embolization. Preoperative and postoperative hemodynamic modalities at aneurysm neck region were analyzed with computational fluid dynamics software using the finite element algorithm. In this study, computational models were set according to transcranial Doppler pulsatile flow, and the part of aneurysm occluded by spring coil is completely independent of the blood flow. RESULTS: In recurrent group, peak systolic wall shear stress and blood flow velocity at the aneurysm neck region were significant increased after the embolization. On the contrary, in recovered group peak systolic wall shear stress and blood flow velocity were significantly reduced after the embolization. The recurrent group also had higher post-embolization peak systolic wall shear stress and blood flow velocity than the recovered group. CONCLUSION: High wall shear stress and blood flow velocity after embolization at the neck region of posterior communicating artery aneurysm may promote early aneurysm recurrence. PMID- 26125486 TI - Stereoselective Determination of Tebuconazole in Water and Zebrafish by Supercritical Fluid Chromatography Tandem Mass Spectrometry. AB - A simple and sensitive method for the enantioselective determination of tebuconazole enantiomers in water and zebrafish has been established using supercritical fluid chromatography (SFC)-MS/MS. The effects of the chiral stationary phases, mobile phase, auto back pressure regulator (ABPR) pressure, column temperature, flow rate of the mobile phase, and compensation pump solvent were evaluated. Finally, the optimal SFC-MS/MS working conditions were determined to include a CO2/MeOH mobile phase (87:13, v/v), 2.0 mL/min flow rate, 2200 psi ABPR, and 30 degrees C column temperature using a Chiralpak IA-3 chiral column under electrospray ionization positive mode. The modified QuEChERS method was applied to water and zebrafish samples. The mean recoveries for the tebuconazole enantiomers were 79.8-108.4% with RSDs <= 7.0% in both matrices. The LOQs ranged from 0.24 to 1.20 MUg/kg. The developed analytical method was further validated by application to the analysis of authentic samples. PMID- 26125487 TI - Complexation and release of DNA in polyplexes formed with reducible linear poly(beta-amino esters). AB - Designing nanocarriers for gene delivery is a multidisciplinary challenge that involves not only DNA condensation with biocompatible polymers, but also DNA release processes. Once the genetic material is introduced into the cell, the rupture of degradable bonds permits the unpacking and release of the load. In this work, a dual-degradable polycation - composed by a linear poly(beta-amino ester) chain in which ester and disulfide bonds coexist - has been used to condense a DNA plasmid. The goal was to reinforce the spontaneous hydrolysis of the ester groups with the intracellular break-up of the disulfide bonds, since these reducible bonds are degraded in the reductive intracellular environment. For a comparative study, two poly(beta-amino ester) molecules differing only in the presence (or absence) of some SS bonds have been tested. DNA condensation, physico-chemical characterization of the polyplexes formed, and degradation studies have been carried out at pH 5 and pH 7. The acidic conditions gave the best nanoparticles, due to a better solubilization of both polymers and to a higher stability of the ester bonds. Despite the synthesis and storage of polyplexes were much more appropriate at pH 5, transfection efficiency in HeLa cells was similar irrespective the original pH used. Only in those polyplexes formed at low polymer:DNA ratios (i.e. 5 and 10 (w/w)) was transfection more effective when the plasmid was condensed at an acidic pH. With regard to the DNA release efficiency in the intracellular medium, degradation of the polymers was practically governed by the rapid hydrolysis of the ester groups, this spontaneous and rapid process masking, unfortunately, any potential contribution associated with the breakup of the disulfide bonds. PMID- 26125488 TI - Gray matter abnormalities in cocaine versus methamphetamine-dependent patients: a neuroimaging meta-analysis. AB - BACKGROUND: Voxel-based morphometry has been used to explore gray matter alterations in cocaine and methamphetamine dependence. However, the results of this research are inconsistent. OBJECTIVES: The current study meta-analytically examined neuroimaging findings of all studies published before 2014 using the Anisotropic Effect-Size Signed Differential Mapping (ES-SDM). METHODS: Independent investigators searched four major databases for relevant neuroimaging studies involving cocaine and methamphetamine dependence. Nine cocaine and four methamphetamine studies met inclusion criteria. RESULTS: Results indicated that cocaine- and methamphetamine-dependent patients share overlapping regional gray matter abnormalities compared to healthy controls. However, subgroup analysis showed some regional differences; with methamphetamine showing more prominent reductions in the left superior temporal gyrus and the right inferior parietal lobe. Reductions in the right insula and the left superior frontal gyrus were more prominent in cocaine dependence. Moderator analyses indicated that with longer use, cocaine is associated with reductions in the right hippocampus, right middle temporal gyrus, and right inferior frontal gyrus, while methamphetamine is associated with reductions in the left precentral gyrus and the right supramarginal gyrus. CONCLUSION: These findings indicate that cocaine and methamphetamine dependence are significantly and differentially associated with gray matter abnormalities. Results also point to possible gray matter recovery after abstinence from methamphetamine. Although the sample size was adequate, these findings should be considered preliminary and analyses should be revisited with additional primary research focusing on long or short-term duration of use, as well as the length of abstinence. PMID- 26125489 TI - Quantitative distribution of Salmonella spp. and Escherichia coli on beef carcasses and raw beef at retail establishments. AB - Salmonella is a foodborne pathogen that commonly inhabits the gastrointestinal tract of a healthy feedlot cattle and can be transferred to the carcass surface during hide removal and evisceration procedures. Numerous investigations on Salmonella prevalence throughout different stages of the beef chain have been conducted. In contrast, limited studies are available on quantitative determinations of Salmonella at different steps in raw meat production. Quantitative data, particularly for pathogenic bacteria such as Salmonella are important for quantitative risk assessment. Salmonella spp. and Escherichia coli populations were enumerated on beef carcass samples collected at abattoirs and also in beef chunks and ground beef samples collected from butcher's shops at retail in Jalisco State, Mexico. Sponge samples from beef carcass sides (n=142) were collected immediately after final water wash and before chilling at three non-federally inspected abattoirs following USDA-FSIS sampling protocols. Beef chunks (n=84) and ground beef (n=65) samples were obtained from 86 butcher's shops. Salmonella enumeration was conducted by the Most Probable Number method and E. coli counts were determined using Petrifilm plates. Salmonella was isolated from 18% of beef carcasses, 39% of beef chunks and 71% of ground beef samples. Salmonella mean counts were 1.3+/-0.9 Log MPN/300 cm(2) on beef carcasses, 1.9+/-0.9 and 2.3+/-1.1 Log MPN/25 g in beef chunks and ground beef samples, respectively. Twenty-six Salmonella serotypes and 11 serogroups were identified among 432 isolates recovered. Salmonella typhimurium (14%), Salmonella sinstorf (12%) and S. Group E1 monophasic (10%) were the most frequent. Escherichia coli was present on 97, 84 and 100% of beef carcasses, beef chunks and ground beef samples, respectively. Escherichia coli mean counts were 3.2+/ 0.7 Log CFU/300 cm(2), 3.9+/-1.1 and 4.5+/-1.2 Log CFU/25 g on beef carcasses, beef chunks and ground beef, respectively. Salmonella prevalence and mean counts found in raw beef were higher than previously reported in studies from other countries. The data collected in this study show a trend in the prevalence of Salmonella to be higher as meat processing is extended at retail. This, together with the diversity of serotypes found, indicates that raw meat is exposed to multiple contamination sources during slaughter and retail processing and highlights the necessity to implement Sanitation Standard Operating Procedures for those establishments. Finally, this study provides quantitative information for future risk assessments associated with the risk of human salmonellosis. PMID- 26125490 TI - Recent Progress in RXLR Effector Research. AB - Some of the most devastating oomycete pathogens deploy effector proteins, with the signature amino acid motif RXLR, that enter plant cells to promote virulence. Research on the function and evolution of RXLR effectors has been very active over the decade that has transpired since their discovery. Comparative genomics indicate that RXLR genes play a major role in virulence for Phytophthora and downy mildew species. Importantly, gene-for-gene resistance against these oomycete lineages is based on recognition of RXLR proteins. Comparative genomics have revealed several mechanisms through which this resistance can be broken, most notably involving epigenetic control of RXLR gene expression. Structural studies have revealed a core fold that is present in the majority of RXLR proteins, providing a foundation for detailed mechanistic understanding of virulence and avirulence functions. Finally, functional studies have demonstrated that suppression of host immunity is a major function for RXLR proteins. Host protein targets are being identified in a variety of plant cell compartments. Some targets comprise hubs that are also manipulated by bacteria and fungi, thereby revealing key points of vulnerability in the plant immune network. PMID- 26125491 TI - Intraspecies Interaction of Fusarium graminearum Contributes to Reduced Toxin Production and Virulence. AB - Fusarium graminearum is a pathogenic fungus that causes Fusarium head blight in wheat and lowers the yield and quality of grains by contamination with the trichothecene mycotoxin deoxynivalenol. The fungi coexist and interact with several different fusaria as well as other plant pathogenic fungi and bacteria in the field. In Canada, F. graminearum exists as two main trichothecene chemotypes: 3-acetyldeoxynivalenol and 15-acetyldeoxynivalenol. To understand the potential interactions between two isolates of these chemotypes, we conducted coinoculation studies both in culture and in planta. The studies showed that intraspecies interaction reduces trichothecene yield in culture and disease symptoms in wheat. To elucidate the genes involved in the intraspecies interaction, expression profiling was performed on RNA samples isolated from coinoculated cultures, and potential genes were identified by using the genome sequences of the respective isolates. PMID- 26125493 TI - Differential Decay of Wastewater Bacteria and Change of Microbial Communities in Beach Sand and Seawater Microcosms. AB - Laboratory microcosm experiments were conducted to determine the decay kinetics of wastewater bacteria and the change of microbial communities in beach sand and seawater. Cultivation-based methods showed that common fecal indicator bacteria (FIBs; Escherichia coli, enterococci, and Clostridium perfringens) exhibited biphasic decay patterns in all microcosms. Enterococci and C. perfringens, but not E. coli, showed significantly smaller decay rates in beach sand than in seawater. Cultivation-independent qPCR quantification of 16S rRNA gene also showed significantly slower decrease of total bacterial densities in beach sand than in seawater. Microbial community analysis by next-generation sequencing (NGS) further illustrated that the decreasing relative abundance of wastewater bacteria was contrasted by the increase in indigenous beach sand and seawater microbiota, and the overall microbial community dynamics corresponded well with the decay of individual FIB populations. In summary, the differential decay of wastewater bacteria in beach sand and in seawater provides a kinetic explanation to the often-observed higher abundance of FIBs in beach sand, and the NGS-based microbial community analysis can provide valuable insights to understanding the fate of wastewater bacteria in the context of indigenous microbial communities in natural environments. PMID- 26125492 TI - Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy. AB - INTRODUCTION: Current gene therapy involves replacement of defective gene by delivery of healthy genetic material to precede normal function. Virus-mediated gene delivery is the most successful and efficient method for gene therapy, but it has been challenged due to serious safety concerns. Conversely, gene delivery using plasmid DNA (pDNA) is considered safer, but its transfection efficiency is much lower than virus-mediated gene transfer. Recently, mRNA has been suggested as an alternative option to avoid undesired insertion of delivered DNA sequences with higher transfection efficiency and stability. AREA COVERED: In this review, we summarize the currently available strategies of mRNA modification to increase the therapeutic efficacy; we also highlight the recent improvements of mRNA delivery for in vivo applications of gene therapy. EXPERT OPINION: The use of mRNA-based gene transfer could indeed be a promising new strategy for gene therapy. Notable advantages include no risk of integration into the genomic DNA, adjustable gene expression and easier modulation of the immune system. By reducing or utilizing the immunogenic properties, mRNA offers a promising tool for gene/or transcript replacement. PMID- 26125494 TI - Crystalline Oligo(ethylene sulfide) Domains Define Highly Stable Supramolecular Block Copolymer Assemblies. AB - With proper control over copolymer design and solvation conditions, self assembled materials display impressive morphological variety that encompasses nanoscale colloids as well as bulk three-dimensional architectures. Here we take advantage of both hydrophobicity and crystallinity to mediate supramolecular self assembly of spherical micellar, linear fibrillar, or hydrogel structures by a family of highly asymmetric poly(ethylene glycol)-b-oligo(ethylene sulfide) (PEG OES) copolymers. Assembly structural polymorphism was achieved with modification of PEG-OES topology (linear versus multiarm) and with precise, monomer-by-monomer control of OES length. Notably, all three morphologies were accessed utilizing OES oligomers with degrees of polymerization as short as three. These exceptionally small assembly forming blocks represent the first application of ethylene sulfide oligomers in supramolecular materials. While the assemblies demonstrated robust aqueous stability over time, oxidation by hydrogen peroxide progressively converted ethylene sulfide residues to increasingly hydrophilic and amorphous sulfoxides and sulfones, causing morphological changes and permanent disassembly. We utilized complementary microscopic and spectroscopic techniques to confirm this chemical stimulus-responsive behavior in self-assembled PEG-OES colloidal dispersions and physical gels. In addition to inherent stimulus responsive behavior, fibrillar assemblies demonstrated biologically relevant molecular delivery, as confirmed by the dose-dependent activation of murine bone marrow-derived dendritic cells following fibril-mediated delivery of the immunological adjuvant monophosphoryl lipid A. In physical gels composed of either linear or multiarm PEG-OES precursors, rheologic analysis also identified mechanical stimulus-responsive shear thinning behavior. Thanks to the facile preparation, user-defined morphology, aqueous stability, carrier functionality, and stimuli-responsive behaviors of PEG-OES supramolecular assemblies, our findings support a future role for these materials as injectable or implantable biomaterials. PMID- 26125495 TI - Correction to Deciphering the Mechanism of Carbonic Anhydrase Inhibition with Coumarins and Thiocoumarins. PMID- 26125496 TI - Prevalence of Enterohemorrhagic Escherichia coli O26, O45, O103, O111, O121, O145, and O157 on Hides and Preintervention Carcass Surfaces of Feedlot Cattle at Harvest. AB - Cattle hides are a main source of enterohemorrhagic Escherichia coli (EHEC) contamination of beef carcasses. The objectives of this study were to (1) determine the prevalence of "top 6" non-O157 plus O157:H7 EHEC (EHEC-7) on feedlot cattle hides and their matched preintervention carcasses; (2) assess the agreement among detection methods for these matrices; and (3) conduct a molecular risk assessment of EHEC-7 isolates. Samples from 576 feedlot cattle were obtained at a commercial harvest facility and tested for EHEC-7 by a culture-based method and the polymerase chain reaction/mass spectrometry-based NeoSEEK(TM) STEC Detection and Identification test (NS). Prevalence data were analyzed with generalized linear mixed models. The cumulative prevalence of EHEC-7 in hide samples as detected by NS was 80.7%, with a distribution of 49.9%, O145; 37.1%, O45; 12.5%, O103; 11.0%, O157; 2.2%, O111; 2.0%, O121; and 0.2%, O26. In contrast, the cumulative prevalence of EHEC-7 in hide samples by culture was 1.2%, with a distribution of 0.6%, O157; 0.4%, O26; 0.2%, O145; and 0%, O45, O103, O111, and O121. The cumulative prevalence of EHEC-7 on matched preintervention carcasses as detected by NS was 6.0%, with a distribution of 2.8%, O157; 1.6%, O145; 1.2%, O103; 1.1%, O45; 0.2%, O26; and 0.0%, O111 and O121. Although the culture-based method detected fewer positive hide samples than NS, it detected EHEC in five hide samples that tested negative for the respective organism by NS. McNemar's chi-square tests indicated significant (p<0.05) disagreement between methods. All EHEC-7 isolates recovered from hides were seropathotype A or B, with compatible virulence gene content. This study indicates that "top 6" and O157:H7 EHEC are present on hides, and to a lesser extent, preintervention carcasses of feedlot cattle at harvest. However, continued improvement in non-O157 detection methods is needed for accurate estimation of prevalence, given the discordant results across protocols. PMID- 26125497 TI - Comparison of the Anti-angiogenic and Anti-inflammatory Effects of Two Antibiotics: Clarithromycin Versus Moxifloxacin. AB - PURPOSE: Clarithromycin is a 14-membered ring macrolide antibiotic with anti inflammatory as well as antibacterial activity, and has been used worldwide. Moxifloxacin is a leading fourth generation quinolone antibiotic that has been used worldwide perioperatively. We intended to evaluate whether clarithromycin can suppress angiogenesis and inflammation in the cornea, and to compare the anti inflammatory and anti-angiogenic effects of the two antibiotics, clarithromycin and moxifloxacin. METHODS: We made a murine corneal suture model and tested the anti-inflammatory and anti-angiogenic effects of clarithromycin (5 mg/ml) and moxifloxacin (5 mg/ml) in two randomly divided groups. Dexamethasone (5 mg/ml) was used as a positive control. After making two sutures on the cornea, we performed subconjunctival injections (10 MUl) on each group on the day of suture, and every day thereafter until the 8th day post-suture. After harvesting corneas on the 8th post-suture day for immunohistochemical staining, we compared neovascularization (NV), lymphangiogenesis (LY) and inflammatory cell infiltration among the groups. RESULTS: Clarithromycin suppressed NV, LY and inflammatory infiltration, compared with phosphate-buffered saline (PBS). However, moxifloxacin did not suppress NV, LY, or inflammatory infiltration, compared with PBS. Comparison between clarithromycin and moxifloxacin, clarithromycin showed a tendency of decreasing LY (p = 0.063) and had less inflammatory cell infiltration (p < 0.05) than did the moxifloxacin group. The anti-(lymph)angiogenic and anti-inflammatory effects of clarithromycin were as high as those of dexamethasone. CONCLUSION: Clarithromycin suppressed LY and inflammation in the cornea, and its anti-inflammatory effect was significantly superior to that of moxifloxacin. PMID- 26125498 TI - Roles of jasmonate signalling in plant inflorescence and flower development. AB - Development of inflorescences and flowers in plants is controlled by the combined action of environmental and genetic signals. Investigations reveal that the phytohormone jasmonate (JA) plays a critical function in plant reproduction such as male fertility, sex determination and seed maturation. Here, we review recent progress on JA synthesis, signalling, the interplay between JAs and other hormones, and regulatory network of JA in controlling the development of inflorescence, flower and the male organ. The conserved and diversified roles of JAs in meristem transition and specification of flower organ identity and number, and multiple regulatory networks of JAs in stamen development are highlighted. Further, this review provides perspectives on future research endeavors to elucidate mechanisms underlying JAs homeostasis and transport during plant reproductive development. PMID- 26125499 TI - Role of plant growth regulators as chemical signals in plant-microbe interactions: a double edged sword. AB - Growth regulators act not only as chemicals that modulate plant growth but they also act as signal molecules under various biotic and abiotic stresses. Of all growth regulators, abscisic acid (ABA) is long known for its role in modulating plants response against both biotic and abiotic stress. Although the genetic information for ABA biosynthesis in plants is well documented, the knowledge about ABA biosynthesis in other organisms is still in its infancy. It is known that various microbes including bacteria produce and secrete ABA, but the overall functional significance of why ABA is synthesized by microbes is not known. Here we discuss the functional involvement of ABA biosynthesis by a pathogenic fungus. Furthermore, we propose that ABA biosynthesis in plant pathogenic fungi could be targeted for novel fungicidal discovery. PMID- 26125500 TI - Degradation of trace concentrations of the persistent groundwater pollutant 2,6 dichlorobenzamide (BAM) in bioaugmented rapid sand filters. AB - Groundwater is an important drinking water resource. Yet, this resource is threatened by pollution from chemicals, such as pesticides and their degradation products. To investigate the potential for remediation of groundwater polluted by trace concentrations of the pesticide residue 2,6-dichlorobenzamide (BAM), we established a pilot waterworks including two sand filters. The waterworks treated groundwater polluted with 0.2 MUg/L BAM at flow conditions typical for rapid sand filters. Bioaugmentation of the sand filter with a specific BAM-degrading bacterium (Aminobacter sp. MSH1) resulted in significant BAM degradation to concentrations below the legal threshold level (0.1 MUg/L), and this without adverse effects on other sand filter processes such as ammonium and iron oxidation. However, efficient degradation for more than 2-3 weeks was difficult to maintain due to loss of MSH1-bacteria, especially during backwashing. By limiting backwash procedures, the period of degradation was prolonged, but bacteria (and hence degradation activity) were still lost with time. Protozoa were observed to grow in the filters to a density that contributed significantly to the general loss of bacteria from the filters. Additionally, the concentration of easily assimilable organic carbon (AOC) in the remediated water may have been too low to sustain a sufficient population of degrader bacteria in the filter. This study shows that scaling up is not trivial and shortcomings in transferring degradation rates obtained in batch experiments to a rapid sand filter system are discussed. Further optimization is necessary to obtain and control more temporally stable systems for water purification. However, for the first time outside the laboratory and at realistic conditions a potential for the biodegradation of recalcitrant micropollutants in bioaugmented rapid sand filters is shown. PMID- 26125503 TI - Mechanism of Magnetostructural Transitions in Copper-Nitroxide-Based Switchable Molecular Magnets: Insights from ab Initio Quantum Chemistry Calculations. AB - The gradual magnetostructural transition in breathing crystals based on copper(II) and pyrazolyl-substituted nitronyl nitroxides has been analyzed by means of DDCI quantum chemistry calculations. The magnetic coupling constants (J) within the spin triads of Cu(hfac)2L(Bu).0.5C8H18 have been evaluated for the X ray structures reported at different temperatures. The coupling is strongly antiferromagnetic at low temperature and becomes ferromagnetic when the temperature increases. The intercluster magnetic coupling (J') is antiferromagnetic and shows a marked dependence on temperature. The magnetostructural transition can be reproduced using the calculated J values for each structure in the simulation of the magnetic susceptibility. However, the MU(T) curve can be improved nicely by considering the coexistence of two phases in the transition region, whose ratio varies with temperature corresponding to both the weakly and strongly coupled spin states. These results complement a recent VT-FTIR study on the parent Cu(hfac)2L(Pr) compound with a gradual magnetostructural transition. PMID- 26125501 TI - Bioactive lipid coating of bone allografts directs engraftment and fate determination of bone marrow-derived cells in rat GFP chimeras. AB - Bone grafting procedures are performed to treat wounds incurred during wartime trauma, accidents, and tumor resections. Endogenous mechanisms of repair are often insufficient to ensure integration between host and donor bone and subsequent restoration of function. We investigated the role that bone marrow derived cells play in bone regeneration and sought to increase their contributions by functionalizing bone allografts with bioactive lipid coatings. Polymer-coated allografts were used to locally deliver the immunomodulatory small molecule FTY720 in tibial defects created in rat bone marrow chimeras containing genetically-labeled bone marrow for monitoring cell origin and fate. Donor bone marrow contributed significantly to both myeloid and osteogenic cells in remodeling tissue surrounding allografts. FTY720 coatings altered the phenotype of immune cells two weeks post-injury, which was associated with increased vascularization and bone formation surrounding allografts. Consequently, degradable polymer coating strategies that deliver small molecule growth factors such as FTY720 represent a novel therapeutic strategy for harnessing endogenous bone marrow-derived progenitors and enhancing healing in load-bearing bone defects. PMID- 26125502 TI - Decellularized skeletal muscle as an in vitro model for studying drug extracellular matrix interactions. AB - Several factors can affect drug absorption after intramuscular (IM) injection: drug solubility, drug transport across cell membranes, and drug metabolism at the injection site. We found that potential interactions between the drug and the extracellular matrix (ECM) at the injection site can also affect the rate of absorption post-injection. Using decellularized skeletal muscle, we developed a simple method to model drug absorption after IM injection, and showed that the nature of the drug-ECM interaction could be investigated by adding compounds that alter binding. We validated the model using the vitamin B12 analog cobinamide with different bound ligands. Cobinamide is being developed as an IM injectable treatment for cyanide poisoning, and we found that the in vitro binding data correlated with previously published in vivo drug absorption in animals. Commercially available ECM products, such as collagen and GelTrex, did not recapitulate drug binding behavior. While decellularized ECM has been widely studied in fields such as tissue engineering, this work establishes a novel use of skeletal muscle ECM as a potential in vitro model to study drug-ECM interactions during drug development. PMID- 26125504 TI - Did we abandon probucol too soon? AB - PURPOSE OF REVIEW: Probucol is a potent antioxidative drug that has been used for prevention and treatment of atherosclerotic cardiovascular diseases and xanthoma. Probucol has been used as a lipid-lowering drug for a long time especially in Japan, although Western countries quitted its use because of the reduction in serum HDL-cholesterol (HDL-C). This review highlights both basic and clinical studies that provide new insights into the pleiotropic effects of probucol. RECENT FINDINGS: Recently, the mechanisms for the pharmacologic actions of probucol have been elucidated at the molecular level with a special focus on HDL metabolism and its functions. Probucol enhances plasma cholesteryl ester transfer protein activity and hepatic scavenger receptor class B type I, causing a decrease in HDL-C. It also accelerates the antioxidative function of HDL via increase in paraoxonase 1 activity. Recent retrospective analyses of probucol treated patients with heterozygous familial hypercholesterolemia and those after coronary revascularization demonstrated a strong beneficial effect of probucol on secondary prevention of cardiovascular events and mortality. SUMMARY: Probucol has pleiotropic and beneficial therapeutic effects on cardiovascular system. Although statins are effective for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease risk, probucol should be considered as an option in case statins are not effective. PMID- 26125505 TI - Sex difference in presentation and outcomes of bladder cancer: biological reality or statistical fluke? AB - PURPOSE OF REVIEW: The impact of sex on the prognosis of patients with muscle invasive bladder cancer (MIBC) is discussed. Reasons for the presumably worse prognosis in female patients may be anatomical differences, different time delays from first symptoms to diagnosis and variations in hormone receptors and tumour biology. This review summarizes literature on this topic published during the period 2012-2015. RECENT FINDINGS: Methodological quality of most available studies analysing the impact of sex on prognosis of MIBC is limited by their retrospective design or lacking standardization of study parameters. Time delay from first symptoms to diagnosis in women with bladder cancer seems possible, although a prognostic impact of this delay has not been proven yet. Recent cystectomy-series predominantly show comparable tumour stages, although strongest deterioration of prognosis in female patients is described in younger patients and in cases with lymphovascular invasion. No survival difference between sexes was found in studies with rigorous statistics using propensity score matching. Interpretation of studies analysing the prognostic impact of hormone receptors is limited by methodological shortcomings and missing definitions of subsequent signal pathways. SUMMARY: Analyses of population-based cancer-registries demonstrate a comparatively higher cancer-specific mortality for female patients, but the reason for this difference remains unclear. Interaction between sex and oncologic outcome of patients with MIBC seems to be multifactorial, while to date, an independent prognostic impact of sex cannot be proven validly. Research activities in the future should include parameters mentioned above. PMID- 26125506 TI - T-cell checkpoint inhibitors in metastatic renal cell carcinoma. AB - PURPOSE OF REVIEW: The advent of checkpoint inhibitors has fostered great expectations for long-term outcome in cancer patients. Inhibitors of programmed death -1, programmed death ligand-1 and cytotoxic T-lymphocyte associated protein 4 are targets of contemporary cancer immunotherapy. Current phase III studies are ongoing and may define a novel treatment paradigm in metastatic renal cell carcinoma (mRCC). This review focuses on current clinical data in mRCC. RECENT FINDINGS: Nivolumab and ipilimumab are the most advanced checkpoint inhibitors in the field of mRCC. Current available data include phase I and randomized phase II trials, investigating single agent or combination therapies in mRCC, with objective responses in 20-52% of patients and 19-26 months overall survival in previously treated patients. SUMMARY: Immunotherapies have fostered great expectations on long-term overall survival in mRCC. As seen with previous cytokine treatment, long-term response is a key clinical outcome. Phase III data for previously treated patients are expected later this year and may define a novel standard for treatment. Combinational therapies have generated promising response data, indicating a potential role in treatment intensification in mRCC. Combination treatment is associated with ample toxicity, which might restrict this approach to selected patients. The major task for the future is to tailor immunotherapy for individual patients. PMID- 26125507 TI - Managing noninvasive recurrences after definitive treatment for muscle-invasive bladder cancer or high-grade upper tract urothelial carcinoma. AB - PURPOSE OF REVIEW: Approximately 50% of patients with muscle invasive urothelial carcinoma will relapse with distant recurrence. Though rates of local recurrence after definitive therapy have improved, management remains a challenge. In this review, treatment strategies for this cohort are re-examined in an effort to enhance patient outcomes. RECENT FINDINGS: Urothelial carcinoma continues to demonstrate high rates of recurrence and low rates of survival. Similarly to the treatment of primary urothelial cancer, treatment of recurrence focuses on cytology, stage, and clinical characteristics. Current areas of interest have focused on identification and causes/predictors of recurrence. SUMMARY: Limited progress has been achieved in differentiating management of recurrent urothelial carcinoma from the treatment of primary urothelial carcinoma. However, there may be an increasing role for endoscopic and organ conserving therapies for carefully selected patients with recurrent noninvasive urothelial carcinoma. Identifying those at risk for early recurrence and early diagnosis of recurrence may be the most beneficial future strategies. The treatment regimen for noninvasive bladder recurrence after radical nephroureterectomy for upper tract urothelial carcinoma should include intravesical chemotherapy or Bacillus Calmette-Guerin to prevent further bladder recurrence or tumor progression. We do not advocate diversion sparing techniques for local recurrence after radical cystectomy. Metastasectomy for distant/metastatic urothelial carcinoma recurrence represents a promising area of future study. PMID- 26125508 TI - Role of metastasectomy in metastatic renal cell carcinoma. AB - PURPOSE OF REVIEW: Management of patients with metastatic renal cell carcinoma is challenging and continues to be delivered in a multidisciplinary context. Even with the advent of systemic targeted therapy, complete remission with these new agents is rare using systemic therapy alone. Surgical resection of the primary tumor and metastatic deposits continues to play an important role in managing patients with metastatic renal cell carcinoma when aiming for complete remissions. To date, despite the lack of level 1 evidence, metastasectomy appears to prolong survival and achieve long-term cure in carefully selected patients. This review examines current evidence for the role of metastasectomy in renal cell carcinoma. RECENT FINDINGS: Studies continue to consistently support a benefit of complete metastasectomy for overall and cancer-specific survival at most sites for resection, with the exception of brain and bone, which tend to perform for symptomatic relief and palliation. Metastasectomy has not yet been examined in a randomized setting. The debate of survival benefit because of selection bias of patients or differences in tumor biology is relevant and has yet to be resolved in the literature. Clearly, careful patient selection remains paramount in optimizing survival benefit from metastasectomy. SUMMARY: Patients with isolated surgically resectable metastatic disease, with long disease-free intervals, and with good performance status are likely to benefit the most from metastasectomy. PMID- 26125509 TI - How should clinicians address intratumour heterogeneity in clear cell renal cell carcinoma? AB - PURPOSE OF REVIEW: Despite the availability of multiple targeted therapies, the 5 year survival rate of patients with metastatic clear cell renal cell carcinoma (ccRCC) rarely exceeds 10%. Recent insights into the mutational landscape and evolutionary dynamics of ccRCC have offered up a plausible explanation for these outcomes. The purpose of this review is to link the research findings to potential changes in clinical practice. RECENT FINDINGS: Intratumour heterogeneity (ITH) dominates the evolutionary landscape in ccRCC at the genetic, transcriptomic and proteomic level. Spatial and temporal separation of tumour subclones within the primary tumour as well as between primary and metastatic sites has been demonstrated at single nucleotide resolution. In the cases analysed to date, approximately two-thirds of somatic mutations are not shared between multiple biopsies from the same primary tumour. Very few of the key disease-driving events are shared across all primary tumour regions (with the exception of VHL and loss of chromosome 3p), whereas the majority are restricted to one or more tumour regions (TP53, SETD2, BAP1, PTEN, mTOR, PIK3CA and KDM5C). SUMMARY: ITH must be considered in the management of ccRCC with respect to diagnostic procedures, prognostic and predictive biomarkers and drug development. PMID- 26125510 TI - Trimodal therapy for invasive bladder cancer: is it really equal to radical cystectomy? AB - PURPOSE OF REVIEW: Trimodal therapy (TMT) is considered the most effective bladder-sparing approach for muscle-invasive urothelial carcinoma of the bladder (MIBC) and an alternative to radical cystectomy. The purpose of this article was to review and summarize the current knowledge on the equivalence of TMT and radical cystectomy based on the recent literature. RECENT FINDINGS: TMT consists of a maximal transuretral resection of the bladder, followed by a concurrent radiotherapy and chemotherapy, limiting salvage radical cystectomy to nonresponder tumors or muscle-invasive recurrence. In large population studies, less than 6% of the patients with nonmetastatic MIBC receive a chemoradiation therapy and this rate is stable. A growing body of evidence exists that TMT provides good oncologic outcomes with low morbidity when compared with radical cystectomy. TMT requires, however, a close follow-up because of the high risk of local recurrence and salvage radical cystectomy in up to 30% of the patients. Salvage radical cystectomy can be performed with adequate results but does not offer the same opportunity of reconstruction and functional outcomes than primary radical cystectomy. SUMMARY: Although radical cystectomy is still the treatment of reference for most of the patients with localized MIBC, TMT represents a reasonable alternative in highly selected patients. Any firm conclusion on the equivalence or superiority of one treatment to the other is still limited by the lack of randomized controlled trials and the heterogeneity of the available literature. Future studies and multidisciplinary approach are mandatory to optimize the patient selection and regimen of TMT. PMID- 26125511 TI - Prognostic significance of substage and WHO classification systems in T1 urothelial carcinoma of the bladder. AB - PURPOSE OF REVIEW: Treatment of T1 urothelial bladder cancer (T1-BC) is challenging as risk assessment criteria for progression are lacking. Histological grade and T1 substage have been identified as important prognostic factors. Currently, no consensus exists regarding the optimal sub-staging and grading systems for T1-BC. We reviewed recent advances in the various grading and sub staging systems and their clinical applicability. RECENT FINDINGS: Stratification by muscularis mucosae invasion is the most explored sub-staging system. Its prognostic value was established by 12/23 (52%) available studies. Importantly, muscularis mucosae identification varied substantially among pathologists. Sub staging based on diameter of invasive carcinoma [T1 microinvasive and T1 extensive-invasive (T1m/e)] proved a more reproducible system with at least equal prognostic value. However, more study is needed to investigate interobserver variation. For nonmuscle-invasive bladder cancer grading, the 1973 and 2004 WHO classifications both provide independent prognostic information. However, remarkably few studies have investigated their applicability in T1-BC only. The available reports suggest that the 1973 WHO classification is superior to WHO 2004. SUMMARY: If multicenter studies confirm the promising results of T1m/e sub staging, it may be incorporated in the Internation Union Against Cancer TNM classification system for urinary bladder cancer. More studies are warranted to define the optimal classification system for grade in T1-BC. PMID- 26125512 TI - Computational Study of Chemical Reactivity Using Information-Theoretic Quantities from Density Functional Reactivity Theory for Electrophilic Aromatic Substitution Reactions. AB - The electrophilic aromatic substitution for nitration, halogenation, sulfonation, and acylation is a vastly important category of chemical transformation. Its reactivity and regioselectivity is predominantly determined by nucleophilicity of carbon atoms on the aromatic ring, which in return is immensely influenced by the group that is attached to the aromatic ring a priori. In this work, taking advantage of recent developments in quantifying nucleophilicity (electrophilicity) with descriptors from the information-theoretic approach in density functional reactivity theory, we examine the reactivity properties of this reaction system from three perspectives. These include scaling patterns of information-theoretic quantities such as Shannon entropy, Fisher information, Ghosh-Berkowitz-Parr entropy and information gain at both molecular and atomic levels, quantitative predictions of the barrier height with both Hirshfeld charge and information gain, and energetic decomposition analyses of the barrier height for the reactions. To that end, we focused in this work on the identity reaction of the monosubstituted-benzene molecule reacting with hydrogen fluoride using boron trifluoride as the catalyst in the gas phase. We also considered 19 substituting groups, 9 of which are ortho/para directing and the other 9 meta directing, besides the case of R = -H. Similar scaling patterns for these information-theoretic quantities found for stable species elsewhere were disclosed for these reactions systems. We also unveiled novel scaling patterns for information gain at the atomic level. The barrier height of the reactions can reliably be predicted by using both the Hirshfeld charge and information gain at the regioselective carbon atom. The energy decomposition analysis ensued yields an unambiguous picture about the origin of the barrier height, where we showed that it is the electrostatic interaction that plays the dominant role, while the roles played by exchange-correlation and steric effects are minor but indispensable. Results obtained in this work should shed new light for better understanding of the factors governing the reactivity for this class of reactions and assisting ongoing efforts for the design of new and more efficient catalysts for such kind of transformations. PMID- 26125514 TI - Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human beta3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects. AB - Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human beta3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant beta3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the alpha1A-AR (EC50 = 219 nM, selectivity: alpha1A/beta3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for beta3-AR agonistic activity versus alpha1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent beta3-AR agonistic activity (EC50 = 13 nM) and high selectivity (alpha1A/beta3 = >769-fold). Compound 11 was also inactive toward beta1 and beta2-ARs and showed dose dependent beta3-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats. PMID- 26125513 TI - Dynamically Allocated Hub in Task-Evoked Network Predicts the Vulnerable Prefrontal Locus for Contextual Memory Retrieval in Macaques. AB - Neuroimaging and neurophysiology have revealed that multiple areas in the prefrontal cortex (PFC) are activated in a specific memory task, but severity of impairment after PFC lesions is largely different depending on which activated area is damaged. The critical relationship between lesion sites and impairments has not yet been given a clear mechanistic explanation. Although recent works proposed that a whole-brain network contains hubs that play integrative roles in cortical information processing, this framework relying on an anatomy-based structural network cannot account for the vulnerable locus for a specific task, lesioning of which would bring impairment. Here, we hypothesized that (i) activated PFC areas dynamically form an ordered network centered at a task specific "functional hub" and (ii) the lesion-effective site corresponds to the "functional hub," but not to a task-invariant "structural hub." To test these hypotheses, we conducted functional magnetic resonance imaging experiments in macaques performing a temporal contextual memory task. We found that the activated areas formed a hierarchical hub-centric network based on task-evoked directed connectivity, differently from the anatomical network reflecting axonal projection patterns. Using a novel simulated-lesion method based on support vector machine, we estimated severity of impairment after lesioning of each area, which accorded well with a known dissociation in contextual memory impairment in macaques (impairment after lesioning in area 9/46d, but not in area 8Ad). The predicted severity of impairment was proportional to the network "hubness" of the virtually lesioned area in the task-evoked directed connectivity network, rather than in the anatomical network known from tracer studies. Our results suggest that PFC areas dynamically and cooperatively shape a functional hub-centric network to reallocate the lesion-effective site depending on the cognitive processes, apart from static anatomical hubs. These findings will be a foundation for precise prediction of behavioral impacts of damage or surgical intervention in human brains. PMID- 26125515 TI - An environmentally safe larvicide against Aedes aegypti based on in situ gelling nanostructured surfactant systems containing an essential oil. AB - HYPOTHESIS: Liquid crystalline precursors, which are in situ gelling nanostructured surfactant systems, can undergo phase transition in aqueous solution and become more structured aggregates, controlling release of larvicides and acting as biotechnology alternatives for dengue control. Such systems can contain bioactive substances as Citrus sinensis essential oil (CSEO) which exhibits biological activity against Aedes aegypti (Ae. aegypti) larvae. EXPERIMENTS: The formulations were composed by fixed concentration of CSEO stabilized by Polyoxypropylene (5) Polyoxyethylene (20) Cetyl Ether (PPG-5 CETETH 20): oleic acid (OA) 2:1, increasing water content. The phase diagram was established and systems structure was evaluated by polarized light microscopy (PLM), small angle X-ray scattering (SAXS) and rheology. Median lethal concentration was determined against Ae. aegypti larvae. FINDINGS: The phase diagram exhibited four regions: liquid crystal (LC), emulsion, microemulsion (ME) and phase separation. The PLM and SAXS distinguished microemulsions, lamellar and hexagonal LC structures. Flow and oscillatory tests showed that increasing water content increases elasticity from Newtonian to non-newtonian behavior confirming the in situ gelation behavior. The larvicidal activity of formulations indicates that these nanostructured systems improved the oil solubility in aqueous medium and in addition are potential environmental larvicide against Ae. aegypti larvae. PMID- 26125516 TI - Protection of open-metal V(III) sites and their associated CO2/CH4/N2/O2/H2O adsorption properties in mesoporous V-MOFs. AB - Metal-organic frameworks with open metal site are potential sorbents for the separation of gas mixtures; however, low valence metal will bind to oxygen in the open air causing a decrease in adsorption ability. We now report open-metal sites V(III) on both MIL-100V(III/IV) and MIL-101V(III/IV) that can be protected with water molecules, and which associated CO2/CH4/N2/O2 adsorption properties on these two mesoporous V-MOFs were investigated. The protective properties of water were investigated and evaluated using density functional theory simulations. The binding energy of single O2 on open-metal V(III) site was 93.278 kJ/mol, which decreased to 26.5 kJ/mol when H2O occupies the site. When the water coating is removed, the X-ray photoelectron spectroscopy pattern of V2p showed that the V MOF changes to MIL-100V(IV) and MIL-101V(IV) at 298 K because of the action of O2. Under these conditions, O2 binds strongly on the open V site significantly reducing the BET (Brunauer-Emmett-Teller) surface and CH4 adsorption volume of the V-MOFs. From the ideal adsorbed solution theory calculated, the adsorption selectivity of CH4/N2 is higher before than after binding of O2 (with V(III) site). In contrast, the adsorption selectivity of CO2/CH4 is higher after than before O2 binding (with no more V(III) sites). PMID- 26125517 TI - Liposomes as nanoreactors for the photochemical synthesis of gold nanoparticles. AB - A simple and novel method for the photochemical synthesis of AuNPs in liposomes is described. Gold salt is co-encapsulated with the photoinitiator Irgacure-2959 in POPC liposomes prepared via traditional thin-film hydration technique. UVA irradiation for 15 min results in encapsulated AuNPs of 2.8+/-1.6 nm in diameter that are primarily dispersed in the aqueous interior of the liposomes. PMID- 26125518 TI - Exploring the Role of La Codoping beyond Charge Compensation for Enhanced Hydrogen Evolution by Rh-SrTiO3. AB - In this theoretical study, we investigate recent observation of enhancement of hydrogen evolution efficiency of Rh-doped SrTiO3 due to codoping with La at the Sr lattice site. Using hybrid density functional theory, we have systematically studied the electronic structure of (Rh, La)-codoped SrTiO3 and compared with that of Rh-doped SrTiO3, La-doped SrTiO3, and undoped SrTiO3. The aim of the present study has been to explore the role of different factors toward the observed enhanced photoactivity of (Rh, La)-codoped SrTiO3. Doping with only Rh significantly reduces the photoabsorption energy by introducing localized acceptor states between the valence band and conduction band. Unfortunately, these states act as efficient sources for charge carrier trapping. Besides, the oxygen vacancy found to be present in the Rh-doped SrTiO3 as a charge compensating defect also accelerates the electron-hole recombination rate. We have shown that codoping with La and Rh leads to the formation of clean band structure without encountering any midgap states. Introduction of La into the Rh doped SrTiO3 not only reduces the quantity of Rh(4+) species but also suppresses the oxygen vacancy due to formation of a charge-compensated system. The presence of La favors Rh doping into the crystal structure of SrTiO3 by reducing the formation energy. Moreover, the conduction band minima are found to be shifted in the upward direction significantly due to codoping with Rh and La, thereby increasing the reducing behavior at the conduction band. This leads to enhancement of hydrogen evolution activity of SrTiO3 during photocatalytic water splitting under visible light. PMID- 26125519 TI - The bladder carcinoma secondary to schistosoma mansoni infection: A case report with review of the literature. AB - INTRODUCTION: Schistosomiasis is a rare condition in Turkey but remains second most prevelant parasitic infestation worldwide. PRESENTATION OF CASE: A 67-years old male patient admitted to a hospital with macroscopic hematuria. Bladder tumor was diagnosed and referred to our department for the treatment. Transurethral resection of bladder tumor was performed and pathological examination revealed high-grade papillary urothelial carcinoma and Schistosoma mansoni eggs. The patient used praziquantel 40mg orally for the treatment of Schistosomiasis and intravesical immunotherapy was applied 6 weeks along per week. Neither recurrence of tumor nor S. mansoni eggs in the urine were detected at the 18th month. DISCUSSION: In spite of well-known etiological relationships between Schistosoma haematobium and bladder cancer, there is very limited number of cases of bladder carcinoma secondary to S. mansoni infestation in the literature. All of the reported 5 cases were from the rural regions of Brazil. On the other hand, it was noticed that pathological examination had been reported in only one of these cases, and the diagnosis was leiomyoma. Therefore, to the best of our knowledge, there is no data in the literature regarding the clinical course of the transitional cell carcinoma secondary to S. mansoni. CONCLUSION: Regarding the increasing travels all around the world, clinicians should remember that Schistosoma infection is certainly a part of the differential diagnosis of bladder carcinoma, even if the patients are not from endemic regions. PMID- 26125520 TI - Acquisition of Consonant Clusters and Acceptable Variants in Chinese-Influenced Malaysian English-Speaking Children. AB - PURPOSE: This study investigated consonant cluster acquisition in Chinese influenced Malaysian English (ChME)-speaking children. METHOD: This cross sectional study involved 262 typically developing ChME-speaking children (138 girls, 124 boys) ages 3 to 7 years old. A single-word picture-naming task, which contained 66 words and targeted 32 syllable-initial (SI) and 14 syllable-final (SF) consonant clusters, was administered. RESULTS: Older children produced more correct productions than younger children, and there was no sex effect for consonant cluster production. SF consonant clusters were more accurate than SI consonant clusters among the younger children. The overall sequence of SI consonant cluster accuracy based on cluster categories from most to least accurate was /s/ + C, C + /w/, C + /j/, C + /l/, and C + /r/, whereas for SF consonant clusters, the order was C + stop, C + /s/, nasal + C, and /l/ + C. Two element clusters consistently had higher accuracy in comparison to three-element clusters across the age groups. The overall consonant cluster accuracy of the present study showed similar patterns to those found in previous studies of Standard English. CONCLUSION: The findings of the study will be useful in the assessment of consonant cluster production of ChME-speaking children. PMID- 26125522 TI - Bio-inspired scale-like surface textures and their tribological properties. AB - Friction, wear and the associated energy dissipation are major challenges in all systems containing moving parts. Examples range from nanoelectromechanical systems over hip prosthesis to off-shore wind turbines. Bionic approaches have proven to be very successful in many engineering problems, while investigating the potential of a bio-inspired approach in creating morphological surface textures is a relatively new field of research. Here, we developed laser-created textures inspired by the scales found on the skin of snakes and certain lizards. We show that this bio-inspired surface morphology reduced dry sliding friction forces by more than 40%. In lubricated contacts the same morphology increased friction by a factor of three. Two different kinds of morphologies, one with completely overlapping scales and one with the scales arranged in individual rows, were chosen. In lubricated as well as unlubricated contacts, the surface texture with the scales in rows showed lower friction forces than the completely overlapping ones. We anticipate that these results could have significant impact in all dry sliding contacts, ranging from nanoelectromechanical and micro positioning systems up to large-scale tribological contacts which cannot be lubricated, e.g. because they are employed in a vacuum environment. PMID- 26125521 TI - Dose-dependent inhibition of Gag cellular immunity by Env in SIV/HIV DNA vaccinated macaques. AB - The induction of a balanced immune response targeting the major structural proteins, Gag and Env of HIV, is important for the development of an efficacious vaccine. The use of DNA plasmids expressing different antigens offers the opportunity to test in a controlled manner the influence of different vaccine components on the magnitude and distribution of the vaccine-induced cellular and humoral immune responses. Here, we show that increasing amounts of env DNA results in greatly enhanced Env antibody titers without significantly affecting the levels of anti-Env cellular immune responses. Co-immunization with Env protein further increased antibody levels, indicating that vaccination with DNA only is not sufficient for eliciting maximal humoral responses against Env. In contrast, under high env:gag DNA plasmid ratio, the development of Gag cellular responses was significantly reduced by either SIV or HIV Env, whereas Gag humoral responses were not affected. Our data indicate that a balanced ratio of the 2 key HIV/SIV vaccine components, Gag and Env, is important to avoid immunological interference and to achieve both maximal humoral responses against Env to prevent virus acquisition and maximal cytotoxic T cell responses against Gag to prevent virus spread. PMID- 26125523 TI - Structural Characterization of Dihydrofolate Reductase Complexes by Top-Down Ultraviolet Photodissociation Mass Spectrometry. AB - The stepwise reduction of dihydrofolate to tetrahydrofolate entails significant conformational changes of dihydrofolate reductase (DHFR). Binary and ternary complexes of DHFR containing cofactor NADPH, inhibitor methotrexate (MTX), or both NADPH and MTX were characterized by 193 nm ultraviolet photodissociation (UVPD) mass spectrometry. UVPD yielded over 80% sequence coverage of DHFR and resulted in production of fragment ions that revealed the interactions between DHFR and each ligand. UVPD of the binary DHFR.NADPH and DHFR.MTX complexes led to an unprecedented number of fragment ions containing either an N- or C-terminal protein fragment still bound to the ligand via retention of noncovalent interactions. In addition, holo-fragments retaining both ligands were observed upon UVPD of the ternary DHFR.NADPH.MTX complex. The combination of extensive holo and apo fragment ions allowed the locations of the NADPH and MTX ligands to be mapped, with NADPH associated with the adenosine binding domain of DHFR and MTX interacting with the loop domain. These findings are consistent with previous crystallographic evidence. Comparison of the backbone cleavage propensities for apo DHFR and its holo counterparts revealed significant variations in UVPD fragmentation in the regions expected to experience conformational changes upon binding NADPH, MTX, or both ligands. In particular, the subdomain rotation and loop movements, which are believed to occur upon formation of the transition state of the ternary complex, are reflected in the UVPD mass spectra. The UVPD spectra indicate enhanced backbone cleavages in regions that become more flexible or show suppressed backbone cleavages for those regions either shielded by the ligand or involved in new intramolecular interactions. This study corroborates the versatility of 193 nm UVPD mass spectrometry as a sensitive technique to track enzymatic cycles that involve conformational rearrangements. PMID- 26125524 TI - Modifying Surface Energy of Graphene via Plasma-Based Chemical Functionalization to Tune Thermal and Electrical Transport at Metal Interfaces. AB - The high mobility exhibited by both supported and suspended graphene, as well as its large in-plane thermal conductivity, has generated much excitement across a variety of applications. As exciting as these properties are, one of the principal issues inhibiting the development of graphene technologies pertains to difficulties in engineering high-quality metal contacts on graphene. As device dimensions decrease, the thermal and electrical resistance at the metal/graphene interface plays a dominant role in degrading overall performance. Here we demonstrate the use of a low energy, electron-beam plasma to functionalize graphene with oxygen, fluorine, and nitrogen groups, as a method to tune the thermal and electrical transport properties across gold-single layer graphene (Au/SLG) interfaces. We find that while oxygen and nitrogen groups improve the thermal boundary conductance (hK) at the interface, their presence impairs electrical transport leading to increased contact resistance (rhoC). Conversely, functionalization with fluorine has no impact on hK, yet rhoC decreases with increasing coverage densities. These findings indicate exciting possibilities using plasma-based chemical functionalization to tailor the thermal and electrical transport properties of metal/2D material contacts. PMID- 26125525 TI - Antimicrobial activity of the synthesized non-allergenic urushiol derivatives. AB - Synthesized urushiol derivatives possessing different carbon atomic length in the alkyl side chain inhibited the growth of food spoilage and pathogenic microorganisms. Particularly, non-allergenic 3-pentylcatechol showed a broad antimicrobial spectrum on an agar plate. Most food spoilage and pathogenic microorganisms were sensitive to urushiol derivatives in the liquid culture. The morphologies of the microorganisms were changed after treatment of 3 pentylcatechol. PMID- 26125526 TI - Chromophoric dissolved organic matter of black waters in a highly eutrophic Chinese lake: Freshly produced from algal scums? AB - Field campaigns and an incubation experiment were conducted to evaluate the sources of chromophoric dissolved organic matter (CDOM) in black water spots in highly polluted regions of the Chinese Lake Taihu. A significant positive correlation (p<0.0001) was found between chlorophyll a (Chl-a) and the CDOM absorption coefficient a(350), indicating that algae degradation was likely the primary source of CDOM in black waters. This is supported by our field results that Chl-a, a(350) and the spectral slope ratio (SR) were significantly higher in the black water samples than in the regular samples (p<0.001). Our incubation experiment further substantiated the primary significance of biological CDOM source where a(350) increased with decreasing Chl-a concentrations. After seven days' incubation, a 72.2% decrease and a 74.9% increase were recorded for Chl-a and a(350), respectively, relative to the initial values. Parallel factor analysis identified five fluorescent components. The maximal fluorescence intensity (Fmax) of tryptophan-like C1 and microbial humic-like C3 of black water samples was significantly higher than in the regular water samples (p<0.0005). This is consistent with incubation experiment results showing a rapid increase in Fmax of the two components, emphasizing the priority of the in situ biological CDOM source in black water spots. PMID- 26125527 TI - Successive self-propagating sintering process using carbonaceous materials: A novel low-cost remediation approach for dioxin-contaminated solids. AB - The disposal of dioxin-contaminated solids was studied using a novel successive self-propagating sintering process (SSPSP) incorporating a carbonaceous material. Among the five types of carbonaceous materials investigated, Charcoal B displayed optimum adsorbent properties and was selected as the best thermal source in the current remediation approach based on economical efficiency aspects. The feasibility of this proposed approach, removal efficiencies, and congener compositions of dioxins were examined using two types of dioxin-contaminated solids (Fugan sediment and Toyo soil) that displayed different characteristics including the initial concentrations of dioxins. The removal efficiencies of DL PCBs ("dioxin-like" polychlorinated biphenyls) were higher than those of PCDD/Fs (polychlorinated dibenzo-p-dioxins/dibenzofurans), achieving 99.9 and 92% removal in the Fugan sediment and Toyo soil, respectively. In contrast, the degradation efficiencies of DL-PCBs were lower (i.e., 89.3 and 88.8%, respectively). The initial concentrations of dioxins, available precursors, and properties of the solids strongly influenced the congener compositions and removal efficiencies of dioxins. Furthermore, the dechlorination reaction pathways of high-chlorinated PCDDs and potential regeneration pathways of PCDFs from PCBs were deduced using isotope labeling. The proposed novel low-cost remediation approach for the removal of dioxins from solids is a highly efficient and environmentally sound treatment technology. PMID- 26125528 TI - Arsenic in rice and diets of children. AB - Levels of arsenic in Australian and imported rice (n = 36) were evaluated using inductively coupled plasma mass spectrometry (ICP-MS) for total arsenic and a hyphenated high-performance liquid chromatography ICP-MS system for arsenic species. The study also assessed the daily intake of total As from diets of healthy children (n = 15), collected over three consecutive days. A wide variation of total As levels (range: <0.05-0.42 mg/kg) in Australian and imported rice was found. The mean level of total As (0.24 +/- 0.09 mg/kg, n = 10) in the Australian rice was relatively higher than imported rice from other countries (0.09 +/- 0.04 mg/kg, n = 26). The mean level (0.25 +/- 0.08 mg/kg, n = 7) of dimethylarsenic acid was considerably higher than that of inorganic As (III) (0.07 +/- 0.03 mg/kg, n = 7) in the Australian rice. Children's daily intakes of total As varied widely, ranging from 1.7 to 31.2 (11.5 +/- 8.9 ug/day), which was comparable to other countries. PMID- 26125529 TI - Geometrically frustrated Fe2P-like systems: beyond the Fe-trimer approximation. AB - Fe(2)P-like structures can be strongly frustrated magnets due to their Kagome/triangular intercalated-layer structure. A complete magnetic solution of the complex spin architecture, and hence the full potential of the magnetic phenomena in Fe(2)P-like material prototypes, is yet to be found. A previous magnetic model for a representative FeCrAs-like system used a mean-field effective-spin to describe the 3g-Wyckoff located Fe-triangles. Such an approach demonstrated the outstanding magnetocaloric properties of the material but left the question of whether the intra-trimer interaction could lead to new physical phenomena and therefore more potentially useful properties. In this work Monte Carlo simulations are employed in order to understand both the influence of the additional degrees of freedom introduced by the Fe-trimers and the changes caused by all the possible exchange couplings between them. Complex scenarios arise, in which FM coupling in the trimers gives rise to both in-plane and out-of-plane inter-layer AFM states; whereas AFM exchange in the trimers gives rise to three distinct states, i.e. AFM-canted layers, a non-collinear superposition of ferromagnetic Kagome/triangular orderings, and tilted inter-planar AFM order. These last three configurations generate a double bifurcated magnetic phase diagram while the first one mimics the behavior seen in a model that treats the trimer as an effective-spin under an applied magnetic field. PMID- 26125530 TI - Clinical Profile and Sex Differences in Brazilian Children and Adolescents Receiving Psychiatric Services in the Emergency Department. AB - OBJECTIVE: We present a survey of sex differences and socio-demographic and clinical variables in children and adolescents receiving a psychiatric consultation service in an emergency department (ED). METHODS: This observational, retrospective, and cross-sectional study included all records of patients (age, <18 years) who received psychiatric services in an ED in a 4-year period (January 2010 to December 2013). RESULTS: Two hundred fifty-nine records of children and adolescents were located. The mean age of the participants was 14.19 years, and most subjects were female (59.5%) and had private health insurance (83.7%). Most participants (87.4%) were accompanied by their parents. The main complaints were suicide attempts (21.8%) and psychomotor agitation/aggressiveness (21.8%). Unipolar depression (37.8%) and adjustment, reactive, and anxiety disorders (13.7%) were the most prevalent diagnoses. Most patients received an indication of psychiatric hospitalization (51.7%). Females had more suicide attempts than males (28.3% vs 12.4%) and less psychomotor agitation/aggressiveness than males (15.5% vs 31.4%). Females also exhibited more unipolar depression (47.6% vs 23.5%), fewer psychotic disorders (4.2% vs 16.3%), and substance use/misuse (1.4% vs 13.3%) than males. Males needed more psychiatric medication during evaluation (37.9% vs 19.2%). CONCLUSIONS: This survey of the profile of pediatric patients evaluated by a psychiatric service in an ED in Brazil was the first of its kind. The large percentage of patients referred for hospitalization highlights the importance of specialized psychiatry care for this age group in this facility, which is a common entry point for mental health care. PMID- 26125531 TI - Prevalence of Inconsistencies in the Recorded Outcomes of Clinical Evaluations. AB - OBJECTIVES: The aims of the study were to determine the prevalence of variations in the recorded outcomes of clinical evaluations by 2 different physicians during a single patient visit and to comment on observations of physician practices regarding history taking and physical examination. METHODS: Structured interviews were conducted with both junior and supervising physicians after they had evaluated patients in a pediatric emergency department who presented with complaints of fever (temperature, >100.4 degrees F) in infants younger than 3 months, fever (temperature, >102.2 degrees F) in infants aged 3 to 12 months, headache in patients older than 5 years, abdominal pain in patients older than 5 years, and head injury in patients younger than 18 years. Data were analyzed with descriptive statistics. RESULTS: Most of the data reported by both junior and supervising physicians showed response disagreement. The questions on fever (temperature, >102.2 degrees F) in infants aged 3 to 12 months showed 29% (10/34) disagreement on fever duration and 45% (5/11) on fever height. Questions on abdominal pain in children older than 5 years showed 24% (24/100) disagreement on reporting right lower quadrant pain and 10% (11/106) on right lower quadrant tenderness on examination; however, the discrepancy rates were 56% (56/100) when considering less than complete agreement on all painful sites and 53% (56/106) on all tender sites. Supervising physicians questioned and examined patients presenting with abdominal pain more often than those presenting with other complaints. CONCLUSIONS: There are significant variations in the recorded outcome of clinical evaluations by 2 different physicians during a single patient visit. Supervising physicians are more cautious to question and examine patients presenting with abdominal pain compared with other chief complaints. PMID- 26125532 TI - Analyses of the Disease Spectrum of Children After the Lushan Earthquake. AB - : An earthquake with a magnitude of 7.0 struck Lushan in Sichuan Province in China on April 20, 2013. Uniformed pediatricians visited the area where the epicenter was located to provide emergency relief care for children 10 days after the earthquake. OBJECTIVES: The aims of the study were to analyze the features of the disease spectrum of children in Baoxing at early time after Lushan earthquake and to provide basis information, which will be useful for the arrangement of the medical resources of pediatrics in the medical relief after Lushan earthquake in similar situation in the future. METHODS: A total of 220 case files were classified and analyzed. These files provided information regarding pediatric patients whose conditions were diagnosed and treated in the mobile hospital established by the Affiliated Hospital of Logistical University of Chinese People's Armed Police Forces in Baoxing from April 20, 2013 to April 30, 2013. The demographic data of all these patients were collected and the disease spectrum was analyzed. RESULTS: Children's ages differed. A total of 59 patients were neonates, infants, and toddlers (27%); 111 were school-aged children (50%) and 50 were adolescents (23%). Common diseases and injuries include respiratory tract infection, dermatosis, and trauma, which were observed 10 days after the earthquake. Trauma was mainly accidental injury. The morbidity rate of infectious diseases was low. CONCLUSIONS: Pediatricians have an important role in the early treatment and subsequent control of infectious diseases during earthquakes. PMID- 26125534 TI - Internal Applicants to Pediatric Emergency Medicine Fellowships and Current Use of the National Resident Matching Program Match: A Survey of Fellowship Directors. AB - OBJECTIVES: Applicants to fellowship programs are divided into the following 2 distinct groups: the external versus internal candidate. Internal fellowship candidates did residency at the same institution they are applying to, whereas the external candidate is from another institution. Internal candidates have likely done rotation(s) within the fellowship's division and are known to faculty, whereas the external candidates are evaluated by their applications and interviews alone. Acceptance of internal fellowship candidates may be complicated by competing interests of the associated residency program and overlapping faculty who have academic roles in both training programs. The current percentage of pediatric emergency medicine (PEM) fellowships exclusively using the National Resident Matching Program (NRMP) Specialties Matching Service (SMS) for filling fellowship slots is not known. METHODS: We surveyed all the current US PEM fellowship directors in April/May 2013 using a 15-question anonymous institutional review board-approved survey. This survey was hosted through http://www.surveymonkey.com and was available between April 08, 2013 and May 08, 2013. The unique link sent to each fellowship director recorded completion of the survey but no individual responses. All questions had to be answered for the results to be recorded. RESULTS: Fifty-four of 70 fellowship directors responded. Each question was individually evaluated. Fellowship directors had different feelings toward internal candidates. The NRMP-SMS exclusive use was high. Possible confounders using the NRMP match seemed uncommon. CONCLUSIONS: Twenty nine percent of current PEM fellows are in training at the same institution where they completed their residency. Both internal and external candidates are valued by PEM fellowship directors. The exclusive use of the NRMP SMS is high and not confounded by internal factors. PMID- 26125533 TI - RNA Biosignatures in Adolescent Patients in a Pediatric Emergency Department With Pelvic Inflammatory Disease. AB - BACKGROUND: Adolescents are at high risk for pelvic inflammatory disease (PID). Because accurate diagnosis of PID is difficult, and complications of untreated PID are significant, novel methods to improve diagnosis are essential. OBJECTIVES: To determine if patients with PID have unique RNA expression patterns compared to controls. METHODS: Peripheral blood was collected from adolescent females with PID in the emergency department, and from control patients in the operating room. RNA was isolated, and microarray analysis was performed. Initial analysis involved a training set of 18 patients (9 PID patients with either Neisseria gonorrhoeae or Chlamydia trachomatis infection and 9 control patients). Supervised and unsupervised cluster analyses were performed, followed by network analysis. The training set was used to classify a set of 15 additional PID patients and 2 controls. RESULTS: Supervised cluster analysis of the training set revealed 170 genes which were differentially expressed in PID patients versus controls. Network analysis indicated that several differentially expressed genes are involved in immune activation. Analysis of additional PID patients based on the training set findings revealed that patients with positive testing for Trichomonas vaginalis partitioned with the PID group, whereas patients with no organism identified partitioned with both groups. CONCLUSIONS: RNA sample collection from adolescents in the emergency department is feasible. Genes were identified which were differentially expressed in PID patients versus controls, many of which are involved in inflammation. Future studies should confirm the training set findings on a larger sample and may lead to improved accuracy of PID diagnosis. PMID- 26125536 TI - Direct aqueous synthesis of non-protected glycosyl sulfoxides; weak inhibitory activity against glycosidases. AB - A flavinium catalyst, in conjunction with hydrogen peroxide as stoichiometric oxidant, allowed the aqueous conversion of non-protected thioglycosides into the corresponding glycosyl sulfoxides. These glycosyl sulfoxides displayed only very weak inhibitory activity against corresponding glycosidases. PMID- 26125535 TI - CTCF-dependent co-localization of canonical Smad signaling factors at architectural protein binding sites in D. melanogaster. AB - The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) pathways transduce extracellular signals into tissue-specific transcriptional responses. During this process, signaling effector Smad proteins translocate into the nucleus to direct changes in transcription, but how and where they localize to DNA remain important questions. We have mapped Drosophila TGF-beta signaling factors Mad, dSmad2, Medea, and Schnurri genome-wide in Kc cells and find that numerous sites for these factors overlap with the architectural protein CTCF. Depletion of CTCF by RNAi results in the disappearance of a subset of Smad sites, suggesting Smad proteins localize to CTCF binding sites in a CTCF-dependent manner. Sensitive Smad binding sites are enriched at low occupancy CTCF peaks within topological domains, rather than at the physical domain boundaries where CTCF may function as an insulator. In response to Decapentaplegic, CTCF binding is not significantly altered, whereas Mad, Medea, and Schnurri are redirected from CTCF to non-CTCF binding sites. These results suggest that CTCF participates in the recruitment of Smad proteins to a subset of genomic sites and in the redistribution of these proteins in response to BMP signaling. PMID- 26125537 TI - Hormonal contraception and postmenopausal hormone therapy in Spain: time trends and patterns of use. AB - OBJECTIVE: This study aims to describe time trends in and patterns of use of hormonal contraception and postmenopausal hormone therapy and to identify factors associated with their use among Spanish women. METHODS: We performed a cross sectional analysis using data from 1,954 population controls (aged 24-85 y) in 12 provinces of Spain who were enrolled in the Multi Case-Control Spain study (2007 2013). Data were collected from a questionnaire conducted face-to-face by trained personnel. We collected information on sociodemographic factors, lifestyle, sleep patterns, reproductive history, and occupational history. RESULTS: Overall, 48.5% of Spanish women reported ever use of hormonal contraception, and 9.8% of women in the postmenopausal group reported use of postmenopausal hormone therapy. Younger cohorts used hormonal contraception for a longer period, whereas postmenopausal hormone therapy use dramatically dropped in the 2000s. Women with higher education levels (including education of partners) and smoking history were the most probable users of hormonal contraception, whereas inverse associations were observed among housewives, obese women, and nulliparous women. Postmenopausal hormone therapy use was associated with a surgical or therapeutic cause of menopause and with occupational history of rotating shifts. CONCLUSIONS: In this Spanish population, several demographic, lifestyle, occupational, and reproductive factors are associated with use of hormonal compounds. Characterizing hormonal users and monitoring trends in the use of these hormonal compounds are essential from a public health perspective. PMID- 26125538 TI - Armodafinil for fatigue associated with menopause: an open-label trial. AB - OBJECTIVE: This study aims to obtain preliminary data on the efficacy of armodafinil for improving menopause-related fatigue and quality of life. METHODS: Women (aged 40-65 y) experiencing menopause-related fatigue received open-label armodafinil therapy (up to 150 mg/d) for 4 weeks. Changes from baseline in Brief Fatigue Inventory score and Menopause-Specific Quality of Life (MENQOL) physical domain score were examined using the Wilcoxon signed rank test. Exploratory analyses examined the effects of armodafinil on hot flashes, overall quality of life, insomnia, depression, anxiety, and perceived cognitive performance. After open-label treatment, participants were randomized to double-blind continuation of armodafinil versus placebo for 2 weeks to examine whether treatment discontinuation would precipitate symptom recurrence. RESULTS: Of 29 eligible participants, 20 women (69.0%) completed the trial. During treatment with armodafinil (mean dose, 120 mg/d), median Brief Fatigue Inventory scores decreased by 57.7% from 5.2 (interquartile range [IQR], 4.6-6.2) to 2.2 (IQR, 1.1 4.4; P = 0.0002), and median MENQOL physical domain scores decreased by 51.3% from 3.9 (IQR, 2.3-4.8) to 1.9 (IQR, 1.3-2.7; P = 0.0001). Median hot flashes for 24 hours decreased by 48.3% from 2.9 (IQR, 1.1-4.6) to 1.5 (IQR, 0.4-2.4; P = 0.0005). Improvements in MENQOL total score (49%; P = 0.0001), cognitive function (59.2%; P = 0.0002), depressive symptoms (64.7%; P = 0.0006), insomnia (72.7%; P = 0.0012), and excessive sleepiness (57.1%; P = 0.0006) were noted. Randomized continuation (n = 10) or discontinuation (n = 10) did not indicate group differences. Armodafinil was well-tolerated; three women (12%) were withdrawn for adverse events. CONCLUSIONS: These preliminary results suggest a therapeutic effect of armodafinil on fatigue affecting quality of life during menopause, and a potential benefit for other menopause-related symptoms. PMID- 26125539 TI - Rhodium-Catalyzed Alkylation of C-H Bonds in Aromatic Amides with Styrenes via Bidentate-Chelation Assistance. AB - Rhodium-catalyzed alkylation reactions of aromatic C-H bonds in aromatic amides with styrene derivatives have been developed by using an 8-aminoquinoline as a bidentate directing group. C-C bond formation selectively occurred between the ortho C-H bonds in aromatic amides and the terminal carbon of the styrene derivatives. The presence of an 8-aminoquinoline moiety is essential for the success of the reaction. PMID- 26125540 TI - Computational analysis of stable hard structures in the Ti-B system. AB - The lowest energy crystalline structures of various stoichiometric titanium boride (Ti-B) intermetallic compounds are sought based on density functional theory combined with the particle-swarm optimization (PSO) technique. Besides three established experimental structures, i.e., FeB-type TiB, AlB2-type, and Ta3B4-type Ti3B4, we predict additional six metastable phases at these stoichiometric ratios, namely, alpha- and beta-phases for TiB, TiB2, and Ti3B4, respectively. Moreover, we predict the most stable crystalline structures of four new titanium boride compounds with different stoichiometric ratios: Ti2B-PSA, Ti2B3-PSB, TiB3-PSC, and TiB4-PSD. Notably, Ti2B-PSA is shown to have lower formation energy (thus higher stability) than the previously proposed Al2Cu-type Ti2B. The computed convex-hull and phonon dispersion relations confirm that all the newly predicted Ti-B intermetallic crystals are thermodynamically and dynamically stable. Remarkably, the predicted alpha-TiB2 and beta-TiB2 show semi metal-like electronic properties and possess high Vickers hardnesses (39.4 and 39.6 GPa), very close to the lower limit of superhard materials (40 GPa). Analyses of band structure, density of states, electronic localization function, and various elastic moduli provide further understanding of the electronic and mechanical properties of the intermetallic titanium borides. We hope the newly predicted hard intermetallic titanium borides coupled with desirable electronic properties and high elastic modulus will motivate future experimental synthesis for applications such as high-temperature structural materials. PMID- 26125541 TI - Adverse Clinical Outcomes and Resource Utilization Associated with Methicillin Resistant and Methicillin-Sensitive Staphylococcus aureus Infections after Elective Surgery. AB - BACKGROUND: Current studies of post-operative Staphylococcus aureus disease focus primarily on surgical site infections and are often limited to infections caused by methicillin-resistant Staphylococcus aureus (MRSA). The objective of this retrospective cohort analysis was to describe the occurrence of and outcomes associated with post-operative MRSA and methicillin-sensitive S. aureus (MSSA) infections in patients undergoing elective surgical procedures. METHODS: Data were extracted from Health Facts for inpatients aged 18 years or older with pre defined International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure codes, meeting additional criteria indicating that the procedure was elective. Post-operative S. aureus infection was identified by one or more qualifying culture positive for MRSA or MSSA. Multivariable regression models compared patients with MRSA, MSSA, and no S. aureus infection. RESULTS: Among 34,866 qualifying patients, the incidence of S. aureus infections was 0.9% during the index admission and 1.7% within 90 d after elective surgery, of which 36.6% and 38.4% were MRSA, respectively. The highest rates were observed among patients undergoing general surgery (2.2% during index admission, 3.2% within 90 d) and plastic surgery (1.8% during index admission, 3.1% within 90 d). Patients with MRSA and MSSA experienced poorer outcomes than uninfected patients, based on index admission length of stay (LOS; mean, 30.2, 22.7, and 5.7 d, respectively), hospital charges ($165,651, $134,313, and $52,077), and hospital mortality (odds ratios, 6.4 for MRSA, 4.8 for MSSA versus uninfected patients). Relative to MSSA infection, MRSA infection was associated with greater total hospital LOS and hospital charges but not with increased re admission or mortality. CONCLUSIONS: The burden of post-operative S. aureus infection is shared among elective surgical procedures, however, rates and types of infections vary. Whereas MRSA infection results in substantially greater health care cost and LOS, mortality and re-admission rates are similar among patients with MRSA and MSSA. In elective surgery, infection control and surveillance for both MRSA and MSSA are warranted. PMID- 26125542 TI - Anharmonic Backbone Vibrations in Ultrafast Processes at the DNA-Water Interface. AB - The vibrational modes of the deoxyribose-phosphodiester backbone moiety of DNA and their interactions with the interfacial aqueous environment are addressed with two-dimensional (2D) infrared spectroscopy on a femto- to picosecond time scale. Beyond the current understanding in the harmonic approximation, the anharmonic character and delocalization of the backbone modes in the frequency range from 900 to 1300 cm(-1) are determined with both diagonal anharmonicities and intermode couplings on the order of 10 cm(-1). Mediated by the intermode couplings, energy transfer between the backbone modes takes place on a picosecond time scale, parallel to vibrational relaxation and energy dissipation into the environment. Probing structural dynamics noninvasively via the time evolution of the 2D lineshapes, limited structural fluctuations are observed on a 300 fs time scale of low-frequency motions of the helix, counterions, and water shell. Structural disorder of the DNA-water interface and DNA-water hydrogen bonds are, however, preserved for times beyond 10 ps. The different interactions of limited strength ensure ultrafast vibrational relaxation and dissipation of excess energy in the backbone structure, processes that are important for the structural integrity of hydrated DNA. PMID- 26125543 TI - Associations among dehydration, testosterone and stress hormones in terms of body weight loss before competition. AB - BACKGROUND: In weight class sports, such as judo, taekwondo and wrestling, reducing body weight before competitions is common. However, it is recommended that weight loss per week should not exceed 1.5% of total body weight otherwise, athletes' metabolism and endocrine parameters are negatively affected, which will deteriorate their physiology and psychology and thus decrease their performance. The aim of this study was to determine weight loss and hydration levels after weight loss before competitions among the elite wrestlers and to explore the association between hydration levels, and stress and testosterone. METHODS: This was an observational study. The study was undertaken with 56 voluntary athletes who participated in wrestling championship. With blood samples taken from the wrestlers, glucose, blood urea nitrogen, sodium (Na), cortisol, prolactin and testosterone hormone analyses were evaluated by a specialist at a biochemical laboratory. RESULTS: It was found out that according to plasma osmolarity levels, there were significant differences between those dehydrated and those who maintained euhydration in terms of cortisol and total testosterone levels (P < 0.001). It was detected that an association was present between plasma osmolarity, and cortisol (r = 0.667) and total testosterone levels (r = -0.627) among the elite wrestlers. CONCLUSIONS: It was discovered that elite wrestlers were subjected to quick and high level of weight losses before competitions in a very short time (1-5 days). It was seen that their hydration levels differed due to the weight loss, which was explored to be causing acute dehydration among the wrestlers. PMID- 26125544 TI - Dose-Dependent Paliperidone Associated With Angioedema. PMID- 26125545 TI - Real-Time Monitoring of Cellular Bioenergetics with a Multianalyte Screen-Printed Electrode. AB - Real-time monitoring of changes to cellular bioenergetics can provide new insights into mechanisms of action for disease and toxicity. This work describes the development of a multianalyte screen-printed electrode for the detection of analytes central to cellular bioenergetics: glucose, lactate, oxygen, and pH. Platinum screen-printed electrodes were designed in-house and printed by Pine Research Instrumentation. Electrochemical plating techniques were used to form quasi-reference and pH electrodes. A Dimatix materials inkjet printer was used to deposit enzyme and polymer films to form sensors for glucose, lactate, and oxygen. These sensors were evaluated in bulk solution and microfluidic environments, and they were found to behave reproducibly and possess a lifetime of up to 6 weeks. Linear ranges and limits of detection for enzyme-based sensors were found to have an inverse relationship with enzyme loading, and iridium oxide pH sensors were found to have super-Nernstian responses. Preliminary measurements where the sensor was enclosed within a microfluidic channel with RAW 264.7 macrophages were performed to demonstrate the sensors' capabilities for performing real-time microphysiometry measurements. PMID- 26125546 TI - Antitumor Properties of the Essential Oil From the Leaves of Duguetia gardneriana. AB - Duguetia gardneriana, popularly known in the Brazilian northeast as "jaquinha", is a species belonging to the family Annonaceae. The aim of this work was to assess the chemical composition and antitumor properties of the essential oil from the leaves of D. gardneriana in experimental models. The chemical composition of the essential oil was analyzed via gas chromatography-flame ionization detector and gas chromatography-mass spectrometry. In vitro cytotoxic activity was determined in cultured tumor cells, and in vivo antitumor activity was assessed in B16-F10-bearing mice. The identified compounds were beta bisabolene (80.99%), elemicin (8.04%), germacrene D (4.15%), and cyperene (2.82%). The essential oil exhibited a cytotoxic effect, with IC50 values of 16.89, 19.16, 13.08, and 19.33 ug/mL being obtained for B16-F10, HepG2, HL-60, and K562 cell lines, respectively. On the other hand, beta-bisabolene was inactive in all of the tested tumor cell lines (showing IC50 values greater than 25 ug/mL). The in vivo analysis revealed tumor growth inhibition rates of 5.37 37.52% at doses of 40 and 80 mg/kg/day, respectively. Herein, the essential oil from the leaves of D. gardneriana presented beta-bisabolene as the major constituent and showed cytotoxic and antitumor potential. PMID- 26125547 TI - Ureteral Hernia Mimicking Retrocrural Lymphadenopathy in 18F-FDG PET/CT. AB - An 82-year-old woman was submitted to (18)F-FDG PET/CT to evaluate an indeterminate solitary lung nodule identified on chest CT. At the examination, there was a hypermetabolic area at the topography of the right retrocrural region, mimicking a lymphadenopathy on axial images. After careful analysis of multiplanar CT images, it was better characterized as a loop of the ureter insinuating itself by a small diaphragmatic hernia. Ureteral hernia is a rare entity with few cases reported in the literature. This case demonstrates the importance of conducting careful evaluation of multiplanar CT images to avoid false-positive results on PET/CT. PMID- 26125548 TI - Bacterial Sugar 3,4-Ketoisomerases: Structural Insight into Product Stereochemistry. AB - 3-Acetamido-3,6-dideoxy-d-galactose (Fuc3NAc) and 3-acetamido-3,6-dideoxy-d glucose (Qui3NAc) are unusual sugars found on the lipopolysaccharides of Gram negative bacteria and on the S-layers of Gram-positive bacteria. The 3,4 ketoisomerases, referred to as FdtA and QdtA, catalyze the third steps in the respective biosynthetic pathways for these sugars. Whereas both enzymes utilize the same substrate, the stereochemistries of their products are different. Specifically, the hydroxyl groups at the hexose C-4' positions assume the "galactose" and "glucose" configurations in the FdtA and QdtA products, respectively. In 2007 we reported the structure of the apoform of FdtA from Aneurinibacillus thermoaerophilus, which was followed in 2014 by the X-ray analysis of QdtA from Thermoanaerobacterium thermosaccharolyticum as a binary complex. Both of these enzymes belong to the cupin superfamily. Here we report a combined structural and enzymological study to explore the manner in which these enzymes control the stereochemistry of their products. Various site-directed mutant proteins of each enzyme were constructed, and their dTDP-sugar products were analyzed by NMR spectroscopy. In addition, the kinetic parameters for these protein variants were measured, and the structure of one, namely, the QdtA Y17R/R97H double mutant form, was determined to 2.3-A resolution. Finally, in an attempt to obtain a model of FdtA with a bound dTDP-linked sugar, the 3,4 ketoisomerase domain of a bifunctional enzyme from Shewanella denitrificans was cloned, purified, and crystallized in the presence of a dTDP-linked sugar analogue. Taken together, the results from this investigation demonstrate that it is possible to convert a "galacto" enzyme into a "gluco" enzyme and vice versa. PMID- 26125549 TI - National Survey of Radiation Dose and Image Quality in Adult CT Head Scans in Taiwan. AB - INTRODUCTION: The purpose of the present study was to evaluate the influence of different variables on radiation dose and image quality based on a national database. MATERIALS AND METHODS: Taiwan's Ministry of Health and Welfare requested all radiology departments to complete a questionnaire for each of their CT scanners. Information gathered included all scanning parameters for CT head scans. For the present analysis, CT machines were divided into three subgroups: single slice CT (Group A); multi-detector CT (MDCT) with 2-64 slices (Group B); and MDCT with more than 64 slices (Group C). Correlations between computed tomography dose index (CTDI) and signal-to-noise ratio (SNR) with cumulated tube rotation number (CTW(n)) and cumulated tube rotation time (CTW(s)), and sub group analyses of CTDI and SNR across the three groups were performed. RESULTS: CTDI values demonstrated a weak correlation (r = 0.33) with CTW(n) in Group A. SNR values demonstrated a weak negative correlation (r = -0.46) with CTW(n) in Group C. MDCT with higher slice numbers used more tube potential resulting in higher effective doses. There were both significantly lower CTDI and SNR values in helical mode than in axial mode in Group B, but not Group C. CONCLUSION: CTW(n) and CTW(s) did not influence radiation output. Helical mode is more often used in MDCT and results in both lower CTDI and SNR compared to axial mode in MDCT with less than 64 slices. PMID- 26125550 TI - Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers. AB - Somatic mutations in the nuclear genome are required for tumor formation, but the functional consequences of somatic mitochondrial DNA (mtDNA) mutations are less understood. Here we identify somatic mtDNA mutations across 527 tumors and 14 cancer types, using an approach that takes advantage of evidence from both genomic and transcriptomic sequencing. We find that there is selective pressure against deleterious coding mutations, supporting that functional mitochondria are required in tumor cells, and also observe a strong mutational strand bias, compatible with endogenous replication-coupled errors as the major source of mutations. Interestingly, while allelic ratios in general were consistent in RNA compared to DNA, some mutations in tRNAs displayed strong allelic imbalances caused by accumulation of unprocessed tRNA precursors. The effect was explained by altered secondary structure, demonstrating that correct tRNA folding is a major determinant for processing of polycistronic mitochondrial transcripts. Additionally, the data suggest that tRNA clusters are preferably processed in the 3' to 5' direction. Our study gives insights into mtDNA function in cancer and answers questions regarding mitochondrial tRNA biogenesis that are difficult to address in controlled experimental systems. PMID- 26125551 TI - Quantitative Characterization of Collagen in the Fibrotic Capsule Surrounding Implanted Polymeric Microparticles through Second Harmonic Generation Imaging. AB - The collagenous capsule formed around an implant will ultimately determine the nature of its in vivo fate. To provide a better understanding of how surface modifications can alter the collagen orientation and composition in the fibrotic capsule, we used second harmonic generation (SHG) microscopy to evaluate collagen organization and structure generated in mice subcutaneously injected with chemically functionalized polystyrene particles. SHG is sensitive to the orientation of a molecule, making it a powerful tool for measuring the alignment of collagen fibers. Additionally, SHG arises from the second order susceptibility of the interrogated molecule in response to the electric field. Variation in these tensor components distinguishes different molecular sources of SHG, providing collagen type specificity. Here, we demonstrated the ability of SHG to differentiate collagen type I and type III quantitatively and used this method to examine fibrous capsules of implanted polystyrene particles. Data presented in this work shows a wide range of collagen fiber orientations and collagen compositions in response to surface functionalized polystyrene particles. Dimethylamino functionalized particles were able to form a thin collagenous matrix resembling healthy skin. These findings have the potential to improve the fundamental understanding of how material properties influence collagen organization and composition quantitatively. PMID- 26125552 TI - A New Model for a Carpool Matching Service. AB - Carpooling is an effective means of reducing traffic. A carpool team shares a vehicle for their commute, which reduces the number of vehicles on the road during rush hour periods. Carpooling is officially sanctioned by most governments, and is supported by the construction of high-occupancy vehicle lanes. A number of carpooling services have been designed in order to match commuters into carpool teams, but it known that the determination of optimal carpool teams is a combinatorially complex problem, and therefore technological solutions are difficult to achieve. In this paper, a model for carpool matching services is proposed, and both optimal and heuristic approaches are tested to find solutions for that model. The results show that different solution approaches are preferred over different ranges of problem instances. Most importantly, it is demonstrated that a new formulation and associated solution procedures can permit the determination of optimal carpool teams and routes. An instantiation of the model is presented (using the street network of Guangzhou city, China) to demonstrate how carpool teams can be determined. PMID- 26125553 TI - Maximising Acute Kidney Injury Alerts--A Cross-Sectional Comparison with the Clinical Diagnosis. AB - BACKGROUND: Acute kidney injury (AKI) is serious and widespread across healthcare (1 in 7 hospital admissions) but recognition is often delayed causing avoidable harm. Nationwide automated biochemistry alerts for AKI stages 1-3 have been introduced in England to improve recognition. We explored how these alerts compared with clinical diagnosis in different hospital settings. METHODS: We used a large population cohort of 4464 patients with renal impairment. Each patient had case-note review by a nephrologist, using RIFLE criteria to diagnose AKI and chronic kidney disease (CKD). We identified and staged AKI alerts using the new national NHS England AKI algorithm and compared this with nephrologist diagnosis across hospital settings. RESULTS: Of 4464 patients, 525 had RIFLE AKI, 449 had mild AKI, 2185 had CKD (without AKI) and 1305 were of uncertain chronicity. NHS AKI algorithm criteria alerted for 90.5% of RIFLE AKI, 72.4% of mild AKI, 34.1% of uncertain cases and 14.0% of patients who actually had CKD.The algorithm identified AKI particularly well in intensive care (95.5%) and nephrology (94.6%), but less well on surgical wards (86.4%). Restricting the algorithm to stage 2 and 3 alerts reduced the over-diagnosis of AKI in CKD patients from 14.0% to 2.1%, but missed or delayed alerts in two-thirds of RIFLE AKI patients. CONCLUSION: Automated AKI detection performed well across hospital settings, but was less sensitive on surgical wards. Clinicians should be mindful that restricting alerts to stages 2-3 may identify fewer CKD patients, but including stage 1 provides more sensitive and timely alerting. PMID- 26125554 TI - HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T Cells in HLA-B27 Transgenic Rats. AB - OBJECTIVES: HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272-specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. METHODS: The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. RESULTS: HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. CONCLUSION: HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders. PMID- 26125556 TI - Detecting Associations between Early-Life DDT Exposures and Childhood Growth Patterns: A Novel Statistical Approach. AB - It has been hypothesized that environmental exposures at key development periods such as in utero play a role in childhood growth and obesity. To investigate whether in utero exposure to endocrine-disrupting chemicals, dichlorodiphenyltrichloroethane (DDT) and its metabolite, dichlorodiphenyldichloroethane (DDE), is associated with childhood physical growth, we took a novel statistical approach to analyze data from the CHAMACOS cohort study. To model heterogeneity in the growth patterns, we used a finite mixture model in combination with a data transformation to characterize body mass index (BMI) with four groups and estimated the association between exposure and group membership. In boys, higher maternal concentrations of DDT and DDE during pregnancy are associated with a BMI growth pattern that is stable until about age five followed by increased growth through age nine. In contrast, higher maternal DDT exposure during pregnancy is associated with a flat, relatively stable growth pattern in girls. This study suggests that in utero exposure to DDT and DDE may be associated with childhood BMI growth patterns, not just BMI level, and both the magnitude of exposure and sex may impact the relationship. PMID- 26125555 TI - Distribution and Inhibition of Liposomes on Staphylococcus aureus and Pseudomonas aeruginosa Biofilm. AB - BACKGROUND: Staphylococcus aureus and Pseudomonas aeruginosa are major pathogens in chronic rhinosinusitis (CRS) and their biofilms have been associated with poorer postsurgical outcomes. This study investigated the distribution and anti biofilm effect of cationic (+) and anionic (-) phospholipid liposomes with different sizes (unilamellar and multilamellar vesicle, ULV and MLV respectively) on S. aureus and P. aeruginosa biofilms. METHOD: Specific biofilm models for S. aureus ATCC 25923 and P. aeruginosa ATCC 15692 were established. Liposomal distribution was determined by observing SYTO9 stained biofilm exposed to DiI labeled liposomes using confocal scanning laser microscopy, followed by quantitative image analysis. The anti-biofilm efficacy study was carried out by using the alamarBlue assay to test the relative viability of biofilm treated with various liposomes for 24 hours and five minutes. RESULTS: The smaller ULVs penetrated better than larger MLVs in both S. aureus and P. aeruginosa biofilm. Except that +ULV and -ULV displayed similar distribution in S. aureus biofilm, the cationic liposomes adhered better than their anionic counterparts. Biofilm growth was inhibited at 24-hour and five-minute exposure time, although the decrease of viability for P. aeruginosa biofilm after liposomal treatment did not reach statistical significance. CONCLUSION: The distribution and anti-biofilm effects of cationic and anionic liposomes of different sizes differed in S. aureus and P. aeruginosa biofilms. Reducing the liposome size and formulating liposomes as positively charged enhanced the penetration and inhibition of S. aureus and P. aeruginosa biofilms. PMID- 26125557 TI - Adult Moyamoya Disease: A Burden of Intracranial Stenosis in East Asians? AB - BACKGROUND: Both Moyamoya disease (MMD) and intracranial atherosclerotic stenosis (ICAS) are more prevalent in Asians than in Westerners. We hypothesized that a substantial proportion of patients with adult-onset MMD were misclassified as having ICAS, which may in part explain the high prevalence of intracranial atherosclerotic stroke in Asians. METHOD: We analyzed 352 consecutive patients with ischemic events within the MCA distribution and relevant intracranial arterial stenosis, but no demonstrable carotid or cardiac embolism sources. Conventional angiography was performed in 249 (70.7%) patients, and the remains underwent MRA. The occurrence of the c.14429G>A (p.Arg4810Lys) variant in ring finger protein 213 (RNF213) was analyzed. This gene was recently identified as a susceptibility gene for MMD in East Asians. RESULTS: The p.Arg4810Lys variant was observed in half of patients with intracranial stenosis (176 of 352, 50.0%), in no healthy control subjects (n = 51), and in 3.2% of stroke control subjects (4 of 124 patients with other etiologies). The presence of basal collaterals, bilateral involvement on angiography, and absence of diabetes were independently associated with the presence of the RNF213 variant. Among 131 patients who met all three diagnostic criteria and were diagnosed with MMD, three-fourths (75.6%) had this variant. However, a significant proportion of patients who met two criteria (57.7%), one criterion (28.6%), or no criteria (20.0%) also had this variant. Some of them developed typical angiographic findings of MMD on follow-up angiography. CONCLUSIONS: Careful consideration of MMD is needed when diagnosing ICAS because differential therapeutic strategies are required for these diseases and due to the limitations of the current diagnostic criteria for MMD. PMID- 26125558 TI - Hippo Stabilises Its Adaptor Salvador by Antagonising the HECT Ubiquitin Ligase Herc4. AB - Signalling through the Hippo (Hpo) pathway involves a kinase cascade, which leads to the phosphorylation and inactivation of the pro-growth transcriptional co activator Yorkie (Yki). Despite the identification of a large number of pathway members and modulators, our understanding of the molecular events that lead to activation of Hpo and the downstream kinase Warts (Wts) remain incomplete. Recently, targeted degradation of several Hpo pathway components has been demonstrated as a means of regulating pathway activity. In particular, the stability of scaffold protein Salvador (Sav), which is believed to promote Hpo/Wts association, is crucially dependent on its binding partner Hpo. In a cell based RNAi screen for ubiquitin regulators involved in Sav stability, we identify the HECT domain protein Herc4 (HECT and RLD domain containing E3 ligase) as a Sav E3 ligase. Herc4 expression promotes Sav ubiquitylation and degradation, while Herc4 depletion stabilises Sav. Interestingly, Hpo reduces Sav/Herc4 interaction in a kinase-dependent manner. This suggests the existence of a positive feedback loop, where Hpo stabilises its own positive regulator by antagonising Herc4 mediated degradation of Sav. PMID- 26125559 TI - Shaped by the Past: The Default Mode Network Supports Cognition that Is Independent of Immediate Perceptual Input. AB - Although many different accounts of the functions of the default mode network (DMN) have been proposed, few can adequately account for the spectrum of different cognitive functions that utilize this network. The current study used functional magnetic resonance imaging (fMRI) to explore the hypothesis that the role of the DMN in higher order cognition is to allow cognition to be shaped by information from stored representations rather than information in the immediate environment. Using a novel task paradigm, we observed increased BOLD activity in regions of the medial prefrontal cortex and posterior cingulate cortex when individuals made decisions on the location of shapes from the prior trial and decreased BOLD activity when individuals made decisions on the location of shapes on the current trial. These data are inconsistent with views of the DMN as a task negative system or one that is sensitive only to stimuli with strong personal or emotional ties. Instead the involvement of the DMN when people make decisions about where a shape was, rather than where it is now, supports the hypothesis that the core hubs of the DMN allow cognition to be guided by information other than the immediate perceptual input. We propose that a variety of different forms of higher order thought (such as imagining the future or considering the perspective of another person) engage the DMN because these more complex introspective forms of higher order thought all depend on the capacity for cognition to be shaped by representations that are not present in the external environment. PMID- 26125560 TI - Development of an Immunochromatographic Test for Diagnosis of Visceral Leishmaniasis Based on Detection of a Circulating Antigen. AB - BACKGROUND: Visceral leishmaniasis (VL) is a life-threatening disease caused by protozoan parasites of the Leishmania donovani complex. Early case detection followed by adequate treatment is essential to the control of VL. However, the available diagnostic tests are either invasive and require considerable expertise (parasitological demonstration of the parasite in tissue smears) or unable to distinguish between past and active infection (serological methods). Therefore, we aimed to develop a lateral flow assay in the form of an immunochromatographic test (ICT) device based on the detection of a circulating Leishmania antigen using monoclonal antibodies (mAbs). METHODOLOGY/PRINCIPAL FINDINGS: mAbs were produced by fusion of murine myeloma cells with splenocytes isolated from a mouse immunized with L. donovani soluble crude antigen. Out of 12 cloned hybridoma cell lines, two secreted mAbs recognizing the same leishmanial protein. These mAbs were used to produce an ICT as a sandwich assay for the detection of circulating antigen in serum and blood samples. The ICT was evaluated with 213 serum samples from VL patients living in VL endemic areas in China, and with 156 serum samples from patients with other diseases as well as 78 serum samples from healthy donors. Sensitivity, specificity and diagnostic efficiency of the new ICT was 95.8%, 98.7% and 97.3%, respectively. Compared with a commercially available antibody detecting ICT, our antigen-based ICT performed slightly better. CONCLUSION/SIGNIFICANCE: The newly developed ICT is an easy to use and more accurate diagnostic tool which fulfils the performance and operational characteristics required for VL case detection under field and laboratory conditions. As our ICT detects a circulating antigen, it will also be useful in monitoring treatment success and diagnosing VL in immunocompromised patients. PMID- 26125561 TI - Network Hubs in the Brain Have the Biggest Impact on Behavior. AB - Are memory deficits better explained by damage to individual brain areas or by an interruption in the flow of information among widely distributed networks in the prefrontal cortex? A new study highlights the importance of task-related function over anatomy. Read the Research Article. PMID- 26125562 TI - A Milk and Ochre Paint Mixture Used 49,000 Years Ago at Sibudu, South Africa. AB - Gas chromatography/mass spectrometry, proteomic and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM/EDS) analyses of residue on a stone flake from a 49,000 year-old layer of Sibudu (South Africa) indicate a mixture of ochre and casein from milk, likely obtained by killing a lactating wild bovid. Ochre powder production and use are documented in Middle Stone Age South African sites but until now there has been no evidence of the use of milk as a binder. Our analyses show that this ochre-based mixture was neither a hafting adhesive nor a residue left after treating animal skins, but a liquid mixture consisting of a powdered pigment mixed with milk; in other words, a paint medium that could have been applied to a surface or to human skin. The significance of our finds also lies in the fact that it establishes the antiquity of the use of milk as a binder well before the introduction of domestic cattle in South Africa in the first millennium AD. PMID- 26125563 TI - Independent Neuronal Origin of Seizures and Behavioral Comorbidities in an Animal Model of a Severe Childhood Genetic Epileptic Encephalopathy. AB - The childhood epileptic encephalopathies (EE's) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dnm1 encodes dynamin 1, a large multimeric GTPase necessary for activity dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Dnm1Ftfl or "fitful" mice carry a spontaneous mutation in the mouse ortholog of DNM1 and recapitulate many of the disease features associated with human DNM1 patients, providing a relevant disease model of human EE's. In order to examine the cellular etiology of seizures and behavioral and neurological comorbidities, we engineered a conditional Dnm1Ftfl mouse model of DNM1 EE. Observations of Dnm1Ftfl/flox mice in combination with various neuronal subpopulation specific cre strains demonstrate unique seizure phenotypes and clear separation of major neurobehavioral comorbidities from severe seizures associated with the germline model. This demonstration of pleiotropy suggests that treating seizures per se may not prevent severe comorbidity observed in EE associated with dynamin-1 mutations, and is likely to have implications for other genetic forms of EE. PMID- 26125564 TI - Switchgrass (Panicum virgatum L.) Genotypes Differ between Coastal Sites and Inland Road Corridors in the Northeastern US. AB - Switchgrass (Panicum virgatum L.) is a North American grass that exhibits vast genetic diversity across its geographic range. In the Northeastern US, local switchgrass populations were restricted to a narrow coastal zone before European settlement, but current populations inhabit inland road verges raising questions about their origin and genetics. These questions are important because switchgrass lines with novel traits are being cultivated as a biofuel feedstock, and gene flow could impact the genetic integrity and distribution of local populations. This study was designed to determine if: 1) switchgrass plants collected in the Long Island Sound Coastal Lowland coastal Level IV ecoregion represented local populations, and 2) switchgrass plants collected from road verges in the adjacent inland regions were most closely related to local coastal populations or switchgrass from other geographic regions. The study used 18 microsatellite markers to infer the genetic relationships between 122 collected switchgrass plants and a reference dataset consisting of 28 cultivars representing ecotypes, ploidy levels, and lineages from North America. Results showed that 84% of 88 plants collected in the coastal plants were most closely aligned with the Lowland tetraploid genetic pool. Among this group, 61 coastal plants were similar to, but distinct from, all Lowland tetraploid cultivars in the reference dataset leading to the designation of a genetic sub-population called the Southern New England Lowland Tetraploids. In contrast, 67% of 34 plants collected in road verges in the inland ecoregions were most similar to two Upland octoploid cultivars; only 24% of roadside plants were Lowland tetraploid. These results suggest that cryptic, non-local genotypes exist in road verges and that gene flow from biofuels plantations could contribute to further changes in switchgrass population genetics in the Northeast. PMID- 26125565 TI - Tooth Retrospective Dosimetry Using Electron Paramagnetic Resonance: Influence of Irradiated Dental Composites. AB - In the aftermath of a major radiological accident, the medical management of overexposed individuals will rely on the determination of the dose of ionizing radiations absorbed by the victims. Because people in the general population do not possess conventional dosimeters, after the fact dose reconstruction methods are needed. Free radicals are induced by radiations in the tooth enamel of victims, in direct proportion to dose, and can be quantified using Electron Paramagnetic Resonance (EPR) spectrometry, a technique that was demonstrated to be very appropriate for mass triage. The presence of dimethacrylate based restorations on teeth can interfere with the dosimetric signal from the enamel, as free radicals could also be induced in the various composites used. The aim of the present study was to screen irradiated composites for a possible radiation induced EPR signal, to characterize it, and evaluate a possible interference with the dosimetric signal of the enamel. We investigated the most common commercial composites, and experimental compositions, for a possible class effect. The effect of the dose was studied between 10 Gy and 100 Gy using high sensitivity X band spectrometer. The influence of this radiation-induced signal from the composite on the dosimetric signal of the enamel was also investigated using a clinical L-Band EPR spectrometer, specifically developed in the EPR center at Dartmouth College. In X-band, a radiation-induced signal was observed for high doses (25-100 Gy); it was rapidly decaying, and not detected after only 24 h post irradiation. At 10 Gy, the signal was in most cases not measurable in the commercial composites tested, with the exception of 3 composites showing a significant intensity. In L-band study, only one irradiated commercial composite influenced significantly the dosimetric signal of the tooth, with an overestimation about 30%. In conclusion, the presence of the radiation-induced signal from dental composites should not significantly influence the dosimetry for early dose assessment. PMID- 26125568 TI - Research collaboration enhances research impact. PMID- 26125567 TI - Depressive Symptom Severity and Community Collective Efficacy following the 2004 Florida Hurricanes. AB - There is a lack of research investigating community-level characteristics, such as community collective efficacy, mitigating the impact of disasters on psychological health, specifically depression. We examined the association of community collective efficacy with depressive symptom severity in Florida public health workers (n = 2249) exposed to the 2004 hurricane season using a multilevel approach. Cross-sectional anonymous questionnaires were distributed electronically to all Florida Department of Health (FDOH) personnel that assessed depressive symptom severity and collective efficacy nine months after the 2004 hurricane season. Analyses were conducted at the individual level and community level using zip codes. The majority of participants were female (81.9%), and ages ranged from 20 to 78 years (median = 49 years). The majority of participants (73.4%) were European American, 12.7% were African American, and 9.2% were Hispanic. Using multilevel analysis, our data indicate that higher community level and individual-level collective efficacy were associated with significantly lower depressive symptom severity (b = -0.09 [95% CI: -0.13, -0.04] and b = -0.09 [95% CI: -0.12, -0.06], respectively) even after adjusting for individual sociodemographic variables, community socioeconomic characteristics, individual injury/damage, and community storm damage. Lower levels of depressive symptom severity were associated with communities with high collective efficacy. Our study highlights the possible importance of programs that enrich community collective efficacy for disaster communities. PMID- 26125566 TI - Neutrophil Gelatinase Associated Lipocalin Is an Early and Accurate Biomarker of Graft Function and Tissue Regeneration in Kidney Transplantation from Extended Criteria Donors. AB - BACKGROUND: Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from extended criteria donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD. METHODS: We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction. RESULTS: Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. In vitro, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio). CONCLUSIONS: NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury. PMID- 26125569 TI - Potential underreporting of medication errors in a psychiatric general hospital in Japan. AB - The purpose of this study was to explore a pattern of underreporting within a psychiatric general hospital in Japan. All the medication errors reported online in 2010 were analysed. This research was approved by the university and the study hospital. There were 651 incidents related to medication errors. Medication error rate per 1000 patient days was 2.14 (range: 0.45-6.05). Medication error rates between two acute care wards with comparable case and staff mix differed. A low proportion of intercepted near-misses and low medication error rates around mealtime in acute care 1 were suggestive of under-reporting. Two dementia care wards with low medication error rates had no report of intercepted errors, which was also suggestive of underreporting. Ward-specific medication error rates and patterns are useful to identify wards with potential underreporting of medication error within the hospital. PMID- 26125570 TI - The mediating and moderating effects of sleep hygiene practice on anxiety and insomnia in hospital nurses. AB - This study aimed to test the mediating and moderating effects of sleep hygiene practice on the relationship between anxiety and insomnia severity in hospital nurses. A cross-sectional survey was employed, and a convenience sample was recruited from one regional hospital in Taiwan. Participants completed the following self-report questionnaires over a 3-month period in 2009: the Insomnia Severity Index, the Beck Anxiety Inventory, and Sleep Hygiene Awareness and Practice Scale. The results indicated that nurses with more anxiety tended to have higher insomnia severity. Further, nurses with poor sleep hygiene practice had more insomnia. Sleep hygiene practice partially mediated the effects of anxiety on insomnia severity. Also, sleep hygiene practice was a moderator in the relationship between anxiety and insomnia severity with age and work units as covariates. Sleep hygiene practice mediated and moderated the relationship between anxiety and insomnia severity after controlling the variables of age and work units. Continuing to learn and train sleep hygiene practice might promote nurses' sleep hygiene, and thereby ameliorate anxiety and reduce the risk of insomnia. PMID- 26125571 TI - Calcium supplementation reducing the risk of hypertensive disorders of pregnancy and related problems: A meta-analysis of multicentre randomized controlled trials. AB - Hypertensive disorders of pregnancy are closely related to maternal mortality and morbidity. Calcium supplementation during pregnancy seems to reduce the risk of hypertensive disorders. No systematic review on multicentre RCTs of calcium supplementation during pregnancy has been published. The purpose of this study was to report a quantitative systematic review of the effectiveness of calcium supplementation during pregnancy on reducing the risk of hypertensive disorders of pregnancy and related problems. Publications over the years of 1991-2012 were searched through PubMed, Science Direct, EMBASE, CINAHL and Web of Science. The literatures were selected of the multicentre RCTs on calcium supplementation during pregnancy in prevention of hypertensive disorders and related problems. Reference lists from the studies were also examined for additional references. Studies were critically appraised by three independent reviewers, and the Cochrane Handbook was used to assess the quality of those included trials. Four studies were included in this systematic review. All included studies were high quality, with low risk of bias. There was an observed risk reduction in hypertension in calcium group. However, there was no reduction in the risk of severe gestational hypertension, pre-eclampsia, severe pre-eclampsia, preterm birth and low birthweight. Calcium supplementation appears to reduce the risk of hypertension in pregnancy. PMID- 26125572 TI - Back massage intervention for relieving lower back pain in puerperal women: A randomized control trial study. AB - This study evaluates the effectiveness of a back massage (BM) intervention in relieving lower back pain (LBP) in post-partum women.This is a randomized controlled trial study. Sixty normal spontaneous delivery women (response rate: 96.7%), who gave birth at our hospital, participated in this study from February to May of 2012. We randomly assigned 30 women to the experimental group and 30 women to the control group. During the 1 month post-partum period, the women in the experimental group received a BM for 5 consecutive days, whereas the women in the control group received routine care only. The LBP score was assessed according to a pain visual analog scale. After 5 days of intervention, the experimental group (n = 30) experienced significantly less LBP than did the control group (n = 30) (2.97 +/- 1.71 vs. 4.43 +/- 1.77, t = 3.26, P = 0.002). BM therapy can effectively reduce LBP during the first post-partum month. Additional studies are required to confirm the effects of BM therapy during extended post partum periods. PMID- 26125573 TI - How do Clostridium difficile infections affect nurses' everyday hospital work: A qualitative study. AB - This qualitative study explored the impact of Clostridium difficile infections on nurses' everyday work in the hospital. Twelve nurses (six in France and six in the United States) were interviewed in depth using a semi-structured interview guide. Thematic analysis of the interviews was performed. Managing diarrhoea and taking precautionary measures for infection control were the two most inconvenient aspects nurses reported with C. difficile patient management. Precautions included contact isolation, hand hygiene and reorganization/coordination of nursing care and ward. Precautions were time consuming and significantly increased nurses' workload when combined with caring for patients with uncontrollable, frequent bouts of diarrhoea. Management of C. difficile infection is extremely burdensome for nurses in their everyday work and disruptive to hospital organizations as a whole. Prevention of C. difficile infections, together with coordinated team work and communication, would therefore contribute to decreasing nurses' workload and the burden to health-care facilities associated with caring for these patients. PMID- 26125574 TI - Application of PRECEDE-PROCEED model to tackle problems identified with diarrhoea burden among under-5s in Botswana. AB - Diarrhoea has been identified as the second leading cause of mortality among under-5s and also claims more life than HIV, measles and malaria combined together in the same category of population. This article is a combination of literature review and personal experience of lessons learnt from past diarrhoea outbreaks in Botswana that caused significant rate of mortality among under-5s. The paper used literature review to identify contributory factors to diarrhoea burden among under-5s in Botswana and applied a community health nursing framework (PRECEDE-PROCEED) to tackle the problems identified. The study revealed that Botswana mothers are lacking in knowledge related to exclusive breastfeeding, prevention and treatment of diarrhoea disease. The paper recommends that health-care workers in Botswana be sensitized on current diarrhoea management to tailor their health education methods appropriately. PMID- 26125575 TI - Fathers' feelings related to their partners' childbirth and views on their presence during labour and childbirth: A descriptive quantitative study. AB - This study examined Chinese fathers' feelings about their partners' delivery and views on their presence during labour and birth. A questionnaire survey was conducted with 403 fathers whose partners gave birth in one provincial hospital in China. Data were analysed by descriptive statistics, chi(2)-test and content analysis. The results indicated that more than 80% of fathers experienced feelings of pride related to fatherhood and of love towards their partners and newborns. Significant differences in fathers' feelings were found between subgroups with regard to age, education, employment, presence in the delivery room, method of birth and whether preparatory visits had been made to the hospital. The majority who answered an open-ended question on the meaning of fathers' presence in the delivery room held a positive attitude towards fathers' presence at labour and birth, as their presence could empower their partners and provide psychological support. This study indicates fathers' presence at delivery and birth is important and that younger fathers need more support. It also provides evidence for clinical practice and future interventions to improve fathers' psychological health and experiences. PMID- 26125576 TI - Vital signs monitoring to detect patient deterioration: An integrative literature review. AB - Vital signs monitoring is an important nursing assessment. Yet, nurses seem to be doing it as part of a routine and often overlooking their significance in detecting patient deterioration. An integrative literature review was conducted to explore factors surrounding ward nursing practice of vital signs monitoring in detecting and reporting deterioration. Twenty papers were included. The structural component of a Nursing Role Effectiveness Model framework, which comprises of patient, nurse and organizational variables, was used to synthesize the review. Patient variables include signs of deterioration displayed by patients which include physical cues and abnormal vital signs. Nursing variables include clinical knowledge, roles and responsibilities, and reporting of deteriorating vital signs. Organizational variables include heavy workload, technology, and observation chart design. This review has highlighted current nursing practice in vital signs monitoring. A myriad of factors were found to surround ward practice of vital signs monitoring in detecting and reporting deterioration. PMID- 26125577 TI - Postpartum social support of women in Singapore: A pilot study. AB - This pilot study aimed to identify the levels of support expected and received by postpartum women in Singapore. Another objective was to compare the different subdomains of social support. A descriptive design was adopted using a self administered questionnaire comprising demographics and the Postpartum Support Questionnaire. The study took place at a subsidized obstetrics and gynaecology clinic at a restructured hospital in Singapore from the end of December 2009 to the end of February 2010. The 25 participants were 6 to 8 weeks postpartum and had delivered healthy term infants. They were recruited via convenience sampling. Data were analysed using descriptive statistics and inferential statistics. The overall support needs of the participants were met. Only their informational support needs were unmet. Assessing the needs of postpartum women and teaching them how to convey and manage expectations are recommended initiatives for health care practitioners to consider. PMID- 26125578 TI - Occupational-related back pain among Jordanian nurses: A descriptive study. AB - Back pain is the leading cause of disability, decreased physical performance at work and absenteeism. Activities leading to the occurrence of back pain include patient transfer and long standing hours. This study aimed to explore the prevalence and determine the activities responsible for the presence of back pain among Jordanian nurses. A descriptive cross-sectional study was conducted on a convenience sample of nurses from governmental hospitals in Jordan. A self-report questionnaire was developed by Stubbs et al. and Harber et al. A descriptive method using mean, standard deviations and percentages was used, in addition to chi-square tests. Baseline findings indicated that more than three-quarters of the nurses studied suffered back pain during their work. Among nurses with back pain, about a fifth of them reported it to administration. The highest percentage of back pain was among critical care nurses. Further, the static factors contributed less commonly to back pain compared with the dynamic factors. Nearly half the participants with back pain reported taking days off more frequently. Jordanian nurses demonstrated one of the highest frequencies of back pain compared with other studies. Focus should be placed on education programmes about the appropriate body mechanics. PMID- 26125579 TI - Self-care management programme for older adults with diabetes: An integrative literature review. AB - This paper summarizes evidence on effectiveness of diabetes self-care interventions for older adults with diabetes, and identifies factors influencing self-care behaviours. The search for articles published from 2002 to 2012 was done using electronic databases, namely, MEDLINE, CINAHL, Scopus, PsycINFO and PubMed. Search terms include diabetes, self-management, self-care, barriers and intervention. Out of 261 articles screened, 21 were selected for review. Findings revealed that interventions using concepts of self-efficacy, self-determination and proactive coping, and interventions incorporating information technology were effective in influencing diabetes self-care behaviours with improved health outcomes. Psychosocial factors influencing self-care include motivation, socioeconomic status, literacy, knowledge, social and health-care providers' support, and particularly for older adults, the key factors were their self efficacy, motor skill and literacy in self-care activities. This review provides important insight for nurse practitioners to address psychosocial issues in developing self-care management programmes for older adults with diabetes. PMID- 26125580 TI - Effectiveness of a community-based diabetes self-management intervention for Chinese adults with type 2 diabetes: A pilot study. AB - This pilot study examined the effects of an intervention on diabetes knowledge and self-management among adults with type 2 diabetes in Wuhan, China. A convenience sample of 29 adults with type 2 diabetes participated in a 6-week diabetes intervention in a community health center. Data on diabetes knowledge, diabetes self-management, fasting blood glucose level, blood pressure, body mass index and waist circumference were collected pre- and postintervention and at 1 month follow-up. The level of diabetes knowledge was significantly greater postintervention, increasing from a score of 12.97 (+/- 4.04) to 17.14 (+/- 3.00) and remaining at 17.03 (+/- 2.23) at 1-month follow-up; Significant improvements in self-monitoring of blood glucose and medication adherence were not found after the intervention. However, fasting blood glucose levels showed a significant decrease from baseline to postintervention and 1-month follow-up. Diabetes self management education was thus an effective way to improve diabetes self-care in this Chinese sample. PMID- 26125581 TI - Using knowledge translation as a framework for the design of a research protocol. AB - Knowledge translation has been defined as the synthesis, dissemination, exchange and ethically sound application of knowledge to improve health, resulting in a stronger health-care system. Using KT activities to aid in the adoption of evidence into practice can address current health-care challenges such as increasing organizational practice standards, alleviating the risk for adverse events and meeting practitioner needs for evidence at the bedside. Two general forms of KT have been identified. These being integrated KT and end-of-grant KT. Integrated KT involves the knowledge users in the research team and in the majority of stages of the research process. End-of-grant KT relates to the translation of findings through a well-developed dissemination plan. This paper describes the process of using an integrated knowledge translation approach to design a research protocol that will examine the effectiveness of a web-based patient educational intervention. It begins with a description of integrated knowledge translation, followed by the presentation of a specific case example in which integrated knowledge translation is used to develop a nursing intervention. The major elements of integrated knowledge translation pertain to need for a knowledge user who represents the broad target user group, and who is knowledgeable in the area under investigation and who as authority to enact changes to practice. Use of knowledge users as equal partners within the research team; exploring all feasible opportunities for knowledge exchange; and working with knowledge users to identify all outcomes related to knowledge translation are the other major elements of integrated knowledge translation that are addressed throughout this paper. Furthermore, the relevance of psychosocial or educational interventions to knowledge translation is also discussed as a source of knowledge. In summary, integrated knowledge translation is an important tool for the development of new interventions, as it helps to apply science to practice accurately. It supports the elaboration of the design while enhancing the relevance of the intervention through the validation of feasibility and acceptability with clinicians and patients. PMID- 26125582 TI - Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues during Carbon Ion Radiotherapy. AB - Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction in normal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, male and female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam at the Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumour volume (average linear energy transfer = 13 keV x MUm(-1)) during patient radiotherapy protocols. The mice were monitored for the remainder of their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following an equivalent dose of 137Cs gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved in radiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared the genetic profile of the carbon ion- and gamma ray-induced tumours. The canonical set of genes previously associated with radiation-induced T cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhat different between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most striking finding was the observation of large interstitial deletions at various sites across the genome in carbon ion induced tumours, which were only seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristic lesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed in radiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing second cancer risk in carbon ion radiotherapy patients. PMID- 26125583 TI - The Czech Surveillance System for Invasive Pneumococcal Disease, 2008-2013: A Follow-Up Assessment and Sensitivity Estimation. AB - BACKGROUND: Invasive pneumococcal disease (IPD) is caused by Streptococcus pneumoniae and mostly presents as pneumonia, sepsis or meningitis. A notable portion of IPD cases is vaccine preventable and the pneumococcal conjugate vaccine (PCV) was introduced into the routine childhood immunization programs in many countries during the last decades. OBJECTIVES: Before PCV introduction in the Czech Republic in 2010, a national surveillance system for IPD was implemented in 2008 and further improved in 2011. In this study, we describe the new surveillance system for the first time and measure its sensitivity between 2010 and 2013 using the capture-recapture method. Furthermore, we describe the recent epidemiological trend of IPD, taking sensitivity estimates into account. RESULTS AND CONCLUSIONS: Between 2010 and 2013 the estimated sensitivity of the overall IPD surveillance increased from 81% to 99%. The sensitivity of individual reporting sources increased from 72% to 87% for the laboratory system and from 31% to 89% for the epidemiological notification system. Crucial for this improvement was the introduction of quarterly report reminders in 2011. Due to positive source dependency, the presented sensitivity estimates are most probably overestimated and reflect the upper limit of reporting completeness. Stratification showed variation in sensitivity of reporting particularly according to region. An effect of the PVC vaccination in the Czech Republic is visible in the incidence of IPD in target age groups (<5 y). This influence was not evident in the total IPD incidence and may interfere with increasing sensitivity of reporting. In 2013, an increase in the IPD incidence was observed. This finding requires further observation and a detailed vaccine impact analysis is needed to assess the current immunization strategy. PMID- 26125585 TI - Failure of PCR to Detect Treponema pallidum ssp. pertenue DNA in Blood in Latent Yaws. AB - Yaws, caused by Treponema pallidum ssp. pertenue, is a neglected tropical disease closely related to venereal syphilis and is targeted for eradication by 2020. Latent yaws represents a diagnostic challenge, and current tools cannot adequately distinguish between individuals with true latent infection and individuals who are serofast following successful treatment. PCR on blood has previously been shown to detect T. pallidum DNA in patients with syphilis, suggesting that this approach may be of value in yaws. We performed real-time PCR for Treponema pallidum ssp. pertenue on blood samples from 140 children with positive T. pallidum Particle Agglutination (TPPA) and Rapid Plasma Reagin (RPR) tests and 7 controls (negative serology), all collected as part of a prospective study of yaws in the Solomon Islands. All samples were also tested by a nested PCR for T. pallidum. 12 patients had clinical evidence of active yaws whilst 128 were considered to have latent yaws. 43 children had high titre rapid plasma reagins (RPRs) of >=1:32. PCR testing with both assays gave negative results in all cases. It is possible that the failure to detect T. pallidum ssp. pertenue in blood reflects lower loads of organism in latent yaws compared to those in latent infection with T. pallidum ssp. pertenue, and/or a lower propensity for haematogenous dissemination in yaws than in syphilis. As the goal of the yaws control programme is eradication, a tool that can differentiate true latent infection from individuals who are serofast would be of value; however, PCR of blood is not that tool. PMID- 26125584 TI - Proliferation-Independent Initiation of Biliary Cysts in Polycystic Liver Diseases. AB - Biliary cysts in adult patients affected by polycystic liver disease are lined by cholangiocytes that proliferate, suggesting that initiation of cyst formation depends on proliferation. Here, we challenge this view by analyzing cyst-lining cell proliferation and differentiation in Cpk mouse embryos and in livers from human fetuses affected by Autosomal Recessive Polycystic Kidney Disease (ARPKD), at early stages of cyst formation. Proliferation of fetal cholangiocyte precursors, measured by immunostaining in human and mouse livers, was low and did not differ between normal and ARPKD or Cpk livers, excluding excessive proliferation as an initiating cause of liver cysts. Instead, our analyses provide evidence that the polycystic livers exhibit increased and accelerated differentiation of hepatoblasts into cholangiocyte precursors, eventually coalescing into large biliary cysts. Lineage tracing experiments, performed in mouse embryos, indicated that the cholangiocyte precursors in Cpk mice generate cholangiocytes and periportal hepatocytes, like in wild-type animals. Therefore, contrary to current belief, cyst formation in polycystic liver disease does not necessarily depend on overproliferation. Combining our prenatal data with available data from adult livers, we propose that polycystic liver can be initiated by proliferation-independent mechanisms at a fetal stage, followed by postnatal proliferation-dependent cyst expansion. PMID- 26125586 TI - The effect of alcohol priming on neural markers of alcohol cue-reactivity. AB - BACKGROUND: Priming doses of alcohol are associated with increased desire to drink and disinhibitory effects on subsequent control over drinking. Despite the importance of alcohol priming in the cue-reactivity literature, the effects of priming on brain responses to alcohol cues remains unclear. Furthermore, evidence suggests this relationship may be moderated by OPRM1 genotype. METHODS: Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent two functional magnetic resonance imaging (fMRI) sessions, before and after a priming dose of alcohol, each including a gustatory alcohol cue reactivity paradigm and self reported craving measures. RESULTS: Self-reported alcohol craving generally increased and remained higher for alcohol versus water cue presentations across pre- and post-priming scans. Compared to alcohol cues delivered during the post priming scan, alcohol cues delivered pre-priming were associated with greater activation in regions including the hippocampus, amygdala, inferior frontal gyrus, temporal cortex, and occipital cortex. Controlling for alcoholism severity increased statistical significance of activation in these regions. Follow-up analyses revealed a positive correlation between alcoholism severity and pre- versus post-priming alcohol cue-reactivity primarily in frontal regions. OPRM1 genotype was also found to moderate alcohol cue-reactivity across scans. CONCLUSION: This study provides initial evidence of alcohol cue-elicited habituation in fronto-temporal regions, despite continued craving, following a priming dose of alcohol. Further, it provides preliminary evidence for moderating roles of alcoholism severity and OPRM1 genotype on priming-related changes in cue reactivity, adding to our understanding of the function of alcohol priming in alcohol dependence. PMID- 26125587 TI - Administration Time for the First Dose of Antimicrobials in Episodes of Fever and Neutropenia in Children With Cancer. AB - BACKGROUND: Early administration of antimicrobial (AM) is relevant in children with cancer, fever and neutropenia (FN). The recommendation is to administer the first dose of AM within the first hour of hospital admission. Our aims were to determine the time from the moment that a child with FN is admitted to the hospital until they receive their first dose of AM and to determine the association with clinical outcomes. METHODS: This prospective, multicenter study evaluated the time elapsed from the admission to the first dose of AM, comparing this variable by admitting hospital and presentation location (Emergency Department/Oncology Units) and evaluating the clinical outcomes by the following variables: days of fever, days of hospitalization, hypotension, transfer to intensive care unit, sepsis and mortality. RESULTS: A total of 226 children with 388 episodes of FN were enrolled from 5 hospitals (July 2012-April 2014). The median time between hospital admission and administration of the first dose of AM was 132 minutes (interquartile range: 60-246 minutes). The median time to AM administration was significantly different between hospitals (70 vs. 200 minutes, P < 0.0001) and between presentation locations (Emergency Department vs. Oncology Units, median: 200 vs. 100 minutes, P < 0.0001). Twenty-five percentage of children received AM within 1 hour of admission. The administration of AM after 60 minutes was not associated with worse outcomes. CONCLUSIONS: Time to AM administration was longer than the recommendation. The findings described provide an opportunity to identify gaps and implement programs aimed at improving the equity and excellence of care in children with cancer and FN. PMID- 26125588 TI - iSMS: single-molecule FRET microscopy software. PMID- 26125589 TI - InferenceMAP: mapping of single-molecule dynamics with Bayesian inference. PMID- 26125590 TI - Chemically defined, albumin-free human cardiomyocyte generation. PMID- 26125591 TI - Mass spectrometrists should search only for peptides they care about. AB - Analysis pipelines that assign peptides to shotgun proteomics mass spectra often discard identified spectra deemed irrelevant to the scientific hypothesis being tested. To improve statistical power, I propose that researchers remove irrelevant peptides from the database prior to searching rather than assigning these peptides to spectra and then discarding the matches. PMID- 26125592 TI - Metabolism: feeding fruit flies. PMID- 26125593 TI - Co-opting CRISPR to deliver functional RNAs. PMID- 26125595 TI - Maternal Exposure to Cadmium and Manganese Impairs Reproduction and Progeny Fitness in the Sea Urchin Paracentrotus lividus. AB - Metal contamination represents one of the major sources of pollution in marine environments. In this study we investigated the short-term effects of ecologically relevant cadmium and manganese concentrations (10(-6) and 3.6 x 10( 5) M, respectively) on females of the sea urchin Paracentrotus lividus and their progeny, reared in the absence or presence of the metal. Cadmium is a well-known heavy metal, whereas manganese represents a potential emerging contaminant, resulting from an increased production of manganese-containing compounds. The effects of these agents were examined on both P. lividus adults and their offspring following reproductive state, morphology of embryos, nitric oxide (NO) production and differential gene expression. Here, we demonstrated that both metals differentially impaired the fertilization processes of the treated female sea urchins, causing modifications in the reproductive state and also affecting NO production in the ovaries. A detailed analysis of the progeny showed a high percentage of abnormal embryos, associated to an increase in the endogenous NO levels and variations in the transcriptional expression of several genes involved in stress response, skeletogenesis, detoxification, multi drug efflux processes and NO production. Moreover, we found significant differences in the progeny from females exposed to metals and reared in metal-containing sea water compared to embryos reared in non-contaminated sea water. Overall, these results greatly expanded previous studies on the toxic effects of metals on P. lividus and provided new insights into the molecular events induced in the progeny of sea urchins exposed to metals. PMID- 26125594 TI - Pathway and network analysis of cancer genomes. AB - Genomic information on tumors from 50 cancer types cataloged by the International Cancer Genome Consortium (ICGC) shows that only a few well-studied driver genes are frequently mutated, in contrast to many infrequently mutated genes that may also contribute to tumor biology. Hence there has been large interest in developing pathway and network analysis methods that group genes and illuminate the processes involved. We provide an overview of these analysis techniques and show where they guide mechanistic and translational investigations. PMID- 26125596 TI - Analytical Validation of AmpliChip p53 Research Test for Archival Human Ovarian FFPE Sections. AB - The p53 tumor suppressor gene (TP53) is reported to be mutated in nearly half of all tumors and plays a central role in genome integrity. Detection of mutations in p53 can be accomplished by many assays, including the AmpliChip p53 Research Test. The AmpliChip p53 Research Test has been successfully used to determine p53 status in hematologic malignancies and fresh frozen solid tissues but there are few reports of using the assay with formalin fixed, paraffin-embedded (FFPE) tissue. The objective of this study was to describe analytical performance characterization of the AmpliChip p53 Research Test to detect p53 mutations in genomic DNA isolated from archival FFPE human ovarian tumor tissues. Method correlation with sequencing showed 96% mutation-wise agreement and 99% chip-wise agreement. We furthermore observed 100% agreement (113/113) of the most prevalent TP53 mutations. Workflow reproducibility was 96.8% across 8 samples, with 2 operators, 2 reagent lots and 2 instruments. Section-to-section reproducibility was 100% for each sample across a 60 MUm region of the FFPE block from ovarian tumors. These data indicate that the AmpliChip p53 Research Test is an accurate and reproducible method for detecting mutations in TP53 from archival FFPE human ovarian specimens. PMID- 26125597 TI - Simultaneous Brain-Cervical Cord fMRI Reveals Intrinsic Spinal Cord Plasticity during Motor Sequence Learning. AB - The spinal cord participates in the execution of skilled movements by translating high-level cerebral motor representations into musculotopic commands. Yet, the extent to which motor skill acquisition relies on intrinsic spinal cord processes remains unknown. To date, attempts to address this question were limited by difficulties in separating spinal local effects from supraspinal influences through traditional electrophysiological and neuroimaging methods. Here, for the first time, we provide evidence for local learning-induced plasticity in intact human spinal cord through simultaneous functional magnetic resonance imaging of the brain and spinal cord during motor sequence learning. Specifically, we show learning-related modulation of activity in the C6-C8 spinal region, which is independent from that of related supraspinal sensorimotor structures. Moreover, a brain-spinal cord functional connectivity analysis demonstrates that the initial linear relationship between the spinal cord and sensorimotor cortex gradually fades away over the course of motor sequence learning, while the connectivity between spinal activity and cerebellum gains strength. These data suggest that the spinal cord not only constitutes an active functional component of the human motor learning network but also contributes distinctively from the brain to the learning process. The present findings open new avenues for rehabilitation of patients with spinal cord injuries, as they demonstrate that this part of the central nervous system is much more plastic than assumed before. Yet, the neurophysiological mechanisms underlying this intrinsic functional plasticity in the spinal cord warrant further investigations. PMID- 26125598 TI - DNA Aptamer Assembly as a Vascular Endothelial Growth Factor Receptor Agonist. AB - Controlling receptor-mediated processes in cells is paramount in many research areas. The activity of small molecules and growth factors is difficult to control and can lead to off-target effects through the activation of nonspecific receptors as well as binding affinity to nonspecific cell types. In this study, we report the development of a molecular trigger in the form of a divalent nucleic acid aptamer assembly toward vascular endothelial growth factor receptor 2 (VEGFR2). The assembly binds to VEGFR2 and functions as a receptor agonist with targeted receptor binding, promoting receptor phosphorylation, activation of the downstream Akt pathway, upregulation of endothelial nitric oxide synthase, and endothelial cell capillary tube formation. The agonist action we report makes this aptamer construct a promising strategy to control VEGFR2-mediated cell signaling. PMID- 26125599 TI - Novel synthetic organic compounds inspired from antifeedant marine alkaloids as potent bacterial biofilm inhibitors. AB - In this paper, we have reported seventeen novel synthetic organic compounds derived from marine bromopyrrole alkaloids, exhibiting potential inhibition of biofilm produced by Gram-positive bacteria. Compound 5f with minimumbiofilm inhibitory concentration(MBIC) of 0.39, 0.78 and 3.125 MUg/mL against MSSA, MRSA and SE respectively, emerged as promising anti-biofilm lead compounds. In addition, compounds 5b, 5c, 5d, 5e, 5f, 5h, 5i and 5j revealed equal potency as that of the standard drug Vancomycin (MBIC = 3.125 MUg/mL) against Streptococcus epidermidis. Notably, most of the synthesized compounds displayed better potency than Vancomycin indicating their potential as inhibitors of bacterial biofilm. The cell viability assay for the most active hybrid confirms its anti-virulence properties which need to be further researched. PMID- 26125600 TI - A role for homologous recombination proteins in cell cycle regulation. AB - Eukaryotic cells respond to DNA breaks, especially double-stranded breaks (DSBs), by activating the DNA damage response (DDR), which encompasses DNA repair and cell cycle checkpoint signaling. The DNA damage signal is transmitted to the checkpoint machinery by a network of specialized DNA damage-recognizing and signal-transducing molecules. However, recent evidence suggests that DNA repair proteins themselves may also directly contribute to the checkpoint control. Here, we investigated the role of homologous recombination (HR) proteins in normal cell cycle regulation in the absence of exogenous DNA damage. For this purpose, we used Chinese Hamster Ovary (CHO) cells expressing the Fluorescent ubiquitination based cell cycle indicators (Fucci). Systematic siRNA-mediated knockdown of HR genes in these cells demonstrated that the lack of several of these factors alters cell cycle distribution, albeit differentially. The knock-down of MDC1, Rad51 and Brca1 caused the cells to arrest in the G2 phase, suggesting that they may be required for the G2/M transition. In contrast, inhibition of the other HR factors, including several Rad51 paralogs and Rad50, led to the arrest in the G1/G0 phase. Moreover, reduced expression of Rad51B, Rad51C, CtIP and Rad50 induced entry into a quiescent G0-like phase. In conclusion, the lack of many HR factors may lead to cell cycle checkpoint activation, even in the absence of exogenous DNA damage, indicating that these proteins may play an essential role both in DNA repair and checkpoint signaling. PMID- 26125601 TI - Nonenzymatic alpha-Linolenic Acid Derivatives from the Sea: Macroalgae as Novel Sources of Phytoprostanes. AB - Phytoprostanes, autoxidation products of alpha-linolenic acid, have been studied in several plant species, but information regarding the natural occurrence of this large family of biologically active oxidized lipids in macroalgae is still scarce. In this work, the free phytoprostane composition of 24 macroalgae species belonging to Chlorophyta, Phaeophyta, and Rhodophyta was determined through a recently validated UHPLC-QqQ-MS/MS method. The phytoprostane profiles varied greatly among all samples, F1t-phytoprostanes and L1-phytoprostanes being the predominant and minor classes, respectively. No correlation between the amounts of alpha-linolenic acid in alga material and phytoprostane content was found. Therefore, it was hypothesized that the observed variability could be species specific or result from interspecific interactions. This study provides new insight about the occurrence of phytoprostanes in macroalgae and opens doors for future exploitation of these marine photosynthetic organisms as sources of potentially bioactive oxylipins, encouraging their incorporation in food products and nutraceutical and pharmaceutical preparations for human health. PMID- 26125603 TI - Antagonism effects of cypermethrin on interleukin-6-induced androgen receptor activation. AB - To identify whether androgen receptor (AR) antagonism by cypermethrin involves interleukin-6 (IL-6)-induced ligand-independent AR signaling, we have developed the AR reporter gene assay. The reporter gene plasmid pMMTV-chloramphenicol transferase (CAT) was transfected into LNCaP cells. IL-6 increased expression of MMTV-CAT significantly (P<0.05). Cypermethrin decreased CAT reporter expression induced by IL-6 (50 ng/ml), and the significant inhibition was detected at 10( 5)M (P<0.05). IL-6 induces ligand-independent activation of AR. Cypermethrin exhibits inhibitory effects on IL-6-induced ligand-independent AR signaling. We provide a novel insight into cypermethrin-mediated antagonism of the IL-6 mediated ligand-independent activation of the AR. PMID- 26125602 TI - Perinatal Generalized Anxiety Disorder: Assessment and Treatment. AB - Perinatal generalized anxiety disorder (GAD) has a high prevalence of 8.5%-10.5% during pregnancy and 4.4%-10.8% postpartum. Despite its attendant dysfunction in the patient, this potentially debilitating mental health condition is often underdiagnosed. This overview will provide guidance for clinicians in making timely diagnosis and managing symptoms appropriately. A significant barrier to the diagnosis of GAD in the perinatal population is difficulty in distinguishing normal versus pathological worry. Because a perinatal-specific screening tool for GAD is nonexistent, early identification, diagnosis and treatment is often compromised. The resultant maternal dysfunction can potentially impact mother infant bonding and influence neurodevelopmental outcomes in the children. Comorbid occurrence of GAD and major depressive disorder changes the illness course and its treatment outcome. Psychoeducation is a key component in overcoming denial/stigma and facilitating successful intervention. Treatment strategies are contingent upon illness severity. Cognitive behavior therapy (CBT), relaxation, and mindfulness therapy are indicated for mild GAD. Moderate/severe illness requires pharmacotherapy and CBT, individually or in combination. No psychotropic medications are approved by the FDA or Health Canada in pregnancy or the postpartum; off-label pharmacological treatment is instituted only if the benefit of therapy outweighs its risk. SSRIs/SNRIs are the first-line treatment for anxiety disorders due to data supporting their efficacy and overall favorable side effect profile. Benzodiazepines are an option for short-term treatment. While research on atypical antipsychotics is evolving, some can be considered for severe manifestations where the response to antidepressants or benzodiazepines has been insufficient. A case example will illustrate the onset, clinical course, and treatment strategies of GAD through pregnancy and the postpartum. PMID- 26125604 TI - Efficient expression of stabilized mRNA PEG-peptide polyplexes in liver. AB - The expression efficiency in liver following hydrodynamic delivery of in vitro transcribed mRNA was improved 2000-fold using a codon-optimized mRNA luciferase construct with flanking 3' and 5' human beta-globin untranslated regions (UTR mRNA) over an unoptimized mRNA without beta-globin UTRs. Nanoparticle UTR mRNA polyplexes were formed using a novel polyacridine polyethylene glycol (PEG) peptide, resulting in an additional 15-fold increase in expression efficiency in the liver. The combined increase in expression for UTR mRNA PEG-peptide polyplexes was 3500-fold over mRNA lacking UTRs and PEG-peptide. The expression efficiency of UTR mRNA polyplex was 10-fold greater than the expression from an equivalent 1 MUg dose of pGL3. Maximal expression was maintained from 4 to 24 h. Serum incubation established the unique ability of the polyacridine PEG-peptide to protect UTR mRNA polyplexes from RNase metabolism by binding to double stranded regions. UTR mRNA PEG-peptide polyplexes are efficient nonviral vectors that circumvent the need for a nuclear uptake, representing an advancement toward the development of a targeted gene delivery system to transfect liver hepatocytes. PMID- 26125605 TI - Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression. AB - Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 * 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (~14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS. PMID- 26125606 TI - Prediction of adeno-associated virus neutralizing antibody activity for clinical application. AB - Patients with neutralizing antibodies (Nabs) against adeno-associated virus (AAV) are usually excluded from the treatment with AAV vectors. To develop a standard assay for detecting Nab inhibition activity, we systematically studied current AAV Nab assays in vitro and in vivo. Several factors were found that influence the Nab titers based on the in vitro assay, including sera volume, AAV dose per cell, cell number and choice of transgenes. When the Nab titer assay was performed in vivo via intramuscular (IM) or systemic administration, a fourfold increase in sensitivity for measurement of Nab titers was observed compared with an identical in vitro test. To better mimic the clinical setting, after passively transferring human Nabs into mice, blood was collected before systemic injection of AAV vector and used for Nab titer analysis in vitro or via IM injection. The results showed that AAV delivered via IM injection had a similar inhibition pattern to systemic administration. These studies indicate critical parameters necessary for optimizing Nab sensitivity and that an in vivo Nab assay is more sensitive than an in vitro assay for inclusion/exclusion criteria. The variables identified by this study may explain some of the compounding clinical data seen to date with respect to efficiency of AAV transduction in various phase I clinical trials. PMID- 26125607 TI - The spread of adenoviral vectors to central nervous system through pathway of cochlea in mimetic aging and young rats. AB - There is no definitive conclusion concerning the spread of viral vectors to the brain after a cochlear inoculation. In addition, some studies have reported different distribution profiles of viral vectors in the central auditory system after a cochlear inoculation. Thus, rats were grouped into either a mimetic aging group or a young group and transfected with adenoviral vectors (AdVs) by round window membrane injection. The distribution of AdV in central nervous system (CNS) was demonstrated in the two groups with transmission electron microscopy and immunofluorescence. We found that the AdV could disseminate into the CNS and that the neuronal damage and stress-induced GRP78 expression were reduced after transfection with PGC-1alpha, as compared with the control vectors, especially in the mimetic aging group. We also found that the host immune response was degraded in CNS in the mimetic aging group after transduction through the cochlea, as compared with the young group. These results demonstrate that viral vectors can disseminate into the CNS through the cochlea. Moreover, mimetic aging induced by D-galactose could facilitate the spread of viral vectors into the CNS from the cochlea. These findings may indicate a new potential approach for gene therapy against age-related diseases in the CNS. PMID- 26125608 TI - AAV1.NT-3 gene therapy attenuates spontaneous autoimmune peripheral polyneuropathy. AB - The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout non-obese diabetic mice shares clinical and histological features with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Secondary axonal loss is prominent in the progressive phase of this neuropathy. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulates neurite outgrowth and myelination. The anti-inflammatory and immunomodulatory effects of NT-3 raised considerations of potential efficacy in the SAPP model that could be applicable to CIDP. For this study, scAAV1.tMCK.NT-3 was delivered to the gastrocnemius muscle of 25-week old SAPP mice. Measurable NT-3 levels were found in the serum at 7-week postgene delivery. The outcome measures included functional, electrophysiological and histological assessments. At week 32, NT-3-treated mice showed increased hind limb grip strength that correlated with improved compound muscle action potential amplitude. Myelinated fiber density was 1.9 times higher in the NT-3-treated group compared with controls and the number of demyelinated axons was significantly lower. The remyelinated nerve fiber population was significantly increased. These improved histopathological parameters from scAAV1.tMCK.NT-3 treatment occurred in the setting of reduced sciatic nerve inflammation. Collectively, these findings suggest a translational application to CIDP. PMID- 26125610 TI - Assessing the Suitability of Historical PM(2.5) Element Measurements for Trend Analysis. AB - The IMPROVE (Interagency Monitoring of Protected Visual Environments) network has characterized fine particulate matter composition at locations throughout the United States since 1988. A main objective of the network is to evaluate long term trends in aerosol concentrations. Measurements inevitably advance over time, but changes in measurement technique have the potential to confound the interpretation of long-term trends. Problems of interpretation typically arise from changing biases, and changes in bias can be difficult to identify without comparison data that are consistent throughout the measurement series, which rarely exist. We created a consistent measurement series for exactly this purpose by reanalyzing the 15-year archives (1995-2009) of aerosol samples from three sites - Great Smoky Mountains National Park, Mount Rainier National Park, and Point Reyes National Seashore-as single batches using consistent analytical methods. In most cases, trend estimates based on the original and reanalysis measurements are statistically different for elements that were not measured above the detection limit consistently over the years (e.g., Na, Cl, Si, Ti, V, Mn). The original trends are more reliable for elements consistently measured above the detection limit. All but one of the 23 site-element series with detection rates >80% had statistically indistinguishable original and reanalysis trends (overlapping 95% confidence intervals). PMID- 26125609 TI - Tightly regulated 'all-in-one' lentiviral vectors for protection of human hematopoietic cells from anticancer chemotherapy. AB - Successful application of gene therapy strategies may require stringently regulated transgene expression. Along this line, we describe a doxycycline (Dox) inducible 'all-in-one' lentiviral vector design using the pTET-T11 (TII) minimal promoter and a reverse transactivator protein (rtTA2S-M2) driven by the phosphoglycerate kinase promoter allowing for tight regulation of transgene expression (Lv.TII vectors). Vector design was evaluated in human hematopoietic cells in the context of cytidine deaminase (hCDD)-based myeloprotective gene therapy. Upon Dox administration, a rapid (16-24 h) and dose-dependent (>0.04 MUg ml(-1) Dox) onset of transgene expression was detected in Lv.TII.CDD gene modified K562 cells as well as in primary human CD34(+) hematopoietic cells. Importantly, in both cell models low background transgene expression was observed in the absence of Dox. Functionality of Dox-inducible hCDD expression was demonstrated by >10-fold increase in cytosine arabinoside (1-beta-d arabinofuranosylcytosine, Ara-C) resistance of Lv.TII.CDD-transduced K562 cells. In addition, Lv.TII.CDD-transduced CD34(+)-derived myeloid cells were protected from up to 300 nm Ara-C (control affected from 50 nm onwards). These data clearly demonstrate the suitability of our self-inactivating lentiviral vector to induce robust, tightly regulated transgene expression in human hematopoietic cells with minimal background activity and highlight the potential of our construct in myeloprotective gene therapy strategies. PMID- 26125611 TI - Removal of copper ions from aqueous solutions via adsorption on carbon nanocomposites. AB - The development of technologies for water purification is critical to meet the global challenges of insufficient water supply and inadequate sanitation. Among all wastewater treatments, adsorption is globally recognized as the most promising method because of its versatility and economic feasibility. Herein, the removal of copper ions (Cu(II)) from aqueous solutions through adsorption on free standing hybrid papers comprised of a mixture between graphene and different types of carbon nanotubes (CNTs) was examined. Results indicate that the rate of adsorption and long-time capacity of the metal ions on the nanocomposites significantly exceeds that of activated carbon by a factor of 4. Moreover, the combination of graphene with CNTs endows an increase in the uptake of Cu(II) up to 50% compared to that of CNTs alone, with a maximum adsorption capacity higher than 250 mg.g(-1). The removal of Cu(II) from water is sensitive to solution pH, and the presence of oxygen functional groups on the adsorbent surface promotes higher adsorption rates and capacities than pristine materials. These hybrid nanostructures show great promise for environmental remediation efforts, wastewater treatments, and separation applications, and the results presented in this study have important implications for understanding the interactions of carbonaceous materials at environmental interfaces. PMID- 26125612 TI - Combined pretreatment with hot compressed water and wet disk milling opened up oil palm biomass structure resulting in enhanced enzymatic digestibility. AB - Combined pretreatment with hot compressed water and wet disk milling was performed with the aim to reduce the natural recalcitrance of oil palm biomass by opening its structure and provide maximal access to cellulase attack. Oil palm empty fruit bunch and oil palm frond fiber were first hydrothermally pretreated at 150-190 degrees C and 10-240 min. Further treatment with wet disk milling resulted in nanofibrillation of fiber which caused the loosening of the tight biomass structure, thus increasing the subsequent enzymatic conversion of cellulose to glucose. The effectiveness of the combined pretreatments was evaluated by chemical composition changes, power consumption, morphological alterations by SEM and the enzymatic digestibility of treated samples. At optimal pretreatment process, approximately 88.5% and 100.0% of total sugar yields were obtained from oil palm empty fruit bunch and oil palm frond fiber samples, which only consumed about 15.1 and 23.5 MJ/kg of biomass, respectively. PMID- 26125613 TI - Application of nano TiO2 modified hollow fiber membranes in algal membrane bioreactors for high-density algae cultivation and wastewater polishing. AB - Polyvinylidene fluoride (PVDF) hollow fiber membranes with nano-TiO2 (5% of PVDF by mass, average size = 25 nm) additives were fabricated and applied for high density algae (Chlorella vulgaris) cultivation. At the average light intensity of 121 MUmol/m(2)/s, the algal membrane bioreactors (A-MBR) operated at a hydraulic retention time of 0.5d and an average solids retention time of 25d had an average algae biomass concentration of 2350 +/- 74 mg/L (in COD units) and algal biomass production rate of 6.5 +/- 0.1g/m(2)/d. The A-MBRs removed an average of 78% of phosphorus from the wastewater at the initial total phosphorus concentrations ranging from 3.5 to 8.6 mg/L. The nano TiO2-embedded membranes had improved surface hydrophilicity with its total resistance about 50% lower than that of the control. This study demonstrated that PVDF/TiO2 nanocomposite membranes had a better antifouling property for high-density algae cultivation and wastewater polishing. PMID- 26125614 TI - High-throughput determination of citrinin in rice by ultra-high-performance liquid chromatography and fluorescence detection (UHPLC-FL). AB - A rapid, simple and effective method for the determination of citrinin in rice by UHPLC coupled to fluorescence detection has been developed and validated. Extraction of citrinin from rice samples was achieved by applying a QuEChERS based extraction/partitioning process with water and acetonitrile, without the need of further extract clean-up. The method was fully validated for white rice, and its applicability in other rice matrices, such as brown and red rice, was confirmed by recovery experiments. Under optimum conditions, recoveries ranged from 72.5% to 92.8%, with relative standard deviations (RSDs) lower than 7.1%. Detection and quantification limits were estimated to be 1.5 and 5.0 ug kg(-1), respectively. Finally, 21 organic rice samples were analysed, but none was contaminated with citrinin above the detection limit of the method. The method proved to be fast and non-laborious. PMID- 26125615 TI - Instrumentation in osteomyelitis-related cervical deformity. PMID- 26125616 TI - Automatic Detection and Reproduction of Natural Head Position in Stereo Photogrammetry. AB - The aim of this study was to develop an automatic orientation calibration and reproduction method for recording the natural head position (NHP) in stereo photogrammetry (SP). A board was used as the physical reference carrier for true verticals and NHP alignment mirror orientation. Orientation axes were detected and saved from the digital mesh model of the board. They were used for correcting the pitch, roll and yaw angles of the subsequent captures of patients' facial surfaces, which were obtained without any markings or sensors attached onto the patient. We tested the proposed method on two commercial active (3dMD) and passive (DI3D) SP devices. The reliability of the pitch, roll and yaw for the board placement were within +/-0.039904 degrees , +/-0.081623 degrees , and +/ 0.062320 degrees ; where standard deviations were 0.020234 degrees , 0.045645 degrees and 0.027211 degrees respectively. CONCLUSION: Orientation-calibrated stereo-photogrammetry is the most accurate method (angulation deviation within +/ 0.1 degrees ) reported for complete NHP recording with insignificant clinical error. PMID- 26125618 TI - Correction: Genomic Selection and Association Mapping in Rice (Oryza sativa): Effect of Trait Genetic Architecture, Training Population Composition, Marker Number and Statistical Model on Accuracy of Rice Genomic Selection in Elite, Tropical Rice Breeding Lines. PMID- 26125617 TI - Complete Taiwanese Macaque (Macaca cyclopis) Mitochondrial Genome: Reference Assisted de novo Assembly with Multiple k-mer Strategy. AB - The Taiwanese (Formosan) macaque (Macaca cyclopis) is the only nonhuman primate endemic to Taiwan. This primate species is valuable for evolutionary studies and as subjects in medical research. However, only partial fragments of the mitochondrial genome (mitogenome) of this primate species have been sequenced, not mentioning its nuclear genome. We employed next-generation sequencing to generate 2 x 90 bp paired-end reads, followed by reference-assisted de novo assembly with multiple k-mer strategy to characterize the M. cyclopis mitogenome. We compared the assembled mitogenome with that of other macaque species for phylogenetic analysis. Our results show that, the M. cyclopis mitogenome consists of 16,563 nucleotides encoding for 13 protein-coding genes, 2 ribosomal RNAs and 22 transfer RNAs. Phylogenetic analysis indicates that M. cyclopis is most closely related to M. mulatta lasiota (Chinese rhesus macaque), supporting the notion of Asia-continental origin of M. cyclopis proposed in previous studies based on partial mitochondrial sequences. Our work presents a novel approach for assembling a mitogenome that utilizes the capabilities of de novo genome assembly with assistance of a reference genome. The availability of the complete Taiwanese macaque mitogenome will facilitate the study of primate evolution and the characterization of genetic variations for the potential usage of this species as a non-human primate model for medical research. PMID- 26125619 TI - The Impact of Climate on the Spread of Rice to North-Eastern China: A New Look at the Data from Shandong Province. AB - Moving crops outside of their original centers of domestication was sometimes a challenging process. Because of its substantial heat requirements, moving rice agriculture outside of its homelands of domestication was not an easy process for farmers in the past. Using crop niche models, we examine the constraints faced by ancient farmers and foragers as they moved rice to its most northerly extent in Ancient China: Shandong province. Contrary to previous arguments, we find that during the climatic optimum rice could have been grown in the region. Climatic cooling following this date had a clear impact on the distribution of rice, one that may have placed adaptive pressure on rice to develop a temperate phenotype. Following the development of this temperate phenotype, rice agriculture could once again become implanted in select areas of north-eastern China. PMID- 26125620 TI - A Colloidal Description of Intermolecular Interactions Driving Fibril-Fibril Aggregation of a Model Amphiphilic Peptide. AB - We apply a kinetic analysis platform to study the intermolecular interactions underlying the colloidal stability of dispersions of charged amyloid fibrils consisting of a model amphiphilic peptide (RADA 16-I). In contrast to the aggregation mechanisms observed in the large majority of proteins and peptides, where several elementary reactions involving both monomers and fibrils are present simultaneously, the system selected in this work allows the specific investigation of the fibril-fibril aggregation process. We examine the intermolecular interactions driving the aggregation reaction at pH 2.0 by changing the buffer composition in terms of salt concentration, type of ion as well as type and concentration of organic solvent. The aggregation kinetics are followed by dynamic light scattering, and the experimental data are simulated by Smoluchowski population balance equations, which allow to estimate the energy barrier between two colliding fibrils in terms of the Fuchs stability ratio (W). When normalized on a dimensionless time weighted on the Fuchs stability ratio, the aggregation profiles under a broad range of conditions collapse on a single master curve, indicating that the buffer composition modifies the aggregation kinetics without affecting the aggregation mechanism. Our results show that the aggregation process does not occur under diffusion-limited conditions. Rather, the reaction rate is limited by the presence of an activation energy barrier that is largely dominated by electrostatic repulsive interactions. Such interactions could be reduced by increasing the concentration of salt, which induces charge screening, or the concentration of organic solvent, which affects the dielectric constant. It is remarkable that the dependence of the activation energy on the ionic strength can be described quantitatively in terms of charge screening effects in the frame of the DLVO theory, although specific anion and cation effects are also observed. While anion effects are mainly related to the binding to the positive groups of the fibril surface and to the resulting decrease of the surface charge, cation effects are more complex and involve additional solvation forces. PMID- 26125621 TI - Semantic Processing Persists despite Anomalous Syntactic Category: ERP Evidence from Chinese Passive Sentences. AB - The syntax-first model and the parallel/interactive models make different predictions regarding whether syntactic category processing has a temporal and functional primacy over semantic processing. To further resolve this issue, an event-related potential experiment was conducted on 24 Chinese speakers reading Chinese passive sentences with the passive marker BEI (NP1 + BEI + NP2 + Verb). This construction was selected because it is the most-commonly used Chinese passive and very much resembles German passives, upon which the syntax-first hypothesis was primarily based. We manipulated semantic consistency (consistent vs. inconsistent) and syntactic category (noun vs. verb) of the critical verb, yielding four conditions: CORRECT (correct sentences), SEMANTIC (semantic anomaly), SYNTACTIC (syntactic category anomaly), and COMBINED (combined anomalies). Results showed both N400 and P600 effects for sentences with semantic anomaly, with syntactic category anomaly, or with combined anomalies. Converging with recent findings of Chinese ERP studies on various constructions, our study provides further evidence that syntactic category processing does not precede semantic processing in reading Chinese. PMID- 26125622 TI - Spacer-Directed Selective Assembly of Copper Square or Hexagon and Ring-Stacks or Coordination Nanotubes. AB - The use of simple self-assembly methods to direct or engineer porosity or channels of desirable functionality is a major challenge in the field of metal organic frameworks. We herein report a series of frameworks by modifying square ring structure of [{Cu2(5-dmpy)2(L1)2(H2O)(MeOH)}2{ClO4}4].4MeOH (1.4MeOH, 5-dmpy = 5,5'-dimethyl-2,2'-bipyridine, HL1 = 4-pyridinecarboxylic acid). Use of pyridyl carboxylates as directional spacers in bipyridyl chelated Cu(II) system led to the growth of square unit into other configurations, namely, square ring, square chain, and square tunnel. Another remarkable characteristic is that the novel use of two isomers of pyridinyl-acrylic acid directs selectively to two different extreme tubular forms-aligned stacking of discrete hexagonal rings and crack-free one-dimensional continuum polymers. This provides a unique example of two extreme forms of copper nanotubes from two isomeric spacers. All of the reactions are performed in a one-pot self-assembly process at room temperature, while the topological selectivity is exclusively determined by the skeletal characteristics of the spacers. PMID- 26125624 TI - Infected Hepatic Echinococcosis: Results of Surgical Treatment of a Consecutive Series of Patients. AB - BACKGROUND: One of the progressive complications of hepatic echinococcosis (HE) is cyst infection and subsequent liver abscess of a hepatic formation (LAHO). To date, this entity has not been studied or reported on extensively. Traditionally, the issue has been addressed with cystectomy and drainage, but this is associated with unsatisfactory outcomes. The aim of this study was to describe the results of surgical treatment in a group of patients with LAHO in terms of post-operative morbidity (POM). METHODS: We describe a case series of 64 consecutive patients with LAHO treated at two medical centers in Temuco, Chile. General and liver laboratory parameters were determined, thoracic radiographs, and abdominal ultrasound and computed tomography scans were performed. Study variables were POM, hospital stay, mortality rate, and recurrence. The minimum follow-up was three months, and clinical checkups were undertaken at months 1, 6, 12, 24, 36, 48, and 60. Descriptive statistics were applied. RESULTS: Sixty-four patients were treated with a median age and cyst diameter of 51 years and 16 cm, respectively. Of the series, 57.8% were female. The median hospital stay was 8 days. General POM and mortality rates were 23.4% and 3.1%, respectively. With a median follow-up of 67 months, non-hydatid recurrences were observed. CONCLUSION: The POM of LAHO is high, and the mortality rate is significant if we consider it a clinical entity within the context of a benign disease. PMID- 26125623 TI - A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers. AB - Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >105-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent accessibility profiles of infectious and non-infectious autocatalytic recombinant PrP conformers are remarkably similar throughout their protease-resistant cores, except for two domains encompassing residues 91-115 and 144-163. Raman spectroscopy and immunoprecipitation studies confirm that these domains adopt distinct conformations within infectious versus non-infectious autocatalytic recombinant PrP conformers. Functionally, in vitro prion propagation experiments show that the non-infectious conformer is unable to seed mouse PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor, including native PrPC. Taken together, these results indicate that having a conformation that can be specifically adopted by post-translationally modified PrPC molecules is an essential determinant of biological infectivity for recombinant prions, and suggest that this ability is associated with discrete features of PrPSc structure. PMID- 26125625 TI - Learning with the Spinal Cord. AB - To what extent does the spinal cord play a role in the learning of motor tasks? A new study that simultaneously images the brain and spinal cord shows that the spinal cord is actively and independently involved in the earliest stages of motor learning. PMID- 26125627 TI - Ion Association in Hydrothermal Sodium Sulfate Solutions Studied by Modulated FT IR-Raman Spectroscopy and Molecular Dynamics. AB - Saline aqueous solutions at elevated pressures and temperatures play an important role in processes such as supercritical water oxidation (SCWO) and supercritical water gasification (SCWG), as well as in natural geochemical processes in Earth and planetary interiors. Some solutions exhibit a negative temperature coefficient of solubility at high temperatures, thereby leading to salt precipitation with increasing temperature. Using modulated FT-IR Raman spectroscopy and classical molecular dynamics simulations (MD), we studied the solute speciation in solutions of 10 wt % Na2SO4, at conditions close to the saturation limit. Our experiments reveal that ion pairing and cluster formation are favored as solid saturation is approached, and ionic clusters form prior to the precipitation of solid sulfate. The proportion of such clusters increases as the phase boundary is approached either by decreasing pressure or by increasing temperature in the vicinity of the three-phase (vapor-liquid-solid) curve. PMID- 26125626 TI - Microevolution of Duplications and Deletions and Their Impact on Gene Expression in the Nematode Pristionchus pacificus. AB - The evolution of diversity across the animal kingdom has been accompanied by tremendous gene loss and gain. While comparative genomics has been fruitful to characterize differences in gene content across highly diverged species, little is known about the microevolution of structural variations that cause these differences in the first place. In order to investigate the genomic impact of structural variations, we made use of genomic and transcriptomic data from the nematode Pristionchus pacificus, which has been established as a satellite model to Caenorhabditis elegans for comparative biology. We exploit the fact that P. pacificus is a highly diverse species for which various genomic data including the draft genome of a sister species P. exspectatus is available. Based on resequencing coverage data for two natural isolates we identified large (> 2 kb) deletions and duplications relative to the reference strain. By restriction to completely syntenic regions between P. pacificus and P. exspectatus, we were able to polarize the comparison and to assess the impact of structural variations on expression levels. We found that while loss of genes correlates with lack of expression, duplication of genes has virtually no effect on gene expression. Further investigating expression of individual copies at sites that segregate between the duplicates, we found in the majority of cases only one of the copies to be expressed. Nevertheless, we still find that certain gene classes are strongly depleted in deletions as well as duplications, suggesting evolutionary constraint acting on synteny. In summary, our results are consistent with a model, where most structural variations are either deleterious or neutral and provide first insights into the microevolution of structural variations in the P. pacificus genome. PMID- 26125628 TI - Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides. AB - Nonsymmetric DiPPro-nucleotides are described as nucleoside diphosphate (NDP) delivery systems. The concept is to attach different bis(acyloxybenzyl) moieties at the beta-phosphate moiety of a NDP. DiPPro compounds bearing two alkanoylbenzyl residues and DiPPro compounds bearing an alkanoylbenzyl or a benzoylbenzyl group as bioreversible prodrug moieties were studied. Compounds bearing short chain alkanoyl esters led to a fast hydrolysis by chemical or enzymatic means. The ester group in the second prodrug group comprised a long lipophilic aliphatic or an aromatic residue. The lipophilicity of this group enabled the prodrug to penetrate the cell membrane. The introduction of two different groups allowed a controlled stepwise removal of the prodrug moieties to achieve a highly selective delivery of the NDP in CEM cell extracts. The compounds were highly active against HIV even in thymidine kinase-deficient CEM cells. Thus, the compounds, although charged at the alpha-phosphate group, were taken up by the cells and released NDPs. PMID- 26125629 TI - Using Hierarchical Linear Modeling to Examine How Individual SLPs Differentially Contribute to Children's Language and Literacy Gains in Public Schools. AB - PURPOSE: The purpose of this study was twofold: (a) to determine the unique contributions in children's language and literacy gains, over 1 academic year, that are attributable to the individual speech-language pathologist (SLP) and (b) to explore possible child- and SLP-level factors that may further explain SLPs' contributions to children's language and literacy gains. METHOD: Participants were 288 kindergarten and 1st-grade children with language impairment who were currently receiving school-based language intervention from SLPs. Using hierarchical linear modeling, we partitioned the variance in children's gains in language (i.e., grammar, vocabulary) and literacy (i.e., word decoding) that could be attributed to their individual SLP. RESULTS: Results revealed a significant contribution of individual SLPs to children's gains in grammar, vocabulary, and word decoding. Children's fall language scores and grade were significant predictors of SLPs' contributions, although no SLP-level predictors were significant. CONCLUSIONS: The present study makes a first step toward incorporating implementation science and suggests that, for children receiving school-based language intervention, variance in child language and literacy gains in an academic year is at least partially attributable to SLPs. Continued work in this area should examine the possible SLP-level characteristics that may further explicate the relative contributions of SLPs. PMID- 26125630 TI - Influence of Seasonal Food Availability on the Dynamics of Seabird Feeding Flocks at a Coastal Upwelling Area. AB - The formation of multi-species feeding flocks (MSFFs) through visual recruitment is considered an important strategy for obtaining food in seabirds and its functionality has been ascribed to enhanced foraging efficiency. Its use has been demonstrated in much of the world's oceans and includes numerous species. However, there is scant information on the temporal stability of the composition and abundance of MSFFs as well as the effect of seasonal food availability on their dynamics. Between July 2006 and September 2014, we conducted monthly at-sea seabird counts at Valparaiso Bay (32 degrees 56' to 33 degrees 01'S, 71 degrees 36' to 71 degrees 46'W) within the area of influence of the Humboldt Current in central Chile. This area is characterized by a marked seasonality in primary and secondary production associated with upwelling, mainly during austral spring summer. Based on studies that provide evidence that flocking is most frequent when food is both scarce and patchy, we hypothesized that seabird MSFF attributes (i.e. frequency of occurrence, abundance and composition) will be modified according to the seasonal availability of food. Using generalized linear models (GLMs), our results show that the contrasting seasonality in food availability of the study area (using chlorophyll-a concentration as a proxy) had no significant influence on MSFF attributes, sparsely explaining their variations (P>0.05). Rather than seasonal food availability, the observed pattern for MSFF attributes at Valparaiso Bay suggests a substantial influence of reproductive and migratory (boreal and austral migrants) habits of birds that modulates MSFF dynamics consistently throughout the whole year in this highly variable and patchy environment. We highlight the importance of visual recruitment as a mechanism by which migratory and resident birds interact. This would allow them to reduce resource unpredictability, which in turn has a major impact on structuring seabird's MSFF dynamics. PMID- 26125631 TI - Information Filtering via Heterogeneous Diffusion in Online Bipartite Networks. AB - The rapid expansion of Internet brings us overwhelming online information, which is impossible for an individual to go through all of it. Therefore, recommender systems were created to help people dig through this abundance of information. In networks composed by users and objects, recommender algorithms based on diffusion have been proven to be one of the best performing methods. Previous works considered the diffusion process from user to object, and from object to user to be equivalent. We show in this work that it is not the case and we improve the quality of the recommendation by taking into account the asymmetrical nature of this process. We apply this idea to modify the state-of-the-art recommendation methods. The simulation results show that the new methods can outperform these existing methods in both recommendation accuracy and diversity. Finally, this modification is checked to be able to improve the recommendation in a realistic case. PMID- 26125633 TI - Accurate Alternative Measurements for Female Lifetime Reproductive Success in Drosophila melanogaster. AB - Fitness is an individual's ability to survive and reproduce, and is an important concept in evolutionary biology. However, accurately measuring fitness is often difficult, and appropriate fitness surrogates need to be identified. Lifetime reproductive success, the total progeny an organism can produce in their lifetime, is thought to be a suitable proxy for fitness, but the measure of an organism's reproductive output across a lifetime can be difficult or impossible to obtain. Here we demonstrate that the short-term measure of reproductive success across five days provides a reasonable prediction of an individual's total lifetime reproductive success in Drosophila melanogaster. However, the lifetime reproductive success of a female that has only mated once is not correlated to the lifetime reproductive success of a female that is allowed to mate multiple times, demonstrating that these measures should not serve as surrogates nor be used to make inferences about one another. PMID- 26125632 TI - Dual Transcriptomic Profiling of Host and Microbiota during Health and Disease in Pediatric Asthma. AB - BACKGROUND: High-throughput sequencing (HTS) analysis of microbial communities from the respiratory airways has heavily relied on the 16S rRNA gene. Given the intrinsic limitations of this approach, airway microbiome research has focused on assessing bacterial composition during health and disease, and its variation in relation to clinical and environmental factors, or other microbiomes. Consequently, very little effort has been dedicated to describing the functional characteristics of the airway microbiota and even less to explore the microbe host interactions. Here we present a simultaneous assessment of microbiome and host functional diversity and host-microbe interactions from the same RNA-seq experiment, while accounting for variation in clinical metadata. METHODS: Transcriptomic (host) and metatranscriptomic (microbiota) sequences from the nasal epithelium of 8 asthmatics and 6 healthy controls were separated in silico and mapped to available human and NCBI-NR protein reference databases. Human genes differentially expressed in asthmatics and controls were then used to infer upstream regulators involved in immune and inflammatory responses. Concomitantly, microbial genes were mapped to metabolic databases (COG, SEED, and KEGG) to infer microbial functions differentially expressed in asthmatics and controls. Finally, multivariate analysis was applied to find associations between microbiome characteristics and host upstream regulators while accounting for clinical variation. RESULTS AND DISCUSSION: Our study showed significant differences in the metabolism of microbiomes from asthmatic and non-asthmatic children for up to 25% of the functional properties tested. Enrichment analysis of 499 differentially expressed host genes for inflammatory and immune responses revealed 43 upstream regulators differentially activated in asthma. Microbial adhesion (virulence) and Proteobacteria abundance were significantly associated with variation in the expression of the upstream regulator IL1A; suggesting that microbiome characteristics modulate host inflammatory and immune systems during asthma. PMID- 26125634 TI - Integrating Multiple Distribution Models to Guide Conservation Efforts of an Endangered Toad. AB - Species distribution models are used for numerous purposes such as predicting changes in species' ranges and identifying biodiversity hotspots. Although implications of distribution models for conservation are often implicit, few studies use these tools explicitly to inform conservation efforts. Herein, we illustrate how multiple distribution models developed using distinct sets of environmental variables can be integrated to aid in identification sites for use in conservation. We focus on the endangered arroyo toad (Anaxyrus californicus), which relies on open, sandy streams and surrounding floodplains in southern California, USA, and northern Baja California, Mexico. Declines of the species are largely attributed to habitat degradation associated with vegetation encroachment, invasive predators, and altered hydrologic regimes. We had three main goals: 1) develop a model of potential habitat for arroyo toads, based on long-term environmental variables and all available locality data; 2) develop a model of the species' current habitat by incorporating recent remotely-sensed variables and only using recent locality data; and 3) integrate results of both models to identify sites that may be employed in conservation efforts. We used a machine learning technique, Random Forests, to develop the models, focused on riparian zones in southern California. We identified 14.37% and 10.50% of our study area as potential and current habitat for the arroyo toad, respectively. Generally, inclusion of remotely-sensed variables reduced modeled suitability of sites, thus many areas modeled as potential habitat were not modeled as current habitat. We propose such sites could be made suitable for arroyo toads through active management, increasing current habitat by up to 67.02%. Our general approach can be employed to guide conservation efforts of virtually any species with sufficient data necessary to develop appropriate distribution models. PMID- 26125635 TI - Paper-Based RNA Extraction, in Situ Isothermal Amplification, and Lateral Flow Detection for Low-Cost, Rapid Diagnosis of Influenza A (H1N1) from Clinical Specimens. AB - The 2009 Influenza A (H1N1) pandemic disproportionately affected the developing world and highlighted the key inadequacies of traditional diagnostic methods that make them unsuitable for use in resource-limited settings, from expensive equipment and infrastructure requirements to unacceptably long turnaround times. While rapid immunoassay diagnostic tests were much less costly and more context appropriate, they suffered from drastically low sensitivities and high false negative rates. An accurate, sensitive, and specific molecular diagnostic that is also rapid, low-cost, and independent of laboratory infrastructure is needed for effective point-of-care detection and epidemiological control in these developing regions. We developed a paper-based assay that allows for the extraction and purification of RNA directly from human clinical nasopharyngeal specimens through a poly(ether sulfone) paper matrix, H1N1-specific in situ isothermal amplification directly within the same paper matrix, and immediate visual detection on lateral flow strips. The complete sample-to-answer assay can be performed at the point-of-care in just 45 min, without the need for expensive equipment or laboratory infrastructure, and it has a clinically relevant viral load detection limit of 10(6) copies/mL, offering a 10-fold improvement over current rapid immunoassays. PMID- 26125636 TI - Complex Evolution of Built-in Potential in Compositionally-Graded PbZr(1 x)Ti(x)O3 Thin Films. AB - Epitaxial strain has been widely used to tune crystal and domain structures in ferroelectric thin films. New avenues of strain engineering based on varying the composition at the nanometer scale have been shown to generate symmetry breaking and large strain gradients culminating in large built-in potentials. In this work, we develop routes to deterministically control these built-in potentials by exploiting the interplay between strain gradients, strain accommodation, and domain formation in compositionally graded PbZr1-xTixO3 heterostructures. We demonstrate that variations in the nature of the compositional gradient and heterostructure thickness can be used to control both the crystal and domain structures and give rise to nonintuitive evolution of the built-in potential, which does not scale directly with the magnitude of the strain gradient as would be expected. Instead, large built-in potentials are observed in compositionally graded heterostructures that contain (1) compositional gradients that traverse chemistries associated with structural phase boundaries (such as the morphotropic phase boundary) and (2) ferroelastic domain structures. In turn, the built-in potential is observed to be dependent on a combination of flexoelectric effects (i.e., polarization-strain gradient coupling), chemical-gradient effects (i.e., polarization-chemical potential gradient coupling), and local inhomogeneities (in structure or chemistry) that enhance strain (and/or chemical potential) gradients such as areas with nonlinear lattice parameter variation with chemistry or near ferroelastic domain boundaries. Regardless of origin, large built-in potentials act to suppress the dielectric permittivity, while having minimal impact on the magnitude of the polarization, which is important for the optimization of these materials for a range of nanoapplications from vibrational energy harvesting to thermal energy conversion and beyond. PMID- 26125637 TI - Vigorous Physical Activity and All-Cause Mortality: A Story That Got Lost in Translation. PMID- 26125638 TI - Energy Expenditure in Adolescents With Cerebral Palsy: Comparison of the SenseWear Armband and Indirect Calorimetry. AB - BACKGROUND: Inactivity and overweight are major health concerns in children and adolescents with disabilities. Methods for the assessment of activity and energy expenditure may be affected negatively by the underlying disability, especially when motor function is impaired. The purpose of this study was to assess the validity of the SenseWear Armband in adolescents with cerebral palsy and hemiparesis. METHODS: Ten volunteers (age: 13.4 +/- 1.6 years) were equipped with SenseWear Armbands on the hemiparetic and nonhemiparetic side of the body. Energy expenditure was measured at rest and during treadmill exercise (speed range: 0.85 to 2.35 m/s). Indirect calorimetry served as independent reference method. RESULTS: The mean error was between -0.6 and 0.8 kcal/min and there were no significant differences between SenseWear and indirect calorimetry at any speed. Differences between body sides in expenditure (mean: -0.2 to 0.0 kcal/min) and step count (mean: -3.4 to 9.7 steps/min) were not significant. CONCLUSIONS: The validity of the SenseWear Armband does not appear to be negatively affected by cerebral palsy during laboratory treadmill exercise. Future field studies are necessary to assess the validity and practicability energy expenditure and physical activity in children and adolescents with physical disabilities. PMID- 26125639 TI - Structural Changes in Pseudoexfoliation Syndrome Evaluated with Spectral Domain Optical Coherence Tomography. AB - PURPOSE: To detect early structural changes of macular ganglion cell complex (GCC), peripapillary nerve fiber layer (pNFL), and optic nerve head (ONH) topography in subjects with pseudoexfoliation (PEX) using 3-D spectral domain optical coherence tomography (SD-OCT, Topcon 3D-2000). MATERIALS AND METHODS: Thirty-five participants with PEX and 29 healthy control subjects were included in the study. All study participants underwent SD-OCT imaging. Macular NFL, ganglion cell layer and inner plexiform layer (GCL + IPL), pNFL, and ONH parameters were measured in each participant. The results were compared within the two groups. RESULTS: In eyes with PEX, the superior and total mNFL thickness; superior, and total GCL + IPL thickness; superior, inferior, and total GCC thickness; and inferior, temporal, nasal, and total pNFL thickness were significantly thinner than the control subjects. In the topographic evaluation of ONH, there was no significant difference in optic disc area (ODA), cup area, rim area, cup to disc ratio (CDR), cup volume, rim volume, linear CDR and vertical CDR between the two groups. CONCLUSIONS: In PEX syndrome, similar decreases of the GCC and NFL occurred, and a high correlation existed between the two. Therefore, GCC can potentially be used to detect the early stages of PEX glaucoma. PMID- 26125640 TI - Directed Amination of Aryl Methyl Ethers Mediated by Ti(NMe2)4 at Room Temperature. AB - An efficient C-O amination of aryl methyl ethers has been achieved. This transformation proceeds via imine-directed Ti(IV)-mediated cross-coupling reactions between aryl methyl ethers and Ti(NR2)4 at room temperature, straightforwardly leading to a series of arylamines. This protocol features a wide substrate scope, exclusive regioselectivity, and mild reaction conditions. PMID- 26125641 TI - Vitamin D, Iron Metabolism, and Diet in Alpinists During a 2-Week High-Altitude Climb. AB - A defensive mechanism against hypobaric hypoxia at high altitude is erythropoesis. Some authors point to the contribution of vitamin D to the regulation of this process. The aim of the present study was to assess the 25 hydroxycholecalciferol (25(OH)D) level and its associations with iron metabolic and inflammatory indices in participants of a 2-week mountaineering expedition. The study sample included 9 alpinists practicing recreational mountain climbing. Every 2 or 3 days they set up a different base between 3200 and 3616 m with the intention of climbing 4000 m peaks in the Mont Blanc massif. Before their departure for the mountains and 2 days after returning to the sea level anthropometric parameters, hematological parameters, serum levels of 25(OH)D and iron metabolic indices were measured in all the participants. The composition of the participants' diet was also evaluated. The comparative analysis showed a significant decrease in body mass, BMI values, total iron, and 25(OH)D concentrations (p<0.05). Also significant increases in unsaturated iron-binding capacity, hematocrit, and C-reactive protein concentrations (p<0.05) were found. It can be concluded that the 2-week climbing expedition contributed to the reduction of 25(OH)D levels and these changes were associated with modulation of immune processes. Moreover, the climbers' diet requires some serious modifications. PMID- 26125642 TI - Regulation of NKCC2 splicing and phosphorylation. AB - PURPOSE OF REVIEW: Transepithelial salt transport in the thick ascending limb of Henle's loop (TAL) crucially depends on the activity of the Na/K/2Cl cotransporter NKCC2. The pharmacologic blockade of NKCC2 leads to pronounced natriuresis and diuresis, which indicate key roles for NKCC2 in renal salt retrieval. The inadequate regulation of NKCC2 and the loss of NKCC2 function are associated with the disruption of salt and water homoeostasis. This review provides a specific overview of our current knowledge with respect to the regulation of NKCC2 by differential splicing and phosphorylation. RECENT FINDINGS: Several mechanisms have evolved to adapt NKCC2 transport to reabsorptive needs. These mechanisms include the regulation of NKCC2 gene expression, the differential splicing of the NKCC2 pre-mRNA, the membrane trafficking, and the modulation of the specific transport activity. Substantial progress has been made over the past few years in deciphering the function of kinases in the regulatory network controlling NKCC2 activity and in elucidating the underlying mechanism and the functional consequences of the regulated differential splicing of the NKCC2 pre-mRNA. SUMMARY: NKCC2 differential splicing and phosphorylation are critically involved in the modulation of the thick ascending limb of Henle's loop reabsorptive capacity and, consequently, in salt homoeostasis, volume regulation, and blood pressure control. PMID- 26125643 TI - FGF23 regulation of renal tubular solute transport. AB - PURPOSE OF REVIEW: Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption in the kidney. The purpose of this review was to highlight the recent advances in the area of FGF23-regulated solute transport in the kidney. RECENT FINDINGS: Recent evidence suggests that FGF23 suppresses phosphate reabsorption in renal proximal tubular epithelium by a Klotho-dependent, FGF receptor (FGFR)-1 and FGFR4-mediated signaling mechanism that may also involve Janus kinase 3. Moreover, it was recently established that FGF23 signaling in the distal renal tubule targets with-no-lysine kinase-4 (WNK4), a key molecule in the regulation of solute transport in the distal nephron. By targeting WNK4, FGF23 has been shown to increase the membrane abundance of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC, resulting in augmented renal calcium and sodium reabsorption. SUMMARY: Significant progress has been made in the further characterization of the signaling pathways involved in the FGF23-induced inhibition of phosphate transport in proximal tubular epithelium, and major new functions of FGF23 in solute transport have been discovered in distal renal tubules. The calcium- and sodium-conserving functions of FGF23 may have major implications for the pathophysiology of cardiovascular diseases. VIDEO ABSTRACT. PMID- 26125645 TI - Hypertension and immunity: mechanisms of T cell activation and pathways of hypertension. AB - PURPOSE OF REVIEW: The role of immune mechanisms to amplify hypertension in patients and animal models has been appreciated for decades. This review briefly summarizes recent studies exploring the mechanistic pathways, whereby the immune system participates in hypertension and renal disease. RECENT FINDINGS: Emphasis in this review is placed upon recent studies exploring the role of T cell subtypes, newly described mechanisms of T cell activation, the identification of potential neoantigens, and environmental influences on immune cell activation. SUMMARY: Significant advancements have been made in the search for antigens and pathways responsible for activation of the adaptive immune response, furthering our understanding of the factors contributing to hypertension and potentially leading to the development of new and more effective therapies. PMID- 26125644 TI - Gut microbiota in hypertension. AB - PURPOSE OF REVIEW: Hypertension, which is present in about one quarter of the world's population, is responsible for about 41% of the number one cause of death - cardiovascular disease. Not included in these statistics is the effect of sodium intake on blood pressure, even though an increase or a marked decrease in sodium intake can increase blood pressure. This review deals with the interaction of gut microbiota and the kidney with genetics and epigenetics in the regulation of blood pressure and salt sensitivity. RECENT FINDINGS: The abundance of the gut microbes, Firmicutes and Bacteroidetes, is associated with increased blood pressure in several models of hypertension, including the spontaneously hypertensive and Dahl salt-sensitive rats. Decreasing gut microbiota by antibiotics can increase or decrease blood pressure that is influenced by genotype. The biological function of probiotics may also be a consequence of epigenetic modification, related, in part, to microRNA. Products of the fermentation of nutrients by gut microbiota can influence blood pressure by regulating expenditure of energy, intestinal metabolism of catecholamines, and gastrointestinal and renal ion transport, and thus, salt sensitivity. SUMMARY: The beneficial or deleterious effect of gut microbiota on blood pressure is a consequence of several variables, including genetics, epigenetics, lifestyle, and intake of antibiotics. These variables may influence the ultimate level of blood pressure and control of hypertension. PMID- 26125646 TI - Chloride secretion by renal collecting ducts. AB - PURPOSE OF REVIEW: Renal collecting ducts maintain NaCl homeostasis by fine tuning urinary excretion to balance dietary salt intake. This review focuses on recent studies on transcellular Cl secretion by collecting ducts, its regulation and its role in cyst growth in autosomal dominant polycystic kidney disease (ADPKD). RECENT FINDINGS: Lumens of nonperfused rat medullary collecting ducts collapse in control media but expand with fluid following treatment with cAMP, demonstrating the capacity for both salt absorption and secretion. Recently, inhibition of apical epithelial Na channels (ENaC) unmasked Cl secretion in perfused mouse cortical collecting ducts (CCDs), involving Cl uptake by basolateral NKCC1 and efflux through apical Cl channels. AVP, the key hormone for osmoregulation, promotes cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl secretion. In addition, prostaglandin E2 stimulates Cl secretion through both CFTR and Ca-activated Cl channels. SUMMARY: Renal Cl secretion has been commonly overlooked because of the overwhelming capacity for the nephron to reabsorb NaCl from the glomerular filtrate. In ADPKD, Cl secretion plays a central role in the accumulation of cyst fluid and the remarkable size of the cystic kidneys. Investigation of renal Cl secretion may provide a better understanding of NaCl homeostasis and identify new approaches to reduce cyst growth in PKD. PMID- 26125648 TI - Characterization of the 2,3-Oxidosqualene Cyclase Gene from Antrodia cinnamomea and Enhancement of Cytotoxic Triterpenoid Compound Production. AB - Antrodia cinnamomea is a scarce, epiphyte, host-specific, brown-rot fungus that produces diverse bioactive compounds with potent biological activity. Natural wild-type fruiting bodies of A. cinnamomea are rare and highly valued, but their artificial culture poses challenges. Triterpenoids are a group of secondary metabolites that contribute to the bioactivities of A. cinnamomea. 2,3 Oxidosqualene cyclase (OSC) is a key enzyme in triterpenoid biosynthesis, which converts 2,3-oxidosqualene (OS) into polycyclic triterpenoids. In this study, we isolated a 2,3-oxidosqualene cyclase gene from A. cinnamomea with degenerate primers and designated it as AcOSC. The full length AcOSC cDNA was subcloned into a yeast expression vector, and AcOSC activity was confirmed. RT-PCR results showed that AcOSC expression was highest in the wild-type fruiting body and correlated with a higher concentration of triterpenoids. Agrobacterium-mediated gene transformation was conducted to enhance the triterpenoid synthesis capacity of the cultured mycelium. Metabolite profiling was conducted by LC-MS/MS and principal component analysis (PCA). The compositions and contents of metabolites in the AcOSC transgenic lines were different from those in the wild-type mycelium and vector control. The levels of two important triterpenoids, dehydrosulphurenic acid (DSA) and dehydroeburicoic acid (DEA), were increased in A. cinnamomea oxidosqualene cyclase overexpression strains compared to controls. In summary an Agrobacterium-mediated gene transformation procedure was established that successfully increased the level of transgene expression and enhanced the triterpenoid content in cultured A. cinnamomea. PMID- 26125649 TI - Application of Computer-Aided Designing and Rapid Prototyping Technologies in Reconstruction of Blowout Fractures of the Orbital Floor. AB - INTRODUCTION: Traumatology of the maxillofacial region represents a wide range of different types of facial skeletal injuries and encompasses numerous treatment methods. Application of computer-aided design (CAD) in combination with rapid prototyping (RP) technologies and three-dimensional computed tomography techniques facilitates surgical therapy planning for efficient treatment. OBJECTIVE: The purpose of this study is to determine the efficiency of individually designed implants of poly-DL-lactide (PDLLA) in the reconstruction of blowout fractures of the orbital floor. METHODS: In the course of a surgical treatment, individually designed implants manufactured by CAD/RP technologies were used. Preoperative analysis and postoperative monitoring were conducted to evaluate the successfulness of orbital floor reconstruction using customized PDLLA implants, based on: presence of diplopia, paresthesia of infraorbital nerve, and presence of enophthalmos. RESULTS: In 6 of the 10 patients, diplopia completely disappeared immediately after surgical procedure. Diplopia gradually disappeared after 1 month in 3 patients, whereas in 1, it remained even after 6 months. In 7 patients, paresthesia disappeared within a month after surgery and in 3 patients within 2 months. Postoperative average Orbital volume (OV) of the injured side (13.333 +/- 3.177) was significantly reduced in comparison with preoperative OV (15.847 +/- 3.361) after reconstruction of the orbital floor with customized PDLLA implant (P < 0.001). Thus, average OV of corrected orbit was not different compared with the OV of the uninjured orbit (P = 0.981). CONCLUSIONS: Reconstruction of blowout fractures of the orbital floor by an individually designed PDLLA implant combined with virtual preoperative modeling allows easier preoperative preparation and yields satisfactory functional and esthetic outcomes. PMID- 26125650 TI - Humanized mice models for primary bone tumor and bone metastasis research. PMID- 26125647 TI - Sodium-glucose cotransport. AB - PURPOSE OF REVIEW: Sodium-glucose cotransporters (SGLTs) are important mediators of glucose uptake across apical cell membranes. SGLT1 mediates almost all sodium dependent glucose uptake in the small intestine, while in the kidney SGLT2, and to a lesser extent SGLT1, account for more than 90% and nearly 3%, respectively, of glucose reabsorption from the glomerular ultrafiltrate. Although the recent availability of SGLT2 inhibitors for the treatment of diabetes mellitus has increased the number of clinical studies, this review has a focus on mechanisms contributing to the cellular regulation of SGLTs. RECENT FINDINGS: Studies have focused on the regulation of SGLT expression under different physiological/pathophysiological conditions, for example diet, age or diabetes mellitus. Several studies provide evidence of SGLT regulation via cyclic adenosine monophosphate/protein kinase A, protein kinase C, glucagon-like peptide 2, insulin, leptin, signal transducer and activator of transcription-3 (STAT3), phosphoinositide-3 kinase (PI3K)/Akt, mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), with-no-K[Lys] kinases/STE20/SPS1-related proline/alanine-rich kinase (Wnk/SPAK) and regulatory solute carrier protein 1 (RS1) pathways. SUMMARY: SGLT inhibitors are important drugs for glycemic control in diabetes mellitus. Although the contribution of SGLT1 for absorption of glucose from the intestine as well as SGLT2/SGLT1 for renal glucose reabsorption has been comprehensively defined, this review provides an up-to-date outline for the mechanistic regulation of SGLT1/SGLT2. PMID- 26125651 TI - Personalized immunotherapy ( AGS-003 ) when combined with sunitinib for the treatment of metastatic renal cell carcinoma. AB - INTRODUCTION: AGS-003 is a novel autologous dendritic cell vaccine currently in Phase III clinical development in combination with sunitinib for patients with intermediate- and poor-risk clear cell metastatic renal cell carcinoma (ccmRCC). AREAS COVERED: In addition to research published within the past 15 years demonstrating the efficacy of novel targeted therapies, early-phase clinical trial results recently published for AGS-003 in combination with sunitinib are discussed, as well as the ongoing Phase III clinical trial Autologous Dendritic Cell Immunotherapy (AGS-003) Plus Standard Treatment of Advanced Renal Cell Carcinoma. EXPERT OPINION: AGS-003 in combination with sunitinib is a rational step forward for the clinical management of patients with ccmRCC. If the Phase III Advanced Renal Cell Carcinoma trial is positive, this treatment modality will provide a significant survival benefit with minimal toxicity and could change the standard of care for ccmRCC. PMID- 26125652 TI - Total Synthesis of (+)-3-Demethoxyerythratidinone and (+)-Erysotramidine via the Oxidative Amidation of a Phenol. AB - Oxidative amidation chemistry provides a unified route to aromatic Erythrina alkaloids through a sequence that illustrates new principles and improved conditions to effect a crucial eliminative Curtius-Schmidt rearrangement. PMID- 26125653 TI - Weight and BMI are the most important predictors influencing the needle insertion distance to the thoracic epidural space. PMID- 26125654 TI - Anharmonic lattice interactions in improper ferroelectrics for multiferroic design. AB - The design and discovery of new multiferroics, or materials that display both ferroelectricity and long-range magnetic order, is of fundamental importance for new electronic technologies based on low-power consumption. Far too often, however, the mechanisms causing these properties to arise are incompatible or occur at ordering temperatures below room temperature. One design strategy which has gained considerable interest is to begin with a magnetic material, and find novel ways to induce a spontaneous electric polarization within the structure. To this end, anharmonic interactions coupling multiple lattice modes have been used to lift inversion symmetry in magnetic dielectrics. Here we provide an overview of the microscopic mechanisms by which various types of cooperative atomic displacements result in ferroelectricity through anharmonic multi-mode coupling, as well as the types of materials most conducive to these lattice instabilities. The review includes a description of the origins of the displacive modes, a classification of possible non-polar lattice modes, as well as how their coupling can produce spontaneous polarizations. We then survey the recent improper ferroelectric literature, and describe how the materials discussed fall within a proposed classification scheme, offering new directions for the theoretical design of magnetic ferroelectrics. Finally, we offer prospects for the future discovery of new magnetic improper ferroelectrics, as well as detail remaining challenges and open questions facing this exciting new field. PMID- 26125655 TI - WITHDRAWN: Group based diabetes self-management education compared to routine treatment, waiting list control or no intervention for people with type 2 diabetes mellitus. PMID- 26125656 TI - Effects of Respiratory Therapy (bagging) on Respiratory Function, Swallowing Frequency and Vigilance in Tracheotomized Patients in Early Neurorehabilitation. AB - OBJECTIVE: Tracheotomized patients often suffer from impairments in mucociliary clearance and limited capacities for active expectoration of secretions. We investigated the effects of a specific respiratory intervention method (bagging) for tracheotomized patients on respiratory parameters (pO2, pCO2, SpO2, respiratory rates), swallowing frequency, vigilance and secretion viscosity. METHODS: The bagging method supports enforced mobilization and expectoration of secretions by application of a series of manual hyperinflations with a resuscitation bag during active inspiration and manual cough support on the chest. 30 tracheotomized neurological patients participated in a multiple baseline study including a three-weeks intervention period and a follow-up measurement three weeks after termination of the treatment. RESULTS: Most outcome parameters improved significantly during the intervention period: pO2 (p < .01), SpO2 (p < .01), respiratory rates (p < .01), swallowing rates (p < .01), and vigilance scores (p < .01). The quality of bronchial secretions improved in all participants. All effects were sustained up to the follow-up measurements. CONCLUSION: This preliminary data indicates positive effects for a respiratory intervention method (bagging) on respiratory function and additional respiration related functions in tracheotomized neurological patients. This easy-to-learn and inexpensive method might expand the range of treatment options for tracheotomized and non-responsive patients. PMID- 26125658 TI - Release of Oxygen from Palladium Oxide Cluster Ions by Heat. AB - Palladium oxide cluster ions, PdnOm(+), were prepared in the gas phase using laser ablation of a palladium rod in the presence of oxygen. The cluster ions were heated to 1000 K downstream from the cluster source (post heating), and the abundance of PdnOm(+) (n = 2-7) was examined using mass spectrometry. Temperature programmed desorption experiments revealed that an oxygen molecule is released from oxygen-rich PdnOm(+), forming oxygen-deficient PdnOm-2(+). It was found that Pd6O4(+) was thermally stable up to 1000 K. The activation energy for oxygen molecule desorption has been obtained and compared with previous results by Lang et al. PMID- 26125657 TI - Transition State Features in the Hepatitis Delta Virus Ribozyme Reaction Revealed by Atomic Perturbations. AB - Endonucleolytic ribozymes constitute a class of non-coding RNAs that catalyze single-strand RNA scission. With crystal structures available for all of the known ribozymes, a major challenge involves relating functional data to the physically observed RNA architecture. In the case of the hepatitis delta virus (HDV) ribozyme, there are three high-resolution crystal structures, the product state of the reaction and two precursor variants, with distinct mechanistic implications. Here, we develop new strategies to probe the structure and catalytic mechanism of a ribozyme. First, we use double-mutant cycles to distinguish differences in functional group proximity implicated by the crystal structures. Second, we use a corrected form of the Bronsted equation to assess the functional significance of general acid catalysis in the system. Our results delineate the functional relevance of atomic interactions inferred from structure, and suggest that the HDV ribozyme transition state resembles the cleavage product in the degree of proton transfer to the leaving group. PMID- 26125659 TI - A Cellular Assay for Inhibitors of the Fatty Acid Biosynthetic Pathway Using Scintillating Microplates. AB - A simplified method for monitoring the incorporation of radiolabeled acetate into lipids in a cellular system is described. The assay eliminates the commonly employed labor-intensive organic extraction step by plating the cells in 96-well tissue culture-treated ScintiPlates((r)) that enable direct measurement of radiolabeled cell membrane-embedded lipids. Since the scintillant is entrenched in the plates, radioactivity in close proximity to the scintillant is measured without the need for liquid scintillation cocktail. The utility of this method for evaluating inhibitors of the de novo fatty acid synthetic pathway is demonstrated here with fatty acid synthase (FASN). Due to the upregulation of FASN activity in many tumor types, development of inhibitors to block the FASN activity in cells shows promise as an attractive and tractable approach for therapeutic intervention. PMID- 26125660 TI - Erratum to Sala et al. "MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice" (Thromb Haemost 2014; 112: 796-802). PMID- 26125661 TI - Erratum to Hillis et al. "Acute phase treatment of VTE: Anticoagulation, including non-vitamin K antagonist oral anticoagulants" (Thromb Haemost 2014; 113: 1193-1201). PMID- 26125662 TI - In Vitro Evaluation of a Novel mRNA-Based Therapeutic Strategy for the Treatment of Patients Suffering from Alpha-1-Antitrypsin Deficiency. AB - In single-gene disorders, like alpha-1-antitrypsin deficiency (AATD), a gene mutation causes missing or dysfunctional protein synthesis. This, in turn, can lead to serious complications for the patient affected. Furthermore, single-gene disorders are associated with severe early-onset conditions and necessitate expensive lifelong care. Until nowadays, therapeutic treatment options are still limited, cost-intensive, or lack effectiveness. For these reasons, we aim to develop a novel mRNA-based therapeutic strategy for the treatment of single-gene disorders, such as AATD, which is based on the induction of de novo synthesis of the functional proteins. Therefore, an alpha-1-antitrypsin (AAT) encoding mRNA was generated by in vitro transcription. After in vitro delivery of the mRNA to different cells, protein expression and functionality, as well as adverse effects and mRNA serum stability, were analyzed. Our results show that the AAT mRNA transfected cells express the AAT protein in high amounts within the first 24 h. Moreover, the expressed AAT protein is highly functional, since the activity of elastase is significantly inhibited. Our data also show that mRNA concentrations up to 1 MUg per 150,000 cells have no adverse effects on cell viability and immune activation. Furthermore, the encapsulated AAT encoding mRNA is stable and functional in human serum for up to 30 min. Overall, the proposed project provides an innovative, highly promising, and safe therapeutic approach and, thus, promises a novel progress in the treatment of single-gene disorders, whereby affected patients could greatly benefit. PMID- 26125663 TI - Downregulation of miR-410 targeting the cyclin B1 gene plays a role in pituitary gonadotroph tumors. AB - MicroRNAs (miRNAs) are small noncoding RNAs that act as posttranscriptional regulators of gene expression, and are frequently altered in human neoplasias. Here, we have analyzed the miRNA expression profile of human gonadotroph adenomas versus normal pituitary tissue using a miRNACHIP microarray. We demonstrate that miRNA-410 is downregulated in gonadotroph adenomas when compared with normal pituitary gland. We validate CCNB1 as target of miRNA-410 since its overexpression reduces CCNB1 at protein and mRNA levels, decreasing cell proliferation. In conclusion, our study suggess that the downregulation of miRNA 410 plays a role in the behavior of gonadotroph tumors. PMID- 26125664 TI - Prevalence of Warfarin Genotype Polymorphisms in Patients with Mechanical Circulatory Support. AB - Polymorphisms for VKORC1 and CYP2C9 are associated with increased warfarin sensitivity. The prevalence of these polymorphisms in patients with mechanical circulatory support (MCS) is unknown. Polymorphisms for VKORC1 and CYP2C9 were determined in 65 patients undergoing MCS surgery. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). A total of 67.7% (44/65) had at least one polymorphism: VKORC1 (44.6%), CYP2C9*2 (7.7%), CYP2C9*3 (4.6%), CYP2C9*2 and VKORC1 (3.1%), or CYP2C9*3 and VKORC1 (7.7%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.21 +/- 1.47 vs. 5.57 +/- 3.72 mg, p = 0.015) and achieved a similar mean INR (2.20 +/- 0.67 vs. 2.19 +/- 0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). One or more polymorphisms for VKORC1 or CYP2C9 (associated with warfarin sensitivity) were found in 67.7% of MCS patients. By using a warfarin genotype-guided approach, MCS patients with polymorphisms received a lower warfarin dosage to achieve a similar INR, with similar bleeding rates, in comparison with no polymorphisms. A warfarin genotype guided approach avoided excessive anticoagulation and its attendant bleeding risks. PMID- 26125665 TI - Contemporary Outcomes of Venoarterial Extracorporeal Membrane Oxygenation for Refractory Cardiogenic Shock at a Large Tertiary Care Center. AB - Refractory cardiogenic shock (RCS) is associated with significant morbidity and mortality, and current mainstays of medical therapy appear inadequate. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) represents an increasingly accepted therapy for RCS. Demographics, past medical history, preoperative characteristics, outcomes, and adverse events were collected for consecutive patients who received VA-ECMO support for RCS at our institution from March 2007 to December 2013. One hundred and seventy-nine patients with a mean age of 56.9 +/- 16.1 years were included. Etiologies of RCS included postcardiotomy shock in 70 patients (39%), acute myocardial infarction in 46 patients (26%), primary graft failure in 17 patients (10%), and acute decompensated heart failure in 24 patients (13%). Mean arterial pressure before VA-ECMO support was 59.4 +/- 22.8 mm Hg and 30.7% (n = 55) were undergoing active cardiopulmonary resuscitation at the time of cannulation. Overall, 38.6% of patients (n = 69) survived to discharge and 44.7% of patients (n = 80) survived to 30 days. Myocardial recovery was achieved in 79.7% of survivors (n = 55) and 39.1% were transitioned to a more durable device. Univariate analysis identified age (p = 0.002) and etiology of RCS (p = 0.041) as the most significant predictors of in-hospital mortality. Venoarterial extracorporeal membrane oxygenation for RCS appears successful as salvage therapy. Age and etiology should be considered when evaluating patients for VA-ECMO. PMID- 26125666 TI - The Effect of Decreasing Flow Rate on Cerebral Hemodynamics During Veno-Arterial Extracorporeal Membrane Oxygenation in Piglets. AB - To explore the influence of decreasing flow rate on cerebral hemodynamics during veno-arterial extracorporeal membrane oxygenation (va-ECMO), six normoxemic and six hypoxemic piglets were put on va-ECMO. The ECMO flow rate was decreased from the maximal achievable level to 50 mL min1 with steps of 50 mL min1 every 2 minutes. Changes in mean arterial blood pressure (MABP), left common carotid artery blood flow (Qcar), and other physiologic variables were continuously measured. Changes in concentrations of oxyhemoglobin and deoxyhemoglobin were measured using near infrared spectrophotometry (NIRS). Changes in difference between cerebral oxygen hemoglobin and deoxyhemoglobin concentration (DeltacHbD) and total hemoglobin concentration (DeltactHb) were calculated. DeltacHbD represents changes in cerebral blood flow (CBF), and DeltactHb reflects changes in cerebral blood volume (CBV). Data analysis was performed using mixed models and demonstrated a significant positive correlation between ECMO flow and, respectively, MABP (r = 0.7, p < 0.001), Qcar (r = 0.7, p < 0.001), cHbD (r = 0.8, p < 0.001), and ctHb (r = 0.7, p < 0.001). There was no significant relation between oxygenation state preceding ECMO and Qcar, cHbD, and ctHb during decreasing ECMO flow rate. We conclude that decreasing ECMO flow rate ultimately leads to concurrent decrease in MABP, CBF, and CBV. PMID- 26125667 TI - Are Fluorination and Chlorination of Morpholinium-Based Ionic Liquids Favorable? AB - Room-temperature ionic liquids (RTILs) constitute a fine-tunable class of compounds. Morpholinium-based cations are new to the field. They are promising candidates for electrochemistry, micellization, and catalytic applications. We investigate halogenation (fluorination and chlorination) of the N-ethyl-N methylmorpholinium cation from the thermodynamics perspective. We find that substitutional fluorination is much more energetically favorable than substitutional chlorination, although the latter is also a permitted process. Although all halogenations at different locations are possible, they are not equally favorable. Furthermore, the trends are not identical in the case of fluorination and chlorination. We link the thermodynamic observables to electron density distribution within the investigated cation. The reported insights are based on the coupled-cluster technique, which is a highly accurate and reliable electron-correlation method. Novel derivatives of the morpholinium-based RTILs are discussed, motivating further efforts in synthetic chemistry. PMID- 26125668 TI - Chemoprophylaxis for Venous Thromboembolism Prevention: Has the Horse Already Left the Barn? PMID- 26125669 TI - Funding for Graduate Medical Education: A Changing Landscape. PMID- 26125670 TI - Publicize or Perish! A Guide to Social Media Promotion of Scientific Articles: Featuring the Plastic and Reconstructive Surgery "Author Tool Kit". PMID- 26125671 TI - Weeds ability to phytoremediate cadmium-contaminated soil. AB - An alternative method to other technologies to clean up the soil, air and water pollution by heavy metals is phytoremediation. Therefore, a pot culture experiment was conducted at the College of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran, in 2014 to determine the potential absorption of cadmium by Portulaca oleracea (Common purslane), Solanum nigrum (Black nightshade), Abutilon theophrasti (Velvetleaf) and Taraxacum officinale (Dandelion). The type of experiment was completely randomized design with factorial arrangement and four replications. The soil in pot was treated with different rates of CdCl2.H2O (0 (control), 10, 20, 40, 60, and 80 mg Cd/kg soil) and the plants were sown. With increasing concentration levels, fresh weight and dry weight of shoots and roots of all plant species were reduced. The reduction severity was ranked according the following order, P. oleracea > A. theophrasti > S. nigrum > T. officinale. Bioconcentration factor (BCF), Translocation factor (TF) and Translocation efficiency (TE%) was ranked according the following order, T. officinale > S. nigrum > A. theophrasti > P. oleracea. The results of this study revealed that T. officinale and S. nigrum are effective species to phytoremediate Cd-contaminated soil. PMID- 26125672 TI - Occipital Nerve Stimulation for the Treatment of Patients With Medically Refractory Occipital Neuralgia: Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline. AB - BACKGROUND: Occipital neuralgia (ON) is a disorder characterized by sharp, electrical, paroxysmal pain, originating from the occiput and extending along the posterior scalp, in the distribution of the greater, lesser, and/or third occipital nerve. Occipital nerve stimulation (ONS) constitutes a promising therapy for medically refractory ON because it is reversible with minimal side effects and has shown continued efficacy with long-term follow-up. OBJECTIVE: To conduct a systematic literature review and provide treatment recommendations for the use of ONS for the treatment of patients with medically refractory ON. METHODS: A systematic literature search was conducted using the PubMed database and the Cochrane Library to locate articles published between 1966 and April 2014 using MeSH headings and keywords relevant to ONS as a means to treat ON. A second literature search was conducted using the PubMed database and the Cochrane Library to locate articles published between 1966 and June 2014 using MeSH headings and keywords relevant to interventions that predict response to ONS in ON. The strength of evidence of each article that underwent full text review and the resulting strength of recommendation were graded according to the guidelines development methodology of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Guidelines Committee. RESULTS: Nine studies met the criteria for inclusion in this guideline. All articles provided Class III Level evidence. CONCLUSION: Based on the data derived from this systematic literature review, the following Level III recommendation can be made: the use of ONS is a treatment option for patients with medically refractory ON. PMID- 26125673 TI - Lack of BRAF-V600E Mutation in Papillary Tumor of the Pineal Region. AB - BACKGROUND: Papillary tumor of the pineal region (PTPR) is a rare central nervous system tumor with a variably aggressive clinical behavior, corresponding to World Health Organization grade II/III. Very little is known about the genetic mutations comprising PTPR. Recent studies have shown that other papillary tumors harbor BRAF-V600E mutations, namely papillary thyroid carcinoma and papillary craniopharyngioma, the latter of which is a midline central nervous system papillary tumor like PTPR. OBJECTIVE: To determine whether PTPR may contain the BRAF-V600E mutation. METHODS: A search of our institutional files was conducted for PTPR cases. Chart review was performed to obtain demographics and pertinent clinical information when possible. Immunohistochemistry was performed with an anti-BRAF-V600E antibody for cases with additional material for testing. RESULTS: We identified 19 PTPR cases occurring in 16 patients. The patient age range was 1 to 73 years (average, 32.2 years). The male-to-female ratio was 1:1. Thirteen patients presented with symptoms of obstructive hydrocephalus, and the other 3 had unknown presenting symptoms. Initial magnetic resonance imaging characteristics tended to include partially cystic masses with heterogeneous postcontrast enhancement. The tumor size ranged from 1.1 to 4.4 cm (average, 2.5 cm). CONCLUSION: Of the 16 patients, 13 had additional material for BRAF-V600E immunohistochemistry, all of which demonstrated negativity for BRAF-V600E. This rate is unlike that of other midline papillary tumors and suggests that these tumors, despite their papillary phenotype, may have a distinctive molecular background. PMID- 26125674 TI - Pregnancy as a Window to Cardiovascular Disease Risk: How Will We Know? PMID- 26125675 TI - Regression of an atlantoaxial rheumatoid pannus following posterior instrumented fusion. AB - OBJECTIVE: Rheumatoid patients may develop a retrodental lesion (atlantoaxial rheumatoid pannus) that may cause cervical instability and/or neurological compromise. The objective is to characterize clinical and radiographic outcomes after posterior instrumented fusion for atlantoaxial rheumatoid pannus. METHODS: We retrospectively reviewed all patients who underwent posterior fusions for an atlantoaxial rheumatoid pannus at a single institution. Both preoperative and postoperative imaging was available for all patients. Anterior or circumferential operations, non-atlantoaxial panni, or prior C1-C2 operations were excluded. Primary outcome measures included Nurick score, Ranawat score (neurologic status in patients with rheumatoid arthritis), pannus regression, and reoperation. Pannus volume was determined with axial and sagittal views on both preoperative and postoperative radiological images. RESULTS: Thirty patients surgically managed for an atlantoaxial rheumatoid pannus were followed for a mean of 24.43 months. Nine patients underwent posterior instrumented fusion alone, while 21 patients underwent posterior decompression and instrumented fusion. Following a posterior instrumented fusion in all 30 patients, the pannus statistically significantly regressed by 44.44%, from a mean volume of 1.26cm(3) to 0.70cm(3) (p<0.001), over 8.02 months. The Nurick score significantly improved from 2.40 to 0.60 (p<0.001), but the marginal improvement of 0.20 in the Ranawat score did not reach significance (p=0.312). Six patients (20%) required reoperations over a mean of 13.18 months. Reoperations were indicated for C1 instrumentation failure in four patients and pseudoarthrosis in two patients. CONCLUSION: Following posterior instrumented fusion, the pannus radiographically regressed by 44.44% over a mean of 8.02 months, and patients clinically improved per the Nurick score. The Ranawat score did not improve, and 20% of patients required reoperation over a mean of 13.18 months. The annualized reoperation rate was approximately 13.62%. PMID- 26125676 TI - Cocoa, blood pressure, and cardiovascular health. AB - High blood pressure is an important risk factor for cardiovascular disease and cardiovascular events worldwide. Clinical and epidemiological studies suggest that cocoa-rich products reduce the risk of cardiovascular disease. According to this, cocoa has a high content in polyphenols, especially flavanols. Flavanols have been described to exert favorable effects on endothelium-derived vasodilation via the stimulation of nitric oxide-synthase, the increased availability of l-arginine, and the decreased degradation of NO. Cocoa may also have a beneficial effect by protecting against oxidative stress alterations and via decreased platelet aggregation, decreased lipid oxidation, and insulin resistance. These effects are associated with a decrease of blood pressure and a favorable trend toward a reduction in cardiovascular events and strokes. Previous meta-analyses have shown that cocoa-rich foods may reduce blood pressure. Long term trials investigating the effect of cocoa products are needed to determine whether or not blood pressure is reduced on a chronic basis by daily ingestion of cocoa. Furthermore, long-term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events. A 3 mmHg systolic blood pressure reduction has been estimated to decrease the risk of cardiovascular and all-cause mortality. This paper summarizes new findings concerning cocoa effects on blood pressure and cardiovascular health, focusing on putative mechanisms of action and "nutraceutical " viewpoints. PMID- 26125677 TI - Multi-residue analysis of pesticides in traditional Chinese medicines using gas chromatography-negative chemical ionisation tandem mass spectrometry. AB - In this study, a residue analysis method for the simultaneous determination of 107 pesticides in traditional Chinese medicines (TCMs), Angelica sinensis, A. dahurica, Leonurus heterophyllus Sweet, Pogostemon cablin and Lonicera japonica Thunb., was developed using gas chromatography coupled with tandem mass spectrometry in negative chemical ionisation mode (GC-NCI-MS/MS). NCI has advantages of high sensitivity and selectivity to chemicals with electron withdrawing groups, and yields low background interference. For sample preparation, QuEChERS (quick, easy, cheap, effective, rugged and safe) was applied. Due to the unique characteristics of TCMs, the clean-up step was optimised by adjusting amounts of primary secondary amine, C18, graphitised carbon black and silica sorbents. Validation was mainly performed by determining analyte recoveries at four different spiking concentrations of 10, 50, 100 and 200 ng g(-1), with seven replicates at each concentration. Method trueness, precision, linearity of calibration curves, lowest calibrated levels (LCLs) and matrix effects were determined to demonstrate method and instrument performance. Among the 107 pesticides tested, approximately 80% gave recoveries from 80% to 110% and < 10% relative standard deviation (RSD). The LCLs for nearly all pesticides were 5 ng g(-1), and as low as 0.1 ng g(-1) for dichlofenthion, endosulfan sulphate, flumetralin, isofenphos-methyl, methyl-pentachlorophenyl sulphide and trifluralin. The results indicate that GC-NCI-MS/MS is an excellent technique for quantitative and qualitative analysis of targeted GC-amenable pesticides at ultra-trace levels, especially in complex matrices such as TCMs. PMID- 26125678 TI - Hierarchical Configuration of NiCo2S4 Nanotube@Ni-Mn Layered Double Hydroxide Arrays/Three-Dimensional Graphene Sponge as Electrode Materials for High Capacitance Supercapacitors. AB - Three dimensional (3D) hierarchical network configurations are composed of NiCo2S4 nanotube @Ni-Mn layered double hydroxide (LDH) arrays in situ grown on graphene sponge. The 3D graphene sponge with robust hierarchical porosity suitable for as a basal growth has been obtained from a colloidal dispersion of graphene oxide using a simple directional freeze-drying technique. The high conductive NiCo2S4 nanotube arrays grown on 3D graphene shows excellent pseudocapacity and good conductive support for high-performance Ni-Mn LDH. The 3D NiCo2S4@Ni-Mn LDH/GS shows a high specific capacitance (Csp) 1740 mF cm(-2) at 1 mA cm(-2), even at 10 mA cm(-2), 1267.9 mF cm(-2) maintained. This high performance composite electrode proposes a new and feasible general pathway as 3D electrode configuration for energy storage devices. PMID- 26125679 TI - Fate of Human Noroviruses in Shellfish and Water Impacted by Frequent Sewage Pollution Events. AB - Knowledge of the fate of human noroviruses (NoV) in the marine environment is key to better controlling shellfish-related NoV gastroenteritis. We quantified NoV and Escherichia coli in sewage from storm tank discharges and treated effluent processed by a UV-disinfection plant following activated sludge treatment and studied the fate of these microorganisms in an oyster harvesting area impacted by frequent stormwater discharges and infrequent freshwater discharges. Oyster monitoring sites were positioned at intervals downstream from the wastewater treatment works (WwTW) outfall impacting the harvesting area. The decay rates of NoV in oysters as a function of the distance from the outfall were less rapid than those for E. coli that had concentrations of NoV of the same order of magnitude and were over 7 km away from the outfall. Levels of E. coli in oysters from more tidally influenced areas of the estuary were higher around high water than around low water, whereas tidal flows had no influence on NoV contamination in the oysters. The study provides comparative data on the contamination profiles and loadings of NoV and E. coli in a commercial oyster fishery impacted by a WwTW. PMID- 26125680 TI - A Fluorescence-Based Assay for Proteinuria Screening in Larval Zebrafish (Danio rerio). AB - Analysis of genes compromising the glomerular filtration barrier in rodent models using transgenic or knockdown approaches is time- and resource-consuming and often leads to unsatisfactory results. Therefore, it would be beneficial to have a selection tool indicating that your gene of interest is in fact associated with proteinuria. Zebrafish (Danio rerio) is a rapid screening tool to study effects in glomerular filtration barrier integrity after genetic manipulation. We use either injection of high-molecular-weight dextrans or a transgenic fluorescent fish line [Tg(l-fabp:DBP:EGFP)] expressing a vitamin D-binding protein fused with eGFP for indirect detection of proteinuria. A loss of high-molecular-weight proteins from the circulation of the fish into the urine can be identified by monitoring fluorescence intensity in the zebrafish eye. Paired with an optimized analysis method, this assay provides an effective screening solution to detect filtration barrier damage with proteinuria before moving to a mammalian system. PMID- 26125681 TI - Stone-dwelling actinobacteria Blastococcus saxobsidens, Modestobacter marinus and Geodermatophilus obscurus proteogenomes. AB - The Geodermatophilaceae are unique model systems to study the ability to thrive on or within stones and their proteogenomes (referring to the whole protein arsenal encoded by the genome) could provide important insight into their adaptation mechanisms. Here we report the detailed comparative genome analysis of Blastococcus saxobsidens (Bs), Modestobacter marinus (Mm) and Geodermatophilus obscurus (Go) isolated respectively from the interior and the surface of calcarenite stones and from desert sandy soils. The genome-scale analysis of Bs, Mm and Go illustrates how adaptation to these niches can be achieved through various strategies including 'molecular tinkering/opportunism' as shown by the high proportion of lost, duplicated or horizontally transferred genes and ORFans. Using high-throughput discovery proteomics, the three proteomes under unstressed conditions were analyzed, highlighting the most abundant biomarkers and the main protein factors. Proteomic data corroborated previously demonstrated stone related ecological distribution. For instance, these data showed starvation inducible, biofilm-related and DNA-protection proteins as signatures of the microbes associated with the interior, surface and outside of stones, respectively. PMID- 26125683 TI - Environmental stability affects phenotypic evolution in a globally distributed marine picoplankton. AB - Marine phytoplankton can evolve rapidly when confronted with aspects of climate change because of their large population sizes and fast generation times. Despite this, the importance of environment fluctuations, a key feature of climate change, has received little attention-selection experiments with marine phytoplankton are usually carried out in stable environments and use single or few representatives of a species, genus or functional group. Here we investigate whether and by how much environmental fluctuations contribute to changes in ecologically important phytoplankton traits such as C:N ratios and cell size, and test the variability of changes in these traits within the globally distributed species Ostreococcus. We have evolved 16 physiologically distinct lineages of Ostreococcus at stable high CO2 (1031+/-87 MUatm CO2, SH) and fluctuating high CO2 (1012+/-244 MUatm CO2, FH) for 400 generations. We find that although both fluctuation and high CO2 drive evolution, FH-evolved lineages are smaller, have reduced C:N ratios and respond more strongly to further increases in CO2 than do SH-evolved lineages. This indicates that environmental fluctuations are an important factor to consider when predicting how the characteristics of future phytoplankton populations will have an impact on biogeochemical cycles and higher trophic levels in marine food webs. PMID- 26125682 TI - Antarctic archaea-virus interactions: metaproteome-led analysis of invasion, evasion and adaptation. AB - Despite knowledge that viruses are abundant in natural ecosystems, there is limited understanding of which viruses infect which hosts, and how both hosts and viruses respond to those interactions-interactions that ultimately shape community structure and dynamics. In Deep Lake, Antarctica, intergenera gene exchange occurs rampantly within the low complexity, haloarchaea-dominated community, strongly balanced by distinctions in niche adaptation which maintain sympatric speciation. By performing metaproteomics for the first time on haloarchaea, genomic variation of S-layer, archaella and other cell surface proteins was linked to mechanisms of infection evasion. CRISPR defense systems were found to be active, with haloarchaea responding to at least eight distinct types of viruses, including those infecting between genera. The role of BREX systems in defending against viruses was also examined. Although evasion and defense were evident, both hosts and viruses also may benefit from viruses carrying and expressing host genes, thereby potentially enhancing genetic variation and phenotypic differences within populations. The data point to a complex inter-play leading to a dynamic optimization of host-virus interactions. This comprehensive overview was achieved only through the integration of results from metaproteomics, genomics and metagenomics. PMID- 26125684 TI - Viral assemblage composition in Yellowstone acidic hot springs assessed by network analysis. AB - Understanding of viral assemblage structure in natural environments remains a daunting task. Total viral assemblage sequencing (for example, viral metagenomics) provides a tractable approach. However, even with the availability of next-generation sequencing technology it is usually only possible to obtain a fragmented view of viral assemblages in natural ecosystems. In this study, we applied a network-based approach in combination with viral metagenomics to investigate viral assemblage structure in the high temperature, acidic hot springs of Yellowstone National Park, USA. Our results show that this approach can identify distinct viral groups and provide insights into the viral assemblage structure. We identified 110 viral groups in the hot springs environment, with each viral group likely representing a viral family at the sub-family taxonomic level. Most of these viral groups are previously unknown DNA viruses likely infecting archaeal hosts. Overall, this study demonstrates the utility of combining viral assemblage sequencing approaches with network analysis to gain insights into viral assemblage structure in natural ecosystems. PMID- 26125685 TI - Making pathogens sociable: the [corrected] emergence of high relatedness through limited host invasibility. AB - Cooperation depends upon high relatedness, the high genetic similarity of interacting partners relative to the wider population. For pathogenic bacteria, which show diverse cooperative traits, the population processes that determine relatedness are poorly understood. Here, we explore whether within-host dynamics can produce high relatedness in the insect pathogen Bacillus thuringiensis. We study the effects of host/pathogen interactions on relatedness via a model of host invasion and fit parameters to competition experiments with marked strains. We show that invasibility is a key parameter for determining relatedness and experimentally demonstrate the emergence of high relatedness from well-mixed inocula. We find that a single infection cycle results in a bottleneck with a similar level of relatedness to those previously reported in the field. The bottlenecks that are a product of widespread barriers to infection can therefore produce the population structure required for the evolution of cooperative virulence. PMID- 26125686 TI - Alleged malpractice in anesthesiology: analysis of a series of private insurance claims. AB - BACKGROUND: Medical malpractice is currently a crucial topic and anesthesia is a key specialty for the improvement of patient safety. However, death and permanent impairment due to anesthesia still occur and studies of insurance analysis data are increasing. We investigated the main features of a major Italian insurance broker's archive in order to identify possible recurrent pitfalls in this critical field of medicine. METHODS: Three hundred seventeen Italian claims were analyzed, filling out a standardized form that recorded information on patient and physician's characteristics, procedures, sequence and location of events and outcomes. The operative setting, the type of anesthesia performed the origin of the multidisciplinary team malpractice hypothesis, the final clinical outcome and the malpractice investigation results were also analyzed. RESULTS: In 225 malpractice claims, the adverse event was surgery-linked, either intraoperatively (114 cases) or postoperatively (111 cases): abdominal surgery (26%), orthopedics (22%), gynecology (20%), heart surgery (11%) and neurosurgery (9.5%) were the most frequently involved surgical specialties. In 92 cases, the claim was unlinked to a surgeon's activity, with dental damage in oral intubation procedures as the greatest contributor (42.3%). Anesthetists' malpractice was technically ascertained in 39% of cases, 74.8% resulting in permanent impairment. CONCLUSIONS: Malpractice was mainly suspected in surgery-linked procedures. Most of the claims were settled for procedural error in performing locoregional anesthesia and oral intubation procedures. 60% of all closed claims resulted in no malpractice ascertained. Confirmed malpractice typically deals with non surgery-linked and non multidisciplinary team cases, causing permanent impairment. PMID- 26125687 TI - International survey on the management of mechanical ventilation during ECMO in adults with severe respiratory failure. AB - BACKGROUND: No consensus exists on the optimal settings of mechanical ventilation during veno-venous extracorporeal membrane oxygenation (ECMO). Our aim was to describe how mechanical ventilation and related interventions are managed by adult ECMO centres. METHODS: A cross-sectional, multi-centre, international survey of 173 adult respiratory ECMO centres. The survey was generated through an iterative process and assessed for clarity, content and face validity. RESULTS: One hundred thirty-three centres responded (76.8%). Pressure control was the most commonly used mechanical ventilation mode (64.4%). Although the median PEEP was 10 cmH2O, 22.6% set PEEP <10 cmH2O and 15.5% used 15-20 cmH2O. In 63% of centres PEEP was fixed and not titrated. Recruitment maneuvres, were never used in 34.1% of centres, or used daily in 13.2%. Centres reported using either a "lung rest" (45.7%), or an "open lung" strategy (44.2%). Only 24.8% used chest CT to guide mechanical ventilation. Adjunctive treatments were never or occasionally used. Only 10% of centres extubated patients on ECMO, mainly in more experienced centres. 71.3% of centres performed tracheostomy on ECMO, with large variability in timing (most frequent on days 6-10). Only 27.1% of ECMO centres had a protocol for mechanical ventilation on ECMO. CONCLUSION: We found large variability in ventilatory practices during ECMO. The clinicians' training background and the centres' experience had no influence on the approach to ventilation. This survey shows that well conducted studies are necessary to determine the best practice of mechanical ventilation during ECMO and its impact on patient outcome. PMID- 26125688 TI - The conundrum of anticoagulation and hemostatic management in ECMO patients. PMID- 26125689 TI - A Rare Cause of Patient Movement Occurring During Carotid Surgery. AB - In this case, we report difficulty in the conduct of carotid surgery during an earthquake. With the epicenter >200 miles away, intraoperative movement was subtle and initially attributed to recovery from neuromuscular blockade. More significant seismic motion in a hospital is accompanied by additional challenges that are discussed. PMID- 26125690 TI - Hemostatic Management of Severe Thrombocytopenia in a Patient Undergoing Pulmonic Valve Replacement. AB - Perioperative management of thrombocytopenia is often focused on platelet transfusion. However, there are thrombocytopenic cases that are refractory to platelet transfusion as a result of immune response or consumptive coagulopathy. Acuity of the disease may necessitate an invasive procedure despite a grossly abnormal platelet count. We describe a case of severe thrombocytopenia refractory to platelet transfusion and hemostatic management after an urgent pulmonary valve replacement and pulmonary embolectomy. PMID- 26125691 TI - Management of a Parturient with Diastrophic Dysplasia. AB - A 27-year-old primigravida patient with diastrophic dysplasia (DTD) presented to our obstetrics clinic at 8 weeks' gestational age. Diastrophic dysplasia is a rare, autosomal-recessive abnormality that presents multiple challenges to perinatal anesthetic management, including difficult airway management and relative contraindications to neuraxial anesthesia. The patient underwent elective cesarean delivery at 35 weeks' gestational age under general anesthesia. In this report, we describe our preoperative evaluation and management strategy that involved a multidisciplinary care team. PMID- 26125692 TI - Intact Survival After Obstetric Hemorrhage and 55 Minutes of Cardiopulmonary Resuscitation. AB - Cardiac arrest occurs in approximately 1:12,000 parturients. Among nonpregnant patients who have in-hospital cardiac arrest, those whose spontaneous circulation does not return within 15 to 20 minutes have a high risk of death and disability, so life support efforts are generally stopped after this period. However, among parturients, witnessed in-hospital arrest is often reversible and has a better prognosis. We describe a successful clinical outcome after maternal cardiac arrest and 55 minutes of advanced cardiac life support. This case underscores the importance of high-quality cardiopulmonary resuscitation and raises questions about the appropriate duration of resuscitation efforts in otherwise healthy young mothers with a potentially reversible cause of arrest. PMID- 26125693 TI - Perioperative Glucose Management: Point-of-Care Testing and Pseudohypoglycemia. AB - Perioperative hypoglycemia has been associated with adverse outcomes. Consequently, perioperative monitoring of blood glucose using convenient point-of care (POC) monitors is frequently used. Although venous or arterial glucose POC testing has been cleared for use in critically ill hospitalized patients, the results of capillary glucose POC testing should be interpreted with caution because capillary POC samples are usually less reliable than those obtained from arterial or venous sites. We describe a case of pseudohypoglycemia using such testing. This case highlights the importance of individualizing perioperative glucose management to venous or arterial rather than capillary sampling in certain clinical situations. PMID- 26125694 TI - SnO2 nanoparticle-loaded activated carbon for simultaneous removal of Acid Yellow 41 and Sunset Yellow; derivative spectrophotometric, artificial neural network and optimization approach. AB - The simultaneous adsorption of Acid Yellow 41 (AY41) and Sunset Yellow (SY) onto SnO2 nanoparticle-loaded activated carbon (SnO2-NP-AC with very high BET surface area of 1278.71 m(2) g(-1)) was investigated. To overcome the severe dyes spectral overlapping, derivative spectrophotometric method and principal component analysis-artificial neural network (PCA-ANN) were successfully applied for the simultaneous determination of AY41 and SY in their binary solutions. By using central composite design (CCD) under response surface methodology, the effects of variables such as contact time, adsorbent dosage, pH, AY41 concentration and SY concentration on responses such as binary dyes removal percentages were examined. Optimal values were found to be 17.9 min, 0.024 g, 3.1, and 15.9 mg L(-1) and 18.7 mg L(-1), respectively. In binary solutions, the best fit to modified-extended Langmuir isotherm was obtained for the whole concentration range. In binary solutions, a synergism was observed for the AY41 and SY dyes adsorption onto SnO2-NP-AC. The adsorption rates at various times were analyzed. It indicated a pseudo-second-order kinetic model for the adsorption of both dyes. PMID- 26125695 TI - Mitochondrial DNA haplogroups and somatic mutations are associated with lung cancer in patients from Southwest China. AB - Mitochondrial DNA mutations play crucial roles in the pathogenesis and progression of human malignancies. Therefore, to determine whether maternal background or mitochondrial DNA somatic mutations were essential cofactors in the lung cancer of Chinese patients as well, the complete mitochondrial DNA displacement loop of the primary cancerous, matched para-cancerous normal and distant normal tissues for 79 Chinese patients with lung cancer were analyzed in this study. Our results indicated that the higher detected frequency of haplogroups prevalent in southern East Asia (53.16%; 42/79) versus those of northern East Asia in the studied population supported the southern East Asian characteristics of the Chinese lung cancer group. Further statistical analysis revealed that the haplogroups F* and G* contributed to the susceptibility to lung cancer in Chinese patients. In addition, by comparing sequences from different tissues of the same patients, a total of eight somatic mutations from six patients were detected. Combined with the fourteen somatic mutations identified in our previous study, the somatic mutation spectrum of the 79 Chinese patients with lung cancer was 25.32% (20/79). Our results suggest that mitochondrial DNA haplogroups and somatic mutations are associated with lung cancer in patients from Yunnan, Southwest China, and that somatic mitochondrial DNA mutations in the displacement loop can serve as potential biomarkers for clinical utility. PMID- 26125696 TI - Aggressiveness of Pseudocercospora griseola strains in common bean genotypes and implications for genetic improvement. AB - The fungus Pseudocercospora griseola, the causal agent of angular leaf spot in the common bean (Phaseolus vulgaris L.), exhibits a broad pathogenic variability that complicates the development of resistant cultivars. For breeding programs to successfully obtain common bean cultivars with durable resistance, knowing the aggressiveness of different strains, as well as the mechanisms of genetic resistance, is important. The aims of this study were to study the variation within race 63.63 by evaluating the aggressiveness of different strains, to analyze the genetic resistance of common bean lines to P. griseola, and to ascertain the implications for genetic improvement in obtaining resistance in this pathosystem. Four strains, collected from different locations, were inoculated in three groups of common bean lines in a greenhouse, and the severity of the disease was subsequently evaluated. Statistical analyses were carried out using the diallel method, which provided information on the vertical and horizontal resistance of host plants, in addition to information regarding the aggressiveness of the strains. The aggressiveness of P. griseola differed between the strains of race 63.63. The diallel method proved to be promising for the identification of horizontal and vertical resistance in the common bean-P. griseola pathosystem, with a predominance of horizontal resistance. Gene pyramiding, using marker-assisted selection, may not be the most effective strategy for obtaining durable resistance. PMID- 26125697 TI - Acetobacter bacteria are found in Zhenjiang vinegar grains. AB - Zhenjiang vinegar, the grains of which contain a unique microbial flora, is one of the four famous traditional Chinese vinegars. We investigated the components of Zhenjiang vinegar grains. Unique acetic acid bacteria were randomly isolated from Zhenjiang vinegar grains, and the obtained strains were qualitatively analyzed to compare their capacities for acetate decomposition and acid production. Acetic acid bacteria with a high acid-producing rate were identified by 16S rDNA sequencing, and further confirmation was performed using the Basic Local Alignment Search Tool comparison method. Six significant strains of acetic acid bacteria were isolated. Qualitative analysis showed that these strains produced no brown precipitate and had a capacity for acetate decomposition. Based on physiological and biochemical evaluation, the two strains with the highest acid yield were sequenced, and the results identified strain W1 as Acetobacter aceti and strain W6 as A. pasteurianus. PMID- 26125698 TI - BRAF overexpression is associated with BRAF V600E mutation in papillary thyroid carcinomas. AB - A common mutation in the BRAF gene, comprising the T1799A nucleotide transversion, which leads to the V600E amino acid substitution in the BRAF protein, has been observed in about 50% of papillary thyroid carcinomas (PTCs). However, BRAF protein expression has been rarely examined in such tumors. Clinical studies have shown important associations between BRAF mutation and clinical parameters in PTC, such as progression, invasion, and recurrence. The aim of this study was to evaluate the association between BRAF protein overexpression and the BRAF V600E mutation in a group of PTC patients. The study group included 116 patients with PTC from Araujo Jorge Hospital, Goiania, Goias, Brazil. Immunohistochemistry was utilized to analyze BRAF protein expression. Presence of the BRAF V600E mutation was determined by polymerase chain reaction amplification and restriction fragment length polymorphism, and confirmed by direct sequencing. The chi-square test with Yates correction and the Fisher exact test were used for statistical analysis. BRAF overexpression was detected in 55 patients with PTC (47.4%) and the BRAF V600E mutation was observed in 74 patients (63.8%). In the studied group, significant associations were observed between the BRAF V600E mutation and BRAF protein overexpression (P = 0.0115), and also between BRAF overexpression and extra-thyroid extension of the tumor (P = 0.0111). This study demonstrated a significant association between BRAF overexpression and the BRAF V600E mutation in PTC, highlighting the importance of these molecular events in the process of PTC carcinogenesis. PMID- 26125699 TI - Observed impacts of insulin therapy on callus cell transforming growth factor beta 1 expression in diabetic rats. AB - The expression of transforming growth factor-beta 1 (TGF-beta1) inside the callus cells of diabetic rats and the impact of insulin therapy on its expression and biomechanics was investigated. The rats were randomly divided as follows: an insulin therapy group (IT), a diabetic model group (DM), and a non-diabetic control group (NC). Bone specimens from each group were extracted at different times for immunohistochemical observation of the expression of TGF-beta1. Concurrently, the destruction torque and torsional stiffness were detected at different times. One to four weeks after fracture, TGF-beta1 was widely expressed in fractured callus cells and periosteal proliferating cells, while the expression inside diabetic cells was significantly reduced. The expression of TGF beta1 decreased over the first 68 weeks, and the mature bone cells never expressed TGF-beta1. The destruction torque (Nm) detected in the 6th week revealed that there was a statistically significant difference between the DM, NC, and IT groups (P < 0.01). In conclusion, TGF-beta1 expression was significantly reduced inside the callus cells of diabetic rats. Insulin therapy increased TGF-beta1 expression inside the callus cells of diabetic rats and improved the biomechanical characteristics of the callus. PMID- 26125700 TI - Physiological quality and gene expression during the development of habanero pepper (Capsicum chinense Jacquin) seeds. AB - Phytohormones have different characteristics and functions, and they may be subject to changes in their gene expression and synthesis during seed development. In this study, we evaluated the physiological qualities of habanero peppers (Capsicum chinense Jacquin) during seed development and the expression of genes involved in germination. Seeds were obtained from fruits harvested at different stages of development [i.e., 14, 21, 28, 35, 42, 49, 56, 63, and 70 days after anthesis (DAA)]. Immediately after harvesting, the seeds were subjected to various tests to determine moisture content, germination, first count germination, and seedling emergence. Real-time polymerase chain reaction was used to evaluate the expression of various genes, including MAN2, NCED, B73, ICL6, and GA3ox. Electrophoresis was used to assess the expression of various enzymes, including alpha-amylase, isocitrate-lyase, and endo-beta-mannanase. Habanero peppers harvested at 70 DAA and subjected to 7 days of rest exhibited higher germination rates and vigor compared to those harvested at all other developmental stages. Peppers harvested at 63 DAA without drying exhibited higher alpha amylase and AmyB73 gene expression levels. Peppers harvested at 70 DAA with 7 days of rest exhibited higher endo-beta-mannanase expression levels. MAN2 gene expression increased during the development of non-dried seeds until 70 DAA. Peppers harvested at 42 DAA exhibited the highest isocitrate-lyase and ICL6 gene activity levels in comparison to those at all other developmental stages. PMID- 26125701 TI - Development of novel microsatellite markers in the Korean rockfish Sebastes schlegeli. AB - The Korean rockfish Sebastes schlegeli is a valuable recreational and commercial fish in China, and is cultured in land-based tanks and net cages. Fifteen microsatellite markers were developed for this species, and their polymorphisms were examined in a population. The allele number of the 15 markers ranged from 2 to 13, with an average of 5.933 per locus. The observed and expected heterozygosity values ranged from 0.063 to 0.938 (averaging 0.585), and 0.062 to 0.908 (averaging 0.642), respectively. Thirteen loci were at Hardy-Weinberg equilibrium (HWE), whereas the other two significantly deviated from the HWE after a Bonferroni's correction. No significant linkage disequilibrium was detected between the comparisons of these loci. These markers are useful for studies of population genetics, linkage mapping, and other relevant studies on S. schlegeli. PMID- 26125702 TI - Development of a new amplification-refractory mutation system for detection of a single nucleotide polymorphism linked to drug resistance in Ancylostoma caninum. AB - Single nucleotide polymorphisms at codons 167, 198, and 200 in the beta-tubulin isotype 1 gene have been associated with benz-imidazole resistance. Until now, the only mutation observed in Ancy-lostoma caninum was at codon 200 of this gene. However, the standard-ized methodologies used to detect mutations in this species are faulty. The objective of this study was to standardize a molecular technique based on amplification-refractory mutation system-polymerase chain reaction (ARMS PCR) for detecting the mutation at codon 200 in the A. caninum beta-tubulin isotype 1 gene. Controls were synthesized both for the absence of the mutation, using conventional PCR, and for the presence of the mutation, using the Megaprimer-PCR technique. After standardization of the ARMS-PCR using the controls, the technique was validated through an analysis of 75 A. caninum DNA samples, fol-lowed by sequencing. The results revealed that the developed technique has high sensitivity, specificity, and reproducibility, which allow its ap-plication in the field. PMID- 26125703 TI - Association of CHRNA4 gene rs1044396 and rs1044397 polymorphisms with Parkinson's disease symptoms and smoking. AB - We assessed the CHRNA4 exon 5 rs1044396 and rs1044397 polymorphisms and investigated their relationship with Parkinson's disease (PD) severity and several non-motor symptoms. Ninety-seven patients with primary PD and 108 controls were recruited, and their smoking history identified. Patients with PD were assessed using the unified PD rating scale (UPDRS), Hoehn & Yahr (H&Y) grade, Hamilton depression rating scale (HAMD), visual analogue 10-points scale (VAS), and the Pittsburgh sleep quality index (PSQI). Polymerase chain reaction amplification and direct sequencing was performed on genomic DNA to identify polymorphic variants. Statistical analysis demonstrated that there were no gender differences in rs1044396(C->T) and rs1044397(G->A) frequencies. More smokers were identified among carriers of rs1044396 CT/TT genotypes. We also found no differences between PD and control groups in frequencies of either polymorphism. However, in women, PD onset was latest in rs1044397 GA/AA (P = 0.015). rs1044396 CT/TT genotype carriers and rs1044397 GG genotype patients with PD had higher VAS scores. No differences were found on the course of PD, H&Y grade, or UPDRS-II or III scores between various genotypes, nor were differences found on scores of HAMD, nocturia, or PSQI in PD patients. Our results suggested that the CHRNA4 rs1044396 CT/TT genotype is related to cigarette smoking, that the rs1044397 polymorphism may associate with PD age of onset in women, and that rs1044396 and rs1044397 may relate to pain in PD patients, but not to the course or severity of disease, or to depression or nocturnal or sleeping disorders. PMID- 26125704 TI - Microsatellite markers for Amazon pellona Pellona castelnaeana (Clupeiformes: Pristigasteridae). AB - The Amazon pellona is one of the few species of Pristigasteridae with recognized commercial value in the Amazon. We isolated 24 and characterized 8 microsatellite loci for this species. The number of alleles ranges from 2-8 per locus. Observed heterozygosities ranged from 0.052-0.823, while expected heterozygosities from 0.052-0.836. These 8 microsatellites are potentially valuable tools for characterizing the levels and distribution of genetic diversity, population structure, and gene flow. They may also be important parameters for the genetic conservation of this species, as well as for its sister taxon Pellona flavipinnis. PMID- 26125706 TI - Effect of ultraviolet A exposure on transport of compatible organic osmolytes in human lens epithelial cells. AB - Compatible organic osmolytes, such as betaine, myoinositol, and taurine, are involved in antioxidant defense, protein stabilization, and stress responses. This osmolyte strategy requires the expression of specific osmolyte transporters such as betaine (BGT-1), myoinositol (SMIT), and taurine (TAUT). In contrast to the kidney, keratinocytes, and neural cells, few studies have examined osmolytes in human lens epithelial cells (HLECs). We examined the expression of mRNA specific for BGT-1, SMIT, and TAUT in HLECs. In comparison to normoosmotic (305 mOsM) controls, there was a 3-5-fold time-dependent reaction of BGT-1, SMIT, and TAUT mRNA levels in HLECs exposed to hyperosmotic stress (405 mOsM). Maximal responses were obtained for BGT-1, SMIT, and TAUT mRNA expression after 3, 24 and 9 h of hyperosmotic exposure, respectively. This expression was correlated with increased osmolyte uptake. In contrast, hypoosmotic (205 mOsM) stimulation led to a significant efflux of osmolytes. Exposure to ultraviolet A (340-400 nm) radiation significantly stimulated osmolyte uptake. Increased osmolyte uptake was associated with upregulation of mRNA steady-state levels for osmolyte transporters in irradiated cells. These results demonstrate that ultraviolet A radiation leads to the accumulation of compatible organic osmolytes in HLECs as hyperosmotic pressure, which can maintain cellular environmental homeostasis. PMID- 26125705 TI - Effects of the Zhikang capsule on healing of the flap after radical breast cancer surgery. AB - This study aimed to investigate the effect and mechanism of trauma flap healing promoted by the Zhikang capsule after radical breast cancer surgery. The enrolled breast cancer patients were randomly divided into two groups: treatment and observation. The patients in the treatment group were treated with the Zhikang capsule in addition to the conventional dressing changes, while patients in the observation group underwent only the regular dressing changes. Serum samples of 98 breast cancer patients (with complete clinical data) who underwent modified radical mastectomy were collected and analyzed for expressions of transforming growth factor beta (TGF-beta) and basic fibroblast growth factor (bFGF). The drainage fluid amount and tissue necrosis rate were found to be lower in the treatment group than in the observation group. Moreover, bFGF expression in peripheral blood was higher in the treatment group than in the observation group. However, no significant difference was found between the two groups in the expression of TGF-beta in peripheral blood. In conclusion, Zhikang capsule is effective in promoting flap healing after radical breast cancer surgery, and the increase of bFGF expression in peripheral blood may be the underlying mechanism. PMID- 26125707 TI - Molecular cloning, characterization, and expression analysis of a Broad-Complex homolog during development in the oriental river prawn Macrobrachium nipponense. AB - Broad-Complex (BR-C) is an early ecdysone-responsive gene encoding a family of zinc-finger transcription factors. In this study, we isolated the full-length cDNA of a BR-C homolog from the testes of the oriental river prawn (Macrobrachium nipponense), according to established expressed sequence tag information, using the rapid amplification of cDNA ends technique. The homolog was designated as MnBR-C. The full-length cDNA of MnBR-C contained a 1095-bp open reading frame encoding a precursor protein of 365 amino acid residues. Comparative and bioinformatic analyses revealed that MnBR-C exhibited a high degree of homology with BR-C proteins, and contained the BTB and Zf-H2C2-2 domains. Real-time quantitative polymerase chain reaction (qPCR) analysis revealed that the MnBR-C expression level varied significantly in the developing embryo, postembryonic larva, and adult tissue. Real-time qPCR showed that the MnBR-C gene was expressed in all of the tissues investigated, with the highest level of expression in the brain. In addition, MnBR-C was more abundantly expressed in the testes than in the ovaries. PMID- 26125708 TI - Genetic structure and diversity in natural and stocked populations of the mandarin fish (Siniperca chuatsi) in China. AB - The Chinese perch, or mandarin fish (Siniperca chuatsi), is a freshwater fish that is endemic to East Asia. In this study, we investigated the genetic diversity and structure of nine natural mandarin fish populations (from the Yangtze River and Amur River basins) and six hatchery stocks (from central and south China) using microsatellite markers. The results show that the genetic diversity of the Yangtze River populations was high and stable, and genetic differences between them were not significant. In contrast, a low level of genetic diversity and strong genetic structure were detected in the Amur River population. These results suggest that the Yangtze River region and the Amur River region should be treated as two separate units in conservation programs. The hatchery stocks exhibited low genetic diversity and significant genetic differentiation compared to natural populations; this may result in a significant impact on the species if escape events occur. Therefore, a scientific aquaculture management strategy is necessary for the long-term development of hatcheries. PMID- 26125709 TI - Meta-analysis of differentially expressed genes in ankylosing spondylitis. AB - The purpose of this study was to identify differentially expressed (DE) genes and biological processes associated with changes in gene expression in ankylosing spondylitis (AS). We performed a meta-analysis using the integrative meta analysis of expression data program on publicly available microarray AS Gene Expression Omnibus (GEO) datasets. We performed Gene Ontology (GO) enrichment analyses and pathway analysis using the Kyoto Encyclopedia of Genes and Genomes. Four GEO datasets, including 31 patients with AS and 39 controls, were available for the meta-analysis. We identified 65 genes across the studies that were consistently DE in patients with AS vs controls (23 upregulated and 42 downregulated). The upregulated gene with the largest effect size (ES; -1.2628, P = 0.020951) was integral membrane protein 2A (ITM2A), which is expressed by CD4+ T cells and plays a role in activation of T cells. The downregulated gene with the largest ES (1.2299, P = 0.040075) was mitochondrial ribosomal protein S11 (MRPS11). The most significant GO enrichment was in the respiratory electron transport chain category (P = 1.67 x 10-9). Therefore, our meta-analysis identified genes that were consistently DE as well as biological pathways associated with gene expression changes in AS. PMID- 26125710 TI - Cyclin D1 G870A gene polymorphism and risk of leukemia and hepatocellular carcinoma: a meta-analysis. AB - Cyclin D1 (CCND1) is a key protein involved in cell-cycle regulation, and the CCND1 G870A polymorphism is associated with many types of malignancy. Studies examining the associations between this G870A polymorphism and susceptibility to leukemia and hepatocellular carcinoma (HCC) have shown inconsistent results. Therefore, we conducted a meta-analysis to clarify these associations. A search of the PubMed database yielded 7 relevant articles: 3 pertaining to leukemia and 4 to HCC. The odds ratios (ORs) from individual studies were pooled using a fixed or random-effect model. A significant association was observed between the CCND1 G870A variant and leukemia under the allele contrast model [P = 0.003, OR = 1.49, 95% confidence interval (CI) = 1.15-1.95], the homozygote contrast model (P = 0.003, OR = 2.30, 95%CI = 1.34-3.96), and the recessive model (P = 0.002, OR = 2.03, 95%CI = 1.29-3.21). A significant association was observed between this variant and HCC under the recessive model (P = 0.0006, OR = 1.62, 95%CI = 1.23 2.14), the dominant model (P = 0.002, OR = 1.59, 95%CI = 1.19-2.14), the homozygote contrast model (P < 0.0001, OR = 2.06, 95%CI = 1.45-2.94), and the allele contrast model (P < 0.0001, OR = 1.43, 95%CI = 1.20-1.69). Our findings suggest that heritable CCND1 status may influence the risk of developing leukemia and HCC, and that more attention should be given to carriers of these susceptibility genes. PMID- 26125711 TI - Effects of changes in serum endostatin and fibroblast growth factor 19 on the chemotherapeutic sensitivity in acute myeloid leukemia patients. AB - The present study aimed to explore the changes in serum endostatin and fibroblast growth factor 19 (FGF-19) in acute myeloid leukemia patients, and to determine their effects on chemotherapeutic sensitivity. Sixty acute myeloid leukemia patients and 30 healthy controls were included in the study. Patient serum endostatin and FGF-19 levels were measured on admission, and then, standard chemotherapy was administered. The patients were divided into 2 groups according to chemotherapeutic effects: 21 patients in the chemotherapeutic sensitivity group (complete remission + partial remission) and 39 in the chemotherapeutic resistance group (no remission + degradation). A receiver operating characteristic (ROC) curve was used to analyze the relationship of serum endostatin and FGF-19 levels with chemotherapeutic sensitivity in acute myeloid leukemia patients. The levels of serum endostatin and FGF-19 in acute myeloid leukemia patients before chemotherapy were significantly higher than those in the control group. Moreover, these levels significantly decreased after chemotherapy (P < 0.01). The levels of serum endostatin and FGF-19 in the chemotherapeutic sensitivity group were lower than those in the chemotherapeutic resistance group, both before and after chemotherapy (P < 0.05 and P < 0.01, respectively). ROC curve analysis showed that the predictive values of endostatin and FGF-19 were good, and there was no significant difference between these results. In conclusion, serum endostatin and FGF-19 can be used as predictors of chemotherapeutic sensitivity for acute myeloid leukemia patients, and may be important for determining prognosis. PMID- 26125712 TI - B-type natriuretic peptide and cirrhosis progression. AB - Brain natriuretic peptide (BNP) is used as a marker of cardiac dysfunction to predict heart failure mortality. The significance of the prognostic ability of BNP for liver cirrhosis remains unknown, although the levels of BNP seen in cirrhosis are high. We aimed to determine whether the BNP level is related to the stage of cirrhosis and could serve as a prognostic marker of cirrhosis (predict the 1-year all-cause mortality). We recruited 92 patients at different stages of cirrhosis and 81 controls matched by age and gender for this study. At admission, cardiac physical examination and BNP measurements were performed. Upon discharge, the 89 patients were followed up for 12 months. The median BNP levels of patients with cirrhosis were 167.0 pg/mL, which were significantly higher than those of the control group (167.0 vs 34.8 pg/mL, P = 0.001). Serum BNP levels were positively correlated with the Child score, the grade of esophageal varices, a history of spontaneous bacterial peritonitis, and the presence of ascites and collateral circulation. BNP levels above the median were associated with an increased occurrence of death within 12 months of discharge (log rank P = 0.025), as determined by univariate and multivariate Cox regression analyses. Esophageal varices, large/medium volume ascites, and BNP levels were related to the clinical outcome (P = 0.034, 0.030, and 0.025, respectively). Together, these results suggested that serum BNP levels are significantly correlated with the stage of cirrhosis, suggesting that BNP levels might serve as a significant predictor for 1-year all-cause mortality. PMID- 26125713 TI - Association between rs9904341 G0.5 x 10(9)/L) was 14 days (range, 10-20 days), and the median time of platelet recovery (>20 x 10(9)/L) was 19 days (range, 14-31 days). The survival rate at the cutoff point of follow-up was 95.0% (19/20). Initial engraftment rate was 95% (19/20). Late graft failure (graft failures occurring 1 year or longer after transplantation) was observed in one patient. Only one patient developed Grade I acute graft-versus-host disease. Two cases suffered from Epstein- Barr virus (EBV)-associated post-transplant lymphoproliferative disorder and remitted after treatment with rituximab. One patient was diagnosed with hyperthyroidism 2.5 years after transplantation. Our study indicated that allogeneic hematopoietic stem cell transplantation is an effective and safe treatment for children with severe aplastic anemia in China. PMID- 26125719 TI - Effect of high-concentrate diet on amino acid transporter expression and milk quality in Holstein dairy cows. AB - In order to evaluate the effect of high-concentrate diet supplementation on milk protein content, six Holstein dairy cows were assigned into high-concentrate diet (HC) or low-concentrate diet (LC) groups (N = 3/group) for 50 days. With regard to milk protein, HC feeding significantly reduced the percentage of milk protein (P < 0.01), and milk protein yield also reduced. The milk somatic cell count numbers and N-acetyl-D-glucosaminidase activity was significantly higher (P < 0.01) in the HC group than in the LC group. A pre-column derivatization procedure of o-phthalaldehyde was used to analyze the milk amino acid profile, the contents of Asp, Gln, Ala, Ile, Leu, and Lys were significantly lower in milk (P < 0.05), but Arg and Phe were significantly higher (P < 0.05) in the HC group than in the LC group. The mRNA abundance for amino acid transporters SLC7A8, SLC7A10 (P < 0.05), SLC1A3 (P < 0.05), and SLC16A10 (P < 0.05) were decreased in the HC group. These data indicate that expression of amino acid transporters alters regulation of amino acid utilization and decreases milk quality in dairy cows. PMID- 26125720 TI - Effect of recombinant human endostatin on the expression of c-Myc and bFGF in mouse gastric cancer cells. AB - The aim of this study was to observe the effects of re-combinant human endostatin on the proliferation and apoptosis of mouse gastric cancer cells, and explore some possible mechanisms of recom-binant human endostatin inhibition of cancer. A murine gastric cancer xenograft model was established. A total of 20 mice were divided into two groups (control and experimental groups). The expression of c Myc and basic fibroblast growth factor (bFGF) was determined by reverse transcription-polymerase chain reaction, Western blotting, and immu nohistochemical staining methods. Tumor volume was measured and a growth curve was calculated. The tumor diameter in the experimental group was significantly smaller than that in the control group after treat-ment with endostatin for 21 days. The expression levels of c-Myc and bFGF in the experimental group were significantly lower than those of the control group (P < 0.05). There was a positive correlation between the expression of c-Myc and bFGF in the experimental group. Microvessel density was significantly inhibited in the experimental group (P < 0.05). These results demonstrated that recombinant human endostatin could in hibit tumor metastasis by inhibition of the expression of c-Myc and bFGF in gastric cancer tissue as well as by inhibition of angiogenesis. PMID- 26125721 TI - Isolation of microsatellite loci for Rhodiola alsia (Crassulaceae), an important ethno-medicinal herb endemic to the Qinghai-Tibetan plateau. AB - Rhodiola alsia, which has been used widely in traditional Chinese medicine for a considerable time, grows on moist habitats at high altitude near the snow line. Microsatellite loci were developed for R. alsia to investigate its population genetics. In total, 17 polymorphic microsatellites were developed based on ESTs from the Illumina HiSeq(TM) 2000 platform. The microsatellite loci were checked for variability using 80 individuals of R. alsia sampled from four locations on the Qinghai-Tibet Plateau. The total number of alleles per locus ranged from 10 to 20, and the observed heterozygosity ranged from 0.000 to 1.000. The null allele frequency ranged from 0.000 to 0.324. These microsatellites are expected to be helpful in future studies of population genetics in R. alsia and related species. PMID- 26125722 TI - Characterization and phylogenetic analysis of the swine leukocyte antigen 3 gene from Korean native pigs. AB - We investigated the phylogenetic relationships between pig breeds, compared the genetic similarity between humans and pigs, and provided basic genetic information on Korean native pigs (KNPs), using genetic variants of the swine leukocyte antigen 3 (SLA-3) gene. Primers were based on sequences from GenBank (accession Nos. AF464010 and AF464009). Polymerase chain reaction analysis amplified approximately 1727 bp of segments, which contained 1086 bp of coding regions and 641 bp of the 3'- and 5'-untranslated regions. Bacterial artificial chromosome clones of miniature pigs were used for sequencing the SLA-3 genomic region, which was 3114 bp in total length, including the coding (1086 bp) and non coding (2028 bp) regions. Sequence analysis detected 53 single nucleotide polymorphisms (SNPs), based on a minor allele frequency greater than 0.01, which is low compared with other pig breeds, and the results suggest that there is low genetic variability in KNPs. Comparative analysis revealed that humans possess approximately three times more genetic variation than do pigs. Approximately 71% of SNPs in exons 2 and 3 were detected in KNPs, and exon 5 in humans is a highly polymorphic region. Newly identified sequences of SLA-3 using KNPs were submitted to GenBank (accession No. DQ992512-18). Cluster analysis revealed that KNPs were grouped according to three major alleles: SLA-3*0502 (DQ992518), SLA-3*0302 (DQ992513 and DQ992516), and SLA-3*0303 (DQ992512, DQ992514, DQ992515, and DQ992517). Alignments revealed that humans have a relatively close genetic relationship with pigs and chimpanzees. The information provided by this study may be useful in KNP management. PMID- 26125723 TI - Short Communication: Effect of heat stress on heat-shock protein (Hsp60) mRNA expression in rainbow trout Oncorhynchus mykiss. AB - The enhanced expression of heat shock proteins (hsps) in organisms can be detected in response to many kinds of stressor. For fish, high temperature is an important stressor, and hsp expression is associated with differences in environmental temperature. In this study, rainbow trout (Oncorhynchus mykiss) that were accustomed to an aquatic temperature of 18 degrees C were exposed to an elevated temperature (25 degrees C), and hsp60 expression in the gill, liver, spleen, heart, and head kidney was quantified using real-time polymerase chain reaction in unstressed and heat-stressed animals. The fish responded to heat stress in a time- and tissue-specific manner. Cardiac hsp60 mRNA levels were largely unchanged, and the greatest induction of hsp60 in heat-stressed animals was recorded in the liver, suggesting that protein damage and the consequent requirement for the Hsp60 protein are probably greater in hepatic tissue. Therefore, fish must be provided with optimal temperature conditions in order to realize their potential growth and maximize fish farm profits. PMID- 26125724 TI - Pre-B-cell colony-enhancing factor is markedly elevated in childhood hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome involving a final common pathway of hypercytokinemia, in which tumor necrosis factor (TNF) alpha, interferon (IFN)-gamma, and soluble interleukin 2-receptor-alpha (sIL 2Ralpha) are the key cytokines. Pre-B-cell colony-enhancing factor (PBEF) is an inflammatory cytokine involved in several inflammatory diseases. However, its role in HLH is unknown. In this study, we examined the role of PBEF in HLH. Plasma was collected from 22 children with HLH and 14 healthy children. The concentrations of plasma PBEF, TNF-alpha, IFN-gamma, and sIL-2Ralpha were determined using an enzyme-linked immunosorbent assay. All clinical data were derived from medical records. In the acute phase, children with HLH had much higher PBEF, TNF-alpha, IFN-gamma, and sIL- 2Ralpha levels than did healthy children (P < 0.05). After treatment, 13 HLH children improved and PBEF, TNF alpha, and IFN-gamma levels decreased to normal levels (P < 0.05); sIL-2Ralpha levels also decreased (P < 0.05), but remained above the normal level (P < 0.05). Two patients were lost to follow-up, while 7 patients showed a bad response to therapy and eventually died, showing high PBEF levels above those of the survivors (P < 0.01). PBEF level was significantly positively correlated with TNF alpha, IFN-gamma, sIL-2Ralpha, serum ferritin, and triglycerides (all P < 0.05), and was negatively correlated with fibrin (P < 0.05). PBEF appears to be involved in the inflammatory process of HLH, and elevated PBEF is related to disease activity. We are currently evaluating the role of PBEF as a marker for the diagnosis and management of patients. PMID- 26125725 TI - Clinical analysis of patients with myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis. AB - This prospective study analyzed the clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis and explored the relationship between MPO-ANCA and clinical manifestations of the associated vasculitis in 132 p-ANCA and MPO-ANCA-positive patients (average age, 62.3 +/- 14.8 years) who were initially diagnosed with ANCA-associated vasculitis. The p ANCA and MPO-ANCA levels in peripheral blood were detected in all patients. Among these, 128 (97%) had microscopic polyangiitis (MPA), 3 (2.3%) had granulomatous polyangiitis, and 1 (0.7%) had eosinophilic granulomatous vasculitis. The average time of diagnosis was 10.2 +/- 18 months; only 14 (10.6%) patients were diagnosed within 1 month. The main organs involved and the corresponding number of patients were: renal, 95 (72%); lung, 89 (67.4%); joints, 35 (26.5%); heart, 26 (19.7%); peripheral nerve, 23 (17.4%); skin rash, 14 (10.6%); and CNS, 13 (9.8%). Older patients were more likely to show lung involvement in the early disease stage, whereas the joints were involved mostly in the younger patients. The p-ANCA levels (mean titers, 1:60) were not correlated with disease activity and extent of organ involvement, and the MPO-ANCA levels were positively correlated with disease activity, but had no correlation with the extent of organ involvement. MPO-ANCA vasculitis is a common occurrence in China; it mainly involves the elderly and presents as clinical manifestations of MPA. However, the multiple organ damage is not specific leading to delay in diagnosis. MPO-ANCA may play a pathogenic role in the associated vasculitis, and the diverse clinical manifestations might be related with the different characteristics of MPO-ANCA. PMID- 26125726 TI - Fyn arrests swainsonine-induced apoptosis in 293T cells via Akt and its phosphorylation. AB - Swainsonine (SW), an extract from Astragalus membranaceus, represents a new class of compounds that inhibit growth and induce apoptosis in a cancer model. In this study, we demonstrated the effect of Fyn on SW-induced apoptosis in 293T cells. Western blotting was used to measure the expression of the apoptosis-related factors caspase-3, Bcl-2, Bax, and the key factor Akt (also known as protein kinase B). Apoptosis increased dramatically after treatment with SW. Unlike the control group, after transfection with Fyn, the expression of Bcl-2, in contrast to Bax, was markedly upregulated. The results also showed that the protein expression levels of Akt and phosphorylated Akt were markedly increased. Our results establish that Fyn can arrest SW-induced apoptosis via the activity of Akt and its effective phosphorylation in 293T cells. PMID- 26125727 TI - Repeatability and genotypic correlations of reproductive and productive traits of crossbred beef cattle dams. AB - Beef cattle production requires reproductive efficiency. However, measures of reproductive traits are not usually collected; consequently, correlated traits that could be used as indicators would be useful. We examined associations between measures of reproductive and productive efficiency that could be used as selection indicators. Data from 194 dams of the genetic groups Angus x Nelore, Caracu x Nelore, and Valdostana x Nelore collected over 4 years were used. The reproductive traits analyzed were days to heat (DH), calving interval (CI), days to calving (DC), and pregnancy rate (PR). The productive traits were dam weight (DW), body condition score (BCS), calf weight (CW), and weaning rate (WR). The effects on the model were: year, genetic group, reproductive status (RS), age, reproductive rest, and breed of bull (CW and WR). Multivariate analyses were performed, using the Bayesian approach via Gibbs sampling. We conclude that the reproductive measures are ineffective as selection indicators, whereas using dam weight may be a good alternative. PMID- 26125728 TI - Investigation of TG gene variants and their effects on growth, carcass composition, and meat quality traits in Chinese steers. AB - Thyroid hormones play an important role in regulating metabolism and can affect metabolism-related traits such as fat deposition. The thyroglobulin (TG) gene produces the precursor of thyroid hormones and has been proposed as a candidate gene for a quantitative trait locus with an effect on fat deposition. In this study, we identified 4 novel single nucleotide polymorphisms (SNPs) in the 5' flanking region of the TG gene using a DNA sequencing method. The SNP marker association analysis indicated that the T1355C SNPs were significantly associated with meat percentage (P < 0.05). A significant association between the G1356A polymorphism and live weight and loin muscle area was also detected (P < 0.05). However, no significant association was found between 4 SNPs and the other growth, carcass composition, and meat quality traits including intramuscular fat. The results of this study suggest that TG gene-specific SNPs may be a useful marker for growth traits in marker-assisted selection programs in beef cattle. PMID- 26125729 TI - Association between C1GALT1 variants and genetic susceptibility to IgA nephropathy in Uygur. AB - Immunoglobulin A (IgA) nephropathy (IgAN) is a common form of primary glomerulonephritis characterized by diffuse glomerular mesangial IgA1 deposition leading to mesangial proliferation and chronic glomerular inflammation. Analyses of serum IgA1 from IgAN patients revealed abnormal galactosylation of the O linked carbohydrate moieties of IgA that may result from altered activity in the core of 1 b1,3-galactosyltransferase (C1GalT1). To evaluate the association between C1GalT1 single nucleotide polymorphisms (SNPs) and IgAN, we performed a case-control study on cohorts from the Uyghur population in China. A total of 180 IgAN patients and 180 healthy controls were recruited for the study. We sequenced 5 SNPs, including SNP1 (rs9639031), SNP2 (-527A/G), SNP3 (rs1008898), SNP4 (rs5882115), and SNP5 (rs1047763) in the C1GalT1 gene in all eligible participants. The frequencies of the I allele and DI genotype of rs5882115 in IgAN patients were significantly higher than those in controls (P < 0.05). The frequency of haplotype GAGDA was significantly higher in patients than in controls (0.0719 vs 0.00, P = 0.024). Polymorphisms in the C1GALT1 gene were associated with genetic susceptibility to Uyghur IgAN. PMID- 26125730 TI - Fatty acid composition evaluation of edible parts of Eriocheir sinensis in intensive ponds of Gucheng waters. AB - In Gucheng Lake, Jiangsu Province, China, randomly selected crabs were fed 2 diet types. Crab crude oil methyl ester analysis was performed using gas chromatography-mass spectrometry. Fatty acid compositions in the 3 edible parts of a crab - the hepatopancreas, gonad, and muscle - were analyzed. C16:1 and C18:2 were significantly higher in most commercial pellet feed-feeding crabs than in small trash fish-feeding crabs, while the opposite was observed for eicosapentaenoic and docosahexaenoic acids. Phytanic acid reached 1.93% in the hepatopancreas of small trash fish-feeding crabs. Furan fatty-acid-DiMe (11,5) contents in the testes of small trash fish-feeding crabs was 1.49%. These values were higher in male crabs than in female crabs. According to a standard ratio of 1:1:1 which meaning the saturated fathy acid (SFA), monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) were 33.33 each, fatty acid structure analysis of crab edible parts showed that SFA:MUFA:PUFA of crab edible parts was 2.3-4.1:2.9-5.0:1.3-4.8. The highest muscle score was 29.53 in male trash fish-feeding crabs, and the lowest hepatopancreas score was -40.81 in female commercial pellet feed-feeding crabs. The n-6/n-3 ratio was 0.36-2.48. Muscle ratio was the lowest in female commercial pellet feed-feeding crabs. Thus, small trash fish-feeding and commercial pellet feed-feeding crabs are healthy foods. Overall, for consumption, the males of small trash fish-feeding crabs were better than the females, the muscle was better than the gonads and hepatopancreas, and the testis was better than the ovary. PMID- 26125731 TI - Expression and role of cyclophilin B in stomach cancer. AB - We elucidated the expression of ciclosporin protein B (cyclophilin B) in stomach cancer tissue and the correlation between cyclophilin B and clinicopathological parameters, and determined the effect of cyclophilin B on growth and proliferation of stomach cancer cells. Pathological sections of stomach cancer and paracancerous tissue were collected for detecting the expression and distribution of cyclophilin B, using immunohistochemistry, and for analyzing the relationship between the expression levels of cyclophilin B in stomach cancer and the clinical pathological parameters of the patients. A cyclophilin BsiRNA lentiviral (LV-cyclophilin B-siRNA) and corresponding control vector (LV-siRNA con) were constructed. MTT and cell cycle assays were used to detect the effect of downregulation of cyclophilin B expression on in vitro growth and proliferation and clone formation capacity of BGC823 and SGC7901 cells. The cyclophilin B-positive rate of stomach cancer tissue was 84.29% (59/70) and that of paracancerous tissue was 56.00% (28/50). The expression of cyclophilin B in stomach cancer tissue was significantly higher than that in paracancerous tissue (P < 0.05). Staining for cyclophilin B was primarily present in the cytoplasm and was seldom present in the cell nuclei. Downregulation of cyclophilin B significantly inhibited growth and proliferation of stomach cancer cells, cell cycle progression, and in vivo tumorigenicity capacity. Cyclophilin B has a high diagnostic value for stomach cancer and its downregulation can effectively inhibit the growth of stomach cancer cells. Thus, cyclophilin B may be a potential therapeutic target for stomach cancer treatment. PMID- 26125732 TI - Molecular phylogenetics of the white-lipped peccary (Tayassu pecari) did not confirm morphological subspecies in northwestern South America. AB - We sequenced the mitochondrial DNA (mtDNA) control region of 59 peccaries (44 white-lipped peccaries, Tayassu pecari, and 15 collared peccaries, Pecari tajacu). We also genotyped 3 DNA microsatellites from 78 white-lipped peccaries representing the 4 putative morphological subspecies (i.e., spiradens, aequatoris, pecari, and albirostris) present in northwestern South America (i.e., Colombia, Ecuador, Peru, and Bolivia). Our results showed: 1) the estimated diversity of the mtDNA control region in the T. pecari population was extremely high, whereas the average genetic diversity for the microsatellites was medium to high and similar to that observed in European pig breeds; 2) there was no significant genetic heterogeneity among the quoted putative morphological subspecies at the mitochondrial marker, but we did detect significant (although relatively small) genetic heterogeneity using microsatellites, indicating that T. pecari albirostris is a uniquely differentiated group; and 3) the phylogenetic mtDNA trees showed that haplotypes were intermixed independent of their "a priori" subspecies classification. In addition, the microsatellite assignation analyses yielded low percentages of well-classified individuals when the analysis considered the geographic morphology of the subspecies. Thus, the molecular results do not support the putative morphological subspecies of T. pecari in northwestern South America. Finally, our results did not detect clear historical demographic changes using the mtDNA control region sequences. These genetic results are discussed in the context of the ecological and social characteristics of T. pecari. PMID- 26125733 TI - Carcass and meat quality traits in Nellore and F1 Nellore-Araguaia crosses. AB - We evaluated and compared carcass traits and meat quality in Nellore cattle and F1 crosses between Nellore and Araguaia, where 17 individuals were from the Nellore group and 19 were 1/2 Nellore and 1/2 Araguaia crosses. All animals belonged to the same birth season and were raised in pasture systems under the same nutritional, environmental, and management conditions. When the animals reached slaughter weight, they were taken to an industrial slaughterhouse where food was not provided for 24 h (free access to water); they were then stunned, bled, the leather was removed, and they were eviscerated. The carcasses were weighed (hot weight), kept in chilled storage for approximately 24 h at 4 degrees C, and weighed again to obtain the chilled carcass weight. Carcass yield, carcass length, carcass width, leg length, thigh perimeter, loin eye area (LEA), retail cuts, cooling loss, pH, fat depth, marbling rate, intramuscular fat, color, and shear force were analyzed and sensory analysis of the meat was conducted. Significant differences (P < 0.05) were observed for the following variables: slaughter weight, hot and chilled carcass weights, carcass and leg lengths, thigh perimeter, LEA, retail cuts, and lightness (L*), where the 1/2 Nellore 1/2 Araguaia individuals showed higher means for all of these traits, except leg length and L*. Therefore, crossbreeding between Nellore and Araguaia did not affect the meat's sensory characteristics, but contributed to an improvement in carcass traits, providing an alternative for farmers that aim for good meat quality, with a higher meat percentage. PMID- 26125734 TI - Relationship between DNA repair gene XPD751 single-nucleotide polymorphisms and prognosis of colorectal cancer. AB - We examined the relationships between single-nucleotide polymorphisms (SNPs) in the DNA repair gene XPD751 and the efficacy and time to disease progression (TTP) in colorectal cancer patients after platinum-based chemotherapy. Ninety-eight patients diagnosed with advanced colorectal cancer were subjected to oxaliplatin and 5-fluorouracil combination therapy. DNA was extracted from venous blood before chemotherapy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect XPD751 SNPs. The relationship between genotypes and prognosis was compared. The frequencies of the XPD751 Lys/Lys, Lys/Gln, and Gln/Gln genotypes were 76 (77.55%), 17 (17.35%), and 5 (5.10%), respectively. The efficiency of XPD751 Lys/Lys, Lys/Gln and Gln/Gln genotypes were 50.00, 29.41, and 20%, respectively. The efficiency rate between XPD751 Lys/Lys and Lys/Gln showed a significant difference (c2 = 4.04, P < 0.05). After adjusting for gender, age, and metastasis location, chemotherapy failure in patients carrying XPD751 Lys/Gln was 3.404-fold higher than in patients carrying the Lys/Lys genotype. Median TTP was 304 days (10.1 months) and median TTP in patients with XPD751 Lys/Lys and >=1 Gln genotype was 340 and 87 days. After comparing TTP in patients carrying Lys/Lys and patients carrying >=1 Gln, the difference was significant. SNPs in the DNA repair gene XPD751 may be associated with oxaliplatin and 5-fluorouracil chemotherapy sensitivity in colorectal cancer patients. These polymorphisms may be associated with TTP in patients with advanced colorectal cancer after first-line chemotherapy of oxaliplatin. XPD751 SNPs may be predictive factors of prognosis in colorectal cancer patients receiving oxaliplatin and 5-fluorouracil chemotherapy. PMID- 26125735 TI - Effects of docetaxel plus three-dimensional conformal radiation therapy on microvessel density and apoptosis expression in local advanced squamous non-small cell lung cancer. AB - We examined the effects of weekly single-agent docetaxel plus three-dimensional conformal radiation therapy (3D-CRT) on apoptotic index (AI) and microvessel density (MVD) in local advanced non-small-cell lung squamous cancer patients and analyzed the correlation of MVD, AI, and 50% tumor shrinkage time (T0.5) The molecular mechanism of docetaxel radiosensitization was investigated. Sixty untreated patients with stage IIIA or IIIB lung squamous cancer were enrolled and randomly divided into two groups: observation (N = 30; 3D-CRT + docetaxel + adjuvant chemotherapy) and control (N = 30; 3D-CRT + adjuvant chemotherapy). From day 1 radiotherapy, the observation group received intravenous docetaxel (36 mg/m(2)) once weekly for 6 weeks. Post-radiotherapy, chemotherapy of docetaxel combined with cisplatin lasted 4-6 cycles in both groups. Before radiotherapy and within 24 h after radiotherapy (20 Gy), bronchoscopic biopsy was performed twice at the same site. To analyze the MVD of tumor specimens with immunohistochemical staining . The AI of lung cancer cells was assessed with TUNEL assay, T0.5 values were calculated. The observation group had significantly lower MVD than the control group (P < 0.05). AI significantly increased before and after treatment in the observation group compared with the control group (P < 0.05). The decreased MVD values negatively correlated with T0.5 values (r = -0.624, P < 0.05), whereas the increased AI values did not correlate with the T0.5 values. Docetaxel radiosensitization may occur by decrease in MVD and increase in AI values. Weekly single-agent docetaxel plus 3D-CRT can improve prognosis and quality of life in local advanced non-small-cell lung squamous cancer patients. PMID- 26125736 TI - Type II deiodinase polymorphisms and serum thyroid hormone levels in patients with mild cognitive impairment. AB - We investigated type II deiodinase (DIO2) polymorphisms and serum thyroid hormone levels in subjects with mild cognitive impairment (MCI) in a Uygur population. We studied the DIO2 Thr92Ala (rs225014) and ORFa-Gly3Asp (rs12885300) polymorphisms of 129 unrelated MCI cases and 131 matched controls. All subjects were genotyped using SNaPshot SNP genotyping assays. Serum thyroid hormone levels were measured by radioimmunoassay. Levels of serum triiodothyronine and thyroxine in the MCI group were significantly lower than those in the control group. Genotype and allele frequencies in the DIO2 gene between the MCI and control groups were not significantly different. There was no association in genotype and allele frequencies of Thr92Ala between genders in both groups. ORFa-Gly3Asp genotype and allele frequencies were significantly different in patients and controls by gender. The Asp allele was less frequent among male MCI patients compared to controls (odds ratio = 0.471, 95% confidence interval = 0.261-0.848). However, female Asp carriers were more frequent among MCI patients than among controls (odds ratio = 2.842, 95% confidence interval = 1.326-6.09). Serum levels of triiodothyronine and thyroxine were lower in individuals of the Ala/Ala genotype than in those with the Thr/Thr or Thr/Ala genotype. Serum levels of triiodothyronine were lower in male Gly/Gly carriers than in Gly/Asp or Asp/Asp carriers. Decreased serum levels of triiodothyronine and thyroxine may influence the incidence of MCI in the Uygur population. DIO2 gene polymorphisms may play a role in the incidence of MCI in male patients. PMID- 26125737 TI - Immunohistochemical detection and clinicopathological significance of JARID1B/KDM5B and P16 expression in invasive ductal carcinoma of the breast. AB - The aims of this study were to investigate the expression of the H3K4 demethylase, jumonji AT-rich interactive domain 1B (JARID1B/KDM5B) and of p16 (multiple tumor suppressor gene MTS1) in breast cancer tissue and determine its clinicopathological significance. JARID1B/KDM5B and P16 protein expression in 176 resected breast cancer specimens and adjacent normal breast tissue was detected by the streptavidin-peroxidase (S-P) immunohistochemical method. The TNM staging grade was assigned according to the World Health Organization (2012) breast classification system. The positive staining rate of JARID1B/KDM5B and p16 protein in cancer tissue was 74.43 and 35.8%, respectively. JARID1B/KDM5B protein expression was positively associated with T grade, Bloom and Richardson (B&R) score and axillary lymph node metastasis (P < 0.05). p16 protein expression was negatively associated with T grade, B&R score, and axillary lymph node metastasis (P < 0.05). JARID1B/KDM5B and p16 protein expression in breast cancer and adjacent normal breast tissue were negatively correlated (r = -0.303, P < 0.001). The data demonstrated that protein expression of p16 and JARID1B/KDM5B is negatively correlated in invasive ductal carcinoma of the breast. PMID- 26125738 TI - Effects of Astragaloside IV on diabetic nephropathy in rats. AB - The aims of this study were to explore the effects of Astragaloside IV on diabetic nephropathy (DN) rats. A total of 38 male Sprague-Dawley (SD) rats were divided into three groups: 10 in the normal (control) group, 14 in the DN model group, and 14 in the AS-IV group. Treatment began one week after the streptozotocin DN model was successfully established. Blood glucose and urine micro-albumin levels were measured every four weeks. After being treated for 12 weeks, all SD rats were sacrificed for blood and renal specimen collec-tion. Renal cortex specimens were observed after hematoxylin and eo-sin and Masson staining. Expression levels of protein beta1, beta1-integrin-linked protein kinase (ILK) and alpha-actinin-4 were also measured. After eight weeks of intervention, blood glucose levels in the AS-IV group decreased significantly when compared with those of the model group (P < 0.01). By the end of the twelfth week, the urine micro-albumin levels showed significant differences (P < 0.01) between the AS-IV and model groups, and the expression levels of integrin beta1, ILK, and alpha-actinin-4 also showed significant differences (P < 0.05, respectively). Concomitantly, expression levels of integrin beta1, ILK, and alpha actinin-4 in the model group were significantly different from those of normal group (P < 0.05). These results suggest that AS-IV can be quite effective in decreasing blood glucose levels, reducing urine albumin excretion, and improving the adhesion function of potocytes, and can thus delay the development of DN. PMID- 26125739 TI - Streptomyces ansochromogenes Tur-10 produces a substance with antifungal bioactivity. AB - The increased incidence of fungal infections and the development of drug resistance have led to the search for microorganisms capable of producing bioactive metabolites with antifungal activity. Among these microorganisms, Streptomyces spp are distinguished mainly owing to their potential to secrete bioactive molecules. The aim of this study was to evaluate the production of secondary metabolites by Streptomyces sp TUR-10 against 12 fungal clinical isolates (yeast and filamentous fungi). In the preliminary screening, Streptomyces sp TUR-10 showed activity against 75% of the clinical isolates, and was selected for fermentation. In this assay, we tested three different media (MPE, M1, and ISP-4) for 96 h at pH 7.0 and 30 degrees C for the production of bioactive metabolites. Increased production of bioactive compounds was observed when using the MPE medium for 48 h, with good activity against Candida pelliculosa. The minimum inhibitory concentration showed significant antifungal activity values ranging from 15.6 to 250 MUg/mL. The actinobacterium was characterized by 16S rRNA analysis and the pattern suggested that the isolate studied belonged to the species Streptomyces ansochromogenes. The biotechnological potential of this strain was also demonstrated by the detection of the nrps and pks genes. These results indicate the production of secondary metabolites of biotechnological interest by actinobacteria from the rhizosphere, suggesting great potential for further research. PMID- 26125740 TI - Blocking the expression of the hepatitis B virus S gene in hepatocellular carcinoma cell lines with an anti-gene locked nucleic acid in vitro. AB - The aim of this study was to investigate the effects of inhibition of the hepatitis B virus (HBV) S gene by polypurine region locked nucleic acid on viral replication in cells. We designed and synthesized a locked nucleic acid, phosphorothioate oligonucleotides, unmodified oligonucleotides, and unrelated control sequence for the hepatitis B virus S gene polypurine region. HepG2.2.15 cells were transfected by cationic liposome, and fluorescence quantitative polymerase chain reaction technology (PCR) and time-resolved fluoroimmunoassay technology was utilized to monitor the content of HBV DNA, HbsAg, and HBeAg at 2, 4, 6, 8 and 10 days post-transfection. The effects on cell metabolism were detected by four methyl thiazolyl tetrazolium assay. The locked nucleic acid had an obvious effect on HBV DNA replication and HBsAg and HBeAg expression in a dose and time dependent man-ner. The inhibition rates were 52.14, 57.48, and 29.63% after 6 days, respectively. The locked nucleic acid had no significant effect on cell metabolism. The HBV S gene polypurine region locked nucleic acid could effectively inhibit the replication of HBV in vitro, and could provide an effective target for the treatment of HBV and a theoretical and experimental basis for anti-gene therapy. PMID- 26125741 TI - Prevalence and genotype distribution of human papillomavirus in women in the Henan Province. AB - We studied human papillomavirus (HPV) prevalence and genotype distribution among women in the Henan Province to provide epidemiological data as a means of preventing cervical cancer and developing a vaccine. A total of 14,873 samples were genotyped by using polymerase chain reaction reverse dot-blot. The overall HPV-positive rate in the sample was 23.98% (3566/14873), of which 69.01% (2461/3566) were infected with high-risk HPV types and 17.33% (618/3566) with low risk types. Eighteen high-risk HPV types were detected; HPV 16 (16.73%) was the most common, followed by 58 (10.17%), 52 (9.11%), 56 (6.48%), 66 (5.76%), 33 (4.74%), 68 (3.92%), 31 (3.60%), 53 (3.13%), 59 (3.00%), 35 (2.53%), 51 (2.00%), 73 (1.08%), 45 (0.94%), 83 (0.84%), 39 (0.69%), 18 (0.61%), and MM4 (0.04%). Four low-risk HPV types were detected; HPV 43 (11.34%) was the most common, followed by 6 (5.17%), 42 (4.76%), and 11 (3.35%). Type 44 was not detected. Among the women positive for HPV, 71.17% (2538/3566) had a single type of infection; of these, 54.66% (1949/3566) had high-risk and 16.52% (589/3566) had low-risk infections. A total of 28.83% (1028/3566) had multiple HPV infections, of which 20.11% (717/3566) had double HPV infections. One peak in HPV prevalence occurred among women younger than age 25; a second peak occurred among women older than age 55. The overall prevalence of HPV infection in the Henan Province was 23.98%, of which the most common type was high-risk HPV and a single type of infection. The leading genotypes were HPV 16, 43, 58, 52, and 56. PMID- 26125742 TI - Effect of atorvastatin on diabetic rat endothelial cells and retinal lesions. AB - We investigated the effect of atorvastatin on vascular endothelial growth inhibitor (VEGI) expression in rats with diabetic retinopathy. Wistar rats were divided into a blank group and diabetic model group, which was further randomly divided into treatment and control groups. Rats in the treatment group received 10 mg/kg atorvastatin daily, while rats in the blank and control groups received normal saline. Rats were randomly euthanized at 3 or 6 months. Immunohistochemical staining was used to determine changes in VEGI and vascular endothelial growth factor, interleukin-4, and tumor necrosis factor alpha levels in rats with diabetic retinopathy. Survival rate in the treatment group was 84% (63/75) after 6 months, which was significantly higher than that in the control group (P < 0.05); rats in the control group showed the lowest survival rate. Survival in the treatment group was higher than that in the control group but not significant compared with the blank group after 3 months. VEGI, vascular endothelial growth factor, tumor necrosis factor alpha, and interluekin-4 expression was lower than that in the control group, but higher than the blank group after 3 months. The expression of each factor decreased to the blank group level in the treatment group and was significantly lower than that in the control group after 6 months (P < 0.05). Expression in control and blank groups was similar at 3 and 6 months. Atorvastatin can inhibit VEGI and vascular endothelial growth factor expression to protect rats from diabetic retinopathy. PMID- 26125743 TI - Cloning and functional analysis of the promoter of a maize starch synthase III gene (ZmDULL1). AB - The ZmDULL1 gene encodes a starch synthase and is a determinant of the structure of endosperm starch in maize (Zea mays L.). However, little is known regarding the regulatory mechanism of the ZmDULL1 gene. In this study, we isolated and characterized the ZmDULL1 promoter (PDULL1), which is the 5' flanking region of ZmDULL1 in maize. Sequence analysis showed that several cis-acting elements important for endosperm expression (GCN4_motif and AACA-element) were located within the promoter. A series of PDULL1 deletion derivatives, PDULL1-1-PDULL1-4, from the translation start code (-1676, -1216, -740, and -343) were fused to the beta-glucuronidase (GUS) reporter gene. Each deletion construct was transformed into rice using the Agrobacterium-mediated method, and then GUS activity was measured in transgenic plants. The results showed that PDULL1 was an endosperm specific promoter. Further analysis showed that the promoter sequence (-343 to -1 base pairs) was sufficient for mediating GUS gene expression in endosperm. These results indicate that the region from -343 to -1 base pairs of PDULL1 is valuable for transgenic rice breeding and genetic engineering studies. PMID- 26125744 TI - Short Communication: Genetic linkage map of Cucurbita maxima with molecular and morphological markers. AB - Cucurbita maxima is one of the most widely cultivated vegetables in China and exhibits distinct morphological characteristics. In this study, genetic linkage analysis with 57 simple-sequence repeats, 21 amplified fragment length polymorphisms, 3 random-amplified polymorphic DNA, and one morphological marker revealed 20 genetic linkage groups of C. maxima covering a genetic distance of 991.5 cM with an average of 12.1 cM between adjacent markers. Genetic linkage analysis identified the simple-sequence repeat marker 'PU078072' 5.9 cM away from the locus 'Rc', which controls rind color. The genetic map in the present study will be useful for better mapping, tagging, and cloning of quantitative trait loci/gene(s) affecting economically important traits and for breeding new varieties of C. maxima through marker-assisted selection. PMID- 26125745 TI - Identification of critical TF-miRNA-mRNA regulation loops for colorectal cancer metastasis. AB - To explore the potential cause of colorectal cancer metastasis, gene expression profiles, GSE21510, and miRNA expression profiles, GSE48074, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes in metastatic colorectal and non metastatic colorectal cancer compared with the normal samples were identified via the limma package in R. The differentially expressed miRNAs in colorectal cancer samples with lymph node metastasis compared with those without lymph node metastasis were screened out by the some method. Differentially expressed genes that were upregulated in colorectal cancer samples with distant metastasis in comparison to that in samples without distant metastasis and normal samples were considered to play important roles in colorectal cancer metastasis. Functional enrichment analysis of these genes was conducted using the Database for Annotation, Visualization, and Integrated Discovery v6.7. Biological processes related to cell differentiation and cell proliferation were significantly enriched. TF (transcription factor)-miRNA-mRNA regulation loops were constructed by using the starBase and ChIPBase databases. Finally, six critical regulation loops were screened out. They were composed of two TFs, two miRNAs, and three mRNAs. Some of these TFs, mRNAs, or miRNAs have previously been identified as critical targets in colorectal cancer metastasis. Additionally, several new targets were identified in our study, which may be helpful to improve metastatic colorectal cancer treatment. PMID- 26125746 TI - Ebp1 protein expression in cervical cancer tissue and its significance. AB - The objectives of this study were to observe the changes in expression of ErbB-3 binding protein (Ebp1) in cervical cancer and to investigate their clinic significance. We detected the expression level of Ebp1 in cancerous and adjacent tissues from 56 patients with cervical cancer. We identified 21 Ebp1 positive samples (37.5%) from among the 56 cervical cancer tissue samples and 5 Ebp1 positive samples (8.9%) in the corresponding adjacent tissues; the difference was statistically significant (P < 0.05). No statistically significant (P > 0.05) differences in the rates of positive Ebp1 expression were found between patients under 60 years of age and those equal to or over this age. No statistically significant differences (P > 0.05) were found between patients whose tumor diameters were under 5 cm and those with tumor diameters over 5 cm. No statistically significant differences (P > 0.05) in the Ebp1 positive rates were found among the cervical cancer samples when stratified by grade (I, II, or III). Together, these results demonstrate that Ebp1 protein expression is upregulated in cervical cancer tissues but is not related to clinical pathologic factors such as patient age or tumor size or differentiation level, suggesting that Ebp1 plays an important role in the genesis and growth process of cervical cancer. PMID- 26125747 TI - Systematic meta-analysis of the association between monocyte chemoattractant protein-1 -2518A/G polymorphism and risk of tuberculosis. AB - Numerous studies have been conducted to investigate the association between 2518A/G polymorphisms in the monocyte chemoattractant protein-1 (MCP-1) gene and the risk of tuberculosis (TB). However, the results have been inconsistent and inconclusive. In this study, we performed a meta-analysis to evaluate the association between the MCP-1 -2518A/G polymorphism and TB. The National Center for Biotechnology Information Global Cross Database and Google Scholar database were searched for relative studies. A total of 22 case-control studies that included 7332 cases and 8004 controls for the -2518A/G single-nucleotide polymorphism were identified. The results revealed an association between the MCP 1 -2518A/G polymorphism and human TB susceptibility under a recessive model (GG vs GA+AA), dominant model (GG+GA vs AA), and homozygote comparison (GG vs AA) model for the entire database. For the dominant model, the overall odds ratio was 1.34 (95% confidence interval, 1.10-1.64, P = 0.004). For the recessive model, the overall odds ratio was 1.46 (95% confidence interval, 1.15- 1.86, P = 0.002). For the homozygote comparison, the overall odds ratio was 1.67 (95% confidence interval, 1.20-2.32, P = 0.002). In the subgroup analysis by ethnicity, significantly elevated risks were found in Asians and Americans, but not in Africans and Europeans. We also used the Begg and Egger tests to examine publication bias, and no major publication bias was detected. Our results indicate that there is an association between the MCP-1 -2518A/G polymorphism and human TB susceptibility. PMID- 26125748 TI - Ulinastatin promotes T lymphocyte apoptosis in rats with severe acute pancreatitis via mitochondrial pathways. AB - We explored the influence of ulinastatin on apoptosis of T lymphocytes in rats with severe acute pancreatitis (SAP) and the effect of ulinastatin on mitochondrial apoptosis pathways in spleen lymphocytes. Thirty-six Wistar rats were randomly divided into three groups (N = 12): a sham operated group, a SAP group, and an ulinastatin-treated SAP group. The SAP model was established by injecting 5% sodium taurocholate into the intrapancreatobiliary duct. Study rats were sacrificed after 24 h, and splenic lymphocytes were then collected. CD4(+) and CD8(+) T lymphocytes were labeled by direct immune fluorescence assays; the percentage of apoptotic cells, mitochondrial membrane potential levels, and mitochondria permeability transition pore opening levels were measured by flow cytometry. In the ulinastatin-treated SAP group, the ratio of CD4(+)/CD8(+) T lymphocytes was significantly higher than that in the SAP group, and the apoptosis percentage of CD4(+) T lymphocytes was significantly decreased. The percentage of lymphocytes with an abnormal opening of the mitochondrial permeability transition pore and lymphocytes with decreased mitochondrial membrane potential in the ulinastatin-treated SAP group were significantly lower than that in the SAP group. Ulinastatin can directly enhance immunological function and attenuate immune suppression in SAP rats through inhibiting the apoptosis of CD4(+) T lymphocytes. These study findings demonstrate that therapeutic effects may occur through inhibiting the apoptosis induced by mitochondrial signaling pathways. PMID- 26125749 TI - Serum level of endothelial cell-specific molecule-1 and prognosis of colorectal cancer. AB - We evaluated the clinical significance and explored the prognostic value of serum endothelial cell-specific molecule-1 (ESM-1) expression in colorectal cancer (CRC) in a Chinese population. Serum samples were obtained from 89 CRC patients undergoing surgical treatment and 90 healthy volunteers (control group). ESM-1 levels in serum samples from CRC patients and controls were measured using a sandwich enzyme-linked immunosorbent assay. Overall survival was analyzed by the log-rank test, and survival curves were plotted according to the Kaplan-Meier method. Univariate Cox regression was performed on each clinical covariate to examine its influence on patient survival. Final multivariate models were based on step-wise addition. Serum ESM-1 expression levels were significantly higher in patients with CRC (66.81 +/- 22.97 pg/mL) than in healthy volunteers (31.50 +/- 16.81 pg/mL, P = 0.012). Expression levels of ESM-1 in CRC patients were significantly correlated with histological differentiation (P = 0.004), TNM stage (P = 0.007), depth of tumor invasion (P = 0.02), and lymph node metastasis (P = 0.001). Kaplan-Meier survival curves revealed that the overall survival was significantly lower in patients with high ESM-1 levels than in those with low levels (29.43 vs 61.20%, P = 0.0166). Multivariate analysis confirmed that the hazard risk of death was significantly higher in patients with high serum ESM-1 expression compared with low expression (hazard risk = 4.09, 95% confidence interval: 2.27-10.88, P < 0.001). Detection of ESM-1 levels in the serum may serve as a tumor biomarker for assessing prognosis in CRC. PMID- 26125750 TI - Association between G-217A polymorphism in the AGT gene and essential hypertension: a meta-analysis. AB - Numerous studies have evaluated the association between the angiotensinogen (AGT) G-217A gene polymorphism and essential hypertension risk. However, the results have been inconsistent. We examined whether the AGT G-217A gene polymorphism confers essential hypertension risk by conducting a meta-analysis. We conducted a literature search of the Google Scholar, PubMed, and China National Knowledge Infrastructure databases for relevant studies that examined the G-217A polymorphism and risk of essential hypertension. Statistical analyses were carried out using Stata 12.0 to combine all relevant studies. Crude odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated to estimate the strength of this association. A total of 2017 patients with psoriasis and 1708 controls from 7 comparative studies were included in this meta-analysis. We found a significant association between the AGT G-217A gene polymorphism and the risk of essential hypertension (AA vs GG: OR = 2.52, 95%CI = 1.68-3.78; AA vs GA: OR = 2.26, 95%CI = 1.48-3.45; dominant model: OR = 0.38, 95%CI = 0.26-0.57; recessive model: OR = 1.20, 95%CI = 1.03-1.39). Further stratified analyses were conducted by ethnicity and sample size and produced similar results. No evidence of publication bias was found. This meta-analysis confirms that the AGT G-217A gene polymorphism is associated with essential hypertension susceptibility. PMID- 26125751 TI - Effects of forkhead box C2 on carcinogenesis and lymphatic metastasis in endometrial carcinoma. AB - We investigated the distribution of endometrial lymphatic vessels and expression of forkhead box C2 (FOXC2) in normal endometrium during menstrual cycle and in endometrial adenocarcinoma. Full-thickness uterine samples and endometrial adenocarcinoma samples were collected for immunohistochemical analysis using D2 40 and FOXC2 mouse monoclonal antibodies. The lymphatic vessel density (LVD) of the endometrium was significantly reduced compared with the myometrium during the cycle. Intra-tumoral LVD was significantly decreased in both stages of endometrioid adenocarcinoma compared with normal endometrium and myometrium. Intra-tumoral LVD significantly decreased from stage IA to stage IIIC. Peri tumoral LVD for stage IA and stage IIIC tumors was significantly increased compared with normal endometrial LVD, but decreased compared with normal myometrial LVD. Stage IIIC showed increased peri-tumoral LVD when compared with stage IA. The positive rate of FOXC2 was 73.3% in proliferative endometrium and 80% in secretory endometrium. Secretory endometrium showed significantly increased FOXC2 expression compared with proliferative endometrium. Endometrioid adenocarcinoma showed significantly increased FOXC2 expression compared with normal endometrium, both in the epithelium and stroma. FOXC2 expression in the stroma significantly increased when pelvic and/or para-aotic lymph nodes were involved. FOXC2 was immunolocalized in low-risk endometrial carcinoma in endometrioid adenocarcinoma, but not in normal endometrium. Endometrial lymphatic vessels were located in normal endometrium and myometrium across the menstrual cycle and in intra-and peri-endometrioid adenocarcinoma, and increased in endometrial adenocarcinoma. Peri-tumoral lymphatics were associated with increased lymphatic metastasis. FOXC2 may be associated with the genesis of endometrial carcinoma and lymphangiogensis in endometrial adenocarcinoma in intra and peri-tumoral lymphatics. PMID- 26125752 TI - Associations between TNF-alpha polymorphisms and susceptibility to rheumatoid arthritis and vitiligo: a meta-analysis. AB - We investigated whether the tumor necrosis factor-a (TNF-alpha) promoter -238 A/G and -308 A/G polymorphisms are associated with rheumatoid arthritis (RA) and vitiligo susceptibility. MEDLINE and EMBASE databases and a manual search were used to identify articles in which TNF-alpha polymorphisms were determined in RA or vitiligo patients and controls. Meta-analysis was used to examine the associations between the TNF-alpha -238 A/G polymorphism and RA and vitiligo using the allelic contrast and dominant models. Fifteen studies (10 RA and 5 vitiligo) involving 3678 cases and 4400 controls were considered. We observed an association between the TNF-alpha -238 A allele and RA when all subjects were considered [odds ratio (OR) = 0.686, 95% confidence interval (CI) = 0.476-0.968, P = 0.043]. After stratification by ethnicity, we found no association between the TNF-alpha -238 A allele and RA in European or Asian populations. We observed no association between the TNF-alpha -308 A allele and vitiligo (OR = 1.787, 95%CI = 0.894-3.573, P = 0.101). However, the adjusted OR by the trim-and-fill technique was significant (OR = 2.064, 95%CI = 1.138- 3.743). After stratification by geographic continent, the TNF-alpha -308 A allele was significantly associated with vitiligo in Middle Eastern populations (OR = 1.569, 95%CI = 1.224-2.013, P = 3.8 x 10(-5)). The TNF-alpha -238 A/G polymorphism was associated with RA susceptibility, and the TNF-alpha -308 A/G polymorphism may be a significant risk factor for vitiligo in Middle Eastern populations. PMID- 26125753 TI - Leptin and leptin receptor gene polymorphisms are correlated with production performance in the Arctic fox. AB - The polymerase chain reaction-single-strand conformation polymorphism technique was employed to measure mononucleotide diversity in the coding region of the leptin and leptin receptor genes in the Arctic fox. The relationships between specific genetic mutations and reproductive performance in Arctic foxes were determined to im-prove breeding strategies. We found that a leptin gene polymorphism was significantly associated with body weight (P < 0.01), abdominal circumference (P < 0.01), and fur length (P < 0.01). Furthermore, a polymorphism in the leptin receptor gene was associated with carcass weight and guard hair length (P < 0.01). Leptin and leptin receptor gene combinatorial genotypes were significantly associated with abdominal circumference, fur length (P < 0.01), and body weight (P < 0.05). The leptin gene is thus a key gene affecting body weight, abdominal circumference, and fur length in Arctic foxes, whereas variations in the leptin receptor mainly affect carcass weight and guard hair. The marker loci identified in this study can be used to assist in the selection of Arctic foxes for breeding to raise the production performance of this species. PMID- 26125754 TI - Effects of intravenous analgesia with combined dezocine and butorphanol on postoperative cognitive function in elderly patients. AB - The aim of this study was to observe the analgesic effects of the combination of dezocine and butorphanol on postoperative cognitive function in elderly patients. Forty elderly patients undergoing upper abdominal surgeries or thoracotomies with general anesthesia were randomly divided into the dezocine and butorphanol group or the butorphanol group (20 patients per group). A visual analog scale was used to evaluate analgesia and the degree of malignant vomiting. The Ramsay scoring method was used to evaluate sedation. The Mini-Mental State Examination (MMSE) was used to evaluate cognitive function. Forty-eight hours after the operation, the pain score of the dezocine and butorphanol group (means +/- SD, 1.75 +/- 0.44) was lower than that of the butorphanol group (2.25 +/- 0.79; P < 0.05), and the nausea and vomiting score of the dezocine and butorphanol group (0) was lower than that of the butorphanol group (0.70 +/- 1.30; P < 0.05). Six hours after the operation, the sedative score of the butorphanol group (3.75 +/- 0.79) was higher than that of the dezocine and butorphanol group (2.15 +/- 0.75; P < 0.05). Compared to 1 day before the operation, the MMSE scores of both groups decreased 6 h after the operation, and the MMSE score of the butorphanol group (15.00 +/- 2.00) was lower than that of the dezocine and butorphanol group (20.95 +/- 1.54; P < 0.05). Dezocine and butorphanol analgesia had transient effects on postoperative cognitive function in elderly patients, and the effect of the combination was superior than butorphanol only. PMID- 26125755 TI - Variation of plasma levels of endothelin, calcitonin gene-related peptide, nitric oxide, and malondialdehyde in acute myocardial ischemia reperfusion injury in a rabbit model. AB - We examined the variation in plasma levels of endothelin (ET), calcitonin gene related peptide (CGRP), nitric oxide (NO), and malondialdehyde (MDA), as well as superoxide dismutase (SOD) activity, in acute myocardial ischemia reperfusion injury in a rabbit model. Seventy rabbits were randomly assigned into 3 groups. Open-chest surgery (OCS) was performed for all rabbits. Group A (N = 20) received sham-surgery, group B (N = 25) was the reperfusion group, and group C (N = 25) was the infarction group. At 12 h after chest clo-sure, plasma ET levels in groups B and C were clearly increased, while CGRP levels were clearly decreased, particularly in group B. At 24 h after chest closure, ET levels were higher than before OCS, while there was no significant difference between groups B and C. ET in group B was decreased, while that in group C was increased at 12 h. No significant difference in CGRP was observed between 12 and 24 h after chest closure. NO levels in groups B and C at 12 h after chest closure were significantly decreased compared to those before OCS. NO levels in group B at 24, 48, and 72 h were significantly lower than those at 12 h, while those of group C were not significantly changed after 12 h. Dynamic monitoring and comparison of plasma levels of ET, CGRP, NO, and MDA as well as SOD activity revealed that appropriate intervention of these factors may reduce reperfusion injury. PMID- 26125756 TI - Cut-and-paste-based cloning strategy for large gene site-directed mutagenesis. AB - Site-directed mutagenesis is an essential technique for investigating the mechanisms of gene regulation on a molecular level, as well as for exploring post translational modifications and functional structure at the protein level. Polymerase chain reaction combining in vitro synthesis of oligonucleotide primers allows for site-directed mutation to be performed with ease. However, site directed mutagenesis is difficult when larger plasmids are involved. Here, we present a novel method for generating large gene site-directed mutagenesis products based on a cut-and-paste-based cloning strategy. This method uses 4 primers, incorporating relevant mutations and restriction enzyme site sequences, to generate 2 DNA fragments by polymerase chain reaction. The fragments are then ligated into TA cloning vectors. Large genes containing mutations of interest were obtained by cutting and then pasting, and then inserting one fragment into another T-vector. We demonstrated the practicality of this method by creating a G59S mutation within the p150(Glued)-encoding gene. PMID- 26125757 TI - FSHR gene Thr307Ala and Asn680Ser polymorphisms in infertile men: an association study in North China and meta-analysis. AB - Male infertility is a complex multifactorial and polygenic disease, and genetic factors play an important role in its formation and development. Recently, the association between follicle stimulating hormone receptor (FSHR) gene polymorphisms and male infertility risk has attracted widespread attention due to the unique biological functions of FSH. The aim of this study was to further explore the associations between the Thr307Ala and Asn680Ser polymorphisms of the FSHR gene and male infertility. A case-control study of 212 infertile and 164 fertile men from North China was performed. FSHR polymorphism genotypes were obtained through direct DNA sequencing. A meta-analysis was also performed. In the single-site association analysis, no significant associations were identified between FSHR Thr307Ala and Asn680Ser polymorphisms and male infertility (P > 0.05). However, we found that the combined genotypic frequency of Thr/Ala + Asn/Asn was higher in infertile patients than in controls (6.6 vs 1.8%; odds ratio (OR) = 3.795; 95% confidence interval (CI): 1.072-13.434, P = 0.027). In the meta-analysis, there was also no evidence of FSHR polymorphism (rs 6165 and rs 6168) association with male infertility (P > 0.05). However, we found that the combined genotypes Thr/Thr + Asn/Asn had an increased risk of male infertility (OR = 1.238; 95%CI: 1.001-1.537, P = 0.049). Our studies further confirmed reports that there were no significant associations between the FSHR Thr307Ala and Asn680Ser polymorphisms and male infertility risk. However, a combined FSHR genotype showed significant association with male infertility. PMID- 26125758 TI - Clinical significance of SHMT1 rs1979277 polymorphism in Asian solid tumors: evidence from a meta-analysis. AB - Published data regarding the association between the cytosolic serine hydroxymethyltransferase (SHMT1) C1420T (Leu474Phe) polymorphism and solid tumor risk have shown inconclusive results. To derive a more precise estimation of the relationship, we performed a meta-analysis of 23 published studies that included 14,409 cancer cases and 16,996 controls. A comprehensive search was conducted to identify all eligible studies of the SHMT1 rs1979277 polymorphism and solid tumor risk. The pooled odds ratios (ORs) and the 95% confidence intervals (95%CIs) were calculated using a fixed- or random-effects model. Heterogeneity was represented by PH; publication bias and sensitivity analysis were also explored. Overall, no significant associations were found for any genetic models tested. However, upon stratification by cancer type, a significant decreased risk of breast cancer risk was identified in the homozygote comparison (OR = 0.79, 95%CI = 0.65-0.97 for TT versus CC). An analysis stratified by ethnicity and source of controls revealed an obvious decrease in risk among Asian groups in all genetic models, and among population-based controls only in the homozygote comparison and recessive model. Therefore, our meta-analysis suggested that the SHMT1 C1420T polymorphism was associated with decreased risk of breast cancer. Significant protective effects were found among Asian populations, but not in Caucasian groups. Due to some minor limitations, our findings should be confirmed by further studies. PMID- 26125759 TI - Polymorphisms in a myostatin gene and associations with growth in a hybrid of Culter alburnus and Ancherythroculter nigrocauda. AB - Myostatin (MSTN) is a member of the transforming growth factor-beta superfamily that negatively regulates skeletal muscle development and growth. In the present study, partial genomic fragments of MSTN were screened for single nucleotide polymorphisms (SNPs) in a hybrid of Culter alburnus (?) x Ancherythroculter nigro cauda (?) individuals from a commercial hatchery population, and two non synonymous SNPs (c.6T>C and c.162G>A) and two synonymous SNPs (c.152G>A and c.155G>A) in exon 2 were identified. The two non-synonymous SNPs caused an amino acid change, from Ser to Pro and from Val to Ile, respectively. Genotyping by the direct sequencing of polymerase chain reaction products for these four SNPs was conducted in 190 individuals from the commercial hatchery population. Association analysis showed that one non-synonymous SNP (c.6T>C) in exon 2 was significantly associated with total length, body length, body height, head length, and body weight. Haplotype analyses revealed that the haplotype combination H1H3 exhibited the best growth performance. Our results demonstrate that some of the SNPs in MSTN may have positive effects on growth, and suggest that MSTN could be a candidate gene for marker-assisted selection in C. alburnus and A. nigrocauda. PMID- 26125760 TI - Autophagy in drug resistance of the multiple myeloma cell line RPMI8226 to doxorubicin. AB - We investigated the effect of autophagy on drug resistance of multiple myeloma (MM) to doxorubicin (DOX). A DOX-resistant MM cell line (RPMI8226/DOX) was developed by progressively increasing the DOX concentration gradient. The drug resistance index was determined using the MTT method. Transmission electron microscopy, anti-light chain 3-fluorescein isothiocyanate immunofluorescence, and Western blotting were used to detect autophagy of MM cells. Flow cytometry was applied to detect changes in apoptosis of RPMI8226/DOX cells (stained with annexin-V/propidium iodide) caused by inhibition by hydroxychloroquine and 3 methyladenine on autophagy. The drug resistance index of RPMI8226/DOX to DOX was 10.8, and autophagy/lysosomal was clearly observed in RPMI8226/DOX cells under transmission electron microscopy, while immunofluorescence showed granular immunofluorescence in cells. Western blot analysis showed that light chain 3-II protein expression level was higher in RPMI8226/DOX cells than in RPMI8226/S cells. The apoptosis test showed that hydroxychloroquine or 3-methyladenine partially reversed the drug resistance of RPMI8226/DOX cells by inhibiting autophagy. Activation of autophagy in MM cells may explain the drug resistance of myeloma. PMID- 26125761 TI - Ara-C and anti-CD47 antibody combination therapy eliminates acute monocytic leukemia THP-1 cells in vivo and in vitro. AB - Leukemia stem cells (LSCs) are regarded as the origin of leukemia and its recurrence. Side population (SP) cells possess some intrinsic stem cell properties and contain numerous LSCs. In this study, we examined the prognostic significance of cluster differentiation 47 (CD47) and identified the appropriate target for eliminating LSCs. We determined the percentage of SP cells in a THP-1 cell population and analyzed CD47 expression in different cell subsets. We then explored whether CD47 affected the phagocytic ability of macrophages to LSCs in vitro. Finally, the effect of anti-CD47 monoclonal antibodies, alone or combination with cytarabine, against leukemic cells was evaluated in vitro and in vivo to identify the optimal targets for the treatment of leukemia. We observed an SP sub-fraction at low frequency (1.81 +/- 0.99%), which was a likely candidate for LSC enrichment. CD47 was more highly expressed on THP-1 LSCs (P < 0.05) and was an independent predictor of survival and refractory disease in THP 1-engrafted mice. Furthermore, the anti-CD47 monoclonal antibody stimulated preferential phagocytosis of LSCs by macrophages in vitro. Finally, single or combination treatment of THP-1 LSC-engrafted mice with cytarabine and anti-CD47 antibody resulted in targeting of LSCs and depletion of leukemia cells. These findings suggest that CD47 is an antibody target in LSCs and combination treatment with cytarabine and anti-CD47 monoclonal antibody represents an attractive option for the therapeutic targeting of acute monocytic leukemia. PMID- 26125762 TI - Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model. AB - The intestinal microflora affects inflammation and immunity, not only locally at the mucosal level but also systemically, raising the question of whether the microflora affects inflammatory processes that contribute to cancer and its therapy. Prebiotics have also been found to play an antitumor role that is not limited to the gut. We investigated the antitumor roles of the intestinal microbiota using the Lewis lung cancer mouse model. In mice treated with cisplatin combined with ABX (an antibiotic cocktail of vancomycin, ampicillin, and neomycin), which can destroy the host commensal microflora, the tumor size was larger than in mice on a single treatment of cisplatin. Moreover, the survival rate of mice treated with cisplatin combined with ABX was significantly reduced. In contrast, mice treated with cisplatin combined with Lactobacillus bacteria had smaller tumors and an improved survival rate. Further study on gene expression indicated that ABX can partially impair the function of cisplatin by upregulating the expression of VEGFA and downregulating the expression of BAX and CDKN1B. The expression of IFN-gamma, GZMB, and PRF1 in the CD8(+) T cells of these mice was reduced by ABX, indicating an immuno-enhancement role of commensal microbiota. Conversely, Lactobacillus co-treatment mice showed an enhanced antitumor response with upregulated IFN-gamma, GZMB, and PRF1 expression. We conclude that the commensal microbiota contributes to the anti-lung cancer response and probiotics co-treatment can enhance the antigrowth and proapoptotic effects of cisplatin. PMID- 26125763 TI - Human leukocyte antigen-B27 alleles in Xinjiang Uygur patients with ankylosing spondylitis. AB - We investigated the distribution of human leukocyte antigen (HLA)-B27 subtypes in Uygur ankylosing spondylitis patients in Xinjiang. B27-positive patients with ankylosing spondylitis were subtyped by using polymerase chain reaction-sequence based typing. The HLA-B27 subtype frequencies of Uygur patients were compared with those in Han patients in Xinjiang and the other areas of China. B*2705 was the predominant subtype in Uygur patients with a frequency of 58.95%, which was much higher than that in Han patients in Xinjiang (31.58%, P < 0.05) and the other areas of China (excluding the Shandong region, which was 63.89%). The frequency of B*2704 (27.37%) in Uygur patients was the lowest and significantly lower than that in Han patients (61.18%, P < 0.05) and in 8 other areas of China. B*2710 has not been previously reported in Uygur ankylosing spondylitis patients; B*2704 was the main (61.18%) subtype in Han patients in Xinjiang, followed by B*2705 (31.58%) and was similar to the characteristics of Han patients in the other areas of China. B*2724 in Han ankylosing spondylitis patients has not been previously reported. Additionally, the B*2702/B*2705 homozygote was identified in Uygur patients. B*2702/B*2704, B*2704/B*2705, and B*2705/B*2705 homozygotes were identified in 3 Han patients. The distribution of HLAB27 subtypes in Uygur ankylosing spondylitis patients in Xinjiang significantly differed from that in Han patients. Understanding the distribution of HLAB27 subtypes in ethnic minority populations of Xinjiang is important for anthropological genetic studies and for analyzing the impact of genetic background on ankylosing spondylitis susceptibility. PMID- 26125764 TI - Genetic diversity of Ceratoides arborescens, a species endemic to China, detected by inter-simple sequence repeat (ISSR). AB - In order to investigate genetic diversity and population structure of Ceratoides arborescens, six populations were selected from different steppe types in Inner Mongolia grasslands of China. Inter-simple sequence repeat (ISSR) markers were used to assess the genetic diversity within and among natural populations of C. arborescens. Thirteen ISSR primers generated 154 discernible DNA bands, of which 151 (98.05%) were polymorphic. High genetic diversity was detected at the species level [percentage of polymorphic loci (PPB) = 98.05%; H = 0.2984; I = 0.4557], whereas, relatively low genetic diversity existed within populations (PPB = 80.62%; H = 0.2675; I = 0.4031). Analysis of molecular variance showed that variation existed mainly within populations (73.25%) rather than among populations (26.75%), which was in line with the high level of gene flow (Nm = 4.3332). The Mantel test found no significant correlation between genetic distance and geographic distance (r = 0.7522, P < 0.05). Six populations were clustered into two main groups, a desert steppe group and a typical steppe group. PMID- 26125765 TI - Development of RAPD-SCAR markers for different Ganoderma species authentication by improved RAPD amplification and molecular cloning. AB - The sequence-characterized amplified region (SCAR) is a valuable molecular technique for the genetic identification of any species. This method is mainly derived from the molecular cloning of the amplified DNA fragments achieved from the random amplified polymorphic DNA (RAPD). In this study, we collected DNA from 10 species of Ganoderma mushroom and amplified the DNA using an improved RAPD technique. The amplified fragments were then cloned into a T-vector, and positive clones were screened, indentified, and sequenced for the development of SCAR markers. After designing PCR primers and optimizing PCR conditions, 4 SCAR markers, named LZ1-4, LZ2-2, LZ8-2, and LZ9-15, were developed, which were specific to Ganoderma gibbosum (LZ1-4 and LZ8-2), Ganoderma sinense (LZ2-2 and LZ8-2), Ganoderma tropicum (LZ8-2), and Ganoderma lucidum HG (LZ9-15). These 4 novel SCAR markers were deposited into GenBank with the accession Nos. KM391935, KM391936, KM391937, and KM391938, respectively. Thus, in this study we developed specific SCAR markers for the identification and authentication of different Ganoderma species. PMID- 26125766 TI - Limitations of cytochrome oxidase I for the barcoding of Neritidae (Mollusca: Gastropoda) as revealed by Bayesian analysis. AB - The mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) gene has been universally and successfully utilized as a barcoding gene, mainly because it can be amplified easily, applied across a wide range of taxa, and results can be obtained cheaply and quickly. However, in rare cases, the gene can fail to distinguish between species, particularly when exposed to highly sensitive methods of data analysis, such as the Bayesian method, or when taxa have undergone introgressive hybridization, over-splitting, or incomplete lineage sorting. Such cases require the use of alternative markers, and nuclear DNA markers are commonly used. In this study, a dendrogram produced by Bayesian analysis of an mtDNA COI dataset was compared with that of a nuclear DNA ATPS alpha dataset, in order to evaluate the efficiency of COI in barcoding Malaysian nerites (Neritidae). In the COI dendrogram, most of the species were in individual clusters, except for two species: Nerita chamaeleon and N. histrio. These two species were placed in the same subcluster, whereas in the ATPS-alpha dendrogram they were in their own subclusters. Analysis of the ATPS-alpha gene also placed the two genera of nerites (Nerita and Neritina) in separate clusters, whereas COI gene analysis placed both genera in the same cluster. Therefore, in the case of the Neritidae, the ATPS-alpha gene is a better barcoding gene than the COI gene. PMID- 26125767 TI - Disease indicators for sepsis and analysis of sepsis treatment in children using the continuous blood purification technique. AB - We analyzed disease severity, inflammation markers, and dynamic changes in cartilage glycoprotein 39 (YKL-40) and C-reactive protein (CRP) levels in children with sepsis before and after treatment with continuous blood purification (CBP). Study participants were 30 children with severe sepsis who were cured from the disease (experimental group) in the Children's Serious Disease Center of In-ner Mongolia People's Hospital between June 2012 and October 2013. Symptomatic CBP treatment was performed after disease severity scoring. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), YKL-40, and CRP levels were tested 0, 12, 24, and 48 h after CBP treatment. YKL-40 mRNA expression in whole blood was determined biochemically, and its expression in peripheral blood was determined with an immunochemical method. We found a significant difference in disease severity scores before and 48 h after CBP treatment (P < 0.05). IL-6, TNF-alpha, YKL-40, and CRP levels in children with sepsis at 12, 24, and 48 h after CBP treatment significantly differed from those before treatment (P < 0.05). The relative expression of YKL-40 mRNA in the experimental group before CBP treatment significantly increased from that of the control group (P < 0.05). We found a positive correlation between IL-6, TNF alpha, YKL-40, and CRP levels 48 h after CBP treatment. In conclusion, CBP is an effective treatment strategy for pediatric sepsis. YKL-40 and CRP can be used to evaluate the effects of sepsis treatment. PMID- 26125768 TI - Development and characterization of microsatellite markers via cross-species amplification of Paramisgurnus dabryanus. AB - The large-scale loach, Paramisgurnus dabryanus, is a small freshwater fish of major economic importance in many Asian countries, particularly China and South Korea. Fifteen polymorphic microsatellite (simple sequence repeat) markers were obtained through cross-species amplification between this loach and a related species, Misgurnus anguillicaudatus (GenBank accession numbers: KC117456 to KC117470). The number of alleles per locus ranged from 5 to 12 among 40 individuals, and the average observed and expected heterozygosities were 0.344 and 0.828, respectively. Three loci showed significant deviations from Hardy Weinberg equilibrium. These polymorphic loci could provide a valuable tool for investigations of the population genetics, phylogeography, and conservation genetics of P. dabryanus. PMID- 26125769 TI - Value of human brain natriuretic peptide in treatment of acute anterior myocardial infarction evaluated via three-dimensional speckle tracking imaging. AB - Three-dimensional ultrasound speckle tracking imaging was used to evaluate the effects of recombinant human brain natriuretic peptide (rhBNP) in acute anterior and extensive anterior myocardial infarction. Ninety patients with acute anterior or extensive myocardial infarction were randomly divided into 3 groups: Group A [emergency percutaneous coronary intervention (PCI)], Group B (emergency PCI + rhBNP early treatment), and Group C (emergency PCI + late rhBNP treatment). Within 6 h of admission and at 1 week and 3 and 6 months after PCI, patients underwent routine transthoracic echocardiography and real-time three-dimensional echocardiography. At 1 week, 1 month, 3 months, 6 months, and 12 months, ejection fraction values in groups B and C were significantly greater than those in group A (P < 0.05), and left ventricular end-diastolic volume and left ventricular end systolic volume values in groups B and C were less than those in group A (P < 0.05). Within 6 h of admission in each group, long-axis, radial, circumferential, and area variables corresponding to anterior descending artery segments showed no significant difference (all P > 0.05). However, at 1 week, 1 month, 3 months, 6 months, and 12 months, long-axis, radial, circumferential and area variables in groups B and C were significantly less than those in group A (P < 0.05). Intervention with rhBNP can im-prove resilience of the local myocardium, left ventricular mechanical function, and cardiac remodeling. Within 6 h of admission or after PCI, rhBNP application showed no significant difference in heart function improvement or myocardial remodeling inhibition. PMID- 26125770 TI - Three branches of phospholipase C signaling pathway promote hepatocyte growth in rat liver regeneration. AB - In general, the phospholipase C (PLC) signaling pathway is involved in many physiological activities, including cell growth. However, little is known regarding how the PLC signaling pathway participates in regulating hepatocyte (HC) growth during liver regeneration (LR). To further explore the influence of the PLC signaling pathway on HCs at the cellular level, HCs of high purity and vitality were isolated using Percoll density-gradient centrifugation after partial hepatectomy. The genes of the PLC signaling pathway and target genes of transcription factors in the pathway were obtained by searching the pathways and transcription factor databases, and changes in gene expression of isolated HCs were examined using the Rat Genome 230 2.0 Microarray. The results suggested that various genes involved in the pathway (including 151 known genes and 39 homologous genes) and cell growth (including 262 known genes and 37 homologous genes) were associated with LR. Subsequently, the synergetic effect of these genes in LR was analyzed using a mathematical model (Et) according to their expression profiles. The results showed that the Et values of G protein-coupled receptor/PLC, integrin/PLC, and growth factor receptor/PLC branches of the PLC pathway were all significantly strengthened during the progression and termination phases of LR. The synergetic effect of target genes, in parallel with target gene-related cell growth, was also enhanced during whole rat LR, suggesting the potential positive effect of PLC on HC growth. The present data indicate that the PLC signaling pathway may promote HC growth through 3 mechanisms during rat LR after partial hepatectomy. PMID- 26125771 TI - Impact of caffeine on beta cell proliferation and apoptosis under the influence of palmitic acid. AB - We examined the influence of caffeine on the proliferation and apoptosis of beta cells cultured in vitro in the presence of the free fatty acid palmitic acid (PA). Different concentrations of caffeine (1-100 mM) and free fatty PA were added to cultured beta cells. The MTT assay was used to analyze cell proliferative activity; flow cytometry was used to measure apoptosis and calculate the apoptosis rate. Compared with the blank control group, cells cultured with 500 mM PA for 24, 48, 72, and 96 h showed inhibition of pancreatic beta cell proliferative activity. In the 10 and 25 mM caffeine groups cultured for 48, 72, and 96 h, beta cell proliferative activity was much higher than that in the 500 mM PA group. The apoptosis rate in the 500 mM PA group was 40.55 +/- 20.33%, which was higher than that in the blank control group. The apoptosis rates in the 10 and 25 mM caffeine group and the PA group were 19.12 +/- 10.56 and 20.97 +/- 9.75%, respectively, which was lower than that in the 500 mM PA group. At some concentrations, caffeine can improve free fatty PA levels and guide pancreatic beta cell proliferation inhibition and cell apoptosis. PMID- 26125772 TI - Screening relevant genes of tolerance to low phosphorus in maize using cDNA amplified fragment length polymorphism. AB - Soil contains a large amount of phosphorus, but plants cannot absorb most of this phosphorus effectively. Low inorganic phosphorus has been singled out as a major constraint that leads to a perpetually low Zea mays (maize) grain yield. The fundamental approach to solving this problem is to screen new genes of low phosphorous (LP) tolerance. Consequently, the exploration and utilization of LP tolerant genes are of great significance in plants. The maize inbred line 178 is an inbred LP-tolerant line. In the current study, the expression of this inbred line was induced under the stress of LP conditions. We applied cDNA-amplified fragment length polymorphism to screen LP-tolerant genes and obtained and sequenced 78 differentially expressed gene fragments. Their functions were predicted via bioinformatic analysis. There were no function annotations for 8 differentially expressed fragments. Nine genes exhibited high homology to Arabidopsis thaliana and Oryza sativa genes involved in phosphorus metabolism. This study lays a good foundation for further cloning and verification of the genes involved in phosphorus metabolism in maize. PMID- 26125773 TI - PUMA gene transfection can enhance the sensitivity of epirubicin-induced apoptosis of MCF-7 breast cancer cells. AB - We explored whether p53 upregulated modulator of apoptosis (PUMA) gene transfection could enhance the sensitivity of epirubicin-induced apoptosis of MCF 7 breast cancer cells. The liposome-mediated recombinant eukaryotic expression vector PU-MA-pCDNA3 and empty vector plasmid were stably transfected into MCF-7 cells. Epirubicin (0.01-100 MUM) was applied to MCF-7, MCF-7/PUMA, and MCF 7/pCDNA3 cells for 72 h. The MTT assay was used to calculate the cell survival rate in each group, and the 50% inhibitory concentration (IC50) was calculated. The IC50 values of epirubicin in MCF-7, MCF-7/PUMA, and MCF-7/pCDNA3 cells were 13 +/- 1.4, 1.8 +/- 0.2, and 10.7 +/- 1.3 MUM, respectively. The sensitivity of MCF-7/PUMA cells to epirubicin increased 7.2-fold. Epirubicin induced apoptosis in MCF-7 cells dose-dependently, but MCF-7/PUMA cell-induced apoptosis was more significant compared to controls. Low concentrations of epirubicin (0.1 MUM) caused low levels of apoptosis of MCF-7/pCDNA3 (1.15 +/- 0.26%) and MCF-7 cells (0.9 +/- 0.24%), but significantly induced apoptosis of MCF-7/PUMA cells (6.44 +/ 1.46%). High epirubicin concentration (1 MUM) induced apoptosis in each group, but the epirubicin MCF-7/PUMA apoptosis rate (35.47 +/- 9.36%) was significantly higher than that of MCF-7 (12.6 +/- 3.73%) and MCF-7/ pCDNA3 (15.2 +/- 5.17%) cells (P < 0 01). Flow cytometry and TUNEL assays for apoptosis detection showed similar results. PUMA protein expression in MCF-7/PUMA cells was significantly higher than that in MCF-7 and MCF-7/pCDNA3 cells by Western blot analysis. There fore, stable transfection of PUMA can significantly enhance epirubicin-induced apoptosis sensitivity of MCF-7 breast cancer cells. PMID- 26125774 TI - Molecular cloning and characterization of a novel Y-box gene from Sepiella maindroni. AB - Y-box proteins are a family of highly conserved nucleic acid binding proteins that interact with genome and transcription product to modulate the transcriptional and translational processes. In the present study, a complete mRNA of Y-box binding protein (designated SmYB) was obtained from Sepiella maindroni by amplification of flanking sequences. The full size of SmYB cDNA was 1502 bp, including 99 bp at the 5? untranslated region (UTR), a 3? UTR of 821 bp with a poly (A) tail, and an open reading frame of 582 bp, encoding a polypeptide of 193 amino acids with the predicted molecular weight of 16.48 kDa. The conserved cold-shock domain and two known RNA binding motifs identified in SmYB strongly suggested that SmYB was a new member of Y-box proteins. Quantitative real-time PCR was performed to examine the expression of SmYB mRNA in various tissues, embryos, and its temporal expression in liver after cold shock. The mRNA transcript of SmYB was detected in all examined tissues, with the highest expression level in testis and ovary. SmYB was abundant in early developmental stages of S. maindroni embryos but diminished in the late post-embryonic development. In addition, cold-shock treatment upregulated the transcription of SmYB mRNA in liver. These results demonstrated that SmYB is involved in embryonic development of S. maindroni and its tolerance to acute low temperatures. PMID- 26125775 TI - Genetic potential of common bean progenies selected for crude fiber content obtained through different breeding methods. AB - Gastrointestinal health is of great importance due to the increasing consumption of functional foods, especially those concern-ing diets rich in fiber content. The common bean has been valorized as a nutritious food due to its appreciable fiber content and the fact that it is consumed in many countries. The current study aimed to evaluate and compare the genetic potential of common bean progenies of the carioca group, developed through different breeding methods, for crude fiber content. The progenies originated through hybridization of two advanced strains, CNFC 7812 and CNFC 7829, up to the F7 generation using three breeding methods: bulk-population, bulk within F2 families, and single seed descent. Fifteen F8 progenies were evaluated in each method, as well as two check cultivars and both parents, us-ing a 7 x 7 simple lattice design, with experimental plots comprised of two 4-m long rows. Field trials were conducted in eleven environments encompassing four Brazilian states and three different sowing times during 2009 and 2010. Estimates of genetic parameters indicate differences among the breeding methods, which seem to be related to the different processes for sampling the advanced progenies inherent to each method, given that the trait in question is not subject to natural selection. Variability amongst progenies occurred within the three breeding methods and there was also a significant effect of environment on the progeny for all methods. Progenies developed by bulk population attained the highest estimates of genetic parameters, had less interaction with the environment, and greater variability. PMID- 26125776 TI - Entoepidemiology of Chagas disease in the Western region of the State of Sao Paulo from 2004 to 2008, and cytogenetic analysis in Rhodnius neglectus (Hemiptera, Triatominae). AB - To complement the epidemiological data and assist in the prophylaxis of Chagas disease in the State of Sao Paulo, we examined entomological lifting conducted in 40 municipalities of the Western region of the state from 2004 to 2008, highlighted the main vector species in this region, and reanalyzed the cytogenetic characteristics of Rhodnius neglectus from 3 different Brazilian states (Formoso/GO, Frutal/MG, Guaira/SP, and Pitangueiras/SP). The municipalities of Castilho and Santo Antonio do Acarangua registered the highest relative amounts of notifications. The main species notified in Western Sao Paulo were Triatoma sordida and R. neglectus. We collected a large number of T. sordida in 2005 and noted the absence of notification of infected insects in 2008. We observed no variation in chromosomal characteristics of R. neglectus of different states. These data are complementary to the survey presented from 1990 to 1999, as the vector species were the same (T. sordida and R. neglectus), with emphasis on T. sordida. We corroborate the future colonization domiciliary initially proposed for T. sordida in the region and underscore the importance of vector control programs in the prophylaxis of Chagas disease. Furthermore, we observed that the populations of R. neglectus in Brazil showed no intraspecific variation and we corroborated the chromosomal patterns originally described. These data are important for understanding the evolution of these hematophagous insects, which are vectors of Chagas disease. PMID- 26125777 TI - Relevance of E-cadherin expression to EGFR-TKI molecular targeted therapy sensitivity/resistance and its clinical significance. AB - We examined the effect of E-cadherin expression on epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) molecular targeted therapy sensitivity/resistance. We treated MCF-7, MDA-MB-231, T24, SiHa, H460, SK-HEP-1, MHCC97-H, and THP-1 cells with the EGFR-TKIs PD153035 and gefitinib, and then tested the drug-resistance and sensitivity using the MTT method, calculated IC50 values for each cell line, and compared the results to E-cadherin content. The MTT assay was used to determine the survival rates of MCF-7, MDA-MB-231, T24, SiHa, H460, SK-HEP-1, MHCC97-H, and THP-1 cells upon the action of EGFR-TKI (PD153035, gefitinib). For PD153035, the IC50 in MCF-7, MDA-MB-231, T24, and SiHa cells differed from that of H460, SK-HEP-1, MHCC97-H, and THP-1 (P < 0.05). Following gefitinib treatment, the IC50 values of MCF-7, MDA-MB-231, T24, and SiHa cells differed from those of H460, SK-HEP-1, MHCC97-H, and THP-1 cells (P < 0.01). The survival rate of MCF-7, MDA-MB-231, T24, and SiHa cells clearly decreased with increasing drug concentration, indicating the cells were sensitive to the drugs and that E-cadherin expression was positive; however, H460, SK-HEP 1, MHCC97-H, and THP-1 cells showed no significant decreased with increasing drug concentration, indicating that they were resistant to the drugs and that E cadherin expression was negative. The survival rate of epithelial tumor cells through the action of EGFR-TKI is related to E-cadherin expression. E-cadherin may play a significant role in the sensitivity regulation of EGFR molecular targeting treatment. E-cadherin may provide important clues for selecting proper EGFR-TKI molecular targeting treatment. PMID- 26125778 TI - Effect of Rhizoma paridis total saponins on apoptosis of colorectal cancer cells and imbalance of the JAK/STAT3 molecular pathway induced by IL-6 suppression. AB - We observed the influence of different concentrations of Rhizoma paridis total saponins (RPTS) on the apoptosis of colorectal cancer cells and explored the internal mechanism involved. We determined whether RPTS influences the interleukin-6 (IL-6)/Janus kinase (JAK)-signal transducer and activator of transcription-3 (STAT3) apoptosis molecular pathway and looked for colon cancer related signal transduction pathways or targets inducing apoptosis. We also cultured SW480 colorectal cancer cells using different concentrations of RPTS (10, 20, 40, and 80 MUg/ mL), and observed the effect of RPTS on SW480 cell morphology under a fluorescence inverted microscope. We detected serum IL-6 using the polymerase chain reaction and the expression of JAK-STAT3 protein by western blot. After treating SW480 with RPTS and Hoechst 33258 dyeing, we found that the typical apoptosis morphology had changed. Secretion of IL-6 in the serum decreased significantly (P < 0.05), and STAT3 levels were reduced. RPTS can significantly promote apoptosis in SW480 colorectal cancer cells. The mechanism may be that it suppresses the secretion of IL-6 and inhibits the IL-6/JAK-STAT3 protein signaling pathway. PMID- 26125779 TI - Correlation between ERCC1 expression and concurrent chemotherapy and radiotherapy in patients with locally advanced nasopharyngeal cancer. AB - In this study, the expression of DNA excision repair cross-complementing gene 1 (ERCC1) in local advanced nasopharyngeal carcinoma has been correlated with the efficacy of concurrent chemoradiotherapy. A total of 76 patients diagnosed with undifferentiated nasopharyngeal carcinoma diagnosed by nasopharyngeal biopsy and undergoing single-agent cisplatin chemotherapy (80 mg/m(2)) with concurrent radiotherapy (on the first, twenty-second, and forty-third day, 5 times per week, mean dose 74 Gy, range 70-78 Gy) at the Affiliated Cancer Hospital of Guangxi Medical University between January and December 2010 were included. After chemoradiotherapy, outcomes and long-term survival were evaluated. Immunohistochemistry was used to detect expression of ERCC1 protein in nasopharyngeal carcinoma. The relationship between the expression of ERCC1 and efficacy of concurrent chemoradiotherapy and long-term survival were analyzed. ERCC1 was expressed in 42.1% of cases. The expression of ERCC1 was correlated with T stage and clinical staging (P < 0.05), but not with gender, age, or N stage. The response rate in the ERCC1-positive and ERCC1-negative groups was 75.0% and 97.7%, respectively (P < 0.05). In the 72 cases with follow-up available, 1-, 2-, and 3-year survival rates were 91.0, 83.3, and 79.0%; they were 92.4, 87.8, 80.5%, respectively, in the ERCC1-positive group, and 87.9, 77.4, 77.4%, respectively, in the ERCC1-negative group. The expression of ERCC1 may be a sensitive prognostic indicator of concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma. PMID- 26125780 TI - Characterization of Ty1/copia-like retrotransposon families from pigeonpea genome. AB - Retrotransposons contribute significantly to the size, organization, and genetic diversity of their host genomes. To characterize novel retrotransposon families in pigeonpea and develop retrotransposon-based sequence-specific amplification polymorphic markers, in silico homology sequence search was carried out against the whole genome shotgun sequence of pigeonpea variety Asha (ICPL87119). For homology searching, 5 copia-like retro elements belonging to soybean, common bean, mungbean, chickpea, and field pea were used as query sequences. Contigs with at least 80% query coverage and >70% similarity were searched for retroelements using the long terminal repeat finder. A total of 28 copia-like retroelements were identified using this method. Multiple sequence alignment for the reverse transcriptase domain indicated conserved reverse transcriptase domains in all 28 elements compared with other reported elements. Phylogenetic analysis based on reverse transcriptase domains revealed 11 families. The copy number per family ranged from 1 (for B, J, and K family) to 8 (I). The sequence specific amplification polymorphic marker-based insertion site profiling for one of the retrotransposon families (G) confirmed multiple insertions of this element across the pigeonpea genome. This study showed that our in silico homology search strategy was efficient for identifying and characterizing the Ty1/copia-like retrotransposon. The results of this study are useful for developing retrotransposon-based sequence-specific amplification polymorphic markers for pigeonpea crop improvement. PMID- 26125781 TI - Predictive value of CK20 in evaluating the efficacy of treatment and prognosis after surgery for colorectal cancer. AB - Herein, correlations between expression levels of CK20 and efficacy of treatment and postoperative prognosis of colorectal cancer were evaluated to elucidate the clinical value of CK20. Postoperative follow-up was performed on 62 patients who underwent surgery for colorectal cancer between January 2010 and December 2010. Samples of tumor tissues and intraperitoneal drainage fluids were collected. Blood samples were obtained during the 2-year follow-up period. The expression of CK20 in surgical specimen, intraperitoneal drainage fluids, and postoperative serum samples was quantified by enzyme-linked immunosorbent assay, RT-PCR, and western blotting. Correlation between the levels of CK20 and postoperative outcomes was investigated by Spearman correlation analysis. In both tumor specimens and intraperitoneal drainage fluids, CK20 levels were lower in patients with earlier cancer stages than in those at later stages. During postoperative follow-up, serum negative CK20 patients had significantly higher 3-year survival rates than serum positive CK20 patients. All differences were statistically significant (P < 0.05). CK20 levels can provide clinically valuable information on the postoperative prognosis of patients with colorectal cancer. PMID- 26125782 TI - Abundance and diversity of sulfate-reducing bacteria in the sediment of the Zhou Cun drinking water reservoir in Eastern China. AB - Sulfate-reducing bacteria (SRB) play an important role in the sediments of bay areas, estuaries, and lakes. However, information regarding the genetic diversity of SRB in the sediments of drinking water reservoirs is scarce. In this study, we collected sediment samples from different sites in the Zhou Cun drinking water reservoir between April and June 2012. To explore the genetic diversity of SRB, we used the most-probable-number (MPN) method, polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE), and a cloning approach. The average content of acid-volatile sulfide at the deepest sampling site was 205.87 MUg/g sediment. This result is often associated with a large abundance of SRB in the associated sediment. The highest MPN estimate (1.15 x 10(5) cells/g sediment) was detected in May at the deepest sampling site. The PCR-DGGE fingerprints of SRB based on the dissimilatory sulfite reductase beta subunit (dsrB) gene varied according to the different sampling sites and dates. The highest abundance of SRB in the sediments was predominantly found at the deepest sampling sites, as expected from the acid-volatile sulfide content. The dominant species were Desulfobulbus sp, Desulfobacterium sp, and uncultured sulfate-reducing bacteria. Redundancy analysis revealed that organic matter and the concentrations of nitrogen and phosphorus in the sediments were significantly correlated with the diversity of SRB communities present. The results of this study provide a better understanding of the sulfate-reducing microbial species in the sediments of the Zhou Cun drinking water reservoir. PMID- 26125783 TI - Cluster analysis of Pinus taiwanensis for its ex situ conservation in China. AB - Pinus taiwanensis Hayata is one of the most famous sights in the Huangshan Scenic Resort, China, because of its strong adaptability and ability to survive; however, this endemic species is currently under threat in China. Relationships between different P. taiwanensis populations have been well-documented; however, few studies have been conducted on how to protect this rare pine. In the present study, we propose the ex situ conservation of this species using geographical information system (GIS) cluster and genetic diversity analyses. The GIS cluster method was conducted as a preliminary analysis for establishing a sampling site category based on climatic factors. Genetic diversity was analyzed using morphological and genetic traits. By combining geographical information with genetic data, we demonstrate that growing conditions, morphological traits, and the genetic make-up of the population in the Huangshan Scenic Resort were most similar to conditions on Tianmu Mountain. Therefore, we suggest that Tianmu Mountain is the best choice for the ex situ conservation of P. taiwanensis. Our results provide a molecular basis for the sustainable management, utilization, and conservation of this species in Huangshan Scenic Resort. PMID- 26125784 TI - Cyclin D1 G870A polymorphism is associated with an increased risk of multiple myeloma. AB - Cyclin D1 is an important cell cycle regulator implicated in the pathogenesis of many cancer types. In particular, translocation and overexpression of cyclin D1 are common events in multiple myeloma (MM), suggesting that it may drive the initiation and progression of this malignancy. However, the association between genetic polymorphisms of cyclin D1 and the risk for developing MM remains poorly characterized. We performed a case-control study with 67 patients with MM and 66 healthy controls in a Chinese population. The cancer-associated G870A single nucleotide polymorphism (SNP) of CCND1, the gene encoding cyclin D1, was determined by polymerase chain reaction and restriction fragment length polymorphism. We found that there was a strong association between the homozygous variant allele (GG) and MM susceptibility, with an odds ratio (OR) of 4.679 [95% confidence interval (CI): 1.081-5.647]. When further stratified analysis was performed, the increased risk was only evident in individuals over 60 years old (OR=3.297; 95%CI: 1.058-10.276). Our results suggest that the CCND1 G870A SNP may be critically involved in MM development. PMID- 26125785 TI - A case-control study on the risk factors of urinary calculus in Uyghur children in the Kashi region. AB - The incidence of urinary calculus (UC) is very high in Uyghur children in the Kashi region of Xinjiang, China, which seriously affects the growth and life quality of these children. This study was aimed at investigating the risk factors of UC in Uyghur children in Kashi region. One hundred fifteen Uyghur children (age <7 years) with UC who were treated in First People's Hospital in Kashi were enrolled in the case group. A 1:1 case-control study with a questionnaire was performed. The results showed that, among the 115 UC patients, there were more boys (71.3%) than girls (28.7%), and most cases had an onset age of 1-3 years (75.7%). A lower than primary school education in the mother, drinking unboiled water, water intake <500 mL/day, and eating too much sweets were risk factors [odds ratio (OR) = 2.385, 9.160, 3.263, and 8.945, respectively], whereas vegetable intake and exposure to summer sunshine of <2 h/day were protective factors against UC onset (OR = 0.154 and 0.344, respectively). Analysis of UC related factors in 99 cases of <3-year-old children revealed that breastfeeding was also a protective factor (OR = 0.007), whereas frequent cow's milk intake within 5 months (OR = 2.414) and frequent "panada" intake (OR = 2.529) were risk factors. The occurrence of UC in Uyghur children in the Kashi region is mainly affected by maternal educational background, quality of drinking water, water intake volume, and dietary pattern. Furthermore, geography may also have a role. PMID- 26125786 TI - Assessment of genetic diversity in lentils (Lens culinaris Medik.) based on SNPs. AB - This study is the first attempt to establish an SNP database for the purpose of estimating the genetic diversity and relatedness of Palestinian lentil genotypes. A total of 14 lentil accessions (11 local, two supplied by ICARDA, and one introduced from Italy) were investigated. By sequencing two genes, lectin and lipid transfer protein 5 (LTP5), four SNPs were detected (three in the first and one in latter gene) with average frequencies of one SNP every 228 and 578 bp, respectively. In addition, in LTP5 two single-nucleotide indels were observed in the non-coding part of the gene. Four haplotypes were identified in the lectin gene, three in LTP5. One lectin haplotype coincided with that present in GenBank belonging to two cultivated varieties, two were rather similar to this, whereas the last one turned out closer to the sequence of one wild lentil accession, indicating the existence of diversity in the Palestinian germplasm. These results, enhancing the available knowledge of lentil genetic resources in Palestine, may contribute to their conservation and utilization in breeding projects. PMID- 26125787 TI - Assessing hygienic behavior of Apis mellifera unicolor (Hymenoptera: Apidae), the endemic honey bee from Madagascar. AB - Hygienic behavior (HB) is one of the natural mechanisms of honey bee for limiting the spread of brood diseases and Varroa destructor parasitic mite. Objective of our study was to measure HB of Apis mellifera unicolor colonies (N = 403) from three geographic regions (one infested and two free of V. destructor) in Madagascar. The pin-killing method was used for evaluation of the HB. Responses were measured from 3 h 30 min to 7 h after perforation of the cells. Colonies were very effective in detecting perforated cells. In the first 4 h, on average, they detected at least 50% of the pin-killed brood. Six hours after cell perforation, colonies tested (N = 91) showed a wide range of uncapped (0 to 100%) and cleaned cells (0 to 82%). Global distribution of the rate of cleaned cells at 6 h was multimodal and hygienic responses could be split in three classes. Colonies from the three regions showed a significant difference in HB responses. Three hypotheses (geographic, genetic traits, presence of V. destructor) are further discussed to explain variability of HB responses among the regions. Levels of HB efficiency of A. mellifera unicolor colonies are among the greatest levels reported for A. mellifera subspecies. Presence of highly hygienic colonies is a great opportunity for future breeding program in selection for HB. PMID- 26125788 TI - Development of novel polymorphic microsatellite markers for the silver fox (Vulpes vulpes). AB - The silver fox (Vulpes vulpes), a coat color variant of the red fox, is one of the most important fur-bearing animals. To date, development of microsatellite loci for the silver fox has been limited and mainly based on cross-amplification by using canine SSR primers. In this study, 28 polymorphic microsatellite markers were isolated and identified for silver fox through the construction and screening of an (AC)n-enriched library. The number of alleles per locus ranged from 2 to 8 based on 48 individuals tested. The expected and observed hetero- zygosity and polymorphism information content per locus ranged from 0.2544 to 0.859, 0.2083 to 0.7917, and 0.2181 to 0.821, respectively. The polymorphic markers presented in this study may be useful for future analysis of the genetic diversity and population structure of farmed silver fox and wild red fox. PMID- 26125789 TI - Expression of hypoxia-inducible factor-1alpha during ovarian follicular growth and development in Sprague-Dawley rats. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) has been identified as a transcription factor that is involved in diverse physiological and pathological processes in the ovary. In this study, we examined whether HIF-1alpha is expressed in a cell- and stage-specific manner during follicular growth and development in the mammalian ovaries. Using immunohistochemistry and Western blot analysis, HIF-1alpha expression was observed in granulosa cells specifically and was significantly increased during the follicular growth and development of postnatal rats. Furthermore, pregnant mare serum gonadotropin also induced HIF 1alpha expression in granulosa cells and ovaries during the follicular development of immature rats primed with gonadotropin. Moreover, we also examined proliferation cell nuclear antigen, a cell proliferation marker, during follicular growth and development and found that its expression pattern was similar to that of HIF-1alpha protein. Granulosa cell culture experiments revealed that proliferation cell nuclear antigen expression may be regulated by HIF-1alpha. These results indicated that HIF-1alpha plays an important role in the follicular growth and development of these 2 rat models. The HIF-1alpha mediated signaling pathway may be an important mechanism regulating follicular growth and development in mammalian ovaries in vivo. PMID- 26125790 TI - Genomic cloning, expression, and single nucleotide polymorphism association analysis of the insulin-like androgenic gland hormone gene in the oriental river prawn (Macrobrachium nipponense). AB - Increasing evidence suggests that the insulin-like androgenic gland hormone (IAG) gene plays an important role in male sexual differentiation, metabolism, and growth in crustaceans. In the present study, we isolated the full-length genome sequence of IAG by genome walking based on the cDNA sequence in Macrobrachium nipponense. Four novel single nucleotide polymorphisms (SNPs) were studied, including 509G>T, 529G>T, 590A>T in intron 1, and 2226A>G in intron 2. The association of genetic variation with growth traits [body length (BL) and body weight (BW)] was analyzed. Individuals with GG geno- type at locus 2226A>G maintained higher mean BL (P < 0.01) and BW (P < 0.05) than AA and GA individuals. These results suggest that IAG SNPs may be useful molecular markers for selecting growth traits in M. nipponense. PMID- 26125791 TI - Association between beta1 adrenergic receptor gene Arg389Gly polymorphism and risk of heart failure: a meta-analysis. AB - Numerous studies have evaluated the association between Arg389Gly polymorphism in the beta1 adrenergic receptor gene and heart failure risk. However, the specific association is still controversial. We performed a meta-analysis of all case control studies that evaluated the association between Arg389Gly polymorphism and heart failure in humans. Studies were identified in the PubMed, Embase, and China National Knowledge Infrastructure databases. Two reviewers independently assessed the studies. Six case-control studies with a total of 1736 participants were included in the meta-analysis, including 882 cases with heart failure and 854 controls, and our results showed no association between the Arg389Gly polymorphism and heart failure [ArgArg vs GlyGly: odds ratio (OR) = 0.84, 95% confidence interval (CI) 0.59-1.20; ArgArg vs ArgGly: OR = 0.95, 95%CI 0.78-1.16; dominant model: OR = 1.08, 95%CI 0.89-1.31; recessive model: OR = 0.96, 95%CI 0.69-1.35]. No publication bias was found in the present study (all P values > 0.05). In conclusion, the beta1 adrenergic receptor gene Arg389Gly polymorphism might not be associated with heart failure risk. Further large and well-designed studies are needed to confirm this conclusion. PMID- 26125792 TI - Molecular cloning, characterization and expression analysis of a Doublesex gene from Daphnia carinata (Crustacea: Cladocera) during different reproductive stages. AB - To better understand the reproductive transformation mechanism of Daphnia carinata, a Doublesex (Dsx) gene was cloned based on rapid amplification of cDNA ends (RACE), and was designated DapcaDsx2. Next, we compared similarities and assumed homology based on deduced amino acid sequences. It showed 97.52, 87.94, and 85.11% identity to orthologous genes in D. magna, D. pulex, and D. galeata respectively. Phylogenetic analysis revealed that DapcaDsx2 clustered in the same class, and was evolutionarily more distant to sequences from other species. qRT PCR showed that DapcaDsx2 was most abundantly expressed during sexual reproduction (P < 0.05). Using digoxigenin-labeled RNA probes, we studied DapcaDsx2 expression in parthenogenetic and sexual females by whole-mount in situ hybridization. The results revealed that DapcaDsx2 was mainly expressed in the second antennae and several sites of the ventral carapace, whereas higher expression levels were found in sexual than in parthenogenetic females. This suggests that the DapcaDsx2 gene is involved in switching modes of reproduction and in sexual differentiation. PMID- 26125793 TI - DNA barcoding and phylogenetic relationships in Timaliidae. AB - The Timaliidae, a diverse family of oscine passerine birds, has long been a subject of debate regarding its phylogeny. The mitochondrial cytochrome c oxidase subunit I (COI) gene has been used as a powerful marker for identification and phylogenetic studies of animal species. In the present study, we analyzed the COI barcodes of 71 species from 21 genera belonging to the family Timaliidae. Every bird species possessed a barcode distinct from that of other bird species. Kimura two-parameter (K2P) distances were calculated between barcodes. The average genetic distance between species was 18 times higher than the average genetic distance within species. The neighbor-joining method was used to construct a phylogenetic tree and all the species could be discriminated by their distinct clades within the phylogenetic tree. The results indicate that some currently recognized babbler genera might not be monophyletic, with the COI gene data supporting the hypothesis of polyphyly for Garrulax, Alcippe, and Minla. Thus, DNA barcoding is an effective molecular tool for Timaliidae species identification and phylogenetic inference. PMID- 26125794 TI - Population structure and genetic variation of the endangered species Elaeagnus mollis Diels (Elaeagnaceae). AB - Elaeagnus mollis Diels is a group of shrubs and dwarf trees endemic to China and are endangered plants. However, the reason why these plants are endangered remains controversial. The current study aimed to explore the endangered status of E. mollis from a genetic perspective and to propose conservation strategies for this species. Using 16 polymorphic allozyme loci, the population genetic structure was investigated for three populations representing the taxa and variants. The variants exhibited relatively high levels of genetic variation compared to other woody shrubs with similar geographic distributions. The overall genetic diversity (HE = 0.352) was elevated compared to long-lived woody angiosperms. The average number of alleles per locus (A), percentage polymorphic loci (P), and observed heterozygosity (HO) were 2.0, 85.2, and 0.371, respectively. Furthermore, gene flow estimates within the population groups were also elevated. The life history and habitats of E. mollis play major roles in the levels of genetic diversity. The results of this study may help to device strategies for preserving the genetic diversity of E. mollis and for promoting planting. PMID- 26125795 TI - Genetic relationships analysis of olive cultivars grown in China. AB - The olive tree is an iconic tree of the Mediterranean, and is used extensively to produce high-quality olive oil. Although the China olive industry has just begun to be valued, there were also existed mislabeling and synonyms in introduced cultivars. The aim of this study was to analyze genetic similarities among olive cultivars in China using SSR and ISSR techniques. Thirty-two samples were collected from Xichang. Five of these cultivars were issued from a Chinese breeding program. Genomic DNA samples were extracted from young leaves and PCR was used to generate SSR and ISSR markers. A total of 107 polymorphic bands were detected on thirteen SSR loci, with an average of eight alleles per locus. The observed heterozygosity ranged from 0.785 (DCA03) to 0.990 (GAPU47), and the expected heterozygosity varied between 0.782 (DCA03) and 0.940 (GAPU103A). The discrimination power ranged from 0.57 to 0.83, while the polymorphism information content values ranged from 0.768 (DCA03) to 0.934 (GAPU103A). Nine ISSR primers generated 85 reproducible bands of which 78 (91.8%) were polymorphic. Based on our data, genetic similarity between cultivars ranged from 0.57 to 0.83. Cluster analysis revealed that 32 cultivars were clustered into six groups, which supports similar morphology such as use, oil content and fruit weight but not similar geographical origins. Our data also allow the identification of unknown cultivars and cases of synonyms. PMID- 26125796 TI - Proteomic analysis revealed the altered kidney protein profile of a Cyld knockout mouse model. AB - The aim of this study was to compare the proteomics pattern of the kidneys from Cyld knockout mice with that from normal mouse kidneys and establish a preliminary understanding of the role of Cyld in the kidney. Proteins from the kidneys of knockout Cyld mice and wild-type mice were extracted, isobaric tags for relative and absolute quantitation (iTRAQ) was performed, and the proteomics patterns of the two groups were compared. The genotypes of the mice were verified by polymerase chain reaction. A total of 1748 proteins with a local false discovery rate of <=5% were identified, among which 1437 proteins were reliably recognized and quantified. The expression of two dysregulated proteins was confirmed by Western blotting. Gene ontology and pathway analyses indicated that the proteins identified were involved in biological processes, cell components, and molecular functions, and participated in different pathways. Some of the proteins identified were relevant to renal function or kidney diseases. The difference between the proteomics profiles of kidneys from Cyld knockout mice and wild-type mice was prominent, which correlates to kidney dysfunction and the development of renal diseases. PMID- 26125797 TI - Effect of leukocyte filtration on the P-selectin expression of apheresis platelets. AB - The aim of this study was to investigate the effect of leukocyte filtration on the P-selectin (CD62P) surface expression of apheresis platelets during the retention period. Ten bags of apheresis platelets stored for 1 day (0-24 h) and 10 bags of apheresis platelets stored for 2 days (24-48 h) were used for leukocyte filtration (experimental group). Ten bags of apheresis platelets with the corresponding retention periods but without filtration were used as a negative control (control group). Thereafter, 100 MUL of platelet suspensions from apheresis platelets with or without leukocyte filtration were sampled before and after leukocyte filtration for the detection of CD62P surface expression by flow cytometry. No statistical difference in the CD62P surface expression of apheresis platelets was observed before and after leukocyte filtration (P > 0.05), neither did the CD62P surface expression exhibit any change among the different retention periods. Leukocyte filtration does not affect the CD62P surface expression of apheresis platelets stored for up to 2 days, which indicates that leukocyte filtration does not damage the activation of apheresis platelets within the retention period. PMID- 26125798 TI - Genetic polymorphisms in the carbonic anhydrase VI gene and dental caries susceptibility. AB - We investigated the role of 7 single nucleotide polymorphisms in the carbonic anhydrase (CA) VI gene (rs2274328, rs17032907, rs11576766, rs2274333, rs10864376, rs3765964, and rs6680186) and the possible association between these polymorphisms and dental caries susceptibility in a Northwestern Chinese population. We collected samples from 164 high caries experience and 191 very low caries experience and conducted a case-control study according to the number of decayed, missing, and filled teeth index and genotyped the 7 polymorphisms using a 384-well plate format with the Sequenom MassARRAY platform. Individuals carrying the rs17032907 TT genotype were more likely to have an increased risk of dental caries compared with carriers of the C/C genotype in the co-dominant model, with an odds ratio (95% confidence interval) of 2.144 (1.096-4.195). We also found that the haplotype (ACA) (rs2274328, rs17032907 and rs11576766) was associated with a low number of decayed, missing, and filled teeth index with an odds ratio (95% confidence interval) of 0.635 (0.440-0.918). However, we found no association between dental caries susceptibility and the rs2274328, rs11576766, rs2274333, rs10864376, rs3765964, and rs6680186 polymorphisms and other haplotypes. The rs17032907 genetic variant and the haplotype (ACA) of CA VI may be associated with dental caries susceptibility. PMID- 26125799 TI - Proapoptotic effects of heme oxygenase-1 inhibitor on Kasumi-1 cells via the ATF4/CHOP/Ire-1alpha pathway. AB - We evaluated the effects of down-regulated heme oxygenase (HO)-1 expression on the proliferation of the acute myelocytic leukemia Kasumi-1 cell line by using the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) in combination with daunorubicin (DNR), and evaluated the mechanism. The proliferation rates of cells treated with 10 mg/mL DNR and 10 mM ZnPPIX individually or in combination for different time periods were detected using the MTT assay. The apoptotic outcomes of the blank control, ZnPPIX, DNR, and ZnPPIX groups in combination with the DNR group were detected by flow cytometry. The expression of HO-1, activating transcription factor 4, CCAAT-enhancer-binding protein homologous protein, and inositol-requiring enzyme-alpha mRNA and proteins were detected by fluorescent quantitative real-time polymerase chain reaction and western blotting, respectively. Combined administration inhibited the cells most potently and time dependently, decreased the expression of HO-1, and significantly increased the expression of activating transcription factor 4, CCAAT-enhancer-binding protein homologous protein, and inositol-requiring enzyme-alpha expression levels. The cell apoptotic rates in the blank control, DNR, ZnPPIX, and combined administration groups were 8.32 +/- 0.53, 39.16 +/- 1.46, 10.46 +/- 0.88, and 56.26 +/- 2.24%, respectively. Inhibiting HO-1 expression can enhance the damaging effects of DNR on Kasumi-1 cells, providing experimental evidence for the improvement of therapeutic effects on acute myelocytic leukemia in clinical practice. PMID- 26125800 TI - Molecular cloning and bioinformatic analysis of the Streptococcus agalactiae neuA gene isolated from tilapia. AB - Cytidine monophosphate (CMP) N-acetylneuraminic acid (NeuNAc) synthetase, which is encoded by the neuA gene, can catalyze the activation of sialic acid with CMP, and plays an important role in Streptococcus agalactiae infection pathogenesis. To study the structure and function of the S. agalactiae neuA gene, we isolated it from diseased tilapia, amplified it using polymerase chain reaction (PCR) with specific primers, and cloned it into a pMD19-T vector. The recombinant plasmid was confirmed by PCR and restriction enzyme digestion, and identified by sequencing. Molecular characterization analyses of the neuA nucleotide amino acid sequence were performed using bioinformatic tools and an online server. The results showed that the neuA nucleotide sequence contained a complete coding region, which comprised 1242 bp, encoding 413 amino acids (aa). The aa sequence was highly conserved and contained a Glyco_tranf_GTA_type superfamily and an SGNH_hydrolase superfamily conserved domain, which are related to sialic acid activation catalysis. The NeuA protein possessed many important sites related to post-translational modification, including 28 potential phosphorylation sites and 2 potential N-glycosylation sites, had no signal peptides or transmembrane regions, and was predicted to reside in the cytoplasm. Moreover, the protein had some B-cell epitopes, which suggests its potential in development of a vaccine against S. agalactiae infection. The codon usage frequency of neuA differed greatly in Escherichia coli and Homo sapiens genes, and neuA may be more efficiently expressed in eukaryotes (yeast). S. agalactiae neuA from tilapia maintains high structural homology and sequence identity with CMP-NeuNAc synthetases from other bacteria. PMID- 26125801 TI - Effect of Xin Mai Jia on atherosclerosis in rats. AB - We investigated the therapeutic effect of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rats. Rat models of AS were established by peritoneally injecting vitamin D, feeding a high-fat diet, and inducing balloon injuries in rats. The stomachs of the rats were irrigated continuously for 10 weeks with XMJ. Blood lipid- and hemorheology-related indices of blood samples were detected. Pathological changes in the right common carotid arterial tissues were also determined. The protein expression levels of endothelial nitric oxide synthase, angio-tensin-1, and endothelin-1 were determined by western blotting. XMJ reduced cholesterol, trigylecride, and low-density lipoprotein levels as well as blood viscosity, sedimentation, and hematocrit. Furthermore, XMJ alleviated vascular endothelial injury and reduced/eliminated atherosclerotic plaques. In contrast, XMJ significantly increased the endothelium-dependent relaxing response of the AS rat models. The western blotting results showed that XMJ upregulated endothelial nitric oxide synthase but downregulated angiotensin-1 and endothelin-1. XMJ prevented the development of AS by regulating blood lipid levels, hemorheology, and vascular function. PMID- 26125802 TI - Integrated miRNA-mRNA analysis of Epstein-Barr virus-positive nasopharyngeal carcinoma. AB - This study aims to identify the crucial miRNAs in Epstein-Barr virus-positive nasopharyngeal carcinoma (NPC) and their target genes. Gene expression profile data (GSE12452) that included 31 NPC and 10 normal nasopharyngeal tissue specimens were downloaded. Differentially expressed genes (DEGs) were identified using significance analysis of microarrays. The underlying function of DEGs was predicted via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. The miRNA sequencing dataset GSE14738 was also downloaded, and expression levels of miRNA were calculated by the number of reads mapped to each miRNA. The selected miRNAs were integrated into the miRecords database to obtain their target genes. Target genes associated with DEGs were used to construct the interaction network via Cytoscape. A total of 1437 DEGs between NPC and control were identified, most of which were enriched in cell cycle and extracellular matrix-receptor interaction signaling pathways. Furthermore, 112 miRNAs were considered upregulated in NPC samples. A total of 2228 relationships between 39 miRNAs and 1247 target genes were obtained, of which 182 relationships between 32 miRNAs and 97 target genes were chosen to construct an interaction network. The interactions between DEGs and the let-7 or miR-29 families appeared strongest in this network, where CDC25A, COL3A1, and COL1A1 were regulated by several let-7 family members, while COL4A1 and COL5A2 were regulated by several miR-29 family members. The let-7 and miR-29 families may be related to the development of NPC by regulating the genes involved in cell cycle and ECM receptor interaction. PMID- 26125803 TI - Polymorphisms in different EST-SSR types derived from the Chinese bayberry Myrica rubra, Myricaceae) transcriptome. AB - Most plant expressed sequence tag-simple sequence repeats (EST-SSRs) are not polymorphic, and it is important to learn the characteristics of highly polymorphic EST-SSRs. In this study, 357 compound and 5557 non-compound EST-SSRs, identified from the transcriptome of the Chinese bayberry (Myrica rubra 'Biqi'), were divided into 11 types based on their characteristics. Polymorphisms in all 11 EST-SSR types were investigated in 10 cultivars. The percentages of polymorphic loci ranged from 12.9 to 87.5%, with 2-ntL having the highest, followed by 3-ntL, Compound B, and Compound A. The number of alleles and the polymorphic information content of 2-ntL and Compound B were the highest, followed by 2-ntM and Compound A. Therefore, we recommend that 2-ntL, Compound B, and Compound A EST-SSRs should be preferentially selected for the screening of polymorphic EST-SSRs in the Chinese bayberry. Our results should facilitate genetic and breeding studies of this species, and provide a reference for similar study in other plant species. PMID- 26125804 TI - Correlation analysis between single nucleotide polymorphism of DRD1 gene and stereotyped behavior of blue fox. AB - This study was performed to investigate the correlation between stereotyped behavior of the blue fox and single nucleotide polymorphisms (SNPs) of the DRD1 gene. We choose the DRD1 gene as a major gene for investigating the correlation of gene polymorphism and self-biting disease by means of direct sequencing. Part of the DRD1 gene exon of the blue fox was cloned; the length of the whole sequence was 864 bp. Four SNPs were detected and analyzed by the chi-square analysis; the results showed that the gene polymorphism of T206C in the DRD1 gene had a significant correlation with self-biting (P < 0.01). Therefore, marker assistant selection on self-biting of blue foxes using these SNPs can be applied to select healthy individuals. PMID- 26125805 TI - Association between polymorphisms in exons 4 and 10 of the BPI gene and immune indices in Sutai pigs. AB - The bactericidal/permeability-increasing protein (BPI) gene has been identified as a candidate gene for disease-resistance breeding. We evaluated whether polymorphisms in exons 4 and 10 of the BPI gene are associated with immune indices [interleukin-2 (IL-2), IL-4, IL-6, interferon-b (IFN-b), IL-10, and IL 12]. In this study, we identified one mutation (C522T) in the BPI exon 4 site and two mutations (A1060G and T1151G) in the BPI exon 10 site. Correlation analysis revealed that in the Sutai pig population, the effect of genotypes at the BPI exon 4 site on the level of IL-6 was significant (P < 0.05), with an effective genotype of CD; moreover, the effect of genotypes at the BPI exon 10 site on the level of IL-12 was significant (P < 0.05), and the effective genotype was AB. The optimal combined genotype was CD-AB, which was more effective regarding the IL-6 and IL-12 levels compared to the other combined genotypes (P < 0.05). These results indicate that single nucleotide polymorphisms and the combined genotypes of BPI exons 4 and 10 affect immune indices in Sutai pigs. Therefore, these genotypes should be further examined as effective markers for disease-resistant breeding of pigs. PMID- 26125806 TI - Comparison between meat quality of Hanzhong White pigs and carcass weight. AB - A total of 48 carcasses of crossbred Hanzhong White pigs were divided into 3 groups (I, 90-99 kg; II, 100-109 kg; III, 110-119 kg) to investigate the influence of carcass weight on meat quality. The intramuscular fat content of the 3 groups increased from 1.90 to 4.90%; for meat color, Warner-Bratzler shear force, drip loss, and oxidation-type muscle fiber percentage, and muscle fiber diameter of the longissimus lumborum, the indices in group II and group III were better than those in group I (P < 0.05). The saturated fatty acid and polyunsaturated fatty acid percentages of the longissimus lumborum muscle (2.80 and 37.30%, respectively) in group II were significantly lower than those in the other 2 groups, while the monounsaturated fatty acid percentage was the highest (59.10%). In conclusion, our results suggest that a carcass weight of 100-109 kg is sufficient to produce acceptable meat quality of Hanzhong White pigs. PMID- 26125807 TI - Impact of enteral nutrition on postoperative immune function and nutritional status. AB - We studied the effects of enteral nutrition (EN) support initiated 1 week before surgery on postoperative nutritional status, immune function, and inflammatory response in gastric cancer patients. A total of 200 gastric cancer patients were randomly divided into two groups: EN starting 1 week before surgery (study group) and EN starting early after surgery (control group). The two groups received EN support, following different therapeutic schedules, until the 9th day after operation. In the patients, body weight, skinfold thickness, upper-arm circumference, white blood cell count, albumin, prealbumin, C-reactive protein, peripheral immunoglobulins (IgA, IgG, and IgM), T lymphocyte subsets, interleukin 6, and tumor necrosis factor-alpha were measured 10 days before and after surgery and on the first day after surgery. There was no statistically significant difference in the results of recovery time of passage of gas by anus, abdominal distension, stomachache, blood glucose, hepatic and renal functions, and electrolytes between the two groups of patients (P > 0. 05). Adverse reactions occurred to both groups at 1 and 2 days after operation. Such conditions was improved after the intravenous drip rate was adjusted. The albumin and prealbumin levels of the patients in both groups decreased at 1 day after operation (P < 0. 05). The levels rose when the research was finished (P < 0. 05). The prealbumin level of the study group was higher than that of the control group at 10 days after operation (P < 0. 05). The IgG level of the study group was higher than that of the control group at 10 days after operation (P < 0. 05). The two groups of inflammatory reaction indicators of the study group were lower than those of the control group at 10 days after operation (P < 0. 05). This study indicates that appropriate preoperative EN support for gastric cancer patients can improve their postoperative nutritional status and immune function, can reduce inflammatory response, and is more conducive to the recovery of patients. PMID- 26125808 TI - Characterization and expression analysis of Toll-like receptor 3 cDNA from Atlantic salmon (Salmo salar). AB - Innate pathway activation is fundamental for early anti-viral defense in fish, but currently there is insufficient understanding of how salmonid fish identify viral molecules and activate these pathways. The Toll-like receptor (TLR) is believed to play a crucial role in host defense of pathogenic microbes in the innate immune system. In the present study, the full-length cDNA of Salmo salar TLR3 (ssTLR3) was cloned. The ssTLR3 cDNA sequence was 6071 bp long, containing an open reading frame of 2754 bp and encoding 971 amino acids. The TLR group motifs, such as leucine-rich repeat (LRR) domains and Toll-interleukin-1 receptor (TIR) domains, were maintained in ssTLR3, with sixteen LRR domains and one TIR domain. In contrast to descriptions of the TLR3 in rainbow trout and the murine (TATA-less), we found a putative TATA box in the proximal promoter region 29 bp upstream of the transcription start point of ssTLR3. Multiple-sequence alignment analysis of the ssTLR3 protein-coding sequence with other known TLR3 sequences showed the sequence to be conserved among all species analyzed, implying that the function of the TLR3 had been sustained throughout evolution. The ssTLR3 mRNA expression patterns were measured using real-time PCR. The results revealed that TLR3 is widely expressed in various healthy tissues. Individuals challenged with infectious pancreatic necrosis virus and immunostimulated with polyinosinic:polycytidylic acid exhibited increased expression of TLR3 at the mRNA level, indicating that ssTLR3 may be involved in pathogen recognition in the early innate immune system. PMID- 26125809 TI - A cultured endophyte community is associated with the plant Clerodendrum inerme and antifungal activity. AB - Fungal endophytes live in the inner tissues of Clerodendrum inerme and may be significant resources for new chemicals in drug discovery. A total of 242 endophytic fungi were recovered from 602 sample segments of C. inerme; 66 were purified. The 66 fungi belonging to 16 taxa and 11 genera (Alternaria, Nigrospora, Bartalinia, Pestalotiopsis, Fusarium, Mycoleptodiscus, Trichoderma, Phomopsis, Diaporthe, Lasiodiplodia, and Curvularia) were identified by morphological characteristics and fungal internal transcribed spacer sequences. The most abundant genera were Alternaria and Lasiodiplodia. Some of the endophytes exhibited tissue specificity. The colonization frequencies of endophytes in the stems were evidently higher than those in the roots and leaves. The crude ethyl acetate extracts were tested against 6 endophytes isolated from C. inerme. Three of 10 (33.3%) endophytes, which were identified as Phomopsis sp, Curvularia sp, and Mycoleptodiscus sp, displayed distinct antifungal activity against >=3 tested fungi. To our knowledge, this is the first report of an endophytic community associated with C. inerme in China and its antifungal activity in vitro. PMID- 26125810 TI - BORIS and CTCF are overexpressed in squamous intraepithelial lesions and cervical cancer. AB - We investigated the expression of Brother of Regulator of Imprinted Sites (BORIS) and CCCTC-binding factor (CTCF) in squamous intraepithelial lesions and cervical cancer. To analyze BORIS and CTCF expression, an endocervical cytobrush sample was taken for total RNA isolation. CTCF and BORIS mRNA was quantified from total RNA using quantitative reverse transcription-polymerase chain reaction. A total of 71 samples were collected and classified according to the Bethesda Classification of squamous intraepithelial lesions. BORIS expression was observed in 9 (12.7%) samples; of these, 5.3, 5.9, 14.8, and 37.5% in the groups that were cytology negative for intraepithelial lesion or malignancy, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical carcinoma, respectively. The expression level of BORIS was significantly higher in the group with invasive cervical carcinoma as compared with the groups negative for intraepithelial lesion or malignancy, LSIL, and HSIL (P < 0.0005). CTCF mRNA was expressed in all samples. CTCF expression was significantly higher in carcinoma groups compared with LSIL, HSIL, and negative for intraepithelial lesion or malignancy groups. We found that BORIS and CTCF expressions in the LSIL and invasive cervical carcinoma groups were higher than expression in cytological normal samples. Additional studies should be conducted to examine the function of transcription factors during different stages of the transformation of cervical cancer cells. PMID- 26125811 TI - Analysis of quantitative trait loci for main plant traits in soybean. AB - Plant traits are important indices for regulating and controlling yield ability in soybean varieties. It is important to comprehensively study the quantitative trait locus (QTL) mapping for soybean plant traits, cloning related genes, and marker assistant breeding. In this study, 236 F2 generation plants and a derivative group were constructed by using Jiyu50 and Jinong18, obtained from Jilin Province. A total of 102 simple sequence repeat markers were used to construct a genetic linkage map. With 2 years of molecular and phenotypic data, QTL analyses and mapping were conducted for soybean maturity, plant height, main stem node, main stem branch, seed weight per plant, and more. Five main plant traits were analyzed via inclusive composite interval mapping using QTL IciMapping v2.2. Using one-dimensional scanning, a total of 30 QTLs were detected and distributed across 1 (A1), 4 (C2), and 12 (G). There were 9 linkage groups, including 16 major QTLs. Using two-dimensional scanning, 7 pairs of epistatic QTL interactions for maturity and plant height were detected in the soybean. PMID- 26125812 TI - Association analysis between SNPs in the 5'-flanking region of the chicken GRP78 gene, thermotolerance parameters, and tissue mRNA expression. AB - Glucose-regulated protein 78 (GRP78) is a molecular chaperone in the endoplasmic reticulum and can be induced by different kinds of environmental and physiological stress. Thus far, the role of the GRP78 gene in thermotolerance in chickens has not been investigated. In the present study, we detected sequence variations in the 5?-flanking region of the GRP78 gene and evaluated several thermotolerance parameters, such as T3, corticosterone, H/L ratio, and levels of CD3(+), CD4(+), and CD8(+) T cells, to further determine its associations at 35 degrees and 15 degrees C. The sequencing results revealed 10 SNPs in the 5' flanking region of the GRP78 gene, and seven mutations were chosen for further genotyping in a White Recessive Rock (WRR) chicken population. The SNP C.-744C>G in WRR chickens was significantly correlated with heat tolerance parameters under both conditions; it may therefore exert a potential hereditary effect on heat tolerance, and the genotype GG may be advantageous for thermotolerance. The heart, liver, brain, and leg muscle tissues of 8-day-old WRR chickens were sampled from heat stress groups, which were defined by exposure to 1, 2, 3, and 6 h of persistent thermal stress, and a control group, which was not exposed to thermal stress. Quantitative real-time polymerase chain reaction assay indicated that the mRNA expression level of the GRP78 gene increased gradually under heat stress, peaked at 3 h, and then decreased. We conclude that the mRNA expression of the GRP78 gene is time- and tissue-dependent. PMID- 26125813 TI - Genetic variation detected by RAPD markers in natural populations of babassu palm (Attalea speciosa Mart.). AB - The purpose of this study was to analyze the effects of management on the genetic structure of natural populations of Attalea speciosa in the State of Piaui, Brazil, using random-amplified polymorphic DNA (RAPD) markers. Three babassu populations under different management systems were selected. Polymerase chain reactions were performed for 20 RAPD primers. A total of 146 bands were generated, 141 of which were polymorphic (96.58%), with a variation of 4 and 12 loci and an average of 7 bands per primer. A dendrogram revealed a clear separation between the three populations (0.57). Data reliability and node consistency were verified by bootstrap values and the cophenetic correlation coefficient (88.15%). Coefficients of similarity between pairs of genotypes ranged from 0.26 to 0.86, with a mean of 0.57. Nei's genetic diversity index (HE) value of the population sampled in Teresina was 0.212, of Esperantina it was 0.195, and of Jose de Freitas it was 0.207. After the HE was decomposed, the complete diversity was found to be 0.3213. Genetic differentiation between populations was 0.362, and the estimation of gene flow between populations was low (0.879). Analysis of molecular variance revealed that 59.52% of the variation was contained within populations, and 40.48% was between populations. RAPD markers were effective for genetic diversity analysis within and between natural babassu populations, and exhibited a high level of polymorphism. Genetic diversity was the highest within populations; variability was lower in the managed populations than in the undisturbed populations. PMID- 26125814 TI - Association between TNFSF4 tagSNPs and myocardial infarction in a Chinese Han population. AB - Tumor necrosis factor superfamily member 4 (TNFSF4) plays an important role in atherosclerosis development. However, the biological significance of TNFSF4 variants on myocardial infarction (MI) pathogenesis remains poorly understood. We investigated the influence of 5 TNFSF4 tagging single nucleotide polymorphisms (rs3861950, rs17346501, rs7518045, rs1234313, and rs3850641) on individual susceptibility to MI in a Chinese population of 285 MI patients and 645 controls. Genotyping was performed using the polymerase chain reaction-ligase detection reaction method. In multivariate logistic regression analysis, only the TNFSF4 tagging single nucleotide polymorphism rs7518045 exhibited a significant effect on MI risk; A allele (odds ratio = 0.68, 95% confidence interval = 0.46-1.00, P = 0.048) and AA genotype (odds ratio = 0.64, 95% confidence interval = 0.42-0.97, P = 0.036) were associated with a decreased risk of MI compared with the G allele and the combined AG/GG genotype, respectively. Moreover, the haplotype rs3861950C rs17346501C-rs7518045A-rs1234313G containing the rs7518045 A allele also exhibited a significant association with a decreased risk for MI (odds ratio = 0.42, 95% confidence interval = 0.21-0.84, P = 0.011). Our study showed that the A allele of the rs7518045 and haplotype rs3861950C-rs17346501C-rs7518045A rs1234313G in the TNFSF4 gene were associated with decreased MI risk in a Chinese Han population. Further studies using larger sample sizes and in diverse ethnic populations are needed to confirm the general validity of our findings. PMID- 26125815 TI - Application of vacuum-assisted closure in seawater-immersed wound treatment under different negative pressures. AB - The therapeutic effect of vacuum-assisted closure (VAC) has been confirmed in many types of complex wounds, but there are few relevant reports regarding seawater-immersed wounds. The aim of this study was to determine the effect of VAC on seawater-immersed wound healing under different negative pressures and explore the optimal negative pressure value. Four purebred miniature pigs were used as the experimental animal models. Four acute, symmetrical wounds were made on each side of the spine and designated as the experimental group (wounds with 2 h of seawater immersion) and the control group (wounds without seawater immersion). Wounds were divided into a conventional dressing group and 3 further groups with different VAC therapies (negative pressure at either 120, 180, or 240 mmHg). The extent of wound healing, and speed of granulation growth and re epithelialization were measured. Bacterial flora distribution in the wounds was observed, and fibronectin levels in the exudate of the wounds were tested. Results showed that seawater immersion aggravated wound injury and that VAC therapy with 180 mmHg negative pressure induced the fastest epidermis migration, obvious edema elimination, significant capillary proliferation, and the highest level of fibronectin, and that in wounds, the proportion of Gram-negative bacteria tended to decrease and that of Gram-positive bacteria tended to increase. Our results show that VAC promotes seawater-immersed wound healing and that 180 mmHg negative pressure may be optimal for wound healing. PMID- 26125816 TI - Vitamin D receptor FokI gene polymorphism and tuberculosis susceptibility: a meta analysis. AB - Numerous studies have evaluated the association between FokI polymorphisms in the vitamin D receptor (VDR) gene and tuberculosis risk. However, the specific association remains controversial. In this study, we performed a meta-analysis to assess the association between the VDR gene FokI polymorphism and tuberculosis. Published studies from the PubMed and Embase databases were retrieved. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effect models. Overall, a significant association was found between FokI polymorphism and tuberculosis risk when all studies were pooled (ff vs FF: OR = 1.36, 95%CI = 1.11-1.66; ff vs Ff: OR = 1.38, 95%CI = 1.14-1.67; dominant model: OR = 0.73, 95%CI = 0.61-0.88). In subgroup analysis by race, a significant association between FokI polymorphism and tuberculosis risk was observed in Asians (ff vs FF: OR = 1.71, 95%CI = 1.02-2.85; ff vs Ff: OR = 1.86, 95%CI = 1.40 2.47; dominant model: OR = 0.55, 95%CI = 0.42-0.72), and no significant association was observed among Caucasians and Africans. In conclusion, the FokI polymorphism in the VDR gene may be related to an increased risk of tuberculosis in Asians. Further large and well-designed studies are needed to confirm these conclusions. PMID- 26125817 TI - Mutation analyses and prenatal diagnosis in families of X-linked severe combined immunodeficiency caused by IL2Rgamma gene novel mutation. AB - We investigated the feasibility of interleukin-2 receptor gamma (IL2Rgamma) gene based on gene mutation analysis and pre-natal diagnosis of X-linked severe combined immunodeficiency (X-SCID). Blood samples of patients and their parents of X-SCID (family 1) and X-SCID (family 2) were collected. IL2Rgamma gene sequences of the 2 families were analyzed using bi-directional direct sequencing by polymerase chain reaction. DNA sequence changes in the IL2Rgamma gene exon region and shear zone were also analyzed. We also sequenced the IL2Rgamma gene in 100 healthy individuals. Prenatal genetic diagnoses for a high-risk fetus in family 1 were performed by chorionic villus sampling after determining each family's genotypes. The suspect fe-male in family 1 underwent carrier detection. Two novel mutations of IL2Rgamma gene were identified, including c.361-363delGAG (p.E121del) in the patient and his mother in family 1, and c.510-511insGAACT (p.W173X) heterozygous mutation in the proband's mother in family 2. These mutations were absent in the 100 controls. Prenatal diagnosis of early pregnancy in the female fetus of family 1 was performed; the fetus was heterozygous, which was confirmed at postnatal follow-up. The suspect female in family 1 showed no mutation in carrier detection. The novel p.E121del and p.W173X mutations in IL2Rgamma may have been the primary causes of disease in 2 families with X-SCID. In couples with an X-SCID reproductive history, prenatal gene mutation analysis of IL2Rgamma can effectively prevent the birth of children with X-SCID and carrier detection for suspected females. PMID- 26125818 TI - Analysis of the GSTM1-null polymorphism in patients with pterygium from Goiania, Goias Brazil. AB - The first reports about pterygium date back to Hippocrates, and this disease still threatens vision health around the world. Pterygium is a formation of fibrous tissue consisting of highly vascularized epithelial and subepithelial tissue that grows excessively and with an abnormal shape on the cornea. Many physical and biological factors are associated with the pathogenesis of pterygium, including heat, dust, and other particles in the atmosphere, and immunological mechanisms, mechanisms involving extracellular matrix reorganization, growth factors, cytokines, apoptosis, and angiogenesis. The aim of this study was to further investigate the association between polymorphisms in GSTM1 and the formation of pterygium. We collected peripheral blood samples from 90 patients diagnosed with pterygium and from 23 subjects with-out the disease in order to perform molecular analysis of the GSTM1 gene. Subjects with one or two copies of the GSTM1 allele had a normal genotype while those without any copies of the allele had a null geno-type. The chi-square test or the Fisher exact test was performed in order to investigate possible associations between the molecular analysis and the risk of pterygium. A significant difference between the frequency of the GSTM1-null genotype in patient and control groups was identified. However, sub-group analysis found that the GSTM1-null genotype was statistically significant in men, but not in women, and in Caucasians, but not in Brown or Black groups. Furthermore, the GSTM1-null geno-type was not related to any of the risk factors analyzed: cases in family, occupational exposure, smoking, hypertension, and diabetes. PMID- 26125819 TI - Pterygium in patients from Goiania, Goias, Brazil. AB - Pterygium is an inflammatory and degenerative ocular surface disease in which the conjunctiva on the cornea grows to form a fibrous tissue in the shape of a triangle. The disorder may be characterized by cell proliferation, inflammatory processes, fibrosis, angiogenesis, and destruction of the extracellular matrix. The anomaly is considered a degenerative eye disease and is erroneously confused with cataract. It displays similar features to those of tumors, such as local invasion, metaplasia of epithelial cells, presence of oncogenic viruses (human papilloma virus), inactivation of tumor suppressor genes (e.g., p53), and loss of heterozygosity. The treatment of pterygium is based on factors such as the evolution and progression of the disease, risk factors, symptoms, and patient age. Considerations about the best technique for the surgical removal of pterygium remain controversial, and complications and recurrence are very common. The development of new surgical techniques and adjuvant drugs is thus necessary. This study aims to analyze and compare the frequency of the GSTT1 genotypes in relation to pterygium through statistical analyzes in order to build a genotypic profile for the Replicon patients. The genotypic profile of the GSTT1-null polymorphism in Goiania showed no significant difference when the frequency of the null genotype was compared between the control and experimental groups. The null genotype was more frequent in the population studied. Furthermore, the GSTT1 genotype was not related to the analyzed risk factors for pterygium, namely gender, ethnicity, family history, occupational exposure, smoking, hypertension, and diabetes. PMID- 26125820 TI - De novo assembly and characterization of the root transcriptome and development of simple sequence repeat markers in Paphiopedilum concolor. AB - Paphiopedilum orchids (Orchidaceae) have attracted much attention from botanists and horticulturists because of their peculiar leaves and beautiful flowers. Furthermore, the dry roots of Paphiopedilum plants have well-known medicinal uses. However, it is unknown how sensitive and plastic the root genes are to environmental changes or how these environmental changes regulate the biosynthesis of active ingredients. In this study, we chose Paphiopedilum concolor for root sequencing, as it is widely used as a parent in breeding experiments. A total of 3.77 Gb of sequence data were generated by Illumina paired-end sequencing. De novo assemblies yielded 72,952 contigs, 67,434 scaffolds, 64,304 unigenes with average lengths of 937, 1022, and 1047 bp, respectively. Based on Basic Local Alignment Search Tool with known protein sequences, 40,815 (63.5%) unigenes were annotated with an E-value cutoff of 1.0E 5. Among the unigenes, 24,605 were classified in the Gene Ontology database, 17,361 were assigned to Cluster of Orthologous Groups, and 14,170 were annotated in Kyoto Encyclopedia of Genes and Genomes. Among these annotations, over 1195 unigenes related to secondary metabolic pathways, as well as 609 unigenes involved in plant hormone synthesis and signal transduction, were identified. In addition, 5322 potential simple sequence repeats (SSRs) were identified, and 4989 primer pairs for 3975 sequences containing SSRs were obtained. This study provides valuable insights into the mechanisms of genes that regulate root growth and development and provides a comprehensive resource for genes related to secondary metabolism in roots and for marker-assisted studies in Paphiopedilum. PMID- 26125821 TI - Protective effects of hydrogen-rich medium on lipopolysaccharide-induced monocytic adhesion and vascular endothelial permeability through regulation of vascular endothelial cadherin. AB - We observed the effect of hydrogen-rich medium on lipopolysaccharide (LPS) induced human umbilical vein endothelial cells (HUVECs), hyaline leukocyte conglutination, and permeability of the endothelium. Endotheliocytes were inoculated on 6-well plates and randomly divided into 4 groups: control, H2, LPS, LPS+H2, H2, and LPS+H2 in saturated hydrogen-rich medium. We applied Wright's stain-ing to observe conglutination of hyaline leukocytes and HUVECs, flow cytometry to determine the content of vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), enzyme-linked immunosorbent assay to measure the E-selectin concentration in the cell liquor, the transendothelial electrical resistance (TEER) to test the permeability of endothelial cells, and Western blot and immunofluorescence to test the expression and distribution of vascular endothelial (VE)-cadherin. Compared with control cells, there was an increase in endothelium-hyaline leukocyte conglutination, a reduction in VCAM-1, ICAM-1, and E-selectin, and the TEER value increased obviously. Compared with LPS, there was an obvious reduction in the conglutination of LPS+H2 cells, a reduction in VCAM-1, ICAM-1, and E-selectin levels, and a reduction in the TEER resistance value, while the expression of VE-cadherin increased. Fluorescence results showed that, compared with control cells, the VE-cadherin in LPS cells was in-complete at the cell joints. Compared with LPS cells, the VE-cadherin in LPS+H2 cells was even and complete at the cell joints. Liquid rich in hydrogen could reduce LPS-induced production of adhesion molecules and endothelium-hyaline leukocyte conglutination, and influence the expression and distribution of VE cadherin to regulate the permeability of the endothelium. PMID- 26125822 TI - Genetic polymorphism at the KIR gene locus: determination of gene, genotype, and haplotype frequencies in the Xinjiang Han population. AB - The aim of this study was to explore the genetic polymorphism, genotype, and haplotype characteristics of the KIR locus in the Xinjiang Han population in order to establish a foundation for future analysis of the relationship between KIR genes and disease. KIR genes were detected by sequence-specific primer polymerase chain reaction in 184 randomly selected, healthy individuals from the Han population in Xinjiang, China. Standard genotype and haplotype analyses were conducted using Hsu's standards classified for analysis. Sixteen KIR genes were detected: 3DL3, 2DL4, 3DL2, and 3DL2 (100%); 2DL1 and 2DP1 (99.46%); 2DL3 (98.91%); and so on. The 2DS2 gene frequency was the lowest at 21.74%. Twenty-one genotypes were detected: AJ (2, 2) was relatively common (42.39%), followed by AH (5, 2), AE (2, 8) and H (2, 4), with frequencies of 17.39, 11.96, and 8.15%, respectively. In addition, six novel genotypes were identified in 11 Han individuals as well as in other populations in China, which could not be classified for analysis. These results indicated that the Xinjiang Han population shares KIR gene, genotype, and haplotype frequency distributions with the Chinese Han population, but also has unique genotypes and haplotypes. PMID- 26125823 TI - Bovine yolk sac: from morphology to metabolomic and proteomic profiles. AB - In several species, placentation involves the presence of two different membranes responsible for maternal-fetal exchanges: the yolk sac and the chorioallantoic placenta. The yolk sac plays important roles in embryonic survival, mainly during the early stages of gestation. In bovine, it is a transitional membrane that is present until day 50-70 of pregnancy. Herein, we evaluated the morphological and molecular aspects of the yolk sac of bovine embryos during 24 to 52 days of gestation. A total of 69 embryos were allocated into three groups according to the crown-rump length and estimated ages. Yolk sac samples were then subjected to morphological and molecular analysis using mass spectrometry and nuclear magnetic resonance techniques. In contrast to alanine, which was observed only in Group I, during all gestational stages, we identified important metabolites such as aspartate, taurine, glycerophosphocholine, creatinine, creatine, hydrouracil, glutamate, glutamine, lactate, lysine, valine, myo-inositol, cadaverine, and choline. In addition, 314 random sequences of proteins were identified in the bovine yolk sac, and 47 of these were considered to be specific. Changes in alpha fetoprotein and carcinoembryonic antigen concentrations during gestation were also evaluated. In conclusion, the majority of these proteins are related to the development of secondary metabolites that are involved in the activation of other proteins and metabolites, and in signaling pathways that are responsible for maternal-fetal exchanges, activation of programmed cell death mechanisms, and cellular differentiation, and also in proteins that are responsible for the yolk sac involution that is required to establish chorioallantoic placentation. PMID- 26125824 TI - Expression of COX-2 and VEGF-C in cholangiocarcinomas at different clinical and pathological stages. AB - The aim of this study was to investigate the expression and clinical significance of cyclooxygenase 2 (COX-2) and vascular en-dothelial growth factor C (VEGF-C) in cholangiocarcinomas at differ-ent clinical and pathological stages. Eighty cholangiocarcinoma sam-ples of patients treated with surgery between January 2012 and January 2014 were collected. Immunohistochemistry was used to detect COX-2 and VEGF-C expression at different clinical and pathological stages. ELISA, real time PCR, invasive chambers, and MTT assay were ap-plied in cultured cholangiocarcinoma cells treated with a COX-2 inhib-itor. Expression of COX-2 and VEGF-C correlated positively with the clinical TNM stage but did not correlate with the differentiation status. Inhibition of COX-2 activity reduced VEGF-C mRNA expression and secretion in cholangiocarcinoma cells and decreased their migration but not proliferation. Because of its ability to inhibit invasion, COX 2 could be a new target for treatment of cholangiocarcinoma. PMID- 26125825 TI - Case Report Diffuse large B-cell lymphoma in the primary bone marrow. AB - This study aimed to improve understanding of the diagnosis, treatment, and prognosis of primary bone marrow (PBM) diffuse large B-cell lymphoma (DLBCL), a rare illness. We report a 56-year-old man with pancytopenia and hyperbilirubinemia but without lymphadenopathy, hepatomegaly, or splenomegaly. Bone marrow aspiration, flow cytometry, biopsy, and immunohistochemistry confirmed DLBCL. Two cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were administered. Blood cell numbers and hyperbilirubinemia improved. Although the patient did not completely recover, he survived for at least 3 years after chemotherapy and receiving blood transfusions. PBM DLBCL is a distinct, aggressive lymphoma characterized by lymphoma cells only in the bone marrow and effectively treated via chemotherapy. Prognoses for PBM DLBCL vary. PMID- 26125826 TI - Antioxidant content and cytological examination of aqueous fluid from patients with age-related cataracts at different stages. AB - We investigated the antioxidant content and conducted a cytological examination of the aqueous fluid and lenses of patients with age-related cataracts at different stages. The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in the aqueous fluid and lenses were determined by the xanthine oxidase method, the colorimetric method, and the improved reduced glutathione (GSH) depletion method, respectively. SOD, CAT, and GSH-PX content in the aqueous fluid and lenses decreased significantly with increasing lenticular nucleus hardness grading. However, the number of white blood cells, neutrophils, monocytes, lymphocytes, and eosinophils did not vary significantly with varying lenticular nucleus hardness. Antioxidant content examination is an important quantitative indicator for clinical diagnosis and treatment of age-related cataracts. Antioxidant content in the aqueous fluid and lenses decreased significantly with increasing lenticular nucleus hardness grading. Lenses at hardness level V had the lowest content of antioxidants. PMID- 26125827 TI - Association between the FCGR2A gene H131R polymorphism and risk of Kawasaki disease: a meta-analysis. AB - Several previous studies have investigated whether the FCGR2A gene H131R polymorphism confers an increased risk of Kawasaki disease (KD), but conflicting results have been reported. To further explore the association of this polymorphism with KD susceptibility, we performed an extensive search of relevant studies and conducted a meta-analysis to obtain a more precise estimate of risk. Systematic searches of the electronic databases Embase, PubMed, and Google Scholar were performed to identify relevant studies. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used for statistical analysis. Six studies were included in the meta-analysis, involving 1709 patients with KD and 3207 controls. Significant association was found between the FCGR2A gene H131R polymorphism and KD risk in analysis of the total population (HH vs RR: OR = 1.97, 95%CI = 1.55-2.50; HH vs HR: OR = 1.38, 95%CI = 1.21-1.57; the dominant model: OR = 0.69, 95%CI = 0.60-0.78; and the recessive model: OR = 1.65, 95%CI = 1.32-2.07). In subgroup analysis by ethnicity, significant association was found between the H131R polymorphism and KD risk in Asians, but not in Caucasians. In addition, we found no significant association between the FCGR2A gene H131R polymorphism and risk of KD-associated coronary artery lesions. In conclusion, this meta-analysis suggested that the H131R polymorphism in the FCGR2A gene might be associated with susceptibility to KD in Asians. PMID- 26125828 TI - Novel polymorphic microsatellite markers in Odontobutis potamophila. AB - We characterized 16 novel polymorphic loci isolated from a partial genomic DNA library of Odontobutis potamophila enriched for CA repeats. We tested the variability of these microsatellites on 51 unrelated individuals collected in China. All loci were polymorphic. The average allele number was 14.6 per locus, ranging from 2 to 27. The observed heterozygosity ranged from 0.35 to 0.90, with an average of 0.70, whereas the average expected heterozygosity was 0.76. Twelve of the 16 microsatellites conformed to Hardy-Weinberg equilibrium and were inherited independently. These developed microsatellites will be useful in studies of population genetics and other genetic studies on this important food species. PMID- 26125829 TI - Hypolipidemic effect of safflower yellow and primary mechanism analysis. AB - We examined the hypolipidemic effect of safflower yellow (SY) on hyperlipidemic mice and its influence on the biological synthesis of cholesterol in cells. Over 4 weeks, the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in serum were detected using a kit; mouse liver samples were acquired for paraffin sections, and mouse liver cells were observed under light microscope. Chinese hamster ovary cells were cultured in vitro, and an amphotericin B-cell model was adopted to observe the inhibitory effect of SY on the biological synthesis of intracellular cholesterol. An enzyme-linked immunosorbent assay was used to detect the survival rate of Chinese hamster ovary cells. The middle and high doses of SY significantly reduced the levels of total cholesterol, triglycerides, and low density lipoprotein cholesterol in the serum of hyperlipidemic mice and low density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (P < 0.05), and the fatty liver of hyperlipidemic mice was significantly alleviated. SY had a protective effect on Chinese hamster ovary cells following amphotericin B injury (P < 0.01). SY exerts significant hypolipidemic effects and prevents fatty liver in a mechanism associated with inhibition of the biosynthesis of intracellular cholesterol. PMID- 26125830 TI - Polymorphisms in the PPARgamma gene and their association with metabolic syndrome in Uyghurs and Kazakhs from Xinjiang, China. AB - We investigated the association between polymorphisms rs1801282 and rs3856806 of the PPARgamma gene and metabolic syndrome (MS) among Uyghurs and Kazakhs. Mass spectrometry techniques were used to detect the PPARgamma genotypes rs1801282 and rs3856806 in 987 subjects, CC genotype and C allele frequencies were 83.6 and 91.7%, respectively, at rs1801282 in Kazakhs, which were higher than those in Uyghurs (72.3 and 85.0%, respectively; P < 0.05). CC genotype and C allele frequencies were 73.6 and 85.3%, respectively, at the rs3856806 loci in Kazakhs, which were higher than those in Uyghurs (60.7 and 77.9%, respectively; P < 0.05). For the rs3856806 polymorphism in Kazakhs, CT/TT genotype and T allele frequencies were 21.2 and 12.4% for MS subjects, which were lower than those for the control group (31.6 and 17.0%, respectively; P < 0.05). Risk analysis of Kazakhs revealed that individuals with the CT and TT genotypes at rs3856806 had an increased risk, 0.524- and 0.770-fold, respectively, of developing MS than those possessing the CC genotype. Individuals with the T allele also had an increase in risk, by 0.699-fold, of developing MS than those with the C allele. For Uyghurs, those with the CC genotype at rs1801282 had higher systolic blood pressure than those with the CG/GG genotype. Among Kazakhs, those with the CC genotype at rs3856806 had higher triglyceride and waist-hip ratio levels but lower high-density lipoprotein cholesterol levels than those with the CT/TT genotype. The rs1801282 and rs3856806 PPARgamma polymorphisms differ between Uyghurs and Kazakhs from Xinjiang Province, China. PMID- 26125831 TI - Associations of miRNA polymorphisms and expression levels with breast cancer risk in the Chinese population. AB - Single-nucleotide polymorphisms in microRNAs (miRNAs) may dramatically affect gene expression and subsequently alter individual susceptibility to cancer, and thus has become a research hotspot for many cancer types, including breast cancer. We recruited 321 breast cancer patients and 290 controls in our study. Four established miRNA single-nucleotide polymorphisms (mir-499 rs3746444 A>G; miR-27a rs895819 A>G; miR-196a2 rs11614913 T>C; miR-146a rs2910164 G/C) were detected using Taqman assays. Mature miRNA expression, allele distribution, and the association with clinical features were further analyzed. Our results showed that the miR146a rs2910164 G/C polymorphism was associated with an elevated risk of breast cancer (odds ratio = 1.85, 95% confidence interval = 1.03-3.32; P < 0.05). Compared with the ancestral T allele in miR-196a2 rs11614913, the variant C allele was consistently associated with an increased risk of breast cancer (odds ratio = 2.20, 95% confidence interval = 1.19-4.09, P < 0.01) and clinical pathological type (P < 0.01). miR-27a rs895819 A>G and miR-499 rs3746444 A>G were not associated with breast cancer risk. Analysis of mature miRNA expression confirmed that the variant C allele in miR146a rs2910164 and miR-196a2 rs11614913 dramatically inhibited production of their mature products. Our results suggested that miR-146a rs2910164 G>C and miR-196a2 rs11614913 T>C may be biomarkers for predicting breast cancer risk in the Chinese population. PMID- 26125832 TI - Karyotype of Philodryas nattereri and Philodryas olfersii with a comparative analysis of the Dipsadidae family. AB - Cytogenetic studies of Philodryas nattereri and Philodryas olfersii revealed a diploid chromosome number 2n = 36 for both species (3 metacentrics, 4 submetacentrics, and 10 acrocentrics, with a fundamental number of 51 and 52, respectively). The results obtained are novel and similar to those previously described for species belonging to the Dipsadidae family. The conventional karyotype is also novel and divergent from other species of the Dipsadidae family, where a higher proportion of macrochromosomes predominate, revealing two distinct groups in this family. The data are reported and discussed considering the cytotaxonomy of the family. These results strongly support the current view that chromosomal alterations, such as centric fusion and Robertsonian's translocations, seems to support the distinct importance of chromosomal rearrangements in speciation within this group. PMID- 26125833 TI - Estimating additive and dominance variances for complex traits in pigs combining genomic and pedigree information. AB - Knowledge of dominance effects should improve ge-netic evaluations, provide the accurate selection of purebred animals, and enable better breeding strategies, including the exploitation of het-erosis in crossbreeds. In this study, we combined genomic and pedi-gree data to study the relative importance of additive and dominance genetic variation in growth and carcass traits in an F2 pig population. Two GBLUP models were used, a model without a polygenic effect (ADM) and a model with a polygenic effect (ADMP). Additive effects played a greater role in the control of growth and carcass traits than did dominance effects. However, dominance effects were important for all traits, particularly in backfat thickness. The narrow-sense and broad-sense heritability estimates for growth (0.06 to 0.42, and 0.10 to 0.51, respectively) and carcass traits (0.07 to 0.37, and 0.10 to 0.76, respec-tively) exhibited a wide variation. The inclusion of a polygenic effect in the ADMP model changed the broad-sense heritability estimates only for birth weight and weight at 21 days of age. PMID- 26125834 TI - DKK1 eukaryotic expression plasmid and expression product identification. AB - We constructed the human dickkopf 1 (DKK1) eukaryotic expression plasmid and expressed, purified, and identified its expression product. We extracted cancer cells from cervical cancer tissue, followed by extraction of mRNA. Reverse transcription-polymerase chain reaction was conducted to obtain DKK1 gene fragments. Using these fragments, we prepared the recombinant plasmid pCMV HA2/DKK1. The recombinant plasmid was restriction enzyme-digested and sequenced, and using liposome vectors, was transiently transfected into Free-Style 293-F cells (serum-free medium). DKK1 protein was detected by western blotting. The amplification product showed the expected size. Restriction enzyme digestion and sequence analysis showed that the recombinant plasmid was PCMV-HA2/DKK1. The expression product was verified properly by western blotting using an anti-DKKI antibody. The successful cloning of the DKKI gene and expression of DKKI protein will be useful for studying the biological activity of tumorigenesis. PMID- 26125835 TI - Screening the first set of polymorphic microsatellite loci in Lunella coronata granulata (Turbinidae). AB - Lunella coronata granulata, from the family Turbini-dae, is an economically important species. The first set of 10 poly-morphic microsatellite loci was screened from L. coronata granulata, and 30 individuals were used to analyze the degree of polymorphism in these loci. The level of observed and expected heterozygosity was 0.0667-0.7333 and 0.0644-0.6628, respectively. The polymorphism information content varied from 0.305 to 0.559. Eight loci were in Hardy-Weinberg equilibrium (HWE) (P > 0.05), while two loci devi-ated significantly from the HWE after Bonferroni's correction (P < 0.005). The isolated microsatellite loci can be utilized in studies of population genetic analysis and they provide important genetic mark-ers for construction of genetic linkage maps and genetic breeding of L. coronata granulata resources. PMID- 26125836 TI - Assessment of the cytotoxic, genotoxic, and antigenotoxic activities of sucupira oil (Pterodon emarginatus). AB - The present study aimed to assess the cytotoxic, genotoxic, and antigenotoxic activities of sucupira oil (Pterodon emarginatus), which is commonly used as an anti-rheumatic, analgesic, antimicrobial, anticercariae, and anti-inflammatory. We used the mouse bone marrow micronucleus test as an experimental model. The experimental groups, which consisted of 5 animals, was administered sucupira oil (100 mg/kg body weight) intraperitoneally and evaluated 24 h after the treatment. The negative control group was treated with sterile distilled water, and the positive control group received an intraperitoneal dose of 4 mg/kg mitomycin C, a dose that corresponds to 80% of its median lethal dose. Cytotoxicity was determined by the polychromatic to normochromatic erythrocytes ratio (PCE/NCE). Sucupira oil had no significant effects (P > 0.05) on the frequency of micronucleated polychromatic erythrocytes as compared to the negative control group. However, the difference was significant (P < 0.005) as compared to the positive control group. The PCE/NCE (100 mg/kg oil and 4 mg/kg mitomycin) ratio did not differ between the experimental group and the positive control group, but it differed significantly when compared to the negative control group (P < 0.05). Thus, these findings suggested that the P. emarginatus oil showed no cytotoxic, mutagenic, or antimutagenic activities at a dose of 100 mg/kg. PMID- 26125837 TI - Association of MDR1 C3435T and C1236T single nucleotide polymorphisms with male factor infertility. AB - Infertility affects 1 in 6 couples and approximately 1 in 25 men. Male factor infertility is a major cause of spermatogenic anomalies, the causes of which are largely unknown. Impaired repro-ductive functions in men might result from physiological, genetic, and/or environmental factors such as xenobiotics. The multi-drug re-sistance1 (MDR1) gene encodes a P-glycoprotein which has a role in the active transport of various substrates providing protection of somatic cells from potentially toxic substances, including xenobi-otics. MDR1 is highly expressed at the luminal surface of capillary endothelial cells, and is expressed in Leydig cells, testicular mac-rophages, and Sertoli cells. We performed genotype and haplotype analyses of MDR1 in 192 infertile and 102 fertile Turkish men for the genetic markers C1236T and C3435T, using polymerase chain reaction restriction fragment length polymorphism analysis. In the overall population, correlations were analyzed in all genotype mod-els. We found that the C3435T polymorphism TT vs CT genotypes showed statistically significant differences in their association with infertility (P = 0.045), and that the CT genotype was associated with high sperm DNA damage (P = 0.02), suggesting that the CT genotype might be a susceptibility factor for infertility. Additionally, the T-T haplotype was significantly more frequent in the control group (13.2 vs 6.5%; odds ratio = 0.459, 95%CI = 0.259-0.814, P = 0.006). This study showed that MDR1 might have a role in male infertility. Fur-ther research in large cohorts with different populations is required to clarify the role of MDR in male fertility. PMID- 26125838 TI - Dynamic changes of virus load in supernatant of primary CEK cell culture infected with different generations of avian infectious bronchitis virus strains Sczy3 as revealed by real-time reverse transcription-polymerase chain reaction. AB - Infectious bronchitis virus (IBV) can multiply effectively in chick embryo kidney (CEK) cells after adapting to the chick embryo. To investigate the dynamic changes in IBV load in the supernatant of primary CEK cells, we developed an SYBR Green I-based real-time polymerase chain reaction assay to quantify nucleic copy numbers of the IBV-Sczy3 strain. The 20, 54, and 87th generations of CEK-adapted IBV-Sczy3 strains were used to infect CEK cells, and then nucleic copy numbers in the samples of supernatant collected at 12, 24, 36, 48, 60, and 72 h were detected. The results showed that the rapid growth period of the virus load of all the 3 generations was approximately 12-36 h post-infection; the peak of the virus load appeared at 36 h post-infection and then decreased gradually in the order of 20th > 54th > 87th for the 3 generations of CEK-adapted strains; the dynamic change curve of the IBV load in the supernatant of primary CEK cells showed a single peak. The results of this study provide a useful reference for CEK-adapted IBV field strains and the production of CEK-attenuated IBV vaccine. PMID- 26125839 TI - Positive association between PPARD rs2016520 polymorphism and coronary heart disease in a Han Chinese population. AB - PPARD encodes peroxisome proliferator-activated re-ceptor delta, which has been shown to play an important role in control-ling lipid metabolism and atherosclerosis. In this case-control study, we explored the relationship between PPARD rs2016520 polymorphism and coronary heart disease (CHD) in a Han Chinese population. A to-tal of 657 CHD cases and 640 controls were included in the associa-tion study. rs2016520 polymorphism genotyping was performed using the melting temperature-shift polymerase chain reaction method. The PPARD rs2016520-G allele reduced CHD risk by 17.9% (chi(2) = 5.061, P = 0.025, OR = 0.821, 95%CI = 0.692-0.975). Furthermore, a signifi-cant difference in CHD risk was observed for the PPARD rs2016520 polymorphism in the dominant model (AG + GG vs AA: chi(2) = 4.751, degrees of freedom (df) = 1, P = 0.029, OR = 0.784, 95%CI = 0.631- 0.976). Analysis by age suggested that the G-allele decreased CHD risk by 14.8% in ages greater than 65 years (chi(2) = 4.446, P = 0.035, OR = 0.852, 95%CI = 0.684 1.060). In contrast, meta-analysis of PPARD rs2016520 among 3732 cases and 5042 controls revealed no associa-tion between PPARD rs2016520 and CHD (P = 0.19). We found that the PPARD rs2016520-GG genotype decreased CHD risk in a Han Chinese population. Moreover, we found an association between serum high-density lipoprotein cholesterol level and PPARD rs2016520 in senior individuals aged >= 65 years. The meta-analysis revealed no association between PPARD rs2016520 and CHD, suggesting ethnic differences in the association between the PPARD locus and CHD. PMID- 26125840 TI - Activity of matrix metalloproteinases 2 and 9 in cultured rabbit corneal epithelium cells stimulated by tumor necrosis factor alpha. AB - We studied the activity of matrix metalloproteinases (MMP) 2 and 9 generated by cultured rabbit corneal epithelium cells that had been stimulated with tumor necrosis factor alpha (TNF-alpha), to investigate the possible regulative mechanisms of MMP-2/9 and their potential effect on corneal inflammatory diseases. The rabbit corneal epithelium cells were cultured in vitro and incubated with different concentrations of TNF-alpha (0, 1, 10, and 100 ng/mL) for 24 h. The activity of MMP-2/9 was examined using gelatin zymography. The results were analyzed by computer image analysis and statistical tests. TNF-alpha stimulated the secretion of MMP-2/9 in a dose-dependent manner, and MMP-2 was activated by TNF-alpha. Inflammatory factors such as TNF-alpha can stimulate MMP 2/9 activity in corneal epithelium cells. This may be a potential manipulating mechanism of MMP expression in the pathogenesis of corneal diseases, and could play an important role in the prevention and treatment of corneal inflammatory diseases. PMID- 26125841 TI - A simplified genomic DNA extraction protocol for pre-germination genotyping in rice. AB - Genotyping is a critical step for molecular marker-assisted selection in rice. Rice genomic DNA samples for genotyping are typically isolated from living tissues such as seedlings. This requires the germination of all candidate seeds and extraction of DNA from the seedlings. Currently, an ideal individual is selected from a very large number of plants, which is time- and labor-consuming, requiring several transplantations of materials and sampling processes. In this study, we developed a simplified genomic DNA extraction protocol in rice by using amylase to treat half-seeds. The yields of genomic DNA from a half-seed of Indica and Japonica rice were greater than 203.8 +/- 32.5 and 143.2 +/- 25.5 ng, respectively, and the 260/280 nm absorbance ratio was 1.75-2.10. The DNA was confirmed to be sufficient for polymerase chain reaction amplification and can be used in a marker-assisted selection program. PMID- 26125842 TI - FlgN plays important roles in the adhesion of Aeromonas hydrophila to host mucus. AB - Adhesion to the host mucus is a crucial step in the early infection stage of pathogenic bacteria. To investigate the mechanisms of the adhesion of Aeromonas hydrophila to its host mucus, a mutant library was constructed using the mini Tn10 transposon mutagenesis system. Of 276 individual colonies, the mutant strain with the most attenuated adhesion ability in this study was screened out and designated A77. Molecular analysis showed that a 414-bp sequence flanking mini Tn10 in A77 had the highest identity (97%) with the bacterial flagellar protein gene flgN. A complemented strain flgN+ was constructed and the biological characteristics of the wild-type, mutant A77, and complemented flgN+ strains were investigated. The results showed that the decreased abilities of motility, adhesion to mucus, and biofilm formation in the mutant strain were partially recovered in the complemented flgN+ strain, which suggested that flgN plays an important role in the adhesion of A. hydrophila to its host. PMID- 26125843 TI - Effect of Ginkgo biloba extract on apoptosis of brain tissues in rats with acute cerebral infarction and related gene expression. AB - We investigated the effect of Ginkgo biloba extract on apoptosis of brain tissues in rats with acute cerebral infarction and apoptosis-related gene expression. Rat models of acute cerebral infarction were constructed using the suture method, and randomly divided into the control group, model, and treatment groups. In the treatment group, 4 mg/kg G. biloba extract was intravenously injected into the rat tail vein. Phosphate-buffered saline solution was injected in the model group. Seventy-two hours after treatment, rats were euthanized, and brain tissues were removed to analyze the changes in caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) mRNA and protein levels, and variation in brain tissue cells' apoptosis indices was measured. Compared with the control group, the model and treatment groups showed significantly upregulated caspase-3, Bcl-2, and Bax mRNA and protein levels in brain tissues, but remarkably downregulated Bcl-2 mRNA and protein levels (P < 0.05). After treatment, in treatment group brain tissues, caspase-3 and Bax mRNA and protein levels were significantly lower than those in the model group, while Bcl-2 mRNA and protein levels were higher than that in the model group (P < 0.05). The model and treatment groups showed increased cell apoptosis indices of brain tissues compared to the control group; after treatment, the apoptosis index in the treatment group was significantly downregulated compared with that in the model group (P < 0.05). In conclusion, G. biloba extract significantly reduced apoptosis in rat brain tissue cells with acute cerebral infarction and thus protected brain tissues. PMID- 26125844 TI - Repair of large segmental bone defects in rabbits using BMP and FGF composite xenogeneic bone. AB - The objective of this study was to determine the ability of bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) to repair large segmental radial bone defects in rabbits. We treated calf cancellous bones with 3 mg/L BMP (Group A), 5 MUg/L FGF (Group B), or 3 mg/L BMP plus 5 MUg/L FGF (Group C). A bone damage model was established using healthy radii from rabbits. The complexes were implanted in the areas of the bone defects in the radii. After successful transplantation, the rabbits underwent radiographic imaging, and bone graft specimens were detected by histopathology methods. Biomechanical indexes were also assessed in order to observe the healing status of the bone defects. Our results indicated that the repair of bone defects was significantly better in Group C compared to the other 2 groups. Therefore, we concluded that combining BMP and FGF significantly promoted bone defect repair and achieved effects that were superior to the use of BMP alone. PMID- 26125845 TI - Effects of exogenous 5-aminolevulinic acid on photosynthesis, stomatal conductance, transpiration rate, and PIP gene expression of tomato seedlings subject to salinity stress. AB - The effects of exogenous 5-aminolevulinic acid (ALA) on photosynthesis, plant growth, and the expression of two aquaporin genes in tomato seedlings under control and salinity conditions were investigated. Exogenous ALA application significantly improved net photosynthetic rate (Pn), total chlorophyll content, and plant biomass accumulation of tomato seedlings under salinity stress. As revealed by real-time PCR analyses, after treatment with ALA alone, expression of both LePIP1 and LePIP2 in the two tomato cultivars was up-regulated at 2 h and subsequently decreased to normal levels. Under salinity stress, transcript levels of LePIP1 in both leaves and roots of salt-sensitive cultivars (cv. Zhongza No.9) increased significantly and were considerably higher than in cultivars exposed to ALA alone. In contrast, the expression levels of LePIP1 and LePIP2 in cvs. Jinpeng No.1 cultivars were slightly lower under salinity stress than under ALA treatment. In addition, transcript levels of both LePIP1 and LePIP2 in the roots of Jinpeng No. 1 cultivars were considerably lower than those in the roots of Zhongza No. 9 cultivars under salinity stress, regardless of ALA supplementation, implying that Jinpeng No. 1 cultivars had a better capacity to maintain membrane intrinsic protein stability. Further, ALA application distinctly counteracted the up- or down-regulation of LePIP1 and LePIP2 in both cultivars under salinity stress, in accordance with the improvements instomatal conductance, transpiration rate, and Pn of tomato leaves. The results presented here indicate that ALA controls aquaporin expression, thus, presumably ALA regulates water homeostasis and enhances salt tolerance of tomato seedlings. PMID- 26125846 TI - Inhibition of human chronic myelogenous leukemia K562 cell growth following combination treatment with resveratrol and imatinib mesylate. AB - To investigate the effect of treatment with resveratrol combined with imatinib mesylate on human chronic myelogenous leukemia K562 cell growth inhibition and apoptosis, in vitro cultured human chronic myelogenous leukemia K562 cells were incubated with different concentrations of resveratrol and imatinib mesylate when the cells were in the logarithmic phase. Next, the cell growth inhibition was evaluated using the MTT assay and cellular morphology observation. Apoptosis was determined using Annexin V fluorescein isothiocyanate/propidium iodide double staining. The results demonstrated that treatment with resveratrol (concentration dependent) and imatinib mesylate showed significantly greater inhibition of K562 cell growth and a higher apoptosis rate of K562 cells than imatinib mesylate medication alone and the control group (P < 0.01). The imatinib mesylate medication alone group showed significant inhibition of K562 cell growth and apoptosis rate of K562 cells compared to the control group (P < 0.01). Our findings indicate that imatinib mesylate and resveratrol are potent drug treatments for human chronic myelogenous leukemia, offering a promising means of inhibiting cell growth and apoptosis. PMID- 26125847 TI - Identification and characterization of novel NBS-LRR resistance gene analogues from the pea. AB - Pea (Pisum sativum) is one of the most cultivated le-gumes in the world, and its yield and seed quality are affected by a variety of pathogens. In plants, NBS-LRR (nucleotide binding site-leucine-rich repeat) is the main class of disease resistance genes. Using degenerate primers deduced from conserved motifs in the NBS domain of known resistance genes, we identified 10 NBS sequences in three varieties of P. sativum. The deduced amino acid sequences of the iden-tified resistance gene analogues (RGAs) exhibited the typical motifs of the NBS domain (P-loop, kinase-2, kinase-3a, and the hydrophobic domain, GLPL) present in the majority of plant proteins belonging to the NBS-LRR class. Phylogenetic analysis showed that seven RGAs belonged to the non-TIR-NBS-LRR subclass and three to the TIR-NBS-LRR subclass. The results of this study provide insights into the structure of this class of resistance genes in the pea, and their evolution-ary relationships with those of other plant species. PMID- 26125848 TI - Genome-wide pathway analysis in amyotrophic lateral sclerosis. AB - The aims of this study were to identify candidate single-nucleotide polymorphisms (SNPs) and mechanisms of amyotrophic lateral sclerosis (ALS) and to generate SNP to-gene-to-pathway hypotheses. An ALS genome-wide association study (GWAS) dataset that included 483,051 SNPs in 276 patients with ALS and 271 controls of European descent was used in this study. Identify Candidate Causal SNPs and Pathway (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 19 candidate SNPs, 8 genes, and 9 pathways, which provided 8 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs9352 alters the role of chromatin assembly factor 1 subunit A in the context of the pathways of chromatin and nucleosome assembly (nominal P < 0.001, false discovery rate (FDR) <= 0.001, 0.018, respectively). The second strongest was rs1046329 -> HILS1 -> chromatin assembly (nominal P < 0.001, FDR = 0.018). The third was rs11100790 -> SMARCA5 -> chromatin and nucleosome assembly (nominal P < 0.001, FDR <= 0.001, 0.018, respectively). The application of ICSNPathway analysis to the ALS GWAS dataset resulted in the identification of candidate SNPs, pathways, and biological mechanisms that might contribute to ALS susceptibility. PMID- 26125849 TI - Characterization of Aspergillus niger endo-1,4-beta-glucanase ENG1 secreted from Saccharomyces cerevisiae using different expression vectors. AB - Heterologous expression of Aspergillus niger endo-1,4-beta-glucanase (ENG1) in Saccharomyces cerevisiae was tested both with an episomal plasmid vector (YEGAp/eng1) and a yeast vector capable of integration into the HO locus of the S. cerevisiae chromosome (pHO-GAPDH-eng1-KanMX4-HO). In both cases, eng1 gene expression in yeast, with its native signal sequence for secretion, was under the control of the strong glyceraldehyde 3-phosphate dehydrogenase (GAPDH) promoter. We aimed to verify how each expression system affects protein expression, posttranslational modification, and biochemical properties. Expression of eng1 from the episomal plasmid vector YEGAp/eng1 significantly slowed the growth of a yeast cell culture. However, expression of eng1 from the vector integrated into the HO locus of the chromosome did not cause growth suppression, and the enzyme activity in a culture supernatant was maintained throughout the incubation time. ENG1 has optimum catalytic activity at pH 6.0, and is stable in the pH range 5.0 9.0. The enzyme's optimum temperature for catalytic activity at pH 6.0 is 70 degrees C; importantly, more than 95% of the enzyme's initial activity remained after a 2-h incubation at 60 degrees C. The biochemical characterization of ENG1 confirmed the correct expression of the protein and showed that ENG1 expressed by the pHO-GAPDH-eng1-KanMX4-HO vector, in addition to its N-linked sites, is overglycosylated at its O-glycosylation sites compared with ENG1 expressed by the YEGAp/eng1 vector. It is likely that the O-glycosylated form of the A. niger ENG1 retains more stable activity during continuous cultivation of recombinant yeasts than the form that is only N-glycosylated. PMID- 26125850 TI - Assessment of apple core collections constructed using phenotypic and genotypic data. AB - Several types of information can be used to select core collections, including passport data, agronomic data, and molecular data. However, little is known about the ability of core collections to retain the genetic diversity and structure of the whole collection for characters that were not considered during the selection, particularly when molecular markers are used. In this study, two core subsets were established for the apple (Malus spp) germplasm bank curated at the Apple Research Station, National Institute of Horticultural and Herbal Science, Korea, based upon genetic diversity estimated with 14 simple sequence repeat markers, and phenotypic diversity based on 23 traits. Comparisons between these two subsets and with the whole collection were used to determine the effect of the data used in the selection on phenotypic and genetic diversity, and population structure. The two subsets had a similar diversity and did not differ from the original collection, according to the Nei and Shannon diversity indices. Allele and class frequencies were also maintained in the two subsets. Overall, the type of data used to construct the core collection had little influence on the phenotypic and genetic diversity retained. Therefore, in the case of apple collections, the use of molecular markers is preferable, because they allow rapid and reliable characterization. PMID- 26125851 TI - Polymorphisms in GSTM1, GSTT1, GSTP1, and GSTM3 genes and breast cancer risk in northeastern Mexico. AB - Glutathione S-transferases (GSTs) are a family of phase II metabolizing enzymes involved in carcinogen detoxification and the metabolism of various bioactive compounds. Several genes that code for these enzymes are polymorphic in an ethnicity-dependent manner, with particular genotypes previously associated with an increased risk of breast cancer. The purpose of this study was to determine the frequencies of polymorphisms in the genes GSTM1, GSTT1, GSTP1, and GSTM3 and to investigate whether an association exists between these genes and breast cancer risk in subjects from northeastern Mexico. Genotypes were determined for 243 women with histologically confirmed breast cancer and 118 control subjects. Gene polymorphisms were analyzed using a DNA microarray. We found an increased breast cancer risk associated with the GSTM1 gene deletion polymorphism (OR = 2.19; 95%CI = 1.50-3.21; P = 0.001). No associations between the GSTT1, GSTP1, and GSTM3 genotypes and neoplasia risk were observed. In conclusion, we determined the genotype distribution of GST polymorphisms in control subjects and breast cancer patients from northeastern Mexico. The GSTM1 null genotype was associated with breast cancer risk. Our findings may be used to individualize breast cancer screening and therapeutic intervention in our population, which displays ethnic characteristics that differentiate it from other populations in Mexico. PMID- 26125852 TI - Population genetic structure of Attalea vitrivir Zona (Arecaceae) in fragmented areas of southeast Brazil. AB - Attalea vitrivir Zona (synonym Orbignya oleifera) is one of the six species of Arecaceae known as "babassu". This species is used to make cosmetics, food, and detergents due to the high concentration of oil in the seeds. It is found only in fragmented areas of southern Bahia State and northern Minas Gerais State, southeast Brazil, and this fragmentation has affected both its ecological and genetic characteristics. We evaluated the genetic diversity and population genetic structure of A. vitrivir in six areas of two different regions at the extremes of its geographical range, in order to gain a better understanding of the factors that affect the distribution and partitioning of its diversity. Nine inter simple sequence repeat (ISSR) markers amplified 74 polymorphic bands, resulting in large diversity values (Shannon diversity index, 0.37-0.47; intrapopulation genetic diversity, 0.25-0.34). Analysis of molecular variance (AMOVA) revealed considerable differentiation between sampling sites (30.03%) and regions (12.08%), although most of the diversity was observed within sampling sites (69%). Further differentiation between sampling sites was noted more in the northern region than in the southern region, highlighting the genetic connectivity between the sampling sites within Rio Pandeiros Environmental Protection Area (southern region). The identification of two distinct genetic clusters (K = 2) corresponded to the northern and southern regions, and corroborated the AMOVA results. We suggest that the northern area, outside Rio Pandeiros Environmental Protection Area, must be included in future management plans for this species. PMID- 26125853 TI - Study of the obp5 gene in Apis mellifera ligustica and Apis cerana cerana. AB - Apis mellifera ligustica and A. cerana cerana exhibit differences in olfactory sensitivity to odors from nectariferous plants and diseased broods. It is presumed that the differences in odorant-binding proteins (OBPs) between these 2 species contribute to their olfactory sensitivity. We compared the sequences, temporal expression pattern, and binding properties of the 2 OBP-encoding genes. We cloned the Amobp5 and Acobp5 genes. Among the ligands tested, phenethyl acetate was the most variable, with AcOBP5 showing high affinity and AmOBP5 having no apparent affinity for this ligand. While AmOBP5 had high affinity to both benzyl alcohol and 2-phenylethanol, the binding affinity of AcOBP5 to these compounds was moderate. However, the fluorescence intensity of these compounds was not decreased below 50%; thus, the dissociation constants could not be calculated. The Amobp5 gene showed significantly higher expression in 10- and 15 day-old workers than in other stages, while the Acobp5 gene had the highest expression in 30-day-old workers. Both the Amobp5 and Acobp5 genes had the lowest expression level in 1-day-old workers. These results suggest that the binding properties and temporal expression patterns of the obp5 genes in A. mellifera and A. cerana play a critical role in the olfactory sensitivity of workers. PMID- 26125854 TI - Phenotypic variation and diversity of Magnolia sprengeri Pamp. in native habitat. AB - The population of Magnolia sprengeri individuals deceased drastically in the late 20th century because of the widespread harvest for traditional Chinese medicinal recipes. In this study, the levels of phenotypic variation and the genetic structure of 2 populations of M. sprengeri were estimated. The phenotypic variation of M. sprengeri characteristics was nonsynchronous, with a coefficient of variation for 37 characters from 9.55-35.87%. The variance stabilizing transformation value ranged from 0.034-52.344%. The variation contribution within the population was greater than the contribution among the population; the among population rate was 2.864%, while the within-population rate was 15.849%; values of repeatability for among-population and within-population were 0.430 and 0.098, respectively. This indicates that more variation arose from within-population and that population repeatability was much greater than individual repeatability. Variation in the flower organ was greater than that in the leaf organ; this means that vegetative variation was more stable than reproductive variation. Variation in the southern population was greater than that in the northern population. PMID- 26125855 TI - Genetic diversity in elite inbred lines of maize and its association with heterosis. AB - The objective of the current study was to apply molecular markers (microsatellites) in the analysis of genetic diversity of 48 lines of the elite maize germplasm stored in the bank of the Cooperativa Central de Pesquisa Agricola - Coodetec, PR, Brazil, and estimate the correlation between genetic distance and heterosis and hybrid performance from the crosses among these maize lines. Forty-four random primers were used and amplification of 124 polymorphic fragments was obtained. The expected findings from the correlation of the yield and heterosis with the genetic distance were non-significant. However, the results suggested that data from the extreme distances could be used in breeding for more productive crosses and heterotic hybrids. Thereby, molecular markers are efficient tools for predicting hybrid performance. PMID- 26125856 TI - Qualitative analysis of the vaginal microbiota of healthy cattle and cattle with genital-tract disease. AB - The microbial community of the reproductive appara-tus, when known, can provide information about the health of the host. Metagenomics has been used to characterize and obtain genetic infor-mation about microbial communities in various environments and can relate certain diseases with changes in this community composition. In this study, samples of vaginal surface mucosal secretions were col-lected from five healthy cows and five cows that showed symptoms of reproductive disorders. Following high-throughput sequencing of the isolated microbial DNA, data were processed using the Mothur soft-ware to remove low-quality sequences and chimeras, and released to the Ribosomal Database Project for classification of operational taxo-nomic units (OTUs). Local BLASTn was performed and results were loaded into the MEGAN program for viewing profiles and taxonomic microbial attributes. The control profile comprised a total of 15 taxa, with Bacteroides, Enterobacteriaceae, and Victivallis comprising the highest representation of OTUs; the reproductive disorder-positive profile comprised 68 taxa, with Bacteroides, Enterobacteriaceae, His-tophilus, Victivallis, Alistipes, and Coriobacteriaceae being the taxa with the most OTU representation. A change was observed in both the community composition as well as in the microbial attributes of the profiles, suggesting that a relationship might exist between the patho-gen and representative taxa, reflecting the production of metabolites to disease progression. PMID- 26125857 TI - Isolation and characterization of polymorphic microsatellite loci in the sea cucumber Holothuria scabra. AB - The sea cucumber Holothuria scabra is an endangered species. In this study, nine new polymorphic microsatellite loci were developed and tested in 30 individuals. The number of alleles ranged from 2 to 5, and the observed and expected heterozygosities ranged from 0.1200 to 0.7391 and from 0.2408 to 0.5983, respectively. No loci significantly deviated from the Hardy-Weinberg equilibrium af-ter a Bonferroni correction, and no significant linkage disequilibrium was found between pairs of loci. These polymorphic microsatellite loci will be useful in studying the genetic diversity of H. scabra and its conservation. PMID- 26125858 TI - IDH1 and IDH2 mutations in different histologic subtypes and WHO grading gliomas in a sample from Northern Brazil. AB - Glioma is a term used to describe tumors derived from glial cells. These tumors are divided into subgroups based on the histological morphology and similarity of their differentiated glia cells. Traditionally, they are classified according to the World Health Organization and include astrocytomas, oligodendrogliomas, ependymomas, and oligoastrocytomas. Like most cancers, gliomas develop as a result of genetic changes that accumulate with tumor progression. Alterations in isocitrate dehydrogenase 1 (IDH1) and IDH2 were found to be relevant in the classification and prognostic of gliomas. Because of the importance of mutations in these genes, particularly in IDH1, in different proposals of the genesis and progression of gliomas, we analyzed the occurrence of mutations in these genes in samples obtained from patients from Belem (PA, Brazil) using polymerase chain reaction-single-strand conformation polymorphism followed by sequencing. We compared the results obtained from tumors of different malignancy grades, evaluating the significance of the associations between different variables. R132H was the only mutation found in 17.6% (6/34) of cases, including in astrocytomas, anaplastic astrocytomas, oligodendroglioma, and anaplastic oligoastrocytoma. No mutations were found in the IDH2 gene. We found no significant relationship between the identified mutations in IDH1 and the variables. Our data could not confirm that mutations in IDH1/IDH2 are indicative of malignancy and prognosis. However, the results support that the mutation in IDH1 gene was an early event in the development of gliomas, as it was found in tumors of different malignancy grades. PMID- 26125860 TI - Cloning and association analysis of KIT and EDNRB polymorphisms with dominant white coat color in the Chinese raccoon dog (Nyctereutes procyonoides procyonoides). AB - The Chinese raccoon dog (Nyctereutes procyonoides procyonoides) is one of the most important fur-bearing animal species. The dominant white individual, a coat color variant in farmed Chinese raccoon dog, shows a completely white phenotype over the entire body. The KIT and EDNRB genes have been reported to be associated with the dominant white coat color in some mammalian species. In the present study, the full-length coding sequences of KIT and EDNRB were amplified from a dominant white and a wild-type Chinese raccoon dog. Sequence analysis revealed that the coding region of KIT and EDNRB in Chinese raccoon dog was 2919 and 1332 base pairs in length (accession No. KM083121 and KM083122), respectively, and 2 single-nucleotide polymorphisms (SNPs; c.600C>T and c.967G>A) in KIT and 1 SNP (c.259A>C) in EDNRB was found only in the dominant white individual. An alternative splicing site at the boundary of 4 and 5 of the KIT gene was identified in both individuals. We further investigated the association between the 3 SNPs of KIT and EDNRB and dominant white coat color by genotyping 18 individuals. We found no association between these SNPs and dominant white coat color. Based on these results, we can exclude the coding regions of the KIT and EDNRB genes as determinants of the dominant white coat color in Chinese raccoon dog. PMID- 26125859 TI - Decreased TIM-3 mRNA expression in peripheral blood mononuclear cells from nephropathy patients. AB - Increasing evidence shows that TIM-1 and TIM-3 in-fluence chronic autoimmune diseases, and their expression levels in immune cells from nephritic patients are still unknown. Real-time transcription-polymerase chain reaction analysis was used to deter-mine expression levels of TIM-1 and TIM-3 mRNA in peripheral blood mononuclear cells (PBMCs) from 36 patients with minimal change glo-merulopathy (MCG), 65 patients with lupus nephritis (LN), 78 patients with IgA nephropathy (IgAN), 55 patients with membranous nephropa-thy (MN), 22 patients with crescentic glomerulonephritis (CGN), 26 patients with anaphylactoid purpura nephritis (APN), and 63 healthy controls. TIM-3 mRNA expression significantly decreased in PBMCs from nephritic patients (LN, P < 0.0001; MCG, P < 0.0001; MN, P = 0.0031; CGN, P = 0.0464; IgAN, P = 0.0002; APN, P = 0.0392) com-pared with healthy controls. In contrast, there was no significant differ-ence in TIM-1 mRNA expression between the patients and the healthy controls. Our results suggest that insufficient expression of TIM-3 mRNA may be involved in the pathogenesis of nephropathy. PMID- 26125861 TI - Screening and characterization of novel polymorphic microsatellite markers from sea cucumber Holothuria leucospilota. AB - The sea cucumber Holothuria leucospilota has high me-dicinal value and rich nutritional edible value, and thus is a commercially important aquatic product in China. Microsatellite loci were developed and screened using a fast isolation protocol and amplified fragment length polymorphism of sequences containing repeats. In this study, 16 novel polymorphic microsatellite markers in H. leucospilota were identified, and the relevant genetic variability index was assessed using 30 individu-als from a wild population. The polymorphic information content ranged from 0.183 to 0.668, and the number of alleles per locus varied from 3 to 5. The observed and expected heterozygosities were 0.0370 0.5000 and 0.0776-0.6250, respectively. With the exception of 3 loci (Y1-15, Y11 1, and Y28), the polymorphic loci were in Hardy-Weinberg equilibrium (P > 0.003125). These polymorphic microsatellite loci will contribute to studies of genetic diversity, the research of population structure, and the design of conservation strategies for H. leucospilota. PMID- 26125862 TI - Apelin polymorphism predicts blood pressure response to losartan in older Chinese women with essential hypertension. AB - We determined whether the blood pressure response to losartan in an older Chinese population with essential hypertension was associated with apelin gene polymorphisms. We genotyped the -1860T>C polymorphism of the apelin gene in a case-control study of 222 patients with hypertension and 250 controls. Following 24 weeks of treatment with losartan (50 mg/day), reductions in systolic blood pressure were significantly different among the additive (CT vs CC vs TT), dominant (TT vs CC/CT), and recessive models (CC vs CT/TT; all P < 0.05) in women but not in men. In the additive model, the TT group showed the greatest reductions in systolic BP (23 +/- 10 mmHg) after treatment. The CT group showed greater reductions in systolic BP (21 +/- 11 mmHg) compared to the CC group (8 +/ 3 mmHg) (P < 0.05). The reductions in systolic BP of the TT and CT/CC groups were 23 +/- 10 and 19 +/- 10 mmHg, respectively. The reductions in systolic BP of the CC and TT/CT groups were 8 +/- 3 and 21 +/- 10 mmHg, respectively. After adjustment for confounding factors, quantitative trait analysis with a general linear model showed that the female patients with TT genotype showed greater reductions in systolic blood pressure after 24 weeks of treatment compared to the patients with the C allele (P < 0.05). The apelin -1860T>C genotype may play an important predictive role in the response to losartan in hypertensive women. PMID- 26125863 TI - Osteoprotegerin polymorphisms in Chinese Han patients with rheumatoid arthritis. AB - In order to investigate the association between osteoprotegerin (OPG) gene polymorphisms and rheumatoid arthritis (RA), we studied OPG rs3102735 T/C and rs2073618 G/C polymorphisms in a Chinese Han population comprising 574 patients with RA and 804 controls. Genotyping by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was conducted. Our data indicated that OPG rs3102735 T/C and rs2073618 G/C polymorphisms were not associated with the risk of RA. However, among older patients (>=55 years), patients with the OPG rs3102735 TC (TC vs TT: OR = 0.68, 95%CI = 0.49-0.96, P = 0.029) and TC/CC (TC+CC vs TT: OR = 0.69, 95%CI = 0.49 0.96, P = 0.026) genotypes showed a significantly lower risk of RA than patients with the TT genotype, while patients with the OPG rs2073618 GC (GC vs GG: OR = 1.53, 95%CI = 1.13-2.07, P = 0.006) and GC/CC (GC+CC vs GG: OR = 1.43, 95%CI = 1.07-1.92, P = 0.015) genotypes showed a significantly higher risk of RA than patients with the GG genotype. We also found a significantly increased risk of RA associated with the OPG rs2073618 GC (GC vs GG: OR = 1.44, 95%CI = 1.07-1.93, P = 0.018) and GC/CC (GC+CC vs GG: OR = 1.39, 95%CI = 1.04-1.86, P = 0.024) genotypes among functional class III+IV patients. Our results were obtained from only a moderate-sized sample and, thus, a larger study with a more diverse ethnic population is needed to confirm these results. PMID- 26125864 TI - Association of miR-21 with esophageal cancer prognosis: a meta-analysis. AB - The present study aimed to explore the relationship between miRNA expression and survival in patients with esophageal cancer (EC) using meta-analysis. We searched PubMed, EMBASE, CNKI, Wanfang, and ISI Web of Science databases without time restrictions, and extracted relevant data, such as the name of first author, publication year, age, gender, number of case, etc. from the studies included. We calculated the pooled hazard ratios (HRs) using the RevMan 5.2 software. A total of five studies involving 504 subjects were included in the meta-analysis, with the purpose of analyzing the association of miRNA-21 expression with EC prognosis. The pooled HR of elevated versus decreased miR-21 expression in EC was 1.87 [95% confidence interval (CI): 1.37-2.55, P < 0.001], with elevated miR-21 expression being associated with poorer prognosis for patients with EC. Our results support a prognostic role for miR-21 in EC. PMID- 26125865 TI - Varicocele and male infertility in Northeast China: Y chromosome microdeletion as an underlying cause. AB - The prevalence of Y chromosome microdeletions among azoospermic, severe oligozoospermic, moderate oligozoospermic, and mild oligozoospermic patients with varicocele-related and idiopathic infertility shows conflicting data in Asian countries. We aimed to detect this frequency in Northeast China, and investigated spermatogenic defects whether associated with varicocele or Y chromosome microdeletions. All samples underwent a thorough physical examination, semen analysis, and PCR analyses for Y chromosome microdeletions. We randomly selected 150 infertile non-obstructive azoospermic patients with left varicocele (Group 1), 150 idiopathic non-obstructive azoospermic infertility patients (Group 2), 150 infertile severe oligozoospermic patients with left varicocele (Group 3), 150 idiopathic severe oligozoospermic infertility patients (Group 4), 150 infertile moderate oligozoospermic patients with left varicocele (Group 5), 150 idiopathic moderate oligozoospermic infertility patients (Group 6), 150 infertile mild oligozoospermic patients with left varicocele (Group 7), 150 idiopathic mild oligozoospermic infertility patients (Group 8), and 60 healthy unrelated men with proven fertility were recruited as control subjects (Group 9). We observed that our samples from Northeastern China had a higher frequency of microdeletions among the non-obstructive azoospermic individuals with varicocele, as compared with other Asian countries. Furthermore, the spermatogenic defect is due to the underlying Y chromosome microdeletion, and not the varicocele itself. Although varicocele is not the cause of male infertility, it may be associated with male infertility in the Northeastern Chinese population. PMID- 26125866 TI - Recombinant adenovirus-mediated overexpression of PTEN and KRT10 improves cisplatin resistance of ovarian cancer in vitro and in vivo. AB - Drug resistance is a major cause of treatment failure in ovarian cancer patients, and novel therapeutic strategies are urgently needed. Overexpression of phosphatase and tensin homolog (PTEN) has been shown to preserve the cisplatin resistance of ovarian cancer cells, while cisplatin-induced keratin 10 (KRT10) overexpression mediates the resistance-reversing effect of PTEN. However, whether overexpression of PTEN or KRT10 can improve the cisplatin resistance of ovarian cancer in vivo has not been investigated. Therefore, we investigated the effects of adenovirus-mediated PTEN or KRT10 overexpression on the cisplatin resistance of ovarian cancer in vivo. Recombinant adenoviruses carrying the gene for PTEN or KRT10 were constructed. The effects of overexpression of PTEN and KRT10 on cisplatin resistance of ovarian cancer cells were examined using the 3(4,5 dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) and TdT-mediated dUTP nick-end labeling (TUNEL) assays in vitro. Subcutaneously transplanted nude mice, as a model of human ovarian cancer, were used to test the effects of PTEN and KRT10 on cisplatin resistance of ovarian cancer in vivo. The MTT assay showed that recombinant adenovirus-mediated overexpression of KRT10 and PTEN enhanced the proliferation inhibition effect of cisplatin on C13K cells. Recombinant adenovirus-mediated overexpression of KRT10 and PTEN also increased the cisplatin induced apoptosis rate of C13K cells. Furthermore, recombinant adenovirus mediated overexpression of KRT10 and PTEN enhanced the inhibitory effect of cisplatin on C13K xenograft tumor growth. Thus, recombinant adenovirus-mediated overexpression of KRT10 and PTEN may improve the cisplatin resistance of ovarian cancer in vitro and in vivo. PMID- 26125867 TI - Partial least squares-based gene expression analysis in preeclampsia. AB - Preeclampsia is major cause of maternal and fetal morbidity and mortality. Currently, the etiology of preeclampsia is unclear. In this study, we investigated differences in gene expression between preeclampsia patients and controls using partial least squares-based analysis, which is more suitable than routine analysis. Expression profile data were downloaded from the Gene Expression Omnibus database. A total of 503 genes were found to be differentially expressed, including 248 downregulated genes and 255 overexpressed genes. Network analysis identified 5 hub genes, including UBB, PIK3R1, MAPRE1, VEGFA, and ITGB1. Three of these, PIK3R1, VEGFA, and ITGB1, are known to be associated with preeclampsia or preeclampsia-related biological processes. Our findings shed light on expression signatures of preeclampsia patients that can be used as theoretical support in future therapeutic studies. PMID- 26125868 TI - FOXO1 is a tumor suppressor in cervical cancer. AB - Forkhead box protein O1 (FOXO1) is an important transcriptional regulator of cell proliferation, and is considered essential for tumor growth and progression. However, the function of FOXO1 in human cervical cancer remains unclear. In this study, we investigated the role of FOXO1 in cervical cancer. Our results showed that FOXO1 expression was lower in cervical cancer than in cervical intraepithelial neoplasia and normal cervix by immunohistochemical analysis (P < 0.05). The level of FOXO1 in high-grade lesions was significantly lower than in low-grade lesion (P < 0.05), indicating that deficient expression of FOXO1 is involved in tumor progression and significantly associated with late-stage tumors (P < 0.05), which was further supported by clinicopathological, real-time polymerase chain reaction, and Western blotting analysis. Moreover, we confirmed that the overexpression of FOXO1 remarkably repressed cell growth and blocked cell proliferation, accompanied by cell-cycle arrest in the G2/M phase and upregulation of caspases-3 and -9 gene expression. Collectively, our data suggest that FOXO1 plays a vital role in inhibiting cervical cancer development by inducing cell-cycle arrest and apoptosis. FOXO1 expression is a favorable prognostic factor for human cervical cancer. PMID- 26125869 TI - Clinical features and treatment of endophthalmitis after cataract surgery. AB - The aim of this study was to investigate the clinical features and treatment results of endophthalmitis after cataract surgery. Five patients with endophthalmitis after phacoemulsification with intraocular lens implantation were enrolled in this study. The pathogenesis, clinical manifestation, and surgical outcomes of 5 patients were compared. Three patients were surgically treated with anterior chamber irrigation and vitrectomy with intravitreal injection. The remaining two patients were medically treated with an intravitreal injection of vancomycin and ceftazidime. Treatment results of the five patients were analyzed. Four patients had positive cultures for bacteria (two cases Staphylococcus epidermidis, one case Enterococcus faecalis, and one case head-like Staphylococcus). The culture of the fifth patient did not have bacterial growth. One year following treatment, four patients had restored visual acuity and a clear vitreous cavity. Retinal detachment and other complications were not observed. The remaining patient had a visual acuity of index at 30 cm one year following treatment. For patients with endophthalmitis after cataract surgery, a biochemical laboratory examination should be promptly performed and should include a bacterial culture and drug sensitivity test. When necessary, vitrectomy combined with an intravitreal injection of vancomycin should be performed to treat the infection early and to help retain useful vision. PMID- 26125870 TI - Karyotype structure of Hypostomus cf. plecostomus (Linnaeus, 1758) from Tapajos River basin, Southern Amazon: occurrence of sex chromosomes (ZZ/ZW) and their evolutionary implications. AB - Hypostomus is a group of fish with numerical and struc-tural karyotypic variability. Among them, only six species, three of which belong to the Amazon basin, show a sex chromosome. In this study, we present the karyotype structure of Hypostomus cf. plecos-tomus from the Teles Pires river basin in the municipality of Alta Flo-resta, MT. The species has 2n = 68 and the karyotype formula 14m+ 24sm+ 14st+ 16a [fundamental number (FN) = 120] in males and 15m+ 24sm+14st+15a (FN = 121) in females and sex chromosomes ZZ/ZW. Argyrophilic nucleolar organizer regions (AgNORs) were identified in two pairs of chromosomes at different positions: short arm of the pair 21and long arm of the pair 27, matching the signals displayed by 18S FISH and indicating multiple NORs. Analysis of band C detected few blocks of constitutive heterochromatin in the pericentromeric regions of most chromosomes and the telomeric regions of some pairs, includ-ing the nucleolar pair 21. However, large blocks on the long arm of the nucleolar pair 27 still stood out. GC-rich heterochromatin (CMA3) was visualized only coincidently with nucleolar sites. Mapping of 5S rDNA sites with FISH revealed markings in eight chromosomes, demonstrat-ing synteny between the 18S and 5S sites. The data obtained for H. cf. plecostomus are important for taxonomic studies of this Amazon com-plex "H. plecostomus group". The occurrence of sex chromosomes in Amazon species of Hypostomus suggests an evolutionary event that is independent of other species in the group. PMID- 26125871 TI - Association between IL-1beta, IL-8, and IL-10 polymorphisms and risk of acute pancreatitis. AB - We assessed the possible correlation between genetic polymorphisms in interleukin (IL)-1beta, IL-8, and IL-10 and risk of acute pancreatitis. Polymorphisms of IL 1beta+3954C/T (rs1143634), IL-1beta-511C/T (rs16944), IL-8 -251T/A (rs4073), IL 10 -1082A/G (rs1800896), and IL-10 -819C/T (rs1800871) were assessed by polymerase chain reaction-restriction fragment length polymorphism. Patients with acute pancreatitis were more likely to have a family history of acute pancreatitis and a habit of tobacco smoking and alcohol drinking. Conditional logistic regression analyses showed that subjects carrying IL-10 -1082A/G and IL 8 -251 AA genotype with the A allele were significantly associated with an increased risk of acute pancreatitis, with adjusted odds ratio (95% confidence interval) of 1.82 (1.01-3.31) and 1.39 (1.02-1.90), respectively. However, we did not observe that IL-1beta +3954C/T, IL-1beta -511C/T, IL-10 -1082A/G, and IL-10 819C/T polymorphisms were associated with the risk of acute pancreatitis. We found that the IL-8 -251T/A polymorphism is associated with an increased risk of acute pancreatitis, and no significant association between IL-1betaand IL-10 gene polymorphisms and risk of acute pancreatitis was detected. PMID- 26125872 TI - Effect of morphine preconditioning in the delayed phase on the expression of p38 mitogen-activated protein kinase in a rabbit model of myocardial ischemia reperfusion injury. AB - This study aimed to investigate the protective effects of delayed morphine preconditioning on myocardial ischemia-reperfusion injury. We randomly divided 30 rabbits into three groups with 10 rab-bits in each group as follows: sham operation group (C group), isch-emia-reperfusion group (I/R group), and morphine pretreatment group (M group). Rabbits in C Group received left coronary without blocking for 160 min. The left descending artery of rabbits in the I/R group was blocked for 40 min and reperfused for 120 min. Rabbits in the M group received intravenous administration of 1.0 mg/kg morphine; after 24 h, rabbits in this group received the same treatment as that administered to the I/R group. We determined tumor necrosis factor alpha (TNF-alpha) levels in blood samples from the internal carotid artery of rabbits in each group 20 min before occlusion of the left descending coronary artery, 20 and 40 min after occlusion of the left descending coronary artery, and 1 and 2 h after myocardial reperfusion. After 120 min of reperfusion, immunoblotting was used to measure the activity levels of myocardial p38 mitogen-activated protein kinase (MAPK); in addition, the infarct size was measured. Compared to the I/R group, the M group showed a significant decrease in TNF-alpha levels, p38 MAPK activity, and the myocardial infarct size (I/R group 37.8% +/- 1.7% vs 21.5% +/- 2.4%; P < 0.05). Thus, morphine preconditioning in the delayed phase may exert protective effects on myocardial I/R injury by inhibiting myocar-dial p38 MAPK activity and decreasing TNF-alpha production. PMID- 26125873 TI - Effects of goal-directed fluid therapy with different lactated Ringer's: hydroxyethyl starch ratios in hemorrhagic shock dogs. AB - The effects of goal-directed fluid therapy, with lactated Ringer's (LR) and 6% hydroxyethyl starch (HES) solution, on hemorrhagic shock dogs are unknown. We aimed to determine the optimal LR: HES ratio for the resuscitation of hemorrhagic shock dogs. Hemorrhagic shock was induced in 40 ventilated dogs by drawing an estimated 60% blood volume. The animals were randomly divided into five groups (N = 8) according to the LR: HES ratio of the resuscitation fluid (3:1, 2:1, 1:1, 1:2, and 1:3), and were then resuscitated for 24 h to reach the stroke volume variation (SVV) and hemoglobin (Hb) goals by fluid infusion and autologous blood perfusion. The extravascular lung water index (EVLWI), pH, partial pressure of oxygen (PaO2), base excess (BE), sodium, chloride, Hb and creatinine clearance (Clearcrea) were checked after 24 h (R24). The EVLWI of the 3:1 group at R24 were higher than that of the 1:3 group and the baseline value (P < 0.05), whereas the PaO2 was lower (P < 0.05). In contrast to the 3:1 group at R24 and baseline, plasma chloride and sodium in the 1:3 and 1:2 groups increased; however, pH, BE, and Clearcrea decreased (P < 0.05). No significant differences were found in the 1:1 and 2:1 groups at R24 compared with baseline (P > 0.05). Resuscitation with LR and HES at 2:1 and 1:1 ratios are superior in maintaining the acid-base, electrolyte, and lung water balances as well as renal function in hemorrhagic shock dogs than at ratios of 3:l, 1:2, and1:3. PMID- 26125874 TI - Non-invasive determination of the immune physiological state of reindeer (Rangifer tarandus) in the Greater Khingan Mountains, China. AB - Immunoglobulin and cortisol levels are good indicators of well-being and living status in animals. In this study, the concentrations of fecal immunoglobulins A ([IgAF]), G ([IgGF]), and M ([IgMF]), and cortisol ([cortisolF]) were examined by enzyme-linked immunosorbent assay in reindeer of the Greater Khingan Mountains of Inner Mongolia, China. [IgAF] was significantly higher than [IgGF] and [IgMF], and [IgGF] was significantly higher than [IgMF] (P < 0.05). Both [IgAF] and [IgGF] were higher in the Adult group than in Aged or Infant groups, and higher in the Young than Infant group (P < 0.05). The four age group [IgMF]s were not significantly different (P > 0.05). [IgAF], [IgGF], and [IgMF] in each age group were higher in females than in males, with a significant difference in the Young group (P < 0.05). The Infant group had the highest [cortisolF], and the Adult group the lowest; [cortisolF] was significantly higher in the Infant group than in other age groups (P < 0.05). In each age group, [cortisolF] was higher in females than males, and there were significant differences among the Infant, Young, and Aged groups (P < 0.05). A significant negative correlation was observed between [cortisolF] and [IgAF] and [IgGF] (P > 0.05). Overall physical condition was better in the Adult and Young groups than in the Aged and Infant groups as determined by the comprehensive analysis of fecal Ig levels in the four age groups, with the Infant group the worst. PMID- 26125875 TI - Case Report Unicentric Castleman disease located in the anterior mediastinum misdiagnosed as invasive thymoma: a case report. AB - Castleman disease is a rare lymphoproliferative disorder of unknown etiology. The localized form, which usually presents as a slow-growing mass, is most commonly located in the mediastinum. Invasion of the vena anonyma by a mass has rarely been reported. We herein describe a case of initially misdiagnosed invasive thymoma in a 72-year-old woman, but postoperatively proven to have anterior mediastinal Castleman disease with invasion of the vena anonyma. PMID- 26125876 TI - Development and characterization of new microsatellite markers of Fenneropenaeus penicillatus. AB - Thirteen new polymorphic microsatellite markers in Fenneropenaeus penicillatus were isolated and characterized. The polymorphism of the thirteen microsatellite markers was tested by 30 individuals from Lianjiang, China. It showed that the number of al-leles per locus ranged from 3 to 6 and the Polymorphism Information Content (PIC) was from 0.324 to 0.706. The observed and expected heterozygosities were 0.3217-0.8023 and 0.1977-0.6783, respectively. Only one loci (LJ-19) deviated significantly from Hardy-Weinberg equilibrium (HWE) (P < 0.00385) after Bonferroni correction, while the other twelve markers were in HWE after Bonferroni correction (P > 0.00385). The thirteen polymorphic microsatellite markers could pro-vide more genetic data for further research on cultivation and recovery of F. penicillatus. PMID- 26125877 TI - Construction of an integrated genetic map for Capsicum baccatum L. AB - Capsicum baccatum L. is one of the five Capsicum domesticated species and has multiple uses in the food, pharmaceutical and cosmetic industries. This species is also a valuable source of genes for chili pepper breeding, especially genes for disease resistance and fruit quality. However, knowledge of the genetic structure of C. baccatum is limited. A reference map for C. baccatum (2n = 2x = 24) based on 42 microsatellite, 85 inter-simple sequence repeat, and 56 random amplified polymorphic DNA markers was constructed using an F2 population consisting of 203 individuals. The map was generated using the JoinMap software (version 4.0) and the linkage groups were formed and ordered using a LOD score of 3.0 and maximum of 40% recombination. The genetic map consisted of 12 major and four minor linkage groups covering a total genome distance of 2547.5 cM with an average distance of 14.25 cM between markers. Of the 152 pairs of microsatellite markers available for Capsicum annuum, 62 were successfully transferred to C. baccatum, generating polymorphism. Forty-two of these markers were mapped, allowing the introduction of C. baccatum in synteny studies with other species of the genus Capsicum. PMID- 26125878 TI - Improving plant transformation using Agrobacterium tumefaciens. AB - Here, we report a quick and low-cost method to improve plant transformation using Agrobacterium tumefaciens. This method involves the use of physical wounding, ultrasound, and an increase in exposure time to the bacteria. We show how the transformation rate increased from 0 to 14% when an ultrasound pulse of 10 s was used in conjunction with 96 h of bacterial exposure in Eclipta alba explants. PMID- 26125879 TI - Association between FTO polymorphism in exon 3 with carcass and meat quality traits in crossbred ducks. AB - The fat mass and obesity-associated gene (FTO) is an excellent candidate gene that affects energy metabolism. Single nucleotide polymorphisms (SNPs) in FTO are associated with carcass and meat quality traits in pigs, cattle, and rabbits. The aim of this study was to investigate the association between novel SNPs in the FTO coding region and carcass and meat quality traits in 95 crossbred ducks, using DNA sequencing. We found two transitions G/A (SNP 387 and 473) within exon 3. SNP 387 was a synonymous mutation, whereas SNP 473 was a missense mutation. Association analysis suggested that SNP g.387G>A was significantly associated with all of the carcass traits measured, the intramuscular fat content (IMF), cooking yield (CY), pH values 45 min after slaughter (pH45m), drip losses from the breast muscle, and the leg muscle (P < 0.05). For SNP g.473G>A, the genotype AA exhibited greater leg muscle weight than the genotypes GG or AG (P < 0.05). The D value suggested that the two SNPs exhibited strong linkage disequilibrium. Three haplotypes (G1G2, G1A2, and A1A2) were significantly associated with IMF, CY, the a* value, and all of the carcass traits measured (P < 0.05). The results suggest that FTO is a candidate locus that affects carcass and meat quality traits in ducks. PMID- 26125880 TI - Hypoxia-inducible factor-1alpha expression in the different stages of rat thromboangiitis obliterans. AB - We investigated the expression and effects of hypoxia-inducible factor-1alpha (HIF-1alpha) in rat thromboangiitis obliterans (TO). Rats were divided into sham and model groups. The model group was further divided into groups based on observation duration. Lauric acid was injected below an artery clamp to simulate TO in the model group; saline was used in the sham group. Clamps were removed 15 min after injection in both groups, and physiological changes were observed at different times (gross observation and hematoxylin and eosin staining). The animals were killed at various times following the operation and serum and muscle tissues were sampled. For the sham group: the endometrium was relatively intact; medial membrane and epineurium lesions were absent; and blood vessels and surrounding tissues had no inflammatory cell infiltration. For the model group: all subgroups displayed inflammation; large numbers of inflammatory cells were gathered; muscle tissue lost its normal texture and structure; and the internal elastic membrane was integrated. Compared with the preoperative status, HIF 1alpha expression increased significantly in all subgroups (P < 0.05); there was no change in the sham group. HIF-1alpha expression in each subgroup was different (F = 14.267, P < 0.05). Femoral artery injection of lauric acid can be used as a rat TO model owing to its simple application and success rate. HIF-1alpha expression increased in the early stage of TO and gradually decreased with the extension of ischemia time; it may play a leading role in TO development and can be used for diagnosis and cure evaluation. PMID- 26125881 TI - Detection of drug-resistance mechanism of Pseudomonas aeruginosa developing from a sensitive strain to a persister during carbapenem treatment. AB - We explored the mechanism of the development from sensitivity to resistance to carbapenem in Pseudomonas aeruginosa. Two P. aeruginosa strains were collected during treatment with carbapenem. Strain homology was investigated using pulsed field gel electrophoresis. Porin oprD2 expression was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The minimum inhibitory concentrations (MICs) of imipenem and meropenem with or without MC207110 were determined using the agar dilution method. The expression level of efflux pump mRNA was tested using real-time polymerase chain reaction. Metallo-lactamases (MBLs) were screened using the EDTA-disk synergy test. Genes encoding MBLs were amplified and then analyzed by DNA sequencing. The two treated strains belonged to the same pulsed-field gel electrophoresis type. The SDS-PAGE profile of the P. aeruginosa strains revealed that the 46-kDa membrane protein OprD2 of IMP(R)MEM(R) type strains was lost, whereas OprD2 of 1 IMP(S)MEM(S) strain was normal. With or without MC207110 treatment, the MIC of carbapenem-resistant P. aeruginosa decreased by 4-fold, while the MIC of carbapenem-sensitive P. aeruginosa did not. Compared with the carbapenem-sensitive strain, MexX mRNA expression in the carbapenem-resistant strain increased by 102.5-fold, while the mRNA expression of other efflux pumps did not markedly increase. Neither carbapenem-resistant nor carbapenem-sensitive P. aeruginosa produced MBL. The mechanism of development from sensitivity to resistance of P. aeruginosa to carbapenem during carbapenem treatment is due to porin oprD2 loss and an increased expression level of MexXY-OprM. PMID- 26125882 TI - Relationship between zinc finger protein 36 (ZFP36) gene polymorphisms and obstructive sleep apnea. AB - Recent data have indicated that inflammation may have an important correlation with obstructive sleep apnea (OSA). Studies have indicated a relationship between OSA and TNF-alpha gene polymorphisms. Zinc finger protein 36 (ZFP36) regulates TNF-alpha mRNAs. However, ZFP36 gene polymorphisms have not been investigated in OSA. Therefore, we conducted the present case-control study to assess whether variances in ZFP36 gene polymorphisms account for differences in TNF-alpha levels in patients with moderate-to-severe OSA. This case-control study aims to investigate the relationship between genetic variations in the ZFP36 gene and moderate-to-severe OSA. Three common single nucleotide polymorphisms of the ZFP36 gene (rs251864, rs3746083, and rs17879933) were evaluated in a group of patients with moderate-to-severe OSA (N = 408) and in a control group (N = 394) by using TaqMan polymerase chain reaction analysis. The moderate-to-severe OSA group and the control group exhibited significant differences in the distributions of rs251864 and rs17879933 genotypes and alleles (P < 0.05). TNF-alpha levels were significantly different not only among the three rs251864 genotypes but also between the II genotype and the DD + ID genotypes of rs17879933. However, no significant differences in sleep apnea parameters in the three ZFP36 gene polymorphisms were observed. Logistic regression analyses demonstrated that TNF alpha and the three ZFP36 gene polymorphisms were not independently associated with OSA. ZFP36 might be involved in TNF-alpha regulation. However, ZFP36 gene variants were not independent risk factors for moderate-to-severe OSA. PMID- 26125883 TI - Multi-objective optimization in systematic conservation planning and the representation of genetic variability among populations. AB - Biodiversity crises have led scientists to develop strategies for achieving conservation goals. The underlying principle of these strategies lies in systematic conservation planning (SCP), in which there are at least 2 conflicting objectives, making it a good candidate for multi-objective optimization. Although SCP is typically applied at the species level (or hierarchically higher), it can be used at lower hierarchical levels, such as using alleles as basic units for analysis, for conservation genetics. Here, we propose a method of SCP using a multi-objective approach. We used non-dominated sorting genetic algorithm II in order to identify the smallest set of local populations of Dipteryx alata (baru) (a Brazilian Cerrado species) for conservation, representing the known genetic diversity and using allele frequency information associated with heterozygosity and Hardy-Weinberg equilibrium. We worked in 3 variations for the problem. First, we reproduced a previous experiment, but using a multi-objective approach. We found that the smallest set of populations needed to represent all alleles under study was 7, corroborating the results of the previous study, but with more distinct solutions. In the 2nd and 3rd variations, we performed simultaneous optimization of 4 and 5 objectives, respectively. We found similar but refined results for 7 populations, and a larger portfolio considering intra-specific diversity and persistence with populations ranging from 8-22. This is the first study to apply multi-objective algorithms to an SCP problem using alleles at the population level as basic units for analysis. PMID- 26125884 TI - Correlation between promoter methylation in the GSTP1 gene and hepatocellular carcinoma development: a meta-analysis. AB - Epigenetic silencing of the GSTP1 gene by promoter methylation has been associated with increased risk and shortened survival in patients with hepatocellular carcinoma (HCC). We therefore conducted a meta-analysis to obtain a more precise estimate of this association. By searching the Cochrane Library, CBM, EMBASE, PubMed, and the Web of Science, we tabulated and analyzed parameters from each study. Results were summarized by meta-analyses using the version 12.0 STATA software. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were also calculated in this analysis. A total of 14 cohort studies (tumor samples = 607, adjacent samples = 356, benign samples = 182, normal samples = 133) were included for the following statistical analysis. Our meta-analysis results demonstrated that the frequency of GSTP1 methylation in cancer tissues was significantly higher than those in adjacent tissues, benign tissues, and normal tissues (all P < 0.05). Further subgroup analysis by country indicated that the frequency of aberrant GSTP1 promoter methylation was correlated to the development of HCC among all the included experimental subgroups (all P < 0.05). The results indicate a significant association between GSTP1 methylation and poor outcomes in HCC patients. PMID- 26125885 TI - Differential gene expression in pre-laying and laying period ovaries of Sichuan White geese (Anser cygnoides). AB - Geese are an economically important poultry species worldwide. Their superior meat production performance and meat qual-ity make them a popular food. However, they are not bred worldwide because their poor laying capacity increases farming costs. To gain a global view of the genes that are differentially expressed between pre-laying (P) and laying (L) periods and to develop a database for further studies, we performed large-scale transcriptome sequencing of ovarian tissue collected from Anser cygnoides. In total, 30,151,422 raw reads, with an average length of 151 bp and a total length of 4,552,864,722 bp, were obtained. After primers and adaptors were removed, 19,167,132 clean reads, with an average length of 134.5 bp and a total length of 2,577,297,281 bp, were obtained, among which 1,268,906,694 bp and 1,308,390,587 bp were from L and P ovarian tissue, respectively. The 16,605 assembled sequences were further functionally annotated by comparing their sequences to different protein and functional domain databases and assigning gene ontology (GO) terms. Of these, 511 as-sembled sequences were considered differentially expressed based on the 2-fold method, among which 396 were assigned at least one GO term. Digital expression analysis using the Kyoto encyclopedia of genes and genomes annotation identified 121 genes that were differ-entially expressed in the P vs L periods. Five of these are of special interest for further investigation of their roles in determining high re productive performance. This study provides valuable information and sequence resources for uncovering genes determining high egg-laying performance and for future functional genomics analysis of geese. PMID- 26125886 TI - QTLs for rice flag leaf traits in doubled haploid populations in different environments. AB - Two rice doubled haploid (DH) populations derived from the crosses of ZYQ8/JX17 and CJ06/TN1 were used to detect quantitative trait loci (QTLs) for flag leaf length (FLL), width (FLW), and angle (FLA) under long-day conditions in Hangzhou (subtropical zone) and short-day conditions in Hainan (tropical zone), China. The four parents differed significantly in all 3 traits. FLL was found to be positively correlated with FLW in the 2 populations. A total of 30 QTLs were identified for flag leaf traits, with a contribution to the phenotypic variation of each QTL from 4.49 to 26.30%. Among these, qFLL-4b, qFLW-12, and qFLA-2a showed larger additive effects on the phenotype and explained more variations compared to the other QTLs. qFLL-1a and qFLL-8 were detected in both environments, while qFLL-2, qFLL-3, qFLL-10, qFLL-12, qFLW11, qFLW2, and qFLA8 were novel QTLs, which may be beneficial to rice ideal-type breeding. PMID- 26125887 TI - Artificial neural networks reveal efficiency in genetic value prediction. AB - The objective of this study was to evaluate the efficiency of artificial neural networks (ANNs) for predicting genetic value in experiments carried out in randomized blocks. Sixteen scenarios were simulated with different values of heritability (10, 20, 30, and 40%), coefficient of variation (5 and 10%), and the number of genotypes per block (150 and 200 for validation, and 5000 for neural network training). One hundred validation populations were used in each scenario. Accuracy of ANNs was evaluated by comparing the correlation of network value with genetic value, and of phenotypic value with genetic value. Neural networks were efficient in predicting genetic value with a 0.64 to 10.3% gain compared to the phenotypic value, regardless the simulated population size, heritability, or coefficient of variation. Thus, the artificial neural network is a promising technique for predicting genetic value in balanced experiments. PMID- 26125888 TI - Identification of smut-responsive genes in sugarcane using cDNA-SRAP. AB - Sugarcane smut, caused by the fungus Sporisorium scitamineum, is one of the main diseases that affect sugarcane worldwide. In the present study, the cDNA-SRAP technique was used to identify genes that are likely to be involved in the response of sugarcane to S. scitamineum infection. In total, 21 bands with significant differential expression during cDNA-SRAP analysis were cloned and sequenced. Real-time qPCR confirmation demonstrated that expression of 19 of these 21 differential bands was consistent with the expression observed during cDNA-SRAP analysis, with a deduced false positive rate of 9.5%. Sequence alignment indicated that 18 of 19 differentially expressed genes showed homologies from 19% to 100% to certain genes in GenBank, including the following genes: topoisomerase (EU048780), ethylene insensitive (EU048778), and tetraspanin (EU048770). A real-time qPCR assay showed that during 0-72 h after pathogen infection, expression of the topoisomerase and the ethylene insensitive genes was upregulated, whereas expression of the tetraspanin gene was downregulated, identical to the expression patterns observed under salicylic acid treatment. Therefore, all three genes are thought to play a role during S. scitamineum challenge, but with different functions. To our knowledge, this is the first report on the application of cDNA-SRAP in differential gene expression analysis of sugarcane during a sugarcane-S. scitamineum interaction. The results obtained also contribute to a better understanding of the molecular mechanisms associated with sugarcane-S. scitamineum interactions. PMID- 26125889 TI - Cloning and expression of an APETALA1-like gene from Nelumbo nucifera. AB - The objective of this study was to clone the full-length cDNA of the APETALA1 (AP1) gene from lotus and analyze its sequence and expression pattern. The full length cDNA sequence of the NnAP1 gene was amplified from the petals of Nelumbo nucifera 'Hongxia' using RT-PCR and rapid amplification of cDNA ends. Bioinformatic methods were used to analyze the sequence characteristics of the gene. Quantitative real-time PCR methods were used to investigate the expression pattern of NnAP1 in various organs and during different developmental stages. The cloned full-length NnAP1 cDNA (GenBank accession No. KF361315) was 902 bp, containing a 795-bp open reading frame encoding 264 amino acids with a relative molecular mass of 30,288.4 and an isoelectric point of 9.13. NnAP1 had a MADS-box domain and a K-box domain, which is typical of the SQUA/AP1 gene family. A protein sequence identity search showed that NnAP1 was 75-96% similar to other plant AP1s. Phylogenetic tree analysis indicated that NnAP1 was very closely related to AP1 of Glycine max, suggesting that they shared the same protein ancestor. Quantitative real-time PCR analysis showed that NnAP1 was expressed in various organs during different developmental stages; it had the highest expression in blooming flowers and had trace expression in the young vegetative and flower senescence stages. Our analysis suggests that NnAP1 plays an important role in controlling floral meristem identity and floral organ formation. PMID- 26125890 TI - Clinical and pathological features and treatment of AIDS-related cutaneous Kaposi's sarcoma in Chinese Han patients. AB - This retrospective study aimed to observe the clinicopathological features and immunological phenotypes, and explore effective treatment and prognosis for 12 Chinese Han patients with acquired immunodeficiency syndrome-related cutaneous Kaposi's sarcoma. All 12 patients were human immunodeficiency virus-positive, and underwent the standard highly active antiretroviral therapy (HAART). Skin lesions mainly presented as purple, or rufous papules, or plaques; skin biopsy showed diffuse or flaky infiltration of spindle cells, active proliferation of slit-like vasculature, erythrocyte exudation, hemosiderin deposition, and inflammatory cell infiltration. Immunohistochemical analysis showed the expression of Ubiquitin C terminal hydrolase L1 (+), and CD31 (+) in T-cells; factor VIII (+) and HHF-35 (+) in the proliferating vascular endothelial cells; vimentin (+) and S-100 protein (-) in the vessel wall; and CD34 (+++) in the spindle cells of 6 cases, with 1 case of negative CD34 expression. Four patients with confined lesions underwent surgery and microwave therapy, and received a favorable prognosis. Two patients with limited lesions underwent microwave therapy, and the lesions subsided. Of six patients with widely distributed sarcomas, five underwent microwave therapy and one received combined chemotherapy; five attained significant efficacy, and one died. There were no significant differences in the clinicopathological features and immunological phenotypes between the Chinese Han patients and those from other populations. Along with basal HAART, patients in early stages, with sarcomas <2 cm in diameter should undergo surgery and microwave therapy, while patients with sarcomas >2 cm in diameter should undergo chemotherapy and microwave therapy. PMID- 26125891 TI - Association between interleukin gene polymorphisms and risk of recurrent oral ulceration. AB - We conducted a case-control study to investigate the association between the functional IL-1beta+3954 (C/T), IL-6-174 (G/C), IL-10-1082 (G/A), and IL-10 819C/T genetic polymorphisms and risk of recurrent oral ulceration (ROU) in a Chinese population. Polymorphisms of IL-1beta+3954C/T, IL-6-174G/C, IL-10-1082A/G and IL-10-819C/T were assessed by polymerase chain reaction-restriction fragment length polymorphism. The genotype distributions of the IL-1beta+3954 C/T and IL 10-819C/T were in Hardy-Weinberg equilibrium in the control group. Conditional logistic regression analyses showed that subjects carrying the IL-1beta+3954CC and IL-10-1082AA genotypes had a significantly increased risk of ROU, with adjusted ORs (95%CI) of 2.86 (1.37-6.33) and 1.72 (1.02-2.89), respectively. In summary, we found that IL-1beta+3954C/T and IL-10-1082A/G polymorphisms are associated with an increased risk of ROU. PMID- 26125892 TI - Expression and significance of S100P, CD147, and OCT4 in different prostate cancer tissue TNM stages. AB - The aim of this project was to investigate the expression and significance of S100P, CD147, and OCT4 in prostate cancer tissue at different TNM stages. We enrolled 54 patients with prostate cancer, 40 with benign prostatic hyperplasia, and 20 subjects with normal prostates. S100P, CD147, and OCT4 were detected by immunohistochemistry. The positive rate of S100P detection was 18.52% in prostate cancer tissues, significantly lower than in normal and benign prostate hyperplasia tissues (P ? 0.05). The positive expression rate of CD147 and OCT4 were 100 and 77.38% in prostate cancer tissue, respectively, both markedly higher than in normal and benign prostate hyperplasia tissue (P ? 0.05). The positive rate of S100P in stage V was 0, which was significantly lower than in stages I (37.50%) and II (35.71%) (P ? 0.05). OCT4 expression in stages III (86.67%) and V (94.12%) was higher than in stage I (37.50%). The positive rate of S100P in patients with distant metastasis was 4%, which was significantly lower than that in patients without metastases (P ? 0.05). In contrast, the positive rate of OCT4 in patients with distant metastasis was 92%. S100P, CD147, and OCT4 expression in prostate cancer patients with different degrees of differentiation had no significant difference (P > 0.05). Overall, our results demonstrated that S100P expression in prostate cancer tissue was significantly decreased, whereas CD147 and OCT4 expression was increased. Their expression levels were closely associated with TNM stage and distant metastasis, but were not related to the degree of differentiation. PMID- 26125893 TI - Expression of TNF-alpha, VEGF, and MMP-3 mRNAs in synovial tissues and their roles in fibroblast-mediated osteogenesis in ankylosing spondylitis. AB - The aim of this study was to explore the mRNA levels of tumor necrosis factor alpha (TNF-alpha), vessel endothelial growth factor (VEGF), and matrix metalloproteinase-3 (MMP-3) in synovial tissues in ankylosing spondylitis (AS), and to analyze the functions of these proteins in the differentiation of AS synovial tissue fibroblasts into osteoblasts (OB) and osteoclasts. Synovial tissue samples from 22 AS patients and 22 normal individuals were collected. In situ hybridization was utilized to detect TNF-alpha, VEGF, and MMP-3 transcripts. After counting numbers of positive cells, Spearman analysis was used to determine the correlation between transcriptional levels of the three mRNAs and the AS disease activity index (BASDAI) and the C-response protein (CRP) levels. With the addition of TNF-alpha, VEGF, or both factors into cultured normal synovial fibroblasts, osteocalcin (bone gla protein, BGP) secretion levels were compared. We found that expression of TNF-alpha, VEGF, and MMP-3 was identified exclusively in the disease group. mRNA levels were significantly positively correlated with BASDAI (r = 0.42, 0.38, and 0.47, respectively; P < 0.05) and CRP (r = 0.44, 0.34, and 0.47 respectively; P < 0.05) scores. The secretion level of BGP in normal synovial fibroblasts increased progressively with increasing concentrations of VEGF or TNF-alpha (P < 0.01 compared to levels before treatment). Furthermore, co-incubation using both VEGF and TNF-alpha significantly elevated BGP levels compared to the single addition of VEGF or TNF alpha (P < 0.01). These results suggest TNF-alpha, VEGF, and MMP-3 might directly participate in the differentiation of fibroblasts into OBs. PMID- 26125894 TI - Association of cytokine gene polymorphisms with susceptibility to invasive candidiasis. AB - The aim of this study was to investigate the role of cytokine genes in the susceptibility to Candida infection. A total of 275 consecutive patients diagnosed with Candida infection were selected between May 2010 and May 2011, along with 305 uninfected controls. Genotyping of the IL-1beta gene polymorphisms (IL1beta) rs1143634, IL1betars16944, IL8 rs4073, IL10 rs1800872, and IL10 rs1800896 was carried out using a 384-well plate format on the Sequenom MassARRAY platform. Patients with invasive Candida infections were more likely to have had an immunocompromised state, hematopoietic stem cell transplantation, solid organ transplant, solid tumor, chemotherapy within the past three months, neutropenia, surgery within the past 30 days, acute renal failure, liver failure, and/or median baseline serum creatinine. Conditional logistic regression analyses found that individuals with the rs1800896 GG genotype were associated with a higher risk of invasive Candida infections than those carrying the AA genotype (odds ratio = 0.61, 95% confidence interval = 0.37-0.94). From the results of this case control study, we suggest that the cytokine IL-10 gene rs1800896 polymorphism might play a role in the etiology of invasive Candida infections. PMID- 26125895 TI - Intracranial aneurysm risk factor genes: relationship with intracranial aneurysm risk in a Chinese Han population. AB - Few studies have examined the genes related to risk fac-tors that may contribute to intracranial aneurysms (IAs). This study in Chinese patients aimed to explore the relationship between IA and 28 gene loci, proven to be associated with risk factors for IA. We recruited 119 patients with aneurysms and 257 controls. Single factor and logistic regression models were used to analyze the association of IA and IA rup-ture with risk factors. Twenty-eight single nucleotide polymorphisms (SNPs) in 22 genes were genotyped for the patient and control groups. SNP genotypes and allele frequencies were analyzed by the chi-square test. Logistic regression analysis identified hypertension as a factor that increased IA risk (P = 1.0 x 10(-4); OR, 2.500; 95%CI, 1.573-3.972); IA was associated with two SNPs in the TSLC2A9 gene: rs7660895 (P = 0.007; OR, 1.541; 95%CI, 1.126-2.110); and in the TOX gene: rs11777927 (P = 0.013; OR, 1.511; 95%CI, 1.088-2.098). Subsequent removal of the influence of family relationship identified between 12 of 119 patients enhanced the significant association of these SNPs with IA (P = 0.001; OR, 1.691; 95%CI, 1.226-2.332; and P = 0.006; OR, 1.587; 95%CI, 1.137-2.213 for rs7660895 and rs11777927, respectively). Fur-thermore, the minor allele of rs7660895 (A) was also associated with IA rupture (P = 0.007; OR, 2.196; 95%CI, 1.230-3.921). Therefore, hypertension is an independent risk factor for IA. Importantly, the TSL-C2A9 (rs7660895) and TOX (rs11777927) gene polymorphisms may be associated with formation of IAs, and rs7660895 may be associated with IA rupture. PMID- 26125896 TI - Investigation of Sclerotinia sclerotiorum strains variability in Brazil. AB - White mold is a common bean disease caused by the fungus Sclerotinia sclerotiorum, resulting in economic losses in Brazil and worldwide. Lack of knowledge about the population structure of the pathogen makes it difficult to control the disease. The aim of this study was to characterize strains of S. sclerotiorum obtained from ex-perimental and commercial common bean fields in Brazil. We analyzed 50 strains of S. sclerotiorum collected at several locations in the state of Minas Gerais. The strains were characterized according to their ability and time for developing apothecia. Morphological and physiological analyses such as the mycelial growth index, colony color, the time re-quired to form the first sclerotia on media, the number of sclerotia per plate, average sclerotium size, and sclerotium shape were performed. We determined the mycelial compatibility, conducted molecular analy-sis of microsatellites, and evaluated the aggressiveness of 28 strains. Most strains had the ability to form apothecia. A small group of strains showed mycelial compatibility, and the strains showed different aggres-siveness levels. Overall, the population studied here demonstrated wide variability based on the morphological, physiological, and molecular traits analyzed. The average size and shape of sclerotia presented a cor-relation of 0.617, whereas the times required to form sclerotia and the number of sclerotia per plate showed a correlation of -0.455. The char acterization of the pathogen population described herein will provide an important tool for promoting the development of bean cultivars re-sistant to white mold. PMID- 26125897 TI - Screening for fragile X syndrome in males from specialized institutions in the northeast region of Brazil. AB - The objective of this study was to perform a study of fragile X syndrome (FXS) in Sao Luis, Maranhao, in males residing in five specialized institutions. Two hundred thirty-eight males with intel-lectual disability of unknown etiology participated in this study. Blood samples were processed and stored until DNA extraction. Screening for FMR1 gene mutations was performed using non-isotopic polymerase chain reaction amplification and DNA sequencing using an ABI Prism 3130 automated sequencer. Two individuals (0.84%) were positive for FMR1 mutations. One had a mutation due to expansion of the CGG repeat beyond normal levels and the other had a deletion in exon 1 of the FMR1 gene, which was confirmed by sequencing. Both probands were over 18 years old, which demonstrates the late diagnosis of the condition in these individuals and reinforces the need to implement ef-fective programs for early diagnosis of FXS in the state of Maranhao. We found that FXS might be transmitted in the families of the two indi viduals bearing the mutation, and that it is important to understand the mutation dynamics to provide better counseling to the family members of these two individuals. PMID- 26125898 TI - Development and cross-species transferability of unigene-derived microsatellite markers in an edible oil woody plant, Camellia oleifera (Theaceae). AB - Camellia oleifera is an important edible oil woody plant in China. Lack of useful molecular markers hinders current genetic research on this tree species. Transcriptome sequencing of developing C. oleifera seeds generated 69,798 unigenes. A total of 6949 putative microsatellites were discovered among 6042 SSR containing unigenes. Then, 150 simple sequence repeats (SSRs) were evaluated in 20 varieties of C. oleifera. Of these, 52 SSRs revealed polymorphism, with the number of alleles per locus ranging from 2 to 15 and expected heterozygosity values from 0.269 to 0.888. The polymorphic information content varied from 0.32 to 0.897. Cross-species transferability rates in Camellia chekangoleosa and Camellia japonica were 90.4 and 78.8%, respectively. The 52 polymorphic unigene derived SSR markers serve to enrich existing microsatellite marker resources for C. oleifera and offer potential for applications in genetic diversity evaluation, molecular fingerprinting, and genetic mapping in C. oleifera, C. chekangoleosa, and C. japonica. PMID- 26125899 TI - Diadenylate cyclase evaluation of ssDacA (SSU98_1483) in Streptococcus suis serotype 2. AB - Cyclic diadenosine monophosphate is a recently identified signaling molecule. It has been shown to play important roles in bacterial pathogenesis. SSU98_1483 (ssDacA), which is an ortholog of Listeria monocytogenes DacA, is a putative diadenylate cyclase in Streptococcus suis serotype 2. In this study, we determined the enzymatic activity of ssDacA in vitro using high-performance liquid chromatography and mass spectrometry. Our results showed that ssDacA was a diadenylate cyclase that converts ATP into cyclic diadenosine monophosphate in vitro. The diadenylate cyclase activity of ssDacA was dependent on divalent metal ions such as Mg(2+), Mn(2+), or Co(2+), and it is more active under basic pH than under acidic pH. The conserved RHR motif in ssDacA was essential for its enzymatic activity, and mutation in this motif abolished the diadenylate cyclase activity of ssDacA. These results indicate that ssDacA is a diadenylate cyclase, which synthesizes cyclic diadenosine monophosphate in Streptococcus suis serotype 2. PMID- 26125900 TI - Brief Note Low diversity of the major histocompatibility complex class II DRA gene in domestic goats (Capra hircus) in Southern China. AB - DRA encodes the alpha chain of the DR heterodimer, is closely linked to DRB and is considered almost monomorphic in major histocompatibility complex region. In this study, we identified the exon 2 of DRA to evaluate the immunogenetic diversity of Chinese south indigenous goat. Two single nucleotide polymorphisms in an untranslated region and one synonymous substitution in coding region were identified. These data suggest that high immunodiversity in native Chinese population. PMID- 26125901 TI - Mechanisms of cytotoxicity induced by the anesthetic isoflurane: the role of inositol 1,4,5-trisphosphate receptors. AB - Isoflurane can induce widespread cytotoxicity. We hypothesized that isoflurane induces apoptosis partly by causing excessive calcium release from the endoplasmic reticulum (ER) via direct activation of inositol 1,4,5-trisphosphate receptors (IP3R). Rat pheochromocytoma cells cultured for seven days with nerve growth factor were divided into four groups: control group (C), IP3R antagonist group (X), isoflurane group (I) and isoflurane + IP3R antagonist group (I+X). Groups I and I+X were treated with 1 MAC isoflurane for 12 h. Groups X and I+X were pretreated with IP3R antagonist. Annexin V/PI apoptosis and TUNEL assays were performed to evaluate cell apoptosis. TEM was used to observe changes in cell ultrastructure. Changes in calcium concentration ([Ca(2+)]i) in the cytoplasm were measured by flow cytometry. RT-PCR was performed to evaluate IP3R mRNA expression. TEM showed that isoflurane treatment altered cell ultrastructure. Compared to group C, cell apoptosis rate and [Ca(2+)]i increased in groups I and I+X (P < 0.05). Compared to group C, IP3R mRNA expression was lower in group X and higher in group I (P < 0.05). Compared to group X, cell apoptosis rate, [Ca(2+)]i and IP3R mRNA expression increased in groups I and I+X (P < 0.05). Compared to group I, cell apoptosis rate, [Ca(2+)]i and IP3R mRNA expression decreased in group I+X (P < 0.05). These results suggest that exposure to 1 MAC isoflurane for 12 h causes excessive calcium release partly by direct activation of IP3R on the ER membrane and triggers cell apoptosis. PMID- 26125902 TI - Decreased microRNA-143 expression and its tumor suppressive function in human oral squamous cell carcinoma. AB - MicroRNA-143 serves as a tumor suppressor in many human malignancies. However, its involvement in oral squamous cell carcinoma (OSCC) is still unclear. In this study, we investigated the effects of miR-143 in OSCC tumorigenesis and development. Using real-time quantitative reverse transcription-polymerase chain reaction, we detected miR-143 expression in 109 pairs of human OSCC and adjacent noncancerous tissues. The associations between miR-143 expression and clinicopathological factors and prognosis of OSCC patients were also statistically analyzed. Further, the effects of miR-143 on the biological behavior of OSCC cells were investigated. miR-143 expression was significantly downregulated in OSCC tissue samples and cell lines. Decreased miR-143 expression was significantly associated with advanced T classifications, positive N classification, advanced TNM stage, and shorter overall survival. In addition, upregulation of miR-143 in Tca8113 cells reduced cell proliferation, invasion, and migration, as well as promoted cell apoptosis in vitro. These findings validate the clinical significance of miR-143 in OSCC and reveal that it may be an intrinsic regulator of tumor progression and a potential prognostic factor for this disease. PMID- 26125903 TI - Clinical significance and levels of blood brain natriuretic peptides in patients with persistent atrial fibrillation before and after catheter ablation. AB - The aim of this study was to observe levels of blood brain natriuretic peptides (BNPs) in patients with persistent atrial fibril-lation (AF) before and after catheter ablation. Thirty-six patients with persistent AF (28 successful surgeries and eight recurrent cases) and 36 healthy controls with normal sinus rhythm were recruited for this study. BNP levels in the AF and control groups were measured before and after catheter ablation. BNP levels before surgery were significantly higher in the persistent AF group than in the control group (P < 0.01). The successful surgery group had distinctly lower BNP levels before ablation than the recurrent group (P < 0.01). In the recurrent group, BNP levels 2 h after ablation were significantly lower than those be-fore ablation (P < 0.01); these levels increased after AF recurrence (P < 0.01) and were comparable with those before ablation (P < 0.01). Logistic regression analysis indicated that the BNP level was an inde-pendent factor for and predictor of AF recurrence (P < 0.01). The BNP level in patients with persistent AF is clinically important in predicting and evaluating AF recurrence after ablation. PMID- 26125904 TI - PDIA3 and PDIA6 gene expression as an aggressiveness marker in primary ductal breast cancer. AB - Changes in the expression of the protein disulfide isomerase genes PDIA3 and PDIA6 may increase endoplasmic reticulum stress, leading to cellular instability and neoplasia. We evaluated the expression of PDIA3 and PDIA6 in invasive ductal carcinomas. Using reverse transcription-quantitative polymerase chain reaction, we compared the mRNA expression level in 45 samples of invasive ductal carcinoma with that in normal breast samples. Increased expression of the PDIA3 gene in carcinomas (P = 0.0009) was observed. In addition, PDIA3 expression was increased in tumors with lymph node metastasis (P = 0.009) and with grade III (P < 0.02). The PDIA6 gene showed higher expression levels in the presence of lymph node metastasis (U = 99.00, P = 0.0476) and lower expression for negative hormone receptors status (P = 0.0351). Our results suggest that alterations in PDIA3/6 expression levels may be involved in the breast carcinogenic process and should be further investigated as a marker of aggressiveness. PMID- 26125905 TI - Inhibition of adipogenic differentiation of bone marrow mesenchymal stem cells by erythropoietin via activating ERK and P38 MAPK. AB - We examined whether erythropoietin (EPO) can inhibit adipogenic differentiation of mesenchymal stem cells (MSCs) in the mouse bone marrow and its underlying mechanism. We separated and extracted mouse bone marrow MSCs and induced adipogenic differen-tiation using 3-isobutyl-1-methylxanthine, insulin, and dexamethasone. Different concentrations of EPO were added to the cells and observed by Oil Red O staining on the 20th day to quantitatively analyze the degree of cell differentiation. mRNA expression levels of peroxysome proliferator activated receptor gamma (PPARgamma), CCAAT enhancer binding protein alpha, and adiponectin were analyzed by real-time quantitative polymerase chain reaction, and the activity of PPARgamma, extracellular sig-nal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (p38 MAPK) were determined by western blotting. EPO significantly inhibited adipogenic differentiation of MSCs after 20 days and reduced absorbance values by Oil Red O staining without affecting proliferation activity. EPO downregulated the mRNA expression of PPARgamma, CCAAT enhancer binding protein alpha, fatty acid binding protein 4, and adiponec-tin during adipogenesis and increased protein phosphorylation of ERK, p38 MAPK, and PPARgamma during differentiation. EPO downregulated the mRNA expression of PPARgamma, CCAAT enhancer binding protein alpha, fatty acid binding protein 4, and adiponectin by increasing protein phosphor-ylation of ERK, p38 MAPK, and PPARgamma during differentiation, which inhibited adipogenic differentiation of MSCs. PMID- 26125906 TI - WY14643 combined with all-trans retinoic acid acts via p38 MAPK to induce "browning" of white adipocytes in mice. AB - The ability of mammals to resist body fat accumulation is linked to their ability to expand the number of "brown adipocytes" within white fat depots. All-trans retinoic acid (t-RA) and peroxi-some proliferator-activated receptor-alpha (PPARalpha) have been implicated in "browning-like" or "browning" programs, respectively. However, a PPARalpha-agonist (WY14643) failed to regulate the expression of the uncoupling protein 1(UCP1) gene unless combined with retinoic acid. This study investigated the effects of the PPARalpha-agonist WY14643 combined with t-RA, on the "browning" of white adipocytes in mice mediated by UCP1, and the molecular mechanisms involved in this process. We compared the effects of WY14643 alone and WY14643 combined with t-RA or the p38 MAPK inhibitor, SB203580, on white adipocytes after 24 h using the expression of UCP1, detected with RT-PCR and western blot. We also determined the mechanism by which p38 MAPK and phospho-p38 MAPK influence the process of "brown-ing" using western blot. All concentrations of WY14643 failed to in-duce UCP1 mRNA expression, protein expression, or phosphorylation of p38 MAPK (P < 0.05). WY14643 combined with t-RA was observed to induce UCP1 mRNA expression, protein expression, and phosphory-lation of p38 MAPK (P < 0.05). SB203580 combined with WY14643 and t-RA suppressed UCP1 mRNA expression, protein expression, and p38 MAPK phosphorylation (P < 0.05). WY14643 combined with t-RA can induce the transformation of white adipocytes to brown adipocytes through activation of the p38 MAPK signaling pathway. PMID- 26125907 TI - Effects of conjugated linoleic acid on the expression levels of miR-27 and miR 143 in pig adipose tissue. AB - In this study, we evaluated the effect and possible mech-anism of action of dietary conjugated linoleic acid (CLA) on pig body fat deposition. Landrace piglets (N = 48) were randomly divided into three groups, which were fed diets containing 0% (control), 1%, or 2% CLA. Dorsal and abdominal subcutaneous adipose tissues were col-lected, and real-time polymerase chain reaction (PCR) was used to de-termine the expression of adipocyte differentiation marker genes and associated microRNAs (miRNAs). Our results indicated that dietary CLA significantly decreased body fat deposition in the pig dorsum. The expression of adipocyte differentiation marker genes, including peroxi-some proliferator activated receptor (PPAR)-gamma and CCAAT/enhancer-binding protein alpha (C/EBPalpha) were not affected, whereas the expression of fatty acid binding protein 4 (FABP4) was significantly enhanced (P < 0.05). The expression of miR-27 and miR-143 in adipose tissue was significantly decreased. Data analysis indicated a significant negative correlation between miR-27 and FABP4 expression in the dorsal sub-cutaneous adipose tissue. In addition, the expression of miR 143 and miR-27 exhibited a significant negative relationship with FABP4 and PPARgamma in the abdominal subcutaneous adipose tissue. Thus, miRNA levels in adipose tissues could be modulated by CLA, thereby affecting adipose metabolism. PMID- 26125908 TI - Expression profile of tumor suppressor gene RASSF1 in lacrimal gland carcinoma. AB - We examined the expression pattern of the tumor sup-pressor gene RAS association domain family gene 1 (RASSF1) in lacri-mal gland carcinoma and analyzed its relationship with the oncogenesis and progression of tumors. Sixty-two patients (30 males, 32 females, average age = 47 +/- 3.5 years) admitted with lacrimal gland carcinoma to the Department of Ophthalmology of our hospital between January 2012 and January 2014 were enrolled in this study. Based on tumor ma lignancy, patients were classified into a malignant group (N = 25) and benign group (N = 37). Healthy lacrimal gland resections from trauma surgery (N = 35) were recruited as a healthy control group. Expres-sion profiles of RASSF1 in all groups were quantified using reverse transcription-polymerase chain reaction and western blotting. Recur-rence of lacrimal gland carcinoma was surveyed through postopera-tive follow-up. Expression levels of RASSF1 in samples from the ma lignant and benign groups were significantly lower than those in the healthy group (P < 0.05). Furthermore, the malignant group showed lower RASSF1 expression than the benign group (P < 0.05). Postopera-tive follow-up identified 22 cases of recurrence in the malignant group, with a recurrence rate of 88%, while 15 cases in the benign group had a recurrence rate of 40.5%. A direct relationship exists between RASSF1 expression levels and the malignancy grade of lacrimal gland carci noma. Patients with lower RASSF1 expression showed a higher recur-rence probability, indicating unfavorable prognosis. Therefore, measur-ing RASSF1 expression can be used as a diagnostic method for lacrimal gland carcinoma. PMID- 26125909 TI - Verification and characterization of chromosome duplication in haploid maize. AB - Doubled haploid technology has been used by various private companies. However, information regarding chromosome duplication methodologies, particularly those concerning techniques used to identify duplication in cells, is limited. Thus, we analyzed and characterized artificially doubled haploids using microsatellites molecular markers, pollen viability, and flow cytometry techniques. Evaluated material was obtained using two different chromosome duplication protocols in maize seeds considered haploids, resulting from the cross between the haploid inducer line KEMS and 4 hybrids (GNS 3225, GNS 3032, GNS 3264, and DKB 393). Fourteen days after duplication, plant samples were collected and assessed by flow cytometry. Further, the plants were transplanted to a field, and samples were collected for DNA analyses using microsatellite markers. The tassels were collected during anthesis for pollen viability analyses. Haploid, diploid, and mixoploid individuals were detected using flow cytometry, demonstrating that this technique was efficient for identifying doubled haploids. The microsatellites markers were also efficient for confirming the ploidies preselected by flow cytometry and for identifying homozygous individuals. Pollen viability showed a significant difference between the evaluated ploidies when the Alexander and propionic-carmin stains were used. The viability rates between the plodies analyzed show potential for fertilization. PMID- 26125910 TI - IL-17A and IL-17F polymorphisms and gastric cancer risk: a meta-analysis. AB - We conducted a meta-analysis of eligible studies to estimate the association between gastric cancer risk and rs2275913G>A IL-17A and rs763780T>C IL-17F polymorphisms. We searched the relevant studies in both Chinese and English through PubMed, the Web of Science, the Cochrane Library, and EMBASE up to January 1, 2014, including 3939 cases and 5407 controls. Seven eligible case control studies were selected, including seven studies on rs2275913G>A IL-17A and four studies on rs763780T>C IL-17F. The rs2275913 AG [odds ratio (OR) = 1.50, 95% confidence interval (95%CI) = 1.04-2.15] and GG (OR = 1.40, 95%CI = 1.00-1.96) genotypes were significantly associated with increased risk of gastric cancer compared with the AA genotype. The rs763780 TC (OR = 1.47, 95%CI = 1.32-1.64) and TT (OR = 1.49, 95%CI = 1.11-1.99) gen-otypes can influence gastric cancer risk. Subgroup analysis showed that rs2275913 GG (OR = 1.35, 95%CI = 1.05-1.73) and rs763780 TC (OR= 1.44, 95%CI = 1.20-1.75) genotypes were not significantly associated with increased risk of gastric cancer in Japanese populations. Our meta-analysis is the first to indicate that the rs2275913G>A and rs763780T>C polymor-phisms are risk factors for gastric cancer development. PMID- 26125911 TI - Construction of a gene-gene interaction network with a combined score across multiple approaches. AB - Recent progress in computational methods for inves-tigating physical and functional gene interactions has provided new insights into the complexity of biological processes. An essential part of these methods is presented visually in the form of gene interaction networks that can be valuable in exploring the mechanisms of disease. Here, a combined network based on gene pairs with an extra layer of re-liability was constructed after converting and combining the gene pair scores using a novel algorithm across multiple approaches. Four groups of kidney cancer data sets from ArrayExpress were downloaded and analyzed to identify differentially expressed genes using a rank prod-ucts analysis tool. Gene co-expression network, protein-protein interac-tion, co-occurrence network and a combined network were constructed using empirical Bayesian meta-analysis approach, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, an odds ratio formula of the cBioPortal for Cancer Genomics and a novel rank algorithm with combined score, respectively. The topological features of these networks were then compared to evaluate their performances. The results indicated that the gene pairs and their relationship rank-ings were not uniform. The values of topological parameters, such as clustering coefficient and the fitting coefficient R(2) of interaction net-work constructed using our ranked based combination score, were much greater than the other networks. The combined network had a classic small world property which transferred information quickly and displayed great resilience to the dysfunction of low-degree hubs with high clustering and short average path length. It also followed distinct-ly a scale free network with a higher reliability. PMID- 26125912 TI - Regulating effects of insertion direction of matrix attachment regions on transgenic expression in stably transformed Chinese hamster ovary cells. AB - We investigated the effects of different directions of insertion of matrix attachment region (MAR) sequences on transgenic expression in stably transformed Chinese hamster ovary (CHO) cells. The MAR sequences were inserted in forward or reverse directions into the expression vectors, and transfected into CHO cells. The expression of the chloramphenicol acetyltransferase (CAT) reporter gene and the relative copy numbers of the CAT gene were analyzed. The CAT gene expression levels in the vector with the MAR sequence inserted in the forward or reverse directions increased compared with expression without the MAR sequence. The relative copy numbers of the CAT gene with MAR sequenced vectors inserted in the reverse and forward directions were lower, than in the control group. The direction of insertion of MAR sequences had no significant effect on expression levels. The expression levels were not proportional to the copy numbers of the gene. PMID- 26125913 TI - Immunomodulatory effect of bone marrow mesenchymal stem cells on T lymphocytes in patients with decompensated liver cirrhosis. AB - We explored the immunomodulatory effects of bone marrow mesenchymal stem cells (BMSCs) on peripheral blood T lym-phocytes in patients with decompensation stage, hepatitis B-associated cirrhosis. MSCs from nine patients were analyzed by flow cytometry. Peripheral blood lymphocytes were isolated for fluorescent staining. Following stimulation by phytohemagglutinin (PHA), peripheral blood lymphocytes were co-cultured with BMSCs in serum and divided into four groups: (1) BMSC + lymphocyte + PHA contact culture group; (2) BMSC + lymphocyte + PHA non-contact culture group; (3) lym-phocyte + PHA positive control group; and (4) lymphocyte only negative control group. Lymphocyte proliferation and frequencies of CD4(+)CD25(+)CD127(-) Tregs and CD4(+)CD8(-)IL-17(+) (Th17) cells were de-tected. Cell proliferation in groups 1 and 2 declined compared with group 3 (P < 0.01), and was notably higher than in group 4 (P < 0.01). CD4(+)CD25(+)CD127(-) Tregs frequencies in groups 1 and 2 were higher than in groups 3 and 4. In an intra group comparison before and after culture, Th17 cell frequencies in groups 1 and 2 were higher than in group 4 (P < 0.01), but lower than in group 3 (P < 0.01). The Treg/Th17 ratio in groups 1 and 2 increased (P < 0.01), but did not change signifi-cantly in groups 3 and 4 (P > 0.05). In a comparison between groups after culture, the Treg/Th17 ratio in groups 1 and 2 increased more than in groups 3 and 4 (P < 0.01). BMSCs from cirrhotic patients can inhibit the proliferation of peripheral blood T lymphocytes, upregulate the ex-pression of CD4(+)CD25(+)CD127( ) Tregs, and improve Treg/Th17 imbal-ance. The mechanism by which this takes place may be associated with immunomodulatory effects induced by the secretion of soluble factors. PMID- 26125914 TI - Relationship between genetic polymorphisms of DNA ligase 1 and non-small cell lung cancer susceptibility and radiosensitivity. AB - The aim of this study was to examine the relationship between genetic polymorphisms in DNA ligase 1 (LIG1) and non-small cell lung cancer (NSCLC) susceptibility and radiosensitivity in a Chinese population. This was a case control study that included 352 NSCLC patients and 448 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was conducted to detect HaeIII polymorphisms in exon 6 of the LIG1 gene in this popula-tion. This information was used to observe the effects of radiation in pa tients with different genotypes in order to determine the genotypes as-sociated with radiosensitivity. The CC genotype and C allele frequency were significantly higher in the NSCLC group than in the control group (P = 0.012 and P = 0.023, respectively). The relative risk of experienc-ing NSCLC was 2.55 [95% confidence interval (CI), 1.12-3.98] for CC homozygous patients and 0.87 (95%CI, 0.46-1.88) for AA homozygous patients. Analysis of LIG1 genetic polymorphisms and radiosensitiv-ity of NSCLC patients showed that AA homozygous patients were sig nificantly more radiosensitive than the control group (AA vs AC, P = 0.014; AA vs CC, P < 0.001; AC vs CC, P = 0.023). Therefore, the LIG1 CC genotype was associated with susceptibility to NSCLC, and the AA genotype demonstrated increased radiosensitivity compared to the AC and CC genotypes. PMID- 26125915 TI - Expression and clinical significance of PIWIL2 in hilar cholangiocarcinoma tissues and cell lines. AB - The objective of this study was to explore the relationship between PIWI-like protein 2 (PIWIL2) and clinicopathological charac-teristics and prognosis after radical resection. To accomplish this, we analyzed PIWIL2 expression in hilar cholangiocarcinoma tissues and cell lines. PIWIL2 expression was detected by immunohistochemistry in 41 hilar cholangiocarcinoma samples and 10 control tissues. Western blotting and immunocytofluorescence were used to investigate PIWIL2 expression in the cholangiocarcinoma cell line QBC939 and the bile duct epithelial cell line HIBEpic. Univariate and multivariate surviv-al analyses were performed using the Kaplan-Meier method for hilar cholangiocarcinoma patients who underwent radical resection. PIWIL2 expression was significantly higher in the hilar cholangiocarcinoma tissues and QBC939 cells than in control tissues and HIBEpic cells, respectively (P < 0.05). Poorly and moderately differentiated cholan-giocarcinoma tissues had significantly higher PIWIL2 expression than well differentiated tissues (P < 0.05). Univariate analysis demonstrated that high PIWIL2 expression was associated with shorter survival time after radical resection (P < 0.05). Multivariate analysis showed that PI-WIL2 expression was an independent prognostic factor after radical re-section of hilar cholangiocarcinoma (P < 0.05). PIWIL2 expression was also associated with tumor node-metastasis stage and differentiation. PIWIL2 was an independent prognostic factor after radical resection of hilar cholangiocarcinoma. PMID- 26125916 TI - Sublingual vein parameters, AFP, AFP-L3, and GP73 in patients with hepatocellular carcinoma. AB - This study evaluated the diagnostic value of alpha-fetoprotein (AFP), AFP heterogeneity 3 (AFP-L3), Golgi protein 73 (GP73), and sublingual vein parameters in hepatocellular carcinoma (HCC). Levels of serum AFP, AFP-L3, GP73, and sublingual vein scores were measured in 34 patients with chronic hepatitis, 65 patients with post-hepatitis B cirrhosis, 71 patients with HCC, and 6 healthy controls. Logistic regression analysis was used to explore potential correlations. Sublingual vein grades in patients with HCC were higher than those in the other three groups; sublingual vein scores were also different between groups; combined diagnosis using AFP, GP73, and sublingual vein grade was superior to the individual parameters alone or when only two were used in different combinations. Thus, sublingual vein grade can be considered as an independent risk factor for diagnosis of HCC. Furthermore, combined detection with AFP, GP73, and sublingual vein grade is simple, inexpensive, and effective. It may therefore be suitable for screening high-risk populations for early diagnosis of HCC. PMID- 26125917 TI - Construction of overexpression vectors of Magnaporthe oryzae genes BAS1 and BAS4 fusion to mCherry and screening of overexpression strains. AB - The aim of this study was to construct overexpression vectors and selecting strains of the Magnaporthe oryzae effectors BAS1 and BAS4. Primer pairs of BAS1, BAS4, and mCherry were designed based on their known nucleotide sequences. The coding sequences of BAS1 and BAS4 were amplified, and the pXY201 plasmid was selected as a template to amplify the mCherry sequence. Fragments of BAS1 and mCherry, and BAS4 and mCherry were ligated into the pCAMBIA1302 vector. The recombinant pCAMBIA-BAS1-mCherry and pCAMBIA-BAS4-mCherry plasmids were transformed into E. coli DH5alpha competent cells. Transformants were screened by PCR, and plasmids from the positive transformants were extracted by enzymatic digestion to obtain pCAMBIA-BAS1-mCherry and pCAMBIA-BAS4-mCherry. The pCAMBIA BAS1-mCherry and pCAMBIA-BAS4-mCherry plasmids were transformed into protoplasts of rice blast strains and the transformed strains were screened by PCR using primer pairs against the hygromycin gene. The result showed that the PCR products corresponded with the theoretical sizes. RT-PCR was used to analyze the expression of BAS1 and BAS4 in five transformed strains of BAS1 and BAS4, and the result showed that the higher expression level of the two genes was occurred in five transformant strains comparing to wild-type strain A3467-40 (the strain containing BAS1 and BAS4), but there was no difference among the five overexpression strains. The sporulation and spore germination of transformed strains was higher than in wild type strain, and there was no difference in the germination time. Construction of overexpression vectors and strains of M. oryzae effectors BAS1 and BAS4 provide reference material for other new effectors. PMID- 26125918 TI - Identification and expression analysis of YABBY family genes associated with fruit shape in tomato (Solanum lycopersicum L.). AB - YABBY family genes play important roles in the development of leaf, flower, and fruit. The purpose of this research was to integrate all the YABBY genes and analyze the correlation between gene expression and fruit shape in tomato. Scanning of 24 genomes of sequenced species demonstrated that YABBY genes were very normal and stable in flowering plants except the seedless plants. Nine YABBY genes in tomato were computationally and experimentally characterized. The phylogeny was constructed based on whole proteins or the YABBY domain, and five distinct clades were observed as described in other angiosperms. A comparison of the expression patterns in tomatoes with large differences in fruit shape and/or size suggested that during the fruit development, YABBY genes had both negative and positive functions. The obtained information could provide a deeper understanding of the evolution of YABBY genes and can also be useful for tomato yield and shape breeding. PMID- 26125919 TI - A novel variant of the beta-lactamase ADC-61 gene in multi-drug resistant Acinetobacter baumannii. AB - The aim of this study was to investigate the existence of a beta-lactamase gene in a group of multi-drug resistant Acinetobacter baumannii. Twenty strains of multi-drug resistant A. baumannii were isolated. Thirty-four beta-lactamase genes and the ISaba1-OXA-23 linkage were analyzed in these strains by polymerase chain reaction (PCR) and verified by DNA sequencing. Three kinds of beta-lactamase genes (TEM, ADC, and OXA-23) were identified, among which the sequence of strain No. 20, ADC, was different from ADC subtypes recorded by GenBank, and was identified as a new variant of beta-lactamase genes (named ADC-61 and registered in GenBank: accession No. JQ753702); all the other 19 strains were ADC-30. Eighteen strains of the OXA-23 group were all positive as indicated by detection of ISaba1-OXA-23 linkage. Gene sequencing indicated that the TEM gene was TEM-1. These results suggest that the three kinds of beta-lactamase genes identified in this study, TEM, ADC, and OXA-23, play a key role in drug resistance in this group of A. baumannii. To our knowledge, this is the first report of an emergent new mutation of the beta-lactamase gene, ADC-61, in China or abroad. PMID- 26125920 TI - Correlation between the genetic polymorphism of ORMDL3 gene and asthma risk: a meta-analysis. AB - While increasing scientific evidence suggests that the ORMDL3 rs7216389 polymorphism may contribute to a higher susceptibility to asthma, many of the current studies have yielded inconclusive results. This meta-analysis aimed to assess the association between the ORMDL3 rs7216389 polymorphism and the risk of asthma. An extensive literature search for relevant studies was conducted in PubMed, Embase, the Web of Science, the Cochrane Library, Chinese National Knowledge Infrastructure, and Google Scholar. This meta-analysis was performed using the STATA 12.0 software. Crude odds ratios (OR) and their 95% confidence intervals (CI) were calculated. Thirteen studies were included with a total of 14,851 subjects, comprised of 6739 patients with asthma and 8112 healthy controls. Our meta-analysis results revealed that the ORMDL3 rs7216389 polymorphism may be associated with an increased risk of asthma (allele model: OR = 1.39, 95%CI = 1.27-1.52, P < 0.001; dominant model: OR = 1.46, 95%CI = 1.31 1.62, P < 0.001; recessive model: OR = 1.57, 95%CI = 1.37-1.81, P < 0.001; homozygous model: OR = 1.58, 95%CI = 1.32-1.90, P < 0.001; heterozygous model: OR = 1.54, 95%CI = 1.30-1.82, P < 0.001). We also found significant associations in our subgroup analyses based on ethnicity and type of asthma. However, in our subgroup analysis based on sources of controls, an association was found in the population-based case-control subgroup but not in the hospital-based case-control subgroup. This meta-analysis indicates that ORMDL3 rs7216389 may contribute to increasing susceptibility to asthma. PMID- 26125921 TI - Expression of glyceraldehyde 3-phosphate dehydrogenase is enhanced in Leishmania spp naturally resistant to nitric oxide. AB - Leishmania spp are the causative agents of a spectrum of diseases termed leishmaniasis that affect mammals, including humans and dogs. Although reactive nitrogen species are employed in the control of parasitism by the immune system, it is known that Leishmania can withstand this oxidative stress. As the mechanism by which these species are resistant to nitric oxide (NO) is poorly understood, the main objective of this study was to evaluate the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in Leishmania amazonensis and Leishmania chagasi promastigotes showing natural resistance to NO. GAPDH transcript levels were quantified by real-time polymerase chain reaction amplification, and GAPDH activity (assessed by levels of NADH oxidation) was measured by spectrophotometry. The level of nitration in total protein was assessed by immunoblotting. The results demonstrated an increase in GAPDH expression in resistant isolates of both species compared to susceptible isolates. The increase in GAPDH expression led to an increase in the activity of GAPDH in L. amazonensis human isolates resistant to NO. The pattern of protein nitration did not differ between sensitive and resistant isolates. Our results suggest that changes in expression of GAPDH may be responsible, at least in part, to natural resistance to NO found in human and canine Leishmania spp. PMID- 26125922 TI - Association between XRCC1 Arg280His polymorphism and risk of hepatocellular carcinoma: a systematic review and meta-analysis. AB - Hepatocellular carcinoma (HCC) is one of the most life-threatening malignancies worldwide. Defects in DNA repair genes may increase the risk of HCC. X-ray cross complementing group 1 gene (XRCC1) is a major DNA repair gene involved in base excision re-pair. Recently, several studies have indicated that an association exists between XRCC1 polymorphism and HCC, particularly the Arg280His polymorphism. However, the data is inconsistent and incomplete. In this study, we conducted a meta-analysis to investigate the association between the XRCC1 Arg280His polymorphism and HCC risk. A total of 10 case-control studies included 1848 HCC cases and 1969 controls were examined in this analysis. Our results suggest that variant geno-types of the XRCC1 Arg280His gene are associated with a significantly increased risk of HCC in homozygote comparison (HisHis vs ArgArg, odds ratio, 1.55, 95% confidence interval, 1.10-2.18, P = 0.013); no het erogeneity was observed (I2 = 0%). Our analysis suggests that the XRCC1 Arg280His polymorphism is associated with a higher risk of HCC. PMID- 26125923 TI - Impact of early enteral and parenteral nutrition on prealbumin and high sensitivity C-reactive protein after gastric surgery. AB - We investigated the impact of early enteral nutrition (EEN) and parenteral nutrition (PN) on prealbumin (PA) and high-sensitivity C-reactive protein (hs CRP) in patients after gastric cancer surgery. Sixty-eight selected patients undergoing gastric cancer surgery were randomly divided into the EEN (N = 34) and PN (N = 34) groups. Body weight (BW), serum albumin (ALB), transferrin (TF), PA, hs-CRP, length of hospital stay, cost of postoperative nutritional support, and incidence of complications were compared between groups. On postoperative day 7, the BW, TF, ALB, and PA for both groups were significantly decreased compared with the values obtained on preoperative day 1 (P < 0.01). A significant decrease was observed in TF and PA in the PN group compared with the EEN group (P < 0.01). There was no significant difference in BW and ALB between the two groups (P > 0.05). The hs-CRP level of both groups was significantly higher than on preoperative day 1. There was a significant increase in hs-CRP in the PN group compared with the EEN group (P < 0.01). The anal exhaust time, length of hospital stay, and nutritional support cost were significantly shorter or lower in the EEN group than in the PN group (P < 0.01). There was no significant difference in the incidence of complications between the two groups (P > 0.05). EEN helps regulate the postoperative response of patients after gastric cancer surgery, promotes rehabilitation, and accelerates the recovery of gastrointestinal function. Furthermore, EEN has the advantage of being inexpensive. PMID- 26125924 TI - Impact of early postoperative enteral nutrition on clinical outcomes in patients with gastric cancer. AB - The impact of early enteral nutrition (EEN) on clinical outcomes of gastric cancer patients was investigated. Three hundred pa-tients undergoing gastric cancer surgery from July 2010 to May 2014 were randomly divided into experimental and control groups (n = 150/group). Experimental group patients received enteral nutrition in water during the early postoperative period. Control group patients received conventional perioperative treatment. Patients' clinical outcomes, post operative immune function, and nutritional statuses were compared, which revealed that the postoperative fever duration (80.2 +/- 6.0 vs 88.1 +/- 8.1 h, P < 0.05), anal exhaust time (78.8 +/- 9.3 vs 85.3 +/- 8.4 h, P < 0.05), and length of hospitalization (7.73 +/- 2.13 vs 9.77 +/- 1.76 days, P < 0.01) differed significantly. Treatment costs in thousands of dol-lars were 31.24 +/- 3.21 for the experimental group and 35.61 +/- 2.32 for the control group; this difference was statistically significant (P < 0.01). The incidence of postoperative complications did not significantly differ between the experimental and control groups [14.0% (21/150) vs 17.3% (26/150), P > 0.05]. At postoperative days 3 and 7, the CD3(+), CD4(+), natural killer cell, albumin, and prealbumin levels and CD4(+)/CD8(+) ra-tio were significantly higher in the experimental group than the control group (all P < 0.05). CD8(+) cell counts were significantly lower in the experimental group than the control group (P < 0.05). Postsurgical oral EEN can improve nutritional status and immune function and promote early recovery of intestinal function in patients with gastric cancer. PMID- 26125925 TI - Analysis of postoperative PSA changes after ultrasound-guided permanent [125I] seed implantation for the treatment of prostate cancer. AB - The aim of this study was to explore postoperative changes in prostate-specific antigen (PSA) levels and risk factors that influence the clinical effects of ultrasound-guided permanent [(125)I] seed implantation in the treatment of prostate cancer. From July 2009 to December 2012, 41 prostate cancer patients who underwent transrectal ultrasound-guided [(125)I] seed implantation were followed up for 3-56 months. The patients were divided into 2 groups according to their results: group A, benign rebound group, 31 cases; and group B, biochemical relapse group, 10 cases. A blood analysis of group A showed that the initial PSA rise after a nadir occurred postoperatively at 16.8 +/- 1.2 months, and in 65.8% (27/41) patients the rise occurred during 15-27 weeks. For group B, the initial PSA rise after a nadir occurred postoperatively at 30.2 +/- 2.1 months, and the difference in the time parameter of the initial PSA rise after the nadir was statistically significant between the 2 groups (P < 0.01). During treatment, age was shown to be a risk factor for group A (P = 0.0027, P < 0.01). Postoperative changes in PSA levels after ultrasound-guided permanent [(125)I] seed implantation contributed to the assessment of the clinical treatment effects. PMID- 26125926 TI - Reaction norms for the study of genotype-environment interaction for growth and indicator traits of sexual precocity in Nellore cattle. AB - The objective of this study was to quantify the magnitude of genotype-environment interaction (GxE) effects on age at first calving (AFC), scrotal circumference (SC), and yearling weight (YW) in Nellore cattle using reaction norms. For the study, 89,152 weight records of female and male Nellore animals obtained at yearling age were used. Genetic parameters were estimated with a single-trait random-regression model using Legendre polynomials as base functions. The heritability estimates were of low to medium magnitude for AFC (0.05 to 0.47) and of medium to high magnitude for SC (0.32 to 0.51) and YW (0.13 to 0.72), and increased as the environmental gradient became more favorable. The genetic correlation estimates ranged from 0.25 to 1.0 for AFC, from 0.71 to 1.0 for SC, and from 0.42 to 1.0 for YW. High Spearman correlation coefficients were obtained for the three traits, ranging from 0.97 to 0.99. The reaction norms along the environmental gradient of 10 sires each with the highest or lowest breeding value for YW predicted by single-trait analysis demonstrated more plastic phenotypes for YW and more robust phenotypes for SC. The effect of GxE was most important for YW and AFC with respect to SC. When animals are selected for higher SC or YW or lower AFC, considering or not the GxE effect, it is expected that the same animals will be selected. The reaction norms obtained based on sire breeding values along the environmental gradient showed that animals with extreme breeding values respond differently as environmental conditions improve. PMID- 26125927 TI - Immunohistochemistry of lymphocytes in benign lymphoadenosis of oral mucosa. AB - Benign lymphoadenosis of oral mucosa (BLOM) is a common oral mucosa disease and may be regarded as a precancerous lesion. However, the association between its biological behavior and lymphocyte distribution remains unclear. Therefore, to investigate the characteristics of BLOM, we studied the infiltration of lymphocytes associated with it. The expression levels of CD74, CD20, CD3, and CD45RO were evaluated by immunohistochemical staining in 14 sam-ples from BLOM, 9 samples from BLOM with atypia hyperplasia, 11 samples from BLOM with canceration, and 10 samples from normal oral mucosa tissues. The results were analyzed by two sample t-test using SPSS 10.0 for Windows, and P < 0.05 was considered to be sig nificant. In normal oral mucosa, positive expression levels of CD3 and CD45RO were presented in the extra-lymphoid follicle, and the expres-sion levels of CD74 and CD20 were negative. In all BLOM groups, the expression level of CD20 was positive except for one case of BLOM with canceration; the expression levels of CD74 were all positive. Posi-tive expression levels of CD3 and CD45RO could be found not only in extra-lymphoid follicles but also in inner-lymphoid follicles in the BLOM groups. The expression levels of CD74 and CD20 in extra-lym-phoid follicles, and CD3 and CD45RO in inner-lymphoid follicles in BLOM were significantly higher than in BLOM with canceration. The infiltrated lymphocytes in BLOM comprise T- and B-cells. This indi-cates that the lymphoid tissue in BLOM is mucosa-associated lymphoid tissue and BLOM is a proliferative lesion. PMID- 26125928 TI - Flow cytometry reliability analysis and variations in sugarcane DNA content. AB - The aim of this study was to evaluate the reliability of flow cytometry analysis and the use of this technique to differentiate species and varieties of sugarcane (Saccharum spp) according to their relative DNA content. We analyzed 16 varieties and three species belonging to this genus. To determine a reliable protocol, we evaluated three extraction buffers (LB01, Marie, and Tris.MgCl2), the presence and absence of RNase, six doses of propidium iodide (10, 15, 20, 25, and 30 MUg), four periods of exposure to propidium iodide (0, 5, 10, and 20 min), and seven external reference standards (peas, beans, corn, radish, rye, soybean, and tomato) with reference to the coefficient of variation and the DNA content. For statistical analyses, we used the programs Sisvar((r)) and Xlstat((r)). We recommend using the Marie extraction buffer and at least 15 MUg propidium iodide. The samples should not be analyzed immediately after the addition of propidium iodide. The use of RNase is optional, and tomato should be used as an external reference standard. The results show that sugarcane has a variable genome size (8.42 to 12.12 pg/2C) and the individuals analyzed could be separated into four groups according to their DNA content with relative equality in the genome sizes of the commercial varieties. PMID- 26125929 TI - Cloprostenol and pregnant mare serum gonadotropin promote estrus synchronization, uterine development, and follicle-stimulating hormone receptor expression in mice. AB - This study investigated the effects of pregnant mare se-rum gonadotropin (PMSG) and cloprostenol (CLO) on estrus induc-tion and synchronization, uterine development, and follicle-stimulating hormone receptor (FSHR) expression in mice. A total of 105 Kunming pre-puberty mice were divided into seven subgroups. Three PMSG sub-groups were injected intraperitoneally with 10, 20, and 40 IU PMSG twice (on days 0 and 4), and three CLO subgroups were injected intra-peritoneally with 10, 15, and 20 MUg cloprostenol acetate twice (on days 0 and 4). The results showed that 93.33 and 66.67% of synchronized mice displayed estrus within 18.68 37.59 h following CLO and PMSG exposure, respectively. Estrus numbers, estrus onset time, and estrus rates in CLO and PMSG groups were greater than in control groups (CG) (P < 0.05). Uterine weights of the PMSG group were higher than that of CLO and CG groups, and the uterine horn longitudinal diameters in experimental mice were greater than CG. Expression levels of FSHR proteins in CLO and PMSG groups increased slightly when compared to CG. In conclusion, CLO and PMSG administration did not clearly af-fect the expression of uterine FSHR proteins in mice. Moreover, PMSG and CLO treatments synchronized estrus and enhanced the uterine de-velopment of mice. The efficacy of CLO on estrus synchronization was greater than PMSG, and the effects of PMSG on uterine development were stronger than CLO. These results have important significance re-garding the modulation of animal reproductive functions. PMID- 26125930 TI - Differential gene expression in drought-tolerant sugarcane roots. AB - Drought is one of the most frequent abiotic stresses limiting the productivity and geographical distribution of sugarcane culture. The use of drought-tolerant genotypes is one approach for overcoming the effects of water stress. We conducted a comparative study to identify gene expression profiles under water stress in tolerant sugarcane roots. Two different cultivars, 1 drought tolerant (RB867515) and 1 drought susceptible (SP86-155), were evaluated at 4 sampling time points (1, 3, 5, and 10 days) using the cDNA-amplified fragment length polymorphism technique. A total of 173 fragments were found to be differentially expressed in response to water stress in the tolerant cultivar. Seventy of these were cloned, sequenced, and categorized. Similarity analysis using BLAST revealed that 64% of the fragments differentially expressed code proteins classified as no hits (23%), hypothetical (21%), or involved in stress response (20%), with others were involved in communication pathways and signal transduction, bioenergetics, secondary metabolism, and growth and development. Four genes were analyzed and validated using real-time quantitative polymerase chain reaction to determine their expression and showed consistency with the cDNA-amplified fragment length polymorphism analyses. Our results contribute insight into the molecular responses to water stress in sugarcane and possibility to the development of cultivars with improved tolerance to drought. PMID- 26125931 TI - Anti-prostate cancer effects of CTL cell induction in vitro by recombinant adenovirus mediated PSMA/4-1BBL dendritic cells: an immunotherapy study. AB - This study aimed to examine anti-prostate cancer immune response induced by dendritic cells (DCs) transduced with PSMA/4-1BBL recombinant adenoviruses in vitro. Ad-PSMA, Ad-4-1BBL, and Ad-GFP were transfected into DCs derived from peripheral blood of healthy volunteers. Ad-PSMA/4-1BBL-DC, Ad-PSMA-DC, Ad-4-1BBL DC, Ad-GFP-DC, and normal-DC, PSMA and 4-1BBL protein levels in DCs were detected by western blot. IL-12, IFN-gamma and IL-10 were measured by ELISA. Mixed lymphocyte reaction and the cytotoxicity of each group targeted to LNCap, Du145, and 22RV prostate cancer cells were determined by CCK-8 assay. PSMA and 4-1BBL protein could express on DC successfully, the IL-12 supernatant content (134.29 +/- 2.22 pg) was higher than others (P < 0.05). The ability to stimulate autologous T lymphocyte proliferation in the co-transfection group was higher than others (P < 0.05). When the DCs were co-cultured with CTLs, the PSMA/4-1BBL DC-CTL group showed the highest content of IFN-gamma (1176.10 +/- 14.37pg/5 x 10(6) cells), but the lowest IL-10 content (75.14 +/- 2.01 pg/5 x 10(6) cells) (P < 0.05), and the strongest anti-tumor effect when the effector to target ratio was 40:1, along with a higher killing ratio of LNCap cells than others (P < 0.05). Overall, Mature DCs transfected with Ad-PSMA/4- 1BBL not only showed high secretion of IL-12, but also induced CTLs to stimulate and enhance the killing effect of PSMA specific effector cells to PSMA positively expressing prostate cancer cells. Furthermore, the DCs infected with two kinds of tumor-associated antigens would induce more effective tumor-specific CTL induction. PMID- 26125932 TI - Potential hippocampal genes and pathways involved in Alzheimer's disease: a bioinformatic analysis. AB - Alzheimer's disease (AD) is a neurodegenerative disor-der and the most common cause of dementia in elderly people. Nu-merous studies have focused on the dysregulated genes in AD, but the pathogenesis is still unknown. In this study, we explored critical hippocampal genes and pathways that might potentially be involved in the pathogenesis of AD. Four transcriptome datasets for the hip pocampus of patients with AD were downloaded from ArrayExpress, and the gene signature was identified by integrated analysis of mul-tiple transcriptomes using novel genome-wide relative significance and genome-wide global significance models. A protein-protein interaction network was constructed, and five clusters were selected. The biologi-cal functions and pathways were identified by Gene Ontology and Kyo-to Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. A total of 6994 genes were screened, and the top 300 genes were subjected to further analysis. Four significant KEGG pathways were identified, including oxidative phosphorylation and Parkinson's disease, Huntington's disease, and Alzheimer's disease pathways. The hub network of cluster 1 with the highest average rank value was de-fined. The genes (NDUFB3, NDUFA9, NDUFV1, NDUFV2, NDUFS3, NDUFA10, COX7B, and UQCR1) were considered critical with high degree in cluster 1 as well as being shared by the four significant path-ways. The oxidative phosphorylation process was also involved in the other three pathways and is considered to be relevant to energy-related AD pathology in the hippocampus. This research provides a perspec-tive from which to explore critical genes and pathways for potential AD therapies. PMID- 26125933 TI - Expression and clinical value of the soluble major histocompatibility complex class I-related chain A molecule in the serum of patients with renal tumors. AB - We investigated the expression and clinical value of the soluble major histocompatibility complex class I-related chain A (sMICA) molecule in the serum of patients with renal tumors. Sixty patients diagnosed with renal tumors were enrolled in the experimental group, whereas 20 healthy volunteers served as the control group. The sMICA levels were measured via enzyme-linked immunosorbent assay, and the results were analyzed in combination with data from pathol-ogy examination. The experimental group had a statistically significant higher sMICA level (P < 0.05) than the control group. The sMICA level was higher in patients with malignant tumors than in those with be-nign tumors. We also observed a positive relationship among different tumor-node-metastasis (TNM) pathological stages with more advanced diseases exhibiting higher sMICA levels. As a tumor associated antigen, MICA has a close relationship with renal tumorigenesis and immune es-cape. Our results indicated that sMICA levels were related to tumor pathol-ogy, TNM stage, and metastasis. Therefore, sMICA might be a potential marker for tumor characteristics, prognosis, and recurrence prediction. PMID- 26125934 TI - Correlation of UGT1A1 and ERCC1 gene polymorphisms with the outcome of combined irinotecan plus cisplatin treatment in recurrent ovarian cancer. AB - The aim of this study was to define the genotypes of UGT1A1 and ERCC1 and to examine their relationship with the efficacy and toxicity of a combination therapy of irinotecan and cisplatin in patients with advanced ovarian cancer. The allelic frequencies of the UGT1A1 and ERCC1 variants in a group of 89 patients with advanced ovarian cancer were determined. The relationship between the adverse events of irinotecan-based chemotherapy and the efficacy of cisplatin in patients with advanced ovarian cancer were analyzed. For patients who carried the UGT1A1*28 wild-type (WW) or the UGT1A1*28 heterozygous and homozygous mutant (WM+MM) genotypes, the incidences of grade 2 or 3 tardive diarrhea were 52.2 and 72.7% respectively, and the difference was statistically significant (P = 0.031, OR = 2.1, 95%CI = 1.6-9.2). For grade 3 or 4 tardive diarrhea, the incidence rates were 7.5 and 36.4% respectively; this difference was also statistically significant (P = 0.000, OR = 4.9, 95%CI = 3.3-15.8). The response rates of ERCC1 WW and ERCC1 WM+MM carriers were 30.3 and 20.2% respectively; this difference was significant (P = 0.032, OR = 3.2, 95%CI = 1.4-9.1). Together, the results from this study suggest that UGT1A1 is a target gene for tardive diarrhea, and that the UGT1A1*28 gene mutation might increase the risk of diarrhea with irinotecan based chemotherapy. Furthermore, the results suggest that ERCC1 WW carriers might obtain a better rate of clinical response from a combined irinotecan and cisplatin regimen than ERCC1 WM+MM carriers. PMID- 26125935 TI - PPARgamma Pro12Ala and His447His polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis. AB - We investigated whether Pro12Ala (C->G) and His447His (C->T) polymorphisms of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the PPARgamma Pro12Ala and His447His polymorphisms and AD in subjects. The meta-analysis was performed according to the apolipoprotein E (APOE) E4 allele status. A total of eight studies were considered in our meta analysis, comprising 2948 patients with AD and 3753 controls. Meta-analysis showed no association between AD and the PPARgamma Pro12Ala G allele in any of the study subjects [odds ratio (OR) = 1.013, 95% confidence interval (95%CI) = 0.906-1.132, P = 0.821] or in the European and Asian populations (OR = 0.997, 95%CI = 0.890-1.118, P = 0.965; OR = 1.409, 95%CI = 0.832-2.387, P = 0.202, respectively). We tested whether the APOE E4 allele affects the association between the PPARgamma Pro12Ala polymorphism and AD. Meta-analysis showed no association between AD and the PPARgamma G allele in any of the study subjects with or without the APOE E4 allele. Meta-analysis showed no association between AD and the PPARgamma His447His T allele in the European population (OR for T allele = 0.912, 95%CI = 0.732-1.136, P = 0.409). This meta-analysis has shown that there is a lack of association between the PPARgamma Pro12Ala and His447His polymorphisms and AD risk. PMID- 26125936 TI - Ion beam transformation with corn DNA alters proteinase expression in rice seedling roots. AB - Corn DNA was introduced into dry seeds of rice (cv. 'YuJing-6') by ion beam irradiation. Proteinase activities in rice seedling roots were subsequently analyzed by renaturation electrophoresis at pH 4.5, 7.0, and 8.5. Proteinase activity was more pronounced on gels at higher pH. Irradiation of rice seedling roots caused the loss of some proteinase bands at all pH conditions although a novel 50-kDa band was found at both pH 7.0 and 8.5. No new proteinase activity was detected at pH 4.5. However, novel bands and bands showing stronger activity were observed at pH 7.0 and 8.5. The data indicate that the expression of proteinases in rice seedling roots was altered following low energy ion beam mediated transformation with corn DNA. PMID- 26125938 TI - Inequitable and Ineffective: Exclusion of Mental Health from the Post-2015 Development Agenda. PMID- 26125937 TI - Identification of Candidate Adherent-Invasive E. coli Signature Transcripts by Genomic/Transcriptomic Analysis. AB - Adherent-invasive Escherichia coli (AIEC) strains are detected more frequently within mucosal lesions of patients with Crohn's disease (CD). The AIEC phenotype consists of adherence and invasion of intestinal epithelial cells and survival within macrophages of these bacteria in vitro. Our aim was to identify candidate transcripts that distinguish AIEC from non-invasive E. coli (NIEC) strains and might be useful for rapid and accurate identification of AIEC by culture independent technology. We performed comparative RNA-Sequence (RNASeq) analysis using AIEC strain LF82 and NIEC strain HS during exponential and stationary growth. Differential expression analysis of coding sequences (CDS) homologous to both strains demonstrated 224 and 241 genes with increased and decreased expression, respectively, in LF82 relative to HS. Transition metal transport and siderophore metabolism related pathway genes were up-regulated, while glycogen metabolic and oxidation-reduction related pathway genes were down-regulated, in LF82. Chemotaxis related transcripts were up-regulated in LF82 during the exponential phase, but flagellum-dependent motility pathway genes were down regulated in LF82 during the stationary phase. CDS that mapped only to the LF82 genome accounted for 747 genes. We applied an in silico subtractive genomics approach to identify CDS specific to AIEC by incorporating the genomes of 10 other previously phenotyped NIEC. From this analysis, 166 CDS mapped to the LF82 genome and lacked homology to any of the 11 human NIEC strains. We compared these CDS across 13 AIEC, but none were homologous in each. Four LF82 gene loci belonging to clustered regularly interspaced short palindromic repeats region (CRISPR)--CRISPR-associated (Cas) genes were identified in 4 to 6 AIEC and absent from all non-pathogenic bacteria. As previously reported, AIEC strains were enriched for pdu operon genes. One CDS, encoding an excisionase, was shared by 9 AIEC strains. Reverse transcription quantitative polymerase chain reaction assays for 6 genes were conducted on fecal and ileal RNA samples from 22 inflammatory bowel disease (IBD), and 32 patients without IBD (non-IBD). The expression of Cas loci was detected in a higher proportion of CD than non-IBD fecal and ileal RNA samples (p <0.05). These results support a comparative genomic/transcriptomic approach towards identifying candidate AIEC signature transcripts. PMID- 26125939 TI - Neisseria gonorrhoeae Modulates Immunity by Polarizing Human Macrophages to a M2 Profile. AB - Current data suggest that Neisseria gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and antigen-presenting cells. The present report is focused on gonococcus evasion mechanism on macrophages (MF) and its impact in the subsequent immune response. In response to various signals MF may undergo classical-M1 (M1-MF) or alternative M2 (M2-MF) activation. Until now there are no reports of the gonococcus effects on human MF polarization. We assessed the phagocytic ability of monocyte-derived MF (MDM) upon gonococcal infection by immunofluorescence and gentamicin protection experiments. Then, we evaluated cytokine profile and M1/M2 specific surface markers on MF challenged with N. gonorrhoeae and their proliferative effect on T cells. Our findings lead us to suggest N. gonorrhoeae stimulates a M2 MF phenotype in which some of the M2b and none of the M1-MF-associated markers are induced. Interestingly, N. gonorrhoeae exposure leads to upregulation of a Programmed Death Ligand 1 (PD-L1), widely known as an immunosuppressive molecule. Moreover, functional results showed that N. gonorrhoeae-treated MF are unable to induce proliferation of human T-cells, suggesting a more likely regulatory phenotype. Taken together, our data show that N. gonorroheae interferes with MF polarization. This study has important implications for understanding the mechanisms of clearance versus long-term persistence of N. gonorroheae infection and might be applicable for the development of new therapeutic strategies. PMID- 26125940 TI - Applicability of ISSR and DAMD markers for phyto-molecular characterization and association with some important biochemical traits of Dendrobium nobile, an endangered medicinal orchid. AB - Dendrobium nobile is an important medicinal orchid having profound importance in traditional herbal drug preparations and pharmacopeias worldwide. Due to various anthropogenic pressures the natural populations of this important orchid species are presently facing threats of extinction. In the present study, genetic and chemical diversity existing amongst 6 natural populations of D. nobile were assessed using molecular markers, and the influence of genetic factors on its phytochemical activity especially antioxidant potential was determined. Molecular fingerprinting of the orchid taxa was performed using ISSR and DAMD markers along with the estimation of total phenolics, flavonoids and alkaloid contents. Antioxidant activity was also measured using DPPH and FRAP assays which cumulatively revealed a significant level of variability across the sampled populations. The representatives from Sikkim in Northeast India revealed higher phytochemical activity whereas those from Mizoram showed lesser activity. Analysis of molecular variance (AMOVA) revealed that variation amongst the populations was significantly higher than within the populations. The data generated by UPGMA and Bayesian analytical models were compared in order to estimate the genetic relationships amongst the D. nobile germplasm sampled from different geographical areas of Northeast India. Interestingly, identical grouping patterns were exhibited by both the approaches. The results of the present study detected a high degree of existing genetic and phytochemical variation amongst the populations in relation to bioclimatic and geographic locations of populations. Our results strongly establish that the cumulative marker approach could be the best suited for assessing the genetic relationships with high accuracy amongst distinct D. nobile accessions. PMID- 26125941 TI - Biologically active vallesamine, strychnan, and rhazinilam alkaloids from Alstonia: Pneumatophorine, a nor-secovallesamine with unusual incorporation of a 3-ethylpyridine moiety. AB - Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine precontracted rat aortic rings. PMID- 26125942 TI - Anti-inflammation furanoditerpenoids from Caesalpinia minax Hance. AB - Cassane skeletons are rare in nature, but often possess valuable medicinal properties. A furanoditerpenoid with an unusual A-seco-rearranged cassane skeleton, neocaesalminin A, and five furanoditerpenoids were isolated from seeds of Caesalpinia minax Hance, along with six known cassane derivatives, 7-O-acetyl bonducellpin C, caesalmin F, caesalmin C, zeta-caesalmin, caesalmin E1 and caesalpinin K. Compound structures were determined by spectroscopy (HR-ESI-MS, UV, IR, 1D NMR, 2D NMR), X-ray crystallography and quantum chemical computation of electronic circular dichroism). Three of the previously known compounds exhibited significant inhibition of nitric oxide production of RAW264.7 macrophages stimulated by lipopolysaccharide (LPS). PMID- 26125943 TI - The sesquiterpene lactone polymatin B from Smallanthus sonchifolius induces different cell death mechanisms in three cancer cell lines. AB - A 8beta-angeloyloxy-9alpha-hydroxy-14-oxo-acanthospermolide and five known melampolide sesquiterpene lactones (uvedalin, enhydrin, polymatin B, sonchifolin, and fluctuanin) were isolated from the leaves of Smallanthus sonchifolius. The compounds were identified by 1D-, 2D-NMR, HRMS, IR and UV analyses. In vitro cytotoxicity assays (MTT) showed that these sesquiterpene lactones display poor cytotoxic effects on peripheral blood mononuclear cells (PBMC) of healthy human subjects, whereas a strong cytotoxicity was observed in leukemia and pancreas cancer cells. For the mechanism of action of polymatin B, oxidative stress seems to be involved. Interestingly, reactive oxygen species (ROS) formation mainly induced different effects: apoptosis in CCRF-CEM cells, necroptosis in CEM ADR5000 cells through induction of RIP1K, neither apoptosis nor necroptosis in MIA-PaCa-2 cells. Additionally, cells also died partly by necrosis. PMID- 26125944 TI - The Amyloid Precursor Protein Controls PIKfyve Function. AB - While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease. PMID- 26125945 TI - Orally Administered Trimethoprim-Sulfamethoxazole and Metronidazole as Infection Prophylaxis in Elective Colorectal Surgery. AB - BACKGROUND: This randomized clinical trial evaluated orally administered trimethoprim-sulfamethoxazole and metronidazole (TSM) in elective colorectal surgery as prophylactic for post-operative surgical site infections (SSI). METHODS: Patients undergoing elective colorectal resection were evaluated for inclusion. Randomized subjects received either orally administered TSM or intravenously administered cefuroxime and metronidazole (control group, CXM). The primary endpoint was the rate of SSI. RESULTS: A total of 1073 subjects were randomized to either control (540) or TSM (533). 486 patients in the TSM group and 499 in the control group were followed-up with after 4 weeks. Thirty-seven (3.8%) patients were afflicted by SSI at discharge from hospital and 69 (7.0%) at follow-up four weeks after surgery. After four weeks, the rate of incisional SSI was 7.0% in the TSM group and 3.6% in the control group (p=0.022). For organ/space SSI and the other complications monitored in the study, no differences were observed between the groups. CONCLUSION: Orally administered TSM as prophylaxis before elective colorectal surgery results in a low rate of organ/space SSI but an increased rate of incisional SSI compared with intravenously administered cefuroxime and metronidazole. Thus, when considering orally administered TSM, because of environmental concerns or for economic reasons, the slightly increased infection rate has to be kept in mind. PMID- 26125946 TI - Effects of Dietary Energy Sources on Post Mortem Glycolysis, Meat Quality and Muscle Fibre Type Transformation of Finishing Pigs. AB - Dietary energy source can influence muscle glycogen storage at slaughter. However, few studies have demonstrated whether the diet-induced change of muscle glycogen is achieved by the transformation of muscle fibre type. This study investigated the effects of dietary energy sources on meat quality, post mortem glycolysis and muscle fibre type transformation of finishing pigs. Seventy-two barrows with an average body weight of 65.0 +/- 2.0 kg were selected and were allotted to three iso-energetic and iso-nitrogenous diets A, B or C, and each treatment consisted of three replicates (pens) of eight pigs each. Diet A contained 44.1% starch, 5.9% crude fat and 12.6% neutral detergent fiber (NDF); diet B contained 37.6% starch, 9.5% crude fat and 15.4% NDF; and diet C contained 30.9% starch, 14.3% crude fat and 17.8% NDF. The duration of the experiment was 28 days. After feed withdrawal 12 h, 24 pigs (eight per treatment) were slaughtered, samples from M. longissimus lumborum (LL) were collected for subsequent analysis. The results showed that pigs fed diet C had lesser average daily gain, average daily feed intake and back fat depth than those fed diet A (P<0.05). Diet C increased pH45min (P<0.05) and decreased drip loss (P<0.05) in LL muscles compared with diet A. Meat from pigs fed diet A showed increased contents of lactate and greater glycolytic potential (GP) compared with those fed diet C (P<0.05). Greater mRNA expression of myosin heavy-chain (MyHC)-I and IIa and lesser expression of MyHC-IIx and IIb (P<0.05) in LL muscles were found in pigs fed diet C, than in pigs fed diet A. In addition, pigs fed diet C resulted in downregulation of miR23a and upregulation of miR409 and miR208b (P<0.05), associated with conserved changes of their corresponding targets. These findings indicated that diets containing low starch and high fibre were beneficial in reducing muscle glycolysis, improving meat quality of finishing pigs. This reduction of GP may be partially associated with the improvement of oxidative fibre composition in LL muscle, and the change in myofibre type may be correlated with the change in the miRNA expression. PMID- 26125947 TI - Impact of Lipid Oxidization on Vertical Structures and Electrostatics of Phospholipid Monolayers Revealed by Combination of Specular X-ray Reflectivity and Grazing-Incidence X-ray Fluorescence. AB - The influence of phospholipid oxidization of floating monolayers on the structure perpendicular to the global plane and on the density profiles of ions near the lipid monolayer has been investigated by a combination of grazing incidence X-ray fluorescence (GIXF) and specular X-ray reflectivity (XRR). Systematic variation of the composition of the floating monolayers unravels changes in the thickness, roughness and electron density of the lipid monolayers as a function of molar fraction of oxidized phospholipids. Simultaneous GIXF measurements enable one to qualitatively determine the element-specific density profiles of monovalent (K(+) or Cs(+)) and divalent ions (Ca(2+)) in the vicinity of the interface in the presence and absence of two types of oxidized phospholipids (PazePC and PoxnoPC) with high spatial accuracy (+/-5 A). We found the condensation of Ca(2+) near carboxylated PazePC was more pronounced compared to PoxnoPC with an aldehyde group. In contrast, the condensation of monovalent ions could hardly be detected even for pure oxidized phospholipid monolayers. Moreover, pure phospholipid monolayers exhibited almost no ion specific condensation near the interface. The quantitative studies with well-defined floating monolayers revealed how the elevation of lipid oxidization level alters the structures and functions of cell membranes. PMID- 26125948 TI - Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics. AB - We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high-throughput docking. Only 17 molecules from the original library of two million compounds were tested in vitro. Optimization of the two low-micromolar hits, the 4-acylpyrrole 1 and acylbenzene 9, was driven by molecular dynamics results which suggested improvement of the polar interactions with the Arg1173 side chain at the rim of the binding site. The synthesis of only two derivatives of 1 yielded the 4-acylpyrrole 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non hydrogen atom. Optimization of the acylbenzene hit 9 resulted in a series of derivatives with nanomolar potencies, good ligand efficiency and selectivity (see Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C.Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00172). The in silico predicted binding mode of the acylbenzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain. PMID- 26125949 TI - The Role of Immunohistochemistry in Rhabdomyosarcoma Diagnosis Using Tissue Microarray Technology and a Xenograft Model. AB - Rhabdomyosarcomas (RMS) may resemble other non-myogenic sarcomas and malignant rhabdoid tumor (MRT). Alveolar rhabdomyosarcoma (ARMS) often harbors a typical translocation, but embryonal rhabdomyosarcoma (ERMS) lacks any specific rearrangement. Histopathology is not always sufficient for an unequivocal diagnosis, necessitating ancillary studies, including immunohistochemistry (IHC). Sixteen genetically tested RMS and two MRT were xenografted and followed in successive passages. Tissue microarrays were constructed including samples from original and xenograft tumors. Desmin, myogenin, CK, EMA, INI1, LSD1, AP2beta, fibrillin-2, HMGA2, nestin, and SIRT1 were tested using immunohistochemical staining. Desmin and myogenin were positive in all RMS, and the epithelial markers were negative in almost all RMS. New markers (LSD1, AP2beta, HMGA2, Nestin, and SIRT1) were positive in all RMS and MRT. There were no differences in IHC expression between the three RMS subtypes tested except fibrillin-2, which was negative in ARMS. Applying new IHC markers can contribute to RMS diagnosis. Nevertheless, most markers are also expressed in MRT, and further studies are needed to confirm their value against this and other small round cell tumors. PMID- 26125951 TI - Tier 2 Language Intervention for Diverse Preschoolers: An Early-Stage Randomized Control Group Study Following an Analysis of Response to Intervention. AB - PURPOSE: The first purpose of this study was to explore the use of a whole class, test-teach-test, dynamic assessment of narratives for identifying participants. The second purpose was to examine the efficacy of a Tier 2 narrative language intervention for culturally and linguistically diverse preschoolers. METHOD: A dynamic assessment was conducted with students from 3 Head Start classrooms. On the basis of the results of the dynamic assessment, 22 children were randomly assigned to treatment (n = 12) and control (n = 10) groups for intervention. Participants received a small-group (4:1), differentiated, narrative intervention for 15-20 min, twice a week, for 9 weeks. Interventionists used weekly progress monitoring data to explicitly focus on individualized narrative and linguistic targets. RESULTS: The treatment group showed significant improvement over the control group on proximal and distal measures of narrative retells, with large effect sizes. Group differences on a measure of children's language in the context of personal stories were not statistically significant. CONCLUSIONS: This early-stage study provides evidence that narrative language intervention is an effective approach to improving the language skills of preschoolers with diverse language needs. Furthermore, the evidence supports the use of dynamic assessment for reducing overidentification and identifying candidates for small-group language intervention. PMID- 26125950 TI - Rational Design and Adaptive Management of Combination Therapies for Hepatitis C Virus Infection. AB - Recent discoveries of direct acting antivirals against Hepatitis C virus (HCV) have raised hopes of effective treatment via combination therapies. Yet rapid evolution and high diversity of HCV populations, combined with the reality of suboptimal treatment adherence, make drug resistance a clinical and public health concern. We develop a general model incorporating viral dynamics and pharmacokinetics/ pharmacodynamics to assess how suboptimal adherence affects resistance development and clinical outcomes. We derive design principles and adaptive treatment strategies, identifying a high-risk period when missing doses is particularly risky for de novo resistance, and quantifying the number of additional doses needed to compensate when doses are missed. Using data from large-scale resistance assays, we demonstrate that the risk of resistance can be reduced substantially by applying these principles to a combination therapy of daclatasvir and asunaprevir. By providing a mechanistic framework to link patient characteristics to the risk of resistance, these findings show the potential of rational treatment design. PMID- 26125952 TI - Nonalcoholic Hepatic Steatosis Is a Strong Predictor of High-Risk Coronary-Artery Plaques as Determined by Multidetector CT. AB - BACKGROUND: Nonalcoholic fatty liver disease is associated with a risk of coronary artery disease (e.g., diabetes mellitus, dyslipidemia, metabolic syndrome). We evaluated whether nonalcoholic hepatic steatosis is associated with high-risk plaques as assessed by multidetector computed tomography (CT). METHODS: This retrospective study involved 414 participants suspected of having coronary artery disease. Nonalcoholic hepatic steatosis was defined as a liver-to-spleen fat ratio of <1.0 and the presence and appropriate characteristics of coronary artery plaques as assessed by coronary CT angiography. High-risk plaques were identified, as were low-density plaques, positive remodeling, and spotty calcification. RESULTS: Compared with patients who did not have nonalcoholic hepatic steatosis, patients with nonalcoholic hepatic steatosis had more low density plaques (21% vs. 44%, p<0.01), positive remodeling (41% vs. 58%, p = 0.01), and spotty calcification (12% vs. 36%, p<0.01). The number of high-risk plaques in patients with nonalcoholic hepatic steatosis was greater than in those without nonalcoholic hepatic steatosis (p<0.01). Patients with nonalcoholic hepatic steatosis were more likely to have high-risk plaques than were those with only an elevated level of visceral adipose tissue (>=86 cm2; 35% vs. 16%, p<0.01). Multivariate analyses that included nonalcoholic hepatic steatosis, amount of visceral adipose tissue, and the presence/absence of traditional risk factors demonstrated that nonalcoholic hepatic steatosis was an independent predictor of high-risk plaques (odds ratio: 4.60; 95% confidence interval: 1.94 9.07, p<0.01). CONCLUSIONS: Diagnosis of nonalcoholic hepatic steatosis may be of value when assessing the risk of coronary artery disease. PMID- 26125953 TI - Positively Charged Chitosan and N-Trimethyl Chitosan Inhibit Abeta40 Fibrillogenesis. AB - Amyloid fibrils, formed by aggregation of improperly folded or intrinsically disordered proteins, are closely related with the pathology of a wide range of neurodegenerative diseases. Hence, there is a great deal of interest in developing molecules that can bind and inhibit amyloid formation. In this regard, we have investigated the effect of two positively charged polysaccharides, chitosan (CHT) and its quarternary derivative N-trimethyl chitosan chloride (TMC), on the aggregation of Abeta40 peptide. Our aggregation kinetics and atomic force microscopy (AFM) studies show that both CHT and TMC exhibit a concentration dependent inhibiting activity on Abeta40 fibrillogenesis. Systematic pH-dependent studies demonstrate that the attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues in Abeta40 play a key role in this inhibiting activity. The stronger inhibiting activity of TMC than CHT further suggests the importance of charge density of the polymer chain in interacting with Abeta40 and blocking the fibril formation. The possible interactions between CHT/TMC and Abeta40 are also revealed at the atomic level by molecular docking simulation, showing that the Abeta40 monomer could be primarily stabilized by electrostatic interactions with charged amines of CHT and quaternary amines of TMC, respectively. Binding of CHT/TMC on the central hydrophobic core region of Abeta40 peptide may be responsible for blocking the propagation of the nucleus to form fibrillar structures. These results suggest that incorporation of sugar units such as d-glucosamine and N-trimethyl-d glucosamine into polymer structural template may serve as a new strategy for designing novel antiamyloid molecules. PMID- 26125954 TI - Reverse Transcriptase in Action: FRET-Based Assay for Monitoring Flipping and Polymerase Activity in Real Time. AB - Reverse transcriptase (RT) of human immunodeficiency virus-1 (HIV-1) is a multifunctional enzyme that catalyzes the conversion of the single stranded viral RNA genome into double-stranded DNA, competent for host-cell integration. RT is endowed with RNA- and DNA-dependent DNA polymerase activity and DNA-directed RNA hydrolysis (RNase H activity). As a key enzyme of reverse transcription, RT is a key target of currently used highly active antiretroviral therapy (HAART), though RT inhibitors offer generally a poor resistance profile, urging new RT inhibitors to be developed. Using single molecule fluorescence approaches, it has been recently shown that RT binding orientation and dynamics on its substrate play a critical role in its activity. Currently, most in vitro RT activity assays, inherently end-point measurements, are based on the detection of reaction products by using radio-labeled or chemically modified nucleotides. Here, we propose a simple and continuous real-time Forster resonance energy transfer (FRET) based-assay for the direct measurement of RT's binding orientation and polymerase activity, with the use of conventional steady-state fluorescence spectroscopy. Under our working conditions, the change in binding orientation and the primer elongation step can be visualized separately on the basis of their opposite fluorescence changes and their different kinetics. The assay presented can easily discriminate non-nucleoside RT inhibitors from nucleoside RT inhibitors and determine reliably their potency. This one-step and one-pot assay constitutes an improved alternative to the currently used screening assays to disclose new anti-RT drugs and identify at the same time the class to which they belong. PMID- 26125955 TI - Inflammatory Vulvar Dermatoses. AB - Inflammatory vulvar dermatoses affect many women, but are likely underdiagnosed due to embarrassment and reluctance to visit a health care provider. Although itch and pain are common presenting symptoms, the physical examination can help distinguish between different disease entities. Because many women's health providers have minimal training in the categorization and management of dermatologic disease, definitive diagnosis and management can be difficult. Herein, strategies for diagnosing vulvar lichen sclerosus, lichen planus, contact dermatitis, lichen simplex chronicus, and psoriasis are discussed along with basic management of these diseases, which commonly involves decreasing inflammation through behavioral change, gentle skin care, topical corticosteroids, and systemic therapies. PMID- 26125956 TI - Vulvovaginal Diseases. Foreword. PMID- 26125957 TI - Benign Tumors and Tumor-like Lesions of the Vulva. AB - A variety of mass lesions may affect the vulva. These may be non-neoplastic, or represent benign or malignant neoplasms. A review of benign mass lesions and neoplasms of the vulva is presented. PMID- 26125958 TI - New Perspectives on the Normal Vagina and Noninfectious Causes of Discharge. AB - An understanding of how the vaginal flora is influenced by hormonal status is crucial in distinguishing normal from abnormal secretions. New studies exploring the vaginal microbiome with culture-independent techniques have led to the discovery of previously uncultivable bacteria on a species level, and have contributed to a better understanding of disease processes including bacterial vaginosis. It is important to note that not all vaginal discharge is abnormal or infectious in etiology, but a thorough evaluation will help reassure both the patient and the provider. PMID- 26125959 TI - Clinical Manifestations and Therapeutic Management of Vulvar Cellulitis and Abscess: Methicillin-resistant Staphylococcus aureus, Necrotizing Fasciitis, Bartholin Abscess, Crohn Disease of the Vulva, Hidradenitis Suppurativa. AB - Infections of the vulva can present a complex differential to the gynecologist, ranging from superficial skin infections to life-threatening necrotizing fasciitis. Recognition and timely treatment remain universal to skin and soft tissue infections as the subcutaneous anatomy of the vulva can facilitate rapid spread to other tissues with significant morbidity and mortality. Ineffective antibiotics or deferring necessary surgical debridement have proven to be costly to the patient, and the gynecologist must maintain an appropriately high index of suspicion. Employing a multidisciplinary team approach to care for vulvar cellulitis can guide treatment from antibiotic therapies to more aggressive surgical debridement. PMID- 26125960 TI - "How-To" Guide to Pelvic Floor Muscle Dysfunction. AB - The purpose of this paper is to assist the clinician in recognizing pelvic floor muscle dysfunction in women with vulvar symptoms, to provide general treatment algorithms, and to facilitate understanding of the scientific rationale behind appropriate treatment. In short, this paper is meant to provide a "how-to" guide to pelvic floor pain management for the Ob/Gyn. PMID- 26125961 TI - Nutrition for Multiples. AB - In 2012 there were 135,943 infants of multiple pregnancies born in the United States, nearly a 2-fold increase since 1980, with twins accounting for 96% of all multiple births. To date, most perinatal morbidities associated with multiple births have proven resistant to technological or pharmaceutical interventions. Maternal nutrition can have a profound effect on the course and outcome of multiple pregnancy, with the goal of achieving optimal intrauterine growth and birthweights, and minimizing prenatal and perinatal complications for the mother and her children. PMID- 26125962 TI - Vulvar and Vaginal Atrophy: Physiology, Clinical Presentation, and Treatment Considerations. AB - Vulvovaginal atrophy is a common condition associated with decreased estrogenization of the vaginal tissue. Symptoms include vaginal dryness, irritation, itching, soreness, burning, dyspareunia, discharge, urinary frequency, and urgency. It can occur at any time in a woman's life cycle, although more commonly in the postmenopausal phase, during which the prevalence is approximately 50%. Despite the high prevalence and the substantial effect on quality of life, vulvovaginal atrophy often remains underreported and undertreated. This article aims to review the physiology, clinical presentation, assessment, and current recommendations for treatment, including aspects of effectiveness and safety of local vaginal estrogen therapies. PMID- 26125963 TI - Vulvodynia. AB - Vulvodynia, a chronic pain disorder, affects women throughout the lifespan. Appropriate evaluation and diagnosis is necessary to enable effective management. The etiology is considered multifactorial. Therapies include self-management, nonpharmacologic, pharmacologic, and surgical. Vulvodynia can have a significant impact upon a patient's quality of life. Emotional and psychological support is invaluable. This article serves to give the primary gynecologist and practitioner a basic framework with which to identify, diagnose, and begin treatment for such patients as well as understanding for referral if necessary. The initial evaluation and physical examination will be discussed in detail. PMID- 26125964 TI - Psychosexual Aspects of Vulvar Disease. AB - Physically, the vulva is an anatomic location of convergence, which includes vascular, neural, hormonal, reproductive, dermatologic, and musculoskeletal systems. Psychosocially, the vulva represents privacy, femininity, sexuality, and intimacy. Because of this intertwined relationship, vulvar disease and dysfunction can significantly impact a woman's physical health as well as her relationships. This article elucidates the impact of vulvar disease on the individual psyche, sexual functioning, and intimate relationships. Psychological concepts are explained, psychological interventions are reviewed, and integrative approaches addressing psychological factors in the clinic are introduced. PMID- 26125965 TI - Speeding Up Non-Parametric Bootstrap Computations for Statistics Based on Sample Moments in Small/Moderate Sample Size Applications. AB - In this paper we propose a vectorized implementation of the non-parametric bootstrap for statistics based on sample moments. Basically, we adopt the multinomial sampling formulation of the non-parametric bootstrap, and compute bootstrap replications of sample moment statistics by simply weighting the observed data according to multinomial counts instead of evaluating the statistic on a resampled version of the observed data. Using this formulation we can generate a matrix of bootstrap weights and compute the entire vector of bootstrap replications with a few matrix multiplications. Vectorization is particularly important for matrix-oriented programming languages such as R, where matrix/vector calculations tend to be faster than scalar operations implemented in a loop. We illustrate the application of the vectorized implementation in real and simulated data sets, when bootstrapping Pearson's sample correlation coefficient, and compared its performance against two state-of-the-art R implementations of the non-parametric bootstrap, as well as a straightforward one based on a for loop. Our investigations spanned varying sample sizes and number of bootstrap replications. The vectorized bootstrap compared favorably against the state-of-the-art implementations in all cases tested, and was remarkably/considerably faster for small/moderate sample sizes. The same results were observed in the comparison with the straightforward implementation, except for large sample sizes, where the vectorized bootstrap was slightly slower than the straightforward implementation due to increased time expenditures in the generation of weight matrices via multinomial sampling. PMID- 26125966 TI - Nanowire Heterostructures Comprising Germanium Stems and Silicon Branches as High Capacity Li-Ion Anodes with Tunable Rate Capability. AB - Here we report the rational design of a high-capacity Li-ion anode material comprising Ge nanowires with Si branches. The unique structure provides an electrode material with tunable properties, allowing the performance to be tailored for either high capacity or high rate capability by controlling the mass ratio of Si to Ge. The binder free Si-Ge branched nanowire heterostructures are grown directly from the current collector and exhibit high capacities of up to ~1800 mAh/g. Rate capability testing revealed that increasing the Ge content within the material boosted the performance of the anode at fast cycling rates, whereas a higher Si content was optimal at slower rates of charge and discharge. Using ex-situ electron microscopy, Raman spectroscopy and energy dispersive X-ray spectroscopy mapping, the composition of the material is shown to be transient in nature, transforming from a heterostructure to a Si-Ge alloy as a consequence of repeated lithiation and delithiation. PMID- 26125967 TI - Choosing a Cluster Sampling Design for Lot Quality Assurance Sampling Surveys. AB - Lot quality assurance sampling (LQAS) surveys are commonly used for monitoring and evaluation in resource-limited settings. Recently several methods have been proposed to combine LQAS with cluster sampling for more timely and cost-effective data collection. For some of these methods, the standard binomial model can be used for constructing decision rules as the clustering can be ignored. For other designs, considered here, clustering is accommodated in the design phase. In this paper, we compare these latter cluster LQAS methodologies and provide recommendations for choosing a cluster LQAS design. We compare technical differences in the three methods and determine situations in which the choice of method results in a substantively different design. We consider two different aspects of the methods: the distributional assumptions and the clustering parameterization. Further, we provide software tools for implementing each method and clarify misconceptions about these designs in the literature. We illustrate the differences in these methods using vaccination and nutrition cluster LQAS surveys as example designs. The cluster methods are not sensitive to the distributional assumptions but can result in substantially different designs (sample sizes) depending on the clustering parameterization. However, none of the clustering parameterizations used in the existing methods appears to be consistent with the observed data, and, consequently, choice between the cluster LQAS methods is not straightforward. Further research should attempt to characterize clustering patterns in specific applications and provide suggestions for best-practice cluster LQAS designs on a setting-specific basis. PMID- 26125968 TI - Safety of Polyacrylamide 1.5% Left in Anterior Chamber in Combined Phacoemulsification and Pars Plana Vitrectomy Surgery. AB - PURPOSE: To evaluate safety, efficacy and postoperative characteristics of polyacrylamide 1.5% ophthalmic viscosurgical device (OVD) left in anterior chamber during and at the end of combined phacoemulsification and pars plana vitrectomy surgery. MATERIALS AND METHODS: This prospective study comprised 20 eyes that received combined phacoemulsification and pars plana vitrectomy performed by the same surgeon. Polyacrylamide 1.5% was left in anterior chamber at the end of the surgery. Preoperative and postoperative examinations (4, 12 and 24 hours; 14 days; 1 and 3 months) included measurement of intraocular pressure (IOP), central corneal thickness (CCT), endothelial cell density and assessment of any ocular adverse reactions. RESULTS: Four of the 20 patients (20%) showed increased IOP at hours postoperatively and needed medical treatment for IOP control. There was no significant difference in IOP between the preoperative visit and postoperative 3 months (p > 0.05). CCT measurements were similar between preoperative and postoperative visits (p > 0.05). A mean endothelial cell density loss of 6.7% was observed at postoperative day 14, however there was no change after this visit. CONCLUSION: Polyacrylamide 1.5% is safe, well-tolerated and protective in eyes undergoing combined phacoemulsification and pars plana vitrectomy. PMID- 26125969 TI - Total Synthesis of the Glycosylated Macrolide Antibiotic Fidaxomicin. AB - The first enantioselective total synthesis of fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is reported. This novel glycosylated macrolide antibiotic is used in the clinic for the treatment of Clostridium difficile infections. Key features of the synthesis involve a rapid and high-yielding access to the noviose, rhamnose, and orsellinic acid precursors; the first example of a beta-selective noviosylation; an effective Suzuki coupling of highly functionalized substrates; and a ring-closing metathesis reaction of a noviosylated dienoate precursor. Careful selection of protecting groups allowed for a complete deprotection yielding totally synthetic fidaxomicin. PMID- 26125970 TI - Similar Impacts of the Interaural Delay and Interaural Correlation on Binaural Gap Detection. AB - The subjective representation of the sounds delivered to the two ears of a human listener is closely associated with the interaural delay and correlation of these two-ear sounds. When the two-ear sounds, e.g., arbitrary noises, arrive simultaneously, the single auditory image of the binaurally identical noises becomes increasingly diffuse, and eventually separates into two auditory images as the interaural correlation decreases. When the interaural delay increases from zero to several milliseconds, the auditory image of the binaurally identical noises also changes from a single image to two distinct images. However, measuring the effect of these two factors on an identical group of participants has not been investigated. This study examined the impacts of interaural correlation and delay on detecting a binaurally uncorrelated fragment (interaural correlation = 0) embedded in the binaurally correlated noises (i.e., binaural gap or break in interaural correlation). We found that the minimum duration of the binaural gap for its detection (i.e., duration threshold) increased exponentially as the interaural delay between the binaurally identical noises increased linearly from 0 to 8 ms. When no interaural delay was introduced, the duration threshold also increased exponentially as the interaural correlation of the binaurally correlated noises decreased linearly from 1 to 0.4. A linear relationship between the effect of interaural delay and that of interaural correlation was described for listeners participating in this study: a 1 ms increase in interaural delay appeared to correspond to a 0.07 decrease in interaural correlation specific to raising the duration threshold. Our results imply that a tradeoff may exist between the impacts of interaural correlation and interaural delay on the subjective representation of sounds delivered to two human ears. PMID- 26125971 TI - The potential of fibroblast growth factor/fibroblast growth factor receptor signaling as a therapeutic target in tumor angiogenesis. AB - INTRODUCTION: Fibroblast growth factors (FGFs) are endowed with a potent pro angiogenic activity. Activation of the FGF/FGF receptor (FGFR) system occurs in a variety of human tumors. This may lead to neovascularization, supporting tumor progression and metastatic dissemination. Thus, a compelling biologic rationale exists for the development of anti-FGF/FGFR agents for the inhibition of tumor angiogenesis in cancer therapy. AREAS COVERED: A comprehensive search on PubMed was performed to identify studies on the role of the FGF/FGFR system in angiogenesis. Endothelial FGFR signaling, the pro-angiogenic function of canonical FGFs, and their role in human tumors are described. In addition, experimental approaches aimed at the identification and characterization of nonselective and selective FGF/FGFR inhibitors and their evaluation in clinical trials are summarized. EXPERT OPINION: Different approaches can be envisaged to inhibit the FGF/FGFR system, a target for the development of 'two-compartment' anti-angiogenic/anti-tumor agents, including FGFR selective and nonselective small-molecule tyrosine kinase inhibitors, anti-FGFR antibodies, and FGF ligand traps. Further studies are required to define the correlation between tumor vascularization and activation of the FGF/FGFR system and for the identification of cancer patients more likely to benefit from anti-FGF/FGFR treatments. In addition, advantages and disadvantages about the use of selective versus non selective FGF inhibitors remain to be elucidated. PMID- 26125972 TI - Implications of Nubian-Like Core Reduction Systems in Southern Africa for the Identification of Early Modern Human Dispersals. AB - Lithic technologies have been used to trace dispersals of early human populations within and beyond Africa. Convergence in lithic systems has the potential to confound such interpretations, implying connections between unrelated groups. Due to their reductive nature, stone artefacts are unusually prone to this chance appearance of similar forms in unrelated populations. Here we present data from the South African Middle Stone Age sites Uitpanskraal 7 and Mertenhof suggesting that Nubian core reduction systems associated with Late Pleistocene populations in North Africa and potentially with early human migrations out of Africa in MIS 5 also occur in southern Africa during early MIS 3 and with no clear connection to the North African occurrence. The timing and spatial distribution of their appearance in southern and northern Africa implies technological convergence, rather than diffusion or dispersal. While lithic technologies can be a critical guide to human population flux, their utility in tracing early human dispersals at large spatial and temporal scales with stone artefact types remains questionable. PMID- 26125973 TI - rs11886868 and rs4671393 of BCL11A associated with HbF level variation and modulate clinical events among sickle cell anemia patients. AB - AIMS: Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia (SCA) by inhibiting deoxy sickle hemoglobin (HbS) polymerization. HbF genes are genetically regulated, and the level of HbF and its distribution among sickle erythrocytes is highly variable. Herein, we aimed to determine whether two functional polymorphisms of BCL11A are implicated in the variation of HbF and clinical events in SCA Tunisian patients. MATERIAL AND METHODS: The studied population consisted of 148 SCA patients with SS phenotype. The group of patients was divided into two subgroups according to the threshold point of %HbF which is 15%. Genotyping of rs11886868 and rs4671393 was performed using PCR/Sequencing. To test for trait association with the candidate SNPs, genotype and allele frequencies between 'group who had %HbF < 15' and 'group who had %HbF >15' (controls) were compared using Pearson's chi-square test (compare 2, version 1.02). The association of each genotype and the combined genotype with complications was performed by logistic regression test. RESULTS: Our findings showed that the majority of patients carried genotype CT of rs11886868 and genotypes AG and GG of rs4671393 present HbF level < 15%. RR = 0.08, RR = 0.176, and RR = 0.189, respectively. The results showed a significant association between the alleles T of rs11886868 and G of rs4671393 and %HbF < 15% with P = 0.016; RR = 0.39 and P = 8.9 * 10-3: RR = 0.567, respectively. Interestingly, the C allele of the rs11886868 and the A allele of the rs46713939 were associated with an ameliorated phenotype in patient's SCA. The combination of the genotypes GG and CT explains more phenotypic variance than the sum of the two BCL11A SNPs taken individually. PMID- 26125974 TI - Use of Powered Prosthesis for Children with Upper Limb Deficiency at Hyogo Rehabilitation Center. AB - BACKGROUND: There has been no research investigating the use of powered prosthetic for children in Japan. OBJECTIVE: To gain better insight into the state of powered prosthesis usage and identify a ratio of rejection among children. METHODS: Subjects were 37 unilateral below elbow amputees between the ages of 0 and 16 at the time of their first experienced fitting with a powered prosthesis at our Center. The information was collected from medical records and through face-to-face interviews, and we examined rejection rate and the factors affecting the use of powered prosthesis. RESULTS: The rate of discontinuation was 21.6% as 8 of the 37 children stopped using powered prosthesis. All of them were fitted their prosthesis after 2 years of age, and they rejected prosthesis between 5 to 19 years. We found that the level of amputation had no influence on the use of a powered prosthesis. CONCLUSIONS: Children fitted before 2 years of age tend to accept their powered prosthesis than those fitted after 2 years. Multidisciprinary team approach, adequate rehabilitation, detailed follow-up and involvement of parents are quite important for introducing powered prosthesis for children. PMID- 26125975 TI - Volumetric relief map for intracranial cerebrospinal fluid distribution analysis. AB - Cerebrospinal fluid imaging plays a significant role in the clinical diagnosis of brain disorders, such as hydrocephalus and Alzheimer's disease. While three dimensional images of cerebrospinal fluid are very detailed, the complex structures they contain can be time-consuming and laborious to interpret. This paper presents a simple technique that represents the intracranial cerebrospinal fluid distribution as a two-dimensional image in such a way that the total fluid volume is preserved. We call this a volumetric relief map, and show its effectiveness in a characterization and analysis of fluid distributions and networks in hydrocephalus patients and healthy adults. PMID- 26125976 TI - Indole Alkaloids from Chaetomium globosum. AB - Two new indole alkaloids chaetocochin J (1) and chaetoglobinol A (8), along with chetomin (2), chetoseminudin A (3), cochliodinol (9), and semicochliodinol (10), were isolated from the rice culture of the fungus Chaetomium globosum. Their structures were elucidated by spectral analysis. Three new epipolythiodioxopiperazines, chaetocochins G-I (5-7), were identified by the combination of UPLC and mass spectrometric analysis. Chaetocochin I contained two sulfur bridges, one formed by three sulfur atoms between C-3 and C-11a, and the other formed by four sulfur atoms between C-3' and C-6'. Chaetocochin I was readily transformed into chetomin (2), chetoseminudin A (3), chaetocochin D (4), chaetocochin G (5), and chaetocochin H (6) by losing sulfur atoms. Compounds 1-3, and 8 exhibited antibacterial activities against Bacillus subtilis with MICs of 25, 0.78, 0.78, and 50 MUg/mL, respectively, but not against Gram-negative bacterium (Escherichia coli). Compounds 2 and 8 were inactive against Candida albicans, Fusarium graminearum, Fusarium vasinfectum, Saccharomyces cerevisiae, and Aspergillus niger even at the high concentrations of 200 and 100 MUg/mL, respectively. Compound 8 showed free radical scavenging capacity against the 1,1 diphenyl-2-picryl-hydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6 sulfonic acid radical (ABTS(+*)), with IC50 values of 143.6 and 45.2 MUM, respectively. The free radical scavenging capacity rates of compounds 1-3 on the DPPH and ABTS(+*) were less than 20% at the test concentrations (89.9-108.3 MUM). The superoxide anion radical scavenging assay indicated that compounds 1-3, and 8 showed 14.8% (90.9 MUM), 18.1% (90.9 MUM), 51.5% (88.3 MUM), and 30.4% (61.3 MUM) superoxide anion radical scavenging capacity, respectively. PMID- 26125977 TI - Progesterone supplementation in the frozen embryo transfer cycle. AB - PURPOSE OF REVIEW: Currently, different modalities with regard to endometrial preparation for frozen-thawed embryo transfer (FTET) are used, the natural and artificial cycles being the most common approaches. This review is aimed to update the current knowledge about progesterone supplementation in both types of protocols. RECENT FINDINGS: Natural cycle-frozen-thawed embryo transfer (NC-FTET) is the favored option for women with normal ovulatory menstrual cycles and may be programmed following two different protocols: the 'true NC-FTET', associated with daily blood or urine luteinizing hormone measurements, and 'modified NC-FTET', triggering ovulation with human chorionic gonadotropin. Both methods of endometrial preparation show comparable reproductive outcomes. In artificial cycle-frozen-thawed embryo transfer, estrogen and progesterone are sequentially administered, being the option of choice for women with irregular menstrual cycles. Nowadays, no differences between the different formulations of progesterone have been observed. Furthermore, there seems to be no agreement on doses and duration of progesterone supplementation during FTET. SUMMARY: We conclude that, according to the current available data, there is no superiority of any one regimen over another with regard to reproductive outcomes. Therefore, the final decision must be based on individualization of the treatment while considering patient characteristics prior to FTET, convenience, optimization of clinical outcomes and cost efficiency of the procedure. PMID- 26125978 TI - A link between human papilloma virus vaccination and primary ovarian insufficiency: current analysis. AB - PURPOSE OF REVIEW: The cause of primary ovarian insufficiency (POI) is multifactorial. Known causes include external factors such as chemotherapy, radiotherapy, exposure to endocrine-disrupting chemicals, infections that lead to a permanent insult to the ovary, autoimmune conditions, and genetic causes. An association between the quadrivalent antihuman papilloma vaccine (HPV4) and POI was recently suggested. RECENT FINDINGS: An increasing number of cases of POI post-HPV4 are being reported. Possible mechanisms for the suspected effect of HPV on female reproductive function are a toxic effect or an autoimmune response. The trigger could be the vaccine immunogen contents or the adjuvants, the latter are used to increase the immune reaction. The adjuvant in HPV4 contains aluminum. Animal models have shown aluminum exposure to inhibit expression of female reproductive hormones and to induce histologic changes in the ovaries. Specific genetic compositions may be more susceptible to developing an autoinflammatory syndrome after exposure to an environmental factor. SUMMARY: The mechanisms responsible for POI are not yet fully understood. Although case reports cannot establish causation, awareness of a possible link between HPV4 and POI will help to identify and manage future cases that may arise. PMID- 26125979 TI - Preoperative assessment and diagnosis of endometriosis: are we any closer? AB - PURPOSE OF REVIEW: The management of endometriosis has progressed vastly with medical treatments providing a large role in controlling endometriosis symptoms. Despite these advances we still lack an accurate noninvasive test to diagnose endometriosis. This has a large role in the delay to diagnosis, management and progression of the disease amongst a population that is choosing to conceive later. RECENT FINDINGS: Endometriosis is now thought to affect 1 in 10 women with patient annual healthcare costs estimated at &OV0556;9579. The diagnosis of this disease is still delayed by an average of 6-9 years allowing disease and symptom progression. Researchers have assessed a wide variety of noninvasive markers from urinary derivatives to MRI. There has been limited success in producing a highly sensitive and specific preoperative test for endometriosis. Novel markers such as miRNA provide the most encouraging diagnostic accuracy. SUMMARY: The development of a noninvasive accurate marker for endometriosis is a research target and priority of the European Society of Human Reproduction and Embryology. The current markers in use have moderate sensitivity and sensitivity. The inflammatory basis for the disease underpins many biomarkers but also many other concomitant diseases reducing accuracy and increasing false positive results. PMID- 26125980 TI - Shape-encoded silica microparticles for multiplexed bioassays. AB - Shape-encoded silica microparticles for use in multiplexed bioassays were fabricated by using optofluidic maskless lithography (OFML) and tetraethylorthosilicate (TEOS) polymerization. These encoded silica microparticles exhibit excellent bioconjugation properties and negligible non specific analyte adsorption. Encoded silica microparticles could be useful in a wide variety of applications, including DNA- and protein-based diagnostics. PMID- 26125981 TI - FT-IR and FT-Raman studies of cross-linking processes with Ca2+ ions, glutaraldehyde and microwave radiation for polymer composition of poly(acrylic acid)/sodium salt of carboxymethyl starch - In moulding sands, Part II. AB - The hardening process of moulding sands on quartz matrices bound by polymer binders containing carboxyl and hydroxyl groups can be carried out by using physical (microwave radiation, thermal holding) and chemical (Ca(2+) cations, glutaraldehyde) cross-linking agents. The highest hardening level obtain moulding sand samples containing binders in a form of the aqueous composition of poly(acrylic acid)/sodium salt of carboxymethyl starch (PAA/CMS-Na) within the microwave radiation field, for which the bending strength is of 1.6 MPa value even after 24h from ending the agent activity. The authors focused, in this study, on finding the reason of this effect. It was shown, by means of the FT-IR and FT-Raman spectroscopic methods, that the chemical adsorption process activated by microwaves plays an essential role. The applied microwaves activate the polar groups present in the polymer composition structure as well as the quartz crystals surfaces (silane groups). Then the chemical adsorption occurs in the binder-matrix system within the microwave radiation field and intermolecular lattices are formed with a participation of hydrogen bridges (SiOH?OC, SiOH?OH) and COSi type bonds. PMID- 26125982 TI - A new dual fluorogenic and chromogenic "turn-on" chemosensor for Cu2+/F- ions. AB - Turn "off-on" chemosensor 2-(-2-((3',6'-bis(diethylamino)-3-oxospiro[isoindoline 1,9'-xanthen]-2-yl)imino)ethylidene)-N-phenylhydrazine-1-carbothioamide (RBS) was designed and synthesized. Using the naked eye, RBS showed favorable observation characteristics with both Cu(2+) and F(-) ions. The various modes of sensitivity shown by RBS toward the Cu(2+) and F(-) ions were investigated by spectral techniques, including UV-Vis, fluorescence and (1)H NMR spectroscopy. The Job's plot indicated the formation of 1:1 complex between RBS and Cu(2+)/F(-). The binding constant of the RBS-guest(-) complexes were found to be 1.3*10(4) and 6.2*10(3)M(-1) for the RBS-Cu(2+) and RBS-F(-), respectively. PMID- 26125983 TI - Synthesis, characterization, low temperature solid state PL and photocatalytic activities of Ag2O.CeO2.ZnO nanocomposite. AB - A novel multi-metal nanocomposite oxide Ag2O.CeO2.ZnO has been prepared by co precipitation of their carbonates from aqueous solutions of the metal nitrates following calcinations and annealing 5h at 450 degrees C and 4h at 600 degrees C. Ag2O.CeO2.ZnO has been characterized by XRD, SEM, EDS and PL spectra. According to XRD results the crystallite size of Ag2O.CeO2.ZnO varies in the range of 19 111 nm with an average size of 50 nm, which is in good agreement with SEM results. Elemental analysis was performed by SEM-EDS. Emissions of Ag2O.CeO2.ZnO has been observed in UV (NBE emission), visible and NIR regions at 325 nm excitation by a line of He-Cd laser. Photocatalytic as well as anti-bacterial activities have been studied. The nano composite Ag2O.CeO2.ZnO shows an excellent photocatalytic dye degradation activity. PMID- 26125984 TI - Synthesis, crystal structures, photoluminescence properties and DNA binding of triazine-nickel(II) complexes for DNA detection. AB - We report here the synthesis of three new nickel(II) complexes: [Ni(PzTA)2CO3].5H2O (PzTA=2,4-diamino-6-(2'-pyrazin)-1,3,5-triazine) in 1, [NiQ(PyTA)(H2O)2]Cl.H2O (HQ=8-hydroxyquinoline, PyTA=2,4-diamino-6-(2'-pyridyl) 1,3,5-triazine) in 2, [NiQ(PzTA)(H2O)2]Cl.H2O in 3, and they were characterized by UV spectroscopy, elemental analysis, molar conductivity and X-ray single crystal diffraction. Binding of the complexes to ct-DNA was investigated with electronic spectroscopy, ethidium bromide displacement from DNA, viscometry and cyclic voltammetry. The results depicted the DNA binding mode of the three complexes was intercalation, and complex 1 together with external static electricity. Moreover, the three complexes also presented potential anti-oxidant activity. Interestingly, we found 1 was sensitive to oxygen and to the polarity of nonaqueous solvents in fluorescence spectroscopy. Fluorescence of 2 and 3 is weak in neutral aqueous solvents, but is greatly enhanced by addition of ct-DNA. Thus, 2 and 3 can be used to DNA detection as DNA fluorescence probes with a LOD of 1.61 ng mL(-1), 4.90 ng mL(-1) for the relative wide linear range of 0.01-20 MUg mL(-1), 0.02-30 MUg mL(-1), respectively. These findings indicate that 1 may be a potential optical probe for oxygen-free environments in nonaqueous form, while 2 and 3 were DNA-targeted probes. PMID- 26125985 TI - Spectroscopic and electrochemical behavior of newly synthesized high fluorescent symmetric 4'-nitrophenyl-3,4,9,10-perylenebisdiimide-azo hybrid dyes. AB - The investigation has been made in the synthesis of azo hybrid rylene dyes. The hybridization of perylene bis-diimide with phenolic azo-dyes was carried out by the nucleophilic substitution (SNAr) reaction of tetrachloroperylene-3,4,9,10 bisdiimide 3 with phenolic azo-dyes 4a-g in basic medium. The hybrid dyes exhibited two absorption maxima lambdamax in the range 300-350, 426-438 nm in ethanol due to presence of azo linkage and highly conjugated framework of pi bonds. Fluorescence spectra of these dyes in water showed sharp emission peaks with small bandwidths in the range 490-495 nm, and fluorescence quantum yield was 0.71-0.83 in comparison with standard reference fluorescein. The structures of perylene-azo dyes were elucidated by FTIR and NMR spectroscopy. Luminescence was determined by LS-100 meter which was found to be excellent in limits 0.208-0.239 cd/m(2). Cyclic voltammetric studies were made by Electrochemical Analyzer CH1830C which showed the oxidation chemical potential of these hybrid dyes. PMID- 26125986 TI - Synthesis and spectroscopic analysis of polydiphenylamine via oxidation with bentonite clay in the solid state. AB - In this study, solids of polydiphenylamine (PDPA) synthesized mechanochemically by reaction with bentonite (PDPAOB) were studied using Raman spectroscopy. It was possible to identify the chemical species in the PDPA-bentonite compound. The spectra obtained were compared to the spectra of PDPA prepared chemically by oxidation of DPA with K2S2O8 in the solid state, and PDPA produced electrochemically, with the aim of studying the characteristic frequencies of the aromatic segments (DPB), radical cation (DPB(+)) and dication (DPB(2+)) of N,N diphenylbenzidine (DPB) in the polymer structure of the PDPA. To analyze the segments present, the band characteristic of CC asymmetric stretching of the aromatic ring in the Raman spectra was deconvoluted because of the widening of the band and shifts observed by irradiation at wavelengths of 532 and 785 nm. This procedure showed that there are three distinct contributions in the spectra which facilitate the monitoring of changes in the contributions of the segments in the materials doped with HCl (PDPAOBD) and de-doped with NH4OH, (PDPAOBR). PMID- 26125987 TI - Formation of plasmonic silver nanoparticles by flavonoid reduction: A comparative study and application for determination of these substances. AB - Formation of plasmonic silver nanoparticles by flavonoid reduction was studied. Effects of the nature and the concentration of a flavonoid and a stabilizer, composition of the solution and the interaction time were revealed. It was found that quercetin, dihydroquercetin, rutin and morin produced an intense surface plasmon resonance band of silver nanoparticles at 415 nm which was linearly related to the concentration of a flavonoid, while chrysin, naringenin and naringin did not produce any remarkable changes. It was used for the spectrophotometric determination of the former four flavonoids with the detection limits of 0.03; 0.06; 0.09 and 0.1 MUg mL(-1), respectively. The developed method was applied for the determination of flavonoids in biologically active food additives. PMID- 26125988 TI - A copper(II) complex with a Cu-S8 bond. Attenuated total reflectance, electron paramagnetic resonance, resonance Raman and atoms-in-molecule calculations. AB - Green [Cu(1,10-phenanthroline)2OH2](ClO4)2 (1) reacts with yellow elemental sulfur at room temperature in methanol to yield turquoise blue [Cu(1,10 phenanthro-line)2(S8)](ClO4)2 (2). A comparative study of the EPR spectra of 1 and 2 in solid state and in methanol glass indicates that the S8 unit in 2 is bound to the metal. High level DFT calculations show that the cation in 2 is five coordinate, distorted square pyramidal with S8 occupying the apical position. The crucial Cu(II)-S bond is around 2.9A. Such long Cu(II)-S bonds occur in oxidized plastocyanin where it is considered to be bonding. Presence of a weak Cu-S8 bond is revealed in the resonance Raman spectra of 2. Satisfactory matching of the calculated and experimental IR spectra vindicates the theoretically derived structure of the cation in 2. PMID- 26125989 TI - Novel multi-component hybrids through double luminescent lanthanide unit functionalized zeolite L and titania. AB - Zeolite L (ZL) is functionalized with inside-outside double modification paths (gas disperse ("ship in bottle") and covalently grafting) with two kinds of luminescent lanthanide species (Tb(3+) complex of acetylacetone (AA), lanthanide polyoxometalate (NaLnW10O36.32H2O, abbreviated as LnW10, Ln=Eu, Tb)) to prepare the hybrid materials. The prepared hybrids show the red and green luminescence, which provides a useful path to obtain multi-component lanthanide hybrids. PMID- 26125990 TI - Photocatalytic activity of TiO2 nanoparticles synthesized in presence of ammonium hexafluorosilicate. AB - A series of silicon incorporated TiO2 with anatase crystalline phase were prepared via sol-gel using ammonium hexafluorosilicate (AHFS). The synthesized products were characterized using X-ray diffraction, FTIR, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), UV-vis diffuse reflectance spectrophotometry (DRS), energy dispersive X-ray analysis (EDX) and BET surface area measurement. Presence of Si-O-Ti bonds is revealed based on the XPS results. The products were tested for their activity as photocatalysts for degradation of congo red as a prob molecule. The 20% AHFS incorporation displayed the highest photocatalytic activity. This adequate amount of AHFS was beneficial for transferring photogenerated electron and reducing the recombination of electron-holes. PMID- 26125991 TI - Conformational and vibrational analyses of meta-tyrosine: An experimental and theoretical study. AB - M-tyrosine is one kind of positional isomer of tyrosine which is widely applied in agrichemical, medicinal chemistry, and food science. However, the structural and vibrational features of m-tyrosine have not been reported or systematically investigated. In this work, potential energy surface (PES) calculations were used for searching and determining the stable zwitterionic conformers of m-tyrosine, and the Raman spectra of m-tyrosine and deuterated m-tyrosine were measured and interpreted based on theoretical computation. For the spectral simulation, several DFT-based quantum chemistry (QC) methods were employed, and the M06-2X functional with SMD solvent model was found to be best in reproducing the Raman spectra and geometrical property. As such, this study has not only presented a detailed study of m-tyrosine's vibrational property which is lack in the literature, but also may shed some light on the optimal choice of QC methods for calculation of conformations and vibrational properties of zwitterionic amino acids. PMID- 26125992 TI - Probing the toxic mechanism of Ag+ with lysozyme. AB - Silver (Ag) is widely used in human activities, which provides possibilities to distribute in organisms and tissues, resulting in harmful effects on human health. In this work, lysozyme was chosen as the target molecule to study the mechanism of toxic interactions between Ag(+) and protein using fluorescence emission spectra, synchronous fluorescence spectra, UV-vis absorption spectra, circular dichroism (CD) spectra, isothermal titration calorimetry (ITC), and enzyme activity assay. The results of fluorescence emission and synchronous fluorescence showed that there were interactions between Ag(+) and lysozyme by eliminating the inner filter effect (IFE). Data from UV-vis spectra indicated that the frame structure of lysozyme became looser with Ag(+) existent, while the micro-environment of aromatic amino acid residues did not show any significant alteration. CD results suggested that the secondary structure of lysozyme presented a decrease in alpha-helix contents with the increasing amount of Ag(+). ITC results showed Ag(+) can spontaneously bind with lysozyme through hydrogen bonding and van der Waals forces with one binding site (Ka=1.93*10(6)). The lysozyme activity was inhibited by Ag(+) according to the enzyme activity assay, revealing that Ag(+) bound to lysozyme at the active site which resulted in inhibition of lysozyme activity. This work showed that Ag(+) can cause damages to the structure and function of lysozyme. PMID- 26125993 TI - Bio-mediated route for the synthesis of shape tunable Y2O3: Tb3+ nanoparticles: Photoluminescence and antibacterial properties. AB - The study reports green mediated combustion route for the synthesis of Tb(3+) ion activated Y2O3 nanophosphors using Aloe Vera gel as fuel. The concentration of Tb(3+) plays a key role in controlling the morphology of Y2O3 nanostructures. The formation of different morphologies of Y2O3: Tb(3+) nanophosphors were characterized by PXRD, SEM, TEM and HRTEM. PXRD data and Rietveld analysis evident the formation of single phase Y2O3 with cubic crystal structure. The influence of Tb(3+) ion concentration on structural morphology, UV-visible absorption and PL emission were investigated systematically. The PL emission of Y2O3: Tb(3+) (1-11 mol%) nanophosphors were studied in detail under 271 and 304nm excitation wavelengths. The CIE coordinates lies well within green region and correlated color temperature values were found to be 6221 and 5562K under different excitations. Thus, the present phosphor can serve as an excellent candidate for LEDs. Further, prismatic Y2O3: Tb(3+) (3 mol%) nanophosphor showed significant antibacterial activity against Pseudomonas desmolyticum and Staphylococcus aureus. The present study successfully demonstrates Y2O3: Tb(3+) nanophosphors can be used for display applications as well as in medical applications for controlling pathogenic bacteria. PMID- 26125994 TI - Ophthalmic and Glaucoma Treatment Characteristics Associated With Changes in Health-related Quality of Life Before and After Newly Diagnosed Primary Open angle Glaucoma in Nurses' Health Study Participants. AB - PURPOSE: To identify attributes related to glaucoma diagnosis or early glaucoma treatment patterns that are associated with changes in health-related quality of life among those with newly diagnosed primary open-angle glaucoma. METHODS: Among Nurses' Health Study participants with incident medical record-confirmed primary open-angle glaucoma diagnosed in 1992 to 2000, we included 317 women who completed the Short Form-36 Health Survey prediagnosis and postdiagnosis. The 2 primary outcomes were 4-year changes (1992 to 1996 or 1996 to 2000) in the physical and mental component summary scores. Multiple regression models were used to estimate differences in score changes by early treatment pattern history and characteristics as of diagnosis (ie, number of eyes affected, history of cataract, macular degeneration, cup-to-disc ratio, intraocular pressure, visual field loss type). RESULTS: In multivariable models, no ophthalmologic characteristics were associated with physical component score change. However, compared with treatment with eye drops or pills only, laser trabeculoplasty treatment (concomitant with history of treatment with eye drops or pills in 84%) was associated with a worse mental component score change over 4 years (-2.5 units; 95% confidence interval: -4.6, -0.3); this association was stronger with a family history of glaucoma (P-interaction=0.04) or with bilateral disease (P interaction=0.001). CONCLUSIONS: Among patients with incident glaucoma, no major factors were associated with change in physical well being. However, compared with medical treatment only, a history of laser trabeculoplasty, which was commonly accompanied with a history of medical treatment and likely represented the need for a second line of treatment, was associated with a worse decline in mental well being. PMID- 26125995 TI - Haematopoietic stem cells and their niches. PMID- 26125996 TI - A theoretical approach based on electromagnetic scattering for analysing dielectric shimming in high-field MRI. AB - PURPOSE: In this study, we analyzed dielectric shimming by formulating it as an electromagnetic scattering problem using integral equations. METHODS: Three dimensional simulations of the radiofrequency field in two configurations using different materials were analyzed in terms of induced currents and secondary fields. A two-dimensional integral equation method with different backgrounds was used to identify the underlying physical mechanisms. This framework was then used to develop an inversion method for the design of dielectric pads. RESULTS: The effects of a dielectric pad can be attributed to the interference of a secondary field that is produced by the currents induced in the dielectric pad, radiating in an inhomogeneous background. The integral equation method with inhomogeneous background reduces the complexity of the forward and inverse problem significantly and can be used to optimize the permittivity distribution for a desired B1+ field. Agreement with experimental B1+ maps was obtained in a cylindrical phantom, demonstrating the validity of the method. CONCLUSIONS: The integral equation method with inhomogeneous background yields an efficient numerical framework for the analysis and inverse design of dielectric shimming materials. PMID- 26125997 TI - Improving attrition rates in Ebola virus drug discovery. AB - INTRODUCTION: The Ebola 2014/2015 outbreak has had devastating effects on the people living in West Africa. The spread of the disease in endemic countries and the potential introduction of sporadic cases in other continents points out the global health threat of Ebola virus disease (EVD). Despite the urgent need for treating EVD, there are no approved treatments. Given the lack of treatments available, alternative therapeutic strategies have had to be used. AREAS COVERED: This article summarizes the unregistered therapeutics that were used to treat patients during the Ebola 2014/2015 outbreak, in addition to approaches used for the selection of candidate drugs. The article also proposes potential theoretical criterion for use in virtual screening of molecular libraries for candidate Ebola drugs. EXPERT OPINION: In the absence of approved therapeutics for EVD, experimental drugs have had to be used. The repurposing of approved drugs for the treatment of EVD, as an alternative therapeutic strategy, has also been suggested. Screening in vitro- and in silico-approved drugs revealed several promising candidates but further testing is required to test their efficacy. All these therapeutic approaches are, however, only short-term solutions and there is still an urgent need for the development of specific drugs for the current and future outbreaks. PMID- 26125998 TI - A combinatorial role for MutY and Fpg DNA glycosylases in mutation avoidance in Mycobacterium smegmatis. AB - Hydroxyl radical (OH) among reactive oxygen species cause damage to nucleobases with thymine being the most susceptible, whilst in contrast, the singlet oxygen ((1)02) targets only guanine bases. The high GC content of mycobacterial genomes predisposes these organisms to oxidative damage of guanine. The exposure of cellular DNA to OH and one-electron oxidants results in the formation of two main degradation products, the pro-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoGua) and the cytotoxic 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua). These lesions are repaired through the base excision repair (BER) pathway and we previously, demonstrated a combinatorial role for the mycobacterial Endonuclease III (Nth) and the Nei family of DNA glycosylases in mutagenesis. In addition, the formamidopyrimidine (Fpg/MutM) and MutY DNA glycosylases have also been implicated in mutation avoidance and BER in mycobacteria. In this study, we further investigate the combined role of MutY and the Fpg/Nei DNA glycosylases in Mycobacterium smegmatis and demonstrate that deletion of mutY resulted in enhanced sensitivity to oxidative stress, an effect which was not exacerbated in Deltafpg1 Deltafpg2 or Deltanei1 Deltanei2 double mutant backgrounds. However, combinatorial loss of the mutY, fpg1 and fpg2 genes resulted in a significant increase in mutation rates suggesting interplay between these enzymes. Consistent with this, there was a significant increase in C -> A mutations with a corresponding change in cell morphology of rifampicin resistant mutants in the Deltafpg1 Deltafpg2 DeltamutY deletion mutant. In contrast, deletion of mutY together with the nei homologues did not result in any growth/survival defects or changes in mutation rates. Taken together these data indicate that the mycobacterial mutY, in combination with the Fpg DNA N-glycosylases, plays an important role in controlling mutagenesis under oxidative stress. PMID- 26125999 TI - Modular, Concise, and Efficient Synthesis of Highly Functionalized 5 Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence. AB - An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines. PMID- 26126000 TI - Self-reported health-related quality-of-life issues for Aboriginal and Torres Strait Islander patients with experience of cancer in Australia: a review of literature. AB - BACKGROUND: Aboriginal peoples and Torres Strait Islander peoples (who comprise the indigenous people or the original inhabitants of Australia before colonization) are more likely to experience cancers with poorer prognoses, are more likely to be diagnosed with cancer at a later stage of disease progression, are less likely to receive adequate cancer treatment and are more likely to pass away due to cancer, compared with other Australians. Cancer and biomedical therapies for cancer often have significant, ongoing effects on patient health related quality of life (HRQL). Therefore, consideration of HRQL for Aboriginal and Torres Strait Islander peoples with experience of cancer in Australia is imperative. This article examines the literature for HRQL issues self-reported by Aboriginal and/or Torres Strait Islander people with experience of cancer in Australia. METHODS: A search of peer-reviewed journal articles, government reports, and other literature was undertaken using electronic databases and citation snowballing. Self-reports from Aboriginal and/or Torres Strait Islander people with experience of cancer were examined. HRQL issues were determined utilizing the Australian Psycho-Oncology Co-operative Research Group's definition of HRQL. RESULTS: Fifty-two documents were found with original data from Aboriginal and/or Torres Strait Islander people who self-reported their experiences of cancer. No published reports were found that specifically examined self-reports from Aboriginal and/or Torres Strait Islander people on the impact of cancer and biomedical treatment on their HRQL. CONCLUSION: Previous literature suggests that there is urgency for improved communication and cultural competency in cancer care for Aboriginal and Torres Strait Islander patients in Australia, with a stronger focus on meeting patient needs and improving HRQL. This review has provided insight into HRQL issues for Aboriginal and Torres Strait Islander patients with cancer in Australia. Further work using patient-reported outcomes measures would provide greater insight into the impact of cancer and biomedical treatments on Aboriginal and Torres Strait Islander patients' HRQL. PMID- 26126001 TI - Control of invasive meningococcal disease: is it achievable? AB - Neisseria meningitidis still leads to deaths and severe disability in children, adolescents and adults. Six different capsular groups of N. meningitidis cause invasive meningococcal disease in the form of meningitis and septicaemia in humans. Although conjugate meningococcal vaccines have been developed to provide protection against four of the capsular groups causing most diseases in humans, vaccines against capsular group B, which causes 85% of cases in Australia and the United Kingdom, have only recently been developed. A capsular group B meningococcal vaccine - 4CMenB (Bexsero) - has recently been licensed in the European Union, Canada and Australia. In Australia, a submission for inclusion of 4CMenB in the funded national immunization programme has recently been rejected. The vaccine will now be introduced into the national immunization programme in the United Kingdom following negotiation of a cost-effective price. With the current low incidence of invasive meningococcal disease in many regions, cost effectiveness of a new capsular group B meningococcal vaccine is borderline in both the United Kingdom and Australia. Cost-effectiveness of an infant programme is determined largely by the direct protection of those vaccinated and is driven by the higher rate of disease in this age group. However, for an adolescent programme to be cost-effective, it must provide both long-term protection against both disease and carriage. The potential of vaccination to reduce the rate of severe invasive disease is a real possibility. A dual approach using both an infant and adolescent immunization programme to provide direct protection to those age groups at highest risk of meningococcal disease and to optimize the potential herd immunity effects is likely to be the most effective means of reducing invasive meningococcal disease. This commentary aims to describe the known disease burden and consequences of meningococcal disease, and the development and potential effectiveness of new capsular group B meningococcal vaccines. PMID- 26126002 TI - Simultaneous Detection of Multiple Proteins that Bind to the Identical Ligand in Supported Lipid Bilayers. AB - Herein, we developed a new separation-based detection method that is capable of simultaneously identifying multiple competitively binding proteins for the same ligand on supported lipid bilayers (SLBs). This strategy used unlabeled target analyte proteins that bind to fluorescently tagged, lipid-conjugated ligands within the SLB. The protein-ligand binding complexes were then focused under an applied potential to different locations within the SLB based on each protein's size and charge. Both protein identity and relative surface concentration information could be obtained, simultaneously. Specifically, the competitive binding of streptavidin and goat anti-biotin for biotin-conjugated lipids was explored. It was found that streptavidin could inhibit the binding of goat anti biotin antibodies for biotin-cap-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine N-(7-nitro-2-1,3-benzoxadiazol-4-yl)(biotin-cap-NBD-PE) lipids and that streptavidin more effectively outcompeted the anti-biotin antibody at lower protein concentrations. Also, modulating the chemical composition of the membrane helped control the ultimate focusing position and separation of the streptavidin bound biotin, anti-biotin-bound biotin, and free biotin-conjugated lipid bands. The assay developed herein provides a simple and convenient strategy for simultaneously monitoring target analytes that bind to the identical ligand and may ultimately be useful in developing assays that help overcome problems associated with cross-reactivity. PMID- 26126003 TI - Calcium supplementation for prevention of primary hypertension. AB - BACKGROUND: Hypertension is a major public health problem that increases the risk of cardiovascular and kidney diseases. Several studies have shown an inverse association between calcium intake and blood pressure. As small reductions in blood pressure have been shown to produce rapid reductions in vascular disease risk even in individuals with normal blood pressure ranges, this review intends to evaluate the effect of calcium supplementation in normotensive individuals as a preventive health measure. OBJECTIVES: To assess the efficacy and safety of calcium supplementation versus placebo or control for reducing blood pressure in normotensive people. SEARCH METHODS: We searched the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomised controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register. We also reviewed reference lists from retrieved studies and contacted authors of relevant papers. We applied no language restrictions. SELECTION CRITERIA: We selected trials that randomised normotensive people to dietary calcium interventions such as supplementation or food fortification versus placebo or control. We excluded quasi-random designs. The primary outcomes were hypertension (defined as blood pressure >= 140/90 mmHg) and blood pressure measures. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, abstracted the data and assessed the risks of bias. MAIN RESULTS: We included 16 trials with 3048 participants. None of the studies reported hypertension as a dichotomous outcome. The effect on systolic and diastolic blood pressure was mean difference (MD) -1.43 mmHg (95% confidence interval (CI) -2.15 to -0.72) and -0.98 mmHg (95%CI -1.46 to -0.50) respectively. The effect on systolic and diastolic blood pressure for those younger than 35 years (7 trials with 399 participants) was -2.11 mmHg (95%CI -3.58 to -0.64) / 2.61 mmHg (95% CI -3.74, -1.49). The effect on systolic and diastolic blood pressure for those 35 years or more (9 trials with 2649 participants) was -0.96 mmHg (95%CI -1.83 to -0.09) / -0.59 mmHg (95%CI -1.13 to -0.06). The effect on systolic and diastolic blood pressure for women (6 trials with 1823 participants) was -1.45 mmHg (95% CI -2.78 to -0.12) / -0.92 mmHg (95% CI -1.71 to -0.14). The effect on systolic and diastolic blood pressure for men (5 trials with 617 participants) was -2.07 (95%CI -3.56 to -0.59] / -1.91 (95%CI -2.80 to -1.02).The quality of evidence for each of these outcomes was high. The effect is consistent in both genders regardless of baseline calcium intake.The effect on systolic blood pressure was 0.08 mmHg (95% CI -2.16 to 2.32) with doses less than 1000 mg, -1.14 mmHg (95% CI -2.01 to -0.27) with 1000 - 1500 mg, and -2.79 mmHg (95% CI 4.71 to -0.86) with more than 1500 mg. The effect on diastolic blood pressure was -0.54 mmHg (95% CI -2.23 to 1.15), -0.71 mmHg (95% CI -1.37 to -0.06) and -1.43 mmHg (95% CI -2.22 to -0.64) respectively. The quality of evidence for each of these outcomes was high.None of the studies reported adverse events. AUTHORS' CONCLUSIONS: An increase in calcium intake slightly reduces both systolic and diastolic blood pressure in normotensive people, particularly in young people, suggesting a role in the prevention of hypertension. These results should be interpreted with caution, since the proposed biological mechanism explaining the relationship between calcium and blood pressure has not been fully confirmed. The effect across multiple prespecified subgroups and a possible dose response effect reinforce this conclusion. Even small reductions in blood pressure could have important health implications for reducing vascular disease.There is a great need for adequately-powered clinical trials randomising young people. Subgroup analysis should involve basal calcium intake, age, sex, basal blood pressure, and body mass index. We also require assessment of side effects, optimal doses and the best strategy to improve calcium intake. PMID- 26126004 TI - Hemostatic Dysfunction in Liver Diseases. PMID- 26126005 TI - [Skin lightening products are a part of everyday life in many parts of the world. Corticosteroids, hydroquinone and mercury are common ingredients]. AB - During the past decade, attention has been drawn towards the globally increased usage of skin-lightening (bleaching) products which are manufactured and sold, particularly in Africa and Asia, but also via the internet and in local shops all over North America and Europe. The active ingredients include hydroquinone, mercury and potent corticosteroids which can have severe health effects. After investigating a patient at our clinic where the symptoms and findings could be linked to the use of bleaching products, we started to search the literature for similar cases. We found a global epidemic of health disorders related to skin lightening products. With this article we want to increase the awareness among Swedish physicians of this growing and harmful cosmetic trend. PMID- 26126006 TI - [The usefulness of pharmacogenetics for a more individualized treatment. The example thiopurines in inflammatory bowel disease and childhood leukemia]. AB - Thiopurines are chemotherapeutic drugs used for treatment of inflammatory bowel diseases and childhood leukemia. Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurines. Individuals lacking TPMT are at increased risk for severe side effects when treated with conventional doses of thiopurines. A research group at the division of drug research at Linkoping University is studying thiopurine pharmacogenetics. Since the year 2000, the lab has determined the TPMT status in over 12000 individuals, as an aid to decide thiopurine doses before starting treatment. New knowledge of how genetic factors influence thiopurine treatment effect are anticipated to improve the possibilities for individualization of thiopurine therapy. PMID- 26126007 TI - [Questions regarding the physician's role in the alcohol locks clarified]. PMID- 26126008 TI - [Crossroads]. PMID- 26126009 TI - [The hidden messages of pain metaphors. About pain as experience and metaphor]. PMID- 26126010 TI - [With the name in the wrong box--the physicians' experience of a different kind of life]. PMID- 26126011 TI - [Train on teamwork for safe obstetric care!]. PMID- 26126013 TI - [Not Available]. PMID- 26126012 TI - [Not Available]. PMID- 26126014 TI - [The debate on ethics, law and new expensive drugs. Speak clearly about health care limitations]. PMID- 26126015 TI - [Good that the quality of laboratory results are observed]. PMID- 26126016 TI - [Not Available]. PMID- 26126017 TI - Carbon Nanohoops: Excited Singlet and Triplet Behavior of Aza[8]CPP and 1,15 Diaza[8]CPP. AB - The excited state properties of two nitrogen-doped cycloparaphenylene molecules, or carbon nanohoops, have been studied using steady-state and time-resolved absorption and emission spectroscopies. Quantum yield of fluorescence (Phif = 0.11 and 0.13) and intersystem crossing (Phiisc = 0.45 and 0.32) were determined for aza[8]CPP and 1,15-diaza[8]CPP, respectively. We also present the proton transfer reaction between trifluoroacetic acid and the nitrogen-doped nanohoops, which resulted in significant modifications to the steady-state absorption and emission spectra as well as the triplet-triplet absorption spectra. From fluorescence quenching data we determine the equilibrium constant for the proton transfer reaction between aza[8]CPP (Keq = 1.39 * 10(-3)) and 1,15-diaza[8]CPP (Keq = 2.79 * 10(-3)) confirming that 1,15-diaza[8]CPP is twice as likely to be protonated at a particular concentration of trifluoroacetic acid. PMID- 26126020 TI - Pattern of lymph node metastases and its implication in radiotherapeutic clinical target volume in patients with non-small-cell lung cancer: a study of 2062 cases. AB - OBJECTIVE: To study the pattern of lymph node metastasis (LNM) of non-small-cell lung cancer (NSCLC) and to clarify which node level should be included while undergoing radiotherapy (RT). METHODS: A total of 2062 patients with NSCLC patients who had undergone thoracotomy were retrospectively examined. The clinicopathological factors related to LNM were analysed. RESULTS: The LNM rates (the number of node-positive patients/the total number of patients) in patients with primary tumours in different lobes (left upper lobe, left lower lobe, right upper lobe, right middle lobe and right lower lobe) were 53.25%, 53.87%, 53.77%, 64.67% and 61.58%, respectively. We have found that in all of the clinicopathological factors, including sex, age, tumour location, histological type, maximum diameter, T stage, degree of differentiation and tumour growth pattern, only maximum diameter (p = 0.336) and histological type (p = 0.360) did not have significant correlation with LNM rate. All of the above factors except tumour growth pattern (p = 0.239) and maximum diameter (p = 0.613) were significantly associated with lymph node ratio [LNR, ratio between metastatic and examined lymph nodes (LNs)] in linear regression. CONCLUSION: For patients with NSCLC, LNM rate and LNR can be recommended as applicable parameters for LN involvement. Multiple clinicopathological factors should be considered comprehensively to design the clinical target volume for RT of NSCLC. ADVANCES IN KNOWLEDGE: This article can provide evidence to radio-oncologists how to choose range of lymph nodal clinical target volume when they are treating inoperable patients with NSCLC patients by analysing data of patients after surgery. PMID- 26126022 TI - Semiconducting transition metal oxides. AB - Open shell transition metal oxides are usually described as Mott or charge transfer insulators, which are often viewed as being disparate from semiconductors. Based on the premise that the presence of a correlated gap and semiconductivity are not mutually exclusive, this work reviews electronic structure calculations on the binary 3d oxides, so to distill trends and design principles for semiconducting transition metal oxides. This class of materials possesses the potential for discovery, design, and development of novel functional semiconducting compounds, e.g. for energy applications. In order to place the 3d orbitals and the sp bands into an integrated picture, band structure calculations should treat both contributions on the same footing and, at the same time, account fully for electron correlation in the 3d shell. Fundamentally, this is a rather daunting task for electronic structure calculations, but quasi particle energy calculations in GW approximation offer a viable approach for band structure predictions in these materials. Compared to conventional semiconductors, the inherent multivalent nature of transition metal cations is more likely to cause undesirable localization of electron or hole carriers. Therefore, a quantitative prediction of the carrier self-trapping energy is essential for the assessing the semiconducting properties and to determine whether the transport mechanism is a band-like large-polaron conduction or a small-polaron hopping conduction. An overview is given for the binary 3d oxides on how the hybridization between the 3d crystal field symmetries with the O-p orbitals of the ligands affects the effective masses and the likelihood of electron and hole self-trapping, identifying those situations where small masses and band-like conduction are more likely to be expected. The review concludes with an illustration of the implications of the increased electronic complexity of transition metal cations on the defect physics and doping, using as an example the diversity of possible atomic and magnetic configurations of the O vacancy in TiO(2), and the high levels of hole doping in Co(2)ZnO(4) due to a self-doping mechanism that originates from the multivalence of Co. PMID- 26126021 TI - An "immune barrier" is formed in the placenta by hepatitis B immunoglobulin to protect the fetus from hepatitis B virus infection from the mother. AB - The effect of hepatitis B immunoglobulin (HBIG) on hepatitis B virus (HBV) DNA load and its protective mechanism are not well understood. Twenty-eight hepatitis B surface antigen (HBsAg)-positive pregnant women and their newborns were assigned to an experimental (n = 12) or control group (n = 16) according to whether they received HBIG during pregnancy. HBV DNA load and markers titer of the mothers and newborns were tested. These markers and HBV DNA load in mothers of the experimental group did not fluctuate significantly and were comparable to the control. In the experimental group, there was a positive correlation between mothers and their newborns with regard to hepatitis B surface antibody titer. Immunohistochemical staining of placenta sections showed that HBsAg-positive areas mainly included trophoblastic cells and villous mesenchymal cells without HBIG colocalization, whereas HBIG-positive areas principally included villous capillary endothelial cells and villous mesenchymal cells. Additionally, compared with the control group, the positive rate and mean density of HBIG in the experimental group were remarkably higher. HBIG deposition was seen in Hofbauer cells. Thus, rather than influencing virus replication, HBIG forms an immune barrier between the mother and fetus to prevent HBV transmission. PMID- 26126024 TI - Revisiting Patient Education in Changing Health Care Times. PMID- 26126023 TI - Characteristics of Fluency and Speech in Two Families With High Incidences of Stuttering. AB - PURPOSE: This study presents data from 2 families with high incidence of stuttering, comparing methods of phenotype assignment and exploring the presence of other fluency disorders and corresponding speech characteristics. METHOD: Three methods for assigning phenotype of stuttering were used: self identification, family identification, and expert identification. Agreement on which individuals were assigned by each of these methods was studied. Multiple measures of fluency and speech production were obtained. RESULTS: Self-reports and descriptions of blocking rather than self-identification as a person who stutters demonstrated the best agreement with expert identification of stuttering. Family identification showed poor agreement with both expert and self identification of stuttering. Using binary categories of fluent or stuttering, 90% of individuals in 1 family were classified by expert consensus. Only 70% of the other family could be similarly categorized. Experts required 2 other categories, cluttering and other fluency disorders, to fully characterize dysfluency within this family. These 2 families also demonstrated differences in speech production. CONCLUSION: Some families with high incidence of stuttering may also have high incidence of other fluency disorders and other speech production difficulties. This finding may have ramifications for genetic studies, including criteria for defining phenotype and collapsing data across multiple families. PMID- 26126025 TI - Tackling Communication Barriers Between Long-Term Care Facility and Emergency Department Transfers to Improve Medication Safety in Older Adults. AB - In 2013, the American College of Emergency Physicians, American Geriatrics Society, Emergency Nurses Association, and Society for Academic Emergency Medicine created geriatric emergency department guidelines, making recommendations for staffing/administration, follow up and transitions of care, education, quality improvement, equipment/supplies, and other policies, procedures, and protocols to be implemented. Awareness of these guidelines, as well as communication barriers, can help improve the delivery of care for older adults during transitions in care, particularly regarding medication safety. PMID- 26126026 TI - Older Adult Inpatient Falls in Acute Care Hospitals: Intrinsic, Extrinsic, and Environmental Factors. AB - The current integrative literature review of 23 studies aimed to identify multidimensional risk factors of falls among older adult patients in acute care hospitals. The incidence rate of fall-related injuries ranged from 6.8% to 72.1%. Advanced age was a major intrinsic risk factor, whereas being a patient in a geriatric unit was a significant extrinsic factor for inpatient falls and fall related injuries based on statistical significance obtained from quantitative data analyses. Other critical risk factors were: (a) cognitive impairment; (b) impaired mobility; (c) prolonged length of hospital stay; and (d) fall history. Environmental/situational factors, such as patient ambulation and fall locations, also contributed to inpatient falls. In clinical practice, nurses need to know who are the most vulnerable patients in the hospital and develop comprehensive interventions to decrease intrinsic, extrinsic, and environmental risk factors. Prospective mixed-methods studies are needed to examine psychosocial factors and consequences of falls. PMID- 26126029 TI - Platelet disorders: an overview. AB - Thrombocytes or platelets are anucleated cells derived from megakaryocytes by process of megakaryopoiesis, with maturation time of 4-5 days. They are small and discoid in shape with size ranging from 2 to 4 MUm. The platelet concentration in blood varies between 150, 000 and 400, 000 cells/MUl of blood. They are involved in both hemostasis and wound healing. Hence, any abnormalities in platelets can lead to various bleeding disorders. Platelet disorders include thrombocythemia and thrombocytosis, thrombocytopenia and platelet dysfunction. Thrombocythemia and thrombocytosis are associated with increased platelet count because of overproduction of platelets. Thrombocytopenia includes decreased platelet count because of failed platelet production, increased sequestration of platelets in spleen, dilution of platelets and combination of these mechanisms. Platelet dysfunction can be because of intrinsic platelet defect or an extrinsic factor that alters the normal platelet function and can be hereditary or acquired. The following review provides a comprehensive overview of the above platelet disorders. PMID- 26126030 TI - Association of selenoprotein S gene polymorphism with ischemic stroke: how strong is the evidence? PMID- 26126031 TI - Retrospective evaluation mean platelet volume in patients with mesenteric ischemia can give us wrong results. PMID- 26126032 TI - Alpha-methylacyl-CoA racemase is expressed in a majority of pancreatic neoplasms of neuroendocrine, acinar, and solid pseudopapillary differentiation. PMID- 26126033 TI - VEGF and VEGFR2 in dentigerous cysts associated with impacted third molars. AB - The aims of this study were to determine the presence and distribution of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR2) in dentigerous cysts compared with normal dental follicles as a control tissue and to evaluate endothelial cells and proliferating cells as indicators of angiogenic activity in these tissues.Twenty specimens histologically diagnosed as dentigerous cysts and 20 dental follicle specimens were included. Immunohistochemistry (IHC) using anti-VEGF and anti-VEGFR2 antibodies stained for the growth factor and its receptor, while anti-CD34 and anti-CD146 antibodies were used to identify endothelial cells. Anti-proliferating cell nuclear antigen (PCNA) antibody detected proliferating cells within the specimens. Slides were examined microscopically and results evaluated using kappa statistics, negative binomial regression and ordinal logistic regression.The mean age for patients with dentigerous cysts was 23 years and they were more common in males. Proteins for VEGF, VEGFR2, PCNA, CD34, and CD146 were expressed in all dentigerous cysts and dental follicles. VEGF and VEGFR2 were expressed on several cell types within the tissues, however there was a significantly greater percentage of positive staining in dentigerous cysts compared with dental follicles (odds ratio = 31.24, p < 0.001). CD34(+), CD146(+), and PCNA(+) cells were observed in both dentigerous cysts and dental follicles but for all markers there were significantly more positive cells in dentigerous cysts (p < 0.001); this was especially evident in cases associated with inflammation. PCNA was seen in most endothelial cells lining small thin walled blood vessels suggesting endothelial proliferation. There was a high level of intra- and inter-examiner agreement (kappa 0.77 and 0.75, respectively).VEGF and VEGFR2 and angiogenic activity are present in dental follicles and dentigerous cysts and may contribute to local bone resorption for tooth eruption or the development and progression of dentigerous cysts. PMID- 26126034 TI - Trends and physiology of common serum biochemistries in children aged 0-18 years. AB - The aim of this study was to visually present and discuss in detail the physiological trends of 22 serum biochemistries in children aged 0-18.A data mining, LMS (lambda, mu, and sigma) approach was employed to derive the smoothed continuous serum biochemistry centile charts, after application of stringent outlier exclusion criteria.Serum sodium and calculated osmolality are low in early life and rise with age due to maturing kidney and body water redistribution. Urea, creatinine and uric acid is high at birth, declines to reach a trough by 1 month of age and gradually rises again thereafter. Serum bicarbonate falls initially during the neonatal and toddler period, then rises with declining respiratory rate, further increasing sodium and suppressing chloride. Potassium, calcium and phosphate are required for somatic growth and are actively accrued during periods of rapid growth. Albumin increases until puberty while globulin rises to age 10 as a result of increased hepatic synthetic capacity and maturing immunity. Serum alkaline phosphatase activity peaks during bone growth spurts in infancy and adolescence due to osteoblast leakage, while creatinine increases with muscle mass. Serum gamma-glutamyl transferase, aspartate aminotransferase and lactate dehydrogenase activities are high at birth and decline with age. Serum alanine aminotransferase activity is low at birth and is induced by increased gluconeogenesis. Serum bilirubin increases continuously with age, mirroring haemoglobin concentration. Serum total cholesterol declines more markedly in boys than girls during puberty due to the combined effects of free testosterone (lowering high-density lipoprotein cholesterol in boys) and oestradiol (lowering low-density lipoprotein cholesterol in boys and girls).It is important to understand trends and biological variation when interpreting results since partitioned reference intervals may mask this information. PMID- 26126035 TI - Unusual presentations of lymphocytic phlebitis of the digestive tract. PMID- 26126036 TI - Reporting unit size and measurement uncertainty: current Australian practice in clinical chemistry and haematology. AB - In this study we aimed to compare the reporting unit size used by Australian laboratories for routine chemistry and haematology tests to the unit size used by learned authorities and in standard laboratory textbooks and to the justified unit size based on measurement uncertainty (MU) estimates from quality assurance program data. MU was determined from Royal College of Pathologists of Australasia (RCPA) - Australasian Association of Clinical Biochemists (AACB) and RCPA Haematology Quality Assurance Program survey reports. The reporting unit size implicitly suggested in authoritative textbooks, the RCPA Manual, and the General Serum Chemistry program itself was noted. We also used published data on Australian laboratory practices.The best performing laboratories could justify their chemistry unit size for 55% of analytes while comparable figures for the 50% and 90% laboratories were 14% and 8%, respectively. Reporting unit size was justifiable for all laboratories for red cell count, >50% for haemoglobin but only the top 10% for haematocrit. Few, if any, could justify their mean cell volume (MCV) and mean cell haemoglobin concentration (MCHC) reporting unit sizes.The reporting unit size used by many laboratories is not justified by present analytical performance. Using MU estimates to determine the reporting interval for quantitative laboratory results ensures reporting practices match local analytical performance and recognises the inherent error of the measurement process. PMID- 26126037 TI - An unusual ampullary adenocarcinoma with Paneth cell and mucinous differentiation. PMID- 26126038 TI - Endometrial carcinosarcoma with prominent neuroectodermal component. PMID- 26126039 TI - Superficial CD34-positive fibroblastic tumour: report of two new cases. PMID- 26126040 TI - Solid-pseudopapillary neoplasm of the pancreas with extensive pleomorphic neuroendocrine differentiation. PMID- 26126041 TI - SWI/SNF complex deficiency and mismatch repair protein expression in undifferentiated and dedifferentiated endometrial carcinoma. AB - Undifferentiated endometrial carcinoma (UEC) is a relatively uncommon but clinically aggressive uterine malignancy. In common with a subset of poorly differentiated carcinomas arising in other sites, UEC may exhibit rhabdoid morphology and be associated with a low-grade tumour component (dedifferentiated carcinoma). Recent studies have implicated inactivation of the SWI/SNF complex subunits in the aforementioned extrauterine tumours. Therefore we have examined INI1 (SMARCB1), BRG1 (SMARCA4), and BAF250a (ARID1A) immunostaining, and also expression of the DNA mismatch repair (MMR) proteins MLH1, PMS2, MSH2 and MSH6 in 22 UEC, seventeen of which were dedifferentiated. Abnormal SWI/SNF subunit expression was detected in four dedifferentiated carcinomas including three with loss of BRG1 staining limited to the undifferentiated tumour component and one case with loss of INI1 expression in both low- and high-grade elements; the latter case also showed BAF250a deficiency in the undifferentiated tumour cells. Abnormal MMR protein expression was identified in 13 tumours (59%) including nine with concurrent loss of MLH1 and PMS2. These findings suggest that SWI/SNF subunit alterations may play a role in the progression/ dedifferentiation of endometrial carcinoma, and that SWI/SNF and MMR protein deficiencies may act synergistically in deregulating DNA repair mechanisms in these tumours. PMID- 26126042 TI - Sternoclavicular septic arthritis caused by Neisseria elongata subspecies nitroreducens. PMID- 26126043 TI - Follicular porokeratosis of the nose: two further cases of an emerging variant of porokeratosis. PMID- 26126044 TI - Endometrial polyp-like lesion arising in adenomyosis: a report of three cases. PMID- 26126045 TI - Effect of HbE trait on measurement of HbA1c by three different methods. PMID- 26126046 TI - Granulosa cell tumour of the adrenal. PMID- 26126047 TI - Recently described entities in the gynaecological tract. AB - In recent years there have been significant advances in our understanding of female genital tract tumours due to the fact that new molecular abnormalities and translocations have been identified in certain neoplasms. Also, terminology of various lesions in the gynaecological tract has changed and a couple of new entities have been described.In this review we will highlight some mesenchymal neoplasms including gynaecological perivascular epithelioid cell tumour (PEComa), inflammatory myofibroblastic tumour (IMT) occurring in the uterus and discuss and review terminology of endometrial stromal neoplasms.A recently described entity, gastric type endocervical adenocarcinoma will be reviewed, summarising its most salient microscopic and clinical features. The newly proposed endocervical adenocarcinoma classification system by Silva and collegues will be reviewed as well.Finally, a particular high-grade endometrial carcinoma (undifferentiated endometrial carcinoma) will be discussed highlighting the importance of its recognition and differential diagnosis. PMID- 26126048 TI - Preparing for Ebolavirus disease: specimen collection, packaging and transport. AB - Ebolavirus is classified by Standards Australia as a Risk Group 4 pathogen for handling in laboratories. Specimens known or reasonably expected to contain Ebolavirus are classified by the United Nations as Dangerous Goods Infectious Substances Category A, UN 2814, which if transported by air must comply with International Air Transport Association (IATA) Hazard Class 6.2 and Packing Instruction 620 and Civil Aviation Safety Authority (CASA) Regulations. As such high risk pathogens are rarely encountered in pathology laboratories in Australia, the possibility of an imported case of Ebolavirus disease occurring in NSW during the current ongoing outbreak which began in West Africa in 2014 prompted a review and rapid implementation of specific risk management protocols for Ebolavirus testing. Here we describe and report on the management of specimen collection, packaging and transport by public and private pathology laboratories agreed by a task force led by NSW Health Pathology and Health Protection NSW. PMID- 26126049 TI - Evaluation of point-of-care testing in critically unwell patients: comparison with clinical laboratory analysers and applicability to patients with Ebolavirus infection. AB - Data on the performance of point-of-care (POC) or near-patient devices in the management of critically unwell patients are limited, meaning that there are demands for confirming POC test results in the routine clinical laboratory and so potentially leading to delay in treatment provision. We evaluated the performance of the i-STAT CHEM 8+ and CG4+, Hemochron Signature Elite, HemoCue Hb 201+ and WBC Diff Systems on whole blood collected from medical and surgical patients admitted to the intensive care unit at an Australian tertiary care hospital. Measurements obtained for haematology, coagulation, biochemistry and arterial blood gas parameters using POC devices were compared against clinical laboratory analysers (XE-5000, STA-R Evolution, Dimension Vista 1500 and ABL800 FLEX). Bland Altman and Passing-Bablok regression plots were constructed to assess agreement. Good correlation was defined as a bias of <10% between the POC device and the reference method. Forty arterial blood samples were collected from 28 patients. There was good correlation demonstrated for sodium, potassium, chloride, ionised calcium, glucose, urea, haemoglobin and haematocrit values (i-STAT Chem 8+); pH, pCO(2), bicarbonate and oxygen saturation (i-STAT CG4+); haemoglobin, white cell, neutrophil count and lymphocyte counts (Hemocue); and internationalised normal ratio (INR; Hemochron Signature Elite), but not creatinine, anion gap, pO(2), base excess, lactate, eosinophil count, prothrombin and activated partial thromboplastin time. POC devices were comparable to clinical laboratory analysers in measuring the majority of haematology, biochemistry and coagulation parameters in critically unwell patients, including those with infections. These devices may be deployed at the bedside to allow 'real-time' testing to improve patient care. PMID- 26126050 TI - Virological diagnosis of Ebolavirus infection. AB - Ebolaviruses, and the other viral causes of haemorrhagic fevers (VHF) have always posed special problems for diagnostic laboratories. These arise from the rarity of human infections, minimal documented experience with test delivery and interpretation, the paucity of established commercial or in-house assays, the lack of clinical material for test development and validation, the high level containment required for handling live virus, the ongoing evolution of the viruses, and the high personal and public health requirements for accurate diagnosis. This article addresses the current situation and the ongoing challenges associated with delivering timely, high quality and safe testing within Australia for people exposed as part of the current major outbreak of Ebolavirus disease (EVD) in Western Africa. The members of the Public Health Laboratory Network have developed deliverable and reliable nucleic acid detection tests, and also have the laboratory capacity to handle the live viruses if necessary. However delivering and maintaining these services necessitates high levels of experience in developing and applying tests for exotic and emerging infections, strong national and international links and collaborations, ongoing monitoring and reassessment of test design and performance, innovative approaches to generation of positive control material, and a regular quality assurance program. PMID- 26126051 TI - The secondary Mullerian system, field effect, BRCA, and tubal fimbria: our evolving understanding of the origin of tubo-ovarian high-grade serous carcinoma and why assignment of primary site matters. AB - It has long been held that most epithelial ovarian carcinomas arise from the ovarian surface epithelium. Theories on origin were based on the assumption that there was a common cell of origin for all ovarian carcinoma histotypes, and that these histotypes were closely related and frequently admixed. It is now recognised that the histotypes are distinct diseases. Recent studies on early, organ-confined, non-uterine high-grade serous carcinoma (HGSC) have led to a change in our understanding of their anatomical site of origin. These studies were initially on patients at high risk of developing HGSC but more recently have been extended to cases without family history or genetic markers of increased risk. These have shown that incidental HGSC, when detected before dissemination, is most commonly identified in the tubal fimbria. As a result, we have had to revisit theories on the cell and site of origin of HGSC. This progress in our understanding has necessitated a change in how we handle cases in clinical practice, as it impacts on primary site assignment, which in turn has implications for staging. In this review we will discuss the evolution of our understanding of the cell of origin of HGSC, the evidence for the tubal fimbria as the anatomical site of origin of most non-uterine HGSC, and the clinical implications of these recent developments. PMID- 26126052 TI - Editorial: Laboratory preparedness for Ebolavirus disease. PMID- 26126053 TI - Redesigning TRACER trial after TRITON. AB - Designing of smart clinical trials is critical for regulatory approval and future drug utilization. Importantly, trial design should be reconsidered if the interim analyses suggest unexpected harm, or conflicting results were yielded from the other trials within the same therapeutic area. With regard to antiplatelet agents, the perfect example is redesigning of the ongoing PRoFESS trial by eliminating aspirin from clopidogrel arm after the earlier MATCH trial results became available. The goal was to aseess the unchanged TRACER trial design in light of the evidence yielded from the earlier completed TRITON trial. TRACER was designed as a triple versus dual antiplatelet trial in NSTEMI patients with no previous long-term outcome data supporting such aggressive strategy. TRITON data represented dual versus dual antiplatelet therapy, and became available before TRACER enrollment starts revealing prasugrel front-loaded early vascular benefit predominantly in STEMI patients with the growing over time bleeding and cancer risks. Moreover, large prasugrel NSTEMI TRITON cohort exhibited trend towards excess mortality in experimental arm warning against aggressive TRACER design. The long-term TRITON results in general, and especially in the NSTEMI patients challenge unchanged TRACER trial design. Applying dual, rather than triple antiplatelet therapy protocol modification should be considered in TRACER to minimize bleeding, cancer, and non-cardiovascular death risks. PMID- 26126054 TI - Impact of statin use on cardiorespiratory fitness in multi-racial men and women: The Henry Ford Exercise Testing (FIT) Project. PMID- 26126055 TI - Unravelling the "adipokine paradox": When the classic proatherogenic adipokine leptin is deemed the beneficial one. AB - Adipokines released by adipose tissue have been recognised as important players in the development of cardiovascular disease. Leptin is a well-studied adipokine with an important role in body metabolism and energy expenditure and leptin deficiency or deficient leptin signalling results in excessive obesity and type 2 diabetes. Studies in cells and animal models support that leptin has a pro atherogenic potential and exerts pro-hypertrophic effects on the heart. However, recent basic and clinical evidence suggests that leptin may also have a beneficial role in cardiovascular physiology. Notably, clinical studies have failed to convincingly link leptin with increased cardiovascular disease risk. We herein summarise the role of leptin in cardiovascular disease as another example of the 'adipokine paradox' and discuss the complexity in using serum adipokine levels as biomarkers in cardiovascular disease. PMID- 26126056 TI - First series of mechanical circulatory support in non-compaction cardiomyopathy: Is LVAD implantation a safe alternative? AB - BACKGROUND: Left ventricular non-compaction (LVNC) is a rare cardiac disorder characterized by prominent trabeculae and deep recesses of the ventricular myocardium. Patients with LVNC may develop severe congestive heart failure refractory to medical therapy. However, heart transplantation is strongly limited due to donor organ shortage. Thus mechanical circulatory support by left ventricular assist devices (LVADs) is a promising alternative. Nevertheless, hypertrabeculation and proarrhythmogenic potential in LVNC might represent important hurdles for success of LVAD therapy in these patients. METHODS AND RESULTS: We retrospectively analyzed the data of a total of 5 patients (3 HVAD, Heartware(r); 2 HeartMate II, Thoratec(r)) with LVNC who underwent LVAD implantation in our institution between 2010 and 2014. Mean follow-up time was 86.5weeks. 30-day survival was 100% without major intrahospital complications. During follow-up, 3 patients developed pump thrombosis requiring pump replacement. Arrhythmias were not detected during follow-up as assessed by ICD interrogation. CONCLUSIONS: LVAD implantation in LVNC can be performed with low intrahospital complication rates. However, we observed a high incidence of pump thrombosis during follow-up, possibly related to thromboembolic predisposition by the underlying LVNC. Therefore, careful management of anticoagulation appears to be critical in these patients. PMID- 26126057 TI - Atrial fibrillation, CHA2DS2-VASc score, antithrombotics and risk of traffic accidents: A population-based cohort study. AB - BACKGROUND: Traffic accidents account for a substantial proportion of premature disabilities and deaths. Whether atrial fibrillation (AF) provokes while antithrombotics prevent from such events remains un-investigated. METHODS: All patients >=40years with newly diagnosed AF in 2005 were scrutinized from the "Longitudinal Health Insurance Database 2005" (1 million beneficiaries) of Taiwan's National Health Insurance Institute as the AF group. Four-fold number of age-, gender-, and comorbidity-matched patients but without AF served as the Non AF controls. Patients were followed till occurrence of hospitalization-requiring traffic injury, death, withdrawal from insurance, or the end of 2010. Cumulative incidence of traffic accidents was compared between groups, and predictors and preventive role of antithrombotics for these accidents were identified by Cox regression analysis. RESULTS: Within a mean follow-up of 4.3years, traffic injury occurred significantly more often in patients with AF (N=1724) than those without it (N=6896) (5.4 vs. 4.9 per 1000 person-years, log-rank p=0.012, HR 1.110, 95% CI 1.013-1.572). Cox models identified age ?65years, hypertension, coronary artery disease, stroke, liver cirrhosis and CHADS2VASC score?1 as risk factors for traffic injury in AF patients, whereas oral anticoagulants (HR 0.576, 95% CI 0.285-0.791, p=0.002) used in patients with CHADS2VASC score ?1 but not antiplatelet therapy (p=0.197) as negative predictors. CONCLUSION: Patients with AF are more vulnerable to traffic accidents especially when with higher CHADS2VASC scores and other comorbidities. This tendency to traffic accidents, however, could be ameliorated by oral anticoagulation in specialized cases but not by antiplatelet therapy. PMID- 26126058 TI - New Scholars Writing for Publication. PMID- 26126059 TI - Mining Patterns Associated With Mobility Outcomes in Home Healthcare. AB - BACKGROUND: Mobility is critical for self-management. Understanding factors associated with improvement in mobility during home healthcare can help nurses tailor interventions to improve mobility outcomes and keep patients safely at home. OBJECTIVES: The aims were to (a) identify patient and support system factors associated with mobility improvement during home care, (b) evaluate consistency of factors across groups defined by mobility status at the start of home care, and (c) identify patterns of factors associated with improvement and no improvement in mobility within each group. METHODS: Outcome and Assessment Information Set data extracted from a national convenience sample of 270,634 patient records collected from October 1, 2008 to December 31, 2009 from 581 Medicare-certified, home healthcare agencies were used. Patients were placed into groups based on mobility scores at admission. Odds ratios were used to index associations of factors with improvement at discharge. Discriminative pattern mining was used to discover patterns associated with improvement of mobility. RESULTS: Overall, mobility improved for 49.4% of patients; improvement occurred most frequently (80%) among patients who were able, at admission, to walk only with the supervision or assistance of another person at all times. Numerous factors associated with improvement in mobility outcome were similar across the groups (except for those who were chairfast but were able to wheel themselves independently); however, the number, strength, and direction of associations varied. In most groups, data mining-discovered patterns of factors associated with the mobility outcome were composed of combinations of functional and cognitive status and the type and amount of help required at home. DISCUSSION: This study provides new data mining-based information about how factors associated with improvement in mobility group together and vary by mobility at admission. These approaches have potential to provide new insights for clinicians to tailor interventions for improvement of mobility. PMID- 26126060 TI - Pain and Aggression in Nursing Home Residents With Dementia: Minimum Data Set 3.0 Analysis. AB - BACKGROUND: Few studies have examined the potential relationship between pain and aggressive behavioral symptoms in nursing home (NH) residents with dementia as a function of resident communicative status (ability to self-report pain). OBJECTIVES: The objective of this study was to examine the relationship between pain and aggression for residents who self-reported pain and for those whose pain was measured by staff evaluation of pain-related behaviors. METHODS: This is a secondary analysis of the comprehensive data collected from January to March 2012 in the national Minimum Data Set (MDS) 3.0 of NH residents, aged 65 years or older, with dementia (N = 71,227). Pain was measured using the MDS Pain Assessment Interview for residents who could communicate or by staff evaluation using the MDS Pain Behavior Scale for residents who could not communicate. The relationship between pain and aggressive behavioral symptoms was estimated from logistic regression models after controlling for covariates (functional/cognitive impairments, pain medications, comorbidities, and sociodemographic variables). RESULTS: In residents who could not communicate, pain was associated with both verbal and physical aggression (verbal aggression: adjusted odds ratio [AOR] = 1.23, 95% CI [1.17, 1.29]; physical aggression: AOR = 1.20, 95% CI [1.14, 1.26]). In residents who could communicate, pain was associated with verbal aggression only (AOR = 1.12, 95% CI [1.04, 1.18]). DISCUSSION: The relationship between pain and aggressive behavioral symptoms varies according to the communicative status of NH residents and disproportionately affects those who cannot articulate their pain. Strategies for enhancing pain management in these residents are needed to adequately treat pain and reduce aggression. PMID- 26126061 TI - Attitudes of Nurses and Physicians About Clinical Autopsy in Neonatal and Adult Hospital Care: A Survey in Sweden. AB - BACKGROUND: The rate of autopsies has dropped to low levels in Western countries. OBJECTIVE: The aim of this study was to describe the experiences and attitudes of registered nurses (RNs) and physicians (MD) toward clinical autopsies in neonatal and adult hospital care in Sweden. METHODS: RNs and MDs in neonatal and adult care specialized clinics at a university-affiliated hospital in Sweden were surveyed. Survey responses were tallied, and free-text comments were assessed with qualitative content analysis. RESULTS: Three hundred thirty-six surveys were distributed; the response rate was 35%. Most RNs and 14% of the MDs had limited or no experience participating in an autopsy. Notably, few RNs and approximately one third of the MDs were familiar with the autopsy processes and the treatment of the deceased person's body after an autopsy. More than one third of RNs had experience with talking to relatives regarding autopsy. Most agreed that an autopsy could be supportive for relatives during the grieving process and beneficial for the quality of healthcare. Most MDs (70%) thought that autopsies should be performed more frequently. Qualitative results emphasized that RNs and MDs thought that autopsy information supported the grieving process of relatives especially parents who had lost a child. DISCUSSION: The survey data confirm belief in the value of clinical autopsies in neonatal and adult hospital care. RNs and MDs should receive training about the autopsy process and procedures for obtaining consent for an autopsy. RNs are in a position to support the decision making of relatives about providing consent for autopsy and have an opportunity to take a more active role in the autopsy process. PMID- 26126062 TI - Nursing Case Management and Glycemic Control Among Brazilians With Type 2 Diabetes: Pragmatic Clinical Trial. AB - BACKGROUND: Type 2 diabetes mellitus is a chronic condition that requires ongoing, life-long care in order to be controlled. OBJECTIVES: The aims of the study were to assess the effect of nursing case management on glycated hemoglobin (HbA1c) levels compared to usual care in people with type 2 diabetes mellitus and to determine if effects of nursing case management varied by gender, age, duration of disease, education, and income. METHODS: This is a pragmatic clinical trial, conducted in the municipality of Bandeirantes, Parana, Brazil, in 2011 and 2012. Eighty individuals were recruited and randomized equally to receive nursing case management or usual care. Covariates were sociodemographic and clinical factors. The outcome was HbA1c measured at baseline, 6 months, and 12 months. RESULTS: The sample consisted predominately of women; most had been diagnosed with type 2 diabetes mellitus within the previous 5 years. Mean age was 50.14 (SD = 7.00), with 5.27 (SD = 4.39) years of schooling and an average HbA1c of 9.90% (SD = 2.49). Hemoglobin A1c was reduced from an average of 10.33% to 9.0% (p < .01) in the nursing case management group and from 9.57% to 8.93% (p = .05) in the usual care group; the group by time effect was not significant. Case management effects varied by younger age (p = .05), duration of type 2 diabetes less than 5 years (p = .03), up to 4 years of schooling (p = .04), and being in the lowest-income stratum (p = .02). DISCUSSION: Both groups showed a statistically significant reduction of HbA1c at 6 and 12 months following baseline. The difference in proportional reduction of HbA1c between groups was not statistically significant. PMID- 26126063 TI - Potential for Self-Management in Chronic Care: Nurses' Assessments of Patients. AB - BACKGROUND: Although self-management interventions are, to some extent, individualized in clinical practice, the decision-making process is not fully understood. Exploring nurses' clinical reasoning about how and to what extent they currently tailor self-management support can provide new insights, enhancing process and outcome of chronic care. OBJECTIVES: The aim of this study was to explore how nurses assess chronic patients concerning the potential of self management and clinical reasoning with regard to tailoring care to the individual patient. METHODS: A qualitative study was conducted using grounded theory. Semistructured interviews were held with 15 nurses working within chronic care. All interviews were carried out from February to July 2013. RESULTS: All nurses provided individualized care; however, a nurse's view of self-management influenced how tailoring was performed. Substantial differences were seen in patient assessments and how care was individualized. Patients' motivation, capacities, mindset, needs, and preferences were obtained through communication, experience, intuition, and trusting relationships. A typology with four patient types emerged: the unmotivated patient, the patient with limited capacities, the oblivious patient, and the ideal patient. Nurses elaborated on using different approaches for patients in each of these groups. DISCUSSION: A nurse's perception of self-management substantially impacted how care was individualized. Patient assessment was the key driver of tailoring, which was performed in various ways, and influenced how and the extent to which care was individualized. To enable responding to the unique wishes and needs of individual patients, both scientific and educational efforts need to be directed toward systematic assessments of patient capacity to self-manage their disease. PMID- 26126064 TI - Sacral Peak Pressure in Healthy Volunteers and Patients With Spinal Cord Injury: With and Without Liquid-Based Pad. AB - BACKGROUND: The prevalence of sacral pressure ulcers in patients with spinal cord injuries is high. The sacral area is vulnerable to compressive pressure because of immobility and because the sacrum and posterior superior iliac prominence lie closely under the skin with no muscle layer in between. OBJECTIVE: The aim of this study was to assess peak sacral pressure before and after use of PURAP, a liquid-based pad that covers only the sacral area and can be applied on any bed surface. METHODS: Healthy volunteers (n = 12) and patients with spinal cord injuries (n = 10) took part; the patients had undergone spine surgery within 7 days before data collection. Participants were in bed, pretest pressure maps were generated, PURAP was placed for 15 minutes, and then posttest pressure maps were generated. Peak pressure was obtained every second and averaged over the entire period. Patients rated whether their comfort had improved when PURAP was in use. RESULTS: For healthy volunteers, mean pretest peak sacral pressure was 74.7 (SD = 16.2) mmHg; the posttest mean was 49.1 (SD = 7.5) mmHg (p < .001, Wilcoxon signed rank test). For patients with spinal cord injuries, mean pretest peak sacral pressure was 105.7 (SD = 22.4) mmHg; the posttest mean was 81.4 (SD = 18.3) mmHg (p < .001, Wilcoxon signed-rank test). The pad reduced the peak sacral pressure in the patient group by 23% (range = 11%-42%) and in the volunteers by 32% (range = 19%-46%). Overall, 70% of the patients reported increased comfort with PURAP. DISCUSSION: Peak sacral pressure was reduced when PURAP was used. It covers only the sacral area but could help many patients with spinal cord injury because the prevalence of sacral pressure ulcers is high in this group. PURAP may be economically advantageous in countries and hospitals with limited financial resources needed for more expensive mattresses and cushions. PMID- 26126065 TI - Motion Sensor Use for Physical Activity Data: Methodological Considerations. AB - BACKGROUND: Physical inactivity continues to be a major risk factor for cardiovascular disease, and only one half of adults in the United States meet physical activity (PA) goals. PA data are often collected for surveillance or for measuring change after an intervention. One of the challenges in PA research is quantifying exactly how much and what type of PA is taking place-especially because self-report instruments have inconsistent validity. OBJECTIVE: The purpose is to review the elements to consider when collecting PA data via motion sensors, including the difference between PA and exercise, type of data to collect, choosing the device, length of time to monitor PA, instructions to the participants, and interpretation of the data. METHODS: The current literature on motion sensor research was reviewed and synthesized to summarize relevant considerations when using a motion sensor to collect PA data. RESULTS: Exercise is a division of PA that is structured, planned, and repetitive. Pedometer data include steps taken and calculated distance and energy expenditure. Accelerometer data include activity counts and intensity. The device chosen depends on desired data, cost, validity, and ease of use. Reactivity to the device may influence the duration of data collection. Instructions to participants may vary depending on the purpose of the study. Experts suggest pedometer data be reported as steps because that is the direct output-and distance traveled and energy expenditure are estimated values. Accelerometer count data may be analyzed to provide information on time spent in moderate or vigorous activity. DISCUSSION: Thoughtful decision making about PA data collection using motion sensor devices is needed to advance nursing science. PMID- 26126067 TI - Causes of endometriosis and prevalent infertility in patients undergoing laparoscopy without achieving pregnancy. AB - BACKGROUND: Endometriosis is a disease with an unknown pathogenesis that can lead to infertility. Endometrial polyps, fibroids, and polycystic ovarian syndrome (PCOS) have relatively high frequency and are causes of infertility. We hypothesized a possible relationship between the presence of polyps, fibroids, and PCOS in infertile women with endometriosis who underwent laparoscopy and did not get pregnant, compared to women in the control group. METHODS: This study was a cross-sectional study of 1243 infertile patients (621 with endometriosis and 622 controls). Endometriosis, Body Mass Index (BMI), infertility duration, age, and smoking habits were analyzed in relation to the presence of endometrial polyps, fibroids, and PCOS. RESULTS: Polyps, 1.8 (95% CI 1.3-2.5); fibroids, 2.5 (95% CI 1.5-4.1); and PCOS, 1.0 (95% CI 0.6-1.6 were observed in the endometriosis group. A total of 285 patients (45.9%) were classified presenting endometriosis grades I and II, and 336 patients (54.1%) with grades III and IV. Our findings showed a significant association between the presence of fibroids in 129 women with endometriosis (20.8%), and in 69 (53.9%) with endometriosis grades III and IV (P=0:04). Among the 31 PCOS patients, 24 (77.4%) showed grades I and II (P<0.001). CONCLUSIONS: Endometriosis and infertility are associated with the presence of polyps and fibroids. Furthermore, associations between the presence of fibroids with endometriosis grades III and IV, and presence of PCOS with grades I and II were observed. PMID- 26126066 TI - The potential predictive role of nuclear NHERF1 expression in advanced gastric cancer patients treated with epirubicin/oxaliplatin/capecitabine first line chemotherapy. AB - Cellular resistance in advanced gastric cancer (GC) might be related to function of multidrug resistance (MDR) proteins. The adaptor protein NHERF1 (Na(+)/H(+) exchanger regulatory factor) is an important player in cancer progression for a number of solid malignancies, even if its role to develop drug resistance remains uncertain. Herein, we aimed to analyze the potential association between NHERF1 expression and P-gp, sorcin and HIF-1alpha MDR-related proteins in advanced GC patients treated with epirubicin/oxaliplatin/capecitabine (EOX) chemotherapy regimen, and its relation to response. Total number of 28 untreated patients were included into the study. Expression and subcellular localization of all proteins were assessed by immunohistochemistry on formalin-fixed paraffin embedded tumor samples. We did not found significant association between NHERF1 expression and the MDR-related proteins. A trend was observed between positive cytoplasmic NHERF1 (cNHERF1) expression and negative nuclear HIF-1alpha (nHIF-1alpha) expression (68.8% versus 31.3% respectively, P = 0.054). However, cytoplasmic P gp (cP-gp) expression was positively correlated with both cHIF-1alpha and sorcin expression (P = 0.011; P = 0.002, respectively). Interestingly, nuclear NHERF1 (nNHERF1) staining was statistically associated with clinical response. In detail, 66.7% of patients with high nNHERF1 expression had a disease control rate, while 84.6% of subjects with negative nuclear expression of the protein showed progressive disease (P = 0.009). Multivariate analysis confirmed a significant correlation between nNHERF1 and clinical response (OR 0.06, P = 0.019). These results suggest that nuclear NHERF1 could be related to resistance to the EOX regimen in advanced GC patients, identifying this marker as a possible independent predictive factor. PMID- 26126068 TI - Vulvodynia: current opinion and treatment strategies. AB - Vulvodynia is a women's health problem that may affect as many as 15% of women who seek gynecological care, and yet little attention is given to this condition and it is frequently dismissed as psychosomatic. Thus, vulvodynia still remains a major health problem in Western countries, leading to significant morbidity and a reduced quality of life for many women. This condition carries large costs incurred as a result of both medical treatment and lost productivity. Vulvodynia is becoming a universal priority in the prevention, care, education, and research areas of pain and its consequences and it remains one of the poorly understood complex chronic pain syndromes, representing a multifactorial clinical syndrome of unexplained vulvar pain and sexual dysfunction. PMID- 26126069 TI - Presenting and getting published in the history of anaesthesia-why and where? PMID- 26126070 TI - Pioneers of laryngoscopy: indirect, direct and video laryngoscopy. AB - Airway management is one of the core skills of the anaesthetist and various techniques of airway management have developed over many years. Initially, the only view of the glottis that could be obtained was an indirect view (indirect laryngoscopy). Late in the 19th century, a direct view of the glottis was obtained via various direct laryngoscopes. Currently, in the early 21st century, there has been a return to indirect laryngoscopy via videolaryngoscopy using a videolaryngoscope. The aim of this paper is to give a historical overview of the development of both direct and indirect laryngoscopy. PMID- 26126071 TI - Developments in labour analgesia and their use in Australia. AB - Since the introduction of chloroform for labour analgesia in 1847, different methods and medications have been used to relieve the pain of labour. The use of heavy sedative medication in the early 1900s was encouraged by enthusiastic doctors and by women empowered by the women's suffrage movement in America. Nitrous oxide by inhalation has been used in Australia since the 1950s and improved methods of administration have made this method of analgesia safe and practical. Caudal epidural analgesia and lumbar epidural analgesia were first made popular in America and by the 1970s these techniques were more widely available in Australia. In 1847, physicians and the public were unsure whether relieving labour pains was the 'right' thing to do. However, many medical and social changes have occurred thanks to the clinical connection between Australia and the United Kingdom and those first settlers to land on Australian shores. Thanks to this historical connection, in today's Australia there is no question that women should use analgesia as a pain relief if they wish. Currently, the majority of women worldwide use some form of analgesia during labour and different methods are widely available. This paper discusses the four milestones of the development of obstetric analgesia and how they were introduced into patient care in Australia. PMID- 26126072 TI - Becoming a physician anaesthetist-difficulties encountered for half a century. AB - William T.G. Morton was not the first to use ether or nitrous oxide as an anaesthetic. However, his public demonstration on 16 October, 1846 (Ether Day), and the notoriety that followed thereafter, are credited for announcing man's victory over surgical pain to the entire world. The use of ether during surgery spread rapidly through most of the world. One would expect that the careers of Ether Day participants would have been greatly affected by this seminal event and that some would go on to become anaesthetists. An examination of the participants' professional lives shows that some became strong advocates of anaesthesia and ether was used extensively for their patients. Some were prolific writers and helped spread the use of anaesthesia. However, attracting physicians to this new discipline proved difficult and there were segments of the medical establishment and society who were unwilling to accept this most significant advancement. In this article, we examine the reasons why many physicians and patients resisted the use of anaesthesia. PMID- 26126073 TI - Pain relief in childbirth: changing historical and feminist perspectives. AB - Pain during human childbirth is ubiquitous and severe. Opium and its derivatives constitute the oldest effective method of pain relief and have been used in childbirth for several thousand years, along with numerous folk medicines and remedies. Interference with childbirth pain has always been criticised by doctors and clergy. The 19th century saw the introduction of three much more effective approaches to childbirth pain; diethyl ether, chloroform and nitrous oxide. Access to pain relief was demanded by the first wave of feminist activists as a woman's right. They popularised the use of 'twilight sleep', a combination of morphine and scopolamine, which fell into disrepute as its adverse effects became known. From the 1960s, as epidural analgesia became more popular, a second wave of feminists took the opposite position, calling for a return to non-medicalised, female-controlled, 'natural' childbirth and, in some cases, valorising the importance of the pain experience as empowering for women. However, from the 1990s, a third wave of feminist thought has begun to emerge, revalidating a woman's right to choose a 'technological', pain-free birth, rather than a 'natural' one, and regarding this as a legitimate feminist position. PMID- 26126074 TI - Pioneering early Intensive Care Medicine by the 'Scandinavian Method' of treatment for severe acute barbiturate poisoning. AB - Between the 1920s and the mid-1950s, barbiturates were the sedative-hypnotic agents most used in clinical practice. Their ready availability and narrow therapeutic margin accounted for disturbingly high rates of acute poisoning, whether suicidal or accidental. Until the late 1940s, medical treatment was relatively ineffective, with mortality subsequently high - not only from the effects of coma, respiratory depression and cardiovascular shock with renal impairment, but also from complications of the heavy use in the 1930s and 1940s of analeptic stimulating agents. Incidence of barbiturate intoxication increased substantially following World War II and this paper details development of what became known as the 'Scandinavian Method' of treatment, which contributed substantially to the earliest establishment of intensive care units and to the practice and methods of intensive care medicine. Three names stand out for the pioneering of this treatment. Successively, psychiatrist, Aage Kirkegaard, for introducing effective anti-shock fluid therapy; anaesthetist, Eric Nilsson, for introducing anaesthesiologic principles, including manual intermittent positive pressure ventilation into management; and, psychiatrist, Carl Clemmesen, for introducing centralisation of seriously poisoned patients in a dedicated unit. Clemmesen's Intoxication Unit opened at the Bispebjerg Hospital, Copenhagen, on 1 October 1949. ICU pioneer Bjorn Ibsen suggested it was the initial ICU, while noting that it supplied Intensive Therapy for one type of disorder only (as had HCA Lassen's Blegdam Hospital unit for Denmark's 1952 to 1953 polio epidemic). Treatment for barbiturate poisoning during the 1950s in some other Scandinavian hospitals will also be considered briefly. PMID- 26126075 TI - The Heister mouth gag or 'speculum oris'. AB - The Heister mouth gag is attributed to Lorenz Heister, an eighteenth century German surgeon. There is no evidence that Heister designed the mouth gag, the earliest known illustration of which is in the 1719 edition of Heister's Chirurgie. In the first half of the twentieth century, the Heister gag was widely available for use during anaesthesia. It is now rarely used by anaesthestists, but occasionally used by surgeons during oral surgery. PMID- 26126076 TI - The Longfellow portrait & ether anaesthesia. PMID- 26126077 TI - Cocoa, glucose tolerance, and insulin signaling: cardiometabolic protection. AB - Experimental and clinical evidence reported that some polyphenol-rich natural products may offer opportunities for the prevention and treatment of type 2 diabetes, due to their biological properties. Natural products have been suggested to modulate carbohydrate metabolism by various mechanisms, such as restoring beta-cell integrity and physiology and enhancing insulin-releasing activity and glucose uptake. Endothelium is fundamental in regulating arterial function, whereas insulin resistance plays a pivotal role in pathophysiological mechanisms of prediabetic and diabetic states. Glucose and insulin actions in the skeletal muscle are improved by insulin-dependent production of nitric oxide, favoring capillary recruitment, vasodilatation, and increased blood flow. Endothelial dysfunction, with decreased nitric oxide bioavailability, is a critical step in the development of atherosclerosis. Furthermore, insulin resistance has been described, at least in part, to negatively affect endothelial function. Consistent with this, conditions of insulin resistance are usually linked to endothelial dysfunction, and the exposure of the endothelial cells to cardiovascular risk factors such as hypertension, dyslipidemia, and hyperglycemia is associated with reduced nitric oxide bioavailability, resulting in impaired endothelial-dependent vasodilatation. Moreover, endothelial dysfunction has been described as an independent predictor of cardiovascular risk and events. Cocoa and cocoa flavonoids may positively affect the pathophysiological mechanisms involved in insulin resistance and endothelial dysfunction with possible benefits in the prevention of cardiometabolic diseases. PMID- 26126078 TI - Developing Polycation-Clay Sorbents for Efficient Filtration of Diclofenac: Effect of Dissolved Organic Matter and Comparison to Activated Carbon. AB - The presence of nanoconcentrations of persistent pharmaceuticals in treated wastewater effluent and in surface water has been frequently reported. A novel organic-inorganic hybrid sorbent based on adsorbing quarternized poly vinylpyridinium-co-styrene (QPVPcS) to montmorillonite (MMT) was designed for the removal of the anionic micropollutants. QPVPcS-clay composites were characterized by X-ray diffraction, FTIR, thermal gravimetric analysis, Zeta potential and element analysis. Based on these measurements polymer-clay micro- and nanostructures, as a function of polymer loading, were suggested. The affinity of the anionic pharmaceutical, diclofenac (DCF), to the composite was high and did not decrease dramatically with an increase of ionic strength, indicating that the interactions are not only electrostatic. The presence of humic acid (HA) did not hinder DCF removal by the composite; whereas, its filtration by granulated activated carbon (GAC) was compromised in the presence of HA. The kinetics and adsorption at equilibrium of DCF to the composite and to GAC were measured and modeled by the time dependent Langmuir equation. The adsorption of DCF to the composite was significantly faster than to GAC. Accordingly, the filtration of micro- and nanoconcentrations of DCF by composite columns, in the presence of HA, was more efficient than by GAC columns. PMID- 26126079 TI - Client Satisfaction with Telehealth in Assisted Living and Homecare. AB - BACKGROUND: The Evangelical Lutheran Good Samaritan Society launched LivingWell@Home (LW@H) to provide telehealth services to clients in assisted living and home healthcare. LW@H assures client safety through remote monitoring of physiological parameters and assessment of nonbiometric parameters. Public policies increasingly support aging in place by allowing older adults with greater levels of impairment avoid or delay nursing home placement through alternative services offered in assisted living facilities and home healthcare agencies. Provider organizations face challenges caring for frail seniors with complex medical needs. Telehealth services may be helpful in supporting frail seniors living at home. MATERIALS AND METHODS: Seniors were recruited into a randomized trial. Telehealth services were provided to 820 experimental subjects. Control subjects (n=762) received usual care. Clients rated their satisfaction at three points in time postimplementation: baseline, 6 months, and 12 months. Fisher's exact test compared client ratings at each measurement interval. RESULTS: No statistically significant differences were found between experimental and control subjects at baseline. Statistically significant differences emerged at follow-up. Experimental subjects in home healthcare agencies reported higher levels of satisfaction relative to controls, whereas experimental subjects in assisted living facilities reported lower levels of satisfaction. CONCLUSIONS: Telehealth services increased the probability that clients will be more satisfied compared with those without telehealth in homecare agencies. The opposite effect resulted among assisted living residents. Value propositions among community dwelling older adults may influence their satisfaction with telehealth services postimplementation. More research is needed to examine the clinical efficacy and cost-effectiveness of these services. PMID- 26126080 TI - Nanoplasmonic chitosan nanofibers as effective SERS substrate for detection of small molecules. AB - The use of surface enhanced Raman spectroscopy (SERS) is limited by low reproducibility and uniformity of the response. Solving these problems can turn the laboratory use of SERS into real-world application. In this regard, soft SERS active substrates can enable portable instrumentation and reduce costs in the fabrication of SERS-based sensors. Here, plasmonic free-standing films made of biocompatible chitosan nanofibers and gold nanoparticles are engineered by a simple protocol varying the concentration of chloroauric acid. The concentration and distribution of gold nanoparticles in films are controlled in a predictable way, and SERS spectra for the standard 2-naphthalenethiol with concentration less than 10(-15) M are acquired in a reproducible way. The statistical analysis reveals a relatively high and locally uniform performance of SERS with an enhancement factor of 2 * 10(5) for 86% of the points on the imaged area of the SERS substrate. Potential SERS detection of small molecules, both Rhodamine 6G and d-Glucose, in the micromolar range is demonstrated. PMID- 26126081 TI - Insights into B-type RR members as signaling partners acting downstream of HPt partners of HK1 in the osmotic stress response in Populus. AB - The B-type response regulators (B-type RRs), final elements of a signaling pathway called "histidine/aspartate phosphorelay system" in plants, are devoted to the regulation of response genes through a transcription factor activity. Signal transduction consists in the transfer of a phosphoryl group from a transmembrane histidine kinase (HK) which recognizes a given stimulus to nuclear RRs via cytosolic shuttle phosphotransfer proteins (HPts). In Arabidopsis, the receptors HK are to date the major characterized candidates to be responsible for initiation of osmotic stress responses. However, little information is available concerning the signaling partners acting downstream of HKs. In Populus, three HPts and five B-type RRs were previously identified as interacting partners of HK1, the Arabidopsis AHK1 homolog. Here, we report the isolation of RR18, a member of the B-type RR family, which shares high sequence similarities with ARR18 characterized to act in the osmosensing signaling pathway in Arabidopsis, from poplar cuttings subjected to osmotic stress conditions. By using yeast and in planta interaction assays, RR18 was further identified as acting downstream of HK1 and its three preferential HPt partners. Besides, our results are in favor of a possible involvement of both RR18 and RR13, the main expressed poplar B-type RR, in the osmotic signaling pathway. Nonetheless, different behaviors of these two B-type RRs in this pathway need to be noted, with one RR, RR13, acting in an early phase, mainly in roots of poplar cuttings, and the other one, RR18, acting in a late phase, mainly in leaves to supply an adequate response. PMID- 26126082 TI - Animal models for influenza virus transmission studies: a historical perspective. AB - Animal models are used to simulate, under experimental conditions, the complex interactions among host, virus, and environment that affect the person-to-person spread of influenza viruses. The three species that have been most frequently employed, both past and present, as influenza virus transmission models-ferrets, mice, and guinea pigs-have each provided unique insights into the factors governing the efficiency with which these viruses pass from an infected host to a susceptible one. This review will highlight a few of these noteworthy discoveries, with a particular focus on the historical contexts in which each model was developed and the advantages and disadvantages of each species with regard to the study of influenza virus transmission among mammals. PMID- 26126086 TI - A scoring system to screen elderly potential kidney transplant recipients: a simple tool for a complex task. AB - Despite the rapid growth in the number of dialysis patients ?65, relatively few of these patients are receiving transplants. Dusseux et al. present a simple scoring system that helps to identify a group of such patients with a higher survival rate on dialysis. They suggest that such a screening tool might help to identify older patients for more comprehensive transplant assessment. PMID- 26126083 TI - Helix 8 of the angiotensin- II type 1A receptor interacts with phosphatidylinositol phosphates and modulates membrane insertion. AB - The carboxyl-terminus of the type 1 angiotensin II receptor (AT1A) regulates receptor activation/deactivation and the amphipathic Helix 8 within the carboxyl terminus is a high affinity interaction motif for plasma membrane lipids. We have used dual polarisation interferometry (DPI) to examine the role of phosphatidylinositdes in the specific recognition of Helix 8 in the AT1A receptor. A synthetic peptide corresponding to Leu(305) to Lys(325) (Helix 8 AT1A) discriminated between PIPs and different charges on lipid membranes. Peptide binding to PtdIns(4)P-containing bilayers caused a dramatic change in the birefringence (a measure of membrane order) of the bilayer. Kinetic modelling showed that PtdIns(4)P is held above the bilayer until the mass of bound peptide reaches a threshold, after which the peptides insert further into the bilayer. This suggests that Helix 8 can respond to the presence of PI(4)P by withdrawing from the bilayer, resulting in a functional conformational change in the receptor. PMID- 26126087 TI - Elevated pulmonary pressure: A novel risk marker in kidney disease? AB - Pulmonary hypertension is associated with adverse cardiac outcomes and death in the general population. Bolignano and colleagues studied the prevalence of higher estimated pulmonary artery systolic pressure (?35 mm Hg) assessed using echocardiogram among patients with stage 1-4 chronic kidney disease. They further examined the associations of higher pulmonary pressures with a composite cardiovascular outcome. These findings suggest the potential role of pulmonary arterial systolic pressure as a risk marker in those with chronic kidney disease. PMID- 26126088 TI - The balance of the evidence on acid-base homeostasis and progression of chronic kidney disease. AB - Normalization of acid-base homeostasis in chronic kidney disease (CKD) holds promise for mitigating disease progression, but whether efforts should focus on patients with low serum bicarbonate or high dietary acid load is unknown. Vallet et al. report that low urinary ammonia excretion independently associates with increased progression in moderate CKD. Whether this finding implicates differences in endogenous acid production or the ability to excrete an acid load in the pathogenesis of progression requires further study. PMID- 26126089 TI - Chronic kidney disease and heart disease: after 179 years, do we yet understand the link? AB - A definitive understanding of the link between heart and kidney disease remains elusive. Bittencourt et al. explore the association between chronic kidney disease (CKD) status, severity of coronary lesions, and clinical outcome in more than 1500 consecutive adult subjects who underwent a clinically indicated coronary computed tomography angiography for the evaluation of the coronary disease. We discuss the implications of their findings in the context of our current understanding of the development of heart disease in CKD. PMID- 26126090 TI - Will introduction of tolvaptan change clinical practice in autosomal dominant polycystic kidney disease? AB - The vasopressin inhibitor tolvaptan is clinically effective in slowing growth of renal cysts and reduction in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD), but these effects are mitigated by the associated polyuria. Changes of total kidney volume, eGFR, and symptoms will guide physicians and patients in tolvaptan treatment. Guidance about when to initiate treatment in the course of ADPKD may be forthcoming. Ongoing long-term observations will inform future recommendations about tolvaptan use in ADPKD. PMID- 26126091 TI - Evaluating central blood pressure in dialysis patients. PMID- 26126092 TI - The Authors Reply. PMID- 26126093 TI - The Authors Reply. PMID- 26126094 TI - Decreasing incidence of renal replacement therapy over time at the critical 50-59 year age range suggests a role for nephroprotective therapy in ADPKD. PMID- 26126095 TI - Improved renal function in diabetic patients with acute gout treated with anakinra. PMID- 26126096 TI - The Authors Reply. PMID- 26126097 TI - The Authors Reply. PMID- 26126098 TI - Coefficient of variation among ferritin measurement methods in hemodialysis and standard serum ferritin level. PMID- 26126099 TI - ROS, P53, and ischemic acute kidney injury in diabetic models. PMID- 26126100 TI - Carfilzomib-induced nephrotoxcity. PMID- 26126101 TI - The Authors Reply. PMID- 26126102 TI - Monoclonal gammopathy of renal significance: systemic involvement by benign condition. PMID- 26126103 TI - The Authors Reply. PMID- 26126104 TI - The Authors Reply. PMID- 26126105 TI - Bone cells, sclerostin, and FGF23: what's bred in the bone will come out in the flesh. PMID- 26126106 TI - Terminal hematuria. PMID- 26126107 TI - Milky urine and struvite crystals. PMID- 26126108 TI - The Case | Bilateral severe mechanical joint pain in the lower limbs in a hemodialysis patient. Hypophosphatemia-induced osteomalacia. PMID- 26126109 TI - Assessment of Disability among the Elderly in Xiamen of China: A Representative Sample Survey of 14,292 Older Adults. AB - BACKGROUND: The unprecedented number of elderly individuals in China presents a serious public health challenge. Limited data are available on the prevalence of disability or factors resulting in disability among the elderly in China. OBJECTIVE: We aimed to assess the prevalence of disability and related risk factors among the elderly of Xiamen, China. METHODS: A cross-sectional study was performed on individuals who were >=60 years of age. The subjects were recruited by multi-stage sampling; a total of 14,292 valid questionnaires were received. Study measurements included activities of daily living (ADL), demographics, and health status. The ADL was assessed by the Katz Index Scale to evaluate disability. Chi-square tests and binary logistic regression were used to identify factors associated with disabilities. RESULTS: Among the valid participants, 4.27% had at least one disability. Bathing was the most frequently reported disability and feeding was the least frequently reported disability. Disabilities were significantly associated with female gender, older age, unmarried status, living with family, urban residence, illiteracy, poor economic status, self-rated bad health, chronic illnesses, lower life satisfaction, bad mood, and feelings of loneliness. CONCLUSION: Functional disability among the elderly requires more public attention. Culturally appropriate policies and programs are also needed to address the care for the disabled elderly. PMID- 26126111 TI - Peer Review Evaluation Process of Marie Curie Actions under EU's Seventh Framework Programme for Research. AB - We analysed the peer review of grant proposals under Marie Curie Actions, a major EU research funding instrument, which involves two steps: an independent assessment (Individual Evaluation Report, IER) performed remotely by 3 raters, and a consensus opinion reached during a meeting by the same raters (Consensus Report, CR). For 24,897 proposals evaluated from 2007 to 2013, the association between average IER and CR scores was very high across different panels, grant calls and years. Median average deviation (AD) index, used as a measure of inter rater agreement, was 5.4 points on a 0-100 scale (interquartile range 3.4-8.3), overall, demonstrating a good general agreement among raters. For proposals where one rater disagreed with the other two raters (n=1424; 5.7%), or where all 3 raters disagreed (n=2075; 8.3%), the average IER and CR scores were still highly associated. Disagreement was more frequent for proposals from Economics/Social Sciences and Humanities panels. Greater disagreement was observed for proposals with lower average IER scores. CR scores for proposals with initial disagreement were also significantly lower. Proposals with a large absolute difference between the average IER and CR scores (>=10 points; n=368, 1.5%) generally had lower CR scores. An inter-correlation matrix of individual raters' scores of evaluation criteria of proposals indicated that these scores were, in general, a reflection of raters' overall scores. Our analysis demonstrated a good internal consistency and general high agreement among raters. Consensus meetings appear to be relevant for particular panels and subsets of proposals with large differences among raters' scores. PMID- 26126110 TI - The Mistreatment of Women during Childbirth in Health Facilities Globally: A Mixed-Methods Systematic Review. AB - BACKGROUND: Despite growing recognition of neglectful, abusive, and disrespectful treatment of women during childbirth in health facilities, there is no consensus at a global level on how these occurrences are defined and measured. This mixed methods systematic review aims to synthesize qualitative and quantitative evidence on the mistreatment of women during childbirth in health facilities to inform the development of an evidence-based typology of the phenomenon. METHODS AND FINDINGS: We searched PubMed, CINAHL, and Embase databases and grey literature using a predetermined search strategy to identify qualitative, quantitative, and mixed-methods studies on the mistreatment of women during childbirth across all geographical and income-level settings. We used a thematic synthesis approach to synthesize the qualitative evidence and assessed the confidence in the qualitative review findings using the CERQual approach. In total, 65 studies were included from 34 countries. Qualitative findings were organized under seven domains: (1) physical abuse, (2) sexual abuse, (3) verbal abuse, (4) stigma and discrimination, (5) failure to meet professional standards of care, (6) poor rapport between women and providers, and (7) health system conditions and constraints. Due to high heterogeneity of the quantitative data, we were unable to conduct a meta-analysis; instead, we present descriptions of study characteristics, outcome measures, and results. Additional themes identified in the quantitative studies are integrated into the typology. CONCLUSIONS: This systematic review presents a comprehensive, evidence-based typology of the mistreatment of women during childbirth in health facilities, and demonstrates that mistreatment can occur at the level of interaction between the woman and provider, as well as through systemic failures at the health facility and health system levels. We propose this typology be adopted to describe the phenomenon and be used to develop measurement tools and inform future research, programs, and interventions. PMID- 26126112 TI - Pulse Wave Transit Time Measurements of Cardiac Output in Septic Shock Patients: A Comparison of the Estimated Continuous Cardiac Output System with Transthoracic Echocardiography. AB - BACKGROUND: We determined reliability of cardiac output (CO) measured by pulse wave transit time cardiac output system (esCCO system; COesCCO) vs transthoracic echocardiography (COTTE) in mechanically ventilated patients in the early phase of septic shock. A secondary objective was to assess ability of esCCO to detect change in CO after fluid infusion. METHODS: Mechanically ventilated patients admitted to the ICU, aged >18 years, in sinus rhythm, in the early phase of septic shock were prospectively included. We performed fluid infusion of 500 ml of crystalloid solution over 20 minutes and recorded CO by EsCCO and TTE immediately before (T0) and 5 minutes after (T1) fluid administration. Patients were divided into 2 groups (responders and non-responders) according to a threshold of 15% increase in COTTE in response to volume expansion. RESULTS: In total, 25 patients were included, average 64+/-15 years, 15 (60%) were men. Average SAPSII and SOFA scores were 55+/-21.3 and 13+/-2, respectively. ICU mortality was 36%. Mean cardiac output at T0 was 5.8+/-1.35 L/min by esCCO and 5.27+/-1.17 L/min by COTTE. At T1, respective values were 6.63 +/- 1.57 L/min for esCCO and 6.10+/-1.29 L/min for COTTE. Overall, 12 patients were classified as responders, 13 as non-responders by the reference method. A threshold of 11% increase in COesCCO was found to discriminate responders from non-responders with a sensitivity of 83% (95% CI, 0.52-0.98) and a specificity of 77% (95% CI, 0.46 0.95). CONCLUSION: We show strong correlation esCCO and echocardiography for measuring CO, and change in CO after fluid infusion in ICU patients. PMID- 26126113 TI - Enhanced Bone Tissue Regeneration by Porous Gelatin Composites Loaded with the Chinese Herbal Decoction Danggui Buxue Tang. AB - Danggui Buxue Tang (DBT) is a traditional Chinese herbal decoction containing Radix Astragali and Radix Angelicae sinensis. Pharmacological results indicate that DBT can stimulate bone cell proliferation and differentiation. The aim of the study was to investigate the efficacy of adding DBT to bone substitutes on bone regeneration following bone injury. DBT was incorporated into porous composites (GGT) made from genipin-crosslinked gelatin and beta-triclacium phosphates as bone substitutes (GGTDBT). The biological response of mouse calvarial bone to these composites was evaluated by in vivo imaging systems (IVIS), micro-computed tomography (micro-CT), and histology analysis. IVIS images revealed a stronger fluorescent signal in GGTDBT-treated defect than in GGT treated defect at 8 weeks after implantation. Micro-CT analysis demonstrated that the level of repair from week 4 to 8 increased from 42.1% to 71.2% at the sites treated with GGTDBT, while that increased from 33.2% to 54.1% at GGT-treated sites. These findings suggest that the GGTDBT stimulates the innate regenerative capacity of bone, supporting their use in bone tissue regeneration. PMID- 26126114 TI - Identification of Personalized Chemoresistance Genes in Subtypes of Basal-Like Breast Cancer Based on Functional Differences Using Pathway Analysis. AB - Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC), and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of these pathways. Therefore, these nine differentially expressed genes and their associated functional pathways should provide the basis for novel personalized clinical treatments of basal-like breast cancer. PMID- 26126115 TI - Automatic Detection of Calcaneal-Fifth Metatarsal Angle Using Radiograph: A Computer-Aided Diagnosis of Flat Foot for Military New Recruits in Taiwan. AB - Flatfoot (pes planus) is one of the most important physical examination items for military new recruits in Taiwan. Currently, the diagnosis of flatfoot is mainly based on radiographic examination of the calcaneal-fifth metatarsal (CA-MT5) angle, also known as the arch angle. However, manual measurement of the arch angle is time-consuming and often inconsistent between different examiners. In this study, seventy male military new recruits were studied. Lateral radiographic images of their right and left feet were obtained, and mutual information (MI) registration was used to automatically calculate the arch angle. Images of two critical bones, the calcaneus and the fifth metatarsal bone, were isolated from the lateral radiographs to form reference images, and were then compared with template images to calculate the arch angle. The result of this computer calculated arch angle was compared with manual measurement results from two radiologists, which showed that our automatic arch angle measurement method had a high consistency. In addition, this method had a high accuracy of 97% and 96% as compared with the measurements of radiologists A and B, respectively. The findings indicated that our MI registration measurement method cannot only accurately measure the CA-MT5 angle, but also saves time and reduces human error. This method can increase the consistency of arch angle measurement and has potential clinical application for the diagnosis of flatfoot. PMID- 26126116 TI - Cognitive Learning, Monitoring and Assistance of Industrial Workflows Using Egocentric Sensor Networks. AB - Today, the workflows that are involved in industrial assembly and production activities are becoming increasingly complex. To efficiently and safely perform these workflows is demanding on the workers, in particular when it comes to infrequent or repetitive tasks. This burden on the workers can be eased by introducing smart assistance systems. This article presents a scalable concept and an integrated system demonstrator designed for this purpose. The basic idea is to learn workflows from observing multiple expert operators and then transfer the learnt workflow models to novice users. Being entirely learning-based, the proposed system can be applied to various tasks and domains. The above idea has been realized in a prototype, which combines components pushing the state of the art of hardware and software designed with interoperability in mind. The emphasis of this article is on the algorithms developed for the prototype: 1) fusion of inertial and visual sensor information from an on-body sensor network (BSN) to robustly track the user's pose in magnetically polluted environments; 2) learning based computer vision algorithms to map the workspace, localize the sensor with respect to the workspace and capture objects, even as they are carried; 3) domain independent and robust workflow recovery and monitoring algorithms based on spatiotemporal pairwise relations deduced from object and user movement with respect to the scene; and 4) context-sensitive augmented reality (AR) user feedback using a head-mounted display (HMD). A distinguishing key feature of the developed algorithms is that they all operate solely on data from the on-body sensor network and that no external instrumentation is needed. The feasibility of the chosen approach for the complete action-perception-feedback loop is demonstrated on three increasingly complex datasets representing manual industrial tasks. These limited size datasets indicate and highlight the potential of the chosen technology as a combined entity as well as point out limitations of the system. PMID- 26126117 TI - An Accurate Model for Biomolecular Helices and Its Application to Helix Visualization. AB - Helices are the most abundant secondary structural elements in proteins and the structural forms assumed by double stranded DNAs (dsDNA). Though the mathematical expression for a helical curve is simple, none of the previous models for the biomolecular helices in either proteins or DNAs use a genuine helical curve, likely because of the complexity of fitting backbone atoms to helical curves. In this paper we model a helix as a series of different but all bona fide helical curves; each one best fits the coordinates of four consecutive backbone Calpha atoms for a protein or P atoms for a DNA molecule. An implementation of the model demonstrates that it is more accurate than the previous ones for the description of the deviation of a helix from a standard helical curve. Furthermore, the accuracy of the model makes it possible to correlate deviations with structural and functional significance. When applied to helix visualization, the ribbon diagrams generated by the model are less choppy or have smaller side chain detachment than those by the previous visualization programs that typically model a helix as a series of low-degree splines. PMID- 26126118 TI - Obstructive Sleep Apnea: A Risk Factor for Surgical Site Infection following Colectomy. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased systemic oxidative stress, endothelial dysfunction, and activation of pro-inflammatory cascades, which increase host susceptibility to infection. OSA has not been evaluated as a risk factor for surgical site infection (SSI) following colectomy. We hypothesized that OSA increases the risk for SSI after colectomy. METHODS: We performed a retrospective review of 507 colectomies that took place between August 2011 and September 2013. Forty-two patients carried the diagnosis of OSA prior to surgery. These 42 patients were matched to 68 patients with no OSA for age, body mass index (BMI), diabetes mellitus (DM), reason for surgery and surgical approach. RESULTS: The rate of SSI was 28.6% (12 of 42) in the patients with and 10.3% (7 of 68) in the patients without OSA (p=0.03). Using logistic regression, the predictors of SSI following colectomy were found to be OSA (odds ratio [OR] of 3.98, 95% confidence interval [CI]=1.29-12.27), and DM (OR of 7.16, 95% CI=2.36-21.96). The average hospital stay after colectomy for patients with OSA complicated with SSI was 16.7 d whereas patients with OSA without SSI stayed 7.4 d (p<0.001). The rate of organ space infections was 9.5% (4 of 42) in the patients with OSA compared with 0 (p=0.02) in patients without OSA. CONCLUSIONS: OSA is an independent risk factor for SSI following colectomy. Patients with OSA have substantially greater rates of organ space SSI and longer hospital stay. PMID- 26126119 TI - The Sbi Protein Contributes to Staphylococcus aureus Inflammatory Response during Systemic Infection. AB - Staphylococcus aureus is an important human pathogen that causes infections that may present high morbidity and mortality. Among its many virulence factors protein A (SpA) and Staphylococcal binding immunoglobulin protein (Sbi) bind the Fc portion of IgG interfering with opsonophagocytosis. We have previously demonstrated that SpA interacts with the TNF-alpha receptor (TNFR) 1 through each of the five IgG binding domains and induces the production of pro-inflammatory cytokines and chemokines. The IgG binding domains of Sbi are homologous to those of SpA, which allow us to hypothesize that Sbi might also have a role in the inflammatory response induced by S. aureus. We demonstrate that Sbi is a novel factor that participates in the induction of the inflammatory response during staphylococcal infections via TNFR1 and EGFR mediated signaling as well as downstream MAPKs. The expression of Sbi significantly contributed to IL-6 production and modulated CXCL-1 expression as well as neutrophil recruitment to the site of infection, thus demonstrating for the first time its relevance as a pro-inflammatory staphylococcal antigen in an in vivo model. PMID- 26126120 TI - Identification and Characterization of a Novel Microvitellogenin from the Chinese Oak Silkworm Antheraea pernyi. AB - Microvitellogenin (mVg) is a relatively small vitellogenic protein only characterized in the eggs of the lepidopteran insects Manduca sexta and Bombyx mori. In the present study, we report a novel mVg (ApmVg) isolated from the Chinese oak silkworm Antheraea pernyi. The obtained ApmVg cDNA sequence contains an open reading frame of 783 bp encoding a protein of 260 amino acids with a predicted molecular weight of 29.96 kDa. This gene does not contain introns. Structural analysis revealed that this protein shares putative conserved domains with the lepidopteran low-molecular weight lipoprotein, which belongs to the lipoprotein_11 superfamily. The protein sequence of ApmVg exhibits 48% sequence identity with mVg from M. sexta and 40-47% sequence identity with the 30K lipoproteins from B. mori. Phylogenetic analysis suggests that ApmVg is a novel member of the lepidopteran low-molecular weight lipoproteins. Transcriptional analysis indicated that ApmVg mRNA is mainly expressed in the fat body (both female and male) during post-diapause development of the pupal stage, and it was also detected in ovaries and spermaries in smaller amounts. RT-PCR and Western blot analyses revealed that ApmVg is synthesized by the fat body and secreted into hemolymph and ultimately accumulates in eggs. The ApmVg transcript can be detected in the fat bodies of female pupae four days after treatment with 20 hydroxyecdysone and shows an expression pattern distinct from that of vitellogenin (Vg), which is detectable throughout diapausing and in post-diapause development. ApmVg decreased dramatically during embryonic development. These results represent the first study of mVg outside M. sexta and B. mori and provide insight into the physiological role and evolution of mVgs. PMID- 26126121 TI - A Dinuclear Platinum(II) N4Py Complex: An Unexpected Coordination Mode For N4Py. AB - The polypyridyl compound N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine (N4Py) acts as a bridging ligand and coordinates to two Pt(II) ions giving an unexpected diplatinum(II) complex, whose photophysical and anticancer properties were investigated. PMID- 26126122 TI - Cholesterol acquisition by Mycobacterium tuberculosis. AB - In this issue of Virulence, Ramon-Garcia et al. demonstrate the requirement of a mycobacterial efflux pump during growth on cholesterol. In this editorial I replace the study in the context of nutrient acquisition by Mycobacterium tuberculosis. PMID- 26126124 TI - Update of patient-specific maxillofacial implant. AB - PURPOSE OF REVIEW: Patient-specific implant (PSI) is a personalized approach to reconstructive and esthetic surgery. This is particularly useful in maxillofacial surgery in which restoring the complex three-dimensional (3D) contour can be quite challenging. In certain situations, the best results can only be achieved with implants custom-made to fit a particular need. Significant progress has been made over the past decade in the design and manufacture of maxillofacial PSIs. RECENT FINDINGS: Computer-aided design (CAD)/computer-aided manufacturing (CAM) technology is rapidly advancing and has provided new options for fabrication of PSIs with better precision. Maxillofacial PSIs can now be designed using preoperative imaging data as input into CAD software. The designed implant is then fabricated using a CAM technique such as 3D printing. This approach increases precision and decreases or completely eliminates the need for intraoperative modification of implants. The use of CAD/CAM-produced PSIs for maxillofacial reconstruction and augmentation can significantly improve contour outcomes and decrease operating time. SUMMARY: CAD/CAM technology allows timely and precise fabrication of maxillofacial PSIs. This approach is gaining increasing popularity in maxillofacial reconstructive surgery. Continued advances in CAD technology and 3D printing are bound to improve the cost-effectiveness and decrease the production time of maxillofacial PSIs. PMID- 26126125 TI - Near-misses are an opportunity to improve patient safety: adapting strategies of high reliability organizations to healthcare. AB - PURPOSE OF REVIEW: Near-miss investigations in high reliability organizations (HROs) aim to mitigate risk and improve system safety. Healthcare settings have a higher rate of near-misses and subsequent adverse events than most high-risk industries, but near-misses are not systematically reported or analyzed. In this review, we will describe the strategies for near-miss analysis that have facilitated a culture of safety and continuous quality improvement in HROs. RECENT FINDINGS: Near-miss analysis is routine and systematic in HROs such as aviation. Strategies implemented in aviation include the Commercial Aviation Safety Team, which undertakes systematic analyses of near-misses, so that findings can be incorporated into Standard Operating Procedures (SOPs). Other strategies resulting from incident analyses include Crew Resource Management (CRM) for enhanced communication, situational awareness training, adoption of checklists during operations, and built-in redundancy within systems. SUMMARY: Health care organizations should consider near-misses as opportunities for quality improvement. The systematic reporting and analysis of near-misses, commonplace in HROs, can be adapted to health care settings to prevent adverse events and improve clinical outcomes. PMID- 26126123 TI - DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites. AB - Protein-protein interactions represent an exciting and challenging target class for therapeutic intervention using small molecules. Protein interaction sites are often devoid of the deep surface pockets presented by "traditional" drug targets, and crystal structures reveal that inhibitors typically engage these sites using very shallow binding modes. As a consequence, modern virtual screening tools developed to identify inhibitors of traditional drug targets do not perform as well when they are instead deployed at protein interaction sites. To address the need for novel inhibitors of important protein interactions, here we introduce an alternate docking strategy specifically designed for this regime. Our method, termed DARC (Docking Approach using Ray-Casting), matches the topography of a surface pocket "observed" from within the protein to the topography "observed" when viewing a potential ligand from the same vantage point. We applied DARC to carry out a virtual screen against the protein interaction site of human antiapoptotic protein Mcl-1 and found that four of the top-scoring 21 compounds showed clear inhibition in a biochemical assay. The Ki values for these compounds ranged from 1.2 to 21 MUM, and each had ligand efficiency comparable to promising small-molecule inhibitors of other protein-protein interactions. These hit compounds do not resemble the natural (protein) binding partner of Mcl-1, nor do they resemble any known inhibitors of Mcl-1. Our results thus demonstrate the utility of DARC for identifying novel inhibitors of protein-protein interactions. PMID- 26126126 TI - Interplay of Dynamical Properties between Ionic Liquids and Ionic Surfactants: Mechanism and Aggregation. AB - The dynamical and aggregation behaviors of sodium dodecyl sulfate (SDS) in 1 ethyl-3-methylimidazolium ethylsulfate [EMIM+][EtSO4-] are characterized experimentally and computationally. A retardation of the ionic liquid (IL) and SDS diffusion coefficients with a concentration increase of SDS is observed. In agreement with experiments, aggregation is detected for concentrations higher than the experimental critical micelle concentration (CMC), which is mostly driven by alkyl tail aggregation. Solvent-exposed hydrophobic patches are observed on the micelle's surfaces. The hydrophobic tails of the IL molecules are found to fill those micelle's hydrophobic patches. Also, penetration of the IL is found in the SDS micelles, indicating that the IL acts as a cosurfactant, allowing the formation of "mixed" micelles. A higher level of Na+ counterion dissociation compared to previous studies of SDS micelles in aqueous solutions is also observed. A multilayering effect of alternating IL anions and cations is detected at the surface of the formed aggregates. The observed increase in system ordering with SDS concentration is what hinders the mobility of each chemical species. PMID- 26126127 TI - Biomechanical Changes of Collagen Cross-Linking on Human Keratoconic Corneas Using Scanning Acoustic Microscopy. AB - PURPOSE: To assess the biomechanical changes of collagen cross-linking on keratoconic corneas in vitro. METHODS: Six keratoconic corneal buttons were included in this study. Each cornea was divided into two halves, where one half was cross-linked and the other half was treated with riboflavin only and served as control. The biomechanical changes of the corneal tissue were measured across the stroma using scanning acoustic microscopy (SAM). RESULTS: In the cross-linked corneas, there was a steady decrease in the magnitude of speed of sound from the anterior region through to the posterior regions of the stroma. The speed of sound was found to decrease slightly across the corneal thickness in the control corneas. The increase in speed of sound between the cross-linked and control corneas in the anterior region was by a factor of 1.039*. CONCLUSION: A higher speed of sound was detected in cross-linked keratoconic corneal tissue when compared with their controls, using SAM. This in vitro model can be used to compare to the cross-linking results obtained in vivo, as well as comparing the results obtained with different protocols. PMID- 26126130 TI - Epidemiology of the high-risk population: perioperative risk and mortality after surgery. AB - PURPOSE OF REVIEW: This review will provide an overview of actual data concerning perioperative risk. Furthermore, strategies to prevent, detect and treat perioperative complications will be discussed. RECENT FINDINGS: Perioperative in hospital mortality rate of 0.4-4% has not improved over the last years possibly resulting in one to several million deaths during or immediately after surgery each year worldwide. Perioperative complications and mortality are determined not only by the type of surgery but also by preexisting comorbidities of the patient. However, most potentially lethal complications have a slow onset like surgical site infections, pneumonia and sepsis. Therefore, a time window of opportunity might exist to detect and treat these complications as well as to improve outcome. In this context, failure to rescue (FTR) has been introduced as an indicator for the quality of perioperative care. There is growing evidence that FTR is a relevant phenomenon in perioperative medicine, possibly accounting for almost half of postoperative mortality. SUMMARY: It is imperative to reliably identify patients at risk for postoperative complications and to implement strategies into clinical practice allowing for prevention, early detection and effective treatment of complications. By bundling best practice concepts in all phases of perioperative care, patient outcome will be effectively improved. PMID- 26126129 TI - Pathogenesis of infection in surgical patients. AB - PURPOSE OF REVIEW: Despite the application of prophylactic antimicrobial therapy and advanced technologies, infection remains one of the most common causes of morbidity and mortality in surgical patients. Understanding the pathogenesis of surgical infection would offer new insights into the development of biomarkers to predict and stratify infection in patients, and to explore specific strategies to minimize this serious postoperative complication. RECENT FINDINGS: The acute nonspecific inflammatory response triggered by endogenous danger signals evoked by surgical insult is beneficial, while paradoxically associated with reduced resistance to infection. There is growing evidence indicating that primed inflammation by surgical insult exaggerates the dysregulation of the immune inflammatory response to the invasion of pathogens postoperatively. Innate immune receptors, such as Toll-like receptors (TLRs), contribute to detecting both pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, and to further amplifying inflammatory responses to infection. Current evidence shows the fascinating role of non-TLRs in the process of infection. Non TLRs, such as membrane-associated triggering receptor expressed on myeloid cells family, cytosolic nucleotide-binding oligomerization domain-like receptors and nuclear receptor nuclear family 4 subgroup A receptors, are also crucial in triggering the immune responses and mounting an effective defense against surgical insults and the second hit of infection. SUMMARY: Understanding the pivotal role of non-TLRs in sensing exogenous and endogenous molecules, and the influence of primed systemic inflammation and depressed immune status on the defense against pathogen after surgical insult, would be helpful to fully explore the relevant sophisticated phenomena of surgical infection, and to elucidate the occurrence of heterogeneous constellations of clinical signs and symptoms among this special population. PMID- 26126131 TI - G protein coupled growth factor receptor tyrosine kinase: no longer an oxymoron. AB - Environmental cues are transmitted to the interior of the cell via a complex network of signaling hubs. Receptor tyrosine kinases (RTKs) and trimeric G proteins are 2 such major signaling hubs in eukaryotes. Canonical signal transduction via trimeric G proteins is spatially and temporally restricted, i.e., triggered exclusively at the plasma membrane (PM) by agonist activation of G-protein-coupled receptors (GPCRs) via a process that completes within a few hundred milliseconds. Recently, a rapidly emerging paradigm has revealed a non canonical pathway for activation of trimeric G proteins by the non-receptor GEF, GIV/Girdin, that has distinctive temporal and spatial features. Such activation can be triggered by multiple growth factor RTKs, can occur at the PM and on internal membranes discontinuous with the PM, and can continue for prolonged periods of time. The molecular mechanisms that govern such non-canonical G protein activation and the relevance of this new paradigm in health and disease is discussed. PMID- 26126132 TI - First Total Synthesis of Pandamarine. AB - The first total synthesis of pandamarine, an alkaloid isolated from Pandanus amaryllifolius is reported. The key step of this extremely short (six steps in total) and protecting group-free synthesis is a highly efficient cascade reaction sequence initiated by the photooxidation of an easily accessible and symmetric difuran precursor. PMID- 26126128 TI - Nonspeech Oral Movements and Oral Motor Disorders: A Narrative Review. AB - PURPOSE: Speech and other oral functions such as swallowing have been compared and contrasted with oral behaviors variously labeled quasispeech, paraspeech, speechlike, and nonspeech, all of which overlap to some degree in neural control, muscles deployed, and movements performed. Efforts to understand the relationships among these behaviors are hindered by the lack of explicit and widely accepted definitions. This review article offers definitions and taxonomies for nonspeech oral movements and for diverse speaking tasks, both overt and covert. METHOD: Review of the literature included searches of Medline, Google Scholar, HighWire Press, and various online sources. Search terms pertained to speech, quasispeech, paraspeech, speechlike, and nonspeech oral movements. Searches also were carried out for associated terms in oral biology, craniofacial physiology, and motor control. RESULTS AND CONCLUSIONS: Nonspeech movements have a broad spectrum of clinical applications, including developmental speech and language disorders, motor speech disorders, feeding and swallowing difficulties, obstructive sleep apnea syndrome, trismus, and tardive stereotypies. The role and benefit of nonspeech oral movements are controversial in many oral motor disorders. It is argued that the clinical value of these movements can be elucidated through careful definitions and task descriptions such as those proposed in this review article. PMID- 26126133 TI - Effects of seated lumbar extension postures on spinal height and lumbar range of motion during prolonged sitting. AB - Prolonged sitting during sedentary work has been reported as a potential risk factor for low back pain. Furthermore, prolonged sitting can result in both reduced spinal height (SH) and lumbar range of motion (LROM). This study compared the effects of no intervention (control) with two recovery postures on SH and LROM (flexion and extension) during prolonged sitting. Twenty-four participants were randomly assigned to three interventions for three consecutive days. The interventions comprised two seated lumbar extension recovery postures (unsupported sustained and supported dynamic lumbar extension postures) and a control. Both interventions facilitated a relatively short recovery period for both SH and LROM. Supported dynamic lumbar extension conditions significantly helped SH recovery, as compared with control condition, after the first recovery posture intervention, and both postures have potential to maintain LROM. However, both postures failed to induce SH recovery over an extended time. PRACTITIONER SUMMARY: Unsupported sustained lumbar extension and supported dynamic lumbar extension postures may serve as effective and practical methods for reducing rate of SH loss and maintaining LROM. However, these postures should be further examined in various 'doses' to define optimal protocol for effectively minimising SH loss over time. PMID- 26126134 TI - Endocannabinoid signaling in female reproductive events: a potential therapeutic target? AB - Nearly 30 years after the discovery in 1964 of the psychoactive ingredient of cannabis (Cannabis sativa), Delta(9)-tetrahydrocannabinol, its endogenous counterparts were discovered and collectively termed endocannabinoids (eCBs): N arachidonoylethanolamine (anandamide) in 1992 and 2-arachidonoylglycerol in 1995. Since then, intense research has identified additional eCBs and an ensemble of proteins that bind, synthesize and degrade them, the so-called eCB system. Altogether, these new compounds have been recognized as key mediators of several aspects of human pathophysiology, and in particular of female fertility. Here, the main features of the eCB system are presented, in order to put in a better perspective the relevance of eCB signaling in virtually all steps of human reproduction and to highlight emerging hopes that elements of this system might indeed become novel targets to combat fertility problems. PMID- 26126135 TI - EFFECTS OF STROBOSCOPIC VISUAL TRAINING ON VISUAL ATTENTION, MOTION PERCEPTION, AND CATCHING PERFORMANCE. AB - It has been shown recently that stroboscopic visual training can improve visual perceptual abilities, such as central field motion sensitivity and anticipatory timing. Such training should also improve a sports skill that relies on these perceptual abilities, namely ball catching. Thirty athletes (12 women, 18 men; M age=22.5 yr., SD=4.7) were assigned to one of two types of stroboscopic training groups: a variable strobe rate (VSR) group for which the off-time of the glasses was systematically increased (as in previous research) and a constant strobe rate group (CSR) for which the glasses were always set at the shortest off-time. Training involved simple, tennis ball-catching drills (9*20 min.) occurring over a 6-wk. PERIOD: In pre- and post-training, the participants completed a one handed ball-catching task and the Useful Field of View (UFOV) and the Motion in Depth Sensitivity (MIDS) tests. Since the CSR condition used in the present study has been shown to have no effect on catching performance, it was predicted that the VSR group would show significantly greater improvement pre-post-training. There were no significant differences between the CSR and VSR on any of the tests. However, changes in catching performance (total balls caught) pre-post training were significantly correlated with changes in scores for the UFOV single task and MIDS tests. That is, regardless of group, participants whose perceptual cognitive performance improved in the post-test were significantly more likely to improve their catching performance. This suggests that the perceptual changes observed in previous stroboscopic training studies may be linked to changes in sports skill performance. PMID- 26126136 TI - Patient Safety: So, What Does It Mean? PMID- 26126138 TI - State of the Society. PMID- 26126137 TI - A Missed Opportunity. PMID- 26126139 TI - 2014 INS Financial Report. PMID- 26126140 TI - Chief Executive Officer's Message. PMID- 26126141 TI - Presidential Address. PMID- 26126142 TI - Evaluating an Educational Module on Home Inotrope Therapy. AB - Educating home health nurses presents significant challenges for nurse educators because of the vast geographical areas served and the types of patient cared for. The integration of technology into the home health care arena offers new and innovative opportunities to address the ongoing educational needs of nurses as required by accrediting bodies. This exploratory study evaluated a Web-based educational module on home inotrope therapy in regard to nurses' perceived knowledge and confidence. PMID- 26126143 TI - One Hospital's Initiatives to Encourage Safe Opioid Use. AB - Pain is the leading reason people seek health care. In an effort to aggressively manage pain in the hospitalized patient, we have seen an increase in the use of opioids. Unfortunately, there has been a similar increase in the number of opioid related adverse events. As a result, The Joint Commission issued a Sentinel Event Alert in August 2012 with suggested evidenced-based actions to help avoid these adverse events. This article describes one hospital's initiatives to provide opioids safely. PMID- 26126144 TI - Moral Distress: Recognition, Diagnosis, and Treatment. AB - Infusion nursing is a unique hybrid of inpatient and ambulatory nursing. The subspecialty of nurses cares for patients requiring treatment over long periods, including cancer patients receiving chemotherapy and patients who require short bursts of treatment, such as those with multiple sclerosis, Crohn's disease, and rheumatoid arthritis. Infusion nurses are exposed to many of the common root causes of moral distress in their practice, similar to nurses caring for terminally ill or critically ill patients. The specific aims of this article are to (1) define moral distress, moral residue, and the crescendo effect; (2) describe ethical stressors that can be confused with moral distress; (3) review the effects of moral distress on different health care providers; and (4) provide strategies to manage moral distress in the workplace using a case example. PMID- 26126145 TI - The Impact of Long-Term Home Parenteral Nutrition on the Patient and the Family: Achieving Normalcy in Life. AB - Home parenteral nutrition (HPN) is a technologically complex, life-sustaining therapy for individuals who have intestinal failure. Accepting an invasive lifelong therapy like HPN is challenging for patients and their family caregivers. There is a desire to maintain a sense of normalcy in life and to carry on as usual. Using qualitative methodology, the authors explored and described the lived experience of HPN-dependent adults and identified normalization as a repeating and strong theme. Understanding how individuals adapt, cope, or experience this complex therapy provides insight into how they manage their lives in as normal a way as possible. By understanding the perspective of normalization, home infusion nurses and nutrition support clinicians can embrace caregiving strategies and tools consistent with the changing social environment in which the HPN experience is lived. PMID- 26126146 TI - (+)- and (-)-Spiroreticulatine, A Pair of Unusual Spiro Bisheterocyclic Quinoline imidazole Alkaloids from the South China Sea Sponge Fascaplysinopsis reticulata. AB - A pair of novel bisheterocyclic quinoline-imidazole alkaloids, (+)- and (-) spiroreticulatine (1), were isolated from the South China Sea sponge Fascaplysinopsis reticulata. The structures and absolute configurations were elucidated by comprehensive spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical calculation methods. Spiroreticulatine is the first example of a sponge-derived natural spiro quinoline-imidazole alkaloid that may derive from tryptophan and 1,3-dimethylurea. Compound 1 showed inhibitory activity on IL-2 production but inactive against normal tumor cell lines. PMID- 26126147 TI - M3C (M: Fe, Co, Ni) Nanocrystals Encased in Graphene Nanoribbons: An Active and Stable Bifunctional Electrocatalyst for Oxygen Reduction and Hydrogen Evolution Reactions. AB - Transition metal carbide nanocrystalline M3C (M: Fe, Co, Ni) encapsulated in graphitic shells supported with vertically aligned graphene nanoribbons (VA-GNRs) are synthesized through a hot filament chemical vapor deposition (HF-CVD) method. The process is based on the direct reaction between iron group metals (Fe, Co, Ni) and carbon source, which are facilely get high purity carbide nanocrystals (NCs) and avoid any other impurity at relatively low temperature. The M3C-GNRs exhibit superior enhanced electrocatalystic activity for oxygen reduction reaction (ORR), including low Tafel slope (39, 41, and 45 mV dec(-1) for Fe3C GNRs, Co3C-GNRs, and Ni3C-GNRs, respectively), positive onset potential (~0.8 V), high electron transfer number (~4), and long-term stability (no obvious drop after 20 000 s test). The M3C-GNRs catalyst also exhibits remarkable hydrogen evolution reaction (HER) activity with a large cathodic current density of 166.6, 79.6, and 116.4 mA cm(-2) at an overpotential of 200 mV, low onset overpotential of 32, 41, and 35 mV, small Tafel slope of 46, 57, and 54 mV dec(-1) for Fe3C GNRs, Co3C-GNRs, and Ni3C-GNRs, respectively, as well as an excellent stability in acidic media. PMID- 26126148 TI - The Effect of Parathyroid Hormone on Osseointegration in Insulin-Treated Diabetic Rats. AB - OBJECTIVES: Uncontrolled diabetes mellitus is associated with impaired osseointegration. Diabetic individuals might benefit from bone anabolic therapies. Intermittent administration of 1-34 parathyroid hormone (PTH) stimulates bone formation in rodent models. However, this anabolic effect fails in diabetic rats. Whether the anabolic effect of PTH can be achieved in insulin controlled diabetic rats has not been investigated yet. MATERIALS AND METHODS: After diabetes induction with streptozotocin in 40 female Wistar rats, the animals were randomly divided into 4 groups: diabetes, diabetes plus PTH, insulin treated diabetes, and insulin-treated diabetes plus PTH. After 1 week, miniscrews were inserted in the tibiae. Osmotic pumps with insulin or saline solution were implanted. Animals received 60 mg/kg PTH or saline solution. Histomorphometric analysis was performed. RESULTS: In diabetic rats, no changes of medullary periimplant bone area or bone-to-implant contacts (BICs) were achieved with or without treatment with PTH. However, also animals treated with insulin failed to response significantly to PTH regarding bone area (7.4 +/- 4.1% and 8.1 +/- 4.1%) and BICs (33.7 +/- 16.9% and 49.9 +/- 11.9%). CONCLUSION: These results demonstrate that the metabolic characteristics of the diabetic rats produced a condition unable to respond to PTH treatment, even when hyperglycemia was controlled with insulin. PMID- 26126149 TI - Speckle-Tracking-Based Evaluation of Vascular Strain at Different Sites of the Arterial Tree in Healthy Adults. AB - Purpose: Vascular ultrasound (US) allows the analysis of vascular strain by speckle-tracking. This study sought to assess the extent to which vas cular strain varies between different segments of the arterial tree. Furthermore, this study aimed to investigate the reproducibility of vascular strain determination as well as of the components that contribute to the variance of vascular strain measurements in different vascular beds. Materials and Methods: Speckle-tracking was used to determine the vascular strain of the abdominal aorta (AA), the common carotid artery (CCA), the common femoral (CFA) and the popliteal artery (PA) of healthy adults. Intra- and interday reproducibility and the components of variance of vascular strain of the respective arteries were determined. Results: A total of 589 US clips obtained in 10 healthy adults (7 males, 28.3 +/- 3.2 years) were analyzable. Vascular strain was 7.2 +/- 3.0 % in the AA, 5.7 +/- 2.1 % in the CCA, 2.1 +/- 1.1 % in the CFA and 1.9 +/- 1.1 % in the PA. The intraday coefficients of variation of vascular strain were 6.2 % (AA), 3.9 % (CCA), 3.3 % (CFA) and 6.1 % (PA), and the interday coefficients of variation were 5.9 % (AA), 8.4 % (CCA), 10 % (CFA) and 4.6 % (PA). The variance of vascular strain mainly depended on the investigated vessel and subject. Individual DUS clips, the day of examination and the (right/left) body side (in paired arteries) had no impact on the variance of vascular strain. Conclusion: Vascular strain substantially varies between different sites of the arterial tree. Speckle-tracking by DUS allows the reliable determination of vascular strain at different arterial sites. PMID- 26126150 TI - The Prospective External Validation of International Ovarian Tumor Analysis (IOTA) Simple Rules in the Hands of Level I and II Examiners. AB - Objective: To externally validate the International Ovarian Tumor Analysis (IOTA) Simple Rules (SR) by examiners with different levels of sonographic experience defined by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and to assess the morphological ultrasound features of the adnexal tumors classified as inconclusive based on IOTA SR. Materials and Methods: In the two-year prospective study adnexal tumors were assessed preoperatively with transvaginal ultrasound by examiners with different levels of experience (level 1- IOTA SR1, level 2-IOTA SR2). Additionally, an expert (level 3) evaluated all tumors by subjective assessment (SA). If the rules could not be applied, the tumors were considered inconclusive. The final diagnosis was based on the histopathological result of the removed mass. The diagnostic performance measures for the assessed model were sensitivity, specificity, negative (LR-) and positive(LR+) likelihood ratios, accuracy (ACC) and diagnostic odds ratio (DOR). Results: 226 women with adnexal tumors scheduled for surgery were included in the stutdy. The prevalence of malignancy was 36.3 % in the group of all studied tumors and was 52.5 % in the inconclusive group (n = 40) (p = 0.215). Fewer tumors were classified as inconclusive by level 2 examiners compared to level 1 examiners [20 (8.8 %) vs. 40 (17.7 %); p = 0.008], resulting from the discrepancy in the evaluation of acoustic shadows and the vascularization within the tumor. For level 1 examiners a diagnostic strategy using IOTA SR1 +MA (assuming malignancy when SR inconclusive) achieved a sensitivity, specificity and DOR of 96.3 %, 81.9 %, 13.624 respectively. For level 2 examiners the diagnostic strategy for IOTA SR2 +MA achieved a sensitivity, specificity and DOR of 95.1 %, 89.6 %, 137,143, respectively. Adding SA by an expert (or level 3 examiner) when IOTA SR were not applicable improved the specificity of the test and achieved a DOR of 505.137 (SR1 +SA) and 293.627 (SR2 +SA). The SA by an expert proved to have the best diagnostic performance with a DOR of 5768.857, and a sensitivity and specificity of 97.6 % and 99.3 % respectively. Within the inconclusive group the most common tumors were unilocular-solid (n-13), solid (n-8) and multilocular solid (n-10) ones. All multilocular tumors were classified as inconclusive because of their size (>= 100 mm) and were found to be benign by pathology. Most of the inconclusive tumors with cystic content presented low-level (43.75 %) echogenicity, followed by ground-glass (34.37 %), mixed (12.5 %) and anechoic (9.4 %). Conclusion: The study results show excellent diagnostic performance of IOTA Simple Rules followed by subjective expert assessment in inconclusive tumors irrespective of the level of experience, while subjective assessment by an expert still has the highest diagnostic odds ratio. The number of inconclusive cases seems to depend on the level of ultrasound expertise and less experienced examiners have a tendency to overestimate blood flow and a presence of acoustic shadows within the tumors. IOTA SR were not applicable either because no benign or malignant features were found or both were identified. Within inconclusive tumors the majority of cases comprise malignant masses that are either unilocular solid, solid tumors or small multilocular-solid ones with a diameter of less than 100 mm. PMID- 26126151 TI - Congenital Lung Lesion: Prenatal Course, Therapy and Predictors of Perinatal Outcome. AB - Purpose To describe the prenatal course and perinatal outcome, and to define prognostic markers for fetuses with congenital pulmonary airway malformation (CPAM) or bronchopulmonary sequestration (BPS). Materials and Methods A retrospective study was performed at the University Hospital Zurich including pregnancies with either fetal CPAM (n = 26) or BPS (n = 11) between 2000 and 2013. Results Three patients decided for termination of pregnancy. Two intrauterine deaths (CPAM) occurred at 25 weeks. Minimally invasive interventions were performed in 9/37 (24 %) fetuses, post-interventional survival was 8/9 (89 %). Mean gestational age at delivery was 38.1 +/-2.8 and 39.1 +/-2.5 weeks in fetuses with CPAM or BPS, respectively. In fetuses with CPAM the perinatal mortality rate was 4/24 (17 %); the rate of invasive interventions or surgery during the early neonatal period (neonatal morbidity) was 9/22 (41 %). Prenatal diagnosis of hydrothorax and/or increasing cystic volume ratio (CVR) until delivery preceded perinatal death in 3/5 (60 %). Absent mediastinal shift showed a neonatal morbidity rate of 1/8 (13 %) without any perinatal mortality. In fetuses with BPS the perinatal morbidity and mortality were both 1/10 (10 %). Hydrops predicted morbidity and mortality in 100 % of cases. Absent hydrops was followed by uncomplicated perinatal outcome. Conclusion Fetuses with CPAM or BPS have a good outcome under optimal perinatal care including the possibility to perform minimally invasive prenatal interventions. CPAM without mediastinal shift and BPS without hydrops have an excellent prognosis. Hydrothorax, increasing CVR or hydrops indicates a high risk for perinatal morbidity and mortality. PMID- 26126152 TI - Sound localization in a changing world. AB - In natural environments, neural systems must be continuously updated to reflect changes in sensory inputs and behavioral goals. Recent studies of sound localization have shown that adaptation and learning involve multiple mechanisms that operate at different timescales and stages of processing, with other sensory and motor-related inputs playing a key role. We are only just beginning to understand, however, how these processes interact with one another to produce adaptive changes at the level of neuronal populations and behavior. Because there is no explicit map of auditory space in the cortex, studies of sound localization may also provide much broader insight into the plasticity of complex neural representations that are not topographically organized. PMID- 26126154 TI - Short communication: feasibility and acceptability of developing a multisite clinical cohort of transgender people with HIV infection. AB - Transgender women bear a disproportionate burden of HIV, yet data among this population are not routinely collected in HIV clinical cohorts. Brief surveys and follow-up qualitative interviews were conducted with principal investigators or designated representatives of 17 HIV clinical cohorts to determine the acceptability and feasibility of pooling transgender-specific data from existing HIV clinical cohort studies. Twelve of 17 sites reported that they already collect gender identity data but not consistently. Others were receptive to collecting this information. Many also expressed interest in a study of clinical outcomes among HIV-infected transgender women using pooled data across cohorts. The collection of longitudinal data on transgender people living with HIV is acceptable and feasible for most North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohorts. HIV clinical cohort studies should make efforts to include transgender individuals and develop the tools to collect quality data on this high-need population. PMID- 26126153 TI - Competition, inhibition, and critical periods of cortical plasticity. AB - Maturation of cortical inhibition just after eye opening is a necessary precedent for the emergence of competitive, experience-dependent ocular dominance plasticity in the visual cortex. What inhibition is doing in this context, though, is not clear. Here I outline new hypotheses on the roles of somatic and dendritic inhibition in the opening and closure of critical periods, and their roles in the competitive processes therein. PMID- 26126155 TI - Addition Rate Constants of Phosphorus- and Carbon-Centered Radicals to Double Bond of Monomers as Studied by a Pulsed Electron Paramagnetic Resonance Method. AB - Addition reaction of a radical to the double bond of a monomer, which is important at early stage of photopolymerization, has been studied by time resolved (TR-) and pulsed electron paramagnetic resonance (EPR) spectroscopic methods. Reactions of one phosphorus-centered and three carbon-centered radicals attacking to several monomers have been employed. Intermediate radicals were identified by analyzing the recorded TR-EPR spectra, and the reaction rate constants were determined by the electron spin-echo detection method proposed by Weber and Turro [J. Phys. Chem. A, 2003, 107 (18), 3326 - 3334]. The quantum chemical calculation shows that the rate constants for the addition reactions are well-explained by introducing two factors of "enthalpy effect" and "polar effect" to control the activation barrier height. It was observed that the rate constants of the phosphorus-centered radical were larger than those of carbon-centered radicals for some monomers. The difference in the rate constants was argued on the basis of frequency factor and activation barrier both of which are influenced by an atom of radical center. PMID- 26126156 TI - Endoscopic drainage of walled-off pancreatic necrosis using a novel self expanding metal stent. AB - BACKGROUND AND STUDY AIMS: This report describes the use of a novel, fully covered, self-expanding metal stent (FCSEMS) for endoscopic ultrasound (EUS) guided drainage of walled-off pancreatic necrosis (WON). PATIENTS AND METHODS: Patients with WON, as defined by the revised Atlanta Criteria, were included in this open-lable, two-center, observational study. The WON was punctured using a cystotome, and the FCSEMS was inserted under fluoroscopic guidance. Necrosectomy procedures were performed as necessary. RESULTS: A total of 19 patients were included. The median maximum collection size was 15 cm with a median of 50 % necrosis. A total of 14/19 patients underwent necrosectomy, requiring a median of 4 procedures. Resolution or reduction in the size of collection by at least 80 % was achieved in all patients. Percutaneous or surgical drainage was required in three patients. Five stents migrated or dislodged. One patient had abdominal pain post-procedure. Five patients died during follow-up (three from multi-organ failure, and two unrelated to pancreatitis). CONCLUSIONS: Use of this stent is feasible and safe for drainage of WON. However, stent displacement rates were high, and improvements to the stent design are required before it can be advocated for routine use in WON. PMID- 26126157 TI - Nonexposure endolaparoscopic full-thickness resection with simple suturing technique. AB - BACKGROUND AND AIM: Current endoscopic full-thickness resection (EFTR) methods are limited by their transmural communication and exposure of tumor to the peritoneum. The aim of this study was to test the feasibility of a new resection technique that does not expose the mucosa to the peritoneum, although it involves an easy and secure suture method, which could be applied in the clinical setting. METHODS: The nonexposure endolaparoscopic full-thickness resection with simple suturing technique was performed in four pigs. This new technique includes the steps of laparoscopic seromuscular suturing, which results in inversion of the stomach wall; EFTR of the inverted stomach wall from inside the stomach; and finally, endoscopic mucosal suturing with endoloops and clips. RESULTS: En bloc and complete resections were achieved without adverse events in all pigs. The mean (+/- standard deviation) operation time was 137.0 +/- 28.2 minutes. All pigs survived with no clinical evidence of illness until euthanasia. Gross and microscopic examination of the resection site showed healing without evidence of leakage or infection. CONCLUSION: The nonexposure endolaparoscopic full-thickness resection with simple suturing technique was feasible in an animal model. PMID- 26126158 TI - Colonoscopy with robotic steering and automated lumen centralization: a feasibility study in a colon model. AB - BACKGROUND AND STUDY AIMS: We introduced a new platform for performing colonoscopy with robotic steering and automated lumen centralization (RS-ALC) and evaluated its technical feasibility. PARTICIPANTS AND METHODS: Expert endoscopists (n = 8) and endoscopy-naive novices (n = 10) used conventional steering and RS-ALC to perform colonoscopy in a validated colon model with simulated polyps (n = 21). The participants were randomized to which modality they were to use first. End points were the cecal intubation time, number of detected polyps, and subjective evaluation of the platform. RESULTS: Novices were able to intubate the cecum faster with RS-ALC (median 8 minutes [min] 56 seconds [s], interquartile range [IQR] 6 min 46 s - 16 min 34 s vs. median 11 min 47 s, IQR 8 min 19 s - 15 min 33 s, P = 0.65), whereas experts were faster with conventional steering (median 2 min 9 s, IQR 1 min 13 s - 7 min 28 s vs. median 13 min 1 s, IQR 5 min 9 s - 16 min 54 s, P = 0.12). Novices detected more polyps with RS-ALC (median 88.1 %, IQR 79.8 % - 95.2 % vs. median 78.6 %, IQR 75.0 % - 91.7 %, P = 0.17), whereas experts detected more polyps with conventional steering (median 80.9 %, IQR 76.2 % - 85.7 % vs. median 69.0 %, IQR 61.0 % - 75.0 %, P = 0.03). Novices were more positive than experts about the new platform (P = 0.02), noting an easier and faster introduction of the colonoscope with RS-ALC than with conventional steering. CONCLUSIONS: Colonoscopy with RS-ALC is technically feasible and appears to be easier and more intuitive than conventional steering for endoscopy-naive novices. PMID- 26126159 TI - Comparing outcome of radiofrequency ablation in Barrett's with high grade dysplasia and intramucosal carcinoma: a prospective multicenter UK registry. AB - BACKGROUND AND STUDY AIM: Mucosal neoplasia arising in Barrett's esophagus can be successfully treated with endoscopic mucosal resection (EMR) followed by radiofrequency ablation (RFA). The aim of the study was to compare clinical outcomes of patients with high grade dysplasia (HGD) or intramucosal cancer (IMC) at baseline from the United Kingdom RFA registry. PATIENTS AND METHODS: Prior to RFA, visible lesions and nodularity were removed entirely by EMR. Thereafter, patients underwent RFA every 3 months until all visible Barrett's mucosa was ablated or cancer developed (end points). Biopsies were taken at 12 months or when end points were reached. RESULTS: A total of 515 patients, 384 with HGD and 131 with IMC, completed treatment. Prior to RFA, EMR was performed for visible lesions more frequently in the IMC cohort than in HGD patients (77 % vs. 47 %; P < 0.0001). The 12-month complete response for dysplasia and intestinal metaplasia were almost identical in the two cohorts (HGD 88 % and 76 %, respectively; IMC 87 % and 75 %, respectively; P = 0.7). Progression to invasive cancer was not significantly different at 12 months (HGD 1.8 %, IMC 3.8 %; P = 0.19). A trend towards slightly worse medium-term durability may be emerging in IMC patients (P = 0.08). In IMC, EMR followed by RFA was definitely associated with superior durability compared with RFA alone (P = 0.01). CONCLUSION: The Registry reports on endoscopic therapy for Barrett's neoplasia, representing real-life outcomes. Patients with IMC were more likely to have visible lesions requiring initial EMR than those with HGD, and may carry a higher risk of cancer progression in the medium term. The data consolidate the approach to ensuring that these patients undergo thorough endoscopic work-up, including EMR prior to RFA when necessary. PMID- 26126160 TI - Bleeding after endoscopic sphincterotomy or papillary balloon dilation among users of antithrombotic agents. AB - BACKGROUND AND STUDY AIMS: Severe bleeding is a potentially lethal complication after endoscopic sphincterotomy (EST) and endoscopic papillary balloon dilation (EPBD) for choledocholithiasis. This study aimed to evaluate the impact of antiplatelet agents and anticoagulants on this complication. PATIENTS AND METHODS: Patients who underwent EST and EPBD were identified in a Japanese nationwide administrative database covering 1090 hospitals. Adjusting for other potential risk factors, we evaluated the association between oral administration of antiplatelet agents and/or anticoagulants (continuation, discontinuation, and non-use) and clinically significant bleeding within 3 days of the procedure. RESULTS: In total, 61 002 patients were analyzed (EST, 54 493 patients; EPBD, 6509). The rate of severe bleeding was 0.8 % in both groups, but EPBD was performed more frequently than EST in patients with chronic renal failure, liver cirrhosis, and in those receiving antiplatelet agents or anticoagulants. The impact of continuation/discontinuation of antiplatelet agents on severe bleeding was not statistically significant in the EST or EPBD groups. The use of anticoagulants was associated with a statistically significant increase in severe bleeding compared with non-use for EST (1.6 % 27 of 1688 patients vs. 0.8 % 429 of 52 805 patients; adjusted odds ratio [OR] 1.70; 95 % confidence interval [CI] 1.10 - 2.63) and for EPBD (3.0 % [8 of 263 patients] vs. 0.7 % 46 of 6246 patients; adjusted OR 2.91; 95 %CI 1.36 - 6.24). CONCLUSIONS: EST and EPBD can be safely performed in patients receiving antiplatelet agents. Users of anticoagulants are at high risk of bleeding, and the periprocedural management of these should be further investigated. PMID- 26126161 TI - Patient position and hypoxemia during propofol sedation for colonoscopy: a randomized trial. AB - AIM: To evaluate the benefits of the left lateral position in avoiding hypoxemic events in patients undergoing colonoscopy. METHODS: We conducted a randomized, prospective, controlled trial at two study sites in Germany. Patients undergoing colonoscopy under propofol sedation were randomized to either the supine or left lateral position. The primary outcome was oxygen desaturation (SaO2<90%). Secondary outcome measures were apneic events, hypotension, patient satisfaction, propofol dosage, cecal intubation time, and adenoma detection. RESULTS: A total of 412 patients were randomized 1:1 to undergo colonoscopy in the supine or left lateral position. No severe adverse events were observed in either group. Intention-to-treat analysis revealed no significant difference in the frequency of desaturation in the left lateral arm compared with the supine arm (6.8% vs. 12.1%; P=0.064). Patients in the left lateral arm showed lower apnea rates (9.4% vs. 16.2%; P= .040), but had more episodes of hypotension (12.3% vs. 2.9%; P<0.001). The frequency of repositioning was higher in the left lateral group. No significant differences were observed in patient satisfaction and cooperation, propofol dosage, or adenoma detection rate. Patients who were repositioned to facilitate endoscope passage were excluded from per-protocol analysis. The incidence of hypoxemia was lower for the left lateral than for the supine group in per-protocol analysis (1.8% vs. 11.2%; P=0.003). CONCLUSION: The positioning of patients in the left lateral position during propofol sedation for colonoscopy results in lower desaturation rates provided the position can be maintained throughout endoscopy. ClinicalTrials.gov NCT02001792. PMID- 26126162 TI - Cap-assisted colonoscopy and detection of Adenomatous Polyps (CAP) study: a randomized trial. AB - BACKGROUND AND STUDY AIM: Cap-assisted colonoscopy has improved adenoma detection in some but not other studies. Most previous studies have been limited by small sample sizes and few participating endoscopists. The aim of the current study was to evaluate whether cap-assisted colonoscopy improves adenoma detection in a two center, multi-endoscopist, randomized trial. PATIENTS AND METHODS: Consecutive patients who presented for an elective colonoscopy were randomized to cap assisted colonoscopy (4-mm cap) or standard colonoscopy performed by one of 10 experienced endoscopists. Primary outcome measures were mean number of adenomas per patient and adenoma detection rate (ADR). Secondary outcomes included procedural measures and endoscopist variation; a logistic regression model was employed to examine predictors of increased detection with cap use. RESULTS: A total of 1113 patients (64 % male, mean age 62 years) were randomized to cap assisted (n = 561) or standard (n = 552) colonoscopy. The mean number of adenomas detected per patient in the cap-assisted and standard groups was similar (0.89 vs. 0.82; P = 0.432), as was the ADR (42 % vs. 40 %; P = 0.452). Cap-assisted colonoscopy achieved a faster cecal intubation time (4.9 vs. 5.8 minutes; P < 0.001), a similar cecal intubation rate (99 % vs. 98 %; P = 0.326), and a higher terminal ileum intubation rate (93 % vs. 89 %; P < 0.028). Cap-assisted colonoscopy resulted in a 20 % increase in ADR for some endoscopists and in a 15 % decrease for others. Individual preference for the cap was an independent predictor of increased adenoma detection in adjusted analysis (P < 0.001), whereas baseline low adenoma detection was not. CONCLUSION: Although the efficiency of cecal and terminal ileum intubation was slightly improved by cap assisted colonoscopy, adenoma detection was not. Cap-assisted colonoscopy may be beneficial for selected endoscopists. TRIAL REGISTRATION: clinicalTrials.gov (NCT01935180). PMID- 26126163 TI - Fecal immunochemical testing results and characteristics of colonic lesions. AB - BACKGROUND AND STUDY AIMS: Fecal immunochemical tests (FIT) are used to detect blood in feces, which might indicate the presence of colorectal neoplasia. The aim of this study was to investigate whether FIT results vary depending on the characteristics of colonic lesions. PATIENTS AND METHODS: This was a retrospective analysis of lesions detected in a cohort of asymptomatic individuals (aged 50 - 75 years) who were invited to participate in a FIT-based screening pilot in The Netherlands. The mean FIT result was compared across subgroups of individuals defined by histopathology of the most advanced lesion detected. In addition, the results were compared with data from a primary colonoscopy screening trial, in which participants also completed a FIT. RESULTS: In three rounds of FIT-based screening, a total of 877 FIT-positive individuals underwent colonoscopy. Higher mean FIT results (hemoglobin [Hb]/g feces) were observed in individuals with carcinomas (199 MUg Hb/g) and advanced adenomas (87 MUg Hb/g) compared with participants with nonadvanced adenomas (50 MUg Hb/g) or those with serrated lesions (46 MUg Hb/g) (P < 0.001). In the primary colonoscopy trial, 1256 participants completed a FIT test and underwent colonoscopy. The number of participants with nonadvanced adenomas as the most advanced lesion was comparable between this group and the FIT-based screening group (20 % vs. 22 %). CONCLUSION: In FIT-based screening, the mean FIT results varied depending on the characteristics of the most advanced colonic lesion. The proportion of participants with a nonadvanced adenoma as the most advanced lesion was similar in the FIT-based screening group and in the primary colonoscopy screening group, suggesting that these lesions are coincidental findings rather than FIT-detected findings. CLINICAL TRIAL REGISTRATION: www.trialregister.nl number NTR2755. PMID- 26126164 TI - Low prevalence of serrated polyposis syndrome in screening populations: a systematic review. AB - BACKGROUND AND STUDY AIMS: The most frequently cited prevalence for serrated polyposis syndrome (SPS) is 1 in every 3000 people screened, but this value is debated. Additionally, changes in 2010 in the World Health Organization (WHO) diagnostic criteria for SPS might affect reported prevalence. An updated estimate of SPS prevalence is necessary to predict the number of cases in screening programs. PATIENTS AND METHODS: A systematic literature search was conducted in the PubMed, EMBASE, and Web of Science databases up to February 2014. Studies reporting the prevalence of SPS, as defined by WHO criteria, in screening populations were selected. RESULTS: Six studies reported prevalence of SPS in screening populations, varying from 0 to 0.66 %. The highest prevalences (0.34 % and 0.66 %) were seen in studies from screening programs with patients pre selected by fecal blood test. Primary colonoscopy-based screening programs, that have the lowest risk of bias, reported SPS prevalences ranging from 0 to 0.09 %. Across studies, 56 patients were diagnosed with SPS of whom 3 presented with synchronous colorectal cancer at index endoscopy. CONCLUSION: The true prevalence of SPS is unclear because of the risk of bias across studies, but is likely to be below 0.09 % as derived from primary colonoscopy screening programs. The prevalence in pre-selected screening populations after positive fecal testing is higher, with reported values of 0.34 % and 0.66 %. Large and high quality primary colonoscopy screening studies, reporting SPS prevalence in adequately described populations, are necessary for better estimation of the true prevalence of SPS in average-risk patients. PMID- 26126165 TI - Development of a Debye heat capacity model for vibrational modes with a gap in the density of states. AB - Low-energy vibrational modes that have a gap in the density of states (DOS) have often been observed in heat capacity data in the form of 'boson' peaks, but the functions used to model these modes are often inadequate or are not physically meaningful. We have adapted the Debye model to represent these gapped modes and have derived the heat capacity equations for these modes in one, two, and three dimensions. Applying these equations to the low-temperature heat capacity data fitting for a large variety of materials substantially improves the fit quality relative to conventional fits. From the fitting parameters, the underlying DOS were estimated, which we show to be comparable to those reported in the literature. This model expands the methods of theoretical low-temperature heat capacity data analysis and improves the procedure of approximating a material's DOS from its low-temperature heat capacity. PMID- 26126166 TI - Entropy-Driven Crystallization Behavior in DNA-Mediated Nanoparticle Assembly. AB - Herein, we report an example of entropy-driven crystallization behavior in DNA nanoparticle superlattice assembly, marking a divergence from the well established enthalpic driving force of maximizing nearest-neighbor hybridization connections. Such behavior is manifested in the observation of a non-close packed, body-centered cubic (bcc) superlattice when using a system with self complementary DNA linkers that would be predicted to form a close-packed, face centered cubic (fcc) structure based solely on enthalpic considerations and previous design rules for DNA-linked particle assembly. Notably, this unexpected phase behavior is only observed when employing long DNA linkers with unpaired "flexor" bases positioned along the length of the DNA linker that increase the number of microstates available to the DNA ligands. A range of design conditions are tested showing sudden onsets of this behavior, and these experiments are coupled with coarse-grained molecular dynamics simulations to show that this entropy-driven crystallization behavior is due to the accessibility of additional microstates afforded by using long and flexible linkers. PMID- 26126167 TI - A case of thrombosis of subcutaneous anterior chest veins (Mondor's disease) as an unusual complication of botulinum type A injection. AB - Mondor's disease is a rare entity, characterized by sclerosing thrombophlebitis classically involving one or more of the subcutaneous veins, including the anterior chest wall. It is usually a self-limited, benign condition, although it may be rarely associated with cancer. The intramuscular administration of botulinum toxin type A (BoNT-A), and also, more recently, type B, is a well established treatment of many neurological, other medical and cosmetic disorders, including strabismus, blepharospasm, cervical and other focal/segmental dystonia, and also hyperhidrosis. Herein, we describe a case of thrombosis of the subcutaneous anterior chest veins, known as Mondor's disease, following botulinum toxin treatment for armpits hyperhidrosis. PMID- 26126168 TI - Haemophilia A and B as a cause for secondary osteoporosis and increased fracture risk. AB - Despite the increasing evidence regarding its association with low bone mineral density (BMD) both in adults and children, haemophilia A or B has not yet been considered among the classic causes of secondary osteoporosis. Although the exact mechanisms are not fully elucidated, physical inactivity and vitamin D deficiency seem to play a fundamental role for such an association. Viral infections and arthropathy further compromise bone mass. Except for low BMD, patients with haemophilia seem to be at increased risk for fracture and falls. The FRAX tool may be of value in this population, for the estimation of fracture risk. Regular exercise, prophylactic factor replacement therapy in severe haemophilia, fall prevention strategies and optimization of calcium and vitamin D intake are recommended. In any case, individualized multidisciplinary approach and careful assessment and management of fracture risk are recommended. PMID- 26126169 TI - Antithrombotic and antiplatelet activities of vicenin-2. AB - Cyclopia subternata is a medicinal plant commonly used in traditional medicine to relieve pain in physiological processes. However, there are limited modern data on its pharmacological effects and active components relating to its traditional use. Here, the anticoagulant and antiplatelet activities of vicenin-2 (VCN), an active compound in C. subternata, were determined. The anticoagulant activities were investigated by monitoring activated partial thromboplastin time (aPTT), prothrombin time (PT), and the activities of thrombin and activated factor X (FXa). The effects of VCN on the expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were evaluated in tumor necrosis factor (TNF)-alpha-activated human umbilical vein endothelial cells (HUVECs). Treatment with VCN resulted in prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, as well as inhibited production of thrombin and FXa in HUVECs. In addition, VCN inhibited thrombin-catalyzed fibrin polymerization and platelet aggregation. VCN also elicited anticoagulant effects in mice. In addition, treatment with VCN resulted in significant reduction of the PAI-1 to t-PA ratio. Collectively, VCN possesses antithrombotic activities and offers a basis for development of a novel anticoagulant. PMID- 26126170 TI - Interest of chest X-ray in tailoring the diagnostic strategy in patients with suspected pulmonary embolism. AB - Current diagnostic strategies for pulmonary embolism rely on the sequential use of noninvasive diagnostic tests including ventilation-perfusion (V/Q) scan and computed tomography pulmonary angiography (CTPA). V/Q scan remains criticized because of a high proportion of nondiagnostic test results, especially when the chest X-ray (CXR) is abnormal. The present study assesses whether CXR results have an impact on the conclusiveness of a noninvasive diagnostic strategy of pulmonary embolism based on the combination of pretest probability, compression ultrasonography, V/Q scan, and CTPA. Patients suspected of having pulmonary embolism were managed according to a validated diagnostic strategy. All patients underwent a CXR within 24 h of the suspicion of pulmonary embolism. CXR results were correlated to strategy conclusiveness, as assessed by the rate of required CTPA as per the diagnostic algorithm. Two hundred and twenty-three patients were retrospectively analyzed. CXRs were considered as normal in 108 (48%) patients and abnormal in 115 (52%) patients. According to the diagnostic algorithm, a CTPA was required to reach a diagnostic conclusion in 11 (10%) patients of the normal CXR group, and in 14 (12%) patients of the abnormal CXR group (P > 0.05). In this study, the presence of CXR abnormalities did not have an impact on the conclusiveness of a diagnostic strategy of pulmonary embolism based on V/Q scan. CXR abnormalities should likely not be regarded as a contraindication to the use of V/Q scan in patients with suspected pulmonary embolism. PMID- 26126171 TI - Cell cycle status dictates effectiveness of rapamycin. PMID- 26126172 TI - Dopant Concentration-Porosity-Li-Ion Conductivity Relationship in Garnet-Type Li5+2xLa3Ta2-xYxO12 (0.05 <= x <= 0.75) and Their Stability in Water and 1 M LiCl. AB - Highly Li-ion conductive Y-doped garnet-type Li5+2xLa3Ta2-xYxO12 (0.05 <= x <= 0.75) were studied to understand the effects of yttrium- and lithium-doping on crystal structure, porosity, and Li-ion conductivity using (7)Li MAS NMR, electrochemical ac impedance spectroscopy, and scanning electron microscopy (SEM), as well as ex situ and in situ powder X-ray diffraction (PXRD) to further explore the potential application of garnets in all-solid-state Li-ion batteries. Solid-state (7)Li MAS NMR studies showed an increase in the Li-ion mobility as a function of Y- and Li-doping in Li5+2xLa3Ta2-xYxO12, which is consistent with the results from ac impedance spectroscopy. The SEM studies on sintered pellets indicated a systematic decrease in porosity and an increase in sinterability as the Y- and Li-doping levels increase in Li5+2xLa3Ta2-xYxO12. These results are consistent with the calculated porosity and densities using the Archimedes method. Using the variable-temperature in situ PXRD in the temperature range of 30-700 degrees C, a thermal expansion coefficient of 7.25 * 10(-6) K(-1) was observed for Li6La3Ta1.5Y0.5O12. To further explore the possibility of a new application for the Li-stuffed garnets, the stability of these materials in aqueous LiCl solution was also studied. A high degree of structural stability was observed in these materials upon 1 M LiCl treatment, making them suitable candidates for further studies as protective layers for lithium electrodes in aqueous lithium batteries. PMID- 26126173 TI - Inert Gas Enhanced Laser-Assisted Purification of Platinum Electron-Beam-Induced Deposits. AB - Electron-beam-induced deposition patterns, with composition of PtC5, were purified using a pulsed laser-induced purification reaction to erode the amorphous carbon matrix and form pure platinum deposits. Enhanced mobility of residual H2O molecules via a localized injection of inert Ar-H2 (4%) is attributed to be the reactive gas species for purification of the deposits. Surface purification of deposits was realized at laser exposure times as low as 0.1 s. The ex situ purification reaction in the deposit interior was shown to be rate-limited by reactive gas diffusion into the deposit, and deposit contraction associated with the purification process caused some loss of shape retention. To circumvent the intrinsic flaws of the ex situ anneal process, in situ deposition and purification techniques were explored that resemble a direct write atomic layer deposition (ALD) process. First, we explored a laser-assisted electron-beam induced deposition (LAEBID) process augmented with reactive gas that resulted in a 75% carbon reduction compared to standard EBID. A sequential deposition plus purification process was also developed and resulted in deposition of pure platinum deposits with high fidelity and shape retention. PMID- 26126174 TI - Experimental philosophy of actual and counterfactual free will intuitions. AB - Five experiments suggested that everyday free will and moral responsibility judgments about some hypothetical thought examples differed from free will and moral responsibility judgments about the actual world. Experiment 1 (N=106) showed that free will intuitions about the actual world measured by the FAD-Plus poorly predicted free will intuitions about a hypothetical person performing a determined action (r=.13). Experiments 2-5 replicated this result and found the relations between actual free will judgments and free will judgments about hypothetical determined or fated actions (rs=.22-.35) were much smaller than the differences between them (etap(2)=.2-.55). These results put some pressure on theoretical accounts of everyday intuitions about freedom and moral responsibility. PMID- 26126175 TI - Mistreatment of Women in Childbirth: Time for Action on This Important Dimension of Violence against Women. PMID- 26126176 TI - Galectin-8 Ameliorates Murine Autoimmune Ocular Pathology and Promotes a Regulatory T Cell Response. AB - Galectins have emerged as potent immunoregulatory agents that control chronic inflammation through distinct mechanisms. Here, we report that treatment with Galectin-8 (Gal-8), a tandem-repeat member of the galectin family, reduces retinal pathology and prevents photoreceptor cell damage in a murine model of experimental autoimmune uveitis. Gal-8 treatment increased the number of regulatory T cells (Treg) in both the draining lymph node (dLN) and the inflamed retina. Moreover, a greater percentage of Treg cells in the dLN and retina of Gal 8 treated animals expressed the inhibitory coreceptor cytotoxic T lymphocyte antigen (CTLA)-4, the immunosuppressive cytokine IL-10, and the tissue-homing integrin CD103. Treg cells in the retina of Gal-8-treated mice were primarily inducible Treg cells that lack the expression of neuropilin-1. In addition, Gal-8 treatment blunted production of inflammatory cytokines by retinal T helper type (TH) 1 and TH17 cells. The effect of Gal-8 on T cell differentiation and/or function was specific for tissues undergoing an active immune response, as Gal-8 treatment had no effect on T cell populations in the spleen. Given the need for rational therapies for managing human uveitis, Gal-8 emerges as an attractive therapeutic candidate not only for treating retinal autoimmune diseases, but also for other TH1- and TH17-mediated inflammatory disorders. PMID- 26126177 TI - Genomic Scans of Zygotic Disequilibrium and Epistatic SNPs in HapMap Phase III Populations. AB - Previous theory indicates that zygotic linkage disequilibrium (LD) is more informative than gametic or composite digenic LD in revealing natural population history. Further, the difference between the composite digenic and maximum zygotic LDs can be used to detect epistatic selection for fitness. Here we corroborate the theory by investigating genome-wide zygotic LDs in HapMap phase III human populations. Results show that non-Africa populations have much more significant zygotic LDs than do Africa populations. Africa populations (ASW, LWK, MKK, and YRI) possess more significant zygotic LDs for the double-homozygotes (DAABB) than any other significant zygotic LDs (DAABb, DAaBB, and DAaBb), while non-Africa populations generally have more significant DAaBb's than any other significant zygotic LDs (DAABB, DAABb, and DAaBB). Average r-squares for any significant zygotic LDs increase generally in an order of populations YRI, MKK, CEU, CHB, LWK, JPT, CHD, TSI, GIH, ASW, and MEX. Average r-squares are greater for DAABB and DAaBb than for DAaBB and DAABb in each population. YRI and MKK can be separated from LWK and ASW in terms of the pattern of average r-squares. All population divergences in zygotic LDs can be interpreted with the model of Out of Africa for modern human origins. We have also detected 19735-95921 SNP pairs exhibiting strong signals of epistatic selection in different populations. Gene gene interactions for some epistatic SNP pairs are evident from empirical findings, but many more epistatic SNP pairs await evidence. Common epistatic SNP pairs rarely exist among all populations, but exist in distinct regions (Africa, Europe, and East Asia), which helps to understand geographical genomic medicine. PMID- 26126178 TI - Cannabis use in children with individualized risk profiles: Predicting the effect of universal prevention intervention. AB - AIM: To study the effect of a universal prevention intervention targeting cannabis use in individual children with different risk profiles. METHODS: A school-based randomized controlled prevention trial was conducted over a period of 33 months (n=1874 sixth-graders, baseline mean age 11.82). We used a two-level random intercept logistic model for panel data to predict the probabilities of cannabis use for each child. Specifically, we used eight risk/protective factors to characterize each child and then predicted two probabilities of cannabis use for each child if the child had the intervention or not. Using the two probabilities, we calculated the absolute and relative effect of the intervention for each child. According to the two probabilities, we also divided the sample into a low-risk group (the quarter of the children with the lowest probabilities), a moderate-risk group, and a high-risk group (the quarter of the children with the highest probabilities) and showed the average effect of the intervention on these groups. RESULTS: The differences between the intervention group and the control group were statistically significant in each risk group. The average predicted probabilities of cannabis use for a child from the low-risk group were 4.3% if the child had the intervention and 6.53% if no intervention was provided. The corresponding probabilities for a child from the moderate-risk group were 10.91% and 15.34% and for a child from the high-risk group 25.51% and 32.61%. School grades, thoughts of hurting oneself, and breaking the rules were the three most important factors distinguishing high-risk and low-risk children. CONCLUSIONS: We predicted the effect of the intervention on individual children, characterized by their risk/protective factors. The predicted absolute effect and relative effect of any intervention for any selected risk/protective profile of a given child may be utilized in both prevention practice and research. PMID- 26126179 TI - Genes associated with the progression of neurofibrillary tangles in Alzheimer's disease. AB - The spreading of neurofibrillary tangles (NFTs), intraneuronal aggregates of highly phosphorylated microtubule-associated protein tau, across the human brain is correlated with the cognitive severity of Alzheimer's disease (AD). To identify genes relevant to NFT expansion defined by the Braak stage, we conducted whole-genome exon array analysis with an exploratory sample set consisting of 213 human post-mortem brain tissue specimens from the entorinal, temporal and frontal cortices of 71 brain-donor subjects: Braak NFT stages 0 (N=13), I-II (N=20), III IV (N=19) and V-VI (N=19). We identified eight genes, RELN, PTGS2, MYO5C, TRIL, DCHS2, GRB14, NPAS4 and PHYHD1, associated with the Braak stage. The expression levels of three genes, PHYHD1, MYO5C and GRB14, exhibited reproducible association on real-time quantitative PCR analysis. In another sample set, including control subjects (N=30), and in patients with late-onset AD (N=37), dementia with Lewy bodies (N=17) and Parkinson disease (N=36), the expression levels of two genes, PHYHD1 and MYO5C, were obviously associated with late-onset AD. Protein-protein interaction network analysis with a public database revealed that PHYHD1 interacts with MYO5C via POT1, and PHYHD1 directly interacts with amyloid beta-peptide 42. It is thus likely that functional failure of PHYHD1 and MYO5C could lead to AD development. PMID- 26126180 TI - Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression. AB - Mitochondrial dysfunction might have a central role in the pathophysiology of depression. Phenotypically, depression is characterized by lack of energy, concentration problems and fatigue. These symptoms might be partially explained by reduced availability of adenosine triphosphate (ATP) as a consequence of impaired mitochondrial functioning. This study investigated mitochondrial respiration in peripheral blood mononuclear cells (PBMCs), an established model to investigate the pathophysiology of depression. Mitochondrial respiration was assessed in intact PBMCs in 22 individuals with a diagnosis of major depression (MD) compared with 22 healthy age-matched controls using high-resolution respirometry. Individuals with MD showed significantly impaired mitochondrial functioning: routine and uncoupled respiration as well as spare respiratory capacity, coupling efficiency and ATP turnover-related respiration were significantly lower in the MD compared with the control group. Furthermore, mitochondrial respiration was significantly negatively correlated with the severity of depressive symptoms, in particular, with loss of energy, difficulties concentrating and fatigue. The results suggest that mitochondrial dysfunction contributes to the biomolecular pathophysiology of depressive symptoms. The decreased immune capability observed in MD leading to a higher risk of comorbidities could be attributable to impaired energy supply due to mitochondrial dysfunction. Thus mitochondrial respiration in PBMCs and its functional consequences might be an interesting target for new therapeutical approaches in the treatment of MD and immune-related comorbidities. PMID- 26126182 TI - Phenomenological Model of the Growth of Ultrasmooth Silver Thin Films Deposited with a Germanium Nucleation Layer. AB - The structural properties of optically thin (15 nm) silver (Ag) films deposited on SiO2/Si(100) substrates with a germanium (Ge) nucleation layer were studied. The morphological and crystallographical characteristics of Ag thin films with different Ge nucleation layer thicknesses were assessed by cross-sectional transmission electron microscopy (XTEM), reflection high-energy electron diffraction (RHEED), X-ray diffractometry (XRD), grazing incidence X-ray diffractometry (GIXRD), X-ray reflection (XRR), and Fourier transform infrared spectroscopy (FTIR). The surface roughness of Ag thin films was found to decrease significantly by inserting a Ge nucleation layer with a thickness in the range of 1 to 2 nm (i.e., smoothing mode). However, as the Ge nucleation layer thickness increased beyond 2 nm, the surface roughness increased concomitantly (i.e., roughing mode). For the smoothing mode, the role of the Ge nucleation layer in the Ag film deposition is discussed by invoking the surface energy of Ge, the bond dissociation energy of Ag-Ge, and the deposition mechanisms of Ag thin films on a given characteristic Ge nucleation layer. Additionally, Ge island formation, the precipitation of Ge from Ag-Ge alloys, and the penetration of Ge into SiO2 are suggested for the roughing mode. This demonstration of ultrasmooth Ag thin films would offer an advantageous material platform with scalability for applications such as optics, plasmonics, and photonics. PMID- 26126181 TI - PhenoWorld: a new paradigm to screen rodent behavior. AB - Modeling depression in animals has inherent complexities that are augmented by intrinsic difficulties to measure the characteristic features of the disorder. Herein, we describe the PhenoWorld (PhW), a new setting in which groups of six rats lived in an ethological enriched environment, and have their feeding, locomotor activity, sleeping and social behavior automatically monitored. A battery of emotional and cognitive tests was used to characterize the behavioral phenotype of animals living in the PhW and in standard conditions (in groups of six and two rats), after exposure to an unpredictable chronic mild stress paradigm (uCMS) and antidepressants. Data reveal that animals living in the PhW displayed similar, but more striking, behavioral differences when exposed to uCMS, such as increased behavioral despair shown in the forced swimming test, resting/sleep behavior disturbances and reduced social interactions. Moreover, several PhW-cage behaviors, such as spontaneous will to go for food or exercise in running wheels, proved to be sensitive indicators of depressive-like behavior. In summary, this new ethological enriched paradigm adds significant discriminative power to screen depressive-like behavior, in particularly rodent's hedonic behavior. PMID- 26126183 TI - Safety effects of fixed speed cameras - An empirical Bayes evaluation. AB - The safety effects of 223 fixed speed cameras that were installed between 2000 and 2010 in Norway were investigated in a before-after empirical Bayes study with control for regression to the mean (RTM). Effects of trend, volumes, and speed limit changes are controlled for as well. On road sections between 100m upstream and 1km downstream of the speed cameras a statistically significant reduction of the number of injury crashes by 22% was found. For killed and severely injured (KSI) and on longer road sections none of the results are statistically significant. However, speed cameras that were installed in 2004 or later were found to reduce injury crashes and the number of KSI on road sections from 100m upstream to both 1km and 3km downstream of the speed cameras. Larger effects were found for KSI than for injury crashes and the effects decrease with increasing distance from the speed cameras. At the camera sites (100m up- and down-stream) crash reductions are smaller and non-significant, but highly uncertain and possibly underestimated. PMID- 26126185 TI - cis-1,2-Aminohydroxylation of Alkenes Involving a Catalytic Cycle of Osmium(III) and Osmium(V) Centers: Os(V)(O)(NHTs) Active Oxidant with a Macrocyclic Tetradentate Ligand. AB - Catalytic activity of [Os(III)(OH)(H2O)(L-N4Me2)](PF6)2 (1: L-N4Me2 = N,N' dimethyl-2,11-diaza-[3,3](2,6)pyridinophane) in 1,2-cis-aminohydroxylation of alkenes with sodium N-chloro-4-methylbenzenesulfonamide (chloramine-T) is explored. Simple alkenes as well as those containing several types of substituents are converted to the corresponding 1,2-aminoalcohols in modest to high yields. The aminoalcohol products have exclusively cis conformation with respect to the introduced -OH and -NHTs groups. The spectroscopic measurements including cold mass spectroscopic study of the reaction product of complex 1 and chloromine-T as well as density functional theory (DFT) calculations indicate that an oxido-aminato-osmium(V) species [Os(V)(O)(NHTs)(L-N4Me2)](PF6)2 (2) is an active oxidant for the aminohydroxylation. The DFT calculations further indicate that the reaction involves a [3 + 2] cycloaddition between 2 and alkene, and the regioselectivity in the aminohydroxylation of unsymmetrical alkenes is determined by the orientation that bears less steric hindrance from the tosylamino group, which leads to the energetically more preferred product isomer. PMID- 26126184 TI - Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping. AB - In the Americas, women with Indigenous American ancestry are at increased risk of intrahepatic cholestasis of pregnancy (ICP), relative to women of other ethnicities. We hypothesized that ancestry-related genetic factors contribute to this increased risk. We collected clinical and laboratory data, and performed biochemical assays on samples from U.S. Latinas and Chilean women, with and without ICP. The study sample included 198 women with ICP (90 from California, U.S., and 108 from Chile) and 174 pregnant control women (69 from California, U.S., and 105 from Chile). SNP genotyping was performed using Affymetrix arrays. We compared overall genetic ancestry between cases and controls, and used a genome-wide admixture mapping approach to screen for ICP susceptibility loci. We identified commonalities and differences in features of ICP between the 2 countries and determined that cases had a greater proportion of Indigenous American ancestry than did controls (p = 0.034). We performed admixture mapping, taking country of origin into account, and identified one locus for which Native American ancestry was associated with increased risk of ICP at a genome-wide level of significance (P = 3.1 x 10(-5), Pcorrected = 0.035). This locus has an odds ratio of 4.48 (95% CI: 2.21-9.06) for 2 versus zero Indigenous American chromosomes. This locus lies on chromosome 2, with a 10 Mb 95% confidence interval which does not contain any previously identified hereditary 'cholestasis genes.' Our results indicate that genetic factors contribute to the risk of developing ICP in the Americas, and support the utility of clinical and genetic studies of ethnically mixed populations for increasing our understanding of ICP. PMID- 26126186 TI - Validating Community-Led Forest Biomass Assessments. AB - The lack of capacity to monitor forest carbon stocks in developing countries is undermining global efforts to reduce carbon emissions. Involving local people in monitoring forest carbon stocks could potentially address this capacity gap. This study conducts a complete expert remeasurement of community-led biomass inventories in remote tropical forests of Papua New Guinea. By fully remeasuring and isolating the effects of 4,481 field measurements, we demonstrate that programmes employing local people (non-experts) can produce forest monitoring data as reliable as those produced by scientists (experts). Overall, non-experts reported lower biomass estimates by an average of 9.1%, equivalent to 55.2 fewer tonnes of biomass ha(-1), which could have important financial implications for communities. However, there were no significant differences between forest biomass estimates of expert and non-expert, nor were there significant differences in some of the components used to calculate these estimates, such as tree diameter at breast height (DBH), tree counts and plot surface area, but were significant differences between tree heights. At the landscape level, the greatest biomass discrepancies resulted from height measurements (41%) and, unexpectedly, a few large missing trees contributing to a third of the overall discrepancies. We show that 85% of the biomass discrepancies at the tree level were caused by measurement taken on large trees (DBH >=50 cm), even though they consisted of only 14% of the stems. We demonstrate that programmes that engage local people can provide high-quality forest carbon data that could help overcome barriers to reducing forest carbon emissions in developing countries. Nonetheless, community-based monitoring programmes should prioritise reducing errors in the field that lead to the most important discrepancies, notably; overcoming challenges to accurately measure large trees. PMID- 26126187 TI - N-Phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATP Competitive DNA Gyrase B Inhibitors: Design, Synthesis, and Evaluation. AB - Bacterial DNA gyrase is a well-known and validated target in the design of antibacterial drugs. However, inhibitors of its ATP binding subunit, DNA gyrase B (GyrB), have so far not reached clinical use. In the present study, three different series of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides were designed and prepared as potential DNA gyrase B inhibitors. The IC50 values of compounds on DNA gyrase from Escherichia coli were in the low micromolar range, with the best compound, (4-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzoyl)glycine (18a), displaying an IC50 of 450 nM. For this compound, a high-resolution crystal structure in complex with E. coli DNA gyrase B was obtained, revealing details of its binding mode within the active site. The binding affinities of three compounds with GyrB were additionally evaluated by surface plasmon resonance, and the results were in good agreement with the determined enzymatic activities. For the most promising compounds, the inhibitory activities against DNA gyrase from Staphylococcus aureus and topoisomerases IV from E. coli and S. aureus were determined. Antibacterial activities of the most potent compounds of each series were evaluated against two Gram-positive and two Gram-negative bacterial strains. The results obtained in this study provide valuable information on the binding mode and structure-activity relationship of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides as promising classes of ATP competitive GyrB inhibitors. PMID- 26126188 TI - Roles of functional groups of naproxen in its sorption to kaolinite. AB - The sorption of acidic anti-inflammatory drugs to soils is important for evaluating their fate and transformations in the water-soil environment. However, roles of functional groups of ionisable drugs onto mineral surfaces have not been sufficiently studied. In this study, batch experiments of naproxen (NPX, anti inflammatory drug) and two kinds of competitors to kaolinite were studied. The Kd of naproxen to kaolinite is 1.30-1.62 L kg(-1). The n-pi electron donor-acceptor (n-pi EDA) interaction between diaromatic ring of naproxen (pi-electron acceptors) and the siloxane oxygens (n-donors) of kaolinite is the dominant sorption mechanism. The carboxyl group of naproxen can contribute to the overall sorption. A conception model was put forward to elucidate to sorption mechanisms, in which the contribution of n-pi EDA and hydrogen bond to overall sorption was quantified. These sorption mechanisms can be helpful for estimating the fate and mobility of acid pharmaceuticals in soil-water environment. PMID- 26126189 TI - Natural attenuation of arsenic in the environment by immobilization in nanostructured hematite. AB - Iron (hydr)oxides are known to play a major role in arsenic fixation in the environment. The mechanisms for long-term fixation into their crystal structure, however, remain poorly understood, especially arsenic partitioning behavior during transformation from amorphous to crystalline phases under natural conditions. In this study, these mechanisms are investigated in Fe-Al-oxisols exposed over a period of 10 years to a sulfide concentrate in tailings impoundments. The spatial resolution necessary to investigate the markedly heterogeneous nanoscale phases found in the oxisols was achieved by combining three different, high resolution electron microscopy techniques - Nano-Beam Electron Diffraction (NBD), Electron Energy-Loss Spectroscopy (EELS), and High Resolution Transmission Electron Microscopy (HRTEM). Arsenic (1.6+/-0.5 wt.%) was unambiguously and precisely identified in mesocrystals of Al-hematite with an As/Fe atomic ratio of 0.026+/-0.006. The increase in the c-axis (c=1.379+/-0.009 nm) compared to standard hematite (c=1.372 nm) is consistent with the presence of arsenic in the Al-hematite structure. The As-bearing Al-hematite is interpreted as a secondary phase formed from oxyhydroxides, such as ferrihydrite, during the long-term exposure to the sulfide tailings. The proposed mechanism of arsenic fixation in the Al-hematite structure involves adsorption onto Al-ferrihydrite nanoparticles, followed by Al-ferrihydrite aggregation by self-assembly oriented attachment and coalescence that ultimately produces Al-hematite mesocrystals. Our results illustrate for the first time the process of formation of stable arsenic bearing Al-hematite for the long-term immobilization of arsenic in environmental samples. PMID- 26126190 TI - A qualitative screening and quantitative measurement of organic contaminants on different types of marine plastic debris. AB - Chemical compounds present on plastic were characterised on different types of plastic litter and beached pellets, using a general GC-MS screening method. A variety of plastic related compounds, such as building blocks, antioxidants, additives and degradation products, were identified next to diverse environmental pollutants and biofilm compounds. A validated method for the analysis of PAHs and PCBs on beached pellets at the Belgian Coast, showed concentrations of ? 16 EPA PAHs of 1076-3007 ng g(-1) plastic, while the concentrations of ? 7 OSPAR-PCBs ranged from 31 to 236 ng g(-1) plastic. The wide variety of plastic compounds retrieved in the general screening showed the importance of plastic as a potential source of contaminants and their degradation products. PMID- 26126191 TI - Pathological Methods Applied to the Investigation of Causes of Death in Developing Countries: Minimally Invasive Autopsy Approach. AB - BACKGROUND AND AIMS: Complete diagnostic autopsies (CDA) remain the gold standard in the determination of cause of death (CoD). However, performing CDAs in developing countries is challenging due to limited facilities and human resources, and poor acceptability. We aimed to develop and test a simplified minimally invasive autopsy (MIA) procedure involving organ-directed sampling with microbiology and pathology analyses implementable by trained technicians in low- income settings. METHODS: A standardized scheme for the MIA has been developed and tested in a series of 30 autopsies performed at the Maputo Central Hospital, Mozambique. The procedure involves the collection of 20 mL of blood and cerebrospinal fluid (CSF) and puncture of liver, lungs, heart, spleen, kidneys, bone marrow and brain in all cases plus uterus in women of childbearing age, using biopsy needles. RESULTS: The sampling success ranged from 67% for the kidney to 100% for blood, CSF, lung, liver and brain. The amount of tissue obtained in the procedure varied from less than 10 mm2 for the lung, spleen and kidney, to over 35 mm2 for the liver and brain. A CoD was identified in the histological and/or the microbiological analysis in 83% of the MIAs. CONCLUSIONS: A simplified MIA technique allows obtaining adequate material from body fluids and major organs leading to accurate diagnoses. This procedure could improve the determination of CoD in developing countries. PMID- 26126192 TI - Identification and Differential Expression of a Candidate Sex Pheromone Receptor in Natural Populations of Spodoptera litura. AB - Olfaction is primarily mediated by highly specific olfactory receptors (ORs), a subfamily of which are the pheromone receptors that play a key role in sexual communication and can contribute to reproductive isolation. Here we cloned and identified an olfactory receptor, SlituOR3 (Genbank NO. JN835270), from Spodoptera litura, to be the candidate pheromone receptor. It exhibited male biased expression in the antennae, where they were localized at the base of sensilla trichoidea. Conserved orthologues of these receptors were found amongst known pheromone receptors within the Lepidoptera, and SlituOR3 were placed amongst a clade of candidate pheromone receptors in a phylogeny tree of insect ORs. SlituOR3 is required for the EAG responses to both Z9E11-14:OAc and Z9E12 14:OAc SlituOR3 showed differential expression in S. litura populations attracted to traps baited with a series of sex pheromone blends composed of different ratios of (9Z,11E)-tetradecadienyl acetate (Z9E11-14:OAc) and (9Z,12E) tetradecadienyl acetate (Z9E12-14:OAc). The changes in the expression level of SlitOR3 and antennal responses after SlitOR3 silencing suggested that SlitOR3 is required for the sex pheromone signaling. We infer that variation in transcription levels of olfactory receptors may modulate sex pheromone perception in male moths and could affect both of pest control and monitoring efficiency by pheromone application after long time mass trapping with one particular ratio of blend in the field. PMID- 26126194 TI - T-cell alloreactivity and transplantation outcome: a budding role for heterologous immunity? AB - PURPOSE OF REVIEW: Despite the association between alloreactive T cells and poor graft survival, the mechanisms behind T-cell-mediated rejection are still under investigation. In this review, we will discuss the latest insights into the impact of T-cell alloreactivity on solid organ transplantation and hematopoietic stem cell transplantation (HSCT), with special emphasis on the potential impact of heterologous immunity. RECENT FINDINGS: A large part of the memory T-cell repertoire is induced upon virus infections, and evidence for a role of T-cell receptor cross-reactivity of virus-induced memory T cells against allogeneic human leukocyte antigen (HLA) is accumulating in experimental and clinical solid organ transplantation studies. In HSCT, strong alloreactive potential of naive T cells causes concerns for graft-versus-host disease while additional HLA-DP matching is suggested to prevent CD4 alloreactivity. Furthermore, virus-induced memory T cells hamper mixed chimerism induction, pointing once more towards a role for heterologous immunity. SUMMARY: Both memory and naive T cells contribute to the alloimmune response after transplantation. Monitoring for T-cell phenotypes could help predict rejection episodes and/or graft-versus-host disease, allowing timely intervention. Tailoring donor lymphocyte infusions and additional HLA matching could prevent strong alloreactivity in HSCT. Furthermore, the potential role of heterologous immunity in T-cell alloreactivity and transplantation is gaining interest. PMID- 26126193 TI - New insights into the mechanisms of Treg function. AB - PURPOSE OF REVIEW: CD4Foxp3 regulatory T cells (Tregs) are crucial in controlling immunity and self-tolerance. Consequently, in transplantation, Tregs play a central role in inhibiting acute rejection and promoting allograft tolerance. A more complete understanding of Treg biology may lead to novel therapeutic approaches to enhance Treg numbers and function. RECENT FINDINGS: The maintenance of self-tolerance in nonlymphoid tissues requires the differentiation of Tregs in secondary lymphoid organs from naive-like central Tregs into effector Tregs. Antigen and environmental cues guide this Treg differentiation, which parallels the types of adaptive immune responses taking place, allowing them to enter and function within specific nonlymphoid tissues. In addition to controlling inflammation, tissue-infiltrating Tregs unexpectedly regulate nonimmune processes, including metabolic homeostasis and tissue repair. Finally, Tregs can be directly and specifically targeted in vivo to augment their numbers or enhance their function in both secondary lymphoid organs and nonlymphoid tissues. SUMMARY: Tregs exhibit a previously unrecognized breadth of function, which includes tissue-specific specialization and the regulation of both immune and nonimmune processes. This is of particular importance in transplantation since allo-reactive memory T cells can act directly within the allograft. Thus, therapeutic approaches may need to promote Treg function in transplanted tissue, as well as in secondary lymphoid organs. Such therapy would not only prevent inflammation and acute rejection, but may also promote nonimmune processes within the allograft such as tissue homeostasis and repair. PMID- 26126195 TI - Novel preservation methods to increase the quality of older kidneys. AB - PURPOSE OF REVIEW: The purpose of this review was to summarize the novel developments in preservation of older kidneys. RECENT FINDINGS: The importance of older donors as a source of renal grafts is increasing, with a concomitant increase of posttransplant failure. Preservation of kidneys retrieved from older donors through hypothermic machine perfusion reduces delayed graft function rate and increases long-term graft survival. Assessment of renal function and selection through biomarkers or perfusion criteria to predict posttransplant function are limited. Normothermic perfusion offers the benefit of reperfusion under ideal circumstances, thereby reducing ischemic injury while having the opportunity to test graft viability and preselect kidneys on graft-specific characteristics. Both preservation methods enable active treatment of the isolated graft prior to transplantation, with stem cells or pharmaceuticals. SUMMARY: Older kidneys are more prone to acute kidney injury during ischemic periods combined with an impaired ability to fully recover after transplantation. Novel preservation and resuscitation methods provide the opportunity to select transplantable kidneys better founded or even repair re-existing damage reducing the risk of impaired graft function and improving survival. PMID- 26126196 TI - Molecular aspects of renal senescence. AB - PURPOSE OF REVIEW: The aging kidney undergoes profound changes that lead to a reduction in stress resistance and impaired repair capacity. In order to improve the outcome of acute and chronic kidney damage, it is instrumental to understand the mechanisms that cause these changes. Cellular senescence has emerged as an important cellular process that contributes to age-associated kidney changes and chronic kidney disease progression. RECENT FINDINGS: New mechanistic insights into excessive intracellular glucose, advanced glycation end products and endoplasmatic reticulum stress further support the importance of cellular senescence in the development of diabetic nephropathy. As telomere length of leukocytic DNA is increasingly used as a biomarker to estimate senescence in clinical cohort studies, this review also summarizes the literature on telomere length with respect to the kidney and evaluates the strengths and weaknesses of this methodology. Furthermore, novel findings on the relationships among telomeres, senescence and autophagy are discussed. SUMMARY: Cellular senescence contributes to the decline in renal function during aging and defective regeneration in kidney diseases. Further insight into the underlying molecular mechanisms of senescence will establish a basis for preventive strategies that improve renal stress resistance and regenerative capacity. PMID- 26126197 TI - Optimizing clinical utilization and allocation of older kidneys. AB - PURPOSE OF REVIEW: With a persisting organ shortage and constant high discard rates, there is an urgent need to optimize the outcome and allocation of marginal grafts. RECENT FINDINGS: The Eurotransplant Senior Program was established as an 'old-for-old' allocation system emphasizing on the importance of keeping ischemic times short when utilizing marginal grafts. In addition to refined allocation systems, brief cold ischemic times, novel preservation techniques, a careful assessment of organ quality the utilization of dual kidney transplantation and donation after cardiac death kidneys from elderly donors may all help to increase the supply for renal transplantation. Moreover, age-adapted immunosuppression, improved patient selection and preparation for transplantation may help in improving outcomes when using marginal kidneys. SUMMARY: There is a significant potential to increase the utilization of marginal grafts with reduced discard rates, an increased utilization of dual kidney transplantation and the application of novel preservation methods. PMID- 26126198 TI - Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly. AB - PURPOSE OF REVIEW: This review presents current knowledge of the impact of age on the pharmacokinetics of maintenance immunosuppressants. RECENT FINDINGS: Over the past decade, there has been a steady increase in older patients on organ transplant waiting lists. As a result, the average age of transplant recipients has significantly increased. The survival and quality-of-life benefits of transplantation in the elderly population have been demonstrated. Advancing age is associated with changes in immune responses, as well as changes in drug handling. Immunosenescence is a physiological part of aging and is linked to reduced rejection rates, but also higher rates of diabetes, infections and malignancies. Physiologic changes associated with age can have a significant impact on the pharmacokinetics of the maintenance immunosuppressive agents. Taken together, these age-related changes impact older transplant candidates and may have significant implications for managing immunosuppression in the elderly. SUMMARY: Despite the lack of formal efficacy, safety and pharmacokinetic studies of individual immunosuppressants in the elderly transplant population, there are enough data available for practitioners to be able to adequately manage their older patients. A proficient understanding of the factors that impact the pharmacokinetics of the immunosuppressants in the elderly is essential to managing these patients successfully. PMID- 26126199 TI - Technical and conceptual advances in histocompatibility and immunogenetics inform on mechanisms of transplant rejection and pave the way to development of novel therapies. PMID- 26126201 TI - Interrelation of Hydration, Collagen Cross-Linking Treatment, and Biomechanical Properties of the Cornea. AB - PURPOSE: The present study was designed to investigate the effects of hydration and collagen cross-linking treatment on biomechanical properties of the cornea. METHODS: The original corneal collagen cross-linking protocol was used to induce cross-links in bovine corneas. The thickness of samples was used as a measure of their hydration and five different thickness groups (n = 5 each) were considered. The cross-linked corneal strips were allowed to hydrate/dehydrate until their thickness reached 500, 700, 900, 1100, and 1500 MUm. The tensile behavior of specimens in each thickness group was characterized by conducting uniaxial tensile experiments. The experiments were done in mineral oil in order to keep the thickness of samples constant and minimize hydration changes. RESULTS: It was observed that collagen cross-linking treatment significantly increased both the maximum tensile stress and the equilibrium (relaxed) stress of the bovine cornea (p < 0.01). Furthermore, with increasing the thickness (hydration) of the collagen cross-linked samples, their tensile stiffness significantly decreased (p < 0.01). An exponential relation and a logarithmic expression successfully represented experimentally measured stress-strain behavior and relaxation response of all groups (r(2 )> 0.99), respectively. CONCLUSION: Hydration and collagen cross-linking treatment concomitantly affect biomechanical properties of the cornea. Therefore, an accurate estimate of stiffening effects of collagen cross-linking treatment option using uniaxial tensile experiments is only possible if the hydration of specimens is fully controlled. PMID- 26126200 TI - Etiology of Severe Febrile Illness in Low- and Middle-Income Countries: A Systematic Review. AB - BACKGROUND: With apparent declines in malaria worldwide during the last decade and more widespread use of malaria rapid diagnostic tests, healthcare workers in low-resource areas face a growing proportion of febrile patients without malaria. We sought to describe current knowledge and identify information gaps of the etiology severe febrile illness in low-and middle-income countries. METHODS AND FINDINGS: We conducted a systematic review of studies conducted in low-and-middle income countries 1980-2013 that prospectively assessed consecutive febrile patients admitted to hospital using rigorous laboratory-based case definitions. We found 45 eligible studies describing 54,578 patients; 9,771 (17.9%) had a positive result for >=1 pathogen meeting diagnostic criteria. There were no eligible studies identified from Southern and Middle Africa, Eastern Asia, Oceania, Latin American and Caribbean regions, and the European region. The median (range) number of diagnostic tests meeting our confirmed laboratory case definitions was 2 (1 to 11) per study. Of diagnostic tests, 5,052 (10.3%) of 49,143 had confirmed bacterial or fungal bloodstream infection; 709 (3.8%) of 18,142 had bacterial zoonosis; 3,488 (28.5%) of 12,245 had malaria; and 1,804 (17.4%) of 10,389 had a viral infection. CONCLUSIONS: We demonstrate a wide range of pathogens associated with severe febrile illness and highlight the substantial information gaps regarding the geographic distribution and role of common pathogens. High quality severe febrile illness etiology research that is comprehensive with respect to pathogens and geographically representative is needed. PMID- 26126202 TI - Generation of Viable Plant-Vertebrate Chimeras. AB - The extreme dependence on external oxygen supply observed in animals causes major clinical problems and several diseases are related to low oxygen tension in tissues. The vast majority of the animals do not produce oxygen but a few exceptions have shown that photosynthetic capacity is physiologically compatible with animal life. Such symbiotic photosynthetic relationships are restricted to a few aquatic invertebrates. In this work we aimed to explore if we could create a chimerical organism by incorporating photosynthetic eukaryotic cells into a vertebrate animal model. Here, the microalgae Chlamydomonas reinhardtii was injected into zebrafish eggs and the interaction and viability of both organisms were studied. Results show that microalgae were distributed into different tissues, forming a fish-alga chimera organism for a prolonged period of time. In addition, microscopic observation of injected algae, in vivo expression of their mRNA and re-growth of the algae ex vivo suggests that they survived to the developmental process, living for several days after injection. Moreover microalgae did not trigger a significant inflammatory response in the fish. This work provides additional evidence to support the possibility that photosynthetic vertebrates can be engineered. PMID- 26126204 TI - Apparent Mineralocorticoid Excess by a Novel Mutation and Epigenetic Modulation by HSD11B2 Promoter Methylation. AB - CONTEXT: Apparent mineralocorticoid excess (AME) is a rare autosomal recessive disease resulting from mutations within the hydroxysteroid (11beta-dehydrogenase2 [HSD11B2]) gene causing a prominent mineralocorticoid receptor activation by cortisol and hypokalemic low renin hypertension as the main clinical feature. OBJECTIVE: The objective of the study was to characterize AME for possible novel HSD11B2 mutations and to define the role of HSD11B2 promoter methylation in the phenotypic expression of the disease. SUBJECTS: Two proband brothers and 10 relatives participated in the study. METHODS: Peripheral blood mononuclear cell DNA was used for HSD11B2 exon sequencing, and a new predicted structure of 11beta hydroxysteroid dehydrogenase type 2 was generated by an in silico three dimensional modeling. Promoter methylation was determined by bisulfite pyrosequencing. Urinary tetrahydrocortisol plus allotetrahydrocortisol to tetrahydrocortisone ratio, a surrogate marker of 11beta-hydroxysteroid dehydrogenase type 2 activity, was measured by gas chromatography-mass spectrometry. RESULTS: A novel homozygous variant at HSD11B2 exon 3 site (c.C662G) resulting in an alanine-to-glycine change at position 221 was discovered by sequencing the DNA of the probands. A monoallelic mutation was found in the DNA of the parents and other four relatives. In silico three dimensional modeling showed that the Ala221Gly substitution could perturb a hydrophobic interaction by reducing the enzymatic affinity for the substrate. The HSD11B2 promoter methylation of normotensive heterozygous relatives was similar to that of wild types, whereas the hypertensive heterozygous subjects showed higher methylation than wild types, consistently with a transcriptional repressive effect of promoter hypermethylation. CONCLUSIONS: A novel HSD11B2 functional mutation accounting for an Ala221Gly substitution causes AME. The hypertension phenotype is also epigenetically modulated by HSD11B2 methylation in subjects heterozygous for the mutation. PMID- 26126203 TI - Speech-Language Dissociations, Distractibility, and Childhood Stuttering. AB - PURPOSE: This study investigated the relation among speech-language dissociations, attentional distractibility, and childhood stuttering. METHOD: Participants were 82 preschool-age children who stutter (CWS) and 120 who do not stutter (CWNS). Correlation-based statistics (Bates, Appelbaum, Salcedo, Saygin, & Pizzamiglio, 2003) identified dissociations across 5 norm-based speech-language subtests. The Behavioral Style Questionnaire Distractibility subscale measured attentional distractibility. Analyses addressed (a) between-groups differences in the number of children exhibiting speech-language dissociations; (b) between groups distractibility differences; (c) the relation between distractibility and speech-language dissociations; and (d) whether interactions between distractibility and dissociations predicted the frequency of total, stuttered, and nonstuttered disfluencies. RESULTS: More preschool-age CWS exhibited speech language dissociations compared with CWNS, and more boys exhibited dissociations compared with girls. In addition, male CWS were less distractible than female CWS and female CWNS. For CWS, but not CWNS, less distractibility (i.e., greater attention) was associated with more speech-language dissociations. Last, interactions between distractibility and dissociations did not predict speech disfluencies in CWS or CWNS. CONCLUSIONS: The present findings suggest that for preschool-age CWS, attentional processes are associated with speech-language dissociations. Future investigations are warranted to better understand the directionality of effect of this association (e.g., inefficient attentional processes -> speech-language dissociations vs. inefficient attentional processes <- speech-language dissociations). PMID- 26126205 TI - Long-Term Natural Course of Pituitary Tumors in Patients With MEN1: Results From the DutchMEN1 Study Group (DMSG). AB - CONTEXT: Guidelines advise lifelong radiological followup for asymptomatic pituitary adenomas (PITs) because of the risk for growth and subsequent visual field defects. In the context of multiple endocrine neoplasia type 1 (MEN1) an even more comprehensive screening is advised because PITs are presumed to manifest more aggressive behavior. We studied the long-term course of MEN1 related PITs, which may be used as a model for sporadically occurring PITs. OBJECTIVE: The aim of our study is to assess the results of systematic pre symptomatic PIT screening and subsequent long-term followup of PITs with emphasis on nonfunctioning microadenomas diagnosed by screening. PATIENTS AND METHODS: A cohort study was performed using the Dutch national MEN1 database, including greater than 90% of the Dutch MEN1 population older than 16 years (n = 323). MAIN OUTCOME MEASURES: Screening results, natural course, and effects of treatment of PIT were assessed. RESULTS: PIT was diagnosed in 123 patients with MEN1 (38.1 %), of whom 66 were diagnosed by MEN1-related screening. Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas (n = 52) responded well to treatment with dopamine agonists. CONCLUSION: Systematic presymptomatic screening for PIT in patients with MEN1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable. PMID- 26126206 TI - New Nordic Diet-Induced Weight Loss Is Accompanied by Changes in Metabolism and AMPK Signaling in Adipose Tissue. AB - CONTEXT: The molecular mechanisms behind diet-induced metabolic improvements remain to be studied. OBJECTIVE: This study sought to investigate whether expression of proteins in skeletal muscle or adipose tissue could explain improvements in glucose and lipid homeostasis after weight loss. DESIGN: Volunteers consumed a New Nordic Diet (NND) or an Average Danish Diet for 26 weeks in a controlled, free-living setting. SUBJECTS: Sixty four moderately obese women and men (44 +/- 2 y; body mass index, 31 +/- 1 kg/m(2)). INTERVENTION: Fasting blood samples and biopsies from the vastus lateralis muscle and subcutaneous abdominal adipose tissue (SCAT) were obtained at week 0 and 26. OUTCOME: Gene and protein expressions were analyzed by real-time PCR and Western blotting. RESULTS: Improved homeostasis homeostatic model of assessment-insulin resistance index and lowered plasma triacylglycerol concentration after NND coincided with molecular adaptations in SCAT but not in skeletal muscle. NND induced greater reduction in fat mass than ADD (-6 +/- 1 kg and -2 +/- 1 kg; P < .01). In SCAT this was associated with increased AMPK and acetyl-CoA carboxylase phosphorylation (P < .05). Concomitantly, NND induced up-regulation of Akt2 and Akt substrate of 160 kDa (P < .05) as well as fatty acid transport protein 4 and membrane associated fatty acid binding protein (P < .05). Indices of increased oxidative capacity were observed, as carnitine palmitoyl transferase 1 mRNA (P = .08) as well as citrate synthase (P = .1) and cytochrome c (P = .05) protein tended to increase. CONCLUSION: NND-induced metabolic improvements were accompanied by increased AMPK signaling in SCAT, suggesting a role of AMPK in these adaptations. The concomitant up-regulation of key glucose and lipid handling proteins suggests an improved metabolic capacity in adipose tissue after weight loss. PMID- 26126207 TI - Increased Cardiovascular and Metabolic Morbidity in Patients With 21-Hydroxylase Deficiency: A Swedish Population-Based National Cohort Study. AB - CONTEXT: Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. OBJECTIVE: This study aimed to study cardiovascular and metabolic morbidity in CAH. DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity. MAIN OUTCOME MEASURES: To study cardiovascular and metabolic morbidity in CAH. RESULTS: In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype. CONCLUSIONS: CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important. PMID- 26126208 TI - Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women. AB - CONTEXT: Serum estradiol (E2) levels are preserved in older reproductive-aged women with regular menstrual cycles despite declining ovarian function. OBJECTIVE: The objective of the study was to determine whether increased granulosa cell aromatase expression and activity account for preservation of E2 levels in older, regularly cycling women. DESIGN: The protocol included daily blood sampling and dominant follicle aspirations at an academic medical center during a natural menstrual cycle. SUBJECTS: Healthy, regularly cycling older (36 45 y; n = 13) and younger (22-34 y; n = 14) women participated in the study. MAIN OUTCOME MEASURES: Hormone levels were measured in peripheral blood and follicular fluid aspirates and granulosa cell CYP19A1 (aromatase) and FSH-R mRNA expression were determined. RESULTS: Older women had higher FSH levels than younger women during the early follicular phase with similar E2 but lower inhibin B and antimullerian hormone levels. Late follicular phase serum E2 did not differ between the two groups. Follicular fluid E2 [older (O) = 960.0 [interquartile range (IQR) 765.0-1419.0]; younger (Y) = 994.5 [647.3-1426.5] ng/mL, P = 1.0], estrone (O = 39.6 [29.5-54.1]; Y = 28.8 [22.5-42.1] ng/mL, P = 0.3), and the E2 to testosterone (T) ratio (O = 109.0 +/- 41.9; Y = 83.0 +/- 18.6, P = .50) were preserved in older women. Granulosa cell CYP19A1 expression was increased 3-fold in older compared with younger women (P < .001), with no difference in FSH-R expression. CONCLUSIONS: Ovarian aromatase expression increases with age in regularly cycling women. Thus, up-regulation of aromatase activity appears to compensate for the known age-related decrease in granulosa cell number in the dominant follicle to maintain ovarian estrogen production in older premenopausal women. PMID- 26126209 TI - Human Preferences for Conformation Attributes and Head-And-Neck Positions in Horses. AB - Human preferences for certain morphological attributes among domestic animals may be entirely individual or, more generally, may reflect evolutionary pressures that favor certain conformation. Artificial selection for attributes, such as short heads and crested necks of horses, may have functional and welfare implications because there is evidence from other species that skull shape co varies with behaviour. Crested necks can be accentuated by flexion of the neck, a quality that is often manipulated in photographs vendors use when selling horses. Equine head-and-neck positions acquired through rein tension can compromise welfare. Our investigation was designed to identify conformations and postures that people are attracted to when choosing their 'ideal' horse. Participants of an internet survey were asked to rate their preference for horse silhouettes that illustrated three gradations of five variables: facial shape, crest height, ear length, ear position and head-and-neck carriage. There were 1,234 usable responses. The results show that overall preferences are for the intermediate, rather than extreme, morphological choices (p=<0.001). They also indicate that males are 2.5 times less likely to prefer thicker necks rather than the intermediate shape, and 4 times more likely to prefer the thinner neck shape. When compared to the novice participants, experienced participants were 1.9 times more likely to prefer a thicker neck shape than the intermediate neck shape and 2.8 times less likely to prefer a thinner neck shape than the intermediate neck shape. There was overall preference of 93% (n=939) for the category of head carriage 'In front of the vertical'. However, novice participants were 1.8 times more likely to choose 'behind the vertical' than 'in front of the vertical'. Our results suggest that people prefer a natural head carriage, concave facial profile (dished face), larger ears and thicker necks. From these survey data, it seems that some innate preferences may run counter to horse health and welfare. PMID- 26126210 TI - Small-Anion Selective Transmembrane "Holes" Induced by an Antimicrobial Peptide Too Short to Span Membranes. AB - Whereas many membrane-destabilization modes have been suggested for membrane spanning antimicrobial peptides (AMPs), few are available for those too short to span membrane thickness. Here we show that ORB-1, a 15-residue disulfide-bridged AMP that is only ~20 A long even when fully stretched like a hairpin, may act by inducing small anion-selective transmembrane "holes" of negative mean curvature. In model membranes of Gram-negative bacteria, ORB-1 induces chloride transmembrane transport and formation of transmembrane channels of negative mean curvature, whereas the inactive analogue, ORB-N, does not, suggesting a correlation between antibacterial activity and ability to induce transmembrane channels. Given that ORB-N is the C-terminus amidated form of ORB-1, our results further suggest that formation of membrane-spanning dimers may be required to initiate the observed channel induction. Moreover, ORB-1 renders model bacterial membranes permeable to anions with effective hydration diameters of <1 nm (e.g., Cl(-) and NO3(-)), but not cations of similar sizes (e.g., H3O(+)), indicative of anion-selective transmembrane channels with an effective inner diameter of <=1 nm. In addition, negative-intrinsic-curvature (NIC) lipids such as phosphoethanolamine (PE) may facilitate the membrane-destabilization process of ORB-1. Our findings may expand current understandings on how AMPs destabilize membranes and facilitate the pharmaceutical development of ORB-1. PMID- 26126211 TI - Using Inverse Probability Bootstrap Sampling to Eliminate Sample Induced Bias in Model Based Analysis of Unequal Probability Samples. AB - In ecology, as in other research fields, efficient sampling for population estimation often drives sample designs toward unequal probability sampling, such as in stratified sampling. Design based statistical analysis tools are appropriate for seamless integration of sample design into the statistical analysis. However, it is also common and necessary, after a sampling design has been implemented, to use datasets to address questions that, in many cases, were not considered during the sampling design phase. Questions may arise requiring the use of model based statistical tools such as multiple regression, quantile regression, or regression tree analysis. However, such model based tools may require, for ensuring unbiased estimation, data from simple random samples, which can be problematic when analyzing data from unequal probability designs. Despite numerous method specific tools available to properly account for sampling design, too often in the analysis of ecological data, sample design is ignored and consequences are not properly considered. We demonstrate here that violation of this assumption can lead to biased parameter estimates in ecological research. In addition, to the set of tools available for researchers to properly account for sampling design in model based analysis, we introduce inverse probability bootstrapping (IPB). Inverse probability bootstrapping is an easily implemented method for obtaining equal probability re-samples from a probability sample, from which unbiased model based estimates can be made. We demonstrate the potential for bias in model-based analyses that ignore sample inclusion probabilities, and the effectiveness of IPB sampling in eliminating this bias, using both simulated and actual ecological data. For illustration, we considered three model based analysis tools--linear regression, quantile regression, and boosted regression tree analysis. In all models, using both simulated and actual ecological data, we found inferences to be biased, sometimes severely, when sample inclusion probabilities were ignored, while IPB sampling effectively produced unbiased parameter estimates. PMID- 26126212 TI - NO CLEAR LINK BETWEEN G LOADINGS AND HERITABILITY: A TWIN STUDY FROM KOREA. AB - A fundamental theoretical question in intelligence research is to what extent the g factor and heritability coefficients of the subtests of an IQ battery are correlated. Five studies from Western countries showed modest to strong positive correlations (range = .43-.77), and six studies from a Japanese meta-analysis showed zero to modest correlations (range = -0.01-0.59). The Western and Japanese studies were compared with a Korean sample of 24 monozygotic and 20 dizygotic young adult twin pairs administered the Korean Wechsler Adult Intelligence Scale Revised (WAIS-R). A univariate twin model was applied to all subscale scores leading to estimates of heritability for all scales. g loadings were also computed using principal-axis factor analysis. Finally, the correlation between the heritabilities and the g loadings of these scales were computed. The correlations of r = -.15 were not in line with previous studies. It could be that Spearman's hypothesis is less strongly confirmed for Northeast Asians, but it is also possible that the study will be an outlier in a future meta-analysis. More primary research and a meta-analysis of all studies are needed. PMID- 26126214 TI - Preface. Nasal Trauma. PMID- 26126213 TI - 1/f Noise Scaling Analysis in Unipolar-Type Organic Nanocomposite Resistive Memory. AB - We studied noise characteristics of a nanocomposite of polyimide (PI) and phenyl C61-butyric acid methyl ester (PCBM) (denoted as PI:PCBM), a composite for the organic nonvolatile resistive memory material. The current fluctuations were investigated over a bias range that covers various intermediate resistive states and negative differential resistance (NDR) in organic nanocomposite unipolar resistive memory devices. From the analysis of the 1/f(gamma) type noises, scaling behavior between the relative noise power spectral density S and resistance R was observed, indicating a percolating behavior. Considering a linear rate equation of the charge trapping-detrapping at traps, the percolation behavior and NDR could be understood by the modulation of the conductive phase fraction phi with an external bias. This study can enhance the understanding of the NDR phenomena in organic nanocomposite unipolar resistive memory devices in terms of the current path formation and the memory switching. PMID- 26126215 TI - An Algorithm for the Initial Management of Nasal Trauma. AB - Nasal fractures are the most common of all facial skeletal injuries. Untreated, these fractures frequently lead to functional and aesthetic problems. Careful history and physical assessment are critical to determine the extent of injury and to determine proper management. Critical aspects of assessment are discussed, as is the role of imaging in management. The unique aspects of pediatric nasal fractures and their management are reviewed. Fractures are classified based on the degree of injury and the involvement of the septum. A simple treatment algorithm is provided to help guide the selection of optimal treatment techniques. A review of instrumentation and treatment techniques is provided. The goal of treatment is to restore the nose to its preinjury shape and function and to minimize the need for secondary septorhinoplasty. PMID- 26126216 TI - Management of Nasal and Perinasal Soft Tissue Injuries. AB - The prominence of the nose renders it susceptible to soft tissue trauma of multiple etiologies. In this review, we present a framework for evaluation and treatment of nasal soft tissue injuries. Initial evaluation of nasal soft tissue injuries should include a complete trauma assessment, history, and physical examination. Mechanisms described include lacerations, abrasions, bites, and thermal injuries. Finally, we discuss wound care and surgical treatment options, including local flap and free tissue transfer. Though timing of repair remains somewhat controversial, most sources indicate that immediate reconstruction should be undertaken when possible. PMID- 26126217 TI - Complex Nasal Fractures in the Adult-A Changing Management Philosophy. AB - Acute management of complex nasal fractures in the adult nose is still frequently conducted using closed reduction techniques as first-line therapy. Treatment outcomes from closed reduction are often disappointing and secondary surgical corrections are required in a sizeable subset of patients. In response to the shortcomings of closed fracture manipulation, classic rhinoplasty techniques have been introduced to improve anatomic fracture reduction. Although these techniques improve the accuracy of skeletal reduction, they also weaken the nose, leaving it susceptible to the deformational forces of healing. To provide optimal anatomic fracture reduction and concomitant stabilization of the skeletal framework, we have been using contemporary strategies derived from open structure rhinoplasty and extracorporeal septal reconstruction for initial fracture treatment. Using wide-field exposure with open rhinoplasty, these strategies provide optimal fracture reduction and rigid stabilization of the septal L-strut using suture based fixation and structural grafting techniques. The result is unsurpassed contour restoration and lasting architectural stability of the nose. When combined with power-driven instruments to cut, shape, mobilize, and create osseous suture holes, open structure stabilization of the disrupted skeletal framework establishes a new benchmark in acute fracture management. PMID- 26126218 TI - Management of the Deviated Nasal Dorsum. AB - The deviated nasal dorsum veers off the ideal straight vertical orientation at midline. Deviations in the dorsum lead to functional and aesthetic consequences that frequently prompt the patient to seek consultation with a rhinoplasty surgeon. Inability to breathe through the nose and self-image perception significantly detracts from the patient's quality of life. Correction of the deviated nasal dorsum represents a challenge for the rhinoplasty surgeon. Anatomic correction of deviations is the goal. Straightening a deviated nasal dorsum will require maneuvers to realign the nose distinct from traditional aesthetic rhinoplasty techniques. The nasal dorsum is formed by the three dimensional structures of the septum, the bony nasal pyramid, and the cartilaginous nasal midvault. Restoring the position of the septum at midline is the first step in providing adequate support to the nasal architecture. Extracorporeal septoplasty and anterior septal transplant are often necessary techniques to correct the septum and achieve dorsal correction. Subsequently, asymmetric maneuvers to bony dorsum and midvault are performed to restore symmetry. Asymmetric hump reduction and nasal osteotomies are often necessary. Supporting the midvault to avoid nasal collapse often requires asymmetric maneuvers to the upper lateral cartilages and asymmetric spreader grafts. Finally, camouflaging grafts to the nasal dorsum may be necessary. Significant rigidity and memory of the native tissues must be overcome to successfully straighten a nose. The surgeon who can master the deviated dorsum will significantly improve the appearance and quality of life of the patients he or she treats. PMID- 26126219 TI - Autologous Rib Grafts in the Management of the Crooked Nose. AB - Rhinoplasty is arguably one of the most challenging procedures a facial plastic surgeon performs. Numerous techniques have been developed since the inception of rhinoplasty to aid in correction of aesthetic and functional issues. Congenital, iatrogenic, and traumatic etiologies can all lead to a crooked nose. Autologous rib or costal cartilage grafting is a powerful tool that can aid the surgeon in successful correction of the crooked nose. PMID- 26126220 TI - Essential Grafting in the Traumatized Nose. AB - Corrective rhinoplasty after significant nasal trauma is a much different entity than elective rhinoplasty or rhinoplasty after minor trauma. The more significant the degree of trauma the patient is subjected to, the greater the deleterious effects will be on the soft tissue and skeletal elements of the patient's nose. With this disruption of the anatomic integrity and dynamics of the nose, the patient experiences deformity and dysfunction of the nose. This may be minor and transient or may be lifelong and disabling. In this article, the authors review some of the more long-term aspects of nasal trauma and provide the reader with insights to the use of cartilage grafting techniques that are useful in the management of posttraumatic nasal deformity and airway obstruction. PMID- 26126221 TI - The Role of Transverse Osteotomies in Severe Nasal Trauma. AB - Facial trauma commonly produces trauma to the nose and perinasal area. In this review, emphasis is on the treatment of the severely deviated nose in terms of excessive shift of the bony dorsum and bony pyramid. In particular, we focus on the problem of centering the severely deviated bony dorsum and when we believe it is helpful to move the entire bony dorsum as a unit, utilizing the transverse osteotomy in addition to traditional osteotomies. PMID- 26126222 TI - Posttraumatic Nasal Deformities: Correcting the Crooked and Saddle Nose. AB - The nose is frequently traumatized in facial injuries and this often results from motor vehicle accidents, sports-related injuries, and altercations. Subsequently, posttraumatic nasal deformity is one of the most common reasons that patients seek consultation in the doctor's office. Depending on the type of nasal deformities, this can result in functional impairment and aesthetic problems. Two challenging problems to be addressed in the posttraumatic nose include the crooked nose deformity and the saddle nose deformity. The numerous publications on these two topics attest to the exacting surgical expertise required in its treatment. The key features in management of these conditions are discussed further. PMID- 26126223 TI - Cosmetic Concerns Related to the Posttraumatic Nose without Nasal Obstruction. AB - Because of its prominent position on the facial skeleton, the nose is commonly injured. Though significant trauma can result in nasal obstruction, there is also considerable concern for potential cosmetic deformity. Repairing traumatic deformities is complex and can involve all aspects of the nose, including the bony and cartilaginous framework as well as the soft tissue envelope. Trauma can result in deflection, asymmetry, and deformity of the bony nasal dorsum, midvault, and nasal tip. Any serious nasal trauma places patients at risk for complications that may include nasal septal hematoma, septal perforation, and possible cerebral spinal fluid leak. Unrecognized or untreated septal hematomas can result in cartilaginous septal necrosis followed by saddle nose deformity. Though damage to structural scaffolding is often the cause of cosmetic deformity following nasal trauma, the nasal soft tissue envelope is also commonly affected. This can result in lacerations, avulsions, and traumatic tattooing. The following will discuss the evaluation, diagnosis, and management of these cosmetic concerns relating to nasal trauma. PMID- 26126224 TI - Management of Posttraumatic Pseudotelecanthus. AB - Injuries to the nose and perinasal region are common. Though the nasal fractures are commonly recognized and properly addressed, injuries to adjacent structures such as the orbit, medial canthus, and midface skeleton can be missed or misdiagnosed leading to improper primary treatment and subsequent secondary deformities. In this discussion, we focus on secondary deformities of the medial canthal region injuries that result from inadequate primary repair of the displaced medial canthal tendon apparatus in naso-orbital-ethmoid fractures. Emphasis is placed on the difference in complexity of the secondary pseudotelecanthus deformity relative to primary fracture treatment. Case examples are used to discuss the complexity of the correction of such deformities. PMID- 26126225 TI - Dorsal Augmentation in Rhinoplasty: A Survey and Review. AB - Understanding the nuanced practices and grafting options of dorsal augmentation will improve outcomes and results in rhinoplasty. To better understand the practices of dorsal augmentation among our colleagues. To review the current literature regarding the indications, safety profiles, and outcomes of different materials used in dorsal augmentation. A PubMed search was performed to capture current articles containing reviews or large series regarding the safety and efficacy of various grafting materials used for dorsal augmentation. Of the many options available, autologous cartilage grafts maintain widespread use for dorsal augmentation and other techniques in rhinoplasty. Homologous cartilage grafts, namely irradiated rib, are a preferred alternative. Irradiated costal cartilage has been shown to have low complication rates and is unique in its abundance of supply, particularly in the revision rhinoplasty. Alloplastic implants, particularly silicone, are prevalent in Asian countries where they are a popular first-line choice. ePTFE has a favorable complication profile in primary rhinoplasty; however, caution is recommended when using ePTFE in revision cases. Porous polyethylene has a higher risk of associated complications than the other alloplastic implants listed, and therefore should be considered thoughtfully. Although cartilage is often the preferred graft for dorsal augmentation, there are many other autogenous, homologous, and alloplastic materials that have been shown to be safe and effective choices when applied in the proper setting. PMID- 26126226 TI - Handheld-Level Electromechanical Cartilage Reshaping Device. AB - We have developed a handheld-level multichannel electromechanical reshaping (EMR) cartilage device and evaluated the feasibility of providing a means of cartilage reshaping in a clinical outpatient setting. The effect of EMR on pig costal cartilage was evaluated in terms of shape change, tissue heat generation, and cell viability. The pig costal cartilage specimens (23 mm * 6.0 mm * 0.7 mm) were mechanically deformed to 90 degrees and fixed to a plastic jig and applied 5, 6, 7, and 8 V up to 8 minutes to find the optimal dosimetry for the our developed EMR device. The results reveal that bend angle increased with increasing voltage and application time. The maximum bend angle obtained was 70.5 +/- 7.3 at 8 V, 5 minutes. The temperature of flat pig costal cartilage specimens were measured, while a constant electric voltage was applied to three pairs of electrodes that were inserted into the cartilages. The nonthermal feature of EMR was validated by a thermal infrared camera; that is, the maximum temperate of the flat cartilages is 20.3 degrees C at 8 V. Cell viability assay showed no significant difference in cell damaged area from 3 to 7 minutes exposure with 7 V. In conclusion, the multichannel EMR device that was developed showed a good feasibility of cartilage shaping with minimal temperature change. PMID- 26126227 TI - Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates. AB - Injection rhinoplasty offers an attractive, reversible alternative to surgery. Here we assessed outcome, longevity of benefits, adverse effects, and patient assessment of injection rhinoplasty, using degradable synthetic fillers. Forty six patients who underwent injection rhinoplasty using degradable fillers over the past 3 years were assessed (calcium hydroxyapatite: 26 patients, hyaluronic acid: 20 patients). Comparison of pre- and postoperative images indicated realistically achievable treatment results. Patient satisfaction was assessed using a 5-point questionnaire at 3 weeks and 9 months posttreatment. Forty-six patients (88 areas) were treated. At 3 weeks posttreatment, 85% of patients were satisfied with treatment results. At 9 months or later posttreatment, 87% of patients were very/completely satisfied with treatment results, regardless of filler used. Treatment longevity varied between 6 and 30 months (mean: 13.5 months). Positive evaluation was mainly due to accurate prediction of achievable results to meet patient expectations. There were one moderate and two severe complications, all following calcium hydroxyapatite treatment. Two resolved completely following treatment and one patient was lost to follow-up. This resulted in subsequent exclusive use of hyaluronic acid filler. Injectable biodegradable fillers are effective for correction of minor nasal deformities or irregularities. Attention must be given to injection technique and adverse effect management. PMID- 26126228 TI - Safety Approach to Otoplasty: A Surgical Algorithm. AB - An algorithm was developed through an evolution of refinements in surgical technique with the goal to minimize risk and morbidity in otoplasty. Key principles were avoidance of cartilage incisions and transections and the use of multiple surgical techniques to distribute the "surgical load" evenly among these techniques. The present retrospective study was designed to test safety and efficacy of the concept in 100 consecutive patients and to discuss the results in light of the literature. Data detailing the surgery, preoperative, and postoperative period were extracted from the record and during patient interviews. Patients were contacted to complete a questionnaire to rate the postoperative pain and their satisfaction with the final outcome on a 6-point visual analog scale (VAS). An expert and a lay panel assessed preoperative and postoperative frontal-view photographs, using the same VAS. Pain in the postoperative was rated as minor (pain level VAS average score, 2.33) and patients' satisfaction was excellent (satisfaction level VAS average score, 1.82). The assessment by the panels of expert and lay evaluators paralleled these outcomes with a postoperative average VAS score of 1.69 and 1.87, respectively. Cartilage incision and transection can be effectively avoided in otoplasty. Even distribution of the surgical load among multiple techniques avoids the problems associated with "overload" of a single technique. The innovative technique of cortical mastoid drill-out is described. High satisfaction with the results, excellent patient comfort, and a favorable safety profile are associated with the present algorithm. PMID- 26126229 TI - The Changes in Histopathology and Mass in Hyperbaric Oxygen-Treated Auricular Cartilage Grafts in a Rabbit Model. PMID- 26126230 TI - Chronic exposure to environmentally-relevant concentrations of fluoxetine (Prozac) decreases survival, increases abnormal behaviors, and delays predator escape responses in guppies. AB - This study evaluates the impact of fluoxetine, an antidepressant drug and common pollutant in aquatic environments, on growth, survival, and behavior in juvenile guppies and on predator escape responses in adult guppies (Poecilia reticulata). In juveniles, the effects of acute (4d) and chronic (35d) exposure on growth and survival were examined, and behavioral changes were noted throughout the chronic experiment. In adults, escape responses to a mock predator during chronic (28d) fluoxetine exposure were videotaped to determine the overall speed of response in treated vs. control fish. The effects of fish gender and the presence of a group/school on escape responses were also determined. Our results show that acute exposure to nominal concentrations of 0.03 and 0.5MUg/L, levels within the environment, did not adversely impact juvenile guppy survival. However, chronic exposure significantly reduced weight, length, and belly width/girth measurements compared to controls. Chronic exposure also resulted in abnormal swimming behavior and reduced survival in juveniles. In adults, fluoxetine exposure significantly delayed predator escape responses in both males and females. Escape responses were also reduced when adults were tested either individually or in a group, with significantly more delayed responses seen in individually tested fish. Taken together, these findings suggest that fluoxetine can impact guppy populations, during both juvenile and adult stages, with chronic exposure resulting in decreased survival and growth and altered behavioral responses. PMID- 26126231 TI - Living organisms influence on environmental conditions: pH modulation by amphibian embryos versus aluminum toxicity. AB - The LC10, 50 and 90/24h of aluminum for Rhinella arenarum embryos at complete operculum stage were 0.55, 0.75 and 1mgAl(3+)/L respectively. Those values did not change significantly by expanding the exposure period till 168h. The aluminum toxicity was evaluated in different pH conditions by means of a citrate buffer resulting for instance, 1mgAl(3+)/L at pH 4, 4.1, 5 and 6 in 100%, 70%, 35% and 0% of lethality respectively. As an outstanding feature, the embryos changed the pH of the maintaining media both in the case of Al(3+) or citrate buffer treatments toward neutral. 10 embryos in 40mL of AMPHITOX solution were able to increase the pH from 4.2 to 7.05, a fact related with a metabolic shift resulting in an increase in nitrogen loss as ammonia. Our study point out the natural selection of the most resistant amphibian embryos both for pH or aluminum as well as the capacity of living organisms (as a population) to alter their chemical environment toward optimal conditions for their survival. As these facts occur at early life stages, it expand the concept that living organisms at ontogenic stages are biomarker of environmental signatures of the evolutionary process (Herkovits, 2006) to a global Onto-Evo concept which imply also the feedback mechanisms from living organisms to shape environmental conditions in a way that benefits them. PMID- 26126232 TI - Creating a Stable Oxide at the Surface of Black Phosphorus. AB - The stability of the surface of in situ cleaved black phosphorus crystals upon exposure to atmosphere is investigated with synchrotron-based photoelectron spectroscopy. After 2 days atmosphere exposure a stable subnanometer layer of primarily P2O5 forms at the surface. The work function increases by 0.1 eV from 3.9 eV for as-cleaved black phosphorus to 4.0 eV after formation of the 0.4 nm thick oxide, with phosphorus core levels shifting by <0.1 eV. The results indicate minimal charge transfer, suggesting that the oxide layer is suitable for passivation or as an interface layer for further dielectric deposition. PMID- 26126233 TI - Posttraumatic Psychological Symptoms are Associated with Reduced Inhibitory Control, not General Executive Dysfunction. AB - Although there is mounting evidence that greater PTSD symptoms are associated with reduced executive functioning, it is not fully understood whether this association is more global or specific to certain executive function subdomains, such as inhibitory control. We investigated the generality of the association between PTSD symptoms and executive function by administering a broad battery of sensitive executive functioning tasks to a cohort of returning Operation Enduring Freedom/Operation Iraqi Freedom Veterans with varying PTSD symptoms. Only tasks related to inhibitory control explained significant variance in PTSD symptoms as well as symptoms of depression, while measures of working memory, measures of switching, and measures simultaneously assessing multiple executive function subdomains did not. Notably, the two inhibitory control measures that showed the highest correlation with PTSD and depressive symptoms, measures of response inhibition and distractor suppression, explained independent variance. These findings suggest that greater posttraumatic psychological symptoms are not associated with a general decline in executive functioning but rather are more specifically related to stopping automatic responses and resisting internal and external distractions. PMID- 26126236 TI - Survey of Speech-Language Pathology Graduate Program Training in Outer and Middle Ear Screening. AB - PURPOSE: The purpose of this study was to determine the national training practices of speech-language pathology graduate programs in outer and middle ear screening. METHOD: Directors of all American Speech-Language-Hearing Association accredited speech-language pathology graduate programs (N = 254; Council on Academic Accreditation in Audiology and Speech-Language Pathology, 2013) were surveyed on instructional formats in outer and middle ear screening. RESULTS: The graduate speech-language pathology program survey yielded 84 (33.1%) responses. Results indicated that some programs do not provide any training in the areas of conventional screening otoscopy using a handheld otoscope (15.5%; n = 13) or screening tympanometry (11.9%; n = 10), whereas close to one half (46.4%; n = 39) reported no training in screening video otoscopy. Outcomes revealed that approximately one third or more of speech-language pathology graduate programs do not provide experiential opportunities in screening handheld otoscopy (36.9%) or tympanometry (32.1%), and most (78.6%) do not provide experiential opportunities in video otoscopy. CONCLUSIONS: The implication from the graduate speech-language pathology program survey findings is that some speech-language pathologists will graduate from academic programs without the acquired knowledge or experiential learning required to establish skill in 1 or more areas of screening otoscopy and tympanometry. Graduate speech-language pathology programs should consider appropriate training opportunities for students to acquire and demonstrate skill in outer and middle ear screening. PMID- 26126237 TI - Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. PMID- 26126238 TI - The Benefits of a 4-Year Anesthesiology Residency Program. PMID- 26126239 TI - Whole-Hearted for the Hole-Hearted. PMID- 26126240 TI - Trends in Androgen Prescriptions From Military Treatment Facilities: 2007 to 2011. AB - INTRODUCTION: The role of testosterone in health and quality of life has become increasingly visible and overtly marketed to the public. Some evidence suggests that testosterone levels in men may be low because of a variety of reasons, including stress and environmental exposures. OBJECTIVE: This study examines trends in testosterone prescriptions dispensed by military treatment facilities (MTFs). METHODS: We examined data from the Department of Defense Pharmacy Data Transaction Service to determine the nature of androgen prescriptions dispensed through MTFs from 2007 through 2011. RESULTS: The number of androgen prescriptions increased more than two-fold across the military from 19,494 in 2007 to 45,270 in 2011. Most prescriptions (99%) were for men. Androgen prescription rates rose 23% per year from 2007 through 2011 (p < 0.001, CI 23 24%). The prescription rate for 35- to 44-year-olds increased more than any other age group, with annual increases averaging 33% (p < 0.001, CI 32-34%). CONCLUSION: The number of androgen prescriptions within MTFs rose significantly from 2007 through 2011. This is similar to rises in androgen prescriptions seen in civilian medical systems. Clinical indications for the sharp increase in testosterone prescriptions are unknown, and the indications for clinically appropriate testosterone replacement need further clarification. PMID- 26126241 TI - Trends in B-Vitamin Prescriptions From Military Treatment Facilities: 2007 to 2011. AB - INTRODUCTION: The use of B-vitamin supplements has increased over the last decade. Although use is widespread in both military and civilian populations, data on patterns of B-vitamin prescription rates are lacking. OBJECTIVE: This study examines trends in B-vitamin prescriptions dispensed by military treatment facilities. METHODS: We examined data from the Department of Defense Pharmacy Data Transaction Service to determine the nature of several B-vitamin prescriptions dispensed through military treatment facilities from 2007 through 2011. The eight B vitamins examined were B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (panthenol), B6 (pyridoxine), B7 (biotin), B9 (folic acid), and B12 (cobalamin). RESULTS: The number of B-vitamin prescriptions dispensed from military treatment facilities decreased 7% from 278,972 in 2007 to 260,472 in 2011. Individual vitamin prescription patterns varied widely. Vitamins B6, B9, and B12 were the most frequently prescribed in each year. Vitamin B2 prescriptions quadrupled between 2009 and 2011, and B12 prescriptions showed a steady increase over time. In contrast, vitamins B3, B6, and B9 prescriptions showed a steady decline, and vitamin B7 prescriptions decreased by 66% between 2008 and 2009. CONCLUSIONS: No single pattern in B-vitamin prescriptions was observed. The driving forces behind increases in prescribed and non-prescribed dietary supplement use remain speculative. PMID- 26126242 TI - Third-Party Evaluation: A Review of Dietary Supplements Dispensed by Military Treatment Facilities From 2007 to 2011. AB - INTRODUCTION: Third-party certification/verification of dietary supplements (DS), although not mainstream, is one way to help ensure high-quality products. In the medical setting, physicians may prescribe DS to correct a deficiency or improve a health care outcome, and they want products of a certain standard of quality, free of adulteration/contamination. OBJECTIVE: We reviewed DS dispensed from all Department of Defense military treatment facilities over a 5-year period to determine which products had been third-party reviewed and certified/verified. METHODS: By using product name, manufacturer, and/or National Drug Codes, we examined product listings on the websites of three independent-evaluating organizations. RESULTS: Over 1.5 million dietary supplement prescriptions consisting of 753 different products were dispensed from 2007 through 2011. Less than 3.6% of the products examined were third-party certified/verified by any of the three most well-known evaluation organizations: 19 were verified by United States Pharmacopeial Convention; 9 products were reviewed and 8 certified by ConsumerLab; and none of the products were certified by NSF International. CONCLUSION: Most DS dispensed by military treatment facilities are not reviewed by a third party. This is not unexpected, as third party certification is not yet mainstream. However, one way to reduce potential hazards and exposure to unsafe products is to encourage use of supplements that have third-party certification/verification. PMID- 26126243 TI - Trends in Mineral Supplement Prescriptions From Military Treatment Facilities: 2007 to 2011. AB - INTRODUCTION: Mineral supplements such as calcium and iron are readily available over the counter and are some of the most frequently consumed dietary supplements. Health care providers also prescribe mineral supplements for treatment of certain conditions and to maintain health. OBJECTIVE: This study examines trends in mineral-supplement prescriptions dispensed by military treatment facilities. METHODS: We examined data from the DoD Pharmacy Data Transaction Service to determine the nature of mineral-supplement prescriptions dispensed by MTFs from 2007 through 2011. RESULTS: Overall, 1,785,158 calcium, 844,655 iron, 166,207 magnesium, and 23,297 zinc prescriptions were dispensed over this 5-year period. Although the number of zinc prescriptions decreased considerably by an average of 30% across the 5-year period, calcium and magnesium prescriptions increased by 3% and 8%, respectively. The number of iron prescriptions dispensed was relatively stable across the 5 years. CONCLUSIONS: Patterns of mineral-supplement prescriptions in the military changed over the 5 year period examined. However, the patterns within the DoD medical system may or may not represent those of the civilian medical system. Because we could not determine the reasons why the mineral supplements were prescribed, we cannot report whether the supplements were effective for the intended uses. PMID- 26126244 TI - Trends in Vitamin A, C, D, E, K Supplement Prescriptions From Military Treatment Facilities: 2007 to 2011. AB - INTRODUCTION: Although prior studies have examined the prevalence of dietary supplement use among various populations, data on single vitamins prescribed by health care providers are limited. OBJECTIVE: This study examined trends in single-vitamin supplement (A, C, D, E, K) prescriptions by providers from military treatment facilities from 2007 to 2011. METHODS: We examined prescription data from the Department of Defense Pharmacy Data Transaction Service to determine trends in the aforementioned single-vitamin supplement prescriptions. Prescription rates per 1,000 active duty personnel were estimated using population data retrieved from the Defense Medical Epidemiology Database (i.e., [number of prescriptions/population size] * 1,000). RESULTS: Across the 5 year period, the number of vitamin D prescriptions per 1,000 active duty personnel increased 454%. In contrast, the number of vitamin A, vitamin E, and vitamin K prescriptions per 1,000 active duty personnel decreased by 32%, 53%, and 29% respectively. Vitamin C prescriptions remained relatively constant. Across all age groups, total single-vitamin supplement prescriptions increased by 180%. CONCLUSION: Together, prescriptions examined in this study increased steadily from 2007 to 2011, primarily because of the increase in vitamin D prescriptions. The exhibited trend reflects the current general-population pattern of dietary supplement use, with large increases in vitamin D and declines in vitamin E. PMID- 26126245 TI - Tyrosine for Mitigating Stress and Enhancing Performance in Healthy Adult Humans, a Rapid Evidence Assessment of the Literature. AB - BACKGROUND: Tyrosine, a precursor of catecholamine neurotransmitters, may help alleviate physical/cognitive performance decrements in humans under conditions of high physical/psychological stress. OBJECTIVE: Determine whether supplemental tyrosine mitigates stress-induced decrements in cognitive and/or physical performance in healthy individuals using Samueli Institute's Rapid Evidence Assessment of the Literature methodology. METHODS: Key databases (PubMed/MEDLINE, CINAHL, Embase, PsycInfo, and Agricola) were searched for randomized controlled trials from inception to October 2012. Scottish Intercollegiate Guidelines 50 criteria and Grading of Recommendation Assessment, Development, and Evaluation framework were used to assess the quality of individual studies and the overall literature pool, respectively. Controlled clinical trials were included later in the overall methodology. RESULTS: 10 randomized controlled trials and 4 controlled clinical trials met our inclusion criteria. On the basis of the available evidence, no recommendation could be made for the effect of tyrosine on physical performance under stressful physical conditions. However, a weak recommendation in favor of tyrosine was made for cognitive stress as all studies showed a positive effect. CONCLUSIONS: This review indicates that the available evidence is insufficient to make confident recommendations on the effectiveness of tyrosine for mitigating stress effects on physical/cognitive performance. However, tyrosine may benefit cognitive performance and is worthy of further study. PMID- 26126246 TI - Phase I Development of an Optimal Integrated Care Pathway for Veterans Discharged From the Armed Forces. AB - BACKGROUND: There is a lack of evidence to manage veterans with service-related mental health problems. This research aimed to develop an optimally effective, feasible, and acceptable integrated care pathway (ICP). METHODS: A prototype ICP was developed through an initial modeling phase. Systematic reviews informed a portfolio of information for key stakeholders to discuss in a series of focus groups and semistructured interviews. They included 16 mental health professionals with expertise in the fields of mental health provision for military personnel, and 6 veterans with a history of mental illness. Data were analyzed through Inductive Thematic Analysis and used to inform the content, delivery, and guidance of an ICP. The prototype was piloted with 20 veterans in two pilot studies and refined on the basis of their quantitative and qualitative feedback. RESULTS: The final ICP was agreed with additional guidance notes. It included three pathways covering referral, intervention, and management of veterans. Qualitative and quantitative results supported its efficacy in terms of reducing mental health symptoms and its acceptability to veterans. CONCLUSIONS: A specific veteran ICP shows promise as an effective and acceptable way of treating veterans with service related mental health problems. PMID- 26126247 TI - Vitamin A-Deficiency Eye Disease Among Soldiers in the U.S. Civil War: Spectrum of Clinical Disease. AB - During the U.S. Civil War, nutritional night blindness was a common problem among soldiers forced to subsist of nutritionally inadequate diets, but medical officers typically attributed this complaint to malingering and did not suspect or appreciate a dietary basis. More than 8,000 cases of night blindness were recorded among Union troops, but many cases were not tabulated because of incomplete data for black soldiers and prisoners of war. From 1864 to 1865, during which comparable data were available for both whites and blacks, the average annual cumulative incidence of night blindness was 4.3 per 1,000 troops for whites, compared with 11.0 per 1,000 troops for blacks. Affected patients had dilated pupils that were poorly responsive to candle light. Approximately 30 cases of keratomalacia were also reported among severely malnourished and emaciated soldiers with chronic diarrhea, generally within 2 weeks before death. The reported clinical manifestations are characteristic of the full range of vitamin A deficiency eye disease from night blindness to corneal ulceration and perforation. Although medical officers typically accused affected soldiers of malingering, malingering cannot account for either the observed abnormalities of pupillary reflexes, or the corneal epithelial pathology and mortality recorded in severe cases. PMID- 26126248 TI - Evaluating MEDEVAC Force Structure Requirements Using an Updated Army Scenario, Total Army Analysis Admission Data, Monte Carlo Simulation, and Theater Structure. AB - In this study, we re-evaluate air ambulance requirements (rules of allocation) and planning considerations based on an Army-approved, Theater Army Analysis scenario. A previous study using workload only estimated a requirement of 0.4 to 0.6 aircraft per admission, a significant bolus over existence-based rules. In this updated study, we estimate requirements for Phase III (major combat operations) using a simulation grounded in previously published work and Phase IV (stability operations) based on four rules of allocation: unit existence rules, workload factors, theater structure (geography), and manual input. This study improves upon previous work by including the new air ambulance mission requirements of Department of Defense 51001.1, Roles and Functions of the Services, by expanding the analysis over two phases, and by considering unit rotation requirements known as Army Force Generation based on Department of Defense policy. The recommendations of this study are intended to inform future planning factors and already provided decision support to the Army Aviation Branch in determining force structure requirements. PMID- 26126249 TI - Assessment of the Risk of Fractures Because of Service on Diesel Submarines: A Retrospective Cohort Study. AB - INTRODUCTION: Submariners are known to have decreased bone mass following periods of long submersion. We examined whether this produces a higher predilection to fractures. METHODS: This is a retrospective cohort study. Data were collected from the computerized medical records of 457 consecutive submariners (serving 1091.42 man-years). The control group included 3,219 consecutive sailors, (serving 5845.04 man-years). Groups were stratified according to age at induction, body mass index, place of birth, and status of service (i.e., compulsory versus professional). Analysis of fracture incidence and comparison of proportions between the groups was conducted using chi(2) tests and Fisher's exact test. The hazard ratio for fractures was performed using a survival analysis regression model for each group (Cox Proportional Hazard Model). RESULTS: Nineteen submariners (4.2%) and 94 sailors (2.9%) were shown to have fractures during their service (RR = 1.42, p = 0.15). A Cox proportional hazard model was employed. No statistically significant difference was found between the 2 groups (HR = 1.037, p = 0.89). No correlation was found between length of service and risk of fracture. Most fractures suffered by submariners occurred outside their work environment. CONCLUSIONS: Submariners are repeatedly exposed to prolonged submersions that are deleterious to bone strength. However, no statistically significant difference in the incidence of fractures was found between submariners and surface sailors. This is an important finding for the bone and occupational health of submariners in general. PMID- 26126250 TI - Clearing the Cervical Spine in a War Zone: What Other Injuries Matter? AB - BACKGROUND: Cervical spine clearance requires clinicians to assess the reliability of physical examination based on a patient's mental status and distracting injuries. Distracting injuries have never been clearly defined in military casualties. METHODS: Retrospective review was conducted of patients entered into Department of Defense Trauma Registry January 2008 to August 2013, identifying blunt trauma patients with cervical spine injury and Glasgow Coma Score >= 14. Physical examination and radiology results were abstracted from medical records and injury diagnoses were obtained from Department of Defense Trauma Registry. Groups were compared, p-value of < 0.05 was considered significant. RESULTS: A total of 149 patients met study criteria; 20 patients (13%) had a negative clinical examination of the cervical spine. Coexisting injuries identified in patients with negative physical examination included injuries in proximity to the neck (head, thoracic spine, chest, or humerus) in 17 (85%) patients. In 3 patients (15%), coexisting injuries were not in proximity to the neck and included pelvic, femur, and tibia fractures. All patients without coexisting injury (n = 37) had a positive physical examination. CONCLUSION: Physical examination of multitrauma casualties with neck injury may be unreliable when distracting injuries are present. When no distracting injuries were present, the physical examination was accurate in all patients. PMID- 26126251 TI - Effects of Cardiac Surgery on Duty Status in the Active Duty Military Population. AB - No modern studies have addressed the impact of cardiac surgery on military duty status, which is associated with constraints not applicable to the general population. A review of all active duty patients undergoing coronary artery bypass grafting (CABG), mitral valve repair (MVrep), bioprosthetic valve replacement (BIOVALVE), mechanical valve replacement (MECHVALVE), and septal defect closure (ASD/VSD) at Naval Medical Center Portsmouth between January 1, 2004 and December 31, 2011 was used to determine final duty status: Return to Full Duty (RTFD), Medical Board Separation or Planned Retirement/Separation. Complete data on final disposition was available for 99% (75/76) of patients. There were 9 Planned Retirement/Separation patients. There was a 100% rate of RTFD for all MVrep, BIOVALVE, and ASD/VSD patients. Patients undergoing CABG had an 83% (20/23) rate of RTFD. MECHVALVE patients had RTFD in only 23% (5/21) of cases. Patients undergoing MECHVALVE are unlikely to be suitable for continued service after surgery, but most if not all military patients undergoing MVrep, ASD/VSD, or BIOVALVE and the vast majority of CABG patients can expect to return to unrestricted active duty after surgery. PMID- 26126252 TI - Assessment of Sleep Disruption and Sleep Quality in Naval Special Warfare Operators. AB - Little is known about sleep in elite military populations who are exposed to higher operational demands, unpredictable training, deployment, and mission cycles. Twenty-nine Naval Special Warfare (NSW) Operators wore an actiwatch for an 8-day/7-night period for objective sleep assessment and completed a nightly sleep log. A total of 170 nights of actigraphically recorded sleep were collected. When comparing objectively versus subjectively recorded sleep parameter data, statistically significant differences were found. Compared with sleep log data, actigraphy data indicate NSW Operators took longer to fall asleep (an average of 25.82 minutes), spent more time awake after sleep onset (an average of 39.55 minutes), and demonstrated poorer sleep efficiency (83.88%) (ps < 0.05). Self-reported sleep quality during the study period was 6.47 (maximum score = 10). No relationships existed between the objectively derived sleep indices and the self-reported measure of sleep quality (rs = -0.29 to 0.09, all ps > 0.05). Strong inter-relationships existed among the subjectively derived sleep indices (e.g., between self-reported sleep quality and sleep efficiency; r = 0.61, p < 0.001). To our knowledge, this is the first study to objectively and subjectively quantify sleep among NSW Operators. These findings suggest sleep maintenance and sleep efficiency are impaired when compared to normative population data. PMID- 26126253 TI - Intimate Partner Violence in the Canadian Armed Forces: The Role of Family Stress and Its Impact on Well-Being. AB - Unique demands of military life (e.g., deployment) can have a significant impact on family life. Although most families cope effectively with military life stressors, some may have difficulty adjusting, experiencing marital conflicts, and violence. Evidence suggests that unmanaged occupational demands may create family stress by interfering with efforts to fulfill family duties. This study examined the effects of work-family conflict and marital satisfaction on intimate violence experienced by Canadian Armed Forces members, and the impact of such violence on their psychological well-being (N = 525). Regression analyses showed that both work-family conflict and marital satisfaction were unique and significant predictors of emotional and physical violence experienced by Canadian Armed Forces members. Moreover, bootstrapping analyses demonstrated that marital satisfaction partially mediated the relationship between work-family and family work conflicts and intimate partner violence. The results point to the importance of examining the interrelationship between family stress and occupational stressors when exploring interpersonal violence and its psychological impact on military personnel. PMID- 26126254 TI - Sexual Functioning Among a Cohort of Treatment-Seeking Canadian Military Personnel and Veterans With Psychiatric Conditions. AB - OBJECTIVE: The aim of this study was to assess potential predictors of sexual dysfunction and dissatisfaction in a sample of 99 current and former Canadian Forces members attending the Parkwood Hospital Operational Stress Injury Clinic for mental health treatment. METHODS: Respondents completed a number of questionnaires assessing sexual functioning, post-traumatic stress disorder symptom severity, health-related quality of life, and self-perceived masculinity traits. RESULTS: Regression analyses revealed that role limitations because of physical problems predicted erectile functioning (beta = 0.107, p = 0.075), whereas vitality predicted orgasmic functioning (beta = 0.044, p = 0.032). Hypermasculinity was the strongest predictor of sexual desire (beta = 0.466, p = 0.036), and sexual satisfaction was significantly predicted by bodily pain (beta = 0.036, p = 0.019). Preliminary analyses revealed a significant mediating effect of bodily pain on the relationship between post-traumatic stress disorder symptom severity. CONCLUSIONS: Results suggest a nuanced interplay between physical health and mental health factors regarding sexual functioning in treatment seeking military personnel and veterans; however, further research is needed to better delineate the relationship between the 2. PMID- 26126255 TI - Group Prenatal Care Outcomes in a Military Population: A Retrospective Cohort Study. AB - OBJECTIVE: To evaluate pregnancy outcomes in Centering Pregnancy patients. METHODS: This was an IRB-approved retrospective cohort study from November 2009 to January 2013 involving 202 Centering Pregnancy patients and 202 Certified Nurse Midwife patients. The primary outcome was mean gestational age at time of delivery. Secondary outcomes included cesarean and operative vaginal delivery rate, triage visit frequency, Neonatal Intensive Care Unit admission rate, 1 and 5 minute APGAR scores, birth weight, breastfeeding rate at discharge and 6 weeks postpartum, third and fourth degree laceration rate, weight gain in pregnancy, and excessive weight gain rate. RESULTS: There was no statistically significant difference in any obstetric outcome including preterm delivery rate. Centering Pregnancy patients were more likely to be active duty (52.0 vs. 35.6%, p = 0.001), younger (24.8 vs. 26.3 years old, p < 0.001), and nulliparous (75.2 vs. 56.9%, p < 0.001). There was a statistically significant increase in triage visit frequency >= 6 for Centering Pregnancy patients (11.9% vs. 8.9%, p = 0.011). CONCLUSION: There were no clinically significant differences in the primary or secondary outcomes. Significant cost savings could be realized by expanding Centering Pregnancy in the military health system. PMID- 26126257 TI - HAM, A Space Pioneer. PMID- 26126256 TI - Characterization of Foot-Strike Patterns: Lack of an Association With Injuries or Performance in Soldiers. AB - OBJECTIVES: Characterize the distribution of foot-strike (FS) patterns in U.S. Army Soldiers and determine if FS patterns are related to self-reported running injuries and performance. METHODS: 341 male Soldiers from a U.S. Army Combined Arms Battalion ran at their training pace for 100 meters, and FSs were recorded in the sagittal plane. Participants also completed a survey related to training habits, injury history, and run times. Two researchers classified FS patterns as heel strike (HS) or nonheel strike (NHS, combination of midfoot strike and forefoot strike patterns). Two clinicians classified the musculoskeletal injuries as acute or overuse. The relationship of FS type with two-mile run time and running-related injury was analyzed (p <= 0.05). RESULTS: The Soldiers predominately landed with an HS (87%) and only 13% were characterized as NHS. Running-related injury was similar between HS (50.3%) and NHS (55.6%) patterns (p = 0.51). There was no difference (p = 0.14) between overuse injury rates between an HS pattern (31.8%) and an NHS pattern (31.0%). Two-mile run times were also similar, with both groups averaging 14:48 minutes. CONCLUSION: Soldiers were mostly heel strikers (87%) in this U.S. Army Combined Arms Battalion. Neither FS pattern was advantageous for increased performance or decreased incidence of running-related injury. PMID- 26126258 TI - Excessive Video Game Use, Sleep Deprivation, and Poor Work Performance Among U.S. Marines Treated in a Military Mental Health Clinic: A Case Series. AB - Excessive use of video games may be associated with sleep deprivation, resulting in poor job performance and atypical mood disorders. Three active duty service members in the U.S. Marine Corps were offered mental health evaluation for sleep disturbance and symptoms of blunted affect, low mood, poor concentration, inability to focus, irritability, and drowsiness. All three patients reported insomnia as their primary complaint. When asked about online video games and sleep hygiene practices, all three patients reported playing video games from 30 hours to more than 60 hours per week in addition to maintaining a 40-hour or more workweek. Our patients endorsed sacrificing sleep to maintain their video gaming schedules without insight into the subsequent sleep deprivation. During the initial interviews, they exhibited blunted affects and depressed moods, but appeared to be activated with enthusiasm and joy when discussing their video gaming with the clinical provider. Our article illustrates the importance of asking about online video gaming in patients presenting with sleep disturbances, poor work performance, and depressive symptoms. Because excessive video gaming is becoming more prevalent worldwide, military mental health providers should ask about video gaming when patients report problems with sleep. PMID- 26126259 TI - A Case Report of Supplement-Induced Hepatitis in an Active Duty Service Member. AB - The incidence of drug-induced hepatic injury has been increasing as a result of more widespread use of workout supplements containing anabolic steroids to increase muscle mass. Synthetic androgenic steroids are shown to cause cholestatic liver injury, but the exact mechanism of injury is not completely understood. We present a case of a healthy, young, active duty Army male soldier who developed pruritis and jaundice shortly after starting to take a body building supplement containing anabolic steroids, and was subsequently found to have significant biopsy proven drug-induced liver injury. PMID- 26126260 TI - A Case of Paraspinal Muscle Rhabdomyolysis in a 22-Year-Old Male After Ingesting a Supplement Containing Higenamine. AB - Rhabdomyolysis is a painful and potentially life-threatening injury in which muscle breaks down in response to an insult. In this case report, we describe the clinical course of a 22-year-old man who developed paraspinal muscle rhabdomyolysis and possible compartment syndrome in association with strenuous activity and the ingestion of an exercise supplement containing the stimulant higenamine. Although he did not experience any renal damage, he did experience a high level of pain acutely and for the next 4 months. A history of exercise supplement intake should increase the index of suspicion for rhabdomyolysis when a patient presents with moderate to severe muscle pain, even if the muscle group is not in a classic location for rhabdomyolysis. PMID- 26126261 TI - A Case of Penile Plaques in Afghanistan. AB - Deployed male soldiers may present with a myriad of dermatological conditions in the genital area. It is important to recognize the more common entities in the differential diagnosis for soldiers to receive optimal guidance and treatment. This is important in the deployed environment for unit strength to be maintained and to avoid unnecessary medical evacuations. We present a patient deployed to Afghanistan who sought care at his battalion aid station for penile plaques that were diagnosed as lichen planus. In this article, we discuss the differential diagnosis for penile plaques and other considerations for deployed patients diagnosed with lichen planus. PMID- 26126262 TI - Airborne Priapism: A Case of Nonischemic Priapism After Military Static-Line Parachute Injury. AB - We report the case of a 21-year-old active duty U.S. Army soldier with painful and nonresolving priapism following blunt pelvic and lower extremity trauma from military static-line parachute injury during training. The patient's condition was initially managed with corporal aspiration and intracavernosal injections of phenylephrine that provided temporary relief but recurrence soon after. Referral to Urology at the site of the patient's injury yielded a diagnosis of penile hematoma. On subsequent evaluation by Urology on return to the patient's home duty station (over 96 hours after injury, with symptoms persisting), the corpora cavernosa were rigid, the corpus spongiosum was soft, and corporal blood gas drawn by the emergency department consistent with arterial blood. Penile duplex ultrasound revealed an isolated arterial-cavernosal fistula within the proximal left corporal body. The patient underwent percutaneous embolization of the fistula with successful resolution of his condition and return of normal erectile function. We discuss this unique case of high-flow priapism occurring after blunt trauma from military parachute injury and review suggested management in a stepwise fashion. The case is significant in that extensive literature review yields no previously described case of priapism following trauma from military parachute injury. PMID- 26126263 TI - Postoperative Urinary Retention With Gross Vulvar Edema After Use of 4% Icodextrin. AB - BACKGROUND: 4% icodextrin is a fluid that can be instilled laparoscopically to prevent adhesion formation. There are few complications reported in the literature associated with its use. CASE: A 38-year-old woman, gravida 2, para 0, abortus 2 underwent laparoscopic salpingectomy. 4% icodextrin was instilled in an effort to prevent adhesion formation. Postoperatively, the patient experienced urinary retention and gross vulvar edema that required foley catheter use until the 4% icodextrin solution had absorbed. CONCLUSION: Postoperative complications that may be associated with the use of 4% icodextrin include urinary retention and vulvar edema. PMID- 26126264 TI - The Curse of the Nine-Banded Armadillo: Case Report and Review. AB - Hansen's disease (leprosy) is an ancient condition characterized by hypopigmented patches that progress to become plaques with hypoesthesia. Several case reports suggest that armadillos may be a source of Mycobacterium leprae for clinical cases, and contact with armadillos has been shown to be a significant risk factor in several case-control studies. Early diagnosis and treatment result in an excellent prognosis and provide an effective means to prevent complications of peripheral nerve injury, social stigma, and disability. We present a case of Hansen's disease in a previously healthy veteran and provide an overview of the diagnosis, classification, and treatment of the condition. Clinicians should consider leprosy in the differential diagnosis when confronted with chronic skin lesions in the appropriate clinical setting. PMID- 26126265 TI - Hysteroscopic Sterilization Failure Following Post-Procedure Confirmatory Test Indicating Tubal Occlusion. AB - BACKGROUND: Hysteroscopic sterilization procedure has gained traction in the past decade as a means of contraception advertised to be 99.83% effective following successful sterilization coil placement and postprocedure hysterosalpingogram confirmation of proper coil positioning and tubal occlusion. CASE: A 44-year-old female underwent a second sterilization procedure after delivering a pregnancy that occurred following a reportedly successful hysteroscopic sterilization procedure and subsequent confirmatory testing demonstrating appropriate sterilization coil placement and tubal occlusion. During the second sterilization procedure, a coil device was visible perforating through the left uterine cornua. CONCLUSION: Following hysteroscopic sterilization, confirmatory testing may demonstrate the appearance of tubal occlusion and proper coil placement when the sterilization devices are incorrectly placed and the fallopian tubes patent. PMID- 26126268 TI - Generation of Autologous Platelet-Rich Plasma by the Ultrasonic Standing Waves. AB - Platelet-rich plasma (PRP) is a volume of autologous plasma that has a higher platelet concentration above baseline. It has already been approved as a new therapeutic modality and investigated in clinics, such as bone repair and regeneration, and oral surgery, with low cost-effectiveness ratio. At present, PRP is mostly prepared using a centrifuge. However, this method has several shortcomings, such as long preparation time (30 min), complexity in operation, and contamination of red blood cells (RBCs). In this paper, a new PRP preparation approach was proposed and tested. Ultrasound waves (4.5 MHz) generated from piezoelectric ceramics can establish standing waves inside a syringe filled with the whole blood. Subsequently, RBCs would accumulate at the locations of pressure nodes in response to acoustic radiation force, and the formed clusters would have a high speed of sedimentation. It is found that the PRP prepared by the proposed device can achieve higher platelet concentration and less RBCs contamination than a commercial centrifugal device, but similar growth factor (i.e., PDGF-betabeta). In addition, the sedimentation process under centrifugation and sonication was simulated using the Mason-Weaver equation and compared with each other to illustrate the differences between these two technologies and to optimize the design in the future. Altogether, ultrasound method is an effective method of PRP preparation with comparable outcomes as the commercially available centrifugal products. PMID- 26126269 TI - Bufferless Compression of Asynchronously Sampled ECG Signals in Cubic Hermitian Vector Space. AB - Asynchronous level crossing sampling analog-to-digital converters (ADCs) are known to be more energy efficient and produce fewer samples than their equidistantly sampling counterparts. However, as the required threshold voltage is lowered, the number of samples and, in turn, the data rate and the energy consumed by the overall system increases. In this paper, we present a cubic Hermitian vector-based technique for online compression of asynchronously sampled electrocardiogram signals. The proposed method is computationally efficient data compression. The algorithm has complexity O(n), thus well suited for asynchronous ADCs. Our algorithm requires no data buffering, maintaining the energy advantage of asynchronous ADCs. The proposed method of compression has a compression ratio of up to 90% with achievable percentage root-mean-square difference ratios as a low as 0.97. The algorithm preserves the superior feature-to-feature timing accuracy of asynchronously sampled signals. These advantages are achieved in a computationally efficient manner since algorithm boundary parameters for the signals are extracted a priori. PMID- 26126266 TI - Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling. AB - Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Galpha binding and activating (GBA) motif, which activates Galphai proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the beta-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Galphai and enhances non canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis. PMID- 26126270 TI - Sparse EEG Source Localization Using Bernoulli Laplacian Priors. AB - Source localization in electroencephalography has received an increasing amount of interest in the last decade. Solving the underlying ill-posed inverse problem usually requires choosing an appropriate regularization. The usual l2 norm has been considered and provides solutions with low computational complexity. However, in several situations, realistic brain activity is believed to be focused in a few focal areas. In these cases, the l2 norm is known to overestimate the activated spatial areas. One solution to this problem is to promote sparse solutions for instance based on the l1 norm that are easy to handle with optimization techniques. In this paper, we consider the use of an l0 + l1 norm to enforce sparse source activity (by ensuring the solution has few nonzero elements) while regularizing the nonzero amplitudes of the solution. More precisely, the l0 pseudonorm handles the position of the nonzero elements while the l1 norm constrains the values of their amplitudes. We use a Bernoulli-Laplace prior to introduce this combined l0 + l1 norm in a Bayesian framework. The proposed Bayesian model is shown to favor sparsity while jointly estimating the model hyperparameters using a Markov chain Monte Carlo sampling technique. We apply the model to both simulated and real EEG data, showing that the proposed method provides better results than the l2 and l1 norms regularizations in the presence of pointwise sources. A comparison with a recent method based on multiple sparse priors is also conducted. PMID- 26126267 TI - The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. AB - Dengue and chikungunya are increasing global public health concerns due to their rapid geographical spread and increasing disease burden. Knowledge of the contemporary distribution of their shared vectors, Aedes aegypti and Aedes albopictus remains incomplete and is complicated by an ongoing range expansion fuelled by increased global trade and travel. Mapping the global distribution of these vectors and the geographical determinants of their ranges is essential for public health planning. Here we compile the largest contemporary database for both species and pair it with relevant environmental variables predicting their global distribution. We show Aedes distributions to be the widest ever recorded; now extensive in all continents, including North America and Europe. These maps will help define the spatial limits of current autochthonous transmission of dengue and chikungunya viruses. It is only with this kind of rigorous entomological baseline that we can hope to project future health impacts of these viruses. PMID- 26126271 TI - METEOR: An Enterprise Health Informatics Environment to Support Evidence-Based Medicine. AB - GOAL: The aim of this paper is to propose the design and implementation of next generation enterprise analytics platform developed at the Houston Methodist Hospital (HMH) system to meet the market and regulatory needs of the healthcare industry. METHODS: For this goal, we developed an integrated clinical informatics environment, i.e., Methodist environment for translational enhancement and outcomes research (METEOR). The framework of METEOR consists of two components: the enterprise data warehouse (EDW) and a software intelligence and analytics (SIA) layer for enabling a wide range of clinical decision support systems that can be used directly by outcomes researchers and clinical investigators to facilitate data access for the purposes of hypothesis testing, cohort identification, data mining, risk prediction, and clinical research training. RESULTS: Data and usability analysis were performed on METEOR components as a preliminary evaluation, which successfully demonstrated that METEOR addresses significant niches in the clinical informatics area, and provides a powerful means for data integration and efficient access in supporting clinical and translational research. CONCLUSION: METEOR EDW and informatics applications improved outcomes, enabled coordinated care, and support health analytics and clinical research at HMH. SIGNIFICANCE: The twin pressures of cost containment in the healthcare market and new federal regulations and policies have led to the prioritization of the meaningful use of electronic health records in the United States. EDW and SIA layers on top of EDW are becoming an essential strategic tool to healthcare institutions and integrated delivery networks in order to support evidence-based medicine at the enterprise level. PMID- 26126272 TI - Detecting the Elusive P-Wave: A New ECG Lead to Improve the Recording of Atrial Activity. AB - GOAL: In this study, we report on a lead selection method that was developed to detect the optimal bipolar electrode placement for recording of the P-wave. METHODS: The study population consisted of 117 lead body surface potential maps recorded from 229 healthy subjects. The optimal bipolar lead was developed using the training set (172 subjects) then extracted from the testing dataset (57 subjects) and compared to other lead systems previously reported for improved recording of atrial activity. All leads were assessed in terms of P-wave, QRS, and STT root mean square (RMS). The P/QRST RMS ratio was also investigated to determine the atrioventricular RMS ratio. Finally, the effect of minor electrode misplacements on the P-lead was investigated. RESULTS: The P-lead discovered in this study outperformed all other investigated leads in terms of P-wave RMS. The P-lead showed a significant improvement in median P-wave RMS (93 versus 72 MUV, p < 0.001) over the next best lead, Lead II. An improvement in QRS and STT RMS was also observed from the P-lead in comparison to lead II (668 versus 573 MUV, p < 0.001) and (327 versus 196 MUV, p < 0.001). Although P-wave RMS was reduced by incorrect electrode placement, significant improvement over Lead II was still evident. CONCLUSION: The P-lead improves P-wave RMS signal strength over all other investigated leads. Also the P-lead does not reduce QRS and STT RMS making it an appropriate choice for atrial arrhythmia monitoring. SIGNIFICANCE: Given the improvement in signal-to-noise ratio, an improvement in algorithms that rely on P-wave analysis may be achieved. PMID- 26126273 TI - Who discovered messenger RNA? AB - The announcement of the discovery of messenger RNA (mRNA) and the cracking of the genetic code took place within weeks of each other in a climax of scientific excitement during the summer of 1961. Although mRNA is of decisive importance to our understanding of gene function, no Nobel Prize was awarded for its discovery. The large number of people involved, the complex nature of the results, and the tortuous path that was taken over half a century ago, all show that simple claims of priority may not reflect how science works. PMID- 26126274 TI - Mating failure. AB - Greenway et al. introduce the concept of mating failure, the failure to produce offspring. PMID- 26126275 TI - Brown. AB - In this Quick Guide, Steven Buck explains how, uniquely among the bright primary perceptual hues, yellow changes its hue when it appears dark, becoming the colour brown. PMID- 26126277 TI - Evolution: The Island of Misfit Mammoths. AB - The genomes of two woolly mammoths have been sequenced. One of the last survivors had reduced genetic diversity. Although divergent in their mitochondrial genomes, the mammoths had similar nuclear genomes, a finding germane to elephant conservation. PMID- 26126276 TI - Aneuploidy. AB - The terms 'haploid' and 'diploid' that describe single (n) and double (2n) chromosome sets in cells were coined by the Polish-German botanist Eduard Strasburger and originate from the Greek terms haploos meaning 'single' and diploos meaning 'double'. The term 'ploidy' was subsequently derived to describe the total chromosome content of cells. Consequently, the term 'euploid' refers to a chromosome complement that is an exact multiple of the haploid number. Therefore, haploids and diploids are both cases of normal euploidy. Euploid types that have more than two sets of chromosomes are 'polyploid' such as 'triploid' (3n), 'tetraploid' (4n), 'pentaploid' (5n), and so forth. There are various natural euploid states with some organisms existing as haploids (fungi), diploids (most mammals), and polyploids (plants). PMID- 26126278 TI - Colour Vision: Understanding #TheDress. AB - A widely-viewed image of a dress elicits striking individual variation in colour perception. Experiments with multiple variants of the image suggest that the individual differences may arise through the action of visual mechanisms that normally stabilise object colour. PMID- 26126279 TI - Cell Division: A New Role for the Kinetochore in Central Spindle Assembly. AB - The central spindle, which is formed between segregating chromosomes, is a critical structure for cell division. However, it was unclear how the central spindle is assembled at anaphase onset. A recent study reveals that a conserved kinetochore protein network plays an essential role in initiation of central spindle assembly. PMID- 26126280 TI - Neural Circuits: Introducing Different Scales of Temporal Processing. AB - A new study describes a novel passive integration mechanism of inhibition in auditory neurons in the dorsal nucleus of the lateral lemniscus that turns extremely well-timed synaptic events into a signal code that is three orders of magnitude slower. PMID- 26126281 TI - Cilia: Organelles at the Heart of Heart Disease. AB - Genetic disorders, such as heterotaxy, first provided a link between cilia and developmental heart defects. Now, a genetic screen in mice shows that ciliary dysfunction may indeed be the major contributing factor in the etiology of congenital heart disease. PMID- 26126282 TI - Neurobiology: Myelin Goes Where the Action Is. AB - There is increasing evidence that neuronal activity modulates how axons are wrapped in myelin. Two recent studies demonstrate that activity-dependent vesicle release from neurons regulates myelination in vivo. PMID- 26126283 TI - Seedling Germination: Seedlings Follow Sunshine and Fresh Air. AB - The journey from seedling to plant requires guidance in the dark to establish which directions the roots and shoots should grow. A new study shows that, after germinating in darkness, plant seedlings sense the oxygen content of the surrounding airspace to guide further development. PMID- 26126284 TI - Cell Migration: Recoiling from an Embrace. AB - For proper spacing or rapid dispersion, some migratory cells are guided by repulsive collisions with their neighbors. A new study reveals that a surprising intercellular coupling of leading edge actin networks forms the basis of mutual repulsion in Drosophila hemocytes. PMID- 26126287 TI - Recurrent-Neural-Network-Based Multivariable Adaptive Control for a Class of Nonlinear Dynamic Systems With Time-Varying Delay. AB - At the beginning, an approximate nonlinear autoregressive moving average (NARMA) model is employed to represent a class of multivariable nonlinear dynamic systems with time-varying delay. It is known that the disadvantages of robust control for the NARMA model are as follows: 1) suitable control parameters for larger time delay are more sensitive to achieving desirable performance; 2) it only deals with bounded uncertainty; and 3) the nominal NARMA model must be learned in advance. Due to the dynamic feature of the NARMA model, a recurrent neural network (RNN) is online applied to learn it. However, the system performance becomes deteriorated due to the poor learning of the larger variation of system vector functions. In this situation, a simple network is employed to compensate the upper bound of the residue caused by the linear parameterization of the approximation error of RNN. An e -modification learning law with a projection for weight matrix is applied to guarantee its boundedness without persistent excitation. Under suitable conditions, the semiglobally ultimately bounded tracking with the boundedness of estimated weight matrix is obtained by the proposed RNN-based multivariable adaptive control. Finally, simulations are presented to verify the effectiveness and robustness of the proposed control. PMID- 26126286 TI - Automated, Depth-Resolved Estimation of the Attenuation Coefficient From Optical Coherence Tomography Data. AB - We present a method for automated, depth-resolved extraction of the attenuation coefficient from Optical Coherence Tomography (OCT) data. In contrast to previous automated, depth-resolved methods, the Depth-Resolved Confocal (DRC) technique derives an invertible mapping between the measured OCT intensity data and the attenuation coefficient while considering the confocal function and sensitivity fall-off, which are critical to ensure accurate measurements of the attenuation coefficient in practical settings (e.g., clinical endoscopy). We also show that further improvement of the estimated attenuation coefficient is possible by formulating image denoising as a convex optimization problem that we term Intensity Weighted Horizontal Total Variation (iwhTV). The performance and accuracy of DRC alone and DRC+iwhTV are validated with simulated data, optical phantoms, and ex-vivo porcine tissue. Our results suggest that implementation of DRC+iwhTV represents a novel way to improve OCT contrast for better tissue characterization through quantitative imaging. PMID- 26126288 TI - Cone Beam Computed Tomography evaluation of palatal bone thickness for miniscrew placement in Down's syndrome. AB - OBJECTIVES: To quantify palatal bone thickness (PBT) in Down's syndrome (DS) patients in order to identify the best areas for miniscrew placement. DESIGN: The study group was formed of 40 DS patients (25 male and 15 female) with a mean age of 18.4+/-6.3 years (range, 9-40 years). A control group of 40 non-syndromic age- and sex-matched individuals was selected. Maxillary CBCT images were available for all participants. Coronal sections of the hard palate were selected at 4, 8, 16 and 24mm posterior to the distal wall of the incisive foramen. PBT measurements were performed at 20 selected points on these coronal sections at the midline and at 3 and 6mm to right and left of the suture. RESULTS: Overall, PBT was similar in DS and controls and it was not affected by age or sex. In both groups PBT decreased progressively with increasing distance from the posterior wall of the nasopalatine foramen in an anteroposterior direction, except along the median palatal suture. PBT along the suture was lower in DS than in controls in all the paracoronal image planes (P=0.02, 0.007, 0.01 and 0.02 at 4mm, 8mm, 16mm and 24mm, respectively, from the incisive foramen). PBT at the most anterior paramedian locations was also lower in DS than in controls (P=0.02 and 0.03, respectively, 3mm to the right and left of midline). CONCLUSIONS: In DS individuals, the most suitable area for miniscrew placement in terms of bone volume is the median palatal suture, irrespective of age or sex, as occurs in the general population, followed by the paramedian sites closest to the incisive foramen. PMID- 26126289 TI - Assessment of masticatory muscle activity and occlusion time in patients with advanced tooth wear. AB - OBJECTIVE: Tooth wear is a basic physiological adjustment mechanism in the masticatory system. Unfortunately, it is not clear what the relationship is between the activity of the masticatory muscles and the tooth hard tissue loss (mainly enamel) in patients with advanced tooth wear. The aims of this study were (1) to compare the occlusion times and (2) to compare the EMG activity in maximal voluntary clench of the masseter and anterior temporalis muscles of patients with advanced tooth wear to the same activity of healthy volunteers. DESIGN: 50 (16F, 34M) patients and 30 (12F, 18M) age matched controls were clinically examined to assess the degree of wear (TWI). Each subject underwent electromyographic analysis (bilateral anterior temporalis, superficial masseter, anterior digastric and sternocleidomastoid muscles) and digital occlusal analysis. RESULTS: Mean values of the electrical potentials of the mandible elevating muscles during clench were higher in the study group compared to the controls. A negative correlation was found between the temporalis and masseter muscle activities during clench and the mean value of TWI (r=-0.383, p=0.009; r=-0.447, p=0.002). Occlusion time was longer in the study group compared to controls (p<0.05). CONCLUSIONS: Mandibular adductors demonstrated lower muscular activities during clenching in the tooth wear patients; however, the cause of this finding is not certain. Prolongation of occlusion time may exacerbate occlusal surfaces wear or excessive wear may prolong occlusion time. PMID- 26126285 TI - Sirtuins and the Metabolic Hurdles in Cancer. AB - The nutrient demands of cancer cannot be met by normal cell metabolism. Cancer cells undergo dramatic alteration of metabolic pathways in a process called reprogramming, characterized by increased nutrient uptake and re-purposing of these fuels for biosynthetic, bioenergetic or signaling pathways. Partitioning carbon sources toward growth and away from ATP production necessitates other means of generating energy for biosynthetic reactions. Additionally, cancer cell adaptations frequently lead to increased production of reactive oxygen species and lactic acid, which can be beneficial to cancer growth but also are potentially toxic and must be appropriately cleared. Sirtuins are a family of deacylases and ADP-ribosyltransferases with clear links to regulation of cancer metabolism. Through their unique ability to integrate cellular stress and nutrient status with coordination of metabolic outputs, sirtuins are well poised to play pivotal roles in tumor progression and survival. Here, we review the multi-faceted duties of sirtuins in tackling the metabolic hurdles in cancer. We focus on both beneficial and adverse effects of sirtuins in the regulation of energetic, biosynthetic and toxicity barriers faced by cancer cells. PMID- 26126290 TI - The Removal of EOG Artifacts From EEG Signals Using Independent Component Analysis and Multivariate Empirical Mode Decomposition. AB - The recorded electroencephalography (EEG) signals are usually contaminated by electrooculography (EOG) artifacts. In this paper, by using independent component analysis (ICA) and multivariate empirical mode decomposition (MEMD), the ICA based MEMD method was proposed to remove EOG artifacts (EOAs) from multichannel EEG signals. First, the EEG signals were decomposed by the MEMD into multiple multivariate intrinsic mode functions (MIMFs). The EOG-related components were then extracted by reconstructing the MIMFs corresponding to EOAs. After performing the ICA of EOG-related signals, the EOG-linked independent components were distinguished and rejected. Finally, the clean EEG signals were reconstructed by implementing the inverse transform of ICA and MEMD. The results of simulated and real data suggested that the proposed method could successfully eliminate EOAs from EEG signals and preserve useful EEG information with little loss. By comparing with other existing techniques, the proposed method achieved much improvement in terms of the increase of signal-to-noise and the decrease of mean square error after removing EOAs. PMID- 26126291 TI - Hybrid k -Nearest Neighbor Classifier. AB - Conventional k -nearest neighbor (KNN) classification approaches have several limitations when dealing with some problems caused by the special datasets, such as the sparse problem, the imbalance problem, and the noise problem. In this paper, we first perform a brief survey on the recent progress of the KNN classification approaches. Then, the hybrid KNN (HBKNN) classification approach, which takes into account the local and global information of the query sample, is designed to address the problems raised from the special datasets. In the following, the random subspace ensemble framework based on HBKNN (RS-HBKNN) classifier is proposed to perform classification on the datasets with noisy attributes in the high-dimensional space. Finally, the nonparametric tests are proposed to be adopted to compare the proposed method with other classification approaches over multiple datasets. The experiments on the real-world datasets from the Knowledge Extraction based on Evolutionary Learning dataset repository demonstrate that RS-HBKNN works well on real datasets, and outperforms most of the state-of-the-art classification approaches. PMID- 26126292 TI - An Improved Artificial Bee Colony Algorithm for Solving Hybrid Flexible Flowshop With Dynamic Operation Skipping. AB - In this paper, we propose an improved discrete artificial bee colony (DABC) algorithm to solve the hybrid flexible flowshop scheduling problem with dynamic operation skipping features in molten iron systems. First, each solution is represented by a two-vector-based solution representation, and a dynamic encoding mechanism is developed. Second, a flexible decoding strategy is designed. Next, a right-shift strategy considering the problem characteristics is developed, which can clearly improve the solution quality. In addition, several skipping and scheduling neighborhood structures are presented to balance the exploration and exploitation ability. Finally, an enhanced local search is embedded in the proposed algorithm to further improve the exploitation ability. The proposed algorithm is tested on sets of the instances that are generated based on the realistic production. Through comprehensive computational comparisons and statistical analysis, the highly effective performance of the proposed DABC algorithm is favorably compared against several presented algorithms, both in solution quality and efficiency. PMID- 26126293 TI - The Emergence of Environmental Health Literacy-From Its Roots to Its Future Potential. AB - BACKGROUND: Environmental health literacy (EHL) is coalescing into a new subdiscipline that combines key principles and procedural elements from the fields of risk communication, health literacy, environmental health sciences (EHS), communications research, and safety culture. These disciplines have contributed unique expertise and perspectives to the development of EHL. Since 1992, the National Institute of Environmental Health Sciences (NIEHS) has contributed to the evolution of EHL and now seeks to stimulate its scientific advancement and rigor. OBJECTIVES: The principal objective of this article is to stimulate a conversation on, and advance research in, EHL. DISCUSSION: In this article, we propose a definition of and conceptual framework for EHL, describe EHL in its social and historical context, identify the complementary fields and domains where EHL is being defined and implemented, and outline a research agenda. Extensive reviews of web and literature searches indicate that the concept of EHL is evolving rapidly, as are the definitions of its scope and inquiry. Although several authors have outlined different frameworks, we believe that a more nuanced model based on Bloom's taxonomy is better suited to EHL and to future research in this area. CONCLUSIONS: We posit that EHL can potentially benefit the conduct and outcomes of community-engaged and health disparities EHS research and can ensure that the translation of research findings will lead to greater understanding of specific risks, reduction of exposures, and improvement of health outcomes for individuals and communities. We provide four recommendations to advance work in EHL. PMID- 26126294 TI - Exposure to Road Traffic Noise and Behavioral Problems in 7-Year-Old Children: A Cohort Study. AB - BACKGROUND: Exposure to traffic noise has been associated with adverse effects on neuropsychological outcomes in children, but findings with regard to behavioral problems are inconsistent. OBJECTIVE: We investigated whether residential road traffic noise exposure is associated with behavioral problems in 7-year-old children. METHODS: We identified 46,940 children from the Danish National Birth Cohort with complete information on behavioral problems at 7 years of age and complete address history from conception to 7 years of age. Road traffic noise (Lden) was modeled at all present and historical addresses. Behavioral problems were assessed by the parent-reported Strengths and Difficulties Questionnaire (SDQ). Associations between pregnancy and childhood exposure to noise and behavioral problems were analyzed by multinomial or logistic regression and adjusted for potential confounders. RESULTS: A 10-dB increase in average time weighted road traffic noise exposure from birth to 7 years of age was associated with a 7% increase (95% CI: 1.00, 1.14) in abnormal versus normal total difficulties scores; 5% (95% CI: 1.00, 1.10) and 9% (95% CI: 1.03, 1.18) increases in borderline and abnormal hyperactivity/inattention subscale scores, respectively; and 5% (95% CI: 0.98, 1.14) and 6% (95% CI: 0.99, 1.12) increases in abnormal conduct problem and peer relationship problem subscale scores, respectively. Exposure to road traffic noise during pregnancy was not associated with child behavioral problems at 7 years of age. CONCLUSIONS: Residential road traffic noise in early childhood may be associated with behavioral problems, particularly hyperactivity/inattention symptoms. PMID- 26126295 TI - OTC Secondary Prevention of Metastatic Colorectal Cancer Moves Closer to Clinical Reality. PMID- 26126296 TI - Disseminating prevention info. PMID- 26126297 TI - Damages award for housing discrimination reversed in part. PMID- 26126299 TI - VA patient contended he did not authorize HIV, drug test. PMID- 26126298 TI - Man with HIV may proceed with ADA discrimination claim. PMID- 26126300 TI - SSI. Court affirms denial of woman's application for benefits. PMID- 26126302 TI - Origin, Incidence, and Management of Nongynecologic Pelvic Masses Seen on Cross sectional Imaging. AB - OBJECTIVE: To characterize the origin of nongynecologic pelvic masses. STUDY DESIGN: Using a radiology database, women who underwent transvaginal ultrasound, CT scan, or MRI for the indication of pelvic mass or pelvic fullness were identified. Demographic information, radiologic data, and outcomes were reviewed. RESULTS: A total of 450 women underwent imaging for the above indications been 2002 and 2012. Of those women, 347 had at least 1 pelvic mass; 3 women had both gynecologic and nongynecologic masses, and 13 women had 2 gynecologic masses. Forty women (12%) had nongynecologic pathology. Of the nongynecologic masses 13 were gastrointestinal in origin, 9 were urologic, and 9 were neuromuscular. Other etiologies included metastatic cancers, iatrogenic masses, and hematologic masses. Seventy-four women had malignant pathology (21%): 17/40 (43%) of nongynecologic pelvic masses and 57/320 (18%) of gynecologic masses (p < 0.05). CONCLUSION: Compared to pelvic masses of gynecologic origin, nongynecologic pelvic masses are more likely to be malignant. PMID- 26126303 TI - Reproductive Outcomes in Women Following Radiofrequency Volumetric Thermal Ablation of Symptomatic Fibroids. A Retrospective Case Series Analysis. AB - OBJECTIVE: To report reproductive outcomes in women who underwent radiofrequency volumetric thermal ablation (RFVTA) of symptomatic uterine fibroids. STUDY DESIGN: Retrospective analysis of fibroid characteristics, treatment parameters, and pregnancy outcomes of 6 subjects in 3 prospective trials of laparoscopic ultrasound-guided RFVTA. RESULTS: Despite the requirement that women enrolled in the RFVTA studies did not desire current or future childbearing and were to continue contraception, 6 subjects conceived at between 3.5 and 15 months postreatment. The number of fibroids treated per patient ranged from 1 to 7, measured between 1.0 cm and 7.6 cm at the greatest diameter, and included multiple types (submucosal, intramural, transmural, and subserosal). Five patients (5/6, 83%) delivered full-term healthy infants: 1 by vaginal delivery and 4 by cesarean section. One patient (1/6, 17%) had a spontaneous miscarriage in the first trimester. CONCLUSION: Viable, full-term pregnancies are possible after RFVTA. Further, in-depth study of pregnancy outcomes following laparoscopic ultrasound-guided radiofrequency, volumetric ablation of fibroids is warranted. PMID- 26126304 TI - Estradiol and Antagonist Pretreatment Prior to Microdose Leuprolide in in Vitro Fertilization. Does It Improve IVF Outcomes in Poor Responders as Compared to Oral Contraceptive Pill? AB - OBJECTIVE: To compare in vitro fertilization (IVF) outcomes in low responders stimulated with microdose leuprolide protocol (ML) following pretreatment with either oral contraceptive pill (OCP) or luteal estradiol (E2) + GnRH antagonist (E2 + antag) for follicular synchronization prior to controlled ovarian hyperstimulation (COH). STUDY DESIGN: This was a retrospective study of 130 women, who were poor responders, undergoing IVF with either OCP/ML or E2+ antag/ML protocols. The main outcome measures were ongoing pregnancy rates, number of oocytes retrieved, and cancellation rate. RESULTS: Both groups were similar in baseline characteristics. There were no significant differences in gonadotropin requirement, cancellation rate, and number of embryos transferred. Ongoing pregnancy rates (40% vs. 15%) were significantly higher in the OCP/ML group. Trends toward greater number of oocytes retrieved (7.7 +/- 3.4 vs. 5.9 +/- 4.2) and improved implantation rates (20% vs. 12%) were also noted, but these did not reach statistical significance. CONCLUSION: E2+antag pretreatment does not appear to improve IVF outcomes in ML protocol when compared to the standard OCP in poor responders. Randomized trials with adequate power to study the optimal method of steroid pretreatments appear justified. PMID- 26126305 TI - Do Obstetrical Providers, Counsel Women About Postpartum Pelvic Floor Dysfunction? AB - OBJECTIVE: To assess prenatal counseling practices of obstetrics providers related to postpartum pelvic floor dysfunction at centers with integrated urogynecology services. STUDY DESIGN: A cross-sectional survey was distributed to obstetrical providers through urogynecology colleagues. The survey included questions about level of training as well as counseling practices related to common postpartum pelvic floor symptoms. All statistical tests were two-sided, and p values < 0.05 were considered statistically significant. RESULTS: A total of 192 surveys were received; 19 respondents did not perform their own prenatal counseling and were excluded. Among the remaining 173 respondents, 94 (56.3%) of those who answered the question reported never discussing postpartum urinary incontinence, and 73.7% reported never discussing postpartum fecal incontinence during prenatal counseling. Obstetrics and gynecology residents were significantly less likely than attending physicians to report discussing various pelvic floor dysfunction topics in prenatal counseling. Among those who reported not counseling women regarding pelvic floor dysfunction, the most common reason cited was lack of time (39.9%) followed by lack of sufficient information (30.1%). CONCLUSION: Prenatal counseling of pelvic floor dysfunction risk is lacking at all levels of obstetrical training. Limitations of time and information are the obstacles most often cited by providers. PMID- 26126306 TI - Effect of Single-Use Negative Pressure Wound Therapy on Postcesarean Infections and Wound Complications for High-Risk Patients. AB - OBJECTIVE: To evaluate the effect of a single-use negative pressure wound therapy (NPWT) system on postoperative complications after cesarean delivery. STUDY DESIGN: A historical control cohort of women was collected as part of a quality improvement project over a 6-month period. All women with at least 1 risk factor for postoperative complications were included in this control cohort. An intervention cohort of 110 women with at least 1 risk factor for postoperative complications was eligible to have a single-use NPWT system placed at the time of cesarean delivery. Primary outcomes were wound/infectious morbidity, including any surgical site infection (deep or superficial) as defined by the Centers for Disease Control, or wound separation without infection. RESULTS: Despite significantly higher overall burden of risk factors for postoperative complications, the intervention group showed a significantly lower rate (21.0% vs. 6.4%, p = 0.0007) of overall wound/infectious morbidity. The rate of isolated wound separation betweenthe 2 groups was not statistically significant (3.8% vs. 2.7%, p = 0.754) and was likely due to the low rate of wound separations. CONCLUSION: Application of an NPWT system to a primarily closed cesarean incision at time of surgery significantly decreased both deep and superficial infectious morbidity in our intervention group, which had more risk factors for wound complications and postoperative infection. PMID- 26126307 TI - Blood Contaminated Amniotic Fluid and the Lamellar Body Count Fetal Lung Maturity Test. AB - OBJECTIVE: To determine if maternal blood contamination falsely elevates the lamellar body count fetal lung maturity test. STUDY DESIGN: Fifty mothers undergoing amniocentesis for fetal lung maturity consented to participation in the study. For each participant a blood-contaminated sample using the patient's own blood was run in tandem with the noncontaminated sample used for clinical practice. RESULTS: Of the 50 study patient samples the lamellar body count decreased by >= 3,000/MUL in 33 (66%) and remained unchanged in 16 (32%). In only 1 case did the value increase--the actual result of 37,000/MUL increased to 44,000/MUL, both of which exceeded the mature level in our institution. CONCLUSION: Maternal blood contamination of amniotic fluid does not falsely increase the lamellar body count in 98% of cases. The result was falsely lowered in 2 out of 3 cases. Therefore, a mature lamellar body count test result in a blood-contaminated sample is reliable PMID- 26126308 TI - The Evidence-based Vulvodynia Assessment Project. A National Registry for the Study of Vulvodynia. AB - OBJECTIVE: To create a national registry for the study of vulvodynia in order to enhance classification of vulvodynia based on multiple phenotypic domains such as pain characteristics, clinical examination, sexual function, psychological functioning, and distress. STUDY DESIGN: Methodology for this prospective cohort registry was institutional review board approved and implemented at 8 enrollment sites starting in 2009. Women underwent gynecologic evaluation and pressure sensory testing for assessment of pain sensitivity in the vaginal mucosa and vaginal muscles. Psychometric questionnaires were used to assess self-described pain, distress, sexual function, and quality of life. RESULTS: More than 300 women were enrolled and 176 charts were analyzed. This cohort had a median age of 29 years and median pain duration of 25.5 months. A total of 84% of participants were previously or currently sexually active in spite of pain. The most common pain comorbidities reported by the women were migraines (34%), chronic pelvic pain (22%), and irritable bowel syndrome (20%). Anxiety affected 41% of the cohort. More than 90% presented with localized vestibular pain, and 90% had muscular examination abnormalities. CONCLUSION: A national registry for the study of vulvodynia was established with successful enrollment of participants at 8 sites. In addition to the cotton swab evaluation for vulvar allodynia, women with vulvar chronic pain should also be routinely screened for musculoskeletal dysfunction, emotional distress with specific emphasis on anxiety, and comorbid pain conditions. PMID- 26126309 TI - Maternal Abortion History and the Risk of Congenital Heart Defects. A Case Control Study. AB - OBJECTIVE: To explore the association between maternal abortion history and congenital heart defect (CHD) risk in subsequent pregnancies. STUDY DESIGN: A multihospital-based case-control study was conducted. The cases included 370 women whose fetuses were diagnosed with CHDs. The controls were 413 women with fetuses without an apparent malformation in the same hospital. All of the participants were investigated by trained interviewers. Univariate analysis was performed, followed by multivariate logistic regression analysis to calculate odds ratio and 95% confidence interval to evaluate the risk of maternal abortion history on CHD risk. RESULTS: There were no statistically significant positive associations between maternal abortion (induced abortion and spontaneous abortion) occurrence and the risk of CHDs. There were no statistically significant positive associations between the number of maternal abortions (induced and spontaneous) and the risk of congenital heart defects. CONCLUSION: Maternal abortion history may not be associated with fetal CHDs. PMID- 26126310 TI - Outcomes of Treatment of Gestational Trophoblastic Neoplasia in a Primarily Indigent Urban Population. AB - OBJECTIVE: To review outcomes of women with gestational trophoblastic neoplasia (GTN) who presented to an inner-city hospital system, given that the rigorous treatment and follow-up for GTN is often problematic for certain women of low socioeconomic status with limited resources and social support. STUDY DESIGN: A retrospective review was performed with IRB approval of patients diagnosed with GTN based on the revised WHO scoring system from 1999-2010 at our institution. SPSS Statistics software was used to perform univariate and multivariate analyses. RESULTS: Forty-nine patients were treated for GTN: 32 low-risk and 17 high-risk. Low-risk patients received an average of 5 cycles of initial single agent chemotherapy. Six patients had persistent disease and were switched to a second single-agent regimen. One patient required multiagent chemotherapy for normalization of human chorionic gonadotropin levels. No patient had recurrence of disease. All high-risk patients were initially treated with multiagent chemotherapy, averaging 8 cycles. Two of the 17 patients persisted; 1 recurred. All 3 currently have no evidence of disease. No patient died of disease. CONCLUSION: Excellent treatment outcomes in patients with GTN may be achieved in disadvantaged populations when compliance to regimens is optimized. PMID- 26126311 TI - Sclerosing Stromal Ovarian Tumor Combined with Early Onset Severe Preeclampsia. A Case Report. AB - BACKGROUND: Sclerosing stromal tumor (SST) of the ovary is an extremely rare, benign, sex cord-stromal tumor. The tumor consists of cells with the multilineage potential of undifferentiated mesenchymal cells and the ability to secrete estrogen or androgen. Current research suggests that the tumor originates in the ovarian cortex. SSTs of the ovary are predominantly found in young women aged 20 30 years; information describing SST during pregnancy is limited. CASE: We report a case of SST of the ovary combined with early onset severe preeclampsia. CONCLUSION: We document the clinical and pathological characteristics of the patient's disease, including the effects on the pregnancy and fetus. PMID- 26126312 TI - Uterine Perforation During Dilation and Evacuation Prior to Fetal Extraction--Now What? A Case Report. AB - BACKGROUND: Uterine perforation is an infrequent but serious complication of dilation and evacuation (O&E). The purpose of this case report is to describe management strategies once a uterine perforation is identified. CASE: A 15-year old female at 15 weeks' gestation presented to a freestanding clinic for elective abortion. After serial cervical dilation, omentum was seen in the suction curette. The patient was transferred to a nearby hospital, she underwent an exploratory laparotomy. A 1.5-cm anterior uterine perforation was found. The uterus was evacuated under direct visualization prior to repair of the defect. CONCLUSION: Uterine perforation during D&E often requires laparotomy to repair the defect and to evaluate for injury to adjacent organs. Evacuation can be completed transcervically under direct visualization or through the perforation site. PMID- 26126313 TI - Cervical Ectopic Pregnancy: Persistence Despite a Serologically Negative beta hCG. A Case Report. AB - BACKGROUND: Cervical pregnancy is a rare type of ectopic pregnancy that can be associated with significant hemorrhage and loss of fertility. Given its rarity, most effective treatment protocols are not well established. CASE: A 33-year-old primigravid woman at 11 weeks' gestation presented to our institution with a cervical ectopic pregnancy with an initial beta-hCG of 114,080 IU/L. She received 2 doses of systemic multidose methotrexate (1 mg/kg) with oral leucovorin on alternating days. Fetal intracardiac potassium chloride injection was also performed. Despite an appropriate decline to undetectable levels of serum beta hCG, as well as resumption of menses, there was persistent sonographic demonstration of the cervical ectopic pregnancy. Surgery was ultimately required to remove the ectopic products of conception. CONCLUSION: Despite seemingly successful medical treatment of the cervical ectopic pregnancy with resultant undetectable serum beta-hCG levels, surgery was necessary for complete resolution of the cervical pregnancy. This report supports the need to integrate both serum beta-hCG levels and ultrasound to ensure complete resolution of these rare pregnancies. PMID- 26126314 TI - Imprinted Genes on Chromosome 6 Are Unlikely to Cause Hydatidiform Mole. A Report of Two Cases. AB - BACKGROUND: Hydatidiform moles are associated with an excess of paternal genome set(s) or abnormal imprinting of multiple imprinted genes. However, it appears unlikely that all imprinted genes are relevant for the pathogenesis of a hydatidiform mole. CASES: We studied two rare cases of triploid, diandric moles that were tetrasomic for chromosome 6. DNA-marker analysis showed that in one mole the fourth chromosome 6 originated in the father, and in the other mole the fourth chromosome 6 originated in the mother. Histopathologic revision disclosed that both moles were partial moles with no significant difference in the phenotypes. CONCLUSION: It is unlikely that a major gene involved in the pathogenesis of hydatidiform mole, or a major gene involved in determining the severity of the molar phenotype, is located on chromosome 6. PMID- 26126315 TI - Anaplastic Large Cell Lymphoma in Pregnancy. A Case Report. AB - BACKGROUND: Anaplastic large cell lymphoma is rarely diagnosed during pregnancy, and patients may be erroneously diagnosed with a dermatosis. CASE: A 34-year-old female was diagnosed with pruritic urticarial papules and plaques of pregnancy in the third trimester. She underwent elective repeat cesarean section with a postoperative course complicated by skin and gingival ulcers and persistent fever. Imaging revealed lung and brain nodules. Video-assisted thoracic surgery lung biopsy demonstrated anaplastic large cell lymphoma. CONCLUSION: It is important to consider the diagnosis of anaplastic large cell lymphoma in a pregnant patient who presents with cutaneous symptoms. PMID- 26126316 TI - Ovarian Vein Thrombosis with Involvement of the Renal Vein After Cesarean Section. A Case Report. AB - BACKGROUND: Ovarian vein thrombosis (OVT) is a rare postpartum venous thromboembolic disease (VTED) which may involve the renal vein and the inferior vena cava. It can cause pulmonary thromboembolism and is a potentially fatal postpartum complication. A high index of suspicion is required for the prompt diagnosis and management in cases with low back or abdominal pain after delivery. CASE: A 32-year-old woman complained of left low back pain at 6 days after cesarean section. On physical examination she had temperature of 37.7 degrees C and localized obvious percussion tenderness in the left renal region. Pelvic examination was unremarkable. Laboratory investigations revealed elevated white blood cell count (12,000) with neutrophilia (84.8%), urine protein 3+, and urine occult blood 3+. Computed tomography scan showed the classical radiological presentation of OVT with involvement of the renal vein. The patient was successfully managed conservatively with low-molecular-weight heparin and antibiotics. CONCLUSION: OVT with involvement of the renal vein is a very rare condition of postpartum VTED and may cause serious complications if left untreated. A high index of suspicion is required in order to diagnose this unusual cause of low back or abdominal pain and fever after delivery. PMID- 26126317 TI - Xanthogranulomatous Oophoritis Presenting as an Adnexal Mass and Bowel Obstruction. A Case Report. AB - BACKGROUND: Xanthogranulomatous inflammation of the female genital tract is a rare entity. When the gynecological organs are affected, it is particularly unusual for xanthogranulomataus inflammation to involve only the ovary. CASE: A 45-year-old woman with an intrauterine device, long-term exposure to nicotine, and hyperlipidemia presented with an adnexal mass and bowel obstruction. She underwent 2 exploratory laparotomies, ureteral stent placement, left salpingooophorectomy, and rectosigmoid resection with end colostomy. Pathology revealed xanthogranulomatous oophoritis without involvement of the associated fallopian tube. CONCLUSION: The synergistic effects of intrauterine device use, abnormal lipid levels, and long-term nicotine exposure may have contributed to the development of this patient's condition. Knowledge of xanthogranulomatous inflammation is essential to avoid misdiagnosis of malignancy and excessive surgical intervention. PMID- 26126318 TI - Emergence of community-acquired methicillin-resistant Staphylococcus aureus in an Iranian referral paediatric hospital. AB - The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals has been changed in recent years due to the arrival of community associated MRSA (CA-MRSA) strains into healthcare settings. The aim of this study is to investigate the distribution of staphylococcal cassette chromosome mec (SCCmec) type V as well as SCCmec IV subtypes, which have been associated with community-acquired infection among healthcare-associated MRSA (HA-MRSA) isolates. Antimicrobial susceptibility, SCCmec type, spa type and the presence of Panton Valentine leukocidin (PVL) genes were determined for all HA-MRSA isolates in an Iranian referral hospital. In this study of 48 HA-MRSA isolates, 13 (27%), three (6.2%), five (10.4%) and one (2%) belonged to SCCmec subtypes IVa, IVb, IVc and IVd, respectively. Only two isolates (4.2%) belonged to SCCmec types V Notably, one isolate was found to harbour concurrent SCCmec subtypes IVb and IVd. MRSA containing SCCmec subtype IVb, IVc and IVd as well as type V isolates were all susceptible to chloramphenicol, clindamycin and rifampicin, while the sensitivity to these antibiotics was lower among MRSA containing SCCmec subtype IVa. The most frequently observed spa ttype was t037, accounting for 88% (22/25). Three other spa type was t002, t1816 and t4478. Large reservoirs of MRSA containing type IV subtypes and type V now exist in patients in this Iranian hospital. Therefore, effective infection control management in order to control the spread of CA-MRSA is highly recommended. PMID- 26126319 TI - The lipaemic index: clinical observations. AB - The lipaemic index can be used to assess whether or not blood samples are suitable for laboratory analysis. However, little is known about which patients have a raised lipaemic index. In this article we study patient demographics and serum lipid concentrations in samples showing a raised lipaemic index. Of the 4271 patient samples measured in the month of July 2014, a total of 310 had a lipaemic index 0.4. Blood samples showing a raised lipaemic index were studied in a retrospective patient case review of laboratory results. Overall, 7.3% of all samples measured had a raised lipaemic index 0.4. This study found that males were more likely to have a high lipaemic index (56%) and neonates were the group most frequently producing lipaemic samples (30.6%). The correlation between the lipaemic index and the triglyceride concentration showed an r2 value of only 0.37 (r = 0.61), and the correlation between cholesterol and lipaemic index showed an r2 value of 0.16 (r = -0.41). Male and neonatal samples were most likely to show a raised lipaemic index. There was a positive correlation between sample triglyceride and lipaemic index and an inverse correlation with cholesterol concentration and the lipaemic index, although this did not account for all the variance. Thus, other factors may also be important in the expression of the lipaemic index. PMID- 26126320 TI - 25-hydroxy vitamin D and ischaemia-modified albumin levels in psoriasis and their association with disease severity. AB - Psoriasis is a T-helper-1 (Th1)/Th17-mediated chronic inflammatory skin disease, characterised by hyperproliferation of keratinocytes. Psoriasis and cardiovascular disease share similar pathogenic mechanisms such as vascular endothelial cell dysfunction, oxidative stress and metabolic syndrome. 25-hydroxy vitamin D is an immune-regulatory hormone, with the ability to reduce cellular proliferation in psoriasis. Ischaemia-modified albumin (IMA) is a marker of oxidative stress. This study examined 25-hydroxy vitamin D, IMA and high sensitivity C-reactive protein (hs-CRP) levels in patients with psoriasis, in comparison with healthy controls and their possible association with disease severity. A total of 43 cases of psoriasis and 43 controls were included in this cross-sectional study, and severity grading was performed according to psoriasis area severity index (PASI) scoring. Serum 25-hydroxy vitamin D, IMA and hs-CRP were evaluated in all study subjects. In psoriasis, 25-hydroxy vitamin D showed a significant decline, while hs-CRP and IMA levels were significantly elevated, as compared with controls. Serum 25-hydroxy vitamin D showed a significant negative correlation with PASI score. hs-CRP and IMA showed a significant positive correlation with PASI score. Significant negative correlation was observed between 25-hydroxy vitamin D and hs-CRP; 25-hydroxy vitamin D and IMA levels in psoriasis. The results indicate that psoriasis is associated with significantly lowered 25-hydroxy vitamin D levels, along with increased systemic inflammation and oxidative stress, especially in severe disease. Thus, vitamin D supplementation might reduce systemic inflammation and oxidative stress and help in delaying the pathogenesis of co-morbidities associated with psoriasis. PMID- 26126321 TI - Pan-cytokeratin markers for rapid frozen section immunocytochemistry from head and facial Mohs cases of basal cell carcinoma: a comparison and evaluation to determine the marker of choice. AB - The application of immunocytochemistry in the field of Mohs micrographic surgery (MMS) is well established. This study evaluates the use of pan-cytokeratins (AE1/AE3, MNF116 and AE1/AE3+PCK26) in the assessment of basal cell carcinoma (BCC) on frozen tissue debulk specimens. Fifty-five cases of BCC, all from head and facial sites, were assessed in the study. In addition to staining all cases for the three cytokeratin antibodies under investigation, sections were also stained with haematoxylin and eosin (H&E) to demonstrate tumour architecture and morphology. All sections for immunocytochemistry were stained on a Roche Ventana BenchMark Ultra automated platform employing a rapid frozen section protocol. Results were assessed based on the intensity of staining of keratinocytes (scale: 0-100%), as well as sensitivity of staining determined by the total percentage of keratinocytes stained within the tissue section. AE1/AE3 demonstrated the most consistent staining both in terms of intensity of staining and sensitivity, with a mean of 99.1% and 99.9%, respectively. AE1/AE3+PCK26 average results indicated scores of 70.6% for intensity and 87.2% for sensitivity, with MNF116 scoring 92.9% for intensity but only 57.3% for sensitivity. The data indicate that AE1/AE3 is the best pan-cytokeratin antibody to use in the assessment of BCC in MMS. The use of cytokeratin immunocytochemistry is justified in morphologically complex cases of BCC, or in cases where dense inflammatory infiltrate surrounding any suspicious cells make identification of small numbers of tumour cells difficult to determine with just an H&E stain. The significant rationale is that cytokeratin staining is a valuable adjunct in the study of tumour cell assessment in cases of MMS for BCC. In addition, the use of anti-AE1/AE3 cytokeratin antibodies provides the most consistent staining results for such cases. PMID- 26126322 TI - Helicobacter pylori: correlation of the virulence marker iceA allele with clinical outcome in a high prevalence area. AB - The association of Helicobacter pylori virulence marker 'induced by contact with epithelium A' (iceA) allele types was determined in H. pylori-related diseases and virulence markers. Gastric biopsies were obtained at EGD from patients for culture, histopathology and polymerase chain reaction (PCR) for iceA types, cagA and vacA alleles. Two hundred and eighty-four H. pylori isolates were examined. iceA type 1 was positive in 177 (62%) and iceA type 2 in 158 (56%). In iceA type 2, gastric ulcer was present in 34 (21%) (P < 0.001) and carcinoma in 28 (25%) (P = 0.002), compared to nine (8%) and 2 (2%) in iceA type 2-negative cases. For iceA type 2, 139 (88%) were associated with chronic active gastritis compared to 95 (75%) (P = 0.006) in iceA type 2-negative. H. pylori cagA was positive in 101 (64%) iceA type 2 strains compared to 57 (45%) in negative strains (P = 0.002). H. pylori iceA type 2 was dominant and associated with cagA, chronic active inflammation, gastric ulcer and carcinoma. PMID- 26126323 TI - Stem cells as a novel therapy for amyotrophic lateral sclerosis. PMID- 26126324 TI - Investigation into the misidentification of Hazard Group 3 gastrointestinal pathogens and associated health and safety risks. PMID- 26126325 TI - Lung cancer: the immune system and radiation. AB - Lung cancer has a known relationship with smoking and is one of the leading causes of cancer-related death worldwide. Although the number of studies discussing lung cancer is vast, treatment efficacy is still suboptimal due to the wide range of factors that affect patient outcome. This review aims to collect information on lung cancer treatment, specially focused on radiation therapy. It also compiles information regarding the influence of radiotherapy on the immune system and its response to tumour cells. It evaluates how immune cells react after radiation exposure and the influence of their cytokines in the tumour microenvironment. The literature analysis points out that the immune system is a very promising field of investigation regarding prognosis, mostly because the stromal microenvironment in the tumour can provide some information about what can succeed in the future concerning treatment choices and perspectives. T cells (CD4+ and CD8+), interleukin-8, vascular endothelial growth factor and transforming growth factor-beta seem to have a key role in the immune response after radiation exposure. The lack of large scale studies means there is no common consensus in the scientific community about the role of the immune system in lung cancer patients treated with radiotherapy. Clarification of the mechanism behind the immune response after radiation can lead to better treatments and better quality life for patients. PMID- 26126327 TI - [How to make examination questions]. PMID- 26126326 TI - Medical uses of marijuana (Cannabis sativa): fact or fallacy? AB - Marijuana (Cannabis sativa) has been used throughout the world medically, recreationally and spiritually for thousands of years. In South Africa, from the mid-19th century to the 1920s, practitioners prescribed it for a multitude of conditions. In 1928 it was classified as a Schedule I substance, illegal, and without medical value. Ironically, with this prohibition, cannabis became the most widely used illicit recreational drug, not only in South Africa, but worldwide. Cannabis is generally regarded as enjoyable and relaxing without the addictive risks of opioids or stimulants. In alternative medicine circles it has never lost its appeal. To date 23 States in the USA have legalised its medical use despite the federal ban. Unfortunately, little about cannabis is not without controversy. Its main active ingredient, delta-9-tetrahydrocannabinol (THC), was not isolated until 1964, and it was not until the 1990s that the far-reaching modulatory activities of the endocannabinoid system in the human body was studied. This system's elucidation raises the possibility of many promising pharmaceutical applications, even as restrictions show no sign of abating. Recreational use of cannabis continues to increase, despite growing evidence of its addictive potential, particularly in the young. Public approval drives medical cannabis legalisation efforts without the scientific data normally required to justify a new medication's introduction. This review explores these controversies and whether cannabis is a panacea, a scourge, or both. PMID- 26126328 TI - [Manual for pathological diagnosis of diabetic nephropathy and hypertensive nephrosclerosis]. PMID- 26126329 TI - [The genetic basis of nephrotic syndrome]. PMID- 26126330 TI - [Alport syndrome]. PMID- 26126331 TI - [Bartter syndrome and Gitelman syndrome]. PMID- 26126332 TI - [Causative genetic variants of pseudohypoaldosteronism type II and essential hypertension]. PMID- 26126333 TI - [Genetic diseases of renal phosphate handling]. PMID- 26126335 TI - [Cystic kidney disease]. PMID- 26126334 TI - [Disturbance of uric acid metabolism]. PMID- 26126336 TI - [Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) -associated glomerulonephritis with acute pancreatitis: a case report]. AB - We report here a case of a 64-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) -associated glomerulonephritis who developed acute pancreatitis. The patient was admitted to our hospital because of abnormal urinalysis findings, edema, and progressive renal failure. Laboratory studies showed a high white blood cell count (11,570/MUL), anemia (hemoglobin 7.8 g/dL), and elevated serum creatinine (2.36 mg/dL) and C-reactive protein (12.20 mg/dL) levels. Furthermore, the MPO-ANCA titer was very high (1,625 U/mL, normal range < 10 U/mL). Histopathological findings of the renal biopsy were consistent with microscopic polyangiitis. Accordingly, we diagnosed MPO-ANCA-associated glomerulonephritis. On the day after the renal biopsy, the patient complained of low back pain. Computed tomography (CT) revealed postbiopsy hemorrhage. Thereafter, the patient's symptoms and laboratory studies gradually worsened. A repeat CT performed a few days later revealed no changes in the perirenal hematoma; however, an enlarged pancreas head was incidentally observed. There was no obvious cause of acute pancreatitis, and MPO-ANCA-associated vasculitis, although rare, was suspected as the cause. We initiated prednisolone pulse therapy for vasculitis along with the administration of nafamostat mesilate and ulinastatin for acute pancreatitis. Subsequently, the levels of pancreatic enzymes gradually increased, but several days later, abdominal magnetic resonance imaging showed improvement in the pancreas head. The pancreatitis gradually resolved over time. Acute pancreatitis occurring concurrently with MPO-ANCA associated glomerulonephritis is extremely rare. To our knowledge, only a few such cases have been reported and have suggested that steroid therapy may play a role in triggering pancreatic involvement. In our case, however, an enlarged pancreas head was observed before steroid therapy was initiated. Therefore, we consider our case to be very rare. PMID- 26126337 TI - To Delete or Not to Delete, That Is the Question. PMID- 26126338 TI - What Is Affordable? PMID- 26126339 TI - Dr. Stumpel responds. PMID- 26126340 TI - The Sum of Its Parts. PMID- 26126341 TI - A Grammar of Ethics. PMID- 26126343 TI - Forensic Odontology. PMID- 26126342 TI - BPA Harms Tooth Enamel in Rats, Mimics MIH. PMID- 26126344 TI - Overview of Forensic Odontology. PMID- 26126345 TI - Atypical Forensic Dental Identifications. AB - Forensic dental identification specialists are typically the last conventional option for postmortem identification. Forensic dental identification is most often accomplished by comparing radiographs of the decedent's teeth with the dental radiographs obtained from the dentist of the suspected victim. Unfortunately, antemortem dental radiographs are not always available. When presented with this challenge, the authors of this article have been successful in completing identifications using means other than dental radiographic comparison. PMID- 26126346 TI - Bite-Mark and Pattern Injury Analysis: A Brief Status Overview. AB - Bite marks are one component of forensic investigation requiring subjective interpretation for determining unknown source evidence to a putative suspect. Recent scrutiny has lead to questions about the scientific validity of patterned evidence, bite-mark analysis in particular, and its role in judicial proceedings. This article discusses some issues that persist in forensic circles and the difficulties surrounding the field of bite-mark analysis that inherently must employ human subjectivity in its execution of duty. PMID- 26126347 TI - Forensic Dental Age Estimation: An Overview. AB - Forensic age estimation is a scientific process that estimates an individual's true chronologic age by assessing skeletal and dental development and maturation. Although human growth and maturation is unique to each individual, dental techniques for estimating age are currently considered the best in assessing true chronologic age particularly during the age range when the dentition is undergoing morphologic development. This article reviews the principles, methodology and commonly used techniques in forensic age estimation cases. PMID- 26126348 TI - The Forensic Dentist: An Overview of Expert Roles in Animal Bite-Mark Investigations. AB - With increasing incidence of human/animal confrontation and the potential for injury or even death, dentists who choose to work in the forensic sciences may be called upon to utilize their skills and training to render opinions in criminal and civil cases. The authors will show how working in a cooperative environment and combining their skills with those of other experts can achieve the best result. PMID- 26126349 TI - Report Employee Injuries Immediately. PMID- 26126350 TI - Uses and Disclosures of Patient Health Information: Part II. PMID- 26126351 TI - [End of life care, efforts to continue]. PMID- 26126352 TI - [Debating the politics of health care]. PMID- 26126353 TI - [Advanced practice nursing, opinion of the French nursing college]. PMID- 26126354 TI - [Will the nursing code of ethics soon be publicized?]. PMID- 26126355 TI - [The National Academy of Medicine is cautious regarding sedation]. PMID- 26126356 TI - [Developing injectable chemotherapy for home use]. PMID- 26126357 TI - [2015 vaccination calendar]. PMID- 26126358 TI - [A new journal for nurses]. PMID- 26126359 TI - [Recommendations for erythrocyte transfusion]. PMID- 26126360 TI - [Status report of the hospital information systems modernization program]. PMID- 26126361 TI - [A new directory of health careers]. PMID- 26126362 TI - [Measuring inpatient satisfaction]. PMID- 26126363 TI - [The right to not reveal pre-existing cancer, an insufficient provision?]. PMID- 26126365 TI - [Health facility overview]. PMID- 26126364 TI - [AIDS seropositivity, 2003-2013 report]. PMID- 26126366 TI - [A new plan for rare disabilities]. PMID- 26126367 TI - [The bill on societal adaptation to aging to be voted on in the Senate]. PMID- 26126368 TI - [Roll out of telemedicine, working group report]. PMID- 26126369 TI - [New rectangular format dressings]. PMID- 26126370 TI - [One step closer to an artificial pancreas]. PMID- 26126371 TI - [The importance of phenotypes in the management of asthma]. PMID- 26126372 TI - [Training and professional attitudes regarding standard precautions]. AB - In 2011, the Hospital Hygiene Practices Assessment Group provided health institutions with a tool to assess he institutional policy and available resources regarding the application of standard precautions as well as training and staff attitudes. The professionals declare that the practices relating to the risk of contact with contaminated equipment and the action to take in the event of the contact of biological fluid with mucosa are good. The practices to improve concern as a priority the wearing of protective equipment, the changing of gloves and the washing of hands between activities. PMID- 26126373 TI - [Type 2 diabetes and eating disorders]. AB - Patients with type 2 diabetes are expected to follow numerous dietary recommendations which can be difficult to adhere to in the long-term. However, to improve the balance of their diabetes and avoid complications, it is important to lose weight and restore a healthy relationship with food. A dietary approach combining therapeutic education principles and a bio-psycho-sensorial approach can be useful in this context. PMID- 26126374 TI - [The "room of errors" called into question]. AB - The "room of errors" called into question. In order to raise caregivers' awareness in relation to patient safety, some hospitals have setup a room of errors. The main aim of this method is to remind caregivers of best practices. However, it can give professionals the feeling of being inadequate and transfers certain responsibilities from the institution to the individual. Consequently, it is perhaps worthwhile reconsidering this approach. PMID- 26126375 TI - [The patient pathway, an essential element of the care project]. AB - Constructing an innovative care project in oncology, common to two healthcare institutions with different statuses, was a challenge for the directors of nursing of the Claudius-Regaud Institute and Toulouse university hospital. The patient care pathway was a major organisational element of the project, keyto ensuring high quality patient care, from the diagnosis through to the personalised post-cancer plan. PMID- 26126376 TI - [Ambulatory surgery. A paradigm change for all]. PMID- 26126377 TI - [Day surgery and public authorities]. AB - France's public authorities finally came to realise that the country was lagging behind in the development of day surgery after the publication of a report by the French audit office in September 2013. An institutional policy to develop this type of care was put in place 10 years ago. PMID- 26126378 TI - [The economic challenges of day surgery]. AB - The development of day surgery requires the hospital system to be restructured in order for real savings to be made. The hospital must therefore modify its organisational set-up to reap the benefits of the efficiency gains resulting from the development of day surgery. PMID- 26126379 TI - [Day surgery: recommendations, tools and feedback]. AB - The ANAP (French agency for supporting medical institutions' performance) has the legal responsibility to provide tools and recommendations and to support institutions in improving their organisational performance. In the context of the public authorities' push for day surgery, the ANAP has specifically addressed this issue, gathering feedback from French and European health institutions. PMID- 26126380 TI - [The organizational challenges of day surgery for hospitals]. AB - The ambulatory and conventional care models should not be opposed to one another as they can in fact feed off and enrich each other. The outpatient culture inspires and encourages the drive for more innovative forms of organisation. As a result, a "patient" model emerges, centred on a holistic approach to organisation and patient care. PMID- 26126381 TI - [Organization of nurses' work in day surgery]. AB - Day surgery articulates strongly the dimensions of time, space and work organisation. This modifies the nursing practice itself, the visibility and the recognition of the tasks: maintaining the flow of the pathways, monitoring, informing the patient and seeing to their comfort. PMID- 26126382 TI - [Setting up a day surgery department]. AB - Day surgery must be treated as a priority. The efficient implementation of an outpatient structure therefore requires strict rigour in terms of patient eligibility, organisation of the flows as well as the safety of the care pathway and the logistics. PMID- 26126383 TI - ["Day surgery, for an efficient patient pathway"]. AB - Working in day surgery requires teams to harmonise their practices and coordinate with each other at all times.We interview Celine Burkhardt, a healthcare manager who oversaw the deployment of a day surgery unit in her hospital. PMID- 26126384 TI - [The challenge of ambulatory surgery]. PMID- 26126385 TI - [Bibliography. Ambulatory surgery]. PMID- 26126386 TI - [Delegation of authority in the hospital sector]. PMID- 26126387 TI - Endometriosis: A Culprit for Chronic Pelvic Pain. PMID- 26126388 TI - Sun, sea, holidays and eczema. PMID- 26126389 TI - Swimming pools and eczema. PMID- 26126390 TI - Here comes the sun. PMID- 26126391 TI - How to handle summer skin. Common eczema queries answered. PMID- 26126392 TI - Novel real-time cell analysis platform for the dynamic monitoring of ionizing radiation effects on human tumor cell lines and primary fibroblasts. AB - Translational research in radiation oncology is important for the detection of adverse radiation effects, cellular responses, and radiation modifications, and may help to improve the outcome of radiation therapy in patients with cancer. The present study aimed to optimize and validate a real-time label-free assay for the dynamic monitoring of cellular responses to ionizing radiation. The xCELLigence system is an impedance-based platform that provides continuous information on alterations in cell size, shape, adhesion, proliferation, and survival. In the present study, various malignant human primary fibroblast cells (U251, GBM2, MCF7, A549, HT-29) were exposed to 0, 5 and 10 Gy of Cobalt60 radiation. As well as the xCELLigence system, cell survival and proliferation was evaluated using the following conventional end-point cell-based methods: Clonogenic, MTS, and lactate dehydrogenase assays, and apoptosis was detected by fluorescence activated cell sorting. The effects of ionizing radiation were detected for each cell line using impedance monitoring. The real-time data correlated with the colony forming assay results. At low cell densities (1,000-2,000 cells/well) the impedance-based method was more accurate at monitoring dose-dependent changes in the malignant human primary fibroblast cell lines, as compared with the end-point assays. The results of the present study demonstrated that the xCELLigence system may be a reliable and rapid diagnostic method for the monitoring of dynamic cell behavior following radiation. In addition, the xCELLigence system may be used to investigate the cellular mechanisms underlying the radiation response, as well as the time-dependent effects of radiation on cell proliferation and viability. PMID- 26126393 TI - Does visualisation during urethrocystoscopy provide pain relief? Results of an observational study. AB - BACKGROUND: To measure the effects of real-time visualisation during urethrocystoscopy on pain in patients who underwent ambulatory urethrocystoscopy. METHODS: An observational study was designed. From June 2012 to June 2013 patients who had ambulatory urethrocystoscopy participated in the study. In order to measure pain perception we used a numeric rating scale (NRS) 0 to 10. Additional data was collected including gender, reason for intervention, use of a rigid or a flexible instrument and whether the patient had had urethrocystoscopy before. RESULTS: 185 patients were evaluated. 125 patients preferred to watch their urethrocystoscopy on a real-time video screen, 60 patients did not. There was no statistically relevant difference in pain perception between those patients who watched their urethrocystoscopy on a real-time video screen and those who did not (p = 0.063). However, men who were allowed to watch their flexible urethrocystoscopy experienced significantly less pain, than those who did not (p = 0.007). No such effects could be measured for rigid urethrocystoscopy (p = 0.317). Furthermore, women experienced significantly higher levels of pain during the urethrocystoscopy than men (p = 0.032). CONCLUSIONS: Visualisation during urethrocystoscopy procedures in general does not significantly decrease pain in patients. Nevertheless, men who undergo flexible urethrocystoscopy should be offered to watch their procedure in real time on a video screen. To make urethrocystoscopy less painful for both genders, especially for women, should be subject to further research. PMID- 26126395 TI - Introduction: (In)famous neurological injuries and disease: cases and events of historical, political, cultural, and scientific impact. PMID- 26126396 TI - Eccentric neurosurgical virtuoso: the life and times of William Sharpe. AB - William Sharpe was an intriguing figure in the history of American neurosurgery. He was an extraordinarily bright and gifted man who led a flamboyant, colorful, and unconventional life. He had an international impact on the field of neurosurgery during the first half of the 20th century, yet few practicing neurosurgeons know his name. In this report, the authors discuss Sharpe's contributions to neurosurgery along with the remarkable quirkiness that came to define his professional and personal life. PMID- 26126397 TI - Clair Engle and the brain tumor that almost derailed the Civil Rights Act. AB - Senator Clare Engle was a United States senator from California who cast an important vote to end the filibuster of the 1964 Civil Rights Act, even as a brain tumor had left him with an expressive aphasia and would claim his life just a month later. This paper reviews the history of Senator Engle's illness in parallel with that of the Civil Rights Act of 1964. PMID- 26126398 TI - Prefrontal lobotomy on Evita was done for behavior/personality modification, not just for pain control. AB - Eva Peron, best known as Evita, underwent a prefrontal lobotomy in 1952. Although the procedure was said to have been performed to relieve the pain of metastatic cancer, the author carried out a search for evidence that suggests that the procedure was prescribed to decrease violence and to modify Evita's behavior and personality, and not just for pain control. To further elucidate the circumstances surrounding the treatment of this well-known historic figure, the author reviewed the development of the procedure known as prefrontal lobotomy and its three main indications: management of psychiatric illness, control of intractable pain from terminal cancer, and mind control and behavior/personality modification. The role of pioneering neurosurgeons in the development of prefrontal lobotomy, particularly in Connecticut and at Yale University, was also studied, and the political and historical conditions in Argentina in 1952 and to the present were analyzed. Evita was the wife of Juan Peron, who was the supreme leader of the Peronist party as well as president of Argentina. In 1952, however, the Peronist government in Argentina was bicephalic because Evita led the left wing of the party and ran the Female Peronist Party and the Eva Peron Foundation. She was followed by a group of hardcore loyalists interested in accelerating the revolution. Evita was also suffering from metastatic cervical cancer, and her illness increased her anxiety and moved her to purchase weapons to start training workers' militias. Although the apparent purpose was to fight her husband's enemies, this was done without his knowledge. She delivered fiery political speeches and wrote incendiary documents that would have led to a fierce clash in the country at that time. Notwithstanding the disreputable connotation of conspiracy theories, evidence was found of a potentially sinister political conspiracy, led by General Peron, to quiet down his wife Evita and modify her behavior/personality to decrease her belligerence, in addition to treating her cancer-related pain. Psychosurgery was purportedly intended to calm Evita and thus avoid a bloody civil war in Argentina. It was carried out in maximum secrecy and involved a distinguished American neurosurgeon, Dr. James L. Poppen, from the Lahey Clinic in Boston. A recorded and videotaped interview with a former scrub nurse and confidante of Dr. James L. Poppen revealed that prior to the lobotomy on Eva Peron, he performed lobotomies on a few prisoners in the prison system in Buenos Aires. Later, Dr. Poppen seems to have regretted his involvement and participation in this sad chapter in Argentine history. The treatment of Evita at the end of her life was influenced by extraordinary circumstances of time and place but also involved general issues of medical professionalism, the ethics of neuroscience, and the risks of being manipulated by labyrinthine byzantine politics. This story serves as a reminder that any physician, even one considered to be one of the best in the world, may act naively and become a pawn in a game he cannot begin to fathom. PMID- 26126399 TI - Joseph Warren: a discussion of his life and analysis of his death. AB - As his fellow soldiers ran past him, Joseph Warren stood bravely on Bunker Hill. It was June 17, 1775, and British troops were fighting the colonists in one of the early battles of the American Revolution. The British had already attempted two major assaults that day, and the third would end with Warren's death. He was a medical doctor, public figure, and general who spent his life and last living moments fighting for freedom for the American colonists. After the battle, there was much confusion about what had happened to Joseph Warren. Some thought he had survived the battle; other accounts differed on how exactly he had died. The details of the events on Bunker Hill remained a mystery until the following year, when Paul Revere helped identify Warren's body by the false teeth that had been implanted years earlier. Warren's remains showed that his head had been struck by a bullet. Analysis of the skull helped to sift through the differing tales of Warren's death and thus unveil the truth about what occurred that day. The smaller bullet wound in the left maxilla suggests that he was not shot while retreating with the rest of the soldiers. The larger exit wound in the right occiput illustrates that the bullet's trajectory crossed the midline of the brain and most likely injured the brainstem. Therefore, contrary to rumors that circulated at the time, Joseph Warren most likely was killed instantly at the Battle of Bunker Hill while heroically facing his enemy. PMID- 26126400 TI - Erratum: Are parenchymal AVMs congenital lesions? PMID- 26126401 TI - Did Emperor Moctezuma II's head injury and subsequent death hasten the fall of the Aztec nation? AB - This article analyzes the head injury of Emperor Moctezuma as one of those injuries that affected the course of history. The Emperor's death arguably changed the fate of an entire nation and led to the destruction of the Aztec civilization. Moctezuma died in the evening hours of June 30, 1520, in his palace in the Aztec capital, Tenochtitlan, while a prisoner of the Spanish conquistadors. The Emperor had been speaking to his people in an effort to persuade them to cease hostilities against Hernan Cortes, his Spanish soldiers, and Indian allies. Both Spanish and Indian contemporary sources document that he sustained a severe head injury when one of his own warriors hit him with a rock thrown from a sling. However, after the Conquest of Mexico some of the information collected by Spanish friars from Indian stories, songs, and pictorial representations raised the possibility that Moctezuma died of strangulation or stabbing at the hands of the Spaniards. There is even a suggestion of suicide. This issue remains unresolved and emotionally charged. The historical and clinical analysis of the events surrounding Moctezuma's death indicates that the Emperor most likely died as a consequence of head injury. The author has attempted to present a neutral analysis but agrees with Benjamin Keen that neutrality may be unattainable, no matter how remote the subject of historical inquiry is from the present. PMID- 26126402 TI - Two bullets to the head and an early winter: fate permits Kutuzov to defeat Napoleon at Moscow. AB - General Mikhail Kutuzov (circa 1745-1813) brilliantly repelled Napoleon's invasion of Russia. Honored as a national hero and a savior of Russia, Kutuzov has a unique medical story. He was shot in the head twice while fighting the Turks (1774 and 1788) and survived the serious injuries seemingly against all odds. The first bullet "ran through the head from one temple to the other behind both eyes." The second bullet entered the cheek, destroyed upper teeth, traveled through the head, and exited the occiput. Massot, a French surgeon with the Russian army, wrote after treating Kutuzov's seemingly two mortal wounds: "It must be believed that fate appoints Kutuzov to something great, because he was still alive after two injuries, a death sentence by all the rules of medical science." Aided by Massot's expert surgical technique, Kutuzov lived to become intimately engaged in events that altered world history. His health did, however, suffer significant effects due to the bullet wounds. In 1812, as Napoleon's Grande Armee approached, Kutuzov realized he could not confront Napoleon and he strategically retreated from Moscow, submitting the French to the harsh winter and Russian cavalry. Napoleon's devastated army retreated to Paris, and Kutuzov became the personification of Russian spirit and character. Kutuzov's survival of two nearly mortal head wounds created the legends, additional mystery, and drama surrounding him, not the least astonishing of which was the skilled neurosurgical care that probably saved his life. PMID- 26126403 TI - Understanding Edward Muybridge: historical review of behavioral alterations after a 19th-century head injury and their multifactorial influence on human life and culture. AB - Edward Muybridge was an Anglo-American photographer, well known for his pioneering contributions in photography and his invention of the "zoopraxiscope," a forerunner of motion pictures. However, this 19th-century genius, with two original patents in photographic technology, made outstanding contributions in art and neurology alike, the latter being seldom acknowledged. A head injury that he sustained changed his behavior and artistic expression. The shift of his interests from animal motion photography to human locomotion and gait remains a pivotal milestone in our understanding of patterns in biomechanics and clinical neurology, while his own behavioral patterns, owing to an injury to the orbitofrontal cortex, remain a mystery even for cognitive neurologists. The behavioral changes he exhibited and the legal conundrum that followed, including a murder of which he was acquitted, all depict the complexities of his personality and impact of frontal lobe injuries. This article highlights the life journey of Muybridge, drawing parallels with Phineas Gage, whose penetrating head injury has been studied widely. The wide sojourn of Muybridge also illustrates the strong connections that he maintained with Stanford and Pennsylvania universities, which were later considered pinnacles of higher education on the two coasts of the United States. PMID- 26126404 TI - Famous head injuries of the first aerial war: deaths of the "Knights of the Air". AB - World War I advanced the development of aviation from the concept of flight to the use of aircraft on the battlefield. Fighter planes advanced technologically as the war progressed. Fighter pilot aces Francesco Baracca and Manfred von Richthofen (the Red Baron) were two of the most famous pilots of this time period. These courageous fighter aces skillfully maneuvered their SPAD and Albatros planes, respectively, while battling enemies and scoring aerial victories that contributed to the course of the war. The media thrilled the public with their depictions of the heroic feats of fighter pilots such as Baracca and the Red Baron. Despite their aerial prowess, both pilots would eventually be shot down in combat. Although the accounts of their deaths are debated, it is undeniable that both were victims of traumatic head injury. PMID- 26126405 TI - Woodrow Wilson's hidden stroke of 1919: the impact of patient-physician confidentiality on United States foreign policy. AB - World War I catapulted the United States from traditional isolationism to international involvement in a major European conflict. Woodrow Wilson envisaged a permanent American imprint on democracy in world affairs through participation in the League of Nations. Amid these defining events, Wilson suffered a major ischemic stroke on October 2, 1919, which left him incapacitated. What was probably his fourth and most devastating stroke was diagnosed and treated by his friend and personal physician, Admiral Cary Grayson. Grayson, who had tremendous personal and professional loyalty to Wilson, kept the severity of the stroke hidden from Congress, the American people, and even the president himself. During a cabinet briefing, Grayson formally refused to sign a document of disability and was reluctant to address the subject of presidential succession. Wilson was essentially incapacitated and hemiplegic, yet he remained an active president and all messages were relayed directly through his wife, Edith. Patient-physician confidentiality superseded national security amid the backdrop of friendship and political power on the eve of a pivotal juncture in the history of American foreign policy. It was in part because of the absence of Woodrow Wilson's vocal and unwavering support that the United States did not join the League of Nations and distanced itself from the international stage. The League of Nations would later prove powerless without American support and was unable to thwart the rise and advance of Adolf Hitler. Only after World War II did the United States assume its global leadership role and realize Wilson's visionary, yet contentious, groundwork for a Pax Americana. The authors describe Woodrow Wilson's stroke, the historical implications of his health decline, and its impact on United States foreign policy. PMID- 26126406 TI - Pierre Curie: the anonymous neurosurgical contributor. AB - Pierre Curie, best known as a Nobel Laureate in Physics for his co-contributions to the field of radioactivity alongside research partner and wife Marie Curie, died suddenly in 1906 from a street accident in Paris. Tragically, his skull was crushed under the wheel of a horse-drawn carriage. This article attempts to honor the life and achievements of Pierre Curie, whose trailblazing work in radioactivity and piezoelectricity set into motion a wide range of technological developments that have culminated in the advent of numerous techniques used in neurological surgery today. These innovations include brachytherapy, Gamma Knife radiosurgery, focused ultrasound, and haptic feedback in robotic surgery. PMID- 26126407 TI - Hitler's parkinsonism. AB - Of the multitude of medical and psychiatric conditions ascribed to Hitler both in his lifetime and since his suicide in April 1945, few are more substantiated than parkinsonism. While the timeline of the development of this condition, as well as its etiology, are debated, there is clear evidence for classic manifestations of the disease, most prominently a resting tremor but also stooped posture, bradykinesia, micrographia, and masked facial expressions, with progression steadily seen over his final years. Though ultimately speculation, some have suggested that Hitler suffered from progressive cognitive and mood disturbances, possibly due to parkinsonism, that affected the course of events in the war. Here, the authors discuss Hitler's parkinsonism in the context of the Third Reich and its eventual destruction, maintaining that ultimately his disease had little effect on the end result. PMID- 26126408 TI - The neurosurgeon as baseball fan and inventor: Walter Dandy and the batter's helmet. AB - Baseball maintains one of the highest impact injury rates in all athletics. A principal causative factor is the "beanball," referring to a pitch thrown directly at a batter's head. Frequent morbidities elicited demand for the development of protective gear development in the 20th century. In this setting, Dr. Walter Dandy was commissioned to design a "protective cap" in 1941. His invention became widely adopted by professional baseball and inspired subsequent generations of batting helmets. As a baseball aficionado since his youth, Walter Dandy identified a natural partnership between baseball and medical practice for the reduction of beaning-related brain injuries. This history further supports the unique position of neurosurgeons to leverage clinical insights, inform innovation, and expand service to society. PMID- 26126409 TI - Genetic variations in the epidermodysplasia verruciformis (EVER/TMC) genes, cutaneous human papillomavirus infection and squamous cell carcinoma of the skin. PMID- 26126410 TI - A reversible fluorescent-colorimetric imino-pyridyl bis-Schiff base sensor for expeditious detection of Al(3+) and HSO3(-) in aqueous media. AB - A reversible fluorescent-colorimetric imino-pyridyl bis-Schiff base receptor (N(1)E,N(4)E)-N(1),N(4)-bis(pyridine-4-ylmethylene)benzene-1,4-diamine for the detection of both Al(3+) and HSO3(-) in aqueous medium has been developed. Receptor exhibits an excellent selective fluorescent-colorimetric response toward Al(3+). The sensitivity of the fluorescent based assay (0.903 MUM) for Al(3+) is far below the limit recommended in the World Health Organization (WHO) guidelines for drinking water (7.41 MUM). From (1)H NMR data, the Job plot and the ESI-MS spectrum, 1 : 2 stoichiometric complexation between and Al(3+) has been established. Receptor shows remarkable detection ability in a wide pH range of 4 11 and was successfully utilised in the determination of Al(3+) in aqueous solution of bovine serum albumin protein, and of HSO3(-) in real food samples. Moreover, shows a highly selective colorimetric response to HSO3(-) by changing its colour from yellow to colorless immediately without any interference from other anions. PMID- 26126413 TI - Aryne generation vs. Truce-Smiles and fries rearrangements during the Kobayashi fragmentation reaction: a new bi-aryl synthesis. AB - Treatment of (ortho-trimethysilyl)aryl phenylsulfonates with a soluble fluoride source initiates a Truce-Smiles rearrangement leading to the formation of functionalized bi-aryls. This new carbon-carbon bond-forming reaction proceeds without recourse to transition metal catalysis, under mild reaction conditions and with good functional group compatibility. PMID- 26126411 TI - Fibroblast viability and phenotypic changes within glycated stiffened three dimensional collagen matrices. AB - BACKGROUND: There is growing interest in the development of cell culture assays that enable the rigidity of the extracellular matrix to be increased. A promising approach is based on three-dimensional collagen type I matrices that are stiffened by cross-linking through non-enzymatic glycation with reducing sugars. METHODS: The present study evaluated the biomechanical changes in the non enzymatically glycated type I collagen matrices, including collagen organization, the advanced glycation end products formation and stiffness achievement. Gels were glycated with ribose at different concentrations (0, 5, 15, 30 and 240 mM). The viability and the phenotypic changes of primary human lung fibroblasts cultured within the non-enzymatically glycated gels were also evaluated along three consecutive weeks. Statistical tests used for data analyze were Mann Whitney U, Kruskal Wallis, Student's t-test, two-way ANOVA, multivariate ANOVA, linear regression test and mixed linear model. RESULTS: Our findings indicated that the process of collagen glycation increases the stiffness of the matrices and generates advanced glycation end products in a ribose concentration-dependent manner. Furthermore, we identified optimal ribose concentrations and media conditions for cell viability and growth within the glycated matrices. The microenvironment of this collagen based three-dimensional culture induces alpha smooth muscle actin and tenascin-C fibroblast protein expression. Finally, a progressive contractile phenotype cell differentiation was associated with the contraction of these gels. CONCLUSIONS: The use of non-enzymatic glycation with a low ribose concentration may provide a suitable model with a mechanic and oxidative modified environment with cells embedded in it, which allowed cell proliferation and induced fibroblast phenotypic changes. Such culture model could be appropriate for investigations of the behavior and phenotypic changes in cells that occur during lung fibrosis as well as for testing different antifibrotic therapies in vitro. PMID- 26126412 TI - Gastrectomy in comprehensive treatment of advanced gastric cancer with synchronous liver metastasis: a prospectively comparative study. AB - BACKGROUND: Systemic chemotherapy is the key treatment for advanced gastric cancer. The benefit of adjuvant surgery following preoperative chemotherapy in gastric cancer with liver metastasis has not been well established. METHODS: Forty-nine gastric cancer patients diagnosed with synchronous liver metastasis initially treated with chemotherapy were categorized into the following two groups: surgery group: 25 patients who underwent gastrectomy and subsequently received postoperative chemotherapy and control group: 24 patients who received chemotherapy alone. RESULTS: The median overall survival of patients in the surgery group and control group was 20.5 and 9.1 months, respectively, (P = 0.006). The median progression-free survival in the surgery group was 10.9 months, with statistical significance when compared with 5.0 months in the control group (P = 0.001). Multivariate analysis demonstrated that response to chemotherapy was the only independent factor in predicting prognosis. The survival of patients who achieved partial response (PR) was prolonged if they received adjuvant surgery (P = 0.024). No significant difference in the survival of patients underwent combined hepatic resection when compared with patients performed gastrectomy only. CONCLUSIONS: For gastric cancer with synchronous liver metastasis, adjuvant gastrectomy followed by chemotherapy might be beneficial for survival comparing with chemotherapy alone, especially in patients response to initial preoperative chemotherapy. PMID- 26126414 TI - Applying Task-Technology Fit Model to the Healthcare Sector: a Case Study of Hospitals' Computed Tomography Patient-Referral Mechanism. AB - With the growth in the number of elderly and people with chronic diseases, the number of hospital services will need to increase in the near future. With myriad of information technologies utilized daily and crucial information-sharing tasks performed at hospitals, understanding the relationship between task performance and information system has become a critical topic. This research explored the resource pooling of hospital management and considered a computed tomography (CT) patient-referral mechanism between two hospitals using the information system theory framework of Task-Technology Fit (TTF) model. The TTF model could be used to assess the 'match' between the task and technology characteristics. The patient-referral process involved an integrated information framework consisting of a hospital information system (HIS), radiology information system (RIS), and picture archiving and communication system (PACS). A formal interview was conducted with the director of the case image center on the applicable characteristics of TTF model. Next, the Icam DEFinition (IDEF0) method was utilized to depict the As-Is and To-Be models for CT patient-referral medical operational processes. Further, the study used the 'leagility' concept to remove non-value-added activities and increase the agility of hospitals. The results indicated that hospital information systems could support the CT patient-referral mechanism, increase hospital performance, reduce patient wait time, and enhance the quality of care for patients. PMID- 26126415 TI - A comparative study of perioperative complications between transforaminal versus posterior lumbar interbody fusion in degenerative lumbar spondylolisthesis. AB - BACKGROUND: Both posterior lumbar interbody fusion (PLIF) and transforaminal lumbar interbody fusion (TLIF) are accepted surgical techniques for the treatment of degenerative lumbar spondylolisthesis (DLS). However, it is still unclear one technique offers distinct advantages over the other. OBJECTIVE: A retrospective study was performed to compare perioperative complications and functional outcomes of patients undergoing TLIF versus PLIF for DLS. METHODS: A total of 226 consecutive patients who underwent surgery for treatment of DLS at three institutions were evaluated from January 2012 to December 2014. In this series, 125 patients underwent PLIF and 101 received TLIF. The operative time, blood loss, allogeneic blood transfusion rate and perioperative complications (including re-operative rate, nerve root injury, dural tear, wound infection) were compared between the two groups. Pain (VAS) and functional outcomes of patients (Kirkaldy-Willis criteria) were quantified before surgery and 1 week after surgery. RESULTS: Patients involved in the two groups had similar baseline demographic, clinical and radiographic characteristics. The PLIF group was associated with a higher incidence of post-operative iatrogenic nerve root dysfunction [12 cases (9.6 %) versus 2 cases (1.9 %), P = 0.018] and dural tears [15 cases (12 %) versus 4 cases (3.9 %), P = 0.030]. The re-operation rate was significantly higher in patients undergoing PLIF [13 cases (10.4 %) versus 2 cases (1.9 %), P = 0.011]. In addition, intra-operative blood loss, operative times, and allogeneic blood transfusion rates were higher in the PLIF group when compared to the TLIF group (P < 0.05). The wound infection rate of the PLIF group was similar to that of the TLIF group (7.2 versus 5.0 %, P = 0.486). VAS scores were decreased from 7.08 +/- 1.13 to 2.84 +/- 0.89 in the PLIF group, and from 7.18 +/- 1.09 to 2.84 +/- 0.91 in the TLIF group, respectively (P = 0.32). 85.6 % of patients in the TLIF group had good or excellent functional outcomes within the first post-operative week compared to 83.2 % in the PLIF group (P = 0.64). CONCLUSION: Both PLIF and TLIF were equally beneficial in improving short-term functional outcomes for patients with DLS. However, PLIFs were associated with statistically significant higher incidences of nerve root injury, dural tears, allogeneic blood transfusion, increased intra-operative times, blood loss and re operations. Therefore, caution should be exercised when considering PLIFs. PMID- 26126416 TI - Repeated total en bloc spondylectomy for spinal metastases at different sites in one patient. AB - PURPOSE: Total en bloc spondylectomy (TES) is accompanied by preoperative embolization of segmental arteries, which is limited to three consecutive levels to avoid the risk of spinal cord ischemia. We retrospectively examined the efficacy and safety of repeated TES with embolization of more than three levels of segmental arteries. METHODS: Seven patients underwent TES twice for spinal metastases at different levels. Every patient underwent embolization of the bilateral segmental arteries before each surgery. We assessed the total number of segmental arteries embolized, the existence of Adamkiewicz arteries during the embolization procedure, intraoperative blood loss, and the motor function of the lower limbs, using the American Spinal Injury Association (ASIA) motor score. RESULTS: No patient experienced any motor deficit after embolization. During the embolization procedure, an Adamkiewicz artery was depicted in five patients, which precluded embolization at that level. The median number of segmental arteries embolized in total was 9 (9-11). Intraoperative blood loss (median, IQR) was 480 (420-630) ml during the first surgery and 520 (280-600) ml during the second surgery. The ASIA motor scores (median, IQR) were as follows; 100 (98-100) (first admission), 100 (100-100) (first discharge), 100 (98-100) (second admission), and 97 (94-100) (second discharge). No patients had developed statistically significant neurological deterioration, and there had been no local recurrence after a median follow-up of 17.8 months (range 1-51 months). CONCLUSION: Repeated TES procedures can be performed safely even if more than three levels of segmental arteries are embolized. PMID- 26126417 TI - Sacroiliac joint luxation after pedicle subtraction osteotomy: report of two cases and analysis of failure mechanism. AB - BACKGROUND: Sagittal decompensation after pedicle subtraction osteotomy (PSO) is considered as late onset complication. Several mechanisms have been suggested, but little attention has been paid to the caudal end of lumbar instrumented fusion, especially sacral iliac joint (SIJ) deterioration. METHODS: Clinical histories and radiographic sagittal parameters of two patients with SIJ luxation after PSO are presented. The biomechanical failure mechanism and risk factors are analysed. RESULTS: Two patients underwent correction of fixed anterior sagittal imbalance by PSO, followed by pseudarthrosis revision surgery. Both of them sustained persistent sacroiliac pain, progressive recurrence of anterior imbalance and progressive pelvic incidence (PI) increase around 10 degrees . An acute bilateral SIJ luxation occurred in both patients leading to sharp increase or PI around 20 degrees . One patient was treated by SIJ fusion and the other patient was placed on non-weight-bearing crutch ambulation for 1 year. Both patients had a high preoperative PI (95 degrees and 78 degrees ). A theoretical match between lumbar lordosis (LL) and PI was not achieved by PSO. Osteopenia was present in both patients. Computed tomography evidenced L5-S1 pseudarthrosis and sacroiliac joint violation by pelvic or sacral ala screws. CONCLUSION: Patients with high PI might seek for further compensation at their SIJ when lacking LL after PSO. Chronic anterior imbalance might lead to progressive weakening of sacroiliac ligaments. Initial circumferential lumbosacral fusion and accurate iliac screw fixation might reduce stress on implants, risk for pseudarthrosis, implant failure and finally SIJ deterioration. Bone mineral density should further be investigated preoperatively. PMID- 26126418 TI - The extension of total gain (TG) statistic in survival models: properties and applications. AB - BACKGROUND: The results of multivariable regression models are usually summarized in the form of parameter estimates for the covariates, goodness-of-fit statistics, and the relevant p-values. These statistics do not inform us about whether covariate information will lead to any substantial improvement in prediction. Predictive ability measures can be used for this purpose since they provide important information about the practical significance of prognostic factors. R (2)-type indices are the most familiar forms of such measures in survival models, but they all have limitations and none is widely used. METHODS: In this paper, we extend the total gain (TG) measure, proposed for a logistic regression model, to survival models and explore its properties using simulations and real data. TG is based on the binary regression quantile plot, otherwise known as the predictiveness curve. Standardised TG ranges from 0 (no explanatory power) to 1 ('perfect' explanatory power). RESULTS: The results of our simulations show that unlike many of the other R (2)-type predictive ability measures, TG is independent of random censoring. It increases as the effect of a covariate increases and can be applied to different types of survival models, including models with time-dependent covariate effects. We also apply TG to quantify the predictive ability of multivariable prognostic models developed in several disease areas. CONCLUSIONS: Overall, TG performs well in our simulation studies and can be recommended as a measure to quantify the predictive ability in survival models. PMID- 26126419 TI - Is cognitive adaptation training (CAT) compensatory, restorative, or both? AB - Cognitive adaptation training (CAT) is a psychosocial treatment incorporating environmental supports including signs, checklists to bypass the cognitive deficits of schizophrenia. Our objective was to examine the association between CAT, functional outcomes, and cognitive test performance (cognition). The two research questions were as follows: 1) Does cognition mediate the effect of CAT intervention on functional outcome? 2) Does CAT impact cognitive test performance? A total of 120 participants with schizophrenia were randomized to one of three treatments: 1) CAT (weekly for 9months; monthly thereafter), 2) generic environmental supports (given to participants on clinic visits to promote adaptive behavior), or 3) treatment as usual (TAU). Assessments of cognition and functional outcome were conducted at baseline, 9 and 24months. Mediation analyses and mixed effects regression were conducted. Mediation analyses revealed that during the initial 9months, the direct path from treatment group to functional outcome on the primary measure was positive and highly significant. CAT significantly improved functional outcome compared to the other treatments. However, paths involving cognition were negligible. There was no evidence that cognition mediated improvement in functional outcomes. At 24months, cognition improved more in CAT compared to other treatment groups. The test for cognition mediating improvement in functional outcomes was not significant at this time point. However, improvement in functional outcome led to better performance on cognitive testing. We concluded that improvement in cognition is not a necessary condition for improvement in functional outcome and that greater engagement in functional behavior has a positive impact on cognition. PMID- 26126420 TI - Bioceramic microneedles with flexible and self-swelling substrate. AB - To reduce the effort required to penetrate the skin and optimize drug release profiles, bioceramic microneedle arrays with higher-aspect-ratio needles and a flexible and self-swelling substrate have been developed. Swelling of the substrate can assist in separating it from the needles and leave them in the skin as a drug depot. The preparation procedures for this bioceramic microneedle are described in the paper. Clonidine hydrochloride, the model drug, was released in a controlled manner by the microneedle device in vitro. Results showed that the microneedle array with a flexible and self-swelling substrate released the drug content faster than the array with a rigid substrate. Disintegration of the needle material and diffusion of the drug molecules are believed as the main control mechanisms of the drug release from these microneedle arrays. Ex vivo skin penetration showed that they can effectively penetrate the stratum corneum without an extra device. This work represents a progression in the improvement of bioceramic microneedles for transdermal drug delivery. PMID- 26126421 TI - An Innovative Approach to Informing Research: Gathering Perspectives on Diabetes Care Challenges From an Online Patient Community. AB - BACKGROUND: Funding agencies and researchers increasingly recognize the importance of patient stakeholder engagement in research. Despite calls for greater patient engagement, few studies have engaged a broad-based online community of patient stakeholders in the early stages of the research development process. OBJECTIVE: The objective of our study was to inform a research priority setting agenda by using a Web-based survey to gather perceptions of important and difficult aspects of diabetes care from patient members of a social networking site-based community. METHODS: Invitations to participate in a Web-based survey were sent by email to members of the PatientsLikeMe online diabetes community. The survey asked both quantitative and qualitative questions addressing individuals' level of difficulty with diabetes care, provider communication, medication management, diet and exercise, and relationships with others. Qualitative responses were analyzed using content analysis. RESULTS: Of 6219 PatientsLikeMe members with diabetes who were sent survey invitations, 1044 (16.79%) opened the invitation and 320 (5.15% of 6219; 30.65% of 1044) completed the survey within 23 days. Of the 320 respondents, 33 (10.3%) reported having Type 1 diabetes; 107 (33.4%), Type 2 diabetes and taking insulin; and 180 (56.3%), Type 2 diabetes and taking oral agents or controlling their diabetes with lifestyle modifications. Compared to 2005-2010 National Health and Nutrition Examination Survey data for individuals with diabetes, our respondents were younger (mean age 55.8 years, SD 9.9 vs 59.4 years, SE 0.5); less likely to be male (111/320, 34.6% vs 48.4%); and less likely to be a racial or ethnic minority (40/312, 12.8% vs 37.5%). Of 29 potential challenges in diabetes care, 19 were categorized as difficult by 20% or more of respondents. Both quantitative and qualitative results indicated that top patient challenges were lifestyle concerns (diet, physical activity, weight, and stress) and interpersonal concerns (trying not to be a burden to others, getting support from family/friends). In our quantitative analysis, similar concerns were expressed across patient subgroups. CONCLUSIONS: Lifestyle and interpersonal factors were particularly challenging for our online sample of adults with Type 1 or Type 2 diabetes. Our study demonstrates the innovative use of social networking sites and online communities to gather rapid, meaningful, and relevant patient perspectives that can be used to inform the development of research agendas. PMID- 26126422 TI - Laparoscopic Approach for Primary Colorectal Cancer Improves Outcome of Patients Undergoing Combined Open Hepatic Resection for Liver Metastases. AB - BACKGROUND: Safety and efficacy of simultaneous resections for patients with colorectal cancer and synchronous liver metastases have been widely reported, while the topic of approach (laparoscopic or open) to hepatic and colorectal resection is still a debated issue. The aim of this study was to assess short term outcome of combined resection of left colon or rectum cancer and liver metastases, comparing the results of the primary tumor resection performed by laparoscopic or open approach. STUDY DESIGN: From January 2004 to March 2014, 106 patients underwent combined resection of colorectal cancer and synchronous liver metastases. Sixty-nine patients underwent laparoscopic colorectal resection (laparoscopic colorectal surgery, LCS Group), and were compared with 37 patients undergoing colorectal resection by laparotomy (totally open surgery, TOS Group). Hepatic resection was performed by open approach in all the patients. RESULTS: Groups were comparable in terms of patients and disease characteristics, extent of liver resection, and length of surgery. In LCS Group, blood loss (400 vs. 650 mL, p < 0.001) and rate of intraoperative transfusions (19.3 vs. 47.2 %, p = 0.04) were lower compared to TOS Group. LCS Group was associated with reduced postoperative morbidity (24.6 vs. 44.4 %, p = 0.039), and shorter postoperative median hospital stay (9 vs. 13 days, p < 0.001). LCS and TOS Groups had comparable oncologic radicality in terms of primary tumor lymphadenectomy (median number of removed nodes 19 and 20, respectively, p NS) and rate of R1 colorectal resections (two patients in both Groups). Multivariate analysis revealed significant correlation morbidity with preoperative chemotherapy, blood loss, and approach to primary tumor. CONCLUSIONS: Laparoscopic resection of colorectal cancer in patients undergoing simultaneous open resection of liver metastases is associated with a reduction of blood loss, morbidity, and postoperative hospital stay, without affecting oncologic radicality. Outcome is mainly conditioned by approach to intestinal surgery, rather than the extent of liver resection. PMID- 26126424 TI - Sonographic Measurement of the IVC Diameter as an Indicator for Fluid Resuscitation: Beware of the Intra-abdominal Pressure. PMID- 26126423 TI - Long-Term Outcome After Resection of Huge Hepatocellular Carcinoma >= 10 cm: Single-Institution Experience with 471 Patients. AB - BACKGROUND: Tumor recurrence is very common after resection of huge hepatocellular carcinoma (HCC). This study intended to evaluate early recurrence and long-term outcomes in patients with huge HCC >= 10 cm after primary resection and treatment of recurrence. METHODS: Recurrence and survival outcomes were retrospectively evaluated in 471 patients with huge HCCs who underwent resection between January 2000 and April 2012. RESULTS: Mean tumor diameter was 13.6 +/- 3.1 cm, with 93 % of patients having single tumors. Anatomic and R0 resection rates were 91.1 and 89.4 %, respectively. Perioperative mortality rate was 1.7 %. Tumor recurrence and patient survival rates were 62.2 and 69.2 % at 1 year and 76.0 and 35.5 % at 5 years, respectively. Of patients with recurrence, 92.5 % received specific treatment. Median patient survival period after initial intrahepatic recurrence was 16 months. Tumor volume did not affect recurrence or survival outcomes. Independent risk factors for tumor recurrence and patient survival were serum alpha-fetoprotein >= 100 ng/mL, hypermetabolic uptake on positron emission tomography, satellite nodules, and microvascular invasion. These four factors were used to develop a risk prediction model, in which 1-year HCC recurrence rates in patients with 0, 1, 2, 3, and 4 risk factors were 18.7, 30.3, 58.7, 79.0, and 92.1 %, respectively, and their 1-year patient survival rates were 100, 97.0, 75.5, 63.9, and 42.1 %, respectively. CONCLUSIONS: In patients with huge HCCs, hepatic resection with active recurrence treatment resulted in improved long-term survival. Our 4-factor risk prediction model appears to contribute to quantitative postoperative risk estimation for early HCC recurrence and patient survival in patients with HCC >= 10 cm. PMID- 26126425 TI - Targeting protein-protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs). AB - In this review we discuss recent progress in targeting the protein-protein interactions made by oncogenic transcription factors. We particularly focus on the challenges posed by the prevalence of intrinsically disordered regions in this class of protein and the strategies being used to overcome them. PMID- 26126426 TI - Movement-based subgrouping in low back pain: synergy and divergence in approaches. AB - BACKGROUND: Classification systems for low back pain (LBP) aim to guide treatment decisions. In physiotherapy, there are five classification schemes for LBP which consider responses to clinical movement examination. Little is known of the relationship between the schemes. OBJECTIVES: To investigate overlap between subgroups of patients with LBP when classified using different movement-based classification schemes, and to consider how participants classified according to one scheme would be classified by another. DESIGN: Cross-sectional cohort study. SETTING: University clinical laboratory. PARTICIPANTS: One hundred and two participants with LBP were recruited from university, hospital outpatient and private physiotherapy clinics, and community advertisements. INTERVENTION: Participants underwent a standardised examination including questions and movement tests to guide subgrouping. MAIN OUTCOME MEASURES: Participants were allocated to a LBP subgroup using each of the five classification schemes: Mechanical Diagnosis and Treatment (MDT), Movement System Impairment (MSI), O'Sullivan Classification (OSC), Pathoanatomic Based Classification (PBC) and Treatment Based Classification (TBC). RESULTS: There was concordance in allocation to subgroups that consider pain relief from direction-specific repeated spinal loading in the MDT, PBC and TBC schemes. There was consistency of subgrouping between the MSI and OSC schemes, which consider pain provocation to specific movement directions. Synergies between other subgroups were more variable. Participants from one subgroup could be subdivided using another scheme. CONCLUSIONS: There is overlap and discordance between LBP subgrouping schemes that consider movement. Where overlap is present, schemes recommend different treatment options. Where subgroups from one scheme can be subdivided using another scheme, there is potential to further guide treatment. An integrated assessment model may refine treatment targeting. PMID- 26126428 TI - A Mixed-Valence Tri-Zinc Complex, [LZnZnZnL] (L=Bulky Amide), Bearing a Linear Chain of Two-Coordinate Zinc Atoms. AB - Reduction of a variety of extremely bulky amido Group 12 metal halide complexes, [LMX(THF)(0,1)] (L=amide; M=Zn, Cd, or Hg; X=halide) with a magnesium(I) dimer gave a homologous series of two-coordinate metal(I) dimers, [L'MML'] (L'=N(Ar(?))(SiMe3), Ar(?)=C6H2{C(H)Ph2}2Pr(i)-2,6,4); and the formally zinc(0) complex, [L*ZnMg((Mes)Nacnac)] (L*=N(Ar*)(SiPr(i)3); Ar*=C6H2{C(H)Ph2}2Me-2,6,4; (Mes)Nacnac=[(MesNCMe)2CH](-), Mes=mesityl), which contains the first unsupported Zn-Mg bond. Two equivalents of [L*ZnMg((Mes)Nacnac)] react with ZnBr2 or ZnBr2(tmeda) to give the mixed valence, two-coordinate, linear tri-zinc complex, [L*Zn(I)Zn(0)Zn(I)L*], and the first zinc(I) halide complex, [L*ZnZnBr(tmeda)], respectively. The analogues [L*ZnMZnL*] (M=Cd or Hg), were also prepared, the Cd species contains the first Zn-Cd bond in a molecular compound. Metal-metal bonding was studied by DFT calculations. PMID- 26126431 TI - Acute rupture of a feeding artery aneurysm after embolization of a brain arteriovenous malformation. AB - BACKGROUND: Staged endovascular embolization of large arteriovenous malformations (AVMs) is frequently performed to gradually reduce flow and prevent abrupt hemodynamic changes. While feeding artery aneurysms have been associated with increased risk of hemorrhage in the setting of AVMs, decisions regarding if and when to treat these aneurysms vary. Acute, fatal rupture of a feeding artery aneurysm following embolization of a large, unruptured AVM has been infrequently reported in the literature. CASE DESCRIPTION: A 69-year-old female presented with headache and mild left hemiparesis referable to a 5 cm right fronto-parieto temporal AVM with surrounding vasogenic edema. The AVM was associated with numerous bilateral feeding artery aneurysms (the largest was a 2 cm right middle cerebral artery (MCA) bifurcation aneurysm). There was also a large, partially thrombosed venous varix. Staged embolization of the AVM was performed. Several hours after the third stage of her embolization, she became obtunded, with a fixed and dilated right pupil. Head computed tomography (CT) showed a large intraparenchymal hemorrhage with midline shift in the right sylvian fissure, remote from the AVM nidus. She was taken to surgery for a decompressive craniectomy and hematoma evacuation. The MCA aneurysm was confirmed to be the source of hemorrhage and it was clipped. Despite aggressive medical and surgical treatments, the patient died. CONCLUSIONS: An increase in AVM feeding artery pressure following endovascular embolization may contribute to the rupture of a feeding artery aneurysm. For this reason, treatment of large arterial aneurysms on feeding pedicles should be considered prior to embolization of the AVM nidus. PMID- 26126432 TI - Discharge before noon: Effect on throughput and sustainability. AB - BACKGROUND: Late afternoon hospital discharges are thought to contribute to admission bottlenecks. We previously described an intervention that resulted in a statistically significant increase in the discharge before noon (DBN) rate on 2 inpatient medicine units. OBJECTIVE: To evaluate (1) the effect of an increased DBN rate on the admission arrival time and the number of admissions per hour and (2) the sustainability of our DBN initiative. DESIGN: Pre-/postintervention retrospective analysis. SETTING: Two acute-care inpatient medicine units in a tertiary care, urban, academic medical center. PATIENTS: For the admission arrival time and admissions per hour analysis, all inpatients admitted to the medical units from June 1, 2011 to June 31, 2013. For the sustainability analysis, all patients discharged from July 1, 2013 to December 31, 2014. INTERVENTION: A multidisciplinary intervention to increase the DBN rate. MEASUREMENTS: Date and time of arrival to all inpatient sites, and discharge date and time of all patients from 2 inpatient medicine units. RESULTS: Concurrent with our increase in DBN rate, we found a statistically significant change in the median arrival time of emergency department (ED) admissions and transfers from 5 pm to 4 pm. High-frequency admission peaks were statistically significantly reduced for ED admissions. The statistically significant increase in DBN rate is sustained at 35%. CONCLUSIONS: Increasing the DBN rate correlates with admissions arriving earlier in the day and reductions in high-frequency peaks of ED admissions. Statistically significant improvements in DBN rates are sustainable. PMID- 26126429 TI - Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors. AB - Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A1AR of rat and mouse), CGS-21680 (for A2A AR of rat), and Cl-IB-MECA (for A3AR of all three species). The functionally selective partial A2B agonist BAY60-6583 was found to additionally bind to A1 and A3AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A1), preladenant (A2A), and PSB-603 (A2B) displayed high selectivity in all three investigated species. MRS 1523 acts as a selective A3AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies. PMID- 26126433 TI - Application of Oncology Research to Resolve a Problem in Neurourology. PMID- 26126434 TI - Is 5'-AMP-Activated Protein Kinase Both Jekyll and Hyde in Bladder Cancer? AB - The 5'-AMP-activated protein kinase (AMPK) is a key regulator of cellular metabolism and energy homeostasis in mammalian tissues. Metabolic adaptation is a critical step in ensuring cell survival during metabolic stress. Because of its critical role in the regulation of glucose homeostasis and carbohydrate, lipid, and protein metabolism, AMPK is involved in many human diseases, including cancers. Although AMPK signaling was originally characterized as a tumor suppressive signaling pathway, several lines of evidence suggest that AMPK plays a much broader role and cannot simply be defined as either an oncogenic regulator or tumor suppressor. Notably, several recent studies demonstrated that the antitumorigenic effects of many indirect AMPK activators, such as metformin, do not depend on AMPK. Conversely, activation of AMPK induces the progression of cancers, emphasizing its oncogenic effect. Bladder cancer can be divided into two groups: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). The molecular mechanisms underlying these two types of cancer are distinct: NMIBC is associated with activation of the Ras pathway, whereas MIBC is characterized by loss of major tumor suppressors. Importantly, both pathways are connected to the mammalian target of rapamycin (mTOR) pathway. In addition, our recent metabolomic findings suggest that beta-oxidation of fatty acids is an important factor in the development of bladder cancer. Both mTOR and beta oxidation are tightly associated with the AMPK pathway. Here, I summarize and discuss the recent findings on the two distinct roles of AMPK in cancer, as well as the relationship between bladder cancer and AMPK. PMID- 26126435 TI - Does Methylphenidate Affect Cystometric Parameters in Spontaneously Hypertensive Rats? AB - PURPOSE: Methylphenidate (MPH) is one of the most commonly prescribed psychostimulants for attention deficit hyperactivity disorder (ADHD). However, there is limited research on its effects on lower urinary tract function. This study investigated changes in cystometric parameters after intragastric administration of MPH in conscious spontaneously hypertensive rats (SHRs), an animal model of ADHD. METHODS: Fourteen- to 16-week-old male SHRs (n=10), weighing between 280 and 315 g, were used. Three micturition cycles were recorded before administering MPH. One hour after each intragastric MPH injection, three cycles of cystometrogram were obtained in the awake condition. Various cystometric parameters were evaluated, including basal pressure (BP), maximal pressure (MP), threshold pressure (TP), bladder capacity (BC), micturition volume (MV), micturition interval (MI), and residual volume (RV). The data were analyzed using paired Student t-tests. RESULTS: Five SHRs were each administered a dose of 3-mg/kg MPH, and the other five received a dose of 6-mg/kg MPH. BP and MP increased significantly in the rats that received the 3-mg/kg MPH injection, but not in those that received the 6-mg/kg injection. BC, MV, and MI significantly increased in the rats that received the 6-mg/kg MPH injection, but not in those that received the 3-mg/kg injection. There were no significant changes in TP after either injection. CONCLUSIONS: Significant increases in BC, MV, and MI after the 6-mg/kg MPH injection suggest that the peripheral and the central nervous systems may play important roles in bladder function in those receiving MPH for ADHD. PMID- 26126436 TI - Urinary MicroRNAs of Prostate Cancer: Virus-Encoded hsv1-miRH18 and hsv2-miR-H9 5p Could Be Valuable Diagnostic Markers. AB - PURPOSE: MicroRNAs (miRNAs) in biological fluids are potential biomarkers for the diagnosis and assessment of urological diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The aim of the study was to identify and validate urinary cell-free miRNAs that can segregate patients with PCa from those with BPH. METHODS: In total, 1,052 urine, 150 serum, and 150 prostate tissue samples from patients with PCa or BPH were used in the study. A urine based miRNA microarray analysis suggested the presence of differentially expressed urinary miRNAs in patients with PCa, and these were further validated in three independent PCa cohorts, using a quantitative reverse transcriptionpolymerase chain reaction analysis. RESULTS: The expression levels of hsa-miR-615-3p, hsv1-miR-H18, hsv2-miR-H9-5p, and hsa-miR-4316 were significantly higher in urine samples of patients with PCa than in those of BPH controls. In particular, herpes simplex virus (hsv)-derived hsv1-miR-H18 and hsv2 miR-H9-5p showed better diagnostic performance than did the serum prostate specific antigen (PSA) test for patients in the PSA gray zone. Furthermore, a combination of urinary hsv2-miR-H9-5p with serum PSA showed high sensitivity and specificity, providing a potential clinical benefit by reducing unnecessary biopsies. CONCLUSIONS: Our findings showed that hsv-encoded hsv1-miR-H18 and hsv2 miR-H9-5p are significantly associated with PCa and can facilitate early diagnosis of PCa for patients within the serum PSA gray zone. PMID- 26126437 TI - Intravesical Sodium Chondroitin Sulphate to Treat Overactive Bladder: Preliminary Result. AB - PURPOSE: This study aimed to verify the efficacy and safety of intravesical treatment with sodium chondroitin sulfate (CS) in patients with overactive bladder (OAB) who are refractory to previous antimuscarinic treatment. METHODS: This study was performed between June 2012 and January 2015 and included 31 consecutive women (mean age, 42.10+/-7.34 years) with OAB who had been previously treated with two types of antimuscarinic drugs. The results of gynecologic and cystoscopic examinations were normal, and OAB comorbidity was absent. Treatment with intravesical instillations containing 40 mL CS (0.2%; 2 mg/mL) was administered for 6 weeks; after weekly treatments, monthly treatments were administered. The OAB-validated 8 (OAB-V8) symptom scores, nocturia, frequency, urgency, urge incontinence, and urinary volumes measured by uroflowmetry were evaluated for all the patients. The values obtained before the treatment were statistically compared with those obtained six months after the treatment. RESULTS: The duration of the symptoms was 18.36+/-6.19 months. A statistically significant improvement of the patients' conditions was observed in terms of the OAB-V8 symptom scores, nocturia, frequency, urgency, urge incontinence, and urinary volumes measured by uroflowmetry after the treatment. CONCLUSIONS: Despite the limitations of this study, the outcomes confirmed that CS therapy is safe and effective for the treatment of OAB. PMID- 26126438 TI - Clinical and Pathological Characteristics of Hard Nodules Resistant to Morcellation During Holmium Laser Enucleation of the Prostate. AB - PURPOSE: To identify the clinical and pathological characteristics of hard nodules resistant to morcellation (HNRM) during holmium laser enucleation of the prostate (HoLEP) for benign prostatic hyperplasia (BPH). METHODS: Between July 2008 and October 2011, 246 patients underwent HoLEP for symptomatic BPH. The first 30 patients were excluded from the analysis due to the learning curve of the procedure. The remaining patients were divided into HNRM (n=29) and non-HNRM groups (n=187), and comparative analysis of the clinical parameters of the two groups was performed. International prostate symptom score analysis and urodynamic studies were performed preoperatively. Histological analysis was performed after hematoxylin and eosin staining and Masson trichrome staining of the HNRM specimens. RESULTS: Twenty-nine patients (13.4%) had HNRM. The patients in the HNRM group had significantly higher proportions of advanced age (>=65 years, P=0.029), total prostate volume >=65 mL (P<0.001), transition zone volume >=35 mL (P<0.001), serum prostate-specific antigen levels >=10 ng/mL (P=0.007), and functional urethral length >=70 mm (P=0.009); larger enucleation weight (P<0.001); longer operation (P=0.001), enucleation (P=0.042), and morcellation times (P<0.001); and higher enucleation ratio (P=0.028) and enucleation efficacy (P=0.001). After adjusting for confounding factors, multivariate logistic regression analysis revealed that age >=65 years and total prostate volume >=65 mL were independent risk factors for HNRM. Pathological examination did not reveal any malignant cells, with mainly dense fibrous tissue found in the HNRM. CONCLUSIONS: HNRM can make morcellation cumbersome and time-consuming, and older patients with larger prostates have a higher incidence of HNRM. However, the histopathology of HNRM revealed mainly fibrotic tissue. PMID- 26126439 TI - Factors Associated With Self-reported and Medically Diagnosed Urinary Incontinence Among Community-Dwelling Older Women In Korea. AB - PURPOSE: The purpose of this study was to examine the prevalence of urinary incontinence (UI) in community-dwelling Korean women 60 years or older, and to identify factors associated with self-reported and medically diagnosed UI. METHODS: This study was a secondary analysis of data from the 2008 Actual Living Condition of the Elderly and Welfare Need Survey, which used a stratified two stage cluster sampling method to select a representative sample of 8,961 elderly Korean women. RESULTS: Of the 8,961 women in this study, 579 (6.5%) had self reported UI, and 209 (2.3%) were medically diagnosed with UI. As patient age and exercise ability of the upper extremities increased, risk for self-reported UI decreased (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-0.99; OR, 0.99; 95% CI, 0.98-0.99, respectively). In contrast, as the number of limited instrumental activities of daily living (IADL) increased, the risk for self reported UI increased (OR, 1.30; 95% CI, 1.24-1.35). Overweight women were 1.94 times more likely to have self-reported UI compared to underweight women. Women with a history of stroke or asthma were more likely to have self-reported UI compared to women with no history. Also, women who reported being in good health were less likely to have UI, compared to women who reported being in poor health (OR, 0.47; 95% CI, 0.31-0.70). Medically diagnosed UI was negatively associated with the number of limited IADL and exercise ability scores for the lower extremities (OR, 0.86; 95% CI, 0.80-0.92; OR, 0.98; 95% CI, 0.97-0.99, respectively). In contrast, as the exercise ability score for the upper extremities increased, so did the risk for medically diagnosed UI (OR, 1.02; 95% CI, 1.01-1.03). CONCLUSIONS: An interventional program for home visit health services is needed for incontinent women who are highly dependent on others for IADL. PMID- 26126440 TI - Alpha-Blocker Treatment Response in Men With Lower Urinary Tract Symptoms Based on Sympathetic Activity: Prospective, Multicenter, Open-Labeled, Observational Study. AB - PURPOSE: In this study, we compared the treatment outcomes for an alpha-blocker between 2 groups of men, one with high sympathetic activity (HSA) and another with low sympathetic activity (LSA) or normal sympathetic activity. METHODS: A total of 159 men (>=50 years of age) with lower urinary tract symptoms resulting from benign prostatic hyperplasia were analyzed. We assigned patients to groups according to their sympathetic activity, which was evaluated by heart ratevariability measurements. HSA was defined as a low frequency/high frequency ratio greater than 1.6. All patients received 10mg of alfuzosin once a day for 12 weeks. The primary end point was a change in the total International Prostate SymptomScore (IPSS) at 12 weeks from baseline. RESULTS: Sixty-seven men were assigned to the HSA group and 92 men were assigned to the LSA group. The baseline characteristics were not significantly different between the 2 groups, and the response to alfuzosin was good in both groups. Themean total IPSS change was not different between the groups. Both groups were not significantly different with respect to the changes in maximal flow rate, IPSS voiding or storage symptom subscores, quality of life, and rates of adverse drug events. TheHSA group showed a similar willingness to continue treatment compared to the LSA group, although their treatment satisfaction rating was lower. CONCLUSIONS: The therapeutic effects of alfuzosin did not differ in regards to the differences in sympathetic activity, but treatment satisfaction ratings were lower in the HSA group. PMID- 26126441 TI - Effect of Continuous Urethro-Vesical Anastomosis Technique in Incontinence After Radical Retropubic Prostatectomy, 1:1 Matching Study. AB - PURPOSE: Vesicourethral anastomosis (VUA) is an important step in radical prostatectomy and can affect clinical course in hospital. However, few studies comparing VUA by standard interrupted and continuous suturing techniques in radical retropubicprostatectomy (RRP) have been reported. We compared the postoperative outcomes and continence recovery rates of patients undergoing these two variations of VUA using 1:1 propensity score matching. METHODS: From January 2008 to January 2014, a total of 188 patients underwent RRP. We conducted 1:1 propensity score matching based on age, prostate volume, pathological stage, status of nerve sparing, and two baseline characteristics (preoperative prostate specific antigen [PSA] level and Gleason score determined by pathology). Patients were assigned to two groups based on the suturing method used (interrupted or continuous). After RRP, incontinence levels were assessed at 1, 3, 6, and 12months based on pad usage per day (0, dry; <=1, social continence; >=2, incontinence). RESULTS: Each group consisted of 47 patients. The continuous group had a lower incidence of VUA site leakage (0% vs. 10.6%, P=0.022), but there were no significant differences in the rates of postoperative urethral stricture (6.4% vs. 6.4%, P=1.00) andpyuria (43.6% vs. 45.0%, P=0.770) between the two groups. The rate of recovery to social continence was greater in the continuous group at postoperative 3 months (85.1% vs. 66.0%, P=0.031). About 50% of patients had no incontinence (pad perday=0) after 6 months (59.6% in the continuous group and 51.1% in the interrupted group, P=0.407) and at postoperative 12 months, the dry rate 61.7% in the interrupted group and 80.4% in the continuous group (P=0.047). The times required toreach social continence (3.21 months vs. 3.77 months, P=0.056) and no incontinence (7.23 months vs. 7.63 months, P=0.132) were also shorter in the continuous group, but these differences were not statistically significant. CONCLUSIONS: The results of this study suggest that earlier recovery to social continence and a higher rate of complete recovery (dry) could be expected with VUA by continuous suturing. Furthermore, if adequate surgical experience is accumulated, VUAwith continuous suturing could be performed without difficulty. PMID- 26126442 TI - The Impact of Lower Urinary Tract Symptoms on Quality of Life, Work Productivity, Depressive Symptoms, and Sexuality in Korean Men Aged 40 Years and Older: A Population-Based Survey. AB - PURPOSE: To examine the impact of lower urinary tract symptoms (LUTS) on health related quality of life (HRQoL) in Korean men aged >=40 years. METHODS: A population-based, cross-sectional door-to-door survey was conducted among men aged >=40 years. Individuals with LUTS were defined as men reporting at least one LUTS using 2002 International Continence Society definitions. Structuredquestionnaires were used to assess several dimensions of HRQoL, including generic health status (EuroQoL-five-dimensions questionnaire), work productivity (work productivity and activity impairment questionnaire), depressive symptoms(center for epidemiologic studies depression scale), and sexual health (sexual satisfaction and erectile dysfunction). The impact of LUTS was assessed by comparing several dimensions of HRQoL among men with and without LUTS. RESULTS: Of the 1,842 participants, 1,536 (83.4%) reported having at least one LUTS. The prevalence of LUTS increased with age (78.3% among those aged 40-49 years to 89.6% among those aged 60 years or older). Those with LUTS reported a significantlylower level of generic health status and worse work productivity compared with those without LUTS. Significantly more individuals with LUTS reported having a higher level of major depressive symptoms compared with those without LUTS.Those with LUTS reported worse sexual activity and enjoyment, and were significantly more likely to have erectile dysfunction than those without LUTS. CONCLUSIONS: LUTS seem to have a substantial impact on several dimensions of HRQoL in Korean men aged >=40 years. PMID- 26126443 TI - Advanced Male Urethral and Genital Reconstructive Surgery. 2nd ed. PMID- 26126445 TI - Vibrational spectra and structures of SinC clusters (n = 3-8). AB - The effects of doping bare silicon clusters with carbon on their physical properties are of fundamental interest for the chemistry of the interstellar medium and the development of novel nanostructures in materials science. Carbon doped silicon clusters (SinC, n = 3-8) are characterized in the gas phase with infrared-ultraviolet two-color ionization (IR-UV2CI) spectroscopy, mass spectrometry, and quantum chemical calculations. Structural identification is achieved by comparing the measured and calculated vibrational absorption spectra of the low-energy SinC isomers identified by global optimization algorithms. Except for planar Si3C, the most stable SinC clusters have three-dimensional configurations. While the Si3C and Si6C structures are uniquely assigned, several stable isomers of Si4C, Si5C, Si7C, and Si8C may co-exist under the present experimental conditions. Interestingly, some of the structures observed here are different from the ground state structures predicted previously. For the small neutral clusters (n <= 5), structures similar to those reported previously for the anions are observed. The highly stable Si3C unit with a nearly linear Si-C-Si motif is identified as characteristic building block in several of the most stable SinC structures. In all identified structures, a large negative charge of almost -2e is located on the C atom, indicating its role as electron donor in the Sin host moiety. The B3LYP/cc-pVTZ level proves reliable in finding the experimentally observed isomers. PMID- 26126444 TI - Matching of received social support with need for support in adjusting to cancer and cancer survivorship. AB - BACKGROUND: Optimal matching theory posits that the effects of social support are enhanced when its provision is matched with need for support. We hypothesized that matching received social support with the needs of persons with cancer, and cancer survivors would be related to better psychosocial adjustment than a mismatched condition. METHOD: In a cross-sectional design, sample 1, consisting of 171 cancer patients, and sample 2, consisting of 118 cancer survivors, completed measures of emotional and instrumental received support, physical debilitation, and psychological distress. RESULTS: The optimal matching theory model was confirmed; those needing support (i.e., greater physical debilitation), who did not receive it, experienced more distress than those who needed support and received it. Patients in treatment benefited from the matching of need and provision for both emotional and instrumental support, whereas survivors only benefited from the matching of emotional support. CONCLUSIONS: The results suggest that social support is contextualized by the degree of physical impairment and may be somewhat different for cancer patients in treatment compared with cancer survivors. The transition to cancer survivorship may involve a transformation in the need for as well as the type and amount of received social support. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26126446 TI - Adjusting for Cell Type Composition in DNA Methylation Data Using a Regression Based Approach. AB - Analysis of DNA methylation in a population context has the potential to uncover novel gene and environment interactions as well as markers of health and disease. In order to find such associations it is important to control for factors which may mask or alter DNA methylation signatures. Since tissue of origin and coinciding cell type composition are major contributors to DNA methylation patterns, and can easily confound important findings, it is vital to adjust DNA methylation data for such differences across individuals. Here we describe the use of a regression method to adjust for cell type composition in DNA methylation data. We specifically discuss what information is required to adjust for cell type composition and then provide detailed instructions on how to perform cell type adjustment on high dimensional DNA methylation data. This method has been applied mainly to Illumina 450K data, but can also be adapted to pyrosequencing or genome-wide bisulfite sequencing data. PMID- 26126447 TI - 5-Hydroxymethylcytosine Profiling in Human DNA. AB - Since its "re-discovery" in 2009, there has been significant interest in defining the genome-wide distribution of DNA marked by 5-hydroxymethylation at cytosine bases (5hmC). In recent years, technological advances have resulted in a multitude of unique strategies to map 5hmC across the human genome. Here we discuss the wide range of approaches available to map this modification and describe in detail the affinity based methods which result in the enrichment of 5hmC marked DNA for downstream analysis. PMID- 26126448 TI - Intracellular Calcium Measurements for Functional Characterization of Neuronal Phenotypes. AB - The central and peripheral nervous system is built by a network of many different neuronal phenotypes together with glial and other supporting cells. The repertoire of expressed receptors and secreted neurotransmitters and neuromodulators are unique for each single neuron leading to intracellular signaling cascades, many of them involving intracellular calcium signaling. Here we suggest the use of calcium signaling analysis upon specific agonist application to reliably identify neuronal phenotypes, being important not only for basic science, but also providing a reliable tool for functional characterization of cells prior to transplantation. Calcium imaging provides various cellular information including signaling amplitudes, cell localization, duration, and frequency. Microfluorimetry reveals a signal summarizing the entire population, and its use is indicated for high-throughput screening purposes. PMID- 26126449 TI - Generation and Characterization of Patient-Specific iPSC Model for Cardiovascular Disease. AB - Advances in differentiation of cardiomyocytes from human induced pluripotent stem cell (hiPSC) were emerged as a tool for modeling of cardiovascular disease that recapitulates the phenotype for the purpose of drug screening, biomarker discovery, and testing of single-nucleotide polymorphism (SNP) as a modifier for disease stratification. Here, we describe the (1) retroviral reprogramming strategies in the generation of human iPSC, (2) methodology in characterization of iPSC in order to identify the stem cell clones with the best quality, and (3) protocol of cardiac differentiation by modulation of Wnt signaling and beta catenin pathway. PMID- 26126450 TI - The piggyBac Transposon as a Platform Technology for Somatic Cell Reprogramming Studies in Mouse. AB - Somatic cell reprogramming to induced pluripotent stem cells (iPSCs) is a revolutionary technology, with repercussions affecting modern functional genomics and regenerative medicine. Still, relatively little is known about the processes underlying this dramatic cellular and molecular metamorphosis. Reprogramming technology based on the implementation of piggyBac (PB) transposons has enabled studies of iPSC reprogramming mechanisms, shedding an increasing light on these processes. Unique characteristics of PB transposons such as efficient genomic integration, unlimited cargo capacity, robust gene expression, and even seamless excision highlight the importance of this transgenic tool in advancing stem cell biology. In this chapter, we provide a detailed overview of versatile primary iPSC generation from mouse somatic cells using PB transposons, and the subsequent establishment of robust secondary reprogramming systems. These protocols are highlighted with examples from recent studies as to how PB has been, and continues to be, conducive to the dissection of reprogramming processes at the cellular and molecular levels. PMID- 26126451 TI - Transgene-Free Disease-Specific iPSC Generation from Fibroblasts and Peripheral Blood Mononuclear Cells. AB - Induced pluripotent stem cells (iPSCs) offer great promise as tools for basic biomedical research, disease modeling, and drug screening. In this chapter, we describe the generation of patient-specific, transgene-free iPSCs from skin biopsies and peripheral blood mononuclear cells through electroporation of episomal vectors and growth under two different culture conditions. The resulting iPSC lines are characterized with respect to pluripotency marker expression through immunostaining, tested for transgene integration by PCR, and assayed for differentiation capacity via teratoma formation. PMID- 26126452 TI - Extranodal natural killer/T-cell lymphoma, nasal type, presenting with altered CD56 expression: A case report. PMID- 26126453 TI - Physician heal thyself. PMID- 26126454 TI - Of SOLOs and ensembles. PMID- 26126455 TI - The pudding, the beef, and conflicts of interest. PMID- 26126456 TI - Is simulation the next best thing? PMID- 26126458 TI - Anastomotic leaks and cancer recurrence: Associations versus causality. PMID- 26126457 TI - Intraoperative molecular imaging can identify lung adenocarcinomas during pulmonary resection. AB - BACKGROUND: More than 80,000 people undergo resection of a pulmonary tumor each year, and the only method to determine if the tumor is malignant is histologic analysis. We propose that a targeted molecular contrast agent could bind lung adenocarcinomas, which could be identified using real-time optical imaging at the time of surgery. METHODS: Fifty patients with a biopsy-proven lung adenocarcinoma were enrolled. Before surgery, patients were systemically administered 0.1 mg/kg of a fluorescent folate receptor alpha (FRalpha)-targeted molecular contrast agent by intravenous infusion. During surgery, tumors were imaged in situ and ex vivo, after the lung parenchyma was dissected to directly expose the tumor to the imaging system. RESULTS: Tumors ranged from 0.3 to 7.5 cm (mean: 2.6 cm), and 46 of 50 (92%) lung adenocarcinomas were fluorescent. No false uptake occurred, and in 2 cases, intraoperative imaging revealed tumor metastases (3 mm and 6 mm) that were not recognized preoperatively. Four adenocarcinomas were not fluorescent, and immunohistochemistry showed that these adenocarcinomas did not express FRalpha. Tumor fluorescence was independent of nodule size, uptake of 2-deoxy-2 ((18)F)fluoro-D-glucose, histology, and tumor differentiation. Molecular imaging could identify only 7 of the 50 adenocarcinomas in situ in the patient without bisection. The most important predictor of the success of molecular imaging in locating the tumor in situ was the distance of the nodule from the pleural surface. CONCLUSIONS: Intraoperative molecular imaging with a targeted contrast agent can identify lung adenocarcinomas, and this technology is currently useful in patients with subpleural tumors, irrespective of size. With further refinements, this tool may prove useful in locating adenocarcinomas that are deeper in the lung parenchyma, in lymph nodes, and at pleural and resection margins. PMID- 26126459 TI - How pathologic is the function of a bicuspid aortic valve? PMID- 26126460 TI - Encouraging durability results for sutureless aortic valve: The new gold standard for aortic valve replacement? PMID- 26126461 TI - For the arch: Where there is urine, there is hope. PMID- 26126462 TI - Nothing comes for free. PMID- 26126463 TI - Respect the aorta. PMID- 26126464 TI - The law of the instrument. PMID- 26126465 TI - Primary pulmonary vein stenosis: Can we expect different results? PMID- 26126466 TI - Acute kidney injury after Fontan completion: Risk factors and outcomes "The good, the bad, and the ugly". PMID- 26126467 TI - Parting ways with routine postoperative chest radiographs: Are we ready to cut the cord? PMID- 26126468 TI - A thorough understanding of the mitral apparatus will improve the results of mitral valve repair. PMID- 26126469 TI - Choosing from the menu. PMID- 26126470 TI - Bioprosthetic valve durability: An industrial pudding? PMID- 26126471 TI - State-of-the-art surgical coronary revascularization: Multiple arterial conduits, minimal aortic manipulation. PMID- 26126472 TI - OPCAB is not for every surgeon and not for every patient. PMID- 26126473 TI - Hard endpoints from large randomized, clinical trials are more important than early reports of surrogate endpoints from small studies. PMID- 26126474 TI - Surgeon versus device in aortic valve replacement. PMID- 26126475 TI - Surgeons and devices in aortic valve replacement. Reply to the editor. PMID- 26126476 TI - Epidurals, intraoperative fluid administration, and hypotension. PMID- 26126477 TI - Epidurals, intraoperative fluid administration, and hypotension. Reply to editor. PMID- 26126478 TI - Resuscitation in cardiac surgery patients. Reply to the editor. PMID- 26126479 TI - Long-term mechanical circulatory support: A new disease state? PMID- 26126480 TI - Pleurectomy and decortication for metastatic renal cell carcinoma. PMID- 26126481 TI - A case of right atrial compression by the elevated liver successfully treated by diaphragmatic plication. PMID- 26126483 TI - Coupled Models for Soft Biological Tissue Disorders. PMID- 26126482 TI - Fatal right coronary artery rupture following blunt chest trauma: detection by postmortem selective coronary angiography. AB - Coronary artery injury is a rare complication following blunt chest trauma (BCT), and can be fatal. Here we report findings on postmortem selective coronary angiography of right coronary artery rupture after an assault involving blunt trauma to the chest. A woman in her 60s died after her son stomped on her chest. There were no appreciable signs of injury on external examination, and cause of death could not be determined by postmortem computed tomography (PMCT). Internal findings indicated that an external force had been applied to the anterior chest, as evidenced by subcutaneous hemorrhage and pericardial and cardiac contusions. Postmortem coronary angiography revealed irregularity of the intima and of the fat tissue surrounding the proximal part of the right coronary artery associated with a local filling defect. Histopathological examination suggested coronary rupture with dissection of the tunica media and compression of the lumen cavity. The key points in the present case are that no fatal injuries could be determined on external examination, and the heart and coronary artery injuries were not evident on PMCT. Criminality might be overlooked in such cases, as external investigation at the crime scene would be inadequate and could result in a facile diagnosis of cause of death. This is the first report of coronary artery rupture with dissection that was detected by CT coronary angiography, and provides helpful findings for reaching an appropriate decision both forensically and clinically. PMID- 26126484 TI - Computational Modeling of Traffic Related Thoracic Injury of a 10-Year-Old Child Using Subject-Specific Modeling Technique. AB - Traffic injuries have become a major health-related issue to school-aged children. To study this type of injury with numerical simulations, a finite element model was developed to represent the full body of a 10-year-old (YO) child. The model has been validated against test data at both body-part and full body levels in previous studies. Representing only the average 10-YO child, this model did not include subject-specific attributes, such as the variations in size and shape among different children. In this paper, a new modeling approach was used to morph this baseline model to a subject-specific model, based on anthropometric data collected from pediatric subjects. This mesh-morphing method was then used to rapidly morph the baseline mesh into the subject-specific geometry while maintaining a good mesh quality. The morphed model was subsequently applied to simulate a real-world motor vehicle crash accident. A lung injury observed in the accident was well captured by the subject-specific model. The findings of this study demonstrate the feasibility of the proposed morphing approach to develop subject-specific human models, and confirm their capability in prediction of traffic injuries. PMID- 26126485 TI - Irritable Bowel Syndrome and Colorectal Neoplasia: "Cause and Effect" or Chance Association? PMID- 26126486 TI - Will the Benefits of Treatment for Chronic Hepatitis C Be Retained in the Interferon-free Era? PMID- 26126487 TI - Evaluation of thrombolysis by using ultrasonic imaging: an in vitro study. AB - The hematocrit of a thrombus is a key factor associated with the susceptibility to thrombolysis. Ultrasonic imaging is currently the first-line screening tool for thrombus examinations. Different hematocrits result in different acoustical structures of thrombi, which alter the behavior of ultrasonic backscattering. This study explored the relationships among thrombolytic efficiencies, hematocrits, and ultrasonic parameters (the echo intensity and backscattered statistics). Porcine thrombi with different hematocrits, ranging from 0% to 50%, were induced in vitro. An ultrasonic scanner was used to scan thrombi and acquire raw image data for B-mode (echo intensity measurements) and Nakagami imaging (backscattered statistics analysis). Experiments on thrombolysis were performed using urokinase to explore the effect of the hematocrit on thrombolytic efficiency. Results showed that the weight loss ratio of thrombi exponentially decreased as the hematocrit increased from 0% to 50%. Compared with the echo intensity obtained from the conventional B-scan, the Nakagami parameter predicts the weight loss ratio, increasing from 0.6 to 1.2 as the weight loss ratio decreased from 0.67 to 0.26. The current findings suggest that using Nakagami imaging characterizing thrombi provides information of backscattered statistics, which may be associated with the thrombolytic efficiency. PMID- 26126488 TI - Screening of beta-Glucosidase and beta-Xylosidase Activities in Four Non Saccharomyces Yeast Isolates. AB - The finding of new isolates of non-Saccharomyces yeasts, showing beneficial enzymes (such as beta-glucosidase and beta-xylosidase), can contribute to the production of quality wines. In a selection and characterization program, we have studied 114 isolates of non-Saccharomyces yeasts. Four isolates were selected because of their both high beta-glucosidase and beta-xylosidase activities. The ribosomal D1/D2 regions were sequenced to identify them as Pichia membranifaciens Pm7, Hanseniaspora vineae Hv3, H. uvarum Hu8, and Wickerhamomyces anomalus Wa1. The induction process was optimized to be carried on YNB-medium supplemented with 4% xylan, inoculated with 106 cfu/mL and incubated 48 h at 28 degrees C without agitation. Most of the strains had a pH optimum of 5.0 to 6.0 for both the beta glucosidase and beta-xylosidase activities. The effect of sugars was different for each isolate and activity. Each isolate showed a characteristic set of inhibition, enhancement or null effect for beta-glucosidase and beta-xylosidase. The volatile compounds liberated from wine incubated with each of the 4 yeasts were also studied, showing an overall terpene increase (1.1 to 1.3-folds) when wines were treated with non-Saccharomyces isolates. In detail, terpineol, 4-vinyl phenol and 2-methoxy-4-vinylphenol increased after the addition of Hanseniaspora isolates. Wines treated with Hanseniaspora, Wickerhamomyces, or Pichia produced more 2-phenyl ethanol than those inoculated with other yeasts. PMID- 26126489 TI - Influence of P-Bonded Bulky Substituents on Electronic Interactions in Ferrocenyl Substituted Phospholes. AB - 2,5-Diferrocenyl-1-Ar-1H-phospholes 3 a-e (Ar=phenyl (a), ferrocenyl (b), mesityl (c), 2,4,6-triphenylphenyl (d), and 2,4,6-tri-tert-butylphenyl (e)) have been prepared by reactions of ArPH2 (1 a-e) with 1,4-diferrocenyl butadiyne. Compounds 3 b-e have been structurally characterized by single-crystal XRD analysis. Application of the sterically demanding 2,4,6-tri-tert-butylphenyl group led to an increased flattening of the pyramidal phosphorus environment. The ferrocenyl units could be oxidized separately, with redox separations of 265 (3 b), 295 (3 c), 340 (3 d), and 315 mV (3 e) in [NnBu4 ][B(C6 F5 )4]; these values indicate substantial thermodynamic stability of the mixed-valence radical cations. Monocationic [3 b](+)-[3 e](+) show intervalence charge-transfer absorptions between 4650 and 5050 cm(-1) of moderate intensity and half-height bandwidth. Compounds 3 c-e with bulky, electron-rich substituents reveal a significant increase in electronic interactions compared with less demanding groups in 3 a and 3 b. PMID- 26126490 TI - Suppressing Synonymy with a Homonym: The Emergence of the Nomenclatural Type Concept in Nineteenth Century Natural History. AB - 'Type' in biology is a polysemous term. In a landmark article, Paul Farber (Journal of the History of Biology 9(1): 93-119, 1976) argued that this deceptively plain term had acquired three different meanings in early nineteenth century natural history alone. 'Type' was used in relation to three distinct type concepts, each of them associated with a different set of practices. Important as Farber's analysis has been for the historiography of natural history, his account conceals an important dimension of early nineteenth century 'type talk.' Farber's taxonomy of type concepts passes over the fact that certain uses of 'type' began to take on a new meaning in this period. At the closing of the eighteenth century, terms like 'type specimen,' 'type species,' and 'type genus' were universally recognized as referring to typical, model members of their encompassing taxa. But in the course of the nineteenth century, the same terms were co-opted for a different purpose. As part of an effort to drive out nomenclatural synonymy - the confusing state of a taxon being known to different people by different names - these terms started to signify the fixed and potentially atypical name-bearing elements of taxa. A new type concept was born: the nomenclatural type. In this article, I retrace this perplexing nineteenth century shift in meaning of 'type.' I uncover the nomenclatural disorder that the new nomenclatural type concept dissolved, and expose the conceptual confusion it left in its tracks. What emerges is an account of how synonymy was suppressed through the coinage of a homonym. PMID- 26126492 TI - OXA-372, a novel carbapenem-hydrolysing class D beta-lactamase from a Citrobacter freundii isolated from a hospital wastewater plant. AB - OBJECTIVES: The objective of this study was to characterize a novel class D carbapenemase, named OXA-372, identified in a carbapenem-resistant Citrobacter freundii strain (Cfr-FI-07) isolated from a hospital wastewater plant in central Italy. METHODS: Cfr-FI-07 was isolated using a selective chromogenic medium for carbapenem-resistant Enterobacteriaceae. Carbapenemase production was confirmed by spectrophotometric assay. WGS was carried out using an Illumina MiSeq platform. The functional profile of OXA-372 was investigated by expression of the cloned gene in Escherichia coli and by analysis of kinetic parameters of the purified enzyme. RESULTS: C. freundii Cfr-FI-07 produced carbapenemase activity, but tested negative for common carbapenemase genes. WGS confirmed the absence of known carbapenemase genes and revealed the presence of a novel class D beta lactamase (DBL) determinant, named blaOXA-372, encoding a protein distantly related to other DBLs. In E. coli, production of OXA-372 conferred resistance to penicillins, including temocillin, and reduced susceptibility to carbapenems, while susceptibility to expanded-spectrum cephalosporins was virtually unaffected. This substrate specificity was confirmed by kinetic characterization of the purified enzyme, which exhibited high catalytic efficiencies for carbapenems (kcat/KM values >= 0.22 s(-1) . MUM(-1)). The blaOXA-372 gene was associated with a genetic platform of original structure consisting of a Tn402/Tn5053 hybrid transposon derivative, named Tn6255, inserted into a TnPa38 like transposon, named Tn6256, located on an IncA/C-IncN plasmid of approximately 140 kb. CONCLUSIONS: OXA-372 is a novel class D carbapenemase, belonging to a new lineage of DBLs, encoded by a gene associated with mobile elements. Functional properties revealed similarities, but also some differences, compared with other class D carbapenemases. PMID- 26126491 TI - PKC412 normalizes mutation-related keratin filament disruption and hepatic injury in mice by promoting keratin-myosin binding. AB - Keratins, among other cytoskeletal intermediate filament proteins, are mutated at a highly conserved arginine with consequent severe disease phenotypes due to disruption of keratin filament organization. We screened a kinase inhibitor library, using A549 cells that are transduced with a lentivirus keratin 18 (K18) construct, to identify compounds that normalize filament disruption due to K18 Arg90Cys mutation at the conserved arginine. High-throughput screening showed that PKC412, a multikinase inhibitor, ameliorated K18 Arg90Cys-mediated keratin filament disruption in cells and in the livers of previously described transgenic mice that overexpress K18 Arg90Cys. Furthermore, PKC412 protected cultured A549 cells that express mutant or wild-type K18 and mouse livers of the K18 Arg90Cys overexpressing transgenic mice from Fas-induced apoptosis. Proteomic analysis of proteins that associated with keratins after exposure of K18-expressing A549 cells to PKC412 showed that nonmuscle myosin heavy chain-IIA (NMHC-IIA) partitions with the keratin fraction. The nonmuscle myosin-IIA (NM-IIA) association with keratins was confirmed by immune staining and by coimmunoprecipitation. The keratin-myosin association is myosin dephosphorylation dependent; occurs with K8, the obligate K18 partner; is enhanced by PKC412 in cells and mouse liver; and is blocked by hyperphosphorylation conditions in cultured cells and mouse liver. Furthermore, NMHC-IIA knockdown inhibits PKC412 mediated normalization of K18 R90C filaments. CONCLUSION: The inhibitor PKC412 normalizes K18 Arg90Cys mutation-induced filament disruption and disorganization by enhancing keratin association with NM-IIA in a myosin dephosphorylation regulated manner. Targeting of intermediate filament disorganization by compounds that alter keratin interaction with their associated proteins offers a potential novel therapeutic approach for keratin and possibly other intermediate filament protein-associated diseases. PMID- 26126493 TI - Avbeta3 integrin: Pathogenetic role in osteotropic tumors. AB - The interplay of cancer cells and accessory cells within the microenvironment drives signals regulating the proliferation, migration and skeleton colonization. Osteotropism of tumor cells depends on chemokine activation, production of soluble factors and defective gene expression that cooperate within the metastatic niche to the bone resorbing functions of osteoclasts. Adhesion of cancer cells to the extracellular matrix is regulated by integrins as alphavbeta3 that enhances their invasiveness, pro-tumor angiogenesis and skeleton invasion. Therefore, alphavbeta3 signaling is implicated in enhancing osteotropism of breast and prostate cancers as well as of multiple myeloma. Targeting of alphavbeta3 has been adopted to restrain the tumor progression in several cancer models leading to improvement of overall survival as effect of the reduction of both tumor burden and osteotropism by malignant cells. Here, we review both the role of alphavbeta3 in malignant osteoclastogenesis and its potential targeting to restrain the bone colonization by skeleton invading cancers. PMID- 26126494 TI - Antiangiogenic agents in gynecological cancer: State of art and perspectives of clinical research. AB - Vascular endothelial growth factor [VEGF] pathway, which plays a key role in angiogenesis, may be blocked by either extracellular interference with VEGF itself (bevacizumab [BEV] or aflibercept), or intracytoplasmic inhibition of VEGF receptor (pazopanib, nintedanib, cediranid, sunitinib and sorafenib). An alternative approach is represented by trebananib, a fusion protein that prevents the interaction of angiopoietin [Ang]-1 and Ang-2 with Tie2 receptor on vascular endothelium. The combination of antiangiogenic agents, especially BEV, and chemotherapy is a rational therapeutic option for primary or recurrent ovarian carcinoma. However, it will be difficult to accept that it represents the new standard treatment, until biological characterization of ovarian carcinoma has not identified subsets of tumors with different responsiveness to BEV. Anti angiogenesis is an interesting target also for recurrent cervical or endometrial cancer, but nowadays the use of anti-angiogenic agents in these malignancies should be reserved to patients enrolled in clinical trials. PMID- 26126495 TI - Risk factors and antibiotic prophylaxis of cellulitis in cirrhosis. PMID- 26126496 TI - Characterization and modeling of multiphase flow in structured microreactors: a post microreactor case study. AB - We study microreactors with internal fields of posts as typical examples of structured microreactors to elucidate flow fields and their implications for mass transfer. Laser-induced fluorescence (LIF) visualization combined with image analysis is used to systematically quantify key features such as interfacial area, phase holdup and the characteristics of the post-wetting layer. The subsequent mass transport analysis yields insight into how the posts contribute to the overall enhanced mass transfer performance compared to open channels, and provides predictions of mass transfer performance under varying operating conditions. Computational fluid dynamic (CFD) simulations of multiphase flow using the volume-of-fluid (VOF) method are in good agreement with experimentally observed multiphase flows. PMID- 26126497 TI - Using Computational Fluid Dynamics in the forensic analysis of a prison fire. AB - On the 8th of December of 2010 a fire killed 81 inmates in a Chilean prison. While the collected evidence (including eye witness' accounts) indicated an intentional fire, started by a group of inmates who were fighting against another group and who ignited a mattress and threw it over a bunk bed inside the cell, it could not be established how fast the fire grew and whether the prison guards acted promptly enough to prevent the tragedy. In this context, the public defender office in charge of the case requested an independent investigation in order to determine the approximated time the fire started, and the temperature evolution of the padlocks at the cell doors during the initial stage, based on the construction characteristics of the prison, the existing materials and the evidence collected during the investigation. Computational Fluid Dynamics (CFD) were used to analyse the movement of the smoke and to match the first appearance of smoke on CCTV recordings at locations away from the fire, allowing for the estimation of the time-line of events. The padlock temperatures as a result of hot gases from the fire was also simulated. It was shown that the fire grew quickly and became uncontrollable before the guards could intervene. By the time the guards arrived at the cells' door, the padlocks were shown to be too hot to be handled without protection. PMID- 26126498 TI - A two-level subject-specific biomechanical model for improving prediction of hip fracture risk. AB - BACKGROUND: Sideways fall-induced hip fracture is a major worldwide health problem among the elderly population. However, all existing biomechanical models for predicting hip fracture mainly consider the femur related parameters. Their accuracy is limited as hip fracture is significantly affected by loading conditions as well. The objective of this study was to develop a biomechanical model for improving assessment of hip fracture risk by subject-specific prediction of fall-induced loading conditions. METHOD: All information required to construct the models was extracted from the subject's whole-body and hip medical image in order to make the models subject-specific. Fall-induced hip fracture risk for eighty clinical cases was calculated under two sets of loading conditions: subject-specific determined by the proposed model, and non-subject specific obtained from empirical functions. The predicted hip fracture risk indices were then compared with clinical observations. FINDINGS: It was found that the subject-specific prediction of fall-induced loading conditions significantly improves the hip fracture risk assessment. Consistent to the clinical observations, the fracture risk predicted by the proposed model suggested that obesity is a protective factor for hip fracture and underweight subjects are more likely to experience a hip fracture. INTERPRETATIONS: This study shows that hip fracture risk is affected by a number of factors, including body weight, body height, impact force, body mass index, hip soft tissue thickness, and bone quality. The proposed model provides a comprehensive, fast, accurate, and non-expensive method for prediction of hip fracture risk which should lead to more effective prevention of hip fractures. PMID- 26126500 TI - Evaluation of diagnostic criteria for IgG4-related tubulointerstitial nephritis. AB - BACKGROUND: IgG4-TIN is the most common pattern of renal involvement in IgG4 related disease. There are several proposed diagnostic criteria of IgG4-TIN recently. Two of them proposed by the Mayo Clinic and JSN are predominant. However, histopathological criteria of the number of IgG4+ plasma cells and several histological features are still under discussion due to low amount of tissue in renal biopsy specimens and low frequency of this kind of specimens. We aimed to screen IgG4-TIN on archived renal biopsy samples and evaluated the application of two proposed diagnostic criteria. METHODS: We selected 480 interstitial inflammation samples for light and electron microscopy and immunohistochemistry of CD138, IgG and IgG4 test. The Mayo Clinic proposed criteria diagnosed high-probability IgG4-TIN and JSN criteria confirmed IgG4-TIN. RESULTS: Twelve high-probability IgG4-TIN were screened by histology, imaging, serology and other organ involvement according to the Mayo Clinic proposed criteria. The previous principal pathological diagnoses were IgAN (n=4), CreGN (n=4), tubulointerstitial nephritis (n=3) and LN (n=1). Three cases showed storiform fibrosis and a bird's eye pattern. The distribution of IgG4+ plasma cells was focal, multifocal or diffuse, with a mixed mild, moderate or strong stainingpattern. Their treatment and clinical outcomes varied depending on different levels of proteinuria, serum creatinine, eGFR and original glomerular disease presentation. Therefore, we applied strict histological criteria of storiform fibrosis and evenly distributed IgG4+ plasma cells by JSN to confirm typical IgG4-TIN. Two cases were finally diagnosed as real IgG4-TIN. One was previously diagnosed as idiopathic interstitial nephritis with rapid response to corticosteroid therapy. The other was CreGN with immune complex deposits, which had poor outcome and long-term hemodialysis. CONCLUSIONS: IgG4-TIN might present concurrently with glomerular disease. The proposed criteria by the Mayo Clinic is flexible, sensitive, and superior in the identification of early-stage or atypical IgG4-TIN, with enhanced risk of misdiagnosis as compared to the proposed criteria by JSN, which is stricter, more specific, and might overlook early-stage or atypical IgG4-TIN. We propose a new set of criteria to improve pathologist derived diagnosis. PMID- 26126501 TI - Prophylaxis and treatment recommendations for sinusoidal obstruction syndrome in adult and pediatric patients undergoing hematopoietic stem cell transplant: a review of the literature. AB - Sinusoidal obstruction syndrome, a complication occurring early after hematopoietic stem cell transplantation, is a concern for clinicians. There are no guidelines to direct clinicians on the optimal way to prevent and treat this disease. Newer data show that defibrotide is a promising drug both for prevention and treatment, although it is not yet FDA approved. PMID- 26126502 TI - Mechanically selflocked chiral gemini-catenanes. AB - Mechanically interlocked and entangled molecular architectures represent one of the elaborate topological superstructures engineered at a molecular resolution. Here we report a methodology for fabricating mechanically selflocked molecules (MSMs) through highly efficient one-step amidation of a pseudorotaxane derived from dual functionalized pillar[5]arene (P[5]A) threaded by alpha,omega diaminoalkane (DA-n; n=3-12). The monomeric and dimeric pseudo[1]catenanes thus obtained, which are inherently chiral due to the topology of P[5]A used, were isolated and fully characterized by NMR and circular dichroism spectroscopy, X ray crystallography and DFT calculations. Of particular interest, the dimeric pseudo[1]catenane, named 'gemini-catenane', contained stereoisomeric meso-erythro and dl-threo isomers, in which two P[5]A moieties are threaded by two DA-n chains in topologically different patterns. This access to chiral pseudo[1]catenanes and gemini-catenanes will greatly promote the practical use of such sophisticated chiral architectures in supramolecular and materials science and technology. PMID- 26126503 TI - Patient attitudes towards prenatal diagnostic testing for inherited retinal disease. AB - OBJECTIVE: To explore factors that influence decision-making in relation to prenatal diagnostic testing (PDT) for inherited retinal disease (IRD). METHOD: Semi-structured interviews were conducted with 50 adults with IRD, selected from a larger sample to provide a diversity of backgrounds and opinions on genetic testing. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Mostly participants supported PDT, believing that it would provide information to help them prepare for and plan the future care of the child and the potential for early access to emerging therapies. Opposition to PDT stemmed from its use to justify termination of pregnancy, with participants feeling that it was not justified as they retained a good quality of life despite their visual impairment. Participants raised concerns about the risk of PDT and the accuracy of the results. However, most suggested that it should be available as an option for others, but for specific reasons and not as a part of routine care. CONCLUSION: The variation in attitudes towards PDT and uncertainty about the risk and accuracy of results suggest that individuals at risk of having a child with IRD should have access to genetic counselling to support decision making. PMID- 26126504 TI - Prevalence of tick-borne encephalitis virus in Ixodes ricinus ticks from three islands in north-western Norway. AB - Tick-borne encephalitis (TBE) is the most important viral tick-borne disease in Europe and can cause severe disease in humans. In Norway, human cases have been reported only from the southern coast. The aim of this study was to investigate the prevalence of tick-borne encephalitis virus (TBEV) in questing Ixodes ricinus ticks from the north-western part of Norway. A total of 4509 ticks were collected by flagging in May and June 2014. A subpopulation of 2220 nymphs and 162 adult ticks were analysed by real-time PCR and positive samples were confirmed by pyrosequencing. The estimated prevalence of TBEV was 3.08% among adult ticks from Sekken in More og Romsdal County and 0.41% among nymphs from both Hitra and Froya in Sor-Trondelag County. This study indicates that TBEV might be more widespread than the distribution of reported human cases suggests. PMID- 26126505 TI - Outcomes of patients resuscitated from cardiac arrest in the setting of drug overdose. AB - OBJECTIVES: To compare the attributes and clinical outcomes of patients with cardiac arrest in the setting of drug overdose (OD) to patients with cardiac arrest from non-drug related etiologies. METHODS: We utilized a US inpatient cardiac arrest registry used to study targeted temperature management (TTM) to identify patients with cardiac arrest in the setting of drug overdose between 2005 and 2013. Data regarding the cardiac arrest, resuscitation interventions, use of post-arrest TTM, urine drug screen, survival, and neurologic outcome were examined. These results were compared to patients suffering cardiac arrest from other causes during the same time period using Wilcoxon rank-sum tests for continuous variables and chi-square tests on categorical variables. RESULTS: Approximately 2.5% (64/2584) of cardiac arrests occurred in the setting of drug overdose. Patients in the OD cohort were younger, more likely to be male, and more likely to have an out-of-hospital cardiac arrest that was unwitnessed with no bystander CPR and from a non-shockable rhythm. However, the patients in the OD cohort had similar rates of survival and good neurologic outcomes (Cerebral Performance Category 1-2) compared to non-OD patients. A fraction of initially resuscitated patients in each group (8% in OD cohort vs. 15% in non-OD cohort, p=ns) did not receive post-arrest TTM due to prompt awakening following resuscitation. CONCLUSIONS: Patients resuscitated from cardiac arrest in the setting of drug OD have neurologic and survival outcomes comparable to non-OD patients despite lower rates of bystander CPR, shockable rhythms, and witnessed arrest. PMID- 26126506 TI - Inferences and conjectures in clinical trials: a systematic review of generalizability of study findings. PMID- 26126508 TI - Lawsuit seeks access to data from hepatitis C drug trial. PMID- 26126509 TI - Slipping with the waste (a wheelie bin hand injury). AB - A right hand dominant man in his 60s was moving his wheelie bin when he tripped and landed still holding on to the handle. His hand was trapped between the handle and the ground. He sustained lacerations at the level of the proximal interphalangeal joints of all the fingers of his right hand. The index and middle fingers had damage to the proximal phalangeal articular cartilage and central slip. The central slip loss in the middle finger required reconstruction. The wounds healed without complication by 4 weeks, at which point the patient's fingers were mobilised; he regained almost full range of movement by 3 months. PMID- 26126510 TI - Protective effect of pyrroloquinoline quinine on ultraviolet A irradiation induced human dermal fibroblast senescence in vitro proceeds via the anti apoptotic sirtuin 1/nuclear factor-derived erythroid 2-related factor 2/heme oxygenase 1 pathway. AB - The aim of the present study was to determine whether pyrroloquinoline quinine (PQQ) exerts a protective effect on ultraviolet A (UVA) irradiation-induced senescence in human dermal fibroblasts (HDFs) and to elucidate its mechanism of action in vitro. A senescence model was constructed as follows: HDFs (1x10(4) 1x10(6)) were cultured in a six-well plate in vitro and then exposed to UVA irradiation at a dosage of 9 J/cm2. Various concentrations of PQQ (50, 100 and 200 ng/ml) were added to the culture medium 24 h prior to UVA exposure. Following 72 h of irradiation, senescence-associated beta-galactosidase staining was performed in order to evaluate the senescence state. Furthermore, mRNA expression of the senescence marker genes matrix-metalloprotease (MMP)1 and MMP3 was determined using reverse transcription quantitative polymerase chain reaction. Protein expression of sirtuin (SIRT)1, SIRT6, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) were detected using western blot analysis. The results showed that the percentage of cells stained by X-gal following 9 J/cm2 UVA irradiation was markedly increased compared with that of the control group (53 and 8%, respectively), while 50 ng/ml PQQ attenuated the ratio of positive staining compared with that of the UVA-only cells (29 vs. 53%, respectively). Expression of fibroblast senescence marker genes MMP1 and MMP3 was decreased in cells treated with UVA and 50 ng/ml PQQ compared with that of cells in the UVA-only group. Western blot analysis revealed significant effects of PQQ on SIRT1 and SIRT6. Nrf2 and HO-1 exbibited mild changes with the same trend when treated with or without UVA and PQQ. In conclusion, the results of the present study showed that pyrroloquinoline quinine may have a protective effect on UVA irradiation-induced HDF aging, which may be associated with the anti-apoptotic SIRT1/Nrf2/HO-1 pathway as well as SIRT6 signaling. PMID- 26126511 TI - CD4 count remission hypothesis in patients with inflammatory bowel disease and human immunodeficiency virus infection: a systematic review of the literature. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) and human immunodeficiency virus (HIV) infection have shown controversial data concerning the remission hypothesis of IBD due to CD4 count depletion caused by HIV. The aim of our systematic review was to investigate the hypothesis whether low CD4 count due to HIV is related to IBD remission. METHODS: We systematically searched PubMed for studies reporting on HIV infection in IBD patients. We extracted characteristics of IBD and HIV disease course and CD4 counts. RESULTS: Thirteen papers (2 case-control studies, 2 case series, and 9 case reports) were eligible including 47 patients with IBD and HIV infection (43 male; 27 with Crohn's disease, 19 with ulcerative colitis, and 1 with indeterminate colitis). The IBD diagnosis criteria were heterogeneous among studies. Remission was reported for patients with IBD and HIV infection in 5 studies, including 4 case-control or case series and 1 case report. Four of 5 studies with IBD cases reported remission related to the CD4 count remission hypothesis but only 2 of them explicitly reported the CD4 count cut-off point (500 cells/MUL and 200 cells/mm3 respectively). On the contrary, 7 case reports described an active IBD course or relapse even in patients under immunosuppression. CONCLUSIONS: Current literature cannot support or reject the CD4 count remission hypothesis in IBD patients with HIV infection. Prospective studies using uniform criteria on IBD and HIV disease course and CD4 counts are needed. PMID- 26126512 TI - Skin pigmentation variation among populations of West Maharashtra, India. AB - OBJECTIVES: Global patterns of skin pigmentation have evolved as an adaptation to local ultraviolet radiation (UVR). Indian populations exposed to intense UVR show great variation in skin pigmentation. The UVR-based selection model cannot satisfactorily address the high prevalence of light skin among these populations. Thus, the present study examines pigmentation variation among populations of West Maharashtra and the Indian subcontinent within the context of population structure and social hierarchy. METHODS: Melanin index (MI) was measured from 555 individuals representing six endogamous populations of West Maharashtra. Skin pigmentation was assessed in terms of variation between populations and differences between and among castes and tribes. A linear regression analysis was run to assess the relationship among MI, UVR, and social hierarchy using published MI data from 13 Indian endogamous populations. RESULTS: Skin pigmentation differed significantly among populations of West Maharashtra. Significant pigmentation variation exists between castes and tribes of West Maharashtra as well as across the Indian subcontinent. We observe a significant negative relationship between social hierarchy and skin pigmentation, whereas the relationship between UVR and MI is weak. CONCLUSIONS: Our results suggest that various factors may have contributed to pigmentation diversity across the Indian subcontinent. The lack of correlation between UVR and MI suggests that natural selection may not have played a significant role in shaping pigmentation variation across the subcontinent. We discuss other possible explanations, including metabolic conservation and cultural factors such as traditional social hierarchies and strict endogamy that have led to the development of population structure. PMID- 26126507 TI - Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory. AB - Emotional arousal enhances perception and memory of high-priority information but impairs processing of other information. Here, we propose that, under arousal, local glutamate levels signal the current strength of a representation and interact with norepinephrine (NE) to enhance high priority representations and out-compete or suppress lower priority representations. In our "glutamate amplifies noradrenergic effects" (GANE) model, high glutamate at the site of prioritized representations increases local NE release from the locus coeruleus (LC) to generate "NE hotspots." At these NE hotspots, local glutamate and NE release are mutually enhancing and amplify activation of prioritized representations. In contrast, arousal-induced LC activity inhibits less active representations via two mechanisms: 1) Where there are hotspots, lateral inhibition is amplified; 2) Where no hotspots emerge, NE levels are only high enough to activate low-threshold inhibitory adrenoreceptors. Thus, LC activation promotes a few hotspots of excitation in the context of widespread suppression, enhancing high priority representations while suppressing the rest. Hotspots also help synchronize oscillations across neural ensembles transmitting high-priority information. Furthermore, brain structures that detect stimulus priority interact with phasic NE release to preferentially route such information through large scale functional brain networks. A surge of NE before, during, or after encoding enhances synaptic plasticity at NE hotspots, triggering local protein synthesis processes that enhance selective memory consolidation. Together, these noradrenergic mechanisms promote selective attention and memory under arousal. GANE not only reconciles apparently contradictory findings in the emotion cognition literature but also extends previous influential theories of LC neuromodulation by proposing specific mechanisms for how LC-NE activity increases neural gain. PMID- 26126513 TI - Nanoparticles Exacerbate Both Ubiquitin and Heat Shock Protein Expressions in Spinal Cord Injury: Neuroprotective Effects of the Proteasome Inhibitor Carfilzomib and the Antioxidant Compound H-290/51. AB - Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H 290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier. PMID- 26126514 TI - Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord. AB - Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI. PMID- 26126515 TI - Obesity Exacerbates Rat Cerebral Ischemic Injury through Enhancing Ischemic Adiponectin-Containing Neuronal Apoptosis. AB - A diet consisting of high levels of saturated fat has been linked to a dramatic rise in obesity. Long-term exposure to high fat, "Western diet" (WD), is detrimental to ischemic brain injury. Adiponectin receptor 1 (ADR-1) activation is also shown to exacerbate ischemic neuronal death. However, it is not known whether increasing percentages of adiponectin (APN)-containing neurons attenuates ischemic neuronal apoptosis by modulating ADRS. To explore the role of APN and its ADRs in the development of acute cerebral injury, we subjected WD and control diet (CD) rats to 1 h of middle cerebral artery occlusion followed by 23 h of reperfusion. Compared with CD rats, WD rats exhibited higher levels of brain infarct, neurologic deficits, brain edema, and apoptosis of APN-containing neurons; upregulation of both ADR-1 and P38 mitogen-activated protein kinase (P38MAPK); and downregulation of ADR-2 in ischemic brain tissues including frontal cortex, striatum, and hippocampus. Increasing percentages of APN containing neurons by baculovirus-mediated administration of APN, in addition to reducing apoptosis of APN-containing neurons in ischemic brain tissues, significantly attenuated brain infarct and edema, neurologic deficits, and altered expression of ADR-1, P38MAPK, and ADR-2 in both WD and CD group rats. These data suggest a negative correlation between percentages of APN-containing neurons and cerebral ischemic injury. Obesity could exacerbate rat cerebral ischemic injury by enhancing apoptosis of APN-containing neurons in ischemic brain tissues probably via modulating ADRs and P38MAPK. PMID- 26126518 TI - Trans-spliced Cas9 allows cleavage of HBB and CCR5 genes in human cells using compact expression cassettes. AB - CRISPR/Cas9 systems have been used in a wide variety of biological studies; however, the large size of CRISPR/Cas9 presents challenges in packaging it within adeno-associated viruses (AAVs) for clinical applications. We identified a two cassette system expressing pieces of the S. pyogenes Cas9 (SpCas9) protein which splice together in cellula to form a functional protein capable of site-specific DNA cleavage. With specific CRISPR guide strands, we demonstrated the efficacy of this system in cleaving the HBB and CCR5 genes in human HEK-293T cells as a single Cas9 and as a pair of Cas9 nickases. The trans-spliced SpCas9 (tsSpCas9) displayed ~35% of the nuclease activity compared with the wild-type SpCas9 (wtSpCas9) at standard transfection doses, but had substantially decreased activity at lower dosing levels. The greatly reduced open reading frame length of the tsSpCas9 relative to wtSpCas9 potentially allows for more complex and longer genetic elements to be packaged into an AAV vector including tissue-specific promoters, multiplexed guide RNA expression, and effector domain fusions to SpCas9. For unknown reasons, the tsSpCas9 system did not work in all cell types tested. The use of protein trans-splicing may help facilitate exciting new avenues of research and therapeutic applications through AAV-based delivery of CRISPR/Cas9 systems. PMID- 26126520 TI - Audit shows shortfall in care for emergency bowel surgery patients. PMID- 26126519 TI - Surgical management of post-cholecystectomy bile duct injuries: referral patterns and factors influencing early and long-term outcome. AB - Cholecystectomy-related bile duct injuries (BDI) remain a cause of significant morbidity and debate concerning optimal management is ongoing. We reviewed our experience with surgical management of BDI to assess patterns of referral along with postoperative and long-term outcomes. During September 1996-August 2013, 35 patients were operated in our tertiary care center for a Bismuth-Strasberg grade >A BDI after a cholecystectomy performed elsewhere. Injury grade distribution was as follows: D, n = 3; E1, n = 4; E2, n = 15; E3, n = 5; E4, n = 5; E5, n = 3. Four patients (11.4%) had an associated vascular injury (arterial, n = 2; portal, n = 1; both, n = 1). Treatment was direct repair + Kehr drain placement (n = 1), hepaticojejunostomy (n = 28), hepaticojejunostomy + hepatic resection (n = 5), and liver transplantation (n = 1). There was one postoperative death (2.8%) due to hepatic failure after liver resection; severe (Dindo-Clavien grade >=3b) complications were observed in 12 (34.3%) patients. Sepsis at referral (OR 17.33, p = 0.007) and laparotomy prior to definitive repair (OR 14, p = 0.04) were the factors associated with severe complications. Median follow-up was 81 (range 12 182) months; two patients were lost to follow-up. Treatment failure (defined as need for reoperation or interventional radiology procedure during follow-up) was observed in 7/32 (21.9%) patients. No association between baseline variables and treatment failure was observed. Post-cholecystectomy BDI represent a heterogeneous entity. The whole armamentarium of the hepatobiliary surgeon is required to achieve proper management. Patients referred with sepsis and requiring laparotomy prior to definitive repair are more prone to develop severe complications. PMID- 26126521 TI - Catalytic oxidation of water and alcohols by a robust iron(iii) complex bearing a cross-bridged cyclam ligand. AB - An iron(iii) complex bearing a cross-bridged cyclam ligand (4,11-dimethyl 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) is an efficient catalyst for the oxidation of both water and alcohols using sodium periodate as the oxidant. In catalytic water oxidation a maximum turnover number (TON) of 1030 is achieved, while in catalytic alcohol oxidation >95% conversions and yields can be obtained. PMID- 26126522 TI - YAP is closely correlated with castration-resistant prostate cancer, and downregulation of YAP reduces proliferation and induces apoptosis of PC-3 cells. AB - Yes-associated protein 65 (YAP65) has been implicated as an oncogene, and its expression is increased in human cancer. Previous studies have demonstrated that alterations in YAP activity may result in tumourigenesis of the prostate. With androgen deprivation therapies becoming progressively ineffective, often leading to life-threatening androgen-resistant prostate cancer (CRPC). The present study aimed to analyse the role of YAP in prostate cancer (PCa), particularly in CRPC. YAP protein was detected using immunohistochemistry and western blot analysis in different prostatic tissues. In addition, three specific RNA interference vectors targeting the human YAP gene were synthesised, and PC-3 cells with a stable inhibition of YAP were obtained by transfection. MTT, flow cytometry, reverse transcription-quantitative polymerase chain reaction and western blot assays were used to analyse the effects of YAP inhibition on the proliferation and apoptosis of PC-3 cells. The frequency of cells that were positive for YAP protein in PCa (78.13%) was significantly higher, compared with para-PCa (26.67%; P=0.007) and benign prostatic hyperplasia (0%; P=0.002). The frequency of cells, which were positive for the expression of YAP exhibited a positive correlation (P=0.008) with the Gleason score, the tumour-node-metastasis staging (P=0.033) and the level of prostate specific antigens (P=0.0032) in PCa. The proliferative capacity of the transfected group was significantly lower, compared with the negative control group (P=0.022). The cell-cycle of the transfected group was arrested in the G1 stage, which was detected using flow cytometry, and there was a significant increase in the apoptosis of cells in the transfected group (P=0.002). The mRNA and protein levels of TEA domain family member 1 were inhibited in the transfected group (P=0.001 and P=0.00, respectively). Therefore, it was concluded that gene transcription and protein expression of YAP may be involved in the development of PCa, particularly CRPC, and may be a novel biomarker for investigation of the occurrence and progression of CRPC. However, the mechanism underlying the modulation of YAP in CRPC remains to be fully elucidated. PMID- 26126523 TI - Transcriptomic analysis of the GCN5 gene reveals mechanisms of the epigenetic regulation of virulence and morphogenesis in Ustilago maydis. AB - Chromatin in the eukaryotic nucleus is highly organized in the form of nucleosomes where histones wrap DNA. This structure may be altered by some chemical modifications of histones, one of them, acetylation by histone acetyltransferases (HATs) that originates relaxation of the nucleosome structure, providing access to different transcription factors and other effectors. In this way, HATs regulate cellular processes including DNA replication, and gene transcription. Previously, we isolated Ustilago maydis mutants deficient in the GCN5 HAT that are avirulent, and grow constitutively as mycelium. In this work, we proceeded to identify the genes differentially regulated by GCN5, comparing the transcriptomes of the mutant and the wild type using microarrays, to analyse the epigenetic control of virulence and morphogenesis. We identified 1203 genes, 574 positively and 629 negatively regulated in the wild type. We found that genes belonging to different categories involved in pathogenesis were downregulated in the mutant, and that genes involved in mycelial growth were negatively regulated in the wild type, offering a working hypothesis on the epigenetic control of virulence and morphogenesis of U. maydis. Interestingly, several differentially regulated genes appeared in clusters, suggesting a common regulation. Some of these belonged to pathogenesis or secondary metabolism. PMID- 26126524 TI - Looking beyond Saccharomyces: the potential of non-conventional yeast species for desirable traits in bioethanol fermentation. AB - Saccharomyces cerevisiae has been used for millennia in the production of food and beverages and is by far the most studied yeast species. Currently, it is also the most used microorganism in the production of first-generation bioethanol from sugar or starch crops. Second-generation bioethanol, on the other hand, is produced from lignocellulosic feedstocks that are pretreated and hydrolyzed to obtain monomeric sugars, mainly D-glucose, D-xylose and L-arabinose. Recently, S. cerevisiae recombinant strains capable of fermenting pentose sugars have been generated. However, the pretreatment of the biomass results in hydrolysates with high osmolarity and high concentrations of inhibitors. These compounds negatively influence the fermentation process. Therefore, robust strains with high stress tolerance are required. Up to now, more than 2000 yeast species have been described and some of these could provide a solution to these limitations because of their high tolerance to the most predominant stress conditions present in a second-generation bioethanol reactor. In this review, we will summarize what is known about the non-conventional yeast species showing unusual tolerance to these stresses, namely Zygosaccharomyces rouxii (osmotolerance), Kluyveromyces marxianus and Ogataea (Hansenula) polymorpha (thermotolerance), Dekkera bruxellensis (ethanol tolerance), Pichia kudriavzevii (furan derivatives tolerance) and Z. bailii (acetic acid tolerance). PMID- 26126525 TI - Xp11.2 translocation renal cell carcinomas in young adults. AB - BACKGROUND: Little is known about the biological behavior of Xp11.2 translocation renal cell carcinomas (RCCs) as few clinical studies have been performed using a large sample size. METHODS: This study included 103 consecutive young adult patients (age <= 45 years) with RCC who underwent partial or radical nephrectomy at our institution from 2008 to 2013. Five patients without complete clinical data were excluded. Of the 98 remaining patients, 16 and 82 patients were included in the Xp11.2 translocation and non-Xp11.2 translocation groups, respectively. Clinicopathologic data were collected, including age, gender, tumor size, laterality, symptoms at diagnosis, surgical procedure, pathologic stage, tumor grade, time of recurrence and death. RESULTS: Xp11.2 translocation RCCs were associated with higher tumor grade and pathologic stage (P < 0.05, Fisher's exact test). During the median follow-up of 36 months (range: 3-71 months), the number of cancer-related deaths was 4 (4.9%) and 3 (18.7%) in the non-Xp11.2 translocation and Xp11.2 translocation groups, respectively. The Kaplan-Meier cancer specific survival curves revealed a significant difference between non Xp11.2 translocation RCCs and Xp11.2 translocation RCCs in young adults (P = 0.042). CONCLUSIONS: Compared with non-Xp11.2 translocation RCCs, the Xp11.2 translocation RCCs seemingly showed a higher tumor grade and pathologic stage and have similar recurrence-free survival rates but poorer cancer-specific survival rates in young adults. PMID- 26126526 TI - Acute exacerbations of COPD are associated with significant activation of matrix metalloproteinase 9 irrespectively of airway obstruction, emphysema and infection. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL). METHODS: COPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,-9,-12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography. RESULTS: We observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking. CONCLUSIONS: The results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline. PMID- 26126529 TI - HIV prevalence is strongly associated with geographical variations in male circumcision and foreskin cutting in Papua New Guinea: an ecological study. AB - OBJECTIVE: To examine the correlation between HIV prevalence and male circumcision and other foreskin cutting practices across the four regions of Papua New Guinea (PNG). DESIGN: An ecological substudy using unique data from an interdisciplinary research programme to evaluate the acceptability, sociocultural context and public health impact of male circumcision for HIV prevention in PNG. METHODS: Published data describing (a) self-reported circumcision status by region from the 'Acceptability and Feasibility of Male Circumcision for HIV prevention in PNG' study and (b) HIV prevalence by region from PNG National Department of Health were used to correlate male circumcision and other foreskin cutting practices and HIV prevalence. Maps were constructed to visually represent variations across the four regions of PNG. RESULTS: Regions of PNG with the highest HIV prevalence had the lowest prevalence of male circumcision and other forms of foreskin cutting and vice versa. Male circumcision and dorsal longitudinal cuts were strongly associated with HIV prevalence and able to explain 99% of the observed geographical variability in HIV prevalence in PNG (p<0.01). CONCLUSIONS: The regional prevalence of HIV infection in PNG appears to be closely correlated with the regional distribution of male circumcision and dorsal longitudinal foreskin cuts. Further research is warranted to investigate causality of this correlation as well as the potential of dorsal longitudinal cuts to confer protection against HIV acquisition in heterosexual men. PMID- 26126530 TI - Have we forgotten? Oral Manifestations of Kaposi's Sarcoma. PMID- 26126531 TI - HIV indicator condition-guided testing to reduce the number of undiagnosed patients and prevent late presentation in a high-prevalence area: a case-control study in primary care. AB - OBJECTIVES: Recent guidelines advocate accelerated provider-initiated HIV testing by general practitioners (GPs). We aimed to identify the number of patient consultations in six general practices in the South-East of Amsterdam, and the incidence of HIV indicator conditions reported in their medical files prior to diagnosis. METHODS: A cross-sectional search in an electronic general practice database. We used a case-control design to identify those conditions most associated with an HIV-positive status. RESULTS: We included 102 HIV cases diagnosed from 2002 to 2012, and matched them with 299 controls. In the year prior to HIV diagnosis, 61.8% of cases visited their GP at least once, compared with 38.8% of controls. In the 5 years prior to HIV diagnosis, 58.8% of HIV cases had exhibited an HIV indicator condition, compared with 7.4% of controls. The most common HIV-related conditions were syphilis and gonorrhoea. The most common HIV-related symptoms were weight loss, lymphadenopathy and peripheral neuropathy. During this period, average HIV prevalence among people aged 15-59 years increased from 0.4% to 0.9%. CONCLUSIONS: This study revealed many opportunities for HIV indicator condition-guided testing in primary care. As yet, however, HIV indicator conditions are not exploited as triggers for early HIV testing. PMID- 26126532 TI - What type, or combination of exercise can improve preferred gait speed in older adults? A meta-analysis. AB - BACKGROUND: Improved preferred gait speed in older adults is associated with increased survival rates. There are inconsistent findings in clinical trials regarding effects of exercise on preferred gait speed, and heterogeneity in interventions in the current reviews and meta-analyses. OBJECTIVE: to determine the meta-effects of different types or combinations of exercise interventions from randomized controlled trials on improvement in preferred gait speed. METHODS: DATA SOURCES: A literature search was performed; the following databases were searched for studies from 1990 up to 9 December 2013: PubMed, EMBASE, EBSCO (AMED, CINAHL, ERIC, Medline, PsycInfo, and SocINDEX), and the Cochrane Library. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials of exercise interventions for older adults >= 65 years, that provided quantitative data (mean/SD) on preferred gait speed at baseline and post-intervention, as a primary or secondary outcome measure in the published article were included. Studies were excluded when the PEDro score was <=4, or if participants were selected for a specific neurological or neurodegenerative disease, Chronic Obstructive Pulmonary Disease, cardiovascular disease, recent lower limb fractures, lower limb joint replacements, or severe cognitive impairments. The meta-effect is presented in Forest plots with 95 % confidence STUDY APPRAISAL AND SYNTHESIS METHODS: intervals and random weights assigned to each trial. Homogeneity and risk of publication bias were assessed. RESULTS: Twenty-five studies were analysed in this meta-analysis. Data from six types or combinations of exercise interventions were pooled into sub-analyses. First, there is a significant positive meta-effect of resistance training progressed to 70-80 % of 1RM on preferred gait speed of 0.13 [CI 95 % 0.09-0.16] m/s. The difference between intervention- and control groups shows a substantial meaningful change (>0.1 m/s). Secondly, a significant positive meta-effect of interventions with a rhythmic component on preferred gait speed of 0.07 [CI 95 % 0.03-0.10] m/s was found. Thirdly, there is a small significant positive meta-effect of progressive resistance training, combined with balance-, and endurance training of 0.05 [CI 95 % 0.00-0.09] m/s. The other sub-analyses show non-significant small positive meta-affects. CONCLUSIONS: Progressive resistance training with high intensities, is the most effective exercise modality for improving preferred gait speed. Sufficient muscle strength seems an important condition for improving preferred gait speed. The addition of balance-, and/or endurance training does not contribute to the significant positive effects of progressive resistance training. A promising component is exercise with a rhythmic component. Keeping time to music or rhythm possibly trains higher cognitive functions that are important for gait. LIMITATIONS: The focus of the present meta-analysis was at avoiding as much heterogeneity in exercise interventions. However heterogeneity in the research populations could not be completely avoided, there are probably differences in health status within different studies. PMID- 26126534 TI - Orally Administered Mucolytic Drug l-Carbocisteine Inhibits Angiogenesis and Tumor Growth in Mice. AB - Angiogenesis, the formation of new blood vessels from pre-existing vessels, is essential for the growth and metastasis of tumors. In this study, we found that l carbocisteine, a widely used expectorant, potently inhibits angiogenesis in vitro and in vivo. An in vivo Matrigel plug assay revealed that l-carbocisteine (2.5 mg/kg i.p. twice daily) significantly inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. l-Carbocisteine also suppressed VEGF stimulated proliferation, migration, and formation of capillary-like structures of human umbilical vein endothelial cells (HUVECs). We examined the signaling pathways affected in VEGF-stimulated HUVECs, and found that l-carbocisteine significantly inhibited VEGF-induced phosphorylation of phospholipase C (PLC) gamma, protein kinase C (PKC) MU, and extracellular signal-related kinases (ERK) 1/2, which have been shown to be essential for angiogenesis. However, these inhibitory effects of l-carbocisteine were not observed in the HeLa human cervical cancer cell line. An in vivo study of Colon-26 tumor-bearing mice found that tumor volumes were significantly smaller in mice treated with l carbocisteine (150 mg/kg administered orally twice daily) in comparison with vehicle-treated mice. However, l-carbocisteine had no direct effect on Colon-26 cell proliferation or ERK activation. Collectively, our results suggest that l carbocisteine inhibits tumor angiogenesis by suppressing PLCgamma/PKC/ERK signaling. PMID- 26126533 TI - Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection. AB - Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2 hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV. Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks postinfection substantially reduced viral load. When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock treated controls. T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice. In conclusion, these results reveal a novel link between LXR stimulation and cell resistance to HIV infection and suggest that LXR agonists may be good candidates for development as anti-HIV agents, in particular for pre exposure prophylaxis of HIV infection. PMID- 26126535 TI - High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-beta1/Smad2/3 Signaling. AB - Epithelial-to-mesenchymal transition (EMT) is a crucial event in the cellular origin of myofibroblasts that secrete extracellular matrix in the progression of pulmonary fibrosis (PF). High-mobility group box 1 (HMGB1) is a novel mediator of EMT. However, whether this process involves the recognized transforming growth factor-beta1 (TGF-beta1)/Smad signaling that also contributes to EMT in PF has not yet been elucidated. Here, we developed a model of PF induced by bleomycin (BLM) in rats and conducted several simulation experiments in A549 (human) and RLE-6TN (rat) alveolar epithelial cell (AEC) lines to unravel the role of TGF beta1/Smad2/3 signaling in HMGB1-mediated EMT. We found that the levels of serum HMGB1 and lung hydroxyproline were severely elevated after BLM administration. Moreover, the protein expression of HMGB1, TGF-beta1, phosphorylated Smad2/3 (p Smad2/3), and mesenchymal markers including alpha-smooth muscle actin, vimentin, and type I collagen were significantly increased with the reduced protein expression of an epithelial marker (E-cadherin) in the rat model by Western blot or immunohistochemical analysis. In addition, the uptake of both exogenous TGF beta1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-beta1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF beta1 deficiency evidently ameliorated HMGB1-mediated EMT with reduced p-Smad2/3 in A549 cells. It provides new insights that HMGB1 release from injured lungs promotes AEC damage through induction of the EMT process, in which TGF beta1/Smad2/3 signaling is activated and contributes to PF. These results suggest that HMGB1 may constitute a therapeutic target for developing antifibrotic agents for abnormal lung remodeling. PMID- 26126537 TI - EDITORIAL RETRACTION: MiR-181c Regulates Human Embryonic Stem Cell. PMID- 26126536 TI - Protein Arginine Methyltransferase 1 Methylates Smurf2. AB - Smurf2, a member of the HECT domain E3 ligase family, is well known for its role as a negative regulator of TGF-beta signaling by targeting Smads and TGF-beta receptor. However, the regulatory mechanism of Smurf2 has not been elucidated. Arginine methylation is a type of post-translational modification that produces monomethylated or dimethylated arginine residues. In this report, we demonstrated methylation of Smurf2 by PRMT1. In vitro methylation assay showed that Smurf2, not Smurf1, was methylated by PRMT1. Among the type I PRMT family, only PRMT1 showed activity for Smurf2. Transiently expressed Smurf2 was methylated by PRMT1, indicating Smurf2 is a novel substrate of PRMT1. Using deletion constructs, methylation sites were shown to be located within amino acid region 224-298 of Smurf2. In vitro methylation assay following point mutation of putative methylation sites confirmed the presence of Arg232, Arg234, Arg237, and Arg239. Knockdown of PRMT1 resulted in increased Smurf2 expression as well as inhibition of TGF-beta-mediated reporter activity. Although it is unclear whether or not increased Smurf2 expression can be directly attributed to lack of methylation of arginine residues, our results suggest that methylation by PRMT1 may regulate Smurf2 stability and control TGF-beta signaling. PMID- 26126538 TI - Tubulin Beta3 Serves as a Target of HDAC3 and Mediates Resistance to Microtubule Targeting Drugs. AB - We investigated the role of HDAC3 in anti-cancer drug-resistance. The expression of HDAC3 was decreased in cancer cell lines resistant to anti-cancer drugs such as celastrol and taxol. HDAC3 conferred sensitivity to these anti-cancer drugs. HDAC3 activity was necessary for conferring sensitivity to these anti-cancer drugs. The down-regulation of HDAC3 increased the expression of MDR1 and conferred resistance to anti-cancer drugs. The expression of tubulin beta3 was increased in drug-resistant cancer cell lines. ChIP assays showed the binding of HDAC3 to the promoter sequences of tubulin beta3 and HDAC6. HDAC6 showed an interaction with tubulin beta3. HDAC3 had a negative regulatory role in the expression of tubulin beta3 and HDAC6. The down-regulation of HDAC6 decreased the expression of MDR1 and tubulin beta3, but did not affect HDAC3 expression. The down-regulation of HDAC6 conferred sensitivity to taxol. The down-regulation of tubulin beta3 did not affect the expression of HDAC6 or MDR1. The down-regulation of tubulin beta3 conferred sensitivity to anti-cancer drugs. Our results showed that tubulin beta3 serves as a downstream target of HDAC3 and mediates resistance to microtubule-targeting drugs. Thus, the HDAC3-HDAC6-Tubulin beta axis can be employed for the development of anti-cancer drugs. PMID- 26126539 TI - Occurrence of glucocorticoids discharged from a sewage treatment plant in Japan and the effects of clobetasol propionate exposure on the immune responses of common carp (Cyprinus carpio) to bacterial infection. AB - The present study evaluated the environmental risks to common carp (Cyprinus carpio) posed by glucocorticoids present in sewage treatment plant (STP) effluent. To gather information on the seasonal variations in glucocorticoid concentration, the authors sampled the effluent of a Japanese STP every other week for 12 mo. Six of 9 selected glucocorticoids were detected in the effluent, with clobetasol propionate and betamethasone 17-valerate detected at the highest concentrations and frequencies. The present study's results indicated that effluent glucocorticoid concentration may depend on water temperature, which is closely related to the removal efficiency of the STP or to seasonal variations in the public's use of glucocorticoids. In a separate experiment, to clarify whether glucocorticoids in environmental water increase susceptibility to bacterial infection in fish, the authors examined the responses to bacterial infection (Aeromonas veronii) of common carp exposed to clobetasol propionate. Clobetasol propionate exposure did not affect bacterial infection-associated mortality. In fish infected with A. veronii but not exposed to clobetasol propionate, head kidney weight and number of leukocytes in the head kidney were significantly increased (p < 0.05), whereas these effects were not observed in infected fish exposed to clobetasol. This suggests that clobetasol propionate alleviated bacterial infection-associated inflammation. Together, these results indicate that susceptibility to bacterial infection in common carp is not affected by exposure to glucocorticoids at environmentally relevant concentrations. PMID- 26126540 TI - A comparison of genomic selection models across time in interior spruce (Picea engelmannii * glauca) using unordered SNP imputation methods. AB - Genomic selection (GS) potentially offers an unparalleled advantage over traditional pedigree-based selection (TS) methods by reducing the time commitment required to carry out a single cycle of tree improvement. This quality is particularly appealing to tree breeders, where lengthy improvement cycles are the norm. We explored the prospect of implementing GS for interior spruce (Picea engelmannii * glauca) utilizing a genotyped population of 769 trees belonging to 25 open-pollinated families. A series of repeated tree height measurements through ages 3-40 years permitted the testing of GS methods temporally. The genotyping-by-sequencing (GBS) platform was used for single nucleotide polymorphism (SNP) discovery in conjunction with three unordered imputation methods applied to a data set with 60% missing information. Further, three diverse GS models were evaluated based on predictive accuracy (PA), and their marker effects. Moderate levels of PA (0.31-0.55) were observed and were of sufficient capacity to deliver improved selection response over TS. Additionally, PA varied substantially through time accordingly with spatial competition among trees. As expected, temporal PA was well correlated with age-age genetic correlation (r=0.99), and decreased substantially with increasing difference in age between the training and validation populations (0.04-0.47). Moreover, our imputation comparisons indicate that k-nearest neighbor and singular value decomposition yielded a greater number of SNPs and gave higher predictive accuracies than imputing with the mean. Furthermore, the ridge regression (rrBLUP) and BayesCpi (BCpi) models both yielded equal, and better PA than the generalized ridge regression heteroscedastic effect model for the traits evaluated. PMID- 26126541 TI - Mapping quantitative trait loci in selected breeding populations: A segregation distortion approach. AB - Quantitative trait locus (QTL) mapping is often conducted in line-crossing experiments where a sample of individuals is randomly selected from a pool of all potential progeny. QTLs detected from such an experiment are important for us to understand the genetic mechanisms governing a complex trait, but may not be directly relevant to plant breeding if they are not detected from the breeding population where selection is targeting for. QTLs segregating in one population may not necessarily segregate in another population. To facilitate marker assisted selection, QTLs must be detected from the very population which the selection is targeting. However, selected breeding populations often have depleted genetic variation with small population sizes, resulting in low power in detecting useful QTLs. On the other hand, if selection is effective, loci controlling the selected trait will deviate from the expected Mendelian segregation ratio. In this study, we proposed to detect QTLs in selected breeding populations via the detection of marker segregation distortion in either a single population or multiple populations using the same selection scheme. Simulation studies showed that QTL can be detected in strong selected populations with selected population sizes as small as 25 plants. We applied the new method to detect QTLs in two breeding populations of rice selected for high grain yield. Seven QTLs were identified, four of which have been validated in advanced generations in a follow-up study. Cloned genes in the vicinity of the four QTLs were also reported in the literatures. This mapping-by-selection approach provides a new avenue for breeders to improve breeding progress. The new method can be applied to breeding programs not only in rice but also in other agricultural species including crops, trees and animals. PMID- 26126544 TI - Correction to: "Activity Suppression Behavior Phenotype in SULT4A1 Frameshift Mutant Zebrafish". PMID- 26126542 TI - Genetic and ecological data reveal species boundaries between viviparous and oviparous lizard lineages. AB - Identification of cryptic species is an essential aim for conservation biologists to avoid premature extinctions of 'unrecognized' species. Integrating different types of data can undoubtedly aid in resolving the issue of species delimitation. We studied here two lineages of the common lizard Zootoca vivipara that display different reproductive mode (the viviparous Z. v. vivipara and the oviparous Z. v. carniolica) and that overlap their distributional ranges in the European Alps. With the purpose of delimiting species' boundaries, we analyzed their ecological, genetic and natural history features. More than 300 samples were collected and analyzed at cytochrome b and 11 microsatellites loci for investigating genetic variation, population structure, individual relatedness and evolutionary histories of the two lineages. Additionally, we compared their ecological niches using eight ecological variables. Genetic data showed contrasting patterns of genetic structure between the two lineages, different demographic dynamics and no hybridization events. Also strong ecological differences (such as temperature) emerged between the two lineages, and niche overlap was limited. Taken together, these results indicate that Z. v. vivipara and Z. v. carniolica should be recognized as two separate species, and particular conservation consideration should be given to the oviparous lineage that tends to live in areas threatened by increasing impact of human activities. However, recent and rapid climate warming might determine an increasing risk for the persistence of the viviparous lineage, being adapted to cold environments. PMID- 26126545 TI - Correction to: "Constitutive Androgen Receptor-Null Mice Are Sensitive to the Toxic Effects of Parathion: Association with Reduced Cytochrome P450-Mediated Parathion Metabolism". PMID- 26126548 TI - Authors' reply. PMID- 26126547 TI - Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. AB - BACKGROUND: P.R4810K of RNF213 (mysterin: rs112735431), which is an AAA(+) ATPase, is the susceptibility polymorphism for moyamoya disease (MMD) in East Asians. However, the role of RNF213 R4810K in the etiology of MMD is unknown. METHODS AND RESULTS: To clarify the role of RNF213 in known angiogenic pathways, RNF213 expression was analyzed in endothelial cells (ECs) treated with several angiogenic and antiangiogenic factors, including interferons (IFNs). RNF213 was upregulated by IFN-beta through signal transducer and activator of transcription x in the promoter and mediated antiangiogenic activity of IFN-beta. RNF213 wild type (WT) overexpression could not lower angiogenesis without IFN-beta, but RNF213 R4810K overexpression could. To correlate biochemical function as ATPase and the role of RNF213 oligomer formation with antiangiogenic activity, we investigated the effects of mutations in the AAA(+) module. A mutation of the Walker B motif (WEQ), which stabilizes oligomerization, inhibited angiogenesis, but AAA(+) module deletion, which cannot initiate oligomerization, did not. Intriguingly, R4810K, similar to WEQ, decreased ATPase activity, suggesting its antiangiogenic activity through stabilizing oligomers. To confirm the antiangiogenic effect of RNF213 upregulation in vivo, vascular EC- or smooth muscle cell-specific Rnf213 R4757K (R4810K ortholog) or WT transgenic (Tg) mice were exposed to hypoxia. Cerebral angiogenesis by hypoxia was suppressed in EC specific Rnf213 R4757K Tg mice, whereas it was not suppressed in other mice. CONCLUSIONS: This study suggests the importance of inflammatory signals as environmental factors and R4810K carriers for susceptibility to cerebral hypoxia. A specific inhibitor of ATP binding to the first AAA(+) could be a promising therapeutic candidate for MMD. PMID- 26126546 TI - Sex-Specific Parental Effects on Offspring Lipid Levels. AB - BACKGROUND: Plasma lipid levels are highly heritable traits, but known genetic loci can only explain a small portion of their heritability. METHODS AND RESULTS: In this study, we analyzed the role of parental levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) in explaining the values of the corresponding traits in adult offspring. We also evaluated the contribution of nongenetic factors that influence lipid traits (age, body mass index, smoking, medications, and menopause) alone and in combination with variability at the genetic loci known to associate with TC, LDL-C, HDL-C, and TG levels. We performed comparisons among different sex-specific regression models in 416 families from the Framingham Heart Study and 304 from the SardiNIA cohort. Models including parental lipid levels explain significantly more of the trait variation than models without these measures, explaining up to ~39% of the total trait variation. Of this variation, the parent-of-origin effect explains as much as ~15% and it does so in a sex-specific way. This observation is not owing to shared environment, given that spouse-pair correlations were negligible (<1.5% explained variation in all cases) and is distinct from previous genetic and acquired factors that are known to influence serum lipid levels. CONCLUSIONS: These findings support the concept that unknown genetic and epigenetic contributors are responsible for most of the heritable component of the plasma lipid phenotype, and that, at present, the clinical utility of knowing age matched parental lipid levels in assessing risk of dyslipidemia supersedes individual locus effects. Our results support the clinical utility of knowing parental lipid levels in assessing future risk of dyslipidemia. PMID- 26126549 TI - Long-term immunologic and virologic responses on raltegravir-containing regimens among ART-experienced participants in the HIV Outpatient Study. AB - OBJECTIVES: Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long term outcomes in routine HIV care. METHODS: We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007-2011.We identified patients who started (baseline date) either continuous >= 30 days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan-Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA < 50 copies/ml, and CD4 cell count (CD4) increase of >= 50 cells mm(- 3) during follow-up. RESULTS: Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205 cells mm(- 3); mean baseline CD4, 460 cells mm(- 3); HIV RNA < 50 copies ml(- 1) in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3 years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA < 50 copies ml(- 1) (P = 0.51); 69 and 58%, respectively, achieved a CD4 increase >= 50 cells mm(- 3) (P = 0.70). DISCUSSION: In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART. PMID- 26126550 TI - Investigating the predictive role of computed tomography in patients with acute pancreatitis: let's not give up. PMID- 26126551 TI - The link between health and wellbeing and constitutional recognition. PMID- 26126552 TI - Celebrating 10 years of collaboration: the Australian Indigenous Doctors' Association and Medical Deans Australia and New Zealand. PMID- 26126553 TI - Time to move to a glycated haemoglobin-based algorithm for diabetes screening and diagnosis? PMID- 26126555 TI - Data sharing in Indigenous health research: guidelines needed. PMID- 26126556 TI - Open speeds on Northern Territory roads: not so fast. PMID- 26126557 TI - Ensuring safe exercise participation in clinical populations: who is responsible? PMID- 26126558 TI - Telehealth in remote Northern Territory: bridging the gap. PMID- 26126559 TI - Strongyloides stercoralis infection and antenatal care. PMID- 26126560 TI - Recent warnings of a rise in crystal methamphetamine ("ice") use in rural and remote Indigenous Australian communities should be heeded. PMID- 26126561 TI - Differing trends in thickness and survival between nodular and non-nodular primary cutaneous melanoma in Victoria, Australia. PMID- 26126562 TI - Equity in vision in Australia is in sight. PMID- 26126563 TI - Facilitators and barriers to implementation of a pragmatic clinical trial in Aboriginal health services. AB - OBJECTIVE: To identify facilitators and barriers to clinical trial implementation in Aboriginal health services. DESIGN: Indepth interview study with thematic analysis. SETTING: Six Aboriginal community-controlled health services and one government-run service involved in the Kanyini Guidelines Adherence with the Polypill (KGAP) study, a pragmatic randomised controlled trial that aimed to improve adherence to indicated drug treatments for people at high risk of cardiovascular disease. PARTICIPANTS: 32 health care providers and 21 Aboriginal and Torres Strait Islander patients. RESULTS: A fundamental enabler was that participants considered the research to be governed and endorsed by the local health service. That the research was perceived to address a health priority for communities was also highly motivating for both providers and patients. Enlisting the support of Aboriginal and Torres Strait Islander staff champions who were visible to the community as the main source of information about the trial was particularly important. The major implementation barrier for staff was balancing their service delivery roles with adherence to often highly demanding trial related procedures. This was partially alleviated by the research team's provision of onsite support and attempts to make trial processes more streamlined. Although more intensive support was highly desired, there were usually insufficient resources to provide this. CONCLUSION: Despite strong community and health service support, major investments in time and resources are needed to ensure successful implementation and minimal disruption to already overstretched, routine services. Trial budgets will necessarily be inflated as a result. Funding agencies need to consider these additional resource demands when supporting trials of a similar nature. PMID- 26126564 TI - Using glycated haemoglobin testing to simplify diabetes screening in remote Aboriginal Australian health care settings. AB - OBJECTIVES: To determine whether a combination of point-of-care (POC) and laboratory glycated haemoglobin A (HbA1c) testing (HbA1c algorithm) is more effective in testing for diabetes in everyday practice in remote Australian Aboriginal primary health care, by providing a more rapid definitive result and diagnosing more cases than the standard glucose algorithm. DESIGN: Cross sectional study that independently classified participants using both diagnostic algorithms and compared their outcomes. PARTICIPANTS: Two hundred and fifty-five Aboriginal Australians aged 15 years or more without confirmed diabetes and due for diabetes testing at participating clinics. SETTING: Six primary health care sites in the Kimberley region of Western Australia from 1 September 2011 to 30 November 2013. MAIN OUTCOME MEASURES: Number of participants with a definitive test result, a completed algorithm and a diagnosis of diabetes; time taken to deliver a test result. RESULTS: Participants were significantly more likely to have a definitive result within 7 days (249 v 199 of 255 participants; P < 0.001), be followed up if an initial laboratory measurement was abnormal (92 v 74 of 167 participants; P = 0.005), and be diagnosed with diabetes (15 v 4 of 255 participants; P = 0.003) using the HbA1c than with the glucose algorithm. Eight participants subsequently diagnosed with diabetes (four using the HbA1c test, four with additional oral glucose tolerance tests that would not normally have been requested) were incorrectly classified as normal by the glucose algorithm. No participants with normal HbA1c measurements were subsequently diagnosed with diabetes. CONCLUSIONS: Use of POC HbA1c testing and collection of venous blood on the same day for a confirmatory laboratory HbA1c testing if the POC HbA1c value is abnormal may simplify diabetes testing in remote areas, provide more timely diagnoses, and increase case detection. PMID- 26126565 TI - Coordinated care versus standard care in hospital admissions of people with chronic illness: a randomised controlled trial. AB - OBJECTIVE: To determine whether Care Navigation (CN), a nurse-led hospital-based coordinated care intervention, reduced the use of hospital services and improved quality of life for patients with chronic illness. DESIGN: Randomised controlled trial; participants were allocated to CN or standard care. PARTICIPANTS AND SETTING: Patients with chronic illness presenting to the emergency department of Nepean Hospital, Sydney, New South Wales. High-risk status for an unplanned admission was defined as i) three or more unplanned hospital admissions in 12 months for patients aged >= 70 or at least one admission for cardiac or respiratory disease in patients aged 16-69 years; or ii) judged by a CN nurse to be high risk and likely to benefit. MAIN OUTCOME MEASURES: Numbers of re presentations or readmissions, quality of life, time to re-presentation, readmission or death, length of stay, and access to hospital and community health services. RESULTS: 500 participants were randomised between May 2010 and February 2011; 359 by previous unplanned admission and 141 by clinical impression. The CN group received more community health services (rate ratio, 1.94; 95% CI, 1.35 2.81; P < 0.001) than participants receiving standard care; however, this did not result in statistically significant differences in number of re-presentations (rate ratio, 0.83; 95% CI, 0.68-1.01; P = 0.07), number of readmissions (rate ratio, 0.85; 95% CI, 0.70-1.04; P = 0.11), quality of life at 24 months (mean difference, 0; 95% CI, - 0.10 to 0.09, P = 0.93), or other measures. CONCLUSIONS: CN did not improve quality of life or reduce unplanned hospital presentations or admissions despite community health services almost doubling. Future service development should explore potential benefits of linking navigated intrahospital care to ongoing, proactive care planning and delivery in the community. TRIAL REGISTRATION: ACTRN12609000554268. PMID- 26126566 TI - First report of Lyme neuroborreliosis in a returned Australian traveller. PMID- 26126567 TI - Tinea hidden by a vemurafenib-induced phototoxic reaction in a patient with metastatic melanoma taking dexamethasone. PMID- 26126568 TI - Alcohol-based hand sanitiser: a potentially fatal toy. PMID- 26126569 TI - Penetrating neck injury in an isolated medical setting. PMID- 26126570 TI - The Alcohol Mandatory Treatment Act: evidence, ethics and the law. AB - The Northern Territory Alcohol Mandatory Treatment Act 2013 (AMT Act) permits mandatory residential alcohol rehabilitation for up to 3 months. International guidelines and human rights law confirm that mandatory rehabilitation should only be used for short periods. Evidence concerning the efficacy of long-term mandatory alcohol rehabilitation is lacking, and minimal data concerning the efficacy of the scheme have been released. Specific legal issues also arise concerning the AMT Act, including its potentially discriminatory application to Aboriginal and Torres Strait Islander peoples. The program only permits referral by police, despite the fact that it is ostensibly a medical intervention. Use of a treatment as a method of effectively solving a public intoxication problem is highly dubious, and should be of concern to the medical community. Given that more cost-effective and proven measures exist to combat alcohol dependence, the utility of the AMT Act is questionable. PMID- 26126571 TI - Muslim doctors in the mainstream. PMID- 26126572 TI - Bond and small-molecule activation with low-valent nickel complexes. AB - The use of nickel compounds in low oxidation states allowed a variety of useful transformations of interest for academia, industry and in the solution of environmental issues. PMID- 26126573 TI - Divergence at the edges: peripatric isolation in the montane spiny throated reed frog complex. AB - BACKGROUND: Peripatric speciation and peripheral isolation have uncertain importance in species accumulation, and are largely overshadowed by assumed dominance of allopatric modes of speciation. Understanding the role of different speciation mechanisms within biodiversity hotspots is central to understanding the generation of biological diversity. Here, we use a phylogeographic analysis of the spiny-throated reed frogs and examine sister pairings with unbalanced current distributional ranges for characteristics of peripatric speciation. We further investigate whether forest/grassland mosaic adapted species are more likely created through peripatric speciation due to instability of this habitat type. RESULTS: We reconstructed a multi-locus molecular phylogeny of spiny throated reed frogs which we then combined with comparative morphologic data to delimit species and analyze historical demographic change; identifying three new species. Three potential peripatric speciation events were identified along with one case of allopatric speciation. Peripatric speciation is supported through uneven potential and realized distributions and uneven population size estimates based on field collections. An associated climate shift was observed in most potentially peripatric splits. Morphological variation was highest in sexually dimorphic traits such as body size and gular shape, but this variation was not limited to peripatric species pairs as hypothesized. The potentially allopatric species pair showed no niche shifts and equivalent effective population sizes, ruling out peripatry in that speciation event. Two major ecological niche shifts were recovered within this radiation, possibly as adaptations to occupy areas of grassland that became more prevalent in the last 5 million years. Restricted and fluctuating grassland mosaics within forests might promote peripatric speciation in the Eastern Arc Biodiversity Hotspot (EABH). CONCLUSIONS: In our case study, peripatric speciation appears to be an important driver of diversity within the EABH biodiversity hotspot, implying it could be a significant speciation mechanism in highly fragmented ecosystems. Extensive peripatric speciation in this montane archipelago may explain the abundance of discrete lineages within the limited area of the EABH, as inferred in remote island archipelagos. Future phylogenetic studies incorporating demographic and spatial analyses will clarify the role of peripatric speciation in creating biodiversity hotspots. PMID- 26126574 TI - Ultrasonic three-dimensional on-chip cell culture for dynamic studies of tumor immune surveillance by natural killer cells. AB - We demonstrate a simple method for three-dimensional (3D) cell culture controlled by ultrasonic standing waves in a multi-well microplate. The method gently arranges cells in a suspension into a single aggregate in each well of the microplate and, by this, nucleates 3D tissue-like cell growth for culture times between two and seven days. The microplate device is compatible with both high resolution optical microscopy and maintenance in a standard cell incubator. The result is a scaffold- and coating-free method for 3D cell culture that can be used for controlling the cellular architecture, as well as the cellular and molecular composition of the microenvironment in and around the formed cell structures. We demonstrate the parallel production of one hundred synthetic 3D solid tumors comprising up to thousands of human hepatocellular carcinoma (HCC) HepG2 cells, we characterize the tumor structure by high-resolution optical microscopy, and we monitor the functional behavior of natural killer (NK) cells migrating, docking and interacting with the tumor model during culture. Our results show that the method can be used for determining the collective ability of a given number of NK cells to defeat a solid tumor having a certain size, shape and composition. The ultrasound-based method itself is generic and can meet any demand from applications where it is advantageous to monitor cell culture from production to analysis of 3D tissue or tumor models using microscopy in one single microplate device. PMID- 26126575 TI - A computational protocol for the study of circularly polarized phosphorescence and circular dichroism in spin-forbidden absorption. AB - We present a computational methodology to calculate the intensity of circular dichroism (CD) in spin-forbidden absorption and of circularly polarized phosphorescence (CPP) signals, a manifestation of the optical activity of the triplet-singlet transitions in chiral compounds. The protocol is based on the response function formalism and is implemented at the level of time-dependent density functional theory. It has been employed to calculate the spin-forbidden circular dichroism and circularly polarized phosphorescence signals of valence n > pi* and n <- pi* transitions, respectively, in several chiral enones and diketones. Basis set effects in the length and velocity gauge formulations have been explored, and the accuracy achieved when employing approximate (mean-field and effective nuclear charge) spin-orbit operators has been investigated. CPP is shown to be a sensitive probe of the triplet excited state structure. In many cases the sign of the spin-forbidden CD and CPP signals are opposite. For the beta,gamma-enones under investigation, where there are two minima on the lowest triplet excited state potential energy surface, each minimum exhibits a CPP signal of a different sign. PMID- 26126576 TI - Intravascular NK-cell lymphoma: a case report and review of the literature. AB - BACKGROUND: Intravascular NK-cell lymphoma (IVNKL) is an extremely rare variant of non-Hodgkin lymphoma. To our knowledge, there are only a few cases reported in the English literature. Here, a case of a 29-year-old male with IVNKL involving the skin of the trunk and 4 extremities and liver is presented. A comprehensive literature review is undertaken to summarize the clinical and pathological features of this disorder. FINDINGS: In our case, large neoplastic lymphoid cells are restricted to the lumen of small vessels and exhibit the phenotype of a true NK cell. The morphology and immunophenotype, positivity of EBER and NK-cell origin are similar to other IVNKL cases. In addition, some cases including ours carry a poor prognosis as multiple systems or vital organs are involved. CONCLUSION: In summary, we report a case of an unusual intravascular lymphoma of NK-cell lineage that displays both clinical and pathological features and compare it with other differential diagnoses. It is important to recognize this rare entity to make an appropriate diagnosis and achieve a better understanding regarding the treatment and prognosis. PMID- 26126577 TI - Protection of rat intestinal epithelial cells from ischemia/reperfusion injury by (D-Ala2, D-Leu5)-enkephalin through inhibition of the MKK7-JNK signaling pathway. AB - Previous studies have demonstrated that (D-Ala2, D-Leu5)-enkephalin (DADLE) protects rats from hepatic ischemia/reperfusion (I/R) injury. In the present study, DADLE was also observed to alleviate IR-induced intestinal epithelial cell injury in rats by inhibiting mitogen-activated protein kinase kinase 7 (MKK7)-c Jun N-terminal kinase (JNK) pathway signaling. To investigate the protective effect of DADLE on hypoxia/reoxygenation injury in rat intestinal epithelial cells, rat intestinal epithelial cells were treated with different concentrations of DADLE, following which the cell survival rate was determined using a tetrazolium (MTT) colorimetric assay, and apoptosis was determined using flow cytometry. To confirm whether the protective effect of DADLE was due to its effect on MKK7-JNK signaling, the phosphorylation levels of MKK7 and JNK were analyzed using western blot analysis following treatment with different concentrations of DADLE. The results demonstrated that, following treatment with DADLE, the survival rate of the rat intestinal cells subjected to I/R-induced injury increased significantly and the apoptotic rate decreased in a concentration-dependent manner. In addition, the levels of phosphorylated MKK7 and JNK decreased in a concentration-dependent manner following treatment with DADLE. Silencing the gene expression of MKK7 using small interfering RNA prior to DADLE treatment resulted in a reduction in the protective effects of DADLE on the rat intestinal epithelial cells subjected to I/R injury. Collectively, the results of the present study demonstrated that the protective effects of DADLE in I/R injury in rat intestinal cells occurred through inhibition of the MKK7-JNK pathway. PMID- 26126578 TI - Self-expanding metallic stent placement with an exaggerated 5-cm proximal tumor covering for palliation of esophageal cancer. AB - BACKGROUND: The study aimed to evaluate the short- and long-term outcomes with a technique of self-expanding metallic stent insertion in palliative esophageal cancer patients. We hypothesized that a systematic attempt at exaggerated (5 cm) proximal tumor covering could prevent both stent migration and tumor overgrowth/undergrowth. METHODS: We reviewed retrospectively all patients who underwent esophageal stenting for palliation of malignant dysphagia over a 24 month period. Consecutive patients were identified from a prospective thoracic surgery interventional endoscopy database. This technique consisted of endoscopic stent insertion with the aim of landing the proximal portion of the stent 5 cm cephalad to the proximal extent of the tumor. All patients were followed at one month post-procedure and every three months thereafter, until death. Short- and long-term complications associated with the procedure and mortality were evaluated. RESULTS: Forty seven patients underwent endoscopic insertion of an esophageal stent in the context of an inoperable esophageal cancer using this technique over a 24-month period. The mean age was 70.4+/-9.6 years. Four (8.5%) patients underwent re-stenting due to proximal tumor overgrowth. No stent migration, perforation, tumor ingrowth or stent occlusion was reported. The mean patient survival was 146+/-26.5 days. CONCLUSIONS: Esophageal stent insertion under endoscopic guidance with proximal tumor covering of 5 cm is effective and safe. No cases of stent migration and a low incidence of tumor overgrowth/undergrowth were observed with this technique. PMID- 26126579 TI - Serotonergic antidepressant use and the risk of fracture: a population-based nested case-control study. AB - This is the first study to investigate the association between the use of selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) and the risk of fractures using a nationwide representative cohort of ethnic Chinese. Current use of SSRI/SNRI and the co-morbidity, especially osteoporosis and history of falling, play an important role in the increased risk of fractures. INTRODUCTION: This nested case-control study examines the association between the timing, intensity, and individual components of serotonergic antidepressant (including SSRIs and SNRIs) use and the risk of all-cause fracture. METHODS: Using the 2002-2011 Taiwan National Health Insurance Research Database, we identified patients who received at least three prescriptions of antidepressants between January 1st 2002 and December 31st 2010 as our study cohort. In the study cohort, we identify 8250 patients who had first admission for fracture and 33,000 matched controls (1:4, matched by age, sex, and cohort entry date). Multivariate conditional logistic regression was used to estimate the association between the use of serotonergic antidepressants and the risk of fracture. RESULTS: Current users of serotonergic antidepressants were associated with an increased risk of fracture (adjusted odds ratio (aOR) 1.16 [95 % confidence interval 1.07-1.25]). Furthermore, a higher risk of fractures was found in patients with osteoporosis (aOR 3.05 [2.73-3.42]) or a history of falling (aOR 6.13 [3.41-11.0]). The risks of fracture between SSRI and SNRI users were comparable. CONCLUSION: Current use of SSRI/SNRI is associated with an increased risk of all caused fractures. Additionally, the co-morbidity, especially osteoporosis and a history of falling, plays an important role in the risk of fractures. PMID- 26126580 TI - Percutaneous CT-Guided Cryoablation as an Alternative Treatment for an Extensive Pelvic Bone Giant Cell Tumor. AB - A giant cell tumor (GCT) is an intermediate grade, locally aggressive neoplasia. Despite advances in surgical and clinical treatments, cases located on the spine and pelvic bones remain a significant challenge. Failure of clinical treatment with denosumab and patient refusal of surgical procedures (hemipelvectomy) led to the use of cryoablation. We report the use of percutaneous CT-guided cryoablation as an alternative treatment, shown to be a minimally invasive, safe, and effective option for a GCT with extensive involvement of the pelvic bones and allowed structural and functional preservation of the involved bones. PMID- 26126581 TI - Proximal Embolization of the Splenic Artery with a Penumbra Occlusion Device (POD): A Novel Occlusion Technique for Blunt Splenic Injuries. PMID- 26126582 TI - Radiation Exposure in Transjugular Intrahepatic Portosystemic Shunt Creation. AB - PURPOSE: Transjugular intrahepatic portosystemic shunt (TIPS) creation is considered as being one of the most complex procedures in abdominal interventional radiology. Our aim was twofold: quantification of TIPS-related patient radiation exposure in our center and identification of factors leading to reduced radiation exposure. MATERIALS AND METHODS: Three hundred and forty seven consecutive patients underwent TIPS in our center between 2007 and 2014. Three main procedure categories were identified: Group I (n = 88)-fluoroscopic-guided portal vein targeting, procedure done in an image intensifier-based angiographic system (IIDS); Group II (n = 48)--ultrasound-guided portal vein puncture, procedure done in an IIDS; and Group III (n = 211)--ultrasound-guided portal vein puncture, procedure done in a flat panel detector-based system (FPDS). Radiation exposure (dose-area product [DAP], in Gy cm(2) and fluoroscopy time [FT] in minutes) was retrospectively analyzed. RESULTS: DAP was significantly higher in Group I (mean +/- SD 360 +/- 298; median 287; 75th percentile 389 Gy cm(2)) as compared to Group II (217 +/- 130; 178; 276 Gy cm(2); p = 0.002) and Group III (129 +/- 117; 70; 150 Gy cm(2) p < 0.001). The difference in DAP between Groups II and III was also significant (p < 0.001). Group I had significantly longer FT (25.78 +/- 13.52 min) as compared to Group II (20.45 +/- 10.87 min; p = 0.02) and Group III (19.76 +/- 13.34; p < 0.001). FT was not significantly different between Groups II and III (p = 0.73). CONCLUSIONS: Real-time ultrasound-guided targeting of the portal venous system during TIPS creation results in a significantly lower radiation exposure and reduced FT. Further reduction in radiation exposure can be achieved through the use of modern angiographic units with FPDS. PMID- 26126583 TI - Visual and structural prognosis of the untreated fellow eyes of unilateral normal tension glaucoma patients. AB - PURPOSE: To investigate the visual and structural prognosis of untreated initial non-glaucomatous fellow eyes of unilateral normal tension glaucoma (NTG) patients. METHODS: In this retrospective observational cohort study, 50 NTG patients with unilateral visual field (VF) loss and no VF defect, retinal nerve fiber layer (RNFL) defect or neuroretinal rim (NRR) notching in the fellow eyes, and those who had initial non-glaucomatous fellow eyes untreated were included. For the fellow eyes, the development of VF defect, RNFL defect, and NRR notching was inspected retrospectively by two observers. Baseline clinical characteristics including initial intraocular pressure (IOP), central corneal thickness, and spherical equivalent (SE) were compared between glaucomatous and fellow eyes. RESULTS: During the mean follow-up period of 8.77 +/- 2.92 years, five patients (10 %) developed RNFL defect and four patients (8 %) developed NRR notching in the fellow eye. Among six patients (12 %) who had developed either RNFL defect or NRR notching, only three patients (6 %) developed VF loss in 1.81, 3.09, and 9.27 years respectively. The initial IOP was significantly higher (p = 0.031), SE was more myopic (p = 0.025), and the occurrence of disc hemorrhage (p = 0.049) was significantly higher in glaucomatous eyes than that in fellow eyes. CONCLUSIONS: The incidence of glaucoma development in the fellow eye is rather low. Therefore, the initial non-glaucomatous fellow eye of the unilateral NTG patient may be observed without treatment until glaucoma develops. PMID- 26126585 TI - Isolated complex limbal choristoma in a newborn baby. PMID- 26126584 TI - Macular structural characteristics in children with Down syndrome. AB - PURPOSE: This prospective study aimed to investigate macular structural characteristics in children with Down syndrome compared to those in healthy children. METHODS: Two groups of children (aged 6-16 years) were enrolled: children with Down syndrome (Down syndrome group, N = 17) and age-matched healthy children who were full-term at birth (control group, N = 18). Eligible patients had visual acuity of 20/100 or better and gestational age at birth of >= 36 weeks. Fourier domain optical coherence tomography was used for imaging of the macular retinal structure, and retinal volume scans centered on the macula were obtained. Central subfield thickness (CST) and the thickness of the inner and outer retinal layer regions were analyzed using the instrument's segmentation software. The analysis of data is provided for the right eye only, since there was no significant difference between right and left eyes for either the Down syndrome or control groups. RESULTS: Children in the Down syndrome group generally had identifiable retinal structure. The CST for the full retina and inner and outer retinal layers were all significantly greater in the Down syndrome group than the control group (independent t test, all p < 0.05). Despite the significantly thicker macula, only about 29 % (5 of 17) of the right eyes of patients with Down syndrome had macular thickness outside the normal range. Visual acuity in the Down syndrome group was not directly correlated with increased CST (t = 1.288, r = 0.326, p = 0.202). CONCLUSIONS: On average, CST in the Down syndrome group was greater than that in the control group, suggesting abnormal macular development in children with Down syndrome. PMID- 26126586 TI - Condoms, Lubricants and Rectal Cleansing: Practices Associated with Heterosexual Penile-Anal Intercourse Amongst Participants in an HIV Prevention Trial in South Africa, Uganda and Zimbabwe. AB - We investigated condom and lubricant use, rectal cleansing and rectal gel use for penile-anal intercourse (PAI), during in-depth interviews with women from South Africa, Uganda and Zimbabwe who formerly participated in VOICE, a five-arm HIV prevention trial of two antiretroviral tablets and a vaginal gel. Few studies have addressed practices related to PAI among women; existing data from Africa on condom and lubricant use for PAI, as well as preparatory practices of PAI such as rectal cleansing, are limited to men who have sex with men. Women demonstrated a lack of awareness of HIV transmission risks of PAI and none of the participants reported using condom-compatible lubricants for PAI. Participants described a variety of preparatory rectal cleansing practices. Some participants disclosed rectal use of the vaginal study gel. Understanding practices related to PAI in Africa is critical to microbicide development, as these practices are likely to influence the acceptability, feasibility, and use of both vaginal and rectal microbicide products. PMID- 26126587 TI - Retrograde nailing of femoral fractures: a retrospective study. AB - BACKGROUND: Retrograde femoral nailing is a common method to repair femoral shaft fractures in polytrauma patients. Studies have reported varying incidences of complications associated with retrograde femoral nailing such as knee pain, nonunion, and arthrofibrosis. The objective of this retrospective study was to describe healing and complication rates of 31 patients who underwent retrograde femoral nailing at our academic medical center. METHODS: Clinical notes and radiographs were reviewed retrospectively. Data points such as demographics, fracture location on femur, time to union after surgery, presence or absence of comminution, associated injuries, and complications were assessed. RESULTS: Average time to union was 4.69 months with no statistically significant relationship found between time to union and age, sex, comminution, or location of fracture. Knee pain was present in 23 % of patients, and distal screw removal was necessary in 19.4 % of patients. DISCUSSION: Retrograde femoral nailing is an effective method of femoral shaft fracture fixation in polytrauma patients. The healing rate of femoral shaft fractures fixed with a retrograde nail is the same regardless of location of fracture, age, sex, or comminution. Prevention of tip of nail lying into the knee and early physical therapy are important to prevent arthrofibrosis knee. PMID- 26126588 TI - Surgical treatment in spine Paget's disease: a systematic review. AB - Paget's disease of bone (PDB) is a disease characterized by a disorder in the bone metabolism. The spine is the second region affected after the pelvis. Surgical treatment is reserved for cases refractory to medical treatment. We performed a systematic review of patients with Paget disease of bone affecting the spine, treated surgically in the last 30 years. The main objective of the review is to find out indications for surgery, outcomes of these patients and also the standard perioperative management. PMID- 26126589 TI - Cloning, Purification and Characterization of Acetyl Xylane Esterase from Anoxybacillus flavithermus DSM 2641(T) with Activity on Low Molecular-Weight Acetates. AB - Family 4 carbohydrate esterases (CE-4) have deacetylate different forms of acetylated poly/oligosaccharides in nature. This family is recognized with a specific polysaccharide deacetylase domain assigned as NodB homology domain in their secondary structure. Most family 4 carbohydrate esterases have been structurally and biochemically characterized. However, this is the first study about the enzymological function of pdaB-like CE4s from thermophilic bacterium Anoxybacillus flavithermus DSM 2641(T). A. flavithermus WK1 genome harbors five putative CE4 family genes. One of them is 762 bp long and encodes a protein of 253 amino acids in length and it was used as reference sequence in this study. It was described as acetyl xylane esterase (AXE) in genome project and this AfAXE gene was amplified without signal sequence and cloned. The recombinant protein was expressed in E. coli BL21 (DE3), purified by nickel affinity chromatography and its purity was visualized on SDS-PAGE. The activity of the recombinant enzyme was shown by zymogram analysis with alpha-naphtyl acetate as a substrate. The enzyme was characterized spectrophotometrically using chromogenic p-nitrophenyl acetate. Optimum temperature and pH were determined as 50 degrees C and 7.5, respectively. Km and Vmax were determined as 0.43 mM and 3333.33 U/mg, respectively under optimum conditions. To our knowledge this is the first enzymological characterization of a pdaB-like family 4 carbohydrate esterase from the members of Anoxybacillus genus. PMID- 26126590 TI - NMR assignments of the C-terminal domain of human galectin-8. AB - Galectins recognize beta-galectosides to promote a variety of cellular functions. Despite their sequence variations, all galectins share the same carbohydrate recognition domains (CRD) and their modes of ligand recognition at a structural level are essentially identical. Human galectin 8 plays an important role in numerous cancer and immune responses. It consists of two CRDs that are connected via a flexible linker. The substrate affinities and specificities of the N- and C terminal domains are quite different. In order to investigate the structural basis of their substrate specificities, we complete the NMR (1)H, (13)C, and (15)N chemical shift assignments of C-terminal domain of human galectin-8 (hG8C). PMID- 26126591 TI - Erythropoietin improves glucose metabolism and pancreatic beta-cell damage in experimental diabetic rats. AB - Previous studies have implicated erythropoietin (EPO) signaling in the regulation of glucose metabolism. Whether EPO can be used treat diabetes and the underlying mechanism remain to be elucidated. The present study aimed to investigate whether EPO affects glucose metabolism, and the underlying mechanisms, in experimental diabetic rats. The effects of EPO (300 U/kg three times a week for 4 weeks) on glucose metabolism, hematopoietic function, blood selenium content and the ultrastructure of pancreatic beta-cells were investigated in low dose (25 mg/kg body weight) streptozotocin-induced experimental diabetic rats provided with a high-fat diet. The results demonstrated that EPO significantly decreased the fasting blood glucose, the area under the curve of the oral glucose tolerance and insulin tolerance tests and L-alanine gluconeogenesis. Ultrastructural examination of the pancreatic islets revealed that EPO prevented the dysfunction of pancreatic beta-cells in experimental diabetic rats, ameliorated cytoplasmic vacuolation and fragmentation of mitochondria, and increased the number of secretory granules. EPO administration increased the activities of superoxide dismutase and glutathione peroxidase, and decreased the level of malondialdehyde. Additionally, EPO increased blood selenium in the diabetic rats and produced a hematopoietic effect. These results indicated that EPO modulated glucose metabolism and improved pancreatic beta-cells damage by increasing anti oxidation. The detailed mechanisms underlying these effects require further investigation. PMID- 26126592 TI - Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain. AB - Modelling complex disorders presents considerable challenges, and multiple sclerosis (MS) is no exception to this rule. The aetiology of MS is unknown, and its pathophysiology is poorly understood. Moreover, the last two decades have witnessed a dramatic revision of the long-held view of MS as an inflammatory demyelinating white matter disease. Instead, it is now regarded as a global central nervous system (CNS) disorder with a neurodegenerative component. Currently, there is no animal model recapitulating MS immunopathogenesis. Available models are based on autoimmune-mediated demyelination, denoted experimental autoimmune encephalomyelitis (EAE) or virally or chemically induced demyelination. Of these, the EAE model has been the most commonly used. It has been extensively improved since its first description and now exists as a number of variants, including genetically modified and humanized versions. Nonetheless, EAE is a distinct disease, and each variant models only certain facets of MS. Whilst the search for more refined MS models must continue, it is important to further explore where mechanisms underlying EAE provide proof-of-principle for those driving MS pathogenesis. EAE variants generated with the myelin component myelin oligodendrocyte glycoprotein (MOG) have emerged as the preferred ones, because in this particular variant disease is associated with both T- and B-cell effector mechanisms, together with demyelination. MOG-induced EAE in the non obese diabetic (NOD) mouse strain exhibits a chronic-relapsing EAE clinical profile and high disease incidence. We describe the generation of this variant, its contribution to the understanding of MS immune and pathogenetic mechanisms and potential for evaluation of candidate therapies. PMID- 26126593 TI - Gene delivery polymer structure-function relationships elucidated via principal component analysis. AB - Principal component analysis was applied to a biomaterial library of poly(beta amino ester)s, useful for non-viral gene delivery, to elucidate chemical parameters that drive biological function. Correlative relationships and principal components were analyzed between 24 physico-chemical polymer properties and 3 cell-based functional variables in human glioblastoma cells (transfection, uptake, and viability). PMID- 26126596 TI - Rapid characterization of human brain aspergillosis by confocal microscopy on a thick squash preparation. PMID- 26126595 TI - Case-control approach application for finding a relationship between candidate genes and clinical mastitis in Holstein dairy cattle. AB - Mastitis is a major source of economic loss in dairy herds. The objective of this research was to evaluate the association between genotypes within SLC11A1 and CXCR1 candidate genes and clinical mastitis in Holstein dairy cattle using the selective genotyping method. The data set contained clinical mastitis records of 3,823 Holstein cows from two Holstein dairy herds located in two different regions in Iran. Data included the number of cases of clinical mastitis per lactation. Selective genotyping was based on extreme values for clinical mastitis residuals (CMR) from mixed model analyses. Two extreme groups consisting of 135 cows were formed (as cases and controls), and genotyped for the two candidate genes, namely, SLC11A1 and CXCR1, using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. Associations between single nucleotide polymorphism (SNP) genotypes with CMR and breeding values for milk and protein yield were carried out by applying logistic regression analyses, i.e. estimating the probability of the heterogeneous genotype in the dependency of values for CMR and breeding values (BVs). The sequencing results revealed a novel mutation in 1139 bp of exon 11 of the SLC11A1 gene and this SNP had a significant association with CMR (P < 0.05). PCR-RFLP analysis leads to three banding patterns for CXCR1c.735C>G and these genotypes had significant relationships with CMR. Overall, the results showed that SLC11A1 and CXCR1 are valuable candidate genes for the improvement of mastitis resistance as well as production traits in dairy cattle populations. PMID- 26126598 TI - Case report of transfusion-related acute lung injury in a pediatric spine surgery patient transfused leukoreduced red blood cells. AB - Despite leukoreduced red blood cells (LR-RBCs) reducing the risk of transfusion related acute lung injury (TRALI), we present a case of a 16-year-old female with kyphosis who received a transfusion of one unit of LR-RBCs, which lead to life threatening, intraoperative TRALI. The clinical presentation included pulmonary edema, severe postoperative lactic acidosis, left ventricular dysfunction, increased creatine phosphokinase, fatty infiltration of the liver, and hemodynamic instability requiring inotropic support. This presentation is not the classic description of TRALI. Our patient improved with supportive treatment and was successfully extubated on postoperative day 4. TRALI work-up revealed antibody formation to HLA A2, A68, B44, and DQA 5 for the LR-RBCs unit administered. PMID- 26126597 TI - Al[18F]NOTA-T140 Peptide for Noninvasive Visualization of CXCR4 Expression. AB - PURPOSE: Chemokine receptor CXCR4 plays an important role in tumor aggressiveness, invasiveness, and metastasis formation. Quantification of CXCR4 expression by tumors may have an impact on prediction and evaluation of tumor response to therapies. In this study, we developed a robust and straightforward F 18 labeling route of T140, a CXCR4 peptide-based antagonist. PROCEDURES: T140 derivative was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA) and labeled with Al[(18)F]. Al[(18)F]NOTA-T140 was evaluated in vitro in cell-based assay and stability in mouse serum and in vivo using CXCR4 positive and negative tumor xenograft models. RESULTS: Labeling of Al[(18)F]NOTA-T140 was completed within 30 min with a radiochemical yield of 58 +/- 5.3 % at the end of synthesis, based on fluoride-18 activity. Al[(18)F]NOTA-T140 accumulated in CHO-CXCR4 positive but not negative tumors. Al[(18)F]NOTA-T140 uptake in the tumors correlated with CXCR4 protein expression. Moreover, Al[(18)F]NOTA-T140 had high accumulation in CXCR4-positive metastatic tumors. CONCLUSIONS: The simplicity of Al[(18)F]NOTA-T140 labeling along with its properties to specifically image CXCR4 expression by tumors warrant further clinical application for the diagnosis of CXCR4 clinically. PMID- 26126599 TI - Myelodysplastic Syndromes Diagnosis: What Is the Role of Molecular Testing? AB - Diagnosing a myelodysplastic syndrome (MDS) can be challenging. Somatic mutations are common in MDS and might have diagnostic utility in patients with idiopathic cytopenias of undetermined significance (ICUS). However, using mutations to diagnose MDS is complicated by several issues: (1) no gene is mutated in most cases, (2) no mutated gene is highly specific for MDS, (3) clonal hematopoiesis is common in older individuals without disease, and (4) we lack outcome data for ICUS patients with clonal cytopenias of undetermined significance (CCUS). Despite these caveats, genetic sequencing can inform the diagnosis of MDS. CCUS patients more closely resemble patients with MDS than age matched controls with somatic mutations. Genetic testing can identify alternative diagnoses in cytopenic patients and help risk stratify those with proven MDS. While we cannot include somatic mutations in the diagnostic definition of MDS now, testing to recognize CCUS will help characterize outcomes in these diagnostically challenging patients. PMID- 26126600 TI - Outlook and Management of Patients with Myelodysplastic Syndromes Failed by Hypomethylating Agents. AB - The DNA hypomethylating agents (HMAs) azacitidine and decitabine are currently the most frequently administered disease-modifying therapies for patients with higher-risk myelodysplastic syndromes (MDS). However, azacitidine and decitabine are not curative, the median response duration is 11-15 months, and only 10-20 % of patients experience complete hematologic and cytogenetic response. Moreover, once an HMA fails the patient, the prognosis is poor, with a median survival of less than 6 months unless the patient undergoes hematopoietic stem cell transplantation (HSCT). Recent insights into the genetic basis of MDS have enhanced biological understanding and prognostication accuracy, but these developments have not yet led to regulatory approval of new therapies. While there are multiple potential approaches to patients with MDS for whom HMAs have failed, including supportive care alone, cytotoxic therapy, lenalidomide, histone deacetylase inhibitors, and HSCT, favorable responses to these approaches are limited and new therapies are greatly needed. Here, we review clinical and biological data about the population of patients failed by HMAs, evaluate currently available approaches to patients in this clinical situation, and discuss prospects for development of novel active agents. PMID- 26126601 TI - Preparing Patients With Myelodysplastic Syndrome for Transplant When Is Pre transplant Cytoreductive Therapy Appropriate? AB - To date, the only treatment option with curative potential for patients suffering from myelodysplastic syndromes (MDS) is allogeneic stem cell transplantation (allo-SCT). However, patient selection for this procedure as well as the choice of the appropriate pre-transplant regime remain challenging. This review discusses both intensive chemotherapy and hypomethylating agents (HMAs) as debulking strategies. Current evidence on the use of AML-like intense chemotherapy suggests that this represents a valuable option especially in fitter and younger MDS patients with aggressive disease, whereas HMAs seem especially indicated in patients presenting with certain mutations and less proliferative disease in order to bridge them to transplant. The actual need for pre-transplant cytoreduction strongly depends on donor availability and disease progression: upfront allo-SCT might be considered for patients with slowly progressing MDS if a donor is readily available. Common to the data discussed in this review is their retrospective nature, making clear recommendations in terms of debulking strategy difficult. Prospective randomized trials are required to explicitly answer this question in the future. PMID- 26126602 TI - Case of concurrence of anti-laminin gamma-1 pemphigoid and scabies. PMID- 26126603 TI - Identification of quantitative trait loci influencing inflammation-mediated alveolar bone loss: insights into polygenic inheritance of host-biofilm disequilibria in periodontitis. AB - BACKGROUND AND OBJECTIVE: The relative contribution of genetic and environmental factors to the onset and progression of periodontitis is inconclusive. Despite the high prevalence, phenotypic heterogeneity and significant local and systemic implications of this disease, early detection and individualized therapy are problematic. Using a murine model of periodontitis in a panel of 17 recombinant inbred mice, the current study addressed the heritability of, and oral dysbiosis associated with, inflammation-mediated alveolar bone loss (iABL), the hallmark of periodontitis. MATERIAL AND METHODS: Quantitative trait locus (QTL) genomics and quantitative PCR for over 99% of known murine oral microbiota were used. RESULTS: It was found that iABL is a polygenic trait with 32.7% heritability. One suggestive QTL, nicknamed inflammation-mediated alveolar bone loss locus (iABLL), was identified on chromosome 2. Eleven genes involved in innate immune responses and bone metabolism, particularly related to macrophage and osteoblast function, namely Etl4, Pdss1, Cobll1, 9330158F14Rik, Xirp2, Stk39, Mettl5, Metapl1, Itga6, Pdk1 and Sp3, were found in the iABLL using cis expression QTL and nonsynonymous single nucleotide polymorphism analyses. Specific oral microbiome shifts in saliva and tongue mucosa are associated with disease in this model. CONCLUSION: Our results indicate that complex host-biofilm interactions generate pathogenic states that extend beyond subgingival biofilms and periodontal tissues. Although no temporal relationship between the onset of iABL and microbiome changes were established, our findings suggest that host factors may be responsible for pathogenic shifts in subgingival biofilms when persistent and undisturbed. PMID- 26126604 TI - An online tool for evaluating diagnostic and prognostic gene expression biomarkers in bladder cancer. AB - BACKGROUND: In the past ~15 years, the identification of diagnostic and prognostic biomarkers from gene expression data has increased our understanding of cancer biology and has led to advances in the personalized treatment of many cancers. A diagnostic biomarker is indicative of tumor status such as tumor stage, while a prognostic biomarker is indicative of disease outcome. Despite these advances, however, there are no clinically approved biomarkers for the treatment of bladder cancer, which is the fourth most common cancer in males in the United States and one of the most expensive cancers to treat. Although gene expression profiles of bladder cancer patients are publicly available, biomarker identification requires bioinformatics expertise that is not available to many research laboratories. DESCRIPTION: We collected gene expression data from 13 publicly available patient cohorts (N = 1454) and developed BC-BET, an online Bladder Cancer Biomarker Evaluation Tool for evaluating candidate diagnostic and prognostic gene expression biomarkers in bladder cancer. A user simply selects a gene, and BC-BET evaluates the utility of that gene's expression as a diagnostic and prognostic biomarker. Specifically, BC-BET calculates how strongly a gene's expression is associated with tumor presence (distinguishing tumor from normal samples), tumor grade (distinguishing low- from high-grade tumors), tumor stage (distinguishing non-muscle invasive from muscle invasive samples), and patient outcome (e.g., disease-specific survival) across all patients in each cohort. Patients with low-grade, non-muscle invasive tumors and patients with high-grade, muscle invasive tumors are also analyzed separately in order to evaluate whether the biomarker of interest has prognostic value independent of grade and stage. CONCLUSION: Although bladder cancer gene expression datasets are publicly available, their analysis is computationally intensive and requires bioinformatics expertise. BC-BET is an easy-to-use tool for rapidly evaluating bladder cancer gene expression biomarkers across multiple patient cohorts. PMID- 26126605 TI - Current status on health sciences research productivity pertaining to Angola up to 2014. AB - BACKGROUND: Health research driven by the healthcare demands of the population can provide an informative evidence base to support decision-making processes on health policies, programmes, and practices. This paper surveyed the production of scientific research concerning health in Angola, specifically to access the publication rate over time, the main research topics and scientific fields, and the contribution of Angolan researchers and institutions. METHODS: The study focused on data collected in a retrospective literature search in Biblioteca Virtual em Saude (BVS) as of June 8, 2014, with the keyword "Angola" and on content information in correspondent publications deposited in PubMed. RESULTS: BVS generated 1,029 hits, 74.6 % of which were deposited in PubMed where 301 abstracts were described. From 1979 to 2003, there were 62 publications and in 2004-2013 the quantity increased four-fold (n = 232); malaria was the most frequent topic (n = 42). Angola was the country with the largest number of publications, taking into account the primary affiliation of the first author (n = 45). Universities, institutes, or research centres accounted for 65 % of the publications and in descending order Portugal, Brazil, and the United States of America occupied the three first positions. Epidemiology was by far the most frequent field of research (n = 165). CONCLUSIONS: The number of publications has increased steadily over the past 10 years, with predominance on malaria topics. Angola was the country with the largest number of major affiliations of the first author, but the contribution of Angolan institutions was relatively low, indicating a need to reinforce academic research institutions in the country. PMID- 26126606 TI - Impact of Clostridium difficile infection among pneumonia and urinary tract infection hospitalizations: an analysis of the Nationwide Inpatient Sample. AB - BACKGROUND: Clostridium difficile infection (CDI) remains one of the major hospital acquired infections in the nation, often attributable to increased antibiotic use. Little research, however, exists on the prevalence and impact of CDI on patient and hospital outcomes among populations requiring such treatment. As such, the goal of this study was to examine the prevalence, risk factors, and impact of CDI among pneumonia and urinary tract infection (UTI) hospitalizations. METHODS: The Nationwide Inpatient Sample (2009-2011), reflecting a 20% stratified sample of community hospitals in the United States, was used. A total of 593,038 pneumonia and 255,770 UTI discharges were included. Survey-weighted multivariable regression analyses were conducted to assess the predictors and impact of CDI among pneumonia and UTI discharges. RESULTS: A significantly higher prevalence of CDI was present among men with UTI (13.3 per 1,000) as compared to women (11.3 per 1,000). CDI was associated with higher in-hospital mortality among discharges for pneumonia (adjusted odds ratio [aOR] for men = 3.2, women aOR = 2.8) and UTI (aOR for men = 4.1, women aOR = 3.4). Length of stay among pneumonia and UTI discharges were also double upon presence of CDI. In addition, CDI increased the total charges by at least 75% and 55% among pneumonia and UTI discharges, respectively. Patient and hospital characteristics associated with CDI included being 65 years or older, Charlson Deyo index for comorbidity of 2 or more, Medicare as the primary payer, and discharge from urban hospitals, among both pneumonia and UTI discharges. CONCLUSION: CDI occurs frequently in hospitalizations among those discharged from hospital for pneumonia and UTI, and is associated with increased in-hospital mortality and health resource utilization. Interventions to mitigate the burden of CDI in these high-risk populations are urgently needed. PMID- 26126608 TI - Use of RNA sequencing to evaluate rheumatic disease patients. AB - Studying the factors that control gene expression is of substantial importance for rheumatic diseases with poorly understood etiopathogenesis. In the past, gene expression microarrays have been used to measure transcript abundance on a genome wide scale in a particular cell, tissue or organ. Microarray analysis has led to gene signatures that differentiate rheumatic diseases, and stages of a disease, as well as response to treatments. Nowadays, however, with the advent of next generation sequencing methods, massive parallel sequencing of RNA tends to be the technology of choice for gene expression profiling, due to several advantages over microarrays, as well as for the detection of non-coding transcripts and alternative splicing events. In this review, we describe how RNA sequencing enables unbiased interrogation of the abundance and complexity of the transcriptome, and present a typical experimental workflow and bioinformatics tools that are often used for RNA sequencing analysis. We also discuss different uses of this next-generation sequencing technology to evaluate rheumatic disease patients and investigate the pathogenesis of rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, juvenile idiopathic arthritis and Sjogren's syndrome. PMID- 26126610 TI - Pharmacophore Modeling, Docking and Molecular Dynamics Studies on Caspase-3 Activators Binding at beta-Tubulin Site. AB - Induction of apoptosis by the activation of caspase 3 makes it a promising target for designing anticancer drugs hence an investigation for the essential structural features mandatory for caspase 3 activation has been carried out using a dataset comprising of caspase 3 activator candidate drug Azixa in phase II clinical trial and its analogs using DS2.0. A training set of 40 compounds was selected for the purpose of model generation from 76 molecules with an activity range spanning from 0.002MUM to 6.9MUM. Among the generated pharmacophore models, the best model Hypo1 constituted by two hydrophobic aliphatic (Hal), two hydrophobic aromatic (Har), and one hydrogen bond acceptor (HBA) features with a correlation coefficient of 0.85, and a cost difference (null cost - total cost) of 46 bits well predicted the test set of 36 compounds (Rpred = 0.8). The key mechanism conferring caspase 3 activation is due to binding of Azixa at beta tubulin site that is located close to or at same site as colchicine. In the absence of co-crystal structure we have proposed a binding mode of Azixa at the tubulin site by performing docking studies and performed molecular dynamics simulation to ascertain the temporal changes of the protein-ligand complex. PMID- 26126609 TI - Hepatoprotective effect of juglone on dimethylnitrosamine-induced liver fibrosis and its effect on hepatic antioxidant defence and the expression levels of alpha SMA and collagen III. AB - The present study aimed to investigate the antifibrotic effects of juglone on dimethylnitrosamine (DMN)-induced fibrosis in rats. Juglone, which is a quinone, significantly decreased DMN-induced rat hepatic fibrosis, which was associated with increased superoxide dismutase (SOD) activity, decreased oxidative stress and reduced levels of alpha-smooth muscle actin (alpha-SMA) and collagen (Col) III in the liver. Serum levels of alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, laminin, type III precollagen and type IV collagen were significantly reduced by treatment with juglone. Liver fibrosis was induced in male Sprague-Dawley rats by subcutaneous injections of DMN solution and hepatic fibrosis was assessed using Massons trichome staining. The expression levels of alpha-SMA and Col III were determined using immunohistochemical techniques. The activities of SOD and malondialdehyde in liver homogenates were also determined. The results suggested that juglone augmented the antioxidative capability of the liver, possibly by stimulating the activity of SOD, which promoted the inactivation of hepatic stellate cells (HSCs) and decreased the accumulation of extracellular matrix collagen in the liver, thereby alleviating hepatic fibrosis. Silymarin was used as a positive control for liver fibrosis protection. It was hypothesized that juglone alleviates or mitigates oxidative stress-mediated hepatic fibrosis by upregulating the expression of peroxisome proliferator-activated receptor gamma and inhibiting the activation of HSC. PMID- 26126611 TI - Mobile radiography units in Balkan Wars. AB - INTRODUCTION: It is known that the first radiological units were widely used during war conflicts, whereas the first application of military radiology took place during the Greco-Turkish War in 1897. However, until recently automobile radiology units were assumed to be used for the first time during World War I. METHOD: Historical archives and reports were researched, and extensive research in available literature was also conducted. RESULTS: The automobile radiology units were purchased from France and were probably constructed under the guidance of Marie Curie (1867-1934). The figure of Dr. Dimitrios Vasilidis (?-1937), a pioneer in Radiology in Greece and the first president of the Hellenic Radiological Society, is highlighted. DISCUSSION: This short historical note describes the first use of a mobile radiology unit during the Balkan Wars (1912 1913), predating its previously presumed first use in World War I. It also briefly highlights the contributions of some notable figures in 20th Century Greek scientific development. PMID- 26126612 TI - Altered Structural and Functional Feature of Striato-Cortical Circuit in Benign Epilepsy with Centrotemporal Spikes. AB - Benign epilepsy with centrotemporal spikes (BECT) is the most common form of childhood idiopathic focal epilepsy syndrome. We investigated quantitative evidence regarding brain morphology and functional connectivity features to provide insight into the neuroanatomical foundation of this disorder, using high resolution T1-weighted magnetic resonance imaging (MRI) and resting state functional MRI in 21 patients with BECT and in 20 healthy children. The functional connectivity analysis, seeded at the regions with altered gray-matter (GM) volume in voxel-based morphometry (VBM) analysis, was further performed. Then, the observed structural and functional alteration were investigated for their association with the clinical and behavior manifestations. The increased GM volume in the striatum and fronto-temporo-parietal cortex (striato-cortical circuit) was observed in BECT. The decreased connections were found among the motor network and frontostriatal loop, and between the default mode network (DMN) and language regions. Additionally, the GM of striatum was negatively correlated with age at epilepsy onset. The current observations may contribute to the understanding of the altered structural and functional feature of striato cortical circuit in patients with BECT. The findings also implied alterations of the motor network and DMN, which were associated with the epileptic activity in patients with BECT. This further suggested that the onset of BECT might have enduring structural and functional effects on brain maturation. PMID- 26126613 TI - Online Epileptic Seizure Prediction Using Wavelet-Based Bi-Phase Correlation of Electrical Signals Tomography. AB - Considerable efforts have been made in order to predict seizures. Among these methods, the ones that quantify synchronization between brain areas, are the most important methods. However, to date, a practically acceptable result has not been reported. In this paper, we use a synchronization measurement method that is derived according to the ability of bi-spectrum in determining the nonlinear properties of a system. In this method, first, temporal variation of the bi spectrum of different channels of electro cardiography (ECoG) signals are obtained via an extended wavelet-based time-frequency analysis method; then, to compare different channels, the bi-phase correlation measure is introduced. Since, in this way, the temporal variation of the amount of nonlinear coupling between brain regions, which have not been considered yet, are taken into account, results are more reliable than the conventional phase-synchronization measures. It is shown that, for 21 patients of FSPEEG database, bi-phase correlation can discriminate the pre-ictal and ictal states, with very low false positive rates (FPRs) (average: 0.078/h) and high sensitivity (100%). However, the proposed seizure predictor still cannot significantly overcome the random predictor for all patients. PMID- 26126615 TI - Comparison of patient-reported quality of life outcome questionnaire response rates between patients treated surgically for renal cell carcinoma and prostate carcinoma. AB - BACKGROUND: We sought to examine differences in response rates to quality of life (QoL) surveys in patients treated surgically for renal cell carcinoma (RCC) and prostate cancer (PCa) and to analyze factors associated with non-response of the surveys. METHODS: Patients who underwent surgery for RCC or PCa between 2006 and 2012 were offered enrollment in respective prospective cancer registries that included baseline and annual QoL assessments. We identified 201 RCC patients and 616 PCa patients who completed a baseline QoL survey and were mailed annual QoL surveys [RCC: SF-36, FACT-G (73 questions), PCa: EPIC, IIEF, Max-PC (80 questions)]. We compared patient characteristics between responders and non responders using a Wilcoxon rank-sum test for continuous variables and a Fisher's Exact test for categorical variables. RESULTS: The overall response rates for the PCa and RCC groups were 63 and 48% (p < 0.001), respectively. This difference in response rates remained when we limited analysis to only those with early stage disease (pT2 for PCa and pT1 RCC, 62% vs. 52%; p = 0.03). PCa characteristics associated with response included older age (64.1 vs 62.6 years, p = 0.032) and robotic versus open surgery (56% vs 44%; p = 0.009). There were no characteristics that were associated with response in RCC patients. CONCLUSIONS: Surgically treated PCa patients have higher QoL mail-based survey response rates compared to patients treated surgically for RCC. This difference holds true for clinically localized cancers as well. PMID- 26126616 TI - Quantifying retention during pre-antiretroviral treatment in a large urban clinic in Uganda. AB - BACKGROUND: Retention studies are usually focused on patients on antiretroviral treatment (ART), however in Sub-Saharan Africa many patients get lost to program (LTP) in the pre-ART care period.. We investigated the proportion of patients not retained in care and factors associated with LTP (dead or lost to follow up >=6 months) in the pre-ART care period. METHODS: We analyzed data from the Infectious Diseases Institute, Kampala, Uganda. We included all adult patients >=18 years, ART naive at program enrollment from 1(st)/Jan/2005. We described the number of patients not retained in care during the 3 steps of enrollment-to-treatment "cascade": Step 1) From enrollment to CD4 count testing, Step 2) ART eligibility assessment. Patients were initially considered eligible if CD4 count was <200 cell/MUL, and <350 cell/MUL from 2012 onwards; Step 3) From eligibility to ART start. We described cumulative probability of being LTP by gender and ART eligibility using Kaplan Meier estimates. We used a Cox proportional hazards model to identify factors associated with being LTP at any stage for all patients and for those with a CD4 count available. Factors considered were age, gender, year of enrollment, and WHO stage. RESULTS AND DISCUSSION: After enrollment in our program, cumulatively, a low proportion of patients (30.8 %) were retained and started on ART. The cumulative probability of being LTP was higher in males and patients not eligible for ART. In the multivariable Cox proportional Hazards model, male gender (HR: 1.19 CI 1.12-1.19) and clinical WHO stage 3 and 4 (HR: 1.20 CI 1.13-1.27) were associated with being LTP while older age was protective (HR: 0.98 0.96-0.99). Patients enrolled in the program more recently were also at lower risk of being LTP. In addition, among patients with CD4 count test, patients with higher CD4 count were at higher risk of being LTP. CONCLUSIONS: In our program there has been suboptimal retention of patients in pre-ART care, particularly of patients not eligible for ART. Since the proportion of eligible patients has recently increased due to the higher recommended threshold for ART eligibility (CD4 count > 500 cell/MUL in 2014), this could lead to an increase in program retention as more people fall under the recommended threshold and seek care. PMID- 26126617 TI - Relationship between Helicobacter pylori infection and multiple sclerosis. AB - BACKGROUND: Recent data indicate the presence of immunomodulating properties of Helicobacter pylori (Hp) (Hp Sydney Strain-1 antigen) in an experimental model of multiple sclerosis (MS), and there are limited contradictory epidemiologic data regarding Hp serology in MS patients. METHODS: The aim of this prospective, comparative study was to validate the incidence of active Hp infection by histology and the endoscopic abnormalities, in 44 patients with relapsing remitting MS and 20 anemic controls. RESULTS: The overall prevalence of histologically confirmed active Hp infection in 44 MS patients was 86.4% vs. 50% in 20 matched anemic control participants (P=0.002, odds ratio 6.33, 95%CI 1.85 21.64). Concomitant diseases of autoimmune origin including hypothyroidism and ulcerative colitis were exclusively present in MS patients. Moreover, a trend of increased presence of pathological endoscopic findings such as hiatus hernia, Barrett's esophagus and duodenal ulcer disease was observed in MS patients compared with controls; Barrett's esophagus and duodenal ulcers were exclusively observed in MS patients. Likewise, Hp (+) MS patients showed exclusive presence of hiatus hernia, esophagitis and duodenal ulcer disease compared with Hp (-) MS patients. CONCLUSION: Hp infection appears to be more frequent in MS patients. If confirmed, this might indicate either a common factor that causes susceptibilities to both MS and Hp infection or that Hp might be a causal factor for developing MS. If a causal link between Hp infection and MS is confirmed in the future, this may have a major impact on the pathophysiology and management of MS. PMID- 26126618 TI - Case of nevoid basal cell carcinoma syndrome with multiple cutaneous keratocysts. PMID- 26126620 TI - A biomechanical comparison of 360 degrees stabilizations for corpectomy and total spondylectomy: a cadaveric study in the thoracolumbar spine. AB - BACKGROUND: To date, there has been no adequate biomechanical model that would allow a quantitative comparison in terms of stability/stiffness between a corpectomy with the posterior column preserved and a total spondylectomy with the posterior column sacrificed. The objective of this study was to perform a biomechanical comparison of 360 degrees stabilizations for corpectomy and total spondylectomy, using the human thoracolumbar spine. METHODS: Five human cadaveric thoracolumbar spines (T8-L2) were tested according to the following loading protocol: axial compression, flexion, extension, lateral bending to the right and left, and axial rotation to the right and left. This loading protocol was applied three times. Each specimen was tested intact, after corpectomy, and after total spondylectomy. The relative stiffness of each motion segment was determined for each test. RESULTS: There was no significant difference in stiffness after reconstruction of total spondylectomy versus corpectomy in our thoracolumbar model. Our construct consisted of an anterior cage and four-level pedicle screw instrumentation (two above and two below) and provided similar stiffness in both models. Despite the additional bone resection in a total spondylectomy versus corpectomy, the constructs did not differ biomechanically. Additionally, there was no significant difference in stiffness between the intact specimen and either reconstruction model. CONCLUSIONS: A classic corpectomy, which leaves the posterior column intact, is no better in terms of stability/stiffness than a total spondylectomy carried out using a shorter cage, followed by compression using posterior instrumentation. PMID- 26126619 TI - The effect of a preparation of minerals, vitamins and trace elements on the cardiac gene expression pattern in male diabetic rats. AB - BACKGROUND: Diabetic patients have an increased risk of developing cardiovascular diseases, which are the leading cause of death in developed countries. Although multivitamin products are widely used as dietary supplements, the effects of these products have not been investigated in the diabetic heart yet. Therefore, here we investigated if a preparation of different minerals, vitamins, and trace elements (MVT) affects the cardiac gene expression pattern in experimental diabetes. METHODS: Two-day old male Wistar rats were injected with streptozotocin (i.p. 100 mg/kg) or citrate buffer to induce diabetes. From weeks 4 to 12, rats were fed with a vehicle or a MVT preparation. Fasting blood glucose measurement and oral glucose tolerance test were performed at week 12, and then total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41012 oligonucleotides. RESULTS: Significantly elevated fasting blood glucose concentration and impaired glucose tolerance were markedly improved by MVT treatment in diabetic rats at week 12. Genes with significantly altered expression due to diabetes include functional clusters related to cardiac hypertrophy (e.g. caspase recruitment domain family, member 9; cytochrome P450, family 26, subfamily B, polypeptide; FXYD domain containing ion transport regulator 3), stress response (e.g. metallothionein 1a; metallothionein 2a; interleukin-6 receptor; heme oxygenase (decycling) 1; and glutathione S transferase, theta 3), and hormones associated with insulin resistance (e.g. resistin; FK506 binding protein 5; galanin/GMAP prepropeptide). Moreover the expression of some other genes with no definite cardiac function was also changed such as e.g. similar to apolipoprotein L2; brain expressed X-linked 1; prostaglandin b2 synthase (brain). MVT-treatment in diabetic rats showed opposite gene expression changes in the cases of 19 genes associated with diabetic cardiomyopathy. In healthy hearts, MVT-treatment resulted in cardiac gene expression changes mostly related to immune response (e.g. complement factor B; complement component 4a; interferon regulatory factor 7; hepcidin). CONCLUSIONS: MVT-treatment improved diagnostic markers of diabetes. This is the first demonstration that MVT-treatment significantly alters cardiac gene expression profile in both control and diabetic rats. Our results and further studies exploring the mechanistic role of individual genes may contribute to the prevention or diagnosis of cardiac complications in diabetes. PMID- 26126621 TI - Ameloblastic Carcinoma. AB - BACKGROUND: Ameloblastic carcinoma secondary type is an extremely rare and aggressive odontogenic neoplasm that exhibits histological features of malignancy in primary and metastatic sites. It arises through carcinomatous de differentiation of a pre-existing ameloblastoma or odontogenic cyst, typically following repeated treatments and recurrences of the benign precursor neoplasm. Identification of an ameloblastic carcinoma, secondary type presenting with histologic features of malignant transformation from an earlier untreated benign lesion remains a rarity. Herein, we report 1 such case. CASE REPORT: A 66-year old man was referred for management of a newly diagnosed ameloblastic carcinoma. He underwent radical surgical intervention comprising hemimandibulectomy, supraomohyoid neck dissection, and free-flap reconstruction. Final histologic analysis demonstrated features suggestive of carcinomatous de-differentiation for a consensus diagnosis of ameloblastic carcinoma, secondary type (de differentiated) intraosseous. CONCLUSIONS: Ameloblastic carcinoma, secondary type represents a rare and challenging histologic diagnosis. Radical surgical resection with adequate hard and soft tissue margins is essential for curative management of localized disease. PMID- 26126622 TI - Pregabalin is only partially effective for neuropathic pain. PMID- 26126623 TI - HPV testing as a screen for cervical cancer. AB - Human papillomavirus (HPV) has been identified as a necessary factor in the development of pre-invasive and invasive cancers of the lower genital tract, of which cervical cancer is the most prevalent. A molecular understanding of malignant transformation and epidemiologic information has led to the development of many strategies for detection and early intervention. Newer tests for oncogenic subtypes of HPV have made it possible to predict the risk of future development of cervical cancer. This review summarizes the current understanding of HPV related disease and examines the role of HPV testing as a screening tool for cervical cancer. It summarizes the data from prospective and randomized controlled trials on HPV screening from Europe and North America and includes smaller studies from low and middle income countries where cervical cancer is the most common cancer in women. PMID- 26126624 TI - High-fidelity target sequencing of individual molecules identified using barcode sequences: de novo detection and absolute quantitation of mutations in plasma cell-free DNA from cancer patients. AB - Circulating tumour DNA (ctDNA) is an emerging field of cancer research. However, current ctDNA analysis is usually restricted to one or a few mutation sites due to technical limitations. In the case of massively parallel DNA sequencers, the number of false positives caused by a high read error rate is a major problem. In addition, the final sequence reads do not represent the original DNA population due to the global amplification step during the template preparation. We established a high-fidelity target sequencing system of individual molecules identified in plasma cell-free DNA using barcode sequences; this system consists of the following two steps. (i) A novel target sequencing method that adds barcode sequences by adaptor ligation. This method uses linear amplification to eliminate the errors introduced during the early cycles of polymerase chain reaction. (ii) The monitoring and removal of erroneous barcode tags. This process involves the identification of individual molecules that have been sequenced and for which the number of mutations have been absolute quantitated. Using plasma cell-free DNA from patients with gastric or lung cancer, we demonstrated that the system achieved near complete elimination of false positives and enabled de novo detection and absolute quantitation of mutations in plasma cell-free DNA. PMID- 26126625 TI - Iodine deficiency and thyroid nodular pathology--epidemiological and cancer characteristics in different populations: Portugal and South Africa. AB - BACKGROUND: The prevalence and pathology pattern of iodine deficiency (ID) related disorders are influenced by the dietary iodine intake: low iodine leads to thyroid nodular enlargement, to an increase in the incidence of thyroid cancer, an increase in anaplastic carcinomas and to an alteration in the papillary to follicular neoplasia ratio. This study aims at highlighting the effects of ID by comparatively evaluating the pattern of thyroid nodular pathology in different populations that, although geographically distant and heterogeneous, both had iodine deficiency at the time of data gathering and are at high altitude: Beira Interior (BI) in Portugal and Johannesburg (JHB) in South Africa. (S.A.) Mandatory salt iodization introduced in S. A. in 1995 has recently been shown to have resulted in the correction of ID. METHODS: Evaluation of thyroid histology reports over a 6 year period in BI and a 5 year period in the JHB area. RESULTS: Region of BI: 278 patients with histology reports-60 were malignancies (21.2 %): 31 papillary carcinomas, 22 follicular cancers (18 follicular carcinomas and 4 Hurthle cell tumours), 3 medullary carcinomas and 4 anaplastic carcinomas. Region of JHB: 136 histology reports- 33 were malignancies (24.3 %): 13 papillary carcinomas, 15 follicular cancers (10 follicular carcinomas and 5 Hurthle cell tumours), 1 medullary carcinoma, 3 anaplastic carcinomas and 1 metastatic carcinoma into the thyroid. There was an overlap in the frequencies of all histology types, of particular relevance in the relatively high anaplastic carcinoma incidences and in the papillary to follicular carcinoma ratios which was close to 1 in both areas- BI area ratio: 1.4 and JHB area ratio: 0.87, with overlapping 95 % CI's, also confirmed by the results of the chi-square calculations. CONCLUSIONS: During the study periods evaluated both study areas displayed pathology patterns usually found in ID. Public information regarding the negative consequences of ID combined with the availability of affordable iodized salt are likely to achieve the goal of the elimination of ID. Sea based nutrition, (naturally iodine containing), may also contribute to the elimination of ID, particularly at times when salt restriction tends to be generally advised. PMID- 26126627 TI - Leisure-Time Spent Sitting and Site-Specific Cancer Incidence in a Large U.S. Cohort. AB - BACKGROUND: Time spent sitting is distinctly different from accumulating too little physical activity and may have independent deleterious effects. Few studies have examined the association between sitting time and site-specific cancer incidence. METHODS: Among 69,260 men and 77,462 women who were cancer-free and enrolled in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, 18,555 men and 12,236 women were diagnosed with cancer between 1992 and 2009. Extended Cox proportional hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) of leisure-time spent sitting with total and site-specific cancer incidence. RESULTS: Longer leisure-time spent sitting, after adjustment for physical activity, BMI, and other factors, was associated with risk of total cancer in women (RR = 1.10; 95% CI, 1.04-1.17 for >=6 hours vs. <3 hours per day), but not men (RR = 1.00; 95% CI, 0.96-1.05). In women, sitting time was associated with risk of multiple myeloma (RR = 1.65; 95% CI, 1.07-2.54), invasive breast cancer (RR = 1.10; 95% CI, 1.00-1.21), and ovarian cancer (RR = 1.43; 95% CI, 1.10 1.87). There were no associations between sitting time and site-specific cancers in men. CONCLUSION: Longer leisure-time spent sitting was associated with a higher risk of total cancer risk in women, and specifically with multiple myeloma, breast, and ovarian cancers, but sitting time was not associated with cancer risk in men. Further research is warranted to better understand the differences in associations between men and women. IMPACT: For women, these findings support American Cancer Society guidelines for cancer prevention to reduce sitting time when possible. PMID- 26126626 TI - Coffee Consumption and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Sex: The Liver Cancer Pooling Project. AB - BACKGROUND: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. METHODS: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. RESULTS: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; Ptrend cups/day = <0.0001). More notable reduced risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no association between coffee consumption and ICC. CONCLUSIONS: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. IMPACT: Further research into specific coffee compounds and mechanisms that may account for these associations is needed. PMID- 26126628 TI - Angiotensin II increases secreted frizzled-related protein 5 (sFRP5) expression through AT1 receptor/Rho/ROCK1/JNK signaling in cardiomyocytes. AB - Secreted frizzled-related protein 5 (sFRP5) is a novel adipokine that functions as an inhibitor of Wnt signaling and is involved in embryonic development, proliferation, atherosclerosis, and apoptosis. Studies have shown that sFRP1-4 is expressed in cardiomyocytes, and sFRP3 and sFRP4 are elevated during heart failure. However, it is unclear whether sFRP5 is expressed in cardiomyocytes or cardiac hypertrophy, and as regards the effects of sFRP5 in the process. Here, we report the expression and the corresponding mechanisms of sFRP5 in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. Neonatal rat ventricular myocytes were exposed to increasing concentrations of Ang II for 12-72 h. Y27632 was used to block ROCK signal. PD98059, SB203580, and SP600125 were used to inhibit ERK1/2, p38 MAPK, and JNK signaling pathways, respectively, and anisomycin was used to activate JNK pathway. RT-PCR and Western-blot determined the expressions of sFRP5. BNP, TNF-alpha, ROCK1, ROCK2, MYPT1, and JNK were examined through Western-blot analysis. Ang II increased sFRP5 mRNA and protein levels in a time- and dose-dependent manner. Telmisartan, Y27632 and SP600125 effectively suppressed the expression of sFRP5. sFRP5 downregulated BNP and TNF-alpha expressions in hypertrophic cardiomyocytes. sFRP5 is expressed in cardiomyocytes, and upregulated in Ang II-induced cardiomyocyte hypertrophy through the AT1 receptor/Rho/ROCK1/JNK signaling pathway. sFRP5 may play an important role during cardiomyocyte hypertrophy. PMID- 26126630 TI - High-throughput characterization of chemical-associated embryonic behavioral changes predicts teratogenic outcomes. AB - New strategies are needed to address the data gap between the bioactivity of chemicals in the environment versus existing hazard information. We address whether a high-throughput screening (HTS) system using a vertebrate organism (embryonic zebrafish) can characterize chemical-elicited behavioral responses at an early, 24 hours post-fertilization (hpf) stage that predict teratogenic consequences at a later developmental stage. The system was used to generate full concentration-response behavioral profiles at 24 hpf across 1060 ToxCastTM chemicals. Detailed, morphological evaluation of all individuals was performed as experimental follow-up at 5 days post-fertilization (dpf). Chemicals eliciting behavioral responses were also mapped against external HTS in vitro results to identify specific molecular targets and neurosignalling pathways. We found that, as an integrative measure of normal development, significant alterations in movement highlighted active chemicals representing several modes of action. These early behavioral responses were predictive for 17 specific developmental abnormalities and mortality measured at 5 dpf, often at lower (i.e., more potent) concentrations than those at which morphological effects were observed. Therefore, this system can provide rapid characterization of chemical-elicited behavioral responses at an early developmental stage that are predictive of observable adverse effects later in life. PMID- 26126631 TI - Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics. AB - Alzheimer disease (AD) is a neurodegenerative disease with many known pathological features, yet there is still much debate into the exact cause and mechanisms for progression of this degenerative disorder. The amyloid-beta (Abeta)-induced oxidative stress hypothesis postulates that it is the oligomeric Abeta that inserts into membrane systems to initiate much of the oxidative stress observed in brain during the progression of the disease. In order to study the effects of oxidative stress on tissue from patients with AD and amnestic mild cognitive impairment (MCI), we have developed a method called redox proteomics that identifies specific brain proteins found to be selectively oxidized. Here, we discuss experimental findings of oxidatively modified proteins involved in three key cellular processes implicated in the pathogenesis of AD progression: energy metabolism, cell signaling and neurotransmission, as well as the proteasomal degradation pathways and antioxidant response systems. These proteomics studies conducted by our laboratory and others in the field shed light on the molecular changes imposed on the cells of AD and MCI brain, through the deregulated increase in oxidative/nitrosative stress inflicted by Abeta and mitochondrial dysfunction. PMID- 26126632 TI - Combusting vegetable oils in diesel engines: the impact of unsaturated fatty acids on particle emissions and mutagenic effects of the exhaust. AB - High particle emissions and strong mutagenic effects were observed after combustion of vegetable oil in diesel engines. This study tested the hypothesis that these results are affected by the amount of unsaturated or polyunsaturated fatty acids of vegetable oils. Four different vegetable oils (coconut oil, CO; linseed oil, LO; palm tree oil, PO; and rapeseed oil, RO) and common diesel fuel (DF) were combusted in a heavy-duty diesel engine. The exhausts were investigated for particle emissions and mutagenic effects in direct comparison with emissions of DF. The engine was operated using the European Stationary Cycle. Particle masses were measured gravimetrically while mutagenicity was determined using the bacterial reverse mutation assay with tester strains TA98 and TA100. Combustion of LO caused the largest amount of total particulate matter (TPM). In comparison with DF, it particularly raised the soluble organic fraction (SOF). RO presented second highest TPM and SOF, followed by CO and PO, which were scarcely above DF. RO revealed the highest number of mutations of the vegetable oils closely followed by LO. PO was less mutagenic, but still induced stronger effects than DF. While TPM and SOF were strongly correlated with the content of polyunsaturated fatty acids in the vegetable oils, mutagenicity had a significant correlation with the amount of total unsaturated fatty acids. This study supports the hypothesis that numbers of double bounds in unsaturated fatty acids of vegetable oils combusted in diesel engines influence the amount of emitted particles and the mutagenicity of the exhaust. Further investigations have to elucidate the causal relationship. PMID- 26126633 TI - Paradox effects of binge drinking on response inhibition processes depending on mental workload. AB - Binge drinking is an increasing problem in Western societies, but we are still only beginning to unravel the effects of binge drinking on a cognitive level. While common sense suggests that all cognitive functions are compromised during high-dose ethanol intoxication, several studies suggest that the effects might instead be rather specific. Moreover, some results suggest that the degrees of automaticity and complexity of cognitive operations during response control modulate effects of binge drinking. However, this has not been tested in detail. In the current study, we therefore parametrically modulate cognitive/"mental" workload during response inhibition and examine the effects of high-dose ethanol intoxication (~1.1 0/00) in n = 18 male participants. The results suggest that detrimental effects of high-dose ethanol intoxication strongly depend on the complexity of processes involved in response inhibition. The results revealed strong effects (eta (2) = .495) and are in line with findings showing that even high doses of ethanol have very specific effects on a cognitive level. Opposed to common sense, more complex cognitive operations seem to be less affected by a high-dose ethanol intoxication. Complementing this, high-dose ethanol intoxication is increasingly detrimental for action control, as stronger automated response tendencies are in charge and need to be controlled. Binge-like ethanol intoxication may take a heavier toll on cognitive control processes than on automated responses/response tendencies. Therefore, ethanol effects are more pronounced in supposedly "easier" control conditions because those facilitate the formation of automated response tendencies. PMID- 26126634 TI - Basal divergence of Eriophyoidea (Acariformes, Eupodina) inferred from combined partial COI and 28S gene sequences and CLSM genital anatomy. AB - Eriophyoids are an ancient group of highly miniaturized, morphologically simplified and diverse phytoparasitic mites. Their possible numerous host-switch events have been accompanied by considerable homoplastic evolution. Although several morphological cladistic and molecular phylogenetic studies attempted to reconstruct phylogeny of Eriophyoidea, the major lineages of eriophyoids, as well as the evolutionary relationships between them, are still poorly understood. New phylogenetically informative data have been provided by the recent discovery of the early derivative pentasetacine genus Loboquintus, and observations on the eriophyoid reproductive anatomy. Herein, we use COI and D1-2 rRNA data of 73 eriophyoid species (including early derivative pentasetacines) from Europe, the Americas and South Africa to reconstruct part of the phylogeny of the superfamily, and infer on the basal divergence of eriophyoid taxa. In addition, a comparative CLSM study of the female internal genitalia was undertaken in order to find putative apomorphies, which can be used to improve the taxonomy of Eriophyoidea. The following molecular clades, marked by differences in genital anatomy and prodorsal shield setation, were found in our analyses: Loboquintus(Pentasetacus((Eriophyidae + Diptilomiopidae)(Phytoptidae-1, Phytoptidae-2))). The results of this study suggest that the superfamily Eriophyoidea comprises basal paraphyletic pentasetacines (Loboquintus and Pentasetacus), and two large monophyletic groups: Eriophyidae s.l. [containing paraphyletic Eriophyidae sensu Amrine et al. 2003 (=Eriophyidae s.str.) and Diptilomiopidae sensu Amrine et al. 2003] and Phytoptidae s.l. [containing monophyletic Phytoptidae sensu Boczek et al. 1989 (=Phytoptidae s.str.) and Nalepellidae sensu Boczek et al. 1989]. Putative morphological apomorphies (including genital and gnathosomal characters) supporting the clades revealed in molecular analyses are briefly discussed. PMID- 26126635 TI - Reactive Attachment Disorder and Disinhibited Social Engagement Disorder in School-Aged Foster Children--A Confirmatory Approach to Dimensional Measures. AB - This study aimed to investigate the factor structure and external correlates of the constructs Reactive Attachment Disorder (RAD) and Disinhibited Social Engagement Disorder (DSED) from the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The following were addressed: First, do our data support the DSM-5 conceptualization of RAD/DSED as two separate constructs? Second, are RAD and DSED distinct from other well-established dimensions of child psychopathology? Third, what are the external correlates of RAD/DSED in this sample? The study sample included 122 foster children aged 6-10 years. Foster parents completed the Strengths and Difficulties Questionnaire (SDQ), and the RAD/DSED-scale from the Developmental and Well-Being Assessment. Child protection caseworkers completed a questionnaire regarding exposure to maltreatment and placement history. Confirmatory factor analysis (CFA) of the RAD/DSED items identified a good fit for a model with a two-factor structure, which is congruent with the DSM-5 definition of RAD and DSED. A new CFA model, which included the RAD and DSED factors together with the four problem factors of the SDQ (emotional, conduct, hyperactivity-inattention, and peer problems), also demonstrated a good fit with our data. RAD and DSED were associated with the SDQ Impact scale and help seeking behavior. This was partly explained by the SDQ externalizing and peer problem subscales. Our findings lend support for the DSM-5 conceptualization of RAD and DSED as separate dimensions of child psychopathology. Thus, the assessment of RAD and DSED provides information beyond other mental health problems. PMID- 26126636 TI - Evaluating cytology for the detection of invasive cervical cancer. AB - OBJECTIVE: To assess the sensitivity, the number needed to screen (NNS) and the positive predictive value (PPV) of cervical cytology for the diagnosis of cancer by age in a screening population. METHODS: A retrospective cohort of women with invasive cervical cancer nested within a census of cervical cytology. All (c. 8 million) women aged 20-64 years with cervical cytology (excluding tests after an earlier abnormality). From April 2007 to March 2010, 3372 women had cervical cancer diagnosed within 12 months of such cytology in England. The sensitivity of cervical cytology to cancer, NNS to detect one cancer and predictive values of cytology were calculated for various 'referral' thresholds. These were calculated for ages 20-24, 25-34, 35-49 and 50-64 years. RESULTS: The sensitivity of at least moderate dyskaryosis [equivalent to a high-grade squamous intraepithelial lesion (HSIL) or worse] for cancer of 89.4% [95% confidence interval (CI) 88.3 90.4%] in women offered screening was independent of age. At all ages, women with borderline-early recall or mild dyskaryosis on cytology (equivalent to ASC-US and LSIL, respectively, in the Bethesda system) had a similar risk of cervical cancer to the risk in all women tested. The PPV of severe dyskaryosis/?invasive and ?glandular neoplasia cytology (equivalent to squamous cell carcinoma and adenocarcinoma/adenocarcinoma in situ, respectively, in the Bethesda System) were 34% and 12%, respectively; the PPV of severe dyskaryosis (HSIL: severe dysplasia) was 4%. The NNS was lowest when the incidence of cervical cancer was highest, at ages 25-39 years, but the proportion of those with abnormal cytology who have cancer was also lowest in younger women. CONCLUSIONS: The PPV of at least severe dyskaryosis (HSIL: severe dysplasia) for cancer was 4-10% of women aged 25-64 years, justifying a 2-week referral to colposcopy and demonstrating the importance of failsafe monitoring for such patients. The sensitivity of cytology for cervical cancer was excellent across all age groups. PMID- 26126638 TI - HbA1c, Fructosamine, and Glycated Albumin in the Detection of Dysglycaemic Conditions. AB - Glycated haemoglobin (HbA1c) is currently the gold standard for glucose monitoring in patients with diabetes, and has been increasingly adopted as a criteria for diabetes diagnosis. However, conditions that determine alterations in haemoglobin metabolism can interfere with the reliability of HbA1c measurements. Glycated albumin and fructosamine (total glycated serum proteins) are alternative markers of glycaemia, which have been recognised to provide additional information to HbA1c or to provide a reliable measure when HbA1c is observed not to be dependable. Additionally, while HbA1c monitors the exposure to circulating glycaemia in the previous 3 months, glycated albumin and fructosamine represent exposure for a shorter period, which may be beneficial to monitor rapid metabolic alterations or changes in diabetes treatment. The present review further discusses the relative value of HbA1c, glycated albumin, and fructosamine, in prediabetes and diabetes diagnosis, evaluation of glucose variability, and complications risk prediction. Also, a novel molecular role for albumin is presented by which glycated albumin contributes to glucose intolerance development and thus to progression to diabetes, besides the role of glycated albumin as a pro-atherogenic factor. PMID- 26126637 TI - Expression patterns, molecular markers and genetic diversity of insect susceptible and resistant Barbarea genotypes by comparative transcriptome analysis. AB - BACKGROUND: Barbarea vulgaris contains two genotypes: the glabrous type (G-type), which confers resistance to the diamondback moth (DBM) and other insect pests, and the pubescent type (P-type), which is susceptible to the DBM. Herein, the transcriptomes of P-type B. vulgaris before and after DBM infestation were subjected to Illumina (Solexa) pyrosequencing and comparative analysis. RESULTS: 5.0 gigabase pairs of clean nucleotides were generated. Non-redundant unigenes (33,721) were assembled and 94.1 % of them were annotated. Compared with our previous G-type transcriptome, the expression patterns of many insect responsive genes, including those related to secondary metabolism, phytohormones and transcription factors, which were significantly induced by DBM in G-type plants, were less sensitive to DBM infestation in P-type plants. The genes of the triterpenoid saponin pathway were identified in both G- and P-type plants. The upstream genes of the pathway showed similar expression patterns between the two genotypes. However, gene expression for two downstream enzymes, the glucosyl transferase (UGT73C11) and an oxidosqualene cyclase (OSC), were significantly upregulated in the P-type compared with the G-type plant. The homologous genes from P- and G-type plants were detected by BLAST unigenes with a cutoff level E value < e(-10). 12,980 gene families containing 26,793 P-type and 36,944 G-type unigenes were shared by the two types of B. vulgaris. 38,397 single nucleotide polymorphisms (SNPs) were found in 9,452 orthologous genes between the P- and G type plants. We also detected 5,105 simple sequence repeats (SSRs) in the B. vulgaris transcriptome, comprising mono-nucleotide-repeats (2,477; 48.5 %) and triple-nucleotide-repeats (1,590; 31.1 %). Of these, 1,657 SSRs displayed polymorphisms between the P- and G-type. Consequently, 913 SSR primer pairs were designed with a resolution of more than two nucleotides. We randomly chose 30 SSRs to detect the genetic diversity of 32 Barbarea germplasms. The distance tree showed that these accessions were clearly divided into groups, with the G-type grouping with available Western and Central European B. vulgaris accessions in contrast to the P-type accession, B. stricta and B. verna. CONCLUSIONS: These data represent useful information for pest-resistance gene mining and for the investigation of the molecular basis of plant-pest interactions. PMID- 26126639 TI - Unusual coordination state of cobalt ions in zeolites modified by aluminum chloride. AB - Co- and Al-modified zeolites (Al-Co-ZSM-5) were prepared by solid-state ion exchange with cobalt acetate or chloride, followed by AlCl3 immobilization from anhydrous toluene solution. Based on data from XRD, X-ray absorption (XANES/EXAFS), X-ray photoelectron spectroscopy and DRIFT spectral studies of adsorbed probe molecules (carbon monoxide, ethane), a new cobalt electronic state, bonded with surface aluminum atoms through oxygen and chlorine atoms, arises on the surface of Al-Co-ZSM-5. A new band at 2192 cm(-1) appears in the DRIFT spectrum, shifted to lower frequencies compared to CO complexes with isolated Co(2+) cations (2205 cm(-1)). Spectral data of the ethane adsorption (new strong bands in the range of 2740-2770 cm(-1)) prove the existence of specific centers of alkane activation on coordinately unsaturated cobalt cations, resulting in the interaction with aluminum chloride. PMID- 26126641 TI - The GAB2 and BDNF polymorphisms and the risk for late-onset Alzheimer's disease in an elderly Brazilian sample--ERRATUM. PMID- 26126642 TI - Outcome of adolescent patients with acute myeloid leukemia treated with pediatric protocols. AB - As past studies of adolescent and young adults (AYA) with acute myeloid leukemia (AML) reported conflicting results, we conducted a retrospective analysis using data from three Japanese pediatric AML studies. Among the 782 patients with de novo AML, 44 were classified as AYA (age >=15 years at diagnosis), 164 as infants (0-1 year), 413 as younger children (2-11 years), and 161 as older children (12 14 years). While the 5-year event-free survival rate of AYA was not different among the groups, the five-year survival rate (54.7 %) was significantly lower than that of the other three groups (P = 0.019): 68.7 % for infants, 73.2 % for younger children, and 75.5 % for older children. No difference in the 5-year cumulative incidence of relapse was observed, but treatment-related death (TRD) of AYA was significantly higher (29.4 %) than that in infants (14.8 %), younger children (10.2 %), and older children (13.8 %). Multivariate analysis showed age >=15 years old at diagnosis was associated with both poor survival rate and high TRD. Adolescents with AML had inferior survival due to a higher incidence of TRD, especially after failure of initial frontline treatment. PMID- 26126643 TI - Novel electrochemical sensing platform based on a molecularly imprinted polymer decorated 3D nanoporous nickel skeleton for ultrasensitive and selective determination of metronidazole. AB - A novel electrochemical sensor has been developed by using a composite element of three-dimensional (3D) nanoporous nickel (NPNi) and molecularly imprinted polymer (MIP). NPNi is introduced in order to enhance the electron-transport ability and surface area of the sensor, while the electrosynthesized MIP layer affords simultaneous identification and quantification of the target molecule by employing Fe(CN)6(3-/4-) as the probe to indicate the current intensity. The morphology of the hybrid film was observed by scanning electron microscopy, and the properties of the sensor were examined by cyclic voltammetry and electrochemical impedance spectroscopy. By using metronidazole (MNZ) as a model analyte, the sensor based on the MIP/NPNi hybrid exhibits great features such as a remarkably low detection limit of 2 * 10(-14) M (S/N = 3), superb selectivity in discriminating MNZ from its structural analogues, and good antiinterference ability toward several coexisting substances. Moreover, the proposed method also demonstrates excellent repeatability and stability, with relative standard deviations of less than 1.12% and 1.4%, respectively. Analysis of MNZ in pharmaceutical dosage form and fish tissue is successfully carried out without assistance of complicated pretreatment. The MIP/NPNi composite presented here with admirable merits makes it a promising candidate for developing electrochemical sensor devices and plays a role in widespread fields. PMID- 26126644 TI - PAMAM G4 dendrimers as inhibitors of the iron storage properties of human L-chain ferritin. AB - Cationic dendrimers, such as PAMAM, are known to be positively charged at neutral pH allowing their unspecific interaction with proteins and other cellular components. Especially, ferritin, which has an important role in iron homeostasis, presents a negative electrostatic potential at the 3-fold channel. This channel is important in the functionality of ferritin because it allows the iron entry into its inner cavity. In this way, the interaction between the protonated terminal amines of the dendrimer and the negatively charged 3-fold channels of ferritin is expected. Experimental measurements demonstrated that PAMAM G4 inhibits the iron storage properties of L-chain human ferritin (L-Ftn). Molecular dynamics simulations have been used to analyze the specific interaction between PAMAM G4 and L-Ftn. Results show that PAMAM G4 effectively interacts with the 3-fold channels of L-Ftn, suggesting that this interaction is responsible for the inhibition of the iron storage properties of L-Ftn. PMID- 26126646 TI - Correction for Electronic Structure Investigation and Parametrization of Biologically Relevant Iron-Sulfur Clusters. PMID- 26126647 TI - Polycaprolactone fiber meshes provide a 3D environment suitable for cultivation and differentiation of melanocytes from the outer root sheath of hair follicle. AB - Melanocytes differentiated from the stem cells of human hair follicle outer root sheath (ORS) have the potential for developing non-invasive treatments for skin disorders out of a minimal sample: of hair root. With a robust procedure for melanocyte cultivation from the ORS of human hair follicle at hand, this study focused on the identification of a suitable biocompatible, biodegradable carrier as the next step toward their clinical implementation. Polycaprolactone (PCL) is a known biocompatible material used for a number of medical devices. In this study, we have populated electrospun PCL fiber meshes with normal human epidermal melanocytes (NHEM) as well as with hair-follicle-derived human melanocytes from the outer root sheath (HUMORS) and tested their functionality in vitro. PCL fiber meshes evidently provided a niche for melanocytes and supported their melanotic properties. The cells were tested for gene expression of PAX3, PMEL, TYR and MITF, as well as for proliferation, expression of melanocyte marker proteins tyrosinase and glycoprotein 100 (gp100), L-DOPA-tautomerase enzymatic activity and melanin content. Reduced mitochondrial activity and PAX-3 gene expression indicated that the three-dimensional PCL scaffold supported differentiation rather than proliferation of melanocytes. The monitored melanotic features of both the NHEM and HUMORS cultivated on PCL scaffolds significantly exceeded those of two-dimensional adherent cultures. PMID- 26126648 TI - The hippocampal commissure: a new finding at prenatal 3D ultrasound in fetuses with isolated complete agenesis of the corpus callosum. AB - OBJECTIVE: The aim of this research was to determine the prevalence and sonographic appearance of the hippocampal commissure in fetuses with isolated complete agenesis of the corpus callosum by three-dimensional neurosonography in the multiplanar mode. METHODS: This was a multicenter observational study. Stored volume datasets of fetuses with isolated complete agenesis of the corpus were retrospectively retrieved for analysis in three tertiary centers. The presence or absence of the hippocampal commissure was independently evaluated in the coronal and midsagittal planes by two operators. Postnatal follow-up was obtained in all cases. RESULTS: From November 2007 to February 2013, 41 cases between 19 and 30 weeks of gestation were retrieved for analysis. The hippocampal commissure was visible in the coronal and sagittal planes in 27/41 (65.8%), absent or not clearly recognizable in the remaining 14 cases. The qualitative analysis of the two operators was concordant in 100% of cases. CONCLUSIONS: In more than half of fetuses with complete callosal agenesis, the hippocampal commissure may be visualized at prenatal ultrasound. This is a residual interhemispheric connection, which in normal cases is hidden by the corpus callosum itself. Further research is needed to establish if this has an impact on postnatal outcome. PMID- 26126649 TI - Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice. AB - The placebo effect has often been considered a nuisance in basic and particularly clinical research. This view has gradually changed in recent years due to deeper insight into the neuro-bio-behavioral mechanisms steering both the placebo and nocebo responses, the evil twin of placebo. For the neuroscientist, placebo and nocebo responses have evolved as indispensable tools to understand brain mechanisms that link cognitive and emotional factors with symptom perception as well as peripheral physiologic systems and end organ functioning. For the clinical investigator, better understanding of the mechanisms driving placebo and nocebo responses allow the control of these responses and thereby help to more precisely define the efficacy of a specific pharmacological intervention. Finally, in the clinical context, the systematic exploitation of these mechanisms will help to maximize placebo responses and minimize nocebo responses for the patient's benefit. In this review, we summarize and critically examine the neuro bio-behavioral mechanisms underlying placebo and nocebo responses that are currently known in terms of different diseases and physiologic systems. We subsequently elaborate on the consequences of this knowledge for pharmacological treatments of patients and the implications for pharmacological research, the training of healthcare professionals, and for the health care system and future research strategies on placebo and nocebo responses. PMID- 26126650 TI - Gastrin-releasing peptide expression and its effect on the calcification of developing mouse incisor. AB - Gastrin-releasing peptide (GRP) is considered to be one of the cancer growth factors. This peptide's receptor (GRPR) is known as a G protein-coupled receptor, regulating intracellular calcium storage and releasing signals. This study is the first to investigate the function of GRP during mouse incisor development. We hypothesized that GRP is one of the factors that affects the regulation of calcification during tooth development. To verify the expression pattern of GRP, in situ hybridization was processed during incisor development. GRP was expressed at the late bell stage and hard tissue formation stage in the epithelial tissue. To identify the genuine function of GRP during incisor development, a gain-of function analysis was performed. After GRP overexpression in culture, the phenotype of ameloblasts, odontoblasts and predentin was altered compared to control group. Moreover, enamel and dentin thickness was increased after renal capsule transplantation of GRP-overexpressed incisors. With these results, we suggest that GRP plays a significant role in the formation of enamel and dentin by regulating ameloblasts and predentin formation, respectively. Thus, GRP signaling is strongly related to calcium acquisition and secretion during mouse incisor development. PMID- 26126652 TI - Assembly of multiple cell gradients directed by three-dimensional microfluidic channels. AB - Active control over the cell gradient is essential for understanding biological systems and the reconstitution of the functionality of many types of tissues, particularly for organ-on-a-chip. Here, we propose a three-dimensional (3D) microfluidic strategy for generating controllable cell gradients. In this approach, a homogeneous cell suspension is loaded into a 3D stair-shaped PDMS microchannel to generate a cell gradient within 10 min by sedimentation. We demonstrate that cell gradients of various profiles (exponential and piecewise linear) can be achieved by precisely controlling the height of each layer during the fabrication. With sequential seeding, we further demonstrate the generation of two overlapping cell gradients on the same glass substrate with pre-defined designs. The cell gradient-based QD cytotoxicity assay also demonstrated that cell behaviors and resistances were regulated by the changes in cell density. These results reveal that the proposed 3D microfluidic strategy provides a simple and versatile means for establishing controllable gradients in cell density, opening up a new avenue for reconstructing functional tissues. PMID- 26126651 TI - Analysis of aquaporin expression in liver with a focus on hepatocytes. AB - A deeper understanding of aquaporins (AQPs) expression and transcriptional regulation will provide useful information for liver pathophysiology. We established a complete AQPs mRNA expression profile in human and mouse liver, as well as protein localization of expressed AQPs. Additionally, the modulation of AQPs mRNA levels in response to various agents was determined in human HuH7 cells and in primary culture of mouse hepatocytes. AQP1, AQP3, AQP7, AQP8, and AQP9 mRNA and protein expressions were detected in human liver, while only AQP6 and AQP11 mRNAs were detected. We reported for the first time the localization of AQP3 in Kupffer cells, AQP7 in hepatocytes and endothelial cells, and AQP9 in cholangiocytes. In addition, we confirmed the localization of AQP1 in endothelial cells, and of AQP8 and AQP9 in hepatocytes. On HuH7 cells, we reported the presence of AQP4 mRNA, confirmed the presence of AQP3, AQP7, and AQP11 mRNAs, but not of AQP8 mRNA. On primary culture of murine hepatocytes, AQP1 and AQP7 mRNAs were identified, while the presence of AQP3, AQP8, AQP9, and AQP11 mRNAs was confirmed. At the protein level, murine endothelial liver cells expressed AQP1 and AQP9, while hepatocytes expressed AQP3, AQP7, AQP8, and AQP9, and macrophages expressed AQP3. Dexamethasone, forskolin, AICAR, rosiglitazone, octanoylated, and non-octanoylated ghrelin regulated some AQP expression in primary culture of murine hepatocytes and human HuH7 cells. Additional studies will be required to further assess the role of AQPs expression in human and murine liver and understand the transcriptional regulation of AQPs in hepatocytes under pathophysiological conditions. PMID- 26126653 TI - The current status and future perspectives of organ donation in Japan: learning from the systems in other countries. AB - The revised Organ Transplant Law came into effect in Japan in July 2010. The law allows for organ procurement from brain-dead individuals, including children, with family consent from subjects who had not previously rejected organ donation. Nevertheless, the number of cadaveric organ donations has not increased as expected. The Spanish Model is widely known as the most successful system in the field of organ donation. The system includes an earlier referral of possible donors to the transplant coordination teams, a new family-based approach and care methods, and the development of additional training courses aimed at specific groups of professionals, which are supported by their corresponding societies. South Korea, a country which neighbors Japan, has recently succeeded in increasing the rates of organ donation by introducing several systems, such as incentive programs, an organ procurement organization, a donor registry, and a system to facilitate potential donor referral. In this review, we present the current status of organ donation in Japan and also explore various factors that may help to improve the country's low donation rate based on the experiences of other developed countries. PMID- 26126654 TI - The relative patient costs and availability of dental services, materials and equipment in public oral care facilities in Tanzania. AB - BACKGROUND: Patient charges and availability of dental services influence utilization of dental services. There is little available information on the cost of dental services and availability of materials and equipment in public dental facilities in Africa. This study aimed to determine the relative cost and availability of dental services, materials and equipment in public oral care facilities in Tanzania. The local factors affecting availability were also studied. METHODS: A survey of all district and regional dental clinics in selected regions was conducted in 2014. A total of 28/30 facilities participated in the study. A structured interview was undertaken amongst practitioners and clinic managers within the facilities. Daily resources for consumption (DRC) were used for estimation of patients' relative cost. DRC are the quantified average financial resources required for an adult Tanzanian's overall consumption per day. RESULTS: Tooth extractions were found to cost four times the DRC whereas restorations were 9-10 times the DRC. Studied facilities provided tooth extractions (100%), scaling (86%), fillings (79%), root canal treatment (46%) and fabrication of removable partial dentures (32%). The ratio of tooth fillings to extractions in the facilities was 1:16. Less than 50% of the facilities had any of the investigated dental materials consistently available throughout the year, and just three facilities had all the investigated equipment functional and in use. CONCLUSIONS: Dental materials and equipment availability, skills of the practitioners and the cost of services all play major roles in provision and utilization of comprehensive oral care. These factors are likely to be interlinked and should be taken into consideration when studying any of the factors individually. PMID- 26126656 TI - Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia? AB - INTRODUCTION: Arthralgia is a common toxicity among women taking aromatase inhibitors (AIs) and can lead to premature discontinuation of therapy. We evaluated the association between arthralgia, co-morbid fatigue and/or insomnia, and inflammatory biomarkers among women taking AIs. METHODS: Women taking AIs for early-stage breast cancer completed a modified version of the Brief Pain Inventory, the Brief Fatigue Inventory, and the Insomnia Severity Index and provided blood samples for simultaneous assessment of 34 inflammatory biomarkers with a Luminex kit. Two-sided t tests were used to compare inflammatory biomarker concentrations for patients with or without moderate to severe arthralgia. Multivariate linear regression analyses were performed to evaluate the relationship between comorbid arthralgia, fatigue, and insomnia with identified biomarker concentrations. RESULTS: Among 203 participants, the severity of arthralgia, fatigue, and insomnia were significantly correlated with each other (p < 0.001 for all comparisons). After controlling for race, chemotherapy history, non-steroidal anti-inflammatory drug use, age, and body mass index, the coexistence of arthralgia, fatigue, and insomnia was associated with elevated C reactive protein (CRP) (beta = 93.1; 95 % confidence interval (CI): 25.1-161.1; p = 0.008), eotaxin (beta = 79.9; 95 % CI: 32.5-127.2; p = 0.001), monocyte chemoattractant protein (MCP)-1 (beta = 151.2; 95 % CI: 32.7-269.8; p = 0.013), and vitamin D-binding protein (VDBP) (beta = 19,422; 95 % CI: 5500.5-33,344; p = 0.006). CONCLUSIONS: Among women taking AIs, the coexistence of arthralgia, fatigue, and insomnia was associated with increased levels of inflammatory biomarkers (elevated CRP, eotaxin, MCP-1, and VDBP). These findings suggest a possible shared inflammatory mechanism underlying these common symptoms. PMID- 26126655 TI - Psychological distress and its relationship with non-adherence to TB treatment: a multicentre study. AB - BACKGROUND: The successful cure of tuberculosis (TB) is dependent on adherence to treatment. Various factors influence adherence, however, few are easily modifiable. There are limited data regarding correlates of psychological distress and their association with non-adherence to anti-TB treatment. METHODS: In a trial of a new TB test, we measured psychological distress (K-10 score), TB related health literacy, and morbidity (TBscore), prior to diagnosis in 1502 patients with symptoms of pulmonary TB recruited from clinics in Cape Town (n = 419), Harare (n = 400), Lusaka (n = 400), Durban (n = 200), and Mbeya (n = 83). Socioeconomic, demographic, and alcohol usage-related data were captured. Patients initiated on treatment had their DOTS cards reviewed at two-and six months. RESULTS: 22 %(95 % CI: 20 %, 25 %) of patients had severe psychological distress (K-10 >= 30). In a multivariable linear regression model, increased K-10 score was independently associated with previous TB [estimate (95 % CI) 0.98(0.09 1.87); p = 0.0304], increased TBscore [1(0.80, 1.20); p <0.0001], and heavy alcohol use [3.08(1.26, 4.91); p = 0.0010], whereas male gender was protective [ 1.47(-2.28, -0.62); p = 0.0007]. 26 % (95 % CI: 21 %, 32 %) of 261 patients with culture-confirmed TB were non-adherent. In a multivariable logistic regression model for non-adherence, reduced TBscore [OR (95 % CI) 0.639 (0.497, 0.797); p = 0.0001], health literacy score [0.798(0.696, 0.906); p = 0.0008], and increased K 10 [1.082(1.033, 1.137); p = 0.0012], and heavy alcohol usage [14.83(2.083, 122.9); p = 0.0002], were independently associated. Culture-positive patients with a K-10 score >= 30 were more-likely to be non-adherent (OR = 2.290(1.033 5.126); p = 0.0416]. CONCLUSION: Severe psychological distress is frequent amongst TB patients in Southern Africa. Targeted interventions to alleviate psychological distress, alcohol use, and improve health literacy in newly diagnosed TB patients could reduce non-adherence to treatment. PMID- 26126657 TI - Integrated cell and process engineering for improved transient production of a "difficult-to-express" fusion protein by CHO cells. AB - Based on an optimized electroporation protocol, we designed a rapid, milliliter scale diagnostic transient production assay to identify limitations in the ability of Chinese hamster ovary (CHO) cells to produce a model "difficult-to express" homodimeric Fc-fusion protein, Sp35Fc, that exhibited very low volumetric titer and intracellular formation of disulfide-bonded oligomeric aggregates post-transfection. As expression of Sp35Fc induced an unfolded protein response in transfected host cells, we utilized the transient assay to compare, in parallel, multiple functionally diverse strategies to engineer intracellular processing of Sp35Fc in order to increase production and reduce aggregation as two discrete design objectives. Specifically, we compared the effect of (i) co expression of ER-resident molecular chaperones (BiP, PDI, CypB) or active forms of UPR transactivators (ATF6c, XBP1s) at varying recombinant gene load, (ii) addition of small molecules known to act as chemical chaperones (PBA, DMSO, glycerol, betaine, TMAO) or modulate UPR signaling (PERK inhibitor GSK2606414) at varying concentration, (iii) a reduction in culture temperature to 32 degrees C. Using this information, we designed a biphasic, Sp35Fc-specific transient manufacturing process mediated by lipofection that utilized CypB co-expression at an optimal Sp35Fc:CypB gene ratio of 5:1 to initially maximize transfected cell proliferation, followed by addition of a combination of PBA (0.5 mM) and glycerol (1% v/v) at the onset of stationary phase to maximize cell specific production and eliminate Sp35Fc aggregation. Using this optimal, engineered process transient Sp35Fc production was significantly increased sixfold over a 12 day production process with no evidence of disulfide-bonded aggregates. Finally, transient production in clonally derived sub-populations (derived from parental CHO host) screened for a heritably improved capability to produce Sp35Fc was also significantly improved by the optimized process, showing that protein-specific cell/process engineering can provide a solution that exceeds the limits of genetic/functional diversity within heterogeneous host cell populations. . PMID- 26126658 TI - Perceived patient satisfaction with in-patient services at Jimma University Specialized Hospital, Southwest Ethiopia. AB - BACKGROUND: Patient satisfaction is an attitude resulting from a person's general orientation towards a total experience of health care. It is a key determinant and a legitimate measure for quality of care. In developing countries, satisfaction studies were conducted mainly on nursing care and outpatient services. OBJECTIVE: This study aims to measure and describe the level of patient satisfaction within inpatient health care services. METHODS: Across sectional study design was conducted from 8 May 2011 to 2 June 2011 at Jimma University Specialized Hospital. Systematic random sampling technique was employed to recruit participants. A standardized structured questionnaire developed by reviewing similar literatures was used to assess the level of patient satisfaction towards the inpatient services. SPSS version 19 statistical packages were used for data management and analysis. RESULT: A total of 189 patients participated. The proportion of overall net patient satisfaction was 117 (61.9%). Majority of the respondents 148 (78.3%) reported that they got the kind of service they anticipated. Cleanliness of the ward 145 (76.7%) and time to get back to home 27 (14.3%) were found to have the highest and the lowest proportion of satisfied respondents, respectively. Patients with no formal education 60 (76.9%) and patients from the rural areas 75 (68.8%) were satisfied higher than those from their counterparts. Patients at medical 22 (61.1%) and ophthalmology 10 (62.5%) wards were less satisfied than patients in other departments. CONCLUSION: Nearly two third of the patients were found to be satisfied by the service they received from the hospital. Most of the patients found to be dissatisfied with the nursing, pharmacy and laboratory services, while some others were still dissatisfied with the level of health education, communication and information they received about their illness. Therefore, the hospital administration system should best work on new innovative approach to keep and improve the administrative system, waiting time, hospital stay, hospital accommodation, access for medications and laboratory services to bring patient satisfaction. Nurses and physicians should have to work best to improve health education, communication and understanding between doctors/nurses and patients. Hospital reformation and modern hospital administration system could work best to keep and improve the level of patient satisfaction. PMID- 26126660 TI - UK law on consent: broad consent or authorisation for research? PMID- 26126659 TI - Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues. AB - Bongkrekic acid (BKA), isolated from the bacterium Burkholderia cocovenenans, is an inhibitor of adenine nucleotide translocator, which inhibits apoptosis, and is thus an important tool for the mechanistic investigation of apoptosis. An efficient total synthesis of BKA has been achieved by employing a three-component convergent strategy based on Kocienski-Julia olefination and Suzuki-Miyaura coupling. It is noteworthy that segment B has been prepared as a new doubly functionalized coupling partner, which contributes to shortening of the number of steps. Torquoselective olefination with an ynolate has also been applied for the efficient construction of an unsaturated ester. Furthermore, it is revealed that 1-methyl-2-azaadamantane N-oxyl is an excellent reagent for final oxidation to afford BKA in high yield. Based on the total synthesis, several BKA analogues were prepared for structure-activity relationship studies, which indicated that the carboxylic acid moieties were essential for the apoptosis inhibitory activity of BKA. More easily available BKA analogues with potent apoptosis inhibitory activity were also developed. PMID- 26126662 TI - Gastrointestinal Kaposi's sarcoma involving stomach, duodenum, and colon. PMID- 26126663 TI - QuickNGS elevates Next-Generation Sequencing data analysis to a new level of automation. AB - BACKGROUND: Next-Generation Sequencing (NGS) has emerged as a widely used tool in molecular biology. While time and cost for the sequencing itself are decreasing, the analysis of the massive amounts of data remains challenging. Since multiple algorithmic approaches for the basic data analysis have been developed, there is now an increasing need to efficiently use these tools to obtain results in reasonable time. RESULTS: We have developed QuickNGS, a new workflow system for laboratories with the need to analyze data from multiple NGS projects at a time. QuickNGS takes advantage of parallel computing resources, a comprehensive back end database, and a careful selection of previously published algorithmic approaches to build fully automated data analysis workflows. We demonstrate the efficiency of our new software by a comprehensive analysis of 10 RNA-Seq samples which we can finish in only a few minutes of hands-on time. The approach we have taken is suitable to process even much larger numbers of samples and multiple projects at a time. CONCLUSION: Our approach considerably reduces the barriers that still limit the usability of the powerful NGS technology and finally decreases the time to be spent before proceeding to further downstream analysis and interpretation of the data. PMID- 26126664 TI - UK law on consent: the need for longer consultations. PMID- 26126665 TI - Multi-Layered Scaffolds for Osteochondral Tissue Engineering: In Vitro Response of Co-Cultured Human Mesenchymal Stem Cells. AB - A promising strategy for osteochondral interface regeneration consists in the development of hybrid scaffolds, composed of distinct but integrated layers able to mimic the different regions of cartilage and bone. We developed multi-layered scaffolds by assembling a gelatin layer with layers containing different amounts of gelatin and hydroxyapatite nanocrystals, and using a gelatin solution (as a glue) to stick layers together. The scaffolds exhibit a high, interconnected porosity and mechanical properties varying with composition along the thickness of the scaffolds up to values of compressive stress and modulus of about 1 and 14 MPa, respectively. In vitro tests demonstrate that the different layers of the scaffolds promote chondrogenic and osteogenic differentiation of Human Mesenchimal Stem Cells (hMSC). PMID- 26126666 TI - Bioconcentration and depuration of (14)C-labeled 17alpha-ethinyl estradiol and 4 nonylphenol in individual organs of the marine bivalve Mytilus edulis L. . AB - Endocrine-disrupting compounds (EDCs), including 17alpha-ethinyl estradiol (EE2) and 4-nonylphenol (4-NP), enter coastal environments primarily in effluents of wastewater treatment facilities and have become ubiquitous in marine surface waters, sediments, and biota. Although EE2 and 4-NP have been detected in marine shellfish, the kinetics of bioconcentration and their tissue distribution have not been thoroughly investigated. The authors performed bioconcentration and depuration experiments in the blue mussel, Mytilus edulis, with 3.37 nM EE2 (0.999 MUg/L) and 454 nM 4-NP (100.138 ug/L). Mussels and seawater were sampled throughout a 38-d exposure and a 35-d depuration period, and 6 tissues were individually assayed. Uptake of EE2 and 4-NP was curvilinear throughout exposure and followed a similar uptake pattern: digestive gland > gill >= remaining viscera > gonad > adductor > plasma. Depuration varied, however, with half-lives ranging from 2.7 d (plasma) to 92 d (gill) for EE2 and 15 d (plasma) to 57 d (gill) for 4-NP. An innovative modeling approach, with 3 coupled mathematical models, was developed to differentiate the unique roles of the gill and plasma in distributing the EDCs to internal tissues. Plasma appears pivotal in regulating EDC uptake and depuration within the whole mussel. PMID- 26126667 TI - The effects of extended conjugation length of purely organic phosphors on their phosphorescence emission properties. AB - We synthesized a series of purely organic phosphors, bromobenzaldehyde derivatives, with varying conjugation length to investigate the effects of conjugation length on their phosphorescence emission properties. As the conjugation length increases phosphorescence efficiency decreases with a redshift in the emission color at 77 K. Our computational results imply that this correlation is related to the intersystem crossing rate and that the rate is determined by spin-orbit coupling strength rather than by simply the energy difference between the lowest lying singlet and triplet states. TD-DFT calculations show that the S1 -> T1 transition occurs more dominantly than the S1 -> T2 transition for all cases. Moreover, singlet excited states are localized on the aldehyde functional group, regardless of the conjugation length, while triplet excited states are evenly distributed over the conjugated backbone. Consequently, as the conjugation length increases, the larger spatial separation between singlet and triplet states diminishes the spin-orbit coupling efficiency, resulting in reduced phosphorescence. PMID- 26126668 TI - Modeling the long-term antibody response of a hepatitis E vaccine. AB - BACKGROUND: The first commercialized hepatitis E vaccine, HEV 239, has been shown to be safe and highly immunogenic, the protection as well as the vaccine-induced anti-HEV maintained for at least 4.5 years. However, the longer term persistence of the vaccine-induced anti-HEV responses is unknown. METHODS: Two statistical models, the power-law model and the modified power-law model, were applied to predict the long-term antibody response of the HEV 239 vaccine. The models were fit using the anti-HEV IgG data from a modeling subpopulation of 1278 baseline seronegative vaccinees who seroconverted within one month after finishing the whole vaccination course in the phase 3 trial of HEV 239. In addition, antibody data from a validation subpopulation were used to validate the robustness of the derived models. RESULTS: In the vaccinees without pre-vaccination immunity, the power-law model and the modified power-law model estimated that the median duration of the detectable antibody (>=0.077 WU/ml) was 8 years and 13 years, respectively. The power-law model and the modified power-law model estimated that 50% of these vaccinees will maintain detectable levels of anti-HEV IgG for 8 years and >30 years, respectively. CONCLUSIONS: The recombinant hepatitis E vaccine HEV 239 is predicted to provide from 8 years to nearly life-long persistence of anti-HEV IgG above detectable levels. Model predictions are based on conservative mathematical assumptions. (NCT01014845). PMID- 26126672 TI - Developing palliative care for children globally. PMID- 26126669 TI - Eliciting neutralizing antibodies against the membrane proximal external region of HIV-1 Env by chimeric live attenuated influenza A virus vaccines. AB - Despite significant efforts directed toward research on HIV-1 vaccines, a truly effective immunogen has not been achieved. However, the broadly neutralizing antibodies (BnAbs) 2F5 and 4E10, targeting the highly conserved membrane proximal external region (MPER) of HIV-1, are two promising tools for vaccine development. Here we engrafted the MPER into the linker domain between the trimeric core structure and the transmembrane domain of influenza A virus HA2 to investigate the potential of such chimeric viruses to elicit HIV-1 neutralizing antibodies. In the context of proliferating attenuated influenza A viruses, these HIV-1 neutralizing antibody epitopes could be continuously expressed and mimicked their native conformation to induce humoral immune responses. While MPER-specific antibodies could be detected in serum of guinea pigs vaccinated with the chimeric viruses, they exhibited only weakly neutralizing activities. These antisera from vaccinated animals neutralized viruses of clades B and BC (tier 1), but not of clades AE (tier 1) and C (tier 2). These results suggest that influenza A virus can be used as a vehicle for displaying MPER and inducing BnAbs, but it provides limited protection against HIV-1 infection. In the future development of HIV-1 vaccines by rational design, a more effective live virus vector or multiple antigens should be chosen to facilitate the process of neutralizing antibody maturation. PMID- 26126673 TI - Nursing intuition: the role of embodied awareness in end-of-life care. PMID- 26126674 TI - Indwelling pleural catheters for malignant pleural effusion. AB - Pleural effusions are a common cause of symptoms in patients with malignancy and can adversely affect quality of life. However, not all effusions in the setting of malignancy are due to the cancer itself and therefore it is essential to perform an extensive assessment to diagnose the underlying aetiology. There are a number of treatment options available to manage a malignant effusion and reduce the associated symptomatology. The choice of intervention depends on a number of factors and, in particular, patient preference. In this paper, we will discuss the role of an indwelling pleural catheter in the outpatient management of individuals with malignant effusions. PMID- 26126675 TI - Management of opioid-induced constipation for people in palliative care. AB - Constipation is common in the palliative population. Opioid medications, which are frequently prescribed to this cohort, represent a significant risk factor for this condition. Opioid-induced constipation may be of such severity that opioid doses are reduced or missed, and analgesia and quality of life are therefore reduced. However, underlying chronic constipation, local and systemic disease effects, and other medications may also precipitate constipation in this population. The assessment and treatment of constipation in a palliative individual should be undertaken in a fashion similar to that used in non palliative patients. Initial management should include minimising exposure to predisposing factors and general measures such as encouraging hydration, fibre intake and mobility. Pharmacological treatment should commence with a stool softener and a stimulant laxative. Recently published literature demonstrates that newer laxatives, including lubiprostone (a chloride channel activator) and prucalopride (a 5-HT4 receptor agonist) can effectively treat opioid-induced constipation. For patients not responding to laxatives, opioid antagonists (non specific or peripherally acting MU-opioid receptor antagonists) can be co prescribed with laxatives. These agents have also proven efficacy in treating opioid-induced constipation. This review discusses the recent literature regarding the management of opioid-induced constipation and provides a rational approach to assessing and managing constipation in the palliative population. PMID- 26126676 TI - Outcomes of children with advanced HIV initiated on antiretroviral therapy in a South African hospice. AB - BACKGROUND: Little is known about the long-term outcome of antiretroviral therapy (ART) for children with advanced-stage HIV. AIM: To assess the outcome in children with advanced HIV initiated on ART. The predictors for survival, general wellbeing and the role of palliative care were assessed. METHODS: Patient files, retained patient records and personal follow-up were used for data collection. Data on baseline characteristics, ART treatment and progress were collected at baseline, 6, 12 and 48 months. Information regarding general wellbeing and school attendance and performance were collected. RESULTS: 37 children were started on ART. At 48 months there were 18 known survivors and 7 known to have died. Another 12 were transferred to another programme or lost to follow-up. There was no significant difference in baseline characteristics between groups. All eligible children attended school and all received medical care. The hospice programme offered holistic care and support. CONCLUSIONS: No baseline characteristic could predict the outcome of children with advanced HIV initiated on ART. A hospice support programme can contribute to positive outcomes even when ART is initiated in children with advanced disease. PMID- 26126677 TI - We are not alone: international learning for professionals caring for children requiring palliative care. AB - BACKGROUND: Educational opportunities for professionals working with children requiring palliative care are central to future development within the specialty across countries. International educational initiatives involving a range of professionals are important for learning with and from others working within the field. AIM: To explore the experiences and value to students from participating in an international online discussion forum. METHOD: This article examines one such initiative; the use of an international asynchronous discussion forum with students in Melbourne, Australia and Belfast, UK who work with children and families. The innovation is examined and student perspectives of the forum's value are presented. RESULTS: Students endorsed the value of the forum, identifying three main areas of learning: differences across locations within countries, respecting different views and being open, and need for continued learning within children's palliative care. The overarching theme 'we are not alone' supported the idea that participation in the international discussion forum enabled students to see a broader perspective. Ideas for future developments of similar forums are also explored. PMID- 26126678 TI - Paediatric death and dying: exploring coping strategies of health professionals and perceptions of support provision. AB - Without question a child's death is a devastating event for parents and families. Health professionals working with the dying child and family draw upon their expertise and experience to engage with children, parents and families on this painful journey. This is a delicate and sensitive area of practice and has strong and penetrating effects on health professionals. They employ physical, emotional, spiritual and problem solving strategies to continue to perform this role effectively and to protect their continued sense of wellbeing. AIM: To explore health professionals' perceptions of bereavement support surrounding the loss of a child. METHODS: The research was underpinned by social constructionism. Semi structured interviews were held with 10 health professionals including doctors, nurses and social workers who were directly involved in the care of the dying child and family in 7 cases of paediatric death. Health professional narratives were analysed consistent with Charmarz's (2006) approach. RESULTS: For health professionals, constructions around coping emerged as peer support, personal coping strategies, family support, physical impact of support and spiritual beliefs. Analysis of the narratives also revealed health professionals' perceptions of their support provision. CONCLUSION: Health professionals involved in caring for dying children and their families use a variety of strategies to cope with the emotional and physical toll of providing support. They also engage in self-assessment to evaluate their support provision and this highlights the need for self-evaluation tools in paediatric palliative care. PMID- 26126680 TI - One size does not fit all for a good death. PMID- 26126682 TI - Prenatal antibiotic use and risk of childhood wheeze/asthma: A meta-analysis. AB - BACKGROUND: Existing body of knowledge suggests that antibiotic use during pregnancy was inconsistently associated with childhood wheeze/asthma. The aim of this study was to determine whether exposure to antibiotic during pregnancy could increase the risk for childhood wheeze/asthma using a comprehensive meta analysis. METHODS: PubMed, MEDLINE, and China National Knowledge Infrastructure (CNKI) were systematically searched for studies up to September 10, 2014, and additional studies were found by searching reference lists of relevant articles. For this meta-analysis, cohort studies and case-control studies assessing the association between antibiotic use during pregnancy and risk of childhood wheeze/asthma were included. Extracted data were mainly pooled using random effects model. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). RESULTS: Ten studies were identified in final analysis. Pooling analysis of these studies showed an OR of 1.20 (95% CI, 1.13-1.27) for wheeze/asthma. After excluding case-control studies and prospective studies without achieving high scores on the NOS, the pooled OR was 1.18 (95% CI, 1.11 1.26). We found the risk of antibiotic use and pooled ORs of wheeze/asthma were 1.09 (95% CI, 0.92-1.29) for the first trimester, 1.14 (95% CI, 1.01-1.29) for the second trimester, and 1.33 (95% CI, 1.11-1.60) for the third trimester, respectively. CONCLUSIONS: This meta-analysis suggests that antibiotic exposure during pregnancy may increase the risk of wheeze/asthma in childhood. Besides, the risk of developing wheeze/asthma in childhood was marked during last two trimesters of pregnancy. Future studies of large-size and prospective cohorts which adequately address concerns for confounder bias are needed to examine the relationship between antibiotic use and risk of childhood asthma. PMID- 26126683 TI - Glucose intolerance and pancreatic beta-cell dysfunction in the anorectic anx/anx mouse. AB - Inflammation and impaired mitochondrial oxidative phosphorylation are considered key players in the development of several metabolic disorders, including diabetes. We have previously shown inflammation and mitochondrial dysfunction in the hypothalamus of an animal model for anorexia, the anx/anx mouse. Moreover, increased incidence of eating disorders, e.g., anorexia nervosa, has been observed in diabetic individuals. In the present investigation we evaluated whether impaired mitochondrial phosphorylation and inflammation also occur in endocrine pancreas of anorectic mice, and if glucose homeostasis is disturbed. We show that anx/anx mice exhibit marked glucose intolerance associated with reduced insulin release following an intraperitoneal injection of glucose. In contrast, insulin release from isolated anx/anx islets is increased after stimulation with glucose or KCl. In isolated anx/anx islets there is a strong downregulation of the mitochondrial complex I (CI) assembly factor, NADH dehydrogenase (ubiquinone) 1alpha subcomplex, assembly factor 1 (Ndufaf1), and a reduced CI activity. In addition, we show elevated concentrations of free fatty acids (FFAs) in anx/anx serum and increased macrophage infiltration (indicative of inflammation) in anx/anx islets. However, isolated islets from anx/anx mice cultured in the absence of FFAs do not exhibit increased inflammation. We conclude that the phenotype of the endocrine pancreas of the anx/anx mouse is characterized by increased levels of circulating FFAs, as well as inflammation, which can inhibit insulin secretion in vivo. The anx/anx mouse may represent a useful tool for studying molecular mechanisms underlying the association between diabetes and eating disorders. PMID- 26126684 TI - Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans. AB - Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% Vo2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurance-trained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1 phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-kappaB activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future. PMID- 26126685 TI - Characterization of lipid metabolism in a novel immortalized human hepatocyte cell line. AB - The development of hepatocyte cell models that represent fatty acid partitioning within the human liver would be beneficial for the study of the development and progression of nonalcoholic fatty liver disease (NAFLD). We sought to develop and characterize a novel human liver cell line (LIV0APOLY) to establish a model of lipid accumulation using a physiological mixture of fatty acids under low- and high-glucose conditions. LIV0APOLY cells were compared with a well-established cell line (HepG2) and, where possible, primary human hepatocytes. LIV0APOLY cells were found to proliferate and express some mature liver markers and were wild type for the PNPLA3 (rs738409) gene, whereas HepG2 cells carried the Ile(148)Met variant that is positively associated with liver fat content. Intracellular triglyceride content was higher in HepG2 than in LIV0APOLY cells; exposure to high glucose and/or exogenous fatty acids increased intracellular triglyceride in both cell lines. Triglyceride concentrations in media were higher from LIV0APOLY compared with HepG2 cells. Culturing LIV0APOLY cells in high glucose increased a marker of endoplasmic reticulum stress and attenuated insulin-stimulated Akt phosphorylation whereas low glucose and exogenous fatty acids increased AMPK phosphorylation. Although LIV0APOLY cells and primary hepatocytes stored similar amounts of exogenous fatty acids as triglyceride, more exogenous fatty acids were partitioned toward oxidation in the LIV0APOLY cells than in primary hepatocytes. LIV0APOLY cells offer the potential to be a renewable cellular model for studying the effects of exogenous metabolic substrates on fatty acid partitioning; however, their usefulness as a model of lipoprotein metabolism needs to be further explored. PMID- 26126686 TI - Eosinophilia in patients infected with human immunodeficiency virus. AB - Eosinophilia is not uncommonly encountered in patients infected with human immunodeficiency virus (HIV), particularly at initiation of care or among those with advanced disease. The clinical manifestation most commonly associated with eosinophilia in this patient population is skin rash. Management of these patients is challenging due to a paucity of data evaluating diagnostic testing and therapeutic strategies. Patients born in or with significant travel to parasite-endemic countries are more likely to have tissue-invasive helminthes, such as Strongyloides or Schistosoma. Patients without such risk factors are unlikely to have parasitic infections and frequently will have self-resolution of eosinophilia. When a detailed history, physical exam, and diagnostic work-up are unrevealing, we sometimes consider empirical therapy with ivermectin. Praziquantel may also be considered for those at risk for schistosomiasis. PMID- 26126688 TI - Analysis of conservative tracer measurement results using the Frechet distribution at planted horizontal subsurface flow constructed wetlands filled with coarse gravel and showing the effect of clogging processes. AB - A mathematical process, developed in Maple environment, has been successful in decreasing the error of measurement results and in the precise calculation of the moments of corrected tracer functions. It was proved that with this process, the measured tracer results of horizontal subsurface flow constructed wetlands filled with coarse gravel (HSFCW-C) can be fitted more accurately than with the conventionally used distribution functions (Gaussian, Lognormal, Fick (Inverse Gaussian) and Gamma). This statement is true only for the planted HSFCW-Cs. The analysis of unplanted HSFCW-Cs needs more research. The result of the analysis shows that the conventional solutions (completely stirred series tank reactor (CSTR) model and convection-dispersion transport (CDT) model) cannot describe these types of transport processes with sufficient accuracy. These outcomes can help in developing better process descriptions of very difficult transport processes in HSFCW-Cs. Furthermore, a new mathematical process can be developed for the calculation of real hydraulic residence time (HRT) and dispersion coefficient values. The presented method can be generalized to other kinds of hydraulic environments. PMID- 26126687 TI - The role of statins in the setting of HIV infection. AB - HIV-infected individuals are at an increased risk of cardiovascular disease (CVD) and other HIV-related co-morbidities. This is due in part to dyslipidemia associated with antiretroviral therapy and increased inflammation and immune activation from chronic HIV infection. Statins not only have potent lipid lowering properties but are also anti-inflammatory and immunomodulators. Studies suggest that statin therapy in the HIV-infected population may decrease the risk of CVD and other non-AIDS-defining co-morbidities. This review summarizes the recent literature on statin use in the HIV setting. PMID- 26126689 TI - Urinary heavy metals, phthalates and polyaromatic hydrocarbons independent of health events are associated with adult depression: USA NHANES, 2011-2012. AB - Links between environmental chemicals and human health have emerged, but the effects on mental health such as depression were less studied. Therefore, it was aimed to study the relationships between different sets of urinary environmental chemical concentrations and adult depression in a national and population-based setting in recent years. Data was retrieved from the US National Health and Nutrition Examination Survey in 2011-2012 including demographics, serum measurements, lifestyle factors, self-reported health conditions and urinary chemical concentrations. Depression was determined by using the Patient Health Questionnaire with a cutoff point at 9/10. Chi-square test, t test and survey weighted logistic regression modeling were performed. Among 5560 American adults aged 20-80 years, 363 (7.8%) people were classified as having depression (Patient Health Questionnaire score >= 10). They tended to have history of health events. After full adjustment including urinary creatinine; demographic characteristics; lifestyle factors; health conditions (such as cardiovascular, neurological, respiratory, digestive and bone diseases, and injury); and subsample weighing; and higher levels of manganese, tin, and phthalates including mono-2-ethyl-5 carboxypentyl, mono-n-butyl, mono-isobutyl, and mono-benzyl were associated with adult depression. Similarly, urinary polyaromatic hydrocarbons including 2 hydroxyfluorene, 3-hydroxyfluorene, 9-hydroxyfluorene, 1-hydroxyphenanthrene, 2 hydroxyphenanthrene, 3-hydroxyphenanthrene, 1-hydroxypyrene, 1-hydroxynaphthalene (1-naphthol), 2-hydroxynaphthalene (2-naphthol) and 4-hydroxyphenanthrene were associated with depression. There were no associations observed in urinary arsenic, phenols, parabens, pesticides, perchlorate, nitrate, thiocyanate and polyfluorinated compounds. Urinary heavy metal, phthalates and polyaromatic hydrocarbons were associated with adult depression, being independent of health events. Further elimination of such harmful chemicals might need to be considered in future mental health and environmental policies. PMID- 26126691 TI - Pathology: Professional challenges and academia combine to give an enjoyable and satisfying 'fun' career. PMID- 26126690 TI - Permissive and protective roles for neutrophils in leishmaniasis. AB - Leishmania parasites are the causative agents of leishmaniasis, a neglected tropical disease that causes substantial morbidity and considerable mortality in many developing areas of the world. Recent estimates suggest that roughly 10 million people suffer from cutaneous leishmaniasis (CL), and approximately 76,000 are afflicted with visceral leishmaniasis (VL), which is universally fatal without treatment. Efforts to develop therapeutics and vaccines have been greatly hampered by an incomplete understanding of the parasite's biology and a lack of clear protective correlates that must be met in order to achieve immunity. Although parasites grow and divide preferentially in macrophages, a number of other cell types interact with and internalize Leishmania parasites, including monocytes, dendritic cells and neutrophils. Neutrophils appear to be especially important shortly after parasites are introduced into the skin, and may serve a dual protective and permissive role during the establishment of infection. Curiously, neutrophil recruitment to the site of infection appears to continue into the chronic phase of disease, which may persist for many years. The immunological impact of these cells during chronic leishmaniasis is unclear at this time. In this review we discuss the ways in which neutrophils have been observed to prevent and promote the establishment of infection, examine the role of anti-neutrophil antibodies in mouse models of leishmaniasis and consider recent findings that neutrophils may play a previously unrecognized role in influencing chronic parasite persistence. PMID- 26126692 TI - Collagenase Clostridium histolyticum (Xiaflex) for the Treatment of Urethral Stricture Disease in a Rat Model of Urethral Fibrosis. AB - OBJECTIVE: To evaluate the treatment effect of collagenase Clostridium histolyticum (CCH) in a rat model of urethral fibrosis. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats (300-350 g) were divided into 5 groups. The rat urethra was injected with normal saline in the sham group and, in the other 4 groups, the rat urethra was injected with 10 MUg of transforming growth factor beta 1 to create fibrosis of the urethra. Two weeks following transforming growth factor beta 1 injection, the rats were injected with varying doses of CCH or vehicles, depending on their group. The rats were then euthanized at 4 weeks after CCH or vehicle injection. Urethral tissue was harvested for histologic and molecular analyses. Type I and III collagen levels were evaluated by Western blot analysis. RESULTS: There was urethral fibrosis and to significant increase in collagen type I and III expressions in the urethral fibrosis group compared with the sham group (P <.05). Urethral injection of CCH appeared to be safe and significantly reduce urethral fibrosis as well as collagen type I and III expressions in the high-dose CCH treatment groups when compared with the treatment control group (P <.01). CONCLUSION: This study demonstrated a beneficial effect of CCH injections in a rat model of urethral fibrosis. These findings suggest a potential role for CCH as a therapeutic option in urethral stricture patients and warrant further investigation. PMID- 26126693 TI - Clinically Insignificant Residual Fragments: Is It an Appropriate Term in Children? AB - OBJECTIVE: To assess the outcome of clinically insignificant residual fragments (CIRFs) after shock wave lithotripsy (SWL) and percutaneous nephrolithotomy (PNL) in children. METHODS: Sixty-one children with CIRFs diagnosed by noncontrast computed tomography (NCCT) 3 months after SWL and 1 month after PNL with documented follow-up >=6 months were included in the study. Children were evaluated by urinalysis, urine culture, plain abdominal radiography, and urinary ultrasonography or noncontrast computed tomography. Outcomes measured were fragment regrowth, spontaneous fragment passage, and secondary interventions. A clinically significant outcome was defined as the need for secondary intervention for development of complications or regrowth of the residual fragment (RF). RESULTS: The study included 42 boys and 19 girls with mean age of 6.2 years (range 1-14). After a median follow-up of 18 months, 16 children (26.2%) passed RF spontaneously. Regrowth of the RF was observed in 15 children (24.6%), and in 4 children (6.6%) the RF (of the same original size) slipped to the ureter and was treated by ureteroscopy. Therefore, a clinically significant outcome occurred in 31.2% of children with RF. Children with history of stone disease were more likely to develop clinical significance with time (HR, 4.38; 95% CI, 1.37-14; P = .013) CONCLUSION: The term CIRF is not appropriate for all children with post-SWL and -PNL fragments, as one-third of patients have had fragments that became clinically significant. History of stone disease was the only predictor of clinical significance. PMID- 26126694 TI - Holmium Laser Enucleation of the Prostate: Simulation-Based Training Curriculum and Validation. AB - OBJECTIVE: To evaluate the face, content, and construct validity of a novel virtual reality simulator for holmium laser enucleation of the prostate (HoLEP) and to assess its feasibility and acceptability as a training model. METHODS: This prospective observational study recruited 53 participants, comprising of 3 groups: HoLEP experts (n = 11), intermediates (n = 24), and novices (n = 18). All participants received an educational package and a 15-minute familiarization exercise with the simulator. All participants then carried out a full enucleation on an identical 60 cm(3) virtual prostate. Performance was assessed using in built simulator metrics, and a questionnaire was distributed assessing face and content validity, as well as feasibility, and acceptability. Novice, intermediate, and expert groups were compared using the Mann-Whitney U test. RESULTS: Construct validity data revealed significant differences in enucleation efficiency (grams enucleated per hour) when comparing experts to intermediates (P = .003), experts to novices (P <.001), and intermediates to novices (P = .001). Face validity was rated by experts as acceptable, with a mean score of 5.6 out of 10 when asked to rate the overall realism. Content validity questions showed that 85% of participants agreed that simulator-based assessment is essential for patient safety and 87% agreed that there was a role for a validated virtual reality simulator for use in HoLEP training. CONCLUSION: This study established face, content, and construct validity for this novel virtual reality HoLEP simulator. The majority of participants also thought that it is a feasible and acceptable model for HoLEP training. PMID- 26126695 TI - Sarcomatoid Carcinoma of the Prostate: Retrospective Review of a Case Series From the Johns Hopkins Hospital. AB - OBJECTIVE: To identify survival differences in patients with sarcomatoid prostate cancer based on initial staging and treatment regimens. METHODS: We retrospectively reviewed the clinical outcomes of patients with a pathologically confirmed diagnosis of sarcomatoid prostate cancer. The primary statistical objective was to estimate overall survival (OS) and to assess the survival of patients at different stages treated with local and/or systemic approaches. RESULTS: We identified 70 transurethral resections, needle biopsies, or prostatectomy specimens that were reviewed by the Department of Pathology at the Johns Hopkins Hospital from 2002-2012 and given the diagnosis of sarcomatoid prostate cancer. Of the 45 patients with available survival data, complete medical histories were obtained for 27 patients who were stratified based on a modified staging system (local disease, local disease with bladder invasion, and metastatic disease). After a median follow-up of 106 months, the median OS of patients in the local disease group was not reached. Notably, 5 of the 9 patients diagnosed with local disease survived >5 years and were treated with surgery and/or external beam radiation therapy. The OS hazard was significantly increased in patients with either clinical evidence of bladder invasion (HR: 20.46 [95% CI: 2.43,172]; P = 0.005) or metastatic disease (HR: 43.34 [95% CI: 4.39,427.4]; P = 0.001), which both demonstrated poor outcomes (median OS: local disease with bladder invasion-9 months; metastatic disease-7.1 months). CONCLUSION: This retrospective analysis suggests that local sarcomatoid prostate cancer can be effectively treated with definitive therapy leading to favorable outcomes. PMID- 26126696 TI - En-Bloc Technique With Anteroposterior Dissection Holmium Laser Enucleation of the Prostate Allows a Short Operative Time and Acceptable Outcomes. AB - OBJECTIVE: To simplify anteroposterior dissection holmium laser enucleation of the prostate by combining it with a novel en-bloc enucleation technique that omits median lobe enucleation and removes the adenoma en-bloc in benign prostatic hyperplasia patients. METHODS: Between September 2013 and May 2014, 65 patients with benign prostatic hyperplasia underwent holmium laser enucleation of the prostate with the en-bloc technique we developed at our institution. Twenty-six patients who underwent surgery performed by the same experienced surgeon were included in our study. We evaluated the surgical parameters, including total operative time, enucleation time, morcellation time, and hemoglobin loss. Peak flow rate and postvoid residual urine volume were assessed 3 months postoperatively, and urinary incontinence was assessed 1 day after catheter removal and at 1 and 3 months postoperatively in all patients. RESULTS: Mean total operating time and mean enucleation time were 56.4 and 26.5 minutes, respectively. Peak flow rate and postvoid residual urine volume significantly improved. The incidence of postoperative incontinence at 3 months was 3%. CONCLUSION: Our en-bloc enucleation method required a short operating time and may address concerns regarding the complexity of the enucleation procedure. We believe the incidence of postoperative incontinence can be further reduced with additional refinements of this procedure. PMID- 26126697 TI - Characteristics of the Peritumoral Pseudocapsule Vary Predictably With Histologic Subtype of T1 Renal Neoplasms. AB - OBJECTIVE: To determine characteristics of the peritumoral pseudocapsule (PC) between renal tumor subtypes. METHODS: The peritumoral PCs of 160 pT1 renal tumors were examined, including 60 clear cell renal cell carcinomas (RCCs), 50 papillary RCCs, 25 chromophobe RCCs, and 25 oncocytoma. Pathologic features (presence or absence of PC, mean thickness, continuity, and invasion by tumor) were analyzed. PC thickness was measured using an ocular micrometer to the nearest 1/10 mm. RESULTS: A complete PC was found in 77% of clear cell tumors, 74% of papillary, 28% of chromophobe, and 4% of oncocytomas. Tumor PC was present but incomplete in 18% of clear cell, 18% of papillary, 44% of chromophobe, and 56% of oncocytoma. The PC was entirely absent in no clear cell tumors, 6% of papillary, 28% of chromophobe, and 40% of oncocytoma. Mean PC thickness and presence of invasion beyond the PC differed significantly by tumor subtype. Clear cell RCC possessed the thickest PC showing invasion through the capsule in 8% of tumors compared to 30% of papillary tumors. Complete PC invasion was not seen in chromophobe RCC or renal oncocytoma. Oncocytoma and chromophobe RCC characteristically exhibited an incomplete or absent PC. CONCLUSION: The characteristics of peritumoral PC vary predictably with histologic subtype of renal neoplasms. Clear cell RCC shows the most consistent PC, with a lower rate of invasion beyond it compared to papillary RCC. Chromophobe and oncocytoma characteristically have an incomplete or absent PC. PMID- 26126698 TI - Chitosan prevents adhesion during rabbit flexor tendon repair via the sirtuin 1 signaling pathway. AB - Chitosan has been demonstrated to exert potent anti-adhesive activity during tendon repair; however, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the preventive effects of chitosan on adhesion in rabbit tendon repair, and to investigate the role of the sirtuin (SIRT)1 signaling pathway in this process. A total of 30 rabbits were divided randomly into three equal groups: Group 1, saline treatment; group 2, chitosan treatment; and group 3, chitosan + nicotinamide treatment. The flexor tendon of each of the rabbits was injured, and subsequently each rabbit was injected with the one of the reagents. Six weeks post-surgery, all of the rabbits were sacrificed and their flexor tendons were harvested for subsequent evaluation of adhesion. Western blotting was used to determine the protein expression levels of specific signaling molecules. An MTT assay was conducted to evaluate the viability of human tenocytes and flow cytometry was used to analyze the apoptotic rate of the cells. The present study demonstrated that treatment with chitosan relieved adhesion in the rabbits with flexor tendon injuries. In addition, chitosan treatment increased SIRT1 expression, and reduced acetylated p65 and p53 expression in the tendons. The effects of chitosan on the tendons were attenuated by treatment with nicotinamide (a SIRT1 inhibitor). In the human tenocytes, pretreatment with chitosan resulted in an inhibition of interleukin (IL)-1beta induced apoptosis. Furthermore, chitosan reversed the IL-1beta-induced downregulation of SIRT1 and upregulation of acetylated p65 and p53. Furthermore, downregulation of Sirt1 by RNA interference abrogated the effects of chitosan on the levels of p65 and p53 acetylation, and the rate of tenocyte apoptosis. In conclusion, chitosan treatment prevented adhesion via the SIRT1 signaling pathway during rabbit flexor tendon repair. These results indicate that SIRT1 may be targeted for therapeutic intervention in flexor tendon injury. PMID- 26126699 TI - Associations between the practice of bullying and individual and contextual variables from the aggressors' perspective. AB - OBJECTIVES: To estimate the prevalence of bullying among Brazilian students from the aggressor's perspective and to analyze its association with individual and contextual variables. METHODS: This was a cross-sectional population-based study carried out with data from the National Survey on Student Health. A total of 109,104 students attending eight grade in public and private schools were included. Data were collected through a self-applied questionnaire. A model of association between bullying and variables in the following domains was tested: sociodemographics, risk behaviors, mental health, and family context. Univariate and multivariate analyses were also performed. RESULTS: The prevalence of aggressors in bullying situations was 20.8%. The following variables remained associated in the final multivariate model: male gender (OR: 1.87; 95% CI: 1.79 1.94), lower participation of 16-year-old students (OR: 0.66; 95% CI: 0.53-0.82), and students from private schools (OR: 1.33; 95% CI: 1.27-1.39). Most aggressors reported feeling lonely (OR: 1.22; 95% CI: 1.16-1.28), insomnia episodes (OR: 1.21; 95% CI: 1.14-1.29), and a high prevalence of physical violence in the family (OR: 1.97 95% CI: 1.87-2.08). Aggressors missed classes more frequently (OR: 1.45; 95% CI: 1.40-1.51), and they regularly consumed more tobacco (OR: 1.21; 95% CI: 1.12-1.31), alcohol (OR: 1.85; 95% CI: 1.77-1.92), and illegal drugs (OR: 1.91; 95% CI: 1.79-2.04); they also demonstrated increased sexual intercourse (OR: 1.49 95% CI: 1.43-1.55) and regular exercise (OR: 1.20; 95% CI: 1.16-1.25). CONCLUSIONS: The data indicate that bullying is an important aspect that affects the learning-teaching process and the students' health. PMID- 26126700 TI - Association between electronic equipment in the bedroom and sedentary lifestyle, physical activity, and body mass index of children. AB - OBJECTIVE: To describe the association between electronic devices in the bedroom with sedentary time and physical activity, both assessed by accelerometry, in addition to body mass index in children from Sao Caetano do Sul. METHODS: The sample consisted of 441 children. The presence of electronic equipment (television, personal computer, and videogames) in the bedroom was assessed by a questionnaire. For seven consecutive days, children used an accelerometer to objectively monitor the sedentary time and moderate-to-vigorous physical activity. Body mass index was categorized as suggested by the World Health Organization. RESULTS: Overall, 73.9%, 54.2% and 42.8% of children had TV, computer, and videogames in the bedroom, respectively, and spent an average of 500.7 and 59.1 min/day of sedentary time and moderate-to-vigorous physical activity. Of the children, 45.3% were overweight/obese. Girls with a computer in the bedroom (45 min/day) performed less moderate-to-vigorous physical activity than those without it (51.4 min/day). Similar results were observed for body mass index in boys. Moderate-to-vigorous physical activity was higher and body mass index was lower in children that had no electronic equipment in the bedroom. Presence of a computer (beta=-4.798) and the combination TV+computer (beta= 3.233) were negatively associated with moderate-to-vigorous physical activity. Videogames and the combinations with two or three electronic devices were positively associated with body mass index. Sedentary time was not associated with electronic equipment. CONCLUSION: Electronic equipment in the children's bedroom can negatively affect moderate-to-vigorous physical activity and body mass index regardless of gender, school, and annual family income, which can contribute to physical inactivity and childhood obesity. PMID- 26126701 TI - Evaluation of factors associated with vertical HIV-1 transmission. AB - OBJECTIVE: To compare the prevalence and factors associated with vertical transmission of human immunodeficiency virus 1 (HIV-1) among pregnant women treated in the periods of 1998-2004 and 2005-2011 in a reference service for the care of HIV-infected patients in southern Brazil. METHODS: This was a descriptive and analytical study that used the databases of laboratories from the CD4 and STDs/AIDS Viral Load National Laboratory Network of the Brazilian Ministry of Health. HIV-1-infected pregnant women were selected after an active search for clinical information and obstetric and neonatal data from their medical records between the years of 1998 and 2011. RESULTS: 102 pregnant women were analyzed between 1998 and 2004 and 251 in the period between 2005 and 2011, totaling 353 children born to pregnant women with HIV-1. It was observed that the vertical transmission rate was 11.8% between 1998 and 2004 and 3.2% between 2005 and 2011 (p<0.001). The increased use of antiretroviral drugs (p=0.02), the decrease in viral load (p<0.001), and time of membrane rupture lower than 4h (p<0.001) were associated with the decrease of vertical transmission factors when comparing the two periods. CONCLUSION: It was observed a decrease in the rate of vertical transmission in recent years. According to the studied variables, is suggested that the risk factors for vertical transmission of HIV-1 were absence of antiretroviral therapy, high viral load in the pregnant women, and membrane rupture time >4h. PMID- 26126702 TI - Visible-Light Induced Trifluoromethylation of N-Arylcinnamamides for the Synthesis of CF3-Containing 3,4-Disubstituted Dihydroquinolinones and 1 Azaspiro[4.5]decanes. AB - The visible-light induced trifluoromethylation of N-arylcinnamamides with Togni's reagent has been explored. This method allows for an efficient and practical synthesis of a variety of CF3-containing dihydroquinolin-2(1H)-ones and 1 azasporo[4.5]decanes bearing various functional groups under mild conditions. PMID- 26126703 TI - Placental vascular indices (VI, FI and VFI) in intrauterine growth retardation (IUGR). A pooled analysis of the literature. AB - OBJECTIVE: I performed a systematic review and pooled analysis to study the utility of the placental vascular flow indices vascularization index (VI), flow index (FI) and vascularization flow index (VFI) in the prediction or identification of in-utero growth restriction (IUGR). METHOD: A comprehensive literature search for relevant studies was conducted using PubMed and Web of Knowledge databases. Included were cohort or case-control studies which reported (1) the statistical position and dispersion of vascular indices in a population of normal pregnancies at various trimesters of pregnancy; (2) correlation between vascular indices and gestational age; or (3) the vascular index values stratified according to the presence of SGA/IUGR versus a population of controls. RESULTS: Seven studies met the criteria of inclusion, for a total of 788 controls and 82 SGA cases in the first trimester, and 169 controls and 80 IUGR cases essentially enrolled in the 3rd trimester. After normalization of the means, the pooled detection rates (DRs) at a 10% false positive rate were 32.5%, 53.8% and 51.0%, respectively, for the vascular indices VI, FI and VFI in the third trimester. No significant discriminant ability was detected in the first trimester. CONCLUSION: A significant DR for IUGR was demonstrated only in the third trimester, thus limiting the utility of vascular indices to predict IUGR. VI and VFI are more reliable and yield better DR and better performance in terms of homogeneity than FI and should be evaluated in the management of third trimester IUGR and prediction of outcome. PMID- 26126704 TI - Shifts in subsistence type and its impact on the human skull's morphological integration. AB - OBJECTIVE: Here we evaluate morphological integration patterns and magnitudes in different skull regions to detect if shifts in morphological integration are correlated to the appearance of more processed (softer) diets. METHODS: To do so, three transitional populations were analyzed, including samples from groups that inhabited the same geographical region and for which the evidence shows that major changes occurred in their subsistence mode. Ninety three-dimensional landmarks were digitized on 357 skulls and used as the raw data to develop geometric morphometric analyses. The landmark coordinates were divided into several different regions of biomechanical interest, following a three-level hierarchically nested scheme: the whole skull, further subdivided into neurocranium (divided into the vault and basicranium), the facial (divided into the lower and upper facial), and the masticatory apparatus (divided into alveolar, temporal, and temporo-mandibular joint). RESULTS: Our results indicate that the morphological integration and variability patterns significantly vary across skull regions but are maintained across the transitions. The alveolar border and the lower facial are the regions manifesting greater value of morphological integration and variability, while the upper facial, the temporo mandibular joint, and the basicranium are highly integrated and poorly variable. CONCLUSIONS: The transition to softer diets increased morphological variation across cranial regions that are more exposed to masticatory strains effects. PMID- 26126705 TI - Estrogens and the control of energy homeostasis: a brain perspective. AB - Despite their prominent roles in the control of reproduction, estrogens pervade many other bodily functions. Key metabolic pathways display marked sexual differences, and estrogens are potent modulators of energy balance, as evidenced in extreme conditions of estrogen deficiency characterized by hyperphagia and decreased energy expenditure, and leading to obesity. Compelling evidence has recently demonstrated that, in addition to their peripheral effects, the actions of estrogens on energy homeostasis are exerted at central levels, to regulate almost every key aspect of metabolic homeostasis, from feeding to energy expenditure, to glucose and lipid metabolism. We review herein the state-of-the art of the role of estrogens in the regulation of energy balance, with a focus on their central effects and modes of action. PMID- 26126706 TI - Combining standard clinical methods with PCR showed improved diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies and prolonged neutropenia. AB - BACKGROUND: We assessed the diagnostic value of standard clinical methods and combined biomarker testing (galactomannan assay and polymerase chain reaction screening) in a prospective case-control study to detect invasive pulmonary aspergillosis in patients with hematological malignancies and prolonged neutropenia. METHODS: In this observational study 162 biomarker analyses were performed on samples from 27 febrile neutropenic episodes. Sera were successively screened for galactomannan antigen and for Aspergillus fumigatus specific nucleic acid targets. Furthermore thoracic computed tomography scanning was performed along with bronchoscopy with lavage when clinically indicated. Patients were retrospectively stratified to define a case-group with "proven" or "probable" invasive pulmonary aspergillosis (25.93 %) and a control-group of patients with no evidence for of invasive pulmonary aspergillosis (74.07 %). In 44.44 % of episodes fever ceased in response to antibiotic treatment (group II). Empirical antifungal therapy was administered for episodes with persistent or relapsing fever (group I). 48.15 % of patients died during the study period. Postmortem histology was pursued in 53.85 % of fatalities. RESULTS: Concordant negative galactomannan and computed tomography supported by a polymerase chain reaction assay were shown to have the highest discriminatory power to exclude invasive pulmonary aspergillosis. Bronchoalveolar lavage was performed in 6 cases of invasive pulmonary aspergillosis and in 15 controls. Although bronchoalveolar lavage proved negative in 93 % of controls it did not detect IPA in 86 % of the cases. Remarkably post mortem histology convincingly supported the presence of Aspergillus hyphae in lung tissue from a single case which had consecutive positive polymerase chain reaction assay results but was misdiagnosed by both computed tomography and consistently negative galactomannan assay results. For the galactomannan enzyme-immunoassay the diagnostic odds ratio was 15.33 and for the polymerase chain reaction assay it was 28.67. According to Cohen's kappa our in-house polymerase chain reaction method showed a fair agreement with the galactomannan immunoassay. Combined analysis of the results from the Aspergillus galactomannan enzyme immunoassay together with those generated by our polymerase chain reaction assay led to no misdiagnoses in the control group. CONCLUSION: The data from this pilot-study demonstrate that the consideration of standard clinical methods combined with biomarker testing improves the capacity to make early and more accurate diagnostic decisions. PMID- 26126707 TI - Rotation is the primary motion of paired human epidermal keratinocytes. AB - BACKGROUND: Collective motion of keratinocytes is involved in morphogenesis, homeostasis, and wound healing of the epidermis. Yet how the collective motion of keratinocytes emerges from the behavior of individual cells is still largely unknown. OBJECTIVE: The aim of this study was to find the cellular behavior that links single and collective motion of keratinocytes. METHODS: We investigated the behavior of two-cell colonies of HaCaT keratinocytes by a combination of time lapse imaging and image processing. RESULTS: The two-cell colonies of HaCaT cells were formed as a contacted pair of keratinocyte clones. Image analysis and cell culture experiments revealed that the rotational speed of two-cell colonies was positively associated with their proliferative capacity. alpha6 integrin was required for the rotational motion of two-cell keratinocyte colonies. We also confirmed that two-cell colonies of keratinocytes predominantly exhibited the rotational, but not translational, motion, two modes of motion in a contact pair of rotating objects. CONCLUSION: The rotational motion is the primary motion of two-cell keratinocyte colonies and its speed is positively associated with their proliferative capacity. This study suggests that the assembly of rotating keratinocytes generates the collective motion of proliferative keratinocytes during morphogenesis and wound healing of the epidermis. PMID- 26126708 TI - Resistance of infection by Plasmodium vivax to chloroquine in Bolivia. AB - BACKGROUND: Chloroquine (CQ) over three days plus primaquine (PQ) for seven days is the treatment of choice of infections by Plasmodium vivax in Bolivia, where 95% of the cases of malaria are attributed to this species. The aim of this study was to evaluate the therapeutic efficacy of CQ in this setting. METHODS: Patients in the Amazon region of northern Bolivia, were included in the study from May to November 2011 and the therapeutic efficacy of CQ was evaluated over a 28-day follow-up period. Patients with P. vivax mono-infection received 25 mg/Kg body weight of CQ over three days. The concentrations of CQ + desethylchloroquine (DCQ) in blood were determined at days 7 and 28 of follow up; at follow-up and on the day of treatment failure was administered PQ. RESULTS: One hundred patients fulfilled the inclusion criteria, two were lost to follow up and another two were later excluded for protocol violation. Of the 96 patients who completed the follow up 10 showed TF; one presented continued parasitaemia until day 7 of follow up, three on day 21 and six on day 28 of follow up. The geometric mean of CQ + DCQ on day 7 was 321.7 ng/ml (range 197-535 ng/ml). In six patients with TF the CQ + DCQ concentrations in blood on the day of TF were >100 ng/ml. The rate of resistance was 6.5%. CONCLUSION: The present study demonstrates the presence of resistance to CQ in the treatment of malaria by P. vivax in the Amazon region of Bolivia. New clinical trials are needed to establish alternative treatments against these parasites in this region of South America. PMID- 26126709 TI - Dietary fiber intake reduces risk of inflammatory bowel disease: result from a meta-analysis. AB - Several epidemiological investigations have been conducted to evaluate the relationship between dietary fiber intake and inflammatory bowel diseases, but the results are inconsistent. This meta-analysis was performed to quantitatively summarize the evidence from observational studies. PubMed, Embase, and Web of Knowledge were searched for relevant articles published up to November 2014. The combined relative risks were calculated with the fixed- or random-effects model. Dose-response relationship was assessed using restricted cubic spline model. We hypothesized that the meta-analysis could yield a summary effect, which would indicate that dietary fiber intake could decrease the risk of ulcerative colitis and Crohn disease (CD). Overall, 8 articles involving 2 cohort studies, 1 nested case-control study, and 5 case-control studies were finally included in this study. The pooled relative risks with 95% confidence intervals of ulcerative colitis and CD for the highest vs lowest categories of dietary fiber intake were 0.80 (0.64-1.00) and 0.44 (0.29-0.69), respectively. A linear dose-response relationship was found between dietary fiber and CD risk, and the risk of CD decreased by 13% (P < .05) for every 10 g/d increment in fiber intake. The results from this meta-analysis indicated that the intake of dietary fiber was significantly associated with a decreased risk of inflammatory bowel disease. PMID- 26126710 TI - Cross-sectional analysis of patient phone calls to an inflammatory bowel disease clinic. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) require close follow up and frequently utilize healthcare services. We aimed to identify the main reasons that prompted patient calls to gastroenterology providers and further characterize the "frequent callers". METHODS: This retrospective cross-sectional study included all phone calls registered in medical records of IBD patients during 2012. Predictive variables included demographics, psychiatric history, IBD phenotype, disease complications and medical therapies. Primary outcome was the reason for call (symptoms, medication refill, procedures and appointment issues). Secondary outcome was the frequency of changes in management prompted by the call. RESULTS: 209 patients participated in 526 calls. The mean number of calls per patient was 2.5 (range 0-27); 49 (23.4%) patients met the criterion of "frequent caller". Frequent callers made or received 75.9% of all calls. Crohn's disease, anxiety, extra-intestinal manifestations and high sedimentation rate were significantly associated with higher call volume. 85.7% of frequent callers had at least one call that prompted a therapeutic intervention, compared to 18.9% of non-frequent callers (P<0.001). The most common interventions were ordering laboratory or imaging studies (15.4%), dose adjustments (12.1%), changes in medication class (8.4%), and expediting clinic visits (8.4%). CONCLUSION: Most phone calls originated from a minority of patients. Repeated calling by the same patient and new onset of gastrointestinal (GI) and non-GI symptoms were important factors predicting the order of diagnostic modalities or therapeutic changes in care. Triaging calls to IBD healthcare providers for patients more likely to require a change in management may improve healthcare delivery. PMID- 26126711 TI - Usefulness of 1H magnetic resonance spectroscopy in human testes: preliminary study. AB - AIM: To identify and quantify the metabolites detected on proton magnetic resonance spectroscopy ((1)H-MRS) in human testes. MATERIALS AND METHODS: The institutional review board approved the study, and all patients provided informed consent. A total of 27 patients consulting the Urology Department underwent single-voxel (1)H-MRS (4000 ms repetition time [RT], 31 ms echo time [TE], 128 averages for each TE) at 1.5 T. Spectroscopy was not evaluable in one patient, and four patients had only one testis; thus, 48 testes were studied. Choline containing compounds (Cho) and methylene lipid (Lip) values were measured and the Cho/Lip ratio was calculated. Testes were classified as normal or abnormal based on conventional magnetic resonance imaging (MRI) findings. The Mann-Whitney U test was used for correlated data and bootstrapping to compare mean Cho/Lip ratios between normal and abnormal testes, and the area under the receiver operating characteristic curve (AUC) was calculated. RESULTS: Thirty testes were classified as normal and 18 as abnormal. The mean Cho/Lip ratio was 1.02+/-0.46 in normal testes and 0.45+/-0.36 in abnormal testes (Mann-Whitney U, p=0.001; bootstrapping mean difference, 0.57; 95% confidence interval (CI) 0.32-0.82; AUC=0.833). CONCLUSION: (1)H-MRS could be useful in routine clinical practice to identify the major metabolites in the testes and help discriminate between normal and abnormal testes. PMID- 26126712 TI - Does normalisation improve the diagnostic performance of apparent diffusion coefficient values for prostate cancer assessment? A blinded independent-observer evaluation. AB - AIM: To evaluate the performance of normalised apparent diffusion coefficient (ADC) values for prostate cancer assessment when performed by independent observers blinded to histopathology findings. MATERIALS AND METHODS: Fifty-eight patients undergoing 3 T phased-array coil magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI; maximal b-value 1000 s/mm(2)) before prostatectomy were included. Two radiologists independently evaluated the images, unaware of the histopathology findings. Regions of interest (ROIs) were drawn within areas showing visually low ADC within the peripheral zone (PZ) and transition zone (TZ) bilaterally. ROIs were also placed within regions in both lobes not suspicious for tumour, allowing computation of normalised ADC (nADC) ratios between suspicious and non-suspicious regions. The diagnostic performance of ADC and nADC were compared. RESULTS: For PZ tumour detection, ADC achieved significantly higher area under the receiver operating characteristic curve (AUC; p=0.026) and specificity (p=0.021) than nADC for reader 1, and significantly higher AUC (p=0.025) than nADC for reader 2. For TZ tumour detection, nADC achieved significantly higher specificity (p=0.003) and accuracy (p=0.004) than ADC for reader 2. For PZ Gleason score >3+3 tumour detection, ADC achieved significantly higher AUC (p=0.003) and specificity (p=0.005) than nADC for reader 1, and significantly higher AUC (p=0.023) than nADC for reader 2. For TZ Gleason score >3+3 tumour detection, ADC achieved significantly higher specificity (p=0.019) than nADC for reader 1. CONCLUSION: In contrast to prior studies performing unblinded evaluations, ADC was observed to outperform nADC overall for two independent observers blinded to the histopathology findings. Therefore, although strategies to improve the utility of ADC measurements in prostate cancer assessment merit continued investigation, caution is warranted when applying normalisation to improve diagnostic performance in clinical practice. PMID- 26126713 TI - Fluoroscopy-guided radiofrequency ablation for small hepatocellular carcinoma: a retrospective comparison with ultrasound-guided ablation. AB - AIM: To compare the therapeutic efficacy of fluoroscopy-guided radiofrequency ablation (F-RFA) and ultrasound-guided RFA (US-RFA) in treatment of small hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between January 2006 and January 2012, 93 patients with small HCCs underwent percutaneous RFA. In 42 patients with 46 HCCs invisible on US, F-RFA was performed following intra arterial iodised oil injection (group A). The remaining 51 patients with 58 HCCs received US-RFA (group B). Technical effectiveness, complications, local tumour progression, and patient survival were retrospectively compared between the two groups. RESULTS: Technical effectiveness was achieved in 45 HCCs of group A (97.8%) and 64 HCCs of group B (96.6%; p=0.65). There was no major complication in either group. The 1-, 3-, and 5-year local tumour progression rates were lower in group A than those of group B with marginal significance (0%, 3.7% and 3.7% in group A, and 13%, 13%, and 13% in group B; p=0.05). The 1-, 3-, and 5-year patient survival rates were 100%, 58.3%, and 51.2% (group A), and 82.4%, 54.9%, and 46.1% (group B; p=0.26). CONCLUSIONS: F-RFA is a feasible and safe treatment for small HCC invisible on US. Its therapeutic efficacy was comparable with that of US-RFA. PMID- 26126714 TI - Identification of malaria parasite-infected red blood cell surface aptamers by inertial microfluidic SELEX (I-SELEX). AB - Plasmodium falciparum malaria parasites invade and remodel human red blood cells (RBCs) by trafficking parasite-synthesized proteins to the RBC surface. While these proteins mediate interactions with host cells that contribute to disease pathogenesis, the infected RBC surface proteome remains poorly characterized. Here we use a novel strategy (I-SELEX) to discover high affinity aptamers that selectively recognize distinct epitopes uniquely present on parasite-infected RBCs. Based on inertial focusing in spiral microfluidic channels, I-SELEX enables stringent partitioning of cells (efficiency >= 10(6)) from unbound oligonucleotides at high volume throughput (~2 * 10(6) cells min(-1)). Using an RBC model displaying a single, non-native antigen and live malaria parasite infected RBCs as targets, we establish suitability of this strategy for de novo aptamer selections. We demonstrate recovery of a diverse set of aptamers that recognize distinct, surface-displayed epitopes on parasite-infected RBCs with nanomolar affinity, including an aptamer against the protein responsible for placental sequestration, var2CSA. These findings validate I-SELEX as a broadly applicable aptamer discovery platform that enables identification of new reagents for mapping the parasite-infected RBC surface proteome at higher molecular resolution to potentially contribute to malaria diagnostics, therapeutics and vaccine efforts. PMID- 26126715 TI - The kinase ABL phosphorylates the microprocessor subunit DGCR8 to stimulate primary microRNA processing in response to DNA damage. AB - The DNA damage response network stimulates microRNA (miRNA) biogenesis to coordinate repair, cell cycle checkpoints, and apoptosis. The multistep process of miRNA biogenesis involves the cleavage of primary miRNAs by the microprocessor complex composed of the ribonuclease Drosha and the RNA binding protein DGCR8. We found that the tyrosine kinase ABL phosphorylated DGCR8, a modification that was required for the induction of a subset of miRNAs after DNA damage. Focusing on the miR-34 family, ABL stimulated the production of miR-34c, but not miR-34a, through Drosha/DGCR8-dependent processing of primary miR-34c (pri-miR-34c). This miRNA-selective effect of ABL required the sequences flanking the precursor miR 34c (pre-miR-34c) stem-loop. In pri-miRNA processing, DGCR8 binds the pre-miR stem-loop and recruits Drosha to the miRNA. RNA cross-linking assays showed that DGCR8 and Drosha interacted with pri-miR-34c, but we found an inverse correlation between ABL-stimulated processing and DGCR8 association with pri-miR-34c. When coexpressed in HEK293T cells, ABL phosphorylated DGCR8 at Tyr(267). Ectopic expression of a Y267F-DGCR8 mutant reduced the recruitment of Drosha to pri-miR 34c and prevented ABL or Drosha from stimulating the processing of pri-miR-34c. In mice engineered to express a nuclear import-defective mutant of ABL, miR-34c, but not miR-34a, expression was reduced in the kidney, and apoptosis of the renal epithelial cells was impaired in response to cisplatin. These results reveal a new pathway in the DNA damage response wherein ABL-dependent tyrosine phosphorylation of DGCR8 stimulates the processing of selective primary miRNAs. PMID- 26126716 TI - WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. AB - Activation of Cl(-)-permeable gamma-aminobutyric acid type A (GABAA) receptors elicits synaptic inhibition in mature neurons but excitation in immature neurons. This developmental "switch" in the GABA function depends on a postnatal decrease in intraneuronal Cl(-) concentration mediated by KCC2, a Cl(-)-extruding K(+)-Cl( ) cotransporter. We showed that the serine-threonine kinase WNK1 [with no lysine (K)] forms a physical complex with KCC2 in the developing mouse brain. Dominant negative mutation, genetic depletion, or chemical inhibition of WNK1 in immature neurons triggered a hyperpolarizing shift in GABA activity by enhancing KCC2 mediated Cl(-) extrusion. This increase in KCC2 activity resulted from reduced inhibitory phosphorylation of KCC2 at two C-terminal threonines, Thr(906) and Thr(1007). Phosphorylation of both Thr(906) and Thr(1007) was increased in immature versus mature neurons. Together, these data provide insight into the mechanism regulating Cl(-) homeostasis in immature neurons, and suggest that WNK1 regulated changes in KCC2 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence. PMID- 26126717 TI - Simple synthetic protein scaffolds can create adjustable artificial MAPK circuits in yeast and mammalian cells. AB - As hubs for eukaryotic cell signaling, scaffold proteins are attractive targets for engineering and manipulating signaling circuits. We designed synthetic scaffolds with a repeated PDZ domain that interacted with engineered kinases of the mitogen-activated protein kinase (MAPK) cascade involved in yeast mating to investigate how modular interactions mediate kinase cascades. The synthetic scaffolds functioned as logic gates of signaling circuits. We replaced the endogenous yeast scaffold Ste5 with designer scaffolds with a variable numbers of a PDZ domain that bound kinases or phosphatases engineered with a PDZ-binding motif. Although association with the membrane was necessary for pathway activity, surprisingly, mating responses occurred when the circuit contained a scaffold with only two PDZ domains, which could only bind two of the three kinases simultaneously. Additionally, the three tiers of the MAPK pathway exhibited decreasing positional plasticity from the top [MAPK kinase kinase (MAPKKK)] to the bottom (MAPK) tier such that binding of a MAPKKK, but not a MAPK, from the osmoregulatory pathway or protein kinase C pathway to the synthetic scaffold activated a reporter of the mating response. We also showed that the output duration and intensity could be altered by recruiting phosphatases or varying the affinity of the recruited proteins for the scaffold and that a designer MAPK scaffold functioned in mammalian cells. Thus, this synthetic approach with designer scaffolds should enable the rational manipulation or engineering of signaling pathways and provide insight into the functional roles of scaffold proteins. PMID- 26126718 TI - Prescription Patterns of Antidiabetic Treatment in the Elderly. Results from Southern Italy. AB - The treatment of diabetes in the elderly is a major challenge both in terms of clinical management and of public health. Evidence about prescribing patterns in the elderly diabetic population is limited. The aim was to describe trends in antidiabetic drug (AD) utilization patterns in the elderly in Southern Italy with a focus on drugs for cardiovascular prevention and pharmaceutical costs. The data used for this study were obtained from pharmacy records of Caserta Local Health Authority, a province in Southern Italy with 1 million of inhabitants, comprising urban and rural areas. Subjects above 65 years who received at least one dispensing of antidiabetic between January 2010 and December 2014 were selected. Prevalence and incidence rates (%) of AD use were calculated for each calendar year and stratified by class therapy and age group. Sub-analyses by cardiovascular co-medication therapy and pharmaceutical cost analysis were performed. The prevalence rate decreases from 22.0% in 2010 to 17.5% in 2014 (p<0.001). Proportion of subjects treated with monotherapy increases over the study period (33.9% in 2010; 38.6% in 2014; p<0.001). In particular, increases the proportion of users of metformin (18.2% in 2010; 23.7% in 2014; p<0.001), while the proportion of users of sulfonylureas dropped (11.0% in 2010; 7.2% in 2014; p< 0.001). About 90% of elderly diabetic patients are treated with drugs for cardiovascular prevention. The per/patient/yearly drug costs were 2,349 ?: 28.5% for AD therapy and 71.5% for other treatments. Trend in drug utilization patterns showed a tendency towards treatment recommendations in older adults. PMID- 26126719 TI - Simultaneous laparoscopic management of Morgagni hernia and cholelithiasis: two case reports. AB - BACKGROUND: Morgagni hernia is a rare type of diaphragmatic hernia. Though in the past, it has been dealt with an open approach, nowadays laparoscopic management is a favored approach. However, there are few controversies in this scenario. CASE PRESENTATION: We present here two females of Aryan ethnicity, one 55 and another 45 years old, who presented with pain at upper abdomen and retrosternal chest pain; on investigations were found to have cholelithiasis along with Morgagni hernia which were managed via the laparoscopic approach in the same sitting. CONCLUSION: Repair of Morgagni hernia also via the minimally invasive technique can be offered to the patients like that for cholelithiasis. PMID- 26126721 TI - Hospital medicine viewed through practice management dictums. PMID- 26126720 TI - Effects of GnRH agonists on the expression of developmental follicular anti mullerian hormone in varying follicular stages in cyclic mice in vivo. AB - Gonadotrophin-releasing hormone (GnRH) agonists (GnRHa) have been widely used to induce a state of downregulation for in vitro fertilization, and its direct effects on the pituitary are well known. However, the effects of GnRHa on the expression of anti-mullerian hormone (AMH) by follicles in varying stages in vivo remain to be fully elucidated. In the present study 84 cyclic mice were randomly divided equally into four GnRHa groups and three cyclic mice were used as a control group. The expression levels of AMH in follicles of varying stages between days 0 and 7 following GnRHa administration were quantified using immunohistochemistry. The expression of AMH in follicles at various stages revealed dynamic changes during the process of downregulation. AMH in primary follicles initially increased and then decreased gradually. In small and large preantral follicles and in granulosa cells (GCs) surrounding the oocyte of small antral follicles, the expression of AMH began to increase on day 1, was attenuated on day 2, and then increased to a peak. The expression levels of AMH in the GCs surrounding the basement membrane, in contrast to the GCs surrounding the oocyte, were significantly lower and did not increase on day 1. In all stages of follicles, the expression of AMH declined gradually between the peak level and last day of downregulation. On day 7, the varying follicular stages all expressed lower levels of AMH than on day 0. This decrease was more prominent in the higher dose groups, compared with the lower dose groups. In conclusion, GnRHa was observed to induce time-dependent changes in the expression of AMH at varying follicular stages, which occurred in a dose-dependent manner. PMID- 26126722 TI - Temperature profiles of patient-applied eyelid warming therapies. AB - PURPOSE: To compare temperature profile characteristics (on and off eye) of two patient-applied heat therapies for meibomian gland dysfunction (MGD): an eye mask containing disposable warming units (EyeGiene((r))) and a microwave-heated flaxseed eye bag((r)) (MGDRx EyeBag((r))). METHODS: In vitro evaluation: surface temperature profiles of activated eye masks and heated eye bags((r)) (both n=10), were tracked every 10s until return to ambient temperature. Heat-transfer assessment: outer and inner eyelid temperature profiles throughout the eye mask and eye bag((r)) treatment application period (10min) were investigated in triplicate. The devices were applied for 12 different time intervals in a randomised order, with a cool-down period in between to ensure ocular temperatures returned to baseline. Temperature measurements were taken before and immediately after each application. RESULTS: In vitro evaluation: on profile, the eye bag((r)) surface temperature peaked earlier (0+/-0 s vs. 100+/-20 s, p<0.001), cooled more slowly and displayed less variability than the eye mask (all p<0.05). Heat-transfer assessment: the eye bag((r)) effected higher peak inner eyelid temperatures (38.1+/-0.4 degrees C vs. 37.4+/-0.2 degrees C, p=0.04), as well as larger inner eyelid temperature increases over the first 2 min, and between 9 and 10 min (all p<0.05). CONCLUSIONS: The eye bag((r)) surface temperature profile displayed greater uniformity and slower cooling than the eye mask, and was demonstrated to be significantly more effective in raising ocular temperatures than the eye mask, both statistically and clinically. This has implications for MGD treatment, where the melting points of meibomian secretions are likely to be higher with increasing disease severity. PMID- 26126723 TI - Firing and intrinsic properties of antennal lobe neurons in the Noctuid moth Agrotis ipsilon. AB - The antennal lobe (AL) of the Noctuid moth Agrotis ipsilon has emerged as an excellent model for studying olfactory processing and its plasticity in the central nervous system. Odor-evoked responses of AL neurons and input-to-output transformations involved in pheromone processing are well characterized in this species. However, the intrinsic electrical properties responsible of the firing of AL neurons are poorly known. To this end, patch-clamp recordings in current- and voltage-clamp mode from neurons located in the two main clusters of cell bodies in the ALs were combined with intracellular staining on A. ipsilon males. Staining indicated that the lateral cluster (LC) is composed of 85% of local neurons (LNs) and 15% of projection neurons (PNs). The medial cluster (MC) contains only PNs. Action potentials were readily recorded from the soma in LNs and PNs located in the LC but not from PNs in the MC where recordings showed small or no action potentials. In the LC, the spontaneous activity of about 20% of the LNs presented irregular bursts while being more regular in PNs. We also identified a small population of LNs lacking voltage-gated Na(+) currents and generating spikelets. We focused on the firing properties of LNs since in about 60% of LNs, but not in PNs, action potentials were followed by depolarizing afterpotentials (DAPs). These DAPs could generate a second action potential, so that the activity was composed of action potential doublets. DAPs depended on voltage, Ca(2+)-channels and possibly on Ca(2+)-activated non-specific cationic channels. During steady state current injection, DAPs occurred after each action potential and did not require high-frequency firing. The amplitude of DAPs increased when the interspike interval was small, typically within bursts, likely arising from a Ca(2+) build up. DAPs were more often found in bursting than in non-bursting LNs but do not support bursting activity. DAPs and spike doublets also occurred during odor-evoked activity suggesting that they can mediate olfactory integration in the AL. PMID- 26126724 TI - Clinical evaluation of 30 patients with localized nasal rosacea. AB - The clinical features of localized nasal rosacea have not been described in detail. This study was designed to analyze the subtypes and severity of localized nasal rosacea. Our present study included 30 patients with localized nasal rosacea. The erythematotelangiectatic subtype (13/30, 43.3%) was the most common type, followed by the phymatous subtype (9/30, 30%). The duration of rosacea was shorter and the severity of localized nasal rosacea was lower in the erythematotelangiectatic subtype cases compared with the patients with mixed or phymatous subtypes. Almost all of the papulopustular eruptions or phymatous lesions were associated with erythematotelangiectatic lesions. These findings suggest that the erythematotelangiectatic subtype may be considered the initial phase of localized nasal rosacea. PMID- 26126725 TI - Cost-effectiveness of strategies for testing current hepatitis C virus infection. AB - Six strategies for identifying hepatitis C virus (HCV) viremia, involving testing for HCV antibody (HCVAb) followed by a nucleic acid test (NAT) for HCV RNA when the antibody test is positive, are compared. Decision analysis was used to determine mean relative cost per person tested and outcomes of HCV viremia detection. Parameters included proportions of test population with HCVAb and viremia plus specificity, sensitivity, and cost of individual tests. For testing a population with an HCVAb seroprevalence of 3.25%, all strategies when adopting quantitative NAT vary little in cost (range, $29.50-$30.70) and are highly viremia specific (>=0.9997). Four of the strategies using venipuncture blood for HCVAb testing (whether laboratory conducted or employing a rapid, point-of-care assay) and for NAT (whether done by reflex or using separately drawn blood) achieve the highest viremia sensitivities (range, 0.9950-0.9954). Point-of-care HCVAb testing in fingerstick blood followed by NAT in venipuncture blood yields relatively lower viremia sensitivity (0.9301). The strategy that requires returning for NAT is even less viremia sensitive (<0.9000) because of follow-up loss. Strategies adopting qualitative rather than quantitative NAT are slightly cheaper (range, $28.90-$29.99), similarly viremia specific (>=0.9997), but less viremia sensitive (<=0.9456). Viremia sensitivity and specificity remain the same regardless of the proportion of HCVAb-seropositive persons in the cohort being tested. CONCLUSIONS: Strategies involving HCVAb testing in venipuncture blood, whether laboratory conducted or using a point-of-care assay, when followed by quantitative NAT done reflexively or in separately drawn blood, are comparably economical and suitably viremia sensitive. Less cost-effective is point-of-care HCVAb testing in fingerstick blood followed by NAT in venipuncture blood. Least cost-effective is the strategy requiring the tested person to return for NAT. PMID- 26126728 TI - Remarkable effects of solvent and substitution on the photo-dynamics of cytosine: a femtosecond broadband time-resolved fluorescence and transient absorption study. AB - Cytosine (Cyt) among all the nucleic acid bases features the most complex and least understood nonradiative deactivation, a process that is crucially important for its photostability. Herein, the excited state dynamics of Cyt and a series of its N1- and C5-derivatives, including the full set of Cyt nucleosides and nucleotides in DNA and RNA and the nucleosides of 5-methyl cytosine, 5 methylcytidine and 2'-deoxy-5-methylcytidine, have been investigated in water and in methanol employing femtosecond broadband time-resolved fluorescence coupled with fs transient absorption spectroscopy. The results reveal remarkable state specific effects of the substitution and solvent in tuning distinctively the timescales and pathways of the nonradiative decays. For Cyt and the N1 derivatives, the nonradiative deactivations occur in a common two-state process through three channels, two from the light-absorbing pipi* state with respectively the sub-picosecond (~0.2 ps) and the picosecond (~1.5 ps) time constant, and the third is due to an optically dark npi* state with the lifetime ranging from several to hundreds of picoseconds depending on solvents and substitutions. Compared to Cyt, the presence of the ribose or deoxyribose moiety at the N1 position of N1-derivatives facilitates the formation of the npi* at the sub-picosecond timescale and at the same time increases its lifetime by ~4-6 times in both water and methanol. In sharp contrast, the existence of the methyl group at the C5 position of the C5-derivatives eliminates completely the sub picosecond pipi* channel and the channel due to the npi*, but on the other hand slows down the decay of the pipi* state which after relaxation exhibits a single time constant of ~4.1 to ~7.6 ps depending on solvents. Varying the solvent from water to methanol accelerates only slightly the decay of the pipi* state in all the compounds; while for Cyt and its N1-derivatives, this change of solvent also retards strongly the npi* channel, prolongs its lifetime from such as ~7.7 ps in water to ~52 ps in methanol for Cyt and from ~30 ps in water to ~186 ps in methanol for deoxycytidine. The spectral signatures we obtained for the pipi* and the npi* states allow unambiguous evidence for clarifying uncertainties in the excited states of Cyt and the derivatives. The results provide a unifying experimental characterization at an improved level of detail about the photophysics of Cyt and its analogues under biologically relevant conditions and may help in understanding the photostability as well as photo-damages of the bases and related DNAs. PMID- 26126727 TI - Phase I study of combination of pasireotide LAR + gemcitabine in locally advanced or metastatic pancreatic cancer. AB - PURPOSE: Pasireotide LAR (SOM230 LAR) is a cyclohexapeptide engineered to bind to multiple somatostatin receptor subtypes to mimic the action of naturally occurring somatostatin with higher affinity to these receptors than octreotide and is a potent inhibitor of insulin-like growth factor-1 (IGF-1). Somatostatin receptors and IGF receptors are highly expressed in pancreatic cancer, thereby potentially making it a valuable target. This phase I study evaluated safety, tolerability and preliminary tumor response of pasireotide LAR in combination with gemcitabine in locally advanced or metastatic pancreatic cancer. METHODS: Patients with previously untreated metastatic pancreatic cancer were included. A 3 + 3 dose-escalation design was used. Patients received gemcitabine on days 1, 8 and 15 and pasireotide LAR IM monthly in a 28-day cycle. Two dose levels of pasireotide LAR were planned: 40 mg IM and 60 mg. Cohort was expanded by ten more patients at the highest tested dose to further assess the safety and efficacy. RESULTS: Twenty patients were consented on this trial, and 16 patients were evaluable for safety and efficacy. No dose-limiting toxicities were observed. Two out sixteen patients (12%) had partial response, and nine of sixteen (56%) had stable disease as best response. Median progression-free survival was 4.1 months (range 1-16 months), and median overall survival was 6.9 months (range 1-25 months). Most common grade 3 or 4 toxicities were hyperglycemia (n = 5), hyperbilirubinemia (n = 1) and thrombocytopenia (n = 2). Median baseline IGF-1 level was lower in patients with stable disease than in those with progressive disease (63 vs 71 ng/ml). CONCLUSION: Pasireotide in combination with gemcitabine was well tolerated with disease control rate of 68%. Larger trials are needed in the future to establish its efficacy in the treatment of pancreatic cancer. CLINICAL TRIAL: NCT01385956. PMID- 26126726 TI - Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma. AB - PURPOSE: Metastatic pancreatic adenocarcinoma is considered a uniformly fatal disease with a median survival of 1 year with modern chemotherapy. While a subset of patients achieve prolonged survival, few of the factors that define this group of patients are known. METHODS: For the determination of overall survival (OS), 549 patients with histologically confirmed metastatic pancreatic adenocarcinoma were evaluated. Emphasis was placed on treatment history and family history of breast, ovarian, and pancreatic cancers. To ensure a uniform metastatic population, patients treated with prior locoregional therapies (i.e., surgery or radiotherapy) were excluded as were patients with a prior history of stage I-III disease. RESULTS: Patients with family history or pedigree history of cancer had superior OS. This was especially true in patients with three or more relatives with either breast, ovarian, or pancreatic cancers [hazard ratio (HR) 0.49, 95 % confidence interval (CI) 0.30-0.80, p = 0.003]. First-line platinum chemotherapy was associated with a poor survival (hazard ratio for death 1.74, 95% CI 1.12 2.71, p = 0.01) for patients without a family history of these cancers but not for those without such a history (p = 0.31). In fact, as the number of relatives with these cancers increased, the OS survival improved for individuals receiving first-line platinum therapy (HR 0.76, 95 % CI 0.65-0.89, p = 0.0004), which was not the case for those receiving other therapies (p = 0.98). CONCLUSIONS: Treatment with platinum chemotherapy in patients with a family history of breast, ovarian, or pancreatic cancers was associated with a longer survival, whereas platinum use in patients without such a family history of cancer was associated with poor survival. These findings suggest that family history may serve as a predictive marker for platinum use in patients with metastatic pancreatic adenocarcinoma. PMID- 26126729 TI - Enhancement of Odor Sensitivity Following Repeated Odor and Visual Fear Conditioning. AB - Odor detection sensitivity can be rapidly altered by fear conditioning; whether this effect is augmented over time is not known. The present study aimed to test whether repeated conditioning sessions induce changes in odor detection threshold as well as in conditioned responses and whether olfactory stimuli evoke stronger conditioned responses than visual stimuli. The repeated conditioning group participated in repeated sessions over 2 weeks whereas the single conditioning group participated in 1 conditioning session; both groups were presented with visual and olfactory stimuli, were paired with an electric shock (CS+) and 2 matched control stimuli not paired with shock (CS-) while olfactory detection threshold and skin conductance responses (SCRs) were measured before and after the last session. We found increased sensitivity for the CS+ odor in the repeated but not in the single conditioning group, consistent with changes in olfactory sensitivity following repeated aversive learning and of a similar magnitude to what has previously been demonstrated in the periphery. SCR to the visual and olfactory CS+ were similar between groups, indicating that sensory thresholds can change without corresponding change in conditioned responses. In conclusion, repeated conditioning increases detection sensitivity and reduces conditioned responses, suggesting that segregated processes influence perception and conditioned responses. PMID- 26126730 TI - Honing in on the ATP Release Channel in Taste Cells. AB - Studies over the last 8 years have identified 3 potential channels that appear to release ATP from Type II cells in response to taste stimuli. These studies have taken different methodological approaches but have all provided data supporting their candidate channel as the ATP release channel. These potential channels include Pannexin 1, Connexins (30 and/or 43), and most recently, the Calhm1 channel. Two papers in this issue of Chemical Senses provide compelling new evidence that Pannexin 1 is not the ATP release channel. Tordoff et al. did a thorough behavioral analysis of the Pannexin1 knock out mouse and found that these animals have the same behavioral responses as wild type mice for 7 different taste stimuli that were tested. Vandenbeuch et al. presented an equally thorough analysis of the gustatory nerve responses in the Pannexin1 knock out mouse and found no differences compared with controls. Thus when the role of Pannexin 1 is analyzed at the systems level, it is not required for normal taste perception. Further studies are needed to determine the role of this hemichannel in taste cells. PMID- 26126731 TI - Hoefavidin: A dimeric bacterial avidin with a C-terminal binding tail. AB - Dimeric avidins are a newly discovered subgroup of the avidin family that bind biotin with high affinity. Their dimeric configuration is a quaternary substructure of the classical tetrameric avidins which lacks the requirement of the critical Trp that defines the tetramer and dictates the tenacious interaction with biotin. Hoefavidin, derived from the bacterium Hoeflea phototrophica DFL 43(T), is the third characterized member of the dimeric avidin subfamily. Like the other members of this group, hoefavidin is a thermostable protein that contains a disulfide bridge between Cys57 and Cys88, thereby connecting and stabilizing the L3,4 and L5,6 loops. This represents a distinctive characteristic of dimeric avidins that compensates for the lack of Trp and enables their dimeric configuration. The X-ray structure of the intact hoefavidin revealed unique crystal packing generated by an octameric cylindrical structure wherein the C termini segments of each monomer is introduced into the entrance of the biotin binding site of an adjacent non-canonical monomer. This anomaly in the protein structure served as a lead toward the design of specific binding peptides. We screened for specific hoefavidin binding peptides derived from the C-terminal region and two peptides were obtained that bind a truncated form of hoefavidin (lacking the last 10 amino acids) with dissociation constants of 10(-5)M. The crystal structure of short hoefavidin complexed with a C-terminal derived peptide revealed the mode of binding. These peptides may form the basis of novel and reversible binders for dimeric avidins. PMID- 26126733 TI - Private companies behave differently from NHS providers. PMID- 26126732 TI - Left atrial structure and functional quantitation using cardiovascular magnetic resonance and multimodality tissue tracking: validation and reproducibility assessment. AB - BACKGROUND: Left atrium (LA) strain, volume and function are important markers of cardiovascular disease and myocardial impairment. We aimed to assess the accuracy of LA biplane volume and function measured by Multimodality Tissue Tracking (MTT). Also we assessed the inter-study reproducibility for cardiovascular magnetic resonance (CMR) derived LA volume and function parameters. METHODS: Thirty subjects (mean age: 71.3 +/- 8.7, 87% male) including twenty subjects with cardiovascular events and ten healthy subjects, with CMR were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA). LA volumes were computed by the modified biplane method from 2- and 4-chamber projections and the Simpson's method from short-axis slices using both methods - manual and semi-automated delineation using MTT. LA total, active and passive ejection fractions were calculated. Pearson's correlation and Bland-Altman analysis were used to compare the measurements. In a second sample of 25 subjects (age: 65.7 +/- 7.1, 72% males) inter study, intra and inter reader reliability analysis was performed. The intra-class correlation coefficient (ICC) was evaluated. RESULTS: Left atrial MTT structural and functional parameters were not different from manual delineation, yet image analysis was only half as time consuming on average with MTT. Maximal volume MTT was not different between the Simpson's and Biplane methods, functional parameters, however were different. MTT allowed us to measure multiple LA parameters with good-excellent (ICC; 0.88- 0.98, p < 0.001) intra-and inter reader reproducibility and fair-good (ICC; 0.44-0.82, p < 0.05-0.001) inter study reproducibility. CONCLUSIONS: MTT derived LA biplane volume and function is accurate and reproducible and is suited for use in longitudinal studies. PMID- 26126734 TI - Diversity, Conflict, and Recognition in Hospital Medical Practice. AB - The hospital is a place of encounter between health care providers, patients and family members, the healthy and the suffering, migrants and non-migrants, as well as social and cultural minorities, and majorities of various backgrounds. It is also a space where multiple conceptions of care, life, quality of life, and death are enacted, sometimes inhibiting mutual understanding between caregivers and the cared for, a scenario that in turn may provoke conflict. Through the lens of conflict, we explore in this article the theme of Otherness within the clinic, basing analysis on an ethnographic study conducted in recent years in three cosmopolitan Canadian cities. Daily practices and-on a larger scale-the social space of the clinic become material here for reflecting on recognition (and non recognition) of the Other as actors in the clinical encounter. The examination of structural and situational conditions that contribute to the emergence of conflict offers an understanding of the diversity of values that pervade the clinic. By way of conclusion, we argue that recognition of diversity, at least on the part of practitioners, is a key condition for the emergence of a pluralist normativity in the social space of the clinic. PMID- 26126735 TI - Fire fit: assessing comprehensive fitness and injury risk in the fire service. AB - PURPOSE: This study sought to develop a comprehensive measure of fitness that is predictive of injury risk and can be used in the fire service to assess individual-level health and fit-for-duty status. METHODS: A retrospective occupational cohort of 799 career fire service employees was observed over the years 2005-2009. An equally weighted score for comprehensive fitness was calculated based on cardiovascular fitness, muscular strength, endurance, flexibility, and body composition. Repeated measures survival analyses were used to estimate the risk of any injury, sprain or strain, and exercise-related injuries in relation to comprehensive fitness. RESULTS: A well-distributed comprehensive fitness score was developed to distinguish three tiers of overall fitness status. Intraclass correlations identified flexibility, total grip strength, percent body fat, and resting heart rate as the most reliable fitness metrics, while push-ups, sit-ups, and aerobic capacity demonstrated poor reliability. In general, individuals with a lower comprehensive fitness status had an increased injury risk of injury as compared to the most fit individuals. The risk of any injury was 1.82 (95% CI 1.06-3.11) times as likely for the least fit individuals, as compared to individuals in the top fire fitness category, increasing to 2.90 (95% CI 1.48-5.66) when restricted to sprains and strains. CONCLUSIONS: This 5-year analysis of clinical occupational health assessments enabled the development of a relevant metric for relating comprehensive fitness with the risk of injury. Results were consistent with previous studies focused on cardiorespiratory fitness, but also less susceptible to inter-individual variability of discrete measurements. PMID- 26126737 TI - Colonoscopic diagnosis of cecal worms (Trichuris trichiura). PMID- 26126736 TI - Age at occupational exposure to combustion products and lung cancer risk among men in Stockholm, Sweden. AB - PURPOSE: Occupational exposure to combustion products rich in polycyclic aromatic hydrocarbons and particles is associated with an increased risk of lung cancer. This study aimed to evaluate whether the risk depended on the age at which the individuals were exposed. METHODS: Data from 1042 lung cancer cases and 2364 frequency-matched population controls selected from all men aged 40-75 years residing in Stockholm County, Sweden, at any time between 1985 and 1990, included detailed questionnaire information on occupational, residential, and smoking history. Occupational exposures were assessed by an occupational hygienist, and exposure to air pollution from road traffic was estimated based on dispersion models. RESULTS: We found that individuals exposed to combustion products in their twenties were at higher risk than those never exposed (adjusted OR = 1.46; 95% CI 1.02, 2.10). The association was still evident after adjusting for a number of potential confounders, including lifetime cumulative exposure and latency. No clear association was found in those exposed at older ages. CONCLUSIONS: Exposure to combustion products at a young age was associated with elevated risk of lung cancer. Exposure-reduction programs should be aware of the susceptibility of the younger employees. PMID- 26126738 TI - Trisomy 15 mosaicism: Challenges in prenatal diagnosis. PMID- 26126739 TI - Late-glacial elevated dust deposition linked to westerly wind shifts in southern South America. AB - Atmospheric dust loadings play a crucial role in the global climate system. Southern South America is a key dust source, however, dust deposition rates remain poorly quantified since the last glacial termination (~17 kyr ago), an important timeframe to anticipate future climate changes. Here we use isotope and element geochemistry in a peat archive from Tierra del Fuego, to reconstruct atmospheric dust fluxes and associated environmental and westerly wind changes for the past 16.2 kyr. Dust depositions were elevated during the Antarctic Cold Reversal (ACR) and second half of the Younger Dryas (YD) stadial, originating from the glacial Beagle Channel valley. This increase was most probably associated with a strengthening of the westerlies during both periods as dust source areas were already available before the onset of the dust peaks and remained present throughout. Congruent with glacier advances across Patagonia, this dust record indicates an overall strengthening of the wind belt during the ACR. On the other hand, we argue that the YD dust peak is linked to strong and poleward shifted westerlies. The close interplay between dust fluxes and climatic changes demonstrates that atmospheric circulation was essential in generating and sustaining present-day interglacial conditions. PMID- 26126741 TI - Distribution and isolation of strains belonging to the order Solirubrobacterales. PMID- 26126740 TI - Patterns of gene expression during Arabidopsis flower development from the time of initiation to maturation. AB - BACKGROUND: The formation of flowers is one of the main model systems to elucidate the molecular mechanisms that control developmental processes in plants. Although several studies have explored gene expression during flower development in the model plant Arabidopsis thaliana on a genome-wide scale, a continuous series of expression data from the earliest floral stages until maturation has been lacking. Here, we used a floral induction system to close this information gap and to generate a reference dataset for stage-specific gene expression during flower formation. RESULTS: Using a floral induction system, we collected floral buds at 14 different stages from the time of initiation until maturation. Using whole-genome microarray analysis, we identified 7,405 genes that exhibit rapid expression changes during flower development. These genes comprise many known floral regulators and we found that the expression profiles for these regulators match their known expression patterns, thus validating the dataset. We analyzed groups of co-expressed genes for over-represented cellular and developmental functions through Gene Ontology analysis and found that they could be assigned specific patterns of activities, which are in agreement with the progression of flower development. Furthermore, by mapping binding sites of floral organ identity factors onto our dataset, we were able to identify gene groups that are likely predominantly under control of these transcriptional regulators. We further found that the distribution of paralogs among groups of co expressed genes varies considerably, with genes expressed predominantly at early and intermediate stages of flower development showing the highest proportion of such genes. CONCLUSIONS: Our results highlight and describe the dynamic expression changes undergone by a large number of genes during flower development. They further provide a comprehensive reference dataset for temporal gene expression during flower formation and we demonstrate that it can be used to integrate data from other genomics approaches such as genome-wide localization studies of transcription factor binding sites. PMID- 26126742 TI - Genome-based analysis of type-I polyketide synthase and nonribosomal peptide synthetase gene clusters in a novel strain taxonomically close to the genus Salinispora. PMID- 26126743 TI - An overproduction of astellolides induced by genetic disruption of chromatin remodeling factors in Aspergillus oryzae. AB - The filamentous fungus Aspergillus oryzae is an important industrial mold. Recent genomic analysis indicated that A. oryzae has a large number of biosynthetic genes for secondary metabolites (SMs), but many of the SMs they produce have not been identified. For better understanding of SMs production by A. oryzae, we screened a gene-disruption library of transcription factors including chromatin remodeling factors and found two gene disruptions that show similarly altered SM production profiles. One is a homolog of Aspergillus nidulans cclA, a component of the histone 3 lysine 4 (H3K4) methyltransferase complex of proteins associated with Set1 complex, and the other, sppA, is an ortholog of Saccharomyces cerevisiae SPP1, another component of a complex of proteins associated with Set1 complex. The cclA and sppA disruptions in A. oryzae are deficient in trimethylation of H3K4. Furthermore, one of the SMs that increased in the cclA disruptant was identified as astellolide F (14-deacetyl astellolide B). These data indicate that both cclA and sppA affect production of SMs including astellolides by affecting the methylation status of H3K4 in A. oryzae. PMID- 26126744 TI - Cytosine-type nucleosides from marine-derived Streptomyces rochei 06CM016. AB - Rocheicoside A (3), a nucleoside analog possessing a novel 5-(hydroxymethyl)-5 methylimidazolidin-4-one substructure, was isolated from marine-derived actinomycete Streptomyces rochei 06CM016, together with a new (4) and three known compounds. Structures of the new metabolites were elucidated by one-dimensional ((1)H and (13)C) and 2D NMR (COSY, HMQC and HMBC) and HR-TOF-MS analyses. All the metabolites exhibited significant antimicrobial activity. A plausible mechanism was proposed for compound 3's formation from amicetin. PMID- 26126745 TI - Self-assembled 2D WSe2 thin films for photoelectrochemical hydrogen production. AB - WSe2--a layered semiconductor that can be exfoliated into atomically thin two dimensional sheets--offers promising characteristics for application in solar energy conversion. However, the lack of controllable, cost-effective methods to scalably fabricate homogeneous thin films currently limits practical application. Here we present a technique to prepare controlled thin films of 2D WSe2 from dispersions of solvent-exfoliated few-layer flakes. Flake self-assembly at a liquid/liquid interface (formed exceptionally from two non-solvents for WSe2) followed by substrate transfer affords large-area thin films with superior 2D flake alignment compared with traditional (liquid/air) self-assembly techniques. We further demonstrate, for the first time, solar-to-hydrogen conversion from solution-processed WSe2 thin films. Bare photoelectrodes with a thickness of ca. 25 nm exhibit sustained p-type photocurrent under simulated solar illumination, and up to 1.0 mA cm(-2) at 0 V versus reversible hydrogen electrode with an added water reduction catalyst (Pt). The importance of the self-assembled morphology is established by photoelectrochemical and conductivity measurements. PMID- 26126746 TI - Estimating sleep from multisensory armband measurements: validity and reliability in teens. AB - Given the recognition that sleep may influence obesity risk, there is increasing interest in measuring sleep parameters within obesity studies. The goal of the current analyses was to determine whether the SenseWear((r)) Pro3 Armband (armband), typically used to assess physical activity, is reliable at assessing sleep parameters. The armband was compared with the AMI Motionlogger((r)) (actigraph), a validated activity monitor for sleep assessment, and with polysomnography, the gold standard for assessing sleep. Participants were 20 adolescents (mean age = 15.5 years) with a mean body mass index percentile of 63.7. All participants wore the armband and actigraph on their non-dominant arm while in-lab during a nocturnal polysomnographic recording (600 min). Epoch-by epoch sleep/wake data and concordance of sleep parameters were examined. No significant sleep parameter differences were found between the armband and polysomnography; the actigraph tended to overestimate sleep and underestimate wake compared with polysomnography. Both devices showed high sleep sensitivity, but lower wake detection rates. Bland-Altman plots showed large individual differences in armband sleep parameter concordance rates. The armband did well estimating sleep overall, with group results more similar to polysomnography than the actigraph; however, the armband was less accurate at an individual level than the actigraph. PMID- 26126748 TI - Two worlds: Adolescents' strategies for managing life with a parent in hospice. AB - OBJECTIVE: This study aimed to generate an explanatory model of the coping strategies that adolescents employ to manage the stressors they experience in the final months of their ill parent's life and shortly after their death. METHOD: The sample included 26 families of adolescents with a parent receiving care in a large hospice program in northeastern Ohio. A semistructured interview was conducted with 14 ill parents, 17 well parents/guardians, and 30 of their adolescent children before the parent's death and, additionally, with 6 of these families after the death. The interviews were audiotaped, transcribed verbatim, and analyzed using a grounded-theory approach. RESULTS: The participants described two worlds that constituted the lives of the adolescents: the well world of normal adolescence and the ill world of having a parent near the end of life. The adolescents experienced a common challenge of living in two worlds and responded to the challenge with a process we labeled "managing two worlds." Five stages through which adolescents manage their worlds were identified: keeping the ill world and the well world separate; having the ill world intrude into the well world; moving between the ill world and the well world; being immersed in the ill world; and returning to the well world having been changed by the ill world. SIGNIFICANCE OF RESULTS: The explanatory model of "managing two worlds" outlines a complex and nuanced process that changes over time. The model can be used by health professionals who seek to help adolescents navigate this critical time when their parents are dying or have recently died. These results can also be used to inform the development of interventions that assist families with strategies tailored to an adolescent's specific needs. Future research should investigate associations among the process of "managing two worlds" and outcomes related to adolescent bereavement. PMID- 26126753 TI - Development and validation of an in-house quantitative analysis method for cylindrospermopsin using hydrophilic interaction liquid chromatography-tandem mass spectrometry: Quantification demonstrated in 4 aquatic organisms. AB - The cyanobacterial toxin cylindrospermopsin (CYN) is of great concern in aquatic environments because of its incidence, multiple toxicity endpoints, and, therefore, the severity of health implications. It may bioaccumulate in aquatic food webs, resulting in high exposure concentrations to higher-order trophic levels, particularly humans. Because of accumulation at primary levels resulting from exposure to trace amounts of toxin, a sensitive analytical technique with proven aquatic applications is required. In the present study, a hydrophilic interaction liquid chromatographic-tandem mass spectrometric method with a lower limit of detection of 200 fg on column (signal-to-noise ratio = 3, n = 9) and a lower limit of quantification of 1 pg on column (signal-to-noise ratio = 11, n = 9) with demonstrated application in 4 aquatic organisms is described. The analytical method was optimized and validated with a linear range (r(2) = 0.999) from 0.1 ng mL(-1) to 100 ng mL(-1) CYN. Mean recovery of the extraction method was 98 +/- 2%. Application of the method was demonstrated by quantifying CYN uptake in Scenedesmus subspicatus (green algae), Egeria densa (Brazilian waterweed), Daphnia magna (water flea), and Lumbriculus variegatus (blackworm) after 24 h of static exposure to 50 MUg L(-1) CYN. Uptake ranged from 0.05% to 0.11% of the nominal CYN exposure amount. This constitutes a sensitive and reproducible method for extraction and quantification of unconjugated CYN with demonstrated application in 4 aquatic organisms, which can be used in further aquatic toxicological investigations. PMID- 26126755 TI - Incorporation of imidazole within the metal-organic framework UiO-67 for enhanced anhydrous proton conductivity. AB - Imidazole was introduced into the channels of the metal-organic framework UiO-67 using an evaporation method. The imidazole@UiO-67 composite presents a high proton conductivity of 1.44 * 10(-3) S cm(-1) at 120 degrees C under anhydrous conditions. With a low activation energy at high temperatures (0.36 eV), the hybrid material can be regarded as a superionic conductor. PMID- 26126749 TI - Treatment for Sleep Problems in Children with Autism and Caregiver Spillover Effects. AB - Sleep problems in children with autism spectrum disorders (ASD) are under recognized and under-treated. Identifying treatment value accounting for health effects on family members (spillovers) could improve the perceived cost effectiveness of interventions to improve child sleep habits. A prospective cohort study (N = 224) was conducted with registry and postal survey data completed by the primary caregiver. We calculated quality of life outcomes for the child and the primary caregiver associated with treatments to improve sleep in the child based on prior clinical trials. Predicted treatment effects for melatonin and behavioral interventions were similar in magnitude for the child and for the caregiver. Accounting for caregiver spillover effects associated with treatments for the child with ASD increases treatment benefits and improves cost effectiveness profiles. PMID- 26126757 TI - Trials on physical activity for smoking cessation in pregnancy missed a trick or two. PMID- 26126756 TI - Blood transfusion and 30-day readmission rate in adult patients hospitalized with sickle cell disease crisis. AB - BACKGROUND: Sickle cell disease (SCD) patients hospitalized with vasoocclusive pain crisis tend to have prolonged length of stay (LOS) and high 30-day readmission rates. We investigated the associations of demographic characteristics, comorbidities, and blood transfusion during hospitalization with these outcomes. STUDY DESIGN AND METHODS: Repeated regression analysis was used to analyze 39,324 admissions of 4348 adults with sickle cell crisis from 2007 to 2012 in the Truven Health MarketScan Medicaid Databases. RESULTS: The mean (95% range) LOS was 5.9 (1.0-19.0) days and the 30-day readmission rate was 39.6% (95% confidence interval [CI], 39.1%-40.0%). Older age; chronic cardiopulmonary, renal, or liver disease; and sepsis were associated with both longer LOS and greater 30-day readmission rate. Female sex, iron overload, acute chest syndrome, acute renal failure, and stroke were additional predictors of longer LOS. Simple red blood cell transfusion was administered in 31.8% of the admissions, and these patients tended to have more severe disease (chronic cardiopulmonary or kidney disease, acute chest syndrome, acute kidney or liver failure, sepsis). Nevertheless, transfusion was associated with a reduced estimated odds ratio (OR) of inpatient mortality of 0.75 (95% CI, 0.57-0.99) and a decreased OR of 30-day readmission of 0.78 (95% CI, 0.73-0.83). CONCLUSION: Our findings point to blood transfusion as a potential means to reduce the 30-day readmission rate among Medicaid patients hospitalized with sickle cell crisis. There is a need for a prospective study to examine the potential benefit and safety of simple blood transfusion for this purpose. PMID- 26126758 TI - Improving gene regulatory network inference using network topology information. AB - Inferring the gene regulatory network (GRN) structure from data is an important problem in computational biology. However, it is a computationally complex problem and approximate methods such as heuristic search techniques, restriction of the maximum-number-of-parents (maxP) for a gene, or an optimal search under special conditions are required. The limitations of a heuristic search are well known but literature on the detailed analysis of the widely used maxP technique is lacking. The optimal search methods require large computational time. We report the theoretical analysis and experimental results of the strengths and limitations of the maxP technique. Further, using an optimal search method, we combine the strengths of the maxP technique and the known GRN topology to propose two novel algorithms. These algorithms are implemented in a Bayesian network framework and tested on biological, realistic, and in silico networks of different sizes and topologies. They overcome the limitations of the maxP technique and show superior computational speed when compared to the current optimal search algorithms. PMID- 26126759 TI - Cranberry capsules (2 taken twice daily for an average 38 days) reduce the risk of postoperative urinary tract infection in women undergoing benign gynaecological surgery involving intraoperative catheterisation. PMID- 26126760 TI - Long term impact of screening for type 2 diabetes mellitus - a commentary on new evidence. PMID- 26126761 TI - Editorial: standard neuropsychological assessments in neurosurgery. PMID- 26126762 TI - Sphenoid sinus aspergilloma in trans-sphenoidal surgery for pituitary adenomas. AB - BACKGROUND: Simultaneous appearance of sphenoid sinus aspergilloma and pituitary adenoma is a very rare finding. METHODS: Retrospective analysis of patients with sellar and sphenoid sinus mass lesions who underwent trans-sphenoidal surgery was performed. Demographic data, medical history, predisposing factors, clinical picture, neurological status and radiological findings were reviewed. All patients underwent a trans-sphenoidal microsurgical treatment, and acquired specimens underwent both histopathological and microbiological analysis. RESULTS: Sphenoid sinus aspergilloma was encountered in seven patients. Three patients had an isolated sphenoid sinus aspergilloma and four patients with pituitary macroadenoma had a sphenoid aspergilloma as an incidental finding. CONCLUSIONS: Sphenoid sinus aspergilloma can be found during trans-sphenoidal surgery for pituitary adenomas. Sphenoid sinus extirpation followed by adenomectomy is the treatment of choice unless invasive aspergilloma is encountered requiring additional antifungal therapy. PMID- 26126763 TI - Meningioangiomatosis of the cerebellum: radiopathologic characteristics of a case. PMID- 26126764 TI - The dependence of age on ulnar nerve conductive study parameter adaptation after compressive ulnar neuropathy operations in the elbow. AB - BACKGROUND: According to some studies, peripheral nerve injury healing is prolonged in elderly patients. Compressive ulnar neuropathy in the elbow (UNE) is the second most common compressive mononeuropathy. To our knowledge, no study has investigated the effect of age on the postoperative ulnar nerve injury repair rate. Our aim was to evaluate age-related differences in the electrophysiological parameters before and approximately 100 days after operations for cubital tunnel syndrome. METHODS: This retrospective study included 103 patients who underwent in situ ulnar nerve decompressions in the elbow. The included patients suffered from paraesthesia and hypoesthesia in their ulnar nerve distribution, hypertrophy, and weakening of the hand muscles, which were innervated by the ulnar nerve. Concurrently, these patients met the EGM diagnostic criteria for UNE. The age dependency on the differences between the preoperative and postoperative parameter values that were measured during the conductive studies was estimated using a regression analysis. RESULTS: A statistically significant deceleration of the monitored parameter adaptation, which included segmental conduction velocity in the elbow area and CMAP amplitude during the above-elbow stimulation of the ulnar nerve, was found. CONCLUSIONS: Ulnar nerve injury repair in the cubital tunnel area after a UNE operation proceeds significantly slower in elderly patients. PMID- 26126765 TI - Letter to the editor of Acta Neurochirurgica: case of an isolated intracranial juvenile xanthogranuloma in a 34-year-old man. PMID- 26126766 TI - Three dimensional multi-cellular muscle-like tissue engineering in perfusion based bioreactors. AB - Conventional tissue engineering strategies often rely on the use of a single progenitor cell source to engineer in vitro biological models; however, multi cellular environments can better resemble the complexity of native tissues. Previous described co-culture models used skeletal myoblasts, as parenchymal cell source, and mesenchymal or endothelial cells, as stromal component. Here, we propose instead the use of adipose tissue-derived stromal vascular fraction cells, which include both mesenchymal and endothelial cells, to better resemble the native stroma. Percentage of serum supplementation is one of the crucial parameters to steer skeletal myoblasts toward either proliferation (20%) or differentiation (5%) in two-dimensional culture conditions. On the contrary, three-dimensional (3D) skeletal myoblast culture often simply adopts the serum content used in monolayer, without taking into account the new cell environment. When considering 3D cultures of mm-thick engineered tissues, homogeneous and sufficient oxygen supply is paramount to avoid formation of necrotic cores. Perfusion-based bioreactor culture can significantly improve the oxygen access to the cells, enhancing the viability and the contractility of the engineered tissues. In this study, we first investigated the influence of different serum supplementations on the skeletal myoblast ability to proliferate and differentiate during 3D perfusion-based culture. We tested percentages of serum promoting monolayer skeletal myoblast-proliferation (20%) and differentiation (5%) and suitable for stromal cell culture (10%) with a view to identify the most suitable condition for the subsequent co-culture. The 10% serum medium composition resulted in the highest number of mature myotubes and construct functionality. Co-culture with stromal vascular fraction cells at 10% serum also supported the skeletal myoblast differentiation and maturation, hence providing a functional engineered 3D muscle model that resembles the native multi-cellular environment. PMID- 26126767 TI - Carbocatalysis: the state of "metal-free" catalysis. AB - The rise in global demand for crucial chemical compounds has driven immense research in the fundamental science of catalysis. Graphene and its derivatives (chemically modified graphene, CMGs) have recently emerged as a new class of heterogeneous catalyst that promises economically viable and greener routes to these compounds. Although CMGs possess unique catalytic properties, the actual active sites are often points of discussion. Current minimal understanding on the possible effects of metallic impurities on the electrocatalytic performances of these CMGs calls forth the need to raise awareness on possible metallic impurities misrepresenting the actual chemical catalytic performances of the CMGs. This Minireview highlights the latest advances in the application of CMGs as catalysts, with an emphasis on the possible effects of metallic impurities on CMG catalysis. PMID- 26126768 TI - The elegance of energy balance: Insight from circuit-level manipulations. AB - Mechanisms of energy balance were first examined using very powerful neuroscience techniques such as lesions and electrical stimulation. This early work identified the hypothalamus as a key structure involved in hunger and feeding; however, neural resolution of cell-defined populations contributing to appetite regulation remained elusive. Recent innovations in neuroscience have produced constructs that allow for a high degree of specificity in loss- and gain-of-function manipulations in molecularly circumscribed neural subsets as well as monosynaptic circuit mapping and in vivo neurophysiology. These complimentary techniques have provided researchers an unprecedented amount of empirical agility. As a result, cell populations in two subregions of the hypothalamus have emerged as key players in the physiological control of feeding behavior. The arcuate nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus contain neural populations that have a direct role in the promotion of hunger and satiety. These include neurons that express agouti-related peptide, pro opiomelanocortin, single-minded homolog 1 protein, and the melanocortin-4 receptor. This review focuses on how these neural subsets communicate with one another, link up to build elaborate networks, and ultimately contribute to alterations in food intake. The continuing advancement of neuroscience tools, as well as a multimodal integration of findings, will be critical in illuminating an exhaustive and clinically relevant hunger circuit. PMID- 26126769 TI - Distinguishing Ophiopogon and Liriope tubers based on DNA sequences. AB - Ophiopogon japonicus is a herbaceous perennial plant in Liliaceae, and its tubers are used in traditional Japanese medicine as Bakumondo, prescribed for treating cough, sputum, and thirst. Liriope is a genus of ornamental plants related to Ophiopogon, and its tubers are used in folk medicine as well. Although tubers from both genera are traded in Korean and Chinese markets, only O. japonicus is defined as the plant of origin for Bakumondo in the Japanese Pharmacopoeia [1], and Liriope tubers cannot legally be used as Bakumondo in Japan. Ophiopogon plants can be distinguished clearly from Liriope by their fruit color and by the morphological characteristics of their flowers. However, the tubers of both species are greatly similar, making it very difficult to differentiate the two genera by the appearance of their tubers. We, therefore, investigated the most appropriate DNA regions to use for practical and accurate identification of Ophiopogon and Liriope tubers. The sequence of the gene for the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (rbcL) was found to be suitable for discriminating Ophiopogon and Liriope tubers. The identification procedure was simplified using restriction enzyme digestion of the amplified rbcL fragment. The detection limit for Liriope contamination was estimated by performing the procedure using mixed samples of powdered Ophiopogon and Liriope tubers. PMID- 26126770 TI - New norditerpenoid alkaloids from Aconitum vilmorinianum Komarov. AB - Aconitum vilmorinianum Komarov is a local medicinal plant used in many well-known clinical preparations to treat rheumatism and pains in Yunnan Province, China. Phytochemical examination of the roots of A. vilmorinianum led to the isolation of three novel imine-type norditerpenoid alkaloids named vilmorrianines E-G (1 3), and a new natural alkaloid N-desethyl-N-formyl-8-O-methyltalatisamine (4), together with 14 known alkaloids. Their structures were elucidated on the basis of spectroscopic evidence. Vilmorrianine E is the first known norditerpenoid alkaloid containing both an imine group and a three-membered ring formed by C8, C9, and C10. PMID- 26126771 TI - Oxomollugin, a potential inhibitor of lipopolysaccharide-induced nitric oxide production including nuclear factor kappa B signals. AB - Mollugin, a naphthoquinone derivative, was reported to possess various biological activities such as anti-inflammatory and anti-tumor activity. Mollugin isolated from Rubia tinctorum roots inhibited lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 macrophages. However, mollugin synthesized for further investigation of its anti-inflammatory mechanism showed weak activity in addition to unstable assay results. From the result of analysis on a degradation product of mollugin, oxomollugin was found to be the main active substance of mollugin degradation, showing a potent inhibitory activity on NO-production including nuclear factor kappa B signals. PMID- 26126772 TI - Proton transport in barium stannate: classical, semi-classical and quantum regimes. AB - Density-functional theory calculations are performed to investigate proton transport in BaSnO3. Structural optimizations in the stable and saddle point configurations for transfer (hopping) and reorientation allow description of the high-temperature classical and semi-classical regimes, in which diffusion occurs by over-barrier motion. At lower temperature (typically below 300 K), we describe the thermally-assisted quantum regime, in which protonic motion is of quantum nature and occurs in "coincidence" configurations favored by thermal fluctuations of the surrounding atoms. Both the non-adiabatic and the adiabatic limits are examined. In the adiabatic limit, the protonic energy landscape in the coincidence configuration is very flat. Path-integral molecular dynamics simulations of the proton in the coincidence potential reveal, in the transfer case, that the density of probability of H(+) has its maximum at the saddle point, because the zero-point energy exceeds the coincidence barrier. Arguments are given that support the adiabatic picture for the transfer mechanism. In the case of reorientation, the time scales for the existence of the coincidence and for protonic motion, as estimated from the time-energy uncertainty principle by using a simple one-dimensional model, are of the same order of magnitude, suggesting that the adiabatic limit is not reached. Protonic transfer and reorientation in this oxide are therefore governed by different mechanisms below room temperature. PMID- 26126774 TI - Outcome of mixed nut biscuit challenges in low-risk patients who are on tree nut exclusion diet. PMID- 26126776 TI - A Bayesian approach to mitigation of publication bias. AB - The reliability of published research findings in psychology has been a topic of rising concern. Publication bias, or treating positive findings differently from negative findings, is a contributing factor to this "crisis of confidence," in that it likely inflates the number of false-positive effects in the literature. We demonstrate a Bayesian model averaging approach that takes into account the possibility of publication bias and allows for a better estimate of true underlying effect size. Accounting for the possibility of bias leads to a more conservative interpretation of published studies as well as meta-analyses. We provide mathematical details of the method and examples. PMID- 26126777 TI - A novel microdeletion affecting the CETP gene raises HDL-associated cholesterol levels. AB - We describe a novel, inherited 16q13 microdeletion that removes cholesteryl ester transfer protein (CETP) and several nearby genes. The proband was originally referred for severe childhood-onset obesity and moderate developmental delay, but his fasting lipid profile revealed relatively high levels of high density lipoprotein cholesterol (HDL-C) and relatively low levels of low density lipoprotein cholesterol (LDL-C) for age, despite his obesity. Testing of first degree relatives identified two other microdeletion carriers. Functional assays in affected individuals showed decreased CETP mRNA expression and enzymatic activity. This microdeletion may or may not be pathogenic for obesity and developmental delay, but based on the lipid profile, the functional studies, and the phenotype of other patients with loss-of-function mutations of CETP, we believe this microdeletion to be antipathogenic for cardiovascular disease. PMID- 26126778 TI - Treating Hypertension in Pregnancy. AB - Hypertension is present in about 10 % of all pregnancies. The frequency of chronic hypertension and that of gestational hypertension is increasing. The management of pregnant women with hypertension remains a significant, but controversial, public health problem. Although treatment of hypertension in pregnancy has shown to reduce maternal target organ damage, considerable debate remains concerning treatment. We review current evidence regarding treatment goals, the ideal treatment starting time, and which drugs are available for the treatment of hypertension in pregnancy. PMID- 26126779 TI - Cerebrovascular Dysfunction in Preeclamptic Pregnancies. AB - Preeclampsia is a hypertensive, multisystem disorder of pregnancy that affects several organ systems, including the maternal brain. Cerebrovascular dysfunction during preeclampsia can lead to cerebral edema, seizures, stroke, and potentially maternal mortality. This review will discuss the effects of preeclampsia on the cerebrovasculature that may adversely affect the maternal brain, including cerebral blood flow (CBF) autoregulation and blood-brain barrier disruption and the resultant clinical outcomes including posterior reversible encephalopathy syndrome (PRES) and maternal stroke. Potential long-term cognitive outcomes of preeclampsia and the role of the cerebrovasculature are also reviewed. PMID- 26126780 TI - Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential. AB - Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e.g. cardiotrophin 1, galectin-3, NADPH oxidases, and neutrophil gelatinase-associated lipocalin), microRNA-induced alterations of collagen gene expression, and matricellular protein- and lysyl oxidase-mediated alterations of collagen cross-linking and deposition. PMID- 26126781 TI - Hydrodynamic interactions of deformable polymeric nanocarriers and the effect of crosslinking. AB - We report theoretical as well as numerical investigations of deformable nanocarriers (NCs) under physiologically relevant flow conditions. Specifically, to model the deformable lysozyme-core/dextran-shell crosslinked polymer based NC with internal nanostructure and subject it to external hydrodynamic shear, we have introduced a coarse-grained model for the NC and have adopted a Brownian dynamics framework, which incorporates hydrodynamic interactions, in order to describe the static and dynamic properties of the NC. In order to represent the fluidity of the polymer network in the dextran brush-like corona, we coarse-grain the structure of the NC based on the hypothesis that Brownian motion, polymer melt reptations, and crosslinking density dominate their structure and dynamics. In our model, we specify a crosslinking density and employ the simulated annealing protocol to mimic the experimental synthesis steps in order to obtain the appropriate internal structure of the core-shell polymer. We then compute the equilibrium as well as steady shear rheological properties as functions of the Peclet number and the crosslinking density, in the presence of hydrodynamic interactions. We find that with increasing crosslinking, the stiffness of the nanocarrier increases, the radius of gyration decreases, and as a consequence the self-diffusivity increases. The nanocarrier under shear deforms and orients along the direction of the applied shear and we find that the orientation and deformation under shear are dependent on the shear rate and the crosslinking density. We compare various dynamic properties of the NC as a function of the shear force, such as orientation, deformation, intrinsic stresses etc., with previously reported computational and experimental results of other model systems. The computational approach described here serves as a powerful tool for the rational design of NCs by taking both the physiological as well as the hydrodynamic environments into consideration. Development of such models is essential in order to gain useful insights that may be translated into the optimal design of NCs for diagnostic as well as targeted drug delivery applications. PMID- 26126782 TI - Satellite lymphovascular space invasion: An independent risk factor in early stage cervical cancer. AB - OBJECTIVE: This study was performed to determine whether satellite LVSI in women with early stage cervical carcinoma is an independent prognostic factor for recurrence and survival. METHODS: A total of 210 eligible patients with FIGO stages IA2 and IB1 cervical carcinoma, who underwent radical hysterectomy or radical trachelectomy with pelvic lymphadenectomy between January 2000 and December 2012, were included. Variables studied included age, histology type, differentiation grade, tumor size (TS), depth of invasion (DI), lymph node metastasis (LNM), conjoined lymphovascular space invasion (LVSI) and satellite LVSI. Univariate and multivariate analyses were performed to define variables that best predict recurrence and survival. RESULTS: Univariate analysis showed that differentiation grade, depth of invasion, tumor size, lymph node metastasis, and both conjoined LVSI and satellite LVSI were significantly associated with recurrence and survival. Using multivariate analysis, differentiation grade (HR 3.63, 95%-CI 1.51-8.72), conjoined LVSI (HR 5.95, 95%-CI 1.57-22.53) and satellite LVSI (HR 7.45, 95%-CI 3.03-18.27) were independent prognostic factors for recurrence; LNM (HR 5.55, 95%-CI 1.52-20.26) and satellite LVSI (HR 8.94, 95% CI 2.43-32.95) were prognostic factors for overall survival. For patients with low-risk cervical cancer without LNM only satellite LVSI correlated significantly with disease-free and overall survival. CONCLUSION: Differentiation grade, DI, TS, LNM, and conjoined LVSI as well as satellite LVSI were prognostic factors for DFS and OS. Satellite LVSI is the most important factor predicting DFS and OS in early stage cervical cancer, especially when lymph nodes are negative. PMID- 26126784 TI - Predictors of lung cancer among former asbestos-exposed workers. AB - OBJECTIVES: Despite extensive literature concerning the risk of lung cancer incidence among asbestos workers there is still lack of data specifying the association between the level of exposure and the frequency of cancer occurrence. The aim of the analysis was to assess the influence of smoking and selected factors related to occupational exposure on the risk of the incidence of lung cancer among the workers who were exposed to asbestos dust in the past. MATERIAL AND METHODS: The assessment was performed based on the case-control studies carried out within a cohort including 7,374 former workers of asbestos processing plants, examined over the years 2000-2013. Analysis of the material was based on the calculation of the odds ratio (OR) using conditional logistic regression modeling, adjusted for cigarette smoking, cumulative exposure, branch and time since last exposure. RESULTS: During the survey period there were 165 cases of lung cancer. Among the individuals who smoked, the relative risk of lung cancer incidence was twice as high in the persons smoking more than 20 pack-years (OR=2.23; 95% CI: 1.45-3.46) than it was in the case of the non-smokers. Analysis revealed that the risk of lung cancer in the group with the highest exposure was two times higher in comparison with the low cumulative asbestos exposure (OR=1.99; 95% CI: 1.22-3.25). The risk continued to increase until 30 years after cessation of asbestos exposure and started to decline many years after the last exposure. Influence of the mentioned above characteristics is particularly visible for tumors located in the lower parts of the lungs. CONCLUSION: Our findings confirm the strong evidence that the lung cancer risk is associated with asbestos exposure and it increases along with the increasing exposure. A strategy of smoking cessation among the individuals exposed to asbestos dust would potentially have health promoting effects. PMID- 26126783 TI - Primary central chondrosarcoma of long bone, limb girdle and trunk: Analysis of 174 cases by numerical scoring on histology. AB - The aims of this study were: (i) to elucidate clinicopathological characteristics of pcCHS of long bones (L), limb girdles (LG) and trunk (T) in Japan; (ii) to investigate predictive pathological findings for outcome of pcCHS of L, LG and T, objectively; and (iii) to elucidate a discrepancy of grade between biopsy and resected specimens. Clinicopathological profiles of 174 pcCHS (79 male, 95 female), of L, LG, and T were retrieved. For each case, a numerical score was given to 18 pathological findings. The average age was 50.5 years (15-80 years). Frequently involved sites were femur, humerus, pelvis and rib. The 5-year and 10 year disease-specific survival (DSS) rates [follow-up: 1-258 months (average 65.5)] were 87.0% and 80.4%, respectively. By Cox hazards analysis on pathological findings, age, sex and location, histologically higher grade and older age were unfavorable predictors, and calcification was a favorable predictor in DSS. The histological grade of resected specimen was higher than that of biopsy in 37.7% (26/69 cases). In conclusion, higher histological grade and older age were predictors for poor, but calcification was for good prognosis. Because there was a discrepancy in grade between biopsy and resected specimens, comprehensive evaluation is necessary before definitive operation for pcCHS. PMID- 26126785 TI - Identification through DNA barcoding of Tabanidae (Diptera) vectors of surra disease in India. AB - Horse flies and deer flies are common names applied to members of the family Tabanidae (Diptera). Tabanid flies are pestiferous and of veterinary and medical importance, with about 244 species in India. They are major vectors of Trypanosoma evansi that causes trypanosomiasis (surra disease). Lack of stable morphological characters, and scarcity of taxonomic expertise, is major impediments for accurate species identification of these important pest and disease vectors. Molecular data, especially DNA barcode data, has been widely used in the identification of Diptera of economic importance. We evaluated the utility of DNA barcode data to discriminate the vectors of surra disease (trypanosomiasis) from India. We used barcode gap and reciprocal monophyly (neighbor-joining and Bayesian tree) criteria to analyze barcode data. A total of 46 specimens belonging to 7 species under four genera in two subfamilies were used for this study. DNA barcode data was not available previously for these species. Analysis revealed that all morphologically identifiable species can be discriminated using DNA barcoding data. Further, our study clearly demonstrated the presence of cryptic species in Chrysops dispar. Moreover, we revealed that closely related species without stable taxonomic distinguishing characters in the "Tabanus striatus species complex" can be discriminated using DNA barcode data. PMID- 26126788 TI - Modular Synthesis of Pyrazolones Using an Alkene Aminocarbonylation Reaction. AB - A variety of pyrazolones were synthesized from enol ethers and hydrazones using a reaction sequence involving aminocarbonylation of enol ethers followed by nucleophile-induced aromatization of the azomethine imines intermediates. Using bases to catalyze the in situ formation of imino isocyanates allowed alkene aminocarbonylation to proceed under milder conditions with reactive substrates and enabled aminocarbonylation reactions of sensitive enol ethers. Aromatization of the azomethine imines could be induced by reduction using NaBH4, or by addition of NH2OH to afford the parent (beta)N-H products. PMID- 26126786 TI - GATA-dependent transcriptional and epigenetic control of cardiac lineage specification and differentiation. AB - Heart progenitor cells differentiate into various cell types including pacemaker and working cardiomyocytes. Cell-type specific gene expression is achieved by combinatorial interactions between tissue-specific transcription factors (TFs), co-factors, and chromatin remodelers and DNA binding elements in regulatory regions. Dysfunction of these transcriptional networks may result in congenital heart defects. Functional analysis of the regulatory DNA sequences has contributed substantially to the identification of the transcriptional network components and combinatorial interactions regulating the tissue-specific gene programs. GATA TFs have been identified as central players in these networks. In particular, GATA binding elements have emerged as a platform to recruit broadly active histone modification enzymes and cell-type-specific co-factors to drive cell-type-specific gene programs. Here, we discuss the role of GATA factors in cell fate decisions and differentiation in the developing heart. PMID- 26126787 TI - Mesenchymal-epithelial interactions during digestive tract development and epithelial stem cell regeneration. AB - The gastrointestinal tract develops from a simple and uniform tube into a complex organ with specific differentiation patterns along the anterior-posterior and dorso-ventral axes of asymmetry. It is derived from all three germ layers and their cross-talk is important for the regulated development of fetal and adult gastrointestinal structures and organs. Signals from the adjacent mesoderm are essential for the morphogenesis of the overlying epithelium. These mesenchymal epithelial interactions govern the development and regionalization of the different gastrointestinal epithelia and involve most of the key morphogens and signaling pathways, such as the Hedgehog, BMPs, Notch, WNT, HOX, SOX and FOXF cascades. Moreover, the mechanisms underlying mesenchyme differentiation into smooth muscle cells influence the regionalization of the gastrointestinal epithelium through interactions with the enteric nervous system. In the neonatal and adult gastrointestinal tract, mesenchymal-epithelial interactions are essential for the maintenance of the epithelial regionalization and digestive epithelial homeostasis. Disruption of these interactions is also associated with bowel dysfunction potentially leading to epithelial tumor development. In this review, we will discuss various aspects of the mesenchymal-epithelial interactions observed during digestive epithelium development and differentiation and also during epithelial stem cell regeneration. PMID- 26126789 TI - Biological activity of sophorolipids and their possible use as antiviral agents. AB - Sophorolipids are surface active glycolipids consisting of a hydrophilic sophorose unit and a hydrophobic portion composed of a fatty acid tail. Crude sophorolipid sample contains both acidic and lactonic forms of sophorolipid with different degrees of acetylation and varying lengths of the fatty acid chains depending on the substrates used in the production process. Carboxylic end in the acidic form of the fatty acid is free, whereas in the lactonic form, it is internally esterified. Sophorolipids show different physicochemical properties with wide range of applications for each structural compound. Lactonic form of sophorolipids shows surface tension reducing ability and biological activity, whereas the acidic form possesses better foam forming ability and higher solubility. Presence of acetyl groups gives hydrophilic nature to the sophorolipids which promotes its antiviral and cytokine-stimulating properties. The aim of this review is to explore and suggest the plausibility of sophorolipids as therapeutic and prophylactic agents for the treatment of viral diseases. PMID- 26126790 TI - Patterns of gene expression in the sheep heart during the perinatal period revealed by transcriptomic modeling. AB - Septa from sheep hearts at 130 days gestation, term, and 14-day-old lambs were used to model the changes in gene expression patterns during the perinatal period using Agilent 15k ovine microarrays. We used Bioconductor for R to model five major patterns of coexpressed genes. Gene ontology and transcription factor analyses using Webgestalt modeled the biological significances and transcription factors of the gene expression patterns. Modeling indicated a decreased expression of genes associated with anatomical development and differentiation during this period, whereas those associated with increased protein synthesis and growth associated with maturation of the endoplasmic reticulum rose to term but did not further increase from the near term expression. Expression of genes associated with cell responsiveness, for example, immune responses, decreased at term but expression returned by postnatal day 14. Changes in genes related to metabolism showed differential substrate-associated patterns: those related to carbohydrate metabolism rose to term and remained stable thereafter, whereas those associated with fatty acid oxidation facility rose throughout the period. The timing of many of these maturational processes was earlier in relation to birth than in the rodent. The importance of the transcription factors, estrogen related receptors, and v-myc avian myelocytomatosis viral oncogene homolog was also highlighted in the pattern of gene expression during development of the perinatal sheep heart. PMID- 26126791 TI - MicroRNA network changes in the brain stem underlie the development of hypertension. AB - Hypertension is a major chronic disease whose molecular mechanisms remain poorly understood. We compared neuroanatomical patterns of microRNAs in the brain stem of the spontaneous hypertensive rat (SHR) to the Wistar Kyoto rat (WKY, control). We quantified 419 well-annotated microRNAs in the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM), from SHR and WKY rats, during three main stages of hypertension development. Changes in microRNA expression were stage- and region-dependent, with a majority of SHR vs. WKY differential expression occurring at the hypertension onset stage in NTS versus at the prehypertension stage in RVLM. Our analysis identified 24 microRNAs showing time dependent differential expression in SHR compared with WKY in at least one brain region. We predicted potential gene regulatory targets corresponding to catecholaminergic processes, neuroinflammation, and neuromodulation using the miRWALK and RNA22 databases, and we tested those bioinformatics predictions using high-throughput quantitative PCR to evaluate correlations of differential expression between the microRNAs and their predicted gene targets. We found a novel regulatory network motif consisting of microRNAs likely downregulating a negative regulator of prohypertensive processes such as angiotensin II signaling and leukotriene-based inflammation. Our results provide new evidence on the dynamics of microRNA expression in the development of hypertension and predictions of microRNA-mediated regulatory networks playing a region-dependent role in potentially altering brain-stem cardiovascular control circuit function leading to the development of hypertension. PMID- 26126792 TI - Significance of transcytosis in Alzheimer's disease: BACE1 takes the scenic route to axons. AB - Neurons have developed elaborate mechanisms for sorting of proteins to their destination in dendrites and axons as well as dynamic local trafficking. Recent evidence suggests that polarized axonal sorting of beta-site converting enzyme 1 (BACE1), a type I transmembrane aspartyl protease involved in Alzheimer's disease (AD) pathogenesis, entails an unusual journey. In hippocampal neurons, BACE1 internalized from dendrites is conveyed in recycling endosomes via unidirectional retrograde transport towards the soma and sorted to axons where BACE1 becomes enriched. In comparison to other transmembrane proteins that undergo transcytosis or elimination in somatodendritic compartment, vectorial transport of internalized BACE1 in dendrites is unique and intriguing. Dysfunction of protein transport contributes to pathogenesis of AD and other neurodegenerative diseases. Therefore, characterization of BACE1 transcytosis is an important addition to the multiple lines of evidence that highlight the crucial role played by endosomal trafficking pathway as well as axonal sorting mechanisms in AD pathogenesis. PMID- 26126794 TI - Vascular access modifies the protective effect of obesity on survival in hemodialysis patients. AB - BACKGROUND: The protective effect of obesity on the survival of patients undergoing hemodialysis (HD) for end-stage renal disease (ESRD), described as the obesity paradox, has been established previously. Survival benefits also have been ascribed to permanent modes of HD access (fistula/graft) compared with catheter at first HD. The purpose of this study is to evaluate the impact of incident HD access type on the obesity paradox. METHODS: A retrospective study of all patients with ESRD in the US Renal Database System who initiated HD between 2006 and 2010 was carried out. Multivariate logistic, Cox regression, and propensity score matched analyses were used to evaluate the association between body mass index (BMI), modes of HD access (fistula/graft vs catheter), and mortality. RESULTS: There were 501,920 dialysis initiates studied; 83% via catheter, 14% via fistula, and 3% via grafts. Mortality was lesser for patients initiating hemodialysis with permanent forms of access compared with catheter (adjusted odds ratio 0.68, 95% confidence interval 0.67-0.69, P < .001). High body mass index (BMI) was associated with lower mortality. Patients with high BMI were more likely to initiate hemodialysis via permanent modes of access compared with patients with normal BMI. CONCLUSION: The highly popularized protective effect of increased BMI on survival in HD patients is significantly influenced by the method of hemodialysis access. There is greater use of permanent access among patients with high BMI compared with patients with normal BMI. There remains a critical need to increase permanent access utilization at incident hemodialysis so as to improve survival irrespective of BMI status. PMID- 26126793 TI - Physical growth of the shuar: Height, Weight, and BMI references for an indigenous amazonian population. AB - OBJECTIVES: Information concerning physical growth among small-scale populations remains limited, yet such data are critical to local health efforts and to foster basic understandings of human life history and variation in childhood development. Using a large dataset and robust modeling methods, this study aims to describe growth from birth to adulthood among the indigenous Shuar of Amazonian Ecuador. METHODS: Mixed-longitudinal measures of height, weight, and body mass index (BMI) were collected from Shuar participants (n = 2,463; age: 0 29 years). Centile growth curves and tables were created for each anthropometric variable of interest using Generalized Additive Models for Location, Scale, and Shape (GAMLSS). Pseudo-velocity and Lambda-Mu-Sigma curves were generated to further investigate Shuar patterns of growth and to facilitate comparison with United States Center for Disease Control and Prevention and multinational World Health Organization growth references. RESULTS: The Shuar are small throughout life and exhibit complex patterns of growth that differ substantially from those of international references. Similar to other Amazonians, Shuar growth in weight compares more favorably to references than growth in height, resulting in BMI curves that approximate international medians. Several additional characteristics of Shuar development are noteworthy, including large observed variation in body size early in life, significant infant growth faltering, extended male growth into adulthood, and a markedly early female pubertal growth spurt in height. Phenotypic plasticity and genetic selection in response to local environmental factors may explain many of these patterns. CONCLUSIONS: Providing a detailed reference of growth for the Shuar and other Amazonian populations, this study possesses direct clinical application and affords valuable insight into childhood health and the ecology of human growth. PMID- 26126795 TI - Treatment and outcomes of adults with remnant intrapancreatic choledochal cysts. AB - BACKGROUND: The purpose of this study is to report our experience with the treatment of remnant intrapancreatic choledochal cysts (CCs) in adults. METHODS: We reviewed retrospectively the records of patients with intrapancreatic remnant CCs who underwent reoperation by our surgical team from January 2000 to December 2012. Postoperative complications, surgical outcomes, and rate of malignancy were noted. RESULTS: A total of 41 patients were included: 35 without malignant transformation after the primary operation and 6 with malignant transformation. After the primary operation, all patients experienced cholangitis, and more than one-half had cholangiolithiasis (66%), pancreatitis (51%), and vomiting (51%). The mean age of the 35 patients (9 males and 26 females) was 49 years (range, 27 69), and the majority had originally a Todani type I cyst (74%). Most patients (74%) had undergone previously subtotal extrahepatic cyst excision and Roux-en-Y hepaticochojejunostomy. After excision of the remnant cyst, the rate of an excellent or good outcome was obtained in 91% of patients. The mean age of the patients with malignant transformation was 51 years (range, 35-70), and the rate of malignancy was 15% (6/41). The average time between the original incomplete CC excision and the diagnosis of malignancy was 140 months (range, 52-265). Four patients underwent pancreatoduodenectomy, and 2 underwent palliative surgery because the lesions were invading adjacent tissues. Five patients died of their disease within 37 months after reoperation. CONCLUSION: Complications seem to be common after incomplete resection of a CC with remnant intrapancreatic CCs, and the malignancy rate is relatively high. To improve outcomes, all attempts at complete resection of the intrapancreatic portion of CCs should be made at the time of the primary operation. PMID- 26126796 TI - Concurrent validity and reliability of a novel wireless inertial measurement system to assess trunk movement. AB - INTRODUCTION: Assessment of movement dysfunctions commonly comprises trunk range of motion (ROM), movement or control impairment (MCI), repetitive movements (RM), and reposition error (RE). Inertial measurement unit (IMU)-systems could be used to quantify these movement dysfunctions in clinical settings. The aim of this study was to evaluate a novel IMU-system when assessing movement dysfunctions in terms of concurrent validity and reliability. METHODS: The concurrent validity of the IMU-system was tested against an optoelectronic system with 22 participants. The reliability of 14 movement dysfunction tests were analysed using generalizability theory and coefficient of variation, measuring 24 participants in seven trials on two days. RESULTS: The IMU-system provided valid estimates of trunk movement in the primary movement direction when compared to the optoelectronic system. Reliability varied across tests and variables. On average, ROM and RM were more reliable, compared to MCI and RE tests. DISCUSSION: When compared to the optoelectronic system, the IMU-system is valid for estimates of trunk movement in the primary movement direction. Four ROM, two MCI, one RM, and one RE test were identified as reliable and should be studied further for inter subject comparisons and monitoring changes after an intervention. PMID- 26126797 TI - Interruption of mgrB in the mediation of colistin resistance in Klebsiella oxytoca. PMID- 26126798 TI - A review of antibiotic therapy for pelvic inflammatory disease. AB - Pelvic inflammatory disease (PID) is a gynaecological inflammatory disorder with a high incidence that can lead to sequelae such as infertility, ectopic pregnancy and chronic pelvic pain. The International Union against Sexually Transmitted Infections (IUSTI) and the US Centers for Disease Control and Prevention (CDC) have issued treatment recommendations for the management of PID. The purpose of this review is to summarise the available evidence for the use of IUSTI- and CDC recommended antibiotic therapies for PID. The main differences between recommendations concern alternative regimens for inpatient treatment and the use of oral moxifloxacin as an alternative outpatient regimen in the IUSTI guidelines. There is evidence supporting the use of the recommended antibiotic regimens, although with some variation in reported cure rates. This variation can be explained, in part, by the different diagnostic and evaluation criteria used in different trials. Adverse events that require discontinuation of antibiotic therapy are rarely observed. The main limitation of the current available evidence is the short-term follow-up, which does not allow full evaluation of the risks of long-term sequelae. PMID- 26126799 TI - Endoscopic and histological features of mycophenolate mofetil colitis in patients after solid organ transplantation. AB - BACKGROUND: Mycophenolate mofetil (MMF) is an immunosuppressive agent commonly used after organ transplantation. Gastrointestinal side effects occur in approximately 45% of patients. The spectrum of histologic features associated with MMF colitis has been well described, but data on the endoscopic features is lacking. The aim of the study was to describe the endoscopic features of MMF colitis in solid organ transplant recipients (SOTRs) as well as the frequency of histologic features and identify associated risk factors. METHODS: A retrospective review of all SOTRs taking MMF and who underwent colonoscopy between 2000 and 2010 was performed. 36 cases of MMF colitis were identified and 361 patients served as controls. Descriptive statistics and data analysis looking for associated risk factors were performed. RESULTS: Among SOTRs taking MMF who underwent colonoscopy, MMF colitis was diagnosed in 9%. Endoscopic findings ranged from erythema (33%) to erosions/ulcers (19%). 47% of patients had a normal colonoscopy and everyone had rectal sparing. Histological findings included acute colitis-like findings (50%), inflammatory bowel disease-like characteristics (36%), ischemia-like findings (5.6%), and graft-versus-host disease-like features (8.3%). Diarrhea occurred in 83%. Kidney transplantation was associated with a higher risk of MMF colitis (OR 5.8 [2.86-11.86], P<0.0001) whereas liver transplantation was associated with a lower risk (OR 0.06 [0.03-0.16], P<0.0001). CONCLUSION: MMF colitis is fairly prevalent in SOTRs taking MMF who undergo colonoscopy. Diarrhea is the most common reason for colonoscopy referral (83%) and up to 47% of patients have normal colonoscopy, suggesting the need for routine biopsies to help confirm the diagnosis. PMID- 26126800 TI - Wideband phase locking to modulated whisker vibration point to a temporal code for texture in the rat's barrel cortex. AB - Rats probe objects with their whiskers and make decisions about sizes, shapes, textures and distances within a few tens of milliseconds. This perceptual analysis requires the processing of tactile high-frequency object components reflecting surface roughness. We have shown that neurons in the barrel cortex of rats encode high-frequency sinusoidal vibrations of whiskers for sustained periods when presented with constant amplitudes and frequencies. In a natural situation, however, stimulus parameters change rapidly when whiskers are brushing across objects. In this study, we therefore analysed cortical responses to vibratory movements of single whiskers with rapidly changing amplitudes and frequencies. The results show that different neural codes are employed for a processing of stimulus parameters. The frequency of whisker vibration is encoded by the temporal pattern of spike discharges, i.e., the phase-locked responses of barrel cortex neurons. In addition, oscillatory gamma band activity was induced during high-frequency stimulation. The pivotal descriptor of the amplitude of whisker displacement, the velocity, is reflected in the rate of spike discharges. While phase-locked discharges occurred over the entire range of frequencies tested (10-600 Hz), the discharge rate increased with stimulus velocity only up to about 60 um/ms, saturating at a mean rate of ~117 spikes/s. In addition, the results show that whisker movements of more than 500 Hz bandwidth may be encoded by phase-locked responses of small groups of cortical neurons. Thus, even single whiskers may transmit information about wide ranges of textural components owing to their set of different types of hair follicle mechanoreceptors. PMID- 26126801 TI - Grasping an object comfortably: orientation information is held in memory. AB - It has been shown that memorized information can influence real-time visuomotor control. For instance, a previously seen object (prime) influences grasping movements toward a target object. In this study, we examined how general the priming effect is: does it depend on the orientation of the target object and the similarity between the prime and the target? To do so, we examined whether priming effects occured for different orientations of the prime and the target objects and for primes that were either identical to the target object or only half of the target object. We found that for orientations of the target object that did not require an awkward grasp, the orientation of the prime could influence the initiation time and the final grip orientation. The priming effects on initiation time were only found when the whole target object was presented as prime, but not when only half of the target object was presented. The results suggest that a memory effect on real-time control is constrained by end-state comfort and by the relevance of the prime for the grasping movement, which might mean that the interactions between the ventral and dorsal pathways are task specific. PMID- 26126802 TI - When locomotion is used to interact with the environment: investigation of the link between emotions and the twofold goal-directed locomotion in humans. AB - Walking as a means to interact with the environment has a twofold goal: body displacement (intermediate goal) and the future action on the environment (final representational goal). This involves different processes that plan, program, and control goal-directed locomotion linked to motivation as an "emotional state," which leads to achieving this twofold goal. The aim of the present study was to determine whether emotional valence associated with the final representational goal influences these processes or whether they depend more on the emotional valence associated with the intermediate goal in young adults. Twenty subjects, aged 18-35 years, were instructed to erase an emotional picture that appeared on a wall as soon as they saw it. They had to press a stop button located 5 m in front of them with their right hand. Their gait was analyzed using a force platform and the Vicon system. The main results suggest that the emotional valence of the intermediate goal has the greatest effect on the processes that organize and modulate goal-directed locomotion. A positive valence facilitates cognitive processes involved in the temporal organization of locomotion. A negative valence disturbs the cognitive processes involved in the spatial organization of the locomotion and online motor control, leading to a deviating trajectory and a final body position that is more distant from the stop button. These results are discussed in line with the motivational direction hypothesis and with the affective meaning of the intended response goal. PMID- 26126803 TI - The effect of synesthetic associations between the visual and auditory modalities on the Colavita effect. AB - The Colavita effect refers to the phenomenon that when confronted with an audiovisual stimulus, observers report more often to have perceived the visual than the auditory component. The Colavita effect depends on low-level stimulus factors such as spatial and temporal proximity between the unimodal signals. Here, we examined whether the Colavita effect is modulated by synesthetic congruency between visual size and auditory pitch. If the Colavita effect depends on synesthetic congruency, we expect a larger Colavita effect for synesthetically congruent size/pitch (large visual stimulus/low-pitched tone; small visual stimulus/high-pitched tone) than synesthetically incongruent (large visual stimulus/high-pitched tone; small visual stimulus/low-pitched tone) combinations. Participants had to identify stimulus type (visual, auditory or audiovisual). The study replicated the Colavita effect because participants reported more often the visual than auditory component of the audiovisual stimuli. Synesthetic congruency had, however, no effect on the magnitude of the Colavita effect. EEG recordings to congruent and incongruent audiovisual pairings showed a late frontal congruency effect at 400-550 ms and an occipitoparietal effect at 690-800 ms with neural sources in the anterior cingulate and premotor cortex for the 400- to 550 ms window and premotor cortex, inferior parietal lobule and the posterior middle temporal gyrus for the 690- to 800-ms window. The electrophysiological data show that synesthetic congruency was probably detected in a processing stage subsequent to the Colavita effect. We conclude that-in a modality detection task the Colavita effect can be modulated by low-level structural factors but not by higher-order associations between auditory and visual inputs. PMID- 26126804 TI - Interaction in planning movement direction for articulatory gestures and manual actions. AB - Some theories concerning speech mechanisms assume that overlapping representations are involved in programming certain articulatory gestures and hand actions. The present study investigated whether planning of movement direction for articulatory gestures and manual actions could interact. The participants were presented with written vowels (Experiment 1) or syllables (Experiment 2) that were associated with forward or backward movement of tongue (e.g., [i] vs. [alpha] or [te] vs. [ke], respectively). They were required to pronounce the speech unit and simultaneously move the joystick forward or backward according to the color of the stimulus. Manual and vocal responses were performed relatively rapidly when the articulation and the hand action required movement into the same direction. The study suggests that planning horizontal tongue movements for articulation shares overlapping neural mechanisms with planning horizontal movement direction of hand actions. PMID- 26126805 TI - Haptic over visual information in the distribution of visual attention after tool use in near and far space. AB - Despite attentional prioritization for grasping space near the hands, tool-use appears to transfer attentional bias to the tool's end/functional part. The contributions of haptic and visual inputs to attentional distribution along a tool were investigated as a function of tool-use in near (Experiment 1) and far (Experiment 2) space. Visual attention was assessed with a 50/50, go/no-go, target discrimination task, while a tool was held next to targets appearing near the tool-occupied hand or tool-end. Target response times (RTs) and sensitivity (d-prime) were measured at target locations, before and after functional tool practice for three conditions: (1) open-tool: tool-end visible (visual + haptic inputs), (2) hidden-tool: tool-end visually obscured (haptic input only), and (3) short-tool: stick missing tool's length/end (control condition: hand occupied but no visual/haptic input). In near space, both open- and hidden-tool groups showed a tool-end, attentional bias (faster RTs toward tool-end) before practice; after practice, RTs near the hand improved. In far space, the open-tool group showed no bias before practice; after practice, target RTs near the tool-end improved. However, the hidden-tool group showed a consistent tool-end bias despite practice. Lack of short-tool group results suggested that hidden-tool group results were specific to haptic inputs. In conclusion, (1) allocation of visual attention along a tool due to tool practice differs in near and far space, and (2) visual attention is drawn toward the tool's end even when visually obscured, suggesting haptic input provides sufficient information for directing attention along the tool. PMID- 26126806 TI - mTOR inhibitor versus mycophenolic acid as the primary immunosuppression regime combined with calcineurin inhibitor for kidney transplant recipients: a meta analysis. AB - BACKGROUND: A number of studies have provided information regarding the risks and benefits of mammalian target of rapamycin inhibitors (mTOR-I) combined with calcineurin inhibitors (CNI) versus mycophenolic acid (MPA). METHODS: Medline, Embase and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials comparing mTOR-I to MPA as the primary immunosuppressive regimen in combination with CNI were selected and meta analyzed. RESULTS: Eleven randomized controlled trials consisting of 4930 patients in total were included. No significant difference was observed in the risk of biopsy-proven acute rejection and patient death between the two groups. However, an increased risk of graft loss (relative risk (RR) = 1.20) and inferior graft function (creatinine clearance, weighted mean difference (WMD) = -2.41 MUmol/L) were demonstrated in mTOR-I-treated patients. Patients treated with mTOR I had a higher risk of new-onset diabetes mellitus (RR = 1.32), dyslipidemia, proteinuria (RR = 1.79), peripheral edema (RR = 1.34), thrombocytopenia (RR = 1.97) and lymphocoele (RR = 1.80), but a lower risk of cytomegalovirus infection (RR = 0.40), malignancy (RR = 0.64) and leucopenia (RR = 0.43). There was no difference in diarrhea, anemia, urinary tract infection, polyoma virus infection and impaired wound healing when mTOR-I was compared with MPA. CONCLUSIONS: mTOR-I showed no particular superiority to MPA. Notably, mTOR-I had an increased risk of graft loss when combined with CNI, even when combined with a reduced dose of CNI. Therefore, the optimal dosage strategies for mTOR-I and CNI need to be further explored. PMID- 26126807 TI - Analysis of short-term heart rate and diastolic period variability using a refined fuzzy entropy method. AB - BACKGROUND: Heart rate variability (HRV) has been widely used in the non-invasive evaluation of cardiovascular function. Recent studies have also attached great importance to the cardiac diastolic period variability (DPV) examination. Short term variability measurement (e.g., 5 min) has drawn increasing attention in clinical practice, since it is able to provide almost immediate measurement results and enables the real-time monitoring of cardiovascular function. However, it is still a contemporary challenge to robustly estimate the HRV and DPV parameters based on short-term recordings. METHODS: In this study, a refined fuzzy entropy (rFuzzyEn) was developed by substituting a piecewise fuzzy membership function for the Gaussian function in conventional fuzzy entropy (FuzzyEn) measure. Its stability and robustness against additive noise compared with sample entropy (SampEn) and FuzzyEn, were examined by two well-accepted simulation models-the [Formula: see text] noise and the Logistic attractor. The rFuzzyEn was further applied to evaluate clinical short-term (5 min) HRV and DPV of the patients with coronary artery stenosis and healthy volunteers. RESULTS: Simulation results showed smaller fluctuations in the rFuzzyEn than in SampEn and FuzzyEn values when the data length was decreasing. Besides, rFuzzyEn could distinguish the simulation models with different amount of additive noise even when the percentage of additive noise reached 60%, but neither SampEn nor FuzzyEn showed comparable performance. Clinical HRV analysis did not indicate any significant differences between the patients with coronary artery disease and the healthy volunteers in all the three mentioned entropy measures (all p > 0.20). But clinical DPV analysis showed that the patient group had a significantly higher rFuzzyEn (p < 0.01) than the healthy group. However, no or less significant difference was observed between the two groups in either SampEn (p = 0.14) or FuzzyEn (p = 0.05). CONCLUSIONS: Our proposed rFuzzyEn outperformed conventional SampEn and FuzzyEn in terms of both stability and robustness against additive noise, particularly when the data set was relatively short. Analysis of DPV using rFuzzyEn may provide more valuable information to assess the cardiovascular states than the other entropy measures and has a potential for clinical application. PMID- 26126809 TI - Tropical Doctor. Editorial. PMID- 26126808 TI - Low-bias phosphopeptide enrichment from scarce samples using plastic antibodies. AB - Phosphospecific enrichment techniques and mass spectrometry (MS) are essential tools for comprehending the cellular phosphoproteome. Here, we report a fast and simple approach for low sequence-bias phosphoserine (pS) peptide capture and enrichment that is compatible with low biological or clinical sample input. The approach exploits molecularly imprinted polymers (MIPs, "plastic antibodies") featuring tight neutral binding sites for pS or pY that are capable of cross reacting with phosphopeptides of protein proteolytic digests. The versatility of the resulting method was demonstrated with small samples of whole-cell lysate from human embryonic kidney (HEK) 293T cells, human neuroblastoma SH-SY5Y cells, mouse brain or human cerebrospinal fluid (CSF). Following pre-fractionation of trypsinized proteins by strong cation exchange (SCX) chromatography, pS-MIP enrichment led to the identification of 924 phosphopeptides in the HEK 293T whole cell lysate, exceeding the number identified by TiO2-based enrichment (230). Moreover, the phosphopeptides were extracted with low sequence bias and showed no evidence for the characteristic preference of TiO2 for acidic amino acids (aspartic and glutamic acid). Applying the method to human CSF led to the discovery of 47 phosphopeptides belonging to 24 proteins and revealed three previously unknown phosphorylation sites. PMID- 26126810 TI - Arginase inhibition protects against hypoxia-induced pulmonary arterial hypertension. AB - The present study aimed to determine the role of arginase (Arg) in pulmonary arterial hypertension (PAH). In vitro, human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions with, or without, the Arg inhibitor, S-(2-boronoethyl)-l-cysteine (BEC), for 48 h, following which the proliferation of the HPASMCs was determined using MTT and cell counting assays. For the in vivo investigation, 30 male rats were randomly divided into the following three groups (n=10 per group): i) control group, ii) PAH group and iii) BEC group, in which the right ventricle systolic pressure (RVSP) of the rats was assessed. The levels of cyclin D1, cyclin-dependent kinase (CDK)4 and p27 were measured in vitro and in vivo. The phosphorylation levels of Akt and extracellular-related kinase (ERK) were also measured in HPASMCs. In vitro, compared with the hypoxia group, Arg inhibition reduced HPASMC proliferation and reduced the expression levels of cyclin D1, CDK4, phosphorylated (p-)Akt and p ERK. By contrast, Arg inhibition increased the expression of p27. In vivo, compared with the control group, the expression levels of cyclin D1 and CDK4 were reduced in the PAH group, however, the expression of p27 and the RVSP increased. In the BEC group, the opposite effects were observed. Therefore, it was suggested that Arg inhibition may reduce the RVSP of PAH rats and reduce HPASMC proliferation by decreasing the expression levels of cyclin D1 and CDK4, increasing the expression of p27, and partly reducing the phosphorylation of Akt and ERK. PMID- 26126811 TI - The Lamarckian chicken and the Darwinian egg. AB - "Which came first, the Chicken or the Egg?" We suggest this question is not a paradox. The Modern Synthesis envisions speciation through genetic changes in germ cells via random mutations, an "Egg first" scenario, but perhaps epigenetic inheritance mechanisms can transmit adaptive changes initiated in the soma ("Chicken first"). PMID- 26126812 TI - Understanding predictors of prolonged hospitalizations among general medicine patients: A guide and preliminary analysis. AB - Targeting patients with prolonged hospitalizations may represent an effective strategy for reducing average hospital length of stay (LOS). We sought to characterize predictors of prolonged hospitalizations among general medicine patients to guide future improvement efforts. We conducted a retrospective cohort study using administrative data of general medicine patients discharged from inpatient status from our academic medical center between 2012 and 2014. Multivariable logistic regression was performed to assess the association between sociodemographic and clinical variables with prolonged LOS, defined as >21 days. Of 18,363 discharges, 416 (2.3%) demonstrated prolonged LOS. Prolonged hospitalizations accounted for 18.6% of total inpatient days and contributed 0.8 days to an average LOS of 4.8 days during the study period. Prolonged hospitalizations were associated with younger age (odds ratio [OR]: 0.80 per 10 year increase in age, 95% confidence interval [CI]: 0.73-0.87) and Medicaid insurance (OR: 1.99, 95% CI: 1.29-3.05, REF = Medicare). Compared to patients without prolonged LOS, prolonged LOS patients were more likely to have methicillin-resistant Staphylococcus aureus septicemia (OR: 8.83, 95% CI: 1.72 45.36); require a palliative care consult (OR: 4.63, 95% CI: 2.86-7.49), ICU stay (OR: 6.66, 95% CI: 5.22-8.50), or surgery (OR: 5.04, 95% CI: 3.90-6.52); and be discharged to a post-acute-care facility (OR: 10.37, 95% CI: 6.92-15.56). Prolonged hospitalizations in a small proportion of patients were an important contributor to overall LOS and particularly affected Medicaid enrollees with complex hospital stays who were not discharged home. Further studies are needed to determine the reasons for discharge delays in this population. PMID- 26126813 TI - The history of sentinel node biopsy in head and neck cancer: From visualization of lymphatic vessels to sentinel nodes. AB - The aim of this report is to describe the history of sentinel node biopsy in head and neck cancer. Sentinel node biopsy is a minimally invasive technique to select patients for treatment of metastatic lymph nodes in the neck. Although this procedure has only recently been accepted for early oral cancer, the first studies on visualization of the cervical lymphatic vessels were reported in the 1960s. In the 1980s mapping of lymphatic drainage from specific head and neck sites was introduced. Sentinel node biopsy was further developed in the 1990s and after validation in this century the procedure is routinely performed in early oral cancer in several head and neck centers. New techniques may improve the accuracy of sentinel node biopsy further, particularly in difficult subsites like the floor of mouth. PMID- 26126814 TI - (-)Epigallocatechin-3-gallate decreases the stress-induced impairment of learning and memory in rats. AB - Stress induces reactive oxygen species (ROS) and causes alterations in brain cytoarchitecture and cognition. Green tea has potent antioxidative properties especially the tea catechin (-) epigallocatechin-3-gallate (EGCG). These powerful antioxidative properties are able to protect against various oxidative damages. In this study we investigated the impact of stress on rats' locomotor activity, learning and memory. Many tea catechins, including EGCG, were examined for their possible therapeutic effects in treating stress-induced impairment. Our results indicated that locomotor activity was decreased, and the learning and memory were impaired in stressed rats (SRs). EGCG treatment was able to prevent the decreased locomotor activity as well as improve the learning and memory in SRs. EGCG treatment was also able to reduce the increased oxidative status in SRs' hippocampi. The above results suggest a therapeutic effect of EGCG in treating stress-induced impairment of learning and memory, most likely by means of its powerful antioxidative properties. PMID- 26126815 TI - A Near-fatal Case of Invasive Pneumococcal Disease in a Vaccinated Child. PMID- 26126816 TI - Immediate allergy due to raw garlic (Allium sativum L.). PMID- 26126817 TI - A Description of Inpatient Palliative Care Actions for Patients With Acute Heart Failure. AB - In a recent randomized trial, inpatient palliative care (PC) visits were associated with improved quality of life and symptom burden for patients with heart failure. To better understand what actions by PC providers may have led to those outcomes, we conducted chart reviews of 101 patients in the intervention group (who received PC). Palliative care actions are described for all patients and for those with higher symptoms. Orders were written for 24% of patients, most frequently for pain. Recommendations to change current care were made for 40% of patients. At least 1 element of future care planning was documented for 99% of patients. Palliative care for inpatients with HF led to additive actions beyond standard care, especially for pain, and promoted HF-specific goals of care discussions. PMID- 26126818 TI - Validity of Oxygen-Ozone Therapy as Integrated Medication Form in Chronic Inflammatory Diseases. AB - The state-of-the-art of oxygen-ozone therapy is now clarified and all the mechanisms of action of medical ozone are within classical biochemistry and molecular biology. The outcomes of standard treatments in peripheral arterial occlusive disease (PAOD) and dry-form of age-related macular degeneration (AMD) have been compared with the documented therapeutic results achieved with ozonated autohemotherapy (O-AHT). On the other hand, the clinical data of O-AHT on stroke remain indicative. As the cost of O-AHT is almost irrelevant, its application in all public hospitals, especially those of poor Countries, would allow two advantages: the first is for the patient, who will improve her/his conditions, and the second is for Health Authorities burdened with increasing costs. The aim of this paper is to report to clinical scientists that O-AHT is a scientific based therapeutic approach without side effects. The integration of O-AHT with effective approved drugs is likely to yield the best clinical results in several chronic inflammatory diseases. PMID- 26126819 TI - Evaluation of a Bone Marrow Dysmyelopoiesis Immunophenotypic Index for the Diagnosis and Prognosis of Myelodysplastic Syndromes. AB - BACKGROUND: Myelodysplastic Syndromes (MDS) are a group of clonal hematopoietic stem cell disorders with significant heterogeneity in their clinical presentation and the prognosis of the patients. Several attempts have been made to incorporate flow cytometry (FC) findings into the diagnostic and/or prognostic criteria of dysplasia, but bone marrow (BM) aspirate morphology evaluation remains the gold standard for diagnosis. The purpose of this study was to provide a diagnostic tool for MDS that relies on BM immunophenotyping and objectifies the interpretation of FC analysis and to validate its capacity to discriminate MDS from other causes of cytopenias. METHODS: To that purpose, a mathematical formula was developed which incorporates granulocytic maturation markers and the percentage of selected myeloid populations and translates them into a single parameter that quantifies the maturation and differentiation defects of BM granulocytes, named Dysmyelopoiesis Index (DMI). Bone marrow samples from 84 MDS patients and 47 non-MDS cytopenic patients were analyzed with FC and DMI was calculated for every patient. RESULTS: DMI detected clonal dysplasia with 84.5% sensitivity and 93.6% specificity, identified as MDS 77.2% of low grade patients and revealed multilineage dysplasia for a number of RA and RARS cases. It discriminated prognostic subgroups of MDS patients (P< .005) and negatively correlated with IPSS (r= - .472, P= .000), WPSS (r= - .481, P= .000) and IPSS-R (r= -.395, P= .000). CONCLUSIONS: DMI represents an accurate quantification of dysmyelopoiesis and an effective stand-alone diagnostic test for MDS, facilitating FC analysis and daily clinical practice. PMID- 26126820 TI - Apixaban in Venous Thromboembolism in an Era of New Oral Anticoagulants. AB - Several new oral anticoagulants (NOAC) have been recently studied and approved for the prevention and treatment of venous thromboembolism (VTE) which includes deep vein thrombosis and pulmonary embolism. Although, NOACs possess several advantages when compared to traditional therapy each has its own limitations; especially in the elderly and in patients with low body weight, renal impairment and in those with high risk of bleeding. Apixaban is a factor Xa inhibitor recently approved for the treatment and prevention of VTE in the United States. The purpose of this manuscript is to review describes the pharmacological properties of NAOC's and to discuss clinical trial results and clinical applications of these agents in the prevention and treatment of VTE with special emphasis on the role of apixaban. PMID- 26126821 TI - Medical education departments: a study of four medical schools in Sub-Saharan Africa. AB - BACKGROUND: Many African countries are investing in medical education to address significant health care workforce shortages and ultimately improve health care. Increasingly, training institutions are establishing medical education departments as part of this investment. This article describes the status of four such departments at sub-Saharan African medical schools supported by the Medical Education Partnership Initiative (MEPI). This article will provide information about the role of these institutional structures in fostering the development of medical education within the African context and highlight factors that enable or constrain their establishment and sustainability. METHODS: In-depth interviews were conducted with the heads or directors of the four medical education departments using a structured interview protocol developed by the study group. An inductive approach to analysis of the interview transcripts was adopted as the texts were subjected to thematic content analysis. RESULTS: Medical education departments, also known as units or centers, were established for a range of reasons including: to support curriculum review, to provide faculty development in Health Professions Education, and to improve scholarship in learning and teaching. The reporting structures of these departments differ in terms of composition and staff numbers. Though the functions of departments do vary, all focus on improving the quality of health professions education. External and internal funding, where available, as well as educational innovations were key enablers for these departments. Challenges included establishing and maintaining the legitimacy of the department, staffing the departments with qualified individuals, and navigating dependence on external funding. All departments seek to expand the scope of their services by offering higher degrees in HPE, providing assistance to other universities in this domain, and developing and maintaining a medical education research agenda. CONCLUSIONS: The establishment of medical education departments in Sub-Saharan Africa is a strategy medical schools can employ to improve the quality of health professions education. The creation of communities of practice such as has been done by the MEPI project is a good way to expand the network of medical education departments in the region enabling the sharing of lessons learned across the continent. PMID- 26126822 TI - A morphodynamic evaluation of the portal and hepatic venous system in cirrhosis can predict a progression of portal hypertension. PMID- 26126823 TI - Thematic Minireview Series: New Directions in G Protein-coupled Receptor Pharmacology. AB - Over the past half-century, The Journal of Biological Chemistry has been the venue for many landmark publications on the topic of G protein-coupled receptors (GPCRs, also known as seven-transmembrane receptors). The GPCR superfamily in humans is composed of about 800 members, and is the target of about one-third of all pharmaceuticals. Most of these drugs target a very small subset of GPCRs, and do so by mimicking or competing with endogenous hormones and neurotransmitters. This thematic minireview series examines some emerging trends in GPCR drug discovery. The first article describes efforts to systematically interrogate the human "GPCR-ome," including more than 150 uncharacterized "orphan" receptors. The second article describes recent efforts to target alternative receptor binding sites with drugs that act as allosteric modulators of orthosteric ligands. The third article describes how the recent expansion of GPCR structures is providing new opportunities for computer-guided drug discovery. Collectively, these three articles provide a roadmap for the most important emerging trends in GPCR pharmacology. PMID- 26126825 TI - Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor beta1 (TGF-beta1) Production in Human Regulatory T Cells. AB - Production of active TGF-beta1 is one mechanism by which human regulatory T cells (Tregs) suppress immune responses. This production is regulated by glycoprotein A repetitions predominant (GARP), a transmembrane protein present on stimulated Tregs but not on other T lymphocytes (Th and CTLs). GARP forms disulfide bonds with proTGF-beta1, favors its cleavage into latent inactive TGF-beta1, induces the secretion and surface presentation of GARP.latent TGF-beta1 complexes, and is required for activation of the cytokine in Tregs. We explored whether additional Treg-specific protein(s) associated with GARP.TGF-beta1 complexes regulate TGF beta1 production in Tregs. We searched for such proteins by yeast two-hybrid assay, using GARP as a bait to screen a human Treg cDNA library. We identified lysosomal-associated transmembrane protein 4B (LAPTM4B), which interacts with GARP in mammalian cells and is expressed at higher levels in Tregs than in Th cells. LAPTM4B decreases cleavage of proTGF-beta1, secretion of soluble latent TGF-beta1, and surface presentation of GARP.TGF-beta1 complexes by Tregs but does not contribute to TGF-beta1 activation. Therefore, LAPTM4B binds to GARP and is a negative regulator of TGF-beta1 production in human Tregs. It may play a role in the control of immune responses by decreasing Treg immunosuppression. PMID- 26126824 TI - The role of mitochondrially derived ATP in synaptic vesicle recycling. AB - Synaptic mitochondria are thought to be critical in supporting neuronal energy requirements at the synapse, and bioenergetic failure at the synapse may impair neural transmission and contribute to neurodegeneration. However, little is known about the energy requirements of synaptic vesicle release or whether these energy requirements go unmet in disease, primarily due to a lack of appropriate tools and sensitive assays. To determine the dependence of synaptic vesicle cycling on mitochondrially derived ATP levels, we developed two complementary assays sensitive to mitochondrially derived ATP in individual, living hippocampal boutons. The first is a functional assay for mitochondrially derived ATP that uses the extent of synaptic vesicle cycling as a surrogate for ATP level. The second uses ATP FRET sensors to directly measure ATP at the synapse. Using these assays, we show that endocytosis has high ATP requirements and that vesicle reacidification and exocytosis require comparatively little energy. We then show that to meet these energy needs, mitochondrially derived ATP is rapidly dispersed in axons, thereby maintaining near normal levels of ATP even in boutons lacking mitochondria. As a result, the capacity for synaptic vesicle cycling is similar in boutons without mitochondria as in those with mitochondria. Finally, we show that loss of a key respiratory subunit implicated in Leigh disease markedly decreases mitochondrially derived ATP levels in axons, thus inhibiting synaptic vesicle cycling. This proves that mitochondria-based energy failure can occur and be detected in individual neurons that have a genetic mitochondrial defect. PMID- 26126826 TI - The Arg Fingers of Key DnaA Protomers Are Oriented Inward within the Replication Origin oriC and Stimulate DnaA Subcomplexes in the Initiation Complex. AB - ATP-DnaA binds to multiple DnaA boxes in the Escherichia coli replication origin (oriC) and forms left-half and right-half subcomplexes that promote DNA unwinding and DnaB helicase loading. DnaA forms homo-oligomers in a head-to-tail manner via interactions between the bound ATP and Arg-285 of the adjacent protomer. DnaA boxes R1 and R4 reside at the outer edges of the DnaA-binding region and have opposite orientations. In this study, roles for the protomers bound at R1 and R4 were elucidated using chimeric DnaA molecules that had alternative DNA binding sequence specificity and chimeric oriC molecules bearing the alternative DnaA binding sequence at R1 or R4. In vitro, protomers at R1 and R4 promoted initiation regardless of whether the bound nucleotide was ADP or ATP. Arg-285 was shown to play an important role in the formation of subcomplexes that were active in oriC unwinding and DnaB loading. The results of in vivo analysis using the chimeric molecules were consistent with the in vitro data. Taken together, the data suggest a model in which DnaA subcomplexes form in symmetrically opposed orientations and in which the Arg-285 fingers face inward to mediate interactions with adjacent protomers. This mode is consistent with initiation regulation by ATP-DnaA and bidirectional loading of DnaB helicases. PMID- 26126827 TI - A Functional and Putative Physiological Role of Calcitriol in Patched1/Smoothened Interaction. AB - The Patched1 (Ptch)-mediated inhibition of Smoothened (Smo) is still an open question. However, a direct Ptch/Smo interaction has been excluded, Smo modulators were identified, but the endogenous signal transmitting molecule remains undiscovered. Here, we demonstrate that calcitriol, the hormonally active form of vitamin D3, is an excellent candidate for transmission of Ptch/Smo interaction. Our study reveals that Ptch expression is sufficient to release calcitriol from the cell and that calcitriol inhibits Smo action and ciliary translocation by acting on a site distinct from the 7-transmembrane domain or the cysteine-rich domain. Moreover calcitriol strongly synergizes with itraconazole (ITZ) in Smo inhibition, which did not result from elevated calcitriol bioavailability due to ITZ-mediated 24-hydroxylase inhibition but rather from a direct interaction of the compounds at the level of Smo. Together, we suggest that calcitriol represents a possible endogenous transmitter of Ptch/Smo interaction. Moreover calcitriol or calcitriol derivatives combined with ITZ might be a treatment option of Hedgehog-associated cancers. PMID- 26126829 TI - The Volumetric Diversity of Misfolded Prion Protein Oligomers Revealed by Pressure Dissociation. AB - Protein oligomerization has been associated with a wide range of diseases. High pressure approaches offer a powerful tool for deciphering the underlying molecular mechanisms by revealing volume changes associated with the misfolding and assembly reactions. We applied high pressure to induce conformational changes in three distinct beta-sheet-rich oligomers of the prion protein PrP, a protein characterized by a variety of infectious quaternary structures that can propagate stably and faithfully and cause diseases with specific phenotypic traits. We show that pressure induces dissociation of the oligomers and leads to a lower volume monomeric PrP state that refolds into the native conformation after pressure release. By measuring the different pressure and temperature sensitivity of the tested PrP oligomers, we demonstrate significantly different void volumes in their quaternary structure. In addition, by focusing on the kinetic and energetic behavior of the pressure-induced dissociation of one specific PrP oligomer, we reveal a large negative activation volume and an increase in both apparent activation enthalpy and entropy. This suggests a transition state ensemble that is less structured and significantly more hydrated than the oligomeric state. Finally, we found that site-specific fluorescent labeling allows monitoring of the transient population of a kinetic intermediate in the dissociation reaction. Our results indicate that defects in atomic packing may deserve consideration as a new factor that influences differences between PrP assemblies and that could be relevant also for explaining the origin of prion strains. PMID- 26126828 TI - Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake. AB - Tauopathies are neurodegenerative diseases characterized by accumulation of Tau amyloids, and include Alzheimer disease and certain frontotemporal dementias. Trans-neuronal propagation of amyloid mediated by extracellular Tau may underlie disease progression. Consistent with this, active and passive vaccination studies in mouse models reduce pathology, although by unknown mechanisms. We previously reported that intracerebroventricular administration of three anti-Tau monoclonal antibodies (HJ8.5, HJ9.3, and HJ9.4) reduces pathology in a model overexpressing full-length mutant (P301S) human Tau. We now study effects of these three antibodies and a negative control antibody (HJ3.4) on Tau aggregate uptake into BV2 microglial-like cells and primary neurons. Antibody-independent Tau uptake into BV2 cells was blocked by heparin, consistent with a previously described role for heparan sulfate proteoglycans. Two therapeutic antibodies (HJ8.5 and HJ9.4) promoted uptake of full-length Tau fibrils into microglia via Fc receptors. Surprisingly, HJ9.3 promoted uptake of fibrils composed of the Tau repeat domain or Alzheimer disease-derived Tau aggregates, but failed to influence full-length recombinant Tau fibrils. Size fractionation of aggregates showed that antibodies preferentially promote uptake of larger oligomers (n >= ~ 20-mer) versus smaller oligomers (n ~ 10-mer) or monomer. No antibody inhibited uptake of full-length recombinant fibrils into primary neurons, but HJ9.3 blocked neuronal uptake of Tau repeat domain fibrils and Alzheimer disease-derived Tau. Antibodies thus have multiple potential mechanisms, including clearance via microglia and blockade of neuronal uptake. However these effects are epitope- and aggregate size-dependent. Establishing specific mechanisms of antibody activity in vitro may help in design and optimization of agents that are more effective in vivo. PMID- 26126830 TI - Introduction of time-based targets has improved the training environment for emergency medicine: Yes. PMID- 26126832 TI - Quantitative Analysis of the Migration and Accumulation of Bacillus subtilis in Asparagus officinalis. AB - Bacillus subtilis B96-II is a broad-spectrum biological control strain. It effectively suppresses soil-borne fungal diseases in vegetables. A green fluorescence protein (GFP) was expressed in B96-II to detect migration of B96-II into the root and stem of asparagus. The GFP-tagged B96-II (B96-II-GFP) strain exhibited bright green fluorescence under a fluorescence microscope. GFP was stable and had no apparent effects on the growth of the strain. Asparagus plants were planted in the soil inoculated with B96-II-GFP. Our results showed that B96 II-GFP was detected in both the root and stem 15, 30, and 45 days after the asparagus seedlings were planted. B96-II-GFP was also detected in leaves but at a lower concentration. The highest concentration was detected in 15 days, and the number of bacteria decreased subsequently irrespective of duration of growth or sampling period. The highest concentration of B96-II-GFP was present in the root base suggesting that the root base served as the hub of bacterial migration from the soil to the stem. PMID- 26126831 TI - Effects of Three Volatile Oxylipins on Colony Development in Two Species of Fungi and on Drosophila Larval Metamorphosis. AB - The aim of this study is to investigate the effects of three volatile oxylipins on colony development in two fungi and on Drosophila larval metamorphosis. Using an airborne exposure technique, three common and volatile oxylipins (1-octen-3 ol, (E)-2-hexenal, and 1-hexanol) were compared for their effects on spore germination and colony growth in Aspergillus niger and Penicillium chrysogenum, as well as for their effects on the morphogenesis of larvae of Drosophila melanogaster. Conidia of both A. niger and P. chrysogenum plated in the presence of low concentrations (50 ppm) of these three volatile organic compounds (VOCs) formed fewer colony-forming units (CFUs) and exhibited reduced radial growth of colonies as compared to controls. When A. niger and P. chrysogenum spores were germinated in the presence of the enantiomers of 1-octen-3-ol, (R)-(-)-1-octen-3 ol had the greatest impact on colony morphology (decreased sporulation and colony diameter), while (S)-(+)-1-octen-3-ol and the racemic form yielded similar morphological changes but to a lesser extent. In addition, Drosophila larvae exposed to vapors of these oxylipins exhibited serious delays in metamorphosis and toxic effects on pupae and adult stages. Low concentration of these three VOCs can significantly inhibit the formation of CFUs and the growth of fungi. (R) (-)-1-octen-3-ol imposed the greatest impact on fungal morphology compared to (S) (+)-1-octen-3-ol and the racemic form. The three volatile oxylipins could also delay the metamorphosis of Drosophila and impose toxic effects on its pupae and adult stages. PMID- 26126833 TI - Structural characterization of functionalized gold nanoparticles for drug delivery in cancer therapy: a NMR based approach. AB - In the present paper, we report results from a study of the structure and physicochemical properties of gold nanoparticles modified with poly(ethylene glycol) (PEG) designed for the drug delivery of the proteasome inhibitor Bortezomib (BTZ) in cancer therapy. A number of advanced analytical techniques were used to define important physicochemical characteristics such as composition, structure, surface properties, particle size and morphology. A new approach based on detailed NMR studies was employed to define specific intermolecular interactions and mechanisms of drug immobilization and location into surface modified gold nanoparticles (AuNPs). Particularly important information was gained from analysis of NMR spectroscopic parameters such as the spectral line shape, translation diffusion, the nuclear Overhauser effect (NOE) and spin-lattice relaxation (T1). The results confirmed the coexistence of two different types of BTZ inclusion into polyethylene glycol coated gold nanoparticles: (i) association with the polymer chains by weak H-bonds and/or dipole-charge interactions and (ii) adsorption on the surface of the gold nanoparticles. The results allowed for determination of the overall structure of Bortezomib loaded PEG coated AuNPs, which is related to the therapeutic drug efficacy and activity in the treatment of cancer. PMID- 26126834 TI - Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report. AB - This is a report on a 2-day joint meeting between the British Society of Toxicological Pathology (BSTP) and the Safety Pharmacology Society (SPS) held in the UK in November 2013. Drug induced adverse effects on the cardiovascular system are associated with the attrition of more marketed and candidate drugs than any other safety issue. The objectives of this meeting were to foster inter disciplinary approaches to address cardiovascular risk assessment, improve understanding of the respective disciplines, and increase awareness of new technologies. These aims were achieved. This well attended meeting covered both 'purely functional' cardiovascular adverse effects of drugs (e.g., electrophysiological and haemodynamic changes) as well as adverse effects encompassing both functional and pathological changes. Most of the presentations focused on nonclinical safety data, with information on translation to human where known. To reflect the content of the presentations we have cited key references and review articles. PMID- 26126835 TI - Acetate-Derived Metabolites from the Brown Alga Lobophora variegata. AB - Seven new nonadecaketides (1-7), lobophorols A-C, lobophopyranones A and B, and lobophorones A and B, along with the first naturally occurring related metabolites (8-10), were isolated from specimens of Lobophora variegata collected from the Canary Islands. Their structures were determined by extensive spectroscopic methods. In addition, an insight into the biosynthesis of these compounds on the basis of the involvement of type III polyketide synthases is proposed. Lobophorol A (1) showed significant antibacterial activity against Staphylococcus aureus. PMID- 26126836 TI - Narcolepsy in a three-year-old girl: A case report. AB - OBJECTIVE: Narcolepsy is characterized by excessive daytime somnolence associated with sleep paralysis, hallucinations when falling asleep or awakening, and cataplexy. Early recognition of pediatric narcolepsy is essential for growth and development. We experienced a case of narcolepsy in a three-year-old girl. METHODS: The patient underwent brain MRI and 24h video-electroencephalogram (EEG) monitoring. Polysomnography (PSG) with multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) DQ typing was performed. RESULTS: The brain MRI was normal. 24h video-EEG monitoring revealed no abnormal slow or epileptiform discharge on interictal EEG, and no EEG change during tongue thrusting, dropping head with laughter, or flopping down, which was consistent with cataplexy associated with narcolepsy. A mean sleep latency of 2.5 min and four episodes of sleep-onset REM periods in five naps were observed in PSG with MSLT. She was positive in HLA-DQB1*0602. Based on these findings, she was diagnosed as narcoleptic with cataplexy. CONCLUSION: The history, combined with PSG and MSLT, was helpful in the diagnosis of narcolepsy. We report a case of early-onset narcolepsy presenting with excessive sleepiness and cataplexy. PMID- 26126837 TI - The expanding phenotypic spectrum of ARFGEF2 gene mutation: Cardiomyopathy and movement disorder. AB - Mutations in ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) gene was recently recognized to cause bilateral periventricular nodular heterotopia, putaminal hyperintensity and movement disorder. A ten year-old girl with severe developmental and growth delay, feeding problems and involuntary movements is presented. Bilateral periventricular nodular heterotopia and putaminal hyperintensity were detected in cranial magnetic resonance imaging. Her echocardiographic examination revealed left ventricular non-compaction cardiomyopathy. Sequence analysis of ARFGEF2 gene demonstrated a homozygous c.5126G>A, p.Trp1709(*) mutation. The mutation is the first nonsense mutation described in ARFGEF2 gene and the case is the second reported case of ARFGEF2 gene mutation with cardiomyopathy. The presented case supports the view that the presence of cardiomyopathy in ARFGEF2 gene mutations is more than a coincidence and thus expands the phenotypic spectrum of ARFGEF2 gene mutations. Mutations in the ARFGEF2 gene must be considered in the presence of bilateral periventricular nodular heterotopia and putaminal hyperintensity in children presenting with movement disorder, severe developmental delay and microcephaly. In case of ARFGEF2 gene mutation, screening for cardiomyopathy may be indicated. PMID- 26126838 TI - Release of bulk cell free DNA during physical exercise occurs independent of extracellular vesicles. AB - PURPOSE: Strenuous exercise induces a rapid and transient elevation of cell free DNA (cfDNA) concentration in blood plasma. The detection of cfDNA in the presence of plasma nucleases could indicate an association of cfDNA with protective vesicular structures. Several cell types release extracellular vesicles (EVs), including exosomes and shedding microvesicles, which are known to mediate the exchange of proteins and nucleic acids (largely RNA) between cells. Here, we assessed whether EVs play a role in the exercise-dependent release of cfDNA in blood plasma. METHODS: Venous blood collected from healthy volunteers before and after incremental treadmill exercise was separated into vesicular (EV) and soluble fractions. Nuclear and mitochondrial DNA content in plasma supernatants and EV fractions was determined by quantitative real-time PCR (qPCR). RESULTS: We show that the majority of cfDNA is located in the plasma supernatants. Only minute amounts of DNA were observed in the EV-associated fractions including microvesicles and exosomes. Nuclear and mitochondrial DNA species differ in terms of their quantities in the several plasma fractions. CONCLUSIONS: Our results indicate that cfDNA liberated in response to acute physical exercise is not released by vesicular means and circulates in a soluble form in blood plasma which could indicate different biological functions exerted by cfDNA and EVs. The different nature of DNA species in plasma has major implications for the preparation of plasma and other bodily fluids prior to analysis. PMID- 26126839 TI - Effects of habitual loading on patellar tendon mechanical and morphological properties in basketball and volleyball players. AB - PURPOSE: Tendon mechanical properties are linked to sports performance and tendon related injuries, such as tendinopathy. Whether habitual loading, such as participation in regular jumping activities, would induce adaptation on tendon mechanical properties remains unclear. METHOD: Forty healthy subjects (10 sedentary, 15 volleyball players, and 15 basketball players) aged between 18 and 35 years were recruited. Supersonic shearwave imaging was used to measure the shear elastic modulus and thickness and cross-sectional area (CSA) of the proximal patellar tendons of both knees at 30 degrees of flexion. RESULT: Significant group differences in tendon shear elastic modulus were found among the three groups. In the dominant leg, reduction in tendon shear elastic modulus by 18.9 % (p = 0.018) and 48.7 % (p = 0.000) were observed in the basketball and volleyball players, respectively, when compared with sedentary subjects. In the non-dominant leg, reduction in tendon shear elastic modulus were 27.3 % (p = 0.034) and 47.1 % (p = 0.02) in the basketball and volleyball players, respectively. The athlete groups were found to have larger CSA but with similar tendon thickness than sedentary group. The CSA were larger by 24-29 % and by 22 24 % in the basketball players and volleyball players, for the dominant and non dominant legs, respectively (all p < 0.05). Age and body mass are related to tendon stiffness and CSA, particularly in the sedentary subjects. CONCLUSION: The proximal patellar tendon can undergo substantial adaptation on tendon mechanical and morphological properties when exposed in jumping sports. Intrinsic factors such as age and body mass could influence tendon properties. PMID- 26126840 TI - Determination of lupenone and beta-sitosterol in Rhizoma Musae by UPLC with DAD and ELSD. AB - Rhizoma Musae has been used for centuries in Miao medicine practice in China, and it usually uses for treating diabetes and bruises. In this study, lupenone and beta-sitosterol in Rhizoma Musae were separated by reversed-phase ultra performance liquid chromatography (RP-UPLC) and simultaneously detected by a diode array detector (DAD) and an evaporative light scattering detector (ELSD) using methanol and 0.1% aqueous acetic acid (100 : 4, v/v) as a mobile phase in 20 min. The flow rate of 0.1 mL/min was set with isocratic, the temperature of column compartment maintained at 50 degrees C and ultraviolet detection set at 206 nm wavelength. The injection volume was 1.0 uL. The parameter for the ELSD was set to a probe temperature of 45 degrees C, and the nebulizer for nitrogen gas was adjusted to 1.5 L/min. The RP-UPLC method was validated for accuracy, precision, limit of detection and limit of quantification. It applied to the quantification of the active chemical constituents of Rhizoma Musae, and results indicated that both DAD and ELSD were suitable for the determination of lupenone and beta-sitosterol, and the DAD has a better sensitivity than the ELSD. PMID- 26126841 TI - Single test for all doctors: urgent need to expand UK undergraduate medical education. PMID- 26126842 TI - Gaps in neonatal demographics may impact on HES data: a plea for early allocation and communication of patient identifiers. PMID- 26126843 TI - Integrating rapid diagnostic testing for congenital CMV into the Newborn Hearing Screening Programme: the audiovestibular physician's perspective. PMID- 26126844 TI - 'Feed and wrap' or sedate and immobilise for neonatal brain MRI? PMID- 26126845 TI - Neonatal organ donation for transplantation in the UK. PMID- 26126846 TI - Management of therapeutic hypothermia for neonatal hypoxic ischaemic encephalopathy in a tertiary centre in South Africa. AB - AIM: Therapeutic hypothermia (TH), shown in developed countries to improve outcome in infants with hypoxic-ischaemic encephalopathy (HIE), was introduced into standard care at Tygerberg Children's Hospital in 2008. We aimed to describe the management and characteristics of infants treated with TH at this tertiary centre as well as the logistical challenges encountered. METHODS: Infants admitted for TH between 2008 and 2011 were included. They fulfilled TOBY study entry criteria and were cooled using a whole-body cooling system. A retrospective analysis of the cooling process and clinical findings was made using data collected during treatment. RESULTS: 100 infants with mild (32%), moderate (45%) and severe (23%) HIE were treated over 3 years. Mean time to admission was 4.87 (+/-1.63) hours, median time from delivery to target temperature was 7.5 h (range 2.5-15.5 h). Mean temperature on admission was 35.5 degrees C (+/-1.5 degrees C). Overall, rectal temperature was within target temperature for 82.8% of the time. Complications noted were clinically suspected/proven infection (45%), abnormal coagulation tests (48%), thrombocytopenia (34%), need for inotropic support (17%), hypoglycaemia (4%) and hyperglycaemia (10%). Rate of follow-up at 1 year among survivors was 57%. Infants not attending 1-year follow-up were more likely to have HIV-infected mothers, but there were no other demographic or clinical differences when compared with those who attended follow-up. CONCLUSIONS: Cooling is feasible in a resource-limited setting, within a strict protocol. With close monitoring, the known and common complications occur as frequently as in less resource-limited settings. Surrogate markers of later outcome need to be explored where follow-up is problematic. PMID- 26126847 TI - An unexpected cause of stridor in a newborn. PMID- 26126848 TI - A novel mutation Ser344Cys in FGFR3 causes achondroplasia with severe platyspondyly. PMID- 26126849 TI - A Pterin-Dependent Signaling Pathway Regulates a Dual-Function Diguanylate Cyclase-Phosphodiesterase Controlling Surface Attachment in Agrobacterium tumefaciens. AB - The motile-to-sessile transition is an important lifestyle switch in diverse bacteria and is often regulated by the intracellular second messenger cyclic diguanylate monophosphate (c-di-GMP). In general, high c-di-GMP concentrations promote attachment to surfaces, whereas cells with low levels of signal remain motile. In the plant pathogen Agrobacterium tumefaciens, c-di-GMP controls attachment and biofilm formation via regulation of a unipolar polysaccharide (UPP) adhesin. The levels of c-di-GMP in A. tumefaciens are controlled in part by the dual-function diguanylate cyclase-phosphodiesterase (DGC-PDE) protein DcpA. In this study, we report that DcpA possesses both c-di-GMP synthesizing and degrading activities in heterologous and native genetic backgrounds, a binary capability that is unusual among GGDEF-EAL domain-containing proteins. DcpA activity is modulated by a pteridine reductase called PruA, with DcpA acting as a PDE in the presence of PruA and a DGC in its absence. PruA enzymatic activity is required for the control of DcpA and through this control, attachment and biofilm formation. Intracellular pterin analysis demonstrates that PruA is responsible for the production of a novel pterin species. In addition, the control of DcpA activity also requires PruR, a protein encoded directly upstream of DcpA with a predicted molybdopterin-binding domain. PruR is hypothesized to be a potential signaling intermediate between PruA and DcpA through an as-yet-unidentified mechanism. This study provides the first prokaryotic example of a pterin-mediated signaling pathway and a new model for the regulation of dual-function DGC-PDE proteins. IMPORTANCE: Pathogenic bacteria often attach to surfaces and form multicellular communities called biofilms. Biofilms are inherently resilient and can be difficult to treat, resisting common antimicrobials. Understanding how bacterial cells transition to the biofilm lifestyle is essential in developing new therapeutic strategies. We have characterized a novel signaling pathway that plays a dominant role in the regulation of biofilm formation in the model pathogen Agrobacterium tumefaciens. This control pathway involves small metabolites called pterins, well studied in eukaryotes, but this is the first example of pterin-dependent signaling in bacteria. The described pathway controls levels of an important intracellular second messenger (cyclic diguanylate monophosphate) that regulates key bacterial processes such as biofilm formation, motility, and virulence. Pterins control the balance of activity for an enzyme that both synthesizes and degrades the second messenger. These findings reveal a complex, multistep pathway that modulates this enzyme, possibly identifying new targets for antibacterial intervention. PMID- 26126850 TI - The Peptidoglycan-Binding Protein SjcF1 Influences Septal Junction Function and Channel Formation in the Filamentous Cyanobacterium Anabaena. AB - Filamentous, heterocyst-forming cyanobacteria exchange nutrients and regulators between cells for diazotrophic growth. Two alternative modes of exchange have been discussed involving transport either through the periplasm or through septal junctions linking adjacent cells. Septal junctions and channels in the septal peptidoglycan are likely filled with septal junction complexes. While possible proteinaceous factors involved in septal junction formation, SepJ (FraG), FraC, and FraD, have been identified, little is known about peptidoglycan channel formation and septal junction complex anchoring to the peptidoglycan. We describe a factor, SjcF1, involved in regulation of septal junction channel formation in the heterocyst-forming cyanobacterium Anabaena sp. strain PCC 7120. SjcF1 interacts with the peptidoglycan layer through two peptidoglycan-binding domains and is localized throughout the cell periphery but at higher levels in the intercellular septa. A strain with an insertion in sjcF1 was not affected in peptidoglycan synthesis but showed an altered morphology of the septal peptidoglycan channels, which were significantly wider in the mutant than in the wild type. The mutant was impaired in intercellular exchange of a fluorescent probe to a similar extent as a sepJ deletion mutant. SjcF1 additionally bears an SH3 domain for protein-protein interactions. SH3 binding domains were identified in SepJ and FraC, and evidence for interaction of SjcF1 with both SepJ and FraC was obtained. SjcF1 represents a novel protein involved in structuring the peptidoglycan layer, which links peptidoglycan channel formation to septal junction complex function in multicellular cyanobacteria. Nonetheless, based on its subcellular distribution, this might not be the only function of SjcF1. IMPORTANCE: Cell-cell communication is central not only for eukaryotic but also for multicellular prokaryotic systems. Principles of intercellular communication are well established for eukaryotes, but the mechanisms and components involved in bacteria are just emerging. Filamentous heterocyst-forming cyanobacteria behave as multicellular organisms and represent an excellent model to study prokaryotic cell-cell communication. A path for intercellular metabolite exchange appears to involve transfer through molecular structures termed septal junctions. They are reminiscent of metazoan gap junctions that directly link adjacent cells. In cyanobacteria, such structures need to traverse the peptidoglycan layers in the intercellular septa of the filament. Here we describe a factor involved in the formation of channels across the septal peptidoglycan layers, thus contributing to the multicellular behavior of these organisms. PMID- 26126851 TI - Wall Teichoic Acid Glycosylation Governs Staphylococcus aureus Nasal Colonization. AB - Nasal colonization by the human pathogen Staphylococcus aureus is a major risk factor for hospital- and community-acquired infections. A key factor required for nasal colonization is a cell surface-exposed zwitterionic glycopolymer, termed wall teichoic acid (WTA). However, the precise mechanisms that govern WTA mediated nasal colonization have remained elusive. Here, we report that WTA GlcNAcylation is a pivotal requirement for WTA-dependent attachment of community acquired methicillin-resistant S. aureus (MRSA) and emerging livestock-associated MRSA to human nasal epithelial cells, even under conditions simulating the nutrient composition and dynamic flow of nasal secretions. Depending on the S. aureus strain, WTA O-GlcNAcylation occurs in either alpha or beta configuration, which have similar capacities to mediate attachment to human nasal epithelial cells, suggesting that many S. aureus strains maintain redundant pathways to ensure appropriate WTA glycosylation. Strikingly, a lack of WTA glycosylation significantly abrogated the ability of MRSA to colonize cotton rat nares in vivo. These results indicate that WTA glycosylation modulates S. aureus nasal colonization and may help to develop new strategies for eradicating S. aureus nasal colonization in the future. IMPORTANCE: Nasal colonization by the major human pathogen Staphylococcus aureus is a risk factor for severe endogenous infections and contributes to the spread of this microbe in hospitals and the community. Here, we show that wall teichoic acid (WTA) O-GlcNAcylation is a key factor required for S. aureus nasal colonization. These data provide a mechanistic explanation for the capacity of WTA to modulate S. aureus nasal colonization and may stimulate research activities to establish valuable strategies to eradicate S. aureus nasal colonization in high-risk hospitalized patients and in the general community. PMID- 26126852 TI - The ParB-parS Chromosome Segregation System Modulates Competence Development in Streptococcus pneumoniae. AB - ParB proteins bind centromere-like DNA sequences called parS sites and are involved in plasmid and chromosome segregation in bacteria. We previously showed that the opportunistic human pathogen Streptococcus pneumoniae contains four parS sequences located close to the origin of replication which are bound by ParB. Using chromatin immunoprecipitation (ChIP), we found here that ParB spreads out from one of these parS sites, parS(-1.6 degrees ), for more than 5 kb and occupies the nearby comCDE operon, which drives competence development. Competence allows S. pneumoniae to take up DNA from its environment, thereby mediating horizontal gene transfer, and is also employed as a general stress response. Mutating parS(-1.6 degrees ) or deleting parB resulted in transcriptional up-regulation of comCDE and ssbB (a gene belonging to the competence regulon), demonstrating that ParB acts as a repressor of competence. However, genome-wide transcription analysis showed that ParB is not a global transcriptional regulator. Different factors, such as the composition of the growth medium and antibiotic-induced stress, can trigger the sensitive switch driving competence. This work shows that the ParB-parS chromosome segregation machinery also influences this developmental process. IMPORTANCE: Streptococcus pneumoniae (pneumococcus) is an important human pathogen responsible for more than a million deaths each year. Like all other organisms, S. pneumoniae must be able to segregate its chromosomes properly. Not only is understanding the molecular mechanisms underlying chromosome segregation in S. pneumoniae therefore of fundamental importance, but also, this knowledge might offer new leads for ways to target this pathogen. Here, we identified a link between the pneumococcal chromosome segregation system and the competence-developmental system. Competence allows S. pneumoniae to take up and integrate exogenous DNA in its chromosome. This process plays a crucial role in successful adaptation to--and escape from- host defenses, antibiotic treatments, and vaccination strategies. We show that the chromosome segregation protein ParB acts as a repressor of competence. To the best of our knowledge, this is the first example of a ParB protein controlling bacterial competence. PMID- 26126853 TI - The Pseudomonas aeruginosa Transcriptional Landscape Is Shaped by Environmental Heterogeneity and Genetic Variation. AB - Phenotypic variability among bacteria depends on gene expression in response to different environments, and it also reflects differences in genomic structure. In this study, we analyzed transcriptome sequencing (RNA-seq) profiles of 151 Pseudomonas aeruginosa clinical isolates under standard laboratory conditions and of one P. aeruginosa type strain under 14 different environmental conditions. Our approach allowed dissection of the impact of the genetic background versus environmental cues on P. aeruginosa gene expression profiles and revealed that phenotypic variation was larger in response to changing environments than between genomically different isolates. We demonstrate that mutations within the global regulator LasR affect more than one trait (pleiotropy) and that the interaction between mutations (epistasis) shapes the P. aeruginosa phenotypic plasticity landscape. Because of pleiotropic and epistatic effects, average genotype and phenotype measures appeared to be uncorrelated in P. aeruginosa. IMPORTANCE: This work links experimental data of unprecedented complexity with evolution theory and delineates the transcriptional landscape of the opportunistic pathogen Pseudomonas aeruginosa. We found that gene expression profiles are most strongly influenced by environmental cues, while at the same time the transcriptional profiles were also shaped considerably by genetic variation within global regulators. The comprehensive set of transcriptomic and genomic data of more than 150 clinical P. aeruginosa isolates will be made publically accessible to all researchers via a dedicated web interface. Both Pseudomonas specialists interested in expression and regulation of specific genes and researchers from other fields with more global interest in the phenotypic and genotypic variation of this important model species can access all information on various levels of detail. PMID- 26126854 TI - Haploid Genetic Screen Reveals a Profound and Direct Dependence on Cholesterol for Hantavirus Membrane Fusion. AB - Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in the Old World and a highly fatal hantavirus cardiopulmonary syndrome (HCPS) in the New World. No vaccines or antiviral therapies are currently available to prevent or treat hantavirus disease, and gaps in our understanding of how hantaviruses enter cells challenge the search for therapeutics. We performed a haploid genetic screen in human cells to identify host factors required for entry by Andes virus, a highly virulent New World hantavirus. We found that multiple genes involved in cholesterol sensing, regulation, and biosynthesis, including key components of the sterol response element-binding protein (SREBP) pathway, are critical for Andes virus entry. Genetic or pharmacological disruption of the membrane-bound transcription factor peptidase/site-1 protease (MBTPS1/S1P), an SREBP control element, dramatically reduced infection by virulent hantaviruses of both the Old World and New World clades but not by rhabdoviruses or alphaviruses, indicating that this pathway is broadly, but selectively, required by hantaviruses. These results could be fully explained as arising from the modest depletion of cellular membrane cholesterol that accompanied S1P disruption. Mechanistic studies of cells and with protein-free liposomes suggested that high levels of cholesterol are specifically needed for hantavirus membrane fusion. Taken together, our results indicate that the profound dependence on target membrane cholesterol is a fundamental, and unusual, biophysical property of hantavirus glycoprotein membrane interactions during entry. IMPORTANCE: Although hantaviruses cause important human diseases worldwide, no specific antiviral treatments are available. One of the major obstacles to the development of new therapies is a lack of understanding of how hantaviruses hijack our own host factors to enter cells. Here, we identified multiple cellular genes that control the levels of cholesterol in cellular membranes to be important for hantavirus entry. Our findings suggest that high concentrations of cholesterol in cellular membranes are required at a specific step in the entry process-fusion between viral and cellular membranes-that allows escape of the hantavirus genome into the host cell cytoplasm to initiate infection. Our findings uncover a fundamental feature of the hantavirus infection mechanism and point to cholesterol-lowering drugs as a potential new treatment of hantaviral infections. PMID- 26126855 TI - Human Urine Decreases Function and Expression of Type 1 Pili in Uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) is the primary cause of community-acquired urinary tract infections (UTIs). UPEC bind the bladder using type 1 pili, encoded by the fim operon in nearly all E. coli. Assembled type 1 pili terminate in the FimH adhesin, which specifically binds to mannosylated glycoproteins on the bladder epithelium. Expression of type 1 pili is regulated in part by phase variable inversion of the genomic element containing the fimS promoter, resulting in phase ON (expressing) and OFF (nonexpressing) orientations. Type 1 pili are essential for virulence in murine models of UTI; however, studies of urine samples from human UTI patients demonstrate variable expression of type 1 pili. We provide insight into this paradox by showing that human urine specifically inhibits both expression and function of type 1 pili. Growth in urine induces the fimS phase OFF orientation, preventing fim expression. Urine also contains inhibitors of FimH function, and this inhibition leads to a further bias in fimS orientation toward the phase OFF state. The dual effect of urine on fimS regulation and FimH binding presents a potential barrier to type 1 pilus-mediated colonization and invasion of the bladder epithelium. However, FimH-mediated attachment to human bladder cells during growth in urine reverses these effects such that fim expression remains ON and/or turns ON. Interestingly, FimH inhibitors called mannosides also induce the fimS phase OFF orientation. Thus, the transduction of FimH protein attachment or inhibition into epigenetic regulation of type 1 pilus expression has important implications for the development of therapeutics targeting FimH function. IMPORTANCE: Urinary tract infections (UTIs) are extremely common infections, frequently caused by uropathogenic Escherichia coli (UPEC), that are treated with antibiotics but often recur. Therefore, UTI treatment both is complicated by and contributes to bacterial antibiotic resistance. Thus, it is important to understand UTI pathogenesis to devise novel strategies and targets for prevention and treatment. Based on evidence from disease epidemiology and mouse models of infection, UPEC relies heavily on type 1 pili to attach to and invade the bladder epithelium during initial stages of UTI. Here, we demonstrate that the negative effect of planktonic growth in human urine on both the function and expression of type 1 pili is overcome by attachment to bladder epithelial cells, representing a strategy to subvert this alternative innate defense mechanism. Furthermore, this dually inhibitory action of urine is a mechanism shared with recently developed anti-type 1 pilus molecules, highlighting the idea that further development of antivirulence strategies targeting pili may be particularly effective for UPEC. PMID- 26126856 TI - Systemic lupus erythematosus in Crohn's disease: drug-induced or idiopathic? AB - Coexistence of Crohn's disease (CD) and idiopathic systemic lupus erythematosus (SLE) is very rare. On the other hand, drug-induced lupus erythematosus (DILE) due to anti-tumor necrosis factor (TNF) agents is a relatively more common entity. DILE due to anti-TNF agents and idiopathic SLE share common serologic and epidemiologic characteristics making the differentiation between those two entities difficult. We present a case of a 35-year-old woman with CD who developed SLE after treatment with adalimumab and denosumab and persisting symptoms eight months after discontinuation of those agents. PMID- 26126857 TI - Redox Linked Flavin Sites in Extracellular Decaheme Proteins Involved in Microbe Mineral Electron Transfer. AB - Extracellular microbe-mineral electron transfer is a major driving force for the oxidation of organic carbon in many subsurface environments. Extracellular multi heme cytochromes of the Shewenella genus play a major role in this process but the mechanism of electron exchange at the interface between cytochrome and acceptor is widely debated. The 1.8 A x-ray crystal structure of the decaheme MtrC revealed a highly conserved CX8C disulfide that, when substituted for AX8A, severely compromised the ability of S. oneidensis to grow under aerobic conditions. Reductive cleavage of the disulfide in the presence of flavin mononucleotide (FMN) resulted in the reversible formation of a stable flavocytochrome. Similar results were also observed with other decaheme cytochromes, OmcA, MtrF and UndA. The data suggest that these decaheme cytochromes can transition between highly reactive flavocytochromes or less reactive cytochromes, and that this transition is controlled by a redox active disulfide that responds to the presence of oxygen. PMID- 26126858 TI - Hypoxia-inducible MiR-182 promotes angiogenesis by targeting RASA1 in hepatocellular carcinoma. AB - BACKGROUND: Hypoxia is a common feature of solid tumors, including HCC. And hypoxia has been reported to play an important role in HCC progression. However, the potential mechanism of miRNAs in hypoxia mediating HCC progression still remains unclear. METHODS: The HCC cells were cultured in the atmosphere of 1 % oxygen to induce hypoxia. The microRNA microarray was employed to search for the hypoxia-inducible miRNAs. RT-PCR, western blot and immunohistochemistry were used to detect the RNA and protein levels. HUVEC were applied to explore the angiogenesis level. RESULTS: We found that miR-182 was upregulated in the hypoxia based microarray. We then revealed that miR-182 was also significantly increased in the HCC tissues compared to the corresponding normal tissues. In vitro capilliary tube formation assays showed that the miR-182 promoted angiogenesis. RASA1 was demonstrated as the direct target of miR-182. In addition, the suppression of RASA1 phenocopied the pro-angiogenesis effects of miR-182. Besides, RASA1 was also decreased in the hypoxia HCC cells while the inhibition of miR-182 partially restored the level of RASA1. CONCLUSIONS: Our data showed that hypoxia regulated the expression of miR-182 and RASA1 to promote HCC angiogenesis. PMID- 26126859 TI - Systematically dissecting the global mechanism of miRNA functions in mouse pluripotent stem cells. AB - BACKGROUND: MicroRNAs (miRNAs) critically modulate stem cell properties like pluripotency, but the fundamental mechanism remains largely unknown. METHOD: This study systematically analyzes multiple-omics data and builds a systems physical network including genome-wide interactions between miRNAs and their targets to reveal the systems mechanism of miRNA functions in mouse pluripotent stem cells. RESULTS: Globally, miRNAs directly repress the pluripotent core factors during differentiation state. Surprisingly, during the pluripotent state, the top important miRNAs do not directly regulate the pluripotent core factors as previously thought, but they only directly target the pluripotent signal pathways and directly repress developmental processes. Furthermore, at the pluripotent state miRNAs predominately repress DNA methyltransferases, the core enzymes for DNA methylation. The decreasing methylation repressed by miRNAs in turn activates the top miRNAs and pluripotent core factors, creating an active circuit system to modulate pluripotency. CONCLUSION: MiRNAs vary their functions with stem cell states. While miRNAs directly repress pluripotent core factors to facilitate differentiation during the differentiation state, they also help stem cells to maintain pluripotency by activating pluripotent cores through directly repressing DNA methylation systems and primarily inhibiting development in the pluripotent state. PMID- 26126860 TI - Maternal and newborn infants amino acid concentrations in obese women born themselves with normal and small for gestational age birth weight. AB - This study was undertaken to compare amino acid concentrations in maternal and newborn infants' serum in normal pregnancy and two groups of obese women who were born themselves with normal and small for gestational age (SGA) birth weight. Maternal cholesterol, lipoproteins concentrations and maternal and infants amino acid concentrations were evaluated at the time of delivery in 28 normal pregnancies, 46 obese pregnant women with normal birth weight (Ob-AGA group) and 44 obese pregnant women born themselves SGA (Ob-SGA group). Mean birth weight of newborn infants in Ob-SGA group was significantly less than in normal and Ob-AGA groups. Cholesterol and lipoproteins were significantly elevated in obese women (more prominent in Ob-SGA group). Most amino acid concentrations and fetal maternal amino acid gradients were significantly lower in Ob-SGA group. These data suggest significant changes in placental amino acid transport/synthetic function in obese women who were born themselves SGA. PMID- 26126861 TI - Misinformation about caesarean sections. PMID- 26126862 TI - Measuring cerebrovascular reactivity: the dynamic response to a step hypercapnic stimulus. AB - We define cerebral vascular reactivity (CVR) as the ratio of the change in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal (S) to an increase in blood partial pressure of CO2 (PCO2): % Delta S/Delta PCO2 mm Hg. Our aim was to further characterize CVR into dynamic and static components and then study 46 healthy subjects collated into a reference atlas and 20 patients with unilateral carotid artery stenosis. We applied an abrupt boxcar change in PCO2 and monitored S. We convolved the PCO2 with a set of first-order exponential functions whose time constant tau was increased in 2-second intervals between 2 and 100 seconds. The tau corresponding to the best fit between S and the convolved PCO2 was used to score the speed of response. Additionally, the slope of the regression between S and the convolved PCO2 represents the steady-state CVR (ssCVR). We found that both prolongations of tau and reductions in ssCVR (compared with the reference atlas) were associated with the reductions in CVR on the side of the lesion. tau and ssCVR are respectively the dynamic and static components of measured CVR. PMID- 26126863 TI - MRI heralds secondary nigral lesion after brain ischemia in mice: a secondary time window for neuroprotection. AB - Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes' occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies. PMID- 26126864 TI - Differential effects of ischemic vascular disease and Alzheimer's disease on brain atrophy and cognition. AB - We previously reported that pathologic measures of arteriosclerosis (AS), cerebral infarction, and Alzheimer's disease (AD) are independently correlated with cortical gray matter (CGM) atrophy measured by in vivo magnetic resonance imaging (MRI). Here, we use path analyses to model the associations between these three pathology measures and cognitive impairment, as mediated by CGM atrophy, after controlling for age and education. In this sample of 116 elderly persons followed longitudinally to autopsy (ischemic vascular disease (IVD) program project), differential patterns were observed between AS and atrophy/cognition versus AD and atrophy/cognition. The total effect of AD pathology on global cognition (beta = -0.61, s.e. = 0.06) was four times stronger than that of AS (beta = -0.15, s.e. = 0.08). The effect of AS on cognition appears to occur through cerebral infarction and CGM atrophy (beta = -0.13, s.e. = 0.04). In contrast, the effects of AD pathology on global cognition (beta = -0.50, s.e. = 0.07) occur through a direct pathway that is five times stronger than the indirect pathway acting through CGM atrophy (beta = -0.09, s.e. = 0.03). The strength of this direct AD pathway was not significantly mitigated by adding hippocampal volume to the model. AD pathology affects cognition not only through brain atrophy, but also via an unmeasured pathway that could be related to synaptic dysfunction before the development of cortical atrophy. PMID- 26126865 TI - miR-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions. AB - Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3beta inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro inflammatory cytokine, tumor necrosis factor-alpha, with/out GSK3beta inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier 'leakiness' in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation. PMID- 26126866 TI - MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4. AB - MicroRNA-29b (miR-29b) is involved in regulating ischemia process, but the molecular mechanism is unclear. In this work, we explored the function of miR-29b in cerebral ischemia. The level of miR-29b in white blood cells was evaluated in patients and mice after ischemic stroke. Brain infarct volume and National Institute of Health stroke scale (NIHSS) scores were analyzed to determine the relationship between miR-29b expression and the severity of stroke. The relationship of miR-29b and aquaporin-4 (AQP4) was further studied in mice. We found that miR-29b was significantly downregulated in stroke patients (P<0.05). MiR-29b level negatively associated with NIHSS scores (r=-0.349, P<0.01) and brain infarct volume (r=-0.321, P<0.05). In ischemic mice, miR-29b in the brain and blood were both downregulated (r=0.723, P<0.05). MiR-29b overexpression reduced infarct volume (49.50+/-6.55 versus 35.48+/-2.28 mm(3), P<0.05), edema (164+/-4% versus 108+/-4%, P<0.05), and blood-brain barrier (BBB) disruption compared with controls (15+/-9% versus 7+/-3%, P<0.05). Aquaporin-4 expression greatly decreased after miR-29b overexpression (28+/-7% versus 11+/-3%, P<0.05). Dual-luciferase reporter system showed that AQP-4 was the direct target of miR 29b (P<0.05). We concluded that miR-29b could potentially predict stroke outcomes as a novel circulating biomarker, and miR-29b overexpression reduced BBB disruption after ischemic stroke via downregulating AQP-4. PMID- 26126867 TI - Multimodal imaging reveals temporal and spatial microglia and matrix metalloproteinase activity after experimental stroke. AB - Stroke is the most common cause of death and disability from neurologic disease in humans. Activation of microglia and matrix metalloproteinases (MMPs) is involved in positively and negatively affecting stroke outcome. Novel, noninvasive, multimodal imaging methods visualizing microglial and MMP alterations were employed. The spatio-temporal dynamics of these parameters were studied in relation to blood flow changes. Micro positron emission tomography (MUPET) using [(18)F]BR-351 showed MMP activity within the first days after transient middle cerebral artery occlusion (tMCAo), followed by increased [(18)F]DPA-714 uptake as a marker for microglia activation with a maximum at 14 days after tMCAo. The inflammatory response was spatially located in the infarct core and in adjacent (penumbral) tissue. For the first time, multimodal imaging based on PET, single photon emission computed tomography, and magnetic resonance imaging revealed insight into the spatio-temporal distribution of critical parameters of poststroke inflammation. This allows further evaluation of novel treatment paradigms targeting the postischemic inflammation. PMID- 26126868 TI - Tissue-type plasminogen activator triggers the synaptic vesicle cycle in cerebral cortical neurons. AB - The active zone (AZ) is a thickening of the presynaptic membrane where exocytosis takes place. Chemical synapses contain neurotransmitter-loaded synaptic vesicles (SVs) that at rest are tethered away from the synaptic release site, but after the presynaptic inflow of Ca(+2) elicited by an action potential translocate to the AZ to release their neurotransmitter load. We report that tissue-type plasminogen activator (tPA) is stored outside the AZ of cerebral cortical neurons, either intermixed with small clear-core vesicles or in direct contact with the presynaptic membrane. We found that cerebral ischemia-induced release of neuronal tPA, or treatment with recombinant tPA, recruits the cytoskeletal protein betaII-spectrin to the AZ and promotes the binding of SVs to betaII spectrin, enlarging the population of SVs in proximity to the synaptic release site. This effect does not require the generation of plasmin and is followed by the recruitment of voltage gated calcium channels (VGCC) to the presynaptic terminal that leads to Ca(+2)-dependent synapsin I phosphorylation, freeing SVs to translocate to the AZ to deliver their neurotransmitter load. Our studies indicate that tPA activates the SV cycle and induces the structural and functional changes in the synapse that are required for successful neurotransmission. PMID- 26126869 TI - Peroxisomal translocation of soluble epoxide hydrolase protects against ischemic stroke injury. AB - Soluble epoxide hydrolase (sEH) contributes to cardiovascular disease, including stroke, although the exact mechanism remains unclear. While primarily a cytosolic enzyme, sEH can translocate into peroxisomes. The relevance of this for stroke injury is not understood. We tested the hypothesis that sEH-mediated injury is tied to the cytoplasmic localization. We found that a human sEH variant possessing increased affinity to peroxisomes reduced stroke injury in sEH-null mice, whereas infarcts were significantly larger when peroxisomal translocation of sEH was disrupted. We conclude that sEH contributes to stroke injury only when localized in the cytoplasm, while peroxisomal sEH may be protective. PMID- 26126870 TI - Arteriole dilation to synaptic activation that is sub-threshold to astrocyte endfoot Ca2+ transients. AB - Ca(2+)-dependent pathways in neurons and astrocyte endfeet initiate changes in arteriole diameter to regulate local brain blood flow. Whether there exists a threshold of synaptic activity in which arteriole diameter is controlled independent of astrocyte endfeet Ca(2+) remains unclear. We used two-photon fluorescence microscopy to examine synaptically evoked synthetic or genetic Ca(2+) indicator signals around penetrating arterioles in acute slices of the rat neocortex. We discovered a threshold below which vasodilation occurred in the absence of endfeet Ca(2+) signals but with consistent neuronal Ca(2+) transients, suggesting endfoot Ca(2+) is not necessary for activity-dependent vasodilation under subtle degrees of brain activation. PMID- 26126872 TI - Comorbid tics have no effect on response to cognitive-behavioral therapy in youth with obsessive-compulsive disorder. PMID- 26126871 TI - A sinogram warping strategy for pre-reconstruction 4D PET optimization. AB - A novel strategy for 4D PET optimization in the sinogram domain is proposed, aiming at motion model application before image reconstruction ("sinogram warping" strategy). Compared to state-of-the-art 4D-MLEM reconstruction, the proposed strategy is able to optimize the image SNR, avoiding iterative direct and inverse warping procedures, which are typical of the 4D-MLEM algorithm. A full-count statistics sinogram of the motion-compensated 4D PET reference phase is generated by warping the sinograms corresponding to the different PET phases. This is achieved relying on a motion model expressed in the sinogram domain. The strategy was tested on the anthropomorphic 4D PET-CT NCAT phantom in comparison with the 4D-MLEM algorithm, with particular reference to robustness to PET-CT co registrations artefacts. The MLEM reconstruction of the warped sinogram according to the proposed strategy exhibited better accuracy (up to +40.90 % with respect to the ideal value), whereas images reconstructed according to the 4D-MLEM reconstruction resulted in less noisy (down to -26.90 % with respect to the ideal value) but more blurred. The sinogram warping strategy demonstrates advantages with respect to 4D-MLEM algorithm. These advantages are paid back by introducing approximation of the deformation field, and further efforts are required to mitigate the impact of such an approximation in clinical 4D PET reconstruction. PMID- 26126873 TI - Aerobic biotransformation of 3-methylindole to ring cleavage products by Cupriavidus sp. strain KK10. AB - 3-Methylindole, also referred to as skatole, is a pollutant of environmental concern due to its persistence, mobility and potential health impacts. Petroleum refining, intensive livestock production and application of biosolids to agricultural lands result in releases of 3-methylindole to the environment. Even so, little is known about the aerobic biodegradation of 3-methylindole and comprehensive biotransformation pathways have not been established. Using glycerol as feedstock, the soil bacterium Cupriavidus sp. strain KK10 biodegraded 100 mg/L of 3-methylindole in 24 h. Cometabolic 3-methylindole biodegradation was confirmed by the identification of biotransformation products through liquid chromatography electrospray ionization tandem mass spectrometry analyses. In all, 14 3-methylindole biotransformation products were identified which revealed that biotransformation occurred through different pathways that included carbocyclic aromatic ring-fission of 3-methylindole to single-ring pyrrole carboxylic acids. This work provides first comprehensive evidence for the aerobic biotransformation mechanisms of 3-methylindole by a soil bacterium and expands our understanding of the biodegradative capabilities of members of the genus Cupriavidus towards heteroaromatic pollutants. PMID- 26126874 TI - Structure and electronic properties of MoVO type mixed-metal oxides - a combined view by experiment and theory. AB - In this review we address recent efforts from experimental and theoretical side to study MoVO-type mixed metal oxides (MMOs) and their properties. We illustrate how structures of MMOs have been evaluated using a large variety of experimental techniques, such as electron microscopy, neutron diffraction, and X-ray diffraction. Furthermore, we discuss the current view on structure-catalysis correlations, derived from recent experiments. In a second part, we examine useful tools of theoretical chemistry for exploring MoVO-type systems. We discuss the need for using hybrid DFT methods and we analyze how, in the context of MMOs studies, semi-local DFT approximations can encounter problems due to a notable self-interaction error when describing oxidic species and reactions on them. In addition, we discuss various aspects of the model that are important when attempting to map complex MMO systems. PMID- 26126875 TI - Longitudinal randomised controlled trials in rehabilitation post-stroke: a systematic review on the quality of reporting and use of baseline outcome values. AB - BACKGROUND: The World Health Organisation stresses the need to collect high quality longitudinal data on rehabilitation and to improve the comparability between studies. This implies using all the information available and transparent reporting. We therefore investigated the quality of reported or planned randomised controlled trials on rehabilitation post-stroke with a repeated measure of physical functioning, provided recommendations on the presentation of results using regression parameters, and focused on the difficulties of adjustment for baseline outcome measures. METHODS: We performed a systematic review of the literature from 2011 to 2013 and collected information on the way data was analysed. Moreover we described various approaches to analyse the data using mixed models illustrated with real data. RESULTS: Eighty-four eligible studies were identified of which 61% (51/84) failed to analyse the data longitudinally. Moreover, for 30% (25/83) the method for adjustment for baseline is not known or not existent. Using real data we were able to show how much difference in results an adjustment for baseline data can make. We showed how to provide interpretable intervention effects using regression coefficients while making use of all the information available in the data. CONCLUSIONS: Our review showed that improvements were needed in the analysis of longitudinal trials in rehabilitation post-stroke in order to maximise the use of collected data and improve comparability between studies. Reporting fully the method used (including baseline adjustment) and using methods like mixed models could easily achieve this. PMID- 26126876 TI - A critical appraisal of time-lapse imaging for embryo selection: where are we and where do we need to go? AB - PURPOSE: The aim of this study was to undertake a critical appraisal of the available evidence for the use of time-lapse imaging for embryo selection in clinical IVF. METHODS: A literature search in PubMed, Scopus, Cochrane Central, ClinicalTrials.gov, Current Controlled Trials, and WHO International Clinical Trials Registry Platform was performed to identify randomized controlled trials that investigated the effect of time-lapse embryo selection and/or the time-lapse incubation system on ongoing pregnancy rate. We then performed a systematic review and assessed the relative risks (RRs) and 95 % confidence intervals (CIs) for ongoing pregnancy rates and the risk of bias of the eligible studies. RESULTS: We identified four eligible randomized studies, three of which investigated the effect of both time-lapse incubation system and selection on ongoing pregnancy rate; the pooled result revealed a benefit of this intervention (relative risk (RR) 1.20; 95 % CI 1.05-1.37). However, the evidence was judged to be of low quality due to study limitations; a beneficial effect was observed in only one study deemed to be at high risk of bias. The single study assessing the effect of only the time-lapse incubation system revealed a non-significant negative effect (RR 0.71; 95 % CI 0.49-1.03). CONCLUSIONS: The findings from this systematic review of the current evidence do not support routine use of time lapse technology in clinical IVF. We therefore believe that the use of time-lapse imaging for embryo selection should remain experimental and that couples should not be subject to a surcharge for having their embryos cultured in a time-lapse imaging system. Future studies evaluating this technology in well-designed trials should be performed. PMID- 26126878 TI - Erratum to: PLCzeta disruption with complete fertilization failure in normozoospermia. PMID- 26126877 TI - IVF for fertility preservation in breast cancer patients--efficacy and safety issues. AB - BACKGROUND: Potential risks on future fertility have become a dominant issue in consultation and management of newly diagnosed young cancer patients. Several fertility preservation strategies are currently available. Of those, ovarian stimulation followed by IVF and embryo cryopreservation is the most established one and is especially applicable in reproductive aged breast cancer patients. AIM: The aim of this study is to provide a comprehensive review on ovarian stimulation and IVF for fertility preservation in newly diagnosed breast cancer patients. METHODS: Review of relevant literature is available through PubMed and Google scholar. RESULTS: The use of IVF for fertility preservation in breast cancer patients raises dilemmas regarding efficacy and safety of controlled ovarian stimulation. Among these are the suggested role of malignancy and BRCA mutation in reducing ovarian response to stimulation, strategies designated to protect against hyper-estrogenic state associated with stimulation (co-treatment with tamoxifen or letrozole), and possible adjustments to accommodate oncologic related time constraints. CONCLUSION: Ovarian stimulation followed by IVF forms an important fertility preservation strategy for newly diagnosed young breast cancer patients, though live born rates following thawed embryo transfer in these patients are still lacking. Recent advances in controlled ovarian stimulation protocols provide practical options for some of the challenges that breast cancer patients present. PMID- 26126879 TI - Phased-array sources based on nonlinear metamaterial nanocavities. AB - Coherent superposition of light from subwavelength sources is an attractive prospect for the manipulation of the direction, shape and polarization of optical beams. This phenomenon constitutes the basis of phased arrays, commonly used at microwave and radio frequencies. Here we propose a new concept for phased-array sources at infrared frequencies based on metamaterial nanocavities coupled to a highly nonlinear semiconductor heterostructure. Optical pumping of the nanocavity induces a localized, phase-locked, nonlinear resonant polarization that acts as a source feed for a higher-order resonance of the nanocavity. Varying the nanocavity design enables the production of beams with arbitrary shape and polarization. As an example, we demonstrate two second harmonic phased-array sources that perform two optical functions at the second harmonic wavelength (~5 MUm): a beam splitter and a polarizing beam splitter. Proper design of the nanocavity and nonlinear heterostructure will enable such phased arrays to span most of the infrared spectrum. PMID- 26126880 TI - Factors determining the use of social support services among elderly people living in a city environment in Poland. AB - Ageing populations entail important social issues. The population of Lodz is characterised by the highest ageing ratio in Poland (17.2% people aged 65 or above). The aim of our study was to present factors determining the use of social support services in the subpopulation of elderly people in a city environment. The study, conducted between 2011 and 2012 with the use of a survey questionnaire, included 466 respondents aged 65 or older, who were looked after by the Municipal Social Welfare Centre, Lodz-Polesie. The response rate was 93.2%. Most beneficiaries were women (77.9%). The respondents were mostly widows (73.9% of women) or widowers (43.7% of men). Most respondents applied for nursing services (79.7%), while 28.3% asked for financial help. In Lodz as a whole, these percentages were 81.0% and 19.0%. A chronic disease was the most common cause of the application for help (73.4%). In 4.1% of applicants, the cause was a low income per capita. Multivariate logistic regression analysis indicated that the variables which contributed to receiving financial support included being a man, aged 65-69 years, being single and receiving a monthly salary per capita below 500.0 PLN (Polish New Zlotys). The variables which contributed to receiving social care service in the form of nursing services included being a woman, aged 85 years or older, receiving a monthly salary per capita between 1001.0 and 1500.0 PLN, suffering from a chronic disease, which was a reason for applying for social support service, a result on the Activities of Daily Living scale confirming disability and a very negative self-evaluation of health. The results of the study have shown that the poor health condition of elderly people is the most frequent reason for applying for social services. Identifying reasons for applying for social care by elderly people might facilitate the introduction of workable solutions in the social and healthcare policy. PMID- 26126881 TI - Gonorrhea and Prostate Cancer Incidence: An Updated Meta-Analysis of 21 Epidemiologic Studies. AB - BACKGROUND: The association between gonorrhea and prostate cancer risk has been investigated widely, but the results remain inconsistent and contradictory. We conducted an updated meta-analysis to obtain a more precise estimate of this association. MATERIAL AND METHODS: PubMed, EMBASE, and the Cochrane Library were searched for papers up to June 2014 to identify eligible studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the influence of gonorrhea on prostate cancer risk. RESULTS: Twenty-one observational studies (19 case-control and 2 cohort) were eligible, comprising 9965 prostate cancer patients and 118 765 participants. Pooled results indicated that gonorrhea was significantly associated with increased incidence of prostate cancer (OR 1.31, 95% CI 1.14-1.52). The association between gonorrhea and prostate cancer was stronger in African American males (OR 1.32, 95% CI 1.06-1.65) than in Whites (OR 1.05, 95% CI 0.90-1.21). CONCLUSIONS: Our findings suggest that gonorrhea is associated with an increased risk of prostate cancer, especially among African American males. These results warrant further well-designed, large-scale cohort studies to draw definitive conclusions. PMID- 26126882 TI - Effect of Registered Partnership on Labor Earnings and Fertility for Same-Sex Couples: Evidence From Swedish Register Data. AB - The expansion of legal rights to same-sex couples is a foot in a number of Western countries. The effects of this rollout are not only important in their own right but can also provide a window on the institution of marriage and the rights bundled therein. In this article, using Swedish longitudinal register data covering 1994-2007, we study the impact of the extension of rights to same-sex couples on labor earnings and fertility. In 1994, registered partnership for same sex couples was introduced, which conferred almost all rights and obligations of marriage--a notable exception being joint legal parenting, by default or election. The latter was added in the 2002 adoption act. We find registered partnership to be important to both gays and lesbians but for different reasons. For gays, resource pooling emerges as the main function of registered partnerships. For lesbians, registered partnership appears to be an important vehicle for family formation, especially after the 2002 adoption act. In contrast to heterosexual couples (included for comparison), we find no evidence of household specialization among lesbians. The lack of specialization is noteworthy given similar fertility effects of registered partnership (after 2002) and the fact that lesbian couples were less assortatively matched (on education) than heterosexual couples--children and unequal earnings power being two factors commonly believed to promote specialization. PMID- 26126883 TI - A New Piece of the Puzzle: Sexual Orientation, Gender, and Physical Health Status. AB - Although research has long documented the relevance of gender for health, studies that simultaneously incorporate the relevance of disparate sexual orientation groups are sparse. We address these shortcomings by applying an intersectional perspective to evaluate how sexual orientation and gender intersect to pattern self-rated health status among U.S. adults. Our project aggregated probability samples from the Behavioral Risk Factor Surveillance System (BRFSS) across seven U.S. states between 2005 and 2010, resulting in an analytic sample of 10,128 sexual minority (gay, lesbian, and bisexual) and 405,145 heterosexual adults. Logistic regression models and corresponding predicted probabilities examined how poor self-rated health differed across sexual orientation-by-gender groups, before and after adjustment for established health risk factors. Results reveal distinct patterns among sexual minorities. Initially, bisexual men and women reported the highest--and gay and lesbian adults reported the lowest--rates of poor self-rated health, with heterosexuals in between. Distinct socioeconomic status profiles accounted for large portions of these differences. Furthermore, in baseline and fully adjusted regression models, only among heterosexuals did women report significantly different health from men. Importantly, the findings highlight elevated rates of poor health experienced by bisexual men and women, which are partially attributable to their heightened economic, behavioral, and social disadvantages relative to other groups. PMID- 26126884 TI - Career and Family Choices Among Elite Liberal Arts Graduates. AB - This study describes how the career and family choices of female graduates of the Claremont Colleges within 15 years of undergraduate graduation (unless otherwise specified) have changed across the graduation years of 1960 to 1994. Specifically, I show that female graduates of the Claremont Colleges have clearly shifted away from having their family first (i.e., having at least one biological child) and a job second (i.e., having a job after 15 years of receiving their undergraduate degree but having very weak labor force attachment prior to that) toward simultaneously having both a career (i.e., very strong labor force attachment) and a family for those that graduated after 1979. Finally, I find that the primary mechanisms that allowed for the observed shift toward "career and family" for those that graduated post-1979 appear to be increased access to paid parental leave and childcare. PMID- 26126885 TI - Better for Baby? The Retreat From Mid-Pregnancy Marriage and Implications for Parenting and Child Well-being. AB - Recent decades have seen a significant decline in mid-pregnancy ("shotgun") marriage, particularly among disadvantaged groups, which has contributed to increasing nonmarital birth rates. Despite public and political concern about this shift, the implications for parenting and child well-being are not known. Drawing on a sample of U.S. black and white mothers with nonmarital conceptions from the NLSY79, our study fills this gap. Using propensity score techniques to address concerns about selection bias, we found that mid-pregnancy marriages were associated with slightly better parenting quality relative to remaining single, although effect sizes were small and limited to marriages that remained intact at the time of child assessment. Mid-pregnancy marriages were not associated with improved children's behavior or cognitive ability. These findings suggest that the retreat from mid-pregnancy marriage may contribute to increasing inequality in parenting resources for children. PMID- 26126886 TI - Can a teaching assistant experience in a surgical anatomy course influence the learning curve for nontechnical skill development for surgical residents? AB - The foundation upon which surgical residents are trained to work comprises more than just critical cognitive, clinical, and technical skill. In an environment where the synchronous application of expertise is vital to patient outcomes, the expectation for optimal functioning within a multidisciplinary team is extremely high. Studies have shown that for most residents, one of the most difficult milestones in the path to achieving professional expertise in a surgical career is overcoming the learning curve. This view point commentary provides a reflection from the two senior medical students who have participated in the Student-as-Teacher program developed by the Department of Anatomy at Mayo Clinic, designed to prepare students for their teaching assistant (TA) role in anatomy courses. Both students participated as TAs in a six week surgical anatomy course for surgical first assistant students offered by the School of Health Sciences at Mayo Clinic. Development of teaching skills, nontechnical leadership, communication, and assessment skills, are discussed in relation to their benefits in preparing senior medical students for surgical residency. PMID- 26126887 TI - Intra-molecular magnetic exchange interaction in the tripyridinium bis[tetrachloroferrate(iii)] chloride molecular magnet: a broken symmetry-DFT study. AB - The investigation of magnetic ordering in magnetic molecular conductors is the subject of ongoing research studies in the fields of condensed matter physics, chemistry and material sciences. Following the photo-magnetic behavior already observed in individual (FeCl4)2(py.H)3Cl molecules at room temperature, magnetic ordering is studied in this work. Calculations are performed using spin projected broken symmetry via density functional theory within the scheme of the B3LYP approximation. The value of the intra-molecular magnetic coupling constant is obtained as J = 13.2062 kJ mol(-1). A field dependent magnetization experiment is conducted to validate the magnitude and the sign of the exchange constant. Reasonable consistency of experimental and theoretical results confirms the presence of a positive intra-molecular indirect exchange interaction. This work paves the way for possible introduction of a new molecule in the development of advanced molecular electronic devices. PMID- 26126888 TI - Thermodynamic characterization of the interaction between the human Y-box binding protein YB-1 and nucleic acids. AB - Y-box binding protein 1 (YB-1) binds to both RNA and DNA to control transcription and translation for the regulation of various cellular systems. YB-1 is overexpressed in some cancer cells and is a potential target for treatment of cancer. Herein, we describe isothermal titration calorimetry analyses of the interaction between a number of recombinant YB-1 domains and nucleic acids to identify the RNA and DNA binding sites and their binding mechanisms. These results demonstrated that the C-terminal domain of the protein interacts with single-stranded DNA and RNA by exothermic and endothermic reactions, respectively. The highly conserved cold-shock domain (CSD) also bound to single stranded RNA and DNA by exothermic and endothermic reactions, respectively. The specific binding manner for RNA is in the CSD, whereas DNA binds with the most affinity to the C-terminal region (amino acids 130-219). We found further that the C-terminal region (amino acids 220-324) regulates the binding stoichiometry of RNA. These quantitative thermodynamic results provide a preliminary indication on the molecular mechanism of binding of the multifunctional protein YB-1 to nucleic acids to regulate its biological function. PMID- 26126890 TI - Corrigendum: Controlling Radical Formation in the Photoactive Yellow Protein Chromophore. PMID- 26126891 TI - Corrigendum: Reconfiguration of Stereoisomers under Sonomechanical Activation. PMID- 26126892 TI - Corrigendum: Well-Defined Copper(I) Fluoroalkoxide Complexes for Trifluoroethoxylation of Aryl and Heteroaryl Bromides. PMID- 26126895 TI - Segregated structures of ring polymer melts near the surface: a molecular dynamics simulation study. AB - We study structural properties of a ring polymeric melt confined in a film in comparison to a linear counterpart using molecular dynamics simulations. Local structure orderings of ring and linear polymers in the vicinity of the surface are similar to each other because the length scale of surface-monomer excluded volume interactions is smaller than the size of an ideal blob of the ring. In a long length scale, while the Silberberg hypothesis can be used to provide the physical origin of the confined linear polymer results, it no longer holds for the ring polymer case. We also present different structural properties of ring and linear polymers in a melt, including the size of polymers, the adsorbed amount, and the coordination number of a polymer. Our observation reveals that a confined ring in a melt adopts a highly segregated conformation due to a topological excluded volume repulsion, which may provide a new perspective to understand the nature of biological processes, such as territorial segregation of chromosomes in eukaryotic nuclei. PMID- 26126897 TI - Facile Assembly of Chiral Metallosquares by Using Enantiopure Tribenzotriquinacene Corner Motifs. AB - A pair of enantiomerically pure metallosquares based on linear platinum diacetylene edges and tribenzotriquinacene corner units was synthesized. Their structures were characterized by (1) H-, (13) C- and (31) P NMR spectroscopy as well as MALDI-TOF mass spectrometry and circular dichroism. Based on DFT calculation, the optimized geometry possesses a distorted square conformation in which the four edges are not sitting on the same plane. The molecular square further self-assembled in the solid state to afford microspheres with diameter of approximately 300 nm, as determined by scanning electron microscopy. PMID- 26126896 TI - Benefits of Acoustic Beamforming for Solving the Cocktail Party Problem. AB - The benefit provided to listeners with sensorineural hearing loss (SNHL) by an acoustic beamforming microphone array was determined in a speech-on-speech masking experiment. Normal-hearing controls were tested as well. For the SNHL listeners, prescription-determined gain was applied to the stimuli, and performance using the beamformer was compared with that obtained using bilateral amplification. The listener identified speech from a target talker located straight ahead (0 degrees azimuth) in the presence of four competing talkers that were either colocated with, or spatially separated from, the target. The stimuli were spatialized using measured impulse responses and presented via earphones. In the spatially separated masker conditions, the four maskers were arranged symmetrically around the target at +/-15 degrees and +/-30 degrees or at +/-45 degrees and +/-90 degrees . Results revealed that masked speech reception thresholds for spatially separated maskers were higher (poorer) on average for the SNHL than for the normal-hearing listeners. For most SNHL listeners in the wider masker separation condition, lower thresholds were obtained through the microphone array than through bilateral amplification. Large intersubject differences were found in both listener groups. The best masked speech reception thresholds overall were found for a hybrid condition that combined natural and beamforming listening in order to preserve localization for broadband sources. PMID- 26126898 TI - Childhood mental disorders: A forgotten problem? PMID- 26126900 TI - Caenorhabditis evolution in the wild. AB - Recent research has filled many gaps about Caenorhabditis natural history, simultaneously exposing how much remains to be discovered. This awareness now provides means of connecting ecological and evolutionary theory with diverse biological patterns within and among species in terms of adaptation, sexual selection, breeding systems, speciation, and other phenomena. Moreover, the heralded laboratory tractability of C. elegans, and Caenorhabditis species generally, provides a powerful case study for experimental hypothesis testing about evolutionary and ecological processes to levels of detail unparalleled by most study systems. Here, I synthesize pertinent theory with what we know and suspect about Caenorhabditis natural history for salient features of biodiversity, phenotypes, population dynamics, and interactions within and between species. I identify topics of pressing concern to advance Caenorhabditis biology and to study general evolutionary processes, including the key opportunities to tackle problems in dispersal dynamics, competition, and the dimensionality of niche space. PMID- 26126899 TI - Evaluating community engagement in global health research: the need for metrics. AB - BACKGROUND: Community engagement in research has gained momentum as an approach to improving research, to helping ensure that community concerns are taken into account, and to informing ethical decision-making when research is conducted in contexts of vulnerability. However, guidelines and scholarship regarding community engagement are arguably unsettled, making it difficult to implement and evaluate. DISCUSSION: We describe normative guidelines on community engagement that have been offered by national and international bodies in the context of HIV related research, which set the stage for similar work in other health related research. Next, we review the scholarly literature regarding community engagement, outlining the diverse ethical goals ascribed to it. We then discuss practical guidelines that have been issued regarding community engagement. There is a lack of consensus regarding the ethical goals and approaches for community engagement, and an associated lack of indicators and metrics for evaluating success in achieving stated goals. To address these gaps we outline a framework for developing indicators for evaluating the contribution of community engagement to ethical goals in health research. There is a critical need to enhance efforts in evaluating community engagement to ensure that the work on the ground reflects the intentions expressed in the guidelines, and to investigate the contribution of specific community engagement practices for making research responsive to community needs and concerns. Evaluation mechanisms should be built into community engagement practices to guide best practices in community engagement and their replication across diverse health research settings. PMID- 26126901 TI - Estrogen and cancers of the colorectum, breast, and lung in postmenopausal women. AB - As estrogens play an important role in maintaining physiological function in various organs, the estrogen decrease after menopause is thought to cause various diseases frequently observed in postmenopausal or elderly women. With the aging of society and a decrease in infectious or vascular diseases, neoplasms have now become the most frequent cause of death in Japan. Cancers of the colorectum, breast, and lung have been rapidly increasing both in incidence and death, especially among postmenopausal women. Interestingly, all three of these cancers are associated with estrogens. In premenopausal women, ovarian estrogens plays major roles in the female reproductive organs through the classic estrogen receptor, ER-alpha. In postmenopausal women, however, estrogens produced/activated by peripherally localized estrogen-metabolizing enzymes such as aromatase, which converts androgen into estrogens, are thought to play physiologically and pathobiologically important roles in various organs through second ER, namely ER-beta, distributing systemically. In this article, the association of estrogens with these cancers in postmenopausal or elderly women are reviewed, especially focusing on the role of ER-beta and peripheral estrogen metabolism. The possibility of prevention or treatment of these diseases through estrogenic control is also discussed. PMID- 26126902 TI - Nanobodies and their Use in GPCR Drug Discovery. AB - Nanobodies are therapeutic proteins derived from the variable domain (VHH) of naturally occurring heavy-chain antibodies. These VHH domains are the smallest functional fragments derived from a naturally occurring immunoglobulin. Nanobodies can be easily produced in prokaryotic or eukaryotic host organisms and their unique biophysical characteristics render these molecules ideal candidates for drug development. They are also emerging as an interesting new class of potential therapeutics for targets such as GPCRs, which have historically been challenging for small molecule drug discovery and even more difficult for biologics discovery. The ability to easily combine Nanobodies with different binding sites and different modes of action can be used to generate highly selective and highly potent drug candidates with very attractive pharmacological profiles. In addition, Nanobodies have been used as crystallization chaperones to enable or facilitate the structural determination of an active GPCR conformation. PMID- 26126903 TI - Exploring the Technology Landscape of 7TMR Drug Signaling Profiling. AB - Seven transmembrane domain receptors (7TMRs) constitute the largest family of transmembrane proteins in vertebrates and are the targets of more than 40% of currently marketed drugs. It is now accepted that these receptors are highly dynamic "microprocessors" that adopt a continuum of functionally distinct active conformations. The novel concept of biased agonism (or functional selectivity) posits that different ligands stabilize unique receptor conformations with each conformation imparting distinct signaling, and thus biological attributes, to a given receptor. The pharmacotherapeutic potential of biased agonism lies in possibility to develop molecules that selectively engage beneficial pathways while inhibiting or remaining inert towards those producing deleterious outcomes. Various strategies are now applied for the discovery of biased ligands. Many assays use second messenger levels (i.e., calcium, inositol trisphosphate, cAMP) as a quantitative readout of G-protein subtype-specific activity. However, due to complex cross-regulation between the various G-protein pathways, second messenger levels alone are not directly reflective of a ligand's activity on a specific pathway. Consequently, direct measurements of receptor-proximal events (such as G protein activation and beta-arrestin coupling) are required for a more accurate quantification of ligand's efficacy (or bias) towards different pathways. The discovery that various ligands of the same receptor can display different efficacies and potencies towards different receptor-downstream signaling pathways has not only revitalized the process of 7TMR drug discovery, but has significantly transformed the field of pharmacology as a whole. This review will showcase the current pharmacological toolbox available for the discovery and validation of biased ligands. PMID- 26126904 TI - G Protein-Coupled Receptors - Targets for Fragment-based Drug Discovery. AB - As the considerable technical challenges involved with generating crystal structures of G (guanine nucleotide- binding) protein-coupled receptors (GPCRs) are starting to be successfully addressed, opportunities to apply fragment-based drug discovery (FBDD) to this class of target are becoming a reality. GPCRs represent a large and important family of drug targets with considerable clinical and commercial interest. While their general seven transmembrane helix bundle structures are amenable to therapeutic intervention with small molecules, to date successful drugs have primarily been discovered using traditional competitive or function-based screening. With advances in biophysical screening techniques such as Surface Plasmon Resonance (SPR) and Target-Immobilised NMR Screening (TINS), being matched to developments in molecular dynamics simulations, virtual screening and stabilisation of biologically relevant conformations of GPCRs, structure-based approaches using fragment starting points are beginning to be applied to the discovery of new generations of small molecules. PMID- 26126905 TI - The Role of Binding Kinetics in GPCR Drug Discovery. AB - Binding kinetics are the rates of association and dissociation of a drug-protein complex and are important molecular descriptors for the optimization of drug binding to G-protein coupled receptors (GPCRs). There are now many examples of binding kinetics in GPCR drug discovery. In this report, the first principles and examples of binding kinetics in GPCR drug discovery are reviewed. Addressed are the influence of binding kinetics on the translation of binding to the therapeutic window in the context of the equilibrium state of the system and molecular mechanisms of slow binding including induced fit, displacement of water, rebinding and heterovalency. PMID- 26126906 TI - Discovery of GPCR Ligands by Molecular Docking Screening: Novel Opportunities Provided by Crystal Structures. AB - G protein-coupled receptors (GPCRs) constitute the largest group of human membrane proteins and have received significant attention in drug discovery for their important roles in physiological processes. Drug development for GPCRs has been remarkably successful and several of the most profitable pharmaceuticals on the market target members of this superfamily. Breakthroughs in structural biology for GPCRs have revealed how their binding sites recognize extracellular molecules at the atomic level. High-resolution crystal structures of GPCR-drug complexes capturing different receptor conformations are now available, which have provided insights into how ligands stabilize different functional states. Recently, the basis for subtype selectivity and novel allosteric binding sites has also been revealed by crystal structures. These accomplishments provide exciting opportunities to identify novel GPCR ligands using in silico structure based methods such as molecular docking. Increased computational power now enables docking screens of large chemical libraries to identify molecules that complement GPCR binding sites, which may provide possibilities to identify ligands with tailored pharmacological properties. This review focuses on prospective docking screens against GPCRs and how this technique can be used to identify lead candidates with specific signaling or selectivity profiles. The current state of this field suggests that molecular docking, in combination with further understanding of GPCR signaling, will play an important role in future drug discovery. PMID- 26126907 TI - GPCR Binding Technologies: An Overview. AB - With the apparition of concepts such as allosteric modulation and functional selectivity the field of G-protein coupled receptors drug discovery has regained its momentum. To better address this paradigm shift new screening technologies were developed. To identify novel GPCR ligands the screening method of choice was based upon functional assay for the last decade and is now being complemented by several innovative binding technologies. An overview of these assays, as well as an example of a fully integrated platform aiming at identifying novel allosteric modulator with the appropriate profile are presented in this review. PMID- 26126908 TI - Disulfide Bridges in Defensins. AB - Defensins are small cationic cysteine rich peptides, which usually contain 18-45 amino acids and possess amphiphilic properties. The term "defensin" was coined as the sequences of rabbit and human leukin/phagocytin molecules were first reported in 1985. Since then, various defensins were isolated and characterized from insects, plants and vertebrates. Using vertebrate defensins as examples, defensins are categorized into three sub-families based on their different patterns of intramolecular disulfide linkages: alpha defensins, beta defensins, and theta defensins. During the past decades, continuous attentions were casted on various defensins for their broad activity against bacteria, fungi and viruses. In this review, we focus on the effect of characteristic intramolecular disulfide bonds on the antimicrobial activity of defensins. The disulfide bonds are important for holding the defensins in their three dimensional structures, while also contribute to their antimicrobial activity and chemotactic activity. This review summarizes the effects of disulfide bonds, their synthetic formation pathways and potential pharmaceutical applications. PMID- 26126909 TI - Translational Peptide-associated Nanosystems: Promising Role as Cancer Vaccines. AB - Cancer is a heterogeneous disease that results from a multi-step process, being characterized by uncontrolled proliferation, invasion and metastasis. The understanding that tumor cells can be recognized by host immune cells has highlighted the potential advantages of using vaccination purposes to eliminate cancer cells, while avoiding severe side effects associated to conventional cancer treatments. Interesting outcomes have been obtained with the new identified tumor associated antigens (TAAs), including recombinant proteins and peptides. However, these molecules are weakly immunogenic, demanding the concomitant use of adjuvants to boost and achieve a strong tumor-specific immune response. Different classes of nanosystems have been used to protect and deliver several vaccine components. In vitro and preclinical studies have emphasized their promising role to attain a prolonged eradication of cancer cells, including metastasis. However, some studies support the co-entrapment of multiple adjuvants and TAAs within a single particulate carrier, while others indicate that stronger immune responses were obtained using a mixture of nanocarriers entrapping different combinations of TAAs and adjuvants. These apparently contradictory results may be related to nanocarrier physicochemical properties, which have a profound impact on their interaction with targeted cells and consequent biological effects. This review discusses the application of nanoscale systems as cancer vaccines, highlighting the particular characteristics of tumor biology and immunology that have been used to guide the design of these nanodelivery tools. We also aim to explore the major weaknesses that have prevented their wide application in the clinic to overcome the delivery, efficacy and safety issues associated to biological entities. PMID- 26126910 TI - Lanreotide and its Potential Applications in Polycystic Kidney and Liver Diseases. AB - Multiple Galphai protein-coupled somatostatin receptors (SSTRs) are expressed in human kidney and liver tissues. Also, aberrant cAMP signaling has been shown to play a critical role in cysto-genesis and enlargement of the human kidney and liver. Thus, somatostatin (SST) analogs become potential and promising alternatives in treating human polycystic kidney disease (PKD) and polycystic liver disease (PLD) via interacting with Galphai protein-coupled SSTRs and further blocking cAMP production. Lanreotide is a synthetic, long-acting SST analog with high binding affinity to SSTR2, and has been clinically approved for the treatment of acromegaly due to excessive growth hormone. Recently, this SST analog has been applied in the treatment of PKD and PLD, and has shown an effective reduction of liver and kidney volume compared to placebo. This review will discuss the discovery of this peptide and its clinical applications in the treatment of PKD/PLD patients. PMID- 26126911 TI - Nuclear Targeting of Gold Nanoparticles for Improved Therapeutics. AB - Nanomedicine is an exponentially growing field, and gold nanoparticles (GNPs) in particular are extensively used in research due to their abilities as anti-cancer drug carriers for chemotherapy and as dose enhancers in radiotherapy. Most GNP research in the past involved a system where GNP localization was in the cytoplasm of the cell. However, it is predicted that therapy response can be enhanced if GNPs can be effectively targeted into the nucleus. With nuclear targeting, there is a possibility in producing additional free radicals in response to irradiation within the nucleus. This can cause more damage to the DNA of cancer cells. In this review article, we discuss the successful NP-based platforms available for nuclear targeting. In addition, we also present the possible mechanisms of nuclear targeting in detail followed by its applications in cancer therapy. PMID- 26126912 TI - The Structural Features of alpha-Conotoxin Specifically Target Different Isoforms of Nicotinic Acetylcholine Receptors. AB - alpha-Conotoxins (alpha-Ctxs) are the major class of Ctxs extracted from the venom of marine cone snails. Most alpha-Ctxs specifically target various subtypes of the nicotinic acetylcholine receptors (nAChRs) with high affinity and potency as antagonists. Therefore, they may be used for the treatment of numerous diseases that nAChRs involved. The subtype affinity and selectivity of alpha-Ctxs arise from their amino acid composition and geometric conformation of microsites. To reveal the structural features of alpha-Ctxs, detailed structural information on the various nAChR subtypes and their ligand complexes is needed. This review article provides an overview of the structural data on alpha-Ctx-nAChR interactions to investigate the prediction and evaluation of the affinity and selectivity of alpha-Ctx. PMID- 26126913 TI - Recent Advances in Peptide Immunomodulators. AB - With the continued rise in antibiotic-resistant bacteria, there is an immense need for the development of new therapeutic agents. Host-defense peptides (HDPs) offer a unique alternative to many of the current approved antibiotics. By targeting the host rather than the pathogen, HDPs offer several benefits over traditional small molecule drug treatments, such as a slower propensity towards resistance, broad-spectrum activity and lower risk of patients developing sepsis. However, natural peptide structures have many disadvantages as well, including susceptibility to proteolytic degradation, significant costs of synthesis and host toxicity. For this reason, much work has been done to examine peptidomimetic structures, in the hopes of finding a structure with all of the desired qualities of an antibiotic drug. Recently, this research has included synthetic constructs that mimic the behavior of HDPs but have no structural similarity to peptides. This review article focuses on the progression of this field of research, beginning with an analysis of a few prominent examples of natural HDPs and moving on to describe how the information learned by studying them have led to the current design platforms. PMID- 26126914 TI - Progress in Self-assembling Peptide-based Nanomaterials for Biomedical Applications. AB - Self-assembled peptide nanomaterials display the advantageous properties of injectability, biodegradability and biocompatibility. These peptide nanomaterials, by self-assembling, can be widely applied in such fields as drug delivery (small molecules and large molecules), regenerative medicine and nanobiotechnology. In this review, we mainly discuss the properties of these peptide nanomaterials in their physical, chemical and biological aspects. Also discussed are recent advances in their potential applications as drug delivery systems and for uses in regenerative medicine. These current advances show a bright future for the development and clinical applications of self-assembled peptide-based nanotechnology and nanomedicine. However, there are still some big challenges for us to face before these peptide nanomaterials eventually can be used for the treatment of human diseases. PMID- 26126915 TI - alphavbeta3 Integrin-Targeted Peptide/Peptidomimetic-Drug Conjugates: In-Depth Analysis of the Linker Technology. AB - Covalent conjugation of anticancer drugs to targeting carriers (e.g., antibodies or small molecules) capable of selectively binding to tumor-specific antigens, is emerging as a successful strategy to overcome the drawbacks of traditional chemotherapy. Due to its overexpression on blood vessels of human tumors, alphavbeta3 integrin is one of the most studied receptors of tumor-targeted therapeutics: several peptides and peptidomimetics, bearing the RGD (Arg-Gly-Asp) recognition sequence, have been developed as integrin ligands and linked to different anticancer drugs. The resulting integrin- targeted small molecule-drug conjugates (SMDCs) are able to release the cytotoxic agents upon cleavage of a linker under specific conditions (i.e., hydrolysis, enzymatic action or reduction). Despite the significant efforts made in this field, alphavbeta3 integrin-targeted SMDCs are still far from the clinic. In this review, we survey this approach with a special focus on the different linkers employed and the reported biological activities in vitro and in vivo. PMID- 26126916 TI - Idiopathic Anaphylaxis and Histamine Intolerance. PMID- 26126917 TI - Depth probing of the hydride formation process in thin Pd films by combined electrochemistry and fiber optics-based in situ UV/vis spectroscopy. AB - We demonstrate a flexible combined electrochemistry and fiber optics-based in situ UV/vis spectroscopy setup to gain insight into the depth evolution of electrochemical hydride and oxide formation in Pd films with thicknesses of 20 and 100 nm. The thicknesses of our model systems are chosen such that the films are thinner or significantly thicker than the optical skin depth of Pd to create two distinctly different situations. Low power white light is irradiated on the sample and analyzed in three different configurations; transmittance through, and, reflectance from the front and the back side of the film. The obtained optical sensitivities correspond to fractions of a monolayer of adsorbed or absorbed hydrogen (H) and oxygen (O) on Pd. Moreover, a combined simultaneous readout obtained from the different optical measurement configurations provides mechanistic insights into the depth-evolution of the studied hydrogenation and oxidation processes. PMID- 26126918 TI - The Use of Venous Coupler Device in Free Tissue Transfers for Oral and Maxillofacial Reconstruction. AB - PURPOSE: Microvascular anastomosis remains the most challenging and important technique affecting the success of free tissue transfers. A microvascular anastomotic coupling device is often used. This study is a retrospective review of the use of a venous coupler for head and neck reconstruction during a 2-year period at the Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China). MATERIALS AND METHODS: Sixty nine consecutive cases of microvascular free flaps from December 2012 through December 2014 were retrospectively reviewed. Patients' demographic information (age and gender), defect location, flap type, recipient vein, anastomotic time, coupler size, microvascular complications, and flap survival rate were collected and analyzed. RESULTS: Sixty-nine anastomotic coupler devices were used for 69 flaps. Of the 69 flaps performed, there were 26 anterior lateral thigh flaps (37.68%), 25 radial forearm flaps (36.23%), 17 fibula flaps (24.64%), and 1 deep inferior epigastric perforator flap (1.45%). The branch of the internal jugular vein was the most common recipient vein (n = 29; 40.03%), followed by the facial vein (n = 25; 36.23%) and the external jugular vein (n = 15; 21.74%). Coupler sizes ranged from 1.5 to 3.5 mm, with most being 2.5 mm (n = 41; 59.42%), followed by 3.0 mm (n = 19; 27.54%), 2.0 mm (n = 7; 10.14%), 1.5 mm (n = 1; 1.45%), and 3.5 mm (n = 1; 1.45%). The average operation time was 3 to 11 minutes for venous anastomosis (~6 minutes on average). Postoperative complications were seen in 7 of 69 flaps (10.14%), and no complications led to complete flap loss. The overall flap success rate was 100%. Total coupler venous thrombosis rate was 4.35% (3 of 69). CONCLUSION: The microvascular coupler shows reliability for venous anatomosis in head and neck reconstruction free tissue transfers. Use of a microvascular anastomotic coupler could simplify vascular anatomosis, considerably shorten operative time, and achieve excellent vessel patency and flap success rate. PMID- 26126919 TI - Emergency Cricothyroidotomy for Difficult Airway Management After Asynchronous Bilateral Neck Dissections: A Case Report and Literature Review. AB - PURPOSE: This report describes a case that required emergency cricothyroidotomy for an upper airway obstruction owing to laryngeal edema after asynchronous bilateral neck dissections. PATIENT AND METHODS: A 57-year-old man was diagnosed with multicentric squamous cell carcinoma of the tongue (T1 and 2N0M0), and partial glossectomy with primary closure was performed. Three months after surgery, secondary metastases in the right cervical lymph nodes were detected, and a right radical neck dissection was performed. Contrast-enhanced computed tomographic (CT) scan taken 2 weeks after the right neck dissection visualized a possible third metastasis in the left cervical lymph node. Four weeks after the right radical neck dissection, left supraomohyoid neck dissection was carried out. In this surgery, the left internal jugular vein (IJV) was preserved. Nine hours after surgery, severe swelling of the face and pharynx was recognized, resulting in a stoppage of respiration and then an emergency cricothyroidotomy. RESULTS: The patient's life was saved without any encephalopathy or airway trouble. Contrast-enhanced CT scan taken the next day confirmed the preserved left IJV patency. CONCLUSION: Oral and maxillofacial surgeons should be aware of the possibility of life-threatening laryngeal edema associated with bilateral neck dissections even if the unilateral IJV is preserved and should know the procedure for emergency cricothyroidotomy. PMID- 26126920 TI - Bone Augmented With Allograft Onlays for Implant Placement Could Be Comparable With Native Bone. AB - PURPOSE: Bone allograft onlays have great potential in alveolar bone augmentation. However, no comparable cohort study is available in the literature showing whether implants placed in bone augmented with allograft onlays would have a success rate comparable to those placed in native alveolar bone. The objective of the cohort study was to investigate whether the quality of bone augmented with allograft onlays was sufficient to place dental implants and achieve success rates comparable to those in un-grafted bone. MATERIALS AND METHODS: Two cohort studies were performed in 46 and 369 patients, respectively. In the first study, the quality and quantity of bone augmented with allograft onlays (21 patients received 68 allograft onlays) were assessed and compared with those of native alveolar bone (25 patients) using histologic techniques. In the second study, the performance of implants placed in allograft-augmented bone (16 patients) was assessed and compared with implants placed in autograft-augmented bone (43 patients) and native alveolar bone (310 patients). RESULTS: The first study showed no significant differences (P = .33) in bone volume between bone augmented with allograft onlay and native alveolar bone. The second study showed that the success rates of implants placed in native bone (95.8%), autograft augmented bone (96.4%), and allograft-augmented bone (96.8%) were similar to one another. CONCLUSION: The quantity and quality of allograft-augmented bone are similar to those of host native alveolar bone, and the success rate of implants placed in allograft onlays is comparable to those placed in autograft onlays or native alveolar bone. PMID- 26126921 TI - Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells. AB - Zoledronic acid (ZA) is the current standard of care for the therapy of patients with bone metastasis or osteoporosis. ZA inhibits the prenylation of small guanosine-5'-triphosphate (GTP)-binding proteins, such as Ras, and thus inhibit Ras signaling. The present study demonstrated that ZA inhibited cell proliferation and the pentose phosphate pathway (PPP) in bladder cancer cells. In addition, the expression of glucose-6-phosphate dehydrogenase (G6PD, the rate limiting enzyme of the PPP) was found to be inhibited by ZA. Furthermore, the stability of TAp73, which activates the expression G6PD was decreased in zoledronic acid treated cells. Decreased levels of Ras-GTP and phosphorylated extracellular signal-regulated kinase 1/2 were also observed following treatment with ZA. This may be due to the fact that activated Ras was reported to stabilize TAp73 inducing its accumulation. The inhibition of Ras activity by PT inhibitor II also significantly reduced the levels of TAp73 and G6PD and the PPP flux. Moreover, knockdown of TAp73, attenuated the PPP flux and eliminated the affection of ZA on the PPP flux. In conclusion, it was proposed that ZA can inhibit stability of TAp73 and attenuate the PPP via blocking Ras signaling in bladder cancer cells. PMID- 26126922 TI - Synthetic growth reference charts. AB - OBJECTIVES: To reanalyze the between-population variance in height, weight, and body mass index (BMI), and to provide a globally applicable technique for generating synthetic growth reference charts. METHODS: Using a baseline set of 196 female and 197 male growth studies published since 1831, common factors of height, weight, and BMI are extracted via Principal Components separately for height, weight, and BMI. Combining information from single growth studies and the common factors using in principle a Bayesian rationale allows for provision of completed reference charts. RESULTS: The suggested approach can be used for generating synthetic growth reference charts with LMS values for height, weight, and BMI, from birth to maturity, from any limited set of height and weight measurements of a given population. CONCLUSION: Generating synthetic growth reference charts by incorporating information from a large set of reference growth studies seems suitable for populations with no autochthonous references at hand yet. PMID- 26126923 TI - Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis. AB - AIM: Single gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in approximately two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants. METHODS: We analyzed the frequency and types of variants in 717 children in whom high-throughput sequencing of the genes SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4 was performed as part of an evaluation for idiopathic intrahepatic cholestasis cholestasis. The frequency of non-synonymous variants (NSV) was compared with those of 1092 control subjects enrolled in the 1000 Genome Project. RESULTS: The frequency of NSV in single genes was similar between disease (25%) and controls (26%, P = 0.518). In contrast, double or triple NSV in two or more genes were more frequent in disease (n = 7%) than controls (n = 4.7%, P = 0.028). Detailed review of clinical and laboratory information in a subgroup of double or triple heterozygous patients revealed variable gamma glutamyltransferase levels and severity of pruritus, with liver biopsies showing stage 2-3 fibrosis. CONCLUSION: Children with idiopathic intrahepatic cholestasis have a higher frequency of double or triple NSV in SERPINA1, JAG1, ATPB1, ABCB11 or ABCB4. These findings raise the potential role for gene-gene relationships in determining the phenotype of cholestatic liver disease in children. PMID- 26126924 TI - Extinction of conditioned taste aversion is related to the aversion strength and associated with c-fos expression in the insular cortex. AB - Taste aversion learning is a type of conditioning where animals learn to associate a novel taste (conditioned stimulus; CS) with a stimulus inducing symptoms of poisoning or illness (unconditioned stimulus; US). As a consequence animals later avoid this taste, a reaction known as conditioned taste aversion (CTA). An established CTA extinguishes over time when the CS is repeatedly presented in the absence of the US. However, inter-individual differences in CTA extinction do exist. Using a model of behavioral conditioning with saccharin as CS and the immunosuppressant cyclosporine A as US, the present study aimed at further elucidating the factors underlying individual differences in extinction learning by investigating whether extinction of an established CTA is related to the strength of the initially acquired CS-US association. In addition, we analyzed the expression of the neuronal activation marker c-fos in brain structures relevant for acquisition and retrieval of the CTA, such as the insular cortex and the amygdala. We here show that animals, displaying a strong CS-US association during acquisition, maintained a strong CTA during unreinforced CS re exposures, in contrast to animals with moderate CS-US association. Moreover, the latter animals showed increased c-fos mRNA expression in the insular cortex. Our data indicate that CTA extinction apparently depends on the strength of the initially learned CS-US association. In addition, these findings provide further evidence that the memory for the initial excitatory conditioning and its subsequent extinction is probably stored in those structures that participate in the processing of the CS and the US. PMID- 26126925 TI - Thalidomide reduces mechanical hyperalgesia and depressive-like behavior induced by peripheral nerve crush in mice. AB - BACKGROUND: It has been shown that chronic pain is able to induce depressive disorders in humans, in part, due to peripheral inflammation that reaches the central nervous system. However, the mechanisms involved remain to be established. The purpose of this study was to investigate whether sciatic nerve crush could produce depression-like behaviors, in addition to pain-related behaviors, in mice. Once confirmed, this model was used to investigate tumor necrosis factor-alpha (TNF-alpha) as a key mediator involved in the pathophysiology of both pain and depression. EXPERIMENTAL APPROACH: Male Swiss mice were divided into three groups, naive, sham and operated. In the operated group, the sciatic nerve was crushed. Following surgery, animals from the operated group were treated daily by oral gavage (p.o.) with saline (10 ml/kg), fluoxetine (20 mg/kg) or thalidomide (10 mg/kg) for 15 days. Mechanical hyperalgesia was evaluated every 3 days by von Frey filaments and depressive-like behavior was assessed at the end of day 15, using the tail suspension test (TST) and the forced swimming test (FST). Then, samples from the prefrontal cortex, hippocampus and sciatic nerve were processed to measure TNF-alpha levels by enzyme-linked immunosorbent assay (ELISA). RESULTS: Crush caused significant mechanical hyperalgesia and depressive-like behaviors and increased TNF-alpha levels in the sciatic nerve, prefrontal cortex and hippocampus of operated animals. Treatment with fluoxetine or thalidomide reversed crush-induced mechanical hyperalgesia, depressive-like behaviors and the increased TNF-alpha levels in the sciatic nerve, prefrontal cortex and hippocampus. CONCLUSIONS: The sciatic nerve crush model represents a good model to study to mechanisms underlying both pain and depressive-like behaviors. Furthermore, inhibitors of TNF-alpha synthesis, like thalidomide, have a potential to treat depressive disorders associated with neuropathic pain. PMID- 26126926 TI - Modulatory effects by CB1 receptors on rat spinal locomotor networks after sustained application of agonists or antagonists. AB - Sustained administration of cannabinoid agonists acting on neuronal CB1 receptors (CB1Rs) are proposed for treating spasticity and chronic pain. The impact of CB1Rs on mammalian locomotor networks remains, however, incompletely understood. To clarify how CB1Rs may control synaptic activity and locomotor network function, we used the rat spinal cord in vitro which is an advantageous model to investigate locomotor circuit mechanisms produced by the local central pattern generator. Neither the CB1 agonist anandamide (AEA) nor the CB1R antagonist AM 251 evoked early (<3h) changes in mono or polysynaptic reflexes or in locomotor rhythms. Application of AEA (24h) significantly decreased the ability of dorsal root (DR) afferents to elicit oscillatory cycles, and left synaptic responses unchanged. Similar application of LY 2183240, or JZL 184, inhibitors of endocannabinoid uptake processes, produced analogous results. Application of the antagonist AM-251 (or rimonabant) for >3-24h largely impaired locomotor network activity induced by DR stimuli or neurochemicals, and depressed disinhibited bursting without changing reflex amplitude or inducing neurotoxicity even if CB1R immunoreactivity was lowered in the central region. Since CB1R activation usually inhibits cyclic adenosine monophosphate (cAMP) synthesis, we investigated how a 24-h application of AEA or AM-251 affected basal or forskolin-stimulated cAMP levels. While AEA decreased them in an AM-251-sensitive manner, AM-251 per se did not change resting or stimulated cAMP. Our data suggest that CB1Rs may control the circuit gateway regulating the inflow of sensory afferent inputs into the locomotor circuits, indicating a potential site of action for restricting peripheral signals disruptive for locomotor activity. PMID- 26126927 TI - Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia. AB - Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 +/- 0.94 mM (normoglycemia) to 20.76 +/- 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 +/- 1.48 mM to 20.76 +/- 1.56 mM) during ischemia had 24.26% increase in infarct volume (P<0.05) and more serious neurological function deficits (P<0.05). The severe hyperglycemic rats also showed dramatically decreased proliferation of neural stem/progenitor cells (NSPCs) (P<0.05) and down-regulation of the phosphorylation of cyclic-AMP response element-binding protein (pCREB) (P<0.05)and brain-derived neurotrophic factor (BDNF) (P<0.05) in ipsilateral SVZ. But the above-mentioned detrimental effects were not observed in rats that were rendered with mild hyperglycemia (9.43 +/- 1.39-10.13 +/- 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling. PMID- 26126928 TI - European Code against Cancer 4th Edition: Ionising and non-ionising radiation and cancer. AB - Ionising radiation can transfer sufficient energy to ionise molecules, and this can lead to chemical changes, including DNA damage in cells. Key evidence for the carcinogenicity of ionising radiation comes from: follow-up studies of the survivors of the atomic bombings in Japan; other epidemiological studies of groups that have been exposed to radiation from medical, occupational or environmental sources; experimental animal studies; and studies of cellular responses to radiation. Considering exposure to environmental ionising radiation, inhalation of naturally occurring radon is the major source of radiation in the population - in doses orders of magnitude higher than those from nuclear power production or nuclear fallout. Indoor exposure to radon and its decay products is an important cause of lung cancer; radon may cause approximately one in ten lung cancers in Europe. Exposures to radon in buildings can be reduced via a three step process of identifying those with potentially elevated radon levels, measuring radon levels, and reducing exposure by installation of remediation systems. In the 4th Edition of the European Code against Cancer it is therefore recommended to: "Find out if you are exposed to radiation from naturally high radon levels in your home. Take action to reduce high radon levels". Non-ionising types of radiation (those with insufficient energy to ionise molecules) - including extremely low-frequency electric and magnetic fields as well as radiofrequency electromagnetic fields - are not an established cause of cancer and are therefore not addressed in the recommendations to reduce cancer risk. PMID- 26126930 TI - Cross-Coupling of [2-Aryl-1,1,2,2-tetrafluoroethyl](trimethyl)silanes with Aryl Halides. AB - The synthesis of arylCF2CF2SiMe3 and their reactivity in cross-coupling reactions with aryl iodides and aryl bromides to afford a range of 1,1,2,2-tetrafluoro-1,2 arylethanes is reported. The use of pyridine as an alternative to phenanthroline, and the ability to carry out the reaction at 60 degrees C or room temperature are the key features of this Cu-Ag mediated cross-coupling methodology. The chemistry is compatible with (hetero)aryl halides, offering a platform to develop products of interest in material and medicinal chemistry. PMID- 26126929 TI - Antiviral therapy leads to histological improvement of HBeAg-negative chronic hepatitis B patients. AB - BACKGROUND: We investigated hepatic histological changes in a cohort of HBeAg negative chronic hepatitis B (CHB) patients (n=50) under long-term antiviral treatment in clinical practice. METHODS: Liver biopsies were obtained at baseline and after prolonged antiviral treatment with lamivudine (42/50), entecavir (6/50), telbivudine (1/50), or tenofovir (1/50). Due to viral resistance to lamivudine a nucleotide analog was added in 17 patients (adefovir n=11; tenofovir n=6). Twenty-two patients had initially received a 12-month course of pegylated interferon-alpha, followed by nucleos(t)ide analogs. Necroinflammatory activity was graded as 1-minimal (histological activity index [HAI]: 0-3), 2-mild (HAI: 4 8), 3-moderate (HAI: 9-12), or 4-severe (HAI: 13-18); staging was performed according to the METAVIR system. RESULTS: Twenty-seven patients were male and 23 female; mean age was 46.9+/-10.7 years. Mean interval between biopsies was 72.6+/ 27.8 months. Improvement in activity was observed in 31/42 patients (74%) (mean drop -1.1 grade, SD=1.0), and in histological staging in 24/50 patients (48%) (mean drop -0.56 stage, SD=0.73). Importantly, the repeat biopsies of 5/10 patients with initial stage F4 were classified as F3 (n=3), F2 (n=1) or F1 (n=1). Worsening of staging was observed in only one patient. Development of resistance to lamivudine had no significant effect on stage improvement. CONCLUSIONS: Sustained hepatitis B virus suppression with antiviral treatment in HBeAg negative CHB patients leads to reduction in necroinflammatory activity and improvement in staging, regardless of transient viral breakthrough. Potent antivirals in common clinical use for CHB can even lead to regression of fibrous septa and architectural improvement of cirrhotic livers. PMID- 26126931 TI - Yeast cell-based analysis of human lactate dehydrogenase isoforms. AB - Human lactate dehydrogenase (LDH) has attracted attention as a potential target for cancer therapy and contraception. In this study, we reconstituted human lactic acid fermentation in Saccharomyces cerevisiae, with the goal of constructing a yeast cell-based LDH assay system. pdc null mutant yeast (mutated in the endogenous pyruvate decarboxylase genes) are unable to perform alcoholic fermentation; when grown in the presence of an electron transport chain inhibitor, pdc null strains exhibit a growth defect. We found that introduction of the human gene encoding LDHA complemented the pdc growth defect; this complementation depended on LDHA catalytic activity. Similarly, introduction of the human LDHC complemented the pdc growth defect, even though LDHC did not generate lactate at the levels seen with LDHA. In contrast, the human LDHB did not complement the yeast pdc null mutant, although LDHB did generate lactate in yeast cells. Expression of LDHB as a red fluorescent protein (RFP) fusion yielded blebs in yeast, whereas LDHA-RFP and LDHC-RFP fusion proteins exhibited cytosolic distribution. Thus, LDHB exhibits several unique features when expressed in yeast cells. Because yeast cells are amenable to genetic analysis and cell-based high throughput screening, our pdc/LDH strains are expected to be of use for versatile analyses of human LDH. PMID- 26126933 TI - Mood and Anxiety Disorders in Pregnant and Postpartum Women. PMID- 26126932 TI - Assessment of In Vivo Clinical Product Performance of a Weak Basic Drug by Integration of In Vitro Dissolution Tests and Physiologically Based Absorption Modeling. AB - Effective integration of in vitro tests and absorption modeling can greatly improve our capability in understanding, comparing, and predicting in vivo performances of clinical drug products. In this case, we used a proprietary drug candidate galunisertib to describe the procedures of designing key in vitro tests, analyzing relevant experimental and trial data, and integrating them into physiologically based absorption models to evaluate the performances of its clinical products. By simulating the preclinical study result, we estimated high in vivo permeability for the drug. Given the high sensitivity of its solubility to pH, supersaturation may play an important role in the absorption of galunisertib. Using the dynamic dissolution test, i.e., artificial stomach duodenum (ASD) model and simulation, we concluded galunisertib in solution or tablet products could maintain supersaturation during the transit in the gastrointestinal tract (GIT). A physiologically based absorption model was established by incorporating these key inputs in the simulation of Trial 1 results of galunisertib solution. To predict the performance of three tablet products, we developed z-factor dissolution models from the multi-pH USP dissolution results and integrate them into the absorption model. The resultant biopharmaceutical models provided good prediction of the extent of absorption of all three products, but underestimated the rate of absorption of one tablet product. Leveraging the ASD result and optimization with the dissolution model, we identified the limitation of the model due to complexity of estimating the dissolution parameter z and its in vitro-in vivo correlation. PMID- 26126934 TI - Sexual transmission of beneficial microbes. AB - Beneficial sexually transmitted infections (STIs) are an understudied phenomenon with important implications for the evolution of cooperation and host reproductive behavior. Challenging the prevailing expectation that sexual transmission leads to pathogenesis, these symbionts provide new opportunities to examine how STIs might influence sexual selection and the evolution of promiscuity. PMID- 26126935 TI - Models for patterning primary embryonic body axes: The role of space and time. AB - Models for the generation and interpretation of spatial patterns are discussed. Crucial for these processes is an intimate link between self-enhancing and antagonistic reactions. For spatial patterning, long-ranging antagonistic reactions are required that restrict the self-enhancing reactions to generate organizing regions. Self-enhancement is also required for a permanent switch-like activation of genes. This self-enhancement is antagonized by the mutual repression of genes, making sure that in a particular cell only one gene of a set of possible genes become activated - a long range inhibition in the 'gene space'. The understanding how the main body axes are initiated becomes more straightforward if the evolutionary ancestral head/brain pattern and the trunk pattern is considered separately. To activate a specific gene at particular concentration of morphogenetic gradient, observations are compatible with a systematic and time-requiring 'promotion' from one gene to the next until the local concentration is insufficient to accomplish a further promotion. The achieved determination is stable against a fading of the morphogen, as required to allow substantial growth. Minor modifications lead to a purely time-dependent activation of genes; both mechanisms are involved to pattern the anteroposterior axis. A mutual activation of cell states that locally exclude each other accounts for many features of the segmental patterning of the trunk. A possible scenario for the evolutionary invention of segmentation is discussed that is based on a reemployment of interactions involved in asexual reproduction. PMID- 26126936 TI - Large-Area Semiconducting Graphene Nanomesh Tailored by Interferometric Lithography. AB - Graphene nanostructures are attracting a great deal of interest because of newly emerging properties originating from quantum confinement effects. We report on using interferometric lithography to fabricate uniform, chip-scale, semiconducting graphene nanomesh (GNM) with sub-10 nm neck widths (smallest edge to-edge distance between two nanoholes). This approach is based on fast, low cost, and high-yield lithographic technologies and demonstrates the feasibility of cost-effective development of large-scale semiconducting graphene sheets and devices. The GNM is estimated to have a room temperature energy bandgap of ~30 meV. Raman studies showed that the G band of the GNM experiences a blue shift and broadening compared to pristine graphene, a change which was attributed to quantum confinement and localization effects. A single-layer GNM field effect transistor exhibited promising drive current of ~3.9 MUA/MUm and ON/OFF current ratios of ~35 at room temperature. The ON/OFF current ratio of the GNM-device displayed distinct temperature dependence with about 24-fold enhancement at 77 K. PMID- 26126937 TI - FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism. AB - Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23 related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism. PMID- 26126938 TI - Uremia Induces Dental Pulp Ossification but Reciprocally Inhibits Adjacent Alveolar Bone Osteogenesis. AB - Uremic patients are predisposed to atrophy of the alveolar bone and narrowing of the dental pulp chamber. Such pulp chamber changes have only been diagnosed radiologically; however, this has not been supported by any pathological evidence. We used a uremic rat model with secondary hyperparathyroidism induced by 5/6 nephrectomy surgery and high-phosphate diet to examine the dental pulp and adjacent alveolar bone pathology. In addition, we collected pulp tissues for real time PCR. We found an opposite histopathological presentation of the ossified dental pulp and the osteomalacic adjacent alveolar bone. Furthermore, pulp cells with positive staining for Thy-1, a surrogate stem cell marker, were significantly reduced in the pulp of uremic rats compared to the controls, indicating a paucity of stem cells. This was further evidenced by the reduced pulp expression of dickkopf-1 (Dkk-1), a Wnt/beta-catenin signaling inhibitor produced by mesenchymal stem cells. In contrast, expressions of receptor activator of nuclear factor kappaB ligand (RANKL) and RANK in uremic pulp were up regulated, probably to counteract the ossifying process of uremic pulp. In conclusion, uremic pulp ossifications were associated with a paucity of stem cells and dysregulated Dkk-1 and RANKL signaling systems, further shifting the imbalance toward osteogenesis. Strategies to counteract such an imbalance may offer a potential therapeutic target to improve dental health in uremic patients, which warrants further interventional studies. PMID- 26126939 TI - Comparative analysis of MDCT and MRI in diagnosing chronic gallstone perforation and ileus. AB - OBJECT: To evaluate MDCT and MRI in identifying chronic gallstone perforation (GSP) and ileus, even the risk factors prior to perforation. METHODS: Twenty three cases of gallstone ileus (GSI) and three cases of calculus gallbladder choledochus perforation were scanned by MDCT before treatment. Meanwhile, twelve patients received two-view abdominal X-ray film and eight patients received MRI examination. All images were analyzed respectively and blindly to the results of surgery or interventional endoscopy, besides five cases of MDCT and one case of MRI images scanned before GSP were analyzed comparatively. RESULTS: MDCT could identify 100.0% of intestinal obstruction and pneumobilia of GSI, it had not statistical difference with abdominal X-ray film. But MDCT could differenciate and precisely locate 88.5% of the ectopic stone, higher than that of abdominal X ray film (50%), p value ? 0.05, moreover it presented cholecystitis, edema or discontinuous walls of gallbladder and intestine and bilio-enteral fistula (26.9%). MRI and MRCP could precisely visualize the fistula (100%) and the ruptured bile duct. Abnormal edema or thin gallbladder wall, large stone size (> 2 cm) and incarceration in the neck of gallbladder, the blurring fat line between gallbladder and duodenum were considered main risk signs prior to GSP. CONCLUSION: MDCT is being considered as an effective and reliable technique to identify GSP and GSI early, however MRI and MRCP will aid to differentiate the complex GSP. It will be a considerable prospective for MDCT and MRI to estimate the risk factors prior to gallbladder perforation. PMID- 26126940 TI - Recovery from prolonged deep rocuronium-induced neuromuscular blockade: A randomized comparison of sugammadex reversal with spontaneous recovery. AB - BACKGROUND: Deep neuromuscular blockade (NMB) may not always be maintained to the end of surgery and the depth of block may be allowed to gradually diminish over time, particularly if reversal of NMB is not routinely performed. AIM: The current study aimed to assess recovery from deep rocuronium-induced NMB with sugammadex compared with placebo, provide data regarding the extent of residual blockade after deep rocuronium-induced NMB (placebo group), and to determine whether complete and reliable recovery could be provided by sugammadex (sugammadex group). MATERIALS AND METHODS: This was a randomized, placebo controlled, safety-assessor-blinded study in adult patients of American Society of Anesthesiologists Class I to III. Patients with clinically relevant kidney or liver insufficiency were excluded. Anesthesia was administered as routinely practiced at each study site. Rocuronium 0.6 mg/kg was administered for intubation, with maintenance doses of 0.1-0.2 mg/kg as needed. After the last rocuronium dose, at deep NMB (target depth 1-2 post-tetanic counts), patients received a single dose of sugammadex 4.0 mg/kg or placebo as randomized. The primary endpoint was time from sugammadex or placebo administration to recovery of the train-of-four (TOF) ratio to 0.9. Safety was assessed through monitoring of adverse events, vital signs and physical examination. Patients were also assessed for evidence of residual or recurrence of NMB. With this design, the study will provide data regarding the extent of residual blockade under these conditions (placebo group), and determine whether complete and reliable recovery could be provided by sugammadex (sugammadex group). RESULTS: Recovery to a TOF ratio of >= 0.9 with sugammadex was significantly faster (~ 40 times) than spontaneous recovery: geometric mean (95 % confidence interval) times were 2.2 (1.9-2.5) and 89.8 (80.1-100.7) min, respectively (p < 0.0001, N = 134); maximum spontaneous recovery was 289.8 min. Safety was comparable between groups, with no recurrence of blockade. CONCLUSIONS: This study confirms a prolonged residual blockade in patients who did not receive sugammadex, with median time to recovery > 1.5 h in the placebo group and one patient taking 4.8 h to achieve a safe level of neuromuscular function recovery following deep NMB. In contrast, sugammadex provided complete and reliable recovery of neuromuscular function (median time to recovery of 2.0 min). Thus, deep NMB with rocuronium until the end of the operation may be possible in combination with sugammadex reversal. PMID- 26126941 TI - Characterization of a halotolerant acetoclastic methanogen highly enriched from marine sediment and its application in removal of acetate. AB - A marine sediment collected from Hiroshima Bay was cultured in artificial seawater, containing 0.51 M NaCl and 60 mM acetate and was found to exhibit active methane production at 37 degrees C. Following four successive serial dilutions of cultures in medium containing 0.51 M NaCl, 60 mM acetate, and antibiotics, the well-acclimated methanogen was found to exhibit growth over a range of NaCl concentration (between 0 M and 2.06 M). The specific growth rates of the highly enriched methanogen, termed strain HA, in the absence of NaCl and in the presence of 1.54 M NaCl were estimated to be 0.037 h(-1) and 0.027 h(-1), respectively. The pH and temperature for optimum growth were determined to be 7.0 8.8 and 37 degrees C, respectively. Although cells that had morphology similar to Methanosaeta sp. became dominant in the culture, methane production was still detected in the medium containing 0.51 M NaCl and other substrates such as methanol, formate, and methylamine, indicating contamination with other methanogens. The phylogenetic tree based on 16S rRNA gene sequences revealed that the strain HA was closely related to Methanosaeta harundinacea 6Ac and 8Ac(T), with sequence similarity of 98% and 97%, respectively. The continuous removal of acetate with upflow anaerobic filter reactor for industrial use of strain HA determined a methane production rate of 70 mM/d under condition of 0.51 M NaCl and successful methane production even under 1.54 M NaCl. PMID- 26126942 TI - Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography. AB - OBJECTIVES: Aim of this study was to quantify the binding of [(123) I]FP-CIT in striatum of healthy tree shrews. [(123) I]FP-CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [(123) I]FP-CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine. EXPERIMENTAL DESIGN: Quantitative in vitro autoradiography with [(123) I]FP-CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [(3) H]raclopride was also performed. PRINCIPAL OBSERVATIONS: Saturation analysis revealed high specificity of [(123) I]FP-CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats (KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats (Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [(3) H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats (Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews (KD = 1.27 versus 0.59 nM). CONCLUSIONS: The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [(123) I]FP-CIT in SPECT studies of living tree shrews. PMID- 26126943 TI - Immunoregulatory and antitumor activity of schizophyllan under ultrasonic treatment. AB - Aim of this study was to investigate the effect of ultrasonic treatment on the biological activities of schizophyllan (SPG) from Schizophyllum commune. The immunoregulatory and antitumor activity in vitro and in vivo of SPG and ultrasonic-treated SPG (USPG) were evaluated by splenic lymphocytes, macrophages RAW264.7 and human breast carcinoma T-47D cells. Compared with SPG, USPG fractions had small molecular weight and narrow distribution. Meantime, more enhancement of NO production in macrophages RAW264.7, lymphocytes proliferation rates, IL-2 and TNF-alpha level from spleen lymphocytes and T-47D cells inhibition rates were observed in USPG fractions groups. This result indicated that the immune-enhancing and antitumor activity of SPG was significantly improved after ultrasonic treatment. USPG60 exhibited the highest biological activity in this study. In conclusion, application of ultrasonic technology on SPG preparation is an efficient approach to get high biological polysaccharide, and USPG60 might be a potential functional component for immunoregulatory and cancer treatment. PMID- 26126944 TI - Isolation and prebiotic activity of inulin-type fructan extracted from Pfaffia glomerata (Spreng) Pedersen roots. AB - Pfaffia glomerata (Amaranthaceae) is popularly known as "Brazilian ginseng." Previous studies have shown that fructose is the major carbohydrate component present in its roots. Inulin-type fructans, polymers of fructose, are the most widespread and researched prebiotics. Here, we isolated and chemically characterized inulin extracted from P. glomerata roots and investigated its potential prebiotic effect. Fructans were isolated and their structures were determined using colorimetric, chromatography, polarimetry, and spectroscopic analysis. The degree of polymerization (DP) was determined, and an in vitro prebiotic test was performed. The structure of inulin was confirmed by chromatography and spectroscopic analysis and through comparison with existing data. Representatives from the genera Lactobacillus and Bifidobacterium utilized inulin from P. glomerata, because growth was significantly stimulated, while this ability is strain specific. The results indicated that inulin extracted from P. glomerata roots represents a promising new source of inulin-type prebiotics. PMID- 26126945 TI - Divalent metal ions binding properties of goat serum mannose binding lectin. AB - Mannose binding lectin (MBL) is a collectin with C-terminus Carbohydrate Recognition Domain (CRD) which binds with pathogen and arbitrate functions like activation of complement pathway, opsonization etc. The CRD required Ca(2+) ions to recognize the sugar moieties. In the present study the binding properties of CRD with divalent ions were characterized by Electron Paramagnetic Resonance (EPR) spectroscopy. The results revealed that the metal binding site of CRD is of approximately 1 A diameter and ions greater than the size are not able to enter. PMID- 26126947 TI - Spatial Moran models, II: cancer initiation in spatially structured tissue. AB - We study the accumulation and spread of advantageous mutations in a spatial stochastic model of cancer initiation on a lattice. The parameters of this general model can be tuned to study a variety of cancer types and genetic progression pathways. This investigation contributes to an understanding of how the selective advantage of cancer cells together with the rates of mutations driving cancer, impact the process and timing of carcinogenesis. These results can be used to give insights into tumor heterogeneity and the "cancer field effect," the observation that a malignancy is often surrounded by cells that have undergone premalignant transformation. PMID- 26126948 TI - Macrophage-specific metalloelastase (MMP-12) immunoexpression in the osteochondral unit in osteoarthritis correlates with BMI and disease severity. AB - BACKGROUND: Metalloproteinase 12 (MMP-12) is induced in chondrocytes during fetal development and malignant transformation. OBJECTIVES: The aim of our study is to examine the expression of MMP-12 in the cartilage and the subchondral bone of patients with osteoarthritis (OA) and to correlate its expression with disease severity and anthropometric characteristics. METHODS: Overall, 60 sections from 20 patients with idiopathic OA, were examined for the immunolocalization of MMP 12. As controls, we used the femoral heads of 4 patients treated with seniarthroplasty after fracture. Demographic characteristics and Body Mass Index (BMI) were calculated for all subjects. RESULTS: Specimens were divided into four groups based on the Mankin histological severity score. The immunohistochemical study showed MMP-12 expression in the cartilage and subchonral bone of OA patients, while there was no expression in normal controls. At the moderate OA changes (Mankin score: 6-7), MMP-12 was detected mainly at the matrix of fibrocartilage tissue. During disease progression, MMP-12 was expressed at the sides of the cartilage and bone erosion and in the bone cysts. Furthermore, it was traced in the osteocytes of the subchondral bone. Osteoblast-like cells and bone lining cells express MMP-12 during the stage of severe OA (Mankin: >=8). Osteoclasts expressing MMP-12 were also detected in the group of severe OA. Interestingly, MMP-12 expression was positively correlated with the age and the BMI of OA patients. CONCLUSION: The increased expression of MMP-12 in the bone cartilage unit of OA patients suggests a possible role in OA pathogenesis and progression. LEVEL OF EVIDENCE: III, prospective comparative study. PMID- 26126949 TI - Lipoprotein apheresis reduces circulating galectin-3 in humans. AB - BACKGROUND: Plasma galectin-3 (Gal-3) is elevated in, and drives, diverse systemic inflammatory disorders, including cancer, cardiovascular diseases, and diabetes. Circulating Gal-3 promotes tumorigenesis and metastasis, as well as fibrotic remodeling, and is a promising therapeutic target. Apheresis has proven utility in reducing circulating disease-promoting substances, exemplified by the success of lipoprotein apheresis (LA) in abrogating cardiovascular disease progression in drug-refractory hypercholesterolemia patients. We compared the clinical utility of two FDA-approved LA systems in reducing plasma Gal-3 in humans. METHODS: Plasma Gal-3 levels were assessed by ELISA in blinded samples drawn pre- and post-apheresis from hypercholesterolemia patients (n = 10/group) undergoing therapeutic LA using either a heparin-induced extracorporeal LDL precipitation (HELP) or dextran sulfate-adsorption (DSA) system. RESULTS: Mean baseline plasma Gal-3 concentrations (+/-SD) were 14.3 +/- 5.1 (range 6.6-22.8) and 14.5 +/- 2.8 (range 10.6-19.8) ng/mL in the HELP and DSA groups, respectively. Post-apheresis Gal-3 levels were respectively reduced by 19.4% and 22.7% in the HELP (P = 0.0094) and DSA (P = 0.0027) systems (paired t-tests); the difference between devices was insignificant (P = 0.5288; Mann-Whitney). Post treatment Gal-3 levels were 11.3 +/- 3.7 (HELP; range 4.5-16.3) and 11.3 +/- 3.8 (DSA; range 7.5-20.7) ng/mL. CONCLUSIONS: Circulating Gal-3 levels showed a statistically significant decrease in humans undergoing therapeutic LA. Although absolute Gal-3 reduction was ~19-23%, this effect, combined with reducing atherogenic LDL and other inflammation mediators (e.g., CRP, fibrinogen, Lp-PLA2 ), may enhance apheresis clinical benefits. Applying new Gal-3-specific extraction technologies to apheresis may be advantageous in treating diverse pathologies that are promoted by elevated plasma Gal-3. J. Clin. Apheresis 31:388 392, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26126950 TI - Adolescent Experiences With Intrauterine Devices: A Qualitative Study. AB - PURPOSE: The purpose of this study was to improve understanding of adolescents' reasons for choosing an intrauterine device (IUD) and to explore experiences that led to continuation or discontinuation of the levonorgestrel intrauterine system (LNG-IUS) and the copper IUD (copper IUD). METHODS: We conducted focus groups (FGs) with adolescents and young women who were current or former IUD users stratified by IUD type and 12-month IUD continuation or discontinuation. All subjects were participants from the Contraceptive CHOICE Project. FG data were supplemented with in-depth interviews (IDIs). Data collection was continued until thematic saturation was reached. Transcripts were independently coded by two researchers, and interrater reliability was calculated using a Kappa coefficient. Analysis followed a standard text-analysis approach. RESULTS: Thirteen FGs and seven IDIs were conducted with 43 young women. Effectiveness, duration of use, convenience, and potential bleeding changes emerged as themes for both choosing and continuing IUDs. Some women chose the LNG-IUS to achieve amenorrhea, whereas copper IUD users wanted a nonhormonal method and continued menses. Copper IUD users cited expulsion and bleeding irregularities as reasons for discontinuation, whereas LNG-IUS users reported bleeding irregularities and continued pain as reasons for removal. IUD users noted an adjustment period of weeks to months in which side effects were present before lessening. CONCLUSIONS: Effectiveness, duration of use, convenience, and potential changes in bleeding patterns drove adolescents' choice and continuation of an IUD. Bleeding changes and pain contributed to IUD discontinuation. Discussion of effectiveness, duration and convenience, and anticipatory guidance regarding post-insertion side effects may be important in counseling young women about IUDs. PMID- 26126951 TI - The effects of physical activity interventions on preventing weight gain and the effects on body composition in young adults with intellectual disabilities: systematic review and meta-analysis of randomized controlled trials. AB - The aim of this study was to examine the literature on randomized controlled trials examining the efficacy of physical activity interventions to prevent weight gain and the effects on body composition in young adults with intellectual disabilities.A systematic search of Medline, Emabse, CINHAL, PsychINFO, Cochrane library and ERIC was conducted from 1946 to September 2014. Eligibility criteria included; randomized controlled trials of a physical activity intervention: objective measure of body weight and body composition; young adults (age range 16 24 years) with intellectual disabilities. Six studies met the eligibility criteria. The interventions varied in their prescription of physical activity including aerobic and strength-based activities. The mean duration of the interventions was 15.3 (range 10-21 weeks). There was no significant effect of physical activity interventions on body weight (weighted mean difference: -0.17 kg, 95% confidence interval, -1.04 kg to 0.72 kg) and body composition outcomes. The meta-analysis showed that physical activity interventions did not prevent weight gain in young adults with intellectual disabilities. Published studies are inadequate to form firm conclusions. Future longer term studies of interventions specifically designed for this population group are required to elucidate the effects of physical activity interventions on body composition and the prevention of weight gain in young adults with intellectual disabilities. PMID- 26126952 TI - Computation of dispersion relations for axially symmetric guided waves in cylindrical structures by means of a spectral decomposition method. AB - In this paper, a method to determine the complex dispersion relations of axially symmetric guided waves in cylindrical structures is presented as an alternative to the currently established numerical procedures. The method is based on a spectral decomposition into eigenfunctions of the Laplace operator on the cross section of the waveguide. This translates the calculation of real or complex wave numbers at a given frequency into solving an eigenvalue problem. Cylindrical rods and plates are treated as the asymptotic cases of cylindrical structures and used to generalize the method to the case of hollow cylinders. The presented method is superior to direct root-finding algorithms in the sense that no initial guess values are needed to determine the complex wave numbers and that neither starting at low frequencies nor subsequent mode tracking is required. The results obtained with this method are shown to be reasonably close to those calculated by other means and an estimate for the achievable accuracy is given. PMID- 26126953 TI - The ontogeny of morphological defenses in Kemp's ridley (Lepidochelys kempii) and loggerhead (Caretta caretta) sea turtles. AB - Marine turtles are large reptiles that compensate for high juvenile mortality by producing hundreds of hatchlings during a long reproductive lifespan. Most hatchlings are taken by predators during their migration to, and while resident in, the open ocean. Their survival depends upon crypticity, minimizing movement to avoid detection, and foraging efficiently to grow to a size too difficult for predators to either handle or swallow. While these behavioral antipredator tactics are known, changes in morphology accompanying growth may also improve survival prospects. These have been only superficially described in the literature. Here, we compare the similarities and differences in presumed morphological defenses of growing loggerhead (Caretta caretta) and Kemp's ridley (Lepidochelys kempii) posthatchlings, related species that differ in growth rate, timing of habitat shift (the return from oceanic to neritic locations), and size at maturity. In both species, vertebral spination and carapace widening increase disproportionally as small turtles grow, but later in ontogeny, the spines regress, sooner in ridley than in loggerhead turtles. Carapace widening occurs in both species but loggerheads are always longer than they are wide whereas in Kemp's ridley turtles, the carapace becomes as wide as long. Our analysis indicates that these changes are unrelated to when each species shifts habitat but are related to turtle size. We hypothesize that the spines function in small turtles as an early defense against gape-limited predators, but changes in body shape function throughout ontogeny-initially to make small turtles too wide to swallow and later by presenting an almost flat and hardened surface that large predators (such as a sharks) are unable to grasp. The extremely wide carapace of the Kemp's ridley may compensate for its smaller adult size (and presumed greater vulnerability) than the loggerhead. PMID- 26126954 TI - SCAMPs: A new tool for an old problem. AB - Standardized Clinical Assessment and Management Plans (SCAMPs) are tools to facilitate learning and discovery in a rapid iterative fashion. SCAMPs aim to reduce practice variation, improve patient outcomes, and identify unnecessary resource utilization. They are a quality improvement initiative that captures targeted data about clinical decision making. These data are then analyzed to change and improve the SCAMP algorithm itself. The purpose of this article is to describe the general SCAMPs methodology and to compare SCAMPs to traditional tools like clinical practice guidelines. PMID- 26126955 TI - An Unusual Presentation of Disseminated Histoplasmosis: Case Report and Review of Pediatric Immunocompetent Patients from India. AB - Histoplasmosis is a progressive disease caused by dimorphic intracellular fungi and can prove fatal. Usually, it is present in immunocompromised individuals and immunocompetent individuals in the endemic zones. We report an unusual presentation of progressive disseminated histoplasmosis. The patient in the present case report was immunocompetent child and had fever, bone pains, gradual weight loss, lymphadenopathy and hepatosplenomegaly. Disseminated histoplasmosis (DH) was diagnosed on microscopic examination and fungal culture of bone marrow, blood, skin biopsy and lymph node aspirate. The patient died on seventh day of amphotericin B. In the absence of predisposing factors and classical clinical presentation of febrile neutropenia, lung, adrenal and oropharyngeal lesions, the disease posed a diagnostic challenge. Progressive disseminated histoplasmosis in children can be fatal despite timely diagnosis and therapy. In India, disseminated histoplasmosis is seen in immunocompetent hosts. All the pediatrics immunocompetent cases from India are also reviewed. PMID- 26126956 TI - Genomic DNA extraction methods using formalin-fixed paraffin-embedded tissue. AB - As new technologies come within reach for the average cytogenetic laboratory, the study of chromosome structure has become increasingly more sophisticated. Resolution has improved from karyotyping (in which whole chromosomes are discernible) to fluorescence in situ hybridization and comparative genomic hybridization (CGH, with which specific megabase regions are visualized), array based CGH (aCGH, examining hundreds of base pairs), and next-generation sequencing (providing single base pair resolution). Whole genome next-generation sequencing remains a cost-prohibitive method for many investigators. Meanwhile, the cost of aCGH has been reduced during recent years, even as resolution has increased and protocols have simplified. However, aCGH presents its own set of unique challenges. DNA of sufficient quantity and quality to hybridize to arrays and provide meaningful results is required. This is especially difficult for DNA from formalin-fixed paraffin-embedded (FFPE) tissues. Here, we compare three different methods for acquiring DNA of sufficient length, purity, and "amplifiability" for aCGH and other downstream applications. Phenol-chloroform extraction and column-based commercial kits were compared with adaptive focused acoustics (AFA). Of the three extraction methods, AFA samples showed increased amplicon length and decreased polymerase chain reaction (PCR) failure rate. These findings support AFA as an improvement over previous DNA extraction methods for FFPE tissues. PMID- 26126958 TI - Metabolism of (-)-cis- and (-)-trans-rose oxide by cytochrome P450 enzymes in human liver microsomes. AB - The in vitro metabolism of (-)-cis- and (-)-trans-rose oxide was investigated using human liver microsomes and recombinant cytochrome P450 (P450 or CYP) enzymes for the first time. Both isomers of rose oxide were incubated with human liver microsomes, and the formation of the respective 9-oxidized metabolite were determined using gas chromatography-mass spectrometry (GC-MS). Of 11 different recombinant human P450 enzymes used, CYP2B6 and CYP2C19 were the primary enzymes catalysing the metabolism of (-)-cis- and (-)-trans-rose oxide. CYP1A2 also efficiently oxidized (-)-cis-rose oxide at the 9-position but not (-)-trans-rose oxide. alpha-Naphthoflavone (a selective CYP1A2 inhibitor), thioTEPA (a CYP2B6 inhibitor) and anti-CYP2B6 antibody inhibited (-)-cis-rose oxide 9-hydroxylation catalysed by human liver microsomes. On the other hand, the metabolism of (-) trans-rose oxide was suppressed by thioTEPA and anti-CYP2B6 at a significant level in human liver microsomes. However, omeprazole (a CYP2C19 inhibitor) had no significant effects on the metabolism of both isomers of rose oxide. Using microsomal preparations from nine different human liver samples, (-)-9-hydroxy cis- and (-)-9-hydroxy-trans-rose oxide formations correlated with (S) mephenytoin N-demethylase activity (CYP2B6 marker activity). These results suggest that CYP2B6 plays important roles in the metabolism of (-)-cis- and (-) trans-rose oxide in human liver microsomes. PMID- 26126959 TI - Drug release mechanisms from amorphous solid dispersions. PMID- 26126957 TI - Expression of a rice glutaredoxin in aleurone layers of developing and mature seeds: subcellular localization and possible functions in antioxidant defense. AB - MAIN CONCLUSION: A rice glutaredoxin isoform (OsGrxC2;2) with antioxidant capacity is expressed abundantly in seed tissues and is localized to storage vacuoles in aleurone layers in developing and mature seeds. Seed tissues undergo drastic water loss at the late stage of seed development, and thus need to tolerate oxidative injuries associated with desiccation. We previously found a rice glutaredoxin isoform, OsGrxC2;2, as a gene expressed abundantly in developing seeds. Since glutaredoxin is involved in antioxidant defense, in the present study we investigated the subcellular localization and expression profile of OsGrxC2;2 and whether OsGrxC2;2 has a role in the defense against reactive oxygen species. Western blotting and immunohistochemistry revealed that the OsGrxC2;2 protein accumulated at a high level in the embryo and aleurone layers of developing and mature seeds. The OsGrxC2;2 in developing seeds was particularly localized to aleurone grains, which are storage organelles derived from vacuoles. Overexpression of OsGrxC2;2 resulted in an enhanced tolerance to menadione in yeast and methyl viologen in green leaves of transgenic rice plants. These results suggest that OsGrxC2;2 participates in the defense against oxidative stress in developing and mature seeds. PMID- 26126960 TI - ALG3-CDG: Report of two siblings with antenatal features carrying homozygous p.Gly96Arg mutation. AB - Congenital disorders of glycosylation (CDG) are a group of inborn errors of metabolism presenting with heterogeneous multisystemic clinical manifestations. To date, more than 60 different types of CDG have been reported. ALG3-CDG is very rare, with only nine patients described so far. We report two affected siblings presenting prenatally with skeletal abnormalities associated with dysmorphic features, cerebellar vermis hypoplasia, corpus callosum agenesis, hepatic fibrosis and poor prognosis. This is the first detailed report of an affected fetus including clinical, radiographic and pathological findings. The patients showed some clinical features previously unreported in ALG3-CDG, such as bone dysplasia, cataract, corneal opacities, and pons hypoplasia. Both patients were homozygous for the previously unreported p.Gly96Arg mutation of the ALG3 gene. One patient showed chondrodysplasia punctata (CDP), which has not been previously reported in CDG. An exhaustive genetic and metabolic assessment, performed in order to rule out other possible causes of CDP, showed abnormally raised levels of anti-nuclear antibodies in the mother who, nevertheless, did not show any clinical sign of autoimmune disease during a 7 years follow-up. We speculate that the observed CDP may be explained by the maternal anti-nuclear antibodies; alternatively, a possible link to the underlying metabolic disorder cannot be ruled out. In conclusion, we report the clinical, pathological, biochemical and molecular characterization of two further patients affected by ALG3-CDG, expanding the phenotypic spectrum of this very rare disease. PMID- 26126961 TI - ent-Abietane-Type and Related Seco-/Nor-diterpenoids from the Rare Chloranthaceae Plant Chloranthus sessilifolius and Their Antineuroinflammatory Activities. AB - Fourteen new ent-abietane-type diterpenoids, sessilifols A-N (1-14), and three related new norditerpenoids (15-17) were isolated from Chloranthus sessilifolius. The absolute configurations were determined by single-crystal X-ray diffraction analysis, the modified Mosher's method, and/or the observed Cotton effects in their electronic circular dichroism spectra. Sessilifols A (1) and B (2) possess an uncommon five-membered C-ring rearranged by oxidative cleavage of the C-13/C 14 bond in abieta-7,13-diene followed by the formation of a new C-C bond between C-12 and C-14. Sessilifol C (3) is a rare 7,8-seco-9-spiro-fused ent-abietane, whereas sessilifol O (15) represents the first example of a naturally occurring 14-norabietane-type diterpenoid. Compounds 6 and 9 were found to have moderate antineuroinflammatory activities by inhibiting the nitric oxide production in lipopolysaccharide-stimulated murine BV-2 microglial cells, with IC50 values of 8.3 and 7.4 MUM, respectively. PMID- 26126962 TI - A simple methodological validation of the gas/particle fractionation of polycyclic aromatic hydrocarbons in ambient air. AB - The analysis of polycyclic aromatic hydrocarbons (PAH) in ambient air requires the tedious experimental steps of both sampling and pretreatment (e.g., extraction or clean-up). To replace pre-existing conventional methods, a simple, rapid, and novel technique was developed to measure gas-particle fractionation of PAH in ambient air based on 'sorbent tube-thermal desorption-gas chromatograph mass spectrometer (ST-TD-GC-MS)'. The separate collection and analysis of ambient PAHs were achieved independently by two serially connected STs. The basic quality assurance confirmed good linearity, precision, and high sensitivity to eliminate the need for complicated pretreatment procedures with the detection limit (16 PAHs: 13.1 +/- 7.04 pg). The analysis of real ambient PAH samples showed a clear fractionation between gas (two-three ringed PAHs) and particulate phases (five six ringed PAHs). In contrast, for intermediate (four ringed) PAHs (fluoranthene, pyrene, benz[a]anthracene, and chrysene), a highly systematic/gradual fractionation was established. It thus suggests a promising role of ST-TD-GC-MS as measurement system in acquiring a reliable database of airborne PAH. PMID- 26126964 TI - Properties of the Mechanosensitive Channel MscS Pore Revealed by Tryptophan Scanning Mutagenesis. AB - Bacterial mechanosensitive channels gate when the transmembrane turgor rises to levels that compromise the structural integrity of the cell wall. Gating creates a transient large diameter pore that allows hydrated solutes to pass from the cytoplasm at rates close to those of diffusion. In the closed conformation, the channel limits transmembrane solute movement, even that of protons. In the MscS crystal structure (Protein Data Bank entry 2oau ), a narrow, hydrophobic opening is visible in the crystal structure, and it has been proposed that a vapor lock created by the hydrophobic seals, L105 and L109, is the barrier to water and ions. Tryptophan scanning mutagenesis has proven to be a highly valuable tool for the analysis of channel structure. Here Trp residues were introduced along the pore-forming TM3a helix and in selected other parts of the protein. Mutants were investigated for their expression, stability, and activity and as fluorescent probes of the physical properties along the length of the pore. Most Trp mutants were expressed at levels similar to that of the parent (MscS YFF) and were stable as heptamers in detergent in the presence and absence of urea. Fluorescence data suggest a long hydrophobic region with low accessibility to aqueous solvents, extending from L105/L109 to G90. Steady-state fluorescence anisotropy data are consistent with significant homo-Forster resonance energy transfer between tryptophan residues from different subunits within the narrow pore. The data provide new insights into MscS structure and gating. PMID- 26126966 TI - Ethnic variation of TET2 SNP rs2454206 and association with clinical outcome in childhood AML: a report from the Children's Oncology Group. PMID- 26126965 TI - Humoral factors in ALS patients during disease progression. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons in the CNS and leading to paralysis and death. There are currently no effective treatments for ALS due to the complexity and heterogeneity of factors involved in motor neuron degeneration. A complex of interrelated effectors have been identified in ALS, yet systemic factors indicating and/or reflecting pathological disease developments are uncertain. The purpose of the study was to identify humoral effectors as potential biomarkers during disease progression. METHODS: Thirteen clinically definite ALS patients and seven non-neurological controls enrolled in the study. Peripheral blood samples were obtained from each ALS patient and control at two visits separated by 6 months. The Revised ALS Functional Rating Scale (ALSFRS-R) was used to evaluate overall ALS-patient functional status at each visit. Eleven humoral factors were analyzed in sera. Cytokine levels (GM-CSF, IL-1beta, IL-2, IL-4, IL 5, IL-6, IL-8, IL-10, and TNF-alpha) were determined using the Bio-Rad Bio Plex(r) Luminex 200 multiplex assay system. Nitrite, a breakdown product of NO, was quantified using a Griess Reagent System. Glutathione (GSH) concentrations were measured using a Glutathione Fluorometric Assay Kit. RESULTS: ALS patients had ALSFRS-R scores of 30.5 +/- 1.9 on their first visit and 27.3 +/- 2.7 on the second visit, indicating slight disease progression. Serum multiplex cytokine panels revealed statistically significant changes in IL-2, IL-5, IL-6, and IL-8 levels in ALS patients depending on disease status at each visit. Nitrite serum levels trended upwards in ALS patients while serum GSH concentrations were drastically decreased in sera from ALS patients versus controls at both visits. CONCLUSIONS: Our results demonstrated a systemic pro-inflammatory state and impaired antioxidant system in ALS patients during disease progression. Increased levels of pro-inflammatory IL-6, IL-8, and nitrite and significantly decreased endogenous antioxidant GSH levels could identify these humoral constituents as systemic biomarkers for ALS. However, systemic changes in IL-2, IL-5, and IL-6 levels determined between visits in ALS patients might indicate adaptive immune system responses dependent on current disease stage. These novel findings, showing dynamic changes in humoral effectors during disease progression, could be important for development of an effective treatment for ALS. PMID- 26126967 TI - Genome-scale definition of the transcriptional programme associated with compromised PU.1 activity in acute myeloid leukaemia. AB - Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild type PU.1. PU.1 induction caused transition from leukaemia phenotype to monocytic differentiation. Global binding maps for PU.1, CEBPA and the histone mark H3K27Ac with and without PU.1 induction showed that mutant PU.1 retains DNA-binding ability, but the induction of wild-type protein dramatically increases both the number and the height of PU.1-binding peaks. Correlating chromatin immunoprecipitation (ChIP) Seq with gene expression data, we found that PU.1 recruitment coupled with increased histone acetylation induces gene expression and activates a monocyte/macrophage transcriptional programme. PU.1 induction also caused the reorganisation of a subgroup of CEBPA binding peaks. Finally, we show that the PU.1 target gene set defined in our model allows the stratification of primary human AML samples, shedding light on both known and novel AML subtypes that may be driven by PU.1 dysfunction. PMID- 26126969 TI - Ternary transition-metal fluoride precursors for the fluorolytic sol-gel route: new insights into speciation and decomposition. AB - The nanoscaled ternary transition-metal fluorides Li3MF6 (M = V, Fe, Mn) and Li2NiF4 are promising candidates for cathode materials in high-voltage lithium ion batteries. The fluorolytic route to these compounds relies on thermal decomposition of a hitherto uncharacterised precursor mixture produced from acetylacetonates and hydrofluoric acid. By addition of pyridine, different cationic, electroneutral and anionic complexes containing the motifs [MFn]((3 n)+) (n = 0-4) have been trapped and characterised by single-crystal X-ray diffraction and IR spectroscopy. Based on the results, a model of successive and incomplete fluorination is proposed for the speciation and formation of the precursor. The decomposition of the latter has been monitored via thermogravimetry (TG) and differential scanning calorimetry (DSC). PMID- 26126968 TI - Anal cancer FDG-PET standard uptake value: correlation with tumor characteristics, treatment response and survival. AB - PURPOSE: The present work studies the correlation of (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) standardized uptake value (SUV) with tumor characteristics, clinical response and prognosis in a series of anal canal cancer patients treated with chemo-radiotherapy. MATERIALS AND METHODS: Fifty-five patients were included in the present analysis. PET maximum SUV (SUVmax) of primary tumor was calculated for each patient. The correlation with clinical parameters, tumor response and survival data were analyzed. RESULTS: SUVmax significantly correlated with T-stage (p = 0.01) and histology (p = 0.03). Median SUVmax was higher for lesions with partial response (PR, 21/55, 38%) than for lesions with complete response (CR, 34/55, 62%) but without statistical significance (p = 0.17). The actuarial disease-free survival (DFS) and overall survival (OS) rates were 53.0 and 77.8% at 2 years and 41.3 and 58.6% at 5 years, respectively. Median SUVmax did not statistically correlate with clinical response or survival. CR and T1-T2 stage were statistically significant prognostic factors for disease-free survival (p < 0.0001 and p = 0.02, respectively) and CR was significant also for overall survival (p < 0.0001). CONCLUSIONS: Our data suggest that pre-treatment FDG-PET/CT SUVmax cannot directly predict tumor response and survival, but it is strongly associated with tumor characteristics such as primary tumor stage and histology, being the first one of the most important and validated prognostic factors for anal cancer. PMID- 26126970 TI - Phase II randomized clinical trial evaluating neoadjuvant chemotherapy regimens with weekly paclitaxel or eribulin followed by doxorubicin and cyclophosphamide in women with locally advanced HER2-negative breast cancer: NSABP Foundation Study FB-9. AB - Locally advanced breast cancer (LABC) is a good setting in which to monitor response to neoadjuvant chemotherapy, to downsize the tumor (which facilitates breast-conserving surgery), and to test newer agents in untreated patients. Eribulin (E) has shown activity in patients who have undergone previous taxane, anthracycline, and capecitabine treatment. We aimed to evaluate the neoadjuvant use of E followed by doxorubicin and cyclophosphamide (AC) in patients with HER2 negative LABC, using as a control a randomized group of women who received weekly paclitaxel (WP). Fifty women with LABC were accrued January-August 2013. Patients were randomized (1:2) to receive either WP (N = 19) for 12 treatments or E (N = 31) every 3 weeks for 4 cycles followed by AC every 3 weeks for 4 cycles before surgery. 17/19 patients who took WP and 25/30 who took E completed all cycles. Patients were evaluated by clinical examination and breast MRI at baseline and after completion of E or WP. Surgical pCR in breast and lymph nodes was determined by a local pathologist following chemotherapy. Forty-nine patients received >=1 dose of neoadjuvant chemotherapy and are included in this analysis. Forty-eight underwent surgery; one had disease that was inoperable (on E) and is included as no-pCR patient. 17/19 of these patients who took WP completed 12 doses; 28/30 on E completed 4 cycles. Six discontinued treatment on WP, E, or AC. Both treatments were well tolerated. pCR on WP = 5/19(26 %) and on E = 5/30(17 %). Both regimens were equally well tolerated with no unexpected toxicities. pCR did not suggest higher activity with E than with other standard regimens in these LABC patients. PMID- 26126971 TI - Decision-making impact on adjuvant chemotherapy allocation in early node-negative breast cancer with a 21-gene assay: systematic review and meta-analysis. AB - Risk stratification based on results provided by a 21-gene assay (Oncotype DX((r))) in early stage breast cancer can help optimize hormone therapy (HT) and/or chemotherapy (CT) decisions. We performed a systematic review and meta analysis of decision impact (DI) and net change in CT use before and after assay results, both in the whole studies' population and by recurrence risk score (RS) strata. A systematic search of studies with prospective data collection reported physician's decision on treatment allocation in early stage node-negative breast cancer was performed. DI reflects the proportion of patients whose management was changed, and net change focuses on CT change. A random-effects model is reported. Fifteen studies (N = 2229) met our inclusion criteria: 50.09, 37.35, and 13.38 % of patients with low, intermediate, and high RS. Treatment decision changed in 29.5 % (95 % CI 26.29-32.86). Net reduction of CT use was 12 % (8-17 %). It was 16 % (12.00-19.00) in the low RS group, 0 % (-3.00 to 3.00) in the intermediate RS group, and increased by 2 % (-1.00 to 3.00) in the high RS group. Use of a 21 gene assay showed a significant impact on treatment decisions. From 100 women tested, 30 could have their treatment optimized, and 12 could avoid CT. Its main effects consist of sparing chemotherapy in low risk patients and slightly increasing it in the high risk category. DI could be higher in selected patient populations with greater uncertainty regarding initial treatment decisions. PMID- 26126972 TI - Prognostic significance of tumor subtypes in male breast cancer: a population based study. AB - Substantial controversy exists about the prognostic role of tumor subtypes in male breast cancer (MaBC). The aim of this study was to analyze the characteristics of each tumor subtype in MaBC and its association with prognosis compared with other factors. We evaluated MaBC patients between 2010 and 2012 with known estrogen receptor, progesterone receptor [together hormone receptor (HR)] status, and human epidermal growth factor receptor 2 (HER2) status reported to the Surveillance, Epidemiology, and End Results program. Patients were classified as: HR-positive/HER2-negative, HR-positive/HER2-positive, HR negative/HER2-positive, and triple-negative (TN). Univariate and multivariate analyses determined the effect of each variable on overall survival (OS). We included 960 patients. Patient distribution was 84.9 % HR-positive/HER2-negative, 11.6 % HR-positive/HER2-positive, 0.6 % HR-negative/HER2-positive, and 2.9 % TN. TN patients were younger, had higher grade, presented with more advanced stage, were more likely to have mastectomy, and to die of breast cancer (all P < 0.05). Univariate analysis showed that HER2 positivity was associated with shorter OS (hazard ratio 1.90, P = 0.031) and TN patients had worse prognosis (hazard ratio 5.10, P = 0.0004). In multivariate analysis, older patients (hazard ratio 3.10, P = 0.032), those with stage IV (hazard ratio 16.27, P < 0.001) and those with TN tumors (hazard ratio 4.61, P = 0.002) had significantly worse OS. We observed significant differences in patient characteristics according to tumor subtype. HER2-positive and TN represented a small proportion of cases. In addition to age and stage, tumor subtype has clear influence on OS in MaBC. PMID- 26126973 TI - Lifetime physical activity and risk of breast cancer in pre-and post-menopausal women. AB - To investigate the association between different types of physical activity (PA) and breast cancer. A case-control study of breast cancer was conducted in Western Australia from 2009 to 2011, in which 1205 women with breast cancer and 1789 frequency age-matched breast cancer-free control women were recruited. A self administered questionnaire was used to collect information about lifetime and age period recreational, household, occupational and transport physical activities. Detailed questions about demographic characteristics, and relevant reproductive, medical and lifestyle factors were also included. Logistic regression and restrictive cubic spline analyses were applied to investigate the association and dose-response relationship between PA and breast cancer risk. Subgroup analysis was performed regarding menopausal status. We found non-linear dose-response associations between PA and risk of breast cancer. Overall, 95-130 MET-hours/week of total lifetime PA was associated with the lowest breast cancer risk. The effects were stronger among post-menopausal women. We also found that the medium amounts of recreational PA (up to 21 MET-hours/week) were associated with lower breast cancer risk among post-menopausal women. Further analysis on the intensity of recreational PA demonstrated different dose-response associations between moderate- and vigorous-intensity recreational PA and breast cancer risk. We found that PA was associated with a reduced risk of breast cancer among post-menopausal women, but not in a linear fashion. Recreational PA of different intensities may have different dose-response associations with risk of breast cancer. PMID- 26126974 TI - Low expression of microRNA-204 (miR-204) is associated with poor clinical outcome of acute myeloid leukemia (AML) patients. AB - BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous neoplasm of the bone marrow with poor prognosis. In clinical practice new prognostic factors are still needed. MicroRNAs (miRs), small endogenous noncoding RNAs, play an essential role in the development and progression of acute leukemia. The aim of the study was to evaluate miR-204 expression in patients with AML at diagnosis and after induction chemotherapy, in comparison to healthy controls. We also investigated, if miR-204 expression correlates with clinical features of AML patients. METHODS: miR-204 expression has been analyzed using RT-PCR in 95 bone marrow specimens from newly diagnosed AML patients in comparison to 20 healthy subject. RESULTS: We showed down-regulated miR-204 expression in AML patients, which was associated with shorter patients' survival. Higher expression of miR-204 in patients after induction therapy was correlated with complete remission achieving. CONCLUSIONS: We showed low miR-204 expression in AML and found it to be an independent prognostic factor in this patient population. PMID- 26126975 TI - Directed altruistic living donation: what is wrong with the beauty contest? AB - This paper explores the specific criticism of directed altruistic living organ donation that it creates a 'beauty contest' between potential recipients of organs. The notion of the beauty contest in transplantation was recently used by Neidich et al who stated that '[a]ltruism should be the guiding motivation for all donations, and when it [is], there is no place for a beauty contest'. I examine this beauty contest objection from two perspectives. First, I argue that, when considered against the behaviour of donors, this objection cannot be consistently raised without also objecting to other common aspects of organ donation. I then explore the beauty contest objection from the perspective of recipients, and argue that if the beauty contest is objectionable, it is because of a tension between recipient behaviour and the altruism that supposedly underpins the donation system. I conclude by briefly questioning the importance of this tension in light of the organ shortage. PMID- 26126976 TI - The challenges of making decisions using uncertain data. AB - All of the experimental compound data with which we work have significant uncertainties, due to imperfect correlations between experimental systems and the ultimate in vivo properties of compounds and the inherent variability in experimental conditions. When using these data to make decisions, it is essential that these uncertainties are taken into account to avoid making inappropriate decisions in the selection of compounds, which can lead to wasted effort and missed opportunities. In this paper we will consider approaches to rigorously account for uncertainties when selecting between compounds or assessing compounds against a property criterion; first for an individual measurement of a single property and then for multiple measurements of a property for the same compound. We will then explore how uncertainties in multiple properties can be combined when assessing compounds against a profile of criteria, a process known as multi parameter optimisation. This guides rigorous decision-making using complex, uncertain data to focus on compounds with the best chance of success, while avoiding missed opportunities by inappropriately rejecting compounds. PMID- 26126978 TI - Dealing with complications of extracorporeal life support. PMID- 26126977 TI - An efficiency analysis of high-order combinations of gene-gene interactions using multifactor-dimensionality reduction. AB - BACKGROUND: Multifactor dimensionality reduction (MDR) is widely used to analyze interactions of genes to determine the complex relationship between diseases and polymorphisms in humans. However, the astronomical number of high-order combinations makes MDR a highly time-consuming process which can be difficult to implement for multiple tests to identify more complex interactions between genes. This study proposes a new framework, named fast MDR (FMDR), which is a greedy search strategy based on the joint effect property. RESULTS: Six models with different minor allele frequencies (MAFs) and different sample sizes were used to generate the six simulation data sets. A real data set was obtained from the mitochondrial D-loop of chronic dialysis patients. Comparison of results from the simulation data and real data sets showed that FMDR identified significant gene gene interaction with less computational complexity than the MDR in high-order interaction analysis. CONCLUSION: FMDR improves the MDR difficulties associated with the computational loading of high-order SNPs and can be used to evaluate the relative effects of each individual SNP on disease susceptibility. FMDR is freely available at http://bioinfo.kmu.edu.tw/FMDR.rar . PMID- 26126979 TI - Could "safe practice" be compromising safe practice? Should anesthetists have to deflate the cuff of the endotracheal tube before extubation? AB - Deflation of the cuff of the endotracheal tube (ETT) before tracheal extubation is considered mandatory and safe practice. However, there are potential shortcomings associated with this practice (e.g., aspiration around the uncuffed ETT, loss of positive airway pressure, difficulty in generating an effective cough at the time of extubation). By contrast, keeping the cuff inflated during extubation will minimize the risk of tracheal aspiration around the ETT, and it will reliably allow maintenance of positive airway pressure until extubation, effective lung recruitment before extubation, and generation of an effective cough during extubation. All of these factors might reduce the overall risk of immediate postextubation and postoperative respiratory and pulmonary complications. Mandatory monitoring of cuff pressure ensures a remaining rather small, highly compressible cuff volume around the ETT which is unlikely to carry per se the risk of producing laryngeal trauma. In my view, as the overall advantages of not deflating the cuff before extubation outweigh the disadvantages, anesthetists should not have to deflate the cuff of the ETT before extubation. Ultimately, only a randomized controlled trial will be able to assess the effect of such practice on patient outcome. PMID- 26126980 TI - Another failed attempt of neuroprotection: progesterone for moderate and severe traumatic brain injury. AB - Two large phase-III prospective, multicenter, controlled, double-blind, randomized clinical trials (the PROTECT III study; the SYNAPSE study) evaluated the effectiveness of an early administration of progesterone in patients with moderate to severe traumatic brain injury (TBI). In the PROTECT III Trial, patients were included if the admission Glasgow Coma Scale (GCS) was within 4-12, whereas the SYNAPSE Trial only included patients with GCS 4-8. The total dose of progesterone was nearly similar in both studies and drug administration was initiated early after injury (within 4 hours for a total of 96 hours in PROTECT; within 8 hours for 120 hours in SYNAPSE). In the PROTECT Trial, primary outcome was 6-month favourable neurological outcome (defined using the Glasgow Outcome Scale), while in the SYNAPSE Trial it was the 6-month Glasgow Outcome Scale (GOS). Secondary outcomes, in both studies, included 6-month mortality. The PROTECT Trial was interrupted for futility after the second interim analysis (882 patients randomized out of the 1140 initially planned); the SYNAPSE Trial included 1195 patients. In PROTECT, the proportion of patients with favourable outcome was similar between groups (51% for progesterone vs. 56% for placebo; RR 3.03 [95% CI 1.96-4.66]); in SYNAPSE, no difference in GOS between the progesterone and placebo group was found (OR 0.96 [95% CI 0.77-1.18]). There was no difference in 6-month mortality or any of the other secondary outcomes between groups in the two trials. These studies demonstrated that early progesterone administration did not provide any benefit on the neurological recovery of TBI patients. PMID- 26126981 TI - Authors' reply to Braillon and Bewley. PMID- 26126982 TI - Simultaneous aromatic-beryllium bonds and aromatic-anion interactions: naphthalene and pyrene as models of fullerenes, carbon single-walled nanotubes, and graphene. AB - The possibility of forming stable BeR2 :ArH:Y(-) (R=H, F, Cl; ArH=naphthalene, pyrene; Y=Cl, Br) ternary complexes in which the beryllium compounds and anions are located on the opposite sides of an extended aromatic system is explored by means of MP2/aug-cc-pVDZ ab initio calculations. Comparison of the electron density distribution of these ternary complexes with the corresponding BeR2 :ArH and ArH:Y(-) binary complexes reveals the existence of significant cooperativity between the two noncovalent interactions in the triads. The energetic effects of this cooperativity are quantified by evaluation of the three-body interaction energy Delta(3) E in the framework of the many-body interaction-energy (MBIE) approach. Although an essential component of the interaction energies is electrostatic and is well reflected in the changes in the molecular electrostatic potential of the aromatic system on complexation, strong polarization effects, in particular for the BeR2 :ArH interactions, also play a significant role. The charge transfers associated with these polarization effects are responsible for significant distortion of both the BeR2 and the aromatic moieties. The former are systematically bent in all the complexes, and the latter are curved to a degree that depends on the nature of the R substituents of the BeR2 subunit. PMID- 26126983 TI - The rotational barrier of ethane and some of its hexasubstituted derivatives in terms of the forces acting on the electron distribution. AB - A novel and alternative explanation of the rotational barrier of ethane and several hexasubstituted derivatives, CX3CX3 (X = H, F, CH3, Cl, Br), is suggested based on the evaluation of the properties of the electron distribution. The forces exerted on the electron density of the topological atoms making up a molecule, the Ehrenfest forces, are analyzed and, with the help of the virial theorem, they are used to explain the experimental rotational barriers. According to this approach, the barrier is mainly a consequence of the decrease of the always attractive Ehrenfest forces (EFs) linking the two C atoms. In addition, the behavior of the EFs is related to a decrease of stability of the central C atoms, which is not compensated by the stabilization of the substituents. Also, during rotation from the staggered to the equilibrium conformation, the electron density at the C-C bond critical point and the electron delocalization between C atoms decrease and are accompanied by an increase of electron delocalization between the substituents. According to the analysis of the EF field lines and to the behavior of the integrated forces, the rotational barrier cannot be explained as a result of any repulsive forces acting on the electron density, although a possible interpretation of the quantum force that balances the EF in stationary states as a measure of traditional Pauli repulsions is also examined. PMID- 26126984 TI - Axially assembled photosynthetic reaction center mimics composed of tetrathiafulvalene, aluminum(III) porphyrin and fullerene entities. AB - The distance dependence of sequential electron transfer has been studied in six, vertical, linear supramolecular triads, (TTF-Ph(n)-py -> AlPor-Ph(m)-C60, n = 0, 1 and m = 1, 2, 3), constructed using tetrathiafulvalene (TTF), aluminum(III) porphyrin (AlPor) and fullerene (C60) entities. The C60 and TTF units are bound to the Al center on opposite faces of the porphyrin; the C60 through a covalent axial bond using a benzoate spacer, and the TTF through a coordination bond via an appended pyridine. Time-resolved optical and EPR spectroscopic methods and computational studies are used to demonstrate that excitation of the porphyrin leads to step-wise, sequential electron transfer (ET) between TTF and C60, and to study the electron transfer rates and exchange coupling between the components of the triads as a function of the bridge lengths. Femtosecond transient absorption studies show that the rates of charge separation, k(CS) are in the range of 10(9) 10(11) s(-1), depending on the length of the bridges. The lifetimes of the charge separated state TTF(+)-C60- obtained from transient absorbance experiments and the singlet lifetimes of the radical pairs obtained by time-resolved EPR are in good agreement with each other and range from 60-130 ns in the triads. The time resolved EPR data also show that population of the triplet sublevels of the charge-separated state in the presence of a magnetic field leads to much longer lifetimes of >1 MUs. The data show that a modest stabilization of the charge separation lifetime occurs in the triads. The attenuation factor beta = 0.36 A( 1) obtained from the exchange coupling values between TTF(+) and C60- is consistent with values reported in the literature for oligophenylene bridged TTF C60 conjugates. The singlet charge recombination lifetime shows a much weaker dependence on the distance between the donor and acceptor, suggesting that a simple superexchange model is not sufficient to describe the back reaction. PMID- 26126985 TI - Ciliated hepatic foregut cyst: report of three cases and review of imaging features. AB - Ciliated hepatic foregut cysts (CHFCs) are rare cystic lesions which are most commonly asymptomatic. They can be clinically important as they may, on rare occasions, undergo malignant transformation or cause mass effect if significantly enlarged. Three cases of CHFCs are presented in this article and their imaging features are reviewed. PMID- 26126986 TI - Redo sphincteroplasty: are the results sustainable? AB - OBJECTIVE: This study aimed to investigate the long-term outcomes of patients who undergo redo sphincteroplasty (RS). METHODS: Patients with fecal incontinence (FI) who underwent RS between November 1988 and December 2011 were retrospectively identified from a prospective database. A questionnaire and telephone survey assessed current Cleveland Clinic Fecal Incontinence Score (CCFFIS; best 0, worst 20) and Fecal Incontinence Quality of Life (FIQoL; best 4.1, worst 1) scale. Success was defined as no further continence surgery, no stoma and CCFFIS <9 at completion of follow-up. The Wilcoxon and Mann-Whitney U tests were used for comparing quantitative variables. Bivariate logistic regression analysis was done to identify predictive factors for success. RESULTS: Fifty-six (66.7%) of 84 patients who underwent RS were available for evaluation at a median follow-up of 74 (range: 12-283) months. The mean CCFFIS decreased from 16.5 +/- 3.7 to 11.9 +/- 6.6 (P < 0.001) at last follow-up. Twelve patients (21.4%) underwent further continence surgery for failed sphincteroplasty, three (5.4%) of whom had a permanent stoma. Eighteen patients (32.1%) had a CCFFIS <9 at the completion of follow-up, and 16 (28.6%) had long-term success. Twenty-four patients evaluated for FIQoL had a mean value of 2.6 (range: 1.0-4.1). Postoperative CCFFIS was correlated with FIQoL (Spearman's correlation coefficient = -0.854, P < 0.001). Logistic regression analysis did not reveal any significant predictive variables for success of RS. CONCLUSION: Based on our criteria for success, the long-term success rate for RS over a median of 74 months is poor. PMID- 26126988 TI - Nanoobjects formed by ionic PAMAM dendrimers: hydrophilic/lipophilic modulation and encapsulation properties. AB - In this paper, we present the preparation and properties of some ionic PAMAM derivatives, which combine hydrophilic and lipophilic carboxylic acid chains as counter-ions for all protonable inner and outer amino groups. The amphiphilic nature of the final ionic codendrimers and, hence, their self-assembling features can be modulated by using different ratios between hydrophilic and lipophilic chains. In the bulk, these new materials self-organize into smectic A liquid crystal phases. In water, they self-assemble into different types of nano-objects depending on the molecular composition. The study of the morphology of these nano structures, their cytotoxicity and their capability to encapsulate a lipophilic anticancer drug are reported herein. Some of these nanoobjects are non-cytotoxic and present good drug trapping ability, which make them interesting nanocarriers for applications in nanotechnology and biomedicine. PMID- 26126987 TI - Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology. AB - Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. A fragment-based chemical screen led to the identification of a novel RET inhibitor, Pz-1. Modeling and kinetic analysis identified Pz-1 as a type II tyrosine kinase inhibitor that is able to bind the "DFG-out" conformation of the kinase. Importantly, from a single-agent polypharmacology standpoint, Pz-1 was shown to be active on VEGFR2, which can block the blood supply required for RET-stimulated growth. In cell-based assays, 1.0 nM of Pz-1 strongly inhibited phosphorylation of all tested RET oncoproteins. At 1.0 mg kg(-1) day(-1) per os, Pz-1 abrogated the formation of tumors induced by RET-mutant fibroblasts and blocked the phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 featured no detectable toxicity at concentrations of up to 100.0 mg kg(-1), which indicates a large therapeutic window. This study validates the effectiveness and usefulness of a medicinal chemistry/polypharmacology approach to obtain an inhibitor capable of targeting multiple oncogenic pathways. PMID- 26126989 TI - 1,2,4-Triazole Links and N-Azo Bridges Yield Energetic Compounds. AB - Triazole links and polynitropyrazole rings give rise to compounds with energetic properties. These materials were fully characterized by NMR and infrared spectroscopy, elemental analysis, and differential scanning calorimetry (DSC). In addition, the structures of compounds 5 and 8 were confirmed by single-crystal X ray diffraction analysis. Detonation properties, calculated from heats of formation and experimental densities, thermal stabilities, and impact and friction sensitivities support the potential use of these materials for explosive applications. PMID- 26126990 TI - CORR Insights((r)): Is MR-guided High-intensity Focused Ultrasound a Feasible Treatment Modality for Desmoid Tumors? PMID- 26126991 TI - Do alumina matrix composite bearings decrease hip noises and bearing fractures at a minimum of 5 years after THA? AB - BACKGROUND: Ceramic-on-ceramic bearing couples are theoretically attractive in total hip arthroplasty (THA) because of low wear, but concerns regarding ceramic fracture and squeaking have arisen. Improved material properties of newer alumina matrix composite (AMC) materials, known as Delta ceramics, may reduce these risks. In addition, the use of thinner liners and larger femoral heads may be helpful clinically to lower the rate of dislocation. However, limited short-term clinical results are available and intermediate-term effects are unclear. QUESTIONS/PURPOSES: (1) What is the frequency of bearing-related complications (dissociation, fracture, and noise) with ceramic-on-ceramic AMC bearings in cementless THA? (2) What other complications arose in patients treated with these bearings? (3) What are the Harris hip scores (HHS) and survivorship free from reoperation and revision at a minimum of 5 years after cementless THA performed with AMC bearings? METHODS: Over a 9-month period in 2009, one surgeon performed 125 THAs, of which 100 (80% of the total) were performed with cementless, AMC bearings. During the period in question, the exclusion criteria for this implant were primary THAs with severe acetabular or femoral bone defect and revision THAs. Of these, 94 hips (95%) in 91 patients were available for analysis at a minimum of 5 years (range, 5-6 years), because five patients (six hips) had died. Mean age at the time of arthroplasty was 55 +/- 14 years. Prostheses with an identical design and Biolox((r)) Delta ceramics were used in all patients. Noise was classified into squeaking, clicking, grinding, and popping. Ceramic fracture, dislocation, and any other complications associated with the use of AMC ceramics were also investigated. Clinical evaluation included the modified HHS preoperatively and at each followup. Survivorship free from reoperation and revision was calculated using the Kaplan-Meier method. RESULTS: Of 91 patients, four developed bearing-related complications, including one with liner dissociation despite initial square seating and three with clicking. No patients had ceramic fractures. A single event of perioperative dislocation occurred in one patient and postoperative periprosthetic fracture occurred in two hips. Mean HHS improved from 56 to 93 points at the final followup (p < 0.001). Survivorship at 5 years free from reoperation and revision was 96.8% and 97.9%, respectively. CONCLUSIONS: Improved material properties combined with the possible use of larger diameter heads make AMC ceramics a promising alternative bearing option with seemingly comparable clinical outcomes reported by others with conventional ceramic bearings. Despite these encouraging results, however, meticulous technical precautions such as square seating and proper impaction in particular should be taken during liner insertion, because we did observe one liner dissociation and several patients with hip noises. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26126993 TI - Eleven-year follow up of boy with Asperger's syndrome and comorbid gender identity disorder of childhood. PMID- 26126994 TI - Methamphetamine absorption by skin lipids: accumulated mass, partition coefficients, and the influence of fatty acids. AB - Occupants of former methamphetamine laboratories, often residences, may experience increased exposure through the accumulation of the methamphetamine in the organic films that coat skin and indoor surfaces. The objectives of this study were to determine equilibrium partition coefficients of vapor-phase methamphetamine with artificial sebum (AS-1), artificial sebum without fatty acids (AS-2), and real skin surface films, herein called skin oils. Sebum and skin oil-coated filters were exposed to vapor-phase methamphetamine at concentrations ranging from 8 to 159 ppb, and samples were analyzed for exposure time periods from 2 h to 60 days. For a low vapor-phase methamphetamine concentration range of ~8-22 ppb, the equilibrium partition coefficient for AS-1 was 1500 +/- 195 MUg/g/ppb. For a high concentration range of 98-112 ppb, the partition coefficient was lower, 459 +/- 80 MUg/g/ppb, suggesting saturation of the available absorption capacity. The low partition coefficient for AS-2 (33 +/- 6 MUg/g/ppb) suggests that the fatty acids in AS-1 and skin oil are responsible for much high partition coefficients. We predict that the methamphetamine concentration in skin lipids coating indoor surfaces can exceed recommended surface remediation standards even for air concentrations well below 1 ppb. PMID- 26126992 TI - Sex-, Stress-, and Sympathetic Post-Ganglionic Neuron-Dependent Changes in the Expression of Pro- and Anti-Inflammatory Mediators in Rat Dural Immune Cells. AB - BACKGROUND: Migraine attacks are associated with sterile inflammation of the dura. Immune cells are a primary source of inflammatory mediators, and we therefore sought to further explore the link between dural immune cells and migraine. OBJECTIVE: Based on the observations that migraine is more common in women than in men, stress is the most common trigger for a migraine attack, and sympathetic post-ganglionic innervation of the dura enables local control of dural immune cells, we hypothesized that stress shifts the balance of inflammatory mediator expression in dural immune cells toward those that trigger a migraine attack, where these changes are larger in females and dependent, at least in part, on sympathetic post-ganglionic innervation of the dura. Our objective was to test this hypothesis. METHODS: Dura were obtained from naive or stressed, intact or surgically sympathectomized, adult male and female rats. Dura were assessed immediately or 24 hours after termination of 4 continuous days of unpredictable, mild stressors. Following enzymatic digestion of each dura, myeloid and lymphoid-derived dural immune cells were isolated by fluorescence activated cell sorting for semi-quantitative polymerase chain reaction analysis. RESULTS: In myeloid-derived dural immune cells, there was an increase in pro inflammatory mediator mRNA following stress, particularly in females, which remained elevated with a 24-hour delay after stress. There was a stress-induced decrease in anti-inflammatory mediator mRNA immediately after stress in females, but not males. The stress-induced changes were attenuated in sympathectomized females. In lymphoid-derived dural immune cells, there was a persistent increase in pro-inflammatory mediator mRNA following stress, particularly in females. A stress-induced increase in anti-inflammatory mediator mRNA was also observed in both males and females, and was further attenuated in sympathectomized females. CONCLUSIONS: Consistent with our hypothesis, there is a stress-induced shift in the balance of pro- and anti-inflammatory mediator expression in dural immune cells that is more pronounced in females, and is dependent, at least in part, on sympathetic post-ganglionic innervation in females. This shift in the balance of inflammatory mediator expression may not only play an important role in triggering migraine attacks, but also suggests it may be possible, if not necessary, to employ different strategies to most effectively treat migraine in men and women. PMID- 26126995 TI - Statistical modeling of the reactions Fe(+) + N2O -> FeO(+) + N2 and FeO(+) + CO > Fe(+) + CO2. AB - The rates of the reactions Fe(+) + N2O -> FeO(+) + N2 and FeO(+) + CO -> Fe(+) + CO2 are modeled by statistical rate theory accounting for energy- and angular momentum-specific rate constants for formation of the primary and secondary cationic adducts and their backward and forward reactions. The reactions are both suggested to proceed on sextet and quartet potential energy surfaces with efficient, but probably not complete, equilibration by spin-inversion of the populations of the sextet and quartet adducts. The influence of spin-inversion on the overall reaction rate is investigated. The differences of the two reaction rates mostly are due to different numbers of entrance states (atom + linear rotor or linear rotor + linear rotor, respectively). The reaction Fe(+) + N2O was studied either with (6)Fe(+) or with (4)Fe(+) reactants. Differences in the rate constants of (6)Fe(+) and (4)Fe(+) reacting with N2O are attributed to different contributions from electronically excited potential energy surfaces, such as they originate from the open-electronic shell reactants. PMID- 26126996 TI - Evaluation of urine fibrinogen level in a murine model of contrast-induced nephropathy. AB - OBJECTIVE: The mechanisms of contrast-induced nephropathy are not fully understood and sensitive biomarkers of contrast-induced nephropathy are yet to be found. We investigated whether urinary fibrinogen could be a potential biomarker for contrast-induced nephropathy. METHODS: To create a contrast-induced nephropathy model, mice received a prostaglandin synthesis inhibitor (indomethacin) and a nitric oxide synthase inhibitor (Nomega-Nitro-L-arginine methyl ester) intraperitoneally followed by a different dose of iodixanol. In the control group, normal saline was administered. Urinary fibrinogen and serum creatinine were analyzed using enzyme-linked immunosorbent assay. Kidneys were used to quantify fibrinogen using qRT-PCR and Western blot and for histopathological examination. RESULTS: Histopathological examination demonstrated mild renal injury in the low-dose group, and moderate renal injury in the high-dose group. Urinary fibrinogen levels were significantly increased in an iodixanol dose-dependent manner (control vs. low-dose group, P < 0.05; control vs. high-dose group P < 0.01). Serum creatinine levels were only increased in the high-dose group (P < 0.01 compared to control), but not in the low-dose group. For fibrinogen-gene expression, in the low-dose group, Fggamma increased (qRT PCR, Western blot, P < 0.05) in the high-dose group, Fgbeta and Fggamma decreased (qRT-PCR, P < 0.01; Western blot, P < 0.05), and Fgalpha increased (qRT-PCR, P < 0.05; Western blot, P < 0.05). CONCLUSIONS: We propose that urinary fibrinogen could be used as a potential biomarker for early contrast-induced nephropathy diagnosis. PMID- 26126997 TI - Naringin promotes differentiation of bone marrow stem cells into osteoblasts by upregulating the expression levels of microRNA-20a and downregulating the expression levels of PPARgamma. AB - Naringin is a dihydrotestosterone flavonoid compound that significantly inhibits bone loss, improves bone density, and enhances biomechanical anti-compression performance. Previous studies have demonstrated that naringin improves the activity levels of osteocalcin (OC) and alkaline phosphatase (ALP) in MC3T3-E1 osteoblast precursor cells. The present study investigated the effects of naringin on osteoblastic differentiation and inhibition of adipocyte formation in bone marrow stem cells (BMSCs). The levels of osteogenesis were modulated via upregulation of the expression levels of microRNA (miR)-20a, and downregulation of the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma). The results indicated that naringin significantly enhanced BMSC proliferation in a dose-dependent manner. In addition, naringin significantly increased the mRNA expression levels of OC, ALP, and collagen type I. Furthermore, naringin decreased the protein expression levels of PPARgamma, and increased the expression levels of miR-20a in the BMSCs. These results suggested that miR-20a may regulate the expression of PPARgamma in BMSCs. To our knowledge, this is the first study to report naringin-induced osteogenesis via upregulation of the expression levels of miR-20a, and downregulation of the expression levels of PPARgamma. These results indicated the important role of naringin in BMSC differentiation. PMID- 26126998 TI - Conceptualising patient empowerment: a mixed methods study. AB - BACKGROUND: In recent years, interventions and health policy programmes have been established to promote patient empowerment, with a particular focus on patients affected by long-term conditions. However, a clear definition of patient empowerment is lacking, making it difficult to assess effectiveness of interventions designed to promote it. The aim in this study was to develop a conceptual map of patient empowerment, including components of patient empowerment and relationships with other constructs such as health literacy, self management and shared decision-making. METHODS: A mixed methods study was conducted comprising (i) a scoping literature review to identify and map the components underpinning published definitions of patient empowerment (ii) qualitative interviews with key stakeholders (patients, patient representatives, health managers and health service researchers) to further develop the conceptual map. Data were analysed using qualitative methods. A combination of thematic and framework analysis was used to integrate and map themes underpinning published definitions of patient empowerment with the views of key UK stakeholders. RESULTS: The scoping literature review identified 67 articles that included a definition of patient empowerment. A range of diverse definitions of patient empowerment was extracted. Thematic analysis identified key underpinning themes, and these themes were used to develop an initial coding framework for analysis of interview data. 19 semi-structured interviews were conducted with key stakeholders. Transcripts were analysed using the initial coding framework, and findings were used to further develop the conceptual map. The resulting conceptual map describes that patient empowerment can be conceived as a state ranging across a spectrum from low to high levels of patient empowerment, with the level of patient empowerment potentially measurable using a set of indicators. Five key components of the conceptual map were identified: underpinning ethos, moderators, interventions, indicators and outcomes. Relationships with other constructs such as health literacy, self-management and shared decision-making are illustrated in the conceptual map. CONCLUSION: A novel conceptual map of patient empowerment grounded in published definitions of patient empowerment and qualitative interviews with UK stakeholders is described, that may be useful to healthcare providers and researchers designing, implementing and evaluating interventions to promote patient empowerment. PMID- 26126999 TI - Effects of light on retinal pigment epithelial cells, neurosensory retinal cells and Muller cells treated with Brilliant Blue G. AB - BACKGROUND: The aim of this study is to evaluate the safety profile of Brilliant Blue G (BBG) with and without exposure to light (L) on three different retinal cell lines. METHOD: ARPE-19, R28 and MIO-M1 cells were treated with BBG: 0.125 mg/mL (0.5x clinical concentration), 0.25 mg/mL (1x) or 0.5 mg/mL (2x) with or without surgical illumination of halogen light exposure for 10 min, 15 min or 30 min. Cells were further cultured after 24 h and then analysed for cell viability, late stages of apoptosis and mitochondrial damage associated with early apoptosis using assays that measure trypan blue dye exclusion, increases in caspase-3/7 activity or changes in mitochondrial membrane potential (DeltaPsim), respectively. RESULT: All three cell lines that were exposed to BBG in the presence or absence of light exposure for 30 min were found to have cell viability and caspase-3/7 activity levels similar to the untreated cultures. The mitochondrial membrane potential (DeltaPsim) was decreased significantly at the 2x + L dose and 2x dose in all three retinal cell lines compared to their respective untreated control cells. At the lower doses of BBG, with or without exposure to light, the DeltaPsim values were similar to the untreated control cultures. CONCLUSION: Exposure to BBG dye concentrations that are used clinically (0.125 mg/mL and 0.25 mg/mL) in the presence up to 30 min of surgically equivalent light intensity is safe for retinal cells. PMID- 26127001 TI - Molecular characterization and expression of buffalo (Bubalus bubalis) DEAD-box family VASA gene and mRNA transcript variants isolated from testis tissue. AB - VASA is a member of the DEAD-box protein family that plays an indispensable role in mammalian spermatogenesis, particularly during meiosis. In the present study, we isolated, sequenced, and characterized VASA gene in buffalo testis. Here, we demonstrated that VASA mRNA is expressed as multiple isoforms and uses four alternative transcriptional start sites (TSSs) and four different polyadenylation sites. The TSSs identified by 5'-RNA ligase-mediated rapid amplification of cDNA ends (RLM-5'-RACE) were positioned at 48, 53, 85, and 88 nucleotides upstream relative to the translation initiation codon. 3'-RACE experiment revealed the presence of tandem polyadenylation signals, which lead to the expression of at least four different 3'-untranslated regions (209, 233, 239 and 605 nucleotides). The full-length coding region of VASA was 2190 bp, which encodes a 729 amino acid (aa) protein containing nine consensus regions of the DEAD box protein family. VASA variants are highly expressed in testis of adult buffalo. We found five variants, one full length VASA (729 aa) and four splice variants VASA 2, 4, 5, 6 (683, 685, 679, 703 aa). The expression level of VASA 1 was significantly higher than rest of all (P < 0.05) except VASA 6. The relative ratio for VASA 1:2:4:5:6 was 100:1.0:1.6:0.9:48. PMID- 26127000 TI - The Impact of Pepsin on Human Nasal Epithelial Cells In Vitro: A Potential Mechanism for Extraesophageal Reflux Induced Chronic Rhinosinusitis. AB - OBJECTIVES: To describe potential mechanisms by which pepsin induces inflammation in refractive chronic rhinosinusitis (CRS). Our hypothesis was that pepsin induces mitochondrial damage and cytokine expression in human nasal epithelial cells (HNEpC) in vitro. METHODS: Western blot was used to detect pepsin in sinus lavages from patients with CRS and controls. The HNEpC cells were treated with pepsin (pH 7; 0.1 mg/mL) for 1 or 16 hours and routine electron microscopy (EM) and MTT assay were performed. Cytokine ELISA was performed on media collected from HNEpC cells 16 hours following a 1-hour pepsin treatment. RESULTS: Pepsin was detected in sinus lavages from 4 out of 6 CRS patients and 0 out of 3 controls. The EM showed mitochondrial damage in pepsin-treated HNEpC cells but not in control cells. The MTT assay demonstrated reduced mitochondrial activity in pepsin-treated HNEpC cells compared to controls (P < .001). Pepsin increased IL-1A (P = .003) and IL-6 (P = .04) expression in HNEpC cells. CONCLUSIONS: Pepsin in sinus lavages from patients with CRS is consistent with previous studies. This study reveals the damaging effect of pepsin on mitochondria in nasal epithelial cells in vitro. Cytokines previously associated with CRS were elevated following pepsin treatment of HNEpC cells in vitro. These results demonstrate mechanisms by which pepsin may potentiate CRS. PMID- 26127002 TI - In silico analysis of functional nsSNPs in human TRPC6 gene associated with steroid resistant nephrotic syndrome. AB - The aim of the present study is to identify functional non-synonymous SNPs of TRPC6 gene using various in silico approaches. These SNPs are believed to have a direct impact on protein stability through conformation changes. Transient receptor potential cation channel-6 (TRPC6) is one of the proteins that plays a key role causing focal segmental glomerulosclerosis (FSGS) associated with the steroid-resistant nephritic syndrome (SRNS). Data of TRPC6 was collected from dbSNP and further used to investigate a damaging effect using SIFT, PolyPhen, PROVEAN, and PANTHER. The comparative analysis predicted that two functional SNPs "rs35857503 at position N157T and rs36111323 at position A404V" showed a damaging effect (score of 0.096-1.00).We modeled the 3D structure of TRPC6 using a SWISS MODEL workspace and validated it via PROCHECK to get a Ramachandran plot (83.0% residues in the most favored region, 12.7% in additionally allowed regions, 2.3% in a generously allowed region and 2.0% were in a disallowed region). QMEAN (0.311) and MUSTER (10.06) scores were under acceptable limits. Putative functional SNPs that may possibly undergo post-translation modifications were also identified in TRPC6 protein. It was found that mutation at N157T can lead to alteration in glycation whereas mutation at A404V was present at a ligand binding site. Additionally, I-Mutant showed a decrease in stability for these nsSNPs upon mutation, thus suggesting that the N157T and A404V variants of TRPC6 could directly or indirectly destabilize the amino acid interactions causing functional deviations of protein to some extent. PMID- 26127003 TI - Correlation of KIF3A and OVOL1, but not ACTL9, with atopic dermatitis in Chinese pediatric patients. AB - Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in Chinese pediatric patients. To date, the genetic susceptibility to AD in this population has not been fully clarified. Three single nucleotide polymorphisms have previously been associated with AD in Europeans, rs2897442 (KIF3A), rs479844 (OVOL1) and rs2164983 (ACTL9). To verify the correlation between AD and these three SNPs in the Chinese pediatric population, we conducted a case-control study including 235 pediatric patients with AD and 200 health controls. We confirmed the correlation between rs2897442 and rs479844 and AD in this population at both the genotype and allele levels. Statistical analysis showed that the C allele of rs2897442 is associated with an increased risk of developing AD, while the A allele of rs479844 is associated with a reduced risk. No correlation between rs2164983 and AD was identified. Our study indicates that KIF3A and OVOL1 are involved in the development of AD in the Chinese pediatric population. PMID- 26127004 TI - HBsAg level and hepatitis B viral load correlation with focus on pregnancy. AB - BACKGROUND: Viral load measurement is necessary to estimate mother-to-child transmission risk for women with chronic hepatitis B (CHB), however, it is expensive. The present study aimed to investigate the relationship between HBsAg and hepatitis B virus (HBV) DNA levels, and to determine potential applications of HBsAg level monitoring for estimating viral load. METHODS: 85 patients with CHB (31 pregnant women, 26 non-pregnant women, 28 men) were included in the study. HBV DNA level was measured by real-time PCR, and HBsAg level by chemiluminescent immunoassay method. Dependency between viral load and HBsAg level was determined by Spearman correlation coefficient rho. RESULTS: The correlation between HBsAg and HBV DNA levels was significant for all patients [rho=0.3762 (P<0.0005; n=85)]. In the group of pregnant women, a low (unmeasurable) HBV DNA level led to a decrease in the Spearman coefficient rho. In almost all cases a low level of the HBsAg corresponded to a low HBV DNA level. Only 2 patients had a low level of HBsAg and a relatively high viral load. By contrast, a high HBsAg level was observed in patients both with high and low viral load. CONCLUSIONS: Correlation between HBsAg and HBV DNA levels is significant. In most cases, a low level of HBsAg indicates a low HBV DNA level, whereas a high HBsAg level does not always correspond to a high viral load. The measurement of HBV DNA level is necessary for pregnant women with a high HBsAg level. PMID- 26127005 TI - The role of vitamin D towards immune tolerance in white adipose tissue (WAT). AB - Vitamin D and its active form 1alpha,25(OH)2D3 has been recently indicated to have a fundamental role in immune regulation. An interplay between gut and white adipose tissue (WAT), mainly mediated by enterogastric hormones and adipokines, such as leptin, adiponectin and ghrelin, actively participate in the immune homeostasis and modulation both of the innate/acquired immune response and between T-cell effector/T-cell regulatory skewing. Particularly for leptin, this action promotes and enhances immune tolerance at the gut level and pro inflammatory effect at WAT level, while calcitriol participates in promoting and increasing an M2 macrophage-like skewing, a T-reg activity at WAT level and a iNKT function at gut level. The role of active vitamin D3 therefore is fundamental in the immune homeostasis of the WAT immune microenvironment and to support the role of WAT as an endocrine, tolerogenic organ. PMID- 26127006 TI - Pelvic lymph node displacement in high-risk prostate cancer patients treated with image guided intensity modulated radiation therapy with 2 independent target volumes. AB - PURPOSE: To evaluate the displacement of the pelvic lymph node (PLN) target when using cone beam computed tomography (CBCT) for localization of the prostate in patients treated with simultaneous integrated boost. METHODS AND MATERIALS: High risk prostate cancer patients treated with image guided intensity modulated radiation therapy with simultaneous integrated boost receiving 60 Gy in 20 fractions to the prostate and proximal seminal vesicles (PTV60) and 44 Gy in the same 20 fractions to the PLN (PTV44) were studied. Two hundred weekly CBCTs of 50 patients were retrospectively reviewed to assess the displacement of the iliac vessels compared with the simulation computed tomography. For each CBCT, possible displacements were analyzed at 3 levels of PTV44: a superior, middle, and inferior slice, making a total of 600 slices reviewed. Geographical miss (GM) was defined when any part of the iliac vessels on the CBCT was outside of the PTV44 contour. RESULTS: GM was found in 7 of the 600 CBCT slices, all in different patients. All GMs were of <=5 mm. Four GMs occurred on the middle slice and 3 on the superior slice. In 3 cases, the GM was related to shifts >=7 mm applied to the prostate. CONCLUSIONS: Our review suggests that for high-risk prostate cancer, the chance of not appropriately covering the PLN target after adjusting the prostate is low. GM was uncommon and in the order of only a few millimeters when it occurred. PMID- 26127007 TI - The association between event learning and continuous quality improvement programs and culture of patient safety. AB - PURPOSE: To present our approach and results from our quality and safety program and to report their possible impact on our culture of patient safety. METHODS AND MATERIALS: We created an event learning system (termed a "good catch" program) and encouraged staff to report any quality or safety concerns in real time. Events were analyzed to assess the utility of safety barriers. A formal continuous quality improvement program was created to address these reported events and make improvements. Data on perceptions of the culture of patient safety were collected using the Agency for Health Care Research and Quality survey administered before, during, and after the initiatives. RESULTS: Of 560 good catches reported, 367 could be ascribed to a specific step on our process map. The calculated utility of safety barriers was highest for those embedded into the pretreatment quality assurance checks performed by physicists and dosimetrists (utility score 0.53; 93 of 174) and routine checks done by therapists on the initial day of therapy. Therapists and physicists reported the highest number of good catches (24% each). Sixty-four percent of events were caused by performance issues (eg, not following standardized processes, including suboptimal communications). Of 31 initiated formal improvement events, 26 were successfully implemented and sustained, 4 were discontinued, and 1 was not implemented. Most of the continuous quality improvement program was conducted by nurses (14) and therapists (7). Percentages of positive responses in the patient safety culture survey appear to have increased on all dimensions (p < .05). CONCLUSIONS: Results suggest that event learning and continuous quality improvement programs can be successfully implemented and that there are contemporaneous improvements in the culture of safety. PMID- 26127008 TI - Stereotactic body radiation therapy and central liver toxicity: A case report. PMID- 26127009 TI - Optimizing efficiency and safety in a radiation oncology department through the use of ARIA 11 Visual Care Path. AB - PURPOSE: Visual Care Path (VCP) is a workflow tool within the ARIA 11 Record and Verify System. The purpose of this study was to quantify the impact of VCP implementation on the metrics of efficiency, safety, and staff satisfaction. METHODS AND MATERIALS: Our multidisciplinary quality improvement team reviewed the entire process of patient care and constructed VCP modules to chart serial and parallel events from consultation to treatment completion. A failure mode and effects analysis was performed to identify high-risk tasks within existing patient care workflow. Data on timeliness of task completion were collected for 612 patients (6560 tasks) in 3 time phases: pre-VCP, transition, and post-VCP. Errors detected during a physics plan check were also monitored. A survey about the VCP was distributed to all staff to evaluate the impact of the VCP on the department. Descriptive statistics were calculated for the metrics of efficiency, safety, and staff satisfaction. RESULTS: Notable improvements in efficiency and safety were observed. Radiation oncologists' compliance with timely completion of the Simulation Preparation VCP tasks increased from 45.9% +/- 14.3% during the pre-VCP phase to 85.8% +/- 10.9% during the post-VCP phase. Compliance with Treatment Planning VCP tasks also increased from 52.6% +/- 9.9% during the pre VCP phase to 76.0% +/- 9.7% during the post-VCP phase. The monthly defect rate (ratio of plans with errors to the total number of plans checked by a physicist) decreased from 19.1% +/- 1.3% during the pre-VCP phase to 5.2% +/- 4.1% during the post-VCP phase. Ninety-four percent of staff members responded to the VCP survey; more than 80% of respondents found the VCP to have a favorable impact. CONCLUSIONS: Implementation of the VCP in our department improved workflow efficiency, reduced the number of errors, and was very well received within the department. PMID- 26127011 TI - Mechanisms of intracellular compartmentalization and disease. PMID- 26127010 TI - Preparation and In Vitro-In Vivo Evaluation of Sustained-Release Matrix Pellets of Capsaicin to Enhance the Oral Bioavailability. AB - Capsaicin has multiple pharmacological activities including antioxidant, anticancer, and anti-inflammatory activities. However, its clinical application is limited due to its poor aqueous solubility, gastric irritation, and low oral bioavailability. This research was aimed at preparing sustained-release matrix pellets of capsaicin to enhance its oral bioavailability. The pellets comprised of a core of solid-dispersed capsaicin mixed with microcrystalline cellulose (MCC) and hydroxypropyl cellulose (HPMC) and subsequently coating with ethyl cellulose (EC) were obtained by using the technology of extrusion/spheronization. The physicochemical properties of the pellets were evaluated through scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). Besides, the in vitro release, in vivo absorption, and in vitro-in vivo correlation were also assessed. More importantly, the relative bioavailability of the sustained-release matrix pellets was studied in fasted rabbits after oral administration using free capsaicin and solid dispersion as references. The oral bioavailability of the matrix pellets and sustained-release matrix pellets of capsaicin was improved approximately 1.98-fold and 5.34-fold, respectively, compared with the free capsaicin. A good level A IVIVC (in vitro-in vivo correlation) was established between the in vitro dissolution and the in vivo absorption of sustained-release matrix pellets. All the results affirmed the remarkable improvement in the oral bioavailability of capsaicin owing to the successful preparation of its sustained-release matrix pellets. PMID- 26127012 TI - Age-specific determinants of post-partum fatigue in primiparous women. AB - AIM: Post-partum fatigue is a serious concern for mothers worldwide. The aim of this study was to identify age-specific determinants of self-perceived fatigue after childbirth among Japanese primiparous women. METHODS: A multicenter prospective cohort study was conducted in Japan. The degree of fatigue was assessed using the Postnatal Accumulated Fatigue Scale during the hospital stay after childbirth. Associated factors were stratified into two age groups (<35 or >=35 years old); data were analyzed using stepwise multiple regression. RESULTS: In the younger group, significant determinants of post-partum fatigue included: anticipated difficulties in child-rearing after discharge; perception of inadequate sleep conditions; dissatisfaction with childbirth; shorter sleep and meal times; longer duration between feeding and infant bedtime; unemployment; and having hyperemesis gravidarum. In the older group, significant determinants of post-partum fatigue included: anticipated difficulties in child-rearing after discharge; perception of inadequate sleep conditions; shorter meal times; formula feeding; and dissatisfaction with childbirth. CONCLUSION: Primiparous mothers who anticipated new life with their infants to be difficult and who had an irregular lifestyle tended to report higher levels of fatigue during the post-partum hospital stay. Nurses and midwives should assess maternal sleep and eating conditions, providing support to ensure adequate maternal rest. Special efforts should be made to reduce anxiety about new life with infants among younger primiparous women who had experienced hyperemesis gravidarum. PMID- 26127013 TI - Hydrodynamic chronoamperometry for probing kinetics of anaerobic microbial metabolism--case study of Faecalibacterium prausnitzii. AB - Monitoring in vitro the metabolic activity of microorganisms aids bioprocesses and enables better understanding of microbial metabolism. Redox mediators can be used for this purpose via different electrochemical techniques that are either complex or only provide non-continuous data. Hydrodynamic chronoamperometry using a rotating disc electrode (RDE) can alleviate these issues but was seldom used and is poorly characterized. The kinetics of Faecalibacterium prausnitzii A2-165, a beneficial gut microbe, were determined using a RDE with riboflavin as redox probe. This butyrate producer anaerobically ferments glucose and reduces riboflavin whose continuous monitoring on a RDE provided highly accurate kinetic measurements of its metabolism, even at low cell densities. The metabolic reaction rate increased linearly over a broad range of cell concentrations (9 * 10(4) to 5 * 10(7) cells.mL(-1)). Apparent Michaelis-Menten kinetics was observed with respect to riboflavin (KM = 6 MUM; kcat = 5.3 * 10(5) s(-1), at 37 degrees C) and glucose (KM = 6 MUM; kcat = 2.4 * 10(5) s(-1)). The short temporal resolution allows continuous monitoring of fast cellular events such as kinetics inhibition with butyrate. Furthermore, we detected for the first time riboflavin reduction by another potential probiotic, Butyricicoccus pullicaecorum. The ability of the RDE for fast, accurate, simple and continuous measurements makes it an ad hoc tool for assessing bioprocesses at high resolution. PMID- 26127014 TI - The interaction of induction and repression mechanisms in the regulation of galacturonic acid-induced genes in Aspergillus niger. AB - Aspergillus niger is an important industrial fungus expressing a broad spectrum of pectinolytic genes. The main constituent of pectin, polygalacturonic acid (PGA), is degraded into galacturonic acid (GA) by the combined activity of endo- and exo-polygalacturonases some of which are specifically induced by GA. The regulatory mechanisms that control the expression of genes encoding PGA-degrading enzymes are not well understood. Based on available genome-wide expression profiles from literature, we selected five genes that were specifically induced by GA. These genes include three exo-polygalacturonases (pgaX, pgxB and pgxC), a GA transporter (gatA), and an intracellular enzyme involved in GA metabolism (gaaB). These five genes contain a conserved motif (5'-TCCNCCAAT-3') in their promoter regions, which we named GARE (galacturonic acid-responsive element). Promoter deletion studies and site-directed mutagenesis of the conserved motif of the pgaX gene showed that the conserved element is required for GA-mediated induction. A set of promoter reporter strains was constructed by fusing the promoter region of the five above-mentioned genes to the amdS reporter gene. Expression of the amdS gene is quantitatively correlated with ability to utilise acetamide as an N-source, hence higher expression of amdS improves growth of the strain on acetamide and therefore can be used as an in vivo reporter for gene expression. Growth analysis of the reporter strains indicated that four genes (pgaX, pgxB, pgxC, and gatA) are specifically induced by GA. The in vivo promoter reporter strains were also used to monitor carbon catabolite repression control. Except for gaaB, all promoter-reporter genes analysed were repressed by glucose in a glucose concentration-dependent way. Interestingly, the strength of glucose repression was different for the tested promoters. CreA is important in mediating carbon catabolite repression as deletion of the creA gene in the reporter strains abolished carbon catabolite repression for most promoters. Interestingly, the pgxC promoter was still repressed by glucose even in the creA null background, suggesting a role for alternative repression mechanisms. Finally, we showed that low concentrations of GA are required to induce gene expression of pgaX, pgxB, and pgxC even under derepressing conditions. The results obtained are consistent with a model in which a GA-specific transcription factor is activated by GA or a GA-derivative, which binds to the conserved motif, possibly in combination with the HAP-complex, to drive GA-specific gene expression. PMID- 26127015 TI - Metabolic responses in Candida tropicalis to complex inhibitors during xylitol bioconversion. AB - During xylitol fermentation, Candida tropicalis is often inhibited by inhibitors in hemicellulose hydrolysate. The mechanisms involved in the metabolic responses to inhibitor stress and the resistances to inhibitors are still not clear. To understand the inhibition mechanisms and the metabolic responses to inhibitors, a GC/MS-based metabolomics approach was performed on C. tropicalis treated with and without complex inhibitors (CI, including furfural, phenol and acetic acid). Partial least squares discriminant analysis was used to determine the metabolic variability between CI-treated groups and control groups, and 25 metabolites were identified as possible entities responsible for the discrimination caused by inhibitors. We found that xylose uptake rate and xylitol oxidation rate were promoted by CI treatment. Metabolomics analysis showed that the flux from xylulose to pentose phosphate pathway increased, and tricarboxylic acid cycle was disturbed by CI. Moreover, the changes in levels of 1,3-propanediol, trehalose, saturated fatty acids and amino acids showed different mechanisms involved in metabolic responses to inhibitor stress. The increase of 1,3-propanediol was considered to be correlated with regulating redox balance and osmoregulation. The increase of trehalose might play a role in protein stabilization and cellular membranes protection. Saturated fatty acids could cause the decrease of membrane fluidity and make the plasma membrane rigid to maintain the integrity of plasma membrane. The deeper understanding of the inhibition mechanisms and the metabolic responses to inhibitors will provide us with more information on the metabolism regulation during xylitol bioconversion and the construction of industrial strains with inhibitor tolerance for better utilization of bioresource. PMID- 26127016 TI - The gene ICS3 from the yeast Saccharomyces cerevisiae is involved in copper homeostasis dependent on extracellular pH. AB - In the yeast Saccharomyces cerevisiae, many genes are involved in the uptake, transport, storage and detoxification of copper. Large scale studies have noted that deletion of the gene ICS3 increases sensitivity to copper, Sortin 2 and acid exposure. Here, we report a study on the Deltaics3 strain, in which ICS3 is related to copper homeostasis, affecting the intracellular accumulation of this metal. This strain is sensitive to hydrogen peroxide and copper exposure, but not to other tested transition metals. At pH 6.0, the Deltaics3 strain accumulates a larger amount of intracellular copper than the wild-type strain, explaining the sensitivity to oxidants in this condition. Unexpectedly, sensitivity to copper exposure only occurs in acidic conditions. This can be explained by the fact that the exposure of Deltaics3 cells to high copper concentrations at pH 4.0 results in over-accumulation of copper and iron. Moreover, the expression of ICS3 increases in acidic pH, and this is correlated with CCC2 gene expression, since both genes are regulated by Rim101 from the pH regulon. CCC2 is also upregulated in Deltaics3 in acidic pH. Together, these data indicate that ICS3 is involved in copper homeostasis and is dependent on extracellular pH. PMID- 26127017 TI - Diversity of Fusarium head blight populations and trichothecene toxin types reveals regional differences in pathogen composition and temporal dynamics. AB - Analyses of genetic diversity, trichothecene genotype composition, and population structure were conducted using 4086 Fusarium graminearum isolates collected from wheat in eight Canadian provinces over a three year period between 2005 and 2007. The results revealed substantial regional differences in Fusarium head blight pathogen composition and temporal population dynamics. The 3ADON trichothecene type consistently predominated in Maritime provinces (91%) over the sampled years, and increased significantly (P<0.05) between 2005 and 2007 in western Canada, accounting for 66% of the isolates in Manitoba by the end of the sampling period. In contrast, 3ADON frequency was lower (22%, P<0.001) in the eastern Canadian provinces of Ontario and Quebec and did not change significantly between 2005 and 2007, resulting in two distinct longitudinal clines in 3ADON frequency across Canada. Overall, genetic structure was correlated with toxin type, as the endemic population (NA1) was dominated by 15ADON isolates (86%), whereas a second population (NA2) consisted largely of 3ADON isolates (88%). However, the percentage of isolates with trichothecene genotypes that were not predictive of their genetic population assignment (recombinant genotypes) increased from 10% in 2005 to 17% in 2007, indicating that trichothecene type became an increasingly unreliable marker of population identity over time. In addition, there were substantial regional differences in the composition of recombinant genotypes. In western and maritime provinces, NA2 isolates with 15ADON genotypes were significantly more common than NA1 isolates with 3ADON genotypes (P<0.001), and the reverse was true in the eastern provinces of Quebec and Ontario. Temporal trends in recombinant genotype composition also varied regionally, as the percentage of 15ADON isolates with NA2 genetic backgrounds increased approximately three fold in western and Maritime provinces, while the opposite trends were observed in Quebec and Ontario. The results indicate that F. graminearum population dynamics in Canada have been influenced by a complex adaptive landscape comprising different regional selective pressures, and do not reflect a simple model of dispersal and integration following the introduction of a novel pathogen population. In addition, we identified F. graminearum strains that produce the recently discovered A-trichothecene mycotoxin (NX-2) for the first time in Canada, representing a significant expansion of the known range of NX-2 producing strains in North America. PMID- 26127018 TI - Effects of aortic counterpulsation in 6 cases of fulminant myocarditis. PMID- 26127019 TI - An unusual cause of recurrent spontaneous pneumothorax: the Mounier-Kuhn syndrome. AB - We present a case of 63-year-old man who was referred to the emergency department with a right-sided pneumothorax. He had a history of spontaneous pneumothorax for 2 times. The chest computed tomographic scan showed tracheobronchomegaly with an increase in the diameter of the trachea and right and left main bronchus. Fiberoptic bronchoscopy revealed enlarged trachea and both main bronchus with diverticulas. These findings are consistent with a diagnosis of Mounier-Kuhn syndrome. Mounier-Kuhn syndrome is a rare clinical and radiologic condition. It is characterized by a tracheal and bronchial dilation. Diagnosis is made by computed tomography and bronchoscopy. Mounier-Kuhn syndrome should be kept in mind in the differential diagnosis of recurrent spontaneous pneumothorax. PMID- 26127020 TI - [LSD score. A new classification system for peristomal skin lesions]. AB - BACKGROUND: Peristomal skin lesions are frequent complications of ostomy; however, there is no generally accepted nomenclature and classification system. OBJECTIVE: An interdisciplinary German expert panel (GESS) composed of ten members, developed an innovative semiquantitative classification system for peristomal skin lesions for further stratification of ostomy therapy. This score is based on criteria which can be assessed by stomal therapists and treating physicians. RESULTS: The new peristomal skin lesion score grades three categories: lesion (L), status of ostomy (S) and disease (D). The L category describes the integrity of the skin as normal (L0), lesion with sustained integrity of skin (L1), integrity destroyed (L2) and local infection (L3). The S category rates the complexity of ostomy therapy as normal (S0), increased (S1) and high but not sufficiently effective (S2). The additional letters for categorization O. R. P. H. E. US describe anatomical pathologies of the stoma itself: ostomy stenosis (O), retraction (R), prolapse (P), hernia (H), edema (E) and unfavorable site (US). A systemic disorder is either absent (D0), irrelevant (D1) or relevant (D2). The LSD score is the basis for a management algorithm. CONCLUSION: The LSD score is comprehensive, standardized and holistic. Its straightforward use by health professionals can improve the consistency of the description of skin lesions and enhance the quality of ostomy therapy. PMID- 26127022 TI - [Anatomical versus non-anatomical liver resection for hepatocellular carcinoma : No impact on recurrence rate]. PMID- 26127023 TI - [Laparoscopic versus open surgery for rectal cancer : Results after 3 years of the COLOR II study]. PMID- 26127021 TI - [Dumping syndrome: Diagnostics and therapeutic options]. AB - BACKGROUND: Dumping syndrome is a common complication after surgery of the upper gastrointestinal tract with symptoms ranging from mild gastrointestinal discomfort and moderate vasomotor disturbances, to severe hyperinsulinemic hypoglycemia. Due to the increasing number of bariatric procedures being performed worldwide, bariatric surgery has become the most common cause for this disease entity. OBJECTIVE: The aim of this review is to highlight the evidence for the physiological mechanisms contributing to dumping syndrome after the two most common bariatric surgery procedures, Roux-en-Y gastric bypass and sleeve gastrectomy, to discuss technical aspects of the procedures underlying the development of the syndrome, patient-related predictive factors and other differential diagnoses, together with diagnostic and therapeutic algorithms. PMID- 26127024 TI - [Liver transplantation in colorectal liver metastases]. PMID- 26127025 TI - Organization of inner cellular components as reported by a viscosity-sensitive fluorescent Bodipy probe suitable for phasor approach to FLIM. AB - According to the recent developments in imaging strategies and in tailoring fluorescent molecule as probe for monitoring biological systems, we coupled a Bodipy-based molecular rotor (BoMe) with FLIM phasor approach to evaluate the viscosity in different intracellular domains. BoMe rapidly permeates cells, stains cytoplasmic as well as nuclear domains, and its optical properties make it perfectly suited for widely diffused confocal microscopy imaging setups. The capability of BoMe to report on intracellular viscosity was put to the test by using a cellular model of a morbid genetic pathology (Hutchinson-Gilford progeria syndrome, HGPS). Our results show that the nucleoplasm of HGPS cells display reduced viscosity as compared to normal cells. Since BoMe displays significant affinity towards DNA, as demonstrated by an in vitro essay, we hypothesize that genetic features of HGPS, namely the misassembly of lamin A protein within the nuclear lamina, modulates chromatin compaction. This hypothesis nicely agrees with literature data. PMID- 26127026 TI - Observing Atoms at Work by Controlling Beam-Sample Interactions. AB - Functional behavior can be initiated and captured in series of images with previously unknown details using a successful effort to effectively control beam sample interactions in high-resolution transmission electron microscopy. The approach uses tunable electron dose rates that can be chosen to be as low as attoamperes per square-Angstrom to delay sample degradation to an unexplored end. Dose rates can be systematically increased to stimulate and observe dynamic object responses. Observations can be made in real time with deep sub-Angstrom resolution and single-atom sensitivity, even if radiation-sensitive matter is probed and either pressure or temperature is raised in the electron microscope. PMID- 26127027 TI - Treatment planning evaluation and optimization should be biologically and not dose/volume based. PMID- 26127028 TI - Robotic real-time translational and rotational head motion correction during frameless stereotactic radiosurgery. AB - PURPOSE: To develop a control system to correct both translational and rotational head motion deviations in real-time during frameless stereotactic radiosurgery (SRS). METHODS: A novel feedback control with a feed-forward algorithm was utilized to correct for the coupling of translation and rotation present in serial kinematic robotic systems. Input parameters for the algorithm include the real-time 6DOF target position, the frame pitch pivot point to target distance constant, and the translational and angular Linac beam off (gating) tolerance constants for patient safety. Testing of the algorithm was done using a 4D (XY Z + pitch) robotic stage, an infrared head position sensing unit and a control computer. The measured head position signal was processed and a resulting command was sent to the interface of a four-axis motor controller, through which four stepper motors were driven to perform motion compensation. RESULTS: The control of the translation of a brain target was decoupled with the control of the rotation. For a phantom study, the corrected position was within a translational displacement of 0.35 mm and a pitch displacement of 0.15 degrees 100% of the time. For a volunteer study, the corrected position was within displacements of 0.4 mm and 0.2 degrees over 98.5% of the time, while it was 10.7% without correction. CONCLUSIONS: The authors report a control design approach for both translational and rotational head motion correction. The experiments demonstrated that control performance of the 4D robotic stage meets the submillimeter and subdegree accuracy required by SRS. PMID- 26127029 TI - A revised dosimetric characterization of the model S700 electronic brachytherapy source containing an anode-centering plastic insert and other components not included in the 2006 model. AB - PURPOSE: The model S700 Axxent electronic brachytherapy source by Xoft, Inc., was characterized by Rivard et al. in 2006. Since then, the source design was modified to include a new insert at the source tip. Current study objectives were to establish an accurate source model for simulation purposes, dosimetrically characterize the new source and obtain its TG-43 brachytherapy dosimetry parameters, and determine dose differences between the original simulation model and the current model S700 source design. METHODS: Design information from measurements of dissected model S700 sources and from vendor-supplied CAD drawings was used to aid establishment of an updated Monte Carlo source model, which included the complex-shaped plastic source-centering insert intended to promote water flow for cooling the source anode. These data were used to create a model for subsequent radiation transport simulations in a water phantom. Compared to the 2006 simulation geometry, the influence of volume averaging close to the source was substantially reduced. A track-length estimator was used to evaluate collision kerma as a function of radial distance and polar angle for determination of TG-43 dosimetry parameters. Results for the 50 kV source were determined every 0.1 cm from 0.3 to 15 cm and every 1 degrees from 0 degrees to 180 degrees . Photon spectra in water with 0.1 keV resolution were also obtained from 0.5 to 15 cm and polar angles from 0 degrees to 165 degrees . Simulations were run for 10(10) histories, resulting in statistical uncertainties on the transverse plane of 0.04% at r = 1 cm and 0.06% at r = 5 cm. RESULTS: The dose rate distribution ratio for the model S700 source as compared to the 2006 model exceeded unity by more than 5% for roughly one quarter of the solid angle surrounding the source, i.e., theta >= 120 degrees . The radial dose function diminished in a similar manner as for an (125)I seed, with values of 1.434, 0.636, 0.283, and 0.0975 at 0.5, 2, 5, and 10 cm, respectively. The radial dose function ratio between the current and the 2006 model had a minimum of 0.980 at 0.4 cm, close to the source sheath and for large distances approached 1.014. 2D anisotropy function ratios were close to unity for 50 degrees <= theta <= 110 degrees , but exceeded 5% for theta < 40 degrees at close distances to the sheath and exceeded 15% for theta > 140 degrees , even at large distances. Photon energy fluence of the updated model as compared to the 2006 model showed a decrease in output with increasing distance; this effect was pronounced at the lowest energies. A decrease in photon fluence with increase in polar angle was also observed and was attributed to the silver epoxy component. CONCLUSIONS: Changes in source design influenced the overall dose rate and distribution by more than 2% in several regions. This discrepancy is greater than the dose calculation acceptance criteria as recommended in the AAPM TG-56 report. The effect of the design change on the TG-43 parameters would likely not result in dose differences outside of patient applicators. Adoption of this new dataset is suggested for accurate depiction of model S700 source dose distributions. PMID- 26127030 TI - Validating FMEA output against incident learning data: A study in stereotactic body radiation therapy. AB - PURPOSE: Though failure mode and effects analysis (FMEA) is becoming more widely adopted for risk assessment in radiation therapy, to our knowledge, its output has never been validated against data on errors that actually occur. The objective of this study was to perform FMEA of a stereotactic body radiation therapy (SBRT) treatment planning process and validate the results against data recorded within an incident learning system. METHODS: FMEA on the SBRT treatment planning process was carried out by a multidisciplinary group including radiation oncologists, medical physicists, dosimetrists, and IT technologists. Potential failure modes were identified through a systematic review of the process map. Failure modes were rated for severity, occurrence, and detectability on a scale of one to ten and risk priority number (RPN) was computed. Failure modes were then compared with historical reports identified as relevant to SBRT planning within a departmental incident learning system that has been active for two and a half years. Differences between FMEA anticipated failure modes and existing incidents were identified. RESULTS: FMEA identified 63 failure modes. RPN values for the top 25% of failure modes ranged from 60 to 336. Analysis of the incident learning database identified 33 reported near-miss events related to SBRT planning. Combining both methods yielded a total of 76 possible process failures, of which 13 (17%) were missed by FMEA while 43 (57%) identified by FMEA only. When scored for RPN, the 13 events missed by FMEA ranked within the lower half of all failure modes and exhibited significantly lower severity relative to those identified by FMEA (p = 0.02). CONCLUSIONS: FMEA, though valuable, is subject to certain limitations. In this study, FMEA failed to identify 17% of actual failure modes, though these were of lower risk. Similarly, an incident learning system alone fails to identify a large number of potentially high-severity process errors. Using FMEA in combination with incident learning may render an improved overview of risks within a process. PMID- 26127031 TI - Dedicated breast computed tomography: Basic aspects. AB - X-ray mammography of the compressed breast is well recognized as the "gold standard" for early detection of breast cancer, but its performance is not ideal. One limitation of screening mammography is tissue superposition, particularly for dense breasts. Since 2001, several research groups in the USA and in the European Union have developed computed tomography (CT) systems with digital detector technology dedicated to x-ray imaging of the uncompressed breast (breast CT or BCT) for breast cancer screening and diagnosis. This CT technology--tracing back to initial studies in the 1970s--allows some of the limitations of mammography to be overcome, keeping the levels of radiation dose to the radiosensitive breast glandular tissue similar to that of two-view mammography for the same breast size and composition. This paper presents an evaluation of the research efforts carried out in the invention, development, and improvement of BCT with dedicated scanners with state-of-the-art technology, including initial steps toward commercialization, after more than a decade of R&D in the laboratory and/or in the clinic. The intended focus here is on the technological/engineering aspects of BCT and on outlining advantages and limitations as reported in the related literature. Prospects for future research in this field are discussed. PMID- 26127032 TI - Surface coating for prevention of metallic seed migration in tissues. AB - PURPOSE: In radiotherapy, metallic implants often detach from their deposited sites and migrate to other locations. This undesirable migration could cause inadequate dose coverage for permanent brachytherapy and difficulties in image guided radiation delivery for patients. To prevent migration of implanted seeds, the authors propose a potential strategy to use a biocompatible and tissue adhesive material called polydopamine. METHODS: In this study, nonradioactive dummy seeds that have the same geometry and composition as commercial I-125 seeds were coated in polydopamine. Using scanning electron microscopy and x-ray photoelectron spectroscopy, the surface of the polydopamine-coated and noncoated seeds was characterized. The detachment stress between the two types of seeds and the tissue was measured. The efficacy of polydopamine-coated seed was investigated through in vitro migration tests by tracing the seed location after tissue implantation and shaking for given times. The cytotoxicity of the polydopamine coating was also evaluated. RESULTS: The results of the coating characterization have shown that polydopamine was successfully coated on the surface of the seeds. In the adhesion test, the polydopamine-coated seeds had 2.1 fold greater detachment stress than noncoated seeds. From the in vitro test, it was determined that the polydopamine-coated seed migrated shorter distances than the noncoated seed. This difference was increased with a greater length of time after implantation. CONCLUSIONS: The authors suggest that polydopamine coating is an effective technique to prevent migration of implanted seeds, especially for permanent prostate brachytherapy. PMID- 26127033 TI - Technical Note: Intrafractional changes in time lag relationship between anterior posterior external and superior-inferior internal motion signals in abdominal tumor sites. AB - PURPOSE: To investigate constancy, within a treatment session, of the time lag relationship between implanted markers in abdominal tumors and an external motion surrogate. METHODS: Six gastroesophageal junction and three pancreatic cancer patients (IRB-approved protocol) received two cone-beam CTs (CBCT), one before and one after treatment. Time between scans was less than 30 min. Each patient had at least one implanted fiducial marker near the tumor. In all scans, abdominal displacement (Varian RPM) was recorded as the external motion signal. Purpose-built software tracked fiducials, representing internal signal, in CBCT projection images. Time lag between superior-inferior (SI) internal and anterior posterior external signals was found by maximizing the correlation coefficient in each breathing cycle and averaging over all cycles. Time-lag-induced discrepancy between internal SI position and that predicted from the external signal (external prediction error) was also calculated. RESULTS: Mean +/- standard deviation time lag, over all scans and patients, was 0.10 +/- 0.07 s (range 0.01 0.36 s). External signal lagged the internal in 17/18 scans. Change in time lag between pre- and post-treatment CBCT was 0.06 +/- 0.07 s (range 0.01-0.22 s), corresponding to 3.1% +/- 3.7% (range 0.6%-10.8%) of gate width (range 1.6-3.1 s). In only one patient, change in time lag exceeded 10% of the gate width. External prediction error over all scans of all patients varied from 0.1 +/- 0.1 to 1.6 +/- 0.4 mm. CONCLUSIONS: Time lag between internal motion along SI and external signals is small compared to the treatment gate width of abdominal patients examined in this study. Change in time lag within a treatment session, inferred from pre- to post-treatment measurements is also small, suggesting that a single measurement of time lag at the session start is adequate. These findings require confirmation in a larger number of patients. PMID- 26127034 TI - Quantification and comparison of visibility and image artifacts of a new liquid fiducial marker in a lung phantom for image-guided radiation therapy. AB - PURPOSE: A new biodegradable liquid fiducial marker was devised to allow for easy insertion in lung tumors using thin needles. The purpose of this study was to evaluate the visibility of the liquid fiducial markers for image-guided radiation therapy and compare to existing solid fiducial markers and to one existing liquid fiducial marker currently commercially available. METHODS: Fiducial marker visibility was quantified in terms of contrast to noise ratio (CNR) on planar kilovoltage x-ray images in a thorax phantom for different concentrations of the radio-opaque component of the new liquid fiducial marker, four solid fiducial markers, and one existing liquid fiducial marker. Additionally, the image artifacts produced on computer tomography (CT) and cone-beam CT (CBCT) of all fiducial markers were quantified. RESULTS: The authors found that the new liquid fiducial marker with the highest concentration of the radio-opaque component had a CNR > 2.05 for 62/63 exposures, which compared favorably to the existing solid fiducial markers and to the existing liquid fiducial marker evaluated. On CT and CBCT, the new liquid fiducial marker with the highest concentration produced lower streaking index artifact (30 and 14, respectively) than the solid gold markers (113 and 20, respectively) and the existing liquid fiducial marker (39 and 20, respectively). The size of the image artifact was larger for all of the liquid fiducial markers compared to the solid fiducial markers because of their larger physical size. CONCLUSIONS: The visibility and the image artifacts produced by the new liquid fiducial markers were comparable to existing solid fiducial markers and the existing liquid fiducial marker. The authors conclude that the new liquid fiducial marker represents an alternative to the fiducial markers tested. PMID- 26127035 TI - Total variation minimization filter for DBT imaging. AB - PURPOSE: Compressed sensing (CS) is a new approach in medical imaging which allows a sparse image to be reconstructed from undersampled data. Total variation (TV) based minimization algorithms are the one CS technique that has achieved great success due to its virtue of preserving edges while reducing image noise. The purpose of this work is to implement and evaluate the performance of a TV minimization filter able to increase the signal difference to noise ratio (SDNR) of digital breast tomosynthesis (DBT) images. METHODS: Assuming a Poisson noise model, the authors present a practical methodology, based on Rudin, Osher, and Fatemi model, which directly applies a TV minimization filter to real phantom and clinical DBT images. Different moments of filter application (before and after image reconstruction) and the suitable Lagrange multiplier (lambda) to be used in filter equation are studied. Also, the relationship between background standard deviation (sigmaB) of unfiltered images and optimal lambda values is determined, in order to maximize the SDNR. Qualitative and quantitative analyses are conducted between unfiltered and filtered images and between the different moments of filter application. The proposed methodology is also tested with one clinical DBT data set. RESULTS: Using phantom data, when the filter is applied to the projections, the authors observed a decrease of 31.34% in TV and an increase of 5.29% and 5.44% in SDNR and full width at half maximum (FWHM), respectively. When applied after reconstruction, a decrease of 35.48% and 2.59% was achieved for TV and FWHM, respectively, and an increase of 8.32% for SDNR. For each moment of filter application, the optimal lambda value found through a comprehensive study was lambda = 85 and lambda = 60 when the filter is applied before and after reconstruction, respectively. The best fit found for the relationship between sigmaB and the corresponding lambda values that allowed the highest filtered SDNR was the logarithmic adjustment. The difference between the lambda values obtained by the first approach and the logarithmic adjustment ranges from 0.11% (filter applied before reconstruction) to 2.54% (filter applied after reconstruction). On the other hand, a decrease of 37.63% and 2.42% in TV and FWHM, respectively, and an increase of 24.39% in SDNR were obtained when the filter is applied to clinical data. This great minimization is present through a visual inspection of unfiltered and filtered clinical images, where areas with higher noise level become smoother while preserving edges and details of the structures. CONCLUSIONS: An optimized digital filter for TV minimization in DBT imaging has been presented. The reliability of a logarithmic relation found between sigmaB and lambda values was confirmed and can be used in future work. Both quantitative and qualitative analyses performed in a clinical DBT image confirmed the relevance of this approach in improving image quality in DBT imaging. The results obtained are very encouraging about increasing SDNR in a short time and preserving the principal variations in image, the structures' boundary. PMID- 26127036 TI - Technical Note: Response measurement for select radiation detectors in magnetic fields. AB - PURPOSE: Dose response to applied magnetic fields for ion chambers and solid state detectors has been investigated previously for the anticipated use in linear accelerator-magnetic resonance devices. In this investigation, the authors present the measured response of selected radiation detectors when the magnetic field is applied in the same direction as the radiation beam, i.e., a longitudinal magnetic field, to verify previous simulation only data. METHODS: The dose response of a PR06C ion chamber, PTW60003 diamond detector, and IBA PFD diode detector is measured in a longitudinal magnetic field. The detectors are irradiated with buildup caps and their long axes either parallel or perpendicular to the incident photon beam. In each case, the magnetic field dose response is reported as the ratio of detector signals with to that without an applied longitudinal magnetic field. The magnetic field dose response for each unique orientation as a function of magnetic field strength was then compared to the previous simulation only studies. RESULTS: The measured dose response of each detector in longitudinal magnetic fields shows no discernable response up to near 0.21 T. This result was expected and matches the previously published simulation only results, showing no appreciable dose response with magnetic field. CONCLUSIONS: Low field longitudinal magnetic fields have been shown to have little or no effect on the dose response of the detectors investigated and further lend credibility to previous simulation only studies. PMID- 26127037 TI - Multi-GPU implementation of a VMAT treatment plan optimization algorithm. AB - PURPOSE: Volumetric modulated arc therapy (VMAT) optimization is a computationally challenging problem due to its large data size, high degrees of freedom, and many hardware constraints. High-performance graphics processing units (GPUs) have been used to speed up the computations. However, GPU's relatively small memory size cannot handle cases with a large dose-deposition coefficient (DDC) matrix in cases of, e.g., those with a large target size, multiple targets, multiple arcs, and/or small beamlet size. The main purpose of this paper is to report an implementation of a column-generation-based VMAT algorithm, previously developed in the authors' group, on a multi-GPU platform to solve the memory limitation problem. While the column-generation-based VMAT algorithm has been previously developed, the GPU implementation details have not been reported. Hence, another purpose is to present detailed techniques employed for GPU implementation. The authors also would like to utilize this particular problem as an example problem to study the feasibility of using a multi-GPU platform to solve large-scale problems in medical physics. METHODS: The column generation approach generates VMAT apertures sequentially by solving a pricing problem (PP) and a master problem (MP) iteratively. In the authors' method, the sparse DDC matrix is first stored on a CPU in coordinate list format (COO). On the GPU side, this matrix is split into four submatrices according to beam angles, which are stored on four GPUs in compressed sparse row format. Computation of beamlet price, the first step in PP, is accomplished using multi GPUs. A fast inter-GPU data transfer scheme is accomplished using peer-to-peer access. The remaining steps of PP and MP problems are implemented on CPU or a single GPU due to their modest problem scale and computational loads. Barzilai and Borwein algorithm with a subspace step scheme is adopted here to solve the MP problem. A head and neck (H&N) cancer case is then used to validate the authors' method. The authors also compare their multi-GPU implementation with three different single GPU implementation strategies, i.e., truncating DDC matrix (S1), repeatedly transferring DDC matrix between CPU and GPU (S2), and porting computations involving DDC matrix to CPU (S3), in terms of both plan quality and computational efficiency. Two more H&N patient cases and three prostate cases are used to demonstrate the advantages of the authors' method. RESULTS: The authors' multi-GPU implementation can finish the optimization process within ~ 1 min for the H&N patient case. S1 leads to an inferior plan quality although its total time was 10 s shorter than the multi-GPU implementation due to the reduced matrix size. S2 and S3 yield the same plan quality as the multi-GPU implementation but take ~4 and ~6 min, respectively. High computational efficiency was consistently achieved for the other five patient cases tested, with VMAT plans of clinically acceptable quality obtained within 23-46 s. Conversely, to obtain clinically comparable or acceptable plans for all six of these VMAT cases that the authors have tested in this paper, the optimization time needed in a commercial TPS system on CPU was found to be in an order of several minutes. CONCLUSIONS: The results demonstrate that the multi-GPU implementation of the authors' column generation-based VMAT optimization can handle the large-scale VMAT optimization problem efficiently without sacrificing plan quality. The authors' study may serve as an example to shed some light on other large-scale medical physics problems that require multi-GPU techniques. PMID- 26127039 TI - Gradient maintenance: A new algorithm for fast online replanning. AB - PURPOSE: Clinical use of online adaptive replanning has been hampered by the unpractically long time required to delineate volumes based on the image of the day. The authors propose a new replanning algorithm, named gradient maintenance (GM), which does not require the delineation of organs at risk (OARs), and can enhance automation, drastically reducing planning time and improving consistency and throughput of online replanning. METHODS: The proposed GM algorithm is based on the hypothesis that if the dose gradient toward each OAR in daily anatomy can be maintained the same as that in the original plan, the intended plan quality of the original plan would be preserved in the adaptive plan. The algorithm requires a series of partial concentric rings (PCRs) to be automatically generated around the target toward each OAR on the planning and the daily images. The PCRs are used in the daily optimization objective function. The PCR dose constraints are generated with dose-volume data extracted from the original plan. To demonstrate this idea, GM plans generated using daily images acquired using an in-room CT were compared to regular optimization and image guided radiation therapy repositioning plans for representative prostate and pancreatic cancer cases. RESULTS: The adaptive replanning using the GM algorithm, requiring only the target contour from the CT of the day, can be completed within 5 min without using high-power hardware. The obtained adaptive plans were almost as good as the regular optimization plans and were better than the repositioning plans for the cases studied. CONCLUSIONS: The newly proposed GM replanning algorithm, requiring only target delineation, not full delineation of OARs, substantially increased planning speed for online adaptive replanning. The preliminary results indicate that the GM algorithm may be a solution to improve the ability for automation and may be especially suitable for sites with small-to-medium size targets surrounded by several critical structures. PMID- 26127038 TI - Using multiscale texture and density features for near-term breast cancer risk analysis. AB - PURPOSE: To help improve efficacy of screening mammography by eventually establishing a new optimal personalized screening paradigm, the authors investigated the potential of using the quantitative multiscale texture and density feature analysis of digital mammograms to predict near-term breast cancer risk. METHODS: The authors' dataset includes digital mammograms acquired from 340 women. Among them, 141 were positive and 199 were negative/benign cases. The negative digital mammograms acquired from the "prior" screening examinations were used in the study. Based on the intensity value distributions, five subregions at different scales were extracted from each mammogram. Five groups of features, including density and texture features, were developed and calculated on every one of the subregions. Sequential forward floating selection was used to search for the effective combinations. Using the selected features, a support vector machine (SVM) was optimized using a tenfold validation method to predict the risk of each woman having image-detectable cancer in the next sequential mammography screening. The area under the receiver operating characteristic curve (AUC) was used as the performance assessment index. RESULTS: From a total number of 765 features computed from multiscale subregions, an optimal feature set of 12 features was selected. Applying this feature set, a SVM classifier yielded performance of AUC = 0.729 +/- 0.021. The positive predictive value was 0.657 (92 of 140) and the negative predictive value was 0.755 (151 of 200). CONCLUSIONS: The study results demonstrated a moderately high positive association between risk prediction scores generated by the quantitative multiscale mammographic image feature analysis and the actual risk of a woman having an image-detectable breast cancer in the next subsequent examinations. PMID- 26127040 TI - Technical Note: Study of the electron transport parameters used in PENELOPE for the Monte Carlo simulation of Linac targets. AB - PURPOSE: The Monte Carlo simulation of electron transport in Linac targets using the condensed history technique is known to be problematic owing to a potential dependence of absorbed dose distributions on the electron step length. In the PENELOPE code, the step length is partially determined by the transport parameters C1 and C2. The authors have investigated the effect on the absorbed dose distribution of the values given to these parameters in the target. METHODS: A monoenergetic 6.26 MeV electron pencil beam from a point source was simulated impinging normally on a cylindrical tungsten target. Electrons leaving the tungsten were discarded. Radial absorbed dose profiles were obtained at 1.5 cm of depth in a water phantom located at 100 cm for values of C1 and C2 in the target both equal to 0.1, 0.01, or 0.001. A detailed simulation case was also considered and taken as the reference. Additionally, lateral dose profiles were estimated and compared with experimental measurements for a 6 MV photon beam of a Varian Clinac 2100 for the cases of C1 and C2 both set to 0.1 or 0.001 in the target. RESULTS: On the central axis, the dose obtained for the case C1 = C2 = 0.1 shows a deviation of (17.2% +/- 1.2%) with respect to the detailed simulation. This difference decreases to (3.7% +/- 1.2%) for the case C1 = C2 = 0.01. The case C1 = C2 = 0.001 produces a radial dose profile that is equivalent to that of the detailed simulation within the reached statistical uncertainty of 1%. The effect is also appreciable in the crossline dose profiles estimated for the realistic geometry of the Linac. In another simulation, it was shown that the error made by choosing inappropriate transport parameters can be masked by tuning the energy and focal spot size of the initial beam. CONCLUSIONS: The use of large path lengths for the condensed simulation of electrons in a Linac target with PENELOPE conducts to deviations of the dose in the patient or phantom. Based on the results obtained in this work, values of C1 and C2 larger than 0.001 should not be used in Linac targets without further investigation. PMID- 26127041 TI - CT dose equilibration and energy absorption in polyethylene cylinders with diameters from 6 to 55 cm. AB - PURPOSE: ICRU Report No. 87 Committee and AAPM Task Group 200 designed a three sectional polyethylene phantom of 30 cm in diameter and 60 cm in length for evaluating the midpoint dose DL(0) and its rise-to-the-equilibrium curve H(L) = DL(0)/D(eq) from computed tomography (CT) scanning, where D(eq) is the equilibrium dose. To aid the use of the phantom in radiation dose assessment and to gain an understanding of dose equilibration and energy absorption in polyethylene, the authors evaluated the short (20 cm) to long (60 cm) phantom dose ratio with a polyethylene diameter of 30 cm, assessed H(L) in polyethylene cylinders of 6-55 cm in diameters, and examined energy absorption in these cylinders. METHODS: A GEANT4-based Monte Carlo program was used to simulate the single axial scans of polyethylene cylinders (diameters 6-55 cm and length 90 cm, as well as diameter 30 cm and lengths 20 and 60 cm) on a clinical CT scanner (Somatom Definition dual source CT, Siemens Healthcare). Axial dose distributions were computed on the phantom central and peripheral axes. An average dose over the central 23 or 100 mm region was evaluated for modeling dose measurement using a 0.6 cm(3) thimble chamber or a 10 cm long pencil ion chamber, respectively. The short (20 cm) to long (90 cm) phantom dose ratios were calculated for the 30 cm diameter polyethylene phantoms scanned at four tube voltages (80-140 kV) and a range of beam apertures (1-25 cm). H(L) was evaluated using the dose integrals computed with the 90 cm long phantoms. The resultant H(L) data were subsequently used to compute the fraction of the total energy absorbed inside or outside the scan range (E(in)/E or E(out)/E) on the phantom central and peripheral axes, where E = LD(eq) was the total energy absorbed along the z axis. RESULTS: The midpoint dose in the 60 cm long polyethylene phantom was equal to that in the 90 cm long polyethylene phantom. The short-to-long phantom dose ratios changed with beam aperture and phantom axis but were insensitive to tube voltage. H(L) was insensitive to tube voltage and CT scanner model. As phantom diameter increased from 6 to 55 cm, E(in)/E generally decreased but asymptotically approached constant levels on the peripheral axes of large phantoms. The curve of E(in)/E versus scan length was almost identical to that of H(L). Similarly, E(out)/E increased with scan length and asymptotically approached the equilibrium for large scan lengths. E(out)/D(eq) was much less than the equilibrium length L(eq) where H(L) = 0.98, even with scan lengths much larger than L(eq). CONCLUSIONS: The polyethylene phantom designed by ICRU Report No. 87 Committee and AAPM Task Group 200 is adequately long for assessing the midpoint dose and its equilibration in CT scanning. The short-to-long phantom dose ratios and the H(L) data provided in this paper allow easy evaluations of the midpoint dose, longitudinal dose distribution, and energy absorption in polyethylene phantoms. The results of dose equilibration and energy absorption presented herein may be insightful for the clinical CT scans with various subject sizes and scan lengths. PMID- 26127042 TI - Report of improved performance in Talbot-Lau phase-contrast computed tomography. AB - PURPOSE: Many expectations have been raised since the use of conventional x-ray tubes on grating-based x-ray phase-contrast imaging. Despite a reported increase in contrast-to-noise ratio (CNR) in many publications, there is doubt on whether phase-contrast computed tomography (CT) is advantageous in clinical CT scanners in vivo. The aim of this paper is to contribute to this discussion by analyzing the performance of a phase-contrast CT laboratory setup. METHODS: A phase contrast CT performance analysis was done. Projection images of a phantom were recorded, and image slices were reconstructed using standard filtered back projection methods. The resulting image slices were analyzed by determining the CNRs in the attenuation and phase image. These results were compared to analytically calculated expectations according to the already published phase contrast CT performance analysis by Raupach and Flohr [Med. Phys. 39, 4761-4774 (2012)]. There, a severe mistake was found leading to wrong predictions of the performance of phase-contrast CT. The error was corrected and with the new formulae, the experimentally obtained results matched the analytical calculations. RESULTS: The squared ratios of the phase-contrast CNR and the attenuation CNR obtained in the authors' experiment are five- to ten-fold higher than predicted by Raupach and Flohr [Med. Phys. 39, 4761-4774 (2012)]. The effective lateral spatial coherence length deduced outnumbers the already optimistic assumption of Raupach and Flohr [Med. Phys. 39, 4761-4774 (2012)] by a factor of 3. CONCLUSIONS: The authors' results indicate that the assumptions made in former performance analyses are pessimistic. The break-even point, when phase contrast CT outperforms attenuation CT, is within reach even with realistic, nonperfect gratings. Further improvements to state-of-the-art clinical CT scanners, like increasing the spatial resolution, could change the balance in favor of phase-contrast computed tomography even more. This could be done by, e.g., quantum-counting pixel detectors with four-fold smaller pixel pitches. PMID- 26127043 TI - 3D delivered dose assessment using a 4DCT-based motion model. AB - PURPOSE: The purpose of this work is to develop a clinically feasible method of calculating actual delivered dose distributions for patients who have significant respiratory motion during the course of stereotactic body radiation therapy (SBRT). METHODS: A novel approach was proposed to calculate the actual delivered dose distribution for SBRT lung treatment. This approach can be specified in three steps. (1) At the treatment planning stage, a patient-specific motion model is created from planning 4DCT data. This model assumes that the displacement vector field (DVF) of any respiratory motion deformation can be described as a linear combination of some basis DVFs. (2) During the treatment procedure, 2D time-varying projection images (either kV or MV projections) are acquired, from which time-varying "fluoroscopic" 3D images of the patient are reconstructed using the motion model. The DVF of each timepoint in the time-varying reconstruction is an optimized linear combination of basis DVFs such that the 2D projection of the 3D volume at this timepoint matches the projection image. (3) 3D dose distribution is computed for each timepoint in the set of 3D reconstructed fluoroscopic images, from which the total effective 3D delivered dose is calculated by accumulating deformed dose distributions. This approach was first validated using two modified digital extended cardio-torso (XCAT) phantoms with lung tumors and different respiratory motions. The estimated doses were compared to the dose that would be calculated for routine 4DCT-based planning and to the actual delivered dose that was calculated using "ground truth" XCAT phantoms at all timepoints. The approach was also tested using one set of patient data, which demonstrated the application of our method in a clinical scenario. RESULTS: For the first XCAT phantom that has a mostly regular breathing pattern, the errors in 95% volume dose (D95) are 0.11% and 0.83%, respectively for 3D fluoroscopic images reconstructed from kV and MV projections compared to the ground truth, which is clinically comparable to 4DCT (0.093%). For the second XCAT phantom that has an irregular breathing pattern, the errors are 0.81% and 1.75% for kV and MV reconstructions, both of which are better than that of 4DCT (4.01%). In the case of real patient, although it is impossible to obtain the actual delivered dose, the dose estimation is clinically reasonable and demonstrates differences between 4DCT and MV reconstruction-based dose estimates. CONCLUSIONS: With the availability of kV or MV projection images, the proposed approach is able to assess delivered doses for all respiratory phases during treatment. Compared to the planning dose based on 4DCT, the dose estimation using reconstructed 3D fluoroscopic images was as good as 4DCT for regular respiratory pattern and was a better dose estimation for the irregular respiratory pattern. PMID- 26127044 TI - Technical Note: Measurement of bow tie profiles in CT scanners using radiochromic film. AB - PURPOSE: To provide a noninvasive technique to measure the intensity profile of the fan beam in a computed tomography (CT) scanner that is cost effective and easily implemented without the need to access proprietary scanner information or service modes. METHODS: The fabrication of an inexpensive aperture is described, which is used to expose radiochromic film in a rotating CT gantry. A series of exposures is made, each of which is digitized on a personal computer document scanner, and the resulting data set is analyzed to produce a self-consistent calibration of relative radiation exposure. The bow tie profiles were analyzed to determine the precision of the process and were compared to two other measurement techniques, direct measurements from CT gantry detectors and a dynamic dosimeter. RESULTS: The radiochromic film method presented here can measure radiation exposures with a precision of ~ 6% root-mean-square relative error. The intensity profiles have a maximum 25% root-mean-square relative error compared with existing techniques. CONCLUSIONS: The proposed radiochromic film method for measuring bow tie profiles is an inexpensive (~$100 USD + film costs), noninvasive method to measure the fan beam intensity profile in CT scanners. PMID- 26127045 TI - DTI template-based estimation of cardiac fiber orientations from 3D ultrasound. AB - PURPOSE: Cardiac muscle fibers directly affect the mechanical, physiological, and pathological properties of the heart. Patient-specific quantification of cardiac fiber orientations is an important but difficult problem in cardiac imaging research. In this study, the authors proposed a cardiac fiber orientation estimation method based on three-dimensional (3D) ultrasound images and a cardiac fiber template that was obtained from magnetic resonance diffusion tensor imaging (DTI). METHODS: A DTI template-based framework was developed to estimate cardiac fiber orientations from 3D ultrasound images using an animal model. It estimated the cardiac fiber orientations of the target heart by deforming the fiber orientations of the template heart, based on the deformation field of the registration between the ultrasound geometry of the target heart and the MRI geometry of the template heart. In the experiments, the animal hearts were imaged by high-frequency ultrasound, T1-weighted MRI, and high-resolution DTI. RESULTS: The proposed method was evaluated by four different parameters: Dice similarity coefficient (DSC), target errors, acute angle error (AAE), and inclination angle error (IAE). Its ability of estimating cardiac fiber orientations was first validated by a public database. Then, the performance of the proposed method on 3D ultrasound data was evaluated by an acquired database. Their average values were 95.4% +/- 2.0% for the DSC of geometric registrations, 21.0 degrees +/- 0.76 degrees for AAE, and 19.4 degrees +/- 1.2 degrees for IAE of fiber orientation estimations. Furthermore, the feasibility of this framework was also performed on 3D ultrasound images of a beating heart. CONCLUSIONS: The proposed framework demonstrated the feasibility of using 3D ultrasound imaging to estimate cardiac fiber orientation of in vivo beating hearts and its further improvements could contribute to understanding the dynamic mechanism of the beating heart and has the potential to help diagnosis and therapy of heart disease. PMID- 26127046 TI - Eye-tracking of nodule detection in lung CT volumetric data. AB - PURPOSE: Signal detection on 3D medical images depends on many factors, such as foveal and peripheral vision, the type of signal, and background complexity, and the speed at which the frames are displayed. In this paper, the authors focus on the speed with which radiologists and naive observers search through medical images. Prior to the study, the authors asked the radiologists to estimate the speed at which they scrolled through CT sets. They gave a subjective estimate of 5 frames per second (fps). The aim of this paper is to measure and analyze the speed with which humans scroll through image stacks, showing a method to visually display the behavior of observers as the search is made as well as measuring the accuracy of the decisions. This information will be useful in the development of model observers, mathematical algorithms that can be used to evaluate diagnostic imaging systems. METHODS: The authors performed a series of 3D 4-alternative forced-choice lung nodule detection tasks on volumetric stacks of chest CT images iteratively reconstructed in lung algorithm. The strategy used by three radiologists and three naive observers was assessed using an eye-tracker in order to establish where their gaze was fixed during the experiment and to verify that when a decision was made, a correct answer was not due only to chance. In a first set of experiments, the observers were restricted to read the images at three fixed speeds of image scrolling and were allowed to see each alternative once. In the second set of experiments, the subjects were allowed to scroll through the image stacks at will with no time or gaze limits. In both static-speed and free scrolling conditions, the four image stacks were displayed simultaneously. All trials were shown at two different image contrasts. RESULTS: The authors were able to determine a histogram of scrolling speeds in frames per second. The scrolling speed of the naive observers and the radiologists at the moment the signal was detected was measured at 25-30 fps. For the task chosen, the performance of the observers was not affected by the contrast or experience of the observer. However, the naive observers exhibited a different pattern of scrolling than the radiologists, which included a tendency toward higher number of direction changes and number of slices viewed. CONCLUSIONS: The authors have determined a distribution of speeds for volumetric detection tasks. The speed at detection was higher than that subjectively estimated by the radiologists before the experiment. The speed information that was measured will be useful in the development of 3D model observers, especially anthropomorphic model observers which try to mimic human behavior. PMID- 26127047 TI - Two-stage atlas subset selection in multi-atlas based image segmentation. AB - PURPOSE: Fast growing access to large databases and cloud stored data presents a unique opportunity for multi-atlas based image segmentation and also presents challenges in heterogeneous atlas quality and computation burden. This work aims to develop a novel two-stage method tailored to the special needs in the face of large atlas collection with varied quality, so that high-accuracy segmentation can be achieved with low computational cost. METHODS: An atlas subset selection scheme is proposed to substitute a significant portion of the computationally expensive full-fledged registration in the conventional scheme with a low-cost alternative. More specifically, the authors introduce a two-stage atlas subset selection method. In the first stage, an augmented subset is obtained based on a low-cost registration configuration and a preliminary relevance metric; in the second stage, the subset is further narrowed down to a fusion set of desired size, based on full-fledged registration and a refined relevance metric. An inference model is developed to characterize the relationship between the preliminary and refined relevance metrics, and a proper augmented subset size is derived to ensure that the desired atlases survive the preliminary selection with high probability. RESULTS: The performance of the proposed scheme has been assessed with cross validation based on two clinical datasets consisting of manually segmented prostate and brain magnetic resonance images, respectively. The proposed scheme demonstrates comparable end-to-end segmentation performance as the conventional single-stage selection method, but with significant computation reduction. Compared with the alternative computation reduction method, their scheme improves the mean and medium Dice similarity coefficient value from (0.74, 0.78) to (0.83, 0.85) and from (0.82, 0.84) to (0.95, 0.95) for prostate and corpus callosum segmentation, respectively, with statistical significance. CONCLUSIONS: The authors have developed a novel two-stage atlas subset selection scheme for multi-atlas based segmentation. It achieves good segmentation accuracy with significantly reduced computation cost, making it a suitable configuration in the presence of extensive heterogeneous atlases. PMID- 26127048 TI - Effect of color visualization and display hardware on the visual assessment of pseudocolor medical images. AB - PURPOSE: Even though the use of color in the interpretation of medical images has increased significantly in recent years, the ad hoc manner in which color is handled and the lack of standard approaches have been associated with suboptimal and inconsistent diagnostic decisions with a negative impact on patient treatment and prognosis. The purpose of this study is to determine if the choice of color scale and display device hardware affects the visual assessment of patterns that have the characteristics of functional medical images. METHODS: Perfusion magnetic resonance imaging (MRI) was the basis for designing and performing experiments. Synthetic images resembling brain dynamic-contrast enhanced MRI consisting of scaled mixtures of white, lumpy, and clustered backgrounds were used to assess the performance of a rainbow ("jet"), a heated black-body ("hot"), and a gray ("gray") color scale with display devices of different quality on the detection of small changes in color intensity. The authors used a two alternative, forced-choice design where readers were presented with 600 pairs of images. Each pair consisted of two images of the same pattern flipped along the vertical axis with a small difference in intensity. Readers were asked to select the image with the highest intensity. Three differences in intensity were tested on four display devices: a medical-grade three-million-pixel display, a consumer grade monitor, a tablet device, and a phone. RESULTS: The estimates of percent correct show that jet outperformed hot and gray in the high and low range of the color scales for all devices with a maximum difference in performance of 18% (confidence intervals: 6%, 30%). Performance with hot was different for high and low intensity, comparable to jet for the high range, and worse than gray for lower intensity values. Similar performance was seen between devices using jet and hot, while gray performance was better for handheld devices. Time of performance was shorter with jet. CONCLUSIONS: Our findings demonstrate that the choice of color scale and display hardware affects the visual comparative analysis of pseudocolor images. Follow-up studies in clinical settings are being considered to confirm the results with patient images. PMID- 26127049 TI - Assessment of radiation dose in nuclear cardiovascular imaging using realistic computational models. AB - PURPOSE: Nuclear cardiology plays an important role in clinical assessment and has enormous impact on the management of a variety of cardiovascular diseases. Pediatric patients at different age groups are exposed to a spectrum of radiation dose levels and associated cancer risks different from those of adults in diagnostic nuclear medicine procedures. Therefore, comprehensive radiation dosimetry evaluations for commonly used myocardial perfusion imaging (MPI) and viability radiotracers in target population (children and adults) at different age groups are highly desired. METHODS: Using Monte Carlo calculations and biological effects of ionizing radiation VII model, we calculate the S-values for a number of radionuclides (Tl-201, Tc-99m, I-123, C-11, N-13, O-15, F-18, and Rb 82) and estimate the absorbed dose and effective dose for 12 MPI radiotracers in computational models including the newborn, 1-, 5-, 10-, 15-yr-old, and adult male and female computational phantoms. RESULTS: For most organs, (201)Tl produces the highest absorbed dose whereas (82)Rb and (15)O-water produce the lowest absorbed dose. For the newborn baby and adult patient, the effective dose of (82)Rb is 48% and 77% lower than that of (99m)Tc-tetrofosmin (rest), respectively. CONCLUSIONS: (82)Rb results in lower effective dose in adults compared to (99m)Tc-labeled tracers. However, this advantage is less apparent in children. The produced dosimetric databases for various radiotracers used in cardiovascular imaging, using new generation of computational models, can be used for risk-benefit assessment of a spectrum of patient population in clinical nuclear cardiology practice. PMID- 26127050 TI - A fast GPU-based Monte Carlo simulation of proton transport with detailed modeling of nonelastic interactions. AB - PURPOSE: Very fast Monte Carlo (MC) simulations of proton transport have been implemented recently on graphics processing units (GPUs). However, these MCs usually use simplified models for nonelastic proton-nucleus interactions. Our primary goal is to build a GPU-based proton transport MC with detailed modeling of elastic and nonelastic proton-nucleus collisions. METHODS: Using the cuda framework, the authors implemented GPU kernels for the following tasks: (1) simulation of beam spots from our possible scanning nozzle configurations, (2) proton propagation through CT geometry, taking into account nuclear elastic scattering, multiple scattering, and energy loss straggling, (3) modeling of the intranuclear cascade stage of nonelastic interactions when they occur, (4) simulation of nuclear evaporation, and (5) statistical error estimates on the dose. To validate our MC, the authors performed (1) secondary particle yield calculations in proton collisions with therapeutically relevant nuclei, (2) dose calculations in homogeneous phantoms, (3) recalculations of complex head and neck treatment plans from a commercially available treatment planning system, and compared with (GEANT)4.9.6p2/TOPAS. RESULTS: Yields, energy, and angular distributions of secondaries from nonelastic collisions on various nuclei are in good agreement with the (GEANT)4.9.6p2 Bertini and Binary cascade models. The 3D gamma pass rate at 2%-2 mm for treatment plan simulations is typically 98%. The net computational time on a NVIDIA GTX680 card, including all CPU-GPU data transfers, is ~ 20 s for 1 * 10(7) proton histories. CONCLUSIONS: Our GPU-based MC is the first of its kind to include a detailed nuclear model to handle nonelastic interactions of protons with any nucleus. Dosimetric calculations are in very good agreement with (GEANT)4.9.6p2/TOPAS. Our MC is being integrated into a framework to perform fast routine clinical QA of pencil-beam based treatment plans, and is being used as the dose calculation engine in a clinically applicable MC-based IMPT treatment planning system. The detailed nuclear modeling will allow us to perform very fast linear energy transfer and neutron dose estimates on the GPU. PMID- 26127051 TI - Commissioning of a proton gantry equipped with dual x-ray imagers and a robotic patient positioner, and evaluation of the accuracy of single-beam image registration for this system. AB - PURPOSE: To check the accuracy of a gantry equipped with dual x-ray imagers and a robotic patient positioner for proton radiotherapy, and to evaluate the accuracy and feasibility of single-beam registration using the robotic positioner. METHODS: One of the proton treatment rooms at their institution was upgraded to include a robotic patient positioner (couch) with 6 degrees of freedom and dual orthogonal kilovoltage x-ray imaging panels. The wander of the proton beam central axis, the wander of the beamline, and the orthogonal image panel crosswires from the gantry isocenter were measured for different gantry angles. The couch movement accuracy and couch wander from the gantry isocenter were measured for couch loadings of 50-300 lb with couch rotations from 0 degrees to +/- 90 degrees . The combined accuracy of the gantry, couch, and imagers was checked using a custom-made 30 * 30 * 30 cm(3) Styrofoam phantom with beekleys embedded in it. A treatment in this room can be set up and registered at a setup field location, then moved precisely to any other treatment location without requiring additional image registration. The accuracy of the single-beam registration strategy was checked for treatments containing multiple beams with different combinations of gantry angles, couch yaws, and beam locations. RESULTS: The proton beam central axis wander from the gantry isocenter was within 0.5 mm with gantry rotations in both clockwise (CW) and counterclockwise (CCW) directions. The maximum wander of the beamline and orthogonal imager crosswire centers from the gantry isocenter were within 0.5 and 0.8 mm, respectively, with the gantry rotations in CW and CCW directions. Vertical and horizontal couch wanders from the gantry isocenter were within 0.4 and 1.3 mm, respectively, for couch yaw from 0 degrees to +/- 90 degrees . For a treatment with multiple beams with different gantry angles, couch yaws, and beam locations, the measured displacements of treatment beam locations from the one based on the initial setup beam registered at the gantry at 0 degrees /180 degrees and couch yaw at 0 degrees were within 1.5 mm in three translations and 0.5 degrees in three rotations for a 200 lb couch loading. CONCLUSIONS: Results demonstrate that the gantry equipped with a robotic patient positioner and dual imaging panels satisfies treatment requirements for proton radiotherapy. The combined accuracy of the gantry, couch, and imagers allows a patient to be registered at one setup position and then moved precisely to another treatment position by commanding the robotic patient positioner and delivering treatment without requiring additional image registration. PMID- 26127052 TI - MagicPlate-512: A 2D silicon detector array for quality assurance of stereotactic motion adaptive radiotherapy. AB - PURPOSE: Spatial and temporal resolutions are two of the most important features for quality assurance instrumentation of motion adaptive radiotherapy modalities. The goal of this work is to characterize the performance of the 2D high spatial resolution monolithic silicon diode array named "MagicPlate-512" for quality assurance of stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) combined with a dynamic multileaf collimator (MLC) tracking technique for motion compensation. METHODS: MagicPlate-512 is used in combination with the movable platform HexaMotion and a research version of radiofrequency tracking system Calypso driving MLC tracking software. The authors reconstruct 2D dose distributions of small field square beams in three modalities: in static conditions, mimicking the temporal movement pattern of a lung tumor and tracking the moving target while the MLC compensates almost instantaneously for the tumor displacement. Use of Calypso in combination with MagicPlate-512 requires a proper radiofrequency interference shielding. Impact of the shielding on dosimetry has been simulated by (GEANT)4 and verified experimentally. Temporal and spatial resolutions of the dosimetry system allow also for accurate verification of segments of complex stereotactic radiotherapy plans with identification of the instant and location where a certain dose is delivered. This feature allows for retrospective temporal reconstruction of the delivery process and easy identification of error in the tracking or the multileaf collimator driving systems. A sliding MLC wedge combined with the lung motion pattern has been measured. The ability of the MagicPlate-512 (MP512) in 2D dose mapping in all three modes of operation was benchmarked by EBT3 film. RESULTS: Full width at half maximum and penumbra of the moving and stationary dose profiles measured by EBT3 film and MagicPlate-512 confirm that motion has a significant impact on the dose distribution. Motion, no motion, and motion with MLC tracking profiles agreed within 1 and 0.4 mm, respectively, for all field sizes tested. Use of electromagnetic tracking system generates a fluctuation of the detector baseline up to 10% of the full scale signal requiring a proper shielding strategy. MagicPlate-512 is also able to reconstruct the dose variation pulse-by-pulse in each pixel of the detector. An analysis of the dose transients with motion and motion with tracking shows that the tracking feedback algorithm used for this experiment can compensate effectively only the effect of the slower transient components. The fast changing components of the organ motion can contribute only to discrepancy of the order of 15% in penumbral region while the slower components can change the dose profile up to 75% of the expected dose. CONCLUSIONS: MagicPlate-512 is shown to be, potentially, a valid alternative to film or 2D ionizing chambers for quality assurance dosimetry in SRS or SBRT. Its high spatial and temporal resolutions allow for accurate reconstruction of the profile in any conditions with motion and with tracking of the motion. It shows excellent performance to reconstruct the dose deposition in real time or retrospectively as a function of time for detailed analysis of the effect of motion in a specific pixel or area of interest. PMID- 26127053 TI - Effects of pulse duration on magnetostimulation thresholds. AB - PURPOSE: Medical imaging techniques such as magnetic resonance imaging and magnetic particle imaging (MPI) utilize time-varying magnetic fields that are subject to magnetostimulation limits, which often limit the speed of the imaging process. Various human-subject experiments have studied the amplitude and frequency dependence of these thresholds for gradient or homogeneous magnetic fields. Another contributing factor was shown to be number of cycles in a magnetic pulse, where the thresholds decreased with longer pulses. The latter result was demonstrated on two subjects only, at a single frequency of 1.27 kHz. Hence, whether the observed effect was due to the number of cycles or due to the pulse duration was not specified. In addition, a gradient-type field was utilized; hence, whether the same phenomenon applies to homogeneous magnetic fields remained unknown. Here, the authors investigate the pulse duration dependence of magnetostimulation limits for a 20-fold range of frequencies using homogeneous magnetic fields, such as the ones used for the drive field in MPI. METHODS: Magnetostimulation thresholds were measured in the arms of six healthy subjects (age: 27 +/- 5 yr). Each experiment comprised testing the thresholds at eight different pulse durations between 2 and 125 ms at a single frequency, which took approximately 30-40 min/subject. A total of 34 experiments were performed at three different frequencies: 1.2, 5.7, and 25.5 kHz. A solenoid coil providing homogeneous magnetic field was used to induce stimulation, and the field amplitude was measured in real time. A pre-emphasis based pulse shaping method was employed to accurately control the pulse durations. Subjects reported stimulation via a mouse click whenever they felt a twitching/tingling sensation. A sigmoid function was fitted to the subject responses to find the threshold at a specific frequency and duration, and the whole procedure was repeated at all relevant frequencies and pulse durations. RESULTS: The magnetostimulation limits decreased with increasing pulse duration (T(pulse)). For T(pulse) < 18 ms, the thresholds were significantly higher than at the longest pulse durations (p < 0.01, paired Wilcoxon signed-rank test). The normalized magnetostimulation threshold (B(Norm)) vs duration curve at all three frequencies agreed almost identically, indicating that the observed effect is independent of the operating frequency. At the shortest pulse duration (T(pulse) ~ 2 ms), the thresholds were approximately 24% higher than at the asymptotes. The thresholds decreased to within 4% of their asymptotic values for T(pulse) > 20 ms. These trends were well characterized (R(2) = 0.78) by a stretched exponential function given by B(Norm)=1+alphae(-T(pulse)/beta(gamma)) , where the fitted parameters were alpha = 0.44, beta = 4.32, and gamma = 0.60. CONCLUSIONS: This work shows for the first time that the magnetostimulation thresholds decrease with increasing pulse duration, and that this effect is independent of the operating frequency. Normalized threshold vs duration trends are almost identical for a 20-fold range of frequencies: the thresholds are significantly higher at short pulse durations and settle to within 4% of their asymptotic values for durations longer than 20 ms. These results emphasize the importance of matching the human-subject experiments to the imaging conditions of a particular setup. Knowing the dependence of the safety limits to all contributing factors is critical for increasing the time-efficiency of imaging systems that utilize time-varying magnetic fields. PMID- 26127054 TI - Quantitative evaluation of image segmentation incorporating medical consideration functions. AB - PURPOSE: A quantitative and objective metric, the medical similarity index (MSI), has been developed for evaluating the accuracy of a medical image segmentation relative to a reference segmentation. The MSI uses the medical consideration function (MCF) as its basis. METHODS: Currently, no indices provide quantitative evaluations of segmentation accuracy with medical considerations. Variations in segmentation can occur due to individual skill levels and medical relevance- curable or palliative intent, boundary uncertainty due to volume averaging, contrast levels, spatial resolution, and unresolved motion all affect the accuracy of a patient segmentation. Current accuracy measuring indices are not medically relevant. For example, undercontouring the tumor volume is not differentiated from overcontouring tumor. Dice similarity coefficient (DSC) and Hausdorff distance (HD) are two similarity measures often used. However, these metrics consider only geometric difference without considering medical implications. Two segments (under- vs overcontouring tumor) with similar DSC and HD measures could produce significantly different medical treatment results. The authors are proposing a MSI involving a user-defined MCF derived from an asymmetric Gaussian function. The shape of the MCF can be determined by a user, reflecting the anatomical location and characteristics of a particular tissue, organ, or tumor type. The peak of MCF is set along the reference contour; the inner and outer slopes are selected by the user. The discrepancy between the test and reference contours is calculated at each pixel by using a bidirectional local distance measure. The MCF value corresponding to that distance is summed and averaged to produce the MSI. Synthetic segmentations and clinical data from a 15 multi-institutional trial for a head-and-neck case are scored and compared by using MSI, DSC, and Hausdorff distance. RESULTS: The MSI was shown to reflect medical considerations through the choice of MCF penalties for under- and overcontouring. Existing similarity scores were either insensitive to medical realities or simply inaccurate. CONCLUSIONS: The medical similarity index, a segmentation evaluation metric based on medical considerations, has been proposed, developed, and tested to incorporate clinically relevant considerations beyond geometric parameters alone. PMID- 26127055 TI - Computer-aided diagnosis for distinguishing between triple-negative breast cancer and fibroadenomas based on ultrasound texture features. AB - PURPOSE: Triple-negative breast cancer (TNBC), an aggressive subtype, is frequently misclassified as fibroadenoma due to benign morphologic features on breast ultrasound (US). This study aims to develop a computer-aided diagnosis (CAD) system based on texture features for distinguishing between TNBC and benign fibroadenomas in US images. METHODS: US images of 169 pathology-proven tumors (mean size, 1.65 cm; range, 0.7-3.0 cm) composed of 84 benign fibroadenomas and 85 TNBC tumors are used in this study. After a tumor is segmented out using the level-set method, morphological, conventional texture, and multiresolution gray scale invariant texture feature sets are computed using a best-fitting ellipse, gray-level co-occurrence matrices, and the ranklet transform, respectively. The linear support vector machine with leave-one-out cross-validation schema is used as a classifier, and the diagnostic performance is assessed with receiver operating characteristic curve analysis. RESULTS: The Az values of the morphology, conventional texture, and multiresolution gray-scale invariant texture feature sets are 0.8470 [95% confidence intervals (CIs), 0.7826-0.8973], 0.8542 (95% CI, 0.7911-0.9030), and 0.9695 (95% CI, 0.9376-0.9865), respectively. The Az of the CAD system based on the combined feature sets is 0.9702 (95% CI, 0.9334-0.9882). CONCLUSIONS: The CAD system based on texture features extracted via the ranklet transform may be useful for improving the ability to discriminate between TNBC and benign fibroadenomas. PMID- 26127056 TI - A general theory of interference fringes in x-ray phase grating imaging. AB - PURPOSE: The authors note that the concept of the Talbot self-image distance in x ray phase grating interferometry is indeed not well defined for polychromatic x rays, because both the grating phase shift and the fractional Talbot distances are all x-ray wavelength-dependent. For x-ray interferometry optimization, there is a need for a quantitative theory that is able to predict if a good intensity modulation is attainable at a given grating-to-detector distance. In this work, the authors set out to meet this need. METHODS: In order to apply Fourier analysis directly to the intensity fringe patterns of two-dimensional and one dimensional phase grating interferometers, the authors start their derivation from a general phase space theory of x-ray phase-contrast imaging. Unlike previous Fourier analyses, the authors evolved the Wigner distribution to obtain closed-form expressions of the Fourier coefficients of the intensity fringes for any grating-to-detector distance, even if it is not a fractional Talbot distance. RESULTS: The developed theory determines the visibility of any diffraction order as a function of the grating-to-detector distance, the phase shift of the grating, and the x-ray spectrum. The authors demonstrate that the visibilities of diffraction orders can serve as the indicators of the underlying interference intensity modulation. Applying the theory to the conventional and inverse geometry configurations of single-grating interferometers, the authors demonstrated that the proposed theory provides a quantitative tool for the grating interferometer optimization with or without the Talbot-distance constraints. CONCLUSIONS: In this work, the authors developed a novel theory of the interference intensity fringes in phase grating x-ray interferometry. This theory provides a quantitative tool in design optimization of phase grating x-ray interferometers. PMID- 26127057 TI - A generic high-dose rate (192)Ir brachytherapy source for evaluation of model based dose calculations beyond the TG-43 formalism. AB - PURPOSE: In order to facilitate a smooth transition for brachytherapy dose calculations from the American Association of Physicists in Medicine (AAPM) Task Group No. 43 (TG-43) formalism to model-based dose calculation algorithms (MBDCAs), treatment planning systems (TPSs) using a MBDCA require a set of well defined test case plans characterized by Monte Carlo (MC) methods. This also permits direct dose comparison to TG-43 reference data. Such test case plans should be made available for use in the software commissioning process performed by clinical end users. To this end, a hypothetical, generic high-dose rate (HDR) (192)Ir source and a virtual water phantom were designed, which can be imported into a TPS. METHODS: A hypothetical, generic HDR (192)Ir source was designed based on commercially available sources as well as a virtual, cubic water phantom that can be imported into any TPS in DICOM format. The dose distribution of the generic (192)Ir source when placed at the center of the cubic phantom, and away from the center under altered scatter conditions, was evaluated using two commercial MBDCAs [Oncentra((r)) Brachy with advanced collapsed-cone engine (ACE) and BrachyVision ACUROSTM ]. Dose comparisons were performed using state-of-the art MC codes for radiation transport, including ALGEBRA, BrachyDose, GEANT4, MCNP5, MCNP6, and PENELOPE2008. The methodologies adhered to recommendations in the AAPM TG-229 report on high-energy brachytherapy source dosimetry. TG-43 dosimetry parameters, an along-away dose-rate table, and primary and scatter separated (PSS) data were obtained. The virtual water phantom of (201)(3) voxels (1 mm sides) was used to evaluate the calculated dose distributions. Two test case plans involving a single position of the generic HDR (192)Ir source in this phantom were prepared: (i) source centered in the phantom and (ii) source displaced 7 cm laterally from the center. Datasets were independently produced by different investigators. MC results were then compared against dose calculated using TG-43 and MBDCA methods. RESULTS: TG-43 and PSS datasets were generated for the generic source, the PSS data for use with the ace algorithm. The dose-rate constant values obtained from seven MC simulations, performed independently using different codes, were in excellent agreement, yielding an average of 1.1109 +/- 0.0004 cGy/(h U) (k = 1, Type A uncertainty). MC calculated dose-rate distributions for the two plans were also found to be in excellent agreement, with differences within type A uncertainties. Differences between commercial MBDCA and MC results were test, position, and calculation parameter dependent. On average, however, these differences were within 1% for ACUROS and 2% for ace at clinically relevant distances. CONCLUSIONS: A hypothetical, generic HDR (192)Ir source was designed and implemented in two commercially available TPSs employing different MBDCAs. Reference dose distributions for this source were benchmarked and used for the evaluation of MBDCA calculations employing a virtual, cubic water phantom in the form of a CT DICOM image series. The implementation of a generic source of identical design in all TPSs using MBDCAs is an important step toward supporting univocal commissioning procedures and direct comparisons between TPSs. PMID- 26127058 TI - Radiation doses in volume-of-interest breast computed tomography--A Monte Carlo simulation study. AB - PURPOSE: Cone beam breast computed tomography (breast CT) with true three dimensional, nearly isotropic spatial resolution has been developed and investigated over the past decade to overcome the problem of lesions overlapping with breast anatomical structures on two-dimensional mammographic images. However, the ability of breast CT to detect small objects, such as tissue structure edges and small calcifications, is limited. To resolve this problem, the authors proposed and developed a volume-of-interest (VOI) breast CT technique to image a small VOI using a higher radiation dose to improve that region's visibility. In this study, the authors performed Monte Carlo simulations to estimate average breast dose and average glandular dose (AGD) for the VOI breast CT technique. METHODS: Electron-Gamma-Shower system code-based Monte Carlo codes were used to simulate breast CT. The Monte Carlo codes estimated were validated using physical measurements of air kerma ratios and point doses in phantoms with an ion chamber and optically stimulated luminescence dosimeters. The validated full cone x-ray source was then collimated to simulate half cone beam x-rays to image digital pendant-geometry, hemi-ellipsoidal, homogeneous breast phantoms and to estimate breast doses with full field scans. 13-cm in diameter, 10-cm long hemi-ellipsoidal homogeneous phantoms were used to simulate median breasts. Breast compositions of 25% and 50% volumetric glandular fractions (VGFs) were used to investigate the influence on breast dose. The simulated half cone beam x rays were then collimated to a narrow x-ray beam with an area of 2.5 * 2.5 cm(2) field of view at the isocenter plane and to perform VOI field scans. The Monte Carlo results for the full field scans and the VOI field scans were then used to estimate the AGD for the VOI breast CT technique. RESULTS: The ratios of air kerma ratios and dose measurement results from the Monte Carlo simulation to those from the physical measurements were 0.97 +/- 0.03 and 1.10 +/- 0.13, respectively, indicating that the accuracy of the Monte Carlo simulation was adequate. The normalized AGD with VOI field scans was substantially reduced by a factor of about 2 over the VOI region and by a factor of 18 over the entire breast for both 25% and 50% VGF simulated breasts compared with the normalized AGD with full field scans. The normalized AGD for the VOI breast CT technique can be kept the same as or lower than that for a full field scan with the exposure level for the VOI field scan increased by a factor of as much as 12. CONCLUSIONS: The authors' Monte Carlo estimates of normalized AGDs for the VOI breast CT technique show that this technique can be used to markedly increase the dose to the breast and thus the visibility of the VOI region without increasing the dose to the breast. The results of this investigation should be helpful for those interested in using VOI breast CT technique to image small calcifications with dose concern. PMID- 26127059 TI - A "loop" shape descriptor and its application to automated segmentation of airways from CT scans. AB - PURPOSE: A novel shape descriptor is presented to aid an automated identification of the airways depicted on computed tomography (CT) images. METHODS: Instead of simplifying the tubular characteristic of the airways as an ideal mathematical cylindrical or circular shape, the proposed "loop" shape descriptor exploits the fact that the cross sections of any tubular structure (regardless of its regularity) always appear as a loop. In implementation, the authors first reconstruct the anatomical structures in volumetric CT as a three-dimensional surface model using the classical marching cubes algorithm. Then, the loop descriptor is applied to locate the airways with a concave loop cross section. To deal with the variation of the airway walls in density as depicted on CT images, a multiple threshold strategy is proposed. A publicly available chest CT database consisting of 20 CT scans, which was designed specifically for evaluating an airway segmentation algorithm, was used for quantitative performance assessment. Measures, including length, branch count, and generations, were computed under the aid of a skeletonization operation. RESULTS: For the test dataset, the airway length ranged from 64.6 to 429.8 cm, the generation ranged from 7 to 11, and the branch number ranged from 48 to 312. These results were comparable to the performance of the state-of-the-art algorithms validated on the same dataset. CONCLUSIONS: The authors' quantitative experiment demonstrated the feasibility and reliability of the developed shape descriptor in identifying lung airways. PMID- 26127060 TI - Erratum: "Independent dosimetric assessment of the model EP917 episcleral brachytherapy plaque" [Med. Phys. 41, 092102 (11pp.) (2014)]. PMID- 26129624 TI - Comparative genomics of Streptococcus pyogenes M1 isolates differing in virulence and propensity to cause systemic infection in mice. AB - Streptococcus pyogenes serotype M1 is a frequent cause of severe infections in humans. Some M1 isolates are pathogenic in mice and used in studies on infection pathogenesis. We observed marked differences in murine infections caused by M1 strain SF370, 5448, 5448AP or AP1 which prompted us to sequence the whole genome of isolates 5448 and AP1 for comparative analysis. Strain 5448 is known to acquire inactivating mutations in the CovRS two-component system during mouse infection, producing hypervirulent progeny such as 5448AP. Isolates AP1 and 5448AP, more than 5448, caused disseminating infections that became systemic and lethal. SF370 was not pathogenic. Phages caused gross genetic differences and increased the gene content of AP1 by 8% as compared to 5448 and SF370. Each of six examined M1 genomes contained two CRISPR-Cas systems. Phage insertion destroyed a type II CRISPR-Cas system in AP1 and other strains of serotypes M1, M3, M6 and M24, but not in M1 strains 5448, SF370, MGAS5005, A20 or M1 476. A resulting impaired defence against invading genetic elements could have led to the wealth of phages in AP1. AP1 lacks genetic features of the MGAS5005-like clonal complex including the streptodornase that drives selection for hypervirulent clones with inactivated CovRS system. Still, inactivating mutations in covS were a common genetic feature of AP1 and the MGAS5005-like isolate 5448AP. Abolished expression of the cysteine proteinase SpeB, due to CovRS inactivation could be a common cause for hypervirulence of the two isolates. Moreover, an additional protein H-coding gene and a mutation in the regulator gene rofA distinguished AP1 form other M1 isolates. In conclusion, hypervirulence of S. pyogenes M1 in mice is not limited to the MGAS5005-like genotype. PMID- 26129625 TI - Diversity and plasticity of microglial cells in psychiatric and neurological disorders. AB - Recent advanced immunological analyses have revealed that the diversity and plasticity of macrophages lead to the identification of functional polarization states (classically activated M1 type and alternatively activated M2 type) which are dependent on the extracellular environment. M1 and M2 polarization states of macrophages play an important role in controlling the balance between pro inflammatory and anti-inflammatory conditions. Microglial cells are resident mononuclear phagocytes in the central nervous system (CNS), express several macrophage-associated markers, and appear to display functional polarization states similar to macrophages. Like M1 macrophages, M1 polarized microglia can produce pro-inflammatory cytokines and mediators such as interleukin (IL) 1beta, IL-6, tumor necrosis factor-alpha, CC-chemokine ligand 2, nitric oxide, and reactive oxygen species, suggesting that these molecules contribute to dysfunction of neural network in the CNS. On the other hand, M2 polarized microglia can produce anti-inflammatory cytokine, IL-10 and express several receptors that are implicated in inhibiting inflammation and restoring homeostasis. In this review, we summarize the diversity, plasticity, and immunoregulatory functions of M1 and M2 microglia in psychiatric and neurological disorders. Based on these aspects, we propose a contribution of imbalance between M1 and M2 polarization of microglia in bipolar disorder, obesity, amyotrophic lateral sclerosis, and Rett syndrome. Consequently, molecules that normalize the imbalance between M1 and M2 microglial polarization states may provide a beneficial therapeutic target for the treatment of these disorders. PMID- 26129626 TI - Evaluation of the 'Prostate Interdisciplinary Communication and Mapping Algorithm for Biopsy and Pathology' (PIC-MABP). AB - INTRODUCTION: Experience from interdisciplinary cooperation revealed the need for a prostate mapping scheme to communicate multiparametric MRI (mpMRI) findings between radiologists, urologists, and pathologists, which should be detailed, yet easy to memorize. For this purpose, the 'Prostate interdisciplinary communication and mapping algorithm for biopsy and pathology' (PIC-MABP) was developed. This study evaluated the accuracy of the PIC-MABP system. METHODS: PIC-MABP was tested and validated in findings of 10 randomly selected patients from routine clinical practise with 18 histologically proven cancer lesions. Patients received an mpMRI of the prostate prior to prostatectomy. After surgery the prostates were prepared as whole-mount step sections. Cancer lesions, which were found suspicious on mpMRI, were assigned to the according PIC-MABP sectors by a radiologist. MpMRI slides were masked and sent to seven urologists from different centres, providing only the PIC-MABP location of each lesion. Urologists marked the accordant regions. Then mpMRI slides were unmasked, and the correctness of each mark was evaluated. RESULTS: One hundred and seventeen of the 126 marks (93%) were correctly assigned. Detection rates differed for lesions >0.5 cc compared with lesions <0.5 cc (p < 0.005): 3/7 (43%) marks were correctly assigned in lesions <0.3 cc, 16/21 (76%) in lesions with 0.3-0.5 cc, and 98/98 (100%) in lesions >0.5 cc. Interobserver agreement was good for lesions >0.5 cc and poor for lesions <0.3 cc (Fleiss Kappa 1 vs. 0.0175). CONCLUSION: PIC-MABP seems to be a reliable system to communicate the location of mpMRI findings >0.5 cc between different disciplines and can be a useful guidance for cognitive mpMRI/TRUS fusion biopsy. PMID- 26129627 TI - Spatiotemporal data visualisation for homecare monitoring of elderly people. AB - OBJECTIVE: Elderly people who live alone can be assisted by home monitoring systems that identify risk scenarios such as falls, fatigue symptoms or burglary. Given that these systems have to manage spatiotemporal data, human intervention is required to validate automatic alarms due to the high number of false positives and the need for context interpretation. The goal of this work was to provide tools to support human action, to identify such potential risk scenarios based on spatiotemporal data visualisation. METHODS AND MATERIALS: We propose the MTA (multiple temporal axes) model, a visual representation of temporal information of the activity of a single person at different locations. The main goal of this model is to visualize the behaviour of a person in their home, facilitating the identification of health-risk scenarios and repetitive patterns. We evaluate the model's insight capacity compared with other models using a standard evaluation protocol. We also test its practical suitability of the MTA graphical model in a commercial home monitoring system. In particular, we implemented 8VISU, a visualization tool based on MTA. RESULTS: MTA proved to be more than 90% accurate in identify non-risk scenarios, independently of the length of the record visualised. When the spatial complexity was increased (e.g. number of rooms) the model provided good accuracy form up to 5 rooms. Therefore, user preferences and user performance seem to be balanced. Moreover, it also gave high sensitivity levels (over 90%) for 5-8 rooms. Fall is the most recurrent incident for elderly people. The MTA model outperformed the other models considered in identifying fall scenarios (66% of correctness) and was the second best for burglary and fatigue scenarios (36% of correctness). Our experiments also confirm the hypothesis that cyclic models are the most suitable for fatigue scenarios, the Spiral and MTA models obtaining most positive identifications. CONCLUSIONS: In home monitoring systems, spatiotemporal visualization is a useful tool for identifying risk and preventing home accidents in elderly people living alone. The MTA model helps the visualisation in different stages of the temporal data analysis process. In particular, its explicit representation of space and movement is useful for identifying potential scenarios of risk, while the spiral structure can be used for the identification of recurrent patterns. The results of the experiments and the experience using the visualization tool 8VISU proof the potential of the MTA graphical model to mine temporal data and to support caregivers using home monitoring infrastructures. PMID- 26129628 TI - Constant time gradient HSQC-iDOSY: practical aspects. PMID- 26129629 TI - Pathological assessment of end-stage heart failure in explanted hearts in correlation with hemodynamics in patients undergoing orthotopic heart transplantation. AB - BACKGROUND: To date, there has been little research, if any, on the pathological correlates of end-stage heart failure in the explanted hearts of orthotopic heart transplant (OHT) recipients in correlation with the patients' hemodynamics. We sought to compare the gross and histopathological parameters in hearts explanted native or previously transplanted-from patients with end-stage heart failure with the clinical hemodynamics parameters at the time of OHT. METHODS: Forty patients undergoing OHT were enrolled in this study and divided into two groups according to whether they suffered from ischemic (ICMP) or nonischemic cardiomyopathy (NICMP). All study patients were treated with OHT for end-stage heart failure at The University of Texas Health Science Center at Houston. The pathological investigations of the hearts were focused on the study of the underlying cause of heart failure leading the patient to OHT; on the quantification of the extent and severity of fibrosis, hypertrophy, and myocytolysis; and on validating a semiquantitative grading scale. Analyses of multiple sections of the explanted hearts were carried out. The heart weights were recorded and compared with the grades of fibrosis, hypertrophy of cardiomyocytes, and myocytolysis. The grades of fibrosis, hypertrophy, and myocytolysis were evaluated in right and left ventricles and atria (with areas of confluent infarction excluded). The pathological parameters were correlated with the patients' clinical parameters. RESULTS: Twenty-two patients (20 men, 2 women, mean age+/-S.E.M., 62.3+/-2.2 years) suffered from ICMP and 18 patients (9 men, 9 women, mean age+/-S.E.M., 56.3+/-2.8 years) from NICMP. All the clinical and pathological measured variables were comparable between the two groups, except for pulmonary vascular resistance, which was higher in the NICMP group of patients, and the grade of myocytolysis, which was significantly higher in the ICMP vs. NICMP group. Most of the clinical and pathological variables were overall linearly correlated. CONCLUSIONS: Both ICMP and NICMP groups of end-stage heart failure requiring OHT presented high grades of fibrosis, hypertrophy, and myocytolysis. Heart failure is the final common pathway of a variety of primary cardiovascular diseases regardless of the ischemic or nonischemic nature of the cardiomyopathy. PMID- 26129630 TI - 5As Team obesity intervention in primary care: development and evaluation of shared decision-making weight management tools. AB - Despite several clinical practice guidelines, there remains a considerable gap in prevention and management of obesity in primary care. To address the need for changing provider behaviour, a randomized controlled trial with convergent mixed method evaluation, the 5As Team (5AsT) study, was conducted. As part of the 5AsT intervention, the 5AsT tool kit was developed. This paper describes the development process and evaluation of these tools. Tools were co-developed by the multidisciplinary research team and the 5AsT, which included registered nurses/nurse practitioners (n = 15), mental health workers (n = 7) and registered dieticians (n = 7), who were previously randomized to the 5AsT intervention group at a primary care network in Edmonton, Alberta, Canada. The 5AsT tool development occurred through a practice/implementation-oriented, need-based, iterative process during learning collaborative sessions of the 5AsT intervention. Feedback during tool development was received through field notes and final provider evaluation was carried out through anonymous questionnaires. Twelve tools were co developed with 5AsT. All tools were evaluated as either 'most useful' or 'moderately useful' in primary care practice by the 5AsT. Four key findings during 5AsT tool development were the need for: tools that were adaptive, tools to facilitate interdisciplinary practice, tools to help patients understand realistic expectations for weight loss and shared decision-making tools for goal setting and relapse prevention. The 5AsT tools are primary care tools which extend the utility of the 5As of obesity management framework in clinical practice. PMID- 26129632 TI - Approaches to supporting lactation and breastfeeding for very preterm infants in the NICU: a qualitative study in three European regions. AB - OBJECTIVES: To explore differences in approaches to supporting lactation and breastfeeding for very preterm infants in neonatal intensive care units (NICU) in 3 European regions. DESIGN: Qualitative cross-sectional study carried out by means of face-to-face semistructured interviews. Verbatim transcripts were coded using a theoretical framework derived from the literature and supplemented by data-driven concepts and codes. SETTING: 4 purposively selected NICUs in each of 3 European regions in 2010 (Ile-de-France in France, Lazio in Italy, and the former Trent region in the UK). PARTICIPANTS: NICU staff members (n=22). RESULTS: Policies and practices for managing mother's own milk for very preterm babies differed between regions, and were much more complex in Ile-de-France than in the Trent or Lazio regions. Staff approaches to mothers to initiate lactation differed by region, with an emphasis on the nutritional and immunological value of human milk in the Trent region and on the 'normalising' effect of breastfeeding on the mother-child relationship in Lazio. French and English staff expressed conflicting opinions about the use of bottles, which was routine in Italy. Italian informants stressed the importance of early maternal milk expression and feeding, but also mentioned discharging infants home before feeding at the breast was established. In Ile-de-France and Trent, successful feeding from the breast was achieved before discharge, although this was seen as a factor that could prolong hospitalisation and discourage continued breastfeeding for some women. CONCLUSIONS: Targeted health promotion policies in the NICU are necessary to increase the number of infants receiving their mother's milk and to support mothers with transfer of the infant to the breast. Integrating knowledge about the different approaches to lactation and breastfeeding in European NICUs could improve the relevance of recommendations in multiple cultural settings. PMID- 26129633 TI - Exploring the potential impact of rotavirus vaccination on work absenteeism among female administrative personnel of the City of Antwerp through a retrospective database analysis. AB - OBJECTIVES: Rotavirus vaccination has been reimbursed in Belgium since November 2006 with a high uptake (>85%). Economic analyses of the vaccine have been reported, including estimates of indirect cost gain related to the reduction in work absenteeism. The objective of this study was to evaluate the latter parameter using real-life data. DESIGN AND SETTING: A simple model estimated the reduction in absent workdays per working mother with a firstborn baby after the introduction of the rotavirus vaccine. Next, data on work absences were retrospectively analysed (from 2003 to 2012) using a database of administrative employees (n=11,600 working women per year) in the City of Antwerp. Observed reductions in absenteeism after the introduction of the vaccine were compared with the results from the model. These reductions would most likely be observed during the epidemic periods of rotavirus (from January to the end of May) for short-duration absences of <= 5 days. We compared data from outside epidemic periods (from June to December), expecting no changes over time prevaccine and postvaccine introduction, as well as with a control group of women aged 30-35 years with no first child. RESULTS: Model estimates were 0.73 working days gained per working mother. In the database of the City of Antwerp, we identified a gain of 0.88 working days during the epidemic period, and an accumulated gain of 2.24 days over a 3-year follow-up period. In the control group, no decrease in absenteeism was measured. Giving vaccine access to working mothers resulted in an estimated accumulated net cost gain of ?187 per mother. CONCLUSIONS: Reduction in absenteeism among working mothers was observed during periods of the epidemic after the introduction of the rotavirus vaccine in Belgium. This reduction is in line with estimates of indirect cost gains used in economic evaluations of the rotavirus vaccine. TRIAL REGISTRATION NUMBER: HO-12-12768. PMID- 26129634 TI - The need for and provision of intrathecal baclofen therapy for the management of spasticity in England: an assessment of the Hospital Episode Statistics database. AB - OBJECTIVES: The aim of this study was to evaluate changes in the uptake of intrathecal baclofen (ITB) following commissioning of this therapy by the National Health Service (NHS) England in April 2013. The specific objectives of this study were: (i) to explore the gap between the need for and the actual provision of ITB services; and (ii) to compare England figures with other European countries with comparable data available. SETTING: Data for ITB -related procedures were obtained from the Hospital Episode Statistics (HES) database from 2009/2010 to 2013/2014. PARTICIPANTS: Patients receiving ITB for the management of spasticity. RESULTS: The available data for implantation of ITB from 2009/2010 to 2013/2014 for the treatment of spasticity due to varied aetiologies show that there has not been an increase in uptake of this therapy. The estimated need for this treatment based on the incidence and prevalence of conditions susceptible to ITB therapy is between 4.6 and 5.7 per million population. Our analysis of the data available from the HES database showed that the actual number of implants is around 3.0 per million population. The same period 2009-2014 has seen an increase in the delivery of other neuromodulation techniques including spinal cord stimulation, deep brain stimulation and sacral nerve stimulation. CONCLUSIONS: There is a considerable gap between the need for and provision of ITB figures nationally. Additionally, within the same area, we have observed important differences in the ITB service delivery between the various trusts. The reasons for this can be multifactorial, including individual experience and opinions, organisational structures, resource and financial limitations. Further research analysing the efficacy and cost-effectiveness of this treatment in the UK might inform the development of Technology Appraisal Guidance for ITB, potentially leading to an improvement in service provision. PMID- 26129635 TI - The correlation between blood pressure and kidney function decline in older people: a registry-based cohort study. AB - OBJECTIVES: To examine the relation between static and dynamic blood pressure (BP) measurements and the evolution of kidney function in older people, adjusted for the presence of multimorbidity. DESIGN: Retrospective cohort study during a 10-year time interval (2002-2012) in three age strata of patients aged 60 and older. SETTING: Primary care registration network with 97 general practitioners working in 55 practices regularly submitting collected patient data. PARTICIPANTS: All patients with at least one BP measurement in 2002 and at least four serum creatine measurements after 2002 (n=8636). A modified Charlson Comorbidity Index (mCCI) at baseline was registered. Change in systolic and diastolic BP (DBP) and pulse pressure (PP) from 2002 onwards was calculated. The relation between kidney function evolution and baseline BP and change in BP was examined using linear and logistic regression analysis. MAIN OUTCOME MEASURES: The slope of the estimated glomerular filtration rate (eGFR, MDRD, Modification of Diet in Renal Disease equation) was calculated by the ordinal least square method. A rapid annual decline of kidney function was defined as >= 3 L/min/1.73 m(2)/year. RESULTS: Rapid annual decline of kidney function occurred in 1130 patients (13.1%). High baseline systolic BP (SBP) and PP predicted kidney function decline in participants aged 60-79 years. No correlation between baseline BP and kidney function decline was found in participants aged 80 years and older. An annual decline of >= 1 mm Hg in SBP and PP was a strong risk factor for a rapid annual kidney function decline in all age strata, independent of baseline BP and mCCI. A decline in DBP as also a strong independent predictor in participants aged 60-79 years. CONCLUSIONS: The present study identified a decline in BP over time as a strong risk factor for kidney function decline in all age strata, adjusted for mCCI and baseline kidney function and BP. PMID- 26129636 TI - Type III home sleep testing versus pulse oximetry: is the respiratory disturbance index better than the oxygen desaturation index to predict the apnoea-hypopnoea index measured during laboratory polysomnography? AB - OBJECTIVES: In its guidelines on the use of portable monitors to diagnose obstructive sleep apnoea, the American Academy of Sleep Medicine endorses home polygraphy with type III devices recording at a minimum airflow the respiratory effort and pulse oximetry, but advises against simple pulse oximetry. However, oximetry is widely available and simple to use in the home. This study was designed to compare the ability of the oxygen desaturation index (ODI) based on oximetry alone with a stand-alone pulse oximeter (SPO) and from the oximetry channel of the ApneaLink Plus (ALP), with the respiratory disturbance index (RDI) based on four channels from the ALP to predict the apnoea-hypopnoea index (AHI) from laboratory polysomnography. DESIGN: Cross-sectional diagnostic accuracy study. SETTING: Sleep medicine practice of a multispecialty clinic. PARTICIPANTS: Patients referred for laboratory polysomnography with suspected sleep apnoea. We enrolled 135 participants with 123 attempting the home sleep testing and 73 having at least 4 hours of satisfactory data from SPO and ALP. INTERVENTIONS: Participants had home testing performed simultaneously with both a SPO and an ALP. The 2 oximeter probes were worn on different fingers of the same hand. The ODI for the SPO was calculated using Profox software (ODI(SOX)). For the ALP, RDI and ODI were calculated using both technician scoring (RDI(MAN) and ODI(MAN)) and the ALP computer scoring (RDI(RAW) and ODI(RAW)). RESULTS: The receiver-operator characteristic areas under the curve for AHI >= 5 were RDI(MAN) 0.88 (95% confidence limits 0.81-0.96), RDI(RAW) 0.86 (0.76-0.94), ODI(MAN) 0.86 (0.77 0.95), ODI(RAW) 0.84 (0.75-0.93) and ODI(SOX) 0.83 (0.73-0.93). CONCLUSIONS: We conclude that the RDI and the ODI, measured at home on the same night, give similar predictions of the laboratory AHI, measured on a different night. The differences between the two methods are small compared with the reported night-to night variation of the AHI. PMID- 26129637 TI - Associations with duration of compensation following whiplash sustained in a motor vehicle crash. AB - CONTEXT: Continued exposure to compensation systems has been reported as deleterious to the health of participants. Understanding the associations with time to claim closure could allow for targeted interventions aimed at minimising the time participants are exposed to the compensation system. STUDY OBJECTIVE: To identify the associations of extended time receiving compensation benefits with the aim of developing a prognostic model that predicts time to claim closure. STUDY DESIGN: Prospective cohort study in people with whiplash associated disorder. OUTCOME MEASURES: Time to claim closure, in a privately underwritten fault based third party traffic crash insurance scheme in New South Wales, Australia. METHOD: Cox proportional hazard regression modelling. RESULTS: Of the 246 participants, 25% remained in the compensation system longer than 24 months with 15% remaining longer than three years. Higher initial disability (Functional Rating Index>=25 at baseline) (HRR: 95% CI, 1.916: 1.324-2.774, p<0.001); and lower initial mental health as measured by SF-36 Mental Component Score (HRR: 95% CI, 0.973: 0.960-0.987, p<0.001) were significantly and independently associated with an increased time-to-claim closure. Shorter time to claim closure was associated with having no legal involvement (HRR: 95% CI, 1.911: 1.169-3.123, p=0.009); and, not having a prior claim for compensation (HRR: 95% CI, 1.523: 1.062-2.198, p=0.022). CONCLUSIONS: Health and insurance related factors are independently associated with time to claim closure. Both factors need to be considered by insurers in their assessment of complexity of claims. Interventions aimed at minimising the impact of these factors could reduce claimants' exposure to the compensation system. In turn insurers can potentially reduce claims duration and cost, while improving the health outcomes of claimants. PMID- 26129638 TI - Virtual reconstruction and description of the cranial endocast of Pristerodon mackayi (Therapsida, Anomodontia). AB - The cranial endocast of Pristerodon mackayi is described, which has been virtually reconstructed on the basis of neutron tomographic data. The gross anatomy of the cranial endocast of Pristerodon resembles other nonmammalian synapsids such as Thrinaxodon liorhinus in having a narrow, tubular forebrain, well developed olfactory bulbs, a large parietal foramen and unossified zone. As it is the case in cynodonts the hindbrain of Pristerodon is broader than the mid- and forebrain. Large paraflocculi are developed. The medulla oblongata can be well distinguished from the pons. The pons is divided by a median ridge into two portions. There is no evidence for a neocortex, which seems to be also reflected in the low encephalization quotient of 0.18 estimated according to the method of Eisenberg. PMID- 26129639 TI - Amoeba-Inspired Heuristic Search Dynamics for Exploring Chemical Reaction Paths. AB - We propose a nature-inspired model for simulating chemical reactions in a computationally resource-saving manner. The model was developed by extending our previously proposed heuristic search algorithm, called "AmoebaSAT [Aono et al. 2013]," which was inspired by the spatiotemporal dynamics of a single-celled amoeboid organism that exhibits sophisticated computing capabilities in adapting to its environment efficiently [Zhu et al. 2013]. AmoebaSAT is used for solving an NP-complete combinatorial optimization problem [Garey and Johnson 1979], "the satisfiability problem," and finds a constraint-satisfying solution at a speed that is dramatically faster than one of the conventionally known fastest stochastic local search methods [Iwama and Tamaki 2004] for a class of randomly generated problem instances [ http://www.cs.ubc.ca/~hoos/5/benchm.html ]. In cases where the problem has more than one solution, AmoebaSAT exhibits dynamic transition behavior among a variety of the solutions. Inheriting these features of AmoebaSAT, we formulate "AmoebaChem," which explores a variety of metastable molecules in which several constraints determined by input atoms are satisfied and generates dynamic transition processes among the metastable molecules. AmoebaChem and its developed forms will be applied to the study of the origins of life, to discover reaction paths for which expected or unexpected organic compounds may be formed via unknown unstable intermediates and to estimate the likelihood of each of the discovered paths. PMID- 26129640 TI - Comparable outcome after single-antigen-mismatched versus matched unrelated donor haematopoietic cell transplantation. AB - PURPOSE: Allogeneic haematopoietic stem cell transplantation (HSCT) is a proven treatment for patients with haematological malignancies. In this retrospective analysis, the impact of donor matching on outcome of unrelated HSCT was analysed in patients transplanted at the University of Leipzig. METHODS: From 2000 to 2009, 206 patients were transplanted from unrelated donors, of which 51 were mismatched (39 in 1 and 12 in >= 2 HLA-antigens), using peripheral blood or bone marrow grafts after total body irradiation and cyclophosphamide or busulfan and cyclophosphamide preparative regimens in combination with ATG. For graft-versus host disease (GvHD) prophylaxis cyclosporine and MTX were administered. RESULTS: After a median follow-up of 49 months, outcome at 5 years in recipients of HLA identical grafts was comparable to that of patients transplanted from HLA incompatible donors with an overall survival (OS) of 52 % (95 % CI 43-61) versus 48 % (95 % CI 34-63), respectively (p = 0.48). Results were also comparable for event-free survival at 5 years [47 % (95 % CI 38-56) vs. 39 % (95 % CI 25-54); p = 0.44], relapse incidence (RI) [29 % (95 % CI 20-38) vs. 41 (95 % CI 25-57); p = 0.22] and non-relapse mortality [24 % (95 % CI 16-33) vs. 20 % (95 % CI 8-33); p = 0.84] in the matched versus mismatched groups. Incidence of acute and chronic GvHD was similar in both groups. Advanced disease (p = 0.02) and low-resolution typing (p = 0.04) are risk factors for OS and RI in univariate and multivariate analysis. CONCLUSIONS: Donors with one antigen mismatch are an acceptable option for patients with malignant disease for whom no fully matched donor is available. PMID- 26129641 TI - Characterization of the annular lipid shell of the Sec translocon. AB - The bacterial Sec translocase in its minimal form consists of a membrane-embedded protein-conducting pore SecYEG that interacts with the motor protein SecA to mediate the translocation of secretory proteins. In addition, the SecYEG translocon interacts with the accessory SecDFyajC membrane complex and the membrane protein insertase YidC. To examine the composition of the native lipid environment in the vicinity of the SecYEG complex and its impact on translocation activity, styrene-maleic acid lipid particles (SMALPs) were used to extract SecYEG with its lipid environment directly from native Escherichia coli membranes without the use of detergents. This allowed the co-extraction of SecYEG in complex with SecA, but not with SecDFyajC or YidC. Lipid analysis of the SecYEG SMALPs revealed an enrichment of negatively charged lipids in the vicinity of SecYEG, which in detergent assisted reconstitution of the Sec translocase are crucial for the translocation activity. Such lipid enrichment was not found with separately extracted SecDFyajC or YidC, which demonstrates a specific interaction between SecYEG and negatively charged lipids. PMID- 26129642 TI - Thin and ordered hydrogel films deposited through electrospinning technique; a simple and efficient support for organic bilayers. AB - Thermal behavior of Dipalmitoylphosphatidylcholine (DPPC) bilayers deposited over hydrogel fibers was examined. Thus, membrane stability, water absorption-release, phase transitions and phase transition temperatures were studied through different methods during heating cycles. Hydrogel films were realized using an oligomer mixture (HEMA-PEGDA575/photo-initiator) with adequate viscosity. Then, the fibers were deposited over silicon wafers (hydrophilic substrate) through electrospinning technique using four different voltages: 15, 20, 25 and 30 kV. The films were then exposed to UV light, favoring polymer chain crosslinking and interactions between hydrogel and substrate. For samples deposited at 20 and 25 kV, hierarchical wrinkle folds were observed at surface level, their arrangement distribution depends directly on thickness and associated point defects. DPPC bilayers were then placed over hydrogel scaffold using Langmuir-Blodgett technique. Field emission scanning electron microscopy (FE-SEM) analysis were used to investigate sample surface, micrographies show homogeneous layer formation with chain polymer order/disorder related to applied voltage during hydrogel deposition process, among other parameters. According to the results obtained, it is possible to conclude that the oligomer deposited at 20 kV produce thin homogenous films (~40 nm) with enhanced ability to absorb water and release it in a controlled way during heating cycles. These scaffold properties confer to DPPC membrane thermal stability, which allow an easy detection of phase(s) and phase transitions. Thermal behavior was also studied via Atomic Force Microscopy (roughness analysis). Contact angle measurements corroborate system wettability, supporting the theory that hydrogel thin films act as DPPC membrane enhancers for thermal stability against external stimuli. PMID- 26129643 TI - Development of a time-resolved fluorescence immunoassay for Epstein-Barr virus nuclear antigen 1-immunoglobulin A in human serum. AB - Enzyme-linked immunosorbent assay (ELISAs) specific for Epstein-Barr virus nuclear antigen 1 (EBNA1)-immunoglobulin A (IgA) are most commonly used in the clinical diagnosis of EBV infection. But they have a low sensitivity and the enzyme-labeled antibodies are unstable. In this study, a novel immunoassay based on an indirect time-resolved fluoroimmunoassay (TRFIA) was developed. Microtiter plates were coated with recombinant EBNA1. We used Eu(3) (+)-labeled anti-human IgA as probe. The precision, sensitivity, specificity, and stability were evaluated, and comparison with traditional and commercially available ELISAs was also made. The cut-off value for our TRFIA was 2.7. Intra- and inter-assay coefficients of variation for the TRFIA were 1.56-4.99% and 3.92-6.95%, respectively; whereas those for the ELISA were 4.54-8.16% and 7.07-10.52%, respectively. Sensitivity was obviously better than traditional ELISA when diluted positive samples serially. Additionally, stability, specificity test and comparison of sensitivity and specificity between the TRFIA and commercial ELISAs all proved satisfactory. In conclusion, the results demonstrated that EBNA1 IgA TRFIA was a sensitive immunoassay and had potential value in large-scale screening of human serum samples in developing countries. PMID- 26129644 TI - Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes. AB - Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging. PMID- 26129645 TI - Quantum-confinement and Structural Anisotropy result in Electrically-Tunable Dirac Cone in Few-layer Black Phosphorous. AB - Two-dimensional (2D) materials are well-known to exhibit interesting phenomena due to quantum confinement. Here, we show that quantum confinement, together with structural anisotropy, result in an electric-field-tunable Dirac cone in 2D black phosphorus. Using density functional theory calculations, we find that an electric field, E ext, applied normal to a 2D black phosphorus thin film, can reduce the direct band gap of few-layer black phosphorus, resulting in an insulator-to-metal transition at a critical field, Ec. Increasing E ext beyond Ec can induce a Dirac cone in the system, provided the black phosphorus film is sufficiently thin. The electric field strength can tune the position of the Dirac cone and the Dirac-Fermi velocities, the latter being similar in magnitude to that in graphene. We show that the Dirac cone arises from an anisotropic interaction term between the frontier orbitals that are spatially separated due to the applied field, on different halves of the 2D slab. When this interaction term becomes vanishingly small for thicker films, the Dirac cone can no longer be induced. Spin-orbit coupling can gap out the Dirac cone at certain electric fields; however, a further increase in field strength reduces the spin-orbit induced gap, eventually resulting in a topological-insulator-to-Dirac-semimetal transition. PMID- 26129647 TI - Thermodynamic Switch in Binding of Adhesion/Growth Regulatory Human Galectin-3 to Tumor-Associated TF Antigen (CD176) and MUC1 Glycopeptides. AB - A shift to short-chain glycans is an observed change in mucin-type O glycosylation in premalignant and malignant epithelia. Given the evidence that human galectin-3 can interact with mucins and also weakly with free tumor associated Thomsen-Friedenreich (TF) antigen (CD176), the study of its interaction with MUC1 (glyco)peptides is of biomedical relevance. Glycosylated MUC1 fragments that carry the TF antigen attached through either Thr or Ser side chains were synthesized using standard Fmoc-based automated solid-phase peptide chemistry. The dissociation constants (Kd) for interaction of galectin-3 and the glycosylated MUC1 fragments measured by isothermal titration calorimetry decreased up to 10 times in comparison to that of the free TF disaccharide. No binding was observed for the nonglycosylated control version of the MUC1 peptide. The most notable feature of the binding of MUC1 glycopeptides to galectin-3 was a shift from a favorable enthalpy to an entropy-driven binding process. The comparatively diminished enthalpy contribution to the free energy (DeltaG) was compensated by a considerable gain in the entropic term. (1)H-(15)N heteronuclear single-quantum coherence spectroscopy nuclear magnetic resonance data reveal contact at the canonical site mainly by the glycan moiety of the MUC1 glycopeptide. Ligand-dependent differences in binding affinities were also confirmed by a novel assay for screening of low-affinity glycan-lectin interactions based on AlphaScreen technology. Another key finding is that the glycosylated MUC1 peptides exhibited activity in a concentration-dependent manner in cell-based assays revealing selectivity among human galectins. Thus, the presentation of this tumor-associated carbohydrate ligand by the natural peptide scaffold enhances its affinity, highlighting the significance of model studies of human lectins with synthetic glycopeptides. PMID- 26129648 TI - Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. AB - Group 2 innate lymphoid cells (ILC2s) have an important role in acute allergic lung inflammation. Given their distribution and function, lung ILC2s are hypothesized to coordinate epithelial responses to the external environment; however, how barrier surveillance is linked to ILC2 activation remains unclear. Here, we demonstrate that alveolar type II cells are the main source of interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) generated in response to chitin or migratory helminths. IL-33 and TSLP synergistically induce an interferon regulatory factor 4 (IRF4)-IL-9 program in ILC2s, and autocrine IL-9 promotes rapid IL-5 and IL-13 production required for optimal epithelial responses in the conducting airways. Thus, ILC2s link alveolar function to regulation of airway flow, revealing a key interaction between resident lymphoid and structural cells that might underlie similar organizational hierarchies in other organs. PMID- 26129649 TI - The effect of timing of antiretroviral therapy on CD4+ T-cell reconstitution in the intestine of HIV-infected patients. AB - Whether and to what extent gut mucosal CD4(+) T cells of HIV-infected patients can be restored by combination antiretroviral therapy (cART) is not yet fully resolved. We studied absolute numbers, differentiation, and activation of mucosal CD4(+) T cells at different stages of HIV infection and assessed the effect of timing of cART initiation on this cell population. Mucosal CD4(+) T-cell numbers were severely reduced at all stages of chronic infection, but normal in patients with acute infection. In patients with initiation of cART during chronic HIV infection, mucosal CD4(+) T cells restored to less than half of the numbers in controls. However, in patients who initiated cART during acute HIV infection, mucosal CD4(+) T-cell numbers were fully preserved and markers of microbial translocation and inflammation reversed to normal. The proportion of mucosal effector memory CD4(+) T cells normalized only if cART was initiated at >350 CD4(+) T cells per MUl blood but not with delayed treatment. In conclusion, mucosal CD4(+) T-cell numbers can be preserved if cART is initiated in acute HIV infection. In chronically HIV-infected patients, early cART improves mucosal CD4(+) T-cell differentiation but cannot prevent the persistent lack of total CD4(+) T cells. PMID- 26129650 TI - Metal-specific CD4+ T-cell responses induced by beryllium exposure in HLA-DP2 transgenic mice. AB - Chronic beryllium disease (CBD) is a granulomatous lung disorder that is associated with the accumulation of beryllium (Be)-specific CD4(+) T cells into the lung. Genetic susceptibility is linked to HLA-DPB1 alleles that possess a glutamic acid at position 69 (betaGlu69), and HLA-DPB1*02:01 is the most prevalent betaGlu69-containing allele. Using HLA-DP2 transgenic (Tg) mice, we developed a model of CBD that replicates the major features of the human disease. Here we characterized the T-cell receptor (TCR) repertoire of Be-responsive CD4(+) T cells derived from the lungs of Be oxide-exposed HLA-DP2 Tg mice. The majority of Be-specific T-cell hybridomas expressed TCR Vbeta6, and a subset of these hybridomas expressed identical or nearly identical beta-chains that were paired with different alpha-chains. We delineated mimotopes that bind to HLA-DP2 and form a complex recognized by Be-specific CD4(+) T cells in the absence of Be. These Be-independent peptides possess an arginine at p5 and a tryptophan at p7 that surround the Be-binding site within the HLA-DP2 acidic pocket and likely induce charge and conformational changes that mimic those induced by the Be(2+) cation. Collectively, these data highlight the interplay between peptides and Be in the generation of an adaptive immune response in metal-induced hypersensitivity. PMID- 26129651 TI - Interaction of IFN-gamma with cholinergic agonists to modulate rat and human goblet cell function. AB - Goblet cells populate wet-surfaced mucosa including the conjunctiva of the eye, intestine, and nose, among others. These cells function as part of the innate immune system by secreting high molecular weight mucins that interact with environmental constituents including pathogens, allergens, and particulate pollutants. Herein, we determined whether interferon gamma (IFN-gamma), a Th1 cytokine increased in dry eye, alters goblet cell function. Goblet cells from rat and human conjunctiva were cultured. Changes in intracellular [Ca(2+)] ([Ca(2+)](i)), high molecular weight glycoconjugate secretion, and proliferation were measured after stimulation with IFN-gamma with or without the cholinergic agonist carbachol. IFN-gamma itself increased [Ca(2+)](i) in rat and human goblet cells and prevented the increase in [Ca(2+)](i) caused by carbachol. Carbachol prevented IFN-gamma-mediated increase in [Ca(2+)](i). This cross-talk between IFN gamma and muscarinic receptors may be partially due to use of the same Ca(2+)(i) reservoirs, but also from interaction of signaling pathways proximal to the increase in [Ca(2+)](i). IFN-gamma blocked carbachol-induced high molecular weight glycoconjugate secretion and reduced goblet cell proliferation. We conclude that increased levels of IFN-gamma in dry eye disease could explain the lack of goblet cells and mucin deficiency typically found in this pathology. IFN gamma could also function similarly in respiratory and gastrointestinal tracts. PMID- 26129653 TI - Laparoscopic Transanal Total Mesorectal Excision (taTME) for Rectal Cancer. AB - Proper treatment of adenocarcinoma of the rectum demands a systematic, multidisciplinary approach where surgery remains the cornerstone of treatment. An evolving shift toward minimally invasive surgical approaches for rectal cancer continues to be hampered by the challenges of reliable pelvic exposure and adequate instrumentation for rectal dissection, distal rectal division, and low pelvic anastomosis. The laparoscopic transanal total mesorectal excision surgery has been developed as a novel alternative that provides solutions to many of the limitations of conventional open, laparoscopic and robotic proctectomy. This manuscript will describe the procedure in detail and attempt to define its role as the optimal surgical approach for rectal resection. PMID- 26129652 TI - Generation and transcriptional programming of intestinal dendritic cells: essential role of retinoic acid. AB - The vitamin A metabolite retinoic acid (RA) regulates adaptive immunity in the intestines, with well-characterized effects on IgA responses, Treg induction, and gut trafficking of T- and B-effector cells. It also controls the generation of conventional dendritic cell (cDC) precursors in the bone marrow and regulates cDC subset representation, but its roles in the specialization of intestinal cDC subsets are understudied. Here we show that RA acts cell intrinsically in developing gut-tropic pre-mucosal dendritic cell (pre-MUDC) to effect the differentiation and drive the specialization of intestinal CD103(+)CD11b(-) (cDC1) and of CD103(+)CD11b(+) (cDC2). Systemic deficiency or DC-restricted antagonism of RA signaling resulted in altered phenotypes of intestinal cDC1 and cDC2, and reduced numbers of cDC2. Effects of dietary deficiency were most apparent in the proximal small intestine and were rapidly reversed by reintroducing vitamin A. In cultures of pre-MUDC with Flt3L and granulocyte macrophage colony-stimulating factor (GM-CSF), RA induced cDC with characteristic phenotypes of intestinal cDC1 and cDC2 by controlling subset-defining cell surface receptors, regulating subset-specific transcriptional programs, and suppressing proinflammatory nuclear factor-kappaB-dependent gene expression. Thus, RA is required for transcriptional programming and maturation of intestinal cDC, and with GM-CSF and Flt3L provides a minimal environment for in vitro generation of intestinal cDC1- and cDC2-like cDC from specialized precursors. PMID- 26129655 TI - Erratum to: Delayed Gastric Emptying After Pancreaticoduodenectomy: Is Subtotal Stomach Preserving Better or Pylorus Preserving? PMID- 26129654 TI - Feasibility and Safety of Urgent Laparoscopic Cholecystectomy for Acute Cholecystitis After 4 Days from Symptom Onset. AB - BACKGROUND: It is preferable to perform laparoscopic cholecystectomy for acute cholecystitis in the acute phase, within 72 h of symptom onset. The feasibility and safety of performing urgent laparoscopic cholecystectomy in the late phase (4 7 days after symptom onset) are unclear. The aim of this study was to clarify the feasibility and safety of late phase urgent laparoscopic cholecystectomy. METHODS: Between 2005 and 2014, 233 patients underwent urgent laparoscopic cholecystectomy for acute cholecystitis within 7 days. We compared clinical features and perioperative outcomes between patients who underwent laparoscopic cholecystectomy within 3 days (early phase group) and 4-7 days after symptom onset (late phase group). RESULTS: There were 193 patients in the early phase group and 40 patients in the late-phase group. Performing laparoscopic cholecystectomy in the late phase did not influence operation time, postoperative complications, or postoperative hospital stay. The rate of conversion to open surgery and blood loss were slightly higher in the late-phase group (8 % and 140 ml) compared with the early phase group (3 % and 69 ml) but were still acceptable. CONCLUSIONS: Late phase urgent laparoscopic cholecystectomy for acute cholecystitis was feasible and safe. PMID- 26129656 TI - Alkynyl triphosphine copper complexes: synthesis and photophysical studies. AB - A rigid triphosphine PPh2C6H4-PPh-C6H4PPh2 () reacted with Cu(+) and a stoichiometric amount of terminal alkyne under basic conditions to give a family of copper(i) alkynyl compounds [Cu()C[triple bond, length as m-dash]CR]. The number of terminal -C[triple bond, length as m-dash]CH groups in the starting ligand determines the nuclearity of the resulting complexes giving mono- (, R = Ph; , R = C6H4OMe; , R = C6H4NO2; , R = C6H4CF3; , R = 2-pyridyl), di- (R = (C6H4)n-, n = 1 (), n = 2, (), n = 3 ()) and trinuclear complexes (, R = 1,3,5 (C6H4)3-C6H3; , R = 1,3,5-(C6H4-4-C2C6H4)3-C6H3). In all the complexes the Cu(i) centers are found in a distorted tetrahedral environment that is achieved by tridentate coordination of the ligand and sigma-bonding to the alkynyl function. The crystal structures of , and were estimated by single crystal X-ray diffraction analysis. The (31)P, (1)H and (1)H-(1)H COSY NMR spectroscopy confirms that all the molecules remain intact in solution. The photophysical studies carried out in the solid state at 298 and 77 K revealed moderate to weak orange luminescence (Phiem up to 19%), tentatively assigned to thermally activated delayed fluorescence for the mononuclear complexes. The quantum yields of emission of demonstrated strong dependence on the nature of the alkynyl ligand, the role of which in the electronic transitions was elucidated by TD-DFT computational studies. PMID- 26129658 TI - Microclimate measuring and fluid-dynamic simulation in an industrial broiler house: testing of an experimental ventilation system. AB - The environment in the broiler house is a combination of physical and biological factors generating a complex dynamic system of interactions between birds, husbandry system, light, temperature, and the aerial environment. Ventilation plays a key role in this scenario. It is pivotal to remove carbon dioxide and water vapor from the air of the hen house. Adequate ventilation rates provide the most effective method of controlling temperature within the hen house. They allow for controlling the relative humidity and can play a key role in alleviating the negative effects of high stocking density and of wet litter. In the present study the results of experimental tests performed in a breeding broiler farm are shown. In particular the efficiency of a semi transversal ventilation system was studied against the use of a pure transversal one. In order to verify the efficiency of the systems, fluid dynamic simulations were carried out using the software Comsol multiphysics. The results of this study show that a correct architectural and structural design of the building must be supported by a design of the ventilation system able to maintain the environmental parameters within the limits of the thermo-neutral and welfare conditions and to achieve the highest levels of productivity. PMID- 26129657 TI - Influence of plaque characteristics on fractional flow reserve for coronary lesions with intermediate to obstructive stenosis: insights from integrated backscatter intravascular ultrasound analysis. AB - The aim of this study was to determine the correlation between the fractional flow reserve (FFR) values and volumetric intravascular ultrasound (IVUS) parameters derived from classic gray-scale IVUS and integrated backscatter (IB) IVUS, taking into account known confounding factors. Patients with unstable angina pectoris with the frequent development of vulnerable plaques often showed the discrepancy between the FFR value and the quantitative coronary angiography findings. Our target population was 107 consecutive subjects with 114 isolated lesions who were scheduled for elective coronary angiography. The FFR was calculated as the mean distal coronary pressure divided by the mean aortic pressure during maximal hyperemia. Various volumetric parameters such as lipid plaque volume (LPV) and percentage of LPV (%LPV) were measured using IB-IVUS. Simple and multivariate linear regression analysis was employed to evaluate the correlation between FFR values and various classic gray-scale IVUS and IB-IVUS parameters. The Akaike information criterion (AIC) was used to compare the goodness of fit in an each model. Both the %LPV (r = -0.24; p = 0.01) and LPV (r = -0.40; p < 0.01) were significantly correlated with the FFR value. Only the LPV (AIC = -147.0; p = 0.006) and %LPV (AIC = -152.9; p = 0.005) proved to be independent predictors for the FFR value even after the adjustment of known confounding factors. The volumetric assessment by IB-IVUS could provide better information in terms of the relationship between plaque morphology and the FFR values as compared to the classic IVUS 2-dimensional gray-scale analysis. PMID- 26129659 TI - Epidemiological survey on Mycoplasma synoviae infection in Portuguese broiler breeder flocks. AB - Since modernization and expansion of the poultry industry, infections with Mycoplasma spp. bacteria have been reported as a cause of considerable economic losses. The prevalence of Mycoplasma synoviae infection in 974,000 Portuguese broiler breeders, belonging to 36 flocks, was investigated from December 2008 to March 2012. This study was conducted using a commercial indirect enzyme-linked immunosorbent assay (ELISA) for the analysis of serum antibodies, and a polymerase chain reaction (PCR) for the tracheal tissue. Twenty-four flocks were simultaneously found positive by ELISA and PCR [66.7%, 95% confidence interval (CI): 43.5-76.9%]. The M. synoviae prevalence among chickens averaged 40.3% (483/1,200), with values ranging from 0.0 to 83.3% per flock. The prevalence of farms where M. synoviae positive birds have been found was determined in different poultry categories such as density, biosecurity, strains, offspring quality, premises'age, and others husbandry factors. Prevalence values were significantly higher among birds housed in new facilities (less than 3 years old) and were also significantly higher in the production period. The high prevalence of M. synoviae infection detected in the present study suggests the need to adopt appropriate control measures. PMID- 26129660 TI - A diagnostic protocol to identify water buffaloes (Bubalus bubalis) vaccinated with Brucella abortus strain RB51 vaccine. AB - The use of live vaccine strain RB51 for vaccination of domestic water buffaloes (Bubalus bubalis) at risk of infection with Brucella abortus is permitted notwithstanding the plans for the eradication and only under strict veterinary control. The antibodies induced by RB51 vaccination are not detectable using conventional diagnostic techniques; therefore, it is necessary to have a specific diagnostic tool able to discriminate vaccinated from unvaccinated animals. The combination of a complement fixation test (CFT) with specific RB51 antigen (RB51 CFT) and a brucellin skin test has been demonstrated to be a reliable diagnostic system to identify single cattle (Bos taurus) vaccinated with RB51. So far, no data are available in the international scientific literature regarding the use of this test association in water buffalo. For this reason the suitability of this test combination has been evaluated in a water buffalo herd. One hundred twenty-seven animals farmed in a herd of Salerno province (Campania, Southern Italy), in the context of a presumptive unauthorized use of RB51 vaccine were chosen for this study. All tested animals resulted negative to Rose Bengal test (RBT) and complement fixation test (CFT) used for the detection of specific antibodies against Brucella field strains. Seventy-one animals (56%) developed RB51 antigen-specific CFT (RB51-CFT) antibodies against RB51 vaccine in a first sampling, while 104 animals (82%) gave positive result to a second serum sampling conducted 11 days after the intradermal inoculation of the RB51 brucellin. One hundred and seven animals (84%) showed a positive reaction to the RB51-CFT in at least 1 sampling, while 111 animals (87%) resulted positive to the RB51 brucellin skin test. Thus, analysing the results of the 3 testing in parallel, 119 animals (94%) were positive to at least 1 of the performed tests. The results suggest that the use in parallel of the RB51 brucellin skin test with RB51-CFT may represent a reliable diagnostic system to identify water buffaloes vaccinated with RB51 vaccine. PMID- 26129661 TI - Reorganization of actin cytoskeleton in L929 cells infected with Coxiella burnetii strains isolated from placenta and foetal brain of sheep (Sardinia, Italy). AB - Coxiella burnetii, the etiological agent of Q Fever, is a zoonotic pathogen distributed worldwide. It has been reported that virulent strains of C. burnetii are poorly internalized by monocytes compared to avirulent variants. Virulence is also associated to the formation of pseudopodal extensions and transient reorganization of filamentous actin. In this article, we investigated the ability of 2 Coxiella strains isolated from ovine aborted samples to induce reorganization of the actin cytoskeleton in mouse fibroblast cells. Cells were exposed for 24 and 48 hours to ovine placenta and foetal brain tissue homogenates and then analysed by polymerase chain reaction (PCR) in order to detect Coxiella infection. The formation of pseudopodal extensions, the polarized distribution of F-actin, and the involvement of C. burnetii strain in cytoskeleton reorganization have been assessed using a laser scanning confocal fluorescence microscope. Results indicate that similarly to the virulent reference strain, strains of C. burnetii isolated from foetal brain induced morphological changes - modification in F-actin distribution and in the localization of bacteria. By contrast, C. burnetii strain isolated from ovine placenta did not induce any significant change in L929 cell morphology. In conclusion, both C. burnetii strains isolated from ovine placenta and foetal brain were pathogenic causing ovine abortion, but in vitro the C. burnetii strain isolated from brain only was able to induce F actin reorganization in L929 infected cells. PMID- 26129662 TI - Loop-mediated Isothermal Amplification assay (LAMP) based detection of Pasteurella multocida in cases of haemorrhagic septicaemia and fowl cholera. AB - Twenty two isolates of Pasteurella multocida were obtained from different tissues of dead birds and animals (cattle, buffalo, sheep, and goat) suspected of fowl cholera and haemorrhagic septicaemia. The isolates were confirmed as P. multocida by various biochemical tests and PM PCR. An attempt was made to standardize Loop mediated isothermal amplification (LAMP) using newly designed primer sequences of KMT1 gene. Loop mediated isothermal amplification was conducted using 6 sets of primers at 65 degrees C for 30 minutes and the result was confirmed by visual observation using SYBR green fluorescence dye as marker of positive reaction under UV transilluminator. On electrophoretic analysis of the products on 2% agarose gel, a ladder like pattern was observed, which suggested a positive amplification, whereas no amplification was observed in negative controls. Additionally, product of positive reaction yielded a green fluorescence following addition of SYBR green under UV transilluminator. It was observed that LAMP is a more sensitive test than polymerase chain reaction (PCR), as the former could detect DNA to lower limit of 22.8 pg/ul, while the latter could detect DNA to lower limit of 2.28 ng/ ul, thus LAMP could detect 100 times lesser concentration of DNA in comparison to PCR. Loop mediated isothermal amplification is a rather newer molecular technique, which can be used for rapid detection of infectious agent at field level and which does not require sophisticated instrument, i.e. thermal cycler. Furthermore, unlike the conventional PCR technique, LAMP requires lesser time to perform and result can be read visually. PMID- 26129663 TI - African horse sickness outbreaks in Namibia from 2006 to 2013: clinical, pathological and molecular findings. AB - African horse sickness (AHS) is a vector-borne viral disease of equids, endemic in Sub-Saharan Africa. This article reports the clinic-pathological and laboratory findings observed in the framework of passive surveillance during the AHS outbreaks which occurred in Namibia between 2006 and 2013. This study was conducted in the framework of the collaboration among the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise (Teramo, Italy), the Namibian Ministry of Agriculture Water and Forestry, and the Namibian National Veterinary Association. A total of 92 horses were investigated, showing different clinical form of AHS: peracute/acute (n = 43), sub-acute (n = 21) and mild AHS fever (n = 19). Clinical data were not available for 9 horses, because they were found dead. Pathological findings have been recorded for 35 horses. At necropsy, pulmonary and subcutaneous oedema, haemorrhages and enlargement of lymph nodes were mainly observed. Diagnosis was confirmed by laboratory testing, AHS virus (AHSV) was isolated from 50 horses and the identified serotypes were: 1, 2, 4, 6, 7, 8, and 9. The phylogenetic analysis of the S10 genome sequences segregated the Namibian AHSV strains in the same clusters of those circulating in South Africa in recent years. The description of AHS clinical, pathological, and laboratory features of AHS provided in this article is of value for differential diagnosis and control of AHS, especially in areas currently free from this disease. PMID- 26129664 TI - Vector species of Culicoides midges implicated in the 2012-2014 Bluetongue epidemics in Italy. AB - In 2012, serotypes 1 and 4 of bluetongue virus (BTV) entered and co-circulated in Sardinia. The following year, BTV-1 spread all over Sardinia and invaded Sicily and the Italian Tyrrenian coast. In 2014, this strain spread extensively in mainland Italy, causing severe outbreaks. In late 2014, BTV-4 was detected in Southern Italy (Apulia region). This study reports the detection of BTV in species of Culicoides (Diptera: Ceratopogonidae) collected in Italy during the epidemics between 2012 and 2014. A total of 2,925 pools (83,102 midges), sorted from 651 collections made on 339 affected farms of 12 Italian regions, were tested for the presence of BTV by real time polymerase chain reaction (RT-PCR). The study clearly shows that Culicoides imicola and Obsoletus complex have played a crucial role in the bluetongue (BT) epidemics in Italy in 2012-2014. Nevertheless, it also shows that other species may have played a role in transmitting BTV during these outbreaks. Culicoides dewulfi and at least 3 species of the Pulicaris complex, namely Culicoides pulicaris, Culicoides newsteadi and Culicoides punctatus, were found positive to BTV. Serotype 1 was detected in all species tested, whereas the BTV-4 was detected in the Obsoletus complex, C. imicola, and C. newsteadi. PMID- 26129665 TI - Bluetongue virus in Oryx antelope (Oryx leucoryx) during the quarantine period in 2010 in Croatia. AB - Bluetongue (BT) is a viral infectious non-contagious disease of domestic and wild ruminants. Insect species of the genus Culicoides (Diptera: Ceratopogonidae) serve as biological vectors that transmit bluetongue virus (BTV) to susceptible hosts. The infection is present in the Mediterranean region. Recently, it has also been reported in Central, Western, and Northern Europe where BTV-8 was recognised as the causative serotype. In the meantime, BTV-14 has appeared in the North-Eastern part of Europe. In the present study, BTV serotype 16 (BTV-16) was detected by virus neutralisation (VNT)-assay and real-time reverse transcription PCR (rRT-PCR) in 1 antelope and BTV-1 in 3 of 10 Oryx antelopes (Oryx leucoryx) imported in Croatia from the Sultanate of Oman. No BTV vectors were collected during the antelope quarantine on the Veliki Brijun Island. Also, no BTV antibodies were detected in sheep, cattle, and deer on the Island. Entomological studies did not reveal any new vector species that may have been introduced with the infected antelopes on their transportation. It was the first time that BTV was demonstrated in animals imported in Croatia. It involved BTV-1, which had never been demonstrated before and BTV-16, which had been previously recorded in domestic ruminants. PMID- 26129666 TI - A new lineage of foot-and-mouth disease virus serotype O in India. AB - The complete nucleotide sequence of a new lineage of foot and mouth disease virus (FMDV) serotype O was determined. The lineage designated as Ind2011 first appeared during 2011 in the Southern region of India. Excluding the poly C tract and poly A tail, the genome of Ind2011 ranged from 8,169 to 8,172 nucleotides. Variation in the genome length was due to insertions/deletions in LF-UTR. The lineage had a higher sequence identity with lineage PanAsia-1 at P1 and P2 regions, and with lineage PanAsia-2 at P3 and L regions. Phylogenetically, the isolates were placed closely to both PanAsia-1 and 2 lineages, and appear to be a novel variant of the PanAsian lineage. PMID- 26129667 TI - First report of Brucella suis biovar 2 in a semi free-range pig farm, Italy. AB - This communication describes the isolation of Brucella suis (B. suis) biovar 2 in semi-free-range pigs located in the province of Rome, Italy. Sera of 28 pigs from a herd with reproductive problems were tested for brucellosis. Twenty-five sera (89%) were found positive to Rose Bengal Test (RBT), while 22 (79%) were positive to Complement Fixation Test (CFT). Two positive pigs were slaughtered, organs were collected and tested for the presence of bacteria. Brucella spp. was isolated from the spleens and the abdominal lymph nodes of the 2 subjects. The isolates were identified as B. suis biovar 2 by biochemical and Polymerase Chain Reaction (PCR) tests. The frequent infringement in the fences of the premises and the birth of striped piglets provided evidence that sows mated with wild boar, the major reservoir of B. suis biovar 2. Conversely, the isolation of B. suis biovar 2 from spleens and lymphnodes of seropositive slaughtered animals only, as well as the constant negative results from all vaginal swabs and the abortion materials tested, raise doubts on the implication of B. suis biovar 2 in the infertility of the holding. PMID- 26129668 TI - Blue-colour variants of the crayfish Austropotamobius pallipes in 2 rivers of the Abruzzo region, Italy. AB - Blue-colour variants have been reported in American and Australian freshwater crayfish species. We report here the observation of 2 Austropotamobius pallipes individuals with a blue-colour carapace in 2 rivers of the Aterno-Pescara river basin, located in the Abruzzo region, Central Italy. PMID- 26129669 TI - Nuclear matrix protein Matrin 3 is a regulator of ZAP-mediated retroviral restriction. AB - BACKGROUND: Matrin 3 is a nuclear matrix protein involved in multiple nuclear processes. In HIV-1 infection, Matrin 3 serves as a Rev cofactor important for the cytoplasmic accumulation of HIV-1 transcripts. ZAP is a potent host restriction factor of multiple viruses including retroviruses HIV-1 and MoMuLV. In this study we sought to further characterize Matrin 3 functions in the regulation of HIV gene expression. RESULTS: Here we describe a function for Matrin 3 as a negative regulator of the ZAP-mediated restriction of retroviruses. Mass spectrometry analysis of Matrin 3-associated proteins uncovered interactions with proteins of the ZAP degradation complex, DDX17 and EXOSC3. Coimmunoprecipitation studies confirmed Matrin 3 associations with DDX17, EXOSC3 and ZAP, in a largely RNA-dependent manner, indicating that RNA is mediating the Matrin 3 interactions with these components of the ZAP degradation complex. Silencing Matrin 3 expression caused a remarkably enhanced ZAP-driven inhibition of HIV-1 and MoMuLV luciferase reporter viruses. This effect was shared with additional nuclear matrix proteins. ZAP targets multiply-spliced HIV-1 transcripts, but in the context of Matrin 3 suppression, this ZAP restriction was broadened to unspliced and multiply-spliced RNAs. CONCLUSIONS: Here we reveal an unprecedented role for a nuclear matrix protein, Matrin 3, in the regulation of ZAP's antiretroviral activity. Suppressing Matrin 3 powers a heightened and broader ZAP restriction of HIV-1 gene expression. This study suggests that this ZAP regulatory mechanism is shared with additional nuclear matrix proteins. PMID- 26129670 TI - Bayesian analysis of the kinetics of quantal transmitter secretion at the neuromuscular junction. AB - The timing of transmitter release from nerve endings is considered nowadays as one of the factors determining the plasticity and efficacy of synaptic transmission. In the neuromuscular junction, the moments of release of individual acetylcholine quanta are related to the synaptic delays of uniquantal endplate currents recorded under conditions of lowered extracellular calcium. Using Bayesian modelling, we performed a statistical analysis of synaptic delays in mouse neuromuscular junction with different patterns of rhythmic nerve stimulation and when the entry of calcium ions into the nerve terminal was modified. We have obtained a statistical model of the release timing which is represented as the summation of two independent statistical distributions. The first of these is the exponentially modified Gaussian distribution. The mixture of normal and exponential components in this distribution can be interpreted as a two-stage mechanism of early and late periods of phasic synchronous secretion. The parameters of this distribution depend on both the stimulation frequency of the motor nerve and the calcium ions' entry conditions. The second distribution was modelled as quasi-uniform, with parameters independent of nerve stimulation frequency and calcium entry. Two different probability density functions for the distribution of synaptic delays suggest at least two independent processes controlling the time course of secretion, one of them potentially involving two stages. The relative contribution of these processes to the total number of mediator quanta released depends differently on the motor nerve stimulation pattern and on calcium ion entry into nerve endings. PMID- 26129672 TI - Synthetic approach to the generation of antibody diversity. AB - The in vitro antibody discovery technologies revolutionized the generation of target-specific antibodies that traditionally relied on the humoral response of immunized animals. An antibody library, a large collection of diverse, pre constructed antibodies, can be rapidly screened using in vitro display technologies such as phage display. One of the keys to successful in vitro antibody discovery is the quality of the library diversity. Antibody diversity can be obtained either from natural B-cell sources or by the synthetic methods that combinatorially generate random nucleotide sequences. While the functionality of a natural antibody library depends largely upon the library size, various other factors can affect the quality of a synthetic antibody library, making the design and construction of synthetic antibody libraries complicated and challenging. In this review, we present various library designs and diversification methods for synthetic antibody library. From simple degenerate oligonucleotide synthesis to trinucleotide synthesis to physicochemically optimized library design, the synthetic approach is evolving beyond the simple emulation of natural antibodies, into a highly sophisticated method that is capable of producing high quality antibodies suitable for therapeutic, diagnostic, and other demanding applications. [BMB Reports 2015; 48(9): 489-494]. PMID- 26129673 TI - Modulation of autophagy by miRNAs. AB - MicroRNAs (miRNAs) can regulate the expression of genes that are involved in multiple cellular pathways. However, their targets and mechanism of action associated with the autophagy pathway are not fully investigated yet. EWSR1 (EWS RNA-Binding Protein 1/Ewing Sarcoma Break Point Region 1) gene encodes a RNA/DNA binding protein that is ubiquitously expressed and plays roles in numerous cellular processes. Recently, our group has shown that EWSR1 deficiency leads to developmental failure and accelerated senescence via processing of miRNAs, but its role in the regulation of autophagy remains elusive. In this context, we further investigated and found that EWSR1 deficiency triggers the activation of the DROSHA-mediated microprocessor complex and increases the levels of miR125a and miR351, which directly target Uvrag. Interestingly, the miR125a- and miR351 targeted reduction of Uvrag led to the inhibition of autophagy in both ewsr1 knockout (KO) MEFs and ewsr1 KO mice. In summary, our study demonstrates that EWSR1 is associated with the posttranscriptional regulation of Uvrag via miRNA processing. The regulation of autophagy pathway in miRNAs-Uvrag-dependent manner provides a novel mechanism of EWSR1 deficiency-related cellular dysfunction. PMID- 26129675 TI - TAGLN2-mediated actin stabilization at the immunological synapse: implication for cytotoxic T cell control of target cells. AB - Actin dynamics is critical for the formation and sustainment of the immunological synapse (IS) during T cell interaction with antigen-presenting cells (APC). Thus, many actin regulating proteins are involved in spatial and temporal actin remodeling at the IS. However, little is known whether or how actin stabilizing protein controls IS and the consequent T cell functions. TAGLN2 - an actin binding protein predominantly expressed in T cells - displays a novel function to stabilize cortical F-actin, thereby augmenting F-actin contents at the IS, and acquiring leukocyte function-associated antigen-1 activation following T cell activation. TAGLN2 also competes with cofilin to protect F-actin in vitro and in vivo. During cytotoxic T cell interaction with cancer cells, the expression level of TAGLN2 at the IS correlates with the T cell adhesion to target cancer cells and production of lytic granules such as granzyme B and perforin, thus expressing cytotoxic T cell function. These findings identify a novel function for TAGLN2 as an actin stabilizing protein that is essential for stable immunological synapse formation, thereby regulating T cell immunity. PMID- 26129674 TI - From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes. AB - Cellular senescence is a process by which cells enter a state of permanent cell cycle arrest. It is commonly believed to underlie organismal aging and age associated diseases. However, the mechanism by which cellular senescence contributes to aging and age-associated pathologies remains unclear. Recent studies showed that senescent cells exert detrimental effects on the tissue microenvironment, generating pathological facilitators or aggravators. The most significant environmental effector resulting from senescent cells is the senescence-associated secretory phenotype (SASP), which is constituted by a strikingly increased expression and secretion of diverse pro-inflammatory cytokines. Careful investigation into the components of SASPs and their mechanism of action, may improve our understanding of the pathological backgrounds of age associated diseases. In this review, we focus on the differential expression of SASP-related genes, in addition to SASP components, during the progress of senescence. We also provide a perspective on the possible action mechanisms of SASP components, and potential contributions of SASP-expressing senescent cells, to age-associated pathologies. PMID- 26129676 TI - Antimicrobial peptide scolopendrasin VII, derived from the centipede Scolopendra subspinipes mutilans, stimulates macrophage chemotaxis via formyl peptide receptor 1. AB - In this study, we report that one of the antimicrobial peptides scolopendrasin VII, derived from Scolopendra subspinipes mutilans, stimulates actin polymerization and the subsequent chemotactic migration of macrophages through the activation of ERK and protein kinase B (Akt) activity. The scolopendrasin VII induced chemotactic migration of macrophages is inhibited by the formyl peptide receptor 1 (FPR1) antagonist cyclosporine H. We also found that scolopendrasin VII stimulate the chemotactic migration of FPR1-transfected RBL-2H3 cells, but not that of vector-transfected cells; moreover, scolopendrasin VII directly binds to FPR1. Our findings therefore suggest that the antimicrobial peptide scolopendrasin VII, derived from Scolopendra subspinipes mutilans, stimulates macrophages, resulting in chemotactic migration via FPR1 signaling, and the peptide can be useful in the study of FPR1-related biological responses. PMID- 26129677 TI - Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine. AB - Drug addiction is a chronic disorder characterized by a cycle composed of drug seeking, intoxication with drug taking and withdrawal associated with negative affect. Numerous studies have examined withdrawal/negative affect after chronic use; however, very few have examined the effect of acute administration on the negative affective state after acute drug withdrawal. One dose of amphetamine was injected into Sprague-Dawley rats. Despair behavior using the modified forced swim test (FST) and dopamine (DA) activity in the ventral tegmental area using in vivo electrophysiological recordings were studied 18, 48 and 72 h after injection of amphetamine. The effects of inactivation of the basolateral amygdala (BLA) and ketamine administration on VTA DA neuron activity and passivity in the modified FST were examined. Eighteen hours following amphetamine withdrawal, there was a substantial decrease in the number of active DA neurons, as well as an increase in time spent immobile in the modified FST, which returned to baseline after 72 h. Inactivation of the BLA after acute amphetamine prevented the decrease in DA neuron tonic activity. Injection of ketamine also prevented the decrease in DA population activity but had no effect on immobility measured in the modified FST. The data support a model in which the negative affective state following acute amphetamine withdrawal is associated with a decrease in DA neuron population activity, driven by hyperactivity of the BLA. Although ketamine reversed the hypodopaminergic state following withdrawal, the failure to reduce immobility in the modified FST indicates that different processes underlying negative emotional state may exist between depression and drug withdrawal. PMID- 26129678 TI - Comparing Pharmacological Modulation of Sensory Gating in Healthy Humans and Rats: The Effects of Reboxetine and Haloperidol. AB - Sensory gating is the brain's ability to filter out irrelevant information before it reaches high levels of conscious processing. In the current study we aimed to investigate the involvement of the noradrenergic and dopaminergic neurotransmitter systems in sensory gating. Furthermore, we investigated cross species reliability by comparing effects in both healthy humans and rats, while keeping all experimental conditions as similar as possible between the species. The design of the human experiment (n=21) was a double-blind, placebo-controlled, cross-over study where sensory gating was assessed following a dose of either reboxetine (8 mg), haloperidol (2 mg), their combination or placebo at four separate visits. Similarly in the animal experiment sensory gating was assessed in rats, (n=22) following a dose of reboxetine (2 mg/kg), haloperidol (0.08 mg/kg), their combination or placebo. The sensory gating paradigms in both experiments were identical. In humans, we found significantly reduced P50 suppression following separate administration of reboxetine or haloperidol, while their combined administration did not reach statistical significance compared with placebo. In the rats, we found a similar significant reduction of sensory gating (N40) following treatment with haloperidol and the combination of haloperidol and reboxetine, but not with separate reboxetine treatment, compared with placebo. Our study indicates that even when experimental conditions are kept as similar as possible, direct human to rat cross-species translation of pharmacological effects on sensory gating is challenging, which calls for more focussed research in this important translational area. PMID- 26129679 TI - Choosing Under the Influence: A Drug-Specific Mechanism by Which the Setting Controls Drug Choices in Rats. AB - Ample evidence shows that the setting can control drug choices in both humans and animals. Here we reveal in rats that a major mechanism of this control involves a regulation of the drug influence on other competing options at the time of choice. Briefly, rats were offered a choice between a drug dose (cocaine or heroin) and a brief access to water sweetened with saccharin in two different settings. In one setting, choosing under the influence was not possible and rats largely preferred saccharin over either cocaine or heroin. In contrast, when the same rats were shifted to a setting where choosing under the influence was possible, they chose the drug either nonexclusively or exclusively depending on whether the drug enhanced or suppressed sweet reward, respectively. Thus, when rats were under the orexigenic influence of heroin at the time of choice, they more frequently chose saccharin in alternation with heroin. In contrast, when rats were under the anorexic influence of cocaine, they stopped choosing saccharin and continued taking cocaine exclusively. These setting- and drug specific changes in preference were rapid and reversible, and could be induced by passively administering cocaine or heroin before choice. Finally, rats behaved as if they were oblivious to the drug influence on their choices. This behavior could explain why rats are vulnerable to harm themselves, sometimes to the point of death, in settings where choices are made under the drug influence, notably if this influence excludes other important options or, conversely, enhances harmful ones. PMID- 26129681 TI - Breaking down the wall: a narrative approach to addiction. PMID- 26129680 TI - Effects of beta-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia Like Behavior in Hypoglutamatergic Mice. AB - Current antipsychotic drugs (APDs) show efficacy with positive symptoms, but are limited in treating negative or cognitive features of schizophrenia. Whereas all currently FDA-approved medications target primarily the dopamine D2 receptor (D2R) to inhibit G(i/o)-mediated adenylyl cyclase, a recent study has shown that many APDs affect not only G(i/o)- but they can also influence beta-arrestin- (betaArr)-mediated signaling. The ability of ligands to differentially affect signaling through these pathways is termed functional selectivity. We have developed ligands that are devoid of D2R-mediated G(i/o) protein signaling, but are simultaneously partial agonists for D2R/betaArr interactions. The purpose of this study was to test the effectiveness of UNC9975 or UNC9994 on schizophrenia like behaviors in phencyclidine-treated or NR1-knockdown hypoglutamatergic mice. We have found the UNC compounds reduce hyperlocomotion in the open field, restore PPI, improve novel object recognition memory, partially normalize social behavior, decrease conditioned avoidance responding, and elicit a much lower level of catalepsy than haloperidol. These preclinical results suggest that exploitation of functional selectivity may provide unique opportunities to develop drugs with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related conditions than medications that are currently available. PMID- 26129682 TI - Reflectance confocal microscopy in infectious diseases. AB - In vivo reflectance confocal microscope (RCM) is a high-resolution non-invasive imaging technique that was initially focused on the diagnosis of skin cancers. A rising number of other indications have been later described for the diagnosis and management of inflammatory and infectious dermatological disorders. RCM can identify cutaneous parasites that are not visible to naked eye such as Sarcoptes scabiei and Demodex folliculorum and it allows to better identify the different body parts of bigger parasites such as ticks. Fungal filaments can also be identified as elongated bright structures in the cutaneous upper layers. RCM cannot observe virus directly. However, the cytopathic effect associated with some virus can be recognized. In addition of being helpful for the diagnosis and follow-up after treatment, thanks to its non-invasiveness, RCM allows pathophysiological studies. PMID- 26129683 TI - Optical coherence tomography in dermatology. AB - AIM: Optical coherence tomography (OCT) was first used in skin imaging in 1997, and since then the technology has undergone significant technological development. With its high resolution and moderate penetration depth OCT fills the imaging gap between High Frequency Ultrasound and Reflectance Confocal Microscopy. Different modalities of OCT have been developed either focusing on higher image resolution or special visualization of tissue with distinct optical properties, including collagen and blood flow. The aim of this study was to describe trends in OCT research on different dermatological diseases and review the results. METHODS: Pubmed, EMBASE, Web of science, Google Scholar and Cochrane databases were searched for the terms "optical coherence tomography", "OCT" and "dermatology" including English articles on studies of human skin tissue in vivo, finding 117 studies of original research and including 64 studies based on predefined criteria and year of publication. RESULTS: In dermatology, most studies of OCT were on non-melanoma skin cancer followed by pigmented lesions, inflammatory skin diseases, nails diseases and anatomical and physiological features investigated by OCT. In non-melanoma skin cancer diagnostic OCT criteria have been proposed and recent studies have shown a high diagnostic accuracy of 87.4% and identified objective scoring criteria for diagnosing non-melanoma skin cancer. In pigmented lesions, morphological features for differentiation of benign naevi and malignant melanoma have also been suggested, though only included small samples of malignant lesions were used in most studies. Results were further limited by a high light absorption in melanin at the used wavelenghts. Studies on skin inflammation have described morphological features of different inflammatory responses such as allergic reactions, but remain at a preliminary stage. Regarding the anatomical and physiological features of the skin, OCT studies have mainly focused on measuring epidermal thickness and morphological changes in the acute response to UV-radiation. CONCLUSION: OCT research in dermatology has undergone significant developments since its first application in 1997. The rising demand for non-invasive monitoring of skin disorders and treatment outcomes emphasize the need for further advances in the field of non-invasive imaging. Combining OCT with other technical modalities that enable quantitative measurements of e.g. blood flow or light reflectance in tissue may aid the usability of OCT in a clinical setting. PMID- 26129685 TI - Arginine vasotocin induces calling behavior with a female social stimulus and interacts with gonadotropins to affect sexual behaviors in male Xenopus tropicalis. AB - Arginine vasotocin (AVT) and the mammalian homologue, arginine vasopressin (AVP), modulate vertebrate social behaviors, including vocalizations in male anurans. To study the impact of AVT and social stimuli on calling in male Xenopus tropicalis, we injected males with vehicle, 1 MUg, or 10 MUg AVT and recorded vocalizations under four social contexts (no stimulus, with male call playback, with a female, and with call playback and a female). More males called when injected with 10 MUg AVT. Furthermore, calling males called only when paired with a female. We identified four call types: long fast trill; short fast trill; slow trill; or click. Next, we injected males with vehicle, 10 MUg, or 20 MUg AVT and recorded vocalizations with or without a female. AVT treatment did not affect calling in this experiment, but we confirmed that more males, regardless of AVT treatment, called when a female was present. Then we evaluated the effect of human chorionic gonadotropin (hCG) on male sexual behavior. 20 IU hCG elevated behavior compared to controls while the 10 IU hCG treatment group was not different from either treatment. Last, we examined the effect of AVT on hCG-induced reproductive behavior. Males were injected with 10 IU hCG or with 10 IU hCG and 20 MUg AVT. Males receiving hCG and AVT clasped and called significantly more than males receiving hCG only. Our results suggest that AVT and a female stimulus induce vocalizations in a male pipid anuran, X. tropicalis, and the interaction between gonadotropins and neurohormones influences reproductive behaviors in this anuran amphibian. PMID- 26129684 TI - Serum reactome induced by Bordetella pertussis infection and Pertussis vaccines: qualitative differences in serum antibody recognition patterns revealed by peptide microarray analysis. AB - BACKGROUND: Pertussis (whooping cough) remains a public health problem despite extensive vaccination strategies. Better understanding of the host-pathogen interaction and the detailed B. pertussis (Bp) target recognition pattern will help in guided vaccine design. We characterized the specific epitope antigen recognition profiles of serum antibodies ('the reactome') induced by whooping cough and B. pertussis (Bp) vaccines from a case-control study conducted in 1996 in infants enrolled in a Bp vaccine trial in Sweden (Gustafsson, NEJM, 1996, 334, 349-355). METHODS: Sera from children with whooping cough, vaccinated with Diphtheria Tetanus Pertussis (DTP) whole-cell (wc), acellular 5 (DPTa5), or with the 2 component (a2) vaccines and from infants receiving only DT (n=10 for each group) were tested with high-content peptide microarrays containing 17 Bp proteins displayed as linear (n=3175) peptide stretches. Slides were incubated with serum and peptide-IgG complexes detected with Cy5-labeled goat anti-human IgG and analyzed using a GenePix 4000B microarray scanner, followed by statistical analysis, using PAM (Prediction Analysis for Microarrays) and the identification of uniquely recognized peptide epitopes. RESULTS: 367/3,085 (11.9%) peptides were recognized in 10/10 sera from children with whooping cough, 239 (7.7%) in DTPwc, 259 (8.4%) in DTPa5, 105 (3.4%) DTPa2, 179 (5.8%) in the DT groups. Recognition of strongly recognized peptides was similar between whooping cough and DPTwc, but statistically different between whooping cough vs. DTPa5 (p<0.05), DTPa2 and DT (p<0.001 vs. both) vaccines. 6/3,085 and 2/3,085 peptides were exclusively recognized in (10/10) sera from children with whooping cough and DTPa2 vaccination, respectively. DTPwc resembles more closely the whooping cough reactome as compared to acellular vaccines. CONCLUSION: We could identify a unique recognition signature common for each vaccination group (10/10 children). Peptide microarray technology allows detection of subtle differences in epitope signature responses and may help to guide rational vaccine development by the objective description of a clinically relevant immune response that confers protection against infectious pathogens. PMID- 26129686 TI - Nitrous oxide as a humane method for piglet euthanasia: Behavior and electroencephalography (EEG). AB - The search for humane methods to euthanize piglets is critical to address public concern that current methods are not optimal. Blunt force trauma is considered humane but esthetically objectionable. Carbon dioxide (CO2) is used but criticized as aversive. This research sought to: 1) evaluate the aversiveness of inhaling nitrous oxide (N2O; 'laughing gas') using an approach-avoidance test relying on the piglet's perspective, and 2) validate its humaneness to induce loss of consciousness by electroencephalography (EEG). The gas mixtures tested were N2O and air (90%:10%; '90 N'); N2O, oxygen and air (60%:30%:10%; '60 N'); and CO2 and air (90%:10%; '90 C'). Experiment 1 allowed piglets to walk freely between one chamber filled with air and another prefilled with 60 N or 90 N. All piglets exposed to 60 N lasted for the 10 min test duration whereas all piglets exposed to 90 N had to be removed within 5 min because they fell recumbent and unresponsive and then started to flail. Experiment 2 performed the same test except the gas chamber held N2O prefilled at 25%, 50%, or 75% or CO2 prefilled at 7%, 14%, or 21%. The test was terminated more quickly at higher concentrations due to the piglets' responses. Time spent ataxic was greater in the middle concentration gradients. Flailing behavior tended to correlate with increasing concentrations of CO2 but not N2O. Experiment 3, using the minimal anesthesia model, showed that both 90 N and 90 C induced isoelectric EEG, in 71 and 59 s respectively, but not 60 N within 15 min. The EEG results together with the observed behavioral changes reflect differences in the animal's perceptive experience. The implications for animal welfare are that N2O is much less aversive than CO2, and 90% N2O can euthanize piglets. PMID- 26129687 TI - Acne inversa complicated by Actinomyces neuii. AB - INTRODUCTION: Acne inversa (AI) is a chronic and recurrent inflammatory skin disease. It occurs in intertriginous areas of the skin and causes pain, drainage, malodor and scar formation. While supposedly caused by an autoimmune reaction, bacterial superinfection is a secondary event in the disease process. METHODS: A unique case of a 43-year-old male patient suffering from a recurring AI lesion in the left axilla was retrospectively analysed. RESULTS: A swab revealed Actinomyces neuii as the only agent growing in the lesion. The patient was then treated with Amoxicillin/Clavulanic Acid 3 * 1 g until he was cleared for surgical excision. The intraoperative swab was negative for A. neuii. Antibiotics were prescribed for another 4 weeks and the patient has remained relapse free for more than 12 months now. CONCLUSION: Primary cutaneous Actinomycosis is a rare entity and the combination of AI and Actinomycosis has never been reported before. Failure to detect superinfections of AI lesions with slow-growing pathogens like Actinomyces spp. might contribute to high recurrence rates after immunosuppressive therapy of AI. The present case underlines the potentially multifactorial pathogenesis of the disease and the importance of considering and treating potential infections before initiating immunosuppressive regimens for AI patients. PMID- 26129688 TI - Epigenetically altered miR-193b targets cyclin D1 in prostate cancer. AB - Micro-RNAs (miRNA) are important regulators of gene expression and often differentially expressed in cancer and other diseases. We have previously shown that miR-193b is hypermethylated in prostate cancer (PC) and suppresses cell growth. It has been suggested that miR-193b targets cyclin D1 in several malignancies. Here, our aim was to determine if miR-193b targets cyclin D1 in prostate cancer. Our data show that miR-193b is commonly methylated in PC samples compared to benign prostate hyperplasia. We found reduced miR-193b expression (P < 0.05) in stage pT3 tumors compared to pT2 tumors in a cohort of prostatectomy specimens. In 22Rv1 PC cells with low endogenous miR-193b expression, the overexpression of miR-193b reduced CCND1 mRNA levels and cyclin D1 protein levels. In addition, the exogenous expression of miR-193b decreased the phosphorylation level of RB, a target of the cyclin D1-CDK4/6 pathway. Moreover, according to a reporter assay, miR-193b targeted the 3'UTR of CCND1 in PC cells and the CCND1 activity was rescued by expressing CCND1 lacking its 3'UTR. Immunohistochemical analysis of cyclin D1 showed that castration-resistant prostate cancers have significantly (P = 0.0237) higher expression of cyclin D1 compared to hormone-naive cases. Furthermore, the PC cell lines 22Rv1 and VCaP, which express low levels of miR-193b and high levels of CCND1, showed significant growth retardation when treated with a CDK4/6 inhibitor. In contrast, the inhibitor had no effect on the growth of PC-3 and DU145 cells with high miR-193b and low CCND1 expression. Taken together, our data demonstrate that miR-193b targets cyclin D1 in prostate cancer. PMID- 26129689 TI - Sperm Release From the Oviductal Epithelium Depends on Ca(2+) Influx Upon Activation of CB1 and TRPV1 by Anandamide. AB - The oviduct acts as a functional sperm reservoir in many mammalian species. Both binding and release of spermatozoa from the oviductal epithelium are mainly modulated by sperm capacitation. Several molecules from oviductal fluid are involved in the regulation of sperm function. Anandamide is a lipid mediator involved in reproductive physiology. Previously, we demonstrated that anandamide, through activation of the cannabinoid receptor type 1 (CB1), promotes sperm release from bovine oviductal epithelial cells, and through CB1 and the transient receptor potential vanilloid 1 (TRPV1), induces sperm capacitation. Herein we investigate co-activation between CB1 and TRPV1, and Ca(2+) influx as part of the mechanism of action of anandamide during sperm release from oviductal cells. Our results indicate that in the absence of Ca(2+) anandamide failed to release spermatozoa from oviductal epithelial cells. Additionally, sperm release promoted by cannabinoid and vanilloid agonists was abolished when the spermatozoa were preloaded with BAPTA-AM, a Ca(2+) chelator. We also determined Ca(2+) levels in spermatozoa preloaded with FURA2-AM co-cultured with oviductal cells and incubated with different cannabinoid and vanilloid agonists. The incubation with different agonists induced Ca(2+) influx, which was abolished by CB1 or TRPV1 antagonists. Our results also suggest that a phospholypase C (PLC) might mediate the activation of CB1 and TRPV1 in sperm release from the bovine oviduct. Therefore, our findings indicate that anandamide, through CB1 and TRPV1 activation, is involved in sperm release from the oviductal reservoir. An increase of sperm Ca(2+) levels and the PLC activation might be involved in anandamide signaling pathway. PMID- 26129690 TI - Lamellar versus Micellar Structures-Aggregation Behavior of a Three-Chain Cationic Lipid Designed for Nonviral Polynucleotide Transfer. AB - The front cover artwork is provided by the groups of Prof. Bodo Dobner, Prof. Andreas Langner, and research partners Dr. Gerd Hause, Dr. Simon Drescher, and Dr. Annette Meister (MLU Halle-Wittenberg) as well as the group of Prof. Gerald Brezesinski (MPI of Colloids and Interfaces). The image shows the space-filling model of a three-chain amino-functionalized lipid designed for gene transfer and the preferred pH-dependent aggregates (multilamellar stacks, vesicles, rod-like micelles). The background shows a Cryo-TEM image of rod-like micelles. Read the full text of the article at 10.1002/cphc.201500188. PMID- 26129691 TI - Seismic shift in policy needed to increase physical activity. PMID- 26129692 TI - Health Care Cost Analysis in a Population-based Inception Cohort of Inflammatory Bowel Disease Patients in the First Year of Diagnosis. AB - BACKGROUND: There are limited prospective population-based data on the health care cost of IBD in the post-biologicals era. A prospective registry that included all incident cases of inflammatory bowel disease [IBD] was established to study disease progress and health cost. AIM: To prospectively assess health care costs in the first year of diagnosis among a well-characterised cohort of newly diagnosed IBD patients. METHOD: Incident cases of IBD were prospectively identified in 2007-2008 and 2010-2013 from multiple health care providers, and enrolled into the population-based registry. Health care resource utilisation for each patient was collected through active surveillance of case notes and investigations including specialist visits, diagnostic tests, medications, medical hospitalisation, and surgery. RESULTS: Off 276 incident cases of IBD, 252 [91%] were recruited to the registry, and health care cost was calculated for 242 (146 Crohn's disease [CD] and 96 ulcerative colitis [UC] patients). The median cost in CD was higher at A$5905 per patient (interquartile range [IQR]: A$1571 $91,324) than in UC at A$4752 [IQR: A$1488-A$58,072]. In CD, outpatient resources made up 55% of all cost, with medications accounting for 32% of total cost [15% aminosalicylates, 15% biological therapy], followed by surgery [31%], and diagnostic testing [21%]. In UC, medications accounted for 39% of total cost [of which 37% was due to 5-aminosalicylates, and diagnostics 29%; outpatient cost contributed 71% to total cost. CONCLUSION: In the first year of diagnosis, outpatient resources account for the majority of cost in both CD and UC. Medications are the main cost driver in IBD. PMID- 26129693 TI - Treating Inflammatory Bowel Disease in Pregnancy: The Issues We Face Today. AB - Many women of childbearing age are living with inflammatory bowel disease [IBD], yet there are limited studies on the use of IBD medications in pregnancy. In this review, we provide a comprehensive update on the safety of these medications during pregnancy, particularly thiopurines and biologicals. Antibiotics, steroids, and aminosalicylates are relatively low risk for use in pregnancy, and growing evidence supports the safety of immunomodulators and anti-tumour necrosis factor agents as well. Available studies on infliximab, adalimumab, and certolizumab pegol show no increase in adverse events during pregnancy or perinatally. Similarly, studies on lactation demonstrate that concentrations of subcutaneous anti-tumour necrosis factor biologicals are undetectable, and levels of thiopurines and infliximab are negligible in breast milk. Less is known about anti-integrins in pregnancy [eg natalizumab and vedolizumab] but currently available data suggest they may be safe as well. Although more studies are needed to examine the long-term effects of these medications on offspring, the available data provide reassuring information for providers caring for women of childbearing age. PMID- 26129695 TI - Molecular dynamics of NH3 induced by core-electron excitation. AB - Nuclear motion in the N1s(-1)4a core-excited state of ammonia is investigated by studying the angular anisotropy of fragments produced in the decay of the highly excited molecule and compared with predictions from ab initio calculations. Two different fragmentation channels (H(+)/NH2(+) and H(+)/NH(+)/H) reveal complex nuclear dynamics as the excitation photon energy is tuned through the 4a1 resonance. The well-defined angular anisotropy of the fragments produced in the dissociation of the molecular dication species suggests a very rapid nuclear motion and the time scale of the nuclear dynamics is limited to the low fs timescale. PMID- 26129694 TI - Preventive Cognitive Therapy versus Treatment as Usual in preventing recurrence of depression: protocol of a multi-centered randomized controlled trial. AB - BACKGROUND: Major depressive disorder (MDD) is projected to rank second on a list of 15 major diseases in terms of burden in 2030. The contribution of MDD to disability and health care costs is largely due to its highly recurrent nature. Therefore, part of the efforts to reduce the disabling effects of depression should focus on preventing recurrence, especially in patients at high risk of recurrence. The best established effective psychological intervention is cognitive therapy, with indications for prophylactic effects after remission. METHODS/DESIGN: In this randomized controlled trial (cost-) effectiveness of Preventive Cognitive Therapy (PCT) after response to Acute Cognitive Therapy (A CT) will be evaluated in comparison with Treatment As Usual (TAU). Remitted patients that responded to A-CT treatment with at least two previous depressive episodes will be recruited. Randomization will be stratified for number of previous episodes. Follow-ups are at 3, 6, 12 and 15 months. The primary outcome measure will be the time to relapse or recurrence of depression meeting DSM-IV criteria for a major depressive episode on the Structured Clinical Interview for DSM-VI Axis I Disorders (SCID-I). Costs will be measured from a societal perspective. DISCUSSION: This study is the first to examine the addition of PCT to TAU, compared to TAU alone in patients that recovered from depressive disorder with A-CT. Alongside this effect study a cost effectiveness analysis will be conducted. Furthermore, the study explores potential moderators to examine what works for whom. TRIAL REGISTRATION: Netherlands Trial Register (NTR): 2599 , date of registration: 11-11-2010. PMID- 26129696 TI - Nonlinear absorption tuning by composition control in bimetallic plasmonic nanoprism arrays. AB - The nonlinear absorption properties of bidimensional arrays of Au-Ag bilayered nanoprisms have been investigated by z-scan measurements as a function of the bimetallic nanoprism composition. A tunable ps laser system was used to excite the ultrafast, electronic nonlinear response matching the laser wavelength with the quadrupolar surface plasmon resonances, in the visible range, of each nanoprism array. Due to the strong electromagnetic field confinement effects at the nanoprism tips, demonstrated by finite element method simulations, these nanosystems proved to have enhanced nonlinear optical properties. Moreover, a tunable changeover from reverse saturable absorption (RSA) to saturable absorption (SA) can be obtained by properly controlling the bimetallic composition of the nanoprisms, without modifying the overall morphology of the nanosystems. This capability makes these nanosystems extremely interesting for the realization of solid-state nanophotonic devices with enhanced ultrafast nonlinear optical properties. PMID- 26129697 TI - Absorption Spectroscopy, Emissive Properties, and Ultrafast Intersystem Crossing Processes in Transition Metal Complexes: TD-DFT and Spin-Orbit Coupling. AB - Absorption spectroscopy, emissive properties, and ultrafast intersystem crossing processes in transition metal complexes are discussed in the light of recent developments in time-dependent density functional theory (TD-DFT), spin-orbit coupling (SOC) effects, and non-adiabatic excited states dynamics. Methodological highlights focus on spin-orbit and vibronic couplings and on the recent strategies available for simulating ultra-fast intersystem crossings (ISC).The role of SOC in the absorption spectroscopy of third-row transition metal complexes is illustrated by two cases studies, namely Ir(III) phenyl pyridine and Re(I) carbonyl bipyridine complexes.The problem of luminescence decay in third row transition metal complexes handled by TD-DFT linear and quadratic response theories including SOC is exemplified by three studies: (1) the phosphorescence of Ir(III) complexes from the lowest triplet state; (2) the emissive properties of square planar Pt(II) complexes with bidentate and terdentate ligands characterized by low-lying metal-to-ligand-charge-transfer (MLCT) and metal centered (MC) states; and (3) the ultra-fast luminescence decay of Re(I) carbonyl bipyridine halides via low-lying singlet and triplet charge transfer states delocalized over the bipyridine and the halide ligands.Ultrafast ISC occurring in spin crossover [Fe (bpy)3]2+, in [Ru (bpy)3]2+, and [Re (Br)(CO)3(bpy] complexes are deciphered thanks to recent developments based on various approaches, namely non-radiative rate theory within the Condon approximation, non-adiabatic surface hopping molecular dynamics, and quantum wave packet dynamics propagation. PMID- 26129698 TI - The synthesis of nanostructured Ni5 P4 films and their use as a non-noble bifunctional electrocatalyst for full water splitting. AB - The investigation of nickel phosphide (Ni5 P4 ) as a catalyst for the hydrogen (HER) and oxygen evolution reaction (OER) in strong acidic and alkaline environment is described. The catalyst can be grown in a 3D hierarchical structure directly on a nickel substrate, thus making it an ideal candidate for practical water splitting devices. The activity of the catalyst towards the HER, together with its high stability especially in acidic solution, makes it one of the best non-noble materials described to date. Furthermore, Ni5 P4 was investigated in the OER and showed activity superior to pristine nickel or platinum. The practical relevance of Ni5 P4 as a bifunctional catalyst for the overall water splitting reaction was demonstrated, with 10 mA cm(-2) achieved below 1.7 V. PMID- 26129699 TI - Social Inequalities on Selected Determinants of Active Aging and Health Status Indicators in a Large Brazilian City (2003-2010). AB - OBJECTIVE: To assess trends in social inequalities among 2,624 elderly living in Belo Horizonte, Brazil, in three domains of the World Health Organization's Active Aging model (physical environment, social determinants, use of health services) and health status indicators. METHOD: Data came from two representative household surveys conducted in 2003 and 2010. Social inequality was measured by the slope and the relative index of inequality. Educational level was used to define socioeconomic status. RESULTS: Significant improvements were observed in the prevalence rates of 7 out of 12 indicators. However, the social inequalities persisted through 10 out of 12 selected active aging and health status indicators, except for fear of falling on the sidewalks/crossing the streets and fear of being robbed. DISCUSSION: Social inequalities persistence might be assigned to the continuity of unequal distribution of resources among groups with different educational levels. PMID- 26129700 TI - Community-Based Long-Term Care Services: If We Build It, Will They Come? AB - OBJECTIVE: This study examines the relationship between caregivers' perception of community-based long-term care (CBLTC) services and the service use. METHOD: We used first two waves of the longitudinal data set of 1,416 dyads of care recipients and their caregivers in Singapore. Four perceived attributes of LTC services--service quality, convenience, social connectedness, and affordability- were measured on a 5-point scale. RESULTS: Among the four perceived attributes, perceived affordability was significantly associated with future utilization for all types of CBLTC services. Perceived service quality and convenience was significantly associated with center-based LTC services use. DISCUSSION: Caregivers are critically involved in the decision of using CBLTC services, and their perception of service characteristics is significantly associated with the uptake of CBLTC services. It is important to incorporate both care recipients' and caregivers' needs and preferences when designing and promoting integrated health care delivery models. PMID- 26129702 TI - Biochemical and Molecular Characterization of a Novel Cu/Zn Superoxide Dismutase from Amaranthus hypochondriacus L.: an Intrinsically Disordered Protein. AB - A novel Cu/ZnSOD from Amaranthus hypochondriacus was cloned, expressed, and characterized. Nucleotide sequence analysis showed an open reading frame (ORF) of 456 bp, which was predicted to encode a 15.6-kDa molecular weight protein with a pI of 5.4. Structural analysis showed highly conserved amino acid residues involved in Cu/Zn binding. Recombinant amaranth superoxide dismutase (rAhSOD) displayed more than 50 % of catalytic activity after incubation at 100 degrees C for 30 min. In silico analysis of Amaranthus hypochondriacus SOD (AhSOD) amino acid sequence for globularity and disorder suggested that this protein is mainly disordered; this was confirmed by circular dichroism, which showed the lack of secondary structure. Intrinsic fluorescence studies showed that rAhSOD undergoes conformational changes in two steps by the presence of Cu/Zn, which indicates the presence of two binding sites displaying different affinities for metals ions. Our results show that AhSOD could be classified as an intrinsically disordered protein (IDP) that is folded when metals are bound and with high thermal stability. PMID- 26129701 TI - Inappropriate Medication Use Among Underserved Elderly African Americans. AB - OBJECTIVE: The goal of this study is to identify correlates and the prevalence of potentially inappropriate medication (PIM) use among underserved elderly African Americans. METHOD: This cross-sectional study recruited 400 elderly African Americans living in South Los Angeles, and used structured, face-to-face surveys. These elicited data pertaining to the type, frequency, dosage, and indications of all medications used by participants. RESULTS: Seventy percent of participants engaged in PIM use and used at least one medication that was classified as "Avoid" (27%) and "Use Conditionally" (43%) through Beers Criteria. Significant correlations emerged between PIM use and the number of autonomic and central nervous system, neurological and psychotherapeutic medications, medication duplications, and drug-drug interactions. DISCUSSION: Our findings point to the need for multidisciplinary team programs of health care providers that include primary and specialist physicians, pharmacists, nurses, and social workers. Together, they can improve health outcomes, enhance the quality of life, and reduce morbidity and mortality due to inappropriate medication use. PMID- 26129703 TI - Effect of Calcium Ions on Dewaterability of Enzymatic-Enhanced Anaerobic Digestion Sludge. AB - Waste-activated sludge (WAS) solubilized remarkably after enzymatic-enhanced anaerobic digestion, but its dewaterability was deteriorated. In this study, a novel method was performed to improve the dewaterability of enzymatic-enhanced anaerobic digestion sludge by adding CaCl2 (0.01~1.00 g/g total sludge). The capillary suction time (CST), moisture content, and filtrate turbidity were employed to characterize the dewaterability of WAS, and the possible mechanisms involved were clarified. The results showed the dewaterability did not worsen when CaCl2 was added before sludge digestion, and the CST, moisture content, and filtrate turbidity were notably reduced with the increase of CaCl2 dosage. It also shown that calcium ions played an important role in the bioflocculation of digested sludge by neutralizing negative charges on the surface of sludge. In addition, soluble protein initially lowered a little and then observably improved with the addition of CaCl2, while soluble carbohydrate was reduced sharply first and then bounced back afterwards. The interactions between calcium ions and the biopolymer further enhanced the dewatering of sludge through bridging of colloidal particles together. PMID- 26129704 TI - WS2 Nanowires as a High-Performance Anode for Sodium-Ion Batteries. AB - We report the synthesis and anode application for sodium-ion batteries (SIBs) of WS2 nanowires (WS2 NWs). WS2 NWs with very thin diameter of ~25 nm and expanded interlayer spacing of 0.83 nm were prepared by using a facile solvothermal method followed by a heat treatment. The as-prepared WS2 NWs were evaluated as anode materials of SIBs in two potential windows of 0.01-2.5 V and 0.5-3 V. WS2 NWs displayed a remarkable capacity (605.3 mA h g(-1) at 100 mA g(-1) ) but with irreversible conversion reaction in the potential window of 0.01-2.5 V. In comparison, WS2 NWs showed a reversible intercalation mechanism in the potential window of 0.5-3 V, in which the nanowire-framework is well maintained. In the latter case, the interlayers of WS2 are gradually expanded and exfoliated during repeated charge-discharge cycling. This not only provides more active sites and open channels for the intercalation of Na(+) but also facilitates the electronic and ionic diffusion. Therefore, WS2 NWs exhibited an ultra-long cycle life with high capacity and rate capability in the potential window of 0.5-3 V. This study shows that WS2 NWs are promising as the anode materials of room-temperature SIBs. PMID- 26129705 TI - Evidences of Reduced Antioxidant Activity in Patients With Chronic Migraine and Medication-Overuse Headache. AB - BACKGROUND: Migraine is a complex multifactorial, neurobiological disorder, whose pathogenesis is not fully understood, nor are the mechanisms associated with migraine transformation from episodic to chronic pattern. A possible role of impaired oxidative mitochondrial metabolism in migraine pathogenesis has been hypothesized, and increased levels of peripheral markers of oxidative stress have been reported in migraine patients, although the literature data are limited and heterogeneous. OBJECTIVES: The aim of this cross-sectional study was to determine plasmatic levels of advanced oxidation protein products, ferric-reducing antioxidant power and total plasmatic thiol groups, all plasmatic markers related to oxidative stress, in a sample of chronic migraine patients and medication overuse headache, compared to a control group of healthy subjects. METHODS: Thirty-three patients with a diagnosis of both chronic migraine and medication overuse headache (International Classification of Headache Disorders,3rd edition, beta version) and 33 healthy, headache-free subjects were enrolled. Patients with comorbid/coexisting conditions were excluded, as well as patients in treatment with migraine preventive drugs. Plasmatic levels of advanced oxidation protein products, ferric-reducing antioxidant power, and total thiol groups were determined in migraine patients and controls; moreover, oxidative stress biomarkers were compared in migraine patients with triptan compared to non steroidal anti-inflammatory drug overuse. RESULTS: The statistical analysis showed significantly lower levels of ferric-reducing antioxidant power and total plasmatic thiol groups, both expression of antioxidant power, in patients with chronic migraine and medication-overuse headache compared to controls (respectively, ferric antioxidant power median [interquartile range] 0.53 [0.22] vs 0.82 [0.11] mmol/L, P < .001; total thiol groups 0.25 [0.08] vs 0.51 [0.11] MUmol/L, P < .001). Moreover, no statistically significant differences in oxidative stress biomarkers were detected between patients with triptan and nonsteroidal anti-inflammatory drug overuse. CONCLUSIONS: The data from the present study suggest that antioxidant capacity is lower in chronic migraine patients and medication-overuse headache compared to healthy headache-free subjects, with no differences between patients with triptan or nonsteroidal anti inflammatory drug overuse. Further investigation is certainly necessary in order to define the causal or consequential role of an imbalance between pro-oxidants and antioxidant defenses in migraine pathogenesis and "chronification" and the possible therapeutic implications in clinical practice. PMID- 26129706 TI - Facial expression perception correlates with verbal working memory function in schizophrenia. AB - AIMS: Facial emotion perception is considered to provide a measure of social cognition. Numerous studies have examined the perception of emotion in patients with schizophrenia, and the majority has reported impaired ability to recognize facial emotion perception. We aimed to investigate the correlation between facial expression recognition and other domains of social cognition and neurocognition in Japanese patients with schizophrenia. METHODS: Participants were 52 patients with schizophrenia and 53 normal controls with no history of psychiatric diseases. All participants completed the Hinting Task and the Social Cognition Screening Questionnaire. The Brief Assessment of Cognition in Schizophrenia was administered only to the patients. Facial emotion perception measured by the Facial Emotion Selection Test (FEST) was compared between the patients and normal controls. RESULTS: Patients performed significantly worse on the FEST compared to normal control subjects. The FEST total score was significantly positively correlated with scores of the Brief Assessment of Cognition in Schizophrenia attention subscale, Hinting Task, Social Cognition Screening Questionnaire Verbal Working Memory and Metacognition subscales. Stepwise multiple regression analysis revealed that verbal working memory function was positively related to the facial emotion perception ability in patients with schizophrenia. CONCLUSIONS: These results point to the concept that facial emotion perception and some types of working memory use common cognitive resources. Our findings may provide implications for cognitive rehabilitation and related interventions in schizophrenia. PMID- 26129707 TI - Short implants compared to implants in vertically augmented bone: a systematic review. AB - OBJECTIVES: To assess relevant data comparing short implants or implants associated with vertical ridge augmentation derived from RCT's and CCT's. MATERIAL AND METHODS: A PubMed and hand search was performed to identify all RCT's and CCT's published in English language comparing short implants to implants associated with vertical ridge augmentation. RESULTS: The initial search resulted in 3387 articles. A total of 17 articles were eligible for full-text analysis and four were finally included. This review tends to demonstrate similar implant survival rates between implants placed in vertically augmented bone and short implants (95.09% vs. 96.24%, respectively) with a follow-up ranging from 1 to 5 years. In terms of prosthetic survival rates, there were no differences between the treatments. More surgical complications were reported when using implants placed in vertically augmented bone compared to short implants (56 patients with surgical complications compared to 18 patients, respectively). CONCLUSIONS: This evidence should, however, be interpreted with caution as it is derived from four RCT's with limited sample size (ranging from 15 to 30 per group), limited follow-up and performed by the same research group. PMID- 26129708 TI - Spin-inversion and spin-selection in the reactions FeO(+) + H2 and Fe(+) + N2O. AB - The reactions of FeO(+) with H2 and of Fe(+) with N2O were studied with respect to the production and reactivity of electronically excited (4)Fe(+) cations. The reaction of electronic ground state (6)FeO(+) with H2 was found to predominantly produce electronically excited (4)Fe(+) as opposed to electronic ground state (6)Fe(+) corresponding to a spin-allowed reaction. (4)Fe(+) was observed to react with N2O with a rate constant of 2.3 (+0.3/-0.8) * 10(-11) cm(3) molecule(-1) s( 1), smaller than the ground state (6)Fe(+) rate constant of 3.2 (+/-0.5) * 10( 11) cm(3) molecule(-1) s(-1) (at room temperature). While the overall reaction of (6)FeO(+) with H2 within the Two-State-Reactivity concept is governed by efficient sextet-quartet spin-inversion in the initial reaction complex, the observation of predominant (4)Fe(+) production in the reaction is attributed to a much less efficient quartet-sextet back-inversion in the final reaction complex. Average spin-inversion probabilities are estimated by statistical modeling of spin-inversion processes and related to the properties of spin-orbit coupling along the reaction coordinate. The reaction of FeO(+) with H2 served as a source for (4)Fe(+), subsequently reacting with N2O. The measured rate constant has allowed for a more detailed understanding of the ground state (6)Fe(+) reaction with N2O, leading to a significantly improved statistical modeling of the previously measured temperature dependence of the reaction. In particular, evidence for the participation of electronically excited states of the reaction complex was found. Deexcitation of (4)Fe(+) by He was found to be slow, with a rate constant <3 * 10(-14) cm(3) molecule(-1) s(-1). PMID- 26129709 TI - Germline mutation rates and the long-term phenotypic effects of mutation accumulation in wild-type laboratory mice and mutator mice. AB - The germline mutation rate is an important parameter that affects the amount of genetic variation and the rate of evolution. However, neither the rate of germline mutations in laboratory mice nor the biological significance of the mutation rate in mammalian populations is clear. Here we studied genome-wide mutation rates and the long-term effects of mutation accumulation on phenotype in more than 20 generations of wild-type C57BL/6 mice and mutator mice, which have high DNA replication error rates. We estimated the base-substitution mutation rate to be 5.4 * 10(-9) (95% confidence interval = 4.6 * 10(-9)-6.5 * 10(-9)) per nucleotide per generation in C57BL/6 laboratory mice, about half the rate reported in humans. The mutation rate in mutator mice was 17 times that in wild type mice. Abnormal phenotypes were 4.1-fold more frequent in the mutator lines than in the wild-type lines. After several generations, the mutator mice reproduced at substantially lower rates than the controls, exhibiting low pregnancy rates, lower survival rates, and smaller litter sizes, and many of the breeding lines died out. These results provide fundamental information about mouse genetics and reveal the impact of germline mutation rates on phenotypes in a mammalian population. PMID- 26129710 TI - LHX6 inhibits breast cancer cell proliferation and invasion via repression of the Wnt/beta-catenin signaling pathway. AB - LIM homeobox domain 6 (LHX6), a member of the LHX family of proteins, has been implicated in cancer development. However, the involvement of LHX6 in the development of breast cancer remains unclear. In the present study, the epigenetic regulation, biological function and associated molecular mechanisms of LHX6 in breast cancer were analyzed. The expression levels of LHX6 were demonstrated to be markedly decreased in breast cancer tissues and cell lines. In addition, it was found that increased LHX6 expression in breast cancer cell lines inhibited cell proliferation and invasion. Furthermore, increased LHX6 expression significantly decreased the expression of beta-catenin in MDA-MB-231 breast cancer cells, and small interfering RNA-beta-catenin enhanced LHX6-induced inhibition of cell proliferation and invasion in MDA-MB-231 breast cancer cells. These results indicate that LHX6 inhibits breast cancer cell growth and invasion through suppression of the Wnt/beta-catenin signaling pathway. Thus, the present study provides a novel insight into the underlying mechanism of tumorigenesis in breast cancer, indicating the therapeutic potential of LHX6 in the treatment of breast cancer. PMID- 26129711 TI - P9a(Cdt-PLA2) from Crotalus durissus terrificus as good immunogen to be employed in the production of crotalic anti-PLA2 IgG. AB - Four proteins with phospholipase A2 (PLA2) activity, designated P9a(Cdt-PLA2), P9b(Cdt-PLA2), P10a(Cdt-PLA2) and P10b(Cdt-PLA2) were purified from the venom of Crotalus durissus terrificus by two chromatographic steps: a gel filtration and reversed phase HPLC. The profile obtained clearly shows that three of them have a similar abundance. The molecular mass, 14193.8340Da for P9a(Cdt-PLA2), 14134.9102Da for P9b(Cdt-PLA2), 14242.6289Da for P10a(Cdt-PLA2) and 14183.8730Da for P10b(Cdt-PLA2), were initially evaluated by SDS-PAGE and confirmed by ESI-Q TOF spectrometry, and all of them displayed a monomeric conformation. Also, partial amino acid sequence of each protein was obtained and their alignments with other crotalic PLA2 revealed a high degree of identity among them. Additionally, we studied some pharmacological activities like neurotoxicity, myotoxicity and lethality, which prompted us to pick two of them, P9a(Cdt-PLA2) and P10a(Cdt-PLA2) that resulted to be less toxic that the others, and further characterize them to be used as immunogen. We next injected these last proteins in mice to produce antitoxins against them and ELISA and dot blots reveled that both toxins do not show immunogenic differences, unlike those other pharmacologic activities tested. Furthermore, the antibodies produced cross-reacted with all the isoforms purified demonstrating the feasibility of using only one of them and ensuring the cross-reaction of all. The results obtained show that P9a(Cdt-PLA2) isoform has the lowest toxicity and also a good purification performance; thus this protein may be a promising candidate to be employed in the production of crotalic antitoxins. PMID- 26129712 TI - Management of diabetic foot disease and amputation in the Irish health system: a qualitative study of patients' attitudes and experiences with health services. AB - BACKGROUND: Diabetes is an increasingly prevalent chronic illness that places a huge burden on the individual, the health system and society. Patients with active foot disease and lower limb amputations due to diabetes have a significant amount of interaction with the health care services. The purpose of this study was to explore the attitudes and experiences of foot care services in Ireland among people with diabetes and active foot disease or lower limb amputations. METHODS: A purposive sample of individuals who had either active foot disease or a lower limb amputation as a result of diabetes were recruited from the Prosthetic, Orthotic and Limb Absence Rehabilitation (POLAR) Unit of an Irish hospital. One-to-one interviews were conducted in the POLAR unit using a semi structured topic guide. Thematic analysis was used to identify, analyse and describe patterns within the data. RESULTS: Ten males participated in the study. Most participants expressed a need for emotional support alongside the medical management of their condition. There were substantial differences between participants with regard to the level of education and information they appeared to have received regarding their illness. There were also variations in levels of service received. Transport and medication costs were considered barriers. Having a medical card, which entitles the holder to free medical care, eased the burden of the patient's illness. A number of participants attributed some of the problems they faced with services to the health care system as a whole rather than health care professionals. CONCLUSION: Results suggest that rehabilitation services should place a strong focus on psychological as well as physical adjustment to active foot disease or lower limb amputations. The delivery of services needs to be standardised to ensure equal access to medical care and supplies among people with or at risk of lower extremity amputations. The wider social circumstances of patients should be taken into consideration by health care professionals to provide effective support while patients adjust to this potentially life changing complication. The patient's perspective should also be used to inform health service managers and health professionals on ways to improve services. PMID- 26129713 TI - Linking Essential Tremor to the Cerebellum: Neuropathological Evidence. AB - A fundamental question about essential tremor (ET) is whether its associated pathological changes and disease mechanisms are linkable to a specific brain region. To that end, recent tissue-based studies have made significant strides in elucidating changes in the ET brain. Emerging from these studies is increasing neuropathological evidence linking ET to the cerebellum. These studies have systematically identified a broad range of structural, degenerative changes in the ET cerebellum, spanning across all Purkinje cell compartments. These include the dendritic compartment (where there is an increase in number of Purkinje cell dendritic swellings, a pruning of the dendritic arbor, and a reduction in spine density), the cell body (where, aside from reductions in Purkinje cell linear density in some studies, there is an increase in the number of heterotopic Purkinje cell soma), and the axonal compartment (where a plethora of changes in axonal morphology have been observed, including an increase in the number of thickened axonal profiles, torpedoes, axonal recurrent collaterals, axonal branching, and terminal axonal sprouting). Additional changes, possibly due to secondary remodeling, have been observed in neighboring neuronal populations. These include a hypertrophy of basket cell axonal processes and changes in the distribution of climbing fiber-Purkinje cell synapses. These changes all distinguish ET from normal control brains. Initial studies further indicate that the profile (i.e., constellation) of these changes may separate ET from other diseases of the cerebellum, thereby serving as a disease signature. With the discovery of these changes, a new model of ET has arisen, which posits that it may be a neurodegenerative disorder centered in the cerebellar cortex. These newly emerging neuropathological studies pave the way for anatomically focused, hypothesis-driven, molecular mechanistic studies of disease pathogenesis. PMID- 26129714 TI - Forward signaling by unipolar brush cells in the mouse cerebellum. AB - Unipolar brush cells (UBCs) are glutamatergic interneurons prominently present in the granular layer of the vestibulocerebellum. UBCs engage in extensive synaptic contact with a single presynaptic mossy fiber and signal to downstream granule cells through an elaborate network of mossy fiber-like axons. Ultrastructural examinations and electrophysiological recordings in organotypic slice cultures have indicated that UBCs target not only granule cells but also other UBCs, thus forming chains of two or perhaps more interconnected UBCs. In this report, we show recordings of spontaneous and evoked (di)synaptic events in granule cells and UBCs in fresh cerebellar slices from juvenile mice (5-7 weeks). The patterns of arrival of synaptic events were consistent with the presence of a presynaptic UBC, and recordings from UBCs displayed spontaneous protracted synaptic events characteristic of UBC excitatory synaptic transmission. These results highlight that chains of UBCs could further extend the temporal range of delayed and protracted signaling in the cerebellar cortical network. PMID- 26129715 TI - A Predictive Model and Risk Score for Unplanned Cardiac Surgery Intensive Care Unit Readmissions. AB - BACKGROUND: Readmissions or "bounce back" to the intensive care unit (ICU) following cardiac surgery is associated with an increased risk of morbidity and mortality. We sought to identify clinical and system-based factors associated with ICU bounce backs in order to generate a Bounce Back After Transfer (BATS) prediction score. METHODS: We prospectively collected the clinical and financial records of all patients undergoing coronary artery bypass grafting (CABG) or surgical aortic valve replacement (AVR) between May 2013 and March 2014. Multivariable logistic regression was used to identify independent predictors of bounce backs to the ICU which served as the basis for our BATS score. RESULTS: Of the 532 patients that underwent CABG or AVR during the study period, 35 (6.6%) were readmitted to the ICU. After risk adjustment, female sex, NYHA class III/IV, urgent or emergent operative status, and postoperative renal failure were the predictors of ICU bounce backs utilized to create the BATS score. Patients in the low (<5), moderate (5-10), and high-risk (>10) score cohorts experienced bounce back rates of 3.0%, 10.4%, and 42%, respectively. After adjusting for preoperative patient risk, ICU bounce back resulted in an increase in $68,030 to a patient's total hospital charges. CONCLUSIONS: A predictive model (BATS) can determine the risk of a bounce back to the ICU after transfer to the floor. We speculate that determination of a patient's BATS upon ICU transfer would allow targeted floor care and decrease bounce back rates, along with postoperative morbidity, mortality, and cost of care. PMID- 26129716 TI - Refining Determination of Cardiac Involvement in Amyloidosis With Three dimensional Speckle Tracking Echocardiography. PMID- 26129717 TI - The Influence of Frailty on Outcomes in Cardiovascular Disease. PMID- 26129718 TI - Educational intervention as an effective step for reducing blood culture contamination: a prospective cohort study. AB - BACKGROUND: Contaminated blood cultures lead to diagnostic challenges and place a burden on healthcare services. AIM: To determine the impact of introducing a clinical skills test (CST) as part of the medical licensing examination and an institutional education programme on the contamination rates of blood cultures. METHODS: A prospective cohort study was conducted from 2009 through 2013 in all wards of a tertiary-care teaching hospital. We evaluated the effects of the CST, which was added to the National Medical Licensing Examination in Korea (KMLE) in 2010 and our institutional education programme, which began in 2013. The medical interns in charge of collection of blood for culture were divided in three groups with presence or absence of CST and the institutional education programme. The primary outcome was the percentage of blood cultures contaminated in each group, which were compared using the Poisson regression model. Participants' self-rated scores for the blood draw procedure were also analysed. FINDINGS: Although introduction of the CST in the KMLE failed to reduce blood culture contamination rate (1.36% vs 1.35%; P = 0.734), the institutional education programme significantly reduced the contamination rate (1.35% vs 1.00%; P < 0.0001). Most participants answered that they always followed each step correctly except for waiting the recommended contact time after applying the antiseptic. CONCLUSION: The educational intervention, not the introduction of CST in the KMLE, was effective in reducing overall contamination rates. PMID- 26129719 TI - Synthesis of New Peptide Derivatives of Galanthamine Designed for Prevention and Treatment of Alzheimer's Disease. AB - New derivatives of galanthamine containing peptide fragments with beta-secretase inhibitor activity were synthesized. In position 6 of the galanthamine new shortened analogues of beta-secretase inhibitor OM 99-2 (Boc-Val-Asn-Leu-Ala-OH and Boc-Val-Asn-Leu-Ala-Val-OH) were included. The new derivatives of the galanthamine in position 11 including Boc and norgalanthamine in P3 or P4 positions, Val in P2' position and benzylamin in P3'-position were also synthesized. All new peptides were investigated on mice for acute toxicity. The test compounds were administered to mice via intraperitoneal (i.p.) route. They have low toxicity (LD50>1000 mg/kg) after i.p. The compound 11-N-demethyl-11-N-N [Boc-Asp(Asp-Leu-Ala-Val-NH-Bzl)]-Galanthamine was investigated by two way active avoidance method. The compound has good influence on the conditioned reflexes, which improved the processes of learning and memory. Inhibition activity of newly synthesized compounds was monitored against BuChE and IC50 values are determined. All compounds show activity in micromolar concentration. Compounds 5 and 6 have around 10 times higher activity than galanthamine. Compounds 4 and 9 also show good activity. All newly synthesized compounds show low acute toxicity. PMID- 26129720 TI - A retrospective analysis of the impact of diastolic dysfunction on one-year mortality after transjugular intrahepatic porto-systemic shunt, liver transplantation and non-transplant abdominal surgery in patients with cirrhosis. AB - BACKGROUND: The incidence of diastolic dysfunction (DD) approaches 40% in patients with cirrhosis. However, the clinical impact of DD remains a subject of considerable debate. Surgery in patients with cirrhosis is innately hazardous. Diastolic heart failure has been linked to increased mortality after transjugular intrahepatic porto-systemic shunt surgery (TIPSS). To date, none of the commonly accepted preoperative risk assessment models applied to patients with liver disease incorporates DD. We aimed to examine the relationship between DD and postoperative outcomes in patients with cirrhosis undergoing abdominal surgery. METHODS: Patients with cirrhosis who underwent abdominal surgery between January 2000 and December 2011 were included if they had preoperative echocardiography done within 3 months of surgery. The echocardiographic images were reviewed using flow and tissue Doppler techniques to identify the presence of DD. Outcomes analyzed included one-year mortality and postoperative complications. RESULTS: A total of 140 patients were included in the study of which 63 patients (45%) met pre-established criteria for DD. Those with DD were older (P < 0.005) and less likely to have an isolated viral etiology of cirrhosis (P<0.05). The one-year mortality rate was 22.2% (14/63) in patients with DD and 20.8% (16/77) in those without DD (P=0.42). Postoperative complications were not statistically different in the two groups. CONCLUSION: DD is common in patients with cirrhosis. In patients with cirrhosis undergoing TIPS and/or abdominal surgery, the presence of DD does not increase post-procedure complications or one-year mortality. PMID- 26129721 TI - Characterization of six small HSP genes from Chironomus riparius (Diptera, Chironomidae): Differential expression under conditions of normal growth and heat induced stress. AB - Small heat shock proteins (sHSPs) comprise the most numerous, structurally diverse, and functionally uncharacterized family of heat shock proteins. Several Hsp genes (Hsp 90, 70, 40, and 27) from the insect Chironomus riparius are widely used in aquatic toxicology as biomarkers for environmental toxins. Here, we conducted a comparative study and characterized secondary structure of the six newly identified sHsp genes Hsp17, Hsp21, Hsp22, Hsp23, Hsp24, and Hsp34. A characteristic alpha-crystallin domain is predicted in all the new proteins. Phylogenetic analysis suggests a strong relation to other sHSPs from insects and interesting evidence regarding evolutionary origin and duplication events. Comparative analysis of transcription profiles for Hsp27, Hsp70, and the six newly identified genes revealed that Hsp17, Hsp21, and Hsp22 are constitutively expressed under normal conditions, while under two different heat shock conditions these genes are either not activated or are even repressed (Hsp22). In contrast, Hsp23, Hsp24, and Hsp34 are significantly activated along with Hsp27 and Hsp70 during heat stress. These results strongly suggest functional differentiation within the small HSP subfamily and provide new data to help understand the coping mechanisms induced by stressful environmental stimuli. PMID- 26129722 TI - High Rates of Depression and Depressive Symptoms among Men Referred for Borderline Testosterone Levels. AB - INTRODUCTION: Men referred for borderline testosterone levels represent an increasingly common clinical scenario, yet there is little literature on this population. AIM: We hypothesized that men referred for borderline testosterone levels would have higher rates of depression and depressive symptoms than the general population. METHODS: Subjects included 200 adult men (mean age of 48 years old) referred for borderline total testosterone levels between 200 and 350 ng/dL (6.9-12 nmol/L). Collected data included demographic information, medical histories, medication use, signs and symptoms of hypogonadism, and assessments of depressive symptoms and/or a known diagnosis of depression or use of an antidepressant. MAIN OUTCOME MEASURES: The main outcome measure was a combination of known depression, current use of an antidepressant, and/or depressive symptoms according to the Patient Health Questionnaire 9 (PHQ-9) with scores >=10 considered positive. RESULTS: Depression and/or depressive symptoms were present in 56% of the subjects. This rate was significantly higher than rates of 6-23% (PHQ-9 scores >=10) seen in general populations. Antidepressant use was 25%. The population was notable for high rates of overweight/obesity and physical inactivity. Common symptoms were erectile dysfunction, decreased libido, fewer AM erections, low energy, and sleep disturbances. CONCLUSIONS: While sexual and nonspecific symptoms (i.e., fatigue) likely prompted measurements of testosterone in this selected population, clinicians should recognize the high rates of depression and depressive symptoms in men referred for borderline testosterone levels. Clinicians should consider screening for depression/depressive symptoms and overweight and unhealthy lifestyle risk factors in men referred for tertiary care for potential hypogonadism. PMID- 26129723 TI - Liquid on Paper: Rapid Prototyping of Soft Functional Components for Paper Electronics. AB - This paper describes a novel approach to fabricate paper-based electric circuits consisting of a paper matrix embedded with three-dimensional (3D) microchannels and liquid metal. Leveraging the high electric conductivity and good flowability of liquid metal, and metallophobic property of paper, it is possible to keep electric and mechanical functionality of the electric circuit even after a thousand cycles of deformation. Embedding liquid metal into paper matrix is a promising method to rapidly fabricate low-cost, disposable, and soft electric circuits for electronics. As a demonstration, we designed a programmable displacement transducer and applied it as variable resistors and pressure sensors. The unique metallophobic property, combined with softness, low cost and light weight, makes paper an attractive alternative to other materials in which liquid metal are currently embedded. PMID- 26129724 TI - Arthroscopic Rotator Cuff Repair With Absorbable Sutures in the Medial-Row Anchors. AB - PURPOSE: To report the retear rate and retear pattern after double-row arthroscopic rotator cuff repair (DR-ARCR) with the use of absorbable sutures as medial anchor sutures and to address the advantage of the use of absorbable sutures in medial-row anchors. METHODS: Fifty-seven shoulders (22 male and 35 female patients; mean age, 66.1 years) with complete rotator cuff tears treated with DR-ARCR using absorbable mattress sutures as medial-row anchor sutures were included in the study. They included 35 medium, 17 large, and 5 massive tears. For the medial row, medial anchor sutures were replaced with absorbable mattress sutures. High-strength simple sutures were used for the lateral anchors. We evaluated retear patterns by magnetic resonance imaging examinations performed at 1 month, 3 months, 6 months, and 1 year postoperatively. The clinical conditions of all patients preoperatively and 2 years postoperatively were assessed by the University of California, Los Angeles rating scale and the American Shoulder and Elbow Surgeons shoulder index. RESULTS: A complete retear of the tendon at the footprint was observed in 5 shoulders. Complete discontinuity at the middle of the tendon around the medial-row anchors with a footprint remnant was observed in 1 shoulder. A thinned repaired rotator cuff was observed in 2 shoulders because of a partial retear of the deep layer. The overall retear rate was 14%. From before to after surgery, the University of California, Los Angeles score significantly improved from 18.4 to 32.9 (P < .0001) and the American Shoulder and Elbow Surgeons index improved from 55.1 to 87.7 (P < .0001). No complications were observed. CONCLUSIONS: The retear rates after DR-ARCR with absorbable sutures as medial-row anchors were 8.8% for complete retears of the tendon at the footprint and 1.7% for complete discontinuity of tendon around the medial-row anchors. This procedure provided a low retear rate around the medial-row anchors. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 26129725 TI - Anatomic Placement of the Femoral Tunnels in Double-Bundle Anterior Cruciate Ligament Reconstruction Correlates With Improved Graft Maturation and Clinical Outcomes. AB - PURPOSE: To compare maturation of reconstructed graft on second-look arthroscopy and clinical outcomes between 2 groups: the provisional anatomic (PA) group, with both the anteromedial (AM) and posterolateral (PL) femoral tunnels in their anatomic location, and the nonanatomic (NA) group, with either 1 of the 2 femoral tunnels beyond its anatomic location after double-bundle anterior cruciate ligament reconstruction. METHODS: We enrolled 154 patients who underwent 3 dimensional computed tomography scanning and second-look arthroscopy after double bundle anterior cruciate ligament reconstruction. All of the patients were divided into the PA and NA groups according to the femoral tunnel position determined by the quadrant method. Graft maturation was evaluated with 3 subsections, including integrity, tension, and synovial coverage with revascularization, on second-look arthroscopy. We also compared Lachman test, pivot-shift test, KT-2000 (MEDmetric, San Diego, CA), and International Knee Documentation Committee grades at the last follow-up. RESULTS: Of the 154 patients, 88 were classified as the PA group and 66 as the NA group by the quadrant method. A difference existed between groups for the AM tunnel position but not for the PL tunnel position. The PA group showed a higher graft maturation score (P < .001 for all comparisons) and better results according to the International Knee Documentation Committee knee rating, Lachman test, pivot-shift test, and KT-2000 assessment (P < .001 for all comparisons). CONCLUSIONS: The PA group with anatomic femoral tunnel placement showed a higher graft maturation score on second-look arthroscopy, along with better clinical outcomes, than the NA group. There was a significant difference in the AM femoral tunnel position but not in the PL tunnel position between the 2 groups. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 26129726 TI - The Bankart Performance Metrics Combined With a Shoulder Model Simulator Create a Precise and Accurate Training Tool for Measuring Surgeon Skill. AB - PURPOSE: To determine if a dry shoulder model simulator coupled with previously validated performance metrics for an arthroscopic Bankart repair (ABR) would be a valid tool with the ability to discriminate between the performance of experienced and novice surgeons, and to establish a proficiency benchmark for an ABR using a model simulator. METHODS: We compared an experienced group of arthroscopic shoulder surgeons (Arthroscopy Association of North America faculty) (n = 12) with a novice group (n = 7) (postgraduate year 4 or 5 orthopaedic residents). All surgeons were instructed to perform a diagnostic arthroscopy and a 3 suture anchor Bankart repair on a dry shoulder model. Each procedure was videotaped in its entirety and scored in blinded fashion independently by 2 trained reviewers. Scoring used previously validated metrics for an ABR and included steps, errors, and "sentinel" (more serious) errors. RESULTS: The inter rater reliability among pairs of raters averaged 0.93. The experienced group made 63% fewer errors, committed 79% fewer sentinel errors, and performed the procedure in 42% less time than the novice group (all significant differences). The greatest difference in errors between the groups involved anchor preparation and insertion, suture delivery and management, and knot tying. CONCLUSIONS: The tool comprised by validated ABR metrics coupled with a dry shoulder model simulator is able to accurately distinguish between the performance of experienced and novice orthopaedic surgeons. A performance benchmark based on the mean performance of the experienced group includes completion of a 3 anchor Bankart repair, enacting no more than 4 total errors and 1 sentinel error. CLINICAL RELEVANCE: The combination of performance metrics and an arthroscopic shoulder model simulator can be used to improve the effectiveness of surgical skills training for an ABR. The methodology used may serve as a template for outcomes-based procedural skills training in general. PMID- 26129727 TI - Use of magnetic circular dichroism to study dinuclear metallohydrolases and the corresponding biomimetics. AB - Magnetic circular dichroism (MCD) is a convenient technique for providing structural and mechanistic insight into enzymatic systems in solution. The focus of this review is on aspects of geometric and electronic structure that can be determined by MCD, and how this method can further our understanding of enzymatic mechanisms. Dinuclear Co(II) systems that catalyse hydrolytic reactions were selected to illustrate the approach. These systems all contain active sites with similar structures consisting of two Co(II) ions bridged by one or two carboxylates and a water or hydroxide. In most of these active sites one Co(II) is five-coordinate and one is six-coordinate, with differing binding affinities. It is shown how MCD can be used to determine which binding site--five or six coordinate--has the greater affinity. Importantly, zero-field-splitting data and magnetic exchange coupling constants may be determined from the temperature and field dependence of MCD data. The relevance of these data to the function of the enzymatic systems is discussed. PMID- 26129728 TI - Fractal model of anomalous diffusion. AB - An equation of motion is derived from fractal analysis of the Brownian particle trajectory in which the asymptotic fractal dimension of the trajectory has a required value. The formula makes it possible to calculate the time dependence of the mean square displacement for both short and long periods when the molecule diffuses anomalously. The anomalous diffusion which occurs after long periods is characterized by two variables, the transport coefficient and the anomalous diffusion exponent. An explicit formula is derived for the transport coefficient, which is related to the diffusion constant, as dependent on the Brownian step time, and the anomalous diffusion exponent. The model makes it possible to deduce anomalous diffusion properties from experimental data obtained even for short time periods and to estimate the transport coefficient in systems for which the diffusion behavior has been investigated. The results were confirmed for both sub and super-diffusion. PMID- 26129729 TI - [Cutaneous granulomatous reactions at botulinum neurotoxin A injection sites: First manifestation of systemic sarcoidosis]. AB - CASE REPORT: We report a case of granulomatous skin reaction after injection of an unknown botulinum neurotoxin (BoNT) A preparation. Four years after occurrence of skin lesions, systemic sarcoidosis became manifest. CONCLUSION: In addition to injection trauma, the BoNT A preparation may have acted as an immunogenic stimulus leading to cutaneous manifestation of sarcoidosis. PMID- 26129730 TI - Localized Neuron Stimulation with Organic Electrochemical Transistors on Delaminating Depth Probes. AB - Organic electrochemical transistors are integrated on depth probes to achieve localized electrical stimulation of neurons. The probes feature a mechanical delamination process which leaves only a 4 MUm thick film with embedded transistors inside the brain. This considerably reduces probe invasiveness and correspondingly improves future brain-machine interfaces. PMID- 26129731 TI - Reliable protocol for shear wave elastography of lower limb muscles at rest and during passive stretching. AB - Development of shear wave elastography gave access to non-invasive muscle stiffness assessment in vivo. The aim of the present study was to define a measurement protocol to be used in clinical routine for quantifying the shear modulus of lower limb muscles. Four positions were defined to evaluate shear modulus in 10 healthy subjects: parallel to the fibers, in the anterior and posterior aspects of the lower limb, at rest and during passive stretching. Reliability was first evaluated on two muscles by three operators; these measurements were repeated six times. Then, measurement reliability was compared in 11 muscles by two operators; these measurements were repeated three times. Reproducibility of shear modulus was 0.48 kPa and repeatability was 0.41 kPa, with all muscles pooled. Position did not significantly influence reliability. Shear wave elastography appeared to be an appropriate and reliable tool to evaluate the shear modulus of lower limb muscles with the proposed protocol. PMID- 26129733 TI - Why Have So Many Intravascular Glucose Monitoring Devices Failed? AB - Secondary to the inherent limitations of both point-of-care and central laboratory glucose technologies, continuous glucose measurement has recently enjoyed a high level of investment. Because of the perceived advantages by some of measuring in the intravascular space compared to the subcutaneous tissue, a number of technologies have been developed. In this review, we evaluate nine systems that have shown promise, although only one of these has been cleared for sale in the United States. The detection methodology, regulatory status, technical issues, and company circumstance surrounding each technology are examined. PMID- 26129734 TI - Images in Vascular Medicine. Rapidly progressive arterial aneurysms in a patient with Ehlers-Danlos syndrome. PMID- 26129732 TI - The organization of the posterior parietal cortex devoted to upper limb actions: An fMRI study. AB - The present fMRI study examined whether upper-limb action classes differing in their motor goal are encoded by different PPC sectors. Action observation was used as a proxy for action execution. Subjects viewed actors performing object related (e.g., grasping), skin-displacing (e.g., rubbing the skin), and interpersonal upper limb actions (e.g., pushing someone). Observation of the three action classes activated a three-level network including occipito-temporal, parietal, and premotor cortex. The parietal region common to observing all three action classes was located dorsally to the left intraparietal sulcus (DIPSM/DIPSA border). Regions specific for observing an action class were obtained by combining the interaction between observing action classes and stimulus types with exclusive masking for observing the other classes, while for regions considered preferentially active for a class the interaction was exclusively masked with the regions common to all observed actions. Left putative human anterior intraparietal was specific for observing manipulative actions, and left parietal operculum including putative human SII region, specific for observing skin-displacing actions. Control experiments demonstrated that this latter activation depended on seeing the skin being moved and not simply on seeing touch. Psychophysiological interactions showed that the two specific parietal regions had similar connectivities. Finally, observing interpersonal actions preferentially activated a dorsal sector of left DIPSA, possibly the homologue of ventral intraparietal coding the impingement of the target person's body into the peripersonal space of the actor. These results support the importance of segregation according to the action class as principle of posterior parietal cortex organization for action observation and by implication for action execution. PMID- 26129735 TI - Soluble vascular endothelial-cadherin and auto-antibodies to human vascular endothelial-cadherin in human diseases: Two new biomarkers of endothelial dysfunction. AB - Vascular endothelial-cadherin is the most important transmembrane component of endothelial adherens junctions, exclusively expressed by endothelial cells in all types of vessels. Targeting either the extracellular domain or the cytoplasmic tail deleteriously affects the junctional strength and leads to vascular permeability. Recently, cytokine-induced phosphorylation of the vascular endothelial-cadherin cytoplasmic domain was reported to trigger cleavage of its extracellular domain, producing the soluble form of the protein - soluble vascular endothelial-cadherin. Hence, the presence of soluble vascular endothelial-cadherin or auto-antibodies to human vascular endothelial-cadherin in human serum could signalize the presence of vascular abnormalities. This systematic review covers many human studies reporting increased levels of soluble vascular endothelial-cadherin, as well as auto-antibodies to human vascular endothelial-cadherin, which could be promising biomarkers of endothelial dysfunction in a large panel of diseases. PMID- 26129736 TI - Analysis of nutritional habits and intake of polyunsaturated fatty acids in veterans with peripheral arterial disease. AB - Inadequate nutrient intake may contribute to the development and progression of peripheral arterial disease (PAD). This study's aim was to assess intake of essential fatty acids and nutrients among veterans with PAD. All 88 subjects had ankle-brachial indices of <0.9 and claudication. A validated food frequency questionnaire evaluated dietary intake, and values were compared to guidelines established by the American Heart Association (AHA) and American College of Cardiology (ACC), as well as the AHA/ACC endorsed Dietary Approaches to Stop Hypertension (DASH) eating plan. The mean age was 69 +/- 8 years. Compared to the AHA/ACC guidelines, subjects with PAD had an inadequate intake of long-chain polyunsaturated fatty acids (n-3 PUFA; 59% consumed >1 gram daily). Our subjects with PAD had an increased intake of cholesterol (31% met the cut-off established in the DASH plan), total fat (5%) and sodium (53%). They had an inadequate intake of magnesium (3%), calcium (5%), and soluble fiber (3%). Dietary potassium intake met the recommended guidelines. In our subjects with PAD, intake of critical nutrients deviated substantially from the recommended amounts. Further prospective studies should evaluate whether PAD patients experience clinical benefit if diets are modified to meet the AHA/ACC recommendations. PMID- 26129737 TI - A Comparison of Bipolar Electrocautery and Chemical Cautery for Control of Pediatric Recurrent Anterior Epistaxis. AB - OBJECTIVE: To compare the outcome of children with anterior epistaxis treated intraoperatively with either bipolar electrocautery or silver nitrate chemical cautery. STUDY DESIGN: Case series with chart review. SETTING: Tertiary-care pediatric otolaryngology practice. SUBJECTS: Children aged 2 to 18 years treated with either intraoperative bipolar electrocautery or silver nitrate chemical cautery of the anterior nasal septum for recurrent anterior epistaxis. METHODS: Any reported bleeding event after surgery was recorded. The mean time from surgery to recurrent epistaxis was compared between groups. RESULTS: Fifty patients underwent bipolar electrocautery, while 60 patients underwent silver nitrate chemical cautery. Within 2 years, 1 (2%) patient in the bipolar electrocautery group and 13 (22%) patients in the silver nitrate chemical cautery group had recurrent epistaxis (P = .003). Two years after treatment, there was no difference between treatment groups. Overall, 4 patients (8%) had recurrent epistaxis postoperatively in the bipolar electrocautery group at a mean of 4.34 years after treatment, while 17 (28.3%) patients recurred after a mean of 1.53 years of treatment in the silver nitrate chemical cautery group (P = .01). CONCLUSION: Compared to those treated with chemical cautery, those treated with bipolar electrocautery had a longer nosebleed-free period and a lower incidence of recurrent epistaxis within 2 years of treatment. Beyond 2 years, the treatment methods are equivocal. Bipolar electrocautery may be a superior treatment in children who will not tolerate in-office chemical cautery, in those with a risk of severe bleeding, or when it can be combined with other operative procedures. PMID- 26129738 TI - Idiopathic Facial Aseptic Granuloma: A Rare, Benign Pediatric Dermatological Lesion. PMID- 26129739 TI - Occult Temporal Bone Facial Nerve Involvement by Parotid Malignancies with Perineural Spread. AB - OBJECTIVE: To characterize disease presentation and outcomes following surgical treatment of parotid malignancies with occult temporal bone facial nerve (FN) involvement. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic referral center. SUBJECTS AND METHODS: Thirty consecutive patients (mean age 58 years; 77% men) who underwent surgery for parotid malignancies with occult perineural involvement of the intratemporal FN were included. Primary outcome measures included margin status and recurrence. RESULTS: The mean duration of clinical follow-up was 49 months, and the most common presenting symptom was FN paresis (n = 23; 77%) followed by pain (n = 15; 50%). To obtain a proximal FN margin, 27 patients (90%) underwent mastoidectomy, and 3 patients (10%) had lateral temporal bone resection. The intratemporal FN margin was cleared in 26 patients (87%), most commonly in the mastoid segment (60%). Adjuvant therapy was given in 25 patients (83%). Ten patients (33%) experienced locoregional (4; 13%) and/or distant (8; 27%) recurrence at a median of 19 months (mean 26, 2-54 months) following surgery. Locoregional failure was significantly more common in cases with a positive intratemporal FN margin (66% vs 8%; P = .045). Overall 1-, 3-, and 5-year disease-specific survival rates were 83%, 79%, and 72%, respectively. CONCLUSIONS: Perineural invasion of the intratemporal FN by parotid malignancy is uncommon. Normal preoperative FN function does not preclude histopathologic involvement. Temporal bone FN exploration should be considered when a positive margin is encountered at the stylomastoid foramen, as failure to do so is associated with an increased rate of locoregional recurrence. PMID- 26129740 TI - The Changing Landscape of Vestibular Schwannoma Management in the United States- A Shift Toward Conservatism. AB - OBJECTIVE: To characterize the evolving management of vestibular schwannoma (VS) in the United States. STUDY DESIGN: Retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database. SETTING: SEER database. SUBJECTS AND METHODS: All patients with a diagnosis of VS were analyzed. Data were described and compared using trend analyses and univariate and multivariable logistic regression. RESULTS: A total of 8330 patients (average age 54.7 years, 51.9% female) were analyzed. The mean incidence was approximately 1.1 per 100,000 per year and did not vary significantly across time; however, from 2004 to 2011, there was a statistically significant decrease in tumor size category at time of diagnosis (P < .01). Overall, 3982 patients (48%) received primary microsurgery, 1978 (24%) radiation therapy alone, and 2370 (29%) observation. Within the microsurgical cohort, 732 (18%) underwent subtotal resection, and of those, 98 (13.4%) received postoperative radiation therapy. Multivariable regression revealed that surgical treatment was more common in younger patients and larger tumor size categories (P < .05). Management trend analysis revealed that microsurgery was used less frequently over time (P < .0001), observation was used more frequently (P < .0001), and the pattern of radiation therapy remained unchanged. Linear regression was used to create an equation that was applied to predict future management practices. These data predict that by 2026, half of all cases of VS will be managed initially with observation. CONCLUSION: While the incidence of VS has remained steady, tumor size at time of diagnosis has decreased over time. Within the United States there has been a clear, recent evolution in management toward observation. PMID- 26129741 TI - Response to 'Ex-vivo Donor Heart Perfusion: Testing the Limits of Cardiac Resilience'. PMID- 26129742 TI - Methods to quantify the velocity dependence of common gait measurements from automated rodent gait analysis devices. AB - BACKGROUND: Walking slowly is a different biomechanical task than walking quickly, thus measures of gait will be different at different velocities, such as pre/post injury. It is necessary to determine if the difference in gait measures are from the experimental changes, or simply from traveling at different speeds. NEW METHOD: Instead of limiting this effect, we have developed techniques to embrace the velocity dependence of gait measures. By translating the pawprints into a body coordinate frame we are able to measure location of paw placement in addition to the standard gait measures. RESULTS: At higher velocities rats have greater consistency of steps, place their forelimb initial contact more medially and anteriorly, and place their hindlimb toe off more medially and posteriorly. Interlimb phasing also becomes more consistent at higher velocities. Following a cervical spinal cord injury consistency is reduced and the velocity dependent behaviors are significantly different. COMPARISON WITH EXISTING METHOD: Translating the coordinate frame improves the ability to measure changes in base of support following spinal cord injury. Employing a treadmill, or limiting analysis to a narrow velocity window does address the effects of velocity. We feel that measuring across all velocities is more appropriate than dictating that the animals match speeds. CONCLUSIONS: Quantifying locomotion with automated gait analysis devices is a great way to evaluate the changes that experimental treatments provide. These new methods allow for a more appropriate way to address the confound of many gait measures being velocity dependent. PMID- 26129743 TI - The influence of construction methodology on structural brain network measures: A review. AB - Structural brain networks based on diffusion MRI and tractography show robust attributes such as small-worldness, hierarchical modularity, and rich-club organization. However, there are large discrepancies in the reports about specific network measures. It is hypothesized that these discrepancies result from the influence of construction methodology. We surveyed the methodological options and their influences on network measures. It is found that most network measures are sensitive to the scale of brain parcellation, MRI gradient schemes and orientation model, and the tractography algorithm, which is in accordance with the theoretical analysis of the small-world network model. Different network weighting schemes represent different attributes of brain networks, which makes these schemes incomparable between studies. Methodology choice depends on the specific study objectives and a clear understanding of the pros and cons of a particular methodology. Because there is no way to eliminate these influences, it seems more practical to quantify them, optimize the methodologies, and construct structural brain networks with multiple spatial resolutions, multiple edge densities, and multiple weighting schemes. PMID- 26129744 TI - [In Process Citation]. PMID- 26129745 TI - Predictors of Chest Wall Toxicity after Lung Stereotactic Ablative Radiotherapy. AB - AIMS: To determine the incidence and predictive factors of rib fracture and chest wall pain after lung stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: Patients were treated with lung SABR of 48-60 Gy in four to five fractions. The treatment plan and follow-up computed tomography scans of 289 tumours in 239 patients were reviewed. Dose-volume histogram (DVH) metrics and clinical factors were evaluated as potential predictors of chest wall toxicity. RESULTS: The median follow-up was 21.0 months (range 6.2-52.1). Seventeen per cent (50/289) developed a rib fracture, 44% (22/50) were symptomatic; the median time to fracture was 16.4 months. On univariate analysis, female gender, osteoporosis, tumours adjacent (within 5 mm) to the chest wall and all of the chest wall DVH metrics predicted for rib fracture, but only tumour location adjacent to the chest wall remained significant on the multivariate model (P < 0.01). The 2 year fracture-free probability for those adjacent to the chest wall was 65.6%. Among those tumours adjacent to the chest wall, only osteoporosis (P = 0.02) predicted for fracture, whereas none of the chest wall DVH metrics were predictive. Eight per cent (24/289) experienced chest wall pain without fracture. CONCLUSIONS: None of the chest wall DVH metrics independently predicted for SABR induced rib fracture when tumour location is taken into account. Patients with tumours adjacent (within 5 mm) to the chest wall are at greater risk of rib fracture after lung SABR, and among these, an additional risk was observed in osteoporotic patients. PMID- 26129746 TI - Prevention and Management of Radiation-induced Late Gastrointestinal Toxicity. AB - In the UK, about 90,000 cancer survivors will suffer from pelvic radiation disease (PRD) due to their curative treatment including radiotherapy. The National Cancer Survivorship Initiative aims to improve the understanding and management of PRD by the oncology community. This overview covers the prevention, investigation and treatment for late radiation-induced gastrointestinal symptoms in PRD. Multiple pharmacological and nutritional interventions have been studied, as prophylaxis for acute gastrointestinal toxicity (aiming to prevent late consequential effects), although predominantly only small randomised controlled trials have been conducted. These have produced mixed results, although promising signals for some agents have been observed. Evidence for the pharmacological prevention of late gastrointestinal toxicity is scarce. Even fewer randomised controlled trials have investigated the late gastrointestinal toxicity profile of advanced radiotherapy technologies. There are nationally agreed algorithms for the investigation and management of PRD, but a lack of awareness means patients still do not get referred appropriately. This overview outlines the management of radiation proctopathy and diarrhoea, and signposts other accessible resources. Finally, we provide recommendations for the management of late gastrointestinal symptoms in PRD and research in this field, especially the need for high-quality clinical trials. PMID- 26129747 TI - Novel transporters from Kluyveromyces marxianus and Pichia guilliermondii expressed in Saccharomyces cerevisiae enable growth on L-arabinose and D-xylose. AB - Genes encoding L-arabinose transporters in Kluyveromyces marxianus and Pichia guilliermondii were identified by functional complementation of Saccharomyces cerevisiae whose growth on L-arabinose was dependent on a functioning L-arabinose transporter, or by screening a differential display library, respectively. These transporters also transport D-xylose and were designated KmAXT1 (arabinose-xylose transporter) and PgAXT1, respectively. Transport assays using L-arabinose showed that KmAxt1p has K(m) 263 mM and V(max) 57 nM/mg/min, and PgAxt1p has K(m) 0.13 mM and V(max) 18 nM/mg/min. Glucose, galactose and xylose significantly inhibit L arabinose transport by both transporters. Transport assays using D-xylose showed that KmAxt1p has K(m) 27 mM and V(max) 3.8 nM/mg/min, and PgAxt1p has K(m) 65 mM and V(max) 8.7 nM/mg/min. Neither transporter is capable of recovering growth on glucose or galactose in a S. cerevisiae strain deleted for hexose and galactose transporters. Transport kinetics of S. cerevisiae Gal2p showed K(m) 371 mM and V(max) 341 nM/mg/min for L-arabinose, and K(m) 25 mM and V(max) 76 nM/mg/min for galactose. Due to the ability of Gal2p and these two newly characterized transporters to transport both L-arabinose and D-xylose, one scenario for the complete usage of biomass-derived pentose sugars would require only the low affinity, high-throughput transporter Gal2p and one additional high-affinity general pentose transporter, rather than dedicated D-xylose or L-arabinose transporters. Additionally, alignment of these transporters with other characterized pentose transporters provides potential targets for substrate recognition engineering. PMID- 26129748 TI - Proteomic analysis of plasma proteins in diabetic retinopathy patients by two dimensional electrophoresis and MALDI-Tof-MS. AB - OBJECTIVE: Diabetic retinopathy is a highly specific vascular complication of diabetes mellitus and progresses from mild non-proliferative abnormalities characterized by increased vascular permeability to moderate and severe proliferative diabetic retinopathy characterized by the growth of blood vessels on the retina. The aim of the study was to identify the differentially expressed proteins in diabetic retinopathy using two-dimensional electrophoresis. METHODS: Blood sample was drawn from subjects with diabetes mellitus (without retinopathy) who served as controls and patients with diabetic retinopathy in tubes containing EDTA as anticoagulant. Albumin and immunoglobulin IgG collectively removed to enrich proteins of lower abundance. 2de was carried out to see if there are any differentially expressed proteins. RESULTS: Approximately 48 and 61 spots were identified in control and diabetic retinopathy respectively, of which three protein spots RBP1 (retinol-binding protein 1), NUD10 (Diphosphoinositol polyphosphohydrolase 3 alpha), NGB (neuroglobin) were down regulated and HBG2 (hemoglobin) and BY55 (CD 160 antigen) were upregulated in diabetic retinopathy. These five protein spots were excised and were subjected to in-gel tryptic digestion, and their identities were determined by ultraflex MALDI-TOF-MS. CONCLUSION: We report a comprehensive patient-based plasma proteomic approach to the identification of potential biomarkers for diabetic retinopathy screening and detection. SIGNIFICANCE OF THE STUDY: We identified 5 different proteins that were differentially expressed in the plasma of control diabetic patients (without retinopathy). Among these five proteins the expression of neuroglobin (NGB) protein varied significantly and may be a potential biomarker in diabetic retinopathy. PMID- 26129749 TI - Participation as a leader in immersion weight loss treatment may benefit, not harm, young adult staff members. AB - Despite the success of weight-management programmes, some researchers caution that participation in an aggressive approach to weight management could promote the development of eating pathology. The current study evaluated the risks and benefits for young adults of serving as staff members in an immersion treatment of adolescent obesity over the course of a summer. Participants included weight loss staff members (n = 108) along with a comparison group of young adults with similar demographic characteristics (n = 136). Participants completed assessments of eating disorder and obesity risk at three time points: the beginning of the summer, the end of the summer and a 6-week follow-up. Weight loss leadership participants who were initially overweight lost weight over the course of the summer, but those at healthy weights maintained their weight. Comparison participants also maintained their weight during the summer. Weight loss staff members also increased dietary restraint over the summer, and increases in dietary restraint appeared to facilitate appropriate weight reduction. Participation as a leader in an immersion weight loss programme seemed to benefit, not harm, young adults; this suggests potential advantages for using weight controlling interventions in a wide range of individuals, including as an obesity prevention strategy. PMID- 26129750 TI - Reply to Crawford. PMID- 26129751 TI - Association of the Functional MICA-129 Polymorphism With the Severity of Chronic Chagas Heart Disease. AB - MICA-129 polymorphism affects the binding affinity of MICA molecules with the NKG2D receptor and influences effector cell function. The genotype met/met was associated with the severity of left ventricular systolic dysfunction (LVSD) in patients with chronic Chagas heart disease, while the val/val genotype was associated with the absence of LVSD. PMID- 26129752 TI - Impact of Hospital Population Case-Mix, Including Poverty, on Hospital All-Cause and Infection-Related 30-Day Readmission Rates. AB - BACKGROUND: Reducing hospital readmissions, including preventable healthcare associated infections, is a national priority. The proportion of readmissions due to infections is not well-understood. Better understanding of hospital risk factors for readmissions and infection-related readmissions may help optimize interventions to prevent readmissions. METHODS: Retrospective cohort study of California acute care hospitals and their patient populations discharged between 2009 and 2011. Demographics, comorbidities, and socioeconomic status were entered into a hierarchical generalized linear mixed model predicting all-cause and infection-related readmissions. Crude verses adjusted hospital rankings were compared using Cohen's kappa. RESULTS: We assessed 30-day readmission rates from 323 hospitals, accounting for 213 879 194 post-discharge person-days of follow up. Infection-related readmissions represented 28% of all readmissions and were associated with discharging a high proportion of patients to skilled nursing facilities. Hospitals serving populations with high proportions of males, comorbidities, prolonged length of stay, and populations living in a federal poverty area, had higher all-cause and infection-related readmission rates. Academic hospitals had higher all-cause and infection-related readmission rates (odds ratio 1.24 and 1.15, respectively). When comparing adjusted vs crude hospital rankings for infection-related readmission rates, adjustment revealed 31% of hospitals changed performance category for infection-related readmissions. CONCLUSIONS: Infection-related readmissions accounted for nearly 30% of all-cause readmissions. High hospital infection-related readmissions were associated with serving a high proportion of patients with comorbidities, long lengths of stay, discharge to skilled nursing facility, and those living in federal poverty areas. Preventability of these infections needs to be assessed. PMID- 26129755 TI - Lyme Disease Comparators. PMID- 26129753 TI - Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection. AB - BACKGROUND: Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. METHODS: CHARTER is an observational study of ambulatory HIV-infected adults. Haplogroups were assigned using mtDNA sequence, and principal components were derived from ancestry-informative nuclear DNA variants. Outcomes were cross-sectional global deficit score (GDS) as a continuous measure, GDS impairment (GDS >= 0.50), and HIV-associated neurocognitive disorder (HAND) using international criteria. Multivariable models were adjusted for comorbidity status (incidental vs contributing), current CART, plasma HIV RNA, reading ability, and CD4 cell nadir. RESULTS: Haplogroups were available from 1027 persons; median age 43 years, median CD4 nadir 178 cells/mm(3), 72% on CART, and 46% with HAND. The 102 (9.9%) persons of genetically determined admixed Hispanic ancestry had more impairment by GDS or HAND than persons of European or African ancestry (P < .001 for all). In multivariate models including persons of admixed Hispanic ancestry, those with haplogroup B had lower GDS (beta = -0.34; P = .008) and less GDS impairment (odds ratio = 0.16; 95% confidence interval, .04, .63; P = .009) than other haplogroups. There were no significant haplogroup associations among persons of European or African ancestry. CONCLUSIONS: In these mostly CART-treated persons, mtDNA haplogroup B was associated with less NCI among persons of genetically determined Hispanic ancestry. mtDNA variation may represent an ancestry-specific factor influencing NCI in HIV-infected persons. PMID- 26129754 TI - Targeting HIV Prevention Based on Molecular Epidemiology Among Deeply Sampled Subnetworks of Men Who Have Sex With Men. AB - BACKGROUND: Molecular epidemiology can be useful in identifying clusters of human immunodeficiency virus (HIV) transmission that can be targeted for prevention. METHODS: Regular screening of 2000 men who have sex with men (MSM) in Beijing, China, for HIV infection every 2 months identified 179 primary infections (2007 2010). HIV-1 pol sequences were obtained and used to infer the transmission network and identify transmitted drug resistance (TDR) among these individuals. We evaluated the use of clinical and network information to target prevention efforts. Prevention efficiency was calculated as the number of infections saved per number of interventions. RESULTS: This cohort was infected with HIV-1 subtype B (28%), circulating recombinant form (CRF)_01 AE (53%), and CRF_07 BC (16%). The overall rate of TDR was low (5%), but the rate of clustering was high (64%), suggesting deep sampling of the subnetwork. Provision of a theoretically high efficacy intervention like antiretroviral therapy to all participants had a prevention efficiency of 23%. The efficiency of targeting prevention based on lower CD4 counts (<200 cells/mL, <350 cells/mL, or <500 cells/mL) and higher viral loads (>100 000 copies/mL and >50 000 copies/mL) was between 10% and 18%. The efficiency of targeting prevention based on number of network connections was much higher (30%-42%). For example, treating the 33 participants with >=5 connections in 2009 would have theoretically prevented 14 infections in 2010 (42% prevention efficiency). CONCLUSIONS: Regular HIV testing of MSM in Beijing can deeply sample the local transmission subnetwork, and targeting prevention efforts based on network connectivity may be an efficient way to deliver prevention interventions. PMID- 26129759 TI - JOSPT Provides Kudos Service to Authors. PMID- 26129756 TI - Combination Treatment for Visceral Leishmaniasis Patients Coinfected with Human Immunodeficiency Virus in India. AB - BACKGROUND: There are considerable numbers of patients coinfected with human immunodeficiency virus (HIV) and visceral leishmaniasis (VL) in the VL-endemic areas of Bihar, India. These patients are at higher risk of relapse and death, but there are still no evidence-based guidelines on how to treat them. In this study, we report on treatment outcomes of coinfected patients up to 18 months following treatment with a combination regimen. METHODS: This retrospective analysis included all patients with confirmed HIV-VL coinfection receiving combination treatment for VL at a Medecins Sans Frontieres treatment center between July 2012 and September 2014. Patients were treated with 30 mg/kg body weight intravenous liposomal amphotericin B (AmBisome) divided as 6 equal dose infusions combined with 14 days of 100 mg/day oral miltefosine (Impavido). All patients were encouraged to start or continue on antiretroviral therapy (ART). RESULTS: 102 patients (76% males, 57% with known HIV infection, 54% with a prior episode of VL) were followed-up for a median of 11 months (interquartile range: 4 18). Cumulative incidence of all-cause mortality and VL relapse at 6, 12, and 18 months was 11.7%, 14.5%, 16.6% and 2.5%, 6.0%,13.9%, respectively. Cumulative incidence of poor outcome at 6, 12, and 18 months was 13.9%, 18.4%, and 27.2%, respectively. Not initiating ART and concurrent tuberculosis were independent risk factors for mortality, whereas no factors were associated with relapse. CONCLUSIONS: In this Bihar-based study, combination therapy appeared to be well tolerated, safe, and effective and may be considered as an option for treatment of VL in HIV coinfected patients. PMID- 26129757 TI - Time From Infection to Disease and Infectiousness for Ebola Virus Disease, a Systematic Review. AB - We systematically reviewed the literature to estimate the incubation and latent periods of Ebola virus disease. We found limited epidemiological data from individuals with discrete 1-day exposures. Available data suggest that the incubation and latent periods may differ, and mathematical models may be improved by distinguishing between the two periods. PMID- 26129760 TI - Enchondroma of the Distal Phalanx. AB - The patient was a 29-year-old woman who was evaluated by a physical therapist in a direct-access capacity for an enlarged distal phalanx on the fourth digit of her left hand. After discussing the patient's presentation with an orthopaedic hand surgeon due to concern for nonmusculoskeletal pathology, radiographs were ordered and findings were thought to be consistent with an enchondroma, which is a benign lesion commonly seen in the hand. PMID- 26129762 TI - Iron as a source of color in river waters. AB - Organic chromophores of total organic carbon (TOC) and those of iron (Fe) contribute to the color of water, but the relative contributions of colored organic carbon (COC%) and Fe (Fe%) are poorly known. In this study, we unraveled Fe% and COC% in 6128 unfiltered water samples collected from 94 Finnish river sites of contrasting catchment properties. According to regression analysis focusing on TOC alone, on average 84% of the mean TOC consisted of COC, while 16% was non-colored or below the color-detection limit. COC and Fe were much more important sources of color than phytoplankton (chlorophyll a as a proxy) or non algal particles (suspended solids as a proxy). When COC and Fe were considered as the only two sources of color, COC% ranged from 16.8% to 99.5% (mean 71%) and Fe% from 0.5% to 83.2% (mean 29%). Similar Fe% and COC% values were obtained when color was estimated from the absorption coefficients of COC and Fe at 490 nm. Fe% increased as a function of the concentration of Fe and was well predicted by the TOC-to-Fe mass ratio. In 608 samples with TOC-to-Fe ratios of <4.5, Fe dominated the color. TOC-to-Fe ratios varied widely within most sites, but in relation to hydrology. In catchments with a peatland coverage of >30%, peak flow exported elevated amounts of TOC relative to Fe and resulted in a high COC%. Base flow, instead, mobilized elevated amounts Fe relative to TOC and resulted in a high Fe%. In a catchment covered with 31% of agricultural fields, peak flow transported eroded soil particles high in Fe and thus resulted in a high Fe%, while during base flow the water was high in COC%. This study demonstrated that Fe% and COC% vary widely in river water depending on the catchment properties and hydrology. PMID- 26129763 TI - The consequences of English language testing for international health professionals and students: An Australian case study. AB - AIM: To discuss the perceptions about the International English Language Testing System (IELTS) and its impact on migration and practice of migrant health professionals in Australia. METHODS: Thematic analysis of interviews with 14 health industry participants and 35 migrated health professionals in Australia. RESULTS AND DISCUSSION: Language testing is a barrier to health professional registration for migrant health workers in Australia. While two English language tests are recognised by the registration authorities in Australia, it is the International English Language Testing System that is most commonly used. This paper reports that study participants had underlying negative perceptions of the International English Language Testing System which they report, affect their move to Australia. These negative perceptions are caused by: frustration due to changes to processes for migration and registration; challenges regarding the structure of IELTS including timing of when test results expire, scoring requirements, cost, and suitability; and the resulting feelings of inadequacy caused by the test itself. CONCLUSION: This study has shown that some respondents have experienced difficulties in relation to the International English Language Testing System as part of their migration process. It was found that there is very little research into the effectiveness of the IELTS as it is currently administered for overseas health care professionals. Several recommendations are provided including areas for further research. PMID- 26129764 TI - Regular budding modes in a zooxanthellate dendrophylliid Turbinaria peltata (Scleractinia) revealed by X-ray CT imaging and three-dimensional reconstruction. AB - The zooxanthellate dendrophylliid coral, Turbinaria peltata (Scleractinia), exhibit various growth forms that increase the photoreception area through the development of coenosteum skeletons. Because it is difficult to make detailed observations of the internal structures, we visualized inner skeletal structures using nondestructive microfocus X-ray computed tomography (CT) imaging. After removal of the coenosteum skeletons from the X-ray CT images, three-dimensional 3D-models were reconstructed for individual corallites. Regular budding was observed from the 3D-model and cross-sectional images as follows: 1) lateral corallites occurred only near the two primary septa on one side, apart from a directive primary septum with distinct polarity; 2) the budding occurred upward at acute angles; and 3) these regular structures and polarity were repeated throughout growth with every generation. Even in zooxanthellate dendrophylliids, the same budding modes as observed in azooxanthellate equivalents control the colonial growth. These characteristics provide clues for understanding the mechanisms that regulate the shapes of modular marine organisms. PMID- 26129765 TI - Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin. AB - PURPOSE: Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. METHODS: A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP optimality. RESULTS: The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of concept study. CONCLUSIONS: This study shows that parsimonious adaptive DP optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study. PMID- 26129766 TI - Effect of siRNA pre-Exposure on Subsequent Response to siRNA Therapy. AB - PURPOSE: An alternative cancer therapy based on RNA interference (RNAi) has shown considerable promise but the possibility of resistance development is not known. This study explored the possibility of therapeutic resistance against siRNA nanoparticles in human cancer cells. METHODS: Two approaches to siRNA treatment were undertaken using lipid-modified polyethylenimines, a single high concentration (shock) and repeated increasing concentrations (gradual). The targets were Mcl-1, RPS6KA5 and KSP in MDA-MB-435 cells. RESULTS: There was no evidence of resistance development in shock-treated cells, while the decrease in mRNA levels of targeted proteins was not as robust in naive cells in gradual treatment. However, silencing efficiency was restored after a 7-day recovery period when expression of suppressed proteins returned to normal levels. Cellular uptake of siRNA was not affected by pre-treatments. Other mediators involved in cell survival and proliferation were altered in siRNA-treated cells, but only JUN silencing led to a heightened loss of viability. In vivo experiments demonstrated similar silencing efficiency at mRNA level after repeat doses. CONCLUSIONS: Human cancer cells responded to repeat siRNA nanoparticles in a similar fashion after a temporary initial alteration and little, if any, resistance was evident against repeated siRNA treatments. PMID- 26129767 TI - Evolutionary genomics of miniature inverted-repeat transposable elements (MITEs) in Brassica. AB - Miniature inverted-repeat transposable elements (MITEs) are truncated derivatives of autonomous DNA transposons, and are dispersed abundantly in most eukaryotic genomes. We aimed to characterize various MITEs families in Brassica in terms of their presence, sequence characteristics and evolutionary activity. Dot plot analyses involving comparison of homoeologous bacterial artificial chromosome (BAC) sequences allowed identification of 15 novel families of mobile MITEs. Of which, 5 were Stowaway-like with TA Target Site Duplications (TSDs), 4 Tourist like with TAA/TTA TSDs, 5 Mutator-like with 9-10 bp TSDs and 1 novel MITE (BoXMITE1) flanked by 3 bp TSDs. Our data suggested that there are about 30,000 MITE-related sequences in Brassica rapa and B. oleracea genomes. In situ hybridization showed one abundant family was dispersed in the A-genome, while another was located near 45S rDNA sites. PCR analysis using primers flanking sequences of MITE elements detected MITE insertion polymorphisms between and within the three Brassica (AA, BB, CC) genomes, with many insertions being specific to single genomes and others showing evidence of more recent evolutionary insertions. Our BAC sequence comparison strategy enables identification of evolutionarily active MITEs with no prior knowledge of MITE sequences. The details of MITE families reported in Brassica enable their identification, characterization and annotation. Insertion polymorphisms of MITEs and their transposition activity indicated important mechanism of genome evolution and diversification. MITE families derived from known Mariner, Harbinger and Mutator DNA transposons were discovered, as well as some novel structures. The identification of Brassica MITEs will have broad applications in Brassica genomics, breeding, hybridization and phylogeny through their use as DNA markers. PMID- 26129768 TI - Identification of suitable grapevine reference genes for qRT-PCR derived from heterologous species. AB - Identification and validation of suitable reference genes that exhibit robust transcriptional stability across many sample types is an absolute requirement of all qRT-PCR experiments. Often, however, only small numbers of reference genes, validated across limited sample types, are available for non-model species. This points to a clear need to assess and validate a wider range of potential reference genes than is currently available. We therefore looked to test and validate a large number of potential reference genes across a wide range of tissue types and treatments to determine the applicability of these reference genes for use in grapevine and other non-model plant species. Potential reference genes were selected based on stability of gene transcription in the model plant species Arabidopsis or due to their common use in the grapevine community. The selected reference genes were analyzed across two datasets consisting of a range of either 'Sauvignon blanc' or 'Pinot noir' tissues. A total of 11 potential reference genes were screened across the two datasets. Gene stability was analyzed by GeNorm, a widely used Excel application, or an ANOVA-based method developed in red clover. Both analysis methods showed that all 11 potential reference genes are stably expressed in the datasets tested, but the rankings of gene stability differed based on the datasets and analysis method used. Furthermore, the transcript stability of these genes, initially identified in Arabidopsis and now validated in grapevine, suggests applicability across a wide range of non-model plant species in addition to their utility in grapevine. PMID- 26129769 TI - Multimodal responses induced by cortical stimulation of the parietal lobe: a stereo-electroencephalography study. AB - The functional complexity of the parietal lobe still represents a challenge for neurophysiological and functional neuroimaging studies. While the somatosensory functions of the anterior parietal cortex are well established, the posterior parietal cortex has a relevant role in processing the sensory information, including visuo-spatial perception, visual attention, visuo-motor transformations and other complex and not completely understood functions. We retrospectively analysed all the clinical manifestations induced by intracerebral bipolar electrical stimulation in 172 patients suffering from drug-resistant focal epilepsy (mean age 25.6, standard deviation 11.6; 44% females and 56% males) with at least one electrode stereotactically implanted in the parietal cortex. A total of 1186 electrical stimulations were included in the analysis, of which 88 were subsequently excluded because of eliciting pathological electric activity or inducing ictal symptomatology. In the dominant parietal lobe, clinical responses were observed for 56 (25%) of the low-frequency stimulations and for 76 (50%) of the high-frequency stimulations. In the non-dominant parietal lobe, 111 (27%) low frequency and 176 (55%) high-frequency stimulations were associated with a clinical response. Body scheme alteration was the only clinical effect showing a lateralization, as they were evoked only in the non-dominant hemisphere. The occurrence of somatosensory sensations, motor symptoms, dysarthria and multimodal responses were significantly associated with stimulation of the postcentral gyrus (odds ratio: 5.83, P < 0.001; odds ratio: 8.77, P < 0.001; odds ratio: 5.44, P = 0.011; odds ratio: 8.33, P = 0.006; respectively). Stimulation of the intraparietal sulcus was associated with the occurrence of sensory illusions or hallucinations (odds ratio: 8.68, P < 0.001) and eyeball/eyelid movements or sensations (odds ratio: 4.35, P = 0.047). To our knowledge, this is the only currently available complete revision of electrical stimulation of the entire parietal cortex with the aim to evaluate the neurophysiology of this relevant brain region. Our analysis offers a general overview of the multiple roles of the parietal cortex and supports its crucial involvement in different networks related to complex integrative functions.media 1vid110.1093/brain/awv187_video_abstractawv187_video_abstract. PMID- 26129770 TI - Nanomedicine for the molecular diagnosis of cardiovascular pathologies. AB - Predicting acute clinical events caused by atherosclerotic plaque rupture remains a clinical challenge. Anatomic mapping of the vascular tree provided by standard imaging technologies is not always sufficient for a robust diagnosis. Yet biological mechanisms leading to unstable plaques have been identified and corresponding biomarkers have been described. Nanosystems charged with contrast agents and targeted towards these specific biomarkers have been developed for several types of imaging modalities. The first systems that have reached the clinic are ultrasmall superparamagnetic iron oxides for Magnetic Resonance Imaging. Their potential relies on their passive accumulation by predominant physiological mechanisms in rupture-prone plaques. Active targeting strategies are under development to improve their specificity and set up other types of nanoplatforms. Preclinical results show a huge potential of nanomedicine for cardiovascular diagnosis, as long as the safety of these nanosystems in the body is studied in depth. PMID- 26129771 TI - Changes in secondary structure of alpha-synuclein during oligomerization induced by reactive aldehydes. AB - The oxidative stress-related reactive aldehydes 4-hydroxy-2-nonenal (HNE) and 4 oxo-2-nonenal (ONE) have been shown to promote formation of alpha-synuclein oligomers in vitro. However, the changes in secondary structure of alpha synuclein and the kinetics of the oligomerization process are not known and were the focus of this study. Size exclusion chromatography showed that after 1 h of incubation, HNE induced the formation of an oligomeric alpha-synuclein peak with a molecular weight of about ~2000 kDa, which coincided with a decreasing ~50 kDa monomeric peak. With prolonged incubation (up to 24 h) the oligomeric peak became the dominating molecular species. In contrast, in the presence of ONE, a ~2000 oligomeric peak was exclusively observed after 15 min of incubation and this peak remained constant with prolonged incubation. Western blot analysis of HNE-induced alpha-synuclein oligomers showed the presence of monomers (15 kDa), SDS-resistant low molecular (30-160 kDa) and high molecular weight oligomers (>=260 kDa), indicating that the oligomers consisted of both covalent and non-covalent protein. In contrast, ONE-induced alpha-synuclein oligomers only migrated as covalent cross-linked high molecular-weight material (>=300 kDa). Both circular dichroism (CD) and Attenuated total reflectance Fourier transform infrared (ATR FTIR) spectroscopy showed that the formation of HNE- and ONE-induced oligomers coincided with a spectral change from random coil to beta-sheet. However, ONE induced alpha-synuclein oligomers exhibited a slightly higher degree of beta sheet. Taken together, our results indicate that both HNE and ONE induce a change from random coil to beta-sheet structure that coincides with the formation of alpha-synuclein oligomers; albeit through different kinetic pathways depending on the degree of cross-linking. PMID- 26129772 TI - Cu(II) promotes amyloid pore formation. AB - The aggregation of alpha-synuclein is associated with dopamine neuron death in Parkinson's disease. There is controversy in the field over the question of which species of the aggregates, fibrils or protofibrils, are toxic. Moreover, compelling evidence suggested the exposure to heavy metals to be a risk of PD. Nevertheless, the mechanism of metal ions in promoting PD remains unclear. In this research, we investigated the structural basis of Cu(II) induced aggregation of alpha-synuclein. Using transmission electron microscopy experiments, Cu(II) was found to promote in vitro aggregation of alpha-synuclein by facilitating annular protofibril formation rather than fibril formation. Furthermore, neuroprotective baicalein disaggregated annular protofibrils accompanied by considerable decrease of beta-sheet content. These results strongly support the hypothesis that annular protofibrils are the toxic species, rather than fibrils, thereby inspiring us to search novel therapeutic strategies for the suppression of the toxic annular protofibril formation. PMID- 26129773 TI - Multifunctional carbon nanomaterial hybrids for magnetic manipulation and targeting. AB - Nanosized materials and multifunctional nanoscale platforms have attracted in the last years considerable interest in a variety of different fields including biomedicine. Carbon nanotubes and graphene are some of the most widely used carbon nanomaterials (CNMs) due to their unique morphology and structure and their characteristic physicochemical properties. Their high surface area allows efficient drug loading and bioconjugation and makes them the ideal platforms for decoration with magnetic nanoparticles (MNPs). In the biomedical area, MNPs are of particular importance due to their broad range of potential applications in drug delivery, non-invasive tumor imaging and early detection based on their optical and magnetic properties. The remarkable characteristics of CNMs and MNPs can be combined leading to CNM/MNP hybrids which offer numerous promising, desirable and strikingly advantageous properties for improved performance in comparison to the use of either material alone. In this minireview, we attempt to comprehensively report the most recent advances made with CNMs conjugated to different types of MNPs for magnetic targeting, magnetic manipulation, capture and separation of cells towards development of magnetic carbon-based devices. PMID- 26129774 TI - Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function. AB - Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase(-/-) mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase(-/-) mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase(-/-) mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. PMID- 26129775 TI - High performance of combined HPV testing and genotyping for HPV16/18/52/58 in triaging women with minor cervical cytological abnormalities in northern Thailand. AB - Human papillomavirus (HPV) infection is an important cause of cervical cancer. Screening with cytology or combined cytology and HPV testing helps to detect early cervical cancers and precancerous lesions (high-grade squamous intraepithelial lesion or worse [HSIL+]). Minor cytological abnormalities (atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) account for the majority of abnormal cervical cytology results, but only 10-20% of women with minor cytological abnormalities have histologic HSIL+. Triage tests are useful to identify the high-risk patients and reduce the colposcopy burden. This study was aimed to evaluate the triage performance of combined HPV DNA testing and genotyping. Cervical samples from women with minor cytological abnormalities, who underwent colposcopy at Chiang Mai University Hospital in northern Thailand between October 2010 and February 2014, were tested for HPV DNA using Hybrid Capture 2 (HC2). Genotyping was performed using Linear Array assay. Of 223 women with cervical histology confirmation, histologic HSIL+ was detected in 25 women (11.2%). The sensitivity, specificity, positive predictive value, and negative predictive value of 3 triage methods for histologic HSIL+ were; 100%, 47.5%, 19.4%, and 100% by HC2 only; 40.0%, 88.4%, 30.3%, and 92.1% by combined HC2 and genotypes HPV16/18; and 96.0%, 75.8%, 33.3%, and 99.3% by combined HC2 and genotypes HPV16/18/52/58. Triage using combined HC2 and genotypes HPV16/18/52/58 showed significantly greater area under the receiver operating curve than the other 2 methods (P < 0.001). Combined HPV DNA testing and genotyping for HPV16/18/52/58 is useful for triaging women with minor cervical cytological abnormalities in northern Thailand. PMID- 26129777 TI - Heritability of attention-deficit hyperactivity disorder in adults. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Symptoms often persist into adulthood, with a prevalence of 2.5-5% in adult populations. Twin studies in childhood consistently report high heritabilities of 70-80%, while studies in adult samples show only moderate heritability of 30-40% when estimated from self-ratings. This review summarizes the available research on the heritability of ADHD in adults. Three key findings are outlined: (i) self-ratings lead to relatively low heritability estimates of ADHD, independent of age and whether ratings refer to current or retrospective symptoms; (ii) studies relying on different informants to rate each twin within a pair (i.e., self-ratings and different parents/teachers rating each twin in a pair) consistently yield lower heritability estimates than studies relying on ratings from a single informant; (iii) studies using cross-informant data via either combined parent and self-ratings or clinical diagnoses information suggest that the heritability of ADHD in adults could be as high as 70-80%. Together, the reviewed studies suggest that the previously reported low heritability of ADHD in adults is unlikely to reflect a true developmental change. Instead, the drop in heritability is better explained by rater effects related to a switch from using one rater for both twins in a pair (parent/teacher) in childhood, to relying on self-ratings (where each twin rates themselves) of ADHD symptoms in adulthood. When rater effects are addressed using cross-informant approaches, the heritability of ADHD in adults appears to be comparable to the heritability of ADHD in childhood. (c) 2015 Wiley Periodicals, Inc. PMID- 26129776 TI - Beta-cell regeneration from vimentin+/MafB+ cells after STZ-induced extreme beta cell ablation. AB - Loss of functional beta-cells is fundamental in both type 1 and type 2 diabetes. In situ beta-cell regeneration therefore has garnered great interest as an approach to diabetes therapy. Here, after elimination of pre-existing beta cells by a single high-dose of streptozotocin (STZ), we demonstrated that a considerable amount of beta-like-cells was generated within 48 hrs. But the newly formed insulin producing cells failed to respond to glucose challenge at this time and diminished afterwards. Insulin treatment to normalize the glucose level protected the neogenic beta-like cells and the islet function was also gradually matured. Strikingly, intermediate cells lacking epithelial marker E-cadherin but expressing mesenchymal cell-specific marker vimentin appeared within 16 hrs following STZ exposure, which served as the major source of insulin-producing cells observed at 24 hrs. Moreover, these intermediate cells strongly expressed alpha-cell-specific marker MafB. In summary, the data presented here identified a novel intermediate cell type as beta-cell progenitors, showing mesenchymal cell feature as well as alpha-cell marker MafB. Our results might have important implications for efforts to stimulate beta-cell regeneration. PMID- 26129778 TI - SCARECROW-LIKE15 interacts with HISTONE DEACETYLASE19 and is essential for repressing the seed maturation programme. AB - Epigenetic regulation of gene expression is critical for controlling embryonic properties during the embryo-to-seedling phase transition. Here we report that a histone deacetylase19 (HDA19)-associated regulator, scarecrow-like15 (SCL15), is essential for repressing the seed maturation programme in vegetative tissues. SCL15 is expressed in and GFP-tagged SCL15 predominantly localizes to, the vascular bundles particularly in the phloem companion cells and neighbouring specialized cells. Mutation of SCL15 leads to a global shift in gene expression in seedlings to a profile resembling late embryogenesis in seeds. In scl15 seedlings, many genes involved in seed maturation are markedly derepressed with concomitant accumulation of seed 12S globulin; this is correlated with elevated levels of histone acetylation at a subset of seed-specific loci. SCL15 physically interacts with HDA19 and direct targets of HDA19-SCL15 association are identified. These studies reveal that SCL15 acts as an HDA19-associated regulator to repress embryonic traits in seedlings. PMID- 26129779 TI - Medical School Experiences Associated with Change in Implicit Racial Bias Among 3547 Students: A Medical Student CHANGES Study Report. AB - BACKGROUND: Physician implicit (unconscious, automatic) bias has been shown to contribute to racial disparities in medical care. The impact of medical education on implicit racial bias is unknown. OBJECTIVE: To examine the association between change in student implicit racial bias towards African Americans and student reports on their experiences with 1) formal curricula related to disparities in health and health care, cultural competence, and/or minority health; 2) informal curricula including racial climate and role model behavior; and 3) the amount and favorability of interracial contact during school. DESIGN: Prospective observational study involving Web-based questionnaires administered during first (2010) and last (2014) semesters of medical school. PARTICIPANTS: A total of 3547 students from a stratified random sample of 49 U.S. medical schools. MAIN OUTCOME(S) AND MEASURE(S): Change in implicit racial attitudes as assessed by the Black-White Implicit Association Test administered during the first semester and again during the last semester of medical school. KEY RESULTS: In multivariable modeling, having completed the Black-White Implicit Association Test during medical school remained a statistically significant predictor of decreased implicit racial bias (-5.34, p <= 0.001: mixed effects regression with random intercept across schools). Students' self-assessed skills regarding providing care to African American patients had a borderline association with decreased implicit racial bias (-2.18, p = 0.056). Having heard negative comments from attending physicians or residents about African American patients (3.17, p = 0.026) and having had unfavorable vs. very favorable contact with African American physicians (18.79, p = 0.003) were statistically significant predictors of increased implicit racial bias. CONCLUSIONS: Medical school experiences in all three domains were independently associated with change in student implicit racial attitudes. These findings are notable given that even small differences in implicit racial attitudes have been shown to affect behavior and that implicit attitudes are developed over a long period of repeated exposure and are difficult to change. PMID- 26129781 TI - Varying Charges and Questionable Costs. PMID- 26129780 TI - Provider Attitudes and Screening Practices Following Changes in Breast and Cervical Cancer Screening Guidelines. AB - BACKGROUND: Changes to national guidelines for breast and cervical cancer screening have created confusion and controversy for women and their primary care providers. OBJECTIVE: To characterize women's primary health care provider attitudes towards screening and changes in practice in response to recent revisions in guidelines for breast and cervical cancer screening. DESIGN, SETTING, PARTICIPANTS: In 2014, we distributed a confidential web and mail survey to 668 women's health care providers affiliated with the four clinical care networks participating in the three PROSPR (Population-based Research Optimizing Screening through Personalized Regimens) consortium breast cancer research centers (385 respondents; response rate 57.6 %). MAIN MEASURES: We assessed self reported attitudes toward breast and cervical cancer screening, as well as practice changes in response to the most recent revisions of the U.S. Preventive Services Task Force (USPSTF) recommendations. KEY RESULTS: The majority of providers believed that mammography screening was effective for reducing cancer mortality among women ages 40-74 years, and that Papanicolaou (Pap) testing was very effective for women ages 21-64 years. While the USPSTF breast and cervical cancer screening recommendations were widely perceived by the respondents as influential, 75.7 and 41.2 % of providers (for mammography and cervical cancer screening, respectively) reported screening practices in excess of those recommended by USPSTF. Provider-reported barriers to concordance with guideline recommendations included: patient concerns (74 and 36 % for breast and cervical, respectively), provider disagreement with the recommendations (50 and 14 %), health system measurement of a provider's screening practices that use conflicting measurement criteria (40 and 21 %), concern about malpractice risk (33 and 11 %), and lack of time to discuss the benefits and harms with their patients (17 and 8 %). CONCLUSIONS: Primary care providers do not consistently follow recent USPSTF breast and cervical cancer screening recommendations, despite noting that these guidelines are influential. PMID- 26129782 TI - Capsule Commentary on Jones et al., Usual Primary Care Provider Characteristics of a Patient-Centered Medical Home and Mental Health Service Use. PMID- 26129784 TI - Occurrence and distribution of phosphorus fractions in sediments of Liangzi Lake under typical hydrodynamic conditions. AB - Understanding the transformation and chronological accumulation of phosphorus (P) forms under typical hydrodynamic conditions of a lake is important for clarifying the process of lake evolution and eutrophication. The occurrence and distribution of sediment P fractions (total, TP; inorganic, IP; and organic, OP), phytate content, and phytase activity at different profile depths (0-8 m) and parent material ages (0.8-11 ka BP) were examined at different ecological locations (inlet, outlet, and center) of the freshwater Liangzi Lake in Hubei Province, China. Sediment P-forms at locations of different hydrodynamic conditions increased from the inlet to the outlet. IP constituted ~40-71% of TP, whereas the OP content was generally lower in the sediment. The two forms of IP extracted by HCl and NaOH varied quantitatively with depth and location: HCl-P ~ NaOH-P (above 0.8 m) or HCl-P > NaOH-P (below 0.8 m) at the inlet; HCl-P > NaOH-P (above 0.8 m) and HCl-P ~ NaOH-P (below 0.8 m) at the outlet; and HCl-P < NaOH-P at the center of the lake. Compared with labile and moderately resistant OP, moderately labile OP exhibited substantial quantitative changes and occurred at high levels. The variation trend in the phytate content coincided with that of TP, whereas phytase activity varied inversely with location. Low levels of P forms occurred in the sediment below 4.5 m and before 8.6 ka BP, consistent with the oligotrophic period of the lake. During 2-4 ka BP, the P forms first increased rapidly and then stabilized thereafter. From that time period until modern times, TP and phytate increased, whereas IP and OP decreased significantly. The results indicate that the hydrodynamic conditions of the water bodies and the sediments of different ages strongly influenced the occurrence and distribution of sediment P forms, and the sediment TP and phytate contents would be candidate indices to reflect the P input and eutrophication history of freshwater lakes. PMID- 26129785 TI - The changing global face of Bluetongue: from the beginning. AB - Bluetongue (BT) was first recognized and described in Southern Africa, and only later elsewhere. It is now known that the causative agent of BT [BT virus (BTV)] occurs throughout temperate and tropical regions of the world. Previous OIE symposia in 1984, 1991 and 2003 clarified the global distribution of BTV and its epidemiology, pathogenesis, and diagnosis. Since the 3rd symposium in 2003, however, there have been significant developments. Notably, BT has emerged in Northern Europe and novel BTV serotypes have appeared in other endemic areas raising substantial questions regarding the environmental and anthropogenic drivers of emergence of BTV, including the invasion and spread of laboratory propagated viruses. Additional BTV serotypes with novel properties have recently been identified in Europe and the Middle East. Recent studies also confirm the importance of the Culicoides vector as the essential overwintering reservoir of BTV in temperate regions such as California and not ruminant livestock, proving wrong the prevailing thesis circulated prior to the 1st symposium in 1984. The challenge for participants of this 4th symposium is to predict collectively what the future might hold in terms of emergence of BTV globally, and what strategies are likely to be most feasible, justified, and effective for its control. PMID- 26129786 TI - Benefits of PCR and decentralization of diagnosis in regional laboratories in the management of Bluetongue in France. AB - Since 1998, Bluetongue virus (BTV) serotypes 1, 2, 4, 6, 8, 9, 11 and 16 have spread throughout Europe. In 2006, BTV serotype 8 (BTV-8) emerged unexpectedly in Northern Europe, in countries such as Belgium, France, Germany, Luxembourg, and the Netherlands, to spread rapidly in the following year throughout the rest of Europe. In 2007, BTV-1 spread in Southern Europe, in Spain and in South of France. In 2008, 2 more BTV serotypes were detected in Northern Europe: BTV-6 in the Netherlands and in Germany, and BTV-11 in Belgium. The European incursion of BTV has caused considerable economic losses, including direct losses from mortality and reduced production, as well as indirect losses generated by ensuing bans on trade of ruminants between infected and non-infected areas. Given the significance of the disease, all affected countries have established control and eradication measures that have evolved together with the availability of detection and prevention tools such as Polymerase Chain Reaction (PCR) tests and vaccines, respectively. This paper describes how the French National Reference Laboratory for BT has managed diagnosis during the fast and massive spread of BTV 1 and 8 in 2007 and 2008. PMID- 26129787 TI - Comparison of the anterior and posterior mitral isthmus ablation lines in patients with perimitral annulus flutter or persistent atrial fibrillation. AB - BACKGROUND: Catheter ablation of left atrial linear lesions is an effective treatment option for perimitral flutter and is often used as a substrate modification approach for persistent atrial fibrillation. The two most popular mitral isthmus lines are those of the anterior or the posterior mitral isthmus. A comparison of these two mitral isthmus ablation approaches is still pending. METHODS: Patients undergoing catheter ablation either at the anterior or the posterior mitral isthmus were included. Procedural success, conduction block, procedure durations, complications, and the necessity of a coronary sinus ablation were analyzed. RESULTS: We investigated 80 consecutive patients, 40 (50%) with an anterior and 40 (50%) with a posterior mitral isthmus line. Twenty (25.0%) patients had perimitral annulus flutter; the remainder of the patients had persistent atrial fibrillation. Bidirectional conduction block was achieved in the same proportion in the anterior group (36; 90.0%) as it was in the posterior group (30; 75.0%) (statistically insignificant). Duration of procedure (18 +/- 12 vs. 34 +/- 24 min, p = 0.001), radiofrequency application (11 +/- 7 vs. 18 +/- 11 min, p = 0.004), and fluoroscopy (2 +/- 2 vs. 8 +/- 8 min, p < 0.001) values were all significantly lower in the anterior group. Only patients in the posterior line group had to be ablated via the coronary sinus 24 (60.0 %). CONCLUSIONS: Ablation at the anterior mitral isthmus shows the same success rate as the posterior mitral isthmus does. Catheter ablation at the anterior mitral isthmus is associated with significantly shorter procedure durations without the need of a coronary sinus ablation. PMID- 26129788 TI - Non-pharmacological interventions for attention-deficit/hyperactivity disorder (ADHD) delivered in school settings: systematic reviews of quantitative and qualitative research. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by age-inappropriate levels of inattention, impulsivity and hyperactivity. School can be particularly challenging for children with ADHD. Few reviews have considered non pharmacological interventions in school settings. OBJECTIVES: To assess the effectiveness of non-pharmacological interventions delivered in school settings for pupils with, or at risk of, ADHD and to explore the factors that may enhance, or limit, their delivery. DATA SOURCES: Twenty electronic databases (including PsycINFO, MEDLINE, EMBASE, Education Resources Information Centre, The Cochrane Library and Education Research Complete) were searched from 1980 to February August 2013. Three separate searches were conducted for four systematic reviews; they were supplemented with forward and backwards citation chasing, website searching, author recommendations and hand-searches of key journals. REVIEW METHODS: The systematic reviews focused on (1) the effectiveness of school-based interventions for children with or at risk of ADHD; (2) quantitative research that explores attitudes towards school-based non-pharmacological interventions for pupils with ADHD; (3) qualitative research investigating the attitudes and experiences of children, teachers, parents and others using ADHD interventions in school settings; and (4) qualitative research exploring the experience of ADHD in school among pupils, their parents and teachers more generally. Methods of synthesis included a random-effects meta-analysis, meta-regression and narrative synthesis for review 1, narrative synthesis for review 2 and meta-ethnography and thematic analysis for reviews 3 and 4. RESULTS: For review 1, 54 controlled trials met the inclusion criteria. For the 36 meta-analysed randomised controlled trials, beneficial effects (p < 0.05) were observed for several symptom and scholastic outcomes. Mean weighted effect sizes ranged from very small (d + < 0.20) to large (d + >= 0.80), but substantial heterogeneity in effect size estimates across studies was reported. Moderator analyses were not able to clarify which intervention features were linked with effectiveness. For review 2, 28 included studies revealed that educators' attitudes towards interventions ranged in positivity. Most interventions were rated positively or neutrally across different studies. The only intervention that consistently recorded positive attitudes from educators was daily report cards. For review 3, 33 studies met the inclusion criteria. Key findings included tensions regarding the preferred format of interventions, particularly how structured interventions were and the extent to which they are tailored to the child with ADHD. There were mixed views about the impact of interventions, although it was clear that interventions both influence and are influenced by the relationships held by children with ADHD and participants' attitudes towards school and ADHD. For review 4, 34 studies met the inclusion criteria. Key findings included the importance of causal attributions that teachers, parents and pupils made about ADHD symptoms, the decisions teachers made about treatment, the self-perceptions pupils developed about themselves, the role of the classroom environment and stigma in aggravating ADHD symptoms, and the significant barrier to treatment posed by the common presence of conflict in relationships between pupils teachers, parents-teachers and pupils-peers in relation to ADHD. An overarching synthesis of the four reviews highlighted the importance of the context affecting interventions. It suggested that ADHD psychoeducation and relationship-building skills are potential implications for interventions. LIMITATIONS: The breadth of both interventions and outcomes in the reviewed studies presented a challenge for categorisation, analysis and interpretation in reviews 1-3. Across reviews, relatively few studies were conducted in the UK, limiting the applicability of findings to UK education. In reviews 1 and 2, the poor methodological quality of some included studies was identified as a barrier to establishing effectiveness or comparing attitudes. In review 3 the descriptive analysis used by the majority of studies constrained theorising during synthesis. Studies in review 4 lacked detail regarding important issues like gender, pupil maturity and school level. CONCLUSION: Findings suggest some beneficial effects of non-pharmacological interventions for ADHD used in school settings, but substantial heterogeneity in effect sizes was seen across studies. The qualitative reviews demonstrate the importance of the context in which interventions are used. Future work should consider more rigorous evaluation of interventions, as well as focus on what works, for whom and in which contexts. Gaps in current research present opportunities for the development and testing of standardised tools to describe interventions, agreement on gold-standard outcome measures assessing ADHD behaviour and testing a range of potential moderators alongside intervention trials. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001716. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 26129789 TI - Assessing the relative efficacy of new drugs: an emerging opportunity. AB - The increasing availability of individual-level data from clinical trials could allow the relative efficacy of new drugs to be assessed in a robust, cost effective and timely way. PMID- 26129790 TI - A beta-lactamase inhibitor revival provides new hope for old antibiotics. PMID- 26129791 TI - The NASH drug dash. PMID- 26129795 TI - Moncef Slaoui. PMID- 26129796 TI - Cancer: LOX does some prepping. PMID- 26129800 TI - Fibrotic diseases: New tools to target an elusive integrin. PMID- 26129804 TI - [Finger or thumb sucking. New interpretations and therapeutic implications]. AB - AIM: Finger sucking is frequently found in children and sometimes in adults too. Often reasons are found to explain why certain children feel the need to suck their thumbs or fingers, but these explanations are always derived from clinical observation without any rational support, searching for motives for this bad habit from family life; strict parents, jealousy at the birth of a sibling, difficulty accepting the end of breastfeeding etc. Some think that a child should continue to suck after actual nutrition has ended and the substitution of the mother's nipple with a thumb or finger could fill this need. Research however, using anatomical and neurophysiological data, explains why an infant forms the habit of thumb sucking from a neurological standpoint abandoning the psychological explanations proposed until now. METHODS: Forty thumb-sucking subjects with ages ranging from 5 to 25 years and a control group of 20 non-thumb sucking subjects with correct swallowing patterns were analyzed evaluating postural and neurological effects of thumb sucking. Instruments used for this evaluation were a device for electromyography to measure the muscular tone and a baropodometer, stabilometer and a scoliosometer to analyse posture. RESULTS: Analyzed subjects had an evident improvement at the baropodometer and stabilometer and a scoliosometer examination to analyze posture and at the electromyography analysis. CONCLUSION: The results obtained confirm that a thumb sucking subject puts the thumb in the mouth to stimulate the nasal-palatal receptors of trigeminus and obtain muscular balance and a release of physical and psychological tension. PMID- 26129803 TI - Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells. AB - BACKGROUND: CD83, a cell surface glycoprotein that is stably expressed on mature dendritic cells, can be transiently induced on other hematopoietic cell lineages upon cell activation. In contrast to the membrane form of CD83, soluble CD83 appears to be immunosuppressive. In an analysis of the phenotype of leukemic CD4(+) T cells from patients with adult T-cell leukemia (ATL), we found that a number of primary CD4(+) T cells became positive for cell surface CD83 after short-term culture, and that most of these CD83(+) CD4(+) T cells were positive for human T-cell leukemia virus type-I (HTLV-I) Tax (Tax1). We hypothesized that Tax1 is involved in the induction of CD83. RESULT: We found that CD83 was expressed selectively on Tax1-expressing human CD4(+) T cells in short-term cultured peripheral blood mononuclear cells (PBMCs) isolated from HTLV-I(+) donors, including ATL patients and HTLV-I carriers. HTLV-I-infected T cell lines expressing Tax1 also expressed cell surface CD83 and released soluble CD83. CD83 can be expressed in the JPX-9 cell line by cadmium-mediated Tax1 induction and in Jurkat cells or PBMCs by Tax1 introduction via infection with a recombinant adenovirus carrying the Tax1 gene. The CD83 promoter was activated by Tax1 in an NF-kappaB-dependent manner. Based on a previous report showing soluble CD83 mediated prostaglandin E2 (PGE2) production from human monocytes in vitro, we tested if PGE2 affected HTLV-I propagation, and found that PGE2 strongly stimulated expression of Tax1 and viral structural molecules. CONCLUSIONS: Our results suggest that HTLV-I induces CD83 expression on T cells via Tax1 -mediated NF-kappaB activation, which may promote HTLV-I infection in vivo. PMID- 26129805 TI - Autism spectrum disorder in Kabuki syndrome: clinical, diagnostic and rehabilitative aspects assessed through the presentation of three cases. AB - Kabuki syndrome (KS) (Kabuki make-up syndrome, Niikawa-Kuroki syndrome) is a rare genetic disorder first diagnosed in 1981. Kabuki make-up syndrome (KMS) is a multiple malformation/intellectual disability syndrome that was first described in Japan but is now reported in many other ethnic groups. KMS is characterized by multiple congenital abnormalities: craniofacial, skeletal, and dermatoglyphic abnormalities; intellectual disability; and short stature. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. The KS is associated with mutations in the MLL2 gene in some cases were also observed deletions of KDM6A. This study describes three children with autism spectrum disorders (ASDs) and KS and rehabilitative intervention that must be implemented. PMID- 26129806 TI - Relationships among HLA-DRB1 Alleles, Helicobacter pylori infection and idiopathic thrombocytopenic purpura in children. PMID- 26129802 TI - The pharmacology of second-generation chimeric antigen receptors. AB - Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging. PMID- 26129807 TI - Watery diarrhea-hypopotassemia-acidosis syndrome like diarrhea in a case with X linked lissencephaly with abnormal genitalia. PMID- 26129808 TI - COMPARISON OF TWO COARSE FRACTIONATED RADIATION PROTOCOLS FOR THE MANAGEMENT OF CANINE PITUITARY MACROTUMOR: AN OBSERVATIONAL STUDY OF 24 DOGS. AB - Radiotherapy is a commonly used treatment for pituitary macrotumors in dogs, but the optimum protocol has not been established. Twenty four dogs with MRI confirmed pituitary macrotumors were treated with one of two radiotherapy protocols. Twelve dogs were treated with 10 fractions of 3.8 Gy/fraction on a "Monday-Wednesday-Friday" schedule, the remaining 12 with five "once-a-week" protocols (1 * 5 Gy, followed by 4 * 8.25 Gy) to a total dose of 38 Gy. The overall median survival time for all dogs was 235 days (range 28-1,328), dogs treated with 10 fractions had a median survival time of 961 days (range 28-1,328) compared to 182 days (range 42-507) in the five-fraction group (P = 0.006). Clinical improvement was found in both groups, and no significant side effects were noted in either group. These results suggest that a "Monday-Wednesday Friday" schedule may improve survival times, as compared to a "once-a-week" protocol. As this study was of an observational nonrandomized nature, future work is necessary to establish whether more highly fractionated protocols or different total doses will further improve outcome. PMID- 26129810 TI - A Systematic Review of Studies Evaluating the Cost Utility of Screening High-Risk Populations for Latent Tuberculosis Infection. AB - BACKGROUND: As tuberculosis screening trends to targeting high-risk populations, knowing the cost effectiveness of such screening is vital to decision makers. OBJECTIVES: The purpose of this review was to compile cost-utility analyses evaluating latent tuberculosis infection (LTBI) screening in high-risk populations that used quality-adjusted life-years (QALYs) as their measure of effectiveness. DATA SOURCES: A literature search of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Web of Knowledge, and PubMed was performed from database start to November 2014. INCLUSION CRITERIA: Studies performed in populations at high risk of LTBI and subsequent reactivation that used the QALY as an effectiveness measure were included. STUDY APPRAISAL AND SYNTHESIS: Quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Data extracted included tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) use, economic, screening, treatment, health state, and epidemiologic parameters. Data were summarized in regard to consistency in model parameters and the incremental cost-effectiveness ratio (ICER), with costs adjusted to 2013 US dollars. RESULTS: Of 415 studies identified, ultimately eight studies were included in the review. Most took a societal perspective (n = 4), used lifetime time horizons (n = 6), and used Markov models (n = 8). Screening of adult immigrants was found to be cost effective with a TST in one study, but moderately cost effective with an IGRA in another study; screening immigrants arriving more than 5 years prior with an IGRA was moderately cost effective until 44 years of age (n = 1). Screening HIV positive patients was highly cost effective with a TST (n = 1) and moderately cost effective with an IGRA (n = 1). Screening in those with renal diseases (n = 2) and diabetes (n = 1) was not cost effective. LIMITATIONS: Very few studies used the QALY as their effectiveness measure. Parameter and study design inconsistencies limit the comparability of studies. CONCLUSIONS: With validity issues in terms of parameters and assumptions, any conclusion should be interpreted with caution. Despite this, some cautionary recommendations emerged: screening HIV patients with a TST is highly cost effective, while screening adult immigrants with an IGRA is moderately cost effective. PMID- 26129809 TI - Is the supine position associated with loss of airway patency in unconscious trauma patients? A systematic review and meta-analysis. AB - BACKGROUND: Airway compromise is a leading cause of death in unconscious trauma patients. Although endotracheal intubation is regarded as the gold standard treatment, most prehospital providers are not trained to perform ETI in such patients. Therefore, various lateral positions are advocated for unconscious patients, but their use remains controversial in trauma patients. We conducted a systematic review to investigate whether the supine position is associated with loss of airway patency compared to the lateral position. METHODS: The review protocol was published in the PROSPERO database (Reg. no. CRD42012001190). We performed literature searches in PubMed, Medline, EMBASE, Cochrane Library, CINAHL and British Nursing Index and included studies related to airway patency, reduced level of consciousness and patient position. We conducted meta-analyses, where appropriate. We graded the quality of evidence with the GRADE methodology. The search was updated in June 2014. RESULTS: We identified 1,306 publications, 39 of which were included for further analysis. Sixteen of these publications were included in meta-analysis. We did not identify any studies reporting direct outcome measures (mortality or morbidity) related to airway compromise caused by the patient position (lateral vs. supine position) in trauma patients or in any other patient group. In studies reporting only indirect outcome measures, we found moderate evidence of reduced airway patency in the supine vs. the lateral position, which was measured by the apnea/hypopnea index (AHI). For other indirect outcomes, we only found low or very low quality evidence. CONCLUSIONS: Although concerns other than airway patency may influence how a trauma patient is positioned, our systematic review provides evidence supporting the long held recommendation that unconscious trauma patients should be placed in a lateral position. PMID- 26129811 TI - Mental health in the Solomon Islands: developing reforms and partnerships. AB - OBJECTIVES: The Solomon Islands face significant shortages and geographical imbalances in the distribution of skilled health workers and resources, which severely impact the delivery of mental health services. The government's Integrated Mental Health Service has emphasised the importance of greater community ownership and involvement in community-based mental health care, and of moving from centralised services to increased local and accessible care. METHODS: From 2012 to 2014, the Solomon Islands Integrated Mental Health service worked with Asia-Australia Mental Health to build workforce capacity and deliver sustainable community mental health programs. RESULTS: Supported by the Australian Aid Program's Public Sector Linkages Program, this project shared resources and fostered links between public sector agencies in Australia, Fiji and the Solomon Islands. CONCLUSIONS: Key learning points from the collaboration included the critical need to establish partnerships with community stakeholders, the importance of sustaining a well-functioning mental health team, and optimising the strengths of the local resources in the Solomon Islands. Through this project, national policies, promotion and service delivery were strengthened, through the exchange of experiences and mobilisation of north-south (Australia-Solomon Islands) and south-south (Solomon Islands-other Pacific nations) technical expertise. This project demonstrates the potential for international partnerships to contribute to the development of culturally appropriate and integrated mental health services. PMID- 26129812 TI - Implementing music therapy on an adolescent inpatient unit: a mixed-methods evaluation of acceptability, experience of participation and perceived impact. AB - OBJECTIVE: We aimed to assess the feasibility of delivering a music therapy program on adolescent psychiatric wards. METHOD: We undertook a mixed-methods evaluation of a pilot program. Various active and receptive techniques were employed in group music therapy sessions delivered as part of a structured clinical program. Data collected in interviews with participants and staff and feedback questionnaires were thematically and descriptively analysed and triangulated. RESULTS: Data from 62 questionnaires returned by 43 patients who took part in 16 music therapy sessions, and seven staff, evidenced strong support for music therapy. Patients typically reported experiencing sessions as relaxing, comforting, uplifting, and empowering; >90% would participate by choice and use music therapeutically in the future. Staff endorsed music therapy as valuable therapeutically, reporting that patients engaged enthusiastically and identified sessions as improving their own moods and ward milieu. CONCLUSIONS: Integration of music therapy in inpatient treatment of adolescents is feasible and acceptable, and is valued by staff and patients as a complement to 'talking therapies'. Participation is enjoyed and associated with outcomes including improvement in mood, expression of feelings and social engagement consistent with recovery. PMID- 26129813 TI - No duty owed to the relatives of a victim of a person with mental illness. AB - OBJECTIVE: To review the case of an acutely psychotic person who was discharged into the care of a friend whom he killed later the same day, and to consider the reasoning of the High Court in the subsequent negligence action of the victim's relatives. CONCLUSIONS: By a narrow interpretation, the High Court found that the exercise of the powers and duties in relation to the involuntary detention of a mentally ill person as prescribed by the Mental Health Act were inconsistent with a common law duty of care to another person or the relatives of another person. PMID- 26129814 TI - Reflections on Aboriginal perinatal mental health, mothers, babies, families and community: A South Australian trainee's experience. AB - OBJECTIVE: This paper explores novel training opportunities that the Expanded Setting Training Program (ESTP) provides for advanced psychiatry trainees. It is a reflection of a trainee's learning experiences during a year-long posting in Aboriginal Perinatal Mental Health, working alongside the Aboriginal Family Birthing Program, coupled with reflection and supervision. CONCLUSIONS: ESTP provided a fertile area to hone an advanced trainee's skills in the niche areas of Aboriginal mental health, perinatal mental health, culture and psychiatry. In addition, it provided skills in the area of leadership, health advocacy and the establishment and maintenance of successful programs in disadvantaged, culturally and linguistically diverse communities. The ESTP Aboriginal Mental Health rotation provides a unique experience for training, and the learning opportunities are limited only by the creativity of the trainee and supervisor. PMID- 26129815 TI - Educating for diversity: an evaluation of a sexuality diversity workshop to address secondary school bullying. AB - OBJECTIVE: To evaluate the potential of a 60-minute sexuality diversity workshop to address bullying in secondary schools. METHODS: Students completed pre- and post-workshop questionnaires. Descriptive statistics were used to summarise results with pre- to immediate post-workshop changes compared using t-tests. Thematic analysis was used to analyse open-ended questionnaire responses. RESULTS: We had 229 students (mean age 13.7 years) attending 10 workshops participate in the study. Three-quarters of students thought the workshop would reduce bullying in schools, and over 95% of the participants thought that other secondary schools should offer the workshop. There was a significant increase in valuing (p < 0.001) and understanding (p < 0.001) sexuality-diverse individuals (e.g. lesbian, gay and bisexual people), between the pre- and post-workshop results. School climates were largely perceived to be 'hard' and included 'bullying/mocking' of sexuality-diverse students; however, many individual students reported a desire to be supportive of their sexuality-diverse peers. CONCLUSIONS: Sexuality-based bullying is commonplace in secondary schools. This form of bullying is associated with depression and suicide attempts. Reducing sexuality-based bullying is very likely to have a positive impact on the mental health of young people. Brief workshops, as a part of a wider suite of interventions, have some potential to create safer school environments. PMID- 26129816 TI - Can understanding the neurobiology of body dysmorphic disorder (BDD) inform treatment? AB - OBJECTIVES: We aim to provide a clinically focused review of the neurobiological literature in body dysmorphic disorder (BDD), with a focus on structural and functional neuroimaging. CONCLUSIONS: There has been a recent influx of studies examining the underlying neurobiology of BDD using structural and functional neuroimaging methods. Despite obvious symptom similarities with obsessive compulsive disorder (OCD), no study to date has directly compared the two groups using neuroimaging techniques. Studies have established that there are limbic and visual cortex abnormalities in BDD, in contrast to fronto-striatal differences in OCD. Such data suggests affect or visual training maybe useful in BDD. PMID- 26129817 TI - Are psychiatrists trained to be leaders in mental health? A survey of early career psychiatrists. AB - OBJECTIVE: The aim of this study was to investigate how early career psychiatrists in 2014 valued the leadership skill education in their training to become psychiatrists. METHOD: All psychiatrists who gained Fellowship since 2009 after training in New Zealand or Australia were invited to take part in a survey. RESULTS: Respondents considered themselves not adequately prepared for the leadership, management and administrative tasks and roles they have as psychiatrists, with preparedness for management tasks scoring the lowest. They valued as most useful to have opportunity to practice with a leadership role, to be able to observe 'leaders at work', to have a supervisor with special interests and skills in leadership and management and to have a formal teaching program on leadership and management. They advised teaching to be given throughout the entire 5 years of the training program by experienced leaders. CONCLUSIONS: Leadership skills training in the education of psychiatrists should contain both practical experience with leadership and management roles and formal teaching sessions on leadership and management skills development. Suggestions for improvement of the leadership and management skills education in the training of psychiatrists have been formulated. PMID- 26129818 TI - Emil Kraepelin's ideas on transcultural psychiatry. AB - OBJECTIVE: Prevailing degeneration theory and an increasing number of people in inpatient mental treatment aroused the famous German psychiatrist Emil Kraepelin's (1856-1926) interest to investigate whether the mental illnesses typical for Europe were also characteristic for 'primitive peoples'. He thus dedicated a period spent in the Dutch East Indies (Java) in 1904 to transcultural psychiatric research. This paper endeavours to compile Kraepelin's key findings, aiming to make readers aware of what kind of transcultural research Kraepelin did and what conclusions he came up with. At the same time it provides some background for the question of whether Kraepelin can really be referred to as the founder of transcultural psychiatry. CONCLUSION: Kraepelin assumed that illnesses with exterior causes depended on the type of stimulants widely used in a given culture. Since he found little evidence for progressive paralysis, he concluded that European brains were particularly prone to sequelae of syphilis. For endogenous psychoses he postulated differences in both symptoms and courses, depressions being rarer and milder, and ceasing sooner. By contrast, he found dementia praecox (mainly covered by the concept of schizophrenias later) to be the most prevalent mental illness in Java, explicitly different in form from that in Europe. PMID- 26129819 TI - Social anxiety disorders in clinical practice: differentiating social phobia from avoidant personality disorder. AB - OBJECTIVE: To outline the problems around overlap between social phobia (SAD) and avoidant personality disorder (AVPD) and provide guidelines that may assist clinicians to differentiate these conditions. CONCLUSIONS: A constellation of symptoms can be identified that may distinguish AVPD from SAD, with key features being a strong and pervasively negative self-concept, a view of rejection as equating to a global evaluation of the individual as being of little worth and a sense of not fitting in socially that dates from early childhood. It is important to identify the presence of AVPD in order to anticipate potential problems with engagement and retention in therapy, to target treatment interventions and optimise outcome. PMID- 26129820 TI - 3D cardiac microtissues encapsulated with the co-culture of cardiomyocytes and cardiac fibroblasts. AB - Cardiac tissue engineering has major applications in regenerative medicine, disease modeling and biological studies. Despite the significance, numerous questions still need to be explored to enhance the functionalities of engineered tissue substitutes. In this study, 3D cardiac microtissues are developed through encapsulation of cardiomyocytes and cardiac fibroblasts, as the main cellular constituents of native myocardium. The geometries of the constructs are precisely controlled and assessed for their role on synchronous contraction of the cells. Cardiomyocytes exhibit a native-like phenotype when co-cultured with cardiac fibroblasts as compared to the monoculture condition. Particularly, elongated F actin fibers with abundance of sarcomeric alpha-actinin and troponin-I are observed within all layers of the constructs. Higher expressions of connexin-43 and integrin-beta1 indicate improved cell-cell and cell-matrix interactions. Amongst co-culture conditions, 2:1 (cardiomyocytes: cardiac fibroblasts) ratio exhibits enhanced functionalities, whereas decreasing the construct size adversely affects the synchronous contraction of the cells. Overall, the study here indicates that the cell-cell ratio and the construct geometry are crucial parameters, which need to be optimized to enhance the functionalities of the engineered tissue substitutes. PMID- 26129822 TI - Inhibition of connective tissue growth factor attenuates paraquat-induced lung fibrosis in a human MRC-5 cell line. AB - Chronic exposure to Paraquat (PQ) may result in progressive pulmonary fibrosis and subsequent chronic obstructive pulmonary malfunction. Connective tissue growth factor (CTGF) has been proposed as a key determinant in the development of lung fibrosis. We investigated thus whether knock down of CTGF can prevent human lung fibroblasts (MRC-5) activation and proliferation with the subsequent inhibition of PQ-induced fibrosis. MRC-5 was transfected with CTGF-siRNAs and exposed to different concentrations of PQ. The siRNA-silencing efficacy was evaluated using western blotting analyses, qRT-PCR and flow cytometry. Next, the viability and migration of MRC-5 was determined. MMP-2, MMP-9, and TIMP-1 accumulation were quantified to evaluate the lung fibrosis exposure to PQ. Over expression of CTGF mRNA was observed in human MRC-5 cell as early as 6 h following PQ stimulation. CTGF gene expression in MRC-5 cells was substantially reduced by RNAi, which significantly suppressed the expression of the lung fibrosis markers such as tissue inhibitor of metalloproteinase-2 (TIMP-2), Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9) that were stimulated by PQ. Inhibition of CTGF expression suppressed impeded the proliferation and migration ability of MRC-5 cells and resulted in cell extracellular matrix (ECM) protein accumulation in cells. Our results suggest that CTGF promoted the development of PQ-induced lung fibrosis in collaboration with transforming growth factor beta1 (TGFbeta1). Furthermore, the observed arresting effects of CTGF knock down during this process suggested that CTGF is the potential target site for preventing PQ-induced pulmonary fibrosis. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1620-1626, 2016. PMID- 26129821 TI - Histone deacetylase inhibition impairs normal intestinal cell proliferation and promotes specific gene expression. AB - Mechanisms that maintain proliferation and delay cell differentiation in the intestinal crypt are not yet fully understood. We have previously shown the implication of histone methylation in the regulation of enterocytic differentiation. In this study, we investigated the role of histone deacetylation as an important epigenetic mechanism that controls proliferation and differentiation of intestinal cells using the histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) on the proliferation and differentiation of human and mouse intestinal cells. Treatment of newly confluent Caco-2/15 cells with SAHA resulted in growth arrest, increased histone acetylation and up regulation of the expression of intestine-specific genes such as those encoding sucrase-isomaltase, villin and the ion exchanger SLC26A3. Although SAHA has been recently used in clinical trials for cancer treatment, its effect on normal intestinal cells has not been documented. Analyses of small and large intestines of mice treated with SAHA revealed a repression of crypt cell proliferation and a higher expression of sucrase-isomaltase in both segments compared to control mice. Expression of SLC26A3 was also significantly up-regulated in the colons of mice after SAHA administration. Finally, SAHA was also found to strongly inhibit normal human intestinal crypt cell proliferation in vitro. These results demonstrate the important implication of epigenetic mechanisms such as histone acetylation/deacetylation in the regulation of normal intestinal cell fate and proliferation. PMID- 26129823 TI - The origin of specificity and insight into recognition between an aminoacyl carrier protein and its partner ligase. AB - Acyl carrier proteins (ACPs) are among the most promiscuous proteins in terms of protein-protein interactions and it is quite puzzling how ACPs select the correct partner between many possible upstream and downstream binding proteins. To address this question, we performed molecular dynamics simulations on dimeric Bradyrhizobium japonicum Gly:CP ligase 1 to inspect the origin of its selectivity towards the three types of carrier proteins, namely holoCP, apoCP, and holoCP Gly, which only differ in the attached prosthetic group. In line with experiments, MM-GBSA analysis revealed that the ligase preferentially binds the holoCP form to both subunits with the binding free energies of -20.7 and -19.1 kcal mol(-1), while the apoCP form, without the prosthetic group, is also recognized, but the binding values of -9.2 and -3.6 kcal mol(-1) suggest that there is no competition for the ligase binding as long as the holoCP is present. After the prosthetic group becomes glycylated, the holoCP-Gly dissociates from the ligase, as supported by its endergonic binding free energies of 2.9 and 20.9 kcal mol(-1). Our results indicate that these affinity differences are influenced by three aspects: the form of the prosthetic group and the specific non-polar hydrophobic interactions, as well as charge complementarity dominantly manifested through Arg220-Glu53 ion pair within the binding region among proteins. A careful examination of the bonding patterns within the ligase active site elucidated the interactions with Arg258, Asp215 and Tyr132 as being predominant in stabilizing the prosthetic group, which are significantly diminished upon glycation, thus promoting complex dissociation. PMID- 26129824 TI - Computer-aided resection and reconstruction in a case of aneurysmal bone cyst of the mandibular condylar head. AB - A case is presented of a 16-year-old girl with an aneurysmal bone cyst (ABC) of the mandibular condyle of the temporomandibular joint (TMJ). This lesion rarely involves the mandibular condyle, and involvement of condylar head is even rarer. To our knowledge, only 12 cases have been reported in the literature so far. This is the first case of ABC of the mandibular condyle with 3D planning of costochondral graft reconstruction described in the literature. PMID- 26129825 TI - Few-layered titanium trisulfide (TiS3) field-effect transistors. AB - Titanium trisulfide (TiS3) is a promising layered semiconductor material. Several mm-long TiS3 whiskers can be conveniently grown by the direct reaction of titanium and sulfur. In this study, we exfoliated these whiskers using the adhesive tape approach and fabricated few-layered TiS3 field-effect transistors (FETs). The TiS3 FETs showed an n-type electronic transport with room-temperature field-effect mobilities of 18-24 cm(2) V(-1) s(-1) and ON/OFF ratios up to 300. We demonstrate that TiS3 is compatible with the conventional atomic layer deposition (ALD) procedure for Al2O3. ALD of alumina on TiS3 FETs resulted in mobility increase up to 43 cm(2) V(-1) s(-1), ON/OFF ratios up to 7000, and much improved subthreshold swing characteristics. This study shows that TiS3 is a competitive electronic material in the family of two-dimensional (2D) transition metal chalcogenides and can be considered for emerging device applications. PMID- 26129827 TI - Bottom-Up Construction of Mesoporous Nanotubes from 78-Component Self-Assembled Nanobarrels. AB - Segmental and continuous hexagonal-packed mesoporous metal-organic nanotubes (MMONTs) with outside diameters of up to 4.5 nm and channel sizes of 2.4 nm were hierarchically constructed by a rational multicomponent self-assembly process involving starting from [L2Pd2(NO3)2] (L=o-phenanthroline or 2,2'-bipyridine) and 4-pyridinyl-3-pyrazole. An unprecedented crystallization-driven cross-linking between discrete nanobarrel building units by spontaneous loss of the capping ligands to form infinite nanotubes was observed. Such a barrel-to-tube transformation provides new possibilities for the fabrication of MMONTs using the solution bottom-up approach. PMID- 26129826 TI - Characterization of Salmonella Typhimurium isolates from domestically acquired infections in Finland by phage typing, antimicrobial susceptibility testing, PFGE and MLVA. AB - BACKGROUND: Salmonella enterica spp. enterica serotype Typhimurium (STM) is the most common agent of domestically acquired salmonellosis in Finland. Subtyping methods which allow the characterization of STM are essential for effective laboratory-based STM surveillance and for recognition of outbreaks. This study describes the diversity of Finnish STM isolates using phage typing, antimicrobial susceptible testing, pulsed-field gel electrophoresis (PFGE) and multilocus variable-number tandem repeat analysis (MLVA), and compares the discriminatory power and the concordance of these methods. RESULTS: A total of 375 sporadic STM isolates were analysed. The isolates were divided into 31 definite phage (DT) types, dominated by DT1 (47 % of the isolates), U277 (9 % of the isolates) and DT104 (8 % of the isolates). Of all the isolates, 62 % were susceptible to all the 12 antimicrobials tested and 11 % were multidrug resistant. Subtyping resulted in 83 different XbaI-PFGE profiles and 111 MLVA types. The three most common XbaI-PFGE profiles (STYM1, STYM7 and STYM8) and one MLVA profile with three single locus variants accounted for 56 % and 49 % of the STM isolates, respectively. The studied isolates showed a genetic similarity of more than 70 % by XbaI-PFGE. In MLVA, 71 % of the isolates lacked STTR6 and 77 % missed STTR10p loci. Nevertheless, the calculated Simpson's diversity index for XbaI-PFGE was 0.829 (95 % CI 0.792-0.865) and for MLVA 0.867 (95 % CI 0.835-0.898). However, the discriminatory power of the 5-loci MLVA varied among the phage types. The highest concordance of the results was found between XbaI-PFGE and phage typing (adjusted Wallace coefficient was 0.833 and adjusted Rand coefficient was 0.627). CONCLUSIONS: In general, the calculated discriminatory power was higher for genotyping methods (MLVA and XbaI-PFGE) than for phenotyping methods (phage typing). Overall, comparable diversity indices were calculated for PFGE and MLVA (both DI > 0.8). However, MLVA was phage type dependent providing better discrimination of the most common phage types. Furthermore, 5-loci MLVA was a less laborious method and easier to interpret than XbaI-PFGE. Thus, the laboratory-based surveillance of the Finnish human STM infections has been conducted with a combination of phage typing, antimicrobial susceptibility testing and 5-loci MLVA since January 2014. PMID- 26129828 TI - Higher Grades and Repeated Recurrence of Hepatic Encephalopathy May Be Related to High Serum Manganese Levels. AB - Hepatic encephalopathy is a serious complication of liver failure. Until now, the precise pathophysiologic mechanisms are not fully determined. It has been demonstrated that manganese plays an important role in the pathogenesis of hepatic encephalopathy. Therefore, we studied manganese levels in serum of cirrhotic patients with hepatic encephalopathy in relation to grading and recurrence of hepatic encephalopathy. One hundred persons were enrolled in the study, 80 cirrhotic patients with or without encephalopathy and 20 healthy controls. Hepatic encephalopathy was diagnosed clinically and by laboratory findings. Serum manganese levels were measured in all participants. The grading of hepatic encephalopathy was significantly correlated to the severity of liver dysfunction. The mean serum manganese level was significantly higher in cirrhotic patients than in controls and in cirrhotic patients with encephalopathy than in those without encephalopathy. It was also significantly higher in patients with advanced grading of hepatic encephalopathy. Serum manganese level was positively correlated to number of recurrences of encephalopathy during a 6-month follow-up period. Serum manganese levels were able to predict recurrence of hepatic encephalopathy within 6 months following the episode. Serum manganese levels are positively correlated to the modified Child-Pugh score of cirrhosis as well as grading and number of recurrences of hepatic encephalopathy. Higher manganese levels seem to be related to worsening of the condition, and its measurement may be used as a predictor of repeated recurrences. PMID- 26129829 TI - Perfluoroalkyl and -aryl zinc ate complexes: generation, reactivity, and synthetic application. AB - A combination of dimethylzinc, perfluoroalkyl iodide, and LiCl afforded a new type of perfluoroalkyl (RF ) zinc ate complex. These complexes show much greater thermal stability than conventional perfluorinated metal species, such as RF lithium species and Grignard reagents, and they can be used at room temperature or higher. The results of DFT calculations on the origin of the enhanced stability are reported and the synthetic utility of RF -zincate complexes is demonstrated. PMID- 26129830 TI - The Course of Headache in Patients With Moderate-to-Severe Headache Due to Aneurysmal Subarachnoid Hemorrhage: A Retrospective Cross-Sectional Study. AB - OBJECTIVES: The purpose of this study was to evaluate the course of headache in patients with moderate-to-severe headache due to aneurysmal subarachnoid hemorrhage (aSAH) and to identify its predisposing factors. BACKGROUND: Little is known about the long-term course of headache in patients with aSAH. METHODS: Since September 2009, patients with aSAH have had their headaches prospectively rated using a numeric rating scale (NRS). From this database containing 838 patients, 217 were included and all included patients met the following criteria: (1) presence of ruptured intracranial aneurysms on computed tomography angiography or magnetic resonance angiography; (2) alert consciousness (Glasgow Coma Scale 15); (3) newly onset moderate-to-severe headache (NRS >= 4) due to ruptured intracranial aneurysms; and (4) good clinical outcome at discharge (modified Rankin Scale 0, 1, or 2). We observed the changes in NRS scores from initial to 12-month follow-up and identified the predisposing factors of NRS changes. RESULTS: Of the 217 patients, 182 (83.9%) experienced improvement in NRS score <= 3 upon discharge. The NRS scores at discharge were significantly lower than those on admission (P < .001). The independent predisposing factors for headache improvement included previous stroke (odds ratio [OR] = 0.141; 95% CI 0.051-0.381; P < .001), previous headache treated with medication (OR = 0.079; 95% CI 0.010-0.518; P = .008), and endovascular treatment (EVT; OR = 2.531; 95% CI 1.141-5.912; P = .026). The NRS scores tended to decrease continuously until the 12-month follow-up. EVT and symptomatic vasospasm were independently associated with a decrease of NRS in the follow-up periods. CONCLUSIONS: The course of headache in patients with aSAH continuously improved during the 12 months of follow-up. Headache improvement might be expected in patients who were treated with EVT and in those who did not have previous stroke or headache. PMID- 26129831 TI - The effect of the video game Mindlight on anxiety symptoms in children with an Autism Spectrum Disorder. AB - BACKGROUND: In the clinical setting, a large proportion of children with an autism spectrum disorder (ASD) experience anxiety symptoms. Because anxiety is an important cause of impairment for children with an ASD, it is necessary that effective anxiety interventions are implemented for these children. Recently, a serious game called Mindlight has been developed that is focused on decreasing anxiety in children. This approach is based on recent research suggesting that video games might be suitable as an intervention vehicle to enhance mental health in children. In the present study it will be investigated whether Mindlight is effective in decreasing (sub) clinical anxiety symptoms in children who are diagnosed with an ASD. METHODS/DESIGN: The present study involves a randomized controlled trial (RCT) with two conditions (experimental versus control), in which it is investigated whether Mindlight is effective in decreasing (sub) clinical anxiety symptoms in children with an ASD. For this study, children of 8 16 years old with a diagnosis of an ASD and (sub) clinical anxiety symptoms will be randomly assigned to the experimental (N = 60) or the control (N = 60) condition. Children in the experimental condition will play Mindlight for one hour per week, for six consecutive weeks. Children in the control condition will play the puzzle game Triple Town, also for one hour per week and for six consecutive weeks. All children will complete assessments at baseline, post intervention and 3-months follow-up. Furthermore, parents and teachers will also complete assessments at the same time points. The primary outcome will be child report of anxiety symptoms. Secondary outcomes will be parent report of child anxiety, child/parent report of depressive symptoms, and parent/teacher report of social functioning and behavior problems. DISCUSSION: This paper aims to describe a study that will examine the effect of the serious game Mindlight on (sub) clinical anxiety symptoms of children with an ASD in the age of 8-16 years old. It is expected that children in the experimental condition will show lower levels of anxiety symptoms at 3-months follow-up, compared to children in the control condition. If Mindlight turns out to be effective, it could be an important contribution to the already existing interventions for anxiety in children with an ASD. Mindlight could then be implemented as an evidence-based treatment for anxiety symptoms in children with an ASD in mental health institutes and special education schools. TRIAL REGISTRATION: Dutch Trial Register NTR5069 . Registered 20 April 2015. PMID- 26129833 TI - Concurrent determination of olanzapine, risperidone and 9-hydroxyrisperidone in human plasma by ultra performance liquid chromatography with diode array detection method: application to pharmacokinetic study. AB - A simple and sensitive ultra-performance liquid chromatography (UPLC) method has been developed and validated for simultaneous estimation of olanzapine (OLZ), risperidone (RIS) and 9-hydroxyrisperidone (9-OHRIS) in human plasma in vitro. The sample preparation was performed by simple liquid-liquid extraction technique. The analytes were chromatographed on a Waters Acquity H class UPLC system using isocratic mobile phase conditions at a flow rate of 0.3 mL/min and Acquity UPLC BEH shield RP18 column maintained at 40 degrees C. Quantification was performed on a photodiode array detector set at 277 nm and clozapine was used as internal standard (IS). OLZ, RIS, 9-OHRIS and IS retention times were found to be 0.9, 1.4, .1.8 and 3.1 min, respectively, and the total run time was 4 min. The method was validated for selectivity, specificity, recovery, linearity, accuracy, precision and sample stability. The calibration curve was linear over the concentration range 1-100 ng/mL for OLZ, RIS and 9-OHRIS. Intra- and inter day precisions for OLZ, RIS and 9-OHRIS were found to be good with the coefficient of variation <6.96%, and the accuracy ranging from 97.55 to 105.41%, in human plasma. The validated UPLC method was successfully applied to the pharmacokinetic study of RIS and 9-OHRIS in human plasma. PMID- 26129832 TI - The association of APOC4 polymorphisms with premature coronary artery disease in a Chinese Han population. AB - BACKGROUND: Hypercholesterolemia arising from abnormal lipid metabolism is one of the critical risk factors for coronary artery disease (CAD), however the roles of genetic variants in lipid metabolism-related genes on premature CAD (<= 60 years old) development still require further investigation. We herein genotyped four single nucleotide polymorphisms (SNPs) in lipid metabolism-related genes (rs1132899 and rs5167 in APOC4, rs1801693 and rs7765781 in LPA), aimed to shed light on the influence of these SNPs on individual susceptibility to early-onset CAD. METHODS: Genotyping of the four SNPs (rs1132899, rs5167, rs1801693 and rs7765781) was performed in 224 premature CAD cases and 297 control subjects (<= 60 years old) using polymerase chain reaction-ligation detection reaction (PCR LDR) method. The association of these SNPs with premature CAD was performed with SPSS software. RESULTS: Multivariate logistic regression analysis showed that C allele (OR = 1.50, P = 0.027) and CC genotype (OR = 2.84, P = 0.022) of APOC4 rs1132899 were associated with increased premature CAD risk, while the other three SNPs had no significant effect. Further stratified analysis uncovered a more evident association with the risk of premature CAD among male subjects (C allele, OR = 1.65, and CC genotype, OR = 3.33). CONCLUSIONS: Our data provides the first evidence that APOC4 rs1132899 polymorphism was associated with an increased risk of premature CAD in Chinese subjects, and the association was more significant among male subjects. PMID- 26129834 TI - Court judgment on consent provides spur for embracing shared decision making. PMID- 26129835 TI - Effectiveness of group cognitive behavioral therapy for somatoform pain disorder patients in Japan: A preliminary non-case-control study. AB - AIMS: Somatoform pain disorder is associated with psychosocial dysfunction, and psychotherapies, such as cognitive behavioral therapy (CBT), are thought to provide useful interventions to address such dysfunction as well as the pain itself. However, little is known about whether CBT for somatoform pain disorder is effective, including the long-term course of the illness, in non-Western populations. We therefore tailored such a program based on an existing CBT protocol and examined its effectiveness in Japan. METHODS: Thirty-four Japanese participants (22 women; mean age = 52.5 years) enrolled in a weekly 12-session group treatment, with 32 completing both wait-list and treatment conditions. The primary outcome measure was pain intensity. Secondary outcome measures included pain characteristics, as measured by pain catastrophizing and psychometric evaluations, including depression, anxiety, and quality of life. The patients were followed up for 12 months after treatment. RESULTS: We found that pain intensity, anxiety, depressive symptoms, and social functioning all significantly improved after treatment compared with the wait-list period, and the improvements in pain intensity, depressive symptoms, and social functioning were sustained at 12 months following the completion of CBT. There were strong positive correlations (P < 0.01) among pre- and post-treatment changes in the affective dimension of pain, depression, anxiety, and pain catastrophizing. CONCLUSIONS: These results show that the present CBT program was effective for Japanese patients with somatoform pain disorder and that gains were maintained over the long term. More work is needed to further clarify the effects of CBT interventions on somatoform symptoms, particularly in Japan. PMID- 26129836 TI - Patient satisfaction and prosthetic aspects with mini-implants retained mandibular overdentures. A 5-year prospective study. AB - PURPOSE: This study aimed to evaluate patient satisfaction and prosthetic aspects during a 5-year prospective clinical study of mini dental implants (MDIs) retaining mandibular overdentures. MATERIALS AND METHODS: This observational prospective clinical study was conducted on a group of completely edentulous patients (n = 28) with retention problems of conventional mandibular dentures. All patients received new maxillary and mandibular conventional dentures. A total of 112 MDIs (four per patient) were inserted using the flapless surgical approach and immediately loaded by the new mandibular dentures (overdentures). Patients indicated satisfaction with their prosthesis using a questionnaire and a visual analogue scale (VAS). Patient satisfaction and prosthetic complications were recorded 6 months (T6 m ), 1 (T1), 3 (T3), and 5 (T5) years after overdenture insertion. RESULTS: The patient satisfaction with eating (hard/soft) food (P < 0.001), talking (P < 0.001), appearance (P = 0.001), comfort (P < 0.001), healing process (P = 0.013), socialization (P < 0.001), stability/retention of mandibular dentures (P = 0.001), ease of oral hygiene (P = 0.008), and ease of handling the dentures (P < 0.001) increased significantly with time. After 5 years, the most common complication was wear/damage of O/rings (n = 235), O/ring replacement (n = 125), maxillary denture relining times (n = 13), worn teeth (n = 10), overdentures relines (n = 10), detachment of the metal housings (n = 9), and fracture of mandibular overdentures (n = 8). Mucositis, soreness, and decubitis ulcer under overdenture occurred most often at T6 m and decreased significantly with time (P = 0.002, 0.005, and 0.024, respectively). CONCLUSION: Within the limitations of this clinical study, patient satisfaction with mini-implant retained mandibular overdentures increased significantly with time. However, this treatment required a considerable amount of prosthetic maintenance and repair after 5 years of service. PMID- 26129837 TI - Narrow-spectrum antibiotics are as effective as broad-spectrum antibiotics in the treatment of community-acquired pneumonia. PMID- 26129838 TI - Timescales of N-H bond dissociation in pyrrole: a nonadiabatic dynamics study. AB - The excitation wavelength dependent photodynamics of pyrrole are investigated by nonadiabatic trajectory-surface-hopping dynamics simulations based on time dependent density functional theory (TDDFT) and the algebraic diagrammatic construction method to the second order (ADC(2)). The ADC(2) results confirm that the N-H bond dissociation occurring upon excitation at the origin of the first excited state, S1(pisigma*), is driven by tunnelling [Roberts et al., Faraday Discuss., 2013, 163, 95] as a barrier of DeltaE = 1780 cm(-1) traps the population in a quasi-bound minimum. Upon excitation to S1(pisigma*) in the wavelength range of 236-240 nm, direct dissociation of the N-H bond takes place with a time constant of 28 fs. The computed time constant is in very good agreement with recently reported measurements. Excitation to the lowest B2 state in the 198-202 nm range returns a time constant for N-H fission of 48 fs at the B3LYP/def2-TZVPD level, in perfect agreement with the experiment [Roberts et al. Faraday Discuss., 2013, 163, 95]. For the same wavelength range the ADC(2)/aug-cc pVDZ decay constant is more than three times longer than the experimentally reported one. The accuracy of the B3LYP/def2-TZVPD dynamics is checked against reference complete-active-space second-order perturbation theory (CASPT2) calculations and explained in terms of correct topography of the pipi* surface and the lack of mixing between the pipi* and the 3px Rydberg states which occurs in the ADC(2) method. PMID- 26129839 TI - MicroRNA-205 regulates ubiquitin specific peptidase 7 protein expression in hepatocellular carcinoma cells. AB - Ubiquitin specific peptidase 7 (UPS7) has a critical role in the development and progression of cancer, at least in part, through its regulation of p53 protein stability. However, its molecular determinants remain to be elucidated. In the present study, it was identified that microRNA-205 (miR-205) may negatively regulate UPS7 protein levels through targeting its 3'-untranslated region in hepatocellular carcinoma (HCC) cells. As a result, miR-205 mimics inhibited USP7 protein levels while antisense miR-205 enhanced USP7 protein levels, thereby modulating the p53 signaling pathway and cell proliferation levels. In conclusion, the data presents a novel molecule for the dysregulated expression of USP7 in HCC, which may assist in elucidating mechanisms underlying the tumorigenesis of HCC. PMID- 26129840 TI - Amorphous drug dispersions with mono- and diacyl lecithin: On molecular categorization of their feasibility and UV dissolution imaging. AB - There is a growing interest in drug-phospholipid complexes and similar formulations that are mostly solid dispersions with high drug load. This study aims to explore the feasibility of such phospholipid-based solid dispersions as well as to characterize them. A particular aim was to compare monoacyl phosphatidylcholine (PC) with the diacyl excipient. The solid dispersions were manufactured using a solvent evaporation technique and characterized by means of differential scanning calorimetry and X-ray diffractometry. Density functional theory was used to calculate molecular frontier orbitals of the different compounds. Finally, the dissolution properties were analyzed in a flow-through cell by means of UV imaging. It was found that the ability to form solid dispersions with the phospholipids containing amorphous or solubilized drug (at equimolar ratio with the lipid) was dependent on the drug's frontier orbital energy, the enthalpy of fusion, as well as the log P value. In a subsequent dissolution study, UV imaging revealed pronounced surface swelling of the solid dispersions. Only the monoacyl PC was found to substantially enhance in vitro dissolution compared to pure drug. The gained understanding will support a future development of solid drug dispersions using phospholipids as matrix components. PMID- 26129841 TI - Future habitat loss and extinctions driven by land-use change in biodiversity hotspots under four scenarios of climate-change mitigation. AB - Numerous species have been pushed into extinction as an increasing portion of Earth's land surface has been appropriated for human enterprise. In the future, global biodiversity will be affected by both climate change and land-use change, the latter of which is currently the primary driver of species extinctions. How societies address climate change will critically affect biodiversity because climate-change mitigation policies will reduce direct climate-change impacts; however, these policies will influence land-use decisions, which could have negative impacts on habitat for a substantial number of species. We assessed the potential impact future climate policy could have on the loss of habitable area in biodiversity hotspots due to associated land-use changes. We estimated past extinctions from historical land-use changes (1500-2005) based on the global gridded land-use data used for the Intergovernmental Panel on Climate Change Fifth Assessment Report and habitat extent and species data for each hotspot. We then estimated potential extinctions due to future land-use changes under alternative climate-change scenarios (2005-2100). Future land-use changes are projected to reduce natural vegetative cover by 26-58% in the hotspots. As a consequence, the number of additional species extinctions, relative to those already incurred between 1500 and 2005, due to land-use change by 2100 across all hotspots ranged from about 220 to 21000 (0.2% to 16%), depending on the climate change mitigation scenario and biological factors such as the slope of the species-area relationship and the contribution of wood harvest to extinctions. These estimates of potential future extinctions were driven by land-use change only and likely would have been higher if the direct effects of climate change had been considered. Future extinctions could potentially be reduced by incorporating habitat preservation into scenario development to reduce projected future land-use changes in hotspots or by lessening the impact of future land-use activities on biodiversity within hotspots. PMID- 26129842 TI - Racial-ethnic variations in paid and unpaid caregiving: Findings among persons with traumatic spinal cord injury. AB - BACKGROUND: The effects of race-ethnicity on the use of paid and unpaid caregivers for those with spinal cord injury (SCI) have received little attention in the literature. OBJECTIVE: Compare the amount of paid and unpaid caregiver hours received and sources of caregiving between non-Hispanic White and non Hispanic Black participants with SCI, controlling for demographic, injury related, and economic variables. METHODS: Participants were identified from a large specialty hospital. Self-report data were collected by mail. Five aspects of caregiving were assessed: (a) paid assistance hours, (b) satisfaction with care, (c) unpaid assistance hours, (d) sources of informal care, and (e) evaluation of whether needs were met. RESULTS: Whites were more satisfied with paid care. Approximately 43.4% of Whites received informal care from their spouse every day, 14.7% higher than Blacks. Blacks were more likely to receive informal care from other family members, friends, church, and others. When controlling for gender, injury severity, chronological age, and years post injury, Blacks reported 1.50 more paid assistance hours (95% CI, 0.31-2.68 hours) and 1.83 less unpaid assistance hours than Whites (95% CI, 0.25-3.41 hours). Differences diminished and were not statistically significant after adding marital status and income into regression models. CONCLUSIONS: The results did not provide strong evidence of racial disparities regarding caregiver assistance for those with SCI. Level of income appears to be directly related to satisfaction of quality caregiving and the use of paid versus unpaid care for those living with SCI. PMID- 26129843 TI - Present or absent on admission: results of changes in National Healthcare Safety Network surveillance definitions. AB - In January 2013, the National Healthcare Safety Network definition of "present on admission" was created. Using existing surveillance data from 2013, we identified health care-associated infections (HAIs) that met prior present on admission criteria but not the new definition. We identified a number of infections classified as HAI despite evidence that infection was clinically present on admission. These findings have important implications for states with mandatory HAI reporting using National Healthcare Safety Network definitions. PMID- 26129844 TI - Models in biology: lessons from modeling regulation of the eukaryotic cell cycle. AB - In this essay we illustrate some general principles of mathematical modeling in biology by our experiences in studying the molecular regulatory network underlying eukaryotic cell division. We discuss how and why the models moved from simple, parsimonious cartoons to more complex, detailed mechanisms with many kinetic parameters. We describe how the mature models made surprising and informative predictions about the control system that were later confirmed experimentally. Along the way, we comment on the 'parameter estimation problem' and conclude with an appeal for a greater role for mathematical models in molecular cell biology. PMID- 26129845 TI - Alterations in Skeletal Muscle Oxidative Phenotype in Mice Exposed to 3 Weeks of Normobaric Hypoxia. AB - Skeletal muscle of patients with chronic respiratory failure is prone to loss of muscle mass and oxidative phenotype. Tissue hypoxia has been associated with cachexia and emphysema in humans. Experimental research on the role of hypoxia in loss of muscle oxidative phenotype, however, has yielded inconsistent results. Animal studies are frequently performed in young animals, which may hinder translation to generally older aged patients. Therefore, in this study, we tested the hypothesis that hypoxia induces loss of skeletal muscle oxidative phenotype in a model of aged (52 weeks) mice exposed to 3 weeks of hypoxia. Additional groups of young (4 weeks) and adult (12 weeks) mice were included to examine age effects. To verify hypoxia-induced cachexia, fat pad and muscle weights as well as muscle fiber cross-sectional areas were determined. Muscle oxidative phenotype was assessed by expression and activity of markers of mitochondrial metabolism and fiber-type distribution. A profound loss of muscle and fat was indeed accompanied by a slightly lower expression of markers of muscle oxidative capacity in the aged hypoxic mice. In contrast, hypoxia-associated changes of fiber-type composition were more prominent in the young mice. The differential response of the muscle of young, adult, and aged mice to hypoxia suggests that age matters and that the aged mouse is a better model for translation of findings to elderly patients with chronic respiratory disease. Furthermore, the findings warrant further mechanistic research into putative accelerating effects of hypoxia-induced loss of oxidative phenotype on the cachexia process in chronic respiratory disease. PMID- 26129846 TI - Diversification of the duplicated Rab1a genes in a hypoxia-tolerant fish, common carp (Cyprinus carpio). AB - Common carp is a widely cultivated fish with longer than 2,000 years domestication history, due to its strong environmental adaptabilities, especially hypoxia tolerance. The common carp genome has experienced a very recent whole genome duplication (WGD) event. Among a large number of highly similar duplicated genes, a pair of Ras-associated binding-GTPase 1a (Rab1a) genes were found fast diverging. Four analogous Rab1a genes were identified in the common carp genome. Comparisons of gene structures and sequences indicated Rab1a-1 and Rab1a-2 was a pair of fast diverging duplicates, while Rab1a-3 and Rab1a-4 was a pair of less diverged duplicates. All putative Rab1a proteins shared conserved GTPase domain, which enabled the proteins serve as molecular switches for vesicular trafficking. Rab1a-1 and Rab1a-2 proteins varied in their C-terminal sequences, which were generally considered to encode the membrane localization signals. Differential expression patterns were observed between Rab1a-1 and Rab1a-2 genes. In blood, muscle, spleen, and heart, the mRNA level of Rab1a-1 was higher than that of Rab1a-2. In liver and intestine, the mRNA level of Rab1a-2 was higher. Expression of Rab1a-1 and Rab1a-2 showed distinct hypoxia responses. Under severe hypoxia, Rab1a-1 expression was down-regulated in blood, while Rab1a-2 expression was up regulated in liver. Compared with the less diverged Rab1a-3/4 gene pair, common carp Rab1a-1/2 gene pair exhibited strong characteristics of sub functionalization, which might contribute to a sophisticated and efficient Ras dependent regulating network for the hypoxia-tolerant fish. PMID- 26129848 TI - Antiproliferative effects of curcumin analog L49H37 in pancreatic stellate cells: a comparative study. AB - BACKGROUND: Pancreatic cancer is a devastating disease with poor prognosis. It is characterized by a pronounced stromal reaction, which resists chemotherapeutics and effective tumor treatment. Pancreatic stellate cells (PSCs) are mainly responsible for this stromal reaction. Moreover, the cancer and stromal interaction seems to promote tumor proliferation. In this study, L49H37, a newly synthesized curcumin analog, was used as intervention to target the stromal compartment of pancreatic cancer. METHODS: In vitro cultures of human PSCs were exposed to curcumin and L49H37. Cell viability as well as growth promoting and survival signaling pathways were monitored by MTT, flow cytometry and western blotting. RESULTS: Curcumin and L49H37 effectively inhibited proliferation and induced apoptosis in PSCs. L49H37 was found to be more potent at a lower concentration than curcumin in the induction of apoptosis, as evidenced by cleaved poly (ADP-ribose) polymerase (PARP). The cells were retained in the G0/G1 phase of the cell cycle through the downregulation of p21WAF1/Cip1. L49H37 significantly decreased the phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). CONCLUSION: The results indicate that curcumin analog L49H37 exhibits more potent inhibitory effects than curcumin itself at a lower concentration, which suggests that it may have a potential for further evaluation of its use against pancreatic adenocarcinoma, either as a single agent but, more probable, as part of a combination regimen. PMID- 26129847 TI - Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. AB - INTRODUCTION: Administration of mesenchymal stem cells (MSCs) represents a promising treatment option for patients suffering from immunological and degenerative disorders. Accumulating evidence indicates that the healing effects of MSCs are mainly related to unique paracrine properties, opening opportunities for secretome-based therapies. Apart from soluble factors, MSCs release functional small RNAs via extracellular vesicles (EVs) that seem to convey essential features of MSCs. Here we set out to characterize the full small RNAome of MSC-produced exosomes. METHODS: We set up a protocol for isolating exosomes released by early passage adipose- (ASC) and bone marrow-MSCs (BMSC) and characterized them via electron microscopy, protein analysis and small RNA sequencing. We developed a bioinformatics pipeline to define the exosome-enclosed RNA species and performed the first complete small RNA characterization of BMSCs and ASCs and their corresponding exosomes in biological replicates. RESULTS: Our analysis revealed that primary ASCs and BMSCs have highly similar small RNA expression profiles dominated by miRNAs and snoRNAs (together 64-71 %), of which 150-200 miRNAs are present at physiological levels. In contrast, the miRNA pool in MSC exosomes is only 2-5 % of the total small RNAome and is dominated by a minor subset of miRNAs. Nevertheless, the miRNAs in exosomes do not merely reflect the cellular content and a defined set of miRNAs are overrepresented in exosomes compared to the cell of origin. Moreover, multiple highly expressed miRNAs are precluded from exosomal sorting, consistent with the notion that these miRNAs are involved in functional repression of RNA targets. While ASC and BMSC exosomes are similar in RNA class distribution and composition, we observed striking differences in the sorting of evolutionary conserved tRNA species that seems associated with the differentiation status of MSCs, as defined by Sox2, POU5F1A/B and Nanog expression. CONCLUSIONS: We demonstrate that primary MSCs release small RNAs via exosomes, which are increasingly implicated in intercellular communications. tRNAs species, and in particular tRNA halves, are preferentially released and their specific sorting into exosomes is related to MSC tissue origin and stemness. These findings may help to understand how MSCs impact neighboring or distant cells with possible consequences for their therapeutic usage. PMID- 26129849 TI - Starting a DNA barcode reference library for shallow water polychaetes from the southern European Atlantic coast. AB - Annelid polychaetes have been seldom the focus of dedicated DNA barcoding studies, despite their ecological relevance and often dominance, particularly in soft-bottom estuarine and coastal marine ecosystems. Here, we report the first assessment of the performance of DNA barcodes in the discrimination of shallow water polychaete species from the southern European Atlantic coast, focusing on specimens collected in estuaries and coastal ecosystems of Portugal. We analysed cytochrome oxidase I DNA barcodes (COI-5P) from 164 specimens, which were assigned to 51 morphospecies. To our data set from Portugal, we added available published sequences selected from the same species, genus or family, to inspect for taxonomic congruence among studies and collection location. The final data set comprised 290 specimens and 79 morphospecies, which generated 99 Barcode Index Numbers (BINs) within Barcode of Life Data Systems (BOLD). Among these, 22 BINs were singletons, 47 other BINs were concordant, confirming the initial identification based on morphological characters, and 30 were discordant, most of which consisted on multiple BINs found for the same morphospecies. Some of the most prominent cases in the latter category include Hediste diversicolor (O.F. Muller, 1776) (7), Eulalia viridis (Linnaeus, 1767) (2) and Owenia fusiformis (delle Chiaje, 1844) (5), all of them reported from Portugal and frequently used in ecological studies as environmental quality indicators. Our results for these species showed discordance between molecular lineages and morphospecies, or added additional relatively divergent lineages. The potential inaccuracies in environmental assessments, where underpinning polychaete species diversity is poorly resolved or clarified, demand additional and extensive investigation of the DNA barcode diversity in this group, in parallel with alpha taxonomy efforts. PMID- 26129851 TI - A Comparison of Single Shot Adductor Canal Block Versus Femoral Nerve Catheter for Total Knee Arthroplasty. AB - The aim of this study was to compare perioperative analgesia provided by single injection adductor canal block (ACB) to continuous femoral nerve catheter (FNC) when used in a multimodal pain protocol for total knee arthroplasty (TKA). A retrospective cohort study compared outcome data for 148 patients receiving a single-injection ACB to 149 patients receiving an FNC. The mean length of stay (LOS) in the ACB group was 2.67 (+/-0.56) and 3.01 days (+/-0.57) in the FNC group (P<0.0001). The median ambulatory distances for the adductor group were further than the femoral group for postoperative days 1 (P<0.0001) and 2 (P=0.01). Single-injection ACB offered similar pain control and earlier discharge compared to continuous FNC in patients undergoing TKA. PMID- 26129850 TI - Diversity and evolution of cytochrome P450 monooxygenases in Oomycetes. AB - Cytochrome P450 monooxygenases (P450s) are heme-thiolate proteins whose role as drug targets against pathogens, as well as in valuable chemical production and bioremediation, has been explored. In this study we performed comprehensive comparative analysis of P450s in 13 newly explored oomycete pathogens. Three hundred and fifty-six P450s were found in oomycetes. These P450s were grouped into 15 P450 families and 84 P450 subfamilies. Among these, nine P450 families and 31 P450 subfamilies were newly found in oomycetes. Research revealed that oomycetes belonging to different orders contain distinct P450 families and subfamilies in their genomes. Evolutionary analysis and sequence homology data revealed P450 family blooms in oomycetes. Tandem arrangement of a large number of P450s belonging to the same family indicated that P450 family blooming is possibly due to its members' duplications. A unique combination of amino acid patterns was observed at EXXR and CXG motifs for the P450 families CYP5014, CYP5015 and CYP5017. A novel P450 fusion protein (CYP5619 family) with an N terminal P450 domain fused to a heme peroxidase/dioxygenase domain was discovered in Saprolegnia declina. Oomycete P450 patterns suggested host influence in shaping their P450 content. This manuscript serves as reference for future P450 annotations in newly explored oomycetes. PMID- 26129852 TI - Application of Rapid Prototyping Pelvic Model for Patients with DDH to Facilitate Arthroplasty Planning: A Pilot Study. AB - Total hip arthroplasty (THA) is challenging in cases of osteoarthritis secondary to developmental dysplasia of the hip (DDH). Acetabular deficiency makes the positioning of the acetabular component difficult. Computer tomography based, patient-individual three dimensional (3-D) rapid prototype technology (RPT) models were used to plan the placement of acetabular cup so that a surgeon was able to identify pelvic structures, assess the ideal extent of reaming and determine the size of cup after a reconstructive procedure. Intraclass correlation coefficients (ICCs) were used to analyze the agreement between the sizes of chosen components on the basis of preoperative planning and the actual sizes used in the operation. The use of the 3-D RPT-model facilitates the surgical procedures due to better planning and improved orientation. PMID- 26129853 TI - An Analysis of Research from Faculty at U.S. Adult Reconstruction Fellowships. AB - We reviewed all articles published in three major orthopaedic journals from January 2010 to December 2014. Any article focusing on adult reconstruction of the hip or knee was reviewed for first and last authorship, institution, and level of evidence. Three institutions had authored work from arthroplasty faculty that fell within the top five most published institutions in all three journals, while one institution ranked first in all three journals. 43 of 67 (64.2%) reconstruction fellowships had at least one publication included in this study. The majority of the adult reconstruction literature published by faculty at U.S. reconstruction fellowships stems from a few academic centers with the ten most prolific institutions accounting for 65.9% of all U.S. fellowship publications. PMID- 26129854 TI - Reperfusion Therapies in Acute Ischemic Stroke. AB - Acute Ischemic stroke (IS) remains a leading cause of mortality and long-term disability. Owing to the time-constraints, only a fraction of acute IS patients receive the established and approved thrombolytic therapy and a sizeable proportion of acute IS stroke survivors remain permanently disabled. Rapid advances in various recanalization strategies have aimed at improving functional outcome and reducing mortality. Existing literature on various treatment approaches, including the evolution of various thrombolytic agents and interventional devices is presented in this review. In addition to describing intravenous drug trials, continual developments in the field of trials for interventional devices have been described. Additionally, some of the important recent patents filed for various experimental approaches are presented. We strongly believe that the recent therapeutic approaches, including endovascular interventional strategies, based on advanced neuroimaging evaluations appear to have a promising future for acute IS patients. PMID- 26129855 TI - Characterization of MHC class I alleles in sooty mangabeys as a tool for evaluating cellular immunity in natural hosts of SIV infection. AB - Although immune pressure exerted by MHC class I-restricted cytotoxic T lymphocytes (CTL) are an important determinant of outcome in pathogenic HIV and SIV infection, lack of data on MHC class I genes has hampered study of its role in natural hosts with nonpathogenic SIV infection. In this study, we cloned and characterized full-length MHC class I genes derived from the cDNA library of two unrelated naturally infected sooty mangabeys (Cercocebus atys) in whom SIV specific CTL epitopes were previously mapped. Twenty one full-length MHC class I alleles consisting of five MHC-A (Ceat-A), 13 MHC-B (Ceat-B), and three MHC-E (Ceat-E) alleles were identified. Sequence-specific primers (SSP) for high throughput screening of genomic DNA by PCR were developed for 16 of the 18 Ceat-A and Ceat-B alleles. Screening of 62 SIV-negative and 123 SIV-infected sooty mangabeys at the Yerkes National Primate Research Center (YNPRC) revealed the presence of up to four MHC-A and eight MHC-B alleles in individual mangabeys, indicating that similar to macaque species, mangabeys have at least two duplications of the MHC-A locus and four duplications of the MHC-B locus in the absence of an MHC-C locus. Using stable transfectants of Ceat MHC Class I alleles in the MHC-null 721.221 cell line, we identified Ceat-B*12:01 as the restricting allele of a previously reported Nef20-28 CTL epitope. Ceat-B*1201/Nef20-28 tetramers identified tetramer-positive CD8+ T lymphocytes in Ceat-B*1201-positive SIV-infected mangabeys. This study has laid the groundwork for comprehensive analysis of CTL and SIV evolution in a natural host of SIV infection. PMID- 26129856 TI - Development of a Standardized Set of Patient-centered Outcomes for Advanced Prostate Cancer: An International Effort for a Unified Approach. AB - BACKGROUND: There are no universally monitored outcomes relevant to men with advanced prostate cancer, making it challenging to compare health outcomes between populations. OBJECTIVE: We sought to develop a standard set of outcomes relevant to men with advanced prostate cancer to follow during routine clinical care. DESIGN, SETTING, AND PARTICIPANTS: The International Consortium for Health Outcomes Measurement assembled a multidisciplinary working group to develop the set. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used a modified Delphi method to achieve consensus regarding the outcomes, measures, and case mix factors included. RESULTS AND LIMITATIONS: The 25 members of the multidisciplinary international working group represented academic and nonacademic centers, registries, and patients. Recognizing the heterogeneity of men with advanced prostate cancer, the group defined the scope as men with all stages of incurable prostate cancer (metastatic and biochemical recurrence ineligible for further curative therapy). We defined outcomes important to all men, such as overall survival, and measures specific to subgroups, such as time to metastasis. Measures gathered from clinical data include measures of disease control. We also identified patient-reported outcome measures (PROMs), such as degree of urinary, bowel, and erectile dysfunction, mood symptoms, and pain control. CONCLUSIONS: The international multidisciplinary group identified clinical data and PROMs that serve as a basis for international health outcome comparisons and quality-of-care assessments. The set will be revised annually. PATIENT SUMMARY: Our international group has recommended a standardized set of patient-centered outcomes to be followed during routine care for all men with advanced prostate cancer. PMID- 26129857 TI - The Fluid Joint: The Soft Spot of Micro- and Nanosystems. AB - Fluid bridges are ubiquitous soft structures of finite size that conform to and link the surfaces of neighboring objects. Fluid joints, the specific type of fluid bridge with at least one extremity constrained laterally, display even more pronounced reactivity and self-restoration, which make them remarkably suited for assembly, actuation, and manipulation purposes. Their peculiar surface and bulk properties place fluid joints at the rich intersection of diverse scientific interests, and foster their widespread use throughout micro- and nanotechnology. A critical survey of the mechanics and of the manifold applications of fluid bridges and joints in micro- and nanosystems is presented here, along with current challenges and multidisciplinary perspectives. PMID- 26129858 TI - Comparing the visual spans for faces and letters. AB - The visual span-the number of adjacent text letters that can be reliably recognized on one fixation-has been proposed as a sensory bottleneck that limits reading speed (Legge, Mansfield, & Chung, 2001). Like reading, searching for a face is an important daily task that involves pattern recognition. Is there a similar limitation on the number of faces that can be recognized in a single fixation? Here we report on a study in which we measured and compared the visual span profiles for letter and face recognition. A serial two-stage model for pattern recognition was developed to interpret the data. The first stage is characterized by factors limiting recognition of isolated letters or faces, and the second stage represents the interfering effect of nearby stimuli on recognition. Our findings show that the visual span for faces is smaller than that for letters. Surprisingly, however, when differences in first-stage processing for letters and faces are accounted for, the two visual spans become nearly identical. These results suggest that the concept of visual span may describe a common sensory bottleneck that underlies different types of pattern recognition. PMID- 26129859 TI - Detection of moving objects using motion- and stereo-tuned operators. AB - A person moving through the world must be able to identify moving objects in order to interact with them and successfully navigate. While image motion alone is sufficient to identify moving objects under many conditions, there may be some ambiguity as to whether an object is stationary or moving, depending on the object's angle of motion and distance from the observer. Adding a measure of depth from stereo cues can eliminate this ambiguity. Here we show that a model using operators tuned to image motion and stereo disparity can accurately locate moving objects and distinguish between stationary and moving objects in a scene through which an observer is moving. PMID- 26129860 TI - Categorical facilitation with equally discriminable colors. AB - This study investigates the impact of language on color perception. By categorical facilitation, we refer to an aspect of categorical perception, in which the linguistic distinction between categories affects color discrimination beyond the low-level, sensory sensitivity to color differences. According to this idea, discrimination performance for colors that cross a category border should be better than for colors that belong to the same category when controlling for low-level sensitivity. We controlled for sensitivity by using colors that were equally discriminable according to empirically measured discrimination thresholds. To test for categorical facilitation, we measured response times and error rates in a speeded discrimination task for suprathreshold stimuli. Robust categorical facilitation occurred for five out of six categories with a group of inexperienced observers, namely for pink, orange, yellow, green, and purple. Categorical facilitation was robust against individual variations of categories or the laterality of target presentation. However, contradictory effects occurred in the blue category, most probably reflecting the difficulty to control effects of sensory mechanisms at the green-blue boundary. Moreover, a group of observers who were highly familiar with the discrimination task did not show consistent categorical facilitation in the other five categories. This trained group had much faster response times than the inexperienced group without any speed accuracy trade-off. Additional analyses suggest that categorical facilitation occurs when observers pay attention to the categorical distinction but not when they respond automatically based on sensory feed-forward information. PMID- 26129861 TI - Crowding is proportional to visual acuity in young and aging eyes. AB - Spatial crowding decreases object recognition and conscious visual perception in clutter. In a previous study we used brief presentation times to reveal the effects of a crowded presentation in the fovea. Here we aimed to test the relationships between varying visual acuity (VA) and crowding in the fovea, under the assumption that in uncorrected presbyopia, the processing is relatively normal, whereas the retinal input is blurred. We tested whether normal participants whose near VA is gradually reduced due to age-related deterioration (presbyopia, or "aging eye") will show an acuity-dependent increase in foveal crowding. We used brief presentations and acuity-threshold letter targets in order to magnify the crowding-effect amplitude in the fovea. A total of 195 participants with an age range of 20-68 years and an average of 44.3 +/- 11.7 years (M +/- SD) were divided into four age groups, all without any optical correction for the near distance. Our findings show that crowding is proportional to VA. This proportionality is affected by VA-age dependency, with a nonlinear S shaped pattern: A steep VA reduction begins to develop, which is compatible with the normal onset age of presbyopia symptoms and a saturation in the VA-age dependency in the oldest age group, for which we propose a VA-eccentricity account. Finally, there is a high variance in the crowding amplitude in the young, even before the onset age of presbyopia symptoms, suggesting crowding conditions with limited presentation times as a highly sensitive measure of VA, which predicts visual performance in complex tasks, such as reading. PMID- 26129862 TI - The oblique effect is both allocentric and egocentric. AB - Despite continuous movements of the head, humans maintain a stable representation of the visual world, which seems to remain always upright. The mechanisms behind this stability are largely unknown. To gain some insight on how head tilt affects visual perception, we investigate whether a well-known orientation-dependent visual phenomenon, the oblique effect-superior performance for stimuli at cardinal orientations (0 degrees and 90 degrees ) compared with oblique orientations (45 degrees )-is anchored in egocentric or allocentric coordinates. To this aim, we measured orientation discrimination thresholds at various orientations for different head positions both in body upright and in supine positions. We report that, in the body upright position, the oblique effect remains anchored in allocentric coordinates irrespective of head position. When lying supine, gravitational effects in the plane orthogonal to gravity are discounted. Under these conditions, the oblique effect was less marked than when upright, and anchored in egocentric coordinates. The results are well explained by a simple "compulsory fusion" model in which the head-based and the gravity based signals are combined with different weightings (30% and 70%, respectively), even when this leads to reduced sensitivity in orientation discrimination. PMID- 26129863 TI - Suppressive effects on motion discrimination induced by transient flankers are reduced by perceptual learning. AB - We investigated spatial suppression of a drifting Gabor target of 0.5 c/ degrees induced by adjacent and iso-oriented stationary Gabors (flankers) whose spatial frequency differed by +/-1 and +/-2 octaves to that of the drifting target. Stimuli (target and flankers) were presented for 33 ms. Results showed greater spatial suppression when the spatial frequency of the stationary but transient flanking Gabors was either equal or 1-2 octaves lower than when it was 1-2 octaves higher than the target's spatial frequency. This asymmetry was evident only for the drifting target, but not for the stationary target. In addition, we investigated whether perceptual learning (PL) reduced the spatial suppression induced by the flankers. We found that PL increased contrast sensitivity for the target, but only when it was reduced by the lateral masking flankers, and its effect did not transfer to an isolated drifting target of equal or higher spatial frequency. These results suggest that PL selectively affects suppressive interactions rather than contrast gain. We suggest that the suppressive effect of low spatial frequency flankers and the lack of suppression with high spatial frequency flankers may reflect two complementary phenomena: camouflage by the transient flankers (i.e., context) and breaking of camouflage by form-motion segmentation. Camouflage may result because both target and flankers activate the motion (magnocellular) system. Breaking of camouflage instead may occur when target and flankers' spatial frequency are more suitable for quasi-independent activation of the form system (by the flankers) and the motion system (by the target). PMID- 26129864 TI - [Dyspnea in airway and pulmonary diseases]. AB - The subjective perception of pulmonary dyspnea varies based on behavioral and physiological responses. Acute pulmonary dyspnea is the most common symptom of diseases of the airways and the lungs and the differential diagnosis includes harmless causes, such as lack of training as well as acute life-threatening diseases, such as thromboembolism, obstruction of the upper or lower airway, pneumonia, pulmonary hemorrhage and pneumothorax. Most cases of chronic pulmonary dyspnea result from asthma, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, pulmonary fibrosis and pleural disorders. Listening to the patient's "language of dyspnea" may already provide indications for the diagnosis. Initial testing includes chest radiography, spirometry, complete blood count and the basic metabolic panel. Measurement of brain natriuretic peptide levels may help to exclude heart failure in COPD and D-dimer testing may help rule out pulmonary embolisms. Computed tomography of the chest is the most appropriate imaging procedure for diagnosing pulmonary embolism and interstitial lung disease. To diagnose pulmonary arterial hypertension echocardiography and right heart catheterization may be necessary. PMID- 26129865 TI - Personalized medicine going precise: from genomics to microbiomics. PMID- 26129867 TI - Propidium monoazide (PMA) and ethidium bromide monoazide (EMA) improve DNA array and high-throughput sequencing of porcine reproductive and respiratory syndrome virus identification. AB - Pan-viral DNA array (PVDA) and high-throughput sequencing (HTS) are useful tools to identify novel viruses of emerging diseases. However, both techniques have difficulties to identify viruses in clinical samples because of the host genomic nucleic acid content (hg/cont). Both propidium monoazide (PMA) and ethidium bromide monoazide (EMA) have the capacity to bind free DNA/RNA, but are cell membrane-impermeable. Thus, both are unable to bind protected nucleic acid such as viral genomes within intact virions. However, EMA/PMA modified genetic material cannot be amplified by enzymes. In order to assess the potential of EMA/PMA to lower the presence of amplifiable hg/cont in samples and improve virus detection, serum and lung tissue homogenates were spiked with porcine reproductive and respiratory virus (PRRSV) and were processed with EMA/PMA. In addition, PRRSV RT-qPCR positive clinical samples were also tested. EMA/PMA treatments significantly decreased amplifiable hg/cont and significantly increased the number of PVDA positive probes and their signal intensity compared to untreated spiked lung samples. EMA/PMA treatments also increased the sensitivity of HTS by increasing the number of specific PRRSV reads and the PRRSV percentage of coverage. Interestingly, EMA/PMA treatments significantly increased the sensitivity of PVDA and HTS in two out of three clinical tissue samples. Thus, EMA/PMA treatments offer a new approach to lower the amplifiable hg/cont in clinical samples and increase the success of PVDA and HTS to identify viruses. PMID- 26129866 TI - Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours. AB - OBJECTIVE: Genome-wide association studies (GWAS) of gastric cancer have reported differences in single-nucleotide polymorphism (SNP) associations for tumour subtypes, particularly when divided by location into the gastric cardia versus the non-cardia. DESIGN: Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric non-cardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 non cardia cases and 7548 controls for replication from two Chinese studies and one Korean study. From the GWAS, we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer and 1 SNP in MUC1 for replication testing. RESULTS: We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p=7.36*10(-12)) and non-cardia cancers (p=2.42*10(-23)) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77 to 0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric non-cardia cancer risk (p=2.50*10(-8)), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47*10(-2)). We also confirmed a previously reported association for rs4072037 in MUC1 with p=6.59*10(-8) for total gastric cancer and similar estimates for cardia and non-cardia cancers. Three SNPs in PSCA previously reported to be associated with gastric non-cardia cancer showed no apparent association for cardia cancer. CONCLUSIONS: Our results suggest that associations for SNPs with gastric cancer show some different results by tumour location in the stomach. PMID- 26129868 TI - Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy? AB - Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expression of markers for vascular smooth muscle cell (VSMC) maturation, markers predictive for ascending aortic dilation in BAV, and expression of fibrillin-1 were investigated. Both MFS and BAV showed an altered distribution and decreased fibrillin-1 expression in the aorta and a significantly lower level of differentiated VSMC markers. Interestingly, markers predictive for aortic dilation in BAV were not expressed in the MFS aorta. The aorta in MFS was similar to the aorta in dilated TAV with regard to the presence of medial degeneration and apoptosis, while other markers for degeneration and aging like inflammation and progerin expression were low in MFS, comparable to BAV. Both MFS and BAV aortas have immature VSMCs, while MFS and TAV patients have a similar increased rate of medial degeneration. However, the mechanism leading to apoptosis is expected to be different, being fibrillin-1 mutation induced increased angiotensin-receptor-pathway signaling in MFS and cardiovascular aging and increased progerin in TAV. Our findings could explain why angiotensin inhibition is successful in MFS and less effective in TAV and BAV patients. PMID- 26129869 TI - Relationship between diastolic ventricular dysfunction and subclinical sleep disordered breathing in atrial fibrillation ablation candidates. AB - Sleep-disordered breathing (SDB) is recognized as a primary factor or mediator of atrial fibrillation (AF). We hypothesized that the severity of SDB among AF ablation candidates would be associated with left ventricular diastolic dysfunction (LVDD) even for subclinical SDB. A total of 246 patients hospitalized for initial pulmonary vein isolation (PVI) were analyzed. Known SDB cases were excluded. We measured the oxygen desaturation index (ODI) by pulse oximetry overnight as an indicator of SDB, and classified SDB severity by 3 % ODI as normal (ODI < 5 events/h), mild (ODI <= 5 to <15 events/h), or moderate-to-severe (ODI >=15 events/h). The LVDD was assessed by echocardiography using combined categories with tissue Doppler imaging and left atrial (LA) volume measurement. Among the participants, 42 patients (17.1 %) had LVDD. The prevalence of LVDD increased with the SDB severity from 8.6 % (normal) to 12.7 % (mild) to 40.0 % (moderate-to-severe SDB) (p < 0.0001). In the multivariate logistic regression analysis, the odds ratio of having LVDD in the moderate-to-severe SDB group (ODI >= 15) vs. normal group (ODI < 5) was 5.96 (95 % CI, 2.10-19.00, P = 0.006). The presence of moderate-to-severe SDB in AF ablation candidates adversely affected LV diastolic function even during a subclinical state of SDB. PMID- 26129870 TI - Serum cystatin C and chitotriosidase in acute P-407 induced dyslipidemia: Can they serve as potential early biomarkers for atherosclerosis? AB - In an attempt to better understand potential biomarkers for, and the role of macrophages in, the development of atherosclerosis, the toxicologic, and any therapeutic pharmacologic effects of carboxymethylated beta-glucan, gadolinium chloride, and poloxamer 407 were studied in mice for their capacity to perturb serum lipids, cystatin C, and chitotriosidase-1. Gadolinium and carboxymethylated beta-glucan dosed separately to control mice had no effect on serum lipids, whereas carboxymethylated beta-glucan, but not gadolinium, exerted a significant (p<0.01) and unexpected hypolipidemic effect in poloxamer 407-induced hyperlipidemic mice. An acute hyperlipidemic state (~4 days), induced with poloxamer 407 administration alone, resulted in a significant (p<0.01) time dependent decrease and increase in serum cystatin C and chitotriosidase, respectively. Carboxymethylated beta-glucan administration to hyperlipidemic mice significantly (p<0.05) increased the serum concentration of cystatin C, but significantly (p<0.01) decreased chitotriosidase activity, when each was compared to mice treated with poloxamer 407 only. Gadolinium administration caused a significant decrease in serum chitotriosidase activity in both controls (p<0.01) and poloxamer 407-induced hyperlipidemic (p<0.001) mice, but had no effect on the concentration of cystatin C in either controls or poloxamer 407-induced hyperlipidemic mice. Gadolinium administration resulted in both morphological and functional changes to liver macrophages, which included incorporation of excess lipids, especially when simultaneously administered with poloxamer 407. It is suggested that serum cystatin C and chitotriosidase may represent potential early biomarkers for eventual atherosclerosis in the poloxamer 407-induced mouse model of atherogenesis, and that two compounds known to either increase (carboxymethylated beta-glucan) or decrease (gadolinium chloride) the number of macrophages in vivo were able to modulate serum chitotriosidase activity, This, in turn, would appear to support the premise that serum chitotriosidase activity may be a more sensitive indicator of macrophage involvement than cystatin C in the context of future atherosclerosis. PMID- 26129871 TI - Massive rotator cuff tears: pathomechanics, current treatment options, and clinical outcomes. AB - Rotator cuff tear size has an important effect on clinical outcomes after repair. Management options for massive rotator cuff tears are numerous, and selection of the most appropriate treatment method for individual patients can be a challenge. An understanding of the pathomechanics, treatment, and clinical outcomes in patients with massive rotator cuff tears can serve as a guide for clinical decision-making. The purpose of this article was to review treatment options and clinical outcomes for the management of massive rotator cuff tears. PMID- 26129872 TI - Regulation of the NADH pool and NADH/NADPH ratio redistributes acetoin and 2,3 butanediol proportion in Bacillus subtilis. AB - Bacillus subtilis produces acetoin as a major product along with several NADH dependent byproducts, especially 2,3-butanediol. In this study, the down regulation of the NADH pool and the redistribution of NADH/NADPH were targeted using external and genetic processes, as a means by which to redistribute the metabolic flux in favor of acetoin synthesis. First, it was found that the use of carbon sources of different oxidation states resulted in very different intracellular NADH/NAD(+) ratios that dictated the total process yield of acetoin. A mixture of glucose and gluconate as substrate produced a relatively low NADH/NAD(+) ratio, and resulted in an increase in acetoin production while byproducts significantly decreased. Metabolic engineering methods using glucose as a substrate could yield a similar effect. Acetoin production was significantly enhanced by overexpression of the oxidative pentose phosphate pathway: increased expression of glucose-6-phosphate dehydrogenase resulted in a decrease in the intracellular NADH/NADPH ratio (1.9-fold) and NADH/NAD(+) ratio (1.7-fold). In fed-batch culture the engineered strain yielded an acetoin concentration of 43.3 g L(-1) , while the production of 2,3-butanediol was only 1.7 g L(-1) . The concept of the manipulation of cofactor levels to redistribute carbon flux by external and genetic means as explored in this paper provides a novel strategy for improving industrial acetoin fermentation. PMID- 26129873 TI - Effect of Preferred Music on Agitation After Traumatic Brain Injury. AB - Agitation is a common behavioral problem after traumatic brain injury (TBI), which threatens the safety of patients and caregivers and disrupts the rehabilitation process. This study aimed to evaluate the effects of a preferred music intervention on the reduction of agitation in TBI patients and to compare the effects of preferred music with those of classical "relaxation" music. A single group, within-subjects, randomized crossover trial design was formed, consisting of 14 agitated patients with cognitive impairment after severe TBI. Patients listened to preferred music and classical "relaxation" music, with a wash-out period in between. Patients listening to the preferred music reported a significantly greater reduction in agitation compared with the effect seen during the classical "relaxation" music intervention (p = .046). These findings provide preliminary evidence that the preferred music intervention may be effective as an environmental therapeutic approach for reducing agitation after TBI. PMID- 26129875 TI - Foregut morphology and ontogeny of the spider crab Maja brachydactyla (Brachyura, Majoidea, Majidae). AB - We describe the morphology of the foregut of the spider crab Maja brachydactyla Balss, 1922, from first larval stage to adult, with detailed stage-specific documentation using light and scanning electron microscopy. A total of 40 ossicles have been identified in the foregut of adults of M. brachydactyla using Alizarin-Red staining. The morphological pattern of the ossicles and gastric mill is very similar to other Majoidea species with only a few variations. The foregut of the zoeae stages appeared as a small and simple cavity, with a cardio-pyloric valve that separates the stomach into cardiac and pyloric regions. The pyloric filter is present from the first zoea, in contrast to the brachyuran species which have an extended larval development. Calcified structures have been identified in the cardio-pyloric valve and pyloric region of the zoeal stages. The most significant changes in foregut morphology take place after the metamorphosis from ZII to megalopa, including the occurrence of the gastric mill. In the megalopa stage, the foregut ossicles are recognizable by their organization and general morphology, but are different from the adult phase in shape and number. Moreover, the gastric teeth show important differences: the cusps of the lateral teeth are sharp (no molariform); the dorsal tooth have a small, dentate cusp (not a well-developed quadrangular cusp); and the accessory teeth are composed of one sharp peak (instead of four sharp peaks). The gastric mill ontogeny from megalopa to adult reveals intermediate morphologies during the earlier juvenile stages. The relationship between gastric mill structures with food preferences and their contribution to the brachyuran phylogeny are briefly discussed. PMID- 26129876 TI - Can a glucagon stimulation test characterized by lower GH cut-off value be used for the diagnosis of growth hormone deficiency in adults? AB - OBJECTIVE: The aim of this study was to assess diagnostic values of insulin tolerance test (ITT), glucagon stimulation test (GST), and insulin like growth factor-I (IGF-I) level, to find optimal GH cut-off values for GST, and to evaluate efficiencies of patient age, gender, body-mass index (BMI), and additional pituitary hormone deficiencies (PHDs) in the diagnosis of growth hormone deficiency (GHD). STUDY DESIGN: This retrospective study involved 216 patients with a pituitary disease and 26 healthy controls. Age, gender, BMI, medical histories, and hormonal data including baseline and stimulated hormone values were evaluated. Three cut-off values for peak GH responses to stimulation tests were evaluated: (a) 3.00 ug/L on ITT, (b) 3.00 ug/L on GST, and (c) 1.07 ug/L on GST. RESULTS: According to the ITT, GST with 3.00 ug/L cut-off, and GST with 1.07 ug/L cut-off, GHD was present in 86.1, 74.5, and 54.2 % patients, respectively. Patient age, BMI, and number of PHDs, but not gender, were found to be correlated with IGF-I and peak GH concentrations. All patients with an IGF-I concentration <=95 ng/ml or >=3 PHD had GHD. None of the patients with adequate GH response to the GST with 1.07 ug/L cut-off, but blunted responses to ITT and GST with 3.00 ug/L cut-off, had >=3 PHDs. 12 out of 26 (46.2 %) healthy subjects failed the GST with 3.00 ug/L cut-off, but not with 1.07 ug/L cut-off. CONCLUSIONS: Patient age, IGF-I, BMI, and number of PHDs are efficient factors associated with the diagnosis of GHD. A 4 h GST with a diagnostic GH threshold of 1.07 ug/L seems to be a good diagnostic method for GHD. PMID- 26129877 TI - Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation. AB - BACKGROUND: Few rare variants in atrial fibrillation (AF)-associated genes have been functionally characterized to identify a causal relationship between these variants and development of AF. We here sought to determine the clinical effect of rare variants in AF-associated genes in patients with lone AF and characterized these variants electrophysiologically and bioinformatically. METHODS AND RESULTS: We screened all coding regions in 12 AF-associated genes in 90 patients with lone AF, with an onset of 47+/-11 years (66 men; mean age, 56+/ 13 years) by high-resolution melting curve analysis and DNA sequencing. The potassium and sodium currents were analyzed using whole-cell patch clamping. In addition to using 4 individual in silico prediction tools, we extended those predictions to an integrated tool (Combined Annotation Dependent Depletion). We identified 7 rare variants in KCNA5, KCNQ1, KCNH2, SCN5A, and SCN1B genes in 8 patients: 2 of 8 probands had a family history of AF. Electrophysiological studies revealed that 2 variants showed a loss-of-function, and 4 variants showed a gain-of-function. Five of 6 variants with electrophysiological abnormalities were predicted as pathogenic by Combined Annotation Dependent Depletion scores. CONCLUSIONS: In our cohort of patients with lone AF, 7 rare variants in cardiac ion channels were identified in 8 probands. A combination of electrophysiological studies and in silico predictions showed that these variants could contribute to the development of lone AF, although further in vivo study is necessary to confirm these results. More than half of AF-associated rare variants showed gain of-function behavior, which may be targeted using genotype-specific pharmacological therapy. PMID- 26129878 TI - High circulating microRNA-122 expression is a poor prognostic marker in patients with hepatitis B virus-related hepatocellular carcinoma who undergo radiofrequency ablation. AB - OBJECTIVES: Aim of this study was to investigate the prognostic potential of plasma microRNA-122 levels in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma after hepatic resection or radiofrequency ablation (RFA). DESIGN AND METHODS: A total of 120 patients with HBV-related hepatocellular carcinoma who underwent hepatic resection (n=63) or RFA (n=57) were included. The pretreatment plasma microRNA-122 level was assessed using quantitative real time polymerase chain reaction, and the correlation between microRNA-122 expression and various clinical parameters was investigated. RESULTS: Multivariate Cox regression analysis demonstrated that, in all patients, a low platelet count (<100*10(9)/L), low albumin level (<=3.5g/dL.), and advanced tumor stage (modified Union for International Cancer Control stage III/IV) were independent prognostic factors for disease-free survival, while a low albumin level and advanced tumor stage were independent prognostic factors for overall survival (OS). In a subgroup analysis of patients who underwent RFA, the patients with high miR-122 expression (>100) had significantly lower OS on Kaplan-Meier analysis (P=0.042). Furthermore, high microRNA-122 expression (hazard ratio [HR]=2.67; 95% confidence interval [CI]=1.12-6.35; P=0.026) and advanced tumor stage (HR=2.27; 95% CI=1.23-4.18; P=0.009) were independent risk factors for poor OS in patients treated with RFA. The combination of microRNA-122 and tumor stage resulted in an area under the curve of 0.818 for predicting 1-year OS in patients who underwent RFA. CONCLUSIONS: High plasma microRNA-122 expression was associated with poor OS in patients with HBV-related hepatocellular carcinoma who underwent RFA. PMID- 26129879 TI - Analytical evaluation of the novel soluble fms-like tyrosine kinase 1 and placental growth factor assays for the diagnosis of preeclampsia. AB - OBJECTIVES: Performance evaluation of the novel BRAHMS KRYPTOR soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) assays. DESIGN AND METHODS: Intra- and inter-assay imprecision, functional sensitivity, linearity in dilution, method comparison, and diagnostic capacity were evaluated. RESULTS: Intra-assay coefficient of variations (CVs) were between 1.1% and 5.3% and inter assay CVs between 3.9% and 11.1%. Functional sensitivity was 6.7ng/L for PlGF and 34ng/L for sFlt-1, respectively. The linearity in dilution was excellent (r>0.995) in the assay-specific relevant range of concentration. The KRYPTOR assay correlated well with the Elecsys sFlt-1 (r=0.996), Elecsys PlGF (r=0.990) and the Elecsys sFlt-1/PlGF ratio (r=0.947) with partially high mean bias values. The optimal cut points for diagnosis of preeclampsia were calculated for KRYPTOR assays at: 60.5ng/L (PlGF), 4725ng/L (sFlt-1), and 99.2 (sFlt-1/PlGF ratio) which were different with the corresponding Elecsys cut points. Nevertheless, the sensitivity, specificity, positive predictive values (PPVs), negative predictive values (NPVs), and areas under the curves (AUCs) were completely comparable in both assay platforms, even when applying the standard cut-off of 85 for sFlt 1/PlGF ratio or gestational age specific "rule in-rule-out" cut-offs for early and late onset preeclampsia. CONCLUSION: The new BRAHMS KRYPTOR sFlt-1 and PlGF immunoassay show excellent precision and reliability. The assay results and the diagnostic capacity were highly comparable to established fully automated immunoassays (Elecsys). Hence, sFlt-1/PlGF ratio generated on KRYPTOR immunoassay platform should be suitable for diagnosing preeclampsia in clinical routine laboratory. PMID- 26129880 TI - A pro-inflammatory glycoprotein biomarker is associated with lower bilirubin in metabolic syndrome. AB - OBJECTIVES: Bilirubin exerts anti-oxidative and anti-inflammatory properties which may beneficially influence the development of cardio-metabolic disorders. A nuclear magnetic resonance (NMR) spectroscopy-based glycoprotein biomarker, designated GlycA, whose signal originates from several glycosylated acute-phase proteins, has been recently developed. We tested whether plasma GlycA is associated with bilirubin in subjects with and without MetS. DESIGN AND METHODS: GlycA (NMR spectroscopy), high sensitivity C-reactive protein (hs-CRP) and bilirubin were measured in 58 fasting subjects with MetS and in 63 subjects without MetS (including 65 subjects with type 2 diabetes mellitus). RESULTS: GlycA and hs-CRP were higher, coinciding with lower bilirubin in MetS (p<0.01 for each). In all subjects combined, GlycA was strongly correlated with hs-CRP (r=0.631, p<0.001). Age-, sex- and diabetes status-adjusted multivariable linear regression analysis demonstrated that GlycA and hs-CRP were both associated positively with the presence of MetS (beta=0.256, p=0.014 and beta=0.259, p=0.012, respectively). GlycA and hs-CRP were negatively related to bilirubin (beta=-0.258, p=0.007 and beta=-0.305, p<0.001, respectively), independent of MetS (p>0.05 for each) and diabetes status (p>0.50 for each). CONCLUSIONS: GlycA is elevated in MetS, and may represent a quantitative measure of a pro inflammatory state. Increased levels of glycosylated acute-phase proteins are associated with lower bilirubin in MetS. PMID- 26129881 TI - Direct comparison of the diagnostic accuracy between blood and cerebrospinal fluid procalcitonin levels in patients with meningitis. AB - OBJECTIVE: To compare the clinical utility of serum and cerebrospinal fluid (CSF) procalcitonin (PCT) for the diagnosis of bacterial meningitis (BM) among patients with suspected meningitis. METHODS: Patients with meningitis-like symptoms (n=120), admitted to the Second People's Hospital of Wuxi or the Changhai Hospital of Shanghai between January 2011 and December 2013, were prospectively and consecutively enrolled in this study. BM was finally diagnosed by CSF culture, Gram staining, quantitative polymerase chain reaction (qPCR), and treatment response. The diagnostic accuracy of the serum and CSF PCT was assessed by receiver operator characteristic (ROC) curve analysis. The relationship between CSF and serum PCT levels as well as the CSF leukocyte count and protein level was analyzed by Spearman's correlation analysis. RESULTS: PCT level in both the serum and CSF was significantly increased in the BM patients. The area under ROC curve of serum PCT for the diagnosis of BM was 0.96 (95% confidence interval (CI): 0.93-1.00), significantly higher than that of CSF PCT (0.90, 95% CI: 0.83 0.96). Using 0.88ng/mL as the threshold, the diagnostic sensitivity, specificity, and accuracy of serum PCT for the diagnosis of BM were 0.87 (95% CI, 0.73-0.95), 1.00 (95% CI, 0.95-1.00), and 95%, respectively. The serum PCT level was positively correlated with the CSF PCT level, leukocyte count, and protein level. CONCLUSION: Both the serum and CSF PCT had a high diagnostic value for BM among suspected meningitis patients, and serum PCT demonstrated a superior diagnostic value compared to CSF PCT. PMID- 26129882 TI - Cardiomyocyte injury induced by hemodynamic cardiac stress: Differential release of cardiac biomarkers. AB - OBJECTIVE: We explored whether hemodynamic cardiac stress leads to a differential release of cardiomyocyte injury biomarkers, used in the diagnosis of acute myocardial infarction (AMI). METHODS: In an observational international multicenter study, we enrolled 831 unselected patients presenting with symptoms suggestive of AMI to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. Hemodynamic cardiac stress was quantified by levels of B-type natriuretic peptide (BNP). Spearman's rho correlation was used to analyze the correlations between BNP and high-sensitivity cardiac troponin T (hs-cTnT), Siemens cTnI-Ultra (cTnI-ultra), CK-MB and Myoglobin. Patients were categorized according to the extent of hemodynamic cardiac stress as quantified by BNP tertiles. RESULTS: Among all patients, the positive pair-wise correlation with BNP was strongest with hs-cTnT and cTnI-ultra (r=0.58 and 0.50, respectively), moderate for Myoglobin (r=0.43), and weakest with CK-MB (r=0.25; p<0.001 for each). Similar pattern of correlations was also observed among AMI patients. Among patients diagnosed with non-cardiac cause of chest pain (n=385, 46%) and cardiac but non-coronary (n=109, 13%), BNP had significant positive correlations with hs-cTnT, cTnI-ultra and Myoglobin (p<0.05), but not with CK-MB (p=NS). A similar pattern of stronger correlation between BNP and hs-cTnT, cTnI-ultra and Myoglobin as compared to that with CK-MB was also observed within the higher BNP tertile range. There was no correlation between BNP and other biomarkers within the 1st BNP tertile group. CONCLUSION: Hemodynamic cardiac stress, as quantified by BNP, as a likely cause of cardiomyocyte injury, is more closely reflected by concentrations of hs-cTnT, cTnI-ultra and Myoglobin than CK-MB. PMID- 26129883 TI - Up-regulation of miR-138 inhibits hypoxia-induced cardiomyocyte apoptosis via down-regulating lipocalin-2 expression. AB - Hypoxia-induced cardiomyocyte apoptosis contributes significantly to the development of numerous cardiac diseases, such as ischemic heart disease, heart failure, etc. Promoting cell survival by inhibiting apoptosis is one of the available strategies to attenuate cardiac dysfunction caused by cardiomyocyte loss. Previous studies have been demonstrated that miR-138 and lipocalin-2 (Lcn2) play important roles in cardiomyocyte apoptosis and survival. We presently determined whether Lcn2 is a target gene of miR-138 involved in hypoxia-induced cardiomyocyte apoptosis. Firstly, mimics of miR-138 were transfected into HL-1 cells to investigate its effect on cell apoptosis. Using 3-(4,5-dimethyl-thiazol 2-y1) 2,5-diphenyl tetrazolium bromide (MTT) and Annexin V-FITC/PI flow cytometer assays, over-expression of miR-138 significantly enhanced the cell growth and significantly attenuated the cell apoptosis in hypoxic conditions. Dual luciferase reporter gene and western blot results confirmed Lcn2 was a direct target of miR-138. Then, the recombinant plasmid, pcDNA3.1/Lcn2 was transfected into the HL-1 cells that over-expressed miR-138. We further observed that the over-expression of Lcn2 diminished the protection of miR-138 over-expression from hypoxia-induced cell survival and apoptosis. In conclusion, our study demonstrated that up-regulation of miR-138 inhibits the hypoxia-induced cardiomyocyte apoptosis via down-regulating the pro-apoptotic gene expression of Lcn2. PMID- 26129884 TI - Equilibrium of sortase A dimerization on Staphylococcus aureus cell surface mediates its cell wall sorting activity. AB - Staphylococcus aureus sortase A (SrtA) transpeptidase is a therapeutically important membrane-bound enzyme in Gram-positive bacteria, which organizes the covalently attached cell surface proteins on the peptidoglycan cell wall of the organism. Here, we report the direct observation of the highly selective homo dimerization of SrtA on the cell membrane. To address the biological significance of the dimerization towards enzyme function, site-directed mutagenesis was performed to generate a SrtA mutant, which exists as monomer on the cell membrane. We observed that the cell surface display of adhesive proteins in S. aureus cells expressing monomeric SrtA mutant is more prominent than the cells expressing the wild-type enzyme. A cell-based invasion assay was also performed to evaluate the activities of wild-type SrtA and its monomeric mutant as well. Our data demonstrated that S. aureus cells expressing SrtA in monomeric form invade host mammalian cells more efficiently than those expressing wild-type SrtA in dimer-monomer equilibrium. The results suggested that the monomeric form of SrtA is more active than the dimeric form of the enzyme in terms of cell surface display of virulence factors for infection. This is the first study to present the oligomerization of SrtA and its related biological function on the cell membrane. Study of SrtA dimerization has implications for understanding its catalytic mechanism at the cellular level as well as the development of novel anti-infective agents. PMID- 26129885 TI - Crimean-Congo hemorrhagic fever with hyperbilirubinemia and ascites: An unusual presentation. AB - Crimean-Congo hemorrhagic fever (CCHF) is a fatal systemic viral infection which is an important health problem in Turkey. Many systemic symptoms have been reported including fever, hemorrhage, headache, fatigue, muscle ache, abdominal pain, nausea and vomiting. A 45-year-old male farmer with CCHF presented with massive peritoneal effusion and hyperbilirubinemia. To our knowledge, this is the first case of peritoneal effusion and hyperbilirubinemia in an adult patient with CCHF. His clinical symptoms successfully improved with supportive therapy. In patients who live in endemic areas with atypical presentation for the diagnosis of CCHF should be kept in mind. PMID- 26129886 TI - New Insulating Antiferromagnetic Quaternary Iridates MLa10Ir4O24 (M = Sr, Ba). AB - Recently, oxides of Ir(4+) have received renewed attention in the condensed matter physics community, as it has been reported that certain iridates have a strongly spin-orbital coupled (SOC) electronic state, J eff = 1/2, that defines the electronic and magnetic properties. The canonical example is the Ruddlesden Popper compound Sr2IrO4, which has been suggested as a potential route to a new class of high temperature superconductor due to the formal analogy between J eff = 1/2 and the S = 1/2 state of the cuprate superconductors. The quest for other iridium oxides that present tests of the underlying SOC physics is underway. In this spirit, here we report the synthesis and physical properties of two new quaternary tetravalent iridates, MLa10Ir4O24 (M = Sr, Ba). The crystal structure of both compounds features isolated IrO6 octahedra in which the electronic configuration of Ir is d(5). Both compounds order antiferromagnetically despite the lack of obvious superexchange pathways, and resistivity measurement shows that SrLa10Ir4O24 is an insulator. PMID- 26129887 TI - Does vaginal douching affect the type of candidal vulvovaginal infection? AB - The normal vaginal microbiota is a dynamic system that continually fluctuates under the environmental changes and different physiological conditions. Yeast infections of the vagina are caused by one of the species of fungus called Candida (C.). The study aimed to evaluate the types of mycobiota in women with vulvovaginal candidiasis (VVC) who were performing vaginal douching (VD) or not. Furthermore, it studied the antifungal sensitivity toward different fungi isolated from the vagina. In a cross-sectional study conducted in Assiut University Hospital, Egypt, women with VVC were interviewed regarding relevant history including the habit of VD. Vaginal swabs were obtained and processed by direct microscope and by culture on CHROMagar Candida and other differential media. The types of Candida in women with the habit of VD were compared with those not having this habit. We found that VD habit was practiced by 67.4% of women with VVC, and Candida albicans was the commonest (78.3%) type observed. There was no significant difference in the percentage of non-albicans types between women performing VD (23.6%) and those not reporting this habit (18.9%). Harboring non-albicans types were significantly increased in regular performers of VD compared with those who had this procedure only after sexual intercourse or after the end of menstruation (36.8%,12.5%, and 16.7%, respectively) (P = .048). Thus, vaginal douching does not influence the type of Candida infection involved in VVC. Frequent performance of VD increases the likelihood of having non albicans types and the resistance to the common antifungal agents. PMID- 26129888 TI - Temporal changes in the skin Malassezia microbiota of members of the Japanese Antarctic Research Expedition (JARE): A case study in Antarctica as a pseudo space environment. AB - The International Space Station (ISS) is located approximately 400 km above the Earth. Astronauts staying at the ISS are under microgravity and are thus unable to bathe or shower; instead, they wash their bodies using wet tissues. For astronauts, skin hygiene management is important to maintain the quality of life during long-term stays on the ISS. In Antarctica, members of a Japanese geological investigation team negotiate their way over land using snowmobiles. During their 3-month stay, they are subject to a "pseudo-space" environment similar to that experienced by ISS astronauts, including the inability to bathe or shower. In this study, temporal changes in the colonization levels of skin lipophilic fungi, Malassezia were investigated in 16 team members. Compared to the levels before their trip to Antarctica, the fold changes in Malassezia colonization levels during the researchers' stay in Antarctica were in the range of 3.0 +/- 1.9 to 5.3 +/- 7.5 in cheek samples, 8.9 +/- 10.6 to 22.2 +/- 40.0 in anterior chest samples, 6.2 +/- 5.4 to 16.9 +/- 25.5 in behind-the-ear samples, and 1.7 +/- 0.9 to 17.4 +/- 33.4 in sole-of-the-foot samples. On the scalp, the level of Malassezia colonization increased dramatically, by 96.7 +/- 113.8 to 916.9 +/- 1251.5 fold. During their stay in Antarctica, the team members experienced itchy scalps and produced a large number of scales. The relative proportions of Malassezia globosa and M. restricta shifted to seborrheic dermatitis/dandruff types. These results provide useful information for the development of skin hygiene management plans for astronauts staying at the ISS. PMID- 26129889 TI - Dectin-2 polymorphism associated with pulmonary cryptococcosis in HIV-uninfected Chinese patients. AB - Dectin-2 is a C-type lectin receptor that can recognize critical structures of fungi and involve in the host immune response after pulmonary fungal infections. We aimed to investigate the association between Dectin-2 genetic polymorphisms and cryptococcosis among a series of human immunodeficiency virus (HIV) uninfected Chinese patients. In this case control study, a total of 251 patients with cryptococcosis and 464 healthy controls were included. One tag-single nucleotide polymorphism (SNP) (rs11045418) located at 5'-flanking region of Dectin-2 gene was selected and genotyped in this study. Among 251 patients, there were 108 (43%) meningitis patients including 73 (67.7%) healthy ones, 74 (29.5%) pulmonary infected patients including 49 (66.2%) healthy ones, and 69 (27.5%) patients with both neural and pulmonary infection including 38 (55.1%) immunocompetent ones. One hundred and forty-three (74 plus 69) patients with pulmonary cryptococcosis and 177 (108 plus 69) patients with cryptococcal meningitis were compared with controls, respectively. Three samples from 143 pulmonary infected patients failed in genotyping. There was a significant difference between 86 immunocompetent pulmonary infected patients and controls in the overdominant model (C/T vs. T/T + C/C; OR, 0.59; 95%CI, 0.37-0.94; P, .026). Similar but not significant difference was found between the overall pulmonary infected patients and the controls in the overdominant model (OR, 0.77; 95%CI, 0.52-1.12; P, .17). No such difference was found between controls and patients with cryptococcal meningitis. Our study firstly showed a genetic association between Dectin-2 and pulmonary cryptococcosis. PMID- 26129890 TI - Effects of host response and antifungal therapy on serum and BAL levels of galactomannan and (1->3)-beta-D-glucan in experimental invasive pulmonary aspergillosis. AB - Galactomannan and (1->3)-beta-D-glucan are useful biomarkers of invasive pulmonary aspergillosis (IPA). However, the effects of immunosuppression on levels of galactomannan or (1->3)-beta-D-glucan in IPA are not well understood or quantified. We therefore studied the simultaneous levels of galactomannan and (1 >3)-beta-D-glucan in two rabbit models of experimental IPA: (1) AraC-induced neutropenia in untreated (UC-AraC) and liposomal amphotericin B-treated (LAMB AraC) rabbits; and (2) nonneutropenic cyclosporine-methylprednisolone immunosuppression in untreated (UC-CsA+M) and LAMB-treated (LAMB-CsA+M) rabbits. Simultaneous levels of galactomannan and (1->3)-beta-D-glucan were determined in bronchoalveolar lavage (BAL) fluid and serial serum specimens and correlated with pulmonary host response. Serum galactomannan index (GMI) and (1->3)-beta-D-glucan concentration-time-curves were higher in UC-AraC vs. UC-CsA+M (Mann-Whitney U test, P < .05). Serum galactomannan and (1->3)-beta-D-glucan in treatment groups demonstrated therapeutic responses with similarly lower levels in comparison to UC (P < .01) in both models. Host differences did not affect BAL fluid GMI or (1 >3)-beta-D-glucan but did affect galactomannan and (1->3)-beta-D-glucan levels in serum. The higher serum GMI and (1->3)-beta-D-glucan concentration-time-curves in UC-AraC correlated with extensive pulmonary infiltration by angioinvasive hyphae and minimal inflammation, while the lower concentration-time-curves in UC-CsA+M were associated with shorter and fewer hyphae in lung tissue and an intensive neutrophil response to Aspergillus hyphae. Thus, serum levels of galactomannan and (1->3)-beta-D-glucan in IPA depended upon immunosuppression, which also affected severity of infection and hyphal morphology, while BAL fluid galactomannan and (1->3)-beta-D-glucan were sensitive biomarkers not affected by host response. PMID- 26129891 TI - Discovery of a sexual stage in Trichophyton onychocola, a presumed geophilic dermatophyte isolated from toenails of patients with a history of T. rubrum onychomycosis. AB - Trichophyton onychocola is a recently described geophilic dermatophyte that has been isolated from a toenail of Czech patient with a history of onychomycosis due to T. rubrum and clinical suspicion of relapse. In this study, we report a similar case from Denmark in an otherwise healthy 56-year-old man. The patient had a history of great toenail infection caused by T. rubrum in 2004 and presented with suspected relapse in 2011 and 2013. Trichophyton onychocola was the only microbial agent isolated at the second visit in 2013 and the identification was confirmed by DNA sequencing. Direct microscopic nail examination was positive for hyphae, however the etiological significance of T. onychocola was not supported by repeated isolation of the fungus. This new species may be an overlooked geophilic species due to the resemblance to some common species, for example, zoophilic T. interdigitale or some species of geophilic dermatophytes. We included differential diagnosis with phenotypically similar species; however, it is recommended that molecular methods are used for correct identification. The MAT locus of Danish strain was of opposite mating type than in the previously isolated Czech strain and the two isolates were successfully mated. The mating experiments with related heterothallic species T. thuringiense and Arthroderma melis were negative. The sexual state showed all typical signs of arthroderma-morph and is described by using optical as well as scanning electron microscopy. The sexual state was induced on a set of agar media, however low cultivation temperature and the presence of keratin source were crucial for the success rather than formulation of medium. PMID- 26129892 TI - Characterization and genetic variability of feed-borne and clinical animal/human Aspergillus fumigatus strains using molecular markers. AB - Aspergillus fumigatus, the major etiological agent of human and animal aspergillosis, is a toxigenic fungus largely regarded as a single species by macroscopic and microscopic features. However, molecular studies have demonstrated that several morphologically identified A. fumigatus strains might be genetically distinct. This work was aimed to apply PCR-restriction length fragment polymorphisms (PCR-RFLP) and random amplification of polymorphic DNA (RAPD) molecular markers to characterize a set of feed-borne and clinical A. fumigatus sensu lato strains isolated from Argentina and Brazil and to determine and compare their genetic variability. All A. fumigatus strains had the same band profile and those typical of A. fumigatus sensu stricto positive controls by PCR RFLP. Moreover, all Argentinian and Brazilian strains typified by RAPD showed similar band patterns to each other and to A. fumigatus sensu stricto reference strains regardless of their isolation source (animal feeds or human/animal clinical cases) and geographic origin. Genetic similarity coefficients ranged from 0.61 to 1.00, but almost all isolates showed 78% of genetic similarly suggesting that genetic variability was found at intraspecific level. Finally, benA sequencing confirmed its identification as A. fumigatus sensu stricto species. These results suggest that A. fumigatus sensu stricto is a predominant species into Aspergillus section Fumigati found in animal environments as well as in human/animal clinical cases, while other species may be rarely isolated. The strains involved in human and animal aspergillosis could come from the environment where this fungus is frequently found. Rural workers and animals would be constantly exposed. PMID- 26129893 TI - Brain calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers. AB - Primary Familial Brain Calcification (PFBC) is a dominantly inherited cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Three causative genes have been identified: SLC20A2, PDGFRB and, recently, PDGFB, whose associated phenotype has not yet been extensively studied. We included in the largest published case series of genetically confirmed PFBC, 19 PDGFB (including three new mutations), 24 SLC20A2 (including 4 new mutations), and 14 PDGFRB mutation carriers, from two countries (France and Brazil). We studied clinical features and applied our visual rating scale on all 49 available CT scans. Among the symptomatic mutation carriers (33/57, 58%), the three most frequently observed categories of clinical features were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%). The median age of clinical onset was 31 years, 25% had an early onset (before 18) and 25% a later onset (after 53). Patients with an early clinical onset exhibited mostly isolated psychiatric or cognitive signs, while patients with a later onset exhibited mostly movement disorders, especially in association with other clinical features. CT scans rating allowed identifying four patterns of calcification. The total calcification score was best predicted by the combined effects of gene (SLC20A2 > PDGFB > PDGFRB mutations), sex (male), and (increasing) age, defining three risk classes, which correlated with the four patterns of calcification. These calcification patterns could reflect the natural history of the calcifying process, with distinct risk classes characterized by different age at onset or rate of progression. PMID- 26129895 TI - Demystifying the Search Button: A Comprehensive PubMed Search Strategy for Performing an Exhaustive Literature Review. AB - A thorough review of the literature is the basis of all research and evidence based practice. A gold-standard efficient and exhaustive search strategy is needed to ensure all relevant citations have been captured and that the search performed is reproducible. The PubMed database comprises both the MEDLINE and non MEDLINE databases. MEDLINE-based search strategies are robust but capture only 89% of the total available citations in PubMed. The remaining 11% include the most recent and possibly relevant citations but are only searchable through less efficient techniques. An effective search strategy must employ both the MEDLINE and the non-MEDLINE portion of PubMed to ensure all studies have been identified. The robust MEDLINE search strategies are used for the MEDLINE portion of the search. Usage of the less robust strategies is then efficiently confined to search only the remaining 11% of PubMed citations that have not been indexed for MEDLINE. The current article offers step-by-step instructions for building such a search exploring methods for the discovery of medical subject heading (MeSH) terms to search MEDLINE, text-based methods for exploring the non-MEDLINE database, information on the limitations of convenience algorithms such as the "related citations feature," the strengths and pitfalls associated with commonly used filters, the proper usage of Boolean operators to organize a master search strategy, and instructions for automating that search through "MyNCBI" to receive search query updates by email as new citations become available. PMID- 26129894 TI - A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis. AB - During angiogenesis, Rho-GTPases influence endothelial cell migration and cell cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis. PMID- 26129896 TI - Placement of a Magnetic Small Bowel Feeding Tube at the Bedside. AB - BACKGROUND: Current methods of achieving postpyloric enteral access for feeding are fraught with difficulties, which can markedly delay enteral feeding and cause complications. Bedside tube placement has a low success rate, often requires several radiographs to confirm position, and delays feeding by many hours. Although postpyloric enteral tubes can reliably be placed in interventional radiology (IR), this involves greater resource utilization, delays, cost, and inconvenience. We assessed the utility of bedside enteral tube placement using a magnetic feeding tube (Syncro-BlueTube; Syncro Medical Innovations, Macon, GA, USA) as a means to facilitate initial tube placement. METHODS: We recorded the time to insertion, location of tube, success rate, and need for radiographs in a series of patients given magnetic feeding tubes (n = 46) inserted by our hospitalist service over an 8-month interval. RESULTS: Of the 46 attempted magnetic tube placements, 76% were successfully placed in the postpyloric position, 13% were in the stomach, and 11% could not be placed. In 83% of the magnetic tubes, only 1 radiograph was needed for confirmation. The median time to placement was 12 minutes (range, 4-120 minutes). CONCLUSION: The use of a magnetic feeding tube can increase the success rate of bedside postpyloric placement, decrease the time to successful placement, and decrease the need for supplemental radiographs and IR. PMID- 26129897 TI - Oral Citrulline Mitigates Inflammation and Jejunal Damage via the Inactivation of Neuronal Nitric Oxide Synthase and Nuclear Factor-kappaB in Intestinal Ischemia and Reperfusion. AB - BACKGROUND: Intestinal ischemia and reperfusion (I/R) is a life-threatening emergency accompanied by inflammation and organ damage. We compared the mechanisms and the effects of arginine, citrulline, and glutamine on inflammation and intestinal damage. MATERIALS AND METHODS: Male Wistar rats underwent 60 minutes of superior mesenteric artery occlusion and either 3 (I/R3) or 24 (I/R24) hours of reperfusion and were orally administered vehicle, arginine, citrulline, or glutamine 15 minutes before reperfusion and at 3, 9, and 21 hours of reperfusion. RESULTS: I/R3 rats experienced jejunal damage and apoptosis, and I/R24 rats had liver dysfunction compared with normal rats (one-way ANOVA, P < .05). Arginine and citrulline administrations improved jejunal morphology, and citrulline and glutamine administrations alleviated the loss of jejunal mass in I/R3 rats. I/R3-increased circulating nitrate/nitrite (NOx), tumor necrosis factor-alpha, and interleukin-6 were significantly decreased by citrulline, glutamine and citrulline, and arginine, glutamine, and citrulline, respectively. These amino acids decreased plasma NOx and interferon-gamma in I/R24, decreased jejunal neuronal nitric oxide synthase (NOS) protein in I/R3 rats, and alleviated jejunal apoptosis in I/R3 and I/R24 rats. In addition, the jejunal phosphorylated to total nuclear factor-kappaB (NF-kappaB) ratio was decreased by arginine and citrulline in I/R24 rats. CONCLUSION: Oral administration of arginine, citrulline, and glutamine may alleviate systemic inflammation, jejunal apoptosis, and neuronal NOS in intestinal I/R. Citrulline may further attenuate jejunal damage by preserving jejunal mass, partially via the inactivation of NOS and the NF-kappaB pathway. In conclusion, oral citrulline may have more benefits than arginine and glutamine in mitigating intestinal ischemia and reperfusion-induced adverse effects. PMID- 26129898 TI - Effects of electro-acupuncture at Tongli (HT 5) and Xuanzhong (GB 39) acupoints from functional magnetic resonance imaging evidence. AB - OBJECTIVE: To explore the specifificity of Tongli (HT 5) and Xuanzhong (GB 39) paired acupionts in aspects of Deqi sensation and brain activation patterns during electroacupuncture. METHODS: In this study, 15 healthy subjects were enrolled. All participants suffered two kinds of functional magnetic resonance imaging (fMRI) examinations randomly: Examination A received electro-acupuncture (EA) at the bilateral Tongli (HT5) and Xuanzhong (GB 39) acupoints (ACU), and examination B received EA at bilateral non-acupoints (NAP). The subjects reported the feeling of Deqi at each examination later respectively. A multi-voxel pattern analysis method and Statistical Program for Social Sciences were used to analyze the data. RESULTS: The ACU group (Exam A) reported fullness, heaviness, numbness, soreness and throbbing of signifificantly greater intensity than the NAP group (Exam B). In addition, there was no statistical signifificance between two groups in aching, tingling, deep pressure, sharp pain, dull pain, warmness and cold. Meanwhile, fMRI data revealed differences between two groups in discriminating accuracy of brain somatosensory cortex and language-related cortices. CONCLUSIONS: Needling HT 5 and GB 39 may modulate language function through a complex brain network, suggesting that it may be benefificial to the recovery of language function in patients with aphasia. PMID- 26129899 TI - Can Ashi points stimulation have specific effects on shoulder pain? A systematic review of randomized controlled trials. AB - OBJECTIVE: To provide an evidence-based overview regarding the efficacy of Ashi points stimulation for the treatment of shoulder pain. METHODS: A comprehensive search [PubMed, Chinese Biomedical Literature Database, China National Knowledge Infrastructure (CNKI), Chongqing Weipu Database for Chinese Technical Periodicals (VIP) and Wanfang Database] was conducted to identify randomized or quasi randomized controlled trials that evaluated the effectiveness of Ashi points stimulation for shoulder pain compared with conventional treatment. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. RevMan 5.0 was used for data synthesis. RESULTS: Nine trials were included. Seven studies assessed the effectiveness of Ashi points stimulation on response rate compared with conventional acupuncture. Their results suggested significant effect in favour of Ashi points stimulation [odds ratio (OR): 5.89, 95% confidence interval (CI): 2.97 to 11.67, P<0.01, heterogeneity: chi(2) =3.81, P=0.70, I (2) =0% ]. One trial compared Ashi points stimulation with drug therapy. The result showed there was a significantly greater recovery rate in group of Ashi points stimulation (OR: 9.58, 95% CI: 2.69 to 34.12). One trial compared comprehensive treatment on the myofascial trigger points (MTrPs) with no treatment and the result was in favor of MTrPs. CONCLUSIONS: Ashi points stimulation might be superior to conventional acupuncture, drug therapy and no treatment for shoulder pain. However, due to the low methodological quality of included studies, a firm conclusion could not be reached until further studies of high quality are available. PMID- 26129900 TI - Dalitong granule combined with electroacupuncture in the treatment of functional dyspepsia: A randomized controlled trial. AB - OBJECTIVE: To explore clinical short and long-term effect of combining dalitong granule (DG) and electroacupuncture group (EA) in the treatment of functional dyspepsia. METHODS: Totally 640 patients with confirmed functional dyspepsia were randomly divided into 4 groups using a randomized digital table: the DG group, the EA group, the combined group and the control group, 160 cases in each group. The DG group was treated with 6 g DG 3 times daily; the EA group was treated with puncture of points Zusanli (ST36), Zhongwan (CV12), Neiguan (PC6), Taichong (LR3) and Gongsun (SP4) twice daily; the combined group with above-mentioned DG and EA; and the control group with 5 mg mosapride 3 times, 20 mg pantoprazole and 25 mg amitriptylines twice daily. The treatment course was 4 weeks for all groups. The symptom score, quality of life score by Short Form 36 Health Survey Questionnaires (SF-36), plasma motilin by radioimmunoassay, electrogastrographic frequencies by electrogastrogram (EGG) and gastric emptying by B-sonography were examined, and adverse reactions were observed before, at the end of treatment and 60 weeks post-treatment. RESULTS: In the DG group 1 case dropped out for not taking medicine strictly and 1 case was lost to follow-up, while 1 case in the EA group and 2 cases in the combined therapy group were lost to follow-up. Compared with pre-treatment, quality of life score, plasma motilin, electrogastrographic frequencies and gastric emptying were all increased significantly, while symptom score was decreased significantly at the end of treatment in each group (P<0.01); in the combined group quality of life score, plasma motilin, electrogastrographic frequencies and gastric emptying were all significantly higher than those in the other groups, while symptom score was significantly lower than in the other groups (P<0.05). Compared with at the end of treatment, these indices changed insignificantly in the combined group and the EA group 60 weeks post-treatment (P>0.05), but the 4 increased indices were all decreased significantly, and symptom score was increased significantly in the DG and the control groups (P>0.05). The short and long-term total effective rates in the combined group were all significantly higher than those in the other treatment groups (P<0.05 or P<0.01). No serious adverse reaction occurred in the four groups. CONCLUSION: Combined treatment of DG and EA could increase both plasma motilin and electrogastrographic frequencies, promote gastric emptying, alleviate the symptom of dyspepsia so as to increase quality of life, with better safety and long-term effect. PMID- 26129901 TI - In vitro antifungal activity of some traditional Persian medicinal plants on pathogenic fungi. AB - OBJECTIVE: To investigate the antifungal activities of the extracts and sub fractions of Phlomis olivieri, Verbascum speciosum, Sambucus ebulus and Erigeron hyrcanicus, four Persian medicinal plants used in Iranian folk medicine. METHODS: Evaluation of the antifungal activity was performed on the clinical isolates of pathogenic fungi including Aspergillus fumigatus, A. flavus, Trichophyton mentagrophytes, T. rubrum, T. verrucosum, Microsporum canis, M. gypseum and Epidermophyton floccosum, and the yeast Candida albicans. The susceptibility tests were done by agar well diffusion method. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of active extracts and sub-fractions were measured using method of National Committee for Clinical Laboratory Standards (NCCLS). RESULTS: Only P. olivieri sub-fractions were found to have fungicidal activity among the other investigated plants. The MIC and MFC was found to be high in petroleum ether, chloroform and ethyl acetate fractions (100 and 200 mg/mL) against the studied pathogenic fungi and the yeast Candida albicans. P. olivieri sub-fractions significantly inhibited the growth of all pathogenic fungi and the yeast studied. CONCLUSION: If the antifungal activity of P. olivieri is confirmed by in vivo studies and if the responsible compound (s) is isolated and identified, it could be a good remedy for mycotic infections. PMID- 26129903 TI - Benthic plastic debris in marine and fresh water environments. AB - This review provides a discussion of the published literature concerning benthic plastic debris in ocean, sea, lake, estuary and river bottoms throughout the world. Although numerous investigations of shoreline, surface and near-surface plastic debris provide important information on plastic types, distribution, accumulation, and degradation, studies of submerged plastic debris have been sporadic in the past and have become more prominent only recently. The distribution of benthic debris is controlled mainly by combinations of urban proximity and its association with fishing-related activities, geomorphology, hydrological conditions, and river input. High density plastics, biofouled products, polymers with mineral fillers or adsorbed minerals, and plastic-metal composites all have the potential to sink. Once deposited on the bottoms of water basins and channels, plastics are shielded from UV light, thus slowing the degradation process significantly. Investigations of the interactions between benthic plastic debris and bottom-dwelling organisms will help shed light on the potential dangers of submerged plastic litter. PMID- 26129902 TI - Influence of Yanyankang Powder on Th1/Th2 in rats with experimental autoimmune uveitis. AB - OBJECTIVE: To study the influence of Yanyankang powder on Th1/Th2 in rats with experimental autoimmune uveitis (EAU). METHODS: The EAU models were induced in Lewis rats by immunization with interphotoreceptor retinoid binding protein (IRBP) 1177-1191 in complete Freund's adjuvant. The rats were randomly divided into 3 groups: a model control group, a Yanyankang group, and a prednisone group, 9 rats in each group. The model control group was intervened with saline solution by gavage. The Yanyankang group was intervened with Yanyankang powder 4 g/(kg day) by gavage. The prednisone group were intervened with prednisone acetate tablets 5 mg/(kg d) by gavage. All groups were intervened after immunization once every 2 days for 18 days and monitored by slit-lamp biomicroscopy daily until day 18. The levels of gamma interferon (INF-gamma) and interleukin-10 (IL-10) in the supernatants of T cells were determined by enzyme-linked immunosorbent assay. Polymerase chain reaction (PCR) technology was used for measuring Th1 and Th2 related cytokine mRNA expressions. RESULTS: Slighter intraocular inflammation was found in the Yanyankang group and the prednisone group than the control group. The levels of the IFN-gamma and IL-10 in the supernatants of the spleen lymph node cells were 382.33+/-6.30, 155.87+/-4.46 MUg/L in the Yanyankang group and 270.93+/-7.76, 265.32+/-11.88 MUg/L in the prednisone group. Both had significant differences compared with the control group (941.53+/-8.59, 20.67+/-4.65 MUg/L; =0.01). The PCR results showed the same tendency. CONCLUSION: Yanyankang powder showed favorable effects in the rats with EAU by influencing the function of Th1 and Th2 cells. PMID- 26129905 TI - Application of SCOPE-C to Measure Social Inclusion Among Mental Health Services Users in Hong Kong. AB - This study describes the construction of the Chinese version of the Social and Communities Opportunities Profile (SCOPE), henceforth, the SCOPE-C, to measure social inclusion among mental health services users in Hong Kong. The SCOPE-C was developed based on concept-mapping and benchmarking of census questions. The questionnaire consisted of 56 items, went through a standardized linguistic validation process and was pilot tested with qualitative feedback from five users of mental health services. Altogether 168 Chinese service users were recruited through various NGO mental health services to have three times face-to-face interview between October 2013 and July 2014. Results indicated that items related to satisfaction with opportunities and perceived opportunities in various social domains had high consistency. Nearly all the Kappa statistics and Pearson correlation coefficients between the baseline and two rounds of re-test were significant. The SCOPE-C was considered a valid instrument for Hong Kong mental health user population. PMID- 26129907 TI - Freezability of Andalusian donkey (Equus asinus) spermatozoa: effect of extenders and permeating cryoprotectants. AB - The aim of this study was to compare the effect of two semen extenders and four permeating cryoprotectants on post-thaw sperm quality of Andalusian donkeys. First, 32 ejaculates were pooled, split and frozen in either Gent B or INRA 96 with egg yolk and glycerol. Second, 12 pooled semen samples were simultaneously frozen in Gent B (glycerol) or Gent A containing ethylene glycol (EG; 1 or 1.5%) or dimethyl sulfoxide (DMSO; 1.5 or 2%). Finally, nine pooled samples were simultaneously cryopreserved in Gent A containing 1% EG (as control), dimethylformamide (DMFA; 1 or 2.5%) or a combination of 1% EG and 1.5% DMFA. Gent B yielded a higher (P<0.01) post-thaw sperm motility than modified INRA96. EG 1% increased the sperm membrane integrity (P<0.001), whereas DMSO affected sperm motility and membrane integrity (P<0.001). DMFA 2.5% yielded higher (P<0.001) values for sperm motility and membrane integrity. We concluded that Gent B improves in vitro post-thaw sperm quality of donkey spermatozoa, but the replacement of glycerol with 1% EG or 2.5% DMFA increased sperm protection against cryodamage. The use of DMSO for freezing donkey semen was unsuccessful and a toxic effect is suspected. These extenders should be included in the pre freeze test for each donkey. PMID- 26129906 TI - Genetics-Based Population Pharmacokinetics and Pharmacodynamics of Risperidone in a Psychiatric Cohort. AB - BACKGROUND: High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. OBJECTIVE: Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. METHODS: Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARalpha, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM((r))). Correlations between trough concentrations of the active moiety (risperidone plus 9 hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. RESULTS: The cytochrome P450 (CYP) 2D6 phenotype explained 52% of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28% higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9 hydroxyrisperidone elimination was decreased by 26% with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. CONCLUSIONS: Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment. PMID- 26129909 TI - Effects of Louisiana crude oil on the sheepshead minnow (Cyprinodon variegatus) during a life-cycle exposure to laboratory oiled sediment. AB - Determining the long-term effects of crude oil exposure is critical for ascertaining population-level ecological risks of spill events. A 19-week complete life-cycle experiment was conducted with the estuarine sheepshead minnow (Cyprinodon variegatus) exposed to reference (uncontaminated) sediment spiked with laboratory weathered South Louisiana crude (SLC) oil at five concentrations as well as one unspiked sediment control and one seawater (no sediment) control. Newly hatched larvae were exposed to the oiled sediments at measured concentrations of < 1 (sediment control), 50, 103, 193, 347, and 711 mg total polyaromatic hydrocarbons (tPAH)/kg dry sediment. Juveniles were exposed through the reproductively active adult phase at measured concentrations of <1 (sediment control), 52, 109, 199, 358, and 751 mg tPAH/kg sediment. Throughout the exposure, fish were assessed for growth, survival, and reproduction. Resulting F1 embryos were then collected, incubated, and hatched in clean water to determine if parental full life-cycle exposure to oiled sediment produced trans generational effects. Larvae experienced significantly reduced standard length (5 13% reduction) and wet weight (13-35% reduction) at concentrations at and above 50 and 103 mg tPAH/kg sediment, respectively. At 92 and 132 days post hatch (dph), standard length was reduced (7-13% reduction) at 199 and 109 mg tPAH/kg dry sediment, respectively, and wet weight for both time periods was reduced at concentrations at and above 109 mg tPAH/kg dry sediment (21-38% reduction). A significant reduction (51-65%) in F0 fecundity occurred at the two highest test concentrations, but no difference was observed in F1 embryo survival. This study is the first to report the effects of chronic laboratory exposure to oiled sediment, and will assist the development of population models for evaluating risk to benthic spawning fish species exposed to oiled sediments. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1627-1639, 2016. PMID- 26129908 TI - Combined HDAC1 and HDAC2 Depletion Promotes Retinal Ganglion Cell Survival After Injury Through Reduction of p53 Target Gene Expression. AB - Histones deacetylases (HDACs), besides their function as epigenetic regulators, deacetylate and critically regulate the activity of nonhistone targets. In particular, HDACs control partially the proapoptotic activity of p53 by balancing its acetylation state. HDAC inhibitors have revealed neuroprotective properties in different models, but the exact mechanisms of action remain poorly understood. We have generated a conditional knockout mouse model targeting retinal ganglion cells (RGCs) to investigate specifically the functional role of HDAC1 and HDAC2 in an acute model of optic nerve injury. Our results demonstrate that combined HDAC1 and HDAC2 ablation promotes survival of axotomized RGCs. Based on global gene expression analyses, we identified the p53-PUMA apoptosis-inducing axis to be strongly activated in axotomized mouse RGCs. Specific HDAC1/2 ablation inhibited this apoptotic pathway by impairing the crucial acetylation status of p53 and reducing PUMA expression, thereby contributing to the ensuing enhanced neuroprotection due to HDAC1/2 depletion. HDAC1/2 inhibition and the affected downstream signaling components emerge as specific targets for developing therapeutic strategies in neuroprotection. PMID- 26129910 TI - Fluoxetine induces lean phenotype in rat by increasing the brown/white adipose tissue ratio and UCP1 expression. AB - The serotonergic system plays a crucial role in the energy balance regulation. Energy balance is mediated by food intake and caloric expenditure. Thus, the present study investigated the mechanisms that might be associated with fluoxetine treatment-induced weight reduction. Wistar male rat pups received daily injections with subcutaneous fluoxetine (Fx-group) or vehicle solution (Ct group) from day 1 until 21 days of age. Several analyses were conducted to verify the involvement of mitochondria in weight reduction. We found that body weight in the Fx-group was lower compared to control. In association to lower fat mass in the Fx-group (25%). Neither neonatal caloric intake nor food intake reveals significant differences. Evaluating caloric expenditure (locomotor activity and temperature after stimulus), we did not observe differences in locomotor activity. However, we observed that the Fx group had a higher capacity to maintain body temperature in a cold environment compared with the Ct-group. Since brown adipose tissue-(BAT) is specialized for heat production and the rate of heat production is related to mitochondrial function, we found that Fx-treatment increases respiration by 36%, although after addition of GDP respiration returned to Ct-levels. Examining ROS production we observe that Fx-group produced less ROS than control group. Evaluating uncoupling protein (UCP) expression we found that Fx-treatment increases the expression by 23%. Taken together, our results suggest that modulation of serotonin system results in positive modulation of UCP and mitochondrial bioenergetics in brown fat tissue. PMID- 26129911 TI - Sleep disordered breathing and sleep quality in children with bronchiolitis obliterans. AB - The incidence of sleep-disordered breathing (SDB) increases in chronic lung diseases. Our aim was to evaluate SDB and sleep quality in children with postinfectious bronchiolitis obliterans (BO) and assess associated risk factors. We hypothesized that children with BO are at increased risk for SDB and have impaired sleep quality. We also hypothesized that severity of SDB and impairment of sleep quality is related to the severity of lung disease. Sleep Related Breathing Disorder (SRBD) subscale of the Pediatric Sleep Questionnaire (PSQ) and Pittsburgh Sleep Quality Index (PSQI) questionnaires; spirometry, impulse oscillometry (IOS), and overnight polysomnography (PSG) were performed. Twenty one patients (14 male, median age: 8.3 years) were enrolled. Five patients (25%) had a PSQ score of >0.33, predictive of a SDB. Ten patients (48%) had poor sleep quality. Four patients (19%) had an OAHI of >1/hr. Nineteen patients (90%) had a high desaturation index. Four patients (19%) had a mean oxygen saturation of <93%. Median central apnea time was 7.5 (IQR: 6.9-9.1) seconds. Central apnea index of the patients correlated positively with R5, R10, R15, R20, Z5, and negatively with X10 and X15 at IOS. There was a positive correlation between the lowest oxygen saturation and FVC, FEV1 , X5, X10, X15, X20 while there was a negative correlation between lowest saturation and the central apnea index at PSG, R5, R10, and Z5 at IOS. Mean oxygen saturation during PSG correlated positively with FVC, FEV1, FEF(25-75), X5, X10, X15, X20 results. The risk of nocturnal hypoxia is increased in patients with BO and correlated to the severity of lung disease determined by pulmonary function tests. Although BO patients have a shorter duration of central apneas, they are more prone to desaturate. PMID- 26129912 TI - Characterization of pseudorabies virus transcriptome by Illumina sequencing. AB - BACKGROUND: Pseudorabies virus is a widely-studied model organism of the Herpesviridae family, with a compact genome arrangement of 72 known coding sequences. In order to obtain an up-to-date genetic map of the virus, a combination of RNA-sequencing approaches were applied, as recent advancements in high-throughput sequencing methods have provided a wealth of information on novel RNA species and transcript isoforms, revealing additional layers of transcriptome complexity in several viral species. RESULTS: The total RNA content and polyadenylation landscape of pseudorabies virus were characterized for the first time at high coverage by Illumina high-throughput sequencing of cDNA samples collected during the lytic infectious cycle. As anticipated, nearly all of the viral genome was transcribed, with the exception of loci in the large internal and terminal repeats, and several small intergenic repetitive sequences. Our findings included a small novel polyadenylated non-coding RNA near an origin of replication, and the single-base resolution mapping of 3' UTRs across the viral genome. Alternative polyadenylation sites were found in a number of genes and a novel alternative splice site was characterized in the ep0 gene, while previously known splicing events were confirmed, yielding no alternative splice isoforms. Additionally, we detected the active polyadenylation of transcripts earlier believed to be transcribed as part of polycistronic RNAs. CONCLUSION: To the best of our knowledge, the present work has furnished the highest-resolution transcriptome map of an alphaherpesvirus to date, and reveals further complexities of viral gene expression, with the identification of novel transcript boundaries, alternative splicing of the key transactivator EP0, and a highly abundant, novel non-coding RNA near the lytic replication origin. These advances provide a detailed genetic map of PRV for future research. PMID- 26129913 TI - Factors affecting jump performance in professional Australian rules footballers. AB - AIM: This study examined factors contributing to jump performance in professional Australian Rules Football (ARF) players. METHODS: Thirty-two ARF players performed a countermovement jump (CMJ) and were divided into groups based on jump performance: high calibre (HC) or low calibre (LC). During CMJ assessment, force, rate of force development, movement velocity and power were measured. Physical measures included mass, height, age, lower body strength, eccentric utilization ratio and leg stiffness (Kleg). HC and LC groups were compared to determine the variables contributing to jump performance and correlation and regression analyses also aided in identifying such variables. CMJ height was higher in the HC group (P<0.001). RESULTS: The HC group demonstrated a higher CMJ velocity (9.8%, P=0.004) and CMJ power (14.4%, P=0.042) when compared to the LC group. Further, the HC group demonstrated 7.5% higher Kleg than the LC group (P=0.019). Spearman's rho correlations demonstrated moderate-large relationships between jump height and strength, velocity and power, while the regression analysis revealed velocity was the sole predictive variable of jump performance. Jumping performance clearly differs within a group of professional ARF athletes. CONCLUSION: Movement velocity appears to be an important factor contributing to jump performance; however, lower body power and Kleg are also important for jump performance. PMID- 26129914 TI - Quantification of physical activity using the QAPACE questionnaire: A two stage cluster sample design survey of children and adolescents attending urban school. AB - BACKGROUND: Quantification of physical activity as energy expenditure is important since youth for the prevention of chronic non communicable diseases in adulthood. It is necessary to quantify physical activity expressed in daily energy expenditure (DEE) in school children and adolescents between 8-16 years, by age, gender and socioeconomic level (SEL) in Bogota. METHODS: This is a Two Stage Cluster Survey Sample. From a universe of 4700 schools and 760000 students from three existing socioeconomic levels in Bogota (low, medium and high). The random sample was 20 schools and 1840 students (904 boys and 936 girls). Foreshadowing desertion of participants and inconsistency in the questionnaire responses, the sample size was increased. Thus, six individuals of each gender for each of the nine age groups were selected, resulting in a total sample of 2160 individuals. Selected students filled the QAPACE questionnaire under supervision. The data was analyzed comparing means with multivariate general linear model. Fixed factors used were: gender (boys and girls), age (8 to 16 years old) and tri-strata SEL (low, medium and high); as independent variables were assessed: height, weight, leisure time, expressed in hours/day and dependent variable: daily energy expenditure DEE (kJ.kg-1.day-1): during leisure time (DEE LT), during school time (DEE-ST), during vacation time (DEE-VT), and total mean DEE per year (DEEm-TY) RESULTS: Differences in DEE by gender, in boys, LT and all DEE, with the SEL all variables were significant; but age-SEL was only significant in DEE-VT. In girls, with the SEL all variables were significant. The Post-hoc multiple comparisons tests were significant with age using Fisher's Least Significant Difference (LSD) test in all variables. For both genders and for all SELs the values in girls had the higher value except SEL high (5-6) The boys have higher values in DEE-LT, DEE-ST, DEE-VT; except in DEEm-TY in SEL (5-6) In SEL (5-6) all DEEs for both genders are highest. For SEL (3-4) all DEEs are lowest. CONCLUSIONS: Children and adolescents in Bogota have less DEE than at other latitudes. Girls have more free time but lower energy expenditure in their different activities. The socioeconomic level has influence in DEE. PMID- 26129915 TI - Physical performance and markers of muscle damage following sport-specific sprints in male collegiate soccer players: repeated bout effect. AB - BACKGROUND: This is the first study to examine the repeated bout effect (RBE) on physical performance parameters in an athletic population. Protocols used by previous studies to induce muscle injury and assess performance following injury, are dissimilar from those utilized by physically trained individuals or are impractical in relation to athletic performance. The present study uses a sport specific protocol to study the effects of exercise induced muscle damage (EIMD) on physical performance to provide a more systematic analysis of the extent of muscle injury. METHODS: Thirty two male collegiate soccer players were randomly assigned into either a repeated bout group (N.=16) or control group (N.=16). The repeated bout group performed 2 bouts of sport-specific sprints separated by 14 days. The control group performed a single bout of the same sprint protocol. Maximum voluntary isometric contraction for quadriceps (MVCQ) and hamstrings (MVCH), knee range of motion (ROM), thigh circumference, muscle soreness, plasma creatine kinase (CK) and lactate dehydrogenase (LDH), in addition to physical performance parameters-speed, agility and power were measured before, 24, 48 and 72 hours following the sprinting bouts. RESULTS: MVCQ, MVCH, ROM, thigh circumference, CK, LDH and agility showed significant group x time interaction (P<0.05), suggesting lesser decrements and better recovery profile for the repeated bout group. Muscle soreness showed a main effect for group (P<0.001). CONCLUSIONS: The physical performance parameters (speed, agility and power) are less affected by EIMD as compared to other markers and therefore did not demonstrate RBE. PMID- 26129916 TI - Validation of a new scale to measure perceived exertion in obese adolescents: the Childhood Obesity Perceived Exertion (Cope-10) Scale. AB - BACKGROUND: The aim of this study was to validate a measurement scale for perceived exertion, named the Childhood Obesity Perceived Exertion Scale (COPE 10), by evaluating concurrent validity, reliability and sensitivity in obese adolescents. METHODS: Thirty obese adolescents (BMI 36.2+/-0.8 kg.m-2), aged 14.2+/-0.3 years, performed two incremental exercise tests (maximal followed by submaximal) before and after a multidisciplinary obesity management program. To standardize workload, physiological variables [heart rate (HR), ventilation (E) and gas exchange (O2)] and perceived exertion (RPE) were modelized (fHR, fVE, fVO2, fRPE). At a rank of 6 on the COPE-10 Scale (RPE6) and at fixed second ventilatory threshold (VT2), we determined respectively the associated power (WPRPE6, WPVT2) and HR (HRRPE6, HRVT2). RESULTS: During maximal exercise, we observed significant correlations between fRPE and each of fHR (r=0.88 ; r=0.91), fVE (r=0.93 ; r=0.94) and fVO2 (r=0.87 ; r=0.89) before and after management respectively, indicating the concurrent validity of the COPE-10 Scale to estimate exercise intensity in obese adolescents. During submaximal exercise, we observed intraclass correlation coefficients of 0.77 before and 0.86 after management, showing reliability. After management, WPVT2 and WPRPE6 increased significantly (+23W and +21W ; P<0.001), and there was a significant correlation between HRVT2 and HRRPE6 (r=0.90), illustrating the scale's sensitivity to change. CONCLUSIONS: The COPE-10 Scale is a valid tool to measure perceived exertion in obese adolescents. This inexpensive and non-invasive instrument could be widely used in rehabilitation programs for obese youths. PMID- 26129917 TI - Timing characteristics of body segments during the maximal instep kick in experienced football players. AB - BACKGROUND: The first aim of this study was to describe duration and relative timing of the phases of the maximal instep kick. The second aim was to describe the concurrence of maximal range of motion, maximal angular acceleration, maximal angular deceleration and maximal angular velocity of body segments with four key points. METHODS: Twenty experienced football players performed three maximal instep kicks. The kicks were analysed using a full body, three-dimensional motion capture system. Camera recordings determined kicking leg events. The concurrence of peak kinematics of body segments with four key points was calculated. RESULTS: Duration and timing of five phases were identified. Key point maximal hip extension (51.4+/-5.0%) concurred significantly with maximal range of motion (ROM) of shoulder extension. Key point maximal knee flexion (63.6+/-5.2%) concurred significantly with maximal angular acceleration of spine flexion and pelvis posterior tilt. Key point knee flexion 90 degrees (69.3+/-4.9%) concurred significantly with maximal angular velocity of shoulder flexion and spine flexion, maximal angular deceleration of hip flexion and maximal angular acceleration of knee extension. Key point ball impact (75.2+/-5.2%) concurred significantly with maximal ROM of hip deflexion and pelvis anterior rotation and with maximal angular deceleration of spine flexion and pelvis anterior rotation. CONCLUSIONS: This study demonstrated that eleven peak kinematics of upper body and kicking leg segments, significantly concurred with four kicking leg positions. These results provide Key points for kicking coordination and stress the importance of dynamical coupling as a kicking mechanism. PMID- 26129918 TI - Selective Laser Melting Technique of Co-Cr Dental Alloys: A Review of Structure and Properties and Comparative Analysis with Other Available Techniques. AB - PURPOSE: The aim of this study was to review the effect of selective laser melting (SLM) procedure on the properties of dental structures made of Co-Cr alloys and to evaluate its quality and compare it to those produced by conventional casting and milling fabrication techniques. MATERIALS AND METHODS: A computerized database search using PubMed and Scopus was conducted for peer reviewed scientific research studies regarding the use of SLM in Co-Cr dental alloys with no restrictions for publication years. The search engines provided hundreds of results, and only 48 scientific research papers, case studies, or literature reviews were considered relevant for this review. RESULTS: The innovative manufacturing concept of SLM offers many advantages compared with casting and milling fabrication techniques. SLM provides different microstructure from casting and milling with minimal internal porosity and internal fitting, marginal adaptation, and comparable bond strength to porcelain. Mechanical and electrochemical properties of SLM structures are enhanced compared to cast, while clinical longevity of single-metal ceramic crowns is comparable to Au-Pt dental alloy. CONCLUSION: The SLM technique provides dental prosthetic restorations more quickly and less expensively without compromising their quality compared with restorations prepared by casting and milling techniques. CLINICAL SIGNIFICANCE: The current SLM devices provide metallic restorations made of Co-Cr alloys for removable and fixed partial dentures without compromising the alloy or restoration properties at a fraction of the time and cost, showing great potential to replace the aforementioned fabrication techniques in the long term; however, further clinical studies are essential to increase the acceptance of this technology by the worldwide dental community. PMID- 26129919 TI - CORRECTION. PMID- 26129921 TI - First human magnetic resonance visualisation of prosthetics for laparoscopic large hiatal hernia repair. AB - PURPOSE: Mesh repair of large hiatal hernias has increasingly gained popularity to reduce recurrence rates. Integration of iron particles into the polyvinylidene fluoride mesh-based material allows for magnetic resonance visualisation (MR). METHODS: In a pilot prospective case series eight patients underwent surgical repair of hiatal hernias repair with pre-shaped meshes, which were fixated with fibrin glue. An MR investigation with a qualified protocol was performed on postoperative day four and 3 months postoperatively to evaluate the correct position of the mesh by assessing mesh appearance and demarcation. The total MR visible mesh surface area of each implant was calculated and compared with the original physical mesh size to evaluate potential reduction of the functional mesh surfaces. RESULTS: We documented no mesh migrations or dislocations but we found a significant decrease of MR-visualised total mesh surface area after release of the pneumoperitoneum compared to the original mesh size (mean 78.9 vs 84 cm(2); mean reduction of mesh area = 5.1 cm(2), p < 0.001). At 3 months postoperatively, a further reduction of the mesh surface area could be observed (mean 78.5 vs 78.9 cm(2); mean reduction of mesh area = 0.4 cm(2), p < 0.037). CONCLUSION: Detailed mesh depiction and accurate assessment of the surrounding anatomy could be successfully achieved in all cases. Fibrin glue seems to provide effective mesh fixation. In addition to a significant early postoperative decrease in effective mesh surface area a further reduction in size occurred within 3 months after implantation. PMID- 26129922 TI - Palladium-catalyzed C(sp(3))-H Arylation of N-Boc benzylalkylamines via a deprotonative cross-coupling process. AB - Diarylmethylamines are key intermediates and products in the pharmaceutical industry. Herein we disclose a novel method toward the synthesis of these important compounds via C?H functionalization. Presented is a reversible deprotonation of N-Boc benzylalkylamines at the benzylic C?H with in situ arylation by a NiXantPhos-based palladium catalyst (50-93 % yield, 29 examples). The method is also successful with N-Boc-tetrahydroisoquinolines. The advantages of this method are it avoids strong bases, low temperatures, and the need to transmetallate to main group metals for the coupling. PMID- 26129923 TI - Ethical Issues for Clinical Studies That use Human Embryonic Stem Cells: The 2014 Revisions to the Japanese Guidelines. AB - The use of human embryonic stem cells (hESCs) in clinical studies has been expanding in recent years. The application of hESCs in clinical studies raises ethical issues from a different standpoint compared with the use of other types of stem cells. In Japan, the Guidelines on the Derivation of Human Embryonic Stem Cells, and Guidelines on the Distribution and Utilization of Human Embryonic Stem Cells had been revised for clinical studies in 2014. In the revised guidelines, the method for protection of personal information was changed to offer the choice between unlinkable anonymization and linkable anonymization, to enable the use of information on diseases suffered by donors and the assurance of traceability for safety. Procedures for re-consent are generally prohibited out of consideration for donors' feelings. However, obtaining re-consent is permitted when consent for re-consent has been received in advance and approval has been given by an ethical review board, in which case the donors may be contacted. Incidental findings obtained from hESCs are not disclosed individually to donors, while the research results should be actively published for the common good. These guidelines have enabled the derivation, distribution, and use of hESCs for clinical studies. PMID- 26129924 TI - Energetic Insight into the Formation of Solids from Aluminum Polyoxocations. AB - The epsilon-Keggin [AlO4Al12(OH)24(H2O)12](7+) ion (AlAl12(7+)) is a metastable precursor in the formation of aluminum oxyhydroxide solids. It also serves as a useful model for the chemistry of aluminous mineral surfaces. Herein we calculate the enthalpies of formation for this aqueous ion and its heterometal-substituted forms, GaAl12(7+) and GeAl12(8+), using solution calorimetry. Rather than measuring the enthalpies of the MAl12(7/8+) ions directly from solution hydrolysis, we measured the metathesis reaction of the crystallized forms with barium chloride creating an aqueous aluminum solution monospecific in MAl12(7/8+). Then, the contributions to the heat of formation from the crystallized forms were subtracted using referenced states. When comparing the aqueous AlAl12(7+) ion to solid aluminum (oxy)-hydroxide phases, we found that this ion lies closer in energy to solid phases than to aqueous aluminum monomers, thus explaining its role as a precursor to amorphous aluminum hydroxide phases. PMID- 26129925 TI - Somatostatin analogues improve health-related quality of life in polycystic liver disease: a pooled analysis of two randomised, placebo-controlled trials. AB - BACKGROUND: Polycystic liver disease is associated with impaired health-related quality of life (HRQL). Somatostatin analogues reduce hepatomegaly in polycystic liver disease. AIM: To determine whether somatostatin analogues improve HRQL and to identify factors associated with change in HRQL in polycystic liver disease. METHODS: We pooled data from two randomized, double-blind, placebo-controlled trials that evaluated HRQL using the Short-Form 36 (SF-36) in 96 polycystic liver disease patients treated 6-12 months with somatostatin analogues or placebo. The SF-36 contains a summarizing physical and mental component score and was administered at baseline and at the end of treatment. We used random effect models to delineate the effect of somatostatin analogues on HRQL. We determined the effect of demographics, height-adjusted liver volume, change in liver volume, somatostatin analogue-associated side effects with change in HRQL. In patients with autosomal dominant polycystic kidney disease, we estimated the effect of height-adjusted kidney volume and change in kidney volume in relation to HRQL. RESULTS: Physical component scores improved with somatostatin analogues, but remained unchanged with placebo (3.41 +/- 1.29 vs. -0.71 +/- 1.54, P = 0.044). Treatment had no impact on the mental component score. Large liver volume was independently associated with larger HRQL decline during follow up (-4.04 +/- 2.02 points per logarithm liver volume, P = 0.049). In autosomal dominant polycystic kidney disease, patients with large liver and kidney volumes had larger decline in HRQL (5.36 +/- 2.54 points per logarithm liver volume; P = 0.040 and -4.00 +/- 1.88 per logarithm kidney volume; P = 0.039). CONCLUSION: Somatostatin analogues improve HRQL in symptomatic polycystic liver disease. Halting the progressive nature of polycystic liver disease is necessary to prevent further decline of HRQL in severe hepatomegaly. PMID- 26129926 TI - Hydrogen-bond acidity of ionic liquids: an extended scale. AB - One of the main drawbacks comprising an appropriate selection of ionic liquids (ILs) for a target application is related to the lack of an extended and well established polarity scale for these neoteric fluids. Albeit considerable progress has been made on identifying chemical structures and factors that influence the polarity of ILs, there still exists a high inconsistency in the experimental values reported by different authors. Furthermore, due to the extremely large number of possible ILs that can be synthesized, the experimental characterization of their polarity is a major limitation when envisaging the choice of an IL with a desired polarity. Therefore, it is of crucial relevance to develop correlation schemes and a priori predictive methods able to forecast the polarity of new (or not yet synthesized) fluids. In this context, and aiming at broadening the experimental polarity scale available for ILs, the solvatochromic Kamlet-Taft parameters of a broad range of bis(trifluoromethylsulfonyl)imide ([NTf2](-))-based fluids were determined. The impact of the IL cation structure on the hydrogen-bond donating ability of the fluid was comprehensively addressed. Based on the large amount of novel experimental values obtained, we then evaluated COSMO-RS, COnductor-like Screening MOdel for Real Solvents, as an alternative tool to estimate the hydrogen-bond acidity of ILs. A three-parameter model based on the cation-anion interaction energies was found to adequately describe the experimental hydrogen-bond acidity or hydrogen-bond donating ability of ILs. The proposed three-parameter model is also shown to present a predictive capacity and to provide novel molecular-level insights into the chemical structure characteristics that influence the acidity of a given IL. It is shown that although the equimolar cation-anion hydrogen-bonding energies (EHB) play the major role, the electrostatic-misfit interactions (EMF) and van der Waals forces (EvdW) also contribute, admittedly in a lower extent, towards the hydrogen-bond acidity of ILs. The new extended scale provided for the hydrogen-bond acidity of ILs is of high value for the design of new ILs for task-specific applications. PMID- 26129927 TI - Diverting attention from financial conflicts of interest. PMID- 26129928 TI - Vitamin C and E supplementation blunts increases in total lean body mass in elderly men after strength training. AB - The aim of this study was to investigate the effects of vitamin C and E supplementation on changes in muscle mass (lean mass and muscle thickness) and strength during 12 weeks of strength training in elderly men. Thirty-four elderly males (60-81 years) were randomized to either an antioxidant group (500 mg of vitamin C and 117.5 mg vitamin E before and after training) or a placebo group following the same strength training program (three sessions per week). Body composition was assessed with dual-energy X-ray absorptiometry and muscle thickness by ultrasound imaging. Muscle strength was measured as one-repetition maximum (1RM). Total lean mass increased by 3.9% (95% confidence intervals: 3.0, 5.2) and 1.4% (0, 5.4) in the placebo and antioxidant groups, respectively, revealing larger gains in the placebo group (P = 0.04). Similarly, the thickness of m. rectus femoris increased more in the placebo group [16.2% (12.8, 24.1)] than in the antioxidant group [10.9% (9.8, 13.5); P = 0.01]. Increases of lean mass in trunk and arms, and muscle thickness of elbow flexors, did not differ significantly between groups. With no group differences, 1RM improved in the range of 15-21% (P < 0.001). In conclusion, high-dosage vitamin C and E supplementation blunted certain muscular adaptations to strength training in elderly men. PMID- 26129929 TI - Gold nanocluster-based vaccines for dual-delivery of antigens and immunostimulatory oligonucleotides. AB - We here report a facile one-pot synthesis of fluorescent gold nanoclusters (AuNCs) via the peptide biomineralization method, which can elicit specific immunological responses. The as-prepared peptide-protected AuNCs (peptide-AuNCs) display strong red fluorescence, and more importantly, as compared to the peptide alone, the immune stimulatory ability of the resulting peptide-AuNCs can not only be retained, but can also be efficaciously enhanced. Moreover, through a dual delivery of antigen peptides and cytosine-phosphate-guanine (CpG) oligodeoxynucleotides (ODNs), the as-prepared peptide-AuNC-CpG conjugates can also act as smart self-vaccines to assist in the generation of high immunostimulatory activity, and be applied as a probe for intracellular imaging. Both in vitro and in vivo studies provide strong evidence that the AuNC-based vaccines may be utilized as safe and efficient immunostimulatory agents that are able to prevent and/or treat a variety of ailments. PMID- 26129930 TI - Development and content validity testing of a patient-reported outcomes questionnaire for the assessment of hereditary angioedema in observational studies. AB - BACKGROUND: Hereditary Angioedema (HAE), a rare genetic disease, manifests as intermittent, painful attacks of angioedema. Attacks vary in frequency and severity and include skin, abdominal and life-threatening laryngeal swellings. This study aimed to develop a patient reported outcome (PRO) tool for the assessment of HAE attacks, including their management and impact on patients' lives, for use in clinical studies, or by physicians in general practice. METHODS: The results of open-ended face to face concept elicitation interviews with HAE patients in Argentina (n = 10) and the US (n = 33) were used to develop the first draft questionnaire of the HAE patient reported outcomes questionnaire (HAE PRO). Subsequently, in-depth cognitive debriefing interviews were performed with HAE patients in the UK (n = 10), Brazil (n = 10), Germany (n = 11) and France (n = 12). Following input from eight multinational clinical experts further cognitive interviews were conducted in the US (n = 12) and Germany (n = 12). Patients who experienced abdominal, cutaneous or laryngeal attacks of varying severity levels were included in all rounds of interviews. Across the rounds of interviews patients discussed their HAE attack symptoms, impacts and treatments. Cognitive debriefing interviews explored patient understanding and relevance of questionnaire items. All interviews were conducted face to face following a pre-defined semi-structured interview guide in the patient's native language. RESULTS: Patients reported a variety of HAE symptoms, attack triggers, warning signs, attack impacts and treatment options which were used to develop the HAE PRO. The HAE PRO was revised and refined following input from patients and clinical experts. The final 18-item HAE PRO provides an assessment of the HAE attack experience including symptoms, impacts, treatment requirements, healthcare resource use and loss of productivity caused by HAE attacks. CONCLUSIONS: Patient and expert input has contributed to the development of a content valid questionnaire that assesses concepts important to HAE patients globally. HAE patients across cultures consider the HAE PRO a relevant and appropriate assessment of HAE attacks and treatment. PMID- 26129931 TI - To Be or Not to Be Patent: The Relationship Between Migraine and Patent Foramen Ovale. AB - OBJECTIVE/BACKGROUND: Migraine is a common neurological disorder with an uncertain pathogenesis. A pathophysiological link has been proposed between the migraine headache and patent foramen ovale (PFO). However, the data about the association of migraine with the presence of PFO are conflicting. The study aims to prospectively investigate the prevalence of PFO in patients with migraine compared with that of control subjects. METHODS: A total of 203 migraineous patients and 212 control subjects with similar demographic characteristics to that of case subjects regarding age and gender were included in the study. Transthoracic echocardiography with agitated saline injection was used to evaluate the presence of PFO. PFO was judged to be present if any microbubble was seen in the left cardiac chambers within the first 5 cardiac cycles from the maximum right atrial opacification at rest or after provocative maneuvers. RESULTS: Mean age of the patients was 37.2 +/- 9.8 years and 93% were female. Migraine with aura was present in 32% (n = 65) of the patients. The prevalence of PFO was similar in patients with migraine and the control subjects (42% vs 44%; odds ratio 0.90, 95% confidence interval 0.61-1.33, P = .61). Likewise, the prevalence of PFO was similar in migraineurs patients with or without aura (41% vs 42%; odds ratio 0.95, 95% confidence interval 0.51-1.76, P = .87). CONCLUSION: This study suggest that PFO is not more common in patients with migraine compared with healthy subjects. Therefore, our findings suggest that the relationship between migraine headache and the presence of PFO is questionable. PMID- 26129932 TI - An LC-MS/MS method for simultaneous determination of cefprozil diastereomers in human plasma and its application for the bioequivalence study of two cefprozil tablets in healthy Chinese volunteers. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometric method was developed for the first time and validated for the determination of cefprozil diastereomers in human plasma. The plasma samples were prepared by protein precipitation using acetonitrile. Detection was performed using an electronic spray ion source in the negative ion mode, operating in the multiple reaction monitoring of the transitions m/z 388.0 to m/z 205.0 for cefprozil diastereomers and m/z 346.1 to m/z 268.1 for cephalexin (the internal standard). The calibration curves of cis-cefprozil and trans-cefprozil were linear in the ranges 0.125-16.0 ug/mL and 0.0403-1.72 ug/mL, respectively. The lower limits of quantification of cis- and trans-cefprozil were 0.125 and 0.0403 ug/mL in human plasma, respectively. The intra- and inter-day precisions of cis- and trans cefprozil were all <9.7%, and the accuracy ranged from 99.2 to 104.7% and from 100.6 to 102.2%, respectively. The validated method was successfully applied to a bioequivalence study of two cefprozil formulations in 24 healthy Chinese volunteers. The two cefprozil tablets were bioequivalent by measurement of cis-, trans- and total cefprozil. We suggest that the bioequivalence of cefprozil formulations can be evaluated only using cis-cefprozil as the analyte in future studies. PMID- 26129933 TI - Characteristics of human umbilical cord mesenchymal stem cells during ex vivo expansion. AB - Human umbilical cord mesenchymal stem cells (hUCMSCs) have potential clinical applications in different types of diseases. In order to acquire enough cells, hUCMSCs have to be expanded ex vivo. However, it remains to be elucidated whether the characteristics of hUCMSCs are altered during ex vivo expansion. In the present study, the quality of hUCMSCs, which is important for successful therapeutic use, was systematically examined during hUCMSC expansion ex vivo. Morphologically, hUCMSCs exhibited no visible changes during culture. In addition, hUCMSCs retained their proliferative ability between passages 0-5. At the molecular level, the cells continued expressing the specific positive surface markers, CD29, CD73 and CD90, and did not express the negative surface markers, CD14, CD34 or CD45, during culture ex vivo. Furthermore, the hUCMSCs exhibited low immunogenicity, which was maintained when cultured for five passages. However, the immunological properties of hUCMSCs were altered at passage 10, at which the percentage of hUCMSCs expressing human leukocyte antigen-I was significantly increased. Collectively, these results suggested that hUCMSCs used for cell-based therapies require obtaining from cells, which have been expanded for fewer than five passages. PMID- 26129934 TI - Clinical manifestations of pediatric obstructive sleep apnea syndrome: Clinical utility of the Chinese-version Obstructive Sleep Apnea Questionaire-18. AB - AIMS: Childhood obstructive sleep apnea syndrome (OSA) affects not only the children's physical health, but also their mental development, behavioral problems and learning difficulties. Therefore, an early diagnosis is important. However, the assessment tools of polysomnography are demanding. The Obstructive Sleep Apnea Questionnaire-18 (OSA-18) is designed to screen OSA and has good reliability and validity. The goal of this study was to validate the Chinese version of the OSA-18, to analyze the frequency of symptoms and find the most common symptoms of OSA in Taiwanese children. METHODS: We validated the OSA-18 in an ethnic Chinese group and compared the treatment outcomes to show the sensitivity of the questionnaire. The caregivers completed the questionnaire twice at an interval of 4 weeks to test reliability. In the validation study, we included 88 OSA children. The OSA-18 and follow-up polysomnography were performed before and 6 months after adenotonsillectomy. RESULTS: Results showed the excellent test-retest reliability (r = 0.84**) of the OSA-18. There was a statistically significant correlation between the OSA-18 and, respectively, the Apnea-Hypopnea Index (r = 0.29*), and the Hypopnea Index (r = 0.29*). Quality of life showed a significant correlation with the Apnea Index (r = 0.43**), central apnea count (r = 0.50***), and mixed apnea count (r = 0.36*). The cut-off point of the OSA-18 total scores for detecting pediatric OSA in children aged 6-12 years was 66. The common symptoms of pediatric OSA were poor attention span, loud snoring, caregiver worried about child's health, difficulty awakening, and mouth breathing. CONCLUSIONS: Our results show that the Chinese version of the OSA-18 is a reliable and valid instrument. The questionnaire also showed improvement in the quality of life of OSA children post-adenotonsillectomy. PMID- 26129935 TI - Energy level modeling of lanthanide materials: review and uncertainty analysis. AB - Energy level schemes are an essential tool for the description and interpretation of atomic spectra. During the last 40 years, several empirical methods and relationships were devised for constructing energy level schemes of lanthanide defects in wide band gap solids, culminating in the chemical shift model by Thiel and Dorenbos. This model allows us to calculate the electronic and optical properties of the considered materials. However, an unbiased assessment of the accuracy of the obtained values of the calculated parameters is still lacking to a large extent. In this paper, error margins for calculated electronic and optical properties are deduced. It is found that optical transitions can be predicted within an acceptable error margin, while the description of phenomena involving conduction band states is limited to qualitative interpretation due to the large error margins for physical observables such as thermal quenching temperature, corresponding to standard deviations in the range 0.3-0.5 eV for the relevant energy differences. As an example, the electronic structure of lanthanide doped calcium thiogallate (CaGa2S4) is determined, taking the experimental spectra of CaGa2S4:Ln(Q+) (Ln(Q+) = Ce(3+), Eu(2+), Tm(3+)) as input. Two different approaches to obtain the shape of the zig-zag curves connecting the 4f levels of the different lanthanides are explored and compared. PMID- 26129936 TI - Protective activity of biflavanones from Garcinia kola against Plasmodium infection. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Garcinia kola is a medicinal plant traditionally used for malaria therapy in Central Africa. AIM OF THE STUDY: To evaluate the antimalarial potencies in vitro and in vivo of pure biflavanones from G. kola. MATERIALS AND METHODS: The pure biflavanones were obtained by bioassay-guided fractionation of a 70% ethanol extract of G. kola seeds and their chemical structures were elucidated by comparison of their NMR ((1)H and (13)C) and mass spectral data with those provided in the literature. Plasmodium falciparum (FCR 3, cycloguanil-resistant strain from Gambia) was used for in vitro assessments of antimalarial activities. Growth inhibition, intraerythrocytic development and parasite morphology were evaluated in culture by the microscopic observation of Giemsa-stained thin blood films. The cytotoxicity of the antimalarial compounds was evaluated against KB 3-1 (human epidermoid carcinoma) cells by MTT assay. In vivo antimalarial activities were determined in mice infected with Plasmodium berghei (ANKA strain) following a four-day suppressive test. RESULTS: The bioassay-guided fractionation of an extract of G. kola resulted in the isolation of three biflavanones (GB-1a, GB-1, and GB-2) as its active principles. These three biflavanones displayed not only potent inhibitory activity in vitro against P. falciparum proliferation but also antimalarial potency through oral administration in mice infected with P. berghei without signs of acute toxicity. GB-1 was found to exhibit the strongest in vitro antimalarial potency on P. falciparum with an IC50 of 0.16MUM, whereas it exhibited a very low in vitro cytotoxicity on KB 3-1 cells with an IC50 of greater than 150MUM. During an in vivo antimalarial assay in mice infected with P. berghei, GB-1 was found to exhibit biological potency with an approximate ED50 of 100mg/kg following oral administration. GB-1 was also shown to increase the average life span of the infected mice significantly compared to that of control mice (p<0.01 Student's t test). CONCLUSIONS: The antimalarial outcome of GB-1a, GB-1, and GB-2 may be related to the traditional utilization of this crude drug against malaria judging from their significant content in G. kola nuts. GB-1 showed the most potent antimalarial activity with a high selectivity index and, therefore could be exploited to identify the molecular target, which subsequently could be helpful to design novel therapeutics against malaria. GB-1 may be considered a promising antimalarial candidate for trial in vivo using higher animals infected with P. falciparum. PMID- 26129937 TI - Anticonvulsant effects of ethanol stem bark extract of Lannea barteri (Anacardiaceae) in mice and chicks. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Preparation of Lannea barteri is used in the treatment of epilepsy, gastritis, childhood convulsions among other uses in northern Nigeria for many years. The popularity of its efficacy is well established among the Traditional Medical Practitioners. AIM OF THE STUDY: The present study aimed at screening the ethanol stem bark extract of Lannea barteri for possible anticonvulsant action. MATERIALS AND METHOD: Anticonvulsant screening was carried out using pentylenetetrazole (PTZ), strychnine (STN) and picrotoxin (PTC) induced seizures in mice while Maximal electroshock (MES) test was carried out in day old chicks. Preliminary phytochemical screening of the extract was performed on the extract. The intraperitoneal median lethal dose (LD50) was carried out in mice. RESULTS: The intraperitoneal (i.p.) LD50 of the extract was estimated to be 567.70 mg/kg in mice. Lannea barteri (160 mg/kg) significantly (p <= 0.05) delayed the mean onset of seizures induced by PTZ when compared with normal saline treated group. Similarly, the extract at 160 mg/kg significantly (p <= 0.05) prolonged the latency of convulsion induced by STN. Lannea barteri (40 mg/kg) significantly (p <= 0.05) delayed the mean onset of seizures induced by picrotoxin in mice. The extracts at all the doses tested showed no observable effect in decreasing the mean recovery time of convulsed chicks in MEST. Flavonoids, alkaloids, tannins, saponins and glycosides were found present in the stem bark extract. CONCLUSION: Our findings revealed that the ethanol stem bark extract of Lannea barteri contained bioactive constituents that may be useful in the management of petit mal epilepsy and supports the ethnomedical claim for the use of its stem bark in the management of epilepsy. PMID- 26129938 TI - A bitter herbal medicine Gentiana scabra root extract stimulates glucagon-like peptide-1 secretion and regulates blood glucose in db/db mouse. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Gentiana scabra root extract (GS) is frequently prescribed as an internal remedy in traditional Korean medicine for treatment of diabetes mellitus. GS contains bitter iridoid glycosides including loganic acid, gentiopicrin, trifloroside, and rindoside. We previously reported that the intestinal bitter taste sensation stimulates GLP-1 secretion, and thereupon hypothesized that the blood glucose regulatory effect of GS is due to its GLP-1 secreting effect in enteroendocrine L cells. MATERIALS AND METHOD: We studied GLP 1 secreting effect of GS treatment and its cellular downstream mechanism in human enteroendocrine NCI-H716 cells using the G protein-coupled receptor (GPCR) pathway inhibitors. Intracellular calcium assay also demonstrated the signal transduction pathway stimulated by the GS treatment. Using db/db mice, we performed oral glucose tolerance test (OGTT) to examine the blood glucose lowering effect of GS administration. We also collected the mouse plasma during the OGTT to measure the GLP-1 and insulin levels. RESULT: We demonstrated dose dependent GLP-1 secreting effect of GS on the NCI-H716 cells. The GLP-1 secreting effect of GS is mediated by the G protein betagamma-subunit and inositol triphosphate. Using db/db mice, we found that the effect of GS on lowering blood glucose is due to its GLP-1 secretion, and consequential insulinotropic effect. The chemical fingerprint of GS was obtained through a direct analysis in realtime mass spectrometry (DART-MS) and high-performance liquid chromatography (HPLC)/MS. Through the GLP-1 secretion study, we found that loganic acid, an iridoid glycoside, contributes to the GLP-1 secreting effect of GS. CONCLUSION: The findings of this study highlight the potential of exploiting the antidiabetic effect of GS on type 2 diabetes mellitus patients. PMID- 26129939 TI - Management of medicinally useful plants by European migrants in South America. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Using the example of Polish migrants living in the subtropics of Argentina, we attempt to expand knowledge about migrant strategies for retaining their agency in medicinal plant procurement. AIM OF THE STUDY: Is to state which environments play a pivotal role as a source of medicinal plants for the study community, and if a gradient of relevance exists in the exploitation of medicinally useful species between the most proximate and the most distant habitats. We particularly aim to answer the following questions: (1) if Polish migrants have changed their patterns of obtaining medicinal plants during the migratory process; and (2) if the choice of strategies for medicinal plants depends on: (a) the degree of floristic and environmental similarity between the home and host country; (b) the perception and usefulness of certain environments as a source of medicinal plants; (c) the degree of contact with the local population in the host country, and/or (d) the degree of contact between migrants and their homeland. MATERIAL AND METHODS: The analysis is grounded in data from different types of interviews and a homegarden inventory addressed to 72 study participants. Voucher specimens of species mentioned were gathered and identified. Two indices were used as proxy measures: (1) the number of species obtained from each habitat, and (2) the number of citations for both modes and places of obtaining medicinal plants. RESULTS: Due to different flora found in Argentina, Polish migrants could reconstruct only bits and pieces of their native pharmacopoeia. They could not acquire medicinal plants either from relatives in Poland or via importation. Therefore they had to develop new strategies for securing medicinal resources. During the migratory process, Poles in Misiones changed forms and places of obtaining medicinal plants. Cultivated species from homegardens play the most important role, while in the native country homegarden species were used sparsely. The second most important environment for medicinal plant procurement is the forest, whose exploitation was increased by contact with local mestizos and indigenous groups. CONCLUSIONS: This study clearly shows that traditional knowledge can be adaptive and resilient. New species have been selected and incorporated from mestizos, and indigenous people, and at the same time the use of some legacy plants has been preserved. The importance of home gardens as a venue for medicinal plants is another facet of this adaptive process. Traditional knowledge is resilient too, because despite the many changes that have occurred, Polish people have maintained phytotherapy as their preferred form of treating ailments, and managed to retain certain species brought from Europe as the most relevant. PMID- 26129941 TI - Proceedings of the ASNC cardiac PET summit meeting, May 12, 2014, Baltimore MD : 5. Advances in radiopharmaceutical availability and development of cardiac PET tracers. PMID- 26129940 TI - Clinical applications of radionuclide imaging in the evaluation and management of patients with congenital heart disease. AB - Non-invasive testing of children with congenital heart disease (CHD) began in the 1950s with the introduction of radionuclide studies to assess shunt fractions, pulmonary blood flow, and ventricular contractile function. Echocardiography and cardiac magnetic resonance imaging have since replaced radionuclide imaging in many of these roles. Concurrently, percutaneous and surgical repairs of complex CHD evolved, creating new roles for radionuclide imaging. In this paper on applications of radionuclide imaging in CHD, we review the multiple mechanisms for myocardial ischemia in CHD. We critically compare optimal radionuclide imaging techniques to other imaging modalities for assessing ischemia in CHD. We present the current role of nuclear imaging for assessing viability and pulmonary blood flow. We highlight the value added by advances in dedicated cardiac SPECT scanners, novel reconstruction software, and cardiac PET in performing low-dose radionuclide imaging in CHD. Finally, we discuss the emerging clinical indications for radionuclide imaging in CHD including coronary flow reserve assessment and evaluation of cardiovascular prosthesis and device infections. PMID- 26129942 TI - Linking ecosystem services and human-values theory. AB - Understanding why people make the decisions they do remains a fundamental challenge facing conservation science. Ecosystem service (ES) (a benefit people derive from an ecosystem) approaches to conservation reflect efforts to anticipate people's preferences and influence their environmental behavior. Yet, the design of ES approaches seldom includes psychological theories of human behavior. We sought to alleviate this omission by applying a psychological theory of human values to a cross-cultural ES assessment. We used interviews and focus groups with fish workers from 28 coral reef fishing communities in 4 countries to qualitatively identify the motivations (i.e., human values) underlying preferences for ES; quantitatively evaluate resource user ES priorities; and identify common patterns among ES motivations and ES priorities (i.e., trade-offs and synergies). Three key findings are evident that align with human values theory. First, motivations underlying preferences for individual ESs reflected multiple human values within the same value domain (e.g., self-enhancement). Second, when averaged at community or country scales, the order of ES priorities was consistent. However, the order belied significant variation that existed among individuals. Third, in line with human values theory, ESs related to one another in a consistent pattern; certain service pairs reflected trade-off relationships (e.g., supporting and provisioning), whereas other service pairs reflected synergistic relationships (e.g., supporting and regulating). Together, these findings help improve understanding of when and why convergence and trade offs in people's preferences for ESs occur, and this knowledge can inform the development of suitable conservation actions. PMID- 26129943 TI - Erratum: Accuracy of microRNAs as markers for the detection of neck lymph node metastases in patients with head and neck squamous cell carcinoma. PMID- 26129944 TI - netview p: a network visualization tool to unravel complex population structure using genome-wide SNPs. AB - Network-based approaches are emerging as valuable tools for the analysis of complex genetic structure in wild and captive populations. netview p combines data quality control with the construction of population networks through mutual k-nearest neighbours thresholds applied to genome-wide SNPs. The program is cross platform compatible, open-source and efficiently operates on data ranging from hundreds to hundreds of thousands of SNPs. The pipeline was used for the analysis of pedigree data from simulated (n = 750, SNPs = 1279) and captive silver-lipped pearl oysters (n = 415, SNPs = 1107), wild populations of the European hake from the Atlantic and Mediterranean (n = 834, SNPs = 380) and grey wolves from North America (n = 239, SNPs = 78 255). The population networks effectively visualize large- and fine-scale genetic structure within and between populations, including family-level structure and relationships. netview p comprises a network-based addition to other population analysis tools and provides user-friendly access to a complex network analysis pipeline through implementation in python. PMID- 26129945 TI - Association between High Blood Pressure and Intakes of Sodium and Potassium among Korean Adults: Korean National Health and Nutrition Examination Survey, 2007 2012. AB - BACKGROUND: The association between dietary sodium and potassium, the ratio of sodium to potassium, and blood pressure remains unclear. OBJECTIVE: We evaluated the associations between blood pressure and dietary sodium and potassium intake in terms of the amount and ratio in Korean adults. DESIGN: This cross-sectional study was based on data from the fourth and fifth Korean National Health and Nutrition Examination Survey, 2007-2012. PARTICIPANTS/SETTING: A total of 24,096 adults (aged >=19 years) without history of antihypertensive medication use were selected. The 24-hour recall method was used for dietary assessment. We categorized the subjects into four groups using median intakes of sodium and potassium, and defined the low sodium/high potassium intake group as the reference group. MAIN OUTCOME MEASURES: High blood pressure (HBP) was defined as mean systolic or diastolic blood pressures of >=140 or >=90 mm Hg, respectively. STATISTICAL ANALYSES PERFORMED: Multivariate logistic regression was performed to estimate the odds ratio and 95% CI to investigate the association between the four groups of sodium and potassium intakes and HBP. RESULTS: Sodium intake was positively associated with diastolic blood pressure, with an increase of 0.21 mm Hg per 1 mg/kcal increase in sodium (P<0.001). In contrast, potassium intake was negatively associated with systolic blood pressure, with a decrease of 1.01 mm Hg per 1 mg/kcal increase in potassium (P<0.001). After adjusting for confounders, the high sodium/low potassium (odds ratio 1.21, 95% CI 1.02 to 1.44) and low sodium/low potassium intake groups (odds ratio 1.19, 95% CI 1.01 to 1.40) were at higher risk of HBP than the reference group. The risk of HBP in the high sodium/high potassium group did not differ from that in the reference group. CONCLUSIONS: Low potassium intake was associated with an increased risk of hypertension. These results suggest that increasing potassium intake might be beneficial for hypertension control among populations with low-potassium diets. PMID- 26129946 TI - Potential Role of Glycogen Synthase Kinase-3beta in Regulation of Myocardin Activity in Human Vascular Smooth Muscle Cells. AB - Glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase with an inhibitory role in glycogen synthesis in hepatocytes and skeletal muscle, is also expressed in cardiac and smooth muscles. Inhibition of GSK-3beta results in cardiac hypertrophy through reducing phosphorylation and increasing transcriptional activity of myocardin, a transcriptional co-activator for serum response factor. Myocardin plays critical roles in differentiation of smooth muscle cells (SMCs). This study, therefore, aimed to examine whether and how inhibition of GSK-3beta regulates myocardin activity in human vascular SMCs. Treatment of SMCs with the GSK-3beta inhibitors AR-A014418 and TWS 119 significantly reduced endogenous myocardin activity, as indicated by lower expression of myocardin target genes (and gene products), CNN1 (calponin), TAGLN1 (SM22), and ACTA2 (SM alpha-actin). In human SMCs overexpressing myocardin through the T-REx system, treatment with either GSK-3beta inhibitor also inhibited the expression of CNN1, TAGLN1, and ACTA2. These effects of GSK-3beta inhibitors were mimicked by transfection with GSK-3beta siRNA. Notably, both AR A014418 and TWS 119 decreased the serine/threonine phosphorylation of myocardin. The chromatin immunoprecipitation assay showed that AR-A014418 treatment reduced myocardin occupancy of the promoter of the myocardin target gene ACTA2. Overexpression of a dominant-negative GSK-3beta mutant in myocardin overexpressing SMCs reduced the expression of calponin, SM22, and SM alpha-actin. As expected, overexpression of constitutively active or wild-type GSK-3beta in SMCs without myocardin overexpression increased expression of these proteins. In summary, our results indicate that inhibition of GSK-3beta reduces myocardin transcriptional activity, suggesting a role for GSK-3beta in myocardin transcriptional activity and smooth muscle differentiation. PMID- 26129947 TI - Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction. AB - AIMS: TOTAL (N = 10 732), a randomized trial of routine manual thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction, showed no difference in the primary efficacy outcome but a significant increase in stroke. We sought to understand these findings. METHODS AND RESULTS: A detailed analysis of stroke timing, stroke severity, and stroke subtype was performed. Strokes were adjudicated by neurologists blinded to treatment assignment. Stroke within 30 days, the primary safety outcome, was increased [33 (0.7%) vs. 16 (0.3%), hazard ratio (HR) 2.06; 95% confidence interval (CI) 1.13 3.75]. The difference in stroke was apparent within 48 h [15 (0.3%) vs. 5 (0.1%), HR 3.00; 95% CI 1.09-8.25]. There was an increase in strokes within 180 days with minor or no disability (Rankin 0-2) [18 (0.4%) vs. 13 (0.3%) HR 1.38; 95% CI 0.68 2.82] and in strokes with major disability or fatal (Rankin 3-6) [35 (0.7%) vs. 13 (0.3%), HR 2.69; 95% CI 1.42-5.08]. Most of the absolute difference was due to an increase in ischaemic strokes within 180 days [37 (0.7%) vs. 21 (0.4%), HR 1.71; 95% CI 1.03-3.00], but there was also an increase in haemorrhagic strokes [10 (0.2%) vs. 2 (0.04%), HR 4.98; 95% CI 1.09-22.7]. Patients that had a stroke had a mortality of 30.8% within 180 days vs. 3.4% without a stroke (P < 0.001). A meta-analysis of randomized trials (N = 21 173) showed an increase in risk of stroke (odds ratio 1.59; 95% CI 1.11-2.27) but a trend towards reduction in mortality odds ratio (odds ratio 0.87; 95% CI 0.76-1.00). CONCLUSION: Thrombectomy was associated with a significant increase in stroke. Based on these findings, future trials must carefully collect stroke to determine safety in addition to efficacy. PMID- 26129948 TI - Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. AB - Corrigendum to: 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases [Eur Heart Journal (2014) 35, 2873-2926,doi:10.1093/eurheartj/ehu281]. In Table 3, the radiation for MRI is "0" and not "-". The corrected table is shown below. PMID- 26129949 TI - N2O accumulation from denitrification under different temperatures. AB - The effects of temperature on nitrous oxide (N2O) accumulation during denitrification and denitritation were investigated. Batch experiments were performed to measure N2O accumulation at 25 and 35 degrees C. More N2O accumulation was observed during denitritation at the higher temperature as compared with full denitrification and low temperature tests. The highest nitrite concentration tested in this study (25 mg/L NO2 (-)N and pH 8.0) did not show inhibitory effect on N2O reduction. It was found that the major cause of more N2O accumulation during denitrification at higher temperature was due to higher N2O production rate and lower N2O solubility. Specific nitrate, nitrite, and N2O reduction rates increased 62, 61, and 41 %, respectively, when temperature rose from 25 to 35 degrees C. The decrease of N2O solubility in mixed liquor at 35 degrees C (when compared to 25 degrees C) resulted in faster diffusing rate of N2O from liquid to gas phase. It was also more difficult for gas phase N2O to be re-dissolved. The diffused N2O was then accumulated in the headspace, which was not available for denitrification by denitrifiers. The results of this study suggest higher temperature may worsen N2O emission from wastewater treatment plants (WWTPs). PMID- 26129950 TI - Antibiotic-induced imbalances in gut microbiota aggravates cholesterol accumulation and liver injuries in rats fed a high-cholesterol diet. AB - Increasing evidence suggests that maintenance of homeostasis between gut microbiota and host plays an important role in human health. Many diseases, such as those affecting the liver, have been linked to imbalances in gut microbial communities. However, it is not clear whether an imbalance in gut microbiota promotes the onset of liver injury or if the imbalance results from the pathological state. In the current study, antibiotics were used to disturb the gut microbiota of both rats fed a high-cholesterol diet and rats fed a normal diet (controls). The prevalence of Bacteroidetes and Firmicutes were reduced, and Proteobacteria was greatly increased in the guts of rats after antibiotic treatment. The antibiotic-induced perturbation of gut microbiota aggravated cholesterol accumulation and liver injury in rats fed a high-cholesterol diet. This may have been due to an increase in intestinal permeability and plasma lipopolysaccharide (LPS), which lead to an increase in LPS absorption and activation of TLR4 signaling, resulting in the synthesis of pro-inflammatory cytokines and chemokines in liver tissues. This study suggests that imbalances in gut microbiota may be a predisposing factor for the onset of metabolic diseases and liver injuries related to cholesterol and high-cholesterol diets. Modulation of gut microbiota could be a novel target for preventing cholesterol-related metabolic disorders. PMID- 26129951 TI - Engineering Yarrowia lipolytica for production of medium-chain fatty acids. AB - Lipids are naturally derived products that offer an attractive, renewable alternative to petroleum-based hydrocarbons. While naturally produced long-chain fatty acids can replace some petroleum analogs, medium-chain fatty acid would more closely match the desired physical and chemical properties of currently employed petroleum products. In this study, we engineered Yarrowia lipolytica, an oleaginous yeast that naturally produces lipids at high titers, to produce medium chain fatty acids. Five different acyl-acyl carrier protein (ACP) thioesterases with specificity for medium-chain acyl-ACP molecules were expressed in Y. lipolytica, resulting in formation of either decanoic or octanoic acid. These novel fatty acid products were found to comprise up to 40 % of the total cell lipids. Furthermore, the reduction in chain length resulted in a twofold increase in specific lipid productivity in these engineered strains. The medium-chain fatty acids were found to be incorporated into all lipid classes. PMID- 26129952 TI - Proteomic analysis of conidia germination in Fusarium oxysporum f. sp. cubense tropical race 4 reveals new targets in ergosterol biosynthesis pathway for controlling Fusarium wilt of banana. AB - Conidial germination is a crucial step of the soilborne fungus Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4), a most important lethal disease of banana. In this study, a total of 3659 proteins were identified by isobaric tags for relative and absolute quantitation (iTRAQ)-based comparative proteomic approach, of which 1009 were differentially expressed during conidial germination of the fungus at 0, 3, 7, and 11 h. Functional classification and bioinformatics analysis revealed that the majority of the differentially expressed proteins are involved in six metabolic pathways. Particularly, all differential proteins involved in the ergosterol biosynthesis pathway were significantly upregulated, indicating the importance of the ergosterol biosynthesis pathway to the conidial germination of Foc TR4. Quantitative RT-PCR, western blotting, and in vitro growth inhibition assay by several categories of fungicides on the Foc TR4 were used to validate the proteomics results. Four enzymes, C-24 sterol methyltransferase (ERG6), cytochrome P450 lanosterol C-14alpha-demethylase (EGR11), hydroxymethylglutaryl-CoA synthase (ERG13), and C-4 sterol methyl oxidase (ERG25), in the ergosterol biosynthesis pathway were identified and verified, and they hold great promise as new targets for effective inhibition of Foc TR4 early growth in controlling Fusarium wilt of banana. To the best of our knowledge, this report represents the first comprehensive study on proteomics profiling of conidia germination in Foc TR4. It provides new insights into a better understanding of the developmental processes of Foc TR4 spores. More importantly, by host plant-induced gene silencing (HIGS) technology, the new targets reported in this work allow us to develop novel transgenic banana leading to high protection from Fusarium wilt and to explore more effective antifungal drugs against either individual or multiple target proteins of Foc TR4. PMID- 26129953 TI - Use of anaerobic green fluorescent protein versus green fluorescent protein as reporter in lactic acid bacteria. AB - Lactic acid bacteria (LAB) are commonly used in the production of fermented and probiotic foods. Development of molecular tools to discriminate the strains of interest from the endogenous microbiota in complex environments like food or gut is of high interest. Green fluorescent protein (GFP)-like chromophores strictly requires molecular oxygen for maturation of fluorescence, which restrict the study of microorganisms in low-oxygen environments. In this work, we have developed a noninvasive cyan-green fluorescent based reporter system for real time tracking of LAB that is functional under anoxic conditions. The evoglow-Pp1 was cloned downstream from the promoters D-alanyl-D-alanine carboxypeptidase and elongation factor Tu of Lactobacillus reuteri CECT925 using pNZ8048 and downstream of the lactococcal P1 promoter using pT1NX. The classical gfp was also cloned in pT1NX. These recombinant expression vectors were electroporated into Lactococccus, Lactobacillus, and Enterococcus strains with biotechnological and/or probiotic interests to assess and compare their functionality under different conditions of oxygen and pH. The expression was analyzed by imaging and fluorometric methods as well as by flow cytometry. We demonstrate that reporter systems pNZ:TuR-aFP and pT1-aFP are two versatile molecular markers for monitoring LAB in food and fecal environments without the potential problems caused by oxygen and pH limitations, which could be exploited for in vivo studies. Production of the fluorescent protein did not disturb any important physiological properties of the parental strains, such as growth rate, reuterin, or bacteriocin production. PMID- 26129954 TI - Expression of brain-specific angiogenesis inhibitor-1 and association with p53, microvessel density and vascular endothelial growth factor in the tissue of human bladder transitional cell carcinoma. AB - The aim of the present study was to investigate the expression levels of brain specific angiogenesis inhibitor-1 (BAI-1) in bladder transitional cell carcinoma (BTCC) at different stages and the mechanism by which it inhibits tumor endothelial cell proliferation. Normal bladder mucosa biopsy specimens were obtained as the control group, and human BTCC biopsy specimens were used as the study group. Immunohistochemical assays were used to detect the expression levels of BAI-1, vascular endothelial growth factor (VEGF) and mutant p53, in addition to microvessel density (MVD) in the tissues. Western blotting was used to analyze the differential expression of BAI-1 in the two samples. Statistical analysis was performed, which indicated that BAI-1 expression levels in the normal bladder mucosa group were significantly higher than those in the BTCC group and were associated with clinical staging. BAI-1 levels in the T1 stage BTCC tissues were higher than those in the T2-4 stage BTCC tissues (P<0.05). BAI-1 expression levels were negatively correlated with those of VEGF (r=-0.661, P<0.001), mutant p53 (r=-0.406, P=0.002) and with the MVD (r=-0.675, P<0.001). BAI-1 may be involved in the negative regulation of BTCC microvascular proliferation, and its expression may be associated with a reduction in p53 mutations. PMID- 26129955 TI - Saline-induced changes of epicuticular waxy layer on the Puccinellia tenuiflora and Oryza sativa leave surfaces. AB - BACKGROUND: The epicuticular waxy layer of plant leaves enhances the extreme environmental stress tolerance. However, the relationship between waxy layer and saline tolerance was not established well. The epicuticular waxy layer of rice (Oryza sativa L.) was studied under the NaHCO3 stresses. In addition, strong saline tolerance Puccinellia tenuiflora was chosen for comparative studies. RESULTS: Scanning electron microscope (SEM) images showed that there were significant changes in waxy morphologies of the rice epicuticular surfaces, while no remarkable changes in those of P. tenuiflora epicuticular surfaces. The NaHCO3 induced morphological changes of the rice epicuticular surfaces appeared as enlarged silica cells, swollen corns-shapes and leaked salt columns under high stress. Energy dispersive X-ray (EDX) spectroscopic profiles supported that the changes were caused by significant increment and localization of [Na(+)] and [Cl( )] in the shoot. Atomic absorption spectra showed that [Na(+)]shoot/[Na(+)]root for P. tenuiflora maintained stable as the saline stress increased, but that for rice increased significantly. CONCLUSION: In rice, NaHCO3 stress induced localization and accumulation of [Na(+)] and [Cl(-)] appeared as the enlarged silica cells (MSC), the swollen corns (S-C), and the leaked columns (C), while no significant changes in P. tenuiflora. PMID- 26129956 TI - THE AMERICAN SOCIETY OF CLINICAL PSYCHOPHARMACOLOGY SURVEY OF PSYCHOPHARMACOLOGISTS' PRACTICE PATTERNS FOR THE TREATMENT OF MOOD DISORDERS. AB - BACKGROUND: Optimal successive treatment decisions are not well established after an initial medication nonresponse in major depressive disorder or bipolar disorder. While practice guidelines offer consensus-based expert treatment recommendations, little is known about "real world" pharmacology decision making by practicing psychopharmacologists. MATERIALS AND METHODS: We surveyed via Internet the national membership of the American Society of Clinical Psychopharmacology (ASCP) to study preferred pharmacotherapy strategies and factors that influence medication choices for patients with mood disorders. RESULTS: Surveys were returned by 154/752 ASCP members (21%). After nonresponse to a serotonin reuptake inhibitor in major depressive disorder, participants equally favored switching within or across antidepressant classes. After a partial response, adjunctive bupropion was the preferred intervention, followed by changing antidepressant classes. Atypical antipsychotic augmentation was only a fourth-line consideration, even though moderate or marked efficacy was perceived in most instances with olanzapine, aripiprazole, and quetiapine. Respondents favored avoiding antidepressants in bipolar I patients with mixed/cycling features or prior antidepressant-associated mania/hypomania. In rapid cyclers, they advocated antidepressant cessation and preferred the use of atypical antipsychotics and lamotrigine. CONCLUSIONS: Participating psychopharmacologists treating adults with mood disorders report prescribing medications that largely mirror the evidence base with only a few notable exceptions, in consideration of the characteristics of definable clinical subpopulations. PMID- 26129957 TI - Redefining the Value of Sports Medicine. PMID- 26129958 TI - Increased Lateral Tibial Slope Is a Risk Factor for Pediatric Anterior Cruciate Ligament Injury: An MRI-Based Case-Control Study of 152 Patients. AB - BACKGROUND: Increased posterior tibial slope is associated with increased risk of anterior cruciate ligament (ACL) injury in adults. A similar association has not been rigorously examined in children and adolescents. PURPOSE: To determine whether alterations in posterior tibial slope are associated with ACL tears in pediatric and adolescent patients and to quantify changes in tibial slope by age. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Magnetic resonance imaging (MRI) studies of the knee were reviewed by 3 raters blinded to each other in a 1:1 sample of cases and age- and sex-matched controls. A total of 76 skeletally immature ACL-injured knees were compared with 76 knees without ACL injury; the mean age of the study population was 14.8 +/- 1.3 years. The posterior slope of the articular surface of the medial tibial plateau and lateral tibial plateau was measured by use of a method similar to that used in previous studies in adult populations. The current study technique differed in that the slope was measured on the cartilage surface, not the subchondral bone. Comparisons between knees were made with t tests, and Spearman correlation analysis was used to assess changes in tibial slope with advancing age. RESULTS: Increased slope of the lateral tibial plateau (LTS) was significantly increased in ACL-injured patients compared with controls (5.7 degrees +/- 2.4 degrees vs 3.4 degrees +/- 1.7 degrees ; P < .001). There was no statistically significant difference in the slope of the medial tibial plateau (MTS) in the ACL-injured and control knees (5.4 degrees +/- 2.2 degrees vs 5.1 degrees +/- 2.3 degrees ; P = .42). There was no difference in LTS between male and female patients (4.46 degrees vs 4.58 degrees ; P = .75). Receiver operating characteristic (ROC) analysis of the LTS revealed that a posterior tibial slope cutoff of >4 degrees resulted in a sensitivity of 76% and a specificity of 75% for predicting ACL tears in this cohort. Spearman correlation analysis revealed that MTS and LTS decreased, or flattened, by 0.31 degrees (P = .028, correlation coefficient r = 0.18) and 0.37 degrees (P = .009, correlation coefficient r = -0.21) per year, respectively, as adolescents age. CONCLUSION: The LTS was significantly associated with an increased risk of ACL injury in pediatric and adolescent patients. The MTS was not associated with risk of injury. Posterior slope was found to decrease, or flatten, with age. A cutoff of >4 degrees for the posterior slope of the lateral compartment is 76% sensitive and 75% specific for predicting ACL injury in this cohort. The LTS did not influence the incidence of ACL injury differently between sexes. PMID- 26129959 TI - Trends in Medial Ulnar Collateral Ligament Reconstruction in the United States: A Retrospective Review of a Large Private-Payer Database From 2007 to 2011. AB - BACKGROUND: Overuse injuries to the elbow in the throwing athlete are common. Ulnar collateral ligament reconstruction (UCLR), commonly known as Tommy John surgery, is performed on both recreational and high-level athletes. There is no current literature regarding the incidence and demographic distribution of this surgical procedure in relation to patient age, location within the Unites States, and sex. PURPOSE: To determine the current demographic distribution of UCLR within the US population included in the PearlDiver database. STUDY DESIGN: Descriptive epidemiology study. METHODS: A retrospective analysis of the PearlDiver supercomputer database, a private-payer database, was performed to identify UCLR procedures performed between 2007 and 2011. The Current Procedural Terminology (CPT) code 24346 (reconstruction of the ulnar collateral ligament of the elbow with the use of a tendinous graft) was used. RESULTS: Between 2007 and 2011, a total of 790 patients underwent UCLR. The average (+/-SD) annual incidence was 3.96 +/- 0.38 per 100,000 patients for the overall population but was 22 +/- 3.4 for patients aged 15 to 19 years. The overall average annual growth was 4.2%. There were 695 males and 95 females. The 15- to 19-year-old patients accounted for significantly more procedures than any other age group (56.8%; P < .001), followed by 20- to 24-year-olds (22.2%). The incidence of UCLR in the 15- to 19-year-old group increased at an average rate of 9.12% per year (P = .009). Significantly more UCLR procedures were performed in the southern United States than in any other region (P < .001). The number of procedures significantly increased over time (P = .039). CONCLUSION: According to this database of a privately insured population, UCLR was performed significantly more in patients aged 15 to 19 than any other age group. The average annual incidence of UCLR per 100,000 people for patients aged 15 to 19 was 22 +/- 3.4. Further, this database showed that the number of UCLR procedures is increasing over time. Further work should address risk reduction efforts in this at-risk population. PMID- 26129960 TI - Outcomes After Combined ACL and ALL Reconstruction: Letter to the Editor. PMID- 26129961 TI - Outcomes After Combined ACL and ALL Reconstruction: Response. PMID- 26129962 TI - Humeral Retrotorsion in Pitchers With GIRD: Letter to the Editor. PMID- 26129963 TI - Humeral Retrotorsion in Pitchers With GIRD: Response. PMID- 26129964 TI - Teaching of the Society for Fetal Urology grading system for pediatric hydronephrosis is improved by e-Learning using Computer Enhanced Visual Learning (CEVL): A multi-institutional trial. AB - INTRODUCTION: It is unclear how clinicians learn to grade pediatric hydronephrosis (HN) and how effective their training has been. We sought to: 1. Assess how clinicians learn to grade HN and their confidence in their training and abilities and 2. To assess Computer Enhanced Visual Learning (CEVL) e Learning to learn the Society for Fetal Urology (SFU) grading system for pediatric HN. METHODS AND MATERIALS: A multi-institutional online survey was distributed to pediatric urologists, nephrologists, and radiologists. Respondents used a 6-point Likert scale (0 = not confident to 5 = very confident) to assess their confidence in knowledge of the criteria, indications, and ability to grade HN, and how they learned to grade. Participants assigned SFU grades to 15 neonatal ultrasounds (US). A CEVL module on the SFU grading system was accessed and a post-CEVL survey completed. Changes in confidence and accuracy of grading were compared before and after CEVL e-Learning. RESULTS: The most common method of learning was "casually during training" (44.5%). Significant increases in confidence in knowledge of criteria, indications, and ability to grade, as well as the accuracy of grading were seen following CEVL e-Learning (Figure A and B). DISCUSSION: Although the SFU grading system is considered the predominant grading system for HN, its application in clinical practice has been inconsistent. While this may be due to the grading system itself, it is possible that deficient training and confidence are the root causes. Our data supports this by demonstrating that most clinicians receive only casual training and accordingly, report low confidence in their knowledge and ability to grade HN. Therefore, we conclude that there exists a strong need to improve the teaching of the SFU grading system. e-Learning has been shown to be effective in teaching difficult topics and skills. We demonstrate that e-Learning with CEVL is effective in increasing both the confidence and accuracy of SFU grading of pediatric HN. Limitations of our study include a small sample size, low response rate, and discrepant participation. Furthermore, we did not assess the extent to which the CEVL module was used or include a control group learning through traditional means. Therefore, we were unable to evaluate the efficiency of learning or be certain that the improvements seen were derived exclusively from CEVL. CONCLUSION: Current training in SFU grading of HN is mostly unstructured and inaccurate grading is common. Learners who use CEVL show improvements in their confidence and ability to SFU grade HN. PMID- 26129965 TI - A study of radiological scoring system evaluating extrapancreatic inflammation with conventional radiological and clinical scores in predicting outcomes in acute pancreatitis. AB - BACKGROUND: A number of scoring systems are available to predict prognosis in acute pancreatitis (AP). The aim of the study was to compare extra-pancreatic inflammation on computed tomography (CT) (EPIC score) and renal rim sign with clinical scores (BISAP, SIRS) and conventional CT severity index (CTSI) and modified CTSI (MCTSI) in predicting persistent organ failure (POF), intervention and mortality. METHODS: The demographic, clinical and radiographic data from patients with AP were retrospectively evaluated. The scores were evaluated by calculating receiver operator characteristic (ROC) curves and area under the ROC (AUROC). RESULTS: Of the 105 patients (65 males; mean age 40.6+/-12.9 years) included, 8 died, 71 developed POF, and 16 needed intervention. The mean CTSI, MCTSI and EPIC scores were 5.8+/-3.0, 7.1+/-2.6 and 4.0+/-1.9 respectively. The AUROC for SIRS, BISAP, CTSI, MCTSI, Renal Rim Score and EPIC score in predicting POF were 0.65 (95%CI 0.53-0.78), 0.75 (95%CI 0.65-0.86), 0.66 (95%CI 0.54-0.78), 0.70 (95%CI 0.58-0.81), 0.64 (95%CI 0.52-0.76), 0.71 (95%CI 0.60-0.83), for radiological/endoscopic intervention were 0.50 (95%CI 0.35-0.65), 0.64 (95%CI 0.49-0.78), 0.51 (95%CI 0.36-0.66), 0.55 (95%CI 0.41-0.70), 0.51 (95%CI 0.36 0.67), 0.66 (95%CI 0.52-0.81), and for mortality 0.57 (95%CI 0.38-0.75), 0.90 (95%CI 0.83-0.97), 0.67 (95%CI 0.50-0.83), 0.68 (95%CI 0.51-0.85), 0.73 (95%CI 0.57-0.89) and 0.77 (95%CI 0.64-0.90) respectively. CONCLUSION: The prognostic performance of various clinical and radiological scoring systems in AP is comparable with BISAP having the highest accuracy for predicting POF and mortality. PMID- 26129966 TI - Magnetic-Induced Luminescence from Flexible Composite Laminates by Coupling Magnetic Field to Piezophotonic Effect. AB - Magnetic-induced luminescence (MIL) is realized via a strain-mediated coupling strategy. MIL composite laminates composed of magnetic actuator and phosphor phases are developed. The MIL performance is tested under low magnetic fields at room temperature. The results provide a novel type of promising luminescent and magnetic material for developing some new concept devices. PMID- 26129968 TI - Heparin interacts with elongation factor 1alpha of Cryptosporidium parvum and inhibits invasion. AB - Cryptosporidium parvum is an apicomplexan parasite that can cause serious watery diarrhea, cryptosporidiosis, in human and other mammals. C. parvum invades gastrointestinal epithelial cells, which have abundant glycosaminoglycans on their cell surface. However, little is known about the interaction between C. parvum and glycosaminoglycans. In this study, we assessed the inhibitory effect of sulfated polysaccharides on C. parvum invasion of host cells and identified the parasite ligands that interact with sulfated polysaccharides. Among five sulfated polysaccharides tested, heparin had the highest, dose-dependent inhibitory effect on parasite invasion. Heparan sulfate-deficient cells were less susceptible to C. parvum infection. We further identified 31 parasite proteins that potentially interact with heparin. Of these, we confirmed that C. parvum elongation factor 1alpha (CpEF1alpha), which plays a role in C. parvum invasion, binds to heparin and to the surface of HCT-8 cells. Our results further our understanding of the molecular basis of C. parvum infection and will facilitate the development of anti-cryptosporidial agents. PMID- 26129970 TI - Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. AB - Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." PMID- 26129971 TI - Ribosomal RNA gene sequencing for early diagnosis of Blastomyces dermatitidis infection. AB - Prompt detection and identification of fungal pathogens at the genus and species level is critical in order to provide timely antifungal therapy. Here, we highlight the vital role of molecular diagnostics in achieving a fast and definitive diagnosis of disseminated blastomycosis in a diabetic patient presenting as a brain mass initially thought to be tumoral in nature. A broad range PCR amplification and sequencing of the fungal ribosomal RNA genes on brain biopsy tissue obtained during elective craniotomy revealed a final microbial identification of Ajellomyces dermatitidis (telemorph of Blastomyces dermatitidis). PMID- 26129969 TI - Core protein: A pleiotropic keystone in the HBV lifecycle. AB - Hepatitis B Virus (HBV) is a small virus whose genome has only four open reading frames. We argue that the simplicity of the virion correlates with a complexity of functions for viral proteins. We focus on the HBV core protein (Cp), a small (183 residue) protein that self-assembles to form the viral capsid. However, its functions are a little more complicated than that. In an infected cell Cp modulates almost every step of the viral lifecycle. Cp is bound to nuclear viral DNA and affects its epigenetics. Cp correlates with RNA specificity. Cp assembles specifically on a reverse transcriptase-viral RNA complex or, apparently, nothing at all. Indeed Cp has been one of the model systems for investigation of virus self-assembly. Cp participates in regulation of reverse transcription. Cp signals completion of reverse transcription to support virus secretion. Cp carries both nuclear localization signals and HBV surface antigen (HBsAg) binding sites; both of these functions appear to be regulated by contents of the capsid. Cp can be targeted by antivirals - while self-assembly is the most accessible of Cp activities, we argue that it makes sense to engage the broader spectrum of Cp function. This article forms part of a symposium in Antiviral Research on "From the discovery of the Australia antigen to the development of new curative therapies for hepatitis B: an unfinished story." PMID- 26129972 TI - Clinical importance and cost of bacteremia caused by nosocomial multi drug resistant acinetobacter baumannii. AB - BACKGROUND: A. baumannii is an important nosocomial pathogen associated with high mortality, morbidity and medical cost. AIM: The aim of this study was to investigate risk factors for MDR A. baumannii bacteremia and also evaluate cost of hospitalization of these patients. METHODS: Study was conducted in Ankara Ataturk Training and Research Hospital. Patients who were hospitalized in ICU and diagnosed for nosocomial blood stream infection (BSI) between January 2007 and December 2010 were checked retrospectively. Patients with nosocomial BSI caused by multidrug resistant A. baumannii were compared with the patients who had BSI caused by other Gram-negative microorganisms in terms of risk factors, mortality and medical costs. FINDINGS: In multivariate analysis previous use of carbapenem, quinolone and metronidazole, and SAPS II score were found as independent risk factors. In case group; immunosupression, SAPS II score, and hospital stay until infection were independently associated with mortality in multivariate analysis. CONCLUSION: Our results suggest that the occurrence of MDR A.baumannii bacteremia was related with the usage of the wide spectrum antibiotics, and mortality rates were increased in patients that high SAPS II scores, long term hospitalization. Infection control procedures and limited antibiotic usage are very important for prevent nosocomial infections. PMID- 26129973 TI - An ELISA using recombinant TmHSP70 for the diagnosis of Taenia multiceps infections in goats. AB - Infections with the tapeworm Taenia multiceps are problematic for ruminant farming worldwide. Here we develop a novel and rapid method for serodiagnosis of T. multiceps infections via an indirect ELISA (iELISA) that uses a heat shock protein, namely, TmHSP70. We extracted the total RNA of T. multiceps from the protoscoleces of cysts dissected from the brains of infected goats. Subsequently, we successfully amplified, cloned and expressed the TmHSP70 gene in Escherichia coli BL21 (DE3). Western blot analysis showed that the recombinant protein (~34 kDa molecular weight) was recognized by the coenurosis positive serum. Given these initial, robust immunogenic properties for recombinant TmHSP protein, we assessed the ELISA-based serodiagnostic potential of this gene. The indirect ELISA was then optimized to 2.70 MUg/well dilution for antigen and 1:80 dilution for serum,while the cut-off value is 0.446. We report that our novel TmHSP ELISA detected T. multiceps sera with a sensitivity of 1:10240 and a specificity of 83.3% (5/6). In a preliminary application, this assay correctly confirmed T. multiceps infection in 30 infected goats, consistent with the clinical examination. This study has revealed that our novel iELISA, which uses the rTmHSP protein, provides a rapid test for diagnosing coenurosis. PMID- 26129974 TI - Multispecies resistance of cattle gastrointestinal nematodes to long-acting avermectin formulations in Mato Grosso do Sul. AB - The use of long-acting avermectins (AVMs) in cattle to treat infections with gastrointestinal nematodes was common in Brazil until its prohibition by state authorities. The prohibition; however, was rescinded in 2015, but a scientific discussion of the pros and cons of the use of these formulations is necessary. We evaluated the levels of resistance to 1.0 and 3.5% doramectin and to 3.15% ivermectin in cattle. The worms in animals treated with 3.5% doramectin were characterized by the suppression of oviposition and by a higher proportion of adult females carrying no eggs. Haemonchus placei, Cooperia punctata, C. pectinata, C. spatulata, and Oesophagostomum radiatum were resistant to the above compositions. The administration of long-acting AVM formulations did not result in a higher efficacy against these helminth populations. PMID- 26129975 TI - Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo. AB - RATIONALE: Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P on activation, little is known about a potential intrinsic effect of S1P on platelet function. OBJECTIVE: To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function. METHODS AND RESULTS: We found a 100 fold reduction in intracellular S1P levels in platelets derived from Sphk2(-/-) mutants compared with Sphk1(-/-) or wild-type mice, as analyzed by mass spectrometry. Sphk2(-/-) platelets also failed to secrete S1P on stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease activated receptor 4-peptide and adenosine diphosphate stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 through modulation of protease-activated receptor 4-peptide and adenosine diphosphate induced platelet activation. Finally, we show by intravital microscopy that defective platelet aggregation in Sphk2-deficient mice translates into reduced arterial thrombus stability in vivo. CONCLUSIONS: We demonstrate that Sphk2 is the major Sphk isoform responsible for the generation of S1P in platelets and plays a pivotal intrinsic role in the control of platelet activation. Correspondingly, Sphk2-deficient mice are protected from arterial thrombosis after vascular injury, but have normal bleeding times. Targeting this pathway could therefore present a new therapeutic strategy to prevent thrombosis. PMID- 26129976 TI - Continuous Video Electroencephalographic (EEG) Monitoring for Electrographic Seizure Diagnosis in Neonates: A Single-Center Study. AB - The objective of this study was to determine the diagnostic yield of continuous video electroencephalographic (EEG) monitoring in critically ill neonates in the setting of a novel, university-based Neonatal Neurocritical Care Service. Patient demographic characteristics, indication for seizure monitoring, and presence of electrographic seizures were obtained by chart review. Among 595 patients cared for by the Neonatal Neurocritical Care Service, 400 (67%) received continuous video EEG. The median duration of continuous video EEG monitoring was 49 (interquartile range = 22-87) hours. Electrographic seizures were captured in 105 of 400 (26% of monitored patients) and of those, 25 of 105 (24%) had no clinical correlate. In addition, 52 of 400 subjects (13%) were monitored due to paroxysmal events concerning for seizures, but never had electrographic seizures. Continuous video EEG monitoring helped confirm or rule out ongoing seizures in more than one third of the cases. This finding helps to support the use of continuous video EEG in critically ill neonates. PMID- 26129977 TI - Regional Microstructural and Volumetric Magnetic Resonance Imaging (MRI) Abnormalities in the Corpus Callosum of Neonates With Congenital Heart Defect Undergoing Cardiac Surgery. AB - The purpose of the study is to investigate the structural development of the corpus callosum in term neonates with congenital heart defect before and after surgery using diffusion tensor imaging and 3-dimensional T1-weighted magnetic resonance imaging (MRI). We compared parallel and radial diffusions, apparent diffusion coefficient (ADC), fractional anisotropy, and volume of 5 substructures of the corpus callosum: genu, rostral body, body, isthmus, and splenium. Compared to healthy controls, we found a significantly lower volume of the splenium and total corpus callosum and a higher radial diffusion and lower fractional anisotropy in the splenium of patients presurgery; a lower volume in all substructures in the postsurgery group; higher radial diffusion in the rostral body, body, and splenium; and a higher apparent diffusion coefficient in the splenium of postsurgery patients. Similar fractional anisotropy changes in congenital heart defect patients were reported in preterm infants. Our findings in apparent diffusion coefficient in the splenium of these patients (pre and postsurgery) are comparable to findings in preterm neonates with psychomotor delay. Delayed maturation of the isthmus was also reported in preterm infants. PMID- 26129978 TI - Facial Expressions in Small for Gestational Age Newborns. PMID- 26129979 TI - Comparison in the incidence of anorectal malformations between a first- and third world referral center. AB - PURPOSE: Aim of study was to evaluate the differences in incidence and presentation of anorectal malformations (ARMs) between selected Pediatric Surgery Divisions in the Republic of South Africa (ZAR) and Italy. METHODS: A retrospective cohort study involved analysis of clinical records of patients with ARM born between 2005 and 2012. Type of ARM, maternal age, birth weight, gestational age, presence of associated anomalies and delayed diagnosis were analyzed. RESULTS: 335 patients were included in this study. Of note, statistically significant differences between the African and European patient groups were observed in a male predominance in the ZAR patient population. In addition, female recto-perineal fistulas were diagnosed in significantly more Italian patients than in ZAR. Furthermore, a more advanced maternal age and a lower gestational age was noted in the European cohort with a minimal delay in initial diagnosis as opposed to the African counterpart. Both centers reported recto-perineal fistula as the most common malformation in male patients. CONCLUSION: With the exception of perineal fistulas in females, the incidence of specific subtypes of ARMs was similar in the two groups. This may be of importance when extrapolating European study conclusion to the South African setting. PMID- 26129980 TI - The management of anorectal malformation with congenital vestibular fistula: a single-stage modified anterior sagittal anorectoplasty. AB - PURPOSE: This study aimed to evaluate the mid-term outcomes of single-stage modified anterior sagittal anorectoplasty (ASARP) for anorectal malformation with vestibular fistula. METHOD: Twenty-six patients with congenital imperforate anus and vestibular fistula underwent single-stage modified sphincter-saving ASARP between January 2008 and December 2012. The ages of the patients at the time of operation ranged from 1 month to 5.1 years. Standard ASARP procedure was modified to avoid the incision of the external sphincter complex. Instead a potential tunnel was created through the center of external sphincter complex under the endoscopic guidance. The patients were evaluated for fecal continence and complications. RESULT: Modified ASARP was successfully performed in all patients. The mean operation time was 52.2 +/- 3.5 min (range 47-61 min). The operative blood loss was minimal. There was no operative complication. Wound infection occurred in 3 patients (3/26, 11.5%). All patients were followed up for 4.2 +/- 1.5 years (range 2-6 years). No patient developed fecal incontinence. Three patients (3/26, 11.5%) had soiling once or twice per week. Four patients (4/26, 15.4%) had constipation amenable to diet management. Mucosal prolapse occurred in 1 patient (1/26, 3.8%). There was no recurrence of fistula, anal stenosis or anterior displacement of the neorectum. CONCLUSION: Mid-term results show that single-stage modified ASARP is an effective and safe option for patients with anorectal malformation and congenital vestibular fistula. PMID- 26129981 TI - Holding a stillborn baby: the view from a specialist perinatal bereavement service. AB - BACKGROUND: Stillbirth is a profoundly distressing event. Little evidence exists to guide best practice bereavement care in the perinatal setting. AIMS: To document parents' experiences and outcomes in relation to seeing and holding a stillborn baby at a hospital with a specialist perinatal bereavement service. MATERIALS AND METHODS: Prospective cohort study of 26 mothers and 11 fathers who experienced a stillbirth at the Mater Mothers' Hospital, Brisbane from September 2007-December 2008. Mailed self-report questionnaires were completed at 6-8 weeks and 6 and 13 months postloss. Validated measures assessed regret regarding the decision to see and hold the baby, parental grief and mental health. RESULTS: Of 78 fetal deaths, 26 mothers and 11 fathers participated. Most (20 mothers; 9 fathers) chose to see and hold their stillborn infant. Little regret was reported, irrespective of the decision. For mothers, seeing and holding was associated with higher 'active grief' at 6-8 weeks (mean difference (MD) = 10.5; 95% CI = 3.3-17.8; P < 0.01), 6 months (MD = 8.0; 95% CI = 0.6-15.4; P = 0.03) and 13 months (MD = 9.9; 95% CI = 1.8-17.9; P = 0.01), but not with 'not coping' or 'despair', or mental health. Fathers reported poorer mental health but small numbers mean estimates are imprecise. CONCLUSIONS: More intense grief does not equate with poorer mental health for mothers who choose to see and hold a stillborn infant. Fathers' experiences warrant further study. Supported decision making is important for bereaved parents, and rigorous evaluation of bereavement care is essential. PMID- 26129982 TI - Quantitative analysis of flavanones from citrus fruits by using mesoporous molecular sieve-based miniaturized solid phase extraction coupled to ultrahigh performance liquid chromatography and quadrupole time-of-flight mass spectrometry. AB - An analytical procedure based on miniaturized solid phase extraction (SPE) and ultrahigh-performance liquid chromatography coupled with quadrupole time-of flight tandem mass spectrometry was developed and validated for determination of six flavanones in Citrus fruits. The mesoporous molecular sieve SBA-15 as a solid sorbent was characterised by Fourier transform-infrared spectroscopy and scanning electron microscopy. Additionally, compared with reported extraction techniques, the mesoporous SBA-15 based SPE method possessed the advantages of shorter analysis time and higher sensitivity. Furthermore, considering the different nature of the tested compounds, all of the parameters, including the SBA-15 amount, solution pH, elution solvent, and the sorbent type, were investigated in detail. Under the optimum condition, the instrumental detection and quantitation limits calculated were less than 4.26 and 14.29ngmL(-1), respectively. The recoveries obtained for all the analytes were ranging from 89.22% to 103.46%. The experimental results suggested that SBA-15 was a promising material for the purification and enrichment of target flavanones from complex citrus fruit samples. PMID- 26129983 TI - On-line two-dimensional countercurrent chromatography*high performance liquid chromatography system with a novel fragmentary dilution and turbulent mixing interface for preparation of coumarins from Cnidium monnieri. AB - This study describes a novel on-line two-dimensional countercurrent chromatography*high performance liquid chromatography (2D CCC*HPLC) system for one-step preparative isolation of coumarins from the fruits of Cnidium monnieri. An optimal biphasic solvent system composed of n-heptane/acetone/water (31:50:19, v/v) with suitable Kd values and a higher retention of the stationary phase was chosen to separate target compounds. In order to address the solvent incompatibility problem between CCC and RP-HPLC, a novel fragmentary dilution and turbulent mixing (FD-TM) interface was successfully developed. In detail, the eluent from the first dimensional CCC column was divided into fractions to form 'sample-dilution' stripes in the two switching sample loops, by the dilution water from the makeup pump. Following this, a long, thin tube was applied to mix the CCC eluent with water by in-tube turbulence, to reduce the solvent effect. Each CCC fraction was alternately trapped on the two holding columns for further preparative HPLC separation. This nationally designed FD-TM strategy effectively reduced post-column pressure and allowed a higher water dilution ratio at the post end of CCC, leading to improved sample recovery and a robust 2D CCC*HPLC isolation system. As a result, in a single 2D separation run (6.5h), eight target compounds (1-8) were isolated from 0.5g crude extract of C. monnieri, in overall yields of 1.3, 2.0, 0.5, 0.5, 0.8, 1.5, 8.2, and 15.0%, with HPLC purity of 90.1, 91.1, 94.7, 99.1, 99.2, 98.2, 97.9, and 91.9%, respectively. We anticipate that this improved 2D CCC*HPLC system, based on the novel FD-TM interface, has broad application for simultaneous isolation and purification of multiple components from other complex plant-derived natural products. PMID- 26129984 TI - Superparamagnetic core-shells anchored onto graphene oxide grafted with phenylethyl amine as a nano-adsorbent for extraction and enrichment of organophosphorus pesticides from fruit, vegetable and water samples. AB - A novel adsorbent composed of silica coated magnetic microparticles (Fe3O4@SiO2) and graphene oxide (GO) functionalized with phenylethyl amine (PEA) was synthesized and characterized using Fourier transform-infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), vibrating sample magnetometry (VSM), and CHN elemental analysis techniques. The adsorbent (Fe3O4@SiO2@GO-PEA) was then used in a magnetic solid phase extraction (MSPE) of six organophosphorous pesticides (OPPs) including methyl parathion, fenitrothion, methidathion, ethion, methyl azinphos and coumaphos prior to gas chromatography nitrogen phosphorus detection (GC-NPD). The fabricated adsorbent combines the advantages of superior adsorption capability of modified GO and magnetic separability of magnetite microparticles to provide high adsorption capacity, and easy isolation from sample solutions. The main experimental parameters affecting the extraction recovery of OPPs including extraction time, pH, adsorbent dosage, salt concentration, and desorption conditions were investigated and optimized. Under the optimal conditions, linear responses were obtained in the concentration range of 0.06-200MUgL(-1) with the determination coefficients (R(2)) between 0.9945 and 0.9996. The limits of detection were from 0.02 to 0.1MUgL(-1) and the intraday and inter-day relative standard deviations (RSDs) were less than 4.8 and 6.4%, respectively. The method was successfully applied for determination of the OPPs in apple, grape, pear, bell pepper, celery and water samples. The obtained recoveries were in the range of 90.4-108.0% (RSDs=1.9-6.6%, n=3) for fruits and vegetables, and 94.6-104.2% (RSDs=2.0-4.8%, n=3) for water samples. The excellent extraction performance of the adsorbent can be attributed to its structure characteristics where the phenyl rings of PEA grafted on the GO nanosheets are accessible to interact effectively with OPPs via delocalized pi-electron system. PMID- 26129985 TI - Parameters optimization using experimental design for headspace solid phase micro extraction analysis of short-chain chlorinated paraffins in waters under the European water framework directive. AB - The water framework directives (WFD 2000/60/EC and 2013/39/EU) force European countries to monitor the quality of their aquatic environment. Among the priority hazardous substances targeted by the WFD, short chain chlorinated paraffins C10 C13 (SCCPs), still represent an analytical challenge, because few laboratories are nowadays able to analyze them. Moreover, an annual average quality standards as low as 0.4MUgL(-1) was set for SCCPs in surface water. Therefore, to test for compliance, the implementation of sensitive and reliable analysis method of SCCPs in water are required. The aim of this work was to address this issue by evaluating automated solid phase micro-extraction (SPME) combined on line with gas chromatography-electron capture negative ionization mass spectrometry (GC/ECNI-MS). Fiber polymer, extraction mode, ionic strength, extraction temperature and time were the most significant thermodynamic and kinetic parameters studied. To determine the suitable factors working ranges, the study of the extraction conditions was first carried out by using a classical one factor-at-a-time approach. Then a mixed level factorial 3*2(3) design was performed, in order to give rise to the most influent parameters and to estimate potential interactions effects between them. The most influent factors, i.e. extraction temperature and duration, were optimized by using a second experimental design, in order to maximize the chromatographic response. At the close of the study, a method involving headspace SPME (HS-SPME) coupled to GC/ECNI-MS is proposed. The optimum extraction conditions were sample temperature 90 degrees C, extraction time 80min, with the PDMS 100MUm fiber and desorption at 250 degrees C during 2min. Linear response from 0.2ngmL(-1) to 10ngmL(-1) with r(2)=0.99 and limits of detection and quantification, respectively of 4pgmL(-1) and 120pgmL(-1) in MilliQ water, were achieved. The method proved to be applicable in different types of waters and show key advantages, such as simplicity, automation and sensitivity, required for the monitoring programs linked to the WFD. PMID- 26129986 TI - Faculty development for fellows: Developing and evaluating a broad-based career development course for critical care medicine trainees. AB - PURPOSE: There is no defined training experience to teach the broad range of professional skills needed to transition from critical care trainee to practitioner. We hypothesized that a durable set of career development skills could be created for critical care medicine (CCM) trainees using a novel curriculum defined by both learners and content experts. MATERIALS AND METHODS: We presented a curriculum focused on professional development skills to 8 second year CCM fellows at a university-based training program. A needs assessment using input from faculty and fellows selected 22 topics for the course. Surveys given precurriculum and postcurriculum and at 3-year follow-up measured the perceived importance of these topics and learner comfort with the skills presented. RESULTS: Average class attendance was 77%. Seven subjects (87.5%) responded to each survey time point. Comfort scores increased from precourse to postcourse survey. Scores were maintained across most content areas from postcourse survey to follow-up. Respondents attributed a high level of importance to receiving training of this kind. CONCLUSIONS: Teaching a broad range of career development skills can result in durable confidence when reinforced by regular use postgraduation. This course fills a critical care educational need, facilitating the transition to practitioner after CCM training. PMID- 26129987 TI - Fibromyalgia is frequent in obstructive sleep apnea and responds to CPAP therapy. PMID- 26129989 TI - Anuran skin and basking behavior: The case of the treefrog Bokermannohyla alvarengai (Bokermann, 1956). AB - We investigated the morphology of the skin and the biochemistry of the lipids in the skin secretion of Bokermannohyla alvarengai, a montane treefrog that is known to bask regularly, motionless in full sunlight for extended periods of time. Our primary goal was to identify structural and biochemical modifications that might assist this frog species to accommodate the conflicting demands for heat exchange and water balance while basking. The modulation of heat exchange in basking B. alvarengai involves changes in skin coloration. We found that this response was supported by a prominent monolayer of large iridophores, whose light reflectance property is adjusted by the response of intervening melanophores. Mucosubstances and lipid compounds, mainly consisted of saturated fatty acids and presumably secreted from granular glands, were detected on the skin of B. alvarengai. These compounds formed an extra-epidermal layer over the animal's dorsal surface that might assist in the prevention of excessive water loss through evaporation. Additionally, we found well-developed skin folds at the ventral region of the frogs that lead to an increment of surface area. This feature combined with the extensive hypervascularization, also noticed for the skin of B. alvarengai, may play an important role in water reabsorption. The suite of structural and biochemical modifications identified for the integument of B. alvarengai seems to conjugate aspects relevant to both, heat exchange and water balance, allowing for this species to explore basking as an efficient thermoregulatory strategy. PMID- 26129988 TI - Ascorbate biosynthesis and its involvement in stress tolerance and plant development in rice (Oryza sativa L.). AB - Ascorbic acid (AsA) biosynthesis and its implications for stress tolerance and plant development were investigated in a set of rice knock-out (KO) mutants for AsA biosynthetic genes and their wild-types. KO of two isoforms of GDP-D-mannose epimerase (OsGME) reduced the foliar AsA level by 20-30%, and KO of GDP-L galactose phosphorylase (OsGGP) by 80%, while KO of myo-inositol oxygenase (OsMIOX) did not affect foliar AsA levels. AsA concentration was negatively correlated with lipid peroxidation in foliar tissue under ozone stress and zinc deficiency, but did not affect the sensitivity to iron toxicity. Lack of AsA reduced the photosynthetic efficiency as represented by the maximum carboxylation rate of Rubisco (Vmax), the maximum electron transport rate (Jmax) and the chlorophyll fluorescence parameter PhiPSII. Mutants showed lower biomass production than their wild-types, especially when OsGGP was lacking (around 80% reductions). All plants except for KO mutants of OsGGP showed distinct peaks in foliar AsA concentrations during the growth, which were consistent with up regulation of OsGGP, suggesting that OsGGP plays a pivotal role in regulating foliar AsA levels during different growth stages. In conclusion, our data demonstrate multiple roles of AsA in stress tolerance and development of rice. PMID- 26129990 TI - Natural variation of the expression pattern of the segmentation gene even-skipped in melanogaster. AB - The evolution of canalized traits is a central question in evolutionary biology. Natural variation in highly conserved traits can provide clues about their evolutionary potential. Here we investigate natural variation in a conserved trait-even-skipped (eve) expression at the cellular blastoderm stage of embryonic development in Drosophila melanogaster. Expression of the pair-rule gene eve was quantitatively measured in three inbred lines derived from a natural population of D. melanogaster. One line showed marked differences in the spacing, amplitude and timing of formation of the characteristic seven-striped pattern over a 50-min period prior to the onset of gastrulation. Stripe 5 amplitude and the width of the interstripe between stripes 4 and 5 were both reduced in this line, while the interstripe distance between stripes 3 and 4 was increased. Engrailed expression in stage 10 embryos revealed a statistically significant increase in the length of parasegment 6 and a decrease in the length of parasegments 8 and 9. These changes are larger than those previously reported between D. melanogaster and D. pseudoobscura, two species that are thought to have diverged from a common ancestor over 25 million years ago. This line harbors a rare 448 bp deletion in the first intron of knirps (kni). This finding suggested that reduced Kni levels caused the deviant eve expression, and indeed we observed lower levels of Kni protein at early cycle 14A in L2 compared to the other two lines. A second of the three lines displayed an approximately 20% greater level of expression for all seven eve stripes. The three lines are each viable and fertile, and none display a segmentation defect as adults, suggesting that early-acting variation in eve expression is ameliorated by developmental buffering mechanisms acting later in development. Canalization of the segmentation pathway may reduce the fitness consequences of genetic variation, thus allowing the persistence of mutations with unexpectedly strong gene expression phenotypes. PMID- 26129991 TI - Abnormal CD4 + T helper (Th) 1 cells and activated memory B cells are associated with type III asymptomatic mixed cryoglobulinemia in HCV infection. AB - BACKGROUND: Mixed cryoglobulinemia (MC) in hepatitis C virus (HCV) infection is associated with abnormal immune responses mediated by T cells and B cells, while the relationships of different subsets of CD4 + T helper (Th) cells, B cells and associated cytokines with type III asymptomatic MC in HCV infection are poorly understood. METHODS: Fifty-four chronic hepatitis C (CHC) patients and 23 healthy controls (HCs) were enrolled in the study. Serum cryoglobulins were detected by cryoprecipitation. The types of cryoglobulin were determined by western blot. The phenotypes and frequencies of Th cell and B cell subsets were detected by flow cytometric analysis. The cytokines IFN-gamma, IL-4, IL-17, IL-21, IL-22, and TGF beta were measured by enzyme-linked immunosorbent assay. RESULTS: Twenty-six CHC patients were detected with type III asymptomatic MC. The frequencies of Th2, Th17, follicular helper T (Tfh cells), Th22, and tissue-like B cells were significantly higher in CHC patients compared to HCs, while these cell subsets were not significantly different between CHC patients and HCV-related MC patients. The frequencies of Th1 and activated memory B cells increased in HCV related MC patients compared to HCs, although the difference between the two cell subsets in CHC patients and HCs was not significant. The frequency of regulatory T cells (Treg cells) was higher in CHC patients than in HCV-related MC patients and HCs. Higher expressions of serum IFN-gamma, IL-17, IL-21, and IL-22 were observed in CHC patients than in HCs, but the differences were not significantly different in CHC patients and HCV-related MC patients. The frequency of Th1 cells was associated with activated memory B cells in HCV-related MC patients, and the frequency of Th1 cells and activated memory B cells was closely related to HCV RNA in HCV-related MC patients. CONCLUSIONS: The increased frequencies of Th17 cells, Tfh cells, Th22 cells, Treg cells, cytokines IL-17, IL-21, IL-22, and tissue-like B cells, were related to HCV infection but not type III asymptomatic MC. Higher frequencies of Th1 cells and activated memory B cells were associated with type III asymptomatic MC in HCV infection. PMID- 26129992 TI - Impact of a Telepsychiatry Program at Emergency Departments Statewide on the Quality, Utilization, and Costs of Mental Health Services. AB - OBJECTIVE: This study estimated the impact of a statewide, centralized telepsychiatry service provided in nonpsychiatric emergency departments (EDs) on use of mental health services. METHODS: Individuals treated via telepsychiatry were compared with a matched control group of individuals with mental health diagnoses who were treated in nonparticipating hospitals. Bivariate and two-part and generalized linear regression models were used to assess differences between the two groups in outpatient follow-up, hospital admission following the ED visit, length of hospital stay if admitted, and inpatient and total costs. RESULTS: Between March 2009 and June 2013, there were 9,066 patients with at least one telepsychiatry visit. Of these, 7,261 had index telepsychiatry visits that the authors were able to successfully match. Compared with the matched control group, telepsychiatry recipients were more likely to receive 30-day outpatient follow-up (46% versus 16%, p<.001) and 90-day outpatient follow-up (54% versus 20%, p<.001). Telepsychiatry recipients were less likely than the control group to be admitted to the hospital during the index ED visit (11% versus 22%, p<.001). The combined effect of having a telepsychiatry consult during the index ED visit was a reduction of .86 days in inpatient length of stay. Thirty-day inpatient costs were $2,336 (p=.04) lower for the telepsychiatry versus the control group, but 30-day total health care costs were not statistically different. CONCLUSIONS: Telepsychiatry delivered in the ED through a centralized coordinated program has great promise for improving linkage with outpatient mental health services while reducing inpatient utilization and hospital costs. PMID- 26129993 TI - Outpatient Provider Contact Prior to Unintentional Opioid Overdose Among VHA Service Users. AB - OBJECTIVES: Prescription opioid medications are the most commonly implicated substances in unintentional overdoses. Outpatient health care encounters represent a potential opportunity to intervene to reduce opioid overdose risk. This study assessed the timing and type of outpatient provider contacts prior to death from unintentional prescription opioid overdose. METHODS: This study examined all adult patients nationally in the Veterans Health Administration (VHA) who died from unintentional prescription opioid overdose in fiscal years 2004-2007 and who used VHA services anytime within two years of their deaths (N=1,813). For those whose final treatment contact was in an outpatient setting (N=1,457), demographic, clinical, and treatment characteristics were compared among patients categorized by the location of their last contact. RESULTS: Among individuals last seen in outpatient settings, 33% were seen within one week of their overdose and 62% within one month of their overdose. A substantial proportion of patients (30%) were last seen within one month of death in mental health or substance use disorder outpatient settings. The majority of patients (86%) did not fill an opioid prescription on their last outpatient visit prior to death from unintentional opioid overdose. CONCLUSIONS: Most patients who died by unintentional prescription opioid overdose were seen in outpatient settings within a month of their overdose. These settings may provide an opportunity to prevent patients from dying from prescription opioid overdoses. Interventions to reduce risk should not be limited to visits during which an opioid is prescribed. PMID- 26129994 TI - Effect of Pediatric Behavioral Health Screening and Colocated Services on Ambulatory and Inpatient Utilization. AB - OBJECTIVE: The study sought to determine the impact of a pediatric behavioral health screening and colocation model on utilization of behavioral health care. METHODS: In 2003, Cambridge Health Alliance, a Massachusetts public health system, introduced behavioral health screening and colocation of social workers sequentially within its pediatric practices. An interrupted time-series study was conducted to determine the impact on behavioral health care utilization in the 30 months after model implementation compared with the 18 months prior. Specifically, the change in trends of ambulatory, emergency, and inpatient behavioral health utilization was examined. Utilization data for 11,223 children ages >=4 years 9 months to <18 years 3 months seen from 2003 to 2008 contributed to the study. RESULTS: In the 30 months after implementation of pediatric behavioral health screening and colocation, there was a 20.4% cumulative increase in specialty behavioral health visit rates (trend of .013% per month, p=.049) and a 67.7% cumulative increase in behavioral health primary care visit rates (trend of .019% per month, p<.001) compared with the expected rates predicted by the 18 month preintervention trend. In addition, behavioral health emergency department visit rates increased 245% compared with the expected rate (trend .01% per month, p=.002). CONCLUSIONS: After the implementation of a behavioral health screening and colocation model, more children received behavioral health treatment. Contrary to expectations, behavioral health emergency department visits also increased. Further study is needed to determine whether this is an effect of how care was organized for children newly engaged in behavioral health care or a reflection of secular trends in behavioral health utilization or both. PMID- 26129995 TI - Reviewing Illness Self-Management Programs: A Selection Guide for Consumers, Practitioners, and Administrators. AB - Illness self-management (ISM) programs for adults with serious mental illness offer strategies to increase self-directed recovery activities to maximize wellness and increase independence from the service delivery system. This article describes five of the most popular ISM programs: Pathways to Recovery, The Recovery Workbook, Building Recovery of Individual Dreams and Goals through Education and Support, Wellness and Recovery Action Planning, and Illness Management and Recovery. It provides guidance for administrators, practitioners, and consumers for the purposes of selecting the program or programs providing the best fit. The framework for describing the five programs encompasses four contextual domains that supplement empirical evidence for a more comprehensive evaluation: structure, value orientation toward recovery, methods of teaching, and educational content. Contextual domains distinguish programs from one another, including length and time commitment, requisite resources, inclusion of group support, utilization of medical language and pathology, degree of traditional didactic education, and prioritization of consumer-driven self exploration. The authors also searched PsycINFO, Google Scholar, and Cochrane Reviews for empirical evidence and evaluated the five programs on the strength of the evidence and the effectiveness of the intervention. Evidence of program effectiveness was found to range from low to moderate. However, empirical evidence alone is insufficient for selecting among the five programs, and contextual domains may offer the most relevant guidance by matching program features with goals of consumers, practitioners, and administrators. PMID- 26129996 TI - Culturally Adapted Cognitive-Behavioral Therapy for Chinese Americans With Depression: A Randomized Controlled Trial. AB - OBJECTIVE: No randomized controlled trials (RCTs) for adults have compared the effectiveness of a well-specified psychotherapy and a culturally adapted version of the same treatment. This study evaluated the effectiveness of cognitive behavioral therapy (CBT) and culturally adapted CBT (CA-CBT) in treating depressed Chinese-American adults. METHODS: This RCT treated 50 Chinese Americans who met criteria for major depression and sought treatment at community mental health clinics. Screening of participants began in September 2008, and the last assessment was conducted in March 2011. Participants were stratified by whether they were already taking antidepressants when they first came to the clinic and randomly assigned to 12 sessions of CBT or CA-CBT. The study did not influence regular prescription practices. The primary outcomes were dropout rates and Hamilton Depression Rating Scale scores at baseline, session 4, session 8, and session 12. RESULTS: Participants in CA-CBT demonstrated a greater overall decrease in depressive symptoms compared with participants in CBT, but the groups had similarly high depression rates at week 12. Differences in dropout rates for the two groups approached, but did not meet, statistical significance (7%, CA CBT; 26%, CBT). CONCLUSIONS: Chinese Americans entered this study with very severe depression. Participants in both CBT and CA-CBT demonstrated significant decreases in depressive symptoms, but the majority did not reach remission. Results suggest that these short-term treatments were not sufficient to address such severe depression and that more intensive and longer treatments may be needed. Results also indicate that cultural adaptations may confer additional treatment benefits. PMID- 26129997 TI - Attitudes About Required Coverage of Mental Health Care in a U.S. National Sample. AB - OBJECTIVE: Recent policy initiatives such as the Affordable Care Act and Mental Health Parity and Addiction Equity Act have expanded coverage of mental health services. However, to what extent the public supports mandated insurance coverage of mental health care relative to other specific medical services is unclear. METHODS: This report presents results of a cross-sectional, national poll of the U.S. adult population. Respondents (N=2,124) were asked whether health plans should be required to provide coverage for mental health care and other types of medical services. Logistic regression was used to assess the association of respondent characteristics with support for coverage. RESULTS: Seventy-eight percent (95% confidence interval=75%-81%) of respondents supported mandated coverage of mental health care. This result was higher than support for birth control medications, equivalent to support for oral or dental care, and lower than support for all other medical services. CONCLUSIONS: True parity for mental health care may be limited if public support lags behind that for other medical services. PMID- 26129998 TI - Noncommissioned Officers' Perspectives on Identifying, Caring for, and Referring Soldiers and Marines at Risk of Suicide. AB - OBJECTIVE: Noncommissioned officers (NCOs) in the U.S. Army and U.S. Marine Corps were surveyed to identify their ability and willingness to identify, intervene on behalf of, and refer fellow soldiers and marines at risk of suicide. METHODS: A total of 1,184 Army soldiers and 796 marines completed surveys. Descriptive statistics were collected, and regression analyses comparing the groups were conducted. RESULTS: Thirty-seven percent of marines and 40% of Army soldiers reported that they could use more suicide prevention training. Compared with trained civilians, NCOs reported greater efficacy to intervene with at-risk peers, but they also reported relatively more reluctance to intervene. Close to 40% of NCOs believed that they would be held responsible for a service member's suicide if they had asked the service member about suicidal thoughts before the suicide occurred. Chaplains were the preferred referral source, primarily because of the confidentiality they afford. CONCLUSIONS: Suicide prevention training for NCOs should focus on strategies for asking about suicide risk, assuring soldiers and marines that they will not be blamed for the suicides of fellow service members, and encouraging referrals. These results can help improve suicide prevention programs in the Army and Marine Corps, including whether current policies may need to be changed to optimize NCOs' ability to identify, intervene on behalf of, and refer service members at risk of suicide. PMID- 26129999 TI - The Health Home: A Service Delivery Model for Autism and Intellectual Disability. AB - Autism spectrum disorder (ASD) and intellectual disability (ID) are lifelong conditions with profound impact on the functioning of affected individuals and their families. Optimizing developmental outcomes requires a lifelong perspective on treatment. The patient-centered health care home (health home) model is currently used to improve health outcomes and care integration in a variety of chronic general medical and psychiatric conditions. The authors propose the health home model as a new conceptual framework from which to build systems of care for persons with ASD or ID and their families. The authors describe essential elements of a health home for these populations, which would be located in a behavioral health setting. They also describe an existing model of such a health home, the Center for Autism and Developmental Disabilities in Pennsylvania. PMID- 26130000 TI - Injurious Assault Rates on Inpatient Psychiatric Units: Associations With Staffing by Registered Nurses and Other Nursing Personnel. AB - OBJECTIVE: The study examined associations between staffing levels by registered nurses (RNs) and non-RNs on psychiatric units and the rate of injurious assaults against hospital personnel, the rate of injurious assaults against other patients, and the total rate of injurious assaults. METHODS: Generalized mixed models were used to analyze 2011-2013 data from 461 adult inpatient psychiatric units in 327 U.S. hospitals. Monthly data were aggregated to the unit level. The analyses considered RN and non-RN hours per patient day (HPPD) as linear and nonlinear predictors of the three assault rates, controlling for hospital ownership, size, and teaching status. RESULTS: Both staffing variables had statistically significant linear associations with assault rates. Higher values of HPPD for non-RNs were associated with a higher rate of assaults against hospital personnel (exp[B]=1.23), a higher rate of assaults against patients (exp[B]=1.31), and a higher total rate of injurious assaults (exp[B]=1.21). Higher values of HPPD for RNs were associated with a higher rate of assaults against hospital personnel (exp[B]=1.11) and a lower rate of assaults against patients (exp[B]=.81). CONCLUSIONS: This is the largest published study to date of the association between psychiatric unit staffing and violence and the first to examine separately assaults against hospital personnel and assaults against patients in relation to staffing. Results confirm and qualify previous findings of a positive staffing-violence association. Injurious assaults against hospital personnel and against patients have different associations with nurse staffing and should be studied as separate phenomena with different causes. PMID- 26130001 TI - MindSpot Clinic: An Accessible, Efficient, and Effective Online Treatment Service for Anxiety and Depression. AB - OBJECTIVE: The main objective of this study was to report the feasibility of delivering online cognitive-behavioral therapy (iCBT) treatments for anxiety and depression in a national public mental health service. METHODS: A prospective noncontrolled cohort study was conducted of all patients who began assessment or treatment at the MindSpot Clinic from January through December 2013. Clinic services were used by a representative cross-section of the Australian population. Mean age at assessment was 36.4+/-13.0 years, and age range was 18-86 years. Patients completed one of four online courses over eight weeks, during which they received weekly support from a therapist via telephone or secure e mail. Primary outcome measures were the nine-item Patient Health Questionnaire (PHQ-9) and the seven-item Generalized Anxiety Disorder scale (GAD-7) administered at posttreatment and three months posttreatment. RESULTS: A total of 10,293 adults who self-identified as having problems with anxiety or depression commenced assessment, and 7,172 completed the assessment and were eligible for analysis. Of these, 2,049 enrolled in a course and 1,471 completed the course, for a course completion rate of 71.8%. Moderate to large noncontrolled effect sizes (Cohen's d=.67-1.66, 95% confidence interval=.08-2.07) were found from assessment to three-month follow-up. At posttreatment and follow-up, reliable recovery ranged from 46.7% to 51.1%, and deterioration ranged from 1.9% to 3.8%. Mean total therapist time per patient was 111.8+/-61.6 minutes. CONCLUSIONS: The MindSpot Clinic produced treatment outcomes that were comparable to results from published clinical trials of iCBT. This model of service delivery represents an innovative method of providing accessible, low-cost, effective, and acceptable mental health services to many people who currently are not receiving care. PMID- 26130002 TI - Job Offers to Individuals With Severe Mental Illness After Participation in Virtual Reality Job Interview Training. AB - OBJECTIVE: Individuals with severe mental illness have low employment rates, and the job interview presents a critical barrier for them to obtain competitive employment. Prior randomized controlled trials (RCTs) indicated that virtual reality job interview training (VR-JIT) improved job interviewing skills among trainees. This study assessed whether VR-JIT participation was associated with greater odds of receiving job offers in the six-months after completion of training. METHODS: To assess the efficacy of VR-JIT, trainees (N=39) in the method and a comparison group (N=12) completed a brief survey approximately six months after participating in the RCTs. Primary vocational outcome measures included receiving a job offer and number of weeks searching for employment. RESULTS: A larger proportion of trainees than comparison participants received a job offer (51% versus 25%, respectively). Trainees were more likely to receive a job offer than comparison participants (odds ratio=9.64, p=.02) after analyses accounted for cognition, recency of last job, and diagnosis. Trainees had greater odds of receiving a job offer for each completed VR-JIT trial (odds ratio=1.41, p=.04), and a greater number of completed VR-JIT trials predicted fewer weeks of searching for employment (beta=-.74, p=.02). CONCLUSIONS: Results provide preliminary support that VR-JIT is a promising intervention associated with enhanced vocational outcomes among individuals with severe mental illness. Given that participants had minimal access to standardized vocational services, future research could evaluate the effectiveness of VR-JIT among individuals with and without access to standardized vocational services as well as evaluate strategies to implement VR-JIT within a large community mental health service provider. PMID- 26130003 TI - Two Birds, One Stone: Unintended Consequences and a Potential Solution for Problems With Recovery in Mental Health. AB - Recovery began as a social justice movement. In more recent years, professionals have joined the movement, unintentionally co-opting and mainstreaming the more radical goals of these earlier activist consumer movements. The goals of the patient-centered care movement in general medical care are similar to those of "professional recovery." If mental health professionals instead adopted the language and goals of patient-centered care as a first step toward joining the two movements, the recovery movement could reclaim its social justice roots, and progress would be made toward reducing the duality between physical and mental health care systems. Professionals should return the recovery movement to those with lived experience, adopt the unified language of patient-centered care, and align professional transformation efforts under one holistic movement. PMID- 26130004 TI - The Recovery-Oriented Care Collaborative: A Practice-Based Research Network to Improve Care for People With Serious Mental Illnesses. AB - Practice-based research networks (PBRNs) create continuous collaborations among academic researchers and practitioners. Most PBRNs have operated in primary care, and less than 5% of federally registered PBRNs include mental health practitioners. In 2012 the first PBRN in the nation focused on individuals with serious mental illnesses-the Recovery-Oriented Care Collaborative-was established in Los Angeles. This column describes the development of this innovative PBRN through four phases: building an infrastructure, developing a research study, executing the study, and consolidating the PBRN. Key lessons learned are also described, such as the importance of actively engaging direct service providers and clients. PMID- 26130005 TI - The Inhibition of the Rayleigh-Taylor Instability by Rotation. AB - It is well-established that the Coriolis force that acts on fluid in a rotating system can act to stabilise otherwise unstable flows. Chandrasekhar considered theoretically the effect of the Coriolis force on the Rayleigh-Taylor instability, which occurs at the interface between a dense fluid lying on top of a lighter fluid under gravity, concluding that rotation alone could not stabilise this system indefinitely. Recent numerical work suggests that rotation may, nevertheless, slow the growth of the instability. Experimental verification of these results using standard techniques is problematic, owing to the practical difficulty in establishing the initial conditions. Here, we present a new experimental technique for studying the Rayleigh-Taylor instability under rotation that side-steps the problems encountered with standard techniques by using a strong magnetic field to destabilize an otherwise stable system. We find that rotation about an axis normal to the interface acts to retard the growth rate of the instability and stabilise long wavelength modes; the scale of the observed structures decreases with increasing rotation rate, asymptoting to a minimum wavelength controlled by viscosity. We present a critical rotation rate, dependent on Atwood number and the aspect ratio of the system, for stabilising the most unstable mode. PMID- 26130006 TI - Rapid thawing and stabilizing procedure improve postthaw survival and in vitro penetrability of boar spermatozoa cryopreserved with a glycerol-free trehalose based extender. AB - Thawing process is important in semen cryopreservation as it brings back the sperm cell to physiologic temperature reactivating the metabolism. Aims of the present study were to evaluate survival rate and in vitro penetrability of boar frozen spermatozoa after rapid and transient thawing at a high temperature followed by a warming procedure at 39 degrees C. Ejaculated semen samples were diluted in an egg yolk-based glycerol-free extender containing 100-mM trehalose and then cryopreserved in 0.5-mL straws according to a common protocol. In experiment 1, when temperature inside the straws was monitored after thawing at 40 degrees C, 60 degrees C, 70 degrees C, and 80 degrees C, the calculated average warming rate in the straws from -196 degrees C to 15 degrees C was much faster when thawed at 70 degrees C and 80 degrees C than at 40 degrees C (P < 0.01). The warming temperature rate inside the straw was 7 to 12 folds faster during the first 2 seconds than the second 2 seconds after immersing in high temperatures. In experiment 2, when frozen straws were thawed at 80 degrees C for 9 seconds, the viability, motility, and acrosomal integrity were significantly improved (P < 0.05), as compared with controls (at 39 degrees C). In experiment 3, frozen straws were thawed at 39 degrees C, 60 degrees C, 70 degrees C, and 80 degrees C for 60, 10, 8, and 6 seconds, respectively, and then maintained at 39 degrees C for 0, 50, 52, and 54 seconds. Higher viability, motility, mitochondria membrane potential, and acrosome integrity were observed (P < 0.05) when frozen straws were thawed at 70 degrees C for 8 seconds and then maintained at 39 degrees C for 52 seconds as compared with the control (39 degrees C for 60 seconds). In experiment 4, in vitro penetrability of frozen spermatozoa thawed at 70 degrees C for 8 seconds and maintained at 39 degrees C for 52 seconds was higher than that of controls. In conclusion, the rapid transient thawing at 70 degrees C for 8 seconds followed by stabilizing procedure at 39 degrees C for 52 seconds maintained the viability, motility, mitochondria membrane potential, acrosome integrity, and in vitro penetrability of spermatozoa frozen in a glycerol-free trehalose extender and recommended as an optimum thawing conditions. PMID- 26130007 TI - Preparation of Biotubes with vascular cells component by in vivo incubation using adipose-derived stromal cell-exuding multi-microporous molds. AB - Biotubes, prepared using in-body tissue architecture (IBTA) technology, have adequate mechanical properties and excellent biocompatibility for vascular grafts. However, they have thin walls, lack vascular constructing cells, and are composed of subcutaneous connective tissues consisting mainly of collagen and fibroblasts. This study aimed to prepare Biotubes with a vascular-like structure including an endothelial cell lining and a smooth muscle cell by IBTA using adipose-derived vascular stromal cell (ADSCs)-exuding specially designed multiporous tubes (outer diameter 5 mm, length 24 mm, pore size 500 MUm, pore number 180, cell number/tube >3.0 * 10(6)). ADSCs were separated from rat subcutaneous fat, suspended in a MatrigelTM solution at 4 degrees C, and then filled into the tubes. After the tubes were embedded into dorsal subcutaneous pouches of the same rats for 2 weeks, robust Biotubes with a wall thickness of >600 MUm were formed surrounding the tubes. The luminal layer of the obtained Biotubes was dominated by the cells positive for an endothelial marker. Almost the entire intima, with a thickness of about 400 MUm, was occupied with cells positive for a smooth muscle marker. Both cells were derived from ADSCs. Biotube walls were constructed by fusing ADSC-derived vascular constructing cells exuded from the tubes and fibroblasts and collagen from the surrounding connective tissue. A robust Biotubes with vascular cells component, were formed after only 2 weeks of subcutaneous incubation of ADSCs-exuding multiporous tubes. PMID- 26130008 TI - DNA-protein crosslink repair. AB - DNA-protein crosslinks (DPCs) are highly toxic DNA adducts, but whether dedicated DPC-repair mechanisms exist was until recently unknown. This has changed with discoveries made in yeast and Xenopus laevis that revealed a protease-based DNA repair pathway specific for DPCs. Importantly, mutations in the gene encoding the putative human homologue of a yeast DPC protease cause a human premature ageing and cancer predisposition syndrome. Thus, DPC repair is a previously overlooked genome-maintenance mechanism that may be essential for tumour suppression. PMID- 26130010 TI - Comparison of the Hemostatic Activity of Quercus persica Jaub. & Spach. (Oak) With Ferric Sulfate in Bony Crypts. AB - Effective tissue hemostasis in periapical surgical site is important in the procedures. Plants with large amount of tannins may act as a local hemostatic agent. We aimed to compare the hemostatic effect of the extract of Quercus persica with one of the common hemostatic material used in periapical surgery. Six standardized bone holes were prepared in the calvaria of 5 Burgundy rabbits. Two hemostatic medicaments were tested for their hemostatic effect and were compared with control defects: Group 1, cotton pellet soaked in 15.5% ferric sulfate solution; Group 2, cotton pellet soaked in pure ethanolic extract of Q. persica. Bleeding score between the groups was compared. The ferric sulfate group exhibited significantly less bleeding than the other 2 groups. Q. persica was found to cause more hemostasis than the control group at 4 and 5 minutes but there were no significant differences between normal saline and Q. persica extract in bleeding control. PMID- 26130009 TI - Forcing cells into shape: the mechanics of actomyosin contractility. AB - Actomyosin-mediated contractility is a highly conserved mechanism for generating mechanical stress in animal cells and underlies muscle contraction, cell migration, cell division and tissue morphogenesis. Whereas actomyosin-mediated contractility in striated muscle is well understood, the regulation of such contractility in non-muscle and smooth muscle cells is less certain. Our increased understanding of the mechanics of actomyosin arrays that lack sarcomeric organization has revealed novel modes of regulation and force transmission. This work also provides an example of how diverse mechanical behaviours at cellular scales can arise from common molecular components, underscoring the need for experiments and theories to bridge the molecular to cellular length scales. PMID- 26130016 TI - Fine mapping and whole-exome sequencing of a familial cortical myoclonic tremor with epilepsy family. AB - Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant epilepsy syndrome. Four loci, including 8q24 (FCMTE1), 2p11.1-q12.2 (FCMTE2), 5p15.31-p15.1 (FCMTE3), and 3q26.32-3q28 (FCMTE4) were previously reported. Herein, we report a new FCMTE1 pedigree from Chinese population with its clinical and genetic study results. Whole genome scan was performed to identify the causative gene region and copy number variants. Whole-exome sequencing was used to identify the causative gene. There were twelve affected members alive in this FCMTE1 pedigree. Nine affected members had both cortical myoclonic tremor and epilepsy, while three affected members had only cortical myoclonic tremor. Electrophysiologic examinations manifested giant somatosensory evoked potentials and long-latency cortical reflex in some affected members. Whole genome scan identified a 20.4 Mb causative gene region at 8q22.3-q24.13. No copy number variants were identified as the causative mutation. Whole-exome sequencing identified a co-segregated mutation (c.206A>T; p.Y69F) in the SLC30A8 gene. However, the evidence supporting this gene as the causative gene of FCMTE1 is not enough. We report the first Chinese FCMTE1 pedigree. No copy number variants, point mutation or small insertion/deletion were detected in the identified region that showed an association with FCMTE1. Further studies could focus on other possible genetic mechanisms while the association between the SLC30A8 and FCMTE1 needs further evidence. PMID- 26130017 TI - Mid-urethral sling operations for stress urinary incontinence in women. AB - BACKGROUND: Urinary incontinence is a very common and debilitating problem affecting about 50% of women at some point in their lives. Stress urinary incontinence (SUI) is a contributory or predominant cause in 30% to 80% of these women. Mid-urethral sling (MUS) operations are a recognised minimally invasive surgical treatment for SUI. MUS involves the passage of a small strip of tape through either the retropubic or obturator space, with entry or exit points at the lower abdomen or groin, respectively. This review does not include single incision slings. OBJECTIVES: To assess the clinical effects of mid-urethral sling (MUS) operations for the treatment of stress urinary incontinence (SUI), urodynamic stress incontinence (USI) or mixed urinary incontinence (MUI) in women. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from CENTRAL, MEDLINE, MEDLINE in process, ClinicalTrials.gov and handsearching of journals and conference proceedings (searched 26 June 2014), Embase and Embase Classic (January 1947 to Week 25 2014), WHO ICTRP (searched on 30 June 2014) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials amongst women with SUI, USI or MUI, in which both trial arms involve a MUS operation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the methodological quality of potentially eligible studies and extracted data from the included trials. MAIN RESULTS: We included 81 trials that evaluated 12,113 women. We assessed the quality of evidence for outcomes using the GRADE assessment tool; the quality of most outcomes was moderate, mainly due to risk of bias or imprecision.Fifty-five trials with data contributed by 8652 women compared the use of the transobturator route (TOR) and retropubic route (RPR). There is moderate quality evidence that in the short term (up to one year) the rate of subjective cure of TOR and RPR are similar (RR 0.98, 95% CI 0.96 to 1.00; 36 trials, 5514 women; moderate quality evidence) ranging from 62% to 98% in the TOR group, and from 71% to 97% in the RPR group. Short-term objective cure was similar in the TOR and RPR groups (RR 0.98, 95% CI 0.96 to 1.00; 40 trials, 6145 women). Fewer trials reported medium-term (one to five years) and longer-term (over five years) data, but subjective cure was similar between the groups (RR 0.97, 95% CI 0.87 to 1.09; 5 trials, 683 women; low quality evidence; and RR 0.95, 95% CI 0.80 to 1.12; 4 trials, 714 women; moderate quality evidence, respectively). In the long term, subjective cure rates ranged from 43% to 92% in the TOR group, and from 51% to 88% in the RPR group.MUS procedures performed using the RPR had higher morbidity when compared to TOR, though the overall rate of adverse events remained low. The rate of bladder perforation was lower after TOR (0.6% versus 4.5%; RR 0.13, 95% CI 0.08 to 0.20; 40 trials, 6372 women; moderate quality evidence). Major vascular/visceral injury, mean operating time, operative blood loss and length of hospital stay were lower with TOR.Postoperative voiding dysfunction was less frequent following TOR (RR 0.53, 95% CI 0.43 to 0.65; 37 trials, 6200 women; moderate quality evidence). Overall rates of groin pain were higher in the TOR group (6.4% versus 1.3%; RR 4.12, 95% CI 2.71 to 6.27; 18 trials, 3221 women; moderate quality evidence) whereas suprapubic pain was lower in the TOR group (0.8% versus 2.9%; RR 0.29, 95% CI 0.11 to 0.78); both being of short duration. The overall rate of vaginal tape erosion/exposure/extrusion was low in both groups: 24/1000 instances with TOR compared with 21/1000 for RPR (RR 1.13, 95% CI 0.78 to 1.65; 31 trials, 4743 women; moderate quality evidence). There were only limited data to inform the need for repeat incontinence surgery in the long term, but it was more likely in the TOR group than in the RPR group (RR 8.79, 95% CI 3.36 to 23.00; 4 trials, 695 women; low quality evidence).A retropubic bottom-to-top route was more effective than top-to-bottom route for subjective cure (RR 1.10, 95% CI 1.01 to 1.19; 3 trials, 477 women; moderate quality evidence). It incurred significantly less voiding dysfunction, and led to fewer bladder perforations and vaginal tape erosions.Short-and medium-term subjective cure rates between transobturator tapes passed using a medial-to-lateral as opposed to a lateral-to-medial approach were similar (RR 1.00, 95% CI 0.96 to 1.06; 6 trials, 759 women; moderate quality evidence, and RR 1.06, 95% CI 0.91 to 1.23; 2 trials, 235 women; moderate quality evidence). There was moderate quality evidence that voiding dysfunction was more frequent in the medial-to-lateral group (RR 1.74, 95% CI 1.06 to 2.88; 8 trials, 1121 women; moderate quality evidence), but vaginal perforation was less frequent in the medial-to-lateral route (RR 0.25, 95% CI 0.12 to 0.53; 3 trials, 541 women). Due to the very low quality of the evidence, it is unclear whether the lower rates of vaginal epithelial perforation affected vaginal tape erosion (RR 0.42, 95% CI 0.16 to 1.09; 7 trials, 1087 women; very low quality evidence). AUTHORS' CONCLUSIONS: Mid-urethral sling operations have been the most extensively researched surgical treatment for stress urinary incontinence (SUI) in women and have a good safety profile. Irrespective of the routes traversed, they are highly effective in the short and medium term, and accruing evidence demonstrates their effectiveness in the long term. This review illustrates their positive impact on improving the quality of life of women with SUI. With the exception of groin pain, fewer adverse events occur with employment of a transobturator approach. When comparing transobturator techniques of a medial-to lateral versus a lateral-to-medial insertion, there is no evidence to support the use of one approach over the other. However, a bottom-to-top route was more effective than top-to-bottom route for retropubic tapes.A salient point illustrated throughout this review is the need for reporting of longer-term outcome data from the numerous existing trials. This would substantially increase the evidence base and provide clarification regarding uncertainties about long term effectiveness and adverse event profile. PMID- 26130018 TI - Yoga for secondary prevention of coronary heart disease. AB - BACKGROUND: Coronary heart disease (CHD) is the major cause of early morbidity and mortality in most developed countries. Secondary prevention aims to prevent repeat cardiac events and death in people with established CHD. Lifestyle modifications play an important role in secondary prevention. Yoga has been regarded as a type of physical activity as well as a stress management strategy. Growing evidence suggests the beneficial effects of yoga on various ailments. OBJECTIVES: To determine the effectiveness of yoga for the secondary prevention of mortality and morbidity in, and on the health-related quality of life of, individuals with CHD. SEARCH METHODS: This is an update of a review previously published in 2012. For this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1 of 12, 2014), MEDLINE (1948 to February week 1 2014), EMBASE (1980 to 2014 week 6), Web of Science (Thomson Reuters, 1970 to 12 February 2014), China Journal Net (1994 to May 2014), WanFang Data (1990 to May 2014), and Index to Chinese Periodicals of Hong Kong (HKInChiP) (from 1980). Ongoing studies were identified in the metaRegister of Controlled Trials (May 2014) and the World Health Organization International Clinical Trials Registry Platform (May 2014). We applied no language restrictions. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) investigating the influence of yoga practice on CHD outcomes in men and women (aged 18 years and over) with a diagnosis of acute or chronic CHD. Studies were eligible for inclusion if they had a follow-up duration of six months or more. We considered studies that compared one group practicing a type of yoga with a control group receiving either no intervention or interventions other than yoga. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies according to prespecified inclusion criteria. We resolved disagreements either by consensus or by discussion with a third author. MAIN RESULTS: We found no eligible RCTs that met the inclusion criteria of the review and thus we were unable to perform a meta-analysis. AUTHORS' CONCLUSIONS: The effectiveness of yoga for secondary prevention in CHD remains uncertain. Large RCTs of high quality are needed. PMID- 26130019 TI - Wogonoside Shows Antifibrotic Effects in an Experimental Regression Model of Hepatic Fibrosis. AB - BACKGROUD: Wogonoside (WO), a flavonoid extracted from Huangqin, plays multiple physiological roles. However, it has remained elusive how WO regulates hepatic fibrogenesis until now. AIM: The purpose of the study was to investigate the potential protective effects of WO against liver fibrosis induced by carbon tetrachloride (CCl4). METHODS: In this study, male rats were randomly allocated into four groups: a control group, the CCl4 group, the CCl4 and WO (4 mg/kg) group, and CCl4 and WO (8 mg/kg) group. Hepatic fibrosis was induced by subcutaneous injection of CCl4 twice a week for a continuous 6-week period. Then the rats were intragastrically administrated with WO daily for 4 weeks before being killed. RESULTS: As expected, histopathological assessment, Masson trichrome staining, and Sirius red staining demonstrated that WO drastically ameliorated the hepatic fibrosis caused by CCl4. WO significantly attenuated the CCl4-induced upregulations of liver indices including alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-alpha, interleukin-1beta, IL-6, hexadecenoic acid and laminin in serum, as well as hydroxyproline, malondialdehyde and phosphatidylinositol 3-kinase (PI3K)/protein Kinase B(Akt)/mechanistic target of rapamycin (mTOR)/nuclear factor-kappa B signalings in liver. Meanwhile, WO also effectively recovered the depletions of superoxide dismutase, glutathione and IL-10. Furthermore, we evaluated the effects of WO on the alpha smooth muscle actin, type I collagen expressions, and PI3K/Akt/ mTOR/ribosomal protein S6 kinase 70 kDa (p70S6K) signaling in transforming growth factor (TGF-beta) stimulated hepatic stellate cell-T6 cells. CONCLUSIONS: These results suggested that WO had significant protective effects against liver fibrosis induced by CCl4. PMID- 26130020 TI - Supercritical fluid extraction of grape seeds: extract chemical composition, antioxidant activity and inhibition of nitrite production in LPS-stimulated Raw 264.7 cells. AB - Grape by-products are a rich source of bioactive compounds having broad medicinal properties, but are usually wasted from juice/wine processing industries. The present study investigates the use of supercritical fluid extraction (SFE) for obtaining an extract rich in bioactive compounds. First, some variables involved in the extraction were applied. SFE conditions were selected based on the oil mass yield, fatty acid profile and total phenolic composition. As a result, 40 degrees C and 300 bar were selected as operational conditions. The phenolic composition of the grape seed oil was determined using LC-DAD. The antioxidant activity was determined by ABTS and DPPH assays. For the anti-inflammatory activity the inhibition of nitrite production was assessed. The grape seed oil extracted was rich in phenolic compounds and fatty acids with significant antioxidant and anti-inflammatory activities. From these results, added economic value to this agroindustrial residue is proposed using environmentally friendly techniques. PMID- 26130024 TI - Photocatalytic Property of TiO2-Vermiculite Composite Nanofibers via Electrospinning. AB - Titanium dioxide (TiO2) is one of the most common photocatalysts. In this study, TiO2-vermiculite composite nanofibers with a mesh structure and a diameter of approximately 300 nm were prepared via sol-gel approach combined with electrospinning technique. The samples were characterized by X-ray diffraction, scanning electron microscopy, ultraviolet-visible spectroscopy, etc. The photocatalytic property was also evaluated. The TiO2-vermiculite composite nanofibers annealed at 550 degrees C for 3 h exhibited the best absorption and photo-degradation ability for the treatment of methylene blue. The results implied that the combination of mineral vermiculite powders with TiO2 enhanced the absorption-degradation performance of the as-prepared photocatalytic materials, consequently promoting the materials' ability to degrade methylene blue. PMID- 26130023 TI - The role of isohydric and anisohydric species in determining ecosystem-scale response to severe drought. AB - Ongoing shifts in the species composition of Eastern US forests necessitate the development of frameworks to explore how species-specific water-use strategies influence ecosystem-scale carbon (C) cycling during drought. Here, we develop a diagnostic framework to classify plant drought-response strategies along a continuum of isohydric to anisohydric regulation of leaf water potential (Psi(L)). The framework is applied to a 3-year record of weekly leaf-level gas exchange and Psi measurements collected in the Morgan-Monroe State Forest (Indiana, USA), where continuous observations of the net ecosystem exchange of CO2 (NEE) have been ongoing since 1999. A severe drought that occurred in the middle of the study period reduced the absolute magnitude of NEE by 55%, though species-specific responses to drought conditions varied. Oak species were characterized by anisohydric regulation of Psi(L) that promoted static gas exchange throughout the study period. In contrast, Psi(L) of the other canopy dominant species was more isohydric, which limited gas exchange during the drought. Ecosystem-scale estimates of NEE and gross ecosystem productivity derived by upscaling the leaf-level data agreed well with tower-based observations, and highlight how the fraction of isohydric and anisohydric species in forests can mediate net ecosystem C balance. PMID- 26130022 TI - Treatment of achalasia in the era of high-resolution manometry. AB - Esophageal achalasia is a primary motility disorder characterized by impaired lower esophageal sphincter relaxation and absence of esophageal peristalsis leading to impaired bolus transit, manifested with symptoms such as dysphagia, regurgitation, retrosternal pain, and weight loss. The standard diagnostic tool is esophageal manometry which demonstrates incomplete relaxation of the lower esophageal sphincter and impaired esophageal peristalsis. Recently, a new advanced technique, high-resolution manometry (HRM) with the addition of pressure topography plotting, using multiple sensors to capture the manometric data as a spatial continuum, allows a detailed pressure recording of the esophageal motility. This technique, currently the gold standard for the diagnosis of achalasia, has led to a subclassification of three manometric types that seem to have different responsiveness to treatment. Because its pathogenesis is as yet unknown, achalasia treatment options are not curative. Type II achalasia patients respond better to treatment compared to those with types I and III. Low-risk patients with type I or II achalasia have good outcome with both graded pneumatic dilatations and laparoscopic Heller myotomy, while type III achalasia patients respond better to laparoscopic Heller myotomy. Although, type III achalasia patients responds less in comparison to types I and II to laparoscopic Heller myotomy. Peroral endoscopic myotomy is a promising new technique but long-term follow-up studies for its safety and efficacy must be performed. This article reviews the current therapeutic options, highlighting the impact of HRM to predict the outcome and the new insights for the treatment of achalasia. PMID- 26130025 TI - New insights into the thermal behaviour of organic ionic plastic crystals: magnetic resonance imaging of polycrystalline morphology alterations induced by solid-solid phase transitions. AB - Organic ionic plastic crystals (OIPCs) show strong potential as solid-state electrolytes for lithium battery applications, demonstrating promising electrochemical performance and eliminating the need for a volatile and flammable liquid electrolyte. The ionic conductivity (sigma) in these systems has recently been shown to depend strongly on polycrystalline morphology, which is largely determined by the sample's thermal history. [K. Romanenko et al., J. Am. Chem. Soc., 2014, 136, 15638]. Tailoring this morphology could lead to conductivities sufficiently high for battery applications, so a more complete understanding of how phenomena such as solid-solid phase transitions can affect the sample morphology is of significant interest. Anisotropic relaxation of nuclear spin magnetisation provides a new MRI based approach for studies of polycrystalline materials at both a macroscopic and molecular level. In this contribution, morphology alterations induced by solid-solid phase transitions in triisobutyl(methyl)phosphonium bis(fluorosulfonyl)imide (P1444FSI) and diethyl(methyl)(isobutyl)phosphonium hexafluorophosphate (P1224PF6) are examined using magnetic resonance imaging (MRI), alongside nuclear magnetic resonance (NMR) spectroscopy, diffusion measurements and conductivity data. These observations are linked to molecular dynamics and structural behaviour crucial for the conductive properties of OIPCs. A distinct correlation is established between the conductivity at a given temperature, sigma(T), and the intensity of the narrow NMR signal that is attributed to a mobile fraction, fm(T), of ions in the OIPC. To explain these findings we propose an analogy with the well-studied relationship between permeability (k) and void fraction (theta) in porous media, with k(theta) commonly quantified by a power-law dependence that can also be employed to describe sigma(fm). PMID- 26130026 TI - Increased circulating fibrocytes are associated with higher reticulocyte percent in children with sickle cell anemia. AB - BACKGROUND: Interstitial lung disease is common in patients with sickle cell anemia (SCA). Fibrocytes are circulating cells implicated in the pathogenesis of pulmonary fibrosis and airway remodeling in asthma. In this study, we tested the hypotheses that fibrocyte levels are: (1) increased in children with SCA compared to healthy controls, and (2) associated with pulmonary disease. PROCEDURE: Cross sectional cohort study of children with SCA who participated in the Sleep Asthma Cohort Study. RESULTS: Fibrocyte levels were obtained from 45 children with SCA and 24 controls. Mean age of SCA cases was 14 years and 53% were female. In children with SCA, levels of circulating fibrocytes were greater than controls (P < 0.01). The fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on the majority of cells and CCR2 and CCR7 expressed on a smaller subset. Almost half of fibrocytes demonstrated alpha-smooth muscle actin activation. Increased fibrocyte levels were associated with a higher reticulocyte count (P = 0.03) and older age (P = 0.048) in children with SCA. However, children with increased levels of fibrocytes were not more likely to have asthma or lower percent predicted forced expiratory volume in 1 sec/forced vital capacity (FEV1 /FVC) or FEV1 than those with lower fibrocyte levels. CONCLUSIONS: Higher levels of fibrocytes in children with SCA compared to controls may be due to hemolysis. Longitudinal studies may be able to better assess the relationship between fibrocyte level and pulmonary dysfunction. PMID- 26130028 TI - Diverse mutants of HIV RRE IIB recognize wild-type Rev ARM or Rev ARM R35G-N40V. AB - The binding of human immunodeficiency virus Rev protein via its arginine-rich motif (ARM) to an internal loop in the Rev-response element region IIB (RRE IIB) is necessary for viral replication. Many variant RNAs and ARMs that bind Rev and RRE IIB have been found. Despite the essential role of Rev asparagine 40 in recognition, the Rev ARM double-mutant R35G-N40V functions well in a Rev-RRE IIB reporter assay, indicating R35G-N40V uses a distinct recognition strategy. To examine how RRE IIB may evolve specificity to wild-type Rev ARM and R35G-N40V, 10 RRE IIB libraries, each completely randomized in overlapping regions, were screened with wild-type Rev ARM and R35G-N40V using a reporter system based on bacteriophage lambda N antitermination. Consistent with previous studies, a core element of RRE IIB did not vary, and substitutions occurred at conserved residues only in the presence of other substitutions. Notably, the groove-widening, non canonical base-pair G48:G71 was mutable to U48:G71 without strong loss of binding to wild-type Rev ARM, suggesting U48:G71 performs the same role by adopting the nearly isosteric, reverse wobble base pair. Originating from RRE IIB, as few as one or two substitutions are sufficient to confer specificity to wild-type Rev or Rev R35G-N40. The diversity of RRE IIB mutants that maintain binding to wild-type Rev ARM and R35G-N40V supports neutral theories of evolution and illustrates paths by which viral RNA-protein interactions can evolve new specificities. Rev RRE offers an excellent model with which to study the fine structure of how specificity evolves. PMID- 26130027 TI - Calcimimetic and vitamin D analog use in hemodialyzed patients is associated with increased levels of vitamin K dependent proteins. AB - Matrix Gla protein (MGP) and bone Gla protein (BGP) are two vitamin K-dependent proteins (VKDPs) involved in the regulation of vascular calcification (VC). We carried out a secondary analysis of the VIKI study to evaluate associations between drug consumption and VKDP levels in 387 hemodialyzed patients. The VIKI study assessed the prevalence of vitamin K deficiency in hemodialysis patients. We evaluated drug consumption, determined BGP and MGP levels, and verified the presence of any vertebral fractures (VF) and VC by spine radiographs. Total BGP levels were twice as high with calcimimetics versus no calcimimetics (290 vs. 158.5 mcg/L, p < 0.0001) and 69 % higher with vitamin D analogs (268 vs. 159 mcg/L, p < 0.0001). Total MGP was 19 % higher with calcimimetics (21.5 vs. 18.1 mcg/L, p = 0.04) and 54 % higher with calcium acetate (27.9 vs. 18.1 mcg/L, p = 0.003); no difference was found with vitamin D analogs (21.1 vs. 18.3 mcg/L, p = 0.43). Median Total BGP level was 29 % lower in patients with >=1 VF (151 vs. 213 mcg/L, p = 0.0091) and 36 % lower in patients with VC (164 vs. 262.1 mcg/L, p = 0.0003). In non-survivors, median BGP and MGP were lower, but only for MGP this difference reached the statistical significance (152 vs. 191 mcg/L, p = 0.20 and 15.0 vs. 19.7 mcg/L, p = 0.02, respectively). Pending studies on vitamin K supplementation, calcimimetics, and vitamin D analogs may play a role in preserving vitamin K-dependent protein activity, thus contributing to bone and vascular health in CKD patients. PMID- 26130029 TI - Action plan co-optimization reveals the parallel encoding of competing reach movements. AB - Several influential cognitive theories propose that in situations affording more than one possible target of action, we prepare multiple competing movements before selecting one. Here we provide direct evidence for this provocative but largely untested idea and demonstrate why preparing multiple movements is computationally advantageous. Using a reaching task in which movements are initiated after one of two potential targets is cued, we show that the movement generated for the cued target borrows components of the movement that would have been required for the other, competing target. This interaction can only arise if multiple potential movements are fully specified in advance and we demonstrate that it reduces the time required to launch a given action plan. Our findings suggest that this co-optimization of motor plans is highly automatic and largely occurs outside conscious awareness. PMID- 26130031 TI - Erratum: Letter (BDJ 2015; 215: 556-557). PMID- 26130030 TI - Do brief alcohol interventions reduce tobacco use among adolescents and young adults? A systematic review and meta-analysis. AB - This meta-analysis synthesizes studies of brief interventions (BIs) that targeted alcohol consumption and reported both alcohol and tobacco outcomes. It examines whether BIs reduce alcohol and tobacco use for adolescents and young adults among interventions that (1) directly targeted tobacco and alcohol use, or (2) did not target tobacco use but measured it as a secondary outcome. Multiple databases and grey literature sources were searched (1980-2012) resulting in the identification of 18 randomized or controlled quasi-experimental studies (5949 participants). Analyses were conducted using random effects inverse-variance weighted three level models. BIs were associated with a significant reduction in alcohol consumption relative to control groups [g = 0.11, 95 % CI (0.04, 0.17)] but not with a significant decrease in tobacco use [g = 0.07, 95 % CI (-0.01, 0.16)]. Directly addressing tobacco was not a significant moderator affecting tobacco use outcomes. Post-hoc exploratory analysis revealed potential questions to address with future research. PMID- 26130032 TI - Feature: Children's dental health--a mother's perspective. PMID- 26130033 TI - Failure to include dentistry in health hurting patients and taxpayers. PMID- 26130034 TI - Be clear on costs, dentists urged. PMID- 26130035 TI - New CDO announced. PMID- 26130036 TI - A day in the life: 12 people. Eight days. One goal. PMID- 26130037 TI - Bringing first smiles to children. PMID- 26130038 TI - BDIA launches its 'Code of Practice for Dental CPD'. PMID- 26130039 TI - BDA and BDIA announce new 'Strategic Partnership'. PMID- 26130043 TI - Enantioselective alpha-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from beta-Cyanoaldehydes. AB - The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective alpha-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (-)-bursehernin. PMID- 26130044 TI - Expanding the Entamoeba Universe: New Hosts Yield Novel Ribosomal Lineages. AB - Removing the requirement for cell culture has led to a substantial increase in the number of lineages of Entamoeba recognized as distinct. Surveying the range of potential host species for this parasite genus has barely been started and it is clear that additional sampling of the same host in different locations often identifies additional diversity. In this study, using small subunit ribosomal RNA gene sequencing, we identify four new lineages of Entamoeba, including the first report of Entamoeba from an elephant, and extend the host range of some previously described lineages. In addition, examination of microbiome data from a number of host animals suggests that substantial Entamoeba diversity remains to be uncovered. PMID- 26130045 TI - Life events and chronic physical conditions among left-behind farmers in rural China a cross-sectional study. AB - BACKGROUND: This study investigates the relationships between life events and chronic physical conditions among left behind farmers, a newly emerged weak group in vast rural China. METHODS: The study collected information about life events, chronic physical conditions, blood pressure and fasting blood glucose from 4681 famers living in 18 randomly selected villages (Lu'an, Anhui, China) from early November 2013 to the end of December 2013. It compared the risk and odds ratios (RRs/ORs) among different subgroups divided according two life event indices derived by adding up un-weighted-ratings and weighted-ratings based on multivariate logistic regression coefficients respectively. RESULTS: A total of 4040 (86.3 % eligible) farmers completed the survey. RRs between farmers with lower than the first 1/15-percentile of life event index and with higher life event index scores ranged 1.43-5.79 for chronic gastritis and 0.42-9.07 for prostatitis, 1.01-4.97 for cervicitis/vaginitis, 1.45-3.28 for cardio cerebrovascular diseases, 1.12-1.58 for hypertension, 1.00-1.66 for diabetes, 1.07-3.35 for pre-diabetes and 5.00-55.00 for "other chronic physical conditions". CONCLUSIONS: Life events were independently linked with most of the chronic physical conditions in a dose-effectiveness way. RRs between subgroups divided by given percentile cutoff points of life event index compiled using logistic regression models turned out to be substantially higher than that between subgroups divided by same cutoff points of life event index produced via summing up the un-weighted Likert ratings of all the events studied. PMID- 26130046 TI - Back injuries in a cohort of schoolchildren aged 6-12: A 2.5-year prospective study. AB - The aims of this prospective school cohort study were to describe the epidemiology of diagnosed back pain in childhood, classified as either nontraumatic or traumatic back injury, and to estimate the association with physical activity in different settings. Over 2.5 years, 1240 children aged 6-12 years were surveyed weekly using mobile text messages to ask about the presence or absence of back pain. Pain was clinically diagnosed and injuries were classified using the International Classification of Diseases version 10. Physical activity data were obtained from text messages and accelerometers. Of the 315 back injuries diagnosed, 186 injuries were nontraumatic and 129 were traumatic. The incidence rate ratio was 1.5 for a nontraumatic back injury compared with a traumatic injury. The overall estimated back injury incidence rate was 0.20 per 1000 physical activity units (95% confidence interval 0.18 0.23). The back injury incidence rates were higher for sports when exposure per 1000 physical activity units was taken into consideration and especially children horse-riding had a 40 times higher risk of sustaining a traumatic back injury compared to the risk during non-organized leisure time physical activity. However, the reasonably low injury incidence rates support the recommendations of children continuously being physically active. PMID- 26130048 TI - Design, fabrication and charge recombination analysis of an interdigitated heterojunction nanomorphology in P3HT/PC(70)BM solar cells. AB - In this work interdigitated heterojunction photovoltaic devices were manufactured. A donor layer of P3HT nanopillars was fabricated by soft nanoimprinting using nanoporous anodic alumina templates. Subsequently, the PC70BM acceptor layer was deposited by spin coating on top of the P3HT nanopillars using a solvent that would not dissolve any of the previous material. Anisole solvent was used because it does not dissolve the bottom donor layer of nanopillars and provides a good wettability between the two materials. Charge extraction was used to determine the charge carrier densities n on the interdigitated heterojunction under operating conditions. Moreover, transient photovoltage measurements were used to find the recombination rate constant in combination with the charge carrier density. At the same time, the interdigitated structure was also compared with bulk heterojunction and bilayer solar cells manufactured with the same polymeric and fullerene materials in order to understand the recombination loss mechanisms in the ordered and disordered nanomorphologies of the active layers. PMID- 26130047 TI - The association of depression and anxiety with dental caries and periodontal disease among Finnish adults. AB - OBJECTIVE: To explore the association of depression and anxiety with two oral health outcomes, dental caries and periodontal disease and assess possible mediators for any of the associations. METHODS: Secondary analysis of the Finnish Health 2000 Survey. Depression was assessed with Beck's Depression Inventory and anxiety with Composite International Diagnostic Interview. Number of decayed teeth included carious lesions reaching dentine; periodontal disease was number of teeth with periodontal pockets of 4 mm or deeper. Third molars were excluded. The association of mental disorders and oral health was tested in regression models adjusted for confounders and potential mediators. RESULTS: Depression was associated with number of decayed teeth only among 35- to 54-year-olds. The association between anxiety and the number of decayed teeth was not statistically significant. Depression and periodontal pocketing were not significantly associated. CONCLUSION: Depression was significantly associated with number of decayed teeth only among participants aged 35-54 old and not with other age groups. Neither depression nor anxiety was significantly related to periodontal disease. PMID- 26130049 TI - Resolution and quantification of arginine, monomethylarginine, asymmetric dimethylarginine, and symmetric dimethylarginine in plasma using HPLC with internal calibration. AB - N(G) ,N(G) -dimethyl-l-arginine (asymmetric dimethylarginine, ADMA),N(G) monomethyl-l-arginine (l-NMMA) and N(G) ,N(G') -dimethyl-l-arginine (symmetric dimethylarginine, SDMA) are released during hydrolysis of proteins containing methylated arginine residues. ADMA and l-NMMA inhibit nitric oxide synthase by competing with l-arginine substrate. All three methylarginine derivatives also inhibit arginine transport. To enable investigation of methylarginines in diseases involving impaired nitric oxide synthesis, we developed a high performance liquid chromatography (HPLC) assay to simultaneously quantify arginine, ADMA, l-NMMA and SDMA. Our assay requires 12 MUL of plasma and is ideal for applications where sample availability is limited. We extracted arginine and methylarginines with mixed-mode cation-exchange columns, using synthetic monoethyl-l-arginine as an internal standard. Metabolites were derivatized with ortho-phthaldialdeyhde and 3-mercaptopropionic acid, separated by reverse-phase HPLC and quantified with fluorescence detection. Standard curve linearity was >=0.9995 for all metabolites. Inter-day coefficient of variation (CV) values were <=5% for arginine, ADMA and SDMA in human plasma and for arginine and ADMA in mouse plasma. The CV value for l-NMMA was higher in human (10.4%) and mouse (15.8%) plasma because concentrations were substantially lower than ADMA and SDMA. This assay provides unique advantages of small sample volume requirements, excellent separation of target metabolites from contaminants and validation for both human and mouse plasma samples. PMID- 26130051 TI - The advent of non-thermal, non-tumescent techniques for treatment of varicose veins. AB - Varicose veins are common and their management has undergone a number of changes over the years. Surgery has been the traditional treatment option, but towards the 21st century, new endovenous thermal ablation techniques, namely, radiofrequency ablation and endovenous laser ablation, were introduced which have revolutionised the way varicose veins are treated. These minimally invasive techniques are associated with earlier return to normal activity and less pain, as well as enabling procedures to be carried out as day cases. They are, however, also known to cause a number of side-effects and involve infiltration of tumescent fluid which can cause discomfort. Non-thermal, non-tumescent methods are believed to be the answer to these unwelcome effects. Ultrasound-guided foam sclerotherapy is one such non-thermal, non-tumescent method and, despite a possible lower occlusion, has been shown to improve the quality of life of patients. The early results of two recently launched non-thermal, non-tumescent methods, mechanochemical ablation and cyanoacrylate glue, are promising and are discussed. PMID- 26130050 TI - Camphor Tree Seed Kernel Oil Reduces Body Fat Deposition and Improves Blood Lipids in Rats. AB - The total and positional fatty acid composition in camphor tree (Cinnamomum camphora) seed kernel oil (CKO) were analyzed, and for the first time, the effect of CKO on body fat deposition and blood lipids in rats was studied. The major fatty acids in CKO were determined to be decanoic acid (C10:0, 51.49%) and dodecanoic acid (C12:0, 40.08%), and uniformly distributed at Sn-1, 3, and Sn-2 positions in triglyceride (TG). Rats were randomly divided into control, CKO, lard, and soybean oil groups. At the end of the experiment, levels of blood lipids and the fats of abdomen in the rats were measured. The main organ were weighted and used for the histological examination. The results showed that body weight and fat deposition in CKO group were significantly lower than the lard and soybean groups. Moderate consumption of CKO was found to improve the levels of blood TG and low density lipoprotein cholesterol. PMID- 26130052 TI - Combined treatment with endovenous laser ablation and compression therapy of incompetent perforating veins for treatment of recalcitrant venous ulcers. AB - Objective Patients with healed venous ulcers often experience recurrence of ulceration, despite the use of long-term compression therapy. This study examines the effect of closing incompetent perforating veins (IPVs) on ulcer recurrence rates in patients with progressive lipodermatosclerosis and impending ulceration. Methods Patients with nonhealing venous ulcers of >2 months' duration underwent duplex ultrasound to assess their lower extremity venous system for incompetence of superficial, perforating, and deep veins. Endovenous laser ablation (EVLA) of perforating veins was performed on patients with CEAP 6 disease with increasing hyperpigmentation, lipodermatosclerosis, and/or progressive malleolar pain. A minimum of 2 months of compressive therapy was attempted before endovenous ablation of IPVs. Demographic data, risk factors, CEAP classification, procedural details, and postoperative status were all recorded. Results Forty ulcers with 46 associated IPVs were treated with EVLA in 36 patients with CEAP 6 recalcitrant venous ulcers. Treated incompetent perforator veins were located in the medial ankle (85.7%), calf (10.7%), and lateral ankle (3.5%). Endovenous laser ablation was successful in 76% (35/46) with the first laser treatment of incompetent perforator veins and 15.2% (7/46) additional ablation procedures were performed. Of the 46 treated IPVs, 42 (91.3%) were occluded on the duplex examination at 12 months. The average energy administrated per perforating vein treated was 162 joule. Two patients reported localized paresthesia, which subsided spontaneously, but no deep venous thrombosis or skin burn was observed. Conclusion Especially in the case of liposclerotic or ulcerated skin in the affected region, PAP of IPVs is highly effective, safe, and appears to be feasible. Patients with active venous ulcers appear to benefit from EVLA of incompetent perforators in order to reduce the risk of ulcer recurrence. PMID- 26130053 TI - Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome. AB - BACKGROUND AND PURPOSE: In some patients with subarachnoid hemorrhage (SAH) a bleeding source cannot be identified. Perimesencephalic (PM) SAH is assumed to have an excellent outcome. Our objective was to analyze the long-term physical and psychological outcome of patients after non-aneurysmal SAH. METHODS: One hundred and seventy-three patients met the inclusion criteria. Short-term follow up 6 months after SAH was assessed according to the modified Rankin Scale (0-2 favorable). A short-form health survey with 36 questions (SF-36) and eight scales was used as questionnaire for long-term follow-up. RESULTS: Thirty-seven answers were received from the two groups, PM and non-perimesencephalic (NPM) SAH, on average 76 months after ictus (range 1.5-14 years). PM- and NPM-SAH without Fisher grade 3 blood pattern have excellent short-term outcomes. The quality of life (QoL) is significantly reduced after non-aneurysmal SAH, especially in NPM SAH. In particular, patients with a Fisher 3 blood pattern had significantly higher risks for cerebral vasospasm, delayed cerebral ischaemia, unfavorable outcome, reduced QoL and mortality in short- and long-term follow-up. CONCLUSIONS: Excluding rolph, only patients with a PM-SAH have a similar QoL at long-term follow-up compared to the standard population. Patients with NPM-SAH have a significantly decreased QoL in long-term follow-up. Furthermore, the Fisher 3 blood pattern group in particular had a significantly worse outcome - at short-term and long-term follow-up. Therefore the NPM-SAH group was stratified into patients with Fisher 3 blood pattern and patients without Fisher 3 in further investigations. PMID- 26130054 TI - Genetic variation in the coagulation factor V gene and risk of femoral head osteonecrosis. AB - Osteonecrosis of the femoral head (ONFH) is characterized by the death of the cellular portion of the femoral head due a reduction or disruption in the blood supply. Certain studies have implicated coagulation disorders, including thrombophilia and hypofibrinolysis, in the pathogenesis of ONFH. The factor V (F5) Leiden mutation has been suggested to be a genetic risk factor for venous thromboembolism and osteonecrosis in Caucasian individuals, however, this association remains controversial in other populations. The present study aimed to identify polymorphisms of the F5 gene and performed a case-control study in a Korean population. The F5 gene was sequenced in 24 unrelated Korean individuals, and 16 polymorphisms were detected. A total of six polymorphisms were genotyped in 423 patients with ONFH and 348 control individuals. Analysis of the association between genotyped single nucleotide polymorphisms and haplotypes and with ONFH was performed. Comparison of the ONFH samples and the control individuals using logistic regression models revealed no statistically significant difference in the frequencies of the F5 polymorphisms and haplotypes. These findings suggested that F5 polymorphisms were not significant in the susceptibility to ONFH in the Korean population. PMID- 26130055 TI - Patients may prefer radiation risk to surgical risk in diagnosing appendicitis.